Copper-Catalyzed Regio- and Stereoselective Iodocyanation and Dicyanation of Alkynes with Cyanogen Iodide

Article abstract of DOI:10.1021/acs.orglett.7b01378

anti-Selective iodocyanation and dicyanation of various internal alkynes has been developed by means of a simple copper catalyst system. The selectivity of the products was switched by tuning the reaction conditions. Mechanistic studies have revealed all of the stepwise pathways including diiodide formation, selective monocyanation, and second cyanation processes.

Full text of DOI:10.1021/acs.orglett.7b01378

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Regio- and Stereoselective Iodocyanation and
Dicyanation of Alkynes with Cyanogen Iodide
Naoki Sakata, Kohei Sasakura, Gaku Matsushita, Kazuhiro Okamoto,* 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: anti-Selective iodocyanation and dicyanation of
various internal alkynes has been developed by means of a simple
copper catalyst system. The selectivity of the products was switched
by tuning the reaction conditions. Mechanistic studies have revealed
all of the stepwise pathways including diiodide formation, selective
monocyanation, and second cyanation processes.
ifunctionalization of alkynes is one of the most efficient
ways of constructing complex olefinic moieties in short
cyanides were obtained through the formation of alkynyl
iodides as an intermediate (Scheme 1, eq 3).11 In this
contribution, we report a copper-catalyzed anti-selective
iodocyanation and dicyanation of alkynes using cyanogen
iodide, in which the two reactions were switched simply by
changing the reaction conditions (Scheme 1, eq 4).12,13
D
steps.1 Of these reactions, metal-catalyzed direct addition of X−
CN bonds (X = C, B, Si, Br, etc.) into alkynes has been
extensively studied for decades in terms of its conceptual
novelty, regio- and stereoselectivity, and product utility
(Scheme 1, eq 1).2−9 However, almost all of the cyanofunction-
First, ester-containing alkyne 1a was reacted with cyanogen
iodide in the presence of 10 mol % of copper(I) acetate and
4,4′-di-tert-butyl-2,2′-bipyridyl (dtbpy) as a ligand in methanol
at 80 °C for 20 h (Table 1, entry 1). Then the corresponding
regioselective anti-iodocyanation product 2a was obtained in
62% yield together with small amounts of dicyanide 3a and
diiodide 4a. Two cyanation products were fully characterized
by NMR and X-ray analysis (see Supporting Information). In
the absence of the ligand and in a higher concentration,
generation of dicyanation product 3a was favored, and 3a was
obtained with high selectivity (Table 1, entries 2 and 3). When
the reaction temperature was lowered to 60 °C, the major
product formed then changed to iodocyanation product 2a
(Table 1, entry 4). The solvent was a key factor for the product
selectivity, and a reaction in toluene selectively afforded the
iodocyanation product 2a (Table 1, entry 5). Finally, the
copper catalyst could be changed into the more accessible
copper(II) acetate, and the catalyst loading was lowered to 5
mol %. Under the optimized conditions using toluene or
methanol as solvents, iodocyanation product 2a was obtained in
89% isolated yield, and dicyanation product 3a was obtained in
75% isolated yield (Table 1, entries 6 and 7). By contrast, the
major product was diiodide 4a in the absence of any copper
catalysts, which indicates that the cyanation proceeds only in
the presence of a copper catalyst (Table 1, entry 8).14
Scheme 1. Addition of X−CN Compounds to Alkynes
alization methods have provided only syn-selectivity. Therefore,
development of anti-cyanofunctionalization methods is im-
portant for the diversity of stereodefined adducts.
