A computational study of regioselectivity in β-lactam iminothiazolidinone formation

Article abstract of DOI:10.1016/j.tetlet.2015.10.101

Density functional theory calculations were performed to explain the different regioselectivity for the formation of β-lactam iminothiazolidinones. Computational results were in agreement with experimental observations that phenyl and cyclohexyl derivativ

Full text of DOI:10.1016/j.tetlet.2015.10.101

Tetrahedron Letters 56 (2015) 6908–6911
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Tetrahedron Letters
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A computational study of regioselectivity in b-lactam
iminothiazolidinone formation
b,
Katarina Vazdar a, , Mario Vazdar
⇑
⇑
a Division of Physical Chemistry, Rudjer Boškovi´c Institute, POB 180, HR-10002 Zagreb, Croatia
b Division of Organic Chemistry and Biochemistry, Rudjer Boškovic´ Institute, POB 180, HR-10002 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2015
Revised 9 September 2015
Accepted 29 October 2015
Available online 30 October 2015
Density functional theory calculations were performed to explain the different regioselectivity for the for-
mation of b-lactam iminothiazolidinones. Computational results were in agreement with experimental
observations that phenyl and cyclohexyl derivatives led to the thermodynamically more stable regioiso-
mers formed by cyclization at the nitrogen atom directly attached to the b-lactam ring which was in
contrast to the n-hexyl derivative where the regioisomer with the b-lactam ring attached to the imino
bond is more stable instead. It was demonstrated that the different regioselectivity was the consequence
of larger steric effects when bulky substituents and the leaving ethoxy group were in close contact during
the cyclization step.
Keywords:
Iminothiazolidinones
Regioselectivity
DFT calculations
Free energy barrier
Steric effects
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
substituted b-lactam iminothiazolidinones.14 This investigation
demonstrated an iminothiazolidinone regioselectivity which could
The b-lactam unit is one of the key synthons in the preparation
of novel molecular scaffolds.1 This motif plays an important role in
delivering chiral information in the asymmetric synthesis of com-
pounds1,2 as well as providing a useful route to different heterocy-
cles.1,3,4 Besides being crucial for the activity of biologically active
compounds such as antibiotics5 and cholesterol absorption
inhibitors,6 it is also vital for the synthesis of various amino acids,
peptides, and nitrogen containing poly-functional molecules.7
The preparation of five membered iminothiazolidinones by the
not be fully explained by known mechanistic details8–11 since
chemically different thiourea substituents mostly led to struc-
turally equivalent regioisomers, regardless of their electronic prop-
erties.14 However, in the case of an n-alkyl substituent, the
regioisomer with a different structural arrangement was isolated
in excess. This unusual regioselectivity pattern prompted us to
perform a more detailed mechanistic analysis of the reaction
mechanism, by employing a detailed quantum-chemical analysis.
Herein, we propose a reaction pathway which reveals an interest-
ing interplay of electronic and, more importantly, steric factors
leading to the observed regioselectivity.
reaction of thioureas and
a-haloalkanoic acids (or their
derivatives) has been previously reported in the literature.8–11
Experimental evidence has shown for the preparation of iminoth-
iazolidinones from non-symmetrical thioureas, two regioisomers
are formed depending on the nitrogen atom involved in the
cyclization and formation of the five-membered ring. In most
cases, one regioisomer predominates and is dependent on the elec-
tronic properties of the starting thiourea substituents. When the
starting thiourea bears substituents with similar electronic proper-
ties, the product regioselectivity is minimal.8–11
Results and discussion
We began with the synthesis of amino-b-lactam 1 according to
known methods.15,16 The treatment of amino-b-lactam 1 with the
corresponding isothiocyanates in CH3CN at RT resulted in the for-
mation of b-lactam thioureas 2a–i.14 Thioureas 2a–i were then
subjected to condensation with ethyl-bromoacetate in the pres-
ence of 2.0 equiv of Na2CO3 to give b-lactam iminothiazolidinones
3a–i/i0 in good yields14 (Scheme 1).
As part of our own synthetic efforts to broaden the versatility of
this reaction,12,13 we have investigated the preparation of variously
In the case of b-lactam substituted thioureas 2a–i (Table 1) the
cyclization reaction gave only one iminothiazolidinone regioiso-
mer 3a–h, except in the case of the n-hexyl substituted thiourea
2i which afforded iminothiazolidinones 3i/i0 which were isolated
⇑
Tel.: +385 1 4561 007; fax: +385 1 4680 245 (K.V.); tel.: +385 1 4561 008; fax:
+385 1 4680 195 (M.V.).
E-mail addresses: katarina.vazdar@irb.hr (K. Vazdar), mario.vazdar@irb.hr
(M. Vazdar).
http://dx.doi.org/10.1016/j.tetlet.2015.10.101
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

