Palladium-catalyzed conjugate addition to electron-deficient alkynes with benzenesulfinic acid derived from 1,2-bis(phenylsulfonyl)ethane: Selective synthesis of (E)-vinyl sulfones

Article abstract of DOI:10.1021/jo102359n

A new, selective method for the synthesis of (E)-vinyl sulfones is presence by palladium-catalyzed C-S bond cleavage/conjugate addition. In the presence of Pd- (OAc)₂ andDMEDA(N¹,N²-dimethylethane-1,2- diamine), 1,2-bis(ph

Full text of DOI:10.1021/jo102359n

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the following: (1) the Knoevenagel condensations of aro-
Palladium-Catalyzed Conjugate Addition to
Electron-Deficient Alkynes with Benzenesulfinic Acid
Derived from 1,2-Bis(phenylsulfonyl)ethane:
Selective Synthesis of (E)-Vinyl Sulfones
matic aldehydes with sulfonylacetic acids,4 (2) Horner-
Emmons reactions of carbonyl compounds and sulfonyl
phosphones,5 (3) β-elimination of selenosulfones or halo-
sulfones,6 and (4) oxidation of the corresponding vinyl
sulfides.7 However, these methods are restricted to relatively
harsh reaction conditions, and inaccessible substrates were
necessary. Recently, a new and efficient route to these com-
pounds is the cross-coupling of sulfinate salts with vinyl
bromides, vinyl triflates, alkenyl boronic acids, or alkenes
with Pd or Cu catalysts (Scheme 1).8 Reeves and co-workers,
for instance, have described a valuable protocol for the
synthesis of vinyl sulfones in moderate to good yields by
palladium-catalyzed coupling of vinyl tosylates with arylsul-
finate salts.8h Here, we report a new approach to (E)-vinyl
sulfones via palladium-catalyzed conjugate additions of
alkynes with 1,2-bis(phenylsulfonyl)ethane (Scheme 1).9 To
the best of our knowledge, it is the first example of using the
commercially available 1,2-bis(phenylsulfonyl)ethane as the
sulfone resource to prepare vinyl sulfones by generating
phenylsulfonyl intermediates in situ for the conjugate addi-
tion to the electron-deficient alkynes.
Ren-Jie Song, Yu Liu, Yan-Yun Liu, and Jin-Heng Li*
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, China
jhli@hunnu.edu.cn
Received November 27, 2010
SCHEME 1. Transition Metal-Catalyzed Synthesis of Vinyl
Sulfones
A new, selective method for the synthesis of (E)-vinyl
sulfones is presence by palladium-catalyzed C-S bond
cleavage/conjugate addition. In the presence of Pd-
(OAc)2 and DMEDA (N1,N2-dimethylethane-1,2-diamine),
1,2-bis(phenylsulfonyl)ethane underwent the C-S bond
cleavage, followed by conjugate addition to numerous
electron-deficient alkynes afforded the corresponding
(E)-vinyl sulfones in moderate to good yields.
Vinyl sulfones are unique architectures found in several
biologically active compounds1 as well as usefully syn-
thetic intermediates in organic synthesis.2 For example,
R,β-unsaturated sulfones were reported as inhibitors of inducible
VACM-1 expression.3 Therefore, considerable effort has
been devoted to the development of new and efficient
methods for the synthesis of vinylsulfones. The traditionally
available methodologies for vinyl sulfones mainly include
The reaction between N-benzyl-N,3-diphenylpropiola-
mide (1a) and 1,2-bis(phenylsulfonyl)ethane (2) was investi-
gated to explore the optimal reaction conditions, and the results
are summarized in Table 1. Initially, a number of solvents, such
as dioxane, MeCN, DMF, and DMF/MeCN, were examined
in the presence of Pd(OAc)2, DMEDA (L1), and KOtBu
(4) (a) Balasubramanian, M.; Baliah, V. J. Chem. Soc. 1954, 1844–1847.
(b) Chodroff, S.; Whitmore, W. F. J. Am. Chem. Soc. 1950, 72, 1073–1076.
(c) Happer, D. A. R.; Steenson, B. E. Synthesis 1980, 10, 806–807.
