Studies of Nitrogen Heterocyclics of Potential Pharmacological Interest

STUDIES OF NITROGEN HETEROCYCLICS OF POTENTIAL PHARMACOLOGICAL INTEREST

THESIS SUBMITTED TO THE ALIGARH MUSLIM UNIVERSITY FOR THE DEGREE OP DOCTOR OF PHILOSOPHY IN CHEMISTRY

B V AHMED KAMAL M. Sc .• M. Phil REGIONAL RESEARCH LABORATORY HYDERABAD 1982 T2510 CERTIFICATE

The iVOAk Ivi tl%a, tkuli, kca, been aafifUzd ouut by

M/l Ahmed Kmal. I cqaX1{iLJ that it kU bona^-lde ivo^k and -li ofiiQ-ivial. It hcu, not bznn submitted ^oA uny othoA cfeg/'Lee o^ thli, on othoA UiUveA6ttlz6.

SATTUK} SZgnatuA& oi the. Guide.

Regional RueoAch LaboAcutoAy (} Hyderabad 500 009 Ind^ GH^m^S riwwartn)'"':: ^f Chemistty Ulil'U, . n >Jai\f. ,:iy a;, -t-H. ACKNOWLEDGMENT

The research work recorded in this thesis was carried out under the supervision of Dr P B Sattur, Deputy Director, Regional

Research Laboratory, Hyderabad. I am indebted to him for his keen interest and valuable guidance. I am grateful to Dr G Thyagarajan,

Director, Regional Research Laboratory, Hyderabad, for providing all facilities to carry out the work presented in this thesis and also to Council of Scientific and Industrial Research, New Delhi, for the award of a Research Fellowship.

I am thankful to Prof W Rahman, Head, Department of Chemistry,

Aligarh Muslim University, Aligarh, for helpful discussions.

I wish to express my thanks to the analytical section of the

Regional Research Laboratory, for carrying out microanalyses and recording of UV, IR, NMR and Mass spectra.

Thanks are due to M/s. Lonza & Sandoz, Switzerland, for the supply of Chlorosulfonyl isocyanate and aminobenzophenones as gift samples.

t The work in this thesis is original and has not been submitted, for any other degree of this or other Universities.

AHMEP KAMAL

Regional Research Laboratory Hyderabad 500 009 CONTENTS

Page Nos.

1. CHAPTER I

i) Introduction ... 1

ii) Present work ... 18

iii) References ... 23

2. CHAPTER II ... 25

i) Part-A ... 26

Reactions of CSI with:

a) 2-Aminobenzaldehyde ... 31

b) 2-Aininoacetophenones ... 32

c) 2-Aininobenzophenone ... 37

ii) Part-B ... 55

Reactions of CSI with:

a) 2-Hydroxybenzaldehydes & 2-hydroxyacetophenones at room temperature ... 58

b) 2-Hydroxybenzophenones at room temperature 63

c) 2-Hydroxybenzaldehydes, 2-hydroxyacetophenones/-benzophenones at elevated temperatures 67

iii) Experimental 78

iv) References 84

3. CHAPTER III 86

i) Part-A 87

Reactions of CSI with:

a) Salicylates & anthranilates at room termperature 89 11.

Page Nos.

b) Salicylates at elevated temperatures 104

ii) Part-B 109

Reactions of CSI with:

a) 2-Aminophenols 110

b) 2-Aininothiophenol 112

iii) Experimental 115

iv) References 121

4. CHAPTER IV 122

i) Part-A

Synthesis of l-substituted-5-aryl-s- triazoloC4,3-aDquinazolines ... 123

ii) Part-B

Synthesis of 5-Aryl-12H-quinazolino- C3,2-aIlquinazolin-12-ones ... 144

iii) Experimental 149

iv) References 152

5. CHAPTER V

Biological evaluation 153

i) Pharmacological activity 154

ii) Results and discussion 165

iii) Antimicrobial activity ... 168

iv) Results 174

v) References 175

6. SYNOPSIS i

7. LIST OF PAPERS PUBLISHED & PATENTS FILED viii

*** NOTE

1. New heterocyclic systems have been named in accordance with the lUPAC recommendations and as suggested by Chemical Abstract Service (Nomen- clature) .

2. IR spectra were recorded on PERKIN-ELMER Models 221 and 283B spectrophotometer equipped with sodium chloride optics in the range 4000-625 cm ^ and 4000-200 cm respectively.

3. NMR spectra were run on JEOL FT FX-90Q, VARIAN EM-390 90 MHz and VARIAN A60A 60 MHz NMR Spectro- meters . All chemical shifts are given in 6 ppm relative to TMS as internal standard in 90 MHz spectra and external standard in case of 60 MHz spectra.

4. Mass spectra were recorded on JEOL D. 300 and HITACHI RMU 6L Mass Spectrometers.

5. Melting points were determined on BUCHI 510 melting point apparatus and BOETUS heating table apparatus. Melting points are uncorrected. CHAPTER I

INTRODUCTION

Chemistry and biological activity of nitrogen heterocycles has been fascinating. Search for newer biologically active molecules through a series of synthetic manoeuvres, mimicking the naturally occuring biologically active molecules has been one of the efficient tools of the medicinal chemist. The development of newer reagents, biotransformation and feedback information from metabolic and pharmacokinetic studies made in recent years the search for new molecules of potential biological importance truly rational.

In search of new and potent molecules of biological significance the programme undergoing in this Laboratory for the last two decades led to a number of interesting biologically active molecules possessing CNS depressant, analgesic, antiinflammatory and cholesterol reducing compounds. In continuation of these efforts an attempt has been made to obtain compounds of biological significance derived from nitrogen heterocycles employing chlorosulfonyl isocyanate (I), a powerful electrophilic reagent.

0 = C = N-SO2CI

I Chlorosulfonyl isocyanate (CSI) is probably the most reactive isocyanate known which has been discovered by 6raf^. 2 3

Several reviews ' on the use of CSI have been published, however, with the emphasis on recent developments of this extremely versatile reagent a brief description is given here.

The reactions of CSI have been broadly classified into three types according to the probablP site of initial attack on CSI molecule by a given nucleophile.

Type I : Nucleophilic addition to the isocyanate

carbonyl function.

Type II : l2+2j C.ycloaddition of carbon-carbon bonds

to the isocyanate C=N.

Type III : Nucleophilic addition to sulphur. Type I : Nucleophilic Addition to the Isocyanate

Carbonyl Function

These reactions involve mainly attachment (nucleophilic attack) of N, S and 0 functions to the carbonyl group of CSI,

As would be expected of an isocyanate, CSI reacts with alcohols (or thiols) and amines to yield carbamate and urea derivatives (II), respectively.

CI502N=C = 0+ H-X ClSOoNHCX- II 0 II

X = 0. SorN

These derivatives (II), still substituted with the reactive N-chlorosulfonyl group, undergo a variety of further 3 transformations .

Because of its high reactivity, CSI also undergoes type I reactions with amides and sulfonamides. The addition products of sulfonamides can be readily converted into sulfonyl isocyanates (III) via pyrolytic elimination of 4 sulfamoyl chloride .

CSI RSO2NH2 R5O2NHCONHSO2CI

RSO2NCO 4 CI5O2NH2 111

Type II : C2+23 Cycloaddltion of Carbon-Carbon Bonds

to the Isocyanate C=N

The ability of chlorosulfonyl isocyanate to undergo cycloaddition to carbon-carbon bonds adds another dimension

to its usefulness. The most studied case to date is the [:2+2i

cycloaddition of CSI to a variety of olefins to produce

B-lactams^ (IV), an example of which is given below.

1) CSI 2) Na^SOa NH

In view of the stereospecific cis-addition of chlorosulfonyl

isocyanate to olefins and the facile cleavage of the resulting B-lactaws, this versatile reagent provides a convenient route to erythro- and threo-B-amino acids .

Rl r3 R R 2iwii i L iim R^

2/ "^R^ 2) H2O N H 0

R' R ^iiiiiii| |tiiiii R'

H2N CO2CO2HH

Type III : Nucleophilic Addition to Sulfur

Compounds that are unreactive toward the isocyanate moiety of CSI may react with the chlorosulfonyl group. An unusual type III reaction occurs between CSI and anisole,the only^product isolated being bis (4-methoxyphenyl) sulfone^ (V)

CSI

H3CO H3CO

Certain experimental conditions also promote type III

reactions. Reaction of CSI with phenols at room temperature produces the normal type I products, namely, carbamates (VI).

Above 100 C, however, this reaction is reversible, and a new type III reaction sets in, producing aryloxysulfonyl isocyanates 8 (VII)

^ ArOCONHSOpCI VI ArOH+ C5I .100 Ar0S02NC0-i- HCI

VII

Recently, CSI has been extensively employed in a variety of reactions leading to interesting compounds, g

Mehta et al ., reported the addition of CSI to indole to provide indole-3-carboxamides (VIII), indole-3-carboxylic acids and indole-3-carbonitriles (IX).

CSI CH3CN One"

DMf\CH3CN

VIII Taberk and Olivera^*^ reacted CSI with indene to yield indene-2-carboxamide (X).

1) CSI 2) H20/CaC03 CONH-

Grand et al.,^^ reacted CSI with aniline derivatives under Friedel-Crafts conditions to yield 1,2,4-benzothiadiazines.

The l,2,4-ben2othiadiazine structures are very interesting in the pharmaceutical field. For instance, the antihypertensive drug diazoxide (XI) can be easily obtained from p-chloroaniline and CSI according to the following pathway.

1) CSI

NH2 AICI3

VIII Reactions of CSI with compounds containing carbon-nitrogen 12 double bonds have been recently investigated giving synthetically useful products. For instance, benzaldehyde azine gives the stable diphenyl-triazolotriazolone (XII).

Ph 1) 2 CSI / ^nAT N-H Ph-CH=N-N=CH-Ph 2) Na250'3 H-N /

XII

13 Karady et al., described recently the reaction of CSI

with 2-aminopyridine to afford 1,2,4,6-thiatriazine-l,1-dioxide

(XIII).

+ CSI

H VIII Similarly, CSI has been reacted with isothioureas and

2-aminothiazo1ine to provide thiatriazine systems^''^ (XIV).

Sv^NH2 Y SO2 LL + CSI • N 0 XIV

Reaction of CSI with 1,2-diamines have been claimed in a German Patent^^ to afford thiatriazepinone system (XV) having diuretic activity.

R R I NH + CSI NH NH I. I I R R

XV The rich chemistry of CSI and its usefulness in the synthetic organic chemistry gave a stimulus to explore its applications in the synthesis of biologically active nitrogen heterocycles by reacting it with BIFUNCTIONAL MOIETIES. With 10

this objective, the reaction of CSI with a variety of bifunctional moieties led to a number of new and interesting nitrogen heterocycles. Hence, it would be most appropriate to review briefly the biological usefulness of some of the nitrogen heterocycles as cited in the literature.

Quinazolinones

It is interesting to observe from the literature that

4(3H)-quinazolinones and 2(lH)-quinazolinones are of immense biological importance. 4(3H)-Quinazolinones have been claimed to exhibit a broad spectrum of biological activity such as CNS depressant, analgesic, antiinflammatory and diuretic actions.

Major breakthrough in the field of 4(3H)-quinazolinones came from this Laboratory from the work of Zaheer and Kacker^^.

Amongst a number of 4(3H)-quinazolinones synthesized and tested for their biological activity, 2-methyl-3-o-tolyl-4(3H)- quinazolinone (Methaqualone, XVI) exhibited profound hypnotic action and was the first non-barbiturate hypnotic drug introduced for therapeutic use under several names through out the world.

N -(CH2)n

n-^r XVI XVII RcRUalkyl n

In structure activity relationship studies, Sattur et al.^^., synthesized a number of modified 4(3H)-quinazolinones represented by general structure (XVII). It has been observed from these studies that the removal of phenyl group at 3-position of 4(3H)- quinazolininone away from the nitrogen makes the molecule devoid of hypnotic activity but confers tranquilizing and antiinflammatory actions. This discovery has led to the synthesis of a spate of compounds in search of better and promising members.

2(lH)-Quinazolinones have been reported to possess a wide range of biological activity ranging from analgesic, antipyretic, antiinflammatory, uricosuric properties to antiviral action.

1R Hans Ott (Sandoz and Wander, Switzerland) working in the field of quinazoline chemistry obtained an interesting lead in l-methyl-2(lH)-quinazolinone (XVIII) which showed a good amount of antiinflammatory, analgesic and antipyretic activity comparable to phenylbutazone. It has no other effects on CNS and cardiovascular system. Structure activity studies in this series and their pharmacological profile led to the synthesis of l-isopropyl-4- phenyl-7-methyl-2(lH)-quinazolinone (XIX). This emerged as the most active member in the series and introduced for clinical usage 19 under the generic name Proquazone (Biarison). Proquazone with its unconventional chemical structure and being nonacidic in nature 12

makes it unique. In various clinical trials of osteoarthritis, gouty arthritis and in patients with symptoms of lumbar nerve root compression syndrome, proquazone has been found to be quite useful and well tolerated. Thus it appears to be a valuable drug.

XIX Clinical success of this drug led to development of many 20-22

other compounds belonging to the 2(lH)-quinazolinone series

such as ciproquazone (XX) and Fluproquazone (XXI).

H-jCO 13

l,3-Benzoxazine-2-ones/-2,4-diones

This class of compounds has not been investigated in much 23 detail. A British Patent claims 1,3-ben2oxazine-2,4-diones (XXII) in composition possessing hypnotic, tranquilizing and analgesic action in animals as well as in humans. Wagner et al.^^ claimed

1,3-benzoxazine-2,4-diones as having fungistatic and bacteriostatic activity.

XXII XXIII

R = H. CH3

.25 .l,3-Benzoxazine-2-ones (XXIII) have not been investigated for their biological and other properties.

1,2,3-Benzoxathiazine-2,2-dioxides

XXIV

R = CH3. CgHg 14

There has been scanty information on this class of compounds (XXIV) except antiseptic and disinfectant properties pfi claimed by Upjohn Co., U.S.A.

Fused-Triazoles

s-Triazole ring system in view of its great potentiality to fuse with other heterocyclic ring systems led to the synthesis of s-triazole fused heterocyclic ring systems such as triazolopyrimidines, triazolopyridines, triazolophthalazines, etc., exhibited interesting biological profile. Some typical examples are highlighted below.

27 Miller and Rose synthesized s-triazoloi:2,3-ci-pyrimidine

(XXV) on account of its structural similarity with theophylline

(XXVI) for evaluating it as bronchodilator.

HaCY^^NyNHz N^N- N

Pr"

XXV XXVI

3-Substituted pyridoc2,l-c:-s-triazoles^® (XXVII) have been claimed to be useful as anticonvulsants and tranquilisers. 15

Interesting cardiovascular activity has been claimed for 29 s-triazoloisoquinolines (XXVIII).

^ N

XXVII XXVIII R = CH3;C6H5

It has been observed that 1-hydrazinophthalazine

(hydralazine, XXIX) metabolizes to its acetyl derivative

(XXX). This made to presume that the acetyl derivative may further undergo an enzymatic cyclization to 3-methyl- s-triazoloL3,4-a:phthalazine (XXXI) which may be responsible for the biological activity.

NH-NH2 NH-NHCOCH3

XXIX XXX 16

Based on the above assumption a variety of substituted- s-triazoloc3,4-a:phtha1azines have been synthesized by Sattur 30 et a1., for evaluating their biological activity. In the midst of this work, Litwin et al reported that 1-hydrazinophthalazine when administered to patients is converted to

3-methyl-s-triazolo[3,4-a:phthalazine (XXXI).

XXXI

A series of 3,6-disubstituted-s-triazolo-c3,4-aDphthalazines

(XXXII) synthesized in this laboratory for testing them as hypotensive agents, were found to be not superior to the reference compound, i.e., hydralazine (XXIX); however, some members exhibited mild and transient fall in blood pressure in experimental animals.

In addition, mild to strong CNS depressant and antiinflammatory activity in some members has also been observed.

Interesting biological activity demonstrated by 3,6- disubstituted-s-triazoloc3,4-a3phthalazines led to synthesize pyridazine incorporated triazoles, i.e., 3,6-disubstituted-s- triazolo:4,3-blpyridazines^^ (XXXIII), as a part of the continuing 17

programme of work in this laboratory. These compounds exhibited

CNS depressant and antiinflammatory actions.

Q N^R .R 11 N— N N — N

XXXII XXXIII

R = R^= CH3 . CGHS PRESENT WORK

An attempt has been made to explore the usefulness of highly reactive and versatile electrophilic reagent, CSI towards its application for the synthesis of nitrogen heterocyclic compounds possessing biological importance. The present thesis comprises the detailed findings generated in the course of the work which is presented as follows.

Chapter I highlights the documented literature information on the reactions of CSI, biological importance of various nitrogen heterocyclic systems such as 4(3H)-quinazolinones, 2(1H)- quinazolinones, 1,3-benzoxazine-2-ones/-2,4-diones, 1,2,3-benzoxathiazine-2,2-dioxides and various s-triazolo-fused ring systems.

Chapter II incorporates the reactions of CSI with a variety of bifunctional moieties such as 2-amino-benzaldehyde,

2-aminoacetophenones, 2-aminobenzophenones, 2-hydroxybenzaldehydes,

2-hydroxyacetophenones and 2-hydroxybenzophenones, employing different reaction conditions.

Chapter III deals with the reactions of CSI with a variety of substituted salicylates, anthranilates, 2-aminophenols and

2-aminothiophenol. 19

Whereas, Chapter IV highlights the synthesis of

I,6-disubstituted-s-triazoloc4,3-aDquinazo1ines and quinazolino- cS ,2-aDquinazol ine-l2-ones.

Chapter V embodies the biological findings of the representative members of the compounds synthesized in Chapters

II, III and IV. 20

Important Salient Findings of the Present Work

1. The reaction of CSI with bifunctional moieties as stated in the present work has led to the development of a new alternate route for the synthesis of the following ring systems.

i) 2(lH)-Quinazolinones

ii) 2H-1,3-Benzoxazine-2-ones

ii i) 1,2,3-Benzoxathiazine-2,2-dioxides

iv) 1,3-Benzoxazine-2,4-diones

v) l,2,3-Ben20xathiazine-^,2-dioxide-4(3H)-ones

vi) Quinazoline-2,4(lH,3H)-diones.

2. The following new and novel class of heterocyclic ring systems have been obtained for the first time.

i) 6-Methyl-l,3,5-benzoxatriazocine-2,4(lH,3H)-

diones (XXXIV)

H H

XXXIV

R = H, Br. N02 21

ii) 3H-l,2,3,5-Benzoxathiadiazepine-2,2-dioxide-

4(5H)-ones (XXXV)

XXXV

R = H, CI

iii) 3H-l,2,3,5-benzodithiadiazepine-2,2-dioxide-

4(5H)-one (XXXVI)

/N^cf N-H

// ° 0 XXXVI 22

3. Significant chemotherapeutic/biological findings

i) A broad spectrum of fungicidal activity has been

exhibited against Pencillium tardum, Helminthos-

porium halodes and Fusarium oxysporium by 7-ch1oro-

5-pheny1-l-styry1 -s-triazo1o[:4,3-a:quinazoline

while other members of the series showed no

significant activity.

ii) Potent antiinflammatory activity has been exhibited

by the following compounds:

(a) 6-Chloro-4-methyl-2H-l,3-benzoxazine-2-one

(b) 6-Chloro-l,2,3-benzoxathiazine-2,2-dioxide

(d) l-(4-Methoxybenzyl )-7-ch^oro-5-phenyl-s-

triazoloc4,3-a:quinazoli^e

(e) 1-(4-Chlorophenoxymethyl)-7-chloro-5-phenyl -

s-triazoloc4,3-aiquinazoline. 23

REFERENCES

1. R. Graf, Org. Syntheses;^, 23 (1966).

2. J.K.Rasmussen and A. Hassner, Chem.Rev. 76(3), 389 (1976).

3. W.A.Szabo, Aldrichima Acta, 10(2), 23 (1977).

4. R.Appel and M.Montenarh, Chem.Ber., 1^706 (1974).

5. D.H.Ane, H.Iwahashi, and D.F.Shellhatner, Tetrahedron Lett. 3719 (1973).

6. A.I.Meyers, "Heterocycles in Organic Synthesis", John Wiley & Sons, Inc., New York, N.Y., 1974, pp 285-286.

7. F.Effenberger, R.GIeiter, L.Heider and R.Niess, Chem.Ber., 1^, 502 (1968).

8. G.Lohaus, Chem.Ber. 105, 2791 (1972).

9. G.Mehta, D.N.Dhar, S.C.Suri, Synthesis, 374 (1978).

10. D.Taberk, De Olivera, Org.Prep.Proced. Int., 8, 243 (1976).

11. Y.Grand, J.G.Atkison, J.Rokach, J.Chem.Soc., Perkin Trans.I, 1043 (1979).

12. H.Suschitzky, E.R.Walrond, R.Hull, J.Chem.Soc., Perkin Trans. I, 47 (1977).

13. S.Karady, J.S.Amato, D.Dortmund, A.A.Patchett, R.A.Reamer, R.J.Tull and L.M.Weinstock, Heterocycles, 12, 815 (1979).

14. S.Karady, J.S.Amato, D.Dortmund, A.A.Patchett, R.A.Reamer, R.J.Tull and L.M.Weinstock, Heterocycles, 12, 1199 (1979).

15. E.Otto, Ger.Offen., 2,409,355; Chem.Abstr., 84, 59606 q (1976).

16. I.K.Kacker and S.H.Zaheer, J.Ind.Chem.Soc., 344 (1951).

17. S.H.Zaheer, G.S.Sidhu, P.B.Sattur, U.K.Sheth and V.H.Shethy, Proc.Sym.CNS drugs, CSIR, New Delhi, 1966, pp 170-189.

18. Hans Ott, Fr. 1,571,271; Chem.Abstr., 72, 100739 c (1970). 19. H.U.Gubler and M.Baggiolini, Scand, J.Rheumatology, Suppl. 21, 8 (1978).

20. R.v.Coombs, R.P.Danna, M.Denzet, G.E.Hardtmann, B.Huegi, G.Koletar, H.Ott, J.Med.Chem., 16, 1237 (1973).

21. H.Yamamoto, C.Saito, S.Inaba, H.Awata, M.Yamamoto, Y.Sakai and T.Komatsu, Arzneim. Forsch. (Drug Res.) 1266 (1973).

22. R.C.Hill, R.W.Foote, D.Roemer, Arzneim, Forsch. (Drug Res.) 31, 871 (1981).

23. Aspro-Nicholas Ltd. Brit.Pat., 9,50,065; Chem.Abstr., 11859 d (1964).

24. G.Wagner, D.Singer and W.Wenffen, Pharmazie, 161 (1966).

25. S.Polazzo and M.G.Marino, Gazz.Chim.Ital., 811 (1964); Chem.Abstr. 16065 g (1964).

26. Upjohn Co. Neth. Pat., 6,604,032; Chem.Abstr., 46440 j (1967)

27. G.W.Miller and F.L.Rose, J.Chem.Soc. 5642 (1963).

28. J.B.Bicking, U.S.Pat., 2,917,511; Chem.Abstr., 54, 8854 (1960).

29. J.R.Geigy, Neth.Pat. 6,614,979 (1967).

30. P.B.Sattur, Personal communication.

31. A.Litwin, L.E.Adams, V.Hess and Joseph, Arthritis and Rhuematism, 16, 2 (1973).

32. K.Rama Rao and P.B.Sattur, Ind.J.Chem. 168, 163 (1978). CHAPTER 11

This chapter is divided into parts 'A' and 'B' which describe the reactions of chlorosulfonyl isocyanate with the following:

PART A

2-aminobenzaldehyde, 2-aminoacetophenones and

2-aminobenzophenones;

Synthesis of

2(1H)-QUINAZ0LIN0NES

PART B

2-hydroxybenzaldehydes, 2-hydroxyacetophenones and

2-hydroxybenzophenones;

Synthesis of

l,3-BENZ0XAZINE-2-0NES &

l,2,3-BENZ0XATHIAZINE-2,2-DI0XIDES 26

PART 'A'

It is known from the earlier literature that reactions of chlorosulfonyl isocyanate (CSI) with various aromatic amines have led to the formation of N-chloro- sulfonylureas^. However, it is interesting to observe that the reaction of CSI with molecules having bifunctionalities such as 2-aminobenzaldehyde, 2-aminoacetophenones and

2-aminobenzophenones have not been investigated. Thus it appeared of interest to carry out the reactions of CSI with 2-aminobenzaldehyde, 2-aminoacetophenones and

2-aminobenzophenones to obtain 2(lH)-quinazolinones.

