A new type of donor-acceptor cyclopropane reactivity: The generation of formal 1,2- and 1,4-dipoles

Article abstract of DOI:10.1002/anie.201306186

A new type of donor-acceptor cyclopropane reactivity has been discovered. On treatment with anhydrous GaCl₃, they react as sources of even-numbered 1,2- and 1,4-dipoles instead of the classical odd-numbered 1,3-dipoles due to migration of positive charge from the benzyl center. This type of reactivity has been demonstrated for new reactions, namely, cyclodimerizations of donor-acceptor cyclopropanes that occur as [2+2]-, [3+2]-, [4+2]-, [5+2]-, [4+3]-, and [5+4]-annulations. The [4+2]-annulation of 2-arylcyclopropane-1,1-dicarboxylates to give polysubstituted 2-aryltetralins has been developed in a preparative version that provides exceedingly high regio- and diastereoselectivity and high yields. The strategy for selective hetero-combination of donor-acceptor cyclopropanes was also been developed. The mechanisms of the discovered reactions involving the formation of a comparatively stable 1,2-ylide intermediate have been studied. Old ring, new reactivity: A new type of donor-acceptor cyclopropane reactivity has been discovered. On treatment with anhydrous GaCl₃, they react as sources of even-numbered 1,2- and 1,4-dipoles instead of the classical odd-numbered 1,3-dipoles owing to the migration of positive charge from the benzyl center.

Full text of DOI:10.1002/anie.201306186

Angewandte
Chemie
DOI: 10.1002/anie.201306186
Carbocycles
A New Type of Donor–Acceptor Cyclopropane Reactivity: The
Generation of Formal 1,2- and 1,4-Dipoles**
Roman A. Novikov, Anna V. Tarasova, Victor A. Korolev, Vladimir P. Timofeev, and
Yury V. Tomilov*
Abstract: A new type of donor–acceptor cyclopropane
reactivity has been discovered. On treatment with anhydrous
GaCl3, they react as sources of even-numbered 1,2- and 1,4-
dipoles instead of the classical odd-numbered 1,3-dipoles due
to migration of positive charge from the benzyl center. This
type of reactivity has been demonstrated for new reactions,
namely, cyclodimerizations of donor–acceptor cyclopropanes
that occur as [2+2]-, [3+2]-, [4+2]-, [5+2]-, [4+3]-, and
[5+4]-annulations. The [4+2]-annulation of 2-arylcyclopro-
pane-1,1-dicarboxylates to give polysubstituted 2-aryltetralins
has been developed in a preparative version that provides
exceedingly high regio- and diastereoselectivity and high yields.
The strategy for selective hetero-combination of donor–
acceptor cyclopropanes was also been developed. The mech-
anisms of the discovered reactions involving the formation of
a comparatively stable 1,2-ylide intermediate have been
studied.
on the reaction conditions and the nature of the aryl
substituent, the reactions give dimers of various classes,
such as arylidenemalonates,[3a] diarylhexenes,[3a,b] cyclohexa-
nes,[3b] tetralins,[3b,c] dihydroanthracenes,[3b] pentaleno[1,6-
a,b]indoles,[3d]
cyclopentanes,[3a,c]
2-oxabicyclo-
[3.3.0]octanes,[3e] and indanes.[3f]
Herein, we discuss a thorough study of DAC transforma-
[3c,e,g]
tions in the presence of the anhydrous Lewis acid GaCl3
under various conditions and the discovery of new reactivity
types for these cyclopropanes. The new strategy uses DACs as
the source of even-numbered 1,2- and 1,4-dipoles, instead of
odd-numbered classical 1,3-dipoles (Figure 1). This is ach-
D
onor–acceptor cyclopropanes (DAC) with donor and
acceptor substituents at the vicinal position are nowadays
popular in organic synthesis as sources of 1,3-dipoles gen-
erated from them in the presence of Lewis acids or heating.[1,2]
The capability of donor–acceptor cyclopropanes to undergo
[2+3]-, [3+3]-, and [3+4]-dipolar cycloaddition with various
substrates is used to construct five-, six-, and seven-membered
carbo- and heterocycles,[1,2] which makes them attractive for
application in organic synthesis.