(5) Popoff, I. C.; Denver, J. L. J. Org. Chem. 1969, 34, 1128–1130.
(6) (a) Gancarz, R. A.; Kice, J. L. Tetrahedron Lett. 1980, 21, 4155–4158.
(b) Asscher, M.; Vofsi, D. J. Chem. Soc. 1964, 4962–4971. (c) Asscher, M.;
Vofsi, D. J. Chem. Soc., Perkin Trans. 1 1972, 1543–1545. (d) Hopkins, P. B.;
Fuchs, P. L. J. Org. Chem. 1978, 43, 1208–1217.
(1) (a) Ettari, R.; Nizi, E.; Francesco, M. E. D.; Dude, M.-A.; Pradel, G.;
Vicik, R.; Schirmeister, T.; Micale, N.; Grasso, S.; Zappala, M. J. Med.
Chem. 2008, 51, 988–996. (b) Mahesh, U.; Liu, K.; Panicker, R. C.; Yao,
S.-Q. Chem. Commun. 2007, 1518–1520. (c) Forristal, I. J. Sulfur Chem. 2005,
26, 163–195. (d) Wang, G.; Mahesh, U.; Chen, G. Y. J.; Yao, S.-Q. Org. Lett.
2003, 5, 737–740.
(2) (a) Pandey, G.; Tiwari, K. N.; Puranik, V. G. Org. Lett. 2008, 10,
3611–3614. (b) Oh, K. Org. Lett. 2007, 9, 2973–2975. (c) Desrosiers, J. N.;
Charette, A. B. Angew. Chem., Int. Ed. 2007, 46, 5955–5957. (d) Noshi,
M. N.; El-Awa, A.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2007, 129,
11242–11247. (e) Mu, L.; Drandarov, K.; Bisson, W. H.; Schibig, A.; Wirz,
C.; Schubiger, P. A.; Westera, G. Eur. J. Med. Chem. 2006, 41, 640–650. (f)
Hof, F.; Schutz, A.; Fah, C.; Meyer, S.; Bur, D.; Liu, J.; Goldberg, D. E.;
Diederich, E. Angew. Chem., Int. Ed. 2006, 45, 138–2141. (g) Wardrop, D. J.;
Fritz, J. Org. Lett. 2006, 8, 3659–3662.
(7) (a) Kirihara, M.; Yamamoto, J.; Noguchi, T.; Hirai, Y. Tetrahedron
Lett. 2009, 50, 1180–1183. (b) Huang, X.; Duan, D.-H.; Zheng, W.-X. J. Org.
Chem. 2003, 68, 1958–1963.
(8) (a) Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423–4425. (b) Nair, V.;
Augustine, A.; George, T. G.; Nair, L. G. Tetrahedron Lett. 2001, 42, 6763–
6765. (c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M.; Bernini, R. J.
Org. Chem. 2004, 69, 5608–5614. (d) Zhu, W.; Ma, D.-W. J. Org. Chem. 2005,
70, 2696–2700. (e) Bao, W.; Wang, C. J. Chem. Res. 2006, 6, 396–397. (f)
Huang, F.; Batey, R. A. Tetrahedron. 2007, 63, 7667–7672. (g) Bian, M.; Xu,
F.; Ma, C. Synthesis 2007, 2951–2956. (h) Reeves, D. C.; Rodriguez, S.; Lee,
H.; Hahhad, N.; Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett.
2009, 50, 2870–2873.
(3) Ni, L.; Zheng, X. S.; Somers, P. K.; Hoong, L. K.; Hill, R. R.; Marino,
E. M.; Suen, K.-L.; Saxena, U.; Meng, C. Q. Bioorg. Med. Chem. Lett. 2003,
13, 745–748.
DOI: 10.1021/jo102359n
r
Published on Web 01/10/2011
J. Org. Chem. 2011, 76, 1001–1004 1001
2011 American Chemical Society

Song et al.
JOCNote
TABLE 1. Screening Optimal Conditionsa
the reaction (entries 4, 17, and 18). It is noted that the loading of
Pd(OAc)2 affected the reaction, and the yield was decreased
to 58% at 5 mol % of Pd(OAc)2 (entry 19).