During the course of our concurrent investigations based on
the unique reactivities of cyanogen halides, our research interest
has recently focused on the difference between cyanogen
bromide (BrCN)9a and cyanogen iodide (ICN).10 Cyanogen
bromide serves as an electrophilic cyanation reagent and is
effectively activated in the presence of Lewis acidic metals such
as GaCl3 (Scheme 1, eq 2).9b,c By contrast, cyanogen iodide
does not work well as an electrophilic cyanation agent but can
be used in combination with a copper catalyst. We have found
that a copper catalyst was effective for the reaction of cyanogen
iodide with alkynes giving alkynyl cyanides, and that the alkynyl
Various alkynes were applied to the present iodocyanation
under the optimized reaction conditions (Table 2). Ester-
containing alkynes were especially effective and gave the
iodocyanation products regio- and stereoselectively. Methyl,
Received: May 8, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b01378
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Letter
Table 1. Copper-Catalyzed Cyanation of Alkynes 1a with
Cyanogen Iodide
Table 3. Copper-Catalyzed Iodocyanation of Simple Alkynes
with Cyanogen Iodide
a
a
b
yield (%)
entry
1
[Cu]
2a
3a
4a
note
CuOAc
62
2
7
MeOH (0.5 M)
with dtbpy (10 mol %)
MeOH (0.5 M)
2
3
4
5
CuOAc
CuOAc
CuOAc
CuOAc
Cu(OAc)2
Cu(OAc)2
none
22
9
67
84
13
15
7
0
0
0
0
0
0
MeOH (2.0 M)
83
84
MeOH (2.0 M), 60 °C
toluene (2.0 M)
cd
,
e
6
7
8
93(89)
toluene (2.0 M)
a
Conditions: alkyne 1 (0.40 mmol), cyanogen iodide (0.80 mmol),
c
f
e
12
0
81(75)
0
MeOH (2.0 M)
b
Cu(OAc)2 (40 μmol) in ethanol (0.20 mL). The reaction was
performed at 120 °C. Toluene as a solvent.
25 MeOH (2.0 M)
c
a
Conditions: ethyl 3-phenylpropiolate (1a, 0.4 mmol), cyanogen
iodide (1.2 mmol), and copper catalyst (40 μmol) at 80 °C for 20 h.
of symmetric diphenylacetylene at 80 °C led to a single
iodocyanation product 2k in 46% yield. Arylalkylacetylenes also
reacted to give regioisomers of anti-iodocyanation products
(2la/2lb and 2ma/2mb). Both regioisomers were characterized
by X-ray crystallography (see Supporting Information). The
steric bulkiness of alkyl moieties of R2 seems to affect the
regioselectivity of iodocyanation. When R2 is n-butyl, the ratio
of adducts 2na and 2nb was in a higher ratio (81:19). When R2
is cyclohexylmethyl, the ratio of 2oa and 2ob reached 91:9.15
Table 4 summarizes the results of the dicyanation of alkynes
using an excess amount of ICN. Alkynes having both a phenyl
b
1
The yields were determined by H NMR using 1,4-dioxane as an
c
d
internal standard. 5 mol % of Cu(OAc)2 was used. 2.0 equiv of ICN
e
f
were used. Isolated yield. 32% conversion of 1a. dtbpy = 4,4′-di-tert-
butyl-2,2′-bipyridine.
Table 2. Copper-Catalyzed Iodocyanation of Directing-
a
Group-Tethered Alkynes with Cyanogen Iodide
Table 4. Copper-Catalyzed Dicyanation of Alkynes with
a
Cyanogen Iodide
a
a
Conditions: alkyne 1 (0.40 mmol), cyanogen iodide (1.20 mmol),
Conditions: alkyne 1 (0.40 mmol), cyanogen iodide (0.80 mmol),
b
Cu(OAc)2 (20 μmol) in methanol (0.2 mL). Isolated yields are shown.
Cu(OAc)2 (20 μmol) in toluene (0.20 mL). Cu(OAc)2 (40 μmol).
b
c
c
Cu(OAc)2 (40 μmol). Toluene as a solvent.
