Polar hetero-Diels-Alder reactions of 4-alkenylthiazoles with 1,2,4-triazoline-3,5-diones: An experimental and computational study

Article abstract of DOI:10.1021/jo7021668

(Chemical Equation Presented) The hetero-Diels-Alder reactions of 4-alkenylthiazoles with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) lead to new heteropolycyclic systems in excellent yields and high levels of stereocontrol through an exclusively suprafaci

Full text of DOI:10.1021/jo7021668

Polar Hetero-Diels-Alder Reactions of 4-Alkenylthiazoles with
1,2,4-Triazoline-3,5-diones: An Experimental and Computational
Study
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 October 5, 2007
The hetero-Diels-Alder reactions of 4-alkenylthiazoles with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD)
lead to new heteropolycyclic systems in excellent yields and high levels of stereocontrol through an
exclusively suprafacial approach. 4-Alkenylthiazoles with a stereogenic center placed at the alkenylic
substituent react with PTAD giving the corresponding chiral cycloadducts in moderate diastereomeric
excesses. The stereochemical course is dominated by the steric interactions at the two diastereomeric
transition states. A computational study of these processes with structurally simpler reagents has been
carried out. A concerted pathway via a highly asynchronous transition state is preferred for 2-unsubstituted
4-vinyl and 4-styrylthiazoles. However, two alternative and equally likely pathways, concerted and
stepwise, have been found to be followed by 2-methyl- or 2-phenyl-substituted 4-styrylthiazoles. The
concerted pathway features a highly asynchronous transition state. For the stepwise pathway, the rate-
determining step is the first one, as the energy barrier for the second step is virtually nonexistent.
Introduction
(intra-annular addition) as far as this nucleus contains in turn a
conjugated diene arrangement.3 Recently, we have demonstrated
The Diels-Alder reaction is one of the most versatile methods
for the construction of six-membered rings, as it has been
extended to a wide range of dienes and dienophiles.1 In general,
alkenyl-substituted aromatic heterocycles and their benzoderiva-
tives undergo Diels-Alder reactions with the concourse of the
diene moiety that includes the side chain double bond (extra-
annular addition).2 In most cases this way of interacting is
preferred to that involving the proper heteroaromatic nucleus
(2) (a) Sepu´lveda-Arques, J.; Abarca-Gonza´lez, B.; Medio-Simo´n, M.
AdV. Heterocycl. Chem. 1995, 63, 339-401. (b) C¸ avdar, H.; Sarac¸ogˇlu, N.
J. Org. Chem. 2006, 71, 7793-7799.
(3) (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.
† Departamento de Qu´ımica Orga´nica.
‡ Servicio de Instrumentacio´n Cient´ıfica.
(1) (a) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 5, pp 315-
399. (b) Fringuelli, F.; Taticchi, A. In The Diels-Alder ReactionsSelected
Practical Methods; Wiley: Chichester, UK, 2002. (c) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668-1698.
10.1021/jo7021668 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/04/2008
J. Org. Chem. 2008, 73, 963-973
963

Alajar´ın et al.
that 4-alkenylthiazoles behave as reactive 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,4
in spite of the fact that the thiazole nucleus loses its aromaticity
in the reaction path and this should lead to relatively less
exothermic reactions when compared to classical Diels-Alder
processes.5 Their reactions with N-substituted maleimides,
maleic anhydride, and naphthoquinone take place with high
levels of stereocontrol to give the corresponding endo-cycload-
ducts in good to excellent yields although, 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.4
1,2,4-Triazoline-3,5-diones (TADs) are among the most
reactive dienophiles due to their low LUMO energies.6 Their
Diels-Alder reactions are exceptionally useful in trapping
unstable intermediates,7 characterizing dienes,8 simplifying the
isolation of dienes from complex product mixtures,9 and
temporarily protecting diene moieties from reacting with chemi-
cal agents.10 The mechanisms of both the [4+2]-cycloaddition
and the ene11 reactions with TADs have generated some
controversy along the years. The main question arises from the
nature of the mechanism and the implication of intermediates.
For the cycloaddition processes, experimental studies indicate
that both concerted and stepwise pathways may occur depending
upon the diene structure.12 Thus, for butadienes with a s-cis
conformation readily available, the concerted pathway domi-
nates, and the hetero-Diels-Alder products are obtained with
high levels of stereocontrol. In contrast, when butadienes are
highly substituted and too sterically hindered to be in the s-cis
conformation, the stepwise mechanism becomes favored leading
to poor levels of stereocontrol. To explain this lack of stereo-
control, the implication of an aziridinium imide intermediate
has been suggested, although without direct experimental
evidence.12 These conclusions parallel those extracted from
computational studies by using structurally simple butadienes.13
Thus, these theoretical investigations indicated that the concerted
pathway dominates with highly asynchronous transition states
except for dienes that are too sterically hindered to arrange in
an s-cis conformation.
An important feature of the Diels-Alder reaction is its
potential for achieving the absolute stereochemical control of
up to four contiguous centers in one step.1
The stereochemistry
of the final product results from the structure of diene and
dienophile but also from their relative orientation, endo or exo,
in the transition state and the endo approach is favored by
stabilizing secondary orbital interactions.1
However, a third
stereochemical feature arises when either of the two reactants
possesses two diastereotopic faces, often by virtue of containing
at least one chiral center.14 Among all the possible combinations
of chiral reactants, the reactions between achiral dienes and
chiral dienophiles, such as acrylates, maleates, and fumarates,
have been extensively studied and are now well-established
synthetic protocols.14
In spite of the use of chiral dienes
providing an alternative pathway, their use is less popular
because they are prepared by more elaborated synthetic routes.15
Herein, we report on the hetero-Diels-Alder reactions of
4-alkenylthiazoles with 4-phenyl-1,2,4-triazoline-3,5-dione
(PTAD). As expected, in these reactions 4-alkenylthiazoles
behave as inner-outer dienes forming new heteropolycyclic
systems in excellent yields. High levels of stereocontrol are
obtained as a result of the suprafacial attack and endo approach
of the dienophile. The facial diastereoselectivity by using chiral
4-alkenylthiazoles with a stereogenic center placed at the
alkenylic substituent also has been studied, although their
reactions with PTAD result in moderate diastereomeric excesses.
Here we also provide an interpretation of the stereochemical
biases of these cycloaddition processes. Finally, the mechanism
of the reaction of some representative 4-alkenylthiazoles with
1,2,4-triazoline-3,5-dione (HTAD) has been scrutinized com-
putationally. The results here disclosed are interesting not only
from the synthetic point of view but also because they shed
some light on the always controvertible mechanism of the [4+2]
cycloaddition of triazolinediones with dienes.
Results and Discussion
Reactions of Achiral 4-Alkenylthiazoles 1a-d with PTAD.
The reactions of 4-alkenylthiazoles 1a-d16 with PTAD were
conducted in toluene at room temperature (Scheme 1). After 5
min the initial purple color of the solution faded totally
indicating that the reaction was complete. The 5,10a-dihy-
drothiazolo[5,4-c]1,2,4triazolo[1,2-a]pyridazin-7,9-diones 2a-d
were isolated by filtration as single diastereoisomers in quantita-
tive yields (Scheme 1 and Table 1).
We have reported that the primary adducts resulting from
the [4+2] cycloaddition of 1 with N-substituted maleimides
experienced 1,3-hydrogen migration at elevated temperatures
causing the rearomatization of the thiazole ring.17 On the
contrary, the thermal treatment of the cycloadduct 2a (toluene,
(4) Alajar´ın, M.; Cabrera, J.; Pastor, A.; Sa´nchez-Andrada, P.; Bautista,
D. J. Org. Chem. 2007, 72, 2097-2105.
(5) Manoharan, M.; De Proft, F.; Geerlings, P. J. Chem. Soc., Perkin
Trans. 2 2000, 1767-1773.
(6) (a) Moody, C. J. AdV. Heterocycl. Chem. 1982, 30, 1-45. (b) Ra´dl,
S. AdV. Heterocycl. Chem. 1997, 67, 119-205.
(7) Anastassiou, A. G.; Yakali, E. J. Chem. Soc., Chem. Commun. 1972,
92-93.
(8) (a) Askani, R.; Chesick, J. P. Chem. Ber. 1973, 106, 8-19. (b)
Imagawa, T.; Sueda, N.; Kawanisi, M. J. Chem. Soc., Chem. Commun. 1972,
388. (c) Kobal, V. M.; Gibson, D. T.; Davies, R. E.; Garza, A. J. Am. Chem.
Soc. 1973, 95, 4420-4421.
(9) (a) Poutsma, M. L.; Ibarbia, P. A. Tetrahedron Lett. 1970, 11, 4967-
4970. (b) Poutsma, M. L.; Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440-
450.
