The Catalytic Hydrogenation of Benzodiazines

Home , Phthalazine, Quinazoline, Sodium bisulfite

THE CATALYTIC HYDROGENATION OF BENZODIAZINES:

I. PHTHALAZINE

II. QUINAZOLINE

A Dissertation

Presented to the

Department of Chemistry

Brigha~ Young University

In Partial Fulfillment

of the Requirements for the Degre~

Doctor of Philosophy

Danny Lee Elder

August 1969 This dissertation, by Danny Lee Elder, is accepted in its

present form b y the Department of Chemistry of Brigham Young

University as satisfying the dissertation requirement for the degree of Doctor of Philosophy.

ii . , TO

Lynette, David, and Douglas

iii ACKNOWLEDGEMENTS

Deep appreciation is expressed to Dr. H. Smith Broadbent, without whose friendly association, patient help, and kindly ex- · tended advice this research problem could not have been carried out. Gratitude is also expressed £or the many extra-academic endeavors Dr. Broadbent has made on my behalf.

Appreciation is extended to the Department of Chemistry of

Brigham Young University for financial support in the form of teaching and research assistantships.

My wife deserves special thanks for her encouragement, patience, understanding, and especially, for making it all worth- while.

Finally, sincere thanks go to a great group of fellow-graduate students--Craig Argyle, Weldon Burnham, Vic Mylroie, Wes

Parish, and Walter Sudweeks--for helpful discussions, comrade- ship, and most of all, for the memorable hours spent at such places as Anderson Lake, Four-Lakes Basin, Klondike Bluff, and of course, "Organic Pass, 11 (Grosebeck Pass).

iv TABLE OF CONTENTS

Chapter Page

I. INTRODUCTION • • • • • • • • • • • • • • • 1

II. LITERATURE REVIEW • • • • • • • • • • • • 4 Phthalaz~ne • • • • ...... 4

Structure and properties • • • • • • • • • · 4 Synthesis of phthalazine • • • • • • • • • 8 Reduced phthalazines • • • • • • • • • • 10 Quinazoline • • • • • • ...... 12 Structure and properties • . . . . • 12 Synthesis of quinazoline • • • • • 15 Reduced quinazolines • • • • 18

Catalytic Hydrogenation of Benzoazines and Benzodiazines • • • • • • • • 20

Quinoline . 21 . Isoquinoline • • . 22 Quinoxalin e ...... • 23 Cinnoline ...... 24 Phthalazine • 24

III. EXPERIMENT AL • ...... • • • • • • 26

,General Experimental Information •••••. 26

Synthesis of Starting Materials • • • • • • . 30 Phthalazine...... • 30 Quinazoline • • ...... • 35 Preparation of Authentic Samples ...... 38

V Chapter Page

Phthalazine hydrogenation products • • • • 38 Quinazoline hydrogenation products . • • • 46

Hydrogenation of Phthalazine and Quinazoline . • . • . • • • • • 48

General procedures • • • • • .-- 48 Preparation of certain inter .. mediates • • • • • • • • ...... 52 IV. DISCUSSION ...... 55 Synthesis of Starting Materials • • • • • • • 55

Phthalazine...... • • • • • • • • 55 Quinazoline...... • • • • • • • • 56

Proposed Hydrogenation Products • • • • • • 57

Proposed phthalazine hydrogenation products • • • • • • • • • • • 58 Proposed quinazoline hydrogenation products • • • • • • • • • • • • • • 59

Identification of Hydrogenation Products 62

Phthalazine hydrogenation products • • • • 62 Quinazoline hydrogenation products • • . • 70 "Minor" quinazoline hydr~genstion products • • • • • • • • • • • • • • 7 2

Quantitative Analysis of Product Mixtures 75

Phthalazine low-pressure hydro .. g enations • • • . • • • • • • • • . • 7 5 Quinazoline low .. pressure hydro-:- g enations • • • . • • • • . . . • • . 79 Phthalazine high ...pressure hydro- :genations • • . • • • • • • • • • . • 79 Quinazoline high .. pressure hydro ... genations • • • • •. • • • • • • • • • 83

Observations and Conclusions. • • • • • • • 83

vi Chapter Page

Relative Activity of Catalysts • • • • • • • • 83

Low-pressure phthalazine hydro .. genations., ••• ., ., •• ., • ...... 85 Low .. pressure quinazoline hydro .. genations • • ,; .; • ...... • • • • • 87 High .. Pressure Reactions ...... • • • • 87

High .. pressure phthalazine hydrogenations • • • • • • • • •.. • • 88 High-pressure quinazoline hydro .. g enations • • • .; • • .; .; • .; .; 89

Proposed Pathway of Hydrogenations. 90

Phthalazine hydrogenation pathway • • • • 90 Quinazoline hydrogenation pathway. • • • • 96

v. SUMMARY •• ...... 110 VI. LITERATURE CITED ...... 111

vii LIST OF TABLES

Table Page

1. Chromatographic Data • • • • e • • ■ • • I • • 64

2. Low .. Pressure Hydrogenation of Phthalazine • • • • • • • • ...... 76 3. Low .. Pressure Hydrogenation of Quinazoline • • . • . • • • ...... 80 4. High--Pressure Hydrogenation of Phthalazin e • • • • • • • • ...... 81 5. High-Pressure Hydrogenation of Quinazoline . • • . • . • • ...... 84 6. Hydrogenation of Certain Intermediates 94

viii LIST OF F1GURES

Figure Page

1. Proposed Phthalazine Hydrogenation Products ...... 60

2. Proposed Quinazoline Hydrogenation Products • • • • • • • • • • • • • • • • • • 61

3. Proposed Pathway for Hydrogenation of Phthalazine • • • • • • • • • • • • • • . 91

4. Proposed Pathway for Hydrogenation of Quinazoline • • • • • • • • . . • . • • • 97

S. Graph of Molar ,Uptake of Hydrogen with Respect to Time in Low-Press~re Hydrogenations • • • • • • • • • • • • • • • 100

ix LIST OF INFRARED, NUCLEAR MAGNETIC

RESONANCE, AND MASS SPECTRA

Spectrum .Page

Infrared Spectra

1. o<, ~ 1 -Diamino-~-xylene • • • • • • • • • • • • 104

2. £_-Methyl benzylamine ...... 104 3. 1, 3-Dihydroisoindole • ...... 104 4. Phthalazine • • • • • • 105 5. 1, 2-Dihydrophthalazine ...... 105 6. 1, 2, 3, 4-Tetrahydrophthalazine ...... 105

Nuclear Magnetic Resonance Spectra 7. Phthalazine • • • • • • • • • ...... 101 8. 1, 2, 3, 4-Tetrahydrophthalazine ...... 101 9. 1, 2-Dihydrophthalazine ...... 101

10. o(,cx' -Diamino-~-xylene • • • • • • • • • • • • 102 11. £_-Methylbenzylamine...... 102 12. 1, 3-Dihydroisoindole • ...... 102 13. Quinazoline • • • • ...... 103 14. 3, 4-Dihydroquinazoline ...... 103

X Spectrum .Page

Mass Spectra 15. 1, 2, 3, 4-Tetrahydrophthalazine ...... 106 16. 1, 3-Dihydroisoindole. 106

17. Phthalazine • • • • • • 107 18. 1, 2-Dih ydrophthalazine • ...... 107 19. (/..~c,:.. 1 -Diamino-;:-xylene ...... 108

20. £_--Methyl benz ylamine ...... 109

xi I. INTRODUCTION

. Catalytic hydrogenation is one of the most powerful tools available to the synthetic organic chemist. It provides a rela- ti vely simple means of bringing about transformations in organic molecules which might be much more difficult to ' achieve by other chemical methods. A great advantage of catalytic hydrogenation is the convenience with which a reaction can be effected,

Many hydrogenation reactions consist of merely agitating catalyst and substrate in a suitable solvent under hydrogen pressure until the theoretical amount of hydrogen has reacted. After filtering the reaction mixture free of catalyst, one can then obtain the desired prodµct by distillation, extraction, or other conventional separation procedure, In many reactions, conditions can be chosen so that high-reaction selectivity-is achieved, giving quantitative yields of the desired product.

A great deal of research effort has been expended in improv- ing the technique of catalytic hydrogenation. Many workers have studied the types of transformations which can be brought

-about by hydrogenation. Much has been done to develop better

1 2· catalyst systems, and to determine the reaction selectivity of

various hydrogenation catalysts.

One important area of study has been the catalytic hydrogen ..

ation of heterocyclic compounds. Many reports have appeared in

the literature concerning the catalytic hydrogenation of hetero--

cycles. However, relatively few of the studies reported have

been concerned with the unsubstituted parent-heterocycles,

Conspicuously absent from the group of heterocycles which

have been studied are the benzodiazines, This group of compounds

is comprised of quinoxaline, quinazoline, cinnoline, and phthaiazine,

Of these four compounds, quinazoline has received the most at-

tention in connection with its catalytic hydrogenation. However,

· the variety of catalyst systems and conditions reported is very

limited.

A systematic study of the catalytic hydrogenation of the ben"".

zodiazines was undertaken at Brigham Young University several

years ago. Studies of the hydrogenation of quinoxaline and cinno ...

line have already been carried out and are reported (23, 98). Ini-

tial research on quinazoline has also been carried out (101), but

a more complete study is necessary. Phthalazine, the fourth

benzodiazine, had not been studied.

The catalytic hydrogenation of quinazoline and phthalazine,

reported herein, was undertaken with the following objectives in 3 mind: (1) to determine the structure of compounds obtained by hydrogenation of phthalazine and quinazoline, (2) to determine the relative activity of various catalysts in the hydrogenation of phthal .. azine and quinazoline, (3) to elucidate the pathway of hydrogen .. ation for each heterocycle, (4) to determine the synthetic utility of hydrogenation for obtaining the various products formed in the hydrogenation reactions, (5) and to obtain data which would be of value in predicting the course of hydrogenation in other hetero- c ye lie systems. II. LITERATURE REVIEW

PHTHALAZINE

Structure and Properties

Phthalazine or benzo d pyridazine is illustrated below and is numbered according to the system employed in Chemical Abstracts (72).

8 I :oo~: 5 4

Phthalazine is a white, crystalline substance. It forms white, hard prisms when crystallized from ethyl ether (54). It is very soluble in water, ethanol, benzene, and ethyl acetate; less soluble in ether; and insoluble in ligroin ( 41). When boiled at atmospheric pressure, it gives off ammonia (41, 55), but it is stable when distilled in vacuo. It forms mono-acid salts, Physical data for phthalazine are listed below:

Physical Properties

3. 5 (5)

0 mp 90--91 C

bp 315°C/l atm, 189° / 29 torr 175°/17 torr (74)

4 5

Derivatives, mp

~ hyd~ochloride 231° (41)

·hydroiodide 203° (74)

picrate 208--210° (41)

chloroplatinate above 260° ( 41)

methiodide 235--240° (42)

ethiodide 204--210° (42)

UV Spectrum>:,

Amax(nm) log t:

252 3.629

259 3.668

267 3.587

290 1.108

296 1.061

• *determined in inethylcyclohexane (8)

Their spectrum is on page 105.

The 100 mHz nmr spectrum for phthalazine is reported by Black and Heffernan (16) and the high-resolution mass spectrum by Bowie and co-workers (20). Several authors report calculated molecular orbital energy levels and rt-electron densities (44, 67, 96). Wait and 6 ·Wesley's Buckel molecular orbital calculations listed below should

serve as a first approximation of charge densities (96).

0.899 0.983cc~1.151 0.986

Phthalazine forms an adduct with benzyl chloride at room temp-

erature, mp 97--99°C, and it reacts with ethylchloroa~etate to form

a hygroscopic substance which in turn forms a picrate, mp 129--131°C,

(42). When phthalazine is oxidized with alkaline permanganate, pyri-

dazine-4, 5-dicarboxylic acid is obtained in 66% yield (37),

Nitration of phthalazine with potassium nitrate in concentrated

sulfuric acid gives 5-nitrophthalazine as the major product with

· some 5-nitro-l, 2(H)-phthalazone (62),

Mustafa has shown that phthalazine forms l-phenyl:-1, 2-dihydro-

. phthalazine with phenylmagnesium bromide. The product then under-

goes auto-oxidation to form 1-phenylphthalazine (69). Similarly, 7 vinyllithiu.m, phenyllithiurh, and methyllithium add to phthalazine to form the corresponding 1-substituted 1, 2-dihydrophthalazines.

The phenyl adduct, after stirring in air, gives 1-phenylphthalazine easily, while the methyl derivative after auto-oxidation gives a mixture of prod:ucts, one of which is believed to be 1-methylphthal- azine because of its analytical data and.chemical behavior. Re- actions carried out with exces·s alkyllithium did not result in the formation of a di-adduct (55).

Popp and Wefer (75) report a 55% yield of a Reissert comp:mnd (I) on reaction of phthalazine with benzoyl chloride and potassium cyanide,

Treatment of the Reissert compound with 2, 4-dinitrophenylhydrazine in concentrated hydrochloric acid gives the corresponding nitro- phenylhydrazone (II) in quantitative yield. With hydrobromic acid in acetic acid, phthalazine-1-carboxylic acid is formed in 89% yield _ from I. Compound III is obtained quantitatively when the Reissert compound is treated with methyliodide -and sodium hydride in

111

DMF. Further reaction of III with sodium hydroxide gives 1-methyl- phthalazine. 8 Hirsch and Orphanos found that phthalazine forms a stable 1:1

· complex with molecular bromine (57). When bromine is added to

a solution of phthalazine in carbon tetrachloride, a precipitate is

formed which can be dried under high vacuum. The precipitate is

crystalline, mp 122 ...... 123° C and is obtained in quantitative yield.

No apparent change occurred in its ir spectrum mp, or chemical properties after six months. The compound gives a yellow .. orange

solution in ether which is decolorized by addition of cyclohexene.

When acetone is added, the solution also becomes colorless and phthalazine hydrobromide is formed. These properties suggest that the compound is a charge-transfer complex.

Synthesis of Phthalazine

Phthalazine was first prepared in 1893 by Gabriel and Pinkus (41)

by heating , , 1, 1 .. tetrachloro•£"xylene and .aqueous hydrazine under pressure for two hours at 150°c. Similarly, it was prepared

by refluxing the tetrachloro ..£ ...xylene '6..,.. 8 hours in water, followed

(8y-CHCl2 + + 4HCI ~CHCl2

by addition of potassium hydroxide and hydrazine sulfate (57). In

both cases, phthalazine was isolated as the hydrochloride from which the free amine was liberated by additidn of base and then subsequent

extraction with benzene. Gabriel (42) later reported that use of 9 , , 1, •~tetrabro1no~•~""xylene gave a more convenient synthesis than

the corresponding tetrachloro ...o ...xylene (88% yield). ' -·.- Paul (74) and Gabriel (37) report the preparation of phthalazine

in 75% yield by reduction of 1:""chlorophthalazine with hydroiodic acid

· and red. phosphorous under reflux.

HI ---c:- ©©i p ©©t+ HCI

When phthalazone is treated with phosphorous pentachloride in

refluxing phosphorous oxychloride, it gives 1 ...chlorophthalazine

which may be reduced catalytically with 5% palladium .. on ...charcoal

to give phthalazine (90).

Mustafa and co ...workers (69) and Smith and Otembra (88) pre ... pared phthalazine by reaction of ~ .. phthalaldehyde with aqueous . hydrazine sulfate in the presence of sodium hydroxide. Yields were

relatively satisfactory (56%).

(8yCHO

·~CHO 10 By boiling 1 ...hydrazinophthalazine monohydrochloride with

· aqueous copper sulfate, foliowed by basification and extraction

with chloroform, Armarego obtained phthalazine in 60% yield (9).

Aq CuS04 ~ . oo~

In the author's experience, the most convenient synthesis

reported to date is that of Hirsch and Orphanos. £--Phthalaldehyde

is used for starting material. This compound is commercially

available or is easily obtained by the procedure described ih "Organic

Synthesis" (77). An ethanolic solution of £-phthalaldehyde is added

dropwise under nitrogen to an ice~cold solution of hydrazine hydrate

in ethanol. After additional stirring at o0 c and then at room temp~

erature 1 the ethanol, water, and excess hydrazine are evaporated.

The resulting yellow oil is clarified with charcoal in ether solution

until colorless. The ether solution yields phthalazine as white, hard

prisms 1 mp 90o,§.. 91°c (yield 96%) (54).

Reduced Phthalazines

Very little research has been reported on reduced phthalazine

compounds.

Phthalazine was reduced to 1, 2, 3, 4etetrahydrophthalazine when

treated with 7o/oNa-Hg amalgam (40, 48). When treated with zinc 11 in aqueous hydrochloric acid, phthalazine yielded , 1 -diamino-o-

Zn HCI - xylene (40, 41, 43). 1, 2, 3, 4-Tetrahydrophthalazine has also been obtained by reaction of , 1 -dibromo-.£_-xylene with di-_!:-butylaz- idodiformate and subsequent decarboxylation (26).

Recently, Elslager reported that , 1 -diamino:-~-xylene was obtained when phthalazine was hydrogenated over 20% palladium-on- ' charcoal, and subsequently over Raney-nickel (33).

I) 20% Pd/C ·2) Ni

Shabarov ~ al. reported the synthesis of 1, 2-dihydrophthalazine in 40% yields by reduction of phthalazone with lithium al~minum '· hydride in ether (84), It should be noted, however, that the reported properties of this compound and its phenylthiourea derivative differ quite markedly from that of a compound obtaifed by catalytic reduction of phthalazine which is also believed to be 1, 2-dihydrophthalazine.

(See page 52),

Smith and Otembra reported that reduction of 2-benzylphthala- zinium chloride with aqueous NaBH 4 gave a crude mixture which upon refluxing with excess methyl iodide gave a 31% yield of 12

2, 2-dimethyl-_l, 2-dihydrophthalazinium iodide. They concluded that at least some debenzylation must have accompanied the reduction to give 1, 2-dihydrophthalazi.ne {88).

