Baylis-Hillman-Type Carbon-Carbon Bond Formation of Alkenylphosphonates by the Action of Lithium Diisopropylamide

Full text of DOI:10.1021/jo981028k

6428
J . Org. Chem. 1998, 63, 6428-6429
Communications
Ba ylis-Hillm a n -Typ e Ca r bon -Ca r bon Bon d
F or m a tion of Alk en ylp h osp h on a tes by th e
Action of Lith iu m Diisop r op yla m id e
Sch em e 1
Yasuo Nagaoka and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
Received J une 1, 1998
Alkylphosphonates are versatile synthetic tools1 as well
as being potent biological components.2 Conjugate addition
of nucleophiles to alkenylphosphonates bearing a second
electron-withdrawing group at the R-position has been
established as a rout to alkylphosphonates.3 Recently, the
conjugate addition of organocoppers4 or enolates5 to al-
kenylphosphonates lacking an activating group has been
reported.6 We have been involved in studies directed toward
the development of enantioselective conjugate additions of
organometallics to activated olefins.7 As part of our program
related to the foregoing,8 we examined a sequence of reac-
tions involving conjugate addition of lithium diisopropyl-
amide (LDA) to alkenylphosphonates 1 and subsequent
aldol-type reaction of the resultant lithiated phosphonates
2 with aldehydes or ketones, giving 3 or further elimination
products 4. It is important to note that 4 is readily converted
to allenes 59 by treatment with a base under Horner-
Wadsworth-Emmons conditions.
4 in good to high yields. Furthermore, we provide mecha-
nistic evidence for the intermediacy of 2. This is contrary
to the formation of the vinylic anion generated by de-
protonation of the dimethyl ester corresponding to
1c (R1 ) Ph) with LDA and found to undergo electrophilic
trapping resulting in the synthesis of dimethyl ester of 4
(R1 ) Ph).12
We began our studies by examining the reaction of diethyl
propenylphosphonate 1b (R1 ) Me) with benzaldehyde with
LDA as a nucleophilic Michael donor. At first, formation of
anion 2b was attempted by dropwise addition of 1b to a
cooled (-78 °C) solution of LDA in THF. After being stirred
20 min, benzaldehyde was added dropwise to the solution
and the reaction continued for 1 h at -78 °C. This route
failed to give the expected products 3 and 4 (7). The only
isolable product was 8, generated from 6b, in 62% yield
(Scheme 1).13 In another attempt, a mixture of 1b and
benzaldehyde in THF added to a solution of LDA in THF
gave the desired product 7 along with 8 each in 21% yield.
These results imply that conjugate addition of LDA to 1b
enables the formation of the kinetic anion 2b, which is not
stable and is converted to the thermodynamic allylic anion
6b as shown. This suggests that addition of LDA to 1b in
the presence of benzaldehyde would increase the yield of 7
because the initially formed anion 2b may react rapidly with
benzaldehyde before the establishment of the equilibrium
with 6b. Thus, addition of a solution of 1.1 equiv of LDA in
THF to a mixture of 1b and an equivalent of benzaldehyde
in THF afforded, after 1 h at -78 °C, the desired product 7
in acceptable 73% yield along with 8 in 11% yield.
The intermediacy of vinylic carbanion 912 is ruled out by
the fact that reaction of 1b with 2 equiv of Davies’ chiral
The conversion of 1 to 4 is equivalent to the Baylis-
Hillman reaction.10,11 We describe herein that treatment of
a mixture of 1 and carbonyl compounds with LDA afforded
(7) Conjugate addition of organolithiums: Asano, Y.; Iida, A.; Tomioka,
K. Chem. Pharm. Bull. 1998, 46, 184-186. Shindo, M.; Koga, K.; Tomioka,
K. J . Am. Chem. Soc. 1992, 114, 8732-8733. Conjugate addition of lithium
thiolate: Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J . Am. Chem.
Soc. 1997, 119, 12974-12975.
(1) Review for phosphonates: Wiemer, D. F. Tetrahedron 1997, 53,
16609-16644. Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3.
(2) Lerner, R. A.; Benkovics, S. J .; Schultz, P. G. Science 1991, 252, 659-
667. Giannousis, P. P.; Bartlett, P. A. J . Med. Chem. 1987, 30, 1603-1609.
Allen, J . G.; Atherton, F. R.; Hall, M. J .; Hassell, C. H.; Holmes, S. W.;
Lambert, R. W.; Nisbet, L. J .; Ringrose, P. S. Nature 1978, 272, 56-58.
(3) Review for vinylphosphonates: Minami, T.; Motoyoshiya, J . Synthesis
1992, 333-349.
(8) Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem., Int. Ed. Engl. 1998,
37, 515-517.
(9) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; J ohn
Wiley and Sons: New York, 1984.
(10) Review: Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001-8062. Recent publication: Brzezinsli, L. J .; Rafel, S.; Leahy, J .
W. J . Am. Chem. Soc. 1997, 119, 4317-4318.
(4) Baldwin, I. C.; Beckett, R. P.; Williams, J . M. J . Synthesis 1996, 34-
36.
(5) Ojea, V.; Fernandez, M. C.; Ruiz, M.; Quintela, J . M. Tetrahedron
Lett. 1996, 37, 5801-5804. Ojea, V.; Ruiz, M.; Shapiro, G.; Pombo-Villar,
E. Ibid. 1994, 35, 3273-3276. Enders, D.; Wahl, H.; Papadopoulos, K.
Liebigs Ann. 1995, 1177-1184.
