SYNTHESES USING ISONITRILES a Thesis Presented by DIONYSIOS PAPAIOANNOU in Partial Fulfilment of the Requirements for the Award

SYNTHESES USING ISONITRILES

A Thesis presented by

DIONYSIOS PAPAIOANNOU

in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON

Hofmann Laboratory Chemistry Department DECEMER 1977 Imperial College London S17 2AY To my Parents and Grandmother 2rovS Tovets kat ytayta you 3

ACKNOWLEDGEMENTS

I wish to thank :

Professor Sir Derek Barton, FRS, for all the encouragement and assistance he has given me, and for

• his patient and perceptive guidance of this project.

Dr. A. G. M. Barrett for cosupervising this project, for reading the manuscript and giving valuable suggestions.

Dr D. A. Widdowson for cosupervising part of this work.

Dr. S. Singh for helpful discussions and Dr. R. W. Read for useful suggestions and for reading this Thesis.

All my friends and colleagues in the Hofmann Laboratory,_ past and present, whose advice, assistance and good-fellowship were of great value.

The staff of the Chemistry Department for their essential analytical, spectral and technical services.

Dionysios Papaioannou

• ABSTRACT

The reactions of isonitriles with carbonyl compounds or their derivatives under basic and acidic conditions and the chemistry of toluene-4-sulphonylmethyl isocyanide (TosMIC) are reviewed. Recent developments in phenol oxidative coupling are also summa.rised. Novel oxidants, including vanadium oxyhalides and thallium(III) trifluoroacetate, and electroorganic coupling are described in full. Isonitriles have been studied and shown to be useful intermediates in the synthesis of 1-benzylisoquinolines. A novel approach to these alkaloids,. based on TosMIC as a C-N-C synthon and the available aromatic aldehyde C6-C1 units, was explored. The reaction of isonitriles with the acetals of electron rich aromatic aldehydes catalysed by trifluoroacetic acid provided in good yield the alkaloid precursor skeleton. The in vitro cyclisation of bisphenolic substrates as models for the biosynthesis of erysodienone.have been examined. TosMIC and derived isonitriles have been employed in the synthesis of novel bisphenolic derivatives. Phenol oxidative coupling of such substrates lacking a nitrogen function gave a carbocyclic analogue of the biosynthetically important dibenzazonine. This gave further support to an initial C-C coupling rather than the alternative C-N coupling in the phenol oxidative coupling step in the biosynthesis of erysodienone. Further oxidation with diphenylseleninic anhydride gave, in a novel reaction, an o-quinone derivative and not the expected biphenonquinone.

• 6

CONTENTS

Acknowledgements 3 Abstract

• CHAPTER 1. ISONITRILES IN ORGANIC SYNTHESIS 8

1.1 Introduction 9

1.2 Acid induced reactions 10 1.2.1 Lewis acid induced reactions 10 1.2.2 Passerini reaction 18 1.2.3 Four component condensation reactions 22 1.2.4 Reactions of isonitriles with acetals 33

1.3 Base induced reactions 35 1.3.1 Introduction 35 1.3.2 Synthesis of heterocycles 37 1.3.3 Extended chain isonitriles 43 1.3.4 Olefin formation 45

1.4 Toluene-4-sulphonylmethyl isocyanide 51 1.4.1 Introduction 51 1.4.2 Construction of heterocycles 55 1.4.3 Miscellaneous transformations '60

CHAPTER 2, RECENT DEVELOPMENTS IN PHENOL OXIDATIVE COUPLING 65

CHAPTER 3, NOVEL SYNTHESES OF 1-BENZYLISOQUINOLINES 86

3.1 Results and Discussion 87

3.2 Experimental 116

•

CHAPTER 4, SOME STUDIES RELATED TO THE BIO-

SYNTHESIS OF ERYTHRINA ALKALOIDS 135

4,1 Results and Discussion 136

4.2 Experimental 163

REFERENCES 188 CHAPTER 1

ISONITRILES IN ORGANIC SYNTHESIS 9

1.1 INTRODUCTION

Isonitriles are readily available compounds, useful for the synthesis of a wide variety of compounds and are commonly prepared, usually in high yields, by dehydration of N-monosubstituted formamides1,2 using phosgene3, phosphoryl chloride4, toluene-4-sulphonyl chloride51 tri- phenylphosphinejtetrachloromethane8, chloromethylenedi- methylammonium chloride7, or dibromotriphenylphosphorane8 in the presence of a base, usually triethylamine. They are also prepared from the corresponding amines by the Hofmann carbylamine reactionl0 , under phase transfer reaction conditions9 The ylide character of isonitriles accounts for their wide variety of reactions where the isonitrile can act either as a nucleophile or an electro- phile. The isocyano group can also stabilise a-carbanions for reasons which are not fully understood. Dipole stabilisation of the anion is suspected11 mesomeric stabilisation playing no part12 The reactions of isonitriles have been frequently reviewed1'57158 and thus this chapter is limited to the acid induced (Section 1.2) and base induced (Section 1.3) reactions with aldehydes, ketones, and their derivatives, and the chemistry of the toluene-4-sulphonylmethyl isocyanide (Section 1.4).

1.2 ACID INDUCED REACTIONS

1 ,2.1 Lewis acid induced reactions

Kabbel3 and Saegusa et al. 14 independently reported

• that with Lewis acid catalysis aldehydes and ketones reacted with isonitriles in the ratio of 1:2 to form the 2,3-diiminooxetanes (1) generally in high yield.

6F3 BF I "-.1, (1 3 :O R CO• 1 ((I+ cif rC-----1■1—R- 3 R1--C—CN—R3 1/ \ 2 ! 2 R R 11

Derivatives with a-hydrogens were isomerised to the unsaturated iminoamides (2), which were further hydrolysed with aqueous acid to form the derived keto- amides15 (3).

13F3 1.4 k.c) zNR3 " 3 RCN-7---C—C—CONHR RC1-1—C--- 3 11 3 1 2 NR R2 NR (2) (1)

3 RCH=C—C—CONHR II R2 0

(3)

The methylenepyruvamide derivatives (3) were also prepared by Muller and Zeeh16 from ketones and isonitriles, in the presence of an equivalent of boron trifluoride etherate in aprotic solvents. The 213-diiminooxetanes (1) could be cleaved with hydrogen halides or aqueous carboxylic acids15 to afford the (3-substituted amides (4).

b 12

H P f\1R3 0 1 ICO NHR3 R—C--CV R—C 3 I 3 1 2 NR - X R- NR

(4)

The diiminooxetanes derived from aldehydes (1, R1=H) gave unsaturated hydroxyacrylamides15 (5) on reaction with carboxylic acids. With bromoacetic acid a 13-lactam. (6) was the sole product17

,„H ( NR3 3 CONHR 2 I-\ (J 4 R —C H —C 3 3 /1 NR • I NR 4 R.. RCO-2 z ) 3 2 .-CONHR , 4 NCOR HO' 1 3

(5)

2 R CONHR3 0 3 / 2 CONHR /C=C\ 3 HO N, R H NR3 /CH2---c( CH /) 2 Br ° Br 0 (5, R4. CH2Br)

3 0 CONHR 2 NR3

(6)

Reactions of isonitriles with aldehydes and ketones lead to different products when one of the components is an aromatic derivative. Thus aromatic isonitriles afforded indoleninesl8 (7) while aromatic carbonyl compounds afforded indole carboxamides19 (8)

0 BF3 C6H5-NC

■••■■••• 2

N CONHC6H5 1/4N-C6H5 (7)

3 \-+ NR 0 -CH3 CH3 3 R CONHR3 R3

(8)

Although aldehydes and ketones react with isonitriles normally with carbon to carbon bond formation, 4-methoxybenzoylmethyl isocyanide (9), on heating, gave 4-methoxyphenyl oxazole (10), in almost quantitative yield. In this case an oxygen to carbon bond was formed2°

CH 0 CHO 3 3

(9) (10)

Schiff bases also reacted with isonitriles, with acid catalysis, to afford various products. Thus aluminium trichloride induced condensation of alkyl isonitriles with the azomethines (11 1' Rl. alkyl) afforded imidazolidines21,22 (12). With the azomethines (11, Rl = phenyl) the N,N'-diphenyl-1-phenyl-2-alkyliminoethylene- diamine (13) was formed22.

2 AICI3 C6H50-1=--NR1 R —N C

(ii)

C6H5

(ii AIC13

C6H5 1 1 1 R—N—CH—C 2 t AtC13 NR

cyclisation R1= C6H5 2.H20 H2O

C 6H5 ..../R1 6H5 H 2 NHCHC NH NR 211 RN H C6H5

(1 2 ) (13) 1.7

On the other hand imine (11, Rl= aryl) on heating with t-butyl isocyanide afforded21 azetidines (14) or indoles (15), depending on the substituent X. Traces of hydrogen chloride usually present in the solvent carbon tetrachloride catalysed the above reactions. •

C6H C6H5CH=N X -F 2 R-2-N H N

2 / 2 R N NR (14)

C6H5CH N

CHC6H5

(15) 18

Consistent with the above mechanism only the 1:2 adduct (14) was formed with the nitro-derivative (X.NO2). In the unsubstituted imine (X=H) the 1:1 adduct (15) and the 1:2 adduct (14) were major and minor products respectively.

1.2.2 Passerini reaction

Isonitriles often undergo multicomponent reactions in which more than two reactants combine to form a single product, usually in high yield. For example isonitriles reacted with carboxylic acids and carbonyl compounds, with the exception23 of sterically hindered ketones or some al p-unsaturated ketones, to form a-acyloxycarboxamides24'25 (16). The above type of reaction is known as the Passerini reaction.

0 11 3 H R-1 C- R 2 + R R -CO2

0 4 R CO-C-CONHR3 1/ \.2 R R

(16)

A variety of different mechanisms has been proposed1 for this reaction but none to date has been experimentally proven. Passerini postulated the geminal diol monocarboxylates (17) as intermediates in this reaction.

2 0 R R 111 2 4 4 \ RCR R CO2H R CO2—C —OH (17)

R3NC

(16)

Baker and Stanonis26 and Dewar27 postulated the dipolar species (18) as an intermediate. 2 0 - R + 31 1 II 2 + R3NC 1. RCR R 0- (18) 4 R CO2H R2

1 n+ 3 (16)-1 R —C—C—NR k OH

0 \R4

Another mechanism, which is consistent with the well-known tendency of isonitriles to undergo a-additions, postulated28 the intermediacy of the iminoester (19).

0 111 2 4 4 „.0 C) R CR R CO2H R —C- 11 0 R2 ---

3 R

0...H 0 R4—C// \r (16) -7R1 0—C/ 1-< (19) NR3 In the Passerini reaction replacement of the carboxylic acid by hydrazoic acid29 or aluminium azide28 gave the derived tetrazole (20). 0 R0 CR2 + R3NC -F HN3 o.

1 R2 1 2 R\ R 3 / 3 — C —N—R HO—C—C N--R HO—C I I I Nw-N

(20) 21

With hydrazoic acid an electrophilic carbonyl compound was required since in a competing reaction the acid was found to react with isonitriles giving the tetrazole (21).

4 R3 + H—N=N-=F1

,H [ 3 C t N NrN (21)

Isonitriles also react with water and carbonyl compounds, in the presence of catalytic amounts of boron trifluoride etherate or mineral acids, especially sulphuric acid, to form a-hydroxyamides1630 (22)

0 R1 R2

R2 RR 3NCNC H2O HO—C—CONHR3 (22)

The hydrates of highly chlorinated ketones and aldehydes do not require acidic catalysis31,32 22

•2• 3 Four component condensation reactions

Isonitriles reacted with aldehydes or ketones, amines and suitable acids to form unstable a-adducts (23) which were readily converted into a-amino acid derivatives33. This reaction is known as a four component condensation (kCC) or the Ugi reaction. 0 11 2 3 5 6 —H20 R CR -1- R NC + HX R NHR c=-

R6 5 1 3 R N—C— C=NR •■••1;:m cr-amino acid dervs. 1 2 1 R X (23)

The following mechanism was suggested by Ugi1 13 :

0 R6 56 —1-100 5 1 2 RC R- -1- HX RNHR R N=-CR + X —

R6 R?

FkS N —CCI. --X

R3NC two-step a-addition single-step

6 2 6 2 R R R R 5 1 51 I R N—C—C=NR3 --1 R N—C—C:-----NR- 3+ X Ii I 11 R X R (23) 4 23

The reaction is general for isonitriles but sterically hindered diaryl ketones fail to react. Ammonia, primary and secondary amines, and hydrazine derivatives can be used as the amine component. Acids which do not form stable a-aminoalkylation product s35,for example hydrogen sulphide or hydrogen cyanide, but which do form a-adducts, are suitable acid components, provided that they can lead to a-amino acid derivatives, via secondary reactions. The nature of the secondary reaction depends on the acid component. Work up in the Ugi reaction is often facilitated by the product crystallising out. Unlike the main reaction, all the potential side reactions are reversible and thus yields are often high. Amine hydrochlorides reacted with isonitriles, potassium cyanate and aldehydes in a I4CC' type of reaction, in aqueous methanol to afford hydantoin-4-imides (24a) whereas use of potassium thiocyanate and ketones36'37 gave rise to 2-thiohydantoin-4-imides (24b). 0 11 2 5 R R3 NC NC + KXCN + R NH -HC1 2

(24) a, X=0 b. X=S

I. 24

The corresponding Schiff bases were alternatively used with pyridine hydrochloride as catalyst in anhydrous methanol/glyco138. Ammonia or primary amines and aldehydes or ketones reacted with carboxylic acids and isonitriles to afford a-acylamino carboxamides3914° (25).

0 i 2 3 4 5 R CRIC -I- R NC + R CO2H R NH2

2 R 3 R R —C—C NH4 R5 / R 0

5 R 4 I 3 R CON -C-CONHR

Ri R2

(25)

M 25 .

This reaction has been recently applied in the synthesis of biogenetically important amides. The bisamide (28) was prepared 1 in excellent yield, from the condensation of the p-acyloxy isocyanide (26), the azomethine (27) and trifluoroacetic acid, in dry benzene/methanol.

-F ArCH=NPh -F GEC° H 3 2 (27)

(26)

OCOCH /1". 3 Ar

..NCOCF Ar 3 Ph

(28)

Ar.

0 26

Secondary amines and aldehydes or the derived enamines (29), reacted with carboxylic acids and isonitriles to afford either amides (30) or N-acylamides (31) resulting from a Mumm rearrangement42.

5 RiC=CHNR + R3NC + R4CO H 2 R2 R6 (29) 1 2 R6 CHR R 6 1 2 R CHR R R'N — CH OH CH 51 I 3 3 R N—CH—CONHR 0 -R 4CO2CH —7 3 C 0 (30) 1 4

CHC13

6 R CHqR2 - 6 1 2 R CHR R R3 5 f CH R 0 51 1 4 R N—CH—C--N / — \, R 4N R 3 0 (31) 27

Formaldehyde and benzaldehyde on condensation with secondary amines, isonitriles and carboxylic acids, afforded the corresponding a-aminoamides37 (31a).

6 4 R R5 N1 —CH—CONHR3 1 R (31a) R C6H5 Secondary amines, aldehydes or ketones and isonitriles reacted with hydrogen thiosulphate or hydrogen selenide43 to pfford a-aminothio- and seleno-amides (32) and (33) respectively. 0 1 H 2 3 5 6 R CR t R NC -I- R NHR

H2 S203/ \-112Se

6 6 1 R R R R 51 1 — ri 3 51 3 R N—CC=NR R N—C—C=NR h 1, R2 S—S031-1 Se-H

R6 R 1 R6 Ri 5 1 1 3 51 I 3 RN—C—C—NHR R N—C—C—NHR 1 2 II R S R1 2 SeH

(32) (33)

• 28.

Schiff bases reacted with a-isocyano acids to produce a-aminoalkyl azlactones" (34).

R 5 1 / R3 5 /0 --CHR + C R R N= 4 HO2C

(34)

The synthesis of p-lactams by cyclisation of (3-amino acids is generally difficult to achieve by standard methods45. However the condensation of (3-amino acids with isonitriles and carbonyl compounds readily provided P-lactams46 (35).

Rs 0 R+ 2 1 2 HO CCH HNH + RCR 0 CCH CHN=----CR R 2 2C 2 2 2 H

R3NC

2 R N CONHR 1--L "J\I t 2 N. I R 0 R5

(35) 0

A3-Thiazolines were readily prepared by the condensation of a-mercapto aldehydes or ketones with ammonia and carbonyl compounds47. These heterocycles being Schiff bases, reacted with isonitriles and carboxylic acids. For example condensation of the t.3-thiazoline (36) gave methyl penicillanic amides (37).

RS CH R5 CH3 H2O R4Cit""rS1---CH3 4 .os'r+ CH N- t- R N CO2H (36) o'C 0

3 R NC V

R5 CH3 5 R 4 )r_S±CH3 CH R CH ''''N miiiiiih 3 ...1 1 H N :_ci ,:z.z. CH3 ,------„ l.. 3 0-' (Ds---- ( NR \\ H , \*1-1+ NHR6 (37)

a.R 5. H, R4= CH3 (48-57%) 4 b.R5= CH3' R H (88-94%)

•

Quinolinium bromides or iodides (38) undergo a-addition to isonitriles in the presence of carboxylate anions. The a-adducts (39) undergo oxygen to carbon acyl transfer giving N-alkyl-3-acyl-1 14-dihydroquinoline- -4-carboxamides" (40).

-+ R3NC f R4C02 N a Br-- (38) Rs 3 NR /R3 CT 0 —N H H-) COR4 /4 ttw 1 5 1 ,

(39) 3 CONHR COR4 N 1 5

(4o)

The piperidine aminals of formaldehyde, isobutyr- aldehyde and benzaldehyde reacted with cyclohexyl isocyanide and sodium azide, in aqueous acetone, to afford tetrazoles5° (41). 31 •

1 R N C I

(41)

Tetrazoles (44a) and (44b) were also formed by the reaction of carbazates (42) or azines (43) with isonitriles and hydrazoic acid51.

5 3 R CONHN=C—R1 + R NC + HN3 1 2 R (42)

Ry 3 R5CONHNH—C 11 R 2 N R 'N' (44a) 2 3 R1—C=N—N=C—R + R NC t HN3 ••■••••••■•C=.0 1 2 2 (43) R 3 RR—C=NNH C N R 2 N 1 2 R `1\1

(44b) 32

When carbazates (42) reacted with isonitriles and carboxylic acids, the N-acylcarbazate derivatives52 (45) were formed.

(42) R3NC R4CO2H —="

R 5 R CONHN—C—CONHR3 4 1 1 2 R 0 C R

(45)

Mono-, di- and tri-substituted hydrazines reacted with aldehydes and cyclohexyl isonitrile to form hydrazine derivatives (46), (47), and (48)55, respectively.

1 R R5N—N(CH—CONH-C-C61-11)2 (46) CH—CONN-c-C6Hii I

R5 N—N(CH—CONH-c-C6H02 (47) 2 1 1 R6 I R2 N—N—CHCONH-c-CoRn (L1-8) I

1.2.4 Reaction of isonitriles with acetals

The condensation of isonitriles with acetals and an equimolar amount of titanium tetrachloride, gave high yields of m-alkoxycarboxamides54 (49).

— R . 3— 11\ Q. Fil 0___ jTICI 3 \ / -I NC --c-- „ c ,C1 c,' ' • T• Cl + R 4/ \-"\s_. I:\ii 3 -r 2/ \ .1 I R \ iC------R R O. 0 R — R —

R CI R2— C — C/ TiCIOR I NR3 OR

2 I R—C--C I NNHR3 OR

(49)

Similarly 2-formylpyridine N-oxides or the derived hemiacetals reacted with cyclohexyl isocyanide, in methanol, to afford N-cyclohexyl-m-oxocarboxamides " (5Q).

34,

+ H 0 j +0-11 H 1 + O0 r-- CCAN

0-H 0 N CONN

(50)

1.3 BASE INDUCED REACTIONS

1.3.1 Introduction

Sch011kopf and Gerhart56, in 1968, discovered that the isocyano group stabilised a-carbanions. These a-metallated isonitriles (51) could act both as nucleophiles through the a-metallated carbon and subsequently as electrophiles, through the isocyano carbon.

+ :-.., + -_-_. 11:----Eu 11.------1 1 + R —C—H --I-- 13ase-M --4.- R—C1 1 • I +M + Base–H RI2 R1 2

(51)

Metallation was usually accomplished57 with butyllithium with or without a complexing agent, potassium tertiary butoxide, sodium ethoxide or hydroxide, or triethylamine. The choice depended on the a-proton acidity. The a-metallated isonitriles were not isolated, since they decompose between -60° and 0°C, but were used in situ Addition of a-metallated isonitriles (51) to polarised multiple bonds (52) lead to adducts (53) which could subsequently cyclise to form heterocycles (55) (Section 1.3.2). 36

X It C A 1 2 R3 R4

(51) (52) 4

- M N4) Rm NiC. I I 4 X R - C -C-R I I 4 R- C--R C 2 3 I 1 2 1 3 R R R2 R (53) (54) E E+

NC XE N'C I I 4 I A R-C -C-R 1 3 2 I 3 R2 R R R (56) (55)

Alternatively the adducts (53) could be trapped with various electrophiles (E+) to afford extended chain isonitriles (56) (Section 1.3.3). The heterocyclic adducts (54) were also transformed to other products by secondary processes (Section 1.3.4). 37

1.3.2 - Synthesis of 2-oxazolines, 2-imidazolines, pyrroles, and pyrrolines

Lithioalkyl isonitriles (51; M=Li) were added to aldehydes and ketones (52; X=0), at -70°, in tetrahydrofuran to yield 2-isocyano alkoxides (53), which exist in mobile equilibrium59 with the oxazolinyl anions (54). Protonation with methanol60 afforded 2-oxazolines (55; X=0, E=H), Similarly 4-mercaptoaryl 2-oxazolines (55; R1=111 R2=SArl X=0, E=H) were formed61 by condensing carbonyl compounds with isocyanomethylaryl sulphides in the presence of n-butyllithium. 2-(Hydroxyalkyl)-2-oxazolines (55; E=R3R4C0H) were formed as byproducts, particularly with aromatic aldehydes or ketones. 2-Oxazolines were also formed on heating isonitriles such as benzyl-, carboethoxymethyl- and allyl isocyanide with an excess of the carbonyl compound, in the presence of a catalytic amount of copper(I) oxide62163. A copper- -isocyanide chelate (57), with a carbon to metal bond, is possibly the crucial reaction intermediate. However a radical mechanism is equally plausible.

