Iodine-mediated diastereoselective cyclopropanation of arylidene malononotriles by 2,6-dimethylquinoline

Article abstract of DOI:10.1055/s-0034-1379496

A novel iodine-mediated reaction of 2,6-dimethylquinoline with Knoevenagel condensation products of malononitrile with benzaldehydes, leading to a facile, one-pot synthesis of 2-aryl-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbonitriles, in moderate t

Full text of DOI:10.1055/s-0034-1379496

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 380–384
380
letter
Synlett
I. Yavari et al.
Letter
Iodine-Mediated Diastereoselective Cyclopropanation of
Arylidene Malononotriles by 2,6-Dimethylquinoline
Issa Yavari*a
CN
Reza Hosseinpoura
Stavroula Skoulikab
I2 (10 mol%)
pyridine
Ar
CN
CN
N
N
N
(i-Pr) NEt, MeCN
2
N
CN
50 °C, 1 h
5
0 °C, 5 h
a
Department of Chemistry, University of Tarbiat Modares,
Ar
P.O. Box 14115-175, Tehran, Iran
+
9
8
2
(
1
8
)
2
8
8
3
4
5
5
yavarisa@modares.ac.ir
Laboratory of Physical Chemistry, Department of Chemistry,
The University of Ioannina, 45110 Ioannina, Greece
b
Received: 17.08.2014
Accepted after revision: 18.10.2014
Published online: 09.01.2015
arylidene malononitrile, generated from condensation of 3
and 2a, in the presence of N,N-diisopropylethylamine at
room temperature in different solvents.
DOI: 10.1055/s-0034-1379496; Art ID: st-2014-d0692-l
As shown in Table 1 (entries 1–7), copper salts such as
Abstract A novel iodine-mediated reaction of 2,6-dimethylquinoline
with Knoevenagel condensation products of malononitrile with benzal-
dehydes, leading to a facile, one-pot synthesis of 2-aryl-3-(6-meth-
ylquinolin-2-yl)cyclopropane-1,1-dicarbonitriles, in moderate to good
yields, is described.
CuBr, CuI, Cu(OAc) , and AgOAc were found to be less effec-
2
tive catalysts for this transformation. Lewis acids such as
AlCl3 and BF ·Et O did not promote the desired reaction.
3
2
Furthermore, the presence of CuBr and CuI in combination
with 1,10-phenanthroline promoted the reaction only
slightly (< 10%).
Keywords diastereoselective reactions, cyclopropanation, small rings,
iodine, N-heterocycles
Iodine (30 mol%), was found to be an effective catalyst,
affording 2-(4-bromophenyl)-3-(6-methylquinolin-2-yl)cy-
clopropane-1,1-dicarbonitrile (4a) in 15% yield (Table 1,
entry 10). The use of THF or MeCN as solvent, led to im-
proved yields (Table 1, entries 11 and 12). These results en-
couraged us to optimize the reaction conditions with io-
dine. The conversion proceeded in better yield (46%) with
50 mol% iodine. In the presence of stoichiometric amounts
of iodine, the reaction was complete after 12 h with up to
60% yield of isolated material (Table 1, entries 13 and 14).
With the optimized reaction conditions in hand, we
prepared a range of 2-(6-methylquinolin-2-yl)-3-arylcyclo-
propane-1,1-dicarbonitriles 4 from 1, pyridine, benzalde-
hydes 2, and malononitrile in the presence of iodine as
Lewis acid and N,N-diisopropylethylamine as Lewis base
(Table 2). Both electron-donating and electron-withdraw-
ing substituents on the benzaldehyde ring were well-toler-
ated, affording the desired products in 52 to 73% yields (Ta-
ble 2).
Cyclopropane and its derivatives are versatile molecules
1
with numerous applications in organic synthesis. Because
of their rigid structure and inherent reactivity, cyclopro-
pane rings can constitute key components in the synthesis
2
of complex molecules. Functionalized arylcyclopropylni-
triles have found utility in organic synthesis as precursors
3
for a wide variety of natural products, bioactive com-
4
5
pounds, and general synthetic targets. Moreover, consid-
erable research efforts have been devoted to the stereose-
lective construction of three-membered carbocyclic rings
6
over the last few decades. The most common methods for
the synthesis of functionalized cyclopropanes are metal-
catalyzed decomposition of α-diazocarbonyl compounds in
7
the presence of alkenes and reaction of electron-deficient
8
olefins with sulfur ylides.
As part of our current studies on the development of
9
new routes to carbocyclic and heterocyclic systems, we re-
port herein a transition-metal-free protocol in which a ni-
trogen ylide generated in situ combines with the Knoevena-
gel condensation products of malononitrile with benzalde-
hydes to afford 2-aryl-3-(6-methylquinolin-2-yl)cyclo-
10
propane-1,1-dicarbonitriles.
Initially, the reaction between 2,6-dimethylquinoline
(
1), 4-bromobenzaldehyde (2a), malononitrile (3), and pyri-
dine in the presence of N,N-diisopropylethylamine was
studied as a model reaction; the results are shown in Table
1
. In all cases, the zwitterionic intermediates, generated
Figure 1 ORTEP diagram of 4a
from 1, Lewis acids, and pyridine were reacted with
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 380–384

