Utility of -Aroyl acrylic acid in heterocyclicsynthesis

S. A. Risk, M. A. El-Hashash, K. K. MostafaChemistry Department, Faculty of Science, Ain Shams

University,Abbsia, Cairo, Egypt

Chemist_koryem@yahoo.comRisk_sameh@yahoo.com

Keywords:-(3,4-dichloro and/or 4-bromobenzoyl) acrylic acid / Pyridazi-none/ Furanone

Abstract:-(4-bromobenzoyl) acrylic acid has been reacted with nitrogen nucleophiles namely ethanolamine & o-aminophenol and yielded the corresponding adduct 1a,b. On the other hand-(3,4-dichlorobenzoyl) acrylic acid has been reacted with carbon nucleophiles namely o-dichlorobenzene under Friedle-Crafts conditions and yielded the corresponding adduct 1c. Behaviour of compounds (1) toward hydrazine hydrate, hydroxylamine and acetic anhydride have been investigated. Acylation and alkylation of pyridazinone derivative also has been described.

Introduction:In a recent previous publication [1-2], we reported the reaction of -aroyl acrylic acid with some nitrogen nucleophiles and the utility of some of the reaction products in heterocyclic synthesis. This prompted us to study the behavior of -[(2-hydroxy-ethylamino), (2-hydroxyphenylamino) and/or (3,4-dichlorophenyl)]. -[(4-bromo-benzoyl and/or 3,4-dichlorobenzoyl)] propanoic acids(1) toward nitrogen nucleophiles and acetic anhydride with the aim of obtaining some interesting cyclic compounds.

Results & Discussion:

1

When -(4-bromobenzoyl) acrylic acid was allowed to reactwith ethanol amine and/or o-aminophenol in dry benzene inthe presence of few drops of piperidine as a catalyst[3]. Itafforded -hydroxyethylamino and 2-hydroxyphenylamino--(4-bromobenzoyl) -propanoic acid (1a) and (1b) and not -aminoderivatives. The addition of amine occurred alpha to thecarboxyl group in their instances, the polarization of thedouble bond by the ketone group strongly outweighed thatexhibited by the carboxyl group, i.e. -carbon atomaccepted the nucleophile more readily than -carbon, thus-(4-bromobenzoyl) acrylic acid resembles, -- unsaturatedketones in its mode of addition.

On the other hand when -(3,4-dichlorobenzoyl)-acrylic acidwas submitted to react with O-dichlorobenzene, it yielded-(3,4-dichlorophenyl)--(3,4-dichlorobenzoyl)-acrylic acid(1c). This is due to the -(3,4-dichlorobenzoyl)-acrylicacid reacts with O-dichlorobenzene under Friedle-Craft'sreaction conditions as -unsaturated carbonyl compoundsrather than -unsaturated acids. IR spectra of acids(1)exhibit strong absorption at (1680-1667 cm-1, CO ofketone), (1700-1694 cm-1, CO of carboxylic acid), (3180-3220 cm-1, NH). The 1HNMR spectra of compound 1a in DMSOexhibits signals at 1.2 (t, CH2-N), 2.9-3 (oct, CH2-C=O,diasteriotopic protons). The two protons of methylene groupadjacent to ketonic group are non equivalent and eachproton appears as doublet (4-lines), each line couple withmethine proton & gives doublet (8-lines), 3.7 (t, CH2O-),4.01 (d.d, N-CH-COOH), 4.8(S,NH), 6.6(S,OH), 7.3-7.7 (d.d,4H, Ar-H), acidic protons are exchangeable in D2O. EI-MSfor compounds 1b m/z : 347 (M.+-CO2).

2

The majority of currently known non steroidal anti-inflammatory and analgesic drugs (NSAIDs), i.e. aspirineand ibuprofen, mainly act peripherally by blocking theproduction of prostaglandins through inhibition of cyclooxygenase (COX) enzymes COX-1 and COX-2, to varyingextents[4]. These drugs tend to produce side effect, such asgastrointestinal ulceration and suppression of renalfunction due to inhibition of the constitution COX-1, whichis responsible for the production of prostaglandins,responsible for gastro protection, and vascular homeostasis[5-7]. Therefore, the main trend nowadays in paintherabyfocuses on improved non-steroidal analgesic which areeffectives as an analgesic but devoid of the side effectswhich are inherent to traditional NSAIDs.

