Cycloaddition chemistry of 1,3-thiazolium-4-olate systems. Reaction with nitroalkenes and interpretation of results using PM3 calculations

Article abstract of DOI:10.1021/jo952275g

1,3-Dipolar cycloaddition of 1,3-thiazolium-4-olates, readily prepared from thioureido derivatives, and trans-β-nitrostyrene at room temperature in methylene chloride (48 h) resulted in two readily separable diastereomeric racemic 4,5-dihydrothiophenes via transient cycloadducts that underwent rearrangement under these reaction conditions. Using chiral carbohydrate-derived nitroalkenes, two diastereomeric dihydrothiophenes were obtained, showing that regiospecificity and facial selectivity were involved in these cycloadditions. ¹H NMR data and trapping experiments with isolated initial cycloadducts indicated that the cycloadditions were reversible and accounted for observed adduct and final product ratios. Single-crystal X-ray determinations established the structures of critical intermediates and products, and PM3 semiempirical MO calculations provide a rationalization for both the reactivity of the thiazolium-4-olates and the regioselectivity observed in the cycloadditions.

Full text of DOI:10.1021/jo952275g

3738
J . Org. Chem. 1996, 61, 3738-3748
Cycloa d d ition Ch em istr y of 1,3-Th ia zoliu m -4-ola te System s.†
Rea ction w ith Nitr oa lk en es a n d In ter p r eta tion of Resu lts Usin g
P M3 Ca lcu la tion s
Mart´ın Avalos,* Reyes Babiano, Andre´s Cabanillas, Pedro Cintas, Francisco J . Higes,‡
J ose´ L. J ime´nez, and J uan C. Palacios
Departamentos de Qu´ımica Orga´nica y Qu´ımica Inorga´nica, Facultad de Ciencias,
Universidad de Extremadura, E-06071 Badajoz, Spain
Received December 28, 1995X
1,3-Dipolar cycloaddition of 1,3-thiazolium-4-olates, readily prepared from thioureido derivatives,
and trans-â-nitrostyrene at room temperature in methylene chloride (48 h) resulted in two readily
separable diastereomeric racemic 4,5-dihydrothiophenes via transient cycloadducts that underwent
rearrangement under these reaction conditions. Using chiral carbohydrate-derived nitroalkenes,
two diastereomeric dihydrothiophenes were obtained, showing that regiospecificity and facial
selectivity were involved in these cycloadditions. 1H NMR data and trapping experiments with
isolated initial cycloadducts indicated that the cycloadditions were reversible and accounted for
observed adduct and final product ratios. Single-crystal X-ray determinations established the
structures of critical intermediates and products, and PM3 semiempirical MO calculations provide
a rationalization for both the reactivity of the thiazolium-4-olates and the regioselectivity observed
in the cycloadditions.
Sch em e 1
In tr od u ction
Mesoionic heterocycles are receiving considerable at-
tention as synthons in modern organic synthesis. These
are five-membered, aromatic heterocycles that cannot be
represented by Lewis forms not involving charge separa-
tion1 and, although the peculiar structure and reactivity
of such systems have elicited great interest in the past,
the current research focuses on the uniqueness of meso-
ionics as masked 1,3-dipoles and their role in cycloaddi-
tion chemistry.2
As a part of our ongoing program on the cycloadditions
of mesoionic compounds,5 we now report on the reactivity
of thioisomu¨nchnones toward nitroalkenes, including
asymmetric syntheses with chiral nitro olefins in which
the auxiliary is a carbohydrate-based template. A pre-
liminary account of this work has appeared.6 In addition,
a theoretical study using the PM3 semiempirical method7
agrees with the regiochemistry and selectivity observed,
thus allowing us to rationalize thioisomu¨nchnone cyclo-
additions.
While mu¨nchnones (1,3-oxazolium-5-olates) have been
the most extensively studied class of mesoionic com-
pounds, two types of isomeric mesoionics, isomu¨nchnones
(1,3-oxazolium-4-olates) and thioisomu¨nchnones (1,3-
thiazolium-4-olates), have received less attention despite
offering rapid access to different heterocyclic compounds
useful in natural product syntheses.3 Both systems are
able to react with a wide variety of alkenic and alkynic
dipolarophiles, including remarkably the recent reactions
of isomu¨nchnones with buckminsterfullerene, C60.4
Resu lts a n d Discu ssion
Syn th esis of Th ioisom u1 n ch n on es. A general syn-
thesis of 1,3-thiazolium-4-olates was developed by Potts
and co-workers by reaction of N-monosubstituted thio-
amides (1,3-binucleophiles) with R-haloacyl halides (1,2-
bielectrophiles) in the presence of Et3N (Scheme 1).8
This one-pot procedure also enables the preparation
of thioisomu¨nchnones arising from N,N,N′-trisubstituted
thioureas which cannot be prepared by the older method
involving the cyclodehydration of thioglycolic acids.9 We
have found, however, that N′-aryl-N-benzyl-N-methyl-
† IUPAC name for thioisomu¨nchnones. The Chemical Abstracts
Service indexes these substances as anhydro-4-hydroxythiazolium
hydroxides.
‡ Departamento de Qu´ımica Inorga´nica. To whom correspondence
regarding X-ray analyses should be addressed.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) (a) Ohta, M.; Kato, H. In Nonbenzenoid Aromatics; Snyder, J .
P., Ed.; Academic Press: New York, 1969; Vol. 1, pp 117-248. (b)
Ollis, W. D.; Ramsden, C. A. Adv. Heterocycl. Chem. 1976, 19, 1-122.
(c) Newton, C. G.; Ramsden, C. A. Tetrahedron 1982, 38, 2965-3011.
(d) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239-2329. (e) Gingrich, H. L.; Baum, J . S. In The Chemistry of
Heterocyclic Compounds. Vol. 45: Oxazoles; Turchi, I. J ., Ed.; Wiley:
New York, 1986; pp 731-961.
(5) (a) Avalos, M.; Babiano, R.; Bautista, I.; Ferna´ndez, J . I.;
J ime´nez, J . L.; Palacios, J . C.; Plumet, J .; Rebolledo, F. Carbohydr.
Res. 1989, 186, C7-C8. (b) Areces, P.; Avalos, M.; Babiano, R.;
Gonza´lez, L.; J ime´nez, J . L.; Palacios, J . C.; Pilo, M. D. Carbohydr.
Res. 1991, 222, 99-112. (c) Avalos, M.; Babiano, R.; Dia´nez, M. J .;
Espinosa, J .; Estrada, M. D.; J ime´nez, J . L.; Lo´pez-Castro, A.; Me´ndez,
M. M.; Palacios, J . C. Tetrahedron 1992, 48, 4193-4208. (d) Areces,
P.; Avalos, M.; Babiano, R.; Gonza´lez, L.; J ime´nez, J . L.; Me´ndez, M.
M.; Palacios, J . C. Tetrahedron Lett. 1993, 34, 2999-3002.
(6) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Dia´nez, M.
J .; Estrada, M. D.; J ime´nez, J . L.; Lo´pez-Castro, A.; Palacios, J . C.;
Garrido, S. P. J . Chem. Soc., Chem. Commun. 1995, 2213-2214.
(7) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.
(8) Potts, K. T.; Chen, S. J .; Kane, J .; Marshall, J . L. J . Org. Chem.
1977, 42, 1633-1638.
(2) (a) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 2, pp 1-82. (b) Padwa, A. Acc.
Chem. Res. 1991, 24, 22-28. (c) Padwa, A.; Krumpe, K. E. Tetrahedron
1992, 48, 5385-5453.
(3) For excellent accounts on isomu¨nchnones/thioisomu¨nchnones: (a)
Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123-141.
(b) Marino, J . P., J r.; Osterhout, M. H.; Padwa, A. J . Org. Chem. 1995,
60, 2704-2713.
(4) Gonza´lez, R.; Knight, B. W.; Wudl, F.; Semones, M. A.; Padwa,
A. J . Org. Chem. 1994, 59, 7949-7951.
S0022-3263(95)02275-4 CCC: $12.00 © 1996 American Chemical Society

Cycloaddition Chemistry of 1,3-Thiazolium-4-olate Systems
J . Org. Chem., Vol. 61, No. 11, 1996 3739
Sch em e 2
ether. When the reaction was conducted in CH2Cl2 at
room temperature for 48 h, the dihydrothiophene 9b was
isolated in 90% yield. Remarkably, a sample of 8b in
CDCl3 at room temperature slowly converted into 9b and
not into the thiophene 10b which was not detected at all
in this entry. The experiments described are consistent
with the retrocycloaddition of cycloadduct 8b occurring
readily at room temperature. In order to test such a
retro-dipolar process, two trapping experiments were
carried out (Scheme 4).
Thus, in the presence of a stoichiometric amount of
methyl propiolate, the cycloadduct 8b gives the pyridone
11, which was also obtained by direct cycloaddition of
3b with methyl propiolate.10 On the other hand, the
reaction of 8b with the thioisomu¨nchnone 3c gave a
mixture of dihydrothiophenes 9b, 9c, and 10c in the ratio
1:1:2 as determined by 1H NMR. These compounds were
separated by preparative thin-layer chromatography, and
they had physical and spectroscopic properties identical
to those of authentic samples. These results demonstrate
the retrocycloaddition of 8b to 3b and â-nitrostyrene.
Likewise, the cycloaddition of 3c with 4 at room
temperature for 4 h afforded a 1:2 mixture of dihydro-
thiophenes 9c and 10c, separable by chromatography.
Again, transient cycloadducts 7c and 8c could be detected
at 0 °C by NMR analysis, but they readily converted into
9c and 10c. Structures of dihydrothiophenes 9 and 10
were determined by homo- and heteronuclear two-
dimensional correlations and selective decoupling experi-
ments. Of particular importance is the high-field chemi-
cal shift of H4 in compounds 9 (∆δH ∼0.1-0.2 ppm), while
the C5 resonances of these compounds were shifted
downfield (∆δC ∼3.5-5.0 ppm) with respect to those of
10. The stereochemical assignment was confirmed fi-
nally by the single-crystal X-ray structure determination
of 10a . The diffraction data were recorded as described
in the Supporting Information.11
thioureas (1a -c), readily prepared from aryl isothio-
cyanates and N-methylbenzylamine, reacted with R-bro-
mophenylacetic acid in benzene/Et3N affording the noniso-
lated thioglycolic acid intermediates 2a -c. Further
cyclodehydration with Ac2O/Et3N gave the thioisomu¨nch-
nones 3a -c, which were usually contaminated with
triethylammonium salts (Scheme 2). Purification was
achieved upon treatment with KHCO3/18-crown-6 in
CH2Cl2/Et2O.
