Direct Synthesis of α-Amino Nitriles from Sulfonamides via Base-Mediated C-H Cyanation

Article abstract of DOI:10.1021/acs.orglett.1c01232

Herein, we disclose a transition-metal-free reaction system that enables α-cyanation of sulfonamides through C-H bond cleavage for the preparation of α-amino nitriles, including difficult-to-access all-alkyl α-tertiary scaffolds. More than 50 substrate examples prove a wide functional group tolerance. Additionally, its synthetic practicality is highlighted by gram-scalability and the late-stage modification of natural compounds. Mechanistic experiments suggest that this process involves in situ formation of an imine intermediate via base-promoted elimination of HF.

Full text of DOI:10.1021/acs.orglett.1c01232

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Letter
Direct Synthesis of α‑Amino Nitriles from Sulfonamides via Base-
Mediated C−H Cyanation
Shasha Shi,# Xianyu Yang,# Man Tang, Jiefeng Hu,* and Teck-Peng Loh*
Cite This: Org. Lett. 2021, 23, 4018−4022
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ABSTRACT: Herein, we disclose a transition-metal-free reaction
system that enables α-cyanation of sulfonamides through C−H
bond cleavage for the preparation of α-amino nitriles, including
difficult-to-access all-alkyl α-tertiary scaffolds. More than 50
substrate examples prove a wide functional group tolerance.
Additionally, its synthetic practicality is highlighted by gram-
scalability and the late-stage modification of natural compounds.
Mechanistic experiments suggest that this process involves in situ
formation of an imine intermediate via base-promoted elimination
of HF.
irect C−H activation adjacent to nitrogen in amine
Dderivatives for coupling transformations is an extremely
effective and important approach in organic synthesis.1,2
Remarkably, Cα−H cyanation of nitrogen-containing com-
pounds has garnered tremendous attention because it can
provide versatile α-amino nitriles, which play key roles in the
synthesis of alkaloids, amino acids, heterocycles, and
pharmaceuticals.3−7 In this context, previous works has been
developed mainly using stoichiometric oxidants,8 biocatalysts,9
or transition metal catalysts,10 including Cu,11 Fe,12 Au,13
Ru,14 V,15 W,16 Co,17 Ti,18 and Ir19 (Figure 1A). Notably,
transition-metal-free Cα−H cyanation is essential and challeng-
ing.20 For example, Lambert presented an example of using the
tropylium ion as a promoter and KCN as a cyano source to
achieve α-cyanation of amines in 2011.21 In 2012, Seidel
described a carboxylic acid catalyzed α-cyanation of amines
with trimethylsilyl cyanide (TMSCN) in toluene at 200 °C.22
In 2016, a nitroxyl-radical-catalyzed oxidative Cα−H cyanation
of sulfonamides was reported by Moriyama.23 In 2018, Stahl
developed an electrochemical approach for Cα-cyanation of
secondary piperidines to synthesize α-amino nitriles employing
9-azabicyclononane N-oxyl as a catalytic mediator.24 However,
the substrate scope of these methods is mainly focused on
benzyl and cyclic amines,25 thus hampering their synthetic
applicability and industrial scale-up potential. Recently, our
group reported a new reaction pattern for the cross-coupling of
sulfonamides with arylimines through strain-release rearrange-
ment. And an imine intermediate, which was generated
through base-assisted HF elimination, was proposed according
to control experiments and theoretical calculations.26 Inspired
by this progress, we speculated that if the imines formed in situ
from sulfonamides would selectively proceed addition reaction
with nucleophile, it would provide a great opportunity for α-
functionalization. Herein, we describe a metal-free Cα−H
cyanation of sulfonamides mediated by a weak base under mild
conditions, affording a broad scope of α-amino nitriles,
including the valuable α-quaternary carbon variants (Figure
1B).
Received: April 13, 2021
Published: May 10, 2021
Figure 1. Cα−H cyanation of amine derivatives.
https://doi.org/10.1021/acs.orglett.1c01232
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4018−4022
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We initiated our Cα−H cyanation studies by monitoring the
reactivity of N-fluorotosylamides 1a derived from amines with
TMSCN (1b) (see the Supporting Information for details).
The results showed that 1.5 equiv of triethylamine (Et3N)
exhibited the best activity in toluene. To demonstrate the
generality of this approach, a variety of amides were evaluated
under the optimized reaction conditions (Scheme 1). The
Next, the transformation was assessed with various
secondary amides under modified conditions (Scheme 2). A
a
Scheme 2. Substrate Scope for Secondary Amides
Scheme 1. Substrate Scope for Primary Amidesa
a
Reaction conditions: A mixture of N-fluorotosylamides a (0.20
mmol), TMSCN 1b (0.50 mmol), and Et3N (0.3 mmol) in MeCN (1
mL) was stirred for 24 h at 60 °C under Ar, isolated yield after
a
b
Reaction conditions: A mixture of N-fluorotosylamides a (0.20
chromatography. A mixture of N-fluorotosylamides a (0.20 mmol),
mmol), TMSCN 1b (0.30 mmol), and Et3N (0.3 mmol) in toluene (1
mL) was stirred for 24 h at 40 °C under Ar, isolated yield after
chromatography.
TMSCN 1b (0.30 mmol), and Et3N (0.3 mmol) in toluene (1 mL)
was stirred for 24 h at 40 °C under Ar, isolated yield after
chromatography.
wide range of benzylamine substrates provided the correspond-
ing products 22c−28c with good yields. Naphthylamides were
favorably coupled with TMSCN to afford the products 29c in
84% yield. A series of carbon chain amides were also tolerated
in this system, affording the various α-amino nitriles in 36%−
88% yield (30c−45c). The reaction could also be applied in
gram-scale synthesis, obtaining 32c with 81% yields on a 5 mol
scale. When 33a is used as the substrate, the α-cyanation
product was obtained in 36% yield while retaining its
enantiopurity. Surprisingly, 45a converted into products 45c