(6) Conjugate addition of organocopper to vinyl phosphine oxides has been
reported. Clayden, J .; Nelson, A.; Warren, S. Tetrahedron Lett. 1997, 38,
3471-3474.
(11) The DABCO-catalyzed Baylis-Hillman reaction of 1a with alde-
hydes was reported to take a long time to completion. Amri, H.; El Gaied,
M. M.; Villieras, J . Synth. Commun. 1990, 20, 659-663.
(12) Atta, F. M.; Betz, R.; Schmid, B.; Schmidt, R. R. Chem. Ber. 1986,
119, 472-481.
(13) Satisfactory analytical and spectroscopic data were obtained for new
compounds described.
S0022-3263(98)01028-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/26/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6429
lithium amide 1014 in the absence of benzaldehyde at -95
°C for 10 min affords 1115 and the isomerized olefin 12, in
23 and 75% yields, respectively.16 Formation of 4 (7), instead
of 3, is probably due to the lower stability of the anionic form
of 3 compared with that of 4 (7).17
Ta ble 1. Rea ction of Alk en ylp h osp h on a te 1 w ith
Ald eh yd e or Keton e w ith LDA Givin g 4 a n d Con ver sion
to 5
entry
1
R1
R2
R3
4a% 5a%
1
2
3
4
5
6
7
8
9
a
a
a
b
b
b
b
c
c
c
c
H
H
H
t-Bu
Et
H
Me
87
80
4-t-butylcyclohexanone
t-Bu
Ph
PhCH2CH2
4-t-butylcyclohexanone
t-Bu
Ph
80b
80c
73c
Me
Me
Me
Me
Ph
Ph
Ph
Ph
H
H
H
78c
53b
90
58d
H
H
H
Me
72e
60e
58f
52g
50
66
78
10
11
PhCH2CH2
Et
Using the conditions established as above, reactions of
alkenylphosphonates 1a -c with aldehydes or ketones were
examined. The results, including conversion of 4 to the
allenes 5, are summarized in Table 1.
a
Yields for products isolated by silica gel column chromatog-
raphy. Three equiv of LDA was used. c Allylphosphonates 8 were
produced in 9-11% yields. Harada, T.; Katsuhira, T.; Osada, A.;
b
d
Vinyl-, propenyl-, or phenylethenylphosphonates 1a -c
were converted to the corresponding Baylis-Hillman reac-
tion-type products 4 in good to high yields. Ketones were
also found to be good carbonyl substrates (entries 2, 3, 7,
and 11). The E geometry of the product 4 was assigned on
the basis of the observed phosphorus and the â-vinylic proton
coupling constant of 25 Hz.18 We were very pleased to find
that reactions with aldehydes and ketones bearing hydro-
gens at the R-position also proceeded smoothly to give the
expected products 4 (entries 2, 3, 6, 7, 10, and 11). It is then
apparent that conjugate addition of LDA to alkenylphos-
phonates is faster than deprotonation of the substrates.
Iwazaki, K.; Maejima, K.; Oku, A. J . Am. Chem. Soc. 1996, 118,
11377-11390. e Elsevier, C. J .; Vermeer, P. J . Org. Chem. 1985,
50, 3042-3045. f Kim, S.; Cho, C. M.; Yoon, J . J . Org. Chem. 1996,
g
61, 6018-6020. Keinan, E.; Bosch, E. J . Org. Chem. 1986, 51,
4006-4016.
Alcohols 4 were readily converted to the corresponding
allenes 5 by NaH in THF under the conditions of the
Horner-Wadsworth-Emmons reaction (Table 1).19
Extension of the present procedure to asymmetric versions
is the subject of current study.20
Ack n ow led gm en t. We gratefully acknowledge finan-
cial support from the J apan Society for Promotion of
Science (RFTF-96P00302) and the Ministry of Education,
Science, Sports and Culture, J apan (to Y.N.: 10771246).
(14) Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996, 7, 1595-
1598 and references therein.
(15) The ratio of diastereomers was determined to be 86:14 by NMR
analysis.
Su p p or tin g In for m a tion Ava ila ble: Experimental procedure
and characterization of 4, 5, 8, 11, and 12 (9 pages).
(16) Warren et al. reported TMSCl-assisted conjugate addition of 10 to
vinyl phosphine oxides. Bartels, B.; Martin, C. G.; Nelson, A.; Russell, M.
G.; Warren, S. Tetrahedron Lett. 1998, 39, 1637-1640.
(17) A plausible explanation for production of 4 is that the initial alkoxide
intermediate of 3 transfers a proton from carbon to oxygen to give a
phosphonate-stabilized carbanion and then the elimination of diisopropyl-
amide anion generates 4 and LDA, which gives the anion of 4 as the
intermediate prior to quench. We thank to a reviewer for the suggestion.
(18) Tavs, P.; Weitkamp, H. Tetrahedron 1970, 26, 5529-5534.
(19) Marszak, M. B.; Simalty, M.; Seuleiman, A. Tetrahedron Lett. 1974,
1905-1908.
J O981028K
(20) Typical procedure (Table 1, run 8): A cooled (-78 °C) solution of
LDA (0.55 mmol) in THF (5 mL) was added to a mixture of 1c (0.5 mmol)
and pivalaldehyde (0.5 mmol) in THF (5 mL) at -78 °C. After being stirred
for 30 min at -78 °C, the reaction mixture was quenched with saturated
NH4Cl (10 mL) and extracted with EtOAc. Concentration and subsequent
purification by silica gel column chromatography (EtOAc-hexane ) 2:3)
afforded 4 (R1 ) Ph, R2 ) t-Bu, R3 ) H) in 90% yield.