Non-dipolar behavior of mesoionic heterocycles: Synthesis and tautomerism of 2-alkylthioisomuenchnones

Article abstract of DOI:10.1002/ejoc.200400049

This paper describes a general preparation of a series of 1,3-thiazolium-4-olates, each bearing an alkyl group at C-2, through reactions between N-arylthiocarboxamides and α-haloacyl halides. Unlike the 2-aryl-substituted derivatives, such alkylated mesoionic compounds exist in equilibria with their non-dipolar tautomers, the corresponding 2-alkylidene-1,3-thiazolidin-4-ones. The unambiguous characterization of such tautomers and their relative stabilities have now been assessed by spectroscopic and computational studies. The presence of o,o′-disubstituted aryl groups at N-3 of the heterocyclic ring slows down free rotation around the N-Ar bond, thus opening access to a promising class of non-biaryl atropisomers. Finally, treatment of N-arylthioformamides with α-haloacyl halides gives rise to N-acylthioformamides instead of the corresponding mesoionic species. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400049

FULL PAPER
Non-Dipolar Behavior of Mesoionic Heterocycles: Synthesis and Tautomerism
of 2-Alkylthioisomünchnones
[a]
[a]
[a]
[a]
[a]
´
´
´
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Martın Avalos, Reyes Babiano, Pedro Cintas, Jesus Dıaz, Jose L. Jimenez,
[a]
[a]
´
Ignacio Lopez, and Juan C. Palacios*
Keywords: Mesoionic heterocycles / Non-biaryl atropisomers / Tautomerism / Thiazolidinones
This paper describes a general preparation of a series of 1,3-
thiazolium-4-olates, each bearing an alkyl group at C-2,
through reactions between N-arylthiocarboxamides and α-
haloacyl halides. Unlike the 2-aryl-substituted derivatives,
such alkylated mesoionic compounds exist in equilibria with
their non-dipolar tautomers, the corresponding 2-alkylidene-
1,3-thiazolidin-4-ones. The unambiguous characterization of
such tautomers and their relative stabilities have now been
assessed by spectroscopic and computational studies. The
presence of o,oЈ-disubstituted aryl groups at N-3 of the het-
erocyclic ring slows down free rotation around the N−Ar
bond, thus opening access to a promising class of non-biaryl
atropisomers. Finally, treatment of N-arylthioformamides
with α-haloacyl halides gives rise to N-acylthioformamides
instead of the corresponding mesoionic species.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The inherent importance of mesoionic compounds, five-
membered aromatic heterocycles that cannot be represented
by Lewis structures not involving charge separation,[1] de-
rives from their behavior as masked dipoles, and they are
therefore amenable and versatile substrates for [3ϩ2] cyclo-
additions.[2] A well-established family of such heterocycles,
anhydro-4-hydroxy-1,3-thiazolium hydroxides (colloquially
referred to as thioisomünchnones), containing thiocarbonyl
ylide dipole components, have proven to be extremely useful
synthons in our hands for almost two decades. Serendipity
played its role when it was observed that the presence of an
amino substituent at C-2 drove their subsequent scission
routes.[3Ϫ6] Thus, by starting from 2-aminothioisomünch-
nones, 2,3-dihydrothiophenes,[3] 1,2,3-triazin-4-ones,[4] β-
lactams,[5,6] and thiiranes[5,6] could be obtained, whereas the
classical 2-aryl-substituted thioisomünchnones gave bicyclic
compounds,[7] 2-pyridones,[7,8] thiophenes,[8] and N-acyl en-
amines,[9] respectively, with the same range of di-
polarophiles.
Scheme 1
aryl-substituted ketones (Scheme 1: compound 2; R ϭ
alkyl, R1 ϭ H), the aromatic counterparts gave α-aryl-sub-
stituted β-diketones (2; R ϭ aryl, R1 ϭ COR).
These results provide the first evidence of differential re-
activity of the tautomeric species of a mesoionic heterocy-
cle. It is fair to say that the equilibrium between a 2-methyl-
thioisomünchnone derivative and its tautomer, the 2-meth-
ylenethiazolidin-4-one, had been detected previously by
Baudy et al. through IR and NMR monitoring.[11] More-
over, valence tautomers in mesoionic chemistry have long
been sought. In the early 1970s, it was suggested that
münchnones (anhydro-5-hydroxy-1,3-oxazolium hydrox-
ides) react with imines to yield β-lactams via the corre-
sponding ketene tautomers.[12] Ketenes have never been de-
tected, however, and formation of β-lactams can now be
interpreted as a classical [3ϩ2] cycloaddition.[5] Likewise,
isomünchnones (anhydro-4-hydroxy-1,3-oxazolium hydrox-
ides) were thought to exist in equilibria with their tautom-
eric oxazol-4(5H)-ones, which would react with acetylenes.
