Stereoselective double lewis acid/organo-catalyzed dimerization of donor-acceptor cyclopropanes into substituted 2-oxabicyclo[3.3.0]octanes

Article abstract of DOI:10.1021/jo300720d

A new approach for the dimerization of donor-acceptor cyclopropanes (2-arylcyclopropane-1,1-dicarboxylates) under double-catalysis conditions by treatment with 20 mol % of GaCl₃ and dimethyl 3,5-dimethyl-1- pyrazoline-3,5-dicarboxylate as a specific organocatalyst has been found. Under these conditions, the starting compounds are regio- and stereospecifically converted into polysubstituted 2-oxabicyclo[3.3.0]octanes. Two new rings, one C-O bond, and two C-C bonds are formed in this process, and four stereocenters are thus created. The reaction mechanism was thoroughly studied by NMR spectroscopy, and a number of intermediates were detected.

Full text of DOI:10.1021/jo300720d

Article
pubs.acs.org/joc
Stereoselective Double Lewis Acid/Organo-Catalyzed Dimerization
of Donor−Acceptor Cyclopropanes into Substituted 2-
Oxabicyclo[3.3.0]octanes
Roman A. Novikov,†,‡ Vladimir P. Timofeev,‡ and Yury V. Tomilov*,†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian
Federation
‡V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov st., 119991 Moscow, Russian Federation
S
* Supporting Information
ABSTRACT: A new approach for the dimerization of donor−acceptor cyclopropanes (2-arylcyclopropane-1,1-dicarboxylates)
under double-catalysis conditions by treatment with 20 mol % of GaCl3 and dimethyl 3,5-dimethyl-1-pyrazoline-3,5-dicarboxylate
as a specific organocatalyst has been found. Under these conditions, the starting compounds are regio- and stereospecifically
converted into polysubstituted 2-oxabicyclo[3.3.0]octanes. Two new rings, one C−O bond, and two C−C bonds are formed in
this process, and four stereocenters are thus created. The reaction mechanism was thoroughly studied by NMR spectroscopy, and
a number of intermediates were detected.
methods for making of the 2-oxabicyclo[3.3.0]octane fragment
generally involve various condensation reactions and are
determined, to a considerable extent, by the structure of the
target compounds. Setting the required stereochemistry of
substituents is also a considerable problem of these methods.2
In this study, we report a new synthetic strategy toward the
2-octabicyclo[3.3.0]octane core through an interaction of two
molecules of donor−acceptor (DA) cyclopropanes that under-
go cyclodimerization under double catalysis conditions.
Donor−acceptor cyclopropanes (cyclopropanes with donor
and acceptor substituents in vicinal position) have recently
received considerable attention in contemporary organic
synthesis as sources of 1,3-dipoles that are generated from
them on treatment with Lewis acids.3 The capability of donor−
acceptor cyclopropanes to undergo [2 + 3]-, [3 + 3]-, and [3 +
4]-dipolar cycloaddition with various substrates4 is currently
used to build five-, six-, and seven-membered heterocycles.
These reactions can be performed enantioselectively,5 which
makes them very attractive for application in organic synthesis.
More than 20 full syntheses of natural compounds of various
classes based on donor−acceptor cyclopropanes have been
carried out to date.6
INTRODUCTION
■
The 2-oxabicyclo[3.3.0]octane fragment occurs in the struc-
tures of more than 80 natural compounds belonging to various
groups and having a broad range of biological activity, such as
antibacterial, antifungal, antifeedant, and immunosuppressant
activity.1 To date, compounds with this fragment were isolated
from various natural sources (Figure 1). The existing synthetic
Figure 1. Examples of natural compounds with biological activity
incorporating the 2-oxabicyclo[3.3.0]octane fragment.
Received: April 9, 2012
© XXXX American Chemical Society
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Scheme 1. Known Pathways of Dimerization of DA Cyclopropanes
It was shown recently7,8 that, in the absence of unsaturated
substrates or other compounds that trap the 1,3-dipoles being
generated, donor−acceptor (DA) cyclopropanes themselves
can undergo dimerization on treatment with Lewis acids;
depending on the conditions and the nature of the aryl
substituent, the reactions can give compounds of various
classes. In fact, dimerization of 2-arylcyclopropanedicarbox-
ylates 1 in the presence of 120 mol % of ZnCl2 or BF3·Et2O in
dichloromethane gave linear tetraesters 2 as the major products.
Reactions of the same DA compounds in the presence of SnCl4
in nitromethane gave cyclohexane-1,1,4,4-tetracarboxylates 3 in
up to 80% yields.8b Treatment of 2-arylcyclopropanedicarbox-
ylates 1, which are not substituted at the ortho-position, with an
equimolar amount of SnCl4 in a low-polar solvent or in the
presence of 10 mol % Sn(OTf)3 in nitromethane gave dimers
with electrophilic substitution in the aromatic ring, viz.
compounds 4 or 5, with yields up to 90%.8b Efficient formation
of tetralin derivative 4a also occurred on treatment of 2-
phenylcyclopropanedicarboxylate 1a with an equimolar amount
of the GaCl3 ·THF complex (20 °C, 12 h).7
option of dimerization of DA cyclopropanes, now involving the
ester group.
RESULTS AND DISCUSSION
■
1. Dimerization of Donor−Acceptor Cyclopropanes
into Substituted 2-Oxabicyclo[3.3.0]octanes. In all of the
conversions of DA cyclopropanes on treatment with Lewis
acids noted above, the formation of dimerization products
occurred exclusively due to the formation of new C−C bonds.
We have found that if a tetrasubstituted 1-pyrazoline derivative,
namely 3,5-dicarboxylate 9, is additionally used in this GaCl3-
promoted reaction, DA cyclopropanes undergo yet another
unusual conversion. As a result of this reaction, the CO
fragment of one of the ester groups is incorporated into the
cyclic system of the product to give polyfunctional 2-
oxabicyclo[3.3.0]octane 10. It was found that this process
only occurred under double-catalysis conditions, i.e., in the
presence of GaCl3 as the Lewis acid and 3,5-dicarboxylate 9 as
the organocatalyst, while no analogues of this process have
been found in the literature.
Heating of indole-containing cyclopropanedicarboxylates in
nitromethane in the presence of SnCl4 resulted in the coupling
of the electrophilic and nucleophilic centers of two activated
cyclopropane molecules followed by electrophilic ipso-attack to
give pentaleno[1,6-a,b]indole derivatives 6 as the major isolable
compounds.9 Unlike some other dimers of DA cyclopropanes,
this polycyclic structure was formed as a single diastereomer.
Yet another unusual direction of dimerization of DA
cyclopropanes independently discovered by two groups of
researchers7,8a involves their conversion to polysubstituted
cyclopentanes E,E- and E,Z-7 in yields higher than 70% on
treatment with 20 mol % of anhydrous GaCl3 in dichloro-
methane7 or with 5 mol % of Yb(OTf)3 in chlorobenzene
under reflux conditions8a (Scheme 1). In the case of the
reaction of methoxyphenyl-substituted cyclopropanes 1 in the
presence of Lewis acids (Sn(OTf)3, Yb(OTf)3, or MgI2) and
molecular sieves, linear dimers 8 were also identified8a in which
the C−C bond, like in diarylcyclopentanes 7, was formed
between carbon atoms of the same type bearing aryl
substituents. Thus, unique pathways of diverse dimerization
of DA cyclopropanes on treatment with Lewis acids have been
revealed using esters of 2-aryl(hetaryl)cyclopropanedicarboxylic
acids as an example. In this work, we have studied yet another
To optimize the conditions of this dimerization, we chose the
most popular DA cyclopropane 1a as well as anhydrous GaCl3
and pyrazoline 9a as catalysts (Table 1); the latter compound
was quantitatively obtained by 1,3-dipolar cycloaddition of alkyl
2-diazopropionates to methyl methacrylate (Scheme 2).11 To
some degree, this catalytic system was selected arbitrarily. The
fact is that, while studying the reactivity DA cyclopropanes
toward various pyrazolines in the presence of Lewis acids10a
and using 9a as a possible acceptor of 1,3-dipolar intermediates,
we observed the formation of a new compound 10a whose
structure represented a dimer of the original cyclopropane,
whereas no reaction products of 1a with pyrazoline 9a were
revealed.
Double catalysts, GaCl3 and 1-pyrazoline 9, should be
present in equal molar amounts; if the molar ratio changes in
any direction, the yield of 2-oxabicyclo[3.3.0]octane 10a
decreases considerably. The use of 20, 30, or 50 mol % of
GaCl3 and the same amounts of organocatalyst 9a almost do
not affect the yield of the target product if the yield is calculated
with respect to converted cyclopropane (brsm, based upon
recovered starting material); if the molar amount of the catalyst
is increased, conversion of 1a decreases and the absolute yield
of the products decreases as well (Table 1, entries 6, 8, and 10).
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higher if E-9a is used compared to the Z-isomer (Table 1,
entries 6 and 13). It is also possible to use a mixture of E- and
Z-isomers (entry 15) formed in the reaction, which makes it
unnecessary to isolate the E-isomer. Along with dimethyl ester
9a, mixed ester 9b can be used just as successfully (entries 6
and 14).
Table 1. Optimization of Reaction Conditions for the
Cyclodimerization Reaction of 1a into 2-
Oxabicyclo[3.3.0]octane 10a
Attempts to use tertiary amines, azobenzene, or other 1-
pyrazolines containing hydrogen atoms at the α-position to the
NN bond only resulted in changes in reaction pathway and
gave known compounds. In fact, the addition of GaCl3 to
cyclopropanedicarboxylate 1a and 1-pyrazoline 11 (Table 1,
entry 16) resulted in a very fast reaction and complete
involvement of the catalyst used10 without observable
formation of 2-oxabicyclooctane 10a.
Other Lewis acids, such as SnCl4, TiCl4, BF3·Et2O, EtAlCl2,
Sc(OTf)3, Yb(OTf)3, In(OTf)3, Ni(ClO4)2, Cu(OTf)2, and
Sn(OTf)2, even in combination with the same organocatalyst
9a, failed to give even traces of 2-oxabicyclo[3.3.0]octane 10a.
In some cases, the reaction progress was rather insignificant,
while in other cases, they followed known pathways without
involving the ester group of the starting cyclopropane 1a. Thus,
the formation of 2-oxabicyclooctane 10a was only observed if
the double catalyst, GaCl3 and 1-pyrazoline 9, was used (Table
1, entries 4−10 and 13−15).
