Facile synthesis of libraries of functionalized cyclopropanes and oxiranes using ionic liquids – A new approach to the classical Corey-Chaykovsky reaction

Article abstract of DOI:10.1016/j.tetlet.2021.153339

The potential of [PAIM][NTf₂]/BMIM-ILs as a base/solvent in the Corey-Chaykovsky reaction is demonstrated by the facile synthesis of libraries of functionalized cyclopropanes from enones and oxiranes from aldehydes and ketones, at room temperature in respectable isolated yields. To demonstrate their application, the synthesized epoxides were employed as substrates for the synthesis of a library of 2,3-disubstituted quinolines, using [BMIM(SO₃H)][OTf]/[BMIM][PF₆] as a catalyst/solvent. The potential for recycling/reuse of the IL solvents was also explored.

Full text of DOI:10.1016/j.tetlet.2021.153339

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of libraries of functionalized cyclopropanes and oxiranes
using ionic liquids – A new approach to the classical Corey-Chaykovsky
reaction
Shruti S. Malunavar a, Suraj M. Sutar a, Pavankumar Prabhala a, Hemantkumar M. Savanur b,
Rajesh G. Kalkhambkar a, , Gopalakrishnan Aridoss c, Kenneth K. Laali d,
⇑
⇑
a Department of Chemistry, Karnatak University’s Karnatak Science College, Dharwad, Karnatak 580001, India
b Department of Studies and Research in Chemistry, P. C. Jabin Science College, Hubli, Karnatak 580021, India
c Anygen Co., Ltd., Gwangju Technopark, Cheomdan Gwagi-ro, Buk-gu, Gwangju 61008, South Korea
d Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The potential of [PAIM][NTf2]/BMIM-ILs as a base/solvent in the Corey-Chaykovsky reaction is demon-
strated by the facile synthesis of libraries of functionalized cyclopropanes from enones and oxiranes from
aldehydes and ketones, at room temperature in respectable isolated yields. To demonstrate their appli-
cation, the synthesized epoxides were employed as substrates for the synthesis of a library of 2,3-disub-
Received 22 July 2021
Revised 9 August 2021
Accepted 15 August 2021
Available online xxxx
stituted quinolines, using [BMIM(SO3H)][OTf]/[BMIM][PF6] as
a
catalyst/solvent. The potential for
recycling/reuse of the IL solvents was also explored.
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Cyclopropanation
Epoxidation
Ionic liquids as base and solvent
Application in quinoline synthesis
Introduction
using an in-situ generated benzyl-sulfonium salt (from tetrahy-
drothiophene (THT)/benzyl alcohol/HBF4-Et2O) with NaH as base,
and in-situ generated sulfonium triflate (from THT/MeOTf), as well
as its asymmetric version using chiral analogs of THT and phosp-
hazene bases, have also been reported [7].
In the classical Corey-Chaykovsky (CC) reaction, ylides derived
from the deprotonation of sulfonium and sulfoxonium halides
using a strong base react with aldehydes and ketones to give oxi-
ranes and with enones to furnish cyclopropyl-ketones as cis/trans
mixtures [1a]. A phase transfer catalysis (PTC) version of this reac-
tion also gave cis/trans mixtures [1b]. Typical bases employed
include NaH, BuLi, and t-BuOK, with DMF, THF, or dioxane as
solvent [1a–3].
Due to the prominence of cyclopropane and oxirane motifs in a
wide range of bioactive natural and synthetic compounds which
are important in drug development [4], numerous studies aiming
to improve on these transformations have been reported. Although
cyclopropanation using milder bases such as DABCO and Et3N in
MeCN proved unsuccessful, guanidine bases (TMG, and MTBD)
were effective, especially when used in excess, forming > 98% trans
isomer [5].
Zinc-derived sulfur ylides generated via the Simmons-Smith
reaction offer an alternative for the epoxidation of aldehydes,
and the cyclopropanation of
using NiCl2 as a catalyst [8,9].
a,b-unsaturated ketones and esters
Despite considerable progress in this area, the development of
alternative methods that utilize mild bases, avoid the use of metals
and high boiling hazardous solvents, and offer the possibility for
recycling/reuse of the solvent is still highly desirable.
In continuation of our studies focusing on the development of
alternative synthetic methods employing ILs as catalysts and sol-
vents [10], and in relation to our long standing interest in onium
salts and their synthetic applications [11], we report herein the
facile synthesis of libraries of functionalized cyclopropanes and
oxiranes at room temperature, employing the piperidine-
appended-IL [PAIM][NTf2] [10f,10i] as base and BMIM-ILs as
solvent (Fig. 1), without metals or additives, and with potential
for recycling/reuse of the IL solvent. These studies underscore the
potential of [PAIM][NTf2]/[BMIM][X] for the in-situ generation of
sulfur ylides from sulfoxonium and sulfonium salts at room
The asymmetric version of the Corey-Chaykovsky cyclopropa-
nation has also been studied [6]. Epoxidation of aryl-aldehydes
⇑
Corresponding authors.
E-mail address: kenneth.laali@unf.edu (K.K. Laali).
https://doi.org/10.1016/j.tetlet.2021.153339
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: S.S. Malunavar, S.M. Sutar, P. Prabhala et al., Facile synthesis of libraries of functionalized cyclopropanes and oxiranes using ionic
liquids – A new approach to the classical Corey-Chaykovsky reaction, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153339

