Access to 2,3-diaryl-4-nitrothiochroman S,S-dioxides from 3-nitrobenzo[bthiophene

Article abstract of DOI:10.1016/j.tet.2011.08.038

The base-induced cyclization of (E)-2-aryl-1-[2-(benzylsulfonyl)phenyl-1- nitroethenes to polysubstituted thiochroman S,S-dioxides exhibits a diastereoselectivity that can be oriented towards a selected isomer by means of appropriate adjustments of the experimental conditions. The interest of such a result also rests on the promising pharmacological activity of the products, whose structure encompasses different well-acknowledged pharmacophores. A conformational ¹H NMR investigation, backed by molecular-mechanics calculations, has also been accomplished.

Full text of DOI:10.1016/j.tet.2011.08.038

Tetrahedron 67 (2011) 8160e8169
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Access to 2,3-diaryl-4-nitrothiochroman S,S-dioxides from 3-nitrobenzo[b]
thiophene
Lara Bianchi a, Massimo Maccagno a, Giovanni Petrillo a, Egon Rizzato b, Fernando Sancassan a,
,
Domenico Spinelli c, Cinzia Tavani a
*
a
ꢀ
Dipartimento di Chimica e Chimica Industriale, Universita di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, Via S. Giacomo 11, I-40126 Bologna, Italy
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, Via Selmi 2, I-40126 Bologna, Italy
b
ꢀ
c
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2011
Received in revised form 2 August 2011
Accepted 15 August 2011
Available online 22 August 2011
The base-induced cyclization of (E)-2-aryl-1-[2-(benzylsulfonyl)phenyl]-1-nitroethenes to poly-
substituted thiochroman S,S-dioxides exhibits a diastereoselectivity that can be oriented towards a se-
lected isomer by means of appropriate adjustments of the experimental conditions. The interest of such
a result also rests on the promising pharmacological activity of the products, whose structure encom-
passes different well-acknowledged pharmacophores. A conformational 1H NMR investigation, backed
by molecular-mechanics calculations, has also been accomplished.
Keywords:
Thiochromans
Ó 2011 Elsevier Ltd. All rights reserved.
3-Nitrobenzo[b]thiophene
Ring-opening/ring-closing reactions
Ring enlargement
Conformations
1. Introduction
In the light of the possible biological interest attached to 6,
a drawback of the synthetic procedure is represented by the low
Within the framework of our long-standing project on the
synthetic exploitation of the ring-opening of nitrothiophenes1e6
we have reported a novel approach to 3,4-disubstituted thiochro-
man S,S-dioxides (6, Scheme 1).4 The pivotal step is represented by
an intramolecular Michael-type addition onto a nitrovinyl moiety
(Scheme 1, step v) and the overall procedure from 3-nitrobenzo[b]
thiophene (1) can be envisaged as a 5 to 6 enlargement of the sulfur
heterocycle, with the carbon atom at position 2 as the new entry,
provided by MeI (step ii).
The cyclization step of 5 to 6 proved very efficient, always pro-
ceeding with high practical yields, thus allowing a more than sat-
isfactory completion of the ring-opening/ring-closure protocol. The
resulting nitrothiochroman S,S-dioxides 6 are polyfunctionalized
molecules of undeniable interest. As a matter of fact, some struc-
tural features make such sulfur heterocycles suitable candidates for
pharmacological/biological evaluation: this is because they contain,
within a relatively simple molecular array, well-known pharma-
cophores, such as the sulfonyl and the nitro groups, while the
electronic properties of the Ar moiety could be modulated by
means of suitable substituents.
diastereoselectivity shown by the cyclization step in the conditions
described (see footnotes of Scheme 1): actually, mixtures of the cis
and trans isomers of 6 were generally formed, with a very small
preference for the cis isomer.3 A somehow more significant dia-
stereoselection was observed only when Ar¼1-naphthyl and o-tolyl
(cis to trans ratio¼3 and 2.2, respectively), so demonstrating some
dependence on steric hindrance.
On these grounds, in order to widen the applicability range of
the ring-enlargement procedure and also with the aim of improv-
ing the diastereoselection of the cyclization step, we have increased
the structural complexity of our system allowing a substituent also
on the incoming carbon atom (e.g., at position 2 of the final het-
eroring): relevant synthetic results are presented and discussed
herein, with particular attention to the stereochemical aspects of
the process.
2. Results and discussion
2.1. Synthetic and diastereoselective aspects
The synthesis of the trisubstituted thiochroman S,S-dioxides 10,
bearing a phenyl substituent at C(2) of the heteroring, was ac-
complished following the procedure already described for the
* Corresponding author. E-mail address: cinzia.tavani@unige.it (C. Tavani).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.038

L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
8161
NO2
NO2
Ar
R'
ring-enlargement
6: R' = H
10: R' = Ph
S
S
O2
1
i
v
NO2
NO2
NO2
NO2
iv
ii
iii
Ar
SCH2R'
NR2
SCH2R'
NR2
Ar
SO2CH2R'
SAg
2
3: R' = H
7: R' = Ph
4: R' = H
8: R' = Ph
5: R' = H
9: R' = Ph
Scheme 1. (i) Pyrrolidine (R2NH, 2 mol equiv)/AgNO3 (2 mol equiv), abs. EtOH, rt, overnight; (ii) excess MeI or PhCH2Cl, 0 ꢁC to rt, 2 h; (iii) ArMgX or ArLi (1.1 mol equiv), THF,
ꢀ78 ꢁC, 15e45 min, followed by acidic quenching; (iv) MCPBA (2 mol equiv), CH2Cl2, rt; (v) LHMDS (1.1 mol equiv), THF, rt, 4 h, followed by NH4Cl quenching, 15 min.
parent compounds 6, as summarized in Scheme 1. The phenyl
moiety can be easily introduced during step ii, employing benzyl
chloride instead of methyl iodide as the alkylating agent for the
trapping of the thiolate intermediate 2, in otherwise similar ex-
perimental conditions.
Replacement of the NR2 group with an aryl moiety by treatment
of nitroenamine 7 with Grignard reagents experienced the same
stereoselectivity as previously observed for the synthesis of 4.
According to a well established procedure,4,7,8 sulfides 8aej
were then treated with MCPBA to give the corresponding sulfones
9aej in very high yield throughout (see Table 1).
Treatment of sulfones 9aej with lithium bis(trimethylsilyl)am-
ide (LHMDS, 1.1 mol equiv) in THF (a solvent capable to solvate
lithium cations) in standard conditions (see footnotes of Scheme 1),
followed by acidic quenching, allowed the isolation of the corre-
sponding cyclized products 10aej (Scheme 1) in more than satis-
factory yields (Table 1).
From the observed relative ratios, reported in Table 1, calculated
versus the signal for the C isomer (usually the lowest), a sizeable
prevalence of A in all cases but for entry 9 (Ar¼2-thienyl) clearly
emerges.
The structures of A, B and C were later identified as depicted in
Fig. 1 by a combined molecular-mechanics and 1H NMR spectro-
scopic investigation (see details in Section 2.2 below); the D
structure was deduced subsequently.
Before considering the stereochemical results shown in the last
two columns of Table 1, it is necessary to analyze the process in
detail. The base-induced cyclization under investigation (i.e., step v
of Scheme 1) is composed of four different, consecutive events
(Scheme 2), namely: (a) proton extraction from 9 to give the
delocalized carbanion 9ꢀ; (b) intramolecular conjugated Michael-
type addition of the anion onto the nitrovinylic moiety, to give
the nitronate anion intermediate 11ꢀ; (c) protonation of the
nitronate, most likely to initially give the corresponding nitronic
acid 11, and then (d) nitronic acid/nitroalkane tautomeric equili-
bration to the observed final product 10.9
It should be remarked that the relative position of the sub-
stituents at C(2) and C(3) is determined during the second event,
while the stereochemistry at C(4) is established after acidic
quenching.
The stereochemical aspect is thus set-up along with step b,
whereby two diastereomeric nitronates (cis-11ꢀ and trans-11ꢀ) are
generated, which would in turn eventually lead to the A/D (D being
never observed throughout in the conditions employed) and the B/
C products, respectively. The cis-nitronate/trans-nitronate ratios
can be deduced from the A:B:C ratios as A:(BþC) and relevant
values are reported in the last column of Table 1.
Such data show that, in the conditions employed, the cyclization
step generally favours the cis-nitronate, the diastereoselectivity
being good for Aryl¼o-tolyl (entry 2, cis/trans¼8.6) and 1-naphthyl
(entry 8, cis/trans¼4.8) but moderate to low in all of the other cases.
For Ar¼2-thienyl, the diastereoselectivity is appreciable but inver-
ted (entry 9, cis/trans¼0.1): this outcome, which is rather surprising
but definitely confirmed by replicate experiments, could be as-
cribed to some steric and/or stereoelectronic effects selectively
played by the 2-thienyl moiety; on the other hand, under kinetic
control (see below in the text) the same derivative lines up nicely
with all of the others (see Table 3).
On the grounds of the just described outcomes, in order to
better understand which parameters might influence the di-
astereomeric ratios, some targeted experiments on the model
compounds 9d and 10d were devised and relevant selected results
are reported in Table 2.
Table 1
Yields for the synthesis of sulfides 8aej, sulfones 9aej and thiochromans 10aej
according to Scheme 1.a Diastereomeric ratios obtained from 1H NMR spectroscopic
analysis for compounds 10aej are also reported
Entry Ar in
ArMgX
8: Yield %b 9: Yield %b 10:
Yield %c A:B:Cd
A:(BþC)e
1
2
3
4
5
6
7
8
9
Ph
8a: 97
8b: 99
8c: 93
8d: 96
9a: 99
9b: 92
9c: 97
9d: 99
9e: 99
9f: 97
9g: 99
9h: 99
9i: 97
9j: 99
10a: 83 10.8:2.1:1 3.5
10b: 82 26.6:2.1:1 8.6
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4 8e: 99
4-ClC6H4
4-BrC6H4
1-Naphthyl 8h: 89
2-Thienyl
3-Thienyl
10c: 88 9.9:2.0:1
10d: 98 9.9:1.8:1
10e: 82 4.6:2.9:1
10f: 90 3.3:1.0:1
10g: 97 2.2:0.7:1
3.3
3.5
1.2
1.6
1.3
8f: 99
8g: 77
10h: 94 18.8:2.9:1 4.8
8i: 96
8j: 99
10i: 93 0.2:0.8:1
10j: 82 4.0:1.1:1
0.1
1.9
10
a
For the reaction conditions, see footnotes of Scheme 1, steps iii, iv and v,
respectively.
b
c
Yields of chromatographically isolated compounds.
Yields of solid crude residues, showing three series of signals by 1H NMR
spectroscopic analysis.
d
Isomer D was never observed (see text).
The significance of the A:(BþC) ratio will be enlightened in the text.
e
In each case investigated, the 1H NMR spectroscopic analysis of
the crude reaction product showed the presence of three series of
similar signals with different relative intensities, which, on the
grounds of the structure of the expected thiochroman, could
straightforwardly be attributed to three different diastereomers,
named A, B and C. Actually, the cyclization process generates three
stereogenic centres and should theoretically give four different
diastereomeric products: thus, the absence of one of them (i.e., D)
immediately appeared somehow intriguing.