QUINAZOLINE

Structure and Properties

QuinazoJine or benzo d pyrimidine {73) is a low-melting, white, crystalline solid (9, 36, 80). On standing in air, it gradually becomes yellow, but the colored impurtties seem to have little affect on its physical properties. It is soluble in most common organic solvents, and gives an alkaline reaction in water {36). When dissolved in water, it: exhibits coval"ent hydration, i_: ~• reversible addition of water 1 across the 3, 4-double bond with protonation of position-3 (6, 7).

The structure of quinazoline is given below, numbered according to the system employed in Chemical Abstracts (73).

G 5 4

1 Because of this, the pK a value obtained depends upon the . method used to determine it. If both protonated, and non-protonated species are anhydrous, the pKa is 1. 9. If both species are hydrated, the pKa value is 7. 8. If the pKa is determined without rapid-reaction apparatus, then the pKa is 3. 5, due to 13 Quinazoline can be distilled without decomposition (9, 36, 80) at atmospheric pressure; it sublimes readily under vacuum (15); and it can be recrystallized from ligroin. Physical data for quinazoline are listed below:

Physical-Properties

mp 48~ .. 48. 5°c (9, 36, 80)

bp 243° /772. 5 torr 241° / 761 torr 120°/17 torr (9, 36, 80)

3. 5 (7. 8, 1. 9) (5, 63)

Derivatives, mp

hydrochloride 127 ~ ...128° (6)

picrate 188 ..."190° (36)

aurichloride 185° (36)

chloroplatinate above 250° (36)

3-methiodide 165° (35)

equilibrium mainly between anhydrous neutral species and the hydrated cation (5). · 14 Spectra

UV (64) (in hydrocarbon solvent)

"A-max (nm) A

330 200

311 2100

267 2810

220 41,000

The nm1• spectrum is on page 103.

The nmr spectrum for quinazoline is ,reported by several workers (14, 16, 44, 65) with assignments for all proton signals in the 100 mHz spectrum appearing in Black and Hefernan 1 s paper (16).

However, their work is in disagreement with the later work of

Katritzky and co.,workers (65). The only available inf~rmation on the mass spectrum of quinazoline is that of Batteham which appears in Armarego 1 s review (24).

Ruckel-orbital calculations for quinazoline are reported by

Wait and Wesley. The values they obtained are given below and should serve as a first approximation of charge densities (96):

1.016 1.223 N 0.969 10.841 1.003 N 1.206 0.973 '0~830 15 Recent work has shown that quinazoline is very reactive towards

nucleophilic attack at position-4, resultin·g in addition to the 3, 4-

double bond. Reagents reported active are sodium bisulfite (6, 53),

hydrogen cyanide (53, 93), acetophenone (49), acetone, 2-butanone,

cyclohexanone (50), several common Grignard reagents (6, 13, 52, 53),

and phenyllithium (53), In aqueous sodium cyanide, quinazoline forms

a product which on mild oxidation yields· 4, 4 1 -biquinazolinyl (14),

Quinazoline nitrates at position-6 in 56% yiel'd (31, 8 2). It under-

goes nucleophilic aromatic substitution with sodamide or hydrazine to give the 4-amino and 4-hydrazino derivatives~ respectively (53).

N-alkylatioh of quinazoline occurs on the number-3 nitrogen (38, 39,

47,79,83).

Oxidation of quinazoline in alkaline permanganate gives pyrimidine-4, 5-dicarboxylic acid with some 3, 4-dihydro-4-oxoquinazoline

(38). When boiled in hydrochloric acid, the products are o-amino-

benzaldehyde, ammonia, and formic acid (36).

Synthesis of Quinazoline

Quinazoline was prepared first by Bischler and Lang in 1895

by heating 2-carboxylquinazoline with calcium oxide (15).

In 1903 Gabriel synthesized quinazoline by oxidation of 3, 4- dihydroquinazoline with potassium ferricy':'-nide (36). The starting material was obtained.by reaction of ~-nitrobenzylamine with formic 16 acid and the subsequent reduction of the o-nitro-N-benzylformamide - t with zinc in hydrochloric acid at -10°c.

~NHCHO ~ efNH ~N 02 H CI ~N)

In a patent in 1915, Riedel described the direct synthesis of quinazoline by the zinc-acetic acid reduction of o-nitrobenzylidene- . . - cliformamide which was prepared from ~-nitrobenzaldehyde and for:namide (1, 18, 80). This is probably the best and mo st direct synthesis reported, but has had limited use because of the high expense of ~-nitrobenzaldehyde.

Several workers have prepared quinazoline by reducing 4-chloroquinazoline catalytically and stopping the reaction after, the absorption of one mole of hydrogen to prevent formation of 3, 4-dihydroquinazoline (29, 31, 53). This method was used by Armarego (9),. and later by

Young (101) to obtain quinazoline in 50-g quantities. The 4-chloroquinazoline is readily obtained by heating anthranilic acid and formamide and then heating the resulting 4-quinazolone in refluxing phosphorous pentachloride and phosphorous oxychloride (9,101). 17 4 ...Chloroquinazoline is difficult to keep for long periods of time

because it readily undergoes auto ...catalyzed hydrolysis to give

-=-~N~ ~NH II 00Cl 0

4 .. quinazolone and hydrochloric acid. Catalytic reductions of

.. 4.,.chloroquinazoline are reported to work better with palladium ...

on~calcj,um carbonate (31), magnesium oxide (53), or with 1. 5

equivalents of sodium acetate in the reaction mixture (9).

Either 2 ... or 4 .. chloroquinazoline can be converted to the cor•

responding N 1 ... toluene ...p ..,sulphonylhydrazinoquinazoline which on

decomposition by heating in an alkaline solution gives quinazoline

in 60% yields (10, 13).

~AyCI ~~

Quinazoline has also been prepared b·y the Bischler synthesis

from~ ... formamidobenzaldehyde and ethanolic ammonia (12).

·rc:3'YcHo N ~NHCHO CHOH 00 18

Reduced Quinazolines

Very little research on reduced quinazolines has been report-

ed. The only unsubstituted, reduced quinazolines reported are

3, 4-dihydroquinazoline, 1, 2, 3, 4-tetrahydroquinazoline, and

5, 6, 7, 8-tetrahydroquinazoline, All of ·the other reduced quina-

zolines reported are substituted,

The 3, 4-dihydroquinazoline obtained by the catalytic reduction of quinazoline has been known for some time, Use of palladium- , on-charcoal (9), palladium-on-calcium carbonate, Raney-nickel, or Adams catalyst under low, hydrogen pressures and ambient temperatures all gave 3, 4-dihydroquinazoline (31). Bogert and Marr

report that hydrogenation of quinazoline stopped after one molar

equivalent of hydrogen was absorbed (17). Adachi found that under more vigorous conditions, 3, 4-dihydroqutnazoline would yield

1, 2, 3, 4-tetrahydroquinazoline when hydrogenated over 1% palladium-

on-charcoal (2).

The 1, 2, 3, 4-tetrahydroquinazoline was also obtained by reaction

of 3, 4-dihydroquinazoline with sodium in alcohol or with sodium

amalgam in alcohol (36), Both 3, 4-dihydro- and 1, 2, 3, 4-tetra-

hydroquinazoline were obtained v,hen sodium borohydride or lithium

aluminum hydride were reacted with quinazoline, With longer reac-

tion time, the latter reagent gave N«-methyltoluene-Gt 2.;.diamine (87). 19 3. 4 ...Dihydroquinazoline was also obtained by reaction of quinazoline in refluxing hydroiodic acid (36). (@;}H)

HI . 6. ©()H

Although 1, 2 .. dihydroquina·zoline is not known, its 3 ...allyl, and

3 .. methyl quaternary salts have been prepared under physiological cond\tions from £_... aminobenzaldehyde, formaldehyde, and the ap ... propriate amines (83).

1 ...Methyl and 1-.benzyl ..l, 4 ...dihydroquinazoline are kn o~n (11, 68), but attempts to obtain the parent 1, 4~dihydroquinazoline by debenzyl.-. ation of the 1.. benzyl compound resulted in 70% yields of 3, 4:"'dihydroN quinazoline _(11).

RI ©() H H r I

Unsubstituted 2, 3-dihydroquinazolines are unknown and would be expected to be very unstable because of the £_... quinoid structures 20 that would be required in both the benzo- and hetero- rings. Some

substituted 2, 3-dihydroquinazolines have been reported (22).

N~ ?' IH ~ NR

Unsubstituted 5, 6, 7, 8-tetrahydroquinazoline is known (21}, but this compound was not obtained from reduction of quinazoline,

It can be considered a 4, 5-dialkylpyrimidine, and indeed, exhibits behavior similar to 4, 5-dimethylpyrimidine (22) •. I Only a few 5, 6-dihydroquinazolines are known, but none of those reported is unsubstituted. None of them result from direct or indirect reduction of quinazolines.

CATALYTIC HYDROGENATION OF BENZOAZINES

AND BENZODIAZINES

It is intended that the cursory review which follows will provide further supplementary information which is relevent to the investigations described in this dissertation. The review is limited to the catalytic hydrogenation of the unsubstituted benzoazines, quinoline and isoquinoline, and the unsubstituted benzodiazines, quinoxaline, cinnoline, quinazoline, and phthalazine,

In all of these benzo-fused heterocycles, the overwhelming

evidence indicates that the hetero- ring is preferentially hydrogenated, 21

Usually resulting in the 1, 2, 3, 4-tetrahydro derivative. In some cases (quinoline, isoquinoline, and quinoxaline), the decahydro compounds have been obtained by employing more drastic reaction conditions.

Quinoline

1, 2, 3, 4-Tetrahydroquinoline was obtained by catalytic reduction of quinoline under a variety of conditions. It was obtained by

Hamilton and Adams (46) using platinum oxid~ in ethanol at relatively low pressure. Adkins and Billica (3) reported similar results using a nickel catalyst at one-to-three atmospi~eres pressure, while

Darzens (28) used reduced-nickel catalysts at elevated temperatures to obtain it.

Several authors reported formation of decahydroquinoline under more drastic conditions. Using nickel oxide at 240°C and 110 atm pressure, Ipatief (61) obtained decahydroquinoline after 12--14 hours.

When Adkins used nickel-on-k~eselguhr at 150°C and 160 atm, he obtained tetrahydroquinoline after one--four hours (4). However, at 175°c and 175 atm and six--eight hours reaction time, he obtained a mixture of cis- and trans -decahydroquinoline. Similarly,

Tsushima reported 71--73% 1, 2, 3, 4-tetrahydroquinoline using a reduced-nickel catalyst at 70--10o 0 c and 70 atm, but at 210°c and 70 atm, he obtained 62% trans-decahydroquinoline (95), Skita 22 obtained decahydroquinoline, using large amounts of colloidal platinum in acetic acid and hydrogenating for nine hours (86); while

Huckel and Step£ (60) reported that employing Skita' s method obtained 6 5% cis - and 35% trans-isomer using acetic acid and excess concentrated hydrochloric acid, but quinoline oxalate in acetic acid gave 80% trans- and 20% cis-isomer. Overhoff found mostly trans- isomer using platinum oxide in acetic acid, but the amounts of cis- isomer increased if quinoline hydrochloride was hydrogenated in ' alcohol. He also reported that the decahydroquinoline was obtained only after exceedingly long reaction times (71). Finally, Sugino obtained mostly trans-decahydroquinoline from 1, 2, 3, 4-tetrahydroquinoline ,by hydrogenating at 260°C over a copper catalyst (92).

Isoquinoline

The hetero-ring in isoquinoline is preferentially reduced and requires more drastic conditions for reduction than quinoline.

In 1923 Helfer obtained onl_y 1, 2, 3, 4-tetrahydroisoquinoline using a colloidal platinum catalyst (51). Elliot (32) and Walters (97) both reported that isoquinoline gave preferential reduction of the hetero-ring. Skita found that he could obtain the octahydroquinoline by adding chloroplatinic acid after the tetrahydroquinoline had formed, or by beginning with enough chloroplatinic acid so that the platinum content was 20% by weight of the substrate (85). 23 Witkop (99} obtained mostly cis-decahydroisoquinoline at low pressure using large amounts of platinum oxide and excess sulfuric acid. If less than a 100% ratio of catalyst-to-compound was used, however, the hydrogenation stopped after formation of 1, 2, 3, 4-tetrahydroisoquinoline. When nickel catalysts were used at 270 atm for

15--18 hours at l00°C, 10% trans-decahydroisoquinoline was obtained.

Friefelder (34} obtained the decahydroisoquinoline in good yields ' at 90°C and 70 atm. R. B. Woodward obtained the decahydroisoquinoline by ac ylation of the 1, 2, 3, 4-tetrahydroisoquinoline, hydrogenation to the decahydro compound, and then deacylation (100}.

Quinoxa.line

Cavagnol reduced quinoxaline over platinum oxide in benzene at room temperature and 50--80 psi to obtain.1, 2, 3! 4-tetrahydroquinoxaline in 92% yields (27}. Broad~ent and co-workers found that 5% rhodium-on-alumina in ethanol at 2000 psi and l00°C gave the 1, 2, 3, 4-tetrahydroquinoxaline, but that by using scrupulously clean equipment, they could obtain 93% cis-decahydroquinoxaline under the same conditions (23).

Quinazoline

Elderfield used palladium-on-carbon, palladium-on-calcium carbonate, Raney-nickel or Adams catalyst to obtain the 3, 4- dihydroquinazoline (31}. Bogert and Marr found (17) that catalytic 24 reduction of quinazoline stopped after one mole of hydrogen was

absorbed, while Adachi reported that the 1, 2, 3, 4-tetrahydroquin"."'

azoline.could be obtained by reducing 3, 4-dihydroquinazoline under

slightly more drastic conditions (2).

Young reported the hydrogenation of quinazoline with 5% rhodium-

on-alumina under a variety of conditions. At low pressure (60 psi)

in both neutral and acidic solvents, he obtained only 3, 4-dihydro-

quinazoline, while at 2000 psi and 125°c, £_-toluidine, Nc,t-methyl-

toluene-~, 2-diamine and N::N"'" -dimethyl-o(., 2-diamine were formed

(101), He did not account for all products,

.Cinnoline

The only published work on the hydrogenation of unsubstituted_

cinnoline is that of Westover, who found that like all other benzo-

heterocycles, the hetero-ring is preferentially hydrogenated, He

reported the use of five different catalysts and a variety of conditions.

1 At low pressure and room temperature, 1, 11 , 4, 4 -dihydrobicinno-

lyl-1, 4-dihydrocinnoline, o-aminophenethylamine, 1, 2, 3, 4-tetra- - l hydrocinnoline.and-indole were the major products while at higher

temperatures (100--150°C) and higher pressures (1500--2000 psi),

cis-octahydroindole_ became a major product (98).

Phthalazine

The only reported catalytic reduction of phthalazine is by

Elslager and co-workers. They obtained d....cA'-diamino-~-xylene 25 by reducing phthalazine at low hydrogen pressures over 20%

Pd/ C until two molar equivalents of hydrogen was absorbed. The reaction stopped, Raney ...nickel was added and the mixture was hydrogenated until one more molar equivalent of hydrogen was absorbed (three molar equivalents total) (33). 24 reduction of quinazoline stopped after one mole of hydrogen was

absorbed, while Adachi reported that the 1, 2, 3, 4-tetrahydroquin-

azoline could be obtained by reducing 3; 4-dihydroquinazoline under

slightly more drastic conditions (2).

Young reported the hydrogenation of quinazoline with 5% rhodium-

on-alumina under a variety of conditions. At low pressure (60 psi)

in both neutral and acidic solvents, he obtained only 3, 4-dihydro-

quinazoline, while at 2000 psi and 125°c, £-toluidine, Not-methyltoluene-~, 2-diamine and N:~N<>C.-dimethyl-oC., 2-diami'i:ie were formed

(101). He did not account for all products.

Cinnoline

The only published work on the hydrogenation of unsubstituted_

cinnoline is that of Westover, who found that like all other benzo- heterocycles, the hetero-ring is preferentially hydrogenated. · He

reported the use of five different catalysts and a variety of conditions.

1 1 At low pressure and room temperature, 1, 1 , 4, 4 -dihydrobicinno-

lyl-1, 4-dihydrocinnoline, £-aminophen~thylamine, 1, 2, 3, 4-tetra- hydrocinnoline and indole were the major products while at higher temperatures (100--150°C) and higher pressures (1500--2000 psi),

· cis-octahydroindole_ became a major product (98).

Phthalazine

The only reported catalytic reduction of phthalazine is by

Elslager and co-workers. They obtained d..,(R-diamino-£-xylene III. EXPERIMENT AL

GENERAL EXPERIMENT AL INFORMATION

Elemental analyses were obtained from M-H-W Laboratories,

Garden City, Michigan.

Infrared spectra were recorded on Beckman IR-5, IR-8, IR-7, and Perkin-Elmer_ 457 and 700 spectrophotometers. Solid samples were run in KBr wafers, and liquid samples were run as neat films between salt plates.

Nuclear magnetic resonance spectra were recorded on a

Varian A-60A spectrometer. Samples were run as neat liquids or as 30% w/v solutions in CDCl3 or CC1 4 contai1:ing TMS as an internal standard.

Mass spectra were obtained on a Finnigan 1015 quadrupole mass spectrometer. All spectra were recorded at 70 volts ionization potential and 200 amps total ion current.

Melting points were obtained on a Thomas-Hoover melting- point apparatus and ·are uncorrected.

Gas chro1natography was carried out on two instruments, A

Varian Aerograph model A-700 was used for preparative work. This instrument was equipped with an automatic sample injector,

26 27 automatic fractio.n collector, and a Honeywell-Brown 11Electronik 11

Recorder. For quantitative determinations of product ratios, a

Perkin-Elmer F-11 was used. The recorder for· this instrument was equipped with a 11Disc 11 integrator.

Several chromatography columns were prepared and examined in an effort to obtain good resolution of all of the hydrogenation components. With each column, isothermal runs were made at various temperatures between 150° and 230°C. Each column was also tested several times using the linear-temp<::rature programmer

set at various heating rates. The columns tried are listed below:

1. 5% silicone grease on firebrick, 80--120 mesh.

2. 10% KOH, 10% SE-30 on Chromosorb G, 80--120 mesh.

