Thionation of mesoionics with isothiocyanates: Evidence supporting a four-step domino process and ruling out a [2 + 2] mechanism

Article abstract of DOI:10.1021/jo900028c

(Chemical Equation Presented) Mesoionic heterocycles derived from 1,3-thiazolium-4-olates (thioisomuenchnones) undergo thionation with aryl isothiocyanates to afford the corresponding 4-thiolate derivatives. Here, we document this transformation in detail

Full text of DOI:10.1021/jo900028c

Thionation of Mesoionics with Isothiocyanates: Evidence Supporting
a Four-Step Domino Process and Ruling Out a [2 + 2] Mechanism
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†
†
†
†
´
David Cantillo,* Mart´ın Avalos, Reyes Babiano, Pedro Cintas, Jose´ L. Jime´nez,
Mark E. Light,‡ and Juan C. Palacios†
Departamento de Qu´ımica Orga´nica e Inorga´nica, QUOREX Research Group, Facultad de Ciencias,
UniVersidad de Extremadura, E-06071 Badajoz, Spain, and Department of Chemistry, UniVersity of
Southampton, Highfield, Southampton SO17 1BJ, U.K.
dcannie@unex.es
ReceiVed January 9, 2009
Mesoionic heterocycles derived from 1,3-thiazolium-4-olates (thioisomu¨nchnones) undergo thionation
with aryl isothiocyanates to afford the corresponding 4-thiolate derivatives. Here, we document this
transformation in detail, giving a crystallographic characterization of the solid-state structures. From the
mechanistic viewpoint, the formal thionation process could be consistent with a [2 + 2] reaction of the
exocyclic C-O bond of the thioisomu¨nchnone with the CdS double bond of the isothiocyanate moiety,
which would be competing with a (3 + 2) process as usual in mesoionic rings. Theoretical computations
at the [B3LYP/6-31G(d):PM3] level, in which only bond-forming and bond-breaking reactions and
neighboring atoms are treated at the DFT level, do reproduce the experimental results and rule out the
expected pathway. Calculations instead suggest the existence of a four-step domino pathway through
several polar intermediates that agrees with the electronic nature of the substituents involved. The
mechanistic hypothesis has further been corroborated by an experiment with isotopically 13C-labeled
PhNCS that unambiguously shows the way in which the exchange reaction occurs.
Introduction
Mesoionic heterocycles decorated with an exocyclic sulfur
atom (i.e., thiolates) have recently gained attention due to their
greater stability and potential behavior as photonic materials
with NLO properties.3 Chasing this structural goal, we have
recently reported the transformation of a chiral imidazo[2,1-
b]thiazolium-3-olate (1) into imidazo[2,1-b]thiazolium-3-thiolate
(2) and 4-thioxoimidazo[1,2-a]pyrimidinium-6-olate (3) systems
by reaction with aryl isothiocyanates (Ar2NCS).4 In these
processes, variable amounts of 4-oxoimidazo[1,2-a]pyrimi-
dinium-6-olates (4) were also isolated.
The possibility of rationalizing chemical reactions, which are
formally cycloadditions, as nonconcerted processes, represents
a challenging domain of theoretical chemistry. A suitable
scenario in this pursuit is provided by mesoionic heterocycles,
which contain a masked allyl-type 1,3-dipole and are able to
react with a variety of dipolarophiles giving rise to synthetically
useful functionalized heterocycles.1 Mesoionics do usually react
via concerted asynchronous pathways, although in some cases,
both theory and experiment point to a stepwise transformation.
Among mesoionic rings, 1,3-thiazolium-4-olates (colloquially
referred to as thioisomu¨nchnones) have proven to be versatile
synthons leading to a variety of heterocycles hitherto unknown
in 1,3-dipolar cycloadditions.2
The kinetic and thermodynamic stability of 2, which can be
stored for long periods without apparent decomposition and does
(3) (a) Bosco, C. A. C.; Maciel, G. S.; Rakov, N.; de Arau´jo, C. B.; Acioli,
L. H.; Simas, A. M.; Athayde-Filho, P. F.; Miller, J. Chem. Phys. Lett. 2007,
449, 101–106. (b) Pilla, V.; de Arau´jo, C. B.; Lira, B. F.; Simas, A. M.; Miller,
J.; Athayde-Filho, P. F. Opt. Commun. 2006, 264, 225–228. (c) Menezes, L. de
S.; de Arau´jo, C. B.; Alencar, M. A. R. C.; Athayde-Filho, P. F.; Miller, J.;
Simas, A. M. Chem. Phys. Lett. 2001, 347, 163–66. (d) Rakov, N.; de Arau´jo,
C. B.; da Rocha, G. B.; Simas, A. M.; Athayde-Filho, P. F.; Miller, J. Chem.
Phys. Lett. 2000, 332, 13–18. (e) Bezerra, A. G., Jr.; Gomes, A. S. L.; Athayde-
Filho, P. F.; da Rocha, G. B.; Miller, J.; Simas, A. M. Chem. Phys. Lett. 1999,
309, 421–426.
