SOME OXIDATION REACTIONS of SUBSTITUTED AMIDES a Thesis

SOME OXIDATION REACTIONS OF

SUBSTITUTED AMIDES

A thesis presented by

ROGER MUNRO UPTON

in partial fulfilment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

•of the

UNIVERSITY OF LONDON

Imperial College

London June 1978 2

Abstract

Recent transition metal-catalysed reactions of peroxides, of preparative value in organic synthesis, have been reviewed. Molybdenum, vanadium, and tungsten compounds typically promote electrophilic oxidations, notably epoxidation and oxidation at nitrogen and sulphur, often involving metal-directed regio- and stereoselecti- vities. A second category of catalysed peroxide reactions involves the formation of hydroxyl, alkoxy, and acyloxy radicals from, for example, iron and copper-catalysed decompositions of various organic peroxides. Secondary amides and heteroaromatic amides have been converted into the corresponding hydroxamic acids by the oxidation of the trimethylsilylamide derivatives using molybdenum pentoxide complexes. Primary amides, ureas, urethanes, and imides were generally inert towards similar oxidation conditions. The oxidation of N-silylated Leterocyclic compounc::. by molybdenum pentoxide (Mo0 5.L) gave the N-oxides of benzimidazole, adenine, and 4-quinolone. The i3C n.m.r. spectra of the parent amides, the ethyl imidates, and the trimethylsilylamides of series of para-substituted acetanilides, aliphatic lactams, and heteroaromatic amides are reported and the concentrations of the trimethylsilylamide tautomers evaluated by integration of their 13C n.m.r. spectra. The trapping of a postulated 1,3-dipole [_c4j,+ generated from diaziridinones, N-chloroureas, -semicarbazides, and -methoxyureas, and from N-carbamylsulphilimines has been unsuccessfully attempted. Alternative reaction 3

pathways gave an imidazoline from dimethylurea, 1-methyl- -4-phenyl-1,2,4-triazolidin-3-one from dimethylsemicarba- zide, and 3,3- dimethyl-4-phenyl-1,2,4-oxazolidin-5-one from hydroxyphenylurea. Furthermore, a silver(I) catalysed conversion of N-chloromethoxyureas into aryl or alkyl urethanes via formation of the free isocyanate was observed. 4

Contents

Abstract 2,3

List of Tables 5

Acknowledgements 6

Part I : Review

1. Some transition metal-catalysed reactions of 8 peroxides:

A. Electrophilic reactions 9

B. Radical reactions 43

References to Part I 62

Part II : Results and Discussion 2. The synthesis of hydroxamic acids by the 71 oxidation of trimethylsilylamides 3. 13C N.m.r. studies of trimethylsilylamides 110 4. Oxidation reactions of molybdenum pentoxide 128 5. Reactions of activated ureas 135 Experimental 155 References to Part II 200 5

List of Tables

1. Silylation and oxidation results for secon- 82 dary amides. 2. Data for silylation of p-substituted 84 acetan ilides. 3. Oxidation data for AVO-trimethylsilylanilides 85 4. Silylation and oxidation data for aryl 88 carboxamides. 5. Silylation and oxidation data for multifunc- 90 tional secondary amides. 6. Silylation and oxidation data for heteroaro- 95 matic amides. 7. Silylation data for ureas, urethanes, and 96 imides. 8. Data from 'H n.m.r. spectra of trimethyl- 103 silylacetanilide. 9. Data from I H n.m.r. spectra of trimethylsilyl- 103 -2-pyrrolidone. 10. 13C Chemical shifts of acetanilide deriva- 116 tives. 11.C Chemical shifts of p-chloroacetanilide 117 derivatives. 12.C Chemical shifts of p-methoxyacetanilide 118 derivatives. 13.C Chemical shifts of p-nitroacetanilide 119 derivatives. 14. Substituent effects on the shielding of 120 aromatic carbon nuclei. 15. 13C Chemical shifts of 2-pyrrolidone deriva- 122 tives. 16.C Chemical shifts of E-caprolactam deriva- 122 tives.

17. 1 3C Chemical shifts of 2-pyridonederivatives. 123 18. t3C Chemical shifts of 4-quinolone and 4- 124 -pyridone derivatives. 19. Concentrations of silylamide tautomers in 126 13C n.m.r. spectra. 20. Silylation and oxidation of nitrogen hetero- 130 cycles. 6

Acknowledgements

The author wishes to express his sincere appreci- ation to Professor P.G. Sammes, for his enthusiastic encouragement and advice during the course of this work. The author is indebted to Shell for providing a C.A.S.E. award and, in particular, to Dr. R.J.G. Searle for his supervision during the work carried out at the Shell Laboratories, Sittingbourne. The author wishes to thank the technical staff at Imperial College --Mr. K.I. Jones for microanalyses, Mrs. Lee for mass spectra, and especially Mr. Jack Peppercorn, Chris, and Dorothy --; the technical staff at the City University; and also Mrs. E. Baldeo for the typescript. Finally, thanks must go to Alan Weedon, Robert Watt, Nigel Walsh, Janet Markham, Lynn Davies, Nigel Broom, Guido Serra-Errante, All Jaxa-Chamiec, and other colleagues who helped with discussions and provided a friendly atmosphere in which to work. 7

PART I

REVIEW 8

CHAPTER 1

SOME TRANSITION METAL-CATALYSED REACTIONS OF PEROXIDES

An extensive body of literature exists on the action of metal ions upon peroxides. This covers a wide range of topics, many of which are of significant industrial value, and which include the use of peroxides, catalysed by metals, as polymerisation initiators, 2 in autoxidation, and in organic syntheses,3 and the inorganic aspects of metal catalysis, particularly in relation to biological processes.4 This introductory review covers recent aspects of the oxidations of organic substrates by peroxides in the presence of transition metals.

Two general classes of metal-catalysed peroxide oxidations have been distinguished. Low-valent transition elements, typically iron (II) and copper (I), catalyse the generation of free radicals and these oxidations are characterised by the redox reactions of radical species with metal ions. 5 The second category comprises reactions catalysed by, for example, molybdenum (VI), vanadium (V) 9

and tungsten (VI) compounds, which form metal-peroxide complexes that promote polar, electrophilic oxidations.

A. Electrophilic Reactions

The earliest examples of electrophilic oxidations relate to the formation of glycols from olefins by the reaction of hydrogen peroxide catalysed by vanadium pentoxide s or tungstic acid .7 The intermediate epoxides were also made accessible with, for example, tungsten trioxide and, later, by the use of organic hydroperoxides, catalysed by soluble metal complexes. 9,10 A general affinity for heteroatoms,11 hydroxylations at carbon and nitrogen, dehydrogenations and the ketolisation of olefins have also been observed. As such, transition metal- catalysed oxidations with hydroperoxides bear resemblance to the reactions of peroxycarboxylic acids and yet these reagents show valuable differences in regio- and stereo- selectivities .12''3 Superior catalytic activity has been attributed to a high degree of Lewis acidity and low oxidation potential of the metal. 14,15 These properties appear to be most effectively combined in 1to(VI), V(V), W(VI), and Ti(IV)16 though many other metals exhibit some catalytic activity.17 Homogeneous or heterogeneous systems can be used, and recently, polymer-supported catalysts18 have demonstrated improved reactivities. However, substitution-labile catalysts are required to permit coordination with the

hydroperoxides (cf. Scheme 1); thus the substitution -inert complexes of EDTA and diethylenetriamine are in-

effective catalysts for epoxidation. 19 Stable metal- 10 peroxo complexes (8) 20 have also been used in organic synthesis and these provide useful additions to the metal- catalysed hydroperoxide oxidations.

1. Epoxidation Owing to its industrial potential the epoxidation of olefins by the catalysis of tert-alkylhydroperoxides has been mainly investigated. 21a Molybdenum compounds appear to be the best homogeneous or heterogeneous catalysts,10 consistently achieving very high epoxide yields over a wide range of conditions. An exception occurs in the epoxidation of allylic alcohols for which vanadium compounds are superior to molybdenum. The scope of catalysts, hydroperoxides, and other reaction parameters have been summarised in earlier reviews.21

Mechanism - Metal-Hydroperoxide Complexes The mechanism of epoxidation of olefins using hydroperoxides in the presence of molybdenum or vanadium catalysts is generally considered to involve an electrp- philic oxidant, 21a demonstrated by the negative correlation between the epoxidation rate of m and p-substituted styrenes and the Taft substituent parameters.22° Competi- tive free radical decomposition of the hydroperoxide also occurs .23 Many groups have examined the kinetics of metal- catalysed epoxidations,1°, 16, 22- 25 and apparent first- order relationships with respect to the hydroperoxide, the olefin substrate, and homogeneous catalysts have been observed. Recent studies 15,22 have established the validi- ty of rate equations that further incorporate the alcohol 11 by-products, which are strong inhibitors of the reaction. These observed kinetics closely relate to the Michaelis- Menton equations for enzyme catalysis with product inhibition. The generally accepted mechanism is outlined in Scheme 1, for vanadium catalysts. 25 Similarly, molybdenum-catalysed reactions involve metal-hydroperoxide intermediates, 15,22 although the roles of molybdenum- olefin complexes 26 and molybdenum-peroxo complexes,2? analogous to the epoxidations by molybdenum pentoxide (Scheme 5), have also been speculated.

Scheme 1

V n+ activation vv [1]

+ RO2H V!--OR [2] I (1) OH

V-11-- R + + H0~ [3] OH

V!--OR + 0`I [4] H

V!-OR + RO2H Vv--OR + ROH [51 H OH

ROH ROH Vv V1-(ROH) --- V- (ROH)2 [6] 12

An initial, rapid oxidation of the catalyst to its highest valence state, i.e. V(V) or Mo(VI), occurs with conversion into a soluble, active catalyst. In the case of molybdenum, these are 1,2-diolates (2) 28 derived from the corresponding epoxides, whereas vanadium catalysts appear to partially retain their original ligands.15 Catalyst activation is followed by reversible complexation with the hydroperoxide (Equation 2). The hydroperoxide is polarised by the strongly Lewis acidic catalysts 1415 and epoxidation is considered to involve rate-determining nucleophilic attack by the olefin substrate on the electron- deficient M-ROOH complex (1), with subsequent proton transfer. Molybdenum compounds are known to form ternary, olefin-molybdenum-hydroperoxide complexes 15,29 and these have also been implicated in the epoxidation step.29 The catalyst is regenerated by ligand exchange between the product alcohol and the hydroperoxide (Equation 5). The formation of non-catalytic complexes (Equations 4-6) demonstrates the potential inhibitive effects of alcohols.

0 1 R1\/ON „70~~ R Mo R2 OZ NO R2 0II

(2) 13

Early proposals 10,25 for the mechanism of epoxidation essentially involved the transition state (3), while Sheldon 23 has postulated the transition states (4) and (5), analogous to peroxycarboxylic acid epoxidations.30

Scheme 2

H Hr~ k ~ " 0: M lr--0i

I R R (3) (4) X O H I I

(5)

(6)

The mechanism via (4) is applicable to oxo-molybdenum and oxo-vanadium catalysts, otherwise the reaction procedes via (5), resembling boron-catalysed epoxidations31 Emphasis has recently been given to the alternative

transition states (6) and (7), in which the metal is coordinated to the less-hindered oxygen of the peroxide.32 Polarisation of the peroxide bond is promoted in (6) by electron donation to the Lewis acidic metal, and in (7) by an acidic proton. These mechanisms initially produce an epoxide complexed to the metal.

Other molybdenum catalysed reactions of hydroperox-

ides 23 , affording a-alkoxyalkanes, usually account for less than l0ō of the total product formation. The competitive radical reaction (Scheme 3) has been shown to be primarily catalysed by Mo(V) species.23'34 Since the formation of hydroperoxide radicals R02 is facilitated by strong oxidants, then Cr(VI), Mn(VII), and even to some extent V(V) catalysts, for example, are less selective towards epoxidation compared with the milder oxidants, and generally superior epoxidation catalysts Mo(VI), W(VI), and Ti(IV) .14,15

Scheme 3

fast lio n + RO2H MoVl + RO'

Mo + • RO;

Movi + .R02 H Mo . ROOH

A second side reaction that is significant at eleva- ted temperatures is the Lewis acid-catalysed ring-opening

of epoxides (Equation 7).10

ROH o6+ + [7]

Metal-Peroxo Complexes Molybdenum pentoxide, which contains chelated peroxy oxygen,20 has also been used for the epoxidation of olefins. Various groups 35 have shown this reaction to proceed via a peroxo-molybdenum-olefin complex (Scheme 5) and, as with other metal-peroxide systems, the inhibition of oxidation by alcohols or donor ligands (Scheme 4).

Scheme 4

M o0 5 . HMPA . L

Mo05.II PA

Oi efi M o0 5 . HMPA . 01 Epoxide

The mechanism of the reaction (Scheme 5) is thought to involve a 7r-complex with olefin substrates, which gives the cyclic or-complex (10) by a 1,3-dipolar cycloaddition (9) . Subsequent displacement of bio=0 affords the epoxide.

Scheme 5

Mein

(8) 0 O 1 jM.o~ ~O O (9)

O O O II O j,Mo + 1~Mof ~O ~ (10) O 0 O/ y

An alternative mechanism (11) has also been postulated. 36,15 A 3-membered transition state as in (11) was inferred from the epoxidation selectivities of molybdenum pentoxide, and also of organic peracids, which differ greatly from those of azide addition and osmylation, typical 5-membered cyclic processes. Moreover in the epoxidation of allyl alcohol by molybdenum pentoxide,36b the olefin does not appear to directly complex with molybdenum, as required in Scheme 5. However, the high stereo-

specificity observed in epoxidations by Mo05.b, relative to both peracids and molybdenum-hydroperoxide reagents,l3 is thought to evince a cyclic intermediate (10), rather than the less-sterically hindered species (11). 17

N,11 40 6F---

Molybdenum-peroxo complexes have been implicated as the active oxidants in molybdenum-catalysed epoxidations by hydroperoxides. 35°' 27 Peroxymolybdates have been isolated from Mo-hydroperoxide mixtures 27 and have been detected by u.v. during epoxidations.27b Recent 180-labelling studies 32 of oxomolybdenum- and oxovanadium-catalysed epoxidations, however, indicated that metal-peroxo species were not formed in these reactions.

Substrates The epoxidation of simple olefins has received much attention in the patent literature, but recently selective oxidations of allylic alcohols, have found use in routine syntheses. Epoxidation rates and yields increase with the elec- 6 tron density of the olefin substrates, 10,1 as expected -for the proposed electrophilic mechanisms given in Scheme 2. The enhancement of epoxidation rate with increased alkyl-substitution and conversely, the retarding effects of electron-withdrawing groups are indicated in Table 1. In the reactions of hexa-l.4-diene (12), 3- and 4-vinylcyclohexene, and isoprene, epoxidation occurs at the most substituted double bonds.'6

Table 1 Substituent Effects in Epoxidation 10,16

Epoxide Reaction Epoxide Substrate Yield (%) Substrate Time Yield (%) (a) (b) (min)

1-Octene - 36 Allylethyl- 30 77 ether

2-Octene 23 76 Allylchloride 120 75 Cyclohexene 30 77 1-Cyclohexenyl- 60 41 acetonitrile 2-Methyl 52 - Ethyl 180 72 -2-pentene methacrylate

O (12a) (6:1 )

\\/\/ (12b) -~' (11:1)

vO (4:1) (13) (14)

(15) (16)

Conjugated dienes are less reactive than isolated olefins and do not generally give diepoxides,16 although crotepoxide (15) has been prepared in 15% yield by the vanadium-catalysed bis-epoxidation of the corresponding dihydroxy cyclohexadiene. 37 The bis-epoxidation of 1,4-dienes has been shown to occur readily with dicyclo-

pentadiene, giving the bis-exo product (16), diallylether and 1,5-cyclo-octadiene,16 with bi(cyclohexenyl)38 and 4-vinylcyclohexene, but not 3-vinylcyclohexene.

Polar substituents that are more remote than the allylic position appear to have little effect on epoxidation. 6-Substituted norbornene derivatives (17) are readily oxidised, the electron-withdrawing substitutents

X = OH, OAc, Cl, CN, CH2OAc, CO2CH3 showing slightly lower rates than for X = H, CH3 , CH2OH.21b Enol-acetates and 39 ethers are quantitatively epoxidised by hydroperoxides with molybdenum or vanadium catalysts and even the very unreactive ethyl methacrylate (Table 1) gives 70% of the epoxide. Allylic epoxidations are sensitive towards the nature of the a-substituents; ethers, halides, and nitriles showing reduced rates (Table 1). The epoxidation of allylic alcohols shows exceptional behaviour in that reaction rates and yields are enhanced 16 , particular- 1 2, 1 6 ly with vanadium catalysts and pertungstates 40, which are often superior to molybdenum compounds - in contrast to other olefin epoxidations. 15' 1 6 3-Hydroxy- hexa-1,5-diene, which affords a 1:1 mixture of the 1,2- and 5,6-oxides with molybdenum catalysts, is rapidly and selectively epoxidised in the presence of vanadium acetylacetonate giving 80% of the 1,2-epoxyhexene (18)16

0 ‘b,x OH

(17) (18)

The rearrangement of allylic hydroperoxides to give epoxyalcohols (Equation 8) is catalysed by vanadium and tungsten compounds and has been related to vanadium-

catalysed electrophilic epoxidations of allylic alcohols ~1,41 Similarly, cyclohexene is converted into the 1,2,3-triol (20) via such a rearrangement of the intermediate allylic hydroperoxide (19).42 In contrast, a radical process has been proposed for the conversion of the allylic hydroperoxides of a,p-unsaturated esters into the corresponding epoxides (Equation 9).43

[8] OOH OH

H OH

(19 ) (20)

OOH OH

CO 2R CO2R [9]

Regio- and Stereoselectivity

Transition metal-catalysed epoxidations by tert- alkylhydroperoxides show high degrees of stereo- and regio- selectivity, owing to the steric requirements of the metal-hydroperoxide oxidising species (1) and also the directive effects arising from neighbouring group complexation with the catalyst.