The resulting cycloadducts would then undergo retro-
DielsϪAlder reactions with loss of isocyanic acid to give
furans.[13] An alternative DielsϪAlder reaction via an enol
tautomer was equally suggested.[14]
Recently, it was also shown that 3,5-diphenyl-2-methyl-
thioisomünchnone, in addition to its dipolar character, also
behaved as a mild nucleophile towards reactive electro-
philes, thereby affording a novel carbonϪcarbon bond-for-
ming reaction.[10] While aliphatic acid chlorides yielded α-
[a]
´
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Departamento de Quımica Organica, Facultad de Ciencias,
Universidad de Extremadura,
Avenida de Elvas s/n, 06071 Badajoz, Spain
Fax: (internat.) ϩ 34-924-271-149
E-mail: palacios@unex.es
Eur. J. Org. Chem. 2004, 2805Ϫ2811
DOI: 10.1002/ejoc.200400049
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2805

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M. Avalos, R. Babiano, P. Cintas, J. Dıaz, J. L. Jimenez, I. Lopez, J. C. Palacios
FULL PAPER
In this paper we introduce a systematic route to 2-alkyl-
Accordingly, compounds 8Ϫ12 were easily prepared by
thioisomünchnones. Their tautomeric equilibria have also treatment of thioamides 3Ϫ7 with 2-chloro-2-phenylacetyl
been explored by spectroscopic and computational (DFT) chloride in CH2Cl2/Et3N. Under such conditions, both the
methods. In addition, several aryl substituents have been alkylation and the subsequent cyclodehydration occur in a
incorporated onto the heterocyclic nitrogen atom. This one-pot procedure (Scheme 3). With the sole exception of
structural feature increases the steric barrier to rotation and the commercially available thioacetanilide (3), thioamides
can be utilized to generate a novel class of non-biaryl atrop- were obtained from the corresponding amides by ultra-
isomers with axial asymmetry. Finally, the reactions be- sound-induced O/S exchange with P4S10 in THF solu-
tween N-arylthioformamides and 2-chloro-2-phenylacetyl tion.[17] Similarly, the amides and formamides employed as
chloride have also been explored in an attempt to obtain raw materials in this study could easily be generated by
unsubstituted thioisomünchnones. An unexpected route to acylation of amines with acetic anhydride or formic acid
unsymmetrical N-acylthioformamides was found neverthe- at reflux.[18]
less.
Tautomeric and Rotational Equilibria
Despite the inherent instability of most thioisomünch-
Results and Discussion
nones in solution, they can be isolated by precipitation or
crystallization at room temperature after conventional
workup. Compounds 8Ϫ12 show NMR signals attributable
to both tautomers. Fortunately, careful recrystallization or
crystallization at lower temperatures allowed us to obtain
samples of the pure tautomers 8b, 10b, 11b, and 12b,
thereby facilitating their spectroscopic characterization.
In CDCl3 solution, such thiazolidinones slowly equilibr-
ate with their tautomeric thioisomünchnones. Moreover, all
attempts to purify the mesoionic structures by chromato-
graphic methods were unsuccessful, and tautomeric mix-
tures were invariably obtained. Table 1 shows a series of
distinctive proton resonances for both sets of tautomers. In
the thiazolidinones the heterocyclic proton at C-5 appears
as singlet at δ ϭ 5.28Ϫ5.19 ppm. The methylidene deriva-
tives 8b, 11b, and 12b show olefinic protons as doublets
with coupling (J ഠ 3 Hz) consistent with their geminal dis-
positions. The upfield resonances have been attributed to
protons in cis dispositions relative to the sulfur atom.[19] In
the ethylidene and 2-propylidene derivatives (9b and 10b,
respectively) these protons appear as singlets at δ ϭ
4.65 ppm. The (Z) geometries around the double bonds
have also been tentatively assigned on the basis of previous
results with 2b (R ϭ CH3, R1 ϭ H), for which the crystallo-
graphic structure is known.[10] In stark contrast, no proton
is directly linked to the mesoionic structures, although the
alkyl fragments at C-2 have a diagnostic value, appearing
Retrosynthetic Analysis and Preparation
Baudy and co-workers were able to prepare a few 2-meth-
ylthioisomünchnones through the reactions between
thioamides and gem-dicyano epoxides.[11,15] Unfortunately,
the latter substances are not readily available, and we there-
fore chose the condensation of thioamides with the com-
mercially available α-haloacyl halides, a strategy that has
proven to be a convenient route for the construction of 2-
aryl-[16] and 2-(dialkylamino)thioisomünchnones.[3Ϫ6]
A
facile retrosynthetic analysis shows that the sulfur and ni-
trogen atoms, as well as the substituent at C-2 of the
thioisomünchnone, are provided by the starting thioamide,
whereas the α-haloacyl halide or dicyano epoxide serve as
synthons for the rest of the heterocycle (Scheme 2).
