Modulable and highly diastereoselective carbometalations of cyclopropenes

Article abstract of DOI:10.1002/chem.201303569

The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from -35 to -20 °C to avoid subsequent fragmentation reaction into stereodefined β,γ-nonconjugated unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper species 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1. Copyright

Full text of DOI:10.1002/chem.201303569

DOI: 10.1002/chem.201303569
Full Paper
&
Carbometalation
Modulable and Highly Diastereoselective Carbometalations of
Cyclopropenes
Dorian Didier,[a] Pierre-Olivier Delaye,[a] Marwan Simaan,[a] Biana Island,[a] Guillaume Eppe,[a]
Hendrik Eijsberg,[a] Amir Kleiner,[a] Paul Knochel,[b] and Ilan Marek*[a]
Abstract: The copper-catalyzed carbomagnesiation reaction
of cyclopropenyl esters 1 leads to various substituted cyclo-
propanes species 3 in good yields with very high diastereo-
selectivities. The reaction proceeds through a syn-chelated
carbomagnesiation reaction and could be extended to vari-
ous cyclopropenylmethyl ester derivatives 5. The potential
of this approach was illustrated by the preparation of two
consecutive all-carbon quaternary stereocenters. However,
the carbometalation reaction needs to be performed at tem-
perature ranging from À35 to À208C to avoid subsequent
fragmentation reaction into stereodefined b,g-nonconjugat-
ed unsaturated esters 4. Alternatively, the carbocupration re-
action with organocopper species could also be performed
to leads to configurationally stable cyclopropyl copper spe-
cies 2[Cu]. Additionally, when the Lewis acid character of
the copper center is decreased (i.e., RCuCNLi), the reaction
proceed with an anti-selectivity. The diastereodivergent be-
havior of these organometallic species is of synthetic inter-
est, since both diastereomers syn-3 and anti-3 can be ob-
tained, at will, from the same precursor cyclopropenyl esters
1.
Introduction
tion of an alkyne usually leads to a single regioisomer, result-
ing from a syn-addition.[3] Moreover, the regioselectivity of the
reaction is typically controlled by the nature of the substitu-
ents on the triple bond (Scheme 1). Stereocontrol, regioselec-
tivity, and mechanism have been investigated in detail in the
Following the pioneering discovery and use of organomagnesi-
um reagents by Grignard in 1900,[1] the formation of carbon–
carbon bonds through the use of organometallic species has
been widely studied. In the repertoire of CÀC bond formation
with organometallic species, the carbometalation reactions of
nonpolarized multiple bonds represent a versatile tool to bi-
functionalize unsaturated systems. Indeed, the addition of
a carbon–metal bond of an organometallic across a carbon–
carbon unsaturated system leading to a new organometallic
species that can be further functionalized is called a carbometa-
lation reaction.[2]
Among all the possible candidates for carbometalation reac-
tions, organocopper derivatives occupy a significant place due
to their high stereo- and chemoselectivity, which enables them
to add smoothly to the triple bond of various alkynes even in
the presence of other functionalities.[3] Indeed, the carbocupra-
Scheme 1.
last few decades and summarized in several reviews.[4] Besides
forming stereodefined polysubstituted double bonds, the car-
bometalation reaction of alkynes can also be considered as
a starting point for the creation of more complex molecular ar-
chitectures when subsequent in-situ functionalizations are per-
formed (Scheme 2). In this context, the regio- and diastereose-
lective carbocupration of a-heterosubstituted alkyne deriva-
tives, such as chiral alkynyl sulfoxides,[5] ynamides,[6] alkynyl
ethers[7] and terminal alkynes,[8] led, after addition of Et2Zn,
CH2I2, and carbonyl electrophiles, to the formation of acyclic
adducts possessing two adjacent sp3 stereocenters, including
the challenging all-carbon quaternary stereocenters,[9] in good
yields and excellent diastereoselectivities (Scheme 2). Alterna-
tively, the vinyl copper intermediate can also react intramolec-
ularly with oxenoids[10] to give stereodefined b,b-disubstituted
[a] Dr. D. Didier, Dr. P.-O. Delaye, M. Simaan, B. Island, Dr. G. Eppe,
Dr. H. Eijsberg, A. Kleiner, Prof. Dr. I. Marek
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)4 829 3709
E-mail: chilanm@tx.technion.ac.il
[b] Prof. Dr. P. Knochel
Department Chemie und Biochemie
Ludwig-Maximilians-Universitꢀt, Butenandtstrasse 5–3
81377 Munich (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303569.
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as that of the starting organo-
metallic species and oligomeriza-
tion reactions typically occur.[12]
Assuming that one can control
the addition of an organometal-
lic species across the double
bond without further oligomeri-
zation, that is, if the reaction is
performed on a a,b-disubstitut-
ed double bond, the issue of re-
gioselectivity is raised. Further-
more, the addition of an electro-
phile leads to the creation of
two stereogenic centers and
issues of diastereoselectivity of
the reaction should also be con-
sidered.[13] Finally, the asymmet-
ric addition of a carbon nucleo-
Scheme 2.
phile (enantiofacial differentia-
tion) across an unactivated
double bond is still a challenging
enolates. The addition of aldehydes (or imines) led to the aldol
(or Mannich-type) adducts possessing the expected quaternary
stereocenter in good yields and high stereoselectivities
(Scheme 2).[11]
Highly substituted alkyl chains possessing contiguous sp3
stereocenters in acyclic systems could alternatively also be ob-
tained through the carbometalation of appropriate alkenes
(Scheme 3). However, such carbometalation reactions are
much more challenging than the carbometalation of alkynes,
since the carbometalated product is usually of similar reactivity
problem despite the fact that it would acquire a significant
utility as a method for the creation of asymmetric vicinal
carbon centers in acyclic systems (Scheme 3).[13]
As can be deduced from this introductory part, enantioselec-
tive carbometalation reactions of unactivated alkenes are
scarce and only few and very specific methods were reported
in the literature.[14] Alternatively, when strained alkenes, such as
cyclopropene (or norbornenes) derivatives are used, the re-
lease of strain associated with the carbometalation reaction
leads to an easier reaction and the resulting configurationally
stable sp3-cyclopropyl organometallic species formed can react
diastereoselectively with various electrophiles. For these rea-
sons, carbometalation of cyclopropenes is a field of intense ac-
tivity and since the pioneering work of Bubnov (carboboration
reaction),[15] Lehmkuhl (carbomagnesiation reaction),[16] Eisch
(carboalumination reaction),[17] and Negishi (carbocupration
and carbozincation reactions),[18] many elegant methods have
appeared in the literature.[19] In more recent years, several so-
phisticated synthesis of diversely substituted cyclopropane de-
rivatives have been reported involving diastereo- and/or enan-
tioselective carbometalation (and hydrometalation) reaction of
cyclopropenes.[20] Particularly appealing is the diastereoselec-
tive copper-catalyzed syn-carbomagnesiation of 3-hydroxyme-
thylcyclopropenes as an entry to functionalized cyclopropanes
with chiral quaternary stereocenters (Scheme 4, Path A).[21] The
corresponding cyclopropenyl esters were assumed to be in-
compatible with Grignard reagents and, therefore, they were
subjected to copper-catalyzed carbozincation (Scheme 4,
Path B).[22] The results were equivalent, but a large excess of
R2Zn is usually necessary to bring the reaction to completion.
In this report, we would like to disclose our results in full
and demonstrate that despite the presence of the ester, cyclo-
propenyl derivatives 1 can undergo a copper-catalyzed syn-car-
bomagnesiation reaction with extremely high diastereoselec-
tivity. Moreover, by changing the nature of the organometallic
Scheme 3.
Abstract in Hebrew:
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cetate derivatives and RhII, CoII, or IrII catalysts are well-estab-
lished methods and as a result, 2-substituted 2-cyclopropene-
carboxylic acid esters 1 are easily obtained with excellent
enantiomeric ratios and yields.[24] Therefore, from enantiomeric
enriched 1, easily prepared from simple terminal alkynes, the
formation of substituted cyclopropanes 3, as single diastereo-
isomers, are easily achieved. It is interesting to note that al-
though phenyl and methyl species are known to react very
sluggishly in carbocupration reaction, the strain release gener-
ated by the carbocupration of cyclopropenyl ester 1 allows the
reaction to proceed quickly and in good yields (Scheme 5, for-
mation of 3a to 3e).
