A radical cascade cyclization to prepare dihydrothiophenes induced by thiyl radicals as sulfur biradical equivalents

Article abstract of DOI:10.1021/jo400975t

Bicyclic dihydrothiophenes are readily prepared by a radical cascade cyclization reaction triggered by the addition of a thiyl radical under thermal or photoirradiation conditions. The translocated radical attacks the sulfur atom in the initial radical donor unit in an S_Hi manner. Sufficient stereoselectivity is achieved when a large excess of disulfide is used for the reaction under photoirradiation conditions. The reaction in the absence of solvents provides vinylsulfides instead of dihydrothiophenes. Thus, the sulfur atom in the thiyl radical serves as a sulfur biradical synthetic equivalent.

Full text of DOI:10.1021/jo400975t

Article
pubs.acs.org/joc
A Radical Cascade Cyclization To Prepare Dihydrothiophenes
Induced by Thiyl Radicals as Sulfur Biradical Equivalents
Akio Kamimura,*,† Koichiro Miyazaki,† Yu Yamane,† Ryuichiro Yo,† Shingo Ishikawa,† Hidemitsu Uno,‡
and Michinori Sumimoto§
†Department of Applied Molecular Science, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
‡Department of Chemistry, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
§Department of Material Chemistry, Graduate School of Science and Engineering, Yamaguchi University, Ube 755-8611, Japan
S
* Supporting Information
ABSTRACT: Bicyclic dihydrothiophenes are readily prepared by a radical
cascade cyclization reaction triggered by the addition of a thiyl radical under
thermal or photoirradiation conditions. The translocated radical attacks the sulfur
atom in the initial radical donor unit in an SHi manner. Sufficient stereoselectivity
is achieved when a large excess of disulfide is used for the reaction under
photoirradiation conditions. The reaction in the absence of solvents provides vinylsulfides instead of dihydrothiophenes. Thus,
the sulfur atom in the thiyl radical serves as a sulfur biradical synthetic equivalent.
the smooth disappearance of 1a. The reaction was carried out
at a concentration of 10−2 M, and the results are summarized in
Table 1.
INTRODUCTION
■
Radical cyclization is recognized as a useful organic reaction for
producing cyclic compounds.1 Activated radicals that promote
cyclization reactions are generated by many methods.2 For
example, the abstraction of halogens or halogen equivalents by
tin radicals, the addition of a radical to α,β-unsaturated alkenes,
and the homolytic fragmentation of carbon−heteroatom or
heteroatom−heteroatom bonds are used frequently. The
addition of thiyl radicals to carbon−carbon double bonds is a
well-known reaction that gives the corresponding conjugate
adducts in quantitative yields. Recently, we discovered an
interesting radical cyclization reaction in which a tin radical
adds to an α,β-unsaturated ester followed by cyclization with a
terminal alkyne to generate a vinyl radical, which then attacks
the tin atom in an SHi manner to give a bicyclic stannolane in
good yields.3 This transformation is the first example of a highly
efficient SHi reaction on a tetraalkyltin unit.4 The SHi reaction
of sulfur atoms has been previously reported and used for the
preparation of benzothiophene derivatives. This method has
also been used for the generation of other carbon- or
heteroatom-centered radicals.5 We were interested in the
potential of thiyl radicals to undergo such an SHi reaction
during an addition−cyclization radical cascade. Herein, we
report a novel radical cascade−SHi reaction using thiyl radicals
that provides stereoselective preparation of bicyclic dihydro-
thiophenes, which are of interest as partial structures of new
drug candidates.6
Table 1. Synthesis of Pyrrolidinostannolane 2
temp
(°C)
2; yield
a
b
entry
X
R (equiv)
initiator
(%)
trans/cis
1
2
H
C8H17 (1.2) AIBN
110
110
25
2a; 45
2b; 57
2a; 0
66/34
55/45
Cl C8H17 (1.2) AIBN
3
H
H
H
H
H
H
H
H
C8H17 (1.2) V70
4
C8H17 (10) Et3B/O2
25
2a; 0
5
C8H17 (5)
AIBN
110
110
85
2a; 62
2a; 49
2a; 66
2a; 53
2a; 0
62/38
55/45
58/42
58/42
6
C8H17 (10) AIBN
7
i-Pr (10)
t-Bu (10)
allyl (10)
AIBN
AIBN
AIBN
AIBN
8
85
9
110
110
10
Bn (10)
2a; 95
60/40
a
b
Isolated yields. Determined by HPLC analysis.
A typical workup and chromatographic purification provided
the desired bicyclic dihydrothiophene 2a in 45% yield (entry
1). Compound 2a comprised two diastereomers in a 66:34
ratio, which were separated by careful flash column
chromatography. Both compounds (major 2a and minor 2a)
RESULTS AND DISCUSSION
■
We first examined octanethiol as the thiyl radical donor.
Treatment of chiral enyne compound 1a, which was prepared
by N-propargylation of optically active α-methylene-β-(N-
tosyl)amine,7 with octanethiol in the presence of a catalytic
amount of azobisisobutyronitrile (AIBN) at 110 °C resulted in
Received: May 4, 2013
© XXXX American Chemical Society
A
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were crystallized, and their X-ray crystallographic analyses
unambiguously indicated that major 2a was trans-2a and minor
2a was cis-2a.8 The NMR spectra of these compounds also
provided the best result; the diastereoselectivity was enhanced
to 90:10 (entry 9).
Using the optimized conditions for the formation of bicyclic
pyrrolidinodihydrothiophene 2, the generality of the reaction
was then examined using various types of enynes 1. The results
are summarized in Table 3.
1
supported the structural assignment because the H signals for
the tert-butyl ester group at C6a in cis-2a and the CH2S group
at C1 in trans-2a exhibited an upfield shift owing to the
presence of the aromatic ring at the C6 position. Use of the p-
chloro derivative 1b also gave a similar result (entry 2). The
initiators 2,2'-azobis(4-methoxy-2.4-dimethyl valeronitrile)
(V70) and Et3B/O2 were employed in an attempt to carry
out the reaction at room temperature; however, no desired
product was obtained (entries 3 and 4). When a large excess
(10 equiv) of octanethiol was used, the yield of 2a increased to
49%, although the stereoselectivity did not improve (entry 6).
Different thiols were also examined, but the yield of 2a was
nearly the same, and the stereoselectivity ranged from
approximately 1:1 to 2:1 (entries 7 and 8). Allylmercaptan
did not give any desired product (entry 9). The use of
benzylmercaptan increased the yield of 2a to 95%, but the
stereoselectivity was unchanged (entry 10).
Table 3. Preparation of Pyrrolidinodihydrothiophenes 2
a
b
c
entry
R
2; yield (%)
trans/cis
trans 2 ee
1
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
2b; 64
2c; 71
2d; 96
2e; 76
2f; 43
2g; 63
2h; 62
2i; 76
2j; 49
2k; 29
90/10
74/26
81/19
87/13
83/17
86/14
80/20
78/22
77/23
50/50
91
98
91
97
93
95
90
93
94
2
3
4
5
We next examined disulfides as the radical promoter of
cyclization. The results are summarized in Table 2.
