As a Selective Reducing Agent for the Reduction of Imines

Indian Journal of Chemistry Vol. 40B, February 2001, pp. 152-156

Note

Butyltriphenylphosphonium tetraborate The Borch method utilising sodium cyanoborohy­ l4 l5 (BTPPTB) as a selective reducing agent for dride and zinc borohydride is, currently, the most the reduction of imines, enamines and oximes popular way to effect this transformation. Other methods include the use of sodium borohydride and and reductive alkylation of aldehydes or trifluroacetic acid 16 or aqueous sulfuric acid 17, zinc ketones with primary amines in methanol or borohydride'8, zinc-modified cyanoborohydride' 9 and under solid-phase conditions l-benzyl-I-azonia-4-azabicyclo(2.2.2]octane tetrabo­ 20 rate . Use of sodium cyanoborohydride and zinc cya­ Abdol Reza Hajipour*', Iraj Mohammadpoor-Baltorkb & noborohydride risks the presence of residual cyanide Mohammadreza Noroallhi in the product or work-up system. The presence of ·Coll ege of Chemistry, Isfahan University of Technology, Isfa­ acid in the reaction medium restricts its use for mole­ han, Isfahan 84156, IR Iran cules containing acid-sensitive. bOepal1ment of Chemistry, Isfahan University, Isfahan 8 1744, IR Iran The present paper describes the reductive proper­ Received 22 July 1999; accepted (revised) 28 March 2000 ties of b tyltriphenylphoshphonium tetraborate (BTPPTB) 1 for reduction of imines and enamines,

Butyltriphenylphosphonium tetra borate (BTPPTB) 1, gener­ reduction of oximes, reductive alkylation of primary ated as white solid from butyltriphenylphosphonium bromide and and secondary amines with aldehydes and ketones and sodium borohydride, is found to be a selective and versatile re­ reductive methylation of aromatic amines with for­ ducing agent. The reagent in methanol or under solvent-free con­ maldehyde. ditions is very useful for the reduction of imines, enamines and ox imes or reducti ve amination of aldehydes and ketones. Under solvent-free conditions the reactions are faster and the yields of the products are higher.

The modification of sodium borohydride has attracted a great deal of attention recentlyl-II . In general, the modification of the usual reducing ability of the so­ The reduction of imines, enamines and oximes with dium borohydride has led to selective reduction of reagent 1 in methanol proceeded smoothly. The reac­ several functional groups which are otherwise inert to tion was normally completed within 0.2-0.4 hr at sodium borohydride alone. For instance, the reduc­ 2 room temperature and the corresponding amines were tions of acid chlorides to aldehydes . and alkenes to obtained in excellent yields. Under the present condi­ 3 saturated hydrocarbons can be achieved by use of the tions, hydrolysis of imines, enamines and oximes was combination of sodium borohydride with Cu (l) and not observed. The present procedure does not require Co (1) respectively, while such conversions can not pH control, though the reduction with cyanoborohy­ be achieved with sodium borohydride alone. dride occurs at an initial pH 5 (for reduction of imines As an extension of our work in this areal2a we have and enamines) and pH 3-4 (for oximes)l3. In the re­ embarked on a project aimed at selective reduction of duction of oximes with this reagent no trace of over imines, enamines and oximes to the corresponding reduction to the amine and dialkylhydroxylamine was ami nes and hydroxylamines, respectively. We also observed. The experimental results are summarised in tri ed reducti ve ami nation of aldehydes and ketones Tables I and II. The reductive alkylation of primary and reductive methylation of amines to the corre­ and secondary amine with aldehydes and ketones with sponding amines by this reagent. Reduction of imines, reducing agent 1 in methanol proceeded smoothly. enamines and oximes, reductive alkylation of primary The reaction was normally completed within 0.8-\.5 amines with aldehydes and ketones and reductive hr at room temperature and the corresponding amines methylation of aliphatic and aromatic amines with were obtained in high yields. The experimental results formaldehyde is widely used in amine synthesis '2b. 13. are summarised in Tables III and IV NOTES 153