With the optimal conditions in hand, the alkynes scope
was explored (Table 2). The results demonstrated that the
reaction could be applied to a wide variety of 3-arylpropio-
lamides, and several N-substituents, either alkyl or aryl
groups, were perfectly tolerated under the standard condi-
tions (entries 1-12). N-Methyl-N,3-diphenylpropiolamide
(1b), for instance, underwent the reaction with 1,2-bis-
(phenylsulfonyl)ethane (2), Pd(OAc)2, L1, and KOtBu to
afford the target product 4 in 65% yield (entry 1). Substrates
1c-h, bearing methyl, methoxy, or fluoro groups on the
N-aryl moiety, were also suitable for the reaction in moderate
to good yields (entries 2-7). To our delight, the optimized
conditions were compatible with both N,N-diethyl-3-phe-
nylpropiolamide (1i) and 1-morpholino-3-phenylprop-2-yn-
1-one (1j), providing two regioselective isomers in 71% and
79% yields, respectively (entries 8 and 9).10 Subsequently,
substituents at the terminal alkyne of N-methyl-N-arylpro-
piolamides were investigated (entries 10-12). Treatment
of substrate 1k, bearing a 2-methylpheneyl group, with
1,2-bis(phenylsulfonyl)ethane (2), Pd(OAc)2, L1, and KOtBu
afforded the corresponding (E)-13 in 60% yield (entry 10).
However, amide 1l with a 4-acetylphenyl group reduced the
yield of (E)-14 to 43% under the same conditions (entry 11).
Gratifyingly, N-methyl-N-phenyl-3-(thiophen-2-yl)propiol-
amide (1m) was still a suitable substrate in 74% yield (entry
12). We found that the optimized conditions were consis-
tent with alkylpropiolamides 1n and 1o in moderate yields
(entries 13 and 14). Notably, 43% yield was still achieved
from another substrate 1p, methyl 3-phenylpropiolate,
under the standard conditions (entry 15). However, the
reactions of 1,3-diphenylprop-2-yn-1-one (1q) or N,3-di-
phenylpropiolamide (1r) were not successful under the
standard conditions with a mixture of products (entries 16
and 17).
entry
[Pd]/ligand
base
solvent
dioxane
MeCN
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KOtBu
Pd(OAc)2/L1 KHCO3
Pd(OAc)2/L1 NaOAc
trace
21
62
73
46
37
40
44
28
0
21
32
70
40
27
25
66
32
58
DMF
DMF/MeCN (1:1)
DMF/MeCN (1:4)
DMF/MeCN (4:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
Pd(OAc)2/L1 LiN(TMS)2 DMF/MeCN (1:1)
KOtBu
KOtBu
KOtBu
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
DMF/MeCN (1:1)
Pd(OAc)2
PdCl2/L1
Pd(PPh3)4/L1 KOtBu
Pd2(dba)3/L1 KOtBu
Pd(OAc)2/L2 KOtBu
Pd(OAc)2/L3 KOtBu
17b Pd(OAc)2/L1 KOtBu
18c Pd(OAc)2/L1 KOtBu
19d Pd(OAc)2/L1 KOtBu
aReaction conditions: 1a (0.2 mmol), 2 (2 equiv), [Pd] (10 mol %),
ligand (20 mol %), base (2 equiv), and solvent (2 mL) at 120 °C for 24 h.
bAt 100 °C. cAt 80 °C. dPd(OAc)2 (5 mol %).