Cu20 CH =C CH2 =CHCH2 NC 2 ,) H •

0 R 4— CH CH 11 4 I I 2— R3 CR CH—C--C—R L—n Cu CH 1 I CH\ +N 0 +/ 2 tti Lc) (57)

Cu—Ln

CH "---CHCH NC 4 2 2 H—trC --C—R I 1 3 ,CH R CH(

4 R C57)

1.=ligand 39

Stabilised a-metallated isonitriles (51; R1 = -CO2R, 9 -CEN, -SO2Ar or -P(OEt)2) reacted with aldehydes and ketones in weakly basic, protic media, to afford the corresponding 2-oxazolines (55; R2=1-11 X=0, E.11). Typically sodium cyanide in ethanol64,65, or copper oxide62163 is employed. The 'cyanide' method affords the thermodynamic- ally favoured trans-isomer (R3/R4), by equilibration on the C-4 atom, via the anion (58). The copper oxide method affords mixed diastereoisomers.

1 Ill 4 (53) (54) R-c --R M+ I3

(58)

When methyl isocyanoacetate was condensed with an aldehyde in the presence of 1 18-diazabicyclo[5.4.0]undec- -7-ene (DBU) in tetrahydrofuran, dimethyl 2,4-pyrrole- -dicarboxylate (59) was formed66,67. The following mechanism, although not fully proven experimentally, has been proposed67

3 U CH 000CH NC R CHO 3 2 THF

/N C C -I- CH3OCOCH NC / 2 H CO0CH L. a-,

NC CH 0 C \ CO2CH3 3 2 H'H DBU 3 1 I -HCN R%- R—C—C—CO2CH3 CO2CH3 I H NC (59)

Conventional 2-oxazoline syntheses start from _2-amino alcohols, which are frequently difficult to obtain. However the conversion of 2-amino alcohols into 2-unsubstituted 2-oxazolines is problematic68. The above method.proceeds with C4-05 bond formation. Since 2-oxazolines, as imino ethers, are easily hydrolysed69, the above 2-oxazoline synthesis offered access to the potential biologically active 2-amino alcohols (61). Hydrolysis of 2-oxazolines was accomplished with aqueous hydrochloric acid in ice-cooled dioxane70 or basic alumina in methano160,71 and led to 2-hydroxyalkyl- formamides (60). Use of warm alcoholic or aqueous hydro- 41

chloric acid72 led directly to the 2-amino alcohols (61).

Xi F1 NHR5 4 1 --R11 R-C C I 2 R3 R

(60) R5= CHO, X.0 (61) R5= H, X=0 (62) X = NR61 R5= H

Hydrolysis of 2-oxazoline-4-carboxylates (55; E.H, R2=H, R1.0O2R) afforded N-f ormylserine esters65173 (60). In neutral or weakly basic media the hydrolysis occurred with retention of the configuration at C-4 and C-5. Hot aqueous hydrochloric acid (6N) afforded serine derivatives74 (61). Since 13-branched and (3-alkoxyphenyl substituted N-formyl serines (60) on acid catalysed deformylation dehydrate57, the hydrolysis of (55) to (61) was best accomplished58 through mild deformylation of amide (60) with toluene-4-sulphonic acid monohydrate in acetone or •dichloromethane 75 Isocyanides with relatively acidic a-protons underwent Michael addition76 to a10-unsaturated ketones, at 70°-80°C, in basic protic media, to afford pyrrolines81 (55; R4.H,

• 42

X.CH-CORS). Pyrrolines were also obtained with copper oxide catalysis62. Lithioalkyl isocyanides (51; R1=111 13.2.11 or Ph) added to Schiff bases to afford 2-imidazolines77 (55; E.H, X=N-R5). 2-Imidazoline-4-carboxylates (55; R2=H, R1 =002R) have also been prepared from the corresponding isonitriles in methanol, at room temperature, presumably in the presence of trace amounts of amine, present in the azomethine used In contrast with the carbonyl compounds, the intermediate (53; X=N-R5) cannot be trapped with electrophiles, presumably because the equilibrium (53) (54) lies far towards the metallated imidazoline (54; X.DT-R5). 2-Imidazolines are biologically active compounds usually synthesized with difficulty78 from vicinal diamines. Acid hydrolysis of 2-imidazolines readily affords vicinal diamines (62) or 2,3-diaminoalkanoic acids79 (62; R2=HI R1 =CO2H) which are also biologically active compounds. 43

1.3.3 Extended chain isonitriles

When lithioalkyl isonitriles were reacted with carbonyl compounds in tetrahydrofuran, at -70°C, and the reaction mixture was quenched with acetic acid, mild work up afforded 2-isocyano alcohols?0 (56; X=0, E.11). 2-Isocyano alcohols can cyclise to 2-oxazolines on treatment with anhydrous acid or base. The alkoxide (53;X=0) could also be trapped with acyl chlorides60'70 to afford 2-isocyanoalkyl esters (56;X,E=0C0R) or with toluene-4-sulphonyl chloride80 to afford 2-isocyanoalkyl tosylates (56; R1=1.11 X=0, E=Ts). Subsequent base induced elimination of toluene- -4-sulphonic acid afforded vinyl isocyanides (63).

/ R43 R (2 = C \ 2 R (63)

Ring expansion of cyclic ketones was accomplished72 by treating the ketone with isocyanomethyllithium and quenching the adduct with acetic acid. The intermediate 2-isocyano alcohol is hydrolysed to the amino stage and subsequently subjected to a Tiffeneau-Demyanov rearrangement to yield the ring-enlarged ketone.

OH 1. LiCH2NC, 2.AcOH

H30

OH HNO2 CHNH2

(CH2 n

Relatively acidic alkyl isonitriles undergo Michael additon76 to al p-unsaturated ketones, in protic ' media, with basic catalysis, at room temperature to afford extended chain isocyanides81 (56; X.CHCOR5, R4.H, E.11), which were cyclised to the corresponding pyrrolines on heating at 70-80° , under basic catalysis.

1.3.4 Olefin formation

Some 2-metallated oxazolines (54), on warming to

4 0 R„„,„,)-5 (-10,„„R1 (53) Li- 2 R3 R 4 (54) R R\ CC= \ LiOCN 3/ 2 R R 2 1 3 4 a. R = -CH=CH2 ,R-R= H ,R =Ph (64) 4 2 3 X=0 b.R =R=H R =R. Ph

room temperature decompose57 to olefins (64) and metal cyanate. This fragmentation can be formulated58 as a [4+2]-cycloreversion82185 of a heterocyclopentenyl anion for which theory requires suprafacial removal of the cyanate ion in a concerted thermal reaction, or a 1,3- dipolar cycloreversion57, which is a rare process compared with the 1,3-dipolar cycloaddition84 The stereo- specificity of this reaction is shown experimentally85, since cis-stilbene (64b) was obtained on decomposition of cis-2-lithio-415-diphenyl-2-oxazoline (54b). The above process represents an alternative to the Wittig reaction86al b which is only applicable when carbanion (54) carries at least one phenyl or vinyl group. Also increased steric

congestion disfavours (54) in the equilibrium with (53), thus irreversible side reactions are able to compete. Occasionally the reaction gives better stereoselectivity than the Wittig reaction. For example lithioallyl iso-' cyanide and benzaldehyde afforded exclusively E-1-phenyl- -1,3-butadiene56'87 (64a). Similarly all-trans retinyl isocyanide (65) and all-trans retinal (66) gave only 87 all-trans P-carotene (67).

(65)

n-BuLi THF

(67)

a-Isocyano phosphonate derivatives (51; M=Li, 0 " R1- P(OEt)2) on reaction with aldehydes or ketones, in aprotic media, afforded vinyl isonitriles88'89 (63).

0i Lit 0 Et0 311 4 R CR Et0-zP—Ci —4. Wee R2

O IP OEt I z0Et- 0 O P OEt '-0Et 4 I ,r1 R—C—C—NC Li 1 2 3 2 R3 R R 1R

(63)

The above reaction could be applied to the Ireparation of the antibiotic xanthocillin (68a). Indeed as a model study for the preparation of (68a), glyoxal and a-iso- cyanophenyl methane phosphonate gave the bisisocyanide88 (68b). H / c C

C C

a. R =OH (68) b. R- H

Stabilised a-metallated isonitriles (51; R2=H,

ILCO2R SO2Ar, 3— or 4-pYriaY1) reacted with carbonyl compounds, in aprotic media, to afford N-(1-alkenyl) formamides (70).

(51) + (52) (53)

M+ 0 (54) zt:= (58) --- R R 43C eiR1 (69)

NHCHO 4 3 / RRC=C R (70) X = 0

Since an oxygen atom is replaced by a formylamino- methylene group the above type of reaction has been named 'formylaminomethylenation,86b The electrocyclic ring opening of the oxazolinyl anion (58) to the hetero- pentadienyl anion (69) can take place in two directions (Scheme 1). Even when R3 and R are substituents with widely different space filling capacity, the two isomeric anions (69a) and (69b) are formed in comparable amounts66 OH 00/ C NO 0,0

(58)

O 0 0 H O 191 0o-OC\9 i, 0 0/0 R3/8/1112 R4 0 9 /0 11 , C ONR1 ■14/0 R4 R7 (69a) (69b) Scheme 1

a-Formylamino acrylic esters86b)90 (70; El.0O2R) are useful intermediates (Scheme 2), especially in the synthesis of certain substituted a-amino acids. Since the a-isocyanoacrylic esters (71) add nucleophiles readily, they are useful for the preparation of heterocyclic rings, for example, 2-imidazolines (72) and 2-thiazolines (73), m 50

NC RA') H 3 CO2R R CO R 2 , 2 C73) H (CH ) SaCH 5 3 211 2 R NC 0 N N (72) R 1 H [97] H2S/Base R4 H R3 CO2R [91] R3 CO R [96] 2 5 1. R M9X [77] NH o3r R5NH2 NC CH3OH 2.H+30 / Rt3 R C c (71) CO2R

[91] NHCHO 4 3 / R R C =C (70,R iz:CO2R) 002R PhCH SH 2 [92] [91]

"IN SCHoPh NHCHO F H S 4 R CH R4 R I 1 NHCHO H 3 RN CO R R3 CO R R CO2R 2 2 H30 (73) [95]

H H R4 1 I N HCHO R CO2R

Scheme 2 5'1

and hence for the preparation of modified penicillins. For example the 6-epipenicillin V analogue (75) was synthesised98 from the thiazoline (74).

Et PhOCH2OCHN Et Et H...... Et NnionfiCO2Bz 2H

(74) (75) N-(1-Pyridy1-1-alkenyl)formamides (70; 3- or 4-substituted pyridyl) on acid hydrolysis afforded 3— or 4-acyl pyridines95(76)

0 1 CH' 1 3 (76)

1.4 TOLUENE-4-SULPHONYLMETHYL ISOCYANIDE (TosMIC)

1.4.1 Introduction

Toluene-4-sulphonylmethyl isocyanide (78) is a stable, crystalline and odourless compound, easily prepared either by condensing lithium methyl isocyanide

14 52

with toluene-4-sulphonyl fluoride99, or more usually by the dehydration10de 00 1102of N-(toluene-4-sulphonylmethyl)-formamide (77).

0 0 II -LiF i. H II + CH S—F + LiCH2NC 3 S-CH N=----C- II II 2 0 Q (78) 0 H 0 CH S— 2 (78) 3 CH2NHCHO 0 (77)

The formamide (77) was prepared by several methods, summarised in Scheme 3, The only reported chemistry of TosMIC to date has been that of its a-metallated derivative (79)

0 m+ Base-M (78) CH3 Base—H 11 0 (79) The oc-metallated TosMIC (79) is commonly generated with n-butyllithium--99,106 or potassium t-butoxide--99 5106 in tetrahydrofuran, at -70°C, sodium hydride in dimethyl-

sulphoxide102 , potassium hydroxide in glyme107 or t-butanol1Ce at 20°C, or potassium carbonate in methanol107 at 65°C,

CH Br H2NCH 0 + (CH2an + HN (CH3)2 3

TsNa OHCNHCH2N(CH3)3 Br (77) -I-. N(CH3)3 NaBr [103]

(CH20)n-h H2NCHO HOCH2NHCHO [104] ,[101]

CH3C02H Ts Na

[105] (77)

- N(C1-13)3 OHCNHCHN2 (CH)33 BT P —01—C614—SNC3 - NaBr

m-CPBA , 0°C or OHC N HCH2- C H3 C77) [102] ,[103] H202 , (CH3C0)20

Scheme 3

Classical a-alkylations76 of TosMIC lead to further a-isocyano sulphones. Doubly alkylated products are usually obtained in high yields. Pure monoalkylated derivatives (80) are difficult to prepare even with equivalent quantities of reagents. These results parallel similar observations by Sch011kopf et al.,1°9 with ethyl a-isocyanoacetate. However, when phase transfer conditions110,111 were used, monoalkylation1 122of TosMIC with primary halides, including allyl bromide and benzyl bromide, proceeded in high yields. Secondary halides gave lower yields of monoalkylated products.

Na0H/H2110/CH2Q12 (78) + RX + - CH3 SO CHNC (n-11.014N I or 2 + .._ PhCH2 N Et3 C( R (80)

The a-metallated TosMIC (79) besides being a typical isonitrile contains the toluene-L--sulphinate leaving group. Therefore TosMIC can be used to add a C-N=C unit to unsaturated molecules, leading to heterocyclic systems. 55

1.4.2 Construction of heterocycles

Reaction of TosMIC with aldehydes, in the presence of potassium carbonate, in refluxing ethanol, afforded 2- oxazolesi°7 (82a). Likewise TosMIC reacted with acyl chlorides and anhydrides107 to give 4-substituted 2- oxazoles (82b). 0 3 11 + R C H TsCH2NC

0 -TsH NO L 3 Ts R (81) (82a) 0 11 TsCH2NC R3CX -HX

I ■./0 le C) Ts CC 3 1 —1 I3 Ts R H R (82h)

X= CI. , OCOR3

The 2-oxazoline (81) could be isolated when the reaction was performed at room temperature. Alternatively 2- -oxazolines were prepared from TosMIC and carbonyl compounds with ethanolic potassium cyanide106 as base. With thallium(I) ethoxide as base, high yields of 4-ethoxy- 56

-2-oxazolines113 / 114 (83) were formed. 0 311 4 TiOEf R4 (:)-7\ TsCH2NC + R C R 0 N 3N + R H30 OEt OH n (83) R4 1 R3 Hr (84) Mild hydrolysis of the oxazolines (83) afforded a-hydroxyaldehydes114 (84). The method provides mostly monomeric (84) in high yields and is much more general and less laborious than previously known procedures115 These earlier methods give (84), in mostly its dimeric form. TosMIC reacted with activated olefins, in a variety of alkaline media to ‘afford pyrroles116 (85)5 in a new and simple procedure.

4 -TsH TsCH2NC + RCH—CHR

4 (85) R =COR ,CN

With al p-unsaturated aldehydes (R4= CHO), 2-oxazolines were obtained instead of pyrroles. This approach has been applied in the synthesis of a pyrrole ring fused with a steroid system. Thus compound (86) was

prepared117 from 170-hydroxy -17 -methylandrosta-1 14 -dien - -3-one and TosMIC in dimethyl sulphoxide/diethyl ether, in the presence of sodium hydride.

OH H3

(86)

Similarly the pyrrole ring of the fungal secondary metabolite Verrucarin E (87) was built up118 using the same approach.

PhCH2OCH2CHO + Ph3P=CHCOCH3

H PhC1-120CH2\ C Ts CH2NC H C=0 CH 3

CH3 3 PhCH 0 CH HOCH 0 2 2 0 Pd/C f=z. I H H (87)

4 TosMIC or its monoalkylated derivatives (80) added to C,N double bonds, in the presence of a base, to afford 115-di (88) and 1 14,5-trisubstituted (89), (90) imidazoles"9,120. The method comprises a straight- forward synthesis of these heterocycles.

TsCH2NC K2CO3(or t-BuNH2) Ts-M+ 3 4 CH 0H(or DME) R CH=NR 3 1 4 (88) 1.NaH/DME K2 CO3 CH3OH 2.H20 Ts H,„„„ H N R3°' 1 4

3 4 NaHIDMSOITHE TsCH2NC + R C=NR Cl

— — N, J t NR Ts H R3

(89)

3 4 t-BuNHAmE TsCH NC + R CH=NR orK2CO3/CH3OH { R or Na H/DME

(90)

113-Thiazoles (91a) were preparedly by condensing TosMIC with the highly reactive thioacylating agents, carboxymethyl dithioates121 or their esters. S 311 4 KOH/ t-BuOH TsCH2NC + R CSCH2CO2R c..

+ , NI SH \ / C=C / \ 3 Ts R _

3 a . R =alkyi. 3 b. R = SR c. R3. SCOR

1,3-Thiazoles (91b) and (91c) were prepared by reaction of TosMIC with carbon disulphide, under phase transfer conditions122

100/0 NaOH (n-Bu)4N Br/CHOI TsCH2NC + C S2

(91b)

(n—Bu)4N+

(91c)

Furthermore 1,2,4-triazoles (92) were efficiently prepared from TosMIC and aryldiazonium compounds123.

TsCH2NC + Ar N=N X .."••••■•CM.

ylv Ar N Ts Ts N N'NJ H Ar (92)

1.4.3 Miscellaneous transformations

When TosMIC was condensed with aldehydes or ketones, in the presence of potassium t-butoxide in tetrahydrofuran, at -5°C, 1-formylamino-1-arylsulphonyl alkenes0,--4)4 1106 (70; R1= toluene-4-sulphonyl) were formed. Alternatively they were also formed by base induced ring opening of the 61

corresponding 2-oxazolines99 (55; E.H, X.0, R2.H, R 1 toluene-4-sulphony1). Acid or base hydrolysis of the 1-formylamino-1-arylsulphonyl alkenes afforded carboxylic acids (93).

NHCHO + H NHCHO 4 3 / H R R C=C R4 I X 3 Is R Ts

H H2O H k,,NHCHOI R4 0 Ts H

H H30 4 I / 0 3 c„. R < -I- [TsH R3 OH (93) s 0 H N—CH , (70:R = CO2R ) HO R4 ) 3 t OH R Ts

0 II H -HOCH 4 1.H0- c..- R C-=-N 4. c'(93) -Ts 3 2.H3.0 R

(9/4)

The above method allows the conversion of a carbonyl compound into the next higher carboxylic 99106 acid • When TosMIC was reacted with ketones and sodium ethoxide in 1,2-dimethoxyethane/ethanol (10:1) or potassium t-butoxide in 112-dimethoxyethane/t-butanol, at 0°C, the nitriles124,125 (94) were formed in high yields.

0 11 TsCH2NC R3 CR

R CTS — S C)ciN c=7.. PR -j EtO Ts R3 R C.N—CHO

4 0 R H30 (94) - C—C=N—CH R3/ EtO

This method represents a 'one pot' direct conversion of a ketone into the next higher nitrile and has found wide application in organic synthesis. For example, 17-oxo-steroids have been converted into 17-acetyl-steroids126 via the corresponding cyano

derivatives. Indanone derivatives (95) were converted into the indan carbonitriles127 (96). Additionally the spiro compound (99), known for its antidepressant activity, was prepared128 from the ketone (97), through lithium aluminium hydride reduction of the carbonitrile (98). The piperidine derivative (102), biological analogue of acetylcholine, was synthesized129 from the ketone (100), through barium hydroxide hydrolysis of the intermediate product, carbonitrile (101).

TsCH2NC

-0 CN

(95) (96)

TsCH2NC

(97) (98; R =CN) (99; R=CH2NH2)

TsCH2NC N

(I) 0'

(100) (101;R =CN) (102;R=CH2CO 2H )

The conversion of a ketone into the next higher nitrile can also be effected by refluxing the alkene (70; R2-, toluene-4-sulphonyl) with sodium methoxide in methanol130

fa/ 65

CHAPTER 2

RECENT DEVELOPMENTS IN PHENOL OXIDATIVE COUPLING 66

The classical Pummerer's ketone (103) is prepared by potassium hexacyanoferrate(III) oxidation of 2—cresol. The mechanism (Scheme 4) of this and similar coupling is described in detail elsewhere131'132'133

(103)

Scheme 4 67

This review will be limited only to recent developments in phenol oxidative coupling especially as applied to the alkaloid biomimetic syntheses. Common reagents used are tabulated. It has been long recognised that an intramolecular phenol oxidative coupling reaction is the key step in the biosynthesis of many classes of natural products131. Furthermore the nonenzymic analogue of this transformation can lead to elegantly simple laboratory syntheses of these compounds153. However full realization of this synthetic potential has been limited by low yieldsl32,133,154. It appears that the formation of the desired intramolecularly coupled product depends on such factors as the correct orientation in space of the two phenol moieties, their relative rates of oxidation (which is a function of their substitution pattern), the stability of the phenoxy radical formed, and the stability of the product towards further oxidation. Even when orientation of the phenol moieties is appropriate for intramolecular coupling, factors like hybridisation of the atoms linking the two phenolic rings can play an important role by lowering the activation energy of the coupling process compared with intermolecular reactions. Thus conformation analysis of the intermediate (105), which possibly resembles the transition state for the oxidative coupling of substrate (104) to give product (106), revealed that if the atom Y was sp2-hybridised, a 1,3-diaxial (C-H) int enaction

• 68

REAGENTS FOR PHENOL OXIDATIVE COUPLING

Reagent Reference

1.Potassium hexacyanoferrate(III) 134,135,136,137,138 Potassium hexacyanoferrate(III)/ phase transfer catalyst 139

2.Iron(III) chloride 137

3.Metal oxides 132,133

4. Manganese(III) tris(acetyl- 140,141,142 acetonate)

5.Molybdenum oxotetrachloride 141,143

6.Iron(III) chloride dimethyl- 144,145 formamide complex

7.Vanadium oxytrichloride 141,146

8.Vanadium oxytrifluoride 143,147,148

9.Thallium(III) trifluoroacetate 141,149

10.Silver(II) trifluoroacetate 141

11.Electrochemical 142,145,150,151,152

would be removed and therefore the cyclisation would be relatively favoured.