6
7
2-furyl
8
2-nephthyl
3-MeOC6H4
Table 2. Synthesis of Pyrrolidinodihydrothiophene 2 in the
Presence of RSSR
9
10
Pr
not determined
a
b
c
Isolated yield. Determined by HPLC. Determined by HPLC using
a ChiralPak ID column.
The radical cascade reaction occurred smoothly under
photoirradiation conditions in the presence of 10 equiv of
MeSSMe. For example, treatment of 1b with MeSSMe resulted
in the smooth formation of 2b in 64% yield. HPLC analysis
revealed that the trans/cis ratio of 2b was 90:10, respectively.
The enantiomeric excess (ee) of trans-2b was determined by
chiral HPLC analysis, which showed that compound 2b was
obtained in 91% ee. The ee of the starting material was 93%;
thus, the reaction progressed with almost no loss of optical
purity (entry 1). Most of the starting materials that possessed
an aromatic group as the R substituent underwent smooth
transformation to compound 2 in good yields, and the trans
isomer of 2 was formed preferentially (entries 2−9). On the
other hand, the reaction of aliphatic derivatives such as 1k was
sluggish, and the formation of 2k occurred only in 29% yield in
an approximate 1:1 mixture of the two diastereomers (entry
10). These trends were also observed in the formation of
stannolopyrroles via a radical cascade process.3
To explore the reaction pathway, the reaction of 1a was next
examined without solvent. Treatment of a mixture of 1a and
dimethyldisulfide under UV irradiation conditions led to the
formation of a diastereomeric mixture of monocyclic
compound 3 in 27% yield (Scheme 1).
Formation of 2a was not observed under these conditions.
The two diastereomers of 3 were separated by careful flash
chromatography. These compounds were monocyclic com-
pounds that contained two methylthio groups. Nuclear
Overhauser effect (NOE) and high-resolution mass spectrom-
etry (HRMS) analyses supported the assignment of the
structures as trans-3a and cis-3a. Thus, the structures of these
compounds were confirmed by 1H NMR analysis where upfield
shifts were observed for the tert-butyl ester in cis-3a and the
CH2SMe group in trans-3a. As mentioned previously, similar
upfield shifts were observed in trans-2a and cis-2a. The alkene
time
(h)
2a; yield
recovery of 1a
a
c
a
entry R (equiv)
(%)
trans/cis
(%)
b
b
1
2
3
4
5
6
7
8
9
Pr (10)
20
20
20
20
20
5
27
83/17
66/34
77/23
65
b
b
i-Pr (10)
t-Bu (10)
allyl (10)
Bn (10)
Me (2)
19
45
b
b
15
16
0
0
b
b
31
85/15
67
0
Me (5)
5
63
72
78
62/38
83/17
90/10
0
0
0
Me (10)
Me (20)
5
5
a
b
c
Isolated yields. LC yields. Determined by HPLC analyses.
This reaction was carried out under photoirradiation
conditions; a UV lamp was used with a Pyrex filter to produce
light with wavelengths greater than approximately 340 nm. The
reaction slowly progressed in the presence of an excess amount
of PrSSPr, and the desired product 2a was isolated in 27% yield
along with recovered 1a in 65% yield after 20 h of reaction time
(entry 1). The reaction seemed to stop at this stage. The use of
other alkyl disulfides, such as i-PrSSi-Pr, t-BuSSt-Bu, and
BnSSBn, did not improve the yield (entries 2, 3, and 5), while
diallyl disulfides afforded a complex mixture (entry 4). On the
other hand, MeSSMe dramatically improved the yield of 2a,
although a large excess of this disulfide was required. For
example, 5 equiv of MeSSMe provided 2a in 63% (entry 7)
yield. The diastereomeric ratio of 2a was determined to be
62:38 by HPLC analysis. The ratio was improved with 10 equiv
of MeSSMe, and 2a was isolated in 72% yield with an 83:17
diastereomeric ratio (entry 8). Twenty equivalents of MeSSMe
B
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In conclusion, we have successfully converted chiral enynes
1, which are readily available asymmetric Aza−Morita−Baylis−
Hillman adducts,7 to bicyclic pyrolidinodihydrothiophenes 2 in
good yields. A thiyl radical serves as a sulfur biradical equivalent
in this reaction and provides dihydrothiophenes in a one-step
reaction via an addition−cyclization−substitution radical
cascade. The stereoselectivity is improved when a large excess
of disulfide is used in the reaction with photoirradiation
initiation. This transformation occurs via a highly cumulated
radical cascade process and is a potentially useful reaction for
the preparation of thiazabicyclic compounds.
Scheme 1. Reaction of 1a without Solvent
EXPERIMENTAL SECTION
■
configuration was determined by NOE analysis; a signal
enhancement of approximately 14% was observed for the
CH2SMe group in cis-3a when the MeSCH= proton was
irradiated.
Preparation of (6S)-tert-Butyl 6-Phenyl-5-tosyl-4,5,6,6a-tet-
rahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2a): Use of 5
equiv of Octanethiol (Table 1, Entry 6). A solution of 1a (1.2795
g, 3.01 mmol), octanethiol (5.3 mL, 30.4 mmol), and AIBN (0.1202 g,
0.73 mmol) in toluene (300 mL) was heated at 110 °C for 20 h under
nitrogen atmosphere. The reaction mixture was cooled and
concentrated in vacuo. The residue was purified through flash
chromatography (silica gel/hexane−EtOAc 20:1 then 5:1 v/v) to
give trans-2a in 27% yield (0.3701 g, 0.81 mmol) and cis-2a in 22%
yield (0.3030 g, 0.66 mmol).
These results clearly support the reaction pathway shown in
Scheme 2. Thus, the thiyl radical, which is generated from
either a thiol under thermal conditions or a disulfide under
photoirradiation conditions, attacks the α,β-unsaturated ester
unit in 1 to give the α-carbonyl radical A, which then undergoes
5-exo-dig mode radical cyclization to give vinyl radical B. This
vinyl radical B is a highly reactive radical that attacks the sulfur
atom in an SHi manner to give bicyclic adduct 2. During the
process, it appears that two pathways are possible: one is a
direct SHi process, and the other is a stepwise SHi process that
passes through intermediate C. Although the latter mechanism
may explain some of the results, such as why a large excess of
disulfide is required, it is less likely because the transformation
from intermediate C to 2 requires an intermolecular SH2
reaction on a carbon atom, which is regarded as a very rare and
difficult reaction pathway.9 Calculation of the structure of
intermediate C was then attempted, but it was found that
intermediate C has no stable structure. Any initial structure for
intermediate C yields the optimized structure for intermediate
B and compound 2.10 Thus, the presence of intermediate C is
unlikely, and it is believed that the SHi process directly
progresses from B to 2. If the reaction is performed without
solvent under photoirradiation conditions, a large excess
amount of dimethyldisulfide exists that serves as a trapping
agent for the vinylic radical B, resulting in the formation of
compounds trans-3a and cis-3a. Thus, we conclude that the SHi
process from B is not very rapid and progresses with a reaction
rate comparable to that of intermolecular trapping by disulfide
when the reaction is performed under high concentration
conditions.
