Push-pull 1,3-thiazolium-5-thiolates. Formation via concerted and stepwise pathways, and theoretical evaluation of NLO properties

Article abstract of DOI:10.1039/c0ob00416b

The transformation of muenchnones (mesoionic rings featuring the 1,3-oxazolium-5-olate core) into their sulfur counterparts (1,3-thiazolium-5- thiolates) by reaction with CS₂, pioneered by Huisgen and his group in the early 1970s, has been re-i

Full text of DOI:10.1039/c0ob00416b

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Push-pull 1,3-thiazolium-5-thiolates. Formation via concerted and stepwise
pathways, and theoretical evaluation of NLO properties†,‡
a
a
a
a
a
b
´
David Cantillo,* Mart´ın Avalos, Reyes Babiano, Pedro Cintas, Jose´ L. Jime´nez, Mark E. Light,
Juan C. Palaciosa and Valent´ın Rodr´ıgueza
Received 12th July 2010, Accepted 23rd August 2010
DOI: 10.1039/c0ob00416b
The transformation of mu¨nchnones (mesoionic rings featuring the 1,3-oxazolium-5-olate core) into
their sulfur counterparts (1,3-thiazolium-5-thiolates) by reaction with CS2, pioneered by Huisgen and
his group in the early 1970s, has been re-investigated in detail by means of both experimental and
theoretical methods. The synthetic strategy can be tuned to incorporate donor and acceptor groups in
appropriate positions. Calculations of molecular hyperpolarizabilities together with orbital topologies
evidence that these sulfur-containing heterocycles exhibit nonlinear optical responses, thereby pointing
to potential applications of mesoionic structures in the NLO field. From a mechanistic viewpoint,
modeling of the whole systems at the B3LYP/6-31G(d) level reveals that concerted and stepwise
pathways are operative depending on the substitution pattern of the parent mu¨nchnone, which also
account for the experimental results.
second-order hyperpolarizabilities unveils the potentiality of such
substances in the field of nonlinear optics.
Introduction
Thionation of mesoionic rings represents a valuable strategy to
incorporate a bulkier and more polarizable atom in such five-
membered aromatic heterocycles. The transformation of 1,3-
oxazolium-5-olate systems (mu¨nchnones) into 1,3-thiazolium-5-
thiolates by reaction with carbon disulfide was first described
by Huisgen and associates more than four decades ago,1 and
since then it has been recognized as a model for the synthe-
sis of mesoionic heterocycles based on tandem cycloaddition–
retrocycloaddition processes.2 The last decade has witnessed a
renaissance of these protocols because they can be applied with
excellent results to the preparation of various mesoionic systems
with potential non-linear optical properties.3 We have also used re-
cently a related methodology to obtain 1,3-thiazolium-4-thiolates
by reaction of thioisomu¨nchnones with aryl isothiocyanates,4 and
finding that a stepwise thionation competes, often favorably, with
the expected cycloaddition–retrocycloaddition reaction.5
Results and Discussion
Synthesis and Structure Elucidation
According to the described procedure,6 1,3-oxazolium-5-olates
can be synthesized by a three-sequence protocol. The first is
actually a multicomponent process in which the iminium ion
(5–7) formed by addition–elimination reaction of an aromatic
aldehyde (1–3) with an alkylammonium halide (4), undergoes
in situ nucleophilic addition of cyanide ion to give an aminonitrile
(8–10) that is subsequently hydrolyzed in acidic solution. The
application of this methodology to benzaldehyde, p-anisaldehyde,
and 4-fluorobenzaldehyde allowed us to obtain the corresponding
C-aryl-N-methylglycine hydrochlorides 11–13 (Scheme 1).
In this paper we report a thorough experimental and theoretical
study aimed at designing a series of push-pull 1,3-thiazolium-
5-thiolates from the corresponding mu¨nchnones and carbon
disulfide. Mechanistic investigations have been performed by DFT
calculations at the B3LYP/6-31G(d) level. Further assessing of
aDepartamento de Qu´ımica Orga´nica e Inorga´nica, QUOREX Research
Group, Facultad de Ciencias, Universidad de Extremadura, E-06006,
Badajoz, Spain. E-mail: dcannie@unex.es
bDepartment of Chemistry, University of Southampton, Highfield,
Southampton, UK, SO17 1BJ
† Dedicated to Prof. Jose´ Fuentes Mota
‡ Electronic supplementary information (ESI) available: Copies of NMR
spectra for all new compounds, UV spectra and cyclic voltammograms
for 1,3-thiazolium-5-thiolate systems, complete Cartesian coordinates and
energies for all calculated structures, crystal data for compounds 14, 15
and 18 data in CIF format, and crystal structure simulation outputs
in PDB format. CCDC reference numbers 784450–784452. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00416b
Scheme 1
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Table 1 Reaction of mu¨nchnones 20–23 with carbon disulfide in DMF
Since p-nitrobenzaldehyde did not react under the above con-
ditions, the synthesis of N-methyl-C-(4-nitrophenyl)glycine (14)
was attempted by conventional nitration of 11 in following the
operational procedure described previously.6 Remarkably, both
1H and 13C NMR data are consistent with the exclusive formation
of N-methyl-C-(3-nitrophenyl)glycine (15), thereby evidencing a
different orientation of the nitro group. N-Acylation of 12 with
4-nitrobenzoyl and 4-fluorobenzoyl chlorides led to the formation
of N-acyl-C-aryl-N-methylglycines, 16 and 17 respectively, while
treatment of 13 and 15 with p-anisoyl chloride gave rise to the
N-acyl derivatives 18 and 19.