† Universidad de Extremadura.
‡ University of Southampton.
(1) Gribble, G. W. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry toward Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley: New York, 2003; pp 681-753.
´
´
(2) Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C. Acc.
(4) Cantillo, D.; Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Light,
Chem. Res. 2005, 38, 460–468.
M. E.; Palacios, J. C. Org. Lett. 2008, 10, 1079–1082.
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10.1021/jo900028c CCC: $40.75 2009 American Chemical Society
Published on Web 04/17/2009

Thionation of Mesoionics with Isothiocyanates
CHART 1
CHART 2
FIGURE 1. Molecular structures of 8, 9b, and 10a as emerged from
X-ray diffraction analyses.
1H NMR spectra of compounds 7-10 are extremely simple,
although they show striking differences that facilitate their
interpretation. Thus, the signals of the ethylene fragments appear
as two well-defined triplets in the spectra of 9a-c, whereas
they addopt the shape of a pair of triple doublets for 7 and
10a-c and resonate as a complex multiplet in the case of 8.
Moreover, distinction between structures 7, 8 and 9, 10 can be
easily obtained by integration of their aromatic proton signals.
13C NMR spectra of 7-10 also exhibit diagnostic differences.
Thiocarbonylic carbons (C-2) of 9a-c resonate at ∼178 ppm,
whereas the corresponding carbonylic carbons of 10a-c appear
at ∼160 ppm, and in both cases, the carbons (C-3) more affected
by the negative charge delocalization are strongly shielded (δ
∼114 and ∼88 ppm for 9a-c and 10a-c, respectively). By
invoking the same argument, the signals of the C-2 carbon atoms
in thioisomu¨nchnones 7 and 8 are also shifted upfield (81.6 and
111.6 ppm, respectively).
At first glance, the transformation of thioisomu¨nchnones 1
and 7 into their thio derivatives 2 and 8, which has no
antecedents in the literature, could be interpreted as an O/S
exchange resulting from a stepwise [2 + 2] cycloaddition
reaction of the C-O- bond of 1 and 7 with the thiocarbonyl
group of the aryl isothiocyanate, in an analogous fashion to the
dimerization of some isothiocyanates.8 This [2 + 2] cycload-
dition could compete with the concerted (3 + 2) cycloadditions
of the thiocarbonyl ylide, masked in 1 and 7, with the CdN
double bonds of the aryl isothiocyanate and the aryl isocyanate
generated during the formation of 2 and 8. In such processes,
betaines 3, 4, 9, and 10 could be formed by sulfur extrusion
from the nonisolated initial cycloadducts (Scheme 1).
not react with aryl iso(thio)cyanates under the same conditions
described for 1, equally explains why the alternative 4-oxoimi-
dazo[1,2-a]pyrimidinium-6-thiolate (5) or 4-thioxoimidazo[1,2-
a]pyrimidinium-6-thiolate (6) systems have never been detected
(Chart 1).
The present paper documents in detail this conceptually
simple oxygen-sulfur exchange, giving further structural
insights into the nature of the polycyclic system attained and
providing a rationale consistent with a stepwise mechanism. That
the heterocumulenic isothiocyanate reacts through a [2 + 2]
pathway as the logical surrogate has also been disproved.
Results and Discussion
Syntheses and Structure. The reaction of 1 with aryl
isothiocyanates exhibits a general pattern. Thus, reactions of
the imidazo[2,1-b]thiazolium-3-olate 75,6 with phenyl-, 4-meth-
oxyphenyl-, and 4-nitrophenyl isothiocyanate afford the imi-
dazo[2,1-b]thiazolium-3-thiolate 8 with variable amounts of the
corresponding 4-thioxoimidazo[1,2-a]pyrimidinium-6-olate
(9a-c) and 4-oxoimidazo[1,2-a]pyrimidinium-6-olate (10a-c)
systems (Chart 2).
Compounds 10a-c were isolated in low yields, although they
could also be synthesized by direct reaction of 7 with phenyl-,
4-methoxyphenyl-, and 4-nitrophenyl isocyanate, respectively,
in CH2Cl2 at room temperature.
Gratifyingly, suitable crystals for X-ray diffraction could be
obtained in the case of compounds 8, 9b, and 10a, thus solving
their structures unequivocally (Figure 1). Crystallographic data
for compounds 8, 9b, and 10a reveal that the formation of the
crystalline lattice is governed by aryl ring interactions, which
adopt favorable edge-to-face or offset stacked arrangements. The
stacking shape depends on dipole-dipole interactions, a struc-
tural motif that can be easily visualized7 (see Supporting
Information).
