A novel anionic domino process for the synthesis of o-cyanoaryl-methylthio/ alkyl/aryl/heteroaryl acetylenes

Article abstract of DOI:10.1021/ol800029c

A novel unexpected anionic domino process involving n-BuLi-induced rearrangement of 3,3-bis(methylthio) or 3-methylthio-3-aryl heteroaryl. alkyl-o-bromoarylacrylonitriles to ocyanoarylacetylenes in synthetically useful yields has been reported. The scope and generality of the reaction has been examined, and a possible mechanism has been proposed.

Full text of DOI:10.1021/ol800029c

ORGANIC
LETTERS
2008
Vol. 10, No. 5
965-968
A Novel Anionic Domino Process for
the Synthesis of o-Cyanoaryl-Methylthio/
Alkyl/Aryl/Heteroaryl Acetylenes‡
Sarvesh Kumar, Saravanan Peruncheralathan, Hiriyakkanavar Ila,* and
Hiriyakkanavar Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur- 208016, India
hila@iitk.ac.in
Received January 6, 2008
ABSTRACT
A novel unexpected anionic domino process involving n-BuLi-induced rearrangement of 3,3-bis(methylthio) or 3-methylthio-3-aryl/heteroaryl/
alkyl-o-bromoarylacrylonitriles to o-cyanoarylacetylenes in synthetically useful yields has been reported. The scope and generality of the
reaction has been examined, and a possible mechanism has been proposed.
Functionalized alkyl and aryl acetylenes are important classes
of molecules1 that have found applications in diverse areas
ranging from biologically active natural products2 (such as
laurencin3 and neocarzinostatin chromophores4) to pharma-
ceuticals, molecular organic materials,1c,5 and nanomaterials.1d
Furthermore, their unsaturated high-energy structure makes
alkynes an attractive functional group for further derivati-
zation in many synthetic transformations6 and natural product
syntheses.7 Metal-catalyzed cross-coupling reactions,8 espe-
cially Sonogashira coupling,9,10 are the most versatile and
efficient methods for the synthesis of conjugated vinyl and
arylacetylenes. Alkyne preparations by combination of two
fragments involving formation of a triple bond via single or
double elimination11 in a one-pot integrated chemical pro-
cess12,13 are also of considerable interest in organic synthesis.
However, development of such transformations has received
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‡ Dedicated to Prof. George A. Olah on his 80th birthday.
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10.1021/ol800029c CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

little attention. In the course of our ongoing program toward
the development of new synthetic routes for biologically
important heterocycles via polarized ketene dithioacetals,14,15
we have uncovered a novel, unexpected anionic rearrange-
ment of 3,3-bis(methylthio)-2-(2-haloaryl)acrylonitriles yield-
ing o-cyanoarylacetylenes through a series of anionic domino
processes. Herein, we report our findings on this rearrange-
ment which constitutes a new method for the synthesis of
aryl, heteroaryl, and alkyl-o-cyanoarylacetylenes.
We planned to develop a general synthesis of substituted
isoquinolines 1C by the treatment of ketene dithioacetals 1A
with n-BuLi followed by intermolecular trapping of the
o-lithiated species with arylnitriles and subsequent 6-endo
cyclization of the resulting lithiated imino adducts 1B (eq
1). However, much to our surprise when 1a was reacted with
entry 6 vs 7). On the other hand, attempted rearrangement
of (2-bromo-4-fluorophenyl)cyano ketene dithioacetal 1f
under identical reaction conditions gave only complex
product mixture (Table 1, entry 8).
The probable mechanism for the formation of alkynes 3
from ketene dithioacetals 1 is depicted in Scheme 1. The
Scheme 1. Proposed Mechanism for the Formation of
Acetylenes 3 from Ketene Dithioacetals 1 and 2
n-BuLi (1.1 equiv, -78 °C) followed by the addition of
benzonitrile, the product isolated was not the desired
isoquinoline, but was characterized as (o-cyanoaryl)meth-
ylthioacetylene 3a (50%) on the basis of its spectral,
analytical, and X-ray diffraction data (Table 1, Figure 1
initially formed o-lithioaryl species 4 by lithium-halogen
exchange of 1 (or 2) undergoes intramolecular nucleophilic
attack on favorably located nitrile group of 1 (Figure 2, X-ray
data of 1a, see Supporting Information)16 furnishing lithiated
benzocyclobutanimine intermediate 5 which in turn frag-
ments to 2-cyanoaryllithium species 6. Subsequent elimina-
tion of methylthiolithium from 6 affords the (o-cyanoaryl)-
methylthioacetylenes 3 in synthetically useful yields (path
a, Scheme 1). Alternatively, the cleavage of the intermediate
lithiobenzocyclobutanimine 5 to alkyne 3 may proceed by a
concerted process with concomitant elimination of methyl-
thiolithium (path b, Scheme 1) which is facilitated by
favorable coordination of lithium ion with the lone pair of
sulfur as shown in 5.17
Table 1. Synthesis of o-Cyanoaryl Methylthioacetylenes 3
from Ketene Dithioacetals 1 and 2
Interestingly, in one of the reactions, when ketene dithio-
acetal 1a was exposed to 2.2 equiv of n-BuLi under similar
reaction conditions, the product isolated was found to be
dethiomethylated terminal (o-cyanoaryl)acetylene 7a (60%)
(Scheme 2). Similarly, the dethiomethylated acetylenes 7b
entry
1, 2
R1
OMe
OMe
-OCH2O-
OMe
H
H
H
R2
X
3
yield (%)a
1
2
3
4
5
6
7
8
1a
2a
1b
1c
1d
1e
2b
1f
OMe
OMe
Br
I
3a
3a
3b
3c
3d
3e
3e
-
68b
73
65
62
78
59
92
c
Br
Br
Br
Br
I
H
Me
H
H
F
Scheme 2. Synthesis and Mechanism of Formation of
Terminal and Substituted Arylacetylenes 7 and 9 from 1
H
Br
a Yield of pure isolated product. b n-BuLi (1.1 equiv)/THF/-78 °C/PhCN
then H2O, yield 50%. c Complex mixture was obtained.
Supporting Information). The acetylene 3a was obtained in
improved yield (68%) when 1a was treated with n-BuLi (1.1
equiv, -78 °C) in the absence of benzonitrile (Table 1). The
generality of this transformation was demonstrated by
subjecting other substituted (o-bromoaryl)cyano ketene dithio-
acetals 1b-e to this rearrangement under identical conditions
furnishing the respective o-cyanoaryl acetylenes 3b-e in
59-78% yields (Table 1, entries 3-6). When similar
reactions were performed with the corresponding o-iodo
derivatives 2a and 2b, the o-cyanoarylacetylenes 3a and 3e
were obtained in higher yields (Table 1, entry 1 vs 2 and
a
t-BuLi (2.2 equiv) was used.
966
Org. Lett., Vol. 10, No. 5, 2008

