Diastereoselective intermolecular cyclopropanation of simple alkenes by fischer alkenyl and heteroaryl carbene complexes of chromium: Scope and limitations

Article abstract of DOI:10.1021/ja000694b

The intermolecular cyclopropanation of simple alkyl-substituted alkenes with Fischer methoxycarbene complexes under thermal conditions is reported. The scope and limitations of this [2 + 1] cycloaddition with respect to the nature of the carbene complex,

Full text of DOI:10.1021/ja000694b

J. Am. Chem. Soc. 2000, 122, 8145-8154
8145
Diastereoselective Intermolecular Cyclopropanation of Simple
Alkenes by Fischer Alkenyl and Heteroaryl Carbene Complexes of
Chromium: Scope and Limitations
Jose´ Barluenga,* Salome´ Lo´pez, Andre´s A. Trabanco, Alvaro Ferna´ndez-Acebes, and
Josefa Flo´rez
Contribution from the Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
Unidad Asociada al CSIC, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo, Spain
ReceiVed February 25, 2000
Abstract: The intermolecular cyclopropanation of simple alkyl-substituted alkenes with Fischer methoxycarbene
complexes under thermal conditions is reported. The scope and limitations of this [2 + 1] cycloaddition with
respect to the nature of the carbene complex, substitution pattern of the electron neutral olefin, and functional
group tolerance in the electron neutral olefin are described in detail. This methodology provides functionalized
cyclopropanes in good to excellent yields and generally with high diastereoselectivity. A mechanism involving
the initial formation of a chelated tetracarbonyl complex intermediate is proposed to account for the observed
results.
Introduction
fashion with alkoxycarbene complexes. The reaction with
electron-rich olefins must be carried out under high pressures
of carbon monoxide in order to avoid the corresponding olefin
metathesis process.4a-c Otherwise, in the cyclopropanation
reactions of electron-deficient olefins, a common side reaction
is the insertion of the carbene ligand into the olefinic â-C-H
bond.3,6 Steric hindrance, caused by either the number or the
size of the substituents on the alkene, seems to be a limitation
of these routes to cyclopropane derivatives.3c The diastereose-
lectivity of these carbene transfer reactions is generally low,
leading to the corresponding cyclopropanes as a nearly equimo-
lecular mixture of cis and trans isomers. However, much higher
stereoselectivities are attained when these carbene transfer
reactions involve a conjugated system either in the alkene or in
the carbene ligand. Thus, better diastereoselectivities have been
observed in the cyclopropanation of either electron-deficient3e
or electron-rich alkenes4d with (alkoxy)(alkenyl)carbene com-
plexes and in the cyclopropanation of 1-azadienes, an electron-
poor alkene type, with (alkoxy)(aryl)carbene complexes.7 In
addition, the cyclopropanation reactions of electron-deficient
1,3-dienes8 and electronically neutral 1,3-dienes3f,9 with Fischer
alkoxycarbene complexes occur regioselectively and with much
higher diastereoselectivity than do similar carbene transfer
reactions to analogous olefins. Otherwise, the reaction of
electron-rich 1,3-dienes with (alkoxy)(alkenyl)carbene com-
plexes of chromium has been reported to produce regio- and
diastereoselectively cycloheptadiene derivatives via in situ Cope
The formal [2 + 1] cycloaddition of group 6 metal hetero-
atom-stabilized pentacarbonyl carbene complexes with olefins
is one of the first and longest studied reactions of Fischer
carbene complexes, and represents a valuable route toward
functionalized cyclopropanes.1 Since Fischer and Do¨tz showed
that electron-deficient alkenes are readily cyclopropanated with
group 6 metal (alkoxy)(aryl)carbene complexes,2 many efforts
have been made to explore the scope and limitations of this
process. The success of this cyclopropanation reaction is not
only highly dependent on the electronic nature of the alkene
but is also influenced by the intra- or intermolecular nature of
the process and the nature of the heteroatom directly bonded to
the carbene carbon. Alkenes substituted with either electron-
withdrawing2,3 or electron-donating4,5 groups can be smoothly
cyclopropanated under thermal conditions in an intermolecular
(1) Reviews: (a) Brookhart, M.; Studabaker, W. B. Chem. ReV. 1987,
87, 411. (b) Reissig, H.-U. In Organometallics in Organic Synthesis; Werner,
H., Erker, G., Eds.; Springer: Berlin, 1989; Vol. 2, pp 311-322. (c) Doyle,
M. P. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone,
F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 387-
420. (d) Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96, 271.
(2) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1970, 103, 1273. (b) Do¨tz,
K. H.; Fischer, E. O. Chem. Ber. 1972, 105, 1356.
(3) (a) Wienand, A.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2315.
(b) Herndon, J. W.; Tumer, S. U. Tetrahedron Lett. 1989, 30, 4771. (c)
Wienand, A.; Reissig, H.-U. Organometallics 1990, 9, 3133. (d) Harvey,
D. F.; Brown, M. F. Tetrahedron Lett. 1990, 31, 2529. (e) Wienand, A.;
Reissig, H.-U. Chem. Ber. 1991, 124, 957. (f) Herndon, J. W.; Tumer, S.
U. J. Org. Chem. 1991, 56, 286.
(4) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1972, 105, 3966. (b) Dorrer,
B.; Fischer, E. O.; Kalbfus, W. J. Organomet. Chem. 1974, 81, C20. (c)
Wulff, W. D.; Yang, D. C.; Murray, C. K. Pure Appl. Chem. 1988, 60,
137. For in situ cyclopropanations with acyloxy chromium carbene
complexes, see: (d) Murray, C. K.; Yang, D. C.; Wulff, W. D. J. Am. Chem.
Soc. 1990, 112, 5660.
(5) For an in situ generated nonheteroatom-stabilized chromium carbene
complex involved in a catalytic synthesis of spirocyclopropanes from diaryl
diazo compounds and electron-rich alkenes, see: (a) Pfeiffer, J.; Do¨tz, K.
H. Angew. Chem., Int. Ed. Engl. 1997, 36, 2828. (b) Pfeiffer, J.; Nieger,
M.; Do¨tz, K. H. Eur. J. Org. Chem. 1998, 1011, 1.
(6) (a) Cooke, M. D.; Fischer, E. O. J. Organomet. Chem. 1973, 56,
279. (b) Wienand, A.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1990,
29, 1129. See also: (c) Barluenga, J.; Gonza´lez, R.; Fan˜ana´s, F. J.
Organometallics 1997, 16, 4525.
(7) Barluenga, J.; Toma´s, M.; Lo´pez-Pelegr´ın, J. A.; Rubio, E. J. Chem.
Soc., Chem. Commun. 1995, 665.
(8) (a) Buchert, M.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2319.
(b) Buchert, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2723. (c) Buchert,
M.; Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1995, 128, 605.
(9) (a) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 8916.
See also: (b) Merlic, C. A.; Bendorf, H. D. Tetrahedron Lett. 1994, 35,
9529.
10.1021/ja000694b CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/15/2000

8146 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Barluenga et al.
rearrangement of an initially formed cis-divinylcyclopropane
intermediate.10
Scheme 1
On the other hand, simple alkyl-substituted alkenes fail to
undergo intermolecular cyclopropanation by heteroatom-
stabilized group 6 metal carbene complexes even under forcing
conditions.11 Nevertheless, these unactivated alkenes can be
easily cyclopropanated if the carbene transfer reaction is carried
out in an intramolecular fashion. Thus, (alkoxy)(alkyl)- or
(alkoxy)(aryl)carbene complexes with a pendent olefin in either
the alkyl group12 or the alkoxy group13 readily undergo
intramolecular cyclopropanation reaction. Furthermore, the
intermolecular reaction of nonheteroatom-stabilized group 6
metal carbene complexes with simple alkenes provides the
corresponding cyclopropanation products.14,15
In contrast, group 6 aminocarbene complexes have been much
less studied and are scarcely able to effectively transfer their
carbene ligands to alkenes. In general, the reaction of this type
of carbene complexes with electron-deficient olefins results in
the formation of formal C-H insertion/hydrolysis products,
which could arise via the corresponding aminocyclopropanes.3c,16
However, two examples of intramolecular cyclopropanation of
(3-butenylamino)(aryl)carbene complexes of tungsten13a,c and
chromium13d are known and only one example of intermolecular
cyclopropanation of electron-deficient alkenes by group 6
pyrrolocarbene complexes has been reported.17 In these latter
complexes, the electron-donating ability of the amino group is
limited and in their reactivity pattern they resemble alkoxycar-
bene complexes more than aminocarbene complexes.18
In a preceding paper, we described the first examples of the
intermolecular cyclopropanation of electronically neutral alkenes
by 2-phenyl- and 2-ferrocenylalkenyl Fischer carbene complexes
of chromium.19 These reactions occurred with good yields
affording vinylcyclopropanes with high diastereoselectivity.
