Donor-acceptor cyclopropanes as three-carbon components in a [4+3] cycloaddition reaction with 1,3-diphenylisobenzofuran

Article abstract of DOI:10.1002/anie.200704438

(Chemical Equation Presented) Dienophiles with a difference: 2-Aryl 1,1-bis(alkoxycarbonyl) cyclopropanes undergo the title reaction under the catalysis of ytterbium triflate (Yb(OTf)₃) in excellent yield (see scheme). Under mild reaction conditions, the major product is the less stable exo isomer. At higher temperatures, the endo isomer is obtained exclusively, as the exo cycloadduct decomposes through cycloreversion.

Full text of DOI:10.1002/anie.200704438

Angewandte
Chemie
DOI: 10.1002/anie.200704438
Cycloaddition
Donor–Acceptor Cyclopropanes as Three-Carbon Components in a
[4+3] Cycloaddition Reaction with 1,3-Diphenylisobenzofuran
Olga A. Ivanova,* Ekaterina M. Budynina, Yuri K. Grishin, Igor V. Trushkov, and
Pavel V. Verteletskii
Substituted cyclopropanes have found broad application in
modern organic synthesis owing to the unique reactivity of the
cyclopropane moiety.[1] Cyclopropanes can often be consid-
rings in similar reactions between dienes and cyclopro-
panones has been reported.[10] However, the equivalent
treatment of cyclopropanone dimethyl acetal failed to yield
cycloaddition products under the same conditions.[11] Thus, it
appears that the transformation of the cyclopropanone into
an oxyallyl cation is required for this cycloaddition to
proceed. Even so, cycloaddition reactions between dienes
and cyclopropanes are not “forbidden” processes: Several
[1,2]
=
ered as three-carbon analogues of C C bonds.
For
example, alkenes and cyclopropanes react with strong elec-
trophiles and various radicals. Both undergo the addition of
hydrogen and can be oxidized at the a position. The reactivity
of cyclopropanes with electron-withdrawing substituents is
similar to that of electron-deficient alkenes.[3] However, the
cycloaddition reactions of alkenes and cyclopropanes are
quite different. In particular, the thermal reactions of alkenes
are represented mainly by [1+2], [3+2], and [4+2] cyclo-
addition processes; thermal [2+2] cycloaddition occurs in
very specific cases only. In contrast, the most well known type
of cyclopropane cycloaddition is the [2p + 2s] reaction with
alkenes.[4] As this reaction yields cyclopentanes, it can also be
considered as a [2+3] cycloaddition. The scope of such [2+3]
cycloaddition reactions has been expanded significantly
through the use of donor–acceptor cyclopropanes.[5] The
presence of both electron-donating and electron-withdrawing
substituents on the cyclopropane ring enables cycloaddition
=
examples of the reaction of vinylcyclopropanes with C C or
=
C X bonds to afford cycloheptane derivatives have been
described.[12] The cyclopropane ring participates in these
processes in place of one double bond of a diene. Therefore,
this type of reaction is analogous to the Diels–Alder cyclo-
addition. Owing to the importance of Diels–Alder-type
reactions in modern organic synthesis, we investigated the
possibility of a [4+3] cycloaddition between cyclopropane
derivatives and appropriate dienes. Herein, we report a new
route to substituted cycloheptenes through the [4+3] cyclo-
addition of dienes to cyclopropanes substituted with two
electron-withdrawing groups at one carbon atom and an
electron-donating group at a second carbon atom.
[6]
[7]
[8]
to various multiple bonds, including[5] C C, C O, C N,
We selected 2-aryl 1,1-cyclopropane diesters 1 as sub-
strates because of the previously reported smooth reactivity
of such donor–acceptor cyclopropanes in [2p + 2s] cyclo-
addition reactions with alkenes.[5] Moreover, substrates 1 are
known to undergo [3+3] cycloaddition to 1,3-dipoles with the
formation of six-membered rings.[13] Our selection of the
diene 1,3-diphenylisobenzofuran (2) as the second substrate
was based on the requirement for high reactivity in the Diels–
Alder reaction and an inability to form [3+2] cycloaddition
products. The latter limitation is related to the potential
competition of [3+2] and [4+3] cycloaddition processes. We
first screened reaction conditions for the model [4+3] cyclo-
addition between 2 and diethyl 2-phenylcyclopropane-1,1-
dicarboxylate (1a; Table 1).
=
=
=
[9]
ꢀ
and C N bonds.
The [4+3] cycloaddition of cyclopropanes with dienes
(Scheme 1) has not been reported previously, although this
Scheme 1. Schematic representation of the [4+3] cycloaddition reac-
tion of dienes with donor–acceptor cyclopropanes.
