Thiol-ene "click" reaction triggered by neutral ionic liquid: The "ambiphilic" character of [hmim]br in the regioselective nucleophilic hydrothiolation

Article abstract of DOI:10.1002/anie.201408721

Thiol-ene "click" chemistry has emerged as a powerful strategy to construct carbon-heteroatom (C-S) bonds, which generally results in the formation of two regioisomers. To this end, the neutral ionic liquid [hmim]Br has been explored as a solvent cum catalyst for the synthesis of linear thioethers from activated and inactivated styrene derivatives or secondary benzyl alcohols and thiols without the requirement of using a metal complex, base, or free radical initiator. Furthermore, detailed mechanistic investigations using ¹H NMR spectroscopy and quadrupole time-of-flight electrospray ionization mass spectrometry (Q-TOF ESI-MS) revealed that the "ambiphilic" character of the ionic liquid promotes the nucleophilic addition of thiol to styrene through an anti-Markovnikov pathway. The catalyst recyclability and the extension of the methodology for thiol-yne click chemistry are additional benefits. A competitive study among thiophenol, styrene, and phenyl acetylene revealed that the rate of reaction is in the order of thiol-yne a?a thiol-ene a?a dimerization of thiol in [hmim]Br.

Full text of DOI:10.1002/anie.201408721

Angewandte
Chemie
DOI: 10.1002/anie.201408721
Click Chemistry
Thiol–Ene “Click” Reaction Triggered by Neutral Ionic Liquid: The
“Ambiphilic” Character of [hmim]Br in the Regioselective
Nucleophilic Hydrothiolation**
Rajesh Kumar, Saima, Amit Shard, Nitin H. Andhare, Richa, and Arun K. Sinha*
Abstract: Thiol–ene “click” chemistry has emerged as a power-
Thiol–ene coupling (TEC) between an olefin and thiol,
better known as hydrothiolation may proceed through an
electrophilic[5]/free radical[6] or nucleophilic pathway[7] lead-
À
ful strategy to construct carbon–heteroatom (C S) bonds,
which generally results in the formation of two regioisomers.
To this end, the neutral ionic liquid [hmim]Br has been
explored as a solvent cum catalyst for the synthesis of linear
thioethers from activated and inactivated styrene derivatives or
secondary benzyl alcohols and thiols without the requirement
of using a metal complex, base, or free radical initiator.
Furthermore, detailed mechanistic investigations using
1H NMR spectroscopy and quadrupole time-of-flight electro-
spray ionization mass spectrometry (Q-TOF ESI-MS)
revealed that the “ambiphilic” character of the ionic liquid
promotes the nucleophilic addition of thiol to styrene through
an anti-Markovnikov pathway. The catalyst recyclability and
the extension of the methodology for thiol–yne click chemistry
are additional benefits. A competitive study among thiophenol,
styrene, and phenyl acetylene revealed that the rate of reaction
is in the order of thiol–yne > thiol–ene > dimerization of thiol
in [hmim]Br.
À
Figure 1. Biologically active scaffolds containing a C S bond.
ing to the branched Markovnikov[5] or linear anti-Markovni-
kov[6,7] product, respectively. Among both products, the less
studied anti-Markovnikov addition is generally performed in
the presence of transition metal/nonmetal complexes[6a–h] and
base.[7] Recently, Tyson and co-workers[6a] reported the use of
a ruthenium catalyst (Ru(bpz)3)2+ in a radical thiol–ene
reaction for anti-Markovnikov hydrothiolation. Beside this,
some metal-free approaches[6i–j] have gained importance in
linear hydrothiolation reactions. However, many of the
existing strategies are still limited due to the expensive
nature and tedious synthesis of the catalysts, cumbersome
product isolation procedures, formation of two regioisomers,
acidic reaction conditions, usage of unstable styrene, and lack
of catalyst recyclability. Hence, the challenge for improving
sustainability is to develop more general and viable routes,
which would be of great relevance to synthetic chemists.
In this context, ionic liquids (ILs) constitute an attractive
alternative for a number of organic transformations[8] due to
catalyst recycling,[8b] improved selectivity, and ease in product
isolation. So far acidic ILs[9] in conjunction with a free radical
initiator[9a] have been utilized for the synthesis of linear
thioethers from thiol and styrene; however, the acidic nature
of the IL may lead to the polymerization of styrene.[10] Thus,
realization of the hydrothiolation reaction by in situ forma-
tion of styrene from innocuous and inexpensive raw materials
(i.e., secondary benzyl alcohol)[11] and subsequent addition to
thiol would be practically useful. In this context, there are
a few reports available utilizing secondary benzyl alcohols for
the synthesis of only branched thioethers[11] rather than linear
ones.
