NOVEL ASPECTS OF THE CHEMISTRY OF THIOAMIDES

A thesis submitted by

ELIZABETH MARY NAYLOR

in partial fulfilment of the

requirements for the award of

DOCTOR OF PHILOSOPHY

OF THE

UNIVERSITY OF LONDON

WHIFFEN LABORATORY

DEPARTMENT OF CHEMISTRY

IMPERIAL COLLEGE

LONDON SW7 2AY DECEMBER 1987

2

Abstract

This thesis comprises three major sections.

Firstly, a review of recent developments in hetero Diels-Alder

chemistry involving mono-heteroatomic dienophiles is presented.

Particular emphasis has been placed upon the synthetic potential of

these cycloadditions and examples, specifically chosen to illustrate

this point, are included.

The second section outlines plans to conduct asymmetric

Diels-Alder reactions with a chiral diene and a chiral dienophile,

both of which were derived from thioamide precursors. The synthesis

of (2S)-2-methoxymethyl-1-(11-methylthio-1',3'-pentadienyl)pyrrolidine

and (2S)-2-methoxymethyl-l-(l'-methylthiopropenyl)pyrrolidine were

achieved; however their instability precluded investigation of the

proposed asymmetric cycloadditions.

The final part of this thesis deals with inter- and intra

molecular hetero Diels-Alder reactions of thioformamide derived

iminium salts and imino thioethers. 2-aza-9-thiabicyclo[4.3.0]-

non-4-ene systems prepared by cycloaddition of iminium iodides could

not be isolated directly. Thus, a variety of trapping reactions were

carried out in an effort to isolate a stable derivative. The thermal

reaction of N-(4,6-heptadienyl)-N-methylthiomethyliminium iodide did

not afford the [4+2]-cycloadduct, l-aza-2-alkylthiobicyclo[4.3.0]-

non-4-ene, instead formyl- and thioformylpyrrol idine derivatives were

isolated. Diels-Alder reactions between S-ethyl tetrafluoroborate

salts of thioformamides and siloxy dienes were prevented by

deprotection of the diene. The use of the tertiary thioamide,

N-benzyl-N-methylthioformamide and rigorous exclusion of proton

sources resulted in the isolation of (E)-1-(3'-(N-benzyl-N-

methylamino)-1'-oxo-2'-propenyl)cyclohexene.

3

4

CONTENTS

Page No

ACKNOWLEDGEMENTS 6

ABBREVIATIONS 8

REVIEW: 10

Diels-Alder Reactions with Mono-heteroatomic Dienophiles in Organic Synthesis

Contents 11

Review 12

References 112

RESULTS AND DISCUSSION: 121

1. Introduction to Asymmetric Diels-AlderReactions 122

1.1. Research strategy

2. Preparation of Diene (39) 137

2.1 Via alkylation of thioforniamide2.1.1 Model studies2.1.2 Preparation of thioamide (45)

2.2 Via oxygen-sulphur exchange2.2.1 Preparation of a/3-unsaturated thioamide (58)2.2.2 Preparation of^7 -unsaturated thioamide (45)2.2.3 Transformation of thioamide (45) to diene (39)

3. Preparation of Dienophile (40) 156

4. Introduction to Hetero Diels-Alder Reactions 150

4.1 Research strategy

5. Diels-Alder Reactions of Thioformamides and Iodides 171

5

5.15.1.15.1.25.1.35.1.4

Iminium salt trapping reactions Via the ketal function Via hydride reduction Via cyanide addition Via indole cyclisation

5.2 Alternative trapping reactions

6. Intramolecular Reaction of Iminium Salt (115) 185

7. Acyl Thioamides as Dienophiles 190

8. Reaction of Imino Thioethers with Siloxy Dienes 194

9. Reaction of Iminium Salts with Siloxy Dienes 200

10. Conclusions and Perspectives 205

APPENDIX 207

EXPERIMENTAL 211

REFERENCES 271

6

ACKNOWLEDGEMENTS

Firstly I wish to thank my supervisor Dr. William Motherwell for

his guidance and enthusiasm during this Ph.D. I would also like to

thank Professor Steven Ley for his assistance over the past three

years.

I am grateful to Mr J.N. Bilton and Dr. J.A. Challis for the mass

spectra and accurate mass measurements, to Mr R. Sheppard for help

with running n.m.r. spectra and to Mr K. Jones and his staff for the

microanalyses included in this thesis.

I would like to thank many members, past and present, of the

Whiffen, Perkin and Barton laboratories for making the top floor of

the Old Chemistry building such an enjoyable and stimulating place to

work. I am particularly grateful to Tony, Peter and Dave for help

with drawing diagrams; to Francine, Peter and Andrew for proof

reading and to Howard for assistance with the molecular mechanics

calculations.

I wish to thank Ian and Liz, and Sean for their very valued

friendship and Joan and Eifion for their great kindness over the

past three years.

I am very grateful to my sister, Maggie for all the time and

effort she has put into typing this thesis.

Finally I would like to thank Brian for his continual support and

understanding.

LIZ.

TO MY PARENTS AND SISTERS

ABBREVIATIONS

Bn - Benzyl

Bz - Benzoate

Cbz - Benzyloxycarbonyl

d.e. - Diastereomeric Excess

DBU - Diazobicyclo[5.4.0]undec-7-ene

DMAP - Dimethyl ami nopyridine

DMPU - Dimethyl Tetrahydropyrimidinone

DMSO - Dimethylsulphoxi de

d-TFA - Deuterated Trifluoroacetic Acid

E. I. - Electron Impact

e.e. - Enantiomeric Excess

Ether - Diethyl Ether

Eu(fod)^ - tris(6,6,7,7,8,8,8-Heptafluoro-2,2-dimethyl-3,5-

octanedionato)europium(III)

Eu(hfc)^ — tris[3-((Heptafluoropropyl)hydroxymethylene)-(+)-

camphorato]europium(III)

FAB - Fast Atom Bombardment

HMPA - Hexamethylphosphorami de

HOMO - Highest Occupied Molecular Orbital

LDA - Lithium Di-isopropylamide

LUMO - Lowest Unoccupied Molecular Orbital

MOM - Methoxymethyl

NCS - N-Chlorosuccinimide

Py - Pyridine

Red-Al - bis(2-Methoxyethoxy)aluminium Hydride

RT - Room Temperature

SM - Starting Material

9

TBDPS tert-Butyldiphenylsilyl

TBS tert-Butyldimethyl silyl

TBSOTF tert-Butyldimethylsilyl Trifluoromethanesulphonate

TES Triethyl silyl

TFA Trifluoroacetic Acid

THF Tetrahydrofuran

TMS Trimethyl silyl

Ts p-Toluenesulphonyl

Ybtfod)^ - tris(6,6,7,7,8,8,8)-Heptafluoro-2,2-dimethyl-3,5-

octanedionato)ytterbium(III)

REVIEW

DIELS-ALDER REACTIONS WITH MONO-HETEROATOMIC DIENOPHILES

IN ORGANIC SYNTHESIS.

11

CONTENTS

1. Introduction

2. C-N Dienophiles

2.1 Activated imines

2.2 Unactivated imines

2.3 Iminium salts

2.4 Imines with heterodienes

2.5 Nitriles

3. C-0 Dienophiles

3.1 Carbonyl compounds under thermal conditions

3.2 Carbonyl compounds under high pressure conditions

3.3 Carbonyl compounds under catalytic conditions

3.4 Formaldehyde

3.5 Carbonyl compounds with heterodienes

4. C-S Dienophiles

4.1 Thioketones

4.2 Thioaldehydes

4.3 Other thiocarbonyl compounds

5. Conclusions

6 . References

12

1. Introduction.-

A comprehensive review of Diels-Alder cycloadditions with

heterodienophiles appeared in the literature in 1982.* Over the past

five years a great deal more research in this area has been undertaken

resulting in a large number of additional publications. Over this

period a greater awareness of the hetero Diels-Alder reaction has led

to a broadening of the range of such cycloadditions with synthetic

potential and consequently to a variety of interesting applications.

However, mechanistic work associated with these Reactions is in many

cases severely limited. The conclusion to be drawn from the available

information is that the mechanisms of these [4+2]-cycloadditions span

the range from a concerted/non-synchronous pathway to a stepwise

dipolar process.

This literature survey is concerned with those heterodienophiles

in which the reacting multiple bond contains one carbon atom and one

heteroatom. Those Diels-Alder reactions in which the dienophiles

have two heteroatoms in the reacting multiple bond e.g. N=0, S=0, N=N

have not been included although in some cases they have provided a

useful tool for organic synthesis.*

Reviews of particular aspects of the Diels-Alder reaction with

2 3heterodienophiles * appeared around the same time as that of Weinreb

and Staib.* More recently resumes of the v/ork of particular groups in

4 5this area have appeared. ’ The aim of this review is to bring

together recent developments in hetero Diels-Alder cycloadditions with

mono-heteroatomic dienophiles with particular emphasis on their

application to organic synthesis.

13

2. C-N Dienophiles.-

2.1 Activated imines.

Diels-Alder reactions with electron deficient imines as2

dienophiles have been known for over twenty years. These imines

e.g. N-sulphonylimines, N-acylimines generally show good regio- and

stereoselectivity.*

R

R

Data from this type of cycloaddition suggests that the imine reacts

via its (E)-isomer and that in general, 7r-substituents on nitrogen are

better endo directors than the equivalent substituent on carbon. This

is exemplified by the synthesis of a bicyclic proline analogue (Scheme

14

O OH

X XPhCH20 ^ NH ^ C 0 2CH3 SOCI2, Et3N

0

PhCH20 ^ S’ C 02CH3

I f )56% W

12 h, RT

^ / V ^ c ° 2H

1. Pd/C, H22. 6N HCI

J r "v C 02CH2Ph

Scheme 1

The cycloaddition of electron deficient imines has been employed

in more complex syntheses. (±)-Isoprosopinine B (2) and

(±)-desoxoprosopinine (3) have been prepared via the common

bicycloadduct (1),7whilst the synthesis of the N(5)-ergoline (6)^

incorporated the hetero Diels-Alder reaction between imine (4),

prepared in situ, and diene (5).

COOCH3

IITsN

OTMS

C6H6,3 h 5 °C - RT

O O

( 2 )

(CHECKS

( 3 )

15

PhCH

The preparation of the 8-aza-9,ll-etheno analogue of

prostaglandin PGHj, has been achieved by two different groups of

researchers both using a similar imino cycloaddition strategy (Scheme

2 ) .9

It has been shown that cyclic electron deficient imines also

undergo Diels-Alder reactions. Reaction of 3-methyl-l,2-

benzisothiazole-1 ,1-dioxide (7) with Danishefsky's diene resulted

in the isolation of the 4-pyridone (8 ) . 10 Replacement of the 3-methyl

16

group by chlorine also gave the desired adduct whilst no reaction

occurred with a methoxy or phenylthio substituent. The lack of

reactivity in the latter cases was attributed to the +M effect of the

substituents deactivating the imine function towards cycloaddition.

