Vinylalumination for the Synthesis of Functionalized Allyl Alcohols, Vinylepoxides, and α-Alkylidene-β-hydroxy-γ-lactones

Article abstract of DOI:10.1021/jo034954u

A modified hydroalumination protocol for the preparation of [α-(ethoxycarbonyl)vinyl]diisobutylaluminum and its β-methyl or -phenyl analogues was developed. These vinylaluminum reagents react with aldehydes and ketones to provide the corresponding functio

Full text of DOI:10.1021/jo034954u

Vin yla lu m in a tion for th e Syn th esis of F u n ction a lized Allyl
Alcoh ols, Vin ylep oxid es, a n d r-Alk ylid en e-â-h yd r oxy-γ-la cton es
P. Veeraraghavan Ramachandran,* Michael T. Rudd, Thomas E. Burghardt, and
M. Venkat Ram Reddy
Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received J uly 2, 2003
A modified hydroalumination protocol for the preparation of [R-(ethoxycarbonyl)vinyl]diisobutyl-
aluminum and its â-methyl or -phenyl analogues was developed. These vinylaluminum reagents
react with aldehydes and ketones to provide the corresponding functionalized allyl alcohols in good
to excellent yields. Perfluoroalkyl and -aryl carbonyl compounds, R-keto esters, R-acyl cyanides,
and R-acetylenic ketones provide the corresponding R-hydroxyalkenes in high yields. The allyl alcohol
product ratios from the vinylalumination of unsymmetrical R-diketones with [R-(ethoxycarbonyl)-
vinyl]diisobutylaluminum and its â-methyl or -phenyl analogues depend on the steric and electronic
environments of the ketones as well as the reagents. The products from the vinylalumination of
R-bromoaldehydes and -ketones were cyclized with K2CO3 or KF under nonaqueous conditions to
provide functionalized vinylepoxides in high yields. Vinylaluminations of keto-protected pyruval-
dehyde provided the products, which were converted to R-alkylidene-â-hydroxy-γ-lactones.
In tr od u ction
to â-substituted olefins. We envisaged that appropriately
substituted vinylaluminum reagents could overcome the
deficiencies of the BH reaction. Accordingly, we under-
took a project to prepare â-substituted vinylaluminums
and treat them with a variety of carbonyl compounds as
an efficient alternative to BH reaction.5
Organoaluminum intermediates have been well stud-
ied in organic chemistry.1 Hydroalumination of acetyl-
enes to prepare vinylaluminum intermediates for ap-
plication in organic syntheses has been known for
decades.2 In 1987, Tsuda, Saegusa, and co-workers
reported the preparation of novel vinylaluminum re-
agents, [R-(alkoxycarbonyl)vinyl]diisobutylaluminum and
aluminum allenoates by the hydroalumination of R,â-
acetylenic carbonyl compounds with diisobutylaluminum
hydride (DIBAL-H) in the presence of hexamethylphos-
phoric amide (HMPA).3 They treated these aluminum
intermediates with protic acid, allyl bromide, and car-
bonyl compounds.3 The reaction with carbonyl compounds
provides functionalized allyl alcohols.
Our initial projects involved the application of[R-(alkoxy-
carbonyl)vinyl]diisobutylaluminums, prepared via the
hydroalumination of propiolate esters in the presence of
HMPA, for the vinylalumination of activated carbonyls,
such as fluorocarbonyls, R-keto esters, etc.5 Li and co-
workers also reported similar observations on aldehydes
and ketones.6 Subsequently, we modified the hydroalu-
mination procedure by replacing carcinogenic HMPA
with 4-methylmorpholine N-oxide (NMO).7 Apart from
reexamining the earlier vinylaluminations, we included
additional classes of carbonyl compounds, particularly
those that could be readily converted to naturally occur-
ring molecules. Our results are described herein.
The recent interest in the Baylis-Hillman (BH) reac-
tion4 (eq 1), which furnishes similar allylic alcohol
products, attracted us to this vinylalumination reaction.
The drawbacks of the DABCO-catalyzed BH reaction
include its slow rate of reaction and the inapplicability
* Corresponding author.
(1) For recent reviews in organoaluminium chemistry, see: (a) Witt,
M.; Roesky, H. W. Curr. Sci. 2000, 78, 410. (b) Cowley, A. H.; Gabbai,
F. P.; Isom, H. S.; Decken, A. J . Organomet. Chem. 1995, 500, 81.
(2) For reviews on hydroalumination, see: (a) Eisch, J . J . In
Comprehensive Organic Synthesis; Trost, B., Fleming, I., Eds.: Per-
gamon Press: Oxford, UK, 1991; Vol. 8, p 311. (b) Zweifel, G.; Miller,
J . A. In Organic Reactions; Dauben, W. G., Ed.; J ohn Wiley: New York,
1984; Vol. 2, p 377.
