Zinc-Mediated Conversion of β-Keto Esters to γ-Keto Esters

Full text of DOI:10.1021/jo970868g

6444
J . Org. Chem. 1997, 62, 6444-6446
Sch em e 1
Zin c-Med ia ted Con ver sion of â-Keto Ester s
to γ-Keto Ester s
J ohn B. Brogan and Charles K. Zercher*
Department of Chemistry, University of New Hampshire,
Durham, New Hampshire 03824
Received May 15, 1997
The efficient preparation of γ-keto esters has been the
goal of numerous research efforts. Although methods
have been developed in which the ketone and ester
functionalities are brought together from different sources,1
reactions which promote the insertion of a single meth-
ylene unit between the carbonyl functionalities of a
readily accessible â-keto ester have dominated these
efforts. The formation and fragmentation of 2-carboxy-
cyclopropyl alcohols have been central to this method-
ological development.2
Three complementary disconnective strategies have
been implemented for the formation of these functional-
ized cyclopropyl alcohols. The most common strategy has
involved exposure of a enol ether to metal carbenoids
generated from diazo esters.3 Cleavage of the ether
linkage in a second separate step and fragmentation of
the mixture of cyclopropanol stereoisomers provided the
corresponding γ-keto ester. A complementary method
utilized Simmons-Smith methodology to generate a
cyclopropane from protected â-keto esters.4 Opening of
the functionalized cyclopropanes was initiated by treat-
ment with aqueous acid or fluoride. A more recently
reported chain extension method involved treatment of
an R-substituted â-keto ester enolate with methylene
bromide followed by exposure to tin hydride.5 Addition
of the primary radical to the carbonyl followed by
fragmentation of the intermediate cyclopropanol radical
provided the ester-stabilized radical. Quenching of the
radical with tri-n-butyltin hydride continued the chain
process and provided the γ-keto ester.
We have recently developed a mild and efficient one-
step method for the formation of γ-keto esters from â-keto
esters which appears to proceed through a similar
cyclopropyl alcohol intermediate 2 (Scheme 1). Exposure
of an R-unsubstituted â-keto ester to a 1:1 mixture of
diethylzinc and methylene iodide results in its clean and
rapid conversion to the chain-extended keto ester. This
zinc-mediated process holds two distinct advantages over
the previously reported chain extension methods. The
most obvious advantage is that no additional steps are
required for the formation of the intermediate enol ether
or for the cleavage of the protected cyclopropyl alcohol.
Second, utilization of diethylzinc is operationally much
more simple than preparation and application of the zinc
amalgam reported by Saigo.4b Since R-unsubstituted
â-keto esters react cleanly under these reaction condi-
tions, this new reaction nicely complements the radical-
based methodology which requires an R-substituent to
prevent elimination.5
The reaction is remarkably efficient with respect to the
substitution pattern about the â-keto ester. Unsubsti-
tuted â-keto esters were efficiently converted into the
corresponding γ-keto esters in yields which ranged from
58% to 81% (Table 1). Chromatographic analysis of the
reactions listed in Table 1 indicated that the only product
formed upon consumption of the starting material was
the γ-keto ester.6 Chain extension proceeded cleanly with
as few as 2.0 equiv of the presumed ethyl(iodomethyl)zinc
reagent, although unreacted starting material was oc-
casionally observed at this stoichiometry. Therefore,
typical reaction conditions consisted of adding the â-keto
ester to a 0 °C solution of methylene chloride which
contained 5 equiv of both methylene iodide and dieth-
ylzinc.
The â-keto esters which contained olefin functionality
(Table 2) were susceptible to concomitant cyclopropane
formation. Substrates which possessed either electron-
rich or electron-poor olefins underwent selective chain
extension of the alkene in preference to cyclopropane
formation. Nevertheless, extended reaction times and
excess ethyl(iodomethyl)zinc provided an appropriate
environment for tandem chain extension and cyclopro-
panation which culminated in the preparation of 20.
Although the chain extension reaction worked very
well for simple â-keto esters, variation from the acyclic
R-unsubstituted â-keto ester series resulted in dimin-
ished efficiency (Table 3). Treatment of acetylacetone 21
for 40 min at room temperature resulted in no observable
reaction, even though addition of methyl acetoacetate (1)
to the reaction mixture and its conversion to methyl
levulinate (4) demonstrated that the active chain exten-
sion reagent was present. Exposure of 1,3-cyclohex-
anedione (22) to the standard reaction conditions gen-
erated in low yield a compound which possessed a
cyclopropyl group. The structure of product 23 was
firmly established by H,H-COSY7 and was shown to be
the result of the expected ring expansion followed by the
rapid addition of a second methylene group.
(1) (a) Miyakoshi, T. Org. Prep. Proc. Int. 1989, 21, 659. (b) Nagata,
W.; Yoshioka, M. Org. React. 1977, 25, 255.
