A practical catalytic reductive amination of carboxylic acids

Article abstract of DOI:10.1039/d0sc02271c

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)₂-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.

Full text of DOI:10.1039/d0sc02271c

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DOI: 10.1039/D0SC02271C
ARTICLE
A Practical Catalytic Reductive Amination of Carboxylic Acids†
a
a
a
b
b
Emma L. Stoll , Thomas Tongue , Keith G. Andrews , Damien Valette , David J. Hirst and Ross M.
Denton*,a
Received 00th January 20xx,
Accepted 00th January 20xx
We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction
DOI: 10.1039/x0xx00000x
exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc) -catalyzed amide
2
reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on large
scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is
exemplified in convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that residual
0
.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with
augmented reactivity, which allow secondary amides, previously unreactive in zinc/silane systems, to be reduced.
INTRODUCTION
Amines and their derivatives are found in a wide range of
fundamentally and commercially important molecules. As a
result, there are numerous methods for the construction of
carbon-nitrogen bonds, such as N-alkylation, Buchwald-Hartwig
1
2
3
coupling, the Ullman reaction and hydroamination. In the
context of N-alkylation, the most important and widely used
methods involve either nucleophilic substitution with alkyl
halides/pseudohalides or reductive amination using
4
aldehydes. In both cases, the required electrophiles are
typically generated from alcohols through either stoichiometric
activation or oxidation. Alternatively, alcohols can be directly
used in the more atom economical “borrowing hydrogen”
5
,6
approach. A much less explored but potentially powerful
method of N-alkylation involves the use of carboxylic acids as
nominal electrophiles. Carboxylic acids are relatively abundant,
inexpensive, easier to handle than aldehydes and avoid the
7–10
toxicity issues associated with alkyl halides.
For these
reasons a general reductive amination protocol using carboxylic
acids would be of significant value.
The first reductive alkylation reactions of amines with carboxylic
acids were reported in the 1970s using super-stoichiometric
metal borohydrides.1
1–13
In general, these alkylations were
narrow in scope and employed liquid carboxylic acids as the
Figure 1. Reductive amination of amines using carboxylic acids exploiting the dual
reaction solvent or were limited to aniline substrates. More reactivity of phenylsilane.
recently, Beller and co-workers disclosed a catalytic N-alkylation
of primary and secondary amines with carboxylic acids, using
Whilst this method represents a clear breakthrough, large
excesses of phenylsilane (up to 10 equiv.) and carboxylic acid
Karstedt’s catalyst and phenylsilane as the terminal reductant
14
(Figure 1A).
(up to 5.5 equiv.) are required to mitigate the non-productive
reduction of aldehyde intermediates (Figure 1A). Further work
15
by Fu and co-workers used polymethylhydrosiloxane (PMHS)
as the reducing agent in the presence of substoichiometric
tris(perfluorophenyl)borane. Again, large excesses of the
carboxylic acid (up to 5 equiv.) and PMHS (up to 8 equiv.) are
required for the reaction, which is also performed under
a.School of Chemistry, University of Nottingham; GlaxoSmithKline Carbon Neutral
Laboratories for Sustainable Chemistry, 6 Triumph Road, Nottingham, NG7 2GA,
UK.
GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
b.
†
Electronic Supplementary Information (ESI) available: Details of experimental
procedures and characterisation of compounds. See DOI: 10.1039/x0xx00000x
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Journal Name
Table 1. Catalytic reduction of a secondary amide: the remarkable eVffieewctAorfticcalerbOonxlyinliec
Schlenk conditions. Following on from these two examples,
further catalytic methods have been documented which involve
acid additives.
DOI: 10.1039/D0SC02271C
16
17
18
19
20
Ru, Rh, Ir, Cu and Pt catalysts in combination with silane
terminal reductants. Additionally, systems involving dihydrogen
as the terminal reductant have also been described.21,22 Despite
these reports a practical method that is applicable to primary
and secondary amines and mediated by an inexpensive catalyst
is yet to be realized. Here we report a general reductive
Entry
PhSiH
equiv.