Herein, we report a thorough study of the cyclopropanation
reaction of simple alkenes with group 6 heteroatom stabilized
carbene complexes, which allows the more accurate assessment
of the scope of this process. In addition, a mechanism that
accounts for the structural requirements of the carbene complex
and the high diastereoselectivity observed for this reaction is
suggested.
Results and Discussion
Preliminary Results. The initial studies were carried out with
chromium carbene complex 1, in which the carbene ligand
contains a ferrocenyl group attached at the â carbon to the
carbene carbon atom.20 This novel heterobimetallic organome-
tallic complex may be regarded as a push-pull π-system in
which the (CO)5Cr fragment acts as the acceptor and the
ferrocenyl substituent acts as the electron donor group.21 The
preliminary experiment of our study is shown in Scheme 1 and
involves treatment of carbene complex 1 with a 20-fold molar
excess of 1-hexene (2) and a catalytic amount (4 mol %) of
2,6-di-tert-butyl-4-methylphenol (BHT) in dimethylformamide
(DMF) at reflux for 0.5 h. After chromatographic purification
(Z)-vinylcyclopropane 3 was isolated with very high diastereo-
selectivity (97% diastereomeric excess (de)) and good chemical
yield (88%).22 When this reaction was refluxed for a longer
period of time (2.5 h), a slightly lower diastereoselectivity (90%
de) was observed, whereas in the absence of BHT, compound
3 was obtained in 75% yield. This additive was initially used
in order to prevent polymerization of the alkene. Acetonitrile
(10) Alkoxydienes: (a) Wulff, W. D.; Yang, D. C.; Murray, C. K. J.
Am. Chem. Soc. 1988, 110, 2653. (b) Takeda, K.; Okamoto, Y.; Nakajima,
A.; Yoshii, E.; Koizumi, T. Synlett 1997, 1181. (c) Hoffmann, M.; Buchert,
M.; Reissig, H.-U. Chem. Eur. J. 1999, 5, 876. Aminodienes: (d) Barluenga,
J.; Aznar, F.; Mart´ın, A.; Va´zquez, J. T. J. Am. Chem. Soc. 1995, 117,
9419. (e) Barluenga, J.; Aznar, F.; Ferna´ndez, M. Chem. Eur. J. 1997, 3,
1629. Moreover, we demonstrated that the later reactions with aminodienes
take place by nucleophilic addition to the carbene carbon followed by
cyclization to the seven-membered ring with 1,2-migration of the M(CO)5
fragment: (f) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J.;
Carbajo, R. J.; Lo´pez-Ortiz, F.; Garc´ıa-Granda, S.; Pertierra, P. Chem. Eur.
J. 1996, 2, 88. (g) Barluenga, J.; Toma´s, M.; Rubio, E.; Lo´pez-Pelegr´ın, J.
A.; Garc´ıa-Granda, S.; Pertierra, P. J. Am. Chem. Soc. 1996, 118, 695.
(11) See, for example: (a) Fischer, E. O.; Heckl, B.; Do¨tz, K. H.; Mu¨ller,
J.; Werner, H. J. Organomet. Chem. 1969, 16, P29. (b) Hegedus, L. S. In
Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed.;
University Science Books: Sausalito, CA, 1999; pp 151-157.
(12) (a) Toledano, C. A.; Rudler, H.; Daran, J.-C.; Jeannin, Y. J. Chem.
Soc., Chem. Commun. 1984, 574. (b) Barluenga, J.; Montserrat, J. M.;
Flo´rez, J. J. Chem. Soc., Chem. Commun. 1993, 1068.
(18) For intramolecular cyclopropanation of simple alkenes with non-
heteroatom-stabilized carbene complexes in situ generated by previous
reaction of an aminocarbene complex with an alkyne, see: (a) Parlier, A.;
Rudler, H.; Yefsah, R.; Alvarez, C. J. Organomet. Chem. 1987, 328, C21.
(b) Hoye, T. R.; Rehberg, G. M. Organometallics 1989, 8, 2070. (c) Hoye,
T. R.; Vyvyan, J. R. J. Org. Chem. 1995, 60, 4184.
(13) (a) Casey, C. P.; Vollendorf, N. W.; Haller, K. J. J. Am. Chem.
Soc. 1984, 106, 3754. (b) Casey, C. P.; Shusterman, A. J. Organometallics
1985, 4, 736. (c) Casey, C. P.; Hornung, N. L.; Kosar, W. P. J. Am. Chem.
Soc. 1987, 109, 4908. (d) So¨derberg, B. C.; Hegedus, L. S. Organometallics
1990, 9, 3113.
(14) (a) Casey, C. P.; Burkhardt, T. J. J. Am. Chem. Soc. 1974, 96, 7808.
(b) Casey, C. P.; Tuinstra, H. E.; Saeman, M. C. J. Am. Chem. Soc. 1976,
98, 608. (c) Casey, C. P.; Albin, L. D.; Burkhardt, T. J. J. Am. Chem. Soc.
1977, 99, 2533. (d) Harvey, D. F.; Brown, M. F. J. Am. Chem. Soc. 1990,
112, 7806. (e) Fischer, H.; Hofmann, J. Chem. Ber. 1991, 124, 981. (f)
Fischer, H.; Volkland, H.-P.; Stumpf, R. Anal. Qu´ım. Int. Ed. 1996, 92,
148. See also: (g) Rudler, H.; Audouin, M.; Parlier, A.; Mart´ın-Vaca, B.;
Goumont, R.; Durand-Re´ville, T.; Vaissermann, J. J. Am. Chem. Soc. 1996,
118, 12045. (h) Gunnoe, T. B.; White, P. S.; Templeton, J. L.; Casarrubios,
L. J. Am. Chem. Soc. 1997, 119, 3171.
(15) For intramolecular cyclopropanations of simple alkenes by non-
heteroatom-stabilized carbene complexes in situ generated by previous
reaction of an alkoxycarbene complex with an alkyne, see for instance:
(a) Parlier, A.; Rudler, H.; Platzer, N.; Fontanille, M.; Soum, A. J. Chem.
Soc., Dalton Trans. 1987, 1041. (b) Hoye, T. R.; Suriano, J. A. Organo-
metallics 1992, 11, 2044. (c) Harvey, D. F.; Brown, M. F. J. Org. Chem.
1992, 57, 5559. (d) Harvey, D. F.; Sigano, D. M. J. Org. Chem. 1996, 61,
2268.
(19) Preliminary communication: Barluenga, J.; Ferna´ndez-Acebes, A.;
Trabanco, A. A.; Flo´rez, J. J. Am. Chem. Soc. 1997, 119, 7591.
(20) Ferrocenylcarbene complexes of Cr, W, and Mn were previously
described: (a) Connor, J. A.; Lloyd, J. P. J. Chem. Soc., Dalton Trans.
1972, 1470. Cyclopropanation of dimethyl fumarate with the Cr derivative
was reported: (b) Connor, J. A.; Lloyd, J. P. J. Chem. Soc., Perkin Trans.
1 1973, 17.
(21) Complexes of these characteristics are attractive synthetic goals due
to their physical and chemical properties. See, for example: (a) Togni, A.;
Rihs, G. Organometallics 1993, 12, 3368. (b) Wong, W.-Y.; Wong, W.-
T.; Cheung, K.-K. J. Chem. Soc., Dalton Trans. 1995, 1379. (c) Sato, M.;
Mogi, E.; Katada, M. Organometallics 1995, 14, 4837. (d) Behrens, U.;
Brussaard, H.; Hagenau, U.; Heck, J.; Hendrickx, E.; Ko¨rnich, J.; van der
Linden, J. G. M.; Persoons, A.; Spek, A. L.; Veldman, N.; Voss, B.; Wong,
H. Chem. Eur. J. 1996, 2, 98. (e) Fischer, H.; Leroux, F.; Roth, G.; Stumpf,
R. Organometallics 1996, 15, 3723. (f) Jayaprakash, K. N.; Ray, P. C.;
Matsuoka, I.; Bhadbhade, M. M.; Puranik, V. G.; Das, P. K.; Nishihara,
H.; Sarkar, A. Organometallics 1999, 18, 3851.
