Nitro Group Participation in Tetrazole Rearrangements

Home , Tetrazole

NITRO GROUP PARTICIPATION IN

TETRAZOLE REARRANGEMENTS

A Thesis submitted by

DAVID FREDERICK PIPE

in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

OF THE

UNIVERSITY OF LONDON

Hofmann Laboratory, Department of Chemistry, Imperial College, London, SW7 2AY. September, 1980. For Charisse The work, described in this thesis was carried out by

the author at Imperial College of Science and Technology, under

the supervision of Professor C.W. Rees. No part of it is

concurrently being submitted for any other degree.

I should like to express my sincere gratitude to

Professor Rees for providing a stimulating environment and for

his invaluable advice and encouragement throughout, and to

Imperial College for the provision of funds and facilities.

My thanks also go to my colleagues in the Hofmann Laboratory

for their help and friendship, particularly to Dr. P.G. Houghton

for the many fruitful discussions, and to the technical staff of

Imperial College for the general high standard of their services.

D.F. Pipe. "The trick, Fletcher, is that we are trying to overcome our limitations in order, patiently.

We don't tackle flying through rock until later in the programme."

Johnathon Livingstone Seagull. ABSTRACT

The decomposition of 1,5-diaryltetrazoles and the synthesis

of carbodiimides are described.

The reactions of o-nitrophenyl derivatives producing five

and six membered heterocycles are briefly reviewed.

The presence of a nitro group in the N-1 ring of 1,5-diaryl-

tetrazoles is shown to increase the rate of thermal decomposition,

and when the nitro group is ortho to the tetrazole ring it

intercepts the intermediate carbodiimide producing 2-arylbenzo-

triazoles.

The intermediacy of the carbodiimide is investigated and

confirmed by using alternative heterocyclic species and thioureas

as precursors to ortho- nitrophenylcarbodiimides. The reaction is shown

to be general for 2-arylbenzotriazoles but 2-alkylbenzotriazoles could not be formed this way. A mechanism for the formation of

2-arylbenzotriazoles involving a series of electrocyclic ring closing and opening reactions is proposed. Mild thermolysis of

the precursors results in the isolation of a second intermediate

in the postulated mechanism, 2-aryl-1,2,4-benzotriazin-3-one 1-oxide.

The reaction is investigated further by thermolysis of

i)1-(8-nitronaphth-l-yl)-3-phenylcarbodiimide which gives

naphth[1,8-c,d]indazole N-oxide and

ii) 1-(2-nitrobiphen-2-yl)-3-phenylcarbodiimide. Vapour phase pyrolysis of l-(2-nitrophenyl)-5-phenyltetrazole gives 2-phenylbenzotriazole and carbazole. 2-Phenyl- benzotriazole is shown to be an intermediate in this reaction for which a mechanism is proposed and investigated.

Photolysis of 1-(2-substituted)-5-phenyltetrazoles shows a tendency for the intermediate imidoyl nitrene to close to

the ortho-blocked position instead of a vacant position when

the ortho-substituent is an ester. CONTENTS

INTRODUCTION

Decomposition of 1,5-Diaryl Tetrazoles 1

Synthesis of Carbodiimides 9

Synthesis of Heterocycles by ortho-Nitro Side-Chain Interactions 15

DISCUSSION

SECTION 1

A. Preparation of Tetrazoles 36

B. Thermolysis of Tetrazoles 41

C. Alternative Precursors to Carbodiimides 55

D. The Mechanism of Transformation 65

E. Alternative Routes to 2-Arylbenzotriazoles 75

F. Extensions to Nitro Group Interactions. 76

SECTION 2

A. The Carbazole Reaction 91

B. The Mechanism of Transformation 93

APPENDIX

Photochemistry of Tetrazoles 100 EXPERIMENTAL

Instrumentation and Experimental Techniques 105

SECTION 1

A. The Preparation of Synthetic Intermediates 109

B. The Preparation of Tetrazoles 111

C. Thermolysis of Tetrazoles 115

D. Identification of Volatile Components 122

E. The Preparation of Alternative Heterocyclic Precursors 124

F. Thermolysis of Alternative Heterocyclic Precursors 125

G. The Preparation of Thioureas 127

H. The Preparation of Carbodiimides and 2-Arylbenzotriazoles 131

I. The Preparation and Reactions of 2-Aryl-1,2,4-benzotriazin- 137

3-one 1-oxides

J, Extensions to Nitro Group Interactions 139

K, Independent Syntheses 142

SECTION 2

A. The Preparation of Precursors to Carbazoles 145

B, Vapour Phase Pyrolysis 1-(2-Nitrophenyl)-5-phenyltetrazole 145

and 2-Phenylbenzotriazole

C. The Preparation and Pyrolysis of 1,2,5-Dibenzotriazepine 147

D. Pyrolysis and Photolysis of Precursors to 3-Methylcarbazole 147

E. Independent Syntheses 150

APPENDIX

The Preparation and Photolysis of Tetrazoles 152

REFERENCES 154 INTRODUCTION 1

Decomposition of 1,5-Diaryl Tetrazoles.

Thermal decomposition of 1,5-diaryltetrazoles occurs in the temperature range 200-230°C, yielding diaryl carbodiimides, 1'2 2-arylbenzimidazoles or both.

The substituent at the 5-position migrates to form diarylcarbodiimide which is the main product of the reaction.

Groups in the 5-position such as p-tolyl which accelerates migration in the Beckmann rearrangement also favour carbodiimide

formation in 1,5-diaryltetrazole pyrolysis; 5-substituents that retard migration in the Beckmann rearrangement, such as p-chloro-

phenyl, retard carbodiimide formation relative to cyclisation

to 2-arylbenzimidazoles.2

Pyrolysis of 1,5-diphenyltetrazole (1) in the melt at 210°C

gave diphenylcarbodiimide (2) as the major product and 2-phenyl-

benzimidazole (3).l Photolysis gave 2-phenylbenzimidazole as

the sole product.3'4

PhN=C=NPh + (3) (2) 65% 14 °l° Ph~..N PhN ,N N'

(1 ) N \ Ph N H (3) 64°l° 2

In the pyrolysis of 5-(4-chlorophenyl)-1-phenyltetrazole the yield of 2-arylbenzimidazole was increased to 19%, a

5-(4-nitrophenyl) group brought about a deep seated decomposition from which no definite products could be found. Thermolysis of

5-methyl-l-phenyltetrazole produced a small amount of 2-methyl- benzimidazole (7%) but carbodiimides or their derivatives could not be detected.

It is significant that no diphenylcarbodiimide, the Curtius rearrangement product, is formed in the photochemical decomposition of (1), although it is the major product of pyrolysis.

It has been suggested that the mechanism of carbodiimide formation involves eauilibrat_ion,ofthe tetrazole with the open

chain imidoyl azide, followed by a concerted migration of the

phenyl group and loss of nitrogen.5 A similar mechanism appears

to operate in the related Curtius rearrangement of acyl azides.6

Ph, (1) (2 ) II k_)-- PhN 7//

Thermal decomposition of ortho-blocked 1-aryltetrazoles gave,

as expected, mainly carbodiimides with minor amounts of product

derived from the rearrangement of N-arylimidoylnitrene through a

3aH-benzimidazole intermediate as shown.7

N NAN Me 600° N=C=NPh Me 0.04mm Me (4) (5) 46%

N`)Ph Me Ph + \ Ph /N Me Me H (6) 30/0 (7) (8) i 10°/°

Photolysis of tetrazole (4) gave the cyclopentapyrimidine (6) in increased yield (17%), the yield of carbodiimide being much reduced (1.5%).7

Thermal decomposition of 1,5-diaryltetrazoles with a carboxyl group in the ortho-position of either aryl group occurs at a lower temperature than with the corresponding tetrazoles without such a substituent.8'9

165-700 CHCl3

(9 ) (10) 80%

N\-0 \-0

HC-0 PhC -0

(11) 8% (12) .4%

CO7H 165-70° N NPh + HN3 CHCl3 / PhNN N I N 0

(13 ) (14) 98°I

On heating (9) at a higher temperature (170-230°C) in the absence of solvent; less benzoxazinone (10) and more products derived from secondary reactions are formed.8 Similar treatment of tetrazole (13) produces (14) in a reduced yield (50%) and

3-phenyltetrahydroquinazoline-2,4-dione (15). 5

O 170-230 (13) • (14) 50010 -~-

This product (15) is not found in thermolysis in chloroform.

That the ortho-carboxyl group participated in the thermal

decomposition reactions of the tetrazole ring is indicated

by the structure of the products, the absence of decarboxylation

and by the comparative stability of 1-(3-carboxyphenyl)-5 -phenyl-

tetrazole, which does not decompose until 230°C, then liberating

carbon dioxide.9

Alternative Precursors of N-Arylimidoylnitrene Derived Products.

1) From 5-Membered Heterocyclic Compounds, , 10-15 The extruded fragment X = Y in structure (16) can be CO2 COS,15 S02f16'17 Ph 3P=0,18 or (Et0)3P=018 (Scheme 1).

Decomposition of (16) XY = CO2 in the presence of triplet

sensitisers such as benzophenone gave no.carbodiimide, but if

the photolysis was carried out in the presence of piperylene, 10,13

60-90°/°

XY =CO2 A or hv 13 Phr-N 18 PhN=C=NPh XY=R3PO PhN Ph N R=Ph 66°1 R=OEt 76 °I° 080°

XY=5O2

XY=COS 15 16,17

PhN=C=NPh 100 0/0

Scheme 1 20

>Ph 20

R' =H MnO2 R=Ph Pb(0Ac) 4 21,22,23

Ph RL H PhSO2Cl NMR R= Ph NaOCI [PhN=C=NPh3 NaOH NR' base R'=OH

H2O R' =CI

Ag 20 25 PhNHCONHPh 23, 24 PhN=C=NPh

010 R Ph 80 PhCh2 52 Me 36

Scheme 2

a triplet quencher, the yield of carbodiimide was increased with respect to photolysis in dioxan alone. This perhaps suggests that carbodiimides arise from a singlet imidoyl nitrene, although the authors14 favour a mechanism involving a phenyl group migration concerted with loss of carbon dioxide. Benzimidazole formation 14 is thought to proceed through a triplet imidoylnitrene intermediate.

Decomposition of (16) XY = SO 2 is presumed to proceed by a 16,17 concerted mechanism.

2) From Amidine-type Precursors

N-Arylimidoylnitrenes may be generated from amidines and their derivatives as summarised in Scheme 2.

3) From Sulphimides.

Thermal decomposition of imidoylsulphimides gave only small amounts of 'nitrene' - derived products. Photochemical decomposition of imidoylsulphimides (17) gave 2-substituted benzimidazoles in good yield, along with the corresponding sulphide.7

NIR 2 hv /CH3CN R 2 + R12 S N--SR2

(17) 9

Photolysis of the ortho-blocked N-arylsulphimide (18) gave some carbodiimide (5) isolated as the crystalline urea derivative

(19), the cyclopentapyrimidine (6) and a large amount of tarry material.

Me hv Ph N=C=NPh + CH3CN 1 Me (18) (5) 12% (6) 13%

H30•

NHCONHPh

(19)

Synthesis of Carbodiimides.

The earliest preparations of carbodiimides involved the 27-31 reaction of mercuric or lead oxide with thioureas.

The most practical methods for the preparation of carbodiimides are summarised in Scheme 3. 10

RNHCSNHR'

33,35 32 P205 Ph~N RSO2Cl/py RNHCSNHR' PhNS' 0 36 ,37 N NaOCl/ NaOH 0 R,R'=Ph • 16,17 RN=C= NR' 33,38 R2 \ g0 Pb0 39,40 C R' O or ( ) 41,42 RNHCSNHR' 2RNCO R"O ~NjCI_ 62 Me

RNHCSNHR'

Scheme 3

1) Elimination Reactions.

Prolonged heating of free isocyanates in the absence of

catalysts gave poor yields of carbodiimides, unless nitrogen 41 was passed through the boiling isocyanate.

41,42,44-48 In thepresence of phosphorus catalysts aromatic

carbodiimides are obtained in high yield under mild conditions

from isocyanates, but not isothiocyanates.41 Aliphatic isocyanates

react more slowly but improved yields are obtained in high boiling

solvents. In the case of aromatic isocyanates, electron with-

drawing groups increase the rate of carbodiimide formation in

proportion to their electron withdrawing power. Electron releasing

groups tend to inhibit the reaction. Thus diphenylcarbodiimide (2)

is formed from phenyl isocyanate (20) after 2.5 h reflux in

anhydrous benzene,41 whereas 4,4'-dinitrodiphenylcarbodiimide

(21) is formed at 60°C in 2 min from isocyanate (22)

2 PhN=C=O Et P40 PhN=C=NPh

(20) (2) 94°/°

N_C=0 EtP 4 0 . 0 2 O,N N=C=N NO2

(22) (21) 100 0t0

These reactions are thought to proceed through four

membered cyclic intermediates [e.g., (23) and (24)].

R 3P-0 R 3P-0 -j- RN=C=0 R3P=NR +CO2 RN -C=0

(23)

RN=C-0 R 3P=NR RN=C=0 I RN=C=NR RN -PR3

(25) (24 ) R3P=0

A compound similar to (25) has been prepared and shown to 50 react with isocyanate groups to give carbodiimides.

) Dehydration of N,N'-Disubstituted Ureas.

The reagents used to effect dehydration of ureas in good

yield are p-toluenesulphonyl chloride and pyridine, as solvent 34 35 and base. ' Other reagents are phosgene,51 phosphorus 47,53 oxychloride,S2 and phosphorus pentachloride. 1,1-Dichloro

compounds have been shown to be intermediates when phosgene and

phosphorus pentachloride react with ureas. 13

3) Oxidation Reactions.

Since substituted thioureas are readily available, the

desulphurisation of N,N'-disubstituted derivatives by

mercuric oxide is one of the best methods available.38 The

preferred solvents are ether, benzene or acetone. The presence

of drying agents such as calcium chloride,54 sodium sulphate,55

or magnesium sulphate,56 remove the water formed, thus preventing

formation of the corresponding urea derivative. Water may also

be removed by distilling it as an azeotrope.57 Other less

effective catalysts are lead oxide,29,31,58 zinc oxide,59 lead

carbonate, lead nitrate and lead chloride.60

The oxidation of N,N'-dialkylthioureas to the corresponding

carbodiimides can also be accomplished in excellent yields by 0 .36,37 alkaline hypochlorites below 0

Sensitive derivatives such as N-acylcarbodiimides were

efficiently generated by the use of diethyl azodicarboxylate and

triphenyl phosphine.61

- DD.E.A.D. E. RNHCSNHR RN=C=NRI+EtO2CNNCO2Et+Ph3PS 3

Another excellent method produced aliphatic and aromatic

carbodiimides in high yield, under mild conditons, by the use

of 2-chloro-l-methylpyridinium iodide (26) and triethylamine

in acetonitrile at room temperature (Scheme 4).62

Et3N R1NHCSNHR 2 + )■1Rl S— C~ \NR 2 H (26)

Et 3N

+ Et3N.HI + R1N=C=NR 2

R1 R 2 time(h) 0/0 Ph Ph 5 85 p-TOL p-TOL 5 97 Ph . C6H11 5 98

Scheme 4

There are many other miscellaneous methods of preparing carbodiimides,63 and one recent method of particular interest involves the pyrolysis of imidoyl-N-imides (27) to give 64 N,N'-diarylcarbodiimides in good yield,

1 Ph N*/ P h / • RN=C=NR' + Ph N- Ph. I NR'

(27) 15

Synthesis of Heterocycles by ortho-Nitro Side-Chain Interactions.

This review is not an exhaustive catalogue of the products of ortho-nitro interactions, but aims to identify the range of processes involved, and to indicate the scope and synthetic value of ortho-nitro side-chain interaction. The types of reactions considered involve redox processes, cyclisations involving intramolecular condensations of the aldol type for which the nitro group provides the electrophilic centre, intramolecular nucleophilic displacements of nitro groups and photochemical and thermal transformations. Two broad mechanisms may be differentiated depending on whether the oxygen or nitrogen of the nitro group is the nucleophilic species. Such postulates do not, however, specify the exact oxidation level of the nitrogen atom when the ring forming step occurs; thus adjustments within the conjugated system must be considered. Full mechanisms are provided for selected transformations.

1) Formation of Five-Membered Rings.

Probably the best route to 1-hydroxyindoles (28) is through 65-69 the base catalysed cyclisation of o-nitrobenzyl derivatives.

R 2 H

(29) (28)

a) R j = H, R2 = R3 = CO2CH3

b) R1 =H, R 2 = COCH3 , R =CO2C2H5

HCN CO2C2H5

Cyclisation occurs readily where the benzyl side chain has

at least one moderately acidic centre. Where two such acidic

centres are present, sometimes with widely varying acidity, the

compounds are remarkably consistent in their ability to yield

derivatives of 1-hydroxyindole. Nevertheless, in certain cases and

in a strongly alkaline environment this type of product is accompanied by another derived from 1-hydroxyquinoline.67

Suitable substrates are available either by the base

catalysed condensation of o-nitrobenzoyl chloride with active methylene compounds (29a, b) or by addition of hydrogen cyanide

to suitable o-nitrobenzylidene derivatives (30). Alternatively,

the 1-hydroxyindole can be prepared directly from the requisite

H CO2Et H NaOH CO2Et 09 COMe COMe ~0H

CN CO2Et CO2Et NO2 CO2Et

hot KOH E t OH Na CO3 CN CO2Et

o-nitrobenzylidene derivative by warming with aqueous ethanolic

potassium cyanide; this reaction presumably involves the

intermediate formation and cyclisation of the corresponding

hydrogen cyanide adducts. This procedure suffers from the

simultaneous formation of quinoline N-oxides except when the 69 benzylidene side chain contains an alkyl group. 18

Indigo (31) is the end product of a number of base-catalysed 70-73 reactions of o-nitrobenzene derivatives.

Indigo formation in alkaline acetone solutions (the Baeyer-

Drewson reaction) has been widely used as a test for o-nitrobenz- 74 aldehydes.

CHO Acetone NO2 Alkali NO2 COMe

1 COMe

0 (31)

The base catalysed condensation of o-nitrobenzaldehyde with indan-1-one is reported to afford the indoxyl (32).75

0 CHO NO2

In general, formation of indoxyl derivatives is of limited synthetic value.

Isatin (33) and it's derivatives are formed in variable yield by the base or acid catalysed transformations of a 76-81 variety of o-nitrobenzene derivatives.70'

base

Reaction of o-nitrobenzylidene anils (34) with aqueous potassium cyanide followed by acetic acid provides a general route to 2-aryl- 81,82 3-cyanoindazole 1-N-oxides (35). These reactions probably involve the intermediate formation and base catalysed cyclisation of the corresponding hydrogen cyanide adducts (36), as evidenced by the conversion of the cyano compound (36) in warm aqueous sodium hydroxide or sodium carbonate or in cold concentrated sulphuric acid into 83 3-cyano-2-phenyl-indazole-1-oxide (35).

20 NC H CN NPh +1N Ph NO2 H N 1

(34 ) (36) (3 5) 0-

Use of methanol as solvent instead of acetic acid modifies the reaction such that 4-arylamino-3-methoxy-cinnoline 1-oxides (37) are 84,85 also formed (15%). The reaction of N-o-nitrobenzylidene-o-nitroaniline (38) gave neither indazole or benzimidazole but mainly the cinnoline 1-oxide (37).

NO2 NH McOH CN OMe NAN 1 (38 ) (37) 0-

The base catalysed cyclisation of dinitrobenzylidene arylhydrazones

(39)affords moderate to high yields of the corresponding 1-arylindazoles

(40)involving intramolecular nucleophilic displacement of an aromatic nitro group.86-93

base \(v O N N Ph (39) (40)

Cyclisation fails when the substituent attached to the hydrazone nitrogen is electron withdrawing,

The standard route94 to benzimidazoles involves the condensation of o-arylenediamines with a carbonyl containing compound, The method is simple and the yields are often high. In the bourse of an

21 investigation into the reductive cyclisation of N-substituted o-nitroanilines95 it was found that N-benzyl-o-nitroaniline underwent thermal uncatalysed cyclisation to yield 2-phenylbenzimidazole. Cyclisation reactions of this type are 95 96 presumed ' to involve the aci-nitro form (42) of the nitro compound (41). H 1\4.1 CHPh --a 220 0

(41) (42)

A similar aci-nitro species has been proposed to explain the thermal cyclisations of 2-methyl-2'-nitro biphenyl to phenan- thridines in diphenyl ether.97

Base catalysed aldol-type cyclisations of N-substituted o-nitroanilines (43) containing an active methylene side chain have been successfully applied to the synthesis of a number of benzimidazole

N-oxide derivatives (44).98'99

base + /RI

(43) (44)

Use of the N-tosyl derivative (45) in sodium methoxide

results in the formation of alkoxybenzimidazoles (46),100

Variation of base and substituents. has extended the process 101 to yield 2-alkoxy-benzimidazole 1-oxides (47),

Ts SO2C6H4CH3 NCH2Ar N. H NO2 N Ar (45) 0 OH

Me0 -S0 2C6H4CH3 N) Ar +NJ~ 0

N N Ar ~>Ar N" OCH3 0 Me-0-502C 6H4CH3

(46 )

NCH2OCOPh Et0 NO2

NNW

(47) 40- 800/o

Intramolecular acid-catalysed cyclisations of N,N-disubstituted 102 o-nitroanilines provide an excellent route to benzimidazole N-oxides.

Photochemical cyclisation of aziridines (48) also produce benzimidazole N-oxides in excellent yield via a seven membered 103 intermediate.

Ph NO2 ,Ph N j 02N 0 N N= 0 (48 )

NO2 H CPh 02N Ph 07N -)N( (0

Ph Ph 02N

95 0/0

Reactions leading to benzisoxazoles (anthranils) include some of the earliest recorded nitro-group side-chain interactions.

A variety of o-nitrobenzylcarbonyl derivatives (49) cyclise under both acidic and basic conditions and thermally to afford simple anthranil derivatives (50). 104-112

R2 CHCOR1

NO2

(49) (50) R1 R2 Me H Me COMe OH H

113 Following earlier work on the reactions of benzhydrol, an ion pair, generated by intramolecular nucleophilic attack of the nitro oxygen has been postulated as the precursor of the two alternate reaction products.of the benzyl bromide derivative (51). 114

A new heterocyclic system, 3,3a-dihydrobenzofuro[3,2-c] isoxazole (52), formed by initial (4 + 2) cycloaddition of a conjugated nitro group with an ynamine has recently been 115 reported, This process has subsequently been extended to 116 other isoxazoles such as (53),

25 0 +N >_0 (51) C— Br H -Ph

Br -

-F HBr

0 \+,, N-- ■ NEt 2 12,/ 16h/5-10. Me

(52)

NO2+ Ph=- N 0

(53) Phil 0 26

o-Nitrobenzene derivatives are key starting materials for 117 the synthesis of benzotriazoles and benzotriazole N-oxides.