Various methods have been documented in literature for the preparation of 2(lH)-quinazolinones and are reviewed below.

2 Gabriel and Posner reported the preparation of

2(lH)-quinazolinones by heating 2-aminobenzaldehyde and urea.

H2N \ c=o H2N / 27

Recently, Kla^ii reported the preparation of

2(lH)-quinazoTinones by reacting 2-(dichlorornethyl )-

phenyl isocyanates with ammonia to obtain the urea derivative which was later cyclized in ethanolic anmonia.

N-C-NH? I II ^ H 0

Armarego and Smith synthesized 4-methyl-

2(lH)-quinazolinones by reacting 2-aminoacetophenone

with ethyl chloroformate in presence of sodium hydroxide.

2-Ethoxy carbonyl aminoacetophenone obtained as an intermediate - was cyclized by heating it with ethanolic

ammonia under pressure.

0 II +• H5C2O-C-CI

NH3

-C-OCoHc I il ^ ^ H 0 28

Gabriel and Stelzner first prepared 4-phenyl-

2(lH)-quinazo1inone by heating 2-aminobenzophenone and urea.

H2N \ x ^N :c=o O H2N / I H

Summitomo Chemical Co., Ltd., Japan, in a recent

Patent^ claimed the preparation of substituted 4-phenyl-

2(lH)-quinazolinones by the reaction of 2-aminobenzophenones

with oxalyl chloride and sodium azide.

+ (CIC0)2 +NaN3

Bell et al7 in an U.S.Patent claimed the preparation

of 4-phenyl-2(lH)-quinazolinones as follows.

C6H5

+ PhOCOCl 29

Oxidation of 2-amino indole by ozonolysis in acetic o acid have been reported by Ishizumi et al. to give 6- chloro-l-methy1-4-phenyl-2(lH)-quinazolinone along with

6-ch1oro-2-imino-3-indol inol.

C6H5

In a German Patent 6-chloro-l-methyl-4-phenyl-2(lH)' quinazolinones have been reported to be prepared by the treatment of indo1e-2-azides with oxidizing agents like chromic oxide or ozone.

X6H5

X/^N-^CONs CH3 30

Recent Japanese Patent^*^ claimed the preparation of

6-ch1oro-l-methyl-4-phenyl-2(lH)-quinazolinone in the following manner.

C6H5

ClC0N=CCl2 + or NH CICONCO CH3

It is thus seen from the literature that most of the methods described for the preparation of 2(lH)-quinazolinones are tedious and the yields are generally unsatisfactory. In the present investigation the electrophilic reagent, CSI which is now commercially available has been employed for the synthesis of 2(lH)-quinazolinones. As already stated earlier, the following bifunctional compounds have been selected for carrying out the reactions with CSI:

1) 2-Aminobenzaldehyde

2) 2-Aminoacetophenones

3) 2-Aminobenzophenones

2-Aminobenzaldehyde 11 , 2-amino-5-bromoacetophenone 12 13 14 2-amino-5-nitroacetophenone , 2-amino-5-chlorobenzophenone

and 5-chloro-2-methylaminobenzophenone^^ required as starting materials for the reactions have been obtained as described

in the literature. 31

REACTION OF 2-AMINOBENZALDEHYDE WITH CSI

+ 0 = C = N-S02CI

Freshly prepared 2-aminobenzaldehyde is reacted with CSI to obtain 2(lH)-quinazolinone (I) in 38% yield,

There has been some tarry material which could not be worked up further. 32

REACTION OF 2-AMINOACETOPHENONES WITH CSI

+ 0 = C=N-502CI

II in IV

R = H, Br, NO2

2-Aminoacetophenone on reaction with CSI gives the following three products.

i) 4-Methyl-2(lH)-quina2olinone (II, Table 1)

ii) 4-Methyl-lH-2,l,3-benzothiadiazine (III, Table 2)

iii) A new heterocyclic ring system, i.e., 6-methyl-

l,3,5-benzotriazocine-2,4(lH,3H)-dione (IV, Table 3)

These have been characterized by elemental analysis and

spectroscopic methods. 33

TABLE 1

4-Methy1-2(lH)-quinazo1inones

Elemental Analysis Yield S.No. Found 0/ (%) (calcd.)^°

1. 42 227-228* 67.32 4.95 17.58 (67.49) (5.03) (17.49)

2. Br 35 242-243 45.52 2.81 11.48 (45.21) (2.95) (11.71)

3. NO. 39 268 52.46 3.23 20.16 (52.69) (3.44) (20.48)

* Lit.^ m.p. 230°C 34

TABLE 1

4-Methy1-lH-2,l,3-benzothiadiazine-2,2-dioxides

Elemental Analysis Found 0/ S.No. R m.p.(°C) (calcd.)^° C ' H

1. H 10 210-211* 49.28 4.21 14.46 (49.49) (4.08) (14.29)

2. Br 8 256-258 39.29 3.28 11.68 (39.53) (2.90) (11.52)

3. NO2 9 260 45.65 3.21 20.15 (45.94) (3.38) (20.09)

* Lit.^^ m.p. 209-211°C 35

TABLE 1

6-Methy]-l,3,5-benz0tria20cine-2,4(lH,3H)-di0ne

Elemental Analysis Found 0/ Yield (calcd.)^° S.No. m.p.(°C) {%) C H

1. 15 283 59.27 4.31 20.81 (59.11) (4.46) (20.68)

2. Br > 300 42.43 2.91 14.98 (42.58) (2.86) (14.90)

3. NOg 12 > 300 48.23 3.18 22.36 (48.39) (3.25) (22.57) i o Lo

«-) o

>- UJ r) o 1 ^ o -irOt CM

-oO o

o -iTo) s

u£ — (9 c

5 I

4 36

The IR spectrum of 6-niethyl-l,3,5-benz0tria20cine-2,

4(lH,3H)-dione (Fig.l) shows NH absorptions between 3410 cm'^ and 3165 cm"^. The two C=0 absorptions are seen at 1670 ctn"^ and 1630 cm"^, while C=N absorption is observed at 1580 cm"^.

TABLE 4

^H-NMR of 6-niethyl-l,3,5-benzotriazocine-2,4(lH,3H)-dione (Fig.2)

Chemical shift No. of Multiplicity Assignment (ppm) protons

11.87-12.12 1 broad hump H^-N-

10.12-10.48 1 broad hump H^-N-

7.0 - 7.54 4 multiplet aromatic

3.2 3 singlet H3.C- 37

REACTION OF 2-AMINOBENZOPHENONES WITH CSI

+ 0=C=N-502CI

NHR

QJL.A .XJNo' . I R

R = H.CH3; X = X' = H,CI

The reaction of 2-aniinobenzophenones with CSI gives

4-aryl-2(lH)-quinazolinones (V, Table 5) along with

4-aryl-lH-2,l,3-benzothiadia2ine-2,2-dioxides (VI, Table

6) as coproducts which are easily separable from the quinazolinones. Thus these reactions afford a novel method of synthesis for 4-aryl-2(lH)-quinazolinones £

tu 6 g CI Ui ucc.

-oO tmx

o o nin o s

lU3 O s ^^ cr u.

o •tn8

-s 38

in good yields. The reaction products have been characteri-

zed by elemental analysis, IR, NMR and mass spectra.

It is observed that in the reaction of 2-aminobenzophenone with CSI, eight membered benzotriazocine system which has been

obtained in case of 2-aminoacetophenones is not formed. This may be due to the decreased reactivity of the benzophenone carbonyl

carbon.

IR spectrum of 4-phenyl-2(lH)-quinazolinone is shown in

Fig.3, N-H absorption is seen at 3005 cm"^ while C=0 absorption

is observed at 1660 cm"^.

IR spectrum of 4-phenyl-lH-2,l,3-benzothiadiazine-2,2-dioxide

is shown in Fig.4, N-H absorption is seen at 3240 cm~^ while SO2

stretchings are observed at 1140 cm~^ and 1305 cm'^. 39

TABLE 5

4-Ary1-2(lH)-quinazo1inones

.1 Yield m.p.(°C) S.No. R (lit. m.p.)

1. H H 66 261-262 (255-256)'

2. H CI H 72 318-320 (318)®

3. CI C1 70 326-328 (330)®

4. CH^ H 78 142-144 (142-143)-

5. CH3 C1 H 81 226-227 (222-223)-

6. CH, CI CI 75 237-239*

Found •Elemental Analysis, (calgdii; C H N 60.24 3.12 9.11 (59.02) (3.30) (9.21) 40

TABLE 1

4-Ary1 - lH-2.1,3-benzothiadiazine-2,2-dioxide ©

Yield m.p.(°C) S.No. R (%) (lit.ni.p.)

1. H H H 8 214.215 (216-217)^^

2. H CI H 6 207-208 (207-209)^^

3. H CI CI 7 197-198

4. . CH3 H H 5 209-210 (206-208)^^

5. CH3 CI H 5 192-193*

6. CH3 CI CI 6 215-217**

Elemental Analysis Found 0/ (calcd.)^° C H N * 55.21 3.46 9.43 (54.73) (3.58) (9.12)

** 49.16 2.79 8.42 (49.28) (2.95) (8.21) 41

The formation of 2(IH)-quinazolinones may proceed as shown in Scheme I.

An initial attack of the lone pair of electrons of the amino group to the electrophilic carbon of CSI and a simultaneous bond formation between CSI nitrogen and acetophenone/benzophenone carbonyl resulting in the formation of cyclized N-sulfonyl chloride intermediate (A).

5O2CI SO2CI

^^^X-^NH? + C II 0

+ H2O

-H2O

SCHEME I 42

Intermediate (A) on treatment with water is hydrolysed to the compound (B) which loses water in acidic medium to give

2(lH)-quinazolinone (C).

The formation of lH-2,1,3-benzothiadiazine-2,2-dioxide may probably proceed as shown in Scheme II.

0=0

SO2CI

(A)

-CO2

-HCl

SCHEME n 43

In the case of benzothiadiazine formation, an initial attack takes place from the C=0 function to the electrophilic carbon of CSI to form a four membered cyclic transition state

(A), which then 1 oses COp to form azomethine intermediate (B).

The intermediate (B) cyclizes to the product (C) by the elimination of HCl.

The formation of 6-methyl-l,3,5-benzotriazocine-2,4-

(lH,3H)-dione by the reaction of CSI with 2-aminoacetophenone may probably proceed as shown in Scheme III.

An initial attack of the lone pair of C=0 function to the electrophilic carbon of CSI takes place to form a four membered cyclic intermediate (A) which reacts with another molecule of CSI to obtain the intermediate (B). The formation of (B) may proceed in a concerted way involving the initial attack of the lone pair of electrons from the amino group of intermediate (A) to the C=0 of the second CSI molecule along with a simultaneous attack of the C=N of CSI on the C=0 of the four membered intermediate (A). The intermediate (B) (not isolated) on treatment with water affords the product (D) via the unstable intermediate (C) by losing a molecule of water. The formation of (D) takes place irrespective of the substitutions in the aromatic nucleus. However, interesting enough is, that if the methyl group is replaced by an aryl moiety, formation of (D) is not observed. 44

H3C ^ /P

"^sojcn

NH2 N SO2CI

H3C OH 5O2CI

+ H2O I

'N—C N- SO2CI I II H 0 H

CN n—H

(D)

SCHEME III Ippm Otfxl r

H cS(CDCIj) . « O2O ochlngi I

1 , 1 :. 1 71 „: i 1 1 I • 1 :: . 1 10 9 s ® ppmiM® 4 3 2 t 0 FIG 5

(CDClj)

•f r PPM (6) Fig 6 45

The ^H -NMR spectra of the following two representative compounds is given in Tables 7 and 8.

TABLE 7

^H-NMR of 4-phenyl-2(lH)-quinazolinone (Fig.5)

Chemical shift No. of m i4.- -4. a • j. (ppm) protons Multipncity Assignment

13.15-13.4 1 broad -N-H^

7.3 - 8.0 9 multiplet aromatic

TABLE 8

^H-NMR of 6-chloro-l-methy1-4-phenyl-2-(lH)-quinazolinone

Chemical shift No. of (ppm) protons Multiplicity Assignment

7.3-8.0 8 multiplet aromatic

3.7 3 singlet -f^'^iia 46

Mass spectral studies

It appeared of interest to study the mass spectra of

4-aryl-2(lH)-quinazolinones, 1-methyl-4-aryl-2(lH)-quinazolinones and 6-methyl-(lH,3H)-l,3,5-benzotriazocine-2,4-dione in view of their structural novelty.

4-Ary1-2(IH)-quinazol inones

In the present work, the fragmentation pathways proposed are supported by deuterium labelling and by the presence of metastable peaks.

Vd, X = H ; X^ = H Vd, X = CI ; H Vf, X = CI ; X^ = CI

The detailed fragmentation pattern in respect of

Va (Fig.7) is given in Scheme IV. The mode of fragmentation

observed in case of Vb and Vc having one and two chlorine

atoms is essentially the same as that of Va. S g 5 RELATIVE INTENSITY*/. 47

A¥ Ivjj -N' h m/t 194(cJ)

•f m/t17» /e4i0(c)

-HCN

m/« 152(h) m/«103(k) 48

The salient features observed in the fragmentation are as follows:

1. (M-1) ion is prominent and is the base peak. This probably occurs by the elimination of H" from -N-H or by participation 18 of hydrogen from the phenyl group (proximity or ortho-effect) ,

1.e., ions (a) and (b), respectively.

This is ascertained by deuteration studies, i.e., from the mass spectrum of l-deutro-4-phenyl-2(lH)-quinazolinone where

(M-2) ion forms the base peak, substantiating that the loss of deuterium from -N-D to be more facile compared to the loss of H' from phenyl group, which may be due to the aromatization of pyrimidine moiety in the quinazoline system.

2. The (M-2) ion (c) is also observed which results by the elimination of two hydrogen radicals by both the above mentioned processes.

3. Loss of CO from the molecular ion gives ion m/e 194 (d) which on rearrangement loses N2 to give ion m/e 166 (e). Ion (e) loses CgHg to give ion, m/e 89 (f).

4. Molecular ion (M"^') loses HNCO to furnish m/e 179 (g) which on rearrangement loses HCN to give ion m/e 152 (h).

5. Loss of NCO' from the molecular ion gives m/e 180 (i) which further loses CgH^ as well as CgHg to give ions m/e 104 (j) and m/e 103 (k), respectively. 49

1-Methyl-4-ary1-2(IH)-qui nazol1 nones

l-Methyl-4-pheny1-2(lH)-quina2o1inones have been subjected to electron impact to study their fragmentation pathway. In the present study the fragmentation mechanisms proposed are supported by deuterium labelling and by the presence of metastable peaks.

Vd, X = H ; X^ =H Ve, X =Cl; X^ =H Vf, X rCl; X^ =Cl

The salient features of the fragmentation with respect to compound Vd (Fig.8) are depicted in Scheme V. The compounds Ve and Vf also exhibit a similar fragmentation pattern.

The study revealed the following interesting observations:

1. In compound Vd when N-1 carries a methyl group, the molecular ion appearing at m/e 236 (M^') forms the base peak.

2. The (M-1) ion m/e 235 (a) is observed which results by the elimination of H' either from -N-CH^ or phenyl group. When both

these processes operate (loss of two hydrogen radicals) one would CD o .mg

o O o 4 - O O o>. S2 rM

a> §

O CO S- o

o s- o f a L fvi b U,

o. O O

§-= § O 00

n U] S s

O O Q oo OOOO oooo o o o o o O CT) 00 <5 IT) ^ 00

V ^ N -C6H5 V +7N II II CH2 CH-

m/e 220(b) m/e 130(e) m/e 207(c)

-CgH^iCN -ch3 -CHO,

-H V -N'^0 m/e 10A(d) CH3 CH3 m/e 235(Q) m/e 236(M'^')

• « -CH3CNO -CH.

m/e 90( f)

CH, m/e 194 51

expect (M-2) ion, but it is interesting to observe the absence of (M-2) ion. The presence of only (M-1) ion peak is probably due to the expulsion of H' from phenyl group and not from -N-CH^. This is confirmed by deuteration studies.

Thus, the mass spectrum of l-{deuterated-methyl)-4-phenyl-

2(lH)-quinazolinone (Vd*) does not show (M-2) ion peak

(loss of D") but exhibits only (M-1) ion peak thereby revealing the loss of H' from the phenyl group.

3. The loss of CH^ takes place from (M-1) ion and not from the molecular ion; this is supported by the appearance of the corresponding metastable peak. The above contention is further evidenced by the appearance of a peak at m/e 220 (b) in the spectrum of deuterated-methyl analogue.

4. It is interesting that the mass spectrum of Vd shows

(M-29) ion (c), instead of (M-CO) ion, probably formed by the elimination of formyl radical from the molecular ion and is substantiated by a corresponding metastable peak. The mechanism of this fragmentation may proceed as shown in Scheme VI. The mass spectrum of deuterated-methyl analogue revealing the loss of CDO" further confirms the proposed pathway.

5. The ion m/e 207 (c) formed by the loss of CHO' from the molecular ion further loses CgH^CN and CgH^ to give ions, m/e 104 (d) and m/e 130 (e), respectively. Ion m/e 104 fragments 52

to give ion m/e 90 (f) by the loss of CH2.

6. The molecular ion loses NCO' and CH^NCO to give ions m/e 194 (g) and m/e 179 (h) respectively. Subsequent fragmentation takes place as shown in Scheme V.

C6H5 C6H5

C6H5 96H5 96H5

-CHO

SCHEME VI 53

6-Methy1-(lH,3H)-1.3.5-benzotriazocine-2,4-dione

6-Methyl-(lH,3H)-l,3,5-ben20triazocine-2,4-dione being a new heterocyclic system is subjected to electron impact (Fig.9) to study its fragmentation pattern which is given in Scheme VII.

The important features observed in the fragmentation pattern are given below.

1. The molecular ion m/e 203 is the base peak.

2. The molecular ion loses H" to give the ion m/e 202.

3. The molecular ion by the loss of OH'gives the ion m/e 186 which fragments by the loss of CO and CH^CN to give the ions m/e 158 and m/e 145, respectively.

4. The ion m/e 145 further loses CN" to give the ion m/e 119.

5. "The molecular ion also loses HNCO to give the ion, m/e 160

i.e., 4-methyl-2(lH)-quinazolinone. This fragments by the

subsequent loss of NCO'and CHj to give the ions m/e 118 and m/e

103.

6. The ion m/e 160 further fragments by the loss of CO to give

the ion m/e 132. n O CM 1-t-gM (D 00 COO

00 0i0n 4s

O oo Jh

-SL "" cnO o -o u O) «0 o _ CO

CO to o

t-C Mo

1 1 r TO 1 r O) 8 R 8 SI? ^ R CoN i:o: O RELATIVE INTENSITY V. 54

COh

mAt 132

ch, C", ch3 I ^ -h ^-hnco f^

I II I H H 0 0 + m/t m/e 160 m/e 203(M'+-') 21 2

-OH -NCO

CH,

-co

^N-C I +y H m/e 158 m/e118 m/el66

-ch, —chjcn

-CN /

m/t 103 m/e U5 m/e 119

SCHEME 311 55

PART 'B'

The reaction of chlorosulfonyl isocyanate (CSI) with phenols at room temperature is known to give N-chlorosulfonyl- 19 arylcarbamates . On the other hand when CSI reacts with phenols at higher temperatures, then corresponding aryloxysulfonyl on isocyanates are formed giving off hydrogen chloride.

Ar0C0NHS02Cl

ArOH • CI5O2NCO

In view of the earlier work on the reactions of CSI

with 2-amino substituted benzaldehydes, acetophenones and

benzophenones, it was considered of interest to further

investigate the reactions of CSI with various 2-hydroxy

compounds such as 2-hydroxybenzaldehydes, 2-hydroxyaceto-

phenones, 2-hydroxybenzophenones at room te mperature as

well .at higher temperatures to synthesize 2H-1,3-benzoxazine-

2-ones and l,2,3-benzoxathiazine-2,2-dioxides, respectively. 56

2H-l,3-Benzoxazine-2-ones

21 In literature 2H-l,3-benzoxazine-2-ones have been synthesized by heating 2-hydroxyacetophenone and urea.

H2N \ ,C = 0 H2N /

Similarly, when 2-hydroxybenzaldehyde was heated with 21 urea, 4-ureido-2H-l,3-benzoxazine-2-one was obtained and not the desired 2H-l,3-benzoxdzine-2-one. ^

H2N SL„X \ C = 0 H2N /

1.2,3-Benzoxathiazine-2.2-dioxides

John B.Wright^^'^^ for the first time reported the

synthesis of 1,2,3-benzoxathiazine-2,2-dioxides by the 57

condensation of 2-hyclroxyacetophenones or 2-hydroxybenzophenones with large excess of sulfamide. This is the only method known

in the literature for the synthesis of this heterocyclic system.

+ H2NSO2NH2

R = CH3.C6H5

In the present study CSI has been employed with a view

to develop a better synthetic route for the preparation of

2H-l,3-benzoxazine-2-ones and 1,2,3-benzoxathiazine-2,2-dioxides.

Thus, CSI has been reacted with the following at room temperature

and at higher temperatures.

1) 2-Hydroxybenzaldehydes

2) 2-Hydroxyacetophenones

3) 2-Hydroxybenzophenones

24 25 2-Hydroxyacetophenone and 5-chloro-2-hydroxy-benzophenone

required as starting materials have been prepared by the literature

methods. §

o l-o ID

o . o o CM z o

o -mO «M

•o O o

o -o 58

REACTION OF 2-HYDROXYBENZALDEHYDES AND 2-HYDR0XY-ACET0PHEN0NE$ WITH CSI AT ROOM TEMPERATURE

+ 0 = C=N-502CI

-C-NH2

R = H , CH3 ; RIH,CI,CH3

The reaction of CSI with 2-hydroxybenzaldehydes and

2-hydroxyacetophenones in dichloromethane or benzene give

2H-l,3-benzoxazine-2-ones (I) in yields ranging from 48-73%

(Table 9), as well as 0-carbamoyl-2-hydroxybenzaldehydes/

O-carbcmoyl-2-hydroxyacetophenones (II), in poor yields

(Table 10) which are easily separable from benzoxazinones.

It is thus seen that this method offers a convenient route for the preparation of 2H-l,3-benzoxazine-2-ones from 2- hydroxybenzaldehydes or 2-hydroxyacetophenones.

