GaCl3-Mediated Isomerization of Donor-Acceptor Cyclopropanes into (2-Arylalkylidene)malonates

Article abstract of DOI:10.1055/s-0035-1561389

A new process for isomerization of donor-acceptor cyclopropanes (2-arylcyclopropanedicarboxylates) by treatment with anhydrous gallium trichloride to give (2-arylalkylidene)malonates in high yields and with good selectivity has been developed. The reactio

Full text of DOI:10.1055/s-0035-1561389

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
R. A. Novikov et al.
Letter
Synlett
GaCl3-Mediated Isomerization of Donor–Acceptor Cyclopropanes
into (2-Arylalkylidene)malonates
Roman A. Novikov
Anna V. Tarasova
Yury V. Tomilov*
1) GaCl3 (1.1 equiv)
0 °C, 10–15 min
CH2Cl2
CO2Me
CO2Me
Ar
CO2Me
CO2Me
2) MeOH (ex.)
N. D. Zelinsky Institute of Organic Chemistry, Russian
Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow,
Russian Federation
Ar
12 examples
72–98%
tom@ioc.ac.ru
Received: 18.11.2015
Accepted after revision: 19.01.2016
Published online: 01.03.2016
Ar
Ar
CO2Me
TMSOTf
PhCl, Δ
previous work:
Adv. Synth. Catal.
2010, 352, 3179
CO2Me
CO2Me
CO2Me
2
3
DOI: 10.1055/s-0035-1561389; Art ID: st-2015-b0897-l
Ar
CO2Me
Abstract A new process for isomerization of donor–acceptor cyclopro-
panes (2-arylcyclopropanedicarboxylates) by treatment with anhydrous
gallium trichloride to give (2-arylalkylidene)malonates in high yields and
with good selectivity has been developed. The reaction involves initial
formation of a 1,2-dipolar gallium complex.
GaCl3
1
this work
CO2Me
Scheme 1 Isomerization of DAC 1
Key words donor–acceptor cyclopropanes, cyclopropanedicarboxyl-
ates, gallium trichloride, isomerization, 1,2-dipole, alkylidenemalonates
Arylethylidenemalonates are widely used in organic
synthesis to construct various carbo- and heterocycles.
Some examples of their application are presented in
Scheme 2.
Donor–acceptor cyclopropanes (DAC) are remarkable
sources for generation of 1,3-dipoles in cycloaddition, an-
nulation, and dimerization reactions and are popular in
modern organic synthesis for building carbo- and heterocy-
cles.1,2 We recently discovered a new type of DAC reactivi-
ty,3 where they act as sources of formal even 1,2- and 1,4-
dipoles due to migration of positive charge in the presence
of anhydrous GaCl3. This type of reactivity was demonstrat-
ed in dimerization,3a,c fragmentation,3d,e and annulation
with alkenes.3a,b
For example, (2-arylethylidene)malonates serve as con-
venient sources for synthesizing other donor–acceptor cy-
clopropanes2c,5d,5h–j and donor–acceptor cyclobutanes5e as
well as their subsequent transformations.1,2,5e,5h–j Further-
more, related intermediates can be generated both from
DAC 1 and from isomeric arylethylidenemalonates 3.6 Cer-
tain (2-arylethylidene)malonates were used in full synthe-
ses of a number of natural compounds, for example, hinoki-
nin5a–c and hypoxyxylerone,5f,g that manifest antiviral, anti-
fungal, and pesticidal activity.5b,c,g
Though it seems at first glance that the Knoevenagel
condensation from the corresponding substituted phenyl-
acetic aldehydes is the easiest way to obtain (2-arylal-
kylidene)malonates 3, it is actually not quite so, taking the
low availability and high price of these aldehydes into con-
sideration. In contrast, cyclopropanedicarboxylates 1 are
currently rather available reagents that can be readily syn-
thesized by a well-proven methodology using the Knoeve-
nagel condensation and the Corey–Chaykovsky reaction7
from the corresponding available benzaldehydes.
