Direct Catalytic Reductive N-Alkylation of Amines with Carboxylic Acids: Chemoselective Enamine Formation and further Functionalizations

Article abstract of DOI:10.1021/acscatal.9b01974

Direct reductive N-alkylation of secondary amines with carboxylic acids using molybdenum hexacarbonyl (5 mol %) as catalyst and diethoxymethylsilane as reducing agent generate enamines in a straightforward fashion in high yields. The formed enamines are without the need for isolation or purification further reacted with trimethylsilyl cyanide in the same reaction flask to yield α-amino nitriles in good yields. In the optimized reaction conditions equimolar amounts of carboxylic acid and amine are reacted under neat conditions, and a catalytic amount of trifluoroethanol (0.1 mol %) is added along with TMSCN for the cyanation step. The reductive N-alkylation reaction is demonstrated to be highly chemoselective, tolerating a multitude of different functional groups present in the starting carboxylic acids and amines. The reaction is scalable and the generated α-amino nitriles are converted to other useful compounds, e.g., α-amino acids or amino-tetrazoles. In addition, the intermediate enamines are further transformed into triazolines, sulfonylformamidines, pyrimidinediones, and TMS-propargylamines, respectively, in high yields under mild reaction conditions. Benzoic acids react with secondary amines under similar conditions to give tertiary amines in high yields, and using this methodology, the biologically active compound Piribedil was isolated in 80% yield in a direct one-pot reaction setup.

Full text of DOI:10.1021/acscatal.9b01974

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Article
Direct Catalytic Reductive N-Alkylation of Amines with Carboxylic Acids:
Chemoselective Enamine Formation and further Functional-izations
Paz Trillo, and Hans Adolfsson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01974 • Publication Date (Web): 09 Jul 2019
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Direct Catalytic Reductive N-Alkylation of Amines
with Carboxylic Acids: Chemoselective Enamine
Formation and further Functionalizations
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Paz Trillo and Hans Adolfsson*
Department of Chemistry, Umeå University, KBC3, Linnaeus väg 10, SE-90187 Umeå,
Sweden
KEYWORDS: chemoselective N-alkylation, carboxylic acids, enamine, hydrosilylation,
functionalization
ABSTRACT. Direct reductive N-alkylation of secondary amines with carboxylic acids
using molybdenum hexacarbonyl (5 mol%) as catalyst and diethoxymethylsilane as
reducing agent generate enamines in a straightforward fashion in high yields. The
formed enamines are without the need for isolation or purification further reacted with
trimethylsilyl cyanide in the same reaction flask to yield α-amino nitriles in good yields.
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In the optimized reaction conditions equimolar amounts of carboxylic acid and amine
are reacted under neat conditions, and a catalytic amount of trifluoroethanol (0.1 mol%)
is added along with TMSCN for the cyanation step. The reductive N-alkylation reaction
is demonstrated to be highly chemoselective, tolerating a multitude of different
functional groups present in the starting carboxylic acids and amines. The reaction is
scalable and the generated α-amino nitriles are converted to other useful compounds,
e.g. α-amino acids or amino-tetrazoles. In addition, the intermediate enamines are
further transformed into triazolines, sulfonylformamidines, pyrimidinediones and TMS-
propargylamines, respectively, in high yields under mild reaction conditions. Benzoic
acids react with secondary amines under similar conditions to give tertiary amines in
high yields, and using this methodology, the biologically active compound Piribedil was
isolated in 80% yield in a direct one-pot reaction set-up.
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INTRODUCTION
Substituted amines are important functional groups present in numerous biologically
active organic compounds such as amino acids, nucleotides and alkaloids. Substituted
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amines play an important role in chemistry and biology, frequently being used as
versatile building blocks for organic and biological systems, agrochemicals and
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pharmaceuticals. Therefore, methods that enable efficient synthesis of substituted
amines have been pursued intensively. Among the different methodologies available,
catalytic reduction protocols of imines and amides constitute fundamental routes for
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their preparation. However, an inherent drawback of such synthetic protocols is the
need of proper starting materials, where the latter frequently needs to be prepared and
isolated prior to the reduction step (Scheme 1, a).3
Direct reductive amination of carbonyl compounds represent a well-established and
practical approach for the formation of substituted amines. In this sense, mainly
aldehydes or ketones are reacted with amines in the presence of a reducing agent to
afford the desired products.4
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Step 1:
Amide formation
Step 2:
Reduction
O
R3
R1
N
(
a) (
X = OH, Cl
or activating agents)
R2
reductant:
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Direct
catalytic reductive N-alkylation
Scheme 1. Methods for reductive N-alkylation of amines: (a) Two-step amide formation
and subsequent reduction using silane, borane or H as reductant. (b) Direct catalytic
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reductive protocol using carboxylic agents as alkylating reagents with silane, borane or
H as reductant.
