C?H Cyanation of 6-Ring N-Containing Heteroaromatics

Article abstract of DOI:10.1002/chem.201703931

Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C?H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.

Full text of DOI:10.1002/chem.201703931

A Journal of
Accepted Article
Title: A C-H Cyanation of 6-Ring N-Containing Heteroaromatics
Authors: Bryony Elbert, Alistair Farley, Timothy Gorman, Tarn
Johnson, Christophe Genicot, Benedicte Lallemand, Patrick
Pasau, Jakub Flasz, Jose Castro, Malcolm Maccoss, Robert
Paton, christopher Schofield, Martin Smith, Michael Willis, and
Darren James Dixon
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201703931
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10.1002/chem.201703931
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A C-H Cyanation of 6-Ring N-Containing Heteroaromatics
Bryony L. Elbert,[a] Alistair J. M. Farley,[a] Timothy W. Gorman,[a] Tarn C. Johnson,[a] Christophe
Genicot,[b] Bénédicte Lallemand,[b] Patrick Pasau,[b] Jakub Flasz,[c] José L. Castro,[c] Malcolm
MacCoss,[d] Robert S. Paton,*[a] Christopher J. Schofield,*[a] Martin D. Smith,*[a] Michael C. Willis,*[a]
and Darren J. Dixon*[a]
Abstract: Heteroaromatic nitriles are important compounds in drug
discovery, both for their prevalence in the clinic and due to the
diverse range of transformations they can undergo. As such, efficient
and reliable methods to access them have the potential for far-
reaching impact across synthetic chemistry and the biomedical
sciences. Here we report an approach to heteroaromatic C-H
cyanation through triflic anhydride activation, nucleophilic addition of
cyanide, and concomitant elimination of trifluoromethanesulfinate to
regenerate the cyanated heteroaromatic ring. This one-pot protocol
is simple to perform, is applicable to a broad range of decorated 6-
ring N-containing heterocycles and has been shown to be suitable
for late-stage functionalization of complex drug-like architectures.
The nitrile group is an important chemical motif, commonly found
in molecules throughout chemistry, biology and medicine. In
chemistry, it is a versatile intermediate that can act as precursor
to a number of functional groups such as amides, amines and
carboxylic acids, and to five- and six-membered heterocycles via
cycloaddition or condensation reactions.[1] In medicine, the
polarity, directionality, and low molecular weight of the nitrile
moiety make it a substituent of choice in SAR studies, both as a
diverse isostere capable of precise hydrogen bonding, and as a
beneficial modifier of physicochemical properties.[2] As a result
of these properties it can be found attached to N-containing
heterocycles in a host of important pharmaceuticals including
the tyrosine kinase inhibitor bosutinib (1), xanthine oxidase
inhibitor topiroxostat (2), and MIV-150 (3), a nonnucleoside
reverse transcriptase inhibitor (Scheme 1a). Owing to their
synthetic relevance and prevalence in biologically active
heterocyclic compounds, there is demand for new and effective
methods to install this important functional group. To this end
recent efforts have largely focused on the discovery of metal-
catalysed coupling procedures[3] as well as the invention of
direct C–H activation protocols.[4] Despite the many advances in
general to many classes of N-containing heterocycles would
likely find application in library generation and target synthesis
and herein we wish to report our findings.
Scheme 1. (a) Nitrile containing drugs: bosutinib (1), tyrosine kinase inhibitor;
topiroxostat (2), xanthine oxidase inhibitor; MIV-150 (3) nonnucleoside reverse
transcriptase inhibitor. (b) proposed three-stage protocol for one-pot C-H
cyanation.
Our plan was to exploit the nucleophilicity of the N-atom
contained within various 6-ring heterocycles as
a general
activation mode to introduce the nitrile moiety. Following initial
nucleophilic addition to a suitable electrophilic species (such as
triflic anhydride), the heteroaromatic ring would be activated
towards subsequent nucleophilic attack of cyanide and
concomitant
base
mediated
elimination
of
trifluoromethanesulfinate anion could generate the cyanated
heteroaromatic ring (Scheme 1b).[5] The activation of N-
containing heteroaromatic species via reaction of various
electrophiles at nitrogen has previously been deployed to effect
the field we recognized that the development of
a
a
range of transformations, and examples of carbon-,
complementary and direct C-H cyanation protocol that was
phosphorus-, and sulfur-based activating groups have been
reported.[6] We hoped to build on this approach to develop a mild
and convenient one-pot cyanation protocol that would be both
general to many 6-ring N-containing heterocycles and useful for
late stage functionalization of drug-like molecules.
