Rapid and convenient microwave-assisted synthesis of primary amines via reductive N-alkylation of methyl carbamate with aldehydes

Article abstract of DOI:10.1055/s-2008-1067040

Microwave-assisted reductive alkylation of methyl carbamate with a range of aldehydes provides, after basic work-up, an experimentally simple, one-pot method for rapid functional group interconversion of structurally diverse aldehydes into primary amines. The method has several advantages over more traditional methods of carrying out this transformation and is particularly amenable to high-throughput synthesis.

Full text of DOI:10.1055/s-2008-1067040

SHORT PAPER
1679
Rapid and Convenient Microwave-Assisted Synthesis of Primary Amines via
Reductive N-Alkylation of Methyl Carbamate with Aldehydes
M
icrowave-
A
r
d
S
e
ynthesis of
d
P
rimary
A
m
r
ines ik Lehmann, Martin Scobie*
Biovitrum AB, Discovery Research, 112 76 Stockholm, Sweden
Fax +46(8)6972533; E-mail: martin.scobie@biovitrum.com
Received 20 February 2008
followed by reduction, are indirect procedures and have
similar shortcomings to those described above.3,4
Abstract: Microwave-assisted reductive alkylation of methyl car-
bamate with a range of aldehydes provides, after basic work-up, an
experimentally simple, one-pot method for rapid functional group
interconversion of structurally diverse aldehydes into primary
amines. The method has several advantages over more traditional
methods of carrying out this transformation and is particularly
amenable to high-throughput synthesis.
We were interested in a recent report by Dube and Scholte
outlining an efficient method for reductively alkylating
benzyl- or tert-butyl carbamate with various aldehydes in
the presence of triethylsilane and trifluoroacetic acid
(Scheme 1).5 The resulting carbamate derivatives 2 may
be converted into the corresponding primary amines 3 by
either hydrogenolysis or acid-catalysed Boc-cleavage. A
later report outlining similar reductive alkylations of
methyl carbamate in the presence of trichlorosilane ap-
peared in the patent literature.6 The resulting methyl car-
bamates 2 can be easily hydrolysed under basic conditions
to furnish the desired primary amines 3.
Key words: aminations, aldehydes, reductive alkylation, carbam-
ates, amines, microwave synthesis
As part of a medicinal chemistry program aimed at the
discovery of new antagonists of the melanin-concentrat-
ing hormone receptor (MCH1R), we required rapid and
parallel synthetic access to novel benzylamine derivatives
from a diverse set of proprietary aldehydes. The conver-
sion of aldehydes into primary amines by reductive ami-
nation using ammonia can often be problematic since the
resulting amine, once formed, is usually more nucleo-
philic than ammonia itself.1 Consequently, secondary and
tertiary amines are commonly formed by over-alkylation.
Additionally, traces of the alcohol are often formed by re-
duction of the unreacted aldehyde. An alternative ap-
proach sometimes used to carry out this transformation is
via the corresponding oxime derivative, which is then re-
duced to furnish a primary amine.2 The latter method has
several drawbacks, firstly, hydroxylamine itself is ex-
tremely toxic and, secondly, reductive cleavage of the in-
termediate oxime can sometimes be problematic or
incompatible with other functionalities. Moreover, reduc-
tion of the oxime can often involve the use of toxic heavy
metals. Other alternatives, such as reduction of an alde-
hyde to the corresponding alcohol, followed by formation
of phthalamido-derivatives and subsequent removal with
hydrazine, or even conversion of the alcohols into azides
A survey of recent literature showed that, despite its po-
tential appeal, this methodology has received surprisingly
little attention to date.7 A drawback these methods suffer
from is the relatively long reaction times, often requiring
one or two days for the synthesis of simple amines. We
considered that development of a rapid, one-pot, micro-
wave-assisted protocol would be ideally suited to our
needs, potentially affording an efficient and general syn-
thetic method which would be appropriate for in-house
high-throughput parallel synthesis. We herein report re-
sults from these studies.
Conversion of 4-bromobenzaldehyde (4) into the corre-
sponding methyl carbamate 5 was initially investigated
using five different silanes, in the presence of trifluorace-
tic acid, using acetonitrile as solvent (Scheme 2). Trieth-
ylsilane (6), triisopropylsilane (7) and trichlorosilane (8)
all furnished the expected product 5, however, tert-bu-
tyldimethylsilane (TBDMSH; 9) gave the corresponding
methyl carbamate 5 in highest yield and overall purity. To
our knowledge, use of this silane has not been previously
O
O
silane, H2NCO2R2
deprotection
R1
NH2
R1
N
OR2
R1
H
TFA, MeCN
H
2
3
1
silane = triethylsilane or trichlorosilane, R2 = benzyl, tert-butyl or methyl
Scheme 1
SYNTHESIS 2008, No. 11, pp 1679–1681
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067040; Art ID: P02408SS
© Georg Thieme Verlag Stuttgart · New York