Polyhalo-2-acyliminopropanes (9) have proved to be very good

dienophiles reacting with cyclopentadiene to give Diels-Alder adducts

(10) in 90-93% yield.** Enhanced reactivity was observed when the

2-acyl group of imine (9a) was replaced by a polyfluoroacyl

substituent (9b, 9c) but successive replacement of fluorine atoms by

chlorine in the isopropylidene group (9c, 9d, 9e) did not lead to a

significant change in the optimum reaction conditions. The formation

of [2+4]-cycloadducts between imine (9a) and acyclic dienes

(butadiene, isoprene, and piperylene) has also been observed, though

in lower yields (30-70%).**

(9 ) (1 0 )

a. R = CH3, X = Y = Fb. R = CF3, X = Y = Fc. R = CH(CF3)2, X =Y = Fd. R = CH(CF3)2, X -Cl. Y - Fe. R = CH(CF3)2> X = Y = Cl

17

A variety of methods have been utilized for the vn situ

generation of N-acylimines prior to their intramolecular Diels-Alder

reaction. Thermolysis of acetate derivatives, such as (12), has

proven to be a useful technique which has been applied to the

4 IPpreparation of several indolizidine alkaloids e.g. slaframine (15).

Synthesis of (15) required conversion of amine (11) to the

acetate (12). In previous syntheses this transformation had been

achieved using formalin and sodium hydroxide but in this case it

gave unreproducible results. A procedure employing cesium carbonate

and paraformaldehyde was found to be more successful. Heating a

solution of acetate (12) in o-dichlorobenzene for four hours afforded

two cycloadducts (13) and (14) in the ratio 1:1.8. Both compounds

were converted to the natural product (15), although the latter

required epimerisation at the silyloxy bearing carbon.

18

59%

1. CS2CO0(HCHO)n, THF

2. AcgO

o-Dichlorobenzene Reflux, 4 h

In the synthesis (vide supra) and other similar ones poor stereo

chemical control in the bridging chain during cycloaddition to the 6/54

fused ring systems was observed.

The question of steroselectivity in the related preparation

of the 6/6 fused ring compounds was addressed through application to

the synthesis of lupinine (20) and/or epi-lupinine (19). The

cycloaddition precursor (16) was readily prepared and upon heating

afforded a single bicyclic lactam (17). None of the epimeric product

(18) was found. Catalytic hydrogenation and borane reduction of (17)

provided epi-lupinine (19).

19

(16)

This stereochemical outcome has been explained on the basis of

cycloaddition occurring via the acylimine arranged in an s-cis

conformation (21). Houk and Paddon-Row have calculated that the

s-cis conformer (21) of N-formylimine is 3 kcal/mol more stable than

the s-trans form (22) and 4 kcal/mol lower in energy than the/ \ 4nonplanar conformer (23).

H

N ' ^ O X

H

N ^ ,

„ A „ „ A „

( 2 1 ) ( 2 2 ) ( 2 3 )

It was assumed that in the preferred transition state the N-carbonyl

group would adopt an endo orientation. Significant experimental

20

evidence in support of this assumption, in both inter- and intra

molecular imino Diels-Alder reactions exists. 1 Two possible

transition states (24) and (25) were proposed. (24) leads to

cycloadduct (17) from which epi-lupinine is obtained. Originally

Weinreb and co-workers considered that the preference for transition

state (24) over (25) arose from an unfavourable interaction between

and Hg (25). However, subsequently molecular mechanics

calculations indicated that an eclipsing interaction between Hc and4

Hp was responsible for the energy difference.

OMe

( 2 6 )

H O

( 2 7 )

Similar methodology has been applied to the synthesis of the

alkaloids cryptopleurine (26)*^ and anhydrocannabisativene (27).^

The latter was readily prepared from the acetate (28) derived from

pentadienylsilane and n-hexanal. Pyrolysis of (28) produced a single

adduct (29) whose structure was confirmed by X-ray crystallography of

the acid (30). The same criteria as previously outlined (vide supra)

can be invoked to explain the observed stereochemical outcome by way

of transition state (31). Product (30) was transformed into alkaloid

(27) in several steps.

21

( 2 8 ) ( 3 1 ) ( 2 9 ) R = Me( 3 0 ) R=H

An intramolecular imino Diels-Alder reaction was utilized for a

synthesis of the drug praziquantel (34), in which both the butadiene

15and imine fragments were generated iji situ. The choice of leaving

group used to generate the imine (33) was found to be crucial. An

acetoxy group (32, I^C^OAC) proved too labile resulting in the

formation of amide (32, R=H). However, when a methoxy group was used

and the reaction conducted in the gas phase cyclobutene (32,

f^^OCHg) cyclised to praziquantel (34) in 49% yield.

Gy49%

NHR

( 3 2 )

An alternative procedure for preparation of imines (for example,

(36)) for intramolecular cycloaddition involves a retro Diels-Alder

reaction.^ Flash vacuum pyrolysis of adduct (35a) gave lactam (37a)

a precursor of 6-coniceine (37b) in an unspecified yield. The latter

has been synthesised by Weinreb et a_l^ via an imino Diels-Alder

reaction in which the acyl imine (36), generated from (35b) was

postulated to take part. Thus, this sequence (Scheme 3) provides good

evidence for the intermediacy of acyl imines in such cycloadditions.

(35a) (37a)

Cb(37b)

S chem e 3

A retro-ene reaction has also been employed as a means of

18generating imines (Scheme 4). Unfortunately the presence of the

carbonyl group which facilitates the Diels-Alder reaction is

detrimental to the retro-ene process and low yields (

23

electron rich dienes e.g. Danishefsky's diene under zinc chloride

catalysis in tetrahydrofuran at room temperature afforded cyclic

adducts in reasonable yield (Table 1). Interestingly the

c^-unsaturated imine (38c) gave the product from the reaction of the

19bimine functionality rather than the classical Diels-Alder adduct.

Better yields were obtained by increasing the molar ratio of

diene:imine. More recently, the cyclocondensation of 1-trimethyl-

20siloxyvinylcyclohexene and N-phenylbenzylimine has been reported.

Table 1

This methodology is nicely illustrated by the synthesis of (±)-

21ipalbidine (Scheme 5).

24

0 40 -45%---------

ch2ci2BFg.EtgO -78°C to RT

Scheme 5

This Lewis-acid catalysed reaction has been applied to tricyclic

22imines. Dihydro-/5-carboline (39a) reacted with siloxydiene (40) to

give a 55% yield of the tetracycloadduct (41a) which has previously

23been converted to the natural product yohimbine. The benzofuran and

benzothiophene analogues of imine (39a) reacted in a similar

22fashion. The choice of solvent for these processes was found to be

critical. Although good yields of these cyclic adducts were obtained

in acetonitrile the reaction was inhibited in tetrahydrofuran.

( 3 9 ) a X = NHb. X = Oc. X = S

OTMS ZnCI2

CHgCN 50 °C

(40) (41) O

25

The optically active dihydro-/?-carboline (42) has been subjected

24to cycloaddition with various siloxydienes (Scheme 6). These

reactions showed complete facial specificity, the diene approaching

anti to the carbomethoxy group. However the ratio of exo to endo

products, (43) and (44) respectively, was only 4:1. Further

investigation and rationalization of the stereoselectivity of this

type of imino Diels-Alder reaction is required if it is to be usefully

applied to complex alkaloid synthesis.

OTES

( 4 3 ) R = CH3, R' = H( 4 4 ) F U H ,R ’ = CH3

The thermal imino Diels-Alder reaction of dihydro-/?-carboline

(45) formed the basis of a synthesis of the aspidosperma alkaloid

vindoline (51) and the related 11-desmethoxy compound vindorosine

26

nc(50). The cycloaddition produced three products (46), (47), and

(48). However, this was not found to be a problem since under the

alkylation conditions employed a single diastereomer (49) was

isolated.

o

FU H, 71% R»O CH3, 88%

Chlorobenzene 120 °C, 4 h

( 4 8 )

(46) + ( 4 7 ) + ( 4 8 )

98% R = H 80% R » OCH3

LDA, Etl

( 5 0 ) R=H( 5 1 ) R-OCHg

27

2.3 Iminium salts.

A few accounts of the use of iminium salts as dienophilic

1 2components in Diels-Alder reactions appear in the literature. *

26A recent advancement has been reported by Grieco and Larson.

Aqueous Diels-Alder reactions between iminium ions (52) (generated

in situ from an amine and aqueous formaldehyde) and various dienes

produced cyclic products (53) in reasonable yield (Table 2). The

cycloaddition occurred with excellent regiochemical control (Table

2, entry 3) which was consistent with previous related

27observations. Chiral induction in this process using

(-)-a-methylbenzylamine hydrochloride was moderately successful giving

a separable mixture of diasterecmers in a ratio of 4:1, (Table 2,

entry 6).

?8

rnh2.hci ------► [ RNH == ch2 c rHCHO,h2o

(52)

R

Iabie 2

Entry Diene Amine Conditions Product % yield

1. O PhCH2NH2.HCI 3h, 25°C ' i - ^ ^ N C H 2Ph 100

2.

< PhCH2NH2.HCI 96h, 55°C AlL ^ N C H 2Ph62

3. X PhCH2NH2.HCI 70h, 35°C X "1H ^ N C H 2Ph 594. o MeNH2.HCI 3h, 25°C 82

5. X nh4ci 96h, 35°C k ^ ^ N H .C I 40

6. o P h ^ s‘ NH2.HC! 20h, 0°C/b v ph

4:1 86

29

The intramolecular version of this reaction has also been

studied. 6-Coniciene hydrochloride (55) has been synthesised from the

diene hydrochloride (54) in 95% yield.

Substitution of formaldehyde by other aldehydes has been

accomplished. Replacement of formaldehyde by acetaldehyde in the

reaction of benzylamine hydrochloride with cyclopentadiene afforded

a 47% yield of exo and endo adducts, (56) and (57) respectively, in a

ratio of 1 .6:1 . ^

CH,

The intramolecular cycloaddition of the iminium salt derived from

dienyl aldehyde (58) and benzylamine hydrochloride afforded a 63%

yield of adducts (59) and (60) ir. a ratio of 2.5:1.^

63%

BnNH2.CI H20, 70 °C, 20 h

( 5 9 ) ( 6 0 )

This methodology has been applied to the synthesis of racemic28

dihydrocannivonine (Scheme 7). J

30

Scheme 7

a-ketoaldehydes e.g. phenylglyoxal and glyoxylic acid have beer,

29employed as substrates in the aza Diels-Alder reaction (Table 3).

