Diels-Alder reactions of 4-alkenylthiazoles: A new approach to thiazole functionalization

Article abstract of DOI:10.1021/jo062417e

Somewhat unexpectedly, the computed highest occupied molecular orbital (HOMO) energies of some 4-alkenylthiazoles afforded values close to those calculated for the Danishefsky-Kitahara and Rawal dienes. In fact, 4-alkenylthiazoles behave as all-carbon die

Full text of DOI:10.1021/jo062417e

Diels-Alder Reactions of 4-Alkenylthiazoles: A New Approach to
Thiazole Functionalization
Mateo Alajar´ın,*,† Jose´ Cabrera,† Aurelia Pastor,† Pilar Sa´nchez-Andrada,† and
Delia Bautista‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, and SerVicio de Instrumentacio´n Cient´ıfica,
UniVersidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
alajarin@um.es
ReceiVed NoVember 23, 2006
Somewhat unexpectedly, the computed highest occupied molecular orbital (HOMO) energies of some
4-alkenylthiazoles afforded values close to those calculated for the Danishefsky-Kitahara and Rawal
dienes. In fact, 4-alkenylthiazoles behave as all-carbon dienes in Diels-Alder reactions with the
participation of the formal C-C double bond of the thiazole ring and the side-chain double bond. The
reactions with N-substituted maleimides, maleic anhydride, and naphthoquinone take place with high
levels of stereocontrol to give the corresponding endo-cycloadducts in good to excellent yields. Depending
on the dienophile, the cycloadduct further transforms under the reaction conditions through either a 1,3-
hydrogen shift, dehydrogenation, or an ene reaction or Michael addition with another molecule of
dienophile. These unprecedented results open new synthetic perspectives for the functionalization of the
thiazole ring.
Introduction
the Diels-Alder approach consists of the use of conjugated
dienes in which one of the double bonds is embedded in a
heteroaromatic nucleus, that is, alkenyl-substituted heterocycles.4
In general, alkenyl-substituted aromatic heterocycles, and their
benzoderivatives, undergo Diels-Alder reactions with the
concourse of the diene moiety that includes the side-chain double
bond (extra-annular addition).4 In most cases the latter way of
interacting is preferred to that involving the proper heteroaro-
matic nucleus (intra-annular addition) as far as this nucleus
contains in turn a conjugated diene arrangement.4b Nevertheless,
the reactivity of these dienes is highly influenced not only by
the nature and number of heteroatoms but also by the aromatic
character of the heterocycle;5 this approach is successful, with
a few exceptions,6 only with π-excessive five-membered
Heteropolycycles are key compounds in the development of
modern pharmaceutical chemistry, this being the reason why
the design of amenable synthetic approaches for the synthesis
of new heterocyclic systems is still an attractive challenge.1
Because its simplicity and efficiency, the Diels-Alder reaction
provides a valuable method for the regioselective and stereo-
selective preparation of these types of compounds.2 Besides the
hetero Diels-Alder methodology,3 another alternative to gener-
ate heterocyclic rings fused to a carbocyclic system by using
† Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica.
‡ Servicio de Instrumentacio´n Cient´ıfica.
(1) Dewick, P. M. In Medicinal Natural Products. A Biosynthetic
Approach, 2nd ed.; Wiley: Chichester, U.K., 2002.
(2) (a) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 5, pp 315-
399. (b) Fringuelli, F.; Taticchi, A. The Diels-Alder ReactionsSelected
Practical Methods; Wiley: Chichester, U.K., 2002. (c) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668-1698.
(4) (a) Sepu´lveda-Arques, J.; Abarca-Gonza´lez, B.; Medio-Simo´n, M.
AdV. Heterocycl. Chem. 1995, 63, 339-401. (b) Fringuelli, F.; Taticchi,
A. The Diels-Alder ReactionsSelected Practical Methods; Wiley: Chich-
ester, U.K., 2002; pp 56-64.
(5) Fringuelli, F.; Taticchi, A. The Diels-Alder ReactionsSelected
Practical Methods; Wiley: Chichester, U.K., 2002; pp 40-41.
(6) (a) Jones, G.; Rafferty, P. Tetrahedron Lett. 1978, 19, 2731-2734.
(b) Jones, G.; Rafferty, P. Tetrahedron 1979, 35, 2027-2033.
(3) Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, CA, 1987.
10.1021/jo062417e CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007
J. Org. Chem. 2007, 72, 2097-2105
2097

Alajar´ın et al.
heterocyclic derivatives.4a However, some disadvantages of this
methodology are the competition of Michael additions, ene
reactions, [2 + 2] cycloadditions and polymerizations with the
desired Diels-Alder reaction.4a
SCHEME 1. Retrosynthetic Analysis of 4-Alkenylthiazoles 1
The involvement of some types of alkenyl heterocycles as
dienes in Diels-Alder reactions has been previously studied.7a-m
Thus, 1-substituted 2- and 3-vinylpyrroles react easily with
electron-deficient dienophiles to provide dihydro- and tetrahy-
droindoles with further 1,3-hydrogen migration in the corre-
sponding cycloadduct.7a,b The 2- and 3-vinylindoles also react
with carbodienophiles to produce carbazoles.7c-f Recently,
Lovely and co-workers7g and Romo and co-workers7h,i have
developed new methods for access to a spirobicyclic system,
related to those found in marine alkaloids such as palau’amines,
based on the Diels-Alder reaction of vinylimidazoles. The [4
+ 2] cycloaddition reactions of vinylfurans and vinylbenzofurans
with dimethyl acetylenedicarboxylate, tetracyanoethylene, R,â-
unsaturated ketones, quinones, and maleimides have been also
investigated.4,7j,k Vinylthiophenes are less reactive than the
analogous furans, reacting only with the most reactive
dienophiles.7l,m Moreover, they behave somewhat differently
from furans and in many cases the corresponding cycloadducts
are unstable and undergo cheleotropic extrusion of sulfur.8
We were interested, for both synthetic and mechanistic
reasons, in [4 + 2] cycloadditions in which alkenylthiazoles
participate by means of the diene moiety that includes the side-
chain double bond. Surprisingly, this type of process has not
been previously investigated, probably due to the general
acceptance that thiazoles have a low reactivity in Diels-Alder
reactions caused by their considerable aromatic stabilization.9
At first sight, 4-alkenylthiazoles (1) may be synthesized from
easily available starting materials. Our retrosynthetic analysis
for the synthesis of these compounds is shown in Scheme 1.
Thus, thiazoles 1 could be prepared from R-chloroketone 2 and
thioamide 3 through a Hantzsch synthesis.10 The R-chloroketone
2 could be derived from (3-chloroacetonylidene)triphenylphos-
phorane (4) and the corresponding aldehyde by means of a
Wittig reaction. Finally, the alkylidenephosphorane 4 could be
easily obtained from 1,3-dichloroacetone by previously de-
scribed procedures.11
CHART 1. Structures of 4-Alkenylthiazoles 1a-j and
Dienes 5 and 6
in this type of process, forming new heteropolycyclic systems
in their reactions with the above-mentioned dienophiles in good
to excellent yields. The reactions take place with a high degree
of stereoselection to give the endo cycloadducts. The results
here disclosed are interesting not only from the synthetic point
of view but also because they open new routes to the function-
alization of the thiazole ring.
