Cyclopropenylcarbinol derivatives as new versatile intermediates in organic synthesis: Application to the formation of enantiomerically pure alkylidenecyclopropane derivatives

Article abstract of DOI:10.1002/chem.200901074

The copper-catalyzed carbomagnesiation (or hydrometalation) reaction of chiral cyclopropenylcarbinol derivatives, obtained by means of a kinetic resolution of secondary allylic alcohols, leads to an easy and straightforward preparation of enantiomerically

Full text of DOI:10.1002/chem.200901074

FULL PAPER
DOI: 10.1002/chem.200901074
Cyclopropenylcarbinol Derivatives as New Versatile Intermediates in
Organic Synthesis: Application to the Formation of Enantiomerically Pure
Alkylidenecyclopropane Derivatives
Samah Simaan,[a] Ahmad Masarwa,[a] Elinor Zohar,[a] Amnon Stanger,[a]
Philippe Bertus,[b] and Ilan Marek*[a]
Dedicated to Professor Yitzhak Apeloig on the occasion of his 65th birthday
Abstract: The copper-catalyzed carbo-
magnesiation (or hydrometalation) re-
action of chiral cyclopropenylcarbinol
derivatives, obtained by means of a ki-
netic resolution of secondary allylic al-
cohols, leads to an easy and straightfor-
ward preparation of enantiomerically
pure alkylidenecyclopropane deriva-
tives. The reaction mechanism is com-
posed of a syn-carbometalation fol-
lowed by a syn-elimination reaction. To
gain further insight into the reaction
mechanism of the carbometalation, the
diastereoselective formation of cyclo-
propylcarbinol was also achieved and
was found to be very sensitive to the
nature of the organometallic species
used for the addition reaction. Cyclo-
propylcarbinol could also be prepared
through a diastereoselective reduction
of cyclopropenylcarbinol derivatives.
Finally, functionalization of enantio-
merically enriched cyclopropenylcarbi-
nols into the corresponding acetate or
phosphinite derivatives leads, under
mild conditions, to various enantiomer-
ically pure heterosubstituted alkylide-
necyclopropanes.
Keywords: alkylidenecyclopro-
panes · carbometalation · cyclopro-
penylcarbinols · sigmatropic rear-
rangement · strained molecules
Introduction
Cyclopropenes as well as alkylidenecyclopropanes are high-
energy-possessing and, therefore, reactive molecules with a
large spectrum of remarkable activities that extend far
beyond simple reactions typical of olefins.[1] Their chemis-
tries have been the subject of numerous reviews and most of
their preparations in the racemic form were developed by
the mid-1980s.[1]
But in the last few years, strain[2] as a design principle for
asymmetric reactions has led to a complete renaissance of
the field.[1a] Indeed, upon breaking the p bond, the trigonally
coordinated ring carbon atoms can pyramidalize, thus reliev-
ing the additional angle strain that results from the presence
in the three-membered ring of carbon atoms that are nomi-
nally sp2- rather than sp3-hybridized. Initially, Wiberg sug-
gested that the introduction of each trigonal carbon center
into a three-membered ring introduces an additional 12–
14 kcalmolÀ1.[3] For instance, the strain energy of methylene-
cyclopropane (R3 =R4 =H) is estimated to be 41 kcalmolÀ1,
whereas the heat of formation of isomeric 1-methylcyclopro-
pene is 10.2 kcalmolÀ1 higher.[4] The three-membered ring
compounds represent the first case in which the exocyclic
double bond is found to be more stable than the endocyclic
[a] Dr. S. Simaan, A. Masarwa, Dr. E. Zohar, Prof. Dr. A. Stanger,
Prof. Dr. I. Marek
The Mallat Family Laboratory of Organic Chemistry
Schulich Faculty of Chemistry, and the Lise Meitner-Minerva
Center for Computational Quantum Chemistry
Technion-Israel Institute of Technology
Technion City, Haifa 32000 (Israel)
Fax : (+972)48293709
E-mail: chilanm@tx.technion.ac.il
[b] Prof. Dr. P. Bertus
CNRS UMR 6011, Unite de Chimie Organique et Moleculaire
ACHTUNGTRENNUNG(UCO2M), Universite du Maine
Avenue O. Messian, 72085 Le Mans Cedex 9 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901074.
Chem. Eur. J. 2009, 15, 8449 – 8464
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8449

double bond. Johnson and Borden concurred with the ex-
planation that increased angle strain does result from the
presence of additional sp2 centers.[5] Taking into account this
strain release, if synthetic transformations could be per-
formed on enantiomerically enriched cyclopropenes, syn-
thetic interests would become clear as a new entry to func-
tionalized enantiomerically enriched compounds. Due to
this mounting interest, the synthesis of enantiomerically
pure 1-substituted cyclopropene derivatives was reported
either by means of the enantioselective metal-catalyzed ad-
dition of diazo species to monosubstituted alkynes,[6] or by
means of optical resolution.[7] However, the preparation of
1,2-disubstituted (internal) cyclopropenes is still a challeng-
ing task and there is still no direct method for their prepara-
tion in an enantiomerically enriched form. Most of the
methods known to date rely on an additional step to func-
tionalize the remaining sp2-carbon center.[6j,8] However, if
Scheme 1. Preparation of cyclopropenylcarbinol derivatives 2a–al.
Table 1. Formation of cyclopropenylcarbinols 2a–al.
Entry
R1
R2
R3
R4
Yield [%][a]
1 (1a)
2 (1b)
3 (1a)
4 (1b)
5 (1 f)
6 (1a)
7 (1b)
8 (1a)
9 (1a)
10 (1b)
11 (1c)
12 (1b)
13 (1a)
14 (1c)
15 (1c)
H
H
H
H
H
H
H
H
H
H
CH3
C4H9
CH3
C4H9
C6H5
CH3
C4H9
CH3
CH3
C6H5
C6H5
C2H5
CH3
CH3
CH3
C6H5 65 (2a)
C6H5 82 (2b)
C2H5 52 (2c)
CH3
CH3
81 (2d)
73 (2e)
À
chemistry on the C H bond is desired, one of the key ques-
C6H5 75 (2 f)
À
tions is the C H bond energy and how it is affected by the
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
57 (2g)
46 (2h)
60 (2i)
56 (2j)
65 (2k)
76 (2l)
61 (2m)
70 (2n)
88 (2o)
85ACHTUNGTRENNUNG(2p)
79 (2q)
66 (2r)
88 (2s)
55 (2t)
55 (2u)
35 (2v)
94 (2w)
92 (2x)
81 (2y)
87 (2z)
62 (2aa)
90 (2ab)
90 (2ac)
88 (2ad)
64 (2ae)
93 (2af)
78 (2ag)
76 (2ah)
77 (2ai)
80 (2aj)
85 (2ak)
78 (2al)
À
strain of the system. A quantitative correlation between C
H bond-dissociation energy (BDE) and the hybridization of
the carbon atom was recently described.[9] Cyclopropanes
are of spn hybridization, where n>3. As a result, the two
CH2CH2Ph
CH2CH2Ph C2H5
CH3 CH3
H
H
CH3 CH3
CH3 CH3
CH2CH2Ph
CH3
C4H9
CH3
C2H5
C2H5
CH2CH2Ph
CH2Ph
CH2CH=CHEt
C2H5
iPr
iPr
CH(Ph)2
c-C6H11
tBu
C6H5
C4H9
CH3
À
other hybridizations of the carbon atoms (at the C H bonds
m
À
but theoretically correct for all C X bonds) are of sp hy-
À
bridization, where m<3. It was shown that a specific C H
BDE can be easily estimated when the hybridization of the
16 (1d) CH3
17 (1d) CH3
18 (1a)
19 (1c)
H
H
CH3
À
carbon at the C H bonding lobe is known. In general, one
H
À
could state that for cyclopropanes, the C H bonds are stron-
CH3 CH3
ger than the respective bonds in unstrained compounds.
Alkylidenecyclopropane derivatives have also proven
their usefulness by their unique reactivity with transition-
metal catalysts.[10] These catalyzed transformations, also
based on the release of the high level of strain, can be per-
formed either on the distal or proximal bonds of the three-
membered ring or on the exo-alkylidene moiety.[11] Howev-
er, the preparation of enantiomerically pure (or even en-
riched) alkylidenecyclopropane derivatives was also in its in-
fancy. In this paper, we describe our approach to the prepa-
ration and reactivity of such challenging entities.
20 (1e) CH3 Me3Si
21 (1a)
22 (1b)
23 (1a)
24 (1c)
25 (1a)
26 (1a)
27 (1b)
28 (1c)
29 (1c)
30 (1a)
H
H
H
CH3
H
CH3
C4H9
CH3
H
CH3
CH3
C4H9
H
H
C6H5
C6H5
CH3 CH3
CH3 CH3
H
p-MeOC6H4
p-MeC6H4
p-MeC6H4
p-BrC6H4
p-MeOC6H4
o-BnOC6H4
3,4,5-(MeO)3C6H2
p-BrC6H4
3,5-(Br)2C6H3
2,3,5-(Me)3C6H2
CH3
H
31 (1d) CH3
32 (1a)
33 (1a)
34 (1a)
35 (1a)
36 (1b)
37 (1a)
38 (1a)
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
C4H9
CH3
CH3
Results and Discussion
Preparation of cyclopropenylcarbinol derivatives: Cyclopro-
penylcarbinol derivatives 2a–al are easily prepared in one-
chemical step and in good to excellent chemical yields from
1,1,2-trihalogenocyclopropanes 1a–f (themselves prepared
by reaction of substituted vinyl halide derivatives with bro-
moform in the presence of phase-transfer catalysts such as
Cetrimide),[12] by a successive 1,2-dehalogenation reaction
followed by a halogen-lithium exchange and reaction with
various carbonyl derivatives as described in Scheme 1 and
Table 1.