R ea ct ion s w it h Nit r oa lk en es. 1,3-Dipolar cyclo-
additions of thioisomu¨nchnones with nitroalkenes have
not been as extensively studied as with other asymmetri-
cally-substituted dipolarophiles,5a,6 and the usefulness
and control exerted by a nitro group are of special
interest. Our experiments with â-nitrostyrene (4) and
the chiral nitroalkenes 5 and 6 are summarized in
Schemes 3 and 5, respectively (vide infra).
The structures attributed to cycloadducts 7 and 8 are
consistent with those proposed for the resulting dihy-
drothiophenes 9 and 10.
Asym m etr ic Syn th eses. Having demonstrated that
thioisomu¨nchnones 3a -c undergo 1,3-dipolar cycloaddi-
tion with â-nitrostyrene to furnish a mixture of two
diastereomeric dihydrothiophenes, we were eager to test
the asymmetric version of this novel process by using a
chiral and enantiomerically pure nitroalkene to induce
facial selectivity in these reaction conditions. We chose
as carbohydrate-based chiral auxiliaries the nitroalkenes
5 and 6 that were readily prepared from the commercially
available D-galactose and D-mannose, respectively, in a
three-step sequence.12 The presence of two chiral side
chains, with opposite configuration at the first stereo-
genic center, will be of benefit in evaluating the influence
of the chiral fragment and determining the stereochem-
ical outcome (Scheme 5).
Thioisomu¨nchnone 3a reacted smoothly with trans-â-
nitrostyrene (4) in CH2Cl2 at room temperature for 48 h
and gave a diastereomeric 3:1 mixture of racemic 4,5-
dihydrothiophenes 9a and 10a in 93% overall yield.
These products were readily separated by column chro-
matography (Scheme 3).
The formation of these dihydrothiophenes should pro-
ceed through transient cycloadducts 7a and 8a . 1H NMR
monitoring (400 MHz) in CDCl3 at 0 °C provided evidence
for the formation of these cycloadducts in a 1:3 ratio,
respectively. The reaction mixture was allowed to warm
at room temperature, and after 1 h, the conversion of 7a
into 9a was complete whereas compound 8a remained
unaltered. The analogous reaction of 3b and 4 at 0 °C
resulted in the formation of 7b and 8b (1:3 ratio). After
1 h at room temperature, the transformation of 7b into
9b was complete, and the cycloadduct 8b was isolated
from the reaction mixture by precipitation with cold
Mesoionic compounds 3 and nitroalkene 5 in toluene
at reflux or in CH2Cl2 at room temperature gave exclu-
(10) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; J ime´nez, J .
L.; Palacios, J . C.; Valencia, C. unpublished results on reactions of
thioisomu¨nchnones with alkynes.
(11) The authors have deposited crystal X-ray diffraction data of
this work with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(9) (a) Duffin, G. F.; Kendall, J . D. J . Chem. Soc. 1951, 734-739.
(b) Ohta, M.; Chosho, H.; Shin, C.; Ichimura, K. Nippon Kagaku Zasshi
1964, 85, 440-443; Chem. Abstr. 1964, 61, 14657h.
(12) (a) Sowden, J . C.; Schaffer, R. J . Am. Chem. Soc. 1951, 73,
4662-4664. (b) Sowden, J . C.; Strobach, D. R. J . Am. Chem. Soc. 1960,
82, 954-955.

3740 J . Org. Chem., Vol. 61, No. 11, 1996
Avalos et al.
Sch em e 3
Sch em e 4
Sch em e 5
sively the 4,5-dihydrothiophenes 14 and 15. Structures
of compounds 14a and 15a were unequivocally assigned
by X-ray diffraction analyses.6 When the reaction was
Furthermore, the unambiguous structures of compounds
19a and 19b have been determined by X-ray diffraction
analyses.13
It should be pointed out that stereocenters at C4 and
C5 of compounds 18 and 19 have the configuration
opposite to those of 14 and 15, respectively. This fact
accounts for the facial selectivity provided by two differ-
ent and complementary carbohydrate auxiliaries and
reveals the discriminating role exerted by the first
stereocenter of acyclic sugar chains.
In flu en ce of Th ioisom u1 n ch n on e Str u ctu r e on th e
R ea ct ivit y. Results summarized above are unprece-
dented in the literature since it is known that reactions
of 1,3-thiazolium-4-olates with olefinic dipolarophiles
provide stable cycloadducts,14,15 often as endo/ exo mix-
tures, which eventually fragment into R-pyridones. In
addition, Padwa and co-workers have described the
preparation of nitrogen- and sulfur-containing polycyclic
1
conducted in CDCl3 at 0 °C and monitored by H NMR,
we succeeded in detecting the intermediates 12 and 13,
whose stability follows the order b > a > c depending
on the substitution pattern of the mesoionic ring. Again,
the transformation of 12 into 14 was faster than that of
13 into 15. This fact allowed us to isolate the cycloadduct
13b by precipitation with cold ether. A CDCl3 solution
of 13b was monitored by 1H NMR showing, after 30 days
at 25 °C, a mixture of 14b and 15b (1:1.4 ratio). This
experiment proves again that a stable cycloadduct may
undergo a retro-dipolar addition yielding starting materi-
als that, after recombination, provide the two cyclo-
adducts. On the other hand, on heating 13b in CH2Cl2
in the presence of silica gel, compound 15b was obtained
quantitatively after 5 h.
Cycloadditions of 3 with chiral nitroalkene 6, bearing
a D-manno carbohydrate side chain, occurred in a way
similar to those outlined above. Again, the transient
cycloadducts 16 and 17 were detected spectroscopically
and the 4,5-dihydrothiophenes 18 and 19 were isolated.
(13) Dia´nez, M. J .; Estrada, M. D.; Lo´pez-Castro, A.; Pe´rez-Garrido,
S. Private communication.
(14) Potts, K. T.; Baum, J .; Houghton, E. J . Org. Chem. 1974, 39,
3631-3641.
(15) Robert, A.; Baudy, M.; Foucaud, A.; Golic, L.; Stanovnik, B.
Tetrahedron 1978, 34, 3525-3530.

Cycloaddition Chemistry of 1,3-Thiazolium-4-olate Systems
J . Org. Chem., Vol. 61, No. 11, 1996 3741
reaction of nitroalkenes 5 and 6 with cyclopentadiene.18
Unequivocal evidence of the stereostructure of these
cycloadducts was obtained from the single-crystal X-ray
determination of 23.11
Sch em e 6
In summary, the cycloadditions of 20 proceeded slowly
and required prolonged heating, while mesoionic com-
pounds 3a -c reacted with nitroalkenes at 0 °C in shorter
reaction times. This distinctive behavior suggests that
the presence of an amino group, instead of aryl substit-
uents, plays a crucial role in the reactivity. In order to
gain further insight into this feature as well as to explain
the regiochemistry and facial selectivity observed, a
theoretical study was undertaken.
R a t ion a liza t ion of Th ioisom u1 n ch n on e Cyclo-
a d d ition s. Semiempirical calculations using the PM3
method7 for the cycloaddition of thioisomu¨nchnone 3a
with 24 were carried out.
Ta ble 1. Com p a r a tive 13C NMR Ch em ica l Sh ifts for
Com p ou n d s 9, 10, a n d 21
trans
cis
9a
9b
9c
10a
10c
21
C2
C3
C4
C5
166.2
120.3
56.7
166.2
120.5
56.4
165.8
121.8
56.1
161.5
121.7
58.4
162.9
122.0
59.8
150.8
130.4
59.1
73.6
73.8
75.1
70.4
70.8
71.4
Sch em e 7
This model system is very close to the real reaction
with chiral nitroalkenes 5 and 6, the differences being
the lack of the carbohydrate skeleton though 24 main-
tains the E disposition around the double bond and the
same configuration at the first stereogenic carbon as in
compound 5. Geometrical parameters, formal charge
distributions, enthalpies of formation at 298 K, and
ionization potentials for 3a and 24 are shown in Figure
1. The charge distributions of +0.122 at the mesoionic
ring and -0.380 at the exocyclic oxygen reflect the
mesoionic character of 3a , thus supporting the model
approach.
Table 2 also shows the values of FMO energies and
coefficients for both reactants. Energy values for HO-
MOs/LUMOs of 3a and 24 lead us to consider that the
HOMOdipole - LUMOdipolarophile interaction was prevalent
(∆E ) -6.77 eV). This agrees with Sustmann’s type I
reactions,19 which are referred to as HOMO-dipole-
controlled cycloadditions.
systems by intramolecular cycloaddition of alkenes at-
tached to 1,3-thiazolium-4-olate systems.16
Initially, we suspected that the difference of reactivity
could likely be ascribed to the nitroalkene rather than
the mesoionic heterocycle itself. In order to obtain
support for this hypothesis, the reactions of thioiso-
mu¨nchnone 20, the first, well-characterized 1,3-thia-
zolium-4-olate system,17 with nitroalkenes were exam-
ined. The reaction of â-nitrostyrene (4) with an excess
(33%) of 20 proceeded slowly, and after 6 days in refluxing
toluene, the racemic 4,5-dihydrothiophene 21 was isolated
in 43% yield (Scheme 6).
The thiophene structure for compound 21 is supported
1
by the NMR data. Besides aromatic signals, its H NMR
spectrum displays two resonances shifted downfield at
7.7 and 6.0 ppm. The former, exchangeable by addition
of D2O, should be ascribed to the NH proton, while the
latter is attributed to H-4. In addition, 13C NMR data
also support this structure because the resonances of C4
and C5 carbon atoms are similar to those of 4,5-dihy-
drothiophenes 10. Table 1 shows a comparison of 13C
resonances for compounds 9, 10, and 21, where cis or
trans refers to the relative orientations of the two phenyl
groups at C4 and C5.
Next, we tried to rationalize the difference of reactivity
found in the reactions of thioisomu¨nchnones 3a -c and
20. PM3 semiempirical calculations were used to evalu-
ate the MO energies of simplified models 25 and 26
(Table 3). The higher value for EHOMO of 25 with respect
to that of 26 (∆E ) 0.15 eV) does justify its higher
reactivity.
The reaction of thioisomu¨nchnone 20 with nitroalkenes
5 and 6 also occurred at reflux over 24-48 h, and an
excess (33%) of thioisomu¨nchnone 20 was also required.
Unlike trans-â-nitrostyrene, reactions with compounds
5 and 6 afforded the cycloadducts 22 and 23, respectively
(Scheme 7).