The reaction of cyclopentadiene with benzylamine hydrochloride in the

presence of phenylglyoxal afforded a 3:2 mixture of exo and endo

adducts (Table 3, entry 1). Replacement of benzylamine hydrochloride

by ammonium chloride provided an 89% yield of exo and endo products

(61a, 61b) (Table 3, entry 2). Treatment of this mixture with zinc in

acetic acid gave the cyclopentene (62), a potentially useful precursor

to carbocyclic analogues of purine ribo- and desoxyribonucleosides.

Similarly cycloaddition of cyclopentadiene and the iminium salt

generated j_n situ from glyoxylic acid and methyl amine (in this case it

is not necessary to use the hydrochloride) produced a good yield of

the bicyclic products (Table 3, entry 3).

Table. 3

Entry Substrate Amine ProductsExo : Endo ratio

% yield

1. P h ^ v HO

PhCH2NH2.HCI

Bn

3 : 2 82

2.o

NH4Q ^ NHCI ■ a61 a-exo/61b-endo

1 :2 89

3.h o ^ y h

0

MeNH2

Me

1.9 : 1 86

31

(61a) + (61b)

PhCO

76%NH2.HCI

Zn, HAc

(62)

2.4 Imines with heterodienes.

The addition of electron rich imines to electron deficient dienes in

an inverse electron demand Diels-Alder fashion has been

accomplished. The reaction of hydrazones and aryl imines with

tetrazine (63) occurred in excellent yield (Table 4). The

analogous cycloaddition with imino ether (64) gave a mixture of

products (65) and (66) in poor yield.

Benzene,Reflux

E = C 02CH3

32

IablS-4

Imine Product % yield

N(Mg)2Ei .A r

t r V 78(M efeN ^

N N(Me)2E

CD2O% EJL ^Ar

90

M e 0 ^ s^V N'A r

E

II

a "

E

N ^ )

TO99

E EN(Me)2 N 'V*' N ̂ V Af (65) 11

N y N H N ^ N(66) 7

MeCrE E

(64) (65) (66)

More successful Diels-Alder reactions of imino ethers and imino

31thioethers were achieved by Boger and Panek. Addition of imidate

(67) or thioimidate (68) to tetrazine (63) afforded the expected

product (71) although the latter proceeded in better yield. The

amidines (69) and (70) failed to produce the desired product. It

is apparent from these results that the cycloaddition is sensitive to

both the nucleophilic character of the dienophile and the leaving

group ability of X (Scheme 8 ) . 31

33

(67) X = OEt 37%(68) X = sch3 68%(69) x = nh2 0%(70) X = NEt2 0%

(71) E = C02CH3

Scheme 8

A formal synthesis of streptonigrin (76) utilizes this

32methodology (Scheme 9). Reaction of thioimidate (72) with

tetrazir.e (63) afforded triazine (73) which underwent an all-carbon

inverse electron demand Diels-Alder reaction to give tetracycle (74)

comprising the complete carbon framework of streptonigrin (76). (74)

was converted in three steps to compound (75), a key intermediate in

33Kende's synthesis of the natural product (76).

o

(7 6 )

34

Scheme 9

Cyclic imines, imidates, thioimidates and amidines have also

34been reacted with tetrazines. Cycloaddition of dihydroisoquinoline

(77) with tetrazines (78) and (63) produced cyclic adducts (79) and

(80) in 25 and 54% yield respectively.

35

R

IN

NIIN

R

+

(63) R = C02CH3 (78 ) R = Ph

The cycloaddition of imines with acyl and thioacyl isocyanates

35 36has been reviewed relatively recently. ’ Trifluoroacetyl

isocyanate reacts with aryl Schiff bases to give oxadiazines (Scheme

10). Thioacyl isocyanates, generated from heterocycles (81), add

37to imine (82) to afford cycloadducts (83) in excellent yields.

Scheme 10

O

X % YieldH 80o c h 3 78N(CH3 )2 77Cl 89n o 2 81

o

R Bu3P

(81)

R = Aryl,Alkyl

88-98%

Ph (82)

ch2ci2

( 8 3 )

36

2.5 Nitriles.

Pyridines and other nitrogen containing heterocycles have been

synthesised by the Diels-Alder reaction of nitriles with different

dienes.* An intramolecular version of this reaction led to the first

38synthesis of pyrazino[2,3-c]quinoline (Scheme 11). The

cycloaddition precursor (84) was heated at reflux in diphenyl ether to

afford the tricyclic adduct (85) and the deacylated, fully aromatic

system (86). In a similar fashion compound (87) was converted to the

benzopyranopyrazine (88) in 45% yield. Sammes et a K previously

39reported a related intramolecular process.

Scheme 11

The fused bicycle (91) has been prepared by a synthetic sequence

involving a Diels-Alder reaction of a nitrile (90) (Scheme 12).^

The initially formed ketene imine (89) undergoes a 1,5-hydrogen

migration to afford diazatriene (90) which then cyclises to triazine

(91).

37

SCH,

^ CN C 0 2 CH3 Ph2 C— N = C

c h 2 c i2,Reflux

CNI

P h2 CO2 CH3

Ic CHPh2 >1 I

Ny N

s c h 3

(89)

1,5-Shift

CH3 0 2C

(91)

Seitz and Mohr have reacted aryl nitriles and cyanamides with

tetrazine (92) to give the inverse electron demand Diels-Alder adduct

(93) which spontaneously loses nitrogen to produce triazines (94)

41(Scheme 13). The reaction conditions employed indicate that the

cyanamides react more readily than the aryl nitriles due to the former

being more nucleophilic.

38

CF3

1N ^ N I IIN^ x N

c f 3

R— C = N

(92) (93)

R %Yield Conditions

-N(CH3)2 41 Toluene, reflux/----V

-N Ov _ y

49 Toluene, reflux

- Q och3 44 Neat, 100 °C, 1 Torr

—̂ N(CH3)2 22 Chlorobenzene, reflux

CF3

N^ N

CF3

R

(94 )

Scheme 13

2-acyliminopropanes (9) which have been shown to be good carbon-

nitrogen dienophiles (vide supra) behave as dienes in the presence of

nitriles affording Diels-Alder adducts (95) in moderate to good

11 42yield. * The mechanism of this reaction is unlikely to be a fully

concerted process;- some degree of charge separation in the transition

state would be expected. A plausible mechanism is outlined in Scheme

14 but it should be noted that the positive and negative charges on

the different intermediates might well be only partially developed.

N = C -F TCF3

c f 3

(9)

F*C

11N ^ RI H ------- N s C - F T

^ C F a

(95)

R* FT % yield

Ph Me 89Ph Ph 73OEt Me 64

R O -

Hn .

X +f3 c ' c f 3R w

N N

F3 Cf CF3

(95)

Scheme 14

3. C-0 Dienophiles.-

3.1 Carbonyl compounds under thermal conditions.

Activated carbonyl compounds are known to behave as dienophilic

components in [4+2]-cyc1oadditions. A typical example of this type of

dienophile is diethyl ketomalonate (96) which reacts with a wide

range of dienes under thermal conditions to afford cyclic adducts in

modest yield (Table 5).^

40

Zable,5.

e = c o 2Et

An interesting ring fused pyran (97) has been synthesised utilizing

the Diels-Alder reaction of this diester (96) prior to a 1,3-dipolar

/ % 44cycloaddition (Scheme 15).

o

E E+

(96)E = C 02Et

Scheme 15

n o 260%

Toluene, 110°C. 15 h

41

Glyoxylate esters are another commonly used carbonyl dienophile.

Reaction of keto-ester (98) with diene (99) provided a mixture of

adducts (100), (101), and (102). Lewis acid catalysed epimerisation

of pyran (101) gave the more stable c*-anomer (102). Transformation of

(102) into the thromboxane intermediate (103) was achieved in a

45further seven steps. A similar cyclocondensation was employed as

the initial step in the synthesis of the phorbol analogue (111)

(Scheme 16).^ Treatment of ethyl glyoxylate with 2-methoxybutadiene

afforded a single pyran product (104). This was converted into the

trienone (105) which underwent an all-carbon Diels-Alder reaction to

give cycloadduct (106). The heterodiene (107), readily prepared from

(106) reacted with ketene acetal (108) to produce the unstable lactone

acetal (109). Ring opening of (109) gave keto ester (110) which upon

further elaboration provided the phorbol analogue (111). This

synthetic sequence encompasses three different types of Diels-Alder

reaction and is, as such, an excellent example of their versatility

and strength.

42

CH3 0 '

OAc

O

, X^ ^ o c h3 h ^ ^ c o o r

(99) (9 8 ) R = (-)-menthyl

^6^6’120 °C, 72 h

rOAc

XX' exCOOR CHaO Nr

OAc

( 1 0 0 )

1 COOR CH3(

(Exo), 30%

( 1 0 1 )

I__________BF3 .Et20

COOR

(Exo), 6 %

( 1 0 2 )

OTBS

(103)

43

c h 3o+

o

COOEt

60%

Toluene,110°C

COOEt

OCH3

52%

Xylene, 145 °C

(104)

(107)

_ v 0Et ( 10 8 )^ ^ O T B SZnCI2, CH2 CI2

( 111 )

72% HF, CH3 CN

Et02C

Scheme 16

44

The hetero Diels-Alder reaction of glyoxylate esters and diethyl

ketomalonate has been utilized in the preparation of a variety of

saccharides.47,48 The antigenic determinants of blood groups A and B,

(115) and (116) respectively, have been synthesised from a common

intermediate (114) derived from pyrans (113a-d) (Scheme 17). The

cyclocondensation of (-)-menthyl glycxylate with the trans diene

(112) produced the four dehydropyranyl ethers (113a-d). Epimerisation

of the /?-D isomer (113a) to the a-D pyran (113c) was accomplished with

boron trifluoride etherate. The required pyran (113c) was thus

obtained in a combined yield of 38%. The product distribution shows

high facial selectivity but poor exo/endo preference. These results

48are consistent with previous findings for related systems. The

regioselectivity has been attributed to the influence of the asymmetry

of the sugar moiety acting through either steric or electronic

effects.4 ̂ The cr-D epimer (113c) was converted to enone (114) and

ultimately to the antigenic determinants.

