Assessing stereoelectronic effects in dipolar cycloadditions yielding fused thiazolopyridone rings

Article abstract of DOI:10.1016/j.tet.2017.01.064

We report a combined experimental and computational study on the cycloadditions of bicyclic 1,3-thiazolium-4-olates, derived from thiazolidin-2-thiones, with asymmetrically-substituted acetylenes. These results provide further mechanistic insights into the above dipolar cycloadditions and enable an unequivocal characterization by NMR spectroscopy of regiochemical patterns as previous derivatives had substituents at both C-2 (in the dipole) and C-6 (in products). Accordingly, new dihydrothiazolopyrid-2-ones have been obtained from a thioisomünchnone lacking substitution at C-2. With the aim of assessing the steric hindrance as well as the facial stereoselection induced by a bulky group on the Si face (relative to C-7a) of the mesoionic heterocycle, a chiral thioisomünchnone has also been obtained along with the resulting optically active thiazolopyridones. A computational study of these particular cycloadditions, largely based on an NBO analysis, allowed us to evaluate the influence of substituents on intermolecular steric repulsions, charge transfers, as well as solvent effects.

Full text of DOI:10.1016/j.tet.2017.01.064

Tetrahedron 73 (2017) 1551e1560
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Assessing stereoelectronic effects in dipolar cycloadditions yielding
fused thiazolopyridone rings
a
,
*
a
a
a, **
ꢀ
ꢀ
Juan García de la Concepcion , Martín Avalos , Reyes Babiano , Pedro Cintas
,
a
b
a
ꢀ
ꢀ
Jose L. Jimenez , Mark E. Light , Juan C. Palacios
a
ꢀ
ꢀ
Departamento de Química Organica e Inorganica, Facultad de Ciencias and IACYS-Unidad de Química Verde y Desarrollo Sostenible, Universidad de
Extremadura, E-06006, Badajoz, Spain
b Department of Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a combined experimental and computational study on the cycloadditions of bicyclic 1,3-
thiazolium-4-olates, derived from thiazolidin-2-thiones, with asymmetrically-substituted acetylenes.
These results provide further mechanistic insights into the above dipolar cycloadditions and enable an
unequivocal characterization by NMR spectroscopy of regiochemical patterns as previous derivatives had
substituents at both C-2 (in the dipole) and C-6 (in products). Accordingly, new dihydrothiazolopyrid-2-
ones have been obtained from a thioisomünchnone lacking substitution at C-2. With the aim of assessing
the steric hindrance as well as the facial stereoselection induced by a bulky group on the Si face (relative
to C-7a) of the mesoionic heterocycle, a chiral thioisomünchnone has also been obtained along with the
resulting optically active thiazolopyridones. A computational study of these particular cycloadditions,
largely based on an NBO analysis, allowed us to evaluate the influence of substituents on intermolecular
steric repulsions, charge transfers, as well as solvent effects.
Received 9 December 2016
Received in revised form
17 January 2017
Accepted 26 January 2017
Available online 5 February 2017
Keywords:
Thioisomünchnone
Cycloaddition
Natural bond orbital (NBO)
Natural localized molecular orbital (NLMO)
Natural steric analysis (NSA)
Natural bond critical point (NBCP)
© 2017 Elsevier Ltd. All rights reserved.
1. Introduction
dipolarophiles, usually in metal-free protocols.7,8 Mesoionic-based
dipolar cycloadditions actually give rise to a variety of heterocy-
Fused heterocycles comprising five- and six-membered rings,
usually containing a ring-junction nitrogen, are privileged scaffolds
in medicinal chemistry and such systems are frequently employed
to assess and develop compound libraries and new leads.1,2 Among
them, thiazolopyridine derivatives in particular have gained some
attention as potential drug candidates against different
pathologies.3,4
The synthesis of densely functionalized heteroatom-containing
rings may be accomplished by different strategies, although
shortcuts often rely on [3 þ 2]-cycloadditions as well as multi-
component reactions capable of assembling the two-unit frame-
work in chemo- and regio-controlled fashions.5,6 Facile and
versatile elaborations harness the pentagonal core of mesoionic
heterocycles, which behaving as masked allyl-type dipoles, enable
further structural fusion and/or elongation with appropriate
clic arrays not easily provided by conventional cycloadditions, as
developed by our group over the last two decades.9
Recently, we have described the synthesis of a new fused-ring
thioisomünchnone (1) and its 1,3-dipolar reactivity toward acti-
vated acetylenes, with a focus on the sulfur extrusion mechanism,10
which constitutes the key step in the chemoselective syntheses of
pyridin-2-ones or thiophenes from the above mesoionic rings.
Despite some controversial results in the literature claiming either
concerted retro-cheletropic reactions or stepwise pathways for the
spontaneous loss of sulfur, or isocyanate, from the resulting mon-
oadducts formed initially in the cycloadditions of thio-
isomünchnones with alkynes, that study unveiled a sigmatropic
mechanism involving the intermediacy of thiirane species. More-
over, the regioselective addition of asymmetrically-substituted
acetylenes to the mesoionic heterocycle (e.g. by reaction of 1 with
methyl propiolate) could be corroborated by single-crystal X-ray
diffractometry of compound 2 and further rationalized by DFT
analysis.10 Unfortunately, in the absence of unequivocal crystal
data, the regiochemical outcome leading spontaneously to thiazolo
[3,2-a]pyridine-5-ones cannot easily be monitored. A phenyl group
* Corresponding author.
** Corresponding author.
ꢀ
E-mail addresses: jugarco@unex.com (J.G. de la Concepcion), pecintas@unex.es
(P. Cintas).
http://dx.doi.org/10.1016/j.tet.2017.01.064
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

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1552
at C-2 in 1, and therefore in C-6 in 2 and its analogous, limits the
diagnostic use of NMR signals to this end. To overcome this hurdle,
the present study reports the synthesis and cycloadditions of an
unsubstituted derivative, namely 5,6-dihydrothiazolo[2,3-b]thia-
zol-4-ium-3-olate (3), which not only allows the straightforward
inspection of the regiochemical pattern by proton NMR, but also
evaluates the influence, if any, of the substituent at C-2. Further-
more, a chiral thioisomünchnone (15) bearing a bulky and inert
group was obtained to check, if any, the issue of facial selection.
Although, as we shall see, the latter cannot be assessed from an
experimental point of view, the computational study still unveils
how such a facial stereodiscrimination would take place and the
influence exerted by the dipolarophile's structure in particular.
5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridines (9e11) (Scheme 1).
