Synthetic studies towards ergot alkaloids

Synthetic studies towards ergot alkaloids.

SHARPE, David Anthony.

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SHARPE, David Anthony. (1989). Synthetic studies towards ergot alkaloids.

Doctoral, Sheffield Hallam University (United Kingdom)..

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SYNTHETIC STUDIES TOWARDS

ERGOT ALKALOIDS

by

DAVID ANTHONY SHARPE

BSc (HONS)

A thesis submitted to the Council for National

Academic Awards in partial fulfilment of the

requirement for the degree of Doctor of philosophy.

Sponsoring establishment:

Department of Chemistry

Sheffield City Polytechnic

Collaborating establishment: Glaxo Group Research

Ware, Hertfordshire

CON T E N T S

Page No.

Abstract

1

CHAPTER 1 : Background and aims

2

1.1 : General

2

1.2 : Pharmacology

7

1.3 : Synthesis of Ergot alkaloids

8

1.3.1 : Biosynthesis

8

1.3.2 : Synthetic Strategies

11

1.4 : 4-Substituted indoles

16

1.5 : Aims

20

CHAPTER 2 : A novel indole synthesis and

elaboration to Uhlesketone

24

2.1 : Background

24

2.2 : Synthesis of N-tosyl-2-methylthioindole

26

2.3 : Attempted synthesis of

3-substituted-2-methyl thioindoles

31

2.3.1 : Modification of the chemistry in 2.2

32

2.3.2 : 3-Substitution of 2-methylthioindoles

34

2.3.3 : Sulphenylation of indole-3-propionic acid 40

CHAPTER 3 : 4-Substituted indoles

53

3.1 : Synthesis of Methyl indole-4-carboxylate 53

3.2 : Cyclisation of aminophenyl ethanols

56

3.3 : Intramolecular nitrile oxide cyclisation

(INOC) route

60

3.3.1 : An alternative Heck reaction

70

3.4 : Uhlefe method

71

3.5 : The Batcho-Leimgruber synthesis

75

3.5.1 : Elaboration of Methyl

Indole-4-Carboxylate

86

3.5.2 : Investigation of the synthesis of the

D ring of the Ergot alkaloids

94

3.6 : Novel synthesis of a 4-substitute^

Indole

102

3.7 : Synthesis of a p-quinones

114

CHAPTER 4 :

CHAPTER 5 : Experimental

127

5.1 : General

127

5.2 : Experimental methods

128

Abbreviations

194

References

196

Study Programme

203

ABSTRACT

Some of the background to the b io synthe sis, synthesis and uses of ergot alkaloids has been reviewed.

A novel synthesis of the indole system has been used in an attempt to synthesise a d e r iv a t iv e of the t r i c y c l i c Uhles ketone. A variation on th is method has been carried out using 3-indole propionic acid as the sta rtin g material. The novel synthesis of the indole ring system has been developed into a synthesis of a 4-substituted indole.

A number of l i t e r a t u r e methods f o r the synthesis o f 4- substituted indoles have been in v e s tig a te d , and t h e i r usefulness in the la b o ra to ry assessed. A modified Reissert synthesis has been carried out, along with a Batcho-Leimgruber synthesis. Also the use of a thallium based method and palladium catalysed carbon-carbon bond formation have been investigated.

A novel synthesis of p-benzoquinones has been discovered, by oxidation of aromatic sulphonamides. This method has not been optimised but low to moderate yields of quinones have been achieved. This method was used in an attempt to synthesise o-benzoquinones, but was found to be unsuitable.

A novel synthesis of aromatic t h i o l esters has been developed starting from s im p le s u b s t i t u t e d benzal dehyde s e s t e r s and methylmethylthiomethylsulphoxide. The r e s u lt in g ketene t h io a c e t a l monosulphoxide was treated under the same conditions as those used in the novel indole synthesis. High yields of thiolesters were obtained.

CHAPTER 1: BACKGROUND AND AIMS. 1.1. GENERAL.

Ergot is the re s tin g stage or dry sch le ro tiu m of the fungus Claviceps purpurea, which attacks cereals, p a r t i c u l a r l y rye. Ergot alkaloids have a ls o been i s o l a t e d from o t h e r groups o f f u n g i (Phycomycetes, Ascomycetes and Basidiomycetes) and some higher plants. Ergot was known as early as 600 B.C., as a scourge that a f f li c t e d many people.

Ergot poisoning was q u ite common and went under a number of names, Holy F ire and St Anthony's F ire (to name but tw o), the names being derived from the burning sensation and resulting gangrene in the extremities, caused by v a s o c o n s tric tio n o f the blood vessels-*-. The e a rlie st alkaloids to be isolated from ergot were obtained in 1905 by Barger C a rr and Dale^. They i s o l a t e d e r g o t o x i n e w hich was a c ry s ta llin e product, and was thus thought to be a single substance. I t was la te r found to be a mixture of three alkaloids; ergocristine (1), ergocornine (2) and ergokryptine (3). To date appro xim ately twenty alkaloids have been isolated from ergot.

(1) R = -C H 2Ph

(2) R = -C H 2CH (CH3)

(

) R (o<) = -CHpCH (CHa)

(3) R (p) = _ CH (CHaj

2

CH3

One of the f i r s t synthetic alkaloids was lysergic acid diethylamide (LSD) (4), the well known hallucinogenic drug. This was synthesised in 193 9 by Albert Hoffman, who discovered its effects by ingestion of a small sample in the laboratory.

X

(4)

All the a lk a lo id s are d e riv a tiv e s of ly s e r g ic acid (5), where the carboxyl ic acid hydrogen has been replaced by various side chains ( e ith e r simple or complex), or the whole acid group has been replaced as in l e r g o t r i l e (6).

HO' c ^ ^ n " CH3_.H

NC

C l

H

(5) (

6

The naturally occurring, pharmacologically active alkaloids are the 1 evo(- ) isomers; the de xtro (+ )isomers are in a c tiv e . The ergot alkaloids all contain the te tracyclic ergolene or ergoline ring system^,

7

The ergot a lk a lo id s can be divided in to f o u r main s t r u c t u r a l groups

1 ) c l a v i ne a l k a l o i d s 2 ) l y s e r g i c a c i d gro u p

ELYMOCLAVINE (7) D-LYSERGIC ACID (5)

3 ) l y s e r g i c a c id amides 4 ) p e p t i d e a l k a l o i d s

H 0

II

II

CHal H

ERGOMETRINE (B)

HO

ERGOTAMINE (9) H

The naturally occurring lysergic acids are divided into compounds with a double bond in the 8-9 p o s itio n (8-ergolenes) and in the 9-10 position (9-ergolenes), and a ll members of the group are methylated at the N-6 position. Also the two asymmetric carbon atoms in positions 5 and 10 ( in 8-ergolenes) or 5 and 8 ( in 9-ergolenes), a 11 ow a f u r t h e r c la s s ific a tio n according to the s te r ic position of the substituents in positions 8 or 10. The 5H atom always has the $-conf iguration?.

