Butadienic building blocks from 2-nitrothiophene as precursors of nitrogen heterocycles: Intriguing dichotomic behavior

Article abstract of DOI:10.1021/jo701460k

(Chemical Equation Presented) With the goal of their exploitation for the synthesis of heterocycles, sulfides 10 and sulfones 11, derived from the initial ring-opening of 2-nitrothiophene (5) with pyrrolidine/AgNO₃ in EtOH, were reacted with di

Full text of DOI:10.1021/jo701460k

Butadienic Building Blocks from 2-Nitrothiophene as Precursors of
Nitrogen Heterocycles: Intriguing Dichotomic Behavior§
Lara Bianchi,† Gianluca Giorgi,‡ Massimo Maccagno,† Giovanni Petrillo,† Valeria Rocca,†
Fernando Sancassan,† Carlo Scapolla,† Elda Severi,† and Cinzia Tavani*,†
Dipartimento di Chimica e Chimica Industriale, UniVersita` di GenoVa, Via Dodecaneso 31,
I-16146 GenoVa, Italy, and Dipartimento di Chimica, UniVersita` di Siena, Via A. Moro,
S. Miniato, I-53100 Siena, Italy
taVani@chimica.unige.it
ReceiVed July 11, 2007
With the goal of their exploitation for the synthesis of heterocycles, sulfides 10 and sulfones 11, derived
from the initial ring-opening of 2-nitrothiophene (5) with pyrrolidine/AgNO3 in EtOH, were reacted
with diazomethane. Interesting dichotomic behavior was found to yield pyrazolines 17 from 10 and
isoxazolines 18 (as the main products) from 11. Intriguingly enough, in the latter case, an unexpected
apparent C-C methylene insertion was also observed, leading to the homologous cyclopropanes 19 as
secondary products.
1. Introduction
In 1974, it was reported1,6 that 2-nitrothiophene (5) undergoes
ring-opening with secondary amines (Scheme 2), leading to
nitrobutadiene disulfides 7 as the result of a fast oxidation of
the expected but never isolated thiols 6 (path a in Scheme 2).
In the presence of AgNO3, the resulting silver thiolates 8
(path b in Scheme 2) could be conveniently isolated and
successively treated with excess MeI, eventually yielding the
Within the frame of a long-standing research project aimed
at the synthetic exploitation of the versatile butadienic building
blocks derived from the ring-opening of nitrothiophenes with
secondary amines,1-3 in the last few years we have reported a
number of successful applications of the highly functionalized
dinitro- (3)1,2 or nitro-butadienes (4)1,3 obtainable from 3,4-
dinitrothiophene4 or 3-nitrothiophene,5 respectively (Scheme 1).
By means of proper modification of the existing functionalities,
both 3 and 4 have actually proven to be effective precursors of
linear molecules as well as of homo- or heterocyclic derivatives.
The results have significantly widened the field of the synthetic
methodologies available, in particular, for access to variously
functionalized oxygen and/or nitrogen heterocycles.1-3
(2) (a) 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
Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.;
Societa` Chimica Italiana: Rome, 2006; Vol. 10, pp 1-23. Dell’Erba, C.;
Novi, M.; Petrillo, G.; Tavani, C. Synthetic Exploitation of the Ring-Opening
of 3,4-Dinitrothiophene. In Topics in Heterocyclic Systems: Synthesis,
Reactions, and Properties; Attanasi, O. A., Spinelli, D., Eds.; Research
Signpost: Trivandrum, India, 1996; Vol. 1, pp 1-12. Dell’Erba, C.; Mele,
A.; Novi, M.; Petrillo, G.; Stagnaro, P. Tetrahedron Lett. 1990, 31, 4933-
4936. Dell’Erba, C.; Mele, A.; Novi, M.; Petrillo, G.; Stagnaro, P.
Tetrahedron 1992, 48, 4407-4418. (b) Armaroli, T.; Dell’Erba, C.;
Gabellini, A.; Gasparrini, F.; Mugnoli, A.; Novi, M.; Petrillo, G.; Tavani,
C. Eur. J. Org. Chem. 2002, 1284-1291. (c) Bianchi, L.; Dell’Erba, C.;
Gasparrini, F.; Novi, M.; Petrillo, G.; Sancassan, F.; Tavani, C. ArkiVoc
2002, ix, 142-158.
§ This paper is dedicated to the memory of Prof. Carlo Dell’Erba.
† Universita` di Genova.
‡ Universita` di Siena.
(1) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Morganti, S.; Petrillo,
G.; Rizzato, E.; Sancassan, F.; Severi, E.; Spinelli, D.; Tavani, C. ArkiVoc
2006, Vii, 169-185.
10.1021/jo701460k CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/02/2007
J. Org. Chem. 2007, 72, 9067-9073
9067

Bianchi et al.
SCHEME 1
has led us first of all to optimize the preparative procedure for
a selected aminonitrobutadiene that could represent the best
compromise between synthesis and further reactivity. In this
respect, 9a (R2N ) pyrrolidinyl) proved to be the most suited,
and its synthesis could be performed one-pot (Scheme 2, and
see Experimental Section), without isolation of 8, raising the
yield to a more than satisfactory 80% by means of a proper
choice of the reaction conditions. As previously reported,1,6 the
ring-opening resulted to be completely diastereoselective, as 9a
was always obtained exclusively in the 1E,3Z configuration
shown in Scheme 2.