Scheme 2
Scheme 3
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Non-Dipolar Behavior of Mesoionic Heterocycles
FULL PAPER
Table 1. Characteristic proton chemical shifts of mesoionic (8aϪ12a) and thiazolidinone (8bϪ12b) structures
Mesoionics (a)
Thiazolidinones (b)
C-5ϪH
Compd.
C-2ϪCHx
R1, R2
b/a ratio
Compd.
C-2ϭCHx
R1, R2
8a
2.46, s, 3 H
3.8:1.0
8b
4.39, d, J ϭ 3.1 Hz, 1 H
4.27, d, J ϭ 3.1 Hz, 1 H
4.67, q, J ϭ 6.8 Hz, 1 H
4.64, t, J ϭ 7.27 Hz, 1 H
4.32, d, J ϭ 2.8 Hz, 1 H
4.05, d, J ϭ 2.8 Hz, 1 H
4.33, d, J ϭ 2.9 Hz, 1 H
4.04, d, J ϭ 2.9 Hz, 1 H
5.22, s, 1 H
9a
10a
11a
3.07, q, 2 H
0.98, t, 2 H
2.34, s, 3 H
2.3:1.0
1.0:1.0
4.3:1.0
9b
10b
11b
5.20, s, 1 H
5.19, s, 1 H
5.26, s, 1 H
2.10, s, 6 H
2.18, s, 3 H
2.12, s, 3 H
2.11, s, 3 H
2.50, dq, 2 H
1.21, t, 3 H
2.17, s, 3 H
2.44, q, 2 H
1.07, t, 3 H
12a
2.36, s, 3 H
2.08, s, 3 H
2.53Ϫ2.40, q, 2 H
1.25Ϫ1.16, t, 3 H
cis-12b
5.28, s, 1 H
trans-12b
4.32, d, J ϭ 2.9 Hz, 1 H
4.04, d, J ϭ 2.9 Hz, 1 H
5.26, s, 1 H
as singlets at δ ഠ 2.4 ppm in 8a, 11a, and 12a. In 9a and 10a stereomer, in which the signal for ArCH2CH3 is most de-
those alkyl groups exhibit the expected coupling patterns at shielded. Unfortunately, no suitable crystals of 12b could be
δ ഠ 3.1 ppm.
obtained for single-crystal diffraction analysis. Remarkably,
In compounds 11 and 12, the ortho substituents on the this cis/trans equilibration proceeds very slowly (several
phenyl ring also cause hindrance to rotation around the days by NMR monitoring) and only occurs when the con-
NϪAr bond. The presence of a stereogenic center at C-5 centration of the mesoionic structure 12a is close to its equi-
makes the ortho-methyl groups of 11b diastereotopic, and librium value. This fact suggests that protonation of 12a at
so they resonate at clearly differentiated chemical shifts C-5 on its upper or lower faces takes place more rapidly
(δ ϭ 2.18 and 2.12 ppm). Furthermore, compound 12b ex- than rotation around the NϪAr bond of the thiazolidinone
hibits an element of axial chirality, due to the existence of component (Scheme 4). This slow interconversion might be
chemically different ortho substituents (Me, Et). In fact, the exploitable for the preparation of a novel class of molecular
tautomeric equilibrium in 12 appears to be particularly switches,[20] which will be studied in future work.
complex. A freshly prepared solution of 12 contains a cis/
Tautomeric equilibria also manifest themselves in 13C
trans mixture (with respect to the relative disposition of the NMR measurements (Table 2). The C-5 and C-4 atoms of
ethyl group and the phenyl substituent at C-5) of the tau- the thiazolidinone ring resonate at δ ഠ 51 and 171 ppm,
tomer 12b in an approximate ratio of 3:1 (in 1H NMR inte- respectively. The latter is more shielded in mesoionic struc-
gration; see Table 1 data), and evolves into a tautomeric tures (δ ഠ 160 ppm). Moreover, C-4 may not be observable
mixture containing 12a (12b/12a ഠ 4.3:1). At equilibrium, in mesoionics under these experimental conditions. The ex-
12b consists of a 1:1 cis/trans mixture. We have tentatively ocyclic carbon at C-2 exhibits resonances typical of olefinic
assigned a cis disposition to the most populated dia- carbon atoms in thiazolidinones and also those character-
Scheme 4
Table 2. 13C NMR chemical shifts of mesoionic (8aϪ12a) and thiazolidinone (8bϪ12b) tautomers
Mesoionics (a)
C-2ϪCHx
Thiazolidinones (b)
Compd.