There are various other classes of compound which are also isolated from ergot. They include pharmacologically active amines such as tyramine, histamine and acetylcholine, and o ils such as ergosterol, which on irra d ia tio n with u ltr a v io le t lig h t forms vitamin D£*

nh

2

r ]'

H

OH

H CHj C H3

I I I

He .C — CHCH 1

HO

E p g o s t e r o 1

1.2. PHARMACOLOGY.

Ergots are some of the oldest drugs known, having been studied as early as 1906 by S i r Henry Dale. They have been used throughout history by midwives in o b s te tr ic s . Ergots are of i n t e r e s t to modern pharmacologists, owing to the multiple actions associated with them. These actions include effects on uterine and vascular smooth muscle, so ergots can be used as a to o l f o r studying the mechanism of the sympathetic nervous system. The newer ergot derivatives show actions in the i n h i b i t i o n of p r o l a c t i n s e c r e t i o n and s t i m u l a t i o n of dopaminergic r e c e p t o r s (e.g. u t i l i s a t i o n in th e t r e a t m e n t of Parkinsons disease). Ergots have been i m p l i c a t e d as p o t e n t i a l therapeutic agents in the treatm ent of many disease sta te s e.g. acromegaly, amenorrhea-galactorrhea, suppression of post-partum lactation, post-partum haemorrhage, breast cancer and possible cancer of the prostate gland.

Ergots when misused can also be d e trim e n ta l to h e a lth , the hallucinogenic drug LSD, being one such compound. However i t has been useful in the development of the f i e l d of pyschopharmacology.

noradrenaline (12) can quite clearly be seen when the above compounds are superimposed onto the ergot skeleton?.

NH2

OH

OH

HO

OH

OH

(10) (ll) (12)

H

Ergot s k

e le t o n

1.3. SYNTHESIS OF ERGOT ALKALOIDS. 1 .3 .1 . BIOSYNTHESIS.

amides* and especially ( i i i ) , the formation of the t r i c y c l i c moiety in the peptide a lk a lo id s . The ergolene skeleton is synthesised from a molecule o f L - t r y p t o p h a n (13) and L - m e v a lo n ic a c id (14). The intermediate 4-dimethyl ally!-L-tryptophan (15) is then converted in a number of steps by o x id a tio n , decarboxylation and c y c l i s a t i o n to agroclavine (16), which is f u r t h e r oxidized in the 8-methyl group to elymoclavine (7) and 6-methyl-8-ergolene-8-carboxylic acid (17). This ultimately isomerises to d - ly s e r g i c acid or i t s d e r iv a t iv e s . The N- methyl group in (7) was introduced in one of the steps between (15) and (16) by L-methionine^, (scheme 1).

Scheme 1.

H

(13)

+

HO,

CH20H

H

■> ■>

HO

H

(15) ₍₇₎

H02C.

H

■>

1 .3 .2 . SYNTHETIC STRATEGIES.

Retrosynthetic an alysis of the s tr u c tu r e of the ergot a lk a lo id s reveals a 4 - s u b s titu te d indole d e r iv a t iv e . Previous syntheses o f ergots have u s u a lly begun w ith such indoles. A number of these syntheses have been reviewed in the l i t e r a t u r e ^ , and o u t lin e d below are j u s t three of these methods. They have been chosen because they are re le va n t to the work c a rrie d out in t h i s p r o je c t , and w i l l be discussed in la te r chapters, in t h e ir context to our own work.

Scheme 2 shows the approach o f Uhle^, which began w ith the readily avai 1able 2 - c h lo r o -6- n i tr o to lu e n e (19), which was converted to a 4 - s u b s titu te d in d o le , and subsequently to the compound now g e n e ra lly known as Uhle‘ s ketone (22), a very im p o rta n t precursor to the ergot alkaloids.

Scheme 2. C l

N02

(19)

C l

n o2

C l

C02H

H

(2 0) ₍₂₁₎

Elaboration of Uhle's ketone (22), by b rom ina tion , fo llo w e d by reaction with a nitrogen nucleophile allows the required nitrogen atom to be in s e rte d (scheme 3)6, and hence the ergot skeleton can be completed by cyclisation to give the D ring.

Scheme 3.

BP

(

22

E t 0 2C

A drawback w ith Uhle's approach to ly s e r g ic a cid , is th a t condensation of the ketone w ith an a c tiv e methylene group would require the use of a strong acid or base. These conditions would cause the known isomerisation of the 9-10 ergolene to the benz[c,d]indoline, outlined below, which is irre ve rsib le under these conditions.

R.

H

1) H

+

R

H

B

e n z [ c , d ] i n d o 1 i ne

This isomerisation has been a major problem in the synthesis of the ergolene skeleton, and has thwarted many attem pts at i t s synthesis.

3-indolepropionic acid (23). This was converted to 1-benzoy 1 -5 - k e to - 1,2,2a,3 ,4 ,5-hexa-hydrobenz[c,d] indole (24 ), which contains three of the f o u r rings required f o r the ergolene skeleton. The ketone was converted to the o c ta h y d ro in d o lo [4 .3 -f ,e] q u in o lin e d e r i v a t i v e (25) and hence to ly s e r g ic acid (5), (schemed).

Scheme 4.

C02H

4 STEPS

H

(23)

4 STEPS

COPh

(24)

0

CH3

(25)

H02C,

7 STEPS >

H

(5)

Scheme 5.

H

H

□M

e

H

H

M e 0 2 C ^ / \ ^OMe

H

H

The above c y c l i s a t i o n is r e l a t e d to th e 1 , 3 - d i p o l a r cycloaddition, using a n i t r i l e oxide and an o l e f i n , as the re a c tin g

H

H

I s o x a z o l i n

e

This reaction w ill be discussed in much more detail in chapter 3, as i t has been used in a synthesis of the te tra c y c lic isoxazoline.