Table I-Reduction of am in es and enamines with red ucing agent,,·b 1

Compd Reaction peri od (hr) Product Reaction peri od (min) bp/mm Hg In-methanol, Yield (%) Under solid-p hase. Yi eld (%) Illp. oC 0 0.4 (90) 0 5 (96) 57-62/2 6 6 c) 0.2 (84) C) 5 (94) 69-72/3 6 6 Q 0.5 (80) Q 7 (88) 53-57/3.5 6 6 0 0.2 (82) 0 6 (92) 67-70/4 Q 0 0 0 0.6 (86) 0 0 10(84) 70-73/2 AAOM ' ~o M e 0.2 (86) 5 (95) 235-39/760 CO CO" M ~D) 0.2 (86) 6 (98) 260-65 I N M ~D)" M,{) MeO 0.3 (76) 8 (88) 111 -14 .~~ 0\1.:0 ".~M e{)

OM (' OMe O~k OMr.' 0.3 (86) 10 (92) 215-17 ""'~ "hH M ,Q 0"'" -~

I I"h- ~: : 0.2 (86) 8 (87) 122-24 :::x:g )"!, i ) .. ""x:g .. -1 n_/ 0.2 (83) 6 (94) oil "'QD?N "'{) ~" t.-h

Heterogeneous reactions that are fac ilitated by sup­ tage of these methods over conventional homogene­ ported reagents on various solid inorganic surfaces ous reacti ons is that they provide greater selectivity, have received attention in recent years21. The advan- enhanced reacti on rates, cleaner products and ma- IS4 INDIAN J. CHEM .• SEC. B, FEBRUARY 2001

Table Il- Reduction of oximes with reducing agent"·b I

Compd Re

CH.1C1-l zC(CH1)=NOf-l 0.4 (SO) Cf-I .1C f-I 2C(Cf-I.1)-Nf-I Of-l 10 (SO) 67 Cf-I lCf-I 1h Cf-I=NOf-l 0.5 (72) Cf-I.l(Cf-I z)2Cf-I-Nf-IOf-l 10 (7 S) 54 CH .1( Cf-I 2),Cf-I=NOH 0.6 (70) Cf-I .1(Cf-I 1),Cf-I-Nf-IOf-l 12 (S9) 62 CH.1 (CH2)6CH=NOH 0.6 (75) CH .1 (CHz)6C HNHOf-l II (92) 74 ar-- Ol l 0.4 (70) a NltOl1 15 (S4) 94 cr NOIl 0.5 (7 5) 0 NII OII 15 (SO) 139 C6H5CH=NOH 0.6 (6S) C6H,CH-NHOH 14 (74) 57 4-NOzC6H4CH=NOH 0.6 (65) 4-N02C(,l-14CI-I-NI-IOH 13 (72) 57 Cr, I-I.\CH(CI-I .1 )=NOI-I 0.5 (70) C6H,CI-I(CH .1 )-NI-IOH 14 (7S) 91

"All yields refer to pure iso lated products. bAli of th e products were fully char

RJ o HN' II + RJ -NH2 reducing agent (1) \ 2 R ~ R 2 methanol, r.1 R'/'R

R2 RJ Re

"All yields refer to pure iso lated products. bA li of th e products were fully ch

Table IV-Reductive methyl ati on of amine with reducing agent •.b 1

Amin e Product Reaction period (hr) Reacti on period (min ) In methanol. Yi eld (%) Under solid-phase. Yi eld (%) Benzylamine N-Methylbenzylamine 1.2 (80) 10(96) Dodecylamine N-Methyldodecylamine 1.0 (82) II (99) Dicyc lohexy lamine N- Methyldi cy lohexylamine 1.3 (69) 13 (91) Ani line N-Meth ylaniline 1.3 (65) IS (94) 4-M ethoxyaniline N-Meth yl-4-methoxyaniline 1.0 (82) II (99) 2-N itroan iline N-Meth yl-2-n itroaniline 0.8 (72) 10 (88) p-Toluidine N-Methyl-p-toluidine 1.1 (71) 12 (93) 4-Bromoaniline N-Methyl-4-bromoaniline 1.2 (68) 14 (89) I-Naphthylamine N-Methyl-I-naphthylamine 1.5 (69) 15 (83)