1680
F. Lehmann, M. Scobie
SHORT PAPER
O
Table 1 One-Pot Conversion of Aldehydes into Primary Amines
via the Corresponding Methyl Carbamates
CHO
N
O
silane 6–10, H2NCO2Me
H
O
O
Br
Br
2 M LiOH
TBDMSH, TFA
MeCN
TFA, MeCN
4
5
R
N
O
R
NH2
R
H
H
THF, MeOH
1
2
3
Cl
Si
Yield (%)a Purity (%)b
Si
Si
Entry
R
Si
H
H
Si
Cl
H
H
H
Cl
H
3a
89
75
99
99
10
7
9
8
6
Scheme 2 Initial optimisation of reaction conditions using different
silanes. tert-Butyldimethylsilane (9) afforded highest yields and puri-
3b
3c
3d
3e
3f
ty.
MeO
MeO
reported in this context. Interestingly, use of diphenyl-
93
72
96
66
99
99
95
99
silane (10) gave only unreacted starting material.
Further optimisation of reaction conditions using TBDMSH
as reductant was carried out with four different benzalde-
hydes; the effects of both reaction temperature and reac-
tion time on yield and purity were investigated. Optimal
conversion into the corresponding methyl carbamates was
achieved by heating at 150 °C for 15 minutes (inferred by
LC-MS analysis of the crude reaction mixtures).
Br
F
Using the optimised reaction conditions, the synthetic
scope was then probed in a high-throughput setting by us-
ing a diverse set of alkyl, vinyl, benzylic and heterocyclic
aldehydes (Table 1). In all cases, excellent conversion
into the expected methyl carbamates 2 was observed by
LC-MS analysis of the crude reaction mixtures. Rather
than isolate these carbamates, we carried out their hydro-
lysis using a one-pot procedure. Thus, after removal of
solvent from the crude reaction mixtures by evaporation,
the carbamates were heated at 120 °C for 10 minutes in a
mixture of 2 M lithium hydroxide, THF and methanol.
Amines 3a–j were conveniently isolated as their hydro-
chloride salts in high yields and with chemical purities
generally well above 90% by using a simple acid-base
work-up.
CF3
3g
3h
3i
93
77
95
99
90
90
O
3j
87
98
In conclusion, we have developed a rapid, chemically ro-
bust, one-pot, microwave-based synthesis of primary
amines. Use of TBDMSH for reductive alkylation of me-
thyl carbamate was superior to other previously reported
alternatives. Using a simple acid-base work-up, pure
products could be obtained in very short reaction times.
The methodology we developed will be applied to the
high-throughput synthesis and biological evaluation of
novel MCH1R antagonists, details of which will be pub-
lished elsewhere.
a Isolated yield of hydrochloride salt.
b Determined by LC-MS and/or NMR analysis.
Smith Synthesizer™ instrument (Biotage) using 2–5 mL Smith Pro-
cess vials fitted with aluminum caps and septa.
Synthesis of 4-Methylbenzylamine Hydrochloride (3a); Typical
Procedure
4-Methylbenzaldehyde (24 mg, 0.2 mmol), methyl carbamate (30
mg, 0.4 mmol), TFA (91 mg, 0.8 mmol) and TBDMSH (114 mg,
0.8 mmol) were dissolved in MeCN (4.0 mL) and heated to 150 °C
for 15 min in a Smith Synthesizer™ microwave apparatus. The
mixture was concentrated in vacuo and the residue was dissolved in
a mixture of THF, MeOH and 2M LiOH (1:1:1, 4 mL) and heated
at 120 °C for 10 min in a Smith Synthesizer™. EtOAc (4 mL) and
1M NaOH (4 mL) were added and the phases were separated. The
organic phase was extracted with 1M HCl (2 × 4 mL) and the aque-
ous extract was evaporated to afford 4-methylbenzylamine as its hy-
drochloride salt (28 mg, 89%). The purity of this material was at
least 99% as determined by LC-MS.
1H NMR spectra were recorded on a Bruker Advance DPX 400
spectrometer at 400 MHz. All spectra were recorded using residual
solvent or TMS as internal standard. Electrospray mass spectrome-
try (MS) were obtained using an Agilent MSD mass spectrometer.
Compounds used in Table 1, entries 3a–h were obtained from
Aldrich. Methyl carbamate and tert-butyldimethylsilane (9;
TBDMSH) were purchased from Aldrich. All solvents were of stan-
dard reagent grade. Microwave irradiation was carried out using a
Synthesis 2008, No. 11, 1679–1681 © Thieme Stuttgart · New York