K. Vazdar, M. Vazdar / Tetrahedron Letters 56 (2015) 6908–6911
6909
Table 2
Free energy differences
D
G in kcal molꢀ1 between selected steps along the reaction
mechanism (Scheme 2) calculated at the SMD/B3LYP/6-311++G(2d,p)/B3LYP/6-31+G
(d) level of theory
Phenyl
Cyclohexyl
n-Hexyl
M-1
M-2
0.0
297.3
0.0
300.3
0.0
300.8
Scheme 1. Synthesis of b-lactam iminothiazolidinones 3a–i/3i0.
Complexation with BrCH2COOEt
M-3
M-TS1
M-4
0.0
8.5
ꢀ23.1
0.0
6.6
ꢀ23.7
0.0
7.1
ꢀ21.9
a
Elimination of Brꢀ
M-5
M-TS2
0.0
14.2
0.0
14.6
0.0
10.5
b
M-6
M-7
ꢀ0.2
ꢀ2.6
ꢀ3.3
ꢀ319.4
ꢀ325.3
ꢀ322.4
Conformational change pathway
c
M-50
2.8
7.1
0.2
2.0
8.3
ꢀ3.0
ꢀ321.5
ꢀ0.7
3.4
7.8
ꢀ2.6
ꢀ321.9
1.9
d
0
M-TS2
M-60
M-70
ꢀ318.0
DDGe
ꢀ2.5
a
Imaginary frequencies: 387i cmꢀ1 (phenyl), 387i cmꢀ1 (cyclohexyl), 382i cmꢀ1
(n-hexyl).
b
Imaginary frequencies: 124i cmꢀ1 (phenyl), 188i cmꢀ1 (cyclohexyl), 183i cmꢀ1
(n-hexyl).
c
Energy relative to M-5.
d
Imaginary frequencies: 154i cmꢀ1 (phenyl), 149i cmꢀ1 (cyclohexyl), 154i cmꢀ1
(n-hexyl).
e
Free energy difference between products M-7 and M-70.
Scheme 2. Model representation of the regioselective iminothiazolidinone forma-
tion mechanism. R1 = phenyl, cyclohexyl, n-hexyl; R2 = methyl.
Table 1
Experimental yields of b-lactam thioureas 2a–i and iminothiazolidinones 3a–i/3i0
R1
Yield of 2 (%)
Yield of 3 (%)
a
b
c
d
e
f
g
h
i
Ph
96
81
94
66
85
97
72
94
54
73
96
92
90
45
84
77
99
p-NO2Ph
2-ClPh
2-FPh
p-N3Ph
p-CNPh
Cy
Norbornyl
n-Hexyl
67 (3i:3i0 = 23:77)a
a
Two regioisomers are formed and their ratio is determined by NMR and HPLC
analysis.
from the reaction mixture in a 23:77 ratio, as confirmed by NMR. In
particular, it was interesting to see that the structures of iminoth-
iazolidinones 3g and 3h bearing electron donating alkyl groups
have the same structural arrangement as iminothiazolidinones
3a–f, which contained aryl substituents that were stabilized by
resonance.
In order to examine these findings in more detail, we chose phe-
nyl, cyclohexyl, and n-hexyl substituents as models in subsequent
density functional theory (DFT) calculations. Phenyl and cyclohexyl
substituents were chosen due to the resonance stabilization effect
(and lack of it, respectively) and their comparable sizes, whereas
an n-hexyl substituent was selected due to its flexible acyclic
structure in comparison to the rigid phenyl and cyclohexyl
substituents.
Figure 1. Schematic representation of energy diagrams in (a) phenyl, cyclohexyl
and (b) n-hexyl derivatives of iminothiazolidinone. Free energy difference is given
in kcal molꢀ1
.
Free energy barriers and protonation/deprotonation free ener-
gies are given in Table 2 while the energy diagram is schematically
presented in Figure 1. In the first part of the mechanism, the reac-
tion path starting from M-1 and leading to M-5 is identical for all
R1 substituents. Initially, deprotonation of the starting compound
M-1 with the first equivalent of Na2CO3 occurs, resulting in the for-
mation of the anion M-2. Although in principle four conformers are
possible in the case of M-1, only the most stable conformation (and
in turn its anion M-2), were considered in further calculations.
Upon deprotonation of the M-2, addition of ethyl-bromoacetate