"A ll yield s refer to pure isolated products. bA li of the products were fully characterised by comparing with known compound s and by their IR and lH NMR spectra. using the reagent 1 in methanol and under solid-phase Reduction of amines, enamines and oximes in conditions. The reduction under solid-phase condi­ methanol. The amine, enamine or oxime (1 mmole) tions provides greater selectivity. enhanced reaction was added to a stirred solution of reducing agent 1 ( 1 rates, cleaner products and manipulative simplicity. mmole, 0.33 g) in methanol (10 mL). The mi xture was stirred at room temperature until TLC sho wed Experimental Section complete disappearance of starting material , which All products were identified by comparison with an required 0.2-0.6 hr depending on the substrate, and authentic samples OR, NMR, and mp). All mps were then the methanol was evaporated under reduced taken on a Gallenkamp melting apparatus and are un­ pressure. Water (50 mL) was then added to the res i­ corrected. Elemental analysis was performed by the due which was extracted with dichloromethane (2x I 5 Research Institute of Petroleum Industry, Tehran, I R mL). The combined extracts were dried over MgS04. Iran. IH NMR spectra were recorded on a Varian EM- Evaporation of the solvent gave amines or hy­ 390 NMR spectrometer operating at 90 MHz, or on a droxylamines. The product was purified by column Varian Unity 250 Fourier Transform NMR spec­ chromatography on silica gel using mixture of ethyl trometer operating at 250 MHz. The spectra were acetate: n-hexane (20:80) as eluent. measured in CDCI) unless otherwise stated, relative to Reductive methylation of primary amines in TMS and mass spectra on a Shimadzu GC-MS-QP methanol. A mixture of amine (l mmole) and for­ 1000PX. maldehyde solution (37%, 1 mmole) was added to a stirred solution of reducing agent 1 (1 mmole, 0.33 g) Synthesis of reducing agent 1. To a solution of in methanol (10 mL). The mixture was stirred at room butyltriphenylphosphonium bromide (19.97 g, 50 temperature until TLC showed complete di sappear­ mmoles) in methanol (50 mL), was added sodium ance of starting material, which required 0.8- 1.4 hr borohydride (1.89 g, 50 mmoles) in one portion. The depending on the substrate, and then the methanol reaction mixture was stirred at room temperature for was evaporated under reduced pressure. Water (50 90 min. The resulting white solid product was col­ mL) was then added to the residue which was ex­ lected. washed with water (10 mL) and dried in a tracted with dichloromethane (2x 15 mL). The mi xture desiccator under vacuum over calcium chloride to was worked-up and purified as above. yield 16.38 g (98 %) of white solid product, mp 270- Reduction of amines, enamines and oximes un­ n 0c. ' H NMR: 8 7.90-7.50 (m, 15 H), 3.5 (d, J = der solid-phase conditions. A mortar was charged 25.6 Hz, CHz-P), 1.8 (m, 4 H), 0.98 (t, 3 H). 13C with amine, enamine or oxime (l mmole) and reduc­ NMR: 8 133.50. 133 .20, 130.20, 129.60, 129.40, ing agent 1 (1 mmole, 0.33 g). The mixture was 128. 10. 127.70, 127.2, 108.30 (d, J = 85.5 Hz, P­ ground at room temperature with a pestl e until TLC CH2)' IR (KBr): 1298, 1269, 1098, 1060, 700, 658, showed complete di sappearance of starting material. 590, 546 cm- I; MS (CI): mlz 334 (100, M+) ;' Anal, The mixture was then extracted with acetone (2xlO Calcd for C22H28BP: C, 79.06; H, 8.44. Found: C, mL). Evaporation of the solvent gave amines or hy­ 78.80; H, 8.80 %. droxylamines. The product was purified by column 156 INDIAN J. CHEM., SEC. 13, FEB RUARY 200 1