T
he overwhelming success of “click” chemistry[1] coined by
Sharpless in 2001 has encouraged researchers to develop
a variety of chemical transformations. Among various click
procedures,[2] the thiol–ene/yne reactions[3] have also come to
the fore as click reaction because of their many inherent
benefits like high atom economy, simple synthetic procedures,
and minimum waste generation, besides their applications[4]
in the fields of nanoengineering, polymer science, and
medicine (Figure 1).
[*] R. Kumar, A. Shard, Richa
Natural Plant Products Division
CSIR-Institute of Himalayan Bioresource Technology
Palampur-176061 (H.P.) (India)
R. Kumar, Dr. A. K. Sinha
Academy of Scientific and Innovative Research (AcSIR)
New Delhi (India)
Saima, N. H. Andhare, Dr. A. K. Sinha
CSIR-Central Drug Research Institute
Lucknow-226031(U.P.) (India)
E-mail: aksinha08@rediffmail.com
ak.sinha@cdri.res.in
[**] R.K., A.S., and N.H.A. thank CSIR for a SRF award. We acknowledge
Director(s) CDRI, Lucknow and IHBT, Palampur for their kind
cooperation and encouragement. Some part of this work was
carried out at IHBT (no. 3541). Thanks to SAIF division of CDRI and
Shiv Kumar of IHBT for providing the spectroscopic data. CDRI
communication no. 8828.
In continuation of ongoing interest in using neutral
[hmim]Br for various chemical transformations,[12] including
the dehydrative Heck reaction[12a] and the oxidative coupling
of thiophenols to form disulfides,[12b] we herein present
a tunable role of [hmim]Br for an exclusive synthesis of
linear thioethers from styrenes or secondary benzyl alcohols
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408721.
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(see SI, Table S1) with ease in recyclability[8c] in [hmim]Br,
which is considered as a neutral[12e–g] reaction medium.
Interestingly,
a
reaction between biarylethene (1a,
0.28 mmol) and thiophenol (2a, 1.2 equiv) at 408C in
[hmim]Br (0.5 mL) for 40 min resulted in the formation of
3a in 89% yield (95% measured by GC-MS; Scheme 3)
under N2 atmosphere or open air condition (see SI).
Scheme 3. Click thiol–ene reaction in [hmim]Br for the synthesis of 3a.
Scheme 1. Thiol–ene reaction in neutral [hmim]Br.
To further increase the yield of 3a, different ILs including
basic and acidic ILs as well as [hmmim]Br (1-hexyl-2,3-
dimethylimidazolium bromide),[12b] a C-2 methylated IL were
screened but none of them led to an increase in the yield of 3a
(see SI, Table S1). Further, hydrothiolation between 1a and
2a in the presence of 10 mol% ascorbic acid (a free radical
quencher; Table S1, entry 10) or in the dark under N2
atmosphere (Table S1, entry 11) provided a still high yield
of 88–86% of 3a, thus ruling out the possibility of a free
radical pathway (see SI, Table S1).
(through in situ dehydration) and thiophenols (Scheme 1) by
overcoming the dimerization of thiol in ILs (see the Support-
ing Information, SI). Furthermore, 1H NMR and Q-TOF ESI-
MS-based mechanistic studies proved that the “ambiphilic”
character of the IL promotes the nucleophilic addition of thiol
to styrene through an anti-Markovnikov pathway.
Initially, a mixture of 1-(4-biphenyl)ethanol[12d] (1b,
0.28 mmol) and thiophenol (2a, 1.0 mmol) in [hmim]Br
(0.5 mL; Scheme 2) was irradiated in a tandem manner with
Having established optimal reaction conditions, we exam-
ined the substrate scope for the thiol–ene coupling reaction
between biarylethene 1a and thiols 2a–2i with varying
electronic character, which afforded the corresponding prod-
ucts 3a–3h in moderate to good yields (Table 1). It was
noticed that starting materials with electron-withdrawing
substituents on the thiol (Table 1, 3 f–3g) and benzylthiol
(Table 1, 3h) required longer reaction time due to their weak
nucleophilicity. However, an aliphatic thiol 3i (Table 1) did
not undergo hydrothiolation with 1a.