The IR spectrum of 2H-l,3-benzoxazine-2-one is given in Fig. 10

C=0 and C=N absorptions are seen at 1720 cm"^ and 1590 cm"^, respectively. 59

CO C\) CO i—t in r^ CO in » » •53- ^

I/) cn cr> to -O >> -l-> r- n3 o E o •=C T3 -O ^ ro CO CTi 00 C U CO t—f CM 00 P^ f—ra O r~rtJ 00 CO Cd C\J +J U_ U C 0)

^ , . —^ CO t—1 (X) —1 o CM CO cn ro 1in in m CM CM CM CM VD in m V - —-

ra CM CM a O O CM —- z ^ 2: — O r-W r— in >4o- z: C_3 CsO- o tc «3- r-l VO 0) in 00 JZ CM c "o 00 I-H 00 r-l 00 CM 0 O ' O - 1 CM 1 CM tt) c LU •f o CM _J N o § 00 CD fO CVJ CM CM C X I 1 I 0 O a.* o N in 00 00 C E CJ CJ CM OJ cn

1—1 1 •o 00 rv. in CM

J- CVJ QQ cx:

zo CO CM CO CM CTl cr> Ln Ln o z: 1 00 LD CM 1-H O 1-1 00 o CM O 00 00 r^ 00 00 00 0—0 —' —' — *I1/1

—. ,—- ^—- ^— ^—^ fO 00 O 00 ro 00 CM CO ro 00 c -a "o 1 1—1 ro CM o CO O OO 1—1 1—1 St C (_> • • • • 3 —r OO OO CM ro Ln Ln —1 O fO —^ ^ —- . in tn re u- u c CD ,—V ^—^ ^—^ E OO CO r^ LD CM LD I—1 LD 1-4 ID

ro E O CM O CM CM CVJ S- ca ^ z: ^ z: ^ O — o ^ o O CM r— VC •— IX) CM 2: CM M- O CJ) cri . cn • c r^ 1—1 LD LD a: Ln Ln o VD a: CT) •r cr^ o r-^ o t^ u zr.CTl «—I CT^ r-l CTl >—1 1—11—1 O —- C_> ^ o —- o —- cr.

CO + - lO

ro CM o <_a:> C3l

m o

ro CO OO OO a: IC n: IECO 0£. CJ tJ o CJ)

O z: 00 <3- lO V£> 00 61

C\J tCoO 0<30- ro O co 00 -a c o u ft3 c "o "o CSJ CO •a: c u OJ o t— O3 (Tr3— (O U- (J •4->

t/> cu cX> a. oI o V£> -O E >> 1 CvJ 1 T3 o E q; o >- JD «S-3 O 1 o C\J o a:

00 CVJ , , , , , , ^ 1—1 ro C!0 CM

CTO T 3 "O d C

O") oo ro ro ro O o O O O z: —. ro^ z: z ^ z: -- o i- o O CM 1— 1X3 f— t—1 CM 1-1 C\ M- CQ C_) CJ KO r-H r-H cri CTl CO ro CO ro ro ^ r^ n: r^ n: >—1 n: r-H •X.o o^ o a nz00 CM CTl I—1 CTl CM CTl Cvl I—1 1—1 rH r- C_3 —^ O —' o "O +-c> o o O CO LD ro o r-v

XJ vo ir> in 00

ro s. IT oo CO to— rr O a: a:

CO r— a: 3: o •c t_p QC

oo CO CO CO CO n: :r IC zc o OZL. o o

• 00 CO ••a-' ID vo 00 63

REACTIONS OF 2-HYDROXYBENZOPHENONE WITH CSI AT ROOM TEMPERATURE

?6H5

+ 0=C=N-S02CI

R =R^= H ,CLCH3

It is interesting to observe that the reaction between

CSI and 2-hydroxybenzophenones, give O-carbamoyl-2-hydroxybenzophenones (III) and not the desired 4-phenyl-2H-l,3- benzoxazine-2-ones (IV), which is probably due to the decreased reactivity of the benzophenone carbonyl carbon.

The compounds obtained are given in Table 11. 64

OU r-H o CO Cvj O 00 •f— in LD X+-J> 01 c >> —s o

fO CO r— o 3 CO O O O t—I CM O tx) l/l t- T—I 1—I • QJ x: a: u-> c 'o i-H Od 1-H CM 0 o —' 0E1 ^ rg OL x N Z C I CD cu o CO d >> o CO o T—I X r—I 0 I I s- a. o T3 00 d- ^ 1 cr CM f—I >> XJ (O CO 1 0) ^ 00 CD JD (ID- <_)

zo CO CM 65

C\J O r^ CTi un C7i ro 00 o ID VD CO Ln tn Ln •a- ^

to CO OJ Ln oo Ln 00 CTl >, -e-s ro ro <-H CM i-H ro C -O T3 ro ro Ln Ln Ln Ln cC C O 3 r- 1— O n3 ro U. O +J -—• C OJ IT) U.O CM CO r^ t—i B U3 cn rooo 0L0n O) o ro Ln CM 1—1

fO ro ro 3 o o O ro o —~ z ^ z ^ o ro ro ro ro CM O ID .—I 1—t • t-H n: tI D in in Ln cn Ln Ln Ln Ln nzLn 00 -o I—I CSJ t-H cnj rH CM <_3 o <—< C^M o o • c o

o CT) 00 o m VD i-H r-H r-H oa I I I < ID IT) 0LT0) VoD

•O vo OJ CO Ch >- 00 cn 00

m ro o C_)

00 a:ro o o

zo C/1 ro Ln VD )C

o .o

o _ino CM

O .O rOo

O -i/O> r' 1

V pi

s ? » to E o u.

.16 66

The products have been characterized by elemental analysis, IR and NMR spectra.

The IR spectrum of 0-carbamoyl-5-chloro-2-hydroxybenzophenone is given in Fig.11, NH^ absorptions are observed at 3420 cm"^ and 3300 cm"^. The carbamoyl C=0 and benzophenone

C=0 absorptions are seen at 1715 cm"^ and 1655 respectively,

TABLE 12

^H-NMR of 0-carbamoyl-5-methyl-2-hydroxybenzophenone (Fig.12)

Chemical shift No. of Multiplicity Assignment (ppm) protons

7.07-7.85 multiplet aromatic

5.03 2 broad -N-H^

2.35 3 singlet -CH3 67

REACTION OF 2-HYDROXYBENZALDEHYDES, 2-HYDROXYACETOPHENONES AND 2-HYDROXYBENZOPHENONES WITH CSI AT HIGHER TEMPERATURES

In view of the earlier observation that the product of reaction of CSI with the phenolic hydroxy group is greatly influenced by temperature, it is desired in the present study to carry out the reaction of CSI with 2-hydroxybenza1dehydes, 2- hydroxyacetophenones and 2-hydroxybenzophenones at elevated temperatures (100-105°C) in toluene or chlorobenzene.

C1S02N = C=0 100-105 °C

R = H,CH3,C6H5 R^ = H , CI R2 = H, CI,CH3

The products of the reaction obtained are 1,2,3- benzoxathiazine-2,2-dioxides (V) in good yields (Table 13) and have been characterized by IR, NMR and mass spectra. 68

This reaction may proceed in a concerted fashion by the evolution of hydrogen chloride and carbondioxide via inter- 20 mediate (A) to give (B) as shown below. It is reported that the reaction of CSI with the hydroxy group of phenols above

100°C proceed irreversibly at the sulfonyl site instead of isocyanate function, giving off hydrogen chloride to form sulfonyl isocyanates.

(A)

-CO2

(B) •

R= H,CH3 . CgHs 69

vo LO CM r^ O CO LD Ln ro cn r-H CM O r-. UD ITS r^ i/i re C X) T3 ^—- ^ s T3 cc c u 1—t tn 1LD 00 CO I—1 -t-J 3 t— 00 I-- cn CO (£3 LD IX) E 1— Ore • • • • • • • • O re Li. u CM 00 11— ! OO ro CM CM o +c0

1— 1/1 OO oo 00 in £ 1 00 o oo o cu u 1 oo —- z —~ 00 —K •p•D— o 1 o CM r— 1X3 o CM I— UD <+- 1 2: • O • O X • • m OO 1— 0 r— 1 00 nr T-H CTl rc 00 •— r o 1 zn I—1 CM 1—1 •O s: 1 o o ^ o CO 00 CVI 1 —' • Cvl CO (SJI LD (U —- Ol CO O 1 LD CQ o • "sa- CM CM OO c Nl O E r-H t—1 t-H (O t t 1 1 1 •r— • 4-) CM CM cn CTl ^ JC CD >—1 I—I OO •t-> • _J T—1 r-H fO t-H oX M c CQ -o CO 00 vo rory O) ^ 00 VO lO Cvj 'I>-— •—^

CM a: o c_>

00 n •I x: o o

o CNJ CO 70

-—^ ^—, y—- cr> Lr> CO vo ir> ro CO lO r-l r-. o r-^ r-l CM in m CO o r-H to ro 00 m in >1/>1 "—' — —

C "O -D ro 1-1 CO cr> 1-H CTi ro O r-l r-. in m < C O t^ UD r-- 00 LO VD O .-1 CM o r-l CM =3 • • » • • • • • • # • * r- O (O CM CM r—» J CM CM CM CM ro u. u 00 ro •a-' "a- ro ro -(-) -—' * • c a> E tu fO CT) ro r-. CO CTl CM ro vo lo rv. CM r^ ro ID •=!• CO rH CM t—< CM CM O m ro in • • » • • • • • » • • • • • 4 • T—1 T—( 1—1 1—1 o o ro ro T—( r-1 en ro LO un in in lO in in in *> ^ '—" '—' ~— -— ^—' — Ln ro fi t/O oo ro u~> CO ro o t/^ o :3 oo o in O •z. ro "Z. E o zr 00 cn 2: CM O r— 5- 2: - CM ^ ro o — r— '—^ f— s: O •— O r— 1— 1—1 O CM zz ro O P^ O CM r-l ro O CO (+- o o s: CTl • CO • t^ • T—1 • r-< • ID r-i cn ^ o: cn a: oo rc 00 •JZ ro 3: r^ ro vD 3: <-H ro ro CTl ro oo •d- o CO CM CO CM cn CM r-H CM T-t CM I—t 00 r-l CM «-< oo O ^ C_) ' O —' o ^ O w O —' u —•

c ^ O. vo.— o o • CO o IX) UD cn in 00 m a e i-H r-H in m ^ I—1 T—t 1 I 1 1 1 1 1 t 1 1 o m in UD f^

CO CO CO a:ro r— 31 oc az O o o 1C_—) CJ o

o 1o— in o o

in m in in CO CO a: 3:un 3: 3: a:ro vo vo •XL l£> o o o o o O O l£J O

z.o to in lO 00 crt cvj o — o o

rtsii

CD O ID u. OD

m (SI

o _o mo

o o a i C

n t*.

•i.

! 71

The IR spectrum of 1,2,3-benzoxathiazine-2,2-dioxide is given in Fig.13, C=N absorption is observed at 1590 cm'^ while SOg absorptions are seen at 1335 cm'^ and 1130

^H-NMR spectra of the following three representative compounds recorded are given in Tables 14-16.

TABLE 14

^H-NMR of l,2,3-benzoxathiazine-2,2-dioxide (Fig.14)

pJoto^s

8.68 1 singlet H-C=N

7.23-7.87 4 multiplet aromatic ho

tn 6

ir> CtiO.

TABLE 15

^H-NMR of 4-methy1-l,2,3-benzoxathiazine-2,2-dioxide (Fig.15)

Chemical shift No. of m i*- -4. « • (ppm) protons Multiplicity Assignment

'7.23 - 7.85 4 multiplet aromatic

2.72 3 singlet H3C-C=N

TABLE 16

^H-NMR of 6,8-dichl0r0-4-methyl-1.2.3-ben20xathiazine-2.2-di0xide (Fig.16)

Chemical shift No. of ^ (ppm) protons Multiplicity Assignment

7.73 1 doublet aromatic (J=2H2)

7.6 1 doublet aromatic (J=2Hz)

2.71 3 singlet ' H3C-C=N 73

Mass Spectral Studies

Electron impact induced fragmentation pattern of 1,3-benzoxazine-

2-ones and 1,2,3-benzoxathiazine-2,2-dioxides has been studied as they have not been dealt with in the literature.

2H-1,3-benzoxazine-2-ones

In the present work a comparative mass spectral study has been carried out for 2H-1,3-benzoxazine-2-one and 4-methyl-2H-1,3-benzoxazine-

2-one. The mass spectra are given in Fig. 17 and the salient features thus observed in the fragmentation pattern (Scheme VIII) are given below.

1. In both the compounds the molecular ion (M"^'), (i) m/e 147 (R=H),

(ii) m/e 161 (R=CH3) by the loss of CO afford ion (a), m/e 119, m/e

133 which further loses RCN to give ion m/e 92 (b). Ion m/e 133 loses

CH^ to give ion m/e 118 (c) while loss of H" from ion m/e 119 is not observed in (i). Ion (c) further loses HCN via hydrogen migration to furnish ion m/e 91 (d).

2. The molecular ion (M"*^") in case of 2H-l,3-benzoxazine-2-one

which has no substituent at 4-position further fragments by the loss

of HCN and CO2 to afford ions m/e 120 (e) and m/e 103 (f) whereas

these loses are not observed in case of 4-methyl substituted compound.

The ion (e) further loses HCO" via hydrogen migration to give ion m/e

91 (d). The ion (f) also further fragments to give ion m/e 76 (g) by

the loss of HCN. )00- h» 90 91

SO- |H7 TO- n^i 60 BO- 40-1 76 30- 65 20- .X)3 > -t 10- % 0 2 -H m 100- 91 z SC 90- ,161 116 80-

70-

60-

80- 133 AO-

30- 65 78 20- 105

10- 0 T" 1 t— "1— -r— 20 AO 60 80 100 120 140 160 180 200 m/e

FIG. 17 74

-HCO -HCN 0=f M I (t) (d) (c)

(0 m/t 120 (l)&(ii) m/* 91 (it) m/e1ie

-HCN -ON

-CO -RCN

(M+') (Q) (b)

(i) R=H \ m/» U7 (I) m/e119 (Oa(ii) m/e 92 (It) R = CH3;m/»16l (ii) m/e 133

-nco* -CO,

+ • H

(h) (f)

(li) m/»119 (i) m/e 103

k. ** "-CHi •HCN -cho O (i) (0)

(ii) m/» 105 (i)a(li) m/f 76

SCHEME TUt 75

3. In case of 4-methyl analogue the molecular ion further fragments by the loss of NCO" to afford ion m/e 119 (h) which in turn fragments by the subsequent loss of CH2 and CHO' to give ions m/e 105 (i) and m/e 76 (g).

6-Chloro substituted benzoxazines also fragment in the above manner.

1,2,3-Ben2oxathiazine-2,2-dioxides

The mass spectra of 1,2,3-benzoxathiazine-2,2-dioxides (Fig.18) having substituents like methyl or phenyl groups and without such substituents at 4-position have been, studied. The important features observed in the fragmentation pattern (Scheme IX) are given below.

1. In all the compounds the molecular ion (M"*"'), (i) m/e 183 (R=H);

(ii) m/e 197 (R=CH3); (iii) m/e 259 (R=CgHg) loses SO2 to give ion

(a), m/e 119; m/e 133; m/e 195 which forms the base peak and fragments by loss of RCN to give ion m/e 92 (b). In case of methyl and phenyl

substituted compounds, ion (b) further fragments by loss of CH^ or

CgHj to afford ion m/e 118 (c).

2. Ion (a) in the 4-methyl substituted benzoxathiazine takes an

interesting course of fragmentation through a rearranged ion m/e 133

(d) which fragments by the loss of HCNO, HCN and CH2 to furnish

ions m/e 90 (e), m/e 106 (f), and m/e 119 (g), respectively. »00- 119 65 91 90- 80-

70- 183 60-

60-

40-

30- 20-

10-

100-' 133 65 106 197 90- 80- s 70- 90 m< 60- 5 50- 92 m 119 W AO-

5 30- 20-

10- 0 I-.1 i. •• 195

90- 259

80- 77 116

70-

60-

50- m- 103

92 30- 165 20- 96 10-

0 "T ~1— —T— -1— 40 60 120 160 200 2A0 280 320 360 m/t FIG.18 76

C„H7 •N I mi* I39(k) ,so {M+-) •H (i) R= H;m/€ie3 4- {ii)R=CH3;m/#197

(if)m/«UO(J) (HOR = C6H5;m/»259

-CO -SO:

R -1 + —RCN I I Cs

(Q) (b) (I) (I) m/e 119 (Iff) m/*166 (li) m/e 133 (•),(»)&( ill) m/e 92 195

nr -HCN 3 H

(h) (d) (c)

(m) m/» 195 (ii) m/e 133 (ii)a(iii) m/e llfl

•CH, -hcno

-hcn

H —!+• H2 isN -0+* kVs

(g) (t) (e)

(H) m/e 119 (ii) m/e 106 (li) m/e 90

scheme n 77

3. Ion (a) in the 4-pheny1 substituted benzoxathiazlne rearranges to give the ion (h) which fragments by the subsequent loss of HCN, CO and H' to give ions m/e 158 (i), m/e 140 (j) and m/e 139 (k), such pc type of CO loss has been reported in literature .

6-Chloro substituted 1,2,3-benzoxathai2ine-2,2-dioxides also fragment in the similar way. 78

EXPERIMENTAL

PART A

REACTION OF 2-AMINOBENZALDEHYDE WITH CSI

Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-aminobenzaldehyde (5,48 g, 0.046 mole) in dry dichloromethane (40 ml).

Chlorosulfonyl isocyanate (CSI) (4 ml, 0.046 moles) in dichloromethane (10 ml) was added dropwise over a period of 20 minutes with stirring and maintaining the temperature 0-5°C.

After completion of the addition, the reaction mixture was stirred for 20 minutes and allowed to warm to ambient temperature

(28°C). The stirring was continued for another 3 hours at this temperature. After removal of dichloromethane under vacuum, water (70 ml) was added to the residue and left overnight.

The solid obtained was filtered, dried and purified by column chromatography on silica gel using chloroform/methanol

(9.5/0.5) to get 2(lH)-quinazolinone.

m.p. 246-247°C Yield 38%

CqH.N.O Found (146.1r?.^^) (calcd.)/" C H N 65.68 4.23 18.98 (65.75) (4.14) (19.17) 79

REACTION OF 2-AMINOACETOPHENONE WITH CSI

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-aminoacetophenone (9.34 g, 0.068 mole) in dry benzene (60 ml). CSI

(6 ml, 0,068 mole) in benzene (15 ml) was added dropwise over a period of 30 minutes with stirring and maintaining the temperature

0-5°C. After completion of the addition, the stirring was further continued for 5 hours at room temperature. Compound separated during the reaction was filtered, washed thoroughly with water and boiled in methanol. Insoluble portion in methanol was filtered and recrystallized from dimethyl sulfoxide/water to get 4-methyl-

2(lH)quinazolinone (Table 1).

The methanol soluble portion, after the removal of methanol, was recrystallized from isopropyl alcohol to get lH-2,l,3-benzothiadiazine-2,2-dioxide (Table 2).

The residue obtained after removing benzene from the filtrate of the reaction mixture, was added to water and the solution neutralized with aqueous sodium bicarbonate (10%). The dark coloured compound separated was recrystalized from dimethyl sulfoxide to get

6-methyl-l,3,5-benzotriazocine-2,4-dione (Table 3).

Similarly, other substituted 2-aminoacetophenones were reacted with CSI. 80

REACTION OF 2-AMINOBENZOPHENQNE WITH CSI

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-aminobenzophenone (4,53 g, 0.023 mole) dissolved in dry benzene (60 ml).

To this was added CSI (2 ml, 0.023 mole) in benzene (6 n;!) dropwise over a period of 30 minutes at 0-5 (ice bath). The reaction mixture was stirred for 30 minutes and allowed to warm to ambient temperature (28°C). The stirring was continued for another 3 hours at this temperature. Then the benzene was removed under vacuum, to the residue obtained was added water (100 ml) and left overnight.

It was filtered and washed thoroughly with water. This residue was dried and subjected to column chromatography on silica gel using benzene/methanol (92/8) as eluent. The two products 4-phenyl-

2(lH)quinazolinone and 4-phenyl-lH-2,l,3-benzothiadiazine-2,2- dioxide were recrystallized from dichloromethane.

Other substituted 2-aminobenzophenones have also been reacted with CSI by employing the above reaction procedure. Whereas in these cases most of the 4-aryl-2(lH)quinazolinones were separated as methanol insoluble portions, while the soluble portions were subjected to chromatography on silica gel using chloroform/methanol

(90/10) as eluent.

The different 4-aryl-2(lH)-quinazolinones and 4-aryl-lH-

2,l,3-benzothiadiazine-2,2-dioxides were listed in Tables 5 and 6. 81

PART 'B'

REACTION OF 2-HYDR0XYBENZALDEHYDE/2-HYDR0XYACET0PHEN0NE WITH CSI

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-hydroxybenzaldehyde or 2-hydroxyacetophenone (5.6 g/6.25 g, 0.046 mole) in dry dichloromethane (50 ml). CSI (4 ml, 0.046 mole) in dichloromethane (8 ml) was added over a period of 30 minutes at room temperature (25-30°C). Stirring was continued for 2 hours at this temperature and dichloromethane was removed under vacuum.

To the residue obtained was added cold water (80 ml) and left overnight.

The benzoxazines were separated as methanol insoluble compounds and on concentrating the methanol soluble portion the crystals separated were that of 0-carbamoylbenzaldehydes/

0-carbamoylacetophenones (II). In case of 5-methyl-2-hydroxyacetophenone the products have been separated by column chromatography using benzene/methanol (90/10) as eluent.

Employing the above procedure, 5-chloro-2-hydroxybenzaldehyde and other substituted 2-hydroxyacetophenones were reacted with CSI.

The various 2H-l,3-ben20xazine-2-0nes and O-carbamoyl-2-hydroxy- bnezaldehydesZ-acetophenones prepared were listed in Tables 9 and 10, 82

REACTION OF 2-HYDROXYBENZOPHENONE WITH CSI

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-hydroxybenzophenone (4.53 g, 0.023 mole) in dry dichloromethane (40 ml).

CSI (2 ml, 0.023 mole) in dichloromethane (3 ml) was added over a period of 20 minutes at room temperature (25-30°C). Stirring was continued for 2 hours at this temperature. The solid separated after the addition was filtered. It was added to cold water (80 ml) with frequent stirring and left overnight. The O-carbamoyl-2- hydroxybenzophenone formed was filtered and recrystallized from ethanol.

.O-Carbamoyl-2-hydroxybenzophenones thus prepared were listed in Table 11. REACTION OF 2-HYDR0XYBENZALDEHYDE/2-HYDR0XYACET0PHEN0NE/ 2-HYDROXYBENZOPHENONE WITH CSI AT HIGHER TEMPERATURES

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-hydroxyacetophenone (12.5 g, 0.092 mole) in toluene (60 ml) at

100-105°C. CSI (8 ml, 0.092 mole) in toluene (18 ml) was added over a period of 40 minutes. Stirring was continued for 3 hours at this temperature. The toluene was then removed under vacuum and the residue was added to cold water (80 ml).

