A one-pot stereoselective synthesis of electron-deficient 4-substituted (E, E)-1-arylsulfonylbuta-1,3-dienes and their chemoselective [3+2] cycloaddition with azomethine ylides - A simple synthesis of 1,3,4-trisubstituted pyrrolidines and pyrroles

Article abstract of DOI:10.1055/s-0033-1339181

A simple and efficient method for the synthesis of (E,E)-1-(arylsulfonyl) buta-1,3-dienes bearing electron-withdrawing substituents like cyano and ethoxycarbonyl at position 4, involving a one-pot alkylation of bis(phenylsulfonyl)methane with trans-ethyl 4-bromocrotonate/trans-4- bromocrotononitrile, and elimination of arylsulfinic acid, is described. These dienes undergo facile mono [3+2] cycloaddition with azomethine ylides chemoselectivity to furnish functionalized 1,3,4-trisubstituted pyrrolidines. Oxidation of these cycloadduct with MnO₂·SiO₂ under mild conditions provides 1,3,4-trisubstituted pyrroles. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339181

LETTER
▌1533
lAetteOr ne-Pot Stereoselective Synthesis of Electron-Deficient 4-Substituted (E,E)-
1-Arylsulfonylbuta-1,3-dienes and Their Chemoselective [3+2] Cycloaddition
with Azomethine Ylides – A Simple Synthesis of 1,3,4-Trisubstituted Pyrroli-
dines and Pyrroles
1,3,4-Trisubstituted Pyrrolidines and Pyrroles
Ulaganathan Sankar,a Susarla Mahalakshmi,a Kalapattu Kuppuswamy Balasubramanian*b
a
Department of Chemistry, Pachaiyappa’s College, University of Madras, Chennai – 600 030, India
b
Department of Chemistry, B.S. Abdur Rahman University, Chennai – 600 048, India
E-mail: kkbalu@hotmail.com
Received: 17.04.2013; Accepted after revision: 13.05.2013
these dienes. Substituted pyrrolidines and pyrroles are the
Abstract: A simple and efficient method for the synthesis of (E,E)-
central skeleton for numerous alkaloids and constitute
1-(arylsulfonyl)buta-1,3-dienes bearing electron-withdrawing sub-
classes of compounds with significant biological activi-
stituents like cyano and ethoxycarbonyl at position 4, involving a
one-pot alkylation of bis(phenylsulfonyl)methane with trans-ethyl
ty.5–7 Since [3+2]-cycloaddition reactions exhibit high
4-bromocrotonate/trans-4-bromocrotononitrile, and elimination of stereospecificity, they are popular for the rapid assembly
of five-membered heterocyclic motifs.8
arylsulfinic acid, is described. These dienes undergo facile mono
[3+2] cycloaddition with azomethine ylides chemoselectivity to
furnish functionalized 1,3,4-trisubstituted pyrrolidines. Oxidation
Intermolecular [3+2]-cycloaddition reaction of azome-
thine ylides with alkenes or alkynes as dipolarophile has
resulted in a number of novel heterocyclic scaffolds which
are particularly useful for the creation of diverse chemical
libraries of druglike molecules for biological screening.8,9
The 1,3-dipolar cycloaddition of azomethine ylide to elec-
tron-deficient alkenes is one of the most powerful meth-
ods for the construction of highly substituted pyrrolidine
rings.10 Such cycloaddition reactions have been utilized
for the preparation of compounds that are of fundamental
importance in diverse fields of chemistry. 1,3,4-Trisubsti-
tuted pyrrolidines containing acidic functionality at the N-
position act as potent CCR5 receptor antagonists with ex-
cellent anti-HIV activity in vitro.11 Surprisingly, there are
only a few reports on trisubstituted pyrrolidines.12,13
of these cycloadduct with MnO2·SiO2 under mild conditions pro-
vides 1,3,4-trisubstituted pyrroles.
