Asymmetric Organocatalysis

Research Article • DOI: 10.2478/asorg-2013-0001 • ASORG • 2013 • 24–31

Trienamines: Their Key Role in Extended Organocatalysis

for Diels-Alder Reactions

Abstract
Silvia Reboredo1, José Alemán2#
Activation via trienamine intermediates is a synthetically useful protocol for
Alejandro Parra2*,
performing asymmetric Diels-Alder reactions controlled by a remote chiral
catalyst (a secondary or primary amine). Key features underpinning this
concept are the conformation towards the trienamine formation and also
1
Departamento de Química Orgánica I, 2
Departamento de Química Orgánica
Facultad de Químicas, Universidad (Módulo 1), Facultad de Ciencias,
the use of highly electrophilic dienophiles. This cycloaddition reaction allows
Complutense de Madrid Universidad Autónoma de Madrid
the application of asymmetric organocatalysis at a remote position, and the Cantoblanco, 28049-Madrid
synthesis of complex molecules short synthetic sequences is possible.

Keywords Received 14 March 2013

Trienamine • Organocatalysis • Asymmetric catalysis • Diels-Alder reaction • Tandem Accepted 06 April 2013
reaction

© Versita Sp. z o.o.

Asymmetric organocatalysis has received increasing the first amino-catalyzed Diels-Alder reaction (DA) by using
attention over the last decade due to the establishment of trienamine intermediates derived from dienals was described.
organocatalysis as a useful synthetic tool. Atypical reactivities This successful approach was rationalized by DFT-calculations
and hitherto unachievable asymmetric transformations are which indicated that ε-activation was favored by a sterically
some of the highlights of organocatalysis [1]. This bio-mimetic demanding single-bond rotation and, in addition, that only one
“organocatalytic revolution” has inspired original modes of of the generated dienes could be selectively activated (Figure 2).
activation, especially in the area of carbonyl group chemistry. NMR experiments showed that a strongly acidic medium
Activation by chiral amines has been demonstrated as a (o-fluorobenzoic acid) was essential for the formation of the
powerful method, since HOMO [2], LUMO [3], and SOMO [4] trienamine intermediate.
activations are well-established techniques and they have The concept was satisfactorily evaluated using 3-olefinic
found widespread use in asymmetric synthesis. The concept oxindoles and cyanoacetates as dienophiles (Scheme 1).
of LUMO lowering activation (β-functionalization) was first Thus, a sterically demanding catalyst, chlorinated solvent, and
employed in 2000 [3], while HOMO raising activation was an acidic additive were crucial to the success of the reaction.
employed for activating both carbonyl groups via enamine The interest in this transformation is related to the wide range
(α-functionalization) [2a-b] in 2000 and dienamine [2c-d] of analogous substituent patterns present in a large number of
catalysis (γ-functionalization) in 2006 (Figure 1). The application natural products [8].
of asymmetric aminocatalysis to more remote sites has long
been considered however, it has taken several years (in contrast
to the remarkably quick achievements in the field of the chiral
auxiliaries [5]) for this goal to be realized.
In order to achieve the aims of remote induction using more
extended conjugated systems with chiral amines, two issues
have to be addressed. On the one hand, the catalytic system
must control the regioselectivity in the α−δ−ε positions (HOMO-
raising positions) [6]. On the other hand, the stereocontrol
performed by the employed amine catalyst must be efficient,
taking into account that six bonds exist separating the chiral
moiety and the reactive position (right panel in Figure 1).
Recently, this new asymmetric activation mode was reported
by Chen and Jørgensen [7]. In this conceptually attractive work, Figure 1. Evolution of activation modes using aminocatalysis.

