Convenient and efficient syntheses of β-keto esters and β-keto amides directly from α-alkylacetyl chlorides

Article abstract of DOI:10.1081/SCC-100105878

The α-alkylacetyl chlorides were slowly treated with dried triethylamine, followed by treatment with alcohols or amines, to produce β-keto esters or β-keto amides, respectively. The process is a convenient alternative to prepare β-keto esters and β-keto amides.

Full text of DOI:10.1081/SCC-100105878

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CONVENIENT AND EFFICIENT SYNTHESES OF β-KETO
ESTERS AND β-KETO AMIDES DIRECTLY FROM α-
ALKYLACETYL CHLORIDES
Kuangsen Sung a & Shin-Yi Wu a
a Department of Chemistry, National Cheng Kung University, Tainan, Taiwan, ROC
Published online: 16 Aug 2006.
To cite this article: Kuangsen Sung & Shin-Yi Wu (2001) CONVENIENT AND EFFICIENT SYNTHESES OF β-KETO ESTERS AND β-
KETO AMIDES DIRECTLY FROM α-ALKYLACETYL CHLORIDES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:20, 3069-3074, DOI: 10.1081/SCC-100105878
To link to this article: http://dx.doi.org/10.1081/SCC-100105878
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SYNTHETIC COMMUNICATIONS, 31(20), 3069–3074 (2001)
CONVENIENT AND EFFICIENT
SYNTHESES OF b-KETO ESTERS
AND b-KETO AMIDES DIRECTLY
FROM a-ALKYLACETYL
CHLORIDES
Kuangsen Sung* and Shin-Yi Wu
Department of Chemistry, National Cheng Kung
University, Tainan, Taiwan, ROC
ABSTRACT
The ꢀ-alkylacetyl chlorides were slowly treated with dried
triethylamine, followedby treatment with alcohols or amines,
to produce b-keto esters or b-keto amides, respectively. The
process is a convenient alternative to prepare b-keto esters
and b-keto amides.
The b-keto esters are useful functional groups since they serve as
synthons of several function groups. Regioselective alkylations or acylations
of the b-keto esters, followed by ester hydrolysis and decarboxylation, may
1a
produce ꢀ-substitutedketones.
Reduction of ketone functional group of
the b-keto esters leads to b-hydroxyl esters1a,b or esters.1a,c
*Corresponding author.
3069
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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SUNG AND WU
Recently asymmetric construction of carbon–carbon bondis one of
hot topics in chemistry.2 Construction of chiral b-dicarbonyl synthon, chiral
b-keto amides, was successfully carried out.3 That involvedhighly diaster-
eoselective acylation reactions of chiral amide enolate anions with acid
chlorides via Claisen condensation.3
Normally the b-keto esters are preparedby Claisen or Dieckmann
condensation reactions, involving reactions of ester enolate anions with
1,4
other esters or acidchlorides.
They couldbe preparedby Reformatsky
reaction too, but the yields were quite low.5 The communication reports an
efficient, convenient, andalternative methodto prepare the b-keto esters
and b-keto amides directly from ꢀ-alkylacetyl chlorides.
In the case of preparation of b-keto esters, one equivalent of dried
triethylamine in dried ethyl ether was slowly added to ꢀ-alkylacetyl chloride
in dried ethyl ether at 0ꢀC. The triethylamine serves as a base andremoves
a proton on ꢀ-carbon of the acid chloride to generate a corresponding
ketene 1 in situ with a precipitate of triethylammonium chloride.6b
(Scheme 1) Since the ketene 1 is unstable andvery easy to hydrolyze, it
is better not to be isolated. After the reaction was run for two more days
at room temperature, the ketene 1 was dimerized to b-lactone 2. To prove
structure of the b-lactone 2 which was formedas an intermeidate in
the whole process, the solution was filteredandthe b-lactone 2 in the filtrate
was purifiedandidentified. Alternatively, it is not necessary to isolate the
intermediate 2 in order to make b-keto esters 3, but the filtrate is added
directly to a solution of an excess alcohol in the presence of sodium acetate
catalyst under reflux to produce a corresponding b-keto ester 3. Regarding
preparation of b-keto amides 4 and 5, the same procedure was applied to
prepare the ketene dimer, b-lactone 2. After removal of triethylammonium
chloride by filtration, the filtrate was slowly added into a solution of one
equivalent of amine to produce the corresponding b-keto amide 4 and 5.
(Scheme 1)
Suitable acidchlorides for the reaction are
ꢀ-alkylacetyl chlorides
with two hydrogen atoms on Cꢀ. In a case of ꢀ-arylacetyl chloride, aryl-
ketene forms on treatment with triethylamine, but the arylketene produces a
pyronone-type trimer at this condition.6a,b In a case of ꢀ,ꢀ-disubstituted
acetyl chlorides, the corresponding disubstituted ketenes form on treatment
with triethylamine, followed by dimerization of the ketenes to produce
cyclobutane-1,3-dione dimers, instead of b-lactone dimers.6b–d Therefore,
neither ꢀ-arylacetyl chloride nor ꢀ,ꢀ-disubstituted acetyl chlorides are
suitable starting materials to prepare b-keto esters and b-keto amides by
the method. The following are typical procedures to prepare b-lactones 2,
b-keto esters 3, and b-keto amides 4 and 5.