[a] Yields determined after purification by column chromatography on
silica gel.
stable and can be stored under normal conditions with the
exception of the aryl-substituted cyclopropene 2e (Table 1,
entry 5), which slowly decomposes in a day. Carbonyl com-
pounds could be either aromatic or aliphatic ketones
(Table 1, entries 1 and 2 and 3–5, respectively), formalde-
hyde (Table 1, entries 7 and 8), or various aliphatic and aro-
matic aldehydes (Table 1, entries 9–25 and 26–38). As far as
aliphatic aldehydes are concerned, a broad nature of R3
The results summarized in Table 1 show that this ap-
proach leads to a large variety of diversely substituted cyclo-
propenylcarbinols. All of these cyclopropenylcarbinols are
8450
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Chem. Eur. J. 2009, 15, 8449 – 8464

Cyclopropenylcarbinol Derivatives
FULL PAPER
groups can be used such as primary (Table 1, entries 9–20),
secondary (Table 1, entries 21–24), and even tertiary alkyl
groups (Table 1, entry 25). Aromatic aldehydes can also be
sterically bulky without any negative effect on the chemical
yields (Table 1, entry 38). Substituent R2 could be an aryl
group (Table 1, entry 5), hydrogen (Table 1, entries 17, 31),
silyl groups (Table 1, entry 20), or various alkyl groups
(Table 1). The only cyclopropenylcarbinol derivative that we
could not isolate was the aryl substituted with R2 =R3 =Ph
(and R1 =R4 =H).
With an easy and straightforward method for the prepara-
tion of racemic cyclopropenylcarbinols, we then turned our
attention to their asymmetric syntheses. Considering that
these derivatives are a particular type of strained allylic al-
cohol, we envisaged their preparation in an enantiomerically
enriched form through a Sharpless kinetic resolution.[13]
When racemic allylic alcohols 2 were subjected to the epoxi-
dation reaction conditions, using (R,R)-(+)-diethyl tartrate
as a chiral ligand, we were pleased to observe, despite the
reactive nature of the strained double bond, a very efficient
kinetic resolution at À208C. Only one enantiomer was ep-
oxidized to lead to the putative unstable chiral 2-oxabicyclo-
under investigation in our research group and results will be
reported in the near future.
Coming back to the kinetic resolution, the remaining non-
oxidized products, namely, cyclopropenylcarbinols 2, were
obtained with very high enantiomeric excesses (ee) and
yields (95–99% ee and 40–47% yield of isolated products)
as described in Scheme 2.[17]
The scope of the kinetic resolution is broad since several
different alkyl groups can be present either on the double
bond of the cyclopropenyl unit (R2 =CH3 and C4H9) or on
the cyclopropene itself (R1 =H or CH3, Table 2).
Table 2. Formation of enantiomerically enriched cyclopropenylcarbinols
2.
Entry
R1
R2
R3
ee [%][a]
Yield [%][b]
1
2
3
4
5
6
7
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
C4H9
CH3
CH3
CH3
C6H5
99
99
96
99
99
99
95
46 (2z)
44 (2af)
42 (2i)
44 (2aa)
45 (2ak)
47 (2ab)
40 (2k)
p-BrC6H4
CH2CH2Ph
C6H5
3,5-(Br)2C6H4
C6H5
CH2CH2Ph
[a] Enantiomeric excess determined by chiral GC; see the Experimental
Section. [b] Yields determined after purification by column chromatogra-
phy on silica gel.
ACHTUNGTRENNUNG[1.1.0]butane 3. Although, Sharpless kinetic resolution im-
plies that 50% of the substrate undergoes an epoxidation
reaction, we were never able to isolate nor to detect this 2-
oxabicycloACHTUNGTRENNUNG[1.1.0]butane intermediate 3. The only products
formed were the two a,b-unsaturated ketols 4 and 5, formed
in almost equal amounts (each in 22–25% isolated yields),
as a result of the isomerization of the postulated intermedi-
ate 3 through a cleavage of the two peripheral s bonds
(Scheme 2).[14] Oxabicyclobutanes have been also postulated
Aryl and alkyl groups can be arbitrarily used as secondary
substituents at the allylic position, although the enantiomer-
ic excess is slightly higher when R3 is an aryl group (ee=
99%; Table 2 entries 1, 2, and 4–6) instead of an alkyl group
(ee=95–96%; Table 2, entries 3 and 7). Although the Sharp-
less kinetic resolution gave outstanding enantiomeric excess-
es and isolated chemical yields for the remaining cyclopro-
penylcarbinols 2, half of our starting material was lost by
the formation of the two enones 4 and 5 (Scheme 2).
Therefore, to have a better conversion, we were also inter-
ested in developing a biocatalytic resolution as depicted in
Scheme 3. Indeed, the irreversible, enzyme-mediated acyla-
Scheme 2. Kinetic resolution of cyclopropenylcarbinol derivatives
(DET=(+)-diethyl l-tartrate; TBHP=tert-butyl hydroperoxide).
2
Scheme 3. Biocatalytic resolution of cyclopropenylcarbinol 2.
tions in organic solvents mediated by the commercially
available Pseudomonas AK (Amano K-10) is a powerful al-
ternative to the Sharpless kinetic resolution.[18]
Generally, the most efficiently resolved alcohols have one
small (R3) and one relatively large group attached to the hy-
droxymethine functionality. In this context, the large group
is the cyclopropenyl group and following this prediction, all
the recovered alcohols have the same absolute configuration
as the one obtained by means of the Sharpless kinetic reso-
lution using (R,R)-(+)-diethyl tartrate (see Table 3).[19] The
several times as intermediates in various thermal and photo-
chemical reactions,[15] but could also never be detected.
However, recent high-level quantum chemical studies on the
unimolecular (and acid-catalyzed) fragmentation of such in-
termediates suggested that this compound should be stable
enough to be detected in chemical reactions. Since this is
not the case, there must be another mechanism, which ex-
cludes the formation of oxabicyclobutane at the intermedi-
ate stage.[16] This very interesting discrepancy is currently
Chem. Eur. J. 2009, 15, 8449 – 8464
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8451

I. Marek et al.
Table 3. Biocatalytic resolution of cyclopropenylcarbinols 2.
tallic species with this OLG moiety. Among all the possible
candidates for either a metal-catalyzed SN2’ process or a car-
bometalation reaction, we were interested in using organo-
copper species since they are known for their high stereo-
and chemoselectivity, which enables them to participate in
many synthetic transformations. Although the second mech-
anistic possibility (tandem carbometalation–elimination re-
actions) requires a perfect control of the stereochemical out-
come for the carbometalation reaction as well as for the b
elimination, we decided to consider first this sequence on a
nonprotected alcohol moiety (LG=H). The stereochemistry
of b-elimination reactions (syn versus anti) may be depen-
dent on the nature of the halide X of the RMgX involved in
the reaction (X=Cl, Br, I),[22] and we first checked, on a
standard copper-catalyzed carbomagnesiation reaction, if
the nature of the halide of the alkylmagnesium species as
well as on the copper salt had an effect on the stereochemis-
try of the reaction. Representative examples of secondary
aliphatic and aromatic alcohols were investigated (2i and
2z, respectively) and the results are reported in Table 4. We
can see from Table 4 that the nature of the halide of the
Entry R2
R3
Yield of 6 ee of 6
Yield of 2 ee of 2
[%][a]
[%]
[%][a]
[%]
1[b]
2[e]
3[g]
4[h]
5
C4H9 CH3
42
39
48
45
25
ND[c]
>95
>95
ND[h]
>99
39
37
41
40
24
>99[d]
95[f]
C4H9 CH2CH2Ph
CH3 CH2CH2Ph
CH3 C6H5
>99[e,f]
20[f]
CH3 p-BrC6H4
99[f]
[a] Yields determined after purification by column chromatography on
silica gel. [b] The reaction requires 17 h to complete. [c] ND=not deter-
mined because separations were difficult with chiral GC. [d] Enantiomer-
ic excess determined by 1H NMR spectroscopy by formation of Mosher
ester; see the Experimental Section. [e] The reaction requires one week
to complete. [f] Enantiomeric excess determined by chiral GC; see the
Experimental Section. [g] The reaction requires 3 d to complete. [h] The
reaction requires 24 h to complete.
enantiomeric excess was determined by either chiral GC or
the transformation of 2 into its Mosher ester and further
1H NMR spectroscopic analyses (see the Experimental Sec-
tion). Both the cyclopropenylcarbinols 2 and esters 6 were
found to be prepared with excellent enantiomeric excess.
This biocatalytic resolution proceeds smoothly when R3
substituents are alkyl groups (Table 3, entries 1–3), but is
either low yielding or non-enantioselective when this sub-
stituent is an aromatic group (Table 3, entries 4 and 5).
In most of the cases, the preparation of racemic and enan-
tiomerically enriched cyclopropenylcarbinol derivatives
could be easily achieved and the reaction of the strained
double bond was then investigated.
Table 4. Effect of the nature of the halide of RMgX on the stereochemis-
try of 7.
Reactivity of cyclopropenylcarbinol derivatives—New access
to alkylidenecyclopropanes: We first focused our attention
on the development of a general method for the formation
of racemic alkylidenecyclopropanes 7 from cyclopropenyl-
carbinol derivatives 2 (Scheme 4).