The solid obtained was filtered, washed with water and recrystallized from ehtanol to get 4-methyl-l,2,3-benzoxathia2ine-2,2- d^oxide,

Similarly, 2-hydroxybenzaldehyde and 2-hydroxybenzophenone were reacted with CSI. The various substituted 1,2,3-benzoxathiazine-

2,2-dioxides thus prepared were listed in Table 13. 84

REFERENCES

1. H.Ulrich, Chem.Rev., 369 (1965).

2. S.Gabriel and T.Posner, Ber.^, 1029 (1895).

3. K.Sasse, Ger.Offen., 2,503,736; Chem.Abstr., 143137 r (1976).

4. W.L.F.Armarego and J.I.C.Smith, J.Chem.,Soc., 234 (1966).

5. S.Gabriel and R.Stelzner, Ber., 1300 (1896).

6. Ishizumi, K.Mori, S.Inaba and H.Yamamoto, Ger.Offen., 2,345,030; Chem.Astr., 146193 p (1974).

7. S.C.Ben and P.Wei, U.S. 3,594,376; Chem.Abstr., 7^, 88634 s (1971)

8. S.Inaba, K.Ishizumi and H.Yamamoto, J.Org.Chem., 2581 (1974).

9. K.Ishizumi, K.Mori, H.Yamamoto, M.Koshiba and H.Yamamoto, Ger.Offen., 2,439,454; Chem.Abstr. 82, 171043 p (1975).

10. K.Ishizumi, Japan Kokai, 75,148,372; Chem.Abstr. 85_, (1976).

11. E.C.Horning, "Organic Syntheses", Collect.Vol.Ill, Wiley, N.Y., 1955, p.56.

12. N.J.Leonard and S.N.Boyd, J.Org.Chem., 405 (1946).

13. C.S.Gibson and B.Levin, J.Chem.Soc., 2388 (1931).

14. J.C.E.Simpson and O.Stephenson, J.Chem.Soc., 353 (1942).

15. L.H.Sternbach, R.I.Fryer, W.Metlesics, G.Sach and A.Stempel, J.Org.Chem., 3781 (1962).

16. E.Cohen and B.Klarberg, J.Am.Chem.Soc., 84, 1994 (1962).

17. W.J.Houlihan (Sandoz, Inc.) U.S. 3,278,532; Chem.Abstr., i^, 20154 c (1966).

18. J.H.Bowie et al., Aust.J.Chem., 2677 (1967).

19. Graf, Chem.Ber., %, 56 (1963).

20. G.Lohaus, Chem.Ber., 105, 2791 (1972). 85

21. S.Polazzo and M.G.Marino, Gazz.Chim. Ital., 811 (1964), Chem.Abstr., 6^, 16065 g (1964).

22. J.B.Wright, J.Org.Chem., 3960 (1965).

23. British Patent 1073,836, Upjohn Co.; Chem.Abstr., 90818 (1967).

24. A.I.Vogel, "A Text Book of Practical Organic Chemistry", 1959,p.676.

25. D.Chakravarti and B.C.Bera, J.Ind.Chem.Soc., 21, 109 (1944). CHAPTER III

This chapter is divided into Parts 'A' and 'B' which describe the reactions of chlorosulfonyl isocyanate with the following:

PART 'A' Salicylates and anthranilates;

Synthesis of

i) l,3-BENZ0XAZINE-2,4-DI0NES

ii) l,2,3-BENZ0XATHIAZINE-2,2-DI0XIDE-4(3H)-

ONES

iii) QUINAZ0LINE-2,4{1H,3H)-DI0NES

PART 'B' 2-Aniinophenols and 2-aminothiophenol;

Synthesis of

i) 3H-1,2,3 ,5-BENZ0XATHIADIAZEPINE-2,2-

DI0XIDE-4(5H)-0NES

ii) 3H-1,2,3,5-BENZ0DITHIADIAZEPINE-2,2-

DI0XIDE-4(5H)-0NES 87

PART 'A'

This part deals with the attempts carried out on the

synthesis of 2H-l,3-benzoxazine-2,4(3H)-diones, 1,2,3-benzoxathiazine-2,2-dioxide-4(3H)-ones and 2,4-(lH,3H)-quinazo-

linediones by employing chlorosulfonyl isocyanate (CSI).

The methods reported in the literature for the preparation

of 1,3-benzoxazine-2,4-diones, 1,2,3-benzoxathiazine-2,2-dioxide•

4-ones 2,4-quinazolinediones are briefly reviewed below,

1,3-Benzoxazine-2,4-diones^ (I) have been prepared by

the condensation of salicylamide with ethyl chloroformate in

presence of pyridine.

2 + CICOOC2H5

The preparation of 1,2,3-Benzoxath^az^ne-2,2-dioxide- 2

4(3H)-one has been reported by the reaction of phenyl benzyl

ether with flourosulfonyl isocyanate followed by hydrogenolytic 88

cleavage of the benzyl group by 5% Pd/C and finally ring closure with sodium hydroxide.

I- CH2CeH5 Q + OCNSO2F

)-CH2CgH5 1) Pd/C

Q :-NH502F 2) NaOH

'2-4-{lH,3H)-Quina2olinedione (III) was prepared from

anthranilic acid and potassium cyanate as follows:

COOH

NH2

H2sq^

III 89

In view of the earlier observations (Chapter II) that the reactions of CSI with bifunctional molecules like 2-aniinobenzophenones and 2-hydroxyacetophenones gave the corresponding heterocyclic systems,

Therefore, it appeared of interest to carry out the reactions of CSI with the following:

1) Various alkyl and aryl esters of salicylic acid and

5-chlorosalicylic acid

2) Substituted methyl anthranilates

4 Methyl/ethyl/isopropyl salicylates , substituted phenyl salicylates^'^ and methyl anthranilates required as starting materials for the reactions have been prepared by the literature methods.

Reaction of salicylic acid esters and methyl anthranilates with CSI

In these reactions it is observed that CSI reaction does not lead to cyclization i.e., to give the expected 1,3-benzoxazine-2,

4-dione or 2,4-quinazolinedione systems. On the contrary, N- chlorosulfonyl-carbamates of salicylic acid esters (IVa) and N- chlorosulfonyl-urethanes of anthranilates (IVb) are obtained

(Table 17 and 18) which are quite stable in the absence of moisture.

These on hydrolysis with cold water give 0-carbamoyl salicylates (Va) and N-carbamoyl anthranilates (Vb) respectively in good yields

(Table 19 and 20). 90

0 =

or'

5-10®C H2O X- C- NH-SO2CI II 0

IVa, XcO Va. X=0 IVb. X=N-r2 Vb. X=N-r2

- X N-H D^xAo via, X =0 Vlb, X = N-R

R = H. CI ; r' = alkyi, aryl

R2=H. CH3. C6H5. CH2C6H5 91

CO Ln 0 CM 0 U5 t-i 0 CO in VL o^ Ln Ln Ln Ln - ' "D• +-C> 00 0 — o re S- re u. (J •cM — •M O) C fC i 00 r-H 00 LD CO CM .-1 r-- Ln CO o • • • • • • I/) 00 00 LD VD QJ CO CO • V ' CfO x: +-cu> s- 3{ U re UD CNJ 1— ix> 0 H 3 1 LD 0 z: C O 1 0 z f— o (/) 1 z CM 0 0 1 r— cn 0 i q- 1 0 0 • <—4 3 • 1 00 "St cn 00 1/1 x r— 1 0 Ln O 0 1 cn CM cn CM r-l CM S- s: 1 0 -— 0 0 o (J I 0 1 0 LD cn 0 1 ^s- CO •o 1 t—1 I-H 1—1 c c » 1 1 1 1 (O Q. 1 00 CM vo • 1 CO t/5 E 1 t—1 T—1 1—i +-(U> ns >, T3 u O) Ln >- cn cn Oi <0 CO 0 (toU -t-> I I re o o E I I re j:: s. Lf) re tn CO u n: CVJ 1 o o o 'h c o o 3 tOo J- o O z 00 CM n 92

I—1 vo ro i-H t-^ 00 1—1 r^ t—< to LO 00 1 z 1 OO O .-H r-. CO CO CM CM CO r-H 0 1 • • • • k • • • • «> • • • • 1 LT) LT) 0 0 CTi CTi 0 0 00 00 00 00 I U) V .—< T-H 1—1 1 N ^ •>—1 'f ^ ^ LT) >1 l~ ' ^ (C ^—^ ,—. —. *•» I C X) -o LO KD CO o cn IX) CT> .-1 00 >X) CM 00 kO 1 ct C U a: 1 ,-H O Lrt ^ LO r^ ID r^ CO t 3 r— • • • • • • • • • • • • • 1 1— O fO CO CO CO CO Cvj CM CO CO CO CO C\J CsJ 1 ns U. O »•, >-1,1-' ^ 1 4-> —- c QJ E ,.«•—-V ..»—. i UJ CNJ ^ LO CO C\J CTk ^ C\J 0 t-- UD 1 CO CO LO tX) ^ UO 1—i 0 CO 0 1 O 1 • • • • • • • • • • • • • • 1 o o 00 00 l-H 1-H CO CO Ln 1 CO CO ID ID Ln Ln 1

LD LD Ln 1 n3 0 1—1 1 LU • CM Ln r^ CO CO CO 1 I E >—( t—( rH 1—4 rH I—1 I—( 1

f•—o . a> ^ OJ U5 "d- ID VO CO ^ 1 cr> CTi cn cr> en O^ 1 >- 3:Ln 11 LD 1 LD 0 1 CO 3Z CM 1 31 yD 3: < 0 0 1 1 1 IC 1 1 1 1 X o O 2: z Z Z Z 1 1 1 1 1 1 1

ID IC :r CO CO CO CO CO 1 t—1 CM CO 3: rc 3: 3: 3: 1 a: O CJ 0 0 0 0 0 1

o£ O 3: a: CJ 3: 3: 1

d z • • • • t • • • 1 to Ln VO 00 CT^ 0 1 93

o oo 1—t 00 CTi vD ir> 2: 1 • • • • ro ro CO CO to ro CO 1I —^ 1 in 1t (>—5 . ,—, 1 ro r-^ m CXD CSJ LO CM ' C T3 -a V£> CO »-H ro ro • 1 cc c a t • • • • •o < 3 <— C\J CJ CO CM CM CM 1 r- O fO •—^ s ^ c 1 (0 Lx. U o 1 ^ o 1I

to Ul oo cu 1 fO ID CO CD +-> 1 O o O fO 1 3 Z1 •Z. z: • B f— CM CM 1 S- o ~ r— —^ f— ^ o 1 o O CD o o o o 1 M- I—1 cr. ' CJi • n: ID :r o o fO 1 cn cn <3- cn in ro •-1 CO T-l CO 1 Os: o -—- o ^ CJ> v.- Oc) JZo. 1 o O 1 o •a- CD CXD , 1 C\J CO CO CO t • 1—1 1—1 1—1 O) 1 D- 1 1 1 -M 1 • CSJ 1—( CO fO 1 E CM fO oo «—1 1—1 1—1 1 1 >- c o 3 to 1 CO o 1 o: x or zr. 0s- o 1 1 C\J 1 a: zn 31 o

1 i-H 1 a; zr. •I

r— 1 a: o n:

1 o 1 z: 1 « • • « 1 CO f-H CM ro 94

1 ^ ^ ^ ^ , , 1 1 00 cn CM 1 I— 1 —, > V 1 nD I CO o ro o 00 CM o r-. V£> 1 C "O T5 1 r^ cTi CM r-l r-< CM in c^ 1 =t C O 1 * • • • • • * * 1 3 r- 1 t—1 r-1 r-4 r-H oo oo CM CM 1 —r O fO 1 -» 1 fO U_ O 4-> c =t 1 — •—' •— ! 1 ^ •— 00 1 1 to oo 00 OO VO O 1 1 O o o O z: 1 3 1 Z •Z. z z: CM 1 E 1 oo ro r— r— —1 1 I. 1 1 , r— O o o 1 o 1 (-> <_> ID O CM f-l CM 1 M- 1 00 • 00 • •a- • 1—< i—t • 1 • 1 "51- n: <5t 31 cn rn 1 r— 1 ^ CM CM cn «£> UO LD O I O 1 .-H i-l CM un .-H ro r-4 1 s: 1 o o —- C_3 •—- o —- O ' 1

tj 1 cn V£> 1 c o 1 CM in CM CM 1 o 1 1—1 1—1 CTv 00 »-H 1 o • 1 1 1 1 t ( 1 Q. I r-^ o CM o CO 1 • 1 CM 00 CM 1 CO E 1 1 I—1 «—1 1

CD < "O 0) 1 CO 1—1 CT^ ^ 1 1 cn cri 00 CO cr> 1 >-

ro oc 1 o :r: in n: 1

CM 1 r— Q: 1 O :i: n: O 1

1—f 00 CO CO 1 r-H n: •X. rn • cs: Lf> O 1 « I—1 o O

Q: ,1 o o zs: 1

d z a 1 0 « • • • t 00 1 uo vo 00 • 95

1 1 1 1 1 1 CT> CO cn .-1 o 1 ^ 1 C\J .-1 00 o 1 «/) 1 • • 1 'r- 1 Ln vo VO 1 1/1 1 KD 1 >, 1 1 r— —^ 1 1 (0 1 1 C -O T3 1 ,—, 1 Ceo 1 .—1 un O 00 o I 3 r- a: 1 un (X) CO 1 I— O n3 1 • • • • • • • fO U_ O 1 CO CO Ln Ln 1 4-> 1 w ^ I C 1 1 QJ 1 c 1 o '1 QEJ 1 o 1 1 > —S 1 LU 1 00 o CVJ rH 1 1 LO 00 o o CO ^ 1 O 1 • • • • • • 1 1 m Ln 1 i un IT) ID in 1 t 1 1 1 1 1 1 fO 1 t r— 1 1 =3 1 1 o o 1/1 1> sE- 1 ST ^ a> 1 o 1 O C\J r- VO ^ 1—1 C^-J 1 <+- 1 z: O I—1 (O 1 • 1 cri Ln 00 cn rr cn r— 1 1 oz cn ^ CM o o •r— 1 o 1 CTl »—1 Ol Od r-t CM c 1 1 C_) ^ O V—' CJ) ^ \ 1 ro 1 1 1 1 sz4-> CM I 1 c X 1 I-— 1 (T3 1 • 1 ^—- 2: 1 Q. 1 LD 1 1 o • 1 o CM OJ OJ 1 1 IT) in 4-» 1 ID1—1 I—11 I—1 I—1 cn CO - o o=o 1! ° • 4J 1 1 1 1— rr // 1 1 Q-'i- 1 cn I—1 o 1 1 • _J 1 Ln Ln >U> X 1 B—- 1 1—1 1—1 •r— —\ 1 f— 1 • v y)) / 1 -O 1 1 ol 1 Q) ^ 1 I—1 CO CO B cn cn CTi ^fO QC 1 s- 1" ^ 1 ra 1 1 o 1 1 1 1 z 1 1 1 1 1 I 1 1 1 1 o 1 X 1 o o o 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Ln 1 1 n zc 1 r-H 1 a: CM 1 1 o ozc O 1 Ol 1 1 1 1 1 1 1 1 1 1 1 1 1 r— 1 1 o :r 1 cx: 1 zr 1 1 1 1 t 1 1 1 1 1 o 1 1 z 1 1 • 1 • • • 1 tn 1 I—1 CM ro 96

00 C\J 00 r-- <—1 ro CO ^ 00 to in to CM in 1 LD .-1 CM ro O CM ro ^ «;>• ro cn 00 1 Z I • • • p • • • • « • « • 1/1 LD in •si- CM CM CO ro o o cn cn 1 • r- -— 1—t I—1 f—1 i-H »-H r-H 1—1 t—1 1 tA r>—) S^ m V ^—- —^ ^ N 1 C "O TD LD CO r-H r^ <3- cn T-i CO f—< t c . CM oo 1 —< O 00 O T-l 00 CTi 00 O CM in to 1 3 t— n: 1 • • • • • • • • • • > • 1 •—Ore LT) LT) in in 00 ro LO ID in in m in I ro Li. o 1 OcJ E ^ • ^ 1

fO r— 3 o ro ro 00 ro 1 z: ro o O o O 1 r— o o CM CM CM OJ 1 o O ^ zz — CM z: — ZI ^ Z. - 1 4- o to CO OJ Z CM 1— lO CM CM >^1- oo to cn 1 • r-4 t—1 • o • o T—1 r—1 t—< • 1 3: ^ ro cn CO rn 00 3: o 3: 1 o O Vf r-t CM re CM o o in r^ to 00 1 s: .-1 CM .-1 CM CTi T—1 cn CM r-< CM ^ CM t CM 1 CJ> ^ C_3 •—- C_5 -w- o o CJ> I

• ,—^ ^ Q. o X+-)> o . CO CPi 00 in o cn O I C^ E <3- CM O CM 00 1 t—t t—1 1—t ^—- CM 1 i-<. '— 1—1 1—i 1 o • -P I 1 1 r^ 1 00 1 .—1 1 1 1 u Q-T- CM r-. vo cn 00 in CM cn 1 • _J CM t-l o ^ ^ CO 1 1—1 1—1 t—1 «— CM ^ T-< 1—1 r—t 1 cri LU —I CQ •o QJ O ro CM o VD O ro 1 00 00 CO 1 , >- cn cr> cn in 1 :rt: o 1i in O 1 ro CM 1 zc to 3: 1 1 1 oc n: <_) o <_5 1 X O CZ) •z. z •z. z Z 1 1 1 1 1 1 1

tn 3: a: ro ro ro ro ro 1 1—1 CM m 31 3: 3: 1 cc o <_1> O o O 1

cc o Ol zc o 3: 3: 31 1

zo: • • • • • • • • t t/1 Ln vo 00 cn O 1 97

CO rv. o 00 o LD CO UD CO

•5}- -a+-> i/i c o fO C\J r-l CM ID C T3 -O C\J CO LO ro Ct c o 3 r— CO CO ro ro t— O ro +-(O> U_— -O c (U E n ,-1 vo I—I lO 0) od 00 r-v vo in vo in un LD Ln Ln Ln

o o 3 E s_ CJ ^ o .— o .-I C^J O UD o vo I—< • I-H • un cr> <—I CM .—I CM <_) —- O .—I CM^ - CO CT> CO o E (0 s- <0 o CO o a:

CMct: o

q:: CJ

CM CO 98

r-H O^ t-H CTi UD O CO IT) CO CO CM ^ CM r-H O CM I—H •"d- LO • • • • • • • • • • CO CO ID LD I/) •r— >1 ^

rO t-. 00 •a- CO CO ^ CO 00 ITJ C -D -O WD t-^ CO r-- 00 r^ cri ecu • • • • • • • » • • 3 I— CM CM CM CM CO CO CO CO I— O (T3 4-(C> U_ —(-J C (£U CO ^ rH LU in tn CO "sS- CO o • • • • • • • • • • I-H t—H 11—1 1X> VD CO 00 LO UO m LD WD tn in ^—-- ^— ^ —'

o o o zr •Z. OJ CM O O •z. •—• o -—- o o" o o I—I CO CO CM 0^ • cn • ^ • .—I • rc •Ji Ln ^ CM ^ CM CTl LD r^ Ln o r-l CO .-I CO CM .-H CM t-H CO O •— o —- <_3 o — tj ' •a +-c> o o o cy> CM O m UD (T) o I—I o I ir> CM 00 o in If) VO O cr>

0) cn CM o >- CO 00 CO 00 cri

CO CXl

CM CJ o csi

CO m CO CO o •XLIT) I—t

CJC o

00 LD 00 (JlN3Da3d ) 3DNViilwSNVbI o 1o2

o ion

o o o m

O O o o

o o o o=< p m S

5 - ^ - o

Uo o-

h o • o

«s d ul

8 •fs iin

o o •tn o

o • o in 1 99

These carbamates as well as urethanes have been cyclized

in presence of anhydrous bases like pyridine, trimethylamine to form the corresponding 1,3-ben2oxazine-2,4-diones (VI) and quinazoline-2,4(lH,3H)-diones (VII) in good to moderate yields

(Table 21).

The products thus obtained have been characterized by spectroscopic methods.

The IR spectra of 0-carbamoyl isopropyl salicylate and

0-carbamoyl methyl-N-methyl anthranilate are given in Figs. 19 and

20. In these carbamates the NH2 absorptions are seen at 3305 cm'^

and 3420 The ester C=0 and the carbamoyl C=0 are observed

at 1730 cm"^ and 1690 cm"^, respectively.

The IR spectrum of l,3-benzoxazine-2,4-dione is given in

Fig."21. The NH absorption is seen at 3460 cm"\ The urethane C=0

and the amide C=0 are observed at 1770 cm"^ and 1720 cm~^.

The IR spectrum of quinazoline-2,4(lH,3H)-dione given in

Fig.22. 100

CO CT^ 00 CTi O 00 H: I ^ LO r-H O CM * 1 • • • • CO CO —' I—t '— 'r-1/1 —. ,—^ ro • ,-H cr> r-t .-H O c: •o -O 1 Cvj o CNJ O oi r-^ ct c o • * • • 3 <— CO CO OO CM OO 00 CO O 13 ^ - - ^ ^ 0 c o ••r—o O) 1 i CO o OO Ln UD LO Ln LD OO CM O 1 m • • • • » CO 00 00 00 cri cri cn in Lo LO un

CVJ ra i I— O) OO c E=> o CM S- ro ^ z: -—- o o O r-H I— Ln CM i-H o 14- Z o n • LO CO LD CM 1 cn 1 O CM Q-'i- CM Ln OO to f/> • _J OO CM OO 0) E CVJ ^ CM —' 0c •r- X31 3: 00 -o - co Ln CM

n fO I I x o o No I I QcJ co CO I o CM

O z CM CO 101

Ln .-H o I—I ld CO o I—I CM 00 CTi t^ O T-l

I/) >> (O c -D "O CO lO «:J- CO CO CTi =t C U Ln ro 0L0n .-H CM 3 1— I— o ro cm c\j +-rtJ> U—-- o c E O) •sj- cyi —I LD 00 CM CM ro •ej- Ln CO o r--. 00 O O co co LO vx)

CM CM CM —, 3 O o o E CM CM CM CM s- Z ^ O z: .—~ o 1— Ln CM CM O CM CM CO M- CJ> t—1 T—1 • LO LO 00 LO IC oo CM r-^ a: en >51- CO zn.Ln in O 00 .-H CTi '—t I—1 CM .-H CM --»-o> 5: CJ ^ o O —' oc. u 00 CM ^ CL o • r-H UJ O cn Ln CO _J O^ E o LD CM CM CQ • +j CO CM 1 CM cc Q-T- 1 O LO 00 Ln LO CM CM CM

•o 'oi CO CM >- Ln Ln Ln

Ln oc in LD CO O VD CM 3: tj o CITJ z I

o tn L£> O) CM

i N z 0 z I u=0 a 1 I - f o=u o n 5 a SS

a "uS

in O) 102

The ^H-NMR spectra of the representative members are given in Tables 22-24.