C-4
Compd.
C-2ϭCHx
C-4
C-5
8a
9a
10a
11a
12a
17.5
45.6
159.9
8b
86.1
96.9
104.4
85.1
171.5
171.3
171.4
170.7
51.4
51.0
51.0
51.5
51.4
9b
10b
11b
12b (cis/trans)
16.8
ca. 17
158.9
ca. 160
85.4
171.0, 170.9
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FULL PAPER
Scheme 5. Computationally generated (B3LYP/6-31G* level) tautomeric and rotameric structures for compound 12
istic of alkyl groups in mesoionic rings. Undergoing cis/ the pronounced nucleophilicity of the sulfur atom, the for-
trans isomerism, compound 12b also exhibits two close res- mation of N-acylated compounds such as 16 or 17 has now
onances for the C-4 atom (δ ϭ 171.0 and 170.9 ppm).
been observed. Nevertheless, S-alkylated intermediates
Lastly, computational results (at PM3 and B3LYP/6- (such as the alternative structures 20 or 21) have sometimes
31G* levels of theory)[21] shed light on the tautomeric struc- been isolated by treatment of thioamides with α-haloacyl
tures. Scheme 5 depicts the situation for compound 12, al- halides.[16a]
though similar behavior, excluding rotational isomerism, is
also observed for 8Ϫ11. The N-aryl moiety is invariably or-
Table 3. Energy and energy differences for the reaction of 13 and
thogonal to the heterocyclic ring. The phenyl group at C-5
15 at the B3LYP/6-31G* level
adopts a coplanar arrangement in mesoionics 8aϪ12a.
In full agreement with the experimentally obtained re-
sults, the tautomeric structures show small energy differ-
ences, thiazolidinones being slightly favored by only 0.01
kcal/mol. A similarly small difference was also observed for
the cis and trans rotamers of 12b, the former moreover be-
ing more stable at both levels, thus accounting for the pre-
vious assignment.
Compd.
13 ϩ 15
16 ϩ HCl 18 ϩ 2 HCl 20 ϩ HCl
E [kcal/mol] Ϫ1321920.9 Ϫ1321914.9 Ϫ1321905.3 Ϫ1321911.1
∆E [kcal/mol] 6.0 15.6 9.8
Table 3 summarizes the energy profile of the reactions
In a final stage, the preparation of derivatives unsubsti- outlined in Scheme 6 for compound 13. At the B3LYP/6-
tuted at C-2 was also envisaged. However, thioformamides 31G* level the three reactions are clearly endothermic, al-
13 and 14 did not afford the corresponding mesoionics 18 though the formation of 16 (6.0 kcal/mol) is more favorable
and 19 upon treatment with 2-chloro-2-phenylacetyl chlo- than those leading to 18 (15.6 kcal/mol) or 20 (9.8 kcal/
ride, either in the presence or in the absence of Et3N. In- mol).
stead, the N-acylthioformamides 16 and 17 could be iso-
The structures of 16 and 17 are consistent with the obser-
lated (Scheme 6). All attempts to promote the cyclization of vation of characteristic carbon resonances at δ ϭ 194.1 (Cϭ
16 and 17, even under Ohta’s conditions with α-halo ac- S), 167.4 (CϭO), and 59.9 (CHCl) ppm. The thioformyl
ids,[22] were unsuccessful and resulted in complex, yellowish and α-carbonyl protons appear as singlets at δ ϭ 10.86 and
mixtures. This negative result paradoxically has one striking 5.18 ppm, respectively. The molecular peak [Mϩ] for 16 and
aspect, as N-acylthioformamide structures have never been [Mϩ ϩ 1] for 16 and 17 could also be detected by mass
isolated in the course of these preparative reactions. Despite spectrometry techniques. As would be expected, the exist-
Scheme 6
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Non-Dipolar Behavior of Mesoionic Heterocycles
FULL PAPER
ence of a stereogenic center and the restricted rotation Experimental Section
around the NϪAr bond give two signals for the dia-
General Remarks: Melting points (m.p.) were determined with a
capillary apparatus and are uncorrected. TLC was conducted on
0.25 mm silica gel plates (Merck F254), whereas flash chromatogra-
phy was employed for preparative separations. IR spectra (KBr pel-
lets) were recorded with a Midac FT-IR spectrophotometer. 1H
and 13C NMR spectra (in CDCl3 solution) were recorded at
400 MHz and 100 MHz, respectively, with a Bruker AM 400 spec-
trometer; the chemical shifts are given in ppm relative to TMS as
internal standard and coupling constants in Hz. Elemental analyses
were performed with a Leco CHNS 932 instrument. Mass spectra
stereotopic ortho-methyl groups of compound 16 in both
1
the H and the 13C NMR spectra. The situation is more
complicated for 17, as the chiral axis and the stereogenic
center cause the existence of a diastereomeric pair, and so
two signal sets can be observed in its NMR spectra (17a/
17b ϭ 4.7:1.0). The anisotropic effect is especially notice-
able for the CH3ϪCH2ϪAr protons, which resonate at δ ϭ
1.26 and 0.79 ppm, respectively.
