Zinc carbenoid-mediated chain extension of β-keto amides

Article abstract of DOI:10.1016/S0040-4020(01)00879-1

The reaction of β-keto amides with ethyl(iodomethyl)zinc provides access to a wide variety of γ-keto amides, including primary, secondary, and tertiary amides. Although the reaction of α-substituted β-keto amides are in many cases unsatisfactory, the method can be applied to a broad spectrum of substrates that possess imide and olefinic functionality.

Full text of DOI:10.1016/S0040-4020(01)00879-1

TETRAHEDRON
Pergamon
Tetrahedron 57 '2001) 8793±8800
Zinc carbenoid-mediated chain extension of b-keto amides
Ramona Hilgenkamp and Charles K. Zercherp
Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA
Received 9 July 2001; accepted 23August 2001
AbstractÐThe reaction of b-keto amides with ethyl'iodomethyl)zinc provides access to a wide variety of g-keto amides, including primary,
secondary, and tertiary amides. Although the reaction of a-substituted b-keto amides are in many cases unsatisfactory, the method can be
applied to a broad spectrum of substrates that possess imide and ole®nic functionality. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
zation and fragmentation of radical intermediates.4
A
complementary approach to the donor±acceptor cyclo-
propanes was reported in which a ketone-derived enol
ether is cyclopropanated through reaction with a rhodium
carbenoid.5
The ability to selectively manipulate the length of a carbon
chain or enlarge an existing carbon framework provides
opportunities for incorporating structural diversity in
molecule assembly. One common strategy in chain
extension and ring enlargement involves formation of
strained ring systems, which fragment upon exposure to
suitable reaction conditions to give longer carbon frame-
works.1 The ef®cient preparation of 1,4-dicarbonyl
compounds from shorter carbon chains through formation
and fragmentation of a cyclopropyl alkoxide ®rst appeared
in the literature twenty-®ve years ago. In this instance a
b-keto ester was converted to an enamine, reacted with
the Simmons±Smith reagent, and fragmented under hydro-
lytic conditions.2 A number of variations on this `donor±
acceptor cyclopropane' strategy were reported, including
the use of a trimethylsilyl enol ether as the nucleophilic
partner3 and a stepwise approach which involves the cycli-
We reported a new chain extension variant in the form of a
one-pot chain extension of b-keto esters through treatment
of a zinc enolate with the Furukawa reagent 'EtZnCH2I).6
A generalized mechanistic description is found in Scheme 1.
The key to the ef®ciency of the reaction appears to be the
stable, unreactive nature of a Reformatsky-like intermediate
4. While providing ef®cient access to simple g-keto esters,
the methodology was much less ef®cient in the formation of
a-substituted g-keto esters, likely due to a destabilization of
intermediate 4. The chain extension reaction was unsuc-
cessful in the formation of g-diketones. We more recently
reported the application of this carbenoid strategy to the
Scheme 1.
Keywords: chain extension; zinc; carbenoid; keto amide.
Corresponding author. Tel.: 11-603-862-2697; fax: 11-603-862-4278; e-mail: ckz@christa.unh.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)00879-1

8794
R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
with a methyl group adjacent to the ketone, the simplicity
and broad applicability to a variety of amines made it the
dominant method chosen for this methodology study.
A series of a-unsubstituted tertiary b-keto amides 9 were
exposed to the Furukawa-modi®ed Simmons±Smith
reagent16 to produce the corresponding g-keto amides 10.
Initially, reaction conditions identical to those employed
with b-keto esters were used. It was later determined that
for most substrates 3equiv. of the zinc carbenoid resulted in
clean conversion of all starting material to product, although
as many as 6 equiv. could be used without detrimental
effects. In some cases the reaction was quenched after
15 min and 1H NMR spectra of the crude reaction mixtures
showed complete conversion of starting material to product.
When reaction times exceeded 45 min, complex reaction
mixtures were observed and yields of the desired products
were reduced accordingly.
Figure 1.
chain expansion of b-keto phosphonates,7 although com-
peting cyclopropanation of ole®n functionality limits its
broad applicability within the phosphonate family 'Fig. 1).
As indicated in the results tabulated in Table 1, a variety of
a-unsubstituted tertiary b-keto amides were chain-extended
cleanly in modest to good yields. The ef®ciency of the
reaction was not hampered by the presence of sterically
Our interest in extending the facile zinc-mediated reaction
to the preparation of g-keto amides is prompted by its utility
in a wide variety of biologically relevant systems. Besides
appearing as an intermediate '6) in the preparation of bio-
logically active compounds like 7,8 g-keto amides are
frequently found in ketomethylene isosteric replacements
8 for the peptide bond.9 The development of an operation-
ally simple approach to the preparation of g-keto amides
would serve to advance both their synthetic accessibility
and utility. However, a report10 that implicated the
Furukawa reagent in the N-methylation of amide function-
ality suggested that N-methylation of b-keto amides might
compete with the chain extension. For these reasons we
undertook a detailed study of the zinc carbenoid-mediated
chain extension of b-keto amides.
1
demanding groups or aromatic groups. H NMR spectra of
the crude reaction mixtures suggested that the desired
g-keto amides, except in one case, were the only products
formed. When N,N-dimethyl 3-oxo-butanamide 9c was
exposed to the zinc carbenoid for greater than 30 min,
evidence for competing product formation was observed
by chromatographic and spectroscopic techniques.
Although the competing products were not identi®ed,
mass spectrometry data suggested that condensation reac-
tions took place and led to the formation of high molecular
weight compounds. A reduction of the reaction time to
15 min led to an acceptable yield of the desired product.
