Tetrahedron Letters,Vol.25,No.32,pp Printed in Great Britain 3415-3418,1984 0040-4039/84 $3.00 + .OO 01984 Pergamon Press Ltd. A GENERAL PROCEDURE FOR MILD AND RAPID REDUCTION OF ALIPHATIC AND AROMATIC NITRO COMPOUNDS USING AMMONIUM FORMATE AS A CATALYTIC HYDROGEN TRANSFER AGENT Siya Ram and Richard E. Ehrenkaufer" Cyclotron/PET Facility, Division of Nuclear Medicine The University of Michigan Medical School, Ann Arbor, Michigan 48109 ABSTRACT Various aliphatic and aromatic nitro compounds were selectively and rapidly reduced to their corresponding amino derivatives in very good yield using anhydrous ammonium formate as a catalytic hydrogen transfer agent. Selective and rapid reductLon of nitro compounds is still area of considerable synthetic interestl, particularly when a molecule has several other reducible moieties. Numerous new reagents*-l4 have been developed for reduction of aromatic nitro compounds, however little attention has been paid to the reduction of aliphatic nitro compound&ry,S, which are traditionally reduced by high pressure catalytic hydrogenation15,16* In the past 30 years catalytic transfer hydrogenation 17-** has demonstrated great potential value in organic and biological chemistry. Cyclohexene/Pd-Chas been most widely studied. Recently, ammonium formate has been successfully employed as a catalytic hydrogen transfer agent in peptide chemistry for deprotection23-24instead of cyclohexene. Reduction of axides and cyano groups26 to the corresponding amines and methyl group has also been reported in the recent literature. In our ongoing program, we were interested in the radioisotopicsynthesis of llC-amino acids (llC-half life = 20.4 min) via nitro acid intermediates. We have thus examined several classes of chemical reducing agents for e.g. FeS04/NHAOH, Cyclohexene/Pd-C, NH%-NH%/Ra-Ni, Zn/AcOH, etc., however these systems failed to yield the amino acid. In this paper we wish to report a mild, simple, rapid and selective reduction of aliphatic and aromatic nitro compounds to the corresponding amino derivatives using ammonium formate (Scheme-I). SCHEME I HCO%NH4 R - NO2 A R - NH% 10% Pd-C, CH30H I R.T. II R = alkyl or aryl A typical experimental procedure for conversion of I to II is as follows. 3415 (1) 3416 TABLE I. Reduction -- of alphatic and -No. Nitro Compound __- aromatic --__ nitro compounds to corresponding ~----___- amines. I___----- Reaction time in min. Productb --_ Yielda % __II_________ 1 CH3CH2CH2N02 < 30 CH3CH2CH2NH2.HC1 31= 2 CH3CH2CH2CH2N02 < 20 CH3CH2CH2CH2NH2.HCl 49c 3 (CH3)2CHCH2CH2N02 < 40 (CH3)2CHCH2CH2NH2.HCl a2 4 C2H502CCH2N02 20 C2H502CCH2NH2.HCl 64 5 HOOC(CH2)2N02 20 -OOC(CH2)2NH3+ 98 6 CB302C(CH2)3NC2 20 CH302C(CH2)3NU2 al 7 CH302CCH2CH2CH(CH3)N02 15 CH302CCH2CH2CH(CH3)NH2 75 and 5-methyl-2-pyrrolidinone a p-02NC6H4C02B 5-10 p-H2NC6H4C02H 52d 9 4-H3COC6H3(3-N02)C02H 5-10 4-H3COC6H3(3-NH2)C02H 75d 10 P-O~NC~H~CH~CO~H 5-10 P-H~NC~H~CH~CO~H 86 11 ~-02NC6H4C02CH3 5-10 p-H2NC6H4C02CH3 a9 12 C6B5NO2 3-5 C6H5NH2 76 13 0-FC6H4N02 3-5 o-FC6H4NH2 70 14 p-H3COC6H4NO2 3-5 p-H3COC6H4NH2 93 15 4-H3CC6H3(2-N02)NH2 3-5 3,4-(NB2)2C6B4CB3 16 p-02NC6H4CH2CrN 120 p-H2NC6H4CH2CsN a5 17 2-B,NC6H3(5-NO,)COC6H5 15 2,5-(NH2)2C6H3COC6H5 91 ia m-O2NC6H4CH2NHC(=NH)NH2 25 wH~NC~H~CH~NHC(=NH)NH~ 70 19 2-I-C6H3(4-N02)CONH2 60 p-H2NC6H4CONH2 31e 20 2-H3C-5-N02-imidazole --- Partial reduction, __---__-__ (a) Isolated yields (b) Products were with rapid product decomposition. -_--------~--------~ are based on the single experiment characterized 79 by comparison with and yields were not optimized; authentic samples (IR, lH-NMR, TLC and m-p.); (c) The low yields n-butylamine (d) These were