In order to assign structures for compounds 17a and 17b,
we performed a preliminary conformational analysis, at the
PM3 level, by rotating the NϪAr bond. The most stable
rotamers obtained by this procedure were further optimized
at this level by rotations around the COϪCHCl bond and,
finally, such minima were fully optimized without any con-
straints at the B3LYP/6-31G* level of theory.
´
were recorded at the Universidad de Cordoba, Spain. Compu-
tational calculations were performed at the PM3 and B3LYP/6-
31G* levels of theory with the Gaussian 98 package.[21]
General Procedure for the Synthesis of 2-Alkyl-3-aryl-5-phenyl-1,3-
thiazolium-4-olates 8a؊12a and 2-Alkylidene-3-aryl-5-phenyl-1,3-
thiazolidin-4-ones 8b؊12b: A solution of 2-chloro-2-phenylacetyl
chloride (6.61 mmol) in CH2Cl2 (5 mL) and then a solution of
Et3N (13.2 mmol) in CH2Cl2 (5 mL) were added dropwise and suc-
cessively to a magnetically stirred solution of thioamide 3Ϫ7
(6.61 mmol) in CH2Cl2 (20 mL). After 15 min at room temperature,
the reaction mixture was washed repeatedly with brine, dried with
anhydrous MgSO4, and concentrated to a quarter of its initial vol-
ume.
Structure 17a (Scheme 7) was found to be more stable by
ca. 3 kcal/mol. The downfield resonance at δ ϭ 1.26 ppm
for the CH3ϪCH2ϪAr moiety of 17a could now be attri-
buted to the deshielding effect caused by the carbonyl group
of the amide function.[18]
2-Methyl-3,5-diphenyl-1,3-thiazolium-4-olate (8a) and 2-Methylid-
ene-3,5-diphenyl-1,3-thiazolidin-4-one (8b): Application of the above
procedure to thioamide 3 gave a solution, which was kept at Ϫ20
°C, yielding yellow crystals of 8 (4.6 mmol, 70%); m.p. 180 °C
(dec.). IR (KBr): ν˜max ϭ 1705, 1628 cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 7.89 (d, J ϭ 7.3 Hz, 1 H, ArH, 8a), 7.53Ϫ7.09 (m,
ArH, 9 H of 8a and 10 H of 8b), 5.22 (s, 1 H, 5-H, 8b), 4.39 (d,
J ϭ 3.1 Hz, 1 H, C-2ϭCHaHb, 8b), 4.27 (d, J ϭ 3.1 Hz, 1 H, C-
2ϭCHaHb, 8b), 2.46 (s, 3 H, CH3, 8a) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 171.6 (C-4, 8b), 159.9 (C-4, 8a), 149.8, 141.4, 137.3,
135.8, 135.3, 133.4, 129.8, 129.8, 129.7, 129.0, 128.9, 128.7, 128.6,
128.5, 128.2, 128.1, 127.8, 127.0, 124.6, 123.6 (ArC, ArN, 8a, 8b),
86.1 (C-2ϭCH2, 8b), 51.4 (C-5, 8b), 17.5 (CH3, 8a) ppm.
C16H13NOS (267.07): calcd. C 71.88, H 4.90, N 5.24, S 11.99;
found C 72.21, H 5.44, N 5.09, S 11.75.