(entries 1-6). The results demonstrated that the effect of
solvents played an important role in the reaction. While a trace
amount of the target product 3 was observed in dioxane
(entry 1), MeCN enhanced the yield of 3 to 21% yield and
DMF gave 62% yield (entries 2 and 3). It was a pleasure to find
that a mixture of DMF/MeCN (v/v = 1:1) afforded the best
results (73% yield, entry 4). The configuration structure of
(E)-3 was unambiguously assigned by the X-ray single-crystal
diffraction analysis.10 Subsequently, three other bases, includ-
ing KHCO3, NaOAc, and LiN(TMS)2, were evaluated, and
they were less effective than KOtBu (entries 4 and 7-9). The
effect of the catalytic systems was also tested (entries 4 and
10-16). The reaction could not take place without Pd catalysts
(entry 10). It was disclosed that 21% yield of 3 was isolated by
using Pd(OAc)2 alone (entry 11), and Pd(PPh3)4 combined with
L1 gave the identical results to those of the Pd(OAc)2/L1
system (entry 13). However, the PdCl2/L1, Pd2(dba)3/L1, Pd-
(OAc)2/L2, and Pd(OAc)2/L3 systems displayed less activity
(entries 12 and 14-16). Among the reaction temperature
examined, it turned out that 120 °C was the most suitable for
SCHEME 2. Controlled Experiments in the Presence of
PhSO2K
To understand the mechanism, two controlled experiments
were carried out using the reported sulfone reagent, PhSO2K
(Scheme 2). No target products 3 were observed by GC-MS
analysis from the reaction between substrate 1a and PhSO2K
under either the reported conditions8 or the present condi-
tions. Notably, the reaction could not take place even in the
presence of t-BuOH under the present reaction conditions.
Therefore, a possible mechanism was proposed as out-
lined in Scheme 3 on the basis of the reported mechanism8
and the present results. Insertion of Pd(0) into 1,2-bis-
(phenylsulfonyl)ethane (2) affords intermediate A, fol-
lowed by complexation with an alkyne gives intermediate
B. Two regioselective additions of intermediate B take
place to yield intermediates C and/or C0 on the basis of
(9) For selected papers on the use of 1,2-bis(phenylsulfinyl)ethane as
an efficient ligand in transition metal-catalyzed transformations, see:
(a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276.
(b) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316–3318.
(c) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131,
11701–11706. (d) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009, 131,
11707–11711. (e) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; M.C. White,
M. C. J. Am. Chem. Soc. 2005, 127, 6970–6971. (f) Covell, D. J.; White, M. C.
Angew. Chem., Int. Ed. 2008, 47, 6448–6451.
(10) See the Supporting Information for detailed results of the X-ray
single-crystal diffraction analysis (3) and 2D spectra (12).
1002 J. Org. Chem. Vol. 76, No. 3, 2011

Song et al.
JOCNote
TABLE 2. Palladium-Catalyzed Conjugate Addition of Alkynes (1) with 1,2-Bis(phenylsulfonyl)ethane (2)a
aReaction conditions: 1 (0.2 mmol), 2 (2 equiv), Pd(OAc)2 (10 mol %), DMEDA (20 mol %), KOtBu (2 equiv), and DMF/MeCN (v/v = 1: 1; 2 mL) at
120 °C for 24 h. bIsolated yield. cA mixture of (E)-N,N-diethyl-3-phenyl-3-(phenylsulfonyl)acrylamide (E-11) and (Z)-N,N-diethyl-3-phenyl-
2-(phenylsulfonyl)acrylamide (Z-110) was obtained, and the ratio of Z/E is 1:2. dE-12/Z-120 = 1:1. e18 h.
the N-substituents. Finally, reductive elimination/proton-
ation of intermediates C affords the target (E)-product,
1-(vinylsulfonyl)benzene, and the active Pd(0) species with
the aid of t-BuOK. It is noteworthy that the generation of
1-(vinylsulfonyl)benzene is obtained and in situ deter-
mined by GC-MS analysis.
We deduce that both the steric hindrance and electronic
effect of the N-substituents may affect the regioselective
addition to intermediate B leading to intermediates C and
C0. Substrates with an N,N-dialkyl group give a mixture of
two regioselective products due to their less steric hindrance
and electron-donating effect, which results in two regiose-
lective products.
In summary, we described a novel, simple protocol for the
synthesis (E)-vinyl sulfones by palladium-catalyzed conju-
gate addition reaction. This method allows a variety of
electron-deficient alkynes reacted with 1,2-bis(phenylsulfo-
nyl)ethane, Pd(OAc)2, and DMEDA leading to the corre-
sponding (E)-vinyl sulfones in moderate to good yields. It is
noteworthy that the sulfone resource, phenylsulfonyl inter-
mediates, is prepared in situ from 1,2-bis(phenylsulfonyl)-
ethane through a C-S bond cleavage.
J. Org. Chem. Vol. 76, No. 3, 2011 1003

Song et al.