Entry
R
R1MgX[a]
CuY
E/Z ratio[b]
1 (2i)
2 (2i)
3 (2i)
4 (2i)
5 (2z)
6 (2z)
7 (2z)
8 (2z)
9 (2z)
10 (2z)
11 (2z)
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
EtMgBr
EtMgI
PhMgBr
PhMgI
BuMgCl
BuMgBr
BuMgBr
BuMgBr
BuMgI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuI
CuBr, CuP
CuI
80:20
100:0
86:14
87:13
80:20
85:15
86:14
70:30
97:3
ACHTUNGERTN(NUNG OEt)3
PhMgBr
PhMgI
CuI
CuI
87:13
87:13
Scheme 4. General preparation of alkylidenecyclopropane derivatives 7.
[a] All the Grignard reagents were prepared in Et2O and titrated before
use. [b] E/Z ratio determined from the NMR spectra of the crude reac-
tion mixture; yields were always higher than 80%.
Such transformations can be seen either as a metal-cata-
lyzed (or promoted) allylic substitution (SN2’ reaction) or as
a two-step mechanism through a carbometalation reaction
of an organometallic species on the strained double bond
followed by a b-elimination reaction. From the two possible
mechanisms, the copper-promoted allylic substitution usual-
ly requires a good leaving group (OLG) such as esters, car-
bamates, sulfonates, phosphates, ethers, acetals, or halides.[20]
Free alcohols are rarely used for such transformations. How-
ever, if one considers the two-steps mechanism, the reaction
proceeds first through a carbometalation reaction, eventual-
ly controlled by the presence of the adjacent heteroatom[21]
(here OLG), followed by a b elimination of the organome-
Grignard reagents has a very important effect on the E/Z
ratio of the formed alkylidenecyclopropane derivatives:
when secondary aliphatic alcohol 2i was treated with
EtMgI, a unique E isomer was obtained whereas the same
starting material leads to two geometrical isomers in a 80:20
ratio when treated with EtMgBr (Table 4, entries 2 and 1,
respectively).[23] However, the nature of the halide (X=Br
versus I) for the copper-catalyzed addition of arylmagnesi-
um halide derivatives has no effect on the stereochemistry
of the formed double bond and both isomers were obtained.
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Cyclopropenylcarbinol Derivatives
FULL PAPER
Similarly, when secondary aromatic aldehyde 2z was used,
the same trend was observed (better E/Z ratio when X=
Y=I) for the addition of aliphatic Grignard but has no
effect again for the addition of aryl Grignard reagents (see
the section “Mechanistic hypothesis” for a tentative ration-
alization). Without copper salt, no reaction was detected.
Having established the best experimental conditions as de-
scribed in Scheme 5, we then decided to generalize the for-
primary alcohols were utilized as starting materials (Table 5,
entries 6 and 7). When secondary alcohols were used (R3 =
alkyl or aryl; R4 =H), the fate of the stereochemistry of the
resulting double bond in the alkylidenecyclopropane deriva-
tives, raised in our previous study (Table 4), was also consid-
ered closely. When aliphatic Grignard reagents RMgI were
added to secondary aliphatic cyclopropenylcarbinols 2 (R3 =
alkyl), only the E isomer of the alkylidenecyclopropanes 7
were formed (Table 5, entries 8, 10, and 12–15). Only when
aromatic Grignard was added to 2m and 2i (Table 5, en-
tries 9 and 11), was a mixture of two E/Z geometrical iso-
mers obtained. Clearly, the added aryl Grignard behaves dif-
ferently. When the substituent of the secondary allylic alco-
hol is aromatic, the E isomer is mainly obtained but some
variations could be found depending on the nature of the
aryl group (Table 5, entries 16–29; in entry 22, the configura-
tion of the double bond was identical but the configuration
of the product is now Z because of the interconversion of
substituents R1 and R2). The stereochemistry of the double
bond could be determined for 7ab by means of NOE ex-
periments (see the Experimental Section). Interestingly, 7
could also be prepared in a single-pot operation from 1 by
the addition of Grignard reagent and copper catalyst to the
intermediate lithium cyclopropenylcarbinol 2·Li as described
in Scheme 6. This one-pot strategy was performed for the
preparation of 7d (83%), 7g (72%), 7h (82%), 7j (85%;
E/Z=90:10), 7q (77%; E/Z=90:10), 7r (89%; E/Z=
88:12), and 7z (90%; E/Z=
Scheme 5. Preparation of alkylidenecyclopropane derivatives 7a–ac.
mation of diversely substituted alkylidenecyclopropane de-
rivatives 7 from cyclopropenylcarbinols 2, and the results re-
ported in Table 5 fulfilled our expectations.[17]
The reaction proceeded smoothly when tertiary alcohols
were used (Table 5, entries 1–5) whatever the nature of the
R2 substituent on the cyclopropenyl units (alkyl or aryl) and
the nature of the Grignard reagents (R5 =alkyl or aryl).
Similarly, the reaction led to methylenecyclopropanes when
92:8).
Table 5. Preparation of alkylidenecyclopropane derivatives 7.
To extend this methodology,
and particularly if aiming to
prepare alkylidenecyclopro-
Entry
R1
R2
R3
R4
R5
E/Z[a]
Yield [%][b]
1 (2c)
2 (2c)
3 (2e)
4 (2a)
5 (2b)
6 (2h)
7 (2g)
8 (2m)
9 (2m)
10 (2i)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
CH3
CH3
C6H5
CH3
C4H9
CH3
C4H9
CH3
CH3
CH3
CH3
CH3
C4H9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C2H5
C2H5
CH3
C6H5
C6H5
H
H
C4H9
C2H5
C2H5
CH3
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C4H9
C6H5
C2H5
C6H5
C6H5
C6H5
C6H13
CH3
C6H5
C2H5
C6H5
C4H9
CH3
C4H9
C2H5
CH3
C2H5
C4H9
C6H5
C2H5
C4H9
CH3
–
–
–
–
–
76 (7a)
81 (7b)
85 (7c)
61 (7d)
62 (7e)
72 (7 f)
82 (7g)
65 (7h)
72 (7i)
85 (7j)
77 (7k)
91 (7l)
80 (7m)
75 (7n)
84 (7o)
81 (7p)
72 (7q)
70 (7r)
66 (7s)
88 (7t)
89 (7u)
91 (7v)
85 (7w)
89 (7x)
91 (7y)
88 (7z)
88 (7aa)
89 (7ab)
92 (7ac)
panes 7 possessing tertiary ste-
reocenters (R1 =R2 =H), the
more challenging tribromocy-
clopropane 1g (R1 =R2 =H),
resulting from the reaction of
bromoform to gaseous bromoe-
thene, had to be used to obtain
1g. Despite many attempts, we
constantly got the tribromocy-
clopropane 1g in very low
yield. Therefore, we thought to
develop an alternative strategy
to obtain 7 (R1 =R2 =H) using
our easily prepared precursors
2 (R1 =H, R2 =alkyl). In such
cases, the formal SN2’ addition
of a hydride to the cycloprope-
nylcarbinols 2 should be the rel-
evant strategy for the formation
of the expected alkylidenecy-
clopropane derivatives 7. The
–
–
100:0
83:17
99:1
87:13
100:0
100:0
100:0
100:0
92:8
96:4
97:3
87:13
95:5
88:12
12:88
88:12
95:5
60:40
86:14
95:5
92:8
92:8
C4H9
CH2CH2Ph
CH2CH2Ph
iPr
11 (2i)
12 (2u)
13 (2v)
14 (2w)
15 (2w)
16 (2z)
17 (2z)
18 (2z)
19 (2z)
20 (2ad)
21 (2ad)
22 (2ae)
23 (2ae)
24 (2ag)
25 (2ah)
26 (2ai)
27 (2af)
28 (2af)
29 (2ak)
iPr
CH(Ph)2
CH(Ph)2
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
o-BnOC6H4
3,4,5-(MeO)3C6H2
p-BrC6H4
p-HOOCC6H4
3,5-Br2C6H3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
C2H5
C2H5
C6H5
C2H5
C5H11
C2H5
H
H
H
copper(I)-catalyzed
hydride
transfer is known to be a mild
and often selective reducing
agent, and among the most ex-
[a] Determined from the 1H NMR spectra of the crude reaction mixture. [b] Determined after purification by
column chromatography.
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8453

I. Marek et al.
rium incorporation (Table 6, entries 2 and 6). Substituents
on the double bond of the cyclopropenyl ring (R2) can be
either methyl or butyl. Substituents R3 and R4 can be either
alkyl or aryl groups, or hydrogen atoms. When secondary al-
cohols are used (R3 =alkyl or aryl; R4 =H; Table 6, entries 5
to 10), we always found that the major isomer was of E con-
figuration. So, the copper-catalyzed hydride addition leads
to the corresponding alkylidenecyclopropanes through a
formal SN2’ process. What would be the chemical outcome
of the addition of LiAlH4 without copper salt? Reduction of
cyclopropenes (non-copper catalyzed) is reported in the lit-
erature for simple substrates,[31] and since diastereoselection
in the hydrometalation of acyclic compounds is controlled
by allylic,[21b,32] homoallylic,[33] and even more remote stereo-
genic centers,[34] we thought that the diastereoselective re-
duction of cyclopropenylcarbinols 2 should be an interesting
and powerful solution to the preparation of cyclopropylcar-
binol derivatives 8 as described in Scheme 8.[35]
Scheme 6. Preparation of alkylidenecyclopropane derivatives 7 directly
from 1.
tensively studied and routinely used is the phosphine-stabi-
lized hexameric complex [{CuHACHTNUTRGNEUNG(PPh)3}6], commonly re-
ferred to as Strykerꢁs reagent.[24] It smoothly effects conju-
gate reductions of various a,b-unsaturated compounds.[25]
More recently, alternatives such as stannanes,[26] boranes,[27]
and in particular silanes[28] have been developed as hydrogen
equivalents in CuH chemistry. Interestingly, since the initial
report of Whitesides that reported the preparation of
copper hydride by means of treatment of iBu2AlH with
CuBr,[29] the use of HCu generated from aluminum species
has never been really developed. We were pleased to find
that the addition of LiAlH4 in Et2O to a solution of
20 mol% of CuI and cyclopropenylcarbinol 2 at À508C
slowly warmed to room temperature overnight gives the ex-
pected alkylidenecyclopropanes 7 in very good yield as de-
scribed in Scheme 7.[30]
Scheme 8. Diastereoselective reduction of cyclopropenylcarbinol 2 into
trans-cyclopropylcarbinol 8.