In terms of this aspect, many studies have been focused on3(2H) pyridazinines which are characterized to possess goodanalgesic and inflammatory activities and also very lowulcerognicity[8-12]. In the reported studies theheterocyclic ring substituted at six position, and thepresence of acetamide side chain that is linked to thelactam nitrogen of pyridazinone ring at position -2 ofpyridazinone ring improved the analgesic and anti-inflammatory activity along. In the present study we havesynthesized the structurally diverse 6(4-bromophenyl)-2(substituted) 4(2-hydroxy ethylamino), 2,3,4,5 tetrahydro3(2H) pyridazinone with expected pharmaceutical activity.

Thus when acid 1a,b was allowed to react with hydrazinehydrate in boiling ethanol afforded 6(4-bromophenyl)-4-(2-hydroxy ethyl or 2-hydroxy phenyl–amino), 2,3,4,5tetrahydro 3(2H) pyridazinone (2). IR spectra of (2) revealstrong absorptions bands at (1677-1651) CO (cycliccarboxamide) and (3340-3400) NH group.

Treating an equimolar amount of pyridazinone derivatives(2a) with acetic anhydride and/or benzoyl chloride inpyridine gave 6(4-bromophenyl)-4-N,O-diacetyl ethanol amino/ or O-benzoyl ethanolamino-2-acetyl / or benzoyl 2,3,4,5tetrahydro pyridazine-3-one (3a and 3b). IR spectra of (3)reveal strong absorptions bands at (1730-1720) cm-1

3

corresponding CO (O-CO-CH3 / O-CO-ph), (1678-1676) cm-1 toCO (N-CO-CH3 / N-CO-ph), 1653 cm-1 to CO (cycliccarboxamide), NH at 3419 cm-1 appear in benzoyl derivativeonly (3b). EIMS for (3a) does not show molecular ion peakbut it does show a peak at m/e 250 which corresponding to6(4-bromophenyl)-2,3-dihydro pyridazinone radical cation,m/e 195 corresponding to 4(N,O-diacetyl ethanolamino),2,3,4,5 tetrahydro pyridazi-none-3-one radicalcation, m/e 171 (250-Br).

Pyridazinone derivatives (2) react with ethyl chloroacetatein the presence of potassium carbonate in dry acetone [14,13]

to give 6(4-bromophenyl)-4-(2-hydroxy ethyl/phenyl–amino)-2-ethoxy carbonyl methyl 2,3,4,5 tetrahydro pyridazinone-3-one(4a,b). The reaction takes place via nucleophilicsubstitution by the lone pair of nitrogen atom on theprimary alkyl halide moiety (SN2 mechanism), the role ofK2CO3 is deattached of the chloride ion. IR spectra of (4a,b)reveal strong absorption bands at (1768-1754) cm-1

corresponding toCO of ester group (1678-1676) cm-1

corresponding to CO cyclic carboxyamide, (3471-3422) cm-1

broad bands corresponding to OH, NH respectively.

In the present work, treatment of (2) with ethylchloroacetate in dioxane instead of dry acetone yielded6(4-bromophenyl)-2-ethoxycarbonylmethyl-2,3-dihydropyridazinone (5) via deamination. The structure ofcompound (5) is evidenced from its microanalytical andspectral data, thus its IR spectrum shows absorptioncorrelated with compound (4) without any bands for OH,NH. The 1HNMR for (5) in DMSO exhibits signals at 1.2(t,3,CH3-CH2-O),4.2(q,2H,CH3-CH2-O), 5(s,2H,O-CH2-CO), 7.1(d, 1Hb), 7.8 (d.d, 4H, Ar-H), 8.05 (d, 1Ha), Ha & Hb

protons of pyridazinone rings.Hydrazinolysis of compound 4a by N2H4 in boiling ethanolafforded the hydrazide derivative (6). The reaction takesplace via tetrahedral mechanism ((characterization for acylfamily) in which the N-C bond was formed before C-OEt whichstarted to break and consequently a lot of energy isaccumulated in the reaction medium which decreases theactivation energy of the reaction and a facile conversion

4

takes place. IR spectra of (6) reveal strong absorptionbands at (1651, 1652, 3252, 3318) cm-1 attributable to COof (-CO-NHNH2), CO cyclic carboxamide, NH of symmetric &anti-symmetric stretching.

