Tetrahedron Letters 52 (2011) 129–132

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Tetrahedron Letters

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Direct Leuckart-type reductive amination of aldehydes and ketones: a facileone-pot protocol for the preparation of secondary and tertiary amines

Danielle O’Connor, Ashley Lauria, Steven P. Bondi, Shahrokh Saba ⇑Department of Chemistry, Fordham University, Bronx, NY 10458, USA

a r t i c l e i n f o

Article history:Received 12 July 2010Revised 29 October 2010Accepted 1 November 2010Available online 5 November 2010

Keywords:Reductive aminationSecondary aminesTertiary aminesAldehydesKetones

0040-4039/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.tetlet.2010.11.006

⇑ Corresponding author. Tel.: +1 718 817 4440; faxE-mail address: saba@fordham.edu (S. Saba).

a b s t r a c t

A high-yielding and facile one-pot Leuckart-type reaction for rapid access to a number of 2� and 3�amines is described.

� 2010 Elsevier Ltd. All rights reserved.

In modern organic synthesis, the direct reductive amination(DRA)1 of aldehydes and ketones is a powerful and highly attrac-tive protocol for the synthesis of primary, secondary, and tertiaryamines.2 Its one-step procedure offers operational convenienceand avoids preformation or isolation of the imine or iminium inter-mediates prior to their reduction. The selective reduction of thein situ formed C@N bond and the stability of the reducing agentunder the reaction conditions, which are often acidic, are criticalto the overall success of the process. Catalytic hydrogenationmethods,3 both economical and eco-friendly, are effective for DRAsbut are not compatible with substrates with reducible moieties,such as cyano4 and nitro5 groups, and may yield alcohols asby-products. Among metal hydride reducing agents, sodium cya-noborohydride (NaBH3CN)6 and sodium triacetoxyborohydride(NaBH(OAc)3),7 both commercially available, have been widelyused. Sodium cyanoborohydride is highly toxic and formation oftoxic by-products, such as HCN and NaCN create problematic dis-posal issues and may contaminate the product.8 Other drawbacksinclude the need to use a fivefold excess of the amine and slowreaction rates with aromatic ketones and amines of lower basicity.Sodium triacetoxyborohydride, though less toxic, is flammable andwater-reactive, and similar limitations are encountered with aro-matic, a,b-unsaturated, and sterically hindered ketones.7a To over-come such limitations, a variety of other reductant systems,though not as widely used, have been developed. The majority ofthese reagents employ a catalyst combined with a reducing agent.9

ll rights reserved.

: +1 718 817 4432.

An alternative DRA approach for the preparation of amines isthe Leuckart reaction,10 whereby an aldehyde or a ketone is heatedin the presence of ammonium formate11 or formamide,12 or mix-tures of formamide and formic acid.13,14 The product of the Leuck-art reaction is often the formyl derivative of the desired amine,11–13

which must be hydrolyzed with acid. This requirement makes theLeuckart reaction unsuitable for substrates with acid-sensitivemoieties. Ingersoll et al.15 improved the original Leuckart proce-dure and expanded the scope of the reaction by developing anammonium formate-formamide reagent that, when combinedwith a ketone and heated in the range of 160–185 �C for severalhours followed by acid hydrolysis, afforded 1� amines in 60–80%yield.

Over the years, different mechanisms have been suggested forthe Leuckart reaction;16 imines, iminium ions, N-formyl imines,or N-formyl iminium cations have been implicated as intermedi-ates in the process.

As part of our continued efforts on the use of simple ammoniumsalts in synthetic transformations,17 we recently reported a high-yielding one-pot procedure for the preparation of a wide range ofiminium salts (1) by direct combination of an aldehyde or a ketonewith a 2� amine free base in the presence of ammonium tetrafluo-roborate, ammonium perchlorate, or ammonium hexafluorophos-phate (Scheme 1).18

Since iminium ions are possible intermediates in the Leuckartreaction, we envisioned that reduction of the in situ formed C@Nbond of 1 should occur readily by substituting ammonium for-mate19 for the ammonium salts previously used for the preparationof iminium salts 1. Therefore, we decided to explore the preparation

R1

C

R2

O

R3

HN

R4

NH4+ NCA

R1

R2

R3

R4

A+ + toluene/benzene NH3 + H2O+ +

A = BF4, ClO4, PF6

heat

1

Scheme 1. One-pot preparation of iminium salts 1.

R1

C

R2

O

R3

HN

R4

NH4+ N

R1

R2

R3

R4

+ + toluene/benzene NH3 + H2O + CO2+heat

432

HCO2 H

Scheme 2. One-pot Leuckart-type preparation of amines 4.