Key words: (E,E)-1-arylsulfonylbuta-1,3-diene, azomethine ylide,
chemoselective cycloaddition, 1,3,4-trisubstituted pyrrolidines,
1,3,4-trisubstituted pyrroles
(E,E)-1,4-Diarylsulfonylbuta-1,3-dienes and 4-substitut-
ed (E,E)-1-arylsulfonylbuta-1,3-dienes have attracted
considerable attention as versatile building blocks.1a Sul-
fonyl dienes serve efficiently as both Michael acceptors
and as 2π partners in cycloaddition reactions.1b In Diels–
Alder-type2 cycloaddition reactions, vinyl sulfones serve
as synthetic equivalents for ethylene, acetylene, ketene,1b
etc. There are only a few reports on the synthesis 1,4-dia-
rylsulfonylbuta-1,3-diene and 4-substituted (E,E)-1-aryl-
sulfonylbuta-1,3-dienes and all these involve a multistep
synthesis.3,4 Hence there is a need for the development of
more efficient methods for the stereoselective synthesis of
In this communication we describe a simple method for
the synthesis of (E,E)-1-arylsulfonyl-4-cyanobuta-1,3-di-
ene and (E,E)-1-arylsulfonyl-4-ethoxycarbonylbuta-1,3-
dienes, 1,3,4-trisubstituted pyrrolidines, and 1,3,4-trisub-
stituted pyrroles based on cycloaddition strategy (Scheme
O
O
O
S
O
S
O
S
O
OEt
(E)
(E)
OEt
O
OEt
O
4
O
MnO2⋅SiO2
1,3-dipolar
cycloaddition
N
R
N
R
alkylative
elimination
5
6
O
S
O
S
1. alkylation
2. oxidation
SH
O
O
3
1
Scheme 1 Retrosynthetic strategy for the synthesis of 1,3,4-trisubstituted pyrrole frameworks
SYNLETT 2013, 24, 1533–1540
Advanced online publication: 11.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339181; Art ID: ST-2013-B0354-L
© Georg Thieme Verlag Stuttgart · New York

1534
U. Sankar et al.
LETTER
R2
(E)
O
R2 = CO2Et, CN
S (E)
R1
O
4a–i
O
S
O
S
SH
a
(E)
S
S
R1
b
Br
R1
R2
R2 = H, Me
R1
R1
O O
O
O
c
S
S
R1
R1
R1
O
O
1a–h
2a–h
3a–h
(E)
R2
R1 = H, 4-OMe, 4-Cl, 4-Br, 3-Br, 2,4-Cl2, 3,4-Cl2, 2,4-F2
R2 = CO2Et, CN, H, Me
5a–d
R1
X
O
R1
O
S
S
O
O
R2
6a–i
Scheme 2 Reagents and conditions: (a) NaOH, EtOH, CH2I2, 60 °C, 2 h; (b) H2O2, AcOH, 100 °C, 5 h; (c) 3a–h (1 equiv), LHMDS
(2.5 equiv), electrophile (1.1 equiv), THF, –15 °C to r.t., 24 h.
1). Backvall et al. and Baker-Glenn et al.14 have reported the reaction stopped with the alkylation step, furnishing
the elimination of benzenesulfinic acid from alkyl aryl the alkylated bissulfones 5a–d (Scheme 2). From this re-
sulfones using KOSiMe3 as base. A few other bases like sult it is clear that electron-withdrawing groups like CO2R
KOt-Bu and NaOMe have also been used to bring about and CN on the electrophile are required to facilitate the
the elimination of arylsulfinic acid15 (references cited elimination of arylsulfinic acid (Table 1). The structures
1
therein for other conditions). Our synthesis of 1,4-disub- of the aryl sulfonyl dienes 4a–i were confirmed by H
stituted 1,3-dienes 4a–i involves a one-pot alkylation of NMR and 13C NMR spectroscopy.
bisarylsulfonyl methane16 3a–h with ethyl 4-bromocro-
tonate, followed by elimination of arylsulfinic acid as out-
lined in Scheme 2.