3
Zn(OAc)
mol%
2
/
Carboxylic Acid Time/ Yield/
a
h
%
amination protocol of carboxylic acids using Zn(OAc)
2
in
combination with phenylsilane, which has been demonstrated
on a 305 mmol scale (Figure 1B). The reductive amination
exhibits predictable selectivity that allows the chemistry to be
deployed in sequential amination processes as well as in API
synthesis. Mechanistic studies demonstrate that excess
carboxylic acid from the amidation stage of the reaction is
responsible for modification of the silane reductant in situ,
which allows previously unreactive substrates to be reduced.
1
2
3
4
5
6
7
1
2
3
2
3
3
3
10
10
10
10
10
10
0
-
6
1
-
6
20
22
27
65
60
0
-
6
-
24
6
C
6
H
5
2
CO H
p-F-C
6
H
4
CO
2
H
6
-
6
aYield determined by 19F NMR spectroscopy using α,α,α-trifluorotoluene as an internal
standard.
RESULTS AND DISCUSSION
In contrast to previous work (Figure 1A) our reaction design
We had previously observed that Brønsted acids react rapidly
with phenylsilane to generate modified silanes with enhanced
reducing properties and, remarkably, the addition of 50 mol%
(
Figure 1B) is based upon the dual reactivity of hydrosilanes,
23–26
which mediate direct amide coupling
in the presence of a metal catalyst.
and amide reduction
34
2
7–30
Combining these
of benzoic acid (entry 5) resulted in a substantial improvement
in the yield to 65%. More significantly, we found that the
carboxylic acid could be changed to match that from which the
secondary amide was derived (entry 6). This result implies that
a 0.5 equivalent excess of carboxylic acid (i.e. 1.5 equiv. at the
beginning of the reaction) should result in the catalytic
reductive amination of primary amines that we sought, in which
phenylsilane functions as an amide coupling reagent and then
as the terminal reductant. Gratifyingly, this proved to be the
case and we therefore surveyed the scope of the carboxylic acid
processes gives a reductive amination reaction in which carbon-
nitrogen bond formation is complete before reduction begins,
thereby avoiding unwanted reduction of the carboxylic acid,
leading to alcohol by-products. Although we had established
proof-of-concept for this general approach using iridium
18
catalysis, the synthesis of secondary amines was complicated
by relatively high iridium loadings and the fact that different
silanes were required for the amidation and reduction step. In
developing a general and more practical catalytic reductive
amination we were attracted to the Zn(OAc)
2
because of its low
2
enhanced Zn(OAc) /phenylsilane reductive amination (Table 2).
cost3 and reported activity for tertiary amide reduction in
combination with triethoxysilane.32 Unfortunately, the
reduction of secondary amides, required for the synthesis of
secondary amines, was known to be poor with
1
Beginning with the secondary amines, previously unattainable
from reduction of secondary amides, it can be seen that a range
of potentially reducible functional groups are tolerated in both
the acid and amine component, including aryl halides (entries 1,
33
Zn(OTf)
catalytic reductive amination, we began by developing a new
Zn(OAc) -catalyzed reduction protocol using phenylsilane as the
2
/phenylsilane. Therefore, in order to realize a general
5
and
and
silane is required in order to compensate for silyl ether
formation (entry ). Alternatively, standard silyl ether protected
8
), acetals (entry
2), nitro (entry 4) and alkenes (entries 3
7
). Free hydroxyl groups are also tolerated but additional
2
terminal reductant.
We first examined the reduction step of the proposed reductive
amination reaction in isolation using a model secondary amide
8
substrates can be used without the requirement for additional
silane (entry 10). Finally, with respect to the carboxylic acid, the
(Table 1). An initial experiment with 1 equivalent of
scope includes electron rich aromatic carboxylic acids (entries
2
4
phenylsilane and 10 mol% Zn(OAc) (entry 1) gave a very poor
2
and
and
3
6
), electron deficient aromatic carboxylic acids (entries
) as well as aliphatic carboxylic acids (entries
conversion of 1% which was increased to a maximum of 22% as
the amount of phenylsilane was increased (entries 2-3). Since
the remainder of the mass balance in these reactions was the
unreacted amide, the reaction time was increased to 24 hours
7
and 10).