Preparation of (6S)-tert-Butyl 6-Phenyl-5-tosyl-4,5,6,6a-tet-
rahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2a): Use of
10 equiv of Dimethyldisulfide under Photoirradiation Con-
ditions (Table 2, Entry 8). A Pyrex flask (100 mL) was charged with
a solution of 1a (211.8 mg, 0.50 mmol) and dimethyldisulfide (0.45
mL, 5.06 mmol) in toluene (50 mL), and the reaction solution was
irradiated by a mercury lamp at ambient temperature under nitrogen
atmosphere for 8 h. The reaction mixture was concentrated, and the
residue was purified through flash chromatography (silica gel/hexane−
EtOAc = 20:1 then 5:1) to give trans-2a in 60% yield (135.7 mg, 0.30
mmol) and cis-2a in 12% yield (27.3 mg, 0.060 mmol).
(6S,6aS)-tert-Butyl 6-Phenyl-5-tosyl-4,5,6,6a-tetrahydro-1H-
thieno[3,4-c]pyrrole-6a-carboxylate (trans 2a). White solid, mp
117.0−118.0 °C; [α]D + 60.8 (c 0.87, CHCl3). The enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) to be 97%
ee, tR 21.9 min (major), tR 28.0 min (minor) [Column ID 0.46 cm ×
1
25 cm, hexane−i-PrOH = 95:5, 1.00 mL/min]. H NMR (500 MHz,
CDCl3) δ 7.43 (d, J = 8.3 Hz, 2H), 7.34−7.19 (m, 3H), 7.11 (d, J = 7.9
Hz, 2H), 6.98 (br, 2H), 6.08 (s, 1H), 5.11 (s, 1H), 4.21 (dd, J = 12.6,
2.2 Hz, 1H), 4.10 (d, J = 1.2 Hz, 1H), 3.10 (d, J = 11.8 Hz, 1H), 2.60
(d, J = 11.8 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 171.8, 143.3, 138.6, 136.0, 133.8 (2C), 129.4 (2C), 128.8
(2C), 128.1, 127.3 (2C), 126.6, 120.9, 82.9, 73.2, 67.8, 47.7, 37.8, 27.8
(3C), 21.6; IR (neat) ν 1720, 1343, 1161, 1143, 1093, 912, 812 cm−1;
HRMS (ESI TOF M + Na) m/z 480.1283. Calcd for C24H27NO4S2Na
m/z 480.1279.
(6S,6aR)-tert-Butyl 6-Phenyl-5-tosyl-4,5,6,6a-tetrahydro-1H-
thieno[3,4-c]pyrrole-6a-carboxylate (cis-2a). White solid, mp
Scheme 2. Plausible Reaction Pathway
C
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1
71.0−72.0 °C; [α]D + 133.5 (c 0.31, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.29−7.21
(m, 5H), 5.78 (s, 1H), 4.68 (s, 1H), 4.42 (dd, J = 14.2, 2.1 Hz, 1H),
4.28 (dd, J = 14.2, 0.9 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 3.25 (d, J =
10.9 Hz, 1H), 2.44 (s, 3H), 1.08 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 168.1, 144.2, 137.5, 135.7, 134.1, 129.8 (2C), 128.2 (2C),
128.0, 127.8 (2C), 126.9 (2C), 119.1, 82.6, 75.2, 72.2, 50.1, 43.2, 27.5
(3C), 21.7; IR (neat) ν 1724, 1350, 1161, 1089 cm−1; HRMS (ESI
TOF M + Na) m/z 480.1291. Calcd for C24H27NO4S2Na m/z
480.1279.
(ESI TOF M + Na) m/z 494.1441. Calcd for C25H29NO4S2Na m/z
494.1436.
(6S,6aR)-tert-Butyl 6-(m-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (cis-2c). Colorless oil;
1
[α]D + 264.4 (c 0.09, CHCl3); H NMR (500 MHz, CDCl3) δ 7.62
(d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H),
7.09−7.01 (m, 3H), 5.79 (s, 1H), 4.66 (s, 1H), 4.42 (dd, J = 14.1, 2.1
Hz, 1H), 4.31 (d, J = 14.8 Hz, 1H), 3.81 (d, J = 10.8 Hz, 1H), 3.26 (d,
J = 10.9 Hz, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 1.09 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 168.2, 144.0, 137.5, 137.2, 135.8, 134.5, 129.7
(2C), 128.7, 128.1, 127.8 (2C), 127.6, 124.1, 119.0, 82.4, 75.2, 72.3,
50.1, 43.2, 27.5 (3C), 21.7, 21.5; IR (neat) ν 1722, 1350, 1163, 912
cm−1; HRMS (ESI TOF M + Na) m/z 494.1426. Calcd for
C25H29NO4S2Na m/z 494.1436.
Preparation of (6S)-tert-Butyl 6-(o-Tolyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2b). A
Pyrex flask (30 mL) was charged with a solution of 1b (90.0 mg,
0.20 mmol) and dimethyldisulfide (0.17 mL, 1.91 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 20:1 then 5:1) to give
2b in 64% yield (60.7 mg, 0.13 mmol); trans-2b/cis-2b was 90:10.
(6S,6aS)-tert-Butyl 6-(o-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (trans-2b). White solid,
mp 72.0−73.0 °C; [α]D + 80.2 (c 0.88, CHCl3). The enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) to be 91%
ee, tR 16.2 min (major), tR 18.6 min (minor) [Column ID 0.46 cm ×
Preparation of (6S)-tert-Butyl 6-(p-Tolyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2d). A
Pyrex flask (30 mL) was charged with a solution of 1d (87.0 mg,
0.20 mmol) and dimethyldisulfide (0.19 mL, 2.14 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 20:1 then 5:1) to give
2d in 96% yield (89.2 mg, 0.19 mmol); trans-2d/cis-2d was 81:19.