2.2. Synthesis of Aryl-Substituted Butadiene Sulfides 10
and Sulfones 11. The treatment of 9a in THF at -30 °C with
1.1 molar equiv of a series of aryl Grignard reagents, followed
by acidic quenching (Scheme 3), has allowed us to isolate
compounds 10a-f in generally high yields (see Table 1). The
reaction proved to be completely regioselective (replacement
occurring exclusively at the enamino moiety) as well as stereo-
specific, proceeding with retention of configuration at both
CdC double bonds.5a Oxidation of the methylthio group of
10a-f with m-CPBA in dichloromethane furnished the sulfones
11a-f in high, when not quantitative, yields (Table 1).
2.3. Reactions of the Nitrobutadienic Building Blocks 10
and 11 with Diazomethane. The cycloaddition reaction of
electron-deficient alkenes with diazomethane represents a useful
access to a number of interesting targets, such as pyrazolines
and pyrazoles and/or cyclopropanes, as is supported in the
literature.9 Nitroalkenes are particularly suited in this regard,
as the resulting nitrocyclopropanes can be in turn considered
important building blocks thanks to the presence of the versatile
nitro group.10 In this context, in the course of a previous study2b
on the synthetic exploitability of the 1,4-diaryl-2,3-dinitro-1,3-
butadienes 12, easily obtainable by the replacement of the two
dialkylamino moieties of 3,1 their treatment with diazomethane
led (Scheme 4) to the isolation of mono- (13, as a single
4-methylsulfanyl-4-nitro-1,3-butadiene-1-amines 9. The just-
mentioned interesting results obtained from 3 and, more re-
cently, from 4 have conceivably fostered a renewed interest
toward the dienes 9 as potential building blocks: the different
stereochemical arrangement of the butadiene moiety and the
functionalization of the nitro-substituted C atom should enforce
original outcomes with respect to molecules such as 3 and/or
4. In agreement with such expectations, we report herein the
attainment of novel, original targets either homo- or hetero-
cyclic in nature following preliminary modifications of the
preexisting functionalities of 9. Such results undoubtedly ex-
pand the pool of methodologies available for the synthesis of
ring systems (such as cyclopropyl7 or isoxazole8 derivatives),
whose interest both in organic and in biological chemistry is
clearly testified by the large amount of papers published on the
subject.
(9) For reviews, see: Helquist, P. Methylene and nonfunctionalized
alkylidene transfer to form cyclopropanes. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, pp 951-997. Bushby, R. J. Methoden Org. Chem. (Houben-Weyl),
4th Ed. 1997, 17, 1059-1135. For recent references, see: Egli, D. H.;
Linden, A.; Heimgartner, H. HelV. Chim. Acta 2006, 89, 2815-2824. Rao,
V. V. V. N. S. R.; Lingaiah, B. P. V.; Yadla, R.; Rao, P. S.; Ravikumar,
K.; Swamy, G. Y. S. K.; Narsimulu, K. J. Heterocycl. Chem. 2006, 43,
673-679. Guseva, E. V.; Volchkov, N. V.; Shulishov, E. V.; Tomilov, Y.
V.; Nefedov, O. M. Russ. Chem. Bull. 2004, 53, 1318-1322. Kozyrev, A.
N.; Alderfer, J. L.; Robinson, B. C. Tetrahedron 2003, 59, 499-504.
Padmavathi, V.; Sarma, M. R.; Padmaja, A.; Reddy, D. B. J. Heterocycl.
Chem. 2003, 40, 933-937. Levai, A. J. Heterocycl. Chem. 2002, 39, 1-13.
Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S. Heterocycles 2002,
56, 273-282. Tomilov, Y. V.; Guseva, E. V.; Volchkov, N. V.; Shulishov,
E. V. Russ. Chem. Bull. 2001, 50, 2113-2120. Muray, E.; Alvarez-Larena,
A.; Piniella, J. F.; Branchadell, V.; Ortun˜o, R. M. J. Org. Chem. 2000, 65,
388-396. Pinto, D. C. G. A.; Silva, A. M. S.; Le´vai, A.; Cavaleiro, J. A.
S.; Patonay, T.; Elguero, J. Eur. J. Org. Chem. 2000, 2593-2599. Midura,
W. H.; Krysiak, J. A.; Mikolajczyk, M. Tetrahedron 1999, 55, 14791-
14802. Martin-Vila`, M.; Hanafi, N.; Jime´nez, J. M.; Alvarez-Larena, A.;
Piniella, J. F.; Branchadell, V.; Oliva, A.; Ortun˜o, R. M. J. Org. Chem.
1998, 63, 3581-3589. For recent references on catalyzed diazomethane
addition via carbene, see: Khanova, M. D.; Sultanova, R. M.; Zlotskii, S.
S.; Dokichev, V. A.; Tomilov, Y. V. Russ. Chem. Bull. 2005, 54, 1003-
1007. Guseva, E. V.; Volchkov, N. V.; Tomilov, Y. V.; Nefedov, O. M.
Eur. J. Org. Chem. 2004, 3136-3144.
2. Results and Discussion
2.1. Optimization of the Ring-Opening of 2-Nitrothiophene
with Pyrrolidine. Our interest in the chemical behavior of 9
(3) (a) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Petrillo, G.; Rizzato,
E.; Sancassan, F.; Severi, E.; Tavani, C. J. Org. Chem. 2005, 70, 8734-
8738. (b) Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi,
M.; Petrillo, G.; Sancassan, F.; Tavani, C. J. Org. Chem. 2003, 68, 5254-
5260. (c) Bianchi, L.; Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.;
Tavani, C. Tetrahedron 2002, 58, 3379-3385.