To further explore the scope and generality of this novel
acetylene synthesis, we next investigated the analogous
rearrangement of the corresponding 3-(methylthio)-3-(aryl/
heteroaryl/alkyl)-2-(2-bromoaryl) acrylonitriles 13 prepared
by the base-induced condensation of nitriles 10 with appro-
priate aryl/heteroaryl/alkyl dithioesters 11 followed by in situ
S-methylation of the resulting enethiolate salts 12 with methyl
iodide (Scheme 3, Table 2). Rearrangement of 13 with 1.1
equiv of n-BuLi under previously described reaction condi-
tions was found to be very facile, yielding various disubsti-
tuted acetylenes in good yields (Scheme 3). These results
are depicted in Table 2. As shown, a number of (o-cyano-
aryl)acetylenes substituted at the other terminal with aryl
(14a-c, entries 1-3), 3-pyridyl (14d, entry 4), and five-
membered heteroaryl groups (14e-m, entries 5-13) could
be obtained in reasonably good yields following the simple
procedure. The methodology could also be extended suc-
cessfully for the synthesis of alkylarylacetylenes (14n-p,
entries 14-16) in good yields from the appropriate 3-meth-
ylthio-3-alkylacrylonitrile precursors 13n-p.
Scheme 3. Synthesis of ï-Cyanoaryl Acetylenes 14a-p from
Adducts 13a-p
and 7c were obtained in good yields from the respective
ketene dithioacetals 1c and 1g upon treatment with 2.2
equiv of n-BuLi (Scheme 2). Formation of 7a-c in the
presence of excess n-BuLi can be rationalized by the cleav-
age of the C-S bond by nucleophilic attack of n-BuLi on
the sulfur atom of acetylene 3 to give lithiated acetylene 8
which on quenching with water yields 7 (Scheme 2).11,18 In
separate experiments, attempts were made to trap the
o-cyanoarylacetylene anion 8a with reactive electrophiles
(MeI, Me3SiCl, PhCHO), yielding the substituted acetylenes
9a-c in moderate yields (Scheme 2).
Interestingly, when the cyclic ketene dithioacetals 1h and
1i from the o-bromoarylacetonitriles were subjected to
rearrangement in the presence of n-BuLi, workup and analy-
sis of the reaction mixture revealed formation of exclusive
products which were characterized as 2-(n-butylthio)-3-
Table 2. Synthesis of (o-Cyanoaryl)aryl/heteroaryl/alkylacetylenes 14a-p from Adducts 13a-p
a Yield of pure isolated product
Org. Lett., Vol. 10, No. 5, 2008
967

cyanobenzothiophenes 15a and 15b, respectively. The prob-
able mechanism for the formation of benzothiophenes 15a
and 15b is shown in the Scheme 4. The o-lithioaryl anion
cleavage of the 1,3-dithiolan ring along with the elimina-
tion of ethylene to furnish 3-cyanobenzothiophene-2-thiolate
salt 17 which upon alkylation with in situ generated
n-BuBr yields the corresponding 15a and 15b in high yields
(Scheme 4).
In summary, we have reported a novel anionic domino
rearrangement of 3,3-(bis-methylthio) or 3-(methylthio)-3-
aryl/heteroaryl/alkyl-2-(o-bromoaryl) acrylonitriles leading
to o-cyanoarylacetylenes in synthetically useful yields. The
proposed mechanism for this rearrangement sequence in-
volves a series of cascade processes consisting of lithium-
halogen exchange, intramolecular nitrile group transfer
through fragmentation of the lithiobenzocyclobutanimine
intermediate, and elimination of thiomethyllithium to give
(o-cyanoaryl)acetylenes. Studies addressing the scope of this
novel rearrangement and attempts to exploit this reactivity
mode for the synthesis of other ortho-functionalized acety-
lenes are currently underway.
Scheme 4. Mechanism for the Formation of Benzothiophenes
15a,b from Cyclic Ketene Dithioacetals 1h,i
Acknowledgment. S.K. and S.P. thank CSIR, New Delhi,
for SRF and RA, respectively.
16 appears to undergo nucleophilic attack on suitably located
sulfur atom of the cyclic ketene dithioacetal with concomitant
Supporting Information Available: Experimental details
and spectroscopic/analytical data for all new compounds;
ORTEP diagrams of 1a and 3a. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(16) X-Ray diffraction data of 1a revealed the conformation in which
o-bromo and cyano groups are in close proximity.
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968
Org. Lett., Vol. 10, No. 5, 2008