In continuation of studies on 1,2-dipolar reactivity of
DAC, in this study we elaborated a new process for isomeri-
zation of cyclopropanedicarboxylates
1 to (2-arylal-
kylidene)malonates 3 on treatment with gallium trichlo-
ride (Scheme 1). Previously, a process for isomerization of
cyclopropanes 1 to styrylmalonates 2 in the presence of
trimethylsilyltriflate was suggested.4a Isomerization to (2-
arylalkylidene)malonates 3 was reported in only a couple of
examples,4a,b without a common synthetic methodology or
a possibility to vary the substituents. In this study, the
isomerization of cyclopropanes
1
to (2-arylal-
kylidene)malonates was elaborated in a synthetic version
ensuring high product yields for various cyclopropanes and
possibility to work with gram-scale amounts.
The methodology for isomerization of cyclopropanes 1
to (2-arylalkylidene)malonates implies that 1,2-dipolar re-
activity of DAC is used. Like in our previous studies, the pro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
R. A. Novikov et al.
Letter
Synlett
HO
OH
O
OH OMe
O
HO
O
O
O
O
O
OMe
O
OH
ref.
5f,g
OH
hypoxyxylerone
ref.
5a–c
O
O
R
hinokinin
R2
Ar
CO2Me
CO2Me
ref. 5j
Y
ref. 5d,h–j
ref. 5e
X
CO2Me
CO2Me
MeO2C
MeO2C
Ar
R1
ref. 7
ref. 5h
NPhth
CO2Me
CO2Me
R1
MeO2C CO2Me
CO2Me
CO2Me
Ar
CO2Me
CO2Me
R4
R2
R3
Ar
Ar
Scheme 2 Some application of arylethylidenemalonates in organic synthesis
Table 1 Isomerization of DAC 1 into (2-Arylalkylidene)malonates 3
MeO
O
MeOH
(ex.)
GaCl3
(1.1 equiv)
GaCl3
CO2Me
CO2Me
CO2Me
O
Ar
CO2Me
Ar
Ar
CH2Cl2
0 °C
OMe
10–15 min
1a–l
4a–l
3a–l
1,2-dipolar intermediate
Entrya
DAC
Ar
Ph
Product
Yield (%)
1
2
1a
1a
1a
1b
1c
1d
1e
1f
3a
3a
3a
3b
3c
3d
3e
3f
48b
90
92c
72
76
81
77
77
80
86
94
98
73
Ph
3
Ph
4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
2-MeC6H4
2-ClC6H4
1-naphthyl
2-naphthyl
MeO2C
5
6
7
8d
9d
10e
11e
12
13
1g
1h
1i
3g
3h
3i
1j
3j
1k
3k
CO2Me
CO2Me
CO2Me
14
1l
3l
75
1l
3l
a Reaction conditions: 1 (0.6 mmol), GaCl3 (1.1 equiv), CH2Cl2, 0 °C, 10–15 min, then MeOH was added.
b 1,2-Dipolar gallium complex was treated with a 2 N solution of HCl.
c 1a in 7.0 g (30 mmol) quantity was used.
d 1 (0.6 mmol), GaCl3 (1.1–1.2 equiv), CH2Cl2, 0 °C, 20–30 min.
e 1 (0.6 mmol), GaCl3 (1.2–1.3 equiv), CH2Cl2, 0 °C, 40–60 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
R. A. Novikov et al.
Letter
Synlett
cess is split into two stages that are carried out using a one-
pot technique.3a,b The first stage involves the generation of
1,2-dipolar gallium complex 4, which, owing to complex-
ation, is essentially a resonance form of the target alkene 3
with separated charges (see the reaction scheme in Table
1).6 Apparently, simple decomplexation of GaCl3 should give
the final product.
Acknowledgment
This work was supported by the Russian Science Foundation (grant
no. 14-13-01054).