Scheme 2. Dehydrative thiol–ene reaction in [hmim]Br.
microwave (MW) irradiation (120 W, 1508C) for 15 min
under N2 atmosphere (to ward off the formation of disulfide
from 2a in IL/O2).[12b] GC-MS analysis of the crude product
revealed the formation of the desired product 3a only in 10%
yield along with unreacted biarylethene[12d] intermediate,
diphenyldisulfide,[12b] and biarylaldehyde (see SI). Thereafter,
varying amounts of thiophenol (1.1–1.3 mmol) and IL (0.75–
1.5 mL) as well as different reaction times (10–30 min) and
temperatures (120–1808C) were taken into account. How-
ever, no significant improvement of the yield of 3a was
observed. Further, the dehydration of 1b (0.28 mmol) in
[hmim]Br (0.5 mL) under MW irradiation (120 W, 1508C) for
15 min, followed by addition of thiophenol (1.2 mmol) and
then stirring at 408C[13] under an N2 atmosphere for 40 min
favored the formation of 3a in 54% yield (62% measured by
GC-MS). However, disulfide and biarylaldehyde (Scheme 2)
side products were still detected, possibly due to oxidative
scission[14] of the biarylethene by in situ-generated water
during the dehydration of 1b (see SI). Similarly 3b was
obtained in 57% yield from 2b and 1b (Scheme 2).
To further demonstrate the versatility of the above-
described TEC protocol, a diverse array of styrenes (Table 2,
1a’–1l’) possessing electron-donating as well as electron-
withdrawing groups were coupled with thiophenol (2a),
Table 1: [hmim]Br-catalyzed anti-Markovnikov hydrothiolation between
biarylethene 1a and different thiols 2a–2i.[a,b]
Based on the above-described encouraging results for the
synthesis of thioethers 3a–3b through dehydrative thiol–ene
reaction (Scheme 2), we next examined the concept of “click
chemistry”[1,3] to get a maximum yield of 3a from 1a and 2a
[a] Reaction conditions: 1a (0.28 mmol), thiol (1.2 equiv), [hmim]Br
(0.5 mL), stir at 408C. [b] Yields of isolated products. [c] Not detected.
2
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To prove this hypothetical interaction[17a,18] between 1c’,
[hmim]Br, and 2a, the reaction was examined by H NMR
Table 2: [hmim]Br-catalyzed anti-Markovnikov hydrothiolation between
thiophenol 2a and different styrene derivatives 1a’–1l’.[a,b]
1
spectroscopy in CDCl3 (Figure 3). When 1c’ was mixed with
[hmim]Br, the proton at the C-2 position (peak c) of the
imidazolium moiety and the vinyl protons of 1c’ (peaks b)
[a] Reaction conditions: 1a (0.28 mmol), thiophenol (1.2 equiv),
[hmim]Br (0.5 mL), stir at 408C for 0.5–2 h. [b] Yields of isolated
products. n.d.=not detected (see SI).
which provided the desired products 4a–4k in good yield.
Interestingly, also the coupling of hydroxy-substituted styr-
enes 1h’–1i’ (Table 2), including commercially unavailable 4-
hydroxy-3,5-dimethoxy-styrene (1i’),[15] with 2a provided the
desired products 4h–4i (Table 2) without the need for
a protection–deprotection strategy for the hydroxy group,
albeit only moderate yields were achieved. Similarly, a-
methyl styrene (1k’) undergoes hydrothiolation, giving 53%
yield of the corresponding diarylalkane motif 4k (Table 2),
which is an integral part of a number of biologically active
compounds.[16]
Figure 3. 1H NMR spectra of a) thiophenol, b) 4-methyl styrene,
c) [hmim]Br, d) the interaction between 4-methyl styrene and [hmim]Br
after 5 min. e,f) The interaction between 4-methyl styrene, [hmim]Br,
and thiophenol in CDCl3 after 15 min (e) and 30 min (f).
