Regioselectivity of vinyl sulfone based 1,3-dipolar cycloaddition reactions with sugar azides by computational and experimental studies

Article abstract of DOI:10.1021/ol500461s

DFT (M06-L) calculations on the transition state for the 1,3-dipolar cycloadditions between substituted vinyl sulfones with sugar azide have been reported in conjunction with new experimental results, and the origin of reversal of regioselectivity has been revealed using a distortion/interaction model. This study provides the scientific justification for combining organic azides with two different types of vinyl sulfones for the preparation of 1,5-disubstituted 1,2,3-triazoles and 1,4-disubstituted triazolyl esters under metal-free conditions.

Full text of DOI:10.1021/ol500461s

Letter
pubs.acs.org/OrgLett
Regioselectivity of Vinyl Sulfone Based 1,3-Dipolar Cycloaddition
Reactions with Sugar Azides by Computational and Experimental
Studies
Debashis Sahu,† Santu Dey,‡ Tanmaya Pathak,*,‡ and Bishwajit Ganguly*,†
†Computation and Simulation Unit, Analytical Discipline & Centralized Instrument Facility, and Academy of Scientific and Innovative
Research, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat 364002, India
‡Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
S
* Supporting Information
ABSTRACT: DFT (M06-L) calculations on the transition
state for the 1,3-dipolar cycloadditions between substituted
vinyl sulfones with sugar azide have been reported in
conjunction with new experimental results, and the origin of
reversal of regioselectivity has been revealed using a
distortion/interaction model. This study provides the scientific
justification for combining organic azides with two different
types of vinyl sulfones for the preparation of 1,5-disubstituted 1,2,3-triazoles and 1,4-disubstituted triazolyl esters under metal-
free conditions.
n almost every area of chemistry, including materials
chemistry, drug discovery, development of sensors, polymer
from commercially available 2,3-dibromopropionic acid10 and
styrene epoxide,4 respectively (see the Supporting Informa-
tion). Vinyl sulfones 3 and 4a were reacted with 1 in toluene
under refluxing conditions to exclusively afford 1,4-DTs 6 and
1,5-DTs 7a, respectively, in good yields (Scheme 1). Structures
I
chemistry, chemical biology, and organic synthesis, the Cu(I)-
mediated alkyne−azide 1,3-dipolar cycloaddition reactions have
been extensively applied during the past decade.1 The
regioselectivity of the 1,3-dipolar cycloaddition reaction mainly
depends on the electronic and steric effects.2 The 1,3-dipolar
cycloaddition reaction in the presence of metal1 or in the
absence of metal3,4 for the synthesis of 1,2,3-triazoles are well-
known in the literature involving the use of alkynes1,3 or
olefinic compounds.4,5
In addition to the wide-ranging applications of 1,4-
disubstituted 1,2,3-triazoles (1,4-DTs),1 the 1,5-disubstituted
1,2,3-triazoles (1,5-DTs), considered to be cis-peptide bond
surrogates, have attracted researchers for reliable and simple
protocols for preparing such heterocycles.1d Importantly,
synthesis of a disubstituted 1,2,3-triazole linkage to sugar
moieties is also an active area of research in organic chemistry.6
Such kinds of sugar moieties linked to heterocycles are found in
many antibiotics that are biologically active.7,8
11
1
of triazoles 6 and 7a were assigned using the H NMR data.
The chemical shift values of C4 and quaternary C5 of 6 arises at
δ 138.6 ppm and δ 130.0 ppm made the Δ (δC4−δC5) value
positive (ca. 8.6 ppm), whereas these two values for 7a arising
at δ 128.2 ppm and δ 147.7 ppm made the Δ (δC4−δC5) value
significantly smaller and negative (ca. −19.5 ppm), as
expected.11b
To explore the origin of regioselectivity in 1,3-dipolar
cycloaddition reactions with sugar azide 1 and vinyl sulfones
2b, 3, and 4a (Scheme 1) in toluene, we have performed DFT
(M06-L) calculations. We have examined the electron-with-
drawing and neutral/weak electron-donating groups present in
vinyl sulfones for the formation of 1,2,3-triazoles with sugar
azides. DFT calculations have unraveled the many intricate
features of 1,3-dipolar cycloaddition reactions with azides and
alkene/alkynes.12−14 Full geometrical optimizations were
carried out in the toluene medium (ε = 2.3741) with a
polarizable continuum model (PCM)15 employing the
Minnesota density functional (M06-L)16 with the standard 6-
31+G(d) basis set.17 Frequency calculations were performed at
the same level of theory to confirm that each stationary point
was a local minimum (with zero imaginary frequency) or a
transition state (with one imaginary frequency). Single-point
energy calculations were performed at the M06-L/6-311+G-
Vinyl sulfones have been exploited to produce 1,4-DTs9 and
1,5-DTs.4 The preferential formation of 1,4-DTs and 1,5-DTs
from the sugar azide 1 (Scheme 1) and substituted vinyl
sulfones establishes beyond doubt that the regioselectivity of
triazole formation is governed by the substituents present in the
olefinic unit.
