Straightforward α-Amino Nitrile Synthesis Through Mo(CO)6-Catalyzed Reductive Functionalization of Carboxamides

Article abstract of DOI:10.1002/anie.201807735

The selective reduction of amides into an intermediate hemiaminal catalyzed by Mo(CO)₆ together with the inexpensive and easy to handle TMDS (1,1,3,3-tetramethyldisiloxane) as reducing agent, followed by subsequent trapping of the hemiaminal with a cyanide source, allows for the straightforward synthesis of α-amino nitriles. The methodology presented here, displays high levels of chemoselectivity allowing for the reduction of amides in the presence of functional groups such as ketones, imines, aldehydes, and acids, which affords a simple route for the synthesis of α-amino nitriles with a broad scope of functionalities in high yields. Furthermore, the applicability of this methodology is demonstrated by scale up experiments and by derivatization of the target compounds into synthetically interesting products. The selective cyanation is successfully applied in late stage functionalizations of amide containing drugs and prolinol derivatives.

Full text of DOI:10.1002/anie.201807735

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Accepted Article
Title: Straightforward α-Amino Nitrile Synthesis Through Mo(CO)6-
Catalyzed Reductive Functionalization of Carboxamides
Authors: Paz Trillo, Tove Slagbrand, and Hans Adolfsson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807735
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Straightforward α-Amino Nitrile Synthesis Through Mo(CO)6-
Catalyzed Reductive Functionalization of Carboxamides
Paz Trillo,[a] Tove Slagbrand[b] and Hans Adolfsson*[a]
Abstract: The selective reduction of amides into an intermediate
hemiaminal catalyzed by Mo(CO)6 together with the inexpensive and
easy to handle TMDS (1,1,3,3-tetramethyldisiloxane) as reducing
agent, followed by subsequent trapping of the hemiaminal with a
cyanide source, allows for the straightforward synthesis of α-amino
nitriles. The methodology presented here, displays high levels of
chemoselectivity allowing for the reduction of amides in the presence
of functional groups such as ketones, imines, aldehydes and acids,
which affords a simple route for the synthesis of α-amino nitriles with
a broad scope of functionalities in high yields. Furthermore, the
applicability of this methodology is demonstrated by scale up
experiments and by derivatization of the target compounds into
synthetically interesting products. The selective cyanation is
successfully applied in late stage functionalizations of amide
containing drugs and prolinol derivatives.
position to the nitrogen. Carboxamides can be activated for this
approach by the use of stoichiometric amounts of electrophilic
reagents (such as Tf2O, POCl3), pre-activation with DIBAL-H or
the Schwartz’s reagent (Cp2ZrHCl) or by catalytic versions
employing mild reduction conditions (Scheme 1).[4]
Bi-functional compounds such as α-amino nitriles are highly
useful synthetic intermediates possessing both amino- and nitrile
functional groups on the same carbon atom, which make them
versatile building blocks in the chemical synthesis of important
and complex molecules within the pharmacological and
biological areas. In addition to act as precursors to α-amino
acids, 1,2-diamines, α-amino carbonyl compounds and β-amino
alcohols, simple α-amino nitriles have been proposed as
prebiotic precursors to nicotinic acids, porphyrins, corrins, and
nucleic acids.[1] Traditionally, the most common method to
access α-amino nitriles is through the Strecker reaction; a
multicomponent reaction between an aldehyde (or ketone), an
amine and a cyanide source. An alternative route involves the
oxidation of a tertiary amine leading to an iminium ion which is
subsequently trapped by a cyanide ion.[2]
The amide functional group is the most stable functionality
among the carboxylic acids derivatives due to the delocalization
of electron density over the the C-N and C-O bonds. Amides are
thus common structural motifs in a wide variety of natural
products and pharmaceutical compounds.[3] However, the use of
amides as synthetic intermediates has been less explored.
The reductive functionalization of amides is a useful
strategy to insert a new carbon-carbon bond in the alpha
Scheme 1. Reductive functionalization of carboxamides. a) P2O5, Tf2O,
DIBAL or CP2ZrHCl; b) Previous catalytic approaches using Indium and
Iridium catalysts.