Herein, we disclose our findings in the Diels-Alder reaction
of 4-alkenylthiazoles with different dienophiles such as N-
substituted maleimides, maleic anhydride, or naphthoquinone.
Contrary to expectations, 4-alkenylthiazoles are versatile dienes
(7) (a) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Sepu´lveda-
Arques, J. J. Org. Chem. 1980, 45, 4515-4519. (b) Xiao, D.; Ketcha, D.
M. J. Heterocycl. Chem. 1995, 32, 499-503. (c) Noland, W. E.; Wann, S.
R. J. Org. Chem. 1979, 44, 4402-4410. (d) Eitel, M.; Pindur, U. J. Org.
Chem. 1990, 55, 5368-5374. (e) Pindur, U.; Kim, M.-H.; Rogge, M.; Massa,
W.; Molinier, M. J. Org. Chem. 1992, 57, 910-915. (f) Back, T. G.;
Pandyra, A.; Wulff, J. E. J. Org. Chem. 2003, 68, 3299-3302. (g) Du, H.;
He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 7, 965-992. (h) Dilley, A.
S.; Romo, D. Org. Lett. 2001, 3, 1535-1538. (i) Dransfield, P. J.; Wang,
S.; Dilley, A.; Romo, D. Org. Lett. 2005, 7, 1679-1682. (j) Marrocchi,
A.; Minuti, L.; Taticchi, A.; Scheeren, H. W. Tetrahedron 2001, 57, 4959-
4965. (k) Le Strat, F.; Vallete, H.; Toupet, L.; Maddaluno, J. Eur. J. Org.
Chem. 2005, 5296-5305. (l) Scully, J. F.; Brown, E. V. J. Am. Chem. Soc.
1953, 75, 6329-6330. (m) Moody, C. J.; Rees, C. W.; Tsoi, S. C. J. Chem.
Soc., Perkin Trans. 1 1984, 915-920.
Results
Synthesis of the Starting Materials. We selected as starting
materials the 4-alkenylthiazoles 1a-e shown in Chart 1, each
of them containing an aromatic substituent attached to the
â-position of the alkenylic side chain. This structural feature
was chosen on the basis of the easier accessibility of the starting
R-chloroketones (2a-c in Scheme 2) prepared by the Wittig
reaction of alkylidenephosphorane 4 and 4-chlorobenzaldehyde,
tolualdehyde, or 4-methoxybenzaldehyde (see Supporting In-
formation). R-Chloroketones 2a-c were allow to react with
thiobenzamide (3a) or thioacetamide (3b) in EtOH under reflux
to give thiazoles 1a-e in high yields (87-95%) (Scheme 2).
HOMO Values. The qualitative application of the frontier
molecular orbital (FMO) theory has frequently proved of value
for predicting the results of Diels-Alder reactions.7d Dienes
possessing substituents capable of donating their electron density
into the conjugated π-system display high reactivity in Diels-
(8) Corral, C.; Lissavetzky, J.; Manzanares, I. Synthesis 1997, 29-31.
(9) Thiazole and its DeriVatiVes; Metzger, J. V., Ed.; Wiley: New York,
1979.
(10) (a) Hantzsch, A. R.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887,
20, 3118-3132. (b) Schwarz, G. Organic Syntheses; Wiley: New York,
1955; Collect. Vol. 3, pp 332-333.
(11) Hudson, R. F.; Chopard, P. A. J. Org. Chem. 1963, 28, 2446-
2447.
2098 J. Org. Chem., Vol. 72, No. 6, 2007

Diels-Alder Reactions of 4-Alkenylthiazoles
SCHEME 2. Synthesis of 4-Alkenylthiazoles 1a-e through
Hantzsch Synthesis
butyldimethylsilyl group of Rawal’s diene by the simpler Me3-
Si (6 in Chart 1). The HOMO energies were obtained through
single-point Hartree-Fock (HF) calculations with the 6-31G
basis set at the B3LYP/6-31G geometries, as this procedure has
been shown to provide more accurate orbital energies than the
B3LYP level.16h
Although it is expected that the s-trans conformation of these
dienes (1f-j, 5, 6) is lower in energy than the s-cis conforma-
tion, we have optimized only the s-cis form as this is the reactive
conformation. Moreover, the trends in reactivity should be the
same for the s-trans and the s-cis series. The computed B3LYP/
6-31G geometries of dienes 1f-j, 5, and 6 are shown in Figure
1.
The s-cis conformers of 5 and 6 are twisted out of planarity
by 26.9° and 25.2°, whereas the s-cis forms of dienes 1f-j
showed, in all the computed cases, a planar geometry. In Table
1 we summarize the HOMO energies and the 2pz eigenvectors
of the HOMOs of all these dienes.
The HOMO energies point out that dienes 1f-j, 4-alkenylthi-
azoles, should behave as activated dienes in [4 + 2] cycload-
dition reactions of normal electronic demand. Whereas dienes
1h-j probably should show a reactivity comparable to 5, dienes
1f and 1g are predicted to be more reactive as their HOMO
energies are closer to that of 6. By comparison of the HOMO
energies of 1f and 1h, it is apparent that the presence of the
phenyl group at C1 contributes to a considerable increase in
the HOMO energy and improves the desired reactivity. There-
fore, dienes possessing a structure similar to that of 1f, such as
those used in the experimental work (1a-e), are predicted to
participate efficiently in Diels-Alder reactions with electron-
deficient dienophiles.
Alder reactions of normal electronic demand.12 According to
the FMO theory this phenomenon, reflected experimentally in
higher reaction rates, is due to the increase of the diene’s highest
occupied molecular orbital (HOMO) energy and, consequently,
the smaller HOMOdiene-LUMOdienophile gap (LUMO ) lowest
unoccupied molecular orbital).13 The reactivity of dienes
increases not only with the number of electron-releasing
substituents but also when they are placed in adequate positions
to cause a cooperative effect. Thus, the Danishefsky-Kitahara
and Rawal dienes, with electron-donor substituents at 1- and
3-positions, display high reactivity in [4 + 2] cycloaddition
reactions.14-16 The enhanced reactivity of both dienes has been
rationalized on the basis of FMO theory, which also afforded
accurate semiquantitative predictions of the behavior of other
dienes and dienophiles in [4 + 2] cycloadditions.17 We have
also used this methodology for investigating the relative
reactivity of dienes 1f-j (Chart 1),18 and here we compare the
results with those obtained for Danishefsky-Kitahara (5 in Chart
1) and Rawal dienes computed at the same level of theory. With
the aim of simplifying the calculations, we substituted the tert-
Reactions of 4-Alkenylthiazoles 1a-e with N-Substituted
Maleimides. First, we tested the reaction of thiazole 1a with
N-phenylmaleimide (NPM). In toluene at 20 °C, no reaction
took place. At higher temperatures, 140 °C, we obtained a
mixture of two compounds (each one being a racemate), endo-
7a and 8a (Scheme 3 and Table 2, entry 1), which were isolated
as result of complete diastereoselection. While endo-7a comes
from the Diels-Alder reaction of both reagents followed by a
1,3-hydrogen migration, compound 8a is the result of the
reaction of one molecule of 1a with two molecules of maleimide.