(105) (106)

Indeed hexacyanoferrate(III) oxidation of the amide (107a) gave the dienone135 (108), in remarkably high yield (67%), while under identical conditions the corresponding amine (107b) gave a complex, strongly coloured mixture.

HO HO CHO CH 0 3 3

CH30 OH

(107) (108)

a. X=0 b. X.112

• Controlling the sites of bond formation on the aromatic rings to produce the desired structural type and substitution pattern is another problem which has been almost solved by using blocking groups. Thus the hexacyanoferrate(III) oxidation of amide (109) gave the enone (110) and only a small amount of the dienone (111) through debromination of the aromatic nucleus136.

CH3

CH3 CH3 0 CH3O Br CH30 OH (110) 71

If the diphenol is complexed (1:1), without oxidation by the potential oxidant, and the oxidation is subsequently allowed to proceed at high dilution, intramolecular coupling is favoured. This process avoids intermolecular coupling which arises because of dissimilar rates of oxidation of the two phenolic functions, or overoxidation. Vanadium oxytrichloride, vanadium oxytrifluoride, molybdenum oxotetrachloride, trifluoroacetate and silver(II) trifluoroacetate achieve this objective. Schwartz and coworkers141 were able to prepare the spirodienones (115), (116) and (117) from the vanadium oxytrichloride oxidation of the corresponding diphenolic compounds (112), (113) and (114).

(112) R1=R2. H (115) R1=R2=H (76%) (113) R1= OCH R2.11 (116) R1= R2=11 (69%) 31 OCH3' (118) R1=111 R2= CN (119) R1=1.11 R2= CN (--)

S 72

HO HO N COCH 3 (114) (117) (50%)

The validity of the method was tested by introducing substituents into one of the rings (113) and increasing the length of the side chain as well as introducing a nitrogen function in the chain (114). The reagent has been successfully employed for diphenolic coupling in syntheses of Amaryllidaceae1551 Erythrina1561 Hasubanan1571 Aporphine158 and Homoaporphine159 alkaloids It has been recently reported146 that intramolecular phenol oxidative coupling with vanadium oxytrichloride can be photocatalysed. Thus, irradiation of an ethereal solution of the bisphenol (118) and vanadium oxytrichloride, with a tungsten lamp, led to the expected spirodienone (119) more rapidly and in distinctly higher yield than without irradiation141 The intermediacy of a photoenergised V03+ species which was more rapidly reduced to V02+ with a more stable configuration was suggested. Investigations from different groups have shown 73

that intramolecular coupling of mono- and nonphenolic substrates is equally successful and in fact advantageous since the nonphenolic intramolecularly coupled product would not overoxidise. This approach would furthermore allow incorporation of 0-alkyl substituents such as the methylenedioxy moiety, often found in alkaloids, at a convenient early stage of the laboratory synthesis. In this way Kupchan and Liepa145 were able to couple, the monophenolic benzylisoquinoline (120) to give the quinonoid aporphine (121), using either vanadium oxytrifluoride in trifluoroacetic acid (59%) or molybdenum oxotetrachloride in trifluoroacetic acid/chloroform (62%).

OCH3 (120)

4 1 R 0 2 R 0

R CH 0 3 OCH3 OCH3

(122) (123) a. R1= CH R2=R3= H, R4= COCF or CH n=1 3' 3 3' 1 b.- R = CH3, R2= H, R3= H or OCH3, PeC CH3 or COCF3, n=2 c R1=R3= H R2= CH R4= COCF n=2 , 3, 3' d. RI =R2.R!4.= CH R3= H, n=1 3' e. R1=R2= CH R3= H, R4= CHO, n=1 3' f. R1=R2= CH R3= H, R= COCF n=2 f. R1=R2= CH3, H, R4= COCF n=2 3' 3' 3' 2 R1= PhCH2, R = CH R3= H, R= COCF3 , n=2 g. R1=R3= H, R2= CH3, R4= COCF3, n=2 g. 3 2 2 3 h R1= CH R = PhCH R3= H, R4= COCF3, n=2 h. R1= CH R =R. = H, R= COOP3, n=2. 3' 2 3' 75

Tetrahydroisoquinolines (122a, b, and c) gave147 respectively aporphines (123a) (70-80%); homoaporphines (123b) (14-46%) and homoproaporphines (124) (4-50); and homoproerythrinadienone (125) (98%).

OCH3

(124)

OCH3

(125)

The same group148 employed vanadium oxytrifluoride in trifluoroacetic acid and dichloromethane to effect nonphenolic oxidative coupling. Thus (±)laudanosine (122d) afforded (+)glaucine148a (123d) (43%), (±)-N-formyl norlaudanosine (122e) gave (+)-N-formyl norglaucine -(123e) (6%) and the spirodienone (127) (55%) through the intermediate (126)148b 76

zOCH3 CH 6) 3 (122e) N CHO

OCH3 CH0 - 3 OCH3 N--CHO (126)

CH30 OCH3 (127) Similarly phenethyltetrahydroisoquinolines (122f,g,h) gave homoaporphines (123f.I gl h), via homoproerythrina- dienones148c Vanadium oxytrichloride in dichloromethane at low temperature has also been used to effect mono- and nonphenolic intramolecular oxidative coupling141 Thus Schwartz and coworkers were able to couple the diarylpropanes (128a) and (128b) to the corresponding spirodienone (129) in excellent yields.

(128) (129) a. R = H b. R = CH3

Phenol (128a) also gave the spirodienone (129) in excellent yield with silver(II) or thallium(III) tri- fluoroacetate141 Thallium(III) trifluoroacetate was employed successfully in the preparation of Amaryllidaceae alkaloids but in poor yields. Taylor and coworkers149

employed thallium(III) trifluoroacetate for the coupling of protected phenolic moieties. Thus the bisaryls (130a) and (130b) were coupled to afford the bridged biphenyls (131a) and (131b) respectively, in excellent yields.

CH3O CH30

■—•■••••C:a.

CH3O CH3O OCH3 OCH3 (130) ( 131 ) a. X = CH2 b X = 0

Application of the method to the tetrahydroisoquinoline (132) afforded (±)-ocoteine (133a) (46%) at low temperature. Coupling at 0°C afforded the acetoxy- ocoteine (133b).

0 0

•••••—•—■4::.•

CH3O OCH3

(132) (133) a. R= H

b. R = OCOCH3 79

Electrooxidation with careful control of potential has been used to prevent overoxidation and intermolecular coupling. The rate of the reaction can be controlled by adjusting the electrode characteristics and potential. Since the reaction takes place at an interface, steric effects can play an important role. The only experimental disadvantage is the coating of the electrode with either the product or polymeric byproducts. However this can be often avoided by solvent change. Electrochemical techniques have been applied in the oxidative coupling of di-, mono- and nonphenolic substrates. Bobbitt and coworkers150 were successful in coupling N-carbethoxy-N-norreticuline (134) to afford the dienone (135) (18%) and the 1-phenethyltetrahydroisoquinolines (136a) and (136b) to the dienones (137a) (23%) and (137b) (36%) respectively. The dienone (137b) was obtained as a mixture of two isomers, in equal proportions, despite the expectation that electrooxidation would lead predominantly to one of them.

CH0 3 CHO HO

HO CH 0 .3 CHp (134) OH

(135) 80

CH 0 3 HO

(136) (137) R = H

b R = OCH3

The monophenolic electrooxidative coupling has been investigated by Ronlan's group151 A series of diarylalkanes (138) were coupled to give the biosynthetically important spirodienones (139) by both electrooxidation and thallium(III) trifluoroacetate oxidation. With diarylethanes (n=2) and diarylbutanes (n=4) anodic oxidation afforded dimers and/or polymers whilst thallium(III) trifluoroacetate oxidation afforded unchanged starting materials. High yields of the desired spirodienones were generally obtained with diarylpropanes (n=3). 81

(CH

(138) (139)

n = 2-4

R1. H, CH3 R4. H, 0CH3 R5. H, CH3, t-Bu, OCH3

Thus phenols (138; R2 or R4,23. OCH3 or R2,R3. OCH20) afforded high yields of the corresponding spirodienones. Similarly phenol(138; R4= 0CH31 R1=R1=R3= H) afforded the corresponding spirodienone in high yield only when was the t-butyl group. Phenol (138; R2....R3=R4., OCH ) 115 3 afforded only polymers. Thallium(III) trifluoroacetate was found generally to be a more efficient reagent than electrooxidation at a platinum anode for the preparation of the spirodienones (139). Miller et al.152 were able to couple the 1-benzyl- tetrahydroisoquinolines (140) to the corresponding morphinadienone alkaloids (141) in 43% to 63% yields. 82

0R4 3 1 R 0 R 0 2 R 0 RO 3 R 0 RSO 0 ( 1 4 0 ) (141 ) a. R1,17t2 =0=R4.CH 3 =R2.0= CH R4. CH b. R1 3, 2 Ph c R1.0.R4. CH31 R2= CH2Ph d. R1=R2=R4= CH3 R3= CH2 Ph

Tobinaga et al.145 electrooxidatively coupled the compound (128b) to the spirodienone (129). For comparisonl" the monophenol (128a) was also coupled with vanadium oxytrichloride (97%) or thallium(III) trifluoroacetate (88%) and the nonphenolic compound (128b) with vanadium oxytrichloride (70%). Application of the method to the synthesis of Amaryllidaceae alkaloids gave distinctly higher yields compared with analogous chemical oxidative couplings. For example dienone (143) was prepared from the nonphenolic substrate (142a) in 62% yield. Thallium(III) trifluoro- acetate160 induced coupling on (142b) gave (143) (19%) whilst the diphenol (142c) afforded the corresponding spirodienone with vanadium oxytrichloride155 (37%) and 83

iron(III) chloride dimethylformamide complex145 (35%). 3 R

'COCF3

(142) (143) a. R1,R2= OCH2O, R3= OCH3 b. R1,R2= OCH20, R3= OH c R1= OCH3, R2=23= OH

Parker and Ronlan142 studied the anodic oxidation of a series of unsymmetrically substituted diarylalkanes (144) and (145) in dichloromethane/trifluoroacetic acid in comparison with manganese(III) tris(acetylacetonate) oxidations.

OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3

(CH )n (CH2)n

OCH OCH 3 3

OCH3 OCH3

(TO ) (146) (145) (14?)

n = 1-4 84

From both methods intramolecular and/or intermolecular coupling products were obtained depending on the number of carbon atoms in the side chain, and the anode potential in the electrooxidation experiments. Electrooxidation could only yield the desired products (146) or (147) with the diarylmethane (1//t, n=1) (33%), the diarylpropanes (144, n=3) (72%) and (145, n=3) (71%), or the diarylbutane (145, n=4) (33%). Manganese(III) tris- (acetylacetonate) oxidation was only effective with the diarylpropanes (144, n=3) (51%) and (145, n=3) (95%). At this point it is possible to comment on the mechanisms involved in the reactions described above. Diphenolic oxidative coupling with vanadium oxytrichloride is considered141 to proceed through a free radical mechanism, the diradical intermediate being formed from the homolytic deComposition of the vanadium phenolate compound. A concerted two electron transfer mechanism133, including the case of the monophenolic coupling, is an attractive possibility. Monophenolic and nonphenolic couplings with vanadium oxytrichloride are suggested141 to proceed through two successive one electron oxidations, the coupling taking place at the cation radical stage. Intermediacy of both ring-thallated161 and 0-thallated intermediates162'1 51a has been proposed in thallium(III) trifluoroacetate oxidations. In either case, whether the coupling occurs concomitant with a concerted two-electron transfer, or via successive one-electron oxidations is 85

not known. Similar mechanisms should operate in silver(II) trifluoroacetate or molybdenum oxotetrachloride oxidations. In summary, diradical dication coupling and coupling through electrophilic attack of the cation radical or the phenoxonium ion of one of the aromatic nuclei on the unoxidised aromatic nucleus, are considered to operate in electrooxidations142 86

CHAPTER 3

NOVEL SYNTHESES OF 1-BENZYLISOQUINOLINES

i• 87

3.1 RESULTS AND DISCUSSION

1-Benzylisoquinoline alkaloids occur frequently in nature, have diverse interesting physiological activities and often undergo unusual chemical transfol.mations. These alkaloids have been synthesised using the Pictet-Spengler1631 the Pomeranz-Fritsch164 and most commonly, the Bischler- -Napieralski165 reaction. The Bischler-Napieralski reaction requires the acyl derivatives of p-phenethylamines (151) as substrates. These are usually prepared from appropriately substituted P-phenethylamines (148) through Schotten- Baumann condensation166 with the appropriate homobenzoyl chlorides (149), or photolytically with w-diazoaceto- phenones167,168 (150) (Scheme 5).

ArCH2CH2NH2 (148)

ArCOCHN hv NaOH ArCH2C0Cl (150) (149)

R ArCH2CH2NCOCH2Ar

(151) R H (152) R = CH2Ph

Scheme 5

Alo

The required 0-phenethylamines and homobenzoyl chlorides are in turn prepared by homologation of the available aromatic aldehydes. Although existing homologation procedures169170 give reasonable overall yields they are usually long and cumbersome. A recent improved procedure171 offers some advantages (Scheme 6).

,SOCH3

ArCHO + CH2 \SCH3

+_ SOCH3 C6N5CH2(CH3)3N OH ArCH=C \SCH3

H+30 ArCH2CO2R ROH

Scheme 6

In an attempt to cut down the number of steps in the homologation process Barton et al. 172 developed a new elegant 4-steps route (overall yield 40%) in the synthesis of amides (152) (Scheme 7).

Ar CH 0 + CH3OCH2CN ArCH=C(OCH3)CN

Ar CH2CONHCH2Ph Ar(CH2)2NHCH2Ph

61...417. (152)

1. NaH ; 2. PhCH2SNa/Phell2NH2 ; 3. LiAlE 4 4, ArCH=C(OCH3)CN/PhCH2SNa

Scheme 7

Isonitriles with acid catalysis react with carbonyl compounds to give amides (pp. 10-21). Electron rich aromatic aldehydes, however, required activation41 and this was accomplished via the derived azomethines. Homologation of the available aromatic aldehydes to the phenethyl- isonitrile stage, required for the condensation with the azomethine, was accomplished by exploiting the well established (pp.35-51 ) reaction of a-metallated isonitriles with carbonyl compounds and subsequently with acetic anhydride (p. 43). The synthesis is summarised in Scheme 8. 90

1 1,2 Ar CHO + CH3 NC Ar CHCH2NC OCOCH3

rCHO + H2NPh ArCH=NPh

OH OCOCH3 1 1 5 1 I 1 NHCOCHAr —c— ArCHCH2NHCOCHAr A r CHCH2 I i F3CCNPh NHPh II 0

A2r (CH2)2NHCOCH2A2r

OCH3 Ar = OR

n=i ; R=CH2Ph n.2 ; R=H (

1. n-Buld ; 2. (CH3CO2)20 ; 3. TsOH ; 4. CF3CO2H ;

5. NaOH ; 6. H2/Pd -C.

Scheme 8 The method offered the advantage of being very short and the yield of all the steps was very high except the last, hydrogenation step,when the cleavage of the benzylic nitrogen bond was difficult and proceeded in only 25% yield. In order to devise a more efficient route to the amides (151) it was necessary to replace the benzylic amino group with a group known to be cleaved easily by hydrogenolysis. Economics on the other hand demanded a new homologation procedure to the phenethylisonitriles. Since the hydrogenolysis of benzyl ethers is a highly efficient and well established process173,174 the phenylamino group was replaced by an alkoxy function. In addition an alkoxy group can generally be easily removed with acidic catalysis to form a double bond. It was therefore hoped that the Bischler-Napieralski reaction of the a-methoxyamide (153) thus prepared, should proceed with subsequent elimination of methanol from the 314-dihydroisoquinoline (155) giving, after tautomerisation,the isoquinoline (156) (Scheme 9) The transformation has analogy in the Pictet-Gams modification175 of the Bischler- -Napieralski reaction. The present work describes reactions of relevance to a more efficient and economically viable route to papaverine (156; R.1 CH3). Papaverine occurs in opium usually to the extent of 0.5-1.0 per cent and is a non-habit forming antispasmodic drug176. Since the cost

1 R 0 2 R 0 - H2O H+

(153) R5= OR R . H, R1= 2=R3=R4= CH (154) 5 3

1 1 R0 R0 R20 RI -H+;- H2O R20

3 ROJ OR OR OR4 OR4 (155)

R10 2 R 0

(156)

Scheme 9 93

of recovery of natural papaverine from opium is high and demand is rapidly increasing, numerous laboratory syntheses of papaverine have been devised1771178 but only a few are industrially economic. The most suitable industrial synthesis177'178 of papaverine is the Bischler- Napieralski cyclisation of homoveratrylhomoveratramide (154) with subsequent catalytic dehydrogenation of the intermediate 314-dihydropapaverine. The amide (154) is in turn prepared from the condensation of homoveratric acid (158) or its derivatives with homoveratrylamine. Both components are prepared by homologation of veratraldehydei usually177 via the homoveratrylnitrile (157) (Scheme 10).

Ar CHO —Li— ArCH2OH ArCH2C1

ArCH2CO2H 4 7.8 ArCH2 CN 5 (158) (154) (156) (157) ArCH2CH2 NH2 (148)

OCH3 OCH3

1. H2/Raney Ni ; 2. SOC12 ; 3. KCN ; 4. KOH ; 5. H2/Raney Ni/NH3 ; 6. A/tetralin ; 7. POC13 ; 8. Pd-C/A/tetralin,

Scheme 10

4 94

To explore the use of isonitriles in isoquinoline syntheses, model studies were carried out with 0-benzylvanillin (160), readily available from vanillin (159) by standard procedure179 Condensations of derivatives of 0-benzylvanillin with cyclohexyl isocyanide (162), derived from N-cyclohexyl formamide (161),were first examined.

1 R 0 2 R 0

(159) R1= CH31 R2= H, X = 0 (160) R1= CH31 12. CH2Ph, X = 0 (163) R1= CH3' 12. CH2Ph, X = NPh (164) Rl. CH2Ph, R2= CH3, X . 0 (171) R1=R2. CH X = 0 3'

+ _ NHCHO N

(161) (162)

Imine (163) was prepared from 0-benzylvanillin (160) and aniline. Condensation" with cyclohexyl isocyanide and trifluoroacetic acid in dry benzene/ methanol at room temperature gave the expected bisamide (165) in 75% yield. 95

(163) + (162) + C F3C 0 2H

COCF 3 NPh 0 CH3O PhCH2O NH

(165)

Since protonated acetals are in equilibrium with the 0-alkylated aldehyde cation and alcohol, acid catalysed condensation of acetals and isonitriles was investigated. Dioxolan (166) prepared from 0-benzylvanillin and ethane-1,2-diol gave two products on reaction with cyclohexyl isocyanide and trifluoroacetic acid under identical reaction conditions with those used for the preparation of bisamide (165). Chromatographic separation gave the less polar dimethoxyacetal of 0-benzylvanillin (167) (n.m.r.) and the expected a-methoxyamide (168). Formulation as amide (168) was in full agreement with spectral data and analysis.

CI-1 30 + (162) + CF3CO2H CH3OH PhCH2O l!l Ph H

(166)

OCH3 CH30 OCH3 PhCH2O CH30 C H2O NH

(167)

(168)

The mechanism of this reaction is summarised (Scheme 11)

OCH3 H+ -1- Ar 2 CH3OH < + (CH 20H)2 O OCH3

CF3C02H 1- CH 3OH OCH3 H+ (162) H ArCHC=N OCH3 CF3CO2 CF3 Ar O H

(168)

Scheme 11 97

It was thus evident that the dioxolan (166) was subjected to a transacetalation reaction prior to reaction with the isocyanide (162). Thus the condensation of the dimethoxyacetal of 0-benzylvanillin181 (167) and cyclohexyl isocyanide in an aprotic solvent (benzene) was investigated. The dimethoxyacetal (167) was consequently prepared with anhydrous methanol and a catalytic amount of dry hydrogen chloride and was used without further purification. The '4CC' condensation at room temperature gave a 76% yield of the expected a-alkoxyamide (168). In order to ascertain the efficiency of hydrogenolysis of the methoxy group the amide (168) on treatment with hydrogen (1 Atm pressure) and 10% palladium on charcoal in methanol at room temperature readily gave the debenzylated amide (169) in excellent yield. Removal of the methoxy group required solvent acetic acid with 60% aqueous perchloric acid catalysis to give the expected amide (170) in 71% yield.

RSO 2 R 0

(169) Rl. CH31 R2= H, R = OCH3 (170) Rl. CH31 R2= H, R = H

During these investigations the titanium tetrachloride induced reactions of acetals with isonitriles (-50°C) (p. 33) was reported. The reaction herein described has the advantage of being 'one pot' from aldehyde and carried out at room temperature. Yields are comparable. Having successfully completed the model studies the synthesis of papaverine from veratraldehyde (171) was examined. Toluene-4-sulphonylmethyl isocyanide (TosMIC) was chosen as a C-N-C synthon (Scheme 12). At this time 'TosMIC' has been used most often in the synthesis of heterocyclic systems from multiple bonds (pp. 55-60).

