A new, efficient method for direct α-alkenylation of β-dicarbonyl compounds and phenols using alkenyltriarylbismuthonium salts

Article abstract of DOI:10.1021/jo0492721

Direct α-alkenylation of β-keto esters, β-diketone, and phenols with alkenyltriarylbismuthonium salts proceeded smoothly in the presence of 1,1,3,3-tetramethylguanidine to afford the corresponding α-alkenylated carbonyl compounds (β,γ-unsaturated carbonyl compounds) in good yields. The high leaving ability of the triarylbismuthonio group is a key driving force to achieve the C-C bond formation at the vinylic carbon under mild conditions.

Full text of DOI:10.1021/jo0492721

SCHEME 1
A New , Efficien t Meth od for Dir ect
r-Alk en yla tion of â-Dica r bon yl Com p ou n d s
a n d P h en ols Usin g
Alk en yltr ia r ylbism u th on iu m Sa lts
Yoshihiro Matano* and Hiroshi Imahori
Department of Molecular Engineering, Graduate School of
Engineering, Kyoto University, Nishikyo-ku,
Kyoto 615-8510, J apan
matano@scl.kyoto-u.ac.jp
Received April 29, 2004
vantage of this property of bismuth, Barton and co-
workers developed a general method for the R-phenyl-
ation of enolizable substrates using phenylbismuth(V)
compounds of the types Ph4BiX and Ph3BiX2,7 where
R-phenylated products are obtained under neutral or
basic conditions together with phenylbismuth(III) com-
pounds. Quite recently, Ooi, Goto, and Maruoka reported
a high-yield synthesis of â,γ-unsaturated ketones using
fluoro(styryl)tris(4-methylphenyl)bismuth(V) and silyl
enolates.8 These results suggested to us that the R-al-
kenylation of enolizable substrates would be also devel-
oped using alkenylbismuth(V) compounds as the alkenyl
cation equivalents. We report herein a new efficient
method for the synthesis of â,γ-unsaturated carbonyl
compounds via direct R-alkenylation of â-dicarbonyl
compounds and phenols using alkenyltriarylbismutho-
nium salts.
Abstr a ct: Direct R-alkenylation of â-keto esters, â-diketone,
and phenols with alkenyltriarylbismuthonium salts pro-
ceeded smoothly in the presence of 1,1,3,3-tetramethylguani-
dine to afford the corresponding R-alkenylated carbonyl
compounds (â,γ-unsaturated carbonyl compounds) in good
yields. The high leaving ability of the triarylbismuthonio
group is a key driving force to achieve the C-C bond
formation at the vinylic carbon under mild conditions.
R-Alkenylation of enolizable compounds with alkenyl
cation equivalents is a reliable method for the synthesis
of â,γ-unsaturated ketones and esters, which are useful
building blocks in organic synthesis. However, it is known
that nucleophilic substitution at a vinylic carbon is
difficult,1 and only a few methods are available for the
direct R-alkenylation of enolates with simple halo-
alkenes.2,3 One of the promising ways to enhance the
nucleofugality of the vinylic ipso carbon is replacement
of the halogen atom by a good leaving group. On the basis
of this concept, alkenyllead triactetates4 and alkenyl-
phenyliodonium salts5 have been developed as the al-
kenyl cation equivalents, both of which undergo R-al-
kenylation of enolizable substrates to give â,γ-unsatur-
ated carbonyl compounds, accompanied by the formation
of lead(II) acetate and iodobenzene, respectively.
Alkenyltriarylbismuthonium salts (3) were prepared
in 84-98% yield by the BF3‚OEt2-promoted metathesis
reaction of triarylbismuth difluorides (1) with alkenyl-
boronic acids (2) according to a previously reported
procedure (Scheme 1).9
In contrast to alkenyllead triacetates, the alkenylbis-
muthonium salts 3 are thermally and air stable and easy
to handle. They are soluble in CH2Cl2 and CHCl3, slightly
1
soluble in toluene, and hardly soluble in ether. In the H
NMR spectra of 3, the R-vinyl protons were observed as
broad signals at around δ 7.8 for the â-alkyl derivatives
and at δ 8.3-8.6 for the â-phenyl derivatives. In the 13C
NMR of 3, the R-vinyl carbons were observed at δ 151-
161. In the FABMS spectra, the [RCHdCHBiAr3]+ ion
was observed as a parent peak.
