Facile synthesis of polysubstituted cyclopropanes using α-tosyloxyketones

Article abstract of DOI:10.14233/ajchem.2018.20926

A facile synthesis of polysubstituted cyclopropanes (5) by the treatment of pyridinium ylides, generated in situ from pyridinium toslyates (2), with arylidenemalonitrile (4) is presented. Pyridinium toslyates (2) were obtained by reacting α-tosyloxyketone

Full text of DOI:10.14233/ajchem.2018.20926

Asian Journal of Chemistry; Vol. 30, No. 3 (2018), 505-507
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.20926
Facile Synthesis of Polysubstituted Cyclopropanes Using α-Tosyloxyketones
1,2
2,*
1,*
NEENA RANA , SONIA NAIN , DINESH KUMAR1,2 and RAVI KUMAR
1Department of Chemistry, Dyal Singh College, Karnal-132 001, India
2Department of Chemistry, Deen Bandhu Chottu Ram University of Science and Technology, Murthal-131 039, India
*Corresponding authors: E-mail: sonianain.chem@dcrustm.org; ravi.dhamija@rediffmail.com
Received: 18 July 2017;
Accepted: 24 October 2017;
Published online: 31 January 2018;
AJC-18732
A facile synthesis of polysubstituted cyclopropanes (5) by the treatment of pyridinium ylides, generated in situ from pyridinium toslyates
(2), with arylidenemalonitrile (4) is presented. Pyridinium toslyates (2) were obtained by reacting α-tosyloxyketones (1) with pyridine in
benzene under reflux.
Keywords: α-Tosyloxyketones, Pyridinium tosylates, Arylidenemalononitrile.
the halogenation of ketones, the unstability and toxicity of α-
haloketones, it appeared attractive to find suitable alternative
to these compounds.
INTRODUCTION
Cyclopropane ring has always been centre of attraction
for the research community because of its strained size and
unique bonding. Cyclopropane containing compounds are
fascinating synthetic intermediates and building blocks for
many other compounds [1-4]. In addition, cyclopropane also
play a prominent role in organic synthesis as they are present
in biologically active compounds and various natural com-
pounds, such as terpenes, pheromones and fatty acid metabolite
[5-8]. Moreover, activities of some biologically active com-
pounds can be altered by incorporating this significant moiety
which may prove advantageousin the field of drugs and medi-
cines [9]. To explore the wide utility of cyclopropane in diffe-
rent fields, continuous efforts are going on to synthesize cyclo-
propane and its derivatives. To date, a number of traditional
methods are available in the literature for cyclopropanation.
Most common methods for synthesis of cyclopropane involve
Negishi cross-coupling reactions [10], Simmon Smith reaction
[11], transition metal-mediated carbene transfer from aliphatic
diazo compounds to carbon-carbon double bonds [12], Michael
initiated ring closure of ylides with electron-deficient olefins
[13],etc. However, metal-free and economical synthetic methods
are always in demand.
Synthesis of α-tosyloxyketones can easily be achieved
by treating a variety of ketones with [hydroxy(tosyloxy)iodo]-
benzene (HTIB, Koser’s reagent) [15]. These compounds are
stable, crystalline solids and provide a safe eco-friendly alterna-
tive route for synthesis of compounds conventionally prepared
through α-haloketones. The ease of preparation of these
substrates, their relative stability and their chemical versatility
allowed the development of several methods for the construc-
tion of a variety of compounds. Prompted by above observations
and our ongoing efforts in exploring the synthetic significance
of hypervalent iodine reagents, we herein report a facile synthetic
route to access polysubstituted cyclopropanes (5) by the treat-
ment of pyridinium ylides, generated in situ from pyridinium
toslyates (2), with arylidenemalonitrile (4). Pyridinium toslyates
(2)were obtained by reacting α-tosyloxyketones (1)with pyridine
in benzene under reflux.
EXPERIMENTAL
Melting points were taken in open capillaries and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 1800
FT-IR spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on Bruker 400 MHz instrument using TMS as an
internal standard. The chemical shifts are expressed in ppm
units downfield from an internal TMS standard. α-Tosyloxy-
ketones (1) were prepared according to the procedure reported
in the literature [15].
α-Halo carbonyl compounds are versatile intermediates
in organic synthesis. α-Halocarbonyl compounds, such as,
phenacyl bromides are well known precursors for the synthesis
of a wide variety of heterocyclic compounds and α-functional-
ized ketones [14]. However, halocarbonyl compounds are
difficult to handle, highly toxic, corrosive and associated with
lachrymatory properties. Due to the hazards associated with
Synthesis of cyclopropane derivatives: In a 100 mL flask,
an equimolar mixture of pyridinium tosylate (2), arylidene-