Scheme 4.
The formation of the new functionalized cyclopropylmagne-
sium species was checked by reaction of 2 with various elec-
trophiles such as D3O+ (formation of 3h–3j, Scheme 5), allyl-
bromide (formation of 3k–3r, Scheme 5), propargyl bromide,
and acetone (formation of 3s and 3t respectively). In all cases,
diastereomeric ratios were excellent. The syn-diastereoselectiv-
ity of the copper-catalyzed carbomagnesiation was determined
by comparison of the formed adducts with authentic samples
from literature[21,22] and can be rationalized by the existence of
a chelated transition state between
species, the opposite anti isomer can also be obtained from
the same starting cyclopropenyl esters 1.
Results and Discussion
As organomagnesium species can tolerate a broad range of
functional groups and in particular esters,[23] we were interest-
ed in developing the copper-catalyzed carbomagnesiation of
cyclopropyl esters 1. We were pleased to observe that the re-
action proceeds very fast under extremely mild conditions
(1.3 equiv RMgX, CuI 10 mol%, Et2O, À358C, 10 to 30 min) to
give the expected cyclopropyl magnesium species 2 that react
with various electrophiles to give functionalized cyclopropanes
3 possessing the all-carbon quaternary stereogenic centers as
described in Scheme 5. Furthermore, the metal-catalyzed enan-
tioselective cyclopropenation of terminal alkynes with diazoa-
the carbonyl of the ester and the
Lewis acid organometallic species
(or with its associated salts,
Figure 1).[25]
Interestingly, even in a more co-
ordinating solvent such as THF, the
syn-chelated adducts are formed
with the same diastereo-
Figure 1.
meric ratios. The syn-ad-
dition of the Grignard species across the double
bond could be inferred by the configuration of deu-
terated species 3h–3j (J=7.9 to 8 Hz). Different
copper salts such as CuBr and CuCN could be used
with equal efficiency. It is important to note that the
copper-catalyzed carbomagnesiation of cyclopropen-
yl ester 1 has to be carried out at temperature
around À358C. Indeed, if the reaction is warmed up
to 08C, a stereospecific fragmentation reaction[26]
occurs to give stereodefined b,g-nonconjugated un-
saturated esters 4 (Scheme 6). The stereochemistry of
the formed alkenes results from a concerted frag-
mentation mechanism and has been determined by
comparison with known similar compounds previous-
ly described in the literature.[27] Such a mechanism
has been recently invoked in the Fe-catalyzed car-
boalumination/fragmentation of doubly activated cy-
clopropenyl carboxylates[27] or in the addition of
Grignard reagents to metalated cyclopropenyl di-
esters.[28]
This method offers an easy access to a wide range
of stereocontrolled alkenes, simply by permuting the
nature of R1 and R2 (on cyclopropene 1 and on the
Grignard reagent, respectively) and the E/Z ratio of
the double bond is directly related to the diastereo-
selectivity of the carbometalation reaction.
Scheme 5.
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Table 1. Carbocupration of cyclopropenyl esters 1.
Entry
R1
R2[Cu][a]
EÀX
d.r.[b]
Yield
[%][c]
1
2
3
4
5
Hex MeCu·MgBr2 H3O+
>98:2 (3b)
87:13 (3b)
97:3 (3 f)
97:3 (3u)
97:3 (3v)
72
71
67
70
65
Hex Me2CuLi
H3O+
H3O+
H3O+
AllylBr
Hex BuCu·LiI
Pr
BuCu·LiI
Hex HexCu·LiI
6
Bu
MeCu·MgBr2
97:3:0:0(3w) 62
7
8
Bu
Bu
MeCu·MgBr2
EtCu·MgBr2
97:3:0:0(3w) 52
97:3:0:0(3x)
43
Scheme 6.
[a] R2[Cu] reflects the stoichiometry of the reagents rather than the exact
structure of the organometallic species. [b] Determined by 1H and
13C NMR spectroscopy and gas chromatography. [c] Yield of isolated pure
products after purification by column chromatography.
Although the copper-catalyzed carbomagnesiation reaction
of cyclopropenyl esters 1 proceeds under very mild conditions
and with excellent diastereoselectivities, the corresponding cy-
clopropylmagnesium species 2 has to react with electrophiles
at low temperature (À35 to À208C) to avoid the fragmenta-
tion into the nonconjugated unsaturated esters 4. Therefore,
to expand the potential scope of reactivity of cyclopropylmetal
species 2 at higher temperature, we hypothesized that the cy-
clopropylcopper species should be more stable towards the
fragmentation and we have therefore examined the carbocup-
ration reaction of 1. Various organocopper species were pre-
pared and reacted with 1 as described in Table 1.
We were pleased to see that all organocopper species
added to cyclopropenyl ester 1 to give 3 in good yields and
similar diastereomeric ratios than the copper-catalyzed carbo-
magnesiation reaction (compare Scheme 5 and Table 1) and
that cyclopropyl copper species 2[Cu] is stable even at room
temperature (no ring fragmentation into b,g-nonconjugated
unsaturated esters 4). Various other sources of copper sources
such as CuI or CuBr·Me2S could be equally used and similar re-
sults were obtained. As the con-
the copper-catalyzed carbomagnesiation and organocopper
species, we then extended our studies to the carbometalation
of cyclopropenylmethyl ester derivatives 5 (Table 2).
For cyclopropenylmethyl carbamates (R3 =N(iPr)2), organo-
copper species generated from alkyllithium with CuBr (Table 2,
entries 1 and 4), with CuI (Table 2, entries 2 and 5) or the
copper-catalyzed carbomagnesiation (Table 2, entries 3 and 6)
led to the same syn-directed carbometalation reactions in
moderate yields, but in excellent diastereoselectivities. When
cyclopropenylmethyl esters 5c,d are used (R2 =Ph, R3 =CH3),
the carbocupration reaction leads to the formation of cyclopro-
panes possessing two adjacent all-carbon quaternary stereo-
centers with an excellent diastereoselectivity (Table 2, entries 7
and 8). These last two examples illustrate the potential of the
carbometalation reaction to generate substrates of higher mo-
lecular complexity. Indeed, one element of structure that invar-
sequence of this greater configu-
rational stability, cyclopropylcop-
Table 2. Carbocupration of cyclopropenylmethyl esters 5.
per species 2[Cu] react with
electrophiles, such as vinyl sul-
fone, through a Michael addi-
tion/elimination (Table 1, entry 6)
and alkynyl sulfone through
Entry
R1
R2
R3
R4[M][a]
d.r.[b]
Yield [%][c]
a
subsequent carbometalation
(Table 1, entries 7 and 8) to give
the corresponding addition ad-
ducts 3w,x. By decreasing the
Lewis acid character of the
copper center by using an orga-
nocuprate, the reaction proceeds
1
2
3
4
5
6
7
8
Hex (5a)
Hex (5a)
Hex (5a)
Pr (5b)
Pr (5b)
Pr (5b)
H
H
H
H
H
H
Ph
Ph
N(iPr)2
N(iPr)2
N(iPr)2
N(iPr)2
N(iPr)2
N(iPr)2
CH3
MeCu·LiBr
MeCu·LiI
MeMgBr, CuI (10 mol%)
MeCu·LiBr
MeCu·LiI
MeMgBr, CuI (10 mol%)
MeCu·LiBr
MeCu·LiBr
97:3
97:3
97:3
97:3
97:3
97:3
97:3
97:3
56 (7a)
60 (7a)
63 (7a)
62 (7b)
66 (7b)
65 (7b)
59 (7c)
63 (7d)
Hex (5c)
Pr (5d)
CH3
with
a
lower syn-selectivity
(Table 1, entry 3).