(4) Dell’Erba, C.; Spinelli, D.; Leandri, G. J. Chem. Soc., Chem.
Commun. 1969, 549.
(5) (a) Dell’Erba, C.; Gabellini, A.; Novi, M.; Petrillo, G.; Tavani, C.;
Cosimelli, B.; Spinelli, D. Tetrahedron 2001, 57, 8159-8165. (b) Surange,
S. S.; Kumaran, G.; Rajappa, S.; Rajalakshmi, K.; Pattabhi, V. Tetrahedron
1997, 53, 8531-8540. Surange, S. S.; Rajappa, S. Tetrahedron Lett. 1998,
39, 7169-7172.
(6) Guanti, G.; Dell’Erba, C.; Leandri, G.; Thea, S. J. Chem. Soc., Perkin
Trans. 1 1974, 2357-2360.
(7) See, for example: Melancon, B. J.; Perl, N. R.; Taylor, R. E. Org.
Lett. 2006, 9, 1425-1428 and references therein. de Meijere, A., Ed.; Special
thematic issue on Cyclopropanes and Related Rings. Chem. ReV. 2003, 103,
931-1648.
(8) Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2005, 9, 925-958.
Kunetsky, R. A.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.;
Tartakovsky, V. A.; Ioffe, S. L. Synthesis 2006, 13, 2265-2270.
(10) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33,
1-18. Rosini, G.; Ballini, R. Synthesis 1988, 833-847. Ono, N. The
Nitrogroup in Organic Synthesis; Wiley: New York, 2001. Ballini, R.;
Palmieri, A.; Fiorini, D. ArkiVoc 2007, 7, 172-194. McCooey, S. H.;
McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494-7497. Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
933-971.
9068 J. Org. Chem., Vol. 72, No. 24, 2007

Butadienic Building Blocks from 2-Nitrothiophene
SCHEME 2
SCHEME 3
SCHEME 4
TABLE 1. Synthesis of 10a-f and 11a-f According to Scheme 3
SCHEME 5
Ar in ArMgX
10 (yield %)a
11 (yield %)a
Ph
10a (84)
10b (91)
10c (92)
10d (78)
10e (85)
10f (69)
11a (95)
11b (96)
11c (95)
11d (88)
11e (99)
11f (78)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
1-naphthyl
2-thienyl
(see the ORTEP representation in the Supporting Information).
Yields of 17a-f are reported in Table 2 and are satisfactory.
Interestingly enough, as mentioned previously, our prior
experience on the reactivity of diazomethane with nitroolefins
led to the direct isolation of cyclopropanation derivatives (13
or 14); no evidence was ever found for the intermediacy of
pyrazoline precursors, although their initial formation followed
by fast nitrogen extrusion at room temperature cannot be
excluded. The result herein is on the contrary in agreement with
literature data,9 which usually testify for the formation of isolable
pyrazolines. As expected for a 1,3-dipolar cycloaddition, the
reaction is completely stereospecific: the original cis/trans
relationships of the substituents in 10 are maintained in 17, and
accordingly, 17a-f are diastereomerically pure racemic mix-
tures. Furthermore, the cycloaddition also proves to be regi-
oselective, involving exclusively the nitrovinyl double bond of
the starting diene system.
a Yield of isolated, pure compound.
diastereoisomer) or bis-cyclopropanes (14, as a mixture of a
d,l and a meso form), depending on the reaction conditions.
The resulting nitrocyclopropyl moieties of 13 or 14 could be
effectively isomerized, in the presence of NaI as the catalyst,
to the corresponding cyclic nitronates, yielding 15 and 16,
respectively, which could be further elaborated.2c
Herein, nitrosulfides 10a-f in THF were added with 2 molar
equiv of diazomethane at 0 °C, and the reaction mixture was
left overnight at room temperature. After removal of the solvent
and purification of the crude residue, NMR analysis showed in
any instance the formation of a single product, definitively
identified as the diastereomerically pure racemic 3-methylsul-
fanyl-3-nitro-4-styryl-4,5-dihydro-3H-pyrazole 17 (Scheme 5)
by means of a single-crystal X-ray analysis on the model 17a
J. Org. Chem, Vol. 72, No. 24, 2007 9069

Bianchi et al.
SCHEME 6
SCHEME 7
TABLE 2. Treatment of Sulfides 10 or Sulfones 11 with
Diazomethane:a Yields of Pyrazolines 17 (Scheme 5), Isoxazoline
N-Oxides 18, and Cyclopropanes 19 (Scheme 6)b
(18b and 18e, respectively). Thus, it seems most likely that a
fast isomerization to the isolated compounds 18 follows the
preliminary formation of cyclopropanes 20 (Scheme 7). Such a
fast 20 to 18 isomerization easily could find its rationale in the
contemporaneous presence of two strongly electron-withdrawing
groups on the same carbon atom of the cyclopropyl ring: we
can reasonably suppose that these substituents would favor the
heterolytic C(1)-C(2) bond breakage involved by means of both
a strong polarization and an effective delocalization of the
negative charge developing on the tertiary C(2) carbon.