at reflux
Substrate
Time/h
Product (yield%)
20
21
22
23
4
4
1
4
24 (34) + 25 (43)
26 (61)
27 (98)
28 (36)
Cyclodehydration of the N-acyl-C-aryl-N-methylglycines 16–19
was conducted with acetic anhydride under argon at temperatures
below 55 ◦C yielding the corresponding 2,4-diaryl-3-methyl-
1,3-oxazolium-5-olates 20–23. These substances must be used
immediately as substrates to avoid further decomposition, which
takes place rapidly in solution or progressively (several days) when
stored under vacuum. From a strategic standpoint, the first two
synthetic stages enable the combination of aryl groups in positions
2 and 4 of the heterocycle en route to different push-pull systems.
Finally, the preparation of 2,4-diaryl-3-methyl-1,3-thiazolium-
5-thiolates 24–28 (Scheme 2, Table 1) was carried out by re-
fluxing a mixture of 20–23 and excess of carbon disulfide in
N,N-dimethylformamide (DMF) solution, until observing the
disappearance of the parent mesoionic (TLC monitoring).
Fig. 1 ORTEP diagrams of the crystal structures of 24, 25 and 28.
24 has been previously described,3d as the only regioisomer of the
cycloaddition reaction; however this process does actually yield
two products as outlined herein.
It is noteworthy the different arrangements adopted by the nitro
group in the molecular structure of compounds 24 and 25. While
in 25 that group is coplanar with the aromatic ring (O–N–C–C
dihedral angle: 2.9◦), the disposition in 24 significantly deviates
from coplanarity (O–N–C–C dihedral angle: 40.5◦).
To rationalize that unexpected inhibition to resonance, we have
also simulated computationally (at the B3LYP/6-31G(d), using
the GAUSSIAN037 package) the crystal lattice of 25 in which
two 4-nitrophenyl groups of vicinal molecules interact each other.
On the basis of crystal data as well, we have also incorporated
the six surrounding molecules possessing a close atom (as sum
of van der Waals radii) to either nitro group of the two above-
mentioned vicinal molecules. This protocol gives rise to a whole
system comprising 8 molecules and 304 atoms (Fig. 2).
Scheme 2
While compound 27 could easily be isolated by spontaneous
crystallization after 1 h-heating, 24, 25, 26 and 28 required longer
reaction times (~4 h) and had to be purified by column chro-
matography (benzene–acetonitrile gradient). When compound 20
was used as starting material, two products (24 and 25) were
formed in a 1 : 1.25 ratio, whose structures could be unequivocally
assigned by single-crystal X-ray diffraction (Fig. 1). Compound
Fig. 2 Crystal structure simulation.
Single-point energy calculations revealed that the supramolec-
ular structure is more stable, by 6.7 kcal mol-1, than an analogous
one for which both nitro groups are coplanar to phenyl rings. NBO
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calculations ruled out intermolecular donor–acceptor interactions
as responsible of the energy difference. Therefore, the origin of such
a stabilizing effect should presumably be ascribed to electrostatic
interactions involving the oxygen atoms of nitro groups with other
oxygen atoms present in contiguous nitro and methoxy groups
(Fig. 3a), which decrease as the 4-nitrophenyl groups deviate from
coplanarity (Fig. 3b).
Fig. 3 Intermolecular interactions involving the oxygen atoms of nitro
and methoxy groups in a hypothetical supramolecular structure having
the 4-nitrophenyl groups in coplanar disposition (a) and the real aggregate
with twisted 4-nitrophenyl groups (b).
Scheme 3
Furthermore, to assess the ability of DFT calculations to
reproduce the crystal lattice of 25, the two 4-nitrophenyl groups
depicted in Fig. 2 have been optimized freezing the Cartesian
coordinates of the remaining atoms (thus preserving the unit cell).
Such an optimization leads to a structure with a dihedral angle
O–N–C–C of 37.7◦, which closely matches the situation found
experimentally (40.5◦).
Unlike 20, the reactions of mu¨nchnones 21–23 with carbon
disulfide resulted in formation of a single product (26–28, re-
spectively) whose structures were assigned on the basis of their
1H and 13C NMR data. Quantitative elemental analysis further
confirmed the existence of two sulfur atoms. Suitable crystals for
X-ray diffraction could be obtained for compound 28, thereby
revealing the meta substitution of the nitrophenyl group.
