Zinc-mediated C-C bond sigmatropic rearrangement: A new and efficient methodology for the synthesis of β-diketones

Article abstract of DOI:10.1021/jo7013627

(Chemical Equation Presented) A new and efficient methodology has been developed for the synthesis of β-diketones from aromatic α-bromo ketones in the presence of Furukawa reagent under mild conditions. The present transformation is proposed to proceed via a Reformatsky-type reaction of α-bromo ketones, followed by C-C bond sigmatropic rearrangement of the aldolate intermediate to give β-diketones in moderate to good isolated yields, while aliphatic α-bromomethyl ketones resulted in the formation of 2,4-disubstituted furans or cis-1,2-disubstituted cyclopropanols in moderate yields. The scope of this process was investigated, and a tentative mechanism was proposed.

Full text of DOI:10.1021/jo7013627

developed for the preparation of â-diketones.6,7 1-Aroylbenz-
imidazoles8 and 1-aroylbenzotriazoles9 have been used for the
aroylations of the anion from acetylacetone or ketones and the
subsequent obtainment of the desired â-diketones. Recently, an
operationally simple and new approach to synthesize the
R-aroylacetones from R-aminonitriles and propargyl bromide
was reported.10 Although these methods provide reliable routes
for the preparation of â-diketones, most of them follow lengthy
procedures and require multistep-preparation of a special
reagent. Therefore, the development of direct and efficient
procedures for these classes of compounds from facile materials
has been the target of synthetic organic chemistry. In 1966,
Furukawa reported that cyclopropanation reagent EtZnCH2I
could be generated by the alkyl exchange between Et2Zn and
Zinc-Mediated C-C Bond Sigmatropic
Rearrangement: A New and Efficient
Methodology for the Synthesis of â-Diketones
Lezhen Li,‡ Peijie Cai,‡ Da Xu,‡ Qingxiang Guo,‡ and
Song Xue*,†,‡
Department of Applied Chemistry, Tianjin UniVersity of
Technology, Tianjin 300191, P.R. China, and Department of
Chemistry, UniVersity of Science and Technology of China,
Hefei 230026, P.R. China
xuesong@ustc.edu.cn
11
CH2I2. From then on, the Furukawa reagent (EtZnCH2I), as
ReceiVed June 29, 2007
cyclopropanation reagent, has been widely used in organic
synthetic chemistry.12 However, the applicability of Furukawa
reagent in organic synthesis has not been fully explored. Our
ongoing interest in organozinc reagents prompted us to inves-
tigate the new application in organic synthetic chemistry. During
the course of our investigation on the reaction of R-bromo
ketones with Furukawa reagent (EtZnCH2I), it was found that
the self-coupling reaction of R-bromo ketones proceeded to
furnish â-diketones, which appears to proceed via a C-C bond
sigmatropic rearrangement. Herein, we wish to report a new
and efficient methodology to synthesize â-diketones from
R-bromo ketones in the presence of Furukawa reagent under
mild reaction conditions.
Initially, we examined the reactivity of R-halo acetophenone
with organozinc species to optimize the reaction conditions. The
results are shown in Table 1. The reaction of R-bromo
acetophenone with 1.2 equiv of Furukawa reagent (EtZnCH2I)
in CH2Cl2 at room-temperature gave â-diketone 2a in 48% yield
along with recovered R-bromo acetophenone. When the reaction
was performed in the presence of 2.0 equiv of organozinc
A new and efficient methodology has been developed for
the synthesis of â-diketones from aromatic R-bromo ketones
in the presence of Furukawa reagent under mild conditions.
The present transformation is proposed to proceed via a
Reformatsky-type reaction of R-bromo ketones, followed by
C-C bond sigmatropic rearrangement of the aldolate inter-
mediate to give â-diketones in moderate to good isolated
yields, while aliphatic R-bromomethyl ketones resulted in
the formation of 2,4-disubstituted furans or cis-1,2-disub-
stituted cyclopropanols in moderate yields. The scope of this
process was investigated, and a tentative mechanism was
proposed.