The base catalysed cyclisation of o-nitrophenylhydrazines to 118,119 1-hydroxybenzotriazoles, and the subsequent related

procedures involving reaction of o-nitroarylhydrazines, provides 120 routes to 2- and 3-substituted benzotriazole N-oxides. In related procedures o-nitrohydrazobenzene derivatives (54) are 121 converted into benzotriazole N-oxides (55) in hydrochloric acid, 122 acetic acid,120 or acetic anhydride or to benzotriazoles (56) 120,123,124 byy heatingg in ethanol or treatment with potassium 125 iodide in acetic acid.

(54)

(56)

The hydrazidic halide (57) is converted by treatment with triethylamine into the benzotriazole (58). A mechanism invoking 126,127 the intermediacy of a nitrile imine has been suggested.

However, use of sodium ethoxide with ethyl cyanoacetate on (59) 128 gave only the benzotriazine (60) and benzoxazole (61).

Ph H ,~ N Br N N/ 0C0Ph (57) (58 )

Ph NIN Br NaOEt i NO2 CNCH2CO2Et Br

(59) (60) (61)

A seven membered ring intermediate is postulated in the

thermolysis of the diazirine (62) to 2-methyl-benzotriazole-l- 129 oxide (63).

N N=NMe Toluene/ a + NMe + 7h / N 0 2N NO2 0

(62) (63) 970/0

130 With few exceptions the available methods for the

' synthesis of benzofuroxans involve nitro-group side-chain

interactions. Thermolysis or photolysis of o-nitroarylazides 131 provides a high yield route to benzofuroxans. A closely

related process is presumably involved in the thermal isomerisation 132 of nitrobenzofuroxans (64 ) 65),

(65)

The thermal rearrangement of 6-chloro-7-nitroanthranil (66) into 7-chloro-4-formylbenzofuroxan (67) provides the first example of a benzofuroxan being formed by an isomerisation of 133 the general type not involving another benzofuroxan,

CHO N\ AcOH / Reflux /O

Cl Cl 0 (66) (67) 770/0

Six-Membered Heterocycles.

Strongly basic catalysts and electron withdrawing groups in o-nitrobenzylidene derivatives (68) favour the formation of the otherwise inaccessible quinoline N-oxides (69) as opposed to 67-69 formation of 1-hydroxyindoles in such reactions.

R3 2 \ R2

~ R1 (69 ) 0 (68) 30

Hitherto unreported 2-acyl-3-hydroxyquinolines (71) are prepared by base catalysed cyclisation of 2_(2'-nitrobenzyl)- derivatives of certain 1,3-diketones (70) in a reaction 134 explained in terms of a new version of the Smiles rearrangement.

0 `R 3 OFF 000CH2R2

(70)

R3 = Me 55- 83 °A OH CORS R3 = Ph 15%

(71)

The base catalysed cyclisation of 2-nitrobiphenyl derivatives

(72) having an activated methylene group in the 2'-position

provides a valuable synthetic route to phenanthridine N-oxides 135,136 (73).

CH 2R

NO2

(72) (73) 50-80°/°

R R

a ' H a H

b COPh d SO2Ph c CO2Me d SO2Ph

(74) 800/°

Cyclisation of the ketone(72b) proceeds with loss of the 136 benzoyl group giving phenanthridone (73a) in good yield.

At high base concentration the ester (72c) likewise gives (73a).

Cyclisation of (72d) fails to give the expected sulphone affording

the cyclic hydroxamic acid (74) instead. Phenanthridine

derivatives are also formed in moderate yields by the photocyclisation 137 138 of o-nitrobiphenyl derivatives such as (75) and (76).

Cl hv

(75) 25 0/0

H NPh CN hv

(76)

Aldol-type condensations between amino and nitro groups in

biphenyl derivatives provides a fairly general synthetic route 136 to benz[c]cinnoline N-oxides,

NH2 N aq NaOH H +N~ NO2 McOH /Reflux/ 2h /~ U

92- 98 °I°

1-Hydroxyquinazoline-2,4-diones (78) are formed in high yield by heating the benzoylaminoacetonitriles (77) in ethanolic 139 sodium ethoxide.

(77) (78)

Similarly, base catalysed condensation of o-nitro acetanilides

(79) provide a valuable route to the formerly unreported 140 quinoxaline-3(4H)-one 1-oxides (80).

R2 ~N~O

(79)

N-O

N%R2 0 (80)

The reaction of electron-deficient arenes or halides with a-phenyl-N,N-disubstituted and unsubstituted amidines has 141 been used as an efficient route to quinoxalines (81) and (82), and similarly to indoles, quinolines, benzoquinolines, iso- 142 143 quinolines, and pteridines,

NH2 -}- PhCH2i=NH 02N Ph NH2 (81). b-

-~ PhCH2 09N Ph

Phenazine (83) is obtained from the thermolysis of o-nitro- 144 diphenylamine, and in a reaction almost certainly involving intramolecular nucleophilic displacement of a nitro group, dibenzodioxans (84) are obtained from catechol and o -chloro- 145 nitrobenzene in warm acetone. 35

The base catalysed cyclisation of o-nitrophenylguanidines and ureas provides an excellent method for the synthesis of 146 1,2,4-benzotriazine 1-oxides. The scope of this reaction has been modified and extended to include a variety of o-nitro- phenylguanidine derivatives (85) which are prepared in situ by the acid catalysed condensation of an o-nitroaniline derivative with cyanamide and subsequently cyclised to benzo-1,2,4-triazine 147-149 1-oxides (86) under alkaline conditions.

"INH2 +~N N I

(8 5 ) (86) 1 50 80010

Closely related to the above reactions are the base catalysed 150 146,150 transformations of o-nitrophenylureas and thioureas into benzotriazinone N-oxides and benzotriazinthione N-oxides. DISCUSSION

SECTION 1

As an extension to a series of tetrazoles used as

N—arylimidoylnitrene precursors, 1-(2-nitrophenyl)-5-phenyl tetrazole was prepared. The aim of this thesis is to report and explain the deep seated thermal rearrangement resulting in the formation of a single major product, to examine the scope of the reaction, and to investigate the role of the nitro group in tetrazole decompositions, and compare the results with those published in the literature.

A. Preparation of Tetrazoles.

The 1,5-diaryltetrazoles were prepared according to the procedure outlined in Scheme 5.

NH2 ArCOCI / Py NHCOAr R 1 R1

PCl 5

Anr N, ~N CCl jv NaN3 / N DMF 0A r R 1

Scheme 5 37

The amines were commercially available or were prepared by literature methods. The imidoyl chlorides were prepared by refluxing the anilide in benzene or toluene, with a slight

excess of phosphorus pentachloride. The imidoyl, chlorides were then converted to tetrazoles by stirring with an excess

of finely ground sodium azide, in dry dimethylformamide.

Excellent yields (80-90%) of high purity tetrazoles (87) were

then obtained by adding sufficient water to dissolve residual 151 salts.

(87)

87 R1 R2 R3 R4

a H x H b H x H c NO2 x H d H x NO2. 0 e H N H f M H x C? g H x C? h H x NO2 i NO2 x C$ j NO2 x NO2 k NO2 x H 38

Attempts to prepare (87k) by this route failed. Reaction of the imidoyl chloride in situ with sodium azide in dimethylformamide produced a moderate yield (51%) of 6-nitrobenzofuroxan (88).

02N

152 Tetrazole (87k) had previously been prepared by reaction of the imidoyl chloride and sodium azide in aqueous acetone of unspecified concentration. The corresponding imidoyl chloride 153 was prepared and isolated. Reaction with sodium azide in a

10:1 acetone-water mixture gave 2,4-dinitrophenyl azide in moderate yield O60%), which was subsequently quantitatively converted into

6-nitrobenzofuroxan in boiling benzene. The following nucleophilic displacement mechanism is proposed for this reaction.

N3 + PhCN -E- NaC l 02N NO2 39

A 1:1 mixture of acetone-water gave the required tetrazole in low yield (30%). 2,6-Dinitroaniline failed to react with benzoyl chloride in refluxing pyridine. Use of catalytic and equimolar amounts of N,N'-dimethylaminopyridine in the reaction, also failed to produce the required benzanilide. Some monoaryltetrazoles such as (89a-c) were also required.

1 / a) R =H N NN b) R = Cl NO2 c) R = CH3 (89)

Compounds (89a and b) were prepared in good yield by 154 literature methods, Compound (89c) was prepared in moderate yield (47%). There appeared to be some reaction of the o-nitro group in the imidoyl chloride producing a mixture with an intense acid chloride carbonyl band (1780 cm-1). This suggests an intramolecular elimination of acetyl chloride initiated by the oxygen of the o-nitro group.

Attempted preparation of ethyl'1-(2-nitrophenyl)-5-carboxylate failed to produce the required product, Attempted preparation of ethyl 1-phenyltetrazole-5-carboxylate also failed to produce the required product, Treatment of ethyl oxanilate (90) with

phosphorus pentachloride in toluene, followed by sodium azide in dimethylformamide gave a pale yellow oil (25%) which was tentatively assigned as structure (91) on spectroscopic evidence.

NHC00O2Et 1) PCL 5 /TOt. 0. NHCCO2Et 2) NaN3 / DMF N3

(90) (91)

Reaction with phosphorus pentachloride in benzene followed ° 155•g by treatement with sodium azide in acetone at 0 C ave an oil with spectral data corresponding to (91). There was also evidence for the presence of phenyl isonitrile: vacuum distillation of the imidoyl chloride formed in refluxing toluene and in the melt, produced a small amount of brown oil with an intense peak -1 at 2280 cm in its i.r. spectrum. There was also spectral evidence for an acid chloride. The following mechanism is proposed to explain the latter results.

The formation of (91) could arise from hydration of the 156 first formed imidoyl azide, since it is known that electron withdrawing groups favour the azide in the tetrazole-imidoyl- azide equilibrium.

-E—r c -°s C=0 Ç OEt OEt CI

N=C -E- C[CO2Et

B. Thermolysis of Tetrazoles.

1. Thermolysis Reactions. _

The mononitrophenyltetrazole (87b) produced a trace of

a high Rf fluorescent product when treated under reflux in

chlorobenzene, under nitrogen. However, heating in bromobenzene

at 165°C for 20 h, and in dichlorobenzene at 185°C and

1,2,4-trichlorobenzene at 215°C for 0.5 h respectively, caused

complete decomposition. The single isolated product was

2-phenylbenzotriazole in each case, (Table 1). 42 TABLE 1

Starting material Product Sol v. Temp. Time Yield (°/0)

0 SS 165 20h 80

P~~ 0 DeB 185 0·5h 91 O:N..N~N (tN, NPh ~ ~N" 0 ~ N02 TeB 215 O'5h 92

P~N 0 - \ ():N\ SS 165 Q·75h 60 O:N'N~N 0~ ,.... )lPh 02N:.:..... NO 2 tJ N

0 Cl~ 8B 165 24h 56 0 ~ -N DeB 185 4h 82 . \ ():N'NOCI ~ ~N' - 0 O:N'N~ TeB 215 2 ·5h 84° ~ N02

a) 0 Ba 165 24h 0)0 (XN,OfJ N02 b) 0 0 02~ ~ --N - DeB 185 5·5h a) 13 ~ -N b) H b) 66 \ 0 O:N'N~N (J(N~N02 TeB 215 5min 0)72 ~ N - ~ N02 b) 0 N02

0 BB 165 24h 0

0;2 0 ~ -N DeB 185 24h 0 \ o:~NPh 81 S.M. ~ ~N/ 0 aN'N-::::N TeB 215 9h 75

Solvents:· BS= Bromobenzene DeB = 1, 2 - 0 i c h lor 0 b en zen e TeB = 1,2,4-Trichlorobenzene 43

Ph~—N N N~ i/11 \ N N" NO2 (87b)

The formation of 2-phenylbenzotriazole is not simply

explained. Tetrazole decompositions normally occur at a

higher temperature, although the presence of an o-carboxyl

group has been shown to reduce the decomposition temperature.8'9

Thermolysis of the dinitrophenyltetrazole (87k) was even

more facile in bromobenzene, producing a good yield (60%) of

the corresponding 2-phenylbenzotriazole in 0.75 h.

Ph /7-77- NNN'N

02N NO2

(87k ) (92)

Under the same conditions 1,5-diphenyltetrazole (87a) failed

to react, as did the 1-(4-nitrophenyl)-5-phenyltetrazole (87c).

Ph / PhN. N . Nr

(87a) (87c)

Refluxing the o-cyano compound (92) in 1,2,4-trichlorobenzene at 215°C for 0.5 h produced exclusively carbodiimide. Under identical conditions, 1,5-diphenyltetrazole remained largely unchanged. Thus, the presence of an ortho-electron withdrawing group in the 1-phenyl ring facilitates decomposition of the tetrazole, this effect being enhanced by the presence of a second electron withdrawing group in the same ring.

2. Identification of Volatile Components.

Transformation of these 1-(2-nitrophenyl)-5-phenyltetrazoles

(87) to 2-phenylbenzotriazoles requires the loss of nitrogen, as expected for a tetrazole, and either carbon dioxide or carbon monoxide and oxygen. Decomposition of 1-(2 —nitrophenyl)-5- phenyltetrazole (87b) diluted with acid-washed sand produced gases at a slow rate which were bubbled through lime water solution producing a copious white precipitate indicating the presence of carbon dioxide. To preclude the presence of carbon monoxide, 45

(87b) was decomposed under argon, in a vacuum line. The gases produced after thermolysis were transferred in the vacuum line - to an evacuated gas cell. The gases were then analysed by high resolution mass spectrometry. There were significant increases in the carbon dioxide and nitrogen peaks but no evidence for carbon monoxide.

Thermolysis under argon in the presence of a pre-coated 157 palladous chloride indicator strip also failed to detect any carbon monoxide. When exposed to carbon monoxide generated from oxalic acid, the strip immediately turned black.

A pungent odour, characteristic of phenyl isocyanate was evident when working up the sand diluted melt thermolyses.

Repetition of this thermolysis under water aspirator vacuum, produced a colourless oil, which partially distilled from the reaction mixture. This oil had a characteristic isocyanate band

(2260 cm-1) in the i.r. spectrum. The product of a solution thermolysis was treated with aniline and pyridine at 80°C for 1 h.

Treatment-with benzene produced 1,3-diphenylurea (4%). Acid catalysed decompositionsof (87b) in refluxing bromobenzene with acetic acid and trifluoroacetic acid produced 2-phenylbenzotriazole in yields of 15% and 11% respectively with a large amount of tarry products. Vapour phase pyrolysis at 400°C produced two compounds with similar Rf values on t.l.c., from which was isolated

2-phenylbenzotriazole (See Section 2). 46

3. Evidence for an Intermediate.

Several pathways may be considered for the transformation

of the 1-(2-nitrophenyl)-5-aryltetrazoles (87 R1 = NO2)

into benzotriazoles. The photochemical decomposition of 1-(o-nitro-

'phenyl)pyrazoles resulting in the formation of 2-substituted benzotriazole N-oxides has recently been reported.159, 160 The

authors were unable to distinguish between two possible

mechanisms: 1,3-dipolar cycloaddition of the nitro group to the

pyrazole moiety or a 1,5-dipolar cyclisation mechanism. This

route involves the intermediacy of an o-nitrosoazo intermediate,

RZ ~R1 R3~NN

NO2

compounds which have not been isolated but are frequently proposed 161-163 as precursors of 2-arylbenzotriazole-l-oxides.

An alternative mechanism may involve nucleophilic attack

of the nitro group oxygen on the tetrazole carbon. However,

the simplest pathway which can be considered for this transformation

appears to involve the carbodiimide (93), which leaves the final

problem of the somewhat curious loss of carbon dioxide. 47

(93) (87e)

Support for this postulate can be found in the thermolysis of (87e) which in 1,2,4-trichlorobenzene at 215°C for:9 h produced 2-phenylbenzotriazole in high yield (75%). 1,5-Diaryl- 1'2 tetrazoles are known to decompose thermally to carbodiimides.

Thev•steric interaction between the nitro-group and the tetrazole ring can be expected to twist the 5-aryl group out of the plane of the tetrazole ring, thus the electron withdrawing effect of the nitro group will be somewhat diminished in the transition state (94) ,

NO2

(94) 48

The increase in potential energy due to the partial loss

of resonance stabilisation, the desire to release strain in the

azacyclopropene ring, and the possible steric or charge transfer

effect of the nitro group oxygens impinging on the nitrogen

leaving group will faciliate the migration of the 5-nitrophenyl

group, This 'ortho-effect' is well known in the Beckmann 164 rearrangement. Thus the carbodiimide (93) could well be a

common intermediate formed from tetrazoles (87b) and (87e).

4. The Role of Substituents in 1,5-Diaryltetrazoles.

The decomposition of tetrazole (87d) and (87f) in the melt

at 210°C, has been described in the literature.1,2 Migration of

the 5-(4chlorophenyl)-group was claimed to be retarded significantly,

relative to migration of a phenyl group, and no products were

obtained with the 5-(4-nitrophenyl)-substituent present.

(87d) (87f )

On thermolysis of (87d) in 1,2,4-trichlorobenzene at 215°C

for 4 h, we found a very similar product distribution compared 1'2 to the products of 1,5-diphenyltetrazole thermolysis,

Thermolysis of (87f) under identical conditions gave a

lower material return with approximately equal amounts of

carbodiimide and imidoyl nitrene derived products. The tetrazoles

(87d) and (87f) are stable at lower temperatures.

Ph —N 210° PhN=C=NPh + PhN~ ,N >Ph N

10 (87a) 80°10 200

Cl BB No Reaction DCB N Ph N~ N N (87d)

TCB PhN=C=N Cl + Cl 215 °

330/0 15°/0 + mixture of disproportionatedl 'ureas 25 °/°

BB No Reaction DCB

(87f) TCB PhN=C=N NO 215°

9 Of -~- mixture of disproportionated1 ureas 20°I°

Thus while the chlorine substituent in (87d) has very

little effect on the migratory aptitude of the 5-aryl group

compared to phenyl migration, the nitro group in (87f)

significantly retards migration. When compared to the above

results, decomposition of tetrazoles (87g) and (87h) show clearly

part of the -function of the o-nitro group in the 1-phenyl ring.

Cl BB 24h 56°I°

N CI DCB 4h 82°/0

TCB 2h 84°/° NO2 (95)

(87g )

NO2 H

(96) (97) BB 24h - No Reaction

DCB 5.5h 13°/° 66% (87h) TCB 5 min 72 °I° 0 51

The o-nitro group reduces the decomposition temperature of the tetrazoles, and promotes decomposition of the tetrazole ring by exerting some influence other than the purely electronic effect, since in bromobenzene the 1-(2-nitrophenyl)-derivatives decompose, whereas the 1-(4-nitrophenyl)-derivatives are stable,

(Tables 1 and 2). Thermolysis of (87g) gives good to excellent yields of the benzotriazole (95). Thermolysis of (87h), however, shows the o-nitro group exerting a compelling influence over the course of the reaction. In 1,2-dichlorobenzene at 185°C, the major product results from the loss of nitrogen from the tetrazole

(or imidoyl azide) followed by cyclisation of. the imidoyl nitrene to the benzimidazole (97), with the minor component of the reaction, benzotriazole (96), attributed to initial migration to a carbodiimide intermediate, and rearrangement. At 215°C in

1,2,4-trichlorobenzene, the only product of the reaction is derived from migration of the 5-(4-nitrophenyl)-group to give benzotriazole

(96), a formerly disfavoured process which is now the sustained mode of action. Nitro groups in the 5-phenyl ring do not reduce the tetrazole decomposition temperature,

Decomposition of compound (89) was less productive.

N a) R = H N N b) R= Cl NO2 c) R = CH3

(89) (9 8) TABLE 1 52

Starting material Product Sol v. Temp. Time Y i e l d (%) l~b 0 0 SB --1:6:5-- 20h 80 Pty=~ 0 :;;..- , DeB 185 O·5h 91 .(XN /N .(j:N NPh I 'N" 0-... ~r{ 0 ~ N02 TCB 215 G'5h 92

P~N ) S-b 0 0 - \ ():N\ BB +G-5- Q-75h 60 O:N'N~N 0::::.... 0-- , NPh 02N ~ NO 2 zN N •

fS{-, ~ 0 CI~ BS 1~ 24h 56 0 ~ -N DCB 185 4h 82 \ ():N'NOCI ~ ~N' - 0 O:N'N~ TCB 215 2 -5 h 84 ~ N02 I

d) 0 B8 --113-5- 24h 0)0 1$(:,0 (tN,N 0 N02 b) G ~ '- I 0 02NO;- N - DCB 185 5 ·5h a) 13 ~ -N b) H . b) 66 \ 0 O:N'N~N (IcN~N02 TCB 215 5min 0)72 N - ~ N02 ~ N02 b) 0

[.!)"'bl;) 0 BB -+&5- 24h 0

0;:2 0 ~ -N DCB 185 24h 0 \ ():~NPh 81 S.M. ON, -::;N 0-.. ~N/ 0 _I N TCB 215 9h 75 0-..

Solvents: BS= Bromobenzene DeB = 1, 2 - 0 i c h lor 0 ben zen e TCB = 1,2,4-Trichlorobenzene TABLE 2 53

Start i ng material Sol v. Ti me (h) Product Y i e 1d (°/0)

carbodiimidel urea Phr=N, TCB 0·6 0 PhN'N~

Cl~ BB 24 a) carbodiimidel urea 98 (SM) DCB 24 77 (SM) ~ -N, b) ben zi mid az ole PhN'N~N TCB 48 59(0) 15(b)

\ N 88 24 NO REACTION 02 Or- a) c arbodii mide I urea DCB 24 73 (SM) ~ -~ b) benzimidazole PhN ,.N 'N/ TCB 48 29(a) 34(b)

carbodii mide lure Cl PhpN\ DCB 24 35 NN'N;:::.N o ~ \

33 UREA .CIO;- BS 24 carbodiimide I urea 5 9(SM) " _N DCB 22 76 UREA \

~N' -;::N TCB 7 92 UREA 02 ,I N

Sol vents: 8 B = Bromobenzene DCB = 1,2 -Dichlorobenzene TCB = 1,2 , 4 -Trichlorobenzene 54

Refluxing (89a) in bromobenzene at 165°C overnight produced a complex mixture (t.l.c.), from which was isolated a small amount of o-nitrophenylcyanamide (98)(5%). Extended thermolysis of (98) did not cause any further rearrangement.

The product (98) is probably formed by migration of hydrogen to give a carbodiimide which then isomerises to the more stable cyanamide. A rapid evolution of gas was noted when (89b) was heated in bromobenzene. The solution became dark red and the -1 reaction mixture exhibited an intense i.r. band at 2260 cm .

Further heating consistently caused considerable decomposition and no products could be isolated. Thermolysis of (89c) generated tarry products only. The reduced ability of alkyl groups to migrate, thereby chang ing the nature of reactions has been noted previously.19

Since we had'no direct evidence for the postulated carbodiimide intermediate in the conversion of tetrazoles into ' benzotriazoles, alternative precursors offering milder routes to the rearrangement products were sought.