45

(114)

Scheme 17

(115 ) R = NHCOCH3(116) R = OH

3.2 Carbonyl compounds under high pressure conditions.

The application of high pressure to carbonyl Diels-Alder

50reactions has been extensively studied by Jurczak and coworkers.

The reaction of Danishefsky's diene or its tert-butyldimethyl si 1yl

analogue with butyl glyoxylate under thermal conditions was

inefficient but when subjected to high pressure a twofold increase in

yield was observed together with improved diastereoselectivity (Table

46

6 ) . ^ a Use of the Lanthanide catalyst, tris(6,6,7,7,8,8,8-hepta-

fluoro-2,2-dimethyl-3,5-octanedionato)europium (Eu(fod)3) at normal

pressure allowed preparation of the desired products in comparable

yield (to the high pressure technique) but with reduced selectivity.

R(CH3)2S O v ^ s .CCfeBu R C H a ^ S iO ^ ^ ^ ^ C C fe B u* TT * X XOCH3 0 °^

(118) (119)

Diene Reaction Conditions Adduct % Yield DiastereomericRatio

(117a) C6 H6, Reflux, 1 atm., 2 0 h (118a):(119a) 40 1 : 1

(117a) Ether, RT, 10 kbar, 24 h (118a):(119a) 80 5 : 1

(117b) C6 H6, Reflux, 1 atm., 15 h (118b):(119b) 30 4 : 1

(117b) Ether, RT, 10 kbar, 24 h (118b):(119b) 85 1 0 : 1

(117b) Ether, RT, 1 Atm.,1% Eu(Fod)3, 48 h (118b):(119b) 75 7 : 3

RfCHgkSiO^^ V o ^

^ + O

0 CH3

(1 1 7 ) a. R ® CH3 b. R ■ t-Bu

Table 6

The utilization of high pressure (15-25 kbar) has allowed simple

aldehydes to be used as carbonyl dienophiles in cyclocondensa-

t i on s. ^ More recently it has been demonstrated that similar

reactions may be carried out at lower pressures (10 kbar) in the

presence of Eu(fod)3< Aldehydes bearing /3heteroatoms gave

significantly better yields than those without hetero substituents

(Table 7). This is probably due to coordination of the europium

catalyst to both the carbonyl oxygon and the /3-heteroatom.

H

47

R'

CH2 CI2, Eu(Fod)3,10 KBar, 50 °C, 20 h

OCH3

Table 7

Entry R’ % Yield Product cisitrans ratio

1 . — CH2 NHC02 CH2Ph 50 1 : 1

2 . — CH(CH3 )OSi(CH3 )2 t-Bu 35 6 :4

3. ------( 53 1 : 1°1

4. — c h 3 15 3 :7

5. — Ph 1 2 1 :1

6 . 17 4:6

OCH3

Under high pressure conditions (22 kbar, 50 °C, ether) the reaction of

chiral aldehyde (120) with 1-methoxybutadiene afforded a mixture of

four diastereomers (121a-d).^ The formation of the major isomer is

rationalized by assuming Cram selectivity and endo alignment. The

diastereomeric excesses (d.e.) of the endo and exo addition routes

were 67 and 52% respectively, although they were found to be dependent

on temperature and pressure. An increase in temperature had a

detrimental effect on the d.e., whilst increasing the pressure

improved the selectivity. An interesting extension of this work

would be the study of the reaction in the presence of Eu(fod)g (vide

supra). Danishefsky and coworkers have investigated the reaction of

aldehyde (120) with the more highly oxygenated diene (117b) under the

influence of Lewis acids at room temperature and normal pressure and

obtained only one isomer whose stereochemistry was consistent with

51Cram selectivity (vide infra).

48

(121a) 66% (121b) 16%

(121c) 13% (121d) 5%

Jurczak et aj_. have applied high pressure techniques to the

cyclocondensation of the sugar derived aldehyde (122) and 1-methoxy

butadiene and obtained a single stereoisomer of the cycloadduct 50e

(123). The improved diastereoselectivity observed in this case

compared to that with aldehyde (120) is attributed to the more

sterically demanding environment of aldehyde (122).

$ \ — o c h 3

( 12 2 ) (123)

49

3.3 Carbonyl compounds under catalytic conditions.

Gramenitskaya and coworkers have reported that the reaction of

a^-unsaturated aldehydes with dienes under the influence of boron

trifluoride etherate gave two products:- the expected, all-carbon

Diels-Alder product (124) and the dihydropyran (125). The ratio

of the two compounds was dependent upon the substituents on the diene

and aldehyde (Table 8).

Table 8

Entry R1 R2 R3 R4 Ratio(124):(125)

% Yield

1 Me Me Me H 9 2 :8 59

2 Me Me Me Me 77:23 63

3 Me Me Me Ph 0 : 1 0 0 70

4 Me H H Ph 1 0 0 : 0 39

5 H H Me Ph 85:15 51

The relative amounts of the dihydropyran (125) formed decreased as

the electrophilicity of the carbon-carbon double bond increased

(R=H>CH2>Ph, Table 8, entries 1,2,3 respectively). The dependence of

the product ratio on the diene substitution pattern (Table 8, entries

3,4,5) can be explained if a two stage mechanism is invoked for the

formation of the dihydropyran (Scheme 18). The greater preference for

formation of the pyran with 1,1,3-dimethylbutadiene reflects the

increased stability of intermediates (126) and (127).

50

More recently highly oxygenated dienes have been shown to react

53 54with aldehydes in the presence of Lewis acid catalysts. ’ A

variety of aldehydes including those with a^-unsaturation react with

l-ethoxy-3-trimethylsilyloxybutadiene and other related dienes in the

presence of bornyloxyaluminium dichloride (ROAIC^) in ether to affordroL

dihydropyrones in moderate yield (Table 9, entries 1-6).

It has also been found that similar reactions take place under

the influence of zinc chloride or boron trifluoride etherate (Table . 54

9, entries 7-15). Although the reaction occurs reasonably well

with alkyl and aryl aldehydes better yields were obtained with

aldehydes bearing a hetero substitution.

1OR

sO R 1

rN2

. R - l A ?

TM SO A , " T M S O ^ k A R<

b Ft*

51

Table 9

Entry R1 R2 R3 R4 Reaction Conditions % Yield Ref.

1 Et H H i-Pr ROAICI2, Ether, 15 min, 75 °C 65 53b

2 Et H H c h c h 2 ROAICI2, Ether, 3 h, 25 °C 60 53b

3 Er H H Ph ROAICI2, Ether, 2 0 min, 50 °C 70 53b

4 Et H Et i-Pr ROAICLj, Ether, 36 h, 50 °C 35 1 53b

5 Et Et H Ph ROAICI2, Ether, 36 h, 50 °C 60 53b

6 Et OEt H Ph ROAICI2, Ether, 24 h, 50 °C 45 53b

7 Me H H CH2 OCH2Ph ZnCI2, C6H6,36h, RT 87 54a,b

8 Me H H CH2SPh ZnCI2, C6H6,36h, RT 70 54a

9 Me H H CH2NHCbz ZnCI2, C6H6,36h, RT 80 54a

1 0 Me H H Ph ZnCI2, C6H6,36h, RT 65 54a

1 1 Me H H o-C6 H4 OCH3 ZnCI2, C6H6,36h, RT 58 54a

1 2 Me H H i-Pr ZnCI2, C6H6,36h, RT 43 54a

13 Me H OTMS CH2 OCH2Ph BF3 .Et2 0 , CH2 CI2, -78 °C 42 54a

14 Me H H c h c h 2 BF3 .Et2 0 , Ether, -78 °C 50 54a

15 Me H H CHCHCHg BF3 .Et2 Of Ether, -78 °C 70 54c

Note 1. Cis and trans mixture (3:1) separated by H.P.L.C.

An extensive study of the stereochemical outcome of these

cyclocondensation processes with different catalyst systems and the

inferences which can be drawn with regard to their mechanisms has5

been conducted by Danishefsky and co-researchers at Yale University.

Diene (128), with its in-built stereochemical markers reacted with a

selection of aldehydes under either zinc chloride or boron trifluoride

etherate catalysis to give dramatically different ratios of pyrones

(129) and (130) (Table 1 0 ) . The catalyst system of zinc chloride in

tetrahydrofuran showed a marked preference towards £^s adducts (129)

whilst boron trifluoride etherate in dichloromethane promoted trans

selectivity.

A « i) BF3 .Et2 0 , CH2 CI2, -78°C ii)7FA

B = i) ZnCI2, THFii) NaHCO,iii) TFA

Evidence for the intermediacy of (131), previously presumed, was

obtained by rapid quenching of the reaction between diene (128) and

benzaldehyde in the presence of zinc chloride which afforded enol

ether (131) in 41% yield together with pyrone (129) (26%). (131)

was converted to (129) on treatment with trifluoroacetic acid (TFA).

Table 1 0

Entry R Method % Yield (1291

% Yield (1301

1 nC5Hn A 2 1 69

2 nC5Hn B 91 2

3 Ph A 23 6 8

4 Ph B 78 < 2

5 Ph(CH2 )3 A 17 64

6 - Ph(CH2 )3 B 83 < 2

(128 ) PhCHO TFA (129 )

Ph

Reaction of a 4:1 mixture of dienes (132) with benzaldehyde for

36 hours under the influence of zinc chloride yielded enol ether

(133) and pyrone (134) in 53 and 31% respectively, together with

unreacted (E,E)-diene (132b). The (E,E)-diene was recovered and

resubjected to the reaction conditions. After 86 hours the cis and

trans adducts (134) and (135) were isolated but only in 3% and 11%

yield respectively.

OTBS OTBS

OCH3 OCH3

(132a) (132b)

TBSO

(133) (134) (135)

The significant difference in the rate of reaction of dienes

(132a) and (132b), the lack of detectable acyclic intermediates and

the strict stereochemical suprafaciality in the mode of diene addition

are all consistent with established findings in the greatly studied

all-carbon pericyclic Diels-Alder reaction. By analogy with the

latter reaction the preference for £i^ isomers can be considered to be

due to endo alignment of the 'R ' group of the aldehyde. Secondary

orbital overlap does not explain this selectivity since such an effect

is observed even when the 'R ' group is aliphatic (Table 10, entry 2).

A reasonable alternative interpretation has been proposed based on the

anti orientation of the 'R ' group relative to the Lewis acid/solvent

array co-ordinated to the carbonyl oxygen. If the catalyst/solvent

array has greater steric requirements than the 'R 1 group then the

apparent endo selectivity for the 1R ’ group actually reflects a

preferential exo orientation of the catalyst/solvent array.