506 Rana et al.
Asian J. Chem.
malononitrile (4) and triethylamine was stirred in acetonitrile
at room temperature for 12-19 h. The progress of reaction
was recorded by TLC. After completion, the reaction mixture
was poured over ice and the separated solid was collected by
filtration. The crude product, thus obtained, was recrystallized
from ethanol to afford pure cyclopropane derivative 5.
2-Benzoyl-3-phenylcyclopropane-1,1-dicarbonitrile
(5a): m.p.: 119 ºC; literature m.p.: 120-121 ºC [16]; yield 82
%; 1H NMR (400 MHz, CDCl3, δ, ppm): 3.91-3.93 (d, 1H, J =
8 Hz), 4.02-4.04 (d, 1H, J = 8 Hz), 7.37-7.40 (m, 2H), 7.45-
7.47 (m, 3H), 7.59-7.63 (t, 2H), 7.72-7.76 (t, 1H), 8.10-8.12
(d, 2H, J = 8.6 Hz).
2-Benzoyl-3-(4-fluorophenyl)cyclopropane-1,1-
dicarbonitrile (5b): m.p.: 152 ºC; literature m.p.: 156 ºC [16];
yield 70 %; 1H NMR (400 MHz, CDCl3, δ, ppm): 3.88-3.89
(d, 1H, J = 7.9 Hz), 3.99-4.00 (d, 1H, J = 7.96 Hz), 7.59-7.63
(t, 1H), 7.63-7.73 (m, 4H), 7.75-7.78 (d, 2H, J = 8.6 Hz),
8.09-8.11(d, 2H, J = 8 Hz).
RESULTS AND DISCUSSION
As described earlier, α-haloketones and α-tosyloxyketones
behave analogously in most of their reactions. Prakash andAneja
[17] demonstrated the synthetic equivalency of these compounds
by achieving successful synthesis of useful thiazole derivatives.
Other significant reports highlighting the synthetic equivalency
of α-tosyloxyketones and α-haloketones are, (i) isolation of
synthetically useful furocoumarins by the reaction of α-tosyloxy-
ketones with 4-hydroxycoumarin [18], (ii) diastereoselective
synthesis of differently substituted trans-2,3-dihydrofuro[3,2-c]-
coumarins [19] and (iii) synthesis of polysubstituted oxazoles
via decarboxylative oxidative cyclization of primary amino
acids and α-tosyloxyketones [20].
Wang et al. [16] reported the synthesis of polysubstituted
cyclpropanes by the reaction of pyridinium ylide, generated
by the reaction of α-haloketones and pyridine, with aromatic
aldehydes and acetonitrile derivatives. Keeping in view the
above observations that α-haloketones and α-tosyloxyketones
behave analogously in most of their reactions, it was anticipated
that the reaction of α-tosyloxyketones (1) with pyridine might
result into pyridinium tosylates, which can be used to generate
pyridinium ylides that might afford polysubstitued cyclo-
propanes (5) on treatment with arylidene-malonitrile (4).
To determine the fate of the above proposal, α-tosyloxy-
acetophenone (1a), obtained by the reaction of acetophenone
and Koser’s reagent (HTIB), was allowed to react with pyridine
in refluxing benzene. N-phenacylpyridinium tosylate (2a), thus
obtained, was reacted with benzylidenemalonitrile (4a) in the
presence of weak base, triethylamine, at room temperature in
acetonitrile as solvent (Scheme-I). Completion of the reaction
was confirmed by TLC using petroleum ether and ethyl acetate.
The spectroscopic studies established the synthesis of 2-benzoyl-
3-phenylcyclopropane-1,1-dicarbonitrile (5a) in 82 % yield.
2-Benzoyl-3-(4-anisyl)cyclopropane-1,1-dicarbonitrile
(5c): m.p.: 92 ºC; literature m.p.: 160-161 ºC [16]; yield 79 %;
1H NMR (400 MHz, CDCl3, δ, ppm): 3.86-3.88 (d, 1H, J = 8.1
Hz), 3.91 (s, 3H), 3.98-4.00 (d, 1H, J = 8.0 Hz), 6.96-6.99 (d, 1H),
7.00-7.03 (d, 2H), 7.29-7.31 (d, 1H, J = 8.7 Hz), 7.58-7.68 (t,
1H), 7.71-7.73 (t, 1H), 7.89-7.93 (d, 2H), 8.09-8.11 (d, 1H, J
= 8.6 Hz).
2-Benzoyl-3-(4-bromophenyl)cyclopropane-1,1-
dicarbonitrile (5d): m.p.: 164 ºC; literature m.p.: 169-170 ºC
[16]; yield 71 %; 1H NMR (400 MHz, CDCl3) δ, ppm): 3.89-3.91
(d, 1H, J = 8), 4.00-4.02 (d, 1H, J = 8), 7.19-7.21 (d, 2H, J = 8),
7.21-7.26 (m, 4H), 7.60-7.64 (t, 1H), 8.10-8.12 (d, 2H, J = 8.0 Hz).
