Structural elucidation of Z- and E- isomers of 5-alkyl-4-ethoxycarbonyl-5- (4′-chlorophenyl)-3-oxa-4-pentenoic acids

Article abstract of DOI:10.3390/50500737

Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-(4′-chlorophenyl)-3- oxa-4-pentenoic acids were prepared via the condensation of p-chloroacetophenone and/or p-chloropropiophenone with diethyl-2,2′-oxydiacetate in the presence of sodium hydride as a basic catalyst. The Z-isomers of 2a and 2b were found to be predominant. The behaviour of the corresponding anhydrides towards the action of hydrazine, phenylhydrazine, primary aromatic amines, hydrocarbons and ethanolysis has also been investigated. The structures and configurations of the products have been elucidated by chemical and spectroscopic means.

Full text of DOI:10.3390/50500737

Molecules 2000, 5, 737-745
molecules
ISSN 1420-3049
http://www.mdpi.org
Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-
ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids
H. M. F. Madkour
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, Ain Shams
University, Abbassiya, Cairo, Egypt
Fax: 00 2024831836, E-mail: hmfmadkour@hotmail.com
Received: 6 September 1999; revised form: 7 November 1999 / Accepted: 7 February 2000 / Published: 20 May 2000
Abstract: Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-
pentenoic acids were prepared via the condensation of p-chloroacetophenone and/or p-
chloropropiophenone with diethyl-2,2`-oxydiacetate in the presence of sodium hydride as a
basic catalyst. The Z-isomers of 2a and 2b were found to be predominant. The behaviour of
the corresponding anhydrides towards the action of hydrazine, phenylhydrazine, primary
aromatic amines, hydrocarbons and ethanolysis has also been investigated. The structures
and configurations of the products have been elucidated by chemical and spectroscopic
means.
Keywords: Aromatic ketones, 2,2'-oxydiacetate, stereoisomeric alkenes.
Introduction
The present study deals with the condensation of aromatic ketones with diethyl-2,2`-oxydiacetate
and structural elucidation of the resulting Z- and E-isomers of 5-alkyl-4-carbethoxy-5-(4`-chloro-
phenyl)-3-oxa-4-pentenoic acids.[1] The investigation is also extended to cover the behaviour of the
corresponding anhydrides towards hydrazines, aromatic amines and hydrocarbons under Friedel-Crafts
acylation conditions [2-5].
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

738
Molecules 2000, 5
Results and Discussion
The condensation of p-chloroacetophenone and p-chloropropiophenone with diethyl-2,2`-
oxydiacetate in the presence of sodium hydride [5] afforded in each case a mixture of the expected
stereoisomeric E- and Z-alkenes. The E-isomers 1a and 1b could be isolated in pure crystalline form,
the remainder being an oily fraction whose composition was revealed by saponification.
COOR3
Cl
Cl
R1
a, CH3
b, C2H5 C2H5
c, CH3
d, C2H5
e, CH3
f, C2H5
R2
C2H5
R3
H
H
H
H
C 2H5
C 2H5
O
COOR2
O
R1
R1
COOR2
H
H
H
H
COOR3
1
2
( ) E-isomer
( ) Z-isomer
Figure 1.
The Z-hemiesters 2a and 2b were obtained in 40% and 42% yields, respectively (vide infra). The
predominance of this configuration can be interpreted in terms of the mechanism involving the forma-
tion of the diastereoisomeric d-lactonic intermediates I and II. The steric course of the condensation
will be controlled by the initial attack by the ester carbanion on the ketone. Out of the possible dia-
stereomeric condensate anions III and IV, III is expected to be more easily formed owing to the tran-
soid orientation of the p-chlorophenyl group and ester groups (larger effective bulk than
OCH2COOC2H5). Cyclisation of III to I was also expected to be enhanced by the diequatorial accom-
modation of the bulky aryl and ester groups when I approaches a chair-like conformation during cycli-
zation. The easier formation of I reasonably explains the higher yields of the Z-hemiesters. Further-
more, the predominance of this configuration in the two investigated ketones, indicates that the ratio of
isomers is almost solely controlled by the conformational factor, and is almost independent of the polar
effect of substituents.
R
R
H
H
Ar
Ar
COOC H5
OCH2COOC2H5
OCH2COOC2H5
COOC H5
2
O
O
2
III
IV
H
COOC2H5
Ar
Ar
COOC H5
H
2
O
O
O
O
R
R
O
O
I
II
Figure 2.