of aliphatic obtained of p-aminobenzoic reaction ing product by trituration acid quired for such water (e) No amines are due b.p. 78") and their volatile with small amount is due to its partial soluble to low boiling of water, solubility (n-propylamine b-p. 48", the low yield in water. Modified in the case workup is re- products; takes place using Pd-C as the catalyst. is the deiodinated points nature; amine, When Raney-Nickel p-aminobenzamide. is used the result- 3417 To a stirred suspension in dry methanol The resulting temperature reaction layer converted argon, on evaporation into the HCl-salt the catalyst gave The residue solvent In benzene cases of iodinated no reaction was the desired aromatic that iodinated compounds m-Nitrobenzylguanidine benzylguanidine CH30H system corresponding 18, yield. amino derivative. evaporation These however of nitro-compounds of other nontoxic the advantages and can be used in conjunction it may be added to the reaction amines speciFically products were The directly In most cases the reaction is time was 120 -19 and 1-iodo-3-nitrowith 2, p-aminobenzamide. reduction of These observations in cases where gKOUpS functional of being readily with either Pd-C yielding reducing reduced to 5-methyl-2-pyrolidi- inexpensive, or Raney-Nickel catalysts. can be easily be of general rapid mild reduction system for wide variety for e.g. -C f N, > C = 0, etc. available, and products will therefore successfully data. and selective in a single portion procedure 7_ was also occurred spectroscopic a rapid versatile in the presence This yielding or the Pd-C catalyst. partial cyclization formate mixture. Some as catalyst methyl-4-nitropentanoate Ammonium the reaction reduced (10 mL - 25 mL), product 2-iodo-4-nitrobenzamide using Raney-Nickel by IR and IH-NMR also has room through a celite either under cyanide 16, the reaction completion Occurred, Although results demonstrate at of ether layer. is shown in Table I. may deactivate amino acid ester, none, which was confirmed portion. stirred which was unable to be reduced to the corresponding m-aminoof conditions 27 , was successEully reduced by 10% Pd-C/HC02NH4 - in the variety in 70% with water without systems, the nitro group as well as deiodination suggest in a single was by filtration was evaporated was triturated procedure observed, (23 mmol) effervescent) was removed filtrate over within 3-40 min, however for p-nitrobenzyl min. and (i.e. ether, CH2C12 OK CHC13) and dried over Na2S04. with ethereal-HCl The scope of this new general (5 mmol) and 10% Pd-C (0.2 - 0.3 g) for-mate was added exothermic (10 mL). The resulting with an organic nitro compound ammonium (slightLy with dry methanol pressure. was extracted organic mixture for 3-40 min under pad and washed at normal of an appropriate (10 ti), anhydrous stable and MOreoveK, separated from use fOK the preparation of is required. ACKNOWLEDGMENTS Research was supported by NC1 Training Graut #5-T32-CA09015-08 and by NINCDS grant #PO1 NS15655-04. REFERENCE 1) R.E. Lyle and J.L. LaMattina; 2) P.J. Romaniuk, Synthesis; 3) N.A. Cortese 4) Y. Akita, M. Inaba, H. Uchida 726 (1974). T.L. Ho and C.M. Wang; D.W. Hughes, R.J. Gregoire, T. Neilson ibid. 45 (1974). and R.A. Bell; .J. Am. 3969 (1978). and R.F. Heck; E.T. Sabourin J. Org. Chem. 5, 3491 (1977). and A. Ohta; Synthesis 5) A. Onochenko, 6) L.B. Din, J.M. T,indley and 0. Meth-Cohn; and C.M. Selwitz; 7) A. Osuka, H. Shimizu and H. Suzuki; 792, (1977). J. Org. Chem. 5, Synthesis Chem. Letters. 23 (1978). 1373 (1983). 3671 (1979). Chem. Sot. 100, 3418 8) J. George 9) A. Ono, H. Sasaki and F. 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