3
81
Synlett
I. Yavari et al.
Letter
Table 1 Optimization of the Reaction Conditions for the Preparation of 2-(4-Bromophenyl)-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbonitrile
a
(4a)
CN
Br
CHO
+
CN
2a
3
i-Pr2NEt
MeCN
NC
CN
Br
I2 (10 mol%)
pyridine
+
N
CN
CN
N
50 °C, 5 h
N
–
N
50 °C, 1 h
1
4a
Br
Entry
Cat. (30 mol%)
Ligand (10 mol%)
none
Solvent
Yield [%]b
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
no reaction
< 10
1,10-phenanthroline
none
no reaction
< 10
CuI
1,10-phenanthroline
Cu(OAc)
Cu(OAc)
AgOAc
2
none
no reaction
no reaction
no reaction
no reaction
no reaction
15
2
1,10-phenanthroline
none
none
none
none
none
none
none
none
none
AlCl
3
BF ·Et
3
2
O
1
1
1
1
1
0
1
2
3
4
5
I
I
I
I
I
I
2
2
2
2
2
2
23
MeCN
MeCN
MeCN
MeCN
38
(50 mol%)
(100 mol%)
(120 mol%)
46
60
1
56
a
Reaction conditions: (i) 1 (0.157 g, 1.0 mmol), pyridine (0.158 g, 2.0 mmol), Lewis acid, 50 °C, 1 h; (ii) arylidene malononitrlile, produced from 2a (0.106 g, 1.0
mmol) and 3 (0.066 g, 1.0 mmol), solvent (3.0 mL), (i-Pr)
Isolated yield after column chromatography.
2
NEt (0.284 g, 2.2 mmol).
b
1
Unambiguous evidence for the structure and stereo-
es, in agreement with the proposed structure. The H and
13
chemistry of 4a was obtained from single-crystal X-ray
C NMR spectra of products 4b–l were similar to those of
4a, except for the aryl moieties, which exhibited character-
istic signals with appropriate chemical shifts.
A mechanistic rationalization for the formation of prod-
ucts 4 is given in Scheme 1. Presumably, the initial event is
activation of 2-methylquinoline by coordination to iodine,
which leads to 1,2-dihydro-1-iodo-2-methylenequinoline
intermediate 5. This intermediate is attacked by pyridine to
afford alkylpyridinium salt 6, which is converted into nitro-
11
analysis. An ORTEP diagram of 4a is shown in Figure 1.
The structure deduced from the crystallographic experi-
ment, can be applied by analogy to the other products on
account of their similar NMR spectra.
1
The H NMR spectrum of product 4a exhibited two
3
sharp doublets (δ = 4.50 and 3.76 ppm, J
= 8.2 Hz) for
H–H
1
the methine protons of the cyclopropane. The H-decou-
pled C NMR spectrum of 4a showed 19 distinct resonanc-
13
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 380–384

