Catalytic reductive N-alkylation of amines using carboxylic acids

Article abstract of DOI:10.1039/c5cc08881j

We report a catalytic reductive alkylation reaction of primary or secondary amines with carboxylic acids. The two-phase process involves silane mediated direct amidation followed by catalytic reduction.

Full text of DOI:10.1039/c5cc08881j

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DOI: 10.1039/C5CC08881J
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Communication
Catalytic Reductive N-Alkylation of Amines using Carboxylic Acids
Keith G. Andrews, Declan M. Summers, Liam J. Donnelly and Ross M. Denton*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a catalytic reductive alkylation reaction of primary preparative system investigated by Cole-Hamilton and co-
or secondary amines with carboxylic acids. The two-phase workers.3g Very recent work by the group of Beller describes
process involves silane mediated direct amidation followed the platinum-catalysed reductive N-alkylation of amines with
by catalytic reduction.
carboxylic acids5 while a metal-free borane-catalysed protocol
Reductive amination between aldehydes and amines (Scheme was disclosed by Fu and Shang.6 A further report from Beller
1A) constitutes one of the most versatile methods for carbon- documents a ruthenium-catalysed process, which exploits
nitrogen bond construction and underpins the synthesis of hydrogen as a terminal reductant.7 Despite these recent
natural products, active pharmaceutical ingredients, breakthroughs, the development of a highly practical method
agrochemicals and advanced materials.1,2 Despite its – the former two reports require Schlenk apparatus; the latter
importance and prevalence there are several disadvantages high pressures in an autoclave – remains a significant
associated with the conventional process, including the challenge.
handling of unstable aldehydes (mostly accessed via
Herein we describe an alternative protocol for catalytic N-
stoichiometric oxidation) and selectivity for monoalkylated alkylation (Scheme 2) that exploits the dual reactivity of
products.
phenylsilane in a two phase process consisting of direct
Replacing aldehydes with carboxylic acids, which are far amidation8 followed by catalytic amide reduction.9
N-alkylation exploiting dual silane reactivity
easier to store and handle (Scheme 1B), would open up a
(A) silane-mediated amidation
O
(B) catalytic reduction
powerful complementary approach to reductive N-alkylation
with high synthetic utility. However, such reductive amination
from the higher oxidation level remains underexplored.3,4
O
RxSiHy
R1
OH
R3
R3
RxSiHy
R1
N
R1
N
+
Ir
(A) Reductive amination using aldehydes and amines
R2/H
R2/H
R2 NH2/HR3
catalyst
O
H
R3
NaBH(OAc)3
AcOH
R3
N
R1
N
+
R1
H
Scheme 2. Catalytic N-alkylation of amines based upon silane dual reactivity.
R2/H
R2/H
The strategic separation of the carbon-nitrogen bond
formation from the reduction is key to our process and
prevents unwanted reduction of the carboxylic acid and the
generation of alcohol by-products.10 The result is a practical,
robust method, which can be carried out in conventional
glassware under standard conditions with favourable loadings
of silane and carboxylic acid.
(B) This work:
Catalytic reductive N-alkylation using carboxylic acids and amines
O
H
R3
R3
Ir catalyst
silane
N
R1
N
+
R1
OH
R2/H
R2/H
Scheme 1. a) Classical reductive amination reaction. b) This work: catalytic reductive
alkylation using carboxylic acids.
We began by examining the amidation phase of the
reductive alkylation procedure. The phenylsilane-mediated
amidation of Ruan and co-workers8 was unsuitable in its
original form due to the high silane loading (3 equivalents of
PhSiH3) and use of DMF as solvent. We therefore developed an
alternative procedure in toluene in which the silane loading
was significantly reduced (Scheme 3A).11
Indeed, until recently, the only reported reductive amination
of higher carboxylic acids was the interesting but non-
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A)
Table 1. Reductive alkylation of secondary amines.
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DOI: 10.1039/C5CC08881J
O
benzoic acid 1.2 equiv.
PhSiH3 0.7 equiv.
