A new efficient synthesis of α-methyl-β-ketoesters through an Eschenmoser sulfide reaction

Article abstract of DOI:10.1139/v04-088

Various α-methyl-β-ketoesters were readily synthesized through Eschenmoser condensation of thioamides with a commercially available bromoester. β-Enaminoesters were easily prepared through this sulfide contraction reaction and were hydrolysed to afford the corresponding β-ketoesters in moderate to good yields.

Full text of DOI:10.1139/v04-088

1289
A new efficient synthesis of ␣-methyl-␤-ketoesters
through an Eschenmoser sulfide reaction
Christian Bellec and Olivier Gaurat
Abstract: Various α-methyl-β-ketoesters were readily synthesized through Eschenmoser condensation of thioamides
with a commercially available bromoester. β-Enaminoesters were easily prepared through this sulfide contraction reac-
tion and were hydrolysed to afford the corresponding β-ketoesters in moderate to good yields.
Key words : α-alkylated-β-ketoesters, Eschenmoser, β-enaminoesters.
Résumé : Divers β-cétoesters-α-méthylés sont facilement préparés par condensation d’Eschenmoser de thioamides avec
un bromoester commercial. Les β-énaminoesters, facilement préparés par cette réaction d’extrusion de soufre, sont hy-
drolysés pour conduire aux β-cétoesters correspondants avec des rendements bons à modérés.
Mots clés : β-cétoesters α-alkylés, Eschenmoser, β-énaminoesters.
Bellec and Gaurat 1293
Introduction
The preparation of β-ketoesters from malonic acid ester
precursors has generally been rarely used for monoalkylated
compounds (2, 4, 13). Other synthetic approaches, using a
modified Reformatsky reaction (14–16), treatment of an
acylpyrazole with an organozinc reagent (17), or α-diazo-β-
hydroxyester rearrangment (18), have been described but do
not have, on the whole, general applicability. Oxidation of β-
hydroxyesters has most often been carried out with
nonalkylated substrates (19, 20).
We wish to report herein a new methodology that provides
direct access to α-substituted β-ketoesters from enaminoesters.
These substrates are readily prepared through an Eschen-
moser sulfide reaction involving condensation of thioamides
with bromoesters and are then hydrolyzed, in a final step, to
afford the desired ketoesters with moderate to good yields.
β-Ketoesters are widely recognized as very useful auxilia-
ries for several organic syntheses. Many synthetic ap-
proaches to α-unsubstituted compounds have been reported
in the literature over the years (1–3). Conversely, investiga-
tions into reactions giving α-alkylated β-ketoesters directly
have been more limited. Most often, these latter compounds
have been obtained by alkylation of unsubstituted moieties,
with the obvious disadvantages associated with this method-
ology (4, 5).
For some time, we have been interested in the synthesis of
β-enaminoesters using the Eschenmoser coupling reaction
(6, 7). Such enaminoesters are particularly suitable interme-
diates for the synthesis of various alkaloids (8, 9). More re-
cently, we became interested in a new application of the
efficient Eschenmoser alkylation sulfur contraction reaction
for a short and convenient access to α-monoalkylated β-
ketoesters that could take its place among other methodolo-
gies.
In the literature, various synthetic routes have been ex-
ploited for access to α-alkylated β-ketoesters. The direct
alkylation method with aliphatic substrates, initially reported
by Robinson (1), has been seldom used and leads generally
to poor yields (10). Indeed, it is often difficult to avoid a
double condensation or an O-alkylation process, although
some recent modifications of the work-up procedure gave
rise to better results (11, 12).
Results and discussion
Synthesis of thioamides
The synthesis of thioamides 2a–2f was carried out by con-
densation of acyl chlorides 1a–1f with pyrrolidine in the
presence of pyridine. Amide moieties obtained in a first step
were not isolated but were directly transformed into thio-
amides using P4S10 (Scheme 1).
Synthesis of ␣-substituted ␤-ketoesters
Various α-substituted β-ketoesters were produced by hy-
drolysis of the corresponding enaminoesters, which were most
often not isolated. The synthesis of these enaminoesters was
first carried out by adapting the modified Eschenmoser cou-
pling reaction previously described for thiolactams (6).