To obtain further insight into the mechanism of the boron

trifluoride mediated cyclocondensation process the reaction between

diene (128) and benzaldehyde was quenched 5 minutes after the addition

of the catalyst. The products consisted of an 8:1 mixture of trans

54

and cis pyrones (136) and (137) respectively in 48% yield and a 2:1

mixture of threo and erythro a 1 do1-like products (138) and (139) in

46% yield. (138) and (139) were converted to the pyrones (136) and

(137) respectively by treatment with trifluoroacetic acid. When a

1.5:1 mixture of the threo and erythro products (138) and (139) was

resubjected to the reaction conditions for 30 minutes, adducts (136)

and (137) were isolated in 28% yield in a ratio of 4:1 together with a

1:1.2 mixture of hydroxy enone starting materials (138) and (139)

respectively. These findings indicate that although alcohols (138)

and (139) do undergo cyclisation the rate is too slow to account for

the formation of the bulk of the pyrones.

1. CH2 CI2, -78 °C, BF3 .Et2 0,5 min2. Quench

(140) (141)

55

These observations (vide supra) together with similar results

obtained from an investigation of the reaction between Danishefsky's

56diene and cinnamaldehyde led to the proposal of siloxonium species

(140) and (141) as intermediates in the process. By analogy with the

ring closure reaction of (138) and (139) it is reasonable to expect

that (140) would cyclise more rapidly than (141), whilst the latter

would prefer to form the alcohol (139). It is apparent from the

ratios of both the pyrones and the aldo!-like products that the

preferred siloxonium species is the threo isomer (140). This threo

selectivity has been observed in the aldol reaction of enol silanes

57with aldehydes in the presence of boron trifluoride etherate.

This methodology has been applied to the synthesis of the lactonecc

(142) (Scheme 19) a key intermediate in Masamune's synthesis ofCO

6o-deoxyerythronolide B aglycone (143). Lactone (143) represents

the Cj-Cg portion of the macrocycle (143). Reaction of chiral

aldehyde (144) with diene (128) under the influence of boron

trifluoride etherate afforded a mixture of cis and trans pyrones (145)

in the ratio 4.3:1 with complete Cram facial control.

56

(128)

♦ V ' -Ph

(144)2. TFA

(145a) 4.3

(145a)

O

(146) R-COOH(147) R = CHO

( 1 2 8 )

(148a)

43%

(148b)

27%

Scheme 19

(149) R = CHO (142) FUH

(1 4 3 )

57

The major isomer (145a) was converted into the Prelog-Djerassi

lactone (146) in four steps.Cyclocondensation of aldehyde (147),

derived from (146), with diene (128) in the presence of zinc chloride

provided a mixture of cis products (148). X-Ray crystallography of

the major stereoisomer confirmed that it was the desired Cram product

(148a) and thus, the minor isomer was concluded to be the opposite

facial isomer (148b). Ozonolysis of (148a) provided the formyl

protected intermediate (149).

This synthesis served a dual purpose; not only did it provide an

attractive illustration of the cyclocondensation methodology but, it

also addressed the question of facial selectivity. The first

cyclocondensation was achieved with complete Cram control whilst the

second occurred with moderate facial specificity. Furthermore, the

utility of the cyclocondensation methodology for the construction of

both cyclic and acyclic stereochemical arrays is highlighted. In the

synthesis (vide-supra) two cyclocondensations replaced the two

58stereo-controlled aldol reactions used by Masamune.

It should be noted that small changes in either the diene

substitution pattern or the solvent system when using the same

aldehyde and catalyst can result in reversal of selectivity. The

reaction of diene (128) with benzaldehyde in the presence of boron

trifluoride etherate in dichloromethane gave a 1:4.6 ratio of the

pyrones (129) and (130). When dichloromethane was replaced by toluene

a 2.2:1 ratio was obtained. It is suggested that the cis preference

of the latter may reflect a greater tendency for the involvement of a

pericyclic mechanism in toluene.

58

When the 4:1 mixture of dienes (132a,b) was reacted with

benzaldehyde under the influence of boron trifluoride etherate a

2.8:1 ratio of ci_s (134) to trans adduct (135) was obtained in 73%

55cyield . This result stands in sharp contrast to the previously

observed trans preference with diene (128). Again greater

contribution from a pericyclic mechanism has been proposed to explain

55cthis selectivity reversal.

Cis-selectivity with either zinc chloride or boron trifluoride

etherate was observed when a mixture of the trioxygenated dienes

(150, R = ^Bu) reacted with acetaldehyde (Scheme 20).^*

o c h 3

R(CH3)2SiO

OCOPh

(150a)

o c h 3

f ^ O C H 3

R(CH3)2SiOx' ' ^ RfCHskSiO

OCOPh

(150b) (1 50c)

r ^ O

OCOPh

CH3CHO Lewis Acid

OCOPh

(151a) (151b)

Scheme 20

CatalystDiene Ratio R = t*Bu(150a):(150b):(150c)

Product Ratio (151a):(151b)

%Yield

ZnCI2 4 : 2 : 1 3.3 : 1 90

BF3 .Et20 3.1 : 3.4 : 1 4 : 1 73

(152 ) (153)

59

This cis preference with boron trifluoride catalyst and the diene

mixture (150, R = ^Bu) is not fully understood. The inductive effect

and potential chelating ability of the benzoyloxy group have been

suggested as candidates to explain these results. The major pyrone

(151a) has been further transformed to the a and /3-methyT fucosideC 1

triacetates (152) and to (±)-methyl 3,4-diacetyldaunosamide (153).

The synthesis of /5-methyl 1incosaminide (157) constituted the

first fully synthetic route to a higher mono-saccharide (Scheme

21). The synthetic sequence contained two key steps. The first

was a cyclocondensation between diene mixture (150, R = Me) and

crotonaldehyde. In the presence of boron trifluoride etherate the

cis pyrone (154) was produced in 67% yield. The trans pyrone could

be detected in the crude reaction mixture. The second critical step

was electrophilic addition of bromohydrin to methyl glycoside (155)

which occurred with high diastereofacial selectivity to afford the

bromohydrin (156). The latter was transformed into the mono

saccharide (157).

60

(150) +

r =ch3

Scheme 21

A similar strategy (vide supra) has been applied to the synthesis

of (±)-3-deoxy-D-manno-2-octulopyranosate (KDO).^ In this case, a

modification to the cyclocondensation step was made in the light of

the poor results obtained with acrolein and suitable dienes. The

synthesis was successfully completed by employing

a-(phenylse1eno)propionaldehyde as an acrolein equivalent.

Danishefsky and Bednarski explored the possibility of using

complexes of oxaphilic rare-earth metals as catalysts for cyclo-

64condensation reactions. Success was achieved with the complex

Euffod)^. The reaction of various aldehydes with the substituted

diene (128) afforded cyclic enol ethers (158). Virtually complete

endo specificity was observed in this reaction with both aromatic and

aliphatic aldehydes. This was contrary to results with Danishefsky's

diene in which aromatic but not aliphatic aldehydes gave good endo

selectivity.

61

(128) + RCHO

R % Yield

Ph 66CH3 66n̂ 6R13 9̂

The Euffod)^ catalysed cyclocondensation of the aldehyde (159),

formed by two all-carbon Diels-Alder reactions, and diene (160) was a

crucial reaction in the synthesis of vineomycinone methyl ester _

(161) (Scheme 22). The mildness of the catalyst system, which allows

the isolation of the enol ether (162), is note worthy. In this

synthesis (vide supra), hydroboration of the enol ether double bond

sets up the chiral centres of the C-glycoside ring (Scheme 22).

TESOH

TESO

TESO,,,.

1.CH2CI2i BH3. Me2S

62

An alternative rare-earth metal complex:- tris(6,6,7,7,8,8-

hep tafluoro-2,3-dimethy1-3,5-octanedionato)ytterbium (Yb(fod)g) was

employed in the synthesis of the monensin lactone (163) (Scheme

23).^ Reaction of aldehyde (164) with diene (165) under the

influence of Ybffod)^ afforded the required Cram product_(166) in 56%

yield. The long reaction time required for complete consumption of

the reagents necessitated the use of the more stable triethylsilyloxy

diene rather than the trimethyl silyloxy derivative to avoid conversion

of the cyclic product into the dihydropyrone (167). The enol ether

(166) was transformed into the desired lactone (163) in six steps.

The latter is a degradation product of monensin and an intermediate ^n

Still's total synthesis of this ionophore.^

Scheme 23

o

The cyclocondensation of aldehydes with 1,1,3-trioxygenated

dienes (168) in the presence of Eu(fod)g has been reported by threero

different sources (Table 11). A particularly significant discovery,

made by Midland and Graham, was that unactivated ketones also react

with diene (168b) under the influence of various Lewis acids (ZnClg*

63

BFg.I^O, Euffod)^) to afford cyclocondensation products (169). The

intermediacy of the readily hydrolyzed, orthoester (170) was proven by

its isolation from the reaction of acetophenone with diene (168b).

Table 11

uon3

(169 )

Diene R4 R5 % Yield (169) Ref.

(168a) Ph H 85 68a,b

(168a) CH3(CH2)5 H 73 68a

(168a) (CH3)2CH H 69 68b

(168a) CHgCH:CH H 70 68b

(168b) Ph H 70 68c

(168b) Ph c h3 40 68c

(168b) CHg c h 3 67 68c

(168b) CHg H3CCi C 63 68c

(168b) -(C2̂ )5 " 52 68c

The availability of both antipodes of the chiral europium

complex, tris[3-(heptafluoropropylhydroxymethylene)-camphorato]-

europium(III) (Eu(hfc)g), provided the opportunity to investigate

the possibility of chiral induction in the cyclocondensation of

aldehydes with siloxy dienes. Reaction of a variety of dienes with

benzaldehyde in the presence of (+)-Eu(hfc)g in deuteriochloroform

afforded cis-pyrans (171) but with only modest enantiomeric enrichment

(Table 1 2 ) . Slight improvements in the enantiomeric excess

64

(e.e.)» ascertained by optical and n.m.r. measurements on

hydroxyesters (172), were found when the methoxy group at in the

diene was replaced by t-butoxy. In each case, reactions performed

with (+)-Eu(hfc)g resulted in an enantiomeric excess in favour of the

L-dihydropyrone (171).

o

o c h 3 o h

V Ph(172 )

Table 12

R1 R2 R3 % ee

c h 3 H H 18

t-Bu H H 38

c h 3 c h 3 c h 3 36

t-Bu c h 3 CHg 42

t-Bu c h 3 H 39

t-Bu OTMS H 42

A second 'approach towards chiral induction in cyclocondensations

utilized chiral auxiliaries installed in the 1-alkoxy group of the

diene. Thus, a selection of dienes were prepared containing either 1-

or d-menthyloxy groups. Their reactions with benzaldehyde in the

presence of the Euffod)^ catalyst afforded approximately equal

quantities of the L- and D-pyranoses (174) and (175) respectively

(Table 13). ^* ^ The ratios obtained with the d-menthyloxy diene

65

(173b) were as expected equal and opposite to those obtained with the

enantiomeric auxiliary (173a).