E-mail: * jose.aleman@uam.es,
#
alejandro.parra@uam.es
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 Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions
Figure 2. Trienamine intermediates and conformational studies.
OH C R1 Ph
N Ph
R4 R3 H OTES
O ( 20 m o l% ), CH 2 C l2
N R5
o-F BA ( 20 m o l% )
R2
R3
Y ie ld: 4 7 -9 9 %
e e : 9 4 -9 9 % R4
d r : 7 8 :22 - >9 5 :5 O A r= P h or
N 4-O Me -3,5- (t-B u) 2 C 6 H 2
R2
Scheme 1. First catalytic asymmetric trienamine reaction by Jørgensen and Chen.
Encouraged by these novel results, Chen et al. [9]
independently explored the possibility of using nitroalkenes
as dienophiles (left equation, Scheme 2). Unfortunately,
these types of styrenes did not provide any product even at
80°C when 2,4-hexadienal was used, indicating that higher
activated dienophiles are required. Thus, the introduction
of electron donating groups in the trienamine moiety
raised the HOMO energy, allowing the reaction of dienals
and nitroalkenes. Almost simultaneously, Jørgensen et al.
[10] studied trienamine formation and its reaction with (Z)-
olefinic azlactones (right equation, Scheme 2). In this case, the
use of o-fluorobenzoic acid was not necessary (higher yields
were obtained without additives), and the obtained aldehyde
was later derivatized to afford α,β-unsaturated products (via
Wittig or Ramirez olefinations). Excellent enantioselectivities
(ee´s) were obtained with diastereomeric ratios (dr) ranging
from 4:1 to 8:1. More interestingly, these final products allowed
amino acid derivatives and polycyclic compounds to be
accessed.
Only a few months later, Melchiorre et al. [11] were able to use
this strategy for the formation of o-quinodimethane derivatives
and described subsequent reactions of these intermediates
with nitroalkenes and methyleneindolines (Scheme 3). The use
of 3-methyl-indoles bearing a α,β-unsaturated aldehyde at the
3-position, which facilitated dearomatization of the system was
a key feature (see the
o-quinodimethane intermediate below, Scheme 3). In the case
of nitroalkenes, the resulting compounds (tetrahydrocarbazoles)
O Ar
N Ar R1
H OTES
(2 0 m o l% ) , C HC l3 OH C
o-F B A (2 0 m o l% )
NC CO 2 R 6
C O2R6
R5 Y ie ld : 71 - 97 %
R1 CN e e : 8 5- 8 9%
d r: 7 8 :2 2 -9 0 :1 0
were obtained in high ee´s (90-93%), good dr´s (11:1 to >20:1),
and low (22%) to excellent yields (96%). For other dienophiles
such as methyleneindolines, the results were also excellent in
terms of enantioselectivity, but in some cases dr’s were found
to be lower (right panel, Scheme 3). Based on computational
studies, a [4+2] process was proposed, using an exo-approach in
the case of nitroalkenes (favored by π(Ph)-π(diene) interactions)
and an endo-approach in the case of methyleneindoline (π(C=O)-
π(diene) interactions). Very recently, in 2013, the same research
group [12] applied this strategy to the stereoselective synthesis
of tetrahydrocarbazoles using sequential Diels-Alder/benzoin
reactions under trienamine-carbene catalysis.
Once again, in 2012, Chen et al. [13] evaluated trienamine
catalysis involving in the Diels-Alder reaction of 2,4-dienones.
The authors demonstrated the inability of performing this reaction
with alkyl-dienyl-ketones because of the low reactivity derived
from the use of primary amine catalyst (cinchona derivatives).
The aryl-dienyl-ketones seemed to be more reactive, which
make them good substrates for the DA reaction. However, this
reaction was only catalyzed when the remote double bond was
disubstituted by an alkyl group (e.g., R2= Me), yielding racemic
products when the double bond was monosubstituted (R2= H)
(Scheme 4).
After initial screening, it was found that a quinine derived
catalyst gave the best results. The reaction tolerated a wide
range of aromatic groups at the ketone moiety, even a 2-styryl
group (R1), whereas the substitution pattern at the double bond
was more restricted (R3= Me, Ph, and R2; R3= cyclohexyl). In all
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 S. Reboredo et al.

