Stepwise cycloadditions of mesoionic systems: Thionation of thioisomunchnones by isothiocyanates

Article abstract of DOI:10.1021/ol702929k

An unusual thionation strategy of mesoionic compounds with aryl isothiocyanates enables a facile synthesis of 1,3-thiazolium-4-thiolate systems. The mechanistic pathway of such a transformation most likely involves a stepwise 1,3-dipolar cycioaddition, which is supported by theoretical calculations performed with a two-layer hybrid method (B3LYP/6-31G(d):PM3).

Full text of DOI:10.1021/ol702929k

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1079-1082
Stepwise Cycloadditions of Mesoionic
Systems: Thionation of
Thioisomu1nchnones by Isothiocyanates
David Cantillo,*,† Mart´ın Avalos,† Reyes Babiano,† Pedro Cintas,†
Ä
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 December 4, 2007
ABSTRACT
An unusual thionation strategy of mesoionic compounds with aryl isothiocyanates enables a facile synthesis of 1,3-thiazolium-4-thiolate systems.
The mechanistic pathway of such a transformation most likely involves a stepwise 1,3-dipolar cycloaddition, which is supported by theoretical
calculations performed with a two-layer hybrid method (B3LYP/6-31G(d):PM3).
Mesoionic heterocycles, which may exhibit large dipole
moments and optical susceptibilities, are attracting consider-
able interest as second- and third-order nonlinear systems
and near-infrared dyes, thus finding a potential niche in
optoelectronics.1 The synthetic manipulation of these het-
eroaromatics is invariably associated to their dipole character
in cycloaddition reactions, a fact successfully exploited in
natural products chemistry and in the construction of other
five- and six-membered rings.2 Recent developments with a
usual family of mesoionic dipoles, 1,3-thiazolium-4-olates
(generally referred to as thioisomu¨nchnones), have unveiled
further reactivity patterns that give rise to three- and four-
membered rings, hitherto unknown in 1,3-dipolar cycload-
ditions.3
This Letter also discloses an unexpected thionation of
thioisomu¨nchnones by reaction with aryl isothiocyanates
leading to the corresponding 1,3-thiazolium-4-thiolates.
Although the reaction of some mesoionic rings with both
isocyanates and isothiocyanates has been known for many
years,4 detailed studies by Potts and associates suggested the
formation of stable 1:1 cycloadducts with such heterocumu-
lenes.5 In the 1980s, however, Hamaguchi and Nagai were
able to demonstrate the mesoionic nature of these adducts
and proposed a pathway to explain their formation.6
(2) (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123-
141. (b) Padwa, A. Top. Curr. Chem. 1997, 189, 121-158. (c) 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. (d) Gribble, G. W. In The
Chemistry of Heterocyclic Compounds, Vol. 60. Oxazoles: Synthesis
Reactions and Spectroscopy, Part A; Palmer, D. A. Ed. Wiley: New York,
2003; Chapter 4.
(3) AÄ valos, M; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C.
Acc. Chem. Res. 2005, 38, 460-468 and references cited therein.
(4) (a) Huisgen, R.; Funke, E.; Schaefer, F. C.; Gotthardt, H.; Brunn, E.
Tetrahedron Lett. 1967, 1809-1814. (b) Kato, H.; Sato, S.; Ohta, M.
Tetrahedron Lett. 1967, 4261-4262.
† Universidad de Extremadura.
‡ University of Southampton.
(1) (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) Langhals, H. Angew. Chem., Int. Ed. 2003,
42, 4286-4288. (c) Rakov, N.; De Arau´jo, C. B.; Da Rocha, G. B.; Simas,
A. M.; Athayde-Filho, P. A. F.; Miller, J. Chem. Phys. Lett. 2000, 332,
13-18.
10.1021/ol702929k CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