Thus, a mixture of triethylamine and triphenylphosphine in
dry acetonitrile was slowly added to a solution of thioamide
2 and commercially available 2-bromopropionic acid ethyl-
ester (3) in refluxing CH3CN (Scheme 2).
Received 10 December 2003. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 2 November 2004.
C. Bellec1,2 and O. Gaurat. Laboratoire de Chimie des
Hétérocycles (UMR 7611), Université Pierre et Marie Curie,
4 Place Jussieu, 75252 Paris CEDEX 05, France.
1Present address: Laboratoire de Chimie organique, Université
Pierre et Marie Curie, Case courrier 64, 4 Place Jussieu,
75252 Paris CEDEX 05, France.
The condensation was monitored by gas chromatography.
Despite a good rate of thioamide transformation (except in
2Corresponding author (e-mail: bellec@ccr.jussieu.fr).
Can. J. Chem. 82: 1289–1293 (2004)
doi: 10.1139/V04-088
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Can. J. Chem. Vol. 82, 2004
Scheme 1. Preparation of thioamides 2a–2f.
Scheme 2. Preparation of β-enaminoesters 5a–5f.
the case of 2c, for which no reaction was observed), several
by-products were observed in the crude reaction mixture.
Besides the α-substituted β-ketoester 5 and the desulfuration
product Ph3P=S, the aminoester 6 (Scheme 3), amide 7, and
sulfide 8 (EtOOC–CH(CH3)–S–CH(CH3)–COOEt) were also
detected.
Scheme 3.
Although the condensation was carried out under a nitro-
gen atmosphere and despite the use of an anhydrous solvent,
some of the thioamide 2 was generally transformed in the re-
action mixture to the corresponding amide 7. Similarly, the
presence of lactam as a by-product in the Eschenmoser sul-
fide contraction of thiolactams with halogenoesters has been
reported by some authors (21, 22). The formation of the
aminoester 6 could be explained by a nucleophilic substitu-
tion of pyrrolidine on the bromoester 3. Indeed, pyrrolidine
was formed in situ by hydrolysis of the enaminoester. Mi-
chael and co-workers reported, in a similar manner, the pres-
ence of the disulfide 9 in an Eschenmoser reaction with
bromoacetophenone (23).
As several by-products were present in the crude reaction
mixture, it was difficult to purify the β-ketoester 5 by chro-
matography on a silica gel column. With various eluents, the
yield of the α-substituted β-ketoester was poor to moderate,
and some fractions always contained Ph3P=S and Ph3P.
Therefore, it was necessary to modify the reaction condi-
tions to minimize the formation of by-products in the
condensation–extrusion process and to facilitate the elimina-
tion of these by-products in the experimental work-up. With
Ph3P as the thiophilic agent, the major difficulty was in
Table 1. Reaction conditions for transformation of 2a to 3a.
Thiophilic reagent
Reaction time (h)
Sulfide 8 (%)
Ph3P
P(OEt)3
P(NR2)3
6
3
1
25
11.5
Traces
eliminating the desulfuration product Ph3P=S. In the case of
thiolactam condensation, this problem was resolved by
acidic extraction of the cyclic enaminoester with HCl
(2 mol/L) (6), but with thioamides, the hydrolysis of the
formed enaminoester, leading to the ketoester, was too rapid
to permit a satisfactory extraction. So our idea was to mod-
© 2004 NRC Canada

Bellec and Gaurat
Table 2. Comparative results for various thiophilic reagents.
