31 REVIEWS Ammonium Formate in Organic Synthesis: A Versatile Agent in Catalytic Hydrogen ‘Transfer Reduc Siya Ram,** Richard E, Ehrenkaufer” + PET Faclty/Division of Nuclear Medicine, Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA * University of Pennsylvania, Cerebrovascular Research Center, Rm, 429 Johnson Pavilion, 6th and Hamilton Walk, Philadelphia, PA 19104, USA) Applications of ammonium formate in organic synthesis ae reviewed, 1. Iateoduction Reduction of Functional Groups Initial Studies Aides Nitro Groups Nites Dehalogenation of Aromatic Chlorocarbons Introduction ‘The development of selective, mild and effective reducing ‘agents is stil an area of considerable interest, particularly when ‘a molecule has multiple reducible or labile moieties. Recently & review on heterogeneous catalytic transfer hydrogenation has ‘appeared in the literature." The present article deals only with ‘application of ammonium formate in organic synthesis, which hnas not yet been reviewed. ‘The preparation of ammonium formate was described in 1941.? It has been generally used in the precipitation of base metals from the salts of the noble metals. The use of ammonium formate in organic synthesis was fist illustrated by Leucart in \which various carbonyl compounds 1 were reacted with am- ‘monium formate 2) to afford the corresponding amines 3, This process was later named as the “Leucart Reation" (Scheme A), 9 We wig + Hit elt 1 2 3 Scheme A ‘The mechanism of Leucart reaction was studied by Wallach,* and in 1949 a comprehensive review on the Leucart reaction was published by Moore.® Later, the Leucart reaction was successfully extended fo the amination of 1,S-diketones® and unsaturated Ketones.” 2. Reduction of Functional Groups 24 Initial Stes The use of ammonium formate as a reducing agent for func- tional groups in moderate reaction conditions is interesting and promising. Hydrazones and azines 4 and 6, on reduction with formic acid or its derivatives such as ammonium formate gave 200d yields of the corresponding hydrazines § and 7° (Scheme By 4. Deprotetion of Functional Groups 41, Deprotection of Polyrter and Carbobenzyloxy Group from Pro- tected Peptides 442. Deprotetion of 0-Benayl Group 5. Regiasletve Symhesis of 1-Olefins {6 Miscellaneous Applications and Other Forme Acid Derivatives, 7. Conclusion Onn a Que) .N.N-Dieyelohexyl Hydrazine Dihydrochorie (7 AA’ mixture of cyclohexanone azine (6; 19.2¢, 0.1 mab, HCO,NH (205g, 0.5mol) and nickel catalyst (0.2e) is refuxed for 6h. The mixture is dilated with twice the amount of water and the product is extracted with benzene, The benzene layer i evaporated and the residue boiled with cone. HCI (SOmL) saturated with HCI gas: yield: 204 g (15%); m.p. 267°C, 22 Aatles Insertion of amino group in the organic molecule via azide is a well known procedure. In past years a number of reagents have been developed for the reduction of azides to amino deriva tives. Recently alkyl azides 8 were successfully reduced to the corresponding primary amines 9 in the presence of palladium) carbon, using ammonium formate as the hydrogen source? (Scheme ©) Scheme € Reduction of Azides; General Procedue:” ‘A mixture of azide (LOmol), HCO;NH, (40mol) and $% Pui (6-13% of azide by weight) in CHjO8 (100 mL.) is stirred for 3-4 hat ambient tcrperature The catalysis removed by filtration and the ‘roduct is isolated by standard procedures yield: 74-93%.2 S.Ram, R.E, Bhrenkaufer 23, Nite Groups Aliphatic nitro compounds are traditionally reduced either by high pressure catalytic or metal-catalyzed transfer hydrogen ation, both of which are time consuming provesses. Recently