Gallium (iii)-catalysed bromocyanation of alkynes: Regio- and stereoselective synthesis of β-bromo-α,β-unsaturated nitriles

Article abstract of DOI:10.1039/c0cc04385k

Treatment of arylacetylenes and cyanogen bromide in ClCH₂CH ₂Cl with a catalytic amount of GaCl₃ afforded (Z)-β-bromoacrylonitriles with high regio- and stereoselectivity.

Full text of DOI:10.1039/c0cc04385k

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COMMUNICATION
Gallium (III)-catalysed bromocyanation of alkynes: regio- and
stereoselective synthesis of b-bromo-a,b-unsaturated nitrilesw
Masahito Murai, Ryo Hatano, Sachie Kitabata and Kouichi Ohe*
Received 13th October 2010, Accepted 26th November 2010
DOI: 10.1039/c0cc04385k
Treatment of arylacetylenes and cyanogen bromide in
ClCH2CH2Cl with a catalytic amount of GaCl3 afforded
(Z)-b-bromoacrylonitriles with high regio- and stereoselectivity.
Next, Lewis acids were screened for bromocyanation of
alkynes, because there is a precedent for the haloacylation of
alkynes in analogous reactions.13 Representative results of the
reaction of cyanogen bromide with phenylacetylene are
shown in Table 1. We found that phenylacetylene underwent
bromocyanation in the presence of AlCl3 (10 mol%) in
1,2-dichloroethane at 80 1C to give b-bromocinnamonitrile
The catalytic addition reactions of X–Y-type substrates to
carbon–carbon multiple bonds are of continued interest due to
the facile access to 1,2-difunctional units from simple alkenes
or alkynes with ideal atom efficiency.1 Among these trans-
formations, addition reactions of X–CN to alkynes simulta-
neously form vinyl–X and vinyl–carbon bonds, both of which
can be used to construct complex structures. Several notable
examples of palladium- or nickel-catalysed regio- and stereo-
selective addition reactions to alkynes with several X–CN
groups have been reported, such as X = H (hydrocyanation),2
X = C (carbocyanation),3 X = Si (cyanosilylation),4 X = Ge
(cyanogermylation),5 X = Sn (cyanostannylation),6 X = B
(cyanoboration),7 X = S (cyanothiolation).8 However, much
less attention has been paid to catalytic regio- and stereo-
selective halocyanation of alkynes9 or alkenes10 using
cyanogen halides. Herein, we report on gallium-catalysed
bromocyanation of alkynes with cyanogen bromide, providing
an efficient route to (Z)-b-bromoacrylonitriles in a high
regio- and stereoselective fashion (Scheme 1). Taking
advantage of (Z)-b-bromoacrylonitriles, we can establish
efficient routes to a wide range of a,b-unsaturated nitriles,11
which are of synthetic value.
1a in 42% yield as
a mixture of Z- and E-isomers
(Z : E = 89 : 11) (Table 1, entry 1). Interestingly, the use of
GaCl3 (10 mol%) instead of AlCl3 led to 1a in a high yield and
stereoselectivity (81% chemical yield, Z : E
= 92 : 8)
(entry 2).14 This is in sharp contrast with the non-catalysed
bromocyanation of ynamines, which gave a low stereo-
selectivity of the adducts (Z : E = 50 : 50 B60 : 40).9a The
reaction using GaCl3 at 70 1C led to a lower yield of 1a, but
with similar stereoselectivity (entry 3). 1,2-Dichloroethane was
the most suitable solvent for bromocyanation, while
other solvents, e.g., CHCl3, toluene, heptane, and 2-methyl-
tetrahydrofuran gave a lower yield of the adducts (entries 4–6),
or no adducts (entry 7).15 Using GaBr3 as a catalyst afforded
Table 1 Lewis acid-catalysed bromocyanation of phenylacetylene
using BrCNa
When we examined the reaction of cyanogen bromide12
and phenylacetylene using palladium or nickel/phosphine
complexes, which are effective catalysts in addition reactions
of X–CN to acetylenes (vide supra), no adducts were generated.
Entry
Catalyst
Solvent
Yieldb (%)
Z : Ec
1
AlCl3
GaCl3
GaCl3
GaCl3
GaCl3
GaCl3
GaCl3
GaBr3
InCl3
InBr3
FeBr3
CuBr2
ZnBr2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CHCl3
Toluene
Heptane
2-MeTHF
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
42
81 (72)
41
62
61
25
0
75
15
32
0
89 : 11
92 : 8
91 : 9
90 : 10
90 : 10
91 : 9
—
96 : 4
93 : 7
95 : 5
—
2
3d
4
5
6
7
8
Scheme 1 Catalytic addition reactions of X–CN to alkynes.
9
10
11
12
13
Department of Energy Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto 615-8510, Japan.
E-mail: ohe@scl. kyoto-u.ac.jp; Fax: +81 75-383-2499;
Tel: +81 75-383-2495
w Electronic supplementary information (ESI) available: Experimental
details and analytical data are provided. CCDC 796829. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc04385k
0
0
—
—
a
Reaction conditions: phenylacetylene (0.48 mmol) and BrCN
(0.40 mmol) in solvent (1.6 mL) were heated in the presence of catalyst
b
(10 mol%). NMR yield (anisole as an internal standard). Isolated
c
d
yield in parentheses. Determined by NMR. At 70 1C.
c
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Table 2 GaCl3-catalysed bromocyanation of alkynes using BrCNa
Entry R1
R2
Product Isolated yield (%) Z : Eb
1
2
3
4
5
6
7
8
4-CH3C6H4
H
H
H
H
H
H
H
1b
1c
1d
1e
1f
70
61
55
71
68
68
20
70
72
56
95 : 5
98 : 2
95 : 5
91 : 9
90 : 10
91 : 9
92 : 8
95 : 5
91 : 9
99 : 1
2-CH3C6H4
2-Naph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
