Tetraalkylammonium Trihydridocyanoborates. Versatile, Selective Reagents for Reductive Aminations in Nonpolar MediaJOC (1981), 46, 3571-3574.Abstract:
Tetrabutylammonium cyanoborohydride or the combination of sodium cyanoborohydride with Aliquat 336 provides useful, convenient reagents for reductive amination of aldehydes and ketones in aprotic or protic media.Trihydridocyanoborate (cyanoborohydide)
1 is well established as a mild, selective, acid-stable reducing agent for a variety of conversions including aldehydes and ketones to alcohols,
2 tosylhydrazones,
3 polar alkenes,
4 and alkyl halides
5 to hydrocarbons, and numerous carbon-nitrogen pi-bond derivatives (imines, oximes, enamines) to amines.
2 This latter transformation has been particularly exploited as an excellent procedure for the reductive amination of aldehydes and ketones.
1,2,6 However, the commercial available sodium derivative suffers the limitation that solubility is restricted to a few polar protic (water, low molecular weight alcohols), aprotic (dimethylsulfate, HMPA), or ether (THF, diglyme) solvent.
8 The reagent is almost totally insoluble and unreactive in most other useful solvents including DCM, chloroform, aromatic and aliphatic hydrocarbons, and diethyl ether.
To circumvent the solubility problem and hence augment the utility of cyanoborohydride, we have explored the use of the tetrabutylammonium derivative
9 and other phase-transfer techniques
10 for typical cyanoborohydride reductions in nonpolar media.
5,9,11 This communication reports the successful application of phase transfer to reductive amination, which extends the useful media for these conversions to include most common organic solvents, including DCM, hexane, benzene and diethyl ether.
Tetrabutylammonium cyanoborohydride (TBACB), prepared as previously described,
9,11 is an air and moisture-stable crystalline solid (MP 144-145*C) which, in contrast to the sodium counterpart, is not hygroscopic. Phase transfer was also used to solubilize sodium cyanoborohydride by employing Aliquat 336, an inexpensive liquid reagent composed of methyltrialkylammonium chlorides with C
8-C
10 chains. Successful reductive aminations were obtained under a variety of conditions, but the most convenient consisted of simply dissolving the aldehyde or ketone (10mmol), amine (60mmol), and TBACB (7mmol) or sodium cyanoborohydride (7mmol) plus Aliquat 336 (7mmol) in 21ml of solvent followed by addition of HCl (20mmol) conveniently added as a 2.5-5.0N solution in methanol or other solvent. Approximately 1g of 4A molecular sieves was added (to absorb water formed), and the mixture was stirred at ambient temperature. Progress of the reactions could be followed by monitoring the disappearance of the carbonyl by IR. Upon completion, isolations were accomplished in standard fashion (experimental), the products purified by short-path distillation, and identified comparison (IR and/or NMR) with authentic samples.
The results for a range of carbonyls and amines are presented in Table I. Examples using the standard method (sodium cyanoborohydride, methanol, 2-3days)
2 are included for comparisons. As illustrated, aromatic and aliphatic aldehydes and ketones react readily with unhindered primary and secondary amines to afford respectable to excellent isolated yields of amines in reasonable times, usually 2.5-24 hours for aldehydes and 24-48 hours for ketones. Two limitations were encountered. Relatively hindered secondary amines (i.e., diethylamine) reacted only reluctantly with ketones and gave inferior yields (<40%) of amine products. Also ammonium and tetraalkylammonium salts generally failed to react in aprotic solvents in which solubility is a problem. In such cases, methanol solvent is clearly superior.
2General Reaction Procedure:The general reaction procedure is illustrated for the preparation of N-cyclohexylpyrrolidine. To a solution containing pyrrolidine (4.26g, 60mmol) in 21ml of DCM was added HCl (20mmol, 8ml of a 2.5N solution in methanol) followed by cyclohexanone (0.98g, 10mmol), sodium cyanoborohydide (0.44g, 7mmol), and Aliquat 336 (2.93g, 7mmol). Approximately 1g of 4A molecular sieves was added, and the mixture was stirred at RT for 48hours. The mixture was filtered, the filtrate acidified (methyl orange indicator), and the solvent removed on a rotary evaporator. The residue was taken up with 10ml of water and extracted with 3x20ml portions of ether (discarded). The aqueous phase was basified (solid KOH, phenolphthalein indicator), 20ml of brine was added, and the mixture was extracted exhaustively with ether.