Two main outcomes clearly emerge from the data collected: (a)
comparison of entries 1 and 2 as well as of entries 3 and 4

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L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
Table 2
Diastereoselectivity tests for the model 9d to 10d transformation: relative percentages of A, B, C by varying the time of permanence of 9d or 10d in basic and/or acidic medium
Entry
Substrate
LHMDS mol
equiv
Time elapsed in
basic medium
Time elapsed in
acidic mediuma
150
150
Prolonged
Prolonged
150
150
A%b
B%b
C%b
cis-11/trans-11
[A:(BþC)]
3
1.9
3.3
1.9
0
0.9
0.7
B:C
1
2
3
4
5
6
7
9d
9d
9d
9d
9d
10d-A
10d-A
1.1
1.1
1.1
1.1
2.5
1.1
1.1
4 h
24 h
4 h
24 h
4 h
4 h
75
66
77
65
d
15
21
5
10
13
18
27
40
21
42
1.5
1.6
0.3
0.3
1.5
1.5
0.4
8
60
31
16
48
42
4 h
Prolonged
a
Quenching: NH4Cl aqueous solution (excess).
Normalized percentage, calculated by 1H NMR spectroscopic analysis.
b
NO2
NO2
NO2
NO2
Ar
Ph
Ar
Ph
Ar
Ph
Ar
Ph
S
S
S
S
O2
C: trans-trans-10
O2
O2
O2
A: cis-trans-10
B: trans-cis-10
D: cis-cis-10
Fig. 1. Structure of the four possible diastereomeric racemic couples for compounds 10.
9
first event: proton
extraction from 9
a
LHMDS
O2N
Ar
SO2CHPh
second event:
intramolecular
Michael addition
9
b
b
NO2
NO2
Ar
Ar
(i)
S
Ph
S
Ph
O2
O2
trans-11
cis-11
third event:
protonation after
acidic quenching
c
c
H
H
O
OH
O
OH
N
N
Ar
Ar
cis-11
trans-11
S
Ph
S
Ph
fourth event:
tautomerization
O2
O2
d
d
d
d
NO2
NO2
NO2
NO2
Ar
Ar
Ar
Ar
S
S
Ph
S
Ph
S
Ph
Ph
O2
O2
O2
O2
10-B
10-C
10-A
10-D
Scheme 2. (i) Represents racemization at C(2) via a dianion in the presence of excess base (see text and Scheme 3 below).
establishes that the cis-nitronate/trans-nitronate [A:(BþC)] ratio is
affected by the time elapsed in basic medium, the cis-nitronate
being significantly favoured at shorter times, and (b) on the other
hand, comparison of entries 1 and 3 as well as of entries 2 and 4
states that the time elapsed after acidic quenching, while unin-
fluent upon the A:(BþC) ratio, strongly affects the B:C ratio, the
latter prevailing at longer times.
diastereoselective: a selectivity which is partly lost because of an
equilibration between the two nitronates prior to acidic quenching.
A rationalization could be offered, at least in principle, by the
reversibility of the Michael addition; actually, besides being in gen-
eral quite controversial,10 herein such an occurrence appears a most
unlikely one, when considering that it would lead to a less stabilized
anion11 through a thermodynamically unfavourable ring-opening.
On the otherhand, directequilibration between cis-11ꢀ and trans-
11ꢀ, as depicted in Scheme 2, cannot occur and a dianion (e.g., cis-
The first outcome above implicitly suggests that the attack of the
anion upon the nitrovinyl moiety could be per se even more

L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
8163
assess that the cis-nitronate (cis-11ꢀ) is the ‘kinetic’ intermediate,
while the trans-nitronate is the ‘thermodynamic’ one, becoming
prevalent at longer times in basic medium; in addition, the pro-
tonation after acidic quenching [step (c) of Scheme 2] kinetically
favours the transecis isomer B, while the transetrans isomer C,
eventually prevails if enough time is allowed for equilibration
(most likely through the nitronic acid 11, by means of an acid cat-
alyzed aci/nitro tautomerism: step d of Scheme 2). Within the A/D
pair, the first is probably favoured both from a kinetic and a ther-
modynamic point of view, an outcome which justifies the total
absence of D.
On the grounds of the considerations above, with the aim of
improving the diastereoselectivity according to a kinetic control,
the same series of reactions as reported in Table 1 was repeated at
ꢀ78 ꢁC, in otherwise unchanged experimental conditions. Besides
to yields (reported in Table 3, column 3) always comparable to
those obtained at room temperature, the noteworthy enhancement
in diastereoselectivity in favour of A (which becomes the major
product even in the case of Ar¼2-Th: entry 9) is evident from the
data in columns 4, 5 and 6: in the latter the ratios A:(BþC) values,
representative of cis-nitronate/trans-nitronate ratios, are compared
at the two temperatures employed.
Table 3
Yields and diastereomeric ratios for the 9 to 10 intramolecular process at ꢀ78 ꢁCa
Entry Ar
10: Yield %b A:B:Cc
A:(BþC) Ratio between
the A:(BþC) values
at ꢀ78 ꢁC and 22 ꢁCd
1
2
3
4
5
6
7
8
9
Phenyl
10a: 84
10b: 88
10c: 81
10d: 97
32.1:1.3:1 14.0
49.9:2.4:1 14.7
24.6:1.6:1 9.5
217.8:3.9:1 44.4
28.8:0.7:1 16.9
4
1.7
2.9
12.7
14.1
5.5
12.6
1.7
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4 10e: 85
4-ClC6H4
4-BrC6H4
1-Naphthyl 10h: 90
2-Thienyl
3-Thienyl
10f: 90
10g: 90
17.5:1.0:1
8.8
32.8:1.0:1 16.4
20.7:1.6:1
17.6:0.9:1
8.0
9.3
10i: 95
10j: 90
93
7.4
10
28.0:1.0:1 14.0
a
Experimental conditions otherwise identical to those for the reactions in Table 1.
Yields of solid crude residues, showing three series of signals by 1H NMR
b
spectroscopic analysis.
c
Isomer D was never observed.
Data from Table 1.
d
112ꢀ, Scheme 3) must be necessarily postulated in the experimental
conditions adopted. As a matter of fact, when considering the
structure of the final thiochroman derivative, not only H(4) (a nitro-
activated hydrogen) but also H(2) (a benzylic hydrogen adjacent to
a sulfonyl group) should conceivably display some acidic character:
on these grounds, the participation of a carbanion as 112ꢀ in the
presence of excess base could reasonably be hypothesized, which
would justify equilibration between cis-11ꢀ and trans-11ꢀ when
admitting some resonance charge delocalization onto the sulfonyl
and/or the phenyl group and hence epimerization at C(2) (Scheme 3).
Finally, we anticipated that an even higher diastereoselectivity
in favour of A could be obtained when avoiding excess base and/or
at shorter reaction times. Accordingly, the experiment of entry 6 of
Table 1 (Ar¼4-ClC6H4: the substrate was purposely chosen as it
displayed one of the lowest stereoselectivities) was repeated
employing exactly 1 equiv of LHMDS and quenching aliquots after 2
NO2
NO2
NO2
NO2
Ar
Ar
Ar
Ar
+ H
− H
S
Ph
S
Ph
S
Ph
S
Ph
O2
O2
O2
O2
2
2
trans-11
cis-11
trans-11
cis-11
epimerization at C(2)
Scheme 3.
The role of excess base (ca. 10% in the experimental conditions
generally applied: see Tables 1 and 2) seems clearly testified by the
results of expt 5 of Table 2, whereby the employment of 2.5 equiv of
base in conditions otherwise similar to those of expt 1 leads, after
comparable reaction times, to the complete disappearance of A in
the final mixture, which only contains B and C in a 1.5 to 1 ap-
proximate ratio. While the absence of any detectable A (besides to
the lack of D) clearly mirrors a high degree of stereoselectivity
favouring the trans-nitronate 11ꢀ, which should be of thermody-
namic origin (see below), interestingly enough, the B:C ratio well
matches the values reported in Table 1 (entry 4, B:C¼1.8) and 2
(entries 1, 2 and 6; B:C¼1.5, 1.6 and 1.5, respectively), firmly stating
that such a ratio is not affected by base concentration/excess and/or
time of permanence in basic medium (see below in the discussion).
Actually, as already mentioned above, all of the data collected
strongly suggest the dependence of the B:C ratio (Table 2, last
column) on the time of permanence in acidic medium after
quenching, moving from the initial 1.5 figure (entries 1 and 2) to
a possibly definitive 0.3 value (entries 3 and 4) obtained after an
overnight permanence. It should be noted that the same initial and
final values for the B:C ratio are obtained when the isolated A
isomer of 10d is subjected to the same experimental procedure as
applied for the cyclization of 9d (entries 6 and 7).
and 4 h. In both cases, the cis-nitronate/trans-nitronate ratio raised
from 8.8 (see Table 3) to 14, thus testifying that if no excess free
base is present in the reaction medium, the preference for cis-11ꢀ
(and hence for A in the final mixture) is further improved; more-
over, in such conditions time elapsing before acidic quenching loses
its significance, as any equilibration between cis-11ꢀ and trans-11ꢀ
through a dianion is practically precluded.
Nitronate cis-11ꢀ was thus confirmed as the kinetically-fav-
oured intermediate with respect to the presumably more stable
trans-11ꢀ. Searching for a possible explanation, we speculate that
the conversion of the carbanion 9ꢀ into the more stable nitronate
11ꢀ should exhibit an early transition state, so that the lower-
energy transition state could not correspond to the more stable
reaction product. It seems reasonable to advance the hypothesis
that the reactive sites of 9ꢀ approach each other as described in I
(Fig. 2), a disposition that preludes to the cis-nitronate. As a matter
of fact, the approach depicted in II, precursor of the trans-nitronate,
would be less energetically advantageous because of the de-
veloping unfavourable 1,3-diaxial-like interaction between the
phenyl and the nitro group.
2.2. Assignment of the stereostructures to AeD isomers
At this stage of our study, at least as far as the model 9d/10d
system is concerned, but presumably in a more general way, we can
The stereostructures of the three observed (A, B and C) enan-
tiomeric pairs have been determined by a careful analysis of the 1H

8164
L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
NO2
H
NO2
side (generating two non-equivalent boats): in the latter case,
though, severe eclipsing at the C(2)eC(3) bond should be expected.
Another possibility is represented by sofa conformations, exhibiting
justone carbon outof the plane and thus partiallyavoidingeclipsing.
For this reason sofa conformations received much attention as
possible competitors to half chairs in related systems.12e15
Ph
H
H
S
S
O2
O2
Ph
Ar
H
I
II
Ar
We have approached the problem by means of MMX3 calcula-
tions (PCMODEL16) on 10a as the model compound. The results
obtained (in the absence of solvent) are in perfect agreement with
what previously observed for the C(2) unsubstituted thiochromans
6, showing that for each diastereomer the most stable conforma-
tions are the two possible half chairs showed in Fig. 3.