The frontier orbital energies of both reactants, calculated at the
B3LYP/6-31G(d) level, evidence that the reaction of mu¨nchnones
with carbon disulfide should be classed as a Sustmann type I cy-
cloaddition controlled by the interaction HOMO (dipole)-LUMO
(dipolarophile), whose coefficients in the reaction centers explain
the formation of thiolates 24 and 26–28, derived from the initial
cicloadducts 30–33 (pathway a). However, the similarity of the c2
and c4 coefficients of the HOMOs in compounds 20–23 does not
rule out the possible formation of cycloadducts 34–37 (pathway b)
in some cases (Table 2). This hypothesis is corroborated by the lack
of regioselectivity observed experimentally in the cycloaddition of
20.
To shed light into the origin of the regioselectivity pattern,
we have optimized, at the same level of theory, the structures
of all stationary states involved in the two possible approaches
of carbon disulfide to mu¨nchnones 20–23. Table 3 shows the
relative free energies of these structures, which almost fully agree
with experimental results; i.e. preferred or exclusive isolation of
Mechanistic Insights
The 1,3-dipolar cycloaddition of 1,3-oxazolium-5-olates with
carbon disulfide should be a concerted reaction controlled by the
symmetry of the frontier orbitals of the reactants. Two possible
orientations (Scheme 3, a or b) may be envisaged. The first
pathway (a) would involve binding of the C-4 carbon atom of the
heterocycle to the thiocarbonyl group of carbon disulfide to form
cycloadducts 30–33. Had the reaction proceeded by route b, the C-
2 carbon would become attached to the thiocarbonyl carbon, thus
yielding cycloadducts 34–37. Both pathways would afford, after
the elimination of carbon dioxide, the expected 1,3-thiazolium-
5-thiolate systems, although the new heterocycles would differ
in the relative positions of substituents R1 and R2 relative to
the endocyclic and exocyclic sulfur atoms. This accounts for the
formation of a mixture (compounds 24 and 25) starting from
mu¨nchnone 20.
Table 2 Frontier orbital energies and coefficients of mu¨nchnones 20–23
and carbon disulfide calculated at the B3LYP/6-31G(d) level
Substrate
MO
Energy/eV
c2
c4
cS
cC
20
HO
LU
HO
LU
HO
LU
HO
LU
HO
LU
-5.00445
-2.83815
-4.51517
-1.65760
-4.55312
-1.54943
-4.95868
-1.81377
-7.55857
-2.03896
-0.27
0.30
-0.26
0.32
-0.25
0.34
-0.24
0.35
0.30
0.18
0.27
0.18
0.29
0.16
0.30
0.14
21
22
23
S2C
0.52
-0.36
0.00
0.49
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Table 3 Relative free energies (in kcal mol-1), calculated at the B3LYP/6-31G(d) level, for all stationary states involved in the cycloadditions of
mu¨nchnones 20–23 with carbon disulfide
Reactants
Pathway
Saddle Point
Intermediate
Saddle Point
Cycloadduct
Products
20 + S2C (0.00)
21 + S2C (0.00)
22 + S2C (0.00)
23 + S2C (0.00)
a
b
a
b
a
b
a
b
SP20→30 (34.00)
SP20→34 (32.60)
SP21→31 (30.34)
SP21→35 (31.68)
SP122→32 (30.32)
SP22→36 (33.83)
SP23→33 (33.32)
SP23→37 (37.87)
—
—
—
—
—
—
—
—
30 (25.24)
34 (22.40)
31 (23.35)
35 (21.17)
32 (24.03)
36 (22.85)
33 (26.55)
37 (26.07)
24 + CO2 (-9.67)
25 + CO2 (-11.50)
26 + CO2 (-10.43)
27 + CO2 (-11.27)
27 + CO2 (-9.90)
26 + CO2 (-9.06)
28 + CO2 (-8.64)
29 + CO2 (-5.82)
I22→32 (29.70)
SP222→32 (31.08)
—
—
—
—
—
—
regioisomers whose formation is kinetically favored. However,
they do not justify the formation of a single product from
mu¨nchnone 21, since the free energies of the two regioisomeric
transition structures (SP21→31 and SP21→35) only differ by 1.34 kcal
mol-1.
The polar nature of the transition structures suggests that
solvent effects might also play a key role. To evaluate this influence
the transition structures SP21→31 and SP21→35 have been optimized
in DMF at the B3LYP/6-31G(d) level using the CPCM model and
UAKS cavities. This solvent effect correction indicates that SP21→31
increases its stability with respect to SP21→35 up to 3.92 kcal mol-1
(Fig. 4).
Fig. 5 Transition structures SP122→32 and SP222→32 and the dipolar
intermediate I22→32
.
also located a dipolar intermediate and two saddle points (Fig. 6),
with an energy barrier of 34.8 kcal mol-1.