C, Alternative Precursors to Carbodiimides.

Other reactions in which carbodiimides are formed are the fragmentation of-other heterocycles and the oxidation or elimination reactions of thioureas, (see Introduction). 55

1. Heterocyclic Precursors.

The formation of diarylcarbodiimides from 1,5-diaryltetrazoles requires the extrusion of the thermodynamically stable fragment

N2 from the molecule.

The oxadiazolone (99),10 the oxadiazolthione (100), and the oxathiadiazole-2-oxide (101) can rearrange to the same carbodiimide

(93) on extrusion of CO2, COS and SO2 respectively.

NOPh~N Ph[=N\ N0 N` ~0 2

II it 0. Ó N0S

(99) (100)

Ph~ NO ~ NN ,0 I I 0

(101) (93) 56

Compound (99) was prepared by the literature route;° and compounds (100) and (101) were prepared by a modification of

the literature route, by treatment of amidoxime (102) with

thiophosgene or thionyl chloride respectively (Scheme 6).

NH2OH

Na/EtOH

Ph__N NO. Ī N O NyPh NC c sc l 2 II Et3N S NO2 NHOH (10 0) 77% (102)

Ph,-N 2 I 0 (101) 67 °/°

Scheme 6 57

The very stable oxadiazoles (99) and (100) required

strong heating (255°C) in boiling diphenyl ether or in the melt and gave 2-phenylbenzotriazole in low yield only (ca.

10%), the major product being that of nitrene cyclisation,

4-nitro-2-phenylbenzimidazole (103) (Table 3). However, the oxathiadiazole (101) decomposed under much milder conditions, in boiling bromobenzene at 165°C or in the melt at 135°C to

give 2-phenylbenzotriazole in good yield (Table 3); formation and decomposition of carbodiimide (93) can be clearly seen -1 inithe infrared spectra (2160 cm ). 3,4-Diaryloxathiadiazole-

2-oxides such as (101) are known to give carbodiimides almost 17 quantitatively on heating (see Introduction).

The formation of 2-phenylbenzimidazole (104) is thought to

arise from closure of the N-arylimidoyl nitrene on to the ortho-

blocked position giving a 3aH-benzimidazole intermediate which then rearranges by a 1,5-sigmatropic shif,t of the nitro group to nitrogen.

The N-nitro group is then lost on work up to give 2-phenylbenzimidazole.

Thermolysis of 4-nitro-2-phenylbenzimidazole in the melt at 260°C

overnight gave unchanged starting material, precluding this as the

source of 2-phenylbenzimidazole.

N-nitro heterocycles have been prepared by low temperature 165 (ice-salt) nitration using nitric acid and acetic anhydride,

but attempts to apply this method to the synthesis of 1-nitro-

2-phenylbenzimidazole failed. TABLE 3

N02 Recovered

Solv. Temp 0 C Time(h) (XN\. NPh (tN :::--...... N' O:~Ph~ N ~ '_JPh Starting Material H % (1070) (1 03) H % (104 ) °/0

Ph 20 255 24 11 34 3 1 8 P'Y=N\ O:'8~0 ~ N02 Melt 255 7 9 37 4 19 (99 )

Ph 20 255 6 4 25 13 13 (XN'Ph, ,,0N\ I ::::-... 'N02~ Mel t 260 4 9 7 4 - (100)

165 88 I Pt;=N\ PhBr 1 - - - Q:N'S"O :--.... I N02 0 Mel t 135 1 64 - - - (101 ) - '------~ - ~ ------_._-

Ln ex>

(99) or (100) NO2 ti

N \>Ph N H

(103) (104)

2.. Thioureas.

The N,N'-disubstituted thioureas shown in Table 4 were 166 prepared in good yield by the procedure outlined below.

NH2 csct 2 NCS NO2 NO2

R1NH2

NHCSNH NHCSNHRI

NO2 NO2

(105 0-g ) (105) 60

Where R1 was an aryl group, substituents are labelled R2,

R3, and R4.

TABLE 4

105 R R1 R2 R3 R4 Yield

a H Ar H H H 80 b H Ar H Me H 40

c H Ar Me H Me 84 d H Ar Me Me Me 72 e H Ar H OMe H 92 f H Ar H NO2 H 68* g Me0 Ar H H H 62

h H t-butyl - - - 93 j H benzyl - - - 72 k H 2-pyridyl - - - 75 1 Me0 2-pyridyl - - - 29 __ _ - * This yield is based on starting material consumed; much being recovered from the reaction.

Attempted synthesis of 1-(2,6-dinitrophenyl)-3-phenylthiourea and 2,2!-dinitrophenylthiourea failed. 61

2a. Preparation of Carbodiimides.

Carbodiimides (106) were prepared in good yield from the alkyl, benzyl and most arylthioureas using mercuric oxide, as described in the Introduction. This method was efficient on a small scale (up to 300 mg) but on a larger scale it was difficult to remove mercury salts from the product. Mercuric oxide failed to produce carbodiimides from the 2-pyridyl- substituted thioureas (105 k and 1), and also from the

3-(4-nitrophenyl)-derivative (105f). The use of silver(II) oxide also failed with these compounds and left metal residues in the carbodiimides, where formed. The use ōf 2-chloro-l-methylpyridinium iodide62 enabled clean, large scale reactions to be performed in short reaction times. However, this reagent did not generate carbodiimide from the 3-(4-nitrophenyl)-derivative (105f) and gave only a very low yield (4%) of carbodiimide from the

3-(2-pyridyl)-derivative (105k) as shown in Table 5. Attempts to prepare the pyridine N-oxide and thus remove the electron withdrawing effect of the pyridine nitrogen failed.

N=C=N-R1 ; R1= Ar = NO2 R4

(106) (106a-f ) 62

TABLE 5

106 R 'R1 R2 R3 R4 Reagent Time Yield (h) (7) **

a H Ar H H H 40 18 76

b H Ar H Me H CMI 5 83 c H Ar Me H Me Hg0 2 92 d H Ar Me Me Me Hg0 18 -

H Ar Me Me Me CMI 2 98 e H Ar H Me0 H 40 18 -

H Ar H Me0 H CMI 0.5 85 f H Ar H NO2 H Hg0 •* 0 H Ar H NO2 H CMI - p h H t-butyl - - - Hg0 18 -

j H benzyl - - - Hg0 18 0 k H 2-pyridyl - - - Hg0 - 0 H 2-pyridyl - - - Ag0 - 0

H 2-pyridyl - - - CMI - 4

CMI = 2-chloro-l-methylpyridinium iodide.

* A wide range of reaction times and conditions failed to produce any carbodiimides.

** Where yields are not quoted the carbodiimide was used directly after isolation.

The symmetrical carbodiimide (106m) was prepared from the isocyanate as shown.^-

NH2 coCl2 NCO NO2 NO2

/Me

0'rP -Ph

(106m) 50 0/o

The use of alternative catalysts such as triphenylphosphine oxide and triphenylarsine oxide gave (106m) in very impure form, in low yield. This is the only arylcarbodiimide with an o-nitro group previously recorded,41 but there is no report of this undergoing rearrangement.

2b. Thermolysis of Carbodiimides.

The carbodiimides as prepared above were isolated pure (t.l.c.), -1 with a characteristic intense band in the i.r. spectrum (2120-2170 cm ) 64

and were used without further purification. The oils or solids were dissolved in a suitable solvent, usually bromobenzene, and heated to reflux temperature under nitrogen. The diarylcarbodiimides

(106a-e) gave 2-arylbenzotriazoles (107a-e) in good overall - yield from the thioureas as shown below and in Table 6. The reaction times varied from a few minutes to several hours depending on the aryl-substituents and the reaction temperature.

The overall yield obviously reflects the efficiency of the carbodiimide formation.

R 3 N, R4 R4 (107) (106) + N2 + CO2

TABLE 6

106 Rggt R RZ R3 R4 Solvent T° . Time Yield (%)

a Hg0 H H H H BB 165 10 min 50 b Hg0 H H Me H BB 165 2 h 37 b CMI H H Me H TCB 215 5 min 43 c Hg0 H Me H Me BB 165 1.5 h 59 d Hg0 H Me Me Me BB 165 1.5 h 54 d CMI H Me Me Me BB 165 15 min 73 e Hg0 H H OMe H BB 165 15 min 25 e CMI H H OMe H BB 165 10 min 55 m - H NO2 H H melt 165 5 min 84*

* This yield was calculated from the carbodiimide. 65

Thermolysis of the t-butyl (106h) and benzyl (106j) carbodiimides failed to give any product. Extensive heating in a range of solvents culminating in 1,2,4-trichlorobenzene at

215°C for long periods failed to cause any rearrangement of the carbodiimide.Infra-red monitoring of the reactions indicated the carbodiimides were extremely stable thermally. The carbodiimide

-N=C=N- stretching vibration at (2120-2170 cm-1) decreases with an associated build up of tarry baseline products over a period of 24 h.

D. Mechanism of Transformation.

1. Isolation of Reaction Intermediates.

Evidence for the intermediacy of a carbodiimide in the transformation of 1-(2-nitrophenyl)-5-aryltetrazoles, and other heterocyclic precursors (99), (100) and (101) is implicit, since owing to the unstable nature of the carbodiimides (106) none have been fully characterised.

Ph N Ph1N Ph1N N09 N07 NO2 N ~C~O NNC 0 N5/

I I II 0 Ó NO0

(99) (100) (101)

The explicit evidence was obtained by generating the carbodiimide

(106a) from the thiourea (105a). The carbodiimide was made up

to a fixed volume and half was hydrolysed to the known urea

(108), which was characterised against an authentic sample,

while half was thermolysed to 2-phenylbenzotriazole (107a) as

shown.

SI NHC NH NO2 (105a)

Hg0

N=C=N NO2

ii N NHCNHPh NPh NO2 N (107a ) (108) 67

Attempted bulb to bulb distillation of carbodiimide (106a) under high vacuum, using a mercury diffusion distillation apparatus, resulted in a red oil distilling from the carbodiimide.

Thin layer analysis of the red oil shows two components, which when heated were converted exclusively to 2-phenylbenzotriazole.

Attempted crystallisation of the carbodiimide (106a) resulted in the formation of two sets of crystals which were mechanically separated. Bright orange needles with a low melting point

(19-21°C) were identified as the carbodiimide (106a). The second product, deep red needles, m.p., 126-128°C corresponded on t.l.c. to the red component from the carbodiimide distillation. Infra-red analysis of the red compound in the solid phase shows a band at

1695 cm-1 and in solution this carbonyl absorption diminishes and a new absorption at 2260 cm-1 (CC$4) appears. On the basis of this spectroscopic evidence, the red solid carbonyl compound was tentatively assigned the structure (1O9a) which is isomerised to structure (11Oa) in solution. Removal of the solvent leaves the red solid with the original infra-red spectrum, demonstrating the reversibility of (109a) -- (110a).

N=C=0

NPh 0

(110a) 68

That the 2-aryl-1,2,4-benzotriazin-3-one 1-oxide is an intermediate in the reaction sequence was shown as follows; low temperature thermolysis in toluene of the oxathiadiazole-

2-oxide (101) and of the carbodiimide (106e), for a longer period produced a red solution in each case from which was isolated a red solid by careful removal of the solvent and crystallisation from acetone.

(101)

N=C= OMe Ar = 4 -methoxyphenyl (109e) NO2

(106 e )

Further heating of the red solution in toluene produced the corresponding 2-arylbenzotriazole quantitatively. Thermolysis of the isolated red compounds in bromobenzene again produced a quantitative yield of the 2-arylbenzotriazole. Elemental analysis 69

supported the assignment of (109a) and (109e) although this

evidence is of less significance since the 2-aryl-1,2,4-benzo-

triazin-3-one 1-oxides are isomeric with other structures up

to the point that carbon dioxide is lost. Further support for

(109a) came from the reaction in benzene with p-anisidine which

produced the corresponding azoxyurea (111). Hydroylsis of (109a)

in aqueous acid gave 2-phenylbenzotriazole. The structure (109a)

was subsequently confirmed by X-ray crystallography

Me0 NH2

NHCNH OMe NAN P h benzene IV—NPh 0 0 (109a) (111 )

To rationalise the transformation of carbodiimide (106a)

into benzotriazole (107a) in which the benzotriazine (109a) is

an intermediate, a sequenceof electrocyclic ring closing and opening reactions is proposed, as in Scheme 7.

2-Aryl-1,2,4-benzotriazin--3-one 1-oxides have not previously

been recorded although the 2H-derivatives have been prepared

by base catalysed condensation of o-nitrophenyl ureas, (see 146,150,167 Introduction), o

N=C=NPh NPh

NO2 0

(106a) (109a)

N N=C=O NPh + 0O2 N N=NPh (107a) 0 (110a)

Scheme 7 72

NHC NH2 base NO2 NH

(112) 0

We were unable to synthesise a 2-phenyl-derivative by treating 1-(2-nitrophenyl)-3-phenylurea with base. Hydrolysis 185 of (112) with aqueous sodium hydroxide produced benzotriazole,

The valence tautomerism of 6-methyl-2-(4-methylpbenyl)-

1,2,4-benzotriazin-3-one (113) and the isocyanate form (114) 168 has previously been investigated by Busch.

(113) (114)

The benzotriazine (113) was shown to be stable to high temperature, aqueous acid and ethanol, whereas ethanolic alkali produced the corresponding carbamate, and reaction with aniline gave the 73

corresponding urea. In a system which requires physical methods

for absolute determination of structure, the author concluded that

the cyclic form (113) existed exclusively, on the basis of

chemical results that predated the use of infrared spectroscopy

as an analytical tool by approximately 40 years.

Mechanism; Stage 1.

The mechanism for transformation of carbodiimide (106a) into

benzotriazole (107a) can be seen as an initial electrocyclic ring

closure followed by a Dimroth type rearrangement to give the

benzotriazin-3-one (109a). However, the fact that the alkyl

and benzyl substituted carbodiimides do not undergo rearrangement

might suggest the first step is nucleophilic attack by the oxygen of the nitro group ōn the carbodiimide carbon.

Q=C=NPh

N0 0

nucleophilic attack electrocyclic ring closure

Thus in the case of aromatic substituents the delocalisation

into the ring increases the electrophilicity of the carbodiimide

carbon atom and thus favours the rearrangement. This is supported

by the fact that the 5-(4-nitrophenyl)-tetrazole precursor (87 h) is

transformed into the benzotriazole in high yield (72%),

the 2,2'-dinitrophenylcarbodiimide (106m) produced a benzotriazole 74

in high yield (84%), whereas the 4-methoxyphenylcarbodiimide

(106e) having less capacity to delocalise the negative charge from

the nitro group oxygen produces the corresponding benzotriazole

in somewhat reduced yield (65%).

—N OMe N=C=N N 'N~ NO2 02N NO2

(106 e ) (87h) (106m)

The inductive effect of the t-butyl group and benzyl group might, therefore, be reducing the electrophilic nature of the

carbodiimide carbon so much that the nitro group oxygen would not

be attracted to that position.

The ability of the system to delocalise negative charge,

and the relative degree of electrophilicity of the carbodiimide

carbon, would not be expected to have such a marked effect on

reactivity in a purely thermal sterically favoured, electrocyclic ring closure.

Mechanism: Stage 2

Valence tautomerism of (109a) to (110a) gives the azoxy

isocyanate which by nucleophilic attack of the azoxy N-oxide

oxygen produces the intermediate (115) which is now set up to lose carbon dioxide and form the final product, 2-phenylbenzotriazole (107a).

E. Alternative Routes to 2-Arylbenzotriazoles.

The use of o-nitrohydrazino derivatives and o-nitroazo compounds reacting through an o-nitrosoazo intermediate was illustrated in the Introduction. Formation of o-nitrosoazobenzene and then 2-phenylbenzotriazole 1-oxide has been achieved by treatment 169 of o-chloromercuryazobenzene (116) with nitrosyl chloride.

N\ NOCI NPh

0 (116 )

170 o-Aminoazobenzenes have been treated with cuprammonium salts, 171 copper acetate in pyridine, and copper sulphate in pyridine,172,173 to give 2-arylbenzotriazoles in good yield. Thermolysis of o-azido- 174 azobenzene also gives 2-phenylbenzotriazole.

Condensation reactions between benzotriazole and chlorobenzene derivatives activated by at least two o-nitro groups give a mixture of 1- and 2-arylbenzotriazoles, the 1-substituted derivative being

175 the major product. Condensation between benzotriazo]e and

2,4-dinitrofluorobenzene gives exclusively the 1-isomer in benzene at 80°C but still gives a 3:2 mixture of the 1- and 2-isomers in 176 dimethylformamide, Thus our new route to 2-arylbenzotriazoles has the advantage of giving exclusively 2-substitution, usually in very high yield.

Conclusion.

The nitro group can clearly be seen to play an important role in the thermal decomposition of 1,5-diaryltetrazoles. The o-nitro group facilitates the formation of the carbodiimide and then intercepts it very efficiently, providing a route to 'the previously unrecorded 2-aryl-1,2,4-benzotriazin-3-one 1-oxides, and subsequently a novel route to 2-arylbenzotriazoles substituted exclusively in the 2-position.

F. Extensions to Nitro Group Interactions.

We found o-nitrophenylisocyanate and the analogous isothiocyanate were stable to thermolysis conditions. The isocyanate had previously been excluded as an intermediate in the thermal rearrangement of o-nitrophenylcarbamates.177

0 I NHCOR 250-270° p -}- CO2 -{- ROH NO2

71°/0

The experimental results favour initial attack by the oxygen of the nitro group at the carbonyl carbon atom.177

C H 30b, H r. NL ~0 I\L.O1 C cOCH3 +~0 - +C0 N 4 N II 11 0 0

In view of the novel interaction of a carbodiimide function with an ortho-nitro group described above, we considered the reactions of peri-naphthalene derivative (117) and 2,2'-disubstituted biphenyl derivative (118) were of interest. 78

N=C=NPh N=C=NPh

NO2 NO2

(117) (118)

1. peri-Naphthalene Interaction.

With compound (117) there is no conjugation between the nitro group and the carbodiimide, whereas in (118) the two function- alities are conjugated through the biphenyl system. Each compound exhibits a considerably changed steric arrangement compared to the o-nitrophenylcarbodiimide. Very few geometries of peri-substituted 178 naphthalenes have been reported.

Evidence for donor-acceptor interactions in 1,8-disubstituted naphthalenes is available from crystallographic data and from

35N p.m.r. measurements,179. The naphthalene derivative (117) was prepared as shown in Scheme 8.

Solution thermolysis of (117) produced only tarry material.

Vapour phase pyrolysis performed by distilling the carbodiimide through a pre-heated quartz tube at 750°C and 0.015 mm gave, after work up, a single crystalline product which was identified by m.p. 180 and mass spectrometry as naphtho[1,8][c,d]indazole N-oxide (119). NH2 NO2 NCS NO2

HNO3/H2504 CSC 12

PhNH2

l I- /C[ I I N=C=NPh +Me NHCNHPh 45

NO2 NO2

(119) (117)

Scheme 8 80

This product could arise from initial nucleophilic attack of the nitro-group oxygen in (117) on the carbodiimide nitrogen or carbon, with the subsequent rearrangements generating either phenyl isonitrile or phenyl isocyanate as the volatile component of the reaction, as indicated in Schemes 9 and 10.

,Q N=C =NPh

+ Ph NC

(119) Scheme 9 81

O N~O

NF,C=NPh _ NPh

-i- PhNCO

(119)

Scheme 10

Owing to the low volatility of the carbodiimide (117), only

a small amount of material distilled through the quartz tube, and

was pyrolysed (10 mg) and the volatile component was not found.

2, 2,2'-Biphenyl Interaction.

The biphenyl derivative (118) was prepared as shown.

Solution thermolysis of (118) in 1;2,4-trichlorobenzene at

215°C for 3 days produced tarry products only. Vapour phase

pyrolysis at 750°C and 0.015 mm gave a single product isolated from a polar mixture by column chromatography. The it spectrum of

NCS NO2 NaSH NH2 cscl2 NO2 NO2 NO2

PhNH2

S N=C=NPh NHCNHPh

NO2 NO2

(118)

a second component suggested this to be phenyl isonitrile and the reaction product isolated from the cold finger had a characteristic pungent isonitrile odour. This suggested the major product might be benzocinnoline di-N-oxide (120), formed by initial attack of the nitro group oxygen on the carbodiimide nitrogen as shown, or the benzocinnoline mono-N-oxide (121) or benzocinnoline

(122) formed by thermal deoxygenation.

N=0 N= 0

(120)

Comparison of the product with independently synthesised 181 (121),182 181 (120), and (122), failed to identify the reaction product as any of these benzocinnoline derivatives.

Mass spectral evidence subsequently indicated the molecular ion of the thermolysis product to be starting material - 47 mass units. This could indicate a product isomeric with the starting material losing a nitro group and one hydrogen in the mass spectrum or less likely, a product formed by rearrangement and denitration of the carbodiimide (118).

Desulphurisation of the thiourea (123) with mercuric chloride 183 to give 6-anilinophenanthridine (124) has been reported.

NHCNHPh HgCl2 NHPh

(123) (124)

That the carbodiimide is an intermediate in this reaction was 183 shown by intercepting the carbodiimide as the urea, by hydrolysis.

We considered that thermolysis of the biphenyl carbodiimide (118) might produce the anilinophenanthridine (125) by an electrocyclic ring closure, followed by a 1,5-hydrogen shift; possible thermal denitration can also be accounted for in Scheme 11.

O -N NPh

(116).

1,5[H]

1,7{NO2 ]

N ti NHPh 02N

(124) (125) Scheme 11 86

Authentic specimens of (124) and (125) were prepared as shown

NCO NH2 coct2 AtCl3 0 NH R C~

N PhNH2 II • C NHPh

R = H (124) R = NO2 (125)

Comparison of spectral data indicates significant similarities between the product of pyrolysis of carbodiimide (118) and compounds (124) and (125), however, the compounds do not correspond 87

on t.l.c. and the nitro group in (125) is stable under identical mass fragmentation conditions, exhibiting a parent ion at M+ 315.

The structure of this thermolysis product is not known at the- present time.

3. Intramolecular Electrophilic Substitution by the Carbodiimide.

The proposed mechanism for formation of 6-anilinophenanthridine

(124) from the biphenylthiourea (123) and mercuric chloride requires the ring closure reaction to be an intramolecular electrophilic substitution reaction, aided by protonation of a carbodiimide nitrogen by hydrogen chloride generated in situ, (See Scheme 12).

If this were the case then the 1-(a-naphthyl)-3-phenylcarbodiimide (126) might be expected to undergo acid catalysed ring closure to (127),

/NHPh H NPh N=C=NPh C N C

Acid

(126) (127)

Vapour phase pyrolysis of the carbodiimide (126) resulted in recovery of unchanged starting material, A stirred solution of

(126) in methylene chloride in the presence of aluminium chloride gave a yellow solid i,r. and n,m.r. spectra of which were complex.

