FeCl3ATMSCl: An effective catalytic system for the conjugate addition of sodium p-toluenesulfinate to αβ-enones

Article abstract of DOI:10.1055/s-2008-1077967

A new protocol for the β-sulfonation of αβ-unsaturated carbonyl compounds is described. The method employs FeCl₃ as catalyst and TMSC1 as additive for conjugate addition of sodiump-toluenesulfinate to enones.

Full text of DOI:10.1055/s-2008-1077967

LETTER
1949
FeCl3/TMSCl: An Effective Catalytic System for the Conjugate Addition of
Sodium p-Toluenesulfinate to a,b-Enones
Conjugate
A
dditi
.
on of Sodium
S
p
-
Toluenesu
r
e
a
,
b
-Enone
e
s
dhar,* M. Amarnath Reddy, P. Surendra Reddy
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: sreedharb@iict.res.in
Received 30 January 2008
Abstract: A new protocol for the b-sulfonation of a,b-unsaturated
SO2Na
carbonyl compounds is described. The method employs FeCl3 as
O
catalyst and TMSCl as additive for conjugate addition of sodium p-
toluenesulfinate to enones.
FeCl3 (20 mol%), TMSCl
CH2Cl2, r.t., 16 h
SO2
O
+
Ph
Ph
Ph
Ph
Key words: b-sulfonyl ketones, conjugate addition, a,b-unsaturat-
ed carbonyl compounds, iron(III) chloride, trimethylsilyl chloride
1
2
3
Scheme 1
The sulfonyl group is a well-established activating moiety
introduced in an intermediate molecule for the construc-
tion of C–C bonds and other transformations.1 Recently,
the use of sulfones has become a common synthetic meth-
odology in many total syntheses and in the generation of
database of functionalized compounds. The ability of the
sulfonyl group to stabilize carbanions is one of the best
known features of these compounds.2 They can also act as
radical stabilizers3 and as cationic synthons.4 Since re-
moval of the sulfonyl group, generally by a reductive pro-
cess or via a base-promoted b-elimination route,5 is
simple, sulfones have become a very popular tool for or-
ganic chemists.
reaction conditions was studied and some of the results
are listed in Table 1.
Among the several Lewis acids screened, InBr3 and FeCl3
gave the product in low yields using acetonitrile as the sol-
vent, whereas all other Lewis acids investigated were in-
effective (entries 1–3). Moreover, other solvents such as
MeCN, DMF, MeOH, CH2Cl2, and a mixture of MeCN–
H2O were also ineffective which may be a result of the
low solubility of sulfinate salts in organic solvents (entries
4–7). On the other hand, when PEG-400 was used as sol-
vent, due to the increase in the solubility of 2 in the reac-
tion medium, the desired product was obtained in
moderate yield (entry 8). Further, to enhance the yield of
the product, various additives were added in the presence
of 20 mol% FeCl3 in different solvents (entries 9 and 10).
The addition of TMSCl as additive in acetonitrile gave the
product in 62% yield within 72 hours (entry 9), whereas
the reaction in dichloromethane gave the product in 85%
yield with a considerable reduction in the reaction time
(entry 10). However, TMSCl alone without FeCl3 was in-
effective for the reaction. Whereas the addition of
TMSOTf as additive, the product was formed in 40%
yield. Among the iron sources, FeCl3 and Fe(acac)3 led to
the best catalysts and afforded in both cases the conjugate
addition product in 85% and 82% yield, respectively (en-
tries 10 and 12). With respect to the catalyst loading, 20
mol% of FeCl3 was found to be optimal. When only 10
mol% of FeCl3 were used, the product was formed in low-
er yield (51%) and no significant improvement was ob-
served with 30 mol% of the catalyst. Moreover, the effect
of temperature on this conjugate addition reaction was
also studied. It was found that at 50 °C the reaction was
completed within 10 hours, and the corresponding conju-
gate addition product was isolated in 83% yield. On the
other hand, FeCl2 and FeSO4 were not effective for this re-
action.