SHORT PAPER
Microwave-Assisted Synthesis of Primary Amines
1681
4-Methylbenzylamine Hydrochloride (3a)
MS (ES+): m/z = 134 [M + H]+.
1H NMR (400 MHz, CD3OD): d = 2.37 (s, 3 H), 4.09 (s, 2 H), 7.27
(d, J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H).
3-Phenylpropylamine Hydrochloride (3j)
1H NMR (400 MHz, CD3OD): d = 2.00 (quin, J = 7.78 Hz, 2 H),
2.74 (t, J = 7.78 Hz, 2 H), 2.95 (t, J = 7.80 Hz, 2 H), 7.16–7.35 (m,
5 H).
MS (ES+): m/z = 122 [M + H]+.
3-Methoxybenzylamine Hydrochloride (3b)
1H NMR (400 MHz, CD3OD): d = 3.84 (s, 3 H), 4.12 (s, 2 H), 7.01
(dd, J = 2.2, 8.0 Hz, 1 H), 7.05–7.11 (m, 2 H), 7.36 (app t, J = 8.0
Hz, 1 H).
MS (ES+): m/z = 136 [M + H]+.
References
MS (ES+): m/z = 138 [M + H]+.
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MS (ES+): m/z = 138 [M + H]+.
4-Bromobenzylamine Hydrochloride (3d)
1H NMR (400 MHz, CD3OD): d = 4.12 (s, 2 H), 7.41 (d, J = 8.0 Hz,
2 H), 7.63 (d, J = 8.0 Hz, 2 H).
MS (ES+): m/z = 186, 188 [M + H]+.
4-Fluorobenzylamine Hydrochloride (3e)
1H NMR (400 MHz, CD3OD): d = 4.03 (s, 2 H), 7.07 (app t, J = 8.0
Hz, 2 H), 7.31 (dd, J = 2.0, 8.0 Hz, 2 H).
MS (ES+): m/z = 126 [M + H]+.
2-(Trifluoromethyl)benzylamine Hydrochloride (3f)
1H NMR (400 MHz, CD3OD): d = 4.25 (s, 2 H), 7.54 (t, J = 7.28 Hz,
1 H), 7.62–7.75 (m, 3 H).
MS (ES+): m/z = 176 [M + H]+.
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7.82–8.08 (m, 4 H).
MS (ES+): m/z = 158 [M + H]+.
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MS (ES+): m/z = 98 [M + H]+.
(E)-Cinnamylamine Hydrochloride (3i)
1H NMR (400 MHz, CD3OD): d = 3.33 (d, J = 6.9 Hz, 2 H), 6.35
(dd, J = 16.0, 6.9 Hz, 1 H), 6.84 (d, J = 16.0 Hz, 1 H), 7.27–7.41 (m,
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Synthesis 2008, No. 11, 1679–1681 © Thieme Stuttgart · New York