1. PhSiH3 1.0 equiv.
O
Ph
N
H
94%
Ph
Ph
NH2
O
H
N
toluene, reflux, 15 h
R2
toluene, reflux, 15 h
R1
N
R1
R3
R2
OH
B)
2. PhSiH3 2.0 equiv.
[Ir(COD)Cl]2 1 mol%
reflux, 3 h
R3
1. PhSiH3 1.2 equiv.
toluene, reflux, 3 h
1.5 equiv.
H
N
N
Ph
+
1
2
3
2. PhSiH3 2.0 equiv.
[Ir(COD)Cl]2 1 mol%
Ph
OH
Isolated
yield (%)
72%
Entry
1
Tertiary amine product
13 h
N
3a
78b
Scheme 3. a) Direct amidation reaction. b) Proof of concept of a one-pot two-step
reductive alkylation reaction from carboxylic acids.
2
3
3b
3c
80b
56b
N
X = CH2
X = NMe
X
This procedure constitutes a synthetically useful amidation
system in its own right and full details, including mechanistic
studies, will be reported in due course. We next tested the
one-pot N-alkylation reaction (Scheme 3B). Gratifyingly the
addition of 1 mol% [Ir(COD)Cl]2 and an additional 2.0
equivalents of phenylsilane gave the amine product in 72%
N
4
5
3d
3e
76b
Ph
F
I
79b,c
N
N
isolated yield. The reduction conditions represent
a
Me
modification of Brookhart and Cheng’s powerful iridium-
catalysed secondary amide reduction methodology; the
original procedure did not report the reduction of tertiary
amides and utilised the more expensive and volatile
diethylsilane.12
N
6
7
3f
67
83
Me
N
3g
MeO
3
With proof-of-concept established we carried out
additional optimisation of the amidation and reduction
phases11 to give a set of general conditions. The scope of the
improved process was then examined with a range of
carboxylic acids and amines (Table 1). Our standard protocol
for the alkylation of secondary amines involved carrying out
reactions in round bottom flasks fitted with a reflux condenser
under a nitrogen or argon atmosphere in toluene. In most
cases anhydrous solvent was used, however, the reaction
could also be carried out in Winchester grade toluene and
open to air with only minor losses.11 In each case 1.5
equivalents of the carboxylic acid and a total of 3.0 equivalents
of phenylsilane were used, which compares favourably with
existing methods.5,6
Good to very good isolated yields were obtained for a
range of aliphatic and aromatic carboxylic acids (Table 1),
including electron poor aryl groups (entries 4-5). Both cyclic
and acyclic amines are effective substrates (e.g. entries 1-4
and 5-6); 5- and 6-membered rings are tolerated (e.g. entries
7-8), including somewhat deactivated amines such as
morpholine and piperazines (e.g. entries 3, 8). More hindered
aliphatic carboxylic acids with α-substitution were tolerated
(entries 10-11). Sterically hindered amines, however, led to
lower conversions (entries 12-13); these lower conversions are
amidation limited. Pyridines are tolerated, and the pyridine-
containing tertiary amine 3e was isolated in 79% yield (entry
5).
N
O
8
3h
72
MeO
3
R
56b
89b
R = H
9
10
3i
3j
N
R = CH3
R
Me
11
3k
78b
N
O
R
R
R = iPr
N
12
13
3l
3m
15
29b
R = Et
MeO
3
N
O
14
15
3n
3o
60b,d
40e
Br
N
O
MeO
Me
N
16
3p
54b,f
OMe
aAll reactions were carried out in 0.6 mL toluene on a 0.5 mmol scale with respect
to starting amine and purified by acid/base work-up. bFurther purified via flash
column chromatography. cReaction also performed on 5.0 mmol scale. dMass
balance includes ~30% enamine. ereaction performed using 1.0 equiv. cinnamic
acid, result is conversion by 1H-NMR; ~16% alkene material remains. carboxylic
f
To demonstrate the general practicability of the reaction, acid 1.5 mmol used.
product 3e was also prepared on gram-scale (5.0 mmol, 1.4 g
This potentially valuable recovery of the carboxylic acid
product) with an identical isolated yield of 79%. In this case,
0.55 of the 1.50 equivalents of carboxylic acid used were
reclaimed during the work-up.