In the reactions of 2-pinene and 3-carene with tert- pentylhydroperoxide and molybdenum pentachioride, complete stereospecificity is observed, as with peroxybenzoic acid epoxidations, with exclusive formation of the a-epoxides 21

(21) and (22); and similarly for 2(10)-pinene and

2-carene. 44 Epoxidation of these bicyclic terpenes with molybdenum pentoxide also affords the ac-oxides.21b

(21) (22)

A comparison of the stereochemical outcomes observed in the epoxidations of 45-steroids is summarised in Table 2. The predominance of cr-epoxi_dation known for 45 organic peracids is paralleled by molybdenum pentoxide, which shows a very high specificity, although the epoxidation of cholesterol has also been reported to yield only 60% of the a -isomer.46 Molybdenum-hydroperoxide reagents appear to be less selective than either Mo05.L or peroxycarboxylic acids, even though the possible inter- mediacy of molybdenum pentoxide has been proposed.47 This lower selectivity of Mo-ROOH oxidants has also led to the novel formation of the less substituted epoxide (14) of isoprene ." a

The more rigorous steric requirements of metal- peroxides are further exemplified by the 4,4-dimethyl- -cholestene (23), which is inert towards both molybdenum pentoxide and t-pentylhydroperoxide with molybdenum pentachloride or hexacarbonyl, whereas (23) readily forms a

mixture of epoxides (82% a.; 18% ) with peracids. 22

13 ' 47 Table 2 Epoxidation of d 5-Steroids

% a -isomer Substrate PhCO3H Mo/ROOH Mo05.L

Cholest-5-ene 90 55 100 3c.-Chlorocholest-5-ene 85 60 95 Cholesterol 90 70 90 Spirost-5-en-3 j3 -ol 90 50 90 3 p -Acetoxy-4,4-dimethyl 82 no reaction -cholest-5-ene (23)

In the epoxidation of hexa-1,4-diene, 76 the cis-isomer (12b) shows the greater reactivity. This con-

trasts with the epoxidation of cis, t r a ns, tra ns -1, 5, 9- cyclododecatriene by a boron-catalysed hydroperoxide, which gave only the mono-epoxide (24) from oxidation of a trans-double bond.48

(24)

The presence of complexing groups, notably OH and OAc, in olefinic substrates can significantly affect the epoxidation products. Vanadium catalysts promote selective epoxidation of allylic alcohols, for example in the predominant formation of 1,2-epoxy-3-hydroxyhex-5-ene (18)!6 Oxidation of geraniol and linalool gives the mono-epoxides (25) and (26) respectively, in high yield and with greater

23 than 95% isomeric purity .1 2 Selective epoxidations have also been observed with cyclohepta- and cyclooctadienols.49

O (25) /0 (26)

Vanadium-catalysed epoxidations of allylic alcohols are postulated to involve the ternary complex (27), which has a favourable geometry for epoxidation, 12, 16 and which is analogous to the proposed transition state (28) of the pertungstate epoxidations of allylic alcohols.4G In the alternative, yet similar transition states (29) and (30), which incorporate the intermediate metal-peroxide oxidants (Scheme 2) recently proposed by Sharpless,32 the geometrical requirements of epoxidation are considered to be more adequately fulfilled.

Scheme 6

R 0 ,O V~~0\ OH (27) N (28) O\/ --~ O 0

H4)

O'I 77R 0 OR

/ ~~O' (29) (30) ~

The improved efficacy of vanadium over molybdenum catalysts has been correlated with the greater stability of vanadium-allyl alcohol complexes.16 This is reflected in the inhibition of epoxidation by alcohols, whereby M-ROH formation (Equation 6) severely retards vanadium- catalysed epoxidations Z5 relative to molybdenum.16

The vanadium-catalysed epoxidations of allylic alcohols is a highly stereospecific process.12'50 2-Cyclohexen-1-ol gives 98% of the syn-epoxide (31), whereas a 40/60 ratio of syn- and anti-isomers is obtained from 1-acetoxy-2-cyclohexene. 12 4-Hydroxycholesterol (33) affords a very high yield of the 5,6p -oxide (34) in greater than 95% isomer purity, with t-Bu00H and V0(acac)2 ; a contrast to peracid oxidations giving ca. 70% of the /3-epoxide .12

OR OR OR

0 +

(31) (32)

(33) ww (34)

HO HO 0

OH OH

(35) (36) (37) 25

The catalysed epoxidation of the medium-ring allylic alcohols (35) affords the syn-epoxyalcohols5° (36; n = 2 to 5). However, only the anti-isomers (37; n = 3,4,5) were observed from peracid oxidation of the larger rings, owing to the predominant conformation of the substrate being incompatible with a syn-directing transition state. The formation of a vanadium-allyl alcohol complex is thought to override the conformational restrictions and promote the syn-epoxidation.

The vanadium-catalysed oxidation of the cycloocta- dienol (38) gives an exo-hydroxy bicyclo-dihydropyran derivative (39) in ca. 80% yield, whereas peracid epoxidation of (38) affords the anti-epoxyalcohol (40) .49 (39) arises from a thermal- or vanadium-catalysed rearrangement of the corresponding syn-epoxyalcohol only, thus the vanadium-hydroperoxide reagent, which strongly promotes syn-epoxidation, produces (39) as the major product.

P, OH 0 HO il iR

(39 )

The epoxidations of acyclic allylic alcohols are also stereoselective; very high proportions of erythro- epoxyalcohols (with less than 2% threo -isomers) are obtained

from both the molybdenum- and vanadium-catalysed oxidations of (41) - (43).51 Conversely, the pentenol derivatives (44) - (46) afford greater than 85% of the

t h r e o - epoxides .

W(41) (42)

OH OH

4) (45) (46)

OH OH OH

The formation of the erythro-epoxyalcohol (47) from vanadium-catalysed epoxidation of 2-methylhept-1-en- -3-ol (43) , followed by specific epoxide-cleavage and deoxygenation, has provided a stereoselective synthesis of the (Z) olefin (49) (Scheme 7) . 5° Stereospecific bis- epoxidation of the bisallylic alcohol (50), and conversion into the triene (51) has been used in the synthesis of d/-C 18 Cecropia juvenile hormone (52).5°

Scheme 7

Bun

(43) H_ ~ H._ (47) 4 HO C H 3 HO CH3

Bu" OH (49) /4 (48) f C / \ H H H3 HO CH3 27

OR -O R

Farnesol

HOM OH O~ OH (50) CO2 Me

(5 2) --— 0

A recent development in stereoselective epoxidations has been the asymmetric epoxidation of allylic alcohols by the use of chiral chelate complexes of molyb- 52 denum and vanadium.53 3-Methylbut-2-en-1-ol, geraniol and nerol have been oxidised by cumene hydroperoxide with the molybdenum complexes of (—)-N-alkylephedrine (53) to give fairly high optical yields (maximum 33% enantiomeric excess, ee), but rather low chemical yields (<48%) of the corresponding epoxyalcohols (54), (2D), and (55).52 Increased chemical yields could be generally obtained at the expense of the optical yield.

O N il Me-- `~ 11 Mo --.. del II 144 R = Me, Et 0 b Ph

(53 ) 28

R1 —/ OH R1 Ov---OH y

R 2 R2

R1 R2

Me Me 2(R) (54) Me 2(R),3(S) (55)

Me 2(R),3(R) (25)

Chiral hydroxamate ligands (56) have also been used for the vanadium-catalysed asymmetric epoxidations of geraniol, a -phenylcinnamyl alcohol (57), and the 1-hydroxy- methylcyclohexene (58), all giving dextrorotary epoxy- acetates, after acetylation.53

Ph- Ph

~OH R\ Ph Ph (57) (59) HOB \O

R = Me, Ph, 2,6-Me2Ph

OH (55) oeOH (58) (60)

The epoxidation of (57) using the N-phenylhydroxamic acid (56; R°Ph) as the chiral ligand afforded 30% of the corresponding epoxide (59) with an induction of 50% ee. At higher reaction temperatures, (59) was formed in 84% yield, but with a lower induction of 40% ee. Geraniol achieved a maximum induction of 30% ee (with 86% conversion to epoxide), and (58) attained an induction of 44%ee 29

(75% conversion).

The epoxidations of homoallylic alcohols also exhibit significant stereospecificity, for example, the Mo- or V-catalysed oxidation of 3-cyclohexen-1-ol gave 95% of the syn-epoxy alcohol (61).12 Selective epoxidation of the cyclopentenol (62) is also effected by molybdenum or vanadium catalysts (Equation 10).54 Even the bishomoallylic alcohol (63) is epoxidised much faster than simple olefins, using vanadium catalysts, but not with molybdenum•12

(61) (64) (15)

OH OH

OH (63)

In a synthesis of crotepoxide (15),37 the vanadium -catalysed oxidation of the 1,3-diene (64) afforded the bis a-epoxide (15) from both allylic and homoallylic syn-directed epoxidations.

Further stereospecific epoxidations occur with 3P-acetoxy- Q5 -steroids.13 Molybdenum-hydroperoxide reagents differ markedly from molybdenum pentoxide and organic peracids, in furnishing predominantly P-epoxides 30

(Table 3). Whereas epoxidation by molybdenum pentoxide is determined by the purely steric requirements of the intermediate cycloadduct (Scheme 5),35 molybdenum-hydroperoxide complexes (1) are considered to coordinate with the 3g-acetoxy groups as in (65), thus promoting epoxide attack on the P-face.

Table 3 Epoxidation of 3p-Acetoxy- 45 -steroids13

% a -isomer Substrate PhCO3H Mo/ROOH Mo05.L

3s-Acetoxyandrost- 65 20 100 -5-en-17-one 3P-Acetoxycholest-5-ene 70 45 80 3J3-Acetoxyspirost-5-ene 65 35 95 3f3-Acetoxypregna- 65 35 90 -5,16-dien-20-one

0 CH3—/ Mo---OR . O' u QH (65) C, /_'.;

A template-directed remote epoxidation of steroidal olefins has recently been described.55 On esterification of the 3a-hydroxyl function of the 17(20)-pregnene (66) and 4,17(20)-pregnadiene (67) derivatives with the iso- propylphenylacetate template (69; n=1), the molybdenum- 31 catalysed epoxidations give ca.60% of the 17,20-oxides as the sole products. Epoxidation does not occur with the extended template (69; n=2), nor with the 9(11), 17(20) pregnadiene (68), reflecting catalysis by a template-Mo complex, which has strict geometrical requirements for oxidation.55 This resembles other template- directed remote oxidations.56

. RO ROR (66) (67)

RO'

OH R= -f-CO(CH2)n (69) R_ -fC0(CH2), (70)

The hydroxyester templates (69) and (70) have also been used for the remote epoxidations of the di- and tri- terpenes (71) and (72).57 At low substrate concentrations, epoxidation is only catalysed by molybdenum complexed to the template and preferentially occurs at the terminal olefins, giving 57-83% of the 10,11-epoxide from (71) and 51-53% of the 14,15-epoxide from (72) plus 22-36% of its 10,11-epoxide. 32

CH 2OR

J `/b 7 CH2OR 6,7 10,11

10,11 V 141f;y 1 (71) (72)

R = (69) or (70)

Since the template-directed epoxidation was intended to occur at the 6,7-double bonds in an extended chain conformation, the terpenes (71) and (72) were considered to have a folded conformation, e.g. as in (73), that would promote epoxidation of the terminal olefins.

(R) R - HO----Mo---OBut OH (R) (73)

2. Oxidation at Carbon Centres In addition to epoxidations, metal-peroxide reagents are known to promote further oxidations of epoxide intermediates, and to effect hydroxylations and other oxidations.

Olefin Oxidations The oxidation of trisubstituted olefins by a large excess of hydroperoxide with molybdenum, tungsten, or vanadium catalysts affords a-hydroxyketones in good yield.23'58 Oxidation of dehydropregnenolone acetate occurs at the

5,6-double bond giving the 5-hydroxy-6-oxo derivative (74): 33

Similarly in the oxidation of cholesterol, the 3,6-dione

(75) has been prepared by the dual oxidation of the

secondary alcohol and the olefin functions.

AcO

This ketolisation reaction has been proposed to

occur via a radical process (Scheme 8),88 although

Sheldon 23 has shown that the reaction is only catalysed by molybdenum pentachloride and attributed this to an acid-

catalysed reaction of an intermediate epoxide with the

hydroperoxide, by adventitious hydrogen chloride.

Scheme 8

H OH / H O

R R R R R R

Dihydropyran is oxidised by molybdenum pentoxide

in chloroform solution to give the dialdehyde (76) via an epoxide intermediate.59 The 2-methoxytetrahydropyran (77) is obtained from reaction in methanol.

Mo05.L OHC—(CH2)30CHO (76)

(77)

CO,H (R1-H) 11 NHCOR2 NH CO R2

Ar-C=C-Ar Ar Ar.CO.CO.Ar 12

I ArCOZR

Indoles are readily oxidised by hydrogen peroxide and sodium molybdate - equivalent to permolybdic acid -

to give amido-ketones or. amido-acids (if R1 =H) (Equation 11)60 Similar cleavage of the 2,3-bond of indoles is effected by molybdenum pentoxide61

The oxidation of diarylacetylenes by molybdenum pentoxide gives benzil, though with t-butylhydroperoxide, catalysed by molybdenum hexacarbonyl, further oxidation 62 occurs giving benzoates (Equation 12). In contrast to the peracid oxidation of acetylenes, which produces

oxirenes that can undergo aryl migrations, the molybdenum-

based oxidants are postulated to form metal-oxocarbene

complexes (78), that inhibit rearrangements.

Hydroxylations

The electrophilic and aprotic oxidant, molybdenum pentoxide has been used for convenient syntheses of

alcohols and phenols by the direct hydroxylation of

carbanions. Both molybdenum pentoxide and the related

chromium pentoxide complexes convert n-butyllithium into

n-butoxylithium (Equation 13),fi3 and similarly aluminium trialkyls give aluminium alkoxides (Equation 14) 4

Mo05•L- B'J L i Bun OL [131 Cr05.L

Al O—AI( ! —►0 H [14] 3 2

MOOPH A rß r Ar MgBr ArOH [15]

OH OH OH /\''c OH 0 0 4. 0 0 [1 6]

OH [17] RO RO R'

The hydroxylation of aryl Grignard reagents

(Equation 15) with Moo 5 .HMPA . Pyridine (MoOPH) readily 36

affords phenols .65 1,2-Dihydroxy- and 1,4-dihydroxy naphthalenes are formed from a-naphthol (Equation 16), though further oxidation to the semiquinone radicals is observed.66 The reaction of lithium enolates of esters and lactones with MoOPH (Equation 17) comprises an efficient method of a-hydroxylation.57 Oxidation of 2-phenyl- cyclohexanone affords the predominantly trans-acyloin (79) from the kinetic enolate, generated with lithium diiso- propylamide (LDA), or the alternative acyloin (80) using potassium hydride as base. Methyl ketone enolates undergo competitive Aldol reactions, but dehydropregnenolone acetate was shown to give the 21-hydroxy derivative (81) in moderate yield by an inverse addition process. a-Hydroxylation of 4-phenylbutan-2-one was achieved by oxidation Of the corresponding oxime dianion (Equation 18).

HO. Ph Ph LDA KH

(79) (80)

(81)

0 OH [18] Ph Ph Ph

Molybdenum pentoxide has also been used in the hydroxylation of a-cyanocarbanions to give cyanohydrins

(Equation 19).68 This method is particularly useful for the preparation of aldehyde cyanohydrins, thus 4-phenyl- butyronitrile, stearonitrile and 3,3,3-triphenylpropano- nitrile afford 55-60% of the corresponding cyanohydrins.

MoOPH R ON [19]

R = Ph (CH2 )2 , CH 3 (CH2 )15, Ph3C

The hydroxylations of carbanions are thought to involve the formation of intermediate mol"l,date esters

(82) by carbanion attack at the electrophilic peroxide bond of the oxidant. (Scheme 9)

Scheme 9

0 O

0 11 /O MO X 0 -- Or (82)

L R L R

X = H, CO 2 R, OCR, CN HO X + OZMo I R •O Miscellaneous Oxidations In contrast to radical-catalysed oxidations of

alcohols, 69 molybdenum-hydroperoxide systems convert a

wide-range of secondary alcohols to the ketones in very

high yields. 70 and similarly a-hydroxyketones are obtained from diols, e.g. trans-cyclohexanediol and 2a,3 -dihydroxy- pinane afford the ketols (83) and (84) respectively and. 3P-acetoxy-5a,6a-dihydroxy steroids give 6-oxo products (Equation 20).

,OH O O (83) (84) OH

[2o] AcO AcO

NO2 0 CH2OH NO2—{ O CHO [21j

Chromium pentoxide has recently been used for an efficient oxidation of p-nitrobenzyl alcohol to the aldehyde (Equation 2l)."

Fused aromatic systems have been oxidised in high yields by hydroperoxides catalysed by molybdenum pentachloride, generally producing quinone derivatives (Equa- tion 22).72 Further oxidation to carboxylic acids (85) is observed with phenanthrene substrates.

0 O 0 22]

..g, CO2H (85) CO2H

R R

R'CO COR' [23]

A facile and near quantitative oxidation of dihydro- pyridines to pyridines has been effected by molybdenum pentachloride and tert-pentylhydroperoxide (Equation 23)73 Subsequent N-oxidation was also achieved with excess hydroperoxide.

3. N-Oxidation The oxidation of aliphatic and aromatic nitrogen- containing compounds by hydroperoxides, catalysed by metals has been known for several years. 74.75 Primary aliphatic amines generally afford oximes,11 • 76 and tertiary aliphatic amines give N-oxides. 77 Oxaziridines 75, 7 are readily formed from azomethines a and nitroso- amines have been oxidised by Mo-ROOH to give nitramines.75 Anilines are generally oxidised to nitroaryls (86), for which vanadium catalysts appear superior to molybdenum79 In addition, azoxyaryls (87) are formed with titanium- (IV)-hydroperoxide systems, 80 as with organic peracids, probably from condensation of the nitroaryl product with the parent anilines.

Azoxyaryls have also been prepared from the Mo -catalysed oxidation of azo compounds (88)81 40

N 02 NH2

V v ROOH Ti n/ (86) ROOH

N=N (87)

(88)

The mechanism of the N-oxidations is considered, 77, from kinetic data and substituent effects, 79 to be closely related to the mechanism of epoxidation (Scheme 1).

Scheme 10

Catalyst Activation

Vv ROOH fast Vv--OR I (1) OH

slow ArNH 2 OH + VV-OR 0H ► NH 2 Ar

fast

ArNHOH + V- ROH (89)

VY--ROH + RO2H V---R02 H + ROH

ArNHOH ROOH ArNO2 (89) (86) 41

A proposed mechanism (Scheme 10) 79 for the oxidation of anilines via a hydroxylamine intermediate (89) involves the rapid, reversible formation of a complex between the activated catalyst and the hydroperoxide, followed by rate-limiting attack of the nitrogen lone-pair on the electrophilic Vv-ROOH complex (1), and rapid proton transfer. The catalyst is regenerated by a ligand-exchange process between RO2H and the product alcohol ROH, and the hydroxylamine is oxidised to the product nitroaryl by hydroperoxide.

In the oxidation of azo-compounds,81 the mechanism is considered to be dependent upon the oxidation state or ligand environment of the catalyst; the proposed transition state (90) is related to Mo(VI) catalysed epoxidations (Scheme 2), while (91) is speculated for low-valent species.

H R Ar 0-0--Movt N—Ar N* Ar—N/ iN OH (90) (91) 0 ~ I o OR \A r

N-Oxidation of heteroaromatic compounds is a common reaction of both organic peracids 82 and metal-catalysed hydroperoxides 75; though faster rates and higher N-oxide yields are generally achieved by the latter reagents.

Pyridines, including the deactivated dibromo- and 4-acet- amidopyridines, quinoline, acridine and phenazine are all converted into the N-oxides in near quantitative yields. 42

The formation of the di-N-oxides of 4,4-bipyridyl, pyrazines and phenazine is also readily achieved. Similarly, e3 pertungstic acid is an efficient oxidant of diaza-arenes, forming N-oxides of 1,8-naphthyridine (92) , 1,2-diazine

(93) and 1,3-diazine. The di-N-oxide of 1,6-diazanaphtha- lene (94) has also been prepared by pertungstic acid oxidation, although unattainable by oxidation with peracetic acid.

0 0 0

(92) (93) (94)

4. S- and P-Oxidation

Vanadium- or molybdenum-catalysed hydroperoxides

quantitatively oxidise sulphides and sulphoxides to sulphones , ", 9G and Tolstikov et al. have shown that tert-pentylhydroperoxide and molybdenum pentachioride

comprises a mild and very selective reagent for S-oxidation 5 Dithienyl sulphide (95) and the halogenated sulphides (96)

and (97), which have labile chlorine substituents, are

quantitatively converted to the corresponding oxides.