With respect to tertiary amine synthesis (Table 2) we note that
the reduction of the amide intermediate in this case is faster
and complete within 2 hours compared to 6 hours for secondary
amide intermediates. Amination was efficient for a wide range
of substituted benzoic acids containing electron donating
(entry 4). However, this resulted in only a very modest
improvement and gave 27% of the amine product.
These initial results were in agreement with related
groups (entries 12
, 15, 16 and 17), electron withdrawing groups
33
observations of Beller and co-workers.
(entries 13 and 20), halides (entries 14, 18 and 19) and a boronic
acid ester (entry 22). Disappointingly aniline substrates (not
depicted) showed poor reactivity in the reaction.
2
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0SC02271C
Table 2. Reductive Amination Substrate Scope
Reaction conditions: Secondary Amine Products - PhSiH
Amine Products - PhSiH (0.75 equiv.), toluene, reflux, 16 h then PhSiH
h then PhSiH (3.0 equiv.), Zn(OAc) (10 mol%), toluene, reflux, 6 h.
3
(0.75 equiv.), toluene, reflux, 16 h then PhSiH
3
(3.0 equiv.), Zn(OAc)
2
(10 mol%), toluene, reflux, 6 h; Tertiary
3
3
(2.0 equiv.), Zn(OAc) (10 mol%), toluene, reflux, 2 h. a - PhSiH (1.75 equiv.), toluene, reflux, 16
2
3
3
2
The latter example provides a good illustration of how the completion of the reductive amination reaction, the crude
reductive amination can be deployed for the construction of a reaction mixture was decanted from the reactor and zinc
tertiary amine building block with two versatile functional precipitate was removed by filtration through Celite. The
groups for further derivatization. Pyridines are tolerated in both product was obtained in an isolated yield of 92% (with an HPLC
the acid and amine component (entries 21
aliphatic carboxylic acids also undergo efficient coupling with treatment of the filtrate with concentrated hydrochloric acid.
both cyclic and acyclic amines (entries 23 24 and 25). In all but In a second study, we examined the construction of
cases, the tertiary amine products were obtained by acid-base differentially N,N-disubstituted piperazines (Scheme 1B). These
work-up without recourse to chromatography. are a privileged class of compounds with biological activities
, 24 and 25) and purity of 93%) as the hydrochloride monohydrate after
,
4
We next sought to explore further the utility and practicality of including antifungals, antidepressants, antivirals, and serotonin
the reductive amination reaction and began by examining a receptor (5-HT) antagonists/agonists.3 The conventional
large-scale reaction (Scheme 1A). Reductive amination between approach to N,N-disubstituted piperazines involves mono Boc-
benzylamine (305 mmol) and benzoic acid was carried out in a protection of piperazine followed by reductive amination or
one litre controllable lab reactor equipped with overhead alkylation, carbamate cleavage and a second reductive
stirring and a heating jacket. Given that hydrogen gas is amination or alkylation. Depicted in Scheme 1B is a more
generated during the amidation-phase of the process, the silane efficient approach using 2-oxopiperazine 27 as a building block
was added by syringe pump at a rate of 2 mL/min. Following in lieu of N-Boc piperazine.
5
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DOI: 10.1039/D0SC02271C
Large-scale reductive amination
A
O
(i) PhSiH3 (0.75 equiv.)
(
ii) Zn(OAc)2 (10 mol%),
PhSiH3 (3.0 equiv.)
N
OH
H2N
H
toluene, 110 oC; HCl
HCl
6, 92%, >90% HPLC purity
70.9 g, no chromatography
2
(
1
457 mmol,
.5 equiv.)