[a] R4[M] reflects the stoichiometry of the reagents rather than the exact structure of the organometallic spe-
cies. [b] Determined by H and 13C NMR spectroscopy and gas chromatography. [c] Yield of isolated pure prod-
1
Encouraged by the excellent
syn-selectivities obtained with
ucts after purification by column chromatography.
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iably increases the difficulty of a chemical synthesis is the pres-
ence in the target molecule of an all-carbon quaternary stereo-
center.[9] The impediment to synthesis presented by such cen-
ters arises from the steric congestion imposed by the four at-
tached carbons. This challenge is exacerbated further when
more than one stereogenic center is created in the final ad-
ducts as in 7c,d.
As described in Table 1, entry 2, when the Lewis acid charac-
ter of the copper center was decreased by using an organo-
cuprate, the reaction proceeded with a lower syn-selectivity.
We were therefore interested in decreasing the electrophilicity
of the copper center even further[29] in order to reverse the se-
lectivity of the carbometalation reaction. Indeed, when CuCN
was added to MeLi, the lower-order cyanocuprate RCuCNLi is
formed,[30] which exhibits a different reactivity towards the cy-
clopropenyl esters, leading to the opposite diastereoisomer
through an anti-directed carbocupration reaction as described
in Scheme 7. This ate complex of copper cannot chelate the
Indeed, this slight excess of RLi forms a “higher-order” cyano-
cuprate (or Lipshutz cuprate) possessing two organic groups
bonded to the copper center and the cyanide group bridges
two lithium cations (1.4MeLi for 1CuCN).[31] These lithium cat-
ions serve a chelating unit between the ester and the cuprate
species and led to the syn-directed adducts similar to the orga-
nocopper and copper-catalyzed carbomagnesiation reaction
(Scheme 8).[32]
Scheme 8.
This diastereodivergent carbometalation reaction of cyclo-
propenyl esters 1 has been used as a new sequence of com-
bined carbometalation/oxidation/selective ring opening of cy-
clopropanes, allowing for the preparation of aldehydes bearing
a-quaternary stereocenters in a one pot-reaction from these
readily available starting materials. Both enantiomers of the
corresponding aldehydes could be obtained from the same ini-
tial cyclopropene ester (Scheme 9).[33]
Scheme 7.
ester moiety and therefore reacts with an anti-selectivity most
probably to avoid steric interactions.
The diastereodivergent behavior of these organometallic
species are of synthetic interest since both diastereomers syn-3
(Scheme 5) and anti-3 (Scheme 7) can be obtained, at will,
from the same precursor cyclopropenyl esters 1. This diaste-
reodivergent carbometalation leading to the anti-adducts was
extended to various starting cyclopropenyl derivatives with
equal efficiency (Scheme 7). Notably, the addition of MeCuCNLi
to functionalized cyclopropenyl ester proceeds nicely despite
the presence of a ketone in the aliphatic chain (formation of
anti-3z). These carbometalation reactions are not restricted to
the introduction of a methyl group. as the addition of Bu-
CuCNLi led to the anti-carbometalated products, in good
yields and diastereomeric ratio. The resulting configurationally
stable cyclopropyl copper anti-2 could also react with electro-
philes as shown by the formation of anti-3m. However, it is ex-
tremely important to have a rigorous stoichiometric ratio be-
tween RLi and CuCN to exclusively form RCuCNLi, as a slight
excess of RLi (0.4 equiv excess) to the CuCN solution complete-
ly changed the stereochemical outcome of the reaction.
Scheme 9.
We also investigated whether the carbometalation reaction
of strained carbocycles could be extended to cyclobutene
ester 8,[34] (Scheme 10). Various organometallic species were
tested for the carbometalation, such as copper-catalyzed car-
bomagnesiation, copper-catalyzed carbozincation, organocop-
per (in Et2O and in THF) and organocuprate, but none of them
gave rise to the desired carbometalated adducts.
Clearly, the difference of behavior between cyclopropenes
1 and cyclobutene 8 towards the addition of organometallic
species across the cyclic double bond is due to the different
strain energy released during the carbometalation reaction (cy-
clopropene to cyclopropane: 30 kcalmolÀ1; cyclobutene to cy-
clobutane: 6 kcalmolÀ1).[35]
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pounds.[24g,41] Compounds 3a–3g, anti-3b, anti-3c, anti-3e, anti-3y
and anti-3z were previously described.[33]
General procedures
General procedure A for the copper-catalyzed carbomagnesia-
tion of cyclopropenes: Alkylmagnesium bromide (1.3 equiv) was
added dropwise to a suspension of CuI (19 mg, 0.1 mmol) in Et2O
(10 mL) and cyclopropene (1.0 mmol) held at À458C. The resulting
mixture (yellowish) was then stirred at À358C (followed by TLC
with hexanes/Et2O 19:1 as eluent, ca. 10 min). The electrophile
(1.8 equiv, 1.8 mmol) was then added and the reaction was
warmed to À208C before quenching with aqueous NH4Cl/NH4OH
(2:1) solution. The aqueous layer was extracted twice with Et2O.
The combined organics were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Crude
mixtures were then purified by flash chromatography using a hex-
anes/Et2O mixture.
Scheme 10.
Conclusion
The copper-catalyzed carbomagnesiation reaction of cyclopro-
penyl esters 1 leads to various substituted cyclopropanes spe-
cies 3 in good yields with very high diastereoselectivities. The
reaction proceeds through a syn-chelated carbomagnesiation
reaction and could be extended to various cyclopropenylmeth-
yl ester derivatives 5. The potential of this approach was illus-
trated by the preparation of two consecutive all-carbon qua-
ternary stereocenters. However, the carbometalation reaction
needs to be performed at temperature ranging from À35 to
À208C to avoid subsequent fragmentation reaction into ster-
eodefined b,g-nonconjugated unsaturated esters 4. Alternative-
ly, the carbocupration reaction with organocopper species
could also be performed to leads to configurationally stable
cyclopropyl copper species 2[Cu]. Additionally, when the Lewis
acid character of the copper center is decreased (i.e., RCuCNLi),
the reaction proceed with an anti-selectivity. The diastereodi-
vergent behavior of these organometallic species is of synthet-
ic interest, since both diastereomers syn-3 and anti-3 can be
obtained, at will, from the same precursor cyclopropenyl esters
1.
General procedure B for the carbocupration reaction of cyclo-
propenes with organocopper species (from alkylmagnesium
species): Alkylmagnesium bromide (1.3 equiv, 1.3 mmol) was
added dropwise to a suspension of CuI (247 mg, 1.3 mmol) in Et2O
(8 mL) at À358C. The bright yellow solution was stirred at À308C
for 30 min. Cyclopropene (1.0 equiv, 1.0 mmol in solution in Et2O:
2 mLmmolÀ1) was then added dropwise at À308C. The solution
was then stirred at the same temperature until completion (fol-
lowed by TLC with hexanes/Et2O 19:1 as eluent, ca. 30 min). The re-
action was then quenched with aqueous NH4Cl/NH4OH (2:1) solu-
tion. The aqueous layer was extracted twice with Et2O. The com-
bined organics were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. Crude mixtures were
then purified by flash chromatography using a hexanes/Et2O mix-
ture.
General procedure C for the carbocupration reaction of cyclo-
propenes with organocopper species (from alkyllithium species):
Alkyllithium (1.3 equiv, 1.3 mmol) was added dropwise to a suspen-
sion of CuX (X=I, 228 mg, 1.3 mmol or X=Br, 186 mg, 1.3 mmol)
in Et2O (8 mL) at À358C. The brown solution was stirred at À358C
for 30 min. Cyclopropene (1.0 equiv, 1.0 mmol in solution in Et2O:
2 mLmmolÀ1) was then added dropwise at À358C. The solution
was then stirred at the same temperature until completion (fol-
lowed by TLC with hexanes/Et2O 19:1 as eluent, ca. 30 min). The re-
action was then quenched with aqueous NH4Cl/NH4OH (2:1) solu-
tion. The aqueous layer was extracted twice with Et2O. The com-
bined organics were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. Crude mixtures were
then purified by flash chromatography using a hexanes/Et2O mix-
ture.
