Stereoselective cross-coupling of baylis-hillman acetates with diphenyl disulfides and diselenides using palladium acetate

Article abstract of DOI:10.1080/00397910903219468

An efficient method is described for the stereoselective synthesis of diorganyl chalcogenides from a variety of Baylis-Hillman acetates and diaryl chalcogens using palladium catalyst. This reaction is a convenient new method to produce unsymmetrical sulfides and selenides in good yields. Copyright Taylor & Francis Group, LLC.

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Stereoselective Cross-Coupling of
Baylis–Hillman Acetates with Diphenyl
Disulfides and Diselenides Using
Palladium Acetate
P. Surendra Reddy a , M. Amarnath Reddy a , B. Sreedhar a & M. V.
Basaveswara Rao b
a Inorganic and Physical Chemistry Division , Indian Institute of
Chemical Technology , Hyderabad, India
b Department of Pharmaceutical Chemistry , Krishna University ,
Machlipatnam, India
Published online: 17 Jun 2010.
To cite this article: P. Surendra Reddy , M. Amarnath Reddy , B. Sreedhar & M. V. Basaveswara
Rao (2010) Stereoselective Cross-Coupling of Baylis–Hillman Acetates with Diphenyl Disulfides and
Diselenides Using Palladium Acetate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:14, 2075-2082, DOI: 10.1080/00397910903219468
To link to this article: http://dx.doi.org/10.1080/00397910903219468
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Synthetic Communications1, 40: 2075–2082, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219468
STEREOSELECTIVE CROSS-COUPLING OF BAYLIS–
HILLMAN ACETATES WITH DIPHENYL DISULFIDES
AND DISELENIDES USING PALLADIUM ACETATE
P. Surendra Reddy,1 M. Amarnath Reddy,1 B. Sreedhar,1 and
M. V. Basaveswara Rao2
1Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
2Department of Pharmaceutical Chemistry, Krishna University,
Machlipatnam, India
An efficient method is described for the stereoselective synthesis of diorganyl chalcogenides
from a variety of Baylis–Hillman acetates and diaryl chalcogens using palladium catalyst.
This reaction is a convenient new method to produce unsymmetrical sulfides and selenides in
good yields.
Keywords: Baylis–Hillman acetates; diaryl chalcogens; stereoselective cross-coupling; thioethers
INTRODUCTION
Thioethers are versatile building blocks for the synthesis of various organosul-
fur compounds, and they also play an important role in biological and chemical
processeses.[1] The thioether linkage has been used to prepare cyclic analogs of
acyclic polypeptides to restrict their conformational mobility and thus to increase
their biological activity and stability against biodegradation.[2] In recent years,
organoselenium chemistry has developed an exceptional class of structures, because
of oranoselenium’s pivotal role in the synthesis of a large number of biological
compounds and important therapeutic products ranging from antiviral and antican-
cer agents to naturally occuring food supplements.[3] Among the transition metals,
palladium-catalyzed cross-coupling reactions of various aryl, alkyl, and vinyl halides
with organoheteroatom compounds having M-M (M¼S, Se, Te) bonds are now
widely used for the synthesis of various diorganyl chalcogens.[4] To the best of our
knowledge, similar reactions of Baylis–Hillman acetates with diphenyl diselenides
and disulfides have not been reported in literature.
The Baylis–Hillman reaction is a powerful carbon–carbon-bond forming
reaction between electrophiles and activated vinylic systems. The products of
this reaction possess hydroxyl, alkene, and electron-withdrawing groups in close
Received April 28, 2009.
Address correspondence to Bojja Sreedhar, Inorganic and Physical Chemistry Division, Indian
Institute of Chemical Technology, Hyderabad 500007, India. E-mail: sreedharb@iict.res.in
2075