dichloromethane at room temperature. Reaction times were
established by monitoring the disappearance of the reagents
by thin-layer chromatography (benzene-acetonitrile, 3:1).
In all cases, the corresponding 1,3-thiazolium-4-thiolate
systems 3a-c could be isolated along with minor amounts
of the mesomeric betaines 4 (Table 1). Remarkably, com-
pounds 5 were equally isolated from the reaction mixtures,
in low to moderated yields, when 4-methoxyphenyl isothio-
cyanate was employed as dipolarophile (entries 2, 5, and 8)
or when an electron-withdrawing group (4-nitrophenyl) was
linked to the imidazolinic nitrogen of 1 (entries 7-9).
It is noteworthy that conversion of 1 into 3 could not be
achieved by usual thionation reagents (e.g., Lawesson’s
reagent).12
Table 1. Reaction of Thioisomu¨nchnones 1 with Aryl
Isothiocyanates
Suitable crystals for X-ray diffraction could be obtained
for compound 3a, thereby revealing the mesoionic nature
of this tricycle (Figure 1).
entry
Ar1
Ar2
compound (% yield)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
3a (23) 4a (16)
4-MeOC6H4 3a (16) 4b (4)
4-NO2C6H4
5b (12)
5e (12)
3a (64) 4c (20)
3b (32) 4d (4)
4-MeOC6H4 Ph
4-MeOC6H4 4-MeOC6H4 3b (26)
4-MeOC6H4 4-NO2C6H4 3b (60) 4f (2)
3c (7) 4g (5)
4-MeOC6H4 3c (5)
4-NO2C6H4 3c (40) 4i (7)
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
5g (37)
5h (22)
5i (31)
Like other cases of chemical serendipity, the present yet
conceptually simple O/S exchange also provides new struc-
tural and mechanistic insights into the unique character of
thioisomu¨nchnones as masked dipoles, which should elicit
additional synthetic pursuits.
Compound 1a (Ar1 ) Ph) was chosen as the parent
thioisomu¨nchnone; this is a stable, inherently chiral me-
soionic structure that can be easily generated from a
carbohydrate precursor.7 Moreover, previous studies have
proven the versatility of this substance toward diverse
dipolarophiles en route to other polycyclic systems derived
from R-pyridones,8 chiral thiiranes,9 1,2,4-triazines,10 and
4-oxopyrimidinium-6-olates (e.g., 4).11
Figure 1. X-ray structure of 3a.
As mentioned above, betaines 4 had also been obtained
by direct reaction of 1 with the corresponding aryl iso-
cyanates and their structures unambiguously inferred from
spectroscopic data.11 In the present study, the solid-state
structure of 4a could also be solved by X-ray crystallography,
although crystal data revealed a reasonable static molecular
disorder, which presumably arises from the unsteady con-
figuration of the imidazolinic nitrogen. Individual molecular
structures of both invertomers, which are found in 4:1 ratio
at the crystal, could be computationally disentangled (Figure
2).
The aryl groups attached to the nitrogen atoms of the
heterocycle adopt an offset stacked arrangement in both
invertomers, thus behaving as a potential class of dynamic
molecular tweezers at room temperature.13
1H NMR spectra of compounds 4, recorded at room
temperature, evidenced the magnetic nonequivalence of the
ortho and meta N-aryl protons in both CDCl3 and DMSO-
d6. These facts point to the existence of a slow nitrogen
With the aim of harnessing the cycloadditive methodology
in the synthesis of new mesomeric betaines containing
exocyclic sulfur atoms, we carried out the reaction of
thioisomu¨nchnones 1a-c with aryl isothiocyanates (2) in
(5) (a) Potts, K. T.; Husain, S. J. Org. Chem. 1972, 37, 2049-2050. (b)
Potts, K. T.; Baum, J.; Houghton, E.; Roy, D. N.; Singh, U. P. J. Org.
Chem. 1974, 39, 3619-3627. (c) Potts, K. T.; Baum, J.; Datta, S. K.;
Houghton, E. J. Org. Chem. 1976, 41, 813-818.
(6) Hamaguchi, M.; Nagai, T. J. Chem. Soc., Chem. Commun. 1985,
726-728.
(7) Areces, P.; AÄ valos, M.; Babiano, R.; Gonza´lez, L.; Jime´nez, J. L.;
Palacios, J. C.; Pilo, M. D. Carbohydr. Res. 1991, 222, 99-112.
(8) Areces, P.; AÄ valos, M.; Babiano, R.; Cintas, P.; Gonza´lez, L.;
Hursthouse, M. B.; Jime´nez, J. L.; Light, M. E.; Lo´pez, I.; Palacios, J. C.;
Silvero, G. Eur. J. Org. Chem. 2001, 2135-2144.
(9) Areces, P.; AÄ valos, M.; Babiano, R.; Gonza´lez, L.; Jime´nez, J. L.;
Me´ndez, M. M.; Palacios, J. C. Tetrahedron Lett. 1993, 34, 2999-3002.
(10) Are´valo, M. J.; AÄ valos, M.; Babiano, R.; Cintas, P.; Hursthouse,
M. B.; Jime´nez, J. L.; Light, M. E.; Lo´pez, I.; Palacios, J. C. Tetrahedron
Lett. 1999, 40, 8675-8678.
(11) AÄ valos, M.; Babiano, R.; Dia´nez, M. J.; Espinosa, J.; Estrada, M.
D.; Jime´nez, J. L.; Lo´pez-Castro, A.; Me´ndez, M. M.; Palacios, J. C.
Tetrahedron 1992, 48, 4193-4208.
(12) It has been reported in the literature that a few mesoionics undergo
O/S exchange with Lawesson’s reagent: Araki, S.; Goto, T.; Butsugan, Y.
Bull. Chem. Soc. Jpn. 1988, 61, 2977-2978.
(13) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem.
Soc., Perkin Trans. 2 2001, 651-669.
1080
Org. Lett., Vol. 10, No. 6, 2008