Cyanogen bromide (1.20 mmol) was used instead of cyanogen
iodide.
and an ester moiety all gave the anti-dicyanation products in
high yields (3a−c). Even when the alkyne possesses a
methoxymethyl group that can coordinate to the copper
species, dicyanide 3j was obtained in moderate yield. Diethyl
acetylenedicarboxylate (1q) was much more reactive even in
toluene and yielded unusually electron-deficient tetrasubsti-
tuted alkene 3q in good yield.
ethyl, and isopropyl esters all reacted to give iodocyanation
products 2a−c in high yields. The reaction of alkynes having
various aromatic moieties or an alkyl group also proceeded
efficiently to give the iodocyanation products 2d−g. When R1 is
a chloroalkyl group, the chloro group did not undergo the
halogen exchange or cyanation (2h). Ketoalkyne 1i also reacted
to give the product 2i in moderate yield. It is important that
this reaction allows the use of alkynes without electron-
deficient substituents. A methoxymethyl-group-substituted
alkyne reacted to give adduct 2j selectively in addition, which
indicates that the ester and methoxymethyl groups might affect
the regioselectivity in the same way. anti-Bromocyanation was
also achieved by using cyanogen bromide (5b).
The time-dependent reaction profile of the reaction of 1a
1
with ICN was observed continuously using H NMR (Scheme
2). The amount of alkyne 1a was gradually decreased after the
10 min induction period, generating iodocyanide 2a and
diiodide 4a. While the yield of 2a was gradually increased, the
yield of 4a increased and reached a ceiling at around 20%, and
then decreased after 4 h. These observations indicate that the
iodocyanide 2a was generated from the intermediate of diiodide
4a. Considering that the diiodination of alkynes could proceed
For simple alkynes, the use of ethanol as a solvent was
effective for the selective iodocyanation (Table 3). The reaction
B
DOI: 10.1021/acs.orglett.7b01378
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Scheme 2. Time-Dependent Distribution of the Recovered
Reactant 1a and Products 2a and 4a in Copper-Catalyzed
Cyanation of Alkynes with Cyanogen Iodide
Scheme 5. A Proposed Catalytic Cycle for Copper-Catalyzed
Iodocyanation and Dicyanation of Alkynes
at least partly without any copper catalyst, albeit quite slowly
(Table 1, entry 8), alkynes would undergo diiodination via
molecular iodine that is generated by two pathways: one, the
noncatalytic comproportionation of ICN, and the other,
copper-mediated ligand exchange as shown in Scheme 3.16
then quickly consumed for diiodination of alkyne 1 to afford
diiodide 4 (Scheme 5, step 2). Oxidative addition of diiodide 4
to copper cyanide B forms intermediate C in a high oxidation
state (Scheme 5, step 3), which leads to the iodocyanation
product 2 by reductive elimination of C, regenerating copper
iodide A (Scheme 5, step 4). In methanol, probably because of
the acceleration of cyanation by a polar solvent effect, the
second cyanation of 2 with copper cyanide B occurs through
the oxidative addition−reductive elimination sequence to give
dicyanide 3, regenerating copper iodide A (Scheme 5, steps 5
and 6). The regioselectivity of the first cyanation of diodide 4
can be explained by assuming carbonyl oxygen-coordinating
intermediate C. In intermediate C, the copper center in the
higher oxidation state is highly stabilized by coordination of the
internal carbonyl moiety, probably lowering the barrier for
activation of cyanation compared with that from its regioisomer
C′.