(10) (a) Ochi, K.; Matsunaga, I.; Nagano, H.; Fukushima, M.; Shindo,
M.; Kaneko, C.; Ishikawa, M.; DeLuca, H. F. J. Chem. Soc., Perkin Trans.
1 1979, 165-169. (b) Bosworth, N.; Emke, A.; Midgley, J. M.; Moore, C.
J.; Whalley, W. B.; Ferguson, G.; Marsh, W. C. J. Chem. Soc., Perkin Trans.
1 1977, 805-809. (c) Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi,
T.; Patin, H.; Widdowson, D. A.; Worth, B. R. J. Chem. Soc., Perkin Trans.
1 1976, 821-826.
(11) Vougioukalakis, G. C.; Orfanopoulos, M. Synlett 2005, 713-731.
(12) (a) Jensen, F.; Foote, C. S. J. Am. Chem. Soc. 1987, 109, 6376-
6385. (b) Clenan, E. L.; Earlywine, A. D. J. Am. Chem. Soc. 1987, 109,
7104-7110.
(14) (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876-
889. (b) Maddaluno, J. Synlett 2006, 41, 2534-2547.
(15) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121,
9562-9573. (b) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J.
Org. Chem. 2000, 65, 9059-9068. (c) Garner, P.; Anderson, J. T.; Turske,
R. A. Chem. Commun. 2000, 1579-1580. (d) Søndergaard, K.; Liang, X.;
Bols, M. Chem. Eur. J. 2001, 7, 2324-2331. (e) Urabe, H.; Kusaka, K.;
Suzuki, D.; Sato, F. Tetrahedron Lett. 2002, 43, 285-289. (f) Kuethe, J.
T.; Brooks, C. A.; Comins, D. L. Org. Lett. 2003, 5, 321-323.
(16) The synthesis of 4-alkenylthiazoles 1a-d has been reported
previously by the authors, see ref. 4.
(13) (a) Chen, J. S.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998,
120, 12303-12309. (b) Singleton, D. A.; Schulmeier, B. E.; Hang, C.;
Thomas, A. A.; Leung, S.-W.; Merrigan, S. R. Tetrahedron 2001, 57, 5149-
5160. (c) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243-1255.
(17) These compounds were obtained from the reaction of dienes 1 with
N-substituted maleimides in acetonitrile at 120 °C, see ref 4.
964 J. Org. Chem., Vol. 73, No. 3, 2008

Diels-Alder Reactions of 4-Alkenylthiazoles with PTAD
TABLE 1. Cycloadducts 2 Resulting from the Reaction of
4-Alkenylthiazoles 1 with PTAD
SCHEME 1. The Reaction of 4-Alkenylthiazoles 1a-d with
PTAD Leading to Cycloadducts 2a-d (R1 and R2 Defined in
Table 1)
thiazole
R1
R2
adduct
yield (%)
1a
1b
1c
1d
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Ph
Me
Ph
Me
2a
2b
2c
2d
quant.
quant.
quant.
quant.
TABLE 2. Reaction Conditions and Yields in the Synthesis of
r-Chloroketones 7a-c and 4-Alkenylthiazoles 4a-c
R-chloroketones 7
thiazoles 4
yield
T
t
yield
SCHEME 2. Thermal Treatment of 2a Leading to a
Mixture of the Starting Thiazole 1a and 3aa
R1
R2 (°C) (days) compd (%)a compd (%)a
Ph
Ph
Me rt
Et 40
rt
7
5
4
7a
7b
7c
80
60
75
4a
4b
4c
63
67
60
-CH2CH2OCH2-
a After purification by column chromatography.
protons show mutual coupling constants in the range of 2.8-
3.8 Hz, typical values for assessing a cis relationship between
H5 and H10a
.
The trans stereochemical relationship of compound 3a was
assigned on the basis of the X-ray structure of another 1:2
4-styrylthiazole-PTAD adduct reported below (compound 10a)
and the similarity of their NMR spectral data. In particular, the
two coupling constants between their respective H4 and H5
protons at the six-membered ring of 3a (see Scheme 2) present
similar values (1.4 Hz). The relative configuration of 3a reveals
valuable information, i.e., the ene reaction of 2a with PTAD is
a highly stereoselective suprafacial process. This stereochemical
fact was recently recognized and holds important implications
for the mechanism of this type of reaction.19
a The compound 3a could be exclusively obtained by treatment of 2a
with PTAD.
SCHEME 3. Reactions of Phosphorane 5 with Chiral
Aliphatic Aldehydes 6a-c and Further Synthesis of
4-Alkenylthiazoles 4a-c (R1 and R2 Are Defined in Table 2)
Study of the Facial Diastereoselectivity in the Cycload-
dition Reactions of Chiral 4-Alkenylthiazoles 4a-c with
PTAD. The chiral, racemic 4-alkenylthiazoles 4a-c possess a
stereogenic center directly attached to the â-carbon atom of the
alkenylic substituent at C4 of the thiazole ring (Scheme 3). They
were easily prepared by a two-step synthetic route. Thus, (3-
chloroacetonylidene)triphenylphosphorane (5) and the corre-
sponding chiral aldehyde 6a-c were reacted in toluene solution
to give R-chloroketones 7a-c. In general, these Wittig reactions
were conducted in the presence of a great excess of aldehyde
and at relatively low temperatures4 to avoid polymerizations
(Table 2). 4-Akenylthiazoles 4a-c were obtained through a
Hantzsch synthesis20 from the R-chloroketones 7a-c and
thiobenzamide (Table 2).
The reaction of 4a with PTAD in toluene at room temperature
for 30 min led to a mixture of three products 8a, 9a, and 10a
in good overall yield (Scheme 4 and Table 3, entry 1). The two
diastereoisomers 8a and 9a are the result of the hetero-Diels-
Alder reaction of 4a and PTAD, involving the approach of the
dienophile to both diastereotopic faces of the diene, while 10a
comes from a subsequent ene reaction of one of these two
diastereoisomers with a second molecule of the reagent. The
three products were easily separated by chromatographic
techniques. After isolation, each primary adduct, i.e., 8a and
9a, was reacted separately with PTAD to elucidate the origin
140 °C) provided a mixture of the starting diene 1a and a new
product 3a that results from the ene reaction of 2a with a second
molecule of PTAD. Both compounds 1a and 3a were separated
and isolated in approximately similar yields, which was 67%
overall (Scheme 2). This finding may be explained taking into
account the partial decomposition of 2a into the starting
materials by a retro hetero-Diels-Alder reaction and the
subsequent combination of the remaining 2a with the PTAD
generated in the reaction mixture. The cycloadduct 3a also could
be prepared in nearly quantitative yield from 2a and PTAD in
refluxing toluene (Scheme 2). The ene reaction of 2a with PTAD
takes place in a highly stereocontrolled manner since 3a was
isolated as a single diastereoisomer.
The relative configurational assignment of the two stereogenic
centers C5 and C10a in compounds 2 (see Scheme 1) was done
by comparison of the coupling constants between their methine
protons with those reported for an analogous structure.18 These
(19) Vassilikogiannakis, G.; Elemes, Y.; Orfanopoulos, M. J. Am. Chem.
Soc. 2000, 122, 9540-9541.
(20) (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. III, pp 332 and 333.
(18) Roa, R.; O’Shea, K. E. Tetrahedron 2006, 62, 10700-10708.
J. Org. Chem, Vol. 73, No. 3, 2008 965

Alajar´ın et al.
SCHEME 4. Reactions of 4a, 8a, and 9a with PTAD
SCHEME 5. Reaction of 4-Alkenylthiazoles 4b or 4c with
PTAD
of 10a (Scheme 4). These reactions led to 10a from 8a, and
11a from 9a, in 92% and 85% yield, respectively.
The reaction of 4a with PTAD was also conducted at lower
temperature, -5 °C, in an attempt aimed either to suppress the
formation of subsequent ene adducts or/and to improve the facial
diastereoselectivity of the cycloaddition step (Table 3, entry 2).
After 30 min, 8a and 9a were exclusively isolated in 93%
combined yield although in a moderate diastereomeric excess,
8a being the major diastereoisomer. Finally, 4a and PTAD were
allowed to react in acetonitrile at -5 °C for 30 min but, under
these conditions, the reaction was practically not diastereose-
lective (Table 3, entry 3).
The diastereoselectivity of the reactions of 4b and 4c with
PTAD was subsequently investigated. In both cases, the hetero-
Diels-Alder adducts 8b/9b and 8c/9c were isolated as mixtures
of diastereoisomers in an approximately 63:37 ratio, 8b and 8c
being the respective major products (Scheme 5). Although the
global yields were excellent (85-90%), we were not able to
resolve the diastereomeric mixtures 8b/9b and 8c/9c (see the
Supporting Information).