3
82
Synlett
I. Yavari et al.
Letter
Table 2 Iodine-Mediated Synthesis of Substituted 2-Aryl-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbonitriles 4a
CN
Ar CHO
+
CN
2
3
i-Pr2NEt
MeCN
CN
Ar
I2 (10 mol%)
pyridine
CN
+
CN
CN
N
N
50 °C, 5 h
N
–
N
50 °C, 1 h
4
1
Ar
Entry
Product
Ar
4-BrC
Yield [%]b
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
6
H
4
60
52
73
54
73
68
48
64
67
52
68
53
Ph
4-ClC
6
H
4
4-MeC
3-O
4-MeOC
2-BrC
3-ClC
1-naphthyl
4-HOC
4-O NC
2-MeC
6
H
4
2
NC
6
H
4
6
H
4
4g
4h
4i
6 4
H
6
H
4
1
0
1
2
4j
6 4
H
1
4k
4l
2
6 4
H
1
6 4
H
a
Reaction conditions: (i) 1 (0.157 g, 1.0 mmol), pyridine (0.158 g, 2.0 mmol), I
2
(0.253 g, 1.0 mmol), 50 °C, 1 h; (ii) arylidene malononitrile, produced from 2
(
0.106 g, 1.0 mmol) and 3 (0.066 g, 1.0 mmol), MeCN (3.0 mL), (i-Pr) NEt (0.284 g, 2.2 mmol).
Isolated yield after column chromatography.
2
b
gen ylide 7 by N,N-diisopropylethylamine. Conjugate attack
of ylide 7 with arylidene malononitrile derivatives generat-
ed in situ, affords intermediate 8, which undergoes cycliza-
tion via intermediate 9 to generate 4.
References and Notes
(1) (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107,
3117. (b) Cousins, G. S.; Hoberg, J. O. Chem. Soc. Rev. 2000, 29,
165.
In summary, we have described a novel synthesis of 2-
aryl-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbo-
nitriles from the reaction of pyridinium ylides, generated
from iodine-mediated reaction of 2,6-dimethylquinoline
and pyridine, with Knoevenagel condensation products of
benzaldehydes with malononitrile, in moderate to good
yields.
(
2) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(b) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
(3) (a) Katagiri, T.; Irie, M.; Uneyama, K. Org. Lett. 2000, 2, 2423.
b) Bryson, T. A.; Koen, J. H. Jr.; Roth, G. A. Synlett 1992, 723.
(
(
4) (a) Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C.
M.; McKenzie, T. C.; Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.;
Lovell, F. M. J. Med. Chem. 1981, 24, 481. (b) Vervisch, K.;
D’hooghe, M.; Törnroos, K. W.; De Kimpe, N. Org. Biomol. Chem.
2009, 7, 3271.
(
5) (a) Kusumoto, T.; Nakayama, A.; Sato, K.; Hiyama, T.; Takehara,
Supporting Information
S.; Osawa, M.; Nakamura, K. Chem. Lett. 1992, 2047.
(
b) Kusumoto, T.; Nakayama, A.; Sato, K.; Hiyama, T.; Takehara,
Supporting information for this article is available online at
S.; Shoji, T.; Osawa, M.; Kuriyama, T.; Nakamura, K.; Fujisawa, T.
Tetrahedron Lett. 1991, 32, 939.
http://dx.doi.org/10.1055/s-0034-1379496.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 380–384

