Nickel-Catalyzed Deaminative Cyanation: Nitriles and One-Carbon Homologation from Alkyl Amines

Article abstract of DOI:10.1021/acs.orglett.1c01959

A nickel-catalyzed deaminative cyanation of Katritzky pyridinium salts has been developed. When it is coupled with formation of the pyridinium salt from primary amines, this method enables alkyl amines to be converted to alkyl nitriles. A less toxic cyanide reagent, Zn(CN)2, is utilized, and diverse functional groups and heterocycles are tolerated. The method also enables a one-carbon homologation of alkyl amines via reduction of the nitrile products, in addition to many other potential transformations of the versatile nitrile group.

Full text of DOI:10.1021/acs.orglett.1c01959

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Letter
Nickel-Catalyzed Deaminative Cyanation: Nitriles and One-Carbon
Homologation from Alkyl Amines
Jianyu Xu, J. Cameron Twitty, and Mary P. Watson*
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ABSTRACT: A nickel-catalyzed deaminative cyanation of Ka-
tritzky pyridinium salts has been developed. When it is coupled with
formation of the pyridinium salt from primary amines, this method
enables alkyl amines to be converted to alkyl nitriles. A less toxic
cyanide reagent, Zn(CN)2, is utilized, and diverse functional groups
and heterocycles are tolerated. The method also enables a one-
carbon homologation of alkyl amines via reduction of the nitrile products, in addition to many other potential transformations of the
versatile nitrile group.
n alkyl nitrile is one of the most common groups in
Abioactive molecules, ranking as the 15th most common
functional group, and is found in 5.2% of bioactive molecules
(Scheme 1A).1 This prevalence is due to nitriles’ effective
bonding in protein active sites.2 A nitrile is also a versatile
precursor for a wide variety of functional groups.3 Because of
this utility, elegant methods have been developed for nitrile
incorporation. These methods typically employ alkyl halides as
substrates and install the nitrile via either an SN2 or transition-
metal-catalyzed reaction with a cyanide source (Scheme 1B).4
Because of the sensitivity of alkyl halides to substitution or
elimination under many reaction conditions, their use
mandates strategic timing of this cyanation sequence, often
at the beginning of the synthesis.
In contrast to an alkyl halide, an alkyl amine offers
tremendous flexibility in synthetic strategy; an amine can be
functionalized early or, via suitable protection, carried through
multiple synthetic steps and revealed for a late-stage trans-
formation.5 In addition, amines are ubiquitous and diverse,
spanning simple starting materials of exceptional availability
and variety to complex pharmaceutical intermediates and
APIs.5,6 We envisioned that a deaminative cyanation would be
possible via a Katritzky pyridinium salt.7 With the alkyl amine
1 as the starting material, condensation with the commercially
available pyrylium salt 2 gives pyridinium 3,8 which would
deliver alkyl nitrile 4 via a nickel-catalyzed cyanation (Scheme
1C). Use of a relatively low toxicity cyanide source, typically
enabled by a transition-metal-catalyzed approach,9 would
further increase the utility of this method. Not only would
this strategy enable complex, druglike alkyl amines to be
converted into alkyl nitriles with potential bioactivity against
new targets, it would also offer the opportunity for a one-
carbon homologation of alkyl amines. As shown by the
comparison of β-alanine and γ-aminobutyric acid, the addition
of a single methylene can have a dramatic effect on the
bioactivity and cost (Scheme 1D).10 However, a one-carbon
homologation of a lead compound would typically require
complete resynthesis. Using a cyanation/reduction sequence
Scheme 1. Alkyl Nitriles and Cyanation Reactions
Received: June 12, 2021
https://doi.org/10.1021/acs.orglett.1c01959
© XXXX American Chemical Society
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A