2076
P. SURENDRA REDDY ET AL.
Scheme 1. Stereoselective cross-coupling of Baylis-Hillman acetates with diphenyldisulfides.
proximity, which makes them valuable in a number of stereoselective processes.[5]
Baylis–Hillman adducts and their acetates are useful precursors for the synthesis
of a wide variety of heterocycles and biologically active natural products including
a-methylene-c-butyrolactones and mikanecic acids, frontalin, and drugs such as
trimethoprim, sarkomycin, and ilmofosine.[6] In continuation of our previous work
on Baylis–Hillman acetates,[7] herein we report on our studies of the feasibility of
coupling Baylis–Hillman acetates with diphenyl diselenides and disulfides using
palladium catalysts (Scheme 1).
RESULTS AND DISCUSSION
To optimize the reaction conditions, typical reactions with a variety of
palladium catalysts and solvent systems were examined using 2-(acetoxy-phenyl-
methyl)-acrylic acid methyl ester and diphenyl disulfide as model substrates
(Table 1).
The greatest yields of the product were obtained when the reaction was
carried out in methanol using 2 mol% of palladium acetate and 10 mol% of tri-
phenylphosphine at room temperature. No reaction was observed in the absence
Table 1. Optimization of reaction conditions for the preparation of diorganyl chalcogenides from
Baylis–Hillman acetates
Entry
Pd catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
PdCl2
Methanol
Methanol
Methanol
Methanol
Methanol
THF
0
0
Pd(OAc)2=PPh3
PdCl2=PPh3
PPh3
82
20
0
Pd(OAc)2=PPh3
Pd(OAc)2=PPh3
Pd(OAc)2=PPh3
Pd(OAc)2=PPh3
65
75
71
45
Moulene
DMSO
Acetonitrile
Note. Reactions conditions: 1 (1 mmol), 1 (0.6 mmol), Pd catalyst (2 mol%), PPh3 (10 mol%), and solvent
(3 ml) at rt for 12 h.

CROSS-COUPLING OF BAYLIS–HILLMAN ACETATES
2077
Table 2. Palladium-catalyzed reaction of disulfides and diselenides with Baylis–Hillman acetatesa
Entry
a
Substrate 1 (EWG¼COOMe)
Productb
3
Time (h)
12
Yield (%)c
82
b
c
12
12
14
24
75
80
73
40
d
e
f
12
12
16
12
12
80
75
g
h
i
60
90d
67d
j
aReaction conditions: Baylis–Hillman acetate (1.0 mmol), diaryl disulfide (0.6 mmol), Pd(OAc)2
(2 mol%), PPh3 (10 mol%) in methanol (3 mL) at rt.
bProducts with (Z)-stereoselectivity.
cIsolated yields.
dProduct with (E)-stereoselectivity.

2078
P. SURENDRA REDDY ET AL.
of palladium catalyst or triphenylphosphine. Among the different solvents
screened, methanol was the solvent of choice because product 3a was formed
in 82% yield. Although the reaction proceeded well while using toluene, acetoni-
trile (ACN), tetrahydrofuran (THF), and dimethylsulfoxide (DMSO), the yields
of the product slightly decreased.
Under the optimized conditions, a wide range of structurally diverse sub-
stituted Baylis–Hillman acetates underwent reaction with diphenyl disulfides by
this procedure to produce corresponding products in good yields with high
stereoselectivity, and the results are summarized in Table 2. The results demon-
strate that the Baylis–Hillman acetates derived from p-methoxy, p-trifluoro-
methyl, and p-chloro benzaldehydes were more reactive and gave the
products in good yields (entries a–d). Baylis–Hillman acetates derived from
p-nitrobenzaldehyde afforded the corresponding product in poor yield (entry e).
Hetero-aryl Baylis–Hillman acetates were equally effective as aryl-substituted
Baylis–Hillman acetates (entries f and g). Alkyl-substituted Baylis–Hillman
acetate required longer reaction time, and the corresponding product was
obtained in moderate yield (entry h). Similarly, Baylis–Hillman acetate 1 under-
went reaction with diphenyl diselenide under identical conditions and gave the
coupled product in excellent yield (Scheme 2). Further, the reaction of Baylis–
Hillman acetates derived from acrylonitrile with both diphenyl disulfide and
diselenide gave the coupling products (3i, 3j, and 5b) in excellent yield with
(E)-stereoselectivity.
The stereochemistry of the products was established by nuclear Overhauser
effect (NOE) experiments, which clearly showed the presence of diagnostic NOEs
between the olefinic proton and methylene protons. However, in products 3a and
3b, no NOE was found between methylene and olefinic protons, which confirms
the (Z)-stereoselectivity.
On the basis of these results, together with the literature reports,[5,8] we pro-
pose a plausible mechanism (Scheme 3). The first step involves the oxidative
addition of diphenyl diselenide or sulfide at the palladium metal center. Coordi-
nation of I with the Baylis–Hillman adduct to form P-complex II, followed by
intramolecular insertion of X-Ph to form III and reductive elimination of metal,
affords the product with more stable (Z)-stereoselectivity and regenerates the
low-valent palladium species. The (Z)-stereoselectivity is presumably a conse-
quence of thermodynamic control.
Scheme 2. Stereoselective cross-coupling of Baylis-Hillman acetates with diphenyldiselenides.