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In contrast, the use of such a strategy starting from carboxylic acids is significantly less
studied due to the lower reactivity of the acids and the intermediate amides.
Nevertheless, direct reductive alkylation of amines with carboxylic acids offer several
advantages. Carboxylic acids are frequently rather stable, non-toxic, and readily
available with large structural variation, which make such compounds most suitable as
N-alkylating agents for the formation of substituted amines (Scheme 1, b).5
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A limited number of methodologies have been presented for the catalytic N-alkylation
of amines with carboxylic acids in the presence of silanes (Scheme 2). The first protocol
reported was by Beller’s group in 2014, where a [Platinum/dppe] complex was used to
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obtain a broad scope of N-alkylamines in high yields (Scheme 2, a). A year later, Fu,
Shang and co-workers reported on a catalytic boron-acid system employing
polymethylhydrosiloxane (PMHS) as hydride source, and they obtained more than
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twenty N-alkylamines in excellent yields (Scheme 2, b). After these pioneering works,
different methodologies have been published by the groups of Kobayashi, Denton and
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Minakawa for the same transformation using rhodium-, iridium-, and ruthenium-
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based catalysts, respectively (Scheme 2, c, d and e).
(
e) Minakawa et al. 2016
[Ru] cat. 2.5 mol%
P(C F ) 7.5 mol%
(
d) Denton et al. 2016
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5 3
[Ir] cat. 1 - 3 mol%
MePhSiH 7.2 equiv
2
o
PhSiH 3 - 3.75 equiv
3
1
00 C, 1,4-dioxane, 3 - 12h
reflux toluene, 4 - 18 h (c) Kobayashi et al. 2015
R1
O
[Rh] cat. 0.25 - 1.5 mol%
H
+
N
R3
PhSiH 4 - 6 equiv
3
R2
R1
OH
N
o
R2
R3
2
30 - 50 C, THF, 20 h
R = H or = H
[
B] cat. 0.5 - 1 mol%
[
Pt] cat. 0.5 - 1 mol%
PMHS 2.5 - 7 equiv
dppe 0.5 - 1 mol%
o
1
00 C, toluene, 13 - 20 h
PhSiH 3.3 - 10 equiv
3
o
rt to 100 C, n-Bu O, 18 h
2
(b) Fu and Shang et al. 2015
(
a) Beller et al. 2014
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Scheme 2. Catalytic N-alkylation of amines with carboxylic acids under hydrosilylation
conditions.
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In spite of the recent breakthroughs and the progress made in this field over the last
years, there are, to the best of our knowledge, no reports on the selective N-alkylation
of amines with carboxylic acids leading to enamines. Carboxylic acids possessing -
hydrogens are particular interesting since partial reduction of the intermediate amide
can lead to the corresponding enamines. Enamines are reactive intermediates present
in a number of organic transformations and can thus serve as suitable synthetic handles
for a number of further elaborations. Herein we describe an un-precedented, mild and
chemoselective catalytic protocol for the reductive N-alkylation of amines using
carboxylic acids under hydrosilylation conditions, which allows for the formation of
enamines and the subsequent functionalization of these into α-amino nitriles (Scheme
3).
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R1
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R2
OH
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Neat
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Scheme 3. This work: Mo(CO) catalyzed selective N-alkylation of amines with
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carboxylic acids under hydrosilylation conditions.
