Diastereoselective cyclopropanation of ketone enols with Fischer carbene complexes

Article abstract of DOI:10.1021/ja074363b

Treatment of aryl/heteroaryl methoxycarbene complexes of chromium with β-substituted ketone lithium enolates between -78 °C and room temperature resulted in the diastereoselective synthesis of 1,2,2,3-tetrasubstituted cyclopropanols. An exception has been observed in the reaction with cyclohexanone lithium enolate that yielded a bicyclic 2-buten-4-olide. 1,2-Dimethoxycyclopropanes and 1-methoxy-2-trimethylsilyloxycyclopropanes were isolated by quenching the reactions with MeOTf or Me₃SiCl, respectively. This novel cyclopropanation process involves formation of lithium (3-oxoalkyl)pentacarbonylchromate intermediates which on warming undergo intramolecular addition to the carbonyl group. This cyclization is equivalent to the cyclopropanation in smooth conditions of electron-rich alkenes with Fischer carbene complexes. Copyright

Full text of DOI:10.1021/ja074363b

Published on Web 02/08/2008
Diastereoselective Cyclopropanation of Ketone Enols with Fischer Carbene
Complexes
Jose´ Barluenga,* Marcos G. Suero, Iva´n Pe´rez-Sa´nchez, and Josefa Flo´rez
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles” Unidad Asociada al CSIC, UniVersidad de
OViedo Julia´n ClaVer´ıa 8, 33006 OViedo, Spain
Received June 15, 2007; E-mail: barluenga@uniovi.es
Table 1. Coupling of Carbene Complex 1a and Lithium Enolates
The addition of metal enolates to the electrophilic carbene carbon
atom of group 6 Fischer carbene complexes (FCCs) generates new
nucleophilic intermediates: γ-oxo functionalized alkylpentacarbo-
nylmetalate species, which have been showing a high synthetic
potential.1,2 So far, the chemical behavior of these anionic species,
which are stable derivatives at low temperature, has been explored
in the case of aryl- and alkenylcarbene complexes providing acyclic
derivatives in the former case3,4 and either acyclic3 or five- and
seven-membered carbocycles5,6 in the later case. A 3-oxoalkylpen-
tacarbonyltungstate derivative has been reported to undergo a CO
insertion reaction leading subsequently to the formation of a cyclic
anhydride.7 In general, alkylpentacarbonylmetalate species are prone
to undergo insertion of CO to give anionic acyltetracarbonylmetalate
intermediates whose further evolution depends on the nature of the
reaction partners.8 On the other hand, the cyclopropanation reaction
of electron-rich alkenes with alkoxy FCCs requires thermal condi-
tions and high pressures of CO to avoid the olefin metathesis
process.9 Apart from transfer of the carbene ligand of acyloxy FCCs
to the CdC bond of â-unsubstituted enol ethers that occurs at low
2a
T ramp
C)b
reaction
product
yield
(%)c
entry
enolate 2
R2
R3
(°
1
2
3
4
5
6
7
8
2ad,e
2ae,f
2bd,g
2cf
Et
Et
Me
Pr
Pr
Ph
A: -55, 20
B: 20
B: 20
A: -55, 20
B: 20
A: -55, 20
B: 20
A: -55, 20
3a
3a
3b
3c
4a
3d
4b
5
62
77
86
74
75
79
68
75
(CH2)5
2cf
(CH2)5
(CH2)6
(CH2)6
(CH2)4
temperature although giving mixtures of diastereoisomers,9c
a
2dd
2df
general method for the cyclopropanation of electron-rich olefins
with FCCs in smooth conditions is still required.
2ef
Herein, we describe a novel reaction of Fischer carbene
complexes of chromium with ketone lithium enolates which allowed
the diastereoselective synthesis of highly substituted cyclopropanols
and that formally represents the cyclopropanation at low temperature
and in the absence of CO of an electron-rich alkene (â-substituted
ketone enol) with a heteroatom-stabilized FCC.
a Reaction conditions: 1.2 equiv of enolate 2. b Method A: -78 to
-55 °C, 10 min and then -55 °C, 1 h and 20 °C, 30 min. Method B:
-78 °C, 5 min and then 20 °C, 45 min. c Yield of isolated, analytically
pure product based on carbene complex 1a. d Enolate prepared from the
appropriate trimethylsilyl enol ether and BuLi. e Enolate geometry E/Z )
17:83. f Enolate prepared from the corresponding ketone and LDA. g Enolate
geometry E/Z ) 2:98.