Mechanistically, there are two plausible pathways for the
synthesis of thioether 4c (Figure 2) either through a free
radical[6] or base-mediated nucleophilic hydrothiolation.[7]
Our studies preclude the use of free radical initiator or
base, therefore, it was presumed that the ambiphilic[12b,17]
“electrophilic and nucleophilic” character of [hmim]Br pro-
motes the nucleophilic addition of thiophenol (2a) to 4-
methyl styrene (1c’) through intermediate (B), in which the S
shifted from d 10.24 to 10.29, from d 5.72, 5.65 to d 5.67, 5.58,
and from d 5.20, 5.16 to d 5.12, 5.08, respectively, after 5 min
of stirring at room temperature (see SI). These shifts could be
considered as evidence that the cation of the IL activates
À
styrene (1c’) through H B formation and similarly that the Br
anion of IL activates thiophenol by accepting the hydrogen
bond as evident from the shifting of peak a from d 3.36 to 3.82
(Figure 3a and e).
À
atom of thiophenol undergoes hydrogen bond (H B) for-
mation[17b] (nucleophilic activation) with the Br anion of the
À
IL due to its H B acceptor ability. Likewise, the C-2 hydrogen
For the direct proof of our perception, we planned to
identify and characterize the intermediate B (Figure 2) using
electrospray ionization mass spectrometry (ESI-MS),[8d,19]
which can be used to efficiently generate ions of noncovalent
adducts in the gas phase. We performed (+ ve) Q-TOF ESI-
MS studies of samples taken after 10 min during the
[hmim]Br-catalyzed reaction of 1c’ with 2a (Figure 4). The
total ion chromatogram (TIC) revealed the presence of ions
at m/z 493.31 (m1), 413.42 (m2) (see SI), 379.31 (m3), 347.21
(m4), 257.10 (m5), 243.07 (m6), 227.09 (m7), 214.26 (m8), and
167.19 (m9) (see SI) corresponding to [B+H+NH3]+,
[B+H+NH3ÀBr]+, [BÀHÀBrÀCH3]+, [BÀHÀNH3Àthiol]+,
[17c]
À
of the hmim cation interacts with 1c’ through H B
(electrophilic activation) formation due to its acidic nature.
Subsequently, nucleophilic attack of thiophenol on styrene
leads to the formation of the C S bond (Figure 2).
À
[B+KÀthiolÀstyreneÀC2H5]+,
[B+KÀthiolÀstyrene–
C3H7]+,
[BÀILÀH]+,
[B+HÀILÀCH3]+,
and
[BÀthiolÀBrÀstyrene]+, respectively (Figure 4), which are
diagnostic of intermediate B. Thus, the mechanistic study
Figure 2. Proposed mechanism of the [hmim]Br-catalyzed thiol–ene
addition.
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obtained a maximum amount of thiol–yne product (67%),
followed by thiol–ene (21%) and disulfide (0%) product on
the basis of GC-MS analysis. The result revealed that the
reaction rates are in the order thiol–yne > thiol–ene > thiol
dimerization.
In conclusion, the neutral [hmim]Br-mediated thiol–ene
“click” chemistry can be described by a single word:
simplicity that leads to ubiquitous implementation. The
developed reaction affords the linear thioether from activated
and inactivated alkenes with thiophenols in good to excellent
yields with high regioselectivity and recyclability of catalyst
under metal-, base-, and radical-free conditions. Moreover,
1
Figure 4. TIC of (+ve) ESI-MS spectra of sample taken after 10 min
from the reaction of 1c’ and 2a catalyzed by [hmim]Br. See SI for the
m1, m2, and m9 peaks.
a mechanistic study based on H NMR spectroscopy and Q-
TOF ESI-MS proved that the “ambiphilic” character of
[hmim]Br promotes the nucleophilic addition of thiols to
styrene through an anti-Markovnikov pathway.
based on 1H NMR spectroscopy and Q-TOF ESI-MS proved
for the first time that the “ambiphilic” character of [hmim]Br
promotes the nucleophilic addition of thiophenol to styrene
Received: September 1, 2014
Revised: October 22, 2014
Published online: && &&, &&&&
À
through intermediate B for the construction of a C S bond
through an anti-Markovnikov pathway.
Keywords: ambiphiles · click chemistry · ionic liquids ·
From an economical point of view, the recyclability of
[hmim]Br for the formation of 3a (Scheme 3) was tested. It
was found that the IL retained a high reactivity for up to five
cycles varying from 95–80% yield (see SI).
.
mass spectrometry · NMR spectroscopy
[1] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int.