RESULTS AND DISCUSSION
We have previously developed a highly chemoselective protocol for the reduction of
amides based on catalytic amounts of Mo(CO)6 and TMDS (1,1,3,3-
tetramethyldisiloxane) as terminal reductant.11 Depending on the reaction conditions
used, we were able to selectively convert amides to either amines or aldehydes, via an
intermediate silylhemiaminal. Performing the reduction on carboxamides bearing α-
hydrogens opened a direct route for the formation of enamines, which were
subsequently further functionalized.12,13 This methodology was successfully applied in
the chemoselective reductive functionalization of amides into bi-functional compounds
such as α-amino nitriles, an essential class of compounds with interesting
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pharmacological and biological properties.13,14 The ready availability of carboxylic acids
and amines prompted us to examine a similar process, where the direct amidation
followed by reductive functionalization would yield highly functionalized compounds
from simple starting materials using a one-pot setup. We started by investigating
different reaction parameters such as testing various silanes, temperatures and solvents
for the reaction between phenylacetic acid (1a) and pyrrolidine (2a). The reductive
vinylation of 2a in the presence of 5 mol% of Mo(CO) and Me(EtO) SiH as hydride
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source, gave the corresponding enamine 3a’ in 89% H NMR yield. To our delight,
performing the reaction under neat conditions and with stoichiometric amounts of the
reagents allowed for full conversion to the enamine in less than 3 hours, hence
demonstrating high efficiency and excellent atom economy (For more details on the
optimization procedure and results, see the Supporting Information).
Enamines are frequently used as reactive intermediates in many organic
transformation. Addition of trimethylsilyl cyanide (TMSCN, 2 equiv) and catalytic
amounts of 2,2,2-trifluoroethanol (TFE) after the initial formation of 3a’ gratifyingly
resulted in the formation of the corresponding α-amino nitrile 3a in 90% in less than 1
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hour (for more information, see the Supporting Information). Attempts to obtain 3a by
addition of TMSCN from the beginning of the reaction sequence did not result in the
desired product and we only observed the formation of the corresponding amide.
With the above conditions in hand, the scope of the catalytic reductive alkylation of
amines into enamines followed by subsequent functionalization into α-amino nitriles in a
one-pot reaction setup was studied in detail. As shown in Scheme 4, a variety of aryl-
and alkyl-acetic acids were successfully used for the vinylation of pyrrolidine generating
the corresponding enamines, which thereafter were further functionalized into the final
products.
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Phenyl acetic acids carrying electron-donating or electron-withdrawing substituents
gave the desired α-amino nitriles 3b, 3c, 3d and 3e, respectively in high yields (Scheme
4). The direct formation of α-amino nitrile 3e without dehalogenation allows for further
functionalizations into even more complex structures. When 2-cyclohexylacetic acid was
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used as alkylating agent, a good H NMR yield was observed in the initial formation of
the corresponding enamine, however, 3f was only isolated in moderate yield. High yield
was achieved for double alkylation using 1,4-phenylenediacetic acid, giving in
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quantitative yield of the corresponding di-cyanation product 3h. Next, we turned out our
attention to carboxylic acids containing different functional groups. Amino group (3i) and
heterocycles (3j, 3k and 3l) were well tolerated giving the corresponding enamines and
subsequent α-amino nitrile in moderate to high yields. In the case of trans-styrylacetic
acid (1n), the conjugated intermediate enamine was quantitatively formed allowing for
the formation of 3n in high yield. This catalytic methodology also tolerated acetals,
terminal olefins and cyano groups and α-amino nitriles 3m, 3o and 3p, respectively,
were obtained in high yields. To our delight, the hydroxyl moiety (3q) was not silylated
under the reaction conditions, which demonstrates the high level of chemoselectivity of
this protocol. When this catalytic protocol was applied on linear aliphatic acids and
phenylacetic acids containing nitro and aldehydes groups, respectively, no or small
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amounts of the corresponding enamines were detected by H NMR analysis.