2-Phenylpyridine (4) was chosen as a model substrate to
enable us to study reactivity and product isomeric ratio
distribution in the planned three-stage, one-pot cyanation
protocol. An initial survey of variables such as electrophilic
activator, cyanide source and base was performed. Inspired by
the work of Corey, triflic anhydride (Tf2O) was found to be
uniquely effective as an activator,[7] while trimethylsilyl cyanide
was identified as the most convenient and effective cyanide
source for productive C-C bond formation. Following full
consumption of the activated pyridinium species, addition of N-
methylmorpholine (NMM) ensured conversion to the final,
[a]
Dr. B. L. Elbert,+ Dr. A. J. M. Farley,+ Dr. T. C. Gorman,+ Dr. T. C.
Johnson,+ Prof. Dr. R. S. Paton, Prof. Dr. C. J. Schofield, Prof. Dr.
M. D. Smith, Prof. Dr. M. C. Willis, Prof. Dr. D. J. Dixon,
Department of Chemistry, Chemistry Research Laboratory
University of Oxford, 12 Mansfield Road, Oxford OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk
[+]
[b]
These authors contributed equally to this work
Dr. C. Genicot, Dr. B. Lallemand, Dr. P. Pasau
Global Chemistry, UCB New Medicines, UCB Biopharma sprl
1420 Braine-L’Alleud (Belgium)
[c]
[d]
Dr. J. Flasz, Dr. J. L. Castro
Global Chemistry, UCB, 216 Bath Road, Slough, SL1 3WE (UK)
Dr. M. MacCoss
Bohicket Pharma Consulting LLC, 2556 Seabrook Island Road,
Seabrook Island, South Carolina 29455 (USA)
Supporting Information for this article is given via a link at the end of
this document.
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10.1002/chem.201703931
Chemistry - A European Journal
COMMUNICATION
heteroaromatic product. Using this combination of reagents,
nitrile 5 was produced as a mixture of isomers in moderate yield,
noteworthy for their potential for further downstream orthogonal
transformations. Of the pyridines surveyed, substitution was
generally favored at the 4-position, with minor, separable
quantities of other isomers produced in some cases. The
isolation of these additional compounds could be valuable as
further analogues for inclusion in SAR studies. Quinolines and
isoquinolines represent an important class of ring system in
medicinal chemistry and accordingly were attractive substrates
to investigate.[8] Pleasingly, cyanated quinolines 20-22 were
produced in excellent yields (Scheme 2b), with substitution at
the 2-position predominating (a reversal of the selectivity
observed for pyridines). Isoquinolines were also highly effective
substrates yielding fully rearomatized 1-substituted nitriles 23
and 24 as single isomers. Diazines (pyridazine, pyrimidine and
pyrazine) represent a diverse class of heterocycle where the
presence of the second nitrogen atom in the 6-membered ring
provides electronically distinct examples; it is thus not
unsurprising that no single reported cyanation procedure is
applicable to members of each class. However, our protocol
Table 1. Selected reaction optimisation data.[a]
CN
Tf2O (1.2 eq.), T1, 1 h;
+
then TMSCN, T2, t1 h
then NMM, T2, 20-t2 h
Ph
N
Ph
N
Ph
N
CN
4
5
5'
T1
T2
(° C)
t1
(h)
Ratio
Entry
Solvent
Yield[b]
(° C)
-78
-78
21
5:5’[c]
53:47
59:41
61:39
62:38
61:39
61:39
59:41
1
2
40
40
0
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
DCE
30%
61%
75%
59%
69%
80%
74%
3
3
40
3
4
21
110
80
3
5
21
3
proved successful across
a diverse range, with cyanated
6
21
60
3
CHCl3
CHCl3
pyridazine (25-27, 34), pyrimidine (28-30, 35) and pyrazine (31-
33) examples produced in moderate to excellent yields (Scheme
2c). Bidentate ligands are ubiquitous in organometallic chemistry,
and new methods to modify and tune them are in constant
demand. We observed straightforward cyanation of 36-38, with
only traces of di-cyanated products observed for 36, allowing
facile synthesis of useful unsymmetrical cyanated ligands.