S-Alkylation of sulfinate anions with alkyl halides is a
well-established method for the synthesis of aliphatic sul-
fones.6 However, the conjugate addition of sulfinate an-
ions has not been investigated, especially with chalcones,
as the formed b-sulfonyl ketones are useful for the synthe-
sis of 1,3-diphenylpropan-1-ol and 1-phenylsulfonylcy-
clopropanes.7
Since the pioneering work of Tamura and Kochi,8 iron
salts have emerged as alternative and promising catalysts
for many organic transformations, in particular for Michael
addition reactions.9 These methods are distinguished by
low cost, ready availability, environmentally benign na-
ture of iron salts, and exceptionally high reaction rates are
observed under mild conditions. Encouraged by these re-
sults, we envisaged the application of iron catalysts in the
conjugate addition of sulfinate nucleophiles with a,b-
enones.
Initially, we sought an effective catalytic system for the
conjugate addition of sulfinate anion, guided by the tem-
plate reaction between benzyl acetophenone 1a and p-tol-
uene sulfinate sodium salt 2 (Scheme 1). A range of
SYNLETT 2008, No. 13, pp 1949–1952
x
x
.x
x
.2
0
0
8
Having determined the optimum reaction conditions, we
investigated the generality of this process. As can be seen
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077967; Art ID: D03008ST
© Georg Thieme Verlag Stuttgart · New York

1950
B. Sreedhar et al.
LETTER
Table 1 Optimization of the Reaction Conditions for the Conjugate Addition of Sodium Sulfinate 2 to Chalcone 1aa
SO2Na
O
SO2
O
FeCl3 (20 mol%), TMSCl
CH2Cl2, r.t., 16 h
+
R1
R2
R1
R2
Entry Catalyst
Solvent
MeCN
Additive
Time (h) Yield (%)
1
2
InBr3
72
72
72
72
72
72
72
72
72
16
15
<10
28
15
0
ZrOCl2, ZrCl4, SmI2, ZnCl2, ZnBr2, BiCl3, CuCl2, Cu(OTf)2, La(OTf)3, Bi(OTf)3 MeCN
3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Fe(acac)3
FeSO4
FeCl2
MeCN
–
4
MeCN–H2O
DMF
–
5
–
6
MeOH
–
10
0
7
CH2Cl2
PEG 400
MeCN
–
8
–
45
62
9
TMSCl
TMSCl
10
11
12
13
14
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
85, 83c, 51d
TMSOTf 16
40
82
32
46
TMSCl
TMSCl
TMSCl
16
16
16
a Conditions: catalyst (20 mol%), 1a (1.0 mmol), 2 (1.5 mmol), additive (1.2 mmol), solvent (3 mL), r.t.
b Isolated yield.
c The amount of 10 mol% of FeCl3 was used.
d Reaction carried out at 45 °C.
from Table 2, a variety of chalcones were sulfonated to The substituent next to the olefinic bond other than phenyl
give the corresponding products in moderate to excellent group, that is, furyl group on reaction with 2 gave the cor-
yields. Chalcones with electron-donating substituents responding product in moderate yield (entry 11).
gave a good yield of products when compared to electron-
withdrawing substituents.