C6-C + Co-C-C-N-C

Co-C C6-C-C-N-C-C-C6

Scheme 12

TosMIC reacts with aldehydes and ketones in the presence of potassium t-butoxide in tetrahydrofuran to afford 1-formylamino-1-arylsulphonyl alkenes (70; R1 ,. Ts) (p. 60). However reaction of veratraldehyde (171) with equimolar amounts99 of TosMIC and potassium t-butoxide gave but low yields of the expected N-formamide (172) 99

and much unreacted veratraldehyde. Veratraldehyde (171) being of low electrophilicity would be expected to condense only slowly with nucleophiles. Since TosMIC slowly self-condensed under basic conditions126 the reaction was modified by using excess of potassium t- butoxide and a slight excess of TosMIC. The N-formamide (172) was thus obtained in 80% yield. Subsequent dehydration with phosphoryl chloride and triethylamine gave the expected vinyl isocyanide (173) in 80% yield. The required dimethoxyaceta1183 (174), prepared in almost quantitative yield via hydrogen chloride or trifluoroacetic acid catalysed acetalation with trimethyl orthoformate183 in (Iry methanol, was used in situ. Reaction with the isocyanide (173) and trifluoroacetic acid gave after filtration through alumina the almost pure acetamide (175) (70%) as a foam which resisted attempted crystallisation and thus it was not fully characterised. The intermediates (172, 173 and 175) were obtained as single isomers (n.m.r.). The double bond geometry could not be unambiguously assigned. The geometry of the isocyanide (173) and the enamide (175) were determined by that of the formamide (172). Consideration of the steric congestion in the intermediate (58; R3= H, R4= veratryl, R1 = Ts) (p.39 ) suggested that the more stable stereochemistry would be with both the aromatic ring and toluene-4-sulphonyl function trans. Consistent with this hypotheSis the

100

formamide (172), isocyanide (173), and enamide (175) were all assigned the E stereochemistry. The next step in the planned synthesis of papaverine (Scheme 13) required reduction of the double bond and removal of the toluene-4-sulphonyl group. Catalytic hydrogenation of alp-unsaturated sulphones has been reported184 to partially proceed, since the platinum catalyst becomes poisoned, to give the saturated sulphones. No reaction however occurred when the enamide (175) was hydrogenated in the presence of platinum black catalyst. Hydrogenation over palladium on carbon in glacial acetic acid containing a catalytic amount of 60% aqueous perchloric acid at 100 atmospheres hydrogen pressure resulted only in partial benzylic methoxy group cleavage (n.m.r.). Sodium borohydride reduction of the enamide (175) proceeded only in boiling ethanol and gave a mixture of products. Separation by p.l.c, gave, as main product, the detosylated enamide (177a) in low yield. This was identified as the cis isomer by comparison (t lc nmr and u.v.) with material prepared by another route (p.106).

H H \ / C=C NHCOCH OCH3

CH30 OCH3 00H3 OCH3

(177a)

101

CH 0 Ts (171) + TsCH2NC'CH30 CH=C NHCHO (172)

OCH Ts / 3 CH CH=C \+ OCH3

(174) (173)

Ts CH= C OCH3 NHCOCH OCH3 OCH3 (175)

CH30 CHP (156 ; R1=R2=R3=R4= CH3 ) 3 OCH3 OCH3

(176)

Scheme 13 102

Although catalytic hydrogenation of the double bond would give the derived saturated amide (176) the low yield of the hydride reduction prompted a search for a better method of removing the toluene-4-sulphonyl group. A possibility would be to eliminate toluene-4- • -sulphinic acid from enamide (175) with base to form the alkynamide (178), which would be subsequently hydrogenated to give the desired product (176).

Ax--= C=C—NHCOCHAr

(178) O:1-4 3 H H / 0 C= C,H3 \ Ar = 0(21-1 3 Ar NHCHO (179)

In the event triethylamine in benzene, at room temperature, gave no reaction. Under the same conditions 11 5-diazabicyclo[4.3.0]non-5-ene (1)BN) caused extensive AecompositiOn. However potassium t-butoxide under the same conditions, besides decomposition, gave an extremely low yield of a compound whose spectral data` possibly indicated the formation of compound (178). Being both non crystalline and available in only poor yield this was not examined further. At this stage it was realised that removal of the toluene-4-sulphonyl group prior to condensation of the isocyanide (173) with the acetal (174) would be useful.

**- 103

Hydrogenation of the enamide (172) was again unsuccessful presumably due to catalyst poisoning. Hexavalent sulphur, however, is not generally considered185 to be a catalyst poison. Lithium-ammonia reduction of enamide (172) gave a low yield of a detosylated mixture of products possibly containing the derived enamide (179) by comparison (t.l.c.) with material prepared by another route. Sodium amalgam in anhydrous alcohols have been used to cleave sulphone groups bonded to sp2 186 or sp3 187 hybridised carbon atoms. Treatment of enamide (172), however, with aluminium amalgam188 in dry tetrahydrofuran/ethanol gave no reaction even on heating at 50°C..Sodium borohydride reduction in ethanol/tetrahydrofuran gave a low yield (22%), after chromatography, of enamide (179), which was raised to 50% with dimethylformamide as the solvent. Comparison of the spectral data of cis-enamide (177a) and enamide (179) suggested the product was also the cis-isomer. Why the less stable cis-isomer is formed as the main product of these reductions is not understood. When the isocyanide (173) was treated with lithium in ammonia it gave a mixture of polar compounds which was not examined further. Sodium borohydride reduction of isocyanide (173), however, proceeded cleanly at 40°C in ethanolic tetrahydrofuran to give the saturated isocyanide (180) (75%). The reaction has analogy in the addition of nucleophiles to the double bond of the corresponding a-isocyanoacrylic esters (71) (Scheme 2). 104

Having prepared, the isocyanide (180) in high yield a number of possible transformations could be envisaged (Scheme 14).

0130_H2 + CH=CH—N=-C CH3(D 0130 NC + – 0.130 (181) (182) reductive cleavage Base

-Ts CH30 CH CH30 N=C (180)

(174) CF3CO2H Ts OCH3 CH30 CH2CHNHCOCH OCH3 CH3O OCH3

(183)

Scheme 14

Thus base elimination of toluene-4-sulphinic acid would afford the vinyl isocyanide (181) which could be possibly hydrogenated to the phenethyl isocyanide (182). 105

This isocyanide (182) would be also possibly prepared from the reductive cleavage of the isocyanide (180). In either way isocyanide (182) would be condensed with the acetal (174) to afford the amide (176). Similarly isocyanide (180) could be condensed with acetal (174) to afford the amide (183), leaving removal of the toluene- -4-sulphonyl group to a later stage. Excess of sodium ethoxide in ethanol or 1 15-diazabicyclo[5.4.0]undec-5-ene (DBU) caused mainly decomposition of the isocyanide (180) after prolonged heating at 60°C. Potassium t-butoxide brought about extensive decomposition even at room temperature. This probably resulted from self-condensation of the isocyanide (180) via the isocyano and sulphonyl stabilised carbanion. Reductive cleavage of the carbon sulphur bond using sodium amalgam187 or Raney nickel189 has been reported previously. Treatment, however, of isocyanide (180) with sodium amalgam190 in tetrahydrofuran/isopropanol at room temperature gave a mixture of polar decomposition products which were not examined further. Similar results were obtained with W-2 Raney nickel191 in ethanol/tetrahydrofuran at 50- 60°C. Isocyanide (180) was therefore condensed with the acetal (174) in the presence of trifluoroacetic acid to give the expected amide (183) in 93% yield as a mixture of the two diastereoisomers (1:2 ratio by n.m.r.). Crystallisation gave the major isomer (n.m.r.). The diastereoisomeric mixture was subsequently used without 106

separation. Partial conversion of the amide (183) to the detosylated product (176) was observed on prolonged reflux with a large excess W-2 Raney nickel in ethanol/ tetrahydrofuran. Amide (176) was isolated by plc and identified by comparison (t.l.c., n.m.r.) with an authentic sample prepared by another route (p.107). Alternatively the toluene-4-sulphonyl group could be eliminated on base treatment of amide (183). Reaction with triethylamine failed to give any product at room temperature. Reaction, however, with ABU in benzene gave the expected product (177) as an equimolar separable (p.l.c.) mixture of the two geometrical isomers, in 90% yield.

H /

NHCOCH 1 OCH3

(177)

(177a) — CiS (177b) —trans

The less polar isomer was obtained as an oil and identified as the cis-isomer (177a) since the vinylic proton, vicinal to the amide group, appeared at g' 5.80 as a doublet with a coupling constant of 10 Hz. The more

4 107

polar trans-isomer was obtained as a crystalline compound, with the same vinylic proton resonating at 8 6.20, as a doublet with a coupling constant of 16 Hz. Both isomers had superimposable mass spectra. The trans-isomer generally absorbed at longer wavelengths in both the i.r, and u.v. spectra. As with amide (183) the mixture of the two isomers (177) was used without further purification in the next step. Attempts to hydrogenate the isomeric mixture (177) with 10% palladium on charcoal in ethyl acetate at room temperature failed to give any reaction. Filtration and hydrogenation of the filtrate over platinum black gave some very slow reaction and almost stopped after two days. It was thus evident that the catalyst was being poisoned possibly because of the presence of sulphur byproducts arising192 from the toluene-4-sulphinic acid. Since purification of the mixture of the two isomers by recrystallisation was not desirable these byproducts would accompany the substrate leading to catalyst poisoning. However hydrogenation of the mixture of the two isomers could be accomplished in 85% yield over 50% by weight of W-2 Raney nickel in methanol/ethyl acetate in four days. These results indicate that Raney nickel is less sensitive to poisoning than palladium or platinum although palladium has been generally considered193 to be the least prone. Thus the synthesis of the a-methoxy-amide (176) was accomplished in 34% overall yield, which is comparable with the yield obtained with similar substrates by the

4 108

methoxyacetonitrile route (Scheme 7). The last step of the planned synthesis of papaverine required the Bischler-Napieralski cyclisation of amide (176). Phosphoryl chloride in acetonitrile has been reported194 to effect Bischler-Napieralski cyclisation even at low temperatures with substrates bearing unprotected phenolic groups. These reaction conditions were first tested on a model compound (187) (Scheme 15).

ArCHO ArCH CH-NO2

(160) (184)

Cl O

ArCH2CH2NHCOCHPh ArCH2CH2NH2 (186) (185)

OCH3 OCH3 ArCH2CH2NHCOCHPh AT = OCH2Ph (187)

Scheme 15 O-Benzylvanillin was condensed195 with nitromethane and the resulting nitrostyrene (184) reduced195 with lithium aluminium hydride to the phenethylamine (185). Condens- ation of amine (185) with a-chloro-phenylacetyl chloride under Schotten-Baumann conditions196 gave several products which were not examined further. Aprotic. reaction using triethylamine as the base gave the a-chloroamide (186) in 75% yield. Sodium methoxide displacement of the chloride gave the a-alkoxyamide (187) in 76% yield. Treatment of amide (187) with phosphoryl chloride in dry acetonitrile at room temperature gave a high yield of the almost pure (t.l.c.) unstable 3,4-dihydroisoquinoline (188a) which was characterised as the derived 2-methyl-1,2,3,4-tetrahydroisoquinoline derivative (190a) by reaction with methyl iodide and sodium borohyc9ride196 in sequence. Similarly amide (176) with phosphoryl chloride in dry acetonitrile,. methyl iodide, and sodium borohydride in sequence gave the expected tetrahydroisoquinoline derivative (190b). The methylamine derivatives (190) were obtained as almost pure mixtures of the two diastereoisomers (n.m.r.). Further purification by p.l.c. afforded pure (190a). in 44% and (190b) in 50% overall yield based on the starting amides (187) and (176) respectively. It was thus evident that, under the Bischler- Napieralski reaction conditions used, the desired transformation (Scheme 9) did not follow the initial

110

1 R.10 R 0 2 2 R 0 R 0

(188) (189)

1 1 R 0 R 0 2 2 RO R 0

(191) (190)

a. R1= CH R2= CH Ph R3.114. H R5= OCH 3, 2 , , 3 b. R1=R2= CH 111 =R4=R5. OCH 3' 3 c. R1= CH R2=R3=R4= HI R5= OCH 3' 3 d. R1= CH3, R2=R3=R4=R5. H

e. Ri= CH3, R2. CH2Ph, R3=R4.0. H 111

formation, of the a-methoxy-314-dihydroisoquinolines (188a and b). The reaction of the dihydroisoquinolines (188a and b) with various acids was therefore investigated. Treatment of the model dihydroisoquinoline (188a) with a catalytic amount of trifluoroacetic acid in dichloromethane at room temperature or 40°C for prolonged periods of time gave no reaction. Reflux with a slight excess of trifluoroacetic acid in chloroform overnight gave only the trifluoroacetate salt of the dihydroisoquinoline (188a). In the n.m.r, spectrum the benzylic methane (8 5.74) and methylene (g 2.80-3.10); and the aryl aromatic protons (S 6.80 and 7.50) were at lower field compsred with the corresponding protons of the starting dihydroisoquinoline (188a). Dissolution of dihydroisoquinoline (188a) in neat trifluoroacetic acid at room temperature gave only the debenzylated 3,4-dihydroisoquinoline (188c). This has literature precedent197 Boron trifluoride etherate as catalyst in benzene gave no reaction at room temperature but heating at 60°C gave an unstable compound with byproducts. Difficulty was experienced in purification. Spectral data ruled out identity with the isoquinoline derivative (191e) although the compound lacked the benzylic methoxy function. The product could not be obtained pure and was not investigated further. Finally treatment of dihydroisoquinoline (188a) with dry hydrogen chloride at room temperature gave but the hydrochloride salt of (188a) (n.m.r.) even after prolonged 112

reaction. It was thus realised that acids simply form the corresponding salts with 314-dihydroisoquinoline preventing further reaction. Attempted oxidation of dihydroisoquinoline (188a) to give the isoquinoline (191a) with 213-dichloro-516- dicyano-114-benzoquinone (DDQ)1983199 gave a mixture of products which were not examined further. The dehydrogenation of 314-dihydropapaverine to afford papaverine has been reported176 to proceed in almost quantitative yield on heating in tetralin with 10% palladium on carbon. Since dehydrogenation is a reversible process and (188a) contains two hydrogenolysable groups, the allyl-benzylic methoxy and the benzylic protecting group, it was hoped that tetralin would effect both dehydrogenation and cleavage of these groups. Such reaction of intermediate (188a) gave after 3 hours mostly a mixture of two air sensitive products. They were difficult to separate by p.l.c. because of very close Rf values. The n.m.r, spectrum of the mixture revealed complete removal of the benzylic protecting group, 50% removal of the methoxy group and resonances corresponding to the expected isoquinoline (191d) by comparison with the n.m.r, spectrum200 of papaverine. Thus it was plausible that the reaction was proceeding in the expected w.gy. The second product was possibly the phenol (188c). Prolonged heating, however,. instead of leading exclusively to the desired compound (191d) complicated the reaction possibly because of 113

hydrogenation of the products. Further investigation was not carried out Although papaverine could not be obtained by acid catalysed demethoxylation of the a-methoxy-314-dihydropapaverine (188b) it could be obtained if prior to the Bischler-Napieralski reaction the methoxy group was cleaved off by hydrogenolysis. Since the mild Bischler- Napieralski reaction is suitable for unprotected substrates,hydrogenolysis,at the same time of benzylic ether functions, usually present in other alkaloid precursors, should not be a problem. Besides being removable by hydrogenolysis the methoxy group allows further transformations either at the amide, or the 3,4-dihydro and tetrahydroisoquinoline stages Furthermore the present approach offers access to the novel 1-(a-alkoxybenzy1)-2-methyl-1 121314-tetrahydroisoquinolines (192a) by a short route. For comparison the analogous a-hydroxy compounds are usually prepared through benzylic oxidation of the corresponding isoquinolines201 1 203 or 314-dihydro 202, or even tetrahydro203isoquinolines and subsequent sodium borohydride reduction2°1 1203 of their corresponding 2-methyl salts. The method could also be applied in the synthesis of 1-(a-alkoxybenzy1)-1,2,314- -tetrahydroisoquinolines (192b) by catalytic reduction of the C-N double bond in the intermediates (188), further hydrogenation leading finally to tetrahydroisoquinolines (192c).

114

1 R3=H

3 (193) R =COR (194)

2 , 4

NH 3 .c%:1 OH R2

(195)

1 2 R = R = H OH ,OCH3

1. CoC1 /Et N ;• 2 Pt/CH CO H ; 3 CF 02H ; 2 3 - 3 2 • KOH.

Scheme 16 115

1 R 0 2 R 0

3 OR 4 • OR

(192)

a. R5. OR, R6- CH - 3 b. R5= OR, R6= H c. 115,,,R6. H.

'By comparison the analogous a-hydroxy-tetrahydroisoquinolines (195) are usually prepared204 either by catalytic reduction and subsequent hydrolysis of the a-hydroxy-isoquinoline esters (193) (46%) or via the oxazolones (194) (63%) (Scheme 16). The first method depends on the availability of a-hydroxy-isoquinoline esters via Reissert compounds2051 whilst the second requires a-hydroxy-isoquinolines usually prepared201 from sodium borohydride reduction of the corresponding a-oxo-isoquinolines Either synthesis is obviously far longer than the present approach. 116

3.2 'EXFERIMENTAL

Unless otherwise stated the following data apply to experiments described in this thesis. Melting points were determined on a Kofler hot stage apparatus and

• are uncorrected. Infra-red spectra (i.r.) were recorded as nujol mulls on a Perkin Elmer 257 grating spectro- photometer. Ultra-violet spectra (u.v.) were recorded in ethanol on a Unicam SP 800 B spectrometer. IH Nuclear magnetic resonance spectra (n.m.r.) were taken in deuteriochloroform with a tetramethylsilane (TMS) internal standard on a Varian T 60 or HA 100 spectrometer. Signals are reported in the order of chemical shift designated on the cSj scale, and within parentheses intensity, multiplicity, coupling constant in Hz, and assignment, with the aid of the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; m, multiplet; b, broad. Mass spectra (m.s.) were recorded with a Perkin Elmer 270 low- resolution spectrometer. All solvents used were 230 purified according to standard procedures Merck Kieselgel GF254 was used for analytical (t.l.c.) and preparative (p.l.c., 1 mm layers) thin layer chromatography. Hopkin and Williams silica gel M.F.C. (100-200 mesh) or neutral alumina of Brockmann activity III were used for column chromatography, with compounds listed in order of increasing polprity. Organic solutions were

4 117

dried over magnesium sulphate and evaporated under reduced pressure. Light petroleum refers to the redistilled fraction with b.p. 40-60°C. 0-Benzylvanillin179(160), N-cyclohexylformamide180 (161), cyclohexyl isocyanide6 (162), N-(toluene-4- -sulphonyl)methyleneformamidel°5 (77), 1-nitro-2- -(3-methoxy-4-benzyloxyphenyl)ethylene195 (184) and 1-amino-2-(3-methoxy-4-benzyloxyphenyl)ethane (185) were prepared according to literature procedures.

Preparation of N-(3-methoxy-4-benzyloxyphenyl)benzylidene- aniline (163) Imine (163), prepared according to a literature procedure41 for the preparation of the 0-benzylisovanillin (164) analogue, was obtained in 80% recrystallised yield as white prisms from ethanol, m.p. 113-4°C, vm ax 1630 cm 1 (Found: C, 79.51; H, 6,05; N, 4.29. C21H19NO2 requires CI 79.47; H, 6,03; N, 4.41%).

Preparation of N-cyclohexy1-2-(N-phenyltrifluoroacetamido)- -2-(3-methoxy-4-benzyloxyphenyl)acetamide (165) Acetamide (165), prepared according to a literature procedure41 for the preparation of the 0-benzylisovanillin (164) analogue, was obtained in 75% yield as white needles from ethyl acetate, m.p. 176-7°C, vmax 3280, 1695 and 1655 cm-1 (Found: C, 66.62; H, 5.74; N, 5.06; F, 10.27. 118

C30H31N204F3 requires C, 66.65; H, 5.78; N, 5.18; F, 10.54%).

Preparation of 2-(3-methoxy-4-benzyloxypheny1)-1,3- dioxolane (166) 0-Benzylvanillin (160) (12.Ig; 0.05 M), ethane- 1,2-diol (2.8 ml; 0.05 M) and toluene-4-sulphonic acid (0.09 g) were dissolved in benzene and heated to reflux until no more water could be removed azeotropically. The clear solution Was washed with saturated aqueous sodium hydrogen carbonate and water, and dried. Evapor- ation of the solvent gave an oil which solidified upon standing at 0°C overnight. Recrystallisation from diethyl ether gave the dioxolane (166) (8.6 g; 61%) as white needles, m.p. 79-81° C, Sj 3.85 (311, s, ArOCH3), 3.92-4.17 (4H, A2B2 m, -CH2CH2-), 5.10 (2H, s, PhCH2), 5.70 (IH, s, ArCH), 6.87-7.04 (3H, m, ArH) and 7.14- -7.60 b (5H, s, PhH) (Found: C, 71.31; H, 6.34. C17H1804 requires C, 71.25; H, 6.20%).

The reaction of the dioxolane (166) with cyclohexyl isocyanide (162) and trifluoroacetic acid Dioxolane (166) (0.715 g; 2.5 moles), cyclohexyl isocyanide (162) (0.278 g; 2.6 moles) and trifluoroacetic acid (0.186 ml; 2.5 moles) were dissolved in anhydrous methanol (4 ml) and dry benzene (2 ml) and left at room temperature for 1 hr. The solution was 119

diluted with benzene, washed with saturated aqueous sodium hydrogen carbonate and water, and dried (Na2SO4). Evaporation of the solvent gave an oil which solidified on standing at room temperature. Column chromatography on alumina gave (eluant benzene) 0-benzylvanillin dimethoxyacetal (167), (0.53 g; 74%), 64 3.32 (6H, s, ArC-OCH3), 3.83 (3H, s, ArOCH3), 5.10 (2H, s, PhCH20), 5.32 (1H, s, ArCH), 6.90-7.06 (3H, m, ArH) and 7.35 b (5H, s, PhH); and (eluant 10% benzene in ethyl acetate) N-cyclohexyl- -2-methoxy-2-(3-methoxy-4-benzyloxyphenyl)acetamide (168), (0.22 g; 23%), as white needles from ethyl acetate, m.p. 133-34°C, vm ax3320 and 1655 cm 1 1 c 1.00-2.10 (envelope, 10H, cyclohexyl), 3.34 (3H, s, benzylic-0CH3), 3.70- -3.90 (1H, m, N-CH), 3.84 (3H, sl ArOCH3), 4.35 (1H, s, ArCH), 5.00 (2H, s, PhCH2O), 6.74 b (3H, s, ArH) and 7,34 b (5H, s, PhH) (Found: C, 72,04; H, 7.62; N, 3,65,

C23H29NO4 requires C, 72.06; H, 7.42; N, 3.57%).