The cis stereochemistry of the central ring of the 5,10a-
dihydrothiazolo[5,4-c][1,2,4]triazolo[1,2-a]pyridazin-7,9-di-
ones 8a-c and 9a-c was again evident from the coupling
constants between the methine protons H4, H5, and H10a (these
positions have been marked in the structures of 8a and 9a in
Scheme 4) with values in the range of 2.0-3.6 Hz close to those
shown by cycloadducts 2. Obviously, each pair of diastereoi-
someric cycloadducts 8 and 9 results from the approximation
of PTAD to both heterotopic faces of each diene 4. The
configurational assessment of 10a was done on the basis of its
crystal structure solved by X-ray analysis (Supporting Informa-
tion), which reveals a trans relationship between protons H4
and H5 and a dihedral angle between the H4-C4-C5 and C4-
C5-H5 planes of 83°. The tridimensional architecture of 10a
in the crystals seems to be kept in solution, as the coupling
constant value between these two protons, H4 and H5, deter-
1
mined from the solution H NMR spectrum of 10a is close to
1 Hz. The X-ray crystal structure of 10a allowed us to assign
unequivocally the relative configuration of the exocyclic ste-
reocenter in compound 8a and, by extrapolation, in 9a and 11a.
To rationalize the stereochemical course of these processes,
we propose the model depicted below, which is exemplified
for the particular case of the reaction of 4a with PTAD. The
vast majority of the reported examples on π-facial diastereo-
controlled [4+2] cycloaddition reactions of chiral dienes involve
substrates with polar functional groups placed at the allylic
position.21 Although, in general terms, the diastereofacial
selectivity is directed by a subtle combination of steric and
electronic effects which depend on the structure of the diene, it
is usually dominated by the preference of the polar group to be
in the plane of the diene and the smallest substituent at the allylic
carbon, usually a hydrogen atom, as the group closest to the
TABLE 3. Reaction Conditions and Ratio of Products 8a, 9a, and
10a Obtained in the Reaction of the Chiral 4-Alkenylthiazole 4a
with PTAD
entry solvent T (°C) 8a:9a:10aa 8a (%)b 9a (%)b 10a (%)b
1
2
3
toluene rt
43:30:27
67:33:00
50:50:00
31
62
45
24
31
42
19
0
0
toluene -5
MeCN
-5
a Determined from the integration of characteristic signals in the 1H NMR
spectra of the crude products; error (5% of the stated value. b After
chromatography.
966 J. Org. Chem., Vol. 73, No. 3, 2008

Diels-Alder Reactions of 4-Alkenylthiazoles with PTAD
SCHEME 6. The Most and Least Favorable Trajectories
for the Approach of PTAD to a Single Enantiomer of
4-Alkenylthiazole 4a
expected that the smallest group, i.e., the allylic hydrogen atom,
occupies the inside position for the sake of minimizing steric
interactions with the incoming dienophile as well as 1,3-allylic
strain.24 The same statements also have been furnished by the
computed transition states of the cycloaddition reactions between
polyenes and maleic anhydride.25 As far as the approach of the
dienophile is concerned, an endo attack is expected to be
strongly preferred as a result of electrostatic repulsions between
the lone pairs of the diazo group and the π-system of the diene
in the alternative exo transition state (exo-lone-pair effect).26
The stereoselectivity deriving of this latter preference is not
reflected in the structure of the reaction products when the
dienophile is PTAD because the nitrogen centers of the
triazolidine moiety undergo rapid inversion. Taking into account
all previous considerations, we propose that the endo approach
of the PTAD to conformer A for the less hindered side is the
most favorable one (Scheme 6). In this model, the phenyl group
at the allylic position is placed antiperiplanar to the approaching
trajectory of the dienophile and the hydrogen atom is located
in the inside position. Alternatively, the approach of the PTAD
to the less hindered face of B, having the diene fragment rotated
180° with respect to A, would be less favored due to the
presence in the corresponding transition state of more notable
steric interactions between the incoming dienophile and the
allylic methyl group, placed close to the forming cyclic
framework. On the basis of this mechanistic scrutiny, the
cycloadduct 8a is expected to be the major diastereoisomer, as
was experimentally observed (Scheme 6). To rationalize the
diastereoselectivities observed for 4b and 4c, we have considered
analogous approaches. The configurational assignment of 8b/
8c and 9b/9c was performed on the basis of this assumption,
and also by considering a similar steric requirement of the Me
and CH2OR groups.27,28
SCHEME 7. Reaction between HTAD (12) and the
Thiazoles 13a-d Leading to the [4+2] Cycloadducts 14a-d
bond formation trajectory.22 After this criterion is met the
dienophile approaches from the less hindered side. On the
contrary, substrates 4a-c lack polar substituents and, as a
consequence, this steering phenomenon. Scheme 6 shows the
two alternative modes of approximating diene and dienophile,
with the participation of the two diastereofaces of a single
enantiomer of diene 4a, which is depicted in its two more
reasonable reactive conformations A and B. These two ap-
proaches are based on previous theoretical calculations reported
by Houk et al., showing that there is a significant tendency for
allylic bonds of acyclic alkenes to adopt a staggered arrangement
with respect to the partially formed bonds in the transition states
of related addition reactions.23 Notably, they also established
that there is a large conformational preference to place the bond
between the largest group attached to the stereogenic carbon
and this atom antiperiplanar to the forming bond.23 It is also
Computational Study
Computational Methods. All structures were optimized
using the functional B3LYP29 and the 6-31+G** basis set as
implemented in the Gaussian03 suite of programs.30 Density
Functional Theory has been shown to reliably predict the results
of [4+2] Diels-Alder and other pericyclic reactions.31 All
energy minima and transition structures were characterized by
frequency analysis. The energies reported in this work include
the zero-point vibrational energy corrections (ZPVE) and are
not scaled. The intrinsic reaction coordinates (IRC)32 were
followed to verify the energy profiles connecting each transition
(24) (a) Johnson, F. Chem. ReV. 1968, 68, 375-413. (b) Hoffmann, R.
W. Chem. ReV. 1989, 89, 1841-1860.
(21) (a) Tripathy, R.; Franck, R. W.; Onan, K. D. J. Am. Chem. Soc.
1988, 110, 3257-3262. (b) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.;
Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4625-4633. (c) McDougal,
P. G.; Jump, J. M.; Rojas, C.; Rico, J. G. Tetrahedron Lett. 1989, 30, 3897-
3900. (d) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J.; Huang,
L.; Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990, 112, 8472-8478. (e)
Adam, W.; Gla¨ser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc. 1995, 117,
9190-9193. (f) Crisp, G. T.; Gebauer, M. G. J. Org. Chem. 1996, 61, 8425-
8431. (g) Ruijter, E.; Schu¨ltingkemper, H.; Wessjohann, L. A. J. Org. Chem.
2005, 70, 2820-2823.
(25) Turner, C. I.; Paddon-Row, M. N.; Willis, A. C.; Sherburn, M. S.
J. Org. Chem. 2005, 70, 1154-1163.
(26) (a) McCarrick, M. A.; Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc.
1992, 114, 1499-1500. (b) McCarrick, M. A.; Wu, Y.-D.; Houk, K. N. J.
Org. Chem. 1993, 58, 3330-3343.
(27) Although steric effects depend so much upon the precise direction
from which a reagent approaches that there can be no single scale for
evaluating the effective size of a group, we assume that H < Me < Ph,
see: Fleming, I.; Lewis, J. J. J. Chem. Soc., Chem. Commun. 1985, 149-
151.
(22) Kaila, N.; Franck, R. W.; Dannenberg, J. J. J. Org. Chem. 1989,
54, 4206-4212.
(28) These steric requirements are based on A values, see: McGarvey,
G. J.; Williams, J. M. J. Am. Chem. Soc. 1985, 107, 1435-1437.
(29) (a) Bartolotti, L. J.; Fluchichk, K. In ReViews in Computational
Chemistry; Lipkowitz, K. B., Boyds, D. B., Eds.; VCH Publishers: New
York, 1996; Vol. 7, pp 187-216. (b) Kohn, W.; Becke, A. D.; Parr, R. G.
J. Phys. Chem. 1996, 100, 12974-12980. (c) Parr, R. G.; Pearson, R. G. J.
Am. Chem. Soc. 1983, 105, 7512-7516. (d) Ziegler, T. Chem. ReV. 1991,
91, 651-667.
(23) (a) Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K.
N. J. Am. Chem. Soc. 1981, 103, 2438-2440. (b) Paddon-Row, M. N.;
Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162-7166. (c)
Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.; Brown, F.
K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986,
231, 1108-1117.