(2) (2) Reissig, H.-H. Top. Curr. Chem. 1988, 144, 73.
(3) (a) Wenkert, E.; McPherson, C. A.; Sanchez, E. L.; Webb, R. L.
Synth. Commun. 1973, 3, 255. (b) Reichelt, I.; Reissig, H.-U. Chem.
Ber. 1983, 116, 3895. (c) Kunkel, E.; Reichelt, I.; Reissig, H.-U. Leibigs
Ann. Chem. 1984, 512. (d) Reichelt, I.; Reissig, H.-U. Leibigs Ann.
Chem. 1984, 531. (e) Saigo, K.; Kurihara, H.; Miura, H.; Hongu, A.;
Kubota, N.; Nohira, H. Synth. Commun. 1984, 787. (f) Reissig, H.-U.;
Grimm, E. L. J . Org. Chem. 1985, 50, 242.
(4) (a) Bieraugel, H.; Akkerman, J . M.; Lapierre Armond, J . C.;
Pandit, U. K. Tetrahedron Lett. 1974, 2817. (b) Saigo, K.; Yamashita,
T.; Hongu, A.; Hasegawa, M. Synth. Commun. 1985, 715.
(5) (a) Dowd, P.; Choi, S.-C. J . Am. Chem. Soc. 1987, 109, 3493. (b)
Dowd, P.; Choi, S.-C. J . Am. Chem. Soc. 1987, 109, 6548. (c) Dowd, P.;
Choi, S.-C. Tetrahedron. 1989, 45, 77. (d) Dowd, P.; Choi, S.-C.
Tetrahedron Lett. 1989, 30, 6129.
The regioselective incorporation of the methylene unit
was addressed through the exposure of R-substituted
(6) All reported reactions were performed on a 1 mmol scale. The
modest yields of the compound in Table 1 apparently reflect the
efficiency of chromatographic purification.
(7) Bax, A.; Freeman, R. J . Magn. Reson. 1981, 44, 542.
S0022-3263(97)00868-2 CCC: $14.00 © 1997 American Chemical Society

Notes
Ta ble 1. Ch a in Exten sion of Sim p le â-Keto Ester s
J . Org. Chem., Vol. 62, No. 18, 1997 6445
Ta ble 3. Ch a in Exten sion of â-Dik eton es a n d
r-Su bstitu ted â-k eto Ester s
The precise zinc species responsible for initiating the
chain extension process is not known at the present time,
although it has been demonstrated that an equimolar
combination of diethylzinc and methylene iodide gener-
ates the moderately stable cyclopropanation reagent
ethyl(iodomethyl)zinc.8 It has yet to be clarified whether
the reactive zinc species performs a direct cyclopropana-
tion of the enolate, a direct cyclopropanation of the enol,
or a stepwise procedure which involves an R-alkylation
of the â-keto ester followed by nucleophilic attack on the
ketone carbonyl. Nevertheless, the similarity of this
reaction to the transformations reported by Dowd and
Saigo suggests that a cyclopropyl alcohol intermediate
is involved.9 At this time there is no direct evidence for
the formation of an intermediate cyclopropane in the
simple chain extension procedure; however, the isolation
of the secondary compound 23 supports its proposed
existence.
Ta ble 2. Ch a in Exten sion of Olefin -Con ta in in g
Su bstr a tes
It is not entirely clear why the addition of the second
methylene unit is so rapid with the cyclic and/or R-sub-
stituted substrates 22, 24, and 26. Disruption of an
equilibrium between, for example, cyclopropanoxide 28
and its isomeric and very reactive ester enolate 29
(Scheme 2) may play a role. The extremely rapid
conversion of 29 into 23 would appear to lend support to
a mechanism in which cyclopropanation events occur
through an enolate intermediate. If the reaction pro-
ceeded through cyclopropanation of the enol, it is unlikely
that rapid addition of a second methylene unit would be
observed.
In summary, we have identified a simple and efficient
procedure for the conversion of â-keto esters to γ-keto
â-keto esters to the standard reaction conditions. Conver-
sion of acyclic â-keto ester 24 into 25 indicated that, in
a fashion similar to the previously reported methodo-
logies,3-5 the new methylene was incorporated adjacent
to the ketone functionality. This conclusion was rein-
forced through the identification of 27 as the major pro-
duct generated from R-carboethyloxycyclohexanone (26).
(8) (a) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron Lett.
1966, 3353. (b) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron
1968, 24, 53. (c) Charette, A. B.; Marcoux, J .-F. J . Am. Chem. Soc.
1996, 118, 4539.
(9) Lenhert, E.; Sawyer, J . S.; McDonald, T. L. Tetrahedron Lett.
1989, 30, 5215.

6446 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
Typ ica l Exp er im en t. A 50 mL round-bottom flask was
equipped with a stir bar and charged with methylene chloride
(15 mL) and diethylzinc (1.0 M in hexanes, 5 mL, 5 mmol).