Recently [15] 2(3H) furanones exhibit rich photochemistry.Furthermore, due to their common occurrence in nature,oxygen containing hetero cycles are frequent and importanttarget, for synthesis either as final products or as usefulsynthesis intermediates. Thus when the acid 1c was allowedto react with acetic anhydride on heating water bath for1hr, it gave 3.5-di (3,4-dichlorophenyl)-2-(3H)-furanone(7). Its structure was inferred from its IR spectrum whichexhibits strong absorption band at (1795 cm-1 attributableto CO (lactonic). On the other hand interaction of theacid 1a with acetic anhydride on hot plate afforded theketone (8). Formation of keton (8) produced fromdecarboxylation of acid (1a) via its heating at hightemperature (boiling point) of acetic anhydride [16]. Herethe author offer a speculation which presented as follows:

IR spectrum of (8) reveal absorption band at (1681, 3279)cm-1 corresponding to CO, NH respectively.

The reaction of acid 1c with hydroxylamine hydrochloride inrefluxing pyridine produced isolated intermediate (9) whichcyclized to 3,5-di-(3,4-dichlorophenyl)-6-OXO-4,5,6-trihydro-1,2-oxazine(10). IR of (9) shows OH (br) at 3422,CO at 1695 cm-1 corresponding to (COOH) group and IRspectrum of (10) shows CO, C=N at (1743, 1633) cm-1

respectively. The 1HNMR of (10) in DMSO exhibits signals at

5

4.1 (d.d, 2H, diasteriotopic protons), 4.4 (d.d, 1H, uponto asymmetric carbon), 7.2, 7.9 (m,6,ArH).

In the present investigation similar treatment of acid 1a

with hydroxylamine hydrochloride in boiling pyridine as asolvent & as a catalyst afforded E,E & Z,E mixture of 3-(4-bromo) benzoyloximo prop-2-enoic acid. The structure of compound (11) is substantiated frommicroanalytical and spectral data. Its IR spectrum devoidof absorption correlated with -amino ethanol group,instead absorption characteristic for C=O (acid), C=Ngroups, at 1681, 1585 respectively. The 1HNMR didn’t showthe coupling pattern of –CH2-CH group, and the absorptionsignals corresponding to -amino ethanol group which infersthe absence of these moieties. The configurationalassignment to compound (11) as a mixture of two E-isomer(11A & B) was based on the 1HNMR (DMSO) it shows fourdoublet signals for the olefinic protons for E/E isomer, 6.8 (d, Ha), 7.9 (d, Hb), 9.8 (br.s, =N-OH exchangeable),for Z/E isomer, 6.7 (d, Ha), 7.5 (d, Hb), 10.2 (br.s, =N-OH exchangeable), 7.4-7.7 (d.d, 4H, ArH), 12.01 (br.s, 1H,COOH).

The relative ratio of the two isomers 11A & B was based onthe integration ratio of both olefinic protons and theoximo-OH proton and it was shown to be 50:50 respectively.

6

7

ExperimentalAll melting points are uncorrected. Elemental analyses werecarried out in the Microanalytical Center, the centerpublication for research, Cairo, Egypt.By Elementar Viro El Microanalysis IR spectra (KBr) wererecorded on infrared spectrometer ST-IR DOMEM HartmanBraun, Model: MBB 157, Canada and H-NMR spectra recorded ona varian 300 MHz (Germany 1999) using TMS as internalstandard. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass spectrometer at 70e.v. homogeneity of allcompounds synthesized was checked by TLC.Characterization and physical data for all synthesizedcompounds are listed on (table 1).

Starting MaterialGeneral Procedure:Anhydrous aluminium chloride (200gm) was added portionwiseto a stirred solution of Maleic anhydride (100gm) inaromatic hydrocarbon, namely bromobenzene & O-chlorobenzene(200ml) in an ice bath. The whole mixture was stirred atroom temperature for further 2hrs and reflux 3hrs on waterbath then left to stand overnight. The participated solidafter addition of ice cold hydrochloric acid (25ml) wasfiltered off, dried and the crude product was crystallizedform benzene to give -aroyl-prop-2-enoic acids.