The yield of 2-oxabicyclooctane 10a is also noticeably
restricted by its low stability in acidic media. The reaction
mixture kept at room temperature for 24 h no longer contained
any noticeable amount of the target compound; hence, the
reaction time should be as short as possible. Furthermore, in
order to isolate 2-oxabicyclooctanes successfully, we developed
a special procedure that involved cooling of the reaction
mixture below 0 °C, GaCl3 deactivation with excess
tetrahydrofuran due to complexation of GaCl3 with the oxygen
of THF molecule, solvent removal in vacuo, and immediate
isolation of the product by means of column chromatography
on silica gel. 2-Oxabicyclooctane 10a obtained in this manner
was found to be a stable compound that did not decompose on
storage in the air or on heating up to 150 °C. Furthermore,
chromatographic separation of the reaction mixture allows a
nearly complete recovery of organocatalyst 9, which can be
reused without degradation of catalytic properties; in some
cases, nonreacted cyclopropane 1 can be recovered as well.
Unlike the known dimers of DA cyclopropanes, e.g.,
compounds 4 and 7, substituted 2-oxabicyclo[3.3.0]octane
10a is formed stereospecifically as a single diastereomer. Its
structure and stereochemistry were determined by mass
a
Optimal time and temperature were defined by NMR monitoring of
b
the reaction in an NMR tube. Isolated yields (in parentheses, yields
based on recovered starting materials). Only dimer 7 was formed as a
single product; for more details, see ref 7. Only dimer 4 (Ar = Ph)
was formed as a single product; for more details, see ref 7. Only
products of addition of 1a to azobenzene were formed; for more
details, see ref 12. Yields determined by H NMR. Dimers 4 and 7
were formed as major products. Dimers 2, 4, and 7 were also formed
as minor products (yields 0−5% depending on conditions). Only the
product of addition of 1a to pyrazoline 11 was formed; for more
details, see ref 10.
c
d
e
f
g
1
h
i
Scheme 2. Synthesis of Tetrasubstituted 1-Pyrazolines 9 as
New Organocatalysts
1
spectrometry as well as H and 13C NMR 1D and 2D COSY,
TOCSY, NOESY, HSQC, and HMBC spectroscopy. The
NMR spectra contained two different isolated CH−CH2 spin
systems, signals of two nonsubstituted phenyl groups and of
four methoxy groups. According to 13C and HMBC NMR
spectra (Figure 2, a), the molecule retained only three CO2CH3
groups, whereas the fourth group went into the formation of
the cyclic system to give OCH3 and a ketal carbon atom with a
chemical shift of δC 118. Overall analysis of all interactions in
the HMBC spectrum allows it to be inferred unambiguously
that the structure of the product is a 2-oxabicyclo[3.3.0]octane
derivative.
However, decreasing the amount of the catalyst to 10 mol %
also results in a decrease in the yield of 2-oxabicyclo[3.3.0]-
octane 10a because of an increase in reaction time and
formation of a number of side products (entry 4). We believe
that the use of GaCl3 and pyrazoline 9 in the amount of 20 mol
% of each at a temperature near 30 °C provides the most
optimal conditions.
It turned out that only α,α′-tetrasubstituted 1-pyrazolines act
as organocatalysts. In this case, the isomeric composition of
pyrazolines 9 only slightly affects the yield of 2-oxabicyclooc-
tanes 10, though the yield of cyclodimer 10a is somewhat
The relative stereochemistry of compound 10a was
1
unambiguously determined using the 2D H NOESY NMR
spectroscopy (Figure 2, b). The observed cross-peaks between
the methoxy group at C(1) and the H(3) proton suggest the
transoid arrangement of the OCH3 and Ph groups at C(3).
C
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Other dimers similar to compounds 2, 4, and 7 (Scheme 1)
were also formed as side products;7,8 they were easily separated
during isolation of 2-oxabicyclooctanes by column chromatog-
raphy on silica gel. The amount of side products depended on
the reaction conditions and sometimes varied noticeably even
when the reaction was reproduced under apparently identical
conditions probably because of traces of water and other
microimpurities in the starting reagents.
Introduction of a nitro group in the phenyl ring (compound
1h) decreased its reactivity significantly (Table 2, entry 8), so
the reaction temperature had to be increased. However, under
these conditions, oxabicyclooctane 10h decomposed consid-
erably as soon as it was formed, and we were unable to isolate it
in pure form. Nevertheless, we succeeded in detecting
compound 10h in the reaction mixture when the reaction
was carried out in an NMR tube, based on characteristic signals
of two different CH−Ar fragments (the chemical shifts differ
only slightly from those of other compounds of this series,
while the coupling constants are exactly the same).
On the contrary, 2-(4-methoxyphenyl)cyclopropane-
dicarboxylate 1i was found to be more reactive than
cyclopropane 1a. In just a few minutes, the reaction carried
out at room temperature gave a mixture of compounds that
contained almost no original cyclopropane 1i, nor the desired
2-oxabicyclooctane 10i. However, by decreasing the temper-
ature to −20 °C, we succeeded in observing the formation of 2-
oxabicyclooctane 10i in ∼20% yield (Table 2, entry 9).
Tetramethyl 3a,4,6,7-tetrahydro-1H-cyclopenta[c]indene-
3,3,5,5-(2H,5aH)-tetracarboxylate 12 formed in ∼50% yield
(Scheme 3) and identical to the compound obtained
previously8b was the major reaction product.
Figure 2. (a) Selected interactions in 1H,13C-HMBC spectra of
compounds 10a used for confirmation of the ring system. (b) Key
cross-peaks in 2D H NOESY spectra of compounds 10a used for
1
determination of the configuration.
Interaction of both CH2 groups with each other and with the
H(3) and H(5) protons, as well as the cross-peaks between the
protons of the phenyl substituents, allowed us to assign all the
other stereocenters in the molecule.
After the optimal conditions for synthesizing 2-oxabicyclooc-
tane 10a were found, we synthesized 2-arylcyclopropane-1,1-
dicarboxylates 1b−j with various substituents in the aromatic
ring13 and studied whether they could be dimerized into
oxabicyclooctanes by treatment with GaCl3 and pyrazolines
E,Z-9b (Table 2). It was found that, in general, a methyl group
Table 2. Lewis Acid/Organocatalyzed Cyclodimerization of
Various Cyclopropanedicarboxylates into Substituted 2-
Oxabicyclo[3.3.0]octanes
The structure and stereochemistry of 2-oxabicyclooctane
1
10b−g,i were determined by H and 13C NMR 1D and 2D
COSY, TOCSY, NOESY, HSQC, and HMBC spectroscopy, as
for compound 10a. The signals of H(3), H2C(4), H(6), and
H2C(7) protons had the same coupling constants and similar
chemical shifts for the entire series of compounds; all
substituted 2-oxabicyclooctanes were individual stereoisomers,
just like compound 10a.
Dimethyl 2-(2-naphthyl)cyclopropanedicarboxylate (1j) was
also rather reactive; in this case, the yield of 2-oxabicyclooctane
10j (Table 2, entry 10) was comparable to that in the
dimerization of the phenyl analogue 1a or the para-substituted
phenylcyclopropanedicarboxylates 1d−g.
2. Mechanism of the Cyclodimerization of Donor−
Acceptor Cyclopropanes into Substituted 2-
Oxabicyclo[3.3.0]octanes. The cyclodimerization of
donor−acceptor cyclopropanes into 2-oxabicyclooctanes 10 is
a new and quite unusual process. Its distinctive features in
comparison with other reactions of DA cyclopropanes include
double catalysis involving a Lewis acid and an organocatalyst,
participation of the CO bond of the ester group, and the
stereospecificity of the transformations that occur. The latter
phenomenon is not so typical of Lewis acid-catalyzed reactions
of DA cyclopropanes:3 in fact, each of the cyclic dimers 3, 4,
and 7 is formed as a mixture of two diastereomers. In order to
identify the mechanism of formation of 2-oxabicyclooctanes 10,
we studied the intermediates formed in this reaction using
NMR spectroscopy on various nuclei.
a
a
temp,
time,
h
yield, %
b,c
entry reagent
Ar
°C
product (brsm, %)
1
2
1a
1b
1c
1d
1e
1f
Ph
30
30
1.5
3
10a
10b
10c
10d
10e
10f
10g
10h
10i
72 (90)
35 (72)
38 (75)
74 (92)
69 (86)
70 (88)
66 (82)
3-ClC6H4
3-BrC6H4
4-FC6H4
3
30
3
4
30
1
5
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
2-naphthyl
30
1
6
30
1
7
1g
1h
1i
30
1
d
8
80
1.5
1
<2
e
9
−20
30
20 (22)
65 (76)
10
1j
0.5
10j
a
The optimum time and temperature were defined by means of NMR
monitoring of the reaction in an NMR tube. Isolated yields (the
numbers in parentheses indicate the yields based on recovered original
materials). Dimers 2, 4, and 7 were also formed as minor products
(yields 0−5% depending on conditions); for more details, see refs 7
and 8. NMR yields in C6D5Cl: product 10h is unstable under the
reaction conditions and decomposes faster than it is formed; therefore,
we failed to isolate compound 10h. Compound 12 was formed as the
b
c
d
e
major product in a ∼50% yield; for more details, see ref 8b.
or halogen atoms (including the fluorine atom) at the meta and
para positions of the phenyl ring, as well as a 2-naphthyl
substituent, do not hinder the reaction to give 2-oxabicyclooc-
tanes 10b−g,j in quite acceptable yields (Table 2, entries 2−7
and 10). meta-Halosubstituted phenylcyclopropanedicarboxy-
lates 1b,c were found to be less reactive than 1a or para-
substituted phenylcyclopropanedicarboxylates 1d−g.
It was originally assumed that on treatment with GaCl3,
cyclopropanedicarboxylate 1 is converted to intermediate I,
which undergoes cyclization into methoxydihydrofuran 13 with
involvement of pyrazoline 93,7,14 and then into lactone 14.
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Scheme 3. Products of Cyclopropane 1i Dimerization
Scheme 4. Two Proposed Mechanisms of the Formation of 2-Oxabicyclooctanes 10
Theoretically, the resulting dihydrofuran 13 might add yet
another cyclopropanedicarboxylate molecule by 1,3-dipolar
cycloaddition (Scheme 4) to give compound 10. However,
this process is unlikely to occur, as additionally shown by
special experiments on generation of methoxydihydrofuran 13
followed by introduction of the latter into the reaction.
Furthermore, direct NMR observation of the formation of 2-
oxabicyclooctanes 10 under double-catalysis conditions did not
reveal even traces of compounds 13 or 14. Moreover, the latter
were not detected in the final reaction mixture, either,
suggesting that the 2-oxabicyclooctanes were formed by a
different mechanism.