Fig. 2. Alternative spatial approaches for the intramolecular Michael addition of
Scheme 2.
NMR spectroscopic data (reported in Table 4), coupled with a con-
formational analysis based on molecular-mechanics calculations
(results in Table 5).
Table 4
1H NMR spectroscopic dataa for the non-aromatic protons of the enantiomeric pairs
10a
Ph
10AeC
Ph
O
S
H
pax
10 Ar
Stereoisomer d d d
(4-H)b (3-H)c (2-H)b J (3-H, 4-H) J (2-H, 3-H)
H
peq
H
peq H
peq
a
b
c
d
e
f
Phenyl
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
6.34
6.13
6.19
6.34
6.04
6.15
6.32
6.12
6.18
6.30
6.10
6.17
6.27
6.10
6.16
6.28
6.10
6.15
6.27
6.11
6.15
6.49
6.27
6.29
6.25
6.19
6.20
6.20
6.14
6.16
5.19
4.84
5.00
5.56
5.04
5.32
5.16
4.79
4.94
5.15
4.80
4.94
5.13
4.78
4.93
5.16
4.83
4.98
5.15
4.82
4.96
6.23
5.74
6.06
5.53
5.09
5.38
5.32
4.99
5.17
4.65
5.98
4.70
4.49
5.96
4.56
4.63
5.96
4.68
4.64
5.96
4.73
4.63
5.93
4.67
4.62
5.92
4.67
4.62
5.91
4.70
4.80
6.14
4.78
4.74
5.96
4.64
4.71
5.93
4.66
11.7
4.8
9.3
12.0
4.8
8.0
12.0
4.8
9.3
11.6
5.2
9.3
11.4
4.5
9.3
11.4
4.5
9.6
11.5
4.7
9.5
12.3
4.2
8.4
3.9
12.9
11.7
3.6
12.6
10.5
3.6
12.6
11.4
3.8
12.8
11.7
3.9
12.6
11.7
3.6
12.9
11.7
3.6
12.8
11.5
3.0
12.3
10.3
4.2
O
S
NO2
O
O
O
Ph
Ph
A'
A"
O
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
NO2
H
pax
H
pax
H
pax
Ph
NO2
Ph
O
S
H
peq
Ph
S
O
NO2
H
peq
H
peq
H
O
B'
pax
B"
H
Ph
pax
Ph
H
pax
H
pax
O
S
Ph
S
H
O
peq
H
peq
g
h
i
4-BrC6H4
NO2
Ph
H
peq
NO2
O
C'
C"
1-Naphthyl A
H
pax
Ph
Ph
B
C
H
H
pax
pax
H
O
pax
2-Thienyl
3-Thienyl
A
B
C
A
B
C
11.1
4.8
9.0
11.1
4.8
9.6
Ph
S
Ph
12.6
11.7
3.9
12.6
11.4
O
H
peq
S
NO2
H
j
O
peq
H
peq
O
D'
NO2
D"
Ph
a
Chemical shifts
d in ppm from internal TMS, coupling constants J in Hz, solvent
CDCl3 no long-range coupling was detected at 300 MHz.
Fig. 3. Most stable, half-chair conformations for stereoisomers AeD.
b
Doublet.
c
Doublet of doublets.
Table 5
Optimization of stereostructures A, B, C, D when Ar¼Ph (10a) according to PCModel (in the absence of solvent)a
10a
Eb
m
Dihedral (degrees)
(kcal/mol)
(Debye)
C(4a)eC(8a)eS(1)eC(2)
C(8a)eC(4a)eC(4)eC(3)
H(2)eC(2)eC(3)eH(3)
H(3)eC(3)eC(4)eH(4)
2-Ph
rot
3-Ph
rotd
NO2
rot
c
e
A0
B0
C0
D0
43.4
41.7
41.4
46.6
2.9
4.5
2.6
2.8
8.1
7.0
5.2
9.1
20.0
22.4
24.1
18.8
57.5
173.2
173.4
59.7
179.5
53.1
177.8
51.2
45.8
80.2
77.1
55.1
47.5
87.9
66.0
48.3
62.7
53.3
63.7
48.3
a
MMX3 program.
Steric energy.
S(1)eC(2)eC(10)eC(20).
C(4)eC(3)eC(100)eC(200).
C(4a)eC(4)eNeO.
b
c
d
e
As a matter of fact, as far as thiochromans 10 are concerned, while
In particular A0, B0 and C0 result to be the most stable because all
of the others (D0, A00, B00, C00, D00) exhibit unfavourable 1,3-
pseudodiaxial interactions between substituents (as indicated in
Fig. 3); it is actually well-known that the stability of six-membered
the sulfur atom and C(4) are coplanar with the condensed benzene
moiety, C(2) and C(3) can be either on opposite sides with respect to
the plane(generatingtwonon-equivalent half chairs) oron the same

L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
8165
rings is ruled by 1,3-diaxial interactions, which usually destabilize
conformations with axial substituents with respect to those with
the same substituents in an equatorial position.
base and/or prolonging the time of permanence in the basic me-
dium prior to acidic quenching), whose molar ratio can be in turn
modulated thanks to equilibration in acidic medium.
In Table 5 we report details of this study relevant to the opti-
mized structures. It should be underlined that isomer D shows the
highest value of steric energy, in agreement with its absence in the
crude product. As far as dihedral angles are concerned, the four
lower-energy conformations do present different values for H(2)e
C(2)eC(3)eH(3) and H(3)eC(3)eC(4)eH(4), but in any case the
calculated values are not far away from the standard values of 180ꢁ
and 60ꢁ expected for trans-diaxial and cis geometries, respectively.
The results obtained from the molecular-mechanics calculations
allowed the interpretation of 1H NMR spectra, on the basis of the
KarpluseConroy rule:17,18 quasi-trans 1,2-pseudodiaxial in-
teractions need large vicinal JHeH coupling constants (10e15 Hz)
while 1,2-pseudoaxial-pseudoequatorial interactions need small
ones (2e5 Hz). Thus, the non-aromatic signals of A, B and C in the
1H NMR spectra of the crude products could be assigned without
uncertainty.
It should be finally mentioned that the introduction on the
thiochroman ring-system of an additional substituent at C(2), be-
sides to the impact on the stereochemical aspects of the cyclization
process represents, with respect to the C(2)-unsubstituted ana-
logues 6 of Scheme 1, a means for further diversification, with
possible effects also on the hydrophilic/hydrophobic character of
the molecule and hence, e.g., on its polar/non polar interactions
with biological sites.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded at 300 MHz and
75 MHz, respectively, chemical shifts (TMS as internal reference)
are reported as
d values (ppm). IR spectra were recorded on a Per-
It is convenient to start our analysis from stereostructures C, as
they exhibit two large (9.0e11.7 Hz) vicinal coupling constants,
unequivocally showing that the main conformation exhibits three
pseudoaxial protons and therefore all of the three substituents are
pseudoequatorial. In this kind of stereostructure, the observed
chemical shift difference between 4-H and 2-H is always
1.44e1.56 ppm, in excellent agreement with the observed differ-
kineElmer 881 Infrared Spectrophotometer. MS(ESI) analyses were
recorded on a Micromass ZMD Waters instrument (30 V, 3.2 kV,
isotopes observed 35Cl and 79Br). HRMS were recorded on
a THERMO FINNIGAN MAT95XP apparatus (isotopes observed 35Cl
79
€
and Br). Melting points were determined with a Buchi 535 ap-
paratus. Petroleum ether and light petroleum refer to the fractions
with bp 40e60 ꢁC and 80e100 ꢁC, respectively. Silica gel
230e400 mesh was used for column chromatography, all solvents
being distilled before use. Tetrahydrofuran (THF) was purified by
standard methods and distilled over potassium benzophenone
ketyl before use. Pyrrolidine was dried and distilled over potassium
hydroxide before use. Lithium bis(trimethylsilyl)amide (LHMDS,
1 M in THF) and all of the other commercially available reagents
were used as received.
Organometallic reagents. All the reagents were THF or Et2O solu-
tions titrated just before use. Phenyl-, 4-methoxyphenyl-, 4-
methylphenyl-, 1-naphthyl-magnesium bromides, 2-methylphenyl-,
3-methylphenyl-magnesium chlorides, 3-thienylmagnesium iodide
were commercial solutions in THF; 4-chlorophenylmagnesium
bromide and 2-thienyllithium were commercial solutions in
Et2O. 4-Bromophenylmagnesium bromide was prepared from the
corresponding commercial 1,4-dibromobenzene using standard
procedures.
ence between CH3NO2
(dH¼4.3 ppm) and CH3SO2R (dH¼2.8 ppm).
Either A or B exhibit both a large and a small vicinal coupling
constant. Therefore 3-H has to be pseudo-axial again, while either
2-H or 4-H are pseudo-equatorial in turn. We can observe that A
and C exhibit similar chemical shifts values, while in B some per-
turbing effect strongly deshields 2-H, very likely as a consequence
of the effect of a pseudo-axial 4-nitro group on a pseudo-axial 2-H.
Accordingly, in most trans-4-nitro-3-arylthiochroman S,S-di-
oxides 6 [see Ref. 3, Table 3], 2-Hpax and 2-Hpeq exhibited very
similar chemical shifts as the nitro group was pseudo-equatorial,
while in the cis forms, where the nitro group was pseudo-axial,
2-Hpax exhibited a further deshielding of 1 ppm.
On the basis of such considerations, the stereostructures AeC
were assigned to the obtained compounds, as reported in Fig. 1.
3. Conclusions
The intramolecular base-induced Michael addition discussed in
the present report represents a convenient approach to the
substituted thiochroman S,S-dioxides 10, obtained in high yields
generally as mixtures of diastereomers.
The renewed interest for the thiochroman ring-system, espe-
cially when densely functionalized, is testified by a number of
publications in the recent literature19e25 and is strictly connected to
a noteworthy biological and pharmacological activity.26e31
On these grounds, the concurrence of different well-
acknowledged pharmacophores makes compounds 10 appealing
for pharmacological tests: it is surely worth mentioning that, in
particular, a promising activity as calcium-channel modulators is
emerging from preliminary tests.32 Thus, the stereochemical as-
pects displayed by the cyclization process herein seem particularly
rewarding: as a matter of facts, while one (namely, D) out of the
four expected racemic pairs is never observed, as far as A, B, and C
are concerned, a remarkable diastereoselectivity, adjustable in de-
pendence of the experimental conditions, allows the obtainment
on one side of mixtures highly enriched in A (reactions carried out
at low temperature and/or avoiding excess of base), from which A
(as a racemic mixture) can be easily isolated in a pure form by
crystallization, or, on the other side, of mixtures of B and C (re-
actions carried out at room temperature, in the presence of excess
4.2. Ring-opening of 3-nitrobenzo[b]thiophene
The ring-opening reaction was performed on 2 g of substrate,
according to conditions previously reported;33 the alkylation of the
obtained silver thiolate was realized with an excess of benzyl
chloride.