Figure 1. New Type of DAC Reactivity: generation of formal 1,2- and
1,4-dipoles.
It was recently shown[3] that, in the absence of unsaturated
substrates or other compounds that trap the 1,3-dipoles being
generated, DAC themselves can undergo dimerization upon
treatment with Lewis acids and organocatalysts. Depending
ieved due to the positive charge shift along the alkyl chain at
the stage of cyclopropane ring opening. This is an exclusive
feature of reactions with GaCl3. Analysis of the entire
diversity of DAC reactions described in the literature[1–3] did
not reveal similar reactions.
The discovered [4+2]-cyclodimerization of DAC is a syn-
thetically valuable process that allows the one-stage assembly
of polysubstituted tetralins from simple and readily available
cyclopropanedicarboxylates with exceptionally high regio-
and diastereoselectivity. The latter may be of interest as
synthons in organic synthesis and as compounds possessing
biological activity. In fact, the aryltetralin moiety occurs in the
structures of a number of compounds that have been isolated
from various natural sources and manifest a broad spectrum
of biological activity,[4] including antitumor activity[4e]
(Figure 2).
[*] R. A. Novikov, A. V. Tarasova, V. A. Korolev, Y. V. Tomilov
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, 47 Leninsky prosp., 119991 Moscow (Russian Federation)
E-mail: tom@ioc.ac.ru
R. A. Novikov, V. P. Timofeev
V. A. Engelhardt Institute of Molecular Biology, Russian Academy of
Sciences, 32 Vavilov st., 119991 Moscow (Russian Federation)
[**] This work was supported by the Russian Federation President
Council for Grants (Program for State Support of Leading Scientific
Schools of the Russian Federation, grant no. NSh-604.2012.3), the
Division of Chemistry and Materials Sciences of the Russian
Academy of Sciences (Program for Basic Research “Theoretical and
Experimental Study of the Nature of Chemical Bonds and
Mechanisms of Important Chemical Reactions and Processes”) and
the Program “Molecular and cell Biology ” of the Presidium of the
Russian Academy of Sciences.
It has been found that compound 1a can undergo
dimerization in the presence of GaCl3 along four different
pathways to give polysubstituted cyclopentane 2a,[3c] tetralin
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306186.
Angew. Chem. Int. Ed. 2014, 53, 3187 –3191
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3187

.
Angewandte
Communications
tion corresponding to [3+2]- and [4+2]-annulation and
formal [2+2]-cycloaddition. All compounds, unlike cyclo-
pentane 2a, are formed as single diastereomers.
The dimerization of compound 1a was found to be very
sensitive to the reaction conditions (Table 1). In fact, cyclo-
propane 1a underwent selective dimerization to cyclopentane
2a at a temperature of about 08C in the presence GaCl3
(20 mol%), whereas other dimers were not formed.[3c] If the
temperature was increased to 408C and the amount of GaCl3
was increased, the regioselectivity of the process changed
abruptly to give tetralin 3a in high yield. The optimum results
were obtained with 75 mol% of the Lewis acid. Under
intermediate reaction conditions, a mixture of dimers 2a and
3a predominated, accompanied by indane 4a and cyclo-
butane 5a.
Once the optimum conditions for the conversion of
cyclopropane 1a to tetralin 3a were found, we studied other
DACs in this process. It was found that [4+2]-cyclodimeriza-
tion also occurred successfully for substituted cyclopropanes
1b–k, in all cases to give 2-aryl-1,3-bismalonyltetralins 3b–k
as the major products, in high yields and with exceptionally
high diastereoselectivity (Scheme 1). The [4+2]-cyclodimeri-
zation of 3-substituted phenyl- (1g,h) and 2-naphthylcyclo-
propanedicarboxylates (1k) also occurred regiospecifically. In
fact, of the two possible directions of electrophilic substitution
at the aromatic ring, the attack exclusively occurred at the less
sterically hindered position, to give compounds 3g,h,k. It was
also found that the use of equimolar amounts of GaCl3 and
tetrahydrofuran as an additional ligand were the optimum
conditions to improve the yield of dimers 3j,k. In this case,
tetrahydrofuran should be added after gallium trichloride.