The use of a mixture of E- and Z-isomers of pyrazoline 9b
was beneficial in comparison with individual isomer E-9a, since
in this case several isomers of complex II were formed (Figure
3) and, though the signals in NMR spectra became much more
As noted above, 1-pyrazoline 9 plays the key role in the
formation of oxabicyclooctanes 10. Monitoring of the reaction
by NMR allowed us to observe the GaCl3-catalyzed reaction of
1-pyrazoline 9 with a molecule of cyclopropanedicarboxylate
1a, in which the formation of intermediate II was detected. The
reaction took a few seconds after GaCl3 was added; i.e., it
occurred by several orders faster than the process as a whole.
After that, intermediate II slowly added one more molecule of
1a to give the end product 10a, whereas GaCl3 and the
pyrazoline were involved in a new cycle.
Figure 3. Isomers of intermediate II formed in the reaction mixture.
Bipolar intermediate II was found to be rather stable and
capable of persisting in a solution for several days even at room
temperature due to the rather strong shielding of the pyrazoline
fragment, which prevents reactions that occur in the case of
other pyrazolines.10 Nevertheless, we were unable to isolate
complex II in individual form due to its sensitivity to moisture;
nor we were able to obtain a solution of this intermediate in
pure form. If equimolar amounts of cyclopropane 1a,
pyrazoline 9, and gallium trichloride were used, a considerable
amount of oligomeric products was formed and the content of
complex II was rather low. Still, we succeeded in obtaining a
sufficient amount of this complex to be able to characterize it
by NMR spectroscopy on various nuclei in CD2Cl2 solution
using an excess of the starting cyclopropane and 50 mol % of
each GaCl3 and pyrazoline 9b.
complex, they gave unambiguous information about the
incorporation of pyrazoline into the complex. In particular,
the ratio of each pair of E- and Z-isomers in the complex
matched the stereoisomer ratio in the starting pyrazoline 9b
(∼3.5:1).
1
The H NMR spectrum of intermediate II (Figure 4, a)
contains characteristic signals of CHPh protons that are
observed as a set of triplets in low field at δ 6.1−6.5. Based
1
on the 2D H COSY spectrum (Figure 4, b), one can find the
counterparts for these signals, which together correspond to the
isolated CH−CH2 fragment. In the 13C NMR spectrum (Figure
4, c), the CHPh key fragment manifests itself as a broadened
signal representing a number of isomers with similar structures,
that has a chemical shift of about δ 100 matching its bonding
E
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Figure 4. NMR spectra (400 MHz) of intermediate II in the reaction mixture. Conditions: 1a (0.1 mmol), E,Z-9b (50 mol %), GaCl3 (50 mol %),
1
1
CD2Cl2 (0.5 mL), 20 °C: (a) H NMR spectrum, t ∼ 10 min; (b) H,1H−COSY, t 15−25 min; (c) 13C{1H} NMR spectrum, t 25−40 min; (d)
71Ga-NMR spectra of intermediate II (bottom) compared with pure GaCl3 in CD2Cl2 (top), t ∼ 12 min. The colors of the compounds correspond
to those in Scheme 5.
with a strong electron-withdrawing group, namely the NN+
III, IV). Under these conditions, complexes II and IV become
unstable and decompose with elimination of a 1-pyrazoline 9b
molecule; monomeric complex II was found to be much more
stable than dimeric complex IV which disappeared almost
instantly to give 2-oxabicyclooctane 10a (Figure 5, III). This
was unambiguously shown in a series of experiments: the
amount of compound 10a that was formed always matched the
amount of decomposed complex IV, whereas oxabicyclooctane
10a was not formed at all if IV was absent in the reaction
mixture. It should be noted that complex II is decomposed only
to a small extent over this period of time; the lifetime of this
complex in the presence of methanol is approximately 24 h.
Ultimately, it decomposes to give lactone 14 (Figure 5, IV;
Scheme 4).
fragment.
The 71Ga NMR spectra also change considerably (Figure 4,
d). Comparison of pure GaCl3, which exists as a dimer in
solution, to complex II shows a downfield shift of the signal to
δ 20; this is quite a typical shift corresponding to gallium
coordination with an oxygen atom.15 Furthermore, the signal in
the 71Ga NMR spectrum of intermediate II was unexpectedly
much narrower than that in the spectrum of GaCl3; hence, it
can be concluded that the surrounding of gallium is rather
symmetrical and the complex should be monomeric and
incorporate the majority of the gallium that is present in the
solution, while dynamic and exchange processes are totally
absent.
Experiments performed in an NMR tube under various
conditions allowed us to detect a number of intermediates and
the sequence of their transformations to the final product
(Figure 5). In fact, addition of GaCl3 to a solution of
cyclopropane 1a and pyrazoline 9b at a molar ratio of 0.8:1:0.5
immediately gives intermediate II and a number of other GaCl3
complexes with the original cyclopropane, which manifest
themselves as a broad multiplet at δH 6 in the spectrum (Figure
5, I). We cannot say exactly what complexes are these due to
lack of information. After 20−30 min, signals of another
intermediate appear in the reaction mixture. They correspond
to structures III or IV (Figure 5, II; Figure 4, b; Schemes 4 and
5) formed from intermediate II due to the addition of a second
cyclopropane molecule.
1H NMR spectra were obtained as a result of monitoring of
the reaction in NMR tube under optimal conditions to achieve
the maximum yield of 2-oxabicyclooctane 10a (pyrazoline 9b
and GaCl3 were used in catalytic amounts; see Figure 6 for
details).
It could be seen that the reaction starts actively at 30 °C and
full conversion requires about 1−1.5 h. The concentration of
intermediate IIa remains constant for the whole experiment
and does not decrease after its termination. Therefore, the real
conversion does not reach 100%. Formation of intermediate IIa
is a key and necessary step for the dimerization process.
For o-C6H4Cl and o-C6H4OCH3 2-substituted cyclopropanes
1, which do not produce the corresponding intermediate II
does, making the corresponding 2-oxabicyclooctanes 10 even in
trace amounts were not successful. It can be seen from the
NMR spectra that 1-pyrazoline 9b binds to the complex IIa not
After that, excess deuteromethanol was added to the reaction
mixture in order to decompose gallium complexes (Figure 5,
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Figure 5. Performing the reaction in an NMR tube for detection of the intermediates and the sequence of their formation (400 MHz). Conditions:
1a (0.13 mmol), E,Z-9b (50 mol %), GaCl3 (80 mol %), CD2Cl2 (0.5 mL), 15 °C. (I) t = 1 min; (II) t = 30 min; (III) t = 30 min, then addition of
CD3OD; (IV) CD3OD, 24 h (the solvent was replaced by CDCl3). Thin green arrows indicate the formation of intermediates and products. The
colors of the compounds correspond to those in Scheme 4.
a
Scheme 5. Possible Catalytic Cycle for Dimerization of Donor−Acceptor Cyclopropanes To Form 2-Oxabicyclooctanes
a
The colors correspond to the signals in the NMR spectra in Figures 4 and 5.
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Figure 6. Monitoring of the dimerization reaction of cyclopropane 1a with formation of 2-oxabicyclooctane 10a in NMR tube (400 MHz). Arrows
indicate the signals of the corresponding compounds. Conditions: 1a (0.25 mmol), E,Z-9b (25 mol %), GaCl3 (25 mol %), CD2Cl2 (0.6 mL), 30 °C.
(a) −10 °C (before GaCl3 was added); (b) 1 min, 0 °C; (c) 2 min, 30 °C; (d) 5 min, 30 °C; (e) 10 min, 30 °C; (f) 20 min, 30 °C; (g) 45 min, 30
°C. The colors of the compounds correspond to those in Scheme 5.
completely, a part of it is involved in another complexes and
another part of it is present in free form in the solution. Toward
the end of the reaction complex IVa (two triplets at 6.0 ppm) is
accumulated in the trace amounts, its concentration can be
notably increased if the reaction is carried out at lower
temperature (Figure 5, II).
All of the same patterns are observed for cyclopropanedi-
carboxylates with other aryl substituents (1b−j) as for the
phenyl-substituted derivative (1a), the mechanism of the
reaction and intermediates are analogous, and NMR spectra
for reaction mixtures are similar.
Thus, the NMR data on various nuclei were used to study
the detailed mechanism of the new reaction, i.e., dimerization of
cyclopropanedicarboxylates to give 2-oxabicyclo[3.3.0]octanes
10 under conditions of double catalysis with gallium trichloride
and 1-pyrazolines. The general mechanism of the trans-
formations observed is presented in Scheme 5.
The mechanism of this process involves two catalytic cycles
including the addition of a Lewis acid (GaCl3) and an
organocatalyst (1-pyrazoline). The main role of the Lewis acid
is to activate the cyclopropane ring by coordination to two
carboxylate groups (intermediate I), whereas the role of the
organocatalyst is to stabilize it by formation of a zwitterion
intermediate II. It was found that these functions could only be
performed by anhydrous GaCl3, on the one hand, and
pyrazolines of type 9, on the other hand.
requirements for such “protection” are very high: it should not
be bound too strongly (otherwise it would not be eliminated
when needed) or too weakly (otherwise it will be removed
prematurely). A compound used as the “protection” should not
give stable complexes with the donor−acceptor cyclopropane
and should have sufficiently bulky substituents to ensure high
stereoselectivity of the reaction.
First, cyclopropane 1 is opened into intermediate I under the
action of GaCl3, and a molecule of 1-pyrazoline 9 is added to I
to give the key intermediate II whose concentration is nearly
constant throughout the reaction. Both processes occur very
quickly. After that, intermediate II slowly adds the second
molecule of cyclopropanedicarboxylate 1 to give intermediates
III and IV, the latter of which is probably detected by NMR
spectroscopy (the key stage in the formation of the first ring).
At the last stage, intermediate IV undergoes SN2 intramolecular
1,5-cyclization with elimination of a 1-pyrazoline 9 molecule to
give the final compound 10. At this stage GaCl3 and the
organocatalyst are regenerated and re-enter the reaction. The
two last stages occur rather slowly and affect the overall process
rate. Since each of 2-oxabicyclooctanes 10 is formed as a single
isomer, it may be assumed that a particular configuration of
substituents is due to the possibility of “folding” of
intermediates II and III, which results in proximity of the
pyrazoline and malonic fragments due to electrostatic
interaction and stereospecific formation of two new C−C
bonds and a C−O bond.
According to spectral data, 1-pyrazoline 9 is not directly
attached to the Lewis acid but plays the role of temporary
protection of the carbocationic center in the catalytic cycle. The
As noted above, intermediate II proves to be unstable to
action of electrophiles, in whose presence it degrades in two
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pathways (Scheme 6). Diluted hydrochloric acid fully
decomposes intermediate II within several minutes eliminating
a stable gallium complex. In the process a molecule of original
cyclopropanedicarboxylate 1 is formed. Namely, intermediate II
decomposes into two initial components from which it formed,
and gallium moves into aqueous phase. This decomposition
route allows us to recover a part of cyclopropane 1 and all
organocatalyst 9 during dimerization reaction.