Formation of 2-hydroxyethylamino--(4-bromobenzoyl)-propanoic acid (1a)

-------------------------------------------------------------------------------------

A solution of -(4-bromobenzoyl)-prop-2-enoic acid(0.01 mole) (2.55gm) and ethylamine 0.016 mole (1ml) in 30ml dry benzene in the presence of few drops of piperidineand leave 1 hour at room temperature. The mixture waswashed by light petroleum ether (b.p 40- 60oC), and thesolid was crystallized from ethanol to give compound (1a).

Formation of 2-hydroxyphenylamino--(4-bromobenzoyl)-propanoic acid (1b)

8

-------------------------------------------------------------------------------------

A mixture of -(4-bromobenzoyl)-prop-2-enoic acid(0.01 mole) (2.55gm) and o-aminophenol 0.01 mole (1gm) in20 ml dry benzene and drops of piperidine was refluxed for4 hours. The product that separated after cooling wasrecrystallized from ethanol to give compound (1b).

Formation of -(3,4-dichlorophenyl)--(3,4-dichlorophenyl)-propanoic acid (1c)

-------------------------------------------------------------------------------------

A mixture of (I) (0.01 mole), o-dichlorobenzene (0.01mole) and anhydrous aluminium chloride (50 gm) that wasadded portion wise to a stirred solution in ice bath. Thewhole mixture was stirred at room temp. for further 6hours, then left to stand overnight. The participated solidafter addition ice cold hydrochloric acid (25 ml) wasfiltered off, dried and the crude product wasrecrystallized from ethanol/methanol.

Formation of 4-bromophenyl-4(2-hydroxyethylamino)-2,3,4,5- tetra hydro-3 (2H) pyridazinone (2a)

-------------------------------------------------------------------------------------A solution of 1a (0.01 mole) in ethanol (30 ml) was treatedwith (0.75ml) and then refluxed for 3 hours. The solid thatseparated after concentration and cooling wasrecrystallized from ethanol to give compound (2a).

Formation of 6-(3,4-dichlorophenyl)-4-(2-hydroxyphenylamino)-2,3,4,5- tetrahydro-3 (2H) pyridazinone(2b)

-------------------------------------------------------------------------------------

9

A solution of 1b (0.01 mole) in ethanol (30 ml) was treatedwith (0.75ml) and then refluxed for 3 hours. The solid thatseparated after concentration and cooling wasrecrystallized from dioxane to give compound (2b).

Formation of 6(4-bromophenyl)-4-N,O-diacetylethylamino-2-acetyl-2,3,4,5-tetra hydropyridazine-3-one(3a)

-------------------------------------------------------------------------------------A solution of 2a (0.01 mole) and acetic anhydride (0.01mole) (1ml) was heated under reflux for 1 hour. Theproducts that separated on cooling was recrystallized fromethanol to give compound (3a).

Formation of 6(4-bromophenyl)-4-O-benzoylethylamino-2-benzoyl-2,3,4,5-tetra hydropyridazine-3-one(3b)

-------------------------------------------------------------------------------------A solution of 2a (0.01 mole) and benzoylchloride (0.01mole) (1.35ml) in 10 ml pyridine was heated under refluxfor 2 hours. The product that separated on cooling wasrecrystallized from ethanol to give compound (3b).

Formation of 6(4-bromophenyl)-4-(2-hydroxyethylamino)-2-ethoxycarbonyl-methyl-2,3,4,5-tetrahydropyridazine-3-one(4a)

-------------------------------------------------------------------------------------A solution of 2a (0.01 mole) and ethylchloroacetate (0.01mole) in dry acetone (20 ml), in the presence of potassiumcarbonate (3 gm) was reflux 24 hours. The reaction mixturewas concentrated, cooled and poured into ice cold water.The participated solid was filtered off, washed, dried andrecrystallized from ethanol to give compound (4a).