PhCHOEu(Fod) 3

( 1 7 3 ) a. R ■ l-Menthyl b. R =d-Menthyl

Table 13 Results with diene (173a)

R' R- Ratio(174a):(175a)

H H 33 : 67

c h 3 H 45 : 55

OAc H 45 : 55

c h 3 c h 3 49 : 51

Chiral induction in cyclocondensations was brought to fruition

by the combined use of menthyloxy dienes and Eu(hfc)g. The results

of (+)-Eu(hfc)g mediated reactions between benzaldehyde and the chiral

dienes (173) are outlined in Table 14.70’̂ Combination of the

modestly L-pyranose selective d-menthyloxy diene with (+)-Eu(hfc)g,

which also has a small intrinsic enantiotopic preference" for the

L-pyranoses, showed little change in overall selectivity from those

obtained with Eu(fod)g. In sharp contrast the reaction of

benzaldehyde with the D-selective L-menthyloxy dienes catalysed by

L-selective (+)-Eu(hfc)g displayed a strong preference for the

L-pyranoses (Table 14).7^ ’71

Ph66

~ y - cWSO/ R'OR

PhCHO,(+)-Eu(hfc) 3

( 1 7 3 ) l*Menthylb. R =d-Menthyl

Ph

Table 14

R* R" Ratio(174a):(175a)

Ratio(174b):(175b)

H H 25 (63): 75 (37) 37 (37): 63 (63)

c h 3 H 8 (55): 92 (45) 41 (45): 59 (55)

OAc H 7 (55): 93 (45) 41 (45): 59 (55)

CHg c h 3 18(51): 87 (49) 49 (49): 51 (51)

Figures in parentheses indicate the facial selectivityobtained for Eu(fod) 3 reactions of the same dienewith benzaldehyde.

The select!vities indicated in Table 14 are not caused by double

diastereoselection in which two isolated complementary steric biases

mutually reinforce one another, since it is the mismatched pair of

chiral moieties which afford good selectivities in these cases. The

cyclocondensations are controlled by a specific interactivity between

the two chiral elements which results in the inherent facial

selectivity of the auxiliary being inverted upon interaction with the

chiral catalyst.

This type of methodology has been applied to the synthesis of

L-glucose (175) (Scheme 24).^ The Eu(hfc)g mediated reaction of

diene (173a, R'=R"=H) with benzaldehyde yielded a 3:1 ratio of L- and

D-pyranose derivatives (174a, R'=R"=H) and (175a, R'=R"=H)

respectively. When the modified diene (176), (incorporating an

1-8-phenmenthyl auxiliary and t-butyldimethylsilyl protection), was

utilized in the cyclocondensation reaction a 25:1 ratio of L- and

D-pyranoses, (177)

67

and (178), was obtained. Treatment of enantiomerically pure (177)

with trifluoracetic acid afforded pyrone (179) in 75% overall yield.

The latter was converted in a series of steps to L-glucose (175).^

Ph Ph

R = l-8 -phenmenthyl

TFA

(175) (179)

It should be noted that this methodology is limited to those

glycosides with a cis relationship between the anomeric substituent

and the side chain at the 5-position (i.e. ^-glycosides) because of

the endo selectivity of Eu(hfc)^. Furthermore no enantioselection70

was obtained (181) with trioxgenated dienes of the type (180).

Thus, in order to prepare chiral galactosides by this type of protocol,

separation of the mixture of pyranoses (181) would be necessary.

TESO

ArCHO(+)-Eu(hfc) 3

( 1 8 0 ) R = Menthyl

The reaction of triethylsilyl 1-menthyloxydiene (183) with

furfural in the presence of Eufhfc)^ afforded a 5:1 mixture of

72products. The major component (184), isolated in 66% yield, was

converted by a sequence of reactions including a novel carbon Ferrier

displacement to the dihydropyran (185). Burke and coworkers have

68

indanomycin and Nicolaou has utilized (186) as an intermediate in

74the total synthesis.

transformed (185) into (186), the dihydropyranoid segment of

73

o

( 1 8 6 )

Burke

When a nr /? hetero substituted aldehydes are used as dienophilic

components in cyclocondensations the stereochemical outcome of the

process is dependent upon whether or not chelation control is

operative. The reaction of aldehyde (187) with diene (188) in the

presence of zinc chloride, boron trifluoride etherate or Ybtfod)^

yielded a mixture of pyrones (189) and (190) in approximately equal

quantities. However, with magnesium bromide in tetrahydrofuran

cycloadduct (189) was isolated as the sole product in 76-80% yield.^

Similarly, high stereoselectivity was obtained in the reaction of

75other a-oxygenated aldehydes with a selection of dienes.

6S

o

Et

(187)

Approach of the diene

(191)

(189)

(190)

The stereochemical assignment of (189) and related systems was

proven by n.m.r. analysis and conversion to rigid bridged ketals.

The latter chemical sequences also served to illustrate some uses of

these cyclocondensation products. For example, pyrone (189) upon

debenzylation, cyclisation, reduction and deoxygenation afforded

75cexo-brevicomin (192). Similarly the debenzylated product (193) was

75rconverted in three steps to the mouse androgen (194).

( 1 8 9 )86%

BF3 .Et2 o,DMS

H

( 1 9 4 )

70

The stereoselectivity of the cyclocondensation reaction (vide

supra) can be explained by invoking the Crain chelation model.

Coordination of the two oxygens by magnesium affords the syn conformer

(191). Approach of the diene from the least hindered a face of (191)

corresponds to the observed stereospecificity. Support for this

hypothesis came from the reactions of diene (128) with benzaldehyde and

the aldehyde (195) in the presence of magnesium bromide. The

former, a control experiment, afforded a mixture of pyrones (196a) and

(197a) in a ratio of 38:1 and in 50% yield. The preferential

formation of the cis. adduct (196a) was consistent with a pericyclic

mechanism and endo topology, analogous to cyclocondensations mediated

55cby zinc chloride. In the case of aldehyde (195) if chelation

control was effective then an exo disposition of the 2-benzyloxy-

propanyl group in the product would be expected. This was borne out

in practice. Reaction of aldehyde (195) with diene (128) and

magnesium bromide catalyst afforded the trans pyrone (197b) as the

sole product in 50% yield.

OCH,

o

T * xTM S O -^^s

( 1 2 8 ) a. R = Phb. R = CH(OCH2 Ph)CH2 CH3 (1 9 5 )

o

When the same two reactions (vide supra) were conducted with

titanium tetrachloride as catalyst completely contrary results were

obtained. The titanium tetrachloride catalysed reaction of aldehyde

(195) with diene (128) afforded a mixture of cyclic and a1dol-like

products. Complete cyclisation was achieved by treatment with

trifluoroacetic acid which provided only the £is pyrone (196b) in 93%

yield. When the reaction was repeated with benzaldehyde a mixture of

71

cis and trans products, (196a) and (197a) respectively was produced

in a 1:8 ratio. The isolation of a 1 do!-like products and the

threo-specificity obtained with benzaldehyde suggested that titanium

75tetrachloride behaves in a similar fashion to boron trifluoride. It

should be noted however that this may well be an over simplification

in view of the ability of titanium to form six-coordinate species; a

facility not available to boron. Again the difference in selectivity

between benzaldehyde and aldehyde (195) suggests that the latter

reacts via the syn conformer (191).

This type of methodology has been applied to the synthesis of

methyl peracetyl-a-hikosaminide (198) (Scheme 25).^ The cyclo

condensation product (200) derived from furfural and diene (199) in

the presence of Eu(fod)^ was converted to the heptodialdose (201).

Magnesium bromide mediated cyclocondensation of aldehyde (201) and

diene (199) afforded the undecose (202) as the sole product in 75%

yield. The latter was then readily transformed into the target

compound (198).

AcO-AcO-

AcO-

CH2 OAc

OAcOAc

OAc

( 1 9 8 )

72

OBz

(199)

( 2 0 2 )

Exo, chelation Control

O

75%

(199)MgBr2, 0 °C, CH2 CI2 : PhCH3

( 2 0 1 )

AcO-AcO-

AcO-

CH2 OAc

OAcOAc

Scheme 25

(198)

The reaction of (R)-glyceraldehyde acetonide (203) with

Danishefsky's diene in benzene in the presence of zinc chloride

produced the (5S,6R)-heptulose (204) in 722 yield. 51 Similar

cyclocondensation of aldehyde (203) with magnesium bromide as catalyst

afforded predominantly heptulose (204) (37%) together with the C^-

epimer (3%). The stereochemistry of (204) is consistent with Cram

formulation. The absence of chelation control with this aldehyde is

73

not properly understood but the same phenomenon has been observed

78with organometal1ic nucleophiles.

o

(203)

+

OTMS

OCH3

OCH(CH3 ) 2

(205)

(204) has been converted into chiral 2,4-dideoxy-D-glucose (205)

which corresponds in both relative and absolute configuration to the

51pyranose portion of the antihypocholestemic agent compactin.

Cyclocondensations of sugar derived aldehydes provides a

75c 79convenient route to carbon linked disaccharides. ’ The boron

trifluoride mediated reaction of aldehyde (206), derived from

D-galactose, with trioxygenated diene (150, R=Me) afforded a crude

product mixture which upon treatment with trifluoroacetic acid

/ % 79provided a single cyclocondensation product (207) in 62% yield. The

stereochemistry of the product indicates reaction occurred with endo

topology and Cram controlled diastereofacial selectivity. This has

been rationalised on the basis of an anti orientation of the

carbon-oxygen bond of the pyran ring and the formyl group (206) which

79minimises the dipole-dipole repulsions. Attack of the diene then

occurs from the least hindered face; opposite to the hexose ring.