To further demonstrate the general applicability of our
methodology we examined more complex heterocyclic
structures which are commonly found in commercial
pharmaceuticals and agrochemicals (Scheme 2e).[8] A series of
cyanated heterocycles were produced (39-51), with excellent
yields obtained in the presence of halides (40, 42, 44, 46, 47),
and non-reactive heterocycles (48, 49, 51). The production of
cyanated analogues of such diverse heterocyclic structures
demonstrates the power of this methodology as a tool for
medicinal chemistry and It is worthy of note that all of the
examples described in Scheme 2 were produced using a single
experimental protocol.
7[d]
21
60
3
[a] Conditions: Tf2O (1.2 eq) added to substrate (100 mg) in solvent (0.1 M) at
T1, stirred 1 h, then TMSCN (5.0 eq) added, warmed to T2 for t1. NMM (1.3
eq.) added, stirred for 20-t1 h before quench with NaHCO3. Fully rearomatised
in each case. [b] Isolated yield. [c] Determined following isolation by flash
column chromatography. [d] Performed on
methylmorpholine.
1 g scale. NMM = N-
but importantly in the absence of any non-aromatized
intermediates (Table 1, entry 1). The timing and temperature of
the different steps in the procedure were found to be important
for reaction yield: delaying addition of base (entry 2) significantly
improved production of 5, with further improvement afforded by
warming the first step of the reaction from –78 °C to room
temperature (entry 3). Switching to higher boiling solvents
allowed us to assess the effect of temperature in the
rearomatization step (entries 4, 5 and 6), and CHCl3 at 60 °C
was identified as optimal, with high yield retained upon scale up
(entry 7). It is noteworthy that the ratio of 5:5’ remained
essentially constant throughout our studies despite temperature
and solvent variation, with a slight preference for cyanation in
the 4-position over the 6-position (5:5’; ~60:40). Products of
cyanation at the 2-, 3- or 5-position of 4 were not observed.
With an optimized general procedure in hand, the substrate
scope of the cyanation was investigated (Scheme 2). Pyridines
are extremely widespread motifs in bioactive compounds, both
in nature and in the clinic, and as such methods for their
functionalization are highly sought after. We were delighted to
see that this practical, one-pot protocol was effective across a
diverse range of heteroaromatic ring systems, giving aromatic
cyanated products in up to 96% yield (Scheme 2a). Substrates
possessing aromatic (5, 6) and electron-withdrawing (8-13)
substituents gave excellent yields, with no competitive addition
to the ester group in 11 observed. Halide (14, 15) and alkyl (7,
16-19) substituents were also well-tolerated in various positions.
The alkyl substituents demonstrate compatibility with electron-
donating groups, while the halopyridines are particularly
Finally, we sought to demonstrate the potential of the
methodology for the late-stage functionalization of complex
substrates, a concept that is becoming increasingly popular
(Scheme 3).[9,10] Using the standard protocol we were able to
cyanate abiraterone acetate (52,
a treatment for prostate
cancer) in excellent yield with three different analogues
produced. Protected erlotinib (53, a treatment for lung and
pancreatic cancer) afforded a good yield of a single isomer,
while mirtazapine (54, an antidepressant) gave a moderate yield
of the 4-CN derivative in the presence of electron-donating
groups on the pyridine moiety. Quinine is included on the World
Health Organization’s List of Essential Medicines for its
important anti-malarial properties; following O-methylation, it
was cyanated in good yield to provide 55 as a single regioisomer.
As well as further extending the scope, the latter two examples
demonstrate the tolerance of the method to basic amine
functionality, although we hypothesize that competitive and
reversible coordination of these groups to the activator results in
low conversion in the case of 54.