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b-KETO ESTERS AND b-KETO AMIDES
3071
Scheme 1.
EXPERIMENTAL
General
Unless otherwise statedreagents were obtainedfrom commercial sup-
pliers andusedas received. NMR spectra were obtainedusing Bruker-200
andBruker-400 NMR spectrometers. High resolution mass spectra were
taken on a VG-70250S mass spectrometer.
Preparation of 3-Alkyl-4-alkylidene-oxetan-2-one (2a,b)
To a solution of ꢀ-alkylacetyl chloride (17.0 mmol) in anhydrous ethyl
ether (5 mL) was added triethylamine (1.72 g, 17.0 mmol) in anhydrous ether
(34 mL) dropwise over a period of 1 hour with vigorous stirring at 0ꢀC
under nitrogen atmosphere. The solution was stirred for 2 more days at
room temperature. Triethylammonium chloride precipitated and was fil-
tered off under nitrogen atmosphere. After evaporation of solvent, the prod-
uct was purifiedby chromatotron moedl-8924 with a mobile phase of
hexane/ethyl acetate (15 : 1) to give the corresponding product 2. 2a: color-
less oil; isolatedyield: 59%; 1H NMR (CDCl3) d 1.38 (3H, d, CH3), 1.65
(3H, d, CH3), 3.93 (1H, q, CH), 4.69 (1H, q, CH); 13C NMR (CDCl3) d 8.21,
9.50, 28.53, 95.32, 147.25, 170.03 ppm; HRMS (EI) for C6H8O2 m/z calcd
112.0524, found112.0523. The compound 2a is known andits 1H NMR

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SUNG AND WU
spectrum has been reported.6a 2b: colorless oil; isolatedyiel:d 54%;
1H NMR (CDCl3) d 0.87 (6H, m, 2CH3), 1.40 (16H, m, 8CH2), 1.76 (2H,
m, CH2), 2.10 (2H, m, CH2), 3.93 (1H, t, CH), 4.69 (1H, t, CH); 13C NMR
(CDCl3) d 13.94, 13.98, 22.45, 22.54, 24.56, 26.21, 27.43, 28.66, 28.79, 29.27,
31.40, 31.51, 53.64, 101.61, 145.52, 169.71 ppm; HRMS (EI) for C6H8O2 m/z
calcd252.2089, found252.2088. The compound 2b is known andits NMR
spectra have not been reported.7a
Preparation of 2,4-Dialkyl-3-oxo-butanoic
Acid Methyl Ester (3a,b)
To a solution of ꢀ-alkylacetyl chloride (17.0 mmol) in anhydrous ethyl
ether (5 mL) was added triethylamine (1.72 g, 17.0 mmol) in anhydrous ether
(34 mL) dropwise over a period of 1 hour with vigorous stirring at 0ꢀC
under nitrogen atmosphere. The solution was stirred for 2 more days at
room temperature. Triethylammonium chloride precipitated and was fil-
tered off under nitrogen atmosphere. The filtrate was slowly added to a
solution of methanol (5 mL) andsodium acetate (2 mg) andthe solution
was refluxed under nitrogen atmosphere for one more day. After evapora-
tion of ether andmethanol, the product was purifiedby chromatotron
model-8924 with a mobile phase of hexane/ethyl acetate (15 : 1) to give the
corresponding b-keto ester 3. 3a: colorless oil; isolatedyield: 63%; 1H NMR
(CDCl3) d 1.07 (3H, t, CH3), 1.34 (3H, d, CH3), 2.46–2.66 (2H, m, CH2),
3.54 (1H, q, CH), 3.72 (3H, s, CH3). 13C NMR (CDCl3) d 7.52, 12.79, 34.59,
52.27, 171.06, 206.45. HRMS (EI) for C7H12O3 m/z calcd144.0786, found
144.0784. The compound 3a is known andits 1H NMR spectrum has been
reported.7b 3b: colorless oil; isolatedyield: 59%; 1H NMR (CDCl3) d 0.84
(6H, m, 2CH3), 1.24 (16H, m, 8CH2), 1.51 (2H, m, CH2), 1.83 (2H, m, CH2),
2.45 (2H, m, CH2), 3.41 (1H, t, CH), 3.69 (3H, s, OCH3). 13C NMR (CDCl3)
d 13.95, 13.98, 22.47, 22.53, 23.40, 23.84, 27.40, 28.24, 28.96, 29.03, 31.44,
31.59, 41.81, 52.17, 58.96, 170.41, 205.45. HRMS (EI) m/z calcdfor
C17H32O3 284.2351, found284.2350.
Preparation of N-Butyl-2,4-dialkyl-3-oxo-butyramide (4a,b)
and 2,4-Dialkyl-1-pyrrolidin-1-yl-butane-1,3-dione (5a,b)
To a solution of ꢀ-alkylacetyl chloride (17.4 mmol) in anhydrous ethyl
ether (5 mL) was added triethylamine (1.76 g, 17.4 mmol) in anhydrous ether
(35 mL) dropwise over a period of 1 hour with vigorous stirring at 0ꢀC
under nitrogen atmosphere. The solution was stirred for 2 more days