component is not possible in reaction manifolds in which over-
reduction of the in situ generated aldehyde is a competing
process.10
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Problematic substrates include those whose derived of the reaction. As before, nitro groups and estersVaierweAnrtioclte wOnelilnle-
12a
DOI: 10.1039/C5CC08881J
iminium ion can rearrange. For example, use of a phenylacetic tolerated due to competing reduction processes.
acid (entry 14) resulted in ~30% of the conjugated enamine of
Table 2. Reductive alkylation of primary amines
product 3n.13 Nevertheless, a reasonable isolated yield of 60%
of the desired amine 3n was achieved. Likewise, cinnamic acids
1. PhSiH3 0.75 equiv.
O
toluene, reflux, 2 h
R2
(e.g. entry 15) were susceptible to some alkene reduction, and
only 40% conversion to the desired amine 3o was observed by
1H-NMR. In this case, both the enamine and allylic amine
products were observed. Attempts to reduce the remaining
alkenes with extended reaction times and increased silane
loadings proved unsuccessful, suggesting reduction occurred
primarily during reduction of the amide/iminium species. In
agreement with the scope of Brookhart and Cheng,12a nitriles,
nitro groups and esters (not shown) led to mixtures of reduced
products, although all three groups are tolerated in the initial
amidation step. Methylaniline underwent alkylation to give 3p
in moderate yield (entry 16); increasing the equivalents of
(recoverable) carboxylic acid improves the initial conversion to
amide for less basic amines. Further tolerated functional
groups include ethers and aryl halides.
R1
N
R2
NH2
R1
OH
2. Et2SiH2 3.0 equiv.
[Ir(COD)Cl]2 3 mol%
2 h
H
1
2
5
Isolated
yield (%)
Entry
Secondary amine product
N
H
1
2
5a
77
N
H
5b
5c
5d
79b
F
Cl
N
3
4
66b,c
H
When secondary amide N-benzylbenzamide was included
as an additive in the standard reaction (not shown), only 40%
of the desired tertiary amine 3a was observed, but 90% of the
secondary amide remained unreacted, indicating that modest
yields of tertiary amines can be obtained in the presence of
secondary amides.
MeO
Cl
H
N
77b
3
3
OMe
H
N
We next examined reductive alkylation reactions of
5
6
5e
5f
81b
primary amines to afford secondary amines,
a more
MeO
challenging transformation due to the decreased Lewis-
basicity of the intermediate secondary amide.
Me
H
N
60b,c,d
In preliminary experiments using the above developed
conditions with phenylsilane as reductant, the amide was
obtained as the major product.11 Therefore, in combination
with the phenylsilane-mediated amidation reaction, we
employed the protocol developed by Brookhart,12a with an
increased iridium but reduced silane loading (Table 2). A
particular strength of this new procedure is the 1:1
stoichiometry of the carboxylic acid and amine. While the
reaction affords good yields after 2 h amidation with 0.75
equivalents of phenylsilane (entry 1, 77%), a longer amidation
phase (16 h) and increased phenylsilane loadings (1.0
equivalent) can give slightly improved yields.
Dibenzylamines with differentially substituted aryl groups
are obtained in good yields (entries 1-3) and primary aliphatic
acids are also particularly good substrates (entries 4-5). More
sterically hindered carboxylic acids are also efficient in the
amination process (entries 6-7). Also of note is the tolerance of
a range of protecting groups, namely TBS ethers (entry 7), aryl
methyl ethers (e.g. entry 4), N-Boc, O-Bn and N-Bn (entry 8),
and acetals (entry 9).
OMe
Me
O
N
OTBDMS
7
8
5g
5h
86b,c
62b
H
Me
O
N
H
N
H
Boc
O
Me
Me
H
N
9
5i
5j
66b,c
63b,c,e
35b,c
O
H
N
3
10
11
12
OMe
5k
5l
NC
N
H
H
N
48b,c,f
Deactivated (entries 6-7) and more hindered (entry 5)
amines are both tolerated, but, as before, anilines require a
modified procedure to give good yields (entry 10). In this case,
the initial amidation step benefits from two (or three)
equivalents of carboxylic acid, which do not hinder the
reduction process and can be recovered unmodified at the end
Br
OH
aStandard conditions: 0.5 mmol acid and amine in 0.6 mL toluene. bAmidation
reaction time length, 16 h. cPhSiH3 1.0 equiv. used in amidation step. d1.2 equiv.
carboxylic acid used. e2.0 equivalents carboxylic acid in amidation step. PhSiH3
f
1.5 equiv. in amidation step.