In order to prove this hypothesis and since theoretical
modeling of the whole polycyclic chiral system would require
an enormous computational cost at an ab initio level, we have
carried out a computational study on the reactivity of 1 (Ar1 )
Ph) with phenyl isothiocyanate using the ONIOM[B3LYP/
6-31G(d):PM3]9,10 method. Taking into account the chiral nature
of 1, we have considered in each case two reaction channels to
simulate the approaches of phenyl isothiocyanate to both faces
of the mesoionic ring of 1. Figure 2 depicts these approaches
(endo and exo) for the optimized structures of both reagents, in
which balls and sticks represent the partial system treated at
the B3LYP/6-31G(d) level while the wire-shaped structure
´
(5) Areces, P.; Avalos, M.; Babiano, R.; Gonza´lez, L.; Jime´nez, J. L.; Me´ndez,
(8) (a) Adams, R. D.; Huang, M. Eur. J. Org. Chem. 1998, 1025–1028. (b)
Dickore, K.; Kuhle, E. Angew. Chem., Int. Ed. Engl. 1965, 4, 430.
(9) Maseras, F.; Morokuma, K. J. Comput. Chem. 1995, 16, 1170–1179.
(10) Froese, R. D. J.; Morokuma, K. In The Encyclopedia of Computational
Chemistry; Schleyer, P. v. R., Allinger, N. L., Clark, T., Gasteiger, J., Kollman,
P. A., Schaefer, H. F., III, Schreiner, P. R., Eds.; John Wiley: Chichester, UK,
1998; pp 1245-1257.
M. M.; Palacios, J. C. Tetrahedron Lett. 1993, 34, 2999–3002.
(6) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jime´nez, J. L.;
Light, M. E.; Lo´pez, I.; Palacios, J. C.; Silvero, G. Chem.sEur. J. 2001, 7,
3033–3042.
(7) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc.,
Perkin Trans. 2 2001, 651–669.
´
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Cantillo et al.
SCHEME 1
FIGURE 2. Approaches (endo and exo) of phenyl isothiocyanate to
thioisomu¨nchnone 1 (Ar1 ) Ph).
SCHEME 2
FIGURE 3. Energy profile for endo and exo [2 + 2] cycloadditions
of 1 with PhNCS.
conclude with the release of phenyl isocyanate and formation
of the imidazo[2,1-b]thiazolium-4-thiolate 2 (Scheme 2 and
Figure 3).
Although we have not yet been able to demonstrate the
existence of an equilibrium between thioisomu¨nchnone 1 and
its valence tautomer 13, their relative electronic energies (∆E
) 5.1 kcal/mol) and the low energy of the transition structure
corresponding to their mutual conversion (∆E ) 8.1 kcal/mol)
suggest that the ketene intermediate 13 could also be involved
in the transformation of 1 into 2, which would likewise occur
through two different approaches of the reactants. The free
rotation of sulfur single bonds in compound 13 together with
the coplanar disposition of phenyl isothiocyanate to the ketene
during its approach to the carbon-oxygen double bond of the
latter impedes use of the terms endo/exo without ambiguity. In
this particular situation, the stereochemical outcome has been
defined in terms of prostereoisomerism descriptors relative to
the E/Z configuration of the carbon-carbon double bond of the
initial cycloadduct (Scheme 3).
Thus, for both approaches (pro-E and pro-Z), we have located
the transition structures (TS13f14 and TS13f15) that lead to the
intermediate cycloadducts (14 and 15) and those coming from
them (TS14f16 and TS15f16) during their respective transforma-
tions into the valence tautomer (16) of 2.
Data collected in Figure 4 show a similar energetics for both
[2 + 2] cycloadditions (pro-E and pro-Z). As a result, the two
approaches would take place with comparable rates had the
ketenic valence tautomers been actually involved in the O/S
exchange. However, the energy barriers of these processes are
corresponds to the molecular fragment assessed at a semiem-
pirical level (PM3).
endo and exo [2 + 2] Cycloadditions. An analysis of the
endo and exo [2 + 2] cycloadditions of the CdS double bond
of phenyl isothiocyanate with the C-O- pseudodouble bond
of 1 led to the location of the first transition structures (TS1f11
and TS1f12) corresponding to the nucleophilic attack of the
oxygen atom to the thiocarbonylic carbon. In both cases, these
transition structures are stabilized by interactions of the sulfur
atom with the hydrogens linked to the C-3′ (endo approach)
and C-2′ (exo approach) carbon atoms of the sugar framework
(S-H3′: 1.864 Å for TS1f11 and S-H2′: 1.811 Å for TS1f12).