(6S,6aS)-tert-Butyl 6-(p-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (trans-2d). White solid,
mp 93.0−94.0 °C; [α]D + 58.2 (c 0.91, CHCl3). The enantiomeric
purity was determined by HPLC analysis (230 nm, 40 °C) to be 91%
ee, tR 19.5 min (major), tR 24.5 min (minor) [Column ID 0.46 cm ×
1
25 cm, hexane−i-PrOH = 95:5, 1.00 mL/min]. H NMR (500 MHz,
CDCl3) δ 7.49 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.13−7.10
(m, 2H), 7.03−6.98 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.07 (s, 1H),
5.43 (s, 1H), 4.26 (dd, J = 12.6, 2.3 Hz, 1H), 4.12 (dd, J = 12.6, 1.2
Hz, 1H), 3.15 (d, J = 11.6 Hz, 1H), 2.58 (d, J = 11.6 Hz, 1H), 2.36 (s,
3H), 2.32 (s, 3H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ
172.0, 143.3, 136.8, 136.2, 135.1, 133.9, 130.4, 129.5 (2C), 127.8,
127.4 (2C), 127.2, 126.6, 121.0, 82.9, 73.0, 64.1, 47.6, 37.2, 27.8 (3C),
21.4, 19.4; IR (neat) ν 1716, 1340, 1162, 1145, 1094, 906 cm−1;
HRMS (ESI TOF M + Na) m/z 494.1426. Calcd for C25H29NO4S2Na
m/z 494.1436.
1
25 cm, hexane−i-PrOH = 95/5, 1.00 mL/min]. H NMR (500 MHz,
CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.03 (d, J
= 7.6 Hz, 2H), 6.87 (d, J = 7.0 Hz, 2H), 6.07 (s, 1H), 5.07 (s, 1H),
4.18 (dd, J = 12.6, 2.2 Hz, 1H), 4.08 (dd, J = 12.5, 1.2 Hz, 1H), 3.08
(d, J = 11.7 Hz, 1H), 2.63 (d, J = 11.8 Hz, 1H), 2.34 (s, 3H), 2.30 (s,
3H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.9, 143.2,
137.9, 136.0, 135.6, 133.9, 129.5 (2C), 129.4 (2C), 127.3 (2C), 127.3
(2C), 120.8, 82.8, 73.2, 67.6, 47.7, 37.9, 27.8 (3C), 21.6, 21.3; IR
(neat) ν 1718, 1342, 161, 1143, 1094, 912 cm−1; HRMS (ESI TOF M
+ Na) m/z 494.1433. Calcd for C25H29NO4S2Na m/z 494.1436.
(6S,6aR)-tert-Butyl 6-(p-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (cis-2d). Colorless oil;
[α]D + 123.8 (c 0.24, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.63 (d,
J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H),
7.08 (d, J = 8.1 Hz, 2H), 5.77 (s, 1H), 4.60 (s, 1H), 4.42 (dd, J = 14.2,
2.1 Hz, 1H), 4.25 (dd, J = 14.2, 0.9 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H),
3.23 (d, J = 10.9 Hz, 1H), 2.44 (s, 3H), 2.30 (s, 3H), 1.12 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 168.2, 144.1, 137.6, 135.7, 134.3, 134.1,
129.8 (2C), 128.8 (2C), 127.8 (2C), 126.9 (2C), 118.9, 82.5, 75.2,
72.2, 50.2, 43.1, 27.6 (3C), 21.7, 21.2; IR (neat) ν 1722, 1350, 1163,
912 cm−1; HRMS (ESI TOF M + Na) m/z 494.1435. Calcd for
C25H29NO4S2Na m/z 494.1436.
(6S,6aR)-tert-Butyl 6-(o-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (cis-2b). Colorless oil;
[α]D + 120.0 (c 0.12, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.63 (d,
J = 8.2 Hz, 2H), 7.46 (dd, J = 7.5, 1.7 Hz, 1H), 7.29 (d, J = 8.0 Hz,
2H), 7.19−7.04 (m, 3H), 5.83 (s, 1H), 4.96 (s, 1H), 4.43 (d, J = 13.0
Hz, 1H), 4.40 (d, J = 14.2 Hz, 1H), 3.81 (d, J = 10.6 Hz, 1H), 3.22 (d,
J = 10.6 Hz, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.02 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 168.9, 144.1, 137.5, 136.5, 135.1, 135.0, 130.1,
129.8 (2C), 128.2, 127.8, 127.6 (2C), 126.0, 118.6, 82.5, 74.9, 68.6,
50.2, 44.9, 27.4 (3C), 21.7, 19.9; IR (neat) ν 1751, 1303, 1288, 1246,
1163, 912 cm−1; HRMS (ESI TOF M + Na) m/z 494.1433. Calcd for
C25H29NO4S2Na m/z 494.1436.
Preparation of (6S)-tert-Butyl 6-(m-Tolyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2c). A
Pyrex flask (30 mL) was charged with a solution of 1c (83.8 mg,
0.19 mmol) and dimethyldisulfide (0.20 mL, 2.25 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 20:1 then 5:1) to give 2c
in 71% yield (63.8 mg, 0.14 mmol); trans-2c/cis-2c was 74:26.
(6S,6aS)-tert-Butyl 6-(m-Tolyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (trans-2c). White solid,
mp 119.0−120.0 °C; [α]D + 66.7 (c 1.02, CHCl3). The enantiomeric
purity was determined by HPLC analysis (230 nm, 30 °C) to be 98%
ee, tR 19.3 min (major), tR 27.2 min (minor) [Column ID 0.46 cm ×
Preparation of (6S)-tert-Butyl 6-(p-Methoxyphenyl)-5-tosyl-
4,5,6,6a-tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate
(2e). A Pyrex flask (30 mL) was charged with a solution of 1e (93.7
mg, 0.21 mmol) and dimethyldisulfide (0.18 mL, 2.03 mmol) in
toluene (20 mL), and the reaction solution was irradiated by a mercury
lamp at ambient temperature under nitrogen atmosphere for 5 h. The
reaction mixture was concentrated, and the residue was purified
through flash chromatography (silica gel/hexane−EtOAc = 20:1 then
5:1) to give 2e in 76% yield (77.9 mg, 0.16 mmol); trans-2e/cis-2e was
87:13.
(6S,6aS)-tert-Butyl 6-(p-Methoxyphenyl)-5-tosyl-4,5,6,6a-tet-
rahydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (trans-2e).
