Wittig–Horner mediated synthesis of 4-vinyl sulfide derivatives of pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2016.06.063

The synthesis of a series of 4-vinyl sulfide derivatives of 1,3-diarylpyrazoles, including their corresponding sulfoxides and sulfones, is reported. Access to the target vinyl sulfides was stereoselectively achieved, in moderate to good yields, by the n-BuLi-mediated Wittig–Horner reaction of 4-formylpyrazoles with arylthiophosphonates and α-chloroarylthiophosphonates in dimethoxyethane. Their oxidation with H₂O₂in AcOH and mCPBA in CH₂Cl₂afforded satisfactory yields of the expected vinyl sulfoxides and vinyl sulfones, respectively. Enrichment in the more stable isomers during both oxidation processes was detected and a plausible general mechanistic explanation was given to these observations.

Full text of DOI:10.1016/j.tetlet.2016.06.063

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Wittig–Horner mediated synthesis of 4-vinyl sulfide derivatives
of pyrazoles
a,
Gustavo Padilha a, Teodoro S. Kaufman b, , Claudio C. Silveira
⇑
⇑
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
b Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531, 2000 Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of 4-vinyl sulfide derivatives of 1,3-diarylpyrazoles, including their correspond-
ing sulfoxides and sulfones, is reported. Access to the target vinyl sulfides was stereoselectively achieved,
in moderate to good yields, by the n-BuLi-mediated Wittig–Horner reaction of 4-formylpyrazoles with
Received 25 May 2016
Revised 13 June 2016
Accepted 14 June 2016
Available online xxxx
arylthiophosphonates and
a-chloroarylthiophosphonates in dimethoxyethane. Their oxidation with
H2O2 in AcOH and mCPBA in CH2Cl2 afforded satisfactory yields of the expected vinyl sulfoxides and vinyl
sulfones, respectively. Enrichment in the more stable isomers during both oxidation processes was
detected and a plausible general mechanistic explanation was given to these observations.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl sulfides
Polysubstituted aryl pyrazoles
Wittig–Horner reaction
Vinyl sulfoxides and sulfones
Stereoselective reaction
Pyrazole is the key structural motif of a handful of natural prod-
ucts and many synthetic compounds. Pyrazole derivatives exhibit a
range of valuable biological activities;1 furthermore, some good
selling pharmaceuticals are also pyrazole-based drugs, like the anti
HIV atorivodine2a and the NSAIDs drugs etoricoxib, celecoxib,2b
and deracoxib.2c
Therefore, in pursuit of our continued interest in the prepara-
tion of new vinyl chalcogenides based on the Wittig and Wittig–
Horner reactions,12 herein we report our study of the synthesis
of vinyl sulfides (1), sulfoxides (2) and sulfones (3) derived from
4-formylpyrazoles (4) by their Wittig–Horner reaction with 5 and
6 (Scheme 1).
On the other hand, organochalcogen compounds play an impor-
tant role in modern organic synthesis;3 some of them also display
very useful biological activities.4 The vinyl chalcogenides are a dis-
tinguished group of organochalcogens that has attracted consider-
able attention in recent years.5 Among them, vinyl sulfides are
particularly interesting, serving as intermediaries for various
organic transformations.6 They are usually prepared by addition
of thiols or thiolates to alkynes7 and by reaction of thiols with vinyl
halides,8 under metal-catalysis. However, the most useful strate-
gies toward these compounds relay on Wittig and Wittig–Horner
reactions.9
The starting 4-formylpyrazoles 4a–c were prepared in 49–65%
overall yield by reaction of the easily available ketones 7a–c with
phenylhydrazine under AcOH catalysis (Scheme 2), followed by
cyclization and subsequent formylation of the resulting hydra-
zones 8a–c13 with the Vilsmeier–Haack reagent (POCl3/DMF).14
The thiophosphonates 5a,b were prepared in 53–55% yield from
diethyl phosphite and paraformaldehyde, followed by tosylation15a
of the so formed hydroxymethyl phosphonate, and tosylate dis-
placement with the appropriate arenethiol (Scheme 3).15b Finally,
the corresponding
a-chlorothiophosphonates 6a,b were obtained
(87% yield) by chlorination of 5a,b with NCS.15c
Despite the abundant literature on polysubstituted pyrazolic
compounds, only scattered syntheses of their 4-vinylsulfide
derivatives have been reported,10 and none of them of a trisubsti-
In order to optimize the proposed Wittig–Horner olefination
toward the expected vinyl sulfide 1a, the model reaction between
the phosphonic ester derivative 5a and the pyrazole aldehyde 4a
was examined.16 Initial studies were carried out in THF, changing
the reaction temperature and time, and employing a series of bases
such as NaH, NaOMe, t-BuOK, and n-BuLi. Some other solvents and
phase transfer catalysts (PTC) were also tested.