TABLE 22

^H-NMR of 0-carbamoy1-5-ch1oro ethyl salicylate (Fig.23)

Chemical shift No. of Multiplicity Assignment (PPm) protons

7.95 doublet H, (aromatic) a (Jab= 2-4 HZ)

7.49 doub et of a Hj^ (aromatic) doub et 7.10 1 doublet H^ (aromatic)

5.14 2 broad

4.35 2 quadret -O-CH2

1.38 3 triplet -CH3 ho

•s 103

TABLE 23

H-NMR of 0-carbamoy1 I'sopropyl salicylate (Fig.24)

Chemical shift No. of Multiplicity Assignment (ppm) protons

8.0 - 8.02 1 doublet of a H, (aromatic) doublet a

7.09- 8.02 3 multiplet (aromatic)

5.26- 5.3 2 broad

5.23 1 septet (CH3)2CH-

1.31 doublet CH % \ CH3

TABLE 24

^H-NMR of 0-carbamoyl-(4-chloro-3-methylphenyl)salicylate (Fig.25)

Chemical shift No. of Multiplicity Assignment (ppm) protons

7.0 - 8.2 7 multiplet aromatic

5.13 2 broad -NH^

2.37 3 singlet -CH3 104

Reaction of salicylic acid esters with CSI at higher temperatures (lOO-lUE^^^Cj"^

+ 0=C=N-S02CI

H2O

0- SO2- N= C=0 -SO2-NH2

VHI

R = CH3. C2H5. C6H5

R' = H. CI. Br

The reaction of salicylates with CSI at elevated temperatures

did not afford cyclized compounds directly instead

0-sulfamoyl salicylates (VIII, Table 25) via 0-sulfonylisocyanates have been obtained. 0-Sulfamoyl salicylates have been further cyclized in presence of anhydrous pyridine to give corresponding l,2,3-benzoxathiazine-2,2-dioxide-4(3H)-ones (IX, Table 26). These have been characterized by spectral methods. 105

cvj (,£> 00 r^ co ^ OJ o I—I CNI Ln l£5 IX) LD LT) Ln Ln

T+-3>

iA O O >1 «:}- CsJ r-i ro r-. (Nj CM O VD LT) Cre T3 "O ct C O ro CO CO ro I— O TO (O Lu (J +J w c

r— oo Ln oo CNI E 1 t/O O m I J- 1 LD H: ^ o ^ o 1 O 1— z: .-H 1 Z O 1—t V) > 1 cn I—1 00 Ln t-H Ln O) r— 1 CO n: •ct •t-i o 1 00 CM zr0 0yo CM cn CM to s: 1 o -—- <_> — O [ m >u> •r— OJ r— LlJ _j 1/re1 ca (-3 Ct r— o H- 00 >, 00 00 cn I cn I re f-- 00 1— 00 cn rj oo o -SJ- LO cvj ai ^ •I>-— "—

ir> oo fO zn x: cm Q1 o CJ) O

c_>

Ln cm CO 106

r^ o i cm CO o CVI CO i cm ••a- un co

to 00 o co o CM re ^ r-l o t-h cm c • * eC T3 -a fo cn lt) id •— rc •—u 4-ra> ou -ta o c q; e 00 o co r-t

00 t/O ID n3 Ln 00 O O LO O O o O VD CO ID r^ O • I—I t-h • t-i cn OJ ac ZC.ID CM id id 'o cn CM t—i po o c_>-t) en O —' c o ir> o OJ co co o Ol I I in

•a vo CO 'oi ^ r-00- >- 00 00

IT) LO ID 3: c\j VC 0 o CJ

00 id «X> 107

•a- CM r^ CTi cn ro cr\ o CO cn 00 O z: 1 » • • • UD r^ LD Ln N ' •r— — 00 r>— , (O ^— ^—^ C "D XI CO CM ^ un CC E O un 00 t^ 3 1— rc 1 • • • • 1— O (0 CM CM 1—t 1—i r—1 r-H (10 Li_ O —• —^ +J c CJ , , OD CTi ro en OO r-H LU CM r-H cc en .-H CM CJ> 1 • CM C^ LTi un o o "a- ro ro ro ro ""—• •—'

O) c o

00 3 OO *a- 1 o O I o 1 z: z: ^ O) 1 O ro r— 5- ro "O 1 z CO • t un cr> ro ^ 00 X 1

cm an i

u csC. CD

t/0 cm ro a 6 !7> t-•Oi

tn .-M

ifi 108

The IR spectrum of 0-sulfamoy1 methyl salicylate is given in Fig.26. The NH2 absorptions are seen at 3280 cm"^ and 3400 cm'^ while the ester carbonyl is observed at 1700 cm"V

The SO2 stretchings are seen at 1160 cm"^ and 1370 cm'^.

TABLE 27

^H-NMR of 0-sulfamoy1 methyl salicylate (Fig.27)

Chemical shift No. of Multiplicity Assignment (ppm) protons

7.84 - 7.95 1 doublet of a H (aromatic) doublet ®

7.25 - 7.58 3 multiplet H , H, & H^ a D C (aromatic)

5.62 2 broad -N^

3.89 3 singlet 109

PART 'B'

In the previous chapters, it has been described that the reaction of CSI with 2-amino/hydroxy acetophenones or benzophenones, salicylates and anthranilates give a variety of heterocyclic compounds. This part deals with the reaction of CSI with some bifunctional compounds having amino, hydroxyl and thiol groups in 2-position, as such reactions have not been attempted earlier.

Thus CSI has been reacted with the following:

1) 2-Aminophenol

2) 2-Amino-5-chlorophenol

3) 2-Pniinothiophenol

It is observed that the reaction of CSI with the above compounds at room temperature give a large number of products.

Hence, the reactions have been carried out at temperatures ranging from 105-115°C. o .2o

o -O in

.8o

'Z u a>

o .o fITM)

.o roo

o -uo» m 110

Reaction of 2-aminopheno1s with CSI at 110-115 C

CIS02N= C = 0

r = H, CI

The reaction between 2-aminophenols and CSI at 110-115°C give a novel heterocyclic ring system, i.e.,, 3H-1,2,3,5- benzoxathiadiazepine-2,2-dioxide-(5H)4-one (I) in good yields

(Table 28). The products have been identified by elemental analysis, IR and mass spectra.

The IR spectrum of 3H-1,2,3,5-benzoxathiadiazepine-2,2- dioxide-(5H)4-one is given in Fig.28, the two NH absorptions are seen at 3330 cm'^ and 3190 cm"^. The C=0 absorption is observed at 1640 cm~^ while SO2 absorptions are seen at 1160 cm"^ and 1290 cm -1 cn fN O u.

RELATIVE INTENSITY V. 146

The mass spectrum of 3H-1,2,3,5-benzoxathiadiazepine-2,2- dioxide-(5H)4-one is given in Fig.29. The salient features observed in the fragmentation are given below.

1. The molecular ion m/e 214 (M"*"') forms the base peak.

2. The molecular ion fragments by the loss of CO and to give the ion m/e 186 (a).

3. It is interesting to observe the absence of SO^ loss from the molecular ion as well from the ion m/e 186.

4. The ion m/e 186 further fragments by the loss of H" and N2H2 to give ions m/e 185 (b) and m/e 156 (c). Ion m/e 156 then loses SO2 to afford ion m/e 92 (d).

m/e ZlACM"^*) m/e 186(a) m/e 156(c)

-H -SO2

m/e 185(b) m/e 92(d) s o iT

S 5 CMNassiwsNvai o o o

^•oo lO

o .o o

2 jj

^ o O U. UtJr

o -o ur> cm

o _o o

o 1 1 2

Reaction of 2-aminothiopheno1 with CSI at 110-115°C

+ C1502N = C=0

0 II NH-C-NH2 -h -SO2NH2

II III

Reaction of CSI with 2-aminothiophenol affords a novel heterocycle, 3H-1,2,3,5-benzodithiadiazepine-2,2-dioxide-

(5H)4-one (II, Table 28) along with N-carbamoyl-S-sulfamoyl'

2-aminothiophenol (III). These have been characterized by elemental analysis, IR and mass spectra.

The IR spectra of II and III are given in Figs.30 and 31, O)c 113 0 1

cu T3

0X 1 x—^ , ( 1 1 co 00 vo r^ 1 -D 1 cm o o cm o r-» 1 1 1 lo z: 1 • . • • CM 1 1 ro ro 1—1 r—1 cm cm 1 1 1/1 1 1—) 1—i T—1 r-t 1—1 r—1 1 C\J i >, 1 ' ^ 1 I o co 1 1 v 1 •51- cm ro 1 CM 1 O 1 o z: O ^ 1 i 1 cm t-1 t— vo cm .-1 1 1 z: o 2: • 1 1 • 1 vo td- U-> 00 O 1 nr 1 r— 1 a: r-i x: ro 1 CO 1 o 1 r-. cm r-. cm cm 1 to 1 s: 1 o — o —- <_) ^ ( O) E o

ii o" 1 ln (X) ' in 1 o 1 00 ol cn 1 1 1 cm cm 1 • 1 1 1 1 1 O) 1 CL 1 ro ro 1 X! 1 • 1 00 en 1 1 cm cm X 1 ^ 0 -o1 c\j 1 -a CO 1 f— v 1 V£> cm ro 1 c1u 1 'r*0") ^ 1 m • Q. (U N4 re "D <0 •r— 1 x 1 o o 00 1 x•4:J reX 0 nl OcJ r— 1 oc 1 nr o rc 1 1 to«« CO cvj

1 d I 1 z x; co 1 LO 1 r-H CM ro 1 RELATIVE INTENSITY 114

Mass spectrum of 3H-l,2,3,5-benzodithiadia2epin-2,2- dioxide-4(5H)-one is given in Fig.32. The important features

observed in the fragmentation pattern are briefly given below.

1. The molecular ion m/e 230 (M"*"') loses H' to give the ion m/e 229. The molecular ion also loses HNSO2 to give ion m/e

151 (b).

2. The m/e 151 further fragments by the subsequent loss of CO

and HNS to give ions m/e 123 (c) and m/e 76 (d), respectively.

-HNSO2 ,C=0

m/e 230(M+') m/e 151(b)

-H

C7H5N252O3+ -CO m/e 229(a)

-HNS U'

m/e 76(d) m/e 123(c) 115

EXPERIMENTAL

PART 'A'

REACTION OF METHYL SALICYLATE WITH CHLOROSULFONYL ISOCYANATE AT 25-30°C

6ener.5T Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken methyl salicylate (6.98 gm, 0.046 mole) in dry dichloromethane (50 ml).

To this was added chlorosulfonyl isocyanate (4 ml, 0.046 mole) in dichloromethane (6 ml) over a period of 30 minutes at room temperature (25-30°C). Stirring was continued for 2 hours at this temperature. The solid separated was filtered and washed with dichloromethane to get N-chlorosulfonyl-0-carbamoyl methyl salicylate.

Employing the similar reaction procedure, other substituted salicylates have been reacted with CSI, The N-chlorosulfonyl- carbamates thus obtained were listed in Tables 17 and 18. 116

REACTION OF METHYL ANTHRANILATE WITH CHLOROSULFONYL ISOCYANATE

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken methyl anthranilate

(6.952 gm, 0.046 mole) in dry benzene (60 ml). Chlorosulfonyl isocyanate (4 ml, 0.046 mole) in benzene (10 ml) was added over a period of 20 minutes at room temperature (25-30*^C). Stirring was continued for 2 hours at this temperature. The solid separated was filtered and washed with benzene to get N-chlorosulfonyl-0-carbamoyl methyl anthranilate.

The different substituted anthranilates have also been reacted with CSI by employing the above procedure. N-Chlorosulfonyl urethanes thus obtained were given in Table 17.

PREPARATION OF O-CARBAMOYL METHYL SALICYLATE

General Procedure

The N-chlorosulfonyl-0-carbamoyl methyl salicylate (7.0 gm) was hydrolysed by adding cold water (100 ml) with stirring and left overnight. The 0-carbamoyl methyl salicylate formed was filtered and recrystallized frcm ethanol.

Employing the similar procedure, other substituted G-carbamoyl

salicylates and N-carbamoyl anthranilates were obtained (Table 19 and

20) by hydrolysing the respective N-chlorosulfonyl compounds. 117

PREPARATION OF 2H-1,3-BENZ0XAZINE-2,4-(3H)DIONE

General Procedure

O-Carbamoyl methyl salicylate (2 gm) was taken in dry pyridine

(50 ml) and refluxed for 5 hours. Pyridine was then removed under vacuum. The solid obtained was washed thoroughly with water and recrystallized from methanol to obtain l,3-benzoxazine-2,4-dione.

Employing the above procedure, other substituted 0-carbamoyl salicylates were cyclized to obtain 1,3-benzoxazine-2,4-diones which were given in Table 21.

PREPARATION OF 2,4-(lH,3H)-QUINAZ0LINEDI0NE

General Procedure

N-Carbamoyl methyl anthranilate (3 gm) was taken in dry pyridine (80 ml) and refluxed for 8 hours. Then pyridine was removed under reduced pressure. The solid obtained was washed well with water. The 2,4-quinazolinedione was purified by dissolving it in aqueous potassium hydroxide (80 ml) and reprecipitation by neutralizing with dilute hydrochloric acid.

Various substituted 2,4-quinazolinediones were obtained by employing the similar procedure and were listed in Table 21. 118

REACTION OF METHYL SALICYLATE WITH CHLOROSULFONYL ISOCYANATE AT 100-105°C

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken methyl salicylate (5.98 Qf*^' 0.046 mole) in toluene (60 ml) and stirred at 100-105°C. At this temperature was added chlorosulfonyl isocyanate (4 ml, 0.046 mole) in toluene (8 ml) over a period of 40 minutes. Stirring was continued fc>- 3 hours. Toluene was removed under reduced pressure. The residue was added to cold water

(80 ml) and left overnight. The solid obtained was filtered and washed well with water and recrystal1ized from ethanol to get 0-sulfamoyl methyl salicylate.

Similarly, other substituted salicylates have been reacted with chlorosulfonyl isocyanate to obtain 0-sulfamoyl salicylates which were given in Table 25.

PREPARATION OF l,2,3-BENZ0XATHIAZINE-2,2-DI0XIDE-4(3H)-0NE

General Procedure

0-Sulfamoyl methyl salicylate (4 gm) was taken in dry pyridine

(60 ml) and refluxed for 7 hours. Pyridine was then removed under vacuum.

The solid obtained was washed thoroughly with water and recrystallized from methanol.

Employing the above procedure other substituted 0-sulfamoyl salicylates were cyclized to obtain l,2,3-benzoxathiazine-2,2-dioxide-4-ones which were given in Table 26. 119

PART 'B'

REACTION OF 2-AMINOPHENOL WITH CHLOROSULFQNYL ISOCYANATE

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer, thermometer, condenser and dropping funnel was taken 2-aminophenol

(4.87 gm, 0.046 mole) in nitromethane (120 ml) and stirred at

100-105°C. At this temperature was added chlorosulfonyl isocyanate

(4 ml, 0.046 mole) in nitromethane (10 ml) over a period of 30 minutes,

Stirring was continued for 4 hours. The solid separated after the addition was filtered and washed with water. Recrystallization from

ethanol gave l,2,3,5-ben20xathiadiazepine-2,2-dioxide-4-one.

Employing the above reaction procedure, 2-amino-5-chlorophenol

was also reacted with chlorosulfonyl isocyanate to obtain 7-chloro-

1,2,3 ,5(3H,5H)-ben20xathiadia2epine-2,2-dioxide-4-one (Table 28). 120

REACTION OF 2-AMINOTHIOPHENOL WITH CHLOROSULFONYL ISOCYANATE

General Reaction Procedure

In a four necked flask fitted with a mechanical stirrer,

thermometer, condenser and dropping funnel was taken 2-aminothiophenol

(5.75 gm, 0.046 mole) in toluene (60 ml) and stirred at 100-105°C.

At this temperature was added chlorosulfonyl isocyanate (4 ml, 0.045 mole) in toluene (8 ml) over a period of 20 minutes. Stirring was

continued for 3 hours. Toluene was removed under reduced pressure and

the residue was added to cold water. The solid obtained was digested

in hot methanol (25 ml) to get methanol soluble and insoluble portions.

Methanol insoluble portion was washed twice/thrice with hot methanol to

get N-carbamoyl-S-sulfamoyl-2-ami nothi ophenol.

From the methanol soluble portion, methanol was completely

removed under reduced pressure and the residue obtained was purified

by column chromatography using benzene/methanol (9.6:0.4) as eluent to

get 1,2,3,5(3H,5H)-benzodithiadiazepine-2,2-dioxide-4-one (Table 28).

m.p.243°C N-Carbamoyl-S-sulfamoyl-2-ami nothi ophenol yield 23%

c^hqnoo^s, found (^7.3)' ' C H N 29.78 3.21 16.45 (34.00) (3.67) (16.99) 121

REFERENCES

1. J.Hoback, J.Crum and D.Carroll, Proc.West V Acad.Sci., 40 (1955).

2. K.Clauss, H.Jense, E.Lueck, Ger.Offen. 2,228,423; Chem.Abstr. 80, 83072a (1974).

3. Organic Syntheses, Coll. Vol.11, John Wiley and Sons,Inc., New York, 1943, p.7.

4. A.I.Vogel, Text book of Practical Organic Chemistry, p.782.

5. Organic Syntheses, Coll.Vol.IV, John Wiley and Sons, Inc., New York, 19, p.178.

6. N.D.Ghatge and S.P.Vernekar, Angew. Makromel. Chem. (1971); Chem.Abstr. 76, 86469 p (1972).

7. E.Grigat and R.Putler, Chem.Ber. 1359 (1965).

8. A.F.Hegarty and T.C.Bruice, J .Am. Chem.See. n, 6575 (1970).

9. S.C.Prakashi and J.Bhattacharyya, Tetrahedron, 24, 1 (1968) CHAPTER IV

In view of the interesting observations from the studies carried out in Chapter II (Part 'A') that the reactions of chlorosulfonyl isocyanate with 2-aminobenzophenones giving rise to 4-aryl-2(lH)-quinazolinones in good yields and further the

broad spectrum of biological activity exhibited by these compounds, a number of quinazoline fused systems have been prepared.

This chapter is divided into Parts 'A' and 'B', which deals with the synthesis of the following compounds derived from 4-aryl-

2(IH)-qui nazoli nones.

PART 'A'

l-Substituted-5-aryl-s-triazoloc4,3-a:-quinazolines.

PART 'B'

5-Aryl-12H-quinazolino:3,2-a:quinazolin-12-ones. 123

PART 'A'

l-SUBSTITUTED-5-ARYL-s-TRIAZ0L0:4.3-a]QUINAZ0LINES

This part of the Chapter deals with the synthesis of s-triazoloc4,3-a:quinazolines. Various intermediates such as

2-ch1oroquinazolines and 2-hydrazino-4-arylquinazo1ines have been prepared.

2-Chloroquinazolines

4-Aryl-2(lH)-quinazolinones described earlier (Table 5) have been converted to their corresponding 2-chloro-4-arylquinazolines by reacting them with phosphorus oxychloride. o. POCI3 OY ^N VxXN^^O H N-" XI

X=X^ = H,Cl

The compounds thus obtained are listed in Table 29. 124

TABLE 29

2-Ch1oro-4-aryl-2(lH)-quinazolines

m.p.(°C) S.No. Ref. (Lit.m.p.)

1. H 115-116 1 (114-115)

2. CI H 160-161 2 (159-160)

3. CI CI 160-162

* Elemental Analysis Found c (calcd.)'

H N

54.46 2.08 8.96 (54.31) (2.26) (9.05) (309.5)

2-Hydrazino-4-ary1quinazo1ines

NH-NH2 II

X = H . CI 125

2-Hydlrazino-4-arylquinazolines (II) have been prepared by reacting 2-chloro-4-arylquinazolines with hydrazine hydrate in alcohol.

The compounds thus obtained are listed in Table 30.

TABLE 30

2-Hydrazino-4-arylquinazolines

S.NO. X x^ ^ i^ef, (Lit.m.p.}

1. H H 156 (155-156)

2. CI H 170-172 (170-171)

3. CI CI 176-177

•Elemental Analysis Found „ (calcd.)'

C H N

Ci/iHinCloN. 55.36 3.12 18.17 (305.2) 126

l-Substituted-5-ary1-s-triazo1o[:4,3-ajquinazo1ines

Triazoles are an important class of heterocyclic compounds containing three nitrogens in a five membered ring. They are of two types i.e., 1,2,3-triazoles or v-triazoles and 1,2,4-triazo1es or s-triazoles.

It is evident from the literature that triazole moiety has a great adaptability in forming fused heterocyclic ring systems such as s-triazolotriazoles, s-triazolopyridines, s-triazolopyrimidines, s-triazoloquinolines. Therefore with an object of unravelling the biological activities and arriving at structure activity relationship, a variety of 5-aryl-s-triazoloc4,3-a:quinazolines (III) having sub-

stituents at 1 and 7 positions have been prepared.

R III X = X^= H,Cl R = alkyl, aryl, aralkyl 127

In literature a recent patent of Sumitomo Chemical Co.Ltd.,

Japan, claimed the preparation of s-triazoloc4,3-aDquinazoline by the following two methods:

The 2-hydrazinoquinazoline was reacted with carboxylic acids to give 2-acyl hydrazinoquinazolines (IV) which were cyclized thermally or in an inert solvent with polyphosphoric acid.

+ RCOOH NH-NH2

A or A PPA NH-COR

IV III R = alkyl,aryl, benzyl 128

It was also obtained by the reaction of a triazolobenzo- phenone with ammonia. o.

oT^i' - nh3

III

In the present investigation, a variety of 1-substituted-

5-aryl-s-triazo1oc4,3-a3quinazolines (V) have been synthesized by the reaction of carboxylic acids with 2-hydrazinoquinazolines,

Reaction of 2-hydrazinoquinazo1ines with carboxylic acids

2-Hydrazino-4-arylquinazolines and carboxylic acids such as benzoic acid, phenylacetic acid, cinnamic acid and phenoxyacetic 129

acid in the presence of phosphorus oxychloride give the corresponding s-triazo1oc4,3-a:qLrinazolines (V) in one step.

rcooh ^^ QIA ^

XrX^ = H

R = aryl , styryl, phenoxyalkyl

Various 5-aryl-s-triazoloc4,3-a:quinazolines obtained are

listed in Tables 31, 32 and 33. These have been characterized

by elemental analysis, IR, NMR and Mass spectra. 130

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00 Ln VD 00 o 141

1 1 , , , ^ ^ 1 IT) cr. CO CO ro t-^ cn CO cn LD ^ CTi 1 O '-H O cri ro ^ Ln CM 1 ro CM z: 1 • • • • • - • • • • » I CVJ CvJ CM CM CM CM t—f I—1 CM CM r—4 1—1 1 (/) 1 T—i r—{ 1 r-H r-H T—1 .—1 I—t .—1 1—1 <—I 1—1 1 'r— 1 —' ^ ^ 1 1 1 >, ^ 1 • -—> y—~ -—V ^—^ 1 r^ CM CO ^ to uo CO cn U3 ro 00 CM CO Ln 1 ro "D "O 1 CO cn •St LO r-H CM 00 un CM --H 00 cr, ro 1 E E (J n: 1 • • • • • • » • 1 cc 3 r- 1 ro ro CO ro ro ro ro ro 00 ro ro ro ro ro f O ro 1 ' ^, ^ ^ 1 U. o 1 1 ro —' 1 1 +-> 1 1 c 1 1 O) 1 -—^ s -—- ^ V 1 E 1 CM ro ix> CO CT^ (TI VO CO ^ 1 ai 1 CM O ro •cj- C\J C\J Ln VD r-H O Ln I r— O 1 • • • • • • • • « • 1 LiJ 1 Ln Ln cr> cn ro ro cri en Ln Ln O CD 1 UD UD Ln Ln LO LO LO LO 1 1 — • ' 1 1 1 1 o o o o o o < fO 1 o 1 i~ 1 z: z sr 1 1 CM CM ro CM z CM ro i ^ 1 r— r— r— r— r— r— 1 ^ 1 LJ ^ O • o .—, CJ O ej -—~ CJ 1 o 1 CO -d- 00 ro CM Ln CO OD r-- 00 1 1 rt i—i ! 1 • 1 1—1 • t—I • 1—t 1 • 1 r-i TH r- ro •r CO zn CM zr: r-H zn Ln 1 r— 1 LD VD ro CTi ro ro ^ 00 Ln vo Ln cn 1 o 1 CM OO 00 CM ^ CM ^ CM CM ^ CM 1 s: 1 O ^ o ^ O — O (_) o — C_) — 1 t 1 I ^ 1 1 -o 1 ^ D. 1 -M 1 o . 1 m (Ti C7I c 1 CO r- LO 00 1 CTi OJ CM CM CM o ' ° ^ ro o 1 • 1 1 1 cn I 1 cn 1 Q.-I- 1 CM ro 1X3 CM r-. 00 CM 1 • _J 1 CO r^ LO 00 CO 1 E'^ 1 CM CM CM CM ro 1 1 1 1 m 1 XJ 1 c 1 VD 00 CO cn vo 1 1 to Lf) r-. WO IT) 1 *- . 1 1 >- 1 J1 1 1 1 OJ 1 O 1— 1 Q: 1 C_) o 2C o •1 nz 1 1 ro ro ro 1 1—1 1 zn zc 1 QC 1 o rc IC a: a: tj o 1 1 1 00 00 oo oo ro 1 n: 3: 1 cm 1 CJ a: o o o 1 1 1 1 1 1—1 1 r— r— 1 X 1 or o <3 o o 1 e> <_> 1 1 1 ^ r— ^ 1 X 1 o (3 o c3 O C_) o 1 1 f 1 1 1 d 1 • z 1 • • • • • • • 1 CM 00 ID UD 00 1 to 1 I—1 t-H t—1 1—1 1—1 r-H 1-H o it)

O .o eog 2 u

LU D o O QJ CX U. o -ion (N

o . o o

L§ o .o 9

o .olf>

o -§ CN Z u

o C

§tl.

o _ion

The IR and ^H-NMR spectra of some representative compounds are given below.