J. Org. Chem, Vol. 73, No. 3, 2008 967

Alajar´ın et al.
state to the correct local minima, by using the second-order
Gonzalez-Schlegel integration method.33 Wiberg bond orders34
and natural atomic charges were calculated within the natural
bond orbital (NBO) analysis.35 The synchronicity of the reactions
was determined by using a previously described approach.36 The
solvent effects have been considered by B3LYP/6-31+G**
single-point calculations using a Self-Consistency Reaction Field
(SCRF)37 method, based on the Polarized Continuum Model
(PCM)38 of Tomasi and co-workers, in toluene and acetonitrile
as solvents.
For simplicity, in order to model the reaction of PTAD with
the thiazoles 1a-d presented in the experimental part of this
work, we selected as reactants the structurally simpler HTAD
(12) and the four thiazoles 13a-d. We have carried out an
intensive exploration of the B3LYP/6-31+G** potential energy
surfaces associated with the [4+2] cycloaddition reactions of
HTAD with the thiazoles 13a-d leading to the cycloadducts
14a-d, respectively (Scheme 7).
FIGURE 1. Qualitative reaction profiles at the B3LYP/6-31+G** level
of the reactions between HTAD (12) and the thiazoles 13a and 13b
leading to the cycloadducts 14a and 14b, respectively, through the
transition states TS1a,b, TS2a,b, and TS3a,b.
Figure 1 displays the qualitative reaction profiles at the
B3LYP/6-31+G** theoretical level and the location of the
stationary points for the Diels-Alder reactions between HTAD
and thiazoles 13a and 13b, while the qualitative reaction profiles
corresponding to the reactions of HTAD with the thiazoles 13b-
d, though the intermediates INT1b,c and INT2d, are shown in
(30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(31) See for example: (a) Goldstein, E.; Beno, B.; Houk, K. N. J. Am.
Chem. Soc. 1996, 118, 6036-6043. (b) Wiest, O.; Montiel, D. C.; Houk,
K. N. J. Phys. Chem. A 1997, 101, 8378-8388. (c) Garcia, J. I.; Martinez-
Merino, V.; Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1998, 120,
2415-2420. (d) Domingo, L. R.; Arno´, M.; Andre´s, J. J. Am. Chem. Soc.
1998, 120, 1617-1618. (e) Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J.
Org. Chem. 1998, 63, 1064-1073. (f) Birney, D. M. J. Am. Chem. Soc.
2000, 122, 10917-10925.
FIGURE 2. Qualitative reaction profiles at the B3LYP/6-31+G** level
of the reactions between HTAD (12) and the thiazoles 13b-d leading
to the cycloadducts 14b-d through the dipolar intermediates INT1b,c
and INT2d, respectively.
Figure 2. Figures 3 and 4 show the geometries of the relevant
stationary points (excluding reactants and cycloadducts), includ-
ing the most significant bond distances. Table 4 contains the
relative and free energies of the stationary points at the B3LYP/
6-31+G** theoretical level and selected geometrical and
electronic parameters. In Table 5 the static global properties
(electronic chemical potential µ, chemical hardness η, and global
electrophilicity ω) of HTAD and the thiazoles 13a-d are
displayed. We will comment only on the electronic energies,
unless otherwise stated.
For the Diels-Alder reaction of HTAD with 13a and 13b,
two endo (TS1a,b and TS2a,b) and one exo (TS3a,b) transition
structures were located. The difference between the two endo
transition structures TS1 and TS2 relies simply in which of the
forming C-N bonds is more advanced. Thus, whereas in TS1
the more advanced forming bond is C5-N, in TS2 it is instead
the C1-N bond (see Table 4).
(32) (a) Fukui, K. J. Phys. Chem. 1970, 74, 4161-4162. (b) Fukui, K.
Acc. Chem. Res. 1981, 14, 363-368.
(33) (a) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-
5527. (b) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1991, 95, 5853-
5860.
(34) Wiberg, K. B. Tetrahedron 1968, 24, 1083-1096.
(35) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
1985, 83, 735-746. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem.
ReV. 1988, 88, 899-926. (c) Reed, A. E.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1990, 112, 1434-1445.
(36) (a) Borden, W. T.; Loncharich, R. J.; Houk, K. N. Annu. ReV. Phys.
Chem. 1988, 39, 213-236. (b) Moyano, A.; Pericas, M. A.; Valenti, E. J.
Org. Chem. 1989, 54, 573-582. (c) These indexes also have been used to
characterize cycloaddition reactions other than [4+2], see for example:
Lecea, B.; Ayerbe, M.; Arrieta, A.; Coss´ıo, F. P.; Branchadell, V.; Ortun˜o,
R. M.; Baceiredo, A. J. Org. Chem. 2007, 72, 357-366.
(37) (a) Tomasi, J.; Persico, M. Chem. ReV. 1994, 94, 2027-2094. (b)
Simkin, B. Y.; Sheikhet, I. Quantum Chemical and Statical Theory of
SolutionssA Computational Approach; Ellis Horwood: London, UK, 1995;
pp 78-101.
(38) (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117-
129. (b) Cammi, R.; Tomasi, J. J. Chem. Phys. 1994, 100, 7495-7502. (c)
Barone, V.; Cossi, M.; Tomasi, J. J. Chem. Phys. 1997, 107, 3210-3221.
The exo transition structures were higher in energy than their
endo counterparts. As stated above, the preference for endo
transition structures can be easily explained on the basis of the
exo-lone-pair effect in hetero-Diels-Alder reactions.26 Accord-
ingly, in the exo transition structures TS3a,b, the lone pairs at
968 J. Org. Chem., Vol. 73, No. 3, 2008

Diels-Alder Reactions of 4-Alkenylthiazoles with PTAD
TABLE 4. Relative Energies with Zero-Point Vibrational Energy
Corrections (kcal‚mol-1), Relative Free Energies (kcal‚mol-1), Bond
Distances (d, in Å), and Bond Orders (BO) of the Forming C-N
Bonds, and Synchronicities (Sy), Calculated at the B3LYP/
6-31+G**// B3LYP/6-31+G** Theoretical Level for the Stationary
Points Found in the Diels-Alder Reactions of HTAD with the
Thiazoles 13a-d Leading to the Cycloadducts 14a-d
rel
energy
rel free
energy
C1-N
d/BO
C5-N
d/BO
structure
Sy
TS1a (endo)
TS2a (endo)
TS3a (exo)
14a
6.37
13.04
16.29
-25.46
9.58
20.00
27.29
29.77
-10.78
23.97
19.73
21.33
24.65
31.14
-1.68
23.50
18.87
20.89
22.92
-3.05
23.60
22.79
15.23
16.75
-2.75
2.776/0.09
1.852/0.52
2.646/0.14
1.456/0.94
2.771/0.11
2.584/0.17
2.246/0.32
1.883/0.50
1.880/0.14
1.420/0.99
2.693/0.12
2.493/0.21
2.334/0.27
1.904/0.48
1.423/0.99
2.688/0.12
1.913/0.47
1.481/0.91
1.481/0.91
1.423/0.99
1.946/0.43
2.638/0.14
1.907/0.49
1.460/0.94
1.871/0.49
1.515/0.85
1.515/0.86
2.724/0.11
2.647/0.52
1.487/0.92
1.882/0.48
1.516/0.86
1.517/0.86
2.754/0.11
1.487/0.92
1.877/0.49
2.774/0.10
2.554/0.19
2.259/0.32
1.487/0.92
0.72
0.73
0.80
TS1b (endo)
INT1b
0.73
5.75
TS4b
6.05
TS2b (endo)
TS3b (exo)
14b
10.31
17.32
-16.45
8.63
0.74
0.74
TS1c (endo)
INT1c
0.73
4.45
TS4c
4.52
TS2c (endo)
14c
8.23
0.72
-18.45
TS1d (endo)
TS2d (endo)
INT2d
8.80
0.75
0.72
8.20
0.60
TS5d
14d
0.83
-17.97
TABLE 5. Calculated Values of Electrophilicity (ω, in eV),
Electronic Chemical Potential (µ, in au), and Chemical Hardness (η,
in au) for HTAD (12) and Thiazoles 13a-d
FIGURE 3. B3LYP/6-31+G**-optimized geometries showing relevant
bond distances of the stationary points found in the reactions of HTAD
(12) with the thiazoles 13a,b leading to the [4+2] cycloadducts 14a,b.
