Cyclodimerization of 2-arylcyclopropane-1,1-diesters. Lewis acid induced reversion of cyclopropane umpolung

Article abstract of DOI:10.1016/j.tetlet.2011.06.059

A novel Lewis acid catalyzed [3+2] cyclodimerization of 2-arylcyclopropane-1,1-dicarboxylates is reported. It is the first example of a reaction wherein a donor-acceptor cyclopropane provides two carbons in a newly formed ring. The described cyclodimeriza

Full text of DOI:10.1016/j.tetlet.2011.06.059

Tetrahedron Letters 52 (2011) 4421–4425
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
[3+2] Cyclodimerization of 2-arylcyclopropane-1,1-diesters. Lewis acid
induced reversion of cyclopropane umpolung
Alexey O. Chagarovskiy a,b, Olga A. Ivanova a, Ekaterina M. Budynina a,b, Igor V. Trushkov a,b
,
Mikhail Ya. Melnikov a,
⇑
a Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russia
b Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Leninsky av. 117, Moscow 117997, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel Lewis acid catalyzed [3+2] cyclodimerization of 2-arylcyclopropane-1,1-dicarboxylates is
Received 28 March 2011
Revised 27 May 2011
Accepted 13 June 2011
Available online 7 July 2011
reported. It is the first example of a reaction wherein a donor–acceptor cyclopropane provides two
carbons in a newly formed ring. The described cyclodimerization represents a general convenient
approach to polyfunctionalized cyclopentanes.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Donor–acceptor cyclopropane
Cyclodimerization
Lewis acid
Umpolung
Cyclopentane
In recent years, the diverse and often unexpected reactivity of
donor–acceptor cyclopropanes (DACs) has attracted significant
attention and stimulated research into new pathways for their syn-
thetic utilization.1–5 To date, the most studied DACs are 2-arylcy-
clopropane-1,1-dicarboxylates due to the simplicity of their
synthesis and potential for variation of the aryl/heteroaryl groups.
[3+n] Cycloadditions are among the most important reactions of
DACs6–17 wherein these compounds participate as a synthetic
equivalent of 1,3-zwitterionic synthon I (path a, Scheme 1). In
these reactions all three carbon atoms of the cyclopropane ring
are incorporated into a newly formed ring. An alternative reactivity
of the DAC as a synthetic equivalent of synthon II (path b) has re-
cently been reported for cyclopropanes containing electron-rich
(hetero)arene substituents.18–21 In this case only one carbon atom
of the three-membered ring is included in the new ring. Examples
of reactions where the DAC provides two carbon atoms (path c)
have not been reported. In processes a and b the DAC reagents
show umpolung,22 while in c, the cyclopropanes should react with
normal reactivity.
into cyclopentane derivatives occurred. In this process one DAC
molecule participates as an equivalent of the common synthon I
(umpolung), while another molecule reacts as an equivalent of
synthon III (normal reactivity). Herein we report the results of
our detailed research of this reactivity.
Our previous studies revealed that 2-arylcyclopropane-1,
1-dicarboxylates containing an electron-rich aromatic substituent
were more reactive than cyclopropanes with an electron-poor aryl
group.7,19–21 Therefore, we started our research using 2,4,6-trime-
thoxyphenyl-substituted cyclopropanes 1a,b as well-proven reac-
tive substrates (Scheme 2). The results obtained are summarized
in Table 1.
During optimization of the [3+2] cyclodimerization of 1a,b, we
found that the best reaction conditions involved reflux of 1 in
C6H5Cl in the presence of Sn(OTf)2 or Yb(OTf)3 (entries 6–8). These
moderately activating Lewis acids have earlier been demonstrated
to be efficient catalysts in various DAC reactions. A high tempera-
ture was crucial for this transformation as treatment of 1 with
Lewis acids at lower temperature failed to give products 4 in good
yields (entries 1–5). Instead, the reaction produced mixtures of
alkenes 2, and dimeric alkenes 3 and 4 in low yields under moder-
ate heating. The use of strong Lewis acids, such as BF3ꢀOEt2, AlCl3,
TiCl4 did not produce [3+2] cyclodimers of type 4 at all.
Recently, we reported the Lewis acid induced cyclopropane-to-
propene isomerization of 2-arylcyclopropane-1,1-dicarboxylates.23
In the course of this research we found that under harsher condi-
tions an unusual cyclodimerization of the parent cyclopropanes
The concentration of cyclopropanes is another factor that
influences the direction of the reaction. Thus, dimers 4 are formed
when concentrated solutions of 1a,b (0.1 M) are used, whereas the
dilution of the reaction mixture leads to exclusive formation of
products 2 even under the optimized reaction conditions.
⇑
Corresponding author. Tel./fax: +7 495 939 1814.
E-mail addresses: melnikov@excite.chem.msu.ru, melnikov46@mail.ru (M.Ya.
Melnikov).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.059