Transition structures (TS1f11 and TS1f12) evolved into two
zwitterionic intermediates (11 and 12), which in the rate-
determining steps of both processes led to two new transition
structures (TS11f2 and TS12f2) corresponding to two internal
concerted nucleophilic substitutions involving formation of C-S
bonds and rupture of C-O bonds. These transformations
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Thionation of Mesoionics with Isothiocyanates
SCHEME 3
SCHEME 4
∼5 kcal/mol higher than the energy barrier corresponding to
the slowest step of the endo [2 + 2] cycloaddition of the same
mesoionic system (Figure 3). This fact, along with the greater
stability of the mesoionic tautomer, suggests that the transfor-
mation of imidazo[2,1-b]thiazolium-3-olate systems into the
corresponding imidazo[2,1-b]thiazolium-3-thiolates through [2
+ 2] cycloaddition reactions would most likely involve the
participation of the mesoionic tautomer.
endo and exo (3 + 2) Cycloadditions. Again, two reaction
channels regarding the orientation of the dipolarophile with
respect to the sugar framework (endo and exo approaches)
should be established to define the 1,3-dipolar cycloaddition of
1 with phenyl isothiocyanate (Figure 2). Assuming that these
cycloadditions follow a concerted mechanism, the first protocol
was to locate the transition structures from the optimized
geometries of cycloadducts 19a and 20a. However, we could
not find one but two transition structures for either approach
(TS1f17a, TS17af19a and TS1f18a, TS18af20a). The transition
structures TS1f17a and TS1f18a involve carbon-carbon bond
formation, whereas structures TS17af19a and TS18af20a are
concerned with the subsequent carbon-nitrogen bond-forming
reactions. In addition, the corresponding zwitterionic intermedi-
ates (17a and 18a) were optimized.
A stepwise sulfur extrusion from both 19a and 20a completes
the betaine formation. Probably, the first step involves the C7-S
bond breaking, a pathway favored by delocalization of a positive
charge into the three neighboring nitrogen atoms of 21a and
22a (Scheme 4 and Figure 5).
For the transition structures TS19af21a and TS20af22a, corre-
sponding to the ring opening of cycloadducts 19a and 20a, the
C6a-S bond lengths are estimated to be 2.724 and 2.610 Å,
respectively. The low energy barriers [E(TS19af21a) - E(19a)
) 8.5 kcal/mol and E(TS20af22a) - E(20a) ) 9.8 kcal/mol] are
consistent with a spontaneous sulfur extrusion as observed
experimentally.
All the above-described [2 + 2] cycloadditions, no matter
the type of substrate that may participate (either the mesoionic
system 1 or its valence tautomer 13), involve the elimination
of 1 equiv of phenyl isocyanate, which can further react with
the remaining thioisomu¨nchnone 1 to give rise to 4-oxoimi-
dazo[1,2-a]pyrimidinium-6-olate 4.
Again, the theoretical study allowed us to locate two transition
structures (TS1f17b, TS17bf19b) and one zwitterionic intermediate
(17b) for the endo aproach, as well as for the exo counterpart
(TS1f18b, TS18bf20b, and 18b) leading to the corresponding
FIGURE 4. Energetics of an alternative pathway involving attacks of
PhNCS to the ketene tautomer 13.
J. Org. Chem. Vol. 74, No. 10, 2009 3701

Cantillo et al.
FIGURE 5. Reaction profiles for endo and exo approaches of PhNCS to 1 during a (3 + 2) cycloaddition.
FIGURE 6. Energy profiles for endo and exo (3 + 2) cycloadditions of 1 and PhNCO.
cycloadducts 19b and 20b, respectively (Scheme 4). Their
relative energies have been collected in Figure 6.
Thionation of Imidazo[2,1-b]thiazolium-3-olates: An
Alternative Mechanism. The transformation of the 1,3-thia-
zolium-4-olate 1 into betaine 3 clearly shows its reactivity as
thiocarbonyl ylide toward the nitrogen-carbon double bond of
an aryl isothiocyanate. However, the theoretical calculations rule
out a concerted mechanism for this 1,3-dipolar cycloaddition;
rather, this reaction proceeds via a nonconcerted pathway that
involves an open dipolar intermediate (17a or 18a). Scheme 4
shows how the nucleophilic nitrogens of the intermediates 17a
and 18a, arising from the attack of the C-2 atom of 1 to the
thiocarbonylic carbon of phenyl isothiocyanate, would ultimately
become linked to the C-5 atom of the original mesoionic, thus
affording the cycloadducts 19a and 20a as precursors of betaine
3. These nucleophilic nitrogens could also attack a vicinal
carbonyl group (C-3 of 1) leading to azetidines 23 and 24 by
an intramolecular N-acylation. This process could also be
favored by the good leaving group character of the thioami-
The energy barrier of the rate-determining step for the
formation of betaine 3 (17.4 kcal/mol, see Figure 5) is
considerably lower than any other energy barrier corresponding
to the O/S exchange rationalized in terms of a [2 + 2]
cycloaddition of phenyl isothiocyanate with thioisomu¨nchnone
1 (36.0 kcal/mol, see Figure 3) or its valence tautomer 13 (41.0
kcal/mol, see Figure 4). Accordingly, the results exposed so
far do not account for the formation of imidazo[2,1-b]thiazo-
lium-3-thiolates (2) by reaction of 1 with aryl isothiocyanates
nor do they satisfactorily explain the prevalence of such
derivatives in many cases.4
On the basis of these premises, we conjectured that the O/S
reaction exchange undergone by imidazo[2,1-b]thiazolium-3-
olate systems (1 or 7) might have taken place by a pathway
other than the [2 + 2] cycloaddition described above.