Colorless oil; [α]D + 34.0 (c 0.96, CHCl3). The enantiomeric purity
was determined by HPLC analysis (230 nm, 30 °C) to be 97% ee, tR
21.9 min (major), tR 28.4 min (minor) [Column ID 0.46 cm × 25 cm,
hexane−i-PrOH = 95:5, 1.00 mL/min]. 1H NMR (500 MHz, CDCl3)
δ 7.42 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 7.5
Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.07 (s, 1H), 5.08 (s, 1H), 4.19 (dd,
J = 12.6, 2.2 Hz, 1H), 4.06 (dd, J = 12.5, 1.2 Hz, 1H), 3.77 (s, 3H),
3.10 (d, J = 11.8 Hz, 1H), 2.66 (d, J = 11.8 Hz, 1H), 2.34 (s, 3H), 1.43
1
25 cm, hexane−i-PrOH = 95:5, 1.00 mL/min]. H NMR (500 MHz,
CDCl3) δ 7.42 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.11−7.15
(br, 1 H), 7.02 (d, J = 7.5 Hz, 1H), 6.83−6.61 (br, 2H), 6.07 (s, 1H),
5.08 (s, 1H), 4.22 (dd, J = 12.6, 2.3 Hz, 1H), 4.08 (dd, J = 12.6, 1.1
Hz, 1H), 3.10 (d, J = 11.7 Hz, 1H), 2.61 (d, J = 11.7 Hz, 1H), 2.34 (s,
3H), 2.26−2.15 (br, 3H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3)
δ 171.9, 143.2, 138.4, 138.3, 136.1, 133.9, 129.3 (2C), 128.9 (2C),
128.7, 128.0, 127.3, 124.5, 120.8, 82.9, 73.1, 67.8, 47.7, 37.9, 27.8 (3C),
21.5; IR (neat) ν 1719, 1341, 1159, 1144, 1094, 812 cm−1; HRMS
D
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The Journal of Organic Chemistry
Article
(s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.9, 159.4, 143.2, 136.2,
133.9, 130.7, 129.4 (2C), 128.6, 127.3 (2C), 120.8, 114.1 (2C), 82.9,
73.3, 67.4, 55.4, 47.6, 37.7, 27.9 (3C), 27.8, 21.5; IR (neat) ν 1719,
1512, 1367, 1341, 1247, 1161, 1143, 1033, 839, 750 cm−1; HRMS
(ESI TOF M + Na) m/z 510.1385. Calcd for C25H29NO5S2Na m/z
510.1385.
J = 12.5, 2.3 Hz, 1H), 4.09 (dd, J = 12.5, 1.2 Hz, 1H), 3.10 (d, J = 11.8
Hz, 1H), 2.59 (d, J = 11.8 Hz, 1H), 2.36 (s, 3H), 1.41 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 171.6, 162.5 (d, J = 247.2 Hz), 143.5,
135.8, 134.6 (d, J = 3.3 Hz), 133.4, 129.5 (2C), 129.1 (2C, d, J = 8.2
Hz), 127.3 (2C), 121.3, 115.8 (2C, d, J = 21.6 Hz), 83.1, 73.1, 67.0,
47.6, 37.8, 27.8 (3C), 21.6; IR (neat) ν 1718, 1508, 1341, 1225, 1155,
1093, 842 cm−1; HRMS (ESI TOF M + Na) m/z 498.1184. Calcd for
C24H26FNO4S2Na m/z 498.1185.
(6S,6aR)-tert-Butyl 6-(p-Fluorophenyl)-5-tosyl-4,5,6,6a-tetra-
hydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (cis-2g). Color-
less oil; [α]D + 82.4 (c 0.52, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.63 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.30−7.26 (m, 2H),
7.00−6.95 (m, 2H), 5.80 (s, 1H), 4.62 (s, 1H), 4.42 (dd, J = 14.1, 2.1
Hz, 1H), 4.27 (dd, J = 14.2, 1.1 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H),
3.23 (d, J = 10.8 Hz, 1H), 2.45 (s, 3H), 1.13 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 168.1, 162.5 (d, J = 246.5 Hz), 144.3, 135.4, 134.0,
133.2 (d, J = 3.0 Hz), 129.9 (2C), 128.7 (2C, d, J = 8.0 Hz), 127.8
(2C), 119.2, 115.1 (2C, d, J = 21.7 Hz), 82.8, 75.2, 71.6, 50.1, 43.0,
27.6 (3C), 21.7; IR (neat) ν 1722, 1508, 1350, 1161, 1089 cm−1;
(6S,6aR)-tert-Butyl 6-(p-Methoxyphenyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (cis-2e).
1
Colorless oil; [α]D + 48.9 (c 0.36, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.62 (dd, J = 8.1, 1.1 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.22
(d, J = 7.7 Hz, 2H), 6.80 (dd, J = 8.9, 1.3 Hz, 2H), 5.78 (s, 1H), 4.58
(s, 1H), 4.42 (d, J = 14.2 Hz, 1H), 4.26 (d, J = 14.1 Hz, 1H), 3.77 (s,
3H), 3.23 (d, J = 10.9 Hz, 1H), 2.44 (s, 3H), 1.14 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 168.3, 159.4, 144.1, 135.7, 134.1, 129.8 (2C),
129.3, 128.2 (2C), 127.8 (2C), 118.9, 113.6 (2C), 82.6, 75.3, 72.0,
55.4, 50.2, 43.0, 27.6 (3C), 21.7; IR (neat) ν 1719, 1514, 1249, 1163,
912 cm−1; HRMS (ESI TOF M + Na) m/z 510.1385. Calcd for
C25H29NO5S2Na m/z 510.1385.
Preparation of (6S)-tert-Butyl 6-(p-Chlorophenyl)-5-tosyl-
4,5,6,6a-tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate
(2f). A Pyrex flask (30 mL) was charged with a solution of 1f (96.2 mg,
0.21 mmol) and dimethyldisulfide (0.17 mL, 1.91 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 20:1 then 5:1) to give 2f
in 76% yield (44.0 mg, 0.089 mmol); trans-2f/cis-2f was 83:17.
(6S,6aS)-tert-Butyl 6-(p-Chlorophenyl)-5-tosyl-4,5,6,6a-tetra-
hydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (trans-2f). Col-
orless oil; [α]D + 38.7 (c 0.69, CHCl3). The enantiomeric purity was
determined by HPLC analysis (230 nm, 30 °C) to be 93% ee, tR 19.1
min (major), tR 24.1 min (minor) [Column ID 0.46 cm × 25 cm,
hexane−i-PrOH = 95:5, 1.00 mL/min]. 1H NMR (500 MHz, CDCl3)
δ 7.46 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.3 Hz, 2H), 7.16 (d, J = 7.8
Hz, 2H), 6.94 (d, J = 7.8 Hz, 2H), 6.10 (dd, J = 2.1, 1.2 Hz, 1H), 5.08
(s, 1H), 4.17 (dd, J = 12.5, 2.2 Hz, 1H), 4.09 (dd, J = 12.5, 1.2 Hz,
1H), 3.10 (d, J = 11.8 Hz, 1H), 2.60 (d, J = 11.8 Hz, 1H), 2.37 (s, 3H),
1.41 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.5, 143.6, 137.3,
135.8, 134.1, 133.3, 129.5 (2C), 129.0 (2C), 128.8, 127.3 (2C), 121.4
(2C), 83.1, 73.1, 67.1, 47.6, 37.8, 27.8 (3C), 21.5; IR (neat) ν 1742,
1370, 1350, 1228, 1163, 1091, 840 cm−1; HRMS (ESI TOF M + Na)
m/z 514.0903. Calcd for C24H26ClNO4S2Na m/z 514.0890.