Studies reported in the literature on the reactivity of 1-ar-
ylsulfonyl and (E,E)-1,4-diarylsulfonylbuta-1,3-dienes
have been limited to only conjugate additions.12,13 The
Treatment of bis(arylsulfonyl)methanes 3a–h with trans- easy access to (E,E)-1-arylsulfonylbuta-1,3-dienes
ethyl 4-bromocrotonate/trans-4-bromocrotononitrile in prompted us to explore the synthesis of highly trisubstitut-
the presence of LHMDS afforded the corresponding hith- ed pyrrolidines involving a mono [3+2] cycloaddition
erto unknown 1,4-disubstituted (E,E)-buta-1,3-dienes 4a– with azomethine ylides as envisaged in Scheme 3 and
i in good yields (Table 1).17 It is interesting to note that, in their further conversion into trisubstituted pyrroles as de-
our case, the reaction pathway leading to cyclopropane picted in Scheme 4. Blumberg et al.12 have reported the
products 6a–i via Michael addition followed by intramo- chemoselective 1,3-dipolar cycloaddition of azomethine
lecular alkylation, or vice versa, encountered in the litera- ylide with a few electron-deficient conjugated dienes, and
ture in similar reactions,18 was not observed. The Beugelmans et al.13 have investigated the 1,3-dipolar cy-
stereochemistry of these dienes was deduced from the 1H cloaddition of azomethine ylide (generated from N-oxide)
1
NMR coupling constants of the olefinic protons. The H with a few electron-rich conjugated dienes. In both cases,
NMR spectrum of 4a exhibited signals at δ = 1.25 (t, 3 H), the reactions led to a mixture of mono- and bispyrro-
4.19 (m, 2 H), 6.25 (d, 1 H, J = 14.94 Hz), 6.66 (d, 1 H, lidines. There are no other reports on the 1,3-dipolar cy-
J = 14.43 Hz), 7.18 (m, 2 H), and 7.54–7.92 (m, 5 H) ppm. cloaddition of azomethine ylides to electron-deficient
The alkene SO2CH=CHCH=CHCO2 proton α to sulfonyl conjugated dienes. According to Merino et al.20a phenyl
resonated at δ = 6.25 (d, 1 H, J = 14.94 Hz) ppm and the vinyl sulfone and ethyl acrylate exhibit the same reactivi-
signal due to proton δ to the sulfonyl was observed at δ = ty, selectivity, and yields towards [3+2] cycloaddition of
6.66 (d, 1 H, J = 14.43 Hz) ppm whereas the signals due nitrone azomethine ylides. However, according to Gonza-
to protons β and γ to the sulfonyl were observed as multi- lez et al. and Carretero et al.20b,c phenyl vinyl sulfone gives
plet at δ = 7.18. A single-crystal X-ray diffraction further better yield and selectivity than ethyl acrylate towards
confirmed the assigned structure.19
[3+2] cycloaddition of α-iminoamides, Tsuge et al.20d
have reported that ethyl acrylate gives better result than
phenyl vinyl sulfone towards decarboxylative cycloaddi-
tion. Thus it is clear that the reactivity of the dipolarophile
is highly influenced by the nature of azomethine ylides.
Houk et al.21 have reported the HOMO–LUMO calcula-
The reaction was highly stereoselective and only the E,E-
isomer was formed. No evidence could be seen in the 1H
NMR spectra of the crude products for the presence of any
other stereoisomer. In the case of a less reactive electro-
phile like 3-bromopropene and 4-bromo-trans-but-2-ene,
Synlett 2013, 24, 1533–1540
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3,4-Trisubstituted Pyrrolidines and Pyrroles
1535
Table 1 4-Substituted (E,E)-1-Arylsulfonylbuta-1,3-dienes
Entry
1
Substrates 3
Products 4a,c
Yield (%)b
O
O
S
O
S
(E)
(E)
S
OEt
75
O
O
O
O
3a
4a
O
S
O
O
S
(E)
(E)
OEt
S
O
O
O
2
3
4
5
6
7
72
62
67
75
65
77
O
MeO
MeO
OMe
4b
3b
O
O
S
O
S
(E)
(E)
S
OEt
O
O
O
O
Br
Br
Br
4c
3c
O
S
O
S
O
S
(E)
(E)
Br
Br
Br
OEt
OEt
O
O
O
O
O
3d
4d
O
S
O
S
O
S
(E)
(E)
O
O
O
Cl
Cl
Cl
Cl
3e
4e
Cl
O
S
O
S
Cl
Cl
O
S
(E)
(E)
OEt
OEt
O
O
O
O
O
Cl
Cl
4f
3f
O
S
O
S
O
S
(E)
(E)
Cl
Cl
Cl
Cl
O
O
O
Cl
Cl
4g
3g
F
O
F
O
O
F
(E)
(E)
S
OEt
S
S
O
O
O
8
9
74
65
O
F
F
F
3h
4h
O
S
O
S
O
S
(E)
(E)
CN
O
O
O
3a
4i
a All reactions were carried out on 1 mmol scale of bis(arylsulfonyl)methanes 3a–h with 1.1 mmol of trans-ethyl 4-bromocrotonate/trans-4-
bromocrotononitrile and 2.5 mmol of LHMDS in THF at –15 °C to r.t., 24 h.
b Isolated yield of the pure product.
c All the compounds are fully characterized by their spectroscopic data (1H NMR, 13C NMR, and LC–MS).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1533–1540

1536
U. Sankar et al.
LETTER
O
OEt
Ha
Hb
Hc
R3
O
S
Hf
(E)
O
He
Hd
N
MeO
N
R3
SiMe3
R1
8a–h
O
S
7a–c
(E)
(E)
OEt
TFA, CH2Cl2
R3 = t-Bu, c-Pen, Bn
O
O
O
R1
OEt
4a–h
(E)
O
S
O
R1
N
R3
9a–h
Scheme 3 Reagents and conditions: (a) 4a–h (1 equiv), 7a–c (1. 5 equiv), TFA (0.1 equiv), CH2Cl2, 0 °C to r.t., 30 min.
