Amides From Carbonyls

DOI: 10.1002/asia.
201801560 Focus Review
Carbonyl Compounds’ Journey to Amide Bond Formation

Thatikonda Narendar Reddy,*[a, b] Adilson Beatriz,[a] Vaidya Jayathirtha Rao,[b] and
DÞnis Pires de Lima*[a]
Dedicated to Maria Rita Marques
Chem. Asian J. 2019, 00, 0 – 0 1 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim & &
These are not the final page numbers! ÞÞ

Focus Review
Abstract: The formation of amide bonds is one of the most ly important. Herein, we have scrutinized a range of metal-
stimulating emerging areas in organic and medicinal chemis- catalyzed and metal-free approaches for the synthesis of
try. Amides are recognized as central building blocks in a amides from aldehydes, ketones, and oximes. In addition,
plethora of interesting pharmaceuticals, proteins, peptides, this Focus Review highlights relevant mechanistic studies, as
polymers, natural products, functional materials, and biologi- well as the potential applications of these methods in the
cally relevant carbocyclic or heterocyclic molecules, and they synthesis of candidate drug molecules. We hope that the
are also found in a variety of industrial fields. Therefore, a data compiled herein will encourage further progress in this
review of recent developments and challenges in the forma- notable area of chemistry research.
tion of amide bonds from carbonyl compounds is particular-
1. Introduction
Functional group transformation (FGT) is a versatile and ex-

tremely powerful tool in the scientific community,[1] and organ-
ic functional groups play a fascinating role in directing and
controlling diverse organic reactions and transformations. In
particular, the conversion of carbonyl compounds into other
functional groups is one of the most useful transformations in
organic chemistry.[2] Of these groups, amides are one of the
most significant functional groups in all branches of chemistry
and has attracted intensive attention from both academic and
industrial researchers.[3] Moreover, chemical strategies and tac-
tics for the formation of amide bonds are among the most
executed transformations in organic chemistry. Indeed, the
construction of amide bonds is frequently found in the synthe-
sis of pharmaceutical compounds, accounting for 16 % of all
reported reactions.[4]
Compounds that contain amide bond linkages are ubiqui-
tous in pharmaceutically active natural products and constitute
Figure 1. Representative pharmaceutical compounds that contain amide
an essential integral part of many polymers, proteins, peptides,
bonds.
biologically relevant carbocyclic or heterocyclic molecules, and
pharmaceutical drugs.[5] Interestingly, according to a medicinal
chemistry database, more than 25 % of the natural and syn- chemicals, such as nitriles, amino acids, peptides, amines, and
thetic pharmaceutical drugs on the market contain one or pharmaceutically active frameworks.[8] In particular, aromatic
more amide functional groups as a core structural motif amides are versatile and crucial structural precursors for a vari-
(Figure 1).[6] Amide groups can also serve as crucial precursors ety of biologically active compounds and pharmaceutical
for industrial applications, such as engineering plastics, deter- drugs. Therefore, owing to their widespread applications and
gent manufacturing, pesticides, lubricants, perfumes, and anti- inherent advantages, such as high bond polarity, good stability,
block reagents.[7] Moreover, they have also been used as inter- and conformational diversity, the installation of amide bond
mediates in organic synthesis to access high-value-added functionality is of immense interest in organic synthesis.
The traditional method for the synthesis of amides is the
ammonolysis of carboxylic acids. However, the existing meth-
[a] Dr. T. Narendar Reddy, Prof. A. Beatriz, Prof. D. P. de Lima
Instituto de Qumica (INQUI) ods are still inadequate and suffer from several flaws, including
Universidade Federal de Mato Grosso do Sul poor atom-efficiency, the need for harsh reaction conditions,
79074-460, Campo Grande the use of stoichiometric amounts of hazardous reagents, and
Mato Grosso do Sul (Brazil)
the generation of large amounts of waste.[9] Recently, several
E-mail: tnarendarreddyphd@gmail.com
denis.lima@ufms.br elegant strategies have been explored for the formation of
[b] Dr. T. Narendar Reddy, Dr. V. Jayathirtha Rao amide bonds by employing metal-catalyzed and metal-free
Crop Protection Chemicals Division conditions. In this context, the direct coupling of carboxylic
CSIR-Indian Institute of Chemical Technology acids or thioacids with amines or amine surrogates,[10] the
Uppal Road, Tarnaka
transamidation of amides,[11] synthesis from oximes and ke-
Hyderabad 500007 (India)
tones[12] or amine surrogates,[13] the hydration of organoni-
The ORCID identification number(s) for the author(s) of this article can be
found under: triles,[14] the N-formylation or oxidation of amines,[15] the oxida-
https://doi.org/10.1002/asia.201801560. tive/reductive amidation of aldehydes,[16] and the oxidative
& & Chem. Asian J. 2019, 00, 0 – 0 www.chemasianj.org 2 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Focus Review
amidation of alcohols[17] have all been explored. Another pow-

erful method is the aminocarbonylation of aryl halides,[18] al-
kynes,[19] and olefins.[20] Of these methods, the formation of
amide bonds from carbonyl compounds (aldehydes, oximes,
Thatikonda Narendar Reddy was born in Kori-
and ketones) has received much attention, owing to their ac- vanigudem, Nalgonda (India). He received his
cessibility and non-toxicity. B.Sc. from Osmania University in 2006 and his
Over the past few years, several groups have reviewed the M.Sc. from Kakatiya University in 2008. In
2014, he obtained his Ph.D. on organic syn-
scope and development of amide synthesis.[21] Although the
thesis from the CSIR-Indian Institute of Chemi-
synthesis of amides from carbonyl compounds has already cal Technology under the supervision of Dr.
been described in some of these previous reviews, no compre- V. Jayathirtha Rao. Then, he joined the Federal
hensive review of this special topic has hitherto been reported. University of Mato Grosso do Sul (UFMS) as a
Postdoctoral Fellow, working with Professor
At this stage, considering the importance of the formation of
DÞnis Pires de Lima. Recently, he moved to
amide bonds in the scientific domain and in our ongoing re- Taiwan and joined the Genomics Research
search,[22] we became interested in filling this gap. This Focus Center, Academia Sinica, as a Postdoctoral
Review explores recent developments and current challenges Fellow. His motivation is the curiosity to learn
something new.
in the formation of amide bonds. Herein, we present and dis-
cuss recent reports on a variety of stylish metal-catalyzed and Adilson Beatriz received his B.Sc. from UFMS,
metal-free methods (including the use of N-heterocyclic car- Brazil, in 1995 and his D.Sc. from the Universi-
ty of S¼o Paulo in 2001. From 2001 to 2002,
benes or ionic liquid catalysts, biocatalysts, photocatalysts, and he was a Postdoctoral Fellow (FAPESP) at the
Lewis acid or base catalysts) for the synthesis of amides from University of S¼o Paulo. In 2006, he was ap-
carbonyl compounds, such as aldehydes, oximes, and ketones. pointed as an Associate Professor at UFMS.
We also present a detailed discussion of the reaction mecha- From 2009 to 2010, he received a Postdoctor-
al Fellowship from Foundation Carolina
nisms of representative reactions. This Focus Review is organ- (Spain) to work at the University of Santiago
ized based on the starting material employed and is subdivid- de Compostela. Currently, he is a Visiting Pro-
ed based on the catalytic reaction conditions. fessor in the group of Professor E. J. Corey at
Harvard University, and an Associate Professor
at UFMS. He has been a Productivity Research
Fellow of the National Council for Scientific
2. General Pathways for the Synthesis of and Technological Development (CNPq) since 2012.
Amides from Aldehydes
V. Jayathirtha Rao was born in Gadwal, Telan-
Aldehydes are important scaffolds for the synthesis of amides, gana (India). He obtained his Ph.D. from the
Department of Organic Chemistry, Indian In-
owing to their accessibility and nontoxicity. As such, a variety
stitute of Science (India), in 1983 under the
of synthetic strategies have been explored for the one-pot supervision of Professor V. Ramamurthy. Then,
coupling of aldehydes with hydroxylamine or amines to afford he held positions as a Postdoctoral Researcher
the corresponding amides. (with Professor R. S. H. Liu) at the University of
Hawaii, USA, and as a Research Associate
(with Professor Koji Nakanishi) at Columbia
University, USA. He has also held the positions
2.1. Oxime and Nitrile Intermediates of Head, Deputy Director, and Chief Scientist
of the Fluoro Agro Chemicals Division at the
The Beckmann rearrangement of oximes is a straightforward Indian Institute of Chemical Technology, Hy-
method for the synthesis of amides from carbonyl compounds derabad. Presently, he is Emeritus Scientist at
that can be accomplished in the presence of stoichiometric the same Institute. He has been an Alexander von Humboldt Fellow and he
was a Visiting Scientist at Tulane University, USA, and at the University of
amounts of strong acids at high temperatures (Scheme 1,
Miami, USA. In 2008, he was honored to become a Fellow of the Royal Society
path A).[23] However, this reaction has several shortcomings, in- of Chemistry “FRSC” (London).
cluding poor atom efficiency, the need for harsh reaction con-
DÞnis Pires de Lima obtained his B.Sc. in Phar-
ditions, low tolerance to acid-sensitive functional groups, and macy from the Federal University of Minas
environmental cost, such as toxicity of the byproducts. Recent- Gerais (UFMG), Brazil, in 1986 and his Ph.D. in
ly, alternative methods have been explored for the rearrange- Organic Synthesis from the same University in
ment of aldehydes into primary amides by using metal cataly- 1994 under the supervision of Professor Ala-
de B. de Oliveira. During his Ph.D., he spent
two years as a Research Fellow at the Depart-
ment of Chemistry, University of Alberta
(Canada), under the supervision of Professor
Derrick Clive. In 1998, he was a Postdoctoral
Fellow at the Department of Chemistry, Uni-
versity of Liverpool (UK). Currently, he works
as a Full Professor and Research Supervisor of
the M.Sc. and Ph.D. programs at UFMS, Brazil.
He was awarded the first prize in the Green and Sustainable Chemistry Chal-
lenge 2017, sponsored by The Elsevier Foundation.
Scheme 1. Rearrangement of oximes into amides. M = metal catalyst.
Chem. Asian J. 2019, 00, 0 – 0 www.chemasianj.org 3 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim & &

Focus Review
sis (Scheme 1, path B). The conversion of an aldehyde into an 3. Synthesis of Amides from Aldehydes
amide is a two-step process. Initially, an aldehyde reacts with
an amine to form an oxime intermediate, which then under-
3.1. Coupling of Aldehydes with Amine Salts, Amines, and
goes a dehydration/hydration sequence to afford the desired
Amides
amide through a nitrile intermediate.
Two different reaction mechanisms have been proposed for In 1966, Nakagawa et al. reported a synthesis of aromatic and
the metal-catalyzed rearrangement of oximes through nitrile allyl amides from aldehydes and ammonia in the presence of
hydration (Scheme 2, paths A and B). In both cases, nitrile in- stoichiometric amounts of nickel peroxide as an oxidant.[26]
termediates are formed through dehydration of the aldoxime. Later, Fukuoka et al. prepared N,N-dimethylbenzamide in good
Subsequently, the obtained nitrile intermediates are rehydrated yield (84.2 %) from benzaldehyde and lithium dimethylcarba-
through the reaction of the second molecule of the aldoxime moylnickel carbonylate.[27] Subsequently, owing to the impor-
or water to give the corresponding amides (Scheme 2).[24] tance of the synthesis of amides from aldehydes in organic
synthesis, several strategies have been developed for this pro-
cess.
3.1.1. Transition-Metal-Catalyzed Conditions

3.1.1.1. Palladium-Catalyzed Reactions
Over the past few years, several transition-metal-catalyzed ap-
proaches have been explored for the amidation of aldehydes
with amines. In 1983, Tamaru et al. reported the first palladi-
um-catalyzed oxidative amidation strategy for the synthesis of
morpholine-based amides through the coupling of aldehydes
with morpholine in the presence of [Pd(OAc)2] as a catalyst,
ArBr as an oxidant, and K2CO3 as a base (Scheme 4 a).[28] The
authors also proposed the mechanism shown in Scheme 4 b.
Scheme 2. General pathways for the synthesis of amides through the hydra-
tion of a nitrile intermediate.
2.2. Hemiaminal Intermediates

Another attractive pathway for the oxidative amidation of alde-
hydes with amines uses an oxidant under metal-catalyzed or
metal-free conditions (Scheme 3). In this reaction, an aldehyde
reacts with an amine to afford a hemiaminal intermediate,
which is oxidized into the desired amide.[25] In some cases, the
hemiaminal intermediate may undergo dehydration to give an
imine. Subsequent reduction of the imine with the liberated
hydrogen would afford the corresponding amine (Scheme 3).
Typically, the product that is formed depends on the stability
of the hemiaminal intermediate and on the presence of an oxi-
dant or metal catalyst. This process has been performed both
in the presence and absence of hydrogen scavengers.
Scheme 4. a) [Pd(OAc)2]-catalyzed synthesis of amides; b) reaction mecha-
nism. DME = 1,2-dimethoxyethane.
In 2008, Suto et al. developed a new [PdCl2]-catalyzed path-

way for the oxidative amidation of aldehydes with amines
(Scheme 5).[29] This reaction employed the combination of
[PdCl2(Xantphos)] as a catalyst and H2O2–urea as an oxidant in
a MeOH/AcOH solvent mixture at 50 8C, thereby giving the de-
sired amides in moderate-to-good yields. Interestingly, benzal-
Scheme 3. General pathway for the synthesis of amides from aldehydes dehydes with electron-poor substituents gave higher yields
through a hemiaminal intermediate. than those with electron-rich substituents and aliphatic alde-

Focus Review
quential dehydration and hydration processes. Their proposed

reaction mechanism is shown in Scheme 6 b.
3.1.1.2. Ruthenium-Catalyzed Reactions

Chang and Chan established a facile and highly efficient ruthe-
nium(II)-catalyzed strategy for the direct amidation of alde-
hydes with PhI=NTs as a nitrogen source at room temperature
(Scheme 7 a).[31] This method tolerated a variety of aliphatic, ar-
Scheme 5. [PdCl2]-catalyzed pathway for the oxidative amidation of alde- omatic, and heteroaromatic aldehydes and was highly chemo-
hydes. Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
selective. The authors proposed a reaction mechanism as
shown in Scheme 7 b.
hydes. Aniline and sterically crowded amines provided the cor-

responding amides in lower yields under the optimized reac-
tion conditions, whilst cyclic amines failed to give the desired
amides. Thus, this method was highly sensitive to electronic
and steric factors.
Alia and Punniyamurthya explored a palladium-catalyzed
process for the synthesis of primary amides from aldehydes
and hydroxylamine hydrochloride (Scheme 6 a).[30] Their reac-
tion was performed in the presence of [Pd(OAc)2] as a catalyst
and Cs2CO3 as a base, by using water as a co-solvent with
DMSO at 100 8C. Control experiments revealed that the ratio of
DMSO to water played a crucial role in this process. A range of
aromatic, heteroaromatic, and aliphatic aldehydes were effi-
ciently amidated under these reaction conditions to afford the
corresponding amides in good-to-high yields. This reaction
proceeded through an oxime intermediate, followed by se-
Scheme 7. a) [Ru(TTP)(CO)]-catalyzed amidation of aldehydes with PhI=NTs;

b) reaction mechanism. TTP = meso-tetra-para-tolylporphyrin, Ts = para-tolue-
nesulfonyl.
Gnanamgari and Crabtree investigated a ruthenium-cata-

lyzed strategy for the synthesis of primary amides from oximes
or aldehydes (Scheme 8).[32] Their reaction was performed in
the presence of a catalytic amount of [Ru(terpy)(PPh3)Cl2] (2;
1 mol %; terpy = 2,2’;6’,2“-terpyridine), with NaHCO3 as an addi-
tive, in toluene at reflux for 15 h. The reaction efficiently toler-
ated a variety of aromatic, heteroaromatic, and aliphatic alde-
hydes by using hydroxylamine hydrochloride. Based on previ-
ous reports and meticulous experiments, the authors suggest-
Scheme 6. a) [Pd(OAc)2]-catalyzed synthesis of primary amides from alde- ed that the transfer of oxygen between the oxime and the ni-
hydes; b) proposed reaction mechanism. AcOH = acetic acid. trile happened inside the coordination sphere of the metal.