Preparation of 0-benzylvanillin dimethoxyacetal (167) O-Benzylvanillin (0,3 g) was dissolved in anhydrous methanol (5 ml) and a catalytic amount of dry hydrogen chloride was bubbled through the solution. After standing at room temperature for 21 h the solution was poured into an excess of saturated aqueous sodium hydrogen carbonate. The white precipitate was filtered off, washed with water and dried to give the acetal (167) (0,33 g, 92% yield), identical with that from the previous reaction. 120

Preparation of N-cyclohezz11-2-methoxy-2-(3-methoxy-47 -benzyloxyphenyl)acetamide (168) Acetal (167) (0.37 g; 1.28 moles) was dissolved with stirring in dry benzene (20 ml) under nitrogen and trifluoroacetic acid (97 ill; 1.28 nimoles) and cyclohexyl isocyanide (0.165 ml; 1.30 moles) were added in sequence. The resulting solution was stirred at room temperature for 1 day, diluted with benzene, washed with saturated aqueous sodium hydrogen carbonate and water, dried, evaporated and recrystallised from ethyl acetate to give (168)(0.37 g; 76% yield), identical with the compound previously described.

E2112genolysis of amide (168) Preparation of N7cyclo- hexyl-2-methoxy-2-(3-methoxy-4-hydroxyphenyl)acetamide (169) Amide (168) (1 g) was dissolved in methanol and hydrogenated under 1 Atm hydrogen pressure, at room temperature, in the presence of 10% palladium on charcoal (0.1 g) for 2 h. The catalyst was filtered off, washed with methanol and the solvent was evaporated to give the crystalline amide (169) (0.75 g; 98% yield). Recrystallisation from aqueous methanol gave white needles, m.p. 119-20°C, vmax 5400, 3300 and 1645 cm 1 1 67'1.00-2.20 (envelope, 10H, cyclohexyl), 3.35 (3H, s, benzylic-OCH3), 3.86 (3H, s, ArOCH3),.3.64-4.00 (1H, m, N-CH), 4.50 (1H, s, ArCH), 5.90 b (1H, NHCO), 6.60 b

4 121

(1H, ArOH) and 6.86 (3H, s, ArH) (Found: C, 65.57; H,

7.91; N, 4.77. C16H23NO4 requires C, 65.50; H, 7.91; N, 4.77%).

Hydrogenolysis of amide (169). Preparation of N-ayc10-

Amide (169) (0.1 g) and 60% aqueous perchloric acid (0.05 ml) were dissolved in glacial acetic acid • (5 m1) and hydrogenated at room temperature for 6 days in the presence of 10% palladium on charcoal (10 mg). The catalyst was filtered off and the filtrate diluted with water, extracted with ether and the extract washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated to give the crystalline acetamide (170) (64 mg; 71% yield). Recrystallisation from ethyl acetate gave white plates, m.p. 151-3°C, g 0.85-2.00 maxax 3370, 3310, 3250, 1650 and 1630 cm 11 (envelope, 10H, cyclohexyl), 3.46 (2H, s, ArCH2), 3.60- -4.00 (1H, m, N-CH), 3.84 (3H, s, ArOCH3), 5.80 b (1H, NH), 6.60-7.00 complex (4H, ArH + ArOH) (Found: C, 68.12; H, 7.70; N, 5.05. C15H21NO3 requires C, 68.41; H, 8.04; N, 5.32%).

Preparation of Toluene-4-sulphonylmethyl isocyanide 'TosMICI (78) TosMIC was prepared according to literature procedures100°01 in 57% yield (lit. 58%) or by the 122

following alternative method. Formamide (77) (1.2 g; 5.5 mmoles) was dissolved in dry triethylamine (14.5 ml; 0.1 11} and dry dichloromethane (10 ml). To the cooled (0°C) solution phosphoryl chloride (0.9 ml; 10 mmoles) was added over ca. 45 1111 under nitrogen and with vigorous stirring. The mixture was allowed to reach room temperature and was subsequently slowly poured into an excess of ice cooled saturated aqueous sodium hydrogen carbonate with vigorous stirring. The organic phase was collected and the aqueous phase further extracted with dichloromethane..The combined organic layers were washed with water, dried and evaporated to afford a brown solid. Filtration through alumina (eluant benzene), evaporation and recrystallisation from ethyl acetate/light petroleum gave TosMIC (1 g; 65% yield).

Preparation91 -2-(toluene-4-sulphonyl)ethylene (172) To a cooled (70 C) degassed suspension of potassium t-butoxide (7.6 g; 68 mmoles) in tetrahydrofuran (130 ml) a degassed solution of TosMIC (2.7 g; 14 moles) in dry tetrahydrofuran (13 ml) was added in less than 3 min, under argon, with vigorous stirring. The resulting mixture was immediately cooled to -200 C and a degassed solution of 0-benzylvanillin (2.27 g; 13.6 mmoles) in dry tetrahydrofuran (14 ml) was added, followed by glacial acetic 123

acid (3.9 ml). The reaction mixture was allowed to warm up to room temperature and THF evaporated at room temperature. Water was added to the residue and the mixture extracted with dichloromethane. The organic phase was dried and evaporated to give a foam. Crystal- lisation from acetone/hexane gave the ethylene (172) (3,93 g; 80% yield) as white plates, m.p. 171-2°C, vmax 3260, 1700, 1635, 1315 and 1.150 cm-1, Xmax 204,

235 (£max 22000), 295 (18000), and 324 (25000) nm, s 2.40 (3H, s, SO2PhCH3), 3,78 (3H, s, ArOCH3), 3.84 (3H, s, ArOCH ) and 6,64-8,18 complex (10H, aromatics + 3 ArCH= + ITHH) (Found: C, 59.80; H, 5.30; N, 3.88; S,

8.87. C181119N05S requires C, 60.05; H, 5.26; N, 3,93; S, 8,93%),

Preparation -(toluene-4-sulphonyl)ethylene (173) To the ethylene derivative (172) (1.3 g; 3.6 mmoles) in anhydrous triethylamine (10 ml) and dry dichloromethane (16 ml) at -30°C was added phosphoryl chloride (0.6 ml) in ca, 45 m, under nitrogen and with good stirring. The reaction mixture was left.to reach room temperature and stirred overnight. The mixture was poured into an excess of saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to give a dark brown solid. Filtration on 124

alumina (eluant benzene) and recrystallisation from benzene/light petroleum gave the isocyanide (173) (0.99 g; 80% yield) as pale yellow needles, m.p. 119-21° C, vmax 2108, 1615, 1330 and 1155 cm 1, Xmax 204, 239 ( Eurax 12000), 324 (12000)-and 338 (15000) nm, g 2./0 (3H, s, ArCH3), 3.86 (3H, s, ArOCH3), 3.92 (3H, s, ArOCH3) and 6.86-8.10 complex (8H, aromatic + ArCH.) (Found: C, 62.95; H, 4.99; N, 4.08; S, 9.34. C181117N04S requires C, 63.00; H, 5.08; N, 3.94; S, 9.40%).

Preparation of veratraldehyde dimethoxyacetal182 (174) Veratraldehyde (1.66 g; 10 mmole) and trimethyl orthoformate (3.2 g; 30 mole) were dissolved in anhydrous methanol (5 ml) and dry hydrogen chloride bubbled through the -solution. After 4 h at room temperature the mixture was poured into an excess of sodium methoxide in methanol. Volatile components of the reaction mixture were removed by evaporation, water added to the residue and the mixture extracted with diethyl ether and the organic phase dried over calcium chloride. Evaporation gave the acetal (174) in almost quantitative yield,g 3.20 (6H, s, ArC-0CH3 3.78 (3H, s, ArOCH3), 3.80 (3H, s, ArOCH3), 5.20 (1H, s, ArCH) and 6.78-6.90 complex (3H, ArH). 125

Preparation of NIIILLILL2f4asyll-2(3,4-2. -dimethoxyphenyl)jethyleny1-2-methoxy-2-(3,4-dimethoxyphenyl)acetamide (175) Veratraldehyde (0.33 g; 2 moles), trimethyl orthoformate (0.64 g; 6 mmoles) and trifluoroacetic acid (15 0,1; 0.2 mmoles) were dissolved in dry methanol (1 ml) and the solution allowed to stand at room temperature for ca. 15 h. Volatile compounds were removed under vacuo and the system was flushed with argon. Whilst constantly stirring trifluoroacetic acid (0.15 ml; 2 mmoles) was added, followed by a solution of the isocyanide (173) (0.7 g; 2.04 mmoles) in dry benzene (8 m1). After 4 h, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with benzene. The combined organic layer was washed with water, dried, evaporated and filtered through alumina (eluant 10% ethyl acetate in benzene) to give almost pure acetamide (175) (0.75 g;

70% yield) as a yellowish foam, max 3250, 1700 and 1640 cm-1, g 2.50 (3H, s, SO2PhCH3), 3.55 (3H, s, benzylic-OCH3), 3.80, 3.95, 4.00 and 4.05 (12H, 4 sl ArOCH3), 4.67 (1H, s, ArCH-), 6.40-8.00 complex (11H, ArH + SO2Phll + ArCH=) and 8.4 b (1H, sl -NHCO-). 126

Sodium borohydride reduction of acetamide (175). Preparation of N4[2-(3,4-dimethoxyphenyl)lethylenyl- -2-methoxy-2-(3,4-dimethoxyphenyl)acetamide (177) The acetamide derivative (175) (0.12 g; 0.25 mmoles) in ethanol (5 ml) was added to a solution of sodium borohydride (60 mg; 1.5 mmoles) in ethanol (5 ml) at room temperature and was subsequently refluxed for ca. 31 h. The solution was cooled to 0°C and neutralised with dilute hydrochloric acid. The solution was extracted with dichloromethane and the organic phase washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated to give a mixture (52 mg). P.l.c, on silica (developing solvent 10% ethyl acetate in benzene) gave the major cis-acetamide (177) (24 mg; 25% yield), identical with an authentic sample (p.130).

Sodium borohydride reduction of N-formamide (172) Preparation of N-[2-(3,4-dimethoxyphenyljjethylenyl- formamide (179) Method A N-Formamide (172) (90 mg; 0.25 mmoles) in absolute ethanol (5 ml) and dry tetrahydrofuran (3 ml) was added to a solution of sodium borohydride (60 mg; 1.5 mmoles) in absolute ethanol (5 ml), at room temperature and the solution heated to 60°C for 2 h. Work up as for compound (177) gave the N-formamide (179) (13 mg; 22% yield). 127

Method B N-Formamide (172) (90 mg; 0.25 mmoles) and sodium borohydride (70 mg; 1.75 mmoles) were heated at 60°C in dry dimethylfoEmamide (10 ml) for ca, i h. The solvent was evaporated and water added to the residue. The solution was extracted with chloroform and the organic phase dried over sodium sulphate and evaporated to give almost pure N-formamide (179) (30 mg; 50% yield) as a

colourless gum, vm ax3400, 1695 and 1655 cm-1, Amax 212 (cm 12000), 225 (12500), 278 (15200) and 292 sh (11400) ME 8j 3.90 (6H, s, Ar00113), 5.80 d, J 8 Hz, -CH.), 6.70- -7.00 complex (4H, ArH + ArCH.) and 8.25 b (1H, s, -NHCO-).

Preparation of 1-(3,4-dimethoxyphen'yl)-2-isocyano-2-

E1211.1 To a stirred suspension of sodium borohydride (0.33 g; 8.7 mmoles) in absolute ethanol (15 ml) under nitrogen was slowly added a solution of the isocyanide (173) (0.86 g; 2.5 mmoles) in dry tetrahydrofuran (15 ml). The suspension was heated slowly to 40°0 and cooled to •room temperature. The solvents were evaporated and water added. The mixture was extracted with dichloromethane and the organic phase dried, evaporated, filtered through alumina (eluant benzene) and recrystallised from benzene/light petroleum to give the isocyanide (180) (0.65 g; 75% yield) as needles, 128

m,p, 159-60°C, max 2140, 1330 and 1135 cm l l g 2,55 (3H, s, ArCH3), 2,95-3,60 (2H, ABX m, ArCH2), 3,90 (6H, s, ArOCH3), 4,50-4,80 .(1H, dd, Ji 3 Hz, J2 12 Hz, methine) and 6,70-6,85 complex (3H, ArH), 7,40 and 7,90

(4H, 2 d, J 9 Hz, SO2Ph-H) (Found: C, 62,59; H, 5,54; N, 4.05; S, 9.28. C18H19NO4S requires C, 62.70; H, 5,68; N, 3,98; S, 9,29%),

Preparation of N-E1rLoluene-4-sulphony1)-2-(3,4-di- methox-yphenyl)]eth d y1)- acetamide (183) Veratraldehyde (1,15 g), dry triethyl orthoformate (2,24 ml), anhydrous methanol (3,5 ml) and dry trifluoroacetic acid (53 pa) were allowed to stand at room temperature for 3 days, After evapbration, a solution of the isocyanide (180) (2,17 g) in dry benzene (100 ml), followed by trifluoroacetic acid (0,54 ml), were added with efficient stirring, under argon, After stirring for Ca, 2 h, the mixture was poured into an excess of saturated aqueous sodium hydrogen carbonate, The benzene layer was separated and the aqueous phase was extracted with more benzene, The combined organic phase was washed with water, dried and evaporated to give a gum, The gum in dichloromethane (5 ml) was vigorously stirred overnight with a solution of 231 sodium metabisulphite (300 ml) and glacial acetic acid (0,5 ml) to remove excess veratraldehyde. The two 129

layers were separated and the aqueous phase extracted with more dichloromethane. The combined organic layers were washed with water, dried and evaporated to give the almost pure acetamide derivative (183). Crystallis- ation from benzene/light petroleum gave plates, m.p.

140-41°C, vmax 3330, 1690, 1310 and 1140 cm 11 g 2.44 (3111 sl ArCH3), 3.10 (2H, dd, Ji 3 Hz, J2 5 Hz, ArCH2), 3.26 (3H, s, benzylic-OCH3), 3.68, 3.71, 3.82 and 3.84 (12H, 4 s, ArOCH3), 4.22 (IH, a, benzylic methine), 5.60 (IH, m, CH-Ts), 6.50-6.80 (6H, m, ArH), 7.37 and 7.90 (4H, 2 d, -SO2PhH-) (Found: C, 61.86; H, 6.12; N, 2.5B; S, 5.90. C281133N08S requires C, 61.56; H, 6.15; N, 2.38; S, 6.17%).

Preparation of ethylenyl- -2-meth2oxy-2-4--2-C3!4-dimed-i-nle thoxyphenyl)acetamide (177) 1,5-Diazabicyclo[5.4.0]undec-5-ene (DBU) (0.82 ml) was added with stirring to the acetamide derivative (183) (3 g) in benzene (50 ml) at room temperature and stirring was continued for 11 days. Evaporation and filtration through alumina (eluant ethyl acetate/benzene 2/3) gave the enamide (177) (2 g; 90% yield) as a mixture of isomers. P.l.c, gave the trans-isomer as white needles (from benzene/light petroleum), m,p. 74-77°C, vm ax 3260,

1665 and 1645 cm-1 Xmax 203 ( E urax 22000), 218 (13400), 285 (15800), 292 (16400), 308 (13600) and 324 sh (8800) nm, .40 (311, s, benzylic-OCH ), 3.84 b (12H, s, ArOCH ) s 3 3 3 ' 130

4.64 (1H, s, benzylic methine), 6.20 (1H, d, J 16 Hz), 6.70-7.00 complex (7H, ArH -NHCO-) and 7.30 (1H, d, J 16 Hz), m/e 387 (11+), 355, 181 (100%), 166 and 151

(Found: C, 65.34; H, 6.46; N, 3,57,C21 H25N06 requires C, 65.10; H, 6.50; N, 3,62%), and the cis-isomer (177a), v max (c1101 ) 3380, 1680 and 1650 cm-1 3 `max 209 (6 max 20000), 227 (17900), 280 (19500) and 294 sh (13300) nm, 5 3.34 (3H, s, benzylic-OCH3), 3.90 and 3.95 (12H, 2 s, ArOCH3), 4,60 (1H, s, benzylic methine), 5,80 (1H, d, J 10 Hz, -CH.), 6.95 b (6H, s, ArOCH3), 6.70-7.00 complex (1H, -NHCO-) and 7,05 (1H d, J 10 Hz, ArCH=), m/e identical to that of the trans-isomer.

Preparation of N-E2-(3,4-dimethoxyphenyl)jethyl-2- -methoxy-2-(3,4-dimethoxyphenyl)acetamide (176) The above mixed isomers (1.9 g) were dissolved in methanol (100 ml) and ethyl acetate (100 ml) and hydrogenated at room. temperature, under 1 Atm hydrogen pressure in the presence of Raney nickel (0,6 g) for 2 days. T.l.c. indicated that only the cis-isomer was completely hydrogenated. Additional Raney nickel (0,4 g) was added and hydrogenation continued for 2 days, The catalyst was filtered off and washed with ethyl acetate. Evaporation of the solvent gave the crude acetamide derivative (176) (1 ,8 g; 94% yield). Crystal- lisation from ethyl acetate/light petroleum gave the pure acetamide derivative (1.6 g; 85% yield), m.P. 131

vmax 3300 and 1650 cm-11 8 2.76 (2H, t, J 7 Hz, ArCH2), 3.32 (3H, s, benzylic-OCH3), 3.40-3.76 (2H, m, -NCH2-), 3.84 (12H, s, ArOCH3), 4.56 (1H, s, benzylic methine) and 6.74-6.86 complex (7H, ArH + -NHCO-)1 m/e 389 (le), 181 (100%), 164 and 151 (Found: C, 64.63; H, 6.86; N, 3.56. C211127N06 requires C, 64.76; H, 6.99; N, 3.60%).

Preparation of N-[2-(3-methoxy-4-benzyloxyphenyl5jethyl- -2-chloro-2-phenylacetaaile11861 Phenethylamine (185) (9.5 g) and anhydrous triethylamine (6 ml) in dry benzene (74 ml) was added over 2 h with stirring to a-chlorophenylacetyl chloride in dry benzene (74 ml). After 2 h, triethylammonium chloride was filtered off and washed with benzene. Evaporation of the solvent gave the crude product • (15 g; 97% yield). Recrystallisation from ethyl acetate/ light petroleum gave the acetamide (186) (11.6 g; 75% yield) as white needles, m.p. 106-7°C, vmax 3340 and 1650 cm 1,E; 2.76 (2H, m, ArCH2), 3.48 (2H, m, -NCH2-), 3.83 (3H, s, ArOCH3), 5.16 (2H, s, PhCH2O), 5,36 (1H, s, benzylic methine), 6.60-6.96 (3H, m, ArH) and ?.37- -7,70 complex (10H, PhH) (Found: C, 70.24; H, 5.97; Cl, 8.67; N, 3.37, 024H2401NO3 requires C, 70,32; H, 5,90; Cl, 8,65; N, 3,42%), 132.

PreparaLion of N-[2-(3-methoxy-4-benzyloxy)]ethyl-2- -methoxy-2-phenylacetamide (187) Sodium (0.16 g) was dissolved in anhydrous methanol (2.3 ml) and the resulting solution was added dropwise with stirring to amide (186) (2 g) in dry tetrahydrofuran (48 ml), at room temperature and stirring was continued for ca. 2 days. Excess sodium methoxide was neutralised with glacial acetic acid and the solvent evaporated. The residue in dichloromethane was washed with water, dried and evaporated to give the crude product (1.82 g; 92% yield). Recrystallisation from diethyl ether afforded amide (187) (1.5 g; 76% yield) ° -1 as white needles, m.p. 70-2 C, m ax3290 and 1645 cm 1 g 2.70 (2H, m, ArCH2), 3.23 (3H, s, benzylic-0CH3), 3.40 (2H, m, -NCH2-)1 3..84 (3H, s, ArOCH3), 4.60 (1H, sl benzylic methine), 5.16 (2H, s, FhCH20), 6.60-6.90 b (3H, ArH) and 7.20-7.50 complex (10H, FhH) (Found: C, 74.01; HI 6.54; N, 3.38. C25H27N04 requires C, 74.05; H, 6.71; N, 3.45%).

Bischler-Napieralski reaction on the amides (187) and (176). Prearationof 1- °c- meth° 13- -6-- bho ----benzi-°Y---=- -3,4-dihydroisoquinoline (188a) Amide (187) (0.48 g; 1.2 mmoles) and phosphoryl chloride (1.2 ml; 13 mmoles) in dry acetonitrile (4.8 ml) was allowed to stand at room temperature for 3 days, under nitrogen. The solvent and excess reagent were 133

evaporated, the resulting reddish gum washed with diethyl ether and dissolved in water. The pale yellow aqueous solution was filtered, made alkaline with 5% aqueous ammonia under nitrogen and rapidly extracted with diethyl ether. The organic phase was dried under nitrogen, filtered and evaporated, to give crude dihydroisoquinoline (188a) (0.39 g; 85% yield), which was stored under argon, at -20001 g 2.70 (2H, m, ArCH2), 3.38 (3H, s, benzylic-OCH3), 3.70-4.00 (2H, m, =NCH2), 3.84 (3H, s, ArOCH3), 4.98 (2H, s, PhCH20), 5.24 (1H, s, benzylic methine), 6.60 (1H, s, ArH), 7.20-7.50 complex (11H, PhH + ArH).

Preparation of 1-(a-methoxy-3,4-dimethoxybenzy1)-6,7- -dimethoxy-3,4-dihydroisoquinoline (188b) Reaction of amide (176) and phosphoryl chloride gave the crude dihydroisoquinoline (188b) (90% yield).