tion for a lot of electronegative alkenes. According to their lent yield (Table 2) as a single diastereomer, whose purity
FMO calculation, the orbital coefficient of LUMO for eth- was checked by HPLC. No evidence could be seen in the
yl acrylate is higher than that of phenyl vinyl sulfone. As 1H NMR spectra of the crude products for the presence of
per their report, carboxylate is a more powerful electron- the isomer 9a arising from addition to the vinyl sulfonyl
withdrawing group compared to that of the phenylsulfo- double bond. Analysis of the crude product by LC–MS
nyl group. Hence one could expect that in the case of showed the presence of <5% of the biscycloadduct. All
monocycloaddition of azomethine ylides to the dienes 4a– the cycloadduct gave satisfactory elemental analyses. The
h, the reaction might exhibit high chemoselectivity and structure of the trisubstituted pyrrolidine adduct 8a was by
would take place at the acrylate double bond leading to the supported by 1H NMR, 13C NMR, and H–H COSY spec-
adducts 8a–j. Against this literature background, we in- troscopy. The 1H NMR spectrum of 8a exhibited a doublet
vestigated the chemoselectivity of the cycloaddition of at δ = 6.30 (d, 1 H, J = 15.80 Hz) ppm for SO2CH=CHCH
azomethine ylides 7a–c with the dienes 4a–h. Azome- proton α to sulfonyl and SO2CH=CHCH proton β to sul-
thine ylides are one of the most common 1,3-dipoles ex- fonyl appeared as a dd at δ = 6.89 (dd, 1 H, J = 15.04 Hz)
tensively investigated both from the synthetic and ppm. The Ha proton of the pyrrolidine moiety resonated at
theoretical point of view.8 Azomethine ylides are unstable δ = 2.72 (m, 1 H) ppm, the Hb and Hc protons resonated at
species which are generated in situ. A number of methods δ = 2.80 (t, 1 H, J = 7.52 Hz) and 2.96 (t, 1 H, J = 8.80 Hz)
have been developed for the generation of azomethine ppm, the Hd and He protons resonated at δ = 2.87 (t, 1 H,
ylides.22 We have studied the cycloaddition reaction of the J = 8.68 Hz) and 2.53 (t, 1 H, J = 7.68 Hz), respectively,
dienes 4a with azomethine ylides generated in situ from and the Hf proton resonated at δ = 3.08 (m, 1 H) ppm. In
the N-alkyl-N-(methoxymethyl)-N-(trimethylsilylmethyl) the H–H COSY spectrum of 8a, coupling between Ha and
amines in dichloromethane in the presence of trifluoro- Hf is very weak. This proved that both protons are trans to
acetic acid.23 The azomethine precursors 7a–c were pre- each other. The 13C NMR spectrum of 8a exhibited a
pared by N-alkylation of benzylamine, cyclopentylamine, downfield shift for the carbonyl signal at δ = 172.85 ppm
and tert-butylamine with chloromethyl trimethylsilane in comparison to that of the starting diene (δ = 165.51
followed by reaction with formaldehyde and potassium ppm), in accordance with the proposed structure. A com-
carbonate in methanol as described in the literature.24
parison of the chemical shift of the olefinic protons of the
starting diene and that of the product clearly reveal that
addition has taken place on the double bond connected to
the carboxylic ester. A trans stereochemistry has been as-
signed based on the syn nature of such [3+2]-cycloaddi-
tion reactions and literature reports. Padwa et al.26
reported the 1,3-dipolar cycloaddition reaction of 7c with
dimethyl fumarate and dimethyl maleate that proceeded
with complete stereospecificity. The chemoselectivity ob-
served, in favor of acrylate double bond over vinyl sulfone
double bond in these mono [3+2] cycloaddition of azome-
thine ylides to 4-substituted (E,E)-1-arylsulfonylbuta-1,3-
dienes, is in accordance with the predictions of Houk et
al.19 and provide an easy access to the synthesis of highly
functionalized 1,3,4-trisubstituted pyrrolidines. In light of
the observations of Gonzalez et al. and Carretero et al.20b,c
it would be worthwhile to look into the chemoselectivity
O
O
OEt
OEt
MnO2⋅SiO2
O
S
O
S
(E)
(E)
O
O
N
N
R3
R3
10a–c
8a–c
Scheme 4 Reagents and conditions: (a) 8a–c (1 equiv), MnO2·SiO2
(freshly prepared, 5 equiv), 1,4-dioxane, reflux, 5 h.