tuted
a-halo derivative. Many congeners have been obtained by
means of a Knoevenagel condensation; however, only a single case
reports their access through a Wittig-type reaction, where the car-
bonyl partner is part of a pyrazole unit.11
As shown in Table 1, low yields and stereoselectivities (deter-
mined by 1H NMR) were obtained with NaH and NaOMe in THF
(entries 1 and 2), and no product was observed when t-BuOK
⇑
Corresponding authors. Tel./fax: +55 55 3220 8754.
E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
http://dx.doi.org/10.1016/j.tetlet.2016.06.063
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Padilha, G.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.063

2
G. Padilha et al. / Tetrahedron Letters xxx (2016) xxx–xxx
O
P
On the other hand, the use of PTC conditions (TEBA-Br and
R1
R1
EtO
S
OEt
R3
(O)n
S
dibenzo-18-crown-6) allowed the reaction to be performed at
room temperature, but at the expense of attaining moderate yields
and essentially no stereoselectivity (entries 7–10).
The optimized conditions of the Wittig–Horner reaction with
the aldehyde 4a were employed to synthesize the series of vinyl
sulfides 1a–l (Table 2), which were obtained in moderate to good
yields, with a high preference for the geometry of the more stable
product. The chloro-substituted vinyl sulfides 1g–l, exhibited a
slightly lower stereoselectivity (entries 7–12).
R2
CHO
4
5
3
R3
+
2N
N
N1
Ph
N
Ph
R3= H, Cl
R2
5 R3= H; 6 R3= Cl
4
1 n= 0; 2 n= 1; 3 n=2
Scheme 1. Proposed synthetic approach toward compounds 1–3.
In the case of olefins 1a–f, the configuration of the major isomer
was found to be E, which places apart their bulkier pyrazolyl and
arylthio motifs. However, according to the Cahn–Ingold–Prelog
priority rules and due to the presence of the chlorine atom, the
most stable isomers among compounds 1g–l were the Z-alkenes,
which also place apart the same bulkier motifs. Therefore, for the
sake of convenience, in order to unequivocally identify the isomers
and establish structure–reaction outcome relationships, the cis and
trans terms are used to designate the isomers carrying their pyra-
zolyl and phenylthio moieties on the same and on different sides of
the double bond, respectively.
R1
Ph
N
CHO
O
N
H
PhNHNH2,
AcOH
(77-96%)
POCl3, DMF,
5 h, 70 ºC
(63-76%)
N
Me
Me
N
Ph
R1
R1
8a-c
4a-c
7a-c
Scheme 2. Synthesis of the 4-formylpyrazoles 4a–c.
Signal attribution of the vinyl sulfides was confirmed by COSY
and NOESY experiments, which enabled the unequivocal identifi-
cation of the vinylic hydrogens (compounds 1a–f) and the subse-
quent determination of their coupling constants (Jtrans ꢀ 15 Hz;
Jcis ꢀ 10–12 Hz) or the establishment of spatial closeness between
substituents in 1g–l. The 1H NMR spectra of the vinyl sulfides
1a–f also revealed an effect of the double bond stereochemistry
on H-5 of the pyrazole. For example, the chemical shift of H-5
was d 8.02 ppm in trans-1a, while the cis-isomer exhibited a reso-
nance at d 8.47 ppm. The outcome of the reaction agreed with lit-
erature precedents for analogous transformations.17
O
O
O
(H2CO)n, K2CO3,
EtOH, 5 h, 75 ºC
(95%)
Et3N, TsCl,
(EtO2)PH
(EtO)2P
OH
(EtO)2P
OTs
r.t., 48 h
(61%)
KOH, EtOH,
r.t., 16 h
R1
SH
S
(92-95%)
NCS, CCl4,
r.t., 4 h
(87-88%)
O
O
R1
(EtO)2P
R1
(EtO)2P
S
Cl
6a,b
5a,b
Scheme 3. Synthesis of the thiophosphonate derivatives 5 and 6.