3. O. 25% SE-30 on glass beads.

4. 15% SE-30 on acid-washed, DMCS-treated Chromosorb W.

5. 10% Versamide 900 on acid-washed, DMCS-treated Chromo- sorb G.

6. 5% SE-30 on acid-washed, DMCS-treated Chromosorb G.

7. 10% Carbowax 20M on acid-washed, DMCS-treated Chromo- sorb G.

8. 10% SE-30 on Fluoropak.

9. 15% SE-30 on acid-washed, DMCS-treated Chromosorb W. This column is identical t6 #4, bl.it was subsequently treated four times with 10-liter amounts of Silyl-8 at 150°c after installation in the chromatograph.

All of these columns were made with 1/8 11 O. D.- x 9 1 aluminum tubing

except for column #3 which was 20' long. Column #9 gave the best 28

results and was used for all analytical work. A preparative column

was made using 1/ 4 11 O. D. x 10 1 ahuninum tubing, and the same

column packing described for column #9 above.

The relative peak areas on the chromatograms were determined

from the "Disc" integrator trace and were corrected by reference

to "known" mixtures. (See page 79 in discussion section.) Reten ...

tion times relative to ethanol were determined for hydrogenation

products and are given in Table 1.

Thin--layer Chromatography; ...... Three types. of thin ...layer chrom ...

atography were employed. For routine qualitative work, micro ..

scope slides coated with silica gel G of O. 25 mm thickness were

used. Quantitative work was carried out on 5 x 20 cm plates coated with a O. 25 mm layer of silica gel G. Preparative thinfflayer work was carried out on 20 x 20 cm plates coated with either a O. 50 mm

or 1. 0 mm layer of silica gel G.

The plates were coated with a 1: 2 (by weight} slurry of silica

gel G in distilled water using a Desaga .. Brinkman thin ...lay~r chrom ..

atog3;aphy spreader. The plates were activated after drying by heating in an oven for one hour at 105°c. They were then stored in a desiccator over CaC1 -until subsequent use. 2 Several developing solvents were tried, and it was determined that either 95% ethanol or 100% methanol gave good separation of the 29

various hydrogenation products. Slightly better resolution of the

phthalazine-hydrogenation products was obtained with 95% ethanol

· than with 100% methanol. The quinazoline-hydrogenation products

were resolved satisfactorily with either solvent. Ethanol solutions

of produc_t mixtures were spotted on the thin-layer plates using

1. 0-liter capillary pipets. All the plates thus spotted were then de-

veloped approximately 10 cm. The plates were visualized by either

allowing them to stand in iodine vapor or spraying with a solution

of 2% ninhydrin im ethanol. Rf values for the various hydrogenation products were determined and the results are reported in Table 1.

Hydrogenation Apparatus. -- The low-pressure hydrogenations

were carried out in a Parr low-pressure reaction apparatus. Re-

action vessels were designed and constructed to provide efficient

agitation of the reaction mixture. Pressure was indicated by a

gauge and was periodically recorded during the reaction.

The high-pressure reactions were effected in a Pressure

Products Industries 330-ml 11Pendaclave 11 Reactor. Glass liners

were used for convenience in transferring and handling of reaction

mixtures, Pres sure and temperature changes were recorded using

a Leeds and Northrup X1-Xz dual-pen recorder. The pressure-

sensing element was a Baldwin SR-4 pressure cell.. An iron-

constantan thermocouple mounted ·in the well of the glass liner

measured the temperature. The temperature was thermostatically 30 controlled to within t3°C of the desired temperature with a Leeds and Northrup Speedomax DAT proportional control unit. The reaction m.ixtures were agitated by a motor-driven pendulum which was set to swing at 60 rpm.

SYNTHESIS OF STARTING MATERIALS

Phthalazine

Method A

r/,.,c,{,1)( 1 ,d,. 1 -Tetrabromo-o-xylene (77), - -In a 2-liter flask equipped with a stirrer, dropping funnel, thermometer, and reflux condenser was placed 117 g (1.1 moles) of reagent-grade £-xylene, The reflux condenser was equipped with a gas absorption trap. After heating the £-xylene to 120°, the stirrer was started and 700 g ( 4. 4 moles) of bromine was added dropwise at such a rate that the bromine color was removed as fast as it was added, A uv lamp was placed in close proximity to the reaction flask to enhance the reaction rate. After approximately one-half the bromine was added, the reaction mixture began to darken. The temperature was slowly increased to 175°c and the remainder of the bromine added at such a rate that no appreciable bromine color was visible in the reflux condenser, The addition time was fifteen hours. The mixture was stirred an additional one hour at 170°c. It was then poured into a large beaker and allowed to cool overnight. 31 The resulting black, solid mass was dissolved in two liters of hot chloroform and treated three times with 100-g portions of decolor.,. izing carbon. The tan .. colored_ filtrate was then concentrated to ap.,. . l proximately 300 ml by distillation and cooled to o° C. The result ... ing tan, crystalline material was filtered off and washed with cold chloroform. The filtrate was concentrated further and cooled to obtain a second crop of crystals. Total yield was 220 g (52%}, mp 114. 5 l to 116°c (lit. ns .....n6°c).

This reaction was repeated three times starting with 1. 4 moles,

O. 94 moles, and 1.1 moles of ~ ...xy~ene. Yields for these reactions were 60%, 67%, and 75%, respectively.

oPO·Phthalaldehyde (Ti) ...... To a one ...liter flask equipped with a stirrer and reflux condenser was added 500 ml of 50% (v/v) ethanol/ water solution. To this was added 40 g (0. 095 moles) of <1-,"--,~•A!... tetrabromo ..~ ...xylene. The mixture was stirred and refluxed for fifty hours. The solution bec·ame clear after 24 hours. About 200 ml of '· solvent was removed by distillation. Trisodium phosphate dodeca- hydrate (100 g) was then added and the mixture was rapidly steam- distilled. The distillate was tested for £ ...phthalaldehyde periodic".' ally by treatment of a small aliquot with concentrated ammonium hydroxide followed by glacial aceti<: acid. The steam distillation was stopped (~ 1200 ml of distillate) when the distillate no longer gave a black.,.color test for £ ...phthalaldehyde. The distillate was then 32 _ saturated with sodium. sulphate at room temperature and extracted three times with 150 ...ml portions of ethyl acetate. The extracts were then dried over anhydrous sodium sulphate, filtered, and concentra ..

ted in vacuo to a yellow oil ,vhich solidified upon cooling, mp 53 .. M

54° C (lit. 55. 5 ....,.56°C}. The yield was 9. 5 g (80%).

This procedure was repeated twice starting with 0. 62 moles, and once starting with 0. 83 moles of c,<,~~•,o<. 1 --tetrabromo ...~"'xylene.

Yields were 49%, 84%, and 86%, respectively.

Phthalazine -(54) ...... A solution of 9. 0 g ·of 95% hydrazine in 60 ml

0 of ethanol was placed in a 250~ml flask and cooled to .o c in an ice bath. To this was added, dropwise and with stirring, a solution of

8. 0 g (0. 062 moles) of £_...,phthalaldehyde in 60 ml of ethanol. The addition rate was adjusted so as to maintain a temperature of o0 c and took approximately 45 minutes. After the addition was complete, the mixture was stirred an additional one hour at 0°C. The reaction mixture was then allowed to warm to room temperature and stir.,. ring was continued an additional two hours. The mixture was then concentrated in vacuo· on the steam bath to a yellow oil which solid ... ified upon cooling. The solid was stored over concentrated H 2SO4 for 24 hours before further workup. It was then dissolved in ethyl ether and clarified with 1. 0 g of decolorizing carbon. After filter ... ing, the solution was evaporated. Two crops of a white, crystalline solid were obtained. The combined yield of 7. 0 g was obtained, (88%}, 33.

0 mp 88--90 C (lit. 90--91°C). This procedure was scaled up to

0.15 moles, 0. 65 moles, 0.12 moles, and 0. 51 moles. Respective yields of 84%, 87%, 87. 5%, and 87. 5% were obtained.

It should be noted that complete evaporation of the ethyl ether gave additional material which was impure. This material was saved from each run, combined, and recrystallized. It is estimated that had this been done for each individual reaction, phthalazine \ would have been obtained in nearly quantitative yields.

Method B

4-Chlorophthalazine (90). - -In ·a 50-:ml flask were placed 2. 0 g

(0. 014 moles) of phthalazone and 7. 0 ml of phosphorous oxychloride.

The mixture was heated on a steam bath, and after three to five minutes, the phthalazone dissolved, giving a green solution. The solution was heated for an additional ten minutes, and then allowed to cool. The cooled solution was then slowly poured onto 40 g of ice and neutralized to pH 7 with 10% Nc:l.OH solution. The resulting flocculent, light-yellow precipitate was· filtered to yield 2. ,2 g

{98%) of light-yellow solid, mp 109--lll°C dee (lit. 113°C). This reaction was scaled up and repeated with comparable results.

Hydrogenolysis of 4-chlorophthalazine. - -Freshly prepared

4-chlorophthalazine was obtained by the reaction described above beginning with 5 g. (0. 034 moles) of phthalazone. Immediately after ' 34 the filtration step, this material was dissolved in 25 ml of benzene and dried over anhydrous sodium sulfate. This solution was decanted into a hydrogenation vess~l to which was then added 0. 68 g of 5%

Pd/ C suspended in 25 ml of benzene and 20 ml of c1:bsolute ethanol.

The mixture ~as hydrogenated for three hours at an initial pressure of 60 psi.. After removal of the catalyst, the filtrate was treated with

5. 0 g of sodiur.p acetate, then extracted with 10% NaOH solution. The organic phase was evaporated on the steam bath to a viscous, brown material. This material was vacuum distilled. A fraction with . bp ll9--122°C/O. 05 torr was collected. Tq_is light-yellow liquid solidified on standing, and weighed 1. 5 g (34%) mp 88--91°C. This material was shown t~ be phthalazine by its ir spectrum.

Miscellaneous

1, 4-Dichlorophthalazine (56). --A mixture of 50. 0 g of PCl5 and

10. 0 g (0. 063 moles) of 1, 4-phthalazinedione was sealed in a Carious tube and heated at 150°c for 6-1/ 2 hours. The tube was then chilled and opened cautiously to allow the HCl gas to escape. The light- yellow solid was added to one liter of ice water and the precipitate broken up with a stirring rod, The mixture was then basified slowly using aqueous ammonia. The compound was filtered off and the filtered cake taken up in CH 2c1 2. Unreacted starting r:naterial was_ remo'{ed by filtration {2. 2 g) and the CHzClz solution evaporated to 35 a thick paste on the steam bath. The paste was triturated with ethyl ether, and the resulting light-yellow crystals filtered off and dried in air, mp 160--161°C (lit. 161--162°C). The yield was 9. 5 g (68%}.

The ir spectrum of this material was identical in all respects with that reported fo the literature,

Attempted Hydrogenolysis of 1, 4-dichlorophthalazine. --A mixture of 4, 0 g (0. 02 moles) of 1, 4-dichlorophthalazine, 1. 2 g of 5% Pd/ C in 10 ml of benzene, 6. 5 g of sodium acetate, and 40 ml of anhydrous ethanol was placed in a low-pressure hydrogenation bottle. The mixture was hydrogenated for six hours at 60 psi initial pressure at which time the reaction ceased. Only O. 66 of the theoreti,cal amount of hydrogen was absorbed, The mixture was filtered and the solution evaporated to a thick, yellow oil which solidified upon cooling. Various attempts to isolate phthalazine from this mixture failed.

Quinazoline

Method A

o-Nitrobenzylidenediformamide· (80}. --A mixture of 25. 0 g

(0 .168 moles) of ~-nitrobenzaldehyde and 38 ml of practical-grade formamide was placed in an open flask. Anhydrous HCl was bubbled l through the solution. After five minutes, a thick, yellow, solid mass formed and the mixture gradually became hot, It was allowed to 36

cool, and then 75 ml of distilled water was added, The yellow cry-

stals were then filtered, The solid was added to 700 ml of boiling water and the resulting solution chilled. The crystals obtained were \.. .

filtered off and subjected to the same recrystallization treatment. l.

The resulting light-yellow crystals were dried for thirty minutes

at 107°c. Weight, 24.1 g (64%), mp l80--181°C (lit. 181--181. 5°C).

This procedure was repeated twice using 0, 336 moles of o-nitro-

benzaldehyde with yields averaging 74%,

Quinazoline {80). --To a one-liter flask were added 25, 0 g

(0. 112 moles) of £-nitrobenzylidenediforrriamide, 84 g of zinc dust,

and 250 ml of ice water {slush}. The flask was placed in an ice bath

and the contents stirred vigorously, Then 80 ml of glacial acetic

acid was added dropwise over a period of one and one-half hours,

Occasionally more portions of zinc and ice were added, The temp- ,,

erature was not allowed to exceed 25°c. After the addition was com-

plete, the mixture was stirred one hour. The ice bath was then re-

moved, and while still being stirred, the mixture was allowed to

attain room temperature. T}1e excess zinc powder was filt~red off.

By.use of an ice bath, the temperature of the filtrate was kept below

20°c while 200 g of ·NaOH in 200 ml of water was slowly added;

Initially, a flocculent precipitate formed which gradually dissolved

as more base was added. The basified mixture was then extracted with

four 150-ml portions of ethyl ether. The combined extracts were 37 dried with anhydrous Na co overnight. The ether was then de- 2 3 canted and dried for an additional two hours over fresh Na co . 2 3 Evaporation of the ether afforded 12.1 g (83%) of a light-yellow oil which solidified upon standing, mp 45--46°c {lit. 46--48°c). This material distilled at 71°C/O. 4 torr to give a white to yellow solid, mp 46--48°c.

This procedure was repeated twice using 0. 224 moles of.£_- nitrobenzylidenediformamide and yields of 82% were obtained.

Method B

4-Quinazolone (9,101). --A mixture of 548 g (4,0 moles) of anth- t ranilic acid and 268 ml of formamide was heated in an open .beaker at 125--13o 0 c for four hours. A solid cake of crystals formed and was filtered off ,and washed with ice-cold ethanol. 4-Quinazolone was obtained in 86% yield (503 g), mp 214--216°c {lit. 215--216°c).

4-Chloroquinazoline (9,101). --A mixture of 240 g (1. 64 moles) of

4-quinazolone, 1920 ml of PO(:1 3, and 540 g of fresh PCl5 was refluxed for eight .hours at which time ':1-solution resulted, The POCl3 was removed by vacuum distillation, leaving the crude 4-chloro- quinazolone as a dark-red residue. Vacuum distillation of this ma~- erial gave a white, crystalline product, mp 96--98°C {lit. 97--

99°C). 38

The 4-chloroquinazoline rapidly undergoes auto-catalyzed hydrolysis to give 4-quinazolone, causing difficulty in subsequent usage.

Because of difficulty in conven;i.ently obtaining sufficient quantities of 4-chloroquinazoline, it was decided to try another method of

synthesizing quinazoline.

PREPARATION OF AUTHENTIC SAMPLES

Phthalazine Hydrogenation Products

1, 2-Dihydrophthalazine (84), First attempt. --Phthalazone (10. 0 g,

O. 067 moles) was added to a suspension of 2. 0 g (0, 052 moles)

LiA1H in freshly-dried tetrahydrofuran (distilled from NaOH pellets, 4 then distilled from LiA1H ). The phthalazone was added through a 4 reflux condens.er at su~h a rate that gentle bubbling of the reaction mixture was maintained, After addition was complete, the mixture was refluxed an additional twenty hours. To the mixture was added

1. 8 ml of distilled HzO, then 1. 8.ml of 15% NaOH solution, then 5, 2 ml of distilled H 20. The mixture was filtered, and the solid material was washed with 20 ml of ethyl ether. The ether layers were ·evaporated to a viscous, yellow oil. An attempt was made to dissolve this material in petroleum ether, but it would not dissolve. Evap- oration of the petroleum ether fraction afforded no detectable amounts of product. The substance was slightly soluble in ethanol. Tritur- ation with ethanol afforded a solid compound with mp 180--181°C, 39 (starting material, mp 182.,..,.134 0 C). Thin ...layer chromatography of the ethanol solution indicated only traces of 1, z.,.dihydrophthalazine.

Second attempt (84) • .,.... A reaction similar to the above was car., ried out: using. a higher molar ratio of LiAlH 4 • Phthalazone, 8. 0 g

(0~ 005 moles}, was added to 60 0 g (0.15 moles) 0£ LiAlH 4 and sus ... pended in dry THFo The reaction mixture was refluxed only five hours instead of twenty. After work ...up similar to that previously

· described and evaporation of. the ether layer, a thick, brown oil resulted~ Thin ...layer chromatography and gas chromatography indicated only traces-of 1, z.,dihydrophthalazine were present.

Third attempt {84) ...... Quantities identical to those employed in the second attempt were used except that the reaction was allowed

· to reflux for twenty~four hours instead of five. Chromatography of the resulting mixture indicated "only traces of 1, z.,.dihydrophthala ... ,. . zine.

Fourth attempt ·{84) ... .,.To 12. 0 g {O. 31-moles) LiAlH 4 suspended in dry THF was added 16. 0 g {0.11 moles) of phthalazone in such a way that gentle refluxing was maintained. After the addition, the mixture was refluxed for one hour and then cooled to room temper .. atureo Distilled H 0 was added sl~wly until excess LiAlH decom ... 2 4 posed. The aqueous mixture was extracted with four 100 ...ml portions of ether.; The aqueous layer was centrifuged and decanted~ It was 40 then added to a saturated salt solution and extracted with ether. After drying over Sikkon, the combined ether layers were evaporated to

yield a thick, yellow oil which solidified upon cooling. This material weighed 14. 5 g, mp 60".".,,65° C. Thin .. layer chromatography and gas chromatography 'indicated only traces of 1, 2 .. dihydrophthalazine.

Attempts to isolate the desired product failed.

Phthalazine hydrochloride ...... Anhydrous HCl was bubbled through a solution of 3. 0 g (0. 023 moles) of phthalazine dissolved in 50 ml anhydrous ethyl ether. A flocculent, white precipitate formed immediately~ The solution was filtered to yield 3. 9 g (98%) of phthalazine hydrochloride, mp z30 ...~231°c {lit. 231°C) {41).

