Efficient preparation of N-benzyl secondary amines via benzylamine-borane mediated reductive amination

Article abstract of DOI:10.1081/SCC-120002129

An efficient one-pot reductive amination protocol for preparing N-benzyl secondary amines is described.

Full text of DOI:10.1081/SCC-120002129

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EFFICIENT PREPARATION OF N-BENZYL SECONDARY
AMINES VIA BENZYLAMINE–BORANE MEDIATED
REDUCTIVE AMINATION
Matt A. Peterson a , Adam Bowman a & Sarah Morgan a
a Department of Chemistry and Biochemistry , Brigham Young University , Provo, UT,
84602, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Matt A. Peterson , Adam Bowman & Sarah Morgan (2002) EFFICIENT PREPARATION OF N-BENZYL
SECONDARY AMINES VIA BENZYLAMINE–BORANE MEDIATED REDUCTIVE AMINATION, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:3, 443-448
To link to this article: http://dx.doi.org/10.1081/SCC-120002129
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SYNTHETIC COMMUNICATIONS, 32(3), 443–448 (2002)
EFFICIENT PREPARATION OF
N-BENZYL SECONDARY AMINES VIA
BENZYLAMINE–BORANE MEDIATED
REDUCTIVE AMINATION
Matt A. Peterson,* AdamBowman, and
Sarah Morgan
Department of Chemistry and Biochemistry,
Brigham Young University, Provo, UT 84602
ABSTRACT
An efficient one-pot reductive amination protocol for prepar-
ing N-benzyl secondary amines is described.
As part of ongoing research, we recently discovered that benzylamine–
borane is an effective reductant for in situ reductive amination of aldehydes
and unhindered ketones. Treatment of the carbonyl compound and benzyl-
amine (1.1 equiv) with benzylamine–borane in the presence of 4 A molecular
sieves gave secondary N-benzyl amines in good yields (Table 1). Imines and
imminium salts are effectively reduced by a number of hydride reducing
agents. However, most of these require pre-formation of the carbon–
nitrogen double bond, since reduction of the ketone or aldehyde is a
competing reaction. Dimethylamine–borane has been used as a reducing
agent for two-step reductive aminations. The reduction is performed in
*Corresponding author.
443
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PETERSON, BOWMAN, AND MORGAN
Table 1. Benzylamine–Borane Promoted Reductive Amina-
tion of Selected Ketones and Aldehydes with Benzylamine

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PREPARATION OF N-BENZYL SECONDARY AMINES
445
glacial acetic acid and its reported use has been limited to aryl aldi-
mines derived from substituted anilines.1 Reductants used for in situ
reductive aminations include pyridine–borane,2 sodium cyanoborohydride
(NaBH3CN),3 sodium triacetoxy borohydride [NaBH(OAc)3],4 zinc
borohydride–zinc chloride [ZnBH4–ZnCl2],5 and hydrogen in the presence
of transition metal catalysts.6 While efficient syntheses of N-benzyl secondary
amines have been achieved with these reagents, they suffer from several
significant drawbacks. These include formation of toxic byproducts
(NaBH3CN), use of excess amine (ꢀ5 equiv) (NaBH3CN), strongly acidic
work-up conditions (1 N HCl) needed to hydrolyze the boron-product
complexes (pyridine–borane, ZnBH4–ZnCl2), and acid catalysis (AcOH)
for optimum reaction rates [NaBH(OAc)3]. The present method employs
stoichiometric amounts of benzylamine under neutral conditions and does
not involve production of the toxic byproducts NaCN and HCN. In addition,
the boron-product complex is effectively cleaved with refluxing NaOMe/
MeOH. Thus, this procedure avoids a number of the drawbacks associated
with previous methods and provides a useful alternative for the preparation
of secondary N-benzyl amines.
We prepared benzylamine–borane by the addition of one molar
equivalent of BH3–THF to benzylamine in THF under N2. The reagent
prepared in this manner could be stored for up to one week at ambient
temperature (under air) without noticeable loss in reactivity, and was effec-
tive in either protic or aprotic solvents.
The reaction was less effective with hindered ketones (Table 1, Entries
6–8). Tthis is consistent with the increased difficulty of imine formation
with hindered ketones.2a Reductive aminations of benzylacetone with
other primary amines (methylamine, butylamine, isopropylamine, or tert-
butylamine), with benzylamine–borane as the reducing agent gave mixtures
of N-benzyl and N-alkyl amine products (Scheme 1). This result can be
rationalized by borane-amine exchange equilibria that favor the less hin-
dered amines which undergo imine formation more readily than the more
hindered amines,7 and an inverse correlation between the product ratio
(9 : 1) and the steric bulk of the amine was observed (Table 2).
Scheme 1.