Next, we focused on the alkylation of different amines (Scheme 5). Moderate basic
amines such as morpholine afforded the enamine and the subsequent α-amino nitrile 3s
in good yield. N-methyl amines are of special interest because of their role in the
regulation of several biological processes.15 In this respect, N-methyl piperazine and
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dimethyl amine were successfully vinylated with phenyl acetic acid to the corresponding
enamines, and subsequently reacted with TMSCN to afford α-amino nitriles 3t and 3u,
respectively, in good isolated yields. Interestingly, no reduction of the ester moiety on
the piperidinyl carboxylate derivative was observed although the enamine (3v’) was only
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formed in 61% H NMR yield. When the amine containing an acetal moiety was used,
high yield was obtained for α-amino nitrile 3y.
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5
5
5
5
5
6
1
) Mo(CO) 5 mol%
6
Me(EtO) SiH 4.5 equiv
2
o
CN
O
neat, 65 C
HN
R1
R1
+
N
OH
2) TMSCN 2 equiv
TFE 0.001equiv, 60 min, r.t.
1
2a
1 equiv)
3
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F3C
Br
CN
CN
CN
CN
MeO
N
N
N
N
4
3
-OMe: 3b 89%(90%)
-OMe: 3c 89%(>95%)
3
a 90%(89%)
3d 90%(>95%)
3e 93%(97%)
N
H N
2
CN
CN
N
CN
N
CN
CN
N
N
3
f 66%(82%)
3g, 88%(>95%)
3h, 91%(>95%)
OMe
3i, 78%(90%)
O
O
CN
CN
CN
HN
CN
X
N
N
N
X = S, 3j 90%(92%)
X = O, 3k 93%(88%)
3l, 73%(77%)
3m, 85%(>95%)
NC
CN
N
CN
HO
CN
N
N
N
3
n, 85%(88%)
3o, 81%(>95%)
3p, 71%(80%)
3q, 87%(90%)
Scheme 4. N-alkylation of 2a with various carboxylic acidsa.
a
Isolated yields. In parenthesis 1H NMR yields for the corresponding enamine using 1,3,5-
trimethoxybenzene as internal standard. Step 1: Mo(CO) (0.05 mmol), carboxylic acid (1.00 mmol),
6
pyrrolidine 2a (1.01 mmol), Me(EtO) SiH (4.50 equiv). For information about temperature and time for
2
each substrate, see Table S3 in Supporting Information. Step 2: TMSCN (2.00 equiv), TFE (100 μL), r.t.,
6
0 min.
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1
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
) Mo(CO) 5 mol%
6
Me(EtO) SiH 4.5 equiv
2
o
R3
CN
O
HN
neat, 65 C
R3
Ph
+
Ph
R2
N
3 R2
2) TMSCN 2 equiv
OH
1a
2
TFE 0.001 equiv, 60 min, r.t.
(1 equiv)
OMe
CN
CN
CN
CN
Ph
Ph
Ph
Ph
N
N
Ph
N
N
O
N
3r, 62% (70%)
3s, 55% (59%)
3t, 65% (70%)
3u, 59% (60%)
CN
Ph
CN
CN
N
N
Ph
N
N
N
O
CO Me
N
2
O
3v, 55% (61%)
3w, 67% (70%)
3y, 87% (94%)
Scheme 5. N-alkylation of different amines with 1aa.
a
Isolated yields. In parenthesis 1H NMR yields for the corresponding enamine using 1,3,5-
trimethoxybenzene as internal standard. Step 1: Mo(CO) (0.05 mmol), 1a (1.00 mmol), amine (1.01
6
mmol), Me(EtO) SiH (4.50 equiv). For information about temperature and time for each substrate, see
2
Table S3 in the Supporting Information. Step 2: TMSCN (2.00 equiv), TFE (100 μL), r.t., 60 min.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Anilines and primary aliphatic amines were poor substrates in this protocol, where N-
1
methyl anilines typically gave less than 20% H NMR yield of the desired enamine (not
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
shown).
O
Mo(CO) 5 mol%
6
H
R3
+
N
OH
R3
Me(EtO) SiH 5 equiv
N
R2
R1
R2
2
R1
o
THF 2M, 65 to 100 C
HCl
N
N
N
N
R
I
4a, 86%
4
b, R = OMe, 73%
4d, 80%
4e, 90%
4c, R = CF , 91%
3
N
N
N
N
Ph
Ph
S
O
4f, 91%
4g, 70%
4h, 73%
4i, 98%
OMe
Scheme 6. N-alkylation of amines with benzoic acidsa.