4.2.1. (E)-1-[2-(2-Benzylsulfanylphenyl)-2-nitrovinyl]pyrrolidine
(7). Yield (2.3 g, 62%). Yellow solid, mp 124e125 ꢁC (toluene); nmax
(Nujol) 1610, 1345, 1258, 1140, 1070, 1019 cmꢀ1 1H NMR (CDCl3)
;
d
1.75 (4H, m), 2.52 (2H, m), 3.60 (2H, m), 4.06 (1H, d, J 12.8 Hz), 4.15
(1H, d, J 12.8 Hz), 7.11e7.36 (9H, m), 8.63 (1H, s); 13C NMR (CDCl3)
d
24.2, 25.9, 37.3, 48.0, 55.1, 122.5, 125.0, 127.0, 127.2, 128.4, 128.9,
129.5, 131.3, 133.4, 136.9, 140.3, 145.7. MS(ESI): m/z 363 [MþNa]þ,
379 [MþK]þ. MS(EI) m/z 340 (Mþ, 4), 294 (100), 223 (56), 203 (37),
134 (46), 91 (55), 84 (51). HRMS calcd for C19H20N2O2S, 340.1246;
found 340.1245.
4.3. Reactions of 7 with aromatic organometallic reagents
The reactions were performed on
1 g of compound 7
(2.94 mmol) following the procedure previously reported for the

8166
L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
related methylthio derivatives.4 Yields of compounds 8aej are
m), 7.44 (2H, app d, J 3.7 Hz), 8.22 (1H, s); 13C NMR (CD3COCD3)
collected in Table 1.
d 38.1, 127.7, 128.1, 129.3, 129.8, 129.8, 130.5, 131.0, 131.7, 131.9, 132.4,
133.3, 135.1, 137.2, 137.8, 139.0, 149.8. MS(ESI): m/z 404 [MþNa]þ,
420 [MþK]þ. MS(EI) m/z 381 (Mþ, 5), 244 (34), 91 (100). HRMS
calcd for C21H16ClNO2S, 381.0590; found 381.0590.
4.3.1. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-phenylethene
(8a). Yield (0.99 g, 97%). Yellow solid, mp 75e76 ꢁC (light petro-
leum); nmax (Nujol) 1646, 1584, 1512, 1493, 1322, 1294, 1211, 1161,
1073, 1031 cmꢀ1; 1H NMR (CDCl3)
d
4.02 (1H, d, J 12.9 Hz), 4.07 (1H,
d, J 12.9 Hz), 7.03 (2H, d, J 7.5 Hz), 7.18e7.34 (10H, m), 7.41e7.43 (2H,
m), 8.28 (1H, s); 13C NMR (CD3COCD3)
38.2, 127.7, 128.1, 129.3,
4.3.7. (E)-1-[2-(Benzylsulfanyl)phenyl]-2-(4-bromophenyl)-1-
nitroethene (8g). Yield (0.96 g, 77%). Yellow solid, mp 123e124 ꢁC
(toluene/light petroleum); nmax (Nujol) 1643,1582,1514,1403,1322,
d
129.7,129.8,130.6,131.6,131.8,131.9,132.2,132.4,132.4,136.4,137.8,
139.1, 149.4. MS(ESI): m/z 370 [MþNa]þ, 386 [MþK]þ. MS(EI) m/z
347 (Mþ, 9), 301 (9), 210 (84), 165 (12), 91 (100). HRMS calcd for
C21H17NO2S, 347.0980; found 347.0980.
1184,1069,1010 cmꢀ1; 1H NMR (CDCl3)
d 4.03 (1H, d, J 12.9 Hz), 4.09
(1H, d, J 12.9 Hz), 6.85 (2H, d, J 8.4 Hz), 7.16e7.19 (1H, m), 7.20e7.30
(6H, m), 7.32 (2H, d, J 8.4 Hz), 7.42e7.44 (2H, m), 8.20 (1H, s); 13C
NMR (CDCl3)
d 38.3, 125.6, 127.1, 127.4, 128.5, 128.9, 129.9, 130.1,
130.8, 131.1, 131.2, 132.1, 132.2, 134.7, 136.4, 138.1, 148.6; MS(ESI): m/
z 448 [MþNa]þ, 464 [MþK]þ. MS(EI) m/z 425 (Mþ, 3), 290 (19), 208
(7), 165 (10), 91 (100). HRMS calcd for C21H16BrNO2S, 425.0085;
found 425.0083.
4.3.2. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-(o-tolyl)ethene
(8b). Yield (1.05 g, 99%). Yellow solid, mp 72e73 ꢁC (light petro-
leum); nmax (Nujol) 1643, 1599, 1581, 1523, 1326, 1240, 1227, 1158,
1069, 1028 cmꢀ1
;
1H NMR (CDCl3)
d
2.46 (3H, s), 4.05 (2H, app d, J
2.9 Hz), 6.61 (1H, d, J 7.8 Hz), 6.82 (1H, td, J 7.8, 2.1 Hz), 7.10e7.24
(9H, m), 7.31e7.38 (2H, m), 8.48 (1H, s); 13C NMR (CD3COCD3)
20.1,
4.3.8. (E)-1-[2-(Benzylsulfanyl)phenyl]-2-(1-naphthyl)-1-
nitroethene (8h). Yield (1.04 g, 89%). Yellow solid, mp 141e142 ꢁC
(toluene/light petroleum); nmax (Nujol) 1646, 1581, 1504, 1317,
d
38.2, 126.6, 127.2, 128.1, 129.3, 129.8, 129.9, 130.2, 131.1, 131.2, 131.3,
131.4, 132.1, 132.8, 134.7, 137.8, 139.2, 139.9, 150.4. MS(ESI): m/z 384
[MþNa]þ, 400 [MþK]þ. MS(EI) m/z 361 (Mþ, 10), 315 (8), 224 (80),
91 (100). HRMS calcd for C22H19NO2S, 361.1137; found 361.1135.
1246, 1067 cmꢀ1 1H NMR (CDCl3)
; d 4.06 (2H, s), 6.90 (1H, d, J
7.2 Hz), 7.07e7.15 (3H, m), 7.21e7.27 (5H, m), 7.33 (1H, app t, J
6.7 Hz), 7.39 (1H, d, J 7.5 Hz), 7.56 (1H, app t, J 6.9 Hz), 7.63 (1H,
app t, J 7.0 Hz), 7.79 (1H, d, J 8.4 Hz), 7.86 (1H, d, J 7.5 Hz), 8.14 (1H,
4.3.3. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-(m-tolyl)ethene
(8c). Yield (0.99 g, 93%). Yellow oil, nmax (Neat) 3057, 3027, 2920,
1950,1701,1647,1602,1583,1512,1494,1453,1435,1366,1327,1247,
d, J 8.1 Hz), 8.98 (1H, s); 13C NMR (CD3SOCD3)
d 36.1, 123.9, 125.0,
126.0, 126.5, 127.1, 127.3, 127.6, 128.1, 128.3, 128.4, 128.6, 128.7,
130.0, 130.3, 130.5, 131.2, 131.7, 132.8, 133.8, 136.7, 137.7, 150.1.
MS(ESI): m/z 420 [MþNa]þ, 436 [MþK]þ. MS(EI) m/z 397 (Mþ, 10),
351 (10), 260 (89), 91 (100). HRMS calcd for C25H19NO2S, 397.1137;
found 397.1133.
1179, 1129, 1096, 1069, 1043, 1030, 1000 cmꢀ1 1H NMR (CDCl3)
;
d
2.19 (3H, s), 4.00 (1H, d, J 12.9 Hz), 4.05 (1H, d, J 12.6 Hz), 6.78 (1H,
d, J 7.5 Hz), 6.88 (1H, s), 7.07 (1H, t, J 7.5 Hz), 7.13 (1H, d, J 7.8 Hz),
7.18e7.31 (7H, m), 7.41 (2H, app d, J 3.7 Hz), 8.25 (1H, s); 13C NMR
(CDCl3)
d
21.3, 38.6, 127.2, 127.3, 128.0, 128.5, 128.7, 128.9, 130.6,
4.3.9. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-(2-thienyl)ethene
(8i). Yield (1.00 g, 96%). Yellow solid, mp 123e124 ꢁC (light pe-
troleum); nmax (Nujol) 1627, 1580, 1514, 1501, 1331, 1311, 1288,
130.6, 130.6, 131.0, 131.4, 131.8, 132.1, 136.2, 136.6, 137.9, 138.4, 148.1.
MS(ESI): m/z 384 [MþNa]þ, 400 [MþK]þ. MS(EI) m/z 361 (Mþ, 2),
312 (12), 224 (22), 119 (21), 91 (100). HRMS calcd for C22H19NO2S,
361.1137; found 361.1134.
1246, 1157, 1068, 1052 cmꢀ1 1H NMR (CDCl3)
; d 4.02 (1H, d, J
13.2 Hz), 4.06 (1H, d, J 13.5 Hz), 7.03 (1H, dd, J 5.4, 3.9 Hz),
7.18e7.25 (5H, m), 7.28e7.40 (4H, m), 7.43e7.51 (2H, m), 8.53 (1H,
4.3.4. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-(p-tolyl)ethene
(8d). Yield (1.02 g, 96%). Yellow solid, mp 121e122 ꢁC (light pe-
troleum). nmax (Nujol) 1639, 1608, 1502, 1367, 1323, 1186,
s); 13C NMR (CDCl3)
d 38.6, 127.3, 127.5, 127.6, 128.5, 129.0, 130.1,
130.8, 130.8, 131.2, 131.9, 133.5, 135.0, 136.2, 136.6, 138.7, 145.3.
MS(ESI): m/z 376 [MþNa]þ, 392 [MþK]þ. MS(EI) m/z 353 (Mþ, 3),
306 (21), 216 (53), 91 (100). HRMS calcd for C19H15NO2S2,
353.0544; found 353.0546.
1070 cmꢀ1 1H NMR (CDCl3)
; d 2.31 (3H, s), 4.02 (1H, d, J 12.9 Hz),
4.07 (1H, d, J 12.9 Hz), 6.93 (2H, d, J 8.4 Hz), 7.02 (2H, d, J 8.1 Hz),
7.19e7.33 (7H, m), 7.41e7.43 (2H, m), 8.28 (1H, s); 13C NMR (CDCl3)
d
21.5, 38.5, 127.2, 127.3, 128.2, 128.5, 128.9, 129.6, 130.5, 130.6, 131.1,
4.3.10. (E)-1-[2-(Benzylsulfanyl)phenyl]-1-nitro-2-(3-thienyl)ethene
(8j). Yield (1.03 g, 99%). Yellow solid, mp 105e106 ꢁC (light petro-
leum); nmax (Nujol) 1633,1581,1313,1248,1174,1067 cmꢀ1; 1H NMR
131.4, 132.1, 136.2, 136.6, 138.0, 141.8, 147.4. MS(ESI): m/z 384
[MþNa]þ, 400 [MþK]þ. MS(EI) m/z 361 (Mþ, 8), 315 (9), 224 (100),
91 (85). HRMS calcd for C22H19NO2S, 361.1137; found 361.1136.