The above thermal cycloaddition could easily be carried out by
mixing 5 and the corresponding dipolarophile (1:1.5 ratio) in
CH2Cl2, then adding dropwise a mixture of acetic anhydride and
triethylamine (1:3), and finally heated at reflux for 1 h. Chro-
matographic purification gave rise to compounds 9e11 in variable
and rather modest yields (15e37%). 1H NMR spectra of 10 and 11
were quite similar and showed two doublet signals at
d ~7.8 and
~6.2 ppm (J ¼ 9.5 Hz) assignable to vicinal H-6 and H-7 protons,
respectively.
As mentioned in the introductory remarks, with the aim of
evaluating the role of steric effects as well as the facial stereo-
selection induced by a bulky substituent located on the Si face
(relative to C-7a) of the mesoionic heterocycle, the chiral thio-
isomünchnone 15 derived from (S)-4-isopropylthiazolidine-2-
thione (13) and
a-bromophenylacetic acid was prepared. Com-
pound 13 has been previously obtained by reaction of (S)-2-amino-
3-methylbutan-1-ol (12) with CS2 in alkaline solution (KOH).11 The
resulting (S)-5-isopropyl-2-phenyl-5,6-dihydrothiazolo[2,3-b]thia-
zol-4-ium-3-olate (15) could be obtained by treating the mixture
containing 14 (not isolated) with Ac2O/Et3N (Scheme 2).
Reactions of 15 with dipholarophiles 6e8 were conducted in
toluene at reflux using an excess of dipolarophile (25%) and the end
point could be easily determined after the complete disappearance
of the characteristic orange color of the mesoionic heterocycle (~2
h). The solvent was removed under reduced pressure and the res-
idue treated with methanol to give pure (S)-3-isopropyl-5-oxo-6-
phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyridines 16e18 in moder-
ate to good overall yields (54e75%). It should be noted that in-
spection of crude mixtures by NMR spectroscopy prior to
purification gave no evidence of any other regioisomer. Moreover,
no signals accounting for the competitive formation of thiophenes
or isocyanates as side products could be observed either. The
modest yields of thiazolopyridones 9e11 in particular, as well as of
16e18 largely result from the thermal lability of the mesoionic
dipole. Thiazolopyridone 16 enables a rapid structural elucidation
by NMR and, gratifyingly compound 17 could be unambiguously
characterized by single-crystal X-ray diffraction (Fig. 1).12
2. Results and discussion
2.1. Synthesis and structural characterization
In principle the preparation of 3 should proceed by a similar
procedure to that described for the preparation of 1, using bro-
moacetic acid as alkylating reagent of thiazolidine-2-thione (4). The
intermediate thioglycolic acid, i.e. 2-[(4,5-dihydrothiazol-2-yl)thio]
acetic acid (5) could be isolated as a white solid in good yield
(>90%). However, unlike the synthesis of 1, conventional cyclo-
dehydration of 5 with Ac2O/Et3N (1:3 ratio) did not afford 3 as a
stable solid. Thus, we devised a one-pot protocol that generates 3 in
situ in the presence of acetylenes 6e8 leading to 8-alkoxycarbonyl-
2.2. Mechanistic insights on the dipolar cycloaddition
As reported previously,10 the reaction of 1 with methyl propio-
late (7) in toluene involves initially a regiospecific stepwise 1,3-
dipolar cycloaddition (rate-determining step) (Scheme 3). The
initial cycloadduct then undergoes a 1,3-sigmatropic rearrange-
ment to give a transient thiirane, which ultimately extrudes sulfur
through a 1,2-elimination leading to pyridone 19 (for a detailed
picture of the reaction pathways, see Figures S1eS3).
A comparison of the energetic profiles for the cycloadditive
steps of thioisomünchnones 1 and 3 with 7, in both toluene and
CH2Cl2, illustrates on the one hand the influence of the substituent
at the C-2 atom of the heterocyclic ring and, on the other, the effect
played by the solvent on the steric course (Fig. 2).
In every case the reaction pathways leading to 10 and 19 involve
two steps with analogous stationary points (black lines in Fig. 2). On
the other hand, the alternative approaches, similar to each other as
well, leading to regioisomers 20 and 21 take place through a single
transition structure (red lines in Fig. 2). At first glance, concerted
pathways are disfavored with respect to stepwise cycloadditions,
pointing to a regiospecific course that is consistent with our
experimental results. Remarkably, reactions of 1 and 7 in both
solvents are characterized by flat free energy profiles in the vicinity
of transition structures [e.g., DDG(TS219t-TS119t) ¼ 0.79 kcal molꢀ1
and DDG(TS219t-I19t) ¼ 1.79 kcal molꢀ1], with formation of the
second CeC bond as the rate-determining step (Fig. 2A and B).
Scheme 1. Synthesis of thiazolo[3,2-a]pyridines 9e11 by dipolar cycloaddition of a
transient dipole (3), generated from 5, with acetylenes.

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
1553
Scheme 2. Preparation of chiral thioisomünchnone 15.
Reactions of 3 and 7, irrespective of the solvent too, show higher
differences in their energy barriers [e.g., DDG(TS110t-TS210t) ¼ 4.03
kcal molꢀ1 and DDG(TS110t-I10t) ¼ 6.88 kcal molꢀ1], being now the
rate-determining step the first CeC bond-forming reaction (Fig. 2C
and D). Moreover, compound 3 reacts with 7 faster than 1 in both
solvents [DDG(TS219t-TS110t) ¼ 2.85 kcal molꢀ1 and DDG(TS219d-
TS110d) ¼ 2.25 kcal molꢀ1). These results demonstrate the influence
exerted by a substituent other than hydrogen as well as solvent
effects on the reactivity of thioisomünchnones and, they also agree
with the higher stabilization of polar zwitterionic intermediates in
structures TS110 and TS119 in either solvent. These results show that
the phenyl group linked to C-2 at the mesoionic heterocycle de-
stabilizes the intermediate, especially as the solvent polarity in-
creases. The major stability of I10 with respect to I19 is somewhat
mirrored by the second transition structures (TS210 and TS219),
given the close similarity in both structure and energy between
those saddle points and the corresponding zwitterionic in-
termediates
DDG(TS219d-TS210d) ¼ 7.16 kcal mol-1].
[
DDG(TS219t-TS210t)
¼
6.88 kcal mol-1 and
In order to understand the greater reactivity of 3 in the above
cycloaddition, we performed a NSA (natural steric analysis)13 for the
approaches of 7 to 1 and 3 in toluene and CH2Cl2, which expresses
the steric exchange repulsion as the energy difference due to NLMO
(natural localized molecular orbital) orbital orthogonalization.14
Table 2 shows the results obtained by comparing the total dE(i)
for each TS (TS119t, TS110t, TS119d, and TS110d) with the total dE(i)
values calculated when both dipolarophile and dipole fragments (7
against dipoles 1 and 3) are separated by a large distance (12.0 Å), in
order to ensure both partners do not interact with each other.