Experimental Section
All glassware was flame dried under vacuum, and cooled under
argon prior to use. All reactions were carried out under positive
pressure of argon. Diethyl ether and THF were dried from Pure-
Solv Purification System (Innovative Technology). Dichloromethane
was distilled from CaH2. Copper iodide, copper cyanide, rhodium
acetate dimer, methyllithium (1.6m in diethyl ether), n-butyllithium
(1.6m in hexanes, methylmagnesium bromide (3.0m in diethyl
ether) were commercially available. Phenylmagnesium bromide
(1.1m in diethyl ether), n-butylmagnesium bromide (1.5m in dieth-
yl ether) and n-hexylmagnesium bromide (1.25m in diethyl ether)
were prepared according to the literature,[37] and freshly titrated
before using with menthol/1,10-phenanthroline.[38] Thin-layer chro-
matography (TLC) was performed using Merck silica gel 60F254
plates. Column chromatography was performed using Bio-Lab
General procedure D for the carbocupration reaction of cyclo-
propenes with organocuprate (from alkyllithium species): Alkyl-
lithium (1.2 equiv, 1.2 mmol) was added dropwise to a suspension
of CuCN (107 mg, 1.2 mmol) in Et2O (10 mL) at À308C. The result-
ing mixture (pale yellow to colorless in the case of MeLi, yellow to
brown in the case of nBuLi) was stirred for 30 min at this tempera-
ture. Cyclopropene (1 equiv, 1.0 mmol in solution in Et2O:
1 mLmmolÀ1) was then added dropwise at À308C. The solution
(yellow in the case of MeLi, orange to brown in the case of nBuLi)
was then stirred at the same temperature until completion (fol-
lowed by TLC with hexanes/AcOEt 9:1 as eluent, ca. 30 min). The
reaction was then quenched with aqueous NH4Cl/NH4OH (2:1) so-
lution. The aqueous layer was extracted twice with AcOEt. The
combined organics were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. Crude mixtures
silica gel 60A (0.040–0.063 mm). H and 13C NMR spectra were re-
corded on Bruker spectrometers DPX200, AV300, or AVIII400, using
1
1
CDCl3 (unless otherwise specified) as solvent. For H NMR, the ab-
breviation “app” stands for apparent and “AB” for an AB system.
The GC chromatograms were recorded using Varian 3800 appara-
tus with Varian CP-Sil 8CB column. HPLC chromatograms were re-
corded using Agilent 1100 Series line with CHIRALPAK AD-H or
CHIRALCEL OD. 1,4-dinitrotoluene was used as internal standard
for the determination of NMR yields. Cyclopropenes were prepared
according to known procedure[39] using alkynes,[40] rhodium acetate
dimer and ethyl diazoacetate in CH2Cl2 and are known com-
Chem. Eur. J. 2014, 20, 1038 – 1048
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1043
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
were then purified by flash chromatography using hexanes/AcOEt
mixture.
anes/Et2O 95:5); yield: 48% (yellowish oil); Rf =0.47 (hexanes/Et2O
95:5); H NMR (CDCl3, 400 MHz): d=0.76 (t, J=6.8 Hz, 3H), 1.07 (t,
1
J=7.2 Hz, 3H), 1.10–1.23 (m, 8H), 1.34–1.41 (m, 1H), 1.43–1.56 (m,
2H), 1.81 (d, J=8.6 Hz, 1H), 2.24–2.31 (m, 1H), 2.35–2.45 (m, 1H),
3.88–3.99 (m, 2H), 4.92 (d, J=10.3 Hz, 1H), 5.02 (d, J=17.3 Hz, 1H),
5.79 (ddt, J=17.3, 10.3, 6.0 Hz, 1H), 7.01–7.03 (m, 2H), 7.12–
7.22 ppm (m, 3H); 13C NMR (CDCl3, 100 MHz): d=14.2, 14.4, 22.7,
26.6, 29.3, 29.5, 29.7, 31.9, 32.0, 39.9, 45.1, 60.0, 114.7, 126.6, 127.9,
130.8, 137.7, 138.1, 170.9 ppm; HRMS (ESI pos): m/z calcd for
General procedure E for the carbocupration reaction of cyclo-
propenes with 1.4 equivalents RLi and 1 equivalent CuCN: Alkyl-
lithium (1.56 equiv, 1.56 mmol) was added dropwise to a suspen-
sion of CuCN (107 mg, 1.2 mmol) in Et2O (10 mL) at À308C. The re-
sulting mixture was stirred for 30 min at this temperature. Cyclo-
propene (1.0 equiv, 1.0 mmol in solution in Et2O: 1 mLmmolÀ1) was
then added dropwise at À308C. The solution was then stirred at
the same temperature until completion (followed by TLC with hex-
anes/AcOEt 9:1 as eluent, ca. 30 min). The reaction was then
quenched with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous
layer was extracted twice with AcOEt. The combined organics were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. Crude mixtures were then purified by
flash chromatography using hexanes/AcOEt mixture.
C21H31O2 [M+H]+: 315.2324; found: 315.2350.
+
(1S*,2S*,3R*)-Ethyl 3-allyl-2-hexyl-2-methylcyclopropanecarboxy-
late (3m) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 86% isolated, 93% without purification, suit-
able for analysis (yellowish oil); Rf =0.56 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 400 MHz): d=0.86 (t, J=6.8 Hz, 3H), 1.13 (q, J=
8.0 Hz, 1H), 1.17 (s, 3H), 1.20–1.37 (m, 13H), 1.42 (d, J=8.8 Hz, 1H),
2.37–2.41 (m, 2H), 4.04–4.10 (m, 2H), 4.94 (dd, J=10.2, 1.3 Hz, 1H),
5.03 (dd, J=17.2, 1.3 Hz, 1H), 5.80 ppm (ddt, 17.2, 10.2, 6.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d=11.6, 14.2, 14.5, 22.7, 26.5, 27.5,
28.0, 28.0, 29.4, 31.8, 32.0, 43.1, 59.7, 114.5, 138.0, 171.9 ppm;
Compound characterization
(1S*,2S*,3R*)-Ethyl 2-ethyl-2-hexyl-(3-2H1) cyclopropane carbox-
ylate (3h) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 65% (colorless oil); Rf =0.65 (hexanes/Et2O
HRMS (ESI pos): m/z calcd for C16H29O2 [M+H]+: 253.2168; found:
+
253.2150.
1
95:5); H NMR (CDCl3, 300 MHz): d=0.80 (d, J=7.9 Hz, 1H), 0.84 (t,
(1S*,2S*,3R*)-Ethyl 3-allyl-2-butyl-2-methylcyclopropanecarboxy-
late (3n) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 80% isolated, 93% without purification, suit-
able for analysis (yellowish oil); Rf =0.55 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 300 MHz): d=0.88 (t, J=7.1 Hz, 3H), 1.14 (dt, J=
8.5, 7.4 Hz, 1H), 1.19 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.25–1.39 (m,
6H), 1.43 (d, J=8.8 Hz, 1H), 2.37–2.45 (m, 2H), 3.99–4.15 (m, 2H),
4.95 (dq, J=10.3, 1.7 Hz, 1H), 5.04 (dq, J=17.1, 1.7 Hz, 1H),
5.82 ppm (ddt, J=17.1, 10.3, 6.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d=11.6, 14.3, 14.5, 22.9, 27.5, 28.0, 28.7, 29.5, 31.9, 42.9, 59.8,
J=7.4 Hz, 3H), 0.87 (t, J=7.1 Hz, 3H), 1.12–1.38 (m, 12H), 1.41–
1.45 (m, 2H), 1.46–1.53 (m, 1H), 1.55–1.63 (m, 1H), 4.11 ppm (q, J=
7.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz): d=11.0, 14.2, 14.5, 20.6 (t,
J=24.6), 21.7, 22.8, 26.2, 26.3, 29.5, 32.0, 32.3, 36.5, 60.3,
173.0 ppm; HRMS (ESI pos): m/z calcd for C14H26DO2 [M+H]+:
+
228.2074; found: 228.2066.