(6) (a) Hauser, C. R.; Swamer, F. W.; Adams, J. T. Org. React. 1954, 8,
59. (b) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrel,
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Chem. 1981, 46, 3771. (d) Beck, A. K.; Hoekstra, M. S.; Seebach, D.
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(11) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett.
1966, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron
1968, 24, 53. (c) Nishimura, J.; Furukawa, J.; Kawabata, N.; Kitayama, M.
Tetrahedron 1971, 27, 1799.
â-Diketones have been important intermediates in organic
synthesis. They have served as key building blocks in the
preparation of heterocyclic compounds such as pyrazoles,1
isoxazoles,2 triazoles,3 and benzopyran-4-ones.4 Moreover, they
have also been used as chelating ligands for lanthanides and
transition metals.5 A variety of synthetic methods have been
† Tianjin University of Technology.
‡ University of Science and Technology of China.
(1) Nagpal, A.; Unny, R.; Joshi, Y. C. Heterocycl. Commun. 2001, 32,
589.
(2) Simoni, D.; Invidiata, F. P.; Rondanin, R.; Grimaudo, S.; Cannizzo,
G.; Barbusca, E.; Porretto, F.; D’Alessandro, N.; Tolomeo, M. J. Med. Chem.
1999, 42, 4961.
(3) Alekseev, V. V.; Zelinin, K. N.; Yakimovich, S. I. Russ. J. Org.
Chem. 1995, 31, 705.
(4) (a) Ellis, G. P. The Chemistry of Heterocyclic Compounds. In
Chromanones and Chromones; Ellis, G. P., Ed.; Interscience: New York;
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1984, 1702.
(5) Garnovskii, A. D.; Kharixov, B. I.; Blanco, L. M.; Garnovskii, D.
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1999, 46, 365-375.
(12) (a) Brogan, J, B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444. (b)
Verbicky, C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615. (c) Lai, S.;
Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J. Org. Lett. 2001,
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and references therein.
10.1021/jo7013627 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/21/2007
J. Org. Chem. 2007, 72, 8131-8134
8131

TABLE 1. Reaction of r-Halo Acetophenone with Organozinc
Species
TABLE 2. Reaction of Aromatic r-Bromo Ketones with Furukawa
Reagent (EtZnCH2I)
organozinc
species
entry
1b
X
solvent
CH2Cl2
time (h)
6
2a yield (%)a
Br
EtZnCH2I
1.2 equiv
EtZnCH2I
2.0 equiv
Et2Zn
2.0 equiv
EtZnCH2I
2.0 equiv
EtZnCH2I
2.0 equiv
EtZnCH2I
2.0 equiv
EtZnCH2I
2.0 equiv
48
2
Br
Br
Br
Br
Cl
I
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
6
8
6
6
5
5
84
3
complex mixture
4
32
0
5c
6
-
62
7d
a Isolated yields. b The recovery of R-bromo acetophenone was observed.
c The reaction was performed at 0 °C. d Trace amount of 1-phenylcyclo-
propanol was obtained.
species, the desired product 2a was obtained in 84% yield (entry
2). Nevertheless, no desired product 2a was detected when using
2.0 equiv of Et2Zn in CH2Cl2 for 8h at room temperature (entry
3). Solvent was also crucial for the course of the reaction. When
the reaction was run in toluene, the desired product 2a was
obtained in 32% yield. The reaction performed in Et2O or THF
afforded a complex reaction mixture. Therefore, CH2Cl2 was
chosen as the most effective solvent for the reaction. Decreasing
reaction temperature to 0 °C gave no desired product 2a (entry
5). Noted that the R-bromo ketones reacted with Furukawa
reagent effectively, the reaction of R-chloro acetophenone with
Furukawa reagent proceeded smoothly in the same reaction
conditions, however, it gave a complicated mixture. Addition-
ally, exposure of R-iodo acetophenone to 2.0 equiv of Furukawa
reagent at room-temperature provided the desired product 2a
in 62% isolated yield along with trace amount of 1-phenylcy-
clopropanol.
