Zinc-mediated ring-expansion and chain-extension reactions of β-keto esters

Full text of DOI:10.1021/jo0512498

â-keto esters, and these reactions are very attractive for
the advantage of ease of execution and specific radical
reaction.
Zinc-Mediated Ring-Expansion and
Chain-Extension Reactions of â-Keto Esters
In 1997, Zercher reported an operationally simple and
efficient approach to the chain extension of â-keto esters
using the Furukawa reagent, ethyl(iodomethyl)zinc.6 The
reaction worked well for R-unsubstituted â-keto esters,7
â-keto amides,8 as well as â-keto phosphonates.9 How-
ever, ring-expansion of cyclic â-keto esters reacted with
diminished efficiency.6 Our interest in CF3COOH en-
hancing the reactivity of zinc reagent has led us to find
that treatment of zinc species CF3CO2ZnCH2I with cyclic
â-keto esters can afford the corresponding ring-expanded
products in moderate to good yields (Table 1).10
Song Xue,* Yong-Kang Liu, Le-Zhen Li, and
Qing-Xiang Guo
Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
xuesong@ustc.edu.cn
Received June 17, 2005
The zinc species CF3CO2ZnCH2I can be readily pre-
pared by stirring ZnEt2 with CF3CO2H in CH2Cl2 at 0
°C for 30 min, followed by addition of CH2I2. Treatment
of benzoclclic â-keto ester 1 with the in situ generated
CF3CO2ZnCH2I (3.0 equiv) in CH2Cl2 at room tempera-
ture for 8 h afforded the desired ring-expansion product
2 in 83% yield. The reaction proceeded smoothly in 2.5
equiv of CF3CO2ZnCH2I for 5 h with a little low yield
(69%). The choice of Et2O and toluene as solvent afforded
the product 2 in 25% and 14% yields, respectively.
Substrate 3 also gave the ring-expansion product 4 in
a good yield. A considerable low yield was obtained in
cyclic â-keto ester 5, which was derived from 1-indanone.
Lengthy reaction time gave no effect on yield. â-Keto
ester 9 derived from cyclohexanone could afford the ring-
expanded product 10 in 67% yield. Likewise, 7-, 8-, and
12-membered ring â-keto esters (11, 13, and 15) were
expanded similarly with zinc species CF3CO2ZnCH2I to
give 8-, 9-, and 13-membered ring products (12, 14, and
16) in good yields, respectively. However, â-keto ester 7
derived from cyclopentanone reacted with diminished
efficiency, providing the corresponding ring-expanded
product in only 20% yield. Low yields were found for
substrates 5 and 7, presumably due to the strain five-
membered ring.
Chain extension of acyclic â-keto esters also proceeded
effectively to generate γ-keto esters in good to high yields.
These results were summarized in Table 2. Exposure of
substrate 17 with 3 equiv of CF3CO2ZnCH2I at room
temperature for 8 h gave the corresponding chain-
extended product 18 in 90% yield. The efficiency of the
reaction was not hampered by the presence of bulky tert
butyl group or phenyl group. But it should be noted that
the reaction of ethyl acetoacetate 25 with CF3CO2ZnCH2I
at room temperature gave trance amount of the desired
product 26, and providing unidentified mixtures. Fortu-
nately, the chain-extended product 26 was obtained in
The reaction of cyclic â-keto esters with CF3CO2ZnCH2I
provided the corresponding ring-expanded products in mod-
erate to good yields. Although R-substituted acyclic â-keto
esters reacted with much less efficient, chain-extension
reaction of simple â-keto esters also proceeded effectively
to generate γ-keto esters in high yields.
Medium size (8-, 9-, and 10-membered) rings are found
to be the structural core of a number of biologically
important natural products.1 Ring-expansion reaction of
cyclic â-keto esters is a useful method for synthesis of
medium- and large-membered ring compounds.2 An ef-
ficient ring expansion is the use of a free radical.3
Treatment of R-halomethyl and R-(3-halopropyl) cyclic
â-keto esters with tributyltin hydride and AIBN in
refluxing benzene solution gave one- and three-carbon
ring-expanded cyclic keto esters in good yields, respec-
tively. A complementary method using indium-mediated
Barbier-type reaction of cyclic â-keto esters in water
provided two-carbon ring-expanded products.4 Recently,
it was reported that one-carbon ring-expansion and
chain-extension reactions of â-keto esters proceeded
smoothly with zinc powder in refluxing aqueous alcohol.5
These methods are efficient for ring-expansion of the
(1) (a) Wender, P. A.; Lechleiter, J. C. J. Am. Chem. Soc. 1980, 102,
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Dowd, P.; Choi, S. C. J. Am. Chem. Soc. 1987, 109, 6548. (c) Dowd, P.;
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Org. Lett. 2002, 4, 905. (b) Xue, S.; He, L.; Han, K. Z.; Liu, Y. K.; Guo,