Ed. 2001, 40, 2004; Angew. Chem. 2001, 113, 2056; b) J. E. Moses,
A. D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249; c) C. R.
Becer, R. Hoogenboom, U. S. Schubert, Angew. Chem. Int. Ed.
2009, 48, 4900; Angew. Chem. 2009, 121, 4998.
After the establishment of the mechanism, the recycla-
bility, and the substrate scope for the TEC (Tables 1 and 2),
we investigated the importance of the terminal hydrogen in
thiol–yne click (TYC)[3] chemistry. To further ascertain the
role of terminal hydrogen, experiments with 4-ethynyltoluene
(0.25 mmol) and thiols (1.0 equiv) were conducted in
[hmim]Br (0.5 mL) at 408C for 30 min, which furnished the
target molecules 5a and 6a in high yield (Scheme 4), which
are key intermediates for the synthesis of bioactive mole-
cules.[20] Moreover, the E/Z ratio in thiol–yne coupling
reactions is generally substrate-dependent.[21]
[2] a) T. Jin, M. Yan, Y. Yamamoto, ChemCatChem 2012, 4, 1217;
b) A. Massi, D. Nanni, Org. Biomol. Chem. 2012, 10, 3791; c) H.
Stçckmann, A. A. Neves, S. Stairs, K. M. Brindle, F. J. Leeper,
Org. Biomol. Chem. 2011, 9, 7303; d) C. Spiteri, J. E. Moses,
Angew. Chem. Int. Ed. 2010, 49, 31; Angew. Chem. 2010, 122, 33.
[3] a) C. E. Hoyle, C. N. Bowman, Angew. Chem. Int. Ed. 2010, 49,
1540; Angew. Chem. 2010, 122, 1584; b) C. E. Hoyle, A. B. Lowe,
C. N. Bowman, Chem. Soc. Rev. 2010, 39, 1355; c) A. Dondoni,
Angew. Chem. Int. Ed. 2008, 47, 8995; Angew. Chem. 2008, 120,
9133; d) R. L. A. David, J. A. Kornfield, Macromolecules 2008,
41, 1151; e) K. L. Killops, L. M. Campos, C. J. Hawker, J. Am.
Chem. Soc. 2008, 130, 5062; f) V. X. Truong, A. P. Dove, Angew.
Chem. Int. Ed. 2013, 52, 4132; Angew. Chem. 2013, 125, 4226.
[4] a) V. T. Huynh, G. Chen, P. Souza, M. H. Stenzel, Biomacro-
molecules 2011, 12, 1738; b) B. Helms, E. W. Meijer, Science
2006, 313, 929.
Scheme 4. [hmim]Br-catalyzed hydrothiolation of phenyl acetylene.
[5] a) K. Griesbaum, Angew. Chem. Int. Ed. Engl. 1970, 9, 273;
Angew. Chem. 1970, 82, 276; b) M. Weꢀwer, L. Coulombel, E.
Dunach, Chem. Commun. 2006, 332; c) M. Takeuchi, H.
Shimakoshi, K. Kano, Organometallics 1994, 13, 1208; d) B.
Basu, S. Kundu, D. Sengupta, RSC Adv. 2013, 3, 22130; e) K. J.
Miller, M. M. A. Omar, Eur. J. Org. Chem. 2003, 1294; f) J. R.
Cabrero-Antonino, A. Leyva-Perez, A. Corma, Adv. Synth.
Catal. 2012, 354, 678.
Under similar reaction condition, an equimolar mixture of
4-ethynyltoluene, styrene, and thiophenol in [hmim]Br
(0.5 mL) was stirred at room temperature for 35 min to
determine the competing rate of reaction among thiol–yne,
thiol–ene, and thiol dimerization reaction (Scheme 5). We
[6] a) E. L. Tyson, M. S. Ament, T. P. Yoon, J. Org. Chem. 2013, 78,
2046; b) C. Munro-Leighton, S. A. Delp, N. M. Alsop, E. D.
Blue, T. B. Gunnoe, Chem. Commun. 2008, 111; c) S. Banerjee, J.
Das, S. Santra, Tetrahedron Lett. 2009, 50, 124; d) S. Banerjee, J.
Das, R. P. Alvarez, S. Santra, New J. Chem. 2010, 34, 302; e) C. C.
Silveira, S. R. Mendes, F. M. Libero, Synlett 2010, 790; f) P.