Focus Review
plexes that were tested for the one-pot conversion of alde-

hydes into amides in the presence of hydroxylamine hydro-
chloride and NaHCO3 under mild reaction conditions
(Scheme 10).[34] A range of aromatic and heteroaromatic alde-
hydes were all found to be active in this process, thereby
giving the corresponding amides in good-to-excellent yields.
Scheme 8. Ruthenium-catalyzed synthesis of primary amides from alde-

hydes.
Muthaiah et al. discovered an efficient in-situ-generated Scheme 10. Synthesis of primary amides catalyzed by a ruthenium(II) car-
ruthenium catalytic system for the conversion of alcohols or al- bonyl complex.
dehydes into the corresponding amides (Scheme 9).[33] The au-
Raja et al. developed an efficient air-stable catalytic system,

[RuCl(CO)(PPh3)(TAC)], from [RuH(Cl)(CO)(PPh3)3] and TAC, a
monoanionic NNO donor ligand. The authors applied this ruth-
enium(II) complex to the one-pot synthesis of amides from al-
dehydes in the presence of hydroxylamine hydrochloride and
NaHCO3 as a base at reflux in toluene (Scheme 11).[35] This reac-
tion was applicable to a range of aromatic, heteroaromatic,
and conjugated aldehydes, thereby affording the correspond-
ing amides in good-to-high yields.
Scheme 9. Synthesis of primary amides from aldehydes catalyzed by a ruthe-

nium(II) hydride.
thors tested a series of ruthenium hydride catalysts and N-het-

erocyclic carbene (NHC) precursors and found that a combina-
tion of the readily accessible [RuH2(PPh3)4] complex with NHC
precursor 3 led to high catalytic activity. In the absence of an
Scheme 11. Ruthenium(II)-catalyzed one-pot synthesis of primary amides.
NHC, the reaction rate dramatically decreased, which implied
TAC = 2-(2-thiazolylazo)-para-cresol.
that it played a crucial role in activating the ruthenium species.
Aryl aldehydes that contained a variety of functional groups
gave the desired amides in good-to-high yields, whilst aliphatic Garca-lvarez et al. reported an efficient ruthenium-cata-
aldehydes afforded slightly lower yields, owing to the forma- lyzed procedure for the synthesis of primary amides by using
tion of imine side products. This catalytic system was also com- aldehydes and hydroxylamine hydrochloride (Scheme 12).[36] In
patible with a variety of primary amines and secondary cyclic the presence of 5 mol % ruthenium catalyst 5, a variety of aro-
amines. Benzaldehyde reacted faster than benzyl alcohol. Inter- matic, heteroaromatic, a,b-unsaturated, and aliphatic primary
estingly, homogeneous ruthenium(0) complexes, including amides were obtained in good-to-excellent yields. The scope
[Ru(cod)(cot)] (cot = 1,3,5-cyclooctatriene) and [Ru3(CO)12], also of this catalytic system was further extended to access a varie-
showed significant catalytic activity for the amidation of alco- ty of useful diamides, such as phthalamide (6 a), isophthala-
hols or aldehydes in the presence of an in-situ-generated NHC mide (6 b), and terephthalamide (6 c). Furthermore, the same
ligand. group also applied this method to the synthesis of ferrocene
Prabhu and Ramesh developed a series of new ruthenium(II) carboxamide (6 d) in good yield, which is a versatile precursor
complexes that contained thiophenealdehyde benzhydrazone in ferrocene chemistry.
ligands. The authors found that complex 4 displayed the high- Nirmala et al. synthesized a series of hexacoordinate ruthe-
est catalytic activity among the ruthenium(II) carbonyl com- nium(II)/hydroxyquinoline thiosemicarbazone complexes (7)

Focus Review
Scheme 12. Ruthenium(II)-catalyzed strategy for the synthesis of primary Scheme 14. a) Ruthenium-catalyzed, oxoammonium-mediated oxidative ami-
amides. dation reaction; b) ruthenium-catalyzed, oxoammonium mediated oxidative
amidation and transamidation reaction sequence. bpy = 2,2’-bipyridine,
ACT = 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (4-acetamido-
from ruthenium(II) precursors and hydroxyquinoline thiosemi- TEMPO), LED = light-emitting diode.
carbazone-based ligands. Later, the same authors employed
these ruthenium complexes for the direct conversion of alde-
hydes into primary amides in the presence of hydroxylamine ployed as active acylating agents in a subsequent transamida-
hydrochloride and sodium bicarbonate as a base in toluene at tion reaction with amines (Scheme 14 b).
reflux (Scheme 13).[37] They found that all of their new com- Recently, Chusov and co-workers described a ruthenium-cat-
plexes displayed good catalytic activity to access a range of ar- alyzed strategy for the synthesis of N-alkylated amides, which
omatic primary amides in good yields. allowed the reductive amidation of aldehydes with primary
amides by using carbon monoxide as a deoxygenating agent
(Scheme 15).[39] Cyclopentadienyl ruthenium complexes
showed high catalytic activity for this process and the authors
found that the cationic ruthenium center played a crucial role
in this reductive amidation reaction. In the presence of 0.5–
1.0 mol % [Ru(C5Me4CH2OMe)(anthracene)]PF6 (8), a variety of
aromatic and aliphatic amides efficiently reacted with a range
of aromatic aldehydes that contained electron-donating sub-
stituents to afford the desired secondary amides in good-to-
high yields. Aromatic aldehydes that contained electron-poor
substituents and aliphatic aldehydes gave lower yields, owing
to the formation of side products. Notably, this reductive ami-
dation reaction proceeded in the absence of an external hy-
Scheme 13. Synthesis of primary amides catalyzed by a hexacoordinate ruth-
drogen source.
enium(II) complex. Py = pyridyl.
Nandi et al. developed a ruthenium-catalyzed, oxoammoni-

um-mediated oxidative strategy for the amidation of aldehydes
with pyrazole (Scheme 14 a).[38] This strategy could be per-
formed in the presence of [Ru(bpy)3(PF6)2] as a catalyst and
ACT as an oxidant, sodium persulfate as a secondary oxidant,
and pyridine in MeCN at room temperature for 24 h. A variety
of aromatic aldehydes and aliphatic aldehydes were found to
be active in this oxidative process. This method was also suita-
ble for triazole and benzotriazole and this strategy provided a
range of N-acyl azoles with excellent functional-group toler-
ance. The authors also efficiently converted a variety of alco-
hols in this oxidative amidation process. Furthermore, the au-
thors found that these acyl azoles could be successfully em- Scheme 15. Ruthenium-catalyzed reductive amidation reaction.

Focus Review
3.1.1.3. Rhodium-Catalyzed Reactions
Tillack et al. developed a rhodium-catalyzed system for the syn-

thesis of amides from aldehydes and secondary amines by
using [Rh(cod)2]BF4 as a catalyst, NMO as an oxidant, and
K2CO3 as a co-catalyst (Scheme 16 a).[40] The oxidant and base
Scheme 17. Rhodium-catalyzed oxidative amidation of allylic alcohols or al-

dehydes. BINAP = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
In the same year, Nguyen and Hull further investigated the

effectiveness of their previous method by using the reaction of
a sterically hindered pivaldehyde with aniline; however, only
the corresponding imine was obtained, instead of the amide.
By changing the solvent to THF and the ligand to dppb, the
desired product was obtained in high yield (method A;
Scheme 18 a).[42] Disappointingly, the reaction of pivaldehyde
with the aliphatic amine morpholine only afforded a very small
Scheme 16. a) Rhodium-catalyzed oxidative amidation of aldehydes; b) pro- amount of the product under the optimized conditions. The
posed reaction mechanism. cod = 1,5-cyclooctadiene, NMO = N-methylmor- authors found that changing the hydrogen scavenger to
pholine N-oxide. methyl methacrylate (MMA) and the ligand to tricyclohexyl-
phosphine provided optimal conditions for the amidation of
pivaldehyde with primary or secondary aliphatic amines (meth-
were found to be essential for promoting the formation of od B). In fact, this method offered a wide substrate scope, with
amides. A catalytic amount of K2CO3 was sufficient for this re- excellent functional-group tolerance. Furthermore, the authors
action. A series of aromatic and aliphatic aldehydes were well- also established optimal conditions for the amidation of steri-
tolerated to afford the desired amides in good-to-excellent cally hindered alcohols with anilines by using Xantphos as a
yields, whilst primary amines, including aniline and n-butyla- ligand and 2,2,2-trifluoroacetophenone as a hydrogen accept-
mine, did not respond under these reaction conditions. Only or. They also proposed a plausible reaction mechanism, as
trace amounts of the tertiary amines were observed as side shown in Scheme 18 b.
products. The authors also proposed a reaction mechanism, as Recently, Chusov and co-workers reported an efficient
shown in Scheme 16 b. [Rh2(OAc)4]-catalyzed process for the reductive amidation of al-
In 2016, Wu and Hull established an accessible and chemo- dehydes with primary amides to afford secondary amides
selective rhodium-catalyzed in situ [Rh(BINAP)]BF4 system for (Scheme 19 a).[43] The authors screened a range of rhodium
the one-pot oxidative amidation of allylic alcohols or aldehydes complexes and found that rhodium(II) acetate exhibited the
with amines or anilines in the presence of acetone (for primary highest catalytic activity. Thus, in the presence of 1 mol %
amines) or styrene (for secondary amines) as a hydrogen ac- [Rh2(OAc)4], a wide range of aromatic aldehydes underwent
ceptor to give amides in good-to-high yields (Scheme 17).[41] A direct amidation with aliphatic and aromatic amides, thereby
wide variety of primary amines and cyclic secondary amines, providing the corresponding amides in good-to-excellent
including 1-methylpiperazine, morpholine, piperidine, pyrroli- yields. The reaction proceeded without the need for an exter-
dine, and tetrahydroisoquinoline, as well as acyclic amines, nal hydrogen source, and carbon monoxide was used as a de-
such as dimethylamine and N-benzylmethylamine, all under- oxygenating agent. Remarkably, the solvent played a crucial
went this transformation, thereby delivering the corresponding role in this process: in THF, the reaction provided amides,
amides in good yields. This reaction was sensitive to steric hin- whilst changing the solvent to MeOH afforded tertiary amines.
drance: cyclohexylamine only afforded the desired amide in Furthermore, the authors also extended this reductive amida-
moderate yield, whilst n-butylamine gave the desired amide in tion reaction to the N-functionalization of pharmaceutically
good yield. Unlike other systems, a range of anilines that con- active piracetam, thereby affording compound 9 in 70 % yield.
tained both electron-rich and electron-poor groups were effi- The authors also proposed a reaction mechanism, as shown in
cient substrates for this transformation. Allylic alcohols and al- Scheme 19 b.
dehydes provided similar yields.

Focus Review
Scheme 19. a) [Rh2(OAc)4]-catalyzed reductive amidation of aldehydes with

primary amides; b) reaction mechanism. L = ligand.
Scheme 18. a) Rhodium-catalyzed oxidative amidation of hindered alde-

hydes; b) reaction mechanism. dppb = 1,4-bis(diphenylphosphino)butane,
CsOAc = cesium acetate, Cy = cyclohexyl.
3.1.1.4. Gold-Catalyzed Reactions
Li et al. developed a facile and efficient gold-catalyzed strategy

for the amidation of aldehydes with amines that employed
KAuCl4 as a catalyst and K2CO3 as a base in MeCN/water (1:1)
at 60 8C for 12 h (Scheme 20 a).[44] Aromatic aldehydes with a
range of functional groups reacted efficiently with a series of
secondary amines to give the desired amides in good-to-excel-
lent yields. A wide range of aliphatic aldehydes and formalde-
hyde were also smoothly converted under the reaction condi-
tions. However, this method was limited to secondary amines.
Primary amines, such as benzylamine and aniline, did not un-
dergo this transformation. This method offered high function-
al-group tolerance, and challenging monosaccharide- and oli-
gosaccharide-based aldehydes with polyhydroxy groups were
Scheme 20. a) KAuCl4-catalyzed synthesis of amides from aldehydes and
coupled with secondary amines to give the corresponding
amines; b) reaction mechanism. TMS = trimethylsilyl.
amides.
The authors proposed a plausible mechanism for this trans-
formation, as shown in Scheme 20 b. Initially, the reaction of an
amine with a gold(III) ion afforded an aminyl radical (10 a), (10 b). Finally, the alkoxyl radical (10 b) provided the desired
which reacted with an aldehyde to give an alkoxyl radical amide with the loss of a hydrogen radical.

Focus Review
3.1.1.5. Iron-Catalyzed Reactions
In 2011, Gowda and Chakraborty reported the reaction of a

wide range of aromatic, a,b-unsaturated, and aliphatic alde-
hydes with hydroxylamine hydrochloride in the presence of
FeCl3 as a catalyst and Cs2CO3 as a base in water at 100 8C,
which gave the corresponding primary amides in good-to-high
yields (Scheme 21).[45] The authors screened several iron salts
Scheme 22. Iron-catalyzed oxidative amidation of aldehydes with amine hy-

drochloride salts. TBHP = tert-butyl hydroperoxide.
Scheme 21. FeCl3-catalyzed synthesis of primary amides from aldehydes.
and identified FeCl3 as the best choice for this process. The re-
action employed environmentally benign conditions to access
a range of primary amides with high functional-group compat-
ibility. Notably, this reaction proceeded under ligand- and addi-
tive-free conditions. The base, iron catalyst, and water were all
essential for this conversion. Furthermore, the authors also suc-
cessfully applied these conditions to the synthesis of the corre-
sponding diamide derivatives, unprotected a-amino amides,
and b-d-ribofuranose amides in good yields with no racemiza-
tion, which are useful intermediates in pharmaceutical com-
pounds. This reaction proceeded through oxime and nitrile in-
termediates through a sequential dehydration/hydration pro-
cess. Scheme 23. a) FeCl2-catalyzed amidation of aldehydes with tertiary amines;
Ghosh et al. reported a mild and efficient iron-catalyzed pro- b) reaction mechanism.
cedure for the synthesis of secondary and tertiary amides in
good-to-high yields through the coupling of aromatic and ali-
phatic aldehydes with a variety of primary and secondary corresponding amides in moderate-to-excellent yields. Sterical-
amine hydrochloride salts by using FeSO4·7 H2O as a catalyst, ly hindered 2,6-diisopropyl-N,N-dimethylaniline and tropinone
TBHP as an oxidant, and CaCO3 as a base in MeCN at 60 8C were efficiently transformed into the desired amides. This reac-
(Scheme 22).[46] This method was vulnerable to steric hin- tion was highly chemoselective, thus suggesting that sterically
drance, although tert-butylamine hydrochloride salt gave the less-hindered a-C H bonds of tertiary amines were preferen-
desired amide in moderate yield. This method was also com- tially oxidized. The authors also proposed a plausible reaction
patible with the amine hydrochloride salts of a range of amino mechanism, as shown in Scheme 23 b.
acids. The same group also employed these conditions for the In 2012, the De Luca group replaced Cu(OAc)2[58] with an
synthesis of antiarrhythmic drug N-acetylprocainamide (11), iron salt for the oxidative coupling of aldehydes with a variety
which proceeded through a hemiaminal intermediate. of mono- and disubstituted N-chloramines (Scheme 24). The
Li et al. explored a new and efficient FeCl2-catalyzed proce- reaction was performed in the presence of FeCl3·6 H2O as a cat-
dure for the oxidative amidation of aldehydes with tertiary alyst and TBHP as an oxidant in MeCN at reflux under base-
amines to afford tertiary amides (Scheme 23 a).[47] The authors free conditions.[48] In the presence of 0.15 mol % FeCl3·6 H2O, a
examined a variety of catalysts and oxidants and found that range of aliphatic, aromatic, and heteroaromatic amides were
the combination of FeCl2 and TBHP gave the best performance obtained in good-to-high yields with high functional-group tol-
for this process. A variety of aliphatic, aromatic, and heteroaro- erance. A variety of acyclic and cyclic N-chloramines were effi-
matic aldehydes underwent this transformation to afford the ciently used as substrates. This reaction also proceeded

Focus Review
Scheme 26. Co2(CO)8-catalyzed reductive N-alkylation of primary amides

Scheme 24. FeCl3-catalyzed oxidative cross-coupling reaction of aldehydes with aldehydes.
with N-chloramines.
timized conditions. The same authors extended this method to

through the cross-coupling reaction of acyl- and nitrogen-cen- the reductive acylation of ketones.
tered radicals. Bai et al. reported the pyrolysis of a cobalt(II)-containing
In 2013, Jagadeesh and co-workers developed a smart nano- metal—organic framework (MOF) to afford a carbon nitrogen
scale Fe2O3-N@C catalyst (Fe-phen/C-800).[49a] More recently, material with embedded cobalt nanoparticles (Co@C N). Then,
they applied this catalytic system to the efficient synthesis of a they applied this heterogeneous cobalt-based catalytic system
range of nitriles and aromatic primary amides through the cou- to the synthesis of amides through the oxidative amidation of
pling of aldehydes with aqueous ammonia in the presence of aldehydes with formamides in the presence of TBHP as an oxi-
1 bar of molecular oxygen or air (Scheme 25).[49b] This method dant (Scheme 27 a).[50] A wide range of aromatic, heteroaromat-
Scheme 25. Fe2O3 N@C-catalyzed synthesis of primary amides. Fe2O3