NMR data did not provide evidence for the transforma-
tion of such intermediates into the corresponding dihy-
drothiophenes. The structures of the cycloadducts were
established by comparison of their NMR data with those
of pure cycloadducts described in this work as well as
with similar bicyclic systems formed by Diels-Alder
(a ) Regioch em istr y. According to FMO postulates,20
after identifying the HOMO/LUMO pair closer in energy,
(18) Roma´n, E.; Hodgson, D. J .; Yokomori, Y.; Eliel, E. L.; Bueno,
M.; Serrano, J . A. Carbohydr. Res. 1988, 180, 263-276.
(19) (a) Sustmann, R. Tetrahedron Lett. 1971, 2717-2720. (b)
Sustmann, R.; Trill, H. Angew. Chem., Int. Ed. Engl. 1972, 11, 838-
840.
(20) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.
(16) Hertzog, D. L.; Nadler, W. R.; Zhang, Z. J .; Padwa, A. Tetra-
hedron Lett. 1992, 33, 5877-5880.
(17) Potts, K. T.; Houghton, E.; Singh, U. P. J . Org. Chem. 1974,
39, 3627-3631.

3742 J . Org. Chem., Vol. 61, No. 11, 1996
Avalos et al.
F igu r e 1. Molecular models of stationary structures of mesoionic compound 3a and nitroalkene 24 describing geometrical
parameters, formal charge distributions, enthalpies of formation at 298 K, and ionization potentials.
Ta ble 2. En er gy a n d Coefficien t Va lu es for F MOs of
Com p ou n d s 3a a n d 24
3a
24
compd
OM
E (eV)
C2
C5
C1
C2
3a
HO
LU
HO
LU
-7.83
-1.40
-11.53
-1.06
-0.35
-0.61
0.55
-0.35
24
0.55
-0.50
0.43
0.67
Ta ble 3. En er gy Va lu es for F MOs of Com p ou n d s 25 a n d
26
compd
EHOMO (eV)
ELUMO (eV)
25
26
-8.09
-8.24
-1.09
-1.49
the relative sizes of the coefficients of the atomic orbitals
will predict the regioselectivity. The four approaches in
which HOMO and LUMO face the coefficients with larger
sizes are represented in Figure 2. In all the cases C2
and C5 carbon atoms of the 1,3-thiazolium-4-olate inter-
act with the C1-C2 bond of the nitroalkene. This
regiochemistry is in agreement with the experimental
results of this 1,3-dipolar cycloaddition.
(b) F a cia l Dia ster eoselectivity. In Figure 2, the
approaches a and b involve the attack of the si(C2)-
re(C5) face of 3a to si(C1)-si(C2) and re(C1)-re(C2) faces
of the nitroalkene 24, respectively. On the other hand,
the approaches c and d involve the interaction of the
re(C2)-si(C5) face of 3a with re(C1)-re(C2) and si(C1)-
si(C2) faces of 24, respectively. Accordingly, Scheme 8
displays the four possible cycloadducts in which R*
replaces the methyl group of 24 and denotes the chiral
fragment of nitroalkenes 5 or 6.
F igu r e 2. Schematic representation of the four possible
approaches of HOMOs and LUMOs of compounds 3a and 24.
Sch em e 8
Opening of such cycloadducts should provide the cor-
responding dihydrothiophenes 31-34 (Scheme 9).
The experimental results with the nitroalkene 5 are
consistent with cycloadducts 27 and 30 only, which would
afford the 4,5-dihydrothiophenes 31 and 34, respectively,
the latter compounds having the same configuration as
15a and 14a . The exclusive formation of 14a and 15a
shows that the nitroalkene 5 reacts with complete facial
diastereoselectivity. This behavior can be ascribed to the
chiral fragment (R*) which, in approaches a and d, moves
away the bulkier substituent (sugar chain) from the
heterocyclic ring (Scheme 10).
The same explanation is also applicable for the ob-
served reactivity of 3a toward D-manno nitroalkene 6.
The approaches depicted in Scheme 11 lead to cyclo-
adducts 16 and 17 that afford the 4,5-dihydrothiophenes
18 and 19, respectively. These results allow us to rule
out the influence of secondary orbital or Coulombic
interactions on the stereochemical outcome because they
should contribute at the same extent in each approach.
Op en in g of Cycloa d d u cts. The particular mode of
opening of the cycloadducts generated by reaction of
thioisomu¨nchones 3a -c with nitroalkenes can be at-
tributed to the presence of a dialkylamino group at the
C2 atom of the mesoionic ring. Moreover, cleavage of
cycloadducts to give the corresponding dihydrothiophenes
proceeded rapidly with electron-withdrawing substitu-

Cycloaddition Chemistry of 1,3-Thiazolium-4-olate Systems
J . Org. Chem., Vol. 61, No. 11, 1996 3743
Sch em e 9
Sch em e 11
Sch em e 10
C1-N2 heterolysis that could certainly then yield the 4,5-
dihydrothiophenes. However, a sample of the stable
cycloadduct 22 and Et3N was shaken in CDCl3 with D2O,
and H/D exchange was not observed. This result clearly
excludes the (E1cB)R path. Furthermore, when the
cycloadduct 22, which does not fragment under the
experimental reaction conditions, was treated with either
Et3N or the mesoionic compound 3b, no cleavage of 22
was detected by NMR analysis after 24 h. The results
also rule out the E2 and (E1cB)ip mechanisms since the
addition of base does not affect reaction rates.
We consider that an intramolecular E1 mechanism
(Scheme 12) is the most plausible pathway, which is in
full agreement with the experimental observations.
Stereoelectronic effects can be invoked to explain both
the opening and cycloreversion of cycloadducts since the
lone pair of the methylbenzylamine nitrogen and the
leaving group should be arranged in an anti disposition.
With an exo nitro group, the substituents on the nitrogen
atom move away, thus favoring the cleavage of the C1-
N2 bond as a consequence of the preferential anti
conformer. With an endo nitro group, however, both the
heterolysis and the competing retrocycloaddition by C1-
C6 cleavage are equally possible, which will be dependent
on the nature of nucleofuges at the N2 atom. Further-
more, the exo nitro group should be able to stabilize
electrostatically the positive charge on the methylbenzyl-
amine nitrogen generated by cleavage of the C1-N2
bond. No such stabilization is possible for the endo nitro
group. Consequently, one might expect that the cleavage
of an exo nitro compound should be faster than that of
an endo nitro compound, leading to the observed prod-
ucts.
ents (4-NO2C6H4) at the N2 atom, whereas electron-
releasing groups (4-MeOC6H4) stabilize considerably such
cycloadducts, which eventually can be isolated and
further characterized.
At first sight, the reaction may take a dissociative
pathway with the initial abstraction of the R-hydrogen
to the nitro group which would provide the driving force
for cycloadduct cleavage. Such a deprotonation may
occur by intermolecular attack of the dialkylamino group,
arising from the cycloadduct itself or the starting meso-
ionic system. The elimination pathway is not consistent
with the E2 mechanism owing to stereoelectronic effects.
Thus, cycloadducts 8, 13, and 17, which do not fragment
or undergo slow transformations, have the favorable
arrangement between the exo proton (H6) and the leaving
group for an anti elimination. However, the ease with
which cycloadducts 7, 12, and 16 fragment into 4,5-
dihydrothiophenes would be consistent with the abstrac-
tion of an endo proton.
It is known that the E1cB mechanism would most
likely be found with substrates containing acidic protons
and poor leaving groups. Among the limiting cases of
this mechanism, the (E1cB)R or the (E1cB)ip variants for
which a substantial effect on leaving groups takes place
would be in agreement with our experimental results.
Thus the relative rates are dependent on the substituents
in the order 4-NO2C6H4 > C6H5 > 4-MeOC6H4. In the
(E1cB)R mechanism, the first step is a rapid and revers-
ible proton exchange between the substrate and the base
followed by the rate-determining process involving the
Cycloadditions of mesoionics 3a -c with other sub-
strates are under way to elucidate whether these or other
possibilities lie on the cleavage pathway.
Con clu sion s. Thioisomu¨nchnones bearing a dialkyl-
amino substituent at the C2 atom react more rapidly with
nitroalkenes than those substituted with aryl groups to
afford transient cycloadducts that convert into 4,5-
dihydrothiophenes. This 1,3-dipolar cycloaddition ap-
pears to be a reversible process as shown by NMR studies
at variable temperatures and trapping experiments. The
utilization of chiral nitroalkenes provides an excellent

3744 J . Org. Chem., Vol. 61, No. 11, 1996
Avalos et al.
Sch em e 12
suspended in 1:1 CH2Cl2/Et2O (100 mL), and the mixture was
stirred with NaHCO3 (2.52 g, 30 mmol) and a catalytic amount
of 18-crown-6 for 24 h at rt. Addition of CH2Cl2 until complete
dissolution, filtration, and evaporation gave oily residues that
crystallized from Et2O/hexane.
2-(N-Meth ylben zyla m in o)-3,5-d ip h en yl-1,3-th ia zoliu m -
4-ola te (3a ): yield 52%, mp 147-149 °C dec; 1H NMR (CDCl3)
δ 7.75-6.92 (m, 15H), 4.23 (s, 2H), 2.74 (s, 3H); 13C NMR
(CDCl3) δ 161.2, 156.2, 136.6, 135.1, 133.8, 129.2, 128.9, 128.2,
127.5, 127.1, 122.2, 79.8, 57.7, 40.0. This substance is
hygroscopic, and satisfactory analytical data ((0.4% for C, H,
N) could not be obtained.
3-(4-Meth oxyph en yl)-2-(N-m eth ylben zylam in o)-5-ph en -
yl-1,3-th ia zoliu m -4-ola te (3b): yield 48%; mp 199-201 °C
dec; 1H NMR (CDCl3) δ 7.74-6.94 (m, 14H), 4.28 (s, 2H), 3.80
(s, 3H), 2.79 (s, 3H); 13C NMR (CDCl3) δ 161.3, 159.9, 156.5,
135.2, 134.0, 129.1, 128.6, 128.3, 127.3, 122.2, 122.1, 114.7,
79.9, 57.6, 55.5, 40.0. Anal. Calcd for C24H22N2O2S: C, 71.62;
H, 5.51; N, 6.96; S, 7.97. Found: C, 71.59; H, 5.51; N, 7.02; S,
7.91.
procedure to obtain diastereoselectively 4,5-dihy-
drothiophene derivatives. The interesting facial selectiv-
ity results from the attack of the mesoionic ring to one
face of the chiral nitroalkene. The reactivity, regiochem-
istry, and diastereoselectivity of these 1,3-thiazolium-4-
olate systems are in agreement with PM3 semiempirical
calculations. The mechanistic considerations described
above suggest that the N,N-dialkylamino group may
participate in cycloadduct opening.