Preparation of 1-(a-methoxybenzy1)-2-methyl-1,2,3,4- -tetrahydroisoquinolines (190a) and (190b) Preparation of 1-(a-methoxybenzy1)-2-methyl-6-methoxy7 -7-benzyloxy-1„,2,_„3,4-tetrchydroisoguinoline (190a) 3,4-Dihydroisoquinoline (188a) (0,39 g) and methyl iodide (3 ml) were heated to reflux in absolute ethanol, under nitrogen, overnight. After evaporation, the residual reddish gum was dissolved in absolute methanol (15 ml) and sodium borohydride (1 g) was added in portions at 0°C. 134

The mixture was allowed to warm up to room temperature and subsequently heated at 40°C for 2 h. To the residue obtained after evaporation was added 5% aqueous ammonia and the solution extracted with diethyl ether. The organic phase was dried (Na2SO4) and evaporated to give the crude product (0.3 g). Plc (developing solvent ethyl acetate/cyclohexane/triethylamine 10/1.5/0.5) and elution with 10% methanol in chloroform gave pure (190a) (0.21 g; 44% yield) as a mixture of two diastereoisomers in the ratio 2.5:1 (n.m.r.),g 2.30-3.10 complex (4H, PhCH2 + NCH2), 2.46 and 2.55 (3H, 2 s, NCH3), 3.17 (3H, s, benzylic-OCH3), 3.60-3.90 (IH, m, ArCHN-)1 3.77 and 3.80 (3H, 2 s, ArOCH3), 4.20-4.40 (1H, m, benzylic methine), 4.65 and 4.95 (2H, 2 s, PhCH20), 6.18, 6.42 and 6.54 (2H, 3 s, ArH) and 6.80-7.50 complex (10H, PhH) (Found: C, 77.16; H, 7.30; N, 3.54. C2029NO3 requires C, 77.39; H, 7.24; N, 3.47%).

Preparation of 1-(a-methoxy-3,4-dimethoxybenzy1)-2- -methy1-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (190b) Tetrahydroisoquinoline (190b) (50% yield), prepared similarly from (188b), was obtained as a 1:1 (n.m.r.) mixture of the two diastereoisomers, 2,40-3.20 complex (4H, ArCH2 + NCH2), 2.47 and 2.57 (3H, 2 s, NCH3), 3.24 b (3H, s, benzylic-0CH3), 3.58-3.90-complex (12H, 6 s, ArOCH3), 4.00-4.60 complex (2H, benzylic methines) and 6.20-6.90 complex (5H, ArH) (Found: C, 68.00; H, 7,53; N, 3.45. C22H29N05 requires C, 68.19; H, 7.54; N, 3.61%). 135

CHAPTER 4

SOME STUDIES RELATED TO THE BIOSYNTHESIS OF ERYTHRINA ALKALOIDS

136

RESULTS AND DISCUSSION.

The Erythrina alkaloids are derived206 in vivo (Scheme 17) from (S)-N-norprotosinomenine (196) via an initial 2-2 phenolic oxidative coupling to give the proerysodienone (197). Dienone-phenol rearrangement of the latter, followed by reduction, gives rise to the dibenzazonine (199). On further oxidation and rearrangement the precursor of the Erythrina alkaloids, (5S)-erysodienone (201a), is formed. The synthesis of Erythrina alkaloids in vitro, however, is based on the early erroneous biosynthetic scheme in which erysodienone (201) was thought to arise from the bisphenethylamine (202), phenol oxidative coupling, and the dibenzazonine (199) (Scheme 18).

OH CH30

NH (199) (200) (201)

CH3O OH

(202)

Scheme 18 137

HO NH CH30 CH3O

....-....Ctr.

CH3O CH30 OH OH (196) (197)

OH OH CH3O CH3O

I CH30 CH3O OH OH

(198) (199)

CH3O

-•-••■■!:::.

CH3O

0 (201)

(200) (201a) : 5S—isomer

Scheme 17 138

Thus Mondon207 and Scott208 independently synthesised erysodienone (201) in 35% yield from bisphenethylamine (202), using alkaline potassium hexacyanoferrate(III). The addition139 of the phase transfer catalyst (benzyltriethylammonium chloride) improved the yield to 44%. Barton et al, investigated the mechanism of this transformation. Two sequences from the bisphenethylamine (202) to erysodienone (201) are conceivable and differ in the order of formation of the C-C and C-N bonds. Thus Scheme 18 involved an initial C-C phenol oxidative coupling to give the 9-membered ring of the dibenzazonine (199), followed by further oxidation to the sterically congested biphenonquinone (200). The latter is rapidly trapped by the amine function to give erysodienone (201). Alternatively an initial radical C-N coupling, followed by a C-C bond formation can be envisaged (Scheme 19).

(201)

(202) (203)

Scheme 19 139

It was first shown206b that reduction of erysodienone (201) to the dibenzazonine (199) and subsequent oxidation under identical conditions with those used to prepare erysodienone (201) gave an 80% yield of the expected erysodienone (201). Further evidence for Scheme 18 was the absence of erysodienone (201) on oxidation of indoline (203). The intermediacy of the biphenonquinone (200) could not be proved directly, but it was shown that both phenolic groups were essential in the oxidation of dibenzazonine (199) to erysodienone (201). This ruled out the alternative carbon nitrogen radical coupling. Further support for the mechanism depicted in Scheme 18 would follow if the amine function was proved unnecessary for the coupling process. This would require substrates either having a less basic or no amine function in the side chain. The required amide (204a) was prepared194 by the methoxyacetonitrile procedure (Scheme 7) and was subjected194 to phenol oxidative coupling conditions. The biphenol (205a) was isolated as the only monomeric product of the reaction, in 8-11% yield allowing for recovered starting material. Assignment as biphenol (205a) was in full agreement with spectral and microanalytical data Addition of the phase transfer catalyst benzyltriethylammonium chloride slightly increased the yield (12%). The studies herein describe the preparation and potassium hexacyanoferrate(III) oxidation of the 140

HO OH

CH3O (204) OCH3

Y X 5 1

HO OH

CH3O H1 H4 OCH3 (205)

a. X = NH, Y = 0

b X = CH21 Y=0 c X = CH Y = H 21 2 bisphenols (204b and c) lacking a nitrogen function in the side chain. Subsequent further oxidation of the expected biphenols (205b and c) would possibly afford the diphenonquinone intermediates analogous to (200). If their reactivity was as high as would be expected for such strained intermediates, characterisation of possible trapped products would be good evidence for. their intermediacy, at least in vitro. Bisphenolic substrates (206) in which the two aromatic nuclei are linked by a carbon chain of various 141

length have been prepared24°9 in high yields.

HO (CH 2)n OH CH3O CHO

(206) 207) n=1-7

(208)

Thus 1 15-di-(4-hydroxylpheny1)-pentane (208) was prepared from anisaldehyde (207) by condensation with acetone, catalytic hydrogenation, Clemmensen reduction, and hydriodic acid demethylation in sequence. Bisphenol (204c) could be similarly prepared from 0-benzylisovanillin (164). Since such methodology is inapplicable to unsymmetrical substrates (eg., 204b) an alternative approach was sought. In addition Wolff-Kishner210 or Clemmensen211 reduction of bisphenol (204b) would subsequently give the bisphenol (204c). In the previous chapter it was shown that TosMIC can be used to homologate a C6C1 to a C6C2NC unit and was used in the preparation of the phenethylisocyanide (180) from veratraldehyde (171). Phenethylisonitriles, such as (180), however, besides reacting through the isocyano carbon should be able to stabilise a-carbanions, 142

Monoalkylation of TosMIC with primary halides proceeded in high yields under phase transfer reaction conditions (P.54 )• It was therefore expected that phenethylisonitriles, such as (180), should give alkylation products on treatment with appropriately substituted halides in the presence of a base Thus the preparation of the required bisphenolic substrates (204b and c) from the phenethylisocyanide (211) and the bromide (216) was examined. Both intermediates were prepared from 0-benzylisovanillin (164), easily accessible from isovanillin by standard procedure179. The phenethylisocyanide (211) was prepared by the same procedure (Scheme 20) as for the preparation of the veratrylethylisocyanide (180).

Ts TsCH2NC ArCH=C NHCHO (209)

Ts Ts / / ArCH2CH ArCH=C \ \ NC NC (211) (210) OCH2Ph Ar= OCH3

Scheme 20 143

Condensation of 0-benzylisovanillin with TosMIC gave the formamide (209) in 75% yield. Subsequent dehydration with phosphoryl chloride and triethylamine gave the vinyl isocyanide (210) in 90% yield. This was subsequently reduced in 75% yield to the phenethylisocyanide (211) with sodium borohydride. The isocyanide (211) was also prepared without purification of intermediates (209) and (210) in 52% overall yield. The intermediates (209) and (210) were obtained as single isomers (n.m.r.) and by analogy with intermediates (172) and (173) were assigned the E stereochemistry. A byproduct of the dehydration of the formamide (209) and subsequent sodium borohydride reduction of the vinyl isocyanide (210) was isolated and characterised as the styrene (212) by its spectral and microanalytical data This is thought to arise via the acetylenic sulphone (213) (Scheme 21). Carbonyl compounds have been condensed with ethyl bromoacetate and triphenylphosphine in the presence of oxiran212 to give a, (3-unsaturated esters in high yield. Condensation of 0-benzylisovanillin with ethyl bromoacetate and triphenylphosphine in the presence of methyl oxiran (propylene oxide) in dichloromethane solution at room temperature gave the expected a,13-unsaturated ester (214) in 82% yield. Ester (214) was assigned the-, trans-stereochemistry since the vinylic proton vicinal to the carbethoxy group was observed in the n.m.r.

144

Et3N:) ..... T H Ts Et N \---). / /s 3 .-c- C —C C=C / \ POC13 / Ar Ar NH=CHOPOC l2 NHCHO ..._ + - Cl _

CH—CH 2 Et OH Ar CTs NaBH4 (213)

OCH2Ph Ar C =C H2 OCH3 Ar (212)

Scheme 21

spectrum at g 6.36 with a coupling constant of 16 Hz. Reduction of cinnamic esters to hydrocinnamyl alcohols has been efficiently accomplished213 with lithium aluminium hydride in diethyl ether at room temperature. Thus reaction of the ester (214) with lithium aluminium hydride at room temperature in tetrahydrofuran and diethyl ether gave the saturated alcohol (215) in 75% yield. Subsequent treatment of this alcohol with phosphorus tribromide214 in diethyl ether and dichloromethane gave a low yield of the expected bromide (216). The major polar byproducts probably resulted from benzylic ether cleavage by hydrogen bromide. Reaction

4. 145

of the alcohol (215) with phosphorus tribromide in the presence of pyridine215 in toluene gave an improved yield (30%).

• C C H3 PhCH20 C C C C)2 1-12 CH30 (214) PhCH2O C1-430

HO (215): X= OH CH30 Br (216): X . Br (217): X . 00SCH (220): R = Br 3 (218): X = OnEt2 (221): R = H (219): X . I

Treatment of xanthate esters of alcohols with bromine in the presence of pyridine at room" temperature has been reported216 to give excellent yields of bromides. Using such methodology the xanthate ester (217) was prepared by standard procedure216 in 96% yield, and subsequently reacted with bromine in the hope of obtaining the bromide (216). Instead the tribromide (220) was obtained in excellent yield.

• 146

Structure assignment was in full agreement with spectral and microanalytical data The required bromination was accompanied by the benzylic ether cleavage with subsequent bromination of the intermediate phenol (221) at both the o- and 2-positions. It was thus confirmed that the benzyl group was not a suitable phenol protecting group in reaction with phosphorus tribromide with or without pyridine, or with bromine and pyridine. Xanthate esters, however, when treated with methyl iodide at 900c216 are reported to give excellent yields of the corresponding iodides. The xanthate (217) and methyl iodide under these reaction conditions gave the iodide (219) in 80% yield. An increase in the nucleo- philicity of the thiocarbonyl function should permit iodide formation at lower temperatures. Reaction of the xanthate ester (217) with diethylamine at room temperature gave a quantitative yield of the corresponding thiocarbamate (218), which was reacted in situ with methyl iodide at 40°C. The expected iodide (219) was obtained in 82% yield. The overall yield of the iodide (219), based on the 0-benzylisovanillin (164); was 4-8%. The condensation of the iodide (219) and isocyanide (211) was then investigated_ Crown ethers have been widely used217 recently in organic synthesis, especially in increasing the rate and yield of SK2 reactions. Prompted by these results it was decided to investigate the condensation of the isocyanide (211) and the iodide 147

(219) with potassium t-butoxide as the base, in the presence of a catalytic amount of 18-crown-6, known to complex the potassium cation. The reaction proceeded smoothly to give the expected alkylation product, the isocyanide (222), in excellent yield.

OR OCH3

(222) : R = CH2Ph, X = -NC, -Ts (223) : R = CH2Ph, X = -N=C=O, -Ts (224) : R = CH2Ph, X . NH (225) : R = CH2Ph, X . 0 (226) : R = CH2Ph, X = N-NHTs (227) : R = CH2Ph, X = H2

(228) : R = 0C0CH3' X = H2

Although the i.r. and n.m.r. spectra of the product were in full agreement with the structure (222), the compound neither could be induced to crystallise nor to give a molecular ion in the mass spectrometer. However it was characterised at the next step, as the ketone (225). Isonitriles have been hydrolysed in the presence of mercuric salts218, especially mercuric acetate or

148

nitrate, to give symmetrical ureas in high yields, presumably via the isocyanates. It was thus hoped that oxidation of the isocyanide (222) with mercuric nitrate would lead to the corresponding isocyanate (223), which on hydrolysis, carbon dioxide and toluene-4-sulphinic rt acid elimination, and hydolysis of the intermediate imine (224) would give the ketone (225) (Scheme 22).

_ + + ,0- H H - Ts -,.. N= L- Hg(NO3)2 Ts N- CAL-) CO c t, kc -- - \--1. (--1 // 3c- -/, H20 H g -0 -N (-_) (222) _ _

HNO3 Ts NH-C O-Hrl 2 H+30 [T ...----- s ,,--N=C= ,- 0 ),-C -TsH I-0O2 (223) NH

(224) (225)

Scheme 22 Reaction of the crude isocyanide (222) with mercuric nitrate in aqueous tetrahydrofuran at room temperature gave the expected ketone (225) in 68% yield, based on iodide (219). The toxicity of mercuric compounds 114-9

however prompted examination of alternative oxidants. Thus on reflux a solution of the crude isocyanide and peracetic acid in tetrahydrofuran gave the ketone (225) in comparable yield (70%). In the standard way the benzylic protecting groups were removed by hydrogenolysis with 10% palladium on charcoal in 77% yield to give the projected bisphenol (204b). Reduction of the ketone (225) to the diarylpentane (227) was found to be unexpectedly inefficient. The Huang-Minlon219 modification of the Wolff-Kishner reduction on ketone (225) gave the expected diarylpentane (227) in only 50% yield Similar yields were obtained when the ketone (225) was reduced via sodium cyanoborohydride reduction220 at high temperature (50%), or 1,3,2-benzodioxaborole (catecholborane) reduction221 at -10°0 and subsequent reflux in chloroform (5&4), of the toluene-4-sulphonylhydrazone (226). The hydrogenolysis of the diarylpentane (227) to the bisphenol (204c) required glacial acetic acid as solvent with a catalytic amount of 60% aqueous perchloric acid at room temperature to give the bisacetate (228) (i.r., n.m.r.) in 88% yield. This was readily saponified at room temperature to give the bisphenol (204c) in 60% yield based on the diarylpentane (227). The bisphenols (204b and c), prepared as above, were subsequently subjected to phenol oxidative coupling 150

reaction conditions with potassium hexacyanoferrate(III). Reaction of the bisphenol (204c) gave a 75% recovery of starting material. No other product was formed (t.l.c.). When the volume of the aqueous phase was doubled and the reaction was carried out for not more than 0,5 h, a complex reaction mixture was produced with a major product more polar than the starting material. Purification by repeated chromatography (p.l.c.) gave a product in 3.6% yield based on recovered starting material. The product was phenolic (i.r.) and had a highest peak in the mass spectrum at m/e 332, indicating simple oxidation of the bisphenol (204c) (m/e 316) and therefore was not examined further. The complexity of the reaction mixture and the difficulty which was experienced in purifying the material prevented further examination of the bisphenol (204c) oxidation. The bisphenol (204b), however, on phenol oxidative coupling gave a mixture of two main products in 16% combined yield, based on recovered starting material. This mixture was separated by repeated p.l.c. to give in very low yield the minor less polar compound, having the molecular ion m/e 328 in agreement with the expected biphenol (205b). The major, more polar compound was also obtained in low yield. The mass spectrum of this apparently homogeneous (t.l.c.) compound revealed it to be a mixture of two compounds having molecular ion peaks at m/e 3/0 and m/e 346. The next most significant peaks were at 151

m/e 328 (le of the expected product) and m/e 330 (M+ of starting material) indicating simple oxidation of product and starting material, The low yield of the desired product prompted a search for more efficient oxidation • conditions, Phenol oxidative coupling of the compound in the dark gave similar results as in daylight; no decrease in reaction rate or yields of products were observed, Careful degassing of the solvents used did not offer any advantage either, A decrease (one half) in the volume of the aqueous layer drastically decreased the yield of the required product, In fact only the byproducts could be isolated (8,4%), When no benzyltriethylammonium chloride was used the reaction was slower and the ratio of byproduct to biphenol (205b) was increased, The use of 18-crown-6 appeared to be advantageous since it led to a higher reaction rate and increased the amount of the biphenol (205b) formed relative to the byproducts, However increase of the scale of the reaction led to byproduct formation (12%) only, the biphenol (205b) being present in trace amounts, Cetyltriethyl- ammonium bromide was examined as an alternative phase transfer catalyst, Reaction over 1 h gave the best results, Further prolonged reaction drastically decreased the yield of biphenol (205b), Slight decrease in yield was also observed on increasing the scale of the reaction, Using cetyltriethylammonium bromide, biphenol (205b) was formed in 7-11% yield accompanied by the byproducts 152

(10-14%). It appears that the formation of the biphenol (205b) is favoured under conditions where efficient contact of substrate and oxidant is possible through effective mixing of the organic with the aqueous phase. The failure of the bisphenol (204c) to produce any isolable biphenol (205c) might be due to the lower solubility in water compared with bisphenol (204b). Introduction of the carbonyl functiOn in the side chain should lower the LAG of the intramolecular phenol coupling by removing unfavourable carbon to hydrogen bond interactions. The structure of the intramolecularly coupled product was assigned as (205b). In the aromatic region of the n.m.r. spectrum there appeared three sharp singlets at g 6.50 (1H), 6.72 (2H) and 6.90 (1H). A Dreiding molecular model of biphenol (205b) revealed that protons H1 and 1-14 are equivalent and are deshielded by the aromatic rings lying almost perpendicular each to the other and therefore H1 and H4 gave rise to the singlet at S 6.72. The same model did not allow unambiguously to determine whether proton H2 was in the deshielding or shielding zone of the carbonyl group. However proton H3 should resonate at lower .5 compared with H1 or le4 Therefore proton H3 gave rise to the singlet at cr 6.50 (J 6.58 for a model compound, the biphenol (235)) and proton H2 was assigned to the singlet at g 6.90. Biphenol (205b) gave a correct 153

microanalysis. The mixture of the byproducts of the reaction was examined by mass spectroscopy at a higher probe temperature. This revealed that, in addition to the oxidised monomers, dimers were also present (m/e 686, 658). This fraction was not examined further, The results described so far provide further evidence in support,of the mechanism of formation of erysodienone (Scheme 18), Further oxidation of the biphenol (205b) to the biphenonquinone (229) was thus examined,

(229)

2,3-Dichloro-516-dicyano-114-benzoquinone (DDQ) has been used in phenolic oxidative coupling to give biphenonquinones via the biphenol. Thus 216-dimethoxy- . phenol (230a) on oxidation with DDQ222 gave biphenonquinone (232a) (62%) and benzoquinone (231a) (13%),

1o, 154

(230) 0 C231)

(232)

a.R OCH 3 b. R = CH 3

Attempts to oxidise the biphenol (205b) with DDQ gave complex reaction mixtures. Since DDQ absorbs in the u.v, spectrum at about the same wavelength (410 nm) with that of the expected biphenonquinone, the intermediacy of any biphenonquinone formed could not be detected. Diphenylseleninic anhydride223 has been used to prepare quinonoid products from phenols. For example 216-dimethylphenol (230b) was oxidised223b to the biphenonquinone (232b) (40%) and the benzoqUinone (231b) (25%). Treatment of the biphenol (205b) with 2.5 equivalents of diphenylseleninic anhydride at room temperature gave a less polar coloured homogeneous product (t.l.c.) and diphenyl diselenide. This product being unstable could not be purified by chromatography either on silica 'or alumina. However most of the diphenyl 155

diselenide could be removed by repeated leaching with hexane although this was accompanied by partial decomposition of the product (t.l.c.). The u.v. spectrum (Xmax 376 nm; cmax 1000) excluded the possibility of being the expected biphenonquinone. The spectral data did not allow structural assignment of this compound, although the 100 MHz n.m.r, spectrum showed only one aromatic methoxy function. Since diphenylseleninic anhydride has been used to oxidise phenols to the corresponding 0-quinones223a it was suspected that a similar reaction was operating. Thus before definite structural assignment could be made, model studies were carried out. The biphenol224 (233), prepared by zinc in acetic acid225 reduction of the biphenonquinone (232b), was oxidised with diphenylseleninic anhydride to give biphenonquinone (232b) and diphenyl diselenide. No other product could be detected (t.lc., u.v.).

0 0 II II Ph Se0SePh HO (232b) Z n/C H3CO2H

(233) 156

The effects of a methoxyl group ortho to the phenolic function and of substituents ortho to the biphenyl bridge on the diphenylseleninic anhydride oxidation were also examined. Biphenol (235) has been prepared via phenol (234) from isovanillin by Clemmensen reduction and subsequent benzoyl peroxide oxidation226.