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b-KETO ESTERS AND b-KETO AMIDES
3073
at room temperature. Triethylammonium chloride precipitated and was
filtered off under nitrogen atmosphere. The filtrate was slowly added into
one equivalent of n-butyl amine or pyrrolidine (18 mmol), and the solution
was refluxed under nitrogen atmosphere for one more day. After evapora-
tion of ether andamine, the proudct was purifiedby chromatotron
model-8924 with a mobile phase of hexane/ethyl acetate (15 : 1) to give the
corresponding b-keto amide 4 and 5. 4a: pale yellow oil; isolatedyield: 65%;
1H NMR (CDCl3) d 0.87 (3H, t, CH3), 1.04 (3H, t, CH3), 1.27 (2H, m, CH2),
1.37 (3H, d, CH3), 1.47 (2H, m, CH2), 2.57 (2H, m, CH2), 3.21 (2H, m,
NCH2), 3.41 (1H, q, CH), 6.36 (1H, s, NH) ppm; 13C NMR (CDCl3) d 7.45,
13.63, 15.19, 19.93, 31.39, 34.77, 39.31, 54.03, 169.49, 210.58 ppm. HRMS
(EI) for C10H19NO2 m/z calcd185.1416, found185.1416. 4b: pale yellow oil;
isolatedyield: 66%; 1H NMR (CDCl3) d 0.87 (9H, m, 3CH3), 1.26 (18H, m,
9CH2), 1.30 (2H, m, CH2), 1.44 (2H, m, CH2), 1.80 (2H, m, CH2), 2.51 (2H,
m, CH2), 3.22 (2H, m, NCH2), 3.35 (1H, q, CH), 6.29 (1H, s, NH) ppm;
13C NMR (CDCl3) d 13.69, 14.01, 14.04, 14.11, 19.98, 22.50, 22.57, 22.64,
23.25, 27.39, 29.00, 31.36, 31.47, 31.57, 31.63, 39.28, 42.99, 60.83, 168.58,
210.70 ppm. HRMS (EI) for C20H39NO2 m/z calcd325.2980, found
325.2979. 5a: pale yellow oil; isolatedyield: 80%; 1H NMR (CDCl3) d 1.04
(3H, t, CH3), 1.37 (3H, d, CH3), 1.83–2.04 (4H, m, CH2), 2.43–2.63 (2H, m,
CH2), 3.45–3.60 (5H, m, CH andCH ) ppm; 13C NMR (CDCl3) d 7.66,
2
13.44, 24.27, 26.09, 32.79, 46.17, 46.91, 52.92, 168.79, 208.02 ppm. HRMS
(EI) for C10H17NO2 m/z calcd183.1259, found183.1260. The compound 5a
is known andits 1H NMR spectrum has been reported.7b 5b: pale yellow oil;
isolatedyield: 94%; 1H NMR (CDCl3) d 0.83 (6H, m, 2CH3), 1.12 (16H, m,
8CH2), 1.44 (2H, m, CH2), 1.85 (6H, m, CH2), 2.44 (2H, t, CH2), 3.35–3.43
(5H, m, CH andCH 2) ppm; 13C NMR (CDCl3) d 13.92, 13.95, 22.46, 22.48,
23.36, 24.18, 25.99, 27.60, 28.85, 28.92, 28.96, 29.06, 31.47, 31.58, 39.14,
46.07, 46.84, 60.08, 167.59, 207.29 ppm. HRMS (EI) for C20H37NO2 m/z
calcd323.2824, found323.2826.
ACKNOWLEDGMENT
Financial support from National Science Council, Taiwan, ROC
(NSC 89-2113-M-006-020) is appreciated.
REFERENCES
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SUNG AND WU
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Receivedin the USA December 4, 2000

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