2-Ethyl-3,5-diphenyl-1,3-thiazolium-4-olate (9a) and 2-Ethylidene-
3,5-diphenyl-1,3-thiazolidin-4-one (9b): Starting from 4, the final
solution was concentrated to dryness and the resulting residue was
crystallized from diethyl ether (4.9 mmol, 75%); m.p. 131.2 °C
(dec.). IR (KBr): ν˜max ϭ 1702, 1646 cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 7.50Ϫ7.25 (m, 10 H, ArH, 9a, 9b), 5.20 (s, 1 H, C-
5ϪH, 9b), 4.67 (q, J ϭ 6.9 Hz, 1 H, C-2ϭCH, 9b), 3.07 (q, J ϭ
7.3 Hz, 2 H, CH3CH2, 9a), 1.65 (d, J ϭ 6.8 Hz, 3 H, CH3CH, 9b),
1.38 (t, J ϭ 7.3 Hz, 3 H, CH3CH2, 9a) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 171.3 (C-4, 9b), 137.7, 135.8, 135.2, 129.6, 128.9,
128.8, 128.3, 128.0 (ArC, ArN, 9a, 9b), 96.9 (C-2ϭCH, 9b), 51.0
(C-5, 9b), 45.6 (CH3CH2, 9a), 12.6 (CH3, 9b), 9.9 (CH3CH2, 9a)
ppm. C17H15NOS (281.09): calcd. C 72.57, H 5.37, N 4.98, S 11.40;
found C 72.40, H 5.34, N 4.92, S 11.9.
Scheme 7. Structures and optimized geometries for 17a and 17b at
the PM3//B3LYP-6-31G*
Conclusion
To sum up, we have developed a general strategy for the
preparation of 2-alkylthioisomünchnones, which exist as
tautomeric mixtures in equilibrium. Some derivatives also
exhibit atropisomeric behavior that has been studied by
spectroscopic and theoretical methods. Further synthetic
studies aimed at selectively trapping the thiazolidinone tau-
tomers, as well as the preparation of stable atropisomers,
are under way.
3,5-Diphenyl-2-propyl-1,3-thiazolium-4-olate (10a) and 3,5-Di-
phenyl-2-propylidene-1,3-thiazolidin-4-one (10b): Starting from 5,
the final solution was concentrated and the resulting residue was
crystallized from diethyl ether to give yellow crystals of 10b
(4.6 mmol, 70%); m.p. 107.7 °C. IR (KBr): ν˜max ϭ 1701, 1664, 1645
cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 7.51Ϫ7.25 (m, 10 H,
.
ArH), 5.19 (s, 1 H, C-5ϪH), 4.64 (t, J ϭ 7.3 Hz, 1 H, C-2ϭCH),
Eur. J. Org. Chem. 2004, 2805Ϫ2811
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FULL PAPER
2.05 (m, 2 H, JCH3ϪCH2 ϭ 7.5, JCH2ϪCH ϭ 14.9 Hz, CH3CH2), 0.97
ArCH3, 12a, cis-12b, trans-12b), 14.4, 14.2, 13.8 (ArCH2CH3, 12a,
(t, J ϭ 7.4 Hz, 3 H, CH3CH2) ppm. 13C NMR (100 MHz, CDCl3): cis-12b, trans-12b) ppm. C19H19NOS (309.12): calcd. C 73.75, H
δ ϭ 171.4 (C-4), 137.7, 135.9, 134.2, 129.6, 128.9, 128.8, 128.3,
128.1 (ArC, ArN, C2), 104.4 (C-2ϭCH), 51.0 (C-5), 21.2
(CH2CH3), 14.1 (CH2CH3) ppm. C18H17NOS (295.10): calcd. C
73.19, H 5.80, N 4.74, S 10.86; found C 72.70, H 5.94, N 4.72, S
10.97. A solution of 10b in CDCl3, if left at room temp. for several
6.19, N 4.53, S 10.36; found C 73.62, H 6.30, N 4.23, S 10.52.
General Procedure for the Preparation of N-Thioformyl-N-acetanil-
ides 16؊17:
A solution of 2-chloro-2-phenylacetyl chloride
(6.61 mmol) in CH2Cl2 (5 mL) was added dropwise, with magnetic
stirring, to a solution of thioformamide 13 or 14 (6.61 mmol) in
CH2Cl2 (20 mL), followed after 25 min by a second solution of
Et3N (13.2 mmol) in CH2Cl2 (5 mL). The organic layer was washed
repeatedly with brine, dried (MgSO4), and concentrated to a quar-
ter of its initial volume.
1
days, evolved into a mixture of 10a and 10b (1:1 ratio). H NMR
(400 MHz, CDCl3): δ ϭ 7.51Ϫ7.25 (m, 10 H, ArH, 10a), 2.60 (t,
J ϭ 7.38 Hz, 2 H, CH3CH2CH2, 10a), 1.70 (m, 2 H, JCH3ϪCH2
ϭ
7.4, JCH2ϪCH2 ϭ 7.5 Hz, CH3CH2CH2, 10a), 0.97 (t, J ϭ 7.5 Hz,
3 H, CH3CH2CH2, 10a) ppm.
N-[Chloro(phenyl)acetyl]-N-thioformyl-2,6-dimethylaniline
(16):
3-(2,6-Dimethylphenyl)-2-methyl-5-phenyl-1,3-thiazolium-4-olate
(11a) and 3-(2,6-Dimethylphenyl)-2-methylidene-5-phenyl-1,3-thia-
zolidin-4-one (11b): Application of the general procedure to thioam-
ide 6 gave a solution. This was concentrated, and the residue was
crystallized from diethyl ether (3.8 mmol, 58%); m.p. 122 °C (dec.).
