Silver-mediated palladium-catalyzed direct C-H arylation of 3-bromoisothiazole-4-carbonitrile

Article abstract of DOI:10.1021/ol200196m

Silver(I) fluoride-mediated Pd-catalyzed C-H direct arylation/ heteroarylation of 3-bromoisothiazole-4-carbonitrile (1a) gives twenty-four 5-aryl/heteroaryl-3-bromoisothiazole-4-carbonitriles. The reaction was partially optimized with respect to catalyst, ligand, and base. During this study 3,3′-dibromo-5,5′-biisothiazole-4,4′-dicarbonitrile (3a) was isolated as a byproduct and subsequently prepared via the silver-mediated Pd-catalyzed oxidative dimerization of 3-bromoisothiazole-4-carbonitrile in 67% yield. The analogous phenylation and oxidative dimerization of 3-chloroisothiazole-4-carbonitrile (1b) gave 3-chloro-5-phenylisothiazole-4- carbonitrile (4) and 3,3′-dichloro-5,5′-biisothiazole-4,4′- dicarbonitrile (3b) in 96% and 69% yields, respectively.

Full text of DOI:10.1021/ol200196m

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1510–1513
Silver-Mediated Palladium-Catalyzed
Direct C-H Arylation of
3-Bromoisothiazole-4-carbonitrile
Heraklidia A. Ioannidou and Panayiotis A. Koutentis*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
koutenti@ucy.ac.cy
Received January 21, 2011
ABSTRACT
Silver(I) fluoride-mediated Pd-catalyzed C-H direct arylation/heteroarylation of 3-bromoisothiazole-4-carbonitrile (1a) gives twenty-four 5-aryl/
heteroaryl-3-bromoisothiazole-4-carbonitriles. The reaction was partially optimized with respect to catalyst, ligand, and base. During this study
3,30-dibromo-5,50-biisothiazole-4,40-dicarbonitrile (3a) was isolated as a byproduct and subsequently prepared via the silver-mediated
Pd-catalyzed oxidative dimerization of 3-bromoisothiazole-4-carbonitrile in 67% yield. The analogous phenylation and oxidative dimerization
of 3-chloroisothiazole-4-carbonitrile (1b) gave 3-chloro-5-phenylisothiazole-4-carbonitrile (4) and 3,30-dichloro-5,50-biisothiazole-4,40-dicarbonitrile (3b) in
96% and 69% yields, respectively.
Isothiazoles display wide-ranging biological activity:
Some are potential anticancer agents that inhibit MEK-1
and MEK-2 kinases,1 while others are prodrugs for the
treatment of hyperproliferative disorders,2 and as active
site inhibitors for the hepatitis C virus NS5B poly-
merase.3 Commercial isothiazoles include the Kathon
preservatives, the artificial sweetener saccharin, and
the antibacterial sulfa drug, sulfasomizole. The chem-
istry of isothiazoles has been reviewed.4 Most strate-
gies for preparing isothiazoles involve construction of
the isothiazole ring with the desired carbon substi-
tuents in place, as such the routes are often product
specific.5
By combining modern transition metal-catalyzed C-C
bond forming reactions with readily available halo-sub-
stituted isothiazole scaffolds, useful nonproduct specific
routes to alkyl-,6 alkenyl-,7 alkynyl-,7a,b,8 aryl-,6,7b,9 and
heteroaryl-substituted6b,7b,9 isothiazoles can be realized.
These reactions, however, require access to organometallic
reagents that are often expensive or need to be prepared.
Furthermore, a shelf stable isothiazole-5-boronate ester
suffered facile protodeboronation under typical Suzuki
reaction conditions.9a
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Chapter 4.05, p 545.