Ph
Ph Ph
3 N O R7 R6
R H OTMS N Ph
R2 R4 (2 0 m o l% ), C HC l3 H OTMS
O
o-F B A (2 0 m ol% ) R1 (1 0 m o l% ), C HC l3 O
R1 N O2 th en PP h 3 =X Ph
NO 2 N
R4 O
R2
C HO R5 R5
R3
Y ie ld: 4 7 -9 3 % N O Y ie ld: 4 7 -9 0 %
e e : 9 1 -9 4 % Ph e e : 9 6 -9 9 %
d r : 8 6 :14 - >9 5 :5 C h e n et al Jø r ge n se n et al d r : 4 :1- 8 :1

Scheme 2. Independent works of Jørgensen and Chen et al. in trienamine chemistry.

R3
O
Ph Ph H
R4 N O Ph
R5 N Ph H N N O2
H OTMS H OTMS
O (2 0 m o l% ) ( 20 m o l% ) R6
R1
OH C BA (2 0 m o l% ) BA (2 0 m o l% )
R1
N B o c CH Cl , 7 0 ºC N
2 2 T olu e n e, 7 0 ºC
R5 N R6 R2
NO
R1 R3 R2 2
Y ield : 53 - 98 % O Y ield : 22 - 96 %
ee : 9 5 ->9 9 % N e e : 9 0- 9 3%
R 4
d r : 1 :1 ->2 0 :1 d r: 1 0 :1 -> 2 0 :1
Ph Ph

OTMS
N

R1
N
R2
o- quinodimethane

Scheme 3. o-Quinodimethane intermediate generated using trienamine strategy.

Scheme 4. Initial trienamine chemistry using ketones (Chen et al.).

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 Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions

cases, yields ranged from moderate to excellent (47–93%), only
one diastereomer was observed (>95:5), and good to excellent
ee´s (82–96%) were obtained (for selected examples, see the top
row in Figure 3). In the same work, it was also demonstrated
that the reaction was compatible with methyleneindolines,
deactivated alkenes, and nitroalkenes as dienophiles (bottom
row, Figure 3).
In the same year, Jørgensen et al. [14] described a novel and
interesting concept termed a “cross-trienamine” intermediate.
This intermediate can be involved in a highly enantioselective
Diels-Alder reaction with different dienophiles, such as 3-olefinic
oxindoles, 5-olefinic azlactones and even with bis-sulfonyl alkenes
(Scheme 5). In all cases, total regioselectivity was observed via
the cross-trienamine, and excellent enantioselectivities (up to
99%) were usually obtained. Very recently, Houk et al. [15] used
theoretical calculations to investigate the selectivities found in
these Diels−Alder reactions. Kinetic and thermodynamic control
in the formation of zwitterionic intermediates could be used
to explain the [4+2] cycloaddition reactions between cyclic
trienamines and oxindoles.
Tetrahydroxanthone derivatives are commonly present
in nature and they possess interesting biological properties.
Jørgensen et al. [16] synthesized a range of these materials
through a H-bonding-directed approach for trienamine mediated
[4+2] cycloadditions. Thus, a squaramide-based organocatalyst
[17] interacted with a nitrile group present in the chromone
derivative (dienophile) by hydrogen bond interaction, ensuring
both high reactivity and diastereoselectivity (Scheme 6). The
obtained adducts were chemoselectively transformed into the
desired products.

O O O
Me Me Ph
N Ph N p-B rC 6 H 4 N p-B rC 6 H 4

O Ph O O
C OPh C OPh
O
Y ie ld : 7 5 % Y ie ld : 8 0 % Y ie ld : 4 6 %
ee: 92% ee: 96% ee: 85%

E tO 2 C Ph p- Br C 6 H 4
CO Ph CN
O CO 2 E t NO 2
N
P hOC p- To lO C
Ts
Y ie ld : 7 0 % Y ie ld : 8 0 % Y ie ld : 7 0 %
e e: 9 4 % e e: 9 0 % e e: 9 1 %
d .r .: >9 5 :5 d .r .: >9 5 :5 d .r .: >9 5 :5

 elected examples from Chen’s research.