With the optimal reaction conditions in hand, subsequently,
we investigated the scope and limitation of this reaction. Various
R-bromo ketones were subjected to the reaction under the
standard conditions, and the representative results are shown
in Table 2. Aromatic R-bromo ketones reacted smoothly with
Furukawa reagent to give the desired â-diketones in moderate
to good yields. Clearly, the substituents on the phenyl ring have
an effect on the yields of the reaction. When the substrates
contained an electron-withdrawing group, such as bromo or
chloro, on its phenyl ring, the yields of the corresponding
â-diketones decreased obviously (entries 2 and 3, Table 2). With
a fluoro group in the para position on the benzene ring, the
desired product 2d was obtained in 82% yield (entry 4).
However, when the fluoro or bromo group was on the meta
position of its phenyl ring, the corresponding â-diketones were
not formed under the same conditions. On the other hand, the
substrates containing an electron-donating group in the para
position of the phenyl ring should be carried out at 0 °C, which
gave rise to the desired products in good isolated yields (entries
5-10, Table 2). When the reaction was performed at room
a Isolated yields. b Reactions were performed at 0 °C.
temperature, the yields of â-diketones decreased, due to the
formation of cyclopropanols from the corresponding â-dike-
tones.13 However, if an electron-donor substituent, such as a
methyl- or methoxyl group, was on the meta position of its
phenyl ring, the reaction should be performed at room temper-
ature, and would afford the desired â-diketones in 62% and
40% yields, respectively (entries 11 and 12, Table 2).
It is notable that when substrate 1a or an electron-withdrawing
group on its phenyl ring was carried out at 0 °C, the
(13) Xue, S.; Li, L. Z.; Liu, Y. K.; Guo, Q. X. J. Org. Chem. 2006, 71,
215.
8132 J. Org. Chem., Vol. 72, No. 21, 2007

TABLE 3. Reaction of Aliphatic r-Bromo Ketones with Furukawa
Reagent (EtZnCH2I)
SCHEME 1
corresponding â-diketone was not detected by TLC analysis,
but a new polar compound was formed. For example, exposure
of R-bromo acetophenone, 1a, and 2-bromo-1-(4-bromophenyl)-
ethanone, 1b, to 2.0 equiv of Furukawa reagent at 0 °C for 8 h
gave the corresponding polar compounds in 90% and 85%
yields, respectively (Scheme 1). These two compounds were
determined to be 4-bromo-3-hydroxy ketones 3a and 3b by
NMR spectra. These results indicated that [1,2]-sigmatropic
migration of the electron-withdrawing aryl group to form
â-diketones did not occur at 0 °C, even prolonging the reaction
time. Thus, the reaction temperature is crucial for the success
of the electron-withdrawing aryl group migration in this reaction.
For better understanding of this reaction, the desired â-diketone
2a was obtained in 88% yield when compound 3a was treated
with 3.0 equiv of Furukawa reagent in CH2Cl2 for 5 h at room
temperature. However, compound 3b was converted into the
product 2b in 80% yield at similar conditions, and longer
reaction time (20 h) was needed necessarily.14 The moderate
yields of 2b and 2c in Table 2 might be ascribed to the slow
conversion from the intermediate 3 to the product 2.
The heteroaromatic R-bromo ketone, such as 2-bromo-1-
(thiophen-2-yl)ethanone, was submitted to this reaction, and the
desired product 2n was obtained in 62% isolated yield.
Employment of 2-bromo-1,2-diphenylethanone as a substrate
resulted in the corresponding product 2o with 72% yield.
However, treatment of 2-bromo-1-phenylpentan-1-one with 2.0
equiv of Furukawa reagent under the same conditions gave no
desired â-diketone 2p as judged by the 1H NMR spectra of the
crude reaction mixtures (entry 16). The structure of products 2
was confirmed unambiguously by microanalysis, which was in
accordance with NMR and HRMS spectra. The â-diketones 2a-
2n contained the corresponding enol forms as major tautomers
with an exception of 2o, which existed in the keto form.