Taking into account the importance of the sulfoxide moiety in
pharmacological agents, pesticides, and in organic chemistry, the
vinyl sulfides 1a–l were oxidized to the corresponding sulfoxides
2a–l with H2O2 in AcOH at room temperature (Table 2).18 For sul-
foxides 2a–f, 1.0 equiv of H2O2 was enough to achieve good yields
(entries 1–6) and trans/cis ratios (up to 96:4, entries 2 and 3), in
4.5 h. However, the reaction toward the more sterically shielded
sulfoxides 2g–l was sluggish, requiring the use of 10 equiv of
oxidant and a reaction time of 7 h (entries 7–12). The expected
was employed as the base (entry 3). A better result (71% yield,
trans/cis = 85:15) was observed by the use of n-BuLi(entry 4).
The substitution of THF for DME as the solvent gave 71% yield
with NaH (entry 5), while the use of n-BuLi as base furnished still
higher yields of 1a (87%) and slightly improved the stereoselectiv-
ity (trans/cis = 88:12, entry 6). In addition, it was observed that the
use of the ethereal solvents (THF and DME) required reflux condi-
tions for the complete solubilization of the reactants in the reac-
tion medium.
Table 1
Optimization of the reaction conditions for the Wittig–Horner synthesis of the vinyl sulfide 1a
CHO
Ph
Ph
S
S
OEt
O
OEt
Conditions
+
N
N
P
N
N
Ph
Ph
4a
5a
1a
Entry N°
Base
Solvent
Temp.
Time (h)
Yield (%)a
E:Zb
1
2
3
4
5
6
7
8
9
NaH
NaOMe
t-BuOK
n-BuLi
NaH
n-BuLi
THF
THF
THF
THF
DME
DME
DCM/H2O
DCM/H2O
DCM/H2O
DCM/H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
Reflux
rt
Reflux
5
5
5
5
5
5
53
25
Traces
71
71
87
77
78
67
58:42
51:49
—
85:15
67:33
88:12
51:49
35:65
55:45
57:43
NaOH/TEBA-Brc
NaOH/TEBA-Brc
NaOH/Crownd
NaOH/Crownd
O/Ne
5
O/Ne
5
10
64
a
b
c
Yield of isolated products.
The trans/cis(E/Z)ratios were determined by 1H NMR.
TEBA-Br = Benzyltriethylammonium bromide.
Crown = Dibenzo-18-crown-6.
d
e
O/N = Overnight.
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G. Padilha et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2
Synthesis of 1,3-diaryl-4-vinylpyrazole derivatives. Sulfides (1a–l), sulfoxides (2a–l) and sulfones (3a–l)
R2
R2
R1
O
P
R1
R1
EtO
S
OEt
R3
O
H2O2, AcOH, r.t., 4.5-7 h
S
R2
S
R3
CHO
R1
n-BuLi, DME,
R3
N
reflux, 5 h
N
Ph
O
+
N
N
S
N
Ph
N
O
mCPBA, CH2Cl2,
r.t., 3 h
R2
5a,b R3= H; 6a,b R3= Cl
Ph
2a-f R3= H; 2g-l R3= Cl
R3
4a-c
1a-f R3= H; 1g-l R3= Cl
N
N
3a-f R3= H; 3g-l R3= Cl
Ph
Entry N° 4-Formyl Phosphonate R1
R2 R3 Vinyl sulfide
Vinyl sulfoxide
Vinyl sulfone
pyrazole
Prod. N° trans:cisa,b Yield (%)c Prod. N° trans:cisa,b Yield (%)c Prod. N° trans:cisa,b Yield (%)c
1
2
3
4
5
6
7
8
4a
4a
4b
4b
4c
4c
4a
4a
4b
4b
4c
4c
5a
5b
5a
5b
5a
5b
6a
6b
6a
6b
6a
6b
H
H
Cl
Cl
H
Cl
H
Cl
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
1a
1b
1c
1d
1e
1f
1g
1h
1i
88:12
89:11
78:22
86:14
90:10
71:29
69:31
81:19
64:36
69:31
71:29
75:25
87
62
66
57
49
54
49
58
61
59
60
48
2a
2b
2c
2d
2e
2f
2g
2h
2i
90:10
96:4
96:4
92:8
91:9
83:17
69:31
78:22
73:27
83:17
75:25
76:24
90
60
92
59
88
63
63
64
72
48
49
60
3a
3b
3c
3d
3e
3f
3g
3h
3i
97:3
98:2
97
85
91
84
68
85
72
74
60
75
33
86
100:0
100:0
94:6
100:0
93:7
88:12
88:12
84:16
96:4
MeO
MeO Cl
H
H
Cl
Cl
H
Cl
H
Cl
H
9
10
11
12
1j
1k
1l
2j
2k
2l
3j
3k
3l
MeO
MeO Cl
92:8
a
b
c
Determined by 1H NMR.