N@C = pyrolyzed Fe2O3 and 1,10-phenanthroline on carbon powder.
offered broad substrate scope with excellent functional-group

tolerance. Notably, the Fe2O3-N@C catalyst could be readily re-
cycled and reused at least five times without loss of catalytic
activity or selectivity, and no leaching of iron in the catalyst
was observed. The authors also performed kinetic studies to
explore the stability of the catalyst. They found that the cata-
lyst was stable and exhibited similar catalytic activity in the Scheme 27. a) Cobalt-catalyzed oxidative amidation of aldehydes with for-
presence of an excess of ammonia, with a prolonged reaction mamides; b) proposed reaction mechanism. IPr = 1,3-bis(2,6-diisopropylphe-
time. nyl)imidazole-2-ylidene.
ic, and aliphatic aldehydes reacted with a variety of alkyl-sub-

3.1.1.6. Cobalt-Catalyzed Reactions
stituted formamides under the optimized conditions to afford
Rubio-Prez et al. reported a stibane-modified cobalt-catalyzed the desired amides in good-to-excellent yields. The authors
reductive amidation of aldehydes with amides (Scheme 26).[16b] found that the catalyst could be readily separated from the re-
This reaction employed a combination of Co2(CO)8 and Sb(o- action mixture by using an external magnetic field, and it
tolyl)3 under external hydrogen pressure. The authors tested a could be reused efficiently without loss of catalytic activity.
series of stibane and phosphine ligands and found that Sb(o- Control experiments revealed that the oxidant was essential
tolyl)3 was the most active ligand for this transformation. A va- for this amidation reaction.
riety of secondary amides were obtained in good-to-excellent The authors proposed the mechanism shown in
yields with excellent functional-group tolerance under the op- Scheme 27 b. The first step involved the generation of tert-bu-

Focus Review
toxyl and tert-butylperoxyl radicals in the presence of the cata-

lyst. Then, these radicals reacted with the aldehyde and forma-
mide to afford acyl and aminyl radicals, respectively (step 2). Fi-
nally, the acyl radical underwent a cross-coupling reaction with
the aminyl radical to give the amide (step 3).
Guo et al. developed a direct oxidative amidation of alde-
hydes with amine hydrochlorides by using a CoI2/TBHP system
in MeCN at 70 8C under basic conditions, thereby providing
the corresponding amides in good-to-excellent yields
(Scheme 28).[51] Primary and secondary amines that contained
Scheme 29. Oxidative amidation reaction catalyzed by a Co Al hydrotalcite.
derwent oxidation and hydrolysis to give benzaldehyde under

the oxidative conditions, and subsequent coupling of benzal-
dehyde with DMF provided the desired N,N-dimethylbenza-
mide. The oxidative amidation of benzaldehydes gave higher
yields than the oxidative amidation of benzylamines. The reac-
tion proceeded through the cross-coupling of acyl and aminyl
radicals, which led to the generation of the amide.
3.1.1.7. Nickel-Catalyzed Reactions

Scheme 28. CoI2-catalyzed oxidative amidation reaction.
Whittaker and Dong developed a new and efficient nickel-cata-
lyzed strategy for the synthesis of esters and amides through a
dehydrogenative cross-coupling reaction of aldehydes with al-
other reactive functional groups were efficiently converted
cohols and amines, respectively (Scheme 30 a).[53] The reaction
under these reaction conditions. The use of benzaldehydes
that contained electron-donating groups gave lower yields,
whereas benzaldehydes that contained electron-withdrawing
groups provided the corresponding amides in excellent yields,
but no amide product was observed with aliphatic aldehydes
under the optimized conditions. Notably, the authors also suc-
cessfully employed amines instead of amine hydrochlorides in
the absence of a base. This method was extended to the cou-
pling reaction of alcohols with amines by using 3.5 equivalents
of TBHP. It was suggested that the aldehyde was the inter-
mediate in this reaction, because it was formed as the side
product in most cases.
Mechanistic studies indicated that the tBuOC/tBuOOC radical
was the active species, and it played the crucial role of hydro-
gen abstraction in this catalytic process. Importantly, water is
an essential reactant for the generation of the hemiaminal
from the imine (Scheme 28).
Gupta et al. reported an oxidative C H functionalization of
benzaldehydes with DMF under the influence of heterogene-
ous Co Al hydrotalcite as a catalyst and TBHP as an oxidant
(Scheme 29).[52] A variety of benzaldehydes with electron-do-
nating and electron-withdrawing substituents reacted with
DMF to give the desired amides. A range of other mono- and
di-N-substituted formamides were also compatible with this
oxidative amidation reaction, thereby forming the correspond-
ing amides in good-to-excellent yields, although formamide
and DPF (N,N-diphenylformamide) did not lead to the corre-
sponding products. This method was also applicable to vari-
ously substituted benzylamines, thereby affording the corre- Scheme 30. a) Nickel-catalyzed synthesis of amides; b) reaction mechanism.
sponding amides in good-to-moderate yields. Benzylamine un- Nu = nucleophile.

Focus Review
was performed in the presence of [Ni(cod)2] as a catalyst, IPr as amides (Scheme 32).[16a] The reaction was performed by using
a ligand, and 2,2,2-trifluoroacetophenone as a hydrogen ac- CuBr as a catalyst and NBS as an oxidant. A great variety of ar-
ceptor. Aromatic aldehydes that contained electron-donating omatic aldehydes were efficiently coupled with a variety of pri-
or electron-withdrawing groups and aliphatic aldehydes were mary and secondary amides to afford the related amides in
efficiently coupled with a range of anilines that contained elec- good-to-excellent yields. The authors also applied these condi-
tron-withdrawing or electron-donating groups under the opti- tions to the synthesis of a cyclic compound through intramo-
mized conditions, thereby giving the corresponding secondary lecular cyclization.
or tertiary amides in good-to-excellent yields. Primary alkyl
amines, hindered amines, benzylic amines, and cyclic amines
were also suitable for this oxidative amidation reaction.
Based on control experiments and previous reports, the au-
thors proposed a reaction mechanism as shown in
Scheme 30 b. Initially, 2,2,2-trifluoroacetophenone coordinated
to the nickel atom to give complex 12 a, which underwent
complexation with an aldehyde to provide intermediate 12 b.
Subsequently, intermediate 12 b rearranged into complex 12 c,
which then reduced the hydrogen acceptor to form acyl
nickel alkoxide intermediate 12 d. Ligand exchange with the
Scheme 32. CuBr-catalyzed oxidative amidation of aldehydes with amides.
nucleophile afforded complex 12 e, and reductive elimination NBS = N-bromosuccinimide.
gave the final product.
Zhu et al. found that the combination of CuI and sodium 2-

3.1.1.8. Copper-Catalyzed Reactions
pyridonate was an effective system for the aerobic oxidative
Yoo and Li developed an elegant copper-catalyzed method for amidation of aromatic aldehydes with secondary amines in tol-
the synthesis of amides from aldehydes and amine hydrochlo- uene at reflux (Scheme 33 a).[54] A variety of sodium 2-pyrido-
ride salts that employed 1 mol % CuI as a catalyst, 1 mol % nate ligands were screened and the authors found that the
AgIO3 as an additive, TBHP as an oxidant, and CaCO3 as a base sodium salt of 2-hydroxy-5-methylpyridine (13) was the most
in MeCN at 40 8C (Scheme 31).[25] A wide range of aromatic al- active for this process. This system enabled the oxidative ami-
dation of aromatic aldehydes with a wide range of functional
groups and heteroaromatic aldehydes to afford the desired
amides. The oxidative amidation of a range of cinnamalde-
hydes proceeded at a lower temperature (100 8C) with a larger
amount of catalyst (20 mol %). None of the desired product
was observed with aliphatic aldehydes, such as 1-octanal and
pivalaldehyde. Both cyclic and acyclic secondary amines were
compatible with this transformation to afford the correspond-
ing amides, whilst primary amines, such as benzylamine and
aniline, gave the undesired imines instead. The monoamide
Scheme 31. CuI-catalyzed oxidative amidation of aldehydes. Bn = benzyl. product was observed predominantly with terephthaldehyde,
which contained two formyl groups. Importantly, CuI and the
2-pyridonate ligand were essential for this transformation. The
authors proposed a reaction mechanism as shown in
dehydes and amine hydrochlorides were compatible with this Scheme 33 b.
transformation, thereby giving the corresponding amides in In the same year, Ghosh et al. developed an elegant and effi-
good-to-excellent yields. Aliphatic cyclohexyl aldehyde was cient oxidative copper-catalyzed strategy for the synthesis of
also tested in this transformation, and the desired amide was primary, secondary, and tertiary amides (Scheme 34).[55] The au-
obtained, albeit in low yield. This method was sensitive to thors screened a range of copper catalysts and found that
steric effects: the sterically bulky tert-butylamine rendered the CuSO4·5 H2O exhibited the highest activity for this reaction.
corresponding amide in low yield. Furthermore, the authors They also found that the copper catalyst, oxidant, and base
extended this oxidative amidation reaction to an optically were all crucial for this transformation to proceed. In the pres-
active amine ester, which afforded the corresponding amide in ence of 5 mol % CuSO4·5 H2O, a wide variety of aldehydes were
high yield without the loss of stereochemistry. Based on these coupled with a range of amine hydrochloride salts by using
results, this method is feasible for the synthesis of secondary TBHP as an oxidant in MeCN at room temperature, thereby af-
amides. The authors proposed a reaction mechanism, and the fording the corresponding secondary and tertiary amides in
reaction proceeded as shown in Scheme 3. good-to-excellent yields, whilst the reactions of aliphatic and
Wang et al. proposed a copper-catalyzed oxidative amida- heteroaromatic aldehydes with amine hydrochloride salts gave
tion of aldehydes with amides to give secondary or tertiary lower yields of the amides. Furthermore, the authors also re-

Focus Review
ported a synthesis of primary amides by using reoptimized re-

action conditions. In the presence of 5 mol % Cu2O, a variety of
primary amides were prepared from the corresponding alde-
hydes and the inexpensive and readily available ammonium
chloride in MeCN/water (2:1) at 80 8C. Pleasingly, the chiral-
amino-acid-derived amine hydrochloride salts were also effi-
ciently converted into the desired amides in high yields with
no racemization. This method was successfully extended to
the synthesis of an antiarrhythmic drug, N-acetylprocainamide
(11).
Ganguly et al. also reported a simple copper(II)-catalyzed
one-pot strategy for the transformation of aldehydes into pri-
mary amides in the presence of hydroxylamine hydrochloride
and sodium acetate under solvent-free conditions
(Scheme 35).[56] After screening a range of copper(II) salts, they
Scheme 35. Copper(II)-catalyzed synthesis of primary amides from alde-

hydes.
found that CuSO4·5 H2O was the best choice for this reaction. A
variety of aromatic, heteroaromatic, and aliphatic primary
amides were efficiently obtained in good-to-excellent yields
under the optimized conditions. Based on control experiments,
Scheme 33. a) Copper(I)-catalyzed aerobic oxidative amidation of aldehydes
with secondary amines; b) reaction mechanism. Boc = tert-butyloxycarbonyl. the authors suggested that the reaction proceeded through
oxime and nitrile intermediates, as shown in Scheme 2, path B.
Martnez-Asencio et al. developed an alternative, environ-
mentally friendly copper-catalyzed process for the synthesis of
primary amides from aldehydes and hydroxylamine
(Scheme 36).[57] Of the catalysts that were tested, Cu(OAc)2
showed the highest activity. The reaction was performed in the
presence of 2 mol % Cu(OAc)2 in water at 100 8C. The amount
of catalyst and the reaction temperature were found to have a
significant effect on amide formation. The catalyst could be re-
cycled and reused up to 10 times whilst retaining high catalytic
activity. A variety of aromatic, heteroaromatic, and aliphatic al-
dehydes were efficiently employed under these catalytic condi-
Scheme 34. Copper-catalyzed oxidative amidation of aldehydes with amines. Scheme 36. Cu(OAc)2-catalyzed one-pot synthesis of primary amides.

Focus Review
tions, thereby affording the desired amides in good-to-excel-

lent yields. This method avoided the need for a base, organic
solvent, and ligand or other additive.
In the same year, De Luca’s group reported an efficient one-
pot procedure for the direct oxidative cross-coupling of alde-
hydes with N-chloramines that were generated from amines
by using Cu(OAc)2 as a catalyst and TBHP as an oxidant under
base-free conditions (Scheme 37 a).[58] No reaction was ob-
Scheme 38. a) Copper-catalyzed synthesis of N-(pyridin-2-yl)benzamides;

b) reaction mechanism.
in moderate-to-good yields. However, only trace amounts of

the desired amides were detected with ortho- and para-nitro-
benzaldehydes. Notably, this method was also sensitive to
steric hindrance on the pyridine ring. The authors also tested
other 2-amino heterocycles, such as 2-aminopyrimidine and 2-
aminobenzimidazole; however, no reaction was observed with
these systems. Air was used as an oxidant and it played a key
role in the oxidative amidation reaction.
The authors proposed a plausible mechanism for the direct
oxidative amidation reaction, as shown in Scheme 38 b. Initial
Scheme 37. a) Cu(OAc)2-catalyzed oxidative cross-coupling reaction of alde- complexation of an aldehyde (15 a) to 2-aminopyridine (15 b)
hydes with N-chloroamines; b) reaction mechanism. in the presence of CuI gave intermediate 15 c, followed by nu-
cleophilic attack of the amine on the carbonyl group to afford
intermediate 15 d. Subsequently, proton transfer took place to
served in the absence of the catalyst or the oxidant. The ami- provide hemiaminal 15 e, which was oxidized under the influ-
dation of a range of aliphatic and aromatic aldehydes proceed- ence of oxygen to give the desired product (15 f).
ed well with primary and secondary acyclic or cyclic N-chlora- Later, Patel et al. also reported a synthesis of N-(pyridine-2-
mines under the optimized conditions, thereby affording the yl)amides from the coupling reaction of aldehydes with 2-ami-
corresponding amides in good-to-excellent yields. A wide vari- nopyridines by using Cu(OTf)2 as a catalyst and I2 as an oxidant
ety of functional groups, including methoxy, methyl, nitro, in the presence of SDS as an amphiphilic surfactant in water
halo, ester, and ketone groups, were well-tolerated under the (Scheme 39).[60] The scope of this oxidative amidation approach
reaction conditions. This method was also not vulnerable to
steric hindrance in the substrates.
The authors proposed a reaction mechanism as shown in
Scheme 37 b. A cross-coupling reaction between an acyl radical
of the aldehyde (14 a) and the amino radical of N-chloramine
(14 b) afforded the desired amide.
In 2013, Yang et al. reported a copper-catalyzed method for
the synthesis of N-(pyridin-2-yl)benzamides from 2-aminopyri-
dines and aldehydes by using CuI as a catalyst in DMF at 80 8C
(Scheme 38 a).[59] The scope and limitations of this strategy
were explored by using a series of substituted benzaldehydes
and 2-aminopyridines under their optimized reaction condi- Scheme 39. Cu(OTf)2-catalyzed synthesis of N-(pyridine-2-yl)amides. Tf = tri-
tions, thereby providing the desired N-(pyridin-2-yl)benzamides fluoromethanesulfonyl, SDS = sodium dodecyl sulfate.