ω
µ
η
∆ω (ω12-ω13)
12
5.4355
1.6400
1.8571
1.7864
1.9574
-0.2262
-0.1469
-0.1421
-0.1380
-0.1408
0.1281
0.1789
0.1480
0.1450
0.1378
13a
13b
13c
13d
3.80
3.58
3.65
3.48
by Houk in the computational study of the Diels-Alder reaction
of HTAD with butadiene.13a,c
For the reaction of HTAD with 4-vinylthiazole (13a), TS1a
is the lowest in energy (6.4 kcal/mol up to reactants), whereas
the other endo transition state (TS2a) is 13.0 kcal‚mol-1 higher
in energy than the reactants. However, after including the
entropy correction, the free energies turned out to be 20.0 and
27.3 kcal‚mol-1 for TS1a and TS2a, respectively (see Table
4). The difference in energy between these endo transition
structures and exo TS3a is 9.92 kcal‚mol-1 between TS1a and
TS3a and 3.25 kcal‚mol-1 between TS2a and TS3a. From these
calculations it seems clear that the preferred channel for the
formation of cycloadduct 13a is via TS1a. For the reaction of
HTAD with 13b the energy difference between both endo
transition states, TS1b and TS2b, is only 0.7 kcal‚mol-1, lower
than in the preceding reaction, again TS2b being higher in
energy than TS1b. The preference for endo transition structures
still dominates with an energy difference of 7.74 kcal‚mol-1
between TS1b and TS3b and 7.01 kcal‚mol-1 between TS2b
and TS3b.39
Interestingly, there is a significant twisting between the diene
fragment of the thiazole and the HTAD ring in the four endo
transition structures, the HTAD ring being tilted 47-50° relative
to the plane of the diene fragment. In contrast, the exo transition
FIGURE 4. B3LYP/6-31+G**-optimized geometries showing relevant
bond distances of the stationary points found in the reactions of HTAD
(12) with the thiazoles 13c,d leading to the [4+2] cycloadducts 14c,d.
(39) Whereas in exo-TS3a the more advanced forming bond is C5-N,
in exo-TS3b it is the C1-N bond. We have located another exo transition
state for the reaction of HTAD with 13b where the more advanced forming
bond is C5-N, but it is higher in energy than exo-TS3b, see the Supporting
Information. In contrast, for the reaction of HTAD with 13a we have only
found one exo transition state, exo-TS3a.
the two double bonded nitrogen atoms of HTAD, which are
endo positioned with respect to the diene π-system, induce a
massive destabilizing effect. Similar results have been reported
J. Org. Chem, Vol. 73, No. 3, 2008 969

Alajar´ın et al.
structures TS3a,b show less significant twisting (see Table S1
in the Supporting Information).40
suggested that the feasibility of a Diels-Alder reaction is related
to the charge transfer along the bond-forming processes, in
correspondence with the more or less polar character of these
reactions.42a,c,43 The B3LYP/6-31+G** natural atomic charges
at the transition states show the charge transferred from the
donor thiazole to the acceptor HTAD. The values of the charge
transferred from 13a-d to 12 vary from 0.34e to 0.47e (see
Table S1 in the Supporting Information). These data reveal that
HTAD is acting as an electron acceptor and the thiazoles 13a-d
as electron donors as the charge transfer fluxes from the dienes
to the dienophile.
With these results in hand, and taking into account the exo-
lone-pair effect (see above), we have not optimized the
corresponding exo transition states for the reactions of HTAD
with the thiazoles 13c and 13d, studying in depth only the endo
approaches. The substitution of the hydrogen atom at the
2-position of the thiazole ring in 13b by a methyl or a phenyl
group (thiazoles 13c and 13d) leads to slight decreases in the
energies of the respective two endo transition structures (TS1c,d
and TS2c,d). The transition states TS2c,d are lower in energy
than TS1c,d, in sharp contrast with the previous results found
in the reactions of 13a,b, where TS1a,b are less energetic than
TS2a,b. Due to the small energy differences between TS1b-d
and TS2b-d the formation of 14b-d may well take place by
any of these two competitive channels.
All these reactions are exothermic processes, their reaction
energies being in the range of -16.4 to -25.46 kcal‚mol-1. In
all the computed reactions, the two types of located endo
transition structures, TS1a-d and TS2a-d, are highly asyn-
chronous. This is not surprising because even the reaction of
HTAD with butadiene, in spite of the symmetry of both
reactants, has been described to proceed through a highly
unsymmetrical and asynchronous transitions state.13 As intro-
duced above, whereas in TS1a-d the formation of the bond
between the exocyclic terminal carbon atom of the diene
fragment and the nitrogen atom (C5-N bond) is notably more
advanced compared to that between the second nitrogen atom
and the endocyclic terminal carbon atom (C1-N bond), the
opposite is found in TS2a-d. Thus, the C1-N and C5-N bond
distances in TS1a-d range from 2.69 to 2.78 Å and 1.87 to
1.95 Å, respectively. In contrast, the same bond distances in
TS2a-d are between 1.85 and 1.91 Å (C1-N) and between
2.64 and 2.75 Å (C5-N).
Both theoretical tools, charge transfers and bond orders,
indicate that these cycloaddition reactions, taking place via
highly asynchronous transition states, are polar processes
characterized by the nucleophilic attack of the thiazole to the
NdN double bond of HTAD. The same conclusions can be
reached from the analysis of the values of the static global
properties (electronic chemical potential µ, chemical hardness
η, and global electrophilicity, ω) of both reaction partners. These
electronic indexes, as defined within the DFT of Pearson, Parr,
and Yang,29c,44 are useful tools for understanding the reactivity
of molecules in their ground states. Thus, the electronic chemical
potential µ describes the changes in electronic energy with
respect to the number of electrons, and it is usually associated
with the charge transfer ability of the system in its ground state
geometry. Apart from this value, it is also possible to obtain a
quantitative estimation of the chemical hardness concept
introduced by Pearson29c,44,45 by calculating the η index. Finally,
Parr et al.46 have introduced a useful definition of global
electrophilicity (ω), which measures the stabilization in energy
when the system acquires an additional electronic charge ∆N
from the environment. In fact, this index has been extensively
used by Domingo42c,43,47 and others42b to classify dienes and
dienophiles on a unique scale of electrophilicity.48 Additionally,
the more or less polar character of a cycloaddition reaction36c
can be measured as the difference between the electrophilicities
of diene and dienophile. All these indexes (µ, η, and ω) can be
calculated by solving very simple operational equations, as
defined in eqs 1-3, in terms of the one-electron energies of
the HOMO (EH) and LUMO (EL) frontier molecular orbitals.29d,44
Compared with the bond distance, the bond order (BO)34 is
a more balanced measure of the extent of a bond-formation or
bond-breaking process along a reaction pathway. This theoretical
tool, quite common in the computational study of reaction
mechanisms,41 also has been successfully used for characterizing
polar Diels-Alder reactions.42 We have computed the Wiberg
bond indexes by using the NBO method. The BO values of the
C1-N and C5-N forming bonds for each transition state, listed
in Table 4, show that whereas in TS1a-d the C5-N bond is
partially formed (the BO ranging from 0.43 to 0.49) there is
little bonding between C1 and the second nitrogen atom (the
BO varying from 0.09 to 0.12). Inversely, in TS2a-d the C5-N
and C1-N BOs range from 0.10 to 0.14 and from 0.47 to 0.52,
respectively. To obtain a precise measure of the relative
asynchronicities of these Diels-Alder reactions, we have also
calculated their synchronicity values (Sy) included in Table 4.
Whereas for a perfectly synchronous reaction Sy ) 1, the values
obtained for the reactions of HTAD with 13a-d through the
different transition states are quite similar and close to 0.7.
Natural population analysis35a,b allows the evaluation of the
charge transfer along the cycloaddition reactions. It has been
µ2
2η
ω )
(1)
(EH + EL)
µ ≈
(2)
(3)
2
η ≈ ΕL - EH
(43) Domingo, L. R.; Aurell, M. J.; Pe´rez, P.; Contreras, R. J. Org. Chem.
2003, 68, 3884-3890.
(44) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford University: New York, 1989.
(40) A similar difference in the degree of twisting has been reported by
Houk for the endo and exo transition states computed for the Diels-Alder
reaction of HTAD with butadiene, see ref 13a.
(41) (a) Varandas, A. J. C.; Formosinho, S. J. F. J. Chem. Soc., Faraday
Trans. 2 1986, 82, 953-962. (b) Lendvay, G. THEOCHEM 1988, 167,
331-338. (c) Lendvay, G. J. Phys. Chem. 1989, 93, 4422-4429. (d)
Lendvay, G. J. Phys. Chem. 1994, 98, 6098-6104.
(42) See for example: (a) Domingo, L. R.; Arno´, M.; Andre´s, J. J. Org.