Kumar, R. K. Pandey, V. R. Hegde, Synlett 1999, 1921; g) B. C.
Ranu, T. Mandal, Tetrahedron Lett. 2006, 47, 6911; h) S.
Kanagasabapathy, A. Sudalai, B. C. Benicewicz, Tetrahedron
Lett. 2001, 42, 3791; i) B. C. Ranu, T. Mandal, Synlett 2007, 925;
Scheme 5. Competitive reaction of thiophenol, 4-ethynytoluene, and
styrene.
4
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j) B. Movassagh, M. Navidi, Arkivoc 2008, xv, 47; k) G. Povie, A.-
T. Tran, D. Bonnaff, J. Habegger, Z. Hu, C. L. Narvor, P. Renaud,
Angew. Chem. Int. Ed. 2014, 53, 3894; Angew. Chem. 2014, 126,
3975.
2009, 11, 1446; c) N. Sharma, U. K. Sharma, R. Salwan, R.
Kasana, A. K. Sinha, Catal. Lett. 2011, 141, 616.
[15] It is imperative to mention that commercially unavailable 4-
hydroxy-3,5-dimethoxystyrene (1i’) was prepared by dehydrat-
ing the corresponding 4-hydroxy-3,5-dimethoxy phenylethanol
in [hmim]Br under microwave[12d] irradiation. After workup, the
obtained 1i’ was used in the hydrothiolation reaction toward the
formation of 4i (see SI).
[7] a) A. B. Lowe, Polym. Chem. 2010, 1, 17; b) B. D. Mather, K.
Viswanathan, K. M. Miller, T. E. Long, Prog. Polym. Sci. 2006,
31, 487; c) J. W. Chan, C. E. Hoyle, A. B. Lowe, J. Am. Chem.
Soc. 2009, 131, 5751.
[8] a) J. P. Hallett, T. Welton, Chem. Rev. 2011, 111, 3508; b) P.
Hapiot, C. Lagrost, Chem. Rev. 2008, 108, 2238; c) U. K. Sharma,
N. Sharma, R. Kumar, R. Kumar, A. K. Sinha, Org. Lett. 2009,
11, 4846; d) A. K. Chakraborti, S. R. Roy, D. Kumar, P. Chopra,
Green Chem. 2008, 10, 1111; e) C. Chiappe, S. Rajamani, Eur. J.
Org. Chem. 2011, 5517.
[9] a) T. Lanza, M. Minozzi, A. Monesi, D. Nanni, P. Spagnolo, C.
Chiappe, Curr. Org. Chem. 2009, 13, 1726; b) Z. S. Qureshi,
K. M. Deshmukh, K. P. Dhake, B. M. Bhanage, RSC Adv. 2011,
1, 1106.
[10] a) M. J. Rosen, J. Org. Chem. 1953, 18, 1701; b) V. Strehmel, H.
Wetzel, A. Laschewsky, Macromol. Symp. 2014, 342, 78.
[11] a) B. C. Ranu, R. Jana, Adv. Synth. Catal. 2005, 347, 1811; b) see
Ref. [5f]; c) S. Biswas, J. S. Samec, Chem. Asian J. 2013, 8, 974.
[12] a) R. Kumar, A. Sharad, R. Bharti, Y. Thopate, A. K. Sinha,
Angew. Chem. Int. Ed. 2012, 51, 2636; Angew. Chem. 2012, 124,
2690; b) R. Kumar, N. Sharma, U. K. Sharma, A. Sharad, A. K.
Sinha, Adv. Synth. Catal. 2012, 354, 2107; c) N. Sharma, U. K.
Sharma, R. Kumar, N. Katoch, R. Kumar, A. K. Sinha, Adv.
Synth. Catal. 2011, 353, 871; d) R. Kumar, A. Sharma, N. Sharma,
A. K. Sinha, Eur. J. Org. Chem. 2008, 5577; e) H. Alireza, Z.
Abdolkarim, S. Mohsen, A. R. Javad, J. Comb. Chem. 2010, 12,
844; f) S. Mohsen, H. Alireza, Ultrason. Sonochem. 2012, 19, 307;
g) M. Xia, Y.-D. Lu, J. Mol. Catal. A 2007, 265, 205.