1291
Thiophilic
reagent
Sulfide
Thioamide 2
transformed (%)
β-Ketoester 5
Yield from
lit.b (%)
Thioamide
8 (%)
isolated yielda (%)
Ph3P
2a
25
11
<1
10
<1
35
<1
27
9
100
94
28
47
60
60
70
30
72.5
40
60
67
58c, 64d
P(OEt)3
P(NR2)3
P(OEt)3
P(NR2)3
P(OEt)3
P(NR2)3
Ph3P
100
95
2b
2d
2e
80e
80
88
75e
86
85
52f, 71g
93
P(OEt)3
P(NR2)3
<1
100
Note: For 2c, no reaction was observed, irrespective of which desulfuration reagent was employed.
aAfter purification by chromatography.
bObtained using other synthetic methods.
cFrom ref. 26.
dFrom ref. 27.
eFrom ref. 15.
fFrom ref. 4.
gFrom ref. 17.
ify the thiophilic reagent. The use of triethylphosphite
(P(OEt)3) in CH3CN and the same work-up as with Ph3P did
not result in a significant modification of the sulfide yield.
On the other hand, when the condensation was carried out
without solvent (5 mL of CH3CN being added in the
desulfuration step to obtain a concentrated but homogeneous
medium), the sulfide yield relative to the enaminoester–
ketoester yield was substantially reduced. Unfortunately, the
solubility of (EtO)3P=S in water is very low, and the work-
up only led to its partial elimination. Hence, another
thiophilic agent, P(NR2)3, was employed. Indeed, tris(alkyl-
amino)phosphines have been reported to be good reagents
for the transformation of disulfides to sulfides and for the re-
duction of thiiranes to olefins (24, 25). The same work-up as
with P(OEt)3 was carried out without solvent, but under a ni-
trogen atmosphere. In the same reaction time, a better trans-
formation rate of the thioamide 2 was observed (Table 1),
but, notably, only traces (<1% by gas chromatographic anal-
ysis) of the sulfide 8 were detected.
Nevertheless, purification of the β-ketoester on a silica gel
column always resulted in some fractions that were contami-
nated with the desulfuration product S=P(NE2)3, no matter
which elution solvent was employed. However, the presence
of 8 in very small amounts permitted an appreciable
improvement in the extraction yield of the α-substituted β-
ketoester 5 in the chromatographic step. Table 2 shows com-
parative results for the various thiophilic agents employed.
For comparison, we have also listed the yields reported in
the literature for many different methods and experimental
conditions.
cient and leads, after extraction, to similar yields to those in
Table 2.
Conclusion
We have shown that several α-substituted β-ketoesters can
be easily obtained by an efficient direct condensation of
bromoesters with thiolactams through the Eschenmoser sul-
fur extrusion reaction. This strategy represents a quick and
convenient route that can take its place among the available
methodologies that provide access to these compounds.
Experimental
General procedure for thioamide synthesis
In a mixture of 150 mL of pyridine and about 0.2 mol of
pyrrolidine, a slight excess (<1.1 equiv.) of acyl chloride 1
was added dropwise at room temperature. The stirred solu-
tion was refluxed for 30 min. After cooling, P4S10 was added
and the mixture was heated for 2 h and then poured into
500 mL of 1 mol/L HCl. The mixture was stirred for 1 h and
was then extracted three times with 150 mL of dichloro-
methane (CH2Cl2). The combined organic layers were
washed successively with 2 × 150 mL of 1 mol/L HCl, 2 ×
150 mL of water, and 2 × 100 mL of a saturated solution of
sodium hydrogen carbonate (NaHCO3), then dried over mag-
nesium sulfate (MgSO4) and evaporated. The residue was
purified by chromatography on a silica gel column.
1-Pyrrolidin-1-yl butan-1-thione (2a)
Thus, with tris(dimethylamino)phosphine or tris(diethyl-
amino)phosphine as the thiophilic reagent, α-alkylated β-
ketoesters were synthesized via an Eschenmoser reaction in
moderate to good yields. We have performed several other
syntheses using different bromoesters, but no other series
has been investigated in a systematic manner. However, even
from these limited experiments, this method remains effi-
Condensation of 15.62 g (0.22 mol) of pyrrolidine and
25 g (0.235 mol, 1.07 equiv.) of butanoyl chloride 1a gave,
after chromatography using ethyl acetate (EtOAc)/cyclohex-
1
ane (1/1), 28.76 g of 2a. Yield 83%. Oil. H NMR: 3.90 and
3.66 (t, J = 7 Hz, 4H), 2.70 (t, J = 7.5 Hz, 2H), 2.10–2.00
(m, 4H), 1.80 (m, 2H), and 1.05 (t, J = 7.5 Hz, 3H). 13C
NMR: 200.6, 50.9, 46.1, 26.6, 24.6, 22.5, and 14.1. IR
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Can. J. Chem. Vol. 82, 2004
(CHBr3): 1480 cm–1. Anal. calcd. (%) for C8H15NS: C
61.12, H 9.62, N 8.91; found: C 61.25, H 9.57, N 8.84.