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€
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r
10.1021/ol200196m
Published on Web 02/11/2011
2011 American Chemical Society

Pd-catalyzed direct C-H arylation overcomes the need
for expensive organometallic reagents.10 The reaction has
been demonstrated on a wide range of heterarenes by using
cheap aryl halides.11 While many publications appear in the
literature about direct C-H arylation of thiazoles,10,12 to the
best of our knowledge, there have been no reported examples
of Pd-catalyzed direct arylation of isothiazoles.
inorganic bases such as KF, CsF, K2CO3, Cs2CO3,
and Na2CO3 and organic bases such as pyridine and i-Pr2-
NEt failed to work. In light of this, we investigated the use
ofsilver(I) salts, which are effectiveadditivesinbothoxida-
tive18 and nonoxidative arylations.12d,19
The addition of AgNO3 assisted the Pd-catalyzed
arylation of allyltrimethylsilanes,20 vinylsilanes,21 while
Ag2O promoted the Pd-catalyzed cross-coupling reactions
of silanols, silanediols, and silanetriols22 as well the reac-
tion between aryl and alkenyl halides with terminal
alkynes.23 Silver(I) fluoride (AgF) served as both an acti-
vator of the electrophilic substitution reaction and as
the oxidant of Pd(0),24 and in combination with Cu(II)
salts aided the arylation of acetanilides.19e Furthermore,
AgF was used as base for the arylation of thiophenes and
thiazoles.12b,25
During ongoing studies on the versatile 3,5-dibromo-
and3,5-dichloroisothiazole-4-carbonitriles,13 wedeveloped
chromatography free gram scale conditions for the regios-
pecific C5 hydrodehalogenations that gave 3-bromo- and
3-chloroisothiazole-4-carbonitriles 1a and 1b, respectively.
Combining the 3-haloisothiazole-4-carbonitriles with Pd-
catalyzed C-H direct arylations can be a new route to
5-arylisothiazole-4-carbonitriles that are important due to
their cytotoxicity14 and antiviral activity.14,15 To date these
compounds have been prepared by either treating arylyli-
denemalononitriles with S2Cl26b,14,16 or by arylating halo-
isothiazolesusing Suzuki, Stille, or Negishi reactions.6b,7b,17
However, the former has limitations due to harsh reaction
conditions that often lead to chlorination of electron-rich
aryls and the latter requires often expensive reagents. Below
we demonstrate for the first time the efficient silver-mediated
Pd-catalyzed direct C5 arylation of 3-bromoisothiazole-4-
carbonitrile (1a) using readily available iodoarenes.
In light of the above, we treated 3-bromoisothiazole-
4-carbonitrile (1a) with PhI (1.2 equiv), AgF (2 equiv),
Pd(dppf)Cl2 DCM (20 mol %), and Ph3P as ligand
3
(10 mol %) in MeCN at ca. 82 °C for 2 h and obtained
the 5-phenylisothiazole (2a) in 73% yield. Substituting PhI
for PhBr or PhCl gave only traces of product after 2 h. The
conditions were subsequently optimized with respect to
catalyst, ligand, and base/oxidant (Table 1). Of the cata-
lysts screened, Pd(Ph3P)2Cl2 gave the highest yield (88%)
in the shortest time (20 min) and was chosen for further
optimization. In contrast Pd2(dba)3 gave a complex reac-
tion mixture, while Pd(OAc)2 and (MeCN)2PdCl2 gave the
desired product in only moderate yields and required
longer reaction times.
Initially, 3-bromoisothiazole-4-carbonitrile (1a) was
treated with either chloro-, bromo-, or iodobenzene (PhI) in
the presence of a Pd catalyst Pd(dppf)Cl2 DCM (20 mol %)
3
and base in MeCN at ca. 82 °C. Surprisingly, the use of
On holding constant the catalyst, Pd(Ph3P)2Cl2 (20
mol %), both the reaction time and product yield were
affected by varying the equivalents of PhI; the highest
yields (88and 84%) were achieved with 1.2 and 1.5 equiv of
PhI over a 20 and 10 min period, respectively. In the
absence of additional ligand, the product can still be
formed in good yield by increasing the PhI equivalents.