4422
A. O. Chagarovskiy et al. / Tetrahedron Letters 52 (2011) 4421–4425
A
A
A
A
X
X
X
II
I
a
[3+n] cycloaddition
A
[3+n] annulation
X
b
A
X
X
III
c
A
X
this work
Scheme 1. DACs as a source of 1-, 2- and 3-carbon units for a new ring formation.
The formation of dimeric products was deduced unambiguously
from mass spectrometry data. According to the 1H and 13C NMR
spectra, cyclopentanes 4a,b were formed as a single diastereomer.
The complete assignments of the 1H and 13C NMR spectra of 4 were
made with the aid of 2D COSY, HETCOR, HMBC and NOESY exper-
iments. The results of the COSY and HMBC experiments revealed
the presence of a five-membered cyclic fragment –(C–CH2–CH–
CH–C(CH)H)– in 4a,b. Thus, one cyclopropane molecule is included
in 4a,b as a C–CH2–CH fragment, while the other is transformed
into a CH–CH–CH moiety. The strong cross-peaks between C(Ar000)
and H(3), C(Ar00) and H(4) in the HMBC spectrum allude to a
Ar00C(3)H-C(4)HAr000 fragment. The relative configurations of the
chiral centers were assigned from NOESY data (Fig. 1).
The proposed mechanism for the formation of 4 is presented in
Scheme 3. Among the possible retrosynthetic disconnections of 4
only one [3+2] disconnection corresponds to reaction of two DAC
molecules. The first reacts as an equivalent of synthon I with reac-
tivity umpolung, typical for the DAC. The second reacts as an
equivalent of the ‘normal’ synthon III in which a negative charge
is localized on the benzylic carbon atom and a positive charge is
localized at the vicinal position. Such polarity can presumably oc-
cur in the enol form of propene 2 which was earlier postulated as
an intermediate in the isomerization of 1 into styrylmalonates 2.23
Similar to a common diene, this dienol reacts with the electrophilic
center of A (or the starting cyclopropane 1) via an AdE reaction pro-
ducing new dimeric zwitterion C. Further protonation of the malo-
nyl anion in C leads to acyclic alkene 3 (path a, Scheme 3), while
intramolecular Michael-like reaction results in cyclic dimer 4 (path
b). Similar cyclizations were described for related substrates.24,25
Therefore, this [3+2] cyclodimerization represents a very inter-
esting example of reactions where transformation of reactivity
umpolung into normal reactivity is required for the reaction with
another ‘umpolung reagent’.
[3+2] Cyclodimerization of the DAC into cyclopentanes was
found to be general for cyclopropanes with various aromatic or
heteroaromatic substituents (Scheme 4, Table 2). Diaryl-substi-
tuted cyclopentane derivatives were formed with exceptional che-
mo- and regioselectivity in good yields. The moderate yield for
pyrrolidine-substituted dimer 4f was ascribed to the low stability
of the parent cyclopropane 1f.
The reactions of 1c–j proceed with very high diastereoselectiv-
ity. Despite the formation of three stereogenic centers in 4c–j, only
two diastereomers with predominance of the trans–trans-2-
[bis(alkoxycarbonyl)methyl]-3,4-diarylcyclopentane-1,1-diesters
were formed. The relative configuration of the major isomers was
determined from NOE experiments using 4c as a reference model
(Fig. 2). Unfortunately, due to partial overlapping of the signals
in NMR spectra we could not determine the relative configuration
of the minor isomers. However, according to our ab initio calcula-
tions at the HF/6-31G level, the second most stable isomer is the
C(4) epimer of 4c which is probably the minor isomer.26
In contrast to 4c–j, the formation of 4a,b as single diastereo-
mers, is probably related to the high steric demands of 2,4,6-trime-
thoxyphenyl groups. As a result, the transition state leading to the
threo-isomer of zwitterion C has much higher energy than that
leading to the erythro-isomer.
As was mentioned above, under unoptimized reaction condi-
tions, acyclic dimers of type 3 were formed in low yields. Screening
of the reaction conditions for cyclopropane 1c allowed the prepa-
ration of mainly 3c in 60% yield as a mixture of two diastereomers
(61:39). For this reaction to occur, 1c was heated at 50–60 °C in
nitroethane in the presence of MgI2 (Scheme 5). Under these con-
ditions styrylmalonate 2c was also formed as a by-product in 30%
yield. Analysis of mass spectrometric and NMR data allowed us to
determine unambiguously the structure of 3c. In particular, a char-
acteristic signal in the 13C NMR spectrum of 3c was the resonance
CO2R
CO2R
CO2R
Ar
CO2R
CO2R
CO2R
CO2R
Yb(OTf)3 or Sn(OTf)2,
Ar
+
+
MeO
RO2C
CO2R
OMe
Ar
4 Å MS , Conditions
CO2R
CO2R Ar
3a,b
Ar
Ar = 2,4,6-(MeO)3C6H2
CO2R
4a,b
2a,b
1a: R = Me
1b: R = Et
MeO
Scheme 2.