Tetrahydrofuran decreases the Lewis acidity of GaCl3 but
does not affect the overall pathway of the process. The
composition of the target products was established by means
of elemental analyses or HRMS. The structure and stereo-
chemistry of the compounds obtained were determined by 1H,
19F and 13C NMR, 1D and 2D COSY, TOCSY, NOESY,
HSQC, and HMBC spectroscopy.
Figure 2. Examples of natural products with biological activity incorpo-
rating the 2-aryltetralin fragment.
3a, indane 4a,[3f] and cyclobutane 5a. The fraction of each
depends on the amount of GaCl3 used and on the reaction
temperature (Table 1). In this case, the formation of com-
pounds 3a–5a represents new types of DAC cyclodimeriza-
Table 1: GaCl3-mediated dimerization of cyclopropane 1a under different
conditions.
We detected cyclodimers 6–8 as admixtures upon [4+2]-
cyclodimerization of 1-naphthylcyclopropane 1j with GaCl3
(Figure 3). The formation of these compounds also represents
a new type of DAC dimerization involving [4+3]-, [5+2]-, and
[5+4]-annulation on the naphthyl ring to give seven- and
nine-membered rings.
We have recently synthesized and characterized hitherto
unknown DAC complexes with Lewis acids, including
GaCl3.[5] Considering the data on the detection of the dipolar
intermediates formed, the mechanisms of the new processes
of DAC cyclodimerization in the presence of GaCl3
(Scheme 2) that we discovered can be proposed.
When GaCl3 is added to cyclopropane 1, it is instantly
bound to give a relatively stable 1,2-dipole II,[5] which is the
key intermediate in DAC dimerization induced by GaCl3 and
exists in the reaction mixture for a rather long time. This
intermediate exists in solution in equilibrium with minor
amounts of much less stable intermediates I and III,[5] which
are continuously consumed in various processes due to their
higher reactivity. The diversity of dimerization processes is
limited to reactions of the three intermediates I–III with each
Entry
GaCl3 [mol%] T [8C]
t [min]
Yield[a,b,c] [%]
3a 4a 5a
2a
85
73
75
35
<10
70
1
2
3
4
5
6
7
8
20
20
50
0
20
0
30
30
30
30
30
30
30
30
90
30
30
13
44
81
16
39
79
34
86
10
50
50
20
40
0
20
40
40
40
80
9
5
100
100
100
100
75
<3
11
<2
<3
9
<2
35
10
9
10
11
<5
75
[a] Yield of isolated products. [b] 1H NMR spectroscopic analysis was
used in the case of unseparated mixtures. [c] Product yields can vary
widely based on the quality of GaCl3 used, and the amount of trace
moisture present.
3188
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 3187 –3191

Angewandte
Chemie
Scheme 2. Proposed mechanism of the GaCl3-mediated cyclodimeriza-
tion reactions of DACs.
other. Cyclobutanes 5 and tetralins 3 are formed in the
reaction of intermediates II and III, which are initially
coupled to give intermediate IV, then either 1,4-cyclization
to compound 5 or electrophilic substitution at the aromatic
ring to give compound 3 occurs (for detailed mechanisms, see
the Supporting Information).
The regioselectivity of [4+2]-cyclodimerization reaction
of DAC is anomalous. The fact is that styrylmalonate III is
generated and reacts as a Ga complex (not in its free form).
=
When its double C C-bond is attacked by the carbocationic
center generated from the second molecule of DAC, the alkyl
carbocation IV is formed, which is highly stabilized by the
negative or partial negative charge from the malonyl anion in
coordination with the GaCl3. The last carbocation is the
analog of very stable 1,2-ylide II[5] and turns out to be much
more stable than the benzylic carbocation which had not
formed (for details, see Supporting Information).