Switching the ligand to dppf (10 mol %) led to a longer
reaction (7 h) and a 67% product yield, while the use of
JohnPhos (10 mol %) gave only traces of product after 4 h.
The catalyst loading was then investigated to find the
minimum needed for the reaction to succeed. Reducing
thecatalystloadingto10mol % with1.2 equivofPhIled to
longer reaction times (7 h) and moderate product yields
(60%) and gavetraces of 3,30-dibromo-5,50-biisothiazole-
4,40-dicarbonitrile (3a) presumably owing to a competing
oxidative C5 dimerization. The formation of the latter can
be suppressed by increasing the PhI to 1.5 or 2 equiv, which
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(c) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40,
35. (d) Roger, J.; Doucet, H. Org. Biomol. Chem. 2008, 6, 169. (e)
Gottumukkala, A. L.; Derridj, F.; Djebbar, S.; Doucet, H. Tetrahedron
Lett. 2008, 49, 2926. (f) Ackermann, L.; Vincente, R.; Born, R. Adv.
Synth. Catal. 2008, 350, 741. (g) Gottumukkala, A. L.; Doucet, H. Adv.
Synth. Catal. 2008, 350, 2183.
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Takamura, K.; Kinoshita, M.; Ikeda, T. Org. Lett. 2004, 6, 2011. (c)
Kobayashi, K.; Ahmed, M. S. M.; Mori, A. Tetrahedron 2006, 62, 9548.
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B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (g) Voutchkova,
A.; Coplin, A.; Leadbeater, N. E.; Crabtree, R. H. Chem. Commun.
2008, 6312. (h) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem., Int. Ed.
2009, 48, 3644.
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Org. Lett., Vol. 13, No. 6, 2011
1511

The formation of a dimer 3a intheabsenceof ArIimplied
that direct palladation of isothiazole 1a by a palladium(II)
species was possible and as such the silver salt served as an
oxidant to support a Pd(II)/Pd(IV) catalytic cycle. This
hypothesis also agreed with the observation that Br re-
mained intact during the catalysis.
Table 1. Reaction of 3-Bromoisothiazole-4-carbonitrile (1a)
(0.25 mmol) with PhI, Pd(Ph3P)2Cl2, AgF, and Ph3P in MeCN
at ca. 82 °C
Control reactions revealed that the presence of both the
Pd catalyst and the AgF was needed for the reaction to
work, while the use of Ph3P was not. Attempts to decrease
the catalyst loading to 5 mol % led to longer reaction time
(12 h) and a drop in yield (51%).
AgF
Pd(Ph3P)2Cl2
(mol %)
Ph3P
Phl
time
(h)
yield of
With these partially optimized arylation conditions,
the need for AgF was further investigated. In our hands,
the use of other silver(I) reagents such as AgBr, AgNO3,
Ag2O, Ag2SO4, AgBF4, AgSbF6, AgOTf, and AgOAc
proved to be ineffective in the arylation reaction of
3-bromoisothiazole-4-carbonitrile (1a) with PhI. Never-
theless, Ag2CO3 was effective with 20 mol % of catalyst
giving the desired 3-bromo-5-phenylisothiazole-4-
carbonitrile (2a) in good yields (68-73%) together with
some amount of dimer (3a). However, attempts to
decrease the catalyst loading to 10 or 5 mol % by using
2 or 3 equiv of Ag2CO3 led to only traces of phenylated
product. As such, further optimizations were restricted
to the use of AgF.
Screening the AgF equivalents needed for the reaction
revealed that 1 equiv was insufficient to drive the reac-
tion to completion within 24 h, while the use of 3 equiv
led to fast reaction times (10 min), a reduced yield of the
desired 3-bromo-5-phenylisothiazole-4-carbonitrile (2a)
(63%), and an increased yield of dimer (3a) (14%).