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Tf2O (1.2 eq), CHCl3, rt, 1 h;
Y
Y
R
R
CN
then TMSCN (5.0 eq), 3 h, 60 °C
NMM (1.3 eq), 60 °C, 17 h
N
N
a) Pyridines
CF3
CN
CO2Me
Ph
F3C
CN
CN
CN
CN
Ph
N
N
N
N
CN
N
N
CN
N
CN
5, 80%
60:40
6, 88%
71:18:11
7, 64%
94:6
8, 72%
9, 41%
90:10
10, 93%
from 4-CN
11, 92%
4-CN:6-CN
4-CN:6-CN:2-CN
4-CN:2-CN
4-CN:6-CN
t-Bu
CN
AcO
Cl
Br
MeO2C
CN
CN
CN
CN
CN
N
N
N
N
CN
N
N
i-Pr
N
13, 61%
51:16:33
4-CN:6-CN:2-CN
14, 63%
69:9:22
4-CN:6-CN:2-CN
15, 79%
70:14:16
4-CN:6-CN:2-CN
16, 59%
17, 40%
12, 96%
63:22:15
4-CN:6-CN:2-CN
18, 58%
71:29
4-CN:6-CN
b) Quinolines and Isoquinolines
CN
CN
N
CN
N
CN
CN
CN
N
N
N
Br
N
19, 64%
20, 85%
77:23
22, 83%
76:24
23, 94%
24, 74%
21, 85%
94:6
2-CN:4-CN
2-CN:4-CN
2-CN:4-CN
c) Diazines
CO2Me
N
Ph
NC
Ph
N
SMe
Ph
N
N
N
N
CN
CN
CN
N
N
N
N
CN
N
CN
N
N
N
CN
25, 95%
26, 62%
27, 46%
28, 62%
84:16
29, 50% 4-CN
+ 30, 8% 2,4-diCN
31, 92%
32, 80%a
82:9:9
2-CN:6-CN
3-CN:6-CN:5-CN
d) Ligands
CN
CN
F3C
N
N
N
N
CN
N
CN
N
N
N
CN
N
CN
N
N
N
33, 52%
34, 84%
35, 50%
36, 57%
75:25
37, 48%
38, 59%
6-CN:4-CN
e) Other drug-like heterocycles and fragments
CN CN
CN
Br
N
Br
N
4
3
7
N
N
N
N
N
N
N
CF3
NC
N
N
NC
N
N
N
N
N
N
5
Br
CN
39, 69%
40, 52%
41, 91%
42, 90%
43, 43%
44, 18%
65:35
77:23
7-CN:5-CN
4-CN:3-CN
CN
CN
CN
CN
CN
O
N
N
Br
N
N
N
N
N
N
N
S
N
MeS
N
N
N
N
N
N
N
CN
48, 28% 2-CNa
+ 49, 19% 2,6-diCN
Br
45, 32%
46, 86% a
47, 75%a
50, 36%
51, 80%
Scheme 2. Substrate scope. Conditions: 0.7 mmol scale, Tf2O (1.2 eq.), CHCl3 (0.1 M wrt substrate), 1 h, rt; then TMSCN (5.0 eq.), 3 h at 60 °C; then NMM (1.3
eq.), 17 h at 60 °C. Yields are of isolated materials. Isomeric ratio determined from isolated amounts of purified material. For consistency, numbering of
functionalized carbon refers to the starting material. [a] <0.7 mmol scale, see SI for details.
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Abiraterone acetate
NC
N
O
O
CN
N
O
O
52, 73%
91:6:3
4-CN:2-CN:6-CN
nucleophilic addition observed in the major (or single)
regioisomer formed (Figure S4, Supporting Information). This is
consistent with the results obtained using condensed Fukui
indices and supports the mechanistic interpretation above.
Chemical shifts of other heterocycles do not match well with the
observed sites of addition (unlike the Fukui index), presumably
due to magnetic effects unrelated to chemical reactivity. We
therefore focus on the use of Fukui indices, which can be
employed by end-users of this methodology to predict site-
selectivity in late-stage heterocycle cyanation. These
calculations consider the substrate only and do not require more
laborious transition state modelling.
N
NAc
Erlotinib acetate
53, 49%
H
H
H
AcO
H
H
CN
O
N
O
N
N
N
Mirtazapine
54, 33%
N
Methyl quinine
55, 53%
CN
+ 63% SM
In conclusion we have developed a direct and general one-
pot protocol that enables C-H cyanation of a wide range of 6-ring
N-containing heterocycles. The procedure is easy to perform
and is suitable for late stage functionalization of drug derivatives
and advanced intermediates. Work to further expand the
generality of this C-H functionalization approach is ongoing and
the results will be reported in due course.