74

Similar cis selectivity with diene (150 R=t-Bu) and acetaldehyde in

the presence of boron trifluoride etherate has been observed (Scheme

20).61

( 1 5 0 )R-CHg

62%

1. BF3 .Et2 0 , Ether, -78 °C2. TFA, CCI4, RT

O

O

( 1 5 0 )

R-CHg

54%

1. BF3 .Et2 0 ,2 . TFA

( 2 0 8 )

When aldehyde (208), derived from D-ribose, was treated with

diene (150 R=Me) under the influence of boron trifluoride etherate,

79the cyclocondensation product (209) was isolated. X-Ray

crystallographic analysis of (209) indicated that the facial

selectivity had again occurred in a Cram controlled manner. However,

a trans substitution pattern in the pyranose ring indicated exo

selectivity. Thus, changing the sugar moiety can have a dramatic

effect on the topology of the reaction. This may be duer to a

reduction of steric encumbrance to exo approach of the diene in the

case of aldehyde (208). Aldehyde (208) has been employed as the

dienophilic component of a cyclocondensation in the synthesis of

80(heptaacetyltunicaminyl)uracil.

75

The lability of /?-alkoxy aldehydes compared to their

a-oxygenated counterparts necessitated an acceleration of the rate of

cyclocondensations with these substrates. This was achieved by

75altering the solvent system. Thus, reaction of/3-alkoxy aldehyde

(210) with diene (128) in the presence of magnesium bromide in 4:1

benzene/ether (c.f. tetrahydrofuran witha-alkoxy aldehydes) produced

a mixture of cyclic and acyclic products which were treated with acid

in the usual way. Two pyrones (211) and (212) were isolated in a

ca .1:1 ratio.^

(128)BnO

( 2 1 0 )

80%

1 . MgBr24:1 C6 H6;Ether2 . TFA

(128) + (210) 94%BnO

1. BF3 .Et20 CH2 CI22 . TFA

(213) 60%

Three other isomers

The enforced solvent change resulted in a shift of reaction

55cmechanism towards the Mukaiyama aldol type. Though good chelation

control was observed there was virtually no endo/exo selectivity.

When the reaction (vide supra) was repeated with boron trifluoride

etherate as catalyst the major product (213) isolated from the four

component isomeric mixture (ratio 22:4:4:1) was that predicted by

Cram controlled diastereofacial selectivity with overall exo

75topology. The search for a catalyst with which chelation control

together with high endo specificity would be achieved led to titanium

tetrachloride. When this was employed as catalyst in the reaction of

76

diene (128) and aldehyde (210) and the resultant product treated with

trifluoracetic acid the only dihydropyrone isolated was (211) in 55%7c

yield. (211) possessed the stereochemistry expected from cis-

chelation control. Cyclocondensation product (211) has been utilized

in the synthesis of the polypropionate sector of the ansa antibiotic

. c 81 rifamycm S.

The first total synthesis of the ionophore zincophorin (214) has

recently been achieved (Scheme 26). The synthetic strategy required

cyclocondensation of aldehyde (215) with diene (128). This was

accomplished in 80% yield using magnesium bromide catalysis in

dichloromethane. The stereochemistry of the resulting product (216)

is that which would be predicted from a chelation controlled process

with exo topology. The high exo selectivity is somewhat surprising in

view of previous observations with aldehyde (210).^ One possible

explanation is the use of dichloromethane as solvent. Modification of

(216) afforded (217) which upon successive ring opening, protection

and oxidation afforded aldehyde (218). The aldehyde (218) formed

from the anomeric site was then subjected to a second cyclo

condensation reaction with the 4E diene (132b) under the influence of

boron trifluoride etherate. The desired product (219), formed in

46% yield, was converted to the aldehyde (220) required for the Julia

coupling reaction. Coupling with the previously synthesised sulphone

(221) followed by reduction, deprotection and esterification afforded

zincophorin methyl ester (222).

77

( 1 2 8 ) +

46%1. BF3 .Et202. PPTS

O

Scheme 26

It is clear (vide supra) that the stereochemical outcome of

cyclocondensation reactions with aldehydes susceptible to chelation is

governed by the catalyst system employed. Table 14 contains a brief

78

summary of cyclocondensations with diene (128) The fourth selectivity

permutation of cis selectivity with Cram control has not yet been

achieved. It should be noted that as examples have shown (vide supra)

small changes in aldehyde, diene or solvent can have a striking effect

upon both the topology and facial selectivity of the cyclocondensation

reaction.

Table 14

Lewis Acid MechanismType

Endo/ExoTopology

Cram/ChelationControl

MgBr2 Pericyclic exo * Chelation

BF3 .Et20 Mukaiyama exo Cram

T iCI4 Mukaiyama endo Chelation

* Poor selectivity observed with beta-alkoxyaldehydes

3.4 Formaldehyde.

B.B. Snider's formal synthesis of pseudomonic acids A and C

incorporates a novel quasi-intramolecular Diels-Alder reaction which

83employs paraformaldehyde as the dienophilic component. The diene

precursor (224) for this cycloaddition was prepared by a dimethyl-

aluminium chloride mediated ene reaction of 1,5-hexadiene (223) with

paraformaldehyde followed by acetylation. Reaction of (224) with

paraformaldehyde in the presence of 4.5 equivalents of ethyl aluminium

dichloride afforded a 37% yield of a 16:1 mixture of (225) and (226).

An outline of the reaction course is included in Scheme 27.

79

EtAICI2

+ ° CH ^OH

37%

HCHO,EtAICIo

0 . o1:1 C H ^C R jN O ., £25 °C, 12 h

(225)

IJ oA

o c oS

TBDPSO

(230)

OH

(2 2 6 )

(2 2 4 )

EtAlCI2I

0+

(227)

HCHO

AcO' .o*°+ -

Al̂Cl' xci

h2o

(225)

OAc

Scheme 27

80

It has been suggested that initially the ethylaluminium dichloride

coordinates to the acetate group which is more basic than

bond so that this second ene reaction occurs at the terminal double

bond affording the complex (227). Formal loss of ethane from (227)

provided (228) which then coordinated further with formaldehyde.

This complex (229) was set up for the quasi-intramolecular Diels-Alder

reaction which occurred in a stereospecific manner to yield (225)

after hydrolysis. The formal synthesis was completed by conversion of

(225) into (230), an intermediate in Kozikowski's synthesis of

84pseudomonic acids A and C.

The quasi-intramolecular reaction of diene (231) with

paraformaldehyde in the presence of dimethylaluminium chlorideoo

afforded the alcohol (232) in 68% yield. When the reaction was

repeated with acetaldehyde a 1 :1.2 mixture of the endo and exo

products, ((233) and (234) respectively), was isolated in 57% yield.

Replacement of acetaldehyde by a more bulky aldehyde could well

improve the selectivity.

83formaldehyde. This apparently deactivates the internal double

(HCHO)nMe2AICICH2CI2, 24 h

(2 3 1 ) ( 2 3 2 )

(CH3 CHO)n Me^lCI CH2CI2, 24 h ( 2 3 3 ) 1 : 12 (2 3 4 )

81

The cyclocondensation of monomeric formaldehyde with the

dioxygenated diene (235, R=Et) has been accomplished by catalysis

with bornyloxyaluminium dichloride. The product (236) was isolated

in 50% yield. 535

OR

HCHOO

TMSO

(2 3 5 )

82

The zinc chloride mediated cyclocondensation of paraformaldehyde with

the diene mixture (150, R=Me) afforded the desired pyrone (237).

Reduction of (237) provided an 8.5:1 mixture of alcohols (238a) and

(238b) respectively. The major isomer (238a) was converted in a three

step sequence to a separable anomeric mixture of arabinopyranosides

(239a/b, 1:1). Deesterification and reprotection of either anomeroc

afforded (±)-diacetone arabinose (240) (Scheme 28). Clearly cyclo

condensations with paraformaldehyde provide a convenient route to

natural products based on pyrans with an unsubstituted 2-position.

3.5 Carbonyl compounds with heterodienes.

The boron trifluoride mediated reaction of 2-aza-l,3-butadienes

with aldehydes provided good yields of dihydrooxazines (241) (TableO C

16). In some cases (Table 16, entries 1,2) the reaction took place

in the absence of the catalyst. Spectral data on (241) established

the c_i_s relationship between the C-5 and C-6 substituents of the

oxazine ring. Such stereochemistry was rationalized in terms of a

concerted [4+2]-cycloaddition with endo selectivity. However, the

reaction of diene (242) with benzaldehyde afforded a 2.5:1 mixture of

trans-oxazines (243) and (244) respectively. This stereochemical

outcome was attributed to a change in the reaction mechanism to a two

step process via the zwitterionic species (245). No explanation was

provided for this mechanistic change, but it would be reasonable to

assume that the presence of the bulky cyclohexyl group disfavours the

more sterically demanding pericyclic mechanism.

+

c h 2 r 2

1N ^ R '

R2

BF3 .OEt2 C6Mb, 608C 1 - 2 days

Table 16

Entry R1 R2 R3 % Ylield

1 Ph Me Ph 95

2 Ph Me 4-N02 *C6 H4 90

3 Ph Me 4-CH3 -C6 H4 75

4 Ph Me c 4 h4o 76

5 Ph Me n-C4 H9 70

6 Ph Me i-C3 H7 75

7 Ph Et Ph 85

8 4-CH3 -C6 H4 Me Ph 80

9 4-CH3 -C6 H4 Me 4*CH3 -C6 H4 75

BF3

84

A variety of carbonyl compounds undergo [4+2]-cycloaddition

reactions with polyfluoro-2-acyliminopropanes (Scheme 29). The

iminopropanes (246) and (9) reacted with aromatic and a#-unsaturated

aldehydes to provide excellent yields of the adducts (247) and (248)

respectively. The process is analogous to the reaction of nitriles

with acyl imines (Section 2.5).

nY ° F 3 + H"

cf2x

A s / V 70 - 90 %

v X — -Ph' Y ° ^ caH

N Oc Xf3c/ cf2x

(2 4 6 ) X»N02 .F Y=H, N02, NMg2, OMg (247 )

y °N^ x CF3

1cf3

0

. J L 60-80%

11 -----------------------y T n

- N °

F3c r c F 3

(9) (248)

R = Me, CF3i CH (CF3) 2 R1 = H, Me

Scheme-29

Thioacyl isocyanates (249), generated from the thermal

decomposition of heterocycles, behave as diene components in

88 89Diels-Alder reactions with carbonyl compounds. * Thus (249)

reacted with aldehydes, ketones and a/3-unsaturated aldehydes to afford

oxathiazinones (250)(Table 17). In the case of the

c^-unsaturated compounds addition occurred across the carbon-oxygen

rather than the carbon-carbon double bond.