We first reduced unsubstituted cyclopropenylcarbinols 2j
and 2c (R1 =H, R2 =alkyl) with 1 equiv of LiAlH4 in Et2O
at +408C. Under these conditions, we were pleased to
obtain in good chemical yields the expected cyclopropylcar-
binol products 8a,b but with only a moderate anti selectivity
(anti/syn 80:20)[36] as described in Table 7, entries 1 and 2.
On the other hand, when the three-membered ring of the
cyclopropenylcarbinol has a geminal dialkyl group such as
in Table 7 (R1 =Me, entries 3–8), excellent diastereoselectiv-
ities are obtained. The reduction of the fully substituted cy-
clopropenylcarbinol 2o occurs readily with 1 equiv of
LiAlH4 in Et2O to give anti-cyclopropylcarbinol 8c as a
single diastereoisomer. If only 0.5 equiv of LiAlH4 is used,
reduced products are obtained but in lower yields. Similarly,
if THF is used as solvent in-
Scheme 7. Copper-catalyzed hydride transfer from LiAlH4.
Tertiary and secondary alcohol derivatives (Table 6, en-
tries 1–4 and 5–10, respectively) led similarly to alkylidene-
cyclopropane derivatives by means of a formal SN2’ reaction
of HCu (the low yield observed for 7af is most probably
due to the volatile nature of the final product; Table 6,
entry 4).
When commercially available LiAlD4 was used as reduc-
ing agent, the alkylidenecyclopropane deuteriated in the al-
lylic position was obtained in good yields with >95% deute-
stead of Et2O, the anti/syn ratio
of the reaction drops to only
Table 6. Copper-catalyzed formal SN2’ process.
Entry
R2
R3
R4
Hydride
E/Z ratio[a]
Yield [%][b]
6:1 in low yield. It should be
noted that the direct cyclopro-
panation of acyclic allylic alco-
hols with halomethylmetal re-
agents such as zinc, samarium,
or aluminum carbenoids is a
well-known process but gener-
ally leads to the syn-cyclopro-
pylcarbinol derivatives.[37] The
direct preparation of anti-cyclo-
propylcarbinol derivatives with
1 (2a)
2 (2a)
3 (2b)
4 (2c)
5 (2i)
CH3
CH3
C4H9
CH3
CH3
CH3
CH3
CH3
C4H9
CH3
C6H5
C6H5
C6H5
C2H5
CH2CH2Ph
CH2CH2Ph
CH2C6H4
C6H5
C6H5
p-HOOCC6H4
C6H5
C6H5
C6H5
C2H5
H
H
H
H
H
H
D
H
H
H
D
H
H
H
H
–
–
–
87 (7ad)
85 ([D]7ad)
82 (7ae)
40 (7af)
68 (7ag)
70 ([D]7ag)
76 (7ah)
60 (7ai)
–
85:15
85:15
93:7
93:7
85:15
90:10
6 (2i)
7 (2r)
8 (2z)
9 (2aa)
10 (2af)
61 (7aj)
H
83[c] (7ak)
1
[a] E/Z ratio determined from H NMR spectra of the crude reaction mixture. [b] Yields determined after pu-
rification by column chromatography on silica gel. [c] Alkylidenecyclopropane (ACP) 7ak was obtained direct-
ly through a bromine–lithium exchange and treatment with CO2, see Experimental Section.
good diastereoselection is
a
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Chem. Eur. J. 2009, 15, 8449 – 8464

Cyclopropenylcarbinol Derivatives
FULL PAPER
Table 7. Diastereoselective reduction of cyclopropenylcarbinols 2.
Entry R1
R2
R3
anti/syn ratio[a] Yield [%][b]
1 (2j)
2 (2c)
3 (2o) CH3 CH3
4 (2n) CH3 CH3
5 (2p) CH3
6 (2x) CH3
7 (2s) CH3 CH3
8 (2t) CH3 Si(CH3)3
H
H
CH2CH2Ph C2H5
80:20
80:20
>98:2
>98:2
>98:2
>98:2
85 (8a)
50 (8b)
86 (8c)
74 (8d)
80 (8e)
75 (8 f)
80 (8g)
64 (8h)
CH3
C2H5
C2H5
CH3
H
H
C2H5
c-C6H11
CH2CH=CHEt >98:2
ACHTUNGTRENNUNG
C2H5
>98:2[c]
[a] Diastereomeric ratio was determined from 1H NMR spectra of the
crude reaction mixture. [b] Yields determined after purification by
column chromatography on silica gel. [c] Diastereomeric ratio of the
trans-cyclopropylcarbinol versus the secondary alcohol; ratio of the cis/
trans-cyclopropane itself is 40:60.
Scheme 9. Deuterium-labeling experiments. The values represent the dia-
stereoselectivity followed by the yield.
On the other hand, when 2o was treated with LiAlH4 fol-
lowed by deuterio hydrolysis, [D2]8c was obtained as the
unique isomer (Scheme 9). Therefore, both deuteriocyclo-
propylcarbinol regioisomers can be selectively prepared.
Considering that the deprotonation precedes the reduction
and assuming that the reaction occurs intramolecularly, thus
inducing the hydroalumination reaction on the same face as
the oxygen atom, the anti-diastereofacial selectivity in the
hydroalumination reaction of cyclopropenylcarbinol deriva-
tives must involve a transition state with the smallest sub-
stituent at the preexisting stereogenic center (hydrogen) ori-
ented “inside” over the face of the transition-state ring.
Minimization of the allylic 1,3-strain (A-1,3-strain)[44] is
therefore the main controlling element for the good diaste-
reocontrol and then the oxygen atom is oriented slightly
“outside” (Houkꢁs transition-state model)[45] as described in
Scheme 10. Moreover, the presence of the geminal dimethyl
much more difficult task and some of these compounds are
accessible by the reduction of the corresponding cyclopropyl
ketone[38] or by a diastereoselective cyclopropanation of
silyl-protected allylic alcohol[39] with use of the zinc carbe-
noid reported by Shi et al.[40] However, primary zinc carbe-
noid is mostly used and only a few examples are described
for the cyclopropanation reaction with less stable secondary
and tertiary carbenoids.[41] The presence of the free hydroxyl
group is absolutely necessary for the reduction of cyclopro-
penylcarbinol derivatives 2. When the alcohol is protected
as its tert-butyldimethylsilyl ether, no reduced product was
observed under our experimental conditions. Similarly, nei-
ther the Schwartz reagent [ZrClCp2(H)] (Cp=C5H5) or dii-
sobutylaluminum hydride (DIBAL-H) led to cyclopropylcar-
binols 8. The cyclopropenylcarbinol can also bear three
alkyl substituents as in 2p (R2 =H, Table 7, entry 5) or be
substituted by a secondary alkyl group (Table 7, entry 6)
without altering the diastereoselectivity of the reduction. As
the heat of hydrogenation for the conversion of cyclopro-
pene to cyclopropane is approximately 54 kcalmolÀ1 and is
considered larger than that for the conversion of ethylene to
ethane,[42] the chemoselective reduction of cyclopropylcarbi-
nol containing an E double bond such as in 2s (Table 7,
entry 7) has been investigated. The expected anti-cyclopro-
pylcarbinol 8g was obtained in good yield as a unique
isomer without any further reduction of the external E
double bond. The silyl cyclopropenylcarbinol 2t (Table 7,
entry 8), treated under our experimental conditions, leads to
the expected product 8h with an anti relationship between
the cyclopropyl and the secondary alcohol moieties, but as a
mixture of trans and cis isomers on the silylcyclopropane
ring itself (trans/cis 60:40). The presence of these two iso-
mers came from the remarkable facile configurational iso-
merization of 1-silyl-1-aluminocyclopropyl derivatives.[43]
The regioselectivity of the hydroalumination reaction on the
cyclopropenyl ring has been mapped out by deuterium-la-
beling experiments. When LiAlD4 was used as the reducing
agent followed by acidic hydrolysis, 2o and 2p led to the
deuteriocyclopropanes [D1]8c and [D1]8e, respectively, as
unique isomers in good chemical yields as shown in
Scheme 9.
Scheme 10. Mechanistic rationalization for the diastereoselective reduc-
tion.
group on the upper carbon of the cyclopropenyl moiety also
has an effect on the diastereoselectivity of the reduction
(compare entries 2 and 3, Table 7). Due to the short bond
lengths of the carbon–carbon bonds in the cyclopropene
ring, syn-pentane interactions (between the R substituent at
the preexisting center and the methyl group) have an impor-
tant effect on the diastereoselectivity.
It should be noted that the regiochemistry of the hydro-
AHCTUNGTRENNUNG
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8455

I. Marek et al.
Table 8. Enantioselective preparation of alkylidenecyclopropanes.