(THF). Following the addition of 15.5 g of P4S10, the mix-
ture was heated for 4 h. Using the same work-up as de-
scribed in the general procedure, 10.9 g of 2f were obtained
after chromatography with EtOAc/cyclohexane (1/2). Yield
3-Methyl-1-pyrrolidin-1-yl butan-1-thione (2b)
1
60%. Oil. H NMR: 3.80 and 3.60 (2t, J = 7 Hz, 4H), 3.63
Using the same procedure, condensation of 6.39 g
(0.09 mol) of pyrrolidine and 12.05 g (0.1 mol, 1.1 equiv.)
of isobutyryl chloride 1b gave, after chromatography using
EtOAc/cyclohexane (1/1), 11.9 g of 2b. Yield 77%. Yellow
(s, 3H), 2.90 and 2.80 (2t, J = 6 Hz, 4H), and 2.10–1.90 (m,
4H). 13C NMR: 197.4, 172.6, 53.4, 51.2, 50.1, 36.3, 32.3,
25.8, and 23.7. IR (CHBr3): 1725 and 1480 cm–1. Anal.
calcd (%) for C9H15NO2S: C 53.73, H 7.46, N 6.96; found:
C 53.82, H 7.38, N 6.93.
1
oil. H NMR: 3.85 and 3.55 (2t, J = 7 Hz, 4H), 2.54 (d, J =
7.5 Hz, 2H), 2.30 (m, 1H), 2.02 and 1.85 (2t, J = 7 Hz, 4H),
and 0.94 (d, J = 7.5 Hz, 6H). 13C NMR: 199.7, 53.6, 51.1,
50.7, 28.9, 26.1, 24.0, and 22.1. IR (CHBr3): 1480 cm–1.
Anal. calcd. (%) for C9H17NS: C 63.13, H 10.00, N 8.18;
found: C 63.03, H 10.11, N 8.23.
General procedure for an Eschenmoser coupling
reaction with Ph3P as the thiophilic agent
Typically, a mixture of thioamide 2 (6.3 mmol) and
bromoester 3 (0.019 mol, 3 equiv.) in 50 mL of acetonitrile
(CH3CN) was heated for 30 min. A solution of 1.26 mmol
(2 equiv.) of Ph3P and 1.26 mmol (2 equiv.) of triethylamine
(Et3N) in CH3CN (30 mL) was added dropwise. After addi-
tion, the mixture was refluxed for 4 h. The solvent was re-
moved in vacuo and the resulting residue was dissolved in
CH2Cl2 (150 mL). The organic layer was washed with a so-
lution of 1 mol/L HCl (150 mL). The aqueous layers were
extracted with CH2Cl2 (3 × 75 mL). The combined organic
phases were successively washed with saturated NaHCO3
solution (50 mL) and water (50 mL) and were then dried
(MgSO4). After evaporation of the solvent, crude β-ketoester
5 was obtained. In some cases, portions of phosphorated by-
products were precipitated out in ethanol at –18 °C. Thus,
purification of the ketoesters by chromatography on a silica
gel column was facilitated.
2,2-Dimethylpyrrolidin-1-yl propan-1-thione (2c)
Using the same work-up, condensation of 14.2 g (0.2 mol)
of pyrrolidine and 25 g (0.21 mol, 1.05 equiv.) of pivaloyl
chloride 1c gave, after chromatography using EtOAc/cyclo-
hexane (1/1), 32.3 g of 2c. Yield 94%. Oil. 1H NMR: 3.90
and 3.75 (2t, J = 7 Hz, 4H), 2.10 and 1.80 (2t, J = 7Hz, 4H),
and 1.36 (s, 9H). 13C NMR: 208.5, 57.6, 52.7, 43.5, 30.2,
27.3, and 22.9. IR (CHBr3): 1430 cm–1. Anal. calcd. (%) for
C9H17NS: C 63.13, H 10.00, N 8.18; found: C 63.27, H
10.02, N 8.12.