(305 mmol, 0.83 M)
Sequential reductive amination
O
O
B
S
OH
OH
1.5 equiv.)
(
1.5 equiv.)
(
O
S
HN
N
(
i) PhSiH3 (0.75 equiv.)
N
(i) PhSiH3 (0.75 equiv.)
N
NH
NH
(
ii) Zn(OAc)2 (25 mol%),
PhSiH3 (3.0 equiv.)
(ii) Zn(OAc)2 (10 mol%),
PhSiH3 (2.0 equiv.)
27
toluene, 110 o
28, 54%
29, 75%
C
toluene, 110 o
C
reductive amination
lactam reduction
unsymmetrical piperazine
no protecting groups
reductive amination
Selective reduction of tertiary amides
O
O
C
OH
NHBoc
HN
PhSiH3 (0.75 equiv.)
N
O
toluene, 110 o
NH
O
C
Boc
0, 81%
(
1.5 equiv.)
3
HCl, dioxane
CH Cl
O
O
2
2
(
i) PhSiH3 (0.75 equiv.)
3o amine formed
without 2 amide
NH
O
OH
(
ii) Zn(OAc)2 (10 mol%),
PhSiH3 (2.0 equiv.)
o
N
(
1.5 equiv.)
reduction
O
N
NH2
31, 83%
O
toluene, 110 o
C
32, 63%, 94% e.e.
Synthesis of API Maraviroc
O
F
F
iPr
F
F
D
direct amidation
OH
N
N
HN
selective
F
reductive amination
N
35
Me
F (1.5 equiv.)
iPr
N
O
3) PhSiH3 (0.5 equiv.),
toluene, µW, 170 C;
O
NH
NH2
O
1) PhSiH3 (0.75 equiv.)
NH
O
o
toluene, 110 o
C
N
OMe
OH
N
2
) NaOH (5 equiv.),
4) PhSiH3 (10 equiv.),
Zn(OAc)2 (25 mol%),
chlorobenzene, 100 oC
N
H2O
Me
33
34
maraviroc, 4 steps, 43%, from 33
previously 7 steps, 25%36, from 33
7
6% (2 steps)
57%
Scheme 1. Large-Scale Reductive Amination and Synthesis Applications
Reductive amination of 2-oxopiperazine 27 affords the Boc-phenylalanine gave amide 30 which was deprotected to
corresponding amine 28, resulting from N-alkylation and lactam give amine 31. Treatment of this primary amine with benzoic
reduction.
thiophenecarboxylic acid afforded the differentially substituted addition of Zn(OAc)
product 29, which demonstrates a modular synthesis of the tertiary amide to afford tertiary amine 32 in good yield and
privileged diamine structures. excellent stereochemical integrity (63%, 97% e.e.). Reduction of
A
second reductive amination with 2- acid formed the secondary amide intermediate and subsequent
2
/phenylsilane resulted in reduction of only
During our optimization studies we established that catalytic the secondary amide was not observed.
reduction of secondary amides is significantly slower than In a final study, we made use of the reductive amination
tertiary substrates. With target synthesis applications in mind, protocol in a short, convergent synthesis of the anti-retroviral
we carried out a study to explore selective reductions (Scheme medicine maraviroc. The construction of the tertiary amine
1
C). Silane-mediated direct amidation of morpholine with N- (Scheme 1D) has proven to be challenging and, in the process
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ARTICLE
developed by Pfizer,36 was accomplished by conventional pharmaceutical ingredient in 57% yield. This synthesis
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DOI: 10.1039/D0SC02271C
reductive amination of an aldehyde. The aldehyde intermediate demonstrates the advantages of a carboxylic acid reductive
37
was derived from β-phenylalanine methyl ester 33, by benzoyl amination in terms of step and redox economy and compares
protection of the amine, ester hydrolysis, reduction of the favourably to the Pfizer synthesis (4 steps versus 7 steps from
derived acid to alcohol and, finally, oxidation of the alcohol. This the common intermediate 33).