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Letter
a
enables the original amine to be directly converted to the
homologated product. Notably, this new amine product could
then be used in the suite of deaminative reactions that have
been developed since 2017.7,11
Scheme 2. Scope
We selected the cyanation of pyridinium 3a for reaction
development. Inspired by the work of Liu and co-workers
using Zn(CN)2 as a less toxic cyanide source in reactions with
alkyl halides, we selected Zn(CN)2 as our coupling partner.4d
Using the bidentate bipy ligand, which is commonly employed
in nickel-catalyzed reactions of pyridinium salts, poor reactivity
was observed (Table 1, entry 1). In contrast, the use of
a
Table 1. Optimization
b
entry
[Ni]
ligand
bipy
additive
yield (%)
1
2
3
4
5
6
7
8
9
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
none
none
none
<5
72
80
87
<5
52
47
<5
<5
Xantphos
Xantphos
Xantphos
t-Bu-Xantphos
DPE-Phos
dppf
ZnCl2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
none
Xantphos
a
Conditions: 3a (0.10 mmol), Zn(CN)2 (1.0 equiv), [Ni] (10 mol
%), ligand (12 mol %), Et2Zn (0.4 equiv), additive (1.0 equiv),
b
DMSO (0.2 M), 80 °C, 16 h, unless otherwise noted. Determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as an internal
standard.
a
Conditions: 3 (1.0 mmol), Zn(CN)2 (1.0 equiv), NiCl2 (10 mol %),
Xantphos provided a 72% yield (entry 2). Notably, Liu also
used Xantphos in their cyanation.4d The yield was further
improved by the addition of zinc halide salts, with 87% yield
being observed when ZnBr2 was used (entries 3 and 4).
Because the Ni/Xantphos catalyst system is unprecedented in
deaminative couplings of pyridinium salts and unusual in NiI/III
catalysis, we investigated the use of related ligands. Although
P-alkyl Xantphos derivatives completely failed (entry 5),
related P-aryl ligands with large bite angles could be used
(entries 6 and 7). These results are consistent with Diao’s
observation that the large bite angle of Xantphos can stabilize
the necessary Ni(I) intermediate and that bulky P-alkyl groups
prevent productive cross-coupling.12 In addition, control
experiments demonstrated that both nickel and ligand are
required (entries 8 and 9); competitive SN2 displacement does
not occur at this reaction temperature for either primary or
secondary alkylpyridinium salts (see 6 in Scheme 2 for the
primary example).
Under these optimized conditions (see Table 1, entry 4), we
observed a broad scope across an array of Katritzky pyridinium
salts. Both primary and secondary alkylpyridinium salts were
compatible (Scheme 2). Various functional groups are well
tolerated, including acetal (6), benzonitrile (7), carbamate (9,
11, 13), tertiary amine (10, 13), and ester (15, 16) groups.
Excellent heterocycle incorporation is exemplified by pyridine
8, azetidine 9, pyrrolidine 10, piperidines 11 and 12,
pyrimidine 12, and piperazine 13. Notably, a reactive benzylic
pyridinium salt could also be utilized in this cyanation with
Xantphos (12 mol %), Et2Zn (0.40 equiv), ZnBr2 (1.0 equiv), DMSO
b
(0.2 M), 80 °C, 16 h, unless otherwise noted. 0.1 mmol scale. Yield
determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an
c
d
e
internal standard. Without ZnBr2. 2.1:1 dr. 24 h.
good yield (14). Additionally, pyridinium salts with β-electron-
withdrawing groups often suffer elimination under basic
reaction conditions.7a However, these types of pyridinium
salts worked well in this cyanation, as shown by nitrile 16.
The generality of this methodology was demonstrated by the
late-stage functionalization of natural products, pharmaceut-
icals, and pharmaceutical intermediates (Scheme 2). The
cyanation of the terpene-derived amines (−)-cis-myrtanyl-
amine (17) and pinanamine (18) proceeded with acceptable
yields. The pyridinium salts of amine intermediates in the
syntheses of the antidepressant drug agomelatine,13 Lipitor,14
and mosapride15 were efficiently converted to nitriles 19−21
in excellent yields. Ester derivatives of the muscle spasticity
treatment baclofen (22)16 and bleeding disorder treatment
tranexamic acid (23)17 were also effective as pyridinium
substrates. Finally, the cyanation of the pyridinium salt of the
diterpene amine leelamine (24)18 proceeded in moderate
yield. Additional functional group robustness was also noticed
in these examples, including ketal 20, morpholine 21, and aryl
chloride 22.
We have also demonstrated the use of this cyanation in an
efficient one-carbon homologation of amine 25 to the Boc-
B
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Letter
protected amine 26 (Scheme 3). We first tried a one-pot
procedure, in which we simply placed the reagents for each
AUTHOR INFORMATION
Corresponding Author
■
Mary P. Watson − Department of Chemistry & Biochemistry,
University of Delaware, Newark, Delaware 19716, United
States; orcid.org/0000-0002-1879-5257;
Email: mpwatson@udel.edu
Scheme 3. One-Carbon Homologation
Authors
Jianyu Xu − Department of Chemistry & Biochemistry,
University of Delaware, Newark, Delaware 19716, United
States
J. Cameron Twitty − Department of Chemistry &
Biochemistry, University of Delaware, Newark, Delaware
19716, United States; orcid.org/0000-0001-9524-1226
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01959
Notes
The authors declare no competing financial interest.
step sequentially in the same reaction vessel. However,
pyridinium formation is incompatible with the use of DMSO
as solvent, and the cyanation was sensitive to EtOH, which
would typically be used for pyridinium formation. In addition,
the presence of DMSO in the nitrile reduction diminishes the
yield by competitive reduction. We found that much higher
yields and cleaner reactions were achieved if a simple filtration
and concentration procedure followed pyridinium formation
and cyanation. Under these conditions, a 44% overall yield was
achieved in the one-carbon homologation of 25 to 26, which
compares favorably to the 53% overall yield observed with
careful purification after each step. This protocol gives
medicinal chemists another useful tool to homologate alkyl
primary amines efficiently.
With respect to the reaction mechanism, key steps likely
include formation of a (Xantphos)Ni(CN) species, single-
electron transfer (SET) from a Ni(0) or Ni(I) intermediate to
the alkylpyridinium salt to generate an alkyl radical, and either
inner- or outer-sphere attack of that radical on a nickel cyanide
intermediate to ultimately deliver the product. The role of
Et2Zn appears to be predominantly as a reductant (see the
Supporting Information), and the formation of both
diastereomers of 15 is consistent with an alkyl radical
intermediate. Further studies are ongoing to establish why
Xantphos is particularly effective, as well as the role of the
ZnBr2 additive.
ACKNOWLEDGMENTS
■
We thank the NIH (R35 GM131816). J.C.T. thanks the
Chemistry-Biology Interface program (NIH T32-GM133395).
Data were acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE0421224,
CHE1229234, CHE0840401, and CHE1048367; NIH P20
GM104316, P20 GM103541, and S10 OD016267).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01959.
Additional optimization and mechanistic experiments,
detailed experimental procedures, and full spectroscopic
data for new compounds (PDF)
C
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