(16) (a) Sierra, M. A.; Soderberg, B.; Lander, P. A.; Hegedus, L. S.
Organometallics 1993, 12, 3769. (b) Barluenga, J.; Aznar, F.; Mart´ın, A.
Organometallics 1995, 14, 1429.
(22) Vinylcyclopropanes are recognized to have high synthetic poten-
tial: (a) Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1996, 35, 971. (b)
Tang, Y.; Huang, Y.-Z.; Dai, L.-X.; Chi, Z.-F.; Shi, L.-P. J. Org. Chem.
1996, 61, 5762.
(17) Merino, I.; Hegedus, L. S. Organometallics 1995, 14, 2522.

DiastereoselectiVe Intermolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 122, No. 34, 2000 8147
Table 1. Cyclopropanation Reactions of Electronically Neutral
Alkenes with 2-Ferrocenylalkenyl Carbene Complex 1a
Scheme 2
occurred regio- and stereoselectively at the terminal double bond
producing compound 10 as a nearly equimolecular mixture of
diastereoisomers, which is due to the presence of a stereogenic
carbon atom in the starting diene (Table 1, entry 7). On the
other hand, the reaction of carbene complex 1 with 2-methyl-
1-buten-3-yne, a conjugated enyne, provided the phenol deriva-
tive 11, which demonstrated that in this case the Do¨tz
benzannulation reaction23 is highly favored over the cyclopro-
panation process (Table 1, entry 8).24,25 The relative configu-
ration of vinylcyclopropanes 4-7 and 9 was likewise determined
by difference NOE experiments (see the Supporting Informa-
tion). The same stereochemistry was assumed for compounds
8 and 10.
In addition, the ferrocenyl group can be removed by oxidative
cleavage of the vinyl portion with ozone.26 Two examples are
shown in Scheme 2, where vinylcyclopropanes 3 and 5, each
as a single diastereoisomer,27 were subjected to ozonolysis,
furnishing the corresponding cyclopropanecarbaldehydes 13 and
14 with high diastereomeric purities.
a Reactions were carried out in DMF at reflux for 25-35 min in the
presence of 4 mol % of BHT. b 20 equiv of alkene was used. c Only
the major diastereoisomer is shown; Fc ) ferrocenyl. d Isolated yield
Optimization of Reaction Conditions. During the develop-
ment of this intermolecular cyclopropanation reaction, it was
found that alkenylcarbene complex 15a, bearing a phenyl
substituent instead of the ferrocenyl group, afforded also the
corresponding vinylcyclopropane 16 when treated with 1-hexene
(2) as shown in Table 2. The first reaction was carried out in
DMF at reflux for 1.5 h using 20 equiv of 2 and produced
compound 16 with high diastereoselectivity (82% de) but
moderate chemical yield (54%) (Table 2, entry 1). In addition
to DMF, acetonitrile and THF were found to serve as effective
solvents for this cyclopropanation reaction (Table 2, entries 2
and 3). Although the reaction run in CH3CN at reflux temper-
ature, using the former conditions (20 equiv of 2), provided
compound 16 with a slightly lower chemical yield (Table 2,
entry 2 vs entry 1), the reaction conducted in THF at reflux
was slower (6 h), giving vinylcyclopropane 16 with lower
1
based on carbene complex 1. e Determined by H NMR at 300 MHz;
integration of MeO signal. f 40 equiv of cyclohexene was used.
g Mixture refluxed for 2-2.5 h. h A 1:1 mixture of diastereoisomers
was formed.
and tetrahydrofuran (THF) were found to be poor solvents for
this cyclopropanation. Thus, when the reaction of Scheme 1
using 20 equiv of 2 and 4 mol % of BHT was conducted in
refluxing acetonitrile (4 h) or in THF at reflux (7 h), cyclopro-
pane 3 was isolated with 50% yield, 82% de and 20% yield,
90% de, respectively. Procedures employing a lower amount
of alkene gave either lower chemical yields and somewhat lower
stereoselectivities when 5-10 equiv of 2 was used, or an
unidentified mixture of products when 2-3 equiv of 2 was
present. The relative stereochemistry of the major isomer 3 was
elucidated by nuclear Overhauser effect (NOE) studies (the
arrow in Scheme 1 indicates the observed NOE enhancement).
A number of other simple alkyl-substituted alkenes were
surveyed in the reaction with carbene complex 1, and the results
are summarized in Table 1. Cyclic olefins such as cyclohexene,
cycloheptene, cyclooctene, and norbornene provided the cor-
responding bicyclic or tricyclic vinylcyclopropane containing
products 4-7, with good diastereoselectivity and moderate
yields (Table 1, entries 1-4). The reaction with cyclohexene
required a larger excess of this alkene (40 equiv) in order to
obtain the corresponding cyclopropanation product 4. A terminal
alkene containing a remote bromine atom such as 6-bromo-1-
hexene was also readily cyclized to the corresponding vinyl-
cyclopropane 8 with a high level of diastereoselectivity (Table
1, entry 5). Unconjugated dienes with either structurally
equivalent or nonequivalent double bonds afforded exclusively
the corresponding monocyclopropanated adducts. Diallyl ether
was converted to cyclopropane 9 (Table 1, entry 6), whereas
the reaction of 4-vinylcyclohexene with carbene complex 1
(23) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587.
(24) This preference has precedents. For example, see ref 1b.
(25) Indeed, carbene complex 1 reacted smoothly with 1-hexyne fol-
lowing the Do¨tz reaction pathway to give regioselectively 2-butyl-6-
ferrocenyl-4-methoxyphenol (12).
The structure of phenols 11 and 12, which corresponds to the expected
regioisomer in the Do¨tz benzannulation reaction with terminal alkynes, was
clearly established from the value of the coupling constant between the
aromatic protons (J ) 3.0-3.1 Hz), which indicates a meta relative
disposition of these hydrogens.
(26) (a) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980,
807. (b) Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am. Chem. Soc.
1995, 117, 10393.
(27) The major diastereoisomer was previously separated by column
chromatography.

8148 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Barluenga et al.
Table 2. Cyclopropanation Reaction of 1-Hexene (2) with
2-Phenylalkenyl Carbene Complex 15a: Optimization of Reaction
Conditions for the Synthesis of 16
presumably lower stability of this aliphatic complex 19 in
comparison with the 2-aryl-substituted alkenylcarbene com-
plexes 1, 15a, 17, and 18 (particularly, 2-ferrocenylvinylcarbene
complex 1 seems to be quite stable). The reactivity of the other
group 6 metal-derived complexes 15b,c was compared to the
structurally analogous chromium complex 15a. Although the
molybdenum carbene complex 15b afforded 16 with moderate
yield (Table 3, entry 5),28 the tungsten complex 15c needed a
higher reaction temperature (160 °C; after 24 h at 100 °C no
reaction was observed) to produce 16 in rather low yield (Table
3, entry 6).29 Nevertheless, in both reactions vinylcyclopropane
16 was isolated as a single diastereoisomer. Heteroarylcarbene
complexes 20 and 21 were also able to successfully transfer
their carbene ligand to 1-hexene (2). The 2-furyl derivative 20
led to cyclopropane 25 under the standard conditions (Table 3,
entry 7), but the N-methyl-2-pyrrolyl complex 21 required 150
°C (no reaction was observed at 100 °C for 15 h) to provide 27
with significantly low yield and roughly as an equimolecular
mixture of diastereoisomers. Conducting the reaction in toluene
at 180 °C produced only improved yield (Table 3, entry 8). In
the experiments with complexes 20 and 21, in addition to the
expected cyclopropane derivatives 25 and 27, the corresponding
heteroaryl ketone 26 or 28 was isolated as a minor component.
These ketones presumably arise from hydrolysis of the ap-
propriate methyl enol ethers generated by formal insertion of
the carbene ligand into a terminal olefinic C-H bond.