To extend the general applicability of this reaction, sever-
al cyclic and acyclic enones (e.g., cyclohexenone, cyclo-
4-Nitro-substituted chalcone gave the product in low yield pentenone, and methyl vinyl ketone) and enoates (e.g.,
(entry 5). 4-Hydroxy-and 2-hydroxy-substituted chal- methyl acrylate) were reacted with p-toulene sulfinate so-
cones were equally effective for the reaction (entries 6, 7). dium salt 2 under optimized conditions, and the results are
O
S
O
S
O–Na+
O–
+
+
Cl Si
NaCl
Si
FeCl3
O
O
FeCl3
+
Ph
Ph
Ph
Ph
O
S
O
O
Ph
Ph
Scheme 2
Synlett 2008, No. 13, 1949–1952 © Thieme Stuttgart · New York

LETTER
Conjugate Addition of Sodium p-Toluenesulfinate to a,b-Enones
1951
Table 3 FeCl3-Catalyzed Conjugate Addition of 2 to Various Cy-
clic and Acyclic a,b-enonesa
Table 2 FeCl3-Catalyzed Conjugate Addition of 2 to Various a,b-
Enonesa
Entry Substrate
Productb
Yield (%)c
SO2Na
O
SO2
O
FeCl3 (20 mol%), TMSCl
CH2Cl2, r.t., 16 h
O
+
O
R1
R2
R1
R2
1
72
S
O2
Entry a,b-Enone 1
Productb Yield (%)c
4a
4b
R1
R2
O
O
1
2
Ph
Ph
3a
3b
3c
3d
3e
3f
85
78
92
90
54
82
75
90
72
75
62
2
63
56
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
Ph
Ph
S
O2
3
Ph
O
4
Ph
O
5
Ph
3
6
4-HOC6H4
S
O2
7
Ph
2-HOC6H4
3g
3h
3i
4c
4d
4e
O
8
Ph
Me
Me
H
O
9
Me
4
81
83
65
S
10
11
Me
3j
O2
fur-2-yl
Ph
3k
O
a Reaction conditions as exemplified in typical experimental proce-
O
H
dure.
5
b All products were characterized by MS, IR, 1H NMR, and 13C NMR
H
S
spectroscopy.
O2
c Isolated yield.
O
given in Table 3. Among the cyclic enones used in this
present study cyclopentenone is more reactive when com-
pared to cyclohexenone, however, the reaction with 3-
methyl cyclopentenone proceeded slowly and gave the
product in moderate yield (entries 1–3). The reaction of
a,b-enones, without any substitution at b-position, gave
the corresponding products in good yields (entries 4–6).
O
MeO
6
OMe
S
O2
4f
a Reaction conditions as exemplified in typical experimental proce-
dure.
b All products were characterized by elemental analysis, MS, IR, 1H
NMR, and 13C NMR spectroscopy.
To get insight into the mechanism, we performed several
experiments to confirm the possibilities of the best reac-
tion system. Although, it is known that TMSCl could ac-
tivate the carbonyl group by initial interaction with
enones,10 it also activates the sulfinate salt by eliminating
NaCl, which precipitates out and facilitate the attack of
sulfinate anion to a,b-enone in the presence of transition-
metal-based Lewis acid (Scheme 2). The precipitated
NaCl was analyzed by XRD and XPS techniques and the
presence of Cl– ion was confirmed by AgNO3 test. The
XPS high-resolution narrow scan at 1072 eV and 200 eV
are attributed due to Na1s, and Cl2p peak clearly suggest
c Isolated yield.
provides significant advantages as a convenient and an
economical method.
Typical Experimental Procedure for Conjugate Addition
To a solution of chalcone 1 (1.0 mmol), TMSCl (1.2 mmol), and
sulfinate sodium salt 2 (1.5 mmol) in CH2Cl2 (3 mL), FeCl3 (20
mol%) was added. The reaction mixture was stirred at r.t. and mon-
itored by TLC. After completion of the reaction, the reaction mix-
that the precipitate is NaCl. The observed XRD pattern is ture was quenched with NaHCO3 (sat. aq). The aqueous layer was
extracted with EtOAc (3 × 20 mL), and the combined organics were
dried over anhyd Na2SO4, concentrated in vacuo, and purified by
column chromatography on SiO2 to afford the pure product. All
in consonance with the observations made by XPS.
In conclusion, we have demonstrated that FeCl3 and
TMSCl catalytic system effectively promotes the direct b-
sulfonation of a,b-unsaturated carbonyl compounds under
mild conditions. This FeCl3-catalyzed conjugate addition
1
products were characterized by MS, IR, H NMR, and 13C NMR
spectroscopy.