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
Me3SO I
O
O
[PAIM][NTf2]
R1
R2
R1
R2
BMIM-ILs, rt
Fig. 2. Cyclopropanation of enones.
temperature. To the best of our knowledge there has only been one
previous report of the CC reaction employing an IL as solvent with
KOH as base [12]. In connection with recent reports regarding the
synthesis of 2,3-disubstituted quinolones [13], application of the
synthesized epoxides for the synthesis of a library of 2,3-disubsti-
Fig. 1. Structures of the key ILs.
Table 1
Cyclopropanation of enones employing ILs as base and solvent.a
Entry
1.
Substrate
Product
IL Solvent
Time (min)
90
Yield (%)b
90c
[BMIM][PF6]
O
O
O
O
O
O
2.
3.
[BMIM][BF4]
[BMIM][PF6]
90
92c
85e
O
O
O
O
O
O
O
O
100
O
O
O
4.
5.
6.
7.
[BMIM][BF4]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][BF4]
90
60
80
80
91c
87d
82e
85d
O
O
O
O
O
O
O
O
O
8.
[BMIM][PF6]
[BMIM][PF6]
[BMIM][BF4]
[BMIM][BF4]
120
120
60
81e
83d
90c
87d
O
O
O
O
O
S
S
9.
O
O
O
N
N
10.
11.
80
a
b
c
Reagents and conditions: enone (1 mmol), trimethylsulfoxonium iodide (1.1 mmol), [BMIM][BF4] or [BMIM][PF6] (5–6 mL), [PAIM][NTf2] (20 mol%), r.t.
Isolated yield.
Yield employing fresh IL.
Yield using recycled IL (2nd cycle).
Yield using recycled IL (3rd cycle).
d
e
2

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
Fig. 3. Graphical representation for recycling/reuse of the ILs in the cyclopropanation reaction.
tuted quinolines using [BMIM(SO3H)][OTf]/[BMIM][PF6] as a cata-
lyst/solvent is also demonstrated.
The cyclopropanation of a variety of electron-deficient alkenes
was effected by the in-situ generated sulfur ylide derived from
trimethylsulfoxonium iodide at r.t., employing [PAIM][NTf2] as a
basic-IL in readily available BMIM-ILs as solvent (Fig. 2 and
Table 1).
Fig. 4. Synthesis of oxiranes.
Table 2
Epoxidation of aldehydes and ketones employing ILs as base and solvent.a
Entry
1.
Substrate
Product
IL Solvent
Time (min)
60
Yieldb (%)
89e
[BMIM][BF4]
O
2.
[BMIM][PF6]
120
83e
O
O2N
3.
4.
[BMIM][PF6]
[BMIM][BF4]
90
88d
81e
O
O
100
5.
6.
[BMIM][BF4]
[BMIM][BF4]
150
80
85d
91c
O
O
Cl
(continued on next page)
3