(6S,6aR)-tert-Butyl 6-(p-Chlorophenyl)-5-tosyl-4,5,6,6a-tetra-
hydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (cis-2f). Color-
less oil; [α]D + 96.6 (c 0.41, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.63 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.25 (s, 4H), 5.80
(s, 1H), 4.61 (s, 1H), 4.41 (dd, J = 14.2, 2.1 Hz, 1H), 4.26 (dd, J =
14.2, 1.1 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.23 (d, J = 10.9 Hz, 1H),
2.45 (s, 3H), 1.13 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 168.0,
144.4, 136.1, 135.3, 133.9, 133.8, 129.9 (2C), 128.4, 128.3 (2C), 127.8
(2C), 119.3 (2C), 82.9, 75.2, 71.6, 50.1, 43.0, 27.6 (3C), 21.7; IR
(neat) ν 1722, 1491, 1346, 1163, 1089 cm−1; HRMS (ESI TOF M +
Na) m/z 514.0901. Calcd for C24H26ClNO4S2Na m/z 514.0890.
Preparation of (6S)-tert-Butyl 6-(p-Fluorophenyl)-5-tosyl-
4,5,6,6a-tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate
(2g). A Pyrex flask (100 mL) was charged with a solution of 1g (271.0
mg, 0.61 mmol) and dimethyldisulfide (0.54 mL, 6.08 mmol) in
toluene (60 mL), and the reaction solution was irradiated by a mercury
lamp at ambient temperature under nitrogen atmosphere for 5 h. The
reaction mixture was concentrated, and the residue was purified
through flash chromatography (silica gel/hexane-EtOAc = 20:1 then
5:1) to give 2g in 63% yield (182.1 mg, 0.38 mmol). trans-2g/cis-2g
was 86:14.
HRMS (ESI TOF
M + Na) m/z 498.1179. Calcd for
C24H26FNO4S2Na m/z 498.1185.
Preparation of 6-(2-Furyl)-5-tosyl-4,5,6,6a-tetrahydro-1H-
thieno[3,4-c]pyrrole-6a-carboxylate (2h). A Pyrex flask (100
mL) was charged with a solution of 1i (250.1 mg, 0.60 mmol) and
dimethyldisulfide (0.54 mL, 6.08 mmol) in toluene (60 mL), and the
reaction solution was irradiated by a mercury lamp at ambient
temperature under nitrogen atmosphere for 5 h. The reaction mixture
was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 15:1 then 3:1) to give
2h in 62% yield (166.8 mg, 0.37 mmol); trans-2h/cis-2h was 80:20.
(6S,6aS)-tert-Butyl 6-(2-Furyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (trans-2h). Yellow oil;
[α]D + 22.8 (c 0.49, CHCl3); The enantiomeric purity was determined
by HPLC analysis (230 nm, 40 °C) to be 90% ee, tR 17.1 min (major),
tR 26.7 min (minor) [Column ID 0.46 cm × 25 cm, hexane−i-PrOH =
1
95:5, 1.00 mL/min]. H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.3
Hz, 2H), 7.13−7.12 (m, 1H), 7.12 (d, J = 7.3 Hz, 2H), 6.25−6.22 (m,
2H), 6.02 (s, 1H), 5.23 (s, 1H), 4.18 (dd, J = 12.5, 2.2 Hz, 1H), 3.93
(dd, J = 12.5, 1.3 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 2.65 (d, J = 11.7
Hz, 1H), 2.35 (s, 3H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3) δ
171.1, 150.8, 143.2, 143.0, 136.0, 134.4, 129.4 (2C), 127.0 (2C), 119.8,
110.3 (2C), 83.2, 72.9, 61.3, 46.8, 36.9, 27.9 (3C), 21.4; IR (neat) ν
1718, 1344, 1276, 1247, 1159, 1094, 813 cm−1; HRMS (ESI TOF M +
Na) m/z 470.1068. Calcd for C22H25NO5S2Na m/z 470.1072.
(6S,6aR)-tert-Butyl 6-(2-Furyl)-5-tosyl-4,5,6,6a-tetrahydro-
1H-thieno[3,4-c]pyrrole-6a-carboxylate (cis-2h). Yellow oil;
1
[α]D + 16.2 (c 0.30, CHCl3); H NMR (500 MHz, CDCl3) δ 7.61
(d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.22 − 7.21 (m, 1H),
6.33 (d, J = 3.3 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 5.84 (s, 1H),
4.61 (s, 1H), 4.35 (dd, J = 13.8, 2.1 Hz, 1H), 3.79 (d, J = 11.1 Hz, 1H),
3.23 (d, J = 11.2 Hz, 1H), 2.43 (s, 3H), 1.31 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 168.4, 149.8, 143.9, 142.3 (2C), 134.8, 129.7 (2C),
127.7 (2C), 119.4, 110.6, 109.3, 82.6, 73.9, 65.9, 49.6, 42.4, 27.7 (3C),
21.7; IR (neat) ν 1719, 1344, 1276, 1159, 1093 cm−1; HRMS (ESI
TOF M + Na) m/z 470.1068. Calcd for C22H25NO5S2Na m/z
470.1072.
Preparation of (6S)-tert-Butyl 6-(2-Naphthyl)-5-tosyl-
4,5,6,6a-tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate
(2i). A Pyrex flask (30 mL) was charged with a solution of 1i (77.7 mg,
0.16 mmol) and dimethyldisulfide (0.18 mL, 2.02 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 15:1 then 5:1) to give 2i
in 76% yield (62.1 mg, 0.13 mmol); trans-2i/cis-2i was 78:22.
(6S,6aS)-tert-Butyl 6-(2-Naphthyl)-5-tosyl-4,5,6,6a-tetrahy-
dro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (trans-2i). White
solid, mp 94.0−95.0 °C; [α]D + 40.4 (c 0.88, CHCl3). The
enantiomeric purity was determined by HPLC analysis (230 nm, 30
°C) to be 93% ee, tR 30.8 min (major), tR 38.0 min (minor) [Column
(6S,6aS)-tert-Butyl 6-(p-Fluorophenyl)-5-tosyl-4,5,6,6a-tetra-
hydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (trans-2g).
White solid, mp 62.0−63.0 °C; [α]D + 51.5 (c 0.84, CHCl3). The
enantiomeric purity was determined by HPLC analysis (230 nm, 30
°C) to be 95% ee, tR 19.9 min (major), tR 25.9 min (minor) [Column
1
ID 0.46 cm × 25 cm, hexane−i-PrOH = 95:5, 1.00 mL/min]. H
NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 7.9,
0.6 Hz, 2H), 7.04−6.85 (m, 4H), 6.10 (s, 1H), 5.10 (s, 1H), 4.18 (dd,
E
dx.doi.org/10.1021/jo400975t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1
ID 0.46 cm × 25 cm, hexane−i-PrOH = 95:5, 1.00 mL/min]. H
NMR (500 MHz, CDCl3) δ 7.79 (dd, J = 6.1, 3.2 Hz, 1H), 7.69 (d, J =
7.4 Hz, 2H), 7.47 (dd, J = 6.1, 3.1 Hz, 3H), 7.41 (d, J = 7.8 Hz, 2H),
7.05 (br, 1H), 6.99 (d, J = 8.1 Hz, 2H), 6.12 (s, 1H), 5.30 (s, 1H), 4.30
(dd, J = 12.6, 1.9 Hz, 1H), 4.20 (d, J = 12.7 Hz, 1H), 3.14 (d, J = 11.8
Hz, 1H), 2.63 (d, J = 11.8 Hz, 1H), 2.25 (s, 3H), 1.48 (d, J = 0.7 Hz,
9H); 13C NMR (126 MHz, CDCl3) δ 171.8, 143.3, 136.0, 135.8,
133.9, 133.2, 133.0, 129.4 (2C), 128.7, 128.2, 127.7, 127.3 (2C), 126.8,
126.5, 126.4, 124.9, 121.0, 83.1, 73.2, 68.0, 47.9, 37.9, 27.9 (3C), 21.5;
IR (neat) ν 1718, 1340, 1273, 1161, 1093, 910 cm−1; HRMS (ESI
TOF M + Na) m/z 530.1431. Calcd for C28H29NO4S2Na m/z
530.1436.