JOCNote
SCHEME 3. Possible Mechanism
(E)-N-Benzyl-N,3-diphenyl(phenylsulfonyl)acrylamide (3):
73% yield (66.1 mg); colorless oil; 1H NMR (500 MHz) δ
7.50 (d, J = 7.5 Hz, 1H), 7.38-7.29 (m, 10H), 7.24 (t, J = 7.5
Hz, 1H), 7.19-7.13 (m, 3H), 6.98 (t, J = 7.5 Hz, 2H), 6.90 (d,
J = 7.0 Hz, 2H), 6.74 (t, J = 7.5 Hz, 2H), 4.76 (s, 2H); 13C
NMR (125 MHz) δ 164.2, 146.4, 140.5, 137.9, 136.5, 133.5,
132.5, 130.1, 129.5, 129.4, 129.1, 129.0, 128.8 (2C), 128.6,
128.5, 128.4, 128.0 (2C), 127.8, 127.4, 127.3, 52.5; IR (KBr,
cm-1) 1653, 1647; LRMS (EI, 70 eV) m/z (%) 453 (Mþ, 1), 211
(100), 123 (61); HRMS (EI) for C28H23NO3S (Mþ) calcd
453.1399, found 453.1397.
(E)-Methyl 3-phenyl-3-(phenylsulfonyl)acrylate (18): 43%
1
yield (26 mg); colorless oil; H NMR (500 MHz, CDCl3) δ
7.57 (t, J = 1.5 Hz, 3H), 7.56-7.39 (m, 2H), 7.35-7.33 (m,
1H), 7.21-7.02 (m, 3H), 7.01 (d, J = 1.5 Hz, 2H), 3.60 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 164.1, 154.9, 137.5, 133.7,
129.8, 129.6, 129.4, 129.0, 128.8, 127.8, 126.6, 51.9; IR (KBr,
cm-1) 1738, 1654; LRMS (EI, 70 eV) m/z (%) 302 (Mþ, 1), 160
(100); HRMS (EI) for C16H14O4S (Mþ) calcd 302.0613, found
302.0610.
1
Vinylsulfonylbenzene:11 colorless oil; H NMR (500 MHz,
CDCl3) δ 7.91 (t, J = 8.0 Hz, 2H), 7.65-7.61 (m, 1H), 7.56 (t,
J = 7.5 Hz, 2H), 6.69-6.64 (m, 1H), 6.68 (d, J = 7.5 Hz, 1H),
6.47 (d, J = 16.5 Hz, 1H), 6.05 (d, J = 9.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 142.5, 138.4, 133.6, 129.3, 129.1, 127.9;
LRMS (EI 70 eV) m/z (%) 168 (Mþ, 21), 125 (100).
Experimental Section
Typical Experimental Procedure for Palladium-Catalyzed Con-
jugate Addition of Alkynes (1) with 1,2-Bis(phenylsulfonyl)ethane (2).
A mixture of alkynes 1 (0.2 mmol), 1,2-bis(phenylsulfonyl)ethane 2
(124 mg, 2 equiv), Pd(OAc)2 (4.5 mg, 10 mol %), N,N-dimethy-
lethane-1,2-diamine (L1, 3.5 mg, 20 mol %), and KOtBu (44.8 mg,
2 equiv) was stirred in DMF/MeCN (v/v = 1:1, 2 mL) at 120 °C for
24 h until complete consumption of starting material as monitored
by TLC and GC-MS analysis. Then the mixture was diluted with
diethyl ether and washed with saturated NaCl. The organic layers
were dried with anhydrous Na2SO4 and evaporated under vacuum;
the residue was purified by flash column chromatography (hexane/
ethyl acetate) to afford the pure product.
Acknowledgment. We thank the Scientific Research Fund
of Hunan Provincial Education Department (No. 08A037),
Natural Science Foundation of China (No. 20872112), and
Hunan Provincial Innovation Foundation for Postgraduate
(No. CX2009B104) for financial support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 3-18 and
vinylsulfonylbenzene. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Volkova, Y. A.; Averina, E. B.; Grishin, Y. K.; Bruheim, P.;
Kuznetsova, T. S.; Zefirov, N. S. J. Org. Chem. 2010, 75, 3047.
1004 J. Org. Chem. Vol. 76, No. 3, 2011