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 2 (continued)
Entry
7.
Substrate
Product
IL Solvent
Time (min)
Yieldb (%)
90c
[BMIM][PF6]
90
90
80
O
O
O
8.
9.
[BMIM][BF4]
[BMIM][PF6]
92c
89c
O
O
O
10.
11.
[BMIM][BF4]
[BMIM][BF4]
120
120
84e
82d
O
O
O
O
CF3
CF3
a
b
c
Reagents and conditions: carbonyl compound (1 mmol), trimethylsulfonium iodide (1.1 mmol), [BMIM][BF4] or [BMIM][PF6] (5–6 mL), [PAIM][NTf2] (20 mol%), r.t.
Isolated yield.
Yield employing fresh IL.
Yield using recycled IL (2nd cycle).
Yield using recycled IL (3rd cycle).
d
e
Fig. 5. Graphical representation for recycling/reuse of the ILs in the epoxidation reaction.
Fig. 6. Synthesis of 2,3-disubstituted quinolines.
4

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 3
Synthesis of 2,3-disubstituted quinolines in ILs.a
Entry
1.
Epoxide
Ar-amine
Product
Time (h)
17
Yield (%)b
43c
O
NH2
2.
18
45e
NH2
O
3.
15
78c
O
O
O
NH2
Cl
O
O
4.
5.
6.
16
18
16
72c
56d
68d
NH2
NH2
O
O
O
O
NH2
Cl
(continued on next page)
5

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 3 (continued)
Entry
7.
Epoxide
Ar-amine
Product
Time (h)
16
Yield (%)b
66c
NH2
O
8.
18
59d
O
9.
18
65c
a
b
c
Reagents and conditions: epoxide (5 mmol), arylamine (1 mmol), [BMIM][PF6] (5–6 mL), [BMIM(SO3H)][OTf] (1 mmol), TEMPO (1 mmol), 4 Å MS (1 g), oil bath (55–60 °C).
Isolated yield.
Yield employing fresh IL.
Yield using recycled IL (2nd cycle).
Yield using recycled IL (3rd cycle).
d
e
Fig. 7. Graphical representation of recycling/reuse of the IL solvent in quinoline synthesis.
6