Azomethine ylides were generated in situ by treatment of
the amines 7a–c with trifluoroacetic acid, in the presence
of diene 4a in dichloromethane at 0 °C to room tempera-
ture.25 A facile reaction was observed in all the cases, and
the reaction was over in 30 minutes, furnishing the func-
tionalized 1,3,4-trisubstituted pyrrolidines 8a–j in excel-
Synlett 2013, 24, 1533–1540
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3,4-Trisubstituted Pyrrolidines and Pyrroles
1537
as well as the regioselectivity of the mono [3+2] cycload- roles 10a–c bearing an (E)-aryl sulfonyl vinyl moiety
dition of these dienes with stabilized azomethine ylides.
have been synthesized in good yields (Table 3) from
1,3,4-trisubstituted pyrrolidines 8a–c via oxidative dehy-
drogenation by using active MnO2·SiO2.29 When the cy-
cloadducts 8a–c were treated with activated MnO2 on
silica in dry 1,4-dioxane under an argon atmosphere they
were smoothly converted into the respective 1,3,4-trisub-
stituted pyrroles 10a–c30 in good yields (Table 3).
Synthesis of highly functionalized and substituted pyr-
roles is an attractive area of research in heterocyclic
chemistry. Introduction of vinylsulfone at 3- (or) 4-posi-
tions of the pyrroles is a challenging task. Liu et al.27 and
Gaunt et al.28a,b have reported the synthesis of 3-vinyl
pyroles through Heck coupling. 1,3,4-Trisubstituted pyr-
Table 2 Synthesis of 1,3,4-Trisubstituted Pyrrolidines 8a–h
Entry
Azomethine precursor
Dienes 4
Products 8a,c
Yield (%)b
O
OEt
O
(E)
S
MeO
N
SiMe3
O
1
4a
85
N
7a
8a
O
OEt
O
S
(E)
MeO
N
SiMe3
O
N
2
4a
70
7b
8b
8c
O
OEt
O
S
(E)
MeO
N
SiMe3
O
Bn
3
4
5
6
4a
4b
4c
4d
83
82
79
86
N
7c
Bn
O
OEt
Bn
O
S
(E)
O
7c
7c
7c
N
MeO
8d
O
OEt
O
(E)
S
O
N
Br
Bn
8e
O
OEt
O
S
(E)
Br
O
N
Bn
8f
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1533–1540

1538
U. Sankar et al.
LETTER
Table 2 Synthesis of 1,3,4-Trisubstituted Pyrrolidines 8a–h (continued)
Entry
Azomethine precursor
Dienes 4
Products 8a,c
Yield (%)b
O
O
O
OEt
O
S
(E)
(E)
(E)
7
7c
4e
74
O
N
N
N
Cl
Bn
8g
OEt
Cl
O
S
O
8
9
7c
7c
7c
4f
78
83
80
Cl
Bn
8h
OEt
O
S
Cl
O
4g
4h
Cl
Bn
8i
O
OEt
F
O
(E)
S
O
10
N
F
Bn
8j
a All reactions were carried out on 1 mmol scale of 1,4-disubstituted diene 4a–h with 1.5 mmol of azomethine ylide precursor and 0.1 mmol of
TFA in CH2Cl2 at 0 °C to r.t., 30 min.
b Isolated yield of the pure product.
c All the compounds are fully characterized by their spectroscopic data (1H NMR, 13C NMR, and LC–MS).
Table 3 Synthesis of 1,3,4-Trisubstituted Pyrroles 10a–c
Acknowledgement
1,3,4-Trisubstrituted Products 10a,c
pyrrolidines 8a
Yield (%)b
The authors thankful to the Principal, Pachaiyappa’s College (Affi-
liated to the University of Madras) for providing the facilities for the
work.
Entry
1
2
3
8a
8b
8c
10a
10b
10c
68
73
76
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
a All reactions were carried out on 1 mmol scale of 1,3,4-trisubstituted
pyrrolidine with 5 mmol MnO2·SiO2 in 1,4-dioxane at reflux, 5 h.
b Isolated yield of the pure product.
References and Notes
(1) For reviews of sulfonyl diene in organic synthesis, see:
(a) Bäckvall, J.-E.; Chinchilla, R.; Nájera, C.; Yus, M.
Chem. Rev. 1998, 98, 2291. (b) Simpkins, N. S. Tetrahedron
1990, 46, 6984.
c All the compounds are fully characterized by their spectroscopic
data (1H NMR, 13C NMR, and LC–MS).
(2) Overman, L. E.; Petty, C. B.; Ban, T.; Huang, G. T. J. Am.
Chem. Soc. 1983, 105, 6335.