Furthermore, the diacetoxy sulphide (98) which is usually

inert towards oxidation, due to shielding of the sulphur

atom, is readily oxidised by C5H11 00H/MoC15. Many other

sulphide substrates have been oxidised. S5 Pertungstic

acid has also been used in the oxidation of the sulphide

(99), giving the sulphone in greater than 90% yield ss

(95) (96)

Ph3C O XWOH ~R R (99) R = Cl (97) R - OAc (98) X - S, SO, SO2

The mechanism of oxidation at sulphur, like N-oxidation, has been correlated with the epoxidation mechanism (Scheme 1), for the reaction is considered to involve a rate-determining attack of sulphur on an electrophilic metal-hydroperoxide complex (1).87 The selectivity of S-oxidations usually results from their faster rates of reaction; for example, the order of reactivity relative to olefin epoxidation is R2S (100) > R2SO (0.15) > olefin

0.01).87 Molybdenum- and vanadium-hydroperoxide reagents have also been used to oxidise triphenylphosphine to the phosphine oxide .", 68

B. Radical Reactions The modification of peroxide reactivity by transition metals has found varied application in organic synthesis from the early use of Fenton's reagent and the Ruff degradation in carbohydrate chemistry 89 to numerous oxidation reactions known at present.3 Although metal-

peroxide systems are often inferior to equivalent organic 44 synthetic reagents, transition metal-catalysed reactions have been used to prepare compounds not readily accessible by other means, in particular via the functionalisation of saturated carbon centres. Earlier reviews have described some of the synthetic aspects from metal-

9ob catalysis of hydrogen peroxide, 90a hydroperoxides, and peroxyesters.91 Metal-catalysed autoxidation 2 and decomposition of hydroperoxides,92 from which many varied products can arise, are generally of very limited preparative value and have not been included in this sur- vey.

The catalysis of peroxides by iron and copper salts, for example, is characterised by the formation of hydroxyl, alkoxy, or acyloxy radicals, and the subsequent course of the reaction is significantly dependent upon the metal catalyst, peroxide, and reaction conditions. The essential features of the redox reactions of radicals with metal complexes have been summarised in the recent review of

Kochi. 5 A general reaction sequence has been evaluated from studies of the catalysed reactions of peroxyesters,91 hydroperoxides and diacylperoxides,93 and hydrogen peroxide 94,95 (Scheme 11), with occasional reference to other peroxides.

Simple cases of the transition metal-catalysis of hydrogen peroxide are considered to involve the hydroxyl radical,94.96 yet in iron-catalysed reactions, oxidation by iron-based oxidants, e.g. a ferryl species Fe02+ has been postulated97 particularly in relation to the biological implications of metal-hydrogen peroxide interactions.

Recent studies have demonstrated a regio- and stereo- 45

selective oxidation of cyclohexanol which features a metal-directed, stepwise hydroxylation process 98 (Scheme 12).

Mechanism of Radical Decomposition

An outline of the iron- and copper-catalysed reactions of peroxides in the presence of oxidisable substrates (Rn- H) is given in Scheme 11. The radical nature of the process has been amply demonstrated by

trapping99 reactivity,100 and e . s . r . studies101 of the initial hydroxyl or alkoxy radicals. Furthermore, the

loss of optical activity of substrates, for' example in

the production of the racemate of bicyclo [3.2.1] oct- -3-en-2-ol (106),702 has implicated the involvement of substrate radicals in the reaction sequence.

Scheme 11

M"+ ROOX (XOOX) XO' + M"t1 + R0(X0) [24] (X = H, Alkyl or Acyl) RC0 2' - R' + CO2 [25]

M"4-1 + ROOH ROZ + M" + HT [26] XO' + R" H R" ' [2 7] RI ' + Fe(III) --- R1+ + Fe(II) [28] 2R2' R2 .R2 [29] R3' + Fe(II) + H4- ---- R3H + Fe(III) [301 R4' + Cu(II)L R4L + Cu(I) [31]

R6' + Cu(II) [p.5_cu] elimination [32] (100)

®-1 S S `R6 R6 [33] 46

An initial, catalysed reductive cleavage of the peroxide occurs forming hydroxyl, alkoxy, or acyloxy radicals, or alkyl radicals from decomposition of the acyloxy radical. Hydroperoxides can undergo an alternative cleavage to the peroxy radical which is accompanied by reduction of the metal ion (Equation 26). In the presence of an oxidisable species (R"-H),. hydrogen abstraction or radical addition generates an intermediatesubstrate radical R" (Equation 4). Various studies of hydrogen peroxide in the presence of iron salts have demonstrated the successful application of kinetic analyses based on the given stoichiometry of the reaction sequence with the three possible outcomes of oxidation, dimerisation or reduction (Equations 28 - 30)94,103 The fate of the substrate radicals generally correlates with the stability of the incipient carbonium ions (R1e)

or carbanions (R3e) tert-Butyl radicals and radicals containing a-substituted electron donors are readily oxidised by iron (III), whereas radicals conjugated with carbonyl groups undergo reduction by iron (II). In the absence of effective oxidants or reductants, dimers are generally formed. In the copper-catalysed reactions of peroxides,5 the intermediate radicals (R") can undergo ligand transfer, dimerisation, or formation of an alkyl-copper species (100). The oxidation step (Equation 31) does not involve a carbonium ion intermediate (cf. iron catalysis), but rather a predominantly inner-sphere ligand transfer from Cu(II)L to the radical R4' and reduction of the metal ion. The choice of ligand is essential to the effi- 47

ciency of such an inner-sphere atom transfer process, for example, a-cyano radicals give halogenated products with copper (II) chloride as catalyst, but in the presence of copper (II) acetate, the major product results from competitive dimerisation. 4 The substitution and elimination reactions

(Equations 32 and 33) are considered to proceed via an alkyl-copper intermediate (100). From the combined rates of elimination and substitution, and from product isotope effects in the reaction of f3-arylethyl radicals,93 a common intermediate that is not a free carbonium ion has been postulated.

(100)

Many examples of substitution reactions of copper- catalysed peroxides appear to involve R+ species, but whether these are free carbonium ions or complexed ions that react within the coordination sphere or the solvent cage of the metal ion, is not known. Norbornadiene affords the 7-butoxyderivative (101) by carbonium ion rearrangement, for specific deuterium labelling shows complete randomisation in the product.105 Similarly, from label scrambling in the substitution reaction of g-arylethyl radicals (Equation 34), the occurrence of the symmetrical bridged species (102) has been implicated.5 48

( 101 )

OAc

[341

(102)

The outer-sphere oxidation of R" by iron (III) is a process which is selective towards the more stable carbonium ions (R1(13) (e.g. R = t-alkyl, or R has a-OH, a-OR, and a-NHCO substituents). The oxidation of isopro- panol affords acetone as the major product (93%), whereas the dimer (103) is formed from tert-butanol .t04 In comparison to iron (III), copper (II), although being a weaker oxidant, can react via ligand transfer involving an alkyl-copper complex (100) and is able to oxidise primary and secondary radicals. Consequently, the addition of copper (II) ions to the oxidation of tert-butanol produces the diol (104), with almost complete inhibition of dimerisation .'03

HO OH -

(103) Fe w

/OH 111 Fe /Cu OH (104)

Other examples have been noted where the course of metal-catalysed peroxide reactions can be altered by the addition of ions. Alkyl radicals form relatively stable complexes with Fe(III), Ni(II), Co(II) and Mn(II )106 and the presence of the ions increases the production of dimers. Conversely, fluoride and phosphate ions complex strongly with iron (III), with consequent inhibition of the oxidation stage (Equation 28)107

Allylic Oxidation The functionalisation of allylic carbons has been one of the most widely employed procedures. 92, 93 The copper-catalysed decompositions of hydroperoxides and peroxyesters in the presence of olefins (Equation 35 and 36) affords 3-peroxy- and 3-acyloxy-l-alkenes, which are readily converted into alcohols. Other functional groups can be introduced by the addition of, for example, carbo-

108 xylic acids, 100 azide ions nitrite ions,109 and phthalimide,170 giving the corresponding 3-substituted olefins (Equation 37).

OOBut

r35],11 + ~ L OOBut 85°/0 (1:9)

112 ~~ OCOPh [36]

X [3 71 X = RCO2 ,N3,ONO,- 900/

The allylic oxidations have been shown to exhibit high stereoselectivity, since acetoxylation of 1-methylene- 4-t-butylcyclohexane gives 85% of the trans-product (105)11 3 However, optical purity is generally lost due to radical intermediates, for example, optically active bicyclo- [3.2.11 oct-2-ene affords, after hydrolysis the racemate of the exo-bicyclooctenol (106)•102

(105)

(106)

The formation of acyloxyolefins has been reported to arise from a ligand transfer reaction (Equation 31) with copper (II) carboxylate and also via a R-Cu complex (Equation 32).91 The latter mechanism has been used to account for the specific oxidations of 1- and 2-alkenes, which both predominantly give 3-acyloxy-l-alkenes.n4 The common formation of the less stable terminal olefin has been discussed in terms of the allyl-copper intermediates (107) and (108). 91,115 The more stable alternative appears to be (107), which contains copper complexed to the least substituted olefin, and this forms the 3-acyloxy-l-alkene.

Stable complexes, e.g. copper phenanthroline, do

• XO—Cu" (107)

Cul OX (108) not show the same specificity of forming terminal olefins;15 for in the absence of rr-complex formation, the reaction follows an outer-sphere electron transfer process to generate an allylic carbonium ion.

Hydroxylation Cyclohexanol is selectively oxidised by hydrogen peroxide and iron (II) in acetonitrile giving the cis-1,3-diol (112), with a stereospecificity of >96% and accounting for >70% of hydroxylated products, though overall conversion is less than 12%." In contrast to other oxidations with Fenton's reagent, this reaction

(Scheme 12) is not considered to involve hydroxyl radicals, since the high degree of selectivity, and solvent and kinetic isotope effects are not compatible with other radical processes. Furthermore, the oxidation of cyclohexanol demonstrates an increased reactivity relative to the parent hydrocarbon.

Scheme 12

The results are discussed in terms of a complexed iron-based oxidant (109) which participates in the reaction as outlined in Scheme 12. The directing effect of the reagent derives from selective hydrogen abstraction, followed by oxidation of the intermediate radical (110) via electron or ligand transfer. In 50% aqueous acetonitrile, the reaction is non-selective, giving a 1:1 mixture of cis-and trans-diols due to competitive hydrolysis of the carbonium intermediate (111). Analogous results have been observed in the reaction of 3-hydroxycyclohexylperoxycarboxylic acid (113) with iron salts, which affords the cis-diol (112) with 85% specificity.16 The iron (II) catalysed decompositions of the cis- and trans-peroxyacids (113) appear to involve the common radical intermediate (114), which is selectively oxidised by the substituent-directed ferryl species. (Scheme 12).

OH OH

CO SH CO2.

(113)

OH OH OH 1

(11 2) (11 4)

In the oxidation of cyclohexanol with Fenton's reagent and in the iron (II) catalysed decomposition of

2-hydroxycyclohexylperoxycarboxylic acid (Scheme 13) the cis-andtrans -1,2-diols are equally formed. This is in marked contrast to the copper-catalysed hydroxylation which affords the trans-diol as the major product. The proposed intermediate species in the iron-catalysed reactions (115) and (116) appear to have a geometry that would allow ligand transfer onto either face.

Scheme Li Few FeII OH HO OH H / \OH

(115) (115)

OH III ,OH OH 0

In the predominant formation of the trans-diol from copper-catalysed oxidations, an alkyl-copper complex (117)

has been implicated, which undergoes a ligand-insertion reaction to give a protonated epoxide (Equation 38)1.16

trans-diol [38]

(117)

The hydroxylation of olefins by Fenton's reagent

(Equation 39) is generally accepted to occur by addition of a hydroxyl radical to Fivegive a trans-diol,, 103 as well as ketones, acids, and hydroxyacids.

OH + cis-diol [391

(11 8)

,/,CO2H HO`.-CO2 H HO~~CO2 H Fein l H+ CO 2 H CO2 H -"CO 2 H

Reduction of hydroxyl radical adducts by Fe(II)

(Equation 30) can also occur, thus malefic acid has been 117 formally hydrated to malic acid (Equation 40). This sequence has also been used in a synthesis of Y-lactones

(119) by addition of hydroxy alkyl radicals to 4-unsatu-

rated acids (Scheme 14)

Scheme 14

HO' + RCH2OH RCHOH ~CO2H R'

Feta (119) CO2 H H+ R'

Hydroxyvinyl radicals (120), generated from hydroxyl radical addition to acetylene, are reduced by iron (II) to give acetaldehyde.95 Vinyl radicals can also be oxidised by copper (II) ions yielding hydroxy- acetaldehyde (Scheme 15). Similarly, the hydroxylation of alkyl oximes by hydrogen peroxide and titanium catalysts involves addition of hydroxyl radicals to the imine bond giving g-hydroxynitroxides."8

Scheme 15

H C=CH + HO' (120) HO

CH;CHO Fe11 HO (120)

HO.CH2 CHO HO

The role of the hydroxy1 radical adduct (118) has, however, been questioned,116 for in the iron (II) catalysed decomposition of 2-hydroxyperoxyacids(Scheme 13), cis-and trans-1,2-dihydroxycyclohexanes are formed in equal proportions via an'iron-directed oxidation of an hydroxyl radical adduct. The trans-diol product from hydroxylation of olefins would not, therefore, be expected to predominate in iron-catalysed reactions involving hydroxylradical adducts. Alternatively, a protonated epoxide (121) may arise from a radical cation intermediate

(122)1" or possibly from oxidation by a ferryl species.116 56

Few-0 OH trans-diol

In the oxidation of aromatic substrates by Fenton's reagent, which has been known for many years, 92120 benzene affords biphenyl and phenol,121 the latter being oxidised further to catechol, hydroquinone and quinones./22,123

However, recent studies of iron (II) - catalysed reactions of substituted arene substrates with hydrogen peroxide, have shown a complex situation in which hydroxyl radical addition to give cyclohexadienyl radicals 724 and electron transfer to form aryl radical cations 125 both feature. An overall view is summarised in Scheme 16, for phenylacetic acid.125

The major pathway produces cyclohexadienyl radicals

(123) which can be oxidised to phenols. The selective oxidant, iron (III), which is sensitive towards aryl carbonium ion stability affords mainly ortho- and some substituted para phenols, however in the presence of copper (II) or oxygen, which interact with the radical intermediate (123), meta-phenol formation is increased.

The cyclohexadienyl radical (123) also undergoes rapid, acid-catalysed conversion to the radical cation

(124) which is either reduced by iron (II) to the original aryl substrate or decomposes to the benzyl radical, from

Scheme 16

1 CO2H H2CO2H I OH' Cu or 02 F e I } OH 1I III CH2CO,H (123) \F‘"e

CH2CO2H

(124)

l C H 2'

Oxido or,

which 1,2-diphenylethane or benzyl alcohol are formed. 95 By a suitable choice of conditions, specific products can predominate, thus phenols are produced in 94% yield at high concentrations of copper ions and low pH, benzyl

alcohol (82%) results from h.'.gh concentration of iron (III) and the dimer, diphenylethane is formed in the absence of any added oxidant.

Radical Coupling

In the absence of oxidising species, such as Fe(III)

and Cu(II), or under particular reaction conditions, dimerisations account for much of the radical content of catalysed reactions of peroxides. Using Fenton's reagent,

dehydrodimers have been prepared from lower aliphatic

acids, nitriles, amides, amines, alcohols, and ketones127 On addition of 1,3-dienes, extended-chain products can result '2S (Equation 41). 58

R. + / R R + branched (41] isomers

The addition of chloride and azide ions has been used by Minisci in the synthesis of diamines and halogenated species. The oxidation of cyclohexene by hydrogen peroxide and ferrous azide produces a 1,2-diazide, which on reduction, gives the 1,2-diamine (125).729 A similar means of functionalisation is observed in the formation of 5-chloro-6-azidochlolestanol (126)?30

Cholesterol HO a- Oxidations In relation to allylic functionalisation, oxidations readily occur at the a-carbons of N,0 and S groups. Dime- thylaniline reacts with t-butylhydroperoxide in the presence of copper to give the N-peroxymethyl derivative (127) 3'

Cyclic amines and amides have been oxidised by peroxyacids or hydroperoxides, catalysed by manganese (II) or (III) salts, to give lactams 132 and imides 133 respectively. Adipimide is prepared in good yield from E-caprolactam (Equation 42) 132 and similarly, piperidine can be oxidised to 2-piperidone.133 The specificity of the reaction is considered to result from metal-amide complex

59 formation. Moreover, the oxidation of 6-methylpiperidone, which undergoes a net dehydrogenation (Equation 43) has been compared 35 to the elimination reactions involving alkyl-copper intermediates.

-{-00H/ Cu' Me PhNMe2 Ph-N~ (127) C H200But

tu Mn /ROOH „ [42j 0 or RCO3H H

[431 N 0 N 0 H H

An a-peroxyketone is produced in 90% yield from oxidation of 2-methylcyclohexanone (Equation 44).131 Ethers react with t-butylperoxyesters to give, initially a-auyioxy derivatives (128), and a facile, thermal rearrangement via an enol-ether affords the observed ketals (129) 34 The addition of alcohols (R'*OH) has been used to intro- duce alternative substituents (Equation 45)135

) Me . [44] e

(90°/0)

Cul t BuOH 0 RCO 3Bu' OCOR 0 R'O H OBut [4 5] (R') (128) (129) 60 '

The copper-catalysed reaction of peroxyesters with sulphides gives a-acyloxy derivatives, e.g. tetrahydro- thiophen affords (130) in ca. 70% yield 136 and thiophenes are similarly oxidised at the C2 position in moderate yield by peroxydicarbonates with copper ions .'37

—~ )""OCOR R~ (s) S S --R& S~O OR'C

(130)

This reaction is complementary with the efficient oxidation of sulphides to sulphoxides and sulphones by molybdenum- and vanadium-catalysed hydroperoxide reagents.85,87

Thiols undergo an alternative oxidation with hydroperoxides

in the presence of iron (II), to give disulphides.138

Miscellaneous Oxidations

Metal-peroxide reagents are also known to react with unactivated carbons, thus the oxidation of cycloheptane

by di-t-butylperoxide and Cu(I) salts affords, after

reaction with benzamide, N-cycloheptylbenzamide in 68%139

-1-oo+/Cul NHCOPh 0 + PhCONH2

The reaction of cholesterol with hydrogen peroxide

in the presence of iron (III) acetylacetonate in aceto-

nitrile affords good yields of the 5 , 6-oxide .'4D Although the epoxidation of olefins is readily catalysed by 61 molybdenum and vanadium, the effective catalysis by Fe(III) appears unusual. Although no mechanism has been postulated, the stereospecificity of epoxidation of the 3-hydroxy and 3-acetoxy steroidal olefins, given in Table 4, which indicates the predominant formation of p-epoxides, contrasts with the equivalent results of molybdenum-catalysis (Tables 2 and 3), for which a polar, electrophilic epoxidation mechanism is accepted.22

tts 140 Table 4 Epoxidation of Steroidal Olefins with Fe /H202

% Yield of Epoxide Substrate a

Cholesterol 17 68 Cholesteryl Acetate 11 46 Cholest-4-en-3/3-ol none 38 3f3-Acetoxycholest- no reaction -4-ene Cholest-4-en-3a.-ol :lone 46 Cholest-4-ene 4 74 Estr-4-en-17p-o1 4 71

The iron (III)-catalysed decomposition of hydrogen peroxide in dialkylsulphoxide solvents produces solvent- derived alkyl radicals, which have been used for the preparative alkylation of aromatic substrates, such as quinones, nitroaryls, thiophenes, furans, pyridines, and quinolines. 2,4,6-Trinitrotoluene is formed in 67% yield from 1,3,5-trinitrobenzene in dimethylsulphoxide141 62