0 HO H 0 CH3 H21 Pd-C FeC13 ., CH3O CH30 (234) CH30 H 3C

HO OH

CH3 OCH 3 (235)

For the purpose of the present investigation phenol (234) was prepared by the catalytic hydrogenation of isovanillin in 63% yield. Subsequent phenol oxidative coupling with iron(III) chloride227 gave the biphenol (235) in 20% yield. Biphenol (235) had the expected n.m.r, spectrum, with singlets for the aryl methyl and methoxy groups (S 1.95 and 3.81) and two singlets in the aromatic region ( 6.58 and 6.78). The protons ortho to the biphenyl linkage were at lower field (dj 6.78) than those ortho to the hydroxy groups (cf 6.58). 157

Oxidation of biphenol (235) with 1.4 equivalents of diphenylseleninic anhydride gave a similar reaction mixture (t.l.c.„ u.v.) to that which was observed from biphenol (205b). Most of the byproduct diphenyl diselenide

• was removed by repeated leaching with hexane. The i.r, spectrum of the almost pure colourless product was almost identical in the carbonyl region (1660 cm 1) to that of the oxidation product of biphenol (205b). The n.m.r, spectrum of the product was considerably different from that of the starting material. There were two methyl signals (or 1 .90 and 2.18), one methoxy singlet (3.90), one broad phenolic OH singlet (Cc 5.80) and four vinyl and aromatic singlets (cr 6.26, 6.40, 6.64 and 6.88). The n.m.r, spectrum was in excellent agreement with the o-quinone (236). 4 H2 H3C. H OC H3

cH3 H (236)

The doublet at S 1.90 was therefore assigned to the vinylic methyl group coupled (J 1.5 Hz) to the proton H2 at JJ 6.40 and the proton resonating at Sj 6.26 assigned to H1 The mass spectrum of the product showed a molecular ion at m/e 260 in accordance with the well established228 tendency of o-benzoquinones to give intense M+2 peaks even if admitted to the source of the mass spectrometer by direct insertion. The o-quinone (236) was trapped with o-phenylenediamine to give the expected substituted phenazine (237).

CH3 OH

HO OH

CH30 (237) 1-13C

(238)

Sodium borohydride reduction of the crude o-quinone (236) in tetrahydrofuran and ethanol at room temperature gave as the major and minor products respectively the biphenol (238) and an addition product of phenyl selenol and the o-quinone (236) (m/e 416). Presumably the phenyl selenide anion produced from borohydride and diphenyl diselenide was trapped by the o-quinone (236). Phenazine (237) and biphenol (238) could not be obtained analytically pure but gave the required spectral and accurate mass data These model studies therefore showed that diphenylseleninic anhydride preferentially gave o-quinone by oxidative cleavage of the o-methoxy group (Scheme 23). 159

OCH3 0CH3 0 OH 0 it --- SePh (235) (),

H3C

0 (-PH O 0 (236) Ph

Scheme 23

The mode of action of diphenylseleninic anhydride is therefore similar to that of sodium periodate and potassium bismuthate229 In contrast lead tetraacetate and potassium nitrosodisulphonate (Fremy's salt) lead to high yields of 2-benzoquinones on oxidation229 of substituted guaiacols. These model studies permitted the interpretation of the spectral data of the oxidation product of biphenol (205b). The i.r, and u.v, spectra were similar in both cases with the only exception being the side chain 160

carbonyl absorption in the product from biphenol (205b). The presence of diphenyl diselenide (m/e 314) complicated the mass spectrum. The 100 MHz n.m.r. spectrum of the product from biphenol (205b) differentiated between the two possible isomeric o-quinonoid structures (239) and (240).

OH HO

H1 H4 OCH3 CH3O (239) (240)

Partial n.m.r, spectral data of biphenol (205b),

o-quinone (236) and o-quinone (239) (0. ppm)

1 2 Proton H H H3 H4 H15 , H25 biphenol (205b) 6.72 6.90 6.50 6.72. 3.19 and 3.40 J/Av = 0.7

o-quinone (236) 6.26 6.40 6.64 6.88

o-quinone (239) 6.34 6_48 6.48 6.78 3.14 and 3.28 Jim) = 2.8 161

The H5 and H25 proton signals in the n.m.r. spectrum of the product resonated at § 3.14 and 3.28 (J/Av = 2.8). The same protons in the n m.r, spectrum of the starting material, biphenol (205b), were at C; 3.19 and 3.40 (J/Av = 0.7). This suggested that the most probable structure for the oxidation product was isomer (239) The three singlets at S 6.34 (1H), 6.48 (2H) and 6.78 (1H) were assigned to protons H11 H2 and H3, and H4 respectively, from a consideration of the n.m.r, spectra of biphenol (205b) and the model o-quinone (236). The trapping of o-quinone (239) with o-phenylenediamine proved to be not as simple as in the model system. Although one equivalent of o-phenylenediamine was used in the trapping experiment the major product was contamin- ated with another byproduct, possibly the phenazine (241) (i.r. 1625 cm 1) and unreacted o-phenylenediamine (i.r., n.m.r.). All three compounds had the same Rf values on silica. The n.m.r. spectrum of the above mixture indicated the major product to be possibly the expected phenazine (242). Treatment of the mixture with excess butane-2,3- dione and subsequent chromatography gave the major product, free of the byproduct and o-phenylenediamine. Although the mass spectrum further suggested formulation of this product as the phenazine (242) (m/e 384), the compound could not be obtained crystalline nor analytically pure and was not characterised further, 162

(al) X = N H2N

(242) X=0

The formation of o-quinone (236) in the model series is a novel reaction of diphenylseleninic anhydride. The intermediacy of biphenonquinone (200) in the oxidation of bisphenol (202) to the erysodienone (201) although not conclusively demonstrated with the above results still remains an attractive possibility. 163

4 .2 EXPERIMENTAL

General directions are as for Chapter 3.2. High resolution mass spectra were recorded with a A.E.I. MS 9 high resolution spectrometer. 0-Benzylisovanillin_ 179 (164) and 1,312-benzodioxa- borole232 (catecholborane) were prepared according to standard procedures.

Preparation of 1-(3-benzyloxy-4-methoxybenzy1)-2-formyl-, amino-2-(toluene-4-sulphonyl)ethylene (209) Potassium t-butoxide (15.2 g) was dissolved in dry tetrahydrofuran (260 ml) and cooled to 7°C, under argon when a solution of TosMIC (5.4 g) in dry tetrahydrofuran (26 ml) was added, over 3 m, with efficient stirring. The resulting mixture was immediately cooled to -20°C and a solution of 0-benzylvanillin (6.58 g) in dry tetrahydrofuran (28 ml) was added. The reaction mixture was then quenched with glacial acetic acid (7.8 ml) and allowed to warm up to room temperature. Solvent was evaporated under reduced pressure, below 25°C, water added to the gummy residue and extracted with dichloromethane. Drying, evaporation and filtration on silica (eluant 2% methanol in dichloromethane) gave crude (209) (10.5 g; 90%) as a foam after evaporation of the solvent. Crystallisation from acetone/hexane gave the ethylene 164

derivative (209) (8.75 g; 75% yield) as white needles, m.P. 188-9°C, vmax 3260, 1695, 1630, 1310 and 1140 cm 11

Amax 208 (emax 34500), 234 (25500), 294 (18700) and 321 (23800) nm, 64 2.40 (3H, s, ArCH3), 3.88 (3H, s, ArOCH3), 5.12 (2H, s, PhCH20) and 6.70-8.00 complex (15H, aromatics + ArCH. + -NHOH)9 (Found: C, 65.65; H, 5.20; N, 3.16; S, 7.411. 022H23NS05 requires C, 65.88; H, 5.30; N, 3.20; S, 7.33%).

Preparation of 1-(3-benzyloxy-4-methoxypheny1)-2-iso- cano-2-toluene-4-s hlene21C) The ethylene derivative (209) (4.43 g) was dissolved in anhydrous triethylamine (28 ml) and dry dichloromethane (45 ml) and the resulting solution was cooled to -30°C, when phosphoryl chloride (1.7 ml) was added, under nitrogen, with vigorous stirring, in ca. 45 in The reaction mixture was subsequently left to reach the room temperature slowly, and was stirred overnight. Similar work up for the isocyanide (173) gave pure isocyanide (210) (3.82 g; 90% yield), which was used without further purification in the next step. An analytical sample was prepared as white needles (from benzene/light petroleum), m.p. 124-5°01 vmax 2110,

1615, 1330 and 1150 cm 1, Amax 202 (cmax 19600), 248 (13300), 320 (10700) and 345 (18200) nm, 8> 2.47 (3H, s, ArCH3), 3.97 (3H, s, ArOCH3), 5,20 (2H, s, PhCH2O), 6,90-8,00 complex (13H, aromatics + Ar0H.) (Found: 165

C, 68.85; H, 4.77; N, 3.32. C24H21N04S requires C, 68.71; H, 5.05; N, 3.34%).

Preparation of 1-isocyano-1-(toluene-4-sulphony1)-2- -(3-benzylox77-4-methoxyphenyl)ethane (211) Isocyanide (210) (3.82 g) in dry tetrahydrofuran (55 ml) was added, at room temperature, to a suspension of sodium borohydride (1.2 g) in absolute ethanol (55 ml), with stirring, under nitrogen. The resulting mixture was slowly warmed up to 40°C and it was subsequently worked up, as for isocyanide (180), to give the crude product (3.71 g; 97%). Recrystallisation from benzene/light petroleum gave the isocyanide (211) (2.8 g; 75%), as prisms, m.p. 137-8°C, vmax 2160, 1335 and 1140 cm 1.,

Xmax 208 (cmax 21000), 227 (16100) and 274 (2410) nm, 64 2.50 (3H, s, ArCH3), 2.65-3.60 (2H, m, ArCH2), 3.86 (3H, s, ArOCH3), 4.50 (1H, dd, Ji 3 Hz, J2 8 Hz, methine), 5.14 (2H, s, FhCH20), 6.80 b (3H, s, ArH), 7.38 b (5H, s, PhH), 7.40 and 7.90 (4H, 2 d, J 10 Hz, SO2PhH), m/e 421 (M+), 382, 164, 132 and 91 (100%) (Found: C, 68.50; H, 5.57; N, 3.45; S, 7.38. C241123N04S requires C, 68.31; H, 5.50; N, 3.32; S, 7.61%). Isocyanide (211) was also prepared from 0-benzylisovanillin via compounds (209) and (210) without purification in 52% recrystallised overall yield (51% . with purification of the intermediates). The byproduct (212) of the above transformations 166

was obtained as crystals, m.p. 63-5°C (from hexane) man 1625 (weak), 1240, 1140 and 1005 cm11 `max (cyclohexane) 218 (cmax 17300), 259 (10400), 266 sh (9900) and 285 sh (3300) nm, S 3.84 (3H, s, ArOCH3), 5.10 (2H, s, PhCH20), 5.07 (IH, dd, J1 1 Hz, J2 9 Hz, =CH), 5.47 (1H, dd, Ji 1 Hz, J2 17 Hz, .CH), 6.57 (IH, dd, I/ 9 Hz, J2 17 Hz, CH.), 6.80-7.06 complex (3H, ArH) and 7.10- -7.60 complex (5H, PhH), m/e 240 (M+), 149, 91 (100%) (Found: C, 80,16; H, 6.73. C101602 requires C, 79.97; H, 6.71%).

Preparation of 1-carbethoxy-2-(3-benzyloxy-4-methoxypheny1)- ethylene (214) _O-Benzylisovanillin (9.7 g; 40 mmoles), triphenylphosphine (10.5 g; 40 mmoles) and propylene oxide (5.6 ml; 80 mmoles) were dissolved, at room temperature, in dry dichloromethane (12 m1). The resulting solution was ice cooled and ethyl bromoacetate (4.5 ml; 40 mmoles) added slowly. The reaction mixture was left to stand at room temperature for 5 days and volatile materials were removed with water aspirator and high vacuum (0.5 mmHg, room temperature) and the solidified residue was chromatographed on silica (eluant benzene) to give a quantitative yield of the crude product. Recrystallisation from diethyl ether gave the ethylene derivative (214) as white needles (10.2 g; 82%), m.p. 96-97,5°C, vmax 1705 -1 urax and 1635 cm `max 207 (E 13000), 237 (11600), 295 167

(12600) and 322 (15000) nm, 6 1.20-1.40 (3H, t, J 6 Hz,

0CH2 CH3 ) 9 3,94• (3H s, 0CH 3 ) 4• 10-4 .40 (2H, q, J 6 Hz,

001120H3)5 5.20 (2H 5 s, PhOH2O), 6.36 (1111 d, J 16 Hz, .CH(CO2Et)) and 6.80-7.78 complex (9H, ArH + PhH + ArCH,), m/e 312 (14+), 277, 238, 224 and 91 (100%) (Found: C, 73.25;

H, 6.40. C19H2004 requires C, 73.05; H, 6.45%).

Preparation of 3-(3-benzyloxy-4-methox7pheny1)-propan- -1-ol (215) The unsaturated ester (214) (7.5 g; 24 moles) in dry tetrahydrofuran (55 ml) was added to a suspension of lithium aluminium hydride (5.3 g; 120 mmoles) in dry diethyl ether (80 ml), at room temperature, over a period of 75 min. 24 h later excess hydride was destroyed with a saturated aqueous solution of sodium sulphate, at 0°C and the precipitate was filtered off and washed with hot tetrahydrofuran. Evaporation of the solvents and crystallisation from methanol/water gave alcohol (215) (4.9 g; 75%) as white needles, m.p. 98-100° C, vmax 3500 (br) cm-1, Xmax 208 (£max 13200), -225 sh (5400) and 278 (1800) nm, 1.60-2.10 (3111. m, RCH2R1 + + OH), 2.40-2.70 (2H, A2B2 m, ArCH2), 3.4073.70 (2H, t, J 6 Hz, CH2OH), 3.85 (3H, s, 00113), 5.14 (2H, s, PhCH20), 6.60-7.00 br (3H, ArH) and 7.20-7.60 br (5H, PhH), m/e 272 (le), 181, 149, 137 and 91 (100%) (Found: C, 75.08; H, 7.32. C17H2003 requires C, 74.97; H, 7.40%). 168

Preparation of 3-0713-benzlo-4 yk-. ,S-methyl dithiocarbonate (217) Sodium hydride (1 g; 42 mmoles), imidazole (0.15 g; 2,2 mmoles), the alcohol (215) (5.7 g; 21 moles) and dry tetrahydrofuran (130 ml) were heated to reflux for 6 hl under nitrogen, cooled to room temperature and carbon disulphide (11.4 ml; 190 mmoles) added slowly, with stirring. The resulting mixture was heated to reflux for 0.5 h and after cooling to room temperature methyl iodide (6.9 ml; 110 moles) added and the solution was heated to reflux for an additional 0,5 h. After cooling to room temperature glacial acetic acid (4.2 ml) was added and the solvent evaporated. Water was added and the mixture extracted with diethyl ether. The ether phase was washed with aqueous saturated sodium bicarbonate and water, dried, evaporated and chromatographed on a short silica column (eluent benzene) to give xanthate (217) (7.3 g; 96%) after removing the solvent. The xanthate _(217) was used without further purification. An analytical sample recrystallised from diethyl ether/ methanol was obtained as white prisms, m.p. 59-60°C, vmax 1220, 1240 and 1055 cm-1, Xmax 277 (Emax 11800), 225 sh (12800) and 211 (13900) nml 1.80-2.27 (2H, m, RCH2R1), 2,55 (3H, s, SMe), 2,55-2,80 (2H1 m, ArCH2), 3.84 (3H, a, ArOMe), 4.44-4.68 (2H, t, J 6 Hz, CH200(=S)SMe) 6.64-685 (3H, m, ArH) and 7.20-7.50 b (5H, s, PhH), m/e 362 (M+), 329, 315, 254, 227, 164, 135 and 91 (100%) 169

(Found: C, 63.01; H, 6.06; S, 17.63. 03S2 requires C, 62.95; H, 6.12; S, 17.69%).

Preparation of 1-(3-benzyloxy-4-methoxypheny1)-3-bromopropane (216) Phosphorus tribromide (0.07 ml; 0.72 mmoles) was dissolved in dry toluene (2 ml) and dry pyridine (0.030 ml) added in ca. 15 m, at room temperature with stirring. The mixture was subsequently cooled to -100 C and a solution of the alcohol (215) (0.54 g; 2 moles) and dry pyridine (0.010 ml; altogether 0.5 mmoles) in dry toluene and dry dichloromethane (5 ml; 3:2) was added slowly, with stirring, over a period of 4 h. Stirring at that temperature was continued for an additional hour and the reaction mixture left to reach the room temperature. During 2 days additional pyridine (0.08 ml) and phosphorus tribromide (0.05 ml) were added in two potions, the excess reagent was destroyed by the addition of methanol (0.5 ml), at -10°C, the dichloromethane was evaporated and the reaction mixture partitioned between toluene and water. The organic layer was washed with aqueous saturated sodium bicarbonate and water, dried, evaporated and chromatographed on silica (eluent benzene) to give the crystalline bromide (216) (0.20 g; 30%). An analytical sample prepared by recrystallisation from ethanol was obtained -1 1 as prisms, m.p. 62-3°C, max 1230, 1150 and 1010 cm 16700), 226 sh (6406) and 279 (2000) nm, X max 207 (E max 170

G 1.80-2.30 (2H, m, RCH2R1), 2.45-2.80 (2H, t, J 6 Hz, ArCH2), 3.10-3.45 (2H, t, J 6 Hz, -CH2Br), 3.85 (3H, s, ArOCH3), 5.10 (2H, s, PhCH20Ar), 6.60-6.90 b.: (3H, s, ArH) and 7.10-7.50 (5H, m, PhH), m/e 334 and 336 (le), 243 and 245 and 91 (100%) (Found: C, 60.81; H, 5.82. H, C17-H19 BrO2 requires C, 60.90; 5.71%).

Preparation of 1-(2,6-dibromo-5-hydroxy-4-methoxypheny1)- -3-bromopropane (220) Xanthate (217) (0.28 g; 0.78 mmoles) was dissolved in dichloromethane (3 ml), pyridine (6 41; 0.08 mmoles) added and the solution was cooled to 0°C. Bromine (0.16 ml; 3.12 moles) in dichloromethane (3 ml) was added over 0.5 h.The mixture was left to reach room temperature, at which it was left to stand for 2 h. After dilution with dichloromethane, the solution was washed with aqueous saturated sodium thiosulphate, sodium bicarbonate and water, dried, evaporated and chromatographed on silica (eluent benzene) to give a quantitative yield of the crystalline bromide (220). An analytical sample prepared by recrystallisation from diethyl ether/light petroleum was obtained as white needles, m.p. 97-8°C, vmax 3400 cm-1, Si 1.90-2.30 (2H, m, RCH2R1), 2 .95-3 .20 (2H, m, ArCH2), 3.40-3.65 (2H, t, J 6 Hz, -CH2Br), 3.90 (3H, s, Ar0CH3), 6.00 (1H, s, ArOH) and 7.07 (1H, s, ArH), m/e 403 and 405 (11+) and 295 (100%) (Found: C, 29.89;

II, 3.01. C10H11Br302 requires C, 29.80; H, 2.75%). 171

Preparation of 1-(3-benzyloxy-4-methoxypheny1)-3-iodo- propane (219) (a)Sealed tube method Xanthate (217) (2.72 g; 7.5 mmoles) was dissolved in methyl iodide (30 ml) and heated, at 85-90°C, in a sealed tube, for 40 h. The solution was diluted with dichloromethane, washed with aqueous saturated sodium thiosulphate and water, dried (MgS°4) and evaporated to afford an oil. Trituration with methanol and recrystallisation from ethanol gave the iodide (219) (2.3 g; 80%).

(b)Via the thiocarbamate (218) Xanthate (217) (8.2 g; 22.6 mmoles) was dissolved in diethylamine (60 ml) and left to stand at room temperature for 5 h, when formation of the thiocarbamate (218) was complete (t.l.c.). The diethylamine was evaporated and the residual oil was dissolved in methyl iodide (80 ml). The solution was refluxed for 15 h. The solvent and byproducts were removed under reduced pressure (80°C/104 mmHg), and the residue was dissolved in dichloromethane, washed with water, dried, evaporated and recrystallised from ethanol to give the iodide (219) (6.3 g). The mother liquor was evaporated and residual volatile byproducts were further evaporated (80°C/10-4mmHg). Crystallisation of the oily residue gave an additional quantity of iodide (219) (0.4 g; 82% in total). An analytical sample prepared by further recrystallisation from ethanol was obtained as colourless plates, m.p. 55°C, 172

vmax 1230, 1140 and 1010 cm 1 1 Amax 209 ("max 2000Q), 226 sh (8500) and 278 (3000) nm, g 1.80-2.24 (2H, m, RCH2R1), 2.40-2.47 (2H, m„ArCH2), 2.96-3.20 (2H, t, J 7 Hz, -CH2I), 3.84, (3H, s, ArOCH3), 5.15 (2H, s, FhCH2O), 6.65-6.95 (3H, m, ArH) and 7.20-7.60 b. (5H, s, FhH), m/e 382 (le), 291, 136, 107 and 9.1 (1001) (Found: C, 53.33; H, 5.22. C17H16102 requires C, 53.41; H, 5.01%).

Preparation of 1,5-bis(3-benzyloxy-4-methoxypheny1)-2- -isocyano-2-(toluene-4-sulphonyl)pentane (222) Potassium t-butoxide (1.74 g; 15.53 moles) and 18-crown-6 (0.33 g;_1.25 moles) in dry tetrahydrofuran (20 ml) was cooled to -10° C and a solution of the isonitrile (211) (5 g; 11.88 mmoles) in iiry tetrahydrofuran (25 ml) added over 3 m, under argon, with vigorous stirring. The solution. of the iodide (219) (4.1 g; 10.73 mmoles) in dry tetrahydrofuran (10 ml) was subsequently added and the reaction mixture left to warm up slowly to room temperature. Excess base was destroyed with dry ice, the tetrahydrofuran evaporated off at room temperature, water added and the solution extracted with dichloromethane. The organic layer was washed with water, dried and evaporated to give a quantitative yield of the crude pentane derivative (222), which was used in the next experiment without purification, v max (CHC1 ) 2120, 1320 and 1130 cm-11 6' 1 .20-2.05 (4H, 3 173

m,R(CH2)2R1),2.20-2.56 (2H, m, ArCH2), 2.46 (3H, s, ArCH3), 3.10 b (2H, s, ArCH2C(NC)(Ts)), 3.90 (6H, s, ArOCH3), 5.10 (4H, s, PhCH20), 6.54-O 84 (6H, m, ArH) and 7.20- -7.95 (1411, m, PhH and S02ArH).