Since 1955 many oth er successful t o t a l syntheses of ergot alkaloids have been achieved, but are not com m ercially v ia b le . The best method of manufacturing them is s t i l l by fermentation.

1.4. 4-SUBSTITUTED INDOLES.

Traditional methods of synthesising the indole skeleton (such as the Fischer indole synthesis) are not very useful in th a t a m ixtu re of products (4 and 6-substituted indoles) is produced. (Scheme 6).

Scheme 6.

N = C

P

h e n y I h y d r a z o n e

H

4 - s u b s t i t u t e d

i n d o l e

6 - s u b s t i t u t e d

i n d o l e

yie ld s, (scheme 7).

Scheme 7.

N0

(26)

N0

(27)

₍₂₈₎

H

The method has been developed by a number of workers, (Kozikowski et a l H , Maehr and S m allheer^S P o n t ic e llo and B a ld w i n ^ and Harrington and Hegedus*’ ), in t o a simple but useful synth esis of 4 - substituted i n d o l e s , e.g. 4 - f o r m y l i n d o le (2 9 )H > 1 2 ,1 3 ancj 4. bromoindole ( 3 0 ) ^ .

H

B r

Further reaction s enable side chains to be b u i l t in t o the 4- position using W i t t i g reactions, f o r (29) and palladium catalysed o le fin c o u p l i n g ^ f o r ( 3 0 ) . Th is method has been e x te n s iv e ly

re v i e w e d ^} and w i l l be discussed in more detail in chapter 3.

Various other novel syntheses of 4-substituted indoles have been developed, u s in g a v a r i e t y o f s t a r t i n g m a t e r i a l s , e.g. 3- nitrophthalic a n h y d r i d e ^ , (equation 1 ) , appropriately substituted 2

-aminophenyl e t h a n o l s ^ , (equation 2) and 3 - f o r m y l i n d o l e ^ * ^ , (equation 3).

N O2

■NH

e q u a t i o n 1

e q u a t i o n 2

CHO

These methods (mentioned above) w i l l be discussed f u r t h e r in chapter 3 as they are a l l re le va n t to work c a r rie d out in t h i s project.

1.5. AIMS.

The ultimate aim of the project was to synthesise lysergic acid (5), by two complementary routes. The f i r s t was to i n i t i a l l y synthesise a 4 - s u b s titu te d indole and convert this to a te tra c y c lic compound

(31), by a 1 , 3 - d ip o la r c y c l o a d d i t i o n r e a c t io n 2 0 , 2 1 . R e d u c tiv e cleavage of the N-0 bond in the te tra c y c lic compound (31) followed by oxidation of the r e s u lt in g in te rm e d ia te alcohol would give the t r i c y c l i c aldehyde (32), (scheme 8).

Scheme 8.

NHR

C H O

OHC.

(

3 1

Scheme 9.

NHR

(32)

CH

O

C

P 0 ( 0 E t ) 2

>

(34)

ethyl arylacetate23 (See la t e r ) , (scheme 10). Scheme 10.

CHO

NHTOS

bL ^ S C H3

c=c:

SOCHa

NHTOS

(35)

₍₃₆₎

SCHa

TOS

(37)

E lectrophilic substitution at position 3 on compound (37), would give a useful intermediate to derivative (38) of Uhle's ketone (22).

TOS

Modification of (38) would then lead to product (40) re la te d to (32), (scheme 11).

Scheme 11.

ho

2

TO

S

TOS

(

3 7

3 9

NHR

TOS

(

3 8

4 0

CHAPTER 2.

A NOVEL INDOLE SYNTHESIS AND ELABORATION TO "UHLE'S" KETONE. 2.1. BACKGROUND.

As outlined in chapter 1, a novel synthesis of the indole skeleton has re c e n tly been discovered in t h i s department. Formation of the ketenethioacetal monosulphoxide (36) was achieved by f o l l o w i n g the method of 0gura^3. Condensation of a benzaldehyde w ith methyl methylthiomethylsulphoxide (MMTS) under basic c o n d itio n s , r e s u lts in the ketenethioacetal monosulphoxide. When Ogura treated th is with acid in ethanol, the product obtained was an ethyl a r y la c e ta te , (scheme

12

).

Scheme 12.

MMTS/Base

_SCH3

S0CH3

Ap

CHO

H

> ArCH2C02R

R=Et

Scheme 13.

1) MMTS/Base 2) HC1/DME

SCH

3

R=CH2C0gCH3

=CH

2

CH=CH

2

I t was hoped th a t by a l t e r i n g the solve nt, the y ie l d s of the t h i o l esters could be improved. However i t was found when dichloromethane was used an .improvement of the y ie ld s of the t h i o l esters did not result. A d i f f e r e n t compound was is o la te d , and was shown to be the chloroketenedithioacetal shown in (scheme 14).

Scheme 14.

TOS

i!l

x o

2

ch

3

2) HC1/DCM

TOS

|!l

_xo

2

ch

3

,s o c h

3

, c = c C

^ ^ S C I-13

and (43) were isolated, (scheme 15) Scheme 15.

h3c^ ^ ^ - c h o

MMT

S/Base

>

'NHTOS

(41)

K . S C H3

c = c C

^ • s o c h 3

NHTOS

h

3

HC1/DCM

>

sch

+

s c h

This method has now been developed into a high yie ldin g general synthesis of the indole skeleton, although 4-substituted indoles are quite d i f f i c u l t to achieve simply (see later).

2 .2 . SYNTHESIS OF N-TOSYL-2-METHYLTHIOINDOLE.

A D I I M I N E

Methyl anthranilate was treated with p-toluenesulphonyl chloride in p y rid in e to form the protected amine (45). M a nipu la tion o f the carbonyl group by reduction w ith l i t h i u m aluminium hydride (LAH), followed by oxidation with pyridinium chlorochromate (PCC), gave the require benzaldehyde (35), (scheme 16).

Scheme 16.

.COaCHs

p - T s C l / { j 3 y r i d i n e

•n h2 (44)

P C C /D C M

NHTOS

(35)

Condensation of the aldehyde (35) w i t h the anion of m e th yl methylthiomethylsulphoxide ( M M T S ' ) 23 gave the k e t e n e t h i o a c e t a l

monosulphoxide (36) in 60% yield. Treatment of this with concentrated hydrochloric acid in dich l oromethane gave a m ix tu re of indoles (37) 37.5% and (47) 36.6%, (scheme 17).

Scheme 17.