The IR spectrum of l,5-diphenyl-s-triazoloc4,3-aDquinazoline

(Fig.33) shows C=N stretching absorption at 1590

The IR spectrum of l-(4-methoxystyryl)-5-phenyl-7-ch1oro- s-tria2oloL4,3-aDquinazoline is given in Fig.34.

143

TABLE 34

Chemical shift No. of Multiplicity Assignment (ppm) protons

7.18 - 8.23 14 muUiplet aromatic

4.91 2 singlet -CH2

TABLE 35

^H-NMR of l-S-phenylethyl-5-phenyl-7-chloro-s-triazo1oc4,3-a3 quinazoline {Fig.36)

Chemical shift No. of Multiplicity Assignment (ppm) protons

7.34 - 8.31 13 multiplet aromatic

3.58 - 3.79 4 broad singlets -C^-CHg- 144

PART 'B'

5-ARYL-12H-QUINAZ0LIN0c3.2-a3QUINAZ0LIN-12-0NES

As already reported earlier that 2(lH)-quinazolinones and

4(3H)quinazolinones display a broad spectrum of physiological activity. This gave a lead to prepare fused quinazolino- quinazoline ring system with a view of enhancing the biological activity. This has been achieved by condensing 2-chloro-4-aryl-

2{lH)-quinazolines with anthranilic acids/esters give 5-aryl-

12H-quinazolinoi:3,2-aDquinazolin-12-one (VIII) in one step and are

listed in Table 36, These compounds have been characterized with

the help of elemental analysis, IR and Mass spectra.

HoN

ROOC

XrX^rH.Cl R=H,CH3 ; R^xR^ = H. CI 145

1 cri CO OO OO C3-1 r-l 1 CTi CNJ »—« ro r-l ro z: 1 • • • • » • • * 1 CM CM 1-H r-l o o o o I vn 1 T—1 I—1 1—t T-H T-t r-M t—» T-l 1 'r— 1 •». ^ • 1 01 C I >> o 1 r— , 1 ^—> „«— u 1 fO 1 en r-t CO ro r-l 1 C T3 -D 1 r-H o m "-H LD OJ o 1 «a: c u 31 1 • • • • • • • • 1 3 !— 1 ^ CO n CSJ OJ ro ro 1 r— O (V 1 ^ ' 1 +fJO LL-—. 'O 1 CD 1 E 1 ^—s ,— ,—V 1 a> 1 r—l r-l tn ^ CO t—1 I r— 1 OO O CTi r-v ro CO VO 1 LiJ O 1 * • • • • • 1 r- 00 r-l r-H CM CM 1 t^ IX) 1 ""—• '—' —' o 1 fO O CO o 1 r— ro ^ OO 1 3 1 o CM z t E 1 CO •Z. r— i- 1 ^ I z: -—- r—O —- U ^ CQ ^ 1 o 1 cn ^ CM C30 I—1 CM CM r^ 1 M- 1 I—t T 1 • 1 1—1 1 • 1 n: CO rc 3: CM 3: c\ ( r— 1 ^ CM »-( r^ I—1 I—1 r-l C 1 o 1 CM ro CM ro OO CM 1 s: 1 CJ • o o ^ O ^ cw 0 CS1J » o I VD CO 1 o 1 CO Lf) I 1 CM CM ^ 00 I • 1 1 1 t Q. 1 CM CM 0 1 • m N 1 CO CM (O I E 1 CM kO c: ro 3 D- n CQ fO 1 -rO— -—^ 1 1 - o 1 CM o 1 Q: 1 3: o 3: MrO C •r— 1 r—1 4. cr 1 a: 1 I o X CO CVJ r-H 1— I 1 a: 1 :r o 3: 'H cSC- 1 i—t IDI 1 X 1 ZJ: 31 3: 3Z

• X 1 31 3r a: 3:

1 C5 1 z: 1 • 1 • « • • 1 00 1 r-l CM CO 146

1 1 1 1 r-l CM CTv '—- CTi VD 0 ^ 00 I—1 in 1 CM r-l 00 r-H rl 0 ro CM CM -—I in ^ VD in • • ' » ro ^ 'Zi •1 • • • 1 r—1 r-H 0 0 • • • • 0 0 C3-^ CTi 00 00 00 CO 00 1 ( I—1 I—1 1—1 CTv CTi (Ti CTi ,—1 r-l V , •r- 1 *• ' - in 1 >> ^^ 1 1 — „ , ,,—^ ^—^ fO 1 00 r-H t-v. in 00 Ln r-. in 00 r- ro C -D "O 1 t-l CM ro in in VD ro CM CTi CO CM 0 C U a: 1 * • • • • • • • • • 3 r— 1 ro ro CM CM CM CM CM CM CM CM CNJ CM r-l r—1 CM CM r— 0 fO 1 —^ - • fO u. 0 1 +-> —' 1 c 1 a; 1 E 1 ^—V —^ ^—^ ^ CU 1 r-l m rj- 00 CO r- in VD CM CO r-H ro CO in T— 1 to r^ 00 r-4 CM 00 ro 1—1 ro CM CM oo UJ 0 1 • • • • • • • • • • • • • • 1 VD yD r-l .—1 r-l r-l VD VD CM CM .—1 r-l 1 to in in in in VD VD in in 1 UD in in in in 1 •—' •—' •—' o 00 or o o O o o z: ro O ro ro ro ro 00 or o cm 3 CM o CM o r— S- S- O —V o ca • O C_3 i- O CVJ 00 I CM O >—I to I CM O UD cj> o cao --H t—I 1 • 1—1 i * I—I cn • 1—I CM n: 10 CM re .-I >—1 r-v •—I >53- I ro r-l I 00 1—( C3~i o OM ro CM CM CM CM ca- CM CM CM "=3- o O O CJ) — o ^ o -— cj> ' O —-

-o 4-> E o cn CM m in O o CO tn <£5 CM o CM CM CM CM CM tD CM CM I 1 I I 1 m I a. o l-H CO CO CM CM CM CO VD r-- ^ CM ro E C0M0 CinM CM CM CM CM

CQ T3 CM VD in ID 0) 5-S in 00 CVJ 00 >- 00 00 vo 00 00

CM O a: O

S- s- cx: o CQ o CD

Qi tJ o

o o

zo: CM 1-i

S o^i

1 147

The IR spectrum of 5-aryl-12-H-quinazo1inoc3,2-a:- quinazoline-12-one (Fig.37) shows C=0 and C=N stretching absorptions at 1685 cm"^ and 1590 cm"^, respectively.

The mass spectra of 5-ary1-12H-quinazolinorS,2-a3 quinazoline-12-ones (Fig.38) has been studied in view of its

structural novelty. The salient features observed in the

fragmentation pattern (Scheme X ) are given below.

1. The molecular ion m/e 323 (M •) fragments by the loss of

H", CO and CgH^ to afford ions m/e 322 (a), m/e 295 (b)

and m/e 246 (c). The ion (a) in turn loses CO to give

ion m/e 294 (d).

2. Ion (b) further fragments by the loss of CgH^CN and CgH^

subsequently to give ions m/e 192 (e) and m/e 116 (f). The

loss of CgHgCN is further substantiated by a metastable peak,

3. Ion (c) furnish ions m/e 218 (g), m/e 142 (h) and m/e 102

(i) by the subsequent loss of CO, CgH^ and CN2.

148

OCL

ml9 46(c) mit 323(M+*) m/» 295(b) * -co

-CgHjCN

CCa +

m/« 218(g) m/e 192(»)

m/e U2(h)

-CN2 -CgH^

T^N

m/e102(i ) m/e 116(1) SCHEME X 149

EXPERIMENTAL

PART 'A'

PREPARATION OF 2-CHL0R0-4-ARYL-QUINAZ0LINES

General Procedure

To 4-aryl-2(lH)quina2olinone, (10 gms) was added phosphorus oxychloride (40 ml) and refluxed at 120-130°C for about 40 minutes. After distilling off about 20 ml of the phosphorus oxychloride the reaction mixture was poured into crushed ice.

It was neutralized with aqueous sodium carbanate and crude product obtained was recrystallized from ethanol.

Employing the above general procedure, the compounds prepared were shown in Table 29.

PREPARATION OF 2-HYDRAZIN0-4-ARYLQUINAZ0LINES

General Procedure

•2-Chloro-4-arylquinazoline (0.1 mole) and hydrazine hydrate (0.15 mole, 95%) were refluxed in ethanol (2 litre) for

3 hours on a water bath. After removal of alcohol to more than half, the crystalline solid separated was washed with plenty of water and filtered. It was further recrystallized from ethanol.

The compounds prepared were listed in Table 30. 150

PREPARATION OF s-TRIAZ0L0c4,3-a:QUINAZ0LINES

General Procedure

A mixture of 2-hydrazino-4-aryl-quinazoline (0.01 mole), carboxylic acid (0.011 mole) and phosphorus oxychloride (10 ml) was refluxed for 3 hours in an oil bath. After the heating was over, the contents were poured on ice, filtered and washed with aqueous sodium bicarbonate (10?; solution). The product thus obtained was recrystal1ized from ethanol/methanol.

The s-triazoloc4,3-a3quinazolines thus prepared were described in Tables 31-33. 151

PART 'B'

PREPARATION OF 5-ARYL-l2H-QUINAZ0LIN0r3.2-a:QUINAZ0LIN-12-0NES

General Procedure

2-Chloro-4-arylquinazo1ine and anthranilic acid/methyl anthranilate were taken in equimolar quantities and heated in an oil bath at 160-170°C for 90 minutes. After the heating was over, the brittle mass obtained was powdered well and washed with sodium bicarbonate solution (10%). It was recrystal1ized from ethanol/methanol to get the pure compound.

The compounds prepared by the above general procedures were described in the Table 36. 152

REFERENCES

1. K. Schofield; J.Chem.Soc. 1927 (1952).

2. Yoritaro Harokos et al., Japan, 20,865; Chem.Abstr. M, 2105 f (1966).

3. Michihiro Yamamoto et al., Ger.Offen.2,508,333; Chem. Abstr. 83, 206322 d (1975). CHAPTER V

BIOLOGICAL EVALUATION

Biological evaluation of compounds synthesized in

Chapters II, III and IV forms the subject of this Chapter.

Primary screening of representative members has been carried out in •experimental animals at the following centres:

i) Department of Pharmacology Osmania Medical College Hyderabad

ii) Department of Pharmacology Grant Medical College Bombay

iii) Department of Pharmacology J.N.Medical College Bel gaum

Antimicrobial activity of the compounds has been carried out at Department of Microbiology, Osmania University, Hyderabad,

The following notations are employed:

- : No action

+ : Mild action

++ : Strong action 1 54

Pharmacological Activity

The primary screening data has been generated in experimental animals for selecting potent compounds and also to study structure activity relationship amongst the series. Pharmacological screening has been carried out as follows:

1. LDgQ value : This is determined in mice by intraperitoneal

route according to the method of Litchfield and Wilcoxon^.

2. Gross observation : During the LD^q studies, mice have been

observed for their behavioural action, i.e., for convulsions,

irritation, piloerection, sedation, ptosis and sleep.

3. Analgesic action : In this study, the analgesic property has

been assessed by Writhing test using acetic acid. Tail clip

and Tail flick methods employing the standard procedures 2 described by Randall and Selitto . Aspirin has been used as a

standard in these tests. 3 4. Antiinflammatory action : This has been determined by carrageenin / 4 formalin-induced edema and cotton pellet-induced granuloma

methods.

The screening results of the compounds are described in Tables

37 to 46. 155

4- o c o c ••- o +-> •r- ro IJD OO co ti- 00 o XIro • CM ro n •f— c c

O ^^ Q- 1/1 C I— 0) o u cn-i- co o cm O rro- U -r- CM ro ro CM

+ c: o + + + + + •r— + + + + + + ro + c + c + c + c E + "D J- E + 1/1 o o o o O CD O 1 c •1- 10 •>- Wl •1— I/) i- •I- in in i.o 4-> •)- 4-> ro-t- -t-> T- •4-> -1- 3 tCLo 4J T- (/) (D•r — ro to ro X ro to ro ro i/i o Q) ro 00 o to +-> -o o "O ro -o o •o •o O XI S- •o o ro 0) +-> 0) (U 4-> Ol q; +j ro QJ -(-> o o > 00 O- it) cc OO D- 00 00 D. _J OO D.

Ol O) (/) o o o o o o o Q o o o o o

cn o ^ o o o o o o m o o o o o o Q CT 00 CO co co 00 -I E

ro X ro ro ozr. t_5 ozn

x o o

o z oo CNJ ro vo 156

c •<1/QJ CD O <—t fO CM cn ro s- S- la o 4- ^ o c co O -r- •t+--> +J« •O E

CO vo oo cnj co ro c c:

+ + + + + + 00 1 E c + E c + 1 C 1 O o O o to i. O 1 •n- •1- (/) •p— •1- CO (/) ai•r — 1 +-> -r- 4-> 't- O t/l +J 1 0) (U +-> > • 00 oo n. 00 C/O D- 0CO0 it] cCo cn O) I/) ^ o o o o O o o o D B

cn o ^ O o o o in ^ o o o o Q C71 co 00 r--. 00

o o

po CO o o

o z t/) 00 CJ1 157

c qa; CT> n3 CO o 00 i- CO CM ro <+o- O c £= o o -r- •1- 4-> •r+--> to£ •r-q- nse ^c 1— I—< C fO 00 00 CO

0C0 + o + + + •r— c c c 4-) o + o o + 00 ro 'r- to •r- •r- 00 t/1 > +J -M •r" o s- ns I/) fO I/O S-

cn o ^ ID o o o o O CD o o O o -J E 00 00

CO 00 a: o

o z CM CO 00 1 58

c CJO) CM cn o lt) rO o cm co 00 ID s- cm cm s- ro cm «—1 fO o ll s-s o c c o O -1- •r- 4J 4-> ta ra 1—1 ro cn o o

t—I c C30 00 <—1 cm T—l 1—1 oo cm co cm co

c o + + + •r- oc co + eo + l/l fO •i— •1- in •t- (/> o > 4-> +j -r- 4-> -r- s- s- (0 fO {/) ro c/i O ttJ •td -a o •a o to cd oj +-> o 00 oo d- D. o

CcoC oi OJ o o o O o o in ^ o o tn o o

o o o o o o o Ln o o o o o o Q cd co vo 00 tn co CO

dc o o

co CO If) lfj o ozn vo o o

o z • IT) o I/O 00 OJ 159

C -(-> o 0) 1 oo CO a^ 00 oo 00 V£) CO o 1 • • • • • • o (1) 1 VD CO cri un C_5 CL 1 ro CNJ ro ro o c Oc -ro- •r-~ 4J s -M ca Q; CD 1—1 TT O CM -5 E Di •I- to rtJ LN CM CO LD JC r- S- CM CM CM C\J C s- CM CM "-I C oro

^—, —• O ^ • T— C T/) •R— co o •—1 CM OL C CD O •4-) ro Ln CM LD 'P- •R— >=1- ro (O -(-> s- c o 3 ct to UJ

c c 1/5 1 o o o 1 C 1 'p— t/> O 1 4J 4-> I/) •r- 1 ( o to •a- o I/)+- > 1 to -tao XJ S-jQ to I i. 0) OJ LU CD o > 1 1- oo oo DQ

cn Ol ^ o O o o o o I/) — o o o o IX . O CD O E

05 o ^ o o o o o o m ^ o o o o o o O C" r>. CO 00 00 CO

I-H 1— A: 1 ZC. O O TJ

I-- 1 ro ro LD in N: IC 1 A: 3: N: CO CO on 1 O O C>0 CM c_> O O 1 1 o o 10 in •t— o 1 • • • • • • • 1 R-4 CM 00 LF> vo 1 CM C«J CM CM CM CM 160

C -TJ 1 O 0) 1 LO to LN LF) in LO +J R— 1 UD o <3- CM CM O LO +-> r- 1 - » — O a C 1 E C 1 -Q E o 1 CTI 00 •R- re cu 1 I—1 O 00 LO CM I—1 ^ r— O) 1 • * * C <+- (D 1 CO m r^ co' 00 CM 1—• c S^- 1( ro ro CO CM 1—1 FO 1 C_J 1

O n 1 •'— — CJ1 1 C 1 cu c •R— 1 o o o O o o O cr> o x: 1 • • • • 1— 'r- -(-> 1 CM o CO CO 00 LD ra •R- 1 tn c^ ID c u t- 1 ra 3 1 + + >1 >) +-> 4J 00 1 + •f— • I— + 1 C ) r— r— 1/1 S- O 1 c •r- c QJ o XI 1 ! o 1 O t/1 4J t •r- (0 ro S- XI re 1 +-> +-> 4-5 CD O > 1 O •1— ro re s- s- -o s- i- s- (U —t 1—t CO

U=zO CD 1 tt) 1 in ^ o o o o O o o O 01 1 V£) vo o o o Q E t 1—1 RH 1—1

_ CJ1 O tn -v. o o o o o o o Q O) o o o o o o o vo r^ ID 00 00 co

CJ oc

CO PO PO zc a: a: oc o cj m o CO cc o o

o z. 00 cr> o CM CO on CVJ CM cvi CO n CO CO 161

E O) IN cu <£) R—1 CM OL C\J CD ro LO M ro o" o s- F—t CM ro s- ofO - o c c o o 4_) •to 10 *r— £ -Q E CO CO •I- ro ro JZ r— 00 00 «=r C CM «-i c

to + + c o c c c c + •r— o o o o •1- •r- •r— •t- in to ro •l") +-> 4-> • !- w > fO ro ro O 1/1 O t. •o T3 •a fO o S- Q> a> CU 0) 5- 4-> O iTi oo OO \r- O. Xio

OJ ^ o O O o o o o o o o O o o o o o o o Qo crE>

D1 O O o o o o o o o o un o o o o o o o o o O C7> 00 00 00 00 co 00 00 co 00

I— I— n:ro nr:o I— Xr o a: o DC o o <_> o o oc o

X O O O (J C_> O O o o

o o cvj OJ CM

o z «5j- LD KD 00 Oi o r-t CM 00 CO ro CO 00 ro CO 162

C +-> 1 } O W 1 LO 1 4-> 1— 1 T 1 1 1 M +-> r— 1 O 1 O O OJ 1 CSJ > C o a. 1 1 c o 1 O -R- 1 -R- C 1 1 -TJ RO 'R— 1 1 'T— £ C 1 1 J2 E QJ 1 T T- (0 QJ 1 > X: 1— CN I CVJ 00 ^ 1 c H- FO 1 » 0 1 • C S- 1 T-H CO 00 CO 1 -1— i- 1 T—» 1—< •5J- 00 13 1 O I

r~» 1 1 r—^ O. t 1 O -J 1 'R— ^—^ R— T 1 1/) O 1 1—1 IX) CVJ O-I I oj c T 1 O) oR ^ 1 (N RO o CO 1 r— •!—*R — 1 1—1 CM R—1 «—t 1 (O 4-) tU 1 1 C Oh- 1 1 =1 mI— ' 1

+ + + >> + -T-^ >> •R- 4-> + to 1 > -t- + + + 1 1 C i •R— R— 1 lO s-O 1 4-> -1- c c c z—z 1 L/L OJ '1— J O o o o 1 O CO-l- > J (D IV •1— •R- '1— 1 i- JD CO 1 S- 4J •L-> -T-> +J » O O > 1 OL t- (0 O re CL S- •o to •o •d- s- 0) S- Q) t/1 (— oo CQ C 1 CD 1 1 a> 1 o o o O 1 1/1 ^ o o r-- CO i o cn 1 t—1 «—1 1 Q E 1

cn 1 I O Jii: 1 o o o o \ Lf) \ 1 o o o o 1 o a> 1 00 00 t^ UD 1 _J e 1

1 t—t n o 1 Ol n; a: C_) o o o m a: 1 cx: n: o n: o o o

^ I— 1 1 X o o o o

1 d I z • • « 1 • 00 un vo 1 LO 163

E +-> 1 1 O CD 1 1 4-> r— 1 CT, 1 It- — -M f— 1 1 • 1 1 o o q; I 00 un 1 c O O- 1 ro CM Od 1 c o I o 1 •!- e: i 1 +--r>- En o•l—C 1I 1 e 4- fO 1 f-H o 1 1—' CS - 1 C\J ro t 't— t- ) C_ro) 11

r—1 1 1 O —- 1 -1- Ccd I1 1 CO -—-•1— 1 O o ro CO 1 0) c ^ 1 1 1 cn o •4-> 1 1—1 S- 1 1 c u 3 1 1 "a: tc

+ 1/1 1 + + + + 1 1 W^- t1 1 i/) w o 1 c c c c 1 to O) t o o o o 1 o t/1 •p i 'r- 'r- 1 '1— 1 s- x) fD 1 +J 1 cd o > 1 ra O ro na -a fO •o •O CD s- Q) cu I/O 1— oo OO IT) 1 cn 1 1 0) > 1 to o o o o o 1 o cr> I o o o t^ o 1 o e 1 i—1 *—i 1—1 t—1 §

1 cn 1 j o ^ 1 o o o o o ) IT) ^ o o o o o 1 a CT) 1 00 00 CO t^ 00 1 _j e 1

1 c>j r— 1 oc •c o 31 o

c 1 i—1 1 DC •c n: 3: zr. o

co ro r •c zsz 1 OH cj> o o

^ ^ r— ^ r— i x o c_> o o o

1 o• 1 z • * • 1 • 00 cn o r-l 1 (/) LD Ln 164

c , •r— ro — - E C CM <+o- C o o u. c •f— o c •r— fO £ E QJ XI (U VO CM trs CO •r— r— cn x: f- ro O •rt c c s- 1—1 »—1 CM •r- s- ro O

n 1 — Q. 1 (J -r- 1 I in o 1 CU C 1 1 1 cn o r— 1 1 -f— 1 (T) ro -t-> ro 1 C O h- 1 (O 1

(/) + + 1 C E c 1/1 S- o O o in oj •1- f- 1 I •t— » O CO +-> s_ jis ro o ro O O > rci -a S- CD —1 00

cn OJ ^ co o o o o o o cn o o o o D E 1 *—I I—< »-H l_uJ

CO x o o o o

co x r- o

o o

o o o u o

cm co lf> vo it) ld it) m it) 165

Results and Discussion

A. Table 37 (S.Nos.l to 6)

Most of these compounds exhibit mild to strong CNS depressant and antiinflanmatory actions. Results of this series are in con- firmity with 2(lH)-quinazolinones which possess profound antiinflammatory and analgesic action. One of the compounds of this class, l-isopropyl-4-phenyl-7-methyl-2(IH)-quinazolinone (proquazone) has been recently introduced for therapeutic use under the name

Biarison.