3702 J. Org. Chem. Vol. 74, No. 10, 2009

Thionation of Mesoionics with Isothiocyanates
SCHEME 5
and 24 (∆E ) 1.1 kcal/mol) by attack of the same nitrogen
atom to the C-3 atom, overcoming in this case energy barriers
of only 2.2 and 5.1 kcal/mol. These low values would also
justify the formation of 23 and 24 as major products at the
expense of cycloadducts 19a and 20a. The optimal disposition
of the imidazoline nitrogen of 23 and 24 facilitates its intramo-
lecular nucleophilic attack onto the thiocarbonyl group of the
azetidine ring, which would lead to two new dipolar intermedi-
ates (27 and 28) and, finally, to the imidazo[2,1-b]thiazolium-
3-thiolate 2.
The preceding analyses reveal two further keypoints as well.
First, a comparison of Figures 5 and 6 reveals the greater
reactivity between 1 and phenyl isocyanate than the combination
of 1 and phenyl isothiocyanate. Second, a similar inspection of
the electronic energy differences (Figure 7) accounts for the
low reactivity of 2 against phenyl isocyanate, a process unlikely
to occur, thereby validating the experimental results still further.
In Search of a Nonconcerted Pathway: A Further
Experimental Assessment. Unlike the expected O/S exchange
reaction resulting from a [2 + 2] cycloaddition (Scheme 1),
the proposed mechanism outlined in Scheme 4 involves the
C-O bond substitution in compound 1 by a new C-S bond
coming from the isothiocyanate partner. Although the above
computational study supports this surmise, we sought a further
experimental verification to reinforce the mechanistic picture.
Having this goal in mind, the mesoionic derivative 1 (Ar1 )
Ph) was reacted with isotopically labeled PhN13CS and the
process monitored by 13C NMR spectroscopy.11 Figure 8 shows
the 13C NMR spectrum of the imidazo[2,1-b]thiazolium-3-
thiolate system obtained in this transformation, in which one
can appreciate both the strong enhancement in intensity for the
pseudothiocarbonyl carbon signal (C-3, δ 148.7 ppm) and the
splitting of the C-2 signal, which appears at 110.6 ppm (JC2,C3
) 77.2 Hz). Moreover, the ꢀ carbon atoms relative to C-3 (i.e.,
C-5a and the phenyl carbon atom linked to C-2) resonate as
doublets: δ 159.7 ppm (J ) 5.2 Hz) and δ 133.2 ppm (J ) 3.8
Hz), respectively. This observation clearly supports the exchange
reaction of the C-O bond by the 13C-S bond during the
thionation of thioisomu¨nchnones with aryl isothiocyanates.
dinium framework. The free rotation around the C-S bonds of
23 and 24 would likewise enable the intramolecular nitrogen
attack onto the azetidinic thiocarbonyl group leading to two new
dipolar intermediates (27 and 28) and, finally, to 2 after
elimination of the corresponding aryl isocyanate fragment
(Scheme 5).
This mechanistic hypothesis has also been theoretically
investigated by means of the ONIOM[B3LYP/6-31G(d):PM3]
method, taking newly into account the two possible trajectories
of reactants (endo and exo). The zwitterionic intermediates 17a
and 18a evolve into the azetidines 23 and 24 through a first
transition structure (TS17af23 and TS18af24). The intramolecular
nucleophilic attack to the thiocarbonyl group of 23 and 24
involves the formation of a first transition structure (TS23f25
and TS24f26), a tetrahedral intermediate (25 and 26), as well as
a new transition structure (TS25f27 and TS26f28) leading to a
dipolar intermediate (27 and 28), which then loses aryl isocy-
anate to give the 1,3-thiazolium-4-thiolate 2 via the transition
structures TS27f2 and TS28f2. Figure 7 compiles the relative
electronic energies for the full-optimized structures.
On the basis of the relative electronic energies for the
structures depicted in Figures 5-7, one can plausibly interpret
the experimental results found in the reactions of the imi-
dazo[2,1-b]thiazolium-3-olates 1 with aryl isothiocyanates.
