Convenient rearrangement reaction of 2-chloroglycidic esters by PPh 3: A new synthetic method of 3-chloro-2-keto esters

Article abstract of DOI:10.1080/00397910600764618

A convenient rearrangement reaction of 2-chloroglycidic esters is reported. Treatment of 2-chloroglycidic esters with PPh₃ under refluxing condition results in the formation of 3-chloro-2-keto esters in good to reasonable yields. Copyright Tayl

Full text of DOI:10.1080/00397910600764618

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Convenient Rearrangement Reaction of
2‐Chloroglycidic Esters by PPh3: A New
Synthetic Method of 3‐Chloro‐2‐keto Esters
Takuzo Komiyama a , Yutaka Takaguchi a & Sadao Tsuboi a
a Department of Material and Energy Science, Graduate School of
Environmental Science , Okayama University , Okayama, Japan
Published online: 16 Feb 2007.
To cite this article: Takuzo Komiyama , Yutaka Takaguchi & Sadao Tsuboi (2006) Convenient Rearrangement
Reaction of 2‐Chloroglycidic Esters by PPh3: A New Synthetic Method of 3‐Chloro‐2‐keto Esters, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:18,
2621-2625, DOI: 10.1080/00397910600764618
To link to this article: http://dx.doi.org/10.1080/00397910600764618
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Synthetic Communicationsw, 36: 2621–2625, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600764618
Convenient Rearrangement Reaction of
2-Chloroglycidic Esters by PPh3: A New
Synthetic Method of 3-Chloro-2-keto Esters
Takuzo Komiyama, Yutaka Takaguchi, and Sadao Tsuboi
Department of Material and Energy Science, Graduate School of
Environmental Science, Okayama University, Okayama, Japan
Abstract: A convenient rearrangement reaction of 2-chloroglycidic esters is reported.
Treatment of 2-chloroglycidic esters with PPh3 under refluxing condition results in the
formation of 3-chloro-2-keto esters in good to reasonable yields.
Keywords: 2-Chloroglycidic ester, Darzens condensation, dichloroacetate, rearrange-
ment reaction
The Darzens reaction is a well-known effective method for the preparation of
glycidic esters. It is of interest because glycidic esters can be transformed to
the corresponding aldehydes and ketones having a higher carbon number
than the starting aldehydes or ketones.[1] Our group is studying the Darzen
reaction of dichloroacetate, and a convenient method for the synthesis of
2-chloroglycidic esters was reported.[2] This polyfunctional 2-chloroglycidic
ester has drawn much attention in organic chemistry, and we reported the
rearrangement of 2-chloroglycidic esters to 3-chloro-2-keto esters by Al2O3
or SiO2.[3] This 3-chloro-2-keto ester has been used as a key intermediate
for the synthesis of thiazole,[2a,4] oxazoline derivatives,[5] and various biologi-
cally active compounds.[2c,6] As other methods for the conversion of 2-chlor-
oglycidic esters to 3-chloro-2-keto esters, magnesium chloride[7] and
hydrogen chloride[2a,8] were reported. During some other research in our
Received in Japan December 17, 2005
Address correspondence to Sadao Tsuboi, Department of Material and Energy
Science, Graduate School of Environmental Science, Okayama University, Okayama
700-8530, Japan. E-mail: stsuboi6@cc.okayama-u.ac.jp
2621