Scheme 6. Two Pathways of the Decomposition of
Intermediate II
Another decomposition route of compound II occurs in the
presence of methanol (Scheme 6, route b). The decomposition
rate in this case is much lower and the other product is
obtained. Intramolecular O-alkylation of gallium enolate release
dihydrofuran 13 which upon hydrolysis lead to lactone 14. It
should be noted that under the conditions of 2-oxabicyclooc-
tanes 10 synthesis during cyclopropane dimerization these
pathways of intermediate II decomposition are not affected; in
particular even traces of compounds 13 and 14 are not
observed.
a molecule of starting 1-pyrazoline 9 as a result of SN2
substitution by the attack of malonyl carbon atom at CHN
fragment (Scheme 6, route a). Apparently, 1-pyrazoline 9 is a
good leaving group. The role of electrophile is likely to destruct
3. Possible Elucidations of Stereochemistry of the
Dimerization Reaction of Donor−Acceptor Cyclopro-
Scheme 7. Elucidation of the Stereochemistry of the Dimerization Process According to the Mechanism in Scheme 5
I
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panes into 2-Oxabicyclo[3.3.0]octanes Using a Pro-
posed Mechanism. Using suggested mechanism of the
dimerization process we were able to predict and explain the
stereochemistry of formed 2-oxabicyclooctanes 10 (Scheme 7).
Intermediate II is a zwitterion in a noncoordinating solvent
such as CH2Cl2, where charges are greatly separated from each
other. Because of the absence of counterions (external
equalizers of the charge), it is favorable for intermediate II to
fold so that positive and negative charges approximated and
compensated each other (structure II′). As a result of this
fragment, 1-pyrazoline is found over the plain of the malonyl
anion, which completely blocks the approach of the second
molecule of donor−acceptor cyclopropane from one side
(structure II′′ and II′′′). It can be considered that the second
molecule of cyclopropane adds in two stages: initially it is
coordinated as a ligand by the ester group on Ga-atom in the
complex II′(intermediate II′′) due to which σ-bond of
cyclopropane ring is activated to form an electrophilic center
(intermediates II′′′ and II′′′′). Aryl substituent in the
intermediate II′′ has less sterically hindered position due to
rotation around C−C bond: the reaction proceeds via more
favorable intermediate II′′′, while less favorable II′′′′ has no time
to react (this stage is slow). As a result of addition of second
molecule of cyclopropane intermediate III is initially formed, in
which two from four stereocenters were already created
stereospecifically.
Intermediate III (as II) is also a zwitterion with well-
separated charges, and likewise, it folds with strong closing of
charged pyrazoline and malonyl fragments for charge
compensation. The resulting complex III′ undergoes intra-
molecular nucleophilic attack by malonyl fragment on carbonyl
group. In this intermediate one of the two ester groups comes
within short distance of the aryl substituent located in between,
which results in full blockade of the attack at this ester group.
As a result the nucleophilic attack of malonyl anion proceeds
only on one ester group. Thus the third stereocenter is formed.
Now we consider the formation of the fourth stereocenter.
Theoretically, formation of two isomeric cyclopentanes IV′ and
IV′′ on carbon atom which was a part of the carbonyl group is
possible. But in contrast to IV′ cyclopentane IV′′ cannot further
undergo intramolecular cyclization because nucleophilic oxygen
is directed to the opposite side of pyrazoline fragment. Because
only one isomer of oxabicyclooctane 10 is formed in rather
high yield, it could be presumed that intermediates IV′ and IV′′
are in equilibrium and ultimately they transform into 10. After
SN2 process inversion of the configuration of one stereocenters
takes place, the final product 10 is obtained as a single
stereoisomer.
EXPERIMENTAL SECTION
■
General Experimental Details. All reagents and solvents used
were commercial grade chemicals without additional purification. All
operations with GaCl3 were carried out under dry argon atmosphere.
TLC analysis was performed on Silufol chromatographic plates. For
preparative chromatography, silica gel 60 (0.040−0.063 mm) was
1
used. H and 13C NMR spectra were recorded on a 400 MHz (400.1
and 100.6 MHz, respectively) and 300 MHz (300.1 and 75.5 MHz,
respectively) spectrometers in CDCl3 containing 0.05% Me4Si as the
1
internal standard. Assignments of H and 13C signals were made with
the aid of 2D COSY, NOESY, HSQC, and HMBC spectra where
necessary. 35Cl, 69Ga, and 71Ga NMR spectra were recorded on a 400
MHz spectrometer (39.2, 96.0, and 122.0 MHz, respectively);
standards, NaCl and Ga(NO3)3 solutions in water, respectively. 19F
NMR spectra were recorded on a 300 MHz spectrometer (282.4
MHz); standard, CFCl3. Monitoring of the reactions in NMR tube
were made in CD2Cl2 solution containing 0.05% Me4Si as the internal
standart. IR spectra were obtained on a FT-IR spectrometer in CHCl3
solution (1%). Mass spectra were recorded using electron impact
ionization (EI, 70 eV, direct inlet probe). High-resolution mass spectra
were obtained using simultaneous electospray (ESI). The elemental
compositions were determined on a CHN alalyzer instrument.
General Procedure for the Synthesis of Cyclopropanes 1a−j.
The solution of aromatic aldehyde (0.1 mol), dimethyl malonate (13.2
g, 0.1 mol), piperidine (0.85 g, 0.01 mol), and acetic acid (1.2 g, 0.02
mol) in 40 mL of C6H6 was refluxed with a Dean−Stark attachment
for 3 h until no water was extracted. The reaction mixture was washed
with HCl (5% in water, 3 × 20 mL) and NaHCO3 (5% in water, 3 ×
20 mL). The organic layer was dried over Na2SO4, and the solvent was
removed in vacuo. The pure arylidenemalonate was prepared as a thick
slightly colored oil in quantity yields, which crystallized on standing.
The melting point and spectroscopic data correspond to described in
the literature.13 The obtained arylidenemalonates were used in the
next step without additional purification.
To a stirred suspension of NaH (0.39 g, 16.1 mmol) in dry DMSO
(15 mL) under argon atmosphere was added trimethylsulfoxonium
iodide (3.60 g, 15.4 mmol) under the same conditions. Then a
solution of arylidenemalonate (14 mmol) in dry DMSO (6 mL) was
added in a single portion. The resulted mixture was stirred at room
temperature, poured into H2O−ice (50 g), and extracted with diethyl
ether (3 × 30 mL). The combined organic layers were washed with
water (3 × 40 mL), dried over MgSO4, and concentrated in vacuo to
give the pure cyclopropanes 1 in good yields.
Dimethyl 2-(3-chlorophenyl)cyclopropane-1,1-dicarboxy-
late (1b): yield 3.0 g, 80%; colorless oil; IR (CHCl3) ν 3020, 2955,
2903, 2849, 1727 br (OCO), 1642, 1599, 1572, 1516, 1479, 1439,
1
1368, 1336, 1286, 1224 cm−1; H NMR (CDCl3, 400.1 MHz) δ 1.74
3
2
3
(dd, 1H, CH2, J = 9.2 Hz, J = 5.3 Hz), 2.15 (dd, 1H, CH2, J = 8.0
2
3
Hz, J = 5.3 Hz), 3.18 (dd, 1H, CH, J = 9.2 and 8.0 Hz), 3.42 and
3.79 (both s, 2 × 3H, 2OCH3), 7.07 (m, 1H, C6H4), 7.20 (m, 3H,
C6H4); 13C NMR (CDCl3, 100.6 MHz) δ 19.1 (CH2(3)), 31.8
(CH(2)), 37.2 (C(1)), 52.3 and 52.9 (2OCH3), 126.7 (CH(4′)),
127.7 (CH(6′)), 128.8 (CH(2′)), 129.4 (CH(5′)), 134.1 (C(3′)),
136.9 (C(1′)), 166.7 and 169.9 (2COO); MS (m/z) 270 (2) and 268
(9) (M+), 238 (3) and 336 (9) (M+ − CH3OH), 210 (6) and 208
(18) (M+ − HCO2CH3), 165 (8), 155 (66), 149 (49), 129 (36), 115
(57), 103 (12), 89 (19), 75 (16), 59 (100), 39 (20); HRMS (ESI)
calcd for C13H1335ClO4 M + H 269.0575, M + Na 291.0395, M + K
307.0134, found m/z 269.0579, 291.0391, 307.0138.
CONCLUSION
■
A new dimerization pathway of donor−acceptor cyclopropanes
(2-arylcyclopropanedicarboxylates) into 2-oxabicyclo[3.3.0]-
octanes has been revealed. It occurs under conditions of
double catalysis with a Lewis acid (GaCl3) and an organo-
catalyst (α,α′-tetrasubstituted 1-pyrazolines). In this process,
donor−acceptor cyclopropanes demonstrate a new type of
reactivity; unlike the other known dimerizations of DA
cyclopropanes, it involves the CO bond of the ester group.
The reaction is accompanied by the formation of two new rings
and four stereocenters with exceptional stereoselectivity. The
dimerization products, i.e., 2-oxabicyclooctanes, may be of
interest as biologically active compounds or as synthetic blocks.
General Procedure for the Synthesis of Pyrazolines 9a,b.
The solution of methyl or ethyl diazopropionate (10 mmol)11 and
methyl methacrylate (25 mmol) in 10 mL of CH2Cl2 was stirred at
room temperature for 24 h to complete decoloration. The solvent was
removed in vacuo to give the pure pyrazoline 9 as a colorless oil
(mixture of diastereomers, E/Z ∼ 3.5:1) in ∼99% yield. The mixture
of diastereomers could be separated by column chromatography on
silica gel (benzene−EtOAc, 20:1) to give the pure products.
(E,Z)-3-Ethyl-5-methyl 4,5-dihydro-3,5-dimethyl-3H-pyra-
zole-3,5-dicarboxylate (9b). The pyrazoline 9b (mixture of
diastereomers, E/Z ∼ 3.5:1) was prepared from ethyl diazopropionate
J
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(1.28 g, 10 mmol) and methyl methacrylate (2.50 g, 25 mmol) as a
colorless oil: yield 2.25 g, 99%. Anal. Calcd for C10H16N2O4: C, 52.62;
H 7.06; N, 12.27. Found: C, 52.82; H, 7.20; N, 12.08. E-Isomer:
(CH2(4)), 52.2 (OCH3), 52.82, 52.85, and 52.87 (3CO2CH3), 65.7
(C(8)), 69.9 (C(5)), 82.0 (CH(4)), 118.0 (C(1)), 123.7, 125.7, 125.8,
127.2, 127.7, 128.1, 129.8, and 130.0 (8CH, 2C6H4), 134.6 (2CCl,
2C6H4), 141.0 and 142.0 (2 i-C, 2C6H4), 168.3, 168.4, and 172.1
(3COO); MS (m/z) 536 (2, M+ − H), 504 (3, M+ − CH3OH − H),
445 (59, M+ − OCH3 − CO2CH3), 366 (31), 334 (41), 314 (25), 267
(25), 207 (19), 191 (19), 138 (97), 113 (59), 71 (53), 59 (100), 43
(79), 29 (73); HRMS (ESI) calcd for C26H2635Cl2O8 M + Na
559.0897, found m/z 559.0891.
