Regioselectivity of Vinyl Sulfone Based 1,3-Dipolar Cycloaddition

Maya Shankar Singh , Sushobhan Chowdhury , Suvajit Koley ... Divya Pratap Singh , Bharat Kumar Allam , Rahul Singh , Krishna Nand Singh , Vinod Prasad...
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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 metalfree conditions.

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from commercially available 2,3-dibromopropionic acid10 and styrene epoxide,4 respectively (see the Supporting Information). 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 of triazoles 6 and 7a were assigned using the 1H NMR data.11 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-withdrawing 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 631+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-

n almost every area of chemistry, including materials chemistry, drug discovery, development of sensors, polymer 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 wellknown in the literature involving the use of alkynes1,3 or olefinic compounds.4,5 In addition to the wide-ranging applications of 1,4disubstituted 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 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-deoxy1,2:3,4-di-O-isopropylidene-α-D-galactose 1 with (E)-1-perfluoroalkyl-2-phenylsulfonylethene 2a (similar to (E)-1-perfluoroalkyl-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 © 2014 American Chemical Society

Received: February 12, 2014 Published: April 3, 2014 2100

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Scheme 1. Synthesis of 1,5-Disubstituted 1,2,3-Triazole and 1,4-Disubstituted 1,2,3-Triazole from 6-Azido-6-deoxy1,2:3,4-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)-1perfluoroalkyl-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)-optimized 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-tosylsulfonyl-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 suggest that the TS leading to formation of 1,4-DTs is energetically favored by 12.6 kJ/mol compared to the corresponding 1,5DTs (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/631+G(d) calculated results in toluene show that the TS leading to formation of 1,4-DTs is favored over its corresponding 1,5DTs 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)-1methylcarboxylate-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 2101

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strain and (ii) the interaction energy(ΔEi⧧), which is dependent on TS electronics, i.e., ΔE⧧ = ΔEd⧧ + ΔEi⧧.23−25 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 regioselectivity 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 1,2diols, 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 activation ΔE⧧, distortion ΔEd⧧, and interaction energies ΔEi⧧ (kJ/mol) for the reaction between protected sugar azide 1 and (E)-1-phenyl-2tosylsulfonylethenes 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

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ASSOCIATED CONTENT

S Supporting Information *

The experimental details and Cartesian coordinates with absolute values. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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Figure 4. 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-methyl-2tosylsulfonylethene 4b. All distances in the TS are in angstroms.

ACKNOWLEDGMENTS 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 1,4DTs (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. To examine the origin of regioselectivity of triazole formation demonstrated by vinyl sulfones 2−4 (Scheme 1), we employed the distortion/interaction model.21,22 This model rationalized many regioselective problems associated with ring strain and other electronic effects.12,22 The distortion−interaction model divides the activation energy (ΔE⧧) of a reaction into two parts, (i) the distortion energy (ΔEd⧧) depending on ground state

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