Copper-Catalyzed Cyanation of Aryl- and Alkenylboronic Reagents with Cyanogen Iodide

Article abstract of DOI:10.1021/acs.orglett.5b01924

Direct catalytic cyanation of organoboronic acids with cyanogen iodide has been achieved by using a copper-bipyridine catalyst system. The cyanation reaction is likely to occur through two catalytic cycles: copper(II)-catalyzed iodination of organoboronic acids and the following cyanidocopper(I)-mediated cyanation of organic iodides.

Full text of DOI:10.1021/acs.orglett.5b01924

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cyanation of Aryl- and Alkenylboronic Reagents
with Cyanogen Iodide
Kazuhiro Okamoto,* Naoki Sakata, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto
615-8510, Japan
S
* Supporting Information
ABSTRACT: Direct catalytic cyanation of organoboronic acids with
cyanogen iodide has been achieved by using a copper−bipyridine
catalyst system. The cyanation reaction is likely to occur through two
catalytic cycles: copper(II)-catalyzed iodination of organoboronic
acids and the following cyanidocopper(I)-mediated cyanation of
organic iodides.
romatic and α,β-unsaturated nitriles constitute an im-
portant class of compounds that are seen in many organic
Scheme 1. Catalytic Transformation of Hydrocarbons with
Cyanogen Halides
A
electronic materials,1 medicinal compounds,2 and natural
resources.3 These compounds are also important as synthetic
intermediates for the development of useful organic molecules
because the cyano group can be transformed into a range of
functional groups such as carboxylic acids, esters, amides, and
aldehydes.4 Conventional cyanation methods for the synthesis of
nitriles typically employ the corresponding organic halides or
diazonium salts with copper cyanide,5 or the combination of
cyanide anion equivalents and transition-metal catalysts.6,7
In contrast to these nucleophilic cyanation reagents, cyanogen
bromide and cyanogen iodide usually behave as electrophilic
cyanation reagents, and such species can be used for the
cyanation of carbon nucleophiles without any additional
oxidant.8,9 Therefore, cyanation reactions using cyanogen halides
are regarded as complementary to traditional cyanation methods
using cyanide anion reagents. We have previously reported that
gallium(III) chloride acts as an efficient catalyst for the activation
of cyanogen bromide in both bromocyanation of alkynes and
Friedel−Crafts-type aromatic cyanation (Scheme 1a,b).10 We
have also shown that copper(I) triflate can effectively catalyze the
C−H cyanation of terminal alkynes with cyanogen iodide
(Scheme 1c).11 In the latter reaction, remarkably, the cyanation
proceeds indirectly through the intermediary formation of
alkynyl iodide rather than through direct cyanation from copper
acetylide.
method to access aromatic nitriles.15,16 However, the reported
methods for such reactions leave much room for development
because of the use of highly expensive rhodium catalyst15c or
because of the requirement for a stoichiometric amount of
copper or silver salt. Based on our previous report, we envisioned
that the catalytic cyanation of organoboronic reagents could be
achieved by utilizing a combination of copper catalyst and
cyanogen iodide. Herein, we detail a methodology that can be
used for the copper-catalyzed cyanation of organoboronic acids
with cyanogen iodide and provide some mechanistic insights on
the activation of cyanogen iodide and boronic acids by the
copper catalyst (Scheme 1d).