(1S*,2R*)-Ethyl
2-butyl-2-ethyl-(3-2H1)cyclopropanecarboxylate
(3i) was prepared according to procedure A: Eluent (hexanes/
Et2O 95:5); yield: 81% (colorless oil); Rf =0.46 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 300 MHz): d=0.79 (d, J=7.9 Hz, 1H), 0.85 (t, J=
7.1 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H), 1.17–1.33 (m, 7H), 1.35–1.47 (m,
4H), 1.51–1.56 (m, 1H), 4.10 ppm (q, J=7.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=10.6, 14.3, 14.5, 20.3 (t, J=24.5 Hz), 23.0, 26.0,
28.0, 29.0, 29.8, 32.2, 60.3, 173.0 ppm; HRMS (ESI pos): m/z calcd
+
114.6, 138.0, 172.0 ppm; HRMS (ESI pos): m/z calcd for C14H25O2
[M+H]+ 225.1855; found: 225.1837.
(1S*,2S*,3R*)-Ethyl 3-allyl-2-ethyl-2-methylcyclopropanecarboxy-
late (3o) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 89% (yellowish oil); Rf =0.54 (hexanes/Et2O
for C12H22DO2 [M+H]+: 200.1761; found: 200.1758.
+
1
95:5); H NMR (CDCl3, 300 MHz): d=0.88 (t, J=7.4 Hz, 3H), 1.09 (dt,
J=8.9, 7.4 Hz, 1H), 1.14 (s, 3H), 1.18 (t, J=7.1 Hz, 3H), 1.26 (q, J=
7.4 Hz, 2H), 1.38 (d, J=8.9 Hz, 1H), 2.31–2.40 (m, 2H), 3.97–4.06
(m, 2H), 4.89 (d, J=10.9 Hz, 1H), 4.99 (d, J=16.8 Hz, 1H), 5.76 ppm
(ddt, J=16.8, 10.4, 6.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=10.5,
11.0, 14.4, 27.4, 27.7, 30.3, 31.6, 35.6, 59.6, 114.4, 137.8, 171.7 ppm;
(1S*,2R*)-Ethyl 2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-2-methyl-
(3-2H1)cyclopropanecarboxylate (3j) was prepared according to
procedure A: Eluent (hexanes/Et2O 95:5); yield: 71% (yellowish
oil); Rf =0.39 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=
0.84 (d, J=8.0 Hz, 1H), 1.04 (s, 9H), 1.13 (s, 3H), 1.22 (t, J=7.2 Hz,
3H), 1.52 (d, J=8.0 Hz, 1H), 1.56 (t, J=6.6 Hz, 2H), 3.72–3.79 (m,
2H), 4.03–4.16 (m, 2H), 7.35–7.45 (m, 6H), 7.65–7.69 (m, 4H);
13C NMR (CDCl3, 75 MHz): d=14.5, 16.4, 19.2, 20.8 (t, J=24.2 Hz),
21.1, 24.4, 26.0, 26.9, 43.2, 60.3, 61.9, 127.8, 129.7, 133.9, 135.7,
HRMS (ESI pos): m/z calcd for C12H21O2 [M+H]+: 197.1542; found:
+
197.1522.
(1S*,2R*,3R*)-Ethyl 3-allyl-2-butyl-2-ethylcyclopropanecarboxy-
late (3p) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 77% as a 95:5 mixture of diastereoisomers
syn-2s and anti-2s (yellowish oil); Rf =0.47 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 400 MHz): d=0.86–0.91 (m, 6H), 1.10–1.19 (m, 3H),
1.23 (t, J=7.1 Hz, 3H), 1.26–1.33 (m, 3H), 1.41 (d, J=8.6 Hz, 1H),
1.44–1.51 (m, 1H), 1.63–1.68 (m, 2H), 2.43–2.46 (m, 2H), 4.06 (q,
J=7.1 Hz, 2H), 4.94 (d, J=10.3 Hz, 1H), 5.04 (d, J=17.2 Hz, 1H),
5.80 ppm (ddt, J=17.2, 10.3, 6.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d=10.3, 14.2, 14.5, 23.1, 23.2, 27.5, 28.0, 29.0, 32.2, 32.4,
34.6, 59.8, 114.6, 138.2, 171.9 ppm; HRMS (ESI pos): m/z calcd for
172.9 ppm; HRMS (ESI pos): m/z calcd for C25H33NaDO3 [M+Na]+:
+
434.2238; found: 434.2231.
(1S*,2S*,3R*)-Ethyl 3-allyl-2-benzyl-2-methylcyclopropanecarbox-
ylate (3k) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 76% (yellowish oil); Rf =0.49 (hexanes/Et2O
1
95:5); H NMR (CDCl3, 300 MHz): d=1.17( s, 3H), 1.24 (t, J=7.1 Hz,
3H), 1.37 (dt, J=8.8, 7.6 Hz, 1H), 1.68 (d, J=8.8 Hz, 1H), 2.43 (dt,
J=7.6, 1.4 Hz, 1H), 2.45 (dt, J=7.6, 1.3 Hz, 1H), 2.61 (d, J=13.9 Hz,
1H), 2.71 (d, J=13.9 Hz, 1H), 4.05–4.13 (m, 2H), 4.96 (dq, J=10.3,
1.5 Hz, 1H), 5.05 (dq, J=17.3, 1.5 Hz, 1H), 5.81 (ddt, J=17.3, 10.3,
6.1 Hz, 1H), 7.17–7.31 ppm (m, 5H); 13C NMR (CDCl3, 75 MHz): d=
12.1, 14.5, 27.2, 27.5, 29.7, 30.6, 48.0, 59.9, 114.8, 126.5, 128.3,
129.4, 137.7, 139.0, 171.7 ppm; HRMS (ESI pos): m/z calcd for
C12H21O2 [M+H]+: 239.2011; found: 239.2032.
+
(1S*,2S*,3R*)-Ethyl 3-allyl-2-{2-[(tert-butyldiphenylsilyl)oxy]eth-
yl}-2-methylcyclopropanecarboxylate (3q) was prepared accord-
ing to procedure A: Eluent (hexanes/Et2O 95:5); yield: 72% (yel-
C17H23O2 [M+H]+: 259.1698; found: 259.1701
+
1
lowish oil); Rf =0.32 (hexanes/Et2O 95:5); H NMR (CDCl3, 300 MHz):
(1S*,2R*,3R*)-Ethyl 3-allyl-2-hexyl-2-phenylcyclopropanecarboxy-
late (3l) was prepared according to procedure A: Eluent (hex-
d=1.06 (s, 9H), 1.14–1.20 (m, 1H), 1.19 (s, 3H), 1.23 (t, J=7.1 Hz,
3H), 1.52–1.60 (m, 3H), 2.38–2.42 (m, 2H), 3.73–3.80 (m, 2H), 3.98–
Chem. Eur. J. 2014, 20, 1038 – 1048
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1044
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
4.16 (m, 2H), 4.95 (dq, J=10.3, 1.5 Hz, 1H), 5.03 (dq, J=17.3,
1.5 Hz, 1H), 5.80 (ddt, J=17.3, 10.3, 6.1 Hz, 1H), 7.36–7.44 (m, 6H),
7.66–7.69 ppm (m, 4H); 13C NMR (CDCl3, 75 MHz): d=11.8, 14.4,
19.2, 26.9, 27.3, 27.5, 27.6, 31.3, 45.3, 59.9, 61.8, 114.7, 127.8, 129.8,
133.8, 135.7, 137.8, 171.9 ppm; HRMS (ESI pos): m/z calcd for
C28H38O3NaSi+ [M+Na]+: 473.2488; found: 473.2480.
(m, 11H), 1.49–1.65 (m, 3H), 1.69 (d, J=6.1 Hz, 1H), 2.14 (d, J=
6.1 Hz, 1H), 2.43 (s, 3H), 2.73–2.79 (m, 1H), 4.11 (q, J=7.1 Hz, 2H),
6.00 (s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.77 ppm (d, J=8.0 Hz,
2H);13C NMR (CDCl3, 100 MHz): d=13.9, 14.2, 14.4, 18.2, 21.7, 22.9,
23.1, 29.2, 30.0, 31.2, 32.7, 33.8, 35.2, 39.1, 60.9, 127.1, 127.3, 130.0,
139.7, 144.2, 156.9, 171.1 ppm; HRMS (ESI pos): m/z calcd for
C24H36O4SNa+ [M+Na]+ 443.2232; found: 443.2274.