Fortunately, the formation of the dimer could be sup-
pressed by increasing the amount of PhI. As such, when
PhI (2 equiv) and AgF (3 equiv) were used the reaction
finished in 5 min affording the desired product in 78%
yield with no dimer byproduct. This last result was
promising and under these conditions the Pd catalyst
loading was reduced from 10 to 5 mol %. Successfully,
the desired product was isolated in high yield (85%) in
very short reaction time (8 min). Reducing the catalyst
loading to 1 mol % gave low yields of the desired
product, while decreasing the PhI to 1.5 equiv with 10
and 5 mol % catalyst loading led to fast reactions and
very high yields of the desired product but traces of the
dimer were also present.
(equiv)
(mol %)
(equiv)
2a (%)
a
1
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
20
20
20
20
20
20
20
10
10
10
5
10
10
10
10
0
1.2
1.2
1
24
-
0.33
2.50
0.17
1
88
60
1.5
1.2
1.5
2
84
73
0
0.50
0.17
7
86
0
86
10
10
10
10
10
10
10
10
10
10
10
10
1.2
1.5
2
62b
80
5
3
73
1.2
1.5
1.2
2
12
72b
60c
63d
78
5
11
20
20
10
5
0.17
0.08
0.10
0.13
0.50
0.12
0.17
2
83
2
85
1
2
17
10
5
1.5
1.5
91b
93b
a Incomplete reaction. b Traces of dimer 3a (TLC). c Dimer 3a (15%)
was also isolated. d Dimer 3a (14%) was also isolated.
led to shorter reaction times (5 and 3 h, respectively) and
the 5-phenylisothiazole (2a) in 80% and 73% yields,
respectively. Further attempts to reduce the catalyst load-
ing to 5 mol % again led to increased reaction times, lower
product yields, and dimer formation.
3,30-Dibromo-5,50-biisothiazole-4,40-dicarbonitrile (3a)
was isolated as colorless plates, mp 286°C (PhCl). Elemental
analysis and mass spectrometry supported a molecular
formula of C8Br2N4S2. Infrared spectroscopy supported
the presence of nitrile functionality ν(CtN) 2230 cm-1
and 13C NMR spectroscopy gave only 4 carbon resonances
indicating a symmetrical molecule. Treating 3-bromoisothia-
zole-4-carbonitrile (1a) with AgF (2 equiv) and Pd(Ph3P)Cl2
(20 mol %) in the absence of PhI gave the 5,50-biisothiazole
(3a) in 67% yield (Scheme 1).
The best conditions were applied to a variety of iodoar-
enes providing a range of 5-aryl- and 5-heteroarylisothia-
zole-4-carbonitriles (Table 2).
The reactions worked well with aryl derivatives bearing
both electron-releasing (e.g., entries 2-6) and electron-
withdrawing (e.g., entries 7-9) groups. Furthermore,
the existence of a second halide (Cl or Br) on the iodoarenes
did not affect the reaction and showed that the reaction
was haloselective (entries 19-23). In most cases iodoheter-
oarenes worked equally well (entries 11-13 and 17-22),
but in some cases dimer was formed (entries 14-16).
Comparatively poor yields were obtained for 4-amino-
3-nitroiodobenzene (entries 10) and the 7-iodoindoles
(entries 16 and 23) and presumably these reactions would
Scheme 1. Oxidative Dimerization
1512
Org. Lett., Vol. 13, No. 6, 2011

Table 2. Reaction of the 3-Bromoisothiazole 1a (0.25 mmol)
with ArI (2 equiv), Pd(Ph3P)2Cl2 (5 mol %), AgF (3 equiv), and
Ph3P (10 mol %) in MeCN at ca. 82 °C
Scheme 2. Arylation and Dimerization of 3-Chloroisothiazole-
4-carbonitrile (1b)
yield of
yield of
entry
Ar
time (h)
2b-x (%)
3a (%)
1
2
4-Tol
3.50
7
2b (82)
2c (89)
2d (91)
2e (81)
2f (73)
2g (79)
2h (89)
2i (83)
2j (98)
2k (41)a
2l (74)
2m (92)
2n (95)
2o (72)
2p (66)
2q (52)
2r (93)
2s (92)
2t (97)
2u (78)
2v (87)
2w (94)
2x (34)b
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2,4-(MeO)2C6H3
4-HOC6H4
3
3
4
2.50
4
5
6
4
7
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
4-H2N-3-O2NC6H3
Pyrid-2-yl
0.67
0.67
0.50
0.17
20
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pyrid-3-yl
5
analogue [Pd(Ph3P)2Cl2 (20 mol %), AgF (2 equiv)] onto
3-chloroisothiazole-4-carbonitrile (1b), the 3,30-dichloro-
5,50-biisothiazole-4,40-dicarbonitrile (3b) was isolated in
69% yield after 2 h (Scheme 2).