Ar
17 (yield %)c
18 (yield %)
19 (yield %)c
Ph
17a (80)
17b (83)
17c (76)
17d (71)
17e (73)
17f (82)
18a (44)
18b (65)
18c (50)
18d (54)
18e (64)
18f (64)
19a (31)
19b (25)
19c (34)
19d (20)
19e (24)
19f (27)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
1-naphthyl
2-thienyl
a CH2N2: 2 molar equiv, THF, 0 °C to rt, 15 h. b Yields of isolated,
pure compounds. c Isolated as single racemic diastereoisomers.
Concomitantly, the incipient positive charge on the secondary
C(1) carbon would be in turn stabilized by the conjugative effect
exerted by the styrene moiety. Furthermore, as our reaction
conditions seem hardly compatible with the existence of singlet
or triplet carbene,12 we can reasonably speculate that, when
reacted with diazomethane, sulfones 11 herein undergo, analo-
gously to sulfides 10, a 1,3-dipolar cycloaddition, to give the
unstable, never observed pyrazolines 21 (Scheme 7 and cf.
Scheme 5). From these, nitrogen extrusion would lead to 20.
The presence, in the conditions described, of the homologous
cyclopropyl derivative 19 (Scheme 6), isolated throughout in
20-34% yield as a single racemic diastereomer (Table 2),
deserves some further comment. The structures of such unex-
When we applied to nitrosulfones 11a-f the same reaction
conditions employed for the nitrosulfides 10 (2 molar equiv of
diazomethane at 0 °C, then overnight at room temperature (rt)),
the outcome was, at a first sight, completely different: the
isoxazoline N-oxides 18a-f (Scheme 6) were isolated as the
main products, always accompanied by minor quantities of the
cyclopropane derivatives 19a-f, according to the data reported
in Table 2.
As far as the isoxazolines 18 are concerned, their formation
may be explained on the grounds of the already cited well-
known nitrocyclopropane to five-membered cyclic nitronate
isomerization (Scheme 7 and cf. Scheme 4).11 Such a process
may be usually induced by thermal activation,11a or by
electrophilic11a or nucleophilic catalysis,11b,c and proceeds
through the selective breakage of the most substituted bond of
the cyclopropane ring. Actually, when the reaction was per-
formed on 11d (Ar ) 4-ClC6H4), the yellow oil 20d was
1
pected products were deduced on the grounds of H and 13C
NMR analysis. Thus, in the case of 19a, the presence of an
allylic moiety was confirmed by the observation that the two
vinyl protons exhibit two doublets of triplets at δ 6.25 (J 15.9
and 6.3 Hz) and 6.51 (J 15.9 and 1.5 Hz). Moreover, NOE
experiments performed on 19a and 19b showed that the allylic
methylene is cis to the methylsulfonyl group; in particular, when
irradiating the methylsulphonyl protons of 19b, the only
appreciable, although small (ca. 0.60%) NOE detectable was
the one relevant to such methylene protons.
It should be noted that the cyclopropyl ring of 19 does not
spontaneously isomerize into the corresponding isoxazoline
N-oxide, well in agreement with the occurrence that, in this case,
the breakage of the C(1)-C(2) cyclopropane bond would
develop a positive charge on a carbon atom in a nonconjugated
position.
1
isolated, whose H and 13C NMR signals were in agreement
with the cyclopropanation of the nitrovinyl moiety (see Experi-
mental Section); during the chromatographic purification, this
underwent extensive isomerization to the corresponding isox-
azoline N-oxide 18d. Also, for 11b (Ar ) 4-MeC6H4) and 11e
1
(Ar ) 1-naphthyl), the H NMR analysis of the crude final
reaction mixture showed the presence of signals most likely
attributable to a cyclopropyl derivative 20, which isomerized
during the workup to the corresponding isoxazoline N-oxide
(11) (a) O’Bannon, P. E.; Daley, W. P. Tetrahedron 1990, 46, 7341-
7358. (b) Seebach, D.; Haner, R.; Vettiger, T. HelV. Chim. Acta 1987, 70,
1507-1515. (c) Vettiger, T.; Seebach, D. Ann. Chem. 1990, 112, 195-
201. (d) Van Velzen, J. C.; Kruk, C.; Spaargaren, K.; de Boer, T. J. Recl.
TraV. Chim. Pays-Bas 1972, 91, 557-564. (e) Van Velzen, J. C.; Kruk,
C.; de Boer, T. J. Recl. TraV. Chim. Pays-Bas 1971, 90, 842-848.
The formation of 19 from 11 formally requires both a
methylene insertion within a C-C single bond and cyclopro-
(12) March, J. AdVanced Organic Chemistry, 5th ed.; Wiley: New York,
2001; pp 247-252.
9070 J. Org. Chem., Vol. 72, No. 24, 2007

Butadienic Building Blocks from 2-Nitrothiophene
SCHEME 8
TABLE 3. Results from Treatment of Sulfone 11c with
Diazomethanea at Different CH2N2/Substrate Molar Ratios
panation of the nitrovinyl moiety. The methylene insertion surely
precedes the cyclopropane formation because the treatment of
the only isolable cyclopropane derivative 20d with diazomethane
did not lead to any appreciable formation of 19d. We can
reasonably assume that 19 is derived from the reaction of
diazomethane with the (never detected) nitroalkene precursor
22 (Scheme 8). The formation of the latter can be in turn
justified by means of nitrogen extrusion (Scheme 8, black
arrows) from 21 coupled with the interesting migration of a
styrene moiety from C(4) to C(5) of the pyrazoline nucleus (blue
arrow: path a in Scheme 8).
entry
CH2N2/11c molar ratio
18c (yield %)b
19c (yield %)b
1c
2c
3
10:1
5:1
2:1
48
51
50
83
30
35
34
14
4d
1.2:1
a THF, 0 °C to rt, 15 h if not otherwise specified. b Yields of isolated
compounds. c Reaction time: 3 h. d Identical results were obtained by
reducing the reaction time to 3 h.