Focus Review
included a diverse array of aromatic, heteroaromatic, and ali- the reaction conditions. However, this method was unsuitable
phatic aldehydes. Aliphatic aldehydes provided lower yields for aromatic amines, such as aniline.
than aromatic aldehydes, owing to the presence of side reac- Recently, the Zhu group reported a new and efficient
tions. 2-Aminopyridines that contained a variety of substitu- copper-catalyzed strategy for the synthesis of a variety of syn-
ents were transformed in this reaction system, although this thetically useful e-CF3-substituted amides from 2-allyl benzalde-
method was not compatible with other amines, such as ani- hydes and amines by using Togni’s reagent (16) under mild re-
lines, 3-aminopyridine, 4-aminopyridine, 2-aminopyrimidine, 2- action conditions.[63] The optimized reaction conditions were
aminobenzimidazole, and aliphatic amines. This reaction pro- found to be 10 mol % CuSO4 as a catalyst and K2CO3 as a base
ceeds through a hemiaminal intermediate, followed by oxida- at room temperature in DMF for 10 h (Scheme 42). This reac-
tion in the presence of I2, which led to the formation of the
amide.
Rostamnia et al. developed a highly efficient heterogeneous
SBA-15/En Cu catalytic system by using copper acetate com-
plexes and ethylenediamine-modified SBA-15 and applied it to
the one-pot conversion of aromatic aldehydes into primary
amides by using hydroxylamine hydrochloride and Na2CO3 as a
base in water (Scheme 40).[61] A variety of aromatic aldehydes
Scheme 42. Copper-catalyzed synthesis of e-CF3-substituted amides.
Scheme 40. Heterogeneous synthesis of primary amides catalyzed by an tion involved the trifluoromethylation of alkenes with a redox-
SBA-15-grafted En Cu complex. En = ethane-1,2-diamine. neutral remote amidation of aldehydes. A wide variety of alde-
hydes with diverse functional groups and a,b-unsaturated al-
dehydes were employed in this transformation, thereby afford-
that contained electron-withdrawing or electron-donating ing the corresponding products (17) in good yields. Neverthe-
groups and heteroaromatic aldehydes efficiently underwent less, none of the desired products were observed with both
this process, thereby affording the desired amides in good-to- hex-5-enal and 2-vinylbenzaldehyde under the optimized con-
excellent yields. This method displayed broad functional-group ditions. In addition, cyclic and acyclic secondary amines were
tolerance. In this reaction, the catalyst was readily recycled and shown to be suitable coupling partners for this transformation,
reused in 14 runs without the loss of its catalytic activity, and whilst primary amines (including n-butylamine and aniline)
no copper leaching was observed. The authors also proposed were not compatible with the reaction conditions.
a reaction mechanism, and the reaction proceeded as shown
in Scheme 2.
Lu et al. investigated a CuCl/TBHP-promoted oxidative cou-
3.1.1.9. Zinc-Catalyzed Reactions
pling reaction of aldehydes with amines under aqueous condi-
tions at 100 8C to give amides (Scheme 41).[62] A wide range of Zhang and Wu developed the first zinc(II)-catalyzed process for
aliphatic, aromatic, and heteroaromatic aldehydes worked well the synthesis of amides under solvent-free conditions
with a variety of aliphatic primary or secondary amines under (Scheme 43).[64] This method provided an alternative route to a
variety of aromatic secondary amides with high functional-
Scheme 41. CuCl-catalyzed synthesis of amides. Scheme 43. ZnBr2-catalyzed synthesis of amides aldehydes and amines.

Focus Review
group compatibility. In the presence of ZnBr2 and TBHP, the ox- played significant roles in the formation of the amides. In addi-
idative amidation of aromatic and heteroaromatic aldehydes tion, primary amines were also found to be suitable for this
with a range of linear aliphatic amines proceeded smoothly, amidation reaction. Benzylamine provided the corresponding
thereby affording the corresponding amides in good-to-high amide in low yield, whilst aniline gave the desired amide in
yields. However, cyclohexylamine only gave a small amount of good yield.
the desired amide, owing to steric hindrance. Aliphatic alde- Li et al. described an efficient heterobimetallic lanthanide/
hydes did not give the desired amides under the standard con- sodium phenoxide catalytic system for the amidation of alde-
ditions. hydes with amines under mild conditions (Scheme 46).[67] The
3.1.2. Lanthanide-Metal-Catalyzed Conditions

Recently, lanthanide-based metal complexes have also been
found to be active for the amidation of aldehydes with
amines. In this context, Zhang et al. explored a Cannizzaro-
type disproportionation reaction of aromatic aldehydes into
the corresponding amides and alcohols.[65] This reaction was
performed in the presence of lithium amide LiN(SiMe3)2 and
YCl3 (5 mol %) at room temperature, or with 1.1 equivalents of
Scheme 46. Synthesis of amides catalyzed by a heterobimetallic lanthanide
[(Me3Si)2N]3Ln(m-Cl)Li(THF)3 at room temperature (Scheme 44).
complex.
The authors mentioned that both catalytic systems displayed
very similar catalytic activities. Once again, the solvent played
a crucial role in this transformation. Furthermore, this method authors examined a series of metals and phenoxide groups in
was also found to tolerate a variety of electron-donating and the bimetallic complexes and found that the combination of
electron-withdrawing substituents on the phenyl ring of the al- samarium metal and 2,6-(tBu)2C6H3O showed the highest activi-
dehyde. ty. In the presence of 3 mol % of the catalyst, a range of aro-
matic amides were obtained in good-to-excellent yields. Inter-
estingly, aromatic aldehydes that contained electron-deficient
groups were more reactive than those that contained electron-
rich substituents. Aliphatic cyclohexane carboxaldehyde afford-
ed the corresponding amide in moderate yield. In addition, pri-
mary amines, such as aniline and benzylamine, and secondary
amines, such as benzylmethylamine, pyrrolidine, piperidine,
and morpholine, were efficiently reacted under the optimized
conditions. The authors mentioned that this bimetallic catalytic
Scheme 44. Cannizzaro-type disproportionation synthesis of primary amides. system was superior to the corresponding monometallic cata-
lytic systems.
Wang et al. proposed an efficient bimetallic catalytic system
Recently, the versatile reactivity of homoleptic Ln[N(SiMe3)2]3 for the amidation of aldehydes with amines.[68] They tested a
lanthanide amido complexes has been elegantly explored for series of lanthanide complexes and found that anionic bridged
a range of chemical transformations. In this context, Seo and lanthanide complexes with lithium metal displayed high cata-
Marks investigated the reactivity of lanthanide amido com- lytic performance in this process, owing to a cooperation
plexes for the amidation of aldehydes with amines effect between the lanthanide and lithium metal (Scheme 47).
(Scheme 45).[66] This efficient reaction was performed at room Thus, in the presence of 2 mol % [Li(DME)3](YbL2), a range of ar-
temperature under base- and oxidant-free conditions to give omatic aldehydes with a variety of substituents underwent the
the desired amides. The authors found that the electronic char-
acter of the aldehyde and the nucleophilicity of the amine
Scheme 47. Amidation of aldehydes with amines catalyzed by a bimetallic

Scheme 45. Lanthanide-catalyzed amidation of aldehydes. complex.

Focus Review
reaction with cyclic and acyclic amines to give the desired with primary, secondary, and aryl amines under a-redox amida-
amides in good-to-high yields. The reaction of aniline gave the tion conditions, thereby providing the desired amides in good-
corresponding amide in good yield, whereas anilines that con- to-high yields. The authors also tested a range of a,b-epoxy
tained either electron-donating or electron-withdrawing and aziridine aldehydes, as well as a,b-unsaturated aldehydes,
groups only furnished the desired amides in low yields. Benzyl- under the optimized conditions, thereby affording the corre-
amine gave the corresponding amide in good yield with high sponding amides in good yields, although an additional
catalyst loading. 10–30 mol % of the base was required for this conversion. The
authors proposed the reaction mechanism shown in
3.1.3. Metal-Free Conditions Scheme 48 b.
In the same year, Bode and Sohn explored an effective NHC-
3.1.3.1. NHC- or Ionic-Liquid-Catalyzed Reactions
catalyzed process for the synthesis of amides through the ami-
Recently, several NHC- or ionic-liquid-catalyzed strategies have dation of formyl cyclopropanes and a,b-unsaturated aldehydes
been reported for the amidation of aldehydes with amines. In with amines. The reaction proceeded in the presence of
this context, Vora and Rovis developed a method for the for- 5 mol % of the NHC catalyst (19), 1.1 equivalents of imidazole
mation of amide bonds from a-reducible aldehydes and as an additive, and 20 mol % of an amine base (DBU or DIPEA)
amines by using a nucleophilic carbene (18) as a catalyst at 40 8C (Scheme 49).[70] Among the additives that were exam-
and HOAt as a co-catalyst under metal-free conditions
(Scheme 48 a).[69] The authors tested a series of co-catalysts and
found that hydroxybenzotriazole (HOBt), 4-dimethylaminopyri-
dine (DMAP), imidazole, and pentafluorophenol (PFPOH) were
effective co-catalysts for this reaction. The authors mentioned
that the presence of a co-catalyst was essential for this trans-
formation. Thus, a variety of a-halo aldehydes were coupled
Scheme 49. NHC-catalyzed, imidazole-mediated amidation of a-functional-

ized aldehydes. EWG = electron-withdrawing group, Mes = mesityl
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
ined, imidazole exhibited the best performance. The authors

found that, in the absence of imidazole, a larger amount of the
imine product was observed instead of the desired amide,
which indicated that imidazole was essential for this process. A
wide range of amines, such as primary and secondary amines,
aniline, and hydroxylamine, were successfully employed by
using this procedure, whilst a variety of formyl cyclopropanes
and a,b-unsaturated aldehydes were efficiently employed
under the optimized conditions.
Thai et al. reported that triazolium-derived carbene 18 was a
powerful NHC catalyst for an intramolecular redox lactamiza-
tion of N-tosyl and N-benzyl prolinals, thereby providing the
desired five- and six-membered lactams in good-to-high yields
(Scheme 50 a).[71] The authors tested a series of bases and
found that iPr2NEt gave the best result. Notably, the tertiary
Scheme 48. a) NHC-catalyzed synthesis of amides from a-reducible alde-
hydes; b) reaction mechanism. HOAt = 1-hydroxy-7-azabenzotriazole, DI- amine base played a dual role in this reaction: 1) it facilitated
PEA = N,N-diisopropylethylamine. the formation of the carbene catalyst through deprotonation;

Focus Review
thors found that an in-situ-generated hexafluoroisopropyl ester

was a key intermediate for the formation of the amide bond.
In addition, the authors also applied this efficient process to
the oxidative azidation of aromatic aldehydes with trimethyl-
silyl azide to give the corresponding aryl azides.
Prasad et al. reported an effective oxidative amidation strat-
egy for the synthesis of new carboxamides from aldehydes
and amines in the presence of an ionic liquid and DIB in CHCl3
at room temperature (Scheme 52).[73] The authors tested a
Scheme 52. [BMiM]+[BF4] -catalyzed synthesis of amides. DIB = diacetoxyio-

dobenzene, BMIM = 1-butyl-3-methylimidazolium.
Scheme 50. a) NHC-catalyzed intramolecular redox lactamization reaction;
b) reaction mechanism. TBDMS = tert-butyldimethylsilyl.
series of ionic liquids and found that [BMIM]+[BF4] gave the
best results. This method provided simple and efficient access
and 2) it enabled the ring-opening step through a hydrogen- to new glycosyl carboxamides. A range of aliphatic and aro-
bonding interaction between its conjugate acid and the nitro- matic amines efficiently reacted with glycosyl uloses to give
gen leaving group. The proposed reaction mechanism is the corresponding glycosyl carboxamides in good-to-high
shown in Scheme 50 b. yields. Moreover, a wide variety of aldehydes, such as aliphatic,
As an extension of their previous work on the oxidative aromatic, and heteroaromatic aldehydes, were also employed
esterification of aldehydes, De Sarkar and Studer reported an in this transformation, and a range of functional groups were
efficient NHC-catalyzed strategy for the oxidative amidation of amenable to this oxidative amidation procedure.
aromatic and unsaturated aldehydes with amines under metal- Khalafi-Nezhad and Mohammadi prepared a CSMIL based on
free conditions (Scheme 51).[72] The reaction was performed by an environmentally benign biopolymer, by using renewable
using 2 mol % of 1,3-dimethyltriazolium iodide as an NHC pre- material chitosan, methylimidazole, and wet/dry FeCl3.[74] They
cursor, DBU, 3,3’,5,5’-tetra-tert-butyl diphenoquinone (20) as an applied this catalytic system to the synthesis of a wide variety
oxidant, and hexafluoroisopropanol as an additive under mild of aromatic, heteroaromatic, and aliphatic nitriles and amides
conditions. Notably, cyclic amines and amino-acid-derived (Scheme 53 a). Dry CSMIL 21 gave nitriles, whilst the wet CSMIL
amines were also suitable substrates in this reaction. The au- afforded amides. In the presence of wet CSMIL, the reaction of
a range of aldehydes with hydroxylamine hydrochloride and
mesyl chloride proceeded well to give the desired amides in
good-to-excellent yields. The authors proposed the reaction
mechanism as shown in Scheme 53 b.
Alanthadka and Maheswari reported an NHC-catalyzed oxi-
dative amidation strategy for the synthesis of amides through
the coupling of aromatic aldehydes to amines under the influ-
ence of NBS as an oxidant (Scheme 54 a).[75] Of the NHC cata-
lysts that were examined, compound 22 displayed the best
performance for this process. The scope of this reaction was
probed by using a series of aryl aldehydes and primary or sec-
ondary aliphatic amines under the optimized conditions, which
gave the desired amides in good yields. In addition, cyclic sec-
ondary amines, including piperidine, morpholine, and pyrroli-
Scheme 51. Oxidative amidation reaction catalyzed by 1,3-dimethyltriazoli- dine, were also efficiently tolerated in this reaction. This
um iodide. method was also compatible with chiral amino acid deriva-

Focus Review
Scheme 53. a) CSMIL-catalyzed synthesis of amides; b) reaction mechanism.

MsCl = methanesulfonyl chloride, CSMIL = chitosan-supported magnetic
ionic liquid.
tives, such as l-valine, l-leucine, and l-alanine methyl ester hy-

drochlorides, to afford the corresponding amides in moderate-
to-good yields with excellent enantioselectivities. Notably, N-
bromoamine was a key intermediate in this oxidative amida- Scheme 54. a) NHC-catalyzed oxidative amidation of aldehydes; b) reaction
mechanism.
tion reaction. A conceivable mechanism for this transformation
is shown in Scheme 54 b.
Recently, Fu et al. explored heteropolyanion-based ionic liq-
uids (HPAILs) as environmentally benign and highly efficient
systems for the synthesis of amides from carboxylic acid deriv-
atives and amines. They found that HPAIL 23 was an efficient
system for the direct oxidative amidation of aldehydes with
amines (Scheme 55).[76] This reaction proceeded through a
dual-catalysis process under solvent-free conditions to give pri-
mary, secondary, and tertiary amides with high functional-
group tolerance. Both primary and secondary amines were
well-tolerated in this reaction. Notably, ammonia, hydrazine hy-
drate, and formic hydrazide were smoothly converted into the
desired amides in good yields. However, aromatic amines, such
as aniline, were resistant to the standard conditions. A series of
Scheme 55. HPAIL-catalyzed synthesis of amides from aldehydes and
aryl aldehydes and heterocyclic aldehydes furnished the corre- amines.
sponding products in good yields, whilst no amide product
was detected with furfural under the reaction conditions. This
method was sensitive to steric hindrance. Moreover, aliphatic through the oxidative amidation of aldehydes with amino het-
aldehydes gave lower yields than aromatic aldehydes, with the erocycles under microwave irradiation (Scheme 56).[77] This oxi-
formation of a large number of side products. dative coupling reaction proceeded in the presence of 1 mol %
In the same year, Fu et al. extended their previous HPAIL- [PyPS]3PW12O40 (23) as a catalyst and TBHP as an oxidant under
based catalytic system to the synthesis of N-heteroaryl amides solvent-free conditions at 70 8C to give the desired N-heteroar-

Focus Review
Premaletha et al. reported a facile and high-yielding synthe-

sis of N-acyl 2-aminobenzothiazoles (26) from aldehydes and
2-aminobenzothiazoles (25) under the influence of NHC 27,
which played a crucial role in this transformation
(Scheme 58 a).[79] The scope of this method was probed by
Scheme 56. HPAIL-catalyzed synthesis of N-heteroaryl amides.
yl amides. The scope of this reaction was explored by using a

variety of aromatic, heterocyclic, and aliphatic aldehydes with
a range of 2-amino pyridines to give the corresponding N-het-
eroaryl amides in moderate-to-good yields. The authors found
that this system was also effective with other heterocyclic
amines, such as aminopyrazine, aminopyrimidine, and amino-
benzothiazole. However, this reaction was not successful with
anilines under the optimized reaction conditions. This reaction
proceeded through a N-directing dual-catalysis process, thus
indicating that the heteroatom on the aromatic nucleus of the
amines was crucial for this transformation.
Davidson and Fuchter developed an excellent amine-mask-
ing NHC-catalyzed redox amidation strategy for the synthesis
of amides from a-functionalized aldehydes under mild condi-
tions (Scheme 57).[78] This transformation proceeded through
Scheme 58. a) NHC-catalyzed synthesis of N-acyl 2-aminobenzothiazoles;

using a series of aldehydes, such as aryl, polyaryl, and heteroar-

Scheme 57. NHC-catalyzed redox amidation strategy for the synthesis of
amides. TCP = tetrachlorophthaloyl. yl aldehydes, with 2-aminobenzothiazoles that contained elec-
tron-donating or electron-withdrawing groups to provide the
desired amides in good-to-high yields. This method was also
the reaction of an amine with CO2 to produce an ammonium suitable for a,b-unsaturated aldehydes with aromatic or ali-
carbamate salt, which contained an ammonium cation and a phatic groups at the b-position and ferrocene carboxaldehyde.
carbamate anion. The ammonium carbamate salt provided a Moreover, the authors also applied this method to the synthe-
free amine nucleophile (for catalyst turnover) and facilitated a sis of a range of biologically prominent N-acyl 2-aminobenzo-
direct catalytic redox amidation reaction. This method was also thiazoles.
applicable to commercially available ammonium carbamate The proposed reaction mechanism is shown in Scheme 58 b.
(H2NCOONH4) as an amine source to give the corresponding This reaction was initiated by the generation of NHC 28 from
primary amide. The authors mentioned that this was the first triazole 27 in the presence of a base, which underwent nucleo-
NHC-catalyzed redox amidation process to give a primary philic attack on the aldehyde and subsequent proton transfer
amide. However, the reaction failed with electron-poor anilines to generate Breslow intermediate 29. In the presence of com-
and trifluoroethylamine, whilst sterically crowded amines were pound 20 (Scheme 51), key acyl-azolium intermediate 30 was
unreactive under the reaction conditions. formed, which underwent nucleophilic 1,2-addition with amine