gives a total of three redox steps associated with the
construction of the carbon-nitrogen bond. We envisioned a
3
7
MECHANISM: ROLE OF THE CARBOXYLIC ACID
Having explored the scope and utility of the Zn(OAc) -catalyzed
2
reductive amination reaction, we next carried out experiments
in order to probe the role played by residual carboxylic acid in
the amide reduction step. Beller and co-workers had previously
reported that the combination of Zn(OTf) and phenylsilane
2
was poor for the reduction of secondary amides and our own
experiments (Table 1) demonstrated that the combination of
more redox economical route based on the reductive
36
amination of carboxylic acid 34 and tropane 35
carboxylic acid was prepared from -aminoester 33 in excellent
yield (76% over two steps) by phenylsilane-mediated direct
. The required
β
38
amidation
with 4,4-difluorocyclohexanecarboxylic acid,
followed by saponification of the methyl ester. Reductive
amination was then performed by treatment of the carboxylic
acid and amine 35 with phenylsilane to effect the difficult
amidation reaction. Selective reduction of the tertiary amide
30
Zn(OAc)
2
gave similar results.
2
using modified conditions (25 mol% Zn(OAc) ) gave the active
Reaction monitoring implicates in situ generated silyl esters
A
O
N
H
Ph
O
O
H N
Ph
2
PhSiH3 (3.0 equiv.),
Zn(OAc)2 (10 mol%)
OH PhSiH3 (0.75 equiv.)
F
OH
N
H
Ph
3
8 65%
19F NMR d = -115.6 ppm
toluene, 110 °C
toluene, 75 °C
F
F
F
Hx
O
3
6
36
0.5 equiv. remaining)
37
(
Si
(
1.5 equiv.)
19F NMR d = -105.6 ppm
19F NMR d = -107.9 ppm
O y
Ph
F
PhSiH3
silyl esters generated
in situ from acid 36 and PhSiH3
19F NMR d = -103.3 to -105.2 ppm
Preformed silyl esters are active terminal reductants
O
B
Hx
Si
O
O
MeN
O
N
Ph
H
O y
Ph
37
PhSiH3 (10 mol%)
toluene, 80 o
F
N
Ph
OH
H
C
F
Zn(OAc)2 (10 mol%),
F
F
toluene, 110 °C; H O workup
2
silyl esters (3 equiv.)
(
3.0 equiv.)
38 65%
36
19F NMR d = -103.9 to -105.2 ppm
19F NMR d = -115.6 ppm
Silane reactivity comparison
Plausibe reduction pathway
C
phenylsilane reacts slowly with Zn(OAc)2
D
silyl ester formation with residual carboxylic acid
O
toluene, 110 °C
hour
Zn(OAc)2
PhSiH3
no reaction
Hx
O
1
R1
OH
1H NMR d = 4.25 ppm
Si
PhSiH3
R1
Ph
1H NMR d = 6.75 - 7.25 ppm
O y
-
H2
40
silyl ester 39 reacts rapidly with Zn(OAc)2
new hydride and
Ar-H environments
silyl esters generate hydride species and activate amide
Zn(OAc)2
Hx
O
H
H
O
HZn(OAc)Ln
toluene, 110 °C
Si
Si
O
R1 40 O y
Ph
Ph
O
Me
Hx
O
R2
1
hour
H
R1
N
R1
N
Si
3
9
LnZn(OAc)2 (cat.)