The major diastereoisomer of cyclopropanes 3, 16, and 22-
25 shown in Table 3 was purified by silica gel column
chromatography. For 27, only the slower moving isomer could
be completely separated from the 1:1 mixture using this
technique. Compounds 23 and above all 25 and 27 must be
stored under N2 at low temperature; they slowly decompose
upon standing at room temperature (after 4-6 days they become
dark). Stereochemical assignments for cyclopropanes 22-25 are
based on either 1D NOE experiments or 2D nuclear Overhauser
enhancement spectroscopy (NOESY) studies (see the Supporting
Information).30
entry equiv of 2 solvent T (°C) t (h)a yieldb (%) dec (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
10
5
DMF
CH3CN
THF
THF
THF
THF
THF
THF
152
81
65
65
65
1.5
1.5
6
18
24
6
54
45
75
73
75
55
30
60
82
82
72
72
72
72
58
70
65
140d
95d
1
3
5
a Reaction time required for complete disappearance of starting
carbene complex 15a. b Isolated yield of product 16 (only the major
diastereoisomer is shown) based on carbene complex 15a. c Diaste-
1
reomeric excess determined from the H NMR spectrum of the crude
product. d Reaction carried out in a sealed flask. Bath temperature.
diastereoselectivity but better chemical yield (Table 2, entry 3
vs entry 1). Under these latter conditions, longer reaction times
(18 and 24 h) did not produce any change in the yield and
diastereoselectivity of the cyclopropanation reaction (Table 2,
entries 4 and 5). Attempts to reduce the number of equivalents
of alkene were performed in THF. Treatment of carbene
complex 15a with 10 equiv of 2 in THF at reflux furnished
cyclopropane 16 with similar reaction time and diastereoselec-
tivity but lower chemical yield (Table 2, entry 6 vs entry 3).
When 5 equiv of 2 was used, the reactions were run in a
resealable Schlenk flask in order to prevent complete displace-
ment of this alkene (1-hexene, bp 64 °C) from the reaction
medium. Heating at 140 °C led to a very fast consumption (1
h) of starting carbene complex 15a, but provided cyclopropane
16 with both quite low chemical yield and diastereomeric excess
(Table 2, entry 7). The same reaction heated at 95 °C needed
some more reaction time (3 h) and allowed both chemical yield
and diastereomeric excess to increase to levels similar to those
observed in the experiment with 10 equiv of 2 (Table 2, entry
8 vs entry 6). The relative configuration of the major isomer
16 was also ascertained from a difference NOE experiment.
Starting from these data, we choose as more convenient
reaction conditions to perform the intermolecular cyclopropa-
nation of simple alkenes with alkenylcarbene complexes those
which involve combining the carbene complex with 5 equiv of
alkene and THF in a resealable flask and heating the flask at
95-100 °C until disappearance of starting carbene complex.
Synthetic Scope: Carbene Complex Survey. The behavior
of different group 6 Fischer carbene complexes in the thermal
reaction with 1-hexene (2) was initially evaluated under the
standard reaction conditions above established, unless otherwise
noted. Table 3 summarizes our findings. Other chromium
alkenylcarbene complexes substituted at the â position by an
aryl 17 or heteroaryl group 18 also underwent this intermolecular
cyclopropanation reaction, giving the corresponding vinylcy-
clopropanes 22 and 23 with high yield (remarkably in the case
of 22; Table 3, entry 1) and good diastereoselectivity (especially
in the case of 23; Table 3, entry 2). Under these standard reaction
conditions 2-ferrocenylvinylcarbene complex 1 provided 3 with
a bit lower yield and diastereoselectivity (see Table 3, entry 3
and Scheme 1). Aliphatic alkenylcarbene complex 19, which
in addition has the CdC double bond inside a six-membered
ring, went through a quite fast reaction yielding 24 with
moderate yield (Table 3, entry 4), which can be credited to the
Regarding the structural nature of the chromium carbene
complex, some limitations to this intermolecular cyclopropa-
nation reaction of simple alkenes with Fischer carbene com-
plexes under the conditions described above have been identified
(Scheme 3). The reaction of (methoxy)methyl complex I with
1-hexene (2) did not give any isolable product. Treatment of
alkynylcarbene complex II or arylcarbene complexes III and
IV with the same olefin and using different solvents (THF,
toluene, CH3CN, DMF) provided only polymers or intractable
mixtures of many compounds. A similar result was obtained
from reaction of 2 with cyclic alkenylcarbene complex V fixed
into an s-cis conformation. After 57 h at 95 °C (THF, sealed
flask) carbene complex V was completely consumed, producing
a mixture of unidentified products. In contrast, bicyclic alke-
nylcarbene complex VI locked into an s-trans conformation
remained perfectly stable in the reaction medium even after
being heated at 150 °C for 20 h.
(28) The relative instability of the molybdenum carbene complexes
compared to chromium and tungsten derivatives is known: see ref 3d.
(29) The reduced bias of tungsten carbene complexes to undergo
cyclopropanation reactions in relation to chromium carbene derivatives has
precedents: see refs 4c, 9, and Barluenga, J.; Aznar, F.; Mart´ın, A.;
Barluenga, S.; Garc´ıa-Granda, S.; Paneque-Quevedo, A. A. J. Chem. Soc.,
Chem. Commun. 1994, 843.
(30) The structural assignments, particularly the cyclopropyl protons,
were based on their 1H and 13C NMR spectra including correlated
spectrosopy (COSY) and proton-detected heteronuclear (1H to 13C) 2D
correlation experiments: heteronuclear multiple quantum coherence (HMQC)
and heteronuclear multiple-bond correlation (HMBC).

DiastereoselectiVe Intermolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 122, No. 34, 2000 8149
Table 3. Cyclopropanation Reaction of 1-Hexene (2) with Different Group 6 Fischer Carbene Complexes 1, 15b,c, and 17-21
a All reactions were performed in THF on a sealed flask using 5 equiv of 1-hexene. b Only the major diastereoisomer is shown. c Isolated yield
1
based on the corresponding carbene complex. d Diastereomeric excess determined from the H NMR spectrum of the crude products. e Mixture
1
refluxed in a normal flask in the presence of 20 equiv of 2 and 4 mol % of BHT. f Only one diastereoisomer observed in H and 13C NMR
spectroscopy. g In this experiment compound 26 was also isolated in 7% yield.
h In this reaction compound 28 was also formed in 10% isolated yield. i Toluene was used instead of THF. j In addition, compound 28 was isolated
in 7% yield.
Scheme 3
same diastereoisomer (Table 4, entry 3). Terminal alkenes
substituted by a bulky group (3,3-dimethyl-1-butene) or an
aromatic ring (styrene) reacted with 15a to provide cyclopropane
derivatives 36 and 37. tert-Butylcyclopropane 36 was isolated
as a diastereomerically pure compound (Table 4, entry 8),
whereas phenylcyclopropane 37 was formed rather less dia-
stereoselectively and it was accompanied by a significant amount
(34%) of ketone 38 when the reaction was run in a sealed flask
(Table 4, entry 9). Different monosubstituted olefins bearing a
silane, hydroxy, silyl ether, carbamate, amine, or halogen
function in the allylic position were next investigated. In all of
the successful examples, a fast reaction was observed (1-4 h)
leading to the appropriate cyclopropane containing product 39-
44 with generally good yields and diastereoselectivities (Table
4, entries 10-15). From allyltrimethylsilane cyclopropane, 39
was obtained (Table 4, entry 10). Cyclopropanation of allyl
alcohol produced cyclopropylmethyl alcohol 40 as a 1:1 mixture
of diastereoisomers (Table 4, entry 11). However, the diaste-
reoselectivity of this cyclopropanation was clearly improved
(70-73% de) by previous protection of the hydroxyl group as
its tert-butyldimethylsilyl (TBDMS) ether (Table 4, entry 12).
In addition, the reaction of carbene complex 15a with only a
stoichiometric amount of allyl tert-butyldimethylsilyl ether
allowed an increase in the chemical yield (95%), presumably
due to the formation of a cleaner reaction crude (no excess of
alkene was present) which would minimize loss of product in
the purification step. By contrast, the reaction with unprotected
cyclic allylic alcohol 2-cyclopentenol produced a 2:1 mixture
Synthetic Scope: Alkene Survey. Employing chromium
carbene complex 15a, we first screened various alkyl-substituted
olefins under the standard reaction conditions previously found.