The terms cis and trans refer to the orientations of the arylthio and pyrazolyl moieties with regards to the double bond.
Yields of isolated products.
sulfoxides were obtained in moderate to high yields and with mod-
erate trans/cis ratios (up to 83:17, entry 10).
The results of the synthesis of the vinyl sulfides exhibited some
useful trends. They revealed that the reactions with 6a,b proceeded
in lower yields than those with 5a,b giving also lower trans/cis
ratios. In addition, among the vinyl chlorides 1g–l, the yields
attained with the pyrazole 4b were better than those obtained
with 4c. The methoxy-substituted compounds were also accessed
in a lower yield in the subset of compounds 1a–f.
For the vinylsulfoxides, statistically significant models were
obtained, which revealed that all three substituents influenced
the yields and the observed trans/cis ratios. They also unveiled
interactions among the substituent of the arylthio-moiety (R2)
with the other two.
The models disclosed that the trisubstituted alkenes 2g–l were
obtained in lower yields and trans/cis ratios than the disubstituted
ones, and that those having 4-chloro-arene substituents exhibited
better trans/cis ratios, whereas the 4-MeO substituted analogs were
obtained in better yields. In addition, among the disubstituted
alkenes 2a–f, the yields and trans/cis ratios were, in general, worse
for the 4-chloro-arylthio derivatives.
Statistically significant models were also obtained for the yields
and trans/cis ratios of the sulfones, exposing interactions among
variables and that all substituents impact the results. They
revealed that the lowest yields were for 4-MeO pyrazoles in case
R2 = R3 = H, but the trans/cis ratios remained high (95:5–99:1).
Trisubstituted alkenes 3g–l afforded sulfones with trans/cis
ratios lower than their congeners 3a–f and in the case of MeO,
drastic yield reduction was observed. Among the 4-chloro arylthi-
ols, trisubstitution of the alkene resulted in lower yields and trans/-
cis ratios regardless the substituent on the pyrazole moiety.
In addition, stereo-enrichment was observed, more notoriously
with sulfones 3g–l. High product yields and enrichment in the
more stable stereoisomers suggested that the latter was not a
result of different oxidation rates of the starting stereoisomers,
but rather a consequence of double bond isomerization.
Vinyl sulfones are also important intermediates in organic syn-
thesis; this prompted their preparation, what was achieved by
reaction of 1a–l for 3 h with 3 equiv mCPBA in CH2Cl2 at rt Gener-
ally, moderate to good yields of 3a–l were obtained.19 Good stere-
oselectivities were observed in all cases toward the more
stableisomers,20 as verified by NMR spectroscopy.21
Careful 1H NMR analysis of the halo derivatives 1–3/g–l also
revealed some trends. Among the sulfides and sulfoxides, the H-5
was more deshielded for the major isomers; however, in the cases
of the sulfones, the major isomers exhibited more shielded H-5
protons than their less abundant counterparts.