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a
Isolated yields. Mo(CO)
6
(0.05 mmol), carboxylic acid (1.00 mmol), starting amine (2.00 mmol),
Me(EtO) SiH (5 equiv), THF (0.5 mL), 65 °C (2h) and then 100 °C (2h).
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We thereafter investigated the use of benzoic acids as alkylating agents. In these
cases, tetrahydrofuran (THF) as reaction media and two equivalents of the starting
amine were required for a successful reaction outcome. Under these conditions, we
studied a series of different benzoic acids, and the corresponding amines were isolated
in good to high yields (Scheme 6). The methodology is applicable for both electron-rich
and electron-poor benzoic acids. Methoxy-, trifluoromethyl- and iodobenzoic acids,
aliphatic and heteroaryl-carboxylic acids were all well tolerated affording 4b, 4c, 4d, 4e
and 4f, respectively, in good yields. Furthermore, functional groups such as olefins (4g)
and esters (4h) remained untouched under the reaction conditions, which highlight the
level of chemoselectivity of this methodology (Scheme 6).
Some limitations using benzoic acids as alkylating agents were found when the
reactions were carried out with acids containing alkyne, nitro and ketone functionalities.
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In these cases we observed no formation of the alkylated amines (for more information,
see the Supporting Information).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
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0
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4
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9
0
APPLICATIONS
α-Amino nitriles are valuable bi-functional compounds due to their widespread use in
chemistry and biology. One mode of reactivity of these compounds is via functional
group interconversion of the nitrile group in which the original carbon atom connectivity
is preserved. Furthermore, a highly relevant aspect in academia and industry is the
ability to scale up catalytic protocols. With these aspects in mind, we performed the
direct α-amino nitrile formation on a preparative scale followed by further
functionalization of the nitrile group (Scheme 7). The α-amino nitrile formation was
efficiently performed on a 10 mmol scale yielding 1.70 g of 3a, which subsequently was
transformed into tetrazole 5, α-amino acid 6 and the carbon extended primary amide 7,
in high yields.
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N N
NH
N
Ph
Ph
N
1
) Mo(CO) 5 mol%
(a)
(b)
(c)
6
5, xx%
Me(EtO) SiH 4.5 equiv
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN
COOH
o
O
2a 1 equiv, neat, 65 C, 4h
HCl
Ph
Ph
N
N
OH 2) TMSCN 2 equiv
TFE 10M, 60 min, r.t.
1
a
3a
1.70 g
6, 83%
1
0 mmol
O
NH2
Ph
7
, 90%
Scheme 7. Preparative scale and derivatization of 3a.a
a
Isolated yields. Step 1: Mo(CO)
6
(0.5 mmol), 1a (10.0 mmol), 2a (10.1 mmol), Me(EtO) SiH (45.0 equiv),
2
6
5 °C, 4h. Step 2: TMSCN (20.0 equiv), TFE (1.0 mL), r.t., 60 min. (a) TMSN
3
(10.0 equiv), Bu SnO (0.6
3
o
equiv), toluene, 70 C, 2 d; (b) HCl (37% wt), reflux, 24 h; (c) H
2
O
2
(2.0 equiv), K
2
CO (1.2 equiv), DMSO,
3
40 °C, 4h.
To further demonstrate the applicability of this methodology we used standard reaction
protocols for the functionalization the enamine 3a’, which was converted into triazoline
8
, sulfonylformamidine 9, pyrimidinedione 10 and the TMS-propargylamine 11,
respectively, in high yields under mild reaction conditions (Scheme 8). In the latter
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
case, compound 11 was generated using trimethylsilyl-acetylene without the need of a
copper source. 16
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
O
Ph
N
O
O
N
8
, 88%
b)
Ph
S
N
(
9
, 80%
(
a) Mo(CO) 5 mol%
6
O
HN
Ph
(c)
(d)
N
CN
N
Ph
+
OH
Me(EtO) SiH 4.5 equiv
2
o
3a'
2a
1
a
neat, 65 C, 2h
(e)
O
O
TMS
N
N
Ph
Ph
CN
10, 85%
11, 79%
Scheme 8. Further functionalization of 3a’.a
a
Isolated yields. (a) Mo(CO)
6
(0.05 mmol), 1a (1.00 mmol), 2a (1.01 mmol), Me(EtO) SiH (4.50 equiv), 65
2
°
C, 3h. (b) 1-(4-azidophenyl)ethan-1-one (1.50 mmol), TFE (100 μL), 40 °C, 2h (c) phenylmethanesulfonyl
azide (1.50 mmol), TFE (100 μL), r.t., 40 min. (d) 4-cyanophenylisocyanate (2.00 mmol), TFE (100 μL), 65
°
C, 2 h. (e) ethynyltrimethylsilane (2.00 mmol), TFE (100 μL), 65 °C, 2 h.