CROSS-COUPLING OF BAYLIS–HILLMAN ACETATES
2079
Scheme 3. Plausible mechanism for the stereoselective cross-coupling of Baylis-Hillman acetates with
diphenyldisulfides=diphenyldiselenides.
CONCLUSION
In conclusion, we describe here the stereoselective synthesis of diorganyl
chalcogenides from a variety of Baylis–Hillman acetates and diaryl chalcogens using
palladium catalyst. This reaction is a convenient new method to produce unsym-
metrical sulfides and selenides. The cross-coupling reactions are stereoselective and
applicable to many types of substrates.
EXPERIMENTAL
Typical Experimental Procedure
To a solution of Baylis–Hillman acetate 1 (1 mmol) and diphenyl disulfide
or diphenyl diselenide 2 (0.6 mmol) in methanol (3 ml), Pd (OAc)2 (2 mol%) and
triphenyl phosphine (10 mol%) were added. The reaction mixture was stirred at room
temperature and monitored by thin-layer chromatography (TLC). After completion
of the reaction, the mixture was concentrated and purified by column chromato-
graphy to give the desired product 3.
Spectroscopic Data for the Products
Compound 3a: 3-Phenyl-2-phenylsulfanylmethyl-acrylic acid methyl
ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.80 (s, 3H), 4.12 (s, 2H), 7.13–7.43
(m, 10H), 7.81 (s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 32.41, 52.16, 126.76,
128.33, 128.62, 128.88, 128.97, 129.46, 130.95, 135.92, 141.51, 167.66. ESI MS
(m=z): 284 (Mþ).