The systematic variation of the substituents on the 3-arylpyra-
zole, arylthio- and double bond, as well as the different oxidation
states of the sulfur moiety, which resulted in a heap of seemingly
unrelated data, suggested that their statistical analysis may be a
suitable approach to shed light on the impact of the different sub-
stituents on product yields and trans/cis ratios. Hence, they were
statistically studied with Design ExpertÒ.
O
R
Ar1
O
X
S
X
S
- H+
..
Ar1
R
O
+
H
On
On
Ar2
H
O-
O
O
N
Ar2
N
N
Ph
N
Ph
Less stable
Rotation
H+
O
Ar2
Ar2
O-
O
O
R
S
S
X
On
On
Ar1
Ar1
H
R= Me, 3Cl-C6H4
X= H, Cl
+ H+
X
- R-CO2H
N
N
n= 0, 1
N
N
Ph
More stable
Ph
Scheme 4. Plausible mechanism for the double bond isomerization.
Please cite this article in press as: Padilha, G.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.063

4
G. Padilha et al. / Tetrahedron Letters xxx (2016) xxx–xxx
7. (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079; (b) Dondoni,
Based on the literature,22 an isomerization mechanism was pro-
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Org. Lett. 2012, 14, 1780; (d) Malyshev, D. A.; Scott, N. M.; Marion, N.; Steven, E.
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(e) Yamashita, F.; Kuniyasu, H.; Terao, J.; Kambe, N. Org. Lett. 2008, 10, 101; (f)
Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614; (g) Kondo, A.
K.; Takami, K.; Yorimitsu, H.; Oshima, K. J. Org. Chem. 2005, 70, 6468; (h)
Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121, 5108; (i)
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posed (Scheme 4), where the alkene moiety undergoes an oxa-
Michael-addition–elimination of the acid (3-ClC6H4CO2H, AcOH)
of the reaction media, accompanied by rotation around the C–C
bond, to afford the most stable alkene isomer.
To sustain this proposal, a Z-enriched solution of vinyl sulfide 1c
(trans/cis = 17:83) in CDCl3 (0.5 mL) was treated with AcOH
(2.0 equiv). It was observed that after 5 h at rt and 15 h at 50 °C,
its 1H NMR spectrum exhibited a trans/cis ratio of 26:74.
The pyrazole ring, which could capture the acid proton and help
to stabilize charges, seems to not necessarily be involved in the
process, since when a sample of [(2-phenylethenyl)sulfanyl] ben-
zene (trans/cis = 63:37) was subjected to the same treatment, the
final trans/cis ratio was 81:19.
8. (a) Kao, H. L.; Lee, C. F. Org. Lett. 2011, 13, 5204; (b) Lin, Y. Y.; Wang, Y. J.; Lin, C.
H.; Cheng, J. H.; Lee, C. F. J. Org. Chem. 2012, 77, 6100; (c) Silveira, C. C.; Santos,
P. C. S.; Mendes, S. R.; Braga, A. L. J. Organomet. Chem. 2008, 693, 3787; (d) Kabir,
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1541564, 2005.
In conclusion, an efficient synthesis of 4-vinyl pyrazole aryl-sul-
fides was achieved by
a Wittig–Horner strategy, from 4-
formylpyrazoles. Related sulfoxides and sulfones were obtained
by oxidation, yielding a whole series of new, previously unknown
compounds. Stereo-enrichment and preference for the stereoiso-
mer with the arylthio and pyrazole moieties on opposite sides of
the double bond were also observed and mechanistically
explained.
12. (a) Bassaco, M. M.; Monçalves, M.; Rinaldi, F.; Kaufman, T. S.; Silveira, C. C. J.
In view that other Wittig–Horner reagents related to 6a,b are
also available and taking into account that diethyl fluoro(phenyl-
sulfonyl)methylphosphonate has been employed as a reactant to
Photochem. Photobiol.
A 2014, 290, 1; (b) Monçalves, M.; Rampon, D. S.;
Schneider, P. H.; Rodembuch, F. S.; Silveira, C. C. Dyes Pigm. 2014, 102, 71; (c)
Silveira, C. C.; Rinaldi, F.; Bassaco, M. M.; Guadagnin, R. C.; Kaufman, T. S.
Synthesis 2011, 1233; (d) Silveira, C. C.; Rinaldi, F.; Guadagnin, R. C.; Braga, A. L.