10

11

Formation of 6(4-bromophenyl)-4-(2-hydroxyphenylamino)-2-ethoxycarbonyl-methyl-2,3,4,5-tetrahydropyridazine-3-one(4b)

-------------------------------------------------------------------------------------A solution of 2b (0.01 mole) and ethylchloroacetate (0.01mole) in dry acetone (20 ml), in the presence of potassiumcarbonate (3 gm) was reflux 24 hours. The reaction mixturewas concentrated, cooled and poured into ice cold water.The participated solid was filtered off, washed, dried andrecrystallized from benzene to give compound (4b).

Formation of 6(4-bromophenyl)-2-ethoxycarbonylphenyl-2,3- dihydropyridazine one(5)

-------------------------------------------------------------------------------------A solution of 2a (0.01 mole) and ethylchloroacetate (0.01mole) in dioxane (20 ml), in the presence of potassiumcarbonate (3 gm) was reflux 20 hours. The reaction mixturewas concentrated, cooled and poured into ice cold water.The participated solid was filtered off, washed, dried andrecrystallized from dioxane to give compound(5).

Formation of hydrazide derivative (6)------------------------------------------------------

-------------------------------A solution of 4a (0.01 mole) and hydrazine hydrate (0.015mole) (0.75ml) in 40 ml ethanol was heated under reflux for3 hours. The product that separated on cooling wasrecrystallized ethanol solvent to give compound (6).

Formation of 3,5-di(3,4 dichlorophenyl)-2(3H) furanone (7)------------------------------------------------------

-------------------------------A solution of 1c (0.01 mole) and acetic anhydride (0.01mole) (1 ml), was heated on water path for 1 hour. Theproduct that separated on cooling was recrystallized frombenzene to give compound (7).

Formation of -hydroxyl ethyl,'(4-bromobenzoyl)ethylamine (8)

12

-------------------------------------------------------------------------------------A solution of 1a (0.01 mole) and acetic anhydride (0.01mole) (1 ml), was heated under refluxed for 1 hour. Theproduct that separated on cooling was recrystallized fromethanol to give compound (8).

Formation of 3,5-di(3,4-dichlorophenyl)-6-OXO-4,5,6-trihydro-1,2-oxazine(9)& (10)

-------------------------------------------------------------------------------------A solution of 1c (0.01 mole) in pyridine (0.01 mole) (10ml), was refluxed with hydroxylamine hydrochloride (0.01mole) for 3 hours. The reaction mixture was left to coolthen poured into cold water. The participated solid wasfiltered off and recrystallized from the suitable solventsto give compounds (9) and (10).

Formation of E,E & Z,E mixture of 3(4-bromobenzoyloximo-prop-2-enoic acid) (11)

-------------------------------------------------------------------------------------A solution of 1a (0.01 mole) and hydroxylamine (0.01mole) , were boiled in pyridine (10ml) for 3 hours. Thereaction mixture was left to cool then poured into coldwater / HCl. The participated solid was filtered off andrecrystallized from the suitable solvent to give compound(11).

13

Table (1) Characterisation and physical data forsynthesized compounds

Comp.

No.

M.P. oC(solventof cryst.)

Yield %

Formula(M.wt)

Analysis %Calcd./Found

C H N Br Cl

1a176 oC

(Ethanol) 90 C12H14O4NBr(316.15)

45.5945.20

4.46

4.31

4.43

4.0

25.2525.17

--

1b172-174 oC(Ethanol) 85 C16H14O4NBr

(3646.19)

52.7752.68

3.87

3.77

3.85

3.79

21.9421.92

--

1c

183 oC(Ethanol/Methanol)

85 C16H10O3Cl4

(392.06)

49.0248.99

2.57

2.50

--

--

36.1736.01

2a220 oC

(Ethanol) 80 C12H15O2N2Br(299.48)

48.5048.52

5.04

4.45

9.43

9.40

26.8926.93

--

2b210 oC

(Dioxane) 80 C16H16O2N3Br(362.22)

53.3553.25

4.45

3.95

11.6711.61

22.1822.10

--

3a250 oC

(Ethanol) 70 C18H22O5N3Br(360.29)

60.3460.29

6.15

5.65

11.7311.70

22.3022.27

--

3b232 oC

(Ethanol) 70 C26H24O4N3Br(522.38)