We found that 1a failed to react with 2 unless the reaction
was promoted by a Lewis acid (Table 1, entry 1). Lewis acid
catalysis was demonstrated previously for the reaction of 1a
with nitrones[13] and imines,[14] as well as in related [3+2][7d]
and [3+1+1][15] cycloaddition reactions of cyclopropanes. We
examined a variety of Lewis acids as catalysts for the [4+3]
cycloaddition between 1a and 2. With SnCl4 and other strong
Lewis acids (TiCl4, BF3·OEt2, trimethylsilyl triflate), the
desired cycloaddition product was formed in only small
amounts, if at all. When EtAlCl2 was used as the catalyst, the
polymerization of the cyclopropane 1a was the main process
observed (Table 1, entry 2). After many attempts, we found
that the target compound 3a was formed under the catalysis
of Yb(OTf)3 (Table 1, entries 4–6).
[4p + 2s] process is a formal analogue of the well-known
Diels–Alder reaction. The formation of seven-membered
[*] Dr. O. A. Ivanova, Dr. E. M. Budynina, Dr. Y. K. Grishin,
Dr. I. V. Trushkov, Dr. P. V. Verteletskii
Department of Chemistry
Lomonosov Moscow State University
Leninskie gory 1–3, Moscow 119992 (Russia)
Fax : (+7)495-939-3969
E-mail: iv@org.chem.msu.ru
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Optimization of the reaction conditions for the model [4+3]
cycloaddition between 1a and 2.
Table 2: Yb(OTf)3-catalyzedreaction of 2-aryl 1,1-cyclopropane diesters
1 with 2.
Entry Solvent Lewis acid T [8C]
t [h] Yield[%] [a] exo/endo
[b]
1
2
3
4
5
6
PhCl
CH2Cl2 EtAlCl2
CH2Cl2 SnCl4
PhCl
PhCl
–
reflux
12
–
–
–
–
–
–
[c]
[d]
ꢁ40!RT 24
ꢁ50!RT 18
25[f]
50[g]
85
<1:19
<1:19
56:44
[e]
[e]
[e]
Yb(OTf)3
Yb(OTf)3
reflux
80
8
26
9
Entry
1
t [h]
T [8C]
3
Yield[%] [a]
exo/endo
CH2Cl2 Yb(OTf)3
reflux
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
9
3
24
1
3
3
reflux
reflux
RT
RT
RT
3a
3b
3c
3d
3e
3 f
85
90
86
89
92
84
56:44
53:47
86:14
77:23
74:26
64:36
[a] Yield of the isolated product. [b] No conversion was observed. [c] The
polymerization of 1a was observedas the main process. [d] Only a small
amount of the product of [4+3] cycloaddition was formed. [e] Catalyst
loading: 5 mol%. [f] Compound 4a was also isolatedin 58% yield.
[g] Compound 4a was also isolatedin 44% yield.
RT
[a] Yieldof the isolatedproduct.
The reaction temperature also influenced the efficiency of
the cycloaddition. At reflux in chlorobenzene, the cyclo-
adduct 3a was formed in just 25% yield. The main product
under these conditions was 1-(2-benzoylphenyl)-1,2-diphe-
nylethene (4a), which was formed from 3a through the
elimination of diethyl methylenemalonate. The decomposi-
tion of 3a decreased with decreasing reaction temperature.
Unfortunately, the rate of formation of 3a also decreased
significantly as the reaction temperature was lowered. Thus,
at room temperature only a trace amount of the desired
cycloadduct 3a was observed after 24 h. The best result for the
[4+3] cycloaddition between 1a and 2 was observed when the
reaction mixture was heated at reflux in dichloromethane for
9 h in the presence of Yb(OTf)3 (Table 1, entry 6).
To determine the scope of the [4+3] cycloaddition, we
treated substrate 2 with a series of 2-aryl 1,1-cyclopropane
diesters under similar reaction conditions (Table 2). We found
the para-fluorophenyl-substituted cyclopropane 1b to be
more reactive than 1a. Furthermore, the cycloadducts 3c–f
were formed efficiently from substrates 1c–f with electron-
donating aryl substituents even at room temperature: The
reaction of the 3,4,5-trimethoxyphenyl-substituted cyclopro-
pane 1d was complete within 1 h.
of 3a–f. Unfortunately, we were unable to determine whether
the endo or exo product is the predominant isomer from the
NMR spectroscopic data. To provide additional insight into
the mechanism of the reaction and to determine the major
isomer of the product, we performed ab initio quantum-
chemical calculations of the geometries and relative stabilities
of the two diastereomers of 3a at the HF/6-31G level.[16] We
found that the chair conformation is more stable for both
diastereomers, and that the endo isomer is more stable than
the exo isomer by 2.0 kcalmolꢁ1.