(1S*,2S*,3R*)-Ethyl 3-allyl-2-[2-(benzyloxy)ethyl]-2-methylcyclo-
propanecarboxylate (3r) was prepared according to procedure
A: Eluent (hexanes/Et2O 95:5); yield: 68% (yellowish oil); Rf =0.42
(hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=1.12–1.20 (m,
7H), 1.48 (d, J=8.9 Hz, 1H), 1.58 (td, J=6.8, 2.1 Hz, 2H), 2.31–2.37
(m, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.95–4.07 (m, 2H), 4.42 (s, 2H), 4.88
(dq, J=10.2, 1.7 Hz, 1H), 4.97 (dq, J=17.2, 1.7 Hz, 1H), 5.74 (ddt,
J=17.2, 10.2, 6.3 Hz, 1H), 7.17–7.30 ppm (m, 5H); 13C NMR (CDCl3,
75 MHz): d=11.9, 14.5, 27.1, 27.3, 27.6, 31.4, 42.5, 59.9, 68.3, 73.2,
114.7, 127.6, 127.7, 128.4, 137.8, 138.5, 171.7 ppm; HRMS (ESI pos):
(1S*,2S*,3R*)-Ethyl 2-butyl-2-ethyl-3-[(E)-1-tosylhex-1-en-2-yl]cy-
clopropanecarboxylate (3x) was prepared according to proce-
dure C: Eluent (hexanes/Et2O 95:5); yield: 43% isolated (colorless
oil); Rf =0.15 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=
0.79–0.90 (m, 9H), 1.01 (q, J=7.2 Hz, 2H), 1.21–1.44 (m, 12H),
1.49–1.54 (m, 2H), 1.66 (d, J=6.3 Hz, 1H), 2.17 (d, J=6.3 Hz, 1H),
2.41 (s, 3H), 2.87–2.97 (m, 1H), 4.09 (q, J=7.2 Hz, 2H), 6.00 (s, 1H),
7.31 (d, J=8.2 Hz, 2H), 7.75 ppm (d, J=8.2 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): d=11.0, 14.0, 14.3, 14.5, 21.8, 23.1, 23.2, 23.7,
29.1, 29.3, 30.6, 31.2, 33.0, 39.4, 40.3, 61.0, 127.2, 127.4, 130.0,
139.8, 144.3, 157.0, 171.1; HRMS (ESI pos): m/z calcd for
C25H38O4SNa+ [M+Na]+ 457.2389; found: 457.2364.
m/z calcd for C19H27O3 [M+H]+: 303.1960; found: 303.1971.
+
(1S*,2S*,3R*)-Ethyl 2-hexyl-2-methyl-3-(propa-1,2-dien-1-yl)cyclo-
propanecarboxylate (3s) was prepared according to procedure
A: Eluent (hexanes/Et2O 95:5); yield: 63% (yellowish oil); Rf =0.63
(hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=0.87 (t, J=
6.6 Hz, 3H), 1.15–1.18 (m, 1H), 1.22 (s, 3H), 1.24–1.38 (m, 12H),
1.65 (d, J=8.5 Hz, 1H), 1.73–1.79 (m, 1H), 4.06–4.14 (m, 2H), 4.74
(d, J=6.7 Hz, 2H), 5.52 ppm (dt, J=9.6, 6.7 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=12.0, 14.2, 14.5, 22.8, 26.3, 29.4, 30.2, 30.3,
31.7, 32.0, 42.6, 60.1, 75.3, 85.9, 171.2, 210.4 ppm; HRMS (ESI pos):
(1S*,2R*,3S*)-Ethyl 3-allyl-2-hexyl-2-methylcyclopropanecarboxy-
late (3manti) was prepared according to procedure D: Eluent (hex-
anes/Et2O 95:5); yield: 63% (yellowish oil); Rf =0.55 (hexanes/Et2O
1
95:5); H NMR (CDCl3, 400 MHz): d=0.84 (t, J=6.8 Hz, 3H), 1.10 (s,
3H), 1.18–1.25 (m, 11H), 1.29–1.54 (m, 4H), 2.02–2.09 (m, 1H),
2.13–2.20 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 4.96 (d, J=10.1 Hz, 1H),
5.02 (d, J=17.2 Hz, 1H), 5.81 ppm (ddt, J=17.2, 10.1, 6.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d=14.1, 14.4, 18.4, 22.7, 26.9, 29.5, 29.5,
31.9, 32.0, 32.4, 32.7, 34.3, 60.2, 115.0, 137.2, 172.8 ppm; HRMS (ESI
m/z calcd for C16H27O2 [M+H]+: 251.2011; found: 251.2009.
+
(1S*,5R*,6S*)-6-Hexyl-4,4,6-trimethyl-3-oxabicyclo[3.1.0]hexan-2-
one (3t) was prepared according to procedure A: Eluent (hex-
anes/Et2O 95:5); yield: 79% (yellowish oil); Rf =0.17 (hexanes/Et2O
95:5); 1H NMR (CDCl3, 300 MHz): d=0.86 (t, J=6.8 Hz, 3H), 1.00–
1.12 (m, 1H), 1.21–1.27 (m, 7H), 1.28 (s, 3H), 1.34–1.39 (m, 2H),
1.42 (s, 6H), 1.72 (d, J=6.0 Hz, 1H), 1.97 ppm (d, J=6.0 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d=14.2, 14.7, 22.7, 22.7, 26.4, 29.3, 29.5,
31.0, 31.8, 31.8, 38.5, 40.3, 83.0, 174.4 ppm; HRMS (ESI pos): m/z
pos): m/z calcd for C16H29O2 [M+H]+: 253.2168; found: 253.2156.
+
(1R*,2S*)-Ethyl 2-benzyl-2-butylcyclopropanecarboxylate (3y)
was prepared according to procedure E: Eluent (hexanes/Et2O
95:5); yield: 65% (colorless oil); Rf =0.39 (hexanes/Et2O=98:2); d.r.:
93:7, determined by GC analysis using Varian CP-Sil 8CB column
(injector 2808C, column oven: 708C hold for 1 min, then 58CminÀ1
until 2508C, flow: 1 mLminÀ1) tR (major)=19.8 min, tR (minor)=
19.9 min; 1H NMR (300 MHz, CDCl3, major diastereoisomer): d=
0.82 (t, J=7.1 Hz, 3H), 0.96 (dd, J=8.0, 4.5 Hz, 1H), 1.10 (dd, J=
5.6, 4.5 Hz, 1H), 1.15–1.27 (m, 6H), 1.36–1.53 (m, 3H), 1.60 (dd, J=
8.0, 5.6 Hz, 1H), 2.54 (dAB, J=14.3 Hz, 1H), 2.79 (dAB, J=14.3 Hz,
1H), 4.10 (q, J=7.1 Hz, 2H), 7.14–7.29 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d=14.2, 14.5, 19.7, 22.8, 25.4, 29.1, 29.1, 31.5,
42.3, 60.4, 126.4, 128.3, 129.4, 138.9, 172.7 ppm; HRMS (ESI pos):
m/z calcd for C17H25O2 [M+H]+: 261.1855; found: 261.1832.
calcd for C14H25O2 [M+H]+: 225.1855; found: 225.1825.
+
(1S*,2R*)-Ethyl 2-butyl-2-propylcyclopropanecarboxylate (3u)
was prepared according to procedure C: Eluent (hexanes/Et2O
95:5); yield: 70% (colorless oil); Rf =0.63 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 300 MHz): d=0.80 (dd, J=7.9, 4.3 Hz, 1H), 0.86 (t,
J=7.2 Hz, 3H), 0.88 (t, J=6.9 Hz, 3H), 1.03 (dd, J=5.6, 4.3 Hz, 1H),
1.10–1.20 (m, 2H), 1.22–1.30 (m, 6H), 1.31–1.39 (m, 4H), 1.43 (dd,
J=7.9, 5.6 Hz, 1H), 1.47–1.54 (m, 1H), 4.10 ppm (q, J=7.2 Hz, 2H);
13C NMR (CDCl3, 75 MHz): d=14.3, 14.3, 14.5, 19.6, 20.9, 23.0, 26.2,
28.5, 29.1, 31.1, 39.3, 60.3, 173.0 ppm; HRMS (ESI pos): m/z calcd
for C13H25O2 [M+H]+: 213.1855; found: 213.1845.