With alkenyltriarylbismuthonium salts 3 in hand, we
first examined the direct R-alkenylation of â-dicarbonyl
compounds under basic conditions. Treatment of 3a with
ethyl 2-oxocyclohexanecarboxylate (4) in the presence of
1,1,3,3-tetramethylguanidine (TMG) in toluene afforded
ethyl 1-((E)-hex-1-enyl)-2-oxocyclohexanecarboxylate (5a )
Like lead(IV) and iodine(III) compounds, organobis-
muth(V) compounds possess high nucleofugality derived
from the facile Bi(V)/Bi(III) redox process.6 Taking ad-
(1) March, J . Advanced Organic Chemistry, 3rd ed.; Wiley: New
York, 1985; pp 295-304.
(2) Transition metal-catalyzed direct R-alkenylation with haloal-
kenes, see: (a) Millard, A. A.; Rathke, M. W. J . Am. Chem. Soc. 1977,
99, 4833. (b) Chieffi, A.; Kamikawa, K.; Ahman, J .; Fox, J . M.;
Buchwald, S. L. Org. Lett. 2001, 3, 1897. (c) Hamada, T.; Buchwald,
S. L. Org. Lett. 2002, 4, 999.
(3) Photoinduced direct R-alkenylation with haloalkenes, see: Bun-
nett, J . F.; Creary, X.; Sundberg, J . E. J . Org. Chem. 1976, 41, 1707.
(4) (a) Moloney, M. G.; Pinhey, J . T. J . Chem. Soc., Chem. Commun.
1984, 965. (b) Moloney, M. G.; Pinhey, J . T. J . Chem. Soc., Perkin
Trans. 1 1988, 2847. (c) Pinhey, J . T. Aust. J . Chem. 1991, 44, 1353.
(d) Parkinson, C. J .; Pinhey, J . T.; Stoermer, M. J . J . Chem. Soc., Perkin
Trans. 1 1992, 1911. (e) Hambley, T. W.; Holmes, R. J .; Parkinson, C.
J .; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1992, 1917. (f)
Hashimoto, S.; Shinoda, T.; Ikegami, S. J . Chem. Soc., Chem. Commun.
1988, 1137. (g) Chen, C.; Layton, M. E.; Shair, M. D. J . Am. Chem.
Soc. 1998, 120, 10784.
(5) (a) Beringer, F. M.; Galton, S. A. J . Org. Chem. 1965, 30, 1930.
(b) Ochiai, M.; Sumi, K.; Takaoka, Y.; Kunishima, M.; Nagao, Y.; Shiro,
M.; Fujita, E. Tetrahedron 1988, 44, 4095. (c) Ochiai, M.; Shu, T.;
Nagaoka, T.; Kitagawa, Y. J . Org. Chem. 1997, 62, 2130. In some cases,
the competing R-phenylation becomes predominant.
(6) The leaving ability of the triphenylbismuthonio group is higher
than that of triflate ion. See: Matano, Y. Organometallics 2000, 19,
2258.
(7) (a) Barton, D. H. R.; Blazejewski, J .-C.; Charpiot, B.; Finet, J .-
P.; Motherwell, W. B.; Papoula, M. T. B.; Stanforth, S. P. J . Chem.
Soc., Perkin Trans. 1 1985, 2667. (b) Barton, D. H. R.; Bhatnagar, N.
Y.; Finet, J .-P.; Motherwell, W. B. Tetrahedron 1986, 42, 3111. (c)
Abramovitch, R. A.; Barton, D. H. R.; Finet, J .-P. Tetrahedron 1988,
44, 3039.
(8) Ooi, T.; Goto, R.; Maruoka, K. J . Am. Chem. Soc. 2003, 125,
10494.
(9) Matano, Y.; Begum, S. A.; Miyamatsu, T.; Suzuki, H. Organo-
metallics 1998, 17, 4332.