Initially, we observed that the reaction of methoxy(phenyl)-
carbene complex 1a with â-substituted ketone lithium enolates
2a-d performed under the reaction conditions summarized in
Table 1 led, after hydrolysis and decoordination of the metal species
by exposure to air and light, to tetrasubstituted cyclopropanols
3a-d, which were formed in each case as a single diastereoisomer.10
Lithium enolates 2 can be alternately generated from the corre-
sponding ketone and lithium diisopropylamide (LDA) or the appro-
priate trimethylsilyl enol ether and BuLi. Two different experimental
conditions in the first step can be used with acyclic lithium enolates
2a,b ((method A) -78 to -55 °C, 10 min; -55 °C, 1 h; 20 °C, 30
min or (method B) -78 °C, 5 min; 20 °C, 45 min; Table 1, entries
1-3). But, the experiments with cyclic lithium enolates 2c,d need
to be conducted under the former slower conditions (method A) in
order to get cyclopropanols 3c,d (Table 1, entries 4, 6). When these
reactions were carried out using the later faster conditions (method
B), the selective formation of bicyclic hydroxycyclobutanones 4a,b
was observed (Table 1, entries 5, 7). In contrast, the reaction of
carbene complex 1a with cyclohexanone lithium enolate (2e),
performed under the above-mentioned slower reaction conditions,
furnished selectively bicyclic 2-buten-4-olide 5 (Table 1, entry 8).
This heterocyclic ring has been generated by the assembly of the
lithium enolate as a three-atom unit and the carbene and a carbonyl
ligands both as one-carbon synthons.11
Cyclopropanols 3a,b show a trans disposition of the enolate
substituents (R2, R3) and a cis orientation of the methoxy and
hydroxy groups, while bicyclic cyclopropanols 3c,d hold both a
cis ring fusion and a cis arrangement of the oxygenated functional
groups. The structure and relative stereochemistry of products 3
and the other new compounds reported here, were ascertained by
1D and 2D NMR spectroscopic experiments.12 The later studies
were carried out with compounds 3b, 4b, 5, and 6d (Table 1). To
establish the relative configuration of bicyclic derivatives 3c,d, it
was necessary to transform these cyclopropyl alcohols into the
corresponding benzoate derivatives 6c,d using 3,5-dinitrobenzoyl
chloride [Et3N, 4-(dimethylamino)pyridine (DMAP), THF, room
temperature]. Furthermore, a single-crystal X-ray analysis of 4a
and 6c,d13 confirmed the structural assignment.
9
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J. AM. CHEM. SOC. 2008, 130, 2708-2709
10.1021/ja074363b CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preparation of 1,2-Dimethoxycyclopropanes 5 and
1-Methoxy-2-trimethylsilyloxycyclopropanes 6a
of the alkylchromate to the ketone carbonyl group) and A′′ (dorsal
attack of the alkylchromate to the carbonyl group),16 respectively.
Chelation of the lithium atom to both oxygenated functional groups
would be controlling the cyclization process. Intermediates B,
formed after CO insertion, would account for the formation of
compounds 4a,b by intramolecular addition of an acylchromate
species to the ketone carbonyl group as shown in conformation B′.
While butenolide 5 could be formed through intermediate C
originated after CO insertion and subsequent â-elimination of the
metal fragment and the methoxy group.8c
enolate
2, Z/Eb
yield
(%)c
entry
FCC 1
R1
R2
R3
7/8
In summary, we have disclosed an efficient and concise synthesis
of cyclopropanols17 by direct combination of methoxycarbene
complexes of chromium and â-substituted ketone lithium enolates.
This strategy represents a valuable approach to a longstanding
elusive reaction in Fischer carbene chemistry.
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1a
1a
1d
Ph
Ph
Ph
2-Naph
pClC6H4
Ph
2ad 83:17
2fd 100:0
2gf -g
Et
Pr
7a
7b
7c
7d
7e
8a
8b
8c
81e
84
77
81e
73
80
84
72
Me
Me
Et
Me
Me
Me
Et
i-Pr
2-Thi
Pr
Ph
Et
2ad 83:17
2bd 98:2
2hf 30:70
2bf 98:2
2af 83:17
Acknowledgment. Financial support for this work from the
Spanish MEC (CTQ-2004-08077-C02-01/BQU) and from the
FICYT (IB05-136) is gratefully acknowledged. M.G.S. and I.P.-S.
thank the MEC (Spain) and the Principado de Asturias for FPU
and FICYT predoctoral fellowships, respectively.
Ph
3-Thi
Ph
Pr
a Reaction conditions: (1) 2 (1.2 equiv), -78 °C, 5 min and then 20 °C,
45 min; (2) removal of THF, addition of Et2O or removal of THF and
i-Pr2NH, addition of THF; (3) MeOTf (2 equiv) or TMSCl (1.5 equiv),
-78 °C, 5 min and then 20 °C, 30 min. 2-Naph ) 2-naphthyl; 2-Thi )
2-thienyl; 3-Thi ) 3-thienyl. b Enolate geometry. c Yield of isolated,
analytically pure product 7 or 8 based on carbene complex 1. d Enolate
prepared from the corresponding trimethylsilyl enol ether and BuLi. e In
this experiment the reaction conditions in the first step were (1) 2 (1.2 equiv),
-78 to -55 °C, 10 min and then -55 °C, 1 h and 20 °C, 30 min. f Enolate
prepared from the corresponding ketone and LDA. g Not determined.
Supporting Information Available: Experimental procedures,
spectral and analytical data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Metal Carbenes in Organic Synthesis; Do¨tz, K. H., Ed.; Topics in
Organometallic Chemistry, Vol. 13; Springer-Verlag: Berlin, 2004. (b)
Barluenga, J.; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E. J. Organomet.
