Reactivity of 2-methyl thioisomünchnone with acid chlorides

Article abstract of DOI:10.1016/S0040-4039(03)01087-6

This work describes the reactivity of 2-alkyl thioisomünchnones, exemplified here by the 2-methyl derivative, which behaves as nucleophile in the presence of both aliphatic and aromatic acid chlorides to give 2-heteroaryl ketones or 2-heteroaryl-1,3-diketones, respectively. However, 2-alkyl thioisomünchnones exhibit its characteristic 1,3-dipole behavior toward unsaturated systems.

Full text of DOI:10.1016/S0040-4039(03)01087-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4657–4660
Reactivity of 2-methyl thioisomu¨nchnone with acid chlorides
a
a
a
a
b
´
Mart´ın Avalos, Reyes Babiano, Pedro Cintas, Jesu´s D´ıaz, Michael B. Hursthouse,
Jose´ L. Jime´nez,a Mark E. Light,b Ignacio Lo´peza and Juan C. Palaciosa,*
aDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Extremadura, Avda. Elvas s/n, E-06071 Badajoz,
Spain
bDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 21 March 2003; revised 23 April 2003; accepted 25 April 2003
Abstract—This work describes the reactivity of 2-alkyl thioisomu¨nchnones, exemplified here by the 2-methyl derivative, which
behaves as nucleophile in the presence of both aliphatic and aromatic acid chlorides to give 2-heteroaryl ketones or 2-heteroaryl-
1,3-diketones, respectively. However, 2-alkyl thioisomu¨nchnones exhibit its characteristic 1,3-dipole behavior toward unsaturated
systems. © 2003 Elsevier Science Ltd. All rights reserved.
The cycloaddition reactions with mesoionic compounds
have stirred enormous interest and progress in the last
decades.1 These substances constitute a synthetically
useful family of masked 1,3-dipoles and not only offer
a potential for natural product syntheses, but also the
possibility of constructing a series of uniquely different
heterocycles from cycloadduct fragmentation. The
anhydro-4-hydroxy-1,3-thiazolium hydroxides (thioiso-
mu¨nchnones), which contain a thiocarbonyl ylide
dipole, can easily be prepared from thioamides and
undergo [3+2] cycloadditions with reactive dipolar-
ophiles.1b The ability to synthesize diverse heterocycles
by this strategy is largely dependent on the substitution
pattern of the parent thioisomu¨nchnone. We have
shown the profound stereodirecting effect exerted by a
dialkylamino residue on the 2-position of the mesoionic
ring leading to a wide range of heterocyclic systems,
hitherto inaccessible by 1,3-dipolar cycloadditions such
as dihydrothiophenes,2 1,2,3-triazin-4-ones,3 azetidin-2-
ones,4 or thiiranes.5
tomerization of oxazol-4(5H)-ones to isomu¨nchnones
which readily react with acetylenes to afford the corre-
sponding cycloadducts. These substances subsequently
underwent a retro-Diels–Alder reaction with loss of
isocyanic acid to give furans.6 These authors also con-
sidered an alternative Diels–Alder pathway via an enol
tautomer.7 Nevertheless, this surmise was ruled out as
other oxazol-4(5H)-ones and thiazol-4(5H)-ones did
not undergo this transformation.
Apparently, only Baudy and co-workers were able to
characterize spectroscopically the equilibrium between
a 2-methyl thioisomu¨nchnone derivative and its non-
mesoionic tautomer 2-methylenethiazol-4(5H)-one.8
Still, the latter compound did react as thioisomu¨nch-
none to produce cycloadducts or heterocycles derived
thereof.9
To shed light into this class of tautomeric equilibria
and their synthetic utility, as well as to develop a
general synthesis of 2-alkyl thioisomu¨nchnones, herein
we describe a detailed exploration of their reactivity
with acid chlorides. 3,5-Diphenyl-2-methyl thioiso-
mu¨nchnone (1a) was prepared by treatment of the
commercially available thioacetanilide and 2-chloro-2-
phenylacetyl chloride,10 according to the improved pro-
It has long been thought that thioisomu¨nchnones and
their cousins the anhydro-4-hydroxy-1,3-oxazolium
hydroxides (isomu¨nchnones) exist in equilibrium with
their neutral tautomeric form, although most experi-
mental evidences suggest that only the zwitterionic
form actually undergoes a 1,3-dipolar cycloaddition. In
the early 1970s, Potts and Marshall reported the tau-
Keywords: cycloadditions; 1,3-dicarbonyl compounds; mesoionics;
tautomerism; thioisomu¨nchnones.
* Corresponding author. Tel.: +34924289380; fax: +34924271149;
e-mail: palacios@unex.es
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01087-6