Supporting Information
Supporting information for this article is available online at
However, it was found that this process should be car-
ried out very carefully in order to eliminate the possibility
of various side reactions (dimerization, oligomerization,
isomerization in styrylmalonate, addition of water, chloride
anion and other nucleophiles, etc.).3a,4b The use of various
substrates has shown that methanol successfully fulfils this
task. Thus, the immediate treatment of the reaction mix-
ture with aqueous HCl gives (2-phenylethylidene) malonate
3a in a yield of not more than 48% (Table 1, entry 1). How-
ever, if an excess of methanol is added to the reaction mix-
ture after generation of a 1,2-dipole, target alkene 3a is
smoothly formed (Table 1, entry 2).8 Scaling of the reaction
under the same conditions was successfully performed
with a 7 gram load of cyclopropane 1a (gram-scale reac-
tion; Table 1, entry 3).
http://dx.doi.org/10.1055/s-0035-1561389.
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References and Notes
(1) For reviews of DAC, see: (a) Reissig, H. U.; Zimmer, R. Chem. Rev.
2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321. (c) De Simone, F.; Waser, J. Synthesis 2009, 3353.
(d) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051.
(e) Campbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.;
Sanders, S. D. J. Org. Chem. 2010, 75, 6317. (f) Melnikov, M. Y.;
Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V. Mendeleev
Commun. 2011, 21, 293. (g) Schneider, T. F.; Kaschel, J.; Werz, D.
B. Angew. Chem. Int. Ed. 2014, 53, 5504. (h) De Nanteuil, F.; De
Simone, F.; Frei, R.; Benfatti, F.; Serrano, E.; Waser, J. Chem.
Commun. 2014, 50, 10912. (i) Novikov, R. A.; Tomilov, Y. V. Men-
deleev Commun. 2015, 25, 1.
The technique that we elaborated works well for various
substituted arylcyclopropanedicarboxylates 1b–l and al-
lows (2-arylalkylidene)malonates 3b–l to be obtained in
high yields (Table 1, entries 4–14).8 In this case, the highest
yields were achieved for phenylcyclopropane (1а) and or-
tho-substituted phenylcyclopropanes 1h–j (Table 1, entries
3, 10–12). Fused cyclopropane 1l also undergoes isomeriza-
tion to give the corresponding alkene 3l in up to 75% yields
(Table 1, entry 14). p-Nitro- and p-methoxy-substituted cy-
clopropanedicarboxylates give the corresponding products
with much lower yields, thereby still limiting the applica-
bility of our strategy. These cyclopropanes require develop-
ment of special approach for 1,2-dipoles generation,3a,b
which will be done in the near future.
The composition of the target arylalkylidenmalonates
3a–l was established by HRMS. The structures of the com-
pounds obtained were determined by 1H NMR and 13C NMR
spectroscopy using 1D and 2D DEPT, COSY, HSQC, and
HMBC.
Thus, we have elaborated a new efficient process for
isomerization of DAC, namely, 2-arylcyclopropanedicarbox-
ylates to (2-arylalkylidene)malonates, by treatment with
anhydrous gallium trichloride followed by decomposition
of the gallium complex with methanol. Furthermore, along
with the previously known process of DAC isomerization to
styrylmalonates in the presence of trimethylsilyltriflate,4a
directed synthesis of isomeric alkenes from a single cyclo-
propanedicarboxylate becomes possible by varying the pro-
cess conditions, which expands the synthetic prospects of
DAC application.
(2) For some recent examples of DAC reactions, see (a) Ivanova, O.
A.; Budynina, E. M.; Khrustalev, V. N.; Skvortsov, D. A.;
Trushkov, I. V.; Melnikov, M. Y. Chem. Eur. J. 2016, 22, 1223.
(b) Novikov, R. A.; Potapov, K. V.; Chistikov, D. N.; Tarasova, A.