Although the exo approach of aryl isothiocyanate is slightly
favored, the similar stability of structures TS1f17a and TS1f18a
(∆E ) 0.6 kcal/mol) requires an assessment of both reaction
pathways, which would lead to the zwitterionic intermediates
17a and 18a (∆E ) 1.0 kcal/mol). Such dipolar species could
now evolve into cycloadducts 19a and 20a (∆E ) 5.8 kcal/
mol) by the anionic nitrogen attack to the C-5a carbon atom of
1, thus overcoming energy barriers of 8.9 and 6.1 kcal/mol,
respectively. Moreover, they could evolve into azetidines 23
Concluding Remarks
The present work provides an in-depth structural, experi-
mental, and theoretical study for the thionation of 1,3-thiazo-
lium-4-olates with aryl isothiocyanates leading to the most
promising and stable thiolate systems. From a mechanistic
viewpoint, this transformation is consistent with a four-step
domino reaction that lacks precedents in the literature. This
aspect is supported by data obtained through the reaction with
13C-labeled phenyl isothiocyanate, thus unequivocally demon-
strating the substitution of the C-O bond by the 13C-S bond
at the mesoionic ring. Furthermore, an ONIOM-based theoretical
methodology has been performed to simulate the complex
chemical reaction at a relatively low computational cost, in
which only the heavy atoms involved in bond-forming and bond-
breaking processes and their immediate (or first sphere)
neighbors are computed at the B3LYP/6-31G(d) level. It is
worth noting that this methodology detects the existence of
zwitterionic intermediates accounting for the range of subsequent
products observed experimentally. In addition, theory discards
J. Org. Chem. Vol. 74, No. 10, 2009 3703

Cantillo et al.
FIGURE 7. Energetics of the domino sequence involving the thionation of 1 with PhNCS.
FIGURE 8. 13C NMR spectra of the chiral imidazo[2,1-b]thiazolium-3-thiolate 2 obtained from thioisomu¨nchnone 1 and PhNCS (top) and PhN13CS
(bottom), respectively.
Reaction of 7 with Phenyl Isothiocyanate. Following the above
general procedure, the condensation of 7 and phenyl isothiocyanate
gave rise to 8 (73%), 9a (10%), and 10a (4%).
an alternative and more logical [2 + 2] cycloaddition with the
heterocumulenic partner.12
2,7-Diphenyl-5H,6H,7H-imidazo[2,1-b] -1,4-thiazolium-3-
thiolate (8): mp 264-265 °C; 1H NMR (400 MHz, CDCl3) δ 8.19
(d, 2H, J ) 7.2 Hz, Ar), 7.48 (t, 2H, J ) 7.6 Hz, Ar), 7.31 (t, 2H,
J ) 7.6 Hz, Ar), 7.25 (t, 1H, J ) 7.6 Hz, Ar), 7.15 (t, 1H, J ) 7.2
Hz, Ar), 7.14 (d, 2H, J ) 8.0 Hz, Ar), 4.67 (m, 4H, 2CH2); 13C
NMR (100 MHz, CDCl3) δ 158.4, 148.3, 137.0, 133.5, 130.2, 128.4,
125.9, 125.4, 125.2, 116.3, 111.6, 52.0, 45.6. Anal. Calcd for
C17H14N2S2: C, 65.77; H, 4.55; N, 9.02; S, 20.66. Found: C, 65.52;
H, 4.76; N, 8.93; S, 20.45.
Experimental Section
General Procedure for the Reaction of Thioisomu¨nchnone
7 with Aryl Isothiocyanates: To a suspension of 7 (3 mmol) in
dichloromethane (30 mL) was added the corresponding aryl
isothiocyanate (15 mmol). The reaction mixture was stirred at room
temperature and monitored by TLC (benzene/acetonitrile 3:1) until
the complete disappearance of 7 (no more than 24 h). Then, it was
evaporated, and the resulting crude mixture was purified by flash
chromatography (benzene/acetonitrile gradient elution from 5:1 to
1:5).
1,3,8-Triphenyl-4-oxoimidazo[1,2-a]pyrimidin-5-ylium-2-
1
thiolate (9a): mp 267-268 °C; H NMR (400 MHz, CDCl3) δ
7.52 (d, 2H, J ) 7.8 Hz, Ar), 7.37 (t, 2H, J ) 7.6 Hz, Ar), 7.24 (t,
1H, J ) 7.6 Hz, Ar), 7.11 (m, 3H, Ar), 6.97 (m, 5H, Ar), 6.79 (d,
2H, J ) 8.0 Hz, Ar), 4.41 (t, 2H, J ) 9.4 Hz, CH2), 4.06 (t, 2H,
J ) 9.4 Hz, CH2); 13C NMR (100 MHz, CDCl3) δ 177.9, 154.8,
150.7, 137.6, 137.4, 136.1, 131.3, 130.6, 129.7, 129.2, 128.8, 128.4,
128.0, 127.6, 126.7, 114.8, 53.8, 41.9. Anal. Calcd for C24H19N3OS:
C, 75.52; H, 4.82; N, 10.57; S, 8.07. Found: C, 75.27; H, 4.87; N,
10.72; S, 7.86.