10.1021/jo0492721 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/09/2004
J . Org. Chem. 2004, 69, 5505-5508
5505

TABLE 1. Rea ction of 3a -e w ith 4
TABLE 2. r-Alk en yla tion of â-Keto Ester s w ith 3
entry
â-keto ester
3
product (yield/%)
1
2
3
4
5
6
4
4
9
11
11
14
3g
3j
3j
5b (86)
5c (88)
10 (90)
12 (48)
12 (96)
15 (90)
3j
3ja
3j
entry
3
products (yield/%)a
a
2 equiv of 3j/TMG was used.
1
2
3a
3b
3c
3d
3e
5a (89), 6a (4), 7a (85), 8a (5)
5a (73), 6b (14), 7b (80), 8b (15)
5a (90), 6c (trace)
5a (91)
no C-C coupling
3b
4b
5
2 equiv of 3j and TMG were used, 12 was obtained in
96% yield based on 11 (entry 5). The R-methine carbon
of ethyl 2-methyl-3-oxobutanoate (14) was smoothly
alkenylated to give 15 in 90% yield (entry 6). In contrast,
the alkenyl group of 3 could not be transferred efficiently
to simple monoketones such as acetophenone and cyclo-
hexanone, which possess less acidic R-protons than the
above substrates. In these reactions alkynes and bis-
muthanes 7 were formed as major products, indicating
that the R-proton abstraction from 3 occurred predomi-
nantly (vide infra).
6-8: a ) p-MeC6H4; b ) Ph; c ) p-MeOC6H4. b Yields of other
products were not determined.
a
and tris(4-methylphenyl)bismuthane (7a ) as major prod-
ucts (Table 1, entry 1). No reaction took place in the
absence of a base, suggesting that an enolate, generated
from 4 and TMG, is the active nucleophile for the
R-alkenylation (vide infra). Careful inspection of the
reaction mixture by 1H NMR showed the presence of
small amounts (<5%) of ethyl 2-oxo-1-(4-methylphenyl)-
cyclohexanecarboxylate (6a ) and ((E)-hex-1-enyl)bis(4-
methylphenyl)bismuthane (8a ). This finding implies that
the transfer of the 1-hexenyl group is preferable to that
of the 4-methylphenyl group. The bismuthanes 7a and
8a precipitated out from the reaction mixture by adding
a small amount of MeOH and were recovered by filtra-
tion. Concentration of the MeOH filtrate gave an oily
residue, which was purified by column chromatography
on silica gel to afford 5a in 89% isolated yield.
To examine the effect of the aryl ligands attached to
the bismuth, similar reactions were carried out using
other bismuthonium salts 3b-e bearing phenyl or sub-
stituted aryl groups (Table 1, entries 2-5). Among the
para- and nonsubstituted compounds 3a -d , the alkenyl
transfer was predominant in all cases and the alkenyl/
aryl selectivity slightly increased by introducing an
electron-donating substituent. On the other hand, intro-
duction of the o-methoxy group dramatically retarded the
reactivity: neither alkenylation nor arylation occurred
between 3e and 4.
Treatment of the â-monosubstituted alkenylbismutho-
nium salts 3a ,f,g,j,l with 2-phenylindan-1,3-dione (16)
in the presence of TMG afforded the corresponding
2-alkenyl-2-phenylindan-1,3-diones (17a -e) in 73-92%
yields (Table 3, entries 1-5). In the reaction of 3l′ (an
Both cyclic and acyclic â-keto esters were R-alkenylated
by 3 under the same reaction conditions to give the
corresponding â,γ-unsaturated carbonyl compounds with
retention of the stereochemistry of the vinyl moiety
(Table 2). In the presence of TMG, 3g,j reacted with 4 to
afford 5b,c in good yields (entries 1 and 2). Similarly, 3j
reacted with ethyl 2-oxocyclopentanecarboxylate (9) to
yield 10 (entry 3). When ethyl 3-oxobutanoate (11) was
treated with 1 equiv of 3j in the presence of 1 equiv of
TMG, R,R-dialkenyl-â-keto ester 12 was obtained in 48%
yield based on 11 (96% yield based on 3j) (entry 4). The
monoalkenylated ketone 13 that would be formed as an
initial product was not obtained at all, suggesting that
the second alkenylation of 13 proceeded much more
rapidly than the first alkenylation of 11. This is probably
because of the higher acidity of the allylic methine proton
of 13 as compared to the methylene protons of 11. When
TABLE 3. Rea ction of 3 w ith 16
entry
3
products (yield/%)
1
2
3
4
5
6
3a
3f
3g
3j
17a (R ) n-Bu, 89), 18a (5)
17b (R ) t-Bu, 92), 18a (trace)
17c (R ) n-C6H13, 86),18a (2)
17d (R ) Ph, 82), 18a (3)
17e (R ) Me, 73), 18a (13)
17e′b (R ) Me, 72), 18a (9)
3l
3l′a
a
b
E/ Z ) 30/70. E/ Z ) 34/66.