Initially, the reaction conditions were optimized by using 3,5-
dimethylphenylboronic acid pinacol ester (1a-Bpin), cyanogen
iodide, base, and copper catalyst (Table 1). Initial attempts at the
cyanation of 1a-Bpin were performed with cyanogen iodide (1.5
equiv), 2,2,6,6-tetramethylpiperidine (TEMP; 2.2 equiv), and
(CuOTf)2·toluene (10 mol %) in THF at 60 °C for 24 h;
Organoboronic acid derivatives are the most widely used class
of building blocks for transition-metal-catalyzed Suzuki−
Miyaura cross-coupling reactions.12 Conventional methods for
the synthesis of organoboronic compounds typically start from
the corresponding halide.13 However, in 2002, Ishiyama,
Miyaura, and Hartwig developed an iridium-catalyzed C(sp2)−
H borylation reaction of arenes that enabled the halide-free
synthesis of arylboronic compounds with completely different
regioselectivity to that generated by using halide-based
methods.14 Given the rapid development in the chemistry of
organoboronic acids, much attention has been paid to the direct
catalytic oxidative cyanation of arylboronic acid derivatives as a
Received: July 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01924
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Copper-Catalyzed Cyanation of Arylboronic Reagent
1a-B with Cyanogen Iodide
Scheme 2. Copper-Catalyzed Cyanation of Arylboroxine 1-
BO with Cyanogen Iodide
a
a
b
yield (%)
temp
(°C)
boronic
reagent
entry ligand
base
2a
3a
c
1
none
TEMP
TEMP
TEMP
TEMP
Et3N
60
1a-Bpin
1a-Bpin
1a-Bpin
1a-Bpin
1a-Bpin
1a-Bpin
1a-Bpin
1a-Bpin
1a-BO
0
2
2
none
60
8
21
25
12
3
3
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
60
27
42
8
4
110
110
110
110
130
130
130
130
5
6
K2CO3
CsF
39
45
61
54
10
14
16
25
8
7
8
CsF
9
CsF
d
d
e
10
11
CsF
1a-BO
73 (66 )
1
none
1a-BO
68
a
Standard conditions: 3,5-dimethylphenylboronic reagent (1a-B)
(0.20 mmol per amount of boron atoms), cyanogen iodide (0.30
mmol), (CuOTf)2·toluene (10 mol %), ligand (22 mol %), and base
a
b
The reaction was carried out with boroxine 1-BO (0.40 mmol per
(0.44 mmol) in MeOH/H2O (4:1 v/v, 1.5 mL). Yields were
1
amount of boron atoms), cyanogen iodide (0.60 mmol), (CuOTf)2·
toluene (15 mol %), dtbpy (33 mol %), and CsF (0.88 mmol) in
MeOH/H2O (4:1 v/v; 3.0 mL). Isolated yields are shown.
determined by H NMR spectroscopic analysis using 1,4-dioxane as
c
internal standard. THF was used as solvent instead of MeOH/H2O.
d
(CuOTf)2·toluene (15 mol %) and dtbpy (33 mol %) were used.
b
e
(CuOTf)2·toluene (30 mol %) and dtbpy (66 mol %) were used.
Isolated yield.
however, the reaction did not afford the expected cyanation
product 2a (Table 1, entry 1). When the solvent was changed
from THF to a 4:1 mixture of MeOH and H2O, a small amount
of nitrile 2a (8% yield) was observed, together with iodoarene 3a
(21% yield) (entry 2). The use of 4,4′-di-tert-butyl-2,2′-dipyridyl
(dtbpy) as a ligand for the copper catalyst increased the yield of
2a to 27% (entry 3). Performing the reaction at higher
temperature (110 °C) led to an improved yield of 2a (entry
4). When the effect of base was examined, cesium fluoride (CsF)
was found to be superior (entries 5−7). At higher temperature
(130 °C), the use of either boronic pinacol ester (1a-Bpin) or
boroxine (1a-BO) afforded nitrile 2a in moderate yield (entries 8
and 9).17 Finally, use of the catalyst precursor (CuOTf)2·toluene
(15 mol %) afforded cyanide 2a in 66% isolated yield (entry 10).
In contrast to these results, iodide 3a was formed as the major
product (68% yield) when the reaction was conducted in the
absence of CsF (entry 11).
of alkenylboronic acids gave the corresponding α,β-unsaturated
nitriles 2q and 2r. Double cyanation of a diboronic acid with a
fluorene framework to give 2s also proceeded successfully by
using double the amount of reagent. Cyclic boronic compound 4
was also used in this cyanation reaction and gave lactone 5, which
can be generated by solvolysis of nitrile 6 in 72% yield (eq 1).