Electronic and Electrochemical data
Electronic absorption spectra of compounds 24–28 showed an in-
tense broad band associated with a one-electron HOMO→LUMO
transition (Fig. 7), which was also calculated at the B3LYP/6-
31G(d) level (Table 4).
The cyclic voltammograms of 24–28 displayed both one ir-
reversible oxidation wave and one irreversible reduction wave,
regardless of the position and nature of the aryl groups linked
to C-2 and C-4 atoms of the heterocyclic moiety. The presence
Fig. 4 Transition structures SP21→31 and SP21→35 optimized in DMF at the
B3LYP/6-31G(d) level using the CPCM model and UAKS cavities.
Table 4 Physical properties of compounds 24–28
The location of a single saddle point for the reactions of 20,
21 and 23 shows that, regardless of the chosen approach, these
processes are concerted. The exception to this behavior was found
in the reaction of 22, for which two transition structures (SP122→32
and SP222→32) along with a dipolar intermediate (I22→32) could be
located for the energetically favored pathway a (Fig. 5) relative to
the concerted route b (DDGπ = 2.75 kcal mol-1).
This result suggests that strong electron-withdrawing groups
attached to the C-4 carbon atom of the heterocycle switch a
concerted 1,3-dipolar cycloaddition mechanism into a two-step
process, which evolves through a high-energy dipolar intermediate.
To confirm this point still further, we have also studied the
hypothetical reaction of the 4-nitrophenyl-substituted mu¨nchnone
(38) with carbon disulfide. In this case the theoretical calculations
Electronic data
max/nma
Electrochemical datad
Oxidation
Reduction
Comp.
l
l
max/nmb [f]c
E0/V
E0/V
24
25
26
27
28
535
436
452
448
443
669 [0.37]
620 [0.22]
529 [0.27]
519 [0.27]
517 [0.19]
0.71
0.71
0.68
0.62
0.72
-0.11
-0.10
-0.23
-0.20
-0.17
a In DMSO. b At B3LYP/6-31G(d) level (vacuum). c Oscillator strength.
d Potentials recorded vs. Ag/AgCl in 0.1 M trioctylmethylammonium
chloride (Adogen 464)/DMSO, using a glassy carbon working electrode
and a Pt counter electrode, at 20 ◦C, with a scan rate of 50 mV s-1
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Fig. 7 (a) Absortion spectra of 24 in DMSO. (b) Cyclic voltammogram
of 24 in 0.1 M trioctylmethylammonium chloride (Adogen 464)/DMSO,
v = 50 mV s-1.
Fig. 6 Transition structures and dipolar intermediate located for the
hypothetical reaction of 38 and CS2.
(pNA) and N,N-dimethylaminonitrostilbene (DANS) (Table 6)
whose experimental b(0) values have been determined to be 17 ¥
10-30 and 55 ¥ 10-30 esu, respectively.9
of a nitro group (compounds 24, 25, and 28) shifts slightly the
Eox values toward more anodic potentials and the Ered toward
less cathodic potentials than does a fluorine atom (compounds 26
and 27). This trend is mirrored by theoretical calculations, which
showed that the nitro group decreases both the EHOMO and ELUMO
values (Table 5).
The b(0)tot values collected in Table 6 reproduce reasonably well
the experimental results when using diffuse basis sets irrespective
of the level (HF or B3LYP) used for calculation. Therefore,
the theoretical calculation of the hyperpolarizabilities of the
1,3-thiazolium-5-thiolates 24–28 was carried out using the FF
method at the B3LYP/6-31+G(d) level, whereas both TDHF and
CPHF methods were conducted at the HF/6-31+G(d) level. Data
thus obtained (Table 7) showed that compound 24 had higher
hyperpolarizabilities than pNA and DANS, while mesoionics 25–
28 showed values higher than those reported for pNA but lower
than those of DANS.
Nonlinear Optical Properties
The second-order NLO properties of compounds 24–28 were
estimated by calculating their molecular hyperpolarizabilities
using the coupled perturbed Hartree–Fock (CPHF), the finite-field
(FF), and the time-dependent Hartree–Fock (TDHF) methods
implemented at the GAUSSIAN037 and GAMESS8 software
packages.