Chem. 1999, 64, 5867-5875. (b) Go´mez-Bengoa, E.; Helm, M.; Plant, A.;
Harrity, J. P. A. J. Am. Chem. Soc. 2007, 129, 2691-2699. (c) Domingo,
L. R. Tetrahedron 2002, 58, 3765-3774.
(45) Pearson, R. G. Chemical Hardness, Applications from Molecules
to Solids; Wiley-VCH Verlag GMBH: Weinheim, Germany, 1997.
(46) Parr, R. G.; von Szentpaly, L.; Liu, S. J. Am. Chem. Soc. 1999,
121, 1922-1924.
(47) (a) Domingo, L. R.; Arno´, M.; Contreras, R.; Pe´rez, P. J. Phys.
Chem. A 2002, 106, 952-961. (b) Domingo, L. R.; Aurell, M. J. J. Org.
Chem. 2002, 67, 959-965. (c) Domingo, L. R.; Asensio, A.; Arroyo, P. J.
Phys. Org. Chem. 2002, 15, 660-666. (d) Domingo, L. R.; Aurell, M. J;
Pe´rez, P.; Contreras, R. J. Phys. Chem. A 2002, 106, 6871-6875.
(48) Domingo, L. R.; Aurell, M. J.; Pe´rez, P.; Contreras, R. Tetrahedron
2002, 58, 4417-4423.
970 J. Org. Chem., Vol. 73, No. 3, 2008

Diels-Alder Reactions of 4-Alkenylthiazoles with PTAD
The electronic chemical potential of HTAD49 (12) (µ )
-0.2262 au) is lower than those of the thiazoles 13a-d (see
Table 5), thereby indicating that the net charge transfer should
take place from the thiazole toward HTAD, as expected for a
Diels-Alder reaction of normal-electron demand. These results
are in agreement with the charge-transfer analysis shown above.
It is worth noting the very high value of the electrophilicity
index for HTAD (ω ) 5.44 eV).50 On the other hand, the large
values of the electrophilicity differences, ∆ω, indicate the highly
polar character of these cycloaddition reactions, which can be
compared with the low value computed for the prototypical
Diels-Alder cycloaddition between butadiene and ethylene (∆ω
) 0.32 eV).50
polarity (toluene and acetonitrile), for the two endo approaches
found in the Diels-Alder reactions of HTAD with 4-styryl-
1,3-thiazole (13b) at the B3LYP/6-31+G** level. With the
inclusion of these solvents, transition states and intermediates
are similarly stabilized relative to reactants, and thus the barriers
are not significantly affected. The product is slightly destabilized
in relation to the reactants, and consequently the exothermicity
of the reaction is now somewhat lower than that in the gas phase
(see Table S6 in the Supporting Information). These results
likely can be extended to the rest of the cycloadditions
considered in this computational study.
We could not locate analogous polar intermediates or
transition states in the rest of the reaction channels indicating
that those other Diels-Alder reactions occur by concerted
mechanisms through very polar and asynchronous transition
states, and that the formation of the less advanced C-N bond
takes place downhill from the transition states toward the
cycloadducts.
Summarizing, this computational study shows that the
scrutinized hetero-Diels-Alder reactions can be considered very
asynchronous and polar processes. A complete analysis of the
computed transition states indicates that these processes are
characterized by the charge transfer from the diene (the thiazoles
13a-d) to the electron-poor triazoline. There are two endo
approaches differing on which forming C-N bond is more
advanced. They are energetically preferred over the exo transi-
tion states due to the exo-lone-pair effect. In spite of the
markedly polar character and the high asynchronicity of these
processes, they take place in a concerted fashion, except in a
few cases occurring in a stepwise manner with the intervention
of dipolar intermediates which transit very easily to the final
cycloadducts.
The high degree of asynchronicity of the processes described
herein led us to explore more intensively their potential energy
surfaces in search of stepwise mechanisms. Moreover, intrinsic
reaction coordinates (IRC) calculations were used to follow all
reaction pathways, showing the connection of each transition
state with the reactants. The IRC paths in the forward direction
stop in geometries where the more advanced Cdiene-Ndienophile
bond in the transition state reaches a distance close to 1.5 Å
and the distance of the other forming C-N bond is longer than
2.4 Å. In general, optimization of these structures led to the
final cycloadducts 14a-d except for the IRC calculations of
TS1b, TS1c, and TS2d, where such optimization led to the three
dipolar intermediates INT1b, INT1c, and INT2d, respectively.
The transition states TS4b, TS4c, and TS5d connecting these
intermediates with the cycloadducts 14b, 14c, and 14d could
also be located, showing only one imaginary frequency corre-
sponding to either the C1-N (TS4b,c) or C5-N (TS5d) bond
formation. INT1b and INT1c are respectively 3.83 and 4.17
kcal‚mol-1 lower in energy than TS1b and TS1c, whereas the
energy of INT2d is lower than that of TS2d by 7.60 kcal‚mol-1
.
In short, the reaction channels leading to cycloadducts 14b-d
via the transition states TS1b, TS1c, and TS2d are thus
characterized as stepwise mechanisms involving the dipolar
intermediates INT1b, INT1c, and INT2d. CASSCF51(6,6)/6-
31G*//B3LYP/6-31+G** calculations were performed in order
to check if these intermediates show biradical characteristics.
The results show that the closed-shell S0 wave function is largely
the predominant one (92-94%). Therefore, these intermediates
are adequately described by a single reference wave function.
The energy barriers for their cyclization through TS4b,c and
TS5d are only 0.3, 0.07, and 0.23 kcal‚mol-1, respectively,
virtually nonexistent. Consequently, the potential energy surfaces
around the polar intermediates INT1b,c and INT2d and the
transition states TS4b,c and TS5d can be qualified as very flat
(see Figure 2), suggesting that intermediates INT1b, INT1c,
and INT2d must have a very short half-life. In fact, their
geometries, highly preorganized to undergo easily the cycliza-
tion, endorse this assumption.
Conclusions
4-Alkenylthiazoles behave as inner-outer dienes in their
reactions with PTAD to give the corresponding cycloadducts
in good yields and excellent levels of stereocontrol. The
stereochemistry of the reaction products indicates that the
approach of the dienophile to the dienes takes place suprafa-
cially. The presence of a stereogenic center attached to the
terminal carbon atom of the diene moderately controls the facial
diastereoselectivity. The stereochemical course of these pro-
cesses is dominated by the steric interactions featured by both
diastereomeric transition states. Finally, the computational study
by using structurally simpler reagents indicates that, in most
cases, these reactions take place in a concerted fashion. They
show polar character and are highly asynchronous, taking place
through endo transition states. In a few cases, the intervention
of dipolar intermediates was observed, although they cyclize
to the final adducts practically without energetic cost.
To evaluate the solvent influence in these cycloadditions we
have carried out single-point calculations by using the Polarized
Continuum Model (PCM), including two solvents of increasing
Experimental Section
General Procedure for the Synthesis of the Cycloadducts 2.
PTAD (0.13 g, 0.75 mmol) was added to a solution of the
corresponding 4-alkenylthiazole 116 (0.75 mmol) in toluene (5 mL).
After 5 min of stirring at room temperature, a white solid
precipitated from the solution, which was isolated by filtration.
Another crop was collected from the mother liquors by adding Et2O
(2 mL) to the residue, obtained after removal of the solvent, and
subsequent filtration of the resulting solid.
(49) A detailed study on the geometric and electronic features of HTAD
can be found in: Anas, S.; Krishnan, K. S.; Sajisha, V. S.; Anju, K. S.;
Radhakrishnan, K. V.; Suresh, E.; Suresh, C. H. New J. Chem. 2007, 31,
237-246.
(50) Compare with the values of the global electrophilicity indexes of
strong electrophiles in ref 48.
(51) (a) Hegarty, D.; Robb, M. A. Mol. Phys. 1979, 38, 1795-1812. (b)
Eade, R. H. E.; Robb, M. A. Chem. Phys. Lett. 1981, 83, 362-368. (c)
Schlegel, H. B.; Robb, M. A. Chem. Phys. Lett. 1982, 93, 43-46.
(5R*,10aR*)-5-(4-Chlorophenyl)-2,8-diphenyl-5,10a-dihydrothi-
azolo[5,4-c][1,2,4]triazolo[1,2-a]pyridazin-7,9-dione (2a). Yield
J. Org. Chem, Vol. 73, No. 3, 2008 971

Alajar´ın et al.