Figure 3. S

O
R3
N Bo c
R1
R4 O
2 R1 R2
Ph R
Ph Ph E tO 2 C
Ph N Ph
H O TMS N
O NR* H O TM S +
N (1 0 m o l% ),C H Cl 3,
BA ( 2 0 m o l% ), (1 0 m o l% ) ,C HC l3 ,
R5 O R3
R2 4 0 -5 0 ºC o- FB A (2 0 m o l% )
R1 R1 N Bo c
O R4 4
R O
O R5
O R2 3 R1 R2
N R O
N E tO 2 C
Ph B oc
th e n P P h 3 C H 2 CO 2 Et,
Y ie ld : 3 4- 5 8% Y ie ld : 5 4 -7 5 %
e e : 9 2 -9 9 % 4 0 ºC
e e : 9 2 -9 9 %
d r: 3 :1 -5 :1 d r: 7 :1 -2 0 :1
 eactivity of cross-trienamine.
Scheme 5. R

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 S. Reboredo et al.

In an attempt to overcome the traditional challenge of the
high energetic barrier for disrupting aromaticity, Jørgensen et al.
[18] proposed direct HOMO-raising activation of polycyclic
π-systems (anthracene derivatives) using aminocatalysis. The
evaluation of the [4+2] cycloaddition model reaction between
nitrostyrene and 2-(anthracen-9-yl)acetaldehyde indicated
that a bifunctional catalyst would be most appropriate (left,
Scheme  7). This catalyst would activate the anthracene
derivative by an enamine formation and also would form a
hydrogen bond with nitrostyrene, thus restricting the approach
of the dienophile to only one of the possible enantiotopic faces.
The reaction requires only 2 mol% of catalyst and is compatible
with a wide range of nitrostyrene derivatives having different
substitution patterns on aryl group and also with various 9,10-
substituted anthracenes. High yields and excellent ee´s were
reported (left, Scheme 7).
In a subsequent work, the same authors [19] performed
DFT calculations in an effort to broaden the developed method
for the Diels-Alder reaction with anthracene derivatives since
it was limited to both the dipole and the dipolarophile being
activated by the catalyst. They found that the reaction can
proceed with maleimide derivatives, and in this case, a C2-
symmetric catalyst was used. The scope of this cycloaddition
included maleimides (aromatic and non-aromatic) with
differing electronic demands as well as maleic anhydride and
cyclopentenedienone. Noncyclic dienophiles, however, turned
out to be unreactive. With regards to anthracene substitution,
substituents on outer rings (R1 and R3) ) gave better results than
inner ring substitution (R2) (Scheme 7).
Ye et al. [20] have recently described an interesting
Diels-Alder reaction between rhodanine derivatives and
2,4-dienals catalyzed by the Jørgensen-Hayashi catalyst. For
pharmacological scientists, analogues of this dipolarophile
prove to be of great importance due to their biological activities.
Rhodadyn was reacted with 2,4-hexadienal in the model reaction.
High yields and excellent diastereo- and enantioselectivities
were achieved under optimized conditions (Scheme 8). The
reactions of thiohydantoin derivatives (R3 and R4) and dienals
(R1 and R2) afforded the desired products in excellent enantio-
and good diastereoselectivities (Scheme 8). It is hoped this work
may lead to further development of valuable motifs in new drug
discovery and the synthesis of natural products.
Very recently, Chen et al. [21] reported the exo-Diels-Alder
reaction by using HOMO-raising trienamine activation. A series
of spirocyclic compounds were prepared by means of a Diels-
Alder reaction between trienamine intermediates derived from
2,4-dienals and methiodide salts of Mannich bases. In order to
generate the reactive vinyl ketone, 2.0 equivalents of sodium
benzoate were used, affording products in good yields (41-75%)
and excellent enantioselectivities (up to 97%) (right, Scheme 9).
Interestingly, in the case of cyclohexenones (as dienophiles) the
use of 20 mol% of (S,S)-TADDOL increased the final conversion