1; 2; 3,; 4;;.Tetrahydrophthalazine (41) ..... To a solution of 1. 0 g

(O. 0060 moles) phthalazine hydrochloride in distilled H 2o was added

10. 0 g of 7% Na ...Hg amalgam in small pieces. (see page48). The reaction solution was decanted from the mercury and saturated with K CO3~ An oil separated_ which was extracted with five 10 ... 2 ml portions of benzene. The benzene was dried over CaC1 2, and then anhydrous HCl was bubbled through the solution. The result.,. ing precipitate was filtered and dried, giving O. 95 g (94%) of

1, 2, 3, 4 ...tetrahydrophthalazine, mp 239 ...~241°c (lit. 231°C, 236 .....

238°C). The free base was liberated by treatment with 20% NaOH ( and extraction with ether. Evaporation of the ether gave a colorless 41

oi} which rapidly became tacky upon standing in air. A portion of

this material was distilled, bp 68°C/ O. 50 torr; ir, page 105; nmr,

• page 101; mass spectrum, page 106.

with a stirrer,: thermometer, dropping funnel, and condenser, 106 g

. 0 (1. 0 moles} of £""xylene was heated to 125 C. The condenser was

fitted with a gas absorption trapo A uv lamp was placed in close prox ... . L

imity to the flask to enhance the reaction rate. To the o--xylene

was added 352 g (2. 2 moles} of reagent ...grade bromine at such a rate

that the bromine color disappeared as rapidly as it was added. The

addition took approximately one and one .. half hours. The brown

solution was stirred an additional 30 minutes at 125° C. The mix ..

ture was then cooled to 60° C, poured into 100 ml of boiling hexane,

cooled to room temperature, and then refrigerated. The tan cry ..

stals that formed were filtered off, pressed between filter paper,

and then stored over NaOH pellets in a vacuum desiccator. The

yield was 130 g (50%) mp ss .... 92°c (lit. s9 ..."94°C).

Method B ...... A five .. liter, three ...neck flask was fitted with a

dropping funnel, a reflux- condenser, and a well containing a mer.-.

cury;.,,vapor lamp,; The condenser was fitted with a gas absorption

trap. To the flask was added 200 g (1. 88 moles) of o ...xylene, three - . liters ofca3,·bon tetrachloride, and 60 0 g of bromine (3. 7 5 moles). 42 The solution was stirred magnetically and the uv lamp turned on.

After about 20 minutes, the bromine color was nearly gone. After

: one hour, the lamp was turned off. Ethylene gas was µubbled through

the solution to react with the excess bromine. The carbon tetra ...

chloride was removed "in vacuo over steam. The remaining tan ..

colo·red oil was pou~ed into boiling pentan.e and refrigerated over ..

night. The resulting crystals were filtered off, pressed between

filter paper, and stored over NaOH pellets in a desiccator. The

yield was 228 g (46%) mp 89" ..91°c (lit. s9 ....,.94°c) (78).

Potassium phthalimide (45) ...... potassium hydroxide (61. 0 g)

was dissolved in 60 ml of H 20 and the resulting solution was added

to 180 ml of absolute , ethanol.

Phthalimide (80. 0 g, O. 54 moles) was added to 1600 ml of

absolute ethanol and refluxed for fifteen minutes. The supernatant

was then decanted from the undissolved solids into 120 ml of the

above KOH/ ethanol solution. The mixture was cooled in an ice bath,

and the resulting precipitate was filtered off. To the filtrate was

added 80:0 g (O. 54 moles) of phthalimide. The mixture was re.,;

fluxed fifteen minutes, and the supernatant decanted free of undis"' i solved solids into the remaining 120 ml of KOH/ ethanol solution. It

was cooled and the potassium phthalimide was filtered off as be~ore.

The combined potassium phthalimide precipitates were washed with

200 ml of acetone and dried in air, yielding 119 g of potassium I . 43 phthalimide. After correction for the undissolved solids (39 g) was made, the yield was 79%,

o-XylylbisphthaJimide (91). --A mixture of 6. 0 g (0. 023 moles) of o<.o<.'-dibromo-o-xylene and 12.0 g (0.648 moles) of potassium phthalimide was ground with a mortar and pestle until it was well- mixed. It was then heated gradually in a flask to 200°c. The

' mixture became soft and then solidified into hard, brown lumps. \ . The brown solid was boiled in 175 ml of water and the resulting solution was cooled in an ice bath. A blue-grey solid formed which was filtered off and stored over KOH pellets. The crude ~-xylyl- · bisphthalimide was recrystallized twice from glacial acetic acid to yield 5. 9 g (65%) of blue-grey needles, mo 260--262°C (dee). This procedure was repeated twice using 21 g (0. 080 moles) and 24 g

(0. 09 2 moles) of tX,0(1 -dibromo-~-xylene. The yields were 98% and 85%, resl?ectively.

"'-, Pl.'-Diamino-o-xylene (91). - -In a one-liter, high-pressure reaction liner was placed 30 g (0. 076 moles) of ~-xylylbi~phthalimide and

300 ml of 6.M HCl. The liner was sealed in a high-pressure reactor casing and heated to 200°c for 2. 5 hours. After cooling, the reaction mixture was added to 300 ml of cold H2O, and the phthalic-acid precipitate was removed by filtration. To the filtrate was added 150 g of NaOH in 400 ml of ice water. The resulting mixture was extracted L. 44 with three 150 ...ml portions of ethyl ethero The extracts were dried \ over K c The ether was distilled and 3. 8 g {22%) of liquid 2co 3

r/..,(1..r...diarnino .,.~... xylene remained. This material was converted

. 0 to the hydrochloride, mp 300 C.

N,.;(p ...toluenesulfonyl.,.)'...-1; 3sdihydroisoindole (19} ...... To 220 ml of anhydrous methanol was added 5. 0 g (0. 22 g .. atoms) of sodium metal and then 17 .1 g (0.100 moles) of p ...toluenesulfonamide. This was added to a refluxing solution of 26. 4 g (0.100 moles) of , 1 .. dibromo ...o ...xylene over a period of fifty minutes. After addition was complete, the mixture was refluxed for two hours. Upon cooling to room temperature, 100 ml of H 20 was added and the solution was taken to pH 7 {11Hydrion 11 paper} with glacial acetic acid. Upon chil .. ling overnight, light.,.tan crystals formed v1hich were filtered off and

recrystallized from 95% ethanol, yield 13. 09 {47, 5%), mp 174 ...0

176°c (dee) (lit. 17 5~""176 ° C). This reaction was repeated starting with 0, 2 moles and 0, 4 moles of C'½~r...dibromo ..2_-xylene, The respective yields were 49% and. 51%.

1., 3;;,,Dihydroisoindole· (19) ...... A mixture of 12. 0 g {0. 04_4 moles) of

N .. (p .. toluenesulfonyl.,)-1, 3-dihydroisoindole, 12. 0 g (0.13 moles) of phenol, 90 ml of 48% HBr and 15 ml of propionic acid was stirred vig~rously and refluxed for two hours under a stream of nitrogen gas. The brown reaction ...mixture was cooled to room temperature and extracted with two 200 .. ml portions of ether. The acidic, 45 aqueous layer was then added dropwise to a cooled solution of

75 g NaOH in 200 ml of H 20. The resulting aqueous mixture was then extracted with five 150-ml portions of ether. The combined

ether extracts were dried over CaCl~. Evaporation of the ether afforded q, brown oil which was vacuum-distilled using a water aspir- l ator. The 3. 0 g (57%) of 1, 3-dihydroisoindole was obtained as a colorless oil which rapidly became tacky upon standing in air, mp

16--16. 5°C (lit. 16--16. s0 c). This procedure was repeated using

48. 0 g (0.175 moles) of N-(p-toluenesulfonyl-)-1, 3-dihydroisoindole, and a yield of 68% was obtained,

o-Methylbenzylamine. --£-Tolunitrile (5. 0 g, 0. 043 moles) was added to a saturated solution of ethanolic ammonia con- tained in a Parr hydrogenation bottle. To this was added 1. 0 g of 5% Rh/ C. The mixture was then hydrogenated at 60 psi initial pressure until the theoretical amount of hydrogen was absorbed,

The catalyst was filtered and the ethanol and ammonia removed in vacuo on a steam bath. The resulting yellow liquid was distilled under vacuum u_sing a water aspirator. From this, 2. 8 g

(54%) of colorless liquid was collected. The ir spectrum of this material is identical in every respect with that reported in the literature (94), When exposed to air, this compound rapidly forms a white solid which is presumed to be a carbonate salt. Quinazoline Hydrogenation Products

N-methyl-o-nitrobenzylamine (58). - -A mixture of 10. 0 g of

£_-nitrobenzylchloride, 60 ml of 40% aqueous methylamine, and 60 ml of 95% ethanol was kept for one week in a stoppered flask. The yellow solution was then shaken with concentrated HCl and evaporated to a brown solid. The solid was dissolved in H 20 and mixed slowly with excess 50% KOH. The resulting dark mixture was extracted with five 100-ml portions of CHC1 3 . The combined extracts were dried over anhydrous Na 2so 4 and then evaporated in vacuo to a dark-brown, oily liquid. Vacuum distillation of this material at s2°c/0. l torr yielded 2. 5 g (25%) of light-yellow oil, hydrochloride mp 168--175°C (lit. 175°C).

N« -methyltoluene-oC., 2-diamine (70). - -N-methyl-~-nitrobenzylamine (2. 0 g) was dissolved in 50 ml of ethanol and was hydrogenated over 1. 0 g of 5% Pd/ C catalyst. The reaction ceased after 3 i. molar equivalents of hydrogen was absorbed. The reaction mixture was filtered free of catalyst and the ethanol removed by di_stillation.

A portion of the residue was vacuum-distilled, bp 77°c/O. 5 torr.

A hydrochloride was prepared, mp 216--218°C (lit. 218°C).

N, N-dimethyl-o-nitrobenzylamine (66). --_To a stoppered flask was added 10. 0 g (0. 058 moles) £_-nitrobenzylchloride, 10. 9 g of dimethylamine, and 83 ml of absolute ethanol. The mixture was 47 allowed to stand for six days. The solvent was removed by dis-

tillation. The residue was shaken with dilute hydrochloric acid . \.

solution and the re_sulting aqueous mixture extracted with 25-ml

-portions of ether. The aqueous phase wc:s then treated with K co 2 3 until an oil separated, and the resulting mixture was extracted with

five 50-ml portions of ether'. The combined extracts were dried

over anhydrous MgSO and then the ether was distilled. · The res- 4

idue was vacuum-distilled, bp 58°C/O. 5 torr. The yield was 3. 7 g .. (43%), Picrate mp 149--150°C (lit. 149--150°C).

N''', N°'-dimethyltolu~ne-o<, 2-diamine (89). --In a low-pressure

hydrogenation bottle was placed 3. 7 g (0. 025 moles) of N , N -di-

methyl-~-nitrobenzylamine with 50 ml of anhy.drous ethanol and

0. 05 g of 5% Pd/ C catalyst. The mixture was hydrogenated until

three moles of H 2 wer~ absorbed (25 hours). The catalyst was

filtered off and the- solvent was removed ~y distillation. The yellow

residue was vacuum-distilled, bp 72--76°C/O. 5 torr, The color-

less N , N -dimethyltoluene- ; 2-diamine formed crystals upon

chilling, mp 34-.-36°c (lit. 33--37°C).

1, 2, 3, 4-Tetrahydroquinazoline (36). --Quinazoline (1. 0 g) was

treated with 10 g of 7% Na-Hg amalgam in 60 ml of water. After one

hour, the solution was decanted from the mercury and treated with

30% KOH solution. An emulsion resulted which was extracted with 48 ether. The ether was dried over CaC1 and then distilled, leaving 2 behind a yellow oil which solidified upon standing at room' temperature for three days, This material was recrystallized from warm water and gave soft crystals of the monohydrate, mp 48--50 0 C

(lit. 49--51°C). When the initial crude product was recrystallized from n-hexane, the mp of the anhydrous product was 76--79°C

(lit. 78--79°C), mass spectrum (70 ev), m/e 134 (parent peak),

Thin-layer chromatography of the initial crude product indicated that 3, 4-dihydroquinazoline was also present.

7% Na-Hg amalgam (76). --Sodiu·m metal (7. 0 g) was washed briefly wit? anhydrous ethanol to remove oxides and give a clean surface. It was then added to 50 ml of molten paraffin wax con- tained in a flask under an atmosphere of nitrogen and then heated until melted. To this was added at once 93 g of reagent-grade mercury. A vigorous exothermic reaction ensued. The hot paraffin wax was decanted and the molten amalgam was poured onto a metal tray, T!)-e amalgam solidified and was then broken into small pieces and stored under petroleum ether.

HYDROGENATION OF _PHTHALAZINE AND QUINAZOLINE

General Procedures

Catalysts. --All of the catalysts were commercially prepared.

The 5% Rh/ C, 5% Rh/ Al 2o 3 , 5% Ru/ C, and 5% Pt/ C catalysts were 49 obtained from Engelhard Industries. The 5% Pd/ C was obtained from A. D. Mackay, Inc. In one reaction, W ...z Raney-nickel was used. It was prepared by the method described in "Organic

Synthesis 11 (59).

Solvents ...... For neutral solvent, commercially ...obtained an .... hydrous ethanol was used. It was distilled from magnesium . ethoxide before use. Anhydrous ethanol containing two equivalents of hydrochloric acid per mole of substrate was used for the acidic

solvent. In a few cases, glacial acetic acid was used as solvent.

When 5% Ru/ C was employed as catalyst, 95% ethanol.was used as the solvent.

Low ...pressure hydrogenations ...... (Low ...pressure hydrogenation is intended to denote those reactions carried out at initial pressure of 6,0 psi}. Many.Jow ..pressure hydrogenations of phthalazine and l

quinazoline were carried out. Since identical procedures were used throughout all of these reactio1:s, they will not be described individ'."' ually. Instead, a detailed description of a typical low.,.pressure hydrogenation reaction is given. Results of each of the individual

reactions are summarized in Table 2 and Table 3.

To a low .. pressure hydrog~nation bottle was added O. 500 g

(0. 00384 moles} of substrate {phthalazine or quinazoline} dissolved

'in 10. 0 ml of anhydrous ethanol or 10. 0 ml pf anhydrous ethanol con°_

taining O. 67 ml of 12 M HCl (0. 00804 eq of Hor 2. 09 eq of acid/mole 50 of substrate). To this solution was added O.100 g of 5% catalyst,

(0. 005 g of metal or 1 g of active metal/100 g of substrate). The reaction vessel was mounted on the Parr low-pressure reaction apparatus. The system was purged with hydrogen gas and then checked for leaks. The pressure was- then set at 60' psi and the shaker started. The reaction was then allowed to proceed until the uptake of hydrogen either became yery slow o: stopped. The pressure reading's were recorded and the molar uptake of hydrogen calculated. The reaction mixture was then removed an_d filtered free of catalyst. When neutral solvent was used, the resulting solution was analyzed directly by thin-layer chromatography and gas chromatography. When acidic solvent was used, it was treated with 3. 0 ml of a 0. 268 M solution of sodium methoxide in methanol after filtration of the catalyst. In the latter case, a precipitate of sodium chloride formed which was removed by filtration. The solution was analyzed by thin-layer chromatography and gas chromatography.

High-pressure hydrogenations. --(High-pressure hydrogenations were run at 2000 psi initial pressure.) Several high-pressure hydrogenations were carr_ied out using identical procedures; therefore, they will not be individually described. Results of the individual high- pressure reactions are summarized in Table 4 and Table 5. 51 In a typical high.,,pres sure reaction, the same quantities of

solvent, catalyst, and substrate were used as in the low ...pressure

hydrogenation reactions. The reaction mixture was placed :in a

glass reaction .. liner. The liner was then sealed and mounted in

the Pendaclave high .. pres sure reaction apparatus. The system

was purged and checked for leaks. The hydrogen pressure was

taken to 2000 psi and then the temperature set at the desired value.

After the temperature of the system had equilibrated, agitation was

initiated and continued for five hours. The agitation was then

stopped, and the system cooled to room temperature. The reaction

mixture was removed and analy~ed in the same manner as des ..

cribed for low ...pressure hydrogenation reactions. No effort was

made to determine the amounts of volatile amines such as am1nonia,

methylamine, or dimethylamine present in the high ...pressure re ..

actions. Because of very small pressure changes.I) no calculations

of molar uptake of hydrogen could be made.

Several hydrogenations were repeated on a larger scale so that

products present in small amounts could be isolated and identified.

Hydrogenation of intermediates~ ...-Several compounds which were

. isolated from hydrogenations were individually reduced to obtain

information concerning the possible pathway of hydrogenation.

These compounds were catalytically reduced, using quantities

and conditions already described for both low'." and high ..pressure 52 reactions. The conditions and results for these hydrogenations

are summarized in Table 6,

Preparation of Certain Intermediates

1, 2,,,Dihydrophthalazine • .,,... In a low..,pressure Parr vessel-was

placed 10. 0 g (0. 075 moles) of phthalazine, I. 5 g of 5% Rh/ C and

50 ml of anhydrous ethanol. The mixture was hydrogenated at an

initial pres sure of 60 psi for two days. Hydrogen uptake was 1•. 0

moles of hydrogen per mole of substrate. The reaction mixture

was filtered free of catalyst, and then the solvent was evaporated

in· vacuo. The crude material was recrystallized twice from H20

and then sublimed under vacuum, mp 85--86, 5°c. The nmr is on

page i0l; ir, page105; and mass spectrum, page 107,

It should be noted that all catalysts tried gaye 1, 2 ...dihydro ...

phthalazine in quantitative yields when the reaction was termi ...

nated after the absorption of one molar equivalent of hydrogen.

Anal~ Calcd for c 8H8N 2: C, 72. 70; H, 6. 0. Found: C, 72. 66;

H, 6. 25.