References to Part I

1. C.W. Walling, 'Free Radicals in Solution,' Wiley, New York, 1957. 2. J.A. Howard in 'Free Radicals,' ed. J.K. Kochi, Wiley, New York, 1973, chp. 12. 3(a) 'Organic Peroxides,' ed. D. Swern, Wiley-Inter- science, New York, 1970, vol. 1-3 ; (b) A.R. Doumaux in 'Oxidation,' eds. R.L. Augustine and D.J. Trecker, Dekker, New York, 1971, vol. 2, p.414. 4. H.S. Mason, Ann.Rev.Biochem., 1965, 34, 595. 5. J.K. Kochi in 'Free Radicals,' ed. J.K. Kochi, Wiley, New York, 1973, chp. 11. 6. N.A. Milas, J.Amer.Chem.Soc., 1937, 59, 2342; W. Treibs, Ber., 1939, 72B, 7. 7. M. Mugden and D.P. Young, J.Chem.Soc., 1949, 2988. 8. G.B. Payne and P.H. Williams, J.Org.Chem., 1959, 24, 54. 9. N. Indictor and W.F. Brill, J.Org.Chem., 1965, 30, 2074. 10. M.N. Sheng and J.G. Zajacek, Adv.Chem.Ser., 1968, 76. 418. 11. F. List and L. Kiihnen, ErdOl. u. Kohle., 1967, 20, 192. 12. K.B. Sharpless and R. C. Michaelson, J.Amer.Chem.Soc., 1973, 95, 6136. 13. G.A. Tolstikov, V.P. Yur'ev, I. Gailyunas and U.M. Dzhemilev, J.Gen.Chem.(U.S.S.R.), 1974, 44, 205. 14. R.A. Sheldon and J.A. Van Doon, J. Catal., 1973, 31, 427. 15. C.C. Su, J.W. Reed and E.S. Gould, Inorg.Chem., 1973, 12, 337. 16. M.N. Sheng and J.G. Zajacek, J.Org.Chem., 1970, 35, 1839; M.N. Sheng, J.G. Zajacek and T.N. Baker, Amer.Chem.Soc.,Div.Petrol.Chem.Prepr., 1970, 2, E19. 17. M. Spadlo and Z. Pōkorska, Chemik, 1974, 27, 124. 18. G.L. Linden and M.F. Farona, J.Catal., 1977, 48, 2821; Inorg.Chem., 1977, 16, 3170; M. Che, F. Figueras, M. Forissier,.J. McAteer, M. Perrin, 63

J.L. Portefaix and H. Praliand, Proc.Internat. Congr.Catal., 6th 1976, 1, 261 (Chem.Abs., 1977, 87, 200509 f). 19. P. Forzatti and F. Trifiro, React.Kinet.Catal.Lett., 1974, 1, 367. 20. H. Mimoun, I.S. de Roche and L. Sajus, Bull.Soc. chim.France, 1969, 1481. 21(a) R. Hiatt. in 'Oxidation,' Vol. 2, eds. R.L. Augustine and D.J. Trecker, Dekker, New York, 1971, p.113; (b) G.A. Tolstikov, V.P. Yur'ev and U.M. Dzhemilev, Russ.Chem.Rev., 1975, 44, 319. 22(a) G.A. Howe and R.R. Hiatt, J.Org.Chem., 1971, 36, 2493; (b) T.N. Baker, G.T. Mains, M.N. Sheng and J.G. Zajacek, J.Org.Chem., 1973, 38, 1145; (c) M.I. Farberov, G.A. Stozhkova and A.V. Bondarēnko, Neftekhimiya, 1971, 11, 578. 23. R.A. Sheldon, Rec.Tray.chim., 1973, 92, 253. 24. D.I. Metelitza, Russ.Chem.Rev., 1972, 41, 807. 25. E.S. Gould, R.R. Hiatt and L.K.C. Irwin, J.Amer.Chem. Soc., 1968, 90, 4573. 26. G. Descotes and P. Legrand, Bull.Soc.chim.France, 1972, 2942. 27(a) J. Kaloustian, L. Lena and J. Metzger, Bull.Soc. chim.France, 1971, 4415; K.E. Khcheyan, L.N. Samter and A.G. Sokolov, Neftekhimiya, 1975, 15, 415; V.M. Belousov, K.B. Yatsimirskii, A.P. Filippov and S.B. Grinenko, Kinet.Catal., 1977, 18, 462; (b) K.B. Yatsimirskii, A.P. Filippov, G.A. Komishevskaya, L.A Oshin, S.B. Grinenko and V.M. Belovsov, ibid., 530. 28(a) R.A. Sheldon, Rec.Tray.chim., 1973, 92, 367; V.A. Gavrilenko, E.L. Evzeriklin, I .I . Moiseev and S.I. Fish, Bull.Acad.Sci. (U.S.S.R.), Div.Chem.Sci., 1977, 1611; (b) G. Descotes and P. Legrand, Bu11.Soc.chim. France, 1972, 2937. 29. R.B. Svitych, N.N. Rzhevskaya, A.L. Buchachenko, P. Yablonskii, A.A. Petukhov and V.A. Belygaev, Kinet.Catal. 1976, 17, 803. 30. V.G. Dryuk, Tetrahedron, 1976, 32, 2855. 31. P.F. Wolf and R.K. Barnes, J.Org.Chem., 1969, 34, 3441. 64

32. A.O. Chong and K.B. Sharpless, J.Org.Chem., 1977 42, 1587. 33. B.N. Bobylev, L.V. Melnik, M.I. Farberov, L.I. Bobyleva and I.V. Subbotina, J.Appl.Chem. (U.S.S.R.), 1977, 50, 589. 34. J. Kaloustian, D. Benlian, L. Lena, J. Metzger and E. Flesia, Bull.Soc.chim.France, 1976, 109; P. Koch and J. .Skibida, . Gazz . chim . Ital . , 1974, 104; 225. 35(a) H.Mimoun, I.S. de Roche and L. Sajus, Tetrahedron, 1970, 26, 37; (b) H. Arakawa, Y. Marooka and A. Ozaki, Bull.Chem.Soc.Japan, 1974, 47, 2958. 36(a) K.B. Sharpless, J.M. Townsend and D.R. Williams, J.Amer.Chem.Soc., 1972, 94, 295; (b) A.A. Achrem, T.A. Timoschtschluk and D.I. Metelitza, Tetrahedron, 1974, 30, 3165. 37. M.R. Demuth, P.E. Garrett and J.D. White, J.Amer. Chem.Soc., 1976, 98, 634. 38. V.P. Yur'ev, I.A. Gailyunas, G.A. Tolstikov and F.G. Valyamova, Neftekhimiya, 1972, 12, 353. 39. Y.P. Yur'ev, I.A. Gailyunas and G.A. Tolstikov, Bull.Acad.Sci. (U.S.S.R.), Div.Chem.Sci., 1973, 1395. 40. H.C. Stevens and A.J. Karna, J.Amer.Chem.Soc., 1965, 87, 734. 41. K.A. Allison, P. Johnson, G.Foster and M. Sprake, Ind.Eng.Chem.Prod.Res.Dev., 1966, 5, 166. 42. Y.M. Paushkin, S.A. Nizova and B.T. Shcherbanenko, Proc.Acad.Sci, (U.S.S.R.), 1971, 198, 539. 43. C. Paquot and J. Mercier, Symp.Int.0xyd.Lipides- Catal. Met . , LC .R .] , 3rd, 1973, 57 (Chem .Abs ., 1975, 82, 111355g). 44. Y.P. Yur'ev, I. Gailyunas, Z.G. Isaeva and G.A. Tolstikov, Bull.Acad.Sci. (U.S.S.R.), Div.Chem.Sci., 1974, 885. 45. L.F. Fieser and M. Fieser, 'Steroids,' Reinhold, New York, 1959, p.193. 46. A.A. Achrem, T.A. Timoschtchluk and D.I. Metelitza, Doklady Akad.Nauk SSSR, 1974, 219, 891. 47. G.A. Tolstikov, U.M. Dzhemilev, V.P. Yur'ev and S.R. Rafikov, Proc.Acad.Sci. (U.S.S.R.), 1973, 208, 45. 65

48. Y. Kobayishi and R. Harada, Jap.P. 7,440,464. (Chem.Abs., 1975, 83, 9755w). 49. T. Itoh, K. Jiksukawa, K. Kaneda and S. Teranishi, Tetrahedron Letters, 1976,- 3157. 50. T. Itoh, K. Kaneda and S. Teranishi, J.C.S. Chem. Comm., 1976, 421. 51. S. Tamaka, H. Yamamoto, H. Nozaki, K.B. Sharpless, R.C. Michaelson and J.D. Cutting, J.Amer.Chem.Soc., 1974, 96, 5254. 52. S. Yamada, T. Mashiko and S. Teranishi, J.Amer. Chem.Soc., 1977, 99, 1988. 53. R.C. Michaelson, R.E. Palermo and K.B. Sharpless, J.Amer.Chem.Soc., 1977, 99, 1990. 54. M. Kobayishi, S. Kurozumi, T. Toru, T. Tanaka, T. Miura and S. Ishimoto, Jap.P. 77, 108, 951 (Chem.Abs., 1978, 88, 22587r). 55. R. Breslow and L.M. Maresca, Tetrahedron Letters, 1977, 623. 56. R. Breslow, R.J. Corcoran, B.B. Snider, R.J. Doll, P.L. Khanna and R. Kaleya, J.Amer.Chem.Soc., 1977 99, 905. 57. R. Breslow and L.M. Maresca, Tetrahedron Letters, 1978, 887. 58. U.M. Dzhemilev, G.A. Tolstikov and V.P. Yur'ev, J.Gen.Chem. (U.S.S.R.), 1973, 43, 2058. 59. A.A. Frimer, J.C.S. Chem.Comm., 1977, 205. 60. T. Suhiro and A. Nakagawa, Bull.Chem.Soc.Japan, 1967; 40. 2919; C. Mentzer and Y. Berguer, Bull.Soc. chim.France, 1952, 218. 61. S.A. Matlin, Ph.D.Thesis, London, 1972. 62. S.A. Matlin and P.G. Sammes, J.C.S. Perkin I, 1973, 2851. 63. S.L. Regen and G.M. Whitesides. J.Organometallic Chem., 1973, 59, 293. 64. G. Schmitt, B. Hessner, P. Kramp and B. Olbertz, J.Organometallic Chem., 1976, 122, 295. 65. N.J. Lewis, S.Y. Gabhe and M.R. DeLaMater, J.Org.Chem., 1977, 42, 1479. 66. A.A. Achrem, S.N. Kiseleva, P.A. Kiselev and D.I. Metelitza, React.Kinet.Catal.Lett., 1975, 2, 375. 66

67. E. Vedejs, D.A. Engler and J.E. Telschow, J.Org. Chem., 1978, 43, 188; E. Vedejs, J.Amer.Chem.Soc., 1974, 96, 5944. 68. E. Vedejs and J.E. Telschow, J.Org.Chem., 1976, 41, 740. 69. S.O. Lawesson and C. Berglund, Arkiv.Kemi., 1961, 17, 485. 70. G.A. Tolstikov, U.M. Dzhemilev and V.P. Yur'ev, J.Gen.Chem. (U.S.S.R.), 1972, 42, 1602. 71. G.W.J. Fleet and W. Little, Tetrahedron Letters, 1977, 3749. 72. V.P. Yur'ev, I.A. Gailyunas and G.A. Tolstikov, J.Gen.Chem. (U.S.S.R.), 1973, 43, 217. 73. G.A. Tolstikov, U.M Dzhemilev, V.P. Yur'ev, Bull. Acad.Sci. (U.S.S.R.), Div.Chem.Sci., 1972, 670. 74. L. Kiihnen, Chem.Ber., 1966, 99, 3384. 75. G.A. Tolstikov, U.M. Dzhemilev, V.P. Yur'ev, F.B. Gershanov,and S.R. Rafikov, Tetrahedron Letters, 1971, 2807. 76. J.L. Russell and J. Kollar, Belg.P. 1965, 668,811 (Chem.Abs., 1966, 65, 8792b);L. Jarkovsky, J. Pasek and V. Ruzicka, Chem.prumysl, 1966, 16, 591. 77. M.N. Sheng and J.G. Zajacek, J.Org.Chem., 1968, 33, 588. 78. P. Tellier and P. Weiss, G.P. 2,351,079 (Chem.Abs., 1974, 81, 91503c). 79. G.R. Howe and R.R. Hiatt, J.Org.Chem., 1970, 34, 4007. 80. K. Kosswig, Annalen, 1971, 749, 206. 81. N.A. Johnson and E.S. Gould, J.Org.Chem., 1974, 39, 407. 82. A.R. Katritsky and J.M. Lagowski, 'The Chemistry of Heteroaromatic N-Oxides,' Academic Press, London, 1971. 83. Y. Kobayishi, I. Kumadaki, H. Sato, Y. Sekine and T. Hara, Chem.Pharm.Bull., 1974, 22, 2097. 84. L. Kiihnen, Angew .Chem .Internat . Ed n.,1966, 5, 893. 85. G.A. Tolsltikov, U.M. Dzhemilev, N.N. Novitskaya, V.P. Yur'ev, and R.G. Kantyukova, J.Gen.Chem. (U.S.S.R.), 1971, 41, 1896; Bull.Acad.Sci. (U.S.S.R.), Sci . , 1972, 2675. 67

86. K.L. Agarwal, Y.A. Berlin, H.J. Fritz, M.J. Gait, D.G. Kleid, R.G. Lees, K.E. Norris, B. Ramamoorthy and H.G. Khoran, J.Amer.Chem.Soc., 1976, 98, 1065. 87: R. Curci,- F. DiFuria, R. Testi and G. Modena, J.C.S. Perkin II, 1974, 752; R.Curci, F.DiFuria and G. Modena, ibid. , 1977, 576. 88. R.R. Hiatt and C . McColeman, Canad.J .Chem . , 1971, 49, 1712. 89. G.J. Moody in 'Advances in Carbohydrate Chemistry,' vol. 19, ed. M.L. Wolfrom, Academic Press, New York, 1964, p. 149. 90(a) G. Sosnovsky and D.J. Rawlinson in 'Organic Peroxides,' vol. 2,ed. D. Swern, Wiley-Interscience, New York, 1971, p. 269; (b) ibid., p. 153. 91. G. Sosnovsky and S.O. Lawesson, Angew.Chem.Internat. Edn., 1964, 3, 269. 92. L.S. Boguslavaka, Russ.Chem.Rev., 1965, 34, 503. 93. J.K. Kochi and A. Bernis, J.Amer.Chem.Soc., 1968, 90, 4038; 4616. 94. J.H. Herz and W.A. Waters, Discuss_.Farad.Soc., 1947, 2, 179; D.F. Sangster in 'The Chemistry of the Hydroxyl Group,' Part 1, ed. S. Patai, Wiley, 1971, p. 133. 95. C. Walling, Ac;:.Chem.Res., 1975, 8, 125. 96. F. Haber and J.J. Weiss, Proc.Roy.Soc., 1934, 147, 332. 97. A.E. Cahill and H. Taube, J.Amer.Chem.Soc., 1952, 74, 2312; G.A. Hamilton, J.W. Hanifin and J.P. Friedman, ibid., 1966, 88, 5269. 98. J.T. Groves and M. Van der Puy, J.Amer.Chem.Soc., 1974, 96, 5274. 99. J.K. Kochi, Rec.Chem.Progr., 1966, 27, 207. 100. C. Walling and A.A. Zavitsas, J.Amer.Chem.Soc., 1963, 85, 2084. 101. W.T. Dixon and R.O.C. Norman, Nature, 1962, 196, 891. 102. H.L. Goring and U. Mayer, J.Amer.Chem.Soc., 1964, 86, 3753. 103. C. Walling and S. Kato, J.Amer.Chem.Soc., 1971, 93, 4275. 68

104. J.K. Kochi and D.M. Mog, J.Amer.Chem.Soc., 1965, 87, 522. 105. P.R. Story, Tetrahedron Letters, 1962, 401; J.Amer.Chem.Soc., 1961, 83, 3347. 106. H.E. DeLaMare, J.K. Kochi and F.F. Rust, J.Amer. Chem.Soc., 1961, 83, 2013. 107. J.R.L. Smith and R.O.C. Norman, J.Chem.Soc., 1963, 2897. 108. F. Minisci and R. Galli, Tetrahedron Letters, 1963, 357. 109. F. Minisci, M. Cecere and R. Galli, Gazz . chim . Ital . , 1963, 93, 1288. 110. M.S. Kharasch and A. Fono, J.Org.Chem., 1958, 23, 325. 111. R. LaLande and C. Filliatre, Bull.Soc.chim.France, 1962, 792. 112. M.S. Kharasch, G. Sosnovsky and N.C. Yang, J.Amer. Chem.Soc., 1959, 81, 5819. 113. B. Cross and G.H. Whitham, J.Chem.Soc., 1961, 1650. 114. J.K. Kochi, J.Amer.Chem.Soc., 1961, 83, 3162. 115. J.K. Kochi, J.Amer.Chem.Soc., 1962, 84, 3271. 116. J.T. Groves and M. Van der Puy, J.Amer.Chem.Soc., 1975, 96, 7118. 117. C. Walling and G.M. El Taliawi, J.Amer.Chem.Soc., 1973, 95, 844. 118. D.J. Edge and R.O.C. Norman, J.Chem.Soc.(B), 1969, 182. 119. M. Kilpatrick and J.G. Morse, J.Amer.Chem.Soc., 1953, 75, 1846. 120. J.H. Merz and W.A. Waters, J.Chem.Soc., 1949, 2074. 121. J.R.L. Smith and R.O.C. Norman, J.Chem.Soc., 1963, 2897. 122. P. Maggioni and F. Minisci, Chim .Ind . (Milan), 1977, 59, 239. 123. P.L. Kolker, J.Chem.Soc.Suppl., 1964, 529. 124. R.O.C. Norman and R.J. Pritchett, J.Chem.Soc.(B), 1967, 926; C.R.E. Jefcoate and R.O.C. Norman, ibid., 1968, 48. 125. M.E. Snook and G.A. Hamilton, J.Amer.Chem.Soc., 1974, 96, 960. 69

126. C. Walling and R.A. Johnson, J.Amer.Chem.Soc., 1975, 97, 363. 127. D.D. Coffman, E.L. Jenner and R.D. Lipscomb, J.Amer.Chem.Soc., 1958, 80, 2864. 128. D.D. Coffman and E.L. Jenner, J.Amer.Chem.Soc., 1958, 80, 2872. 129. F. Minisci and R. Galli, Tetrahedron Letters, 1962, 533. 130. F. Minisci, R. Galli and M. Cecere, Gazz.chim.Ital., 1964, 94, 67. 131. M.S. Kharasch and A. Fono, J.Org.Chem., 1959, 24, 72. 132 J.E. McKeon and D.J. Trecker, U.S.P. 3,678,096 (Chem.Abs., .. 1972, 76, 72397 b). 133. A.R. Doumaux and D.J. Trecker, J.Org.Chem., 1970, 35, 2121; A.R. Doumaux, J.E. McKeon and D.J. Trecker, J.Amer.Chem.Soc., 1969, 91, 3992. 134. G. Sosnovsky, Tetrahedron, 1961, 13, 241. 135. S.O. Lawesson and. C. Berglund, Acta Chem.Scand., 1960, 14, 1854. 136. C. Berglund and S.O. Lawesson, Arkiv Kemi., 1964, 20, 225; G. Sosnovsky, J.Org.Chem., 1961, 26, 281. 137. A.P. Manzara and P. Kovacic, J.Org.Chem., 1974, 39, 504. 138. A.L.J. Beckwith and B.S. Low, J.Chem.Soc., 1964, 2571. 139. A.B. Evnin and A.V. Lam, J.C.S. Chem.Comm., 1968, 1184. 140. M. Kimura, M. Tohma and T. Tomita, Chem.Pharm.Bull., 1973, 21, 2521; M. Tohma, T. Tomita and M. Kimura, Tetrahedron Letters, 1973, 4359. 141. K. Torsell, Angew.Chem.InternaLEdn., 1972, 11, 241; Acta Chem.Scand., 1970, 24, 3590; 1971, 25, 2183. 70