B. Table 38 (S.Nos. 7-10)

Mild to strong CNS depressant and potent antiinflammatory action have been observed in this class of compounds.

C. Table 39 (S.Nos. 11-14)

These compounds did not warrant any further investigation.

D. Table 40 (S.Nos. 15-20)

Mild CNS depressant action and moderate to strong antiinfla/n- matory activity is observed. 166

E. Tables 41 & 42 (S.Nos.21-33)

Members of this series have shown interesting profile of analgesic and antiinflammatory activity. Some compounds are undergoing detailed investigation to assess their therapeutic efficacy.

F. Tables 43 & 44 (S.Nos. 34-46)

These compounds exhibit mild CNS depressant and moderate antiinflammatory activity. Most of these compounds possess LD '50 value more than 800 mg/kg.

G. Table 45 (S.Nos. 47-51)

Compounds of this class exhibit mild to strong analgesic and antiinflammatory actions. Some members of this series are undergoing detailed investigation.

H. Table 46 (S.Nos. 52-56)

These compounds do not show any significant biological properties.

Since this primary screening of the compounds is not complete,

it is not possible to arrive at structure activity relationship.

Anongst the compounds which have been screened, the following members are undergoing detailed studies to evaluate their efficacy

and margin of safety. 167

i) 6-Chloro-4-methyl-2H-l,3-benzoxazine-2-one (S.No.lO)

ii) 6-Chloro-l,2,3-benzoxathiazine-2,2-dioxide {S.No.16) iii) 0-Carbamoyl phenyl salicylate (S.No.27)

iv) l-(4-Methoxybenzyl)-7-chl oro-5-phenyl-s-triazolo-

L4,3-ajquinazoline (S.No.39)

v) l-(4-Chlorophenoxymethyl)-2-chloro-5-phenyl-s-triazolo-

c4,3-a:quinazoline (S.No.48) 168

Antimicrobial Activity

The compounds synthesized in the present work have been subjected to antimicrobial screening against the following:

i) Bacillus subtil is vi) Pseudomonas aeruginosa

ii) Escheritia coli vii) Aspergillus flovus

iii) Staphylococcus aureus viii) PeniciIlium tardum

iv) Streptococcus faecal is ix) Helminthosporium halodes

v) Salmonella typhimurium x) Fusarium Oxysporium

Method

The test compounds have been screened against the above mentioned species of bacteria and fungi for their antimicrobial activity using the disc method.

The test compounds have been dissolved in various solvents at the concentration of 10 mg/ml and several dilutions of these compounds are made in the same solvent (8, 6, 4, 3, 2 and 1 mg/ml) and tested against each organism. Minimum Inhibition Concentration (MIC) and Minimum.Inhibition Dilution (MID) have been obtained. The inhibition zones are expressed in millimeters. Ampicillin and Nystatin have been used as reference compounds. The compounds showing activity are tabulated in the following Tables (47 to 50). 169

TABLE 47

Antimicrobial activity Cone, used* S.No, against Pencillium mg/ml tardum

1. 10 12

9 10

8 9

7 7 MIC

6 Nil

2. CI H 10 18

9 17

8 13 7 11

6 8 MIC

5 Nil

•Solvent-acetone 170

TABLE 47

Cone.used* Antimicrobial activity against S.No. R R 1 mg/ml Asperigillus PeniciIlium Furarium flavus tardum oxysporium

3. H H 10 19 10 10

9 17 9 MIC 9 MIC

8 14 Nil ' Nil

7 12

6 10 MIC

5 Nil

4. H CI 10 15 15 Nil

9 14 14

8 13 14

7 12 13 6 10 11

5 9 MIC 9 MIC

4 Nil Nil

*Solvent-acetone 171

TABLE 47

Cone.used* Antimicrobial activity S.No. mg/ml against Staphylococcus aureus

5. CI H CI 10 10

9 10

8 9

7 9

6 8

5 9'

4 8.5

3 8.5

2 8

1 8 MIC

900 ug Nil

contd. 172

TABLE 49 (contd.)

J Cone.used* Antimicrobial activity S.No. X X R mo/ma against Staphylococcus aureus

6. CI H CH3 10 12

9 11

8 11

7 10.5

6 10.5

5 10

4 10

3 9

2 8 MIC

1 Nil

7. • CI H OCH3 10 12

9 11

8 11

7 10

6 10

5 9

4 9

3 8 MIC

2 Nil

*Solvent-acetone 173

TABLE 47

S.No. used* PeniciIlium Helmintho Fusarium mg/ml tardum sporium oxysporium halodes

8. CI H 10 28 30 21

9 24 26 20

8 22 24 18

7 21 21 17

6 17 18 14

5 14 16 12

4 12 13 10

3 11 12 10 MIC

2 10 11 Nil

1 10 MIC 10

900 ug Nil 10 MIC

800 ug Nil

*Solvent-acetone 174

Results

Compounds 1 and 2 amongst the 4-ary1-2(lH)-quinazolines show activity against Pencil!ium tardum only. (Table 47).

Compounds 3 and 4 amongst the 1,2,3-benzoxathiazine-2,2- d^oxides exhibit activity against Asperigillus flavus and

Penicillium tardum. Compound 3 showed marginal activity against

Fusarium oxysporium (Table 48).

Amongst l-substituted-s-tria2olo[:4,3-a3quinazoline series, compounds 5,6 and 7 show activity against staphylococcus aureus and were inactive against other species of bacteria and fungi

(Table 49). Compound 8 belonging to 1-styryl-s-triazoloc4,3-a:- quinazolines, exhibits broad spectrum of fungicidal activity against Penicillium tardum, Helmintho sporium halodes and Fusarium oxysporium (Table 50). 175

REFERENCES

1. J.T. Litchfield, E.Wilcoxon, J.Pharmacol., %, 246 (1964)

2. L.O.Randall, J.J.Selitto, Arch.Int., Pharmacodyn. Ther.

Ill, 409 (1957).

3. C.A.Winter, E.A.Risley, G.W.Nuss, Proc.Soc.Exp.Biol.Med.

Ill, 544 (1962).

4. C.A.Winter, C.C.Porter, J.Am.Pharm.Ass. (Sci.Edn.),

515 (1957). SYNOPSIS

Search for biologicany active molecules has been a challenging task for the medicinal chemists. For a long time nature had baffled the chemists with its intricate synthesis which from times irmemorial were used as medicinals for the relief of pain. Earlier emphasis on the search for newer therapeutically useful compounds rested mainly on naturally

occurring physiologically active molecules which provoked the

chemists. Rational approach towards the synthesis resulted

from the advances made in the discovery of newer reagents and

techniques, understanding of biological phenomena such as

absorption, distribution, metabolism and excretion. Amongst

these significant developments, particularly the wider applications

of new reagents and a better understanding of biological processes

have led to discover potent biologically active molecules. Efforts

in this direction throughout the world have led to discover newer

areas and have given tremendous relief to the suffering humanity.

Diseases which were uncontrollable and devastating to mankind

have been completely brought under control by the use of effective

medicinals.

As a part of the continuing efforts in this direction at

this laboratory on the synthesis of a variety of new and novel 11

molecules, the present work significantly brings out the following.

A powerful electrophilic reagent chlorosulfonyl isocyanate has been employed for the synthesis of a variety of nitrogen heterocycles.

This work also describes the synthesis of some novel nitrogen heterocycles and newer methods for a number of heterocyclic ring systems.

The work has been presented in the following manner.

Chapter I highlights the salient features of the chemistry of chlorosulfonyl isocyanate (CSI) and also the important biological activities of hterocyclic ring systems related to the synthesis of ccmpounds described in subsequent chapters, i.e., 2(lH)-quinazolinones,

4(3H)-quinazolinones, 1,3-benzoxazine-2-ones , 1,2,3-benzoxathiazine-2,

2-dioxides and fused s-triazoles.

Chapter II is divided into two parts.

Part A describes the reactions of CSI with 2-aminobenzaldehyde, 2- aminoacetophenones and 2-aminobenzophenones leading to the synthesis of various 2(lH)-quinazolinones (1,11).

I R II

R = H. CH3 R = H, CH3 rU H. Br. NO2 X = X' = H. CI Ill

Part B deals with the reactions of CSI with Z-hydroxybenzaldehydes, 2-hydroxyacetophenones/-ben2ophenones affording 2H-

1,3-benzoxa2ine-2-ones (III) as well 1,2,3-benzoxathiazine-

2,2-dioxides (IV) at room and elevated temperatures, respectively.

III IV R = H, CH3 R= H. CH3. CgHs H. CI R'= H. CI

Chapter III is divided into two parts.

Part A deals with the reactions of CSI with a variety of

salicylates and anthranilates at room temperature as well

higher temperatures to obtain 0-carbamoyl/-sulfamoyl

salicylates and 0-carbamoyl anthranilates. IV

Carbamates, sulfamates and urethanes thus formed have been cyclized to 1,3-benzoxazine-2,4-diones (V), 1,2,3- benzoxathia2ine-2,2-dioxide-4(3H)-ones (VI) and quinazoline-

2,4(lH,3H)-diones (VII), respectively.

N-H

VII

R= H, CI R'= H. CH3, CgHs. CH2C^H5

Part B describes the synthesis of new and novel heterocyclic systems, i.e., 3H-1,2,3,5-benzoxathiadiazepine-2,2-dioxide- (5H)4-ones (VIII) and 3H-1,2,3,5-benzoclithiadiazepine-2,2- dioxide-(5H)4-ones (IX) obtained by the reactions of CSI with

2-aminophenols and 2-aminothiophenol, respectively.

VIII IX

R = K CI

Whereas, Chapter IV incorporates the synthesis of fused quinazolines and is divided into two parts.

Part A deals with the synthesis of l-substitutes-5-aryl-s- triazoloc4,3-aDquinazolines (X).

X = x'= H. CI XI = aryl, aralkyl, styryl aryloxyalkyi R = R'= R^= H, CI VI

Part B describes the synthesis of 5-aryl-12H-quinazalino- c3,2-a: quinazo1in-12-one (XI).

Chapter V embodies the biological findings in experimental animals of various compounds synthesized in the course of the present work and described in Chapters II, III and IV. Some of the important findings are as follows:

Pharmacological evaluation of these compounds have been carried out at Departments of Pharmacology, Grant Medical College,

Bombay and J. N, Medical College, Bel gaum while antimicrobial properties have been determined at Department of Microbiology,

Osmania University, Hyderabad.

Pharmacological activity

4-Aryl-2(lH)-quinazolinones exhibit mild to strong analgesic, antiinflammatory and CNS depressant activity.

l,3-benzoxazine-2-ones and 1,2,3-benzoxathiazine-2,2-dioxides show mild to strong antiinflammatory action.

0-Carbamoyl salicylates exhibit mild to strong analgesic and antiinflammatory actions.

1-Substituted-s-triazoloc4,3-aiquinazolines display an interesting profile of analgesic and antiinflammatory properties. REPRINT

5-Aryl-12H-quinazo1inoc3,2-a3quinazolin-l2-ones show mild antiinflammatory activity.

Some members of the above series are undergoing detailed studies to assess their clinical usefulness.

Antimicrobial activity

7-Chloro-5-phenyl-l-styryl-s-triazoloc4,3-aDquina2oline exhibits broad spectrum of fungicidal activity against PenciIlium tardum, Helminthosporium halodes and Fusarium oxysporium while other compounds did not show appreciable antimicrobial activity. REPRINT

LIST OF PUBLICATIONS AND PATENTS FILED

1. A new route to 4-phenyl-2(1H)-quinazolinones,

Ahmed Kamal, K. Rama Rao and P.B. Sattur,

Synth. Commun. j_0, 799 (1980).

2. Synthesis of 7,2,3-benzoxathiazine-2,2-dioxides,

Ahmed Kamal and P.B. Sattur,

Synthesis, 272 (1981 ) .

3. Mass spectral studies of 4-phenyl-2(1H)-quinazo-

linones,

Ahmed Kamal and P.B. Sattur,

Indian J. Chem. Sect. B, 600 (1981 ).

4. Reactions of chlorosulfonyl isocyanate? Formation

of 1 ,3-ben2oxazine-2-ones,

Ahmed Kamal and P.B. Sattur,

Synth. Commun. (in Press).

5. A process for the preparation of 0-carbamoyl

salicylates,

Ahmed Kamal, P.B. Sattur and G. Thyagarajan,

Patent filed in September, 1981. SYNTHETIC COMMUNICATIONS, 10(10), 799-804 (1980)

A NEW ROUTE TO 4-PHENYL-2(1H) QUINAZOLINONES; REACTIONS OF 2-AMINO BENZOPHENONES WITH CHLOROSULFONYL ISOCYANATE

Ahmed Kamal, K. Rama Rao and P.B. Sattur Regional Research Laboratory, Hyderabad 500009, India

We have been interested in the synthesis of substituted quinazolinones as a part of our continuing research programme in search of potent physiologically active molecules. The present communication explores further synthetic uses of chlorosulfonyl isocyanate 1 2 (CSI), a reagent developed by Graf ' and extensively employed in the preparation of a wide variety of heterocyclic systems as well in various synthetic conversions^.

The preparation of 4-phenyl-2(1H) quinazolinone4-7s has been reported in literature by various methods such as by reacting 2-amino benzophenones with (a) urea, (b) potassium cyanate, (c) oxalyl chloride and sodium azide. Some of the reported procedures are quite tedious and the yields generally unsatisfactory. We now wish to report a novel and useful method for the synthesis of 4-phenyl-2( 1H) quinazolinones of

799

0=C=N—SO2CI or CH2CI2

I R 3 a-e A a-e

1,3,4 R X2 a H H H b H CI H c H CI CI d CH^ H H e CH^ CI H 4-PHENYL-2(lH) QUINAZOLINONES 801

biological importance by reacting CSI with 2-amino benzophenones, using benzene or dichloromethane as solvents. It is observed that the reaction of CSI with 2-ainino benzophenones give 4-phenyl-2(1H) quinazolinones in good yields ranging from However AoAndre and M. Jean reported 5-chloro-4-phenyl-2(1H) quinazolinone in about 50% yield by employing urea and potassium cyanate reagents, whereas in the present method it is obtained in 72% yield. 4-Phenyl-lH-.2,1,3-

q -i q benzothiadiazine-2,2-dioxides^'' are obtained as coproducts in these reactions and are easily separable from the quinazolinones. The results are stunmarized in the Table. The products have been characterized by elemental analysis, IR, NMR, Mass spectra and by 4 Q independent synthetic methods described earlier

EXPERIMENTAL Typical Reaction Procedure (3a-e; 4a-e); To a stirred solution of 2-amino benzophenone la (4,53g, 0.023 mol) in dry benzene (60 ml) is added chlorosulfonyl isocyanate (2 ml, 0.023 mol) In benzene (6 ml) over a period of 30 min at 0-5® (ice bath). The reaction mixture is stirred for 30 mln and allowed to warm to ambient temperature (28®). The stirring was continued for another 3 h at this temperature. Then the 802 KAMAL, RAO, AND SATTUR

TABLE Reactions of 2-Amino Benzophenones with CSI

Compound I.R. (KBr) (Lit.m.p.) cm

3a 66 261-262° 3050,1665,1580^ (255-256°)^ 3b 72 318-320° 3050,1650,1580^ (318°)^ 3c 70 326-328° 3060,1650,1590® (330°)^ 3d 78 142-144° 1680,1590 (142-143°)® 3e 81 226-227° 1685,1590 (^22-223°)^ 4a 8 214-215° 3240,l600,1120,1310 (216-217°)^ 4b 6 207-208° 3220,1590,1125,1310 (207-209°)^° 4c 7 197-8° 3230,1590,1125,1325 4d 5 209-210° 1595,1135,1330 (206-208°)^ 4e 5 192-3° 1605,1575,1130,1335

a Nujol 4-PHENYL-2(lH) QUINAZOLINONES 803 benzene was removed under vacuum, to the residue obtained was added water (100 ml) and left overnight. It was filtered and washed with plenty of water. This residue was dried and subjected to chromatography on silica gel using benzene/methanol (92/8) as eluent. The two products 3a and 4a separated by column chromatography were recrystallised from dichloromethane. The compounds 3b-e and 4b-e were obtained by employing the similar reaction procedure. In these cases most of the compounds 3b-e were separated as methanol insoluble portions, while the remaining soluble portions were subjected to chromatography on silica gel using chloroform/methanol (90/10) as eluent.

Acknowledgement! We are thankful to Dr. G.S. Sidhu, Director, Regional Research Laboratory, Hyderabad, for his interest in the work. One of us (AK) is also thankful to CSIR for the award of the research fellowship.

References; * To whom correspondence should be addressed, 1. R. Graf, Chem. Ber. 82, 1071 (1956). 2. R, Graf, Org, Syntheses, 46, 23 (l966), 3. J.K. Rasmussen and A. Hassner, Chem. Rev, 76 (3) 389 (1976), 804 KAMAL, RAO, AND SATTUR

4. S. Gabriel and R. Stelzner, Ber. 22, 1300 (1896).

5. R,V. Coombs et al., J. Med. Chem. 16, 1237 (l973). 6. A. Andre, M. Jean, French Patent 1520743, Roussel- UCLAF, Apr. 12, 1968; C.A. 21. ^9975 (1969). 7. Ishizumi, Kikuo et al., German Patent 2345030, Sumitomo Chemical Co., Japan Mar. 21, 1974; C.A. 80, 146193 (l974). 8. Hans Ott and Max Denzer, J. Org. Chem, ^3, 4263 (1968), 9. E. Cohen and B. Klarberg, J. Am. Chem. Soc. 84, 1994 (1962). 10. William J. Houlihan, U.S. Patent 3278532, Sandoz Inc., Octo. 11, 1966; C.A. 20154 (1966). REPRINT

International Journal 1981 of Methods in Synthetic No. 4: SYNTHESIS Organic Chemistry April

With Compliments of the Author.

GEORG THIEME VERLAG • STUTTGART • NEW YORK April 1981 Communications 271

Table 1. 2-Trimethylsilyloxyalkanamines 2 (0-Silylated /3-Aminoalcohols)

Prod- R' R2 R^ Yield" b.p. LR. (neat) 'H-N.M.R. (CDCl,)" uct [%] [°C]/torr i/[cm-'] 8 [ppm]

2a H CH3 88 85V15 3340; 3260; 0.10 (s, 9H); 1.00 (s, 6H); 0.7-1.7 (m, 7H); 1.75 (s, 1570; 1240 2H); 3.3 (m, IH) 2b -(CH,)4- CH3 80 58V0.3 3370; 3300; 0.15 (s, 9H); 1.10 (s, 6H); 1.4-1.9 (m, 8H); 1.90 (s, 1610; 1200 2H) 2c -(CH^),- /I-C4H9 92 134V0.5 3390; 3330; 0.10 (s, 9H); 0.9 (m, 6H); 1.0-2.0 (m, 24H) 1610; 1250 2d C.H5 H CH, 89 78V1 3340; 3260; 0.05 (s, 9H); 1.02 (s, 3H); 1.15 (s, 3H); 2.50 (s, 2H); 3040; 1250 4.40 (s, IH); 7,27 (s, 5H) 2e HjC CH-CHj CH3 CH3 75 70V1.2 3380; 3320; 0.16 (s, 9H); 1.10 (s, 6H); 1.23 (s, 3H); 1.3-2.4 (ra, 3080; 1650; 4H); 1.95 (s, 2H); 5.0 (m, 2H); 5.8 (m, 1 H) 1250; 910

" Yield of pure, distilled product. '' Dichloromethane as internal standard, shift values converted to TMS = 0 ppm.

Table 2. ;3-Aminoalcohols 3

Prod- Yield" b.p, ["CJ/torr Molecular formula" I,R, (neat) 'H-N.M.R. (CDClj) [%] uct' or m,p. [°C] or Lit. m.p. or b.p. i/[cm '] S [ppm]

3a 75 58° 5go,6 3340; 1590'' 1.02 (s, 3H); 1.10 (s, 3H); 0.7-1,8 (m, 7H); 2.50 (s, 3H); 3.2 (m, IH) 3b 85 92V13 C,H„NO (143.2) 3360; 1590 1.18 (s, 6H); 1.3-2.3 (m, 11 H) 3c 90 119V0.1 C.jHj.NO (241.4) 3400; 1590 0.97 (t, 6H); 1.2-2.0 (m, 25 H) 3d 82 101" 96-99°^' 3400; 3050; 1580'' 0.90 (s, 3H); 1.10 (s, 3H); 2.60 (s, 3H); 4.30 (s, IH); 7.4 (m, 5H) 3e 73 43V0.2 C,H„NO (157,3) 3380; 3080; 1.14 (s, 9H); 1.3-2.5 (m, 7H); 5.1 (m, 2H); 5.9 (m, 1 H) 1650; 1600; 910