Scheme 1. GaCl3-mediated [4+2]-cyclodimerization of DACs 1a–k
giving 2-aryltetralines 3a–k. Reaction conditions: [a] GaCl3 (0.75 equiv),
408C, 30 min. [b] GaCl3 (0.6 equiv), 408C, 30 min. [c] GaCl3 (0.75
equiv), 208C, 30 min. [d] GaCl3 (1 equiv), 408C, 4 h. [e] GaCl3 (1 equiv),
408C, 6 h. [f] GaCl3 (1 equiv), 08C, then THF (1 equiv), 0!208C, 6 h.
The high stability of 1,2-ylide Ga complex II makes it
possible to develop an effective strategy for the [4+2]-
annulation of DAC in a variant of strictly controlled hetero-
combination of two different DAC molecules, or a combina-
tion of DAC with alkenes. This approach consists of the
generation of the key dipolar intermediate from the necessary
DAC molecule in situ, and its further introduction in the
combination with the second substrate (DAC or alkene)
under heating (Scheme 3). This preserves the diastereoselec-
tivity of the reaction and each injected fragment gets into
a strictly defined position in the final tetralin and the
homodimerization products, whereas only a minor amount
of random heterodimerization products are formed. In
essence, this is the first example of selective DAC hetero-
dimerization. This strategy significantly expands the possibil-
ities of the DAC [4+2]-annulation reactions. In the future, we
intend to develop this reactivity in order to include DAC
reactions with various substituents and substrates.
The mechanism of the [4+2]-heterodimerization of DAC
is similar to the homodimerization one. The key Ga inter-
mediate that allows control of the cross-dimerization reaction
is ylide II. It is a relatively stable complex in which Ga is
strongly associated with the ester groups,[5] and therefore this
Figure 3. Minor products formed in the GaCl3-mediated dimerization
of cyclopropane 1j.
Angew. Chem. Int. Ed. 2014, 53, 3187 –3191
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3189

.
Angewandte
Communications
intermediate hardly exchanges gallium trichloride with other
molecules and intermediates (for a detailed mechanism, see
the Supporting Information). This allows high selectivity in
the cross-dimerization reaction and makes this process
possible. As almost all GaCl3 is complexed in II, the second
molecule of DAC cannot react with GaCl3 to give corre-
sponding ylide II’. Therefore, it isomerizes in styrylmalonate
III’ under the action of the Ga complexes (for example, II).
Then reaction of intermediates II and III’ takes place
(Scheme 4).
In summary, we have discovered new DAC cyclodimeri-
zation processes initiated by anhydrous GaCl3, which occur as
[2+2]-, [3+2]-, [4+2]-, [5+2]-, [4+3]-, and [5+4]-annulation
reactions and represent a new type of DAC reactivity wherein
the latter serve as sources of even-numbered 1,2- and 1,4-
dipoles instead of the classical odd-numbered 1,3-dipoles; this
is due to migration of positive charge along the carbon chain
from the benzyl center. A preparative version of regio- and
diastereospecific DAC [4+2]-annulation to give tetralins has
also been developed.
Received: July 16, 2013
Revised: December 18, 2013
Published online: February 19, 2014
Keywords: annulation · carbocycles · cyclodimerization ·
.
donor-acceptor systems · lewis acids
[1] Reviews of DAC: a) H. U. Reissig, R. Zimmer, Chem. Rev. 2003,
103, 1151; b) M. Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321;
c) F. De Simone, J. Waser, Synthesis 2009, 3353; d) C. A. Carson,
M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051; e) M. J. Campbell,
J. S. Johnson, A. T. Parsons, P. D. Pohlhaus, S. D. Sanders, J. Org.
Chem. 2010, 75, 6317; f) M. Y. Melnikov, E. M. Budynina, O. A.
Ivanova, I. V. Trushkov, Mendeleev Commun. 2011, 21, 293.
[2] For recent examples, see: a) M. R. Emmett, H. K. Grover, M. A.
Kerr, J. Org. Chem. 2012, 77, 6634; b) A. F. G. Goldberg, N. R.
OꢀConnor, R. A. Craig, B. M. Stoltz, Org. Lett. 2012, 14, 5314;
c) Y.-Y. Zhou, L.-J. Wang, J. Li, X.-L. Sun, Y. Tang, J. Am. Chem.