3
83
Synlett
I. Yavari et al.
Letter
pyridine
pyridine
(i-Pr)2NEt
+
N
+
–
+
N
– pyridinium
iodide
N
C
I–
(i-Pr)2NEtHI
I–
N
CH2
H2
I
I
5
6
ArCHO
+
CH2(CN)2
(i-Pr)2NEt
CN
CN
Ar
H
+
+
N
N
N
–
N
H
CN
–
Ar
7
CN
8
N
H
CN
CN
+
– pyridine
anti elimination
N
N
H
Ar
CN
–
Ar
CN
9
4
Scheme 1 Mechanistic rationalization for the formation of product 4
(
6) (a) Burgess, K.; Ho, K. K.; Moye-Sherman, D. Synlett 1994, 575.
removed in vacuo, and the residue was diluted with CHCl3 (20
mL), and washed with saturated K CO solution (3 × 10 mL), and
(b) Stammer, C. H. Tetrahedron 1990, 46, 2231. (c) Doyle, M. P.;
2
3
Forbes, D. C. Chem. Rev. 1998, 98, 911. (d) Papageorgiou, C. D.;
Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int.
Ed. 2004, 43, 4641. (e) Ishikawa, S.; Sheppard, T. D.; D’Oyley, J.
M.; Kamimura, A.; Motherwell, W. B. Angew. Chem. Int. Ed.
H O (3 × 10 mL). The organic layer was evaporated to give the
2
crude product, which was purified by silica gel (Merck 230–240
mesh) column chromatography (gradient hexane–EtOAc) to
afford 4.
2
013, 52, 10060. (f) Zhu, C.; Yoshimura, A.; Ji, L.; Wei, Y.;
Nemykin, V. N.; Zhdankin, V. V. Org. Lett. 2012, 14, 3170.
g) Hartikka, A.; Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874.
h) Goudreau, S. R.; Marcoux, D.; Charette, A. B. J. Org. Chem.
009, 74, 470. (i) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am.
2-(4-Bromophenyl)-3-(6-methylquinolin-2-yl)cyclopropane-
1,1-dicarbonitrile (4a): Yield: 0.23 g (60%); colorless powder;
1
(
(
2
mp 200–202 °C. R = 0.71 (hexane–EtOAc, 5:1). H NMR (400
f
MHz, CDCl ): δ = 8.18 (d, J = 8.2 Hz, 1 H), 8.01 (d, J = 8.7 Hz, 1 H),
3
7.65–7.56 (m, 5 H), 7.36 (d, J = 8.2 Hz, 2 H), 4.50 (d, J = 8.2 Hz,
13
Chem. Soc. 2007, 129, 10886.
1 H), 3.76 (d, J = 8.2 Hz, 1 H), 2.58 (s, 3 H). C NMR (100 MHz,
(7) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev.
CDCl ): δ = 148.3 (C), 146.2 (C), 137.6 (C), 136.8 (CH), 132.8
3
2
003, 103, 977.
(CH), 132.4 (2 CH), 130.2 (2 CH), 129.9 (C), 129.1 (CH), 127.9 (C),
126.5 (CH), 123.7 (C), 121.7 (CH), 113.1 (CN), 112.3 (CN), 38.9
(
(
8) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
9) (a) Yavari, I.; Hosseinpour, R.; Pashazadeh, R. Synlett 2012, 1662.
(CH), 37.3 (CH), 21.7 (Me), 16.0 [C(CN) ]. IR (KBr): 2244, 1590,
2
–1
+
(
(
b) Yavari, I.; Hosseinpour, R.; Pashazadeh, R. Synlett 2012, 2103.
c) Yavari, I.; Hosseinpour, R.; Pashazadeh, R.; Ghanbari, E. Tet-
1490 cm . MS (EI): m/z (%) = 387 (5) [M] , 360 (10), 353 (7), 307
(15), 282 (10), 266 (5), 242 (12), 232 (15), 207 (10), 182 (100),
157 (13), 142 (46), 127 (11), 115 (48), 101 (8), 89 (27), 75 (18),
rahedron Lett. 2013, 54, 2785. (d) Yavari, I.; Pashazadeh, R.;
Hosseinpour, R. Helv. Chim. Acta 2012, 95, 169. (e) Yavari, I.;
Hosseinpour, R.; Pashazadeh, R.; Ghanbari, E.; Skoulika, S. Tetra-
hedron 2013, 69, 2462.
63 (25), 51 (24). Anal. Calcd for C21H14BrN : C, 64.96; H, 3.63; N,
3
10.82. Found: C, 64.98; H, 3.67; N, 10.78.
X-ray Crystal-Structure Determination of 4a: Formula:
C21H14BrN3; Mr 388.26; monoclinic; space group P21/n;
(
10) Diastereoselective Synthesis of 4; General Procedure:
mixture of 2,6-dimethylquinoline (0.157 g, 1 mmol), pyridine
0.158 g, 2 mmol), and I2 (0.253 g, 1 mmol) was warmed to
0 °C for 1 h. A solution of aryl aldehyde (1 mmol), malononi-
A
a = 9.844(1),
V = 1828.1(3) Å ; Dcalc. = 1.411 Mg/m3; Mo Kα radiation
(0.71073 Å), T = 293(2) K; 3644 reflections collected on
b = 14.911(1),
c = 12.959(1) Å;
Z = 4;
3
(
5
a
trile, and (i-Pr) NEt (0.284 g, 2.2 mmol) in MeCN (3 mL) was
then added and the reaction mixture was stirred for 5 h. Upon
completion of reaction, as evidenced by TLC, solvent was
Bruker P4 diffractometer, 3179 unique (Rint = 0.0670), 1555
unique reflections with I > 2σ(I). All non-hydrogen atoms have
been located by difference Fourier maps and refined anisotropi-
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 380–384

3
84
Synlett
I. Yavari et al.
Letter
cally. The hydrogen atoms have been placed on calculated posi-
tions and refined isotropically by using the Riding model. Final
indices [I > 2σ(I)]: R1 = 0.0556, wR2 = 0.0999, GOF = 0.979. The
crystallographic data of 4a have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publica-
tion number CCDC-976608. Copies of the data can be obtained,
free
of
charge,
via
the
internet
(http://www.ccdc.cam.ac.uk/data_request/cif), e-mail: data_re-
quest@ccdc.cam.ac.uk, or fax: +44(1223)336033.
(11) Burnett, A. M. N.; Johnson, C. K. Oak Ridge National Laboratory
Report ORNL-6895; Oak Ridge National Laboratory: Tennessee,
1996.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 380–384

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.