Similar problems were not encountered when N,N-dimethyl
3-oxo-3-phenyl-propanamide 9g was chain extended, even
when the reaction was allowed to run for 45 min. Yields of
water-soluble products were compromised by the necessity
to remove the zinc salts through extraction and aqueous
work-up.
2. Results and discussion
A wide variety of methods are available for the preparation
of the necessary b-keto amide starting materials, including
addition of amines to diketene,11 acetoacetylation of amines
with 2,2,6-trimethyl-4H-1,3-dioxin-4-one,12 reaction of
amines with b-keto esters or b-keto thioesters,13 conden-
sation of ketones and isocyanates,14 and aminolysis of
acyl Meldrum's acid.15 Although the addition of amines to
diketene is limited in that it only provides b-keto amides
The tertiary substrates described above did not contain any
acidic protons which would likely interfere with the chain
extension reaction. The impact of modestly acidic hydrogen
atoms on the amide nitrogen was ®rst tested by applying
the one-pot zinc carbenoid-mediated chain extension
method to two secondary b-keto amides. N-Cyclohexyl
3-oxo-butanamide 9h reacted very cleanly and provided
the chain-extended product, N-cyclohexyl 4-oxo-pentana-
mide 10h, as a pure compound in 81% yield. In contrast,
attempted chain extension of 9i provided material whose 1H
NMR spectrum of the crude reaction material was more
complex than anticipated. The desired product, N-phenyl
4-oxo-pentanamide 10i, was isolated, although in only
33% yield after recrystallization. No other products were
identi®ed, but the 33% yield for the chain-extended product
was signi®cantly lower than those obtained for most other
Table 1.
Substratea
R
R1
R2
Yieldb '%)
9a
9b
9c
9d
9e
9f
9g
9h
9i
CH3
CH3
CH3
CH3
C6H5
C'CH3)3
C6H5
CH3
CH3
CH3
±'CH2)4±
47
70
88
60
42
60
59
81
3
n-C4H9
CH3
CH3
n-C4H9
C6H5
CH3
CH2C6H5
CH2C6H5
CH3
CH2C6H5
CH2C6H5
CH3
c-C6H11
C6H5
H
H
H
H
3
substrates. Since ef®cient chain extension of N-phenyl-N-
9j
10
methyl 3-oxo-butanamide 10c had already demonstrated
that the toleration of an aromatic group on the amide
nitrogen, the reduced yield in the chain extension of 9i is
likely due to the enhanced acidity of the amide hydrogen.
a
Speci®c reaction conditions for each substrate are contained in the
Section 4.
Isolated yield of puri®ed material.
b

R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
8795
Scheme 2.
However it is important to note that in this substrate, as well
as others, no N-methylated products were observed.10
The one-pot chain extension method was also applied to a
primary b-keto amide, acetoacetamide 9j. Once again the
1H NMR spectrum of the crude reaction mixture was more
complex than that of the chain extension reactions reported
above. The expected product, levulinamide 10j, was
isolated, but the dif®culty experienced in extracting the
water-soluble product after the aqueous work-up and the
generation of numerous unidenti®ed byproducts were
responsible for the 10% yield.
Scheme 4.
amide 15 was subjected repeatedly to the zinc carbenoid
for 30 min, no reaction was observed 'Scheme 3). When
the reaction time was extended to several hours, none of
the desired chain-extended product was observed. Analysis
by 1H- and 13C NMR spectra suggested that substrate
decomposition had occurred. No evidence for the formation
of chain-extended products were observed with 1-'2-methyl-
1,3-dioxobutyl)pyrrolidine 12, and 2-oxo-cyclohexane-
carboxylic acid dibenzyl amide 17.
Substrates containing ole®n functionality were successfully
chain-extended when exposed to a zinc carbenoid 'Scheme
2). When N-'2-propenyl) 3-oxo-butanamide 11 was sub-
jected to zinc-mediated chain extension reaction conditions,
the reaction time was limited to 15 min in an effort to
prevent cyclopropane formation. The simple chain-
extended product 12 was formed in 55% yield. An
inseparable byproduct, presumed to be due to concomitant
cyclopropane formation, was present in a trace amount
'estimated at less than 5% by 1H NMR analysis).
Similar results were obtained when N,N-dibenzyl 3-oxo-6-
heptenamide 13 was treated with the Furukawa reagent for
30 min. The simple chain-extended keto amide 14 was again
the major product formed; only a trace of cyclopropanated
A control reaction was performed to insure that the lack
of reactivity of these substrates was not due to inactivation
of the zinc carbenoid. A mixture of equal molar amounts of
1-'1,3-dioxobutyl)pyrrolidine 9a and 1-'2-methyl-1,3-dioxo-
butyl)pyrrolidine 16 was subjected to chain extension reac-
tion conditions. The 1H NMR spectrum of the crude reaction
mixture indicated that compound 9a was consumed with
concomitant formation of the chain-extended product 10a.
Once again no evidence for the formation of the anticipated
a-substituted chain-extended product was indicated.
1
product 'estimated at less than 5% by H NMR analysis)
was evident in the 1H NMR spectrum of the puri®ed
product.
We reported in an earlier communication6 that attempts to
prepare g-keto esters from a-substituted b-keto esters
resulted in complex mixtures of products and only modest
yields of the desired a-substituted 1,4-dicarbonyl
compounds. It was anticipated that similar complications
would arise when the one-pot zinc-mediated chain exten-
sion reaction was applied to a-substituted b-keto amides.