(3) (a) Wang, X.; Ni, Z.; Lu, X.; Hollis, A.; Banks, H.;
Rodriguez, A.; Padwa, A. J. Org. Chem. 1993, 58, 5377.
(b) Xiaojin, L.; Lantrip, D.; Fuchs, P. L. J. Am. Chem. Soc.
2003, 125, 14262.
(4) Bunce, R. A.; Wamsley, E. J.; Pierce, J. D.; Shellhammer, A.
J.; Drumright, R. E. J. Org. Chem. 1987, 52, 464.
(5) (a) Alkaloids: Chemical and Biological Perspectives;
Monlineux, R. J.; Pelletier, S. W., Eds.; Wiley: New York,
1987, Chap. 1. (b) Liu, J.-H.; Chan, H.-W.; Wong, H. N. C.
J. Org. Chem. 2000, 65, 3274.
In summary, we have developed a simple and efficient
one-pot synthesis for electron-deficient 4-substituted
(E,E)-1-arylsulfonylbuta-1,3-dienes. These dienes under-
go facile 1,3-dipolar cycloaddition with various unactivat-
ed azomethine ylides to give 1,3,4-trisubstituted
pyrrolidines in excellent yields. These trisubstituted pyr-
rolidines undergo oxidative aromatization to furnish
1,3,4-trisubstituted pyrroles.
Synlett 2013, 24, 1533–1540
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LETTER
1,3,4-Trisubstituted Pyrrolidines and Pyrroles
solid with 75% yield; mp 71.5–72.5 °C.
1539
(6) Fujimori, S. JP 88-2912, 1990; Chem. Abstr. 1990, 112,
98409.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.92 (m, 5 H), 7.18
(m, 2 H), 6.66 (d, 1 H, J = 14.43 Hz,), 6.25 (d, 1 H, J = 14.94
Hz), 4.19 (q, 2 H, J = 7.14 Hz, CH2CH3), 1.25 (t, 3 H,
J = 7.11 Hz, CH2CH3) ppm. 13C NMR (75 MHz, DMSO-d6):
δ = 165.51, 140.23, 139.22, 138.54, 134.47, 130.24, 127.77,
126.95, 119.40, 60.96, 14.48 ppm. DEPT-NMR (75 MHz,
CDCl3): δ = 139.23, 137.70, 134.49, 130.90, 130.25, 127.78.
60.97, 14.48 ppm. LC–MS: m/z = 267.1 [M+ + 1]. Anal.
Calcd for C13H14O4S: C, 58.63; H, 5.30; S, 12.04. Found: C,
58.52; H, 5.36; S, 11.98.
(7) (a) Wagner, G. Chem. Eur. J. 2003, 9, 1503. (b) Sun, X. M.;
Wang, M. H.; Liu, P.; Bian, W. S.; Feng, D. C.; Cai, Z. T. J.
Mol. Struct. (Theochem) 2004, 73, 679. (c) Domingo, L. R.;
Arno, M.; Merino, P.; Tejero, T. Eur. J. Org. Chem. 2006,
3464. (d) Merino, P.; Tejero, T.; Chiacchio, U.; Romeo, G.;
Rescifina, A. Tetrahedron 2007, 63, 1448.
(8) For reviews on 1,3-dipolar cycloaddition on nonstablized
azomethine ylides, see: (a) Harwood, L. M.; Vickers, R. J.
Synthetic Application of 1,3-Dipolar Cycloaddition
Chemistry toward Heterocycles and Naturals Products; Vol.
59; Padwa, A.; Pearson, W. H., Eds.; Wiley: New York,
2002, 169–252. (b) Padwa, A. 1,3-Dipolar Cycloaddition
Chemistry; Vol. 1 and 2; Wiley: New York, 1984.
(9) Grigg, R.; Sridharan, V. In Advances in Cycloaddition; Vol.
3; Curran, D. P., Ed.; JAI Press: London, 1993, 161.
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Ed. 2005, 44, 6272; Angew. Chem. Int. Ed. 2005, 117, 6428.
(b) Gothelf, K. V. In Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S.; Jorgensen, K. A., Eds.; Wiley-
VCH: Weinheim, 2002, 211. (c) Gothelf, K. V.; Jorgensen,
K. A. Chem. Rev. 1998, 98, 863. (d) Gothelf, K. V.;
Jørgensen, K. A. Chem.Commun. 2000, 1449. (e) Pandey,
G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
(11) (a) Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.;
Chapman, K. T.; Mills, S. G.; MacCoss, M.; Malkowitz, L.;
Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano, S.
J.; Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Emini, E. A. Bioorg. Med. Chem.