The results are listed in Table 4. 1,2-Disubstituted olefins with
either an acyclic structure (cis-2-pentene, trans-2-pentene, and
trans-3-hexene) or a cyclic nature (cyclopentene, cyclohexene,
norbornene and indene) were readily transformed to the corre-
sponding vinylcyclopropanes 29-35 with moderate to good
yields and high diastereoselectivity (Table 4, entries 1-7), with
the exception of cyclopropane 30, which was generated without
any diastereomeric excess (Table 4, entry 2). It is noteworthy
that while the cyclopropanation reaction with cis-2-pentene was
completely diastereoselective, the same reaction with the trans
diastereoisomer was totally nondiastereoselective (Table 4,
entries 1 and 2). On the other hand, the reaction with trans
equally disubstituted alkene (trans-3-hexene) afforded a single
diastereoisomer 31, given that in this case both orientations of
the carbene ligand in the cyclopropanation process led to the

8150 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Barluenga et al.
Table 4. Cyclopropanation Reactions of Simple Alkenes by Alkenyl Carbene Complexes 15a, 19
a All reactions were conducted in THF on a sealed flask using 5 equiv of the corresponding alkene, unless otherwise noted. b Only the major
diastereoisomer is shown. c Isolated yield based on the corresponding carbene complex 15a or 19. d Diastereomeric excess determined by 1H NMR
1
analysis of the crude products. e Only one diastereoisomer observed in H and 13C NMR spectroscopy. f Both orientations in the cyclopropanation
reaction led to the same diastereoisomer. g Mixture refluxed in a normal flask in the presence of 20 equiv of alkene. h In this experiment compound
38 was also isolated in 34% yield.
i A small amount of the formal insertion product, which has not been quantified, seems to be present in the 1H NMR spectrum of the crude reaction
mixture. j Diastereomeric excess based upon 1H NMR analysis of the products after column chromatography. k Reaction run with 1 equiv of alkene.
l Diastereomeric excesses for 42a and 42b, respectively, which refer to the relative configuration at the new stereocenters created in the cyclopropanation
reaction. m Reaction refluxed in a normal flask in the presence of 5 equiv of alkene.

DiastereoselectiVe Intermolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 122, No. 34, 2000 8151
Scheme 4
final experiment with carbene complex 15a was performed with
the 1,6-enyne allyl 3-(tert-butyldimethylsilyl)-2-propynyl ether.
Even in this case the thermal reaction with the internal alkyne
was faster than that with the terminal alkene, giving the Do¨tz
benzannulation reaction product 46 as a single regioisomer
(Table 4, entry 17). Finally, two other reactions with cyclohex-
enylcarbene complex 19 were successfully performed as given
in Table 4, entries 18, 19. With this carbene complex, however,
the diastereoselectivity of the cyclopropanation reaction of allyl
tert-butyldimethylsilyl ether was low (Table 4, entry 19).
Chromatographic purification on a silica gel column allowed
the major diastereoisomer of cyclopropanes 33-35, 37, 39, 41-
44, 47, and 48 to be isolated. For phenylcyclopropane 37 it was
also possible to isolate the minor diastereoisomer in pure form.
From the 1:1 mixture of diastereoisomers 40, only the isomer
with the higher Rf value was obtained in pure form from the
column. Likewise, diastereomeric alcohols 42a,b were easily
separated. Conversely, column chromatography of the roughly
1:1 mixture of isomers 30, led scarcely to enriched fractions in
one of the two diastereoisomers. The relative configuration
shown for compounds 29, 32, 33, 37, 41, 42a,b, 44, and 50
and the structure of 46 were ascertained by either 2D NOESY
or difference NOE experiments (see the Supporting Informa-
tion).30 In addition, the observed coupling constant (J ) 10.0
Hz)9a between the cyclopropane protons of compound 29 is in
agreement with a cis disposition of these hydrogens, proving
that the stereochemistry of the alkene is retained in the
cyclopropanation reaction. The stereochemistry assigned to
cyclopropanes 31, 34-36, 39, 43, 47, and 48 has been assumed
by analogy.
Regarding the nature of the alkyl-substituted alkene, some
limitations of this route to cyclopropanes have been found. 1,1-
Disubstituted olefins (2-methyl-1-pentene and methylenecyclo-
pentane) and trisubstituted olefins (2-methyl-2-butene and
1-methyl-1-cyclopentene) failed to undergo cyclopropanation
with carbene complexes 15a or 18. After 6-13 h at 95-100
°C in THF (sealed flask) unidentified mixtures of products were
obtained. Similarly, no cyclopropanes could be detected in the
complex reaction mixtures that originated when carbene com-
plex 15a was treated with diallylamine or allyl chloride.
Proposed Reaction Mechanism. For this thermal intermo-
lecular cyclopropanation reaction of electronically neutral
alkenes, we assume a mechanism analogous to the one which
was initially proposed by Casey and Cesa to explain the
cyclopropanation of electron-deficient olefins with Fischer
carbene complexes.32 This mechanistic proposal involves initial
CO dissociation from the carbene complex, followed by
coordination of the alkene and generation of a metallacyclobu-
tane from which reductive elimination of the metal fragment
leads to the cyclopropane derivative. On the other hand, our
results demonstrate that only methoxy carbene complexes
containing either an alkenyl group or a heteroaryl group directly
bonded to the carbene carbon were able to transfer their carbene
ligand to simple alkenes. In addition, this process showed
generally a high degree of diastereoselectivity. The major
diastereoisomer in each of these transformations was that in
which the alkenyl or the heteroaryl group is cis-positioned with
respect to the vicinal cyclopropane methine proton. Accordingly,
a plausible mechanism to explain all of these results is presented
in Scheme 6. Dissociation of a CO ligand from alkenyl carbene
complex 52 generates a coordinatively unsaturated intermediate
53 which would be in equilibrium with chelated carbene-alkene
π complex 54a.33,34 This intramolecular coordination of the Cd
Scheme 5
of diastereomeric alcohols 42a and 42b, each of which was
found to be a diastereomerically highly enriched compound.
Comparable results with a bit higher yield were observed when
the reaction was conducted with only 1 equiv of this nonvolatile
alkene (Table 4, entry 13). The allylamine derivatives N-(tert-
butoxycarbonyl)allylamine and N-allylaniline were also cyclo-
propanated to give compounds 43 and 44. Both yield and
diastereoselectivity were better with the less basic carbamate
derivative (Table 4, entries 14,15). On the other hand, the
reaction of allyl bromide with carbene complex 15a was a
slower process and afforded the noncyclopropane containing
product 45 (Table 4, entry 16). Formation of this methyl ester
45 can be interpreted as resulting from the successive ring
opening of vinylcyclopropane 49a, isomerization of 1,5-diene
49b in a [3,3] sigmatropic rearrangement, and addition of water
to ionic ketene intermediate 49c (Scheme 4). In an attempt to
find some evidence for the initial formation of cyclopropane
49a, an aliquot of the reaction of 15a with allyl bromide in
THF at reflux was worked up after 4 and 10 h of reaction. The
1H NMR analysis of both crude reaction mixtures showed the
signals of 45 (estimated yield 17 and 30%, respectively) without
any indication of the presence of 49a. To rule out an alternative
reaction pathway which could involve an initial alkylation of
the metal by the highly reactive allyl bromide, two reactions
were carried out. A mixture of carbene complex 15a and benzyl
bromide (5 equiv) in THF and otherwise a THF solution of
allyl bromide (5 equiv) and pentacarbonyl[(methoxy)(phenyl)-
methylene]chromium were heated for 9-10 h at 100 °C (sealed
flask). Both experiments produced complex reaction mixtures.
In addition, indirect evidence of the intermediacy of cyclopro-
pane 49a could be attained by alternative synthesis and
subsequent heating (reflux of THF) of cyclopropane 51a
(Scheme 5), whose unique difference with 49a is the presence
of a tosylate group instead of the bromine atom (both of
comparable leaving group ability). However, tosylation of
cyclopropylmethyl alcohol 40 as summarized in Scheme 531
afforded triene derivative 50 (4.5:1 mixture of diastereoisomers;
only the major isomer is shown), indicating that tosylated
cyclopropane 51a is unstable even at room temperature and
undergoes a similar ring opening reaction. In the basic reaction
medium, 1,5-diene intermediate 51b, analogous to 49b, leads
to enol ether 50 by elimination of p-toluenesulfonic acid. A
(31) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
(32) Casey, C. P.; Cesa, M. C. Organometallics 1982, 1, 87.

8152 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Barluenga et al.