A. O. Chagarovskiy et al. / Tetrahedron Letters 52 (2011) 4421–4425
4423
Table 1
Optimization of the reaction conditions for the cyclodimerization of 1a,b into 4a,b
Entry
R
LA (mol %)
Conditions
Yielda (%)
Solvent
T (°C)
Reaction time (h)
2
3
4
1
2
3
4
Et
Et
Me
Et
Et
Me
Et
Me
Sn(OTf)2 (10)
Sn(OTf)2 (10)
Sn(OTf)2 (10)
Yb(OTf)3 (5)
Sn(OTf)2 (10)
Sn(OTf)2 (10)
Sn(OTf)2 (10)
Yb(OTf)3 (10)
CH3NO2
C6H6 or CH2Cl2
CH2Cl2
CH2Cl2
C6H6
C6H5Cl
C6H5Cl
C6H5Cl
20
20
42
42
80
132
132
132
4
23
4
4
6
3
3
3
8823
—
—
—
—
31
38
78
75
80
13–18b
—
10b,c
15–20c
c
c
c
5
15
25
—
—
—
c
c
c
5
15
6d
7d
8d
—
—
—
a
b
c
Isolated yields.
Polymers and
NMR yield.
c
-aryl-a-(alkoxycarbonyl)butyrolactone were also detected in the reaction mixture.
d
The most efficient reaction conditions are marked in bold font.
H
H
CO2R
CO2R
Ar'''
H
CO2Me
CO2Me
CO2R
Ar
5
Yb(OTf)3 or Sn(OTf)2,
4
3
1
2
CO2R 4 Å MS , Conditions
H
H
CO2R
Ar
Ar
1'
Ar''
MeO2C
CO2Me
CO2R
H
1c-j
4c-j
4a: Ar = 2,4,6-(MeO)3C6H2
Scheme 4.
Figure 1. NOESY data for compound 4a.
theory that minor isomers of 4c–h have a cis-relationship between
the aryl groups.
of the tertiary carbon atom at dC 149 indicating the presence of an
alkylidenemalonate moiety. It is possible that the major isomers of
3c and 4c have the same relative configuration for the CHAr–CHAr
fragment, as do the minor isomers. This is consistent with our
In conclusion, we have described a novel [3+2] cyclodimeriza-
tion of DACs. This atom-economic process represents a simple
and convenient route to polysubstituted cyclopentanes which are
useful substrates in both synthetic organic and medicinal
Retrosynthetic (3+2) disconnection
Reversion of umpolung
RO
O
RO
O
LA
LA
Ar
CO2R
OR
OR
Ar
Ar
Ar
Ar
LA
H
O
CO2R
I
O
O
A
CO2R
CO2R
CO2R
Ar
CO2R
RO
RO
O
Ar
LA
LA
Ar
RO2C
RO2C
CO2R
1
OR
OR
4
III
Ar
CO2R
OH
B
2 (in enol form) OH
Dimerization
RO
RO
O
O
LA
OR
O
LA
OR
LA
RO
Ar
RO
Ar
OR
a
Ar
Ar
CO2R
CO2R
LA
A
O
H
OH
O
O
RO
RO
O
Ar
LA
Ar
Ar
1
b
OR
LA
O
O
LA
O
C
RO
RO
OH
path a
path b
CO2R
B
Ar
Ar
CO2R
CO2R
CO2R
RO2C
CO2R
Ar
Ar = 2,4,6-(MeO)3C6H2
CO2R Ar
RO2C
3
4
Scheme 3. Proposed mechanism for the [3+2] cyclodimerization of 1 into 4.