Soc. 2012, 134, 9066; d) R. A. Novikov, E. V. Shulishov, Y. V.
Tomilov, Mendeleev Commun. 2012, 22, 87; e) M. R. Emmett,
M. A. Kerr, Org. Lett. 2011, 13, 4180; f) V. R. Espejo, X.-B. Li,
J. D. Rainier, J. Am. Chem. Soc. 2010, 132, 8282; g) Y. V. Tomilov,
R. A. Novikov, O. M. Nefedov, Tetrahedron 2010, 66, 9151; h) K.
Sapeta, M. A. Kerr, Org. Lett. 2009, 11, 2081; i) O. A. Ivanova,
E. M. Budynina, Y. K. Grishin, I. V. Trushkov, P. V. Verteletskii,
Angew. Chem. 2008, 120, 1123; Angew. Chem. Int. Ed. 2008, 47,
1107; j) C. Perreault, S. R. Goudreau, L. E. Zimmer, A. B.
Charette, Org. Lett. 2008, 10, 689.
Scheme 3. GaCl3-mediated [4+2]-cross-dimerization and annulation
with styrenes of DACs. [a] Isolated with 50–85% purity. [b] Yields
1
determined by H NMR spectroscopy. [c] Not isolated.
[3] For dimerization reactions of DACs, see: a) A. O. Chagarovskiy,
O. A. Ivanova, E. M. Budynina, I. V. Trushkov, M. Y. Melnikov,
Tetrahedron Lett. 2011, 52, 4421; b) O. A. Ivanova, E. M. Budy-
nina, A. O. Chagarovskiy, I. V. Trushkov, M. Y. Melnikov, J. Org.
Chem. 2011, 76, 8852; c) R. A. Novikov, V. A. Korolev, V. P.
Timofeev, Y. V. Tomilov, Tetrahedron Lett. 2011, 52, 4996;
d) O. A. Ivanova, E. M. Budynina, A. O. Chagarovskiy, E. R.
Rakhmankulov, I. V. Trushkov, A. V. Semeykin, N. L. Shimanov-
skii, M. Y. Melnikov, Chem. Eur. J. 2011, 17, 11738; e) R. A.
Novikov, V. P. Timofeev, Y. V. Tomilov, J. Org. Chem. 2012, 77,
5993; f) Y. A. Volkova, E. M. Budynina, A. E. Kaplun, O. A.
Ivanova, A. O. Chagarovskiy, D. A. Skvortsov, V. B. Rybakov,
I. V. Trushkov, M. Y. Melnikov, Chem. Eur. J. 2013, 19, 6586;
g) R. A. Novikov, Y. V. Tomilov, Helv. Chim. Acta 2013, 96, 2068.
Scheme 4. Proposed mechanism of the GaCl3-mediated selective
[4+2]-cross-dimerization of DACs.
3190
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 3187 –3191

Angewandte
Chemie
[4] a) A. Fiorentino, B. DꢀAbrosca, S. Pacifico, A. Natale, P. Monaco,
Phytochemistry 2006, 67, 971; b) A. Fiorentino, B. DꢀAbrosca, S.
Pacifico, R. Iacovino, A. Izzo, P. Uzzo, A. Russo, B. D. Blasio, P.
Monaco, Tetrahedron 2008, 64, 7782; c) M. Royer, V. Eparvier, B.
Thibaut, D. Stien, G. Herbette, J. Beauchene, Phytochemistry
2010, 71, 1708; d) J. Piel, K. Hoang, B. S. Moore, J. Am. Chem.
Soc. 2000, 122, 5415; e) H. Xu, M. Lv, X. Tian, Curr. Med. Chem.
2009, 16, 327; f) M. Gordaliza, P. A. Garcia, J. M. Miguel del Cor-
ral, M. A. Castro, M. A. Gomez-Zurita, Toxicon 2004, 44, 441.
[5] R. A. Novikov, D. O. Balakirev, V. P. Timofeev, Y. V. Tomilov,
Organometallics 2012, 31, 8627.
Angew. Chem. Int. Ed. 2014, 53, 3187 –3191
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3191