Scheme 3
To gain insight into the mechanism generating each product
2a, 3a, and 4a, a series of control experiments were conducted
(Scheme 4). The reaction of alkyne 1a with molecular iodine in
Scheme 4. Control Experiments
The reaction products could be transformed by taking
advantage of the iodide substituents (Scheme 6). Iodocyanation
Scheme 6. Derivatization of Iodocyanation Product 2b
the absence of copper in toluene at 80 °C produced diiodide 4a
in good yield (Scheme 4, eq 5).17 The reaction of diiodide 4a
with a stoichiometric amount of copper(I) cyanide in toluene at
80 °C gave iodocyanide 2a as a sole product quantitatively, of
which the regio- and stereoselectivity was ideal (Scheme 4, eq
6). The isolated 2a was further reacted with copper(I) cyanide
in methanol at 80 °C, the dicyanide 3a being obtained in high
yield (Scheme 4, eq 7). These experiments suggest that two
cyanation products 2a and 3a are produced stepwise from
diiodide 4a by cyanation with copper(I) cyanide.18−20
A proposed catalytic cycle for the present cyanation reactions
using ester-containing alkyne 1 as a typical substrate is
described in Scheme 5.21 First, in situ generated low-valent
copper iodide species A undergoes ligand exchange by
cyanogen iodide to generate copper cyanide species B together
with molecular iodine (Scheme 5, step 1). Molecular iodine is
product 2b was treated with a palladium catalyst and an
arylstannane reagent to undergo the Stille coupling reaction
with high efficiency, affording the tetrasubstituted alkene 6 in
88% yield. Similarly, Sonogashira−Hagihara coupling with an
arylalkyne gave the enyne 7 in 87% yield.
In summary, we have developed regio- and stereoselective
copper-catalyzed iodocyanation and dicyanation reactions of
alkynes with cyanogen iodide. The stepwise mechanism for the
formation of iodocyano- and dicyanoalkene has been revealed
from NMR observations and stoichiometric experiments.
C
DOI: 10.1021/acs.orglett.7b01378
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Organic Letters
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Obtained products could be useful as synthetic intermediates
and further elaborated with high stereospecificity.
ASSOCIATED CONTENT
* Supporting Information
■
́
(9) (a) Morris, J.; Kovacs, L.; Ohe, K. Cyanogen Bromide. In
S
Encyclopedia of Reagents for Organic Synthesis; VCH: New York, 2015.
(b) Murai, M.; Hatano, R.; Kitabata, S.; Ohe, K. Chem. Commun. 2011,
47, 2375. (c) Okamoto, K.; Watanabe, M.; Murai, M.; Hatano, R.;
Ohe, K. Chem. Commun. 2012, 48, 3127.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01378.
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examined, but only trace amounts of cyanation products were
obtained.
(15) The copper-catalyzed reaction of (4-methylphenyl)acetylene
(1p) with cyanogen iodide gave a mixture of iodocyanation product,
diiodide, dicyanide, and the corresponding ketone as hydration
product.
(16) CuI may be formed via initial ligand exchange of Cu(OAc)2 by
treatment of ICN forming CuI2 followed by the decomposition of
CuI2 forming CuI and 1/2 I2. The latter step is a well-known
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(18) Conversions from 4a into 2a and from 2a into 3a were also
observed under the copper-catalyzed conditions using ICN (see the
Supporting Information).
(19) For examples of copper-catalyzed cyanation of alkenyl iodides,
see: (a) Pradal, A.; Evano, G. Chem. Commun. 2014, 50, 11907.
(b) Nitelet, A.; Zahim, S.; Theunissen, C.; Pradal, A.; Evano, G. Org.
Synth. 2017, 93, 163.
Experimental procedures, additional experimental data,
and compounds characterization data (PDF)
X-ray crystallographic analysis of compound 2b (CIF)
X-ray crystallographic analysis of compound 2ma (CIF)
X-ray crystallographic analysis of compound 2mb (CIF)
X-ray crystallographic analysis of compound 3a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kokamoto@scl.kyoto-u.ac.jp.
*E-mail: ohe@scl.kyoto-u.ac.jp.
ORCID
Kazuhiro Okamoto: 0000-0001-8562-3167
Kouichi Ohe: 0000-0001-8893-8893
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially partly by JSPS KAKENHI
Grant Number 26410119. K. Okamoto also thanks the Kyoto
Technoscience Center, the Society of Iodine Science, and
Nippo Chemicals Co., Ltd. for financial support.
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