60.0160.05

4.63

4.22

8.07

8.00

15.3615.39

--

4a187 oC

(Ethanol) 66 C16H20O4N3Br(398.19)

48.2648.37

5.06

5.15

10.5610.80

20.0720.18

--

4b170 oC

(Benzene) 65 C20H22O4N3Br(448.31)

54.0754.13

4.94

4.13

9.46

9.43

17.9817.92

--

14

5 166 oC(Dioxane) 60 C16H20O4N3Br

(398.25)

48.2548.24

5.06

5.04

10.5510.49

20.0620.01

--

6 200 oC(Ethanol) 50 C14H20O3N5Br

(386.24)

43.7643.74

5.21

4.70

18.2318.22

20.8020.81

--

7 190 oC(Benzene) 70 C16H8O2Cl4

(374.05)

51.3851.39

2.16

2.20

--

--

37.9137.93

8 215 oC(Ethanol) 65 C11H14O2NBr

(272.14)

48.5548.57

5.19

5.20

5.15

5.13

29.3629.35

--

9 205 oC(Ethanol) 75 C16H11O3NCl4

(407.08)

47.2147.25

2.72

2.70

3.44

3.41

--

34.8434.81

10 196 oC(Benzene) 75 C16H9O2NCl4

(389.01)

49.4049.42

2.33

2.38

3.60

3.59

--

36.4636.44

11 223 oC(Ethanol) 70 C10H8O3NBr

(270.08)

44.4744.48

2.99

2.94

5.19

5.17

29.5929.58

--

References

1. M. A. El-Hashash, G. A. Abd El-Mageid, S. S. El-Kady, S. A. Mohammed, (under publication).

2. A. S. Yousef, H. M. F. Madkour, M. I. Marzouk, A. M. A. El-Soll and M. A. El-Hashash Afinidal, 61,304, (2003).

3. A. Sammour, and M. El-Hashash, J. Parket Chemie (314), 906, (1972).

4. E. A. Meade, W. L. Smith and , D. L. Dewitt, J.Boil Chem. 268, 6610, (1993).

15

5. P. Brooks, P. Emery, J. F. Evans, H. Fener, C. J. Hawkey, C. Protono, J. Smolen, F. Breedveld, R. Day, M. Dougados, E. W. Ehrich, J. G. Banos, T. K. Kvien, H. M. Vn Kijswijk, T. Wamer, and H. Zeider ,Rhevma Tology, 38,779, (1999).

6. D. Clinch, A. K. Banerjce, G. Ostrick, and W. D.Levy, J. R. Coll, Physicians Loand, 17, 228 (1983).

7. C. Patrono, and M. J. Dunn, Hidney Int., 32, 1 (1987).

8. C. Rubat, P. Coudert, J. Couqvelet, P. Bastide, and J. Bastide, Chem Pharm. Bull, 36, 1558 (1988).

9. C. Rubat, P. Coudert, E. Albuissan, J. Bastide, J. Couqvelet, and P. Tronche, J. Pharm. sci, 81, 1084 (1992).

10. F. Rohat, C. Rubat, P. Coudert, E. Albuissan andJ. Couqvelet. Chem Pharm. Bull, 44, 980 (1996).

11. P. Coudert, C. Rubat, F. Rohat, F. Leal, J. Fialip and J. Couqvelet. Pharm. Pharmucol-Commun, 6, 387 (2000).

12. S. D. Dogrver, M. F. Sahin, S. Unlu, and I. Shigeru. Arch. Pharm, 333, 79 (2000).

13. G. H. Ayed, A. A. Ismail, F. Rohat, M. El-Mobayed, and S. M. Mohamed. Commun. Fac. Sci. Univ,Ankara Ser., B. Chem. Eng. 36, 53 (1990); Chem. Abstr. 123, 25662sv (1995).

14. M. A. El-Hashash and S. I. El-Nagdy, J. Chem. Eng. Data, 29, 316 (1983).

15. Ambily M. Jacob, Roshinik. Thumpakkara, sreedharan Prathapas and Binoy Jose Tetrahedron, 61, 4601 (2005).

16. M.M Mohamed, M.A. El-Hashash, I Islamand O.A. Abo-Baker. Review roman dichimie (27), 865 (1982).

16