wwe reported use of ammonium formate in catalytic hydrogen transfer reductions, in which nitroalkanes, nitro esters and aromatic nitro compounds such as nitrobenzene derivatives, aromatic nitro acids and esters can be selectively and rapidly reduced to the corresponding amino derivatives 11 in high eld!" (Scheme D). nog ECON MeOH 0 1" Pat Scheme D scNitto esters can be rapidly reduced to the corresponding a= amino esters, however, a-nitro acids on reduction decarboxy- late to the corresponding alkylamines. Attempts were made 10 minimize the decarboxylation using sodium acetate/acetic acid buffer (pH = 5.0), but with only limited success. Reduction of nitro heterocyclic compounds such as 2-methyl-S-nitroimid- azole was partial, for e.g. S-nitrouracil was recovered as un- reacted starting material, Similar result was observed with nitro styrene In most cases (excluding the above exceptions), the reaction is over in 3-40) min.1°"" These results demonstrate a rapid versatile and selective reducing system for wide variety of nitro ‘compounds in the presence of other functional groups such as nitrile, carbonyl ete Reduction of Nitro Groups; General Procedure: ‘To a stirred suspension of the appropriate nitro compound (S mmol) and 10% PajC (0.2-0.3g) in dry CH,OH (10 mL) at room tempera- ture is added antydrous HCO; NH (23 mmol) ina single postion under an argon atmosphere. The resulting mixture (slightly exothermic and effervescent) is stirred at room temperature for 3-40 min, the catalysis removed by ftration through a elite pad and washed with dry CH,OH (iOmL), The filtrate is evaporated either under reduced or at normal pressure. The residue is titurated with water (10mL-25mL), the Producti extracted with orzanic solvents, ic. ether, CHC, of CHCl, and dried (Na,SO,). The filtrate on evaporation gives the desired amino derivatives. Some products are directly converted into the hydrochlor- ide salt with ethereal HCI without evaporation of the ether solution, viel: 31-98%. 24, Nites Reduction of the nitrile group to an alkylamine by complex metal hydrides or catalytic hydrogenation under pressure is a general procedure," Diret conversion ofthe nti group into 4 methyl group often requires drastic conditions."? Recently, a mild direct transformation of aromatic nitriles 12 into the corresponding methyl derivative 13 with ammonium formate vvas reported" (Scheme E), This general procedure is only applicable for reduction of aromatic nitriles to methy! deriv tives , Scheme E SYNTHS Reduction of Nitiles to Methyl Groups; General Procedure: See Synthesis 1982, 1036. 3, Dehalogenation of Aromatic Chlorocarbons Dehalogenation is generally carried out by high pressure cata- Istic hydrogenation, hydride reductions using lithium alumi- num hydride or disobutylaluminum hydride or pyrolysis. Dur- ing our search for a mild reducing agent for the reduction of nitro compounds, we had observed that 2-iodo-4-itrobenz- amide can be reduced and deiodinated to the corresponding 4 aminobenzamide using Raney nickeljammonium formate sy- stem, however no reaction takes place when 10% palladium- {earbon-ammonium formate system was used. We did not explore this further, however, recently similar observation has bbeen made,"* in which various mono- or polychlorinated aromatic compounds 14 or 16, on treatment with ammonium formate in presence of palladium on carbon at room tempera- ture, afforded dehalogenated compounds 18 or 17 (Scheme F), This reaction is very mild and rapid PenciNeansMeoe e # QO : ‘Toa solution ofthe ary] halide (1 mmol) and HCO;NH, (40 5 mmol) in MeOH or AcOH (0 mL), the catalyst 10% PSC (1/8 