Pyrid-4-yl
20
Pyrazinyl
2
16
20
28
Indol-5-yl
3
Indol-7-yl
2
In conclusion, 3-bromoisothiazole-4-carbonitrile (1a)
readily undergoes Pd-catalyzed direct CH arylation at
C5 with a range of iodoarenes in the presence of AgF to
give twenty-four 5-aryl- and heteroarylisothiazole-4-
carbonitriles in good yields. Furthermore, treating 3-bro-
moisothiazole-4-carbonitrile (1a) with AgF and Pd cata-
lyst led to oxidative dimerization affording 3,30-dibromo-
5,50-biisothiazole-4,40-dicarbonitrile (3a). Similarly, phe-
nylation at C5 and oxidative C5 dimerization were
demonstrated for 3-chloroisothiazole-4-carbonitrile (1b)
affording the chloro-phenylated and dimerized analog-
ues 4 and 3b in 96% and 69% yields, respectively. The
method is simple and effective, uses cheap commercially
available iodoarenes, and is suitable for obtaining other-
wise difficult to access 5-aryl-/ heteroarylisothiazole-4-
carbonitriles.
Thien-2-yl
0.33
0.67
1.50
6
Thien-3-yl
3-BrC6H4
2-Cl-Pyrid-4-yl
2-Br-Pyrid-4-yl
7-Cl-Quinolin-4-yl
5-Br-Indol-7-yl
4
1.50
20
a Reaction finished immediately but 24% of ArI was recovered.
b Yield based on 43% recovered starting isothiazole 1a.
require additional optimization to maximize the product
yields.
The best conditions for the direct arylation of 3-bromo-
isothiazole-4-carbonitrile (1a) were also used with the
3-chloroisothiazole (1b). The chemistry was subtly differ-
ent. Treating 3-chloroisothiazole-4-carbonitrile (1b) with
PhI (2 equiv) in the presence of AgF (3 equiv), Ph3P (10
mol %), and Pd(Ph3P)2Cl2 (5 mol %) in MeCNat ca. 82 °C
gave after 15 min 3-chloro-5-phenylisothiazole-4-carboni-
trile (4) in moderate yield (58%) and traces of 3,30-
dichloro-5,50-biisothiazole-4,40-dicarbonitrile (3b). In light
of the above study we rationalized that decreasing the AgF
to 2 equiv could help avoid the competing oxidative
dimerization and indeed obtained in 25 min the desired
product(4) inexcellentyield (96%) withnotracesof dimer.
The influence of the 3-halogen was surprising since it
was not near the reaction site, but presumably chlorine
being more electronegative than bromine would make the
C5 hydrogen marginally more acidic and this may play a
role. This is now under further study. Finally, by applying
the conditions used for the dimerization of the bromo
Acknowledgment. The authors wish to thank the
Cyprus Research Promotion Foundation [grant no.
ΠENEK/ENIΣX/0308/83], the State General Laboratory,
the Agricultural Research Institute, and the Ministry of
Agriculture. Furthermore, we thank the A. G. Leventis
Foundation for helping to establish the NMR facility at
the University of Cyprus. The authors are indebted to the
referees for pointing out the possible presence of a Pd(II)/
Pd(IV) catalytic cycle.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new com-pounds
are available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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