Chem. 2005, 690, 539-587. (c) Barluenga, J.; Flo´rez, J.; Fan˜ana´s, F. J.
J. Organomet. Chem. 2001, 624, 5-17.
(2) (a) Barluenga, J.; Pe´rez-Sa´nchez, I.; Rubio, E.; Flo´rez, J. Angew. Chem.,
Int. Ed. 2003, 42, 5860-5863. (b) Barluenga, J.; Pe´rez-Sa´nchez, I.; Suero,
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references therein.
Scheme 1. Proposed Mechanism
(3) Casey, C. P.; Brunsvold, W. R. Inorg. Chem. 1977, 16, 391-396.
(4) Concello´n, J. M.; Bernad, P. L., Jr. Tetrahedron Lett. 1998, 39, 7967-
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Eur. J. 2005, 11, 4995-5006.
(6) The 1,2-addition of a vinylogous lithium enolate to alkynyl(methoxy)-
carbene complexes of W has been reported: Barluenga, J.; Garc´ıa-
Garc´ıa, P.; Ferna´ndez-Rodr´ıguez, M. A.; Aguilar, E.; Merino, I. Angew.
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To gain insight into the scope of this new cyclopropanation
reaction we next tested the behavior of other FCCs and other
â-substituted ketone lithium enolates. Given that cyclopropanols 3
are somewhat unstable compounds,14 we decided to quench the
reaction with methyl triflate or trimethylsilyl chloride as a means
to facilitate the characterization of the final products. Accordingly,
stable and diastereomerically pure 1,2-dimethoxycyclopropanes
7a-e (Table 2, entries 1-5) or 1-methoxy-2-trimethylsilyloxycy-
clopropanes 8a-c (Table 2, entries 6-8) were produced under the
experimental conditions summarized in Table 2. Apart from
phenylcarbene complex 1a and lithium enolates 2a-d, aryl- and
heteroarylcarbene complexes 1b-d reacted successfully with
lithium enolates 2f-h. THF has to be replaced for Et2O to avoid
polymerization by adding MeOTf; and i-Pr2NH must be removed
to get success in the experiments with Me3SiCl. The stereochemical
assignment of products 7 and 8 is based on a 2D NMR study12
effected with compound 7a and on a single-crystal X-ray diffraction
study performed with 1,2-dimethoxycyclopropane 7c.13
(7) Rudler, H.; Parlier, A.; Alvarez, C.; Vaissermann, J. J. Organomet. Chem.
2005, 690, 4087-4089.
(8) See for example: (a) Stadtmu¨ller, H.; Knochel, P. Organometallics 1995,
14, 3163-3166. (b) Fuchibe, K.; Iwasawa, N. Chem. Eur. J. 2003, 9,
905-914. (c) Rudler, H.; Parlier, A.; Certal, V.; Lastennet, G.; Audouin,
M.; Vaissermann, J. Eur. J. Org. Chem. 2004, 2471-2502. See also
reference 2.
(9) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1972, 105, 3966-3973. (b)
Wulff, W. D.; Yang, D. C.; Murray, C. K. Pure Appl. Chem. 1988, 60,
137-144. (c) Murray, C. K.; Yang, D. C.; Wulff, W. D. J. Am. Chem.
Soc. 1990, 112, 5660-5662.
(10) For other synthesis of cyclopropanols from FCCs and simple olefins,
see: Barluenga, J.; Lo´pez, S.; Trabanco, A. A.; Flo´rez, J. Chem. Eur. J.
2001, 7, 4723-4729.
(11) This heteroannulation reaction is a general process when analogous
experiments are conducted with â-unsubstituted ketone lithium enolates.
(12) 1H, 13C, DEPT, HSQC, HMBC, COSY and NOESY NMR spectra were
measured and in some cases selective NOE experiments.
(13) Full details of the X-ray crystal-structure studies of 4a, 6c,d and 7c will
be described separately.
(14) Upon standing (5 °C) they slowly decomposed. In some cases a clean
transformation to the corresponding 1,3-diketone has been observed.
(15) This reactivity has been proposed to explain the reaction of methoxy-
(phenyl)carbene complex of Cr with methyl isobutyrate lithium enolate
and allylmagnesium bromide; see reference 2b.
This cyclopropanation process involves the diastereoselective
formation of intermediates A,2 which subsequently undergo ring
closure by intramolecular addition of the alkylchromate moiety to
the carbonyl group (Scheme 1).15 The diastereoselection attained
in the cyclization step from either acyclic or cyclic enolates can be
rationalized through the reacting conformations A′ (frontal attack
(16) Casey, C. P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699-1704.
(17) Cyclopropanols and in particular cyclopropanediol derivatives provide
building blocks of valuable synthetic potential. (a) Kulinkovich, O. G.
Chem. ReV. 2003, 103, 2597-2632. (b) Takeda, K.; Okamoto, Y.;
Nakajima, A.; Yoshii, E.; Koizumi, T. Synlett 1997, 1181-1183. (c) Ukai,
K.; Oshima, K.; Matsubara, S. J. Am. Chem. Soc. 2000, 122, 12047-12048.
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