(3) (a) Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J . Org.
Chem. 1987, 52, 1624. (b) Tsuda., T.; Yoshida, T.; Saegusa, T. J . Org.
Chem. 1988, 53, 1037.
(4) For reviews on the Baylis-Hillman reaction, see: (a) Basavaiah,
D.; Rao, A. J .; Satyanarayana, T. Chem. Rev. 2003, 103, 811. (b)
Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.; J ohn Wiley:
New York, 1999; Vol. 51, p 201. (c) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001.
(5) (a) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.; de Alaniz,
J . R. Tetrahedron Lett. 1998, 39, 8791. (b) Ramachandran, P. V.; Reddy,
M. V. R.; Rudd, M. T. Tetrahedron Lett. 1999, 40, 627.
(6) Li, G.; Wei, H.-X.; Willis, S. Tetrahedron Lett. 1998, 39, 4607
(7) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem.
Commun. 1999, 1979.
10.1021/jo034954u CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/28/2003
9310
J . Org. Chem. 2003, 68, 9310-9316

Vinylalumination for the Synthesis of Functionalized Allyl Alcohols
TABLE 1. Vin yla lu m in a tion of Ald eh yd es a n d Keton esa
Resu lts a n d Discu ssion
reagent
no.
R′COR′′
R′
product
yieldb (%)
En vir on m en ta lly Ben ign Vin yla lu m in a tion . Al-
though known for over a decade, the lack of extensive
utilization of Tsuda’s vinylalumination procedure3 may
be due to the presence of a carcinogenic material, HMPA,8
as the complexing agent with DIBAL-H for the hydroalu-
mination of propiolates. Several possible replacements
for HMPA, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU),9 1,3-dimethyl-2-imidazolidinone
(DMEU or DMI),10 and quinuclidine N-oxide (QNO),11
have been reported in the literature. Since DMPU and
DMI might undergo reduction with DIBAL-H and QNO
is not economical, we studied a series of other amine
oxides as a complexing agent. Although mixtures of
DIBAL-H and aromatic amine oxides, such as pyridine
and picoline N-oxides, did not provide the desired hy-
droalumination product, aliphatic trialkylamine oxides,
such as trimethylamine N-oxide and NMO, were found
to be suitable complexing agents for the hydroalumina-
tion of propargylic esters and ketones. Our study with
the relatively inexpensive NMO revealed it to be an
excellent HMPA-alternative for vinylaluminations, im-
proving the reaction conditions and providing very good
yields of the products.7 It is very interesting that NMO
aids in the formation of the vinylalanes cleanly and does
not oxidize them.12
Vin yla lu m in a tion of Ald eh yd es. The addition of
DIBAL-H to a suspension of NMO in THF provided a
clear solution. The reaction of ethyl propiolate in THF
with 1.5 equiv of DIBAL-H/NMO complex at 0 °C
provided the [R-(ethoxycarbonyl)vinyl]diisobutylaluminum
(1). The corresponding â-substituted vinylaluminum
reagents, [R-(ethoxycarbonyl)-â-methylvinyl]diisobutyla-
luminum (2) and the R-(ethoxycarbonyl)-â-phenyl]vinyl-
diisobutylaluminum (3), were prepared similarly with 1.8
equiv of DIBAL-H/NMO. Initially, we examined the
reaction of aldehydes with these reagents. Benzaldehyde
(4a ) was added to 1 at 0 °C and warmed to rt. The
reaction was complete within 4 h. Hydrolysis using 1.0
M HCl followed by chromatography provided 96% yield
of the product 5a (eq 2). We observed that the hydrolysis
was much more facile when compared to the reactions
using HMPA.
entry
R
no.
R′′
no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
2
3
1
2
3
1
1
1
2
3
1
2
3
H
4a
4a
4a
Ph
Ph
Ph
n-Pr
n-Pr
n-Pr
i-Pr
t-Bu
Ph
Ph
Ph
Et
Et
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
5a
6a
7a
5b
6b
7b
5c
5d
5e
6e
7e
5f
96
82
80
90
90
75
88
72
74
72
70
75
80
70
Me
Ph
H
Me
Ph
H
4b
4b
4b
4c
4d
4ec
4ec
4ec
4fc
4fc
4fc
H
H
Me
Ph
H
Me
Ph
6f
7f
Et
a
The reactions were carried out in THF at rt with 1.2 equiv of
b
the carbonyl compound. All of the yields are of isolated, purified
products. c One equivalent of BF3‚OEt2 was added.
yield (eq 2, Table 1, entry 2). The â-phenylvinyldiisobu-
tylaluminum reagent 3 yielded 80% of the corresponding
Z-product 7a . In contrast to the previously reported
procedure involving HMPA,6 both of these reactions do
not require the presence of Lewis acid or low tempera-
tures (-78 °C). The reaction provided high yields of the
products with all of the aldehydes examined, viz. bu-
tyraldehyde (4b), isobutyraldehyde (4c), and pivalalde-
hyde (4d ). The results are summarized in Table 1 (entries
1-8).