This species 8a could be isolated as the major product when
1a and NPM were allowed to react in a 1:4 ratio without solvent
at 120 °C (Table 2, entry 3). Under these reaction conditions,
8a was obtained in 66% yield along with endo-7a (21%). We
investigated whether in these processes 8a would form by the
reaction of endo-7a with another molecule of NPM. However,
after these two latter compounds were heated together in toluene
solution at 140 °C for 24 h, they were recovered unaltered
(Scheme 3). Finally, just a solvent change from toluene to
acetonitrile allowed the formation of endo-7a as a single product
in excellent yield when the reaction was conducted at 120 °C
in a sealed tube for 48 h (Table 2, entry 4).
(12) For reviews see (a) Petrzilka, M.; Grayson, J. I. Synthesis 1981,
753-786. (b) Jorgensen, K. A. Eur. J. Org. Chem. 2004, 2093-2102.
(13) (a) Fukui, K. Tetrahedron Lett. 1965, 6, 2009-2015. (b) Fukui, K.
Acc. Chem. Res. 1971, 4, 57-64. (c) Hoffmann, R.; Woodward, R. B. Acc.
Chem. Res. 1968, 1, 17-22. (d) Woodward, R. B.; Hoffmann, R. In The
ConserVation of the Orbital Theory; Verlag Chemie: Weinheim, Germany,
1970. (e) Fleming, I. In Frontier Orbitals and Organic Chemical ReactiVity;
Wiley: New York, 1976. (f) Houk, K. N. In Pericyclic Reactions; Lehr, R.
E., Marchand, A. P., Eds.; Academic Press: London, 1977; Vol. 2, p 181.
(g) Houk, K. N. Acc. Chem. Res. 1975, 8, 361-369.
(14) (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807-
7808. (b) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400-406. (c) Banville,
J.; Brassard, P. J. Chem. Soc., Perkin. Trans. 1 1976, 1852-1856. (d)
Danishefsky, S.; Singh, R. K.; Gammill, R. B. J. Org. Chem. 1978, 43,
379-380. (e) Ibuka, T.; Mori, Y.; Inubushi, Y. Tetrahedron Lett. 1976,
17, 3169-3172.
(15) For 1,3-bis(dimethylamino) dienes, see (a) Gompper, R.; Sobotta,
R. Tetrahedron Lett. 1979, 20, 921-924. (b) Gompper, R.; Heinemann, U.
Angew. Chem., Int. Ed. Engl. 1980, 19, 216-217.
(16) For 1-amino-3-siloxy dienes, see (a) Smith, A. B., III; Wexler, B.
A.; Tu, C.-Y.; Konopelski, J. P. J. Am. Chem. Soc. 1985, 107, 1308-1320.
(b) Comins, D. L.; Al-awar, R. S. J. Org. Chem. 1992, 57, 4098-4103. (c)
Schlessinger, R. H.; Pettus, T. R. R.; Springer, J. P.; Hoogsteen, K. J. Org.
Chem. 1994, 59, 3246-3247. (d) Kozmin, S. A.; Rawal, V. H. J. Org.
Chem. 1997, 62, 5252-5253. (e) Kozmin, S. A.; Janey, J. M.; Rawal, V.
H. J. Org. Chem. 1999, 64, 3039-3052. (f) Kozmin, S. A.; Rawal, V. H.
J. Am. Chem. Soc. 1997, 119, 7165-7166. (g) Kozmin, S. A.; Rawal, V.
H. J. Am. Chem. Soc. 1999, 121, 9562-9573. (h) Kozmin, S. A.; Green,
M. T.; Rawal, V. H. J. Org. Chem. 1999, 64, 8045-8047.
This latter solvent and temperature combination was utilized
in the rest of the reactions of 4-alkenylthiazoles 1a-e with
N-phenyl-, N-methyl-, and N-ethylmaleimide (Table 2, entries
4-16). In all the cases the corresponding endo adducts, endo-
7a-m, were obtained as the major products in excellent yields,
although in some cases accompanied by small quantities of exo-7
and 8 (Table 2, entries 7-15).
(17) (a) Sustmann, R.; Schubert, R. Tetrahedron Lett. 1972, 13, 2739-
2742. (b) Sustmann, R.; Schubert, R. Angew. Chem., Int. Ed. Engl. 1972,
11, 840. (c) Overman, L. E.; Taylor, G. F.; Houk, K. N.; Domelsmith, L.
N. J. Am. Chem. Soc. 1978, 100, 3182-3189. (d) Kawasaki, I.; Sakaguchi,
N.; Khadeer, A.; Yamashita, M.; Ohta, S. Tetrahedron 2006, 62, 10182-
10192. (e) Sheng, Y.; Leszczynski, J. Tetrahedron 2006, 62, 7014-7020.
(f) Landreau, C.; Janvier, P.; Julienne, K.; Meslin, J. C.; Deniaud, D.
Tetrahedron 2006, 62, 9226-9231. (g) See also ref 16h.
(18) 4-Alkenylthiazoles 1f-i have not been described previously in the
literature. For the preparation of thiazole 1j, see Schilling, C. L., Jr.;
Mulvaney, J. E. Macromolecules 1968, 1, 445-451.
Alternatively, when the reactions of 4-alkenylthiazoles 1a,
1c, and 1e with NPM were conducted under milder conditions
J. Org. Chem, Vol. 72, No. 6, 2007 2099

Alajar´ın et al.
FIGURE 1. Computed B3LYP/6-31G geometries of dienes 1f-j, 5, and 6 in their respective s-cis conformations.
TABLE 1. HOMO Values for 4-Alkenylthiazoles 1f-j and Dienes
agrees with its higher electron density as well as with the HOMO
energy value of s-cis-1g, the highest one among all the computed
HOMO energies of these thiazoles (Table 1). As presumed,
when endo-9m was stirred at 120 °C for 36 h, it clearly
isomerized to compound endo-7m in 85% yield, by recovering
the aromaticity of the thiazole ring through the expected 1,3-
hydrogen shift (Scheme 4).
Many reactions are accelerated by Lewis acid catalysts, and
the catalyzed reactions show also increased regio- and stereo-
selectivities over the uncatalyzed reactions.19 The reaction
between 1a and NPM was investigated under Lewis acid
catalysis (Et2AlCl, BF3‚Et2O or ZnCl2), but unfortunately, poorer
conversions and lower yields were obtained compared to the
reactions conducted under thermal conditions.