chromatography on si li ca gel using mi xture of eth yl 10 Eg li R A, Hell' Clrilll ACla. 5 1, 1968. 2090. acetate: II-h exane (20:80) as elu ent. II Firo ll zabadi H & Afshari far G R. Bill/ Cirelli Soc JplI , 68, Reductive methylation of amines under' solid­ 1995.2662 12 (a) Hajipour A R, Moharn madpoor-Bal Lo rk & Rah i A. Ill dia ll phase conditions. A mortar wa charged with amine J Cir elli. (in press). ( I mmole), form aldehyde soluti on (3 7%, I mmole) (b) Lane C F, SYllllresis, 1975, 135. and reducing agent 1 ( I mmole, 0.33 g) . The mixture 13 (a) HlItchi ne R 0 & Natale N. Oq: Prep Proced 1111 . II , was ground at room temperature wi th a pestle until 1979, 20. TLC showed complete di sappearance of starting ma­ (b) Ahm ed F, Abdel-Majid, Maryanoff C A & Carson K G, terial. The mixture was then extracted wi th acetone Telralredroll Lell. 3 1. 1990.5595 (2x I 0 mL). Evaporation of the solvent gave amines. 14 Borch R F, Bernstein M D & Durst H D, J Alii Cirelli Soc, 93,1971. 2897. The product was purified by co lumn chromatography 15 I3hattach aryya S, Chattelj ee A & Duttachowdhury S K. J on si li ca gel usin g mixture of ethy l acetate: n-hexane Cirelli Soc Perk ill Trails. I, 1994, i. (2 0:80) as elu ent. 16 (a) Gribbk G W, Lord P D. Skotnicki J. DietzS E, Eaton J T & John son J L. J Alii Cir elli Soc, 96, 1974.78 12. Acknowledgement (b) Gribble G W. Jas in ski J M, Pelii cone J T & Panetta J A. Parti al support of thi s work by th e Isfahan SYllllr esi.l'. 1978.766. Univers ity of Tech nol ogy Research Council is 17 Verdo G, Gilllllanin i A G, StraZlo1ini P & Poiana M, SYllllre­ sis. 1993, 12 1. gratefully acknowledged. 18 Kotsll ki H. Yoshimura N. Kadota I, Ushio Y & Ochi M, Syllliresis. 1990, 40 1. Rcfet'ences 19 130 ldrini P, Panlln zio M & Umani -Ronch i A. Syllllresi.l'. 1 (a) Corey E J. Anderson N H. Carlson R M, Paust J, Vedj s E, 1974.261. Vlattas I & Winter R E K, J Alii Cirelli Soc, 90, 1968,3245. 20 Hajipour A R. Telralredroll. 53, 1997.1 6883. (b) Nakata T & Oi shi T, Telralr etlroll Lell. 2 1, 1980,1 64 1. 2 1 l3ann G, LO llpy A. Maj doub M, Gutierrc:z E & Rui z- Ilitzky 2 Fleet G W J & Harding P J C. Telralretlroll Lell. 20, 1979, E, Telralr edrOIl. 46. 1990.5167. 975 . 22 Haji pour A R. Mohalllmadpoor-l3aJt ork I & Nikbaghat K. 3 Chun g S-K. J Org Gelll, 44, 1979. 10 14. SYIlIIr COIIIIII/IIl .. 29, 1999. 1697. 4 Tsuda Y, Sano T & Watanabe H. SYllllr esis, 1977.602. 5 Satoh T. Mitslld N, Ni shiki M, Inoue Y & Ooi Y, Cir elli 23 Haj ipour A R, Malia kpour S E & Im anzadeh I, J Cirelli Re­ searclr(S). 1999,228. Plrarlll BIII/. 29, 1981, 1443. 6 John stone R AW & Telford R P, J Cirelli Soc Cir elli CO III - 24 Hajipour A R. Mal lakpour S E & Imanzadeh 1. Cir elli Lell. 1111111. 1978.354. 1999,99. 7 Luche J-L, J Alii G elll Soc, 100, 1978.2226. 25 Hajipour A R, Illdiall J Gelll, 3613. 1997. 1069. 8 Nishiki M. Miyataka H. Niiono Y, Mit sll o N & Satoh T. 26 I-iajipour A R. Mallakpour S E & Imanzadeh I. Telralr edroll. Telralr edroll Lell. 23, 1982, 193. 55, 1999, 23 1 1. 9 Lin S-T & Roth J A. J Org Gelll. 44, 1979,309. 27 Hajipouf A R & Islami F, Illdiall J Chelll. 3813, 1999.461.