SCHEME 9
Although unprecedented, to our knowledge, in the pyrazoline
chemistry, such an occurrence finds some tight analogies in
previous reports on the migration of aryl moieties in a similar
context.13,14 On the other hand, at least in a different system, a
higher migrating aptitude of styryl versus phenyl toward an
adjacent positively charged C atom has been acknowledged for
long time.15
Interestingly enough, no definite evidence for a hydride 1,2-
shift (which would lead to the isomer 23; see red arrow in
Scheme 8: path b) has been collected, notwithstanding that its
occurrence is more frequently reported within the thermal
decomposition of pyrazolines;14,16,17 such an outcome can be
tentatively rationalized on conformational grounds, assuming
for the styryl moiety a pseudo-equatorial position, reportedly
more favorable for the 1,2-shift to be performed.13
Well in agreement with the pivotal role assigned to the
pyrazoline 21 in directing the reaction toward the eventual
formation of either 18 (Schemes 7 and 8, path c) or of 19
(Scheme 8, path a), the competition of the styryl migration
versus cyclopropane ring formation is sizeably favored, as
already noticed,13 by electron-donating aryl substituents (34 vs
20% yield of 19 for Ar ) 4-MeOC6H4 and 4-ClC6H4,
respectively: cf. Table 2).
A further interesting facet of the system under examination
is unveiled by the results reported in Table 3, relevant to runs
carried out at different diazomethane/substrate ratios on the
model nitrosulfone 11c. Actually, as expected on the grounds
of the proposed reaction scheme and of the nature of the iso-
lated final cyclopropyl derivatives 19 (whose structure re-
quires the uptake of two CH2 moieties), entries 1-3 in Table 3
clearly show that the yield of 19c levels off above a 2:1 reac-
tant/substrate molar ratio. On the other hand, in the case of a
lower diazomethane to 11c ratio (Table 3, entry 4), the fore-
seable significant decrease of the yield of 19c is accompanied
by a sizable increase in that of the isoxazoline derivative 18c.
Such a result, which encompasses the evident practical advan-
tage of allowing significant optimization of the yield of 18
bypassing the concurrent formation of 19, is justifiable within
Scheme 8 only when admitting that, following the competitive,
irreversible transformation of the common intermediate 21 into
20 and 22, the latter (or a derivative) can convert into 18 in the
case of the absence of residual diazomethane in the reaction
mixture. Given its synthetic and mechanistic implications, this
particular aspect of the reactivity of nitrosulfones 11, which does
not influence the main conclusions herein, is presently under
further investigation. Thus far, we can only hypothesize a
thermodynamically favored isomerization (Scheme 9) of the
surviving alleged 1,4-butadiene 22 to the conjugated tautomer
24, which seems a more reasonable candidate for the conversion
into 18.
3. Conclusion
The present study represents a further significant advancement
in exploitation of the ring-opening of nitrothiophenes as a means
to provide polyfunctionalized building blocks. As a first
(13) Nagai, W.; Hirata, Y. J. Org. Chem. 1989, 54, 635-640.
(14) Cativiela, C.; Diaz de Villegas, M. D.; Mele´ndez, E. Synthesis 1986,
418-419.
(16) Jime´nez, J. M.; Bourderlande, J. L.; Ortun˜o, R. M. Tetrahedron
1997, 53, 3777-3786.
(17) Engel, P. S. Chem. ReV. 1980, 80, 99-150.
(15) Herz, W.; Caple, G. J. Org. Chem. 1964, 29, 1691-1699.
J. Org. Chem, Vol. 72, No. 24, 2007 9071

Bianchi et al.
4.2.1. 1-Methyl-4-[(1E,3Z)-(4-methylsulfanyl-4-nitrobuta-1,3-
dienyl)]benzene (10b). (1.000 g, 91%). Yellow solid, mp 99.6-
breakthrough inside the potential applications of the nitrodi-
enamine 9a, the replacement of the pyrrolidine moiety with aryl
Grignard reagents is high-yielding, regioselective, and ste-
reospecific. The resulting (methylthio)nitrobutadienes 10 and
their oxidation products 11 have in turn proved to be valuable
intermediates toward a number of homocycles as well as
nitrogen and/or oxygen heterocycles following an initial,
completely regio- and stereoselective 1,3-dipolar addition of
diazomethane onto the nitrovinyl moiety. Interestingly enough,
the final outcome of the reaction dramatically depends on the
stability, in the reaction conditions, of the alleged primarily
formed pyrazolines (17 and 21 from 10 and 11, respectively)
and hence on the nature of the substituents present in the
butadiene system. In this respect, the oxidation level of the sulfur
atom geminal to the nitro group seems to play a decisive role.
From a mechanistic point of view, the 1,2-styryl migration
eventually leading to 19 surely represents an interesting behavior
of pyrazolines 21. It should be remarked that 2-nitrothiophene
is quite peculiar in providing, via ring-opening and successive
transformations, a 1,3-butadiene moiety possessing two geminal
strongly electron-withdrawing groups such as NO2 and SO2R:
a structural feature that is surely bound to characterize the
chemical behavior of building blocks such as 11. Thanks to the
embedded functionalities, the heterocyclic (17 and 18) as well
as homocyclic (19) derivatives isolated herein should in turn
be regarded as intermediates of potentially valuable interest
toward the synthesis of, for example, isoxazoles and their ring-
opening products.