In addition we targeted the pharmaceutical active compound Piribedil, a dopamine D2
17
agonist used in the treatment of Parkinson disease and for circulatory disorders. The
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use of the molybdenum-based catalytic protocol allowed a facile alkylation of N-
pyrimidylpiperazine with piperonylic acid, and Piribedil was isolated in 80% yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 9).
H
N
O
O
O
N
Mo(CO) 5 mol%
6
O
N
N
+
N
OH
Me(EtO) SiH 5 equiv
2
O
N
N
o
o
N
THF 2M, 65 C 2d to 80 C 2h
Piribedil
yield: 80%
Treatment for parkinsons diseases
Scheme 9. One pot synthesis of Piribedil.
REACTION PATHWAYS
With respect to the reaction mechanism, two main pathways have been proposed for
the alkylation of amines with carboxylic acids. Conventional reductive amination of
18
aldehydes, generated by reduction of the corresponding acid, or a direct condensation
reaction promoted by the hydrosilane to generate the subsequent carboxamide
intermediate followed by in situ reduction.7b,19
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1
1
1
1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In order to obtain more information about the reaction mechanism, several control
experiments were conducted. Since amide formation was detected during the
optimization of reaction conditions and the evaluation of the scope of this protocol, initial
formation of a carboxamide intermediate followed by a subsequent reduction of the
amide appears to be a plausible reaction pathway. Indeed, the reaction of 2-phenyl-1-
pyrrolidinylethan-1-one 12, under same reaction conditions generated the enamine
intermediate quantitatively (Scheme 10, a). When the reaction between 1a and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pyrrolidine (2a) was carried out only in presence of Me(EtO) SiH at 65 °C, we observed
2
full conversion to amide 12 in 90 minutes. Moreover, using the same reaction setup
without adding the silane, but with a catalytic amount of Mo(CO) present, resulted in
6
full recovery of the starting materials after heating the reaction mixture at 65 °C for 90
minutes (Scheme 10, b). Additionally, we investigated if Mo(CO) had any effect on the
6
reaction rate in the amidation step. We set up a series of experiments using
phenylacetic acid (1a) and pyrrolidine (2a) as model substrates for the reactions,
1
sampled aliquots at different time points and analyzed these by H NMR. Figure 1
displays the kinetic profiles for two different reaction setups, one using the standard
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conditions, and in the second no catalyst was added. Both reactions were performed
with the same initial concentrations of 1a and 2a. The results clearly demonstrate that
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mo(CO) increase the rate of amide formation in comparison to the catalyst-free
6
reaction, and most interestingly, first upon full conversion of amine and acid to amide,
the enamine starts to form. Hence, the molybdenum catalyst plays a dual role in 1)
increasing the rate of amide formation and 2) being essential in the enamine generating
process.