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While nitriles participate in the amidation reaction without
issue, they are reduced in presence of iridium and only modest
yields are obtained (entry 11). Aryl halides are tolerated
(entries 2, 3, 12). Phenols may become silylated during the
amination process; however, the phenol-containing amine
product is recoverable after work-up (entry 12).
Our current mechanistic hypothesis involves the initial
base-catalysed dehydrogenative formation of silyl ester
intermediates,14 which act as acylating agents in the presence
of the amine nucleophile.15 The ability of phenylsilane (PhSiH3)
to form multiply-substituted silicon centres allows
substoichiometric silane loadings in the amidation step. The
reduction phase requires activation of the Lewis-basic amide,
probably by O-silylation from a species of type R3Si-[Ir]-H. The
reduction of the activated species may be performed by Ir-H
species as proposed by Brookhart and co-workers,12a or in the
case of the iminium ion, directly by phenylsilane (or
augmented silyl-hydride containing species).
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Notes and references
1
2
3
(a) F. Abdel-Magid, K. G. Carson, B. D. DHOarI:r1is0,.1C0.3A9/.CM5CaCry0a88n8o1fJf
and R. D. Shah, J. Org. Chem., 1996, 61, 3849; (b) V. I.
Tararov and A. Börner, Synlett, 2005, 203; (c) R. I. Storer, D.
E. Carrera, Y. Ni and D. W. C. MacMillan, J. Am. Chem. Soc.,
2006, 128, 84; (d) S. Hoffmann, M. Nicoletti and B. List, J.
Am. Chem. Soc., 2006, 128, 13074.
N-alkylation reactions between alcohols and amines, another
important, complementary method. For reviews, see; (a) A.
J. A. Watson and J. M. J. Williams, Science, 2010, 329, 635;
(b) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv.
Synth. Catal., 2007, 349, 1555. See also: (c) T. Yan, B. L.
Feringa and K. Barta, Nat. Commun., 2014, 5, 5602.
(a) G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T.
Eaton and J. Johnson, J. Am. Chem. Soc., 1974, 96, 7812; (b)
G. W. Gribble and P. W. Heald, Synthesis, 1975, 650; (c) P.
Marchini, G. Liso, A. Reho, F. Liberatore and F. Micheletti
Moracci, J. Org. Chem., 1975, 40, 3453; (d) G. W. Gribble, J.
M. Jasinski, J. T. Pellicone and J. A. Panetta, Synthesis, 1978,
766; (e) G. Trapani, A. Reho and A. Latrofa, Synthesis, 1983,
1013; (f) C. Perrio-Huard, C. Aubert and M.-C. Lasne, J. Chem.
Soc. Perkin Trans. 1, 2000, 311; (g) A. A. Núñez Magro, G. R.
Eastham and D. J. Cole-Hamilton, Chem. Commun., 2007,
3154.
For reductive N-alkylation of amines with esters and nitriles,
see: (a) W. B. Wright, J. Org. Chem., 1962, 27, 1042; (b) J. M.
Khanna, V. M. Dixit and N. Anand, Synthesis, 1975, 607; (c)
Y.-H. Wang, J.-L. Ye, A.-E. Wang and P.-Q. Huang, Org.
Biomol. Chem., 2012, 10, 6504; (d) Y. Han and M. Chorev, J.
Org. Chem., 1999, 64, 1972; (e) H. Sajiki, T. Ikawa and K.
Hirota, Org. Lett., 2004, 6, 4977; (f) R. Nacario, S. Kotakonda,
D. M. D. Fouchard, L. M. V. Tillekeratne and R. A. Hudson,
Org. Lett., 2005, 7, 471.
I. Sorribes, K. Junge and M. Beller, J. Am. Chem. Soc., 2014,
136, 14314.