LAH/Et20/CTC

'NHTOS

(46)

.CHO

M M TS/Base

SCHs

SOCH

(35)

C l

(37)

(47)

The id e n tity of (47) was confirmed by treatment of the mixture of indoles w ith sulphuryl c h lo rid e . The product obtained had id e n t ic a l TLC properties to the product obtained when pure (37) was treated with sulphuryl chloride. I t is known that indoles are halogenated in the 3 - position by e le c t r o p h il ic s u b s t i t u t i o n ^ i.e. "Cl+" is needed to do this. This was readily available in the form of sulphuryl chloride.

The s t r u c t u r e of (47) was confirmed by NMR and Mass Spectral data. I t was l a t e r found t h a t d u r in g the c y c l i s a t i o n s t e p , i f dichloromethane was presaturated w ith hydrogen sulp hide gas, only a single product (37) was formed in over 70% yield.

below:-(A) 2 C 1 -> C 1 2 HC1

.NHTO

S

.S0CH3

Q— C

H"

^SCH

(b) 2C1tf>Cl

HCl/HaS

.NHTOS

^.SCHa c = c C

VT

+ C l2

Cl: M/

SOT.

Cl

V

TOS

\ / SCH3

C l ^ > l ^ H+

-c h3s h

TOS

.NHTOS

'•'SCH3

QSOCH

-CH

SOH

Cl

T O S

- H C 1

2 .3 . ATTEMPTED SYNTHESIS OF 3-SUBSTITUTED-2-METHYL-THI0IND0LES.

2 .3 .1 . MODIFICATION OF THE CHEMISTRY IN 2.2.

The required starting material fo r the sequence was the ketone (49), which was prepared from the aldehyde (35), by use of a Grignard reagent. This gave the secondary alcohol (48), which was then oxidized to the ketone with pyridinium chlorochromate, in high y ie ld , (scheme

i8)

.

Scheme 18.

.CHO

'NHTOS

(35)

1) CH3Mg I

T - >

2) H30

NHTOS

(4B)

PCC/DCM

(49)

The proposed reaction of the ketone with MMTS, and t r i t o n B resulted in no reaction, and starting material was isolated, in high y ie ld .

An a l t e r n a t i v e to t h i s d ir e c t method of s y n th e s is in g the ketenethioacetal monosulphoxide, was to synthesise the

of (50) w ith potassium t-b u to x id e in t - b u t a n o l, would give the ketenethioacetal monosulphoxide (51), (scheme 19).

Scheme 19.

NHTO

S

(49)

1

) MMTS/nBuLi

2)

AC.O

H3C OAC

yC

/.SOCHa

SCH

NHTOS

(50).

tBuOK/tBuOH

H

C.

.SOCHa

^ S C H3

NHTOS

(51)

2 .3 .2 . 3 -SUBSTITUTION OF 2-METHYLTHI0IND0LES.

An alternative route towards 3-substituted-2-methyl t h i oi ndol es would

be:-R

R

Since the required s t a r t i n g m a teria l was a v a ila b le from our in d o le synthesis we thought i t worthwhile investigating th is process.

3-functionalisation o f in d o le s has been c a r r i e d ou t by alkylation reactions, in p a rticu la r "Michael" (conjugate) addition to unsaturated carbonyl compounds or similar.

Before atte m p tin g to elaborate the 3 - p o s itio n o f the in d o le (37), a number of model re a ctio n s were t r i e d on the more r e a d i l y a v a ila b le indole (52) i t s e l f . This was to e s ta b lis h the best ro ute to an in d o le with the appropriate three carbon side chain. A number of methods were found in the lite r a tu r e , which involved the addition to the indole-3- position of an e le c tro n d e f i c i e n t o l e f i n (or e q u iv a le n t), such as a c ry lic a c i d ^ , di-serine^?, a-acetamidoacrylic acid^S#

0 u +

IP > H ^ V Cv . H2C— CCT CHa

H

H

□ H I

+

H2C— C'C CH3 H

CH3

H-r 0.

H

H

it

CHa HO

H

CHa

H

The synthesis of N-acetyl tryptophan (53) from in d ole and a-acetamidoacrylic acid in acetic anhydride/acetic acid^S was f i r s t trie d. A f t e r working up the re a ctio n , a brown s o l i d was obtained,

which was quite insoluble in most solvents used fo r NMR analysis. An infra red spectrum was obtained of the brown s o lid , but t h i s did not agree w ith a published spectrum of N-acetyl tryptophan. The paper suggested a 57% y ie ld f o r this reaction, (scheme 20).

Scheme 20.

H

(52)

H2C ~ C NHCOCHa C02H

Ac20 / A cOH

NHCOCHa

H 02C

H

(53)

The synthesis was repeated, but d l-s e rin e ^ was used instead of a-acetamidoacrylic acid, (scheme 21).

Scheme 21.

H

h o c h2c h ( n h2 ) c o2h

— — * - >

(52)

n h c o c h3

H 02c

H

This re a c tio n again re s u lte d in a brown s o lid , whose i n f r a red spectrum did not agree w ith t h a t published. A s i m i l a r r e a c tio n was carried out using a c r y l i c acid and sodium acetate in a c e tic acid, hoping to obtain indole-3-propionic acid (23)27, (scheme 22).

Scheme 22.

H

H2C=CHC0

H

—

NaOAc/HOAc

H02C

H

(52)

(23)

This reaction also gave a brown solid, which would not

re c ry s ta llis e from ethanol. I n f r a red and NMR spectra did not agree with those'obtained from an authentic sample (purchased from ALDRICH). From these f a i l e d re a c tio n s , the published methods f o r adding an electron deficient o le fin to an indole under acidic conditions seem to be unsuitable in practice, at least, in our hands.

gramine with a liph atic n itr o compounds37>38r followed by reduction of the n itr o group to the amine.

H02C

H

_H

(13)

₍₅₄₎

The method involved q u a te rn is a tio n of gramine

(55) t o . i t s quaternary ammonium s a lt (56), which was then used as an alkylating agent, (scheme 23).

Scheme 23.

H

(52)

C

H20/CH3NH/A

OH

(57%)

H

(55)

CHal/EtOH

>

(81%)

N(CH3)3I

CH2(C0aE t)a/N aH

THF/reflux (84%)

£

C02H

N aO H /r

eflux

(20%)

H

_H

(57)

_(5B)

Heat

(6 9%)

(23)

C02H

y ie ld s are those

obtained by us

discussed below in s e c tio n 2.3.3.