Furthermore, a closer analysis of the structure-property re-
lationship suggests that the hyperpolarizability acquires higher
values when the 1,3-thiazolium-5-thiolate system possesses an
To establish the appropriate level of theory, we performed a
preliminary calculation of the b(0)tot values for 4-nitroaniline
Table 6 b(0)tot values (¥ 10-30 esu) calculated for pNA and DANS through
the FF, TDHF, and CPHF methods
Table 5 Frontier orbital energies (eV) for compounds 24–28 calculated
at the B3LYP/6-31+G(d) level
Basis set
FF (B3LYP)
TDHF (HF)
CPHF (HF)
Compound
EHOMO
ELUMO
DEHOMO–LUMO
pNA
11.44
14.87
11.45
11.34
14.61
14.49
DANS pNA DANS
pNA
6.83
8.01
6.72
6.62
7.95
7.84
DANS
6-31G(d)
6-31+G(d)
6-311G(d)
6-311G(d,p)
6-311+G(d)
6-311+G(d,p)
210.61 16.44
260.94 15.72
216.67 15.97
217.19 15.69
259.31 15.84
259.73 15.54
203.53
196.88
207.94
208.50
206.65
207.12
69.15
78.38
70.61
70.87
78.66
78.93
24
25
26
27
28
-5.27
-5.20
-4.84
-4.83
-5.11
-3.37
-2.82
-2.24
-2.12
-2.83
1.90
2.38
2.60
2.71
2.28
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Table 7 b(0)tot and b(w)totavalues (in 10-30 esu) calculated for compounds
24–28 through the FFb, TDHFc, and CPHFc methods
a large nonlinear response to occur.10 However, the LUMO of
25 is very spread along the aryl groups attached to C-2 and C-4
(Fig. 8, right). Accordingly, when this material is coupled with a
strong electric field, its polarization will be reduced due to partial
cancellation of contributions directed toward the 4-nitrophenyl
and 4-methoxyphenyl groups. As a result, compound 25 does
not behave like a typical push-pull system in which both sides
(nucleophilic and electrophilic) are clearly differentiated.
The energy difference between HOMO and LUMO orbitals
should equally be checked in the search for molecular candidates
with nonlinear optical responses. It is generally accepted that there
is an inverse relationship between the first hyperpolarizability and
the HOMO–LUMO energy gap, thereby enabling the overlap of
orbitals and charge transfers from the donor to acceptor groups.
As inferred from Table 5, the HOMO–LUMO energy gaps (in eV)
calculated at the B3LYP/6-31+G(d) for compounds 24–28, are
similar to the value found for DANS (2.76 eV) and lower than
that of pNA (4.14 eV), two push-pull molecules which have good
nonlinear responses.
FF
TDHF
CPHF
Compound
b(0)tot
b(0)tot
b(w)tot
b(0)tot
b(w)tot
24
25
26
27
28
286.79
98.65
55.16
30.65
21.24
380.96
62.93
122.68
93.13
68.44
527.74
79.11
157.41
118.99
87.76
134.39
17.01
39.00
25.72
16.21
188.51
20.07
49.93
33.27
21.86
a
w = 1064 nm. b At B3LYP/6-31+G(d) level. c At HF/6-31+G(d) level.
electron-withdrawing group attached to C-2 and an electron-
releasing group on the C-5 atom; a structural situation encoun-
tered in compounds 24 and 26. The effect caused by a fluorine
atom is significantly lower than that produced by the nitro group
at the same position.
A further inspection of the frontier orbitals in compounds
24–28 reveals that their HOMOs are mainly located over the
C4 C5–S- heterocyclic framework while the corresponding
LUMO topologies are determined by the position and electronic
nature of aryl groups linked to the C-2 and C-4 atoms. Thus, the
LUMO of 24 largely concentrates on the 4-NO2C6H4-C2 group
and the pictures of both frontier orbitals (Fig. 8, left) make it
possible to imagine the charge transfer taking place between such
orbitals when the material is stimulated with a strong electric
field. This charge transfer, in which the C-2 carbon atom act
as the overlapping path of transition, will induce a change in
the polarization that is oriented in the direction of the electron-
attracting group (4-nitrophenyl); in fact a necessary condition for
Conclusions
Condensations of 1,3-oxazolium-5-olates with carbon disulfide
in refluxing DMF yield the corresponding thiazolium-5-thiolates
in moderate to good yields. Compounds 21–23 afford a single
product, while two regioisomeric substances are isolated in the
case of mu¨nchnone 20, and whose structures and particular crystal
packing have been elucidated by X-ray crystallography.
A mechanistic analysis conducted at the B3LYP/6-31G(d)
level suggests two possible reaction channels for the dipolar
cycloaddition to occur. Gas-phase calculations do satisfactorily
predict the experimental results, while solvent effects appear to be
important in the case of compound 21, for which only a correction
using the CPCM model explains the observed regioselectivity.
While most reactions follow a concerted pathway, the presence
of a strong electron-withdrawing group at the C-4 atom (e.g. 22)
triggers a stepwise reaction for which the dipolar intermediate and
saddle points have been determined.
Compounds 24–28 exhibit intense electronic absorptions in the
visible range and undergo irreversible redox processes. Compu-
tation of hyperpolarizabilities and orbital geometries evidences
that these push-pull 1,3-thiazolium-5-thiolates show promising
perspectives as a novel family of molecules with NLO responses.
Further experimental and theoretical studies in this context are
currently under way.
