One-Pot Synthesis of Homoallylic Ketones from the Addition of Vinyl Grignard Reagent to Carboxylic Esters

Article abstract of DOI:10.1021/ol0359822

(Equation Presented) Fifteen homoallylic ketones have been synthesized in 26-77% yields on treatment of aromatic, aliphatic, and α-amino methyl carboxylates with excess vinylmagnesium bromide and catalytic amounts of a copper salt in THF. α-Amino homoallylic ketones derived from N-protected α-amino esters possessing aliphatic and alcohol side chains were synthesized in ≥98% enantiomeric purity.

Full text of DOI:10.1021/ol0359822

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4887-4890
One-Pot Synthesis of Homoallylic
Ketones from the Addition of Vinyl
Grignard Reagent to Carboxylic Esters
Karl A. Hansford, James E. Dettwiler, and William D. Lubell*
De´partement de Chimie, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
Received October 11, 2003
ABSTRACT
Fifteen homoallylic ketones have been synthesized in 26−77% yields on treatment of aromatic, aliphatic, and r-amino methyl carboxylates
with excess vinylmagnesium bromide and catalytic amounts of a copper salt in THF. r-Amino homoallylic ketones derived from N-protected
r-amino esters possessing aliphatic and alcohol side chains were synthesized in g98% enantiomeric purity.
The γ,δ-unsaturated carbonyl unit is often found in natural
products.1 Homoallylic ketones of this type have served as
important versatile building blocks for the synthesis of
pyrroles,2 dihydropyrroles,3 pyridines,4 isoquinolines,4a cy-
clopropanes,5 cyclopentyl derivatives,6 cyclic peroxides,7
8-oxabicyclo[3.2.1]octanes,8 bromopyranes,9 and bishomoal-
lyllithium reagents.10 Furthermore, γ,δ-unsaturated ketones
have been the topic of many physical organic studies
involving their rearrangement under thermal,11a photo-
chemical,11b and Lewis acid-induced conditions.11c
Several methods exist for the construction of the γ,δ-
unsaturated carbonyl unit. For example, 1,4-addition of
lithium vinyl cuprates,12 organoboranes,13 2-benzotriazolyl-
2-arylethylsilanes,14 and R-zirconated vinylsilanes15 to R,â-
unsaturated compounds has given homoallylic ketones in
good yield. Alternative protocols include the allylation of
(1) (a) Yamamoto, I.; Tanaka, S.; Fujimoto, T.; Ohta, K. J. Org. Chem.
1989, 54, 747-750. (b) Agatsuma, T.; Ogawa, H.; Akasaka, K.; Asai, A.;
Yamashita, Y.; Mizukami, T.; Akinaga, S.; Saitoh, Y. Bioorg. Med. Chem.
2002, 10, 3445-3454. (c) Ru¨ngeler, P.; Castro, V.; Mora, G.; Go¨ren, N.;
Vichnewski, W.; Pahl, H. L.; Merfort, I.; Schmidt, T. J. Bioorg. Med. Chem.
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12810.
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Chem. Commun. 1993, 143-145. (b) Leitich, J.; Schaffner, K. Angew.
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A. Synlett 1996, 993-994. (c) Jacob, P.; Brown, H. C. J. Am. Chem. Soc.
1976, 98, 7832-7833.
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63, 9987-9988.
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145. (b) Koganemaru, Y.; Kitamura, M.; Narasaka, K. Chem. Lett. 2002,
784-785. (c) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1998,
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10.1021/ol0359822 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/14/2003