2 .3 .3 . SULPHENYLATION OF INDOLE-3-PROPIONIC ACID.

A t h i r d approach, which a c tu a lly appears very d i r e c t , was to sulphenylate in d o le - 3 - p r o p io n ic acid d e r iv a tiv e s . This method was eventually chosen in preference to the one described in 23.2.

A methylthio group may be added to the indole-2-position, by the method of Fontana et al39, which adds a sulphenyl side chain into the 2-position of tryptophan residues, in peptides. The method, which uses sulphenyl h a lid e s , has been shown to be a general procedure f o r the sulphenylat ion of indole derivatives.

Methanesulphenyl c h lo rid e was prepared by m o d if ic a t io n of the method of Brintzinger^O, by dropwise addition of sulphuryl chloride to dimethyl disulphide in dichloromethane at 0°C. This solution was then added dropwise to a susp e n sio n of in d o le - 3 - p r o p io n ic acid in dichloromethane. The suspension dissolved during the re a c tio n , and a fte r working up a w h ite c r y s t a l l i n e product was obtained. However when the product was analysed by NMR, an extra s i n g le t peak was observed at around 1.5ppm, and in t e g r a t io n suggested th a t t h i s was a methyl peak. This was l a t e r confirmed by mass spectrom etry and microanalys is.

H02C

H

CH

S C I/D CM

(23)

HOsC

What appears to have happened is t h a t one e q u i v a l e n t of methanesulphenyl c h lo r id e has reacted w ith in d o le -3-p r o p io n ic acid, giving an i n i t i a l p r o d u c t (5 9 ), w hich was more s o l u b l e in dichloromethane than indole-3-propionic acid. This then reacted faster with the remaining methanesulphenyl chloride, than the i n i t i a l indole-3-propionic acid, s t i l l in suspension. The mechanism f o r t h is is

outlined below, in (scheme 24).

Scheme 24.

H02C

H

(23)

C l

H02C

S— CH3

H

H

(59)

H02C

SCH

A double e l e ctr o p h i 1ic attack at pos itio n 3 has occurred,

however the second methylthio group is unable to migrate to position

2, thus the r esu lt i n g compound was an i n do l e n i n e , 2,3-

dimethyldithioindoleline-3-propionic acid (60), iso late d in 64% y i e l d .

The desired 2-methylthio derivative (59) was obtained when one

molar equivalent of methanesulphenyl chloride in dichloromethane, was added dropwise, to a solution of indole-3-propionic acid in

tetrahydrofuran, (scheme 25).

Scheme 25.

H

(23)

c h3s c i/ d q m

THF/0° c

H 0 2C

S C H 3

(59)

This product was obtained in 70% yield. Having developed a method fo r the p repa ratio n of (59), we turned to an i n v es t ig a t io n of the cyclisation to form the ergot C ring.

The precedent fo r our synthesis of the indole p r o p io n ic acid derivative (59) was th a t of Uhies ketone d e r iv at ive (62) w ith a carboethoxy group in the 2-position, synthesised by Meyer and Kruse^l, from the corresponding indole pro p io n ic acid d e r iv at ive (61), by a Friedel-Crafts cyclisation in polyphosphoric acid, (equation 4).

the 2-pos i t io n ^ , (equation5).

e q u a tio n 5

H

P P A

Barrett et a l ^ attempted the Friedel-Crafts cyclisation on the

N-protected-4-substituted indole propionic acid derivative (63), using diethylchlorophosphate and aluminium chloride to give the Uhles ketone

(64). However they iso late d a higher y i e l d of the 2 - c y c l is a t io n product (65), (scheme 26).

Scheme 26.

TOS

(63)

1) (E t0)2P0Cl

---2) AlClo

TOS

(64)

+

(5%)

TOS

e q u a t i o n 4

PPA

H H

0

H

(

61

6 2

Although B a r r ett's compound (63) had an e as ily disp la ced s i l y l group, the pre fe rre d c y c l is a t io n was to the 2 - p os itio n . The angle

stra in required f o r the c y c l is a t io n to the 4 - p os itio n was o b v io us ly

great enough to overcome the influence of the trimethyl s i l y l group. From the above two examples i t would seem th a t the re is a good

precedent fo r our synthesis o f Uhle's ketone w ith a meth y lth io group blocking the 2 - p os itio n . When the c y c l is a t io n was tr i e d on compound (59), with polyphosphoric acid, no cyclisation product was observed on TLC p late (no re a ctio n w ith DNP spray), and a black t ar r esu lte d , which remained on the base l i n e of the TLC plate. We thought t h a t

because of th is a milder method might be required fo r the cyclisation. The acid (59) was reacted with oxalyl chloride followed by anhydrous

*

aluminium c h lo rid e . No re a ctio n was observed, and a high y i e l d o f

starting material was recovered.

We then decided to p rote ct the nitrogen of the in d o le as the

tosyl de r iv at ive , hoping th a t c y c l i s a t io n might occur w itho ut degradation of the ind ole system by PPA. An attempt was made to

tosylate the fre e acid by using the method o f Bowman et a l4 4 s which

uses anhydrous potassium carbonate in refluxing methyl ethyl ketone, as the base. Only s t art i n g m a te ria l was recovered under these

esterified. Th is was achieved by s t ir r i n g the a c id at room temperature, in methanol with conc. sulphuric acid.

The tos y l a t io n of the este r was attempted using a number of d iffe re nt methods, the f i rs t being a repeat of Bowmans work, using potassium carbonate in methyl ethyl ketone. The imino n itro g e n is

readily tosylated under these conditions when an electron withdrawing

group is present in the 3, 4 or 5-position of the indole. The electron withdrawing group delocal ises the electrons in the lone p a ir of the

nitrogen, rendering the imino proton more acidic. However, this group of workers f a i le d to tos y la te the nitroge n in methyl i n do l e -2- carboxylate. We also f a i l e d to tos y la te the nitro g e n w ith our 2-

methylthio group present, and recovered only starting material.

The second method tr i e d , was to use potassium hydroxide as the base, in dimethoxyethane. However, again only s t art i n g m a te ria l was

recovered.

The method of tos y la t io n which was e v e ntu a lly used was th a t of

Barrett et a l^ ^ , which uses potassium hydride as the base, which is much more powerful in it s a b i l i t y to deprotonate the imino n itro g e n

than e ithe r potassium carbonate or potassium hydroxide. The tosylated

indole was obtained in 70% y i e l d by t h i s method. The es te r was hydrolysed back to the acid by warming to 60°C f o r three hours w ith

Scheme 27.