739
Molecules 2000, 5
Structure and Configuration of the Hemiesters
-1
The crystalline E-hemiesters 1a and 1b exhibited strong bands at 1712 and 1686 cm for a ,b-
unsaturated ester and non-conjugated carboxyl groups, respectively [6]. Saponification of the crystal-
line E-hemiester of 1a and 1b gave the corresponding E-diacids 1c and 1d. The oily Z-hemiester 2a
and 2b gave fairly high yields of the Z-diacids 2c and 2d in pure crystalline state. The dibasic acids 1c,
1d, 2c and 2d were converted to the corresponding cyclic anhydrides 3a-d by the use of N,N`-
dicyclohexylcarbodiimide (DCC) as dehydrating agent. The anhydrides 3a-d exhibited the expected
carbonyl coupling bands [6].
R1
O
Cl
O
O
R2
O
COOH
O
R
O
( )
3
( )
4
R1
a, -C6H4-Cl-p
R
2
-CH3
a, R = CH3
b, -C6H4-Cl-p
c, -CH3
-C2H5
b, R = C2H5
-C H4-Cl-p
6
d, -C2H5
-C H4-Cl-p
6
Figure 3.
The configuration of the E-hemiesters 1a and 1b was confirmed from cyclization of the derived an-
hydrides 3a and 3b with anhydrous aluminium chloride to the corresponding oxoindenyl acids 4a and
4b in good yields. Similar treatment of the Z-anhydrides 3c and 3d gave the corresponding dibasic
acids 2c and 2d as the sole acidic products.
Beside elementary analyses, solubility in sodium carbonate solution, yellow colour, and formation
of 2,4-dinitrophenylhydrazones, each of the indenyl acids 4a and 4b showed two bands for nC=O. The
position of the maxima in the electronic spectra (l
253 and 296; e
18500 and 16500), closely
max
max
resemble those of 2-carboxymethyl analogues [7].
Treatment of the anhydrides 3a and 3b with hydrazine hydrate and phenylhydrazine in refluxing
ethanol [2,3] led to cleavage at the non-conjugated carbonyl and gave the hydrazide derivatives 5a-d.
Amidation of the E-anhydrides 3a and 3b with aromatic amines, namely, aniline, p-toluidine, a -
naphthylamine and benzylamine at 170oC afforded the 5-alkyl-N-aryl-4-carboxy-5-(p-chlorophenyl)-3-
oxapent-4-enoic imides 6a-h.

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Molecules 2000, 5
Cl
Cl
O
COOH
O
Ar
O
R
NH NHR2
N
O
R1
O
5
( )
6
( )
R1
R2
H
R
Ar
a, CH3
a, CH3
C6H5
b, C2H5
c, CH3
d, C2H5
H
C6H5
C6H5
b, C2H5
c, CH3
d, C2H5
e, CH3
f, C2H5
g, CH 3
h, C2H5
C6H5
C6H4-CH3-p
C6H4-CH3-p
a
a
-C10 C7
-C10 C7
CH2C6H5
CH2C6H5
Figure 4.
On the other hand, the anhydride 3b was subjected to reactions with aromatic hydrocarbons such as
benzene, toluene, cumene and anisole in the presence of anhydrous aluminium chloride under Friedel-
Crafts' reaction conditions and gave the 2-aroyl-methoxy-3-(p-chlorophenyl)-pent-2-enoic acids 7a-d.
Cl
Ar
a, C6H5
b, C6H4-CH3-p
c, C6H4-C3H7-(iso)-p
d, C6H4-OCH3-p
COOH
O
Ar H
3b
Ar
AlCl
3
C2H5
O
7
( )
Scheme 1.
The carboxy hemiesters 1e, 1f, 2e and 2f were obtained through ethanolysis of the anhydrides 3a-d
in ca 80% yield. The presence of non-conjugated ester and a ,b-unsaturated carbonyl groups was
-1
shown by the nC=O at 1745 and 1700 cm , thus providing additional proof for the position of unsatura-
tion in the original hemiesters.
Experimental
General
All elemental analyses gave satisfactory results : C ± 0.36, H ± 0.16, N ± 0.31, Cl ± 0.42. IR (KBr
disks) and U.V. spectra were measured with Unicam SP 1400 and SP1800 spectrophotometers, re-