silyl enol ethers16 and various allylations of unsaturated
compounds under ruthenium,17 palladium,18 and copper
catalysis.19 The Claisen-Cope20 and Carroll rearrangements21
and Wittig22 methodology have also found utility in the
construction of γ,δ-unsaturated carbonyl compounds.
In our program aimed at â,â-dialkyl-substituted serine
analogues,23 the addition of excess vinylmagnesium bromide
to N-(Boc)serine methyl ester 1j at -78 °C in THF gave
homoallylic ketone 2j as a major side-product (Scheme 1
Table 1. Examples of Homoallylic Ketones 2 Obtained by
Reaction of 1 with CH2dCHMgBr (300-500 Mol %),
Cu(OAc)2 (30-50 Mol %) in THF at -45 °C
Scheme 1
and Table 1), in addition to the expected tertiary alcohol 3j
(1:1 ratio). Formation of homoallylic ketone 2 was presumed
to be due to collapse of the tetrahedral intermediate with
expulsion of methoxide ion, followed by conjugate addition
to the resulting enone (Scheme 2). This side reaction has
Scheme 2
not been widely discussed in the literature, though it has been
previously observed during the addition of excess vinylmag-
(16) (a) Mukaiyama, T.; Nagaoka, H.; Ohshima, M.; Murakami, M.
Chem. Lett. 1986, 1009-1012. (b) Kudo, K.; Saigo, K.; Hashimoto, Y.;
Houchigai, H.; Hasegawa, M. Tetrahedron Lett. 1991, 32, 4311-4312. (c)
Kudo, K.; Hashimoto, Y.; Houchigai, H.; Hasegawa, M.; Saigo, K. Bull.
Chem. Soc. Jpn. 1993, 66, 848-856.
(17) Trost, B. M.; Martinez, J. A.; Kulawiec, R. J.; Indolese, A. F. J.
Am. Chem. Soc. 1993, 115, 10402-10403.
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7625-7627. (b) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903-3906. (c) Tsuji,
J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 1325-1326.
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2002, 124, 7440-7447.
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(d) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978-
4979. (e) Bu¨chi, G.; Vogel, D. E. J. Org. Chem. 1985, 50, 4664-4665.
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1998. (b) Carroll, M. F. J. Chem. Soc. 1940, 704-706.
a Reaction performed in absence of copper. b Reaction performed in the
presence of 30-40 mol % CuCN. c PhF ) N-(9-phenylfluoren-9-yl).
d Starting material was recovered in 30% yield.
nesium chloride to R-hydroxycarboxylic ester derivatives.24
Moreover, the addition of vinylmagnesium bromide to
amides has been shown to furnish â-aminoethyl ketones by
(22) (a) Nishiyama, T.; Woodhall, J. F.; Lawson, E. N.; Kitching, W. J.
Org. Chem. 1989, 54, 2183-2189. (b) Cornish, C. A.; Warren, S. J. Chem.
Soc., Perkin Trans. 1 1985, 2585-2598.
(23) Dettwiler, J. E.; Lubell, W. D. J. Org. Chem. 2003, 68, 177-179.
4888
Org. Lett., Vol. 5, No. 25, 2003