Table 1One-pot preparation of 2� and 3� amines (4)

Entry Aldehyde/ketone Amine Product Yield (%) Time (h)

Benzene Toluene

1O N H

3a

N84 54 1.5

2 O 3a N 89 72 1.5

3O

3aN

80 73 1.5

4O

OO 3a

O

ON 87 75 1.5

5 O 3a N 82 71 1.5

6O

3a N 79 71 1.5

7

O

3aN

66 75 1.5

8

CHO

Me2N2a

3a

N

Me2N 89 70 1.5

9 2a

HN3b

N

Me2N85 75 1.5

10

O

O

CHO

2b

3a

O

O

N

76 73 1.5

11 2b 3a

O

O

N73 72 1.5

130 D. O’Connor et al. / Tetrahedron Letters 52 (2011) 129–132

Table 1 (continued)

Entry Aldehyde/ketone Amine Product Yield (%) Time (h)

Benzene Toluene

12

CHO

2c

3a

N

77 68 1.5

13 2c 3b

N

80 69 1.5

14 O 3b N 67 68 1.5

15O

NH2

3c

HN

85 74 1.5

16

CHO

3c NH

93 71 1.5

17O NH2 H

N 86 60 1.5

D. O’Connor et al. / Tetrahedron Letters 52 (2011) 129–132 131

of amines 4 by a direct, one-step procedure: heating an aldehyde ora ketone (2) with a 1� or 2� amine (3) in the presence of solid ammo-nium formate (Scheme 2). In this Letter, we report the preparationand characterization of various 2� and 3� amines by this Leuckart-DRA procedure.

Typically, amines 420 are prepared by heating a mixture of analdehyde or a ketone, a 1� or 2� amine and solid ammonium for-mate in toluene or benzene in a Dean-Stark apparatus with contin-uous removal of water formed. After the theoretical quantity ofwater was collected, the solution was cooled and the solvent wasremoved by rotary evaporation. The crude products were thenpurified by distillation under reduced pressure. A number of 2�and 3� amines were prepared in high yields by this method in veryshort time (Table 1). While the isolated yield for most of theamines prepared were slightly higher in benzene, good yields ofthe products were obtained in the less toxic and more eco-friendlysolvent toluene. This reaction also worked well with substratescontaining acid-labile acetal groups (Table 1, entries 4 and 10). Fur-thermore, NMR spectra of the crude products did not reveal forma-tion of N-formylamines as by-products, avoiding the need forsubsequent acid hydrolysis. We are currently adapting this DRAprotocol to employ arylamines but we describe herein a samplingof amines derived from iminium ions that we previouslyreported.18

In conclusion, a one-pot, high-yielding, direct reductive amina-tion protocol was developed using commercially available andinexpensive bulk chemicals for rapid access to a variety of 2� and3� amines. A further advantage of this new variant of the Leuckartreaction is the avoidance of subsequent acid hydrolysis of oftenformed N-formyl derivatives of 2� amines and formation of 3�amines as their formates under previously reported Leuckart reac-tion conditions.10

Acknowledgments

The authors gratefully acknowledge financial support fromFordham University and the National Science Foundation’s Divi-sion of Undergraduate Education through Grant DUE #9650684for the NMR spectrometer at Fordham. The authors also thankthe Fordham College Dean’s Office for a Summer Science Internshipaward to S.P.B. Thanks also go to James A. Ciaccio for helpful com-ments on the manuscript.

References and notes

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19. For a review on the use of ammonium formate in hydrogen transfer reactions,see: Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91–95.

20. Typical procedure for one-pot preparation of secondary and tertiary amines 4(Table 1, entry 10): To a 50-mL round-bottomed flask containing ammoniumformate (0.69 g, 11 mmol) was added piperonal (1.65 g, 11 mmol) followed bypyrrolidine (0.78 g, 11 mmol) and toluene (20 mL). The mixture wasmagnetically stirred and heated at reflux with continuous removal of thewater formed (Dean–Stark trap). The mixture was then cooled to roomtemperature and the solvent was removed by rotary evaporation. The crudeproduct was purified by distillation under reduced pressure and afforded theamine as a colorless oil (1.65 g, 73%; bp 163–165 �C/11 torr); 1H NMR(300 MHz, CDCl3): d 6.85 (s, 1H), 6.75–6.72 (m, 2H), 5.92 (s, 2H), 3.51 (s, 2H),2.50–2.46 (m, 4H), 1.79–1.73 (m, 4H); 13C NMR (75 MHz, CDCl3): d 147.48,146.34, 133.38, 121.81, 109.34, 107.82, 100.77, 60.40, 53.99, 23.37.