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M. A6alos et al. / Tetrahedron Letters 44 (2003) 4657–4660
4658
tocol reported by Potts et al.11 This sequence is more
advantageous than that of Baudy and associates who
employed the condensation of thioamides with gem-
dicyano epoxides.8 Both such a dicyano epoxide and
the a-halo-a-phenylacetyl chloride provide the same
heterocyclic fragment: the C-4 and C-5 atoms and their
1
substituents. IR and H NMR spectra of 1 reveal that
this substance does exist in a tautomeric equilibrium
(1a:1b=1:3.8, Scheme 1).
We have computed the energy difference between these
tautomers and found that they have approximately the
same stability (DE<0.02 kcal/mol at the PM3 or
B3LYP/6-31G* levels of theory).12 An analysis of Mul-
liken charges at the B3LYP/6-31G* level evidences the
nucleophilic character of the exocyclic carbon and,
therefore we did envisage the possibility of trapping the
2-methylenethiazol-4(5H)-one (1b) tautomer with reac-
tive electrophiles. To this end, reactions of 1 with acid
chlorides were conducted under mild conditions in the
presence of triethylamine to capture the hydrogen chlo-
ride released.13
Figure 1.
With acetyl, propanoyl and butanoyl chlorides, the
monosubstituted derivatives 2b–4b were obtained.
NMR spectra showed that only the thiazol-4(5H)-ones
(2b–4b) form exist. The cis relationship between the
sulfur atom and the side chain acyl substituent could be
unequivocally determined by X-ray diffraction analysis
of 2b (Fig. 1).14 Remarkably both phenyl groups adopt
an orthogonal disposition with respect to the hetero-
cyclic ring, to presumably alleviate the steric conges-
tion. It is equally interesting worth noting that the
solid-state conformation found for the acyl group
should be attributed to the intramolecular non-bonded
interaction S···O (1,5-intra mode), which has its origin
Scheme 2.
tomers, whereas 7 and 9 appear to be equilibrated
between both forms (Scheme 2, Table 1).
in n(CꢀO)–s*
orbital overlap effect.15
(CꢁS)
Data collected in Table 1 also evidence that the forma-
tion of mono or diacylated derivatives invariably occurs
regardless of the amount of acid chloride employed
(entries 1–6, 9). Moreover, attempts to introduce a
third acyl group by using a large excess of benzoyl or
4-chlorobenzoyl chlorides failed as well (entries 6 and
9).
On the other hand, reactions of 1 with benzoyl, 4-
methoxybenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, or
4-nitrobenzoyl chlorides produced the corresponding
2-heteroaryl-1,3-diketones 5–9. In this case, however,
NMR spectra of compounds 5, 6, and 8 suggest the
exclusive existence of their thioisomu¨nchnone tau-
Table 1. Reactions of 1 with acyl chlorides and triethylamine
Entry
R
RCOCl (equiv.)
Et3N (equiv.)
Product (%)a
Tautomeric ratiob
1
2
3
4
5
6
7
8
Me
Et
Prop
C6H5
C6H5
C6H5
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2-FC6H4
4-NO2C6H4
2
2
2
2
1
4
2
2
4
2
2
2
2
2
2
1
4
2
2
4
2
2
2b (52)
3b (46)
4b (70)
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
2.5:1
2.5:1
>99:1
2:1
5a (36)
5a (76)c
5a (40)
6a (72)
7a+7b (55)
7a+7b (70)
8a (50)
9
10
11
9a+9b (78)
a Yields refer to isolated, crystalline compounds.
b Determined by 1H NMR integration at 400 MHz in CDCl3.
c Calculated with respect to the limiting amount of PhCOCl.