Q. X. Synlett. 2005, 8, 1247.
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10.1021/jo0512498 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/02/2005
J. Org. Chem. 2005, 70, 8245-8247
8245

TABLE 1. Ring Expansion of â-Keto Esters Using
TABLE 2. Chain Extension of â-Keto Esters Using
CF3CO2ZnCH2I
CF3CO2ZnCH2I
a Isolated yields. b The reaction was performed at 0 °C. c Using
4 equiv of CF3CO2ZnCH2I.
contained electron-poor olefin, underwent selective chain-
extended reaction in preference to cyclopropanation of
the olefin under our standard reaction conditions. How-
ever, â-keto ester 29 with terminal olefin functionality
provided the chain-extension and cyclopropanation prod-
uct 30 in 70% yield along with a small amount of chain-
extended product under the same conditions. When 4
equiv of CF3CO2ZnCH2I was submitted to the reaction,
the sole product 30 was obtained in 95% yield.
a Isolated yields. b 2.5 equiv of CF3CO2ZnCH2I was used. c Per-
formed in Et2O solvent. d Performed in toluene solvent.
good yield when the reaction was carried out at 0 °C.
â-Keto esters which possessed olefin functionality were
susceptible to concomitant cyclopropanation, since olefins
could be converted into cyclopropanes efficiently by this
zinc species CF3CO2ZnCH2I.11,12 Substrate 27, which
(12) (a) Carter, K. N.; Taverner, T.; Schiesser, C. H.; Greenberg, M.
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8621. (b) Lorenz, J. C.; Long, J.; Yang, Z. Q.; Xue, S.; Xie, Y. N.; Shi,
Y. J. Org. Chem. 2004, 69, 327.
8246 J. Org. Chem., Vol. 70, No. 20, 2005

SCHEME 1. A Plausible Mechanism of the
Ring-Expansion Reaction
using zinc reagent CF3CO2ZnCH2I (Scheme 1). The
obvious advantage of the reaction is mild condition, and
no preparation of R-halomethyl â-keto esters.
Experimental Section
General Procedure for Ring Expansion and Chain
Extension of â-Keto Ester with CF3COOZnCH2I. To a
solution of ZnEt2 (90 µL, 0.9 mmol, 3 equiv) in 3 mL of CH2Cl2
at 0 °C was added dropwise CF3COOH (70 µL, 0.9 mmol, 3 equiv)
slowly via syringe under N2. After the mixture was stirred for
30 min at 0 °C, methylene iodide (75 µL, 0.9 mmol, 3 equiv) was
added dropwise with stirring. The suspension was stirred for
30 min, and then â-keto ester 1 (66 mg, 0.3 mmol) was added
rapidly by syringe. The mixture was stirred at room temperature
for 8 h. The reaction was quenched with saturated aqueous NH4-
Cl and extracted with Et2O (10 mL × 3). The combined organic
extracts was washed with brine, dried over MgSO4, and con-
centrated under reduced pressure to an oil residue. The desired
product 5-Ethoxycarbonyl-1,2-benzo-3-oxocycloheptenone 2 (58
mg, 83%)13 as a colorless oil was isolated by flash silica gel
column chromatography. 1H NMR (300 MHz, CDCl3): δ ) 7.63
(dd, 1H, J ) 7.6, 1.5 Hz), 7.37 (td, 1H, J ) 7.5, 1.5 Hz), 7.25 (td,
1H, J ) 7.5, 1.2 Hz), 7.14 (d, 1H, J ) 7.5 Hz), 4.15 (q, 2H, J )
7.2 Hz), 3.05-2.75 (m, 5H), 2.22 (m, 1H), 2.09 (m, 1H), 1.15 (t,
3H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3): δ ) 202.9, 174.3,
140.8, 138.2, 132.6, 129.8, 128.8, 127.0, 61.0, 42.8, 38.3, 31.2,
28.6, 14.2.