Experimental Section
N-methyl-C-phenyglycine hydrochloride (11)
Following the described procedure6 compound 11 was obtained
(62%); mp 231–233 ◦C, 1H NMR (400 MHz, DMSO-d6) 10.02 (sa,
2H), 7.59–3.34 (m, 5H), 5.07 (s, 1H), 2.38 (s, 3H).
C-(4-Methoxyphenyl)-N-methylglycine hydrochloride (12)
Following the described procedure6 compound 12 was obtained
(42%); mp 227–229 ◦C, 1H NMR (400 MHz, DMSO-d6) 10.07 (sa,
1H), 9.63 (sa, 1H), 7.45 (d, J 8.8 Hz, 2H), 7.01 (d, J 8.8 Hz, 2H),
4.99 (s, 1H), 3.76 (s, 3H)
Fig. 8 Calculated orbital topologies (B3LYP/6-31G(d) level) for the
HOMOs (below) and the LUMOs (above) of 24 (left) and 25 (right).
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C-(4-Fluorophenyl)-N-methylglycine hydrochloride (13)
2-(4-Nitrophenyl)-4-(4-methoxyphenyl)-3-methyl-1,3-oxazolium-
5-olate (20)
To a solution of 4-fluorobenzaldehyde (4.9 g, 39.1 mmol) in
methanol (8 mL) was added a solution of sodium cyanide (1.9 g,
39,4 mmol) and methyl ammonium chloride (3.0 g, 44,4 mmol) in
water (8 mL). The mixture was stirred at room temperature for 4
h, then diluted with water (20 mL), and extracted with benzene
(3 ¥ 7 mL). The organic phase was extracted again with HCl 6M
(3 ¥ 8 mL), the aqueous layer was separated and heated at reflux
for 10 h. The solution was cooled to room temperature, and the
resulting crystals were filtered and washed with CCl4 (3.7 g, 43%);
mp 198–199 ◦C; 1H NMR (400 MHz, DMSO-d6): 9.99 (sa, 2H),
7.61 (dd, J 8.0 Hz, J 5.2 Hz, 2H), 7.33 (t, J 8.8 Hz, 2H), 5.14 (s,
1H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 169.4, 163.2,
131.7, 127.9, 116.6, 62.5, 31.0; IR (KBr, cm-1) 3500, 2500, 1744,
836. Anal. Calcd for C9H11ClFNO2: C, 49.22; H, 5.05; N, 6.38.
Found: C, 49.49; H, 5.15; N, 6.46.
Following the descr◦ibed procedure6 compound 20 was obtained
(42%); mp 190–192 C, 1H NMR (400 MHz, DMSO-d6) 8.37 (d,
J 9.2 Hz, 2H), 7.98 (d, J 9.2 Hz, 2H), 7.47 (d, J 8.8 Hz, 2H), 7.04
(d, J 8.8 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H).
2-(4-Fluorophenyl)-4-(4-methoxyphenyl)-3-methyl-1,3-oxazolium-
5-olate (21)
A suspension of 18 (3 mmol) in acetic anhydride (5 mL) was
stirred under argon atmosphere at 55 ◦C. When the substrate was
completely dissolved the solvent was removed under vacuum. The
resulting solid was filtered off and washed with ethyl ether (37%);
◦
1
mp 134–135 C, H NMR (400 MHz, DMSO-d6) 7.84 (ddd, J
7.2 Hz, J 5.2 Hz, J 2.4 Hz, 2H), 7.47 (t, J 8.8 Hz, 2H), 7.43 (d, J
8.8 Hz, 2H), 7.01 (d, J 8.8 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6): 163.6, 160.0, 157.7, 141.5, 131.0,
121.9, 120.1, 117.0, 114.6, 95.4, 55.6, 36.5; IR (KBr, cm-1) 1689.
Anal. Calcd for C17H14FNO3: C, 68.22; H, 4.71; N, 4.68. Found:
C, 68.50; H, 4.78; N, 4.81.
C-(3-Nitrophenyl)-N-methylglycine hydrogen sulfate (15)
Following the procedure reported for the synthesis of C-(4-
nitrophenyl)-N-methylglycine hydrogen sulfate (14),6 compound
◦
1
15 was obtained (78%); mp 163–165 C; H NMR (400 MHz,
DMSO-d6) 8.43 (s, 1H), 8.33 (d, J 6.0 Hz, 1H), 7.94 (d, J 6.8 Hz,
1H), 7.81 (t, J 7.6 Hz, 1H), 5.33 (s, 1H), 2.51 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) 169.0, 148.5, 135.9, 133.7, 131.4, 125.2,
124.1, 62.8, 31.6.
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-methyl-1,3-oxazolium-
5-olate (22)
To a solution of 12 (3.0 g, 12.9 mmol) and NaOH (1.61 g,
40.3 mmol) in water (24 mL) was added dropwise 4-fluorobenzoyl
chloride (1.98 g, 12.5 mmol). The reaction mixture was stirred for
4 h, and then HCl 12M (3.5 mL) was added. The resulting oil was
extracted with CH2Cl2 and the organic phase dried with Na2SO4.
