Metal-Free Direct C?H Cyanation of Alkenes

Article abstract of DOI:10.1002/anie.201807303

A metal-free and direct alkene C?H cyanation is described. Directing groups are not required and the mechanism involves electrophilic activation of the alkene by a cyano iodine(III) species generated in situ from a [bis(trifluoroacetoxy)iodo]arene and tri

Full text of DOI:10.1002/anie.201807303

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Accepted Article
Title: Metal-Free Direct C-H Cyanation of Alkenes
Authors: Xi Wang and Armido Studer
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10.1002/anie.201807303
Angewandte Chemie International Edition
COMMUNICATION
Metal-Free Direct C-H Cyanation of Alkenes
Xi Wang[a] and Armido Studer*[a]
Abstract: A metal-free direct alkene C-H cyanation is described.
Directing groups are not required and the mechanism involves
electrophilic activation of the alkene by a cyano iodine(III) species
NCTS (N-cyano-N-phenyl-p-methylbenzenesulfonamide) as the
cyanation reagent. However, non-directed alkene C-H cyanation
has not yet been described. We report herein transition-metal-free
alkene cyanation using an aryl(biscyano)iodine(III)reagent as
alkene activator and cyanide source.
generated in situ from
a [bis(trifluoroacetoxy)iodo]arene and
trimethylsilyl cyanide as the cyanide source. This C-H
functionalization can be conducted at gram-scale and for non-cyclic
1,1- and 1,2-disubstuted alkenes high stereoselectivity is achieved,
rendering the method highly valuable.
The nitrile functionality is an important structural moiety that
can be found in various natural products, drugs, agrochemicals,
and in polymers.[1] Moreover, the cyano group can be used as a
synthetic
equivalent
for
primary
amines,
tetrazoles,
aldehydes/ketones and their related functionalities.[2]
Aryl nitriles are generally prepared by cyanation of halides,
pseudohalides, diazonium salts, and organometallic reagents.[3]
Step- and atom-economy in the synthesis of cyanated arenes and
alkenes can be improved following a direct C-H cyanation
strategy. Significant advances in directing group (DG) assisted
arene C-H cyanation have been achieved using transition metal
catalysis (e.g., Pd, Cu, and Rh).[4] Along these lines, direct C-H
cyanation of indoles has also been reported.[5] Recently, Wang
and coworkers disclosed a Fe-catalyzed electrophilic cyanation of
arenes and heteroarenes using aryl(cyano)iodonium triflates,[6a]
and the Nicewicz group reported aromatic C-H cyanation with
trimethylsilyl cyanide using photoredox catalysis.[6b]
Figure 1. Various “CN” sources and oxidants tested (Ts = p-tolylsulfonyl, Tf =
trifluoromethylsulfonyl, TMS = trimethylsilyl).
-Phenylstyrene 1a was chosen as a model substrate and
various electrophilic cyanation reagents were screened in
combination with or without an additive in dichloroethane (DCE)
at 70 °C for 15 h (Table 1, Figure 1).[3g,4b,4c,4i,5d,11] C-H cyanation
of 1a with reagents 2a-d, 2i and 2j failed (Table 1, entries 1-6).
Traces of nitrile 4a were detected when benziodoxole 2e was
employed in combination with catalytic CuCl or Fe(OAc)2 (Table
1, entries 7 and 8). No improvement was noted by using reagent
2f (Table 1, entries 9 and 10). TMSCN paired with oxone,
(NH4)2S2O8, or t-BuOOH did not provide 1a (Table 1, entries 11-
13). Product 4a was obtained in 7% yield using reagent 2e in
combination with TMSCN (Table 1, entry 14). Replacing 2e by 2f
led to a significant improvement of the yield (Table 1, entry 15,
32%). The electronic nature of the substituents at the aryl moiety
in the I(III)-reagent is important: the activity of 2h was superior to
that of 2f and 2g (Table 1, entries 15-17). Pleasingly, direct C-H
cyanation using the more stable and easily accessible
[bis(trifluoroacetoxy)iodo]arene 3d, that reacts in situ via
sequential ligand exchange with TMSOTf and TMSCN to
aryl(cyano)iodonium triflate 2h,[12] gave a comparable result
(Table 1, entry 18, 88%). The best yield (90%) was achieved upon
Scheme 1. Direct C–H cyanation of alkenes.
Established approaches for the synthesis of acrylonitriles
comprise
carbocyanation,[7]
heterocyanation,[8]
and
hydrocyanation[9] of alkynes with X-CN-type reagents (X = C, Si,
B, Sn, Ge, S, O, Br, H). However, as compared to arene C-H
cyanation, direct alkene C-H cyanation has not been well
investigated. Anbarasan[10a] and Fu[10b] reported Rh-catalyzed
direct C(sp2)-H cyanation of alkenes bearing directing groups with
o
lowering the temperature to 40 C (Table 1, entries 19 and 20).