Focus Review
25 to give aminal intermediate 31. Subsequently, intermediate

31 afforded the desired amide 26, along with the regeneration
of carbene 28.
Recently, Ma and co-workers explored an elegant NHC-cata-
lyzed approach for the direct oxidative N-acylation of primary
amides with aldehydes (Scheme 59 a).[80] The reaction proceed-
Scheme 60. NHC-catalyzed synthesis of secondary and tertiary amides.
catalyst, DBU as a base, and 1,2,4-triazole as a co-catalyst to

afford the desired amides in good-to-excellent yields with high
functional-group compatibility. A variety of aromatic aldehydes
that contained electron-rich or electron-deficient functional
groups and heterocyclic aldehydes were efficiently amidated
with primary or secondary amines to give the corresponding
amides. Interestingly, phenazine was crucial for this reaction,
and it could be recycled efficiently after the reaction by expo-
sure to air. The authors suggested that benzil, which was gen-
erated in situ from the aldehyde, acted as an acylating agent
in this process. This strategy was efficiently applied to the syn-
thesis of anti-depressant drug moclobemide (35) from para-
chlorobenzaldehyde in 92 % yield.
More recently, Ta and Sunden developed a clever and che-
moselective NHC-catalyzed oxidative amidation strategy for
the synthesis of N-acylated indoles (37) under mild conditions
(Scheme 61 a).[82] This method provided synthetically valuable
acyl indoles in good-to-excellent yields with broad substrate
Scheme 59. a) NHC-catalyzed direct N-acylation of amides with aldehydes; scope. A wide variety of functional groups on both the alde-
b) reaction mechanism. DPQ = tetra-tert-butyldiphenoquinone, Mes = mesi- hyde and indole were well-tolerated. This method was also
tyl. suitable for other heteroaromatic amines, including pyrrole
and indazole. Aliphatic conjugated aldehydes were also suita-
ble for this transformation.
ed in the presence of 10 mol % of the NHC precursor (32) as a The process was initiated by the formation of carbene 38 a,
catalyst, tBuOK as a base, and DPQ as an oxidant at room tem- followed by nucleophilic addition to an aldehyde to give Bre-
perature. The choice of NHC precursor and oxidant played a slow intermediate 38 b. Subsequently, intermediate 38 b under-
crucial role in this transformation. This method provided effi- went oxidation under the influence of compound 20
cient access to a variety of N-sulfonylcarboxamides, N-sulfinyl- (Scheme 51) to form acyl azolium species 38 c, which was at-
carboxamides, and dicarboxyimides in good-to-excellent yields. tacked by deprotonated indole 38 d to afford the acylated
In addition, a range of aromatic, heterocyclic, and a,b-unsatu- indole (37) and regenerate catalyst 38 a (Scheme 61 b).
rated aldehydes reacted well under the reaction conditions. Recently, a variety of elegant synthetic strategies have been
This method was not applicable to simple alkyl aldehydes; developed to access diverse molecular frameworks by employ-
however, methanesulfonamide was also found to be a suitable ing ionic liquids based on choline chloride–zinc chloride as effi-
partner under the reaction conditions, thereby affording the cient catalysts. For instance, Patil et al. identified a
corresponding N-sulfonylcarboxamide in high yield. A possible ChCl·2 ZnCl2-based ionic liquid as an efficient catalytic system
mechanism for this process is shown in Scheme 59 b. for the formation of primary amides from aldehydes and hy-
Kumar and Connon reported an NHC-catalyzed oxidative droxylamine hydrochloride under mild conditions
process for the synthesis of secondary or tertiary amides from (Scheme 62 a).[83] In the presence of a deep eutectic solvent
aldehydes and amines (Scheme 60).[81] This reaction proceeded system, a variety of aromatic aldehydes with electron-donating
in the presence of phenazine (34) as an oxidant, NHC 33 as a or electron-withdrawing-groups and aliphatic aldehydes were

Focus Review
of amides from nitriles, although a small quantity of water was

required to enhance the yield. The authors mentioned that this
method was superior to other reported methods and they pro-
posed the reaction mechanism as shown in Scheme 62 b.
3.1.3.2. Quaternary-Ammonium-Salt-Catalyzed Reactions

Liang et al. explored a one-pot process for the synthesis of
amides through the oxidative amidation of a series of aromatic
aldehydes with amines by using a combination of NaOCl and
Bu4NHSO4 under environmentally benign PEG-mediated condi-
tions (Scheme 63 a).[84] Although the reaction failed with ali-
phatic aldehydes, a variety of anilines and aliphatic primary
and secondary amines were good substrates for this transfor-
mation. The authors proposed a plausible reaction mechanism
as shown in Scheme 63 b.
Scheme 61. a) NHC-catalyzed synthesis of N-acylated indoles; b) reaction

mechanism.
Scheme 63. a) Bu4NHSO4/NaOCl/PEG-catalyzed synthesis of amides; b) pro-

posed reaction mechanism. PEG = poly(ethylene glycol).
In 2012, Tan et al. reported an organocatalytic cross-coupling

strategy for the amidation and esterification of aldehydes by
using a range of activating reagents (39), such as N-hydroxyi-
mides (39 a), hexafluoroisopropyl alcohol (39 b), and sulfoni-
mides (39 c; Scheme 64).[85] This cross-coupling strategy was
performed by using tetrabutylammonium iodide or bromide as
a catalyst and TBHP in decane as an oxidant in EtOAc at 70 8C
to give activated esters or imides (40) in moderate-to-excellent
yields, which could be smoothly transformed into the desired
amides or esters by the addition of an amine or alcohol at
Scheme 62. a) Synthesis of primary amides catalyzed by choline chloride– room temperature, respectively. The reaction conditions were
zinc chloride; b) reaction mechanism. compatible with a range of aromatic, heteroaromatic, and con-
jugated aldehydes to give the desired amides, although ali-
phatic aldehydes were not tolerated in this reaction. This
effectively transformed into the corresponding amides in excel- method was successfully applied to a broad range of primary
lent yields. Phthalimide was obtained in excellent yield from and secondary amines, anilines, and amines with chiral centers.
phthalic anhydride under the optimized reaction conditions. Both the catalyst and the oxidant played crucial roles in this
The same catalytic system was also applicable to the synthesis transformation. The authors also explored a one-pot transfor-

Focus Review
Mai et al. explored a new strategy for the direct amidation

of aldehydes with aromatic tertiary amines by using the com-
bination of nBu4NI as a catalyst and TBHP as an oxidant under
metal-free conditions (Scheme 66 a).[87] Considering the find-
Scheme 64. Organocatalytic amidation of aldehydes with activating re-

agents. AG = activating group.
mation of aldehydes into amides in good yields through the

direct addition of benzylamine to a mixture of an aldehyde
and N-hydroxysuccinimide (NHSI).
Liu et al. developed an efficient metal-free strategy for the
cross-coupling reaction between the acyl radicals of aldehydes
and the aminyl radicals of N,N-disubstituted formamides by
using a combination of Bu4NI as a catalyst and TBHP as an oxi-
dant (Scheme 65).[86] This method enabled the C H functionali-
Scheme 66. a) nBu4NI-catalyzed amidation of aldehydes with aromatic

amines; b) reaction mechanism. DCE = 1,2-dichloroethane, SET = single-elec-
tron transfer.
ings, the reaction involved a demethylation of the tertiary

amine and dehydrogenation of the aldehyde. This reaction
provided an alternative strategy for the formation of amide
Scheme 65. TBAI-catalyzed amidation of aldehydes with N,N-disubstituted bonds. Both the catalyst and the oxidant were crucial for this
formamides. TBAI = tetra-n-butylammonium iodide.
transformation. Aldehydes that contained weak electron-with-
drawing groups and electron-donating groups all efficiently
provided the corresponding amides in moderate-to-good
zation of aldehydes and the decarbonylation of formamides. A yields, whereas those that contained strong electron-withdraw-
wide variety of aromatic aldehydes that contained electron- ing groups (F, NO2, and CF3) remained unreacted under these
withdrawing or electron-donating groups and heteroaromatic conditions. A variety of furfural and unsaturated aldehydes
aldehydes were efficiently reacted under the optimized condi- were also smoothly transformed in this reaction. However, N-
tions, thereby affording the desired amides in moderate-to- methyl dialkyl tertiary amines, such as 1-methylpiperidin-4-one,
good yields, although only small amounts of the products 1-methylpiperidine, and 4-methylmorpholine, were not suita-
were observed with aliphatic aldehydes under the reaction ble substrates. The authors proposed a reaction mechanism as
conditions. This method was suitable for a range of cyclic and presented in Scheme 66 b.
acyclic formamides. Pyrazole and amino acid derivatives were Wang et al. reported a facile pathway for synthesis of pri-
also active in this transformation and gave the desired amides mary amides through the oxidative amidation of aldehydes
in moderate yields. However, no amide product was observed with ammonium salts by using Et4NI as a catalyst and TBHP as
with N,N-diphenylformamide. an oxidant (Scheme 67 a).[88] Of the ammonium salts that were

Focus Review
hydes, which gave the desired amides in good-to-high yields.

In addition, a variety of primary and secondary N-chloramines
were also compatible with this transformation. However, no
product was observed when benzylamine was used instead of
N-chloramine, which indicated that N-chloramine was essential
for this process. The authors also investigated the oxidative
amidation of primary alcohols with N-chloramines.
3.1.3.3. Iodine-Catalyzed Reactions

Shie and Fang explored a new one-pot strategy for the synthe-
sis of primary amides from the reaction of aldehydes with
aqueous ammonia in the presence of iodine at room tempera-
ture to afford nitrile intermediates, which were trapped by hy-
drogen peroxide to give the corresponding primary amides in
moderate-to-high yields (Scheme 69).[90] Furthermore, this strat-
egy also encompassed the synthesis of tetrazoles and triazines,
which play a crucial role as versatile building blocks in synthet-
ic organic chemistry, as well as exhibiting a plethora of biologi-
cal activities.
Scheme 67. a) Et4NI-catalyzed synthesis of amides; b) reaction mechanism.
screened, ammonium bicarbonate gave the best result in this

transformation. In the presence of 10 mol % Et4NI, the reaction
proceeded smoothly with a variety of aromatic and heteroaro-
matic aldehydes to give the corresponding primary amides in
moderate-to-good yields. Alkyl aldehydes were also tested, but
they provided lower yields of the desired amides. The authors
also reported that the oxidative amidation of acetophenone
with ammonium iodide afforded the primary ketoamide in
40 % yield. Furthermore, they also extended this method to
the direct conversion of alcohols into amides. This Et4NI-cata-
lyzed reaction also proceeded through a hemiaminal inter-
mediate, as shown in Scheme 67 b. Scheme 69. I2-catalyzed synthesis of primary amides.
Achar and Mal explored a facile system for the oxidative
coupling of aldehydes with N-chloramines to afford amides
under solvent-free conditions at 50 8C or under ball-milling Rajender Reddy et al. proposed an efficient KI-catalyzed pro-
conditions at room temperature (Scheme 68).[89] The reaction cedure for the oxidative amidation of aldehydes or alcohols
proceeded through metal-free C H activation of the aldehyde with amines under metal-free conditions (Scheme 70).[91] This
by using a combination of TBAI and TBHP. The scope of this oxidative coupling reaction proceeded in the presence of KI as
oxidative amidation reaction was explored by using a series of a catalyst and TBHP as an oxidant under aqueous conditions at
functionalized aromatic, heteroaromatic, and aliphatic alde- 80 8C for 15 h. A variety of amides were obtained in moderate-
to-good yields from a variety of aromatic aldehydes and
Scheme 68. TBAI-catalyzed amidation of aldehydes with N-chloramines. Scheme 70. KI-TBHP-mediated synthesis of amides.

Focus Review
amines. However, aliphatic aldehydes gave lower yields of the

desired amides. Moreover, this method was also suitable for
chiral amino acid derivatives, which are crucial intermediates in
synthetic organic chemistry and in the pharmaceutical indus-
try.
Achar and Mal reported a cross-dehydrogenative coupling
(CDC) reaction between aryl aldehydes and benzylamines that
proceeded through C H activation (Scheme 71).[92] The target
Scheme 71. PhI(OAc)2-mediated mechanochemical synthesis of amides. Scheme 72. a) PhI(OAc)2-promoted synthesis of N-acetoxy-N-arylamides;
amides were isolated in good-to-high yields by using phenylio-

dine diacetate (PIDA) and NaHSO4 under solvent-free mecha- tramolecular rearrangement afforded intermediate 43 c. Subse-
nochemical (ball-milling) conditions. This reaction tolerated a quently, intermediate 43 c underwent deprotonation in the
range of aromatic aldehydes that contained electron-withdraw- presence of acetate to give intermediate 43 d. Finally, acyl-
ing or electron-donating groups. The authors performed iso- group migration and isomerization provided the desired prod-
thermal titration calorimetric (ITC) studies to estimate the en- uct (42).
thalpy of the reaction in the presence or absence of NaHSO4.
The reaction exploded in the absence of NaHSO4. The acid salt
3.1.4. Photocatalyzed Conditions
sodium bisulfate (NaHSO4) was crucial to this transformation,
because it prevented an explosion and promoted the chemical Leow developed a photocatalyzed aerobic oxidative amidation
reaction. The authors did not employ volatile aliphatic amines, of aldehydes with amines (Scheme 73 a).[94] This reaction pro-
owing to the solvent-free conditions. This reaction was not ceeded in the presence of a phenazinium salt as a photocata-
compatible with more-reactive secondary amines, such as pyr- lyst (44), air as an oxidant, and a 24 W compact fluorescent
rolidine, dibenzylamine, and 4-methoxybenzylamine. lamp (CFL) as a visible-light source in inhibitor-free THF at
Zhang et al. reported an efficient diacetoxyiodobenzene-pro- room temperature for 20 h. A variety of aromatic aldehydes ef-
moted method for the synthesis of N-acetoxy-N-arylamides ficiently reacted with five- or seven-membered cyclic amines to
from hydroxylamines and aldehydes (Scheme 72 a).[93] A range afford the desired amides in good-to-high yields. However, aro-
of functional groups on both the aromatic aldehyde and the matic aldehydes that contained electron-withdrawing groups
N-aromatic hydroxylamine were well-tolerated to give the de- proceeded more efficiently than those that contained electron-
sired products (42) in good-to-excellent yields. None of the de- donating groups. On the other hand, aliphatic aldehydes, such
sired products were obtained with aliphatic aldehydes or aro- as cyclopropane aldehyde, gave the desired amide in lower
matic ketones under the optimized conditions. In addition, this yield (20 %), owing to the formation of unidentified side prod-
method was not suitable for aliphatic hydroxylamines, such as ucts. This amidation reaction was not compatible with primary
N-methylhydroxylamine and N-(tert-butyl)hydroxylamine. This aliphatic amines or aromatic amines. A plausible reaction path-
reaction involves a double acylation of hydroxylamines: the ni- way is shown in Scheme 73 b.
trogen atoms of the hydroxylamines were acylated with alde- Wang et al. developed an elegant photoredox-catalyzed
hydes, whilst the oxygen atoms of the hydroxylamines were aerobic oxidative procedure for the synthesis of amides from
acylated with the acetyl groups of diacetoxyiodobenzene. aromatic aldehydes and amines by using boron-dipyrrome-
The authors proposed the reaction mechanism shown in thene (BODIPY) as photosensitizer (45) and BHT as a radical in-
Scheme 72 b. The reaction was initiated by the formation of ni- hibitor under the irradiation of a 3 W blue LEDs in MeCN at
trone 43 a from the aldehyde and hydroxylamine 41. Then, ni- room temperature for 12 h (Scheme 74).[95] A wide variety of ar-
trone 43 a attacked PIDA to produce intermediate 43 b, and in- omatic aldehydes with a range of cyclic amines were probed

Focus Review
thors verified that radical inhibitor BHT played a crucial role in

this process.
Recently, Papadopoulos and Kokotos reported a photo-orga-
nocatalytic procedure for the direct synthesis of amides from
aldehydes and amines by using phenylglyoxylic acid as a
photo-organocatalyst with DIAD (Scheme 75).[96] The reaction
Scheme 75. Photo-organocatalytic synthesis of amides. DIAD = diisopropyl

azodicarboxylate.
Scheme 73. a) Photocatalyzed aerobic oxidative amidation of aldehydes

with amines; b) reaction mechanism. worked well in the presence of common household lamps as a
visible-light source. Initially, the aldehyde reacted with DIAD to
give the carbonyl imide intermediate (46), which underwent
reaction with an amine to afford the desired amide. A variety
of aliphatic primary or secondary amines and amino-acid-de-
rived amines were smoothly coupled with aliphatic and aro-
matic aldehydes under the reaction conditions, thereby afford-
ing the corresponding amides in good-to-excellent yields. This
process was also successfully applied to the synthesis of Mo-
clobemide (35).
3.1.5. Miscellaneous Conditions

Sharghi and Sarvari reported a facile method for the
direct conversion of aldehydes into amides in high yields by
using wet-Al2O3/MeSO2Cl under solvent-free conditions
(Scheme 76).[97] A variety of aromatic and aliphatic aldehydes
were successfully reacted under these conditions. The authors
also found that, under the same reaction conditions, nitriles
Scheme 74. Photoredox-catalyzed aerobic oxidative synthesis of amides.
BHT = 3,5-di-tert-butyl-4-hydroxytoluene.
to explore the efficiency and scope of the reaction under the

optimized reaction conditions, and the desired amides were
formed with excellent functional-group tolerance. However,
this procedure did not work with aliphatic aldehydes, whilst
benzylamine and N-methylbenzylamine were not tolerated
under the reaction conditions. In addition, this method was
not suitable for primary amines or aromatic amines. The au- Scheme 76. Synthesis of amides by using wet alumina.