1
colorless oil. H NMR (CDCl3, 400.1 MHz) δ 1.30 (t, 3H, CH2CH3,
3J = 7.1 Hz), 1.66 (s, 6H, 2CH3), 2.01 (s, 2H, CH2(4)), 3.80 (s, 3H,
OCH3), 4.24 (q, 2H, CH2CH3, 3J = 7.1 Hz); 13C NMR (CDCl3, 100.6
MHz) δ 13.9 (CH2CH3), 22.6 (2CH3), 38.4 (CH2(4)), 52.9 (OCH3),
61.9 (CH2CH3), 97.87 and 97.95 (C(3) and C(5)), 170.3 and 170.9
1
(2COO). Z-Isomer: colorless oil; H NMR (CDCl3, 400.1 MHz) δ
1.27 (t, 3H, CH2CH3, 3J = 7.1 Hz), 1.715 and 1.723 (both s, 2 × 3H,
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(3-bromo-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10c).
The title compound was prepared according to the general procedure
as a single diastereomer in 118 mg yield (38%, 75% brsm). Compound
10c: colorless thick oil; IR (CHCl3) ν 3020, 2977, 2954, 2846, 1735 br
(OCO), 1596, 1569, 1517, 1478, 1435, 1360, 1332, 1252, 1223
2
2CH3), 1.32−2.77 (both d, 2 × 1H, CH2(4), J = 13.5), 3.76 (s, 3H,
OCH3), 4.20 (q, 2H, CH2CH3, 3J = 7.1 Hz); 13C NMR (CDCl3, 100.6
MHz) δ 15.2 (CH2CH3), 23.5 and 23.8 (2CH3), 38.8 (CH2(4)), 52.6
(OCH3), 61.8 (CH2CH3), 97.1 (C(3) and C(5)), 170.0 and 170.7
(2COO).
1
2
cm−1; H NMR (CDCl3, 400.1 MHz) δ 1.30 (dd, 1H, syn-H(4), J =
General Procedure for GaCl3/Pyrazoline-Catalyzed Dimeri-
zation Reaction of Donor−Acceptor Cyclopropanes into 2-
Oxabicyclo[3.3.0]octanes. All operations were performed under dry
argon atmosphere. A solution of cyclopropane 1 (1 mmol) and
pyrazoline 9 (0.2 mmol, 20 mol %) in 5 mL of dry dichloromethane
was cooled to −10 °C. Then the solid GaCl3 (0.2 mmol, 20 mol %)
was added in one portion at −10 °C under vigorous stirring, and
reaction mixture was heated to 30 °C and stirred for the time indicated
in Table 2. The reaction mixture was cooled to −10 °C, the cold
tetrahydrofuran (THF, 1 mL) was added for the destruction of gallium
complexes, and the solvent was evaporated under vacuum at −10 °C.
The residue was separated immediately by column chromatography on
silica gel (benzene−EtOAc, 20:1) to afford starting cyclopropane 1
(15−50% was recovered), oxabicyclooctane 10 (yields, see Table 2)
and starting pyrazoline 9 (∼96−99% was recovered). If necessary, the
resulting oxabicyclooctane 10 may be additionally purified by flash
chromatography on silica gel (hexane−acetone, 5:1) to give a pure
product.
3
2
3
13.0, J = 11.0 Hz), 2.41 (dd, 1H, anti-H(4), J = 13.0, J = 4.5 Hz),
2
3
2.54 (dd, 1H, anti-H(7), J = 13.6, J = 5.6 Hz), 2.89 (dd, 1H, syn-
2
3
H(7), J = 13.6, J = 14.3 Hz), 3.50 (s, 3H, OCH3), 3.81, 3.86, and
3.89 (all s, 3 × 3H, 3CO2CH3), 4.71 (dd, 1H, H(6), 3J = 14.3 and 5.6
Hz), 5.25 (dd, 1H, H(3), 3J = 11.0 and 4.5 Hz), 7.06 (m, 1H, H(6′)),
7.11 (m, 1H, H(5′)), 7.18 (m, 1H, H(6′′)), 7.19 (m, 1H, H(5′′)), 7.29
(m, 1H, H(2′)), 7.32 (m, 1H, H(4′)), 7.40 (m, 1H, H(4′′)), 7.41 (m,
1H, H(2′′)); 13C NMR (CDCl3, 100.6 MHz) δ 35.5 (CH2(7)), 42.9
(CH(6)), 43.1 (CH2(4)), 52.2 (OCH3), 52.82, 52.84, and 52.89
(3CO2CH3), 65.7 (C(8)), 69.9 (C(5)), 81.9 (CH(4)), 118.0 (C(1)),
122.7 and 122.8 (2CBr, 2C6H4), 124.1 (CH(6′′)), 126.2 (CH(6′)),
128.7 (CH(2′′)), 130.1 (CH(5′)), 130.2 (CH(5′′)), 130.3 (CH(4′)),
130.6 (CH(2′)), 131.0 (CH(4′′)), 141.3 and 142.2 (2 i-C, 2C6H4),
168.3, 168.4, and 172.1 (3COO); MS (m/z) 534 (3, M+ − OCH3 −
CO2CH3), 410 (3), 378 (3), 313 (8), 282 (8), 251 (7), 202 (11), 182
(100), 159 (13), 145 (42), 113 (38), 103 (14), 77 (9), 59 (90), 32
(29); HRMS (ESI) calcd for C26H2679Br2O8 M + Na 646.9887, found
m/z 646.9884.
(1R*,3S*,5S*,6S*)-Trimethyl 1-methoxy-3,6-diphenyl-2-
oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10a). The title
compound was prepared according to the general procedure as a
single diastereomer in 169 mg yield (72%, 90% brsm). Compound
10a: colorless thick oil; IR (CHCl3) ν 3055, 2987, 2955, 1735 br (C
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(4-fluoro-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10d).
The title compound was prepared according to the general procedure
as a single diastereomer in 186 mg yield (74%, 92% brsm). Compound
10d: colorless thick oil; IR (CHCl3) ν 3020, 2954, 1734 br (OCO),
1
O), 1603, 1550, 1495, 1436, 1423 cm−1; H NMR (CDCl3, 400.1
1
1608, 1513, 1458, 1436, 1332, 1284, 1252 cm−1; H NMR (CDCl3,
MHz) δ 1.39 (dd, 1H, syn-H(4), 2J = 13.1, 3J = 11.2 Hz), 2.37 (dd, 1H,
2
3
anti-H(4), 2J = 13.1, 3J = 4.5 Hz), 2.56 (dd, 1H, anti-H(7), 2J = 13.6, 3J
400.1 MHz) δ 1.31 (dd, 1H, syn-H(4), J = 13.0 Hz, J = 11.1 Hz),
2.32 (dd, 1H, anti-H(4), 2J = 13.0 Hz, 3J = 4.4 Hz), 2.52 (dd, 1H, anti-
H(7), 2J = 13.6 Hz, 3J = 5.6 Hz), 2.93 (dd, 1H, syn-H(7), 2J = 13.6 Hz,
3J = 14.3 Hz), 3.49 (s, 3H, OCH3), 3.804, 3.807, and 3.88 (all s, 3 ×
3H, 3CO2CH3), 4.70 (dd, 1H, H(6), 3J = 14.3 and 5.6 Hz), 5.24 (dd,
2
3
= 5.6 Hz), 2.99 (dd, 1H, syn-H(7), J = 13.6, J = 14.3 Hz), 3.50 (s,
3H, OCH3), 3.80, 3.82, and 3.89 (all s, 3 × 3H, 3CO2CH3), 4.74 (dd,
1H, H(6), 3J = 14.3 and 5.6 Hz), 5.26 (dd, 1H, H(3), 3J = 11.2 and 4.5
Hz), 7.14 (m, 2H, 2 o-CH, Ph at C(6)), 7.16 (m, 1H, p-CH, Ph at
C(6)), 7.22 (m, 2H, 2 m-CH, Ph at C(6)), 7.27 (m, 2H, 2 o-CH, Ph at
C(3)), 7.28 (m, 1H, p-CH, Ph at C(3)), 7.32 (m, 2H, 2 m-CH, Ph at
C(3)); 13C NMR (CDCl3, 100.6 MHz) δ 35.6 (CH2(7)), 43.2
(CH(6)), 43.4 (CH2(4)), 52.0 (OCH3), 52.6 and 52.7 (3CO2CH3, 1C
and 2C respectively), 65.9 (C(8)), 70.1 (C(5)), 82.9 (CH(4)), 118.0
(C(1)), 125.7 (2 o-CH, Ph at C(3)), 126.8 (p-CH, Ph at C(6)), 127.5
(2 o-CH, Ph at C(6)), 127.9 (p-CH, Ph at C(3)), 128.5 (2 m-CH, Ph
at C(6)), 128.6 (2 m-CH, Ph at C(3)), 139.0 (i-C, Ph at C(6)), 140.1
(i-C, Ph at C(3)), 168.5, 168.7, and 172.6 (3COO); HRMS (ESI)
calcd for C26H28O8 M + Na, 491.1676, 2M + Na 959.3461, found m/z
491.1672, 959.3444.
3
1H, H(3), J = 11.1 and 4.4 Hz), 6.92 (m, 2H, 2 m-CH, Ar at C(6),
3JHF = 8.7 Hz), 7.00 (m, 2H, 2 m-CH, Ar at C(3), 3JHF = 8.7 Hz), 7.12
(m, 2H, 2 o-CH, Ar at C(6), 4JHF = 5.4 Hz), 7.24 (m, 2H, 2 o-CH, Ar
4
at C(3), JHF = 5.4 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 35.9
(CH2(7)), 42.5 (CH(6)), 43.3 (CH2(4)), 52.1 (OCH3), 52.73 and
52.78 (3CO2CH3, 1C and 2C respectively), 65.7 (C(8)), 70.0 (C(5)),
2
82.3 (CH(4)), 115.3 (d, 2 m-CH, Ar at C(6), JCF = 21.1 Hz), 115.5
(d, 2 m-CH, Ar at C(3), 2JCF = 21.5 Hz), 117.9 (C(1)), 127.4 (d, 2 o-
3
3
CH, Ar at C(3), JCF = 8.1 Hz), 129.0 (d, 2 o-CH, Ar at C(6), JCF
=
7.8 Hz), 134.5 (d, i-C, Ar at C(6), 4JCF = 3.1 Hz), 135.8 (d, i-C, Ar at
C(3), JCF = 3.0 Hz), 161.9 (d, p-C, Ar at C(6), JCF = 245.6 Hz),
162.5 (d, p-C, Ar at C(3), JCF = 246.2 Hz), 168.4, 168.6, and 172.3
4
1
1
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(3-chloro-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10b).