85

(250)

Table _17

R1 R2 R3 % Yield Ref

OEt PhCH:CH H 65 89b

OEt PhCHC H 62 89b

OEt n o 2 -c 6 h4 H 48 89b

OEt CHg CHgCO 69 89b

OEt -(CH2 )5 - 63 89b

CI-C6 H4 CH2 :C(CH3 ) H 35 89a

c i-c 6 h 4 CH2 :C(Ph) H 64 89a

4. C-S Dienophiles.-

4.1 Thioketones.

Many Diels-Alder reactions using a diverse array of thioketones

are recounted in the literature.* The susceptibility of- simple

aliphatic thioketones to enethiolization and polymerisation has

generally restricted the use of these substrates. However, polycyclic

aliphatic thioketones such as adamantanethione (251) readily undergo

90cycloadditions with a variety of dienes. The reaction of thione

86

(251) with substituted butadienes afforded the desired cycloadducts in

90moderate to excellent yield (Scheme 30).

(2 5 1 )

R

(251 )

toluene 110°C , 48 hr

(2 5 2 )

a. R1 « Me, 80% ^b. R1 a H, R2 a Me 82% 4 5 55

(2 5 1 )

OMe

OTMStoluene

110 °C, 24 hr

OMe

64%

H +

( 2 5 4 )

Scheme 30

The unsymmetrical diene, piperylene provided a single cycloadduct

(252a). However, isoprene yielded a 55:45 mixture of regioisomers

(252b) and (253b). Frontier molecular orbital theory predicted

products which did not coincide with the experimental observations.

The outcome of the reaction between piperylene and (251) was explained

on the basis of the steric interaction between the adamantane skeleton

87

and the terminal methyl group of the diene disfavouring formation of

(253a). Similar reasoning was proposed to rationalize the formation

of adduct (254), the sole product of the reaction between (251) and

Danishefsky's di e n e . ^

The cycloaddition of adamantanethione (251) with isoindole and

isobenzofuran afforded the adducts (255) in good yields. Similar

reactions with furan and 1,3-diphenyl-isobenzofuran were unsuccessful.

P

p

o^-Unsaturated carbonyl compounds behave as dienes in their

91reactions with thione (251) (Scheme 31). The stability of the

4H-1,3-oxathiines (256) isolated from these cycoadditions was

dependent upon diene substitution. Crystals of (256a) were stable to

the atmosphere at room temperature whilst (256d), an oil, decomposed

at 5 °C. o-Quinone methanides (257), generated in situ from

substituted sal icy! alcohols (258a) or the amines (258b) proved to be

91beffective diene components in Diels-Alder reactions with (251).

The high regiospecificity of these cycloadditions has been explained

in terms of frontier molecular orbital theory in which the dominant

overlap is between the LUMO of the diene and the HOMO of the

91dienophile; an inverse electron demand Diels-Alder reaction. Data

88

from kinetic studies was consistent with a second order rate

expression. The activation parameters were similar to those reported

for 'conventional' Diels-Alder reactions and the rate constants were

found to be almost independent of solvent polarities. These findings91suggested a pericyclic mechanism.

a R1 = R2 = R3 = H 94%b. R1 = R3 = H, R2 = Me 71%c. R1 *= R2 *= H, R3 = Me 29%d . R1 =M ef R2 = R3 = H 82%

(258b )

a W = X = Y = Z = H 90%b. W = Y = Z = H, X = Me 55%c. W = X = Z = H ,Y = N 0 2 89%d. X = Y»=Z = H, W = OMe 51%

Scheme 31

The cycloaddition of thiobenzophenone with acrolein occurred at

140 °C but the adduct was too unstable to be isolated. However,

thiobenzophenone reacted with o-quinone methanide (257a) to afford

the diphenyl cycloadduct (259) in 79% yield.

89

Dondoni has reported an unusual hetero Diels-Alder reaction of

thiobenzophenone (258) and N-ary1 ketenimines (Scheme 32). The

reaction of C,C-diphenyl- and C,C-dimethylketenimines (259) with (258)

provided the [4+2]-cycloadducts (260) in good yields. The analogous

reaction with N-phenylmethylketenimine (261) produced the

benzothiazine (262) together with the thietane (263). Thietanes

(264) were the sole products in the reactions of (258) with C,C-

disubstituted ketenimines where in the N-aryl group possesses ortho

(259)

a R = Ph, X = 4-CHg 85% b R = Me, X = 4-CHg 80% c R - Me, X - 3-OCHg 85%

1 J

(263)47%

(2 5 8 ) +

R

°^NAr CCl4 ,45 - 60 °C

(265)

R

(264)

R = Me, Ar = 2,6-(CH3 )2 C6 H3 30%R - Ph, Ar - 2,4,6-(CH3 )3 C6 H3 30%

Scheme 32

90

From kinetic and theoretical studies on these two cycloaddition

pathways it was concluded that both processes occurred by pericyclic

mechanisms. The relative amounts of thietanes and benzothiazines

formed was rationalized by a combination of steric and electronic

effects. With C,C-disubstituted ketenimines the electronically

favoured 1,2-cycloaddition pathway is suppressed due to inhibition of

approach of the thione to the carbon carbon double bond from either

face. In the case of ortho substituted N-aryl ketenimines the

reaction across the heterodiene is restricted so thietane formation

is preferred.

When C-vinylketenimines are reacted with thione (258) a third

mode of cycloaddition is possible. This new reaction pathway was

promoted by a judicious choice of substrate (266) which contained the

elements necessary to suppress the alternative addition processes.

Thus, reaction of (258) with (266) afforded the adduct (267) in 86%

yield.93

(266)

+ (258)

4.2 Thioaldehydes.

Simple aliphatic thioaldehydes, like their thioketone

counterparts, are unstable. Over the past few years several methods

of generating both aliphatic and aromatic thioaldehydes in situ have

91

94-96been developed. Baldwin and Lopez prepared thioacetaldehyde

and thiobenzaldehyde by thermolysis of the appropriate thiosulphinate

(268) in toluene. The thiocarbonyl compounds (269) were immediately

94trapped with a selection of dienes (Scheme 33). With 2-ethoxy-

butadiene and thiobenzaldehyde a mixture of regioisomeric

dihydrothiopyrans (270) were formed which hydrolysed to the thianones

(271).

Ft ^ S '

(268)

cri;

IX]

[ X(269)

(272a)

Heat

Toluene, 1 0 0 °C

RCHjSOH * [X](269)

_ Toluene,OEt 1 0 0 “C E,°

XL, • "°XlPh(270a)

I

(270b)

I

Ph

(271a)

31%

(271b)

13%

R'

x x(272a) R = Ph, R' = H 97%(272b) R *P h , R’ *=Me 87% (273a) R - Me, R '» H 82% (273b) R - Me, R’ - Me 76%

( 2 7 4 ) R = Ph 95%R ts Me 83%

Scheme 33

The anthracene adduct of thiobenzaldehyde (272a) proved to be a

good source of the thioaldehyde. When (272a) was heated with

2,3-dimethylbutadiene, dihydrothiopyran (274) was isolated together

92

with anthracene. In the case of thioacetaldehyde, the anthracene

adduct (273a) proved resistant to thermolysis. However the

9.10- dimethyl analogue (273b) liberated thioacetaldehyde which was

trapped by 2,3-dimethylbutadiene. The lability of the

9.10- dimethyl anthracene adduct (273b) to thioaldehyde extrusion

compared to the unsubstituted case (273a) is, as the authors suggest,

most likely the result of the relief of steric congestion. This

method of generating thioaldehydes has the advantage that the

by products, anthracene and 9,10-dimethylanthracene, are relatively

inert. Thus, the possibility of incorporating more sensitive

functionality into the diene component of the reaction is available.

An intramolecular Diels-Alder reaction of an aliphatic

thioaldehyde was accomplished by the thermolysis of the sulphinate

(275) and afforded a l z l mixture of thiabicyclononenes (276).^

An alternative method of generating thioaldehydes is by the

fluoride induced /^-elimination of stabilized aryl thiolate anions

from a-silyldisulphides (277).^ The efficiency of the elimination

and the stability of (277) is dependent upon the stability of the

aryl thiolate leaving group. 2-nitro and 4-chlorophenyldisulphides

were relatively stable but on exposure to fluoride underwent

93

*elimination to the desired thioaldehydes. These were trapped by

cyclopentadiene to afford a mixture of exo and endo adducts (278)

95(Table 18). In each case the endo isomer predominated.

SiMe2 R'

R ^ S - S /^

(277)

R R* X Conditions Exo/Endo % Yield

H Me 4-CI A - 67

Et Ph 2-N0 2 A 1 : 6 92

i-Pr Ph 2-NOz B 1 :7 6 6

Ph Me 4-CI A 1 :7 90

c-Hex Ph 2-N0 2 B 1 :5 58

i " - 1

Ph 2-N0 2 A 1 :4 65

Method A CsF, THF, RT Method B Bu4 NF, 0 °C

The first stable aliphatic thioaldehyde was isolated by Vedejs

and Perry. Photolysis of phenacyl neopentyl sulphide (279)

afforded an insoluble white polymer (280). Vacuum distillation of

(280) provided 2,2-dimethylpropanethial (281). This is stable in

solution for up to 16 h at 20 °C. Reaction of thial (281) with

Danishefsky's diene provided the desired adduct (282) after acidic

workup in 25% yield.

94

PhY ^ S^ C(CH3)3O

(279)

59%

C6H6, hv

(C u S 0 4, filter)

ft-BuCHS^

(280)

40 - 50%

250 °Ct-BuCHS

(281)

t-BuCHS +

TMSO

OMe

25%

1 . CH2 CI2 ,RT 5 min

2 . THF, HCI

t-Bu

(282)

The photolysis of phenacyl sulphides has been used to generate a

variety of thioaldehydes which were subsequently trapped by various

dienes in a Diels-Alder fashion (Tables 19,20). This thioaldehyde

preparation is thought to proceed by a six centre Norrish type

/ % 97fragmentation (Scheme 34).

Scheme 34

The process has been applied to the synthesis of thioaldehydes

with aliphatic and aryl substituents and also to those possessing, 97

electron withdrawing groups (for example acyl, ester, cyano).

Diels-Alder reactions of the latter class of thiocarbonyl compounds,

acceptor substituted thioaldehydes, occurred readily with a 1-2 fold

excess of diene providing the desired adducts in reasonable yield

(Table 19).97

96

The regio- and stereospecificity of the reactions

closely resemble the outcome of 'conventional' Diels-Alder

processes. The major isomers formed are those in which the

thioaldehyde substituents are 'ortho' or 'para' to the diene donor

group. This selectivity is opposite to that obtained with activated

carbonyl dienophiles such as ethyl glyoxylate. (Section 3.1). The

major component of the thiocarbonyl Diels-Alder product mixtures

results from an endo orientatio