with hydroxyl group in 68% yield under standard conditions,
and this process involved the hydrolysis of methyl esters. More
importantly, this methodology enables the late-stage derivati-
zation of complex molecules (46c−53c). The structure of 50c
was characterized by X-ray crystallographic analysis (Scheme
3).
primary amine derivatives 2a−16a bearing different functional
groups on the carbon chain proceeded smoothly. For example,
substrates possessing phenyl (2a), cycloalkyl (3a), ether group
(4a and 5a), and TBS-protected hydroxyl (6a) were well
tolerated. Additionally, this cyanation process was not affected
by halo substituents such as F (7c), CF3, (8c), Cl (9c), and Br
(10c) on the substrates, highlighting its potential in
combination with subsequent cross-coupling transformations.
Amide derivatives with ester group and alkenyl motif were also
compatible with our standard conditions and successfully
converted to the desired α-amino nitriles (11c−13c).
Interestingly, common heterocyclic cores (14c−16c) were
found to successfully undergo Cα−H cyanation. Notably, this
reaction was competent for electron-donating, electron-neutral,
and electron-withdrawing arylsulfonamide derivatives (17c−
20c). Excitingly, ethanesulfonamides effectively reacted with
TMSCN, giving products 21c in 90% yield.
To probe the mechanism of this cyanation reaction, we
conducted several control experiments. First, the standard
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not hinder the smooth progress of the transformation.
Subsequently, when R-54a (99% ee) was allowed to react
with TMSCN under standard conditions, racemic product 54c
was observed in 82% yield (Scheme 4II). When removing
cyano reagents from standard conditions, α,β-unsaturated
imines 1d was generated from the self-coupling of 1a (Scheme
4III). On the basis of these investigations, we have
hypothesized that the imine species may be an intermediate
in the process. To further confirm this conclusion, imine 1e
was applied to our conditions (Scheme 4IV). And we indeed
detected the corresponding product with 34% using Et3N·3HF
as base. In addition, when employing N-chloro amide 1f
instead of 1a, no α-amino nitrile was detected, and 1g was
isolated with 56% yield (Scheme 4V). These observations
show that the fluorine atom was an important driving force for
this C−H cyanation. In view of the above results and previous
works,26,27 we propose a possible experimental mechanism
(Scheme 4VI). An imine intermediate was generated from N-
fluorotosylamide through a base-assisted HF elimination.
Subsequently, this imine was attacked by TMSCN, which
was simultaneously activated by the formed HF species,
offering the corresponding product. To further confirm the
practicality of this method, a facile deprotection process of α-
amino nitriles bearing mesitylenesulfonyl group (55c) was
shown in Scheme S19 (Supporting Information).
In summary, we have developed an effective and metal-free
system, which is capable of achieving α-C−H bonds
dehydrocyanation of aliphatic amides under mild condition,
providing a broad scope of α-amino nitriles with an all-carbon
quaternary stereocenter. We also illustrated that sulfonamides
derived from complex molecules can be applied to carry out
Cα−H cyanations with good yields. Given how widespread the
cyano group are in chemicals, we anticipate that this
methodology will simplify the synthesis elaboration of α-
amino nitriles for research in chemistry, medicine, and biology,
and open up new frontiers in metal-free C−H functionalization
of amides.
Scheme 3. Late-Stage Functionalizations
a
Reaction conditions: A mixture of N-fluorotosylamides a (0.20
mmol), TMSCN 1b (0.30 mmol), and Et3N (0.3 mmol) in toluene (1
mL) was stirred for 24 h at 40 °C under Ar, isolated yield after
b
chromatography. A mixture of N-fluorotosylamides a (0.20 mmol),
TMSCN 1b (0.50 mmol), and Et3N (0.3 mmol) in MeCN (1 mL)
was stirred for 24 h at 60 °C under Ar, isolated yield after
c
chromatography. Using 2.5 equiv of TMSCN, the reaction was
carried out in MeCN (1 mL) for 24 h at 80 °C.
reaction was carried out in the presence of 1.0 equiv of
TEMPO or BHT (Scheme 4I). These radical inhibitors did
Scheme 4. Mechanistic Experiments
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01232.
Experimental procedures, characterization data, and
NMR spectra (PDF)
Accession Codes
CCDC 2059493 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Jiefeng Hu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials,
Nanjing Tech University, Nanjing 211816, China;
orcid.org/0000-0001-7906-5947; Email: iasjfhu@
njtech.edu.cn
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2015, 6, 7105−7111.
Teck-Peng Loh − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials,
Nanjing Tech University, Nanjing 211816, China; Division
of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore; orcid.org/
0000-0002-2936-337X; Email: teckpeng@ntu.edu.sg
Authors
Shasha Shi − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials,
Nanjing Tech University, Nanjing 211816, China
Xianyu Yang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials,
Nanjing Tech University, Nanjing 211816, China
Man Tang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials,
Nanjing Tech University, Nanjing 211816, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01232
Author Contributions
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#S.S. and X.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21901114), the Natural Science
Foundation of Jiangsu Province (BK20180685), the Natural
Science Foundation of Jiangsu Provincial Department of
Education (18KJB150017), and the Start-up Grant from
Nanjing Tech University (38274017102). The SICAM
Fellowship by Jiangsu National Synergetic Innovation Center
for Advanced Materials is also acknowledged.
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