The title compound was prepared according to the general procedure
as a single diastereomer in 95 mg yield (35%, 72% brsm). Compound
10b: colorless thick oil; IR (CHCl3) ν 3020, 2954, 2928, 2854, 1734 br
(OCO), 1598, 1573, 1518, 1478, 1458, 1435, 1367, 1332, 1251,
1223 cm−1; 1H NMR (CDCl3, 400.1 MHz) δ 1.30 (dd, 1H, syn-H(4),
(3COO); 19F NMR (CDCl3, 282.4 MHz) δ −116.6 (tt, 1F, 2JFH = 8.7
Hz, 3JFH = 5.4 Hz), −115.1 (tt, 1F, 2JFH = 8.7 Hz, 3JFH = 5.4 Hz); MS
(m/z) 413 (1), 318 (3), 282 (2), 269 (2), 259 (6), 251 (9), 241 (4),
220 (3), 191 (3), 159 (3), 145 (8), 139 (10), 133 (23), 122 (100), 113
(15), 109 (24), 96 (6), 83 (5), 69 (3), 59 (60), 45 (5), 32 (6); HRMS
(ESI) calcd for C26H26F2O8 M + Na, 527.1488 found m/z 527.1487.
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(4-chloro-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10e).
The title compound was prepared according to the general procedure
as a single diastereomer in 185 mg yield (69%, 86% brsm). Compound
10e: colorless thick oil; IR (CHCl3) ν 3020, 2977, 2955, 2926, 2899,
3
2
3
2J = 13.0, J = 11.1 Hz), 2.39 (dd, 1H, anti-H(4), J = 13.0, J = 4.5
2
3
Hz), 2.54 (dd, 1H, anti-H(7), J = 13.6, J = 5.6 Hz), 2.89 (dd, 1H,
syn-H(7), 2J = 13.6, 3J = 14.2 Hz), 3.49 (s, 3H, OCH3), 3.80, 3.85, and
3.88 (all s, 3 × 3H, 3CO2CH3), 4.71 (dd, 1H, H(6), 3J = 14.2 and 5.6
3
Hz), 5.24 (dd, 1H, H(3), J = 11.1 and 4.5 Hz), 7.01 (m, 1H, C6H4),
7.12 (m, 2H, C6H4), 7.16 (m, 2H, C6H4), 7.24 (m, 3H, C6H4); 13C
1734 br (OCO), 1522, 1495, 1436, 1419, 1249 cm−1; H NMR
1
NMR (CDCl3, 100.6 MHz) δ 35.5 (CH2(7)), 42.9 (CH(6)), 43.1
(CDCl3, 400.1 MHz) δ 1.28 (dd, 1H, syn-H(4), 2J = 13.0 Hz, 3J = 11.1
K
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz), 2.33 (dd, 1H, anti-H(4), 2J = 13.0 Hz, 3J = 4.5 Hz), 2.51 (dd, 1H,
anti-H(7), 2J = 13.6 Hz, 3J = 5.6 Hz), 2.90 (dd, 1H, syn-H(7), 2J = 13.6
Hz, 3J = 14.3 Hz), 3.49 (s, 3H, OCH3), 3.804, 3.810, and 3.87 (all s, 3
temperature under vigorous shaking. After that, the reaction mixture
was heated to 80 °C and was allowed to stand during 1.5 h without
rotation. The NMR spectra were recorded from the reaction mixture
3
1
× 3H, 3CO2CH3), 4.70 (dd, 1H, H(6), J = 14.3 and 5.6 Hz), 5.23
at regular time intervals. The compound 10h was observed in H
3
NMR spectra of the reaction mixture. Its yield did not exceed 2% and
its concentration was permanent during 1 h (because the rates of
formation and decomposition were similar), after that 10h completely
decomposed. Attempts to isolate the compound 10h were
unsuccessful due to its decomposition. 10h: part of 1H NMR
(dd, 1H, H(3), J = 11.1 and 4.5 Hz), 7.08 (m, 2H, C6H4), 7.19 (m,
2H, C6H4), 7.20 (m, 2H, C6H4), 7.29 (m, 2H, C6H4); 13C NMR
(CDCl3, 100.6 MHz) δ 35.6 (CH2(7)), 42.6 (CH(6)), 43.2 (CH2(4)),
52.1 (OCH3), 52.76, 52.79, and 52.82 (3CO2CH3), 65.7 (C(8)), 69.9
(C(5)), 82.2 (CH(4)), 117.9 (C(1)), 127.0, 128.7, 128.8, and 128.9
(8CH, 2C6H4), 132.9 and 133.8 (2 p-C, 2C6H4), 137.3 and 138.4 (2 i-
C, 2C6H4), 168.4, 168.5, and 172.2 (3COO); MS (m/z) 275 (1), 207
(3), 205 (3), 203 (3), 159 (3), 155 (6), 149 (10), 145 (8), 140 (36),
139 (19), 138 (100), 125 (12), 113 (21), 103 (11), 77 (8), 59 (92), 41
(11); HRMS (ESI) calcd for C26H2635Cl2O8 M + Na, 559.0897, found
m/z 559.0894.
3
(CDCl3, 400.1 MHz) δ 4.67 (dd, 1H, H(6), J ∼ 13 and 5 Hz), 5.59
3
(dd, 1H, H(3), J = 11 and 5 Hz). Other signals overlapped with
signals of the major compounds.
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(4-methoxy-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10i). A
solution of cyclopropane 1i (150 mg, 0.57 mmol) and pyrazoline 9b
(26 mg, 0.11 mmol, 20 mol %) in 3 mL of dry dichloromethane was
cooled to −40 °C. Then the solid GaCl3 (20 mg, 0.11 mmol, 20 mol
%) was added in one portion at −40 °C under vigorous stirring, and
the reaction mixture was heated to −20 °C and stirred for 1 h. After
that the cold tetrahydrofuran (0.7 mL) was added for the destruction
of gallium complexes and the solvent was evaporated under vacuum at
−20 °C. The residue was separated immediately by column
chromatography on silica gel (benzene−EtOAc, 20:1) to afford
starting cyclopropane 1i (15 mg, 10%), oxabicyclooctane 10i (30 mg,
20% (22% brsm)), compound 12 (75 mg, 50% (56% brsm)), and
starting pyrazoline 9b (25 mg, 97%). The resulting oxabicyclooctane
10i was additionally purified by flash chromatography on silica gel
(hexane−acetone, 5:1) to give a pure product. Compound 10i:
colorless thick oil; IR (CHCl3) ν 3020, 2976, 2956, 2936, 2900, 2841,
1731 br (OC−O), 1613, 1515, 1461, 1437, 1392, 1249, 1224 cm−1;
1H NMR (CDCl3, 400.1 MHz) δ 1.39 (dd, 1H, syn-H(4), 2J = 13.0 Hz,
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(4-bromo-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10f).
The title compound was prepared according to the general procedure
as a single diastereomer in 220 mg yield (70%, 88% brsm). Compound
10f: colorless thick oil; IR (CHCl3) ν 3020, 2954, 2846, 1734 br (O
CO), 1594, 1517, 1491, 1458, 1436, 1411, 1367, 1332, 1251, 1223
1
2
cm−1; H NMR (CDCl3, 400.1 MHz) δ 1.28 (dd, 1H, syn-H(4), J =
13.0 Hz, 3J = 11.1 Hz), 2.33 (dd, 1H, anti-H(4), 2J = 13.0 Hz, 3J = 4.5
Hz), 2.51 (dd, 1H, anti-H(7), 2J = 13.5 Hz, 3J = 5.6 Hz), 2.89 (dd, 1H,
2
3
syn-H(7), J = 13.5 Hz, J = 14.3 Hz), 3.48 (s, 3H, OCH3), 3.804,
3.810, and 3.87 (all s, 3 × 3H, 3CO2CH3), 4.69 (dd, 1H, H(6), J =
3
14.3 and 5.6 Hz), 5.22 (dd, 1H, H(3), 3J = 11.1 and 4.5 Hz), 7.02 (m,
2H, 2 o-CH, Ar at C(6)), 7.13 (m, 2H, 2 o-CH, Ar at C(3)), 7.35 (m,
2H, 2 m-CH, Ar at C(6)), 7.45 (m, 2H, 2 m-CH, Ar at C(3)); 13C
NMR (CDCl3, 100.6 MHz) δ 35.5 (CH2(7)), 42.7 (CH(6)), 43.2
(CH2(4)), 52.1 (OCH3), 52.76, 52.79, and 52.82 (3CO2CH3), 65.7
(C(8)), 69.9 (C(5)), 82.2 (CH(4)), 118.0 (C(1)), 121.0 (CBr, Ar at
C(6)), 121.9 (CBr, Ar at C(3)), 127.3 (2 o-CH, Ar at C(3)), 129.3 (2
o-CH, Ar at C(6)), 131.6 (2 m-CH, Ar at C(6)), 131.8 (2 m-CH, Ar at
C(3)), 137.8 (i-C, Ar at C(6)), 139.0 (i-C, Ar at C(3)), 168.3, 168.5,
and 172.2 (3COO); MS (m/z) 592 (1, M+ − CH3OH − H2), 534 (10,
M+ − OCH3 − CO2CH3), 412 (9), 378 (11), 313 (20), 282 (14), 251
(16), 201 (20), 184 (100), 145 (80), 113 (72), 77 (20), 59 (100), 32
(70); HRMS (ESI) calcd for C26H2679Br2O8 M + Na 646.9887, found
m/z 646.9877.