5 and 6 in Their s-cis Conformation
2pz coefficients
diene
eigenvalue (eV)
C1
C2
C3
C4
s-cis-1f
s-cis-1g
s-cis-1h
s-cis-1i
s-cis-1j
s-cis-5
-7.47
-7.35
-8.01
-8.41
-8.65
-8.13a
-7.18b
-0.21
-0.20
-0.19
-0.26
-0.28
-0.22
-0.19
-0.21
-0.22
-0.12
-0.19
-0.20
-0.23
-0.30
0.17
0.15
0.22
0.25
0.25
0.21
0.14
0.25
0.24
0.28
0.30
0.29
0.34
0.29
s-cis-6
a -8.08 in ref 16h. b -7.18 in ref 16h.
(refluxing acetonitrile) some of them yielded mixtures of endo-7
and endo-9 in different ratios and overall yields depending on
the R substituent (Scheme 4). Compounds endo-9 are just the
expected initial cycloadducts, from which compounds endo-7
derive by subsequent 1,3-hydrogen migration. While 1a showed
no conversion at all under these reaction conditions, 1e displayed
the highest overall yields leading to endo-9m in 50% yield as
a single diastereomer (racemic mixture). These results indicate
an increase of the reactivity along the series R ) Cl, Me, OMe
(Scheme 4). The higher reactivity of 1e compared to 1a and 1c
We investigated also the reaction of 1a with NPM under
controlled microwave irradiation (270-440 W). Microwave
radiation is an alternative to conventional heating for introducing
energy into reactions20 and a number of Diels-Alder reactions
(19) (a) Houk, K. N.; Strozier, R. W. J. Am. Chem. Soc. 1973, 95, 4094-
4096. (b) Carruthers, W. In Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K., 1990; pp 50-53. (c) Fringuelli, F.; Taticchi,
A. The Diels-Alder ReactionsSelected Practical Methods; Wiley: Chich-
ester, U.K., 2002; pp 99-142.
2100 J. Org. Chem., Vol. 72, No. 6, 2007

Diels-Alder Reactions of 4-Alkenylthiazoles
SCHEME 3. Reactions of 4-Alkenylthiazoles 1a-e with N-Substituted Maleimides
TABLE 2. Reactions between 4-Alkenylthiazoles 1a-e and
N-Substituted Maleimides
SCHEME 5. Reactions of 4-Alkenylthiazoles 1c,d with
Maleic Anhydride and Naphthoquinone
entry compd
R1
R2 R3 solvent endo-7 (%) exo-7 (%) 8 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
a
a
a
b
c
d
e
f
g
h
i
j
k
l
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph Ph toluenea
46
25
21
94
92
86
91
74
88
80
86
88
74
66
90
90
0
0
0
0
0
0
0
6
4
0
7
7
0
8
3
0
18
42
66
0
0
0
8
0
0
20
0
0
8
13
0
0
b,c
Ph Ph
Ph Ph
-
-
c,d
Ph Ph MeCNe
Ph Me MeCNe
Ph Et MeCNe
Me Ph MeCNe
Me Me MeCNe
Me Et MeCNe
4-MeC6H4 Ph Ph MeCNe
4-MeC6H4 Ph Me MeCNe
4-MeC6H4 Ph Et MeCNe
4-MeC6H4 Me Ph MeCNe
4-MeC6H4 Me Me MeCNe
4-MeC6H4 Me Et MeCNe
4-MeOC6H4 Ph Ph MeCNe
m
a 1:maleimide ratio 1:1.3; 140 °C. b 1:maleimide ratio 1:2. c Neat; 120
°C. d 1:maleimide ratio 1:4. e 1:maleimide ratio 1:3; 120 °C.
SCHEME 4. Reaction between 4-Alkenylthiazoles 1a, 1c,
and 1e and N-Phenylmaleimidea
Reactions with Maleic Anhydride and Naphthoquinone.
We investigated the reaction of thiazole 1c with maleic
anhydride (Scheme 5). Both reagents were allowed to react in
acetonitrile at 120 °C for 48 h, leading to the compound endo-
10 in moderate yield and as a single diastereomer (racemic
mixture). Compound endo-10 is the result of the reaction of 1c
with 2 equiv of maleic anhydride. No other cycloadducts could
be isolated from the reaction mixture.
Finally, we investigated the reactions of thiazoles 1c,d with
naphthoquinone. These reactions took place in acetonitrile at
120 °C for 72 h, leading to 11a,b in moderate yields (Scheme
5) along with high quantities of recovered starting thiazole
(40%).
Configurational Assignments of endo-7, exo-7, 8, endo-9,
and endo-10. The relative configurational assignment of the
four newly formed stereocenters in compounds endo-9 was done
by comparison of selected coupling constants in endo-9g and
endo-9m with those of analogous structures described in the
literature.21 The assignment of the relative configuration of
endo-7 and exo-7 was achieved by performing 1H-1H NOESY
experiments (see Supporting Information). Before the measure-
ment of the NOESY spectra, we calculated the B3LYP/6-
31+G** optimized structures of endo-7h and exo-7h (see
Supporting Information). Both minimum energy structures
a Under milder conditions this reaction gives mixtures of endo-7 and
endo-9. Treatment at 120 °C of endo-9m leads to endo-7m.
have been performed with great success under these reaction
conditions, especially those requiring the use of high temper-
atures and long reaction times. However, in our case the use of
microwave radiation did not improve the results obtained under
thermal conditions since 1:1 mixtures of endo-7a and 8a were
obtained, albeit in lower overall yields (49-63%).
(20) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-6284. (b)
Ferna´ndez Sainz, Y.; Raw, S. A.; Taylor, R. J. K. J. Org. Chem. 2005, 70,
10086-10095. (c) Pinto, D. C. G. A.; Silva, A. M. S.; Brito, C. M.;
Sandulache, A.; Carrillo, J. R.; Prieto, P.; D´ıaz-Ortiz, A.; de la Hoz, A.;
Cavaleiro, J. A. S. Eur. J. Org. Chem. 2005, 2973-2986. (d) Silva, V. L.
M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A. S. Synlett 2006,
1369-1373.
(21) (a) Lovely, C. J.; Du, H.; Rasika Dias, H. V. Org. Lett. 2001, 3,
1319-1322. (b) Lovely, C. J.; Du, H.; He, Y.; Rasika Dias, H. V. Org.
Lett. 2004, 6, 735-738.
J. Org. Chem, Vol. 72, No. 6, 2007 2101

Alajar´ın et al.
FIGURE 3. Selected coupling constants (in red) of endo-10 supporting
the relative configurational assignment. A long-range coupling due to
a zigzag arrangement between protons H4′ and H5b was observed (in
blue).
aromatic stabilization,9 the computed energies for the HOMOs
of 4-alkenylthiazoles 1f-j revealed that they should be prone
to participate as reactive dienes in this type of process (see
above). In fact, when they were allowed to react with classical
dienophiles such as maleimides, maleic anhydride, or naphtho-
quinone, we could isolate the corresponding cycloadducts
although in most cases they were involved in subsequent
transformations. Thus, mixtures of endo-7, exo-7, and 8 were
obtained when N-substituted maleimides were used as dieno-
philes and the reactions were conducted above 100 °C (Scheme
3). Under milder reaction conditions (Scheme 4), cycloadducts
endo-9 were isolated as single compounds (endo-9m, racemate)
or as mixtures (endo-7g/endo-9g, both racemates). The treatment
of endo-7a with an excess of NPM did not lead to 8a but instead
the starting material was recovered unaltered (Scheme 3). From
all these results, it is clear that 7 and 8 may be formed from a
common intermediate, that is, the primary Diels-Alder adduct
9 (Scheme 6). Spontaneous, formal 1,3-hydrogen shift may
produce compounds 7 or, alternatively, an ene reaction with
another molecule of maleimide may give compounds 8. Both
processes, the 1,3-hydrogen migration and the ene reaction,
caused the rearomatization of the thiazole ring.