V.; Grigoriev, M. S.; Timofeev, V. P.; Tomilov, Y. V. Organometal-
lics 2015, 34, 4238. (c) Wang, Z.; Chen, S.; Ren, J.; Wang, Z. Org.
Lett. 2015, 17, 4184. (d) Ma, W.; Fang, J.; Ren, J.; Wang, Z. Org.
Lett. 2015, 17, 4180. (e) Liu, H.; Yuan, C.; Wu, Y.; Xiao, Y.; Guo,
H. Org. Lett. 2015, 17, 4220. (f) Liu, Q.-J.; Yan, W.-G.; Wang, L.;
Zhang, X. P.; Tang, Y. Org. Lett. 2015, 17, 4014. (g) Cheng, Q.-Q.;
Qian, Y.; Zavalij, P. Y.; Doyle, M. P. Org. Lett. 2015, 17, 3568.
(h) Ghosh, A.; Pandey, A. K.; Banerjee, P. J. Org. Chem. 2015, 80,
7235. (i) Xu, H.; Hu, J.-L.; Wang, L.; Liao, S.; Tang, Y. J. Am. Chem.
Soc. 2015, 137, 8006. (j) Rakhmankulov, E. R.; Ivanov, K. L.;
Budynina, E. M.; Ivanova, O. A.; Chagarovskiy, A. O.; Skvortsov,
D. A.; Latyshev, G. V.; Trushkov, I. V.; Melnikov, M. Y. Org. Lett.
2015, 17, 770. (k) Tabolin, A. A.; Novikov, R. A.; Khomutova, Y.
A.; Zharov, A. A.; Stashina, G. A.; Nelyubina, Y. V.; Tomilov, Y. V.;
Ioffe, S. L. Tetrahedron Lett. 2015, 56, 2102. (l) Ivanov, K. L.;
Villemson, E. V.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V.;
Melnikov, M. Y. Chem. Eur. J. 2015, 21, 4975. (m) Garve, L. K. B.;
Pawliczek, M.; Wallbaum, J.; Jones, P. G.; Werz, D. B. Chem. Eur. J.
2016, 22, 521.
(3) For 1,2-dipolar DAC reactivity, see: (a) Novikov, R. A.; Tarasova,
A. V.; Korolev, V. A.; Timofeev, V. P.; Tomilov, Y. V. Angew. Chem.
Int. Ed. 2014, 53, 3187. (b) Novikov, R. A.; Tarasova, A. V.;
Korolev, V. A.; Shulishov, E. V.; Timofeev, V. P.; Tomilov, Y. V.
J. Org. Chem. 2015, 80, 8225. (c) Novikov, R. A.; Tarasova, A. V.;
Tomilov, Y. V. Mendeleev Commun. 2015, 25, 341. (d) Novikov, R.
A.; Tarasova, A. V.; Suponitsky, K. Y.; Tomilov, Y. V. Mendeleev
Commun. 2014, 24, 346. (e) Novikov, R. A.; Tarasova, A. V.;
Tomilov, Y. V. Russ. Chem. Bull. 2014, 63, 2737.
(4) (a) Chagarovskiy, A. O.; Ivanova, O. A.; Rakhmankulov, E. R.;
Budynina, E. M.; Trushkov, I. V.; Melnikov, M. Y. Adv. Synth.
Catal. 2010, 352, 3179. (b) Novikov, R. A.; Korolev, V. A.;
Timofeev, V. P.; Tomilov, Y. V. Tetrahedron Lett. 2011, 52, 4996.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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R. A. Novikov et al.
Letter
Synlett
4
(5) (a) Yamada, K.; Konishi, T.; Nakano, M.; Fujii, S.; Cadou, R.;
Yamamoto, Y.; Tomioka, K. J. Org. Chem. 2012, 77, 5775.
(b) Tomioka, K.; Ishiguro, T.; Iitaka, Y.; Koga, K. Tetrahedron
1984, 40, 1303. (c) Yoshiki, Y.; Ishiguro, T. Yakugaku Zasshi
1933, 53, 73. (d) Martelli, J.; Gree, R. J. Chem. Soc., Chem.
