Isomerization of enol esters derived from 2-acyl-1,3-cyclohexanediones: Mechanism and driving force

Article abstract of DOI:10.1016/S0040-4039(03)00554-9

A series of 2-acyl-1,3-cyclohexanediones were prepared and isomerization mechanisms of the corresponding enol esters were investigated. The driving force for this migration is likely that the intrinsic electrostatic repulsion between the 2-acyl oxygen atom and the two 1,3-diketone oxygens caused deformation of enol esters from planarity and resulted in their high susceptibility to enolization and subsequent isomerization.

Full text of DOI:10.1016/S0040-4039(03)00554-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3137–3141
Isomerization of enol esters derived from
2-acyl-1,3-cyclohexanediones: mechanism and driving force
Hun-Ge Liu, Chung-Shieh Wu, Jen-Fei Wang and Ding-Yah Yang*
Department of Chemistry, Tunghai University, 181, Taichung-Kang Rd. Sec. 3, Taichung, Taiwan 40704
Received 24 May 2002; revised 17 February 2003; accepted 21 February 2003
Abstract—A series of 2-acyl-1,3-cyclohexanediones were prepared and isomerization mechanisms of the corresponding enol esters
were investigated. The driving force for this migration is likely that the intrinsic electrostatic repulsion between the 2-acyl oxygen
atom and the two 1,3-diketone oxygens caused deformation of enol esters from planarity and resulted in their high susceptibility
to enolization and subsequent isomerization. © 2003 Elsevier Science Ltd. All rights reserved.
2-Acyl-1,3-cyclohexanediones and their derivatives have
long been known for their extensive application as
biologically active substances. For example, the two
solvent, as shown in Scheme 1. The structure of 4f was
unequivocally characterized by X-ray crystallographic
analysis as depicted in Figure 1.8 In this paper, we
address the issues of the mechanism and driving force
of this isomerization.
classes
sethoxydim1 and sulcotrione,2 which both contain a
2-acyl-1,3-cyclohexanedione moiety, are potent
inhibitors of aceyl-CoA carboxylase (ACCase)3 and
4-hydroxyphenylpyruvate dioxygenase
(HPPD),4
of
commercially
available
herbicides
A series of 2-acyl-1,3-cyclohexanediones with a differ-
ent side chain on the 2-acyl group were prepared to test
the broadness of this migration as well as to explore the
factors affecting the rate of the isomerization. The
synthetic route to compounds 2a–e is outlined in
Scheme 2. The first event was O-acylation of 1,3-cyclo-
hexanedione by appropriate acyl chloride to give enol
ester 1, which on treatment with cyanide ion and a base
rearranged to the corresponding C-acyl isomers 2a–e.9
Compounds 2a–e were then subjected to the migration
by treating with an excess of acetyl chloride or cyclo-
propanecarbonyl chloride. The isomerization products
were isolated and characterized as shown in Scheme 3.10
The two ester groups on 5a–j can be removed readily
upon microwave irradiation (in montmorillonite K10,
800 W, 2–3 min) to recover quantitatively the starting
respectively. Recently, the triketone functionality in
2-acyl-1,3-cyclohexanediones has also been used as a
primary amine protection group5 and a linker in solid
phase peptide synthesis.6 In our continuing efforts to
explore a new type of potent HPPD inhibitors to serve
as an alternative treatment for the life-threatening
tyrosinaemia type I disease,7 we discovered an unex-
pected isomerization of enol esters derived from 2-acyl-
1,3-cyclohexanediones. When 2-isobutyryl-1,3-cyclo-
hexanedione 2c was treated with cyclopropanecarbonyl
chloride in the presence of triethylamine as a base in
methylene chloride, the corresponding ester 3f formed
quantitatively. The resulting enol ester 3f isomerized to
compound 4f at room temperature with or without
Scheme 1.
Keywords: isomerization; mechanism; driving force.
* Corresponding author. Tel.: 886-4-2359-7613; fax: 886-4-2359-0426; e-mail: yang@mail.thu.edu.tw
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00554-9