5506 J . Org. Chem., Vol. 69, No. 16, 2004

SCHEME 2
E/Z mixture: E/ Z ) 30/70) with 16, the stereochemistry
of the vinyl moiety is mostly retained, affording 17e′ with
an E/Z ratio of 34/66 (entry 6). On the other hand, the
â,â-dimethyl derivative 3m reacted with 16 to afford
R-alkenyl and R-phenyl ketones 17f and 18b in 45% and
30% yield, respectively, together with 7b and 8c (eq 1).
Thus, the selectivity of the alkenyl vs aryl transfer (17
vs 18) strongly depended on the â-substituents of the
vinyl moiety, which was found to be in the order â-alkyl,
â-phenyl > â-methyl > â,â-dimethyl.
the E/Z ratio of 17e differs considerably from that of
17e′.14 The addition-elimination mechanism, proposed
for the nucleophilic substitution of alkenyliodonium salts
bearing an electron-withdrawing substituent at the
â-position,15 explains the retention of the stereochemistry.
In compounds 3, however, the vinylic â-carbon bears no
electron-withdrawing group that is necessary for stabiliz-
ing a betain intermediate. In contrast to the above
pathways, the ligand exchange-ligand coupling16 mech-
anism well explains not only the stereochemical outcome
but also the substituent effects on the reactivity and
selectivity. Thus, the enolate attacks the bismuth center
to generate pentacoordinate species 24 or 24′, followed
Phenols were also alkenylated at the R-position (ortho-
position) using alkenylbismuthonium salts 3. Thus, 3j
reacted with 2,6-dimethylphenol (19) in the presence of
TMG to give 2,6-dimethyl-6-styrylcyclohexa-2,4-dienone
(20) in 76% yield (eq 2). When 2-naphthol (21) was used
as the substrate, R,R-dialkenyl ketone 22 was obtained
in a good conversion yield (eq 3). As was observed for
the reaction of 11, monoalkenylated ketone was not
formed at all.
by ligand coupling to give the products (Scheme 2).17
A
key driving force of the last step is the high leaving ability
of the triarylbismuthonio group. The low reactivity
recognized for 3e might be due to the coordination of the
three o-methoxy oxygen atoms to the cationic bismuth
center,18 which prevents the nucleophilic attack of the
enolate to the bismuth both electronically and sterically.
When the R-proton of enolizable substrates is less acidic
than the R-vinyl proton of 3, however, the R-proton
abstraction from 3 becomes a main pathway.
We developed a new efficient method for the synthesis
of â,γ-unsaturated ketones and esters by the TMG-
promoted reaction of alkenyltriarylbismuthonium salts
with â-dicarbonyl compounds and phenols. It should be
noted here that a quaternary, allylic R-carbon center is
readily constructed from the active methylene or methine
compounds under mild conditions. Although the enoliz-
able substrates are limited to those having relatively
There are several conceivable mechanisms for the
present R-alkenylation: SN2 reaction, SN1 reaction, C-H
insertion via an alkylidene carbene, addition-elimina-
tion, and ligand exchange-ligand coupling.10 Among
them, the SN2 and SN1 mechanisms can be discarded
because they cannot explain the retention of the stere-
ochemistry.11 Furthermore, the generation of a vinylic
cation in toluene seems to be unlikely.12 The alkylidene
carbene, generated by the R-proton abstraction from 3,
is a possible intermediate.13 In fact, terminal acetylenes
23 were formed exclusively from 3 and TMG (eq 4), which
is the main side reaction in the present system. However,
the free carbene mechanism cannot explain the stereo-
chemical outcome of the R-alkenylation with 3l and 3l′:
(14) If the reaction proceeds via the C-H insertion of a free
alkylidene carbene, the E/Z ratio of 17e should be the same as that of
17e′.
