An efficient method for reductive amination of carbonyl compounds under nonacidic conditions

Article abstract of DOI:10.1055/s-0032-1316683

A high yielding reductive amination procedure for ketones and aldehydes under neutral conditions is described. The key advantage for the method is the applicability to acid-sensitive substrates, and the procedure is applicable to a wide range of primary and secondary amines, on a multigram scale. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316683

2176▌
LETTER
lAettner Efficient Method for Reductive Amination of Carbonyl Compounds under
Nonacidic Conditions
Reductive Amination of Carbonyl Compounds
Julian A. Hudson,*a J. B. Sweeney*b
a
Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Fax +44(1625)516667; E-mail: Julian.Hudson@astrazeneca.com
b
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield West Yorkshire, HD1 3DH, UK
E-mail: j.b.sweeney@hud.ac.uk
Received: 17.05.2012; Accepted after revision: 08.06.2012
perfectly suited to amination of carbonyl compounds
Abstract: A high yielding reductive amination procedure for
containing acid-sensitive functionality.
ketones and aldehydes under neutral conditions is described. The
key advantage for the method is the applicability to acid-sensitive
substrates, and the procedure is applicable to a wide range of prima-
ry and secondary amines, on a multigram scale.
As part of a drug discovery program, we wished to carry
out a reductive amination of tetrahydro-4H-pyran-4-one
using (R)-N-[2-oxo-2(pyrrolidin-3-ylamino)ethyl]-3-(tri-
fluoromethyl)benzamide (1) as the amine component
(Scheme 2). Using standard conditions of acetic acid and
sodium cyanoborohydride, with tetrahydrofuran as the
solvent, the product amine 2 was obtained in 49% yield
(after purification by silica gel chromatography).3 We
concluded that the low yield of the reaction was due to in-
compatibility of the substrates with the acidic conditions
and therefore sought a protocol which proceeded at neu-
tral or nonacidic pH. We therefore carried out the reaction
under a range of neutral conditions and were delighted to
observe that the pyranone reacted with sodium triacetoxy-
borohydride in the presence of magnesium sulfate and
N,N-diisopropylethylamine to deliver our target tertiary
amine in a much-improved yield of 86% (Scheme 3).
Moreover, the amine was obtained essentially pure there-
by obviating the need for chromatography.
Key words: reductive amination, nonacidic conditions, carbonyl
compounds, amines, imine formation, reduction
The construction of carbon–nitrogen bonds by reductive
amination is one of the most widely used methods for
preparation of industrially relevant amines.1 The two-step
process most often involves acid-catalysed imine forma-
tion (by condensation of an aldehyde or ketone with an
amine) followed by reduction by an acid-stable metal hy-
dride (Scheme 1).
H
N
R1
R4
R3
R3
R4
O
N
H
R1
R2
Brønsted or Lewis acid, [H]
R2
Scheme 1 Reductive amination of carbonyl compounds with
amines: a well-exploited process
We next examined the scope of our procedure using a
range of amines and carbonyl compounds, which were
reacted under the same conditions (Table 1).4 Aldehydes
reacted smoothly in the reaction (entries 1–4) and in good
yields (69–97%). It is particularly noteworthy that acid-
sensitive functionalities (such as Boc group, entries 3–5)
were stable under this protocol and that hydroxy group
was not subject to elimination reaction (entries 6–9), em-
phasising the nonacidic reaction environment. Cyclic
five- and six-membered ketones (often sluggish substrates
under acid-catalysed reactions) were also aminated in
good yields in the reaction (entries 5–9), and ester func-
tionality was not affected (entry 8). From the perspective
of the amine coupling partner, the reaction proceeded ef-
ficiently for piperidines (entries 1–3), piperazines
(entry 4) and pyrrolidines (entries 5–9). Amide function-
ality (entries 5–10) and N-benzyl protecting groups (en-
tries 2 and 4) were tolerated under the reaction conditions.
The only substrate class found to react poorly under the
conditions were anilines (known5 to be sluggish substrates
for reductive amination) with which products were ob-
tained only in low yields.
The most-often used protocol for reductive amination
uses complex metal hydrides reductants (such as sodium
cyanoborohydride and sodium triacetoxyborohydride) in
the presence of stoichiometric acid catalysts; the latter is
usually essential both for formation of the intermediate
imine and for the key reduction step. However, due to the
competing equilibria in play, product yields are often sub-
optimal and in particular Brønsted catalysis is not suitable
for acid-sensitive substrates. We report here the prelimi-
nary results of our study of a reliable and high yielding
reductive amination procedure for carbonyl compounds
with primary or secondary amines which avoids the use of
acid catalysts. Thus a range of aldehydes and ketones un-
dergo reduction amination by primary and secondary
amines by sodium triacetoxyborohydride,2 in the presence
of magnesium sulfate. The reaction is efficient and since
it is carried out under essentially neutral conditions, it is
SYNLETT 2012, 23, 2176–2178
Advanced online publication: 14.08.2012
In conclusion we have demonstrated a high-yielding re-
ductive amination procedure for carbonyl compounds
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316683; Art ID: ST-2012-D0432-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Amination of Carbonyl Compounds
2177
H
N
O
H
N
N
CF3
O
H
O
O
O
1
N
O
H
NaBH3CN, AcOH, THF
49%
N
Ar
N
H
O
2
Scheme 2 Reductive amination of dipeptidyl amine 1: acid catalysis is an inefficient process
H
N
O
H
N
O
N
CF3
H
O
O
O
1
N
NaBH(OAc)3, EtNiPr2, MgSO4, THF
86%
O
H
N
Ar
N
H
O
2
Scheme 3 Reductive amination of dipeptidyl amine 1: nonacidic conditions improve yield
which proceeds under nonacidic conditions and can be ry and secondary aliphatic amines and is of broad applica-
carried out on a multigram scale. The procedure delivers bility.
a range of pharmacologically relevant amines from prima-
Table 1 Nonacidic Reductive Amination of Ketones and Aldehydes: A General Process
H
N
R1
R4
R3
R3
R4
O
N
H
R1
R2
NaBH(OAc)3, EtNiPr2, MgSO4, THF
R2
Entry
1
Amine
Carbonyl compound
Product
Yield (%)
96
O
HN
OH
N
N
OH
N
Ph
O
N
N
2
3
4
97
75
80
ClH2N
HN
N
Ph
O
O
H
O
N
N
Boc
Boc
N
N
O
N
N
N
HN
Boc
O
Boc
O
H
N
O
N
5
86
H
O
N
N
H
H
N
O
N
H
O
O
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2176–2178