[a]
Dr. X. Wang, Prof. Dr. A. Studer
Westfälische Wilhelms-Universität
Organisch-Chemisches Institut
Corrensstraβe 40, 48149 Mꢀnster, Germany
E-mail: studer@uni-muenster.de
With 2 equivalents of TMSCN, a lower yield resulted but using 3
and 4 equivalents provided good results (Table 1, entries 22-24).
Benziodoxole 3e as an oxidant provided a worse result (Table 1,
entry 21, 34%). Other cyanide sources such as NaCN, KCN and
Bu4NCN did not lead 4a (Table 1, entries 25-27).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807303
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization studies.a
Table 2. Substrate scope.[a,b]
Entry
“CN” 2
(equiv)
Oxidant
(equiv)
Additive (equiv)
Yield
(%)[b]
[a]
1
2a (2.0)
2b (2.0)
2c (2.0)
2d (2.0)
2i (2.0)
none
none
NP
NP
NP
NP
NP
NP
traces
traces
traces
traces
NP
NP
NP
7
2
none
AuCl3 (0.05)
CuCl (0.1)
BF3·Et2O (2.0)
none
3
none
4
none
5
none
6
2j (2.0)
none
none
7
2e (2.0)
2e (2.0)
2f (2.0)
none
CuCl (0.1)
Fe(OAc)2 (0.1)
none
8
none
9
none
10
11
12
13
14
15
16
17
18
19[c]
20[e]
21
22[c]
23[c]
24[c]
25[c]
26[c]
27[c]
2f (2.0)
none
Fe(OAc)2 (0.1)
none
2k (2.0)
2k (2.0)
2k (2.0)
2k (4.0)
2k (4.0)
2k (4.0)
2k (4.0)
2k (5.5)
2k (5.5)
2k (5.5)
2k (5.5)
2k (2.0)
2k (3.0)
2k (4.0)
NaCN (5.5)
KCN (5.5)
Bu4NCN (5.5)
3a (2.0)
3b (2.0)
3c (2.0)
2e (1.5)
2f (1.5)
2g (1.5)
2h (1.5)
3d (1.5)
3d (1.5)
3d (1.5)
3e (1.5)
3d (1.5)
3d (1.5)
3d (1.5)
3d (1.5)
3d (1.5)
3d (1.5)
none
none
none
none
32
none
44
none
87
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
TMSOTf (1.5)
88
90[d]
14
34
27
81
85
NP
NP
NP
[a] Reaction condition: 1a (0.20 mmol, 1.0 equiv), 2, oxidant, additive, DCE (2
mL), 70 oC, 15 h. [b] Yield determined by 1H NMR analysis using MeNO2 as an
internal standard. [c] Conducted at 40 oC. [d] Isolated in 87% yield. [e]
Conducted at room temperature.
[a] Reaction condition: 1 (0.20 mmol, 1.0 equiv), 2k (1.1 mmol, 5.5 equiv), 3d
(0.30 mmol, 1.5 equiv), TMSOTf (0.30 mmol, 1.5 equiv), DCE (2 mL), 40 oC, 15
h. [b] Yields refer to the isolated yield of the major isomer if not otherwise noted.
[c] Conducted at 70 oC. [d] These yields are based on 1H NMR analysis with
MeNO2 as internal standard. [e] Combined yield of both isomers. [f] 2k (1.1
mmol, 7.0 equiv), 3d (0.30 mmol, 1.5 equiv), TMSOTf (0.30 mmol, 1.5 equiv).
[g] 2k (0.30 mmol, 1.5 equiv), 2h (0.30 mmol, 1.5 equiv). [h] The ratio of the
major isomer to other isomers is given in parentheses.
Under optimized conditions, various alkenes were tested
(Table 2). -Methylstyrenes possessing electron withdrawing or
electron donating groups at the para position of the arene ring
afforded acrylonitriles 4b-l in moderate to high yields with good to
excellent E-selectivity. Generally, systems bearing electron-
withdrawing groups provided lower E-selectivities in this series.
An -methylstyrene bearing a meta-substituent (4m) worked well
and the -naphthyl congener reacted with similar efficiency (4n).
Increasing the size of the -alkyl substituent in the styrene
substrate leads to diminished selectivity, as shown by switching
from -methylstyrene to the n-propyl derivative (4o) and reversed
selectivity was obtained for the -cyclohexyl styrene (4p).
A bicyclic styrene with exocyclic double bond reacted in
excellent selectivity (4q) and 1,3-enynes engage in this
transformation providing the Z-product as major isomer (see 4r).