Vin yla lu m in a tion of Keton es. Unactivated ketones
fail to undergo BH reaction.4 We extended the modified
vinylalumination procedure to such ketones as an alter-
native to BH reaction. However, the reaction of acetophen-
one (4e) with 1 was sluggish. Workup of the reaction after
2 days yielded only 12% of the product 5e along with 25%
of recovered 4e and a mixture of unidentified products.
Addition of 10% of a Lewis acid, such as BF3‚OEt2,
provided a small amount of the product with most of the
ketone recovered. Upon addition of 1 equiv of BF3‚OEt2,
the reaction was complete within 4 h, and workup
provided a 74% yield of 5e (eq 3). 2-Butanone (4f) reacted
similarly, in the presence of 1 equiv of BF3‚OEt2, provid-
ing the product in 75% yield. Reagents 2 and 3 gave
similar results with these ketones (Table 1, entries 9-14).
Reagent 2 reacted with 4a smoothly to provide ethyl
(2Z)-2-[hydroxy(phenyl)methyl]but-2-enoate (6a ) in 82%
Rea ction of F lu or oca r bon yl Com p ou n d s. Due to
the importance of fluoroorganic compounds13 in agro-
chemistry, biochemistry, materials, and medicinal chem-
istry, we undertook the vinylalumination of fluorocarbo-
nyl compounds.5a The difficulties encountered in the BH
reaction of fluorocarbonyl compounds provided additional
impetus to undertake this project.14,15
(8) (a) Schmutz, J . F. Chem. Eng. News 1978, 56, 201. (b) Spencer,
H. Chem. Ind. 1979, 728.
(9) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385.
(10) J uaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 1243.
(11) O’Neil, I. A.; Lai, J . Y. Q.; Wynn, D. Chem. Commun. 1999, 59.
(12) NMO is known to oxidize carbon-boron bonds: Soderquist, J .
A.; Najafi, M. R. J . Org. Chem. 1986, 51, 1330.
J . Org. Chem, Vol. 68, No. 24, 2003 9311

Ramachandran et al.
TABLE 2. Vin yla lu m in a tion of F lu or oca r bon ylsa
TABLE 3. Vin yla lu m in a tion of Activa ted Ca r bon yl
Com p ou n d s
reagent
no.
RFCOR′
product
yieldb (%)
reagent
entry no.
R-C(O)-R′′
R′
product
entry
R
no.
RF
R′
no.
R
no.
R′′
OEt
OEt
OEt
OMe
OMe
OMe
CN
CN
CN
no. yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
1
2
3
1
2
3
1
2
3
1
3
1
H
4g
4g
4g
4h
4h
4h
4i
4i
4i
4j
4j
CF3
H
H
H
H
H
H
H
H
5g
6g
7g
5h
6h
7h
5i
6i
7i
5j
6j
80
70
75
77
72
76
82
70
78
65
70
75
95
78
96
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
CF3
CF3
C3F7
C3F7
C3F7
C6F5
C6F5
C6F5
CF3
CF3
CF3
CF3
CF3
CF3
1
2
3
4
5
6
7
8
9
1
2
3
1
2
3
1
2
3
1
2
3
H
4n
4n
4n
4o
4o
4o
4p
4p
4p
4q
4q
4q
C(O)Me
C(O)Me
C(O)Me
C(O)Ph
C(O)Ph
C(O)Ph
Me
Me
Me
Me
Me
5n
6n
7n
5o
6o
7o
5p
6p
7p
5q
6q
7q
95
70
81
80
60
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
75
72b
70b
72b
51
H
Me
Me
Me
Ph
Ph
10
11
12
C≡CH
C≡CH
C≡CH
4j
7j
45
46
4k
4k
4l
5k
7k
5l
Me
Ph
H
a
b
All of the yields are of isolated, purified products. Yields
obtained from the reaction with HMPA.
2-Thioph
a
The reactions were carried out in THF at rt with 1.2 equiv of
b
the carbonyl compound. All of the yields are of isolated, purified
nonenolizable R-diketones undergo the BH reaction, other
activated ketones, such as R-acetylenic and acyl cyanides,
fail to provide the products.17 We envisaged vinylalumi-
nation of these activated carbonyls as a general reaction
to provide BH products.
products.