The intermolecular dE(i) values associated to the approach of 7
and 1 are higher than that of 7 with 3 (36.66 kcal molꢀ1 in toluene
and 19.37 kcal molꢀ1 in CH2Cl2). However, as expected, the inter-
molecular dE(i) values are very similar for the regioisomeric
concerted processes.
CH2Cl2
[
DDG(I19t-I19d) ¼ 1.28 kcal molꢀ1 and DDG(I10t e I10d) ¼
2.41 kcal molꢀ1]. Table 1 shows the energy gaps (DDE, DDH, and
DDG) that separate the first saddle points of the stepwise cyclo-
additions from the corresponding zwitterionic intermediates,
determined in both toluene and CH2Cl2.
Inspection of DDE, DDH and DDG values indicates that the sta-
bilization of I10 is greater than that of I19 with respect to transition
Concerted vs Stepwise Processes. The intermolecular steric
exchange [DdE(i)total] is disfavored for the concerted cycloadditions
(TS110t-TS21t ¼ ꢀ31.66 kcal molꢀ1, TS119d-TS20d ¼ ꢀ19.93 kcal
molꢀ1, and TS110d-TS21d ¼ ꢀ43.80 kcal molꢀ1) with the exception
of TS119t-TS20t (8.18 kcal molꢀ1), thus suggesting that in this case
the intermolecular steric repulsion is not responsible for a prefer-
ential stepwise process (vide infra).
Although structures TS119t and TS119d are quite similar, their
dE(i)total values differ by 34.14 kcal molꢀ1. In order to justify this
energy difference we compared the NLMO contributions to the
total steric exchanges for saddle points TS119t and TS119d. Results
show a very similar orbital distribution and energy contributions,
although for TS119t the LPC8 (for the sake of clarity, numbering is
shown in Fig. 3) contributes significantly (26.60 kcal molꢀ1) to
dE(i)total, thus destabilizing the system. The major portion of this
contribution corresponds to the interactions of LPC8
LPC8 sC6-S9 NLMO pairs (Fig. 4).
-sC5-C6 and
-
As collected in Table 3, the stabilization by charge transfer (CT) is
always higher for the stepwise processes, especially for the reaction
of 1 and 7 in toluene (521.46 kcal molꢀ1). The highest total CT for
TS119t (1847 kcal molꢀ1) should be attributed to the methyl pro-
piolate contribution (749.32 kcal molꢀ1). TS119t and TS119d exhibit
very similar NBO (natural bond orbital)15 distribution and energy
contribution to CT, though the CT of the NBO LPC8 stabilizes the
system by 305.98 kcal molꢀ1. In fact the highest CT value for TS119
t
corresponds to transfer from LPC8 to )
p*
(170.19 kcal molꢀ1
C20-O21
Fig. 1. Solid-state structure of compound 17. Crystal data were collected at 100(2) K;
orthorhombic crystal system (P212121 space group); ellipsoids drawn at 50%
probability.
(Fig. 5). The greater stabilization of TS119t provided by charge
transfer would then account for a favorable process leading to 19

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
Scheme 3. Regiochemical approaches of methyl propiolate (7) to mesoionic 1 and 3.
with respect to the concerted pathway, thereby offsetting the
intramolecular steric exchange exerted by the dipolarophile.
The CTs from dipole to dipolarophile are greater in the saddle
points of stepwise processes than those of concerted pathways. For
TS119t the highest contribution corresponds to the interaction of
LPC6 with LVC7 and RY(1)C7 (23.92 and 95.45 kcal molꢀ1, respec-
Fig. 9 shows the energetic profiles for the four possible reaction
channels involving the cycloaddition of thioisomünchnone 15 with
7 in toluene. Again, the regiochemistry is related to the concerted or
non-concerted nature of the process, and the calculated energy
barriers (Fig. 9A) are quite similar to those previously found for the
reaction of 1 and 7 (Fig. 2A), which clearly reflects the close
structural similarity of thioisomünchnones 1 and 15.
tively). In the case of TS119d the CT goes from LPC6 to
p(2)*C7-C8
(128.29 kcal molꢀ1) (Fig. 6).
The stepwise cycloadditions leading to thiazolopyridone 17
constitute the most favored reactions. When the dipolarophile at-
tacks to the Re-2,Re-7a face of 15, namely the opposite face to the
isopropyl group (Fig. 9A), the energy barrier is 5.46 kcal molꢀ1
lower than that for a concerted mechanism (red line), thereby
pointing to the sole formation of cycloadduct 24. The same
happens when 7 approaches to 15 through the Si-2,Si-7a face
For the cycloaddition of thioisomünchnone 3, the greater con-
tributions to CT in TS110t correspond to the interaction of pC6-S9 and
p*
to p
(2)*C7-C8 (13.03 and 98.66 kcal molꢀ1 respectively).
C6-S9
Finally, the NBOs of TS110d are identical to those of TS110t, though
with slightly lower energy values (12.40 and 90.77 kcal molꢀ1
,
respectively) (Fig. 7).
In TS119t and TS119d the major contribution involved in CT arises
from the donor NBO LPC6, while for TS110t and TS110d there is an
important contribution from the pC6-S9 orbital. Such a difference
can be attributed to electron delocalization of LPC6 with the phenyl
group in TS119t and TS119d, absent in TS110t and TS110d, for which
the charge is instead delocalized with the sulfur atom. The acceptor
[
DDGǂ(TS27eTS125) ¼ 4.99 kcal molꢀ1] giving rise to cycloadduct 25.
Both cycloadducts (24 and 25) evolve to the same thiazolopyridone
(17) after sulfur extrusion. Surprisingly, the interaction of 7 with the
Si-2,Si-7a face of 15 (TS125) is kinetically favored (Fig. 9B) with
respect to TS124 (by 1.41 kcal molꢀ1 only), a fact consistent with the
poor facial stereoselection exhibited by thioisomünchnone 15. The
lack of stereoselection could also be interpreted in geometric terms,
i.e. compound 7 is rather linear-shaped and lies far to the stereo-
NBO for TS119d, TS110t, and TS110d is the
for TS119t the acceptor role is played by the empty NBOs at C7. The
lack of (2)C7-C8 and (2)*C7-C8 orbitals in TS119t could be ascribed
p(2)*C7-C8 orbital, whereas
p
p
discriminating isopropyl group in TS125.
to the high electron delocalization of LPC8 with the methox-
ycarbonyl group (Fig. 5).