Focus Review
were obtained in good yields when dry alumina was used in-
stead of wet alumina.
Ekoue-Kovi and Wolf reported the first metal-free strategy
for the oxidative amidation of aromatic aldehydes with amines
under mild conditions. This reaction proceeded in the presence
of TBHP as an oxidant in MeCN at reflux for 5 h
(Scheme 77 a).[98] This method provided straightforward access
Scheme 78. a) Oxone-promoted synthesis of amides; b) reaction mechanism.
drochloride in DMSO at 100 8C under metal-free conditions.[100a]

Subsequently, the same authors extended this strategy to the
synthesis of primary amides from aldehydes (Scheme 79).[100b]
The reaction of an aldehyde with hydroxylamine hydrochloride
afforded a nitrile intermediate, which underwent hydrolysis in
the presence of basic hydrogen peroxide to give the desired
amide.
Scheme 77. a) TBHP-mediated synthesis of amides; b) reaction mechanism.
to a wide variety of aromatic amides in good-to-high yields. A

series of secondary amines, including pyrrolidine, morpholine,
piperidine, and N-methylbenzylamine, were smoothly amidat-
ed by using this procedure, although a low yield of the corre-
sponding amide was obtained with diethylamine. Proline-de-
rived amides were also synthesized in high yields without race-
mization under the optimized conditions. This method avoided
the need for metal catalysts, additives, and bases. The reaction
Scheme 79. Synthesis of primary amides by using basic H2O2.
mechanism is shown in Scheme 77 b.
Gao and Wang explored an efficient oxone-promoted oxida-
tive amidation strategy for the synthesis of aromatic amides Tank et al. explored a metal-free procedure for the synthesis
through a coupling reaction of aryl aldehydes with anilines by of amides from aldehydes and cyclic amines under the influ-
using oxone as an oxidant under ball-milling conditions ence of hydrogen peroxide as a “green” oxidant
(Scheme 78 a).[99] This method provided alternative access to ar- (Scheme 80).[101] A diverse array of aromatic and heterocyclic al-
omatic amides in moderate-to-good yields under solvent- and
metal-free conditions. This oxidative system was found to be
compatible with a variety of anilines that contained electron-
donating or electron-withdrawing groups, as well as aromatic
aldehydes that contained electron-withdrawing groups. How-
ever, aromatic aldehydes that contained electron-donating
groups and aliphatic aldehydes did not react under these con-
ditions. Notably, the presence of oxidant oxone was crucial for
this transformation. The mechanism of this oxidative amidation
reaction is shown in Scheme 78 b.
In 2009, Chill and Mebane explored a one-pot procedure for
the synthesis of nitriles from aldehydes and hydroxylamine hy- Scheme 80. H2O2-mediated synthesis of amides.

Focus Review
dehydes smoothly reacted with cyclic amines to give the de- aromatic amides were efficiently obtained in moderate-to-high
sired amides in good-to-high yields. Only trace amounts of the yields. The base and the solvent ratio were crucial parameters
desired amides were detected with acyclic secondary amines, in this reaction.
including diethylamine, dipropylamine, and diisopropylamine, In the same year, Ambreen and Wirth also investigated the
whilst acyclic secondary amines that contained a small N-alkyl previous reaction by using a metal flow reactor system at high
group, such as N-methylpropylamine, gave N-methyl-N-propyl- temperature.[104] They performed the reaction in a mixture of
benzamide with 52 % conversion. On the other hand, sterically THF and water (1:1) with Cs2CO3 as a base at 250 8C for 5 min
more-crowded aldehydes and amines led to lower conversions. (Scheme 83). A variety of aliphatic and aromatic aldehydes
The authors also extended the scope of this oxidative system
to the esterification of aldehydes with primary alcohols.
Later, Liu and Jensen also reported an oxidative amidation
strategy for the coupling reaction of aromatic aldehydes with
secondary amines in the presence of aqueous hydrogen perox-
ide (30 wt. %) as an oxidant by using a continuous flow micro-
reactor to give amides within 40 min (Scheme 81).[102] This
Scheme 83. Synthesis of amides under flow chemistry conditions.
were amenable to these flow chemistry conditions. The scope

and applicability of more-sensitive aldehydes were further ex-
plored. For this purpose, the authors applied this method to
the conversion of a series of alcohols into the corresponding
amides in the presence of an external oxidant. This flow
Scheme 81. H2O2-mediated synthesis of amides by using a continuous-flow
method offered several advantages, such as short reaction
microreactor.
times, simple product isolation, excellent yields, and metal-free
conditions. As such, this flow method was superior to the cor-
method allowed for precise scanning of the reaction parame- responding batch process.
ters, such as temperature, pressure, and reactant concentra- Antoniak et al. reported a direct conversion of aromatic alde-
tion, as well as efficient optimization of the reaction condi- hydes into amides in the presence of liquid ammonia and po-
tions. The scope of this amidation method was explored by tassium permanganate as an oxidant (Scheme 84).[105] However,
testing a wide variety of aldehydes and amines. The authors
also effectively extended this strategy to the acylation of chiral
amino acids, such as d- or l-proline tert-butyl ester, without
racemization. In addition, aliphatic primary amines and aniline
gave imines instead of the desired amides.
Wang et al. explored a simple base-mediated pathway for
the synthesis of primary aromatic amides from aromatic alde-
hydes and hydroxylamine hydrochloride by using a mixture of
DMSO and water (3:1) at 125 8C for 48 h under metal-free con-
ditions (Scheme 82).[103] The aldehyde reacted with hydroxyla-
mine hydrochloride to afford an aldoxime intermediate in the Scheme 84. Synthesis of primary amides by using KMnO4.
presence of Cs2CO3, which underwent a dehydration/hydration
sequence to give the amide. A variety of aromatic and hetero- the scope of the reaction was limited to aromatic aldehydes
that contained electron-withdrawing substituents. Notably, ani-
saldehyde and aliphatic aldehydes failed to form the desired
amides, instead giving carboxylic acids as the main side prod-
ucts.
In 2015, Yang et al. described an efficient catalyst-free proce-
dure for the direct amidation of aldehydes with primary and
secondary amines by using TCCA (Scheme 85).[106] This reaction
worked smoothly and efficiently in both aqueous solutions
and organic solvents. A variety of aromatic and aliphatic alde-
hydes were efficiently employed with primary and secondary
Scheme 82. Cs2CO3-mediated synthesis of amides. amines to synthesize the desired amides.

Focus Review
azoles (Scheme 87).[108] A wide variety of aromatic and aliphatic

aldehydes efficiently underwent the reaction with pyrazole in
the presence of Bobbitt’s salt (48; 4-acetamido-2,2,6,6-tetrame-
thylpiperidine-1-oxoammonium tetrafluoroborate) as an oxi-
Scheme 85. Cascade reaction for the direct amidation of aldehydes with
amines. TCCA = trichloroisocyanuric acid.
Devi et al. investigated a metal- and additive-free oxidative

amidation of aldehydes with aminopyridines by using aqueous
H2O2 as a terminal oxidant in water at 80 8C for 4 h
(Scheme 86 a).[107] This reaction proceeded under environmen-
Scheme 87. Synthesis of amides mediated by Bobbitt’s salt.
dant and pyridine as a base at room temperature under mild

conditions, thereby affording the corresponding N-acyl azoles
in good-to-excellent yields. Next, the authors extended their
method to alcohols by using 2,6-lutidine as a base instead of
pyridine, thereby providing the corresponding N-acyl azoles in
comparable yields. A wide range of azoles were employed in
this reaction, thereby giving the desired products in good
yields, usefully notwithstanding of the substitution pattern or
electronic character of the aromatic ring. The authors found
that the obtained N-acyl azoles were suitable reaction partners
for further chemical manipulation.
Recently, Narendar Reddy et al. developed an elegant strat-
egy for the synthesis of primary amides by using the aldehydes
of Baylis–Hillman adducts and hydroxylamine hydrochloride at
reflux in MeOH for 2–3 h (Scheme 88).[22b] The authors found
that the solvent and reaction temperature played crucial roles
Scheme 86. a) Oxidative amidation of aldehydes with aminopyridines by in the efficiency of this process. This method provided practical
using H2O2 ; b) reaction mechanism.
access to a variety of cyanocinnamyl amides, which are versa-
tile scaffolds in organic and medicinal chemistry, as well as
tally benign conditions to give N-(pyridin-2-yl)benzamides with building blocks for fluorescent agents. A diverse array of cya-
high functional-group tolerance. The scope of this reaction nocinnamaldehydes were efficiently reacted under the opti-
was explored by using a variety of aromatic aldehydes that mized conditions, thereby giving the corresponding cinnamyl
contained electron-donating or electron-withdrawing groups, amides in moderate-to-excellent yields. The structure was con-
heteroaromatic aldehydes, and aliphatic aldehydes with a vari- firmed by X-ray crystallography. This method was not influ-
ety of 2-aminopyridines, thereby providing the desired amides
in good-to-excellent yields. In addition, 3-aminopyridine and 4-
aminopyridine were also suitable coupling partners in this re-
action. The presence of H2O2 was shown to be crucial for the
reaction to be successful.
Initially, the addition of an amine to the aldehyde afforded
hemiaminal intermediate 47 a, which provided imine 47 b on
dehydration. Subsequently, the addition of H2O2 afforded hy-
droperoxide intermediate 47 c, and a second dehydration step
provided the desired amide (Scheme 86 b).
The Leadbeater group explored an efficient oxidative amida-
tion procedure to access a range of synthetically useful N-acyl Scheme 88. Synthesis of cyanocinnamyl amides.

Focus Review
enced by steric and electronic factors. Furthermore, this reac-

tion did not require a catalyst, oxidant, or base, and exhibited
several additional advantages: high functional-group tolerance,
short reaction times, and simple reaction procedure. However,
benzaldehyde and simple cinnamaldehyde failed to give the
corresponding amides under the optimized conditions.
3.2. Coupling of Aldehydes with Nitroarenes as an Amine

Source
Jain et al. developed a new manganese-catalyzed method for
the synthesis of amides and hydroxamic acids from aldehydes
and nitroarenes (Scheme 89).[109] The reaction proceeded
Scheme 90. a) Amidation of aldehydes with nitrosobenzene; b) reaction

Scheme 89. Manganese-catalyzed synthesis of amides from aldehydes and mechanism.
nitroarenes.
3.4. Coupling of Aldehydes with Anthranils as an Amine

Source
through the thermal deoxygenation of nitrobenzenes to give
nitroso intermediates, which reacted with aldehydes to give Recently, Debbarma and Maji explored an efficient rhodium(III)-
amides and hydroxamic acids. In the presence of KOH, this re- catalyzed method for the direct C(sp2) H amidation of alde-
action afforded hydroxamic acids as the major product, where- hydes (49) with anthranils (50) as an amine source by using
as in the presence of acetic acid, the reaction afforded amides [{Cp*RhCl2}2] as a catalyst and AgSbF6 as a co-catalyst in the
as the sole product. A variety of aromatic and heteroaromatic presence of CsOAc as a base under mild conditions
aldehydes were efficiently employed under the optimized reac- (Scheme 91 a).[111] The authors found that the reaction was un-
tion conditions. Nitrobenzene and heterocyclic nitrene reacted successful in the absence of a base or with a strong base, thus
efficiently, although the reactions of aliphatic nitro compounds, implying its crucial role in the reaction. A wide range of aro-
o-iodo-nitrobenzene, and o-bromo-nitrobenzene were ineffi- matic and heteroaromatic sulfonyl 2-aminobenzaldehydes
cient, instead leading to the formation of side products. were compatible with a variety of isoxazole derivatives that
contained alkyl, aryl, heteroaryl, and alkenyl groups under the
optimized reaction conditions, thereby affording the corre-
sponding amides (51) in good-to-excellent yields. Surprisingly,
3.3. Coupling of Aldehydes with Nitroso Compounds as an
acetyl-, pivaloyl-, and tert-butyloxycarbonyl-protected 2-amino-
Amine Source
benzaldehydes did not undergo this transformation, whilst al-
Wong et al. explored a simple and efficient NHC-catalyzed dehydes that contained hydroxy directing groups afforded the
strategy for the synthesis of N-arylhydroxamic acids through corresponding amides in good yields. No product was ob-
the amidation of aldehydes with aryl nitroso compounds served with ortho-methoxybenzaldehydes, which suggested
(Scheme 90 a).[110] The authors tested a series of NHC catalysts that a free hydroxy group was necessary for this process. A
and found that triazolium salt 18 provided the best results for plausible mechanism for this amidation reaction is shown in
this transformation. This reaction proceeded through the addi- Scheme 91 b.
tion of an acyl anion to aryl nitroso compounds under mild
conditions. The scope of this NHC-catalyzed method was inves-
3.5. Coupling of Aldehydes with Isocyanides as an Amine
tigated by using a range of aldehydes and nitroso compounds.
Source
A variety of aromatic, aliphatic, and heterocyclic N-arylhydroxa-
mic acids were efficiently obtained in good-to-excellent yields, Recently, Liu et al. developed a new and highly efficient
and the products are useful compounds in organic and medici- copper-catalyzed process for the radical coupling of aromatic
nal chemistry. The proposed reaction mechanism is shown in aldehydes with isocyanides as an amine source to access the
Scheme 90 b. desired amides by using a combination of CuI and KBr in the

Focus Review
Scheme 92. a) Copper-catalyzed synthesis of amides from aldehydes and

isocyanides; b) reaction mechanism.
Scheme 91. a) [Cp*RhIII]-catalyzed directed amidation of aldehydes; b) reac-

tion mechanism. DG = directing group, Cp* = 1,2,3,4,5-pentamethylcyclopen-
tadiene.
presence of TBHP as an oxidant under a nitrogen atmosphere

(Scheme 92 a).[112] The authors mentioned that the yield of the
amide decreased dramatically in the presence of water. This
method provided a new route for the formation of C N
bonds. These results indicated that isocyanides displayed a
new reactivity profile and acted as an N1 synthon. A wide
range of aromatic aldehydes were efficiently reacted with alkyl
or aromatic isonitriles under the optimized conditions. Howev- Scheme 93. Rhodium-catalyzed amidation of aldehydes with azides.
er, the reaction did not work for 4-pyridinecarboxaldehyde and
the method was not compatible with aliphatic aldehydes. The
authors also proposed a reaction pathway as shown in hydes to give the corresponding amides in good yields. Ben-
Scheme 92 b. zaldehyde was unresponsive under the reaction conditions.
Notably, the directing group on the aldehyde substrate played
3.6. Coupling of Aldehydes with Azides as an Amine Source a crucial role in this C H functionalization reaction. This strat-
egy provided efficient access to a variety of N-aryl amides, N-
3.6.1. Metal-Catalyzed Conditions
alkyl amides, and acylsulfonamides (53).
In 2013, Zhou et al. reported the first example of a rhodium- N-Fluoroaryl amide functionalities are found in many syn-
catalyzed amidation of aldehydes (52) with azides as an amine thetic frameworks of pharmaceutical importance. The prepara-
source, by using [Cp*Rh(MeCN)3](SbF6)2 as a catalyst in air tion of N-fluoroaryl amide derivatives from fluoroanilines is
under mild conditions (Scheme 93).[113] A broad variety of challenging, owing to their poor nucleophilicity and poor sub-
azides, such as alkyl, aryl, and sulfonyl azides, were well-tolerat- strate scope. Therefore, the C H amination of aldehydes with
ed in this transformation. This catalytic system worked well for fluoroaryl azides is a highly attractive strategy for the synthesis
both 8-quinolinecarbaldehydes and 2-(methylthio)benzalde- of N-fluoroaryl amides under catalytic conditions. In this con-