(CDCl3)
5.1, 1.2 Hz), 7.12 (1H, dd, J 5.1, 3.0 Hz), 7.17e7.35 (8H, m), 7.43 (2H,
app d, J 3.4 Hz), 8.32 (1H, s); 13C NMR (CDCl3)
38.5, 126.7, 127.1,
d 4.00 (1H, d, J 13.2 Hz), 4.05 (1H, d, J 13.2 Hz), 6.41 (1H, dd, J
4.3.5. (E)-1-[2-(Benzylsulfanyl)phenyl]-2-(p-methoxyphenyl)-1-
nitroethene (8e). Yield (1.10 g, 99%). Yellow solid, mp 107e108 ꢁC
(light petroleum); nmax (Nujol) 1633, 1599, 1302, 1258, 1171, 1071,
d
127.3, 127.7, 128.4, 128.9, 129.9, 130.5, 130.7, 131.4, 131.9, 132.5, 133.1,
136.5, 138.0, 146.8. MS(ESI): m/z 376 [MþNa]þ, 392 [MþK]þ. MS(EI)
m/z 353 (Mþ, 6), 307 (11), 216 (65), 91 (100). HRMS calcd for
C19H15NO2S2, 353.0544; found 353.0547.
1029 cmꢀ1 1H NMR (CDCl3)
; d 3.77 (3H, s), 4.01 (1H, d, J 13.1 Hz),
4.07 (1H, d, J 13.1 Hz), 6.72 (2H, d, J 9.0 Hz), 6.97 (2H, d, J 9.0 Hz),
7.18e7.31 (7H, m), 7.41e7.43 (2H, m), 8.28 (1H, s); 13C NMR (CDCl3)
d
38.3, 55.3, 114.4, 123.5, 127.1, 127.3, 128.5, 128.9, 130.3, 130.5, 131.4,
4.4. Oxidation of sulfides 8aej to sulfones 9aej
132.1, 133.1, 136.0, 136.6, 138.1, 145.9, 161.9. MS(ESI): m/z 400
[MþNa]þ, 416 [MþK]þ. MS(EI) m/z 377 (Mþ, 5), 330 (14), 240 (100),
225 (25), 197 (24), 91 (81). HRMS calcd for C22H19NO3S, 377.1086;
found 377.1083.
Reactions were performed on 2 mmol of the appropriate 8,
according to the conditions described in Ref. 3. Yields are reported
in Table 1.
4.3.6. (E)-1-[2-(Benzylsulfanyl)phenyl]-2-(4-chlorophenyl)-1-
nitroethene (8f). Yield (1.11 g, 99%). Yellow solid, mp 125e126 ꢁC
(light petroleum); nmax (Nujol) 1642, 1590, 1512, 1405, 1325, 1302,
4.4.1. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-phenylethene
(9a). Yield (750 mg, 99%). Yellow solid, mp 139e140 ꢁC (ethanol);
nmax (Nujol) 1642, 1514, 1310, 1203, 1155, 1116, 1068 cmꢀ1; 1H NMR
1210, 1181, 1092, 1068, 1013 cmꢀ1
;
1H NMR (CDCl3)
d
4.03 (1H, d, J
(CDCl3)
d 4.21 (1H, d, J 13.5 Hz), 4.34 (1H, d, J 13.5 Hz), 7.03 (2H, d, J
12.9 Hz), 4.09 (1H, d, J 13.2 Hz), 6.93 (2H, d, J 8.4 Hz), 7.15e7.31 (9H,
7.5 Hz), 7.19e7.37 (9H, m), 7.45e7.52 (2H, m), 7.62e7.67 (1H, m),

L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
8167
8.39 (1H, s); 13C NMR (CD3COCD3)
d
61.8, 128.7, 129.2, 129.5, 129.9,
(20), 176 (22), 165 (16), 91 (100). Anal. Calcd for C21H16ClNO4S (MW
413.87): C, 60.9; H, 3.9; N, 3.4%. Found: C, 60.7; H, 3.9; N, 3.5%.
131.5, 131.8, 131.9, 131.9, 132.0, 132.1, 132.7, 134.9, 135.5, 135.8,
139.5, 148.3. MS(ESI): m/z 402 [MþNa]þ, 418 [MþK]þ. MS(EI) m/z
333 (Mꢀ46, 20), 178 (11), 91 (100). Anal. Calcd for C21H17NO4S
(MW 379.43): C, 66.5; H, 4.5; N, 3.7%. Found: C, 66.4; H, 4.6; N,
3.6%.
4.4.7. (E)-1-[2-(Benzylsulfonyl)phenyl]-2-(4-bromophenyl)-1-
nitroethene (9g). Yield (910 mg, 99%). Yellow solid, mp 185e186 ꢁC
(ethanol/dioxane). nmax (Nujol) 1657, 1579, 1522, 1319, 1159, 1116,
1073, 1004 cmꢀ1; 1H NMR (CDCl3)
d 4.27 (1H, d, J 13.8 Hz), 4.37 (1H,
4.4.2. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-(o-tolyl)ethene
d, J 13.8 Hz), 6.86 (2H, d, J 8.7 Hz), 7.21e7.25 (2H, m), 7.28e7.38 (6H,
(9b). Yield (723 mg, 92%). Yellow solid, mp 171e172 ꢁC (ethanol);
m), 7.47e7.50 (2H, m), 7.60e7.68 (1H, m), 8.31 (1H, s); 13C NMR
nmax (Nujol) 1599, 1309, 1201, 1152, 1115, 1067 cmꢀ1
;
1H NMR
(CDCl3) d 61.7, 125.9, 127.6, 128.7, 129.0, 129.7, 130.4, 130.6, 131.3,
(CDCl3)
d
2.50 (3H, s), 4.24 (1H, d, J 13.5 Hz), 4.38 (1H, d, J 13.8 Hz),
132.3, 132.4, 132.6, 133.2, 134.6, 134.9, 138.0, 147.6; MS(ESI): m/z 480
[MþNa]þ, 496 [MþK]þ. MS(EI) m/z 413 (Mꢀ46, 10), 176 (10), 91
(100). Anal. Calcd for C21H16BrNO4S (MW 457.90): C, 55.0; H, 3.5; N,
3.1%. Found: C, 55.1; H, 3.4; N, 3.2%.
6.69 (1H, d, J 8.1 Hz), 6.87 (1H, td, J 8.1, 2.1 Hz), 7.14e7.23 (4H, m),
7.27e7.41 (6H, m), 7.49e7.57 (1H, m), 8.58 (1H, s); 13C NMR
(CD3SOCD3) d 20.3, 60.9,126.6, 128.3, 129.1,129.4, 129.5, 130.1,130.7,
131.1, 131.4, 131.6, 131.7, 131.8, 134.1, 135.0, 135.2, 138.7, 139.8, 148.7.
MS(ESI): m/z 416 [MþNa]þ, 432 [MþK]þ. MS(EI) m/z 347 (Mꢀ46,
30), 191 (11), 91 (100). Anal. Calcd for C22H19NO4S (MW 393.46): C,
67.2; H, 4.9; N, 3.6%. Found: C, 67.1; H, 4.7; N, 3.6%.
4.4.8. (E)-1-[2-(Benzylsulfonyl)phenyl]-2-(1-naphthyl)-1-
nitroethene (9h). Yield (849 mg, 99%). Yellow solid, mp 197e198 ꢁC
(ethanol/dioxane); nmax (Nujol) 1658, 1525, 1321, 1247, 1196, 1162,
1154, 1118 cmꢀ1; 1H NMR (CDCl3)
d 4.26 (1H, d, J 13.8 Hz), 4.39 (1H,
4.4.3. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-(m-tolyl)ethene
(9c). Yield (762 mg, 97%). Yellow solid, mp 148e149 ꢁC (ethanol);
nmax (Nujol) 1644,1565,1516,1327,1311,1249,1202,1151,1130,1116,
d, J 13.8 Hz), 7.06 (1H, d, J 7.2 Hz), 7.14e7.21 (4H, m), 7.26e7.43 (6H,
m), 7.56 (1H, app t, J 6.7 Hz), 7.64 (1H, app t, J 7.0 Hz), 7.77 (1H, d, J
8.1 Hz), 7.84 (1H, d, J 8.1 Hz), 8.14 (1H, d, J 8.4 Hz), 9.04 (1H, s); 13C
1068 cmꢀ1
;
1H NMR (CDCl3)
d
2.21 (3H, s), 4.19 (1H, d, J 13.5 Hz),
NMR (CDCl3) d 61.6, 123.7, 125.3, 126.7, 127.5, 127.7, 128.2, 128.6,
4.33 (1H, d, J 13.2 Hz), 6.76 (1H, d, J 7.5 Hz), 6.90 (1H, s), 7.09 (1H, t, J
7.5 Hz), 7.14 (1H, d, J 7.8 Hz), 7.19 (2H, app d, J 7.8 Hz), 7.27e7.39 (4H,
m), 7.48e7.51 (2H, m), 7.63e7.69 (1H, m), 8.34 (1H, s); 13C NMR
128.9, 128.9, 129.0, 130.0, 130.6, 130.8, 131.3, 131.9, 132.2, 133.3,
133.6, 133.8, 134.0, 138.2, 149.7. MS(ESI): m/z 452 [MþNa]þ, 468
[MþK]þ. MS(EI) m/z 429 (Mþ, 2), 383 (13), 228 (11), 91 (100). HRMS
calcd for C25H19NO4S, 429.1035; found 429.1035.
(CD3SOCD3)
d 20.7, 60.2, 127.3, 127.8, 128.3, 128.6, 128.8, 129.8,
130.4, 130.9, 131.1, 131.2, 131.8, 131.8, 134.0, 134.7, 135.1, 137.7, 138.2,
146.4. MS(ESI): m/z 416 [MþNa]þ, 432 [MþK]þ. MS(EI) m/z 347
(Mꢀ46, 16), 91 (100), 69 (11). Anal. Calcd for C22H19NO4S (MW
393.46): C, 67.2; H, 4.9; N, 3.6%. Found: C, 67.0; H, 5.0; N, 3.7%.