With the optimized conditions in hand, the substrate scope of
the cyanation reaction was explored (Scheme 2). The reaction
was found to tolerate a range of arylboroxine derivatives bearing a
variety of functional groups including methoxy, N,N-dimethyla-
mino, chloro, methoxycarbonyl, nitro, and hydroxyl groups, to
afford the cyanation products 2b−g in good yields. The reaction
also succeeded with boroxine derivatives bearing an alkene or
alkyne moiety at the para-position (2h and 2i) and ortho-
substituted boroxines (2j−l). In addition, polyaromatic or
heteroaromatic boroxines also underwent cyanation efficiently
to give the corresponding nitriles 2m−p in good yield. Cyanation
The formation of aryl iodide 3a as the principle component
when the reaction was performed in the absence of CsF (Table 1,
entry 11) suggests the involvement of iodide 3a in the present
cyanation.18 To investigate this hypothesis, we performed two
control experiments. First, in the absence of arylboroxine 1a-BO,
the standard reaction conditions were applied to aryl iodide 3a,
which was prepared separately; unexpectedly this afforded a
B
DOI: 10.1021/acs.orglett.5b01924
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
crude mixture containing only 4% nitrile 2a together with 96%
recovered iodide 3a (eq 2). Second, when CsF was subsequently
added to the mixture obtained from the reaction performed in
the absence of CsF, and the reaction was continued at 130 °C for
a further 12 h, nitrile 2a was observed as a major product (eq 3).
These contrasting results imply that the cyanation of iodide 3a
requires both CsF and the boronic moiety to proceed.
We then performed the reaction in several batches under the
same conditions to determine how the distribution of aromatic
compounds (1a-BO, 2a, and 3a) evolved as the reaction
progressed (Figure 1). It was found that even at the beginning
arylcopper(II) complex C. Reductive elimination from complex
C releases aryl iodide 3, regenerating copper(I) complex A (cycle
(i)). With the reaction proceeding through cycle (i), HCN and
boric acid (B(OH)3) accumulate in the reaction mixture, which
then generates cesium cyanide (CsCN) as the active cyanation
agent in the presence of CsF. CsCN reacts readily with dimeric
copper(I) triflate A to form cyanidocopper(I) complex D, which
would be an irreversible step. Complex D can also catalyze the
cyanation of aryl iodide 3 with consumption of CsCN to form
nitrile 2 (cycle (ii)).19,20
In conclusion, we have demonstrated a copper-catalyzed
cyanation reaction of aryl- and alkenylboronic acids using
cyanogen iodide. The reaction proceeds efficiently under
aqueous conditions with a combination of copper(I) triflate
and a bipyridine ligand in the presence of cesium fluoride as base.
Aryl- and alkenylboronic acids with a range of functional groups
at the ortho-, meta-, or para-positions reacted with cyanogen
iodide under the optimized conditions to give the corresponding
nitriles in moderate to high yields. Control experiments and an
analysis of the time-dependent behavior of the species present in
the reaction enabled us to propose a reasonable reaction
mechanism that involves multiple catalytic cycles producing
iodides or nitriles.
ASSOCIATED CONTENT
* Supporting Information
■
Figure 1. Time-dependent distribution of the recovered reactant 1a-BO
and the products 2a and 3a.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01924.
of the reaction (5−30 min), detectable amounts of nitrile 2a were
already formed. When the starting arylboronic compound had
been consumed, the amount of nitrile 2a then increased in
proportion to the decrease in the amount of iodide 3a. Such time-
dependent behavior implies that nitrile 2a is formed through
both direct cyanation of an arylboronic compound and cyanation
of iodide 3a.
Based on the results presented above, we propose the reaction
mechanism shown in Scheme 3. During the earlier stages of the
reaction, Cu(I)−dtbpy complex A, which is initially generated by
complexation, is readily oxidized to Cu(II) cationic complex B,
which is accompanied by the generation of hydrogen cyanide
(HCN). Aqueous protic solvent may be necessary in this step.
Even in the absence of cesium fluoride (CsF), complex B
undergoes transmetalation with arylboronic acid 1 to form
Experimental procedures and compounds characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kokamoto@scl.kyoto-u.ac.jp.
*E-mail: ohe@scl.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported partly by JSPS KAKENHI Grant
Number 26410119. K. Okamoto also thanks the financial
support from the Kyoto Technoscience Center and the Society
of Iodine Science.
Scheme 3. Proposed Mechanism for Copper-Catalyzed
Cyanation
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Org. Lett. XXXX, XXX, XXX−XXX