2622
T. Komiyama, Y. Takaguchi, and S. Tsuboi
Scheme 1.
group, we unexpectedly discovered that PPh3 is also an effective catalyst for
the rearrangement of 2-chloroglycidic esters. Therefore, we report a novel and
convenient method for the preparation of 3-chloro-2-keto esters 2 by the
treatment of 2-chloroglycidic esters 1 with PPh3 as shown in Scheme 1.
The starting material, 2-chloroglycidic ester 1, can be prepared easily
from various aldehydes via the Darzens condensation reaction with dichloro-
acetate (Scheme 2).[2]
Treatment of 2-chloroglycidic esters 1a–g with PPh3 gave the corre-
sponding 3-chloro-2-keto esters 2a–g in good to reasonable yields
(Table 1). Although the treatment of ethyl 2-chloro-2,3-epoxyhexanoate (1a)
without PPh3 resulted in recovery of the starting material, the reaction with
1.0 equiv. of PPh3 in benzene provided ethyl 3-chloro-2-oxohexanoate (2a)
in 88% yield after purification by silica-gel flash chromatography (entries 1
and 2). Then we investigated the effect of the amount of PPh3 in this
reaction, and we found 1a was converted to 2a in good yields even with a
catalytic amount of PPh3 (entries 3 and 4). Next, we investigated ethyl
2-chloro-2,3-epoxyheptanoate (1b) in this reaction. There are previous
reports that rearrangement reaction of 1b by magnesium halide resulted in
recovery of a 1 : 1 mixture of the starting material and rearrangement
product 2b.[3,7a] On the other hand, in our case, 1b was converted to
2b smoothly by the treatment of 0.5 equiv. of PPh3 (entry 5). Other
2-chloroglycidic esters 1c–g were also transformed to the corresponding
3-chloro-2-keto esters 2c–g by the treatment of PPh3 in good to reasonable
yields (entries 6–10).
The 3-chloro-2-keto esters obtained by this reaction are very useful
compounds for synthetic organic chemistry because they have many useful
functional groups, such as chlorine, ketone, and ester, which enable them to
convert to various precursors for the target compound. Furthermore, by
attaching these useful functional groups in the neighborhood in their
molecule, they would have much greater potential as synthetic tools. Indeed,
3-chloro-2-keto esters have shown fascinating roles in organic chemistry.[9]
Scheme 2.

Rearrangement of 2-Chloroglycidic Esters by PPh3
2623
Table 1. Rearrangement reaction of 2-chloroglycidic ester 1 with PPh3
Equiv. of
PPh3
Time
(h)
Product/
yield (%)
Entry
Substrate
R
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
C3H7
C3H7
C3H7
C3H7
C4H9
C5H11
—
8
8
No reaction
2a/88
1.0
0.5
0.2
0.5
0.5
12
32
12
12
2a/90
2a/87
2b/93
2c/87
7
8
1d
0.5
3.0
30
6
2d/82
2e/46
1ea
9
1f
0.5
0.5
96
14
2f/76
2g/88
10
1g
aMethyl ester was used as a substrate.
The reaction conditions of this PPh3 rearrangement are mild. Furthermore, the
starting material can be prepared very easily, so we believe this preparation
method of 3-chloro-2-keto esters from 2-chloroglycidic esters is very useful
in organic chemistry.
In conclusion, we have developed an efficient and novel method for the
synthesis of 3-chloro-2-keto esters by the reaction of 2-chloroglycidic esters
with PPh3. Further exploitation of this strategy toward the synthesis of
natural products and biologically active compounds are in progress and will
be reported in the near future.
EXPERIMENTAL
All chemicals were used as received. Reactions were monitored by thin-layer
chromatography (TLC). NMR spectra were recorded on JEOL JNM-AL300
instrument and calibrated using residual undeuterated solvent as an internal
reference. IR spectra were recorded on a Thermo Nicolet Avatar 360T2
infrared spectrophotometer. For TLC, aluminum sheets of Merck silica-gel-
coated 60 F254 plates were used, and the plates were visualized with UV
light and phosphomolybdic acid (5% in EtOH). Merck silica gel 60 N
(spherical, neutral) (40–50 mm) was used for the flash chromatography.