The Diels-Alder reactions of 1a-e with maleimides take
place in a highly stereocontrolled manner. This assertion is
substantiated by the relative configurational assignment of endo-
7, 8, and endo-9, which were isolated as single or major
diastereomers (racemic mixtures). Probably, the favorable
secondary frontier orbital interactions control the stereochemistry
of the endo Diels-Alder transition state, before the formal 1,3-
hydrogen shift or the ene reaction takes place, leading to 7 or
8. This assertion would be valid only when the subsequent
hydrogen shift or ene reaction are not rate-limiting steps. The
same behavior has been previously observed in the reaction of
other alkenylheterocycles with maleimides.7d
FIGURE 2. Significant NOE effects (blue arrows) and coupling
constants (red arrows) for endo-7h and exo-7h.
display a distorted boat conformation of the central cyclohexene
ring in which the 4-tolyl substituent placed at C5 may be situated
in an equatorial or an axial arrangement (endo-7h or exo-7h,
respectively) depending on the absolute configuration of this
carbon atom (Figure 2). NOESY data revealed the spatial
proximity of protons H5/H8a, H5b/H8a, Hortho/H5, and Hortho/H5b
for endo-7h and that of protons Hortho/H8a, H5b/H8a, Hortho/H5,
and Hortho/H5b for exo-7h (blue arrows in Figure 2). These NOE
contacts agree with the energy-minimized structures of both
diastereomers since all the protons involved are less than 4.5 Å
apart. This assignment was unambiguously confirmed by X-ray
analysis of endo-7c (see Supporting Information). Selected 1H-
1
1H coupling constants calculated from the H NMR spectra of
endo-7h and exo-7h are depicted in Figure 2. Finally, the relative
configuration of the five newly formed stereogenic centers in
compounds 8 was assigned following the X-ray structure
determination of 8j (see Supporting Information).
The relative configurational assignment of endo-10 was done
1
by comparison of its H NMR data (in particular the coupling
constants between protons H5/H4, H5/H4′, and H5/H5b) with those
of endo-7h (Figure 3, in red). A long-range coupling between
H4′ and H5b was also observed due to a zigzag arrangement of
these two protons (Figure 3, in blue).22 The relative configuration
of the remaining stereogenic carbon atom at the pendent
oxolane-2,5-dione ring remains unknown.
In none of these reactions was it possible to detect either a
betaine intermediate originating from a stepwise process or a
Michael-type adduct. This experimental observation and the high
levels of stereocontrol of the Diels-Alder reaction point to a
concerted mechanism.23 However, the lower temperature re-
quired when the reactions are run in acetonitrile compared to
that in toluene seems to indicate that the transition state is highly
polarized. Taking into account these facts, we consider that the
Discussion
In spite of the general acceptance that thiazoles may have
low reactivity in Diels-Alder reactions due to their considerable
(22) Jackman, L. M.; Sternhell, S. In Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Synthesis; Pergamon Press: Oxford,
U.K., 1969; pp 334-341.
(23) (a) Tietze, L. F.; Bratz, M.; Machinek, R.; v. Kiedrowski, G. J.
Org. Chem. 1987, 52, 1638-1640. (b) Shimizu, T.; Murakami, H.;
Kamigata, N. J. Org. Chem. 1999, 64, 8489-8494.
2102 J. Org. Chem., Vol. 72, No. 6, 2007

Diels-Alder Reactions of 4-Alkenylthiazoles
SCHEME 6. Proposed Mechanism for Rationalizing the Formation of Compounds endo-7 and 8 from 4-Alkenylthiazoles 1 and
N-Substituted Maleimides
(50 mL) was added the corresponding thioamide 3 (3.0 mmol),
and the reaction mixture was stirred under reflux for 5 h. The solvent
was removed under reduced pressure and 5% NaHCO3 aqueous
solution (50 mL) was added. Then the reaction mixture was
extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts
were dried with MgSO4, the solvent was removed, and the residue
was purified by silica-gel column chromatography.
first step of the sequence yielding 9 is a concerted HOMOdiene
-
LUMOdienophile-controlled Diels-Alder process. The relative
configuration of 8 indicates that the subsequent ene reaction
takes place endo-stereoselectively.
The reaction of 4-alkenylthiazole 1c with maleic anhydride
parallels that with maleimides in the first step, leading to the
corresponding [4 + 2] cycloadduct through an endo approach.
The resulting product would add to a second molecule of maleic
anhydride in a Michael-type fashion to give compound endo-
10.
The formation of 11 may be explained through a Diels-Alder
reaction of 1c,d with naphthoquinone with subsequent 1,3-
hydrogen shift and dehydrogenation of the p-benzoquinone ring.
The last step would be favored by the presence of the
naphthoquinone in the reaction mixture, acting as an oxidant.7e,24
4-[(E)-2-(4-Chlorophenyl)ethenyl]-2-phenylthiazole (1a). AcOEt/
hexane (1:5) was used as eluent (Rf ) 0.49); yield 87%; mp 102-
105 °C (colorless prisms, CHCl3/Et2O); IR (Nujol) 1494, 1442,
1091, 1001, 978, 821, 755, 682 cm-1; 1H NMR (CDCl3) δ 7.09 (d,
1H, J ) 15.9 Hz), 7.17 (s, 1H), 7.33 (d, 2H, J ) 8.6 Hz), 7.44-
7.50 (m, 5H), 7.55 (d, 1H, J ) 15.9 Hz), 8.00-8.04 (m, 2H); 13C
NMR (CDCl3) δ 115.7 (d), 121.9 (d), 126.8 (2 d), 127.9 (2 d),
129.0 (2 d), 129.1 (2 d), 130.3 (d), 130.4 (d), 133.5 (s), 133.6 (s),
135.7 (s), 154.8 (s), 168.3 (s); MS (EI, 70 eV) m/z (rel int) 299
(M+ + 2, 20), 298 (M+ + 1, 18), 297 (M+, 53), 296 (21), 194
(45), 159 (33), 158 (22), 149 (52), 121 (100), 115 (79), 104 (38).
Anal. Calcd for C17H12ClNS (297.80): C, 68.56; H, 4.06; N, 4.70;
S, 10.77. Found: C, 68.21; H, 4.23; N, 4.79; S, 10.62.