4.4.9. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-(2-thienyl)ethene
(9i). Yield (747 mg, 97%). Yellow/orange solid, mp 178e179 ꢁC
(ethanol/dioxane); nmax (Nujol) 1631, 1501, 1339, 1312, 1245, 1159,
1150, 1119, 1066 cmꢀ1; 1H NMR (CDCl3)
d 4.21 (1H, d, J 13.8 Hz), 4.32
4.4.4. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-(p-tolyl)ethene
(9d). Yield (778 mg, 99%). Yellow solid, mp 143e144 ꢁC (ethanol);
nmax (Nujol) 1647, 1603, 1515, 1319, 1307, 1214, 1184, 1160,
(1H, d, J 13.8 Hz), 7.04 (1H, dd, J 5.1, 3.6 Hz), 7.20e7.22 (2H, m),
7.27e7.36 (4H, m), 7.41 (1H, d, J 4.8 Hz), 7.50 (1H, d, J 8.1 Hz),
7.55e7.58 (2H, m), 7.72e7.78 (1H, m), 8.61 (1H, s); 13C NMR
1117 cmꢀ1
;
1H NMR (CDCl3)
d
2.28 (3H, s), 4.19 (1H, d, J 13.6 Hz),
(CD3SOCD3) d 60.5, 127.3, 128.2, 128.3, 128.6, 128.9, 130.0, 131.0,
4.34 (1H, d, J 13.8 Hz), 6.91 (2H, d, J 8.4 Hz), 7.03 (2H, d, J 8.0 Hz),
7.18e7.39 (6H, m), 7.44e7.54 (2H, m), 7.61e7.69 (1H, m), 8.37 (1H,
131.6, 131.7, 134.1, 134.5, 135.2, 135.3, 138.1, 138.5, 143.2. MS(ESI): m/
z 408 [MþNa]þ, 424 [MþK]þ. MS(EI) m/z 339 (Mꢀ46, 72), 184 (36),
171 (10), 136 (11), 91 (100). Anal. Calcd for C19H15NO4S2 (MW
385.46): C, 59.2; H, 3.9; N, 3.6%. Found: C, 59.1; H, 3.9; N, 3.7%.
s); 13C NMR (CDCl3)
d 21.5, 61.6, 127.7, 127.9, 128.6, 128.9, 129.8,
130.3, 131.1, 131.2, 131.4, 132.5, 133.5, 134.5, 136.3, 137.9, 142.1, 146.1.
MS(ESI): m/z 416 [MþNa]þ, 432 [MþK]þ. MS(EI) m/z 347 (Mꢀ46,
24), 192 (11), 91 (100). Anal. Calcd for C22H19NO4S (MW 393.46): C,
67.2; H, 4.9; N, 3.6%. Found: C, 67.2; H, 4.8; N, 3.5%.
4.4.10. (E)-1-[2-(Benzylsulfonyl)phenyl]-1-nitro-2-(3-thienyl)ethene
(9j). Yield (762 mg, 99%). Pale yellow solid, mp 127e128 ꢁC (eth-
anol); nmax (Nujol) 1649, 1518, 1332, 1309, 1252, 1199, 1152, 1131,
4.4.5. (E)-1-[2-(Benzylsulfonyl)phenyl]-2-(p-methoxyphenyl)-1-
nitroethene (9e). Yield (810 mg, 99%). Yellow solid, mp 129e130 ꢁC
(ethanol); nmax (Nujol) 1649, 1595, 1505, 1318, 1303, 1254, 1212,
1118 cmꢀ1 1H NMR (CDCl3)
; d 4.20 (1H, d, J 13.8 Hz), 4.33 (1H, d, J
13.5 Hz), 6.34 (1H, dd, J 5.4, 1.2 Hz), 7.16 (1H, dd, J 5.1, 3.0 Hz),
7.19e7.22 (2H, m), 7.27e7.37 (4H, m), 7.43 (1H, d, J 7.2 Hz),
7.49e7.56 (2H, m), 7.68e7.74 (1H, m), 8.41 (1H, s); 13C NMR (CDCl3)
1198, 1172, 1157, 1115, 1026 cmꢀ1 1H NMR (CDCl3)
; d 3.76 (3H, s),
4.22 (1H, d, J 13.5 Hz), 4.35 (1H, d, J 13.5 Hz), 6.75 (2H, d, J 8.7 Hz),
6.96 (2H, d, J 9.3 Hz), 7.20e7.40 (6H, m), 7.46e7.55 (2H, m),
d 61.8, 127.2, 127.6, 127.7, 128.6, 128.9, 130.2, 130.5, 130.9, 131.2,
132.5, 132.8, 133.2, 133.5, 134.5, 137.9, 145.4. MS(ESI): m/z 408
[MþNa]þ, 424 [MþK]þ. MS(EI) m/z 339 (Mꢀ46, 76), 184 (46), 171
(16), 139 (15), 91 (100). Anal. Calcd for C19H15NO4S2 (MW 385.46):
C, 59.2; H, 3.9; N, 3.6%. Found: C, 59.0; H, 3.7; N, 3.5%.
7.64e7.70 (1H, m), 8.38 (1H, s); 13C NMR (CDCl3)
d 55.4, 61.6, 114.6,
123.2, 127.8, 128.6, 128.9, 130.2, 131.3, 131.3, 132.6, 133.4, 133.5,
134.6, 136.4, 138.0, 144.7, 162.1. MS(ESI): m/z 432 [MþNa]þ, 448
[MþK]þ. MS(EI) m/z 409 (Mþ, 1), 363 (31), 136 (10), 91 (100). HRMS
calcd for C22H19NO5S, 409.0984; found 409.0982.
4.5. Reaction of sulfones 9aej with LHMDS at room
temperature or at L78 ꢁC
4.4.6. (E)-1-[2-(Benzylsulfonyl)phenyl]-2-(4-chlorophenyl)-1-
nitroethene (9f). Yield (802 mg, 97%). Yellow solid, mp 191e192 ꢁC
(ethanol/dioxane); nmax (Nujol) 1651, 1584, 1567, 1524, 1409, 1319,
1302, 1250, 1211, 1197, 1161, 1116, 1091, 1008 cmꢀ1; 1H NMR (CDCl3)
Reactions at 22 ꢁC were performed on 0.3 mmol of the appro-
priate 9, at first according to the conditions described in Ref. 4.
Yields are reported in Table 1. The crude solid residues showed at
the 1H NMR analysis three series of signals, due to the presence in
different relative quantities of three pairs of diastereomers [in-
dicated as A (cis,trans), B (trans,cis), C (trans,trans)]. In all cases, the
spectroscopic data reported refer to the crude mixture; in some
cases (10aed, h) stereoisomer A was obtained in a pure form by
crystallization from ethanol, and could be fully characterized; in
d
4.26 (1H, d, J 13.5 Hz), 4.37 (1H, d, J 13.8 Hz), 6.94 (2H, d, J 8.7 Hz),
7.19 (2H, d, J 9.0 Hz), 7.22e7.24 (2H, m), 7.28e7.39 (4H, m),
7.45e7.51 (2H, m), 7.60e7.68 (1H, m), 8.33 (1H, s); 13C NMR (CDCl3)
d
61.7, 127.6, 128.7, 129.0, 129.3, 129.3, 130.4, 130.6, 131.3, 132.3,
132.6, 133.2, 134.6, 134.8, 137.3, 138.0, 147.5. MS(ESI): m/z 436
[MþNa]þ, 452 [MþK]þ. MS(EI) m/z 367 (Mꢀ46, 30), 349 (23), 212

8168
L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
addition, for compound 10h, a change in the crystallization solvent
(ethanol/dioxane) allowed to obtain stereoisomer B as a pure solid,
fully characterized by spectroscopic data.
When the reactions just described above were performed at
ꢀ78 ꢁC instead of 22 ꢁC, the crude solid residues, obtained in yields
(see Table 3) always comparable to those obtained at room temper-
ature (see Table 1), were generally pure by 1H NMR analysis and
showed a change in the diastereomeric ratios of compounds 10, the
reactions being much more stereoselective. In all cases, crystallization
of the cruderesidues from ethanol affordeddiastereomericallypure A.
3.6 Hz), 4.73 (1H C, d, J 11.7 Hz), 4.80 (1H B, dd, J 12.6, 4.2 Hz), 4.94
(1H C, dd, J 11.4, 10.8 Hz), 5.15 (1H A, dd, J 11.7, 3.6 Hz), 5.95 (1H B, d,
J 12.9 Hz), 6.10 (1H B, d, J 4.5 Hz), 6.17 (1H C, d, J 9.3 Hz), 6.31 (1H A,
d, J 12.0 Hz), 6.71e8.15 (13 of A, 13H of B, 13H of C). A could be
isolated as a white solid by crystallization from ethanol, mp
207e208 ꢁC; nmax (Nujol) 1551, 1314, 1230, 1191, 1149, 1127,
1069 cmꢀ1; 1H NMR (CDCl3)
d 2.30 (3H, s), 4.64 (1H, d, J 3.6 Hz), 5.15
(1H, dd, J 11.7, 3.9 Hz), 6.31 (1H, d, J 12.0 Hz), 6.73 (2H, d, J 7.8 Hz),
6.77 (2H, d, J 8.1 Hz), 7.03 (2H, d, J 7.8 Hz), 7.24 (2H, app t, J 7.2 Hz),
7.36 (1H, app t, J 7.5 Hz), 7.54e7.57 (1H, m), 7.70e7.78 (2H, m),
8.15e8.18 (1H, m); 13C NMR (CD3COCD3)
d 21.0, 48.4, 70.5, 88.2,
4.5.1. 4-Nitro-2,3-diphenylthiochroman S,S-dioxide (10a). Yield
125.6, 129.10, 129.4, 129.6, 129.9, 130.2, 130.3, 130.5, 131.3, 132.5,
132.8, 134.7, 139.3, 139.7; MS: m/z 394.1 (MþH)þ. HRMS [MþH]þ
calcd for C22H20NO4S, 394.1113; found 394.1109.
(94 mg, 83%, mixture of three racemic pairs). 1H NMR (CDCl3)
d 4.66
(1H A, d, J 3.9 Hz), 4.70 (1H C, d, J 11.7 Hz), 4.84 (1H B, dd, J 12.9,
4.8 Hz), 5.00 (1H C, dd, J 11.4, 9.3 Hz), 5.20 (1H A, dd, J 11.4, 3.6 Hz),
5.98 (1H B, d, J 12.9 Hz), 6.13 (1H B, d, J 4.8 Hz), 6.19 (1H C, d, J 9.3 Hz),
6.34 (1H A, d, J 12.0 Hz), 6.70e8.18 (14H of A, 14H of B, 14H of C). A
could be isolated as a white solid after crystallizations from ethanol,
mp 193e194 ꢁC; nmax (Nujol) 1603, 1550, 1306, 1215, 1151, 1124,
4.5.5. 3-(p-Methoxyphenyl)-4-nitro-2-phenylthiochroman
oxide (10e). Yield (101 mg, 82%, mixture of three racemic pairs). 1H
NMR (CDCl3) 3.70 (3H B or C, s), 3.71 (3H C or B, s), 3.77 (3H A, s),
S,S-di-
d
4.63 (1H A, d, J 3.9 Hz), 4.66 (1H C, d, J 11.7 Hz), 4.78 (1H B, dd, J 12.6,
4.5 Hz), 4.93 (1H C, dd, J 11.7, 9.3 Hz), 5.13 (1H A, dd, J 11.7, 3.9 Hz),
5.93 (1H B, d, J 12.6 Hz), 6.10 (1H B, d, J 4.5 Hz), 6.16 (1H C, d, J
9.3 Hz), 6.27 (1H A, d, J 11.4 Hz), 6.70e8.19 (13H of A, 13H of B, 13H
of C). Crystallization of the crude residue from ethanol brought to
only a slight modification of the diastereomeric ratio; the crystal-
lized material was a yellow solid, mp 120e150 ꢁC. A as a pure
product was obtained by reaction at low temperature. Pale yellow
solid, mp 148e150 ꢁC; nmax (Nujol) 1610, 1553, 1512, 1309, 1255,
1071 cmꢀ1; 1H NMR (CDCl3)
d 4.65 (1H, d, J 3.9 Hz), 5.20 (1H, dd, J 11.1,
3.6 Hz), 6.34 (1H, d, J 12.0 Hz), 6.72 (2H, d, J 7.5 Hz), 6.90 (2H, d, J
7.2 Hz), 7.21e7.39 (6H, m), 7.56e7.59 (1H, m), 7.71e7.79 (2H, m),
8.16e8.19 (1H, m); 13C NMR (CDCl3)
d 47.6, 70.4, 86.9, 125.4, 127.2,
128.4,128.7,128.9,128.9,129.0,129.5,129.9,131.6,133.8,134.1,139.0
(two carbons are accidentally isochronous); MS: m/z 380.1 (MþH)þ.