1
100.1 °C (petroleum ether); H NMR (CDCl3) δ 2.39 (6H, two
partially overlapped s), 7.14-7.35 [4H in all, partially overlapped
dd (J 15.6 and 10.5 Hz) and m], 7.48 (2H, d, J 8.1 Hz), 8.13 (1H,
d, J 10.5 Hz); 13C NMR (CDCl3) δ 18.1, 21.6, 122.4, 128.1, 129.8,
132.9, 141.1, 142.7, 146.4, 146.6; GC-MS: Rt 13.35, m/z 235 (M+).
Anal. Calcd for C12H13NO2S (235.30): C, 61.25; H, 5.57; N, 5.95%.
Found: C, 61.21; H, 5.45; N, 5.87%.
4.2.2. 1-Chloro-4-[(1E,3Z)-(4-methylsulfanyl-4-nitrobuta-1,3-
dienyl)]benzene (10d). (0.931 g, 78%). Yellow solid, mp 73.6-
1
74.3 °C (petroleum ether); H NMR (CDCl3) δ 2.40 (3H, s), 7.15
(1H, d, J 15.3 Hz), 7.31 (1H, dd, J 15.3 and 10.8 Hz), 7.38 (2H, br
d, J 8.6 Hz), 7.51 (2H, br d, J 8.6 Hz), 8.10 (1H, d, J 10.8 Hz); 13
C
NMR (CDCl3) δ 18.1, 123.8, 129.1, 129.3, 134.0, 136.2, 141.7,
144.4, 147.7; GC-MS: Rt 13.83, m/z 255 (M+). Anal. Calcd for
C11H10ClNO2S (255.72): C, 51.66; H, 3.94; N, 5.48%. Found: C,
51.70; H, 3.85; N, 5.36%.
4.3. Oxidation of Sulfides 10a-f to Sulfones 11a-f. Oxidations
were performed with 2 mmol of substrate, according to conditions
already described.3b After the workup, a crude residue was obtained,
generally pure by 1H NMR analysis. Compounds 11 were crystal-
lized in the cold to avoid stereomutation, as was noticed (although
not further investigated) in some instances. Relevant yields are
reported in Table 1.
4.3.1. 1-[(1E,3Z)-(4-Methanesulfonyl-4-nitrobuta-1,3-dienyl)]-
4-methylbenzene (11b). (0.513 g, 96%). Yellow solid, mp 163.0-
163.7 °C (petroleum ether/methylene chloride); 1H NMR (CDCl3)
δ 2.41 (3H, s), 3.42 (3H, s), 7.25 (2H, d, J 8.3 Hz), 7.40 (1H, d, J
15.3 Hz), 7.54 (2H, d, J 8.3 Hz), 8.01 (1H, dd, J 15.3 and 12.2
Hz), 8.28 (1H, d, J 12.2 Hz); 13C NMR (CDCl3) δ 21.8, 44.9, 118.5,
129.5, 130.0, 132.0, 143.4, 143.5, 147.1, 155.8; GC-MS: Rt 14.46,
m/z 267 (M+). Anal. Calcd for C12H13NO4S (267.30): C, 53.92;
H, 4.90; N, 5.24%. Found: C, 53.72; H, 4.89; N, 5.12%.
4.3.2. 1-Chloro-4-[(1E,3Z)-(4-Methanesulfonyl-4-nitrobuta-
1,3-dienyl)]benzene (11d). (0.506 g, 88%). Yellow solid, mp
4. Experimental Section
4.1. Ring-Opening of 2-Nitrothiophene with Pyrrolidine and
Silver Nitrate. The reaction of 2-nitrothiophene 5 with some
secondary amines and silver nitrate in absolute ethanol has been
previously described.6 In our optimized conditions, pyrrolidine (5.0
g, 70.3 mmol) was added dropwise to a solution of AgNO3 (1.5 g,
8.83 mmol) in ethanol (30 mL). Then, 2-nitrothiophene (1.0 g, 7.75
mmol) in ethanol (30 mL) was added, and immediately a dark-red
precipitate was obtained. The resulting suspension was kept at rt
in the dark for ca. 3 days and then treated with excess methyl iodide.
After the standard workup, column chromatography over silica gel
(petroleum ether/diethyl ether gradients as eluent) allowed isolation
of 80% of the ring-opening product 9a. (1E,3Z)-1-(4-Methylsul-
fanyl-4-nitrobuta-1,3-dienyl)pyrrolidine (9a): (1.331 g, 80%). Red
1
208.4-209.5 °C (petroleum ether/methylene chloride); H NMR
(CDCl3) δ 3.43 (3H, s), 7.35 (1H, d, J 15.2 Hz), 7.43 (2H, d, J 8.4
Hz), 7.57 (2H, d, J 8.4 Hz), 8.03 (1H, dd, J 15.2 and 12.0 Hz),
8.26 (1H, d, J 12.0 Hz); 13C NMR (CDCl3) δ 45.0, 119.9, 129.7,
130.4, 133.1, 138.4, 143.3, 146.0, 153.3; GC-MS: Rt 14.84, m/z
287 (M+). Anal. Calcd for C11H10Cl NO4S (287.72): C, 45.92; H,
3.50; N, 4.87%. Found: C, 45.84; H, 3.49; N, 4.80%.