M.-C. Fu, R. Shang, W.-M. Cheng and Y. Fu, Angew. Chem.,
Int. Ed. 2015, 54, 9042.
amidation phase
H
N
H
O
O
H
N
+
R1
OH
R3
R1
O
R3
R2
PhSiH3
– H2
4
R2
O
H
H
H
O
x
x
Si
N
+
Si
R3
R2
O
R
Ph
Ph
O
R
y-1
y
OH
active silyl ester
OSiHxRyPh
+
O
reduction phase
R3
N
R3
R1
R1
N
[Ir(COD)Cl]2
PhSiH3
[IrH]
R2
R2
5
6
7
8
9
PhRyHxSi
O
R3
[IrH]
or
R3
R3
R1
N
R1
N
R1
N
PhSiH3
I. Sorribes, K. Junge and M. Beller, J. Am. Chem. Soc., 2014,
136, 14314–14319.
Z. Ruan, R. M. Lawrence and C. B. Cooper, Tetrahedron Lett.,
2006, 47, 7649.
For a review, see (a) D. Addis, S. Das, K. Junge and M. Beller,
Angew. Chem. Int. Ed., 2011, 50, 6004. For representative
catalytic methods, see (b) S. Hanada, E. Tsutsumi, Y.
Motoyama, and H. Nagashima, J. Am. Chem. Soc., 2009, 131,
15032; (c) E. Blondiaux and T. Cantat, Chem. Commun., 2014,
50, 9349; (d) S. Das, D. Addis, S. Zhou, K. Junge, and M.
Beller, J. Am. Chem. Soc., 2010, 132, 1770.
– PhRyHxSiOH
R2
R2
R2
Scheme 7. Proposed general mechanism for reductive alkylation of secondary amines.
In conclusion we have established a robust, direct reductive N-
alkylation reaction of amines with carboxylic acids. Notably,
the reaction is more practical than existing methodologies,5–7
amenable to a typical flask/condenser set-up instead of
Schlenk/autoclave conditions, and has been demonstrated at
gram scale (5.0 mmol).
10 Alcohols have been produced as unwanted by-products in
the Beller protocol (ref. 5). Carboxylic acid reduction is also
possible in the Fu protocol (ref 6).
Conceptually, the N-alkylation protocol differs from
previous reports as it operates in
a
distinct
amidation/reduction manifold. Separating C-N bond formation
and reduction avoids the requirement for sacrificial carboxylic
acid and large excesses of silane, allowing unused carboxylic
acid to be reclaimed upon work-up. This strategic approach is
important as many compatible catalytic silane-mediated amide
reduction methods are known,9 and the opportunity to
develop the procedure with cheaper catalysts and
hydridosilanes has not escaped our attention.
Finally, the catalytic formation and high reactivity of the
silyl ester species generated in the amidation step represents
an underexplored and potentially useful method of carboxyl
activation.
11 For details refer to the Supporting Information.
12 (a) C. Cheng and M. Brookhart, J. Am. Chem. Soc., 2012, 134,
11304. See also a related process with a different iridium
complex: (b) S. Park, D. Bézier and M. Brookhart, J. Am.
Chem. Soc., 2012, 134, 11404.
13 A similar result was observed in a recent amide reduction
methodology report: O. O. Kovalenko, A. Volkov and H.
Adolfsson, Org. Lett., 2015, 17, 446.
14 (a) E. Lukevics and M. Dzintara, J. Organomet. Chem., 1984,
271, 307; (b) H. Gilman, G. E. Dunn, H. Hartzfeld and A. G.
Smith, J. Am. Chem. Soc., 1955, 77, 1287.
15 (a) Y. K. Yur’ev and Z. V Belyakova, Russ. Chem. Rev., 1960,
29, 383; (b) T.-H. Chan and L. T. L. Wong, J. Org. Chem., 1969,
34, 2766; (c) T.-H. Chan and L. T. L. Wong, J. Org. Chem.,
1971, 36, 850.
We are grateful to Dr. Mick Cooper, Graham Coxhill,
Shazad Aslam and Kevin Butler for analytical support.
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