PART II

RESULTS AND DISCUSSION 71

CHAPTER 2

THE SYNTHESIS OF HYDROXAMIC ACIDS BY THE OXIDATION OF TRIMETHYLSILYLAMIDES

1. Introduction

The structure of hydroxamic acids has been established from chemical and substantial spectroscopic evidence2 as the N-hydroxy amide (1). Recent studies have led to an increasing awareness of the wide participation of the hydroxamic acid function in natural systems? Hydroxamth acids have, however, made few appearances in the chemical field, notably as a component of the Lassen rearrangement 2,4 and as a bidentate metal chelating agent (2),6 thus significant use has been made of the functionality in analytical chemistry.6 Furthermore, the complexation of metals, in particular iron, is considered an important factor in the biological activity of hydroxamic acids. More recently, the oxidation of hydroxamic acids has been used for the preparation of stable acyl nitroxides.8 72

0 R Metal R2~ O R N H—O H '

(1) (2)

Natural Occurrence of Hydroxamic Acids

Hydroxamic acids predominantly occur within micro- bial metabolism. The biological and pharmacological roles of hydroxamic acids and their derivatives have been the subject of several recent reviews.3'7'9 The more common functions of hydroxamic acids involve the macrocyclic iron (III) trihydroxamates as growth factors and a wide range of natural and synthetic hydroxamic acid derivatives which possess antibiotic properties. It is thought that hydroxamic acids act as growth factors by their ability to form stable coordination complexes with iron under physiological conditions and are thus able to provide a means of transport of exogenous iron through the cell membrane,3•7 The iron (III) hydroxamates may also be instru- mental in the transfer of essential metals to porphyrin or enzyme centres, for which a redox control between the iron- (III) and the less stable iron (II) hydroxamates is operative.7 Conversely, within the group of hydroxamic acids possessing antibiotic properties, the ability of hydroxamic acids to remove metals essential for growth has frequently been implicated.10 Other biological functions of hydroxamic acids incorporate antimicrobial action as shown by their herbicidal and pesticidal properties,11 specific enzyme

73 inhibition and reactivation, and the formation of red pigments. One final reference to the use of hydroxamic acids is that of N-hydroxyurea - a chemotherapeutic agent for cancer .12

Synthesis of Hydroxamic Acids

The methods for synthesising hydroxamic acids have been comprehensively reviewed by Coutts,3 Bapat et a/.9 and many other authors t3 and certain basic approaches are apparent. The most commonly encountered synthetic procedures comprise the acylation reactions of hydroxylamine derivatives, either by an intermolecular reaction or by intramolecular reductive cyclisations, for example of nitro- esters 14 (Equation 1) or oximinoesters 15 (Equation 2). Furthermore, the biosynthesis of hydroxamic acids generally employs the condensation of an hydroxylamine and an acyl derivative ,13a

02 ,\/NHOH [1] Q.„\ CO2Et CO2Et

iJV—OH NHOH [ CO2Et ,COZEt 2]

In relation to these reactions several examples of intramolecular acyl migration giving hydroxamic acids have been described. In the acid-catalysed reactions of

74 oC-nitroketones, the formation of N-hydroxyimides16 has been interpreted (Scheme 1) as a rearrangement of the postulated intermediate oxaziridine (3).

Scheme 1

d;r1:02

6c0 O

(3) N-0 ./N-OH O GH

In a more general reaction procedure recently reported by Ganen,'7 O-acylhydroxylamines were shown to undergo an acyl migration to the thermodynamically more stable N-acylhydroxylamines (Equation 3).

0 N—OAc

HB 3- R~~NH-OAc ^M e [3] R OH

A second group of preparative methods incorporate a-oxygenation reactions of N-oxides. Heteroaromatic N-oxides or nitrones are converted into hydroxamic acids by a-oxidation using lead tetra-acetate 18 or ferric chloride19 Alternatively N-hydroxypyridones, for example, are produced by base hydrolysis of 2-bromopyridine-N-oxides 20

Further methods of hydroxamic acid synthesis are known that primarily involve nitrogen-oxygen bond formation

The oxidation of 2-alkoxypyridines with peracid and subsequent acid-catalysed hydrolysis has been applied to the synthesis of several N-hydroxypyridones (Equation 4)2' Similarly, many O-alkylimidates have been oxidised by peracid giving, amongst other products, low yields of hydroxamic acids 22,23 (Equation 5).

[4]

N OEt Ī OEt N O 0 OH

~OR 0 OR HO / l ~N- • [5J R~ R2 R1 R 2 R1 R 2

Recently, a procedure related to Equation 5 has been described in which trimethylsilylamides (4) are converted to the corresponding molybdenum hydroxamates (2a) by oxidation with molybdenum pentoxide (5).24

The N-hydroxylation of amide derivatives has also frequently been postulated in biological processes, as in the oxidation of anilides,25 the biosyntheses of aspergillic acid,26 mycelianamide,27 and N-hydroxybenzoxazinones,28 and in the carcinogenesis of amides.29 It is with emphasis upon N-hydroxylation of amides, in particular by the oxidation of silylamides (Equation 6), that further discussion ensues.

0 SiMe3

R1 s"'N

R2 Mo05.HMPA

(4) Mo 02

(2a) [61

N Z

R 2

2. Oxidation of Trimethylsilylamides

The peracid oxidation of imino-ethers (Equation 5) often proceeds in low yield with respect to hydroxamic acid formation 22 because further oxidation of the products leading to nitrosoalkanes appears to be a significant course of the reaction. 23 Consequently, it was found that the reaction with the milder oxidant, molybdenum pentoxide, could furnish hydroxamic acids in moderate yield from secondary amides, where the amide or imide function was 'activated', for example by the trimethylsilyl group.Z4 The activating effects of trimethylsilyl groups have frequently been noted and are generally ascribed to changes in the

physical and electronic properties of the substrates or, more significantly, to a direct influence of the silicon 77

atom in reaction sequences ,30,31

In comparison to alternative methods for synthesising hydroxamic acids, the silylation and oxidation processes

(Equation 6) are both effected under very mild conditions.

Since the neutral and covalent diperoxo-molybdenum com-

plexes (5) are less reactive oxidants than organic peracids

30°•32 and since silyl species can act as protecting groups , the overall reaction may find particular use in cases which

are sensitive towards peracids or acidic media. Furthermore, the absence of free hydroxylamine obviates a common source

of reaction by-products. Yet there are various limitations to the oxidation of silylamides, being only •

applicable to certain secondary amidic environments and

giving only moderate to low yields of hydroxamic acids.

Silylation and Molybdenum Complexes

In the oxidation of silylamides by molybdenum pentoxide, there are various practical aspects that are perti-

nent to the particular natures of the trimethylsilyl group and of the oxidant.

There have been many reviews on silylation of organic

compounds and, in particular, that of Pierce 33 emphasises more practical aspects of application. Owing to facile

hydrolysis, ~ 4 trimethylsilyl derivatives of NH and OH species generally require strictly anhydrous conditions

(cf. Ref. 35).

A wide variety of reagents, e.g. chlorotrimethylsilane (CTMS), hexamethyldisilazane (HMDS), bis(trimethylsilyl)acetamide (BSA), trimethylsilylimidazole and bis(tri-

methylsilyl)urea have been employed in the silylation of 78 amides. For the standard reagent, CTMS in the presence of a tertiary base, purification of the intermediate silylamides was essential for it was found that residual soluble salts, for example triethylamine hydrochloride, suppress the oxidation of silylamides by molybdenum pentoxide. An alternative to this method has involved the addition of chlorotrimethylsilane to an amide anion generated with lithium alkyls 36 or sodium hydride and very high yields of silylamides were achieved by this process. HMDS and occasionally BSA have found specific use in the reaction sequence (Equation 6), because the silylation byproducts

(NH3 or trimethylsilylacetamide) are volatile and silylation and oxidation could be readily effected. Molybdenum pentoxide complexes (5) are stable, covalent diperoxo species. Many complexes are known in which Ll and L2 are occupied by the donor ligands hexamethylphos- phoramide (HMPA) , dimethylf ormatuide (DMF) , aromatic N- oxides, pyridine (Py) and pyridinium cations, tetracyanoethylene and water.37 Most complexes have limited solubility in polar organic solvents and due to an equilibrium between free and liganded species in solution, the complexes generally decompose above 40°-50°C.

The complexes (5a)-(5e) and (6) were prepared according to the method of Mimoun,37 (5b) and (5d) being obtained by dehydration of (5a) and (5c) under vacuum with phosphorus pentoxide. Use of a modified procedure 38 was adopted for the preparation of (5f).

L1 L2 HMPA H20 (5a) HMPA (5b) I DMF H20 (5c) 1 L2 DMF (5d) DMF DMF (5e) HMPA Py (5f)

[(02)2Mo-0-Mo(02)2 ~ 2 (6)

Mo0 5 .2DMF (5e) has been the preferred oxidant for, although the HMPA complexes are more readily prepared since they precipitate from aqueous media, the water soluble DMF complexes are more stable on storage and there is no residual H2O ligand which might inhibit the subsequent oxidation. Furthermore any residual DMF interferes less in the work- up procedures than HMPA. Oxidations using the various complexes differed very little, other than the fully coordinated species (5e) and (5f) requiring longer reaction times. Since the oxidation is thought to involve substrate-molybdenum complex formation (cf. epoxidation reactions of molybdenum pentoxide39), 80 then strong donor ligands or very polar solvents will com- petitively inhibit the reaction. Consequently, chloroform and dichloromethane were generally superior solvents for the oxidation of silylamides.

The initial product which results from the oxidation of silylamides is usually a molybdenum (VI) dihydroxamate (2a). These complexes can be isolated and are relatively stable, apart from a facile deoxygenation to give the parent amide. 24 Molybdenum hydroxamates have been independently prepared from Mo C[5 and hydroxamic acids. 40 Transition metal complexes of hydroxamic acids have been extensively studied' and the liberation of the free hydroxamic acid is dependent upon the equilibrium characteristics of the system. Molybdenum hydroxamates can be cleaved under strongly acidic or basic conditions, though the application of exchange reactions with oxine or EDTA is a preferred general method. The optimum pH for EDTA exchange is in the order of pH 9, however, in order to. facilitate the isolation of the hydroxamic acids, the basic medium was acidified to pH 7-7.5 prior to continuous extraction of the aqueous phase with organic solvents.

3. Scope of Oxidation

The silylation and oxidation of amides have been categorised into several basic series consisting of secondary amides and anilides, primary amides, heteroaromatic amides and multifunctional amides. Other functionalities which incorporate an amide bond have also been studied; these include imides, ureas, urethanes and thio-analogues of amides. 81.

Secondary Amides

The oxidation reactions of silylated secondary amides show broad trends corresponding to the nature of the substituents on nitrogen and of the acyl fragment. Generally, higher yields of hydroxamic acids were obtained from aryl substituted amides than from aliphatic amides, however yields were not found to exceed 50%.

Aliphatic Amides Data for the silylation and oxidation reactions of the aliphatic amides are given in Table 1. The silylation procedures all involved the use of ch1orotrimethylsilane in the presence of the tertiary base, triethylamine, either in inert or basic solvents, e.g. benzene or triethylamine. The yields were much reduced by the necessary filtration, under dry nitrogen, of the by-product, triethylamine hydrochloride.

SiMe3

R 2 R' R2

Pr" Bu" (7) Pr" Bu" (12) Me But (8) Me But (13) -(CH2) 3 - (9) -(CH2) 3 - (14) -(CH2)4 - ' (10) -(CH2)4 - (15) -(CH2) 5 - (11) -(CH2 )5 - (16)

OH Mo02 N \ R 2 I 2 i R

Rt R2 R1 R2 Pr" Bu" (17) Pr" Be (21) -(CH2 )2 - (18) Me But (22) -(CHZ )~ - (19) -(CH2) 4 - (23) -(CH2 )5 - (20) -(CH2 )5 - (24)

Table 1 Silylation and Oxidation Results for Secondary Amides

Silylation Oxidation Oxidant Reaction Product Product Ligand Time Yield Yield (MoO5L) (days) b

(12) 73a (17) HMPA 6 14

(21)c - - 12

(13) 62 (22) 2DMF 2 16

(14) 70 (18) HMPA 14 trace

(18) 2DMF d 14 0

(15) 56a (19) HMPA 2 14

(23)` - - 14

(16) 71 (20) DMF 1.5 42

(24)c - - 37

(16) 605 (20) HMPA 3 23

(24)c - - 22

°Data from Ref. 41. b Based on silylamide conversion. `After treatment with EDTA. d At 40°C. 83

The oxidations of the silylated aliphatic amides (12) - (16) gave, with the exception of the caprolactam derivative, low yields (<16%) of the corresponding hydroxamic acids. In the series of lactams LNHCO-(CH2),, (7) - (11), the range of hydroxamic acid yields from 0% (n=3) to 14% (n=4) and 42% (n=5) may reflect the effects of intramolecular freedom in the oxidation reaction or in the stability of molybdenum hydroxamates. Whereas the molybdenum complex of N-hydroxy-2-piperidone (19) has been synthesised independently, 41 attempted preparation of a molybdenum complex of the.5-membered ring hydroxamic acid, N-hydroxysuccinimide did not afford the molybdenum hydroxamate but resulted in net hydrolysis to give succinic acid. Although there is little information pertinent to the stability of molybdenum complexes of small ring hydroxamic acids, these hydroxamic acids do form iron (IīI) complexes, as indicated by typical purple colourations with ferric chloride. Though the yields of oxidation were low, the method may still constitute a useful alternative to known preparative methods for N-hydroxylactams and some N-hydroxy- amides, which are similarly low-yielding.

Anilides

The second group of secondary amides comprising the anilides are summarised in Tables 2 and 3. 84

C H 3

x x H (25) H (29) Cl (26) Cl (30) OMe (27) OMe (31) NO2 (28) NO2 (32)

Table 2 Data for Silylation of p-Substituted Acetanilides

Product Reagent Solvent % Yield

(29) CTMS/Et3N C6 H6 56

BSA C5H5N 95a 95b HMDS/HT - " NaH + CTMS THF 85

(30) Nall + CTMS THF 75 (31) HMDS/H+ - 83

It NaH + CTMS THF 89

(32) HMDS/H+ - 90

NaH + CTMS THF 80

a Estimated by g.l.c. b Estimated by 1 H n.m.r.

The silylation of anilides was generally a facile, high-yielding reaction as shown by those methods where further manipulation of the silylamide, other than evaporation of the by products, was not required, e.g. with hexamethyldisilazane and bis(trimethylsilyl)acetamide. 85

Table 3 Oxidation Data for N/O-Trimethylsilylanilides

Mole Oxidant Product Equi- • Solvent Reaction % MoO5L valents Time (h) Yield

(33) HMPA 1 CH2C12 4.5 45

(34) - - - - 42a

DMF 3.5 CH2C12 4 40 b

" DMF 10 CH2C12 4 25 DMF 0.2 CH2C12 4 30

DMF 1 CH 2C12 6 45b

DMF 1 C6H6 4 43

DMF 1 CH3NO2 24 lld

HMPA , Py 2 CH2C12 6 43e

(PyH+) 1 CH2C12 6 37b

2DMF 2 CH2C12 15 42-8

(35) 2DMF 2 CH2C12 15 42

(36) 2DMF 2 CH2C12 15 41

(3'7) 2DMF 1 CH2C12 15 45

,, 2DMF 2.2 CH2C12 15 48

aFrom (33) after treatment with EDTA; yield based on silylamide conversion. bRecovery of parent amide (25) 51-53% CYield based on Mo05.L conversion. d Recovery of parent amide (25) 83%. e Pyridine-N-oxide (10%) was also observed. 0 HO

\ --3 X Mo02 H (34) Ph Cl (35) OMe (36) • NO2 (37) (33) 86

The silylanilides showed marked differences in their susceptibility towards hydrolysis, in that, qualitatively, the observed order of stability was OMe > H ~.Cl>> NO2 . This is in accord with solvolytic experiments described by Klebe .3"

All the silylated anilides were oxidised more rapidly and in significantly higher yields than the corresponding N-alkyl silylamides. Hydroxamic acid yields of 41 - 487 were obtained and these could be consistent]y reproduced over a wide range of experimental conditions.

An excess of either substrate or oxidant did not produce any increase in yield, but a decrease owing to hydrolysis of the silylamide with a large quantity of oxidant or, in the latter case, because of difficulty in separation of the hydroxamic acid from the excess of amide.

The tautomeric structures of the silylanilides (29)-

(32) have been shown to be dependent upon the electronic nature of the aryl substituents; the p-nitro silylanilide appears to be exclusively in the imino-ether form (32b), whereas the amide isomer (31a) is predominant in the p-methoxy species. However, very little variation in the

oxidation results was observed.

The choice of ligands of the oxidant, Mo05.L , appeared to influence the reaction only in that the mono-

liganded complexes had shorter reaction times. In relation, the use of the polar, mildly donating solvent, nitromethane

had a marked effect on the reaction time and significantly reduced the hydroxamic acid yield, possibly due to

inhibitive solvation. 87

N-hydroxyanilides are readily prepared by the acylation of aryl hydroxylamines, yet the current amide hydroxylation process is applicable to the synthesis of, for example, N-hydroxynitroanilides, for which the preparation of the nitroarylhydroxylamine precursors generally. requires electrochemical techniques 4z

Aryl Carboxamides

The reactions for a series of amides derived from aryl carboxylic acids are given in Table 4. The silyl derivatives of aryl carboxamides were prepared in moderate to low yield for which, in the case of benzanilide, the solubility of the parent amide had been implicated. Steric hindrance due to the 2,6-dimethyl moiety in (45) may also be a significant factor of the reduced yield of silylamide. The oxidations of N-propyl and N-phenyl silylbenza- mides (39) and (42) by molybdenum pentoxide both occurred in ca.35% yield, whereas the silylated mesitoamide (46) gave only traces of hydroxamic acid, as indicated by a positive ferric chloride test. If the oxidation proceeds via a silylamide-molybdenum complex, similar to amide transition metal complexes in which the substrate bonds through the carbonyl oxygen, 43 the highly hindered 2,4,6-trimethyl- benzamide derivative would not be expected to form a stable complex, with consequent inhibition of oxidation.

Primary Amides

Mono and bis-trimethylsilylated primary amides have

been well documented 4445 and are readily prepared with

Table 4 Silylation and Oxidation Data for Aryl Carboxamides

Silylation Oxidation Oxidant Reaction Product Reagent Yield Product % Yield" Mo05L Time (h)

(39) CTMS/Et3N 50 (40) 2DMF 15 34

(42) CTMS/Et3N.. 32 (43) HMPA 3 38

(44) b - 34

(46) HMDS 40 (47) 2DMF 120 trace

°Based on Silylamide conversion. bFrom (43) after treatment with EDTA; yield based on silylamide conversion

0 0 0 Y X X X PhN/ H (38) Ph AN» II (41) N H (45) I SiMe3 (39) I SiMe3 (42) I SiMe3 (46) Pr OH (40) Ph -0)2M002 (43) Me OH (47) OH (44) 89 chlorotrimethylsilane in greater than 70ō yield.