Surprisingly, when N,N-dibenzyl 2-methyl-3-oxo-butan-
Previous studies on the chain extension reaction7 had shown
that diethyl zinc could be used to form the zinc enolate of a
b-keto phosphonate. Addition of the zinc enolate generated
in this fashion to a solution of the zinc carbenoid provided
the chain-extended product. When this variation was
applied to the a-substituted substrate 15, neither ethane
gas evolution nor g-keto amide products were observed.
When 1-'2-methyl-1,3-dioxobutyl)pyrrolidine 16 was
treated with one equivalent of neat diethyl zinc and the
1
solvent removed under reduced pressure, a H NMR spec-
trum of the crude residue revealed no evidence of enolate
formation. For comparison, the same procedure was applied
to the a-unsubstituted b-keto amide 9a. In this case the H
1
NMR spectrum showed clearly that the expected enolate
had been formed, although some starting material 9a was
also evident. A lactam, 3-benzoyl-1-methyl-2-pyrrolidone
18, was subjected to chain extension reaction conditions.
A 1H NMR of the crude reaction mixture showed a mixture
of starting material and the desired chain-extended product
19. By extending the reaction time to 2 h, starting material
was fully consumed and the pure chain-extended product
was obtained in 58% yield 'Scheme 4).
Scheme 3.

8796
R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
of starting material, enolate, and dissolved ethane gas.
While the intermediacy of a zinc enolate appears to be a
suf®cient for the reaction, an intermediate enol form18 will
experience similar destabilizing interactions to those of the
enolate 'Scheme 6).
In contrast to the tertiary amides, a-substituted secondary
amides were expected to react when subjected to chain
extension reaction conditions, since steric interactions
between the single substituent on the nitrogen and the
a-substituent could be avoided by placement of the amide
alkyl substituent syn to the amide carbonyl. Indeed, the
behavior of N-cyclohexyl 2-methyl-3-oxo-butanamide 20
was very different from that of the tertiary substrates.
When the reaction of 20 with 5 equiv. of the zinc carbenoid
was allowed to proceed for 30 min, an extremely complex
reaction mixture was observed. Efforts to obtain cleaner
reaction mixtures and to consume starting material through
variation of carbenoid equivalents and variation of reaction
times from 30 s to 6 h were unsuccessful. Exposure of an
a-substituted primary b-keto amide, 2-oxocyclohexane-
carboxamide 21, to chain extension reaction conditions
also provided a complex mixture which included signi®cant
amounts of starting material. The rapid consumption of the
`excess' zinc carbenoid by the chain extension intermediate
appears to be responsible for the complex reaction mixtures,
consisting of higher molecular weight materials. One
explanation for this behavior is that the presence of the
a-substituent promotes isomerization of a relatively unreac-
tive carbon-bound zinc intermediate 2219 to a more reactive
O-metallated species 23. This nucleophilic O-metallated
species reacts with various electrophilic species to produce
a complex array of products, including homologated
products. The lack of reactivity of an a-disubstituted
secondary b-keto amide 24 with the zinc carbenoid demon-
strates that the complex reaction mixtures observed with 20
and 21 were not due to the presence of the secondary amide
nitrogen.
Scheme 5.
Scheme 6.
The inability of the unreactive a-substituted substrates to
form enolates is consistent observations of Evans and
coworkers.17 They reported that a-substituted b-keto imides
exhibited surprisingly low acidity as evidenced by their
resistance to epimerization and H±D exchange in acidic
and weakly basic media. The low acidity was attributed to
the predisposition of the acyclic methine hydrogen to lie
nearly orthogonal to the p-system of the adjacent imide
carbonyl function in order to minimize A'1,3) steric inter-
actions 'Scheme 5).
A b-keto imide was used to further test the limitations of the
chain extension reaction 'Scheme 7). N-Acetyl acetoaceta-
mide 25 was prepared by reacting diketene with acetamide
in the presence of pyridine. Exposure of 25 to the zinc
carbenoid for 15 min gave the chain-extended product 26
in 47% yield. Although it had been feared that the enhanced
acidity of the imide hydrogen would interfere with the chain
extension reaction, the successful preparation of 26 indi-
cated that the presence of acidic protons does not forecast
failure. The conclusion that imide functionality, isosteric
with the b-dicarbonyl functionality, does not participate
in the zinc-mediated reaction was tested by the reaction of
two imides, succinimide and diacetamide. Both of these
substrates failed to react when exposed to the zinc carbenoid
and returned only starting material. The successful chain
extension of the b-keto imide 25, but not of the two imides,
The suggestion that enolate formation was involved in chain
extension was supported by the NMR investigation of the
sole a-substituted-b-keto amide '18) that underwent chain
extension. Treatment of a CDCl3 solution of a-benzoyl
lactam 18 with diethyl zinc resulted in the evolution of a
gas and provided a 1H NMR spectrum that showed a mixture
Scheme 7.
Scheme 8.

R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
8797
suggest that acidity alone is not a predictor of success
'Scheme 8).
dibenzylamine. The reaction mixture was heated with
stirring in a 1608C oil bath for 3h and the methanol by-
product of the reaction was removed by distillation. The
reaction mixture was cooled, diluted with diethyl ether,
and neutralized with dilute hydrochloric acid. The organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The
residue was chromatographed on silica '5:1, hexanes/ethyl
acetate; Rfˆ0.25) to yield 262 mg '27%) of b-keto amide 13
as a clear yellow oil. Ketone and enol tautomers were
3. Conclusion
In conclusion, the reaction of b-keto amides with the
Furukawa reagent provides access to a wide variety of
g-keto amides, including primary, secondary, and tertiary
amides. Although the reactivity of the a-substituted b-keto
amides is in many cases unsatisfactory, the method can be
applied to a broad spectrum of substrates that possess imide
and ole®nic functionality. Efforts are underway to further
extend this chain extension reaction to amides systems of
biological relevance.