O
Mo(CO) 5 mol%
6
Ph
Ph
Ph
N
(
a)
b)
N
Me(EtO) SiH 4.5 equiv
neat, 65 C, 3h
2
o
3
a'
12
1
>
95% H NMR
O
O
Ph
Ph
+
2
a 1 equiv
N
N
(
o
OH neat, 65 C
12
3a'
1a
(
b.1) Me(EtO) SiH 4.5 equiv, 90 min
>95%
-
-
2
(b.2) Mo(CO) , 90 min
-
6
Scheme 10. Mechanistic experiments.a
a 1H NMR yields using 1,3,5-trimethoxybenzene as internal standard (a) Mo(CO)
(0.05 mmol), 12 (0.50
6
mmol), Me(EtO)
2
SiH (4.5 equiv), 65 °C, 3h. (b) 1a (1.0 mmol), 2a (1.01 mmol), (b.1) Me(EtO) SiH (4.5
2
equiv), 65 °C, 90 min. (b.2) Mo(CO)
6
(0.05 mmol), 65 °C, 90 min.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
Ph
Ph
N
N
12
12
1
00
8
6
4
2
0
0
0
0
0
Me(EtO)
2
2
SiH 4.5 equiv
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mo(CO)
Me(EtO)
6
5 mol%
SiH 4.5 equiv
Ph
N
3a'
0
20
40
60
80
100
120
time (minutes)
Figure 1. Kinetics profile using standard conditions and under absence of Mo(CO)6.a
a 1H NMR yields using 1,3,5-trimethoxybenzene as internal standard. Mo(CO)
(0.05 mmol), 1a (1 mmol),
6
2
a (1.01 mmol), Mo(CO)
6
(0.05 mmol), Me(EtO) SiH (4.5 equiv), 65 °C, 90 min.
2
On the basis of the above-mentioned results and previous mechanistic investigations on
20
the Mo(CO) -catalyzed amide reduction by Pannell and co-workers, a plausible
6
reaction mechanism is depicted in Scheme 11. The initial direct condensation reaction
to generate the carboxamide intermediate is likely to proceed via formation of a silyl-
ester in a reaction between the carboxylic acid and the Mo-silane system. The silyl-ester
act as an acylating agent reacting with the amine nucleophile to generate the amide. A
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possible Lewis-acid activation of the silyl-ester by the Mo-catalyst is expected and can
explain the increased reaction rate in this step. The reduction step where the enamine is
generated requires a hydride-attack, catalyzed by the Mo-silane system, on the C=O
bond of the amide to generate an intermediate silylhemiaminal which collapse into the
enamine via a deprotonation-elimination step. As presented in Figure 1, the enamine
1
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3a´ starts to form first upon completion of the amide generating step. A possible
explanation for this behavior could be an inhibition of the Mo-catalyst by coordination of
free amine to the metal center. Hence, at low amine concentration, the Mo-silane
system becomes active and facilitate the formation of the enamine.
O
O
Mo(CO)6
R1
R1
O[SiR3]
OH
R Si-H
3
H
H
HNR R3
2
Mo-catalyzed
amidation step
HOSiR3
O
H
H OM
N
R1
R3
Mo(CO)6
R1
R3
Deprotonation
Elimination
R1
R3
N
R2
N
R Si-H
3
R2
H
R2
H
Mo-catalyzed
reduction step
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Scheme 11. A plausible reaction mechanism for the amidation-enamine formation
reaction.
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SUMMARY
In conclusion, we have developed a general and straightforward molybdenum-
catalyzed reductive N-alkylation of amines with a variety of carboxylic acids in the
presence of diethoxymethylsilane as reducing agent, which generate tertiary amines or
enamines. The generated enamines were efficiently in situ trapped with various
reagents to generate a variety of more complex organic compounds, e.g. α-amino
nitriles, heterocycles and propargylamines. This green alkylation protocol, which avoid
the isolation of synthetic intermediates, allows for a direct route to structurally diverse
organic compounds from simple starting material, in a straightforward fashion. This
catalytic protocol display an excellent level of chemoselectivity and it can furthermore be
run on a preparative scale. The synthetic utility of this methodology on the formation of
complex biologically active compounds was demonstrated in the preparation of the drug
molecule, Piribedil.
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AUTHOR INFORMATION
Corresponding Author
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*
hans.adolfsson@umu.se
ORCID
Hans Adolfsson: 0000-0001-5887-4630
Paz Trillo: 0000-0001-9540-630X
ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge.
Text, tables, and figures giving experimental procedures and characterization data
(PDF)
ACKNOWLEDGMENT
We would like to thank Drs. Tove Slagbrand, Fredrik Tinnis and Alexey Volkov for
fruitful discussions in the early stage of this project. Financial support from the Swedish
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Research Council (grant # 2016-05316) and from Umeå University is gratefully
acknowledged.
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