S.S. Malunavar, S.M. Sutar, P. Prabhala et al.
Tetrahedron Letters xxx (xxxx) xxx
The isolated yields were in the 89–90% range when using fresh
ILs, decreasing only slightly in reused/recycled ILs. Fig. 3 is a graph-
ical representation of the cyclopropanation reaction using recov-
ered/reused ILs up to 4 cycles, with entry 10 in Table 1 as a
model reaction.
and GC-MS. They also thank ALR Labs, Hyderabad for 1H NMR
and 13C NMR spectroscopy. S. S. Malunavar is grateful to Govern-
ment of Karnataka for Vidyasiri fellowship. Thanks are also given
to Planning, Monitoring and Evaluation Board KUD Project No.
KU/PMEB/2020-21/69 for financial assistance.
The predominant trans stereochemistry (>97%) of the cyclo-
propanation products in the present study was determined based
on 1H NMR spectroscopy along with GC–MS and by comparison
with the reported NMR data (see ESI).
Turning our attention to epoxidation, structurally diverse alde-
hydes and ketones were conveniently transformed into oxiranes
via the in-situ generated sulfur ylide derived from trimethylsulfo-
nium iodide at r.t., employing [PAIM][NTf2] as a basic-IL in readily
available BMIM-ILs as solvent (Fig. 4 and Table 2). The isolated
yields were in the 89–92% range when using fresh ILs, decreasing
only slightly when employing reused/recycled ILs.
Fig. 5 is a graphical representation of the epoxidation using
recovered/reused ILs up to 4 cycles, with entry 8 in Table 2 as a
model reaction, showing only a minor decrease in the isolated
yields.
There has been renewed interest in the synthesis of 2,3-disub-
stituted quinolones [13], in particular via the condensation of
epoxides with anilines using Sc(OTf)3 in THF [13a]. To
demonstrate application, in the context of the present study, and
for comparison with the literature data, we prepared a library of
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2021.
153339.
References
[1] (a) E.J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 87 (1965) 1353–1364;
(b) A. Merz, G. Märkl, Angew. Chem., Int. Ed. Engl. 12 (1973) 845–846.
[2] (a) J.A. Ciaccio, A.L. Drahus, R.M. Meis, C.T. Tingle, M. Smrtka, R. Geneste,
Synth. Commun. 33 (12) (2003) 2135–2143;
(b) J.A. Ciaccio, C.E. Aman, Synth. Commun. 36 (10) (2006) 1333–1341.
[3] (a) L. Liu, R. Tian, S. Liu, X. Chen, L. Guo, Y. Che, Bioorg&Med. Chem. 16 (2008)
6021–6026;
(b) M. Watanabe, T. Hirokawa, T. Kobayashi, A. Yoshida, Y. Ito, S. Yamada, N.
Orimoto, Y. Yamasaki, M. Arisawa, S. Shuto, J. Med. Chem. 53 (2010) 3585–
3593;
(c) H.-K. Zhang, L.-F. Yu, J.B. Eaton, P. Whiteaker, O.K. Onajole, T. Hanania, D.
Brunner, R.J. Lukas, A.P. Kozikowski, J. Med. Chem. 56 (2013) 5495–5504;
(d) J.X. Qiao, D.L. Cheney, R.S. Alexander, A.M. Smallwood, S.R. King, K. He, A.R.
Rendina, J.M. Luettgen, R.M. Knabb, R.R. Wexler, P.Y.S. Lam, Bioorg. Med. Chem.
Lett. 18 (2008) 4118–4123;
2-benzyl-3-aryl-quinolines
employing
[BMIM(SO3H)][OTf]/
(e) J. Salaun, M.S. Baird, Cur. Med. Chem. 2 (1995) 511–542.
[4] (a) M.D. Delost, D.T. Smith, B.J. Anderson, J.T. Njardarson, J. Med. Chem. 61
(2018) 10996–11020;
[BMIM][PF6] (Fig. 6 and Table 3). In line with the earlier reported
study, TEMPO was used as an additive to avoid the formation of
side products [13a]. Isolated yields were in the 43–78% range,
depending on the choice of epoxide and aniline, which is similar
to the previously reported outcomes (10–96%) [13a].
Fig. 7 is a graphical representation of the quinoline synthesis
using recovered/reused [BMIM][PF6] up to 4 cycles, with entry 3
in Table 3 as a model reaction, showing only a small decrease in