In the reactions of the primary silylamides (48) - (50) with molybdenum pentoxide, only the benzamide derivative (49) indicated any significant oxidation, and this in only

3% yield; yet BSA (50) did show unreproducible hydroxamate formation. The occurrence of stable molybdenum complexes of primary hydroxamic acids has been demonstrated by the conversion of benzohydroxamic acid into its corresponding molybdenum dihydroxamate (51).

SiMe3 0 O

R' "NH—SiMe3 C H3 N—SiMe3

R (50) Me (48) Ph (49)

Multifunctional Amides

The oxidations of a series of multifunctional com-

pounds containing secondary amide units are summarised in

Table 5.

Pencillin G S-oxide (56), being thermally labile" required the use of BSA at ambient temperatures in order

to effect silylation to the tristrimethylsilylated product

(58). An interesting feature of the silyl pencillins is

the occurrence of a facile and reversible epimerisation at

47,48 C6. The interconversion of these epimers is claimed 90

PhCH2CO Ns S

(X) 0 CO2(

X X H (54) H (56) SiMe3 (55) SiMe3 (58)

OZ Me Me fN~O X Y Z H H H (62) H Me H (67) SiMe3 H SiMe3 (63) X Ph SiMe3 Me SiMe3 (68) OH H SiMe3 (64) X OH Me SiMe3 (69) H (59) OH H H (65) SiMe3 (60) OH Me H (70)

Table 5 Silylation and Oxidation Data for Multifunctional Secondary Amides

Silylation % Yield Oxidant % Yield Substrate Reagent Silylamide Mo05.L Hydroxamic Acid (54) CTMS !Et3 N 16 DMF 0

(56) BSAC b 2DMF 0

(59) ENIDS b HMPA trace

(62) HMDS >95` 2DMF 33 (67) H`,ID S b 2DMF 29

°At room temperature for 14 days. b Silylamide used for oxidation reaction. `Estimated by 'H n.m.r.

to proceed via a silyl enol-ether in the f3-lactam ring (58). The S-oxide appears to be a necessary function for it is thought to catalyse the reaction by increasing the

acidity of the H6 proton. On hydrolysis of (58), the

major product was the trans-isomer (57), identified by

the n.m.r. spectrum in which the H6 proton at 4.901

was shifted upfield relative to H6 in the cis-isomer, which occurs at 4.25T

O Me3Si I 0 1;1 F-11 Fil / PhCH2CONH ; , PitCH2CON~ BSA r,, (58) N Me3SiO %% CO2 H Me3

(56)

[7)

PhCH2CONH..

(57) ō CO2H

The oxidations of the silylpencillin (58) and the silylated acetamidocrotonate (55) gave no indication of hydroxamic acid formation. Both these species may be expected to undergo oxidation for they contain essentially isolated secondary amide functions. The availability of several complexing centres in the molecules could possibly inhibit the formation of a molybdenum-substrate complex that is specific for the oxidation process.

The oxidations of the benzoxazinones (62) and (67)

to the corresponding hydroxamic acids provide examples of

92 the potential usefulness of this synthetic procedure in relation to alternative preparative methods. Syntheses of cyclic hydroxamic acids have frequently employed preparations of hydroxylamine intermediates, for which, in the presence of other reactive groups, protection-deprotec- tion sequences are necessary. 3'9 The syntheses of the natural herbicides, the 2,4-dihydroxybenzoxazinones, reported by Virtanen et a/.49 used this approach (scheme 2) to prepare (65) and (71) in overall yields of less than 1%.

Scheme 2

NO2 Np2

OH C H O•

O jlCOCHCl2 jICOCHCl 2 OH OH OH R H (65) 7-Me 0 (71)

The NH analogues (62) and (67) were prepared by a similar method in high yield (75-85q) from the 2-amino- phenols (scheme 3). The conversion of these stable lactams into the 2,4-dihydroxybenzoxazinones (65) and (70) via silylation and oxidation with molybdenum pentoxide has been accomplished in ca.30% yield, representing an overall yield of 20% from the aminophenol. 93

The lactams (62) and (67) were silylated by the reaction with refluxing hexamethyldisilazane (b.p. 126°C), though alternatively, silylation could be effected with

BSA at lower temperatures. The in situ oxidation of the bis(trimethylsilyl)benzoxazinones afforded the 2-trimethylsilyloxy derivatives of the free hydroxamic acids (64) and

Scheme 3

NHZ

R R H (61) H (62) Me (66) Me (67)

OH OSiMe3 N.„...... 3

.:2,-.O ....". N R N ~0 R i ~` O I OH OH SiMe3 R R R H (65) H (64) H (63) Me (70) Me (69) Me (68)

(69), which were readily hydrolysed to the requisite dihydroxy species (65) and (70). The failure to form isolable molybdenum hydroxamates is a notable feature of many heterocyclic systems.

Molybdenum pentoxide does not appear to provide a useful method for N-oxidation of the dioxopiperazine (59) for very low yields of hydroxamic acid were indicated by ferric chloride tests. However, similar reactions with barbiturates have recently afforded both mono- and di-AL oxides in reasonable yields.5o 94

Heteroaromatic Amides

Two heteroaromatic amides have been studied (Table 6). The results from in situ silylation and oxidation reactions show major differences from other substrates, in that very high yields of N-hydroxy derivatives were obtained from the amides (72) and (75). The silyl derivative of (72) has been shown to exist as 2-silyloxypyridine (73) rather than as the N-silyl tautomer (cf. chapter 3) and therefore the aromatic nature of these substrates could provide a different reaction pathway relating more to aromatic N- oxide formation, of which molybdenum pentoxide is capable

( cf. the reaction of Mo05.HMPA.Py in Table 3) . Similarly, 2-pyridinol N-oxides 21 and 2-quinolinol N-oxides 51 can be prepared by peracid oxidation of the corresponding 2- alkoxy aromatic derivatives.

x x X x H (72) H (75) OH (74) OH (77)

N ~ 'OSiMea N OSiMe3

(73) (76)

Table 6 Silylation and oxidation Data for Heteroaromatic Amides

Oxidant % Yield Silylation Yield Mo05.L Hydroxamic Substrate Reagent Silylamide (Equi- valents) Acid

(72) CTMS/Et3 N 42 DMF (1.0) 48

NaH + CTMS 56 2DMF (2.0) 91

HI1DS° 95

(75) HMDS 95 2DMF (2.0) 90

a Estimated by 'H n.m.r.

Carboxamide Derivatives

All the silylated substrates given in Table 7, com-

prising ureas, urethanes, and imides have been completely unsusceptible to oxidation; only hydrolysis of the silyla-

ted derivatives being observed.

X Y X

N.CO.N N.CO.NEt2 Ph \Ph Ph

X y X H H (78) H (81) H SiMe3 (79) SiMe3 (82) SiMe3 SiMe3 (80)

N.CO 2 R 2 X-N

RT 0 R' R2 X X. Ph Me H (83) H (87) Ph Me SiMe3 (84) SiMe3 (88) Pr"Et H (85) Pr" Et SiMe3 (86) 96

Table 7 Silylation Data for Ureas, Urethanes, and Imides.

Product Reagent % Yield

(79) PhNCO + HMDS 56 (80) PhNCO + HMDS 42 (82) PhNCO + Et2 NSiMe3 0 TP HMDS 30 NaH + CTMS 86

(84) CTMS/Et3 N 25 (85) HMDS 50a

PhNCO + EtOSiMe3 0

(87) CTMS/Et3N 38

Accompanied by isocyanate formation

The formation of silylureas has been accomplished by the reactions between silylamines and isocyanates 52,53

and by the reaction of bis(trimethylsilyl)mercury 54 with isocyanates.55 Accordingly, the mono- and bis(trimethylsilyl)ureas (79) and (80) were prepared by the method out-

lined in Equation 8; whilst a comparable method 53 for synthesising the monosilylated urea (82) from diethyl(tri-

methylsilyl)amine failed to produce the silylurea. Similarly, an attempt to prepare the silylated urethane (86) by the reaction of a silyl ether with an isocyanate was unsuccessful. Alternatively, the reaction of the urethane (85) with chlorotrimethylsilane and treatment of the urea (81) with hexamethyldisilazane or sodium hydride and chlorotrimethylsilane did afford the requisite products. 97

2 PhNCO Me3S1 SiMe3 /S iMe3 N.CO.N --- PhNH.CO.N [8] Ph \Ph \ Ph (Me3S1)2NH

(80) (79)

An interesting feature of the silylureas (79) and (82) and the silylurethane (86) was a thermal decomposition to give the corresponding carbodiimide or isocyanate. These reactions occurred during silylation with hexamethyldisilazane (at 126°C) and during vacuum distillation at temperatures greater than 100°C. Similar processes have been noted to occur under varying conditions (-20°C to +150°C), with many silylated substrates.3ob,52

Thioamides and Sulphonamides

Oxidation of two thio analogues of amides, thioacetanilide and benzenesulphonamide, and their silylated derivatives has been examined.

X X X CH3 N H (89) PhSO2 NHX H (91) SiMe3 (90) SiMe3 (92) Ph

The primary sulphonamide (91) was readily monosilylated with hexamethyldisilazane, yet subsequent reaction with molybdenum pentoxide indicated that no N-oxidation had 98 occurred, as with several primary carboxamides. Silylated thioamides, which have been prepared using a lithium alkyl and chlorotrimethylsilane, 36 and recently by the addition of lithium bis(trimethylsilyl)amide to thiourethanes,56 have been reported to undergo 1,3-silyl a6 migrations, similar to carboxamides, though not always reversibly.57 The thioamide (89) was silylated by the analogous use of sodium hydride and chlorotrimethylsilane. The oxidation of both thioacetanilide and its trimethylsilyl derivative (90) afforded no thiohydroxamates nor an S-oxide from a possible mild oxidation of sulphur, by comparison to the reaction with hydrogen peroxide.58 Instead, both (89) and (90) gave quantitative yields of acetanilide - the typical product from peracid oxidation of isothioamides and the oxidation of thioamides by basic hydrogen peroxide59

Alternative Reagents Various alternatives to the trimethylsilyl group as an activating species and molybdenum pentoxide as oxidant for the N-oxidation of acetanilide have been briefly investigated. The reaction of acetanilide with sodium hydride or butyl-lithium gave the sodium (93) or lithium (94) species, whilst the magnesium derivative (95) was prepared according to a method for related metallo-amide species,60 by the reaction of methylmagnesium iodide with phenylisocyanate. Treatment of the anilide anion (93) with the appropriate chlorosilane or chlorostannane afforded triphenylsilyl- (97), trimethyl- (98), or tri-n-butylstannylacetanilide

(99). The ethyl imidate (96) was prepared by the alkylation of acetanilide with triethyloxonium tetrafluoroborate. 99

X X X Na (93) (0)-Et (96) CH3 ~N Li (94) SiPh3 (97), MgI (95) SnMe3 (98) Ph SnBu3 (99)

In contrast to the hydroxylation of carbanions61,s2 by molybdenum pentoxide, the sodium and lithium anilides

(93) and (94) were not oxidised by Moo 5. L . Only the group IV derivatives (97) - (99) reacted with molybdenum pentoxide to give hydroxamic acids, but slowly and in low yields (

4. Aspects of Oxidation

Various aspects of the oxidation of trimethylsilylacetanilide have been considered; including product analysis, 100

monitoring of the active oxygen, and determination of the silyl and amide components by ~ H n.m.r.

After separation of the products by t..l.c., molybdenum hydroxamates and the parent anilide accounted for greater than 96S of the material, with no other N-aryl products being observed. The trimethylsilyl moiety is converted to hexamethyldisiloxane, which was isolated by direct distillation from the reaction medium; the product having identical properties with independently prepared authentic material ' Other than as a hydroxamic acid complex, the remainder of the molybdenum content has not been identified, though permolybdates are known to decompose to molybdates with loss of oxygen.65

The oxidation reaction does not appear to be a radical process, for the addition of either the radical promo- ter, benzoyl peroxide, or the inhibitor, di-t-butylphenol, had no effect on the reaction time nor on product distribution. The addition of a Lewis acid, e.g. boron trifluoride, had a small deleterious effect on the yield of hydroxamic acid with minor formation of numerous by-products.

The molybdenum pentoxide complexes have been analysed by permanganate,iodiometric, and ceric ion 66 titrations, though only the last was reproducible in the presence of organic materials. The rate plot derived from monitoring the peroxide content during the oxidation reaction

(Figure 1) does not show a simple first-order relationship, but indicates the possibility of two processes. 101

1.2 -

N 0 0.9- 0 N 0

0•5- °

0.3

• i f time (min) 25 15 30 60 120

Figure 1 Rate plot of peroxide concentration [ Or] during the oxidation of AVO-trimethylsilylacetanilide (29) with 11o05.2DMF in CH2C12 at 25°C.

N.m.r. Studies

The oxidation reactions of trimethylsilylacetanilide (29) and trinethylsilyl-2-nyrrolidone-(14) have been investigated by monitoring the changes in the 1 H n.m.r. spectra with time. Of these substrates, (29) is oxidised in 48% yield, whereas (14) is apparently not oxidised.

The analysis of the n.m.r. spectra of (29), summarised in Table 8, was concentrated upon the acetyl CH3 absorptions (7.8 - 8.5T) and the Si(CH3) absorptions (9.6 - 10.O-r). In the methyl region, separate peaks corresponding to the silylamide (8.20T), parent amide (7.83-t), and the molybdenum hydroxamate (7.75-r), were observed and the relative 102 concentrations evaluated by integration. In the narrow band of the silyl region, specific absorptions could not be assigned, other than the high field signal of hexamethyldisiloxane (9.98T). Owing to the ill-defined n.m.r. spectra of (14), the results, outlined in Table 9, were limited to the silyl components, as for (29).

The formation of hexamethyldisiloxane appears to be independent of hydroxamate formation for the relative rates of production show no correlation. In addition, the silylpyrrolidone (14) shows a complete conversion to hexamethyldisiloxane and parent amide, yet no oxidation occurs.

There is a rapid appearance of acetanilide followed by a slow increase in amide concentration which probably reflects net hydrolysis. The initial occurrence of amide is not, however, accompanied by an equivalent formation of hexamethyldisiloxane —the hydrolysis product—, which suggests an intermediate silylated species. An indication of a silyl transfer process is also gained from the decrease in the silylamide concentration, which is much faster than the formation of the final product, hexamethyldisiloxane. A similar observation was made during the oxidation of the silylated p-nitroacetanilide (32).

From a comparison with the monitoring of the molybdenum pentoxide concentration, the consumption of active oxygen roughly parallels hydroxamic acid formation, from which a common process involving both functions might be inferred. 103

Table 8 Data from 1 11 N.m.r. Spectra of Trimethylsilyl- Acetanilide

a b Time c °' ,ā o % MOB (h) (Me3Si)20 Silyl Silyl- Hydrox- Parent species amide amate Amide

0 3 97 97 0 3 0.2 14 86 43 4 36 1.2 18 72 12 12 36 3.5 20 80 6 26 36 20 32 68 0 32 37 92 78 22 0 36 40 120 85 15 .0 43 46

From integration of silyl region. b % Total silyl absorptions excluding hexamethyldisiloxane component. From integration of acetyl CH3 absorptions. Remaining material observed as an intermediate at 7.952.

Table 9 Data from 1 H N.m.r. Spectra of Trimethylsilyl- -2-pyrrolidone

Time (h) Silylamidea % (Me 3Si),0°

0 100 0 0.2 64 36 48 0 100

'Based on integration of the silyl absorptions. 104

5. Discussion

Certain aspects of the oxidation of silylamides have been considered that reflect the peracid oxidations of imino-ethers and the epoxidation reactions of molybdenum pentoxide.

As in the peracid oxidation of imines to give oxaziridines, 67 the products from the oxidation of imino- ethers, which include hydroxylamines, esters and nitroso compounds,23 and. hydroxamic acids,22 are considered to result from rearrangement or hydrolysis of the intermediate alkoxyoxaziridine (Equation 5). Yet, these oxaziridines have been isolated in several cases.23 In the epoxidation of olefins by molybdenum pentoxide, one reported mechanism of the reaction compares directly with the electrophilic oxidation of peracids, implicating a 3-membered intermediate (100).68 Similar intermediates have been described for the'epoxidation reactions of

O- O N tA1 0236o+c-- (100 ) I O

69 hydroperoxides catalysed by molybdenum and vanadium.70 However, Mimoun et a 1. 39 have proposed that Moos. L forms an initial T -complex with the substrate and that oxygen transfer involves a 1,3-dipolar cycloaddition to the olefin with subsequent rearrangement to the epoxide (Scheme 4). 105

Scheme 4

I 4 o -}- O \O

The conversion of silylamides to give hydroxamic acids may be directly analogous to the peracid oxidation of imines and consequently, only the 0-silyl tautomer would be expected to react. From 13 C n.m.r. studies of silylamides (Chapter 3), the equilibrium distributions of the silylated p-substituted anilides (29) - (32) were shown to range from ca. 96% O-silyl isomer for the strongly electron withdrawing p-nitro group (32) to ca. 95% N- silyl isomer in the p-methoxy substrate (31). However, the yields of hydroxamic acids in the anilide series were fairly constant in the range 40 - 48%. The results from H n.m.r. studies of the silylamide oxidations also appear to be independent of tautomerism. In the silylated lactam series of 2-pyrrolidone (14), 2-piperidone (15), and E-caprolactam (16) derivatives, (14) and (16) showed no example of silyl tautomerism; the 106

N-silyl isomer apparently being exclusively present. The silyllactams were oxidised to hydroxamic acids in yields ranging from 0 to 42%, which seems to imply that, even in the absence of a detectable tautomerism, the N- silylamide isomer is capable of undergoing oxidation. An example of an exclusive O-silylimino-ether occurs with 2-trimethylsilyloxypyridine. The silyl heteroaromatic amide (73) may not, however, be a comparable substrate, for the oxidation results appear anomalous in furnishing very high yields (>90%) of N-hydroxypyridone and the reaction may resemble the peracid oxidation of pyridines.

Further examples which relate to the aspect of tautomerism are the oxidations of the sterically hindered silylamides (13) and (46). N-t-Butyltrimethylsilylacetamide

(13) is postulated to occur solely in the O-silyl form. This is in agreement with the 1 H n.m.r. spectra which show a sharp high-field singlet (9.85t) that is assigned to a trimethylsilyloxy group, for which no exchange reaction leads to line broadening. Conversely, the n.m.r. spectra of the trimethylsilyl mesitoamide (46) shows a sharp lower field signal (9.63r), which is indicative of a N-SiMe3 group.71 The oxidation results of (14) and (46) are not directly comparative since aryl substituted amides are generally oxidised in higher yields than aliphatic amides.