SCH3

(59)

SCHa

H

(66)

>90*

KH/p-TsCl

—

-70 c/THF/N

TOS

NaQH/CHaW/60 c

(67)

(72%)

H02C

TOS

It was la te r found that a higher y ie ld of compound (66) could be obtained i f in d o le -3 -p r o p io n ic acid was es te r i f i e d f i rs t and then

Scheme 28.

(23)

H3C0 2C ' ^ N

c . HgS Q4/^C H3O H

(23a)

(100%)

CH3S C I / D C M

(

66

93

The next step was to attempt to c y c lise to the Uhles ketone

d e r iv ative (38), using polyphosphoric acid. This again resu lte d in a black tar which remained on the base line of the TLC plate. From this

and previous attempts at the polyphosphoric acid cyclisation , it would

seem t h a t the su lp h u r has an adverse e f f e ct on the r e q u i r e d cyclisation, and probably allows degradation of the indole system to occur.

Again we decided to tr y one of the m ilde r , low er y i e l d i n g

Scheme 29.

H02C

TO

S

(6B)

( E t O ) 2POCl

>

□CM/O c

C I O C

s c h

3

TOS

(69)

TOS

(38)

From t h i s re a ctio n only the s t art i n g acid was recovered, which

suggests th a t i f the acid c h lo rid e (69) had been formed, then cyclisation did not occur, as on work up it would have hydrolysed

back to the acid. From t h i s we cannot say fo r c e rt a in t h a t the acid chloride was not formed in the f i rs t step.

A second method of preparing the acid c h lo rid e was looked at, which uses oxalyl chloride and dimethyl formamide in dichloromethane

to 15°C and anhydrous aluminium chloride was added, which should then

have resulted in a straightforward Friedel-Crafts acylation. However on work up, the NMR spectrum showed only s t art i n g m a te ria l to be present. From t h i s we concluded again th a t somehow the su lp h u r was

in te rferring with the expected cyclisation reaction.

It was proposed that to make our compound more l ik e that used by Meyer and Kruse^l, we should, then o x id ise the sulp hide to the

sulphone. The reagent we chose to do t h is was " OXONE " (potassium peroxymonosulphate), which is a good reagent fo r the above mentioned

conversion. It was i n i t i a l l y trie d on 2-methyl thioindol e-3- prop ionic acid, but was found to be too strong an oxidising reagent. No product

or s t art i n g m a te ria l was iso late d . A TLC p late showed a s tre a k from

the base line up the plate. It is known that unprotected indoles, are very susceptible to attack by oxidising agents, which break down the fiv e membered ring. It was therefore thought a better idea to oxidise

the tosylated ester (67).

Compound (67) was added to a so lutio n of "OXONE" in a cetic acid:

ethanol: water: conc. sulphuric acid (1:1:1:0.5), over 20 minutes, and le ft to s t ir at room temperature^. A fte r three and a h a lf hours, the

reaction was worked up and the TLC showed a number of spots. The main spot was iso late d by column chromatography and an NMR was obtained. The NMR however was not as expected; instead a q u a rtet (3.9ppm) and tr i p l et (l.lppm) appeared, which suggested that the methyl ester (70)

Scheme 30.

TOS

H3C 0 2C

s c h 3 •• O XO N E » / H ^ 3 0 4 A c 0 H / E t 0 F f / H 20

(67)

S 0 2CH3

TO S

(70)

>

TO S

S 0 2CH3

(71)

This was confirmed when the ester was hydrolysed to the acid (72), by

sodium hydroxide, although the NMR of the product indicated that some detosylation had also occurred, (scheme 31).

Scheme 31.

TOS

h o 2c ' ^ N

NaOH/60 c

S 0 2CH3 ---■---> S0 2CH3

TO S

/

H

(73)

The required compound (70) was synthesised by c a r ry in g out the oxidation in a c etic acid, methanol, water and su lp h u ric acid. This prevents the tra nses te rific atio n from occurring. Attempted hydrolysis

of t h i s es te r w it h sodium hydroxide at 60°C again r esu lte d in some detosylation of the product. The hydrolysis of the ester was achieved, without detosylation, by refluxing the ester in a mixture of water and concentrated h y d ro c h lo ric acid.

S02CH;

PS

f 1ux

TOS

TOS

(67)

(72)

should have resulted in the cyclisation to the Uhles ketone derivative

(74).

0

H

0

PPA/95°c

SO2CH3

_>

TOS

TOS

(72)

(74)

When the re a ctio n was worked up, a brown so l i d p r e c ip it a te d , which was f i l te r e d o ff, and washed with both water and ethyl acetate.

The so lid was in so lu b le in both of these solvents. A brown o i l was

extracted, in very low y ie ld , however the NMR of this did not suggest that the product was compound (74). The methyl s i n g let at3.5ppm was not present, also the aromatic peaks had almost disappeared. This would suggest th a t again the c y c l is a t io n had f a i l e d , but we were

unable to proceed any f u rt he r w ith t h is i n ves t ig a t io n due to lack of

time. The c y c l is a t io n may have been achieved by one of the acid

CHAPTER 3 .

3 ^-SUBSTITUTED INDOLES.

As was seen in Chapter 1, 4-substituted indoles are very useful

compounds from which to begin a synthesis of the ergot a lk a lo ids . As was also mentioned they are q u ite d i f f i c u lt to synthesise by

tra d itio n a l methods. We have evaluated a number of lite r atu r e methods,

to assess the ir p r a ctic a lity in terms of y ie ld and ease of synthesis. Where appropriate, modifications have been attempted in order to make improvements on the published procedures. This work is described in

the following sections.

3.1 SYNTHESIS OF METHYL IND0LE-4-CARB0XYLATE.

The procedure followed f o r th is synthesis was that of Watanabe et a l ^ , which begins with 3-nitro phth alic anhydride (75). This was fused

with ammonium carbonate, to give the product, 3-nitrophthalimide (76) in 67% yie ld . It was found that i f the ammonium carbonate was replaced

with urea, a higher y i e l d (85%) of 3 - n itr o p hth a l imide was obtained. The 3-nitrophthali mi de was then treated with sodium borohydride in 90% aqueous methanol, to give 3-hydroxy-4-nitrophthalimidine (77), which was subsequently hydrolysed with 20% hydrochloric acid at re flu x, to give 3-hydroxy-4-nitrophthalide (78), (scheme 32).

Scheme 32.