the isolated yields.
(b) M.M. Heravi, S. Asadi, N. Nazari, B.M. Lashkariani, Cur. Org. Syn. 13 (2016)
308–333;
(c) F. Moschona, I. Savvopoulou, M. Tsitopoulou, D. Tataraki, G. Rassias,
Catalysts 10 (2020) 1117;
(d) D.G. Brown, H.J. Wobst, J. Med. Chem. 64 (5) (2021) 2321–2338;
(e) P. Bhutani, G. Joshi, N. Raja, N. Bachhav, P.K. Rajanna, H. Bhutani, A.T. Paul,
R. Kumar, J. Med. Chem. 64 (2021) 2339.
[5] R.J. Paxton, R.J.K. Taylor, Synlett (No. 4) (2007) 633–637.
[6] (a) H. Kakei, T. Sone, Y. Sohtome, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc.
129 (2007) 13410–13411;
In summary, we have shown that [PAIM][NTf2]/BMIM-ILs
represents a suitable medium for the in-situ generation of sul-
fur ylides from sulfoxonium and sulfonium salts, thus enabling
access to libraries of functionalized cyclopropanes from enones,
and oxiranes from aldehydes and ketones, at room tempera-
ture in respectable isolated yields, with reasonable prospects
for the reuse/recycling of the IL solvent. The synthesized oxi-
ranes were employed as starting materials for the synthesis
of a small library of 2-benzyl-3-aryl-quinolines using [BMIM
(SO3H)][OTf]/[BMIM][PF6] as catalyst/solvent. The reported
cyclopropanation and epoxidation methods avoid the use of
strong bases and high boiling solvents typically employed in
the CC reaction.
(b) A.B. Charette, M.K. Janes, H. LeBel, Tetrahedron: Asymm. 14 (2003) 867–
872.
[7] a) E. Alfonso, J.W.L. Mendoza, A.B. Beeler, Beilstein. J. Org. Chem. 14 (2018)
2308–2312;
b) A. Piccinini, S.A. Kavanagh, P.B. Connon, S.J. Connon, Org. Lett. 12 (3) (2010)
608–611.
[8] V.K. Aggarwal, A. Ali, M.P. Coogan, J. Org. Chem. 62 (1997) 8628–8629.
[9] J. Xu, N.B. Samsuri, H.A. Duong, Chem. Commun. 52 (2016) 3372–3375.
[10] (a) S.M. Sutar, P. Prabhala, H.M. Savanur, R.G. Kalkhambkar, G. Aridoss, K.K.
Laali, ChemistrySelect 6 (2021) 1–10;
(b) S.S. Malunavar, S.M. Sutar, H.M. Savanur, R.G. Kalkhambkar, K.K. Laali,
Tetrahedron Lett. 61 (2020) 151509;
(c) P. Prabhala, H.M. Savanur, S.M. Sutar, S.S. Malunavar, R.G. Kalkhambkar, K.
K. Laali, Tetrahedron Lett. 61 (2020);
(d) S.S. Malunavar, S.M. Sutar, P. Prabhala, R.G. Kalkhambkar, K.K. Laali,
Tetrahedron Lett. 61 (2020);
(e) P. Prabhala, H.M. Savanur, R.G. Kalkhambkar, K.K. Laali, Eur. J. Org. Chem.
(2019) 2061–2064;
(f) H.M. Savanur, R.G. Kalkhambkar, K.K. Laali, Eur. J. Org. Chem. (2018) 5285–
5288;
Declaration of Competing Interest
(g) S.M. Sutar, H.M. Savanur, S.S. Malunavar, P. Prabhala, R.G. Kalkhambkar, K.
K. Laali, Eur. J. Org. Chem. (2019) 6088–6093;
(h) S.M. Sutar, H.M. Savanur, C. Patil, P. Prabhala, G. Aridoss, R.G. Kalkhambkar,
ChemistrySelect 5 (2020) 12324–12327;
(i) H.M. Savanur, R.G. Kalkhambkar, K.K. Laali, App. Cat. A, Gen. 543 (2017)
150–161;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
(j) K.K. Laali, Arkivoc (2016) 150–171.
[11] G.A. Olah, K.K. Laali, Q. Wang, G.K.S. Prakash, Onium Ions, Wiley, New York,
1998.
[12] S. Chandrasekhar, C. Narasihmulu, V. Jagadeshwar, K.V. Reddy, Tetrahedron
Lett. 44 (2003) 3629–3630.
[13] (a) M.-S. Al Mehedi, J.J. Tepe, J. Org. Chem. 85 (2020) 6741–6746;
(b) J.T. Zhang, L.X. Wang, J.F. Xiang, J. Cui, B.Q. Hu, L. Yang, Y.L. Tang,
ChemistrySelect 4 (2019) 9392–9395.
K. L. thanks University of North Florida for the Outstanding Fac-
ulty Scholarship and Presidential Professorship awards, UNF Foun-
dation Board grant, and the Dean’s Leadership Council award. The
authors at Karnatak Science College, Dharwad thank the University
Sophisticated Instrument Center and DST-SAIF KUD for IR, NMR
7