. O O CF3
TF A
O ( 16 m o l% ) O
O N N
N H H CF 3 O
CN H CN
+ R1
R1 R4
CH Cl 3 (0 .0 5 M ), DE A (8 e q.), 4 0 -6 0 o C R4
O
R 2 O R2
H 3
R3 R
Yie ld : 5 9 -9 8 %
e e: 8 5 -9 1 %
d r: > 20 :<1

 nantioselective synthesis of tetrahydroxanthones.

Scheme 6. E

. O O CF3
TF A
( 2 m o l% ) Ph P h ( 10 m o l% )
N N N
N H H H
CF 3
H P h CO 2 H ( 10 m o l% ), CH Cl 3 O
N O2 1 ) D EA ( 2 e q .), C H 2 Cl 2, r t, C HO
O X X
Ar N O2 O
OH Ar
OH C O
2 ) Na B H 4 , M e O H , 0 o C -3 0 to 4 0 o C , 2 4 or 4 8 h
R2 R1 R2 R3 R2
R1 R3
R 1 =R 3 = H
Y ield : 6 9- 9 8% Yie ld : 7 0 -9 6 %
e e : 9 2 -9 8 % ee : 7 6 -9 6 %

Scheme 7. Asymmetric Diels-Alder reaction with anthracene derivatives.

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 Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions

since the intermediate ketone can be activated by hydrogen development, for instance, reactions other than the Diels-Alder
bonding interactions (left, Scheme 9). reaction may be explored.
In conclusion, Jørgensen and Chen demonstrated a new
protocol for carrying out asymmetric Diels-Alder reactions Abreviations
controlled by a remote chiral catalyst (a secondary or primary
amine). Key features underlying this process are the conformation DA: Diels-Alder
towards the trienamine formation and also the use of highly o-FBA: ortho-Fluorobenzoic acid
electrophilic dienophiles. A limited number of aldehydes/ketones BA: Benzoic Acid
and some very reactive dienophiles have been employed TADDOL: α,α,α,α-Tetraaryl-1,3-dioxolane-4,5- dimethanol
successfully. This new mode of activation is open to further DEA: Diethylacetamide

O Ph O
N Ph (2 0 m o l% ) S
H OTMS
S X
R1
+
o-FB A (2 0 m o l% ) R2 N R4
X 4
N R
R3 O
C DC l3 5 0 o C R3
O 1
R
R2
Y ie ld : 6 4- 9 8%
e e : 9 2 -9 9 %
d r : 1 0:1 ->1 9 :< 1

 minocatalyzed Diels-Alder reaction.

Scheme 8. A

R3
O R2 A r= 3 ,5 -t-Bu 2 -4 -M eO C 6 H 2 A r= 3 ,5 - t-B u 2 - 4- M e O C 6 H 2
R5 Ar
R1 Ar Ar
N Ar
H O T ES O N R3
n C HO H O TE S
(1 0 m ol% ),CH Cl 3 , O R2
T A DD O L (2 0 m o l% ), (2 0 m o l% ) ,
or P h CO 2 N a (2 e q .) P h CO 2 N a (2 e q.)
R3 R1 R4 R1
O R3 O X
O R2 R2 CH O
R 5
N I N I
4
R1 R Y ie ld : 4 1 -7 5 %
X e e : 8 3 -9 7 %
R6 n
CH O or C H 2 Cl 2 , 6 0 ºC d r: 9 :1 -1 9 :1
O

Y ield : 3 2- 7 6% N I
e e : 8 4 -9 7 %
d r: 4 :1 ->1 9 :1 R6
n

Scheme 9. e xo-Diels-Alder reaction reported by Chen et al.

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