Studies on the reduction of beta-enamino ketones

Abstracts

Reduction of beta-enamino ketones 1 with NaBH(OAc)3 in glacial acetic acid gave beta-amino ketones 3 in 65% to 67% yield. These data and others observed in the reduction of beta-enamino ketones 1 to preferentially syn gamma-amino alcohols 2 with NaBH4/HOAc suggest that in this last reaction we have firstly the reduction of the beta-enamino ketones 1 to produce the beta-amino ketones 3, and then this compound is reduced to the gamma-amino alcohols 2. We can say from this results that the diastereosselectivity of the reduction of beta-enamino ketones 1 to mainly syn gamma-amino álcohols 2, can be analysed as a competition between a chair-like transition state and a boat-like transition state, obtained from the beta-amino ketones 3.

amino alcohols; enamino ketones; amino ketones; Mannich base

A redução de beta-enamino cetonas 1 com NaBH(OAc)3 em ácido acético glacial produziu beta-amino cetonas 3 em 65% a 67% de rendimento. Esses resultados, juntamente com outros, obtidos nas reduções de beta-enamino cetonas 1 a gama-amino álcoois 2, preferencialmente syn, com NaBH4/HOAc, sugerem que o curso reacional desta última reação passa inicialmente pela redução de beta-enamino cetonas 1 a beta-amino cetonas 3 e estas são reduzidas posteriormente a gama-amino álcoois 2. Com esses resultados podemos dizer que a diastereosseletividade da redução de beta-enamino cetonas 1, a gama-amino álcoois 2 dando preferencialmente produtos syn pode ser analisada como o resultado de uma competição entre um estado de transição tipo bote e um estado de transição tipo cadeira, obtidos a partir das beta-amino cetonas 3.

SHORT REPORT

Studies on the reduction of b-enamino ketones

Melina A. Machado; Maria Inês N. C. Harris; Antonio C. H. Braga^*

Instituto de Química, Universidade Estadual de Campinas CP 6154, 13084-971 Campinas-SP, Brazil

ABSTRACT

Reduction of b-enamino ketones 1 with NaBH(OAc)₃ in glacial acetic acid gave b-amino ketones 3 in 65% to 67% yield. These data and others observed in the reduction of b-enamino ketones 1 to preferentially syn g-amino alcohols 2 with NaBH₄/HOAc suggest that in this last reaction we have firstly the reduction of the b-enamino ketones 1 to produce the b-amino ketones 3, and then this compound is reduced to the g-amino alcohols 2. We can say from this results that the diastereosselectivity of the reduction of b-enamino ketones 1 to mainly syn g-amino álcohols 2, can be analysed as a competition between a chair-like transition state and a boat-like transition state, obtained from the b-amino ketones 3.

Keywords: amino alcohols, enamino ketones, amino ketones, Mannich base

RESUMO

A redução de b-enamino cetonas 1 com NaBH(OAc)₃ em ácido acético glacial produziu b-amino cetonas 3 em 65% a 67% de rendimento. Esses resultados, juntamente com outros, obtidos nas reduções de b-enamino cetonas 1 a g-amino álcoois 2, preferencialmente syn, com NaBH₄/HOAc, sugerem que o curso reacional desta última reação passa inicialmente pela redução de b-enamino cetonas 1 a b-amino cetonas 3 e estas são reduzidas posteriormente a g-amino álcoois 2. Com esses resultados podemos dizer que a diastereosseletividade da redução de b-enamino cetonas 1, a g-amino álcoois 2 dando preferencialmente produtos syn pode ser analisada como o resultado de uma competição entre um estado de transição tipo bote e um estado de transição tipo cadeira, obtidos a partir das b-amino cetonas 3.

Introduction

Recently, we reported an easy and efficient method to produce g-amino alcohols 2 by reduction of b-enamino ketones 1 with NaBH₄ in glacial acetic acid, which has been sucessfully used in our laboratory.¹ Our results showed that the reaction of b-enamino ketones 1 with NaBH₄ in glacial acetic acid (3 hours at room temperature) produces a mixture of syn/anti g-amino alcohols 2 in 70% to 98% yield with diastereomeric excesses preferentially for the syn product, from 44% to 90%. The use of NaBH₄ in a carboxylic acid medium is well known,² but its use in the reduction of b-enamino ketones 1 has not been explored. To continue our studies on the reduction of b-enamino ketones 1, and to understand the diastereoselectivity observed in the reduction to g-amino alcohols 2 and the real reducing agent, we wish to report herein our results obtained with the reduction of b-enamino ketones 1 using NaBH(OAc)₃/HOAc.