For the opposite regiochemistry, the CT from the dipolarophile
to the dipole is greater than in the reverse direction. For all tran-
sition structures (TS20t, TS20d, TS21t and TS21d) the main contri-
In following the same methodology reported above, we per-
formed an NSA13 intermolecular study for both approaches of 7 to
15 (TS124 and TS125). Results are given in Table 4.
The dE(i) values obtained for saddle points TS124 and TS125
indicate that the intermolecular steric exchange between the
dipole and its dipolarophile is 9.22 kcal molꢀ1 lower when 7 ap-
proaches to 15 at the Si-2,Si-7a face, which contains the bulky
isopropyl group, than the addition at the rear face.
bution to CT goes from the p2C7-C8 to p*C8a-N4 (65.66, 69.94, 44.25,
and 47.96 kcal molꢀ1, respectively) (Fig. 8). All in all, these results
would justify the prevalent approach of the C6-C7 bond to the C8a-
C7 fragment.
In order to understand the origin of these results, we performed
a natural bond critical point analysis (NBCP).16 The CPs are points
2.3. Facial stereoselection
where the gradient of the electronic density, [V
they are characterized by three eigenvalues (l1 l2
sian matrix of (r). The CPs are identified as (r,s) according with
their rank (number of nonzero eigenvalues) and signature (alge-
braic sum of eigenvalues signs). A (3,-1) CP in which (r) diminishes
in two directions and increases in the third, is a saddle point of (r)
found between two neighboring atoms and it defines the linkage
between them (BCP). When the Laplacian of
(r) [V2r(r)], namely
the sum of three eigenvalues (l1 l2 l3), is negative the electronic
r
(r)], is zero, and
,
,
l3) of the Hes-
Taking into account the chiral nature of thioisomünchnone 15,
its cycloaddition with 6 could take place by any of the two faces of
the heterocycle to give the initial cycloadducts 22 and 23. In the
case of unsymmetrically-substituted alkynes such as 7 and 8, the
corresponding approaches could also occur through two different
orientations, leading to cycloadducts 24e27 and 28e31,
respectively.
r
r
r
r
,
,

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1555
Fig. 2. Relative free energy barriers (kcal molꢀ1) for transition structures and intermediates involved in the 1,3-dipolar cycloadditions of 1 (A and B) and 3 (C and D) with methyl
propiolate (7) in toluene (A and C) and CH2Cl2 (B and D). Black lines describe the more favored route whereas the regioisomeric pathways are depicted in red.
charge is concentrated within the region of the BCP which is
characteristic of covalent or polarized bonds, namely a shared layer
interaction. However, a positive V2r(r) corresponds to a charge
leakage area, characteristic of a closed shell interaction. In the
transition structure TS125 the calculated distance between the
carbonyl oxygen of 7 (O21 in Fig. 5) and the nearest methyl
hydrogen of 15 (H11 in Fig. 10) is 2.60 Å, and the eigenvalues of the
Hessian matrix are l1 ¼ 0.0403, l2 ¼ ꢀ0.0067, and l3 ¼ ꢀ0.0068.
Accordingly, this CP is identified to be a first-order saddle point [(3,-
1)]. The magnitudes of r
(r) and V2r(r) for the aforementioned CP
are quite small (0.0085 and 0.0268 au, respectively), pointing a
weak interaction, and the positive value of V2r(r) suggests a closed
Table 1
Table 2
Electronic energy, enthalpy, and free energy gaps between the first saddle point and
the corresponding intermediate (in kcal molꢀ1) for cycloadditions of 1 and 3 with 7,
in toluene and CH2Cl2.
Occupied NLMO contributions [dE(i), kcal molꢀ1] to intermolecular steric exchange
energy in transition structures TS119t, TS110t, TS119d, TS110d, and TS20t, TS21t, TS20d,
TS21d.
Structure
TS119
D
Ea
D
Ha
D
Ga
DD
E
DD
H
DDG
Structure
TS119
TS110t
TS119d
TS110d
dE(i)total
dE(i)total at 12.0 Å
DdE(i)total
DDdE(i)total
t
9.16
5.32
10.40
4.02
6.68
9.76
7.02
10.70
5.68
7.32
22.92
21.92
23.37
20.64
20.86
13.98
21.62
11.57
3.84
6.38
9.05
11.73
2.74
5.02
7.59
10.21
1.00
2.73
6.88
10.05
t
1419.89
846.56
1385.75
837.54
1256.68
720.01
1249.65
720.81
163.21
126.55
136.10
116.73
36.66
I
19t
TS119d
19d
19.37
I
TS110t
I10t
TS110d
ꢀ2.37
ꢀ0.27
TS20
t
1448.39
903.14
1444.53
904.54
1293.36
744.93
1288.50
744.01
155.03
158.21
156.03
160.53
ꢀ3.18
ꢀ4.50
7.63
8.23
TS21t
TS20d
TS21d
I
10d
ꢀ4.10
ꢀ1.98
a
Relative to reagents.

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Fig. 3. M06-2X/6e311þþG(d,p)-optimized structures of TS110t, TS119t, TS20t, and TS21t in toluene (SMD method).
shell interaction. The NLMO contributions to
BCP are shown in Table 5.
r
(r) and V2r(r) for this
TS124 (33.10 kcal molꢀ1). The delocalization between the hetero-
cycle and the alkyne reagent is quite similar for both saddle points
(only 4.76 kcal molꢀ1 higher in energy for TS124), albeit electron
delocalization of the LPC6 orbital with the phenyl group is higher in
TS125 (31.04 kcal molꢀ1) than in TS124 (1.53 kcal molꢀ1). Likewise,
electron delocalization of LPC6 with the Rydberg orbitals of C6, C5,
S9, and C14 is somewhat higher in TS125 (21.85 kcal molꢀ1) than in
TS124 (13.19 kcal molꢀ1). Together these data account for a prefer-
ential cycloaddition of 7 to 15 on the Si-2,Si-7a face of the latter
(TS125).
The correlation (in percentage) of such NLMOs with their parent
localized NBOs is extremely high, all over 98.8%, which points to a
high electron localization at these NLMOs. The charge transfer (CT)
energy between these NBOs goes from the first lone pair of the O21
atom to the
s
*
C11-H11 orbital (0.21 kcal molꢀ1) and from the second
0
pair of the same oxygen atom to the
s
*C11-H11 and
s
*
orbitals
C11-H11
(0.34 and 0.10 kcal molꢀ1, respectively). Overall, these interactions
stabilize the system and their total value (0.65 kcal molꢀ1) can be
interpreted in terms of a weak van der Waals interaction.