Exp er im en ta l Section
All mps were determined on a capillary apparatus and are
uncorrected. Optical rotations were measured at 18 ( 2 °C.
IR spectra were recorded in KBr pellets unless otherwise
specified. 1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. Chemical shifts were reported in ppm
(δ) using Me4Si as internal standard. Column chromatography
was carried out with silica gel Merck 60 (230-400 mesh).
Analytical TLC was developed on precoated plates with silica
gel Merck 60 GF254 of 2 mm thickness. Elemental analyses
were performed by the Servicio de Microana´lisis, CSIC,
Barcelona. Reagents were purchased from commercial sup-
pliers or prepared by literature methods.
Syn th esis of Th iou r ea s 1a -c. Gen er a l P r oced u r e. To
a stirred solution of aryl isothiocyanate (30 mmol) in Et2O (50
mL) at 0 °C (external ice bath) was added dropwise N-
methylbenzylamine (4.2 mL, 32 mmol). The resulting crystal-
line thioureas were filtered, washed with cold Et2O, and used
without further purification. The characteristic spectral data
for various thioureas are given below.
N-Ben zyl-N-m eth yl-N′-p h en ylth iou r ea (1a ): yield 81%;
mp 134-136 °C; 1H NMR (CDCl3) δ 7.37-7.20 (m, 11H), 4.99
(s, 2H), 3.07 (s, 3H); 13C NMR (CDCl3) δ 182.0, 139.5, 135.8,
128.6, 128.2, 127.5, 127.0, 125.5, 56.7, 38.2. Anal. Calcd for
C15H16N2S: C, 70.27; H, 6.29; N, 10.93; S, 12.51. Found: C,
70.35; H, 6.30; N, 10.90; S, 12.70.
N-Ben zyl-N′-(4-m eth oxyph en yl)-N-m eth ylth iou r ea (1b):
yield 99%; mp 141-143 °C; 1H NMR (CDCl3) δ 7.35-6.80 (m,
10H), 5.04 (s, 2H), 3.74 (s, 3H), 3.14 (s, 3H); 13C NMR (CDCl3)
δ 182.9, 157.7, 136.2, 132.7, 128.8, 127.8, 127.7, 127.2, 57.0,
55.4, 38.4. Anal. Calcd for C16H18N2OS: C, 67.10; H, 6.34;
N, 9.78; S, 11.19. Found: C, 67.09; H, 6.45; N, 9.80; S, 11.16.
N-Ben zyl-N-m et h yl-N′-(4-n it r op h en yl)t h iou r ea (1c):
yield 96%; mp 168-169 °C; 1H NMR (CDCl3) δ 8.17-7.26 (m,
10H), 5.09 (s, 2H), 3.36 (s, 3H); 13C NMR (CDCl3) δ 181.7,
145.6, 143.9, 135.2, 129.3, 128.4, 127.2, 124.4, 123.1, 57.2, 39.6.
Anal. Calcd for C15H15N3O2S: C, 59.78; H, 5.02; N, 13.94; S,
10.64. Found: C, 59.86; H, 5.16; N, 14.01; S, 10.63.
2-(N-m eth ylben zyla m in o)-3-(4-n itr op h en yl)-5-p h en yl-
1
1,3-th ia zoliu m -4-ola te (3c): yield 46%; mp 166-168 °C; H
NMR (CDCl3) δ 8.17-6.91 (m, 14H), 4.12 (s, 2H), 2.64 (s, 3H);
13C NMR (CDCl3) δ 161.4, 155.5, 147.4, 141.9, 134.8, 133.2,
129.2, 129.0, 128.4, 126.9, 124.3, 122.4, 122.2, 79.8, 58.1, 40.5.
Anal. Calcd for C23H19N3O3S: C, 66.17; H, 4.59; N, 10.07; S,
7.68. Found: C, 66.24; H, 4.52; N, 10.18; S, 7.70.
R ea ct ion of Mesoion ic Com p ou n d 3a w it h â-Nit r o-
st yr en e (4). To a solution of 4 (0.20 g, 1.34 mmol) in dry
CH2Cl2 (10 mL) was added 3a (0.5 g, 1.34 mmol). After 48 h
at rt, the solvent was evaporated to give a 3:1 mixture of
dihydrothiophenes 9a and 10a (0.65 g, 93% overall). Purifica-
tion by preparative TLC (benzene-Et2O, 10:1, three elutions)
gave pure samples.
(4R,5R)- a n d (4S,5S)-2-(N-Meth ylben zyla m in o)-3-n itr o-
4 ,5 -d i p h e n y l -5 -( p h e n y l c a r b a m o y l ) -4 ,5 -d i h y d r o -
th iop h en e (9a ): crystals from CHCl3-Et2O; mp 248-250 °C
dec; 1H NMR (CDCl3) δ 7.66-6.87 (m, 21H), 5.74 (s, 1H), 4.79
(d, J ) 15.3 Hz, 1H), 4.60 (d, J ) 15.3 Hz, 1H), 3.13 (s, 3H);
13C NMR (CDCl3) δ 166.5, 166.2, 141.4, 137.0, 136.3, 134.5,
129.5, 129.1, 128.9, 128.8, 128.7, 128.6, 128.4, 128.3, 127.9,
126.3, 125.1, 120.7, 120.3, 73.6, 61.9, 56.7, 44.0. Anal. Calcd
for C31H27N3O3S: C, 71.38; H, 5.22; N, 8.06; S, 6.15. Found:
C, 71.20; H, 5.16; N, 7.96; S, 6.15.
(4R,5S)- a n d (4S,5R )-2-(N-Meth ylben zyla m in o)-3-n i-
t r o -4,5-d ip h e n y l-5-(p h e n y lc a r b a m o y l)-4,5-d ih y d r o -
th iop h en e (10a ): crystals from CHCl3-Et2O; mp 221-223 °C
dec; 1H NMR (CDCl3) δ 7.74-7.05 (m, 21H), 5.92 (s, 1H), 4.92
(d, J ) 15.8 Hz, 1H), 4.67 (d, J ) 15.8 Hz, 1H), 3.26 (s, 3H);
13C NMR (CDCl3) δ 169.1, 161.5, 137.4, 136.9, 135.0, 133.3,
129.2, 129.0, 128.7, 128.5, 128.3, 127.9, 127.8, 127.2, 124.8,
121.7, 119.9, 70.4, 61.6, 58.4, 44.7. Anal. Calcd for C31H27N3-
O3S‚CHCl3: C, 59.96; H, 4.40; N, 6.55; S, 5.00. Found: C,
60.24; H, 4.58; N, 6.86; S, 4.95.
Syn th esis of Th ioisom u1 ch n on es 3a-c. Gen er a l P r epa -
r a tion . To a stirred suspension of the corresponding thioureas
1a -c (11.7 mmol) and R-bromophenylacetic acid (2.5 g, 11.7
mmol) in benzene (100 mL) was added dropwise Et3N (1.6 mL,
11.7 mmol). After 15 h at rt, the reaction mixture was filtered
and the solvent was evaporated. The residue was treated with
Ac2O (12 mL) and Et3N (3 mL). The resulting solid was
NMR Mon itor in g. A solution of 3a (38 mg, 0.1 mmol) and
4 (15 mg, 0.1 mmol) in CDCl3 (0.5 mL) at 0 °C was monitored
by 1H NMR. At that temperature the formation of

Cycloaddition Chemistry of 1,3-Thiazolium-4-olate Systems
J . Org. Chem., Vol. 61, No. 11, 1996 3745
(1S,4R,5R,6R)- and (1R,4S,5S,6S)-1-(N-methylbenzylamino)-
6-n it r o-3-oxo-2,4,5-t r iph en yl-7-t h ia -2-a za bicyclo[2.2.1]-
heptane (7a ), and (1R,4S,5R,6R)- and (1S,4R,5S,6S)-1-(N-
methylbenzylamino)-6-nitro-3-oxo-2,4,5-triphenyl-7-thia-2-
azabicyclo[2.2.1]heptane (8a ) was detected in 1:3 ratio: 1H
NMR (CDCl3) (7a ) δ 6.19 (d, J ) 4.0 Hz, 1H), 4.71 (d, J ) 4.0
Hz, 1H), 3.97 (m, 2H), 2.38 (s, 3H); (8a ) δ 6.17 (d, J ) 4.5 Hz,
1H), 4.87 (d, J ) 4.5 Hz, 1H), 3.98 (d, 2H), 2.55 (s, 3H).
R ea ct ion of Mesoion ic Com p ou n d 3b w it h â-Nit r o-
styr en e (4). (4R,5R)- a n d (4S,5S)-5-[(4-Meth oxyp h en yl)-
ca r b a m oyl]-2-(N -m e t h ylb e n zyla m in o)-3-n it r o-4,5-d i-
p h en yl-4,5-d ih yd r oth iop h en e (9b). To a solution of 4 (0.24
g, 1.34 mmol) in dry CH2Cl2 (10 mL) was added 3b (0.5 g, 1.34
mmol). After 48 h at rt, the solvent was evaporated to afford
crystals of 9b (0.67 g, 90%): mp 242-244 °C; 1H NMR (CDCl3)
δ 7.72-7.71 (m, 20H), 5.84 (s, 1H), 4.77 (d, J ) 15.3 Hz, 1H),
4.57 (d, J ) 15.3 Hz, 1H), 3.66 (s, 3H), 3.10 (s, 3H); 13C NMR
(CDCl3) δ 166.9, 166.2, 156.8, 141.6, 137.3, 134.5, 129.4, 129.3,
129.0, 128.7, 128.6, 128.3, 128.2, 127.9, 126.3, 122.7, 120.5,
113.7, 73.8, 61.9, 56.4, 55.3, 43.9. Anal. Calcd for
C32H29N3O4S: C, 69.67; H, 5.30; N, 7.62; S, 5.81. Found: C,
69.42; H, 5.29; N, 7.55; S, 5.60.