>99%; mp 174-176 °C (colorless prisms, CHCl3/Et2O); IR (nujol)
2-Phenyl-4-[(E)-3-phenyl-1-butenyl]thiazole (4a).53 AcOEt/
hexane (1:20) was used as eluent (Rf 0.36). Yield 63%; yellow oil;
1785, 1714, 1545, 1506, 1492, 1426, 1269, 1145, 1269, 1145, 769,
1
1
692 cm-1; H NMR (CDCl3) δ 5.83 (t, 1H, J ) 3.5 Hz), 6.02 (t,
IR (neat) 1488, 1451, 1275, 1107, 1003, 967, 762, 690 cm-1; H
1H, J ) 3.0 Hz), 6.11 (dd, 1H, J ) 3.8 Hz, J ) 2.9 Hz), 7.32-
7.36 (m, 3H), 7.40-7.45 (m, 6H), 7.47-7.51 (m, 2H), 7.55-7.60
(m, 1H), 7.94-7.97 (m, 2H); 13C NMR (CDCl3) δ 56.1 (d), 65.4
(d), 116.2 (d), 125.0 (2 × d), 128.40 (d), 128.41 (2 × d), 128.9 (2
× d), 129.08 (2 × d), 129.12 (2 × d), 129.8 (2 × d), 130.6 (s),
132.0 (s), 132.9 (d), 134.5 (s), 135.2 (s), 149.8 (s), 153.6 (s), 155.1
(s), 173.9 (s). MS (EI, 70 eV) m/z (rel intensity) 472 (M+, 1), 299
(25), 298 (25), 297 (68), 296 (40), 194 (46), 177 (30), 149 (45),
121 (100), 119 (88), 115 (72), 104 (33), 91 (52), 64 (39). Anal.
Calcd for C25H17ClN4O2S (472.95): C, 63.49; H, 3.62; N, 11.85;
S, 6.78. Found: C, 63.23; H, 3.72; N, 11.89; S, 6.90.
NMR (CDCl3) δ 1.41 (d, 3H, J ) 7.0 Hz), 3.59 (quintd, 1H, J )
6.9 Hz, J ) 1.3 Hz), 6.35 (dd, 1H, J ) 15.6 Hz, J ) 1.3 Hz), 6.80
(dd, 1H, J ) 15.6 Hz, J ) 6.8 Hz), 6.88 (s, 1H), 7.11-7.15 (m,
1H), 7.20-7.26 (m, 4H), 7.30-7.34 (m, 3H), 7.86-7.88 (m, 2H);
13C NMR (CDCl3) δ 21.1 (q), 42.4 (d), 113.6 (d), 121.8 (d), 126.2
(d), 126.6 (2 × d), 127.4 (2 × d), 128.5 (2 × d), 128.8 (2 × d),
129.9 (d), 133.6 (s), 138.5 (d), 145.3 (s), 155.0 (s), 167.7 (s). MS
(EI, 70 eV) m/z (rel intensity) 291 (M+, 46), 238 (32), 217 (30),
188 (30), 135 (100), 105 (69), 103 (53), 77 (61).
General Procedure for the Synthesis of the PTAD Adducts
8 and 9. PTAD (0.13 g, 0.75 mmol) was added to a solution of the
corresponding 4-alkenylthiazole 4 (0.75 mmol) in toluene (5 mL),
precooled at -5 °C. The reaction mixture was stirred at the same
temperature for 30 min. The solvent was removed under reduced
pressure and the residue purified by silica gel column chromatog-
raphy. Only the mixture of diastereoisomers 8a and 9a could be
resolved. The other two examples, 8b/9b and 8c/9c, were isolated
as diastereomeric mixtures (Supporting Information).
(4R*,5R*)-5-(4-Chlorophenyl)-2,8-diphenyl-4-(4-phenyl-3,5-
dioxo-1,2,4-triazolidin-1-yl)-4,5-dihydrothiazolo[5,4-c][1,2,4]-
triazolo[1,2-a]pyridazin-7,9-dione (3a). PTAD (0.02 g, 0.11
mmol) was added to a solution of 2a (0.05 g, 0.11 mmol) in toluene
(5 mL). The reaction mixture was stirred under reflux for 20 min.
After removal of the solvent under reduced pressure, the residue
was purified by silica gel column chromatography eluting with 1:1
AcOEt/hexane (Rf 0.33). Yield 97%; mp 164-166 °C (colorless
prisms, CHCl3/Et2O); IR (nujol) 1781, 1725, 1563, 1500, 1410,
(5R*,10aS*)-2,8-Diphenyl-5-[(1S*)-1-phenylethyl]-5,10a-dihy-
drothiazolo[5,4-c][1,2,4]triazolo[1,2-a]pyridazin-7,9-dione (8a).
AcOEt/hexane (1:2) was used as eluent (Rf 0.30). Yield 62%; mp
151-153 °C (colorless prisms, CHCl3/Et2O); IR (nujol) 1771, 1709,
1
760, 690 cm-1; H NMR (CDCl3) δ 5.89 (broad s, 1H), 5.95 (d,
1H, J ) 1.4 Hz), 7.20 (d, 2H, J ) 8.6 Hz), 7.31 (d, 2H, J ) 8.6
Hz), 7.33-7.44 (m, 13H), 7.84-7.86 (m, 2H), 8.67 (broad s, 1H,
NH); 13C NMR (CDCl3) δ 55.2 (d), 59.4 (d), 125.4 (2 × d), 125.6
(2 × d), 126.4 (2 × d), 128.2 (2 × d), 128.5 (d), 128.8 (d), 129.2
(2 × d), 129.25 (2 × d), 129.32 (2 × d), 129.6 (s), 129.7 (2 × d),
130.0 (s), 130.3 (s), 130.5 (s), 130.9 (d), 132.3 (s), 132.5 (s), 135.8
(s), 146.0 (s), 149.6 (s), 152.9 (s), 153.7 (s), 162.5 (s). MS (EI, 70
eV) m/z (rel intensity) 648 (M+ + 1, 15), 473 (43), 471 (90), 393
(49), 322 (92), 149 (100), 109 (53), 107 (47). Anal. Calcd for
C33H22ClN7O4S (648.09): C, 61.16; H, 3.42; N, 15.13; S, 4.95.
Found: C, 60.83; H, 3.59; N, 15.29; S, 5.07.
1
1541, 1419, 1273, 953, 852, 759, 684 cm-1; H NMR (CDCl3) δ
1.45 (d, 3H, J ) 7.3 Hz), 3.81 (quint, 1H, J ) 7.0 Hz), 5.09 (dt,
1H, J ) 6.2 Hz, J ) 3.5 Hz), 5.70 (t, 1H, J ) 3.0 Hz), 6.30 (dd,
1H, J ) 3.6 Hz, J ) 2.9 Hz), 7.10-7.12 (m, 2H), 7.20-7.24 (m,
3H), 7.39-7.57 (m, 8H), 7.87-7.89 (m, 2H); 13C NMR (CDCl3)
δ 17.4 (q), 41.8 (d), 57.6 (d), 64.5 (d), 113.8 (d), 125.3 (2 × d),
127.6 (d), 128.2 (4 × d), 128.4 (3 × d), 128.8 (2 × d), 129.3 (2 ×
d), 130.8 (s), 132.1 (s), 132.7 (d), 139.7 (s), 149.9 (s), 154.0 (s),
154.1 (s), 173.3 (s). MS (EI, 70 eV) m/z (rel intensity) 465 (M+
-
1, 39), 361 (73), 213 (27), 186 (36), 121 (38), 119 (32), 105 (100),
77 (27). Anal. Calcd for C27H22N4O2S (466.55): C, 69.51; H, 4.75;
N, 12.01; S, 6.87. Found: C, 69.34; H, 4.80; N, 11.92; S, 6.95.
(5R*,10aS*)-2,8-Diphenyl-5-[(1R*)-1-phenylethyl]-5,10a-dihy-
drothiazolo[5,4-c][1,2,4]triazolo[1,2-a]pyridazin-7,9-dione (9a).
AcOEt/hexane (1:2) was used as eluent (Rf 0.33). Yield 31%; mp
112-114 °C (colorless prisms, CHCl3/n-hexane); IR (nujol) 1774,
General Procedure for the Preparation of R-Chloroketones
7a-c. The corresponding aldehyde 6 (14.15 mmol) was added to
a suspension of 552 (2.00 g, 2.83 mmol) in dry toluene (25 mL)
and the reaction mixture was stirred at room temperature or 40 °C
(for exact temperature and reaction times see every particular case
in Table 2). After removal of all volatiles under reduced pressure,
the residue was purified by silica gel column chromatography.