3138
H.-G. Liu et al. / Tetrahedron Letters 44 (2003) 3137–3141
observed when a relatively small 2-acyl group like
acetyl or propionyl was used as the substrate. More-
over, 2-acyl-1,3-cyclohexanedione with a smaller 3-enol
ester group rearrange faster than with a bulkier ester
group. For example, compound 2 with those R3 being a
methyl group always gives a better isomerization yield
than with R3 being a cyclopropyl group. In addition,
when a 2-cyclopropanecarbonyl-1,3-cyclohexanedione
was used as a starting material, no desired isomeriza-
tion product was detected even after 1 week. This
observation implies that the isomerization may involve
a keto-enol tautomerization of 2-acyl group who’s the
relative stability affects the rate of isomerization. The
proposed mechanism of this isomerization is shown in
Scheme 4. The first step involves the intrinsic keto-enol
tautomerization of the 2-acyl group. The resulting enol
oxygen then attacks to the ester carbonyl group to give
the tetrahedral carbonyl addition intermediate 6. Final
collapse of 6 generates the isomerized product. In the
presence of excess acyl chloride and triethylamine, it
undergoes a second esterification to afford the final
diester. Several hydrogen–deuterium exchange experi-
ments were performed to gain evidence supporting this
isomerization mechanism, as depicted in Scheme 5.
First, compound 3i prepared in Scheme 3 was dissolved
in D2O at room temperature for 24 h. The mixture was
then extracted with ethyl acetate, dried in MgSO4,
concentrated in vacuo, and purified by column chro-
matography to give the pure 2e, which were then
subjected to NMR spectroscopic determination. It was
Figure 1. X-Ray structure of 4f. ORTEP diagram showing
the crystallographic atom-numbering scheme; small open cir-
cle represents a hydrogen atom.
materials 2a–e. The isomerization yields and E/Z ratios
of possible geometrical isomers were examined and
summarized in Table 1. According to Table 1, the yield
for the isomerization reaction is governed by the bulki-
ness of both the side chains on 2-acyl group and the
3-ester functionality. A rapid and complete isomeriza-
tion of 2-acyl-1,3-cyclohexanedione enol ester was
Scheme 2.
Scheme 3.

H.-G. Liu et al. / Tetrahedron Letters 44 (2003) 3137–3141
Table 1. Reaction yields for the isomerization products 5a–j
3139
Entry
Compound
R1
R2
R3
Yield (%)a
Z/Eb
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
CH3
CH3
H
H
H
H
H
CH3
CH(CH2)2
CH3
CH(CH2)2
CH3
CH(CH2)2
CH3
CH(CH2)2
CH3
CH(CH2)2
97
85
70
60
55
50
30
10
B5
0
–
–
CH3
CH3
CH3
CH3
C2H5
C2H5
C5H11
C5H11
4.9/1
8.1/1
–
–
7.3/1
12.6/1
3/1
10
5j
H
–
a After column chromatography.
b Determined by 1H NMR integration.
Scheme 4.
Scheme 5.
easily undergo keto-enol tautomerization. A control
experiment was carried out by using 2e as a reference
compound under the exact same condition, and no
detectable hydrogen–deuterium exchange of the 2-acyl
a hydrogen was observed.
found that 45% of the hydrogen atom a to 2-acyl
carbon of 2e was exchanged with deuterium, deter-
mined by H NMR integration using a triplet signal of
1
4-H at 2.49 ppm as an internal reference of intensity, as
shown in Figure 2. In an effort to confirm that the
enolization is not solely catalyzed by the product acetic
acid presence in the solution during hydrolysis, com-
pound 2e was methylated by diazomethane and was
treated with D2O under the same condition as 3i, in this
case 20% of the hydrogen atom was found to be
exchanged with deuterium. These results indicate that
the a-hydrogen on the 2-acyl group of 3i and 7 can
Although 2-acyl-cyclohexan-1,3-diones have up to 12
possible keto-enol and enol–enol tautomeric forms,
recent evidence, which includes X-ray structures11 and
molecular modeling studies,12 suggests that the C-2
carbonyl moiety of 2 is coplanar and conjugated with
the cyclohexene ring system by an intramolecular

3140
H.-G. Liu et al. / Tetrahedron Letters 44 (2003) 3137–3141
Figure 2. Partial 1H NMR spectra (CDCl3, 300 MHz) of 3i and 7 after treatment with D2O. The integration around the
absorption at 3.86 ppm in (a) and (b) relative to the triplet signal of 4-H at 2.49 ppm indicates that 45 and 20% of a-hydrogen
atom on the acyl group were exchanged by deuterium.
enolize due to the stereoelectronic reason. Thus, we
anticipated that this intrinsic electrostatic repulsion per-
haps serves as the driving force for 3 to undergo the
isomerization reaction. In an effort to obtain further
insight into this speculation, we prepared 3-chloro-2-(2-
nitrobenzoyl)-1,3-cyclohexadien-1-ol (8) and 3-meth-
oxy-2-(2-nitrobenzoyl)-2-cyclohexen-1-one (9) from 3-
hydroxy-2-(2-nitrobenzoyl)cyclohex-2-en-1-one (10) and
examined their stability under ambient temperature. It
was found that both 8 and 9 slowly decomposed back
to 10 even when stored at −20°C with or without
solvent, as depicted in Scheme 6. On the basis of the
outcome of this model study, the dipolar repulsions
hydrogen bond of the C-3 hydroxyl hydrogen to the
oxygen atom of C-2 carbonyl group as indicated in
Scheme 2. After esterification of the C-3 hydroxyl
group, the intramolecular hydrogen bond of 2 was
disrupted and the intrinsic electrostatic repulsion
between the 2-acyl oxygen atom and the two 1,3-dike-
tone oxygens caused deformation of 3 from planarity
and resulted in their high susceptibility to enolization
and subsequent isomerization. Furthermore, molecular
modeling studies suggested that there exists a beautiful
syn-periplanar relationship between the carbonyl group
and one of the a-hydrogens in 3 and 7. Such orientation
might make them highly feasible for 2-acyl group to
Scheme 6.