of the wt. of aryl halide} is added under N atmosphere. The restion progtess is ‘monitored by reverse phase high pressute liquid chromatograph. After completion of the eaction, the catalyst is removed by filtration and the filtrate concentrated under reduced pressure. The produc is isolated either by precipitation with water or by extraction with an organic solvent (CHCI, of E100) 4, Deprotection of Functional Groups 4.1. Deprotestion of Polymer and Carbobenzslony Group from Protect os Peptides Rapid and selective removal of protecting groups under mode- rate seaction conditions is often a necessary step in the area of peptide chemistry. A number of reagents have been developed for this purpose. Recently ammonium formats has been used et severl stages in the synthesis of leucineenkephalin'® for the Feductive cleavage ofthe benzyloxyearbonyl group (Seheme G), Z-Leu-OCiHy-t HeLeu-004Hs-t 8 19 2-Gly-Gly-Phe-Leu-OCiMs-t 20 H-Gly-Gly-Phe-Leu-OCyHart 21 Scheme GFebruary 1988 The yields of final products are > 90% and the reactions are complete within 1 minute at room temperature and ambient pressure. It was shown that deprotection with ammonium Formate is faster than formic acid under idemtical reaction conditions.'® Deprotecton of Protected Peptides; General Procedure: See Synthesis 1980, 923, Farther, ammonium formate has been applied to the simulta- neous deprotection and release of pentapeptide leucine- enkephalin (23) from the Merrifield peptide polystyrene resin 22'7*" under moderate reaction conditions and pressure in & neutral medium (Scheme H). The yields were quantitative Ose HCO Coe-tyt-Giy-Gly-Phe-Leu-OCH,-Polymer _2#utt 0 22 HN Tyr-Gly-Gly-Pha- Leu-oH 2a Scheme H Polymer Deprotection and Removal of Peptides Using Ammonium For- mate, Typical Procedure:!” Chz~Tyr—Gly ~Gly ~Phe -Leu—OCH, Polymer (22: 1.0 is swelled in DMF (12 mL) containing Pé(OAe), (.0g) for 2, Upon addition of 4 solution of HCO,NE, (1.08) in water 0.5m), & deposition of palladium i observed with rapid evolution of gases following a 1 min indaction period. Aer string for 2, the resin ie itered and washed with 50% aqueous AcOH (2 30 mL), The trate is evaporated under reduced pressure at low temperature and the residue 4 purified by column chromatography on Sephadex G-15 using 30% aqueous AcOH as an eluent. The appropriate fractions on evaporation gives lewine- enkephalin acetate (23); yield: 231 mg (94°), 42. Deprotection of O-Beary! Group Benzyl ethers play an important role in carbohydrate chemis- ty. Deprotection of the benzyl group is generally carried out either by catalytic or chemical hydrogenolysis, bromination- hydrolysis or bromination-acetolysis. Formic acid/palladium carbon!” or palladium hydroxide on earbonjeyclohexene?” has been used for deprotection of O-benzyl group, The reported results are variable in both cases. The O-benzyl group in 24 was selectively cleaved by catalytic hydrogenation using 10% palladiumjcarbon and ammonium formate?" as the hydrogen donor (Scheme J). In these reactions glycosidic O-methyl gyoups are unaffected, Cathy _PACCIMCODNMe ert ow 25 Scheme 1 Geavage of O-Benzyl Group; General Procedure: See Synthese 1985. 16, 15. Regioselective Synthesis of 1-Olefins A useful regioselective synthetic method for 1-olefins has been developed.?