Fluoral (4g) was added to 1-3 at -78 °C and was
warmed to rt. The reactions were complete within 4 h
(Table 2, entries 1-3). The generality of the reaction was
examined by condensing a series of aliphatic and aro-
matic perfluorocarbonyl compounds, such as 2,2,3,3,4,4,4-
heptafluorobutyraldehyde (4h ), pentafluorobenzaldehyde
(4i), 1,1,1-trifluoroacetone (4j), 2,2,2-trifluoroacetophen-
one (4k ), and 2-trifluoroacetylthiophene (4l), with 1-3.
In all of the cases, high yields of the product alkenols
were obtained (eq 4) (Table 2, entries 4-15). It is
noteworthy that, unlike the hydrocarbon analogues,7 the
fluoro-ketones underwent reaction without the presence
of any Lewis acid.
Ethyl pyruvate (4n ) was added to 1 at rt, and the
reaction was complete within 4 h. Hydrolysis using 1.0
M HCl followed by chromatography provided an almost
quantitative yield of the product 5n (eq 6). An aromatic
keto ester, methyl benzoylformate (4o), also underwent
ready reaction with 1 to form the product 5o in 80% yield
(Table 3, entry 4). We then extended this reaction to the
â-substituted vinylaluminums. Reagent 2 also reacted
with 4n and 4o smoothly to provide the corresponding
hydroxyalkenyl diester products 6n and 6o. Reagent 3
provided the products 7n and 7o from the R-keto esters
4n and 4o. It is noteworthy that unlike the BH reaction,
the vinylalumination is very facile with both aliphatic
and aromatic keto esters and the yields of the products
are consistent (eq 6, Table 3, entries 1-6).
The reaction of fluoral was compared with the chloro
analogue, chloral (4m ). We obtained similar results for
the vinylalumination of 4m with reagents 1 and 3 (eq
5).
Although we succeeded in carrying out the vinylalu-
mination of R-keto esters with reagents derived from
(13) For several recent reviews, see: (a) Asymmetric Fluoroorganic
Chemistry: Synthesis, Applications, and Future Directions; Ramachan-
dran, P. V., Ed.; ACS Symposium Series 746; American Chemical
Society: Washington, DC, 2000. (b) Enantiocontrolled synthesis of
fluoro-organic compounds: stereochemical challenges and biomedical
targets; Soloshonok, V. A., Ed.; J . Wiley: Chichester, NY, 1999. (c)
Biomedicinal Frontiers in Fluorine Chemistry; Ojima, I., McCarthy,
J . R., Welch, J . T., Eds.; ACS Symposium Series 639; American
Chemical Society: Washington, DC, 1996.
(14) Fluoral and 1,1,1-trifluoroacetone polymerize instantaneously
in the presence of amines: (a) Busfield, W. K.; Whalley, E. Polymer
1966, 7, 541. (b) Dhingra, M. M.; Tatta, K. R. Org. Magn. Reson. 1977,
9, 23.
Vin yla lu m in a tion of Activa ted Ca r bon yl Com -
p ou n d s. The vinylalumination of fluorocarbonyl com-
pounds without the addition of a Lewis acid prompted
us to examine the reaction of other activated carbonyls,
such as R-keto esters, R-acyl cyanides, R-acetylenic
ketones, and R-diketones. Although R-keto esters16 and
9312 J . Org. Chem., Vol. 68, No. 24, 2003

Vinylalumination for the Synthesis of Functionalized Allyl Alcohols
TABLE 4. Vin yla lu m in a tion of Dik eton es
propiolates and DIBAL-H/NMO, we failed to achieve the
vinylalumination of acyl cyanides with this reagent. The
reaction mixture darkened upon addition of acyl cyanide,
and TLC analysis indicated no clean product formation.
However, we encountered no problems in obtaining the
products when the vinylalumination of acyl cyanides was
carried out using reagents prepared from propiolates and
DIBAL-H/HMPA.
The results noted below are those obtained with the
reagent prepared using HMPA as the additive. No
difficulty was experienced in condensing pyruvonitrile
(4p ) with all of the three vinylaluminum reagents 1-3
(eq 7). The reactions were complete within 4 h, and acidic
workup provided the R-alkenyl-â-cyano-â-hydroxy esters
in 70-72% yields (Table 3, entries 7-9). The BH reaction
of this class of carbonyl compounds is too slow to be of
any practical use.
reagent
entry no.
R′-C(O)-C(O)R′′
product(s)
R
no.
R′
R′′
no.