1-Pyrrolidin-1-yl hexan-1-thione (2d)
Condensation of 12.6 g (0.177 mol) of pyrrolidine and
25 g (0.186 mol, 1.05 equiv.) of hexanoyl chloride 1d gave,
after chromatography with EtOAc/cyclohexane (1/1), 30.2 g
of 2d. Yield 92%. Oil. 1H NMR: 3.80 and 3.50 (2t, J = 7 Hz,
4H), 2.62 (t, J = 7 Hz, 2H), 2.05 and 1.88 (2q, J = 7 Hz, 4H)
1.70 (m, 2H), 1.32–1.25 (m, 4H), and 0.84 (t, J = 7 Hz, 3H).
13C NMR: 201.2, 54.3, 51.0, 44.6, 32.0, 29.1, 26.8, 24.8,
22.9, and 14.4. IR (CHBr3): 1430 cm–1. Anal. calcd. (%) for
C10H19NS: C 64.83, H 10.34, N 7.56; found: C 64.90, H
10.28, N 7.51.
General procedure for an Eschenmoser coupling
reaction with triethylphosphite as the thiophilic agent
A mixture of 5.4 mmol of thioamide 2 and 8.11 mmol of
bromoester 3 (1.5 equiv.) was heated at 80 °C for 30–
45 min. Then a mixture of triethylamine (8.11 mmol,
1.5 equiv.) and 8.11 mmol (1.5 equiv.) of P(OEt)3 was
added. A precipitate of ammonium bromide was formed, and
5 mL of CH3CN was added. The residue was refluxed until
no further change in the ratio of the different compounds
was observed by gas chromatography (2–5 h). After addition
of CH3CN (15 mL) and 1 mol/L HCl (1 mL) at room tem-
perature, the resulting mixture was stirred and hydrolysis of
the enaminoester was monitored by TLC. The solvent was
removed and CH2Cl2 (50 mL) was added. The organic layer
was washed with a saturated NaHCO3 solution. The aqueous
layer was extracted with CH2Cl2 (2 × 50 mL). The combined
organic layers were dried (MgSO4) and condensed to give
crude β-ketoester 5, which was chromatographed on a silica
gel column using various mixtures of EtOAc/cyclohexane as
eluant.
1-Thiobenzoyl pyrrolidine (2e)
Condensation of 5.32 g (0.075 mol) of pyrrolidine and
11.24 g (0.08 mol, 1 equiv.) of benzoyl chloride 1e gave, af-
ter chromatography with EtOAc/cyclohexane (1/1), 14 g of a
1
yellow solid 2e. Yield 97.5%; mp 73 °C. H NMR: 7.30–
7.20 (m, 5H), 3.90 and 3.39 (2t, J = 7 Hz, 4H), and 2.00–
1.90 (m, 4H). 13C NMR: 197.4, 144.3, 129.0, 128.6, 126.0,
54.2, 53.8, 26.8, and 25.0. IR (CHBr3): 1505, 1490, and
1475 cm–1. Anal. calcd. (%) for C11H13NS: C 69.09, H 6.85,
N 7.33; found: C 68.98, H 6.80, N 7.40.