Conclusions
In spite of the general acceptance that thiazoles, due to their
considerable aromatic character, may have low reactivity in [4
+ 2] cycloadditions, the computed HOMO energies for 4-alk-
enylthiazoles predict their participation as activated dienes in
this type of process of normal electronic demand, as these energy
values are close to those of Danishefsky-Kitahara and Rawal
dienes. Thus, contrary to some expectations, 4-alkenylthiazoles
1a-e have been demonstrated to behave as reactive all-carbon
dienes in Diels-Alder reactions. Their reactions with N-
substituted maleimides and maleic anhydride take place in a
highly stereocontrolled manner to give the corresponding endo
cycloadducts, which further transform through either a 1,3-
hydrogen shift or an ene reaction or Michael addition with
another molecule of dienophile. Additionally, the reaction of
1c,d with naphthoquinone leads to the corresponding Diels-
Alder adducts, followed by a 1,3-hydrogen shift and partial
dehydrogenation of the heteropolycyclic system. These results
are unprecedented in the chemistry of substituted thiazoles.
Reaction between 4-Alkenylthiazole 1a and N-Phenylmale-
imide without Solvent: Synthesis of Cycloadducts endo-7a and
8a (see Table 2, entry 3). A mixture of alkenylthiazole 1a (0.10 g;
0.34 mmol) and NPM (0.23 g; 1.34 mmol) was stirred at 120 °C
for 4 h. After cooling, the residue was purified by silica-gel
chromatography by use of 1:3 f 1:1 AcOEt/hexane as eluent.
(5R*,5aR*,8aS*)-5-(4-Chlorophenyl)-2,7-diphenyl-4,5,5a,8a-
tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-7a). Rf )
0.13 in 1:3 AcOEt/hexane; yield 21%; mp 250-251 °C (colorless
prisms, CHCl3/Et2O); IR (Nujol) 1782, 1704, 1495, 1191, 1169,
1
1107, 1091, 790, 763, 745, 689 cm-1; H NMR (CDCl3) δ 3.40
(dd, 2H, J ) 5.8 and 1.4 Hz), 3.83 (dt, 1H, J ) 5.8 and 5.4 Hz),
3.91 (dd, 1H, J ) 8.1 and 5.4 Hz), 4.49 (dt, 1H, J ) 8.1 and 1.4
Hz), 6.81 (d, 2H, J ) 7.2 Hz), 7.15 (d, 2H, J ) 8.7 Hz), 7.26 (d,
2H, J ) 8.7 Hz), 7.33-7.38 (m, 3H), 7.47-7.49 (m, 3H), 7.98-
8.00 (m, 2H); 13C NMR (CDCl3) δ 29.7 (t), 39.5 (d), 41.5 (d),
45.8 (d), 121.8 (s), 126.1 (2 d), 126.5 (2 d), 128.78 (2 d), 128.79
(d), 129.06 (2 d), 129.07 (2 d), 129.8 (2 d), 130.5 (d), 131.0 (s),
133.3 (s), 133.5 (s), 138.1 (s), 152.2 (s), 169.1 (s), 173.7 (s), 175.0
(s). MS (EI, 70 eV) m/z (rel int) 472 (M+ + 2, 39), 471 (M+ + 1,
30), 470 (M+, 100), 345 (34), 323 (73), 198 (31). Anal. Calcd for
C27H19ClN2O2S (470.97): C, 68.86; H, 4.07; N, 5.95; S, 6.81.
Found: C, 68.77; H, 3.82; N, 5.88; S, 6.74.
Experimental Section
General Procedure for Synthesis of Thiazoles 1a-e. To a
solution of the corresponding R-haloketone 2 (3.0 mmol) in ethanol
(24) Partial or full dehydrogenation of cycloadducts resulting from the
reaction of dienes with quinones is well documented; see (a) Tominaga,
Y.; Lee, M. L.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 967-972. (b)
Noland, W. E.; Konkel, M. J.; Tempesta, M. S.; Cink, R. D.; Powers, D.
M.; Schlemper, E. O.; Barnes, C. L. J. Heterocycl. Chem. 1993, 30, 183-
192.
(4R*,5S*,5aS*,8aR*)-5-(4-Chlorophenyl)-4-[(3S*)-2,5-dioxo-
1-phenylpyrrolidin-3-yl]-2,7-diphenyl-4,5,5a,8a-tetrahydropyr-
rolo[3,4-g]benzothiazole-6,8-dione (8a). Rf ) 0.06 in 1:3 AcOEt/
J. Org. Chem, Vol. 72, No. 6, 2007 2103

Alajar´ın et al.
hexane); yield 66%; mp 255-257 °C (colorless prisms, CHCl3/
(5R*,5aR*,8aS*,8bR*)-5-(4-Methoxyphenyl)-2,7-diphenyl-5,-
5a,8a,8b-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-
9m). AcOEt/hexane (1:1) was used as eluent (Rf ) 0.16); yield
50%; mp 204-206 °C (colorless prisms, CHCl3/Et2O); IR (Nujol)
1
Et2O); IR (Nujol) 1710, 1495, 1184, 760, 692 cm-1; H NMR
(CDCl3) δ 2.33 (dd, 1H, J ) 17.8 and 6.0 Hz), 2.58 (dd, 1H, J )
17.8 and 9.5 Hz), 3.29-3.37 (m, 2H), 3.87 (dd, 1H, J ) 7.8 and
4.2 Hz), 4.47 (dt, 1H, J ) 11.4 and 2.4 Hz), 4.56 (dd, 1H, J ) 7.8
and 2.1 Hz), 7.09-7.12 (m, 2H), 7.28-7.55 (m, 15H), 7.70-7.72
(m, 2H); 13C NMR (CDCl3) δ 30.0 (t), 38.0 (d), 41.2 (d), 42.8 (d),
44.3 (d), 45.7 (d), 125.3 (s), 126.2 (2 d), 126.5 (2 d), 126.9 (2 d),
128.4 (d), 128.89 (2 d), 128.94 (3 d), 129.1 (2 d), 129.2 (2 d),
130.8 (d), 131.0 (s), 131.1 (2 d), 132.2 (s), 132.7 (s), 134.2 (s),
135.5 (s), 151.7 (s), 169.9 (s), 173.5 (s), 174.2 (s), 175.1 (s), 178.1
(s). MS (EI, 70 eV) m/z (rel int) 645 (M+ + 2, 25), 644 (M+ + 1,
22), 643 (M+, 50), 471 (42), 470 (38), 469 (100). Anal. Calcd for
C37H26ClN3O4S (644.14): C, 68.99; H, 4.07; N, 6.52; S, 4.98.
Found: C, 68.73; H, 4.03; N, 6.87; S, 5.04.
