Direct Leuckart-type reductive amination of aldehydes and ketones: A facile one-pot protocol for the preparation of secondary and tertiary amines

Article abstract of DOI:10.1016/j.tetlet.2010.11.006

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

Full text of DOI:10.1016/j.tetlet.2010.11.006

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 facile
one-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
a b s t r a c t
Article history:
Received 12 July 2010
Revised 29 October 2010
Accepted 1 November 2010
Available online 5 November 2010
A high-yielding and facile one-pot Leuckart-type reaction for rapid access to a number of 2° and 3°
amines is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Reductive amination
Secondary amines
Tertiary amines
Aldehydes
Ketones
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 tertiary
amines.2 Its one-step procedure offers operational convenience
and avoids preformation or isolation of the imine or iminium inter-
mediates prior to their reduction. The selective reduction of the
in situ formed C@N bond and the stability of the reducing agent
under the reaction conditions, which are often acidic, are critical
to the overall success of the process. Catalytic hydrogenation
methods,3 both economical and eco-friendly, are effective for DRAs
but are not compatible with substrates with reducible moieties,
such as cyano4 and nitro5 groups, and may yield alcohols as
by-products. Among metal hydride reducing agents, sodium cya-
noborohydride (NaBH3CN)6 and sodium triacetoxyborohydride
(NaBH(OAc)3),7 both commercially available, have been widely
used. Sodium cyanoborohydride is highly toxic and formation of
toxic by-products, such as HCN and NaCN create problematic dis-
posal issues and may contaminate the product.8 Other drawbacks
include the need to use a fivefold excess of the amine and slow
reaction rates with aromatic ketones and amines of lower basicity.
Sodium triacetoxyborohydride, though less toxic, is flammable and
water-reactive, and similar limitations are encountered with aro-
An alternative DRA approach for the preparation of amines is
the Leuckart reaction,10 whereby an aldehyde or a ketone is heated
in 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 the
Leuckart reaction unsuitable for substrates with acid-sensitive
moieties. Ingersoll et al.15 improved the original Leuckart proce-
dure and expanded the scope of the reaction by developing an
ammonium formate-formamide reagent that, when combined
with a ketone and heated in the range of 160–185 °C for several
hours followed by acid hydrolysis, afforded 1° amines in 60–80%
yield.
Over the years, different mechanisms have been suggested for
the 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 ammonium
salts in synthetic transformations,17 we recently reported a high-
yielding one-pot procedure for the preparation of a wide range of
iminium salts (1) by direct combination of an aldehyde or a ketone
with a 2° amine free base in the presence of ammonium tetrafluo-
roborate, ammonium perchlorate, or ammonium hexafluorophos-
phate (Scheme 1).18
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 of
these reagents employ a catalyst combined with a reducing agent.9
Since iminium ions are possible intermediates in the Leuckart
reaction, we envisioned that reduction of the in situ formed C@N
bond of 1 should occur readily by substituting ammonium for-
mate19 for the ammonium salts previously used for the preparation
of iminium salts 1. Therefore, we decided to explore the preparation
⇑
Corresponding author. Tel.: +1 718 817 4440; fax: +1 718 817 4432.
E-mail address: saba@fordham.edu (S. Saba).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.006

130
D. O’Connor et al. / Tetrahedron Letters 52 (2011) 129–132
R3
R1
R1
R3
+
toluene/benzene
heat
C
O
+
A
+
HN
NH4
NH3 + H2O
+
A
C
N
+
R2
R4
R2
R4
A = BF4, ClO4, PF6
1
Scheme 1. One-pot preparation of iminium salts 1.
R3
R4
R1
R3
R1
+
toluene/benzene
C
O
+
NH3 + H2O + CO2
+
+
HN
NH4
HCO2
H
N
heat
R2
R4
R2
2
3
4
Scheme 2. One-pot Leuckart-type preparation of amines 4.
Table 1
One-pot preparation of 2° and 3° amines (4)
Entry
Aldehyde/ketone
Amine
Product
Yield (%)
Time (h)
Benzene
84
Toluene
N
H
N
O
O
1
2
3
54
72
73
1.5
1.5
1.5
3a
3a
N
N
89
80
3a
O
O
O
O
O
O
N
4
5
3a
3a
87
82
75
71
1.5
1.5
O
N
O
O
N
6
7
3a
3a
79
66
71
75
1.5
1.5
N
CHO
N
N
8
3a
89
70
1.5
Me2N
Me2N
2a
H
N
9
2a
85
76
75
73
1.5
1.5
3b
Me2N
O
CHO
O
O
N
N
10
3a
3a
O
2b
O
O
11
2b
73
72
1.5

D. O’Connor et al. / Tetrahedron Letters 52 (2011) 129–132
131
Table 1 (continued)
Entry Aldehyde/ketone
Amine
Product
Yield (%)
Time (h)
Benzene
77
Toluene
68
CHO
N
N
12
3a
1.5
1.5
2c
13
2c
3b
3b
80
69
14
15
O
O
N
67
85
68
74
1.5
1.5
NH2
H
N
3c
CHO
16
17
3c
93
86
71
60
1.5
1.5
N
H
NH2
H
O
N
of amines 4 by a direct, one-step procedure: heating an aldehyde or
a 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 preparation
and characterization of various 2° and 3° amines by this Leuckart-
DRA procedure.
Acknowledgments
The authors gratefully acknowledge financial support from
Fordham University and the National Science Foundation’s Divi-
sion of Undergraduate Education through Grant DUE #9650684
for the NMR spectrometer at Fordham. The authors also thank
the Fordham College Dean’s Office for a Summer Science Internship
award to S.P.B. Thanks also go to James A. Ciaccio for helpful com-
ments on the manuscript.
Typically, amines 420 are prepared by heating a mixture of an
aldehyde 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 of
water was collected, the solution was cooled and the solvent was
removed by rotary evaporation. The crude products were then
purified by distillation under reduced pressure. A number of 2°
and 3° amines were prepared in high yields by this method in very
short time (Table 1). While the isolated yield for most of the
amines prepared were slightly higher in benzene, good yields of
the products were obtained in the less toxic and more eco-friendly
solvent toluene. This reaction also worked well with substrates
containing 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 for
subsequent acid hydrolysis. We are currently adapting this DRA
protocol to employ arylamines but we describe herein a sampling
of amines derived from iminium ions that we previously
reported.18
References and notes
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132
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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 ammonium
formate (0.69 g, 11 mmol) was added piperonal (1.65 g, 11 mmol) followed by
pyrrolidine (0.78 g, 11 mmol) and toluene (20 mL). The mixture was
magnetically stirred and heated at reflux with continuous removal of the
water formed (Dean–Stark trap). The mixture was then cooled to room
temperature and the solvent was removed by rotary evaporation. The crude
product was purified by distillation under reduced pressure and afforded the
amine 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.