2624
T. Komiyama, Y. Takaguchi, and S. Tsuboi
Starting materials 1a–g were prepared by the treatment of dichloroacetate
with corresponding aldehydes in the presence of NaOEt in ether.[2c]
General Procedure for 2a–g (Synthesis of 2a from 1a)
PPh3 (34 mg, 0.13 mmol) was added to a stirred solution of 2-chloroglycidic
ester 1a (50 mg, 0.26 mmol) in benzene (5 mL) and the reaction mixture was
stirred for 12 h under refluxing condition. Then the reaction mixture was
allowed to cool to room temperature. After evaporation of the solvent, the
crude product was purified by column chromatography (hexane/EtOAc
30 : 1 to 5 : 1) to give ethyl 3-chloro-2-oxohexanoate (2a) (45 mg, 90% yield).
Data
1
Ethyl 3-chloro-2-oxohexanoate (2a)[3]: Colorless oil; H NMR (300 MHz,
CDCl3): d 0.98 (t, J ¼ 7.2 Hz, 3H), 1.39 (t, J ¼ 7.2 Hz, 3H), 1.43–2.04
(m, 4H), 4.37 (q, J ¼ 7.2 Hz, 2H), 4.95 (dd, J ¼ 5.4, 8.6 Hz, 1H); IR (neat):
1733, 1298, 1241, 1062 cm21. Spectral data were identical with those of the
authentic sample.[3]
1
Ethyl 3-chloro-2-oxoheptanoate (2b)[3]: Colorless oil; H NMR (300 MHz,
CDCl3): d 0.93 (t, J ¼ 7.2 Hz, 3H), 1.39 (t, J ¼ 7.2 Hz, 3H), 1.40–1.57
(m, 4H), 1.86–1.95 (m, 1H), 2.01–2.13 (m, 1H), 4.38 (q, J ¼ 7.2 Hz, 2H),
4.93 (dd, J ¼ 5.4, 8.4 Hz, 1H); IR (neat): 1732, 1300, 1234, 1058 cm21
.
Spectral data were identical with those of the authentic sample.[3]
1
Ethyl 3-chloro-2-oxooctanoate (2c)[3]: Colorless oil; H NMR (300 MHz,
CDCl3): d 0.90 (t, J ¼ 7.2 Hz, 3H), 1.31–1.37 (m, 4H), 1.39 (t, J ¼ 7.2 Hz,
3H), 1.39–1.57 (m, 2H), 1.84–1.96 (m, 1H), 2.00–2.12 (m, 1H), 4.38
(q, J ¼ 7.2 Hz, 2H), 4.93 (dd, J ¼ 5.4, 8.7 Hz, 1H); IR (neat): 1732, 1300,
1255, 1065 cm21. Spectral data were identical with those of the authentic
sample.[3]
1
Ethyl 3-chloro-2-oxo-4-phenylbutanoate (2d): Pale yellow oil; H NMR
(300 MHz, CDCl3) d 1.37 (t, J ¼ 7.2 Hz, 3H), 3.16 (dd, J ¼ 8.1, 14.1 Hz,
1H), 3.45 (dd, J ¼ 6.6, 14.1 Hz, 1H), 4.35 (q, J ¼ 7.2 Hz, 2H), 5.17 (dd,
J ¼ 6.6, 8.1 Hz, 1H), 7.26–7.35 (m, 5H); IR (neat): 1732, 1256, 1093,
1068, 1028 cm21. Anal. calcd. for C12H13O3Cl: C, 59.88; H, 5.44. Found:
C, 60.11; H, 5.68.
Methyl 3-chloro-2-oxo-4,5-O-isopropylidenepentanoate (2e): Yellow oil;
1
main isomer: H NMR (300 MHz, CDCl3) d 1.34 (s, 3H), 1.44 (s, 3H), 3.93
(s, 3H), 4.10 (dd, J ¼ 3.6, 9.3 Hz, 1H), 4.20 (dd, J ¼ 6.0, 9.3 Hz, 1H), 4.58

Rearrangement of 2-Chloroglycidic Esters by PPh3
2625
(ddd, J ¼ 3.6, 6.0, 9.0 Hz, 1H), 4.91 (d, J ¼ 9.0 Hz, 1H); IR (neat): 1736,
1255, 1067, 835 cm21. Anal. calcd. for C9H13O5Cl: C, 45.68; H, 5.54.
Found: C, 46.01; H, 5.70.
Ethyl 3-chloro-5-methyl-2-oxohexanoate (2f)[3]: Colorless oil; 1H NMR
(300 MHz, CDCl3) d 0.97 (d, J ¼ 6.6 Hz, 3H), 0.99 (d, J ¼ 6.6 Hz, 3H),
1.40 (t, J ¼ 7.2 Hz, 3H), 1.79–1.96 (m, 3H), 4.39 (q, J ¼ 7.2 Hz, 2H), 4.99
(t, J ¼ 7.2 Hz, 1H); IR (neat): 1732, 1302, 1243, 1070 cm21. Spectral data
were identical with those of the authentic sample.[3]
Ethyl 3-chloro-5,9-dimethyl-2-oxo-8-decenoate (2g): Colorless oil; 1H
NMR (300 MHz, CDCl3) d 0.97 (d, J ¼ 6.3 Hz, 3H), 1.26–1.31 (m, 1H),
1.40 (t, J ¼ 7.2 Hz, 3H), 1.61 (s, 3H), 1.69 (s, 3H), 1.72–1.81 (m, 2H),
1.90–2.09 (m, 3H), 4.38 (q, J ¼ 7.2 Hz, 3H), 4.99–5.04 (m, 1H), 5.05–
5.15 (m, 1H); IR (neat): 1732, 1301, 1243, 1065 cm21. Anal. calcd. for
C14H23O3Cl: C, 61.19; H, 8.44. Found: C, 61.46; H, 8.68.
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