2-Benzoyl-3-(4-chlorophenyl)cyclopropane-1,1-
dicarbonitrile (5e): m.p.: 170 ºC; literature m.p.: 175-176 ºC
[16]; yield 90 %; 1H NMR (400 MHz, CDCl3, δ, ppm): 3.88
(d, 1H, J = 7.8 Hz), 3.99 (d, 1H, J = 7.8 Hz), 7.33 (t, 2H), 7.44 (d,
2H, J = 7.2 Hz), 7.61 (t, 2H), 7.74 (t, 1H), 8.10 (d, 2H, J = 6.6 Hz).
2-(4-Anisyl)-3-(4-methylbenzoyl)cyclopropane-1,1-
dicarbonitrile (5f): m.p.: 80-83 ºC; yield 66 %; IR (νmax, cm-1):
3436, 1672, 1254, 1216, 847, 828; 13C NMR (100 MHz, δ, ppm):
15.29, 29.70, 35.50, 37.83, 83.38, 112.35-111.13, 113.45,
127.80, 129, 130.98, 131.85, 132.82, 133.95, 136.19, 141.18,
158.29, 165.60, 187.67; 1H NMR (400 MHz, CDCl3) δ(ppm)
2.43 (s, 3H), 3.84 (s, 3H), 3.91-3.93(m, 2H), 6.95-6.96 (d,
2H, J = 11.6 Hz), 7.26-7.30(m, 2H), 7.73-7.76 (d, 2H, J =
12.9 Hz), 7.94-7.97 (d, 2H, J = 12.9 Hz); m/z 323 (M+).
2-(4-Chlorophenyl)-3-(4-nitrobenzoyl)cyclopropane-
1,1-dicarbonitrile (5g): m.p.: 198-199 ºC; literature m.p.: 201
Ar'
CN
CN
CH2(CN)2
Ar'CHO
3
EtOH, reflux
H
4
PhI(OH)OTs
N
OTs
ArCOCH3
ArCOCH2OTs
N
Benzene
Reflux
CH3CN
CH2COAr
1
2
Ar'
5
Ar
a
C H
C H
6
5
6
5
5
Ar'
CN
CN
Et3N, CH3CN
rt, 12-19 h
b
c
4-FC H
6 4
C H
6
H
4-OMeC H
6
C H
6
1
4
5
4
ºC [16]; yield 80 %; H NMR (400 MHz, CDCl3, δ, ppm):
4-BrC H
C H
d
e
6
4
4
6
5
5
3.70 (2d, 2H, J = 9.0 Hz), 7.50-7.54 (m, 3H), 7.84-7.87 (d,
2H), 7.9 (d, 2H), 8.12-8.14 (d, 2H, J = 8.4 Hz).
NC
H
CN
H
4-ClC H
C H
6
6
4-OMeC H
6
f
4
4-MeC H
6 4
2-(4-Bromobenzoyl)-3-(4-chlorophenyl)cyclopropane-
Ar'
COAr
5
4-ClC H
g
4-NO C H
2 6 4
6
4
4
1,1-dicarbonitrile (5h): m.p.: 203-204 ºC; yield 85 %; IR (νmax
,
KBr, cm-1): 3438, 1682, 1258, 1219, 846, 833; 13C NMR (100
MHz, δ, ppm): 15.27, 29.37, 29.70, 35.53, 37.80, 111.08, 111.82,
127.77, 129.67, 129.61, 129.71, 130.09, 131.00, 132.84, 133.94,
187.60; 1H NMR (400 MHz, CDCl3, δ, ppm): 3.87-3.93 (2d,
2H), 7.30-7.33 (d, 2H, J = 8.4 Hz), 7.44-7.60 (d, 2H, J = 8.4 Hz),
7.75-7.78 (d, 2H, J = 10.8 Hz), 7.95-7.98 (d, 2H, J = 8.6 Hz); m/z
385 (M+).
4-ClC H
6
4-BrC H
6 4
h
Scheme-I
The formation of cyclopropane 5a from this reaction is
an encouraging observation because such cyclopropanes are
important precursors for the synthesis of variety of compounds.
So, it was considered worthwhile to assess the generality of

Vol. 30, No. 3 (2018)
Facile Synthesis of Polysubstituted Cyclopropanes Using α-Tosyloxyketones 507
9. J. Salaün, Cyclopropane Derivatives and their Diverse Biological
this approach for the synthesis of differently substituted cyclo-
propanes.Accordingly, substituted α-tosyloxyketones (1) were
treated with pyridine to give pyridinium tosylates (2). Pyridi-
nium tosylates (2) were then reacted with arylidenemalonitrile
(4) to afford corresponding polysubstituted cyclopropanes (5)
in moderate to good yields (Scheme-I). Structures of the
cyclopropanes (5) were established on the basis of thorough
analysis of their spectral data.
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The results obtained from the present study offer an easy
and eco-friendly approach for the synthesis of polysubstituted
cyclopropanes (5). These results reveal that α-tosyloxyaceto-
phenones can be used as synthetic equivalents to α-haloketones
towards reactions with pyridine derivatives. The most remark-
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lachrymatory phenacyl halides.
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The authors are highly thankful to Department of Science
and Technology (DST), New Delhi (Grant no SERB/F/0696/
2012-2013) for providing financial assistance to accomplish
this research work. We are also grateful to Dyal Singh College,
Karnal for providing infrastructural facilities to carry out this
work.
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