The functionalization can either proceed by trapping of the
electrophilic (iminium ions) or the nucleophilic (enamines)
intermediates formed. Chida/Sato and co-workers have
developed several protocols for this purpose using the
Schwartz’s reagent to reduce tertiary, secondary and N-methoxy
amides, forming different Zr-adducts, which by addition of
different additives and nucleophiles produced the corresponding
alkylated amines.[5] Regarding catalytic methods, the group of
Baba reported on a InI3-catalyzed protocol for the reduction of N-
sulfonyl amides into the corresponding iminium ions, which
subsequently were trapped by the addition of silyl cyanide or
silyl enolates.[6] The Ir-based protocol developed by Nagashima
for the reduction of amides under hydrosilylation conditions[7]
was elegantly exploited in the activation-functionalization of
amides employing nucleophiles such as silyl ketene acetals,
allyltin reagents, alkynes, TMSCN and Grignard reagents.[8] In
particular, Dixon and co-workers successfully employed Vaska´s
Ir-complex in the reductive Strecker reaction with TMSCN as
nucleophile, forming α-amino nitriles in good to excellent yields
from a variety of different tertiary amides (Scheme 2a).[8]
Although important advances have been made in this field, the
number of efficient catalytic protocols for the mild and
chemoselective functionalization of amides is scarce.
[a]
[b]
Dr. P. Trillo, Prof. Dr. H. Adolfsson
Department of Chemistry
Umeå University
KBC3, Linnaeus väg 10, 90187 Sweden
E-mail: paz.trillo@umu.se
hans.adolfsson@umu.se
Dr. T. Slagbrand
During last years, we have developed an efficient catalytic
protocol for the chemoselective reduction of tertiary amides into
amines and aldehydes using Mo(CO)6 together with TMDS
(1,1,3,3-tetramethyldisiloxane) as hydride source.[9] This catalytic
system was furthermore applied in the conversion of amides into
the corresponding enamines, which subsequently were
Department of Organic Chemistry
Stockholm University
106 91 Stockholm (Sweden)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807735
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transformed into 4,5-dihydrotriazoles, dihydroisoxazoles, N-
sulfonylformamides, and pyrimidinediones, respectively.[10]
As part of our ongoing interest in chemoselective reduction
of carboxamides, we envisioned that the partial reduction of
tertiary amides into a hemiaminal intermediate based on the Mo-
catalyzed protocol, would serve as a starting point for the
formation of α-amino nitriles using a suitable cyanide source.
Herein we present an operationally simple one-pot procedure for
the chemoselective formation of α-amino nitriles from
carboxamides based on catalytic amounts of Mo(CO)6 in
combination with the inexpensive and easy-to-handle hydride
source, TMDS (Scheme 2).
(Scheme 3 and see Supporting Information for further details).
As shown in Scheme 3, amides containing different electronic
properties (1a-1f) were efficiently converted into the
corresponding α-amino nitrile.
The α-amino nitrile 2c, which is demonstrated to own
insecticides properties acting against Aedes aegypti larvae,[12]
was readily prepared from amide 1c. This protocol was
applicable to aryl halides and heterocycles (such as furane
derivatives), giving products 2f and 2g in 97% and 96% yields,
respectively, and lactam 1h was converted into 2h in 78% yield
(Scheme 3).
Next, we evaluated the functional group tolerance of the
protocol. Substrates containing different reducible functional
groups such as nitro- (1e), vinyl- (1i) and nitrile (1j) were
converted into their corresponding α-amino nitriles in 78%, 95%
and 90% isolated yields, respectively. We continued the
evaluation with different carbonyl substituted amides, and
gratifyingly aldehyde-, ketone-, imine-, ester-, carboxylic acid-,
and carbamate- groups were well tolerated. In the case of the
carbamate-substituted amide 1k, it was difficult to completely
avoid amine formation in the initial reduction step, however 2k
was obtained in 83% isolated yield. No over-reduction of the
ester functionality was detected allowing for the formation of the
target compound 2l in excellent yield. The carboxylic acid
functionality was well tolerated and 2m was isolated in 90% yield.
Gratifyingly, ketones and aldehydes remained untouched under
the reaction conditions (2n and 2o, respectively), and
carboxamide 1p containing an imine functional group was
converted into 2p in 96% yield. Amides with different N-
substituents such as morpholine (1q), N,N-dimethylamine (1n
and 1o), N,N-dibenzylamine (1r) and N-methylaniline (1s) were
also reactive in this protocol, giving the corresponding α-amino
nitriles in high yields (Scheme 3). Additional substituted tertiary
benzamides (e.g. hydroxy- and amino) were evaluated using this
protocol, however, these compounds failed to yield the desired
α-amino nitriles (see Supporting information).