5r
6r
7r
5s
5t
ratio yielda (%)
1
2
1
2
3
1
1
1
2
3
1
2
3
H
4r
Me
Me
Me
Et
Me
Me
Me
Et
Ph
Et
Et
Et
Ph
Ph
Ph
70
60
72
81
78
Me 4r
Ph 4r
3
4
5
6
H
H
H
4s
4t
4u
Ph
Me
Me
Me
Me
Me
Me
5u /5′u 45:55b
6u /6′u 39:61b
7u /7′u 20:80b
5v/5′v 75:25
6v/6′v 65:35
7v/7′v 52:48
80c
66c
80c
88c
71c
83c
7
8
Me 4u
Ph 4u
9
H
4v
10
11
Me 4v
Ph 4v
a
b
All of the yields are of isolated, purified products. The
products could not be separated. Ratios given were obtained from
1H NMR analysis. c Combined yield.
isobu tyla lu m in u m . The BH reaction of R-diketones is
limited to only nonenolizable diketones.20 Enolizable and
nonenolizable R-diketones were subjected to vinylalumi-
nation to show the generality of this process. In addition,
the possibility of studying the effect of sterics and
electronics in the case of unsymmetrical R-diketones21
persuaded us to undertake such a study.
2,3-Butanedione (4r ) was added to 1, and the reaction
was complete within 4 h. Hydrolysis using 1.0 M HCl
and purification on silica gel provided 70% of the product
5r (eq 10). The â-substituted vinylaluminum reagents 2
and 3 reacted with 4r smoothly to provide the â-hydroxy-
γ-keto esters 6r and 7r in 60% and 72% yields, respec-
tively. 3,4-Hexanedione (4s) furnished a slightly better
yield (81%) of the product 5s for a reaction with 1. An
aromatic diketone, benzil (4t), afforded 78% yield of the
corresponding R-keto R′-ethoxycarbonyl allylic alcohol 5t.
The results are summarized in Table 4 (entries 1-5).
However, the reagents 1-3 prepared with NMO re-
acted readily with another class of activated carbonyls,
R-acetylenic ketones. 3-Butyn-2-one (4q) provided the
products in 45-51% yields (eq 8) (Table 3, entries 10-
12). Addition of a Lewis acid (BF3‚OEt2) did not improve
the yields. The results for the vinylalumination of
activated carbonyls are summarized in Table 3.
Hoffmann18 and Basavaiah16 had reported the prepa-
ration of activated dienes for the Diels-Alder reaction
from similar products obtained from the BH reaction of
R-keto esters (eq 9).18 The dienes could be converted into
many useful synthons, including substrates for the
preparation of molecular rods, which has applications in
nanotechnology.19
The reaction of an unsymmetrical R-diketone, 2,3-
pentanedione (4u ), with 1 followed by workup provided
an 80% yield of a mixture of alcohols, 5u and 5′u , that
were difficult to separate by column chromatography. A
(15) (a) Ramachandran, P. V., Reddy, M. V. R., Rudd, M. T. Chem.
Commun. 2001, 757. (b) Reddy, M. V. R., Rudd, M. T., Ramachandran,
P. V. J . Org. Chem. 2002, 67, 5382.
(16) Basavaiah, D.; Bharathi, T. K.; Gowriswari, V. V. L. Tetrahe-
dron Lett. 1987, 28, 4351.
(17) Ramachandran, P. V.; Rudd, M. T.; Reddy, M. V. R. Tetrahedron
Lett. 1999, 40, 3819.
(18) Grundke, C.; Hoffmann, H. M. R Chem. Ber. 1987, 120, 1461.
(19) (a) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y.
Tetrahedron Lett. 1987, 28, 6671. (b) Kotera, M.; Lehn, J .-M.; Vigneron,
J .-P. Tetrahedron 1995, 51, 1953. (c) Kotera, M.; Lehn, J .-M.; Vigneron,
J .-P. J . Chem. Soc., Chem. Commun. 1994, 197.
(20) Strunz, G. M.; Bethell, R.; Sampson, G.; White, P. Can. J . Chem.
1995, 73, 1666.
(21) For a study of the effects of Grignard additions to unsym-
metrical R-diketones, see: Maruyama, K.; Katagiri, T. J . Phys. Org.
Chem. 1991, 4, 158.
Ster eoelectr on ic Effects in th e Vin yla lu m in a tion
of R-Dik eton es w ith [R-(Eth oxyca r bon yl)vin yl]d i-
J . Org. Chem, Vol. 68, No. 24, 2003 9313

Ramachandran et al.
1H NMR examination revealed modest preferential vi-
nylalumination of the carbonyl bearing the methyl group
(55%) over the carbonyl bearing the ethyl group (45%)
(eq 11). When the â-methyl-substituted reagent 2 was
used, the corresponding products 6u and 6′u were formed
in a 2:3 ratio. The preference toward the methyl side
increased considerably with reagent 3. The corresponding
products 7u and 7′u were formed in a 1:4 ratio. Clearly,
the steric interactions of the reagent and the carbonyl
group determine the outcome of the vinylalumination.