(1R,4S,5R,6R)- a n d (1S,4R,5S,6S)-2-(4-Meth oxyp h en yl)-
1-(N-m et h ylb en zyla m in o)-6-n it r o-3-oxo-4,5-d ip h en yl-7-
th ia -2-a za bicyclo[2.2.1]h ep ta n e (8b). To a solution of 4
(0.47 g, 2.48 mmol) in dry CH2Cl2 (20 mL) at -10 °C was added
3b (1.0 g, 2.48 mmol). After 4 h at that temperature, the
solvent was evaporated to dryness. Trituration with ether,
filtration, and further washing with ether gave a yellow solid
(0.98 g, 67%): mp 221-223 °C; 1H NMR (CDCl3) δ 7.40-6.82
(m, 19H), 6.15 (d, J ) 4.4 Hz, 1H), 4.84 (d, J ) 4.4 Hz, 1H),
4.01 (d, J ) 13.01 Hz, 1H), 3.60 (d, J ) 13.01 Hz, 1H), 3.74 (s,
3H), 2.53 (s, 3H); 13C NMR (CDCl3) δ 171.6, 158.0, 136.0, 135.9,
131.7, 129.1, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 127.7,
127.4, 127.2, 122.6, 113.7, 104.5, 95.9, 68.5, 59.4, 55.3, 55.2,
37.6. Anal. Calcd for C32H29N3O4S: C, 69.67; H, 5.30; N, 7.62;
S, 5.81. Found: C, 69.48; H, 5.41; N, 7.47; S, 5.57.
d r oth iop h en e (9c): crystals from CHCl3; mp 244-246 °C dec;
1H NMR (acetone-d6) δ 8.09-7.18 (m, 20H), 5.83 (s, 1H), 4.90
(d, J ) 15.6 Hz, 1H), 4.69 (d, J ) 15.6 Hz, 1H), 3.19 (s, 3H);
13C NMR (acetone-d6) δ 168.0, 165.8, 144.7, 144.4, 142.7, 138.7,
136.4, 130.1, 129.8, 129.7, 129.6, 129.0, 128.9, 128.7, 128.4,
126.9, 125.3, 121.8, 120.4, 75.1, 61.9, 56.1, 44.8. Anal. Calcd
for C31H26N4O5S: C, 65.71; H, 4.62; N, 9.89; S, 5.66. Found:
C, 65.81; H, 4.72; N, 9.73; S, 5.47.
(4R,5S)- a n d (4S,5R)-2-(N-Meth ylben zyla m in o)-3-n itr o-
5-[(4-n it r op h e n yl)ca r b a m oyl]-4,5-d ip h e n yl-4,5-d ih y-
d r oth iop h en e (10c): crystals from CHCl3; mp 238-240 °C
dec; 1H NMR (acetone-d6) δ 8.23-7.03 (m, 20H), 5.83 (s, 1H),
5.04 (d, J ) 15.9 Hz, 1H), 4.81 (d, J ) 15.9 Hz, 1H), 3.33 (s,
3H); 13C NMR (acetone-d6) δ 171.7, 162.9, 145.8, 144.3, 138.2,
136.9, 134.4, 129.8, 129.7, 129.2, 129.0, 128.8, 128.6, 128.3,
127.8, 125.5, 122.0, 120.4, 70.8, 61.8, 59.8, 45.3. Anal. Calcd
for C31H26N4O5S: C, 65.71; H, 4.62; N, 9.89; S, 5.66. Found:
C, 65.66; H, 4.57; N, 9.78; S, 5.49.
NMR Mon itor in g. A solution of 3c (42 mg, 0.1 mmol) and
4 (15 mg, 0.1 mmol) in CDCl3 (0.5 mL) at 0 °C was recorded
by 1H NMR. Experiments evidenced the direct transformation
of starting materials into 4,5-dihydrothiophenes without de-
tecting the bridged cycloadducts.
R ea ct ion of Mesoion ic Com p ou n d 3a w it h Nit r o-
a lk en e 5. To a solution of 5 (1.16 g, 2.68 mmol) in dry CH2Cl2
(20 mL) was added 3a (1.0 g, 2.7 mmol). After 5 h at rt, the
reaction mixture was stirred with silica gel (1.0 g) for an
additional period of 5 h. After filtering off, the solvent was
evaporated and the residue purified by flash chromatography
(hexane-AcOEt, 1:1) to give compounds 14a and 15a .
(4S,5R)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ga la cto-p en ti-
t ol-1-yl)-2-(N-m et h ylb en zyla m in o)-3-n it r o-5-p h en yl-5-
(p h en ylca r ba m oyl)-4,5-d ih yd r oth iop h en e (14a ): crystals
from Et2O (0.6 g, 29%); mp 184.5-186 °C; [R]D -183.4° (c 0.5,
1
CHCl3); H NMR (CDCl3) δ 7.44-7.08 (m, 16H), 5.93 (d, J )
7.7 Hz, 1H), 5.35 (m, 3H), 4.90 (d, J ) 7.7 Hz, 1H), 4.64 (d, J
) 15.3 Hz, 1H), 4.39 (d, J ) 15.3 Hz, 1H), 4.21 (dd, J ) 4.7,
11.7 Hz, 1H), 3.76 (dd, J ) 7.9, 11.7 Hz, 1H), 2.92 (s, 3H),
2.34 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.24 (s,
3H); 13C NMR (CDCl3) δ 173.2, 170.2, 170.1, 169.9, 169.5,
168.1, 165.2, 140.1, 136.3, 133.7, 129.5, 128.9, 128.2, 127.7,
126.3, 125.2, 120.3, 115.9, 73.8, 70.1, 67.8, 67.4, 65.9, 62.0, 61.9,
42.3, 20.9, 20.8, 20.5, 20.4, 19.3. Anal. Calcd for
C40H43N3O13S: C, 59.62; H, 5.38; N, 5.21; S, 3.98. Found: C,
59.63; H, 5.42; N, 5.21; S, 3.80.
NMR Mon itor in g. A solution of 3b (40 mg, 0.1 mmol) and
4 (15 mg, 0.1 mmol) in CDCl3 (0.5 mL) at 0 °C was monitored
by 1H NMR, thus evidencing the formation of 7b and 8b in
1:3 ratio. On warming at rt 7b converted into 9b, but the
transformation of 8b into 10b could not be detected. 7b: 1H
NMR (CDCl3) δ 6.14 (d, J ) 4.0 Hz, 1H), 4.75 (d, J ) 4.0 Hz,
1H), 4.02 (m, 2H), 3.88 (s, 3H), 2.39 (s, 3H).
Th er m a l Tr a n sfor m a tion of 8b in to 9b. A solution of
cycloadduct 8b (0.5 g, 0.9 mmol) in dry CH2Cl2 (5 mL) was
kept at rt for 48 h. Solvent evaporation gave 9b (0.45 g, 90%),
having spectroscopic properties coincidental with those of an
authentic sample.
(4S,5S)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ga la cto-pen titol-
1-y l)-2-(N -m e t h y lb e n zy la m in o )-3-n it r o -5-p h e n y l-5-
(p h en ylca r ba m oyl)-4,5-d ih yd r oth iop h en e (15a ): crystals
from Et2O (0.6 g, 29%); mp 221-223 °C dec; [R]D -220.2° (c
0.5, CHCl3); 1H NMR (CDCl3) δ 7.80-7.06 (m, 16H), 5.19 (dd,
J ) 7.5, 1.0 Hz, 1H), 5.13 (m, 2H), 5.01 (d, J ) 7.5 Hz, 1H),
4.69 (d, J ) 15.8 Hz, 1H), 4.58 (d, J ) 15.8 Hz, 1H), 4.41 (dd,
J ) 1.0, 10.0 Hz, 1H), 4.03 (dd, J ) 5.0, 11.4 Hz, 1H), 3.70
(dd, J ) 7.2, 11.4 Hz, 1H), 3.04 (s, 3H), 2.26 (s, 3H), 2.01 (s,
3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H); 13C NMR (CDCl3)
δ 170.9, 170.2, 170.1, 169.8, 169.3, 168.1, 163.6, 137.2, 134.2,
131.8, 129.7, 129.0, 128.9, 128.7, 128.4, 128.2, 127.2, 124.5,
119.7, 117.4, 68.8, 67.4, 67.3, 66.6, 61.7, 61.6, 51.5, 43.6, 20.8,
20.6, 20.4. Anal. Calcd for C40H43N3O13S: C, 59.62; H, 5.38;
N, 5.21; S, 3.98. Found: C, 59.56; H, 5.30; N, 5.24; S, 3.83.
NMR Mon itor in g. A solution of 3a (22 mg, 0.06 mmol)
and 5 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) at 0 °C was
Rea ction of 8b w ith Meth yl P r op iola te. To a solution
of 8b (0.05 g, 0.09 mmol) in dry CH2Cl2 (5 mL) was added
methyl propiolate (0.01 mL, 0.11 mmol), and the reaction
mixture was kept at rt for 10 h. The solvent was evaporated
to dryness, and the residue was treated with Et2O to give
1
crystals of 11 (0.015 g, 38%): mp 170-172 °C dec; H NMR
(CDCl3) δ 8.09 (s, 1H), 7.73-6.87 (m, 14H), 3.96 (s, 2H), 3.86
(s, 3H), 3.79 (s, 3H), 2.48 (s, 3H); 13C NMR (CDCl3) δ 165.6,
163.0, 159.2, 157.7, 139.6, 136.1, 131.1, 129.8, 128.8, 128.5,
128.1, 128.0, 127.5, 127.4, 125.9, 114.4, 104.5, 58.9, 55.5, 52.0,
40.0. Anal. Calcd for C28H26N2O4: C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.87; H, 5.71; N, 6.15.
Rea ction of 8b w ith 3c. To a solution of 8b (0.1 g, 0.18
mmol) in dry CH2Cl2 (5 mL) was added mesoionic compound
3c (75 mg, 0.18 mmol), and the reaction mixture was kept at
rt for 10 h. The solvent was evaporated, and compounds 9b,
9c, and 10c were separated by flash chromatography (hexane-
AcOEt, 3:1) and further crystallized from CHCl3-Et2O in each
case.
R ea ct ion of Mesoion ic Com p ou n d 3c w it h â-Nit r o-
styr en e (4). To a solution of 4 (0.27 g, 1.8 mmol) in dry
CH2Cl2 (20 mL) was added 3c (0.75 g, 1.8 mmol). After 4 h at
rt, the solvent was evaporated to afford a mixture of com-
pounds 9c and 10c in 1:2 ratio (1.0 g, 98% overall) which were
separated by preparative TLC (hexane-AcOEt, 1:1).
(4R,5R)- a n d (4S,5S)-2-(N-Meth ylben zyla m in o)-3-n itr o-
5-[(4-n it r op h e n yl)ca r b a m oyl]-4,5-d ip h e n yl-4,5-d ih y-
1
monitored by H NMR. At that temperature the formation of
(1S,4R,5S,6R)- and (1R,4S,5S,6R)-5-(1′,2′,3′,4′,5′-penta-O-
acetyl-D-ga la cto-pentitol-1-yl)-1-(N-methylbenzylamino)-6-
nitro-3-oxo-2,4-diphenyl-7-thia-2-azabicyclo[2.2.1]heptane (12a
and 13a ) in a 1:1.7 ratio was observed. The reaction mixture
was allowed to warm to rt, and thus 12a was converted into
14a while 13a slowly transforms into 15a : 1H NMR (CDCl3)
(12a ) δ 6.44 (d, J ) 3.5 Hz, 1H); (13a ) δ 6.33 (d, J ) 3.3 Hz,
1H).