741
Molecules 2000, 5
1
spectively. The H-NMR spectra were measured on a Varian EM-390 at 90 MHz using TMS as the
internal lock and reference compound.
Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-[4`-chlorophenyl]-3-oxa-4-pentenoic acids 1a,b and
2a,b
The ketone, diethyl-2,2`-oxydiacetate and sodium hydride (1:1.5:1.5 mol.) in excess dry benzene
were stirred at 60-70° for 10 hrs and the reaction mixtures were worked up as usual. [8]
(a) p-Chloroacetophenone (0.01 mole; 15.5g) gave an acidic product (20.7g; 69.2%) which was
separated by dissolution in benzene into: (i) the less soluble E-isomer 1a, isolated as colourless crystals
1
(7.1g). M.p. 155-7°. H-NMR (DMSO-d ): d 1.3 (t, 3H, J = 7.5 Hz CH CH ), 2.1 (s, 3H, CH C=C),
6
2
3
3
3.6 (q, 2H, J = 7.5 Hz, CH CH ), 4.1 (s, 2H, OCH COO) and 7.1-7.3 (m, 4H, Ar-H). (ii) The soluble
2
3
2
oily hemiester fraction (13.6g) whose composition was revealed by saponification (see below).
(b) p-Chloropropiophenone (0.01 mole; 16.8g) gave an acidic product (22.6g; 72.2%) which was
separated by dissolution in benzene-light pertroleum into two fractions: (i) the less soluble E-hemi-
ester 1b, colourless crystals (8.2g), m.p. 160-2°. (ii) The soluble oily hemiester fraction (14.4g) whose
composition was revealed by saponification (see below).
Saponification of the hemiesters
The hemiesters were hydrolyzed by refluxing with 10% aqueous sodium hydroxide (10 ml of alkali
solution/1g of the hemiester) for 3 hrs. The pure crystalline hemiesters 1a, 1b gave the corresponding
diacids 1c and 1d in ca. 80% yield. The oily hemiester (13.6g) from p-chloroacetophenone gave an
acidic product (12.1g) which was digested with ether to give (i) the above E-diacid 1c (1.3g) as insolu-
ble fraction and (ii) the Z-diacid 2c as soluble fraction (10.7g).
The oily hemiester (14.4 g) from p-chloropropiophenone gave an acidic product (13.2g) which was
treated with boiling benzene to give (i) the E-diacid 1d (1.2g) as insoluble fraction and (ii) The Z-
diacid 2d as soluble fraction (12g). (cf. Table 1).
1
The H-NMR spectra of compound 1d shows the following peaks at d 1.1 (t, 3H, J = 7.5Hz,
CH CH ), 2.6 (q, 2H, J = 7.5 Hz, CH CH ), 3.7 (s, 2H, OCH COO) and 7.4-7.6 (m, 4H, Ar-H).
2
3
2
3
2
The relative amounts of products given in (a) should thus now be modified as follows : Total hemi-
ester mixture (20.7g), E-configuration hemiester (7.1g + 1.43g = 8.58g, 29% yield). Z-configuration
hemiester (11.83g, 40% yield). For case (b), total hemiester mixture (22.6g), E-configuration hemiester
(1.32g + 8.20g = 9.52g, 30% yield). The yield of Z-configuration hemiester is 13.29 g (42% yield).
Formation of cyclic anhydrides 3a-d
A mixture of the diacid and N,N`-dicyclohexylcarbodiimide (DCC) (1:1 molar ratio) in excess dry
benzene was stirred at room temperature for 2 hrs, left to stand overnight, then worked up as usual [7-
1
8]. The H-NMR spectrum of compound 3a displayed peaks at d 1.8 (s, 3H, CH C=C), 4.2 (s, 2H,
3