Scheme 6
not undergo the cyclopropanation process either, which in this
case could be due to the formation of a too stable chelate
tetracarbonyl structure which would prevent the subsequently
required intermolecular coordination of the olefin. As presented
in Scheme 6, carbene-alkene π complex 55 undergoes a formal
[2 + 2] cycloaddition to provide 16 electron metallacyclobutanes
5636 which could be in rapid equilibrium with the 18 electron
π-allyl complexes 57. A similar equilibrium was proposed by
Harvey and Lund to explain the cyclopropanation of simple 1,3-
dienes9a and later applied by Reissig and co-workers for the
same reactions of electron-deficient 1,3-dienes8b and also to
explain a formal [3 + 2] cycloaddition of chromium alkenyl-
carbene complexes to electron-deficient olefins.37 Finally,
reductive elimination from one of these intermediates 56 or 57
followed by decomplexation of the metal fragment from 58 leads
to cyclopropanes 59, where 59b has the relative configuration
of the major diastereoisomer isolated in these cyclopropanations.
This cyclopropane stereochemistry would be determined by
steric interactions between the alkenyl (or heteroaryl) substituent
of the carbene ligand and the olefin alkyl chain in the initial
π-complex 55 and at the subsequent cyclopropane forming
stages 56-58,38 which would significantly disfavor the forma-
tion of the corresponding minor isomer 59a. This proposal
accounts for the observation of higher diastereoselectivity by
increasing the size of either the R1 (see for example ferrocenyl
vs Ph) or R2 (see for example t-Bu vs Bu) group. Similarly,
cis-disubstituted olefins are predicted by this model to produce
cyclopropane products with a high degree of diastereoselectivity
(for example: cis-2-pentene, 99% de), whereas the correspond-
ing trans isomers will generate diastereoisomeric intermediates
55-58 of comparable stability and, therefore, nearly equimo-
lecular diastereoisomeric mixtures of cyclopropanes (trans-2-
pentene, 0% de).39 The lack of diastereoselectivity observed in
the cyclopropanation of allyl alcohol could be justified by the
presence of electronic interactions working in opposite direction
to the steric effects which would deteriorate the diastereose-
lectivity of the cyclopropanation reaction. Intermediate 58′a,
which has the alkenyl and hydroxymethyl groups relatively cis-
positioned, allows the simultaneous coordination of both of these
groups to the metal center (18-electron configuration) which
increase its stability in relation with the corresponding isomeric
16-electron complex containing the alkenyl and hydroxymethyl
groups relatively trans-positioned and which do not have this
ability.8b,9a This electronic stabilization makes the formation of
the corresponding minor diastereoisomer 59a less unfavorable.
Silylation of the alcohol with the bulky TBDMS group or the
rigidity imposed by the ring in 2-cyclopenten-1-ol hampers this
bidentate coordination. In addition, the observation of consider-
ably lower diastereoselectivity with an aromatic amine (N-
allylaniline) than with a carbamate [N-(tert-butyloxycarbonyl)-
allylamine] supports this interpretation. A similar argument
C double bond to the metal center helps to stabilize reactive
tetracarbonyl intermediate 53, promoting its formation and
therefore the cyclopropanation by increasing the probability of
alternative stabilization by intermolecular coordination with the
alkyl-substituted olefin to give carbene-alkene π complex 55.
For 2-heteroaryl carbene complexes 20 and 21, either the
heteroatom or the adequately positioned ring unsaturation could
be playing a similar role, giving rise to chelate structures 54b
or 54c. Formation of chelated carbene complexes 54a is only
possible if alkenylcarbene complexes 52 can readily adopt an
s-cis conformation of the vinylcarbene functionality. This would
explain why cyclic alkenylcarbene complex VI, which is locked
in an s-trans conformation, failed to react.35 However, cyclic
alkenylcarbene complex V, locked in an s-cis conformation, did
(35) In addition, the aromatic nature of carbene complex VI will decrease
its reactivity as indicated by the high thermal stability of this complex.
(36) This regioselectivity could be predicted based on the polarization
of both the olefin carbon-carbon double bond and metal-carbene carbon
bond of the carbene complex and is the one deduced from the constitution
of formal insertion-hydrolysis products 26, 28, and 38.
(37) Hoffmann, M.; Reissig, H.-U. Synlett 1995, 625.
(38) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organo-
metallics 1984, 3, 53.
(39) Alternatively, the non existing diastereoselectivity in the cyclopro-
panation reaction of trans-2-pentene could be due to low regioselectivity
in the formation of the corresponding metallacyclobutanes 56. This trans
olefin with two similar substituents could form two regioisomeric metal-
lacyclobutane intermediates of comparable stability which finally would
lead to two different diastereoisomers. In this case, it can be said that this
cyclopropanation reaction of cis and trans olefins is stereospecific. We thank
one of the referees for calling our attention to this possibility.
(33) A group 6 C-C double-bond chelated amino vinylcarbene complex
analogous to 54a has been isolated: (a) Barluenga, J.; Aznar, F.; Mart´ın,
A.; Garc´ıa-Granda, S.; Pe´rez-Carren˜o, E. J. Am. Chem. Soc. 1994, 116,
11191. For examples of the corresponding nonheteroatom stabilized
derivatives, see: (b) Garrett, K. E.; Sheridan, J. B.; Pourreau, D. B.; Feng,
W. C.; Geoffroy, G. L.; Staley, D. L.; Rheingold, A. L. J. Am. Chem. Soc.
1989, 111, 8383. (c) Mayr, A.; Asaro, M. F.; Glines, T. J.; Van Engen, D.;
Tripp, G. M. J. Am. Chem. Soc. 1993, 115, 8187. For a review about the
chemistry of η3-allylidene complexes, see: (d) Mitsudo, T. Bull. Chem.
Soc. Jpn. 1998, 71, 1525.
(34) This equilibrium has been previously identified by a density
functional study and by NMR analysis; see, respectively: (a) Gleichmann,
M. M.; Do¨tz, K. H.; Hess, B. A. J. Am. Chem. Soc. 1996, 118, 10551. (b)
Barluenga, J.; Aznar, F.; Gutie´rrez, I.; Mart´ın, A.; Garc´ıa-Granda, S.;
LLorca-Baragan˜o, M. A. J. Am. Chem. Soc. 2000, 122, 1314.

DiastereoselectiVe Intermolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 122, No. 34, 2000 8153
(w), 2054 (m), 1939 (s), 1575 (m), 1541 (w), 1423 (w), 1217 (s); low-
resolution mass spectroscopy (LRMS) (70 eV, EI) m/z (%) 446 (M+,
20), 418 (15), 332 (30), 306 (80), 270 (90), 237 (25), 220 (45), 205
(46), 186 (75), 149 (40), 121 (100); high-resolution mass spectroscopy
(HRMS) (70 eV, EI) calcd for C19H14CrFeO6 (M+) 445.9545, found
445.9564. Anal. Calcd for C19H14CrFeO6: C, 51.15; H, 3.16. Found:
C, 51.22; H, 3.06.
could be invoked to explain the low diastereoselectivity attained
with styrene. In this case the ability of complex 58′′a to
coordinate the Cr(CO)4 fragment to both the alkenyl and the
phenyl (η2 fashion) substituents would relatively favor formation
of the minor diastereoisomer. Finally, the minor insertion-
hydrolysis products 26, 28, and 38 isolated in some reactions
could arise from intermediate 56 through a formal â-hydrogen
elimination, giving hydridochromium complex 60 which un-
dergoes reductive elimination affording methyl enol ethers
61.6b,40,41 Hydrolysis of enol ethers 61 during workup and mainly
at the time of the chromatographic purification finally led to
ketones 62.
General Procedure for the Cyclopropanation Reactions in DMF
with 20 equiv of Olefin. A mixture of carbene complex 1 (223 mg,
0.5 mmol), the corresponding alkene (10 mmol), and 2,6-di-tert-butyl-
4-methylphenol (BHT, 5 mg, 0.02 mmol) in DMF (20 mL) was refluxed
for a period of 25-35 min (2-2.5 h for compounds 4, 7, and 11).
Upon cooling to room temperature the solvent was removed under
reduced pressure and the resulting residue was dissolved in hexane and
filtered throught a plug of Celite. Evaporation of the volatiles and
column chromatography (silica gel) afforded pure compounds 3-11.
For compounds 3, 5, and 9, the major diastereoisomer was separated
by this procedure. Yields are described in Scheme 1 and Table 1.