(11) Ares, J. J.; Fowble, J. W.; Urchek, T. G.; Miller, D. D. Biochem. Biophys.
Res. Commun. 1987, 142, 1064–1071.
(12) One of the reviewers has suggested to compute the corresponding
transition structures for the rate-determining step of both domino and [2 + 2]
reactions of compound 7 and PhNCS at a pure B3LYP/6-31G(d) level and using
the IRC method. In doing so, we were able to obtain a significant energy
difference between such TSs (21.8 kcal/mol), thereby fully corroborating the
mecanistic proposal and supporting the ONIOM[B3LYP/6-31G(d):PM3] method
as a reliable approach (see Supporting Information).
3704 J. Org. Chem. Vol. 74, No. 10, 2009

Thionation of Mesoionics with Isothiocyanates
1,3,8-Triphenyl-4-oxoimidazo[1,2-a]pyrimidin-5-ylium-2-
olate (10a): mp 378-380 °C; H NMR (400 MHz, DMSO-d6) δ
4.15 (dt, 2H, J ) 2.0, 6.8 Hz, CH2); 13C NMR (100 MHz, DMSO-
d6) δ 159.7, 158.8, 149.3, 147.2, 140.1, 137.5, 136.6, 132.3, 130.6,
129.5, 128.6, 128.0, 127.4, 124.6, 123.6, 88.9, 52.9, 42.4. Anal.
Calcd for C24H18N4O4: C, 67.60; H, 4.25; N, 13.14. Found: C, 67.28;
H, 4.29; N, 13.19.
General Procedure for the Reaction of 7 with Aryl Iso-
cyanates: To a suspension of 7 (3 mmol) in dichloromethane (30
mL) was added the corresponding aryl isocyanate (3 mmol). The
reaction mixture was stirred at room temperature and monitored
by TLC (benzene/acetonitrile 3:1) until the complete disappearance
of 7 (no more than 24 h). Then, it was evaporated, and the resulting
crude mixture was purified by flash chromatography (benzene/
acetonitrile, gradient elution from 3:1 to 1:5).
1
7.66 (d, 2H, J ) 8.0 Hz, Ar), 7.19 (t, 2H, J ) 7.6 Hz, Ar), 7.03
(m, 11H, Ar), 4.20 (t, 2H, J ) 8.8 Hz, CH2), 4.11 (t, 2H, J ) 8.4
Hz, CH2); 13C NMR (100 MHz, DMSO-d6) δ 160.1, 158.7, 149.6,
138.0, 137.0, 133.9, 130.6, 130.5, 129.2, 128.7, 128.5, 128.2, 127.8,
127.2, 124.2, 88.8, 53.1, 42.2. Anal. Calcd for C24H19N3O2: C,
75.57; H, 5.02; N, 11.02. Found: C, 75.63; H, 5.27; N, 11.06.
Reaction of 7 with 4-Methoxyphenyl Isothiocyanate. Follow-
ing the general procedure, reaction of 7 and 4-methoxyphenyl
isothiocyanate afforded 8 (9%), 9b (34%), and 10b (4%).
3,8-Diphenyl-1-(4-methoxyphenyl)-4-oxoimidazo[1,2-a]py-
1
rimidin-5-ylium-2-thiolate (9b): mp 284-285 °C; H NMR (400
MHz, CDCl3) δ 7.54 (d, 2H, J ) 8.0 Hz, Ar), 7.36 (t, 2H, J ) 7.6
Hz, Ar), 7.22 (t, 1H, J ) 7.6 Hz, Ar), 7.10 (m, 3H, Ar), 6.82 (d,
2H, J ) 8.8 Hz, Ar), 6.75 (d, 2H, J ) 7.2 Hz, Ar), 6.44 (d, 2H, J
) 8.8 Hz, Ar), 4.30 (t, 2H, J ) 9.2 Hz, CH2), 3.92 (t, 2H, J ) 9.4
Hz, CH2), 3.64 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ
178.1, 159.5, 155.0, 150.8, 137.8, 137.7, 131.7, 131.5, 129.5, 128.8,
128.4, 127.9, 127.7, 126.5, 114.4, 113.6, 55.3, 53.6, 41.9. Anal.
Calcd for C25H21N3O2S1: C, 70.24; H, 4.95; N, 9.83; S, 7.50. Found:
C, 70.25; H, 5.11; N, 9.90; S, 7.41.
Reaction of 7 with Phenyl Isocyanate. Following the general
procedure from 7 and phenyl isocyanate, compound 10a was
obtained in 52% yield.
Reaction of 7 with 4-Methoxyphenyl Isocyanate. Following
the general procedure, reaction of 7 with 4-methoxyphenyl isocy-
anate produced 10b (52%).
Reaction of 7 with 4-Nitrophenyl Isocyanate. Following the
general procedure, reaction of 7 and 4-nitrophenyl isocyanate gave
10c (18%).