(E)-1-Chloro-5-phenyl-3-hexen-2-one (7a). Temperature and
reaction time: 25 °C, 7 days. AcOEt/hexane (1:5) was used as
eluent (Rf 0.63). Yield 80% (yellow liquid); IR (neat) 1712, 1697,
1626, 1601, 1493, 1452, 1399, 1292, 1177, 1076, 1013, 978, 761,
1714, 1541, 1501, 1409, 1260, 953, 761, 687 cm-1 1H NMR
;
(CDCl3) δ 1.34 (d, 3H, J ) 7.2 Hz), 3.91 (qd, 1H, J ) 7.1 Hz, J
) 4.7 Hz), 5.04 (dt, 1H, J ) 4.7 Hz, J ) 3.4 Hz), 5.87 (t, 1H, J )
3.1 Hz), 5.93 (t, 1H, J ) 3.1 Hz), 7.27-7.31 (m, 1H), 7.35-7.42
(m, 5H), 7.45-7.51 (m, 4H), 7.53-7.57 (m, 3H), 7.90-7.92 (m,
2H); 13C NMR (CDCl3) δ 13.2 (q), 40.8 (d), 58.3 (d), 65.3 (d),
113.5 (d), 125.2 (2 × d), 127.2 (d), 128.0 (2 × d), 128.3 (2 × d),
128.4 (d), 128.7 (2 × d), 128.8 (2 × d), 129.2 (2 × d), 130.8 (s),
132.1 (s), 132.7 (d), 140.5 (s), 149.0 (s), 154.3 (s), 155.1 (s), 173.1
(s). MS (EI, 70 eV) m/z (rel intensity) 466 (M+, 21), 464 (36), 376
(40), 361 (89), 316 (55), 215 (70), 121 (63), 119 (72), 105 (100),
103 (51), 91 (55), 77 (68). Anal. Calcd for C27H22N4O2S (466.55):
C, 69.51; H, 4.75; N, 12.01; S, 6.87. Found: C, 69.13; H, 4.88; N,
12.21; S, 6.99.
Synthesis of Compounds 10a and 11a. PTAD (0.02 g, 0.11
mmol) was added to a solution of 8a or 9a (0.05 g, 0.11 mmol) in
toluene (5 mL). The reaction mixture was stirred at room temper-
ature for 12 h. After removal of the solvent under reduced pressure,
the residue was purified by silica gel column chromatography.
(4R*,5R*)-2,8-Diphenyl-4-(4-phenyl-3,5-dioxo-1,2,4-triazoli-
din-1-yl)-5-[(1S*)-1-phenylethyl]-4,5-dihydrothiazolo[5,4-c][1,2,4]-
triazolo[1,2-a]pyridazin-7,9-dione (10a). AcOEt/hexane (1:1) was
used as eluent (Rf 0.37). Yield 92%; mp 164-166 °C (colorless
1
700 cm-1; H NMR (CDCl3) δ 1.44 (d, 3H, J ) 6.9 Hz), 3.65
(quintd, 1H, J ) 6.9 Hz, J ) 1.5 Hz), 4.20 (s, 2H), 6.27 (dd, 1H,
J ) 15.9 Hz, J ) 1.5 Hz), 7.11 (dd, 1H, J ) 15.9 Hz, J ) 6.9 Hz),
7.16-7.23 (m, 2H), 7.24-7.27 (m, 1H), 7.29-7.35 (m, 2H); 13C
NMR (CDCl3) δ 20.0 (q), 42.3 (d), 47.0 (t), 124.5 (d), 126.9 (d),
127.2 (2 × d), 128.7 (2 × d), 142.6 (s), 153.5 (d), 191.2 (s). MS
(EI, 70 eV) m/z (rel intensity) 210 (M+ + 2, 17), 208 (M+, 54),
173 (46), 159 (89), 144 (64), 141 (53), 134 (45), 131 (100), 129
(95), 116 (46), 115 (55), 105 (74), 103 (44), 91 (58), 79 (41), 77
(62). HRMS (EI): m/z calcd for C12H13ClO 208.065493, found
208.065532.
General Procedure for the Preparation of 4-Alkenylthiazoles
4a-c. Thiobenzamide (0.62 g; 4.50 mmol) was added to a solution
of the corresponding R-haloketone 7 (3.00 mmol) in ethanol
(50 mL) 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.
(53) Thiazole 7a was obtained with minor impurities after purification
by column chromatography. It was used for the next step without further
purification. The NMR spectra shown in the Supporting Information were
obtained from a first fraction obtained in a second chromatography.
(52) Hudson, R. F.; Chopard, P. A. J. Org. Chem. 1963, 28, 2446-
2447.
972 J. Org. Chem., Vol. 73, No. 3, 2008

Diels-Alder Reactions of 4-Alkenylthiazoles with PTAD
prisms, CHCl3/n-hexane); IR (nujol) 1767, 1724, 1700, 1502, 1434,
1291, 1149, 760, 687 cm-1; 1H NMR (CDCl3) δ 1.37 (d, 3H, J )
7.0 Hz), 2.99 (dq, 1H, J ) 10.5 Hz, J ) 7.0 Hz), 5.03 (dd, 1H, J
) 10.5 Hz, J ) 0.9 Hz), 5.44 (d, 1H, J ) 0.9 Hz), 7.17-7.20 (m,
2H), 7.27-7.47 (m, 16H), 7.80-7.83 (m, 2H), 8.52 (broad s, 1H,
NH); 13C NMR (CDCl3) δ 19.2 (q), 42.0 (d), 52.3 (d), 61.5 (d),
125.5 (2 × d), 125.7 (2 × d), 126.3 (2 × d), 127.4 (2 × d), 127.9
(d), 128.2 (d), 128.6 (d), 129.06 (2 × d), 129.09 (2 × d), 129.25
(2 × d), 129.28 (2 × d), 129.8 (s), 129.9 (s), 130.4 (s), 130.50 (s),
130.52 (d), 132.5 (s), 140.2 (s), 146.7 (s), 149.4 (s), 151.4 (s), 153.4
(s), 161.9 (s). EM (FAB+) m/z (%): 642 (M+ + 1, 46). Anal. Calcd
for C35H27N7O4S (641.72): C, 65.51; H, 4.24; N, 15.28; S, 5.00.
Found: C, 65.32; H, 4.32; N, 15.30; S, 5.11.
130.0 (s), 130.61 (s), 130.64 (d), 132.4 (s), 139.5 (s), 146.0 (s),
148.4 (s), 152.3 (s), 153.4 (s), 162.0 (s). EM (FAB+) m/z (%): 642
(M+ + 1, 37). Anal. Calcd for C35H27N7O4S (641.72): C, 65.51;
H, 4.24; N, 15.28; S, 5.00. Found: C, 65.39; H, 4.35; N, 15.33; S,
5.07.
Acknowledgment. We are grateful to the “Ministerio de
Educacio´n y Ciencia” (MEC) of Spain and FEDER (Project
CTQ2005-02323/BQU) as well to the “Fundacio´n Se´neca-
CARM” (Project 00458/PI/04) for funding. J.C. is also grateful
to the MEC for a fellowship. This work is warmly dedicated to
Prof. Dr. Waldemar Adam on the occasion of his 70th birthday.
(4R*,5R*)-2,8-Diphenyl-4-(4-phenyl-3,5-dioxo-1,2,4-triazoli-
din-1-yl)-5-[(1R*)-1-phenylethyl]-4,5-dihydrothiazolo[5,4-c][1,2,4]-
triazolo[1,2-a]pyridazin-7,9-dione (11a). AcOEt/hexane (1:1) was
used as eluent (Rf 0.29). Yield 85%; mp 303-305 °C (colorless
prisms, CHCl3/n-hexane); IR (nujol) 1775, 1713, 1555, 1150, 873,
721 cm-1; 1H NMR (CDCl3) δ 1.59 (d, 3H, J ) 6.9 Hz), 2.91 (dq,
1H, J ) 10.4 Hz, J ) 6.9 Hz), 4.87 (dd, 1H, J ) 10.4 Hz, J ) 0.9
Hz), 5.95 (d, 1H, J ) 0.9 Hz), 6.87-6.89 (m, 2H), 7.16-7.45 (m,
17H), 7.85-7.87 (m, 2H); 13C NMR (CDCl3) δ 18.9 (q), 41.8 (d),
53.7 (d), 62.5 (d), 125.4 (2 × d), 125.5 (2 × d), 126.2 (2 × d),
128.1 (d), 128.3 (2 × d), 128.37 (d), 128.44 (d), 128.6 (2 × d),
128.9 (2 × d), 129.1 (2 × d), 129.2 (2 × d), 129.4 (s), 129.6 (s),
Supporting Information Available: Full characterization of
compounds 2b-d, 8b,c, 9b,c, R-chloroketones 7b-c, and thiazoles
1
4b,c; figure showing the X-ray crystal structure of 10a; H and
13C NMR spectra for new compounds; Cartesian coordinates,
electronic energies and low frequencies, relevant geometrical and
electronic parameters (natural charges), and relative energies using
the PCM-method of the local minima and transition structures
discussed in the text; crystallographic information file (CIF) for
10a. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7021668
J. Org. Chem, Vol. 73, No. 3, 2008 973