We next extended the reaction to aliphatic R-bromomethyl
ketones and cyclic R-bromo ketones under standard conditions.
The results are shown in Table 3. The procedures described
above for obtaining â-diketones became invalid when aliphatic
R-bromomethyl ketones were submitted to this reaction, but,
1,2-disubstituted cyclopropanols or 2,4-disubstituted furans were
obtained with moderate yields according to the steric feature
of the substrates. For example, reactions of 1-bromo-4-phe-
nylbutan-2-one and 1-bromoheptan-2-one with 2.0 equiv of
Furukawa reagent give rise to the 1,2-disubstituted cyclopro-
panols 4a and 4b in 50% and 48% yields, respectively (entries
1 and 2, Table 3). The relative stereochemistry of alkyl
substitutes on the cyclopropane ring was absolutely cis, which
was firmly established by NOESY studies.15 On the contrary,
the 1,2-disubstituted cyclopropanols obtained from â-diketones
by using organozinc reagent were trans.13
a Isolated yields. b Trace amount of 1,2-disubstituted cyclopropanols was
detected. c NR ) no reaction.
products were obtained as major products along with trace
amounts of 1,2-disubstituted cyclopropanols. Treatment of
2-bromo-1-cyclohexylethanone and 2-bromo-1-cycloheptyle-
thanone with 2.0 equiv of Furukawa reagent furnished the
products 2,4-dicyclohexylfuran 5a and 2,4-dicycloheptylfuran
5b in 56% and 45% yields, respectively (entries 3 and 4, Table
3).16 However, no reaction was observed when a large, bulky
alkyl substrate, such as, 1-bromo-3,3-dimethylbutan-2-one, was
submitted to this reaction (entry 5, Table 3). Cyclic R-bromo
ketones were converted into the corresponding cyclopropanols
under the same conditions. The reaction of 2-bromocyclooc-
tanone and 2-bromocyclododecanone with Furukawa reagent
afforded the cyclopropanols 6a and 6b in 75% and 50% yields,
respectively (entries 6 and 7, Table 3).17
On the basis of these experiments, the mechanistic pathway
for this new Reformatsky-type reaction of R-bromo ketones with
Furukawa reagent is proposed as shown in Scheme 2. The first
step of the reaction is initiated by the insertion of organozinc
into the halogen-carbon bond to form an enol 7, an analogue
of Reformatsky species, derived from R-bromo ketones 1 reacted
with Furukawa reagent (EtZnCH2I). Nucleophilic addition of
the enol 7 to a second R-bromo ketone 1 gives the self-
condensation species 3, which is the key intermediate of the
reaction. When R is an aryl group, the intermediate 3 undergoes
When aliphatic R-bromomethyl ketones with steric hindrance
were submitted to this reaction, the 2,4-disubstituted furan
(14) Treatment of 4-bromo-3-hydroxy ketones 3b with 3.0 equiv of
Furukawa reagent in CH2Cl2 for 5 h at room temperature gave product 2b
in 32% yield along with recovered 4-bromo-3-hydroxy ketones 3b.
(15) See the Supporting Information for details.
(16) Treatment of R-bromo ketones with zinc afforded furans; see:
Spencer, T. A.; Britton, R. W.; Watt, D. S. J. Am. Chem. Soc. 1967, 89,
5727.
(17) Ito, S.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 5253.
J. Org. Chem, Vol. 72, No. 21, 2007 8133

SCHEME 2. Tentative Mechanistic Pathway for the
Reaction of r-Bromo Ketones with Furukawa Reagent
In conclusion, we have developed a new and efficient
synthetic methodology for the synthesis of â-diketones from
R-bromo ketones. The reaction of aromatic R-bromo ketones
with Furukawa reagent (EtZnCH2I) afforded the desired â-dike-
tones in good yields under mild conditions. Although aliphatic
R-bromo ketones resulted in diminished efficiency for the
synthesis of â-diketones, 2,4-disubstituted furans or cis-1,2-
disubstituted cyclopropanols were obtained in moderate yields
under the same conditions.