Scheme 3. Late-stage cyanation of drug and natural product derivatives.
Conditions: Tf2O (1.2 eq.), CHCl3 (0.1 M wrt substrate), 1 h, rt; then TMSCN
(5.0 eq.), 3 h at 60 °C; then NMM (1.3 eq.), 17 h at 60 °C. Isomeric ratio
determined from amounts of purified material.
We performed DFT (M06-2X/def2-SVP) calculations to
understand the site-selectivity of cyanation in terms of each
heterocycle’s electronic structure.[11] We found that the
condensed Fukui index, f+(r), is a good quantitative predictor for
the position(s) of attack and the level of selectivity observed.[12]
A large value of f+(r) for a given carbon atom is associated with a
large change in chemical potential when electron density is
added – it indicates greater susceptibility towards nucleophilic
attack. Functionalization at the most electrophilic position(s) of
the N-triflyl cation is consistent with irreversible, selectivity-
determining nucleophilic attack by cyanide. For 29 of the
substrates studied experimentally, the largest Fukui index
predicts the major site of cyanation 23 times; in the other 6
cases cyanation occurs at the second most electrophilic position.
This is attributable to the absence of steric effects in this
electronic model (see Figures S2 and S3, Supporting
Information). Differences in atomic Fukui indices match the
experimental regioselectivities well (particularly for pyridines and
quinolines/isoquinolines).
Experimental Section
Triflic anhydride (1.2 eq.) was added dropwise to a 0.1M solution of the
substrate (1.0 eq.) in anhydrous CHCl3 in a vial capped with a septum at
room temperature under an atmosphere of argon. The resulting solution
was stirred for 1 h, then trimethylsilyl cyanide (5.0 eq.) was added. The
septum was exchanged for a screw cap and the mixture stirred at 60 °C
for 3 h. The reaction was removed from the heating source, and N-
methylmorpholine (1.3 eq.) added quickly before the vial was resealed.
The mixture was then stirred at 60 °C for a further 17 h before cooling to
room temperature and quenching with sat. NaHCO3 solution. The phases
were separated, and the organic phase extracted twice with CH2Cl2. The
combined organic phase was dried (MgSO4) and concentrated in vacuo.
The crude residue was purified via silica flash column chromatography.
Acknowledgements
We are grateful to UCB Pharma for genereous financial support,
and to Heyao Shi for assistance with characterisation.
100%
60%
23%
0.13
0.20
0.22
Keywords: cyanation • nitriles • heterocycles • late-stage
-0.01
Ph
0.01
0.12
0.01
Tf
N
functionalisation
0.21
0.07
N
N
[1]
[2]
A. J. Fatiadi, in Triple-Bonded Funct. Groups Vol. 2, John Wiley & Sons,
Ltd., Chichester, UK, 1983, 1057–1303.
Tf
Tf
0.03
40%
77%
100%
a) F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J. Med.
Chem. 2010, 53, 7902–7917. For a recent example, see: b) L.-C.
Campeau, Q. Chen, D. Gauvreau, M. Girardin, K. Belyk, P. Maligres, G.
Zhou, C. Gu, W. Zhang, L. Tan, et al., Org. Process Res. Dev. 2016, 20,
1476–1481.
6%
CF3
0.24
0.02
0.06
N
SMe
0.18
Tf
N
N
0.07
N
0.15
0.10
0.02
N
N
0.11
[3]
For reviews of C–X functionalization methods: a) J. Lindley,
Tetrahedron 1984, 40, 1433–1456; b) G. P. Ellis, T. M. Romney-
Alexander, Chem. Rev. 1987, 87, 779–794; c) C. Galli, Chem. Rev.
1988, 88, 765–792; d) M. Sundermeier, A. Zapf, M. Beller, Eur. J. Inorg.
Chem. 2003, 3513–3526. For selected recent examples: e) M.
Sundermeier, A. Zapf, M. Beller, Angew. Chem. Int. Ed. 2003, 42,
1661–1664; f) P. Anbarasan, H. Neumann, M. Beller, Chem. Eur. J.
2011, 17, 4217-4222.