NHCNHPh HgC12 N=C=NPh + HgS + 2 HCl

(123)

N ! + HCl H~NHPh

(124 )

Scheme 12

The parent ion in the mass spectrum was at 488 m.u., suggesting a dimer. As a means of simplifying the problem 1,3-diphenylcarbodiimide was prepared by an analogous route and treated with aluminium chloride in methylene chloride as before. A yellow solid was again produced, exhibiting similar spectral characteristics to the product of the naphthylcarbodiimide, the mass spectrum again indicating a dimer. This product was identical with that obtained

by quaternisation of 1,3-diphenylcarbodiimide using fluoroboric acid, and is thus 2-phenylamino-3-phenyl-4-phenyliminoquinazoline 184 (128).

2 Ph N= C=NPh NPh (128)

By analogy, the product of the 1-naphthyl-3-phenyl-carbodiimide reaction is considered to be one of the several corresponding naphthoquinazolines, e.g ,, (129).

ALCl3

N=C=NPh 90

Intramolecular cyclisation across the peri-position has thus not occurred, presumably because of the strain in the five-membered ring which would be formed; intermolecular reaction has supervened.

SECTION 2

A) The Carbazole Reaction

Thermolysis of 1-(2-nitropheny1)-5-phenyltetrazole (87b)

has been shown in the preceeding section to give 2-phenylbenzotri-

azole (107a) in good yield. Vapour phase pyrolysis of tetrazole

(87b) at 400°C and 0.05 mm/Hg gave a second component which had

a similar Rf to 2-phenylbenzotriazole and was difficult to

isolate. Pyrolysis of 2-phenylbenzotriazole under the same

conditions gave the same product (tic) and on increasing the

pyrolysis temperature to 800°C we were able to transform

2-phenylbenzotriazole in good yield to the second component (80%).

This was subsequently identified as carbazole (130), by mixed

. m.p., and comparison of the i,r. spectrum of an authentic sample.

Ph - N NN 400°C 0.05mm NO2 N la 800°C (87b) (107a 0.05mm (130)

Owing to the difficulty we experienced in separating

carbazole from unreacted 2-phenylbenzotriazole, a range of temperatures

was used, see Table 7, to find the optimum conditions for this

transformation. The pyrolysis product was recovered with very 92

little material loss and after removal of traces of baseline material by column chromatography the two component mixtures were analysed by h.p.l.c. There seems to be a rapid increase in product formation after 700°C with the optimum

temperature at about 1000°C.

Temp. Carbazole °C. Yield (%)

300 0

500-20 0

600 < 1

700-20 17

750 76

800 56

900 91

The projected optimum temperature was above the working range of the apparatus and was not attempted. 2-Phenylbenzotriazole was found to be stable photochemically. The synthesis of carbazole and substituted carbazoles is well known, several reviews covering I86-188 this extensive literature. Although carbazoles have been prepared by thermal and photochemical rearrangement of 1-arylbenzotriazoles, there is no record of 2-arylbenzotriazoles undergoing this rearrangement.

( 93

B) The Mechanism of Transformation.

The stoichiometry of the transformation of 2-phenylbenzotriazole (107a) to carbazole (130) demands loss of nitrogen (N2).

H (107a) (130)

The similarity between this transformation and the Graebe- 186 Ullmann synthesis of carbazole from 1-phenylbenzotriazole cannot be ignored. Thus, a logical postulate would be migration of the phenyl group from the 2- to the 1-position followed by loss of nitrogen as shown below.

N~--1 ~~ `,~1N---Ph —.. ~N N Ph (107a)

A second mechanism worthy of consideration involves ring opening of 2-phenylbenzotriazole, without migration of the phenyl group, to give an azobenzene nitrene. The nitrene could then insert into the C-H bond of the phenyl group followed by two

[1,5]H or a [1,7]H shift to give 1,2,5-dibenzotriazepine (131) as an intermediate.

(107 a )

2x1,5[H]

or 1,7[H]

(131)

Pyrolysis of the dibenzotriazepine (131), which was synthesised from o-dinitrodiphenylamine (132) as shown, added some support to the postulated mechanism in giving carbazole as the only isolated product.

H NO2 Zn / NaOH 2

(132 ) FVP (131) O 800 c

(130) 30 0/0

1) Tests for the Postulated Mechanisms.

The introduction of a label into the 2-arylbenzotriazoles seemed an obvious way to investigate the rearrangement pathway.

Introduction of a label in the 5-position of the benzotriazole ring was convenient since 5-nitro-2-phenylbenzotriazole was readily available from 1-(2,4-dinitrophenyl)-5-phenyltetrazole

(87k) .

However, substituents in this position can give rise to two isomeric products in mechanisms 1 and 2, and thermolysis of 1-arylbenzotriazoles with nitro groups in either ring have 189 been shown to give very poor yields of carbazoles, (3%).

A label in the 2-aryl ring offers a means of detecting the mode of rearrangement unambiguously.

Mech 1

(132)

(107b)

Mech 2

(133) 96

Pyrolysis of 2-(4-methylphenyl)benzotriazole (107b) would

thus be expected to give 3-methylcarbazole (132) by migration

to the 1-position followed by loss of nitrogen and ring closure,

and 2-methylcarbazole (133) through the azobenzene nitrene

mechanism. Vapour phase pyrolysis of (107b) at 850°C and 0.05 mm

was incomplete. The pyrolysis product after removal of baseline material was not resolvable by t.l.c. H.p.l.c. analysis of the mixture enabled us to identify starting material (14%), with two

other components. To identify the rearrangement product authentic

specimens of 3-methylcarbazole and 2-methylcarbazole were

prepared. The synthesis of 2-methylcarbazole required 4-methyl-

2f-nitrobiphenyl (134) as a precursor. Many attempts using

o-nitroaniline and toluene or p-toluidine and nitrobenzene in

the Gomberg-Bachmann reaction190 failed completely to produce

the required biphenyl (134). The intermediate (134) was prepared

by a modified Ullman reaction as an oil, which was converted

directly to 2-methylcarbazole (133) as shown.

(Et0)3P 4Ilis 02N

(134) 97

3-Methylcarbazole (132) was prepared by the standard literature route as shown.

NHNH2 -}-

HAc

Me o-chloranil .-

(132)

H.p.1,c. analysis of the authentic samples (compared to the pyrolysis mixture) shows a mixture of 2- and 3-methylcarbazole to be inseparable. This mixture does however, correspond with a second component of the pyrolysis mixture. Analysis of the n.m.r. spectra of the two authentic samples and the pyrolysis mixture shows clearly that there is no 2-inethylcarbazole in the mixture.

A 1-proton doublet at 67.06 in the n.m.r. spectrum of 2-methylcarbazole is not present in the n.m.r. spectrum of the mixture.

There is no resonance in that area of the spectrum of the

pyrolysis mixture. Thus, we are able to conclude that the most likely mechanism for rearrangement of 2-phenylbenzotriazole

to carbazole is by migration of the 2-phenyl group to the

1-position followed by loss of nitrogen in the Graebe-Ullmann mode of carbazole synthesis.

Given this result we considered the intermediate 1-(p-tolyl)-

benzotriazole (136) might be the third component of the pyrolysis.

H.p.l.c. analysis of an authentic sample prepared from the diphenylamine, compared with the pyrolysis mixture shows this is riot the case.

i) H2 ii) HNO2/H'

The third component of the pyrolysis is as yet unidentified. 99

Conclusion to Section 2.

The investigation of the carbazole synthesis shows the most likely mechanism for the rearrangement, to be migration of the

2-arylsubstituent to the 1-position of the benzotriazole, followed by the loss of nitrogen and ring closure. The optimum temperature requirements for rearrangement are significantly above the safe operating conditions of the flash vacuum pyrolysis apparatus. Thus, in our hands, the scope of this novel rearrangement is limited. 100

APPENDIX

Photochemistry of Tetrazoles.

1) Introduction

The products of photochemical decomposition of N-arylimidoyl-

nitrenes in which both ortho-positions are blocked by alkyl

substituents have been described.192 3aH-Benzimidazoles were

suggested as intermediates in these reactions, the products

being derived from these intermediates by way of sigmatropic

skeletal rearrangements, or at higher temperatures sigmatropic

alkyl shifts. In order to test this hypothesis further tetrazoles

with one ortho-substitutent that would migrate more easily than

alkyl were investigated. The preliminary investigation was

carried out on tetrazole (137) which when photolysed gave (138)

and (139) with other products.

Ph~N` e NAN N h'v >Ph -F ~ N>Ph CO2Me CO2Me (137) (138) (139)

The structure of benzimidazole (138) was confirmed by authentic

synthesis; 4-methyl-2-phenylbenzimidazole (139) was shown to derive from (138) on chromatographic work up. 101

Formation of (138) and hence (139) requires the nitrene

to cyclise at the carbon bearing the methoxycarbonyl group;

alkoxycarbonyl groups are known to undergo sigmatropic shifts 193,194 very readily. It has been noted, previously that alkoxy-

carbonyl groups and other groups which migrate easily tend to move to an adjacent nitrogen rather than an adjacent carbon atom. Surprisingly, no products were detected which could have

come from closure of the nitrene on to the methyl bearing carbon

atom.

2) Investigation of Mono ortho-Substituted Tetrazoles.

The above results encouraged us to investigate the

analogous photolysis of tetrazoles (140), (141) and naturally

(87b).

Ph~N Phl---N NN iN N N NN/N NO2 CO2Me '

(87b) (140)

It was hoped that the tendency of the nitrene to close

on to the carbon bearing a single electron withdrawing substituent

102

would still be maintained in competition with closure at the unblocked position. This apparent directing effect had previously been noted in the thermolysis of the oxadiazolone

(99) and the oxadiazolthione (100), (as discussed in Section 1),

N NO2Ph~-N N07 Phr NNC,O NNC O ' II 0 SI (99) (100)

from which 2-phenylbenzimidazole was obtained in yields of 4% and

13% respectively.

a) Photolysis of Tetrazoles.

The tetrazoles had previously been prepared as described in the literature.195 Photolysis of tetrazole (87b) gave only one product, derived from closure of the imidoyl nitrene to the vacant ortho-position followed by rearrangement of the 3aH-benzimidazole.

Phr=_—N h N N Ph N\N/ NO2

(87b) 103

Photolysis of the amide substituted tetrazole (141) gave a good yield of product derived from closure to the vacant ortho- position with only a very small amount of 2-phenylbenzimidazole.

N hv Ph + \ Ph N H 1.10/0

However, photolysis of the tetrazole ester (140) gave products

derived from closure to both the vacant and blocked ortho-positions without any apparent selectivity.

CO Me N N N \ Ph (140) h" \) Ph Ph -f- N H N

41% 29% CO2Me 10%

Photolysis of an ortho-cyano substituted tetrazole had

previously been shown to give exclusively the product derived 195 from closure to the vacant ortho-position. 104

This selection of ortho-substituents enables us to see whether there is any through space interaction, which would enhance the directing effect in the nitro, amide and ester tetrazoles, or whether a conjugated electron withdrawing species alone is directing towards the blocked position.

The results show that the directing effect in the photochemical decomposition of tetrazoles is peculiar to the ortho-ester derivative (139). Neither the electron withdrawing capacity of the substituent nor its potential for 'through space' interaction satisfactorily accounts for these results.

3) Conclusion

The results are consistent with the basic hypothesis that

N-arylbenzimidoyl nitrenes cyclise to 3aH-benzimidazole intermediates which subsequently rearrange by way of sigmatropic shifts. The unexpected directing effect of the methoxycarbonyl group lacks a convincing explanation at present. Cyclisations onto a substituted position when vacant positions are available is certainly very rare; one example involving thermal cyclisations of a stable side-chain onto a benzene ring, is provided by the Claisen rearrangement of an allyl phenyl ether where closure occurs at an acetylated as well as an unsubstituted position. EXPERIMENTAL 105

INSTRUMENTATION AND EXPERIMENTAL TECHNIQUES

1) Spectra

-1 Infrared spectra (ir) were recorded in the range 600-4000 cm using Perkin Elmer 257 and 298 spectrophotometers and calibrated against polystyrene. Spectra of solids were taken as Nujol mulls and liquids as thin films between sodium chloride plates unless otherwise stated. Abbreviations used are strong (s), weak (w) and broad (br).

Ultra-violet and visible spectra (uv) were recorded in the range 200-700 nm using a Pye Unicam SP 800 recording spectrophotometer and calibrated against holmium glass. Solvents used are indicated in the experimental data. Where no extinction coefficients are quoted the specta were of a qualitative nature only.

Proton nuclear magnetic resonance spectra (nmr) were recorded using Varian T60 (operating at 60 MHz), Perkin Elmer R32 (operating at 90 MHz) or Bruker WM 250 (operating at 250 MHz) instruments, with an internal tetramethylsilane reference. Signals are quoted as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), or broad (br). Solvents are indicated in the experimental data. 106

Low resolution mass spectra (ms) were recorded on

A.E.T. M S12 and VG Micromass 7070 B instruments. High resolution spectra were recorded on the VG Micromass 7070 B instrument.

All spectra were recorded at 70 eV using a direct insertion probe.

2) Melting Points.

Melting points (mp) and mixed melting points (mixed mp) were carried out on a Kofler Hot Stage apparatus and are uncorrected.

3) Solvents.

Petrol refers to petroleum ether, b.p., 40-60° unless

otherwise stated, and was distilled before use. Dichloromethane

was distilled prior to use. Acetonitrile and dimethylformamide

were dried by refluxing over calcium hydride, followed by

distillation directly into the reaction vessel. Hydrocarbon

solvents were dried by standing over sodium wire. Acetone,

chloroform, ethyl acetate, ethanol and methanol were used as

supplied commercially unless otherwise stated.

4•j Chromatography.

Column chromatography was carried out on Silica Gel H Art 7736

(Merck), under pump pressure. Thin layer chromatography (tic) was

used extensively as a qualitative analytical technique for following 107

the progress of reactions and assessing the purity of compounds; silica gel GF254 (Merck) was used.

Preparative layer chromatography was carried out on

20 x 20 cm or 20 x 40 cm glass plates coated with a layer of silica gel PF254 (Merck). Loading of material varied according

to the efficiency of the separation. All plates were observed under ultra violet light (254 nm). This technique was eventually

discontinued in favour of the low pressure column chromatography method.

High pressure liquid chromatography (hplc) was performed using an Altex 110A pump, an ODS reverse phase column and a

Cecil CE2012 ultra violet detector. Samples were injected as methanol solutions and were eluted with methanol-water mixtures as indicated.

5) Photolysis.

Photochemical reactions were carried out using a Rayonet

photochemical reactor with lamps of 253.7, 300 or 350 nm wavelength.

The solvent used was dry acetonitrile unless otherwise stated.

6) Vapour Phase Pyrolysis. 197 This technique has been fully described elsewhere. The apparatus consists of a quartz tube with a carbon dioxide condenser

and a connection to a vacuum pump fitted at one end. A 50 ml 108

round bottom flask containing the sample is attached to the bottom end of the quartz tube and is heated in an oil bath or Kugelrohr oven. The sample in the flask is then heated under vacuum until it vapourises, the vapour passing through the pre-heated quartz tube, the temperature of which can be varied up to 900°C, and the products condense on the cold. head . The pyrolysate is then worked up in a conventional manner. 109

SECTION 1

A) THE PREPARATION OF. SYNTHETIC INTERMEDIATES.

1. Amines. 198 1-Amino-8-nitronaphthalene and 2-amino-21 -nitro-

biphenyl199 were prepared by the literature procedures.

Other anilines were used as suppled commercially.

2. Amides. 200 Amides were prepared by standard methods, and were known

compounds. The following amides were prepared. 201 Benzanilide, m.p., 164-5°C (lit., 163°C) 201 2-Nitrobenzanilide, m.p., 152-4°C (lit., 155°C) 202 2'-Nitrobenzanilide, m.p., 94-5°C (lit., 96-7°C) 204 4-Nitrobenzanilide, m.p., 214°C (lit. , 216°C) 201 4'-Nitrobenzanilide, m.p., 214°C (lit., 199°C) 203 21 ,4'-Dinitrobenzanilide, m.p., 199°C (lit., 201-2°C) 204 21 ,4-Dinitrobenzanilide, m.p., 223°C (lit., 223°C) ,205 4,4'-Dinitrobenzanilide, m.p., 272-3°C (lit. 268-9°C) 214 4-Chloro-2'-nitrobenzanilide, m.p., 160.5-162°C (lit., 155-6°C) ,206 4-Chloro-4'-nitrobenzanilide, m.p., 220-1°C (lit. 222-3°C) 207 4-Chlorobenzanilide, m.p., 206-7°C (lit., 195-6°C) 208 2'-Nitroacetanilide, m.p., 93-4°C (lit., 93°C)

Ethyl oxanilate, m.p., 65-7°C (lit.,209 66-7°C) ,201 Ethyl 2'-Nitrooxanilate, m.p., 113°C (lit. 113°C) 110

2,6-Dinitroaniline failed to give the corresponding benzanilide under standard conditions. The use of catalytic amounts or equimolar amounts of 4-N,N-dimethylaminopyridine at room temperature for several days or under reflux in pyridine, failed to generate the required amide; the starting amine was recovered in > 90% yield from these reactions.

3. N-Arylimidoyl Chlorides.

These were prepared from the corresponding amide by stirring a solution of the amide in toluene with a slight excess (10%) of phosphorus pentachloride, at room temperature. When the reaction did not go to completion, as indicated by residual carbonyl absorption in the it spectrum, the solutions were refluxed for 1 h, The imidoyl chlorides were used without further purification with the exception of N-(2,4-dinitrophenyl)benzimidoyl 153 chloride, m.p., 118-20°C (lit., 117.5-120.5°C).

This procedure failed to give the corresponding imidoyl chloride from ethyl 2V-nitrooxanilate. Refluxing a solution of ethyl oxanilate in dry benzene for 2 h failed to form any imidoyl chloride, Reaction of ethyl oxanilate and phosphorus pentachloride in the melt, at 130°C, for 24 h produced a yellow oil with an intense absorption at 2260 cm-1 suggesting the formation of phenyl isonitrile.

The characteristic isonitrle odour was apparent. Melt thermolysis at 160°C under partial aspirator pressure for 30 min produced an 111

-1 oil with a band at 1780 cm in the it spectrum. Ethyl oxanilate, in dry benzene with a slight excess (10%) of phosphorus pentachloride was refluxed for 3 days. The reaction was cooled, quenched with water and the organic phase separated.

The benzene solution was dried over sodium sulphate and the solvent removed at the pump. At this stage the isonitrile odour was apparent. Tlc analysis (CHC€3) of the residue shows the recovered material to be starting material. Thus, any decomposition occurring is a very minor reaction, since work up of the reaction gave ethyl oxanilate (90%), m.p.,

65-7°C (lit.,209 66-7°C) .

B) THE PREPARATION OF TETRAZOLES.

The tetrazoles were made according to the method of 151 Kadaba, as outlined below.

The appropriate N-arylimidoyl chloride (0.012 mol) in dry dimethylformamide (15 ml) was added dropwise over a period of 45 min to an excess of finely ground sodium azide'(0.024 mol) in dry dimethylformamide (15 ml) with vigorous stirring. The reaction temperature was kept below 25°C during the addition by means of a cold water bath. When the addition was complete, the suspension was stirred for a further 45 min. Water, sufficient to dissolve any residual inorganic salts and then to cause turbidity (1-10 ml) was then added and the solution placed in the cold room (5°C) for 1-4 days. The crystals thus produced were filtered, washed with water and crystallised from ethanol. 112

The following tetrazoles were thus prepared. 151 1,5-Diphenyltetrazole (87a), m.p., 145 -6°C (lit., 145-6°C) 1-(2-Nitrophenyl)-5-phenyltetrazole (87b), m.p., 167-9°C (lit.,151 168-9°C) 1-(4-Nitrophenyl)-5-phenyltetrazole (87c), m.p., 153.5-155°C (lit.,151 155-7°C) 151 5-(4-Nitrophenyl)-1-phenyltetrazole (87d) m.p., 181-3°C (lit., 182-3°C) 151 5-(2-Nitrophenyl)-1-phenyltetrazole (87e), m.p., 175-7°C (lit., 179-81°C)

5-(4-Chlorophenyl)-1-phenyltetrazole (87f),m.p., 155-7°C (lit.,2 155.5°C) 5-(4-Chlorophenyl-1-(4-nitropheny])tetrazole (87i), m.p., 187-8°C, (lit.,210 188-9°C) 211 1,5-Di(4-nitrophenyl)tetrazole (87j) m.p., 264°C (dec) (lit., 262°C)

5-Methyl-1-(2-nitrophenyl)tetrazole, (89c) m.p., 113-116°C (lit.,212 116.5-7°C)

5-(4-Chlorophenyl)-1-(2-nitrophenyl)tetrazole, (87 g), (58%), m.p., 163-4°C (ethanol)(Found: C, 51.79; H, 2.64; N, 23.23. C13H8N5Ci02 requires C, 51.75; H, 2.67; N, 23.21%); vmax 1600,

1520, 1340 (s), 1090, 850, 820, 780 and 730 (s); Amax (CHC13) 249 nm (20 326); S(CDC(3) 7.26-7.64 (5 H, m), 7.75-7.95 (2 H, m), 8,19-8.35 (1 H, m); m/e 301 M+ 273 153 (base), 139, 125.

1-(2-Nitropheny1) -5-(4--nitrophenyl) tetrazole, (87h) , (46%) , m.p., 210-212°C (ethanol) (Found: C, 50.12; H, 2.60; N, 26.89.

C13H8N604 requires C, 50.00; H, 2.58; N, 26.92%); vmax 1610, 1540 (s), (CHCl3) 267 nm (24960); 1520 (s), 1345 (s), and 860 cm 1; Amax S(DMSO-d5) 8.12 (4 H, br, m) 8.17 (4 H, q); m/e 313 (M+ + 1), 284, 240, 164, 150, 134, 120, 90 (base). 113

The 5-chloro and 5-H-1-(2-nitrophenyl)tetrazoles were 154 prepared by the method of Kauer et al. 154 1-(2-Nitropheny])tetrazole (89a), m.p., 84-5°C (lit., 85-6°C) 154 5-Chloro-1-(2-nitrophenyl)tetrazole, (89b), m.p., 85-7°C (lit., 88.8-9.6°C).

152 The method of Bianchetti, et al., was used for the preparation of 1-(2,4-dinitrophenyl)-5-phenyltetrazole. In this procedure the solvent is acetone-water (1:1). 1-(2,4-Dinitrophenyl)-5-phenyltetrazole (87k), m.p., 183°C (dec) (lit.,152 183°C).

Attempted preparation of (87k) using the method of Kadaba as outlined above gave after work up a low melting solid, m.p., 30-5°C, with an intense band at 2120 cm-1-in the it spectrum. The mass spectrum gave M+ 181. The solid was very unstable and difficult to purify. The structure was postulated as 2,4-dinitrophenylazide.