Scheme 9), whereas the addition of a catalytic amount of
copper(I) salt to LiAlH4 reverses completely the chemical
outcome of the reaction via a postulated copper hydride
species. When R3 is an aromatic group (Scheme 11), the re-
Entry ee of 2
R3
R5 E/Z
ratio[a]
ee of 7
Yield
[%][c]
[%]
[%][b]
1 (2i) 96
2 (2z) 99
3 (2z) 99
4 (2z) 99
CH2CH2Ph C2H5 >99:1
95
95
97
97
99
85 (7j)
72 (7q)
70 (7r)
66 (7s)
88 (7aa)
C6H5
C2H5
C4H9
C6H5
C2H5
96:4
97:3
87:13
95:5
C6H5
C6H5
5
99
p-BrC6H4
(2af)
6
99
p-MeC6H4 C2H5
95:5
99
88 (7t)
(2ad)
[a] E/Z ratio determined from 1H NMR spectra of the crude reaction
mixture. [b] Enantiomeric excesses of the E isomers were determined by
gas chromatography analyses on a chiral column (cyclodextrin B); see
the Experimental Section. [c] Yields determined after purification by
column chromatography on silica gel.
Scheme 11. Fragmentation of cyclopropylaluminum species into dienes.
duction also occurs but the resulting vinyl aluminum species
obtained before acidic hydrolysis undergoes a ring fragmen-
tation into polysubstituted dienes 9.[46] The same trend was
observed when the intermediate cyclopropylaluminum spe-
cies possessing alkyl groups R3 was heated either at 808C in
benzene (or stirred for a longer period of time in Et2O at
reflux).[46,47]
alkylidenecyclopropane 7aa into a crystalline product as de-
scribed in Scheme 13.
Treatment of 7aa with tBuLi in Et2O at low temperature
leads to the corresponding aryl lithium species, which was
reacted with enantiomerically pure (À)-menthyl-(S)-p-tolu-
ene sulfinate[49] to give the corresponding alkylidenecyclo-
propane 10 possessing an arylsulfoxide moiety. The reaction
with sulfinate ester proceeds stereospecifically with inver-
sion of configuration at the sulfur atom.[49] Then, the reac-
tion of PhI=NTs (Ts=tosyl) with sulfoxide 10 in the pres-
ence of a catalytic amount of copper(II) salts afforded the
corresponding N-tosylsulfoximines 11 in high yield. This
method proceeds with complete retention of configuration
at sulfur.[50] The absolute configuration of the stereogenic
center on cyclopropane 11 was unambiguously determined
by using X-ray analysis[51] (Figure 1) and the other reaction
products described in Table 8 were assigned analogously.
The Z isomer of alkylidenecyclopropanes has the opposite
absolute configuration.
Preparation of enantiomerically enriched alkylidenecyclo-
propane derivatives: By following the strategy that we de-
scribed in Scheme 5 for the preparation of racemic alkylide-
necyclopropanes from cyclopropenylcarbinols, enantiomeri-
cally pure alcohols 2 were treated with various Grignard re-
agents in the presence of 20 mol% of CuI as described in
Scheme 12.
Scheme 12. Preparation of enantiomerically enriched alkylidenecyclopro-
panes.
However, every synthetic organic chemist has at some
time faced the problem of getting a single crystal of good
quality for X-ray crystallography and this technique, al-
though extremely powerful, may be time consuming. There-
fore, we also developed an alternative approach in which ex-
perimental circular dichroism (CD) data of our alkylidene-
The reaction proceeds with an excellent transfer of chiral-
ity from chiral cyclopropenylcarbinols to alkylidenecyclo-
propanes regardless of the nature of the secondary alcohols
(Table 8; R3 =alkyl (entry 1) or
aryl (entries 2–6)) and of the
alkyl
magnesium
iodides
(Table 8; R5 =aryl (entry 4) or
alkyl (entries 1–3, 5, 6)) used in
this transformation. The synthe-
sis of alkylidenecyclopropane
derivatives possessing enantio-
merically pure quaternary ste-
reocenters is therefore easily
achieved.[48] The results are
summarized in Table 8.
To establish the absolute con-
figuration and therefore to have
some insight into the reaction
mechanism, we had to convert Scheme 13. Derivatization of 7aa into crystalline product 11.
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Chem. Eur. J. 2009, 15, 8449 – 8464

Cyclopropenylcarbinol Derivatives
FULL PAPER
rection was applied to the correction of the wavelength of
the computed CD spectra (see Figure 2).
On the top spectra, the simulated R enantiomer (gray
line) does not fit with the experimental CD (black line). On
Figure 1. X-ray crystal structure determination of the absolute configura-
tion of 11.
cyclopropane derivatives were compared with calculated
CD spectra of both enantiomers.
Time-dependent DFT (TD-DFT) calculations have
proven to be very successful in predicting electronic spectra.
In flexible compounds, the calculation of the electronic and
CD spectra may become complicated since each of the con-
formers has different spectral characteristics and the ob-
served spectra are a weighted average of the different con-
formers. However, in rigid molecules like the one discussed
here, one or two (see below) conformations are enough to
describe the molecules.
Figure 2. Simulated CD (gray circles) and experimentally measured
(black circles) spectra of the R (top) and S (bottom) enantiomers of 7aa.
The geometries of the molecules were optimized at the
B3LYP/6-311G(d) theoretical level, which is sufficient for an
accurate description of the geometry. The spectral calcula-
tions should be carried out with a polarized and augmented
basis set in the presence of solvent. In general, the TD-DFT
simulations were carried out at the B3LYP/aug-cc-PVDZ
level, using the polarizable continuum model (PCM) for the
solvent description on B3LYP/6-311G(g) geometries. In
some cases convergence problems appeared. It was found
that TD-B3LYP/6-311+G(d) produced very similar spectra
but generally shows no convergence problems. Thus, in
some cases the latter computation level was used.
The number of transitions that were calculated was
always twenty to be sure that tails of strong absorbencies
that are outside of the measured region were included. Each
absorbance maximum was placed in a center of a Gaussian
with a line width of 20 nm, and the computed spectra are
the sum of such twenty Gaussians. As a standard procedure
the UV/Vis spectra were calculated and compared to the ex-
perimental spectra. This comparison allowed us to obtain
the wavelength difference, typically between 5 and 17 nm,
between the calculated and experimental spectra. This cor-
the other hand, the spectra on the bottom (please note that
the scales of the graphs are different) show the calculated
CD (gray line) is similar to the experimental CD (black
line). There is no complete superposition since the simulated
CD was for the pure (E)-alkylidenecyclopropane 7aa,
whereas the experimental alkylidenecyclopropane is formed
as an E/Z mixture of 95:5.
Mechanistic hypothesis: The absolute configuration of the
starting cyclopropenylcarbinol 2af and the final alkylidene-
cyclopropane 7aa implies an overall syn SN2’ displacement
of the alcohol moiety. However, starting at À508C, when
the stirred mixture was slowly warmed to room temperature
and carefully monitored by analyses of hydrolyzed aliquots,
we were able to isolate the addition product 12 in the range
of 30 to 40% and then this cyclopropylmetal (12·Cu or
12·MgX) disappears in favor of the alkylidenecyclopropane
7aa, which is obtained in good yields. Considering that the
deprotonation of the alcohol precedes the addition, the
most stable conformer of the cyclopropenylcarbinolate is
given in Scheme 14 with the smallest substituent at the pre-
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8457

I. Marek et al.
Scheme 15. Carbometalation of cyclopropenylcarbinol species with
RCu·MgBr2.
tives 12·Cu are stable towards b-elimination reactions
(Table 9). The formation of the trans-cyclopropylcarbinols
can be rationalized by a syn-directed carbocupration reac-
tion as indicated in Scheme 15. As summarized in Table 9,
Table 9. Diastereoselective carbocupration of cyclopropenylcarbinols 2.
Scheme 14. Mechanistic hypothesis for the formation of alkylidenecyclo-
propane derivatives.
À
Entry
R
E X
E
anti/syn ratio[a]
Yield [%][b]
1 (2i)
2 (2u)
3 (2w) CH(Ph)2
4 (2y)
5 (2z)
CH2CH2Ph
iPr
H3O+
H3O+
H3O+
H3O+
H3O+
I2
H
H
H
H
H
I
C3H5
75:25
>95:5
>95:5
>95:5
85:15
76 (13a)
82 (13b)
73 (13c)
92 (13d)
70 (13e)
84 (13 f)
81 (13g)
existing stereocenter (hydrogen) oriented “inside” and the
aryl group “outside”, away from the allylic methyl substitu-
ent (minimum A-1,3-strain). Thus, this catalytic reaction is
composed of 1) a syn copper-catalyzed carbomagnesiation
reaction leading to the corresponding cyclopropylcopper
12·Cu, followed by 2) a transmetalation reaction into the
corresponding cyclopropylmagnesium 12·Mg, and then 3) a
syn-elimination reaction (Scheme 14).
tBu
C6H5
6 (2w) CH(Ph)2
7 (2w) CH(Ph)2
>95:5
>95:5
allyl-Br
[a] Diastereomeric ratios were determined from the 1H NMR spectra of
the crude reaction mixture. [b] Yields determined after purification by
column chromatography on silica gel.
As the E/Z ratio is dependent on the nature of the halide
used (see Table 4), the percentage of syn versus anti elimina-
tion may be indeed dependent of the size of halide X in the
cyclic transition state of 12·Mg (Scheme 14); if X=I, a
cyclic transition state may be responsible for a syn elimina-
tion, whereas if X=Br or Cl, the size of the halide may not
accommodate the cyclic transition state and a certain per-
centage of anti b elimination can result.
the carbometalation reaction has been successfully extended
to a large variety of substrates (R=primary, secondary, and
tertiary alkyl groups; and aromatic groups; see entries 1 to
5, respectively, Table 9).