Synlett 2008, No. 13, 1949–1952 © Thieme Stuttgart · New York

1952
B. Sreedhar et al.
LETTER
Representative Spectroscopic Data
1,3-Diphenyl-3-(toluene-4-sulfonyl)propan-1-one (3a)
2.90 (t, 2 H, J = 7.5 Hz), 3.28 (t, 2 H, J = 7.5 Hz), 7.35 (d, 2 H,
J = 8.3 Hz), 7.76 (d, 2 H, J = 8.3 Hz) ppm. 13C NMR (75 MHz,
CDCl3): d = 21.5, 29.8, 35.9, 50.5, 127.9, 129.9,135.7, 144.8, 203.8
ppm. LC-MS: m/z = 249 [M + Na]+.
IR (KBr): n = 2912, 1648, 1490, 1286, 1136, 808 cm–1. H NMR
(300 MHz, CDCl3): d = 2.40 (s, 3 H), 3.86 (dd, 1 H, J1 = 9.7 Hz,
J2 = 18.0 Hz), 4.09 (dd, 1 H, J1 = 3.9 Hz, J2 = 18.0 Hz), 4.81 (dd, 1
H, J1 = 3.9 Hz, J2 = 9.7 Hz), 7.12–7.21 (m, 6 H), 7.37–7.55 (m, 6H),
7.94 (d, 2 H, J = 7.8 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = 21.6,
37.0, 66.5, 128.1, 128.4, 128.7, 129.0, 129.4, 129.7, 132.7, 133.6,
134.0, 136.2, 144.7, 194.9 ppm. ESI-MS: m/z = 365.1 [M + 1]+,
387.1 [M + Na]+.
1
Acknowledgment
P.S.R. thanks the Council of Scientific and Industrial Research
(CSIR), India, for a Senior Research Fellowship.
3-(4-Bromophenyl)-1-phenyl-3-(toluene-4-sulfonyl)propan-1-
one (3b)
References and Notes
1
IR (KBr): n = 2884, 1671, 1341, 1332, 1152, 1064, 810 cm–1. H
(1) (a) Patai, E. S.; Rappoport, Z.; Stirling, C. The Chemistry of
Sulphones and Sulphoxides; John Wiley and Sons:
Chichester, 1988. (b) Simpkins, N. S. Sulphones in Organic
Synthesis; Pergamon Press: Oxford, 1993. (c) Backvall,
J.-E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 1998,
98, 2291. (d) Back, T. G. Tetrahedron 2001, 57, 5263.
(e) Chemla, F. J. Chem. Soc., Perkin Trans. 1 2002, 275.
(2) Najera, C.; Sansano, J. M. Recent Res. Dev. Org. Chem.
1998, 2, 637.
NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 3.78 (dd, 1 H, J1 = 9.3
Hz, J2 = 18.0 Hz), 4.05 (dd, 1 H, J1 = 3.9 Hz, J2 = 18.0 Hz), 4.77
(dd, 1 H, J1 = 3.9 Hz, J2 = 9.3 Hz), 7.10–7.24 (m, 7 H), 7.37 (d, 2 H,
J = 8.5 Hz), 7.57 (d, 2 H, J = 8.5 Hz), 7.82 (d, 2 H, J = 8.5 Hz) ppm.
13C NMR (75 MHz, CDCl3): d = 21.5, 37.1, 65.9, 121.3, 127.4,
128.3, 128.7, 128.8, 129.2, 130.0, 130.6, 131.2, 133.2, 133.5, 144.7,
198.3 ppm. ESI-MS: m/z = 455 [M + 1]+, 467 [M + Na]+.
(3) Paquette, L. A. Synlett 2001, 1.
(4) Chinchilla, R.; Najera, C. Recent Res. Dev. Org. Chem.
4-(Toluene-4-sulfonyl)pentan-2-one (3i)
IR (KBr): n = 2924, 1710, 1596, 1455, 1282, 1134, 1080, 812, 658
cm–1. 1H NMR (300 MHz, CDCl3): d = 1.20 (s, 3 H), 2.47 (s, 3 H),
2.82 (dd, 1 H, J1 = 9.2 Hz, J2 = 17.6 Hz), 3.21 (dd, 1 H, J1 = 3.8 Hz,
J2 = 17.6 Hz), 3.61–3.66 (m, 1 H), 7.34 (d, 2 H, J = 8.1 Hz), 7.70 (d,
2 H, J = 8.1 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = 18.9, 21.4,
29.0, 45.8, 64.1, 129.6, 130.1, 131.2, 145.1, 206.8 ppm. LC-MS: m/z =
263 [M + Na]+.