O
CN
IrCl(CO)(PPh3)2
R2
R2
R1
R1
a)
b)
N
R3
N
R3
TMDS
TMSCN
O
CN
O[Si]
TMSCN
-O[Si]
Mo(CO)6
R2
R2
H
R1
R2
R1
R1
N
R3
N
R3
N
R3
TMDS
EtOAc
Scheme 2. a) Reductive Strecker reaction developed by Dixon and co-
workers. b) This work: Reductive functionalization of amides catalyzed by
Mo(CO)6 for the chemoselective synthesis of α-amino nitriles.
Initial experiments were performed on amide 1a as a model
substrate in order to optimize the formation of the intermediate
silyl hemiaminal. We were especially pleased to see that the
reaction could be performed in the green solvent ethyl
acetate.[11] From the optimization experiments (see Supporting
information), we found that the formation of the hemiaminal was
complete within 3 hours using 5 mol% of Mo(CO)6, and 4
equivalents of TMDS in EtOAc at room temperature. At this point,
trimethylsilyl cyanide (TMSCN, 2 equiv.) was added, and
gratifyingly we observed the formation of α-amino nitrile 2a in
1
96% yield (based on H NMR) in less than two hours when the
reaction mixture was held at room temperature. Attempts to
obtain 2a by the addition of TMSCN from the beginning of the
reaction did not result in the desired product, and the starting
amide was recovered as the main product (see Supporting
information).
Once we had established the optimized reaction conditions,
we focused on studying the generality of the catalytic protocol
for the reductive functionalization of carboxamides into α-amino
nitriles (Scheme 3). In general, we obtained high yields of the
products formed in the cyanation from a broad range of
differently substituted aryl amides. The catalytic protocol
displays very high levels of chemoselectivity, and in line with
previous observations, allows for the selective reductive
functionalization of a series of substrates containing reactive and
reducible functional groups. The selective formation of the silyl
hemiaminal intermediate is crucial for the outcome of the
cyanation reaction. In most of the evaluated substrates, this step
of the reaction could be performed at room temperature within 2
- 16 h, however amides 1j, 1k and 1m, required higher reaction
temperature (40 - 50 °C) for efficient hemiaminal formation. The
subsequent cyanation step was completed in all cases within 2 h
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10.1002/anie.201807735
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Scheme 4. Evaluation of tertiary amides containing α-hydrogens in the
reductive functionalization protocol into α-amino nitriles. Amide (1 mmol),
Mo(CO)6 (2 mol%), TMDS (1.5 mmol), dried EtOAc (1 mL). Yields refer to the
isolated products. For information about the conditions of each substrate, see
Table S3 in the Supporting Information.
Scheme 3. Evaluation of the amide scope in the reductive functionalization
protocol into α-amino nitriles. Amide (1 mmol), Mo(CO)6 (5 mol%), TMDS (4.0
mmol), dried EtOAc (2 mL). Yields refer to the isolated products. PMP = para-
methoxyphenyl. [a] 5 equiv. of TMDS. [b] Reaction temperature for reductive
step, 0 °C. [c] Reaction temperature for reductive step, 50 °C. [d] Reaction
temperature for reductive step, 40 °C. For information about the conditions of
each substrate, see Table S2 in the Supporting Information.
To demonstrate the versatility of the procedure for the
formation of α-amino nitriles, we evaluated the protocol on a
preparative scale by performing the reaction starting with 1.9 g
(10 mmol) of amide 1a, which was converted into 1.71 g of 2a
(86% yield, Scheme 5).
Next, we turned our attention to carboxamides bearing α-
hydrogen atoms. In this case, the formation of the target
compounds needed longer reaction times in order to give high
yields. Amide 3a was initially used as model substrate, and after
screening different reaction parameters, we obtained 4a in 87%
yield using two equivalents of TMSCN at room temperature for 4
hours (Scheme 4, and Supporting Information for details). The
initial reductive step of this reaction performed at 65 - 75 °C for
0.5 - 5 h, involves the formation of an enamine, as observed
using 1H-NMR spectrometry, and subsequent addition of
TMSCN resulted in the formation of the desired α-amino nitriles.