Table 6 shows the steric interactions of occupied NLMOs of
methyl propiolate (7) with the isopropyl group of 15 in TS125. Again
these steric interactions are very small [SdE(i,j) ¼ 3.61 kcal molꢀ1],
thus proving that the isopropyl group does not destabilize the
system by steric repulsions, at least to an appreciable extent. Since
this alkyl group does not appear to be responsible for the greater
stability of TS125, we then considered the saddle point moiety in
which both transition structures (TS124 and TS125) match, namely
formation of the C6-C7 bond (Table 7).
Table 3 showed that for TS119t a high charge transfer takes place
in the dipolarophile fragment (749.32 kcal molꢀ1). For TS124 and
TS125 these values are quite similar (735.03 and 799.72 kcal molꢀ1).
In fact, the most important contribution to CT is given by the
interaction of LPC8 to
p
*
with energy values of 157.91 and
C20-O21
190.07 kcal molꢀ1 for TS124 and TS125, respectively, exactly the
same as for TS119t. Also, Table S4 shows the CT from the donor NBO
LPC6 to LVC7 and RY(1)C7 for TS124 and TS125. In such interactions
the orbital participation is identical to those shown in Fig. 6A and B
for TS119t, and the corresponding CT values are quite similar as well.
In short, transition structure TS119t has the same orbital distribu-
Both BCPsC6-C7 in TS124 and TS125 are very similar with small
values for
r
(r) and V2r(r). However V2r(r) is positive for TS124, and
tion and almost identical energy values as those of TS124 and TS125,
therefore indicative of a closed shell interaction, while it is negative
all of them optimized in toluene.
for TS125, which corresponds to a shared layer interaction. Table 8
shows the NLMO contributions to
Clearly, in both TSs the largest contributor to
r
(r) and V2r(r) for these BCPs.
r(r) in such BCPs is
the LPC6 orbital, and the corresponding V2r(r) values suggest that
the electron densities are highly localized in those NLMOs; or in
other words, they reflect the nucleophilic character of the carbon
atom in question, which is slightly higher in TS125. The low corre-
lation percentage of these NLMOs with their parent localized NBOs
(57.86% for TS124 and 57.33% for TS125) suggests a significant level
of electron delocalization, which in turn justifies a high charge
transfer (CT) efficiency between these NBOs and the closer empty
NBOs (see Table S4).
The total stabilization energy by CT ascribed to the lone pair that
initiates the nucleophilic attack is higher for TS125 than that for
Fig. 4. Main contributions of the NLMO LPC8 to steric repulsion in TS119t. Left: LPC8
-
sC5-C6 interaction; right: LPC8 sC6-S9 interaction.
-

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
1557
Table 3
Different charge transfer (kcal molꢀ1) contributions from occupied to empty NBOs for transition structures TS1t, TS1d, TSt and TSd.
Structure
Within dipole
From dipole to dipolarophile
From dipolarophile to dipole
Within dipolarophile
Total CT
DCT
TS119
TS20t
TS119d
TS20d
TS110
TS21t
TS110d
TS21d
t
930.62
867.03
945.64
867.70
569.23
460.48
578.39
464.31
147.8
57.39
163.11
59.52
140.94
67.02
130.82
69.93
19.95
96.34
15.18
102.30
12.2
66.04
11.06
70.44
749.32
305.47
306.51
304.55
311.56
296.67
308.92
297.87
1847.69
1326.23
1430.44
1334.07
1033.93
890.21
521.46
96.37
t
143.72
126.64
1029.19
902.55
Fig. 7. Charge transfers from NBO pC6-S9 (left) and
TS110d.
p*
(right) to
p
(2)*C7-C8 in
C6-S9
Fig. 5. Highest CT in TS119t from NBO LPC8 to
p*
.
C20-O21
3. Conclusions
a phenyl group at C-2 of the mesoionic dipole lead to higher energy
barriers for these cycloadditions. All concerted transformations are
disfavored, a fact that can be rationalized in terms of intermolecular
steric repulsions during the dipole-dipolarophile interaction, which
are indeed greater for all concerted pathways with the sole
exception of TS119t. This behavior is well counterbalanced by a large
stabilization due to charge transfer in TS119t of the LPC8 (in the
Two structurally rigid thioisomünchnone dipoles (3 and 15)
have been prepared by condensation of -haloacids with thiazoli-
a
din-2-thiones (4 and 13) under basic conditions. The mesoionic
dipole 3 was generated in situ and then trapped with acetylenes,
thus providing a one-pot route to novel 8-alkoxycarbonyl-5-oxo-
3,5-dihydro-2H-thiazolo[3,2-a]pyridines (9e11). The structural
characterization of products derived from asymmetrically-
substituted dipolarophiles could be successfully accomplished
through NMR spectroscopy due to the vicinal disposition of
hydrogen atoms at C-6 and C-7 of the heterocycles. Cycloadditions
conducted with chiral thioisomünchnone 15 afforded optically
active products, namely (S)-3-isopropyl-5-oxo-6-phenyl-3,5-
dihydro-2H-thiazolo[3,2-a]pyridines 16e18, whose structural
characterization could be achieved by comparing their spectro-
scopic data to those of 17, the latter being unequivocally elucidated
by single-crystal X-ray diffraction. In all cases, the use of
asymmetrically-substituted dipolarophiles proceeded with com-
plete regioselectivity.
The experimental results have been corroborated by a detailed
DFT study, at the M062-X/6-311þþG(d,p) level of theory, with in-
clusion of solvents effects (through the SMD model) in toluene and
CH2Cl2. All cycloadditions involving methyl propiolate (7) giving
rise to the regioisomer isolated experimentally are stepwise pro-
cesses, while an opposite orientation of the dipolarophile turned
out to be a concerted mechanism. Data collected in Fig. 2 show that
dipolarophile's fragment), thereby accounting for
a stepwise
pathway too. Moreover, this behavior for TS119t can also be inferred
from a comparative analysis with transition structures TS124 and
TS125, which have also been optimized in toluene and exhibit an
almost identical orbital distribution to TS119t.
