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Article

Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids

Synthetic Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya, Cairo, Egypt
Molecules 2000, 5(5), 737-745; https://doi.org/10.3390/50500737
Submission received: 6 September 1999 / Revised: 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.

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 [2,3,4,5].

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.
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 δ-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.

Structure and Configuration of the Hemiesters

The crystalline E-hemiesters 1a and 1b exhibited strong bands at 1712 and 1686 cm-1 for α,β- 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].
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 νC=O. The position of the maxima in the electronic spectra (λmax 253 and 296; εmax 18500 and 16500), closely 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, α- naphthylamine and benzylamine at 170oC afforded the 5-alkyl-N-aryl-4-carboxy-5-(p-chlorophenyl)-3- oxapent-4-enoic imides 6a-h.
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.
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 α,β-unsaturated carbonyl groups was shown by the νC=O at 1745 and 1700 cm-1, 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-spectively. The 1H-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 (7.1g). M.p. 155-7°. 1H-NMR (DMSO-d6): δ 1.3 (t, 3H, J = 7.5 Hz CH2CH3), 2.1 (s, 3H, CH3C=C), 3.6 (q, 2H, J = 7.5 Hz, CH2CH3), 4.1 (s, 2H, OCH2COO) and 7.1-7.3 (m, 4H, Ar-H). (ii) The soluble 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).
The 1H-NMR spectra of compound 1d shows the following peaks at δ 1.1 (t, 3H, J = 7.5Hz, CH2CH3), 2.6 (q, 2H, J = 7.5 Hz, CH2CH3), 3.7 (s, 2H, OCH2COO) and 7.4-7.6 (m, 4H, Ar-H).
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 [7,8]. The 1H-NMR spectrum of compound 3a displayed peaks at δ 1.8 (s, 3H, CH3C=C), 4.2 (s, 2H, OCH2CO) and 7.3 (m, 4H, Ar-H). The 1H-NMR spectrum of compound 3d exhibited peaks at δ 1.6 (t, 3H, J = 6.5 Hz, CH2CH3), 3.6 (q, 2H, J = 6.5 Hz, CH2CH3), 4.0 (s, 2H, OCH2CO) and 7.7-7.9 (m, 4H, Ar-H).

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 acid 4a as yellow needles from benzene, (44% yield), m.p. 205-7°. 1H-NMR (DMSO-d6): δ 2.1 (s, 3H, CH3), 4.0 (s, 2H, OCH2COOH) and 7.4-7.6 (m, 3H, Ar-H), 11.2 (s, 1H, COOH). The DNP (dinitro-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, m.p. > 300°. 1H-NMR (DMSO-d6) : δ 1.4 (t, 3H, J = 6.0 Hz, CH2CH3), 2.8 (q, 2H, J = 6.0 Hz, CH2CH3), 3.7 (s, 2H, OCH2COOH), 7.3-7.5 (m, 3H, Ar-H) and 10.9 (s, 1H, COOH).

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-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 give 6a-h (cf. Table 2). The 1H-NMR spectrum (DMSO-d6) of compound 6d displayed the following peaks at δ 1.2 (t, 3H, J = 6.5 Hz, CH2CH3), 2.1 (s, 3H, CH3-Ar), 2.8 (q, 2H, J = 6.5 Hz, CH2CH3) 3.8 (s, 2H, OCH2CO) and 6.9-7.4 (m, 8H, Ar-H). The 1H-NMR spectrum (DMSO-d6) of compound 6g ex- hibited the following peaks at δ 1.9 (s, 3H, CH3C=C), 3.6 (s, 2H, OCH2CO), 5.1 (s, 2H, N-CH2Ph) and 6.7-7.7 (m, 9H, Ar-H).

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 appropriate solvent to give 7a-d (cf. Table 3). The 1H-NMR spectrum (DMSO-d6) of compound 7c displayed peaks at δ 1.1 (t, 3H, J = 7.0 Hz, CH2CH3), 1.4 (d, 6H, CH(CH3)2), 2.7 (q, 3H, J = 7.0 Hz, CH2CH3), 3.1-3.5 (m, 1H, CH(CH3)2) and 7.2-7.9(m, 8H, Ar-H). The 1H-NMR spectrum (DMSO-d6) of compound 7d exhibited peaks at δ 1.2 (t, 3H, J = 7.0 Hz, CH2CH3), 2.8 (q, 2H, J = 7.0 Hz, CH2CH3), 3.7 (s, 3H, OCH3), 4.1 (s, 2H, OCH2CO) and 7.0-7.8 (m, 8H, Ar-H).

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).

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.
  6. Bellamy, L.J. The Infrared Spectra of Complex Molecules,3rd Edn.; Chapman & Hall: London, 1975; Vol. 1. [Google Scholar]
  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.
Figure 1.  
Figure 1.  
Molecules 05 00737 g001
Figure 2.  
Figure 2.  
Molecules 05 00737 g002
Figure 3.  
Figure 3.  
Molecules 05 00737 g003
Figure 4.  
Figure 4.  
Molecules 05 00737 g004
Scheme 1.  
Scheme 1.  
Molecules 05 00737 sch001
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.
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.
CompoundM.p (°C) & SolventIR (cm-1)
νC=OνOH
1c2351700-1698br. 3100-3500
Benzene
1d230-21705-1688br. 3110-3460
Light petroleum1
2c2181700-1690br.3080-3500
Light petroleum1
2d207-91710-1695br.3180-3480
Light petroleum1
3a173.51780-1742
Light petroleum
3b176.81772-1753
Benzene
3c167-91780-1750
Light petroleum1
3d135-71775-1742
Light petroleum1
1b.p. 80-100°C.
Table 2. Physical data of hydrazide derivatives 5a-d and 1,4-oxazine derivatives 6a-h.
Table 2. Physical data of hydrazide derivatives 5a-d and 1,4-oxazine derivatives 6a-h.
CompoundM.p (°C) & SolventIR (cm-1)
νC=OνNH,OH
5a190-21705-16603510-3210
Benzene
5b210-21696-16563450-3205
Methanol
5c122-31692-16783480-3250
Light petroleum
5d220-21700-16623510-3200
Benzene
6a140-21782-1705
Light petroleum
6b165-71776-1700
Benzene
6c205-71780-1705
Methanol
6d2001772-1690
Methanol
6e240-21785-1710
Benzene
6f205-71760-1700
Methanol
6g172-31782-1710
Benzene
6h196-71777-1700
Methanol
Table 3. Physical data of products of the reaction of 3 with aromatic hydrocarbons and ethanol.
Table 3. Physical data of products of the reaction of 3 with aromatic hydrocarbons and ethanol.
CompoundM.p (°C) & SolventIR (cm-1)
νC=OνNH,OH
7a>2801702-1696br. 3400
Ethanol
7b260-21700-1686br. 3210-3450
Benzene-methanol
7c>3001700-1698br. 3430
Benzene-methanol
7d250-217072-1688br. 3510
Benzene-methanol
1e117-91732-105br. 3500-3180
Light petroleum
1f220-31728-1700br. 3480-3120
Benzene

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MDPI and ACS Style

Madkour, H.M.F. Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids. Molecules 2000, 5, 737-745. https://doi.org/10.3390/50500737

AMA Style

Madkour HMF. Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids. Molecules. 2000; 5(5):737-745. https://doi.org/10.3390/50500737

Chicago/Turabian Style

Madkour, H. M. F. 2000. "Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids" Molecules 5, no. 5: 737-745. https://doi.org/10.3390/50500737

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