Reaction works on -substituted styrenes and indene was
converted to 4s in a good yield. A trans--methylstyrene and
trans-stilbene reacted with complete regio and good
stereoselectivity (4t,4u). Both acyclic and cyclic trisubstituted
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10.1002/anie.201807303
Angewandte Chemie International Edition
COMMUNICATION
styrenes could be converted (4v-x) and conjugated dienes were
also competent reaction partners, affording the monocyanated
products with high regioselectivity (4y-4aa). To document the
practicability, reaction of 1a in gram scale gave 4a in 91% yield.
Unfortunately, styrene did not react to cinnamonitrile.
Notably, Z-selectivity of 4p could be improved from 1.2:1 to
17:1 upon E→Z isomerization under UV-irradiation (402 nm)
following a Gilmour protocol in presence of (−)-riboflavin (Scheme
2).[13] This method was also applied to isomerize (E)-4q to its Z-
derivative, showing that both isomers are accessible using our
approach.
Scheme 2. E→Z isomerization.
To elucidate the mechanism, control experiments were
conducted. A radical pathway[14] could be excluded based on the
result obtained with the radical probe 1y that reacted to 4y without
formation of any ring-opening product 5 (Scheme 3a). In the
absence of Lewis acid, the cyanation did not occur, indicating that
TMSOTf is essential for generating the active I(III) species
(Scheme 3b, left). ArI(CN)OTf 2h (1.5 equiv) in combination with
TMSCN (4 equiv) provided 4a in comparable yield showing that
ArI(CN)OTf 2h is a potential active reagent that can be formed by
reaction of 3d with TMSCN and TMSOTf (Scheme 3b, right).
However, we found that 2h is not an active I(III) species, since
cyanation of 1a with 2h did not provide 4a, and 1a decomposed
(Scheme 3c, left). Other nucleophilic CN-reagents such as NaCN,
KCN, (n-Bu)4NCN did not work in combination with 2h showing
the importance of the TMS-moiety (Scheme 3c, right). Replacing
TMSCN by TMSCl provided the chlorination product 6 in 34%
yield and nitrile 4a was not formed (Scheme 3d). The analogue
Ph2IOTf was not a competent oxidant for cyanation of 1a with
TMSCN and the phenylated product 7 was also not identified
(Scheme 3e). These results revealed that the active I(III) reagent
is likely the highly electrophilic [bis(cyano)iodo]arene[15] formed in
situ from 2h and TMSCN.
Scheme 3. Mechanistic studies.
Based on these investigations, the following mechanism is
suggested (Scheme 4). The aryl(cyano)iodonium triflate 2h
generated from 3d through ligand exchange undergoes renewed
ligand exchange with TMSCN to give the active species
[bis(cyano)iodo]arene A and TMSOTf. The electrophilic activation
of alkene 1 with A, which is additionally supported by interaction
with TMSOTf, then reversibly leads to the cyclic iodonium
intermediate B.[17] Regioselective ring-opening of B by the
cyanide anion provides the intermediate C and diastereoselective
deprotonation of C in a conformation where the cyano group is
positioned anti to the bulkier RL-substituent eventually provides 4.
We also determined intermolecular and intramolecular kinetic
isotope effects (KIE). -Phenylstyrene (1a) and [D2]-1a (1:1) were
subjected to the reaction conditions and a kH/kD value of 1.1 was
measured for the intermolecular KIE (Scheme 3f). A significant
intramolecular KIE of 3.3 was determined for cyanation of [D1]-1a
(Scheme 3g). These KIE experiments indicate that activation of
the alkene by the I(III) reagent is likely reversible and CH bond
cleavage is a slow step.[16]
Scheme 4. Suggested mechanism.
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10.1002/anie.201807303
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COMMUNICATION
In summary, we have described a metal-free C(sp2)–H
cyanation of various alkenes using TMSCN in combination with
[bis(trifluoroacetoxy)iodo]arene 3d. Reactions proceed under mild
conditions and show broad substrate scope: 1,1-disubstituted,
1,2-disubstituted, and trisubstituted alkenes are smoothly
converted into the corresponding cyanated products in high yield
and good to excellent diastereoselectivity.
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Acknowledgements
We thank the European Research Council (ERC Advanced
Grant agreement No. 692640) for financial support.
Keywords: Cyanation • Hypervalent Iodine(III) Reagents • C-H
functionalization • Acrylonitriles
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10.1002/anie.201807303
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Xi Wang, Armido Studer*
Page No. – Page No.
Metal-Free Direct C-H Cyanation of
Alkenes
Dual role. An in situ generated aryl(biscyano)iodine(III)reagent activates various styrene derivatives and additionally also acts
as a cyanide source in the direct CH cyanation of various alkenes. Reactions occur under mild conditions in the absence of
any transition metal in good chemical yield and high stereoselectivity.
This article is protected by copyright. All rights reserved.