Pre•aration of 1 -bis -bent lo -4-metho hen 1 -.entan- -2-one (221 Method A Crude isocyanide (222) (1 g; 1.48 moles) was dissolved in tetrahydrofuran (7.5 ml) and water (0.6 ml) and mercuric nitrate (0.58 g; 1.85 mmoles) added with vigorous stirring, in one portion, at room temperature. 7 h later tetrahydrofuran was removed by evaporation, benzene added and the mixture was filtered through an alumina column (eluent benzene/ethyl.acetate :10/1). Evaporation of the solvents gave the crystalline ketone (225) (0.46 g; 68% yield on iodide (219)).

Method B Crude isocyanide (222) (2 g; 2,96 mmoles) was dissolved in tetrahydrofuran (15 ml) and a solution of peracetic acid (1 ml; 8.4 mmoles) added at room temperature. The solution was subsequently heated to reflux for 20 h. After cooling excess saturated aqueous potassium iodide was added with stirring, followed by an excess of saturated aqueous sodium thiosulphate. After dilution with water, the mixture was extracted with diethyl ether. 174.

The organic phase was washed with water, dried, evaporated and chromatographed (as in method A) to give ketone (225) (1 ,16 g; 85%), Recrystallisation from acetone/hexane gave pure ketone (225) (1 g; 70% on iodide (219)) as prisms, m,p, 84-6°C, VIII 1710 cm 1 1 Xmax 208 (cm 45000), 225 sh (16600) and 280 (5600) nm, CSS 1.60-2,00 (2H, m, RCH2R1), 2,18-2,50 (4H, m, C(.0)CH2R and ArCH2-), 3,50 (2H, s, ArCH2C(=0)), 3.88 (6H, s, ArOCH3), 6,68-7,50 (6H, m, ArH) and 7,30-7,50 b (10H, s, PhH), m/e 510 (M+), 419, 227, 193, 137 and 91 (100%) (Found: C, 77.37; H, 6.70. 0 H 0 requires C, 77,62; H, 6,71%), 33 34 5

Preparation of 1 1 5-bis(3-benzyloxy-4-methoxypheny1)- pentane (227) Method A Potassium hydroxide (1,23 g; 22 moles) and hydrazine hydrate (2,25 ml; 45 moles) in 2-hydroxyethyl ether (7,25 ml) were heated to 155°C, under nitrogen, until all the hydroxide was dissolved. The solution was cooled and ketone (225) (0,37 g; 0,725 moles) added in one portion, The mixture was kept at 155° C for an additional 12 h and excess hydrazine and water were distilled off with simultaneous increase in the temperature of the bath until the vapour temperature was raised to 200°C. The solution was kept at that temperature for 30 min and cooled to room temperature, Dichloromethane was added and the solution was washed several times with brine, 175

dried, evaporated and chromatographed on alumina (eluent benzene) to give the crystalline pentane derivative (227) (0.17 g; 50%).

Method B Ketone (225) (60 mg; 1.17x10-4 M) and toluene-4- vol sulphonylhydrazine (34.5 mg; 1.85x10 4 M) were heated to reflux in methano.l (2 ml) for 3 h, when the formation of the toluene-4-sulphonylhydrazone (226) was complete (t.l.c.). The solvent was removed by evaporation and a mixture of dimethylformamide/sulpholane (0.6 ml; 1:1) and toluene-4-sulphonic acid monohydrate (3 mg; 1.6x10-5 M) were added. The solution was heated to 105°C, under nitrogen, when sodium cyanoborohydride (30 mg; 4.77x10 4 M) was added in one portion. The mixture was left at 105° C for 1 h , cooled to room temperature, diluted with water, extracted with diethyl ether, washed with water, dried, evaporated and chromatographed (as in method A) to give crystalline (227) (30 mg; 50%).

Method C Ketone (225) (0.5 g; 0.98 moles) and toluene-4- sulphonylhydrazine (0.38 g; 2 moles) were heated to reflux for 2 h in methanol (15 ml). Methanol was removed under reduced pressure and the residue was dried overnight at room temperature over phosphorus pentoxide (1 mmHg pressure). The residue was dissolved in dry chloroform (2 ml), cooled to -10°C, and catecholborane (0.28 ml; 176

2.6 mmoles) added with vigorous stirring, under nitrogen. Stirring was continued for 20 min and sodium acetate tri- hydrate (0.8 g; 5.88 mmoles) subsequently added. The resulting viscous mixture was left to reach the room temperature and subsequently heated to reflux for 1 h. After cooling to room temperature, chloroform was added and the mixture washed with water, dried, evaporated and chromatographed on silica (eluent benzene) to give crystalline (227) (0.35 g; 70%). Crystallisation from ethanol gave pure (227) (0.28 g; 56%). An analytical sample prepared by recrystallisation from diethyl ether/ light petroleum was obtained as needles, m.p. 79-80°C, -1 max 1240, 1140 and 1010 cm , X max (cyclohexane) 207 (emax 30600), 225 sh (10300) and 278 (3200) nm, 5 1.0°- 1.90 (6H, m, -(CH2)3-)1 2.20-2.70 (4H, m, ArCH2), 3_85 (6H, s, ArOCH3), 5.10 (4H, s, MCH20), 6.60-6.80 (6H, m, ArH) and 7.10-7.60 (10H, m, PhH), m/e 496 (M+), 405, 227,

137 and 91 (100%) (Found: C, 79.75; H, 7.26. c33H3604 requires C, 79.80; H, 7.31%).

(-1-roeno tanederi--a-aLLY-21222/-22E2Eara- 1,5-bis(3-acetoxy-4-methoxypheny1)-pentane (228). Hydrolysis of pentane derivative (228). Preparation of 1,5-bis(3- -hydroxy-4-methoxypheny1)-pentane (2040 Pentane derivative (227) (132 mg; 26.6x10-5 M) was hydrogenolysed with palladium on charcoal (10%) (25 mg) in glacial acetic acid (5 ml) containing a catalytic 177

amount of 60% perchloric acid, at room temperature, under 1 Atm pressure of hydrogen, for 4 h. The solution was concentrated, poured into iced water and extracted with chloroform. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated to give the bisacetate (228) as a yellow oil

(90 mg; 88% yield), "max (CHC13) 1750 cm-1 1 6 1.10-1.90 (6H, m, -(CH2)3-)1 2.24 (6H, s, CH3CO2-), 2.20-2.70 (4H, m, ArCH2-)1 3.80 (6H, s, ArOCH3) and 6.70-7.00 (6H, m, ArH). The bisacetate (228) (90 mg; 2.25x10-4 M) was dissolved in methanol (1 ml) and potassium hydroxide pellets (0.11 g; 2x10 3 M) added, at room temperature, under nitrogen. After 2 h the solution was cooled in ice, acidified with 2 N aqueous hydrochloric acid, diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and water, dried, evaporated and chromatographed on silica (eluent benzene/ethyl acetate : 10/1) to give after evaporation of the solvents crystalline crude bisphenol (204c) (70 mg; 83% based on pentane derivative (227)). Recrystallisation from methanol/water gave pure bisphenol (204c) (50 mg; 60%). An analytical sample prepared by recrystallisation from a small volume of chloroform was obtained as needles, m.p. 125-70 C, , X (EtOH) 207 (ems 11600), vmax (CHC13) 3540 cm 1' max m 220 (7700) and 281 (3600) nm, ax (EtOH/KOH) 211 (33000), Xm 243 (9300) and 294 (4900) nm,(5j1.20-1.90 (6H, m, -CH2-)1 178

2.30-2.70 (4111 ml ArCH2), 3.85 (6H, m, ArOCH3), 5.60 b (2H, s, OH) and 6.60-8.85 (6H, m, ArH), m/e 316 (M+), 137 (100%) and 122 (Found: C, 72.03; HI 7.47. 019H2404 requires C, 72.12; H, 7.65%).

Phenol oxidative coupling of (204c) Bisphenol (204c) (100 mg; 0,32 mmoles) in chloroform (157 ml) was added, under nitrogen, to a rapidly stirred solution of potassium hexacyanoferrate(III) (1.24 g; 3.77 moles), sodium hydrogen carbonate (1.60 g; 19 moles), and benzyltriethylammonium chloride (31 mg; 0.135 mmoles) in water (30 ml). After 0.5 h the phases were separated and the aqueous layer extracted several times with chloroform. The combined organic layers were dried, evaporated and the residue was separated by p.l.c. on silica (developing solvent benzene/ethyl acetate : 19/1) to give the crude major product of the reaction (8.4 mg; 15% based on recovered starting material). Repeated p.l.c, on silica (developing solvent acetone/1,2-dichloroethane : 3/50) gave a purified sample (2 mg; 3.6%), vmax (CHC13) 3515 cm 1 , m/e 332 (le), 316, 153 and 137 (100%). 179

Hydrogenolysis of ketone (225). Preparation of 1,5-bis- (3-hydroxy-4-methoxypheny1)-pentan-2-one (204b) Ketone (225) (2 g; 3,9 mmoles) was dissolved in ethyl acetate (40 ml) and hydrogenolysed, at room temperature and 1 Atm hydrogen pressure, in the presence of palladium on charcoal (10%) (0.48 g), for 2 days. Filtration to remove the catalyst, evaporation of the solvent and recrystallisation of the residue from acetone/ hexane gave bisphenol (204b) (1.00 g; 77%) as rosettes 1 of needles, m.p. 124-6°C, m. ax 3400 and 1710 cm , X max 210 (Emax 20000), 225 Lan. (14000) and 281 (7100) nm, kmax (EtOH/KOH) 216 (Eurax > 25000), 239 sh (14000) and 296 (7900) nm, 64 1.65-2.05 (2H, m, alkyl methylene), 2,20- -2,75 (4H, m, ArCH2 -C(.0)CH2-), 3.55 b (2H, s, ArCH2C(.0)), 3.85 (6H, two very close singlets, ArOCH3), 4.80-5.40 b (2H, OH) and 6.70 (611, m, ArH), m/e 330 (11+), 193 (100%) and 137 (Found: C, 69.10; HI 6.71. C19H2205 requires C, 69.07; H, 6.71%).

Phenol oxidative coupling of bisphenol (204b)_ Preparation of 6,7„819-tetrahydro-3,11-dihydroxy-2,12-dimethoxy-5H- -dibenz[f h]cyclononen-6-one (205b) Method A Bisphenol (204b) (100 mg; 3.03x10-4 M) in chloroform (160 ml) was added with vigorous stirring, under nitrogen, to a solution of potassiumhexacyanoferrate(III) (0,62 g; 1.88 moles), sodium hydrogen carbonate (0,8 g; 9,5 mmoles) and benzyltriethylammonium chloride (15 mg; 6.5x10-5 M) 180

in water (15 ml) After 0.5 h usual work up and on silica (developing solvent light petroleum/ethyl acetate : 40/60) gave only byproducts (5.2 mg; 8.4% on recovered starting material).

Method B Bisphenol (204b) (100 mg; 3.03x10-4 M) in chloroform (160 ml) was added, under nitrogen, to a rapidly stirred solution of potassium hexacyanoferrate(III) (0.62 g; 1.88 mmoles), sodium hydrogen carbonate (0.8 g; 9.5 mmoles) and 18-crown-6 (8 mg; 3.03x105 M) in water (40 ml). After 0.5h usual work up gave byproducts (7 mg; 12% based on recovered starting material) and only traces of biphenol (205b).

Method C Bisphenol (204b) (100 mg; 3.03x10-4 M) in chloroform (160 ml) was added, under nitrogen, to a rapidly stirred mixture of potassium hexacyanoferrate(III) (0.62 g; 1.88 moles), sodium hydrogen carbonate (0.8 g; 9.5 mmoles) and cetyltriethylammonium bromide (24 mg; 6x105 M) in water (15 ml). After 1 h usual work up and p.l.c..gave pure biphenol (205b)(Rf 0.39, developing solvent light petroleum/ethyl acetate : 40/60) (7.3 mg; 10% on recovered starting material (RI. = 0.57)) and byproducts (RI, = 0.28) (yield not reported). On larger scale reactions (300-600 mg) of substrate, 11-7% yields of biphenol (205b) and 14-10% yields.of the byproducts were obtained. yields. are 181

calculated allowing for recovered starting material. An analytical sample of biphenol (205b) was prepared by crystallisation from benzene/light petroleum, m.p. 171-4°C, ymax (CHC13) 3530 and 1690 cm-11 Xmax (EtOH) 210 (Eurax 35000) and 289 (8000) nm, Xmax (EtOH/KOH) 213 (cm > 43000), 248 sh (16000) and 308 (7200) nm, S (100 MHz) 1.70-2.72 (6H, m, methylenes), 3.19 and 3.40 (2H, AB q, J 16 Hz, ArCH2C(.0)), 3.80 (3H, s, ArOCH3), 3.87 (3H, s, ArOCH3), 5.54 (1H, s, OH), 5.62 (1H, s, OH), 6.50 (1H, s, ArH), 6,72 (2H, s, ArH) and 6.90 (1H, s, ArH), m/e 328 (11+; 100%), 300, 271 and 241 (Found: C, 69.69; H, 6.22. 019H2005 requires C, 69.49; H, 6.14%).

Preparation of 4,4'-dihydroxy-3,3',5,5'-tetramethyl- biphenyl (233) Biphenonquinone (232b) (24 mg; 0.1 mmoles) in 80% acetic acid (2 ml) and zinc powder (38 mg; 0.57 moles) were vigorously stirred for 3 h. Solids were filtered off and washed with chloroform. The filtrate was washed with water and the aqiieous layer extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated. The crystalline residue was recrystallised from benzene to give biphenol (233) (20 mg; 80%), m.p. (lit. 224°C 2240226c) , vm 3300 (br) cm 1,(d6-acetone) 1.90 (12H, s, ArCH3), 6.60 (2H, s, ArOH) and 6.78 (4H, s, ArH). 182

Oxidation of 4,4'-dihydroxybiphenyls with diphenylseleninic anhydride_ General procedure Anhydrous tetrahydrofuran was added to a mixture of the 4,4'-dihydroxybiphenyl and diphenylseleninic anhydride under dry nitrogen. The reaction mixture was stirred at room temperature for 15-30 min. After completion (t.l.c.) the solvent was evaporated, chloroform added and the solution washed with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated. Diphenyl diselenide, a known byproduct of diphenylseleninic anhydride oxidations, was not isolated but identified by t.l.c.

Oxidation of biphenol (233) with diphenylseleninic anhydride_ Preparation of the 3,3',51 5'-tetramethyl- biphenonouinone (232b) Reaction of biphenol (233) (3.8 mg; 1.6x10-5 M) and diphenylseleninic anhydride (6 mg; 1.7x10-5 M) in tetrahydrofuran (0.2 ml) for 15 m gave only the biphenonquinone (232b) and diphenyl diselenide (t.l.c.).

Oxidation of biphenol (205b) with diphenylseleninic anhydride Reaction of biphenol (205b) (5.7 mg; 1_71X10 5 M) and diphenylseleninic anhydride (15 mg; 3.75x10 5 M) in tetrahydrofuran (0.15 ml) for 0.5 h and work up gave a mixture of diphenyl diselenide and product. Repeated 183

leaching with redistilled hexane, although causing some decomposition (t.l.c.), removed most of the diphenyl diselenide. The product was obtained as a reddish powder, vmax (CHC13) 3540, 1705, 1665, 1655 and 1645 cm-1,

Xmax (tetrahydrofuran) 220 (Emax 21000), 289 (6000) and 376 (1000) nm, g (100 MHz) 1.74-2.90 complex (6H, methylene), 3.14 and 3.28 (2H, AB q, J 16 Hz, ArCH2C0-), 3.87 (3H, s, ArOCH ), 5.465.94 b (1H, Ar0H), 6.34 (1H, s, ArH), 6.48 3 (2H, ArH) and 6.78 (1H, s, ArH).

Preparation of 1-methoxy-5-methylphenol (234) Isovanillin (3.0 g; 20 mmoles) was dissolved in glacial acetic acid (10 ml) and methanol (10 ml) and hydrogenated with 10% palladium on charcoal (0,3 g), at room temperature, under 1 Atm pressure of hydrogen, for 5 h. The catalyst was subsequently filtered off and washed with methanol. The filtrate was evaporated, water added and the mixture extracted with chloroform. The organic phase was washed .with saturated aqueous sodium hydrogen carbonate and water, dried and eva27:::!..50:11/e residue was distilled (78°C/1.5 mmHg; lit. 40 'mmHg) to give phenol (234) (1.7 g; 63%), max (CHC13) 3545 cm 1, 2.30 (3111 s, ArCH3), 3.84 (3H, s, Ar0CH3), 5.56 b (1H, s, Ar0H) and 6.50-6.94 complex (3H, ArH). 184

Preparation of LE14'-dihydroxy-5,5'-dimethoxy-212'- -dimethylbiphenyl (235) To a stirred solution of phenol (234) (0.5 g; 3.6 mmoles) in ethanol (1.2 ml) an ice cold solution of anhydrous iron(III) chloride (1.17 g; 7.2 mmoles) in water (12 ml) was added with vigorous stirring, under nitrogen, at room temperature. Stirring was continued for 2 la, when the reaction mixture was extracted with diethyl ether. The ether layer was washed with water, dried and evaporated to give a mixture. Starting material was removed by distillation and the residue purified by p.l.c. (developing solvent ethyl acetate/light petroleum : 2/3) to give the crude biphenol (235). Recrystallisation from aqueous ethanol gave pure biphenol (235) (0.1 g; 20%) as plates, m ap, 190-2°C7(lit.226 192-4°C), vmax (CHC13) 3550 cm 1, dr 1_95 (6H, s, ArCH3), 3,81 (6H, s, Ar0CH3), 5.50 b (2H, s, ArOH), 6.58 (2H, s, ArH) and 6.78 (2H, s,ArH),

Oxidation of biphenol (235) with dipbenylseleninic anhydride Biphenol (235) (41 mg; 0,15 mmoles) and diphenylseleninic anhydride (62 mg; 0,17 mmoles) in tetrahydrofuran (2 ml) were stirred at room temperature for 15 min when an additional portion of anhydride (10 mg) was added. The reaction was complete (t.l.c.) in a further 15 min Work up in the usual way gave a mixture of diphenyl diselenide and product. Most of the diphenyl diselenide 185

was removed by leaching with hexane to give the product as a reddish powder, vmax (CHC13) 3540, 1665, 1655 and 1650 cm-1 1 Xmax (tetrahydrofuran) 220 (emax 16000), 280 (4000) and 374 (800) nm, g 1.90 (3H, d, Hz, =C-CH3), 2,18 (3H, s, ArCH3), 3.90 (3H, s, ArOCH3), 5,80 b (11-11 ATOM, 6.26 (1H, s, =CH), 6.40 b (1H, s, =CH), 6.64 and 6.88 (2H, 2 s, ArH)„ m/e 260 (11++2; 100%), 227.

Trapping of the product of the diphenylseleninic anhydride oxidation of biphenol (235) with o-phenylenediamine Biphenol (235) (41 mg; 0,15 mmoles) was oxidised as above and the crude reaction product was dissolved in chloroform and o-phenylenediamine (49 mg; 0,45 moles) was added at room temperature. The reaction was complete (t.l.c.) in 5 min. The reaction mixture was separated by p.l.c. (developing solvent ethyl acetate/light petroleum : 2/3) to give the trapped product (237) (20 mg; 40%) as a yellowish gum, vmax (CH013) 3550 cm-1 , g 2.02 (3H, s, ArCH3), 2.35 (3H, sl ArCH3), 3.85 (3H, s, ArOCH3), 4.60 b (1H, Ar0H), 6.68 (1H, s, ArH), 6.90 (1H, s, ArH) and 7.50-8.40 complex (6H, aromatics), m/e 330 (le; 100%) and 315 (Found: M4-1 330.1374. C211110202 requires le, 330.1368).

Sodium borohydride reduction of the product of the diphenylseleninic anhydride oxidation of biphenol (235) Biphenol (235) (41 mg; 0.15 mmoles) was oxidised as previously described and after completion, sodium 186

borohydride (40 mg; 1.00 mmoles) was added in three portions, followed by ethanol (0.2 ml). The reaction mixture was subsequently cooled to 000 and glacial acetic acid (0.4 ml) was added to destroy excess sodium borohydride. The solvents were removed by evaporation, water was added and the organic material was extracted with chloroform The organic phase was washed once with saturated aqueous sodium hydrogen carbonate and water, dried and evaporated to give a mixture of two products more polar than the starting Material (235) and diphenyl diselenide. Separation by p.l.c. (developing solvent ethyl acetate/light petroleum : 2/3) gave the minor (less polar) product (6 mg) as a colourless gum? vmax (CH013) 3560 and 3400 cm 1, m/e 416 (le; 100%), 260, 227, 190 and 157, and the major product (238) (18 mg) as a colourless foam, vmax (CHC1 ) 3550 and 3270 cm-1, 3 1.96 (6H, sl ArCH3), 3.82 (3H, sl ArOCH3), 4.40-5.40 b (3H, Ar0H), 6.56 and 6.61 (2H, 2 s, ArH) and 6.80 b (2H, ArH), m/e 260 (M4-; 100%) and 227 (Found: M+, 260.1050.

C15H1604 requires 11+ 260.1048).

Trapping of the product of the diphenylseleninic anhydride oxidation of the biphenol (205b) with o-phenylenediamine Biphenol (205b) (27 mg;- 8.2x10-5 M) and diphenylseleninic anhydride (74 mg; 2x10-4 M) in tetrahydrofuran (0.7 ml) were stirred at room temperature for 0.5 h. 187

Usual work up gave a product and diphenyl diselenide which were dissolved in chloroform (0.5 ml) and treated with o-phenylenediamine (9 mg; 8.2x10-5 M) at room temperature for 15 in The reaction mixture was separated by p.l.c. (developing solvent ethyl acetate/light petroleum : 60/40) and the major most polar zone was extracted with 10% methanol in chloroform. The solvents were evaporated and the residue was dissolved in chloroform (0.25 ml) and treated with an excess butane-2,3-dione (0.1 ml) at room temperature. Subsequent plc gave a purified product (4 mg), vmax (CHC13) 3550 and 1710 cm 11 m/e 384 (le), 341, 327, 260 and 132 (100%). 188

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