Experimental Section
General Procedure for the Reaction of R-Bromo Ketones with
Furukawa Reagent. A 25-mL round-bottom flask was equipped
with a stir bar and charged with freshly distilled methylene chloride
(3 mL), and neat diethylzinc (100 µL, 1.0 mmol) was added via
syringe under an atmosphere of nitrogen at 0 °C. Then methylene
iodide (80 µL, 1.0 mmol) was added dropwise via syringe under
nitrogen, and the resulting white suspension was stirred for
additional 10 min R-Bromo ketone (0.5 mmol) was added to the
reaction mixture, and then the ice bath was removed. The solution
was allowed to stir at room temperature until TLC indicated
complete consumption of the starting R-bromo ketones. The reaction
mixture was quenched by saturated aqueous ammonium chloride
solution and extracted with diethyl ether (3 × 10 mL). The
combined organic layers were washed with brine and then dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to give the crude products, which were purified by column
chromatograph packed with silica gel using petroleum ether/ethyl
acetate (50:1 to 10:1) as eluent to afford the pure products.
1,4-Diphenylbutane-1,3-dione20(2a). The title compound was
prepared from 2-bromo-1-phenylethanone (99.5 mg, 0.5 mmol)
according to the general procedure, and the desired â-diketone (50.0
mg, 84% yield) was obtained as a white solid after flash chroma-
tography on silica gel (50:1 petroleum ether/EtOAc). 1H NMR (300
MHz, CDCl3; δ, ppm): 15.95 (s, 1H), 7.73 (d, J ) 7.2 Hz, 2H),
7.41 (t, J ) 7.2 Hz, 1H), 7.38 (t, J ) 7.2 Hz, 2H), 7.20 (m, 5H),
6.04 (s, 1H), 3.65 (s, 2H); 13C NMR (75 MHz, CDCl3; δ, ppm):
194.9, 183.5, 135.3, 134.9, 132.4, 129.5, 128.9, 128.7, 127.2, 127.1,
96.3, 46.2; IR (neat; cm-1): V 2962, 1599, 1262, 698. HRMS
(EI): calcd for C16H14O2 (M+), 238.0994; found: 238.0999.
an elimination of Br anion and C-C bond sigmatropic rear-
rangement of the aryl group to provide the desired â-diketones
2.18,7f The experimental results mentioned above indicate that1,2
sigmatropic migration of the aryl group to form â-diketone is
the rate-controlling step in the reaction. The aryl group with
electron-donor substituents on its phenyl ring transfers faster
than that with electron-withdrawal substituents. The latter does
not undergo rearrangement at 0 °C, and the intermediates 3 can
be isolated in good yields (Scheme 1). At room temperature,
both kind substituents can undergo migration smoothly to form
the desired â-diketones.
When R is an alkyl group, the R group has a low migratory
aptitude (i.e., contributes little to resonance stabilization of the
transition state).19 Thus, deprotonation of intermediate 3 with a
base generates an enol 8 in preference to the C-C bond
sigmatropic rearrangement. The species 8 undergoes cyclopro-
panation with Furukawa reagent to give the intermediate 9,
followed by a ring-opening reaction and intramolecular SN2
displacement to form cis-1,2-disubstituted cyclopropanols 4.
When R is a bulky alkyl group, the intermediate 8 undergoes
SN2 displacement (which is an intramolecular nucleophilic attack
of the enol oxygen upon the electrophilic carbon on which Br
is attached), and then the Br anion leaves to furnish the
intermediates 11, followed by dehydration to generate 2,4-
disubstituted furan 5. The reaction of cyclic R-bromo ketone
with one equivalent of Furukawa reagent afforded zinc enolates,
which undergo cyclopropanation with a second equivalent of
the zinc species to give the product 6.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (20572104) and the Program of
NCET for financial support.
Supporting Information Available: Detailed experimental
procedures and characterization data for all previously unknown
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7013627
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