Focus Review
3.6.2. Metal-Free Conditions
In 2013, Kulkarni et al. developed a base-mediated amidation

reaction for the synthesis of amides from aromatic aldehydes
and benzyl azides under mild conditions (Scheme 95 a).[115] The
Scheme 94. a) [Co(P1)]-catalyzed synthesis of N-fluoroaryl amides; b) reac- Scheme 95. a) Base-mediated amidation of aromatic aldehydes with benzyl
tion mechanism. azides; b) reaction mechanism.
text, Zhang and co-workers reported the application of scope of this reaction was explored by using a series of benzyl
[Co(P1)] (54) as an effective catalytic system for the synthesis azides and a wide variety of aromatic aldehydes, which provid-
of N-fluoroaryl amides through the C H amination of alde- ed the corresponding amides in moderate-to-high yields. Inter-
hydes with fluoroaryl azides (Scheme 94 a).[114] This metalloradi- estingly, a-azido amides were also efficiently employed to de-
cal system employed aryl azides as a nitrene source for the C liver the desired diamides in moderate yields. However, these
H amination of aldehydes with broad functional-group toler- reaction conditions were not suitable for aliphatic aldehydes,
ance. This reaction proceeded under neutral, non-oxidative, ad- owing to the presence of a more-acidic a-proton, as well as ar-
ditive-free conditions, and a broad range of aldehydes, includ- omatic and aliphatic azides.
ing aromatic, heteroaromatic, aliphatic, and a,b-unsaturated al- The authors proposed a plausible reaction mechanism, as
dehydes, were found to be compatible with these reaction shown in Scheme 95 b. Initially, the abstraction of a proton
conditions to deliver the corresponding N-fluoroaryl amides in from benzyl azide (55 a) in the presence of a base generated
good-to-excellent yields. Notably, a variety of fluoroaryl azides, reactive intermediate 55 c through anion 55 b, which reacted
such as monofluoro-, difluoro-, trifluoro-, and tetrafluoroaryl with the benzaldehyde to give intermediate 55 d. Subsequent-
azides, as well as bromotetrafluorophenyl azide, were also suit- ly, intermediate 55 d underwent a 1,5-hydride shift to afford tri-
able substrates for this process. Furthermore, the authors also azenide intermediate 55 e, followed by intramolecular nucleo-
reacted 2,6-dichlorophenyl azide and 2-pyrimidine azide to philic attack to afford cyclic species 55 f. Finally, a retro-[2+2]
afford the desired amides, albeit in low yields. Interestingly, cycloaddition reaction furnished the desired amide after the
this amination reaction was found to be highly chemoselective loss of molecular nitrogen.
for aldehydic C H bonds over other C H bonds, such as ben- Subsequently, Carbone et al. reported a straightforward and
zylic, allylic, and aliphatic C H bonds. The proposed reaction efficient amidation reaction for the synthesis of 4-nitroaromatic
pathway is shown in Scheme 94 b. amides through a tert-butoxide-mediated coupling of alde-

Focus Review
hydes with para-nitro azides under the influence of a thiazoli- worked well under the reaction conditions to afford the de-
um salt (56) as a catalyst (Scheme 96).[116] The authors also ex- sired amides in good-to-high yields. This ionic liquid catalyzed
plored a one-pot diazotization/azidation/amidation sequence the reaction under mild conditions with high functional-group
through the reaction of 4-nitroaniline with TMSN3 by using tolerance. However, disappointingly, this method was not suit-
able for aliphatic azides or tosyl azides. This method was appli-
cable to a variety of enolizable aldehydes, with the exception
of benzaldehyde, owing to the absence of enolizable protons.
The mechanism of this rapid reaction is outlined in
Scheme 97 b. In the presence of [BMIM]OH, cyclohexane carbal-
dehyde afforded enolate 57 a, which underwent cycloaddition
with the azide to give intermediate 57 c through intermediate
57 b. Subsequent rearrangement gave the desired amide.
Xie et al. proposed an efficient strategy for the construction
of aryl amides from aryl azides and aldehydes under base-cata-
lyzed conditions (Scheme 98 a).[118] A wide range of aryl azides
Scheme 96. Synthesis of amides catalyzed by a thiazolium salt.
tBuONO in THF at 0 8C, followed by amidation with an alde-

hyde at 25 8C to give the corresponding amide. The reaction
of a range of electron-deficient anilines with electron-rich aro-
matic aldehydes proceeded well to give the desired amides in
good-to-high yields, whilst electron-deficient aromatic alde-
hydes afforded lower yields. In addition, heteroaromatic and
aliphatic aldehydes were also smoothly amidated under these
conditions.
Gu et al. developed a [BMIM]OH-catalyzed method for the
synthesis of amides from azides and aldehydes
(Scheme 97 a).[117] A variety of aryl azides that contained elec-
tron-deficient or electron-rich groups and heterocyclic azides
Scheme 98. a) Synthesis of amides from aryl azides and aldehydes by using
a base; b) reaction mechanism.
and aldehydes were used to investigate the scope of this reac-

tion under the optimized conditions and this method was
found to offer a straightforward approach to a wide range of
N-aryl amides, although no amide product was formed with
2,6-dimethylphenyl azide or tosyl azide. Cyclopropane carbal-
dehyde and non-enolizable benzaldehyde also did not give
the desired amide products. Furthermore, the authors also em-
ployed a-unsubstituted aldehydes by using tBuOK instead of
K2CO3 and THF/tBuOH as the solvent at room temperature to
provide the corresponding amides in good yields. Notably, this
method was efficiently applied to the synthesis of perfluoroaryl
amides in high yields, which were useful auxiliaries for C H ac-
tivation.
Scheme 97. a) [BMIM]OH-catalyzed amidation of aldehydes with azides;
b) reaction mechanism. BMIM = 1-n-butyl-3-methylimidazolium hydroxide This reaction proceeds through an azide–enolate cycloaddi-
[BMIM]-OH). tion reaction to give triazoline intermediate 58 b through inter-

Focus Review
mediate 58 a, which subsequently underwent rearrangement

under either thermal conditions (20–140 8C) or aqueous acid
workup at room temperature to give the target amide
(Scheme 98 b).
Xie et al. reported an efficient DEU-catalyzed strategy for the
amidation of phenylacetaldehydes with electron-deficient aryl
azides in DMSO at room temperature (Scheme 99 a).[119] In the
Scheme 100. a) Copper-catalyzed synthesis of amides from methyl ketones;

Scheme 99. a) DEU-catalyzed synthesis of amides; b) reaction mechanism.

DEU = N,N-diethylurea. dure, thereby affording the corresponding amides in good
yields. Interestingly, this method was also suitable for challeng-
ing aryl alkyl ketones, thereby giving the desired benzamides
presence of 20 mol % DEU, a series of perfluorophenyl azides in moderate yields. Moreover, 2-ethoxybenzamide, an anti-in-
smoothly reacted to deliver the corresponding amides in flammatory and analgesic drug under the brand name Ethen-
good-to-high yields. The authors also efficiently engaged other zamide (60), was synthesized in 59 % yield under these reac-
electron-deficient aryl azides, such as o-bromo, o-nitro-, and p- tion conditions. Notably, 3,4-dimethoxybenzamide and 3,4,5-
nitrophenyl azides under the reaction conditions. However, trimethoxybenzamide, which are useful precursors for pharma-
this method was not suitable for phenyl azide and tosyl azide, ceutical drugs, such as dyspepsia drug Itopride (61) and antie-
as well as benzaldehyde. metic drug Trimethobenzamide (62), were efficiently obtained
This reaction was initiated by the formation of an activated by using this process. This reaction was highly chemoselective
enol species (59 a) from the aldehyde in the presence of DEU, and proceeded through aerobic oxidative cleavage of the
which underwent (3+2) cycloaddition with the electrophilic C(CO) C(alkyl) bond of the ketone, followed by C N bond for-
azide to afford a triazoline intermediate (59 b). Subsequently, mation. Based on control experiments, the authors proposed
the reactive triazoline intermediate underwent rearrangement the reaction mechanism shown in Scheme 100 b.
and hydride shift to give the aryl amide with the extrusion of Ding and Song reported a copper-catalyzed chemoselective
nitrogen (Scheme 99 b). aerobic oxidative amidation of aryl methyl ketones with azoles
to give azole tertiary amides in good yields by employing CuBr
as a catalyst and molecular oxygen as an oxidant
4. Synthesis of Amides from Ketones (Scheme 101).[120] This method provided highly efficient access
to a variety of azole amides, which are useful scaffolds in or-
4.1. Metal-Catalyzed Conditions
ganic and medicinal chemistry. Molecular oxygen was found to
Tang and Jiao proposed a highly efficient copper-catalyzed be essential for this process. A variety of aryl methyl ketones
strategy for the direct synthesis of amides from methyl ketones and azoles were well-tolerated under the reaction conditions.
and sodium azide in the presence of TEMPO and O2 in DMF at Polyphenylene acetophenones, including 1-acetonaphthone, 4-
120 8C (Scheme 100 a).[12c] In the presence of CuCl2, a series of phenylacetophenone, 2-acetonaphthone, and 4-phenylethyny-
aryl methyl ketones that contained electron-donating or elec- lacetophenone, were efficiently transformed under the opti-
tron-withdrawing groups on the aryl ring and heteroaryl mized conditions to provide the corresponding products in
methyl ketones were efficiently amidated by using this proce- good yields. This method was also suitable for 1,3-dicarbonyl

Focus Review
Scheme 101. CuBr-catalyzed synthesis of amides.
compounds, such as ethyl 3-oxo-3-phenylpropanoate and 1,3-

diphenylpropane-1,3-dione. The authors found that benzalde-
hyde was inert under these reaction conditions.
Wu et al. described a copper-catalyzed, iodide-mediated pro-
cess for the synthesis of amides from aryl methyl ketones and
amines that proceeded through aerobic oxidative C C bond
cleavage and C N formation (Scheme 102).[121] The optimal
Scheme 103. a) Cu(OAc)2-catalyzed synthesis of amides; b) reaction mecha-

nism.
Scheme 102. CuI-catalyzed amidation of ketones with amines. NMP = 1-

drance and occurred through chemoselective cleavage of the
methylpyrrolidin-2-one. C C bond, thereby leading to the formation of a C N bond
with the chelation assistance of N-containing directing groups,
thus suggesting that the N atom played an essential role in
conditions for this transformation involved a combination of this transformation. This method is an example of an emerging
CuI and KI in a mixture of NMP and water (15:1) at 40 8C. Con- strategy for the synthesis of amides and a new strategy for C
trol experiments revealed that molecular oxygen was crucial C bond cleavage in organic synthesis. A plausible reaction
for this process. Aryl methyl ketones that contained electron- mechanism is outlined in Scheme 103 b.
donating and electron-withdrawing groups smoothly reacted
with cyclic and acyclic secondary amines under these reaction
conditions. However, this method was not applicable to pri-
4.2. Metal-Free Conditions
mary amines, such as aniline and n-butylamine.
Recently, a convenient and readily accessible Cu(OAc)2-cata- In 2004, Ishihara and Yano found that sterically hindered LDA
lyzed system for the transformation of inactivated ketones into was an efficient catalyst for the direct synthesis of N-alkylcar-
the desired amides was reported by Ma et al. in the presence boxamides through a Haller–Bauer (HB) reaction
of sodium azide as a nitrogen source (Scheme 103 a).[122] The (Scheme 104).[123] In the presence of LDA, a range of structural-
reaction was achieved by using a combination of Cu(OAc)2 as ly diverse ketones reacted with lithium N-alkyl amides to
a catalyst with AcOH as an additive in DMSO at 80 8C under an smoothly afford the corresponding N-alkylcarboxamides in
O2 atmosphere. The authors found that the picolinamide di- good-to-high yields. Furthermore, the authors also applied this
recting group was superior to other directing groups for this method to the synthesis of alkylcarboxamides from aldehydes
transformation. A series of ketones were tested under these re- through a Cannizzaro-type reaction. A range of aromatic and
action conditions, thereby affording the corresponding amides aliphatic aldehydes reacted with lithium N-alkyl amides
in good-to-high yields. This method was sensitive to steric hin- through C H activation to afford the corresponding dialkylcar-

Focus Review
Scheme 104. LDA-catalyzed synthesis of amides. LDA = lithium diisopropyla-

mide.
Scheme 106. One-pot oxidative synthesis of amides.
boxamides. This method provided a new route to alkylcarboxa-

mides through HB and Cannizzaro reactions. the catalyst, and it could be readily recycled from the reaction
Cao et al. proposed a new strategy for the conversion of mixture by using vacuum distillation. This method was also ap-
methyl ketones into primary amides in the presence of aque- plied to the synthesis of pharmaceutically useful N-acetyl-4-
ous ammonia as an amine source and molecular iodine as a aminophenol from 4-hydroxy-acetophenone.
catalyst in using water as the solvent (Scheme 105 a).[124] A
5. Synthesis of Amides from Oximes

5.1. Metal-Catalyzed Conditions
5.1.1. Palladium-Catalyzed Reactions
In 1976, Leusink et al. reported a Beckmann rearrangement of
aldoximes in the presence of transition metal salts, such as pal-
ladium and nickel acetylacetonates, to produce amides
(Scheme 107).[126] The acetaldoxime quickly isomerized into the
Scheme 107. Palladium-catalyzed synthesis of acetamide. acac = acetylaceto-

nate.
corresponding acetamide in the presence of palladium bis(ace-

Scheme 105. a) I2-catalyzed conversion of methyl ketones into primary
amides; b) reaction mechanism.
tylacetonate) in benzene at 80 8C, through a dehydration/hy-
dration sequence. In addition, the authors studied the effect of
a series of metal salts on this transformation. Of the salts that
wide range of vinyl, heteroaryl, and ethynyl methyl ketones, as were tested, [Pd(Ph3P)4] and [(Ph3P)2PdCl2] were inactive, whilst
well as aryl methyl ketones with electron-donating or electron- [Pd(acac)(CH2NO2)(PPh3)], [Ni(OAc)2], and [Ni(acac)2] showed
withdrawing groups, were efficiently employed in this reaction, comparable catalytic activity to [Pd(acac)2]. These findings sug-
thereby giving the corresponding primary amides in good-to- gested that the anti-oxime was more reactive than the syn-
high yields. The authors found that other ammonium salts oxime under the reaction conditions. Nitriles were also con-
were not suitable for this transformation. Owing to the occur- verted into amides by using this procedure, although ketox-
rence of side reactions, 4-acetylpyridine did not furnish the de- imes did not give the corresponding amides under these con-
sired product. Notably, the addition of excess ammonia was es- ditions.
sential for this approach, because it acted as a weak base to
neutralize the hydrogen iodide that was generated from the
5.1.2. Ruthenium-Catalyzed Reactions
reaction. This approach was extended to methyl carbinols to
afford the corresponding primary amides. This reaction oc- Williams and co-workers reported an efficient ruthenium-cata-
curred through a Lieben–Haller–Bauer strategy, as shown in lyzed strategy for the rearrangement of aldoximes into their
Scheme 105 b. corresponding primary amides (Scheme 108).[127] The reaction
Aric et al. reported an efficient one-pot oxidative reaction was performed in the presence of [Ru(PPh3)3(CO)H2] as a cata-
for the synthesis of aromatic and aliphatic amides from ke- lyst, dppe as a ligand, and TsOH·H2O as an additive in toluene
tones and hydroxylamine hydrochloride in the presence of tri- at reflux. A wide range of aromatic aldoximes with either elec-
fluoroacetic acid (Scheme 106).[125] This reaction was sensitive tron-donating or electron-withdrawing groups were efficiently
to steric hindrance and proceeded through a Beckmann rear- tolerated in this transformation. Both E- and Z-oximes led to
rangement. Trifluoroacetic acid acted as both the solvent and similar results. Interestingly, the reaction was successful with

Focus Review
into primary amides through oxime intermediates by using

NaHCO3 as a base in MeCN instead of toluene. The proposed
reaction mechanism is shown in Scheme 109 b.
Kumar et al. reported the synthesis of a series of rutheniu-
m(II) complexes that contained polypyridyl ligands. Some of
these complexes exhibited good inhibitory activities against
DNA topoisomerase II (DNA-Topo II). In addition, the authors
found that 1 mol % of ruthenium(II) complex 63 led to high
catalytic activity for the rearrangement of a variety of aldox-
Scheme 108. Ruthenium-catalyzed rearrangement of aldoximes into amides. imes into the corresponding primary amides (Scheme 110).[129]
dppe = ethane-1,2-diylbis(diphenylphosphane). Based on these results, the authors inferred that the H and
OH groups of the oxime were both crucial for this transforma-
unsaturated and saturated aliphatic oximes, thereby affording tion. This reaction failed with benzonitrile, which indicated that
the corresponding amides in good yields. However, this the reaction mechanism did not proceed through a free nitrile
method was not responsive to ketoximes. Control experiments intermediate.
revealed that the reaction sequence involved dehydration of
the oxime to give a nitrile intermediate (or a coordinated ni-
trile) and subsequent hydration to give the desired amide.
Hull et al. reported a new and simple ruthenium-catalyzed
strategy for the conversion of aldoximes into primary amides
that employed 5 mol % [Ru(DMSO)4Cl2] as a catalyst at reflux in
toluene (Scheme 109 a).[128] This reaction proceeded under
ligand- and additive-free conditions. Both the E- and Z-oximes
of benzaldehydes and heterocyclic aldoximes were efficiently
tolerated under the reaction conditions to give the desired
amides in high yields, whilst strongly electron-withdrawing al-
doximes gave lower yields. In addition, the authors extended Scheme 110. Ruthenium(II)-catalyzed rearrangement of aldoximes into
this catalytic system to the one-pot conversion of aldehydes amides.
Garca-lvarez et al. developed a ruthenium(II)-catalyzed

method for the rearrangement of aldoximes into primary
amides (Scheme 111).[24] This reaction was performed smoothly
in water at 100 8C without the need for a co-catalyst. In the
presence of ruthenium(II) complex 5 (5 mol %), a variety of aro-
matic, heteroaromatic, a,b-unsaturated, and aliphatic aldox-
imes were readily transformed into the corresponding primary
amides in good-to-high yields within short reaction times. The
lack of reactivity of salicylaldoxime and pyridine-2-carboxaldox-
ime prevented the formation of the desired amide, and the
Scheme 109. a) Ruthenium(II)-catalyzed synthesis of amides; b) reaction

mechanism. Scheme 111. Ruthenium-catalyzed rearrangement of aldoximes into amides.