The 1,3-dipolar cycloaddition reaction of 6-azido-6-deoxy-
1,2:3,4-di-O-isopropylidene-α-D-galactose 1 with (E)-1-per-
fluoroalkyl-2-phenylsulfonylethene 2a (similar to (E)-1-per-
fluoroalkyl-2-tosylsulfonylethene 2b, used for calculations) only
forms the 1,4-DTs 5.9 In this study, we have further synthesized
a set of 1,4-DTs and 1,5-DTs with sugar azide 1 and other vinyl
sulfones (3 and 4a). Vinyl sulfones 3 and 4a were synthesized
Received: February 12, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Letter
Scheme 1. Synthesis of 1,5-Disubstituted 1,2,3-Triazole and
1,4-Disubstituted 1,2,3-Triazole from 6-Azido-6-deoxy-
1,2:3,4-di-O-isopropylidene-α-D-galactose 1
Figure 1. M06-L/6-311+G(d,p)//M06-L/6-31+G(d) calculated
⧧
activation ΔE⧧, distortion ΔEd , and interaction energies ΔEi⧧ (kJ/
mol) for the reaction between protected sugar azide 1 and (E)-1-
perfluoroalkyl-2-tosylsulfonylethene 2b. All distances in the TS are in
angstroms.
activation ΔG⧧ at M06-L/6-31+G(d) level also predicts the
similar results in this case (Figure 2).
(d,p) level17 of theory with the polarizable continuum model
(PCM) in toluene employing the M06-L/6-31+G(d)-opti-
mized geometries. The free energies of activation, ΔG⧧,
calculated at the M06-L/6-31+G(d) level of theory have been
reported here. All DFT calculations were performed with
Gaussian 09 suite of programs.18
First, we have examined the regioselectivity between
protected sugar azide 1 and (E)-1-perfluoroalkyl-2-tosylsulfon-
yl-ethenes 2b in toluene (Scheme 1). The transition state (TS)
geometries of 1,4-DTs and 1,5-DTs have been located with
M06-L/6-31+G(d) level of theory. The M06-L/6-311+G-
(d,p)//M06-L/6-31+G(d) calculated activation energies sug-
gest that the TS leading to formation of 1,4-DTs is energetically
favored by 12.6 kJ/mol compared to the corresponding 1,5-
DTs (Figure 1) which corroborates the experimental
observation.9 The free energy of activation ΔG⧧ calculated
for the formation of 1,4-DTs and 1,5-DTs also predicts the
similar result (Figure 1). The trifluoromethyl-substituted
alkenes with formyl azides also showed the preference for
1,4-addition regiochemistry in the solution phase as predicted
with trifluoromethyl-substituted vinyl sulfone.9,19
The other set of reaction performed with CO2Me substituted
vinyl sulfone, (E)-1- methylcarboxylate-2-tosylsulfonyl-ethenes
3 and sugar azide 1 showed the preference for 1,4-addition than
the 1,5-addition. The DFT (M06-L/6-311+G(d,p)//M06-L/6-
31+G(d) calculated results in toluene show that the TS leading
to formation of 1,4-DTs is favored over its corresponding 1,5-
DTs by 5.8 kJ/mol (Figure 2). The calculated free energy of
Figure 2. M06-L/6-311+G(d,p)//M06-L/6-31+G(d) calculated
⧧
activation ΔE⧧, distortion ΔEd , and interaction energies ΔEi⧧ (kJ/
mol) for the reaction between protected sugar azide 1 and (E)-1-
methylcarboxylate-2-tosylsulfonylethenes 3. All distances in the TS are
in angstroms.
Although the electron-withdrawing substituents on vinyl
sulfones 2a and 3 yield 1,4-addition as a major product, the
experimental studies reveal that the phenyl-substituted vinyl
sulfone 4a with 1 leads to 1,5-addition as a major product. It
should also be noted that vinyl sulfones functionalized with
alkyl groups4a,c including sugar molecules4b also afford 1,5-DTs.