It is known that most common 1,3-dipolar cycloadditions can be
interpreted as Sustmann type I processes involving a nucleophilic
attack from the dipole to the dipolarophile. This kind of cycload-
ditions is consistent with stepwise cycloadditions studied herein,
for which the nucleophilic addition involves the C-6 atom of the
dipole and the C-7 atom of the dipolarophile. Data gathered for the
opposite orientation of 7 suggest that the nucleophilic attack goes
from C-7 of the dipolarophile to C-8a of the dipole, thus becoming a
Sustmann type III cycloaddition. The saddle points TS124 and TS125
correspond to the approach of 7 to both faces of chiral thio-
isomünchnone 15. Subsequent comparative analyses of intermo-
lecular steric repulsions for the above TSs have ultimately proven
that the isopropyl group does not exert a marked steric repulsions;
in fact there is actually a minor stabilization by charge transfer.
Fig. 6. NBOs CT from LPC6 to LVC7 (A) and RY(1)C7 (B) in TS119t, and to
p(2)*C7-C8 (C) in TS119d.

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
Table 4
Occupied NLMO contributions [dE(i) in kcal molꢀ1] to the intermolecular steric
exchange energy for transition structures TS124 and TS125 in toluene.
Structure
dE(i)total
dE(i)total at 12.0 Å
dE(i)total - dE(i)total at 12.0 Å
TS124
TS125
1647.12
1650.30
1504.13
1516.53
142.99
133.77
with the Jmol software.22 All of the relative energies shown are free
energies calculated at 298.15 K with respect to the reagents.
Fig. 8. Charge transfers from NBO
p
2C7-C8 to
p
*
in TS20t and TS21t.
C8a-N4
4.2.1. 2-((4,5-Dihydrothiazol-2-yl)thio)acetic acid (5)
4. Experimental section
To a solution of thiazolidine-2-thione (4) (8.4 mmol) in CH2Cl2
and bromoacetic acid (8.4 mmol) was added triethylamine and the
mixture was stirred a room temperature for 72 h. Then, the
resulting triethylammonium bromide was filtered off. In order to
remove dissolved salts the, the solution was also passed through a
silica gel [Merck 60 (400-230 mesh)] column using ethyl acetate as
eluent. The solvent was evaporated to dryness to give a white solid
(91%). Mp 125e126 ꢁC. FTIR (KBr) nmax 3002, 2957, 2786, 2365,1885,
1710, 1557, 1388, 1317, 1186, 1036, 895, 678, 656, 447 cmꢀ1. 1H NMR
4.1. General methods
Solvents and reagents were purchased from commercial sup-
pliers and used without further purification. The identity of all
compounds was confirmed by their elemental analysis, high-
resolution mass spectra, mps, and NMR data (see SI).
(500 MHz, CDCl3, 25 ꢁC)
d
4.25 (t, 2H, J ¼ 8.0 Hz), 3.71 (s, 2H), 3.56 (t,
4.2. Computational details
2H, J ¼ 8.0 Hz) ppm. 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d 173.6, 169.1,
61.8, 36.5, 35.4 ppm. Anal. Calcd for C5H7NO2S2: C, 33.90; H, 3.95; N,
7.91; S, 36.16. Found: C, 34.11; H, 4.12; N, 7.83; S, 36.26.
All calculations reported in this work were carried out using the
Gaussian09 package.17 The M06-2X18 density functional method in
conjunction with the 6-311þþG(d,p)19 basis set were selected for
all the geometry optimizations and frequency analysis. The geom-
etries were optimized including solvation effects in toluene and
CH2Cl2, which have been determined by the density-based self-
consistent reaction field theory of bulk electrostatic, i.e., the well-
known solvation model density (SMD)20 method that takes into
account different contributions such as long-range electrostatic
polarization (bulk solvent effect). Frequency calculations at 298.15
K on all the stationary points were carried out at the same level of
theory as the geometry optimizations to ascertain the nature of the
stationary points. Ground and transition states were characterized
by none and one imaginary frequency, respectively. NSA (natural
steric analysis),13 which evaluates the occupied NLMO contributions
[dE(i)], NBCP (natural bond critical point analysis)16 and CT (charge
transfer) analysis were all carried out with the NBO 6.0 package.21
Main orbital [NBO15 (natural bond orbital) and NLMO14 (natural
localized molecular orbital)] interactions have been represented
4.2.2. (S)-5-Isopropyl-2-phenyl-5,6-dihydrothiazolo[2,3-b]thiazol-
4-ium-3-olate (15)
A
mixture of (S)-4-isopropylthiazolidine-2-thione (13) (23
mmol), 2-bromo-2-phenylacetic acid (23 mmol), and triethylamine
(23 mmol) in benzene (50 mL) was stirred at room temperature for
72 h. The resulting precipitate of triethylammonium bromide was
filtered off. To remove dissolved salts the solution was also passed
through a silica gel [Merck 60 (400-230 mesh)] column using ethyl
acetate as eluent. The solvent was evaporated to dryness to give an
oily residue (5.4 g), which contained the intermediate thioglycolic
acid 14. To this oil a mixture of triethylamine an acetic anhydride
(3:1, 40 mL) was added. The mixture was softly heated for a few
minutes, yielding the title compound as orange crystals which were
collected by filtration and washed with diethyl ether (50%). Mp
190e192 ꢁC. [
a]
D 177.8ꢁ (c 5.1, CH2Cl2). FTIR (KBr) nmax. 3052, 3023,
2961, 2917, 2864, 1645, 1504, 1495, 1443, 1189, 754, 697, 687 cmꢀ1
.
Fig. 9. Relative free energy barriers (kcal molꢀ1) for transition structures and intermediates involved in the regioselective approaches of 7 to the Re-2,Re-7a (Figure A) and Si-2,Si-7a
(Figure B) faces of 15 in toluene. In every case, black lines denote the more favored route whereas the regioisomeric pathways are depicted in red.

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
1559
Fig. 10. M06-2X/6-311þþG(d,p)-optimized structures of TS124 and TS25 in toluene (SMD method).
Table 5
NLMO contributions to
The solvent was removed to dryness and the residue was treated
with diethyl ether to give the thiazolopyridones 9e11, which were
further recrystallized from ethyl acetate.
r
(r) and V2r(r) for the BCPO21-H11 in TS125
.
NLMO
%
r
(r)
V
2r(r) (au)
LP(1)O21
LP(2)O21
sC11- H11
15.90%
33.50%
45.50%
2.80%
0.0058
0.0061
0.0125
0.0004
4.2.4. Dimethyl 5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-7,8-
dicarboxylate (9)
0
sC11-H11
Compound 9 was obtained from 3 and 6 after 1 h. Recrystallized
from ethyl acetate (15%) had mp 131e135 ꢁC. FTIR (KBr) nmax 3463,
3019, 2958, 1737, 1693, 1651, 1442, 1265, 1143, 1056, 986, 839, 786
cmꢀ1. 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d
6.24 (s, 1H), 4.53 (t, 2H, J ¼
Table 6
Steric exchange energies (in kcal molꢀ1) for i,j NLMOs of 7 with the isopropyl group
8.0 Hz), 3.88 (s, 3H), 3.83 (s, 3H), 3.38 (t, 2H, J ¼ 8.0 Hz) ppm. 13
C
of 15 in TS125
.