In general, these reactions exhibit excellent yields but the
diastereomeric ratio is dependent on the steric hindrance of
the R group at the carbinol center (compare Table 9, en-
tries 1 and 5 with entries 2–4). The anti/syn ratio is higher
than 95:5 with secondary and tertiary alkyl groups but only
moderate with primary alkyl and aromatic groups. The reac-
tion can also be performed with only two equivalents of
RMgBr instead of three equivalents as quoted in Table 9
(1 equiv is necessary for the deprotonation reaction) with
1 equiv of CuI (i.e., 2i leads to 13a in identical diastereo-
meric ratio) but the reaction takes longer. The stereochemis-
try was deduced from comparison with authentic samples.[36]
The presence of a discrete organometallic species was
checked by iodinolysis or by reaction with allyl halide
(Table 9, entries 6 and 7, respectively). Without copper salt,
the reaction does not proceed. So, clearly, the carbometala-
tion of RCu·MgX2 is stereochemically controlled by the sub-
stituent R, but more importantly, no b elimination was ob-
served, which suggests that the formation of alkylidenecy-
clopropanes (see Scheme 14) resulted from the contra-ther-
modynamic transmetalation of cyclopropylcopper 12·Cu into
cyclopropylmagnesium halide 12·Mg and the stereochemis-
try of the b elimination was dependent on the halide used
(Grignard reagents with different halides lead to the same
diastereoisomer for the conversion of 2i into 13a).
As quoted before, it was suggested that the elimination
proceeds only when the contra-thermodynamic copper to
magnesium transmetalation reaction occurs, as the inter-
mediate 12 could be isolated in the range of 30–40% by hy-
drolysis of aliquots (with only 20 mol% copper salt from the
beginning). Therefore, if such a transmetalation reaction
could be avoided, then the carbometalated product 12·Cu
would be more stable towards b elimination (the carbon–
copper bond is usually less prone to b elimination than the
carbon–magnesium bond),[52] and should react with different
electrophiles to give functionalized cyclopropylcarbinol de-
rivatives 13. To achieve this goal, the carbometalation reac-
tion should therefore be performed with a stoichiometric
amount of copper salt. Therefore, the same carbometalation
reaction has been performed but using a full equivalent of
copper salt. When cyclopropenylcarbinols 2 were treated
with an excess of Grignard reagents (2 or 3 equiv) in the
presence of 1 equiv of CuI in Et2O at 08C, we were pleased
to observe a fast carbometalation reaction that led to the
corresponding trans-cyclopropylcarbinol 13 after hydrolysis
(Scheme 15).[53]
Under such conditions, alkylidenecyclopropanes 7 were
not observed, which indicates that cyclopropylcopper deriva-
Surprisingly, when the same reaction was performed with
an organocuprate coming from nBuLi (instead of
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Cyclopropenylcarbinol Derivatives
FULL PAPER
nBuMgBr) with the same copper salt, the observed diaste-
reomeric ratio was 5:95 in favor of the syn isomer in good
isolated yield (Scheme 16)! A complete reversal of stereose-
lectivity was therefore observed when dialkyl cuprate is
used (compare Schemes 16 and 15).
preparation of functionalized cyclopropylcarbinols in good
to excellent yields.[53]
Here again, alkylidenecyclopropanes 7 were not observed,
which suggests that the cyclopropylcopper derivatives
formed after the carbocupration reactions are stable towards
b-elimination reactions. The formation of each of the two
possible diastereoisomers of polysubstituted cyclopropylcar-
binols 13 and 14 from a unique cyclopropenylcarbinol deriv-
ative 2, just by variation of the nature of the organometallic
species is synthetically interesting but mechanistically puz-
zling. Efforts are still being directed towards elucidating the
reaction mechanism. As nonracemic cyclopropenylcarbinols
are now easily accessible by means of the kinetic resolution
upon Sharpless epoxidation, this reaction represents a new
and versatile preparation of cyclopropyl derivatives that
possess two stereogenic quaternary stereocenters.
Scheme 16. Carbometalation of cyclopropenylcarbinol species with
R2CuLi.
This discrepancy is only valid for the carbometalation of
cyclopropenylcarbinol and cannot be extended to various
different allylic alcohols.
Formation of heterosubstituted alkylidenecyclopropane de-
rivatives: To further enrich the chemistry of cyclopropenyl-
carbinol derivatives 2 in synthesis, we also thought to use
the release of strain of the three-membered ring to promote
easy sigmatropic rearrangements[54] as a new route to alkyli-
denecyclopropanes that possess polar functionalities, such as
acetoxyalkylidenecyclopropane derivatives. Most of the
methods known to date for their preparation concern either
the reaction of alkylidene carbene with enol ether,[55] photo-
Although we still do not have a rational explanation for
this stereodivergent carbocupration reaction (we may
assume that different aggregation states of the organocopper
may lead to different stereoisomers), we have, however,
concentrated our efforts to improve the scope of this reac-
tion in favor of the syn isomer. The same syn/anti ratio can
also be obtained when the carbocupration reaction is per-
formed with only 1 equiv of lithium dialkyl cuprate on the
pre-lithiated cyclopropenylcarbinol 2. Whatever the stoichi-
ometry used in the preparation of the organocopper deriva-
tives from alkyllithium species and CuI (1–4 equiv of
Bu2CuLi, Bu2CuLi+nBuLi, Bu2CuLi+2nBuLi, Bu2CuLi+
2CuI, or Bu2CuCNLi2), the major isomer is always the syn
isomer, although this ratio depends on the experimental
conditions. Under our best conditions (see Table 10), the
AHCTUNGTRENNUNG
lysis of dithiolactone,[56] or through the addition of tBuOH
to 1,4-di-tert-butylmethylenecyclopropene.[57] Racemic cyclo-
propenylcarbinols 2 were first transformed easily into cyclo-
propenylacetate derivatives 15 through a classical esterifica-
tion reaction and the sigmatropic rearrangement of tertiary
cyclopropenylcarbinol was observed during the simple pu-
rification using column chromatography on silica gel to lead
to acetoxyalkylidenecyclopropane derivatives (Scheme 17).
Table 10. Diastereoselective carbocupration of cyclopropenylcarbinols 2
with R2CuLi.
À
Entry
R
E X
E
anti/syn ratio[a] Yield [%][b]
1 (2i)
CH2CH2Ph H3O+
iPr
CH(Ph)2
tBu
C6H5
H
H
H
H
H
H
I
5:95
10:90
6:94
5:95
10:90
1:99
78 (14a)
87 (14b)
81 (14c)
83 (14d)
75 (14e)
75 (14h)
86 (14 f)
77 (14g)
2 (2u)
3 (2w)
4 (2y)
5 (2z)
6 (2al) mesityl
7 (2w)
8 (2w)
H3O+
H3O+
H3O+
H3O+
H3O+
I2
Scheme 17. ACTHNUTRGNE[NUG 3,3] Sigmatropic rearrangement of cyclopropenylacetate 15.
Therefore, the [3,3] sigmatropic rearrangement of tertiary
allylic ester 15a can be performed under very mild condi-
tions either by simple filtration by column chromatography
on silica gel (Method A; see Table 11, entry 1), by heating
at reflux in CH2Cl2 (Method B; see Table 11, entry 2), or by
addition of dry acidic ion-exchange resin Amberlyst-15
(Method C; see Table 11, entry 3).[58] In all cases, the rear-
rangement occurs to give the expected 2-(diphenylmethy-
lene)-1-methylcyclopropyl acetate 16a in quantitative yields.
The relief of ring strain is again the driving force for such a
mild rearrangement (See Table 11).
CH(Ph)2
CH(Ph)2
6:94
6:94
allyl-Br C3H5
[a] Diastereomeric ratios were determined from 1H NMR spectra of the
crude reaction mixture. [b] Yields determined after purification by
column chromatography on silica gel.
scope of the reaction is broad since it proceeds similarly on
primary (Table 10, entry 1), secondary (Table 10, entries 2
and 3), tertiary (Table 10, entry 4), and even aromatic
(Table 10, entries 5 and 6) cyclopropenylcarbinols. The pres-
ence of the organometallic species was checked by reaction
with different electrophiles, such as iodine (Table 10,
entry 7) and allylbromide (Table 10, entry 8) to lead to the
Substituents on the double bond of the cyclopropenylace-
tate (R1) can be either alkyl or aryl (Table 11, entries 1–3
and 4), whereas substituents R2 and R3 are either alkyl, aryl,
Chem. Eur. J. 2009, 15, 8449 – 8464
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8459

I. Marek et al.
Table 11.
Entry
ACHTUNGTRENNUNG[3,3] Sigmatropic rearrangement of cyclopropenylacetate 15.
Such [2,3] sigmatropic rear-
rangements proceed extremely
fast at room temperature within
a few minutes, due to the re-
lease of strain, for primary
(Table 12, entry 1), secondary
(Table 12, entries 4–8), and ter-
tiary (Table 12, entries 2 and 3)
cyclopropenyldiphenylphos-
phinite derivatives. In all cases,
the corresponding phosphane
oxide of methylene- and alkyli-
denecyclopropanes was ob-
tained in excellent yields. When
secondary phosphinites were
R1
R2
R3
R4
Method[a]
E/Z ratio[b]
Yield [%][c]
1 (15a)
2 (15a)
3 (15a)
4 (15b)
5 (15c)
6 (15d)
7 (15e)
8 (15 f)
9 (15g)
10 (15h)
CH3
CH3
CH3
C6H5
CH3
CH3
CH3
CH3
CH3
C4H9
C6H5
C6H5
C6H5
CH3
C6H5
H
H
H
H
H
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
A
B
C
A
A
C
C
C
C
C
–
–
–
90 (16a)
92 (16a)
87 (16a)
91 (16b)
83 (16c)
75 (16d)
76 (16e)
70 (16 f)
60 (16g)
77 (16h)
–
CH3
2:1
>99
>99
>99
>99
>99
p-BrC6H4
C6H5
Ar[d]
Ar[d]
p-BrC6H4
[a] Method A: the rearrangement is performed during the purification of cyclopropenylacetates 15 by column
chromatography on silica gel; Method B: the rearrangement is performed at reflux in CH2Cl2; Method C: the
rearrangement is performed at RT overnight in the presence of Amberlyst-15 in CH2Cl2. [b] Determined from
1
the H and 13C NMR spectra of the crude reaction mixture. [c] Determined after purification by chromatogra-
phy on silica gel. [d] Ar=3,5-dibromophenyl.