H.-G. Liu et al. / Tetrahedron Letters 44 (2003) 3137–3141
3141
between the C-2 carbonyl group and the C-1 carbonyl
group as well as the C-3 oxygen or chlorine atom
apparently rendered 8 and 9 in an unfavorable high
energy status. Since 8 and 9 can not undergo isomeriza-
tion like 3, they react instead with moisture in the air
via a nucleophilic 1,4-addition and then subsequent
elimination reaction to regain the planar structure and
intramolecular hydrogen bonding.
R.; Hamilton, G. A. Methods Enzymol. 1987, 142, 132–
138.
5. (a) Bycroft, B. W.; Chan, W. C.; Chhabra, S. R.; Tees-
dale-Spittle, P. H.; Hardy, P. M. J. Chem. Soc., Chem.
Commun. 1993, 776–777; (b) Bycroft, B. W.; Chan, W.
C.; Chhabra, S. R.; Hone, N. D. J. Chem. Soc., Chem.
Commun. 1993, 778–779.
6. Bannwarth, W.; Huebscher, J.; Barner, R. Bioorg. Med.
Chem. Lett. 1996, 6, 1525–1528.
In summary, the factors affecting the rate of the iso-
merization of enol esters derived from 2-acyl-1,3-cyclo-
hexanediones and its mechanism were investigated. The
results suggest the isomerization involves the intrinsic
keto-enol tautomerization, follows by intramolecular
attack of the enol oxygen to ester carbonyl group. The
driving force for this migration is likely that the intrin-
sic electrostatic repulsion between the 2-acyl oxygen
atom and the two 1,3-diketone oxygens caused defor-
mation of enol esters from planarity and resulted in
their high susceptibility to isomerization.
7. Lindblad, B.; Lindstedt, S.; Steen, G. Proc. Natl. Acad.
Sci. USA 1977, 74, 4641–4645.
8. Crystallographic data (excluding structure factors) for 4f
has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers
CCDC 184437. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
9. Montes, I. F.; Burger, U. Tetrahedron Lett. 1996, 37,
1007–1010.
10. All new compounds exhibited satisfactory 1H and 13C
NMR, IR, and low and high resolution mass spectro-
scopic data for the indicated structures. Representative
procedure for preparation of 5a–j: To a solution of
2-acetyl-3-hydroxy-2-cyclohexenone (2a, 100 mg, 0.65
mmol) in methylene chloride (5 mL) was added acetyl
chloride (127 mg, 1.62 mmol) and Et3N (177 mg, 1.75
mmol). After completion of the reaction (monitored by
TLC), water (5 mL) was added to the mixture and the
product was extracted twice with methylene chloride. The
combined organic extracts were dried over MgSO4,
filtered, and concentrated. The resulting crude product
was purified by column chromatography (EtOAc:
hexanes=4:6) to give a light brown liquid of 2-[1-
(methylcarbonyloxy)-1-ethenyl]-3-(methylcarbonyloxy)-2-
cyclohexen-1-one (5a) with a 97% yield. 1H NMR
(CDCl3, 300 MHz) l 5.20 (d, J=1.8 Hz, 1H), 4.94 (d,
J=1.8 Hz, 1H), 2.50 (t, J=6.3 Hz, 2H), 2.23 (s, 3H), 2.09
(s, 3H), 2.06 (quintet, J=6.3 Hz, 2H). 13C NMR (CDCl3,
75 MHz) l 196.0, 168.4, 167.6, 167.0, 143.8, 125.4, 108.4,
37.1, 28.9, 20.8, 20.8, 20.2. IR (KBr) w 1769, 1682, 1635
(CꢀO), 1208, 1158 (CH2ꢀC-O) cm−1. HRMS: calcd for
C12H14O5, 238.2420, found 238.2435.
Acknowledgements
The financial assistance provided by National Science
Council of Republic of China is gratefully acknowl-
edged. The authors also thank the reviewers for their
helpful suggestions and encouragement.
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