4.4. Reaction of Compounds 10a-f and 11a-f with Diaz-
omethane. The substrate (1 mmol) was dissolved in dry THF (38
mL) and cooled to 0 °C; diazomethane (2 mmol) in ether was added,
and the reaction mixture was left to reach room temperature and
kept overnight under magnetic stirring. At the end of the reaction,
evaporation of the solvent under reduced pressure yielded a crude
residue, which was purified by chromatography over silica gel
(petroleum ether/ethyl acetate gradients as eluent). While com-
pounds 17 were the sole reaction products from 10, when starting
from 11, both 18 and 19 (as a secondary product) were always
obtained. Yields of compounds 17-19 are reported in Table 2.
4.4.1. (E) (3S,4S)- and (3R,4R)-4-[2-(4-Methylphenyl)vinyl]-
3-methylsulfanyl-3-nitro-4,5-dihydro-3H-pyrazole (17b). (0.229
g, 83%). Pale yellow solid, mp 79.7-80.6 °C (taken up with
1
solid, mp 135.4-136.5 °C (ethanol); H NMR (CDCl3) δ 1.93-
2.14 (4H, m), 2.24 (3H, s), 3.40 (2H, app s), 3.61 (2H, app t), 5.60
(1H, t, J 12.5 Hz), 7.35 (1H, d, J 12.0 Hz), 8.25 (1H, d, J 12.6
Hz); 13C NMR (CDCl3) δ 17.3, 25.0, 47.6, 52.9, 98.2, 129.8, 149.0,
152.9 (two carbons are accidentally isochronous). Anal. Calcd for
C9H14N2O2S (214.28): C, 50.45; H, 6.59; N, 13.07%. Found: C,
50.37; H, 6.61; N, 13.00%.
4.2. Reactions of 9a with Aromatic Organometallic Reagents.
To a suspension of 1-(4-methylsulfanyl-4-nitrobuta-1,3-dienyl)-
pyrrolidine (9a; 1.0 g, 4.67 mmol) in THF (55 mL), cooled to -30
°C, the organometallic reagent (1.1 molar equiv) in THF or Et2O
was slowly added under argon by syringe. The reaction mixture
was kept under stirring for 20 min (the end of the reaction being
judged by TLC analysis) and eventually poured into a dichlo-
romethane/ice/HCl (1.1 molar equiv) mixture. After separation of
the two layers, the aqueous phase was extracted with dichlo-
romethane, and the collected organic extracts were washed with
water and dried over Na2SO4. Concentration under vacuum of the
extracts gave a crude product that was purified by column
chromatography over silica gel (petroleum ether/dichloromethane
gradients as eluent). Yields of compounds 10a-f are collected in
Table 1.
1
petroleum ether); H NMR (CDCl3) δ 2.34 (3H, s), 2.51 (3H, s),
3.48 (1H, q, J 8.4 Hz), 4.47 (1H, dd, J 18.0 and 7.8 Hz), 5.16 (1H,
dd, J 18.0 and 8.4 Hz), 5.89 (1H, dd, J 15.6 and 8.4 Hz), 6.54 (1H,
d, J 15.6 Hz), 7.13 (2H, d, J 8.1 Hz), 7.25 (2H, d, J 8.1 Hz); 13C
NMR (CDCl3) δ 13.0, 21.2, 47.0, 81.8, 118.8, 126.5, 128.1, 129.4,
132.8, 137.0, 138.6; GC-MS: Rt 13.25, m/z 249 (M+ - 28). Anal.
Calcd for C13H15N3O2S (277.34): C, 56.30; H, 5.45; N, 15.15%.
Found: C, 56.19; H, 5.34; N, 15.20%.
4.4.2. (E) (3S,4S)- and (3R,4R)-4-[2-(4-Chlorophenyl)vinyl]-
3-methylsulfanyl-3-nitro-4,5-dihydro-3H-pyrazole (17d). (0.202
g, 71%). Pale yellow solid, mp 57.9-58.8 °C (taken up with
petroleum ether); 1H NMR (CDCl3) δ 2.53 (3H, s), 3.49 (1H, q, J
9072 J. Org. Chem., Vol. 72, No. 24, 2007

Butadienic Building Blocks from 2-Nitrothiophene
8.4 Hz), 4.47 (1H, dd, J 18.0 and 8.1 Hz), 5.17 (1H, dd, J 17.7 and
7.8 Hz), 5.93 (1H, dd, J 15.9 and 8.7 Hz), 6.54 (1H, d, J 15.9 Hz),
7.24-7.34 (4H, m); 13C NMR (CDCl3) δ 12.9, 46.8, 81.6, 120.6,
127.7, 127.8, 128.9, 134.0, 134.2, 135.8; GC-MS: Rt 13.77, m/z
269 (M+ - 28). Anal. Calcd for C12H12ClN3O2S (297.76): C, 48.40;
H, 4.06; N, 14.11%. Found: C, 48.27; H, 4.05; N, 14.12%.