1997, 1, 437.
(5) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(6) (a) Krug, R. C.; Rigney, J. A.; Tichelaar, G. R. J. Org. Chem.
1962, 27, 1305. (b) Burger, J. J.; Chen, T. B. R. A.;
DeWaard, E. R.; Huisman, H. O. Tetrahedron 1980, 36,
723. (c) Naf, F.; Decorzant, R.; Escher, S. D. Tetrahedron
Lett. 1982, 23, 5043. (d) Solladie, G. In Comprehensive
Organic Synthesis, Vol. 6; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991, 133–170; and references cited
therein. (e) Crandall, J. K.; Pradat, C. J. Org. Chem. 1985,
50, 1327; and references cited therein.
(7) Skarzewski, J.; Siedlecka, R.; Wojaczynska, E.; Zielinska-
Blajet, M. Tetrahedron: Asymmetry 2002, 13, 2105.
(8) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93,
1487. (b) Tamura, M.; Kochi, J. K. Synthesis 1971, 303.
(c) Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1971, 31,
289.
3-(Toluene-4-sulfonyl)cyclohexanone (4a)
IR (KBr): n = 3053, 2948, 1703, 1529, 1428, 1424, 1260, 1127, 818,
1
556 cm–1. H NMR (300 MHz, CDCl3): d = 1.54–1.97 (m, 2 H),
2.15–2.36 (m, 4 H), 2.47 (s, 3 H), 2.53 (d, 2 H, J = 7.3 Hz), 3.19–
3.34 (m, 1 H), 7.36 (d, 2 H, J = 8.1), 7.72 (d, 2 H, J = 8.1) ppm. 13
C
NMR (75 MHz, CDCl3): d = 21.4, 23.3, 23.7, 40.3 (2 C), 62.2,
128.8, 129.9, 133.4, 145.1, 206.3 ppm. ESI-MS: m/z = 252 [M+],
275 [M + Na]+.
3-(Toluene-4-sulfonyl)cyclopentanone (4b)
(9) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev.
2004, 104, 6217; and references cited therein. (b) Sayed,
A. A.; Wadia, M. S. J. Chem. Res., Synop. 2001, 9, 362.
(c) Kohler, E. P.; Larsen, R. G. J. Am. Chem. Soc. 1936, 58,
1518.
(10) (a) Xu, L.-W.; Xia, C.-G.; Hu, X.-X. Chem. Commun. 2003,
2570. (b) Yang, L.; Xu, L.-W.; Xia, C.-G. Tetrahedron Lett.
2007, 48, 1599.
IR (neat): n = 2923, 1748, 1596, 1403, 1295, 1144, 1086, 816, 582
cm–1. 1H NMR (300 MHz, CDCl3): d = 2.15–2.26 (m, 2 H), 2.35–
2.44 (m, 3 H), 2.48 (s, 3 H), 2.59 (dd, 1 H, J1 = 7.5 Hz, J2 = 18.1
Hz), 3.63–3.73 (m, 1 H), 7.36 (d, 2 H, J = 8.3 Hz), 7.75 (d, 2 H,
J = 8.3 Hz) ppm. 13C NMR (75 MHz, CDCl3): d = 21.7, 23.2, 36.9,
38.6, 60.6, 128.4, 130.0, 134.2, 145.2, 212.8 ppm. LC-MS: m/z =
251 [M + Na]+.
4-(Toluene-4-sulfonyl)butan-2-one (4d)
IR (neat): n = 2922, 1716, 1597, 1445, 1304, 1271, 1144, 1088, 524
cm–1. 1H NMR (300 MHz, CDCl3): d = 2.18 (s, 3 H), 2.46 (s, 3 H),
Synlett 2008, No. 13, 1949–1952 © Thieme Stuttgart · New York