A small amount of this material was refluxed with phenyliso ...

cyanate and gave a phenylthiourea, mp 127 .... 128. s0 c,

l; 2, 3; 4;,,Tetrahydrophthalazine {33) • .,,..,To a low ...pressure Parr

· vessel was added 5. 00 g (O. 0385 moles) of phthalazine, 0. 64 g . ' of 5% Pd/ C, and 100 ml of anhydrous ethanol. The mixture was 53 hydrogenated for twelve hours, at which time 2. 0 moles of hydrogen had been taken up. The reaction mixture was filtered free of the catalyst. A 20 .. ml aliquot was removed and anhydrous HCl was bubbled through the remaining 80 ml of solution. The white, cry ..._ stalline 1, 2, 3; 4 .. tetrahydrophthalazine hydrochloride which formed was recrystallized in ethanol. The yield was 4. 38 g (84%, I?as ed on 80% of the original starting material), mp 236e.•238°c (lit.

236 ...... 23s 0 c).

Anal~ Calcd for c 8H11ClNz: C, 56. 3; H, 6. 5; N, 16. 5.

Found: C, 56. 29; H, 6. 46; N, 16. 29.

The remaining 20. 0 ml aliquot of the reaction solution was vacuum ....distilled, giving a 1, 2, 3, 4 ...tetrahydrophthalazine fraction, \. bp 68°C/O. 50 torr. The yield was O. 98 g (95%, based on 20% of the original starting material), mp 37.,.":'.'40°c. Their is on page 105; nmr, page 101; and mass spectrum, page 106.

o(,(){' .. Diamino .. o-xylene (33) • .,,... A mixture of 5. 00 g {O. 038_51 moles) of phthalazine, 0. 64 g of 5% Pd/ C, and 100 ml of anhydrous ethanol was placed in a lowepressure vessel and hydrogenated at 60 psi initial pres sure until hydrogen ...uptake ceased (2. 0 molar equivalents).

The catalyst was filtered off. "To 60 ml of the resulting solution was I added 1. 0 g of W ...2 Raney ...nickel and the mixture was remounted on the Parr apparatus. The hydrogen pres sure was set at 50 psi. The reaction mixture was heated to 65°C and then hydrogenated for six 54 hours. One molar equivalent of hydrogen was absorbed. The reaction mixture was filtered and anhydrous HCl was bubbled through the filtrate. The crude amine hydrochloride was recrystallized in 95% ethanol and formed a monohydrate, mp 300°C (lit. mp 300°c).

Anal. Calcd for c H 6C1NzO: C, 43,184; H, 7.10; N, 12. 38, 8 1

Found: C, 43. 86; H, 7, 09; N, 12. 53,

The free base was liberated with NaOH, extracted with CHC1 , 3 and the resulting extracts dried over anhydrous sodium sulfate,

The CHC1 3 was distilled off, leaving , '-diamino-5:-xylene as a colorless liquid which rapidly formed a white solid when exposed to air. This solid is probably a carbonate salt. The nmr is on pagel02;ir, pagel04; and mass spectrum, page 108, IV. DISCUSSION

SYNTHESIS OF STARTING MATERIALS

Phthalazine

When this research was initiated, a survey of the literature revealed several plausible synthetic approaches to phthalazine.

These approaches are described in the Literature Review s·ection and will not be reiterated here. Two methods for phthalazine synthesis were tried.

The first method started with 4-phthalazone which was already available. It was converted to 4-chlorophthalazine by heating in phosphorous oxychloride. This reaction was straight-forward, and gave a 98% yield of product. However, the 4-chlorophthalazine proved to be difficult to work with because it rapidly underwent an auto-catalyzed reaction to give 4-phthalazone and hydrogen chloride. An attempt to form phthalazine by hydrogenolysis of 4-chlorophthalazine gave only a 34% yield of product. A similar approach was tried using 1, 4-phthalazinedione. The corresponding

1, 4-dichlorophthalazine was obtained in 68% yields and could easily be purified, but this compound appeared to undergo an auto- catalyzed reaction even more rapidly than 4-chlorophthalazine,

55 56. An attempt was made to obtain phthalazine by hydrogenolysis of the dichloro compound, but it £ailed.

The second method tried was that of Hirsch and Orphanos (46) which employed the condensation of £-phthalaldehyde with hydrazine.

Of the two methods tried, this latter method was the more success- ful and more convenient. £-Phthalaldehyde was readily obtained by the method described in "Organic Synthesis" (90), and was condensed with hydrazine to form phthalazine in nearly quantitative yields.

Quinazoline

Previously in this laboratory, Young had prepared quinazoline by Armarego I s method (9). This synthetic route consisted of obtaining 4-quinazolone from the condensation of anthranilic acid and formamide. The 4-quinazolone was then converted to 4-chloroquinazoline with phosphorous oxychloride followed by catalytic hydrogenolysis to give quinazoline. This procedure was undertaken and both 4-quinazolone and 4-chloroquinazoline were obtained readily.

A great deal of difficulty was encountered in purification and stor- age of the 4-chloroquinazoline which rapidly underwent auto-catalyzed hydrolysis to give 4-quinazolone. This problem was reporte<;l by Young to be the source of a great deal of difficulty in the subsequent hydrogenolysis step.

In the meantime, it was decided to try the method of Riedel (45} which is a more direct synthesis, involving the formation of 57 £_-nitro-benzylidenediformamide and subsequent cyclization to form

quinazoline. Previously, Riedel 1 s method was systematically studied

by Strong in this laboratory. Strong found that the yield of quinazoline

was strongly dependent on the purity of £-nitrobenzylidenediforma-

mide, the temperature, and the degree of agitation during the re-

duction-cyclization step. The latter route was undertaken incor-

porating Strong's findings, and it proved to be the most convenient

source of quinazoline, The desired product was obtained in over-all

yields of 55%,

Young found that his over-all yields of quinazoEne, using the

· method of Armarego, averaged only approximately 20%. Even

though £_-nitrobenzaldehyde is a more expensive starting material

than anthranilic acid, additional considerations such as over-all

yield, cost of other chemicals required, and convenience, indicate

. that Riedel I s method is superi?r to Armarego' s for laboratory

preparation of quinazoline.

PROPOSED HYDROGENATION PRODUCTS

At the outset of this research, a review of the literature on

catalytic reduction of benzoazines indicated that the hetero- ring is

preferentially reduced. Reductions of quinoline, isoquinoline, cin-

noline, quinoxaline, and preliminary work on quinazoline supported

this generalization. In the case of quinoline, isoquinoline, and

quinoxaline, reduction of the benzo- ring occurred only after the

/ 58 hetero--ring was fully hydrogenated. For each of the latter group of compounds, a decahydro compound was reported. The reported research on cinnoline and quinazoline indicated that after initial saturation of the hetero:--ring, cleavage of the hetero.-.ring by hydro ... genolysis occurred preferentially to reduction of the benzo ...ring, giving substituted benzene compoundsa Neither of the reports on cinnoline or quinazoline indicated that the octahydro or decahydro heterocycle was obtained. This evidence led to the proposal of several possible hydrogenation products for phthalazine and quin ... azoline which are summarized in Figs. 1 and 2.

Proposed Phthalazine.Hydrogenation Products {Fig. 1)

After reaction with one mole of hydrogen, phthalazine could give either 1, 2 .. dihydrophthalazine (II) or 1, 4.,,dihydrophthalazine (I).

Compound II seemed to be the most likely choice because of greater stability due to conjugation of the 3, 4 ...double bond with the benzo ...ring.

The 1, l', 2, 2 1 -tetrahydro ...l, 11 -biphthalazyl (III) was considered a possibility because an analogous compound was obtained by

Westover (98) from hydrogenation of cinnoline. The biphthalazyl {III) could result from reaction of phthalazine with O. 5 molar equivalents of hydrogen.

Reaction of phthalazine with two moles of hydrogen would likely give 1, 2, 3, 4 .. tetrahydrophthalazine (IV). Subsequent hydrogenation could give c:{,0(1 ... diamino ...-..o ...xylene (V), -.-o:""methylbenzylamine (VI), 59

~ ...xylene (VII), and a mixture of 1, 2 ...dimethylcyclohexanes (IX). The

i, 3 ...dihydroisoindole (VIII) was proposed because it was conceivable

that if II was formed in the reaction, it could undergo hydrogenolysis

of the 2, 3 .. bond to give an intermediate amino ...aldimine (reaction b,

Fig. 3) which could then undergo nucleophilic attack at C-1 with

subsequent loss of ammonia to give VIII. Westover (98) obtained

dihydroindole from the hydrogenation of cinnoline which was presumed

to be formed by a mechanism analogous to that just described.

Proposed Quinazoline Hydrogenation Products (Fig. 2)

Research on the hydrogenation of quinazoline was greatly facili ...

tated by the preliminary work of Young (101) which was carried out

in this laboratory. Quinazoline was hydrogenated by him under low pressure (60 psi) and high pres sure (2000 psi) using both neutral and

acidic solvents, and 5% Rh/ Al 2o3 as catalyst. Four compounds were isolated and identified from these quinazoline'hydrogenations

(Fig. 2). The compounds were 3, 4~dihydroquin'azoline (X), Net..

methyltoluene.o(, 2'."'diamine (XIII), Nol, Nc,(, ...dimethyltoluene'."'o{, z.,,

diamine (XIX) (see Fig. 4A) and o--toluidine (XVII). Young also ob"' tained lesser amounts of other products which were not identified.

Since Young's work only involved th.e use of on<: catalyst, it

seemed probable that products other than those reported might be

obtained when different catalysts we_re employed. Further hydrogen ...

ation of X (Fig. 2) should result in 1, 2, 3, 4 .. tetrahydroquinazoline (XI) 60

( I ) ( II)

( 111)

(IV) ( V) (VI) (VII)

OCNH

(VIII)

Fig. 1. ~-Proposed phthalazine hydrogenation products 61

r-AroNN~'l ~NI-I

( X } (XI)

(XII} ( X 111) (XIV}

· ( XV) (XVI)

(XVII) (XVIII)

Fig. 2. --Proposed quinazoline hydrogenation products 62 as Adachi observed {64). Conceivably, ring cleavage of XI could then take place at position A resulting in N-{o-tolyl)-methandiamine

2 (XIV); at position B yielding N -methyltoluene-c<, 2-diamine (XII); or at position C giving XIII. Compound XIII was the one obtained by Youhg. Further hydrogenolysis of XII, XIII, and XIV could then give o(-amino-6-toluidine (XV), N-methyl-5:-toluidine (XVI), and

5:-toluidine {VII). In addition, both cis- and trans-2-methylcyclo- hexylamine (XVIII) were considered a·s possible products resulting from further reduction of o-toluidine.

IDENTIFICATION OF HYDROGENATION PRODUCTS

Phthalazine Hydrogenation Products

Initially, several phthalazine hydrogenations were carried out to determine the nature and complexity of the product mixtures.

Chromatography

A great deal of effort was expe~ded in obtaining a gas chromatograph column which would give minimum peal<.-tailing and adequate resolution of the high-boiling amines present in the phthalazine hydrogenation mixtures. The columns which were examined are enumerated on page

Thin-layer chromatography proved to be a less formidable problem. Immediate success was obtained using the method described by

Westover (93) which employed glass plates coated with silica gel G 63 and 9 5% ethanol as the developing solvent. Visualization of thin"" layer chromatograms was accomplished using ninhydrin spray, iodine vapor, and ultra .. violet light.

Gas chromatography and thin .. layer chromatography data are ' . . summarized on Table 1, page 64.

Product mixtures from phthalazine hydrogenations appeared to be sensitive to air and would deteriorate after a few days. The relative proportions of the various components initially present in the reaction mixtures appeared to change with time; and after stand ... ing for several days, compounds not initially present could be detected by thin-layer chromatography and gas chromatography.

Authentic Samples

At this point, it was decided to obtain as many authentic samples of proposed phthalazine hydrogenation products as possible and assign tentative structures to the various components of the phthalazine hydrogenation mixtures by comparison of their chromatographic be ... havior with that of the authentic samples • . Shabarov and co~\vorkers (84) had previously reported the syrithe ... sis of 1, 2 .. dihydrophthalazine by the reduction of 4 ..phthalazone with

LiAlH 4 • Several unsucces·sful attempts were made to repeat their work. A compound with the properties they reported ....,.mp 47 ....,.48° C, phenylthiourea mp 21z ..., .. 213°c .. :'could not be-isolated. The crude reaction mixture which was obtained by Shabarov's method was TABLE 1

CHROMATOGRAPHIC DATA

Color,' Compound Ra Rd Color withe t f I2 Ninhydrin spray

Phthalazine Hydrogenation Products

e phthalazine 3. 5b 12. 0 o. 62 yellow purple 1, 2-dih yd:r:ophthalazine 2.7 9.2 0.85 yellow yellow 1, 2, 3, 4 .. tetrahydrophthalazine 7.8 . 23.0 0.33 yellow yellow "'~ rJ..,rJ...1-diamino ...5:.-xyleneg 2.6 8.8 0.05 yellow red-purple o.,,methylbenzylamine 1. 6 5.7 0.28 yellow purple-brown 1, 3-dihydroisoindoleg 1.8 6.0 0.16 yellow ' yellow-brown 5:.-xylene 1. 3 4.0 - - - cis-1, 2-dimethylcyclohexane 1.2 . 3. 6 ...... - ~ns -1, 2-dimethycyclohexane 1.1 3.4 .. .. -

Quinazolin.e Hydrogenation Products

quinazoline 8.6 0.73 yellow yellow-red 3, 4 .. dih ydroquinazoline (8. 6{ 0.35 yellow yellow-purple 1, 2, 3, 4 .. tetrahydroquinazoline 8.4 0.54 yellow orange-brown 1 N \.methyltoluene--l( 2-diamine 6.0 0.15 I yellow yellow TABLE 1 (Continued)

Compound ~a Rd Color, Color with f Iz Ninhydrin sprayc

N"', N"'-dimethyltoluene- t(, 2-diamine 7.5 0.65 yellow purple o-toluidine 5.1 0.85 yellow purple ~ yclo.hexylamino compounds 4.8 0.05 yellow purple-brown (4. 5) (0.04}

a Retention time relative to ethanol. O" \J1

b Isothermal run: column #9; flow-rate, 80 ml/min; column temp. 210°c; inj. temp. 250°c.

c The hyphen between two colors indicates a change in color of spot with time.

d Solvent: 95% ethanol {phthalazine products}; 100% methanol (quinazoline products).

e Temperature-programmed run: column temp. 50--80°C @6° / min; inj. temp. 230°C; column #9.

f A retention volume could not be determined since 3, 4-dihydroquinazoline dehydro- genates to quinazoline.

g Blue fluorescence in uv light. 66 chromatographically compared to a low-pressure phthalazine-hydrogenation mixture. A small amount of material was present in the ' reaction mixture obtained by Shabarov' s method which corresponded to the major product of the low-pressure phthalazine-hydrogenation mixture. The compound which was common to both reaction mixtures was thought to be 1, 2-dihydroph,thalazine. Several attempts were made to obtain this compound by Shabarov 1s method, but sufficient material for characterization could not be isolated. It was later found that the compoun~ in question could be obtained in nearly quantitative yields by hydrogenation of phthalazine; however, its propertieS( differed markedly from those reported by Shabarov who evidently did not isolate 1, 2-dihydrophthalazine, in spite of his report. The compound obtained by the reaction of phthalazine with equimolar amounts of hydrogen was assigned the 1, 2-dihydrophthalazine structure (II, Fig. 1) on the basis of its elemental analyses, ir, nmr, and mass spectra which _appear on pages 52 , 105 , 101 , and 107, respec- , tively. A good procedure was developed for making this compound by hydrogenation of phthalazine, and it is given on page 52 . It should be noted that it can be obtained by using 5% Rh/ C, 5% Pt/ C, and

5% Pd/ C in neutral solvents, or by using 5% Pd/ C or 5% Pt/ C in acidic solvents .if the reaction is terminated after the consumption of only one molar equivalent of hydrogen. 67

The 1, 2, 3, 4-tetrahydrophthalazine was obtained by reduction of phthalazine hydrochloride with 7% sodium amalgam. Co-chromatography of a lov,r-pressure phthalazine-hydrogenation mixture with

1, 2, 3, 4-tetrahydrophthalazine indicated that it was a product of phthalazine hydrogenation. Subsequently, it was found that 1, 2, 3, 4- tetrahydrophthalazine could be obtained in high yields by hydrogenation of phthalazine at 60 psi over 5% Pd/ C in anhydrous ethanol.

The compound was isolated and purified as the hydrochloride and then obtained as the free base by treatment with alkali. The elemental analysis, nmr, ir, and mass spectra are found on pages

53 , 105 , 101 , and 106, respectively, and are consistent with the assigned structure. A suitable procedure for obtaining_ 1, 2, 3, 4- tetrahydrophthalazine is reported on page 52.

An authentic sample of ()(,o<.'-diamino-~-xylene was prepared by the Gabriel synthesis using o(.,oC.1 -dibromo-~-xylene and pot~ssium phthalimide as starting materials {91). Hydrolysis of the resulting

~-xylylbisphthalimide gave~•""' -diamino-~-xylene which was shown to be chromatographically identical to one of the components present in some phthalazine-hydrogenation mixtures.

In the meantime, Elslager {33) had reported that he obtained a, ot1 -diamino-o-xylene by hydrogenation of phthalazine over 20% - . ~ Pd/ C in methanol at 60 psi until two molar equivalents of hydrogen was absorbed, followed by addition of Raney-nickel and further 68 hydrogenation at 60 psi and 65°c until one additional molar equivalent of hydrogen was absorbed, Elslager 1 s method was tried, using

5% Pd/ C, anhydrous ethanol, and W ~2 Raney-nickel, The ir, and nmr spectra of the material obtained by this method were identical in every respect with the d,o<1 -diamino-£-xylene obtained by the Gabriel synthesis, described in the previous paragraph. The elemental analysis, ir, nmr, and mass spectra are on page 54, 104, 102, and

108, respectively.