R ea ct ion of Mesoion ic Com p ou n d 3b w it h Nit r o-
a lk en e 5. To a solution of 5 (0.54 g, 1.24 mmol) in dry CH2Cl2
(10 mL) was added 3b (0.5 g, 1.24 mmol), and the mixture
was kept at rt for 5 h. Then, silica gel (0.5 g) was added, and
the reaction mixture was stirred for 5 h. After filtration, the

3746 J . Org. Chem., Vol. 61, No. 11, 1996
Avalos et al.
solvent was evaporated, and the crude products were purified
by flash chromatography (hexane-AcOEt, 1:1) to give com-
pounds 14b and 15b.
was added 3c (1.0 g, 2.4 mmol). After 4 h at rt, the reaction
mixture was evaporated and the residue was several times
treated with Et2O. Compounds 14c and 15c were separated
by flash chromatography (hexane-AcOEt, 1:1).
(4S,5R)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ga la cto-p en ti-
t ol-1-yl)-5-[(4-m et h oxyp h en yl)ca r b a m oyl]-2-(N-m et h yl-
b e n zyla m in o)-3-n it r o-5-p h e n yl-4,5-d ih yd r ot h iop h e n e
(14b): precipitate from Et2O-hexane (0.30 g, 29%); mp 126-
(4S,5R)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ga la cto-p en ti-
t ol-1-yl)-2-(N-m e t h ylb e n zyla m in o)-3-n it r o-5-[(4-n it r o-
ph en yl)car bam oyl]-5-ph en yl-4,5-dih ydr oth ioph en e (14c):
precipitate from Et2O-hexane (0.2 g, 10%); mp 148-150 °C;
1
128 °C dec; [R]D -162.6° (c 0.38, CHCl3); H NMR (CDCl3) δ
1
7.34-6.77 (m, 15H), 5.87 (d, J ) 7.9 Hz, 1H), 5.31 (m, 3H),
4.82 (d, J ) 7.9 Hz, 1H), 4.60 (d, J ) 15.5 Hz, 1H), 4.34 (d, J
) 15.5 Hz, 1H), 4.16 (dd, J ) 4.6, 11.6 Hz, 1H), 3.74 (dd, J )
7.9, 11.6 Hz, 1H), 3.72 (s, 3H), 2.87 (s, 3H), 2.28 (s, 3H), 2.20
(s, 3H), 2.00 (s, 3H), 1.93 (s, 3H), 1.26 (s, 3H); 13C NMR (CDCl3)
δ 173.2, 170.3, 170.1, 169.9, 169.5, 168.3, 165.0, 157.1, 140.3,
133.8, 129.5, 128.9, 128.2, 127.7, 126.3, 122.1, 116.0, 114.0,
73.7, 70.2, 67.9, 67.6, 66.0, 62.1, 62.0, 55.4, 49.9, 43.2, 20.9,
20.8, 20.6, 19.5. Anal. Calcd for C41H45N3O14S: C, 58.91; H,
5.43; N, 5.03; S, 3.84. Found: C, 58.81; H, 5.53; N, 4.89; S,
3.63.
[R]D -155° (c 0.5, CHCl3); H NMR (CDCl3) δ 8.21-7.18 (m,
15H), 5.87 (dd, J ) 7.7, 1.2 Hz, 1H), 5.36 (m, 2H), 5.17 (dd, J
) 1.2, 9.5 Hz, 1H), 4.89 (d, J ) 7.7 Hz, 1H), 4.64 (d, J ) 15.4
Hz, 1H), 4.41 (d, J ) 15.4 Hz, 1H), 4.20 (dd, J ) 4.6, 11.7 Hz,
1H), 3.73 (dd, J ) 8.1, 11.7 Hz, 1H), 2.95 (s, 3H), 2.34 (s, 3H),
2.21 (s, 3H), 2.06 (s, 3H), 1.98 (s, 3H), 1.37 (s, 3H); 13C NMR
(CDCl3) δ 173.2, 170.1, 169.6, 169.4, 167.6, 165.9, 144.0, 142.1,
139.4, 133.5, 129.6, 129.1, 128.8, 128.2, 127.5, 126.2, 124.7,
119.7, 115.5, 73.4, 70.0, 67.8, 67.6, 65.9, 61.9, 61.8, 49.7, 43.3,
20.8, 20.6, 20.4, 20.3, 19.6. Anal. Calcd for C40H42N4O15S: C,
56.47; H, 4.98; N, 6.58; S, 3.77. Found: C, 56.50; H, 4.93; N,
6.44; S, 3.65.
(4S,5S)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ga la cto-pen titol-
1-yl)-5-[(4-m eth oxyp h en yl)ca r ba m oyl]-2-(N-m eth ylben -
zyla m in o)-3-n itr o-5-p h en yl-4,5-d ih yd r oth iop h en e (15b):
crystals from Et2O (0.30 g, 29%); mp 173-175 °C dec; [R]D
-200.4° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.80-6.76 (m, 15H),
5.19 (dd, J ) 7.5, 1.5 Hz, 1H), 5.12 (m, 2H), 5.01 (d, J ) 7.5
Hz, 1H), 4.69 (d, J ) 15.8 Hz, 1H), 4.58 (d, J ) 15.8 Hz, 1H),
4.41 (dd, J ) 1.5, 10.0 Hz, 1H), 4.03 (dd, J ) 5.1, 11.4 Hz,
1H), 3.70 (dd, J ) 7.2, 11.4 Hz, 1H), 3.76 (s, 3H), 3.04 (s, 3H),
2.26 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.96 (s,
3H); 13C NMR (CDCl3) δ 170.9, 170.2, 170.1, 169.8, 169.3,
168.0, 163.9, 156.5, 134.2, 132.0, 130.3, 129.6, 129.0, 128.8,
128.4, 128.2, 128.1, 121.5, 117.3, 113.8, 68.8, 68.7, 67.5, 67.1,
66.6, 61.7, 61.6, 55.3, 51.5, 43.7, 20.8, 20.6, 20.4. Anal. Calcd
for C41H45N3O14S: C, 58.91; H, 5.43; N, 5.03; S, 3.84. Found:
C, 59.07; H, 5.60; N, 4.78; S, 3.47.
(4S,5S)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ga la cto-pen titol-
1-y l)-2-(N -m e t h y lb e n z y la m in o )-3-n it r o -5-[(4-n it r o -
ph en yl)car bam oyl]-5-ph en yl-4,5-dih ydr oth ioph en e (15c):
recrystallized from AcOEt-Et2O (1.26 g, 62%); mp 140-142
1
°C dec; [R]D -217° (c 0.5, CHCl3); H NMR (CDCl3) δ 8.14-
7.22 (m, 15H), 5.16 (dd, J ) 7.6, 1.2 Hz, 1H), 5.13 (m, 2H),
4.99 (d, J ) 7.6 Hz, 1H), 4.69 (d, J ) 16.0 Hz, 1H), 4.59 (d, J
) 16.0 Hz, 1H), 4.37 (dd, J ) 1.2, 10.0 Hz, 1H), 4.03 (dd, J )
5.2, 11.6 Hz, 1H), 3.69 (dd, J ) 7.7, 11.6 Hz, 1H), 3.06 (s, 3H),
2.26 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.97 (s,
3H); 13C NMR (CDCl3) δ 171.0, 170.2, 170.0, 169.8, 169.2,
168.9, 163.9, 143.4, 134.0, 131.2, 130.0, 129.0, 128.4, 128.2,
127.1, 124.6, 119.2, 117.2, 68.8, 68.5, 67.3, 67.2, 66.3, 61.7, 51.4,
43.6, 20.8, 20.7, 20.6, 20.5, 20.4. Anal. Calcd for
C40H42N4O15S: C, 56.47; H, 4.98; N, 6.58; S, 3.77. Found: C,
56.14; H, 4.89; N, 6.37; S, 3.57.
(1R,4S,5S,6R)-5-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ga la cto-
p en t it ol-1-yl)-2-(4-m et h oxyp h en yl)-1-(N-m et h ylb en zyl-
a m in o)-6-n itr o-3-oxo-4-p h en yl-7-th ia -2-a za bicyclo[2.2.1]-
h ep ta n e (13b). To a solution of 5 (0.32 g, 0.74 mmol) at -10
°C was added 3b (0.30 g, 0.74 mmol). After 5 h at that
temperature, the solvent was evaporated below 25 °C and the
resulting residue was dissolved in Et2O, from which crystals
of the title compound were obtained (0.25 g, 40%): mp 153-
NMR Mon itor in g. A solution of 3c (24 mg, 0.06 mmol)
and 5 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) at 0 °C was
monitored by 1H NMR. Initially, the transient cycloadducts
were detected as broad signals, but they rapidly evolved to
give the 4,5-dihydrothiophenes 14c and 15c.
R ea ct ion of Mesoion ic Com p ou n d 3a w it h Nit r o-
a lk en e 6. To a solution of 6 (1.20 g, 2.70 mmol) in dry CH2Cl2
(20 mL) was added 3a (1.0 g, 2.68 mmol), and the reaction
mixture was kept at rt for 5 h. Then silica gel (1.0 g) was
added, and the stirring was continued for another 5 h. After
filtering the solvent was evaporated and compounds 18a and
19a were separated by flash chromatography (hexane-AcOEt,
3:2).
(4R,5S)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ma n n o-p en titol-
1-y l)-2-(N -m e t h y lb e n zy la m in o )-3-n it r o -5-p h e n y l-5-
(p h en ylca r ba m oyl)-4,5-d ih yd r oth iop h en e (18a ): crystals
from Et2O (0.50 g, 23%); mp 107-109 °C; [R]D +152.2° (c 0.5,
CHCl3); 1H NMR (CDCl3) δ 7.67-7.03 (m, 16H), 5.85 (m, 2H),
5.63 (dd, J ) 2.0, 5.5 Hz, 1H), 5.21 (s, 1H), 5.03 (m, 1H), 4.72
(d, J ) 15.3 Hz, 1H), 4.58 (d, J ) 15.3 Hz, 1H), 4.20 (dd, J )
3.4, 12.2 Hz, 1H), 4.05 (dd, J ) 6.2, 12.2 Hz, 1H), 3.06 (s, 3H),
2.09 (s, 3H), 2.06 (s, 3H), 1.97 (s, 3H), 1.86 (s, 3H), 1.83 (s,
3H); 13C NMR (CDCl3) δ 170.9, 170.3, 170.2, 169.6, 169.5,
169.4, 165.8, 140.3, 136.6, 134.0, 129.3, 128.9, 128.8, 128.7,
128.4, 127.6, 125.9, 124.9, 120.1, 114.2, 73.2, 70.9, 69.6, 69.0,
62.1, 60.9, 50.0, 43.0, 21.0, 20.7, 20.4, 20.3. Anal. Calcd for
C40H43N3O13S: C, 59.62; H, 5.38; H, 5.21; S, 3.98. Found: C,
59.55; H, 5.48; N, 5.00; S, 3.73.