1
present in a 90:10 ratio: H NMR '360 MHz, CDCl3) d
14.80 's, 1H, enol), 7.02±7.50 'm, keto and enol aromatic
protons), 5.72±5.84 'm, keto and enol), 5.20 's, 1H, enol),
4.94±5.04 'm, keto and enol), 4.61±4.62 'm, keto and enol
benzylic protons), 4.41 'm, keto and enol benzylic protons),
3.61 's, 2H, keto), 2.67 'm, keto and enol), 2.26±2.37 'm,
keto and enol); 13C NMR '90 MHz, CDCl3) d 203.7, 178.0,
172.0, 167.5, 136.7, 136.0, 129.1, 128.9, 128.7, 128.4,
128.1, 127.9, 127.5, 126.7, 126.4, 115.6, 50.6, 49.2, 48.4,
42.3, 35.3, 30.5, 27.5 'both keto and enol forms); IR '®lm)
3100±2900, 1717, 1700, 1653, 1636, 1457; HRMS 'EI) M1
Calcd for C21H23NO2: 321.1727, found: 321.1732.
4. Experimental
4.1. General
All reactions were run in oven-dried glassware under nitro-
gen atmosphere and stirred with te¯on-coated magnetic
stir-bars. The terms concentrated in vacuo or under reduced
pressure refer to the use of a rotary-evaporator. Tetrahydro-
furan and diethyl ether were distilled from purple benzo-
phenone ketyl prior to use. Methylene chloride was distilled
from phosphorous pentoxide. Ethyl acetate and hexanes
were distilled prior to use. Reagents were purchased from
commercial suppliers and used without further puri®cation.
Diethyl zinc was used as a 1.0 M solution in hexanes.
Methylene iodide 'CH2I2) was purchased from commercial
suppliers and non-oxidized copper wire was added as a
stabilizer. Column chromatography was performed on EM
Science ¯ash silica gel '35±75 mm). Mobile phases were
used as noted. Thin Layer Chromatography 'TLC) was
carried out on EM Science F254 glass plates and visualized
by UV and anisaldehyde or phosphomolybdic acid stains.
The Rf values were determined with the same solvent used
for column chromatography. Melting points were deter-
mined using an Electrothermal 9100 digital melting point
apparatus and are uncorrected. Low Resolution Mass
Spectroscopy were performed by the University of New
Hampshire Instrumentation Center on a Perkin±Elmer
2400 Analyzer. High Resolution Mass Spectroscopy was
performed at the University of California Riverside Mass
Spectrometry Facility.
4.2.2. N,N-Dibenzyl 2-methyl-3-oxo-butanamide 015). A
25 mL round-bottom ¯ask was equipped with a stir bar,
attached to a distillation head, and charged with 3.6 g
'25.0 mmol) of ethyl 2-methyl-acetoacetate and 4.92 g
'25.0 mmol) of dibenzylamine. The reaction mixture was
heated with stirring in a 1608C oil bath for 3h and the
ethanol by-product of the reaction was removed by distil-
lation. The reaction mixture was cooled, diluted with diethyl
ether, and neutralized with dilute hydrochloric acid. The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The residue was chromatographed on silica '3:1, hexanes/
ethyl acetate; Rfˆ0.25) to yield 5.02 g '68%) of b-keto
amide 15 as a viscous yellow oil. Only the ketone tautomer
was evident by NMR: 1H NMR '360 MHz, CDCl3) d 7.15±
7.40 'm, 10H), 4.88 'd, 1H, Jˆ15.7 Hz), 4.59 'd, 1H, Jˆ
17.4 Hz), 4.42 'd, 1H, Jˆ15.7 Hz), 4.37 'd, 1H, Jˆ17.4 Hz),
3.66 'q, 1H, Jˆ6.9 Hz), 2.17 's, 3H), 1.42 'd, 3H, Jˆ
6.9 Hz); 13C NMR '90 MHz, CDCl3) d 205.0, 171.2,
137.0, 136.2, 129.1, 128.7, 128.2, 127.9, 127.6, 126.3,
51.6, 50.1, 48.6, 27.4, 14.1; IR '®lm) 3100±2850, 1725,
1653, 1600, 1496, 1455, 1420, 1357; HRMS 'EI) M1
Calcd for C19H21NO2: 295.1572, found: 295.1566.