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K. Vazdar, M. Vazdar / Tetrahedron Letters 56 (2015) 6908–6911
(BrCH2COOEt) led to the formation of weakly bound complex
M-3. Nucleophilic attack of the sulfur group to the electrophilic
carbon atom in BrCH2COOEt resulted in the formation of com-
pound M-4. This reaction is exergonic, as shown by the free energy
barriers of 6–8 kcal molꢀ1 followed by stabilization of M-4 by
22–24 kcal molꢀ1 (depending on the substituents). In order to fol-
low the further reaction steps more easily, the Brꢀ anion was
removed from complex M-4 since it was not essential in the subse-
quent reaction steps.
After removal of Brꢀ anion from molecule M-4 and deprotona-
tion with a second equivalent of Na2CO3, M-5 is formed which rep-
resents a branching point for regioselective reactions. The first
possible pathway proceeds via direct nucleophilic attack of the
nitrogen atom substituted with R1 groups leading to M-6. In the
case of phenyl and cyclohexyl groups, the calculated barrier for
cyclization was around 14 kcal molꢀ1, which contrasted with the
n-hexyl group where the barrier was lowered by 4 kcal molꢀ1
.
After cyclization, M-6 is protonated in the reaction mixture leading
to elimination of EtOH and the final product M-7. The second pos-
sible pathway involves cyclization of the nitrogen atom directly
connected to the b-lactam ring. In order for this reaction to occur,
an additional conformational change is necessary to position the
reactive nitrogen and carbon centers in closer contact. Unfortu-
nately, the barrier for the process could not be computationally
determined due to the complex conformational change, but it
was calculated that isomers M-50 were destabilized by
2–3 kcal molꢀ1 with respect to M-5. Regardless of this energeti-
cally slightly unfavorable step, in the cases of phenyl and cyclo-
hexyl group the ensuing products M-60 were found to be more
easily accessible when compared to the pathway without confor-
mational change (7.1 and 8.3 kcal molꢀ1 versus 14.2 and
14.6 kcal molꢀ1, respectively). Moreover, after protonation and
elimination of EtOH, thermodynamically more stable products
M-70 are obtained with energy differences compared to M-7 being
ꢀ2.5 and ꢀ0.7 kcal molꢀ1, respectively. In the case of the n-hexyl
group, regardless of the lower barrier leading to M-60 as compared
to M-6 (7.8 versus 10.5 kcal molꢀ1, respectively), a thermodynam-
ically less stable product was obtained with energy difference to
M-7 being +1.9 kcal molꢀ1. These results were in agreement with
the experimental data presented in Table 1 where M-70 was iso-
lated in the case of phenyl and cyclohexyl substituent (compounds
3a and 3g) while in the case of n-hexyl substituent (compound 3i0)
M-7 was isolated in excess. While the exact ratio of structural
regioisomers could not be predicted based on the free energy dif-
ferences between M-7 and M-70, it was gratifying to note that
the regioselectivity pattern was reproduced with DFT calculations.
Next we explain the reasons for the different regioselectivities.
In order to demonstrate this more clearly, the geometries of the
relevant structures in the conversion of M-5 to the regioisomer
M-6 formed by cyclization with the R1-nitrogen atom (Fig. 2a) in
the case of phenyl substituent were compared (geometries of the
cyclohexyl derivatives are not shown due to a qualitatively similar
picture). At the same time we also show the cyclization step lead-
ing to regioisomer M-60 formed by cyclization with the nitrogen
atom directly attached to the b-lactam ring (Fig. 2b). It can be seen
that product M-6 is destabilized compared to the transition struc-
ture M-TS2 as reflected by a very long C–N bond of 1.64 Å. This was
also visible in the relative energy of M-6, which is only
0.2 kcal molꢀ1 more stable than the transition state M-TS1
(Table 1). The same situation held true for product M-60 which is
less stable (but only when thermal correction is taken into account,
Figure 2. Optimized geometries during the five-membered ring cyclization step for
phenyl derivatives of iminothiazolidinone. (a) Transformation from M-5 to M-6; (b)
transformation from M-50 to M-60 after conformational change of M-5 to M-50.
reflected by the calculated free energy barriers (14.2 kcal molꢀ1
versus 7.1 kcal molꢀ1, respectively). Although both products M-6
and M-60 are relatively unstable due to a negligible barrier for
the reverse reaction, they are immediately protonated in the
reaction mixture leading to the final products M-7 and M-70, where
M-70 is 2.5 kcal molꢀ1 more stable than M-7. Therefore, the forma-
tion of M-70 is preferred both kinetically (due to steric reasons and
in turn the lower free energy barrier for cyclization of M-50 to M-60)
and thermodynamically (as witnessed by the larger stability of
product M-70). A similar situation also held for cycꢀlo1hexyl deriva-
tives and the final product M-70 was 0.7 kcal mol more stable
than M-7. However, products M-6 and M-60 were both slightly sta-
0
bilized compared to the transition state M-TS2 and M-TS2 , respec-
tively, (see Table 2 for relative free energy barriers), but this does
not affect the regioselectivity.
In the case of the n-hexyl substituent, a diminished steric repul-
sion between ethoxy and n-hexyl groups changed the regioselec-
tivity pattern. In contrast to the phenyl substituent, M-6 in
n-hexyl derivative had a C–N bond distance of 1.54 Å (Fig. 3a),
which was 0.10 Å shorter than the corresponding phenyl derivative
(Fig. 2a). This is a result of larger flexibility of n-hexyl chain which
see ESI) than M-TS2 by 0.2 kcal molꢀ1, also having a relatively long
0
C–N bond distance of 1.58 Å. Still, there are notable differences in
these two cyclization steps, and it was determined that it was
twice as expensive to bring the ethoxy and phenyl groups together
(Fig. 2a) than the b-lactam ring and phenyl group, (Fig. 2b) as
Figure 3. Optimized geometries during the five-membered ring cyclization step for
n-hexyl derivatives of iminothiazolidinone. (a) Transformation from M-5 to M-6;
(b) transformation from M-50 to M-60 after conformational change of M-5 to M-50.