£_-Methylbenzylamine was prepared by catalytic reduction of o-tolunitrile over 5% Rh/ Al 2O3 at 60 psi in anhydrous ethanol saturated with ammonia. Co-chromatography with hydrogenation mixtures confirmed that £-methylbenzylamine was a product in some phthalazine-hydrogenation mixtures. A sample of £-methylbenzylamine was isolated by preparative gas chromatography of several combined phthalazine-hydrogenation mixtures. The ir spectrum of the compound isolated was identical in every respect to that reported in the literature (94) and of the authentic sample. The ir, nmr, and n1ass spectra are on pages 104, 102, and 109, respectively,

1, 3-Dihydroisoindole was prepared by the method of Bornstein and Lashua (19). o(,c<.'-Dibromo-£-xylene was reacted with p-toluenesulfonamide to give N-(p-toluenesulfonyl-)-1, 3-dihydroisoindole which was then hydrolyzed in constant boiling hydrobromic acid to give the desired product. Co-chromatography of the 1, 3- dihydroisoindole with phthalazine-hydrogenation mb, ..1:ures indicated 69 this compound ,vas also a product of hydrogenation. 1, 3.,Dihydro- isoindole was present only in phthalazine hydrogenations run in ( neutral solvent using 5% Rh/ C, 5% Rh/ AlzOy and 5% Pt/ C. The

Pt/ C hydrogenation gave the greatest relative percentage of 1, 3ndi- hydroisoindole, The product mixtures from several phthalazine hydrogenations over Pt/ C were combined and a small amount of

1, 3 ...dihydroisoindole was isolated from them by preparative thin- layer chromatography. The 1, 3~_dihydroisoindole obtained by pre .. parative thin ...layer chromatography was vacuum-distilled in a

Craig concentric ...tube apparatus. The ir spectrum of the distilled material was identical with that of the authentic sample. The ir, nmr, and mass spectra are on pagesl04 ,102, andl06.

Pure ~.,.xylene obtained commercially was compared by gas chromatography with phthalazine ...hydrogenation mixtures. It gave the same retention volume as one of the phthalazine ..hydrogenation products. In addition, the reaction solution from the highnpressure hydrogenation of 10. 0 g phthalazine over 5% Pt/ C in neutral solvent was treated with anhydrous HCl. The mixture was then vacuum ... distilled leaving a residue of the crude amine salts. The distillate was then redistilled, giving a fraction (bp 140°c/ 640 torr) which was shown to be o~xylene by its ir spectrum.

Both cis.;;. and trans.,.l, z.,,dimethylcyclohexane were obtained commercially (J. T. Baker). The presence of these compounds 70 in phthalazine.,,hydrogenation mixtures was indicated by gas chrom .. atographic analysis. Their presence was confirn.1.ed by hydrogen ... ating phthalazine at high pressure using 5% Pd/ C in acidic solvent.

The reaction mixture was then vacuum:-distilled, leaving a residue of crude amine salts. The distillate was redistilled, giving a .fraction

(bp 130 .. -138°C/ 645 torr} which had an ir spectrum identical to that obtained for the products of hydrogenation of ~ ...xylene under the : same conditions.

Quinazoline Hydrogenation· Products

The major products of the hydrogenation of quinazoline using

5% Rh/ A1 o as catalyst had previously been isolated and identified 2 3 by Young (101). It seemed probable that similar results might be obtained with other catalysts although it was expected that the relative amounts of the various compounds would vary.

Since 3 1 4 .. dihydroquinazoline had been established by many workers, including Young, to be the major product of the low• pressure hydrogenation of quinazolihe, an authentic sample was not prepared. It was found that 3, 4 ...dihydroquinazoline could be obtained in nearly quantitative yields from all of the low~pressure hydrogenations using either neutral or acidic solvents. The com ... ' pound obtained by low ...pressure hydrogenation of quinazoline had properties consistent with those reported in the literature for

3, 4adihydroquinazoline. The nmr spectrum is on page 103. 71

1, 2, 3, 4-Tetrahydroquinazoline was obtained by reduction of

quinazoline with 7% sodium amalgam (36). Co-chromatography of

1, 2, 3, 4-tetrahydroquinazoline with quinazoline-hydrogenation mix-

tures indicated that one of the minor products of hydrogenating

quinazoline was 1, 2, 3, 4-tetrahydroquinazoline, Attempts to iso-

late 1, 2, 3, 4-tetrahydroquinazoline from hydrogenation mixtures

failed because it was present in such small amounts. Therefore,

identification was based only on chromatographic comparison.

Adachi (64) reported that l, 2, 3, 4-tetrahydroquinazoline was obtained by catalytic reduction of 3, 4-dihydroquinazoline, but no

attempt was made to repeat this work.

Chromatographic analyses of several high-pressure quinazoline

hydrogenations run under conditions similar to those used by Young

(2000 psi, 125°C) but with a variety of catalysts indicated that the

same three major products were present in-all mixtures and that

these three products were the sam·e ·compounds reported previously

by Young. With some catalysts, an apparent fourth product was

present, The three major products were identified by co-thin-layer

o( chromatography and co-gas chromatography as N -methyltoluene- o(, 2-diamine (XIII), ~-toluidine (XVII), and No<.,N°'-dimethyltoluene-

~' ·2-diamine (XIX). Co-chromatography of quinazoline hydrogen-

~~i~n mixtures with authentic samples of NZ-methyltoluene-d, 2-di-

amine (XII), ~-aminobenzylamine (XV), and N-methyl-~-toluidine (XVI) 72 indicated that none was a hydrogenation product. Authentic samples

of compounds XVI and XVII were obtained commercially while coma

pounds XIII and XIX were obtained by reaction of ~".'nitrobenzyl

chloride with the appropriate amines, followed by catalytic reduc ...

tion of the nitro.,,group {pgs.46 and47). Authentic samples of

compounds XII and XV, previously prepared by Young, were re-

distilled and us ed.

Since Young had already carried out the isolations of the afore-

mentioned components from high ...pressure quinazoline ...hydrogenation mixtures and had identified them by comparing their ir spectra with the ir spectra of authentic samples, no further attempt was made to isolate and purify them.

Chromatographic data for quinazoliner().ydrogenation products

appear in Table 1.

"Minor n Quinazoline Hydrogenation Products

Upon close examination, we determined that the fourth and

minor component of high ...pressure quinazoline hydrogenation was

actually a mixture of two or more compounds. Several unsuccess- ful attempts were made to resolve these compounds by gas chroma- • tography and thin .. layer chromatography.

On the gas chromatogram, these 11minorn compounds appeared

as one peak which had only a slight valley at the top of the peak.

Under the best conditions found, this valley was less than 5% of the 73 peak height. Careful thinrolayer chromatography of high-pres sure quinazoline ...hydrogenation mixtures indicated that at least two

"minor" components other than the three major products (XIII, XVII,

XIX) were present. The Rf values of these 11minor 11 products were so nearly alike, however, that even under the best conditions found, complete resolution could not be achieved.

In an attempt to further identify the 11minor 11 components, a new series of high ...pressure quinazoline hydrogenations was run, using a variety of catalysts, both acid and neutral solvents, and slightly more vigorous conditions than those used in the first series of hydrogenations (2000 psi, 150°C as opposed to 2000 psi, 125°c used in the previous series). A chromatographic study of this latter series of quinazoline hydrogenations provided the following information concerning the 11minor" products in question: they were not present in hydrogenations using Pt/ C catalyst with either neutral or acidic solvent; the only product in hydrogenations over

Pt/ C was ~ ...toluidine; they were present in higher proportion in hydrogenations over Pd/ C than over Rh/ C or Rh/ AlzO3 in neutral solvent; and finally, in acidic solvents, they were the exclusive products in hydrogenations over Rh/ C, Rh/ Al 2o 3, and Pd/ C catalysts.

Since it has long been known that palladium and rhodium are active in catalyzing reduction of aromatic rings while platinum is not, these observations suggested that the "minor" products of 74 quinazoline hydrogenation were benzene ...ring~educed compounds.

These 11'rninor" products probably came from hydrogenation of the benzene ring of ~ ...toluidine which is the major product in some quinazoline hydrogenations.

In order to test this postulate, ~ .. toluidine was hydrogenated at

0 . 150 Cover 5% rui/ Al 2,03 in acidic solvent. The product mixture of this reaction was chromatographicall y identical to the product mix .. ture obtained when quinazoline was hydrogenated under the same conditions. An nmr analysis made on each of the crude ..product mixtures gave virtually negligible indication of proton signals in the aromatic region. However, a very complex array of peaks was present in the O. 75 .... z. 5 range.

A third series of high-pressure quinazoline hydrogenations was undertaken using the same conditions (2000 psi; Rh/ C, Rh/ Al 203,

Pt/ C, Pd/ C; acid and neutral solvents) except for temperature which was kept·at 100°c. Chromatographic analyses indicated only traces of these "minor" compounds present. It was therefore con- eluded that these "minor" products probably consisted of a mixture of various methyl substituted cyclohexyl amino compounds. In add ... ition to cis ... and trans· ...z~methylcyclohexylamines, other possible compounds would be 2, 21~dimethyldicyclohexylamines which are known to be. formed by reductive coupling in the hydrogenation of certain substituted aniline derivatives (81). No further attempt was made to separate or identify these minor compounds. 75

Chromatographic data for all the compounds from hydrogenation of quinazoline are summarized in._Table 1.

QUANTITATIVE ANALYSIS OF PRODUCT MIXTURES

Phthalazine Low-Pressure Hydrogenations (Table 2)

Low-pressure hydrogenation of phthalazine gave 1, 2-dihydrophthalazine (I) and 1, 2, 3, 4-tetrahydrophthalazine (VI) as products.

Both of these compounds were found to undergo dehydrogenation on the gas chromatograph, making quantitation by gas chromatography very difficult. The problem of determining relative percentages of products in low-pressure phthalazine hydrogenations was simp- lified by the fact that the hydrogenation reaction either did not take

. " . place (as with Rh/ C in acidic solvent), or it ceased after 1. 0 or

2. 0 molar equivalents of hydrogen was absorbed (as with Rh/ A1 2o 3 or Pd/ C, respectively, in neutral solvent. See Fig. SA and Table 2).

In most cases, only one major product could be detected by thin- layer chromatography.

As a typical example, the low-pressure phthalazine-hydrogenation product obtained using 5% Rh/ AlzO3 as catalyst in neutral l. solvent was analyzed by both gas chromatography and thin-layer chromatography. The thin-layer chromatogram of this material had one major spot and two barely detectable minor spots, indicating that the yield of the major component was essentially quantitative. The major spot was due to I, and the minor spots were due to phthalazine 76

TABLE 2

LOW-PRESSURE HYDROGENATION OF PHTHALAZINE

Relative Percentage of Products Catalyst OCNH2 ooz ©CZH©O~ NH2

Neutral Solvent

5% Rh/C tr. 10_0 ·tr 0

5% Rh/A1 2o 3 tr 100 tr 0

5% Pd/ C 0 tr 100 tr

So/a Pt/C tr 100 tr 0

5% Ru/ C 75 25 0 0

Acidic Solvent

5% Rh/ C 98 2 tr 0

5% Rh/ A120 3 98 2 tr 0

5% Pd/ C 0 0 100 tr

5% Pt/ C 0 100 tr 0

5% Ru/C 100 0 0 0

Reaction Conditions: ambient temperature; 60 psi initial pressure; reaction terminated when Hz uptake ceased or became negligible. 77 and VI (Fig. l). A gas chromatogram of the same mixture had one major peak and two minor peaks. The major peak was due to I, and the minor peaks were due to phthalazine and compound VI, seemingly

confirming the results obtained by thin ...layer chromatography. How ...

ever, it appeared by examination of the gas chromatogram that con ...

siderably more phthalazine was present than would have been pre-

dieted by examination of the thin~layer chromatogram. A similar observation was made in the case of 1, 2, 3, 4~tetrahydrophthalazine; however, it appeared to be insignificant,

In order to resolve this discrepancy, a sample of 1, 2-dihydrophthalazine was purified until no traces of impurities could be de .. tected by thin ...layer chromatography. The pure sample was then sub ... , . jected to gas-chromatographic analysis which indicated that consider ... able amounts of phthalazine were present. It was concluded that the phthalazine present was due to dehydrogenation of 1, z... dihydro ... phthalazine either in the gas chromatograph column or injection

chamber. The gas chromatography conditions summarized in Table I are a result of attempts to minimize the problem of dehydrogenation in the gas chromatograph.

Because of the problem of dehydrogenation of 1, 2 .. dihydro .. phthalazine in the gas chromatograph, it was decided to determine the relative pe.rcentages of low-pressure phthalazine-:-hydrogenation . products on the basis of; molar equivalents of hydrogen absorbed in 78 .the reaction, thin.,,layer chromatography, and percentage yield based

on the weight of material isolated from the reaction mixtures. This

method was employed to determine yields for all of the low.,,pressure

phthalazine ...hydrogenation mixtures except for one in which Ru/ C

was used as catalyst.

In the case where 5% Ru/ C ~as used as a catalyst for hydrogen"

ation of phthalazine, only two compounds were detectable by thinelayer

chromatography. The major component was phthalazine _and the

minor component was I. The relative percentage of each was esti ...

mated by calculation of the molar equivalent of hydrogen absorbed

in the reaction.

Chromatographic analysis of product mixtures obtained by

hydrogenating phthalazine in a~idic solvent ove'r Rh/ C and Rh/ Alz03

indicated that only a small amount of 1, 2-dihydrophthalazi~e had

been formed. The amount of 1, 2 ...dihydrophthalazine present was

estimated by determining the areas of the peaks appearing on the

. gas chromatogram. The peak areas were corrected for the error

due to the dehydrogenation of 1, 2-dihydrophthalazine by reference to the gas chromatogram of a pure sample of 1, 2~dihydrophthalazine.

A more detailed explanation of how this correction was accom ...

plished is in the section,on high ...pressure 'phthalazine reactions,

page 79. 79 Quinazoline Low-Pressure Hydrogenations {Table 3)

Only one major product was obtained in the low-pressure hydro-

genations of quinazoline. The compound was 3, 4-dihydroquinazoline,

and it could be isolated and purified in nearly quantitative yields.

A minor component of low-pressure quinazoline hydrogenations

which was shown to be 1, 2, 3, 4-tetrahydrophthalazine was detect-

able only by thin-layer chromatography. Further justification

for the quantitative yield reported for 3, 4-dihydroquinazoline was provided by the fact that all of the reactions ceased after the absorption of essentially 1. 0 molar equivalents of hydrogen.

Phthalazine High-Pres sure Hydrogenations {Table 4)

Difficulty was encountered in determining relative product ratios

for high-pres sure phthalazine hydrogenations. This difficulty was

due mainly to dehydrogenation of 1, 2-dihydrophthalazine to phthala-

zine in the gas chromatograph. All of the mixtures were analyzed

by gas chromatography and the results were compared with their

corresponding thin-layer chromatograms.

In a typical analysis of a high-pressure phthalazine-hydrogen-

ation mixture, a gas chromatogram of the mixture was first obtained and the various peak areas were determined. Next, the

mixture was analyzed by thin-layer chromatography to verify the

assignment given each peak of the corresponding gas chromato-

gram and to confirm the presence of phthalazine in the hydrogenation 80

TABLE 3

LOW-PRESSURE HYDROGENATION OF QUINAZOLINE

Relative Percentage of Products Catalyst fnrN1 ~NH

Neutral Solvent

5% Rh/C 0 100 tr

5% Rh/ Al 2o 3 0 100 tr

5% Pd/ C 0 100 tr

5% Pt/ C 0 100 tr

5% Ru/C 0 100 tr

Acidic Sol vent

5% Rh/C 0 100 tr

5% Rh/ Al 2o 3 0 100 tr

5% Pd/ C 0 100 tr

5% Pt/ C 0 100 tr

Reaction Conditions: ambient temperature; 60 psi initial, . pressure; reaction terminated when Hz uptake ceased or became negligible. TABLE 4

HIGH-PRESSURE HYDROGENATION OF PHTHALAZINE

Neutral Solvent 00 I-' 5% Rh/ C 0 7 tr 34 51. tr 7 · tr 5o/o Rh/ Al2O 3 0 2 tr 47 49 tr 2 tr 5% Pd/ C 0 0 23 12 ., 21 0 2 tr So/aPt/ c· 2 84 3 2 ' 2 .6 1 0 So/oRu/ C 30 29 34 3 0 0 0 0 -.

· Acidic Solvent

5o/oRh/C 0 23 67 7 . 3 0 0 0 70 8 3 0 0 5o/oRh/ Al 2o 3 0 19 ' o. 5% Pd/ C a 0 0 18 9 0 3 70 So/oPt/ C 0 76 4 9 9 0 2 0

Reaction Conditions: 2000 psi initial pressure; 150°C; 5. 0 hours reaction time. 82 mixture. If the gas chromatogram indicated that .both phthalazine

and 1., 2 .. dihydrophthalazine were present but the thin ...layer chrom ...

atogram indicated only 1, 2 .. dihydrophthalazine was present, then the peak area for both compounds was totaled and used as the peak

area for 1., 2 .. dihydrophthalazine in subsequent calculations. If, however, the thin .. layer chromatogram. confirmed the presence of

both compounds, the amount of dehydrogen_ation taking place in the

gas chromatograph was estimated by reference to the gas chrom ..

atogram of a pure sample of 1, 2~dihydrophthalazine, and an ap~ propriate correction applied to the peak areas in question.

In all cases, all correction of the gas chromatographic peak areas was made t_o rectify the differences in the sensitivity·of the

flame,.,ionization detector of the gas chromatograph to the various hydrogenation products. A standard solution containing known

quantities of each high ..pressure phthalazine ...hydrogenation product was prepared.· A gas chromatogra1n of this standard solution was

obtained and the relatiye sensitivities of the various components

·of the mixture were determined. The relative sensitivites were then used to correct peak areas of the corresponding compounds in the gas chromatograms of the phthalazine ...hydrogenation mixtures.