4.2.3. 1-02-Methyl-1,3-dioxobutyl)pyrrolidine 016). A
100 mL two-necked round-bottom ¯ask was equipped
with a stir bar and a re¯ux condenser and charged with
30 mL of absolute ethanol. Sodium metal '460 mg,
20.0 mmol) was added slowly under nitrogen. When the
sodium had reacted completely, 1-'1,3-dioxobutyl)pyrro-
lidine 9a '2.95 g, 19.0 mmol) was added to the ¯ask by
syringe and the solution was heated to re¯ux using a heating
mantle. Methyl iodide '2.84 g, 20.0 mmol) was added drop-
wise and re¯uxing was continued for 12 h. The reaction
mixture was cooled and the ethanol was removed under
reduced pressure. The residue was diluted with ethyl
acetate, washed with saturated aqueous ammonium chloride
and brine, dried over anhydrous sodium sulfate, and concen-
trated under reduced pressure. The residue was chromato-
graphed on silica 'ethyl acetate; Rfˆ0.3) to yield 1.65 g
4.2. Starting material preparation
Starting materials 9a,20 9b,20 9c,21 9d,22 9h,20 9i,21 9j,23 11,23
and 2524 were prepared by reaction of diketene with the
appropriate amine. Starting materials 9e25 and 9f,25 were
prepared by treating a b-keto ester with the corresponding
amine. Starting material 1826 and 9g25 were prepared by a
Claisen reaction. Compound 2027 was prepared by methyl-
ation of the b-keto amide 9h. Compound 21 was prepared
by a literature procedure.28
4.2.1. N,N-Dibenzyl 3-oxo-6-heptenamide 013). A 25 mL
round-bottom ¯ask was equipped with a stir bar, attached to
a distillation head, and charged with 468 mg '3.0 mmol) of
methyl 3-oxo-6-heptenoate29 and 591 mg '3.0 mmol) of

8798
R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
'51%) of a-methyl b-keto amide 16 as a clear colorless
liquid. Only the ketone tautomer was evident by NMR: H
solution was cooled to 08C and methylene iodide '0.40 mL,
5.0 mmol) in methylene chloride '2.5 mL) was added drop-
wise. The resulting white suspension was stirred for 10 min,
then 1-'1,3-dioxobutyl)pyrrolidine 9a '155 mg, 1.0 mmol)
was added rapidly by syringe. The mixture was stirred for
30 min at 08C, quenched with saturated aqueous ammonium
chloride, and extracted three times with ethyl acetate. The
combined organic extracts were washed with brine, dried
over anhydrous sodium sulfate, ®ltered, and concentrated
under reduced pressure. The residue was chromatographed
on silica 'ethyl acetate; Rfˆ0.2) to yield 79 mg '47%) of
g-keto amide 10a as a clear colorless liquid that provided
spectra consistent with those reported in the literature.26 1H
NMR '360 MHz, CDCl3) d 3.41±3.49 'm, 4H), 2.80 't, 2H,
Jˆ6.5 Hz), 2.53't, 2H, Jˆ6.5 Hz), 2.22 's, 3H), 1.92±2.00
'm, 2H), 1.81±1.89 'm, 2H); 13C NMR '90 MHz, CDCl3) d
208.1, 170.0, 46.4, 45.7, 37.9, 30.2, 28.4, 26.0, 24.4; IR
'®lm) 2975±2875, 1716, 1627, 1455, 1367, 1167.
1
NMR '360 MHz, CDCl3) d 3.42±3.56 'm, 5H), 2.19 's, 3H),
1.84±1.92 'm, 2H), 1.95±2.05 'm, 2H), 1.37 'd, 3H, Jˆ
7.1 Hz); 13C NMR '90 MHz, CDCl3) d 205.4, 168.5, 53.6,
46.9, 46.1, 27.1, 26.1, 24.3, 13.3; IR '®lm) 3000±2850,
1718, 1635, 1457, 1438; HRMS 'EI) M1 Calcd for
C9H15NO2: 169.1103, found: 169.1106.
4.2.4. 2-Oxo-cyclohexanecarboxylic acid dibenzylamide
017). A 25 mL round-bottom ¯ask was equipped with a stir
bar, attached to a distillation head, and charged with 4.25 g
'25.0 mmol) of ethyl 2-cyclohexanonecarboxylate and
4.92 g '25.0 mmol) of dibenzylamine. The reaction mixture
was heated with stirring in a 1608C oil bath for 3h and the
ethanol by-product of the reaction was removed by distil-
lation. The reaction mixture was cooled, diluted with diethyl
ether, and neutralized with dilute hydrochloric acid. The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The solid residue was recrystallized from 95% ethanol to
yield 2.60 g '32%) of b-keto amide 17 as a white solid
'mpˆ141.5±142.58C). Only the ketone tautomer was
4.3.2. N,N-Dibutyl 4-oxo-pentanamide 010b). In the same
fashion as described above, N,N-dibutyl 3-oxo-butanamide
9b was treated with 5 equiv. of the Furukawa reagent for
45 min at 08C. After aqueous work-up the crude residue was
chromatographed on silica '3.5:1, hexanes/ethyl acetate;
Rfˆ0.2) to yield 70% of g-keto amide 10b as a clear color-
less liquid.3 0 1H NMR '360 MHz, CDCl3) d 3.23±3.33 'm,
4H), 2.78 't, 2H, Jˆ6.4 Hz), 2.59 't, 2H, Jˆ6.4 Hz), 2.23's,
3H), 1.44±1.60 'm, 4H), 1.25±1.37 'm, 4H), 0.89±0.97 'm,
6H); 13C NMR '90 MHz, CDCl3) d 207.7, 170.6, 47.3, 45.5,
37.9, 30.6, 29.8, 29.5, 26.7, 19.9, 19.8, 13.53, 13.49; IR
'®lm) 2960, 2932, 1718, 1631, 1457; HRMS 'EI) M1
Calcd for C13H25NO2: 227.1885, found: 227.1881.
1
evident by NMR: H NMR '360 MHz, CDCl3) d 7.11±
7.39 'm, 10H), 5.24 'd, 1H, Jˆ15.1 Hz), 4.44 'd, 1H, Jˆ
17.4 Hz), 4.23'd, 1H, Jˆ17.4 Hz), 4.06 'd, 1H, Jˆ15.1 Hz),
3.59 'dd, 1H, Jˆ10.7, 5.7 Hz), 2.57 'm, 1H), 2.26±2.39 'm,
2H), 2.13'm, 1H), 2.00±2.03'm, 2H), 1.84 'm, 1H), 1.63
'm, 1H); 13C NMR '90 MHz, CDCl3) d 207.6, 170.5, 136.9,
136.5, 129.0, 128.6, 127.9, 127.7, 127.3, 126.3, 54.6, 49.9,
48.4, 42.0, 30.5, 27.0, 23.7; IR 'KBr) 3100±2850, 1710,
1652, 1600, 1495, 1455, 1419; HRMS 'EI) M1 Calcd for
C21H23NO2: 321.1727, found: 321.1733.