Commun. 1980, 355. (e) De Nanteuil, F.; Waser, J. Angew. Chem.
Int. Ed. 2013, 52, 9009. (f) Chevenier, E.; Lucatelli, C.; Pandya, U.;
Wang, W.; Gimbert, Y.; Greene, A. E. Synlett 2004, 2693.
(g) Edwards, R. L.; Fawcett, V.; Maitland, D. J.; Nettleton, R.;
Shields, L.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun. 1991,
1009. (h) Wang, Z.; Wang, Z.; Ren, J. Org. Lett. 2013, 15, 5682.
(i) Zhu, W.; Ren, J.; Wang, Z. Eur. J. Org. Chem. 2014, 3561.
(j) Xing, S.; Pan, W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem. Int.
Ed. 2010, 49, 3215.
=CH, 3J = 7.9 Hz), 7.13–7.20 (m, 2 H, 2 o-H, JHF = 5.3 Hz). 13C
NMR (100.6 MHz, CDCl3): δ = 35.1 (CH2), 52.41 and 52.44 (2
OMe), 115.7 (d, 2 m-CH, 2JCF = 21.5 Hz), 128.3 (=C), 130.3 (d, 2 o-
3
4
CH, JCF = 8.1 Hz), 132.8 (d, ipso-C, JCF = 3.2 Hz), 147.4 (=CH),
162.0 (d, p-CF, JCF = 245.3 Hz), 164.2 and 165.6 (2 COO). 19F
1
3
4
NMR (282.4 MHz, CDCl3): δ = –116.6 (tt, 1F, JHF = 8.7 Hz, JHF
=
5.3 Hz). MS: m/z (%) = 252 (2) [M+], 220 (16) [M+ – HOCH3], 188
(21), 133 (100), 109 (36), 83 (24), 59 (93), 29 (24). HRMS: m/z
calcd for C13H13O4F: 253.0871 [M + H]+, 275.0690 [M + Na]+;
found: 253.0867; 275.0685.
Dimethyl 2-[2-(1-Naphthyl)ethylidene]malonate (3j)
The title compound was prepared according to the general pro-
cedure in 283 mg (98%) yield as a colorless thick oil. IR (CHCl3):
ν = 3027, 3011, 2955, 2904, 2848, 1731 (C=O), 1645, 1598,
1511, 1488, 1438, 1396, 1372, 1303, 1268 cm–1. 1H NMR (400.1
MHz, CDCl3): δ = 3.76 and 3.92 (2 s, 2 × 3 H, 2 CO2Me), 4.12 (d, 2
H, CH2, 3J = 7.5 Hz), 7.23 (t, 1 H, =CH, 3J = 7.5 Hz), 7.36 (br d, 1 H,
H2′ or H4′, 3J = 7.1 Hz), 7.42 (dd, 1 H, H3′, 3J = 7.1 and 8.1 Hz),
7.48–7.53 (m, 1 H, H6′ or H7′), 7.53–7.58 (m, 1 H, H6′ or H7′),
7.78 (br d, 1 H, H2′ or H4′, 3J = 8.1 Hz), 7.86–7.90 (m, 1 H, H5′ or
H8′), 7.96–8.01 (m, 1 H, H5′ or H8′). 13C NMR (100.6 MHz,
CDCl3): δ = 33.2 (CH2), 52.42 and 52.45 (2 OMe), 123.5, 125.7,
125.9, 126.5, 126.9, 127.9 and 128.9 [7 CH(Ar)], 128.2 (=C),
131.8, 133.6 and 134.0 [3 C(Ar)], 148.4 (=CH), 164.3 and 165.8
(2 COO). MS: m/z (%) = 284 (11) [M+], 252 (28) [M+ – HOCH3],
220 (57), 209 (25), 192 (18), 165 (100), 152 (29), 141 (15), 115
(29), 84 (76), 75 (12), 59 (27), 47 (41), 35 (36). HRMS: m/z calcd
for C17H16O4: 307.0941 [M + Na]+; found: 307.0942.