Procedure for Synthesis of Ethyl 6-Cyclopropyl-4-oxo-
hexanoate (30) Using CF3COOZnCH2I. To a solution of ZnEt2
(120 µL, 1.2 mmol, 4 equiv) in 3 mL of CH2Cl2 at 0 °C was added
dropwise CF3COOH (93 µL, 1.2 mmol, 4 equiv) slowly via syringe
under N2. After the mixture was stirred for 30 min at 0 °C,
methylene iodide (100 µL, 1.2 mmol, 4 equiv) was added
dropwise with stirring. The suspension was stirred for 30 min,
and then â-keto ester 29 (51 mg, 0.3 mmol) was added rapidly
by syringe. The mixture was stirred at room temperature for 8
h. The reaction was quenched with saturated aqueous NH4Cl
and extracted with Et2O (10 mL × 3). The combined organic
extracts was washed with brine, dried over MgSO4, and con-
centrated under reduced pressure to an oil residue. The desired
product 30 (56 mg, 95%) as a colorless oil was isolated by flash
silica gel column chromatography. IR (neat, cm-1): 3077, 2984,
2927, 1736, 1448, 1411, 1373, 1350, 1194, 1095, 1017. 1H NMR
(300 MHz, CDCl3): δ ) 4.15 (q, 2H, J ) 7.2 Hz), 2.75 (t, 2H, J
) 6.5 Hz), 2.60-2.51 (m, 4H), 1.5 (q, 2H, J ) 7.3 Hz), 1.2 (t, 3H,
J ) 7.2 Hz), 0.68 (m, 1H), 0.5-0.35 (m, 2H), 0.01 (dd, 2H, J )
10.2, 5.4 Hz). 13C NMR (75 MHz, CDCl3): δ ) 209.2, 173.0, 60.7,
42.9, 4.3, 29.1, 28.1, 14.3, 10.6, 4.6. HRMS (EI)L calcd for
C11H18O3 198.1257 [M+], found 198.1256.
The zinc species CF3CO2ZnCH2I worked well for ring-
expansion reaction of cyclic â-keto esters; however,
R-substituted â-keto esters resulted in diminished ef-
ficiency (Table 2). Reaction of 31 gave the chain-extended
product 32 in 36% yield. Substrate 33 with a tert-butyl
group was submitted to this reaction, no chain-extended
product was formed and the starting material was
recovered (>90%). These results suggest the steric hin-
drance between R-methyl group and γ-substituted group
has obvious influence on the reaction.
Based on the work of Zercher,6,7 a plausible mechanism
of the reaction is shown in Scheme 1. The first step of
the reaction is formation of the enolate 34, which
consumes 1 equiv of CF3CO2ZnCH2I. Enolate 34 then
undergoes cyclopropanation with second equivalent of
zinc species to give cyclopropyl intermediate 35, followed
by cleavage to give an intermediate 36, then quenched
by saturate aqueous NH4Cl to provide the ring-expanded
product. Compared to ethyl(iodomethyl)zinc, the CF3CO2-
ZnCH2I was found to afford the ring-expanded product
in much higher yields. The reason may be that ionization
of the electron deficient CF3CO2 group creates a vacant
coordination site on the zinc permitting coordination of
the iodine of a second CF3CO2ZnCH2I species that results
in activation of the methylene group toward reaction with
enolates resulting in formation of cyclopropanaes.11 Here,
CF3CO2H accelerated the cyclopropanation reaction of
olefins dramatically, and the ring-expanded products
were effectively formed. Unfortunately, the chain-exten-
sion of R-substituted â-keto esters reacted with much less
efficient. The increased steric hindrance of the resultant
enolate may be responsible.
Acknowledgment. We express our appreciation to
the National Natural Science Foundation of China
(20202009) and the Natural Science Foundation of
Anhui province (050460302) for financial support.
Supporting Information Available: 1H and 13C NMR
spectra for products 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,
26, 28, 30, and 32. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0512498
(13) Treatment of CF3CO2ZnCH2I (9 mmol) with 5-ethoxycarbonyl-
1,2-benzo-2-oxocyclohexenone 1 (650 mg, 3 mmol) gave the desired
product 2 in comparable yield (562 mg, 81%) under the same procedure.
See the Supporting Information for details.
In this paper, we have developed a simple and efficient
procedure for the ring-expansion of cyclic â-keto esters
and chain-extension of R-unsubstituted â-keto esters by
J. Org. Chem, Vol. 70, No. 20, 2005 8247