3J = 11.2 Hz), 2.30 (dd, 1H, anti-H(4), 2J = 13.0 Hz, 3J = 4.5 Hz), 2.50
(dd, 1H, anti-H(7), 2J = 13.6 Hz, 3J = 5.6 Hz), 2.95 (dd, 1H, syn-H(7),
2J = 13.6 Hz, 3J = 14.5 Hz), 3.48 (s, 3H, OCH3), 3.73 and 3.78 (both s,
2 × 3H, 2OCH3 from Ar), 3.79 and 3.87 (both s, 6H and 3H,
3
respectively, 3CO2CH3), 4.66 (dd, 1H, H(6), J = 14.5 and 5.6 Hz),
3
5.21 (dd, 1H, H(3), J = 11.2 and 4.5 Hz), 6.76 (m, 2H, 2 m-CH,
C6H4′), 6.85 (m, 2H, 2 m-CH, C6H4′′), 7.07 (m, 2H, 2 o-CH, C6H4′),
7.21 (m, 2H, 2 o-CH, C6H4″); 13C NMR (CDCl3, 100.6 MHz) δ 35.9
(CH2(7)), 42.5 (CH(6)), 43.4 (CH2(4)), 52.0 (OCH3), 52.6 and 52.7
(1C and 2C respectively, 3CO2CH3), 55.3 and 55.4 (2OCH3 from
Ar), 65.9 (C(8)), 70.1 (C(5)), 82.7 (CH(4)), 113.9 (2 m-CH, C6H4′),
114.0 (2 m-CH, C6H4′′), 117.8 (C(1)), 127.0 (2 o-CH, C6H4′′), 128.6
(2 o-CH, C6H4′), 131.0 and 132.3 (2 i-C, 2C6H4), 158.5 and 159.5 (2
p-C, 2C6H4), 168.6, 168.8, and 172.7 (3COO). MS (m/z, %): 331 (1),
303 (1), 291 (4), 279 (1), 265 (7), 250 (2), 234 (2), 225 (5), 203
(11), 190 (6), 173 (7), 164 (7), 151 (29), 145 (47), 135 (57), 134
(100), 121 (26), 91 (24), 77 (20), 59 (62); HRMS (ESI) calcd for
C28H32O10 M + Na, 551.1888, found m/z 551.1888.
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(4-methyl-
phenyl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10g).
The title compound was prepared according to the general procedure
as a single diastereomer in 164 mg yield (66%, 82% brsm). Compound
10g: colorless thick oil; IR (CHCl3) ν 3020, 2977, 2954, 2926, 1733 br
(OC−O), 1517, 1476, 1435, 1331, 1249, 1224 cm−1. 1H NMR
(CDCl3, 400.1 MHz) δ 1.38 (dd, 1H, syn-H(4), 2J = 13.1 Hz, 3J = 11.2
Hz), 2.25 (s, 3H, CH3, Ar at C(6)), 2.31 (s, 3H, CH3, Ar at C(3)),
2.33 (dd, 1H, anti-H(4), 2J = 13.1 Hz, 3J = 4.5 Hz), 2.52 (dd, 1H, anti-
H(7), 2J = 13.6 Hz, 3J = 5.6 Hz), 2.96 (dd, 1H, syn-H(7), 2J = 13.6 Hz,
3J = 14.3 Hz), 3.48 (s, 3H, OCH3), 3.794, 3.799, and 3.87 (all s, 3 ×
(1R*,3S*,5S*,6S*)-Trimethyl 1-Methoxy-3,6-bis(2-naphthyl)-
2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10j). The title
compound was prepared according to the general procedure as a single
diastereomer in 185 mg yield (65%, 76% brsm). Compound 10j:
colorless thick oil; IR (CHCl3) ν 3020, 2976, 2954, 2846, 1733 br
(OCO), 1633, 1602, 1510, 1436, 1392, 1337, 1328, 1252, 1223
3
3H, 3CO2CH3), 4.68 (dd, 1H, H(6), J = 14.3 and 5.6 Hz), 5.22 (dd,
1H, H(3), 3J = 11.2 and 4.5 Hz), 7.02 (s, 4H, 2 o-CH and 2 m-CH, Ar
at C(6)), 7.12 (m, 2H, 2 m-CH, Ar at C(3)), 7.17 (m, 2H, 2 o-CH, Ar
at C(3)); 13C NMR (CDCl3, 100.6 MHz) δ 21.0 (CH3, Ar at C(6)),
21.2 (CH3, Ar at C(3)), 35.7 (CH2(7)), 42.9 (CH(6)), 43.5
(CH2(4)), 52.0 (OCH3), 52.6 and 52.7 (3CO2CH3, 1C and 2C
respectively), 65.9 (C(8)), 70.1 (C(5)), 82.9 (CH(4)), 117.9 (C(1)),
125.7 (2 o-CH, Ar at C(3)), 127.4 (2 o-CH, Ar at C(6)), 129.1 (2 m-
CH, Ar at C(3)), 129.2 (2 m-CH, Ar at C(6)), 135.9 (i-C, Ar at C(6)),
136.4 (p-C, Ar at C(6)), 137.2 (i-C, Ar at C(3)), 137.6 (p-C, Ar at
C(3)), 168.6, 168.8, and 172.6 (3COO). MS (m/z) 405 (1), 347 (1),
255 (1), 187 (3), 185 (2), 159 (3), 145 (3), 136 (7), 129 (16), 118
(100), 105 (15), 91 (10), 59 (11); HRMS (ESI) calcd for C28H32O8 M
+ Na, 519.1989, found m/z 519.1979.
1
2
cm−1; H NMR (CDCl3, 400.1 MHz) δ 1.53 (dd, 1H, syn-H(4), J =
13.0 Hz, 3J = 11.2 Hz), 2.43 (dd, 1H, anti-H(4), 2J = 13.0 Hz, 3J = 4.5
Hz), 2.70 (dd, 1H, anti-H(7), 2J = 13.5 Hz, 3J = 5.5 Hz), 3.16 (dd, 1H,
syn-H(7), 2J = 13.5 Hz, 3J = 14.2 Hz), 3.56 (s, 3H, OCH3), 3.84, 3.88,
and 3.95 (all s, 3 × 3H, 3CO2CH3), 4.94 (dd, 1H, H(6), 3J = 14.2 and
3
5.5 Hz), 5.46 (dd, 1H, H(3), J = 11.2 and 4.5 Hz), 7.26 (dd, 1H,
CH(3′′), 3J = 8.6 Hz, 4J = 1.7 Hz), 7.35−7.47 (m, 5H, CH(3′), CH(6′),
CH(7′), CH(6′′) and CH(7′′)), 7.62 (br.s, 1H, CH(1′′)), 7.67 (d, 1H,
3
CH(4′′), J = 8.6 Hz), 7.69−7.81 (m, 6H, CH(1′), CH(4′), CH(5′),
CH(8′), CH(5′′) and CH(8′′)); 13C NMR (CDCl3, 100.6 MHz) δ 35.8
(CH2(7)), 43.1 (CH2(4)), 43.4 (CH(6)), 52.1 (OCH3), 52.73 and
52.78 (3CO2CH3, 1C and 2C respectively), 66.0 (C(8)), 70.1 (C(5)),
83.0 (CH(4)), 118.2 (C(1)), 123.5 (CH(3′)), 124.5 (CH(1′)), 125.78,
125.85, 126.01, 126.10, 126.15, and 126.25 (CH(1′′), CH(3′′), CH(6′),
CH(7′), CH(6′′) and CH(7′′)), 127.5, 127.7, 127.9, 128.0, 128.1, and
(1R*,3S*,5S*,6S*)-Trimethyl 1-methoxy-3,6-bis(4-nitrophen-
yl)-2-oxabicyclo[3.3.0]octane-5,8,8-tricarboxylate (10h). The
reaction was performed in an NMR tube. To a solution of
cyclopropane 1 (0.2 mmol) and pyrazoline 9 in 0.5 mL of dry
C6D5Cl was added the solid GaCl3 in one portion at room
L
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX

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128.4 (CH(4′), CH(4′′), CH(5′), CH(8′), CH(5′′) and CH(8′′)),
132.4 (C(4a′′)), 133.15, 133.22, and 133.31 (C(4a′), C(8a′) and
C(8a′′)), 136.6 (C(2′′)), 137.4 (C(2′)), 168.6, 168.8, and 172.6
(3COO); MS (m/z): 535 (5, M+ − CH3OH − H), 477 (1), 428 (5),
382 (11), 368 (15), 350 (7), 336 (12), 322 (8), 308 (9), 291 (8), 277
(32), 249 (15), 223 (18), 165 (52), 154 (100), 141 (23), 128 (16),
113 (14), 59 (67), 32 (31); HRMS (ESI) calcd for C34H32O8 M + Na
591.1989, found m/z 591.1990.
Kanematsu, Y. Chem. Pharm. Bull. 1965, 13, 687. (c) Nohara, T.;
Miyahara, K.; Kawasaki, T. Chem. Pharm. Bull. 1974, 22, 1772.
(d) Talapatra, S. K.; Bhaumik, A.; Talapatra, B. Phytochemistry 1992,
31, 2431. (e) Cool, L. G.; Kim, Y.-K.; Zavarin, E.; Ball, G. E.
Phytochemistry 1994, 36, 1283. (f) Tchuendem, M.-H. K.; Ayafor, F. J.;
Connolly, J. D.; Sterner, O. Tetrahedron Lett. 1998, 39, 719.
(g) Fujimoto, H.; Nakamura, E.; Okuyama, E.; Ishibashi, M. Chem.
Pharm. Bull. 2000, 48, 1436. (h) Schuehly, W.; Heilmann, J.; Calis, I.;
Sticher, O. Helv. Chim. Acta 2000, 83, 1509. (i) Khuong-Huu, Q.;
Chiaroni, A.; Riche, C.; Nguyen-Ngoc, H.; Nguyen-Viet, K.; Khuong-
Huu, F. J. Nat. Comp. 2000, 63, 1015. (j) Zhang, H.; Odeku, O. A.;
Wang, X.-N.; Yue, J.-M. Phytochemistry 2008, 69, 271. (k) Nihei, K.-I.;
Asaka, Y.; Mine, Y.; Yamada, Y.; Iigo, M.; Yanagisawa, T.; Kubo, I. J.
Nat. Comp. 2006, 69, 975.
(2) (a) Zhong, W.; Xie, J.; Peng, X.; Kawamura, T.; Nemoto, H.
Tetrahedron Lett. 2005, 46, 7451. (b) Lee, J. S.; Cao, H.; Fuchs, P. L. J.
Org. Chem. 2007, 72, 5820. (c) Nicolaou, K. C.; Sasmal, P. K.;
Roecker, A. J.; Sun, X.-W.; Mandal, S.; Converso, A. Angew. Chem., Int.
Ed. 2005, 44, 3443. (d) Ishihara, J.; Nonaka, R.; Terasawa, Y.; Shiraki,
R.; Yabu, K.; Kataoka, H.; Ochiai, Y.; Tadano, K. J. Org, Chem. 1998,
63, 2679. (e) Posner, G. H.; Hatcher, M. A.; Maio, W. A. Org. Lett.