The results are shown in Table 4 (entries 6-8).
-ketones via vinylalumination.26 Similar to several acti-
vated carbonyls, the vinylalumination of R-bromocarbo-
nyls also proceeds without Lewis acid catalysis and the
products were readily converted to functionalized vinyle-
poxides.
Vinylalumination of bromoacetaldehyde (4w ) was com-
plete in 15 h at rt. Dilute HCl workup provided 65% yield
of the product bromohydrin 5w (eq 13). The reaction was
then extended to representative bromo ketones. Phenacyl
bromide (4x) and 1-bromo-3,3,3-trifluoro-2-propanone
(4y) provided the corresponding bromohydrins 5x and 5y
in 74% and 60% yields, respectively (eq 13).
We then studied the vinylalumination of an unsym-
metrical R-diketone with differing electronic surround-
ings. With 1-phenyl-1,2-propanedione (4v), reagent 1
reacted preferentially with the carbonyl adjacent to the
phenyl ring to give a 3:1 ratio of 5v and 5′v (eq 12).
However, â-methyl substitution of the reagent (2) de-
creases the preference for the aryl carbonyl. The bulkier
â-phenyl-substituted reagent (3) provides the products
in an almost 1:1 ratio. These results reveal that steric
as well as electronic factors play a role in the regiochemi-
cal outcome of the reaction. Unlike in the case of 4u , the
products from 4v could be readily separated by column
chromatography. The results of vinylalumination of
diketones are summarized in Table 4 (entries 6-11).
We avoided strong aqueous alkaline conditions for the
cyclization of these bromohydrins due to the presence of
the ester moiety. The epoxide formation from 5w and 5x
was successfully carried out with K2CO3 as base (eq 13).
We conducted the cyclizations in dry acetone and ob-
tained 75-88% yields of the vinylepoxides. However, the
trifluoromethyl bromohydrin 5y afforded only 65% yield
of the corresponding epoxide 8y, and we improved the
yield to 82% by replacing K2CO3 with KF.27
Vin yla lu m in a tion of Keto-P r otected P yr u va ld e-
h yd e: Syn th esis of R-Alk ylid en e-â-h yd r oxy-γ-la c-
ton es. Several natural products contain R-alkylidene-â-
hydroxy-γ-methylbutyrolactone moiety.28 Listenolides are
a group of such molecules; they have been isolated in the
1970s from the roots and leaves of Listea japonica
belonging to Lauraceae family.29 Listenolides are divided
into two series: X1 and X2, having Z and E alkylidene
units, respectively. Several syntheses of these molecules
have been reported.30 We applied our vinylalumination
protocol for the synthesis of representative R-methylene-
â-hydroxy-γ-butyrolactone 9 and its â-substituted ana-
logue listenolide A1 (10).
Vin yla lu m in a tion of r-Ha loca r bon yls: Syn th esis
of F u n ction a lized Vin ylep oxid es. Vinylepoxides are
an important class of synthons in organic chemistry.22
They constitute an important component of natural
molecules, such as carotenoids.23 Vinylepoxides have been
utilized in the preparation of molecules with pharma-
ceutical applications24 and are commonly used in polymer
chemistry.25 The importance of vinylepoxides in organic
syntheses prompted us to examine the preparation of the
vinyl halohydrin precursors from R-haloaldehydes and
Our protocol is shown in Scheme 1. â-Substituted
substrate for the hydroalumination, ethyl tetradec-13-
(22) (a) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2,
4087. (b) Zaidlewicz, M.; Krzeminski, M. P. Org. Lett. 2000, 2, 3897.
(c) Lindstro¨m, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P.
Tetrahedron Lett. 1997, 38, 2027. (d) Gorzynski-Smith, J . Synthesis
1994, 629.
(26) Ramachandran, P. V.; Krzeminski, M. Tetrahedron Lett. 1999,
40, 7879.
(27) Lundt, I.; Pedersen, C. Synthesis 1992, 662.
(23) Rønnekleiv, M.; Lenes, M.; Norgård, S.; Liaaen-J ensen, S.
Phytochemistry 1995, 39, 631. (b) Ogata, Y.; Kosugi, Y.; Tomizawa, K.
Tetrahedron 1970, 26, 5939.
(24) (a) Habashita, H.; Kawaski, T.; Takemoto, Y.; Fujii, N.; Ibuka,
T. J . Org. Chem. 1998, 63, 2392. (b) Clive, D. J .; Wickens, P. L.; Dasilva,
G. V. J . J . Org. Chem. 1995, 60, 5532. (c) Wei-Shan, Z.; J iang, B.; Pan,
X.-F. J . Chem. Soc., Chem. Commun. 1989, 612.