in 29% yield (36.5 mg, 0.09 mmol) as an inseparable diastereomeric
mixture. The diastereomeric ratio was about 1:1.
Colorless oil; H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 5.0 Hz,
1
2H for one isomer), 7.68 (d, J = 5.0 Hz, 2H for another isomer), 7.32
(dd, J = 8.5, 0.5 Hz, 2H for one isomer), 7.28 (d, J = 8.0 Hz, 2H for
another isomer), 5.99 (s, 1H for one isomer), 5.72 (s, 1H for one
isomer), 4.21 (dd, J = 14.1, 2.1 Hz, 1H for one isomer), 4.05 (dd, J =
14.1, 1.1 Hz, 1H for one isomer), 4.00−3.95 (m, 1H for one isomer),
3.93 (dd, J = 12.9, 2.3 Hz, 1H for another isomer), 3.88 (dd, J = 12.9,
1.4 Hz, 1H for another isomer), 3.74 (d, J = 11.0 Hz, 1H for one
isomer), 3.45 (d, J = 11.6 Hz, 1H for another isomer), 3.37 (dd, J =
9.9, 3.3 Hz, 1H for one isomer), 3.35 (dd, J = 7.9, 6.2 Hz, 1H for
another isomer), 3.05 (d, J = 11.1 Hz, 1H for another isomer), 2.44 (s,
3H for one isomer), 2.40 (s, 3H for another isomer), 1.47 (s, 9H for
one isomer), 1.77−1.19 (m, 4H for both isomers), 1.29 (s, 9H for
another isomer), 0.90 (t, J = 7.7 Hz, 3H for one isomer), 0.88 (t, J =
7.4 Hz, 3H for another isomer); 13C NMR (126 MHz, CDCl3) δ
172.2, 169.2, 143.9, 143.5, 136.0, 135.9, 135.2, 134.9, 130.0, 129.9,
129.8 (2C for one isomer), 129.7, 127.8, 127.6 (2C for one isomer),
127.5 (2C for another isomer), 127.1, 119.1, 118.2, 82.9, 82.5, 72.7,
71.7, 69.4, 63.6, 49.8, 46.9, 42.6, 37.5, 35.7, 34.5, 28.0 (3C for one
isomer), 27.7 (3C for another isomer), 21.7, 21.6, 19.3, 18.3, 14.2,
14.0; HRMS (ESI TOF M + Na) m/z 446.1428. Calcd for
C21H29NO4S2Na m/z 446.1436.
Preparation of (2S,Z)-tert-Butyl 3-((Methylthio)methyl)-4-
((methylthio)-methylene)-2-phenyl-1-tosylpyrrolidine-3-car-
boxylate (3): (Scheme 1). In a Pyrex flask (20 mL), compound 1a
(45.0 mg, 0.11 mmol) was dissolved in dimethyldisulfide (0.1 mL, 1.13
mmol), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated under reduced pressure, and the yellow
residue was purified through flash chromatography (silica gel/hexane−
EtOAc = 8:1 then 5:1) to give 3 in 27% yield (15.0 mg, 0.03 mmol).
Compounds 3a and 3b were separated by careful chromatography
followed by recycle GPC separation. The diastereomeric ratio of 3a
and 3b was approximately 1:1.
(6S,6aR)-tert-Butyl 6-(2-Naphthyl)-5-tosyl-4,5,6,6a-tetrahy-
dro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (cis-2i). White
1
solid, mp 92.0−93.0 °C; [α]D + 108.5 (c 0.39, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.80−7.70 (m, 4H), 7.63 (d, J = 8.2 Hz, 2H),
7.47−7.41 (m, 2H), 7.39−7.33 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.84
(d, J = 0.7 Hz, 1H), 4.85 (s, 1H), 4.50 (dd, J = 14.1, 2.1 Hz, 1H), 4.38
(d, J = 14.1 Hz, 1H), 3.87 (d, J = 10.8 Hz, 1H), 3.37 (d, J = 10.9 Hz,
1H), 2.41 (s, 3H), 0.96 (s, 9H); 13C NMR (126 MHz, CDCl3) δ
168.2, 144.2, 135.7, 134.7, 134.4, 133.2, 133.0, 129.8 (2C), 128.1,
127.9, 127.8 (2C), 127.7, 126.2, 126.1, 126.0, 124.9, 119.1, 82.6, 75.4,
72.5, 50.2, 43.2, 27.5 (3C), 21.7; IR (neat) ν 1751, 1340, 1163, 912
cm−1; HRMS (ESI TOF M + Na) m/z 530.1428. Calcd for
C28H29NO4S2Na m/z 530.1436.
Preparation of (6S)-tert-Butyl 6-(m-Methoxyphenyl)-5-tosyl-
4,5,6,6a-tetrahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate
(2j). A Pyrex flask (30 mL) was charged with a solution of 1j (83.9 mg,
0.18 mmol) and dimethyldisulfide (0.20 mL, 2.25 mmol) in toluene
(20 mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 15:1 then 5:1) to give 2j
in 49% yield (44.5 mg, 0.09 mmol); trans-2j/cis-2j was 77:23.
(6S,6aS)-tert-Butyl 6-(m-Methoxyphenyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (trans-2j).