(NH4) 2C03/h e a t (67%)

or

(NHa) 2C 0 /h e a t (B5X)

NaBH„/90%Me0H

>

no

2

(77)

H

20%HCl/heat

>

(7B)

Treatment of (78) with excess diazomethane was reported to result

in the formation of the nitrostyrene oxide (81). However, because (78) was in so lu b le in ethe r, it was dissolved in methanol, and cooled in

ice, whi le. di azomethane was bubbled through. On work up the product isolated was not the n itr os t yr e n e o x id e , but 3 - met ho x y - 4 -

nitrophthalide (79) (confirmed by NMR spectroscopy). Watanabe claims that t h i s product can be iso late d when (78) is tr e ate d w ith warm methanol, or d ilute acid in methanol, (scheme 33).

Scheme 33.

N02 OH

H CH2N2/MeOH/0° c

>

(MeOH/warm or acid)

NOp OCHa

(78) (79)

The reaction with diazomethane was repeated, but a suspension of (78) in ether was used. The compound iso late d again was not the nitrostyrene oxide, but met h y l- 2 - fo rm y l-3 -n itro b e n z o ate (80). This

compound was tre ate d w ith a fu rt he r excess of diazomethane, and the desired n itr os t yr e n e oxide (81) was iso late d in 68% y i e l d , (scheme 34).

Scheme 34.

N 02 oh

(78)

CHpN2/ E t 20

- >

(81%)

CH2N2/ E t 20

>

(6 8%)

N 02

.CHO

'CQ2CH3

(8 0) N 02

The next step was to reductively cyclise the nitrostyrene oxide,

to the indole (82), by c at a l y t i c hydrogenation, using platinum (IV)

oxide as catalyst. The reaction gave a number of products (TLC), none of which was the desired indole. The major product (12.6%) was isolated, and NMR suggested t h is to be an aminophenyl ethanol (83),

although this was not fu l l y characterised, (scheme 35). Scheme 35.

N 02 0

P t 0 p / H2

—

X >

COpCHs

(Bl)

n h2

c o2ch3

(03)

H (B2)

This route was not continued, due to a number of d i f f i c u lt ies arising during the synthesis: ( i ) the d i f f i c u lt y in o bta in in g the nitrostyrene oxide in a large scale re a ctio n , being l im i te d by the

amount of diazomethane we coul d s a fe ly produce, and ( i i ) the f ai 1 ure of the c ata ly tic hydrogenation to give the desired indole.

3 .2 CYCLISATION OF AMINOPHENYL ETHANOLS.

undertaken. This method uses an aminophenyl ethanol as the s t art i n g

material, w h ic h is c y c l i se d .to the i n d o l e , us i n g tr is - triphenylphosphine ruthe n ium (11) c h lo r i d e as a c a t a l y s t . We

investigated the method, to tr y to synthesise 4-formylindole (29). The s t art i n g m a te ria l f o r t h i s synthesis was 2 -meth y l-3 - nitrobenzaldehyde (86), which was made from 3-nitro-o-xylene (84), by way of. a Thiele, o x i d at io n ^ , which uses ch.romyl acetate as the

oxidant. The r esu lt in g d ia ceta te (85) was re flu x e d w ith ethanol and conc. sulphuric acid, to give the aldehyde (86) (scheme 36).

Scheme 36.

AcaO/CrOa/AcOH

CH ( OAc

(

3 4

CHO

E t 0 H / c . H

S04/

r e f l u x

(36)

It was decided at t h i s stage th a t i t would be se ns ib le to

aldehyde was then treated with paraformaldehyde and tr ito n B (40% in

water) in dimethyl sulphoxide at 95°C, (a lower y ie ld of alcohol (88) was obtained when tr ito n B 40% in methanol was used), fo llo w e d by

reduction of the n itr o group to the amine, using z in c and calcium chloride in water. This reduction gave poor results in our hands, (20% yield) so nickel (11) c h lo rid e and sodium borohydride in me t h a n o l ^ ?

was used but only a low y i e l d (46%) of the amine (89) was obtained, a

number of other by products being produced as shown by TLC, (scheme 37).

Scheme 37.

H

0CH2CH20 H /C 6H

N

Q2 p - T S A / r e f

1

ux

CHO

(87)

DMSO

(HCHO) n/ T r i t o n B/

>

N i C l

/N a B H 4/

M

eOH

OH

NH

(89)

The cyclisation reaction was attempted, i n it i a l l y , on compound (90),

which would have led to 4-chloroindole (91), (scheme 38).

Scheme 38.

Cl

r i

nh

(90)

OH

r e f l u x / (92%)

H

(91)

A y ie ld of 92% was quoted by Tsuji et a l ^ , but in our hands this

was not duplicated, and the reaction produced no indole. Two products

were seen on TLC, both of which f a i l e d to give a p o s it ive te st fo r an

indole w ith E hrlich s reagent (i.e . pink to mauve c o lo u r); both

compounds gave a y e llo w c olo ur, which suggested they were amines

rather than indoles. The re a ctio n was the re fo re not tr i e d on the

dioxolane, which had not been obtained in pure form and only in low

the c at a ly s t was considered too high to enable the synthesis to be

carried out on a multigram scale.

3 .3 . INTRAMOLECULAR NITRILE OXIDE CYCLISATION (INOC) ROUTE

This route began w ith the indole skeleton already formed and

followed the s y nt he s is used by Somei et a l ! 8 , 1 9 # l n do l e - 3 -

carboxaldehyde (92) was tre ate d w ith t h a llium tr i f 1 uoroacetate in

tr iflu o r o a c etic acid to give the thallium intermediate (93), which was

not isolated. This was then treated with aqueous potassium iodide, in

the dark, fo r 24 hours . The product was then f ilte r e d o ff and soxhlet

extracted fo r three days to give 4 -io do in dole -3-carboxald ehyd e (94),

in 46% y i e l d, ( scheme 39).

Scheme 39.

CHO

(CF

C0

)T1

CHO~

T1 (CF

C02)3/TFA

H

H

(92)

I

CHO

K I / H

/ d a r k

H

Organothal 1 ium re a g e nts are ve ry u s e fu l and v e r s at i le in the

syntheses of aromatic^? and hete r o c y c l i c ^ iodine compounds, which

ultim ately lead to a variety of products, by a variety of substitution

reactions. However they are not w ide ly used because of the high

to x ic it y associated w ith them* The most w ide ly used organ oth al! ium

reagent is thallium tr is -tr iflu o r o a c eta te (although others are used).