These combined extracts were dried (magnesium sulfate), concentrated, and distilled in a Kugelrohr apparatus to yield 1.43g (94%) of N-cyclohexylpyrrolidine, identified by comparison (IR) with an authentic sample. GLC analysis indicated >98% purity.In conclusion, phase-transfer techniques greatly augment the utility of cyanoborohydride for reductive aminations of carbonyls and complement analogous conversions in protic media.
Acknowledgement: We gratefully thank The National Science Foundation for support of our programs on hydride chemistry.
Reference:(1)For reviews of cyanoborohydride chemistry, see (a) Hutchins, R. O.; Natale, N. R.
Org. Prep. Proced. Int., (1979), 11, 201. (b) Lane, C.F.
Synthesis, (1975), 135; Lane, C.F.
Aldrichemica Acta, (1975), 8,3.
(2) Borch, R.F.; Bernstein, M.D.; Durst, H.D.
JACS, (1971), 93, 2897. Recently, the intermediacy of iminium ions in certain reductive aminations has been questioned: Tadanier, J.; Hallas, R.; Martin, J.R.; Stanaszek, R.S.
Tetrahedron Letters, (1981), 37, 1309; Kapnang, H.; Charles, G.; Sondengam, B.L.; Hemo, J.H.
Tetrahedron Letters, (1977), 3469.
(3)Hutchins, R.O.; Maryanoff, B.E.; Milewaki, C.A.
JACS, (1975), 40, 923.
(4) Hutchins, R.O.; Rotstein, D.; Natale, N.R.; Fanelli, J.; Dimmel, D.
JOC, (1976), 41, 3328.
(5) Hutchins, R.O.; Kandasamy, D.; Maryanoff, C.A.; Masilamani, D.; Maryanoff, B.E.
JOC, (1977), 42, 82.
(6)
Other reagent systems recently introduced for reductive amination include: (a)potassium hydridotetracarbonylferrate, Bodrini, G.P.; Panunzio, M.; Umani-Ronchi, A.
Synthesis (1974), 261;
(b) NaBH
4/H
2SO
4, Giumanini, A.G.; Chiavari, G.; Musiani, M.M.; Rossi, P.
Synthesis, (1980), 743;
(c) the Leukart reaction; see, for example, Baeh, R.D.
JOC, (1968), 33, 1647.
(d) NaBH
4 in carboxylic solvents, Schellenburg, K.A.
JOC, (1963), 28, 3259; Gribble, G.W.; Lord, P.D.; Skotnicki, J; Dietz, S.E.; Eaton, J.T.; Jonson, J.L.
JACS, (1974), 96, 7812; Marchini, P.; Liso, G.; Reho, A.; Liborate, F.; Moracci, F.M.
JOC, (1975), 40, 3453.
(e) ion-exchange resin supported BH
3CN
-, Hutchins, R.O.; Natale, N.R.; Taffer, I.M.
J. Chem. Soc. Commun., (1978), 1088.
(7) From Alfa or Aldrich Chemical
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Wade, R.C.; Sullivan, E.A.; Bershied, J.R.; Purcell, K.F.
Inorg. Chem., (1970), 9, 2146.
(9) Hutchins, R.O.; Kandasamy, D.
JACS, (1973), 95, 6131; a number of other tetraalkylammonium cyanoborohydrides are also readily available: Reparasky, J.E.; Weidig, C.; Kelly, H.C.
Syn. React. Inorg. Met-Org. Chem. , (1975), 5, 337.
(10) For excellent, general reviews of phase-transfer reactions, including reductions, see Weber, W.P.; Gokel, G.W. “Phase Transfer Catalysis in Organic Synthesis”; Springer-Verlag: New York, (1977),; Keller, W.E. “Compendium of Phase-Transfer Reactions and Related Synthetic Methods”; Fluka AG, Ch-9470 Buchs, Switzerland, (1979).
(11) Hutchins, R.O.; Kandasamy, D.
JOC, (1975), 40, 2530.
Would somebody please pick up and post the articles in Reference (6) (a) and (e)