2005, 7, 4301. (f) Quan, W.; Yu, B.; Zhang, J.; Liang, Q.; She, X.; Pan,
X. Tetrahedron 2007, 63, 9991. (g) Morzycki, J. W.; Perez-Diaz, J. O.
H.; Santillan, R.; Wojtkielewicz, A. Steroids 2010, 75, 70.
Monitoring of the Reaction in an NMR Tube. All operations
were performed under dry argon atmosphere in an NMR tube. A
solution of cyclopropane 1 (0.2 mmol) and pyrazoline 9 in 0.5 mL of
dry CD2Cl2 was cooled to −30 °C. Then the solid GaCl3 was added in
one portion at temperature under vigorous shaking, the NMR tube
was placed in NMR spectrometer, reaction mixture was gradually
heated to a target temperature and was standing for a necessary time
without rotation. The NMR spectra were recorded from the reaction
mixture at regular time intervals. If it was necessary the 0.1−0.2 mL
CD3OD was added to a NMR tube for the destruction of gallium
complexes. Spectroscopic data of intermediate IIa. Red solution in
CD2Cl2 (mixture of eight regio- and stereoisomers, ratio
∼1:1:1:1:3.5:3.5:3.5:3.5): 1H NMR (CD2Cl2, 400.1 MHz) δ 1.20−
1.45 (all t, 54H, 8 × CH2CH3, 3J = 7.1−7.2 Hz), 1.60−1.80 (all s, 54H,
8 × CH3 at C(3)), 1.95−2.05 (all s, 54H, 8 × CH3 at C(5)), 2.10−
2.25 (all s, 28H, E-isomer, 4 × CH2(4)), 2.70−2.95 (all d, 8H, Z-
isomer, 4 × CH2(4)), 2.80−3.05 (m, 36H, 8 × CH2(2′), 3J = 7.4, 6.4,
6.3 Hz), 3.35−4.05 (all s, 162H, 24OCH3), 4.30−4.55 (all q, 36H, 8 ×
CH2CH3, 3J = 7.1−7.2 Hz), 6.18 (2 × t, 2H, Z-isomer, 2 × H(1′), 3J =
6.3 Hz), 6.25 (4 × t, 14H, E-isomer, 4 × H(1′), 3J = 6.4 Hz), 6.39 (2 ×
(3) For reviews of donor−acceptor cyclopropanes, 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, 20, 3353. (d) Campbell, M. J.; Johnson, J. S.; Parsons, A. T.;
Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. 2010, 75, 6317.
(e) Mel’nikov, M. Ya.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V.
Mendeleev Commun. 2011, 21, 293.
3
t, 2H, Z-isomer, 2 × H(1′), J = 7.4 Hz), 7.15−7.60 (m, 90H, 8Ph);
13C NMR (CD2Cl2, 100.6 MHz, all signals are broad) δ 15.3
(CH2CH3), 24.0 and 24.3 (CH3 at C(3)), 25.1 (CH3 at C(5)), 40.5
and 43.0 (CH2(4) and CH2(2′)), 52−56 (OCH3), 64.0 (CH2CH3),
C(3) − overlapped with other signals, 93.0 (C(5)), 99.0 (CH(1′)),
109.0 (C(3′)), 127−133 (CH, Ph), 139.5 (i-C, Ph), 154.9 (C(4′)),
169−173 (COO), 176.0 (COO); 35Cl NMR (CD2Cl2, 39.2 MHz) δ
235 (br s, W1/2 ∼ 7800 Hz); 69Ga NMR (CD2Cl2, 96.0 MHz) δ 251
(s, W1/2 ∼ 750 Hz); 71Ga NMR (CD2Cl2, 122.0 MHz) δ 250.5 (s,
W1/2 ∼ 350 Hz).
(4) For some examples of the reactions of donor−acceptor
cyclopropanes, see: With alkenes: (a) Beal, R. B.; Dombroski, M. A.;
Snider, B. B. J. Org. Chem. 1986, 51, 4391. (b) Shimada, S.;
Hashimoto, Y.; Sudo, A.; Hasegawa, M.; Saigo, K. J. Org. Chem. 1992,
57, 7126. With allenes: (c) Yadav, V. K.; Sriramurthy, V. Org. Lett.
2004, 6, 4495. With acetylenes: (d) Yadav, V. K.; Sriramurthy, V.
Angew. Chem. 2004, 116, 2723. With aldehydes: (e) Pohlhaus, P. D.;
Johnson, J. S. J. Org. Chem. 2005, 70, 1057. (f) Min, S.; Yang, Y. H.;
Bo, X Tetrahedron 2005, 61, 1893. (g) Bernard, A. M.; Frongia, A.;
Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2005, 7, 4565. With
isocyanates: (h) Graziano, M. L.; Iesce, M. R. J. Chem. Res. 1987, 362.
With imines: (i) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70,
8242. (j) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313.
(k) Saigo, K.; Shimada, S.; Hasegawa, M. Chem. Lett. 1990, 905. With
diazenes: (l) Graziano, M. L.; Iesce, M. R.; Cermola, F. J. Chem. Res.
1996, 82. With nitriles: (m) Yu, M.; Lynch, V.; Pagenkopf, B. L. Org.
Lett. 2001, 3, 2563. (n) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc.
2003, 125, 8122. With α,β-unsaturated ketones: (o) Liu, L.;
Montgomery, J. J. Org. Lett. 2007, 9, 3885. With azomethinimines:
(p) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org.
Lett. 2008, 10, 689. With nitrones: (q) Cardona, F.; Goti, A. Angew.
Chem. 2005, 117, 8042. (r) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P. J. Am.
Chem. Soc. 2005, 127, 5764. (s) Ganton, M. D.; Kerr, M. A. J. Org.
Chem. 2004, 69, 8554. With dienes: (t) Ivanova, O. A.; Budynina, E.
M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int.
Ed. 2008, 47, 1107. (u) Ivanova, O. A.; Budynina, E. M.; Grishin, Y.
K.; Trushkov, I. V.; Verteletskii, P. V. Eur. J. Org. Chem. 2008, 5329.
(5) For some examples of the enantioselective reactions of donor−
acceptor cyclopropanes, see: (a) Parsons, A. T.; Johnson, J. S. J. Am.
Chem. Soc. 2009, 131, 3122. (b) Yu, M.; Pagenkopf, B. L. J. Am. Chem.
Soc. 2003, 125, 8122. (c) Kang, Y. B.; Sun, X. L.; Tang, Y. Angew.
Chem., Int. Ed. 2007, 46, 3918.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel/Fax: +7 499 135 6390. E-mail: tom@ioc.ac.ru.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was financially supported by the Russian Federation
President Council for Grants (Program for the State Support of
Leading Scientific Schools of RF, Grant NSh-604.2012.3) and
by the Division of Chemistry, Materials Science of the Russian
Academy of Sciences (Programme for Basic Research
“Theoretical and Experimental Study of the Nature of Chemical
Bond and Mechanisms of the Most Important Reactions and
Processes”) and the Program “Molecular and cell Biology” of
Presidium of Russian Academy of Sciences.
(6) For some examples of the synthesis of natural compounds using
donor−acceptor cyclopropanes, see: (a) Snider, B. B.; Ahn, Y.;
O’Hare, S. M. Org. Lett. 2001, 3, 4217. (b) Fuerst, D. E.; Stoltz, B. M.;
Wood, J. L. Org. Lett. 2000, 2, 3521. (c) Fischer, C.; Meyers, C.;
Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175. (d) Leduc, A. B.;
Kerr, M. A. Angew. Chem., Int. Ed. 2008, 47, 7945. (e) Carson, C. A.;
REFERENCES
■
(1) For some examples of natural compounds with biological activity
incorporating the 2-oxabicyclo[3.3.0]octane fragment, see: (a) Mudur,
S. V.; Swenson, D. C.; Gloer, J. B.; Campbell, J.; Shearer, C. A. Org.
Lett. 2006, 8, 3191. (b) Takeda, K.; Komeno, T.; Tokutake, N.;
M
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Kerr, M. A. Org. Lett. 2009, 11, 777. (f) Morales, C. L.; Pagenkopf, B.
L. Org. Lett. 2008, 10, 157. (g) Carson, C. A.; Kerr, M. A. Angew.
Chem., Int. Ed. 2006, 45, 6560. (h) Young, I. S.; Williams, J. L.; Kerr,
M. A. Org. Lett. 2005, 7, 953. (i) Young, I. S.; Kerr, M. A. J. Am. Chem.
Soc. 2007, 129, 1465.
(7) Novikov, R. A.; Korolev, V. A.; Timofeev, V. P.; Tomilov, Yu. V.
Tetrahedron Lett. 2011, 52, 4996.
(8) (a) Chagarovskiy, A. O.; Ivanova, O. A.; Budynina, E. M.;
Trushkov, I. V.; Melnikov, M. Ya. Tetrahedron Lett. 2011, 52, 4421.
(b) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Trushkov, I.
V.; Melnikov, M. Ya. J. Org. Chem. 2011, 76, 8852.
(9) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.;
Rakhmankulov, E. R.; Trushkov, I. V.; Semeykin, A. V.;
Shimanovskii, N. L.; Melnikov, M. Ya. Chem.Eur. J. 2011, 17, 11738.
(10) (a) Tomilov, Yu. V.; Novikov, R. A.; Nefedov, O. M.
Tetrahedron 2010, 66, 9151. (b) Novikov, R. A.; Shulishov, E. V.;
Tomilov, Yu. V. Mendeleev Commun. 2012, 22, 87.
(11) For the synthesis of pyrazoline 9, see: Novikov, R. A.; Platonov,
D. N.; Dokichev, V. A.; Tomilov, Yu. V.; Nefedov, O. M. Russ. Chem.
Bull. 2010, 59, 984.
(12) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de
Meijere, A. J. Org. Chem. 2007, 72, 7504.
(13) Starting cyclopropanes 4 were synthesized from the
corresponding aromatic aldehydes through a standard synthetic
sequence of Knoevenagel/Corey−Chaykovsky reactions: (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.
(14) Chagarovskiy, A. O.; Ivanova, O. A.; Rakhmankulov, E. R.;
Budynina, E. M.; Trushkov, I. V.; Melnikov, M. Y. Adv. Synth. Catal.
2010, 352, 3179.
(15) For some reviews of 71Ga NMR spectra, see: (a) Hinton, J. F.;
Briggs, R. W. in Group III  Aluminum, Gallium, Indium, and Thallium
// NMR and Periodic Table; Mann, B. E.; Harris, R. K.-L., Ed.;
Academic Press: New York, 1978; pp 279−308. (b) Akitt, J. W.;
Greenwood, N. N.; Storr, A. J. Chem. Soc. 1965, 8, 4410. (c) Bock, S.;
Noth, H.; Wietelman, A. Z. Naturforsch. 1990, Bd 45B (7), 979.
N
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX