An efficient, facile, and general stereoselective synthesis of heterosubstituted alkylidenecyclopropanes

Article abstract of DOI:10.1002/anie.200702713

(Chemical Equation Presented) With just a nudge (in the form of silica gel, an acidic ion-exchange resin, or heating at about 40°C), the acetate derivatives of enantiomerically enriched cyclopropenyl alcohols undergo sigmatropic rearrangement to give alky

Full text of DOI:10.1002/anie.200702713

Angewandte
Chemie
DOI: 10.1002/anie.200702713
Synthetic Methods
An Efficient, Facile, and General Stereoselective Synthesis of
Heterosubstituted Alkylidenecyclopropanes**
Ahmad Masarwa, Amnon Stanger, and Ilan Marek*
Dedicated to Professor Herbert Mayr on the occasion of his 60th birthday
Over the last few decades, the chemistry of racemic methyl-
enecyclopropane and alkylidenecyclopropane derivatives[1] in
the presence of transition-metal catalysts has been explored
extensively.[2] The reactive nature of these compounds is
commonly attributed to the strained double bond.[3] The
Alternatively, nonbonding interactions with substituents
on the substrate may serve as the dominant stereochemical
control element. In certain cases, reagents have been reported
to preassociate with polar functional groups in the vicinity of
the reactive center and to influence the stereochemical
outcome of the process. Such interactions are frequently
stronger than purely steric interactions and may lead to the
opposite stereochemical outcome to that predicted on the
basis of steric effects alone. Those cases in which such
contrasteric selectivity has been observed have invariably
involved substrates with polar functional groups and metal-
based reagents.[6] In this context, a particularly interesting
example would be the preparation of acetoxy-substituted
alkylidenecyclopropane derivatives. Most of the methods
known to date for the preparation of such compounds involve
the reaction of an alkylidenecarbene with an enol ether,[7] the
photolysis of a dithiolactone,[8] or the addition of tBuOH to
1,4-di-tert-butylmethylenecyclopropene.[9]
To further enrich the chemistry of alkylidenecyclopro-
panes in synthesis, in particular for the creation of quaternary
stereocenters, we report herein the preparation of racemic
and enantiomerically enriched alkylidene cyclopropane
derivatives with polar functionalities through sigmatropic
rearrangements.[10] Thus, racemic cyclopropenyl alcohols 1
were first transformed readily into cyclopropenyl acetate
derivatives 3, the rearrangement of which fulfilled our
expectations (Table 1).
À
mode of ring opening (at the distal C3 C4 bond or at the
À
proximal C2 C3bond) depends mainly on the choice of
catalyst.[2c] The regioselectivity of the addition of an organo-
metallic derivative RM across the exomethylene double bond
À
C1 C2 depends on the nature of both the organometallic and
the alkylidenecyclopropane derivative.[2] Furthermore, the
presence of a carbon stereocenter on the cyclopropyl ring may
lead to a transfer of chirality to the final product.[2] The
presence of quaternary stereocenters in the alkylidenecyclo-
propane would be particularly interesting, as insertion into
the distal bond may be inhibited completely. Unfortunately,
as a result of inherent difficulties with their preparation, the
availability of enantiomerically enriched methylenecyclopro-
panes and alkylidenecyclopropanes with quaternary stereo-
centers is rather limited.[4] In this context, we reported the
copper-catalyzed addition of Grignard reagents to enantio-
merically pure cyclopropenyl alcohols 1 to give alkylidenecy-
clopropane derivatives 2 with very high enantioselectivity
[Eq. (1)].[5]
The [3,3] sigmatropic rearrangement of the tertiary allylic
ester 3a proceeded under very mild conditions upon simple
filtration through a column of silica gel (method A; Table 1,
entry 1), upon heating at reflux in CH2Cl2 (method B;
Table 1, entry 2), or upon the addition of dry amberlyst-15,
an acidic ion-exchange resin (method C; Table 1, entry 3).[11]
In all cases, the desired rearrangement occurred to give the
expected product 2-diphenylmethylene-1-methylcyclopropyl
acetate (4a) in excellent yield. The relief of ring strain (an
[*] A. Masarwa, Prof. A. Stanger, Prof. I. Marek
The Mallat Family Laboratory of Organic Chemistry
Schulich Faculty of Chemistry and
The Lise Meitner–Minerva Center for Computational
Quantum Chemistry
alkylidene cyclopropane is less strained than cyclopropene by
[12]
10.3kcalmol À1
)
is the driving force for rearrangement
Technion—Israel Institute of Technology
Haifa 32000 (Israel)
Fax: (+972)4-829-3709
under such mild conditions.
It was found that the substituent R1 on the double bond of
the cyclopropenyl acetate can be either alkyl or aryl (Table 1,
entries 1–4), whereas the substituents R2 and R3 can be alkyl,
aryl, or hydrogen atoms. When secondary alcohols were used
(R2 = H, R3 = Ar),[13] the issue of the configuration of the
double bond was raised. In almost all experiments, only the
E isomer of the product was detected (as determined by NOE
experiments). The E isomer results from a chairlike confor-
mation A in the transition state in which the R3 substituent
E-mail: chilanm@tx.technion.ac.il
[**] This research was supported by a grant from the German–Israeli
Project Cooperation (DIP-F.6.2), by the Israel Science Foundation
administrated by the Israel Academy of Sciences and Humanities
(459/04), and by the Fund for the Promotion of Research at the
Technion. I.M. is holder of the Sir Michael and Lady Sobell Academic
Chair.
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: [3,3] Sigmatropic rearrangement of cyclopropenyl acetates 3.[a]
Table 2: [2,3] Sigmatropic rearrangement of cyclopropenyldiphenylphos-
phinites 5.
Entry
3
R1 R2 R3
Method[b]
4
E/Z[c] Yield [%][d]
1
2
3
4
5
6
7
8
9
3a Me Ph Ph
3a Me Ph Ph
3a Me Ph Ph
3b Ph Me Me
3c Me Ph Me
A
B
C
A
A
C
C
C
C
C
4a
4a
4a
4b
–
–
–
–
90
92
87
91
83
Entry
1
R1
R2
R3
6
E/Z[a]
Yield [%][b]
1
2
3
4
5
6
7
8
1g
1b
1h
1e
1i
1 f
1j
1k
Bu
Ph
H
H
Me
Me
Ph
6g
6b
6h
6e
6i
6 f
6j
6k
–
–
–
94
87
93
90
93
90
85
85
Me
Me
H
H
H
4c 2:1[e]
Bu
Me
Bu
Me
Me
Bu
3d Me
3e Me
3 fa Me
3 fb Me
3g Bu
H
H
H
H
H
p-BrC6H4-
Ph
4d >99:1 75
4e >99:1 76
4 fa >99:1 70
4 fb >99:1 60
4g >99:1 77
4:1[c]
4:1[c]
4:1[c]
4:1[c]
4:1[c]
Ph
Ar[f]
Ar[d]
Ar[f]
p-BrC6H4
H
H
CH2CH2Ph
CH(Ph)2
10
[a] R4 =Me with the exception of entry 9 where R4 =Ph. [b] See the
Experimental Section for details of methods A–C. [c] The E/Z ratio was
determined by 1H and 13C NMR spectroscopy of the crude product.
[d] The yield was determined after purification by chromatography on
silica gel. [e] The configuration of the major isomer was determined by
comparison with literature data (Ref. [7]). [f] Ar=3,5-dibromophenyl.
[a] The E/Z ratio was determined by 1H and 31P NMR spectroscopy of the
crude product. [b] The yield was determined after purification by
chromatography on silica gel. [c] The two geometrical isomers can be
separated readily by column chromatography. [d] Ar=3,5-dibromo-
phenyl.
configuration of the double bond was confirmed by X-ray
analysis of (Z)-6 f and deduced by analogy for the other
reaction products.
occupies a pseudoequatorial position (Table 1, entries 6–10).
Only for 3c, which was prepared from a nonsymmetrical
ketone, were two geometrical isomers formed, in a 2:1 ratio
(Table 1, entry 5). Because of the concerted, suprafacial
nature of such rearrangements, 1,3-transfer of chirality can
be expected. Indeed, when enantiomerically enriched cyclo-
propenyl acetates 3d,e (> 98% ee; readily obtained by kinetic
resolution upon Sharpless epoxidation of the corresponding
cyclopropenyl alcohols 1d,e)[5] were treated with amberlyst-
15 (Table 1, entries 6 and 7), the corresponding (E)-2-
arylidene 1-methylcyclopropyl acetates (S)-4d,e were
obtained with the same ee value (> 98% ee; 100% chirality
transfer).[14,15]
As the design and preparation of chiral phosphines for
asymmetric catalysis is an active area of research,[16] we also
investigated the [2,3] sigmatropic rearrangement[17] of allylic
diphenylphosphinites of the general structure 5. Although
there have been a considerable number of reports on the
rearrangement of propargylic phosphinites,[18] very few have
addressed the stereochemical outcome of the rearrangement
of an open-chain allylic system.[19] Herein, we describe
the application of this sigmatropic rearrangement to the
preparation of racemic and chiral diphenylphosphine
oxides with a quaternary center (Table 2).
When enantiomerically pure cyclopropenyl alcohols 1i,f,j
(> 99% ee; Table 2, entries 5—7; see Scheme 1 for a repre-
sentative example) were treated with chlorodiphenylphos-
phane at room temperature, the expected E and Z alkylide-
necyclopropane diphenylphosphine oxide derivatives 6i,f,j
were obtained in an 4:1 ratio with complete transfer of
chirality (> 99% ee; Scheme 1).[15] As opposed to the well-
defined transition state A for cyclopropenyl acetates 3 (see
Table 1), the transition state for phosphinite intermediates 5
involves a five-memebered ring, and the conformational
issues with respect to such ring systems have to be
addressed.[20] Thus, the major isomer forms via B, whereas
the formation of the minor isomer is due to a rotation of the
cyclopropenyl ring as shown in C.
Calculations were carried out to elucidate the absolute
configurations of 4d,e and 6i,f (for both E and Z isomers).[5,21]
The geometries of the different isomers and enantiomers
were optimized at the B3LYP/6-311G(d) computational level,
Such [2,3] sigmatropic rearrangements proceed
extremely fast at room temperature and are complete
within a few minutes for primary (Table 2, entry 1),
secondary (Table 2, entries 4–8), and tertiary (Table 2,
entries 2 and 3) cyclopropenyldiphenylphosphinite deriv-
atives as a result of the release of strain. In all cases, the
corresponding phosphine oxide of a methylenecyclopro-
pane or alkylidenecyclopropane was obtained in excel-
lent yield. When secondary phosphinites were used, two
geometrical isomers of the corresponding phosphine
oxide were obtained in an E/Z ratio of 4:1. The isomers
were separated readily by column chromatography. The
Scheme 1. [2,3] Sigmatropic rearrangement of the cyclopropenyldiphenyl-
phosphinite derived from 1 f via the transition-state conformations B and C,
which lead to the E and Z isomer of the product 6 f, respectively.
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and analytical frequency calculations were carried out to
ensure that real minima were found (Nimg = 0). Only one
stable conformer each was found for 4d and 4e and was used
for the calculation of the spectra, whereas two rotamers were
and (E)-6 f, on the basis of which the configurations of the
enantiomers prepared experimentally were determined.
Finally, phosphine oxide derivatives 6 can be converted
readily into the corresponding phosphines 7 upon reduction
with HSiCl3 [see Eq. (2) for a representative example].[23]
=
identified as minima for 6 f, one with the P O bond syn and
=
the other with the P O bond anti with respect to the three-
membered ring. For (E)-6 f and (Z)-6 f, the anti rotamers are
more stable than the syn rotamers by 765 calmolÀ1 and
2.95 kcalmolÀ1, respectively. Thus, the anti rotamers have a
population of 76.53and 99.25%, respectively, at room
temperature. As the CD spectra of the two rotamers of
each isomer are rather different (see the Supporting
Information), a weighted average of the two CD spectra
was used for comparison with the experimental spectrum (see
Figure 1).
To generate the electronic and CD spectra, TD-DFT
calculations were carried out at the B3LYP/6-311 + + G(d)
and B3LYP/aug-cc-pVDZ levels in dichloromethane (within
PCM model)[22] for 20 singlet transitions. The comparison of
The preparation of alkylidenecyclopropane diphenyl-
phosphines as a new family of chiral ligands and their
applications in asymmetric catalysis are currently under
investigation.
these spectra with the experimentally measured electronic Experimental Section
Method A: Rearrangement to give 4 occurred during the purification
of 3 by column chromatography on silica gel (eluent: hexane/ethyl
acetate 50:1).
and CD spectra allowed straightforward determination of the
absolute configurations. Figure 1 shows the correlation
between the measured and computed CD spectra of (Z)-
Method B: A solution of 3 (1 mmol) in CH2Cl2 (3mL) was heated
at reflux overnight. The solvent was then removed under reduced
pressure, and the crude product 4 was purified by column chroma-
tography on silica gel (eluent: hexane/ethyl acetate 50:1).
Method C: A solution of 3 (1 mmol) in CH2Cl2 (5 mL) was
treated with an excess of amberlyst-15 under argon, and the resulting
mixture was stirred at room temperature overnight. The mixture was
then filtered, and the solvent was removed under reduced pressure.
The crude product 4 was purified by column chromatography on silica
gel (eluent: hexane/ethyl acetate 50:1).
General procedure for the synthesis of 6:
A solution of
chlorodiphenylphosphane (0.18 mL, 1 mmol) was added dropwise
to a vigorously stirred mixture of 1 (1 mmol), 4-(N,N-dimethylami-
no)pyridine (12.4 mg, 0.1 mmol), and triethylamine (0.14 mL,
1 mmol) in THF (5 mL) at 08C under argon in a 50-mL Schlenk
flask. The ice bath was then removed, and the mixture was stirred for
1 h at room temperature. The precipitated salts were filtered off, the
THF was removed under reduced pressure, and the crude product 6
was purified by column chromatography on silica gel (eluent: Et2O).
The E and Z isomers of 6 were separated by column chromatography
(eluent: Et2O) on silica gel.
Received: June 20, 2007
Revised: July 24, 2007
Published online: September 14, 2007
Keywords: alkylidenecyclopropanes · chiral phosphanes ·
.
cyclopropenes · sigmatropic rearrangement · synthetic methods
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