4.3.3. N-Phenyl-N-methyl 4-oxo-pentanamide 010c). In
the same fashion as described above N-phenyl-N-methyl
3-oxo-butanamide 9c '191 mg, 1.0 mmol) was treated
with 5 equiv. of the Furukawa reagent for 30 min at 08C.
Afer aqueous work-up, the crude residue was chromato-
graphed on silica '1:1, hexanes/ethyl acetate; Rfˆ0.2) to
4.2.5. N-Cyclohexyl 2,2-dimethyl-3-oxo-butanamide 024).
A 50 mL round-bottom ¯ask was equipped with a stir bar
and charged with 15 mL of anhydrous benzene, 7.5 mL of
freshly distilled dimethylformamide, and sodium hydride
'48 mg of a 60% dispersion in mineral oil, 1.2 mmol). The
mixture was cooled to 108C, then N-cyclohexyl-2-methyl-3-
oxo-butanamide 20 '197 mg, 1.0 mmol) was dissolved in
1 mL of dimethylformamide and added by syringe. After
stirring for 30 min, methyl iodide '284 mg, 2.0 mmol) was
added by syringe and the mixture was heated for 15 min in a
408C oil bath. The mixture was cooled, 10 mL of deionized
water was added, and after stirring for 10 min the two
phases were separated. The organic phase was washed
twice with brine, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure. The residue was
chromatographed on silica '1:1, hexanes/ethyl acetate;
Rfˆ0.3) to yield 175 mg '80%) of b-keto amide 24 as a
1
yield 88% of g-keto amide 10c as a clear yellow oil. H
NMR '360 MHz, CDCl3) d 7.41±7.45 'm, 2H), 7.32±7.36
'm, 1H), 7.24±7.28 'm 2H), 3.26 's, 3H), 2.71 't, 2H, Jˆ
6.3Hz), 2.31 't, 2H, Jˆ6.3Hz), 2.17 's, 3H); 13C NMR
'90 MHz, CDCl3) d 207.7, 171.8, 143.9, 129.8, 127.9,
127.4, 38.4, 37.3, 30.0, 28.3; IR '®lm) 3100±2900, 1717,
1654, 1596, 1497, 1389; HRMS 'EI) MH1 Calcd for
C12H14NO2: 205.1103, found: 205.1105; HRMS 'EI) M1
Calcd for C12H15NO2: 205.1102, found: 205.1102.
4.3.4. N,N-Dimethyl 4-oxo-pentanamide 010d). In a
similar fashion as described above, N,N-dimethyl 3-oxo-
butanamide 9d was treated with 3equiv. of the Furukawa
reagent for 15 min at 08C. After aqueous work-up, the resi-
due was chromatographed on silica '1.5:1, hexanes/acetone;
Rfˆ0.2) to yield 60% of g-keto amide 10d as a clear color-
less liquid. 1H NMR '360 MHz, CDCl3) d 3.03 's, 3H), 2.93
's, 3H), 2.77 't, 2H, Jˆ6.4 Hz), 2.59 't, 2H, Jˆ6.4 Hz), 2.22
's, 3H); 13C NMR '90 MHz, CDCl3) d 208.1, 171.5, 38.1,
37.0, 36.0, 30.2, 27.2; IR '®lm) 3000±2800, 1725, 1625;
HRMS 'EI) M1 Calcd for C7H13NO2: 143.0946, found:
143.0944.
1
yellow oil. H NMR '360 MHz, CDCl3) d 5.69 's, 1H),
3.74 'm, 1H), 2.23 's, 3H), 1.83±1.87 'm, 2H), 1.58±1.71
'm, 3H), 1.36 's, 6H), 1.02±1.34 'm, 5H); 13C NMR
'90 MHz, CDCl3) d 209.4, 171.0, 56.0, 48.5, 32.7, 26.0,
25.4, 24.7, 22.3; IR '®lm) 3325, 2950±2800, 1750, 1675.
4.3. Chain extension reactions
4.3.1. 1-01,4-Dioxopentyl)pyrrolidine 010a). A 50 mL
round-bottom ¯ask was equipped with a stir bar and charged
with 15 mL of methylene chloride and diethyl zinc '1.0 M in
hexanes, 5.0 mL, 5.0 mmol) under an inert atmosphere. The
4.3.5. N,N-Dibenzyl 4-oxo-4-phenyl-butanamide 010e). In

R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
8799
the same fashion as described above, N,N-dibenzyl 3-oxo-3-
phenyl-propanamide 9e was treated with 4 equiv. of the
Furukawa reagent for 30 min at 08C. After aqueous work-
up, the solid residue was recrystallized in 95% ethanol to
yield 42% of g-keto amide 10e as a white crystalline solid
diethyl ether to yield 33% of g-keto amide 5i as a white
solid 'mpˆ100.5±101.48C; lit mpˆ99±1008C) that was
4
1
consistent with the literature.3 H NMR '360 MHz,
CDCl3) d 7.80 's, 1H), 7.48±7.50 'm, 2H), 7.26±7.31 'm,
2H), 7.06±7.10 'm 1H), 2.88 't, 2H, Jˆ6.2 Hz), 2.61 't, 2H,
Jˆ6.2 Hz), 2.21 's, 3H); 13C NMR '90 MHz, CDCl3) d
208.0, 170.3, 137.9, 128.9, 124.1, 119.7, 38.6, 31.1, 30.0;
IR 'KBr) 3355, 3200±2800, 1725, 1679, 1546.