1712, 1514, 1250, 1178, 1030, 825, 727, 690 cm-1 1H NMR
;
(CDCl3) δ 3.53 (dd, 1H, J ) 8.4 and 6.0 Hz), 3.71-3.74 (m, 1H),
3.81-3.85 (m, 4H), 4.87 (dt, 1H, J ) 7.5 and 3.1 Hz), 6.75 (t, 1H,
J ) 3.8 Hz), 6.94 (d, 2H, J ) 8.7 Hz), 7.07-7.09 (m, 2H), 7.27-
7.35 (m, 5H), 7.42-7.51 (m, 3H), 7.92-7.95 (m, 2H); 13C NMR
(CDCl3) δ 42.8 (d), 43.4 (d), 45.0 (d), 49.3 (d), 55.2 (q), 113.8 (2
d), 118.3 (d), 126.3 (2 d), 128.4 (2 d), 128.5 (d), 128.7 (2 d), 128.9
(2 d), 129.8 (2 d), 130.3 (s), 131.4 (s), 132.1 (d), 132.7 (s), 158.7
(s), 159.3 (s), 173.1 (s), 173.9 (s), 174.1 (s). MS (EI, 70 eV) m/z
(rel int) 467 (M+ + 1, 18), 466 (M+, 48), 294 (51), 293 (100), 292
(57), 190 (33), 173 (60), 147 (42), 145 (30), 121 (58). Anal. Calcd
for C28H22N2O3S (466.55): C, 72.08; H, 4.75; N, 6.00; S, 6.87.
Found: C, 71.68; H, 4.87; N, 5.68; S, 7.01.
(5R*,5aR*,8aS*)-8a-(2,5-Dioxo-3-oxolanyl)-5-(4-methylphenyl)-
2-phenyl-5,5a-dihydro-4H-furo[3,4-g]benzothiazole-6,8-dione (en-
do-10). A solution of thiazole 1c (0.20 g; 0.72 mmol) and maleic
anhydride (0.22 g; 2.16 mmol) in acetonitrile (10 mL) was kept at
120 °C in a sealed tube for 48 h. The solvent was removed and the
residue was purified by silica-gel chromatography by use of AcOEt
f 2:1 AcOEt/MeOH as eluent (Rf ) 0.12 in 2:1 AcOEt/MeOH);
yield 38%; mp 247-249 °C (colorless prisms, MeCN); IR (Nujol)
1776, 1702, 1299, 1231, 956, 722 cm-1; 1H NMR (CD3CN) δ 2.36
(s, 3H), 2.81 (dd, 1H, J ) 17.6 and 6.5 Hz), 2.90 (dd, 1H, J )
17.6 and 5.0 Hz), 3.17 (dd, 1H, J ) 16.2 and 12.9 Hz), 3.32 (ddd,
1H, J ) 16.2, 4.3, and 1.1 Hz), 3.38 (dt, 1H, J ) 12.9 and 4.3 Hz),
3.91 (dd, 1H, J ) 6.5 and 5.0 Hz), 4.39 (dd, 1H, J ) 4.3 and 1.1
Hz), 7.22 (d, 2H, J ) 8.0 Hz), 7.39 (d, 2H, J ) 8.0 Hz), 7.49-
7.52 (m, 3H), 7.95-7.98 (m, 2H); 13C NMR (CD3CN) δ 21.4 (q),
29.1 (t), 32.7 (t), 39.5 (d), 49.1 (d), 50.4 (d), 54.5 (s), 125.8 (s),
127.7 (2 d), 129.2 (2 d), 130.3 (2 d), 130.7 (2 d), 132.3 (d), 134.4
(s), 137.96 (s), 138.04 (s), 157.7 (s), 170.7 (s), 170.8 (s), 174.0 (s),
174.1 (s), 174.2 (s). MS (EI, 70 eV) m/z (rel int) 473 (M+, 8), 401
(17), 373 (24), 303 (24), 302 (100). Anal. Calcd for C26H19NO6S
(473.50): C, 65.95; H, 4.04; N, 2.96; S, 6.77. Found: C, 65.62;
H, 4.37; N, 2.54; S, 6.97.
Reaction between 4-Alkenylthiazoles 1a-e and N-Substituted
Maleimides in Acetonitrile: General Procedure for Synthesis
of Compounds endo-7, exo-7, and 8 (see Table 2, entries 4-16).
To a solution of the corresponding 4-alkenylthiazole 1 (0.75
mmol) in acetonitrile (10 mL) was added the appropriate
maleimide (2.25 mmol). The reaction mixture was kept at 120
°C in a sealed tube for 48 h. The solvent was removed and the
residue was purified by silica-gel chromatography.
(5R*,5aR*,8aS*)-5-(4-Chlorophenyl)-2,7-diphenyl-4,5,5a,8a-
tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-7a). AcOEt/
hexane (1:2) was used as eluent (Rf ) 0.20); yield 94% (for
spectroscopic and analytical data see above).
(5R*,5aR*,8aS*)-5-(4-Chlorophenyl)-7-methyl-2-phenyl-4,5,-
5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-
7b). AcOEt/hexane (1:2) was used as eluent (Rf ) 0.17); yield 92%;
mp 188-190 °C (colorless prisms, CHCl3/Et2O); IR (Nujol) 1781,
1714, 1495, 1436, 1331, 1285, 1109, 1092, 1016, 802, 761, 728,
1
684 cm-1; H NMR (CDCl3) δ 2.77 (s, 3H), 3.24 (ddd, 1H, J )
16.3, 8.8, and 1.6 Hz), 3.34 (dd, 1H, J ) 16.3 and 5.0 Hz), 3.63
(dt, 1H, J ) 8.8 and 5.0 Hz), 3.72 (dd, 1H, J ) 8.0 and 5.0 Hz),
4.33 (d, 1H, J ) 8.0 Hz), 7.18 (d, 2H, J ) 8.7 Hz), 7.28 (d, 2H,
J ) 8.7 Hz), 7.44-7.46 (m, 3H), 7.93-7.95 (m, 2H); 13C NMR
(CDCl3) δ 24.7 (q), 29.2 (t), 39.3 (d), 41.7 (d), 46.0 (d), 122.20
(s), 126.40 (2 d), 128.6 (2 d), 129.0 (2 d), 129.4 (2 d), 130.4 (d),
133.1 (s), 133.3 (s), 138.3 (s), 152.3 (s), 168.7 (s), 174.8 (s), 175.8
(s). MS (EI, 70 eV) m/z (rel int) 410 (M+ + 2, 40), 409 (M+ + 1,
21), 408 (M+, 100), 323 (31), 283 (87), 198 (46), 185 (30), 184
(47). Anal. Calcd for C22H17ClN2O2S (408.90): C, 64.62; H, 4.19;
N, 6.85; S, 7.84. Found: C, 64.16; H, 4.22; N, 6.88; S, 7.94.
General Procedure for Synthesis of Compounds 11. A mixture
of the corresponding 4-alkenylthiazoles 1c,d (0.30 mmol) and
naphthoquinone (0.14 g; 0.30 mmol) was dissolved in acetonitrile
(5 mL) and kept at 120 °C in a sealed tube for 72 h. The solvent
was removed and the residue was purified by silica-gel chroma-
tography.
5-(4-Methylphenyl)-2-phenyl-4,5-dihydroantra[2,1-d]thiazole-
6,11-dione (11a). Et2O/hexane (1:5) was used as eluent (Rf ) 0.18);
yield 51%; mp 254-256 °C (red prisms, CHCl3/Et2O); IR (Nujol)
General Procedure for the Preparation of Compounds endo-
9. N-Phenylmaleimide (0.13 g; 0.72 mmol) was added to a solution
of thiazole 1 (0.24 mmol) in acetonitrile (15 mL). The reaction
mixture was stirred under reflux for 96 h. The solvent was removed
and the residue purified by silica-gel chromatography.