Ph
Scheme 2 Transformation of 1a. (a) (4-CH3C6H4)SnBu3, Pd(PPh3)4,
CuI, dioxane, 100 1C, 8 h. (b) BzSnBu3, Pd(OAc)2, PPh3, dioxane,
100 1C, 12 h. (c) Phenylacetylene, Pd(PPh3)4, CuI, Et3N, THF, rt, 5 h.
(d) NiBr2(PPh3)2, PPh3, Zn, dioxane, 80 1C, 6 h. (e) Ethyl thioglycolate,
NaOEt, EtOH, 70 1C, 12 h. (f) 1,3-Dimethoxybenzene, Cu(OTf)2,
ClCH2CH2Cl, H2O, 80 1C, 15 h. Ar = 2,4-(MeO)2C6H3.
1g
1h
CH3 1i
n-Bu 1j
Ph
9
Ph
Ph
10c
1k
a
Reaction conditions: alkynes (0.48 mmol) and BrCN (0.40 mmol) in
ClCH2CH2Cl (1.6 mL) were heated in the presence of GaCl3
b
(10 mol%). Determined by NMR. Reaction carried out in toluene
c
observed, with the signal of the CN moiety being observed at d
149.5 ppm. This result clearly shows that electrophilic addition of
the BrCN and GaCl3 complexes to alkynes21 occurs, even at
room temperature, and a high temperature is required in the
catalytic reaction conditions to release GaCl3 from the cyano
moiety of the adduct.
at 100 1C.
almost the same result as GaCl3 (entry 8). Other Lewis acid
catalysts, such as InCl3 and InBr3, showed marginal catalytic
activity and gave lower yields of 1a (entries 9 and 10), while
FeBr3, CuBr2, and ZnBr2 exhibited no catalytic activity for
bromocyanation (entries 11–13). It should be noted that
no chlorocyanation adducts were obtained even when
Lewis acid catalysts bearing chloride ligands were used
(entries 1–7 and 9).
The synthetic utility of (Z)-b-bromo-a,b-unsaturated
nitriles obtained from the bromocyanation of alkynes
was demonstrated by the cross-coupling reactions of the
representative product 1a (Scheme 2). The Stille coupling
reactions of 1a with organostannanes afforded the stereo-
defined structures 2 or 3 in good yields. The Sonogashira
coupling reaction of 1a with phenylacetylene gave enyne 4
quantitatively, with complete stereoselectivity. The nickel-
catalysed reductive homo-coupling of 1a produced 3,4-
diphenyl-2,4-hexadiene-1,6-dinitrile 5.22 Moreover, we
demonstrated the synthetic utility of 1a and its derivative 3
in the preparation of the biologically active heterocycles 623
and 7.11
With the optimized reaction conditions established
(10 mol% GaCl3 in 1,2-dichloroethane at 80 1C), we then
examined the substrate scope of alkynes (Table 2).
Arylacetylenes having a range of aromatic rings underwent
bromocyanation of the alkyne moieties to give the corresponding
(Z)-adducts, 1b–h16 in good yields with high regio- and
stereoselectivity (entries 1–7), while 1-octyne and 1-(trimethyl-
silyl)acetylene gave no adducts. Reactions with internal
aliphatic or alicyclic alkynes, such as 4-octyne and cyclooctyne,
gave complex mixtures, while internal alkynes substituted by a
phenyl ring produced bromocyanation adducts 1i17 and 1j,
having a cyano group at the b position to the phenyl group in
good yields with high regio- and stereoselectivities (entries 8
and 9). Although the reaction of diphenylacetylene was
sluggish, and required an elevated temperature (100 1C), the
corresponding bromocyanation adduct 1k was obtained in a
56% yield with excellent stereoselectivity (entry 10).
In summary, we developed gallium(III)-catalysed bromo-
cyanation of alkynes using cyanogen bromide. This method
enables the regio- and stereoselective introduction of the
synthetically useful Br and cyano functionalities to carbon–
carbon triple bonds in single operation. Further investigations
into the reaction mechanism, substrate scope, and the
synthetic application are currently underway in our laboratory.
This work is financially supported by a Grant-in-Aid for
Scientific Research from MEXT. M. M. thanks the JSPS
Research Fellowships for Young Scientists.
The alkynophilicity18 of trivalent GaX3 leading to the
formation of cationic vinylgallium species is well known, and
some notable synthetic applications have been demonstrated.19
To gain insight into the present bromocyanation of alkynes, we
carried out an NMR study on a stoichiometric reaction. When
GaCl3 was added to a solution of BrCN in CDCl3 at room
temperature, the signal of CN (d 76.1 ppm) in BrCN shifted to a
new peak at d 88.2 ppm. The downfield shift of the CN peak
suggested the possibility of the formation of a complex between
BrCN and GaCl3.20 When an equimolar amount of 1-phenyl-1-
hexyne was added to a CDCl3 solution of this complex at room
temperature, the quantitative formation of the bromocyanation
product 1j (Z : E = 98 : 2) coordinated with GaCl3 was
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2376 Chem. Commun., 2011, 47, 2375–2377
This journal is The Royal Society of Chemistry 2011

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supplementary crystallographic data for this paper.
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9 For
uncatalysed
bromocyanation
of
ynamines,
see:
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provides
investigation.
22 For application of
a
Z-adduct. Precise mechanism awaits further
5
to electrophotographic photoreceptor,
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2375–2377 2377