(15) For example, see: (a) Ochiai, M.; Oshima, K.; Masaki, Y.
Tetrahedron Lett. 1991, 32, 7711. (b) Ochiai, M.; Oshima, K.; Masaki,
Y. Kunishima, M.; Tani, S. Tetrahedron Lett. 1993, 34, 4829. (c) Zefirov,
N. S.; Koz’min, A. S.; Kasumov, T.; Potekhin, K. A.; Sorokin, V. D.;
Brel, V. K.; Abramkin, E. V.; Struchkov, Y. T.; Zhdankin, V. V.; Stang,
P. J . J . Org. Chem. 1992, 57, 2433.
(16) (a) Oae, S.; Uchida, Y. Acc. Chem. Res. 1991, 24, 202. (b) Finet,
J .-P. Ligand Coupling Reactions with Heteroatomic Compounds;
Elsevier: London, 1998, and references therein.
(17) A similar ligand coupling mechanism was proposed by Barton
and co-workers for the R-phenylation of enolizable substrates with
tetraphenylbismuthonium salts. See ref 7.
(18) X-ray crystallographic analyses of bismuthonium salts bearing
o-anisyl groups disclosed the intramolecular coordination between the
o-methoxy oxygens and the bismuth center. Suzuki, H.; Ikegami, T.;
Azuma, N. J . Chem. Soc., Perkin Trans. 1 1997, 1609. See also ref 6.
(10) For reviews on the nucleophilic vinylic substitutions, see: (a)
Rappoport, Z. Acc. Chem. Res. 1992, 25, 474. (b) Rappoport, Z. Acc.
Chem. Res. 1981, 14, 7. (c) Modena, G. Acc. Chem. Res. 1971, 4, 73.
(11) If the alkenylation proceeds through an SN2 or SN1 mechanism,
the stereochemistry of the vinylic moiety is inverted or lost signifi-
cantly.
(12) Richey, H. G., J r. In The Chemistry of Alkenes; Zabicky, J . Ed.;
Wiley: London, 1970; Vol. 2, Chapter 2, pp 39-114.
(13) For a review, see: Stang, P. J . Chem. Rev. 1978, 78, 383.
J . Org. Chem, Vol. 69, No. 16, 2004 5507

Rea ction of 3 w ith TMG. To a CDCl3 solution (ca. 0.5 mL)
of 3a ,f,j (0.02 mmol) was added TMG (0.02 mmol), and the
resulting mixture was monitored at room temperature by 1H
NMR spectroscopy. In all cases examined, bismuthane 7a and
acetylene 23 were formed in good yields.
acidic R-protons, the present method qualifies as a
reliable addition to the existing methods for the direct
R-alkenylation of carbonyl compounds.
Exp er im en ta l Section
Rea ction of 3 w ith Ca r bon yl Com p ou n d s in th e P r es-
en ce of TMG. Gen er a l P r oced u r e. To a mixture of 3 (0.50
mmol), carbonyl compound (0.50 mmol), and toluene (5 mL) was
added TMG (65 µL, 0.50 mmol) at -50 °C. The resulting mixture
was allowed to warm to room temperature with vigorous stirring.
Water (5 mL) and Et2O (5 mL) were added to the mixture, and
the organic phase was washed with water (2 mL × 3), dried over
MgSO4, and concentrated under reduced pressure. Adding a
suitable amount of MeOH (5-10 mL) to the residue caused
precipitation of the bismuthane as a colorless solid. After
removal of the bismuthane by filtration, the filtrate was
concentrated in vacuo to give an oily residue, which was
chromatographed on silica gel using hexane/ethyl acetate as
eluents to afford â,γ-unsaturated carbonyl compounds.
Ack n ow led gm en t. This work was partially sup-
ported by a Grant-in-Aid (No. 14540494) from the
Ministry of Education, Science, Sports and Culture of
J apan and a Toray Award in Synthetic Organic Chem-
istry, J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization data for 3 and the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0492721
5508 J . Org. Chem., Vol. 69, No. 16, 2004