(1S*,2R*)-2-Butyl-1-[(E)-2-ferrocenylethenyl]-1-methoxycyclo-
Conclusion
The results reported herein represent the first developed
intermolecular cyclopropanation of electronically neutral alkenes
with heteroatom-stabilized group 6 Fischer carbene complexes.
The reaction, which occurs under thermal conditions, is general
between alkoxy(alkenyl)- or alkoxy(2-heteroaryl)carbene com-
plexes of chromium and terminal or either acyclic or cyclic 1,2-
disubstituted simple olefins, and in addition takes place with a
high degree of diastereoselectivity, representing a useful method
for the diastereoselective synthesis of functionalized alkoxycy-
clopropanes. This [2 + 1] cycloaddition reaction can be
successfully carried out with only equimolecular amounts of
starting materials when nonvolatile alkenes are employed.
Unconjugated dienes underwent regioselective cyclopropanation
at the less substituted carbon-carbon double bond, while with
enynic substrates the reaction with the alkyne is largely favored.
The process showed a good functional group tolerance at the
olefin allylic position. However, alkenes with a good leaving
group at the allylic position seem to generate unstable cyclo-
propanes which alternatively have been found to undergo
spontaneous ring opening due to the 1,2 substitution by an
electron-donating group (OMe) and an alkyl chain (CH2Br, CH2-
OTs) containing a good leaving group at the R position. The
ability of the carbene complex to generate a chelated tetracar-
bonyl complex intermediate is proposed as a key step in the
suggested reaction mechanism, whereas the cyclopropane ster-
eochemistry can be explained mainly on the basis of steric
interactions.
1
propane (3). Orange oil; Rf ) 0.30 (hexane: CH2Cl2, 4:1); H NMR
(300 MHz, CDCl3) δ 0.60 (dd, J ) 7.01, 4.58 Hz, 1H), 0.84-1.00 (m,
5H), 1.42-1.50 (m, 5H), 1.64 (m, 1H), 3.39 (s, 3H), 4.13 (s, 5H), 4.21
(t, J ) 1.83 Hz, 2H), 4.33 (t, J ) 1.83 Hz, 2H), 5.64 (d, J ) 15.8 Hz,
1H), 6.21 (d, J ) 15.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 14.1,
18.3, 22.5, 27.4, 28.0, 31.9, 55.5, 65.5, 66.2, 66.4, 68.3, 69.0, 83.3,
124.3, 128.8; LRMS (70 eV, EI) m/z (%) 338 (M+, 100), 307 (10),
214 (10), 186 (20), 121 (20), 44 (15), 36 (20); HRMS (70 eV, EI)
calcd for C20H26FeO (M+) 338.1333, found 338.1332. Anal. Calcd for
C20H26FeO: C, 71.01; H, 7.75. Found: C, 70.79; H, 7.97.
meso-(1R,2S,3S,4R,5S)-3-[(E)-2-Ferrocenylethenyl]-3-methoxy-
tricyclo[3.2.1.02,4]octane (7). Orange solid. Data on the 95:5 mixture
1
of diastereoisomers; Rf ) 0.30 (hexane/EtOAc, 4:1); H NMR (300
MHz, CDCl3) δ 0.81 (d, J ) 5.3 Hz, 1H), 0.98 (s, 2H), 1.20-1.48 (m,
2H), 1.41-1.62 (m, 2H), 1.92 (d, J ) 5.3 Hz, 1H), 2.63 (s, 2H), 3.35
(s, 3H), 4.11 (s, 5H), 4.18 (s, 2H), 4.31 (s, 2H), 5.42 (d, J ) 15.6 Hz,
1H), 6.18 (d, J ) 15.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 29.7,
30.9, 32.6, 36.9, 54.9, 66.2, 68.3, 68.6, 68.9, 83.6, 123.5, 129.7; LRMS
(70 eV, EI) m/z (%) 349 (20), 348 (M+, 100), 333 (10), 317 (15); HRMS
(70 eV, EI) calcd for C21H24FeO (M+) 348.1176, found 348.1168.
(1S*,2S*)-2-(3-Cyclohexenyl)-1-[(E)-2-ferrocenylethenyl]-1-meth-
oxycyclopropane (10). Orange oil. Data on the 1:1 mixture of
diastereoisomers; Rf ) 0.56 (hexane/EtOAc, 9:1); 1H NMR (200 MHz,
CDCl3) δ 0.66, 0.78 (m, 1H), 0.82-0.92 (m, 2H), 1.39-1.60 (m, 2H),
1.82-1.98 (m, 2H), 2.09-2.25 (m, 3H), 3.38 (s, 3H), 4.11 (s, 5H),
4.20 (t, J ) 1.83 Hz, 2H), 4.33 (t, J ) 1.83 Hz, 2H), 5.60-5.71 (m,
3H), 6.20, 6.22 (2d, J ) 15.8 Hz, 1H of each isomer); 13C NMR (50.0
MHz, CDCl3) δ 16.8, 25.0, 28.2, 29.2, 31.3, 31.9, 32.8, 33.0, 33.7,
33.9, 55.5, 65.4, 65.7, 66.3, 66.5, 68.4, 69.0, 83.3, 124.3, 126.5, 126.6,
127.1, 128.9; LRMS (70 eV, EI) m/z (%) 362 (M+, 100), 266 (10),
229 (10), 199 (25), 186 (20), 121 (15); HRMS (70 eV, EI) calcd for
C22H26FeO (M+) 362.1333, found 362.1337. Anal. Calcd for C22H26-
FeO: C, 72.94; H, 7.23. Found: C, 72.66; H, 7.38.
Experimental Section42
Pentacarbonyl[(E)-3-ferrocenyl-1-methoxy-2-propenylidene]chro-
mium (1). To a solution of pentacarbonyl[(methoxy)(methyl)methylene]-
chromium (6.3 g, 25 mmol) in Et2O (150 mL) at room temperature
were successively added triethylamine (13.94 mL, 100 mmol), fer-
rocenecarbaldehyde (6.42 g, 30 mmol), and chlorotrimethylsilane (9.52
mL, 75 mmol). The mixture was stirred at room temperature for 48 h.
Silica gel (ca. 25 g) was then added, and the solvent was removed
under reduced pressure. The residue was loaded onto a silica gel column
under N2. Elution with hexane gave 8.35 g (18.72 mmol, 75%) of
carbene complex 1 as a dark violet solid. Melting point 105-107 °C;
Rf ) 0.30 (hexane); 1H NMR (200 MHz, CDCl3) δ 4.22 (s, 5H), 4.60
(br s, 4H), 4.70 (s, 3H), 7.19 (d, J ) 15.0 Hz, 1H), 7.52 (d, J ) 15.0
Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 65.6, 69.9, 70.3, 72.6, 78.3,
137.5, 138.0, 217.1, 224.2, 326.0; IR (KBr) υ 3020 (s), 2401 (w), 2361
General Procedure for the Cyclopropanation Reactions in THF
with 5 or 1 equiv of Olefin. A mixture of the appropriate carbene
complex 1, 15a,b,c, 17-21, I-VI (1 mmol) and the corresponding
alkene (5 or 1 mmol) in THF (15 mL) was introduced in a sealed flask
and was heated in an oil bath at 95-110 °C (unless otherwise noted in
Tables 2-4) until disappearance of the color of the starting carbene
complex (reaction times are given in Tables 2-4). Most often an initial
dark red solution turned brown. For carbene complexes 1 and VI, the
initial THF solutions are violet and those of carbene complexes 17
and 21 are orange. When allyl alcohol and 2-cyclopenten-1-ol were
used as alkenes, green final solutions were observed. After thermolysis,
the reaction mixture was cooled to room temperature, the solvent was
removed under reduced pressure, and the residue was dissolved in
hexane and exposed to sunlight and air during 0.5-1 h to remove metal
species. The resulting mixture was filtered through a short pad of Celite
and then the volatiles were evaporated. The remaining oil was purified
by column chromatography (silica gel) to give compounds 3, 16, and
22-48. Yields are listed in Tables 2-4. The major diastereoisomer of
16, 22-25, 33-35, 37, 39, 41-44, 47, and 48 was separated by this
(40) It was suggested that enol ethers similar to 61 are formed by acid-
catalyzed rearrangement from the corresponding donor-acceptor-substituted
cyclopropanes: see ref 3c.