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M. A6alos et al. / Tetrahedron Letters 44 (2003) 4657–4660
4659
because they are considerably less reactive than carbon-
ates or formates. Likewise, Lewis acid-catalyzed
acylation of enols is often hampered by other func-
tional groups susceptible of undergoing complexation.17
In addition, aldol, Claisen and related reactions are
prone to give self-condensation products, although the
problem can be circumvented by immobilization tech-
niques.18 Further studies with the present protocol
along with extensions to other electrophiles are cur-
rently under way.
With carbonꢁcarbon unsaturated functionalities, com-
pound 1 exhibits the typical dipole character of thioiso-
mu¨nchnones.1–3,9 Reactions of 1 with acryloyl chloride
in CH2Cl2 at room temperature gave the corresponding
2-aza-3-oxo-7-thiabicycle 10 in moderate yield (60%)
and with complete regioselectivity (Scheme 3). The
stereochemical outcome arises from an exo approach of
the dipolarophile facing its C-2 and C-3 atoms to C-5
and C-2 positions respectively, of 1. It is also remark-
able the strong bias to favor a cycloaddition pathway in
the case of acryloyl chloride, even though it is a good
electrophile. Compound 10 was isolated as its acid
derivative after chromatographic purification (Scheme
3). Crystals of 10 suitable for X-ray diffraction could
not be obtained. However, its stereochemistry was
established by comparison with the spectroscopic data
of the cycloadduct 11 arising from reaction of 1 with
methyl vinyl ketone, whose regiochemistry was deter-
mined by X-ray diffractometry (Fig. 2).16
Acknowledgements
We thank the Spanish Ministry of Science and Technol-
ogy (Grants No. BQU2000-0248 and PB98-0997) for
financial support and J. D´ıaz thanks the Ministry of
Education for a Ph.D. fellowship.
To sum up, we have demonstrated that 2-methyl
thioisomu¨nchnones are in equilibrium with their 2-
methylenethiazol-4(5H)-ones. This feature can be har-
nessed to develop a novel synthesis of 2-heteroaryl
ketones and 2-heteroaryl-1,3-diketones by reaction with
alkanoyl or aroyl chlorides, respectively. Moreover, the
resulting substances contain a functionalized heteroaro-
matic ring, which can undergo further synthetic explo-
ration en route to fused heterocycles. Within this
context it should also be pointed out the facile incorpo-
ration of the 1,3-dicarbonyl moiety into the heterocyclic
fragment, while other classical procedures possess
important drawbacks. Thus, esters of aromatic acids
are used rather less frequently in cross-Claisen reactions
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CH2Cl2 (5.0 mL) and, after 25 min, a solution of triethyl-
amine (13.2 mmol) in CH2Cl2 (5.0 mL). After 15 min,
Figure 2.

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M. A6alos et al. / Tetrahedron Letters 44 (2003) 4657–4660
4660
14. The authors have deposited crystallographic data for
the reaction mixture was washed with a saturated solution
of NaCl (3×120 mL), dried (MgSO4), and the solvent was
removed under reduced pressure. The resulting residue
crystallized on cooling as a yellow solid (60%). IR (KBr):
compound 2b (CCDC 194712) with the Cambridge Crys-
tallographic Data Centre. Copies of this material can be
obtained from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, UK. Crystal
data for 2b, C18H15NO2S, Mr=309.37, monoclinic, P21/c,
1
1628 (1a), 1705 (1b) cm−1; H NMR (CDCl3, 400 MHz):
l 2.46 (s, 3H) (tautomer 1a), 5.22 (s, 1H), 4.39 (d, J=3.1
Hz, 1H), 4.27 (d, J=3.1 Hz, 1H) (tautomer 1b).
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,
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v=2.23 cm−1, F(000)=648, T=120(2) K, GooF2=1.031,
independent reflections=2272 [Rint=0.0624] of a total of
3635 collected reflections, R(F) obeying F2>2|(F2)=
0.0824, wR(F2)=0.2176, R(all data)=0.1122, wR(F2)=
0.2481.
3
,
,
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in CH2Cl2 (2.0 mL) were added acetyl chloride (26.6 mL,
0.37 mmol) and triethylamine (52.2 mL, 0.37 mmol). After
48 h at room temperature, the solvent was evaporated and
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phy (ethyl acetate:hexane, 1:3) to afford 2, which was
further crystallized from ethyl acetate (30 mg, 52%); mp:
156°C: IR (KBr): 1720, 1647, 1510 cm−1; 1H NMR (CDCl3,
400 MHz): l 7.56–7.25 (m, 10H), 5.65 (s, 1H), 5.09 (s, 1H),
2.11 (s, 3H); 13C NMR (CDCl3, 100 MHz): l 196.1, 173.3,
158.0, 135.6, 130.1, 129.8, 129.1, 128.6, 128.3, 127.9, 100.9,
50.0, 30.1.
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16. The authors have deposited crystallographic data for
compound 11 (CCDC 197967) with the Cambridge Crys-
tallographic Data Centre. Copies of this material can be
obtained from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, UK. Crystal
data for 11, C20H19NO2S, Mr=337.42, monoclinic, P21/c,
,
a=6.16440(10), b=10.8967(3), c=24.7631(7) A, V=
3
1660.48(7) A , Z=4, Dcalcd=1.350 g cm−3, u(MoKa)=
,
0.71073 A, v=2.07 cm−1, F(000)=712, T=120(2) K,
GooF2=1.035, independent reflections=2901 [Rint
,
=
0.0243]of a total of 5309 collected reflections, R(F) obeying
F2>2|(F2)=0.0352, wR(F2)=0.0810, R(all data)=
0.0506, wR(F2)=0.0867.
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