'mpˆ85.0±86.58C; lit mpˆ84±858C).3 H NMR '360
MHz, CDCl3) d 8.02±8.10 'm, 2H), 7.21±7.61 'm, 13H),
4.62 's, 2H), 4.57 's, 2H), 3.43 't, 2H, Jˆ6.4 Hz), 2.90 't,
2H, Jˆ6.4 Hz); 13C NMR '90 MHz, CDCl3) d 199.1, 172.4,
137.3, 136.8, 136.4, 133.1, 129.0, 128.6, 128.5, 128.2,
128.1, 127.6, 127.4, 126.6, 49.9, 48.4, 33.8, 27.3.
1
1
4.3.10. 4-Oxo-pentanamide 010j). In a similar fashion to
that described above, acetoacetamide 9j was treated with
4 equiv. of the Furukawa reagent for 30 min at 08C. After
an aqueous work-up, the residue was chromatographed on
silica '1:1, hexanes/acetone; Rfˆ0.2) to yield 10% of g-keto
amide 10j as a clear colorless oil that provided spectra
consistent with those reported in the literature.3 5 H1 NMR
'360 MHz, CDCl3) d 5.65 's, 1H), 5.38 's, 1H), 2.81 't, 2H,
Jˆ6.4 Hz), 2.25 't, 2H, Jˆ6.4 Hz), 2.20 's, 3H).
4.3.6. N,N-Dibenzyl 5,5-dimethyl-4-oxo-hexanamide 010f).
In the same fashion as described above, N,N-dibenzyl 4,4-
dimethyl-3-oxo-pentanamide 9f was treated with 4 equiv. of
the Furukawa reagent for 30 min at 08C. After an aqueous
work-up, the residue was chromatographed on silica '10:1,
hexanes/ethyl acetate; Rfˆ0.2) to yield 60% of g-keto amide
1
10f as a white solid 'mpˆ74.5±75.58C). H NMR '360
MHz, CDCl3) d 7.18±7.39 'm, 10H), 4.59 's, 2H), 4.52 's,
2H), 2.94 't, 2H, Jˆ6.3Hz), 2.68 't, 2H, Jˆ6.3Hz), 1.20 's,
9H); 13C NMR '90 MHz, CDCl3) d 214.9, 172.4, 137.2,
136.4, 128.9, 128.5, 128.0, 127.5, 127.2, 126.5, 49.8, 48.2,
43.9, 32.0, 27.0, 26.6; IR 'KBr) 3100±2850, 1703, 1647;
HRMS 'CI/NH3) MH1 Calcd for C22H28NO2: 338.2120,
found: 338.2127.
4.3.11. N-02-Propenyl) 4-oxo-pentanamide 012). In a
similar fashion to that described above, N-'2-propenyl)
3-oxo-butanamide 11 was treated with 5 equiv. of diethyl
zinc and methylene iodide for 15 min at 08C. After an
aqueous work-up, the residue was chromatographed on
silica 'ethyl acetate; Rfˆ0.3) to yield 55% of g-keto
1
amide 12 as a clear colorless liquid. H NMR '360 MHz,
CDCl3) d 5.93's, 1H), 5.82 'ddt, 1H, Jˆ17.2, 10.2, 5.5 Hz),
5.18 'dd, 1H, Jˆ17.2, 1.4 Hz), 5.12 'dd, 1H, Jˆ10.2,
1.4 Hz), 3.84±3.88 'm, 2H), 2.82 't, 2H, Jˆ6.4 Hz), 2.45
't, 2H, Jˆ6.4 Hz), 2.19 's, 3H); 13C NMR '90 MHz, CDCl3)
d 207.9, 171.7, 134.1, 116.3, 42.0, 38.6, 29.94, 29.88; IR
'®lm) 3300, 1717, 1700, 1653, 1559, 1541; HRMS 'EI) M1
Calcd for C8H13NO2: 155.0496, found: 155.0551.
4.3.7. N,N-Dimethyl 4-oxo-4-phenyl-butanamide 010g).
In a similar fashion to that described above, N,N-dimethyl
3-oxo-3-phenyl-propanamide 9g was treated with 3equiv.
of the Furukawa reagent for 15 min at 08C. Following an
aqueous work-up, the residue was chromatographed on
silica '2:1, hexanes/acetone; Rfˆ0.15) to yield 59% of
g-keto amide 10g of a clear yellow oil which provided
spectra consistent with those reported in the literature.32
1H NMR '360 MHz, CDCl3) d 8.00±8.04 'm, 2H), 7.52±
7.58 'm, 1H), 7.43±7.48 'm, 2H), 3.35 't, 2H, Jˆ6.6 Hz),
3.09 's, 3H), 2.96 's, 3H), 2.77 't, 2H, Jˆ6.6 Hz); 13C NMR
'90 MHz, CDCl3) d 199.3, 171.7, 136.9, 133.0, 128.5,
128.1, 37.1, 35.5, 33.7, 27.3; IR '®lm) 3100±2900, 1685,
1647.