for δm and δd of 5.97 and 5.41 ppm, respectively, with an
rms error of 0.003 and having K ) 23.6 M-1. Figure 3 shows
Figure 3. Plot of δ (ppm) versus c (mg/mL) for the H-1′ signals
of 4b.
Figure 2. ORTEP for the major (up) and minor (down) invertomers
of 4a.
the calculated curve and the observed proton shifts for the
H-1′ signals of 4b.
inversion and/or a slow rotation of N-aryl bonds on the NMR
time-scale. Variable temperature experiments allowed us to
calculate, for instance, a rotational barrier of 18.7 kcal.mol-1
for the N-aryl bond of 4d in DMSO-d6.
The structure of compounds 5 was deduced from their
NMR spectra, which are analogous to those of 4, although
the pseudothiocarbonyl group, which resonates at ∼178 ppm,
shifts downfield (∼25 ppm) the signal of the adjacent C-Ph.
Elemental analyses and mass spectra agree with the thion-
ation of the pyrimidium ring, and the sulfur position was
established by proving that 3 does not react with aryl
isocyanates under the same conditions that produce the
betaine derivatives 5.
Although a conventional 1,3-dipolar cycloaddition of 1
with the aryl isothiocyanate, followed by the removal of
sulfur from the initial cycloadduct 6, could explain the
formation of 5, the isolation of 4 equally uncovers the
transient existence of the corresponding aryl isocyanate,
which must be formed during the conversion of 1 into 3.
Scheme 1 shows a putative reaction mechanism that involves
However, 1H and 13C NMR spectra of betaines 4 showed
only one signal set for the sugar framework at temperatures
ranging from 295 to 235 K, thus evidencing the fast
interconversion of both invertomers in CDCl3 solution. On
the other hand, chemical shifts of the H-1′, H-2′, and H-3′
sugar protons are strongly dependent on concentration (see
Supporting Information). At first glance and as concentration
increases, one could envisage the existence of intermolecular
interactions that would be analogous to those encountered
in the crystalline state, where aryl groups at C-3 and N-1 of
the imidazopyridinium system of vicinal molecules are in
edge to face close contact (see Supporting Information).14
Accordingly, such an interaction between adjacent molecules
can be viewed as a dimerization process, for which the
corresponding equilibrium can be formulated.
Scheme 1. Possible Reaction Mechanism
Equation 1 gives the observed chemical shift as a function
of the monomer (δm) and dimer (δd) chemical shifts and the
equilibrium constant (K), where c is the concentration.15
δobs ) δm + (δd - δm)[1 + 4cK - (1 + 8cK)1/2]/4cK (1)
A further iterative analysis of the dilution plot of the H-1′
proton versus δm, δd, and K variations gave optimal solutions
(14) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525-5534.
(15) Abraham, R. J.; Rowan, A. E.; Mansfield, K. E.; Smith, K. M. J.
Chem. Soc., Perkin Trans. 1991, 2, 515-521.
Org. Lett., Vol. 10, No. 6, 2008
1081