2,4-Dinitrophenylazide, as formed above, (0.53 g) was dissolved in dry benzene (15 m1) and refluxed for 2 h. The solvent was removed and the solid produced crystallised from acetic acid giving 6-nitro- 213 benzofuroxan (88) (0.4 g, 51%), m.p., 67-9°C (lit., 68-9°C).

The Kadaba procedure also failed to produce ethyl 1-phenyltetrazole-5-carboxylate. This tetrazole had previously been 155 prepared by Lozinskii, et al., but we were unable to repeat this reaction. 114

Attempted Preparation of Ethyl 1-Phenyltetrazole-5-Carboxylate .

Ethyl oxanilate (3.0 g, 0.016 mol) was dissolved in dry toluene, to which was added phosphorus pentachloride (4.2 g, 0.02 mol).

The solution was refluxed overnight (17 h). Removal of the solvent gave an oil, which was dissolved in dry dimethylformamide (5 ml) and added to a suspension of finely ground sodium azide (3.94 g, 0.06 mol) in dry dimethylformamide (15 ml) during 30 min. The mixture was stirred for a further 45 min. Sufficient water was added to

produce a clear solution, from which an oil separated. The solution was placed in the cold room (5°C) for 5 days, but failed to crystallise.

The oil was purified by column chromatography, from which a major

component was isolated. On the basis of the following spectral

evidence the structure was postulated as ethyl 2-azido-2-hydroxyanilino-

3400, 3340 (NH and OH), 2130 (N3), 1700 3-carboxylate (91),(25%). vmax (s'), 1600, 1530, 1440, 1235, 1050, 755 and 690 cm-1; d(CDCe3) 1.26

(3 H, t), 3.84 (2 H, q), 4.20 (1 H, s), 7.05-7.75 (5 H, m), 8.30-8.60

(1 H, br s); m/e 182 (M-44), 167, 133, 105, 104, 91 (base).

Ethyl oxanilate (2 g, 0.01 mol) and phosphorus pentachloride

(2,37 g, 0.11 mol) were refluxed in dry benzene (30 ml) overnight.,

The solvent was removed and the residual oil dissolved in acetone

(5 ml). The acetone solution was added dropwise to a suspension of

finely ground sodium azide (2,23 g, 0.034 mol) at 0-5°C and the

mixture stirred at 0-50C for a further 6 h. The reaction was

quenched with sufficient water to form a clear solution and was 115

worked up as above. The isolated'.oil was not distinguishable from the product previously isolated, by tic or comparison of it spectra.

C) THERMOLYSIS OF TETRAZOLES

1. Solution Thermolysis: General Procedure.

To a 25 ml round bottom flask was added the solid tetrazole.

To the flask was then added freshly distilled solvent (1 ml/ 50 mg

tetrazole). The solvents used were bromobenzene (BB), b.p., 165°C,

1,2-dichlorobenzene (DCB), b,p., 185°C, and 1,2,4-trichlorobenzene

(TCB), b,p., 215°C. The flask was fitted with an air condenser

and the apparatus flushed out with dry nitrogen. A nitrogen supply,

as a nitrogen balloon or bubbler, was fitted to the top of the

air condenser. The flask was placed in a Wood's metal bath,

preheated to between 20-30°C above the boiling point of the solvent.

The solutions rapidly attained reflux temperature, and were then

monitored by tic until all starting material had been consumed

or until a period of at least 24 h had elapsed without any

indication of reaction occurring. The flask was allowed to cool

and the solvent removed by short path distillation. The products

were purified by column chromatography and crystallisation.

Unstable carbodiimides were hydrolysed by refluxing in dioxan-30%

aqueous hydrochloric acid for 1 h. 116

The following tetrazoles were thermolysed.

1. 1-(2-Nitrophenyl)-5--phenyltetrazole (87b).

The tetrazole (87b) (140 mg, BB, 20 h) gave 2-phenylbenzotriazole, 215 (81 mg, 80%), m.p., 108-9°C, mixed m.p., 108.5-110.5°C (lit.,

104-6°C); (87b), (152 mg, DCB, 0.5 h) gave 2-phenylbenzotriazole

(101 mg, 91%); (87b) (200 mg, TCB, 0.5 h) gave 2-phenylbenzotriazole

(134 mg, 92%) .

2. 1-(2,4-Dinitrophenyl)tetrazole (87k).

The tetrazole (87k) (112 mg, BB, 0.75 h) gave 5-nitro-2-phenyl- ,216 benzotriazole(51 mg, 60%) m.p., 175-7°C (lit. 176.6-7°C).

3. 5-(2-Nitrophenyl)-1-phenyltetrazole, (87e). Thermolysis of (87e) (500 mg, BB, 24 h) followed by tic analysis

of the reaction mixture showed only a faint trace of a fluorescent blue

spot, corresponding to 2-phenylbenzotriazole. The major component

corresponded to starting material. The tetrazole (87e) (200 mg,

DCB, 24 h) gave 2-phenylbenzotriazole (7.5 mg, 5%) and the

tetrazole (87e) (161 mg, 817); (87e) (500 mg, TCB, 9 h) gave

2-phenylbenzotriazole (272 mg, 75%).

4, 5-(4-Chlorophenyl)-1-(2-nitrophenyl)tetrazole (87g).

The tetrazole (87g) (500 mg, BB, 24 h) gave 2-(4-chlorophenyl)- 215 benzotriazole (95), (213 mg, 56%) m.p., 169-70°C (lit., 170-71°C).

The tetrazole (87g) (35 mg, 7%) was recovered. Tetrazole (87g)

(200 mg, DCB, 4 h) gave 2-(4-chlorophenyl)benzotriazole, (124 mg, 82%);

(87g) (500 mg, TCB, 2.5 h) gave 2-(4-chlorophenyl)benzotriazole,

(320 mg, 84%). 117

5. 1-(2-Nitrophenyl)-2-(4-nitrophenyl)tetrazole (87h).

The tetrazole (87h), (100 mg, BB, 24 h), gave a pale yellow

solution. Tic of this solution showed one component which corresponded

to starting tetrazole (87h). The tetrazole (87h)(200 mg, DCB, 5.5 h)

gave 4-nitro-2-(4-nitrophenyl)benzomidazole (97) (121 mg, 66%) m.p., 284-5°C, and 2-(4-nitrophenyl)benzotriazole (96), ,218 (20 mg, 13%), m.p., 284°C (lit. 282°C); (87h) (200 mg, TCB, 5 min)

gave a yellow solution from which crystallised a pale yellow solid.

The product was filtered and crystallised (ethanol-dimethylformamide)

producing 2-(4-nitrophenyl)benzotriazole, (110 mg, 72%).

6. 2-(5-Phenyltetrazol-1-yl)benzonitrile, (92).

The tetrazole (92) (50 mg, TCB, 0.5 h) gave a solution which

showed one component on tic. The ir spectrum showed an intense -1 band at 2140 cm indicating the product to be 2-(1-phenylcarbodiimid-

3-yl)benzonitrile. The solvent was removed and the remaining oil

was placed in a Wood's metal bath at 268°C. The yellow oil rapidly

darkened. After 20 min at 268°C tic and ir show no change; the

carbodiimide was still present.

6a. Control Thermolysis.

1,5-Diphenyltetrazole(87a) was thermolysed (TCB, 40 min). Tic

showed one major component corresponding to tetrazole (87a).

There was a trace of high Rf material. 118

7. 5-(4-Chlorophenyl)-1-phenyltetrazole, (87f).

The tetrazole (87f) (500 mg, BB, 24 h) did not react. Starting material (87f) (490 mg, 98%) was recovered; (87f) (200 mg, DCB, 24 h) gave a mixture of three components. Tlc.showed the mixture was mainly tetrazole (87f). After hydrolysis in hydrochloric acid= dioxan, the solution was neutralised, extracted into ethyl acetate, dried (MgSO4) and the solvent removed producing a solid. The solid was identified as tetrazole (87f) (154 mg, 77%). No other products were isolated. (87f) (300 mg, TCB, 48 h) gave an oil, -1 a single component on tic, it 2120 cm , 1-(4-chlorophenyl)-3- phenylcarbodiimide (87 mg, 33%), a colourless solid 2-(4-chlorophenyl)benzimidazole (39 mg, 15%), m.p., 292°C (lit.,219 296°C) and a colourless solid, 77 mg. Tlc showed the solid to be one component but a sharp melting point could not be obtained. Ir showed bands at 3380 (NH) and 1650 cm-1 (s, > C=0) suggesting a urea. However, the mass spectrum showed m/e 280 (M+) with a chlorine isotope pattern for two chlorine atoms (10:6:1: at M, M + 2, M + 4).

M-16 gave m/e 262 with the same chlorine isotope pattern.

Superimposed on this spectrum was m/e 246, with an isotope pattern for one chlorine atom (3:1 at M, M + 2) with M-16 giving m/e

228 with the same one chlorine isotope pattern. The molecular weight of the symmetrical 1,3-di(4-chlorophenyl)urea is 280. The unsymmetrical 1-(4-chlorophenyl)-3-phenylurea has a molecular weight of 246, Thus, the third component is a disproportionated mixture of the above ureas.1 119

8. 5-(4-Nitrophenyl)-l-phenyltetrazole (87d).

The tetrazole (87d) (300 mg, BB, 24 h) gave unreacted starting material, identified by tic and ir (87d) (300 mg, DCB, 24 h) gave unreacted starting material (218 mg, 73%) and no other products were isolated ; (87d) (300 mg, TCB, 48 h) produced an orange solution from which crystallised an orange solid. The solid was washed with methylene chloride and dried giving (i) 2-(4-nitrophenyl)benzimidazole, 220 (90 mg, 34%), m.p., 325°C (lit., 329°C),(ii) an oil, one component by tic, identified by ir (2130 cm 1) as l-(4-nitropheny1)-3-phenylcarbodiimide with a trace of solvent (253 mg, 9%) and (iii) a solid which could not be crystallised to a constant, sharp melting point. Mass spectral evidence suggests the product is a mixture of 1-(4-nitrophenyl)-3-phenylurea mle 257, which loses water to give m/e 239, and the disproportionated 1,3-di(4-nitrophenyl)- carbodiimide.) The total yield was 58 mg representing ca. 20% product derived from migration of the 5-(4-nitrophenyl)-group in the first -1 formed imidoyl.nitrene. Ir showed bands at 3280 (NH) and 1635 cm

(>C=0). There was a small band at 2120 cm-1.

9. 1-(4-Nitrophenyl)-5-phenyltetrazole (87c).

The tetrazole (87c) (353 mg, DCB, 24 h) gave a clear solution from which on cooling was deposited a grey solid. The solvent was removed and the residue triturated under diethyl ether. The solid was removed by filtration and the residue chromatographed to produce a further yield of the same solid (tic), 1-(4-nitrophenyl)-3-phenyl- 120

221 carbodiimide (110 mg, 35%) m.p., 240°C (sub) (lit., 238°C).

Two Unidentified minor components (7 mg) were eluted from the column.

10. 5-(4-Chlorophenyl)-1-(4-nitrophenyl)tetrazole (87i).

The tetrazole (87i) (300 mg, BB, 24 h) gave, after hydrolysis and column chromatography of the product (i) tetrazole (87i)

(178 mg, 59%) (ii) a solid, the it spectrum of which suggested a urea or mixture of ureas with bands at 3380 (NH), 3340 (NH),

1725 (>C=0) and 1740 cm l (>C=0). The mass spectrum clearly indicated a disproportionated mixture' of 1-(4-chloropheny1)-3-

(4-nitropheny1)urea, m/e 291 with a single chlorine isotope pattern

(3:1 at M, M + 2) and 1,3-di(4-chloropheny1)urea, m/e 281, with a two chlorine isotope pattern (10:6:1 at M, M + 2, M + 4). The yield was 93 mg (ca. 33%) of carbodiimide derived products. The tetrazole

(87i) (300 mg, DCB, 22 h) gave, after hydrolysis of the product

1-(4-chlorophenyl)-3-(4-nitrophenyl)urea (220 mg, 76%), m.p., 295-305°C

(ethanol) (lit.,222 250°C); vm 3380, 3340, 1735, 1630, 1600, 1540, -1 1335, 1300, 1180 and 1110 cm ; m/e 291 (M+) 273, 164, 153, 138 (base)

127 and 108. The tetrazole (87i) (300 mg, TCB, 7 h) after hydrolysis of the thermolysis product gave 1-(4-chlorophenyl)-3-(4-nitrophenyl)- urea (266 mg, 92%), m.p., 305°C, m/e 291 (M+). 121

11. 1-(2-Nitrophenyl)tetrazole, (89a).

The tetrazole (89a) (50 mg, BB, 19 h) gave 2-nitrophenyl- 201 cyanamide (5.3 mg, 12.5%) m.p., 148-50°C (lit., 150-2°C). The remainder of the thermolysis product was an extremely complex, multicomponent mixture as analysed by tic.

11a. Control Thermolysis.

2-Nitrophenylcyanamide (30 mg) was refluxed in bromobenzene for 24 h. Tlc showed one component corresponding to a sample of 2-nitrophenylcyanamide. There were no other products.

12, 5-Chloro-1-(2-nitrophenyl)tetrazole (89b).

The tetrazole (89b) (50 mg, TCB) was placed in a pre-heated

Wood's metal bath. A rapid and steady evolution of gas was noted

during which time the solution became deep red. Ir of the reaction

solution after 10 min at 215°C showed a band at 2240 cm 1. After

heating at 215°C for 1 h the solution was still red;., the band at

2240 cm-1 in the it spectrum was no longer present. Tlc showed a

dark base line only.

13. 5-Methyl-1-(2-nitrophenyl)tetrazole (89c).

The tetrazole (89c) (160 mg, BB, 24 h) gave after plc, four

components, one of which was starting material (89c) (20 mg, 12.5%).

The remaining three components totalling 50 mg of material were all

impure. A second component (17 mg) was replated from which was recovered

3 mg of material. Replating a third component (12 mg) gave < 1 mg of

material. The remainder of the reaction product was on the baseline. 122

D) IDENTIFICATION OF THE VOLATILE COMPONENTS FROM THE THERMOLYSIS

OF 1-(2-NITROPHENYL)-5-PHENYLTETRAZOLE (87b).

1. Carbon Dioxide.

The tetrazole (87b, 509 mg) was finely ground and mixed with acid-washed sand (5 g). The mixture was placed in a 25 ml round bottom flask to which was added a wide bore gas outlet, the open end of which was placed in a lime water solution. The diluted tetrazole mixture was heated in a Wood's metal bath at 210°C. A slow rate of bubbling was noted;' the tetrazole melted with an increase in gas evolution. A copious precipitate was formed, by the evolved gases, in the lime water solution. Under identical conditions a flask containing acid washed sand (5 g) was heated. A few bubbles of gas were expelled from the flask into the lime water solution; no precipitate was formed. Tlc of the thermolysis residue showed

2-phenylbenzotriazole as the major component.

2a, Carbon Dioxide, Carbon Monoxide.

The tetrazole (87b, 200 mg) was placed in a thermolysis vessel attached to a vacuum line. The system was evacuated and filled with argon. The vessel was placed in a Wood's metal bath and heated at 210°C. The solid melted and gas was slowly evolved. The evolved gases were transferred to a gas cell which was then attached directly to a mass spectrometer. The spectrometer background has peaks at m/e 28.00615 (N2), 28.0313 (C2H4), 43.9898 (CO2), 44.0011 (N20) 123 -

and 44.0626 (C3H8). There was no background peak at 27.9949 (CO).

Analysis of the gas sample showed an increase in the peaks for

N2, CO2 and argon. There was no peak at 27.9949 (CO).

2b. Carbon Monoxide.157

The tetrazole (87b, 200 mg) was ground with acid-washed sand

(5 g) and placed in a vacuum bottle. From inside the neck of the bottle

was suspended an indicator strip impregnated with aqueous palladous

chloride solution. The system was evacuated and filled with argon.

The flask was heated at 210°C'_in a Wood's metal bath. The sample

melted, gases were evolved but caused no colour changetin the indicator strip, confirming the absence of carbon monoxide.

PdC.C2 + CO + H2O Pd + 2HC( + CO2

The thermolysis product was chromatographed producing

2rphenylbenzotriazole (27Z).

The palladous chloride test strip was exposed to carbon monoxide,

generated:'_by heating oxalic acid, and immediately became black.

3. Phenyl Isocyanate.

The tetrazole (87b, 517 mg) was mixed with acid-washed sand

(30 g) and place in a round bottom flask to which was attached a

1171 tube. The system was maintained under partial aspirator pressure,

with the 111' tube immersed in liquid nitrogen. The diluted tetrazole

was thermolysed at 240°C for 10 min. The 'U' tube was removed from

P hr= N Ph --N NO N07 11 NO2 N NN VO NNC ,O 5,0 I I 0 s 0

(99) (100) (101) 124

the cold trap and the liquid collected was allowed to evaporate.

A colourless oil remained in the entrance of the 'U' tube, which had a pungent odour. The it spectrum showed an intense peak at 2260 cm-1.

In a separate experiment tetrazole (87b, 628 mg) was refluxed in bromobenzene (10 ml) for 20 h. The solvent was removed and the residue treated with pyridine (1 drop) and aniline (2 ml). The mixture was heated on a water bath (80°C) for 1 h. Removal of the solvent and addition of benzene produced a precipitate from which was crystallised 1,3-diphenylurea (19.6 mg, 4%), m.p., 235-7°C 221 (ethanol) (lit., 2380C).

E)* THE PREPARATION OF ALTERNATIVE HETEROCYCLIC PRECURSORS.

1, The alternative heterocyclic precursors (99), (100), and (101), were prepared from N-(2-nitrophenyl)benzamidoxime m.p., 185°C 223 (lit., 184-5°C). Reaction of the benzamidoxime with ethyl chloroformate 10 by the procedure of Bacchetti, et al., gave 4-(2-nitrophenyl)-3- phenyl-1,2,4-oxadiazol-5-one (99), m.p., 126°C (lit. 10 125°C) .

2. 3-(2-Nitropheny1)-4-phenyl-1,2,3,5-oxathiadiazol-2-one (101), (67%).

To a solution of N-(2-nitrophenyl)benzamidoxime (1 g, 0.004 mol), in dry benzene (200 ml) was added thionyl chloride (0.46 g,

0,0.0.4 mol), The mixture was stirred at room temperature for 1 h, filtered and the solvent removed without heating. The pale yellow solid was crystallised from ethanol, m.p., 102-3°C (benzene-hexane).

Denotes experiment performed by Dr. P.G. Houghton. 125

(Found: C, 51.22; H, 2.85; N, 13.74. C13119N304S requires

C, 51.48; H, 2.99; N, 13.85). v 1530, 1350, 1205, 845, 770 and max 695 cm (CHC?3) 242 (10468); S 7.33-8.06 (br, m, 9 H); 1; Amax m/e 303 (M+), 239 (base) 195, 119.

3. 4-(2-Nitrophenyl)-3-phenyl-1,2,4-oxadiazol-5-thione, (100), (77%).

To a solution of N-(2-nitrophenyl)benzamidoxime (1.07 g,

0.004 mol) in dry benzene (300 ml) at room temperature was added thiophosgene (0.46 g, 0.004 mol). A few drops of triethylamine were added and the mixture stirred at room temperature for 1.5 h.

The solvent was evaporated and the orange solid purified . by column

chromatography. The pale yellow solid was crystallised from aqueous

ethanol, m.p., 126-8°C (Found: C, 56.11; H, 2.97; N, 13.93;

C14H9N305 requires C, 56.18; H, 3.03; N, 14.04); \max 1610, 1530,

1350, 1265, 1170, 850, 785 and 690 cm-1; Amax (CHCt3) 222 (11976), 248 (23053), 285.5 (23952) nm; S 7.1-8.35 (m, 9 H); m/e 299 (M+),

242, 225, 149,105 (base).

F)* THERMOLYSIS OF COMPOUNDS (99), (100), and (101).

Solution thermolyses were performed as previously described

in the general procedure for tetrazole thermolysis. Melt thermolyses

were performed by placing the solid sample in a 25 ml round bottom

flask to which was attached an it condenser and nitrogen supply.

The flask was placed in a preheated Wood's metal bath at 255-60°C.

After heating for 1 h the flask was removed and the products worked

up by column or layer chromatography. 126

1.* 4-(2-Nitrophenyl)-3-phenyl-1,2,4-oxadiazol-5-one (99).

A solution of the oxadiazole (99) (245 mg, diphenylether, 24 h)

gave after plc (CHC(3-EtOAc 9:1/Si02) (i) 2-phenylbenzotriazole

(19 mg, 11%), (ii) 4 -nitro-2 -phenylbenzimidazole (103), (70 mg, 34%)

m.p., 192-4°C (lit.,10 194-6°C) (iii) starting material (99), (44 mg,

18%) and (iv) 2-phenylbenzimidazole (104) (5 mg, 3%) identified

by comparison with an authentic sample by tic.

Melt thermolysis of the oxadiazole (99) (200 mg, 1 h) gave

(i)2-phenylbenzotriazole (13 mg, 9%) (ii) starting material

(38 mg, 19%), (iii) 4-nitro-2-phenylbenzimidazole (62 mg, 37%)

and (iv) 2-phenylbenzimidazole (6 mg, 4%).

2. 4-(2-Nitropheny1)-3-phenyl-1,2,4-oxadiazol-5-thione (100).

The oxadiazole (100) (190 mg, diphenylether, 6 h) gave after

plc (CHCt3-EtOAc 9:1) (i) 2-phenylbenzotriazole (5 mg, 4%),

(ii)starting material (25 mg, 13%), (iii) 4-nitro -2-phenylbenzimidazole

(38 mg, 25%) and (iv) 2-phenylbenzimidazole (16 mg, 13%). Melt

thermolysis of the oxadiazole-5-thione (100) (193 mg, 260°C, 4 h)

gave 2-phenylbenzotriazole (11 mg, 9%), 4-nitro-2-phenylbenzimidazole

(10 mg, 7%) and 2-phenylbenzimidazole (5 mg, 4%).

3 3! -(2-Nitropheny1)-4-pheny1-1,2,3,5-oxathiadiazol-2-one (101).

Solution thermolysis of the oxathiadiazol-2-one (101), (200 mg,

BB, 1'h) gave 2-phenylbenzotriazole (113 mg, 88%). Melt thermolysis

at 135-40°C for 1 h gave after plc (CHCl3-EtOAc, 9:1/Si02) 2-phenyl-

benzotriazole (103 mg, 64%).

Denotes experiment performed by Dr. P.G. Houghton. 127

4. Control Thermolysis

4-Nitro-2-phenylbenzimidazole(103) (50 mg) was thermolysed

in the melt overnight. Tlc of the melt reaction showed one

component, corresponding to starting material (103).

G) THE PREAPARATION OF THIOUREAS

General Procedure.