Organothallium reagents react at the 4 - p o s it io n in indoles i f a

carbonyl function is present in the 3 -position allowing co-ordination

between the thallium and the carbonyl oxygen. Secondly the 2-position

is more strongly deactivated than the 4-position in the presence of a

carbonyl group. T h a llium reagents do not react w ith 3 - a l k y l indoles,

and only r e s u lt in decomposition of the st art i n g m a te r ia l. Arom atic

organothal 1 ium intermediates can also lead to other classes of

compounds, f o r example, carbonyl compounds^, by carbonyl at ion using

carbon monoxide and palladium (0), and o l e f i n s , by o le f in atio n ^ O , as

outlined below

:-1

•C02H

T 1 (CF

C0

h

c = c h r

>

P d C l

/C H 3CN

4*

co

2

C— CHR

4-Iodoindole-3-carboxaldehyde was tr e ate d w it h tr im e t h y l s i l y l

acetylene and a pal ladium (0) c a t a ly s t , a re a ctio n very s im i l ar to a

Heck re a ctio n ^ l^ ^ jh -js j S a very USeful method of forming a carbon-

carbon bond, by v i n y l a t io n of an organic h a lid e f o r example. .

A

+

h

c = c h c o

ch

B a s e / P d L

X

h c = c h c o

ch

The reaction is c ata ly tic in the amount of palladium used i f a cuprous

halide is present; the d et a i le d mechanism has not been f u l l y

established, but a f a ir l y accurate approximation is outlined below^^.

C a t a l y s t f o r m a t i o n

PdX2 + / C —cC + 2L

x\

PdL2 + hx +

C a t a l y t i c c y c le

PdL2 + RX > RPdL2X

H |

> + HPdL2X

HPdLsX + Base ■> Pdl_2 + B a s e . H* X

R = a r y l , h e t e r o c y c l i c , b e n z y l or v i n y l . X = h a l i d e .

L = l i g a n d ( e . g . t r i p h e n y l p h o s p h i n e ) .

When a palladium (11) complex or s a lt is used, it must be reduced

under the re a ctio n c o n d itio n s , presumably by o x id is in g some o f the

o le fin present. The palladium (0) formed then reacts with some of the

organic h a lid e to form the organopal ladium h a lide inte rme d iate . The

organopalladium complex adds to the double bond of the o l e f i n , the

resulting in te rme d iate is then believed to undergo e l im i n a t io n o f a

hydridopalladium h a lide . In the presence of base, t h i s d is so c iate s

reversibly and the base s h ifts the equilibrium to palladium (0), which

then begins the cycle a g a i n ^ .

The c o n d itio n s used were those described by Au stin et a l5 3 # who

converted a number of aromatic halides to the corresponding acetylenes

C = C H

K2C03

> R

The R groups varied from simple monosubstituted groups such as o, p, m-

CHO to complicated aromatic systems consisting of 4 or 5 rings. Thus a

good precedent fo r tr y i n g the reaction on our ind ole system was

available. 4 -i odoindole-3-carboxal dehyde (94) was tr e ate d w it h

tr imeth y ls ily l acetylene in the presence of bis trip h e n y lp h o s p h in e

palladium acetate, cuprous iodide, and tr iet h y l amine, to give the 4-

tr imeth y ls ily l acetylene d e r iv at ive (95). This was then d e s i ly l ate d

with potassium carbonate in methanol to give the acetylene (96),

(scheme 40).

Scheme 40.

CHO

(CH

)

S iC = C

CHO

( CH

)

S i C = C H / C u I / N E t

( Ph3P )2Pd ( 0Ac )

/CH3CN

H

H

H C =

K2CG3/ C H 3GH

(96)

Somei et a l54 prepared 1-(3- f ormy 1 in do l-4 -y l)-3 -meth y l-l-buten-3-ol

(97) by a s i m i l ar 'Heck' re a ctio n using palladium acetate as a

catalyst.

OH

CHO

H

{94)

P d ( 0 A c

D M F /N E t

CHO

H

(9 7 )

In our compound we required a v in y l group in the 4 - p o s it io n of

the ind ole, so reduction of the acetylene was necessary. This was

f i r st attempted by c a ta ly tic hydrogenation using Lin dlar catalyst (10%

palladium on calcium carbonate, poisoned w ith lead). However it was

on reducing through to the ethyl derivative (98), whose structure was

confirmed by NMR spectroscopy, (scheme 41).

Scheme 41.

CHO

H

CHO

(96)

L i n d 1 a r

c a t a l y s t

>

Quinoline/H2

The reduction was s u c c e s s fu lly stopped at the v in y l stage when 10%

palladium on barium sulphate was used as a c at a ly s t and p yr id in e as

the s o lv e nt^ (scheme 42).

Scheme 42.

HCEErC CHO

H

(96)

10%Pd/Ba

S04/H

>

P y r i d i n e

CHO

i

H

(99)

The compound that is needed to enable the intramolecular n itr i l e

oxide c y c l i s at io n to take place has a 2- n itr o et h y l group at the

nitromethane and ammonium acetate56, followed by selective reduction

of the inte r n a l double bond of the n itr o eth y le n e (100) w ith sodium

borohydride in chloroform and isopropanol, in the presence of s i l i c a

gg-157,58^ (scheme 4 3).

Scheme 43.

CHO

H

(99)

CH

N0

/NH

0Ac

>

150° c

n o2

H

(

100

NaBH

/

S i 0 2/

>

i-PrOH/CHCla

N0 2

(

101

The presence of the n itr o group makes the double bond of the

nitroethylene much more re a ctive towards re d u ctio n , than is the

terminal alkene, thus leading to s e l e ct i v i t y in the re d u ctio n . The

a-carbanion, which is resonance st a b i l i se d , before it can undergo a

Michael a d d itio n ^? , e.g.

H

,

NaBH

^R

R—C=C

N0

H R

I I +^0

R C C

_

< --- >

I - 0

H

V

H

from

s i l i c a gel

H R

n 1 1 +

R— C— C—NCT

I O'

H

V

D i m e r i s a t i o n

H R

R—C— C—N0

I I

H H

1

?

R—c—c:

ch

2

.no

'H

The n itr o et h y l de r iv at ive (101) now had the c o r re ct groups, and

correct o r ie nt a t io n to allow n itr i l e oxide fo rm a tio n , and r e s u lt i n g

cyclisation of the re a ctive d ip o le , w ith the o l e f i n , to g ive the