Focus Review
starting material was recovered in both cases. Chiral aldoximes Yang et al. developed a series of ionic ruthenium complexes
were also good substrates for this reaction. and found that tridentate complex 65 showed high catalytic
Gonzlez-Liste et al. found that the commercially available activity for the rearrangement of aldoximes into primary
bis(allyl) ruthenium(IV) complex (64) was an efficient catalyst amides under mild conditions (Scheme 113 a). This reaction
for the rearrangement of aldoximes into primary amides under
environmentally benign conditions (Scheme 112 a).[130] The re-
Scheme 113. a) Ruthenium-catalyzed synthesis of primary amides; b) reac-

tion mechanism.
proceeded in water at 110 8C for 12 h.[131] A range of aromatic,

Scheme 112. a) Ruthenium(IV)-catalyzed rearrangement of aldoximes into
heteroaromatic, and conjugated aldoximes were found to be
amides; b) reaction mechanism. MW = microwave irradiation.
suitable substrates for this transformation, thereby giving the
desired amides in good-to-high yields with excellent function-
al-group compatibility. Moreover, the same group also extend-
action was performed in a mixture of water and glycerol (1:1) ed this catalytic system to the one-pot synthesis of amides
under thermal heating or microwave irradiation within a short from aldehydes in the presence of hydroxylamine hydrochlo-
reaction time. The scope of this catalytic reaction was explored ride and sodium carbonate as a base. This reaction tolerated a
by using a variety of aromatic, heteroaromatic, aliphatic, and broad range of aldehydes, including aromatic, conjugated, and
a,b-unsaturated aldoximes, thereby affording the desired aliphatic aldehydes, and the method was also amenable to
amides in moderate-to-high yields. Many functional groups large-scale preparation. The authors proposed a plausible reac-
were tolerated in this reaction. In addition, the catalyst was ef- tion mechanism for this transformation, which is shown in
ficiently reused up to six times without the loss of its catalytic Scheme 113 b.
activity. Interestingly, the rearrangement of aromatic, heteroar-
omatic, and aliphatic aldoximes provided higher yields under
5.1.3. Rhodium-Catalyzed Reactions
microwave irradiation, whilst a,b-unsaturated aldoximes afford-
ed higher yields under thermal conditions. The proposed reac- Park et al. reported a strategy for the conversion of aldoximes
tion mechanism is outlined in Scheme 112 b. into amides catalyzed by Wilkinson’s complex (Scheme 114).[12b]

Focus Review
be readily recovered and reused with high catalytic activity. A

variety of aliphatic (linear, branched, and cyclic), aromatic, and
heteroaromatic aldoximes reacted efficiently to afford the cor-
responding amides in good-to-excellent yields. Notably, O-alky-
lated aldoximes and ketoximes did not react under the opti-
mized conditions, thus suggesting that the OH and H groups
were essential for this transformation. Moreover, this catalytic
system could be applied to the one-pot synthesis of primary
Scheme 114. Synthesis of amides catalyzed by Wilkinson’s complex. amides from the corresponding aldehydes in the presence of
hydroxylamine. The authors proposed a reaction mechanism
as shown in Scheme 115 b.
The authors screened a series of rhodium and ruthenium com- Kim et al. developed an efficient rhodium-catalyzed, nitrile-
plexes and found that the rhodium complexes exhibited facilitated method for the synthesis of amides from aldoximes
higher catalytic activity than the ruthenium complexes. In the (Scheme 116 a).[133] This transformation was achieved by using
presence of [RhCl(PPh3)3], several aromatic, heteroaromatic,
and aliphatic amides were obtained in good-to-high yields. A
wide range of functional groups were well-tolerated in this
transformation, whilst syn-aldoximes were transformed with
higher conversion rates than the corresponding anti-aldoximes.
The catalytic system was also amenable to a large-scale reac-
tion. This reaction proceeded under additive- and ligand-free
conditions.
Fujiwara et al. employed a Rh(OH)x/Al2O3 complex as an ef-
fective heterogeneous catalytic system for the one-pot synthe-
sis of primary amides from aldoximes in water
(Scheme 115 a).[132] The authors found that this catalyst could
Scheme 116. a) Rhodium-catalyzed rearrangement of aldoximes into amides;

b) reaction mechanism. IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazolium.
a combination of [Rh(cod)(IMes)Cl] and TsOH in the presence

of a complementary nitrile as an additive in toluene at 80 8C
for 6 h. Notably, the nitrile additive was essential for this con-
version, which increased the rate of reaction and provided
higher yields of the products. A variety of aromatic amides
with electron-donating or electron-withdrawing substituents
and heteroaromatic amides were obtained in high yields by
using this method. In addition, aliphatic aldoximes were also
tested, and the desired amides were obtained in moderate
yields, irrespective of the presence of nitrile additives. Based
on additional assays, the authors suggested a reaction mecha-
nism, as shown in Scheme 116 b. The reaction proceeded
Scheme 115. a) Rh(OH)x/Al2O3-catalyzed synthesis of amides; b) reaction through the intramolecular electrophilic addition of the aldox-
mechanism. ime to a rhodium-metal-bound nitrile complex.

Focus Review
5.1.4. Iridium-Catalyzed Reactions Later, Sun et al. developed an efficient and environmentally
friendly iridium-catalyzed approach for the synthesis of amides
In 2007, Williams and co-workers explored a new and effective from aldoximes, which employed water as a solvent in air
iridium-catalyzed strategy for the rearrangement of oximes (Scheme 118).[12a] The authors screened a series of water-solu-
into primary amides (Scheme 117 a).[134] This reaction was per- ble {Cp*Ir} complexes and found that [Cp*Ir(H2O)3](OTf)2 exhib-
ited the highest catalytic activity for this process. This reaction
occurred under oxidant- and ligand-free conditions and, in the
presence of 1.5 mol % of the catalyst, a range of aromatic, ali-
phatic, and unconjugated or conjugated unsaturated amides
were obtained in good-to-excellent yields. This method offered
high functional-group tolerance and the authors extended this
system to the one-pot synthesis of amides from aldehydes and
hydroxylamine hydrochloride in the presence of sodium car-
bonate as a base. A range of aromatic, aliphatic, and unsaturat-
ed aldehydes were found to be suitable substrates for this
transformation.
5.1.5. Gold-Catalyzed Reactions

Ramon et al. explored the first gold-based catalytic system for
the rearrangement of aldoximes into the corresponding
amides (Scheme 119).[135] The authors screened a series of cata-
Scheme 117. a) Iridium-catalyzed rearrangement of aldoximes into amides;

formed at reflux in toluene. In the presence of [{Ir(Cp*)Cl2}2], a

range of aromatic, heteroaromatic, and aliphatic oximes were
successfully transformed, thereby giving the corresponding
amides in good-to-excellent yields. Notably, both E and Z isom-
ers of the oxime could be efficiently transformed into the cor-
responding amides. Interestingly, both the hydrogen and hy-
droxy groups of the oxime were essential for this transforma- Scheme 119. Gold-catalyzed rearrangement of aldoximes into amides.
tion. Moreover, the authors found that this catalytic system
was also applicable to the one-pot conversion of a range of
benzylic alcohols into the desired amides in moderate-to lysts and co-catalysts and found that the combination of
good-yields, although the conversion of aliphatic alcohols was [(IPr)AuCl] as a catalyst and AgBF4 as a co-catalyst displayed
unsuccessful. The authors proposed a reaction mechanism as the highest activity for this process. The reaction was per-
shown in Scheme 117 b. formed under solvent-free and acid-free conditions and a
number of aromatic and heteroaromatic primary amides were
efficiently obtained in good-to-excellent yields. The authors
also tested aliphatic and unsaturated aldoximes; however, the
desired amides were only obtained in low yields.
5.1.6. Nickel-Catalyzed Reactions

Williams and co-workers reported a simple and straightforward
nickel-catalyzed procedure for the reaction of aldoximes with
amines to afford secondary or tertiary amides in good yields,
by using NiCl2·6 H2O as a catalyst and xylene as the solvent
(Scheme 120 a).[136] This method provided efficient access to
secondary or tertiary amides from aldoximes. A variety of aro-
matic and aliphatic aldoximes worked well with a range of pri-
mary and secondary amines, with the exception of more-steri-
cally hindered secondary amines and less-nucleophilic amines.
This method was not suitable for ketoximes and oxime ethers.
Scheme 118. Iridium-catalyzed synthesis of amides. The authors also applied this catalytic system to the one-pot

Focus Review
Scheme 121. Cu(OAc)2-catalyzed rearrangement of aldoximes into amides.
5.1.8. Indium- and Zinc-Catalyzed Reactions
In 2010, Williams and co-workers established a cost-effective

indium- or zinc-catalyzed approach for the rearrangement of
aldoximes into primary amides in good-to-excellent yields
(Scheme 122).[138] Their method was efficiently applied to a
Scheme 120. a) Nickel-catalyzed synthesis of secondary or tertiary amides;

Scheme 122. Indium-/zinc-catalyzed synthesis of primary amides.
conversion of aldehydes into secondary and tertiary amides.

This method had some inherent advantages, such as the acces- range of aromatic and aliphatic aldoximes. However, remarka-
sibility of the catalyst, its simple reaction procedure, and its bly, 2-furyl aldoxime failed to give the desired amide with the
high functional-group tolerance. The authors proposed the re- indium catalyst, although the zinc catalyst was effective for
action mechanism shown in Scheme 120 b. this substrate, thereby affording the desired amide in excellent
yield. This method was sensitive to steric hindrance with both
catalysts. Furthermore, the same group also extended this in-
expensive system to the one-pot synthesis of primary amides
from aldehydes.
5.1.7. Copper-Catalyzed Reactions
In 2011, Williams and co-workers established an atom-efficient
5.2. Metal-Free Conditions
and cost-effective copper-catalyzed procedure for the rear-
rangement of oximes into the corresponding primary amides Recently, Fernndez-Stefanuto et al. synthesized and character-
(Scheme 121).[137] They found that homogeneous Cu(OAc)2 was ized a cyanoguanidinium para-toluenesulfonate salt from N-cy-
effective for this transformation. The reaction was efficiently anoguanidine and para-toluenesulfonic acid. They found that
performed under either conventional or microwave heating. A cyanoguanidinium para-toluenesulfonate salt was an efficient
variety of aromatic, heteroaromatic, and aliphatic amides were catalyst for the synthesis of e-caprolactam, which is a versatile
readily prepared under their optimized reaction conditions. In- precursor to nylon-6 (Scheme 123).[139] Water was found to be
terestingly, the same group also found that CuO/ZnO on acti- the optimal solvent for this transformation, which proceeded
vated carbon was an efficient and reusable heterogeneous cat- through a Beckmann rearrangement under mild conditions.
alyst for the rearrangement of oximes into the corresponding The product was readily isolated in high yield from the reac-
primary amides. tion mixture by using sublimation. This process did not require

Focus Review
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Focus Review
FOCUS REVIEW
Thatikonda Narendar Reddy,* Journey to the center of the flask:
Adilson Beatriz, Vaidya Jayathirtha Rao, Recent progress in the direct synthesis
DÞnis Pires de Lima* of amides from the reaction of alde-
hydes, ketones, and oximes with amines
&& – &&
or amine surrogates is described. The
Carbonyl Compounds’ Journey to reactivity of a range of catalytic systems,
Amide Bond Formation substrate scope, mechanistic studies,
and relevant applications are briefly ex-
plored. We hope that this Focus Review
will encourage further progress in this
notable area of chemistry research.

Amides From Carbonyls

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Amides From Carbonyls

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DOI: 10.1002/asia.

201801560 Focus Review

Carbonyl Compounds’ Journey to Amide Bond Formation

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Functional group transformation (FGT) is a versatile and ex-

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amidation of alcohols[17] have all been explored. Another pow-

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3.1.1. Transition-Metal-Catalyzed Conditions

2.2. Hemiaminal Intermediates

In 2008, Suto et al. developed a new [PdCl2]-catalyzed path-

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quential dehydration and hydration processes. Their proposed

3.1.1.2. Ruthenium-Catalyzed Reactions

hydes. Aniline and sterically crowded amines provided the cor-

Scheme 7. a) [Ru(TTP)(CO)]-catalyzed amidation of aldehydes with PhI=NTs;

Gnanamgari and Crabtree investigated a ruthenium-cata-

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plexes that were tested for the one-pot conversion of alde-

Scheme 8. Ruthenium-catalyzed synthesis of primary amides from alde-

Raja et al. developed an efficient air-stable catalytic system,

Scheme 9. Synthesis of primary amides from aldehydes catalyzed by a ruthe-

thors tested a series of ruthenium hydride catalysts and N-het-

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Nandi et al. developed a ruthenium-catalyzed, oxoammoni-

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3.1.1.3. Rhodium-Catalyzed Reactions

Tillack et al. developed a rhodium-catalyzed system for the syn-

Scheme 17. Rhodium-catalyzed oxidative amidation of allylic alcohols or al-

In the same year, Nguyen and Hull further investigated the

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Scheme 19. a) [Rh2(OAc)4]-catalyzed reductive amidation of aldehydes with

Scheme 18. a) Rhodium-catalyzed oxidative amidation of hindered alde-

3.1.1.4. Gold-Catalyzed Reactions

Li et al. developed a facile and efficient gold-catalyzed strategy

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3.1.1.5. Iron-Catalyzed Reactions

In 2011, Gowda and Chakraborty reported the reaction of a

Scheme 22. Iron-catalyzed oxidative amidation of aldehydes with amine hy-

Scheme 21. FeCl3-catalyzed synthesis of primary amides from aldehydes.

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Scheme 26. Co2(CO)8-catalyzed reductive N-alkylation of primary amides

timized conditions. The same authors extended this method to

Scheme 25. Fe2O3 N@C-catalyzed synthesis of primary amides. Fe2O3

offered broad substrate scope with excellent functional-group

ic, and aliphatic aldehydes reacted with a variety of alkyl-sub-

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toxyl and tert-butylperoxyl radicals in the presence of the cata-

derwent oxidation and hydrolysis to give benzaldehyde under

3.1.1.7. Nickel-Catalyzed Reactions

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Zhu et al. found that the combination of CuI and sodium 2-

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ported a synthesis of primary amides by using reoptimized re-

Scheme 35. Copper(II)-catalyzed synthesis of primary amides from alde-

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tions, thereby affording the desired amides in good-to-excel-

Scheme 38. a) Copper-catalyzed synthesis of N-(pyridin-2-yl)benzamides;

in moderate-to-good yields. However, only trace amounts of

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Scheme 42. Copper-catalyzed synthesis of e-CF3-substituted amides.

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3.1.2. Lanthanide-Metal-Catalyzed Conditions