(25) (a) Koizumi, T.; Imai, T.; Endoz, T. J . Polymer Sci. 2003, 41,
476. (b) Koizumi, T.; Sakamoto, J .; Gondo, Y.; Endo, T. Macromolecules
2002, 35, 2898.
(28) Hoffmann, H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl.
1985, 24, 94.
(29) (a) Takeda, K.; Sakurawi, K.; Ishii, H. Tetrahedron 1972, 28,
3757-3766. (b) Tanaka, H.; Nakamura, T.; Ichino, K.; Ito, K.; Tanaka,
T. Phytochemistry 1990, 29, 857-859.
(30) (a) Rollinson, S. W.; Amos, R.; Katzenellenbogen, J . J . Am.
Chem. Soc. 1981, 103, 4114. (b) Chen, S.-Y.; J oullie´, M. Tetrahedron
Lett. 1983, 24, 5027. (c) Wood, W.; Watson, G. J . Chem. Soc., Perkin
Trans. 1 1987, 2681. (d) Wakabayashi, S.; Ogwa, H.; Ueno, N.;
Kunieda, N.; Mandai, T.; Nokami, J . Chem. Lett. 1987, 875.
9314 J . Org. Chem., Vol. 68, No. 24, 2003

Vinylalumination for the Synthesis of Functionalized Allyl Alcohols
SCHEME 1
en-2-ynoate, was prepared by treatment of 1-bromo-11-
undecene with sodium acetylide, followed by the addition
of ethyl chloroformate according to a literature proce-
dure.31 The carbonyl substrate, 2-methyl-1,3-dithiane-2-
carbaldehyde (4z), was made from acetaldehyde and 1,3-
propanedithiol using the literature protocols.32
responding hydroxyalkenyl products in moderate to high
yield. We extended the vinylalumination of activated
carbonyl compounds to enolizable and nonenolizable
R-diketones. Unsubstituted and â-methyl- and -phenyl-
substituted [R-(ethoxycarbonyl)vinyl]diisobutylaluminum
provide the corresponding R-methylene-â-hydroxy-γ-keto
esters in moderate to high yields. In the case of unsym-
metrical R-diketones, the regioselectivity of the reaction
depends on the steric and electronic surroundings of the
carbonyl groups and the vinylaluminum reagent. A
convenient synthesis of functionalized vinylepoxides via
the vinylalumination of R-bromocarbonyls has also been
developed. The products from the vinylalumination of
keto-protected pyruvaldehyde were converted to R-alkyl-
idene-â-hydroxy-γ-lactones, such as listenolide A1. We
believe that this modified environmentally benign vinyl-
alumination will find applications in organic synthesis.36
Addition of 4z to the vinylaluminum reagents 1 and
11 and stirring overnight at room temperature, followed
by workup with aq NH4Cl and filtration through silica
gel, afforded the desired dithiane hydroxy esters 12 and
13 in moderate yields (46-49%). A minor difficulty was
experienced during the deprotection of the dithianes.33
Deprotection with HgCl2 required heating of the sub-
strate and was proceeding only in ∼50% yield. Use of
ceric ammonium nitrate34 made the deprotection and
workup easier; however, the yields were still unsatisfac-
tory and inconsistent (43-70%). Fortunately, deprotec-
35
tion with N-chlorosuccinimide in the presence of AgNO3
afforded the desired ketones 14 and 15 in good yields.
Reduction of the ketones with Zn(BH4)2 furnished the
desired diols 16 and 17 in excellent yields and good anti
diastereoselectivities. Lactonization by refluxing in CH2-
Cl2 in the presence of CF3COOH yielded the desired
lactone 9 and listenolide A1 (10). Comparison with the
1H NMR spectral values reported by Ishii and co-
workers29a confirmed that the desired Z stereochemistry
was obtained in the case of 10.
Exp er im en ta l Section
General procedures for vinylalumination using NMO are
described below. Other experimental procedures, the reaction
yields, and physical data of individual reaction products are
provided in the Supporting Information.
Exp er im en ta l P r oced u r e for Vin yla lu m in a tion Usin g
â-Un su bstitu ted Reagen t (1): P r epar ation of Eth yl 2-(Hy-
d r oxyp h en ylm eth yl)a cr yla te (5a ). To a stirred suspension
of NMO (2.3 g, 20 mmol) in anhydrous THF (50 mL) was added
DIBAL-H (2.7 mL, 15 mmol) at 0 °C and the mixture stirred
for 0.5 h. Ethyl propiolate (1.0 mL, 10 mmol) was added, and
the mixture was stirred at 0 °C for 1 h, followed by the addition
of benzaldehyde (4a ) (1.2 mL, 12 mmol). The mixture was
warmed to rt, stirred for 4 h, and quenched with 10 mL of aq
1.0 M HCl, and the product was extracted with ether (3 × 50
mL). The combined ether layers were washed with brine and
dried over MgSO4. Removal of the solvents and purification
by column chromatography over silica gel (95:5, hexanes/ethyl
acetate) provided 2.5 g (9.5 mmol, 95%) of 5a .