For R', R^ and R', see Table 1. Yield of pure product based on 1. Satisfactory microanalyses obtained: C ±0.21, H ±0.24, N ±0.20; exception: 3c, C -0.5. Nujol mull. genated nitrile'" " '^. We present here the application of this The preparation of 5-hexen-2-one has been described''*. All the other ke- reaction to the O-silylated cyanohydrins 1 leading to 2-trime- tones and the aldehydes are commercially available. Trimethylsilyl cya- thylsiloxyalkanamines 2 and, by desilylation, to /3-aminoalco- nohydrin ethers 1 were prepared according to Refs.^" from trimethylsi- hols 3 in good yields. lyl cyanide" and the appropriate carbonyl compound. O-Silylated /3-Aminoalcohols 2: Compounds 1, readily obtained from any aldehyde or ke- To a solution of 1 (20 mmol) in diethyl ether (~20 ml) is added, under a tone^- react with two equivalents of the organolithium reagent nitrogen atmosphere, the organolithium reagent (45 mmol; commercial to give the 0-siIylated /3-aminoaIcohols 2, which can be isolated solution). The reaction mixture is stirred for 5-6 h at room temperature, (Table 1). It should be possible to use this form of 2, where the then cooled to 0 °C, and hydrolysed by addition of an approximately hydroxy function is selectively protected, for synthetic purposes equal volume of a saturated ammonium chloride solution, followed by if only the reaction of the amino function is desired. Thus, if 2 is rapid extraction with diethyl ether (4 x 50 ml). The combined extracts are washed with brine and then dried with magnesium sulphate. Evapora- treated with aqueous acetic acid solution, /3-aminoalcohol 3 is tion of the solvent gives crude 2 with >9096 purity (estimated by G.L.C. obtained in good yields (Table 2). analysis). In some cases (products 2b and 2e), a partial desilylation is observed during the hydrolysis step. This can be avoided by hydrolysing There is no limitation as to the nature of the substituents R', R^, the mixture with ammonium chloride solution (~3 ml), filtering, and and R' in 2 and 3, while comparable yields are obtained with drying the etheral solution with magnesium sulfate (Table 1). both ketone and aldehyde cyanohydrins 1. In contrast with our previous observations in the case of a-alkoxynitriles'° ", no side ^-Aminoalcohols 3: The crude product 2 (5 mmol) is dissolved in approximately 25% aque- reaction is observed with compounds 1. ous acetic acid solution (10 ml) and the mixture is stirred for about 12 h at room temperature. The solution is extracted 1-2 times with diethyl The two additions of the organolithium reagent to compounds 1 ether (~ 10 ml portions) to eliminate any impurity, then the aqueous so- proceed with similar rates so that it is not yet possible, under the lution is saturated with sodium carbonate, extracted with dichlorome- experimental conditions used, to introduce successively two dif- thane (4x ~15 ml), washed with brine, and dried with magnesium sul- ferent R' groups. phate. The resulting aminoalcohol 3, after evaporation of the solvent, has >95% purity (G.L.C. estimation). Further purification for analytical purposes is performed by distillation or recrystallisation (petroleum ether Melting points were taken with a Biichi capillary apparatus. For G.L.C. b.p. 40-60 °C for product 3a; heptane for 3c) (Table 2). identification and purity determinations, we used an Intersmat IGC 12 M (2.5 m column 20% Carbowax 20 M on Chromosorb or 3 m column 15% SE-30 on Chromosorb). I.R. spectra were determined with a Perkin- Elmer model 337 instrument; 'H-N.M.R. spectra were obtained in Received: July 14, 1980 CDClj solution with a Bruker WP-80CW spectrometer. (Revised form: October 24, 1980) 272 Communications SYNTHESIS

dioxides 3 by reacting chlorosulfonyl isocyanate (2) with suita- J. Maillard et al., Bull. Soc. Chim. Fr. 1967, 2110. bly substituted 2-hydroxybenzaldehydes and 2-hydroxyaceto- I. Olcada, K. Ichimura, R. Sudo, Bull. Chem. Soc. Jpn. 43, 1185 (1970). phenones or -benzophenones 1. D. Evans, G. L. Caroll, L. K. Tmesdale, J. Org. Chem. 39, 914 (1977); and references cited. toluene , P. A. S. Smith, D. R. Baer, Org. React. 11, 157 (1960). 100 -105 °C (a) F. Bruce, J. L. Szabo, S. Tubis, U. S. Patent 2597445, 1952; C. A. + CI-S02-NC0 47, 2771 (1953). S-^OH (b) M. Bochmiihl, L. Stein, G. Ehrhart, German Patent 849665, 1952; X2 C. A. 48, 10764 (1954). 1a-h (c) British Patent 916789, Wallace & Tierman Inc., 1963; C. A. 59, 2712 (1965). B. Tchoubar, Bull. Soc. Chim. Fr. 1949, 160. M. Schlosser, Z. Brich, Helv. Chim. Acta 61, 1903 (1978). H. J. Dauben et al., J. Am. Chem. Soc. 73, 2359 (1951). W. S. Emerson, J. Am. Chem. Soc. 67, 516 (1945). M. Chastrette, G. P. Axiotis, R. Gauthier, Tetrahedron Lett. 1977, 1,3 R X' 1,3 R X' X^ 23. R. Gauthier, G. P. Axiotis, M. Chastrette, J. Organometal. Chem. a H H H e CH3 CI CI 140, 245 (1977). b H CI H f CeH, H H M. Chastrette, G. P. Axiotis, Synthesis 1980, 889. c CH3 H H g QH5 CI H D. A. Evans, L. K. Truesdale, G. L. Caroll, J. Chem. Soc. Chem. d CH3 CI H h C6H5 CI CI Commun. 1973, 55. F. Barbot, D. Mesnard, L. Miginiac, Org. Prep. Proc. Int. 10, 261 (1978). Reaction of chlorosulfonyl isocyanate (2) with 2-hydroxybenzal- J. K. Rasmussen, S. M. Heilmann, Synthesis 1979, 523. dehydes (la, b), 2-hydroxyacetophenones (Ic-e), and 2-hy- H. B. Hass, B. M. Vanderbilt, U. S. Patent 2164271, Purdue Re- droxybenzophenones (If-h) in toluene at 100-105 °C gave the search Foundation; C. A. 33, 8335 (1939). corresponding benzoxathiazines 3 in yields of 66-83% (Table). There is only one method reported for the synthesis of the above compounds^ ' " which involves the condensation of 2-hydroxyacetophenones and 2-hydroxybenzophenones with large excess of sulfamide. The reaction of 2-hydroxyacetophenone with sulf- A Facile Synthesis of 1,2,3-Benzoxathiazine 2,2- amide gave 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide' in 42% Dioxides yield, whereas with the present method 3c is obtained in 68% yield. Ahmed KAMAL, P. B. SATTUR The experimental simplicity and the commercial availability of Regional Research Laboratory, Hyderabad-500009, India chlorosulfonyl isocyanate make the present method convenient and useful for the preparation of 1,2,3-benzoxathiazine 2,2-diox- In earlier studies, we reported' the reactions of the powerful ides 3. electrophilic reagent, chlorosulfonyl isocyanate, with substituted 2-aminobenzophenones leading to 4-phenyl-2-(l//)-quinazoli- 1,2,3-Benzoxathiazine 2,2-Dioxides 3; General Procedure: nones. This work prompted us to investigate further applications To a stirred solution of the 2-hydroxy compound 1 (0.046 mol) in toluene of this reagent for the synthesis of e.g. 1,2,3-benzoxathiazine 2,2- (40 ml) at 100-105 °C is added chlorosulfonyl isocyanate (2; 4 ml, 0.046

Table. 1,2,3-Benzoxathiazine 2,2-Dioxides (3a-h)

Prod- Yield m.p. [°C] Molecular I.R. (KBr) 'H-N.M.R. (CDCI3) uct [%] (Lit. m.p.) formula' .-[cm'] S [ppm]

3a 73 92-94° C7H5NO3S 1590, 1335, 1130 7.3-8.1 (m, 4H); 8.73 (s, IH) (183.2) 3b 81 142-143° C7H4CINO3S 1595, 1335, 1120 7.3-8.0 (m, 3H); 8.95 (s, 1 H) (217.6) 3c 68 119-120° C8H7NO3S 1590, 1340, 1115 2.76 (s, 3H); 7.3-8.1 (m, 4H) (119-121°)^ (197.2) 3d 66 134-136° C8H6CINO3S 1590, 1345, 1120 2.74 (s, 3H); 7.5-8.2 (m, 3H) (231.6) 3e 68 146-148° C8H5CUNO3S 1600, 1350, 1120 2.71 (s, 3H); 7.60 (d, IH, 7=2 Hz); 7.73 (d, IH, 7=2 Hz) (266.1) 3f 72 115-116° C,3H,N03S 1595, 1340, 1125 b (115-116°)" (259.3) 3g 83 158-159° CnHsCINOjS 1600, 1345, 1125 7.5 (s, IH); 7.7-8.0 (m, 7H) (156-165°)" (293.7) 3h 75 167-168° C„H7Cl2N03S 1605, 1340, 1120 b (328.2)

" The microanalyses were in satisfactory agreement with the calculated values: C, ±0.28; H, ±0.17; N, ±0.27. '' Aromatic multiplet.

mol) in toluene (5 ml) over a period of 20 min. Stirring is continued for 3 h at this temperature. The toluene is then removed under vacuum and the residue is added to cold water (50 ml). The solid is filtered, washed 1b with water, and recrystallized from ethanol/methanol to give the desired benzoxathiazine 2,2-dioxide 3 (Table). Received: October 20, 1980 1c

' A. Kamal, K. Rama Rao, P. B. Sattur, Synth. Commun. 10, 799 (1980). ^ J. B. Wright, J. Org. Chem. 30, 3960 (1965). ' Netherlands Patent Appi 6604032, Upjohn Co. (1966); C. A. 66. 46440 (1967). Durch Diels-Alder-Reaktionen elektronen-reicher Diene, insbe- " British Patent 1073836, Upjohn Co. (1967); C. A. 67, 90818 (1967). sondere solcher mil Alkoxy- und Acyloxy-Substituenten, wurden zahlreiche funktionell substituierte, sechsgliedrige Ringe aufgebaut und zur Synthese von Nalurstoffen und Derivaten ge- nutzt' ". Die Umsetzung von la mit verschiedenen elektronen- armen Dienophilen lieferte bequem enlsprechende amino-sub- Synthese und Cycloaddltionen von trans,trans-\,'Xr stituierte Cycloaddukte (3-9). Bis[ethoxycarbonylainino]-l,3-butadien'

Richard R. SCHMIDT*, Adalbert WAGNER

Fakultat fur Chemie, Universitat Konstanz, Postfach 5560, D-7750 Kon- stanz, Bundesrepublik Deutschland H nQ ,N-C-0G2H5 Ungesattigte Kohlenhydrate^, insbesondere Pseudoglycale^-^ (Hex-2-enopyranosen) sind von wachsendem Interesse als Syn- these-Zwischenstufen, da die Doppelbindung leicht modifiziert vk-erden kann, z. B. durch Hydroxylierung" ', Epoxidierung'-'^ N-C-OC2H5 und Hydroxyaminierung'. Zur direkten Synthese 4-amino-sub- 3-9 stituierter Pseudoglycale, deren Bedeutung beispielsweise durch die Strukturen der Antibiotika Blasticidin S und Mildiomycin Die Reaktion mit Maleinsaure-anhydrid lieferte das Addukt 3, unterstrichen wird, wurden Cycloadditionen von 1,4-Diamino- das beim Erhitzen uber den Schmelzpunkt in Phthalsaure-anhy- butadienen mil Carbonyl-Verbindungen und anderen Dieno- drid (10) Ubergefiihrt wurde. philen begonnen*. Das ?/'a/w,/ran5-l,4-Bis[ethoxycarbonylainino]- 1,3-butadien (la) konnten wir durch Curtius-Abbau von CjHBO-C-NH^ H" 9 fran^.rra/ii-Muconsaure (2a) erhalten. Dazu wurde intermediar V das gemischte Anhydrid 2b und daraus das Azid 2c hergestellt und 2c der Thermolyse in Ethanol unterworfen. C2H5O-c W 10 CI-C-OCjHj /I/-C3H7)2N-C2H5/ HO DMF/Aceton Das prittiare Cycloaddukl des Tetracyanoethylens cyclisierle so- OH fort zum Pyrimidin-Derivat 4. 1,4-Naphthochinon und 5-Hy- 2a droxy-l,4-naphthochinon ergaben mit la unter Dehydrierung die Anthrachinon-Derivate und 6. Mit Acetylendicarbonsau- NaNj/HzO re-ester wurde das Cyclohexadien-Derival 7 erhalten, welches C2H5O- mit Mangandioxid quantitativ zum bekannten 3,6-Diamino- phthalsaure-Derivat 11'^ dehydriert wurde. ° 2b

0 C2H5OH/Toluol V .C-OC2H5 C^HbO-C-N H® HlX^^COOCHj MnOi/CHCla ,C00CH3 COOCH, ^C00CH3 C2H5O-C-N H' HN. C-OC2H5 1a 7 11 0 amit steht neben dem 1,4-Diacetoxybutadien lb', dem 1,4- Als Helerodienophile wurden aufierdem Azodicarbonsaure-

Tabelle 1. Cycloaddukte (3-9) aus l,4-Bis[ethoxycarbonylaminol-butadien (Ic) und Dienophilen

Dienophil Cycloaddukt Reaktions- Ausbeute" F [°C] Rr" Summenformel' bedingungen [96] (molare Masse)

C2H5O-C-N H« ,(• \/ , H^' c h o-c-n'^sh^'c J J 20h/80°C 70 183-204 "C" 0.25 ChHisN^O, 11 H (326.3)

•OCjHs y

5 min/25 °C 75 175 °C 0.40 Ck,H,6N,04 (356.3)

H= 0

3 h/80°C 65 220 °C 0.77 CjoH.sNjGs Zers. (382.4)

3.5 h/40°C 69 234 °C 0.83 C2oH,8N207 Zers. (398.4)

COOCHj C2H50-C-N^ H® s h=-JX_cooch3 c H"A^C00CH3 COOCH3 C2HSO-C-N H' 20 h/80°C 72 96-97 "C 0.43 C,.H22N20, (370.4)

COOCzHs CjHsO-C-N H' li OC2H5 N II N cooc2h5 C2H,0-C-N H'IJ 20 h/80°C 80 01 0.33 C,6H26N408 (402.4) C2H5O-C-N czhsooc^ .cooc2h5

C2H5O-C-N H' 44h/80°C 34' 01 0.43 c,7h2<,n20, fTisch-Autoklav) (402.4)

" Isoliertes Produkt. Laufmittel: Petrolether/Ethyl-acetat 1/1. Die Mikroanalysen stimmten mil den berechneten Werten gut iiber- ein: C, ±0.20; H, ±0.14; N, ±0.26. '' Umwandlungsbereich in Phthalsaureanhydrid. ' Bezogen auf 70% Umsatz von la.

ester; 33 g, 0.30 mol) in wasserfreiem Aceton (30 ml) tropfen und nach 'H-N.M.R. (DMSO-I/A): 6 = 9.30 (d, 2 N—H, /,,NH = 9 HZ); 6.20-6.7: 30 min eine eisgekuhlte Losung von Natriumazid (39 g, 0.30 mol) in (m, AA'BB'-Spektrum 1-H, 4-H; 5.50-5.95 (m, AA'BB -Spektrum 2-H Wasser (90 ml). Man riihrt noch 15 min, gieBt das Gemisch dann auf Eis- 3-H); 4.15 (q, 4H, 2 CHj); 1.25 ppm (t, 6H, 2 CH3). wasser (400 ml) und extrahiert mit Toluol (10 x 300 ml). Die Toluol-Pha- se wird mit Natriumsulfat getrocknet, auf 250 ml eingeengt und die so er- haltene Azid-Suspension (2c) in eine siedende Losung von (-Butylbrenz- (ran5,rran.s-l,4-Bi$[ethoxycarbonylaniino]-l^butadien (la) katechin (50 mg) in wasserfreiem Ethanol (69 g, 1.5 mol) und Toluol (75 /r

Mass Spectral Studies of 4-Phenyl-2(lJEf)-quinazolinones

Ahmed Kamal & P. B. Sattur* Regional Research Laboratory, Hyderabad 500 009

Received 18 September 1980; revised 10 November 1980; accepted m/d 821 (lOOV.) 6 December 1980

Mass spectra of some 4-phenyl-2(l/0-qu'nazol'nones (I, II) have been studied. It is observed that compounds with no substi- tuentonN-1, undergo fragmentation by the loss of two hydrogen radicals and a CO molecule. When N-1 carries a methyl group, only one hydrogen atom is lost to give (M -1) ion which fragments further through the expulsion of a methyl radical; a direct loss of the formyl radical from the molecular ion is also observed. Fragmentation pathways proposed are supported by deuterium labelling and by the presence of metastable peaks.

ECENTLY we have reported a novel method R for the synthesis of 4-phenyI-2(l//)-quina2oli- nones^(I). We now report their mass spectral fragmentations in view of their novel structure. 180116V.1 m/« 220(157.1

Compound la with no substituent on N-1 shows » i-hcn (M-1) ion at mje 221 as the base peak besides a + peak for (M-2) ion (15%). The former peak CsNH probably results from the elimination of H- froms —N—H or by participation of a hydrogen from the phenyl group (proximity or o/*?/zo-effect)®, while the m/8 152(10%) m/c 104 (10 v.) loss of both the hydrogen radicals gives (M-2) ion. However, in the mass spectrum of l-deutro-4- SCHEME 1 phenyl-2(lif)-quinazolinone (la*), (M-2) ion forms the base peak indicating the loss of deuterium from —^N—D to be more facile compared to the loss of H' from phenyl group, which may be due to the aromatization of pyrimidine moiety in the system. In addition to the loss of H- from M+-, loss of NCO-, CO and HNCO also occur. The salient features of the fragmentations involved are depicted in Scheme 1. Compounds lb and Ic having one and two chlorine atoms respectively, also exhibit a similar pattern (Scheme 1). In compound Ila which has a methyl substituent on N-1 the molecular ion appearing at mje 236 forms the base peak. The (M-1) ion can result by the elimination of H- either from —N—CHg or phenyl group. When both these processes operate (loss of two hydrogen radicals) one would expect (M-2) ion, but it is interesting to observe the absence of (M-2) ion in Ha. The presence of only (M-1) ion peak is OMtlOl probably due to the expulsion of H- from phenyl group and not from —N—CH3. This is confirmed scheme s by deuteration studies. Thus, the mass spectrum of 1 -(deuterated-methyl)-4-phenyl-2(l H)-quinazoli- Apart from the loss of H-, CH3NCO and NCO-, none(IIa*) does not show (M-2) ion peak (loss the mass spectrum of Ila shows (M-29) ion, instead of (M-CO) ion, probably formed by the elimination of D-), but exhibits only (M-1) ion peak thereby of formyl radical from the molecular ion and is sub- revealing the loss of H- from the phenyl group.

1 It is generally observed that in compounds of the type II, the methyl group can be easily cleaved from the molecular ion, whereas in the present study it is observed that the loss of CHg takes place from (M-1) ion and not from the molecular ion; this is CH2 supported by the appearance of the corresponding m/c 207 (13 V.I metastable peak. The above contention is further supported by the appearance of a peak at m/e 220 in the spectrum of deuterated-methyl analogue. These • -CgHjCN fragmentations are briefly illustrated in Scheme 3. Compounds lib and lie also show similar fragmentation pattern (Scheme 3). The mass spectra were recorded on JEOL D.300 m/a 104(18'/.) CH3 CH3 and Hitachi RMU-6L mass spectrometers at 70 eV. m/e 23s(3sv.) m/« 236(M+")(100'/.l l-Deutro-4-phenyl-2(lH)-quinazolinone (la*) was -nc prepared by deuterium exchange with DaO, while -CH3NCO -CHj l-deuterate(i-methyl-4-phenyl-2(l/?)-quinazolinone (Ila*) was obtained by using CDgBr via the sodium salt with sodium hydride. The authors express their thanks to Dr G. S. Sidhu, Director, RRL, Hyderabad for his interest m/« i94(i9v«) m/«I79(ieV.) mltSOWM in the work and to CSIR, New Delhi for the award of a senior research fellowship to one of them SCHEME 3 (A. K.). stantiated by a corresponding metastable peak. This References fragmentation may proceed as shown in Scheme 2. 1. KAMAL, A., RAMA RAO, K. & SATTUR, P. B., Synth. The mass spectrum of deutetrated-methyl analogue Commun, 10 (1980), 799. 2. BOWIE, J. H., COOKS, R. G., DONAGHUE, P. F., HALLE- revealing the loss of CDO° further confirms the DAY, J. A. & RODDA, H. J., Aust. J. Chem.. 20 (1967), proposed pathway. 2677. Synth. Co-imun. 12(2)

REACTIONS -vITH CHLOROSULFONYL ISOCYANATE:

FORMATION OF 2H-1,3-BENZOXAZINE-2-ONES

Ahmed Kamal and P.B.Sattur*

Regional Research Laboratory, Hyderabad 500 009, India

In recent years chlorosulfonyl isocyanate (CSI), an electrophi1ic reagent has been extensively employed in the synthesis of heterocyclic compounds. We have earlier reported on the reactions of CSI with 2-aminoben2ophenones leading to the formation of 4-aryl-2(lH)-quinazolinones^ and with 2-hydroxybenzaldehydes, 2-hydroxyacetophenones or -benzophenones at elevated temperature (100-105°) giving rise to 1,2,3-ben20xathiazine-2, 2

2-dioxides . It is known that the temperature profoundly influences the course of the reaction and formation of the products

1n case of phenolic compounds, it was considered of interest to carry out the reaction of CSI with 2-hydroxycompounds (la-e; 6a-e) at room temperature (25-30°), to obtain 1,3-benzoxazine-2-ones which have attracted considerable attention due to their biological activity.

* To whom correspondence should be addressed. It has been reported in 1 iteratu-c'^ that 4-methyl

1.3-b ••zox6zir,p-?-cncs were syntHesi70(< by the reaction of

2-hydro;'yacetonhenones with urea, whtrecs the 2-hydroxyben7a 1- dehyde on reacting with urea yielded 4-ureido-?H-l,3-benzoxa- zinc-2-one (5) and not the desired 2H-1,3-benzoy.azine-2-ones (3a) 0 ii NH-C-Nh'

It is observed in the present investigation that the reaction of CSI with 2-hydroxybenza1dehydes (la-b) and 2-hydroxyacetophenones (Ic-e) in dichloromethane or benzene afforded 2H-l,3-benzoxazine-2-onas {3a-e) in yields 48-73%. In addition to the above products 0-carbamoyl-2-hydroxybenza1dehydes (4a-b) and 0-carbamoy1-

2-hydroxyacetophenones (4c-e) are also formed in meagre amounts

(4-10%).

However, it is interesting to observe that reactions with

2-hydroxybenzophenones (6a-e) did not give the desired 4-phenyl-

2H-1,3-benzoxazine-2-ones (8) but 0-carbamoyl-2-hydroxybenzophenones (7a-e) are obtained in high yields (84-93%), which may be due to the decreased reactivity of the benzophenone carbonyl carbon. CH2CI2 or 0=C=:N-502CI

1a-e R

+ 0-C-NH,

3a-e 40-c ^

0-C=N-S02CI

1.3.4 R R' 6,7 R R'

a H H a H H b H b H 01 c CH3 H c H CH3 d CH3 CI d CI H

e CH3 CH3 e CH3 €1 The present method offers a convenient route for the

preparation of 2H-1,3-benzoxa2ine-2-ones from 2-hydroxybenzal-

dehydes or -acetophenones.

The products have been characterized by elemental analysis,

IR, NMR and Mass spectra. The results are suimarized in the Table.

EXPERIMENTAL

Melting points are uncorrected. The IR spectra were recorded on a Perkin Elmer 221 spectrophotometer.

General Reaction Procedure (3a-e; 4a-e; 7a-e):

To a stirred solution of 2-hydroxy compound 1;6 (0.046 mol)

in dry dichloromethane (50 ml) was added chlorosulfonyl isocyanate

2 (4 ml, 0.046 mol) in dichloromethane (8 ml) over a period of 30 min at room temperature (25-30°). Stirring was continued for 2 h

at this temperature. The solid separated was filtered but where no solid separated the dichloromethane was removed under vacuum.

The residue obtained or to the solid filtered was added cold water

(80 ml) and left overnight. The solid thus formed was filtered and washed with water.

The benzoxazinones 3a-d were separated as methanol Isoluble

compounds and on concentrating the methanol soluble portion the

crystals separated were that of carbamates 4a-d, while the products 3e and 4e were separated by column chromatography using benzene/ methanol (90/10) as eluent.

0-:d>"iiarnoy'!-?-hydroxybenzophenones 7a-e thus obtained were recrystal iized fron ethanol/methanol.

Acknowledgment:

We are thankful to Dr.G.S.Sidhu, Director, Regional Research

Laboratory, Hyderabad, for his interest in this work. One of us

(AK) is also thankful to CSIR for the award of Senior Research

Fellowship.

References:

1. Ahmed Kamal, K, Rama Rao and P.B. Sattur, Synth.Conmun.,

799 (1980).

2. Ahmed Kamal and P.B. Sattur, Synthesis, 272(1981).

3. S. Polazzo and M.G. Marino, 6azz. Chim. Ital., 94, 811 (1964),

(G.A.6i, 16065g). TABLE:

Reactions of CSI with 2-Hydroxyben2aldehydes,

2-Hydroxyacetophenones and -Benzophenones

I.R.(KBr;1 Yield Product m. p. "k ^Cfr,-^

3a 48 270-274° 1720, 1590

3 b 67 1590

3c i'c 1735, ] 6nn

3d 73 c c-dh 1730,

3e 72 212-215" 1730, 1600

43 10 160-162° 3420, 3305, 1720, 1645

4b 4 176-178° 3420, 3300, 1725, 1650

4c 7 165-168° 3415, 3300, 1720, 1650

4d 5 184-186° 3410, 3310, 1725, 1645

4e 5 205-207° 3400, 3300, 1725, 1640

7a 84 130-132° 3425, 3310, 1715, 1650

7b 93 144-145° 3420, 3300, 1720, 1655

7c 88 158-159° 3410, 2990, 1730, 1650

7d 91 146-148° 3420, 3310, 1725, 1650

7e 89 160-161° 3415, 3300, 1725, 1645

Compounds 3a-e melt with decomposition. J + Lit.m.p. 260° .