[13] In most cases, the molecular level of interaction with an ionic
liquid is studied at ambient temperature ( ꢀ 408C) or room
temperature (see Ref. [8d] and [12b]), because at higher temper-
ature disruption of molecular interaction may occur that could
be the reason for better hydrothiolation at 408C rather than
under MW irradiation at 1508C.
[16] a) P. J. Skabara, I. M. Serebryako, I. F. Perepichka, Synth. Met.
1999, 102, 1336; b) J. Jacob, L. Oldridge, J. Y. Zhang, M. Gaal,
E. J. W. List, A. C. Grimsdale, K. Mullen, Curr. Appl. Phys. 2004,
4, 339.
[17] a) A. K. Chakraborti, S. R. Roy, J. Am. Chem. Soc. 2009, 131,
6902; b) R. Lungwitz, M. Friedrich, W. Linert, S. Spange, New J.
Chem. 2008, 32, 1493; c) R. Lungwitz, S. Spange, New J. Chem.
2008, 32, 392; d) A. Sarkar, S. R. Roy, A. K. Chakraborti, Chem.
Commun. 2011, 47, 4538.
[18] a) A. Wulf, K. Fumino, R. Ludwig, Angew. Chem. Int. Ed. 2010,
49, 449; Angew. Chem. 2010, 122, 459; b) A. G. Avent, P. A.
Chaloner, M. P. Day, K. R. Seddon, T. Welton, J. Chem. Soc.
Dalton Trans. 1994, 3405; c) P. S. Schulz, N. Mꢁllar, A. Bosmann,
P. Wasserscheid, Angew. Chem. Int. Ed. 2007, 46, 1293; Angew.
Chem. 2007, 119, 1315; d) M. Zanatta, A.-L. Girard, N. M.
Simon, G. Ebeling, H. K. Stassen, P. R. Livotto, F. P. dos Santos,
J. Dupont, Angew. Chem. Int. Ed. 2014, DOI: 10.1002/
anie.201408151.
[19] a) T. S. Rodrigues, V. H. C. Silva, P. M. Lalli, H. C. B. de Oli-
veira, W. A. da Silva, F. Coelho, M. N. Eberlin, B. A. D. Neto, J.
Org. Chem. 2014, 79, 5239; b) P. M. Lalli, T. S. Rodrigues, A. M.
Arouca, M. N. Eberlin, B. A. D. Neto, RSC Adv. 2012, 2, 3201.
[20] a) P. Johannesson, G. Lindeberg, A. Johansson, G. V. Nikifor-
ovich, A. Gogoll, B. Synnergren, M. L. Grꢂves, F. Nyberg, A.
Karlꢃn, A. Hallberg, J. Med. Chem. 2002, 45, 1767; b) E.
Marcantoni, M. Massaccesi, M. Petrini, G. Bartoli, M. C.
Bellucci, M. Bosco, L. Sambri, J. Org. Chem. 2000, 65, 4553.
[21] a) R. Sarma, N. Rajesh, D. Prajapati, Chem. Commun. 2012, 48,
4014; b) A. Kondoh, K. Takami, H. Yorimitsu, K. Oshima, J.
Org. Chem. 2005, 70, 6468; c) A. Shard, R. Kumar, Saima, N.
Sharma, A. K. Sinha, RSC Adv. 2014, 4, 33399.
[14] a) X. Baucherel, J. Uziel, S. Juge, J. Org. Chem. 2001, 66, 4504;
b) B. Feng, Z. Hou, X. Wang, Y. Hu, H. Li, Y. Qiao, Green Chem.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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www.angewandte.org
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Angewandte
Communications
Communications
Click Chemistry
R. Kumar, Saima, A. Shard,
N. H. Andhare, Richa,
A. K. Sinha*
&&&& — &&&&
Thiol–Ene “Click” Reaction Triggered by
Neutral Ionic Liquid: The “Ambiphilic”
Character of [hmim]Br in the
Regioselective Nucleophilic
Hydrothiolation
Linear thioethers are obtained by an
atom-efficient thiol–ene “click” reaction
in neutral [hmim]Br without the need for
base or metal complexes. Detailed
mechanistic studies using H NMR
spectroscopy and quadrupol time-of-
flight electrospray ionization mass spec-
trometry showed that the “ambiphilic”
character of the ionic liquid promotes the
regioselective nucleophilic addition of
thiol to styrene through an anti-Markov-
nikov pathway.
1
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!