K. Vazdar, M. Vazdar / Tetrahedron Letters 56 (2015) 6908–6911
6911
effectively alleviates the repulsion induced by the interaction with
Acknowledgments
the ethoxy group. In the case of regioisomer M-60, the C–N bond
distance was 1.57 Å (Fig. 3b) which was only 0.01 Å shorter than
the C–N bond distance in phenyl derivative M-60 (Fig. 2b). This
was unsurprising since in this regioisomer the ethoxy and b-lactam
groups are in interaction, as in the case of phenyl derivative. This is
also reflected in the free energy barriers for this reaction (Table 2),
which are very similar for all substituents. Therefore, reduced
steric interactions between the n-hexyl and ethoxy groups are
the key reason for the increased stability of M-6 versus M-60 (see
ESI for exact energies) which in turn results in the final
product M-7 being more stable by 1.9 kcal molꢀ1 versus M-70
regardless of the lower free energy barrier for the reaction of
M-50 to M-60.
K.V. thanks Croatian Ministry of Science, Education and Sports
(Program 098-0982915-2948) for funding. M.V. is grateful to the
Croatian Academy of Science and Arts for their support.
Supplementary data
Supplementary data (Experimental details, calculated electronic
energies, thermal corrections to free energies at 298 K, single point
energies and total free energies for phenyl, cyclohexyl and n-hexyl
derivatives M-1–M-7 (Tables S1, S2, S3). References for Supple-
mentary Data) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.101.
Conclusions
References and notes
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In order to explain the different regioselectivity between aryl
and cycloalkyl derivatives versus n-alkyl derivatives, density func-
tional theory calculations were performed using model compounds
describing the preparation of b-lactam iminothiazolidinones by the
reaction of differently substituted b-lactam thioureas and ethyl-
bromoacetate. Computational results were in agreement with
experimental observations, showing that phenyl and cyclohexyl
derivatives led to the thermodynamically more stable regioisomers
which are formed by cyclization at the nitrogen atom directly
attached to the b-lactam ring. In particular, they are more stable
by ꢀ2.5 and ꢀ0.7 kcal molꢀ1, respectively, than the other possible
regioisomer. This occurs due to larger steric effects resulting from
the repulsion between bulky substituents and ethyl bromoacetate
when cyclization occurs at the nitrogen atom bearing the
substituents. Conversely, in the case of n-hexyl derivatives the
repulsion between the n-hexyl and ethoxy groups is lowered due
to the larger conformational flexibility of the n-alkyl chain. This
in turn results in the formation of the regioisomer with the
b-lactam ring attached to the imino bond which is 1.9 kcal molꢀ1
more stable than the other regioisomer.
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