Starting from 13, the CH2Cl2 solution was diluted with diethyl
ether and petroleum ether until incipient precipitation. The re-
sulting suspension was kept at Ϫ20 °C, and crystallized on standing
(3.3 mmol, 50%); m.p. 143 °C. IR (KBr): ν˜max. ϭ 1724 cmϪ1 1H
.
NMR (400 MHz, CDCl3): δ ϭ 10.86 (s, 1 H, CSH), 7.37Ϫ7.02 (m,
10 H, ArH), 5.19 (s, 1 H, CH), 2.23 (s, 3 H, ArCH3), 1.34 (s, 3 H,
ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 194.1 (CS), 167.4
(CO), 137.4, 135.8, 134.4, 133.5, 130.3, 130.0, 129.3, 129.0, 128.7
(ArC, ArN), 57.9 (CH), 17.9 16.9 (ArCH3) ppm. C17H16NOSCl
(317.06): calcd. C 64.24, H 5.07, N 4.41, S 10.09; found C 63.78,
H 5.06, N 4.04, S 11.04. HRMS (IQϩ): calcd. for C17H16ClNOS
317.06411; found 317.06660; ∆ ϭ 4.6 ppm. HRMS (BARϩ): calcd.
for C17H16ClNOS ϩ Hϩ 317.07194; found 318.071839; ∆ ϭ
0.3 ppm.
IR (KBr): ν˜max ϭ 1697, 1646, 1596 cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 7.91 (d, J ϭ 7.6 Hz, 1 H, ArH, 11a), 7.53Ϫ7.11 (m,
ArH, 9 H of 11a and 10 H of 11b), 5.26 (s, 1 H, CH, 11b), 4.32 (d,
J ϭ 2.8 Hz, 1 H, C-2ϭCH2, 11b), 4.05 (d, J ϭ 2.8 Hz, 1 H, C-2ϭ
CH2, 11b), 2.34 (s, 1 H, CH3, 11a), 2.18, 2.12 (s, 6 H, ArCH3, 11b),
2.10 (s, 6 H, ArCH3, 11a) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
170.7 (C-4, 11b), 158.9 (C-4, 11a), 139.0, 137.1, 136.6, 136.4, 135.1,
133.8, 133.0, 129.9, 129.3, 128.9, 128.8, 128.7, 128.6, 128.5, 128.3,
124.5, 123.4, 85.1 (C-2ϭCH2, 11b), 51.5 (C-5, 11b), 17.6, 17.4
(CH3Ar, 11a, 11b), 16.8 (C-2ϪCH3, 11a) ppm. C18H17NOS
(295.10): calcd. C 73.19, H 5.80, N 4.74, S 10.86; found C 72.66,
H 6.07, N 4.549, S 11.11. HRMS (CIϩ): calcd. for C18H17NOS
295.10308; found 295.102895; ∆ ϭ 0.6 ppm. HRMS (FABϩ): calcd.
for C18H17NOSHϩ 296.11091; found 296.111390; ∆ ϭ Ϫ1.6 ppm.
The above mixture of tautomers 11a and 11b was dissolved in
CH2Cl2, diluted with diethyl ether until precipitation, and kept at
N-[Chloro(phenyl)acetyl]-2-ethyl-6-methyl-N-thioformylaniline (17):
Starting from 14, the CH2Cl2 solution was diluted with diethyl
ether and petroleum ether until incipient precipitation. The re-
sulting suspension was kept at Ϫ20 °C, and an orange solid crys-
tallized (2.4 mmol, 36%); m.p. 140.5 °C. IR (KBr): ν˜max ϭ 2945,
1785 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 10.89 (s, 1 H, CSH,
17b), 10.88 (s, 1 H, CSH, 17a), 7.42Ϫ7.02 (m, 10 H, ArH, 17a,
17b), 5.20 (s, 1 H, CH, 17a), 5.16 (s, 1 H, CH, 17b), 2.60Ϫ2.46 (m,
J ϭ 7.7 Hz, 2 H, ArCH3CH2, 17a, 17b), 2.24 (s, 3 H, ArCH3, 17a),
2.16 (s, 3 H, ArCH3, 17b), 1.26 (t, J ϭ 7.4 Hz, 3 H, ArCH3CH2,
17a), 0.79 (t, J ϭ 7.4 Hz, 3 H, ArCH3CH2, 17b) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 194.5 (CSH, 17a, 17b), 167.5 (CO, 17a,
17b), 142.1, 141.1, 137.2, 133.8, 133.4, 130.4, 130.0, 129.1, 129.0,
128.7, 127.0, 126.6 (ArC, ArN, 17a, 17b), 58.0 (CH, 17a), 57.6 (CH,
17b), 23.7 (ArCH2CH3, 17a), 22.6 (ArCH2CH3, 17b), 17.9
(ArCH2CH3, 17b), 16.9 (ArCH2CH3, 17a), 13.9 (ArCH3, 17a), 12.9
(ArCH3, 17b) ppm. C18H18NOSCl (331.08): calcd. C 65.15, H 5.47,
N 4.22, S 9.66; found C 64.80, H 5.57, N 4.61, S 9.42. HRMS
Ϫ20 °C. Tautomer 11b crystallized on standing. IR (KBr): ν˜max
ϭ
1695, 1595 cmϪ1
.