To a vigorously stirred solution of the appropriate 2-nitro- 166 phenylisothiocyanate (0.01 mol) in dry benzene (10 ml) was

added a solution of freshly distilled (or crystallised) amine

(0.01 mol) in dry benzene (5 ml). The solution was stirred at

room temperature for 5 min. If a solid was not produced during

that time the solution was warmed on a water bath (80°C) for 10 min.

On cooling a copious precipitate was formed. The mixture was

stirred for a further 30 min, filtered and the solid crystallised.

The thioureas prepared by the above procedure were all new

compounds except 1-(2-nitrophenyl)-3-phenylthiourea (105a), m.p., ,224 142-40C (lit. 142°C), 1-(2-nitrophenyl)-3-(4-nitrophenyllthiourea 166 (105f) m.p., 145-8°C (lit., 153°C) and 1-(4-methylphenyl)-3-(2-nitro- ,166 207 phenyl)thiourea (105b) m.p., 207°C (lit. °C).

1-(2,6-Dimethylphenyl)-3-(2-nitrophenyl)thiourea, (105c) (84%).

m,p., 171-3°C (ethanol), (Found: C, 59.83; H, 5.02; N, 13.93; 3350, 3160, C13H15N302S requires C, 59.78; H, 5.02; N, 13.94; vmax 1610, 1550, 1520, 1460, 1265, 1210, 855, 780, 725, and 710 cm-1;

(EtOH) 208 (20463), 216 (2007) nm; 6 (acetone-d6) 2.37 (s, 6 H), Amax [7.16-7.61 (m, 7.67-8.08 (t), 8.08-8.35 (d), 8.37-9.02 (m) 7 H],

9.15-9.59 (br, s, NH, D20 exchangeable); m/e 300 (M+ - 1), 255 (base),

163, 138 and 130. 128

1-(2,4,6-Trimethylphenyl)-3-(2-nitrophenyl)thiourea (105d), (72%). m.p., 175-7°C, (Found; C, 60.84; H, 5.45; N, 13.32; C16H17N302S requires C, 60.93; H, 5.43; N, 13.32%); vmax 3340, 3130, 1615, (EtOH) 236 1535, 1350, 1270, 1230, 860, 790, and 750 cm-1, Xmax (18716), 308 (3785) nm; S (acetone-d6) 2.30 (s, 9 H), 6.80-8.16 (m, 5 H), 8.54-9.38 (m, 2 H); m/e 314 (M+ - 1), 269 (base), 177.

1-(4-Methoxyphenyl)-3-(2-nitrophenyl)thiourea, (105e),(92%). m.p., 165-7°C (ethanol), (Found: C, 55.42; H, 4.27; N, 13.83; v C141113N303S requires C, 55.43; H, 4.32; N, 13.85%); max 3180, 1610, 1590, 1520, 1455, 1350, 1250, 1170, 1030, 830, 785, and 745 cm1;

Xmax (EtOH) 205 (22608), 245 (20000), 262 (17174) nm; 6 (acetone-d5) 3.86 (s, 3 H), 7.26 (q, 4 H, J = 8.1 Hz), 7.76 (t, 2 H) 8.13 (d, 1 H),

8.50 (d, 1 H), 9.50-9.80 (br, s, 1 H); m/e 303 (M+), 285, 269, 257, 180, 165 (base), 150, 138, 108.

1-(4-Methoxy-2-nitrophenyl)-3-phenylthiourea, (105g), (62%). m.p„ 159-61°C (Found: C,56.19; H, 4.23 ; N, 14.26 ;.'C14H13N303S 3340, 3100, 1605, 1550, requires C, 55.43; H, 4.32; N, 13.85%); max 1535, 1380, 1370, 1230, 1040 and 860 cm-1; Amax (EtOH) 214 (18181), 250 (16969), 265 (17424) nm; 6 (acetone-d6) 3.90 (s, 3 H), 7.00-8.10

(m, 9 H), 9.03-9.67 (br, m, 2 H); m/e 303 (M+) 257, 168, 138, 135, 93 (base).

1-(t-Butyl)-3-(2-nitrophenyl)thiourea, (105h), (93%). m.p., 155-65°C (ethanol) (Found: C, 52.33; H, 6.03; N, 16.57;

C11H15N302S requires C, 52.15; H, 5.97; N, 16.59%); vmax 3280, 3220, 1610, 1565, 1510, 1470, 1350, 1270, 1190, 865, 780, and 720 cm-1; 129

X (EtOH) 205 (12791), 204 (20284) nm; S (acetone-d max 6) 1.58 (s, 9 H), 7.37 (t, 1 H), 7.73 (t, 1 H), 8.16 (t, 2 H), 9.30-9.47 (br, s, 1 H, D20 exchangeable); m/e 254 (M+ + 1), 219, 207, 189, 163, 151, 138, 133.

1-Benzyl-3-(2-nitrophenyl)thiourea, (105j), (72%). m.p., 119.5-121°C, (Found: C, 58.73; H, 4.55; N, 14.65;'C14H1sN302S requires C, 58.52; H, 4.56; N, 14.62%); vmax 3240, 3180, 1610, 1595, 1510, 1480, 1460, 1350, 975, 780, 740, and 700 cm l; A (EtOH) ax 204.5 (15171), 239.5 (16 313)nm; S (acetone-d6) 4.96 (s, 2 H), [7.42 (br, m), 7.73 (t), 8.13 (d), 8.48-8.70 (br, m), 9.52-9.80 (br, m), (11 H)]; m/e 287 (M+), 241, 220, 180, 164, 106, 91 (base).

1-(2-Nitrophenyl)-3-(2-pyridyl)thiourea, (105k), (75%). 0 m.p., 191-2 C, (Found: C, 52.67; H, 3.71; N, 20.08; C1211104025 requires C, 52.54; H, 3.68; N, 20.43%); 3240, 1610, 1550, 1520, vmax 1485, -1 1350, 1325, 1260, 1190, 1155 and 775 cm (EtOH) 255.5 (22 222), ; Xmax 299 (16 186) nm; S (acetone-d6) 7.14-7.86 (m, 9 H); m/e 274 (M+) 242, 228, 196, 168, 136, 120, 78 (base).

1-(4-Methoxy-2-nitrophenyl)-3-(2-pyridyl)thiourea (105?), (29%) zn.p., 199-201°C, (Found: C, 51.10; H, 3.92; N, 18.26;'C13H12N403S requires C, 51.31; H, 3.98; N, 18.41%); vmax 3250, 1610, 1590, 1530, 1385, 1325, 1280, 1240, 1190, 1155, 1030 and 780 cm -1, Xmax (Et0H) 209 (12 633), 259 (18873), 295.5 (14612) nm; S (acetone-d6) 3.89 (s, 3 H), 7.04-8.70 (m, 9 H); m/e 304 (M+) 258, 226, 168, 136, 120, 78 (base). 130

Attempted synthesis of 1-(2,6-dinitrophenyl)-3-phenylthiourea failed, since it was not possible to prepare the corresponding

2,6-dinitrophenylisothiocyanate. 2,6-Dinitroaniline (1 g, 0.0055 mol) and thiophosgene (0.48 ml of solution in 15% CCt4, 0.0055 mol) were added to a solution of toluene (5 ml) and aqueous hydrochloric acid

(1 ml, Mt: 5 ml, H20). The mixture was gently refluxed for 8.5 h, after which time tic showed only starting material.

Mixing aniline and phenylisothiocyanate in equimolar amounts in 201 benzene gave 1,3-diphenylthiourea (53%) m.p. 154°C (lit., 154-5°C).

Warming equimolar amounts of 1-naphthylamine and phenylisothiocyanate in ethanol gave 1-(1-naphthyl)-3-phenylthiourea (66%), m.p., 172-4°C 201 (lit., 162-3°C).

A mixture of 2-amino-2'-nitrobiphenyl199 (200 mg, 0.00095 mol), thiophosgene (125 mg, 0.00095 mol), concentrated hydrochloric acid

(1 -ml) in water (5 ml) and toluene (5 ml) was refluxed for 2.5 h.

The cooled mixture was separated, the organic phase washed once with water, dried over magnesium sulphate and the solvent removed. The isothiocyanate thus formed was dissolved'in benzene to which was added aniline (88.5 mg, 0.00095 mol). The solution was heated on a water bath.for 2 min•and the solvent removed. Addition of petrol (5 ml) followed trituration produced a yellow solid which was crystallised from ethanol giving 1-(2'-nitrobiphen-2-)-3-phenylthiourea (150 mg,

45%, (from amine)), m.p., 155-6°C, (Found: C, 65.12, H, 4.33; N, 12.03;

3360, 3150, C191115N302S requires C, 65.31; H, 4.43; N, 11.84%); vmax (CHCt3) 245, 273 nm; 1530, 1360, 1240, 855, 790, 770 and 755 cm 1; Xmax 131

S (dmso-d 6) 7.03-7.58 (m, 11 H), 7.65 (t, 1 H), 7.76 (t,1 H),

8.08 (d, 1 H), 9.12 (s, 1 H), 9.50 (s, 1 H); m/e 350 (M+ + 1),

315, 303, 285, 269, 256, 167, 135, 93.

1-Amino-8-nitronaphthalene198 (1 g, 0.0053 mol), thiophosgene

(0.69 g, 0.0053 mol), concentrated hydrochloric acid (1 ml) in

water (10 ml) and toluene (10 ml) were refluxed for 1.75 h. The

cooled organic phase was separated and washed with water, dried

over sodium sulphate and the solvent removed. The red oil was

dissolved in benzene (5 ml) to which was added aniline (0.5 g, 0.0053 mol).

After 2-3 min a yellow solid was precipitated which after

crystallisation from ethanol-dimethylformamide gave 1-(8-nitronaphth-l-yl)-

3-phenylthiourea (1.7 g, 42% (from amine)), m.p., 186-8°C

(Found: C, 63.23; H, 4.08; N, 12.79;'C17H13N302S requires C, 63.14;

H, 4.05; N, 13.00%); 3320, 3160, 1515, 1375, 1240, 825, 765, umax

755, and 740 cm 1; (EtOH) 216 (49 838) nm; d (dmso-d 6 ) Xmax 7.20-8.43 (m, 1 H), 9.26 (br, s, 1 H, D20 exchangeable), 9.82 (br,

s, 1 H, D20 exchangeable); m/e 277 (M+ - 46 (NO2)) 230, 184, 172,

140, 93 (base) .

H) THE PREPARATION OF CARBODIIMIDES AND THENCE 2-ARYLBENZOTRIAZOLES

1. Two general procedures were used for the preparation of

carbodiimides, depending on the reagent used to eliminate H2S

from the corresponding thioureas. 132

Method a; for metal oxides HgO, AgO.

To a solution of the corresponding thiourea (0.001 mol) in a suitable solvent (methylene chloride or acetone) was added the metal oxide (generally 0.002 mol) and an excess of magnesium sulphate as dessicant. The suspension was vigorously stirred until tic showed complete consumption of starting material.

The metal salts were removed by filtration and the solvent removed producing the carbodiimide. The carbodiimides thus produced were thermolysed without purification.

62 Method b; for 2-chloro-l-methylpyridinium iodide.

To a solution of the appropriate thiourea (0.001 mol) in dry acetonitrile (10 ml) was added a slight excess of 2-chloro-l- methylpyridinium iodide (0.0012 mol). To the rapidly stirred suspension was added triethylamine (0.002 mol). The suspension rapidly became a clear solution from which was precipitated a solid. The reaction was stopped when tic showed complete consumption

of starting material. The solvent was removed at the pump and

the residue suspended in dry methylene chloride (ca. 3 ml). The methylene chloride suspension was loaded onto a prepared

chromatography column (Silica H - petrol) and eluted with petrol

(100 ml) under hand pump pressure! The column was then eluted

with mixtures of methylene chloride-petrol (usually 1:1) which rapidly removed the carbodiimide from the column as a fast running

band. The solvent was removed and the carbodiimide used without

further purification. The carbodiimides were in contact with the silica for very short periods (ca. 2-5 min). 133

2. Thermolysis of Carbodiimides. The carbodiimide as prepared above, were dissolved in freshly distilled bromobenzene in a 25 ml round bottom flask, to which was attached an air condenser and a nitrogen supply. The solutions were placed in a pre-heated Wood's metal bath and rapidly came to reflux.

The solutions were refluxed until tic showed complete consumption to starting material. The solvent was removed u.r.p. and the resulting solid purified by low pressure column chromatography (Si021i,gradient elution) and crystallisation. The following 2-arylbenzotriazoles were thus prepared; 2-Phenylbenzotriazole, (107a), 50% (method a, HgO, 18 h) (BB, 10 min), m.p., 109-110°C (lit.,215 104-6°C). 2-(4-Methylphenylbenzotriazole, (107b) 37% (method a, HgO, 18 h), 215 (BB, 2 H); 43% (method b, 5 h), (TCB, 5 min) m.p., 119-121°C (lit., 120-121°C). 2-(4-Methoxyphenyl)benzotriazole (107e) 25% (method a, HgO, 18 h), (BB, 215 15 min); 55% (method b, 0.5 h) (BB, 10 min) m.p., 111-3°C, (lit. , 108-110°C).

2-(2,6-Dimethylphenyl)benzotriazole, (107c).59% (method a, HgO, 2 h),

(BB, 1.5 h) m.p., 91-491 -4° C '(Found: C, 75.32; H, 5.88; N, 18.83; Ci4H13N3 requires C, 75.31; H, 5.87; N, 18.82%); vmax 1340, 1275, 1230, 970, 815, and 1, X 3) 1.90 790 755 cm max (EtOH) 277 (1227), 208 (2008) nm; 6 (CDCe (s, 6 H), 7.06-7.60 (m, 5 H), 7.82-8.05 (m, 2 H); m/e 223 (M+), 207, 195, 118, 91.

2-(2,4,6-Trimethylphenyl)benzotriazole, (107d) 54% (method a, HgO, 18 h), (BB, 1.5 h); 73% (method b, 2 h), (BB, 15 min). M.p. 117-117.5°C (Found:

C, 75.72; H, 6.37; N, 17.74;'C15H15N3 requires C, 75.92; 134

H, 6.37; N, 17.71%); v 1345, 1285, 1275, 1225, 970, 860 and 740 cm 1; max (EtOH) 210 (29830), 277 (15254) nm; d (CDC?3) 1.86 (s, 6 H), Amax 2.30 (s, 3 H), 6.96 (s, 2 H), 7.35-7.46 (m, 2 H), 7.80-8.00 (m,

2 H); m/e 237 (M+, base), 222, 209.

Attempts to prepare 2-t-butyl- and 2-benzylbenzotriazoles from the readily available carbodiimides failed.

1-(t-Butyl)-3-(2-nitrophenyl)carbodiimide (106h) was prepared from the appropriate thiourea (0.2 g, 0.008 mol), (method a, HgO,

18 h). The ir spectrum showed an intense band at 2140 cm-1. The carbodiimide was dissolved in bromobenzene and refluxed under nitrogen for 18 h. Tlc and ir showed that carbodiimide was still

present. The solvent was removed and replaced with I,2,4-trichloro-

benzene. The solution was refluxed under nitrogen for 24 h after which time there was no longer evidence for carbodiimide (tic, ir).

The solvent was removed and the black residue chromatographed

(SiO2 H) producing a low melting solid (12.5 mg) as the only

isolated component, which was not identified.

1-Benzyl-3-(2-nitrophenyl)carbodiimide (106j) was prepared

(method a, HgO, 18 h). Thermolysis in bromobenzene for 3 h resulted in consumption of the carbodiimide (ir, tic) with the formation of a tarry residue.

Attempted preparation of carbodiimides from thioureas containing

1-pyridyl substitutents or 4-nitrophenyl substitutents failed in

the nitro case and gave carbodiimide in very low yield in the pyridyl

case. 135

1-(2-Nitrophenyl)-3-(4-nitrophenyl)thiourea (105f) (100 mg,

0.00035 mol) and mercuric oxide (151 mg, 0.0007 mol) were reacted in methylene chloride according to method a. Tlc indicated no reaction after 18 h at room temperature. The mixture was refluxed in methylene chloride for 18 h then replaced with benzene

(24 h reflux) and toluene (24 h reflux). After this time tic showed the thiourea was one component not distinguishable from an authentic sample. The thiourea (105f) was treated with

2-chloro-l-methylpyridinium iodide by method b. Tic of the reaction mixture after 6 h showed the thiourea to be one component.

1-(4-Methoxy-2-nitrophenyl)-3-(2-pyridyl)thiourea•(105?) (130 mg,

0.0004 mol) was treated with 2-chloro-l-methylpyridinium iodide according to general method b. Tic after 6 h at room temperature showed one component corresponding to thiourea (105?).

1-(2-Nitrophenyl)-3-(2-pyridyl)thiourea (105k) (300 mg, 0.0011 mol) was treated according to method a, (AgO,. 6 h, room temperature), tic showed one spot corresponding to starting material. A further

18 h at room temperature and 8 h reflux in methylene chloride failed to produce any reaction (tic). Treatment of the thiourea (105k)

(300 mg, 0.0011 mol) by method b gave a complex mixture (tic) with a high Rf component in the usual region for carbodiimides.

Column chromatography gave a single colourless crystalline product

(10,4 mg, 4%) with an intense band at 2120 cm-1 in the ir spectrum.

The above reaction was repeated in refluxing acetonitrile for 2 h producing (9.6 mg, 4%) of the same compound (ir, tic). 136

Attempted preparation of the pyridine N-oxide of the thiourea

(105k) failed. A solution of the thiourea in methylene chloride was treated with a 25% excess of m-chloroperbenzoic acid at room

temperature for 3 h and then at reflux for 18 h. Tlc showed one component corresponding to (105k). The same result was achieved with m-chloroperbenzoic acid in dioxan at room temperature and under reflux conditions. The use of sulphuric acid, hydrogen

peroxide and either acetic or trifluoroacetic acid at room

temperature or 80°C failed to affect any reaction (tic).

1-(2-Nitrophenyl)-3-phenylthiourea (105a) (0.5 g, 0.0018 mol)

was treated with mercuric oxide by method a. The carbodiimide

(106a) thus produced was dissolved in acetone and made up to

50 m1, A 25 ml aliquot was withdrawn and the solvent removed.

Thermolysis in bromobenzene according to the general procedure gave

2-phenylbenzotriazole (107a) (81 mg, 30%); the second 25 ml

aliquot was withdrawn and the solvent removed. The oil was

dissolve in dioxan-water (20 ml, 4-1) to which was added concentrated

hydrochloric acid (1 ml). The solution was refluxed for 1.5 h

poured into ice cold water and the oil separated. Trituration

gave a solid which was crystallised from ethanol, l-(2-nitrophenyl)-

3-phenylurea (108) (148 mg, 31% (from thiourea)), m.p., 168-70°C, 120 Clit,, 1700C),

Attempted distillation of carbodiimide (106a) (0.003 mm -

90-130°C) as prepared above, produced a red oil which appeared

as three components on tic. Further heating of the red oil at

atmospheric pressure gave 2-phenylbenzotriazole exclusively. 137

Crystallisation of carbodiimide (106a), as prepared above,

from petroluem spirit (40-60) produced two crystal forms, orange

needles, which corresponded to 1-(2-nitrophenyl)-3-phenylcarbodiimide

(106a), m.p., 19-21°C; v (neat) 2150, 1605, 1590, 1520, 1490, max 1; 1355, 1215, 1070, 860, 760., 740, and 690 cm m/e 239 (M+),

and red needles, m.p., 126-28°C.

Attempts to prepare the symmetrical 1,3-di(2,2'-nitrophenyl)

carbodiimide (106m) using triphenylphosphine oxide or triphenyl

arsine oxide as catalyst by the method of Monagle44 gave only

impure products (tic) in poor yield. The use of 3-methyl-l-phenyl-

3-phospholine-1-oxide in the method of Monagle, et al.,41 gave

1,3-di(2,2'-nitrophenyl)carbodiimide (106m), (50%), m.p., 94-6°C

(lit.,41 97-98.5°C). Thermolysis of (106m) in the melt (165°C,

5 min) gave, after column chromatography (SiO2 H) and crystallisation

(ethanol) 2-(2-nitrophenyl)benzotriazole (107m)(84%), m.p., 127-30°C ,

(lit.,l73 132.8-3.8°C),

THE PREPARATION AND REACTIONS OF 2 -ARYL-1,2,4-BENZOTRIAZIN--3-

ONE 1-OXIDES

A solution of 3-(2-nitropheny1)-4-pheny1-1,2,3,5-oxathiadiazol-

2-one (101) (200 mg, 0.00066 mol) in dry toluene (15 ml) was

thermolysed at reflux under nitrogen for 3 h. The solvent was

evaporated and the red product crystallised from acetone giving

2-phenyl-1,2,4-benzotriazin-3-one 1-oxide (109a) (81 mg, 51%),

m.p., 124°C (Found: C, 65.12; H, 3.86; N, 17.36; CIKH9N302 requires

C, 65.27; H, 3.79; N, 17.56%); (CC€4) 2260, 1695, 1610 cm-1 (KBr) Umax 1690, 1610, 1470, 1445, and 1350 cm 1; X (CHC$3) 242 (6425) 319 (4183)nm; d (dmso-d6) 6.56-8.02 (m, 9 H); m/e 239 (M+), 195.

Denotes experiment performed by Dr. P.G. Houghton. 138

A few crystals of (109a) were heated in the melt at 145°C

for 5 mins, resulting in complete transformation to 2-phenyl-

benzotriazole (tic). Addition of dilute sulphuric acid to (109a)

(100 mg) after neutralisation, extraction and crystallisation gave

2-phenylbenzotriazole (107a) (75 mg, 93%). * To a warm solution of (109a) (200 mg, 0.00084 mol) in dry benzene (15 ml) was added 2 anisidine (103 mg, 0.00084 mol). The solution was heated under reflux for 15 min. The solid

produced was filtered and crystallised from ethanol 1-(4-methoxyphenyl)-

3-(2-azoxyphenyl)phenylurea (277 mg, 91%) (111) m.p., 183-4°C

(Found: C, 66.05; H, 5.01; N, 15.37; C20H18N403 requires C, 66.29;

H, 5.01; N, 15.46%); v max 3270, 1665, 1590, 1380, 1250, 760 and 725 cm 1; X (CHCt,) 244 (13496), 319 (6612) nm; S(CDCt 3) 3.8 max (s, 3 H), 6.5-8.7 (m, 14 H), 9.9 (br, s, 1 H); m/e 362 (M+),213, 197, 195,

149, 134.