(41) Indeed, 1H NMR analysis of the crude reaction mixtures suggested
the presence of 61 (a triplet signal appearing at δ 4.80 (precursor of 26),
4.92 (precursor of 28), 5.00 (precursor of 38) and a multiplet at 2.30
(precursor of 26), 2.06 (precursor of 28), or doublet signal at 3.69 (precursor
of 38)).
(42) General information, experimental procedures, and spectral data for
compounds not described here are provided in the Supporting Information.

8154 J. Am. Chem. Soc., Vol. 122, No. 34, 2000
Barluenga et al.
procedure. This technique also allowed the minor diastereoisomer of
37 and diastereomeric alcohols 42a,b to be separated.
(m, 5H), 3.46 (s, 3H), 5.95 (d, J ) 16.1 Hz, 1H), 6.44 (d, J ) 16.1 Hz,
1H), 7.20-7.39 (m, 5H); 13C NMR (75.5 MHz, CDCl3) δ 24.9, 26.4,
32.9, 55.7, 69.4, 125.7, 126.0, 126.6, 128.3, 131.7, 137.0; LRMS (70
eV, EI) m/z (%) 214 (M+, 7), 213 (12), 105 (100), 91 (50), 77(45);
HRMS (70 eV, EI) calcd for C15H18O (M+) 214.1358, found 214.1352.
Anal. Calcd for C15H18O: C, 84.06; H, 8.46. Found: C, 84.00; H, 8.37.
(1S*,2R*)-2-Butyl-1-methoxy-1-[(E)-2-phenylethenyl]cyclopro-
1
pane (16). Colorless oil; Rf ) 0.27 (hexane/CH2Cl2, 9:1); H NMR
(300 MHz, CDCl3) δ 0.70 (dd, J ) 6.41, 4.88 Hz, 1H), 0.87-1.00 (m,
4H), 1.03-1.12 (m, 1H), 1.38-1.49 (m, 5H), 1.59-1.75 (m, 1H), 3.41
(s, 3H), 5.99 (d, J ) 16.2 Hz, 1H), 6.51 (d, J ) 16.2 Hz, 1H), 7.20-
7.26 (m, 1H), 7.28-7.43 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ
14.1, 18.8, 22.5, 27.5, 28.5, 31.8, 55.8, 65.5, 125.8, 126.4, 126.8, 128.5,
132.3, 137.1. Anal. Calcd for C16H22O: C, 83.43; H, 9.63. Found: C,
83.54; H, 9.59.
(1R*,2S*)-2-(tert-Butyldimethylsilyloxymethyl)-1-methoxy-1-[(E)-
2-phenylethenyl]cyclopropane (41). Colorless oil; Rf ) 0.40 (hexane/
1
EtOAc, 95:5); H NMR (200 MHz, CDCl3) δ 0.12 (s, 3H), 0.13 (s,
3H), 0.87 (dd, J ) 7.1, 5.6 Hz, 1H), 0.95 (s, 9H), 1.01 (dd, J ) 9.5,
5.6 Hz, 1H), 1.42 (apparent dq, J ) 9.5, 6.9 Hz, 1H), 3.43 (s, 3H),
3.84 (d, J ) 6.7 Hz, 2H), 6.05 (d, J ) 16.0 Hz, 1H), 6.55 (d, J ) 16.0
Hz, 1H), 7.20-7.43 (m, 5H); 13C NMR (75.5 MHz, CDCl3) δ -5.24,
-5.21, 17.3, 18.3, 25.9, 29.6, 55.7, 61.8, 65.5, 126.0, 127.1, 127.6,
128.4, 130.8, 136.8; LRMS (70 eV, EI) m/z (%) 318 (M+, 3), 317 (9),
287 (60), 186 (65), 173 (62), 89 (100), 73 (89); HRMS (70 eV, EI)
calcd for C19H30O2Si (M+) 318.2015, found 318.2021. Anal. Calcd for
C19H30O2Si: C, 71.64; H, 9.49. Found: C, 71.78; H, 9.36.
(1S*,2R*)-2-Butyl-1-(1-cyclohexenyl)-1-methoxycyclopropane (24).
1
Colorless oil; Rf ) 0.60 (hexane/EtOAc, 95:5); H NMR (400 MHz,
CDCl3) δ 0.28 (dd, J ) 5.6, 4.2 Hz, 1H), 0.75-0.84 (m, 2H), 0.91 (t,
J ) 7.0 Hz, 3H), 1.24-1.39 (m, 5H), 1.52-1.66 (2m, 5H), 1.94-2.11
(m, 4H), 3.15 (s, 3H), 5.59 (t, J ) 1.6 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 14.1, 15.1, 22.5, 22.6, 22.8, 25.0, 25.2, 25.5, 27.4, 32.2, 54.3,
68.4, 123.3, 136.4.
(1S*,2R*)-2-Butyl-1-(2-furyl)-1-methoxycyclopropane (25). Yel-
low oil; Rf ) 0.33 (hexane/EtOAc, 95:5); 1H NMR (400 MHz, CDCl3)
δ 0.66 (dd, J ) 6.7, 5.4 Hz, 1H), 0.91 (t, J ) 7.0 Hz, 3H), 1.10 (dd,
J ) 9.6, 5.4 Hz, 1H), 1.14-1.25 (m, 1H), 1.32-1.49 (m, 5H), 1.61-
1.71 (m, 1H), 3.30 (s, 3H), 6.18 (m, 1H), 6.30 (dd, J ) 3.2, 1.6 Hz,
1H), 7.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 17.4, 22.5,
26.7, 27.1, 31.8, 55.8, 61.4, 106.1, 110.0, 141.5, 155.3; LRMS (70
eV, EI) m/z (%) 194 (M+, 17), 163 (13), 137 (100), 95 (16). HRMS
(70 eV, EI) calcd for C12H18O2 (M+) 194.1307, found 194.1310. Anal.
Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.17; H, 9.38.
(1R*,2S*,3R*)-2-Ethyl-1-methoxy-3-methyl-1-[(E)-2-phenylethe-
nyl]cyclopropane (29). Colorless oil; Rf ) 0.40 (hexane/EtOAc, 95:
Acknowledgment. Support for this research by the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica (DGICYT) of
Spain (grants PB92-1005 and PB97-1271) is gratefully ac-
knowledged. A.F.A. thanks the Departamento de Educacio´n,
Universidades e Investigacio´n del Pa´ıs Vasco, for a postdoctoral
fellowship.
Supporting Information Available: General experimental
information; analytical and spectral data for compounds 4-6, 8,
9, 11, 12, 22, 23, 26-28, 30, 31, 33-40, 42a,b and 43-48;
experimental procedures and spectral data for 13, 14, and 50;
and schemes showing observed difference NOE’s enhancements
for compounds 4-7, 9, 22, 23, 29, 32, 37, 41, and 44 and NOEs
enhancements from 2D NOESY spectra for compounds 24, 25,
29, 33, 42a,b, 46, and 50. This material is available free of
charge via the Internet at http://pubs.acs.org. See any current
masthead page for ordering information and Web access
instructions.
1
5); H NMR (300 MHz, d6-PhH) δ 0.89 (dt, J ) 10.0, 7.1 Hz, 1H),
1.00-1.15 (m with t at 1.13, J ) 7.4 Hz, 4H), 1.22 (d, J ) 6.3 Hz,
3H), 1.52-1.80 (2m, 2H), 3.34 (s, 3H), 6.16 (d, J ) 16.1 Hz, 1H),
6.62 (d, J ) 16.1 Hz, 1H), 7.10-7.40 (m, 5H); 13C NMR (75.5 MHz,
CDCl3) δ 6.8, 14.0, 15.6, 22.5, 30.7, 55.8, 65.6, 125.7, 126.3, 126.7,
128.3, 133.1, 137.0; LRMS (70 eV, EI) m/z (%) 216 (M+, 4), 215 (10),
131 (27), 105 (100), 91 (28), 77 (41); HRMS (70 eV, EI) calcd for
C15H20O (M+) 216.1514, found 216.1509.
meso-(1R,5S,6S)-6-Methoxy-6-[(E)-2-phenylethenyl]bicyclo[3.1.0]-
hexane (32). Colorless oil; Rf ) 0.90 (hexane/EtOAc, 95:5); 1H NMR
(300 MHz, CDCl3) δ 1.62 (m, 2H), 1.66-1.84 (m, 1H), 1.98-2.05
JA000694B