4-Pyrrolidin-1-yl-4-thioxobutanoic acid methylester (2f)
For the synthesis of the intermediate amide, the following
specific procedure was used: 6.39 g (0.09 mol) of pyrro-
lidine was condensed with 15.05 g (0.1 mol, 1.1 equiv.) of 3-
carbomethoxy propanoyl chloride. After reaction, pyridine
was evaporated under reduced pressure. Dichloromethane
(200 mL) was added. The mixture was washed twice with
100 mL of water. The organic layer was dried (Na2SO4) and
concentrated to give the crude amide (yield 79%), which
was used directly without further purification in the next
step. The thionation was achieved with a solution of 13 g
(0.07 mol) of amide in 400 mL of dried tetrahydrofuran
General procedure for an Eschenmoser coupling
reaction with tris(dimethylamino)phosphine as the
thiophilic agent
A mixture of 5 mmol of thioamide 2 and 7.5 mmol
(1.5 equiv.) of bromoester 3 was heated at 80 °C for 30–
45 min under a nitrogen atmosphere. A mixture of 6 mmol
(1.2 equiv.) of Et3N and 7.5 mmol (1.5 equiv.) of
tris(dimethylamino)phosphine was then added, followed by
the addition of dry CH3CN (5 mL). The resulting mixture
© 2004 NRC Canada

Bellec and Gaurat
1293
was refluxed until no further change in the ratio of the dif-
ferent compounds was observed by gas chromatography. Af-
ter addition of CH3CN (10 mL) and 1 mol/L HCl (1 mL) the
mixture was stirred for an additional 30 min and the same
type of work-up as previously described in the second proce-
dure was achieved. Thus, crude β-ketoester 5 was obtained
and then chromatographed as above.
1.43–1.32 (2t, J = 7 Hz, 6H). 13C NMR: 172.6, 172.5, 61.0,
60.9, 41.2, 41.1, 17.6, 16.8, 13.9, and 13.8. IR (CHBr3):
1735 cm–1. Anal. calcd. (%) for C10H18O4S: C 51.26, H
7.74; found: C 51.19, H 7.71.
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26 Hz, 2H), 1.52 (m, 2H), 1.27 (d, J = 7 Hz, 3H), 1.25–1.22
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14.5, 13.8, and 12.7. IR (CHBr3): 1750 and 1720 cm–1.
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2-Methyl-3-oxo-3-phenyl propanoic acid ethylester (5e)
1
Oil. H NMR: 12.5 (broad s, weak), 7.90–7.35 (m, 5H),
4.30 (q, J = 7.1 Hz, 1H), 4.05 (q, J = 7 Hz, 2H), 1.42 (d, J =
7.1 Hz, 3H), and 1.15 (t, J = 7 Hz, 3H). 13C NMR: 196.0,
170.8, 134.2, 131.8, 127.1, 126.9, 61.3, 48.3, 13.9, and 13.7.
IR (CHBr3): 1740, 1680, and 1595 cm–1. Anal. calcd. (%)
for C12H14O3: C 69.88, H 6.84; found: C 69.79, H 6.78.
2-Methyl-3-oxo-hexandioic acid-1-ethyl-6-methylester (5f)
1
Oil. H NMR: 4.12 (q, J = 7 Hz, 2H), 3.60 (s, 3H), 3.50
(q, J = 7 Hz, 1H), 2.85–2.75 (t, J = 6.5 Hz, 2H), 2.56 (t, J =
6.5 Hz, 2H),), 1.30 (d, J = 7 Hz, 3H), and 1.21 (t, J = 7 Hz,
3H). 13C NMR: 203.9, 172.6, 170.1, 61.1, 52.6, 51.5, 35.7,
27.5, 13.8, and 12.4. IR (CHBr3): 1730 cm–1 (broad). Anal.
calcd. (%) for C10H16O5: C 55.54, H 7.46; found: C 55.62, H
7.53.
24. D.N. Harpp and J.G. Gleason. J. Org. Chem. 35, 3259 (1970).
25. N.P. Neureiter and F.G. Bordwell. J. Am. Chem. Soc. 81, 578
(1958).
26. K. Tsuzuki, M. Akeyoshi, and S. Omura. Bull. Chem. Soc.
Jpn. 58, 395 (1985).
27. H.J. Bestman, G. Graf, H. Hartung, and S. Kolewa. Chem. Ber.
103, 2794 (1970).
2-(1-Ethoxycarbonyl-ethylsulfanyl)-propanoic acid
ethylester (8)
1
Oil. H NMR: 4.15–4.05 (2q, J = 7 Hz, 4H), 3.60–3.45
(2q, J = 7.2 Hz, 2H), 1.55–1.45 (2d, J = 7.2 Hz, 6H), and
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