Results and Discussion

The reaction of NaBH₄ with neat carboxylic acids leads to the formation of acyloxyborohydrides.² Reaction with glacial acetic acid leads to the formation of acetoxyborohydrides of different hydride-donating abilities. Presumably the reactivity order (^–BH₃OAc > ^–BH₂(OAc)₂ > ^–BH(OAc)₃) is a consequence of both the inductive electron-withdrawing ability of the acetoxy group and the steric bulk surrounding the B-H bond.³ Although the reaction of b-enamino ketones 1 with NaBH₄ in glacial acetic acid for 3 hours at room temperature leads to products from total reduction (g-amino alcohols 2),¹ under the same conditions, using NaBH(OAc)₃ as a reducing agent we have the Mannich base 3 as a product (Scheme 1, Table 1). These results are obtained when we add comercial NaBH(OAc)₃ to a solution of b-enamino ketone 1 in glacial acetic acid or when firstly we add NaBH₄ to glacial acetic acid and then add the b-enamino ketones 1,^4,5 and shows that in the reduction of the b-enamino ketones 1 to g-amino alcohols 2, the reducing agent is not the NaBH(OAc)₃ as it is normally interpreted in this type of reaction.⁷ These data imply that sodium borohydride added directly to acetic acid, as it is used in the total reduction of b-enamino ketones 1 to g-amino alcohols 2, does not quantitatively give sodium triacetoxyborohydride.⁶

Early information showed that, when the reduction reaction of b-enamino ketones 1 to g-amino alcohols 2 with NaBH₄/HOAc is carried out without temperature control, the reaction produces the corresponding a,b-unsaturated ketone, while at 0 °C (using hexane/HOAc, CH₂Cl₂/HOAc or HOAc as solvent) the product is a mixture of reactant 1, g-amino alcohol 2 and the corresponding Mannich base 3.¹ This information suggests that the Mannich base 3 acts as an intermediate in this reaction. The parcial reduction of b-enamino ketones 1 to b-amino ketones 3 with NaBH(OAc)₃/HOAc and the observation in some cases the corresponding a,b-unsaturated ketones reinforces this suspicion. The b-amino ketones 3 obtained are very unstable and decompose rapidly to the corresponding a,b-unsaturated ketones. They were immediately analysed on a Shimadzu GC/MS Class 500 chromatograph equipped with a Simplicity-1 (SUPELCO) column. All the chromatograms presented only one compound with the MS showing a typical fragmentation, as seen in Figure 1 and Table 2.

Another important observation is that it is not possible to reduce 3-(N-benzylamino)-2-cyclohexen-1-one using either NaBH₄/HOAc or NaBH(OAc)₃/HOAc.

In conclusion, these observations suggest that in the reduction of b-enamino ketones 1 to g-amino alcohol 2 we have firstly the reduction of the b-enamino ketones 1 to b-amino ketones 3, then this compound is further reduced to the g-amino alcohols 2 (Scheme 2). The stereochemical course of these reductions, producing preferentially the syn-g-amino alcohols 2, may be rationalised via the different energies of the diastereomeric transition states resulting in a competition between a chair-like transition state and a boat-like transition state (Scheme 3), when the syn product is obtained by the lower energy route.

Experimental

General procedure to obtain b-amino ketones (3)

To a solution of b-enamino ketone (1, 1 mmol) in glacial acetic acid (6 mL), was slowly added NaBH(OAc)₃ (4 mmol). The reaction was kept at 18-20 ºC. The reaction was stirred for 3 hours, and then neutralized with an aqueous solution of 30% NaOH (approximately 12 mL) in an ice bath. The reaction mixture was extracted with CH₂Cl₂ and the organic phases were combined, dried over MgSO₄, and concentrated. The products were immediately analysed.

Acknowledgments

The authors thank FINEP-Financeira de Estudos e Projetos for financial support, FAPESP-Fundação de Amparo à Pesquisa do Estado de São Paulo for a scholarship to Melina A. Machado, Dr. Ronaldo Aloise Pilli for reagents and lab facilities and Prof. Dr. Carol H. Collins for her kind attention in revising this manuscript.

References

1. Harris, M. I. N. C.; Braga, A. C. H.; J. Braz. Chem. Soc. 2004, 15, 971; Harris, M. I. N. C.; Ph.D. Thesis, Universidade Estadual de Campinas, Brazil, 1993; Braga, A. C. H.; Harris, M. I. N. C.; Br PI 9.502.467-0, 1995. (CA 128:243740).

2. For a comprehensive review of uses of borohydrides in carboxylic acid media see: Gribble, G. W.; Nutaitis, C. F.; Org. Prep. Proced. Int. 1985, 17, 317; Gribble, G. W.; Chem. Soc. Rev. 1998, 27, 395.

3. For a better understanding of this reactivity, theoretical studies are in progress.

4. When sodium borohydride is added to excess acetic acid, hydrogen is liberated rapidly. The species in this reaction has been suggested to be sodium triacetoxyborohydride.

5. Marchini, P.; Liso, G.; Reho, A.; J. Org. Chem. 1975, 40, 3453.

6. Evans, D. A.; Chapman, K. T.; Carreira, E. M.; J. Am. Chem. Soc. 1988, 110, 3560.

7. Palmieri, G.; Cimarelli, C.; Arkivoc 2006, 104.

Received: March 28, 2006

Published on the web: August 30, 2006

FAPESP helped in meeting the publication costs of this article.

Publication Dates

• Publication in this collection
  29 Jan 2007
• Date of issue
  Dec 2006

History

• Accepted
  30 Aug 2006
• Received
  28 Mar 2006