Lett. 2002, 12, 3001. (b) Hale, J. J.; Budhu, R. J.; Mills, S.
G.; MacCoss, M.; Malkowitz, L.; Siciliano, S.; Gould, S. L.;
DeMartino, J. L.; Springer, M. S. Bioorg. Med. Chem. Lett.
2001, 11, 1437.
(18) Prempree, P.; Radviroongit, S.; Thebtaranonth, Y. J. Org.
Chem. 1983, 48, 3553.
(19) Sankar, U.; Sabari, V.; Suresh, G.; Uma, R.; Aravindhan, S.
Acta Crystallogr., Sect. E.: Struct. Rep. Online 2012, 68,
o1093.
(20) (a) Merino, P.; Tejero, T.; Diez-Martinez, A.; Gultekin, Z.
Eur. J. Org. Chem. 2011, 6567. (b) Gonzalez-Esguevillas,
M.; Adrio, J.; Carretero, C. J. Chem. Commun. 2012, 48,
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47, 6784. (d) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka,
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(21) (a) Houk, K. N. In Pericyclic Reactions; Vol. 2; Marchand,
A. P.; Lehr, R. E., Eds.; Academic Press: New York, 1977,
203. (b) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J.
J. Am. Chem. Soc. 1973, 95, 7301.
(22) (a) Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362.
(b) Kurkin, A. V.; Sumtsova, E. A.; Yurovskaya, M. A.
Chemistry of Heterocyclic Compounds 2007, 43, 1.
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(25) General Procedure for the Synthesis of (3S,4R)-Ethyl 1-
tert-Butyl-4-[(E)-2-(phenylsulfonyl)vinyl]pyrrolidine-3-
carboxylate (8a)
(12) Blumberg, L. C.; Costa, B.; Goldstein, R. Tetrahedron Lett.
2011, 52, 872; and references cited therein for cycloaddition
chemistry.
(13) Beugelmans, R.; Benadjila, I. L.; Chastanet, J.; Negron, G.;
Roussi, G. Can. J. Chem. 1958, 63, 725.
TFA (0.38 mmol) in CH2Cl2 (1 mL) was added to a stirred
solution of (E,E)-1-arylsulfonyl-4-ethoxycarbonylbuta-1,3-
diene (4a, 3.8 mmol) and N-(methoxymethyl)-N-
[(trimethylsilyl)methyl]tert-butylamine (7a, 4.7 mmol) in
anhyd CH2Cl2 (15 mL) at 0 °C under N2 atmosphere, the
reaction mixture was allowed to warm to r.t. and stirred for
30 min. After completion of reaction (monitored by TLC),
the reaction mixture was quenched with a 10% aq solution of
NaHCO3 (30 mL) and extracted with CH2Cl2 (2 × 30 mL),
washed with H2O (30 mL) and brine (30 mL), and the
organic layer was dried over MgSO4. The solvent was
evaporated under vacuum, and the crude product was
subjected to column chromatography (25% EtOAc in
n-hexane) to yield analytically pure (3S,4R)-ethyl 1-tert-
butyl-4-[(E)-2-(phenylsulfonyl)vinyl]pyrrolidine-3-
carboxylate (8a) as a pale yellow gummy liquid; yield 76%.
1H NMR (400 MHz, CDCl3): δ = 7.79 (m, 2 H), 7.45–7.57
(m, 3 H), 6.89 (dd, 1 H, J = 15.0 Hz), 6.30 (d, 1 H, J = 15.8
Hz), 4.01 (q, 1 H, J = 7.2 Hz), 3.08 (m, 1 H), 2.96 (t, 1 H,
J = 8.8 Hz), 2.87 (t, 1 H, J = 8.7 Hz), 2.80 (t, 1 H, J = 7.5
Hz), 2.72 (q, 1 H, J = 7.8 Hz), 2.55 (t, 1 H, J = 7.7 Hz), 1.18
(t, 3 H, J = 7.1 Hz), 1.08 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.85, 146.98, 140.37, 133.28, 130.75, 129.19,
127.54, 60.90, 52.37, 51.14, 49.06, 48.15, 43.04, 25.75,
14.02 ppm. DEPT-NMR (100 MHz, CDCl3): δ = 133.80,
133.42, 128.97, 128.80, 125.31, 121.68, 60.23, 30.37, 14.42
ppm. LC–MS (EI): m/z = 366.1 [M + 1]. Anal. Calcd for
C19H27NO4S: C, 62.44; H, 7.45; S, 8.77; N, 3.83. Found: C,
62.53; H, 7.37; S, 8.92; N, 3.93.
(14) (a) Baker-Glenn, C. A. G.; Anthony, G. M.; Barrett, A. G.