a sequential 1,2-addition of the vinyl Grignard reagent
followed by 1,4-addition of the displaced amine onto the
enone intermediate.25 Conditions have now been developed
to favor formation of homoallylic ketone 2 using a diverse
set of carboxylic esters, the results of which are reported
herein (Table 1).
Table 2. Influence of Added Copper Salts on the Ratio of 2:3a
Reaction conditions were initially optimized using N-
(Boc)serine methyl ester 1j as a substrate. The yield of
homoallylic ketone 2j was augmented by the addition of
copper salts.26 For example, sequential addition of 10 mol
% anhydrous Cu(OAc)2, followed by a THF solution of 1j
to the vinyl Grignard reagent (500 mol %) at -45 °C, gave
1
a 4:1 mixture of 2j:3j as determined by H NMR spectros-
copy of the crude product. Although this ratio could be
improved by increasing the proportion of Cu(OAc)2 (>99:1
with 100 mol %), ketone 2j was typically accompanied by
increased amounts of unreacted starting material (1j:2j )
30:70). Substitution of Cu(OAc)2 with Cu(OAc)2‚H2O and
with CuCN (30-50 mol %) gave equally successful results
using commercial and freshly prepared Grignard reagent.
With appropriate conditions in hand,27 a variety of methyl
esters were examined in this reaction (Table 1). Aliphatic,
aromatic, and R-amino methyl esters all furnished the
respective homoallylic ketone 2 in moderate to good yields,
demonstrating that the reaction conditions were tolerant of
a wide variety of functional groups. Reactions were suc-
cessfully performed on a 1-13 mmol scale.
a As determined by 1H NMR spectroscopy. b In absence of copper
catalyst. c In presence of copper catalyst. d Performed with 50 mol %
Cu(OAc)2. e Performed with 30 mol % Cu(OAc)2. f Performed with 30 mol
% CuCN.
were inconsistent with the spectroscopic observations, sug-
gesting that poor mass recovery may be due to purification.
Exposure of compound 2g to a slurry of silica gel and the
appropriate chromatography solvent did not provide evidence
of decomposition after several days; however, limited success
was achieved with different workup procedures and chro-
matography absorbents (silica gel, alumina, florisil). Silica
When tertiary alcohol formation was significant (25-50%)
with Grignard reagent alone, the addition of copper salts
generally promoted higher ketone:alcohol ratios (Table 2).
In the absence of copper, sterically encumbered substrates
(Table 1, entries i, l, and m) gave 2 contaminated with e5%
1
gel chromatography of crude 2g (observed by H NMR
spectroscopy as a 90:10 mixture of 2g:3g) resulted typically
in 40-55% isolated yields. Alternatively, distillation of the
crude mixture followed by chromatography over basic
alumina to remove 3g gave an improved yield of 2g (60%,
Table 1). Thus, the yields given in Table 1 may be improved
by further optimization of the catalytic conditions and
purification procedure.
R-Amino ketones29 are useful precursors in the synthesis
of natural products and biologically active substances.
R-Amino homoallylic ketones have been previously synthe-
sized from N-(Boc)-R-amino acids in 75-92% yields by
preactivation of the carboxylate as N,O-dimethyl hydrox-
amates30a and S-pyridinyl esters;30b,c however, the enantio-
1
tertiary alcohol, as shown by H NMR analysis; however,
complete reaction required generally several days at room
temperature.28
Although TLC analysis of crude product on silica gel
1
always showed baseline material, H NMR spectroscopic
examination of crude product after extractive workup often
revealed clean spectra with little evidence of unreacted
starting material. Chromatographic purification was facili-
tated by the fact that ketone 2 always eluted faster than
alcohol 3; nonetheless, typical isolated yields of ketone 2
(24) (a) Schmidt, B.; Wildemann, H. J. Chem. Soc., Perkin Trans. 1
2000, 2916-2925. (b) Schmidt, B.; Wildemann, H. Synlett 1999, 1591-
1593.
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Koenig, R. J.; Lee, C.-H. J. Org. Chem. 2001, 66, 3613-3616. (c) Wuts,
P. G. M.; Putt, S. R.; Ritter, A. R. J. Org. Chem. 1988, 53, 4503-4508.
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Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128-3141.
(c) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308-
2316. (d) Organocopper Reagents: A Practical Approach; Taylor, R. J.
K., Ed.; Oxford University Press: New York, 1994.
(27) A solution of vinylmagnesium bromide in THF (1 M, 8.4 mL, 8.4
mmol) was cooled to -45 °C (dry ice/acetonitrile). Solid Cu(OAc)2 (113.4
mg, 0.63 mmol) was added in one portion and the slurry stirred for 10
min. Ester 1b (408 mg, 2.1 mmol) was then added dropwise. After 1 h, the
reaction mixture was warmed to 0 °C, stirred for 1 h, and then brought to
room temperature with overnight stirring. Workup and purification proce-
dures and characterization data for 2b are presented in Supporting
Information.
(29) (a) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am. Chem. Soc.
1984, 106, 1095-1098. (b) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc.
1988, 110, 7447-7455. (c) Buckley, T. F.; Rapoport, H. J. Am. Chem.
Soc. 1981, 103, 6157-6163. (d) Folmer, J. J.; Acero, C.; Thai, D. L.;
Rapoport, H. J. Org. Chem. 1998, 63, 8170-8182. (e) Lubell, W. D.;
Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990, 55, 3511-3522. (f)
Knudsen, C. G.; Rapoport, H. J. Org. Chem. 1983, 48, 2260-2266. (g)
Klix, R. C.; Chamberlin, S. A.; Bhatia, A. V.; Davis, D. A.; Hayes, T. K.;
Rojas, F. G.; Koops, R. W. Tetrahedron Lett. 1995, 36, 1791-1794. (h)
Florjancic, A. S.; Sheppard, G. S. Synthesis 2003, 1653-1656. (i) Bonini,
B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.; Varchi,
G. Synlett 1998, 1013-1015. (j) De Luca, L.; Giacomelli, G.; Porcheddu,
A. Org. Lett. 2001, 3, 1519-1521.
(30) (a) DiMaio, J.; Gibbs, B.; Lefebvre, J.; Konishi, Y.; Munn, D.; Yue,
S. Y.; Hornberger, W. J. Med. Chem. 1992, 35, 3331-3341. (b) Almquist,
R. G.; Chao, W. R.; Judd, A. K.; Mitoma, C.; Rossi, D. J.; Panasevich, R.
E.; Matthews, R. J. J. Med. Chem. 1988, 31, 561-567. (c) Osterkamp, F.;
Ziemer, B.; Koert, U.; Wiesner, M.; Raddatz, P.; Goodman, S. L. Chem.
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(28) Steric crowding promotes 1,4-addition over 1,2-addition of Grignard
reagents to enones. Cluzeau, J.; Lubell, W. D. Israel J. Chem. 2001, 41,
271-281 and references therein.
Org. Lett., Vol. 5, No. 25, 2003
4889