Me
O y
Ph
H
R2
1H NMR d = 4.25 ppm
1H NMR d = 3.55 - 4.00 ppm
1H NMR d = 7.00 - 8.00 ppm
HZn(OAc)Ln
1H NMR d = 6.75 - 7.25 ppm
Scheme 2. The Role of the Carboxylic Acid in the Reduction Phase of the Amination Reaction
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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However, the addition of a carboxylic acid resulted in a be further activated and then reduced tDoOtI:h1e0.1a0m39in/De0pSCro02d2u7c1tC.
significantly improved reduction process (Table 1, entries 5 and Finally, we note that although zinc has been depicted with
6
). We reasoned that the carboxylic acid was modifying the acetate ligands, exchange with the residual carboxylic acid is
silane in situ generating a more reactive species, which, in possible but has not been depicted for the sake of clarity.
combination with Zn(OAc) , was able to reduce secondary
amides at enhanced rates. In order to investigate this
2
1
9
Conclusions
possibility, we carried out a F NMR study using carboxylic acid
. We first examined the 19F NMR spectrum of the crude
reaction mixture at the end of the amidation phase of the
3
6
2
We have demonstrated a practical Zn(OAc) -catalyzed N-
alkylation reaction of amines that allows carboxylic acids to be
used directly in lieu of aldehydes and alkyl halides. The reactions
are conducted in conventional laboratory glassware, are
tolerant of other potentially reducible functional groups and
have been demonstrated on a large scale (305 mmol with
respect to the amine component). Finally, the elucidation of the
role played by the residual carboxylic acid provides mechanistic
insight that can potentially be transferred to the design of new
reduction reactions in which silane reactivity is augmented in
situ using Brønsted acids.
1
9
reaction (Scheme 2A). As expected, amide 37 was visible ( F
δ=‒107.9) along with the remaining 0.5 equivalents of
carboxylic acid 36 ( F δ=‒105.6). Subsequent addition of
Zn(OAc) and additional phenylsilane resulted in the generation
of hydrogen gas and a broad range of new F environments
19
40
2
1
9
1
9
40
downfield of the carboxylic acid ( F δ=‒103.3 to ‒105.2).
These signals we attribute to multiple silyl esters that are
generated by a dehydrogenative silylation process which could
be catalyzed by residual amine from the amidation step or, as
the reaction progresses, by the amine product.
Having observed species that we believed to be silyl ester
3
4
intermediates in the reduction phase of the reaction, we carried Conflicts of interest
out a further experiment in which carboxylic acid 36 was treated
with phenylsilane and catalytic N-methylmorpholine (Scheme
There are no conflicts to declare.
3
4
2
B) – conditions which will generate a mixture of silylesters.
19
19
Gratifyingly, a similar F NMR profile was observed ( F δ=‒
Acknowledgements
1
03.9 to ‒105.2) along with some residual carboxylic acid.4
0
The authors thank Prof Hon Wai Lam for the use of chiral HPLC
equipment and Mr. Andrew Payne for assistance with process
safety studies. The authors are gratefully acknowledge funding
2
Subsequent addition of secondary amide 37 and Zn(OAc) to
this mixture gave amine 38 in 65% yield. This experiment
provides further evidence that silyl esters participate in the
amide reduction.
(CASE studentship E.S.L. and PDRA funding T.T.) from
GlaxoSmithKline.
In a final experiment we sought to compare the reactivity of
phenylsilane with an independently prepared silyl ester 39
4
0
(
Scheme 2C). Refluxing phenylsilane with Zn(OAc)
2
(1 equiv.)
1
Notes and references
for one hour resulted in no observable reaction as judged by H
NMR spectroscopy. However, the reaction of silyl ester 39 with
1
2
3
4
5
6
7
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Zn(OAc)
2
resulted in a range of new aromatic environments ( H
1
δ=8.15 to 7.45), the disappearance of species 39 and new broad
1
hydride environments ( H δ=4.15 to 3.55) upfield of
5
phenylsilane. These observations are consistent with silane
modification, and, possibly, the formation of a zinc hydride
41
species. On the basis of these observations we can derive a
plausible pathway for the catalytic amide reduction (Scheme
2
D). We speculate that the residual carboxylic acid from the
amidation step of the reaction undergoes dehydrogenative
silylation to afford a mixture of silyl esters depicted as the
general structure 40. Once formed this mixture reacts with
Zn(OAc)
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more rapidly than the parent silane and this
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have been invoked by Mlynarksi and co-workers in Zn(OAc) -
4
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6
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