But, using relative comparisons to cognate species, the O- silylated t-butylacetamide, which is oxidised in 16% yield, is not dissimilar from other aliphatic amides; thus the

O-silyl tautomer is apparently readily oxidised. The N- silylated mesitoamide, however, shows a large reduction in the yield of hydroxamic acid from the normal value of 107

ca. 35% for aryl carboxamides. This observation is not necessarily due to a limitation in the oxidation of the N-silyl isomer, because the highly hindered carbonyl function of the mesitoamide could influence the formation of a silylamide-molybdenum complex, since amide complexes with transition metals are only known to interact via the carbonyl oxygen.43 Moreover, there is evidence for the involvement of a substrate-molybdenum complex as inferred from the extended reaction times with the fully coordinated oxidants (5e) and (5f) relative to (5b) and (5d), and with donor solvents. A simple epoxidation mechanism related to peracid oxidation may not necessarily be operative because attempted oxidations of other imine functions, i.e. Schiff bases, aldoximes, carbodiimides, and isocyanates, all failed; only hydrolysis being observed. This accords with the apparent role of the silyl moiety (p. 102). Since the involvement of a silylated intermediate is indicated from IH n.m.r. studies, the apparent maximum oxidation yield of 50% might be interpreted as the additional use of the silylamide as a silyl donor. In consideration of the possible role of a silylated oxidant, unsuccessful attempts were made to generate a molybdenum silylperoxide by the reaction of bis(trimethylsilyl)peroxide 72 with molybdenum trioxide - by analogy to the formation of bis(trimethylsilyl)persul- phates and -perchromates.73 Furthermore, the use of excess substrate or additional non-reactive silylating reagents, e.g. N-trimethylsilylimidazole, did not achieve increased hydroxamic acid yields.

108

An alternative view of the oxidation of silylamides involves the insertion of an oxygen atom into the nitrogen

-silicon bond by electrophilic attack of the peroxo group at the amide nitrogen. Apparent increases in the nucleo- philicity of amides and amines have been observed due to the introduction of silyl groups. 30b, 74

OSiMe3 [91

R2 /Si Mea

R2 0 OSiMe3

SiMe3 Ph Ph ~~ NEt

CH3 CON .; N Et - C i~ ~NCOCH3 Ph

Silylated secondary amides react with alkyl or aryl aldehydes to yield N-(silyloxyalkyl)amides (Equation 9),75 and similarly in the reaction with epoxides (Equation 10)76 A further example has been noted in the reaction of trimethylsilylacetanilide with a chloroimine (Equation 11).77 Although the reactions of silylamides with epoxides and 75 with ketones are generally catalysed by NaOSiMe3 , which is thought to generate an amide anion, the silicon atom has been considered to increase the electrophilic properties of the aldehyde or epoxide by complexation, as a 109

Lewis acid, in a 4-membered cyclic intermediate. 75 This may bear resemblance to the activating effects of silicon in the oxidation of silylamides. 110

CHAPTER 3

13C N.M.R. STUDIES OF TRIMETHYLSILYLAMIDES

Trialkylsilyl derivatives of amides have been known for many years 30'78 and the tautomeric nature of the species has been a continual subject for discussion.44,45,71 As part of the study of the oxidation of silylamides, a relationship between the tautomeric equilibrium of silylamides and the oxidation reaction with molybdenum pentoxide was sought. Quantitative evaluations of the ratios- of the silylamide isomers (4a) and (4b) have been made from the

13C FT n.m.r. spectra of series of silylated secondary amides.

1. Structure and Tautomerism

There are two accepted structures of mono-and bis- (trimethylsilyl)amides, possessing either the N-SiMe3 group (4a) or the O-SiMe3 group (4b).

111

0-- --SiMe3 OSiMe3

N/SiMe3 II R1-- \ I R2 (SiMe3) PMe2(Si 3) R2 (SiMe3)

(4a) (101) (4b)

The amide form (4a) of silylamides has been assigned, from 1 H n.m.r. and i.r. data, to the structure of a wide variety of substrates, e.g. mono-silylated primary amides,45 aliphatic amides and lactams,30c and bis(trimethylsilyl)- formamide. 44 '' O-Silylimino-ethers represent the structures of the heteroaromatic silylamides, e.g. 2-silyloxypyridine 79 and many bis(trimethylsilyl) primary amides.44'45 Various, more complex' molecules contain discrete N- and 0-silyl functions," whereas other silylamides, in particular the silylanilides, are considered to be mixtures of tautomers .77 Various. factors have been reported to account for the predominance of particular silylamide isomers. Birkofer 3o has commented upon the divergent effects of resonance stabilisation, which is significant in amides but not imidates, and the greater bond stabilisation energy of the 0-Si bond in (4b) relative to the N-Si bond in (4a). Alternatively, the difference in structure between bis- (trimethylsilyl)formamide and -acetamide has been discussed in terms of the extent of Tr-character of the C-N bond 45 The facile interconversion between the N- and 0-silyl tautomers of silylamides is considered to derive from the participation of a pentacoordinate silicon atom in an 112

intramolecular transition state (101). 44x,71 Displacement reactions at silicon are generally accepted to involve pentacoordinate s p 3 d species. 31.81 The occurrence of an intermediate involving silicon in an expanded valency state has also been considered to account for the greater hydrolytic instability of silyīamides relative to other silylated species.34

Spectroscopic techniques have been extensively employed in studies of silylamide.tautomerism; thus variable temperature 'H n .m. r . 45 and line-shape analysis 82 of the SiMe3 group and 15 ti n.m.r. spectroscopy, 44e in conjunction with i.r. studies of the carbonyl and imine absorptions, in- corporating 15 N isotope effects, 45 and nitrogen-silicon absorptions, 44d.45,83 have yielded much evidence on the composition of bis(trimethylsilyl)amides and trimethylsilyl migration rates.84

Little quantitative data pertaining to the tautomerism of silylated secondary amides is extant. Low temperature 'H n.m.r. has been used to evaluate the first- order equilibrium constants of p-substituted acetanilide derivatives, 71 whereas earlier reports, 30° based on 'H n.m.r. and i.r. data, did not acknowledge the occurrence of tautomeric mixtures. Use has also been made of 29Si-

'H satellite peaks in the spectra of N-methyisilylamides.85

Further 'H n.m.r. studies of trimethylsilyl derivatives of ureas. 71 thioamides,57 and other .1,3-heteroacyclic systems 86 have demonstrated that facile tautomerisms are operative in many related species. Silyl exchange reactions have also been studied by 13C FT n.m.r. spectroscopy, e.g. of 2-silyloxytropolones 87 and cyclopentadienyl 113

derivatives.88 The recent assignment of a silylthio-

formamide structure has also used 13C n.m.r.56

2. Analysis by t3C N.m. r.

13C N.m.r. has certain inherent advantages over

1 H n.m.r. for the analysis of reaction equilibria. 89

Proton decoupled 13C n.m.r. spectra generally contain completely resolved absorptions for each carbon atom and, owing to the simplicity of the spectra, many carbons of

the amide derivatives studied exhibited distinct chemical

shift variations, accompanying the structural modifications. An internal correlation of the quantitative measurements

is thus provided and also an availability to wide ranges of substrates.

The fast exchange process of silylamide tautomerism 84

results in coalescence of the silyl absorptions in the 1H n.m.r. spectra, though several silylanilides have been

resolved at low temperature. In contrast the 13C n.m.r. spectra at ambient temperatures consist of discrete ab-

sorptions for each isomer. This observation is probably

due to the large difference in shielding between proton

and carbon nuclei for coalescence is dependent inter alia upon relative chemical shifts.90

Integration

A significant disadvantage of 13C n.rn.r. spectroscopy relates to the problems of quantitative measurements,91

which derive partially from the long and differential re-

laxation times of carbon nuclei and the nuclear Overhauser 92 effect (NOE) - a phenomenon arising from the perturba- 114 tion of dipole relaxation processes and which results in enhanced signal absorptions (<3x) of carbons with directly bonded hydrogens. The integration of 13C n.m.r. spectra has however been accomplished, with limitations,93,94 by the suppression of NOE using gated decoupling 95 or by the addition of paramagnetic relaxation reagents.96 Other reports of quantitative analyses of 13C n.m.r. spectra have shown that the suppression of NOE is not essential for determining isomer concentrations 97 or mixtures of closely related compounds,94 when carbon nuclei with similar relaxation times and NOE values are compared.

3. t3C N.m.r. of Silylamides

In order to observe the efficacy of 13C n.m.r. for the determination of isomer ratioes, data for various silylated anilides and lactams have been compiled for comparison to 1 11 n.m.r. studies. The series of amides studied are p-substituted anilides, aliphatic lactams and heteroaromatic lactams. For each substrate, 13 C n.m.r. spectra of three derivatives have been recorded, i.e. the parent amide, the ethyl imidate and the trimethylsilylamide.

Spectral assignments have been deduced from literature sources, by computation using chemical shift additivities,98 and by analogy to related materials. Further use has been made of off-resonance and specific proton decoupling, and the paramagnetic additive, chromium tris-

(acetylacetonate), to increase the sensitivity of quaternary carbons and carbonyl carbon atoms.

The concentrations of the silylamide tautomers have been measured using a gated decoupling mode. Since a major 115

disadvantage of this process is a significant reduction in signal to noise ratio, 89,94 concentrated sample solutions (20-50% in CDC13 and 90% in (CD3)2 C0) and extended data accumulation times were employed.

The spectra did not show consistent integrations for

all carbon atoms, the quaternary carbons being very low.

However quantitative measurements that were restricted to comparisons between carbon nuclei in closely related

chemical surroundings, and therefore assumed to have similar relaxation times and integrations, demonstrated good internal correlations of integral ratios. Peak height

analyses of the silylamide isomers without NOE suppression94 were also considered, but were generally inconsistent with

other integration results with the exception of the acetyl

methyl carbons.

Silylacetanilides

The 13C n.m.r. spectra of the acetanilide series and

the p-chloro-, p-methoxy-, and p-nitroacetanilide series

are summarised in Tables 10 - 13, respectively.

In the spectra of the acetanilide derivatives the

methyl groups (saturated carbon) occur in the region 15 -

25 ppm and aromatic carbons occur at about 129 ppm unless

influenced by 0,N or halogen whence they usually range

from 120 to 150 ppm. The carbonyl and imine carbon atoms

generally appear further downfield in the. region 160 -

ISO ppm from TMS. The assignments of the carbon atoms within the amide

group were straightforward. In order to differentiate the

aromatic absorptions use has been made of chemical shift Table 10 13C Chemical Shifts a of Acetanilide Derivatives

OCH 2CH 3 Me3Si OSiMe3 N= NCOCH3 N CH3

I. (25) (102) (29a) (29b)

C1 138.2 149.3 (150.1)b 142.7` 143.4d(143.6)b 149.0` * d (149.4)b C2 1.20.4 121.2 (121.5) 128.9 128.9 (129.2) 120.8 121.7 (121.3)

C3 128.8 129.0 (129.6) 129.7 129.7 (129.9) 129.7 129.7 (129.8)

C4 124.2 122.8 (123.5) 127.3 127.3 (127.3) 122.7 123.4 (124.2)

C-X 169.5 161.1 176.6 176.0 160.0 160.8 C0C1I3 24.2 16.2 23.3 23.3 17.1 17.3

CH2 CH3 - 61.5 - - CH2CH3 - 14.3 - -

°In ppm from THIS, for 25% solutions in CDC13 . Italics denote tentative assignments. b Estimated from additivity values. `Data converted from S CDCI3 77.2 ppm. d 90% in d5 -pyridine; * indicates solvent interference. n Table 11 13C Chemical Shifts of p-Chloroacetanilide Derivatives

OCHZ CH3 Me3 S OSi M e3 N NCO CH3 N CH3 \C H3

CI CI CI CI

(26) (103) (30a) (30b)

136.4 148.1 (152.1)b 141.5c (141.6)b c b C1 147.8 (147.4)

C2 121.1 122.7 (122.5) 129.6 (130.2) 122.5 (122.3) C3 129.0 129.0 (129.8) 129.6 (130.1) 129.6 (130.0)

C4 129.0 129.0 (129.9) 132.2 (133.8) 129.6 (130.6) C=X 165.8 161.7 176.6_ 161.0

COCH3 24.6 16.1 23.5 17.4

CH2 CH3 61.6

CH2 CH3 14.3

b a In ppm from TMS, for 20% solutions in CDC13 . Estimated from additivity values. `Data converted from 6CDCl3 77.2 ppm. Table 12 13C Chemical Shifts of p -Methoxyacetanilide Derivatives

OCH2CH3 Me3SI OSi Mea J NHCOCH3 CH NCOCH3 3 N~CH3

4 0Me OMe OMe OMe (27) (104) (31a) (31 b)

C1 131.4 143.0 (141.2)b 135.7` 136.5d (134.7)b 140.3` 142.7d (140.5)b

C2 122.3 122.3 (121.5) 129.3 130.2 (129.2) * 122.8 (121.3)

C 3 114.2 114.6 (114.1) 115.3 115.2 (1:L4.4) * * (114,3)

C 4 156.6 155.9 (153.7) 159.2 159.2 (157.6) * * (154.4) C=X 169.0 162.1 176.9 176.9 * 161.1

COCH3 24.2 15.1 23.2 23.2 17.7 16.9

CH2 CH3 - 61.5 - - - -

CH2CH3 - 14.3 - - - -

OCH 3 55.6 55.6 55.6 55.6 55.6 55.6

°In ppm from TMS, for 20% solutions in CDC13 .. * indicates peaks not discernible. b Estimated from additivity values. 'Data converted from Ō CDCl3 77.2 ppm. d 90% in d 6 -acetone. Table 13 "C Chemical Shifts° of p-Nitroacetanilide Derivatives

jOCH2CH3 Me3 OSiMe3 J NHCOCH 3 NCOCH3 CH 3 NCH 3

3 y NO2 NO2 NO2 N O2 (28) (105) (32a) (32b)

C1 145.4b 155.3 (156.1)c * d (149.6)c 155.3e 155.4f (155.4)` CZ 119.3 121.6 (122.3) 129.2 (130.0) 121.4 121.7 (122.1)

C3 125.1 125.1 (124.3) * (124.6) 124.8 124.9 (124.5) C4 143.1 142.4 (143.1) * (147.0) 143.5 143.E (143.8) C=X 169.9 161.5 * 160.8 161.1 COCH3 24.6 16.6 23 17.7 17.6

CH2 CH3 - 62.4 -

CH2 CH3 - 14.3 -

° In ppm from TMS, for 20% solutions in CDC13. "1 20% in . CDC13 - 116-DMSO (1 :1) . `Estimated from additivity values. d*indicates peaks not discernible. eData converted from 77.2 ppm. 6coct 3 1 95% in d6 -acetone . 120

additivities,93 whereby each substituent contributes an additive factor to the shielding of each of the aromatic carbon nuclei. The assignments for the parent amides (25) - (28) have been determined from the additivity values collated by Stothers, 9g whilst the additivity values of the imidate substituent, which were used in the assignments of (102) - (105), were computed from the observed spectra and are listed in Table 14.

Table 14 Substituent Effects on the Shielding of Aromatic Carbon Nuclei

a Q Substituent

X C l C2 C3 C 4

b —NHCOCH3 +11.1 -9.9 +0.2 -5.6

OCH2CH3 +21.4 -7.2 +0.9 -5.2

CH 3

—N +14.9 +0.5 +1.2 -1.3 COCH3 05iMe3 —N--/ +20.7 -7.4 +1.1 -4.5 H 3

° &X indicates variation (in ppm) from benzene absorption (128.7 ppm); (+) denotes increased deshielding. bFrom Ref . 98 121

For analysis of the spectra of the silylanilides, an assumption was used that the N-SIMe3 tautomers would give spectra similar to the parent amides and likewise, the O-SiMe3 tautomers would resemble the O-alkylimidates A good correlation was observed for the methyl carbons, and the imine and carbonyl carbon atoms of the N-silyl and O-silyl forms also demonstrated similar relationships to the non-silylated species. But, an unambiguous assignment of the aromatic carbon atoms based on comparisons with the spectra of the anilides and imidates was not possible because the N-silylanilide spectra, as shown from the relative additivities (Table - 14), correlate poorly with the spectra of the parent anilides. Consistent assignments could, however, be determined from the computed additivity values

of each of the silylamide substituents (cf. Tables 10 13).

Silyllactams

The 13C n.m.r. data for 2-pyrrolidone and E-caprolactam and their O-alkyl and trimethylsilyl derivatives are presented in Tables 15 and 16. The spectra of the parent amides (9) and (11) have been assigned from reported data 99 and the assignments for the lactim and silyllactam spectra have been correlated with those of the amides. The relationships between the carbonyl and imine carbons and the a-carbon atoms in the amide and imidate functions parallel those observed in the anilide series. Accordingly the silyllactams do not appear to demonstrate a rapid tautomerism and are thought to be the N-silyl isomers, for the carbonyls in (14) and (16) occur at lower 122

Table 15 13C Chemical Shifts of 2-Pyrrolidinone Derivatives

(14)

C=X 179.8 173.4 183.7b C 3 30.4 31.3 32.8 C4 20.8 23.2 21.7

C5 42.5 44.0 46.6 CH2 CH3 63.9 CH9CH3 14.6

°In ppm from TITS, for 25% solutions in CDC13 . b Data converted from 5 77.2 ppm. C D CL 3

Table 16 13C Chemical Shifts° of E-Caprolactam Derivatives

CH3C H20 N

(11) (107) (16)

C=X 180.1 169.5 182.6 b C 3 37.0. 32.5 37.4 C. 23.2 23.5 23.1 C5 29.8 27.9 29.4

C5 30.7 31.2 30.0 C7 42.8 48.7 44.1 CH2 CH3 - 60.6 CH2C H3 - 14.3 a,bSee footnotes to Table 15. Italics denote assignments unconfirmed. 123

field than in the parent lactams. This is ratified by the relative shieldings of the a-methylene carbons in the caprolactam series; the pyrrolidones do not show significant chemical shift variations.

Silylated Heteroaromatic Amides

The 13C n.m.r. data for the derivatives of 2-pyridone and 4-quinolone are given in Tables 17 and 18. The spectra of the pyridone and quinolone series are very dependent upon the aromatic nature of the heterocycles. The 13C n.m.r. spectrum of the silylated pyridone (73) is virtually superimposible upon that of 2-methoxypyridine and dissimilar from that of 2-pyridone and consequently, (73) is considered to exist exclusively as 2-trimethylsilyloxypyridine.

Table 17 13C Chemical Shifts ° of 2-Pyridone Derivatives

4 5 3

OMe 'NOSiMe3

(72) (108) (73)

C, 165.3 b 163.1c 162.6d C3 119.8 110.5 112.4 C4 140.8 138.7 138.6 C5 104.8 116.7 116.4

C5 135.2 146.6 146.9 CH3 - 52.8

°In ppm from TOSS. b Data from Ref .99; in CDC13 . `Data from Ref .100; in CS2. din (CD3 )2C0. Table 18 73C Chemical Shifts a of 4-Quinolone and 4-Pyridone Derivatives

1 3

H (109) (110) (111)

C2 139.5 b 151.3` 150.0d 139.8e 150.9 e

C 3 108.8 108.3 120.8 115.9 109.8

C4 177.2 159.1 135.7 175.7 164.9

C5 125.0 122.5 127.6

C6 123.1 125.5 126.3

C7 131.5 129.8 129.2

Co 118.3 129.3 129.2

C8a 140.1 150.4 148.1

C5a 125.9 124.0 128.0

° In ppm from TMS. bData from Ref .101 ; in d6 -DMSO. `In CDC13 ; data converted from 6 CMa3 77.2 ppm. d Data from Ref . 99 . °Data from Ref .102 ; in d6-DMSO. 125

For interpretation of the silylated quinoline (110) spectrum, the heterocyclic ring carbons have been assigned by comparison to the reported spectra of 4-pyridone and

4-methoxypyridine t02 and by off-resonance proton decoupling, which was used to differentiate the ring junction carbons Csa and C sa. Consequently the silylquinoline exists as the fully aromatic tautomer (110). The assignments for the remaining aromatic carbons have been tentatively based on the chemical shifts of the carbon nuclei of quinoline (111)99;with the exception of C5 , which is apparently shielded by the 4-silyloxy group.