1
1668, 1652, 1592, 1507, 1340, 1300, 1267, 731 cm-1; H NMR
(CDCl3) δ 2.28 (s, 3H), 3.52-3.62 (m, 2H), 4.86 (dd, 1H, J ) 7.8
and 2.8 Hz), 6.99 (d, 2H, J ) 8.0 Hz), 7.14 (d, 2H, J ) 8.0 Hz),
7.44-7.48 (m, 3H), 7.71-7.76 (m, 2H), 8.02-8.06 (m, 2H), 8.07-
8.10 (m, 1H), 8.16-8.18 (m, 1H); 13C NMR (CDCl3) δ 21.0 (q),
32.2 (t), 36.3 (d), 120.7 (s), 126.5 (d), 126.6 (3 d), 127.1 (2 d),
129.1 (2 d), 129.5 (2 d), 130.7 (d), 131.2 (s), 132.6 (s), 133.48 (d),
133.54 (s), 134.3 (d), 135.0 (s), 137.1 (s), 138.50 (s), 138.54 (s),
157.4 (s), 174.4 (s), 183.1 (s), 183.2 (s). MS (EI, 70 eV) m/z (rel
int) 434 (M+ + 1, 29), 433 (M+, 100), 432 (25), 431 (32), 430
(46), 416 (75), 342 (31). Anal. Calcd for C28H19NO2S (433.52):
C, 77.57; H, 4.42; N, 3.23; S, 7.40. Found: C, 77.33; H, 4.63; N,
3.29; S, 7.52.
(5R*,5aR*,8aS*,8bR*)-5-(4-Methylphenyl)-2,7-diphenyl-5,5a,-
8a,8b-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-
9g). AcOEt/hexane (1:2) was used as eluent (Rf ) 0.12); yield 24%;
mp 145-147 °C (colorless prisms, CHCl3/Et2O); IR (Nujol) 1713,
1563, 1175, 964, 722, 689 cm-1; 1H NMR (CDCl3) δ 2.36 (s, 3H),
3.53 (dd, 1H, J ) 8.4 and 6.0 Hz), 3.71 (m, 1H), 3.80 (t, 1H, J )
8.0 Hz), 4.84 (dt, 1H, J ) 7.4 and 2.9 Hz), 6.77 (t, 1H, J ) 3.8
Hz), 7.06-7.09 (m, 2H), 7.21 (d, 2H, J ) 8.0 Hz), 7.25-7.35 (m,
5H), 7.42-7.45 (m, 2H), 7.48-7.51 (m, 1H), 7.92-7.95 (m, 2H);
13C NMR (CDCl3) δ 21.1 (q), 43.1 (d), 43.4 (d), 45.0 (d), 49.3 (d),
118.1 (d), 126.3 (2 d), 128.4 (2 d), 128.5 (d), 128.6 (2 d), 128.7 (2
d), 128.9 (2 d), 129.2 (2 d), 131.3 (s), 132.1 (d), 132.7 (s), 135.3
(s), 137.0 (s), 159.3 (s), 173.1 (s), 173.9 (s), 174.0 (s). MS (EI, 70
eV) m/z (rel int) 451 (M+ + 1, 26), 450 (M+, 100), 345 (32), 303
(64), 302 (35), 277 (78), 276 (38), 174 (33), 198 (42), 173 (34), 91
(35). Anal. Calcd for C28H22N2O2S (450.55): C, 74.64; H, 4.92;
N, 6.22; S, 7.12. Found: C, 74.42; H, 4.87; N, 6.48; S, 7.27.
2-Methyl-5-(4-methylphenyl)-4,5-dihydroantra[2,1-d]thiazole-
6,11-dione (11b). AcOEt/hexane (1:5) was used as eluent (Rf )
0.16); yield 45%; mp 164-166 °C (red prisms, CHCl3/Et2O); IR
1
(Nujol) 1655, 1591, 1508, 1335, 1308, 1266, 728 cm-1; H NMR
(CDCl3) δ 2.23 (s, 3H), 2.77 (s, 3H), 3.49 (d, 2H, J ) 5.4 Hz),
4.80 (t, 1H, J ) 5.4 Hz), 6.98 (d, 2H, J ) 8.1 Hz), 7.10 (d, 2H, J
) 8.1 Hz), 7.70-7.73 (m, 2H), 8.06-8.08 (m, 1H), 8.12-8.15
2104 J. Org. Chem., Vol. 72, No. 6, 2007

Diels-Alder Reactions of 4-Alkenylthiazoles
(m, 1H); 13C NMR (CDCl3) δ 19.5 (q), 21.0 (q), 32.1 (t), 36.2 (d),
120.2 (s), 126.5 (d), 126.6 (d), 127.0 (2 d), 129.5 (2 d), 131.2 (s),
132.5 (s), 133.4 (d), 134.2 (d), 135.0 (s), 137.0 (s), 138.2 (s), 138.6
(s), 156.0 (s), 173.4 (s), 183.1 (s), 183.2 (s). MS (EI, 70 eV) m/z(rel
int) 372 (M+ + 1, 18), 371 (M+, 100), 280 (47), 139 (24), 91 (25).
Anal. Calcd for C23H17NO2S (371.45): C, 74.37; H, 4.61; N, 3.77;
S, 8.63. Found: C, 74.09; H, 4.69; N, 3.87; S, 8.49.
frequency calculations at each level of theory verified the identity
of each stationary point as a minimum and were used to provide
an estimation of the zero-point vibrational energies (ZPVE).
Acknowledgment. We are grateful to the “Ministerio de
Educacio´n y Ciencia” (MEC) of Spain and FEDER funds
(Project CTQ2005-02323/BQU) as well to the “Fundacio´n
Se´neca-CARM” (Project PI-1/00749/FS/01) for funding. J.C.
and A.P. are also grateful to the MEC for a fellowship and for
a contract in the frame of the “Ramo´n y Cajal” program,
respectively.
Computational Methods. All calculations were carried out with
the Gaussian0325 suite of programs. The optimizations of dienes
were done at the HF/6-31G26 theoretical level and then with the
B3LYP27 functional by use of the 6-31+G basis set. Endo-7h and
exo-7h were optimized at the B3LYP/6-31+G** level. Harmonic
Supporting Information Available: Full characterization of
R-chloroketones 2a and 2c, thiazoles 1b-e, and compounds endo-
7c-m, exo-7e-f, exo-7h,i, exo-7k,l, 8d, 8g, and 8j,k; 1H-1H
NOESY spectra of endo-7h and exo-7h; crystallographic informa-
tion files (CIF) for endo-7c and 8j; B3LYP/6-31+G** optimized
structures of endo-7h and exo-7h; and Cartesian coordinates,
electronic energy, and first frequency of thiazoles 1f-j and dienes
5 and 6 optimized at the B3LYP/6-31G theoretical level and of
cycloadducts endo-7h and exo-7h optimized at the B3LYP/6-
31+G** level. This material is available free of charge via the
Internet at http://pubs.acs.org.
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