M.; Gray, A. A.; Procopiou, P. A.; Ruston, M. Tetrahedron
Lett. 2005, 46, 7427. (b) Plobeck, N. A.; Backvall, J. E. J.
Org. Chem. 1991, 56, 4508. (c) Backvall, J. E.; Ericsson, A.
M.; Plobeck, N. A.; Juntunen, S. K. Tetrahedron Lett. 1992,
33, 131.
(15) Vedejs, E.; Little, J. D. J. Org. Chem. 2004, 69, 1794.
(16) Cao, Y.-J.; Lai, Y.-Y.; Cao, H.; Xing, X.-N.; Wang, X.;
Xiao, W.-J. Can. J. Chem. 2006, 84, 1529.
(17) General Procedure for the Synthesis of (2E,4E)-Ethyl 5-
(Phenylsulfonyl)penta-2,4-dienoate (4a)
LHMDS (8.4 mmol, 1.06 M solution in THF) was added
dropwise to a –15 °C cooled solution of bis(phenylsulfonyl)-
methane (3a, 3.4 mmol) in distilled THF (15 mL) under
argon. After being stirred at –15 °C for 1 h, trans-ethyl 4-
bromocrotonate (3.7 mmol) in distilled THF (5 mL) was
added dropwise over the period of 10 min and the reaction
mixture was cooled to r.t. over a period of 1–2 h and stirred
at r.t. for 24 h. The reaction mixture was quenched with sat.
NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL),
washed with H2O (2 × 20 mL) and brine (20 mL), and the
organic layer was dried over MgSO4. Evaporation of the
solvent under vacuum furnished the desired crude product.
The crude product was purified by column chromatography
on silica gel (230–400 mesh) with 17–20% of EtOAc in
hexane afforded the corresponding product (2E,4E)-ethyl 5-
(phenylsulfonyl)penta-2,4-dienoate (4a) as a colourless
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1533–1540

1540
U. Sankar et al.
LETTER
stirred at reflux for 5 h (monitored by TLC), the reaction
mixture was filtered through a pad of Celite, and the pad was
washed with 1,4-dioxane. Evaporation of the filtrate under
vacuum furnished the crude product, which was subjected to
column chromatography (25% EtOAc in n-hexane) to yield
analytically pure ethyl 1-tert-butyl-4-[(E)-2-(phenylsulfonyl)-
vinyl]-1H-pyrrole-3-carboxylate (10a) as a pale yellow
gummy liquid in 68% yield.
(26) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235.
(27) Liu, J. H.; Chan, H. W.; Wong, H. N. C. J. Org. Chem. 2000,
65, 3274.
(28) (a) Fiatiadi, A. J. Synthesis 1976, 65, 133. (b) Beck, E. M.;
Grimster, N. P.; Hatley, H.; Gaunt, M. J. J. Am. Chem. Soc.
2006, 128, 2528. (c) Beck, E. M.; Hatley, H.; Gaunt, M. J.
Angew. Chem. Int. Ed. 2008, 47, 3004.
(29) Boualem, Q.; Bernard, G.; Mohammed, M. Can. J. Chem.
1994, 72, 2483.
(30) General Procedure for the Synthesis of Ethyl 1-tert-
Butyl-4-[(E)-2-(phenylsulfonyl)vinyl]-1H-pyrrole-3-
carboxylate (10a)
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, 1 H, J = 15.4 Hz),
7.93 (m, 2 H), 7.51 (m, 4 H), 7.11 (s, 1 H), 6.98 (d, 1 H,
J = 15.4 Hz), 4.26 (q, 2 H), 1.38 (s, 9 H), 1.34 (t, 3 H) ppm.
13C NMR (400 MHz, CDCl3): δ = 164.13, 138.47, 133.73,
133.34, 128.89, 128.73, 125.23, 121.60, 116.08, 116.04,
60.15, 56.78, 30.29, 14.36 ppm. LC–MS (EI): m/z = 384.4
[M+ + Na]. Anal. Calcd for C19H23NO4S: C, 63.13; H, 6.41;
S, 8.87; N, 3.88. Found: C, 63.47; H, 6.47; S, 8.52; N, 3.68.
Activated MnO2 on silica (13.7 mol, freshly prepared) was
added to a stirred solution of ethyl 1-tert-butyl-4-[(E)-2-
(phenylsulfonyl)vinyl]pyrrolidine-3-carboxylate (8a, 2.74
mol) in anhyd 1,4-dioxane (20 mL) under argon. After being
Synlett 2013, 24, 1533–1540
© Georg Thieme Verlag Stuttgart · New York