After this second correction was applied, the relative percentage

of each compound was calculated. 83

Quinazoline H:gh-Pressure Hydrogenations (Ta?le 5)

An approach similar to that just described above for determining relative amounts of high-pressure phthalazine-hydrogen.ation products was used for determining relative amounts of the various products of high-pressure quinazoline-hydrogenation reactions. Both

3, 4-dihydroquinazoline and 1, 2, 3, 4-tetrahydroquinazoline were present in high-pressure quinazoline hydrogenations, but only in smalL quantities. Although 3, 4-dihydroquinazoline (X) and 1, 2, 3, 4-tetrahydroquinazoline (XI) were found to undergo dehydrogenation in the gas. chromatograph, no effort was made to determine the amount of dehydrogenation accurately because they were present in such small quantities relative to the major products present. The percentages reported for X and XI in Table 5 should be taken as a.rough estimate. 'The relative percentages of the remainder of the compounds present in high-pressure quinazoline mixtures were determined by gas chromatography, using a technique similar to that described for quantitative determination of high-pressure phthalazine-hydrogenation products; i.e., determination of relative sensitivities of the ionization detector I to each component adding appropriate corrections to the peak areas.

OBSERVATIONS AND CONCLUSIONS

Relative Activity of' Catalysts

All of the catalysts employed in this research were obtained from commercial sources and were used without further treatment. TABLE 5

HIGH-PRESSURE HYDROGENATION OF QUINAZOLINE

Relative Percentage of Products

0 ,100°c 15o c I lO0OC 150°c 100°c I 150°C 100°c 150°c 100°c 150°c 100°c 1500C Neutral Solvent co ~ 5% Rh/C 2 0 2 0 21 0 24 0 52 · 70 tr 30 5% Rh/ A1 2o 3 tr 0 tr 0 3 0 32 0 48 70 tr 30 5% Pd/ C , 0 0. . 5 0 3 0 5 0 . 91 43 tr 57 5% Pt/ C tr 0 tr 0 8 0 10 0 81 100 0 0 5% Ru/ C 0 5 18 34 45 tr ------I -- -- I Acidic Solvent ·

5o/o Rh/C 0 0 5 0 18 0. 31 0 48 tr tr 100 .. 5% Rh/ AI 2o 3 0 0 0 0 17 0 35 0 48 tr tr 100 5% Pd/ C 0 0 0 0 2 0 2 0 96 tr tr 100 5% Pt/ C tr 0 tr 0 7 0 7 0 '85 100 0 tr

Reaction Conditions: 2000 psi initial pressure; 5. 0 hours reaction time. 85 It should not be assumed, however, that catalysts obtained from two or more presumably identical preparations will give exactly the same results. In order for the results obtained to have some relative significance, the same individual catalyst~batches were used ' throughout, .:_•.]•, the Pd/ C catalyst used ip. all hydrogenations over

Pd/C came from the same supplier, batch, and container.

Low .. Pressure Phthalazine Hydrog~nations· (Fig. 5, Table 2}

In the low~pressure hydrogenations of quinazoline and phthal ... azine, a study was made to determine the relative activity of the various catalysts us ed. The results of this study are presented in Fig. 5.

For low ...pressure phthalazine hydrogenations, the relative order of increasing activity is Ru/ C Rh/ C Rh/ Al o Pt/ C· 2 3 Pd/ C in neutral solvent. The results for Ru/ C were not plotted because the reaction rate was extremely slow. In acidic solvent, the Pt/ C and Pd/ C catalysts show the same relative reactivity and • their rates of reaction with respect to solvent acidity do'es not change appreciably. In acidic solvent almost no reaction was observed when rhodium catalysts were used. Initially, it ':'as thought that the low activity of the rhodium catalysts might be due to agglomer .. ation of the catalyst. However,. when glacial acetic acid was used as solvent in which agglomeration did not occur, similar·results were obtained; and when the hydrochloric ...acid concentration in the 86 ethanol solvent was increased, the activity of the rhodium catalyst

did not increase.

In low .. pressure phthalazine hydrogenations using Pt/ C, Rh/

Al 0y and Rh/C in neutral sol~ents and Pt/ C in acidic solvents, the 2 reaction rate became very slow after one molar equivalent of hydro ...

gen was absorbed. When reactions were terminated after reaction with 1. 0 molar equivalents of hydrogen, 1, 2-dihydrophthalazine was obtained in quantitative yields (Table 2). If the reactions were allowed to continue, small amounts of other products such as IV and V would begin to form.

Palladium ...on ...carbon demonstrated the greatest difference in

activity compared to the other catalysts tried in low ..pres sure phthalazine hydrogenations. Iri both acidic and neutral solvents, the hydrogenation of phthalazine over Pd/ C proceeded smoothly unt~l

essentially 20 molar equivalents of hydrogen was absorbed. The product was 1, 2, 3, 4 ...tetrahydrophthalazine, exclusively. After

20 molar equivalents of hydrogen was absorbed, W ...2 Raney .. nickel

could be added and the reaction would proceed smoothly until 1. 0

additional molar equivalent was absorbed, giving quantitative

yields of OC,&<'."".'diamino..~ ...xylene. When the .low ..pressure hydro-

genation over Pd/ C was terminated after 1. 0 molar equivalent of hydrogen was absorbed, the product was 1, 2 ...dihydrophthalazine. 87 Low .. Pressure Quinazoline Hydrogenations {Fig. 5, Table 3)

Low ...pressure hydrogenation of quinazoline under all conditions tried {Table 3) gave essentially one product, 3, 4 .. dihydroquinazoline with traces of 1, 2, 3, 4-tetrahydroquinazoline. The relative activity of the catalyst {see fig. 5) is Ru/ C Pt/ C Rh/ A1 2o3 · Rh/ C Pd/ C.

In the quinazoline hydrogenations, the activity of all catalysts tried increased with respect to acidity of the solvent. The Ru/ C catalyst was the least active catalyst and gave complete reaction of quin .. azoline with 1. 0 molar equivalent of hydrogen only after four days.

The Pt/ C hydrogenation of quinazoline gave 3, 4 .. dihydroquinazoline after 36- .. 45 hours.

· In general, by comparing the reaction time with respect to molar uptake of hydrogen, it c·an be seen that the hydrogenation of quinazoline was generally more rapid than the hydrogenation of phthalazine. Comparison of the relativ~ susceptibility of quina" zoline and phthalazine to hydrogenation with that of quinoxaline and cinnoline was not possible because of insufficient data on the latter two benzodiazines.

High .. Pres sure Reactions

Because high .. pres sure hydrogenations were run on small amounts of starting material and the free volume_ of the reaction flask was large, it was not possible to determine the molar equivalent of hydrogen absorbed in each reaction. A general idea of the 88 relative activities of the catalyst can be obtained by examination of the relative product ratios for phthalazine and quinazoline high- pres sure hydrogenations (see Tables 4 and 5). In both tables, the products are arranged from left to right in order of increasing degree of hydrogenation.

Under identical reaction conditions, quinazoline appears to be much more susceptible to catalytic reduction than phthalazine as was evidenced by the fact that the major products of high-pressure quinazoline hydrogenation at _150°C and 100° C are o"'toluidine and

cyclohexylamino compounds while phthalazine, even at 150°C 1 gives

much smaller relative amounts of .£_.. xylene and 11 2--dimethylcyclo-- hexanes. This observation is consistent with the relative ease of hydrogenation of phthalazine compared to quinazoline observed at low pressures (see previous section and fig. 5) •.

High--Pressure Phthalazine Hydrogenations (Table 4}

In high~pressure phthalazine hydrogenations, the activity of

Pt/ C and Pd/ C catalysts increases in acidic solvent, while the rhodium catalyst shows a decrease in activity (compare the rel .. ative amounts of'°',"'-' .. diamino~.£_ .. xylene and .£_... methylbenz~lamine obtained in neutral and acidic solvents). This observation is con ...

sistent with the results of the low~pressure hydrogenations (see

Table 4 and Fig. 5). 89 The Ru/ C appears to be less active than Pt/ C in catalyzing formation of 1, 2-dihydrophthalazine from phthalazine (Table 4).

However, Ru/ C appears to be more active towards subsequent hydrogenation of 1, 2-dihydrophthalazine than Pt/ C catalyst (compare relative amounts of 1, 2, 3, 4-tetrahydrophthalazine for each catalyst in Table 4). The Pd/ C catalyst appears to be more active than the

Pt/C in hydrogenating 1, 2-dihydrophthalazine to subsequent products (consistent with results of low pressure) but less active than the rhodium catalysts. On the other han~, comparison of the

relative amounts of primary amines present in product mixtures indicates that hydrogenolysis of the 2, 3-bond of 1, 2, 3, 4-tetrahydrophthalazine is catalyzed more rapidly by rhodium cataly_sts than by the palladium catalyst,· and that hydrogenolysis of the C-N bonds is catalyzed more rapidly by Pd/ C than by the rhodium catalysts.

The presence of small amounts of 1, 3:..dihydroisoindole in high- ' pressure phthalazine-reaction mixtures suggested the possibility of a minor concurrent pathway of hydrogenation, for which a mechanism is discussed on page 93 (see Fig. 3).

High-Pressure Quinazoline Hydrogenations

Comparisons similar to those _made for J.iigh-pressure phthalazine reactions can be made with the results of high-pressure hydrogen-

ations of quinazoline .. The. hydrogenation products are listed from ! 90 left to right (Table 5) in order of the increasing degree of hydrogenation.

The relative activities of catalysts are the same in both neutral and acidic solvents. The relative activity of each catalyst is in'- creased in acidic solvents. Since 3, 4-dihydroquinazoline and 1, 2, 3, 4- tetrahydroquinazoline were present in small quantities, no signifi- cant correlations of the relative activity of .various cataiysts to give subsequent compounds such as XIII and XIX can be made,

The relative amounts of 5:-toluidine present in high-pressure reaction mixtures indicate that the overall relative catalyst'activity in hydrogenolysis of the amino compounds is Rh/ Al 2o 3 Rh/ C

Pt/C .Pd/C. However, since o-toluidine can come from both XIII or XIX, the relative activity of catalysts in benzylic hydrogenolysis cannot be surmised on this evidence alone. In addition, a simple correlation of catalyst activity is complicated by the fact that XIV may be present in the reaction mixture as a short-lived intermediate which could also be a source of 5:-toluidine (see page 98 ), Platinum- on-carbon failed to catalyze the reduction of the benzo- ring while the rhodium and palladium catalysts did so readily.

PROPOSED PATHWAYS OF HYDROGENATION

Phthalazine Hydrogenation Pathway (Fig. 3)

A study' of the various product ratios led to the proposal of the hydrogenation pathway depicted in Fig. 3. Reaction (a) 91 ooi (a) lH2 Hz NH ( f) NH oc~( 11) ocr(IV) . (b)!H2 (g) lH2 H2 2 ( h) oc::2 .[~tJ Ila) . (V) 2 (c)I ( i ) !H 2,-N H3 H2,-NH300HH2 OCNH2 (d) (e) OOj( 11 b) (VIII) ... (VI) 3 (J) lH2, -NH3 C(H3 3H2 ( k) CH3 or:::(VII) Cis----- and trans (IX)

Fig. 3. --Proposed pathway for hydrogenation of phthalazine 92 is well-established as the exclusive reaction of phthalazine with 1. 0 molar equivalent of hydrogen since 1, 2-dihydrophthalazine was obtained in quantitative yields when reactions were terminated after

1. 0 molar e_quivalent of hydrogen was absorbed. When aliquots of low-pressure phthalazine hydrogenations were checked prior to absorption of 1. 0 molar equivalent of hydrogen, only II and phthalazine were present. This evidence precludes initial formation of a com-

1 1 1 pound such as 1, 1 , 2, 2 -tetrahydro-1, 1 -.biphthalazyl followed by hydrogenol ysis to give II. After formation of II, it is conceivabl'e that two hydrogenation pathways may exist.

In the fir st route, after initial formation, compound II could add one mole of hydrogen across the 3, 4-bond to give IV (reaction f). Compound IV was shown to be the exclusive product in the low-pres sure hydrogenation of phthalazine over Pd/ C. Hydro- genolysis of the 2, 3-N bond in IV could give VI (reaction g) and subsequent hydrogenolytic cleavage of ammonia could give VI and VII.

~-Xylene VII could be further reduced to a mixture of cis- and trans-1, 2-dimethylcyclohexane, This pathway appears to the author to be the most straight-forward in explaining the presence of all the.hydrogenation products except 1, 3-dihydroisoindole (VIII) which is discussed in the next paragraph.

Alternatively, after formation of II, a second mole of hydrogen could add across the 2, 3-bond (reaction b), forming an intermediate 93 amino-aldimine compound (Ila}. This could immediately react by adding hydrogen (reaction h) to form V, or it could undergo internal nucleophilic attack of the amino group on the electro- philic aldimine carbon, followed by a prototropic shift to give l- amino-1, 3-dihydroisoindole (lib}. It is expected that this compound, which can be thought of as a hemi-aminal, would be very unstable.

Subsequent loss of ammonia from IIb by hydrogenolysis ·could give

1, 3-dihydroisoindole (VIII). 1, 3-Dihydroisoindole could then be reduced to VI, VII, and IX.

A second alternative was considered which would also explain the presence of 1, 3-dihydroisoindole. Dehydrogenation of compound V (reverse of reaction h} could form the amino-aldimine

(IIa) intermediate which could undergo the process just described in the previous paragraph to form VIII.

The proposed pathways were tested by hydrogenating II, IV, and

V. The conditions and results of these reactions are summarized in Table 6. The 1, 3-dihydroisoindole was detected only in the reaction where II was the starting material, implying that if Ila is an intermediate, it probably does not come from IV or V, but could come from II. This evidence supports the reaction sequence b-c-d for the formation of VIII rather than a-f-g-h.

Examination of relative product ratios for both high- and low- pressure phthalazine hydrogenations indicates that the reaction TABLE 6

HYDROGENATION OF CERTAIN INTERMEDIATES

Cl) •,-{ t:ll 1-l Compound - .µ . Products (%) u p.. ::l .-I> 0 0 0 ro ~ -~ ::r:: Cl)_ u

Phthalazine Intermediates -- 1, 2-dih ydrophthalazine I 150 I 2000 I 5 · I Nal Pt/C j II (10), IV (23), V (33), VI (12), VIII (7), VII (5). .i:,.. I I I I I I '° 1, 2, 3, 4-tetrahydrophthalazine 150 2000 5 N· Pt/C V (tr), VI (5), VII (95). c{,cx.1 -diamino-~-xylene 150 2000 2 N Pt/C V (tr), VI (10), VII (90). c,(,,cx' -diamino-~-xylene 150 2000 5 N Pt/C I VII (100).

1, 3-dihydroisoindole rt 60 8 N Rh/ A1 2o 3 I VII (55), IX (45).

~-xylene I rt I 60 I 4 I N I Rh/ A12o 3 I IX(lO0), cis-(85), trans- (15). TABLE 6 ( Continued) - Cf.) •,-! -(/) 1--1 . u 0.. ::! > ,I-,> Compound 0 0 ...-I Products(%) 0 cu E-t -~ ::r: Cl) u

Quinazoline Intermediates

a( N -methyltoluene- , 2-diainine 100 2000 5 Nb Rh/C XVII ( 5), XVIII (9 5).

~. Nr:,(-dimethyltoluene- 0( , 2-diamine · 100 2000 5 N Rh/C XVII (7), ·xrx (7), XVIII(86 ) . '°\J1 -o-toluidine 150 2000 5 Ac Pd/C XVIII (100).

aNeutral solvent (anhydrous ethanol)

b Anhydrous ethanol saturated with methylamine

c Anhydrous ethanol plus 2. 0 eq of HCl/ mole of substrate d Room temperature 96 sequence f-g-i-j-k is probably the major pathway while b-c-d is a minor, competing pathway, It is interesting to note, however, that

1, 3-dihydroisoindole undergoes hydrogenolysis under relatively mild conditions (Table 6). This could mean that reaction sequence b-c-d is a major rather than a minor pathway, but that buildup of VIII in the reaction mixture is prevented by rapid hydrogenolysis of

VIII to other products.

It would be impossible to predict the relative rates of the various reactions outlined in Fig. 3 without hydrogenating each intermediate compound under all of the conditions described.

Quinazoline

A pathway of hydrogenatio!l for quinazoline has already been proposed by Young (101). This pathway is depicted in Fig. 4A. Young proposed that Nc,C.,No<-dimethyltoluene..:.c<, 2-diamine (XIX) resulted from reaction of Nlll-methyltoluene-~, 2-diamine (XIII) with methylamine by the reaction sequence in Fig. 4B. The methylamine was presumed to come from hydrogenolysis of XI, giving £-toluidine and methylamine. The methylamine thus formed could then undergo dehydrogenation to give formaldimine (reaction e). The oC-amino group of XIII could then undergo elecJrophilic attack by the formaldimine carbon (reaction f), followed by prototropic .shift

(reaction g) to form an N-substituted formaminal. The formaminal could then readily lose ammonia by hydrogenolysis (reaction h) -97 Figure 4

( d) (XI) ( X 111)

( XVII)

(h) C

H 2 0 0 -----R-CH=O-◄'---kR-CH-O

R-CH-NH2. _H_2_ I ( I ) OH 98 to form XIX. Precedent for this type of reaction which is a well-known process used for ~he commercial synthesis of some amines is summarized in Fig. 4C.

A test of Young's _hypothesis was made by hydrogenating XIII in the presence of methylamine (see Table 6). Compound XIX was obtained as one of the products, but it was present in relatively

small amounts, This evidence indicates that dehydrogenation of methylamine must be taking place. However, this should not be taken to mean that dehydrogenation of methylamine is the_ only explanation for presence of XIX in quinazoline-hydrogenation mixtures.

An alternative rationale which does not require/dehydrogen-

ation of methylarriine can also be made. If, after formation of

1, 2, 3, 4-tetrahydroquinazoline· (XI} a benzylic hydrogenolysis occurs

'(position a; see Fig. 2), then XIV would be the product. Compound

XIV can be thought of as a .hemi-formaminal which would be

expected .to be unstable. After initial formation of XIV, this

compound would likely undergo prototropic shift and loss of 2_-toluidine to form formaldimine. The formaldimine thus formed could·

then undergo the same reaction sequence as previously described

(reactions f and g, Fig. 4B), eventually giving XIX. This latter 99 explanation has the favorable feature that formation of XIV from XI would occur by a benzylic hydrogenolysis which would b~ predicted to be favored over hydrogenolysis at position c (Fig. 2, compound XI).