Table 12.
phosphinites 15.
ACHTUNGTREN[NUNG 2,3] Sigmatropic rearrangement of cyclopropenyldiphenyl-
or hydrogen. When secondary aromatic alcohols were used
(R2 =H, R3 =Ar), only the E isomer was found in all experi-
ments (determined by NOE experiments) due to the chair-
like conformation in the transition state in which the R3 sub-
stituent occupies a pseudoequatorial position (Scheme 17
and Table 11, entries 6–10). When R2 =H and R3 =alkyl, the
reaction does not proceed under such mild conditions. Only
for 15c, which is produced from a nonsymmetric ketone,
were two geometrical isomers of 16c formed in a 2:1 ratio
(Table 11, entry 5). Due to the concerted, suprafacial nature
of such a rearrangement, a 1,3-chirality-transfer process can
be expected. Indeed, when enantiomerically enriched cyclo-
propenylacetates 15d,e were treated with Amberlyst-15
(Table 11, entries 6 and 7), the corresponding (S,E)-2-aryli-
dene-1-methylcyclopropyl acetates 16d,e were obtained with
the same enantioselectivity (>98% ee, 100% chirality trans-
fer).[59]
Entry
R1
R2
R3
E/Z ratio[a]
Yield [%][b]
1 (2g)
2 (2e)
3 (2d)
4 (2z)
5 (2aa)
6 (2ak)
7 (2i)
C4H9
C6H5
C4H9
CH3
C4H9
CH3
H
CH3
CH3
C6H5
H
–
–
–
94 (18a)
87 (18b)
93 (18c)
90 (18d)
93 (18e)
90 (18 f)
85 (18g)
85 (18h)
CH3
CH3
H
H
H
80:20
80:20
80:20
80:20
80:20
C6H5
Ar[c]
CH3
C4H9
CH2CH2Ph
CH(Ph)2
H
H
8 (2w)
[a] Determined from the 1H and 31P NMR spectra of the crude reaction
mixture. [b] Determined after purification by chromatography on silica
gel. [c] Ar=3,5-dibromophenyl.
used, two geometrical isomers of the corresponding phos-
phane oxides were obtained in a 80:20 E/Z ratio. Both iso-
mers are readily separated by using column chromatogra-
phy. The stereochemistry of the double bond was confirmed
by X-ray analysis for (Z)-18 f and deduced analogously for
the other reaction products.
When enantiomerically pure cyclopropenylcarbinols such
as 2aa, 2ak, and 2i were treated with diphenylchlorophos-
phane at room temperature, the expected (E)- and (Z)-alky-
lidenecyclopropane diphenylphosphane oxide derivatives
18e,f,g were obtained in a 80:20 ratio with a complete trans-
fer of chirality (>99% ee, respectively, Scheme 19).[64] In
As the design and the preparation of chiral phosphines
for asymmetric catalysis is an active area of research,[60] the
[2,3] sigmatropic rearrangement[61] of allylic diphenylphos-
phinites of general structure 17 was also investigated
(Scheme 18). Although a considerable number of reports in-
Scheme 18. ACHTUNGTRENNUNG[2,3] Sigmatropic rearrangement of cyclopropenyldiphenyl-
phosphinites 17.
vestigate the rearrangement of propargylic phosphinites,[62]
very few have addressed the stereochemical outcome of an
open-chain allylic system.[63] Herein, the application of this
sigmatropic rearrangement for the preparation of racemic
and chiral diphenylphosphane oxide bearing a quaternary
center was developed.
Scheme 19. Transfer of chirality in [2,3] sigmatropic rearrangement of cy-
clopropenyldiphenylphosphinites.
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Cyclopropenylcarbinol Derivatives
FULL PAPER
contrast to the well-defined transition state A for cyclopro-
penylacetates 15 (see Scheme 17), the transition state of
phosphinite intermediates 17 requires that the conforma-
tional issues of five-membered ring systems be addressed.[65]
The formation of the major isomer can be therefore ration-
alized by B, whereas the formation of the minor isomer is
due to a rotation of the cyclopropenyl ring as shown in C
(Scheme 19).
Theoretical calculations were employed for the elucida-
tion of the absolute configurations of 16d,e and 18e,f (for
both E and Z isomers). The different isomers and enantio-
mers were geometrically optimized at the B3LYP/6-311G(d)
computational level and underwent analytical frequency cal-
culations to ensure real minima (Nimg =0). For 16d and 16e,
only one stable conformer was found for each and used for
the calculation of the spectra, whereas two rotamers were
identified as minima for 18 f. One with the P=O bond syn
and one anti with respect to the three-membered ring. For
(E)-18 f and (Z)-18 f, the anti rotamers are more stable than
the syn rotamers by 0.765 and 2.95 kcalmolÀ1, respectively.
Thus, the anti rotamers populate 76.53 and 99.25%, respec-
tively, at room temperature. Since the CD spectra of each
rotamer are rather different (see the Supporting Informa-
tion), the CD spectrum that was used for comparison with
the experimental spectra is the weighted average of the two
for each isomer (see Figure 3).
TD-DFT calculations at the B3LYP/6-311++G(d) and
B3LYP/aug-cc-pVDZ levels in dichloromethane (using the
PCM model) for twenty singlet transitions were used for
generating the electronic and CD spectra. These spectra
were compared with the experimentally measured electronic
and CD spectra, thus allowing straightforward determina-
tion of the absolute configurations. Figure 3 shows the corre-
lation between the measured CD spectrum of (Z)- and (E)-
18 f and the computed ones, which allows the assignment of
the experimentally prepared enantiomers.
Figure 3. CD spectra of (Z)-18 f (top), and (E)-18 f (bottom): experimen-
tal (c); S enantiomer (g); R enantiomer (a).
Finally, phosphane oxide derivatives 18 f were readily con-
verted into the corresponding phosphanes 19 after reduction
with HSiCl3 (Scheme 20).[66]
Scheme 20. Reduction of phosphane oxide 18 into phosphane 19.
Conclusion
Cyclopropenylcarbinol 2, an easily accessible starting mate-
rial, is revealed to be an extremely versatile synthon in syn-
thetic organic chemistry. A copper-catalyzed carbomagnesia-
tion followed by a b elimination or a copper-catalyzed hy-
dride addition leads to the preparation of alkylidenecyclo-
propane derivatives in good to excellent chemical yields.
The reduction of 2 opens a new route to the diastereoselec-
tive preparation of anti-cyclopropylcarbinol, and the carbo-
metalation reaction with either an organocopper from a
Grignard reagent or from an alkyllithium species leads, at
will, to the two opposite diastereoisomers. The strain result-
ing from this 3-membered ring can also be easily released
through [3,3] and [2,3] sigmatropic rearrangements. As cy-
clopropenylcarbinol derivatives can be prepared enantio-
merically pure, all of these transformations lead to enantio-
merically enriched and pure functionalized substrates.
Experimental Section
General procedure for the preparation of cyclopropenylcarbinol deriva-
tives 2a–al: nBuLi (20 mmol) was added at À708C to a solution of 1,1,2-
tribromocyclopropane (10 mmol) dissolved in dry diethyl ether (70 mL).
The temperature was allowed to reach À108C over 30 min, was then
cooled to À208C, and an aldehyde or a ketone (12 mmol) was added.
The mixture was allowed to reach room temperature and the evolution
of the reaction was monitored by TLC.
After quenching with a saturated solution of ammonium chloride, the
aqueous layer was extracted with diethyl ether (3ꢂ20 mL), and the or-
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8461

I. Marek et al.
ganic phases were combined and washed with brine (1ꢂ20 mL), separat-
ed, dried, and evaporated. The crude product was purified by column
chromatography on silica gel (eluent: hexane/ethyl acetate 8:1 until the
appearance of the product, then 5:1).
(0.5 mmol) was added to a solution of Cu
AHCTUNGTRENNUNG
ACHTUNGRTEN(NUNG OTf)2 (0.5 mmol; Tf=tri-
was then added in one batch. The reaction was monitored by the rapid
disappearance of the yellowish powder from the reaction mixture, which
turned homogeneous and green after two minutes. MeCN was removed
in vacuo and the crude material was purified by flash chromatography on
silica gel (10 g; hexane/AcOEt 7:3) to yield sulfoximine as a yellow solid
(70%).