Then, the solvent was evaporated and the residue treated with
acetic anhydride under argon, and stirred at 55 ◦C until it was
completely dissolved. The solvent was evaporated and the solid
filtered off and washed with ethyl ether (20%); mp 158–159 ◦C; 1H
NMR (400 MHz, DMSO-d6) 7.75 (d, J 8.8 Hz, 2H), 7.54 (dd, J
8.8 Hz, J 2.8 Hz, 2H), 7.24 (t, J 8.8 Hz 2H), 7.18 (d, J 8.8 Hz,
2H), 3.87 (s, 3H), 3.34 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
161.8, 159.8, 144.0, 130.5, 128.4, 128.3, 126.6, 126.6, 115.9, 115.7,
115.4, 115.3, 94.1, 56.1, 36.8; IR (KBr, cm-1) 1685. Anal. Calcd
for C17H14FNO3: C, 68.22; H, 4.71; N, 4.68. Found: C, 67.90; H,
4.88; N, 4.72.
C-(4-Methoxyphenyl)-N-methyl-N-(4-nitrobenzoyl)glycine (16)
Following the described procedure,6 compound 16 was obtained
(42%); mp 148–149 ◦C; 1H NMR (400 MHz, DMSO-d6) 8.22–6.89
(m, 8H), 5.96 (s, 1H), 3.68 (s, 3H), 2.50 (s, 3H).
C-(4-Fluorophenyl)-N-(4-methoxybenzoyl)-N-methylglycine (18)
To a solution of 13 (3.0 g, 13.7 mmol) and NaOH (1.6 g, 40.3 mmol)
in water (24 mL) was added dropwise 4-methoxybenzoyl chloride
(2.14 g, 12.5 mmol). The reaction mixture was stirred for 4 h,
and then HCl 12M (3.5 mL) was added. The result◦ing solid was
filtered off and washed with water (76%); mp 57–58 C; 1H NMR
(400 MHz, DMSO-d6) 7.42–6.99 (m, 8H), 5.99 (sa, 1H), 3.80 (s,
3H), 2.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 171.5, 167.5,
162.3, 160.9, 131.8, 131.5, 129.7, 128.1, 123.4, 116.0, 114.2, 61.1,
55.7, 35.8; IR (KBr, cm-1) 3500, 2500, 1729, 1688. Anal. Calcd for
C17H16FNO4: C, 64.35; H, 5.08; N, 4.41. Found: C, 64.51; H, 5.35;
N, 4.53.
2-(4-Methoxyphenyl)-3-methyl-4-(3-nitrophenyl)-1,3-oxazolium-5-
olate (23)
Following the procedure reported for the synthesis of 2-
(4-methoxyphenyl)-3-methyl-4-(4-nitrophenyl)-1,3-oxazolium-5-
olate,6 compound 23 was similary obtained (49%), 1H NMR
(400 MHz, DMSO-d6) 8.42 (t, J 2.0 Hz, 1H), 7.95 (d, J 8.0 Hz,
1H), 7.91 (dd, J 8.0 Hz, J 1.6 Hz, 1H), 7.80 (d, J 8.8 Hz, 2H), 7.65
(t, J 8.0 Hz, 1H), 7.20 (d, J 9.2, 1H), 3.93 (s, 3H), 3.88 (s, 3H).
N-(4-Methoxybenzoyl)-N-methyl-C-(3-nitrophenyl)glycine (19)
Following the procedure reported for the synthesis of N-(4-
General Procedure for the Preparation of
1,3-Thiazolium-5-thiolate Systems
methoxybenzoyl)-N-methyl-C-(4-nitrophenyl)glycine,6
com-
pound 19 was obtained (36%). 1H NMR (400 MHz,
DMSO-d6) 8.42 (s, 1H), 8.33 (d, J 8.4 Hz, 1H), 8.03 (d,
J 8.4 Hz, 1H), 7.82 (t, J 8.0 Hz, 1H), 7.55 (d, J 8.4 Hz,
2H), 7.07 (d, J 8.4 Hz, 2H), 6.25 (sa, 1H), 3.88 (s, 3H),
2.84 (s, 3H).
A mixture of the mu¨nchnone (20–23) (1 mmol) and CS2 (1 mL)
in DMF (3 mL) was heated at reflux. The reaction mixture was
monitored by TLC (benzene–acetonitrile 2 : 1) until the complete
disappearance of the parent mesoionic ring (1–4 h). Then, it was
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purified by flash chromatography (benzene–acetonitrile gradient
elution from 5 : 1 to 1 : 5).
Acknowledgements
The Spanish Ministry of Education and Science (CTQ2007-
66641/BQU) and FEDER, and the Junta de Extremadura
(PRI07-A016) have supported financially this investigation. Spe-
cial thanks go to Ara Cantillo for her bibliographical assistance.