4.3.12. N,N-Dibenzyl 4-oxo-7-octenamide 014). In a
similar fashion to that described above, N,N-dibenzyl
3-oxo-6-heptenamide 13 was treated with 5 equiv. of the
Furukawa reagent for 30 min at 08C. After an aqueous
work-up, the residue was chromatographed on silica '5:1,
hexanes/ethyl acetate; Rfˆ0.2) to yield 70% of g-keto amide
1
14 as a clear yellow oil. H NMR '360 MHz, CDCl3) d
7.18±7.40 'm, 10H), 5.81 'ddt, 1H, Jˆ16.9, 10.1, 6.5 Hz),
5.04 'dd, 1H, Jˆ16.9, 1.6 Hz), 4.98 'dd, 1H, Jˆ10.1,
1.6 Hz), 4.58 's, 2H), 4.49 's, 2H), 2.82 't, 2H, Jˆ6.2 Hz),
2.72 't, 2H, Jˆ6.2 Hz), 2.62 't, 2H, Jˆ7.4 Hz), 2.34±2.40
'm, 2H); 13C NMR '90 MHz, CDCl3) d 209.1, 172.2, 137.2,
136.4, 129.0, 128.6, 128.2, 127.6, 127.4, 126.5, 115.2, 49.9,
48.3, 42.0, 37.4, 27.8, 27.1; IR '®lm) 3100±2900, 1713,
1650; HRMS 'CI/NH3) MH1 Calcd for C22H26NO2:
336.1963, found: 336.1971.
4.3.8. N-Cyclohexyl 4-oxo-pentanamide 010h). In a
similar fashion to that described above, N-cyclohexyl
3-oxo-butanamide 9h was treated with 5 equiv. of the
Furukawa reagent for 30 min at 08C. After an aqueous
work-up, the residue was chromatographed on silica '1:1,
hexanes/ethyl acetate; Rfˆ0.2) to yield 81% of g-keto amide
10h as a white solid 'mpˆ105.7±106.58C) that provided
spectra consistent with those reported in the literature.33
1H NMR '360 MHz, CDCl3) d 5.57 's, 1H), 3.67±3.78
'm, 1H), 2.79 't, 2H, Jˆ6.5 Hz), 2.39 't, 2H, Jˆ6.5 Hz),
2.18 's, 3H), 1.85±1.94 'm, 2H), 1.65±1.74 'm, 2H),
1.56±1.65 'm, 1H), 1.28±1.41 'm, 2H), 1.06±1.22 'm,
3H); 13C NMR '90 MHz, CDCl3) d 207.5, 171.0, 48.2,
38.7, 33.1, 30.2, 30.0, 25.5, 24.8; IR 'KBr) 3295, 2934,
2854, 1709, 1632, 1558, 1436.
4.3.13. 1-Methyl-3-phenacyl-2-pyrrolidone 019). In a
similar fashion to that described above, 3-benzoyl-1-
methyl-2-pyrrolidone 18 was treated with 4 equiv. of the
Furukawa reagent for 2 h at 08C. After aqueous work-up,
the residue was chromatographed on silica '2:1, hexanes/
acetone; Rfˆ0.2) to yield 58% of g-keto amide 19 as a clear
yellow oil which provided spectra consistent with those
reported in the literature.3 6 H1 NMR '360 MHz, CDCl3) d
7.97±7.99 'm, 2H), 7.54±7.60 'm, 1H), 7.43±7.49 'm, 2H),
3.71 'm, 1H), 3.30±3.43 'm, 2H), 2.94±3.05 'm, 2H), 2.89
's, 3H), 2.48 'm, 1H), 1.68 'm, 1H); 13C NMR '90 MHz,
CDCl3) d 198.3, 175.8, 136.6, 133.2, 128.6, 128.0, 47.7,
4.3.9. N-Phenyl 4-oxo-pentanamide 010i). In a similar
fashion to that described above, then N-phenyl 3-oxo-
butanamide 9i '531 mg, 3.0 mmol) was treated with
3equiv. of the Furukawa reagent for 30 min at 0 8C. After
aqueous work-up, the solid residue was recrystallized in

8800
R. Hilgenkamp, C. K. Zercher / Tetrahedron 57 +2001) 8793±8800
12. Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50 '14),
2431±2435.
40.7, 37.7, 29.9, 25.7; IR '®lm) 3100±2850, 1685 'broad),
1600, 1500, 1460, 1410, 1275; HRMS 'EI) M1 Calcd for
C13H15NO2: 217.1103, found: 217.1107.
13. 'a) Malmberg, W.-D.; Voss, J.; Weinschneider, S. Liebigs
Ann. Chem. 1983, 1694±1711. 'b) Ley, S. V.; Woodward,
P. R. Tetrahedron Lett. 1987, 28, 3019±3020.
14. Lasley, L. C.; Wright, B. B. Synth. Commun. 1989, 19, 59±62.
15. Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992, 1213±
1214.
4.3.14. N-Acetyl 4-oxo-pentanamide 026). In a similar
fashion, N-acetyl acetoacetamide 25 was treated with
3equiv. of the Furukawa reagent for 15 min at 0 8C. After
an aqueous work-up, the residue was chromatographed on
silica '1.5:1, hexanes/ethyl acetate; Rfˆ0.3) to yield 47% of
16. Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968,
24, 53±58.
1
g-keto imide 26 as a white solid 'mpˆ111.3±112.68C). H
NMR '360 MHz, CDCl3) d 8.86 's, 1H), 2.80 's, 4H), 2.33
's, 3H), 2.22 's, 3H); 13C NMR '90 MHz, CDCl3) d 207.0,
173.0, 172.0, 37.2, 31.1, 29.9, 25.0; IR '®lm) 3250, 3150,
1735, 1715, 1701; HRMS 'CI/CH4) M1 Calcd for
C7H11NO3: 219.1259, found: 219.1255.
17. Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G.
J. Am. Chem. Soc. 1984, 106 '4), 1154±1156.
18. The possibility that the enol form reacts to give the inter-
mediate cyclopropane cannot be dismissed.
19. The proposed intermediate 22 is similar to a Reformatsky
reagent 'see compound 4), which has been demonstrated to
be dimeric in non-polar solvents. An alternate explanation
would be to propose a stable dimeric species which is de-
stabilized 'made more reactive) by the presence of a-sub-
stituents.
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