If the reaction proceeds by a stepwise mechanism, with
the Lewis acid catalyzed electrophilic attack of cyclopropanes
1a–f on the substrate 2, followed by the cyclization of a
zwitterionic intermediate, the predominant formation of the
more stable endo isomer might be expected. However, the
calculated values of the 3J coupling constants for the less
stable exo isomer were in full agreement with the experi-
mental values for the major cycloadduct; the experimental
J values for the minor isomer were in excellent agreement
with the calculated data for the endo product. This conclusion
was confirmed by single-crystal X-ray diffraction analysis,
which proved unambiguously the structure of the major
isomer. The diffraction data revealed the structure of the
energetically less favorable exo isomer with a chair confor-
mation of the six-membered ring.[16,17]
Comparison of the NMR spectroscopic data for 3b with
the data for the products formed in the other reactions
showed that in all cases the major isomer was the less stable
exo isomer. This phenomenon can be explained by a
concerted cycloaddition mechanism that accounts for possible
approaches of the reagents and orbital symmetry rules
(Scheme 2).
The formation of the less stable exo isomer 3a as the main
product is also supported by the results of the reaction
between 1a and 2 at higher temperatures (Table 1, entries 4–
6). We found that the major isomer exo-3a decomposed
during prolonged heating in the presence of the catalyst with
According to the NMR spectroscopic data, products 3a–f
were formed as mixtures of two diastereomers in ratios of
approximately 1.1:1 to 6.1:1. The data reveal a conformational
distinction between the isomers caused by the orientation of
the aryl group. The vicinal JH,H coupling constants for the
ꢁ
ꢁ
ꢁ
C(Ar)H CH2 fragment of the six-membered ring differ
significantly for the two isomers. The values of the 3J coupling
constants were approximately 6 and 1 Hz for the major
isomers of 3a–f; for the minor isomers these values were
approximately 12 and 4 Hz. In agreement with the Karplus
rule, these parameters show a clear-cut distinction in the
HCCH dihedral angles of the diastereomers. The Haxial–Haxial
coupling (3J ꢂ 12 Hz) was observed for one isomer only. From
these data, one may conclude that the six-membered ring
adopts a similar (chair or boat) conformation in both isomers
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In conclusion, we have developed an analogue of the
Diels–Alder reaction with donor–acceptor cyclopropanes as
dienophiles. This formal [4+3] cycloaddition between 2-aryl
cyclopropane diesters and 1,3-diphenylisobenzofuran (2)
proceeds under mild reaction conditions to yield two isomeric
cycloadducts in a combined yield of 84–92%. The predom-
inant formation of the less stable exo isomer suggests a
concerted mechanism with orbital control of the stereochem-
ical course of the reaction. We are investigating the extension
of this reaction to other dienes.
Scheme 2. Proposedmechanism of the [4 +3] cycloaddition between 1
and 2, andconfiguration of the main product 3.
the elimination of diethyl methylenemalonate to form 4a. In
contrast, the minor isomer endo-3a was stable under these Experimental Section
General procedure for the cycloaddition: 1,3-Diphenylisobenzofuran
(2; 284 mg, 1.05 mmol), (1 mmol), and Yb(OTf)3 (31 mg,
conditions. Similar results were observed for other cyclo-
propane substrates. These observations are consistent with
the higher stability of the minor endo isomer. The decom-
position product 4 can exist as the E or the Z isomer.
However, the exo adducts 3a,b,e decomposed to form a single
isomer of 4 at reflux in benzene in the presence of Yb(OTf)3
(Table 3). Unfortunately, the differentiation of the two
1
0.05 mmol) were dissolved in dry CH2Cl2 (4 mL), and the resulting
mixture was stirred with activated 4-Š molecular sieves under argon
at the appropriate temperature (Table 2) until TLC and 1H NMR
spectroscopy indicated the complete consumption of the cyclopro-
pane diester. The reaction mixture was then filtered, the solvent was
evaporated under vacuum, and the residue was purified by column
chromatography (SiO2, eluent: hexane–CHCl3 1:1) to yield 3.[16]
Table 3: Yb(OTf)3-catalyzed decomposition of cycloadducts 3.
Received: September 26, 2007
Revised: October 22, 2007
Published online: January 4, 2008
Keywords: cycloaddition · cyclopropanes · dienes · Lewis acids ·
.
synthetic methods
Entry
3
t [h]
4
Yield[%] [a]
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10
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4c
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81
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Z geometry.[16,17]
The formation of the Z product 4 may appear unusual.
However, the results of quantum-chemical calculations (HF/
6-31G) of the two isomers showed that the Z isomer is more
stable than the E alkene by 2.2 kcalmolꢁ1. Moreover, the
Z geometry is predicted by orbital symmetry rules for the
product of the concerted cycloreversion process (Scheme 3).
Scheme 3. Disrotatory mechanism of ring opening (closure) for the
transformation of 3 into 4 (andthe reverse reaction).
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