#* in which various terminal allylic compounds such as allylic esters, phenyl ethers, carbonates, chlorides and vinyl epoxides 26 of 27 were reacted with ammonium formate in the presence of palladium-tributylphosphine complex as a catalyst to afford t-olefins 30 (Scheme J}, Ammonium Formate in Organic Synthesis 3 RO 26 L-i-ocho 28 X= ote 0644, 06046%, 1 Scheme J Tt was also demonstrated that the role of the catalyst palladium-tributylphosphine, is critical. If other catalysts such as. palladium-triphenylphosphine, Pé[P(CjH.)s]4 or Pa(dba) CHCl, -P(OC;H,), are used, the yield of isomeric 2olefins is significantly increased. The best results were ob- tained with palladium-tribucylphosphine. 1-Octene-T-one{30, R = CH CO(CH,),; Typical Procedue:** A mixture of Pés(dba),CHCl, (00128mol), PBuy (0.1 mmol) HCO,NH, (2:mmol and the allyie acetate 26 [R= CH,CO(CH,)3} (1 mmo} i dioxane (3 mL is tired at 100°C for 1 hand then dered (Floris). Removal ofthe solvent followed by elution on silica gel with cthershexane (1:20) gives the product; yield: 79% (100% seletvity. GO), Ally esters 32. were albo converted into the corresponding acids in very good yield 33 using PA[P(C,H.),], and am- ‘monium formate syiem (Scheme K) ° « 8 ato 7 No 22 33 R= GHICHak or CygcH Scheme K In the above reaction the allyl group was removed by hydro- genolysis, but the double bond in the acid molecule remained intact. Other salts of formic acid were also used 10 study the reaction.?? 6. Miscellaneous Applications and other Formic Acid Derivatives Ammonium formate also has been used in ester plasticizers? {and in the synthesis of eopper formate.** Besides ammonium formate, sodium formate and uiethylammonium formate also have been studied in organie synthesis, Sodium formate**in the presence of surfactant has been applied to the preparation of biaryls 3§ from aromatic halides 34 (Scheme L) ax Satan 9 ar a4 35 Scheme L94 S.Ram, R.E,Ehrenkaufer ‘The yield of biaryl is dependent on the surfactant used, which apparently plays an important role in this reaction.?* Cetyltrimethylammonium bromide is the most generally ap- plicable surfactant for a wide variety of compounds. Xylene is, also used as a cosolvent ‘Biaryl General Procedure: See Synthese 1978, 537 Various nitro and eyano aromatic halides 36, 38 were reduced to the corresponding dehalogenated amino and cyano deriva- tives 37, 39, respectively, with triethylammonium formate?” in the presence of palladium/carbon or a soluble triarylphos- phine-palladium acetate catalyst (Scheme M) Q see. § ° : Scheme M Phenyl conjugated and double bond conjugated acetylenes 40 have been reduced with triethylammonium formate using pal= ladium on carbon as a catalyt.** In general cis olefins were obtained in very good yield (Scheme N and 0). O-O~ B= OTC Scheme N ‘The reaction in general leads only to the reduction of the ‘acetylenic bond and not the double bond, however, sometimes completely reduced produets were obtained, petal ‘conc Citarn 42 43 Scheme 0 This method was further extended to the reduction of allylic amine derivatives 442 All reductions give mixture of two isomeric olefins 45 and 46 arising from both direct reduction of the amine carbon atom and addition of hydrogen to the more distant carbon of the double bond with double bond migration aand loss of amino group (Scheme P). This may be duc to a allylic palladium hydride species as an intermediate in the reduction, PacnieomeNs%e Oy eee 45 (9% 46 3% + 002 Scheme P ‘The usefulness of reaction is limited since a mixture of isomeric olefins are produced. The reduction of secondary allylic amine and diallyl amine gave mainly .-ally! formamide, Reduction of Acetylenes and Allylic Amines; General Procedur:?* ‘To a stined minture of the substrate, catalyst and NEt, is added dropwise 97% formic acid at room temperature. The reaction 1s allowed to proceed atthe desired temperature until GC analysis shows that al of the substrate has been reduced ot no further reduction has ‘aken place. The catalyst is removed by filtration and the residue i washed twice with ether. The combined filtrate is washed with disiled water, dried (MgSO,), and evaporated in vacuo to give the desired product ?