4424
A. O. Chagarovskiy et al. / Tetrahedron Letters 52 (2011) 4421–4425
Table 2
[3+2] Cyclodimerization of 1c–j into cyclopentanes 4c–j
1,4
R
Ar
LA (mol %)
Conditions
T (°C)
Yield of 4a (%) (dr)b
Solvent
C6H5Cl
Reaction time (h)
5
c
d
e
f
Me
Me
Et
MeO
Yb(OTf)3 (5)
Yb(OTf)3 (5)
Yb(OTf)3 (5)
Yb(OTf)3 (5)
Yb(OTf)3 (5)
132
132
42
79 (77:23)
80 (67:33)
75 (78:22)
50 (72:28)
73 (76:24)
Me2N
Me2N
C6H5Cl
CH2Cl2
CH2Cl2
C2H4Cl2
5
5
5
4
Me
Me
N
42
g
O
N
84
h
i
Me
Me
Me
Sn(OTf)2 (10)
Yb(OTf)3 (5)
Yb(OTf)3 (5)
C6H5Cl
C6H5Cl
C6H5Cl
132
132
132
3.5
7
67 (61:39)
75 (51:49)
70 (56:44)
S
j
11
a
Isolated yields.
According to NMR data.
b
OMe
CO2Me
CO2Me
MeO2C
MgI2, 4Å MS
+
2c
EtNO2, 50-60 oC, 3 h MeO2C
CO2Me
CO2Me
MeO
1c
3c, 60%, dr 61:39
30%
MeO
Scheme 5.
MeO
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.059.
CO2Me
CO2Me
5
4
3
1
H
H
2
CO2Me
References and notes
2.4%
1'
4.2%
H
H
CO2Me
1. Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–1196.
2. Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347.
3. Agrawal, D.; Yadav, V. K. Chem. Commun. 2008, 6471–6488.
4. De Simone, F.; Waser, J. Synthesis 2009, 3353–3374.
MeO
H
7.8%
Figure 2. NOE data for the major isomer of 4c.
5. Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060.
6. Parreault, C. S.; Goudreau, R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10,
689–692.
7. Ivanova, O. A.; Budynina, E. M.; Grishin, Yu. K.; Trushkov, I. V.; Verteletskii, P. V.
Angew. Chem., Int. Ed. 2008, 47, 1107–1110.
8. Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541–2544.
9. Fang, J.; Ren, J.; Wang, Z. Tetrahedron Lett. 2008, 49, 6659–6662.
10. Bajtos, B.; Pagenkopf, B. L. Eur. J. Org. Chem. 2009, 1072–1077.
11. Sapeta, K.; Kerr, M. A. Org. Lett. 2009, 11, 2081–2084.
12. Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830–6841.
13. Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem.
Soc. 2008, 130, 8642–8650.
14. Moustafa, M. M. A.; Pagenkopf, B. L. Org. Lett. 2010, 12, 3168–3171.
15. Tomilov, Yu. V.; Novikov, R. A.; Nefedov, O. M. Tetrahedron 2010, 66, 9151–
9158.
chemistry. In this reaction the DAC demonstrates both typical reac-
tivity umpolung acting as an equivalent of a 1,3-zwitterion, and
unusual for cyclopropanes, ‘normal’ reactivity providing a two car-
bon unit for the newly formed ring. Presumably, normal reactivity
is provided via double reactivity umpolung or, in other words,
reversion of cyclopropane umpolung.
Acknowledgments
We thank the Russian Foundation of Basic Research (Project 09-
03-00244-a) for financial support of this work.
16. Hu, B.; Xing, S.; Ren, J.; Wang, Z. Tetrahedron 2010, 66, 5671–5674.
17. Yang, G.; Shen, Y.; Li, K.; Sun, Y.; Hua, Y. J. Org. Chem. 2011, 76, 229–233.

A. O. Chagarovskiy et al. / Tetrahedron Letters 52 (2011) 4421–4425
4425
18. Venkatesh, C.; Ila, H.; Junjappa, H.; Mathur, S.; Hush, V. J. Org. Chem. 2002, 67,
9477–9480.
19. Ivanova, O. A.; Budynina, E. M.; Grishin, Yu. K.; Trushkov, I. V.; Verteletskii, P. V.
Eur. J. Org. Chem. 2008, 5329–5355.
20. Chagarovskiy, A. O.; Budynina, E. M.; Ivanova, O. A.; Grishin, Yu. K.; Trushkov, I.
V.; Verteletskii, P. V. Tetrahedron 2009, 65, 5385–5392.
22. Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258.
23. Chagarovskiy, A. O.; Ivanova, O. A.; Rakhmankulov, E. R.; Budynina, E. M.;
Trushkov, I. V.; Melnikov, M. Ya. Adv. Synth. Catal. 2010, 352, 3179–3184.
24. Novikov, A. V.; Kennedy, A. R.; Rayner, J. D. J. Org. Chem. 2003, 68, 993–996.
25. Beltran-Rodil, S.; Donald, J. R.; Edwards, M. G.; Raw, S. A.; Taylor, R. J. K.
Tetrahedron Lett. 2009, 50, 3378–3380.
21. Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Kaplun, A. E.; Trushkov, I.
V.; Melnikov, M. Ya. Adv. Synth. Catal. 2011, 353, 1125–1134.
26. See Supplementary data.