General procedure for the kinetic resolution of cyclopropenylcarbinol de-
rivatives 2 by means of a Sharpless epoxidation: (+)-Diethyl l-tartrate
(250 mg, 1.2 mmol) along with the corresponding cyclopropenylcarbinol
(1 mmol) were added to a flame-dried three-necked flask containing 4 ꢃ
molecular sieves and dry CH2Cl2 (10 mL). The temperature was lowered
General procedure for the preparation of cyclopropylcarbinols 13a–g: A
solution of nBuMgBr (1.1m/Et2O, 6 mmol, 5.5 mL) was added to a sus-
pension of CuI (0.38 g, 2 mmol) in diethyl ether (35 mL) at 08C. The mix-
ture was stirred for 15 min and a solution of cyclopropenylcarbinol 1a–e
(2 mmol) in diethyl ether (5 mL) was added very slowly so that the tem-
perature did not rise above 08C. The reaction was followed by TLC anal-
ysis of hydrolyzed aliquots (eluent: ethyl acetate/hexane, 1:9) and was
generally over after 30 min. After quenching with a saturated solution of
ammonium chloride, the aqueous layer was extracted with diethyl ether
(3ꢂ20 mL), and the organic phases were combined and washed with
brine (1ꢂ20 mL), separated, dried, and evaporated. The crude product
was purified by column chromatography on silica gel (eluent: hexane/
ethyl acetate 9:1).
to À208C and Ti
ACHTUNGTRENNUNG(OiPr)4 (1 mmol) was added. After this had been left
stirring for 30 min, tBuOOH (0.65 mmol) was added and stirred at the
same temperature for an additional 30 min. 30% NaOH (10 mL) was
added to the reaction mixture and the mixture was stirred for 30 min.
After extraction and phase separation, the organic phase was washed sev-
eral times with water, then separated, dried, and evaporated. The pure
product was separated by column chromatography on silica gel (eluent:
hexane/ethyl acetate 8:1).
General procedure for the enzymatic resolution of cyclopropenylcarbi-
nols 2: The racemic alcohol 2 (1 mmol) was dissolved in freshly distilled
pentane (20 mL) containing activated 4 ꢃ molecular sieves. Pseudomonas
cepacia lipase (0.15 g, 0.5 mass equiv) was added to the solution along
with distilled vinyl acetate (0.69 g). The solution was heated at reflux and
the course of the reaction was followed by either ꢄH NMR spectroscopy
or GC analysis. The solution was filtered, and volatiles were removed by
reduced pressure.
General procedure for the preparation of cyclopropylcarbinols 14a–h: A
solution of nBuLi (1.6m/hexane, 8 mmol, 5.0 mL) was added to a suspen-
sion of CuI (4 mmol, 0.76 g) in diethyl ether (35 mL) at À508C. The mix-
ture was stirred for 30 min while the temperature was raised slowly up to
À208C and stirred at the same temperature for an additional 15 min. The
mixture was cooled down to À508C and a solution of cyclopropenylcarbi-
nol 1a–e (2 mmol) in diethyl ether (5 mL) was added very slowly so that
the temperature did not rise above À508C. TLC analysis of hydrolyzed
aliquots (eluent: ethyl acetate/hexane, 1:9) showed that a reaction took
place when the temperature reached À208C, and was over 2 h later at
the same temperature. After quenching with a saturated solution of am-
monium chloride, the aqueous layer was extracted with ether (3ꢂ20 mL),
and the organic phases were combined and washed with brine (1ꢂ
20 mL), separated, dried, and evaporated. The crude product was puri-
fied by column chromatography on silica gel (eluent: hexane/ethyl ace-
tate 9:1).
General procedure for the preparation of alkylidenecyclopropane deriva-
tives 7a–ac: The cyclopropenylcarbinol (0.5 mmol) was dissolved in dry
diethyl ether (10 mL) containing CuI (0.1 mmol). The temperature was
lowered to À508C and the Grignard reagent (1.5 mmol) was added. The
reaction mixture was warmed to 08C very slowly (over 6 h) then to room
temperature over an additional 3h. The reaction was hydrolyzed with a
saturated solution of ammonium chloride and stirred until the aqueous
phase became blue. The aqueous layer was extracted with diethyl ether
(3ꢂ10 mL). The organic phases were combined and washed with brine
(1ꢂ10 mL), separated, dried, and evaporated. The crude product was pu-
rified by column chromatography on silica gel (eluent: hexane).
General procedure for the preparation of alkylidenecyclopropane deriva-
tives 7ad–ak: Cyclopropenylcarbinol 2 (1 mmol) was added to a dry
three-necked flask containing CuI (0.2 mmol) in dry diethyl ether
(20 mL). The temperature was lowered to À508C and a 1m solution of
LiAlH4 in THF (1.0 mL) was added. The reaction mixture was heated
slowly to room temperature overnight. After quenching with an aqueous
saturated solution of ammonium chloride, the aqueous layer was extract-
ed with diethyl ether (3ꢂ20 mL), the organic phases were combined and
washed with brine (1ꢂ20 mL), separated, dried, and evaporated. The
crude product was purified by column chromatography (eluent: hexane).
General procedure for the preparation of cyclopropenylacetate deriva-
tives 15a–h: 4-N,N-Dimethylaminopyridine (DMAP; 13.6 mg, 1.1 mmol)
was slowly added to
a stirred solution of cyclopropenylcarbinol 2
(1 mmol) in CH2Cl2 (2 mL). Acetic anhydride (1.3 mL) in Et2O (5 mL)
was then added at 08C. The reaction mixture was warmed to 258C and
stirred for an additional 30 min. The organic layer was washed with an
aqueous 1m HCl (3 mL) solution until neutral pH was reached, and was
then washed with brine (5 mL) and the aqueous layer was extracted with
Et2O (3ꢂ5 mL). The combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. The crude product
was purified by column chromatography on silica gel (eluent: hexane/
ethyl acetate 15:1 until the appearance of the product, then 5:1).
General procedure for the hydroalumination of cyclopropenylcarbinol
derivatives: LiAlH4 (1.4 mL, 1.0m solution in Et2O, 1.4 mmol) was added
to a stirred solution of 2 (0.28 g, 1.386 mmol) in Et2O (7 mL) at 08C. The
reaction mixture was heated to +408C for 4.5 h and was then quenched
with a 1m aqueous solution of HCl (5 mL). The aqueous layer was ex-
tracted with Et2O (3ꢂ10 mL) and the combined organic layers were
dried over MgSO4, filtered, and the solvent was removed under reduced
pressure. Chromatography on silica gel (eluent: hexane/ethyl acetate
10:1) gave the cyclopropyl derivative.
General procedures for the preparation of acetoxyalkylidenecyclopro-
pane derivatives 16a–h:
Method A: The rearrangement was performed during the purification of
cyclopropenylacetate 15 by column chromatography on silica gel (eluent:
hexane/ethyl acetate 50:1).
Method B: The rearrangement was performed when a solution of 15
(1 mmol) in CH2Cl2 (3 mL) was left at reflux overnight. The solvent was
then removed from the solution in vacuo. The crude product was purified
by column chromatography on silica gel (eluent: hexane/ethyl acetate 50:1).
Preparation of 4-(2-methyl-2-ethylcyclopropylidenemethyl)-p-tolylsulfox-
ide (10): Alkylidenecyclopropane (1 mmol) was dissolved in dry diethyl
ether (50 mL). The temperature was lowered to À788C and tBuLi
(2 mmol) was added. The mixture was stirred at À788C for 30 min then
allowed to reach À508C and 40 was added. The solution was warmed to
room temperature over 3 h, then hydrolyzed with a saturated aqueous so-
lution of NH4Cl. After extraction with diethyl ether (3ꢂ25 mL), the com-
bined organic layers were washed with brine (2ꢂ25 mL), separated,
dried, and evaporated. The crude product was purified by column chro-
matography on silica gel (eluent: hexane/ethyl acetate 15:1). The product
was isolated in 80% yield as a yellow solid.
Method C: The rearrangement was performed when a solution of 15
(1 mmol) in CH2Cl2 (5 mL) was treated with an excess of Amberlyst-15
under an argon atmosphere. The solution was stirred at room tempera-
ture overnight. Then the solution was filtered and the solvent was re-
moved from the solution under reduced pressure. The crude product was
purified by column chromatography on silica gel (eluent: hexane/ethyl
acetate 50:1).
Preparation of 4-(2-methyl-2-ethylcyclopropylidenemethyl)-p-tolylsulfox-
imine (11): 4-(2-Methyl-2-ethylcyclopropylidenemethyl)-p-tolylsulfoxide
General procedure for the preparation of alkylidenecyclopropanediphe-
nylphosphane oxide derivatives 18: A 50 mL Schlenk flask was charged
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Cyclopropenylcarbinol Derivatives
FULL PAPER
with
2
(1 mmol), DMAP (12.4 mg, 0.1 mmol), and triethylamine
[8] a) S. Chuprakov, M. Rubin, V. Gevorgyan, J. Am. Chem. Soc. 2005,
127, 3714; b) L-a. Liao, N. Yan, J. M. Fox, Org. Lett. 2004, 6, 4937;
c) S. Untiedt, A. de Meijere, Chem. Ber. 1994, 127, 1511; d) I. Zrin-
ski, N. Novak-Coumbassa, M. Eckert-Maksic, Organometallics 2004,
23, 2806 .
(0.14 mL, 1 mmol) in THF (5 mL) under an argon atmosphere. The mix-
ture was vigorously stirred at 08C and a solution of chlorodiphenylphos-
phine (0.18 mL, 1 mmol) was added dropwise to the solution. The ice
bath was then removed and the mixture was stirred for an additional
hour at room temperature. The precipitated salts were filtered off and
the THF was removed from the solution under reduced pressure. The
crude product was purified by column chromatography on silica gel (with
Et2O as eluent). The E and Z isomers of 18 can be easily separated by
using column chromatography on silica gel.
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Acknowledgements
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 (70/08), by a grant
from the G.I.F., the German–Israeli Foundation for Scientific Research
and Development (I-871-62.5/2005), and by the Fund for Promotion of
Research at the Technion. I.M. is holder of the Sir Michael and Lady
Sobell Academic Chair.
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Received: April 22, 2009
Published online: July 16, 2009
8464
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Chem. Eur. J. 2009, 15, 8449 – 8464