Methylene iodide (0.4 mL, 5 mmol) in 2.5 mL of CH2Cl2 was
added dropwise with stirring. The resulting suspension was
stirred for 10 min, and methyl acetoacetate (1) (116 mg, 1.0
mmol) was added rapidly by syringe. The mixture was stirred
for 30 min, quenched with saturated aqueous NH4Cl, and
extracted with diethyl ether. The combined organic extracts
were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude oil was purified
by chromatography on silica (20% EtOAc in hexanes) and yielded
methyl levulinate (4) (106 mg, 81%).
Sch em e 2
tr a n s-4,5-Dicyclop r op yl-2-(5-(ca r boxym eth yl)-3-oxop en -
tyl)-2-m eth yl-1,3-d ioxola n e (20). A large excess (12 equiv)
of the proposed ethyl(iodomethyl)zinc reagent was necessary to
form this product cleanly, 40%: 1H NMR (CDCl3) δ 3.7 (s, 3H),
3.1 (t, 1H, J ) 8.3 Hz), 2.9 (t, 1H, J ) 8.3 Hz), 2.7 (t, 1H, J )
6.7 Hz), 2.55 (m, 4H), 2.0 (m, 2H), 1.35 (s, 3H), 0.7-0.9 (m, 4H),
0.2-0.5 (m, 4H); 13C NMR (CDCl3) δ 208.4, 173.3, 108.2, 86.7,
86.0, 51.7, 36.4, 36.9, 33.9, 27.7, 25.6, 12.6, 11.9, 2.9, 2.8, 1.6;
IR (film) 3000-2900, 1741, 1718 cm-1; MS (CI, NH3) 328, 311,
293, 279, 204, 187, 167, 155, 125; HRMS (CI, CH4) ([M + H]+)
calcd for C17H27O5 311.1858, found 311.1865.
esters which has distinct advantages when compared to
existing methodology. The reaction works remarkably
well for R-unsubstituted â-keto esters. Substrates in
which the ketone is incorporated into a small ring or
which possess R-substitution of the â-keto ester react
with diminished efficiency, although these limitations can
most likely be overcome through prior formation of the
trimethylsilyl enol ether in a fashion similar to that
reported by Saigo. The intermediacy of a cyclopropyl
alcohol has been implicated by product formation, al-
though details of its formation are still under investiga-
tion. Efforts are underway to optimize the reaction
conditions and to define more clearly the scope and
synthetic utility of this chain extension reaction.
1
7-Hyd r oxybicyclo[5.1.0]octa n -3-on e (23): 25%; H NMR
(CDCl3) δ 3.1 (br s, 1H), 2.8 (ddd, 1H, J ) 14.5, 6.7, 1.3 Hz), 2.7
(apparent pentet, 1H, J ) 6.4 Hz), 2.4 (dt, 1H, J ) 15.1, 4.0
Hz), 2.3 (ddd, 1H, J ) 12.2, 8.7, 5.7 Hz), 2.0 (m, 1H), 1.88 (dd,
1H, J ) 14.3, 9.3 Hz), 1.75 (m, 1H), 1.45 (ddd, 1H, J ) 15.2,
12.2, 3.1 Hz); 13C NMR (CDCl3) δ 212.0, 58.1, 44.7, 44.0, 34.5,
24.0, 21.2, 18.8; IR (film) 3418, 2945, 1700, 1450 cm-1; MS (CI,
NH3) 174, 158, 144, 134, 127; HRMS (CI, NH3) (MNH4+) calcd
for C4H18NO2 158.1180, found 158.1186.
Exp er im en ta l Section
Ack n ow led gm en t. We express our appreciation to
the National Institutes of Health (R15 GM51064) and
the University of New Hampshire for financial support.
We appreciate an informative conversation with Profes-
sor Paul Helquist.
Methylene chloride was distilled from calcium hydride. Col-
umn chromatography was performed on Baker 40 µm silica gel.
The reactions were monitored by thin layer chromatography
(TLC) on EM Science F254 glass plates which were visualized
by short wavelength UV and anisaldehyde stain. All reactions
were run in oven-dried glassware under a nitrogen atmosphere.
Starting materials 1, 5, 7, 9, 11, 21, 22, 24, and 26 were
purchased from commercial sources and used as received.
Compound 1310 was prepared according to the procedure of
Roskamp,11 and compounds 1512 and 1713 were prepared through
application of the procedure of Masamune.14 Compound 19 was
prepared in a multistep sequence from levulinic acid.15 Char-
acterization data of the purified products 4,16 6,17 8,18 10,19 12,20
14,21 16,22 18,23 25,24 and 2725 were shown to be consistant to
the literature values.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data, including 1H and 13C NMR, for all products and non-
commercially available starting â-keto esters. 1H and 13C
NMR spectra for 20 and 23, including an H-H COSY for
compound 23 (8 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O970868G
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