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PETERSON, BOWMAN, AND MORGAN
Table 2. Reductive Amination of Benzylacetone
with Primary Amines and Benzylamine–Boranea
Amine
Product
Yield (%)b
CH3NH2
1 (14)
1 (32)
1 (61)
1 (52)
9a (71)
9b (33)
9c (0)
CH3CH2CH2CH2NH2
(CH3)2CHNH2
(CH3)3CNH2
9d (0)
aReactions were performed in THF.
bYields refer to isolated product.
TYPICAL EXPERIMENTAL
Benzylamine–borane (0.5 M/THF; 4.0 mL), was added to a stirred
mixture of the carbonyl compound (2.00 mmol), benzylamine (2.20 mmol),
and powdered activated 4 A sieves (0.400 g) in dried THF (6 mL) and the
reaction was stirred overnight at ambient temperature. Volatiles were
removed under reduced pressure and the slurry was filtered with Celite
(EtOAc wash). The filtrate was evaporated, and the residue was refluxed
overnight in NaOMe/MeOH. Chromatography8 (EtOAc/Hexanes) gave
1
N-benzyl secondary amines in >95% purity as determined by H NMR.9
1
Products gave the expected H and 13C NMR spectra and representative
data are provided.10
Spectroscopic Data
N-Benzyl-(1-methyl-3-phenyl)propylamine (1): 1H NMR (CDCl3,
200 MHz) d 7.33–7.16 (m, 10H), 3.79 (dd, J ¼ 12.9, 21.5 Hz, 2H), 2.79–2.63
(m, 3H), 1.92–1.61 (m, 2H), 1.39 (s, 1H), 1.15 (d, J ¼ 6.2Hz, 3H); 13C NMR
(CDCl3, 50 MHz) d 142.4, 140.7, 128.4, 128.3, 128.2, 126.8, 125.6, 51.9, 51.2,
38.6, 32.1, 20.2; MS (CI) m/z 240.1739 (MHþ [C17H22N] ¼ 240.1752).
N-Benzyl-(1-methyl)hexylamine (2): 1H NMR (CDCl3, 200 MHz)
d 7.34–7.24 (m, 5H), 3.79 (dd, J ¼ 13.2, 21.8 Hz, 2H), 2.72–2.63 (m, 1H),
1.48–1.21 (m, 9H), 1.08 (d, J ¼ 6.4 Hz, 3H); 0.88 (t, J ¼ 6.5 Hz, 3H); 13C NMR
(CDCl3, 50 MHz) d 139.3, 126.8, 126.5, 125.2, 50.8, 49.7, 35.4, 30.4, 24.0,
21.0, 18.6, 12.4; MS (CI) m/z 206.1903 (MHþ [C14H24N] ¼ 206.1909).
Dibenzylamine (3): 1H NMR (CDCl3, 200 MHz) d 7.35–7.25 (m, 10H),
3.82(bs, 4H), 1.75 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 138.8, 126.9, 126.7,
125.4, 51.5; MS (CI) m/z 198.1277 (MHþ [C14H16N] ¼ 198.1283).

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PREPARATION OF N-BENZYL SECONDARY AMINES
N-Benzyl-(4-chlorophenyl)methylamine (4):
1H NMR
447
(CDCl3,
200 MHz) d 7.35–7.26 (m, 9H), 3.79 (s, 2H), 3.77 (s, 2H), 1.60 (s, 1H);
13C NMR (CDCl3, 50 MHz) d 138.6, 137.3, 131.0, 127.9, 126.93, 126.88,
126.6, 125.5, 51.5, 50.7; MS (CI) m/z 232.0901 (MHþ [C14H15N35Cl] ¼
232.0893).
N-Benzylcyclohexylamine (5): 1H NMR (CDCl3, 200 MHz) d 7.32–7.23
(m, 5H), 3.88 (d, J ¼ 2.8 Hz, 2H), 2.47 (m, 1H), 1.92–1.06 (m, 11H);
13C NMR (CDCl3, 50 MHz) d 139.4, 126.8, 126.5, 125.1, 54.5, 49.3, 31.8,
24.5, 23.3; MS (CI) m/z 190.1591 (MHþ [C13H20N] ¼ 190.1591).
N-Butyl-(1-methyl-3-phenyl)propylamine (9b): 1H NMR (CDCl3,
200 MHz) d 7.35–7.15 (m, 5H), 2.75–2.45 (m, 5H), 1.8–1.6 (m, 2H), 1.57–
1.24 (m, 4H), 1.10 (d, J ¼ 5.6 Hz, 3H), 0.92(t, J ¼ 7.0 Hz, 3H); 13C NMR
(CDCl3, 50 MHz) d 142.5, 128.3, 125.7, 52.7, 46.9, 38.6, 32.5, 32.3, 29.6,
26.0, 20.5, 20.2, 13.9; MS (CI) m/z 206.1914 (MHþ [C17H22N] ¼ 206.1909).
ACKNOWLEDGMENT
Acknowledgment is made to the donors of the Petroleum Research
Fund, administered by the ACS, for partial support of this research.
A. Bowman acknowledges the Brigham Young University Office of
Research and Creative Activities for an undergraduate research scholarship.
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PETERSON, BOWMAN, AND MORGAN
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Received in the USA March 19, 2001

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