NMR (125 MHz, CDCl3, 25 ꢁC)
d 167.0, 164.0, 160.4, 158.9, 145.0,
NLMO(i)
LP(1)O21
NLMO(j)
dE(i,j)
113.5, 101.6, 52.8, 52.4, 50.9, 27.7 ppm. Anal. Calcd for C11H11NO5S:
C, 49.07; H, 4.10; N, 5.20; S, 12.00. Found: C, 48.90; H, 4.21; N, 5.27;
S, 12.04.
sC11-H11
0.42
0.05
0.09
0
sC11-H11
LP(2)O21
sC11-H11
0
sC11-H11
0.80
4.2.5. Methyl 5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-8-
carboxylate (10)
00
sC11-H11
0.08
2.04
0.07
0.06
pC7-C8
sC11-H11
0
sC11-H11
Compound 10 was obtained from 3 and 7 after 1 h. Recrystal-
lized from ethyl acetate (37%) had mp 170e174 ꢁC. FTIR (KBr) nmax
3052, 2988, 2951, 1687, 1659, 1508, 1435, 1298, 1206, 1124, 1020,
00
sC11-H11
SdE(i,j) ¼ 3.61
834, 781 cmꢀ1. 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d
7.82 (d,1H, J ¼ 9.5
Hz), 6.24 (d, 1H, J ¼ 9.5 Hz), 4.56 (t, 3H, J ¼ 7.5 Hz), 3.83 (t, 2H, J ¼ 7.5
1H NMR (500 MHz, CDCl3, 25 ꢁC)
d
7.74 (dd, 2H, J ¼ 1.0 Hz, J ¼ 8.5
Hz), 3.87 (s, 3H), 3.37 (t, 2H, J ¼ 8.0 Hz) ppm. 13C NMR (125 MHz,
Hz), 7.29 (dd, 2H, J ¼ 7.5 Hz, J ¼ 8.0 Hz), 7.05 (m, 1H), 4.91 (m, 1H),
4.11 (dd, 1H, J ¼ 9.0 Hz, J ¼ 11.0 Hz), 3.77 (dd, 1H, J ¼ 2.5 Hz, J ¼ 11.5
Hz), 2.98 (m, 1H), 1.09 (d, 3H, J ¼ 7.0 Hz), 0.95 (d, 3H, J ¼ 7.0 Hz)
CDCl3, 25 ꢁC)
d 165.1, 161.9, 157.6, 139.5, 114.2, 104.5, 52.1, 50.6, 27.6
ppm. Anal. Calcd for C9H9NO3S: C, 51.17, H, 4.29, N, 6.63, S, 15.18.
Found: C, 51.12, H, 4.22, N, 6.60, S, 15.29.
ppm. 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d 156.1, 152.6, 134.3, 128.6,
124.1, 122.71, 97.4, 67.3, 36.3, 29.3, 19.0, 15.7 ppm. Anal. Calcd for
14H15NOS2: C, 60.65; H, 5.42; N, 5.05; S, 23.10. Found: C, 60.51; H,
5.37; N, 5.02; S, 22.70.
4.2.6. Ethyl 5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-8-
carboxylate (11)
C
Compound 11 was obtained from 3 and 8 after 1 h. Recrystal-
lized from ethyl acetate (32%) had mp 112e115 ꢁC. FTIR (KBr) nmax
2958, 2925, 2854,1697,1640,1511,1443,1412,1293,1128,1035, 823,
4.2.3. Cycloadditions of 3 with acetylenic dipolarophiles 6e8
To a mixture of 5 (2.8 mmol) and the dipolarophile (4.2 mmol) in
CH2Cl2 (20 mL) were added acetic anhydride and triethylamine
(1:3, 3 mL) and the reaction mixture was heated at reflux for 1 h
(TLC analysis: ethyl acetate:hexane 2:1 v/v). The products were
isolated by column chromatography on silica gel [Merk 60 (400-
230 mesh)] using ethyl acetate and hexane (1:1 and 2:1) as eluents.
778, 589 cmꢀ1. 1H NMR (400 MHz, CDCl3, 25 ꢁC)
d
7.84 (d, 1H, J ¼ 9.6
Hz), 6.25 (d, 1H, J ¼ 9.2 Hz), 4.52 (t, 2H, J ¼ 8.0 Hz), 4.33 (q, 2H, J ¼
7.2 Hz), 3.37 (t, 2H, J ¼ 8.0 Hz), 1.37 (t, 3H, J ¼ 7.2 Hz) ppm. 13C NMR
(100 MHz, CDCl3, 25 ꢁC)
d 164.6,162.0,157.3, 139.6, 114.1, 104.8, 61.2,
50.6, 27.6, 14.4 ppm. Anal. Calcd for C10H11NO3S: C, 53.32, H, 4.92, N,
6.22, S, 14.23. Found: C, 53.12, H, 4.89, N, 6.21, S, 14.09.
Table 7
Bond lengths, Hessian eigenvalues of r(r), r .
(r) and V2 r(r) for BCPs of incipient bonds C6-C7 in TS124 and TS125
Structure
BCP
Bond lenght (Å)
Eigenvalues of Hessian of
r
(r)
r
(r) (au)
V
2r(r) (au)
TS124
TS125
BCPC6-C7
BCPC6-C7
1.94
1.93
0.2483
0.2529
ꢀ0.1192
ꢀ0.1241
ꢀ0.1264
ꢀ0.1306
0.0976
0.0999
0.0027
ꢀ0.0018

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J.G. de la Concepcion et al. / Tetrahedron 73 (2017) 1551e1560
1560
4.2.7. Cycloadditions of 15 with acetylenic dipolarophiles 6e8
A mixture of 15 (1.4 mmol), the dipolarophile (1.8 mmol), and
toluene (25 mL) was heated at reflux until the disappearance of the
orange color (TLC analysis: ethyl acetate:hexane 1:2 v/v). The sol-
vent was evaporated to dryness and the resulting residue was
suspended in methanol or ethanol to yield the corresponding
pyridones (16e18), which were further recrystallized from ethyl
acetate.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.01.064.