Exp er im en ta l P r oced u r e for Vin yla lu m in a tion Usin g
â-Su bstitu ted Rea gen ts (2, 3, a n d 11): P r ep a r a tion of
Eth yl (2Z)-2-(Hyd r oxyp h en ylm eth yl)-3-p h en yla cr yla te
(7a ). To NMO (2.3 g, 20 mmol) slurried in anhydrous THF (50
mL) was added DIBAL-H (2.7 mL, 15 mmol) at 0 °C, and the
mixture was stirred for 0.5 h. Ethyl 3-phenylprop-2-ynoate (1.4
mL, 8.5 mmol) was added, and the mixture was warmed to rt
and stirred for 4 h, followed by the addition of benzaldehyde
(4a ) (1.0 mL, 10 mmol) and overnight stirring. The reaction
was quenched with 10 mL of 1.0 M HCl, and the product was
extracted with ether (3 × 50 mL). The combined ether layers
were washed with brine and dried over MgSO4. Removal of
the solvents and purification by column chromatography over
Con clu sion s
We have described a significantly improved procedure
for the vinylalumination of a variety of carbonyl com-
pounds with [R-(ethoxycarbonyl)vinyl]diisobutylaluminum.
Replacement of carcinogenic HMPA with readily avail-
able and inexpensive NMO in the hydroalumination step
makes this procedure environmentally benign. The work-
up is simpler, and the yields of the products are very good
in most cases. Activated carbonyl compounds, such as
R-keto esters, acyl cyanides (with HMPA), and R-acetyl-
enic ketones undergo facile condensation with unsubsti-
tuted and â-methyl- or -phenyl-substituted [R-(ethoxy-
carbonyl)vinyl]diisobutylaluminum to provide the cor-
(31) Piers, E.; Wong, T.; Ellis, K. A. Can. J . Chem. 1992, 70, 2058.
(32) (a) Seebach, D.; Corey, E. J . J . Org. Chem. 1975, 40, 231. (b)
Poulton, G. A.; Cyr, T. D. Can. J . Chem. 1982, 60, 2821.
(33) For a detailed examination of various protocols to deprotect
dithiane, see: Smith, A. B.; Dorsey, B. D.; Visnick, M.; Maeda, T.;
Malamas, M. S. J . Am. Chem. Soc. 1986, 108, 3110.
(34) Ho, T.-S.; Ho, H. C.; Wong, C. M. J . Chem. Soc., Chem.
Commun. 1972, 791.
(35) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553.
(36) Mart´ınez, I.; Andrews, A. E.; Emch, J . D.; Ndakala, A. J .; Wang,
J .; Howell, A. R. Org. Lett. 2003, 5, 399.
J . Org. Chem, Vol. 68, No. 24, 2003 9315

Ramachandran et al.
silica gel (95:5, hexanes/ethyl acetate) provided 1.8 g (6.8
mmol, 80%) of 7a .
purification by column chromatography over silica gel (95:5,
hexanes/ethyl acetate) provided 2.5 g (11.3 mmol, 74%) of 5e.
Note: For the â-substituted vinylaluminum reagents (2, 3),
the solution has to be stirred for 4 h at rt prior to addition of
the ketones.
Exp er im en ta l P r oced u r e for Vin yla lu m in a tion of Un -
a ctiva ted Keton es: P r ep a r a tion of Eth yl 2-(1-Hyd r oxy-
1-p h en yleth yl)a cr yla te (5e). To a stirred suspension of NMO
(4.17 g, 35.6 mmol) in anhydrous THF (30 mL) was added
DIBAL-H (1 M in hexanes; 32 mL, 32 mmol) at 0 °C, and the
mixture was stirred for 0.5 h. Ethyl propiolate (2.8 mL, 27.5
mmol) was added, and the mixture was stirred at 0 °C for 1 h.
Next, acetophenone (4e) (1.8 mL, 15.3 mmol) was added,
followed by addition of BF3‚OEt2 (1.9 mL, 15.3 mmol). The
mixture was warmed to rt, stirred for 4 h, and quenched with
10 mL of 1.0 M HCl, and the product was extracted with ether
(3 × 50 mL). The combined ether layers were washed with
brine and dried over MgSO4. Removal of the solvents and
Ack n ow led gm en t. The financial assistance from
Eastman Kodak Co. is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures, the spectral data (1H, 13C, and 19F NMR
spectra), and other physical characteristics of the compounds
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034954U
9316 J . Org. Chem., Vol. 68, No. 24, 2003