(1S*,2S*)-Ethyl 2-methyl-2-(4-oxooctyl)cyclopropanecarboxylate
(3z) was prepared according to procedure E: Eluent (hexanes/
AcOEt 95:5); yield: 76% (colorless oil); Rf =0.26 (hexanes/Et2O=
90:10); d.r.: 97:3, determined by GC analysis using Varian CP-Sil
8CB column (injector 2808C, column oven: 708C hold for 1 min,
then 58CminÀ1 until 2508C, flow: 1 mLminÀ1) tR (major)=19.1 min,
(1S*,3R*)-Ethyl 3-allyl-2,2-dihexylcyclopropanecarboxylate (3v)
was prepared according to procedure C: Eluent (hexanes/Et2O
95:5); yield: 65% (colorless oil); Rf =0.52 (hexanes/Et2O 95:5);
1H NMR (CDCl3, 300 MHz): d=0.84–0.90 (m, 6H), 1.17–1.19 (m, 1H),
1.21–1.39 (m, 22H), 1.40–1.50 (m, 3H), 2.04–2.23 (m, 2H), 4.10 (q,
J=7.1 Hz, 2H), 4.98 (dq, J=10.2, 1.6 Hz, 1H), 5.04 (dq, J=17.1,
1.6 Hz, 1H), 5.83 ppm (ddt, J=17.1, 10.2, 6.4 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=14.2, 14.2, 14.5, 22.8, 22.8, 26.6, 26.6, 29.6,
29.7, 30.1, 31.6, 32.0, 32.0, 32.1, 32.3, 32.5, 36.0, 60.3, 115.1, 137.4,
1
tR (minor)=19.6 min; H NMR (300 MHz, CDCl3, major diastereoiso-
mer): d=079 (dd, J=8.1, 4.4 Hz, 1H), 0.87 (t, J=7.3 Hz, 3H), 1.02
(dd, J=5.5, 4.4 Hz, 1H), 1.14 (s, 3H), 1.18–1.33 (m, 7H), 1.43 (dd,
J=8.0, 5.5 Hz, 1H), 1.48–1.54 (m, 2H), 1.60–1.70 (m, 2H), 2.36 (t,
J=7.4 Hz, 2H), 2.37 (t, J=7.3 Hz, 2H), 4.03–4.14 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=13.9, 14.5, 16.0, 20.8, 21.1, 22.5, 26.1,
26.4, 26.4, 40.2, 42.3, 42.7, 60.3, 172.6, 211.1 ppm; HRMS (ESI pos):
m/z calcd for C15H27O3 [M+H]+: 255.1960; found: 255.1944.
172.9 ppm; HRMS (ESI pos): m/z calcd for C12H39O2 [M+H]+:
+
323.2950; found: 323.2910.
(E)-Ethyl 4-methyldec-3-enoate (4a) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 82% isolated, 91%
without purification, suitable for analysis (colorless oil); Rf =0.48
(hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=0.87 (t, J=
6.8 Hz, 3H), 1.22–1.32 (m, 9H), 1.34–1.44 (m, 2H), 1.61 (s, 3H),
(1S*,2S*,3R*)-Ethyl 2-butyl-2-methyl-3-[(E)-1-tosylhex-1-en-2-yl]-
cyclopropanecarboxylate (3w) was prepared according to proce-
dure B: Eluent (hexanes/Et2O 95:5); yield: 52% isolated (colorless
oil); Rf =0.15 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d=
0.85 (t, J=7.1 Hz, 3H), 0.90 (t, J=6.7 Hz, 3H), 0.94(s, 3H), 1.14–1.43
Chem. Eur. J. 2014, 20, 1038 – 1048
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1.98–2.03 (m, 2H), 3.02 (d, J=7.0 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H),
5.30 ppm (t sext, J=7.1, 1.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=
14.2, 14.3, 16.4, 22.8, 27.8, 29.0, 31.9, 33.9, 39.7, 60.6, 115.6, 139.5,
60.6, 115.1, 145.2, 172.7 ppm; HRMS (ESI pos): m/z calcd for
C12H23O2 [M+H]+: 199.1698; found: 199.1701.
+
(E)-Ethyl 4-benzylhex-3-enoate (4h) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 42% (colorless oil); Rf =
172.7 ppm; HRMS (ESI pos): m/z calcd for C13H25O2 [M+H]+:
+
213.1855; found: 213.1845.
1
0.31 (hexanes/Et2O 95:5); H NMR (CDCl3, 400 MHz): d=0.97 (t, J=
(E)-Ethyl 4-methyloct-3-enoate (4b) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 78% (colorless oil). Rf =
7.6 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H), 2.01 (q, J=7.6 Hz, 2H), 3.12 (d,
J=7.3 Hz, 2H), 4.00 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 5.43 (t, J=
7.3 Hz, 1H), 7.21–7.24 (m, 3H), 7.29–7.33 ppm (m, 2H); 13C NMR
(CDCl3, 100 MHz): d=12.9, 14.4, 23.0, 33.7, 43.2, 60.7, 117.8, 126.2,
128.4, 129.1, 140.0, 144.2, 172.4 ppm; HRMS (ESI pos): m/z calcd.
1
0.48 (hexanes/Et2O 95:5); H NMR (CDCl3, 300 MHz): d=0.87 (t, J=
7.2 Hz, 3H), 1.21–1.29 (m, 5H), 1.32–1.41 (m, 2H), 1.59 (s, 3H),
1.97–2.02 (m, 2H), 3.00 (d, J=7.1 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H),
5.29 (t sext, J=7.1, 1.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d=14.1,
14.3, 16.3, 22.4, 33.9, 39.3, 60.5, 115.6, 139.4, 172.6 ppm; HRMS (ESI
for C15H21O2 [M+H]+: 233.1542; found: 233.1530.
+
(2-Hexylcycloprop-2-en-1-yl)methyl diisopropylcarbamate (7a)
was prepared according to procedure A (yield: 63%), procedure
C (yield: 60%) or procedure D (yield: 56%): Eluent (hexanes/
EtOAc 90:10); (yellowish oil). Rf =0.44 (hexanes/EtOAc 90:10);
1H NMR (CDCl3, 400 MHz): d=0.15 (t, J=4.9 Hz, 1H), 0.50 (dd, J=
8.7, 4.5 Hz, 1H), 0.87 (t, J=6.9 Hz, 3H), 0.92–0.96 (m, 2H), 1.07 (s,
3H), 1.20–1.37 (m, 23H), 3.77 (dd, J=11.4, 9.6 Hz, 1H), 4.08 (br s.,
2H), 4.33 ppm (dd, J=11.4, 6.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d=14.2, 17.5, 18.1, 20.3, 21.2 (br s.), 22.4, 22.8, 27.0, 29.7, 32.1,
41.3, 45.7 (br s.), 66.1, 156.2 ppm; HRMS (ESI pos): m/z calcd for
pos): m/z calcd for C11H21O2 [M+H]+: 185.1542; found: 185.1533.
+
(E)-Ethyl 4-methylhept-3-enoate (4c) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 75% (colorless oil); Rf =
1
0.49 (hexanes/Et2O 95:5); H NMR (CDCl3, 300 MHz): d=0.86 (t, J=
7.3 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.36–1.49 (m, 2H), 1.61 (s, 3H),
2.00 (t, J=7.5 Hz, 2H), 3.03 (d, J=7.0 Hz, 2H), 4.13 (q, J=7.2 Hz,
2H), 5.31 ppm (t sext, 7.1, 1.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d=13.8, 14.4, 16.3, 21.0, 340, 41.8, 60.6, 115.9, 139.2, 172.7 ppm;
C18H35NO2 [M+H]+: 298.2746; found: 298.2794.