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d 7.32 (m, 5H), 5.17 (m, 1H), 3.83 (s, 3H), 3.57 (s, 3H),
3.48 (dd, 1H, J ¼ 9.0 Hz, J ¼ 11.5 Hz), 3.17 (dd, 1H, J ¼ 1.5 Hz, J ¼ 12.0
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129.7, 128.2, 128.0, 125.1, 100.8, 68.5, 52.4, 52.2, 29.3, 28.3, 19.4, 16.4
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thiazolo[3,2-a]pyridine-8-carboxylate (17)
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7.40 (m, 2H), 7.32 (m, 1H), 5.22 (m, 1H), 4.35 (m, 2H), 3.49 (dd, 1H, J
¼ 9.0 Hz, J ¼ 11.5 Hz), 3.19 (dd, 1H, J ¼ 1,5 Hz, J ¼ 12.0 Hz), 2.64 (m,
1H), 1.37 (t, 3H, J ¼ 7.0 Hz) 1.03 (d, 3H, J ¼ 7.0 Hz), 0.94 (d, 3H, J ¼ 7.0
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ꢀ
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(b) Cantillo D, Avalos M, Babiano R, et al. Org Lett. 2008;10:1079e1082;
Hz) ppm. 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d 165.3, 160.6, 156.6,
(c) Cantillo D, Avalos M, Babiano R, et al. J Org Chem. 2009;74:3698e3705;
ꢀ
137.2, 135.8, 128.4, 128.2, 127.7, 125.6, 103.8, 68.0, 52.0, 29.3, 28.3,
19.4, 16.3 ppm. Anal. Calcd for C18H19NO3S: C, 65.63, H, 5.81, N, 4.25,
S, 9.73. Found: C, 65.58, H, 5.79, N, 4.22, S, 9.55.
ꢀ
(d) Cantillo D, Avalos M, Babiano R, Cintas P, Jimenez JL, Light ME, et al. J Org
Chem. 2009;74:7644e7650;
ꢀ
ꢀ
ꢀ
(e) Sanchez B, Arevalo MJ, Bravo JL, Lopez I, Light ME, Silvero G. Austr J Chem.
2009;62:356e359;
ꢀ
ꢀ
(f) Sanchez B, Lopez I, Light ME, Silvero G, Bravo JL. Eur J Org Chem. 2010:
1648e1652.
ꢀ
4.2.10. (S)-Ethyl 3-isopropyl-5-oxo-6-phenyl-3,5-dihydro-2H-
thiazolo[3,2-a]pyridine-8-carboxylate (18)
ꢀ
ꢀ
10. de la Concepcion J García, Avalos M, Babiano R, Cintas P, Jimenez JL, Light ME,
et al. Tetrahedron. 2016;72:4665e4670.
11. Delaunay D, Toupet L, Le Corre M. J Org Chem. 1995;60:6604e6607.
12. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-1519821.
13. (a) Badenhoop JK, Weinhold F. J Chem Phys. 1997;107:5406e5421;
(b) ibid. 5422e5432, (c) Badenhoop JK, Weinhold F. Int J Quantum Chem.
1999;72:269e280.
Compound 18 was obtained from 15 and 8 after 2 hRecrystal-
lized from ethyl acetate (64%) had mp 108e111 ꢁC. [ 326.2ꢁ (c
a]
D
5.4, CH2Cl2). FTIR (KBr) nmax 3065, 2961, 2935, 2873, 1694, 1639,
1596, 1521, 1445, 1395, 1303, 1255, 1237, 1168, 1102, 1035, 777, 700,
597, 542 cmꢀ1. 1H NMR (500 MHz, CDCl3, 25 ꢁC)
d 8.02 (s, 1H), 7.68
(m, 2H), 7.41 (t, 2H, J ¼ 7.0 Hz), 7.33 (m, 1H), 4.35 (m, 2H) 3.49 (dd,
1H, J ¼ 9.0 Hz, J ¼ 11.5 Hz), 3.20 (dd, 1H, J ¼ 1.0 Hz, J ¼ 11.5 Hz), 2.64
(m,1H),1.37 (t, 3H, J ¼ 7.0 Hz),1.03 (d, 3H, J ¼ 7.0 Hz), 0.95 (d, 3H, J ¼
14. Reed AE, Weinhold F. J Chem Phys. 1985;83:1736e1740.
15. Foster JP, Weinhold F. J Am Chem Soc. 1980;102:7211e7218.
16. Weinhold F. J Comput Chem. 2012;33:2440e2449.
17. Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 09, Revision D.01. Wall-
ingford, CT: Gaussian, Inc.; 2009.
7.0 Hz) ppm. 13C NMR (125 MHz, CDCl3, 25 ꢁC)
d 164.9, 160.6, 156.4,
18. Zhao Y, Truhlar DG. Theor Chem Acc. 2008;120:215e241.
19. a) Ditchfield R, Hehre WJ, Pople JA. J Chem Phys. 1971;54:724e728;
b) Hehre WJ, Ditchfield R, Pople JA. Mol Phys. 1974;27:209e214;
c) Gordon MS. Chem Phys Lett. 1980;76:163e168;
137.3, 135.8, 128.5, 128.2, 127.7, 125.6, 104.2, 68.0, 61.2, 29.3, 28.3,
19.4, 16.4, 14.4 ppm. Anal. Calcd for C19H21NO3S: C, 66.45, H, 6.16, N,
4.08, S, 9.34. Found: C, 66.39, H, 6.14, N, 3.97, S, 9.30.
d) Hariharan PC, Pople JA. Theor Chem Acc. 1973;28:213e222;
e) Francl MM, Pietro WJ, Hehre WJ, et al. J Chem Phys. 1982;77:3654e3665.
20. a) Marenich AV, Cramer CJ, Truhlar DG. J Phys Chem B. 2009;113:4538e4543;
b) Marenich AV, Cramer CJ, Truhlar DG. J Phys Chem B. 2009;113:6378e6396;
c) Ribeiro RF, Marenich AV, Cramer CJ, Truhlar DG. J Comput.-Aided Mater.
2010;24:317e333;
d) Halim MA, Shaw DM, Poirier RA. J Mol Struct. 2010;960:63e72;
e) Saielli G. J Phys Chem A. 2010;114:7261e7265.
21. Glendening ED, Badenhoop JK, Reed AE, et al. Theoretical Chemistry Institute.
Madison: University of Wisconsin; 2013.
Acknowledgements
Financial support from the Ministry of Economy and Competi-
tiveness (Grant CTQ2013-44787P), and the Junta de Extremadura
(Ayuda a Grupos de Investigacion, Grant GR15022) is greatly
ꢀ
ꢀ
ꢀ
acknowledged. We also thank Cenits and Fundacion Computaex for
allowing us the use of Supercomputer LUSITANIA.
22. http://www.jmol.org/.