3-(2-Ethyl-6-methylphenyl)-2-methyl-5-phenyl-1,3-thiazolium-4-
olate (12a) and 3-(2-Ethyl-6-methylphenyl)-2-methylidene-5-phenyl-
1,3-thiazolidin-4-one (12b): Diethyl ether was added to the CH2Cl2
solution resulting from thioamide 7 to give crystals of 12a and 12b
(4.0 mmol, 60%); m.p. 107.1 °C (dec.). IR (CDCl3, solution):
ν˜max ϭ 1710, 1629 cmϪ1. Alternatively, diethyl ether was added
to the CH2Cl2 solution resulting from thioamide 7 until incipient
precipitation and the mixture was kept at Ϫ20 °C, yellow crystals
of 12b (cis/trans) thus being obtained (1.3 mmol, 20%). IR (KBr):
ν˜max ϭ 1697, 1601 cmϪ1 1H NMR (400 MHz, CDCl3) (cis-12b):
.
(BARϩ): calcd. for C18H18ClNOS
ϩ
Hϩ 332.08759; found
δ ϭ 7.53Ϫ7.12 (m, 10 H, ArH, cis-12b, trans-12b), 5.28 (s, 1 H,
CH, cis-12b), 5.26 (s, 1 H, CH, trans-12b), 4.33 (d, J ϭ 2.9 Hz, 1
H, C-2ϭCHaHb, cis-12b), 4.32 (d, J ϭ 2.8 Hz, 1 H, C-2ϭCHaHb,
trans-12b), 4.04 (d, J ϭ 2.9 Hz, 1 H, C-2ϭCHaHb, cis-12b, trans-
12b), 2.50 (dq, 2 H, J ϭ 7.4 Hz, ArCH2CH3, cis-12b), 2.44 (q, J ϭ
7.4 Hz, 2 H, ArCH2CH3, trans-12b), 2.17 (s, 3 H, ArCH3, trans-
12b), 2.11 (s, 3 H, ArCH3, cis-12b), 1.21 (t, J ϭ 7.5 Hz, 3 H,
ArCH2CH3, cis-12b), 1.07 (t, J ϭ 7.5 Hz, 3 H, ArCH2CH3, trans-
332.090286; ∆ ϭ Ϫ8.1 ppm.
Acknowledgments
This work was supported by the Spanish Ministry of Science and
Technology (Grants BQU2000-0248, BQU2002-00015 and
BQU2003-05946). J. D. thanks the Ministry of Education for a pre-
doctoral scholarship.
1
12b) ppm. H NMR (400 MHz, CDCl3) (12a): δ ϭ 7.53Ϫ7.12 (m,
9 H, ArH), 7.91 (d, J ϭ 7.0 Hz, 1 H, ArH), 2.53Ϫ2.40 (q, J ϭ
7.52 Hz, 2 H, ArCH2CH3), 2.36 (s, 3 H, C-2ϪCH3), 2.08 (s, 3 H,
ArCH3), 1.25Ϫ1.16 (t, J ϭ 7.6 Hz, 3 H, ArCH2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 171.0, 170.9 (C-4, 12a, 12b), 159.2
(C-4, 12a), 142.3, 139.6, 139.6, 137.2, 136.6, 132.4, 130.1, 129.5,
128.9, 128.6, 128.5, 128.4, 128.3, 127.0, 123.4 (ArC, ArN, C-2, 12a,
12b), 85.4 (C-2ϭCH2, 12b), 51.5 (C-5, 12b), 24.1, 24.0, 23.8
(ArCH2CH3, 12a, 12b), 17.6, 17.5, 17.4, 17.0 (C-2ϪCH3, 12a,
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Received January 26, 2004
Eur. J. Org. Chem. 2004, 2805Ϫ2811
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2811