The reversal of regiochemistry has also been examined with the
M06-L/6- 311+G(d,p)//M06-L/6-31+G(d) level of theory
(Figure 3). The calculations suggest that the TS for 1 and 4a of
1,5-DTs is energetically preferred by 1.7 kJ/mol compared to
the corresponding 1,4-DTs (Figure 3), which is in agreement
with the experimental observed result. The calculated free
energy of activation ΔG⧧ also predicts that the formation of
1,5-DTs is preferred by 10.4 kJ/mol compared to the
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Organic Letters
Letter
strain and (ii) the interaction energy(ΔEi⧧), which is
23−25
⧧
dependent on TS electronics, i.e., ΔE⧧ = ΔEd + ΔEi⧧.
The distortion and interaction energies for the cycloadditions
of 1 with 2b, 3, and 4a in toluene are calculated at the M06-L/
6-311+G(d,p)//M06-L/6-31+G(d) level of theory. The
distortion/interaction model reveals that the regioselectivity
of sugar azide 1 and vinyl sulfones 2−4 generally arises due to
the differences in the distortion energies of 1,3-dipole and
dipolarophile rather than the frontier molecular orbital (FMO)
interactions for the same addends (Figures 1−4).12,14,21,22
However, the interaction energy also governs the regioselec-
tivity for the cycloaddition reaction between sugar azide 1 and
trifluoromethyl-substituted vinyl sulfones 2b. It has been
observed that FMO interaction energies are higher with
fluorine substitutions.14 The interaction energies calculated in
other cases seem to be smaller than the distortion energies.
This work demonstrates the origin of regioselectivity for the
triazole formation of a sugar azide and substituted vinyl
sulfones with computational and experimental studies. Since
vinyl sulfones are easily synthesized from a wide variety of 1,2-
diols, olefins, epoxides, aldehydes, and dibromides,4c,10 this
study builds the scientific basis of the strategy of using the vinyl
sulfone/azide combination for a metal-free and general
methodology for the regioselective synthesis of 1,5-DTs.4 On
the other hand, the theoretical and experimental observation
related to the regioselective formation of the 1,4-disubstituted
triazolyl ester 6 also opens up a possible general route for
accessing related 1,4-DTs through a metal-free route. Initial
experimental studies in this direction indicate that the strategy
is indeed capable of generating a wide-range of carboxylated
1,4-DTs.
Figure 3. M06-L/6-311+G(d,p)//M06-L/6-31+G(d)-calculated acti-
⧧
vation ΔE⧧, distortion ΔEd , and interaction energies ΔEi⧧ (kJ/mol)
for the reaction between protected sugar azide 1 and (E)-1-phenyl-2-
tosylsulfonylethenes 4a. All distances in the TS are in angstroms.
corresponding 1,4-DTs. The phenyl group is considered to be a
neutral/weak electron-donating group.20
We have also extended the computational study with the
methyl group attached to the vinyl sulfone unit, namely
compound 4b (Figure 4). The DFT-calculated results show
ASSOCIATED CONTENT
* Supporting Information
■
S
The experimental details and Cartesian coordinates with
absolute values. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ganguly@csmcri.org.
*E-mail: tpathak@chem.iitkgp.ernet.in.
Notes
The authors declare no competing financial interest.
Figure 4. M06-L/6-311+G(d,p)//M06-L/6-31+G(d)-calculated acti-
⧧
vation ΔE⧧, distortion ΔEd , and interaction energies ΔEi⧧ (kJ/mol)
ACKNOWLEDGMENTS
■
for the reaction between protected sugar azide 1 and (E)-1-methyl-2-
tosylsulfonylethene 4b. All distances in the TS are in angstroms.
CSIR-CSMCRI Communication No. 032/2014. We thank
DST (New Delhi) and MSM, SIP, CSIR (New Delhi), for
financial support. D.S. thanks UGC (India) and S.D. thanks
CSIR (India) for fellowships. D.S. is also thankful to AcSIR for
enrollment in the Ph.D. program. We thank the anonymous
reviewers for their valuable suggestions/comments.
that the TS leading to formation of 1,5-DTs is energetically
favored (3.8 kJ/mol) in toluene over the corresponding 1,4-
DTs (Figure 4). The free energy of activation ΔG⧧ for the
formation of 1,5-DTs is also preferred by 5.1 kJ/mol compared
to the corresponding 1,4-DTs.
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