(4R,5R)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ma n n o-pen titol-
1-y l)-2-(N -m e t h y lb e n zy la m in o )-3-n it r o -5-p h e n y l-5-
(p h en ylca r ba m oyl)-4,5-d ih yd r oth iop h en e (19a ): crystals
from Et2O (0.61 g, 29%); mp 185-187 °C dec; [R]D +132.8° (c
0.5, CHCl3); 1H NMR (CDCl3) δ 7.90-7.03 (m, 16H), 5.47 (dd,
J ) 7.0, 2.0 Hz, 1H), 5.38 (dd, J ) 2.0. 8.0 Hz, 1), 5.30 (d, J )
2.5 Hz, 1H), 5.07 (dd, J ) 2.5, 7.0 Hz, 1H), 4.93 (m, 1H), 4.79
(d, J ) 15.9 Hz, 1H), 4.68 (d, J ) 15.9 Hz, 1H), 4.18 (dd, J )
3.1, 12.8 Hz, 1H), 3.98 (dd, J ) 5.0, 12.8 Hz, 1H), 3.18 (s, 3H),
2.09 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.90 (s,
3H); 13C NMR (CDCl3) δ 170.5, 170.0, 169.5, 169.3, 168.9,
168.3, 163.6, 137.0, 134.3, 132.7, 129.2, 129.0, 128.9, 128.7,
1
155 °C (Et2O-hexane); [R]D +49.4° (c 0.35, CHCl3); H NMR
(CDCl3) δ 7.56-6.80 (m, 14H), 6.29 (d, J ) 3.4 Hz, 1H), 5.24
(d, J ) 2.1 Hz, 1H), 5.08 (dd, J ) 2.1, 9.5 Hz, 1H), 5.00 (m,
2H), 4.15 (dd, J ) 4.8, 11.8 Hz, 1H), 3.88 (d, J ) 12.7 Hz, 1H),
3.66 (dd, J ) 7.2, 11.8 Hz, 1H), 3.47 (d, J ) 12.7 Hz, 1H), 3.74
(m, 4H), 3.49 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 1.98 (s, 3H),
1.99 (s, 3H), 1.73 (s, 3H); 13C NMR (CDCl3) δ 170.5, 170.4,
169.7, 169.5, 168.8, 158.0, 135.7, 131.0, 129.5, 129.2, 129.0,
128.6, 128.4, 128.3, 127.7, 127.6, 127.3, 127.1, 105.3, 88.6, 71.1,
67.9, 67.5, 67.2, 66.5, 62.1, 59.5, 55.3, 51.2, 37.3, 21.0, 20.7,
20.5, 20.3, 20.2. Anal. Calcd for C41H45N3O14S: C, 58.91; H,
5.43; N, 5.03; S, 3.84. Found: C, 58.57; H, 5.24; N, 4.78; S,
3.62.
NMR Mon itor in g. A solution of 3b (23 mg, 0.06 mol) and
1
5 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) was monitored by H
NMR at different temperatures. At 0 °C the formation of
cycloadducts 12b and 13b in 1:1.7 ratio was observed. When
the reaction was allowed to warm to rt, compound 12b
converted into 14b whereas 13b slowly converts into 15b.
12b: 1H NMR (CDCl3) δ 6.40 (d, J ) 3.6 Hz, 1H).
Tr a n sfor m a tion of 13b in to 15b Ca ta lyzed by Silica
Gel. A solution of 13b (40 mg, 0.05 mmol) in dry CH2Cl2 (5
mL) was stirred with silica gel (40 mg) for 24 h. After this
period, silica gel was filtered off and washed several times with
MeOH. The resulting solution was evaporated to give pure
15b (40 mg, 100%).
Th er m a l Tr a n sfor m a tion of 13b in to 14b a n d 15b. A
solution of 13b (40 mg, 0.05 mmol) in CDCl3 (0.5 mL) was kept
at rt and recorded periodically by 1H NMR. After 30 days,
the conversion was complete and compounds 14b and 15b were
observed in 1:1.4 ratio.
Rea ction of Mesoion ic Com p ou n d 3c w ith Nitr oa lk en e
5. To a solution of 5 (1.04 g, 2.4 mmol) in dry CH2Cl2 (20 mL)

Cycloaddition Chemistry of 1,3-Thiazolium-4-olate Systems
J . Org. Chem., Vol. 61, No. 11, 1996 3747
128.3, 127.9, 126.9, 124.7, 119.9, 116.4, 70.3, 69.5, 68.7, 67.7,
61.7, 61.5, 52.8, 44.2, 20.8, 20.6, 20.5, 20.4. Anal. Calcd for
C40H43N3O13S: C, 59.62; H, 5.38; N, 5.21; S, 3.98. Found: C,
59.68; H, 5.23; N, 5.21; S, 3.84.
dec; [R]D +179.8° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 8.23-7.24
(m, 15H), 5.83 (m, 2H), 5.61 (dd, J ) 3.2, 5.1 Hz, 1H), 5.25 (d,
J ) 1.3 Hz, 1H), 5.04 (m, 1H), 4.75 (d, J ) 15.4 Hz, 1H), 4.61
(d, J ) 15.4 Hz, 1H), 4.24 (dd, J ) 3.6, 12.3 Hz, 1H), 4.09 (dd,
J ) 6.1, 12.3 Hz, 1H), 3.13 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H),
2.07 (s, 3H), 1.89 (s, 3H); 13C NMR (CDCl3) δ 171.1, 170.5,
170.3, 169.6, 169.5, 169.3, 166.5, 143.9, 142.6, 139.6, 133.8,
129.6, 129.0, 128.5, 127.5, 125.8, 124.7, 119.7, 113.9, 73.4, 71.3,
71.0, 69.7, 69.0, 62.2, 60.0, 50.0, 43.3, 21.0, 20.8, 20.6. 20.4,
20.3. Anal. Calcd for C40H42N4O15S: C, 56.47; H, 4.98; N, 6.58;
S, 3.77. Found: C, 55.87; H, 5.09; N, 6.24; S, 3.21.
(4R,5R)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ma n n o-pen titol-
1-y l)-2-(N -m e t h y lb e n z y la m in o )-3-n it r o -5-[(4-n it r o -
ph en yl)car bam oyl]-5-ph en yl-4,5-dih ydr oth ioph en e (19c):
crystals from Et2O (0.8 g, 40%); mp 140-142 °C dec; [R]D
+155.6° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 8.13-7.25 (m, 15H),
5.42 (m, 2H), 5.26 (d, J ) 2.6 Hz, 1H), 5.04 (dd, J ) 2.6, 6.2
Hz, 1H), 4.95 (m, 1H), 4.80 (d, J ) 16.1 Hz, 1H), 4.70 (d, J )
16.1 Hz, 1H), 4.17 (dd, J ) 2.8, 12.4 Hz, 1H), 4.01 (dd, J )
5.4, 12.4 Hz, 1H), 3.23 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01
(s, 3H), 1.98 (s, 3H), 1.93 (s, 3H); 13C NMR (CDCl3) δ 170.4,
170.0, 169.5, 169.3, 169.1, 168.9, 163.9, 143.6, 143.1, 134.2,
132.0, 129.5, 129.2, 129.0, 128.3, 127.8, 127.0, 124.6, 119.4,
116.2, 70.3, 69.4, 68.8, 67.8, 61.8, 61.5, 52.7, 44.4, 20.8, 20.5.
Anal. Calcd for C40H42N4O15S: C, 56.47; H, 4.98; N, 6.58; S,
3.77. Found: C, 56.40; H, 5.09; N, 6.41; S, 3.61.
NMR Mon itor in g. A solution of 3a (21 mg, 0.06 mmol)
and 6 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) at 0 °C was
recorded by 1H NMR. At that temperature the formation of
(1R,4S,5R,6S)- and (1S,4R,5R,6S)-5-(1′,2′,3′,4′,5′-penta-O-
acetyl-D-ma nno-pentitol-1-yl)-1-(N-methylbenzylamino)-6-
nitro-3-oxo-2,4-diphenyl-7-thia-2-azabicyclo[2.2.1]heptane (16a
and 17a ) in 1:1.2 ratio was observed. When the reaction
mixture was allowed to warm to rt, the cycloadduct 16a
converted into 18a while 17a slowly transforms into 19a : 1H
NMR (CDCl3) (16a ) δ 6.11 (d, J ) 3.8 Hz, 1H); (17a ) δ 6.27 (d,
J ) 3.3 Hz, 1H).
R ea ct ion of Mesoion ic Com p ou n d 3b w it h Nit r o-
a lk en e 6. To a solution of 6 (1.08 g, 2.48 mmol) in dry CH2Cl2
(20 mL) was added 3b (1.0 g, 2.48 mol), and the reaction
mixture was kept at rt for 5 h. Then silica gel (1.0 g) was
added, and the stirring was continued for other 5 h. After
filtering, the solvent was evaporated and compounds 18b and
19b separated by flash chromatography (hexane-AcOEt,
1:1).
(4R,5S)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ma n n o-p en titol-
1-yl)-5-[(4-m eth oxyp h en yl)ca r ba m oyl]-2-(N-m eth ylben -
zyla m in o)-3-n itr o-5-p h en yl-4,5-d ih yd r oth iop h en e (18b):
crystals from Et2O (0.41 g, 20%); mp 105-107 °C; [R]D +152.4°
NMR Mon itor in g. A solution of 3c (24 mg, 0.06 mmol)
and 6 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) at 0 °C was
1
(c 0.5, CHCl3); H NMR (CDCl3) δ 7.59-6.79 (m, 15H), 5.86
1
(m, 2H), 5.67 (dd, J ) 4.7, 2.0 Hz, 1H), 5.18 (s, 1H), 5.07 (m,
1H), 4.72 (d, J ) 15.5 Hz, 1H), 4.57 (d, J ) 15.5 Hz, 1H), 4.22
(dd, J ) 3.6, 12.3 Hz, 1H), 4.10 (dd, J ) 6.3, 12.3 Hz, 1H),
3.74 (s, 3H), 3.07 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.02 (s,
3H), 1.90 (s, 3H), 1.80 (s, 3H); 13C NMR (CDCl3) δ 171.0, 170.3,
169.6, 169.4, 165.7, 156.8, 140.5, 134.0, 129.6, 129.4, 129.0,
128.7, 128.4, 127.6, 125.9, 122.1, 114.3, 113.9, 73.1, 71.0, 69.7,
69.0, 62.2, 61.0, 55.3, 50.2, 43.0, 21.0, 20.8, 20.6, 20.5, 20.3.