4.4.3. (E) 3-Methanesulfonyl-5-[2-(4-methylphenyl)vinyl]-4,5-
dihydroisoxazole 2-Oxide (18b). (0.183 g, 65%). Pale yellow solid,
mp 107.1-108.3 °C (petroleum ether/methylene chloride); 1H NMR
(CDCl3) δ 2.36 (3H, s), 3.28 (3H, s), 3.40 (1H, dd, J 17.1 and 8.4
Hz), 3.70 (1H, dd, J 16.8 and 9.3 Hz), 5.45 (1H, q, J 8.4 Hz), 6.20
(1H, dd, J 15.9 and 7.8 Hz), 6.74 (1H, d, J 15.9 Hz), 7.17 (2H, d,
J 8.1 Hz), 7.31 (2H, d, J 8.1 Hz); 13C NMR (CDCl3) δ 21.3, 35.9,
40.7, 78.7, 117.0, 121.5, 127.0, 129.5, 132.0, 136.6, 139.3; ESI-
MS: m/z 282.1 [M + H+]. Anal. Calcd for C13H15NO4S (281.33):
C, 55.50; H, 5.37; N, 4.98%. Found: C, 55.47; H, 5.23; N, 5.04%.
4.4.4. (E) 5-[2-(4-Chlorophenyl)vinyl]-3-methanesulfonyl-4,5-
dihydroisoxazole 2-Oxide (18d). (0.163 g, 54%). Pale yellow solid,
which gradually carbonized with heating; 1H NMR (CDCl3) δ 3.28
(3H, s), 3.40 (1H, dd, J 16.8 and 8.1 Hz), 3.70 (1H, dd, J 16.8 and
9.3 Hz), 5.45 (1H, qd, J 8.4 and 0.9 Hz), 6.23 (1H, dd, J 15.9 and
NO4S (295.35): C, 56.93; H, 5.80; N, 4.74%. Found: C, 56.78;
H, 5.86; N, 4.74%.
4.4.6. (E) (1R,2S)- and (1S,2R)-1-Chloro-4-[3-(2-methane-
sulfonyl-2-nitrocyclopropyl)propenyl]benzene (19d). (0.063 g,
20%). Colorless oil; 1H NMR (CDCl3) δ 2.15-2.31 (1H, m), 2.44-
2.59 (2H, m), 2.83 (2H, t, J 6.0 Hz), 3.39 (3H, s), 6.21 (1H, dt, J
15.9 and 6.3 Hz), 6.47 (1H, d, J 15.9 Hz), 7.24-7.32 (4H, m); 13
C
NMR (CDCl3) δ 20.9, 29.6, 34.8, 43.5, 81.7, 126.4, 127.4, 128.9,
131.6, 133.5, 134.9; ESI-MS: m/z 313.8 [M - H]-. Anal. Calcd
for C13H14ClNO4S (315.77): C, 49.45; H, 4.47; N, 4.44%. Found:
C, 49.48; H, 4.46; N, 4.38%.
4.4.7. (E) (1S,2S)- and (1R,2R)-1-Chloro-4-[2-(2-methane-
sulfonyl-2-nitrocyclopropyl)vinyl]benzene (20d). A yellow oil of
satisfactory purity was recovered by fast column chromatography;
20d underwent extensive conversion to 18d on silica gel. 1H NMR
(CDCl3) δ 2.53 (1H, dd, J 9.6 and 7.2 Hz), 2.76 (1H, dd, J 10.2
and 7.2 Hz), 3.06 (1H, app q, J 9.9 Hz), 3.29 (3H, s), 6.18 (1H,
dd, J 15.9 and 9.3 Hz), 6.79 (1H, d, J 15.9 Hz), 7.27-7.35 (4H,
m); 13C NMR (CDCl3) δ 20.7, 38.0, 42.3, 81.9, 121.0, 127.8, 129.1,
133.8, 134.6, 137.2. The low stability of the product prevented a
full (microanalysis and/or mass spectroscopy) characterization.
7.5 Hz), 6.73 (1H, dd, J 15.9 and 0.9 Hz), 7.30-7.39 (4H, m); 13
C
NMR (CDCl3) δ 35.9, 40.7, 78.0, 116.8, 123.3, 128.2, 129.1, 133.3,
135.0, 135.1; ESI-MS: m/z 302.1 [M + H+]. Anal. Calcd for
C12H12ClNO4S (301.75): C, 47.76; H, 4.01; N, 4.64%. Found: C,
47.61; H, 4.00; N, 4.55%.
Acknowledgment. Financial support was provided by grants
from the University of Genova and from Ministero dell’Istruzione,
dell’Universita` e della Ricerca (MIUR, PRIN-2005).
4.4.5. (E) (1R,2S)- and (1S,2R)-1-[3-(2-Methanesulfonyl-2-
nitrocyclopropyl)propenyl]-4-methylbenzene (19b). (0.074 g,
25%). Yellow oil; H NMR (CDCl3) δ 2.15-2.27 (1H, m), 2.34
(3H, s), 2.42-2.58 (2H, m), 2.81 (2H, t, J 6.3 Hz), 3.39 (3H, s),
6.17 (1H, dt, J 15.9 and 6.3 Hz), 6.47 (1H, d, J 15.9 Hz), 7.13
(2H, d, J 7.8 Hz), 7.24 (2H, d, J 7.8 Hz); 13C NMR (CDCl3) δ
20.6, 21.1, 29.6, 35.0, 43.4, 81.7, 124.6, 126.0, 129.4, 132.5, 133.6,
137.7; GC-MS: Rt 14.49, m/z 295 (M+). Anal. Calcd for C14H17-
Supporting Information Available: General experimental
methods and characterization data of 10, 11, 17, 18, and 19a,c,e,f;
1H NMR spectra for all new compounds; ORTEP, X-ray crystal-
lography, and crystallographic data for 17a. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
JO701460K
J. Org. Chem, Vol. 72, No. 24, 2007 9073