742
Molecules 2000, 5
1
OCH CO) and 7.3 (m, 4H, Ar-H). The H-NMR spectrum of compound 3d exhibited peaks at d 1.6 (t,
2
3H, J = 6.5 Hz, CH CH ), 3.6 (q, 2H, J = 6.5 Hz, CH CH ), 4.0 (s, 2H, OCH CO) and 7.7-7.9 (m, 4H,
2
3
2
3
2
Ar-H).
Table 1. Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic acids
and their corresponding anhydrides 1-3.
-1
IR (cm )
M.p (°C)
& Solvent
Compound
n
n
C=O
OH
235
Benzene
1700-1698
1705-1688
1700-1690
1710-1695
1780-1742
1772-1753
1780-1750
1775-1742
br. 3100-3500
br. 3110-3460
br.3080-3500
br.3180-3480
1c
230-2
1d
2c
2d
3a
3b
3c
3d
Light petroleum1
218
Light petroleum1
207-9
Light petroleum1
173.5
Light petroleum1
176.8
Benzene
167-9
Light petroleum1
135-7
Light petroleum1
1b.p. 80-100°C.
Action of anhydrous aluminium chloride upon the cyclic anhydrides 3a,b
To a solution of the anhydride (1 mole) in dry tetrachloroethylene (10 mL per g anhydride) anhy-
drous aluminium chloride (1.2 mole) was added and the mixture was stirred for 10 hrs at room tem-
perature, left to stand overnight, then worked up as usual [7,8]. The anhydride 3a gave the oxoindenyl
1
acid 4a as yellow needles from benzene, (44% yield), m.p. 205-7°. H-NMR (DMSO-d ): d 2.1 (s, 3H,
6
CH ), 4.0 (s, 2H, OCH COOH) and 7.4-7.6 (m, 3H, Ar-H), 11.2 (s, 1H, COOH). The DNP (dinitro-
3
2
phenyl) hydrazone of 4a was obtained as red crystals from light-petroleum (b.p. 90-110°), m.p. 267°.
The anhydride 3b gave the oxoindenyl acid 4b as yellow crystals from a mixture of benzene-methanol,
54% yield, m.p. 240-2°. The DNP hydrazone of 4b was obtained as orange crystals from methanol,
1
m.p. > 300°. H-NMR (DMSO-d6) : d 1.4 (t, 3H, J = 6.0 Hz, CH CH ), 2.8 (q, 2H, J = 6.0 Hz,
2
3
CH CH ), 3.7 (s, 2H, OCH COOH), 7.3-7.5 (m, 3H, Ar-H) and 10.9 (s, 1H, COOH).
2
3
2
Formation of hydrazide derivatives 5a-d
A solution of 3 (0.01 mol) and hydrazine hydrate and/or phenylhydrazine (0.05 mol) in 50 mL etha-

743
Molecules 2000, 5
nol was refluxed for 2 hrs. Evaporation of alcohol left a solid product which crystallised from a suit-
able solvent to give 5 (cf. Table 2).
Formation of 4-aryl-2-(2'-alkyl-2'-(4-chlorophenyl)methylene-3,5-dioxo-2,3,5,6-tetrahydro-1,4-[4H]
oxazine derivatives 6a-h
A mixture of 3 (0.01 mol) and the appropriate amines (0.01 mol) was fused at 170°C for 2 hrs. The
solid formed after cooling and treatment with ice/HCl was crystallised from the appropriate solvent to
1
give 6a-h (cf. Table 2). The H-NMR spectrum (DMSO-d6) of compound 6d displayed the following
peaks at d 1.2 (t, 3H, J = 6.5 Hz, CH CH ), 2.1 (s, 3H, CH -Ar), 2.8 (q, 2H, J = 6.5 Hz, CH CH ) 3.8
2
3
3
2
3
(s, 2H, OCH CO) and 6.9-7.4 (m, 8H, Ar-H). The 1H-NMR spectrum (DMSO-d6) of compound 6g ex-
2
hibited the following peaks at d 1.9 (s, 3H, CH C=C), 3.6 (s, 2H, OCH CO), 5.1 (s, 2H, N-CH Ph)
3
2
2
and 6.7-7.7 (m, 9H, Ar-H).
Table 2. Physical data of hydrazide derivatives 5a-d and 1,4-oxazine derivatives 6a-h.
-1
IR (cm )
M.p (°C)
& Solvent
Compound
n
n
C=O
NH,OH
190-2
Benzene
210-2
Methanol
122-3
1705-1660
1696-1656
1692-1678
1700-1662
1782-1705
1776-1700
1780-1705
1772-1690
1785-1710
1760-1700
1782-1710
1777-1700
3510-3210
3450-3205
3480-3250
3510-3200
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
Light petroleum
220-2
Benzene
140-2
Light petroleum
165-7
Benzene
205-7
Methanol
200
Methanol
240-2
Benzene
205-7
Methanol
172-3
Benzene
196-7
6g
6h
Methanol