Anal. Calcd for C41H45N3O14S: C, 58.91; H, 5.43; N, 5.03; S,
3.84. Found: C, 59.03; H, 5.60; N, 4.94; S, 3.62.
monitored by H NMR. The intermediate cycloadducts were
detected as broad signals that rapidly converted into 4,5-
dihydrothiophenes 18c and 19c.
R ea ct ion of Mesoion ic Com p ou n d 20 w it h â-Nit r o-
styr en e (4). (4R,5S)- a n d (4S,5R)-3-Nitr o-2,4,5-tr ip h en yl-
5-(p h en ylca r ba m oyl)-4,5-d ih yd r oth iop h en es (21). To a
solution of 4 (0.22 g, 1.5 mmol) in dry toluene (25 mL) was
added 20 (0.65 g, 2 mmol), and the resulting suspension was
refluxed with stirring for 6 days. The solvent was evaporated
until a final volume of 10 mL, crystallizing the title compound
as yellow needles (0.3 g, 43%): mp 244-246 °C dec; 1H NMR
(CDCl3) δ 7.71 (s, 1H), 7.58-7.07 (m, 20H), 6.06 (s, 1H); 13C
NMR (CDCl3) δ 169.6, 150.8, 140.1, 137.4, 134.8, 133.4, 130.7,
130.4, 129.1, 128.6, 128.5, 128.3, 128.0, 127.8, 125.0, 120.0,
71.4, 59.1. Anal. Calcd for C29H22N2O3S: C, 72.78; H, 4.63;
N, 5.85. Found: C, 72.45; H, 4.89; N, 5.63.
(4R,5R)-4-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ma n n o-pen titol-
1-yl)-5-[(4-m eth oxyp h en yl)ca r ba m oyl]-2-(N-m eth ylben -
zyla m in o)-3-n itr o-5-p h en yl-4,5-d ih yd r oth iop h en e (19b):
crystals from Et2O (0.84 g, 41%); mp 191-193 °C; [R]D +127.8°
1
(c 0.5, CHCl3); H NMR (CDCl3) δ 7.93-6.74 (m, 15H), 5.47
(dd, J ) 6.9, 1.9 Hz, 1H), 5.37 (dd, J ) 1.9, 7.8 Hz, 1H), 5.29
(d, J ) 2.4 Hz, 1H), 5.07 (dd, J ) 2.4, 6.9 Hz, 1H), 4.94 (m,
1H), 4.77 (d, J ) 16.0 Hz, 1H), 4.68 (d, J ) 16.0 Hz, 1H), 4.17
(dd, J ) 2.8, 12.6 Hz, 1H), 3.99 (dd, J ) 5.3, 12.6 Hz, 1H),
3.70 (s, 3H), 3.18 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.96 (s,
3H), 1.90 (s, 3H), 1.85 (s, 3H); 13C NMR (CDCl3) δ 170.3, 169.9,
169.4, 169.2, 168.8, 168.3, 163.8, 156.6, 134.3, 132.9, 130.1,
129.0, 128.9, 128.8, 128.2, 127.9, 126.9, 121.8, 113.7, 116.4,
69.4, 70.3, 68.7, 68.7, 67.7, 61.6, 61.5, 52.8, 55.2, 44.2, 20.7,
20.7, 20.5, 20.4. Anal. Calcd for C41H45N3O14S: C, 58.91; H,
5.43; N, 5.03; S, 3.84. Found: C, 58.73; H, 5.40; N, 4.96; S,
3.68.
Rea ction of Mesoion ic Com p ou n d 20 w ith Nitr oa lk en e
(5). (1R,4R,5S,6R)-5-(1′,2′,3′,4′,5′-P en ta-O-acetyl-D-ga la cto-
p e n t it o l-1-y l)-6-n it r o -3-o x o -1,2,4-t r ip h e n y l-7-t h ia -2-
a za bicyclo[2.2.1]h ep ta n e (22). To a solution of 5 (0.65 g,
1.5 mmol) in dry toluene (25 mL) was added 20 (0.65 g, 2
mmol), and the resulting suspension was refluxed with stirring
for 48 h. The solvent was evaporated and the residue
chromatographed (hexane-AcOEt, 4:1) to give an oil that was
precipitated from Et2O-hexane (0.5 g, 44%): mp 90-92 °C;
1
[R]D +67.2° (c 0.5, CHCl3); H NMR (acetone-d6) δ 7.94-7.06
(m, 15H), 6.68 (d, J ) 3.8 Hz, 1H), 5.47 (dd, J ) 2.8, 5.9 Hz,
1H), 5.26 (m, 2H), 5.10 (dd, J ) 5.9, 8.6 Hz, 1H), 4.15 (dd, J )
4.6, 11.8 Hz, 1H), 3.92 (t, J ) 2.8 Hz, 1H), 3.83 (dd, J ) 6.9,
11.8 Hz, 1H), 2.07 (s, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.92 (s,
3H), 1.86 (s, 3H);
NMR Mon itor in g. A solution of 3b (23 mg, 0.06 mmol)
and 6 (25 mg, 0.06 mmol) in CDCl3 (0.5 mL) at 0 °C was
1
monitored by H NMR. At that temperature the formation of
(1R,4S,5R,6S)- and (1S,4R,5R,6S)-5-(1′,2′,3′,4′,5′-penta-O-
acetyl-D-manno-pentitol-1-yl)-2-(4-methoxyphenyl)-1-(N-meth-
ylbenzylamino)-6-nitro-3-oxo-4-phenyl-7-thia-2-azabicyclo[2.2.1]-
heptane (16b and 17b) in 1:1.3 ratio was observed. When the
reaction mixture was allowed to warm to rt, the cycloadduct
16b converted into 18b while 17b slowly transforms into
19b: 1H NMR (CDCl3) (16b) δ 6.05 (d, J ) 3.8 Hz, 1H); (17b)
δ 6.25 (d, J ) 3.3 Hz, 1H).
Rea ction of Mesoion ic Com p ou n d 3c w ith Nitr oa lk en e
6. To a solution of 6 (1.04 g, 2.4 mmol) in dry CH2Cl2 (20 mL)
was added 3c (1.0 g, 2.4 mmol) and the reaction mixture was
kept at rt for 5 h. The solvent was evaporated, and compounds
18c and 19c were separated by flash chromatography (hex-
ane-AcOEt, 11:2).
13C NMR (CDCl3) δ 172.0, 170.3, 170.2, 169.9,
169.4, 169.3, 135.0, 131.1, 130.2, 129.4, 129.2, 129.1, 128.9,
128.7, 128.5, 128.4, 128.2, 91.4, 83.1, 69.9, 68.2, 67.9, 67.1, 64.8,
61.8, 60.2, 20.6, 20.5, 20.3, 20.2. Anal. Calcd for
C38
H38N2O13S: C, 59.84; H, 5.02; N, 3.67; S, 4.20. Found: C,
60.20; H, 4.96; N, 3.55; S, 3.82.
Rea ction of Mesoion ic Com p ou n d 20 w ith Nitr oa lk en e
(6). (1R,4R,5S,6R)-5-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-m a n n o-
p e n t it o l-1-y l)-6-n it r o -3-o x o -1,2,4-t r ip h e n y l-7-t h ia -2-
a za bicyclo[2.2.1]h ep ta n e (23). To a solution of 6 (0.65 g,
1.5 mmol) in dry toluene (25 mL) was added 20 (0.65 g, 2
mmol), and the resulting suspension was refluxed with stirring
for 24 h. The solvent was evaporated and the residue
chromatographed (hexane-AcOEt, 4:1) to give an oil that
crystallized from Et2O (0.68 g, 60%): mp 184-185 °C; [R]D
-20° (c 0.5, CHCl3); 1H NMR (acetone-d6) δ 8.07-7.13 (m,
15H), 6.58 (d, J ) 3.8 Hz, 1H), 5.43 (t, J ) 4.0 Hz, 1H), 5.39
(dd, J ) 1.5, 4.0 Hz, 1), 5.12 (dd, J ) 4.1, 6.9 Hz, 1H), 4.80 (m,
(4R,5S)-4-(1′,2′,3′,4′,5′-P en ta -O-a cetyl-D-ma n n o-p en titol-
1-y l)-2-(N -m e t h y lb e n z y la m in o )-3-n it r o -5-[(4-n it r o -
ph en yl)car bam oyl]-5-ph en yl-4,5-dih ydr oth ioph en e (18c):
precipitated from Et2O-hexane (0.3 g, 14%); mp 115-117 °C

3748 J . Org. Chem., Vol. 61, No. 11, 1996
Avalos et al.
1H), 4.23 (dd, J ) 3.8, 1.5 Hz, 1H), 4.13 (dd, J ) 3.2, 12.3 Hz,
1H), 3.99 (dd, J ) 5.9, 12.3 Hz, 1H), 2.14 (s, 3H), 2.01 (s, 3H),
1.97 (s, 3H), 1.95 (s, 3H), 1.9 (s, 3H); 13C NMR (CDCl3) δ 172.0,
170.4, 170.0, 169.7, 169.4, 169.3, 135.2, 131.1, 130.3, 129.3,
129.0, 128.6, 128.3, 128.2, 91.7, 84.2, 70.9, 68.8, 68.4, 67.9, 64.7,
61.2, 57.0, 20.7, 20.6, 20.5. Anal. Calcd for C38H38N2O13S: C,
59.84; H, 5.02; N, 3.67; S, 4.20. Found: C, 59.86; H, 4.98; N,
3.57; S, 4.15.
work was also supported by the J unta of Extremadura-
Fondo Social Europeo under award no. EAI94-32. We
also thank the reviewers for their help and valuable
comments.
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra of
compounds 3a , 10a , 10c, 14b, 14c, 18c, and 21 and ORTEP
drawings and X-ray experimental data for 10a and 23 (29
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. We wish to thank the Spanish
Direccio´n de Investigacio´n, Cient´ıfica y Te´cnica for
support through a Grant (PB92-0525-C02-01). This
J O952275G