Reaction of 2,5-Diphenyl-(3,5,6-tri-O-acetyl-1,2-dideoxy-
r-D-glucofurano)[1′,2′:4,5]-4aH,4bH-imidazo[2,1-b]thiazoli-
um-3-olate (1) with 13C-Labeled Phenyl Isothiocyanate. To a
solution of 1 (1 mmol) in dichloromethane (20 mL) was added
PhN13CS (1 mmol). The reaction mixture was kept at room
temperature and monitored by TLC (benzene/acetonitrile 3:1) until
observing the disappearance of 1 (no more than 48 h). Then, it
was filtered off, evaporated, and the resulting crude mixture was
purified by flash chromatography (benzene/acetonitrile, gradient
elution from 10:1 to 1:3) to give 13C-labeled 2 (Ar1 ) Ph) (19%)
and 4 (Ar1 ) Ar2 ) Ph)4 (17%).
3,8-Diphenyl-1-(4-methoxyphenyl)-4-oxoimidazo[1,2-a] pyr-
1
imidin-5-ylium-2-olate (10b): mp 319-320 °C; H NMR (400
MHz, DMSO-d6) δ 7.68 (dd, 2H, J ) 1.2, 8.4 Hz, Ar), 7.19 (t, 2H,
J ) 7.6 Hz, Ar), 7.01 (t, 1H, J ) 7.6 Hz, Ar), 6.95 (dd, 2H, J )
2.4, 6.8 Hz, Ar), 6.52 (dd, 2H, J ) 2.0, 6.8 Hz, Ar), 4.19 (dt, 2H,
J ) 2.4, 10.4 Hz, CH2), 4.10 (dt, 2H, J ) 2.4, 10.4 Hz, CH2); 13
C
NMR (100 MHz, DMSO-d6) δ 160.3, 159.2, 158.6, 149.8, 138.1,
137.1, 131.5, 130.4, 129.1, 127.9, 127.9, 127.1, 126.4, 124.1, 113.7,
88.7, 55.8, 53.0, 42.2. Anal. Calcd for C25H21N3O3: C, 72.98; H,
5.14; N, 10.21. Found: C, 72.76; H, 5.03; N, 10.43.
Reaction of 7 with 4-Nitrophenyl Isothiocyanate. Following
the general procedure, reaction of 7 and 4-nitrophenyl isothiocyanate
gave rise to 8 (81%), 9c (3%), and 10c (5%).
Acknowledgment. This work was supported by the Minis-
terio de Educacio´n y Ciencia and FEDER (CTQ2005-07676 and
CTQ2007- 66641) and the Junta de Extremadura (PRI07A016
and PRI08A032). D.C. thanks the Spanish Ministerio de
Educacio´n y Ciencia for a fellowship.
3,8-Diphenyl-1-(4-nitrophenyl)-4-oxoimidazo[1,2-a]pyrimid-
in-5-ylium-2-thiolate (9c): mp 198-199 °C; 1H NMR (400 MHz,
CDCl3) δ 7.81 (d, 2H, J ) 8.8 Hz, Ar), 7.50 (d, 3H, J ) 7.2 Hz,
Ar), 7.38 (t, 3H, J ) 7.6 Hz, Ar), 7.16 (m, 4H, Ar), 6.86 (d, 2H,
J ) 7.6 Hz, Ar), 4.47 (t, 2H, J ) 9.4 Hz, CH2), 4.16 (t, 2H, J )
9.4 Hz, CH2); 13C NMR (100 MHz, CDCl3) δ 184.5, 155.7, 150.4,
147.4, 132.0, 131.2, 130.1, 129.5, 128.1, 127.8, 127.0, 123.4, 118.0,
114.1, 53.8, 42.1. Anal. Calcd for C24H18N4O3S: C, 65.14; H, 4.10;
N, 12.66; S, 7.25. Found: C, 64.86; H, 4.27; N, 12.62; S, 7.12.
3,8-Diphenyl-1-(4-nitrophenyl)-4-oxoimidazo[1,2-a]pyrimid-
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds, crystal data for compounds 8,
9b, and 10a in CIF format, and computational data for all
structures computed at the ONIOM[B3LYP/6-31G(d):PM3].
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
in-5-ylium-2-olate (10c): mp 350-351 °C; H NMR (400 MHz,
DMSO-d6) δ 7.85 (dd, 2H, J ) 4.0, 6.8 Hz, Ar), 7.66 (d, 2H, J )
7.2 Hz, Ar), 7.42 (dd, 2H, J ) 4.0, 6.8 Hz, Ar), 7.20 (t, 2H, J )
7.6 Hz, Ar), 7.07 (m, 6H, Ar), 4.21 (dt, 2H, J ) 1.8, 6.8 Hz, CH2),
JO900028C
J. Org. Chem. Vol. 74, No. 10, 2009 3705