HRMS [MþH]þ calcd for C21H18NO4S, 380.0957; found 380.0911.
4.5.2. 4-Nitro-2-phenyl-3-(o-tolyl)thiochroman S,S-dioxide (10b).
1180, 1153, 1128, 1030 cmꢀ1 1H NMR (CDCl3)
; d 3.76 (3H, s), 4.63
Yield (97 mg, 82%, mixture of three racemic pairs). 1H NMR (CDCl3)
(1H, d, J 3.9 Hz), 5.13 (1H, dd, J 11.7, 3.9 Hz), 6.28 (1H, d, J 12.0 Hz),
6.73e6.81 (5H, m), 7.22e7.39 (4H, m), 7.53e7.56 (1H, m), 7.70e7.78
d
2.54 (3H A, 3H B, 3H C, s), 4.49 (1H A, d, J 3.3 Hz), 4.56 (1H C, d, J
9.9 Hz), 5.04 (1H B, dd, J 12.6, 4.8 Hz), 5.32 (1H C, dd, J 10.8, 8.4 Hz),
5.56 (1H A, dd, J 12.0, 3.6 Hz), 5.96 (1H B, d, J 12.6 Hz), 6.04 (1H B, d, J
4.8 Hz), 6.15 (1H C, d, J 8.1 Hz), 6.34 (2H A, app d, J 11.1 Hz),
6.66e8.20 (12H of A, 13H of B, 13H of C). A could be isolated as
a white solid by crystallization from ethanol, mp 206e207 ꢁC; nmax
(2H, m), 8.14e8.18 (1H, m); 13C NMR (CDCl3)
d 46.9, 55.2, 70.4, 87.2,
114.2, 125.3, 125.9, 127.2, 128.7, 128.8, 129.0, 129.5, 129.6, 129.9,
131.5, 133.7, 138.8, 159.8. MS(ESI): m/z 432 [MþNa]þ, 408 [MꢀH]ꢀ.
HRMS calcd for C22H19NO5S, 409.0984; found 409.0980.
(Nujol) 1551, 1316, 1226, 1199, 1150, 1128, 1071 cmꢀ1
;
1H NMR
2.54 (3H, s), 4.49 (1H, d, J 3.3 Hz), 5.56 (1H, dd, J 12.0,
4.5.6. 3-(p-Chlorophenyl)-4-nitro-2-phenylthiochroman S,S-dioxide
(CDCl3)
d
(10f). Yield (111 mg, 90%, mixture of three racemic pairs). 1H NMR
3.6 Hz), 6.34 (2H, app d, J 11.1 Hz), 6.67 (2H, d, J 7.2 Hz), 6.92 (1H, t, J
7.2 Hz), 7.15e7.25 (4H, m), 7.33e7.38 (1H, app t, J 7.4 Hz), 7.57 (1H,
dd, J 6.6, 2.1 Hz), 7.71e7.80 (2H, m), 8.18e8.21 (1H, m); 13C NMR
(CDCl3) d 4.62 (1H A, d, J 3.6 Hz), 4.67 (1H C, d, J 11.7 Hz), 4.83 (1H B,
dd, J 12.9, 4.5 Hz), 4.98 (1H C, dd, J 11.1, 9.9 Hz), 5.17 (1H A, dd, J 11.7,
3.9 Hz), 5.92 (1H B, d, J 12.9 Hz), 6.10 (1H B, d, J 4.5 Hz), 6.15 (1H C, d,
J 9.6 Hz), 6.28 (1H A, d, J 11.4 Hz), 6.73e8.18 (13H of A, 13H of B, 13H
of C). Crystallization of the crude residue from ethanol brought to
only a slight modification of the diastereomeric ratio; the crystal-
lized material was a white solid, mp 130e150 ꢁC. A as a pure
product was obtained by reaction at low temperature. White solid,
mp 173e174 ꢁC; nmax (Nujol) 1552, 1310, 1153, 1127, 1092,
(CD3COCD3)
d 19.4, 43.6, 69.0, 87.9, 125.7, 126.6, 128.0, 128.6, 129.3,
129.51, 129.9, 130.3, 130.4, 131.2, 132.1, 132.5, 133.6, 134.7, 137.8,
140.0; MS: m/z 394.1 (MþH)þ. HRMS [MþH]þ calcd for C22H20NO4S,
394.1113; found 394.1103.
4.5.3. 4-Nitro-2-phenyl-3-(m-tolyl)thiochroman S,S-dioxide (10c).
Yield (104 mg, 88%, mixture of three racemic pairs). 1H NMR (CDCl3)
1014 cmꢀ1 1H NMR (CDCl3)
; d 4.62 (1H, d, J 3.6 Hz), 5.17 (1H, dd, J
d
2.23 (3H A, s), 2.29 (3H B or C, s), 2.33 (3H C or B, s), 4.63 (1H A, d, J
11.7, 3.9 Hz), 6.28 (1H, d, J 11.4 Hz), 6.74 (2H, d, J 7.5 Hz), 6.83 (2H, d, J
8.4 Hz), 7.21e7.29 (4H, m), 7.38 (1H, app t, J 7.3 Hz), 7.55e7.57 (1H,
m), 7.72e7.80 (2H, m) 8.15e8.18 (1H, m); 13C NMR (CD3SOCD3)
3.6 Hz), 4.68 (1H C, d, J 11.1 Hz), 4.79 (1H B, dd, J 12.6, 4.5 Hz), 4.95
(1H C, dd, J 11.7, 9.6 Hz), 5.16 (1H A, dd, J 12.0, 3.6 Hz), 5.96 (1H B, d, J
12.6 Hz), 6.12 (1H B, d, J 4.8 Hz), 6.18 (1H C, d, J 9.0 Hz), 6.32 (1H A, d,
J 12.0 Hz), 6.61e8.18 (13H of A, 13H of B, 13H of C). A could be
isolated as a white solid by crystallization from ethanol, mp
174e175 ꢁC; nmax (Nujol) 1608, 1553, 1309, 1240, 1186, 1153, 1131,
d
46.6, 67.4, 86.1, 124.5, 128.5, 128.6, 128.8, 129.0, 129.1, 129.3, 130.3,
130.5, 131.8, 133.1, 133.8, 134.1, 137.1. MS(ESI): m/z 436 [MþNa]þ,
412 [MꢀH]ꢀ. HRMS calcd for C21H16ClNO4S, 413.0489; found
413.0479.
1070 cmꢀ1; 1H NMR (CDCl3)
d 2.23 (3H, s), 4.63 (1H, d, J 3.9 Hz), 5.16
(1H, dd, J 11.7, 3.6 Hz), 6.31 (1H, d, J 11.7 Hz), 6.61e6.64 (1H, m),
6.70e6.72 (3H, m), 7.10 (2H, d, J 4.8 Hz), 7.21e7.26 (2H, m),
7.34e7.39 (1H, m), 7.55e7.58 (1H, m), 7.71e7.79 (2H, m), 8.16e8.19
4.5.7. 3-(p-Bromomophenyl)-4-nitro-2-phenylthiochroman S,S-di-
oxide (10g). Yield (134 mg, 97%, mixture of three racemic pairs). 1H
NMR (CDCl3) d 4.62 (1H A, d, J 3.6 Hz), 4.70 (1H C, d, J 11.6 Hz), 4.82
(1H, m); 13C NMR (CD3COCD3)
d
21.3, 48.7, 70.5, 88.0, 125.6, 126.3,
(1H B, dd, J 12.8, 4.7 Hz), 4.96 (1H C, dd, J 11.5, 9.5 Hz), 5.15 (1H A,
dd, J 11.4, 3.6 Hz), 5.91 (1H B, d, J 12.8 Hz), 6.11 (1H B, d, J 4.7 Hz),
6.15 (1H C, d, J 9.5 Hz), 6.27 (1H A, d, J 11.7 Hz), 6.72e8.16 (13H of A,
13H of B, 13H of C). A as a pure product was obtained by reaction at
low temperature. White solid, mp 196e197 ꢁC (ethanol); nmax
129.1, 129.4, 129.5, 129.9, 130.2, 130.3, 130.4, 130.5, 131.2, 132.5,
134.7, 135.7, 139.2, 139.8; MS: m/z 394.1 (MþH)þ. HRMS [MþH]þ
calcd for C22H20NO4S, 394.1113; found 394.1075.
4.5.4. 4-Nitro-2-phenyl-3-(p-tolyl)thiochroman S,S-dioxide (10d).
(Nujol) 1552, 1310, 1185, 1153, 1128, 1070, 1010 cmꢀ1 1H NMR:
;
Yield (116 mg, 98%, mixture of three racemic pairs). 1H NMR (CDCl3)
d
4.62 (1H, d, J 3.6 Hz), 5.15 (1H, dd, J 11.4, 3.6 Hz), 6.27 (1H, d, J
d
2.15 (3H B or C, s), 2.19 (3H C or B, s), 2.28 (3H A, s), 4.64 (1H A, d, J
11.7 Hz), 6.76 (4H, app t, J 8.7 Hz), 7.24e7.29 (2H, app t, J 7.9 Hz),

L. Bianchi et al. / Tetrahedron 67 (2011) 8160e8169
8169
7.37e7.41 (3H, m), 7.55e7.58 (1H, m), 7.73e7.80 (2H, m), 8.15e8.18
(1H, m); 13C NMR (CDCl3)
47.1, 70.0, 86.8, 123.4, 125.4, 127.2, 128.3,
128.5, 129.2, 129.7, 129.9, 130.1, 131.7, 132.2, 133.0, 133.9, 138.8.
MS(ESI): m/z 480 [MþNa]þ, 458 [MꢀH]ꢀ. HRMS calcd for
C21H16BrNO4S, 456.9983; found 456.9980.