1-(4-Methoxyphenyl)-3-(2-nitrophenyl)thiourea (105e) (500 mg,

0.0016 mol) was treated with 2-chloro-l-methylpyridinium iodide

according to method b, (p.132). The carbodiimide thus produced

(266 mg, 85%) was dissolved in toluene and refluxed under nitrogen

for 20 min. The solvent was removed and the red solid crystallised

from acetone giving 2-(4-methoxyphenyl)-1,2,4-benzotriazin-3-one

1-oxide (109e) (80 mg, 22%), m.p., 109-112°C, (Found: C, 62.09;

H, 4.07; N, 15.54;'C14Ha1N302 requires C, 62.44; H, 4.12; N, 15.61%);

vmax (Nujol) 1690, 1615, 1510, 1440, 1350, 1170, 1030 and 840 cm1 , 139

(CC-C4 3 ) 2260 cm-1 ; Xmax (CHC€ ) 244 (10224) nm; d(CDC?3) 3.92 (s, 3 H), [7.07 (d), 8.82 (d).4 H, J = 9HZ], [7.20-7.65 (m),

7.90 (d) 4 H]; m/e 225(M+ -44), 210, 182, 154, 121, 106.

Attempted synthesis of 2-phenyl-1,2,4-benzotriazin-3-one

1-oxide by base catalysed condensation of 1-(2-nitrophenyl)-3- 150 phenylurea according to the method of Wolff et al., failed to give the required product.

J) EXTENSIONS TO NITRO-GROUP INTERACTIONS

1. Thermolysis of 2-Nitrophenylisocyanate.

Melt thermolysis of 2-nitrophenylisocyanate224 at 170°C for 30. min showed starting material (tic).

2, Thermolysis of 2-Nitrophenylisothiocyanate.

2-Nitrophenylisothiocyanate (560 mg, 0.003 mol) was dissolved in benzene and refluxed for 20 h, after which time tic showed no reaction. The isothiocyanate was refluxed successively in toluene, chlorobenzene (135°C), bromobenzene (165°C), and 1,2,4-trichlorobenzene (215°C). Before thermolysis in 1,2,4-trichlorobenzene the isothiocyanate absorption was still present in the it spectrum.

Reflux for 24 h at 215°C produced a dark solution which was a multicomponent mixture (tic).

3. Preparation and Thermolysis of 1-(8-Nitronaphth-l-yl)-3-Phenyl-

carbodiimide (117).

The synthesis of 1-(8-nitronaphth-l-yl)-3-phenylthiourea was described previously (p. 131). The carbodiimide (117) was prepared using 2-chloro-l-methylpyridinium iodide (method b, p. 132). 140

Thermolysis of the carbodiimide (117) in 1,2,4-trichlorobenzene under nitrogen produced a solution in which black particles were visible after 5 h at 215°C. Tlc showed one component corresponding

to starting material with insoluble black baseline material.

The carbodiimide (117) (145 mg) was distilled through a

pre-heated quartz tube at 750°C (0.015 mm). After 5 h, starting material (117, 135 mg) was recovered from the bottom flask.

An orange compound was washed from the cold finger. Removal of methylene chloride gave a solid which was crystallised from

petroluem ether (60-80°) producing benz[1,8-c,d]indazole N-oxide (119) ,180 (4 mg), m.p., 145°C (lit. 156-7°C); m/e 170 (M+).

4. The Preparation and Thermolysis of 1-(2'Nitrobiphen-2-yl)-3-

phenylcarbodiimide (118).

The preparation of 1-(21 -nitrobiphen-2-yl)-3-phenylthiourea

was described previously (p. 130). The carbodiimide (118) was prepared using 2-chloro-1 methylpyridinium iodide (method b, p. 132)

The carbodiimide (118, 200 mg) was dissolved in bromobenzene and refluxed for 20 h. Tlc showed one component corresponding to starting material (118), Thermolysis in 1,2,4-trichlorobenzene

under nitrogen for 3 days gave tarry products with some starting material still remaining (tic). Vapour phase pyrolysis of carbodiimide (118) at 650°C and 0.015 mm gave after chromatography an oil in trace amounts. The it spectrum of the oil was not

distinguishable from their spectrum of an authentic sample of

phenylisonitrile; V 2140, 1590, 1485, 1200, 750 and 690 cm-1. max A colourless solid, m.p., 136-140°C was isolated in low yield. 141

Vapour phase pyrolysis of (118, 248 mg) at 750°C and 0.015 mm gave after column chromatography a polar, colourless solid (90 mg) which was crystallised from petroleum ether-methylene chloride and the crystalline solid sublimed. M.p., 145-6°C; vmax 3350 (br), -1 1530, 1440, 1370, 1260, 755 and 730 cm ; S(CDCfs) 7.27 (s), 7.45-7.60 (m), 7.65-7.85 (m), 8.05-8.15 (d) 8.32-8.48 (t), 8.55 (d),

8.65 (d), 8.94 (d); m/e 268 (SM - 46), 164, 134.

5. The Preparation and Reaction of 1-('1-Naphthyl)-3-phenyl

carbodiimide (126).

The preparation of 1-(1-naphthyl)-3-phenylthiourea was described earlier (p. 130 ). Distillation of the carbodiimide (126) at 750°C and 0.015 mm through the quartz tube resulted in recovery , of unreacted starting material (tic).

5a. Reaction with Aluminium Chloride.

The carbodiimide (126, 605 mg) was dissolved in methylene chloride, to which was added aluminium chloride (330 mg). The mixture was stirred at room temperature for 7 days, quenched with water, the organic phase separated, washed with water and dried over sodium sulphate. The solvent was removed and the solid crystallised _ from petroluem ether (60-80°C)-methylene chloride giving one of the isomeric quinazolines (129) (200 mg, 33%), m.p., 226-8°C

(pound; C, 82,05,' H, 4.95; N,11.14; Cs4H24N4 requires C, 83.58; H, 4,95; N, 11,47%); 3410, 1640, 1580, 1530, 1390, 1330, vmax 770 and 760 cm-1; 234, 280, 320, 357 nm; S (CDC?g) 6.10 (br, s, 1 H, Amax D20 exchangeable), 6.70-6.90 (d, 1 H), 7.14-7.95 (m, 23 H), 8.80-8.98

(br, m, 1 H); m/e 488 (M+), 411, 396, 244, 140, 127, 77 (base). 142

6. Preparation and Reaction of 1,3-Diphenylcarbodiimide.

1,3-Diphenylthiourea was prepared as described on p.130

The carbodiimide was prepared using 2-chloro-l-methylpyridinium iodide (method b, p.'132). The carbodiimide (376 mg, 0.0019 mol) was dissolved in methylene chloride to which was added aluminium chloride (257 mg, 0.0019 mol). The suspension was stirred at room temperature for 48 h. The reaction was quenched with water, the organic phase separated, washed with water and dried over magnesium sulphate. The solvent was evaporated and the yellow solid crystallised from petroluem ether (40-60)-methylene chloride, producing 2-phenylamino-3-phenyl-4-phenyliminoquinazoline (128),

(340 mg, 40%), m.p., 175°C (lit. transition 171°C, m.p., 181-5°C); m/e 388 (M+) .

K) INDEPENDENT SYNTHESES

1, 5-Nitro-2-Phenylbenzotriazole (87k).

The reaction of 2,4-dinitrochlorobenzene with phenylhydrazine 216 by the method of Mallory et al., gave 5-nitro-2-phenyl-benzotriazole

(25%) m.p., 178-79°C (lit,,216 176-7°C).

2, Benzocinnoline (122). 225 Reduction of 2,2'-dinitrobiphenyl with lithium aluminium

hydride according to the method of Badger, et a1.236 gave benzocinnoline 181 (14%) m.p., 155-6°C (lit., I54-6°C).

3. Benzocinnoline N-oxide (121).

Reduction of 2,2'-dinitrobiphenyl225 with sodium hydrosulphide

according to the method of King, et al.,182 gave benzocinnoline N-oxide 182 (31%) m.p., 139-41°C (lit., 138°C ). 143

4. Benzocinnoline di-N-oxide (120).

Reduction of 2,2'-dinitrobiphenyl with zinc and potassium 181 hydroxide according to the method of Tauber gave benzocinnoline 181 di-N-oxide (46%) m.p., 243°C (lit., 243°C).

5. 6-Anilinophenanthridine (124).

Treatment of 6-chlorophenanthridine with aniline according to 226 the method of Seidler gave 6-anilinophenanthridine (60%) m.p., ,226 156-7°C (lit. 156-7°C).

6. 6-Anilino-10-nitrophenanthridine (125).

2-Nitro-2'-biphenylisocyanate prepared by using the analogous 227 route of Fraenkel-Conrat, et al., was treated with aluminium 228 chloride according to the procedure of Butler gave 10-nitro-6(5H)- phenanthridone (10%) m.p., 319-320°C (lit.,229 316-18°C).

10-Nitro-6(5 H)phenanthridōne (100 mg, 0.00042 mol) was refluxed with an excess of phosphoryl chloride for 4 h. Excess phosphoryl

chloride was evaporated leaving an orange oil which crystallised on cooling. To the solid was added a 6-fold excess of aniline in benzene (5 ml), and the solution refluxed overnight. The solution was cooled, washed with water and the organic phase dried over sodium sulphate. The solvent was removed and the yellow oil triturated under ethanol-water (20 ml, 1:1). The yellow solid was filtered and crystallised from petroluem ether (60-80°)-methylene chloride producing 6-anilino-l0-nitro-phenanthridine (125) (85 mg, 65%) m.p., 144-7°C (Found:C, 72.44; H, 4.31; N, 13.27;'C19H13N302 144

requires C, 72.37; H, 4.16; N, 13.33%); vmax 3440, 1590 (w),

cml; X (CHCt3) 353 (7098) nm; 1525, 1370, 750, 705 and 690 max 6 (CDC-(3) [6.88-7.02 (m), 7.08 (t), 2.5 H], 7.20 (s, 2 H), 7.36 (t, 3 H), 7.50-7.78 (m,.3 H), 7.85 and 8.18 (2 x d, 2.5 H); m/e 315 (M+) 268, 182, 157, 129 (base). 145

SECTION 2-

A) THE PREPARATION OF PRECURSORS TO CARBAZOLES.

1. Tetrazoles.

The preparation of tetrazoles has already been described on p. 111.

2. 2-Arylbenzotriazoles.

The preparation of 2-arylbenzotriazoles has already been described on p. 131.

B) VAPOUR PHASE PYROLYSIS OF 1-(2-NITROPHENYL)-5-PHENYLTETRAZOLE (87b)

AND 2-PHENYLBENZOTRIAZOLE (107a).

1. 1-(2-Nitrophenyl)-5-phenyltetrazole (87b).

The tetrazole (87b, 242 mg, 0.0009 moles) was vapourised at

120°C and 0.02 mm Hg, and the vapour passed through a quartz tube at 400°C. Tetrazole (87b, 185 mg, 0.0007 mol) was recovered unsublimed. Column chromatography (SIX/2H) gave a crystalline product which was two spots on tic. We were not able to separate the two components. The mixture showed -NH vibration at 3490 cm-1 in the it spectrum. Comparative tic suggested one component was

2-phenylbenzotriazole. Crystallisation from petroleum ether (60-80°)- methylene chloride gave 2-phenylbenzotriazole (19 mg, 40%). 146

2. 2-Phenylbenzotriazole (107a). a) 2-Phenylbenzotriazole (107a, 187 mg, 0.00096 mol) was vapourised at 90°C and 0.08 mm Hg and the vapour passed through a quartz tube at 600°C. The pyrolysate was crystallised from petroleum ether

(60-80°)-methylene chloride producing carbazole (23 mg, 14.4%) 201 m.p., 235-8°C (lit., 246).

b) Yield Optimisation Experiments.

General Procedure

2-Phenylbenzotriazole (107a) was vapourised at between 80-85°C and the vapour passed through a quartz tube pre-heated to the required temperature (see Table, p. 92 ). The pyrolysate was chromatographed to remove any baseline material and the weight of recovered material was established. In only one case was the material return less than 95% (900°C, 76%). The pyrolysate was analysed by hplc with authentic specimens as reference, using a reverse phase column, eluting with methanol-water mixtures (4:2 or 7:3) with a UV detector at 293 nm. The yields were calculated by first finding the response factor for a carbazole 2-phenylbenzotriazole mixture of known concentration, then applying the constant to find the relative peak areas of the mixtures of unknown concentration.

The following results are given as pyrolysis temperature, percentage carbazole; 300°C, 0; 500-20°, 0; 600°C, < 1; 700-20°C,

17; 750°C, 76; 800°C, 56; 900°C, 91. 147

C) THE PREPARATION AND PYROLYSIS OF 1,2,5-DIBENZOTRIAZEPINE (131).

1. Preparation of 1,2,5-dibenzotriazepine (131). 230 Reduction of 2,2'-dinitrodiphenylamine (132) with zinc dust 231 and sodium hydroxide using the method of Grundon gave after column chromatography and crystallisation 1,2,5-dibenzotriazepine 231 (131) 15% , m.p., 192°C (lit., 190-1°C).

2. Vapour Phase Pyrolysis of 1,2,5-Dibenzotriazepine (131).

1,2,5-Dibenzotriazepine (131, 110 mg, 0.00056 mol) was vapourised at 110°C and 0.03 mm Hg and the vapour passed through a quartz tube at 800°C. The pyrolysate was chromatographed (Si02 H) producing starting material (131) (22.4 mg, 20%) and a colourless solid which ,was crystallised from petroleum ether (40-60°)-methylene chloride giving carbazole (130) (29 mg, 31%).

D) PYROLYSIS AND PHOTOLYSIS OF PRECURSORS TO 3-METHYLCARBAZOLE

1. Pyrolysis of 2-(4-methylphenyl)benzotriazole (107b).

2-(4-Methylphenyl)benzotriazole (107b, 62 mg) was vapourised at 100°C and 0.015 mm Hg and the vapour passed through a quartz tube at 850°C. The pyrolysate was chromatographed (Si02 H) to remove baseline material and the product mixture analysed by hplc. 148

HPLC Analysis.

The pyrolysis product was shown to be a mixture of three

components. Co-injection of the pyrolysis mixture with an authentic

sample of 2-(4-methylphenyl)benzotriazole (107b) identified one

component as benzotriazole (107b). Conditions under which the

pyrolysis product mixture could be separated failed to resolve

authentic specimens of 2-methylcarbazole and 3-methylcarbazole.

Co-injection of the pyrolysis mixture with 2-methylcarbazole and

then with 3-methylcarbazole identified a second component as

2-methylcarbazole (133) or 3-methylcarbazole (132) or a mixture of

the two compounds. Co-injection of 1-(4-methylphenyl)benzotriazole

(136) and the pyrolysis mixture showed that this compound did not

correspond to any component in the pyrolysis mixture.

b) NMR Analysis.

Since the second component of the pyrolysis could not be

determined as 2-methylcarbazōle (133) or 3-methylcarbazole (132) or

a mixture of (132) and (133), the nmr spectra were compared.

2-Methylcarbazole (133) d (CDC-(3) 1.54 (s, 1 H, D20 exchangeable), 2.52

(s, 3 H), 7.06 (d, 1 H), 7.16-7.29 (m, 1 H), 7.35-7,42 (m, 2 H), 7.86-8.08

(m, 3 H) . 3-Methylcarbazole (132).d (CDC?3) 2.52 (s, 3 H), 7.17-7.40 (m, 6 H),

7.86 (s, 1 H), 8.03 (d, 1 H).

2-(4-Methylphenyl)benzotriazole (107b) d(CDC?3)2.45 (s, 3 H), 7.25-7.45

(m, 4 H), 7.85-8.00 (m, 2 H), 8.26 (d, 2 H). 149

Pyrolysis Mixture 6 (CDC€s) 1.26 (br, s), 1.56 (br, s), 2.44 (s,

107b - CH3), 2.52 (132-CH3), 7.13-7.32 (m), 7.36-7.40 (m),

7.36-7.50 (m), 7.85-7.98 (m), 8.02-8.10 (t), 8.25 (d).

Analysis of the spectra shows the presence of starting material (107b) with a methyl group at 6 2.44 and a doublet at

6 8.25, which is part of an AB quartet. The 2- and 3-methyl groups in the monomethyl carbazoles 232 have been shown to have identical resonance positions.

Thus, either 2- or 3-methylcarbazole is present in the pyrolysis mixture, 6 2.52 (3 H, CH3). The nmr spectrum of 2-methylcarbazole has a one proton doublet at C°7.06. This resonance does not occur in 3-methylcarbazole or in the pyrolysis mixture.

2. Photolysis of 2-(4-methylphenyl)benzotriazole (107b).

2-(4-Methylphenyl)benzotriazole (150 mg) was photolysed in dry, degassed acetonitrile (150 ml) at 300 nm for 30 h. Tlc showed a single component corresponding to starting material (107b).

3. Melt Thermolysis of 1-(4-methylphenyl)benzotriazole (136).

1-(4-Methylphenyl)benzotriazole (136, 200 mg) was thermolysed in the melt at 350°C under nitrogen for 2 h. Column chromatography of the pyrolysate produced colourless crystals which were crystallised from petroleum ether-methylene chloride producing 3-methylcarbazole 233 (132) (80 mg, 40Z), m.p „ 199-202°C (lit,, 199-202°C). 150

E) INDEPENDENT SYNTHESES

1. 2-Methylcarbazole (133).

Attempts to prepare the required 4-methyl-2'-nitrobiphenyl 200 (134) following the Voge1 procedure for the Gomberg-Bachmann

reaction190 failed to produce the require product. p-Iodotoluene

(1 g, 0.0046 mol), 2-bromonitrobenzene (0.93 g, 0.0046 mol) and

copper powder (0.88 g, 0.0014 g'atom) were mixed with dry dimethyl-

formamide (5 ml) and the mixture refluxed for 18 h. The reaction

mixture was cooled, poured into cold water (400 ml) and stirred

for 2 h. The aqueous phase was decanted, the residue extracted

into hot chloroform, filtered, dried over magnesium sulphate and

the solvent removed. Column chromatography (SiO2 H) gave 4-methyl-2'-

nitrobiphenyl (134) as a yellow oil (153 mg, 16%) S (CDC-(3)

2.20 (s, 3 H), 7.26-8.15 (m, 8 H). The oil was used without further

purification.

Treatment of 4-methyl-2'-nitrobiphenyl (134) (150 mg, 0.00074 mol)

with triethyl phosphite under nitrogen for 24 h according to the 215 method of Cadogan, et a1., gave after crystallisation from 233 ethanol 2-methylcarbazole (133) (84 mg, 66%) m.p., 257-9°C (lit.,

259°C) .

2. 3-Methylcarbazole (132).

6-Methyl-1,2,3,4-tetrahydrocarbazole was prepared by the 234 procedure of Rogers, et a1. 151

6-Methyl-1,2,3,4-tetrahydrocarbazole (90 mg, 0.00049 mol)

was dissolved in dry toluene (5 ml) and the solution warmed.

To the hot, but not refluxing solution was added o-chloranil

(287 mg, 0.0012 mol) and the solution refluxed for 18 h. Column

chromatography (Si02 H,twice) failed to separate the two product

components. Plc (CHC€ 3 - Petrol, 4:1) gave 3-methylcarbazole 233 (132) (25 mg, 28%), m.p., 199-202°C (lit., 199-202°C).

3. 1-(4-Methylphenyl)benzotriazole (136). 191 Reduction and diazotisation of 4 -methyl-2'-nitrodiphenylamine 235 using the method of Fitton, et al., gave 1-(4-methylphenyl)benzo- 237 triazole (136, 46%), m.p., 85-8°C (lit., 84°C). 152

APPENDIX

1. The Preparation of Tetrazoles.

The preparation of tetrazoles has already been described

on p. 111 and in reference 195.

2. Photolysis of Tetrazoles.

a) Photolysis of 1-(2-nitrophenyl)-5-phenyltetrazole (87b).

The tetrazole (87b) (400 mg, 0.0015 mol) was photolysed in

dry, degassed acetonitrile (150 ml) under nitrogen at 254 nm for- 92 h. Plc (chloroform-ethyl acetate 50:1, twice) followed by

column chromatography and crystallisation from petroleum ether (60-80°)-

methylene chloride gave 4-nitro-2-phenylbenzimidazole (68 mg, 17%) 195 m.p., 192-4°C (lit., 194-6°C). Tetrazole (87b) (14 mg, 3.5%)

was recovered.

b)Photolysis of 1-[2-(5-phenyltetrazol-1-yl)benzoyl]pyrrolidine (140).

The tetrazole (140) (600 mg, 0.0019 mol) was photolysed in

dry, degassed acetonitrile (120 ml) under nitrogen for 14 h.

Removal of solvent and plc of the mixture gave 1-[2-(2-phenylbenzimidazol-

4-yl)benzoyl]pyrrolidine (343 mg, 63%), m.p., 139-141°C (lit.,195

138-40°C) and 2-phenylbenzimidazole (4 mg, 1.1%). 153

c) Photolysis of Methyl 2-(5-phenyltetrazol-1-yl)benzoate (139).

The tetrazole (139) (1.00 g, 0.0036 mol) was photolysed in dry, degassed acetonitrile, under nitrogen for 12 h. Column chromatography gave tetrazole (139) (325 mg); methyl-2-phenylbenzimidazole-1-carboxylate (175 mg, 29%) which was identical with an authentic specimen; methyl-2-phenylbenzimidazole-4-carboxylate 195 (250 mg, 41%) m.p., 125°C (lit., 127°C); 2-phenylbenzimidazole

(50 mg, 10%) . REFERENCES 154

REFERENCES

1. P.A.S. Smith, E. Leon, J. Amer. Chem. Soc., 1958, 80, 4647.

2. J. Vaughan, P.A.S. Smith, J. Org. Chem., 1958, 23, 1909.

3. W. Kirmse, Angew. Chem.,, 1959, 71, 537.

4. R.M.Moriarty, J.M. Kliegman, J. Amer. Chem. Soc., 1967, 89, 5959.

5. P.A.S. Smith in 'Nitrenes', ed. W. Lwowski, Interscience,

New York, 1970, p. 152.

6. S. Linke, G. Tisue, W. Lwowski, J. Amer. Chem. Soc., 1967, 89, 6308.

7. C.J. Moody, Ph.D. Thesis, Univeristy of Liverpool, 1976.

8. H. Behringer, H.J. Fischer, Chem. Ber., 1961, 94, 1572.

9. H. Behringer, H.J. Fischer, Chem. Ber., 1961, 94, 2562.

10. T. Bacchetti, A. Alemagna, Atti. Accad. naz. Lincei. Rend. Classe

Sci. Fis. mat. nat., 1960, 28, 824; Chem. Abs., 1962, 56, 7304c.

11. T. Bacchetti, A. Allemagna, Rend. Ist. Lomb. Sci. Lett. A,

1960, 94A, 242; Chem. Abs., 1961, 55, 16527a.

12. T. Bacchetti, A. Alemagna, Gazzetta, 1961, 91, 1475.

13. J. Sauer, K.K. Mayer, Tetrahedron Letters, 1968, 325.

14. J.H. Boyer, P.J.A. Frints, J. Heterocyclic Chem., 1970, 7, 59.

15. R.L. Ellsworth, D.F, Hinckley, E.F. Schaenwaldt, F.P. 2014402;

Chem. Abs., 1971, 74, 76422.