2178
J. A. Hudson, J. B. Sweeney
LETTER
Table 1 Nonacidic Reductive Amination of Ketones and Aldehydes: A General Process (continued)
H
N
R1
R4
R3
R3
R4
O
N
H
R1
R2
NaBH(OAc)3, EtNiPr2, MgSO4, THF
R2
Entry
Amine
Carbonyl compound
Product
Yield (%)
Ph
H
N
O
H
N
N
6
72
O
N
CF3
O
H
HO
H
N
O
N
CF3
H
HO
O
AcO
H
N
O
O
O
H
N
7
8
78
95
O
N
N
H
CF3
O
HO
H
O
N
N
CF3
H
HO
O
BocN
H2•O2CCF3
N
O
O
Boc
N
N
H
N
O
H
N
H
CF3
N
HO
N
CF3
O
H
HO
O
N
OH
H
N
CF3
O
N
9
65
H
N
O
N
H
N
OH
O
H
O
N
N
CF3
H
HO
O
(b) Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res.
Dev. 2006, 10, 971.
Acknowledgment
(3) Key data for 2: 1H NMR (400 MHz, DMSO): δ = 8.61 (s, 1
H), 8.11–8.26 (m, 2 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.60–7.79
(m, 2 H), 4.12–4.36 (m, 1 H), 3.77–4.03 (m, 4 H), 3.32 (t, J
= 11.2 Hz, 2 H), 2.74 (dt, J = 8.0, 25.5 Hz, 2 H), 2.41–2.49
(m, 2 H), 2.30 (t, J = 10.2 Hz, 1 H), 2.00–2.18 (m, 1 H), 1.74
(d, J = 12.1 Hz, 2 H), 1.62 (dd, J = 12.8, 6.5 Hz, 1 H), 1.31–
1.55 (m, 2 H). MS (ES+): m/z = 400.30 [M + H]+.
J.B.S. acknowledges the support of AstraZeneca, the Royal Society
and EPSRC for provision of an Industry Fellowship.
References
(1) For reviews, see: (a) Margaretha, P. In Science of Synthesis,
Knowledge Updates; Vol. 2010/4, Section 40.1.1.1.2;
Procter, D. J.; Molander, G. A., Eds.; Thieme: Stuttgart,
2011, 405–442. (b) Tripathi, R. P.; Verma, S. S.; Pandey, J.;
Tiwari, V. K. Curr. Org. Chem. 2008, 12, 1093. (c) Baxter,
E. W.; Reitz, A. B. Org. React. (N. Y.) 2002, 59, 1.
(d) Hutchins, R. O.; Hutchins, M. K. In Comprehensive
Organic Synthesis, Vol. 8; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991, 25–78. (e) Lane, C. F.
Synthesis 1975, 135. (f) Emerson, W. S. Org. React. (N. Y.)
1948, 4, 174.
(4) General Procedure: MgSO4 (0.75 mmol) was added to a
solution of the primary or secondary amine (1.28 mmol),
the carbonyl compound (1.28 mmol) and N,N-di-
isopropylethylamine (3.83 mmol) in THF (30 mL).
The resulting suspension was stirred at r.t. for 5 min.
NaBH(OAc)3 (2.55 mmol) was added and stirring was
continued overnight. The solvent was removed in vacuo, and
the residue was dissolved in CH2Cl2 (150 mL). The solution
was washed with sat. aq NaHCO3 (50 mL), dried (Na2SO4)
and concentrated in vacuo to yield the desired product.
(5) See, for instance: Righi, M.; Bedini, A.; Piersanti, G.;
Romagnoli, F.; Spadoni, G. J. Org. Chem. 2011, 76, 704.
(2) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
Synlett 2012, 23, 2176–2178
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