Synthesis 2009, 469; (e) Silveira, C. C.; Rinaldi, F.; Bassaco, M. M.; Kaufman, T. S.
Tetrahedron Lett. 2008, 49, 5782.
produce (a
-fluoro)vinyl sulfides,23 it is not unlikely that our proto-
col may also find use to access 4-vinylpyrazole aryl-sulfide deriva-
tives carrying halogens other than chlorine.
13. Mokhtari, J.; Naimi-Jamal, M. R.; Hamzeali, H.; Dekamin, M. G.; Kaupp, G.
ChemSusChem 2009, 2, 248.
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Maldonado, J.; Vanelle, P. Eur. J. Med. Chem. 2002, 37, 671.
Acknowledgment
15. (a) Jeanmaire, T.; Hervaud, Y.; Boutevin, B. Phosphorus Sulfur Silicon Relat. Elem.
2002, 177, 1137; (b) Cao, Y.; Hidaka, A.; Tajima, T.; Fuchigami, T. J. Org. Chem.
2005, 70, 9614; (c) Kim, T. K.; Oh, D. Y. Tetrahedron Lett. 1985, 26, 3479.
16. Typical procedure for the synthesis of the vinyl sulfides 1a–l: A solution of the
thiophosphonate (1 mmol) in DME (5 mL) under argon was cooled to À78 °C
and treated dropwise with n-BuLi (1 mmol). After stirring for 15 min, the
aldehyde (1 mmol) was added and the reaction was heated under reflux for
5 h. Water (20 mL) was added and the reaction mixture was extracted with
CH2Cl2 (2 Â 30 mL). The organic phase was washed with saturated NH4Cl
solution (20 mL), dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography.
The authors are thankful to MCT/CNPq and CAPES, for financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
063.
17. (a) Wnuk, S. F.; Garcia, P. I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047; (b) Andrei, D.;
Wnuk, S. F. J. Org. Chem. 2006, 71, 405; (c) Berkowitz, D. B.; de la Salud-Bea, R.;
Jahng, W.-J. Org. Lett. 1821, 2004, 6; (d) Otten, P. A.; Davies, H. M.; Van Der Gen,
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References and notes
18. Typical procedure for the synthesis of the vinyl sulfoxides 2a–l: A solution of the
vinyl sulfide (1 mmol) in AcOH (5 mL) was treated with 30% H2O2 (0.12 mL,
1 mmol for 2a–f; 1.2 mL, 10 mmol for 2g–l). The reaction was stirred for 4.5–
5.0 h, at rt, when it was diluted with CH2Cl2 (25 mL) and washed with
saturated NaHCO3 solution (2 Â 30 mL). The organic phase was dried (MgSO4),
concentrated under reduced pressure and the residue was chromatographed.
19. Typical procedure for the synthesis of the vinyl sulfones 3a–l: A solution of the
vinyl sulfide (1 mmol) in CH2Cl2 (25 mL) was cooled to 0 °C and treated with
50% mCPBA (1.03 g, 3 mmol). The reaction was stirred for 3 h at rt, when a
saturated solution of NaHCO3 was added (30 mL). The products were extracted
with CH2Cl2 (2 Â 15 mL) and the extracts were washed with brine (20 mL). The
organic layer was dried (MgSO4) and concentrated in vacuum, and the residue
was purified by column chromatography.