We are also grateful to the Ministry of Education and Science for
a grant to D.C.
4-(4-Methoxyphenyl)-3-methyl-2-(4-nitrophenyl)-1,3-thiazo-
lium-5-thiolate (24). 34%; mp 213–214 ◦C; 1H NMR (400 MHz,
DMSO-d6) 8.41 (d, J 8.8 Hz, 2H), 8.02 (d, J 8.8 Hz, 2H), 7.55 (d,
J 8.8 Hz, 2H), 7.10 (d, J 8.8 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H);
13C NMR (100 MHz, DMSO-d6) 162.0, 160.0, 149.1, 148.8, 141.7,
133.4, 133.1, 131.4, 128.8, 124.8, 122.7, 114.4, 55.7, 41.7; IR (KBr,
cm-1) 1607, 1593, 1523, 1351. Anal. Calcd for C17H14N2O3S2: C,
56.96; H, 3.94; N, 7.82; S, 17.89. Found: C, 56.67; H, 3.87; N, 8.04;
S, 18.01.
References
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2-(4-Methoxyphenyl)-3-methyl-4-(4-nitrophenyl)-1,3-thiazo-
lium-5-thiolate (25). 43%; mp 216–217 ◦C; 1H NMR (400 MHz,
DMSO-d6) 8.37 (d, J 8.8 Hz, 2H), 8.01 (d, J 8.8 Hz, 2H), 7.73 (d,
J 8.8 Hz, 2H), 7.20 (d, J 8.8 Hz, 2H), 3.87 (s, 3H), 3.67 (s, 3H);
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132.6, 132.0, 128.8, 123.8, 119.2, 115.4, 56.2, 41.9; IR (KBr, cm-1)
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H, 3.94; N, 7.82; S, 17.89. Found: C, 56.68; H, 3.95; N, 8.02; S,
18.13.
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2-(4-Fluorophenyl)-4-(4-methoxyphen◦yl)-3-methyl-1,3-thiazo-
lium -5-thiolate (26). 61%; mp 244–245 C; 1H NMR (400 MHz,
DMSO-d6) 7.81 (ddd, J 8.8 Hz, J 2.0 Hz, J 1.2 Hz, 2H), 7.53
(d, J 8.4 Hz, 2H), 7.48 (t, J 8.4 Hz, 2H), 7.09 (d, J 8.4 Hz, 2H),
3.83 (s, 3H) 3.57 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 162.8,
159.8, 159.7, 152.0, 140.2, 133.0, 132.8, 132.7, 124.1, 123.1, 117.2,
117.0, 114.3, 55.7, 41.2; IR (KBr, cm-1) 1606, 1597. Anal. calcd
for C17H14FNOS2: C, 61.61; H, 4.26; N, 4.23; S, 19.35. Found: C,
60.89; H, 3.98; N, 4.49; S, 19.50.
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4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-3-methyl-1,3-thiazo-
lium-5-thiolate (27). This compound crystallized from the reac-
tion medium after heating for 1h. The solid was filtered and washed
◦
1
with diethyl ether (98%); mp 204–205 C; H NMR (400 MHz,
DMSO-d6) 7.69 (m, 4H), 7.36 (t, J 8.8 Hz, 2H), 7.18 (d, J 8.8 Hz,
2H), 3.86 (s, 3H), 3.60 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) 162.4, 162.1, 159.1, 154.6, 138.8, 134.0, 131.8, 127.6, 119.5,
115.8, 115.4, 56.1, 41.4; IR (KBr, cm-1) 1604, 1498. Anal. calcd
for C17H14FNOS2: C, 61.61; H, 4.26; N, 4.23; S, 19.35. Found: C,
61.33; H, 3.94; N, 4.36; S, 19.42.
2-(4-Methoxyphenyl)-3-methyl-4-(3-nitrophenyl)-1,3-thiazo-
lium-5-thiolate (28). 36%; mp 192–193 ◦C; 1H NMR (400 MHz,
DMSO-d6) 8.61 (s, 1H), 8.27 (dd, J 8.0 Hz, J 2.0 Hz 1H), 8.11 (d,
J 7.6 Hz, 1H), 8.01 (t, J 8.0 Hz, 1H), 7.72 (d, J 8.8 Hz, 2H), 7.18
(d, J 8.8 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) 162.3, 159.9, 156.0, 148.1, 138.2, 137.5, 132.6, 131.9,
130.3, 126.5, 123.5, 119.2, 115.4, 56.1, 41.7. IR (n, KBr): 1602,
1568, 1525, 1346. Anal. calcd for C17H14N2O3S2: C, 56.96; H,
3.94; N, 7.82; S, 17.89. Found: C, 56.92; H, 3.83; N, 7.94; S,
18.20.
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5374 | Org. Biomol. Chem., 2010, 8, 5367–5374
This journal is
The Royal Society of Chemistry 2010
©