The methoxy-subtituted amide 3b gave α-amino nitrile 4b
in high yield (Scheme 4), however, attempts to cyanate the
corresponding nitro-substituted amide failed even though we
observed formation of the intermediate enamine (Supporting
information). A good level of chemoselectivity was observed in
the reaction, and groups such as esters and nitriles were
tolerated giving α-amino nitriles 4d and 4e in 83% and 79% yield,
respectively (Scheme 4). Amides derived from cyclic and
noncyclic amines were studied, and the corresponding cyanated
products were obtained in moderate to high yields (Scheme 4).
Additional amides containing reducible functionalities (e.g.
aldehyde, ketone, and imine) were evaluated, however, no or
incomplete reaction with TMSCN were observed (see
Supporting information).
α-Amino nitriles are versatile synthetic building blocks for
the formation of different compounds, including heterocycles and
are therefore useful precursors in drug discovery and
development. With this in mind, α-amino nitrile 2a was readily
transformed into α-amino acid 5, the benzylated compound 6,
tertiary amine 7 and the α-amino tetrazole 8 in high yields,
respectively (Scheme 5). Donepezil, a FDA (Food and Drug
Administration)-approved drug, is
a potent, selective and
reversible AChE inhibitor. It has been discovered that rational
modifications of the Donepezil scaffold, incorporating
multifunctional groups, improves its selectivity and efficiency.[13]
Donepezil can be prepared via a late stage chemoselective
reduction of amide 9 to the corresponding benzyl amine.[9],[14] To
further demonstrate the synthetic utility of the herein described
catalytic protocol, taking into consideration the often
accentuated biological activity imposed by the nitrile functionality
in several drugs,[15] we envisioned that the corresponding α-
amino nitrile could be obtained from amide 9, which in turn could
open for a new chemical entity possessing an advantageous
pharmacological profile. Gratifyingly, keto-amide
9
was
selectively converted into the target α-amino nitrile 10 in 83%
isolated yield (Scheme 6). The piperazine containing drug
Piribedil is a dopamine agonist of the nonergotic class, working
as a D2/D3 agonist and an alpha-2a antagonist and is used in
the treatment of Parkinson’s disease.[16] Amide 11 is a precursor
of Piribedil and in line with the example presented above, we
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10.1002/anie.201807735
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successfully converted this compound into α-amino nitrile 12 in
78% yield (Scheme 6).
The catalytic system based on Mo(CO)6 and TMDS efficiently
allows for the partial reduction of carboxamides into hemiaminal
intermediates which subsequently are trapped in situ with
TMSCN to form the target compounds in high yields. The
reaction is performed in the environmentally friendly solvent
ethyl acetate and is applicable on a broad scope of differently
functionalized amides. The protocol displays excellent
chemoselectivity in reductive cyanation of amides, tolerating
functional groups such as ketones, aldehydes, carboxylic acids
and imines. Furthermore, the protocol can be carried out on a
preparative scale and allows for the selective cyanation of
amide-containing drugs and N-prolinol derivatives, thus being an
attractive route for α-amino nitrile synthesis in academia and
industry.
N-Cyanoalkyl prolinol derivatives possess significant
biological activity, and are also important as synthetic
intermediates. In addition, these compounds are widely used as
optically active ligands in asymmetric catalysis.[17] By using the
herein presented catalytic protocol for the reductive cyanation of
amides, we obtained the N-cyanoalkyl prolinol derivative 14 in
good yield and excellent diastereoselectivity (20:1), even when
the reaction was scaled up to 5 mmol (Scheme 6).
Acknowledgements
Umeå University, the K & A Wallenberg Foundations, and the
Swedish Reasearch Council are gratefully ackowledged for
financial support.
Keywords: molybdenum • chemoselective • hydrosilylation •
reductive functionalization of amides • cyanation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An operationally simple one-pot
procedure for the chemoselective
formation of α-amino nitriles from
carboxamides based on catalytic
amounts of Mo(CO)6 in combination
with TMDS is herein presented. This
P. Trillo, T. Slagbrand, H. Adolfsson*
Page No. – Page No.
Straightforward α-Amino Nitrile
Synthesis Through Mo(CO)6
Catalyzed Reductive
Functionalization of Carboxamides
protocol
displays
excellent
chemoselectivity tolerating functional
groups such as ketones, aldehydes,
carboxylic
acids
and
imines.
Moreover, the reaction can be carried
out on a preparative scale and allows
for the selective cyanation of amide
containing drugs and N-Prolinol
derivatives.
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