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21. Spectral data for selectedcompounds. E–1a: 1H NMR (400 MHz, CDCl3, d): 6.67 (d,
J = 15.4, 1H), 6.78 (dd, J = 0.6, 15.4, 1H), 7.2–7.33 (m, 4H), 7.36–4.4 (m, 3H),
7.41–7.46 (m, 4H), 7.69–7.75 (m, 4H), 8.03 (d, J = 0.6, 1H). 13C NMR (100 MHz,
CDCl3, d): 119.0, 119.3, 122.4, 123.2, 124.5, 126.5, 126.7, 128.1, 128.4, 128.5,
129.1 (2C), 129.4, 132.9, 135.6, 139.8, 151.1. MS (m/z, rel. int.%): 355 (26) [M]+,
354 (100), 321 (22), 245 (59), 244 (26), 233 (12), 142 (15), 115 (46), 104 (14),
77 (91). Anal. Calcd. for C23H18N2S: C, 77.93; H, 5.12; N, 7.90. Found: C, 77.92;
H, 5.31; N, 7.81. E–1f: 1H NMR (400 MHz, CDCl3, d): 3.85 (s, 3H), 6.59 (d,
J = 15.4, 1H), 6.78 (d, J = 15.4, 1H), 6.98 (d, J = 8.8, 2H), 7.28–7.3 (m, 5H), 7.41–
7.46 (m, 2H), 7.6–7.63 (m, 2H), 7.71–7.75 (m, 2H), 8.02 (s, 1H). 13C NMR (100
MHz, CDCl3, d): 55.3, 114.1, 118.8, 119.0, 121.1, 124.5, 125.4, 126.5, 129.2,
129.4 (2C), 129.7, 130.5, 132.7, 134.4, 139.8, 151.1, 159.8. MS (m/z, rel. int.%):
420 (41) [M]+, 419 (30), 418 (100), 385 (20), 373 (14), 275 (77), 263 (21), 260
(17), 232 (38), 231 (21), 145 (15), 115 (15), 104 (14), 91 (14), 77 (71). Anal.
Calcd. for C24H19ClN2OS: C, 68.81; H, 4.57; N, 6.69. Found: C, 68.98; H, 4.68; N,
6.71. E–2a: 1H NMR (400 MHz, CDCl3, d): 6.69 (d, J = 15.5, 1H), 7.33 (dd, J = 7.4,
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Please cite this article in press as: Padilha, G.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.063

G. Padilha et al. / Tetrahedron Letters xxx (2016) xxx–xxx
5
7.5, 1H), 7.43 (d, J = 15.5, 1H), 7.44–7.47 (m, 5H), 7.48–7.56 (m, 3H), 7.68 (dd,
J = 1.4, 7.5, 4H), 7.74 (dd, J = 1.0, 8.4, 2H), 8.14 (s, 1H). 13C NMR (100 MHz,
CDCl3, d): 116.6, 119.2, 124.5, 126.4, 127.1, 127.9, 128.5, 128.6, 128.7, 129.3,
129.5, 130.9, 132.1, 132.3, 139.3, 144.2, 152.7 MS (m/z, rel. int.%): 370 (1) [M]+,
354 (20), 323 (26), 322 (99), 321 (38), 261 (13), 245 (48), 244 (30), 243 (15),
233 (15), 219 (14), 218 (19), 217 (18), 216 (16), 142 (11), 115 (30), 104 (18), 77
(100). Anal.Calcd.for C23H18N2OS: C, 74.57; H, 4.90; N, 7.56. Found: C, 74.78; H,
4.92; N, 7.58. E–3f: 1H NMR (400 MHz, CDCl3, d): 3.89 (s, 3H), 6.66 (d, J = 15.3,
1H), 7.03 (d, J = 8.7, 2H), 7.35 (t, J = 7.4, 1H), 7.47 (dd, J = 7.4, 8.0, 2H), 7.52 (d,
J = 8.6, 2H), 7.56 (d, J = 8.7, 2H), 7.72 (d, J = 15.3, 1H), 7.73 (d, J = 8.0, 2H), 7.85
(d, J = 8.6, 2H), 8.19 (s, 1H). 13C NMR (100 MHz, CDCl3, d): 55.3, 114.4, 115.1,
119.3, 124.1, 125.2, 127.3, 127.4, 128.9, 129.5 (2C), 129.9, 134.0, 139.1, 139.7,
139.8, 153.4, 160.3. MS (m/z, rel. int.%): 452 (15), 450 (38) [M]+, 276 (20), 275
(100), 271 (69), 260 (18), 259 (13), 232 (41), 231 (38), 145 (13). Anal. Calcd. for
C24H19ClN2O3S: C, 63.92; H, 4.25; N, 6.21. Found: C, 63.67; H, 4.32; N, 6.16.
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Karukurichi, K. R.; de la Salud-Bea, R.; Jahng, W. J.; Berkowitz, D. B. J. Am. Chem.
Soc. 2007, 129, 258.
Please cite this article in press as: Padilha, G.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.06.063