2080
P. SURENDRA REDDY ET AL.
Compound 3b: 2-Phenylsulfanylmethyl-3-(4-trifluoromethyl-phenyl)-
acrylic acid methyl ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.80 (s, 3H),
3.94 (s, 2H), 7.21–7.43 (m, 7H), 7.56 (d, 2H, J ¼ 8.0 Hz), 7.64 (s, 1H). 13C NMR
(75 MHz, CDCl3): d (ppm) 32.33, 52.45, 122.08, 125.43 (q, JC-F ¼ 3.3 Hz), 125.68,
127.23, 128.91, 129.34, 130.27, 130.67 (d, JC-F ¼ 3.3 Hz), 131.70, 135.09, 138.29,
139.25, 167.16. ESI MS (m=z): 373 (M þ Na)þ.
Compound 3c: 3-(4-Methoxy-phenyl)-2-phenylsulfanylmethyl-acrylic
acid methyl ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.74 (s, 3H), 3.80 (s,
3H), 3.94 (s, 2H), 7.02 (d, 2H, J ¼ 8.0 Hz), 7.25–7.34 (m, 7H) 7.68 (s, 1H). 13C
NMR (75 MHz, CDCl3): d (ppm) 32.41, 52.33, 55.51, 114.01, 126.67, 127.3,
129.15, 131.99, 134.29, 140.18, 160.10, 167.79. ESI MS (m=z): 314 (Mþ).
Compound 3d: 3-(4-Chloro-phenyl)-2-phenylsulfanylmethyl-acrylic acid
methyl ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.80 (s, 3H), 3.95 (s, 2H),
7.19–7.30 (m, 7H), 7.35 (d, 2H, J ¼ 7.9 Hz), 7.64 (s, 1H). 13C NMR (75 MHz,
CDCl3): d (ppm) 32.15, 51.92, 126.76, 127.98, 128.32, 128.85, 129.11, 134.43,
135.74, 141.31, 167.52. LC MS (m=z): 318 (M)þ.
Compound 3e: 3-(4-Nitro-phenyl)-2-phenylsulfanylmethyl-acrylic acid
methyl ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.84 (s, 3H), 3.90 (s, 2H),
7.22–7.25 (m, 3H), 7.31–7.37 (m, 2H), 7.40 (d, 2H, J ¼ 8.3 Hz), 7.68 (s, 1H), 8.15
(d, 2H, J ¼ 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 32.43, 52.66, 123.64,
127.55, 128.99, 129.85, 131.15, 138.19, 167.56. LC MS (m=z): 350 (M þ Na)þ.
Compound 3f: 2-Phenylsulfanylmethyl-3-thiophen-2-yl-acrylic acid
methyl ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.75 (s, 3H), 4.17 (s, 2H),
7.06 (dd, 1H, J ¼ 3.8 Hz), 7.17–7.27 (m, 3H), 7.31 (d, 1H, J ¼ 3.8 Hz), 7.42 (d, 2H,
J ¼ 6.8 Hz), 7.47 (d, 1H, J ¼ 4.5 Hz), 7.84 (s, 1H). 13C NMR (75 MHz, CDCl3): d
(ppm) 32.41, 52.21, 126.24, 128.15, 129.20, 132.49, 134.50, 136.56, 140.37, 167.72.
ESI MS (m=z): 290 (Mþ).
Compound 3g: 3-Furan-2-yl-2-phenylsulfanylmethyl-acrylic acid methyl
ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.76 (s, 3H), 4.23 (s, 2H), 6.40–6.43
(m, 1H), 6.60 (d, 2H, J ¼ 3.7 Hz), 7.16–7.25 (m, 2H), 7.38–7.43 (m, 3H). 13C
NMR (75 MHz, CDCl3): d 32.55, 52.05, 112.12, 116.37, 126.75, 126.81, 128.50,
132.02, 144.56, 167.10. ESI MS (m=z): 274 (Mþ).
Compound 3h: 2-Phenylsulfanylmethyl-hex-2-enoic acid methyl
ester. 1H NMR (300 MHz, CDCl3): d (ppm) 0.86 (t, 3H, J ¼ 7.5 Hz), 1.25–1.39 (m,
2H, J ¼ 6.7 Hz), 1.92 (q, 2H, J ¼ 7.5 Hz), 3.74 (s, 3H), 3.76 (s, 2H), 6.77 (t, 1H,
J ¼ 7.6 Hz), 7.19–7.28 (m, 3H), 7.39 (d, 2H, J ¼ 7.6 Hz). ESI MS (m=z): 250 (Mþ).
Compound 3i: 3-Phenyl-2-phenylsulfanylmethyl-acrylonitrile. 1H NMR
(300 MHz, CDCl3): d (ppm) 3.72 (s, 2H), 7.21–7.41 (m, 10H), 7.90 (s, 1H). 13C NMR
(75 MHz, CDCl3): d (ppm) 41.08, 110.23, 117.03, 127.95, 128.65, 128.77, 129.14,
130.38, 132.05, 132.90, 144.73. ESI MS (m=z): 290 (M þ K)þ.
Compound
3j:
3-(2-Methoxy-phenyl)-2-phenylsulfanylmethyl-
acrylonitrile. 1H NMR (300 MHz, CDCl3): 3.86 (s, 3H), 4.07 (s, 2H), 6.87 (d,
1H, J ¼ 8.3 Hz), 7.02 (t, 1H, J ¼ 7.6 Hz), 7.28–7.46 (m, 6H), 7.70 (s, 1H), 7.98 (d,

CROSS-COUPLING OF BAYLIS–HILLMAN ACETATES
2081
1H, J ¼ 8.3 Hz). 13C NMR (75 MHz, CDCl3): d (ppm) 41.12, 55.56, 106.34, 110.71,
118.34, 120.75, 128.31, 127.25, 128.47, 130.11, 131.68, 139.69, 157.41. ESI MS (m=z):
281 (Mþ).
Compound 5a: 3-Phenyl-2-phenylselanylmethyl-acrylic acid methyl
ester. 1H NMR (300 MHz, CDCl3): d (ppm) 3.80 (s, 3H), 4.01 (s, 2H), 7.18–7.30
(m, 10H), 7.78 (s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 24.93, 52.16, 127.42,
128.44, 128.64, 129.28, 129.75, 134.20, 139.85, 167.72. ESI MS (m=z): 331 (Mþ).
Compound 5b: 3-Phenyl-2-phenylselanylmethyl-acrylonitrile. 1H NMR
(300 MHz, CDCl3): d (ppm) 3.68 (s, 2H), 7.22–7.99 (m, 10H), 7.82 (s, 1H). 13C NMR
(75 MHz, CDCl3): d (ppm) 21.08, 104.30, 117.10, 127.41, 128.62, 128.71, 128.76,
131.72, 134.12, 140.21. ESI MS (m=z): 321 (M þ Na)þ.
ACKNOWLEDGMENTS
P. S. R. and M. A. R. thank the Council of Scientific and Industrial Research
(CSIR), India, for the award of senior research fellowships.
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