Unfortunately, a method for obtaining XIV has not been reported in the literature, and repeated attempts by Young to synthesize it were of no avail. ' 100 Figure 5

A. Phthalazine 2.0 Neutral Acid

Cl) Rh/Al203 0 0 -....C Rh/C D (N.R.) Pf/C b. A V, .a- Pd/C "v V :, V,

Q) ·O- E 1.0 (\J ':c

V, Cl) 0 ~

5 10 15 20 25

1.0

Cl) -0.... B. Quinazoline V, .a- :, (/) Cl) 0.5 ', 0 E ' (\J Neufra I Acid :c Rh/Al 203. 0 e (/) Rh/C D D Cl) -0 Pt/C b. A ~ Pd/C "v V

2 3 4 5 6 7 8 Hours 101

2.0 ,.o 4.0 s'.o ,p~{T) 6.0 7.0 ,.o 9.0 ,b ,. o-r;_t 'i T

.' ii-I H H JOO II I I>-- f /i :J~' li I

I.O 7.0 6.0 5.0 Pf'Ml61 4.0 3.0 2.0 ,.o

__J.0 3.0 4.0 s'.o PPM -r 6.0 7.0 ,.o ,.o ,b ,. o>--;t

i H NH ii II 19()H H H r

,\J,

-1.0 .0 6.0 5.0 PPM ! .. 3.0 2.0 ,.o

2.0 3.0 4.0 s'.o ""' .,. 6.0 7.0 1.0 9.0 ,b ,. .. 0 >-;;" +T

(al H H

(al (bl (cl (dl I (b)

H l.,H (c) H H H "OC•(d)

1.0 7.0 6.0 5.0 PPM 6 4,0 3.0 2.0 1.0 102

20 30 40 s'o PPM{Tl 6.0 70 10 ,o I'o ,. ' ~ ,., ,., o>-;? "" +T

-~--H O NH: H H H ,-- L l--

\ ~ ✓ 1 I I

1.0 7.0 6.0 ,.o P?M{,$/ 4.0 3.0 2.0 1.0 0

2.0 3.0 4.0 s'.o PPM T} 6.0 7.0 1.0 ,.o ib ,. >-e> i • = i !

: NH,

IQ(> H

~ ~ -~ j jl

1.0 7.0 6.0 s.o PPM 6 4.0 3.0 2.0 1.0

2.0 3.0 4.0 s'.o PPMl;l 6.0 7.0 1.0 ,.o ib

,. ~ ,., i .. .>-;;t T T

:00:,H H ~ H -

I : \ ' i I ! ' i : I l l ~ I I \ I f I 1.0 1.0 6.0 s.o 1'1'.:-m----4.o 3.0 2.0 1.0 103

..,,,.I"I I 1:1,k l"I ....,.,. ,., ... ,w f I ., f'I 1 4 •

1.0 7.0 6.0 5.0 PPM. 0 1 4.0 3.0 2.0 1.0

2.0 3.0 4.0 ,:o Pf'M 'T 6.0 7.0 1.0 9.0 1b i i +

:OCcH H H

1.0 7 .0 6.0 5. PPM. 4.0 3.0 2.0 1.0 0 104 105

2.5 10 MIClON S 60 7.0 •o

~ ~ m =WAVENUM6ER fC,, = \ .) • 106

Mass Spectrum: 1, 2, 3, 4-tetrahydrophthalazine

m/e % of base peak

28 25.1 29 10.6 30 10,0 39 7.53 50 7.54 51 9.81 77 12.5 78 15.5 103 14.8 104 47.1 105 9.50 ll6 11. 3 131 8.8 133 27. 2 134 .(P) 100. 135 (P+l) 10.3

Mass Spectrum: l, 3-dihydroisoindole

m/e. % of base peak

28 100. 38 21.3 39 62. 0 50 21.2 51 25.0 (58. 5) 25.0 62 15.9 63 38.5 65 24.5 89 21. 2 90 .13. 6 91 25. 5 ll8 87.5 119 (P) 22.5 120 (P+ 1) 1.50 107

Mass Spectrum: phthalazine

m/e % of base peak

50 55.5 51 26. 5 . 63 20. 0 74 23.5 75 26. 5 76 57.5 102 17. 1 103 28. 3 130 {P) 100. 131 {P+l) 11. 8

Mass Spectrum: 1, 2-dihydrophthalazine

m/e % of base peak

28 73.0 29 19.8 38 10.4 39 15.7 50 36.5 51 39.3 52 11. 5 63 13.6 74 13. 8 / 75 15.6 76 23.7 77 36.4 102 11.6 104 17. 8 130 13. 6. 131 100. 132 {P) 33.6 133 {P+l) 2.7 134 {P+2) 0.2 108

Mass Spectrum: o<,o<.1 -diamino-£-xylene

m/e % of base peak

27 15.6 28 91.0 29 26. 4 30 85.0 31 17.4 39 31.2 41 16.5 50 13.4 51 27. 3 52 10.1 63 14.7 65 21.3 77 30.8 91 52.5 92 36.6 104 24.3 117 22.6 118 71.5 119 100. 136 (P) 6.70 137 (P-\-1) 0.60 109

Mass Spectrum: ~-methylbenzylamine

m/e % of base peak

28 42.5 39 34.5 50 11. 8 51 21. 2 63 18.2 65 24.2 77 27. 8 78 21. 2 79 16.0 89 10.0 91 31. 2 93 14.5 103 12.7 104 100. 105 14.3 106 17. 2 118 10.6 120 13.6 121 (P) 15.0 122(P+l) 1. 30 V. SUMMARY

Quinazoline and phthalazine were hydrogenated at low pressure

(60 psi) and high pressure (2000 p·si) in neutral and acidic solvents

over 5% Pd/ C, 5% Ru/ C, 5% Rh/ A12o 3, 5% Rh/ C, and 5% Pt/ C.

The low ...pressure reactions were run at room temperature, and

0 the high-pres sure reactions were run at 100 C and 150° C.

A chromatographic method for determining the qualitative

and quantitative composition of hydrogenation mixtures was devel;,,.

oped. The composition of qui~azoline and phthalazine ...hydrogenation mixtures was determined.

Eight phthalazine-hydrogenation products were detected and isolated: (1) 1, 2-dihydrophthalazine, (2) 1, 2, 3, 4 ...tetrahydro-- phthalazine, (3) a<.,o<.1 ... diamino ...~ ..xylene, (4) ~ ....methylbenzylamine,

(5) 1, 3 ...dihydroisoindole, (6) ~-xylene, (7 and 8) cis" and trans ...

1, 2 ...dimethylcyclohexane. These products were identified by isolating them from reaction mixtures and comparing their ir,

nmr, and mass spectra with those of authentic samples~

A pathway of hydrogenation was proposed for both quinazoline

arid phthalazine, and evidence for each pathway was presented.

110 LITERATURE CITED

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(11} Ibid., 1961, 2697.

( 12) Ibid. , 196 2, 4094.

(13) W. Armarego, J. Smith, J. Chem. Soc., 1965, 5360.

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(15) A. Bixchler, M. Lang, Chem. Ber,,~' 279 (1895),

(16) P.J. Black, M.L. Heffernan, Aust, J. Chem,, 18, 707 (1965).

111 112

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(30) K. Dziewonske, L. H. Sternbach, Bull. Intern. Acad~ Pol., Classe Sci. Mat, Nat., 1953A, 1933A, 1935A. cf. CA, 30, 2971 (1936), CA, 28, 2717, (1934),

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r' 113

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(34) M. Freifelder, Advan. Catal., 14, 203 (1963).

(35) D; J. Fry, J. D,; Kendall, A. J. Morgan, J. Chem. Soc., 1960, 5062.

J (36) S. Gabriel, Chem. Ber., 36, 800 (1903).

(37) . Ibid., p 3373

(38) S. Gabriel, J. Colman, Chem. Ber., 37, 3643 (1904).

(39) S. Gabriel, J. Colman, German Patent 101401 (1908).

(40) S. Gabriel, G. Eschenbach, Chem, Ber., ~• 3022 (1897).

(41) S. Gabriel, G. Pinkus, Chem, Ber., 1._§,2210 (1893}.

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(43) S. Gabriel, A. Neuman, Chem. Ber.,~' 521, 705 (1893).

(44) A.H. Gawer, B.P. Dailey, J. Chem. Phys.,_±?, 2658 (1965),

(45} H. Gilman, A.H. Blatt (ed.), "Organic Synthesis Collective Volume I" 2nd ed., John Wiley and Sons, inc., New York, N. Y., 1962, p 119.

(46) T.S. Hamilton, R.J. Adams, J. Amer. Chem. Soc., 50, 2260 (19 28}.

(47) W.E. Hanford, P. Liang, R. Adams, J. Amer. Chem. Soc., 56, 2780 (1934).

(48) H. H. Hatt, E. Stephenson, J. Chem. Soc., 1943, 658.

(49) E. Hayashi, T. Higashino,· Chem. Pharm. Bull., (Tokyo), 12, 1111 (1964).

(50) Ibid., .!2_, 291 (1965).

(51} L. Helfer, Helv. Chim. Acta.; 6, 785 (1923). 114

(52) T. Higashino, Chem. Pharm, Bull., (Tokyo), 10, 1043 (1962).

(53) T. Higashino, J. Pharm. Soc .. Jap., 80, 245 (1960).

(54) A. Hirsch, D. Orphanos, J. Heterocycl. Chem., 2, 206 (1965).

(55) Ibid., ~ 38 (1966).

(56) A. Hirsch, D. Orphanos; Can. J. Chem., 43, 2708 (1965).

(57) Ibid., 46, 1455 (1968).

(58) E.L. Holmes, C.K. Ingold, J. Chem. Soc., 1925, 1800.

(59) E. C. Horning, "Organic Synthesis Collective Volume III", John Wiley and Sons, inc., New York, N. Y., 1955, p 181.

(60) W. Buckel, F. Step£, Justus Liebigs Ann. Chem., 453, 163 (1927).

(61) V. Ipatief, Chem Ber., 41, 991' (1908).

(62) A. Kanahara, Yakugaku Zasshi, 84, 483(1964) cf, CA,~' 8304c(l964)

(63) A. R. Katritsky, "Physical Methods in Heterocyclic Chemis- try, 11 Vol. I, Academic Press, New York, N. Y., p 21.

(64) Ibid,, Vol. II, p 24.

(65) A.R. Katritzky, R.E. Reavill, F.J. Swinbourne, J. Chem. · Soc., B, 1966, 351.

(66) J. Knabe, U.R. Shuka, Arch. Pharm., 295, 69 (1962).

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(68) M. Lora-Tamayo, R. Madronera, G. Munoz, Chem. Ber., 94, 208 (1961).

(69) A. Mustafa, A. H; Harhash, A. A. S. Saleh, 2.:..,_luner·: Chem. Soc., 82, 2735 (1960). 115

(70) A.-R. Osborn, K. Schofield, J. Chem. Soc,, 1956, 3977.

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(72) A. M. Patterson, L. T .- Capell, D. F. Walker, "The Ring Index, 11 2nd ed., American Chemical Society, Washington D.- C., 1960, p 210, (See compound #1628). ,

(73) Ibid., compound #1626,

{74) V. Paul, Chem, Ber., 32, 2014 (1899).

{75) F.D. Popp, J.M. Wefer, Chem, Commun,, 1967, 59,

(76) N. Rabjohn, "Organic Synthesis Collective Volume IV, 11 John Wiley and Sons, inc., New York, N.; Y., 1963, p 509.

(77) Ibid. , p 807.

{78) Ibid,, p 984,

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(,85)_ A. Skita, Chem. Ber., 2_], 1977 (1924),

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(88) R. Smith, E. Otembra, J. Org. Chem,, 27, 879 (1962). ' ---"---- - (89) E. Stedman, J. Chem. Soc., 1927, 1904.

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(101) K. B, Young, Masters Thesis, Brigham Young University, Provo, Utah, 1968, APPENDIX I

Oral Research Proposition Examination, Outline,

26 November 1968 1 Cyclisative Condensation

of Nitroalkanes with i ...Diketones

Statement of Proposition

It is proposed to react simple nitroalkanes such as nitromethane and nitroethane with (\ .. diketones in a base-catalyzed

condensation. The aim of this research is: (1) to determine the feasibility of effecting a dieocondensation in order to obtain

2 .. nitrocyclopentane-l, 3~diols, (2) to elucidate t_he structure of the various possible isomers, (3) to subsequently use the nitro ..

dials in known reactions to obtain new compounds.

Literature Background

The base ...catalyzed condensation of an aldehyde with nitro ... methane has been used for the synthesis of a variety of products

since its discovery by Henry in 1895. The analogous reaction of nitromethane with ketones has alf,a been well ...established and used in the synthesis of ~ ...nitroalcohols.

117 118 The extension of this reaction to cyclisations using dialdehydes was first carried out in 1910, using nitromethane and ~..,phthal .. aldehyde (1). The product,formed was 2 .. nitroindcnol. Analogous

_cyclisations have been carried,..out using naphthalene ...2, 3-dicarbox .. aldehyde (2), indane.,5, 6 ...dicarboxaldehyde (3), homophthalaldehyde (2) and 2, 2 1abiphenyldicarboxaldehyde (3). _ Lichtenthaler indicates that maleicdialdehyde gave (4), with nitromethane in sodium methoxide, a cyclic ~... nitro salt with the probably structure I, but it formed

an unidentifiable polymer upon neutralization, and no nitrocyclo ... pentanediol could be isolated.

The same author also reports that glutaraldehyde in sodium carbonate gives a mixture of 2-nitrocyclohexane ...l, 3 ...diols which are assigned structure on the basis of nmr evidence (8). Glutar .. aldehyde was also condensed with nitroethane (5), and 2-nitro ... ' ethanol (9) to yield analogous products. Nitro ethane also con .. denses with ~"."phthalaldehyde, naphthalene-2, 3 .. dicarboxaldehyde, and 2, 2 1 ... biphenyldicarboxaldehyde to yield n .....rv, respectively. 119 Glutaraldehyde yields the corresponding z.,.nitrocyclohexane ...1,

3--diols upon condensation with l~nitropropane and phenylnitro .. methane (7).

There is only one reported condensation of a diketone with a nit:roalkane which yields a cyclic nitrodiol. This reaction reported by Statter (10) involves the condensation of bicyclo 1, 3, 3 nonaneA3,

7 .. dione with nitromethane in sodium methoxideo The resulting

N02 z... nitroadamantane.,.l, 3 .. diol is obtained in 79% yield,;

Based on the known condensation reaction of ketones with nitro ... alkanes, i • .=_o, the c yclisative condensation of certain dialdehydes and a diketone with nitroalkanes, it seems theoretically possible that other diketones should lead to 2-nitro .. l, 3-dialkylcycloalkane- l, 3 .. diolso

Significance of Proposition ,

This research would: (1) determine the feasibility of effecting di-condensation of nitroalkanes with diketones to obtain cyclic pro ... ducts, (2) give evidence as to the relative importance of steric and electrostatic effects in product formation, (3) provide a series of new compounds which could be used in the synthesis of 120 additional new compounds with potential biological interest, such as aminodiols, pyrroles, and pyrrolidines.

Outline of Res ear ch Procedure

I. Reaction of 2, 5 ...hexanedione with nitromethane

A. Separation of the products

1. Simple recrystallization, distillation.

2.; Preparative thin ...layer and gas chromatography

Bo Identification of products

1. Preliminary

a. Ir for ~N0 2, "OH, C 0

b. Elemental analysis

c. Mass spectra for loss of ...H, •OH, ~NOz

2. Structure of various isomers

a. Nmr for equivalence of (,\eMe groups

b. Formation of acetoxy derivatives

c. Nmr study of acetoxy derivatives

. d. Reduction of .--NOz to NHz and acetylation

e. Comparison of a, c, d

II. Reactions of other diketones with other nitroalkanes

III. Reaction of nitrodiols to form other compounds o LITERATURE CITED

(1) J. Thiele, E. Weitz, Justus I.A.ebigs Ann. Chem., 15, 377 {1910).

{2) F. W. Lichtenthaler, Tetrahedron Lett., 775 (1963).

{3) F. W. Lichtenthaler, A. El Scherbiny, Newer Methods of Organic Synthesis, 4, 159-188 {1968).

(5) F. W. Lichtenthaler, .Angew, Chem., 73, 654 (1961).

{6) H. Stetter, J. Mayer, ibid., -2_!, 430 {1959),

(7) F. W.Lichtenthaler, H. Lienert, Chem, Ber., 101, 908 (1967).

(8) H. Stetter, P. Tacke, ibid., _1§, 694 {1963).

121 THE CATALYTIC HYDROGENATION OF BENZODIAZINES:

I. PHTHALAZINE

II. QUINAZOLINE

An Abstract of

A Dissertation

Presented to the

· Department of Chemistry

Brigham Young University

In Partial Fulfillment

of the Requirements for the Degree

Doctor of Philosophy

Danny Lee Elder

August 1969 This abstract, by Danny Lee Elder, is accepted in its present form by the Department of Chemistry of Brigham Young

University as satisfying the dissertation requirement for the degree of Doctor of Philosophy.

.. ABSTRACT

Quinazoline and phthalazine were hydrogenated at low pressure and temperature {60 p~i, room temperature) and high pressure and

0 . temperature (2000 psi, 100°c, 150 C} in neutral and acidic solvents over 5% Pd/ C, 5% Ru/ C, 5% Rh/ A12o3 , 5% Rh/ C, and 5% Pt/ G.

Chromatographic methods for determining the qualitative and quantitative composition of hydrogenation mixtures were developed.

The compositions of quinazoline and phthalazine-hydrogenation mixtures were determined,

Eight phthalazine-hydrogenation products were detected and isolated: (1) 1, 2-dihydrophthalazine, (2} 1, 2, 3, 4-tetrahydrophthalazine, (3) c,(, C{' -diamino-o-xylene, (4) £-methylbenzylamine,

(5) 1, 3-dihydroisoindole, (6) £-xylene, (7 and 8) cis- and~-

1, 2-dimethylcyclohexane. These products were identified by isolating them from reaction mixtures and comparing their ir, nmr, and mass spectra with those of authentic samples.

Pathways of hydrogenation were proposed for both quinazoline and phthalazine, and eyidence for each pathway was presented,