electrophilicity of the C(a) atom (entries 7-9), while an
electron-releasing substituent on Ar2 increases the nucleo-
philicity of its contiguous N atom (entries 2, 5, 8). Overall,
the synergy of both effects results in a higher yield of
compound 5.
Table 2. 1,3-Dipolar Cycloaddition of the Thioisomu¨nchnone
1a with Phenyl Isothiocyanatea
In stark contrast, more electron-donating groups on Ar1
(entries 1-6) favor a preferential attack of the N atom to
the carbonyl group of 7, thus accounting for the formation
of 8 and subsequently of 3.
The presence of electron-withdrawing substituents on Ar2
increases the global reaction yield, presumably due to the
enhanced electrophilicity of the thiocarbonyl group.
Further experimental support of this pathway comes from
the fact that 5 could not be obtained by reaction of 4 with
aryl isothiocyanates.
In order to clarify the concertedness degree of the 1,3-
dipolar cycloaddition, we have investigated the geometries
and energies associated with the reactants, products and
transition structures that take place along the reaction of 1a
and PhNCS using an ONIOM(B3LYP/6-31G(d):PM3)
method.16 Table 2 shows the transition structures TS1 and
TS2, the high-energy zwitterionic intermediate 7, and the
cycloadduct 6 located for the endo 1,3-dipolar cycloaddition
of 1 and 2. Comparable structures were also found for the
exo approach of the reagents.17
In conclusion, this contribution highlights a facile and
unexpected transformation of 4-olate- into 4-thiolate-based
mesoionic rings, together with betaine derivatives, which
overall reveal the existence of a cascade cycloaddition.
Further structural investigations and synthetic applications
are under way.
structureb
energyc
Ca-N
Ca-S
Cb-Cc
Cb-S
TS1
7
TS2
6
18.03
9.32
15.50
-1.04
3.107
2.985
2.186
1.488
1.705
1.701
1.766
1.897
2.226
1.615
1.600
1.565
1.842
1.962
1.925
1.903
a Ball and stick and wireframe formats correspond to the layers treated
at the B3LYP/6-31G(d) and PM3 levels, respectively. b Atoms Ca, Cb, and
Cc are identified in the structure 6 of Scheme 1. c Relative to electronic
energy of the reagents, in kcal mol-1
.
the stepwise 1,3-dipolar cycloaddition of 1 and the aryl
isothiocyanate. The zwitterionic intermediate 7 could lead
to the cycloadduct 6, and then to betaine 5 or the azetidine
8 by nucleophilic attack of the nitrogen onto the next
carbonyl group. The opposite process, starting from 8, would
justify the formation of both 3 and the corresponding aryl
isocyanate, which is required for the synthesis of betaines
4.
Acknowledgment. This work was supported by the
Ministerio de Educacio´n y Ciencia and FEDER (CTQ2005-
07676 and CTQ2007-66641), and the Junta de Extremadura
(PRI07A016).
Supporting Information Available: Synthetic proce-
1
dures, H and 13C NMR spectra for all new compounds,
The mechanistic insight outlined in Scheme 1 appears to
be consistent with the above experimental results (Table 1).
Thus, an electron-withdrawing group on Ar1 increases the
crystal data for compounds 3a and 4a in CIF format, and
computational data for both intermediates (6 and 7) and
transition structures (TS1 and TS2). This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Maseras, F.; Morokuma, K. J. Comp. Chem. 1995, 16, 1170-1179.
(17) Since 3 could also be generated by a [2 + 2] cycloaddition of 1
with ArNCS, we have computed this process at the same level of theory,
finding instead higher (∼2-fold) activation energy barriers.
OL702929K
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Org. Lett., Vol. 10, No. 6, 2008