744
Molecules 2000, 5
Reaction of 3b with aromatic hydrocarbons: formation of 7a-d
A solution of 3b (0.01 mol) in 100 mL of distilled aromatic hydrocarbon was added gradually to a
cold suspension of anhydrous aluminium chloride (0.01 mol) in a large excess of aromatic hydrocar-
bon (100 mL). The whole mixture was then added to cold hydrochloric acid. The organic layer was
separated and dried; the evaporation of solvent left a semisolid product which was crystallized from an
1
appropriate solvent to give 7a-d (cf. Table 3). The H-NMR spectrum (DMSO-d6) of compound 7c
displayed peaks at d 1.1 (t, 3H, J = 7.0 Hz, CH CH ), 1.4 (d, 6H, CH(CH ) ), 2.7 (q, 3H, J = 7.0 Hz,
2
3
3 2
CH CH ), 3.1-3.5 (m, 1H, CH(CH ) ) and 7.2-7.9(m, 8H, Ar-H). The 1H-NMR spectrum (DMSO-d6)
2
3
3 2
of compound 7d exhibited peaks at d 1.2 (t, 3H, J = 7.0 Hz, CH CH ), 2.8 (q, 2H, J = 7.0 Hz,
2
3
CH CH ), 3.7 (s, 3H, OCH ), 4.1 (s, 2H, OCH CO) and 7.0-7.8 (m, 8H, Ar-H).
2
3
3
2
Ethanolysis of anhydrides 3a and 3b
The anhydride was refluxed for 3 hrs with excess absolute ethanol (99.0%). Evaporation of alcohol
left the isomeric hemiesters 1e and 1f (cf. Table 3).
Table 3. Physical data of products of the reaction of 3 with aromatic hydrocarbons and ethanol.
-1
IR (cm )
M.p (°C)
& Solvent
Compound
n
n
C=O
NH,OH
>280
Ethanol
260-2
1702-1696
1700-1686
1700-1698
17072-1688
1732-105
br. 3400
7a
br. 3210-3450
br. 3430
7b
7c
7d
1e
1f
Benzene-methanol
>300
Benzene-methanol
250-2
Benzene-methanol
117-9
Light petroleum
220-3
br. 3510
br. 3500-3180
br. 3480-3120
1728-1700
Benzene
References and Notes
1. Madkour, H.M.F.; Salem, M.A.I.; Abdel-Rahman, T.M.; Azab, M.E. Heterocycles 1994, 38, 57.
2. El-Hashash, M.A.; Madkour, H.M.F.; Amine, M. S. Pak. J. Sci. Ind. Res. 1991, 34, 288.
3. Mahmoud, M.R. Ind. J. Chem. 1994, 33B, 1028-1032.
4. Mahmoud, M.R. J. Chem. Soc. Pak. 1989, 11, 144-150.
5. El-Newaihy, M.F.; Salem, M.R.; Enayat, E.I.; El-Bassiony, F.A. Aust. J. Chem. 1979, 32, 1159.

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Molecules 2000, 5
6. Bellamy, L.J. The Infrared Spectra of Complex Molecules,3rd Edn.; Chapman & Hall: London,
1975; Vol. 1.
7. Abdel-Hamid, H. A.; Enayat, E. I.; Mahmoud, M. R. J. Chem. Soc. Pak. 1990, 12, 128-133.
8. Mahmoud, M.R.; El-Nagdy, S.; El-Bassiouny, F.A. J. Chem. Soc. Pak. 1988, 10, 261-267.
Samples Availability: Not available.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.