+
HRMS (ESI pos): m/z calcd for C10H19O2 [M+H]+: 171.1385; found:
+
[(1S*,2S*)-2-Methyl-2-propylcyclopropyl]methyl diisopropylcar-
bamate (7b) was prepared according to procedure A (yield:
65%) or procedure D (yield: 66%): Eluent (hexanes/EtOAc 90:10);
(yellowish oil). Rf =0.46 (hexanes/EtOAc 90:10); 1H NMR (CDCl3,
400 MHz): d=0.14 (t, J=4.8 Hz, 1H), 0.50 (dd, J=8.7, 4.7 Hz, 1H),
0.88 (t, J=7.0 Hz, 3H), 0.91–0.98 (m, 2H), 1.07 (s, 3H), 1.18–1.43 (m,
16H), 3.79 (dd, J=11.5, 9.6 Hz, 1H), 3.90–4.20 (m, 2H), 4.33 ppm
(dd, J=11.5, 6.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=14.4, 17.4,
18.0, 20.0, 20.1, 21.1 (br s.), 22.4, 43.5, 45.9 (br s.), 66.1, 156.2 ppm;
171.1375.
(E)-Ethyl 4-methyl-5-phenylpent-3-enoate (4d) was prepared ac-
cording to procedure A and then warmed to room temperature
before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 65% (color-
less oil); Rf =0.43 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz):
d=1.26 (t, J=7.1 Hz, 3H), 1.55 (s, 3H), 3.07 (d, J=7.2 Hz, 2H), 3.33
(s, 2H), 4.14 (q, J=7.1 Hz, 2H), 5.47 (t sext, J=7.1, 1.2 Hz, 1H),
7.16–7.30 ppm (m, 5H); 13C NMR (CDCl3, 75 MHz): d=14.3, 16.2,
34.0, 46.1, 60.7, 118.0, 126.2, 128.4, 129.0, 138.3, 139.8, 172.4 ppm;
HRMS (ESI pos): m/z calcd for C15H29NO2 [M+H]+: 256.2277;
+
HRMS (ESI pos): m/z calcd for C14H19O2 [M+H]+: 219.1385; found:
+
found: 256.2275.
219.1379.
[(1S*,2S*)-2-Hexyl-2-methyl-1-phenylcyclopropyl]methyl acetate
(7c) was prepared according to procedure D: Eluent (hexanes/
EtOAc 90:10); yield: 59% (yellowish oil); Rf =0.57 (hexanes/EtOAc
(Z)-Ethyl 4-methyloct-3-enoate (4e) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 76% (colorless oil); Rf =
0.51 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d=0.87–0.92
(m, 3H), 1.23–1.38 (m, 7H), 1.72 (s, 3H), 1.98–2.03 (m, 2H), 3.02 (d,
J=7.1 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H), 5.28–5.33 ppm (m, 1H);
13C NMR (CDCl3, 75 MHz): d=14.2, 14.3, 22.8, 23.6, 30.1, 31.9, 33.7,
60.6, 116.2, 139.7, 172.7 ppm; HRMS (ESI pos): m/z calcd for
1
90:10); H NMR (CDCl3, 300 MHz): d=0.56–0.65 (m, 1H), 0.74 (d, J=
4.9 Hz, 1H), 0.81 (t, J=7.0 Hz, 3H), 0.97 (d, J=4.9 Hz, 1H), 1.01–
1.22 (m, 8H), 1.27 (s, 3H), 1.31–1.48 (m, 1H), 1.98 (s, 3H), 4.26 (d,
J=11.5 Hz, 1H), 4.31 (d, J=11.5 Hz, 1H), 7.16–7.30 ppm (m, 5H);
13C NMR (CDCl3, 100 MHz): d=14.1, 18.6, 21.0, 22.6, 23.4, 26.0, 26.7,
29.5, 31.9, 34.3, 37.5, 70.8, 126.4, 128.0, 130.2, 141.6, 171.1 ppm.
HRMS (ESI pos): m/z calcd for C19H28O2Na+ [M+Na]+: 311.1987;
found: 311.1985.
C11H21O2 [M+H]+: 185.1542; found: 185.1530.
+
(Z)-Ethyl 4-propyloct-3-enoate (4 f) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 81% (colorless oil); Rf =
[(1S*,2S*)-2-Methyl-1-phenyl-2-propylcyclopropyl]methyl acetate
(7d) was prepared according to procedure D: Eluent (hexanes/
EtOAc 90:10); yield: 63% (yellowish oil); Rf =0.56 (hexanes/EtOAc
1
0.46 (hexanes/Et2O 95:5); H NMR (CDCl3, 300 MHz): d=0.87 (t, J=
1
90:10); H NMR (CDCl3, 300 MHz): d=0.46–0.62 (m, 1H), 0.70 (t, J=
7.3 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.29–1.36
(m, 4H), 1.38–1.45 (m, 2H), 1.97–2.02 (m, 4H), 3.04 (d, J=7.2 Hz,
2H), 4.13 (q, J=7.1 Hz, 2H), 5.30 ppm (t, J=7.1 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=14.0, 14.2, 14.4, 21.2, 23.0, 30.2, 30.6, 33.7,
39.1, 60.6, 115.8, 143.5, 172.8 ppm; HRMS (ESI pos): m/z calcd for
7.1 Hz, 3H), 0.74 (d, J=5.3 Hz, 1H), 0.96 (d, J=5.0 Hz, 1H), 1.12–
1.23 (m, 2H), 1.25 (s, 3H), 1.38–1.49 (m, 1H), 1.97 (s, 3H), 4.24 (d,
J=11.5 Hz, 1H), 4.29 (d, J=11.5 Hz, 1H), 7.17–7.28 ppm (m, 5H);
13C NMR (CDCl3, 100 MHz): d=14.4, 18.5, 20.0, 21.1, 23.5, 25.9, 34.2,
39.7, 70.9, 126.5, 128.0, 130.3, 141.6, 171.3 ppm; HRMS (ESI pos):
m/z calcd for C16H22O2Na+ [M+Na]+: 269.1517; found: 269.1517.
C13H25O2 [M+H]+: 213.1855; found: 213.1864.
+
(E)-Ethyl 4-ethyloct-3-enoate (4g) was prepared according to
procedure A and then warmed to room temperature before hy-
drolysis: Eluent (hexanes/Et2O 95:5); yield: 73% (colorless oil); Rf =
Acknowledgements
1
0.49 (hexanes/Et2O 95:5); H NMR (CDCl3, 400 MHz): d=0.88 (t, J=
7.1 Hz, 3H), 0.95 (t, J=7.6 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.27–1.31
(m, 2H), 1.34–1.41 (m, 2H), 2.00–2.05 (m, 4H), 3.03 (d, J=7.2 Hz,
2H), 4.12 (q, J=7.1 Hz, 2H), 5.26 ppm (t, J=7.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d=13.0, 14.1, 14.3, 22.6, 23.5, 30.3, 33.6, 36.3,
This research was supported by grants from the German–Israel
Project Cooperation (DIP) and by the Israel Academy of Scien-
ces and Humanities (140/12). H.E. thanks the Volontariat Inter-
Chem. Eur. J. 2014, 20, 1038 – 1048
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Org. Lett. 1999, 1, 929; l) F. Ferreira, C. Herse, E. Riguet, J.-F. Normant,
Tetrahedron Lett. 2000, 41, 1733; m) D. Beruben, I. Marek, J.-F. Normant,
N. Platzer, J. Org. Chem. 1995, 60, 2488.
national Program of the French Embassy, G.E. thanks the Israeli
Ministry of Foreign Affairs and the WBI (Wallonie Bruxelles In-
ternational) for funding. The authors thank Lea Sebag for her
help. I.M. is holder of the Sir Michael and Lady Sobell Academic
Chair.
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Keywords: carbometalation
·
chelation
·
copper
·
cyclopropene · diastereodivergence
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Received: September 9, 2013
Published online on December 12, 2013
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