® Isoprene has been reduetively dimerised with formic acid and triethylamine at room temperature using 1% palladium- ‘organophosphine catalyst.” This dimerization proceeds head 10 tail £0 give monoterpenes in up to 79% yield Recently phenols have been selectively deoxygenated by redue- ing the corresponding aryl trffates with triethylammonium formate in the presence of 2 homogenous palladium catalyst (Scheme Q).° 7. Conclusion ‘The ammonium formate-palladium on carbon is very versatile, selective and rapid method for catalytic hydrogenolysis of wide variety of functionalities. Ammonium formate also has advan- tages of being readily available, inexpensive, stable and non- toxic and can be used in conjunction with either palladium on carbon (or other palladium derivates) or Raney-Nickel catalyst, Moreover it can be added to the reaction in a single portion and products can be easily separated ftom the reaction mixture, Mee would like 10 acknowledge the Department of Radiology, Duke University Medical Center (SR) and NIB Grant NS 14867 (REE) for ‘the financial support ofthis work and Ms. Patricia Gallagher and Ms. Maria Mokan for their eforts in preparing this manuscript Received: 11 January 1987 (1) Johnstone, R.A.W., Wilby, A.HL Chem. Rer. 1985, 85, 129. (2) Zulfani, S.J. Am. Cherm Soe. A941, 65, 3123, (3) Leveart, R. Ber. Dish Chom. Ges. 1885, 18,2341 (4) Walluch, 0. Her. Disch. Chem. Ges. 1891, 24,3992 (9) Moore, ML, Org. React. 1941, 5,301 (6) Chubb, F, Hay. AS. Sandin, R-B. J Amn. Chem. Soc. 1983, 6042, and deferenoes cited therein,February 1988 (7) Mousseron, M., Jacques, R., Zagdoun, R. Bull. Soe. Chim. Fr 1953, 974 (8) Kost, A.N., Grandberg, L1. 2k, Obsohch. Khim. 1985, 25, 1719; C.A. 1956, 50, 5544 (9) Garter, T, Selve, C., Delpuech, J-. Terahedron Lets 1983, 24 1608. (10) Rum, S, Ehrenkaufer, R.E, Tetrahedron Let. 1984, 25, 3415 (U1) Ram, Sy Ehrenkaufer, RE, Spshesis 1986, 133 (12) Rabinowitz, M, ins The Chemisiry of the Cyano Group, Rap "2, (ed,), Interscience Publishers, London, 1970, p. 307. (13) Andrade, 3.0, Maier, W.F, Zapp, L. Sehleyer, Bv.R. Symtesis 1980, 802 (14) Brown, G.R., Foubiser, A. Spmibesis 1982, 1036, (45) Anwer, MK. Spatola, A-F. Tetrahedron Lett. 1985, 26.1381 U6) Anwer, MK. Spatola, A-F. Synthesis 1980, 929. (7) Anwer, MK. Spatola, A-F, Terrahedron Let, 1981, 22,4369 (8) Anwer, MK. Spatola, A-F, Bossinger, C.D. Flanigan, E., Liv, R.C,, Olsen, D.B., Stevenson, D. J. Org. Chem. 1983, 48, 3303, (19) Rao, VS. Peli, A.S. Carbohydr. Res. 1980, 83, 175, Synthetic Applications of Double Functionalization 95 (20) Hanessian, S., Liak, TJ, Vanasse, B. Spnhesis 1981, 296 (Qt) Big, T, Szoi, W. Synthesis 1985, 76. (02) Tsu, J Shimizu, 1, Minar, 1 Chem, Let, 1984, 1017 (23) Teuj J, Yamakawa, T. Tevrahedron Let. 1979, 613. (G4) Hughes, V.L. Kirshendaum, 1. Scheelich, A.A. US Patent 2003477 (1959), Esso Research and Engineering Co, C.A. 1960, 54, 962. (25) French Patent 969024 (1950), Compagnie de produits chimiques et ‘ectrométallugiques Alsi, Froges & Camargue: C.A. 1952, 46, 800, (26) Bamfield, P, Quam, PM. Synthesis 1978, $37 (21) Cortese, N'A, Heck, RIE J. Org, Chem. 1977, 42, 349 references cited therin. (28) Weir JR, Patel, B.A. Heck, RP J. Org. Chem. 1980, 45, 4926, and references cited therein, (29) Neilun, J.P, Laine, R.M., Cortese, N., Heck, R.F. J. Ore. Chem: 1976, 41,3455, (30) Cacti, $, Gat, P.G.. Morera, E., Or 1986, 27, 3541 and -G, Tetrahedron Let