0.07
Tf
Tf
94%
100%
Figure 1. The magnitude of computed atomic Fukui indices for N-triflyl
heterocycles, f+(r) (green circles), correlate with the site of nucleophilic attack
(blue/grey arrows). Results for several other substrates are shown in the
Supporting Information.
We also computed 13C NMR chemical shifts of the activated
pyridines. The most deshielded nucleus matches the site of
[4]
For reviews of recent C–H functionalization methods: a) P. Anbarasan,
T. Schareina, M. Beller, W. Inoue, K. Suda, J. Ding, G.-W. Qin, J. Ng, R.
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Larsen, M. Martinelli, Chem. Soc. Rev. 2011, 40, 5049–5067; b) Q.
Wen, J. Jin, L. Zhang, Y. Luo, P. Lu, Y. Wang, Tetrahedron Lett. 2014,
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[5]
While similar concepts have previously been reported, the scope is
limited to quinolones and isoquinolines: a) D. L. Boger, C. E. Brotherton,
J. S. Panek, D. Yohannes, J. Org. Chem. 1984, 49, 4056–4058; to
pyridines: b) A. R. Katritzky, E. F. Scriven, S. Majumder, H. Tu, A. V.
Vakulenko, N. G. Akhmedov, R. Murugan, Synthesis 2005, 993–997; or
to pyridazines c) W. Dostal, G. Heinisch, Heterocycles 1986, 24, 793–
797; d) S. Wang, Z. Geng, R. Guo, J. Li, D. Zou, Y. Wu, Y. Wu,
Tetrahedron Lett. 2016, 57, 3067-3070; or requires triselenium cyanide
e) S. Goswami, A. C. Maity, N. K. Das, D. Sen, S. Maity, Synth.
Commun. 2009, 39, 407–415.
[6]
For a general review: a) J. A. Bull, J. J. Mousseau, G. Pelletier, A. B.
Charette, Chem. Rev. 2012, 112, 2642–2713. The Reissert and
Reissert-Henze reactions are two classical examples which fall into this
category but which suffer from several limitations. The Reissert reaction
produces non-aromatic products, and is usually limited to quinolines or
isoquinolines: b) A. Reissert, Berichte der Dtsch. Chem. Gesellschaft
1905, 38, 1603–1614; c) J. M. Grosheintz, H. O. L. Fischer, J. Am.
Chem. Soc. 1941, 63, 2021–2022; d) W. E. McEwen, R. L. Cobb,
Chem. Rev. 1955, 55, 511–549; Use of AlCl3 as an additive broadens
scope somewhat e) S. Ruchirawat, N. Phadungkul, M.
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[7]
See SI for full details. Corey reported a single example of the use of
Tf2O in combination with cyanide to produce a cyanated dihydropyridine
derivative in 25% yield, but did not demonstrate rearomatisation to the
cyanopyridine: a) E. J. Corey, Y. Tian, Org. Lett. 2005, 7, 5535–5537.
For a recent report on use of Tf2O to activate pyridines towards
phosphines, see: b) M. C. Hilton, R. D. Dolewski, A. McNally, J. Am.
Chem. Soc. 2016, 138, 13806–13809.
[8]
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10.1002/chem.201703931
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Bryony L. Elbert, Alistair J. M. Farley,
Timothy W. Gorman, Tarn C. Johnson,
Christophe Genicot, Bénédicte
Lallemand, Patrick Pasau, Jakub Flasz,
José L. Castro, Malcolm MacCoss,
Robert S. Paton,* Christopher J.
Schofield,* Martin D. Smith,* Michael C.
Willis,* and Darren J. Dixon*
Y
Y
Y
Y
Tf2O
NMM
TMSCN
H
R
R
R
R
3
N
S
CN
N
1
N
S
O
2
N
CN
O
O
rearomatisation
activation
addition
49 examples
up to 96%
O
CF3
CF3
A direct, reliable and general one-pot N-heteroaromatic C-H cyanation procedure
via triflic anhydride N-activation, nucleophilic addition of cyanide, and concomitant
elimination of trifluoromethanesulfinate, is reported. The protocol is simple to
perform, has computationally predictable site selectivity, and is applicable to a
broad range of decorated 6-ring N-containing heterocycles, including complex drug-
like architectures.
Page No. – Page No.
A C–H Cyanation of 6-Ring N-
Containing Heteroaromatics
This article is protected by copyright. All rights reserved.