Colorless oil; [α]D + 47.3 (c 0.63, CHCl3). The enantiomeric purity
was determined by HPLC analysis (230 nm, 40 °C) to be 94% ee, tR
35.8 min (major), tR 53.8 min (minor) [Column ID 0.46 cm × 25 cm,
hexane−i-PrOH = 95:5, 1.00 mL/min]. 1H NMR (500 MHz, CDCl3)
δ 7.44 (d, J = 8.2 Hz, 2H), 7.15 (t, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz,
2H), 6.76 (dd, J = 8.2, 2.5 Hz, 1H), 6.62−6.54 (br, 1H), 6.48−6.39
(br, 1H), 6.07 (s, 1H), 5.08 (s, 1H), 4.21 (dd, J = 12.6, 2.2 Hz, 1H),
4.07 (d, J = 12.7 Hz, 1H), 3.73−3.64 (br, 3H), 3.12 (d, J = 11.7 Hz,
1H), 2.64 (d, J = 11.7 Hz, 1H), 2.35 (s, 3H), 1.44 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 171.9, 159.4, 143.2, 136.2, 133.9, 130.7, 129.4
(2C), 128.6, 127.3 (2C), 120.8, 114.1 (2C), 82.9, 73.3, 67.4, 55.4, 47.6,
37.7, 27.9 (3C), 27.8, 21.5; IR (neat) ν 1718, 1601, 1489, 1340, 1284,
1161, 1093, 1039, 914, 842 cm−1; HRMS (ESI TOF M + Na) m/z
510.1385. Calcd for C25H29NO5S2Na m/z 510.1385.
(2S,3S,Z)-tert-Butyl 3-((Methylthio)methyl)-4-((methylthio)-
methylene)-2-phenyl-1-tosylpyrrolidine-3-carboxylate (3a).
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.2 Hz,
2H), 7.20 (t, J = 7.6 Hz, 1H), 7.17−7.10 (br, 2H), 7.01 (d, J = 8.4 Hz,
2H), 6.90−7.05 (br, 2H), 6.11 (t, J = 2.0 Hz, 1H), 5.50 (s, 1H), 4.07
(s, 2H), 2.66 (d, J = 12.5 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 2.11 (d, J
= 12.4 Hz, 1H), 1.86 (s, 3H), 1.47 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 170.2, 142.7, 137.7, 136.3, 133.4, 129.2, 129.1 (2C), 128.2
(2C), 128.0 (2C), 127.2 (2C), 123.8, 82.9, 68.9, 63.4, 50.2, 37.4, 27.9
(3C), 21.5, 18.1, 17.7; HRMS (ESI TOF M + Na) m/z 542.1462.
Calcd for C26H33NO4S3Na m/z 542.1469.
(2S,3R,Z)-tert-Butyl 3-((Methylthio)methyl)-4-((methylthio)-
methylene)-2-phenyl-1-tosylpyrrolidine-3-carboxylate (3b).
1
Colorless oil; H NMR (500 MHz, CDCl3) δ 7.21 (d, J = 8.1 Hz,
2H), 7.17−7.14 (m, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.99 (d, J = 8.4 Hz,
2H), 6.99 (d, J = 7.3 Hz, 2H), 6.70 (t, J = 2.2 Hz, 1H), 4.89 (s, 1H),
4.10 (dd, J = 14.4, 2.6 Hz, 1H), 4.02 (dd, J = 14.4, 2.1 Hz, 1H), 3.26
(d, J = 13.3 Hz, 1H), 2.76 (d, J = 13.2 Hz, 1H), 2.41 (d, J = 0.4 Hz,
3H), 2.31 (s, 3H), 2.08 (d, J = 0.5 Hz, 3H), 1.00 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 168.0, 143.0, 142.4, 138.0, 129.2 (2C), 128.4
(2C), 128.2 (2C), 128.1, 127.2 (2C), 126.8, 126.4, 81.9, 72.0, 62.8,
50.0, 44.0, 27.4 (3C), 21.5, 18.0, 17.6; HRMS (ESI TOF M + Na) m/z
542.1456. Calcd for C26H33NO4S3Na m/z 542.1469.
(6S,6aR)-tert-Butyl 6-(m-Methoxyphenyl)-5-tosyl-4,5,6,6a-
tetrahydro-1H-thieno-[3,4-c]pyrrole-6a-carboxylate (cis-2j).
1
Colorless oil; [α]D + 110.5 (c 0.19, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.19 (t, J
= 7.9 Hz, 1H), 6.89−6.82 (br, 2H), 6.77 (dd, J = 8.1, 2.6 Hz, 1H), 5.78
(s, 1H), 4.65 (s, 1H), 4.41 (d, J = 14.1, 1H), 4.29 (d, J = 14.2, 1H),
3.82 (d, J = 10.8 Hz, 1H), 3.76 (s, 3H), 3.25 (d, J = 10.9 Hz, 1H), 2.44
(s, 3H), 1.11 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 168.1, 159.4,
144.2, 138.9, 135.7, 134.3, 129.8 (2C), 129.2, 127.8 (2C), 119.3, 119.0,
113.3, 113.0, 82.5, 75.2, 72.1, 55.3, 50.1, 43.2, 27.5 (3C), 21.7; IR
(neat) ν 1742, 1587, 1350, 1163, 912 cm−1; HRMS (ESI TOF M +
Na) m/z 510.1391. Calcd for C25H29NO5S2Na m/z 510.1385.
Preparation of (6S)-tert-Butyl 6-Propyl-5-tosyl-4,5,6,6a-tet-
rahydro-1H-thieno[3,4-c]pyrrole-6a-carboxylate (2k). A Pyrex
flask (30 mL) was charged with a solution of 1k (117.6 mg, 0.30
mmol) and dimethyldisulfide (0.30 mL, 3.38 mmol) in toluene (30
mL), and the reaction solution was irradiated by a mercury lamp at
ambient temperature under nitrogen atmosphere for 5 h. The reaction
mixture was concentrated, and the residue was purified through flash
chromatography (silica gel/hexane−EtOAc = 15:1 then 5:1) to give 2k
ASSOCIATED CONTENT
■
S
* Supporting Information
Compound characterization data and CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ak10@yamaguchi-u.ac.jp.
F
dx.doi.org/10.1021/jo400975t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Notes
The authors declare no competing financial interest.
(9) (a) Jackson, R. A.; Townson, M. Tetrahedron Lett. 1973, 14, 193.
(b) Jackson, R. A.; Townson, M. J. Chem. Soc. Perkin Trans. 2 1980,
1452. (c) Anpo, M.; Chatgilialoglu, C.; Ingold, K. U. J. Org. Chem.
1983, 48, 4104.
(10) Geometry optimizations were carried out using the B3PW91/6-
311G(d), B3LYP-D/6-311G(d), and MP2/6-31G(d) methods. Initial
structure for intermediate C gave compound 2 (by B3LYP-D/6-
311G(d)) or intermediate B (by B3PW91/6-311G(d) or MP2/6-
31G(d)) through optimization. All these calculations were performed
with the Gaussian 09 program package.
ACKNOWLEDGMENTS
■
We are grateful to have financial aid from the Sasakawa
Scientific Research Grant (to K.M.) and from Yamaguchi
University’s Strategic Program for Fostering Research Activities
(2010−2011, 2013−2014). We are also grateful to Dr.
Tsuyoshi Arai and Dr. Yousuke Oota, UBE Scientific Analysis
Laboratory Inc. for their NMR analyses of several compounds.
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G
dx.doi.org/10.1021/jo400975t | J. Org. Chem. XXXX, XXX, XXX−XXX