16. P. Rajagopalan, H.U. Daeniker, Angew.Chem.Internat.Ed., 1963, 2, 46.

17, P. Rajagopalan, B. Advani, J. Org. Chem., 1965, 30, 3369.

18. R. Huisgen, J. Wulff, Chem, Ber., 1969, 102, 1848.

19, F. Eloy, Helv. Chim. Acta, 1965, 48, 380. 155

20. R.M. Ellsworth, D.F. Hinckley, E.F. Schaenwaldt, F.P. 2014324;

Chem. Abs., 1971, 74, 87975.

21. V.J. Grenda, R.E. Jones, G. Gal, M. Sletzinger, J. Org. Chem.,

1965, 30, 259.

22. M. Osone, S. Tanimoto, R. Oda, Yukei Gosei Kogaku Kyokai Shi,

1966, 24, 562; Chem. Abs., 1966, 65, 10577g.

23. E. Haruki, T. Inaike, E. Imoto, Bull. Chem. Soc.,_ Japan, 1968, 41, 1361.

24. E. Haruki, T. Inaike, E. Imoto, Bull. Chem. Soc., Japan, 1965, 38, 1806.

25. M.W. Partridge, H.A. Turner, J. Chem. Soc., 1958, 2086.

26. Merck and Co., Inc., B.P., 988784; Chem. Abs., 1965, 63, 16357c.

27. W. Weitu, Chem. Ber., 1873, 6, 1389.

28. R. Rotter, Monatsh. 1926, 47, 355.

29. F. Zetche, A. Fredrich, Chem. Ber., 1940, 73, 1114.

30. Farbenfabriken Bayer Akt. Ges., Ger. Pat., 129 417.

31. I.W. Herzog, Angew. Chem., 1920, 33, 140.

32. C.L. Stevens, G.H. Spinghal, A.B. Ash, J. Org. Chem., 1967, 32, 2895.

33. J.C. Sheehan, P.A. Cruickshank, G.L. Boshart, J. Org. Chem.,

1961, 26, 2525.

34. G. Amiard,R. Heymes, Bull. Soc. Chim. France., 1965, 1360.

35. J.C. Sheehan, P.A. Cruickshank, Org. Synth., 1968, 48, 83.

36. E. Schmidt, R. Schnegg, U,S. Pat., 2656383.

37. E. Schmidt, R. Schnegg Ger. Pat., 823445.

38. H.G. Khorana, J. Chem. Soc., 1952, 2081.

39. W. Weith, Chem, Ber., 1875, 8, 1530.

40. E. Schmidt, W. Striewsky, F. Hitzler, Annalen, 1948, 560, 222. 156

41. T.W. Campbell, J.J. Monagle, V.S. Foldi, J.Amer.Chem.Soc.,. 1962, 84, 3673.

42. W.B. McCormack, Org. Synth., 1963, 43, 73.

43. T. Shibanuma, T. Mukaiyama, Chem. Letts., 1977, 575.

44. J.J. Monagle, J. Org. Chem., 1962, 27, 3851.

45. J.J. Monagle, T.W. Campbell, H.F. McShane, Jr., J. Amer. Chem. Soc.,

1962, 84, 4288.

46. K. Hunger, Tetrahedron Letters, 1969, 5929.

47. H. Ulrich, Ā.A.R. Sayigh, J. Chem. Soc., 1963, 5558.

48. H. Ulrich, B. Tucker, A.A.R. Sayigh, J. Org. Chem., 1967, 32, 1360.

49. T.W. Campbell, J.J. Monagle, J. Amer. Chem. Soc., 1962, 84, 1493.

50. H. Staudinger, J. Meyer, Helv. Chim. Acta, 1919, 2, 636.

51. J.S. Jochims, Chem. Ber., 1965, 98, 2128.

52. H. Walther, Ger (east) Pat. 22437.

53. H. Eilingsfield, M. Seefeelder, H. Weidinger, Angew. Chem., 1960, 72, 836.

54. R. Rotter, E. Schandy, Monatsh, 1931, 58, 245.

55. E. Schmidt, F. Hitzler, E. Lande, Chem. Ber., 1938, 71, 1933.

56. G.D. Meakin, R.J. Moss, J. Chem, Soc., 1957, 993.

57. F. Zetscher, E. Luescher, H,E. Meyer, Chem. Ber., 1938, 71B, 1088.

58. N. Zinin, Jahresber. Fortsch. Chem. Verw. Wiss., 1852, 628.

59. R.F. Coles, U.S. Pat., 2946819.

60, J.C. Sheehan, U.S. Pat., 3135748.

61. 0. Mitsonobu, M. Tomari, H. Morimoto, T. Sato, M. Sudo,

Bull, Chem. Soc., Japan, 1977, 45, 3607.

62. T. Shibanamu, M. Shiono, T. Mukaiyama, Chem. Letts., 1977, 575.

63. Organic Functional Group Preparations, S.R. Sandler, W. Karo,

Academic Press, New York, London, 1971, p. 219. 157

64. A.R. Katritzky, P-L. Nie, A. Dondoni, D. Tassi, J. Chem. Soc., Perkin I,

1979, 1961.

65. A. Reissert, Chem. Ber., 1896, 29, 639.

66. S. Gabriel, W. Gerhard, R. Wolter, Chem. Ber., 1923, 56, 1024.

67. J.D. Loudon, I. Wellings, J. Chem. Soc., 1960, 3462.

68. J.D. Loudon, G. Tennant, J. Chem. Soc., 1960, 3466.

69. I.P. Sword, J. Chem. Soc. C, 1970, 1916.

70. A. Baeyer, Chem. Ber., 1880, 13, 2254.

71. A. Baeyer, V. Drewsen, Chem. Ber., 1882, 15, 2856; 1883, 16, 2205.

72. I. Tanasescu, A. Georgescu, J. Prakt. Chem., 1934, 139, 189.

73. I. Tanasescu, E. Tanasescu, Bull. Soc. Chim. France, 1936, 3, 865.

74. L.E. Kinkel, E.E. Ayling, W.H. Morgan, J. Chem. Soc., 1932, 985.

75. A. Hassner, D.R.Fitchman, Tetrahedron Letters, 1966, 1991.

76. A. Baeyer, Chem. Ber., 1881, 14, 1741.

77. J.D. Loudon, G. Tennant, J. Chem. Soc., 1963, 4268.

78. A. Reissett, Chem. Ber., 1897, 30, 1030.

79. J.M. Gulland, R. Robinson, J. Scott, S. Thornley, J. Chem. Soc.,

1929, 2924.

80. H. Burton, L. Stoves, J. Chem. Soc., 1937, 402.

81. G. Heller, G. Spielmeyer, Chem. Ber., 1925, 58, 834.

82. K. Akoshi, Bull. Inst. Phys. Chem. Res. (Tokyo), 1941, 20, 798;

Chem. Abs., 1949, 43, 7934.

83. A. Reissert, F. Lemmer, Chem. Ber., 1926, 59, 351.

84. D. Johnston, D.M. Smith, Tetrahedron Letters, 1975, 1121.

85. D. Johnston, D.M. Smith, J. Chem. Soc., Perkin I, 1976, 399.

86. V. Meyer, Chem. Ber., 1889, 22, 319.

87. W. Borsche, Chem. Ber., 1909, 42, 601. 158

88. S. Reich, G. Gaigailian, Chem. Ber., 1913, 46, 2380.

89. K.V. Auwers, E. Frese, Chem. Ber., 1925, 58, 1369.

90. W. Borsche, K. Diacant, Annalen, 1934, 510, 287.

91. W. Borsche, L. Butschli, Annalen, 1936, 522, 285.

92. K. Schimmltschmidt, H. Hoffmann, Annalen,

1964, 677, 157.

93. A. Prakash, I.R. Ghambir, J. Indian. Chem. Soc., 1966, 43, 529.

94. J.B. Wright, Chem.Rev., 1951, 48, 397.

95. R.H. Smith, H. Suschitzky, Tetrahedron, 1961, 16, 80.

96. H. Suschitzky, M.E. Sutton, Tetrahedron Letters, 1967, 3933.

97. G. Smolinsky, B.I. Feuer, J. Org. Chem., 1966, 31, 3882.

98. J.D. Loudon, G. Tennant, J. Chem. Soc., 1963, 4268.

99. G.W. Stacey, T.E. Wollner, T.R. Oakes, J.Heterocyclic.Chem., 1966, 3, 51.

100. H. McNab, D.M. Smith, J. Chem. Soc., Perkin I, 1973, 1310.

101. J. Machin, D.M. Smith, J. Chem. Soc., Perkin I, 1979, 1371.

102. R. Fielden, 0. Meth-Conn, D. Price, H. Suschitzky,

Chem. Comm., 1969, 772.

103. W. Heine, G.J. Blosiek, G.B. Lowrie, Tetrahedron Letters, 1968, 4801.

104. S.S. Joshi, I.R. Gambhir, J. Amer. Chem. Soc., 1956, 26, 3714.

105. S.S. Joshi, I.R. Gambhir, J. Org. Chem., 1961, 26, 3714.

106. H,G. Gary, J. Org. Chem„ 1962, 27, 3683.

107. D.R, Eckroth, T.G. Cochran, J. Chem. Soc., C, 1970, 2660.

108. R.M, Acheson, R.G, Bolton, I, Hunter, J, Chem. Soc., C„ 1970, 1067.

109. D.H, Hey, A,L. Palluel, J. Chem. Soc., 1956, 4123,

110. J,M. Gulland, J, Chem. Soc., 1931, 2872.

111, M.P. Cava, M.V. Lakshimikantham, J. Org. Chem., 1970, 35, 1867. 159

112. C.A. Grob, 0. Weissbach, Helv. Chim. Acta, 1961, 44, 1748.

113. W.B. Dickinson, J. Amer. Chem. Soc., 1964, 86, 3580.

114. S.S. Ball, L.J. Andrews, R.M. Keefer, J. Org. Chem., 1979, 44, 525.

115. A.D. de Wit, W.P. Trompenaars, D.N. Reinhoudt, S. Harkema,

G.J. van Hummel, Tetrahedron Letters, 1980, 1779.

116. M.L.M. Pennings, D. Reinhoudt, Tetrahedron Letters, 1980, 1781.

117. E.H. Rodd, ed., 'Chemistry of Carbon Compounds', Vol. IVA,

Elsevier, Amsterdam, 1964, p. 449.

118. M. Freund, Chem. Ber., 1889, 22, 1663.

119. C. Willgerodt, M. Ferko, J. Prakt. Chem., 1888, 37, 345.

120. R.S. Kapil, S.S. Jochi, J. Indian.Chem. Soc., 1959, 36, 417.

121. M. Guia, M. Guia, Gazette, 1923, 53, 165.

122. A. Mongini, C. Deliddo, Gazetta, 1935, 65, 214.

123. A. Prakash, I.R. Gambhir, J. Indian Chem. Soc., 1964, 41, 845.

124. T. Zincke, E. Scharff, Annalen, 1909, 41, 845.

125. C. Willgerodt, H. Klein, J. Prakt. Chem., 1899, 60, 97.

126. M.S. Gibson, Chem. and Ind., (London), 1965, 1699.

127. R. Huisgen, V. Webendorfer, Chem. Ber., 1967, 100, 71.

128. S. Sunder, N.P. Peet, J. Heterocyclic Chem., 1979, 16, 33.

129. H.W. Heine, P.G, Willard, T,R. Hoye, J. Org. Chem., 1972, 37, 2980.

130. A.J. Boulton, P.B. Ghosh, Adv. Heterocyclic Chem., 1969,10, 1.

131, R.A. Abramovitch, B,A. Davis, Chem. Rev., 1964, 64, 149.

132, A.J, Boulton, A.C. Gripper-Gray, A,R. Katritzky, J. Chem. Soc.,

1965, 5958,

133, A.J. Boulton, R.C. Brown, J, Org. Chem„ 1970, 35, 1662.

134. D.W. Bayne, A.J. Nicol, G, Tennant, Chem. Comm., 1975, 782. 160

135. C.W. Muth, J.C. Ellers, O.F. Folmer, J.Amer.Chem.Soc., 1957, 79, 6500. 136. C.W. Muth, N. Abraham, M.L. Linfield, R.B. Wotring, E.A. Pacovsky, J. Org. Chem., 1960, 25, 736.

137. E.C. Taylor, B. Furth, M.P. Fau, J.Amer.Chem. Soc., 1965, 87, 1400. 138. E.C. Taylor, R.E. Buntrock, J. Org. Chem., 1971, 36, 634. 139.. T.W.M. Spence, G. Tennant, Chem. Comm., 1969, 194. 140. G. Tennant, J. Chem. Soc., 1963, 2428.

141. M.J. Strauss, D.C. Palmer, R.R. Bard, J. Org. Chem.,1978, 43, 2041. 142. R.R. Bard, M.J. Strauss, J. Org. Chem., 1977, 42, 435. 143. B. De Croix, M.J. Strauss, A. De Fusco, D.C. Palmer, J. Org..Chem., 1979, 44, 1700.

144.R.H. Smith, H.Suschitzky, Tetrahedron, 1961, 16,'80. 145. J.D. Loudon, F. McCapra, J. Chem. Soc., 1959, 1899.

146. F. Arndt, Chem. Ber., 1913, 46, 3522. 147. F.J. Wolff, K. Pfister, R.M. Wilson, C.A. Robinson, J. Amer. Chem. Soc., 1954, 76, 3551.

148. J. Jiu, G.P. Mueller, J. Org. Chem., 1959, 24, 813. 149. J.C. Mason, G. Tennant, J. Chem. Soc. B, 1970, 911. 150. F.J. Wolff, A.M. Wilson, J.K. Pfister, M. Tishler, J. Amer. Chem. Soc., 1954, 76, 4611.

151. P.K. Kadaba, J. Org. Chem., 1976, 41, 1073. 152. G. Bianchetti, D. Pocar, P. Della Croce, Gazetta, 1964, 94, 340. 153. D.Y. Curtin, L.L. Miller, J. Amer. Chem. Soc., 1967, 89, 637. 154. J.C. Kauer, W.A. Sheppard, J. Org. Chem., 1967, 3580. 155. M.O. Lozinskii, V.S. Dmitrukha, A.A. Rykov, A.G. Bratolyubova, J. Org. Chem.(USSR),1974, 10, 71.

156. E.C. Taylor, I.J. Turchi, Chem. Rev., 1979, 2, 181. 161

157.''Encyclopedia. of Industrial Chemical Analysis' Vol. 8,

F.D. Snell, L.S. Ettre, Eds., John Wiley, Interscience, 1969.

158.J.J.A. Campbell, P. Halliwell, P.W. Manley, Chem. and Ind., (London), 1978, 842.

159. P. Bouchet, C. Coquelet, J. Elguero, R. Jacquier, Tetrahedron Letters,

1973, 891.

160. P. Bouchet, C. Coquelet, J. Elguero, R. Jacquier, Bull. Soc. Chim.

France, 1976, 1-2, 184.

161. K. Elbs, J. Prakt. Chem., 1924, 108, 209.

162. G. Charrier, G.B. Grippa, Gazetta, 1923, 53, 462.

163. G. Charrier, G.B. Grippa, Gazetta, 1926, 56, 207.

164. L.G. Donaruma, W.Z. Heldt, Organic Reactions, John Wiley, 1960,

Vol. 11, 1.

165. P. Cohen-Fernandes, C.L. Harbraken, J. Org. Chem., 1971, 36, 3084.

166. J. Dyson, J. Chem. Soc., 1934, 176.

167. F.J. Wolff,K. Pfister, U.S. Patent 2 489 353, Chem. Abs., 1950, 44, 3537b.

168. M.Busch, Chem. Ber., 1899, 32, 2959.

169. R.J. Cross, N.H. Tennant, J. Organomet. Chem., 1973, 61, 33.

170. Ger. Pat., 338,926, Chem. Abs., 1922, 16, 2869 2.

171. J. Arient, J. Dvorak, Chem. Listy., 1956, 50, 1856; Chem. Abs.,

1957, 51, 43630.

172. British Patent, 922,943.

173. R.A. Carboni, J.C. Kauer,'J.E. Castle, H.E. Simmons,

J. Amer. Chem. Soc., 1967, 89, 2618.

174. H.J. Hall,J. Org. Chem., 1968, 33, 2954.

175. M. Kamel, M.I. Ali, M.M. Kamel, Tetrahedron, 1967, 23, 2863. 162

176. J.F.K. Wilshire, Austral. J. Chem., 1966, 19, 1935. 177. J.M. Prokipcak, P.A. Forte, D.D. Lennox, Canad. J. Chem., 1969, 47, 2482.

178. V. Balasubramaniyan, Chem. Rev., 1966, 60, 567.

179. I.I. Schuster, J.D. Roberts, J. Org. Chem., 1980, 45, 284.

180. R.W. Alder, G.A. Niazi, M.C. Whiting, J. Chem. Soc. C, 1970, 1693.

181. E. Tauber, Chem. Ber., 1891, 24, 3081.

182. F.E. King, T.J. King, J. Chem. Soc., 1945, 824.

183. A-M. M.E. Omar, N.S. Habib, O.M. Aboulwafa, Pharmazie, 1977, 32, 758.

184. K. Hartke, F. Rossbach, M. Radau, Annalen, 1972, 762, 167.

185. J.A. Carbon, J. Org. Chem., 1962, 27, 185.

186. N. Campbell, B.M. Barclay, Chem. Rev., 1947, 40, 359.

187. N.V. Sidgewick,'The Organic Chemistry of Nitrogen Compounds',

Oxford University Press, 1966, Ch. 26.

188. W.C. Sumpter, F.M. Miller,'The Chemistry of Heterocyclic Compounds`,

Interscience, 1954, Vol. 8,

189. R,W.G. Preston, S.H. Tucker, J.M.L. Cameron, J. Chem. Soc., 1942, 500.

190. M. Gomberg, W.E. Bachmann, J. Amer. Chem. Soc., 1924, 46, 2339.

191, J.J. Kulagowski, C.W, Rees, Synthesis, 1980, 215.

192. T.L, Gilchrist, C.J. Moody, C,W. Rees, J. Chem. Soc., Perkin I,

1979? 1871.

193, C.W. Spangler, Chem. Rev., 1976, 76, 187.

194. M. Franck-Neumann, C. Dietrich-Buchecker, Tetrahedron Letters,

1973, 2069.

195. T.L. Gilchrist, P.F. Gordon, D.F. Pipe, C.W. Rees, J. Chem. Soc. Perkin I,

1979, 2303. 163

196. C.P. Falshaw, S.A. Lane, W.D. 011is, Chem. Comm.,

1973, 491.

197. D.J. Anderson, D.C. Norwell, E. Stanton, T.L. Gilchrist,

C.W. Rees, J. Chem. Soc. Perkin I, 1972, 1317.

198. Brit. Patent, 725,790, Chem. Abs., 1956, 50, 5757b.

199. J.A. Cade, A. Pilbeam, J. Chem. Soc., 1964, 114.

200. A.I. Vogel, 'Textbook of Practical Organic Chemistry', Longmans,

'London, 1978.

201. Dictionary of Organic Compounds, Eyre and Spottiswood,

London, 1965.

202. P.F. Gordon, Ph.D. Thesis, University of Liverpool, 1978.

203. F. Reverdin, Helv. Chim. Acta, 1918, 1, 208.

204. P. Grammaticakis, Bull. Soc. Chim. France, 1960, 1956.

205. M.W. Partridge, H.J. Vipond, J. Chem. Soc., 1962, 632.

206. B.M. Wepster, P.H. Witjens, Rec. Tray. Chim., 1951, 70, 127. ti 207. S.J. Walia, J. Singh, S.M. Chattha, M. Satynarayana, Tetrahedron Letters, 1969, 195.

208. J. Boesken, Rec, Tray. Chin;., 1912, 31, 351.

209, R. Huisgen, E. Laschtuvka, Chem. Ber., 1960, 93, 65.

210. J,P. Horwitz, V.A. Grakauskas, J. Ore. Chem., 1954, 19, 194.

211. 0, Diinroth, G. De Montmollin, Chem. Ber., 1910, 43, 2907.

212. R.M. Herbst, C,W. Roberts, H.T, Givens, E.K. Harvill, J. Org. Chem.,

1952, 17, 262.

213. R.K. Harris, A,R. Katritzky, S. Oksne, A.S. Bailey, W.G. Paterson,

J. Chem. Soc., 1963, 197,

214, J. Bowie, T. Blumenthal, I. Walsh, Org. Mass. Specrometry, 1971, 5, 777.

215, J.I.G, Cadogan, M. Cameron-Wood, R.K. Mackie, R.J.G. Searle,

J. Chem. Soc., 1965, 4831. 164

216. F. Mallory, C.S. Wood, B. Hurwitz, J. Org. Chem., 1964, 29, 2605.

217. R.A. Khmel'nitskii, U.A. Efremov, N.V. Fedainov,

Izv. Timiryazevsk, S-kh. Akad., 1978, 3, 199.

218. K. Fries, W. Frank, W. Bruns, Annalen, 1934, 511, 241.

219. L. Krbechek, H. Takimoto, J. Org. Chem., 1964, 29, 3630.

220. F.F. Stephens, J.D. Bower, J. Chem. Soc., 1949, 2971.

221.'Handbook of Chemistry and Physics',57th Edition, R.C. Weast,

CRC Press, Cleveland, Ohio.

222. A. Sammaer, A.F.M. Fahmy, G. Hosni, Egyptian J. Chem., 1973, 16, 481.

223. L.H. Briggs, R.C. Combie, I.C. Dean, P.S. Rutledge, Austral. J. Chem.,

1976, 29, 357.

224. F. Ho.eke, Rec. Tray. Chico., 1935, 54, 505.

225. N. Kornblum, D.L. Kendall, J. Amer. Chem. Soc., 1952, 74, 57.82.

226, M.W. Partridge, M.F.G. Stevens, J. Chem. Soc., 1954, 2329.

227. H. Fraenkel-Conrat, H.S. Olcott, J. Amer. Chem. Soc., 1944, 66, 845.

228, J.M. Butler, J. Amer. Chem. Soc., 1949, 71, 2578.

229. A.G. Caldwell, L.P. Walls, J. Chem, Soc., 1952, 2156,

230., A. Eckert, K. Steiner, Monatsh, 1914, 35, 1153.

231. M.F. Grundon, B.T. Johnston, A.S. Wasfi, J. Chem. Soc., 1963, 1436.

232. W. Carruthers, J. Chem. Soc. C, 1968, 2244.

233, N. Campbell, B.M. Barclay, J. Chem. Soc., 1945, 530.

234. C.U. Rogers, B.B, Carson, Org. Synth., 1950, 30, 90.

235, A.O. Fitton, R.K. Smalley, 'Practical Heterocyclic Chemistry',

Academic Press, London, 1968, p. 46.

236. G.M. Badger, J.H. Seidler, B. Thomson, J. Chem. Soc., 1951, 3207.

237. W. Borsche, M. Feise, Chem. Ber., 1907, 40, 378.