(6) Novikov, R. A.; Balakirev, D. O.; Timofeev, V. P.; Tomilov, Y. V.
Organometallics 2012, 31, 8627.
(7) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(b) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson,
J. S. J. Am. Chem. Soc. 2008, 130, 8642.
(8) General Procedure for the Synthesis of (2-Arylal-
kylidene)malonates 3a–l
All operations were performed in dry argon atmosphere. To a
solution of cyclopropane 1a–l (0.6 mmol) in dry CH2Cl2 (5 mL)
was added the solid GaCl3 (0.66 mmol, 1.1 equiv) in one portion
at 0 °C under vigorous stirring. The reaction mixture was stirred
at the same temperature during 10–15 min, then MeOH (1.5
mL) was added. After that aqueous solution of HCl (5%) was
added at r.t. until pH 2–3 was achieved, and the reaction
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic
layer was dried over MgSO4, and the solvent was removed in
vacuo. The residue was separated by column chromatography
on silica gel (eluent: from benzene to benzene–EtOAc, 10:1) to
afford target (2-arylalkylidene)malonates 3a–l as thick colorless
oils. If necessary, the obtained products 3a–l can be additionally
purified by second column chromatography on silica gel eluting
with hexane to hexane–acetone (10:1). For details, see Table 1
and Supporting Information. Analytical data for representative
samples 3c,j,l are provided below.
Dimethyl 2-[3,4-Dihydronaphthalen-2(1H)-ylidene]malonate
(3l)
The title compound was prepared according to the general pro-
cedure in 116 mg (75%) yield as a colorless thick oil. IR (CHCl3):
ν = 3012, 2954, 2905, 2846, 1730 (C=O), 1629, 1493, 1455,
1436, 1349, 1331, 1295, 1262, 1243 cm–1. 1H NMR (400.1 MHz,
CDCl3): δ = 2.72–2.85 (m, 4 H, CH2CH2), 3.74 and 3.77 (2 s, 2 × 3
H, 2 CO2Me), 3.87 (br s, 2 H, CH2), 7.03–7.15 [m, 4 H, 4 H(Ar)].
13C NMR (100.6 MHz, CDCl3): δ = 28.8 and 30.2 (CH2CH2), 35.2
(CH2), 52.0 (2 OMe), 122.5 (=C), 126.4, 126.6, 127.4 and 128.1 [4
CH(Ar)], 134.1 and 137.2 [2 C(Ar)], 159.2 (=C), 165.6 and 165.9
(2 COO). MS: m/z (%) = 260 (7) [M+], 228 (45) [M+ – HOCH3], 200
(16), 168 (36), 157 (11), 141 (86), 128 (100), 115 (65), 103 (7),
91 (9), 77 (20), 65 (17), 59 (51), 51 (10), 39 (26). HRMS: m/z
calcd for C15H16O4: 261.1121 [M + H]+, 283.0941 [M + Na]+,
299.0680 [M + K]+; Found: 261.1120; 283.0940; 299.0682.
Dimethyl 2-[2-(4-Fluorophenyl)ethylidene]malonate (3c)
The title compound was prepared according to the general pro-
cedure in 115 mg (76%) yield as a colorless thick oil. IR (CHCl3):
ν = 3015, 3008, 2955, 2903, 2848, 1732 (C=O), 1648, 1605,
1511, 1438, 1366, 1264 cm–1 1H NMR (400.1 MHz, CDCl3): δ =
.
3.59 (d, 2 H, CH2, 3J = 7.9 Hz), 3.77 and 3.86 (2 s, 2 × 3 H, 2
3
CO2Me), 6.95–7.02 (m, 2 H, 2 m-H, JHF = 8.7 Hz), 7.07 (t, 1 H,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D