(1H, d, J 5.1 Hz), 6.80 (2H, app d, J 7.2 Hz), 6.90 (1H, d, J 1.5 Hz),
7.23e7.28 (3H, m), 7.37 (1H, app t, J 7.4 Hz), 7.55e7.57 (1H, m),
d
7.71e7.79 (2H, m), 8.14e8.17 (1H, m); 13C NMR (CDCl3)
d 43.3, 69.4,
87.7, 124.6, 125.3, 126.8, 126.8, 127.4, 128.6, 128.8, 129.0, 129.6, 129.8,
131.6, 133.8, 134.6, 138.9. MS(ESI): m/z 408 [MþNa]þ, 384 [MꢀH]ꢀ.
HRMS calcd for C19H15NO4S2, 385.0443; found 385.0444.
4.5.8. 3-(1-Naphthyl)-4-nitro-2-phenylthiochromanS,S-dioxide(10h).
Yield (121 mg, 94%, mixture of three racemic pairs). 1H NMR (CDCl3)
Acknowledgements
d
4.78 (1H C, d, J 9.9 Hz), 4.80 (1H A, d, J 3.3 Hz), 5.74 (1H B, dd, J 12.6,
4.2 Hz), 6.06 (1H C, dd, J 10.5, 8.4 Hz), 6.14 (1H B, d, J 12.6 Hz), 6.23 (1H
A, dd, J 12.0, 3.0 Hz), 6.27 (1H B, d, J 4.2 Hz), 6.29 (1H C, d, J 8.4 Hz)
6.47e6.51 (3H, 1Aþ 2 Ar, m), 6.68e8.43 (14H of A, 16H of B, 16H of C).
A could be isolated as a white solid after crystallizations from ethanol,
The authors wish to thank Miss Stefania Zappia for skilful con-
tributions with the experimental work. Financial support was
provided by grants from the Universities of Genova and Bologna,
ꢀ
and from Ministero dell’Istruzione, dell’Universita e della Ricerca
mp 211e212 ꢁC; nmax (Nujol) 1552, 1310,1232, 1153, 1129,1069 cmꢀ1
;
(MIUR-Roma, PRIN 20085E2LXC).
1H NMR (CDCl3)
d 4.80 (1H, d, J 3.0 Hz), 6.23 (1H, dd, J 12.3, 3.0 Hz),
6.47e6.51 (3H, 1Aþ2 Ar, m), 6.69 (1H, d, J 7.2 Hz), 7.12e7.33 (4H, m),
References and notes
7.58e7.64 (2H, m), 7.72e7.83 (4H, m), 7.93 (1H, d, J 7.8 Hz), 8.25 (1H,
dd, J 7.5, 1.8 Hz), 8.42 (1H, d, J 8.4 Hz); 13C NMR (CDCl3)
d 42.0, 68.8,
1. Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.; Tavani, C.
‘2,3-Dinitro-1,3-butadienes: versatile Building-blocks from the Ring Opening of
3,4-dinitrothiophene’ in Targets in Heterocyclic SystemsdChemistry and
86.0, 121.9, 124.5, 124.7, 125.4, 126.5, 126.9, 128.0, 128.6, 128.8, 129.2,
129.3, 129.3,129.5, 129.6,130.6,131.6,133.8,134.3,139.2 (two carbons
are accidentally isochronous). B was isolated by crystallization from
ꢀ
Properties, SocietaChimicaItaliana: Rome; 2006, Vol. 10, pp 1e23.
2. Bianchi, L.; Maccagno, M.; Petrillo, G.; Rizzato, E.; Sancassan, F.; Severi, E.;
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the Ring Opening of 2- and 3-nitrothiophenes’ in Targets in Heterocyclic Sys-
temsdChemistry and Properties, SocietaChimicaItaliana: Rome; 2007, Vol. 11,
pp 1e20.
1
ethanol/dioxane as a white solid, mp 242e243 ꢁC; H NMR (CDCl3)
d
5.74 (1H, dd, J 12.3, 4.2 Hz), 6.14 (1H, d, J 12.3 Hz), 6.27 (1H, d, J
ꢀ
4.2 Hz), 6.96 (1H, d, J 7.2 Hz), 7.15e7.22 (4H, m), 7.34e7.36 (2H, m),
7.52 (1H, d, J 7.5 Hz), 7.60 (1H, d, J 7.2 Hz), 7.66e7.72 (3H, m), 7.77 (1H,
app t, J 7.8 Hz), 7.91 (1H, d, J 7.8 Hz), 8.18 (1H, d, J 8.7 Hz), 8.24 (1H, d, J
3. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Petrillo, G.; Rizzato, E.;
Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. ARKIVOC 2006, vii, 169e185.
4. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Novi, M.; Petrillo, G.;
Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. Tetrahedron 2004, 60,
4967e4973.
5. Bianchi, L.; Giorgi, G.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Severi, E.;
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7. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.;
Sancassan, F.; Tavani, C. J. Org. Chem. 2003, 68, 5254e5260.
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7.8 Hz); 13C NMR (CDCl3)
d 39.9, 62.7, 89.1, 120.8, 125.3, 125.4, 126.2,
127.0, 127.3, 127.7, 128.6, 129.1, 129.2, 129.4, 129.4, 130.0, 130.7, 131.2,
132.1, 133.4, 134.0, 139.8 (two carbons are accidentally isochronous);
MS: m/z 430.1 (MþH)þ. HRMS [MþH]þ calcd for C25H20NO4S,
430.1113; found 430.1072.
4.5.9. 4-Nitro-2-phenyl-3-(2-thienyl)thiochroman S,S-dioxide (10i).
Yield (107 mg, 93%, mixture of three racemic pairs). 1H NMR (CDCl3)
9. Sato, M.; Kitamura, Y.; Yoshimura, N.; Yamataka, H. J. Org. Chem. 2009, 74,
1268e1274.
d
4.64 (1H C, d, J 11.7 Hz), 4.74 (1H A, d, J 4.2 Hz), 5.09 (1H B, dd, J
12.6, 4.8 Hz), 5.38 (1H C, dd, J 11.7, 9.0 Hz), 5.53 (1H A, dd, J 11.1,
4.2 Hz), 5.96 (1H B, d, J 12.6 Hz), 6.18e6.21 (1H Bþ 1H C, m), 6.25
(1H A, d, J 11.1 Hz), 6.69e8.16 (12H of A, 12H of B, 12H of C). Crys-
tallization of the crude residue from ethanol brought to only a slight
modification of the diastereomeric ratio; the crystallized material
was a white solid, mp 202e204 ꢁC. A as a pure product was
obtained by reaction at low temperature. White solid, mp
10. Rai, V.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2006, 4693e4703.
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13. Bolger, B. J.; Hirwe, A.; Marathe, K. G.; Philbin, E. M.; Vickars, M. A.; Lillya, C. P.
Tetrahedron 1966, 22, 621e628.
14. Clark-Lewis, J. W. Aust. J. Chem. 1968, 21, 2059e2075.
15. Katekar, G. F. Aust. J. Chem. 1966, 19, 1251e1257.
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808e811.
21. Gao, Y.; Ren, Q.; Wu, H.; Li, M.; Wang, J. Chem. Commun. 2010, 42, 9232e9234.
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M.; Langer, P.; Tolmachev, A. A.; Sosnovskikh, V. Y. Synthesis 2010, 42, 671e677.
23. Mercey, G.; Legay, R.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Levillain, J.;
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24. Dodda, R.; Goldman, J. J.; Mandal, T.; Zhao, C.-G.; Broker, G. A.; Tiekink, E. R. T.
Adv. Synth. Catal. 2008, 350, 537e541.
202e203 ꢁC; nmax (Nujol) 1547, 1298, 1232, 1153, 1133, 1069 cmꢀ1
;
1H NMR (CDCl3)
d
4.75 (1H, d, J 4.2 Hz), 5.54 (1H, dd, J 11.1, 3.9 Hz),
6.26 (1H, d, J 10.8 Hz), 6.70 (1H, d, J 3.3 Hz), 6.84e6.90 (3H, m), 7.22
(1H, d, J 4.5 Hz), 7.25e7.30 (2H, m), 7.39 (1H, t, J 7.5 Hz), 7.59e7.62
(1H, m), 7.72e7.79 (2H, m), 8.13e8.16 (1H, m); 13C NMR (CDCl3)
d
43.2, 70.0, 88.6, 125.4, 126.5, 126.9, 127.5, 127.9, 128.4, 128.5, 129.1,
129.8, 130.1, 131.7, 133.9, 136.2, 138.5. MS(ESI): m/z 407.6 [MþNa]þ,
423.6 [MþK]þ. MS(EI) m/z 385 (Mþ, 2), 338 (96), 321 (32), 274 (100),
241 (38), 197 (40), 186 (80), 173 (58), 91 (33). HRMS calcd for
C19H15NO4S2, 385.0443; found 385.0446.
25. Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130,
10498e10499.
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4.5.10. 4-Nitro-2-phenyl-3-(3-thienyl)thiochroman S,S-dioxide (10j).
Yield (95 mg, 82%, mixture of three racemic pairs). 1H NMR (CDCl3)
28. Bolognesi, M. L.; Bortolini, M.; Cavalli, A.; Andrisano, V.; Rosini, M.; Minarini, A.;
Melchiorre, C. J. Med. Chem. 2004, 47, 5945e5952.
d
4.63 (1H C, d, J 11.1 Hz), 4.71 (1H A, d, J 3.9 Hz), 4.98 (1H B, dd, J
13.2, 4.8 Hz), 5.17 (1H C, dd, J 11.1, 9.3), 5.32 (1H A, dd, J 11.1, 3.9 Hz),
5.94 (1H B, d, J 12.6 Hz), 6.13e6.17 (1H Bþ 1H C, m), 6.20 (1H A, d, J
11.1 Hz), 6.59e8.16 (12H of A, 12H of B, 12H of C). Crystallization of
the crude residue from ethanol brought to only a slight modification
of the diastereomeric ratio; the crystallized material was a white
solid, mp 183e185 ꢁC. A as a pure product was obtained by reaction
at low temperature. White solid, mp 199e200 ꢁC; nmax (Nujol) 1553,
29. Vliet, L. A. V.; Rodenhuis, N.; Dijkstra, D.; Wikstrom, H.; Pugsley, T. A.; Serpa, K.
A.; Meltzer, L. T.; Heffner, T. G.; Wise, L. D.; Lajiness, M. E.; Huff, R. M.; Svensson,
K.; Sundell, S.; Lundmark, M. J. Med. Chem. 2000, 43, 2871e2882.
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31. Spruce, L. W.; Rajadhyaksha, S. N.; Berlin, K. D.; Gale, J. B.; Miranda, E. T.; Ford,
W. T.; Blossey, E. C.; Verma, A. K.; Hossain, M. B.; Helm, D. V. D.; Breitman, T. R. J.
Med. Chem. 1987, 30, 1474e1482.
32. Preliminary unpublished results.
33. Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.; Cosimelli, B.;
Spinelli, D. Tetrahedron 2001, 57, 8159e8165.
1310, 1231, 1193, 1151, 1124, 1071 cmꢀ1; 1H NMR (CDCl3)
d, J 3.6 Hz), 5.32 (1H, dd, J 11.1, 3.6 Hz), 6.21 (1H, d, J 11.1 Hz), 6.60
d 4.71 (1H,