diastereomer shown).34 Deprotection of the 3:1 mixture with
TFA in CH2Cl2, followed by acylation with D,L-N-benzene-
sulfonylprolyl chloride,29a gave a 3:3:1:1 mixture of dia-
stereomeric amido alcohols 5, displaying distinct methyl
doublets in the 1H NMR spectrum (400 MHz, CDCl3) at 1.13,
1.15, 1.19, and 1.22 ppm, respectively. By analogy, coupling
of L-N-benzenesulfonylprolyl chloride29a to the diastereomeric
Scheme 3
1
mixture 4 provided product (2′S)-5 in which no H NMR
signals for the upfield methyl doublet (δ 1.13) were observed.
Incremental additions of (2′RS)-5 to (2′S)-5 demonstrated
that diastereomeric 1H NMR signals were detectable at levels
of ∼1%. Hence, the enantiomeric purity of amino ketone
2h is presumed to be g98%. Considering the effectiveness
of alternative protecting groups (SO2Ph and PhF), and the
potential of ionizable side chain substituents to prevent
R-epimerization on reaction with organometallic reagent due
to polyanion formation,29f compounds 2i and 2j are also
presumed to be enantiopure. This result demonstrates that
minimal epimerization at the R-center occurs and that
R-amino homoallyl ketones 2h-m can be synthesized in high
enantiomeric purity.
Fifteen homoallylic ketones have been synthesized in 26-
77% yields on treatment of methyl carboxylates 1 with excess
vinylmagnesium bromide and catalytic amounts of copper
salts in THF. Our straightforward method for making γ,δ-
unsaturated ketones offers a practical alternative for the
synthesis of these versatile building blocks.
meric purity of the ketone products was not addressed. Both
the Cu(acac)2-catalyzed 2,3-sigmatropic rearrangement of
allyl sulfonium ylides31a and the desulfonation of R-alkylated
γ-amino-â-ketosulfones31b were reported to furnish enan-
tiopure R-amino homoallyl ketones. The acylation of the
lithio dianion of methyl hippurate with 4-pentenoyl chloride
also provided entry into R-amino homoallyl ketones,32 albeit
in racemic form. Because multiple steps and expensive
reagents are often necessary for producing R-amino homo-
allyl ketones by these sequences, we investigated the addition
of vinylmagnesium bromide to a series of N-protected
R-amino esters 1h-m. 1H NMR spectroscopic examination
of products 2k-m did not show evidence of R-epimerization,
as judged by the absence of diastereomeric signals. The
enantiomeric purity of R-amino homoallyl ketone was
ascertained by conversion of N-(Boc)alanine-derived ketone
2h to amido alcohols 4 (Scheme 3). Ketone 2h was reduced,
respectively, with LiAl(OtBu)3H33 and NaBH4 to provide
97:3 and 3:1 diastereomeric mixtures of alcohols 4 (major
Acknowledgment. This work was supported by grants
from Fonds Que´be´cois de la recherche sur la nature et les
technologies (FQRNT), Valorisation-Recherche Que´be´c
(VRQ), and Conseil de recherches en sciences naturelles et
en ge´nie du Canada (CRSNG). We thank Valeria Zanzarova
for technical assistance.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0359822
(33) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002,
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(34) Diastereomers 4 were inseparable by column chromatography but
could be separated (g99:1) by crystallization from hexane. The anti
configuration of the major diastereomer (2R,3S)-4 was assigned by analogy
(see ref 33) and confirmed by examination of the 1H NMR NOESY spectrum
of oxazalidinone 6 in CDCl3 solution.
(31) (a) Sengupta, S.; Mondal, S. Tetrahedron Lett. 2000, 41, 2965-
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4890
Org. Lett., Vol. 5, No. 25, 2003