Tautomer Concentrations

The spectra of the silyllactams (14) and (16), and the silylated heteroaromatic species (73) and (100) do not show any detectable tautomerism - in accord with previous results. 30,71,77

The integration results for the silylanilides are summarised in Table 19. The determinations of the percentage isomer ratios were limited to the acetyl CH3 , carbonyl/ imine, and C1 aromatic carbons, for only these carbon atoms exhibited distinct resonances for both isomers.

There is a very close correlation between the peak area measurements for each carbon atom. Equivalent results were also obtained from peak height measurements of the methyl carbons in normal t3C n.m.r. spectra, without NOE suppression by gated decoupling.

A wide range of isomer ratios is apparent, for which the electron withdrawing groups favour the imidate form whilst the amide isomer is predominant with electron donors. Table 19 Concentrations of Silylanilidc Tautomers in 13C N.m .r . Spectra

Silyl- % N-SiMe3 Tautomer a %, K A.cetanilide Solvent 0-Si.14Ic3 [0-SiMe3 Substituent CII3 C-X C1 CII3 'I'auLumer ■/'[N-SiMe3 ] p-II (29) C5D5 N 50 50 50 41 50 1.0 0.82 c

CDC13 72 73 73 74 27 0.37 (2.2)4 p-Cl (30) IT 57 57 56 57 . 43 0.75 1.58 p-OCH3 (31) 96 - - 95 4 0.04 0.17 p-NO2 (32) 4 - - 4 96 23 20

a From integration of specified carbon nuclei, using gated decoupling. Italics denote approximate values. 'From peak height measurements without suppression of NOE. CFrom Ref. 71 , for solution in d5 -pyridine at 0°C. dIn CC14. 127

The equilibrium constants for the unimolecular tautomerism of the silylanilides are compared in Table 19 to the results of Klebe, from integration of the SiMe3 peaks using low temperature proton n.m.r. 71 As with the reported data ( e = +1.6) a large, positive correlation between log K and the Hammett oi, constants was found

( e = +2.6), though under different solvent and temperature conditions. 128

CHAPTER 4

OXIDATION REACTIONS OF MOLYBDENUM PENTOXIDE

Molybdenum pentoxide has been used for various oxidative processes, e.g. the hydroxylation of carbanions and the epoxidation of olefins, 61 and these reactions have been reviewed in Chapter 1. Further examples of

MoO5 as an oxidant have been investigated.

1. N-Trimethylsilyl Heterocycles

The conversion of trialkylsilylamides into the corresponding N-hydroxy derivatives by molybdenum pentoxide Equation 6 has prompted a brief study of the oxidation of N-silylated heterocyclic compounds. The silylation of amines and amides is known to increase their susceptibility towards electrophilic reactants Sob and this effect has been described in terms of a polarisation of the nitrogen- silicon bond103 and the participation of silicon in reactions.75 Secondary amides, upon silylation, react with aldehydes,75 epoxides,76 and chloroimines 77 (Equations

9-11). Silylated amino-acids have found particular use in

129

peptide syntheses3ob The reactions of N-trimethylsilyl-

azoles 103 (Equations 12 & 13), o-diaminoaryls, 79 and W-diaminoalkanes, 80 with acid halides and azides 104 proceed more readily and in higher yields than with the

parent NH compounds.

R. N ~ N R [12] R 77 NCO i} CO si ~CI Mea -

XCI2 El 3]

X= CO, CS, S

.SiMe3 NH SiMe3 N \ X02 X [14] rJNSiMe3 / SiMe3 In view of the increased nucleophilic character

associated with the silylation of nitrogen compounds, it was considered that the electrophilic peroxo group of

io05 may have been reactive enough to effect N-oxidation of N-silylated heterocycles. The results of these attempted

reactions are summarised in Table 20.

/N `\ ` v/ N N I X X

X X H (114) H (116) SiMe3 (115) SiMe3 (117) OH (118) 130

NHX

X X H (119) H (121) SiMe 3 (120 ) SiMe3 (122)

X X H (109) (110) OH (123)

Table 20 Silylation and Oxidation of Nitrogen Heterocycles

Substrate Silylation N-Oxidation Reagents r Yield % Yield

(114) HMDS 86 0

(116) HMDS 92 10

(119) HMDS b 5

(121) CTMS/Et3N 36 0

(109) HMDS b 55

(72) HMDS 95 b,c 91 a HMD S = hexamethyldisilazane, CTMS = chlorotrimethylsilane. b Oxidised in situ. `Estimated from 1H n.m.r.

Hexamethyldisilazane was found to be a convenient and efficient reagent for the silylation of the heterocyclic substrates. The use of chlorotrimethylsilane gave low yields of the silylindole (122). 131

The reaction of trimethylsilylimidazole (115) with Mo05 gave no indication of oxidation, a virtually quantitative yield of the hydrolysed product, imidazole, being recovered. In contrast, the silylbenzimidazole (117) was slowly oxidised to give the corresponding N-oxide (118) in low yield. The physical and spectroscopic properties of (118) were in accord with authentic benzimidazole-3- oxide.145 The reactions of imidazoles with peroxidic reagents do not generally produce N-oxides.106 Imidazole is converted by neutral hydrogen peroxide into oxamide or gives ureas with peracids; an isolable intermediate from this reaction has been tentatively assigned the unlikely structure (124)107 Benzimidazoles have been reported to give benzimidazolones 1Q8 from peracid oxidation.

NH 2

H H (12 4) (125)

From the oxidation reaction of bis(trimethylsilyl)- adenine (120), a product C5H5 N50, corresponding to the addition of one oxygen atom, was isolated in less than 5% yield along with adenine itself. The structure of the oxidised material as the 1-oxide (125) was based on comparisons of its m.p. and spectroscopic (u.v. and i.r.) _properties with the known adenine-l-oxide.109 The conversion of adenine into the 1-oxide is also readily accomplished by standard peracid reagents.11° 132

The indole nucleus is very reactive towards peroxides, a common process being cleavage of the 2,3-bond 111a in its reactions with peracids, and also with molybdenum pentoxide to give the ketoamide (126)41b

The presence of a N-trimethylsilyl group was found to

have little effect on the product distribution after oxidation with molybdenum pentoxide, compared to the direct oxidation of indoles. No products corresponding to N-

hydroxyindole nor its supposed dimer (127) 111b were detected.

CH3 (127) NHCHO

(125)

As discussed in Chapter 2, the N-oxidation of 2-

trimethylsilyloxypyridine (72) has been effected by MOO5 in high yield. Similarly, 4-trimethylsilyloxyquinoline,

which has been shown by 13 C n.m.r. (p. 124 ) to exist as the aromatic O-silyl quinoline tautomer (124) rather than

in the N-silyl 4-quinolone form, was readily oxidised in

55% yield. Molybdenum pentoxide was also found to oxidise 4-quinolone, 2-pyridone and pyridine, albeit very slowly

and in low yields; pyridines tend to complex with Mo05. This contrasts with the facile N-oxidation of pyridines 105 by organic peracids and transition metal-catalysed

peroxides .112

The limited success of molybdenum pentoxide as an

oxidant of silyl heterocycles has led to the investigation 133 of several, more powerful reagents; however the hydrolytic lability of the N-silyl moiety restricts the scope for such oxidants. Attempts at oxidation of the N-silylazoles (115) and (117), and the silyloxy pyridine (72) using the trimethylsilyl ester of m-chloroperbenzoic acid, benzo[c,d]indazole-1,2-dioxide, and ozone (as a solution in dichloromethane) all proved unsuccessful.

2. Miscellaneous Reactions

Molybdenum pentoxide is capable of mild oxidation of sulphur, parallel to the molybdenum catalysed reactions of hydroperoxides reviewed in Chapter 1. The oxidation of the olefinic sulphide (128) by Mo05 showed no epoxide formation, giving instead, the sulphoxide (129) with.one equivalent of oxidant or the sulphone (130) with excess reagent.

0 1\0

(128) (129) (13 0)

The selectivity of oxidation is probably due to the relative rates of reaction, since sulphides are oxidised approximately 100 times faster than olefins with metal- hydroperoxide reagents )'3 134

An interesting example of peroxide catalysis has been observed in the hydrolysis of dimethylhexanamide by t-butylhydroperoxide in the presence of molybdenum trioxide; the corresponding hexanoic acid being isolated as the major product (Equation 15). Metal-catalysed base hydrolyses of amides are known,t14 as is the catalysis by peroxide anions,115 whereas the present example demonstrates effective hydrolysis under non-aqueous conditions.

0 M ovt COZH [[15] NMe2 Bu t OOH

In relation to the recently reported cc-hydroxylation 61 of lithium enolates by Mo05.L (5f) , sa, various phenols and their lithium and silyl derivatives have been treated with molybdenum pentoxide to effect a-hydroxylation. The sole recovery of parent phenols, however, indicated no reaction other than hydrolysis of the organometallic species. 135

CHAPTER 5

REACTIONS OF ACTIVATED UREAS

Diaziridinones (131) are tautomeric with the acyclic species (134), (135) and (136),116 which are potentially useful 1,3-dipoles. The trapping of the dipolar urea derivative (134) has been investigated in the thermal and acid-catalysed reactions of diaziridinones, and in various reactions of chloroureas and carbamylsulphilimines.

1. Diaziridinones

Diaziridinones (131) are 3-membered cyclic ureas containing a nitrogen-nitrogen bond and show an inherent instability towards nucleophiles and reducing agents 117 that is reminiscent of the chemistry of aziridinones (a-lactams).118 Greene and coworkers have demonstrated the existence of the relatively stable di-t-butyldiaziri- 116 dinone (131) and the kinetic lability of diaziridinones is inferred from observed enhanced reactivities corresponding to decreased substituent sizes.119 136

O R1 = R2 = But (131)

N N R1 = R2 = Me (132) R1/ \R 2

Several preparative methods for the formation of diaziridinones (Equations 16 - 19) have been described by Greene et a/.,116.119 involving the potential dipolar intermediates (134) to (136). Quast and Bieber 720 have also reported that dimethyldiaziridinone (132) is generated in the photolysis of 2-tetrazolinones.

R-i CO.NHR KOBut R

CI (134) (133) 1

R-N—C O CI KOBut RNA 'NR [17] R-N H

R-NC -I- R-NO R—N [i 8]

O peracid R— N=C=N—R R—N=C=N---R

(136)

137

Trapping reactions of the species (134) and (136) have only been successful for the latter intermediate, where 1,2,4-oxadiazolidines (137) were formed by the reaction with an isocyanate.tt9 Diaziridinones have also been shown to undergo cycloaddition reactions via a carba- zyl intermediate (135) giving the triazolidine (138) with isocyanates, 121 and the triazoline (139) with nitriles in the presence of boron trifluoride.122

NR 0 O RFN A But \ Ī NPh I N /N 'N Bū O R

(137) (138) (139)

Attempts have been made to react the diaziridinone tautomer (134) with olefins, and also with dienes, for the postulated acyclic dipole (134) may be considerea as a 2r- -electron system, and consequently a thermally promoted cycloaddition might be expected to occur with 4ir substrates, e.g. dienes, by analogy to the electrocyclic reactions of other (4n+2)rt- heterocyclic systems.123 The thermolytic ring-opening reactions of di-t-butyldiaziridinone (131) were generally carried out in evacu- ated sealed tubes, using a ten-fold excess of the various addends, i.e. furan, 2,3-dimethylbutadiene or cyclopentadiene, and with no additional solvents. Reactions were followed by i.r. spectroscopy, which provides a sensitive means for monitoring the presence of diaziridinones due to 138:

the characteristic carbonyl absorptions at 1860 and 1880 -1 cm .

For reaction temperatures less than 80°C, the diaziridinone was recovered in high yield from the reaction medium. However, after heating at 150°C in a sealed tube, or at 80°C under reflux conditions, no diaziridinone could be detected and the major product in ca. 45% yield was di-t-butylurea, having identical properties to authentic material.

The reaction probably occurs via a homolytic cleavage of the ring and radical abstraction of hydrogen, or possibly by disproportionation. Reductive cleavage of the nitrogen-nitrogen bond is a characteristic feature 11 of the diaziridinone system, 7 although the thermal decomposition of diaziridinones has been reported to proceed via decarbonylation.121

In order to promote an ionic cleavage reaction, solvents with high dielectric constants, e.g. DMF, were used but, in the event, these proved unsuccessful in the trapping reactions. Furthermore, the use of Lewis acids was ineffective, since even mild reagents such as zinc chloride had deleterious effects on the more active trapping agents.

The failure to demonstrate discrete intermediates such as (134) in the heterolysis of the diaziridinones has been attributed to steric hindrance of the tert- alkyl substituents or an insufficient concentration of the dipole (134), }76 the latter probably due to (134) being electronically unfavourable.124 Yet, the related diaziri- dinimine (141) has been shown to react with phenyliso- 139

cyanate to give the cycloadduct (142)125 Similarly, the dipolar tautomexs(144) of thiaziridinimines (145),

thermally generated from thiatriazolinimines (143)126

or in the reaction of azides with isothiocyanates,t27 readily react with electron-rich addends. Thus enamines yield aminothiazolidines (146) and isocyanates give thia- diazolidines (147).126

PhN N

(141) (142)

R2 N RF N i+ N=N R1N

(14 3 ) (144) (145)

RL N

NR 4 0

(147)

2. Chloroureas

Diaziridinones have been prepared by the base-

catalysed cyclisation of chloroureas (Equation 16), and

Greene et al.116 have attempted to trap the postulated

intermediate (134), during the reaction of (133) to (131)

with cyclohexene and norbornene, and with the electron- 140 deficient olefins, maleic anhydride and tetracyanoethylene; but no adducts were observed. The intermediate (134) may, however, only reflect a transition state of maximum energy of the cyclisation of the chlorourea - by analogy to the Favorskii reaction of a -haloketones.128 Yet, despite this restriction, a related dipolar species (149), generated by the reaction of the N-chloroamidine (148) with base, has been trapped with enamines to give the dihydroimida- zole (150),129 which eliminates morpholine if the R substituent is hydrogen.

NCI N

Ph-N Ph Ph —N Ph H

(148) (149)

/ N = H ) h N Ph ( P R Ph P / N Ph Ph Ph (150)

From the reaction of N-chlorodimethylurea (155) with 1-pyrrolidinocyclohexene in the presence of an equivalent of the base, sodium hydride, an adduct was isolated by chromatography in 17% yield. The structure of the adduct, C9H14 N20 , which corresponds to the addition of cyclohexene to 1,3-dimethylurea, is considered to be 141

the cyclic urea (151) resulting from reaction across the N,N terminii; rather than an oxazolinimine (152), formed from addition to the N and 0 atoms.

0 NMe Me MeN NMe MeN^0 MeN ,N

(151) (152) (153)

A symmetrical structure is inferred from the n.m.r. spectrum, which contained only three signals at 6.8 (6H),

7.6 (4H) and 8.2 r(4H) corresponding to N-CH3 , vinyl- CH 2 and saturated-CH2 protons respectively. A strong ab- -1 sorption in the i.r. spectrum at 1680 cm (in CHC13 solution) is characteristic of a urea carbonyl. The mass spectrum is also consistent with the proposed imidazolinone (151). The normal fragmentation pattern of ureas30 involves cleavage of the N-CO bonds to give isocyanates, which further fragment with loss of carbon monoxide, and amines. All the major peaks in the mass spectrum of the adduct correspond to the proposed fragmentations of the amino- isocyanate (154) resulting only from the urea (151)

(Scheme 5).

142

Scheme 5

-CO mle 138

(154) mle 166 / / i +H transfer /

MeN(H) 1+ McNHCO mle 58

mie 110

MeNH n mle 30 mie 82 Scheme 6

• Me /N / NMe Meli. O MeN MeN + -CO -MeN -l-H transfer

mle 166 mle 138 mle 110

An alternative adduct is the diazolinone (153), which might result from addition to the incipient diaziridinone (132) - by analogy to the reactions of diaziridinones with isocyanates 121 and nitriles122 Whereas the i.r. and mass spectroscopic data (Scheme 6) accord with

143 the structure, the n.m.r. spectrum is less consistent with the diazolinone (153) than with the imidazolinone (151). The formation of the adduct (151) does not verify the role of a 1,3-dipolar intermediate because alternative mechanisms can be postulated, for example, that of Scheme 7.

Scheme 7 + N., Me Me N- CI O—( 0 NHMe NHMe (155)

INN ) Me L■'"■,, Me Base O

NH CI Me Me

Me CN Base N J

Me H

Silver (I) salts have been employed as co-reagents

in reactions, owing to their ability to form i-complexes131 32 and a large affinity for the halogens.63 Taydoni et a/.1, for example, have shown that the intramolecular olefin addition of the N-chloroamine (156) is catalysed by silver (I) (Equation 20).

144

Ag +

( 156) X = Cl, Solvent

However, no addition products were detected in attempted silver (I) catalysed reactions of N-chlorodi- t-butylurea (133) with various dienes.

3. Semicarbazides and Methoxyureas

An estimation 124 of the stability of the diaziridinone tautomer (134), which has been based on the additivity of bond-energy data and viewed qualitatively in terms of the localisation on the negative charge and the poor stabilisation afforded by the positive charge in the diaza- allyl cation, indicates (134) to be an unstable species, relative to the dipolar valence isomers of cyclopropanones, a-lactones and a-lactams.

0 - O)

X—N •I--Y

(134) (157) 145

An intended stabilisation of the diaziridinone isomer (157) has involved the incorporation of both electron-donating (X = R 2N, RO) and electron-delocalising (Y = Aryl) groups into the molecule. Attempted cycloadditions using these semicarbazides and alkoxyreas were found to follow different reaction courses. The dimethyl semicarbazide (158) was prepared from 1,1-dimethylhydrazine and phenylisocyanate. Chlorination of (158) by tert-butyl hypochlorite, followed by reaction with two equivalents of potassium tert-butoxide afforded, besides the recovered semicarbazide (158), one major product in 18% yield, that is considered to be 1-methyl-4- phenyl-1,2,4-triazolidin-3-one (159). A carbonyl absorption occurs at 1685 cm (for CHC13 solution) and the

Scheme 8

MeN NPh NNZ

mle 177 CO H+ CO i• HĪ MeNNPh MeNNPh

+• PhNCO mle 119 PhNCH2 mle 10 6

+ MeN-NHCO PhN mle 91 mle 71 Me

CH2 -N—NHC ~ +

C6H 5 mle 77 mle 85

146

n.m.r. contains, apart from N-methyl, phenyl and NH resonances, a low field AB quartet, 5.40 (J =14 Hz) and 4.97 (J = 14 Hz), compatible with the N-CH2-N system. The mass spectrum exhibits a strong molecular ion at m/e 177 and the subsequent fragmentations of this species, which are summarised in Scheme 8, follow two pathways. The elimination of phenylisocyanate is characterised by the series of peaks, m/e 119, 91 and 77, whereas the major pathway involves fragmentation of the molecule into the two abundant ions, m/e 106 and 71.

Scheme 9

But OCt Me2 N—NH.CO.NHPh Me2N-NH.CO.NHPh

(158) CL

KOBut

CH3 + N—NH.CO.NHPh CH3—N+ NH.CO.NHPh CH2 H CH2 CI;

KOBut

CH3 CH3 "- N—NH N—NH

CH2 O \N O Ph Ph (159) 147

One possible mechanism of formation for the triazolidinone is given in Scheme 9. The initial exothermic chlorination probably occurs on the more basic dialkyl nitrogen. A precedent for the latter stages of this reaction process exists in reactions of the semi- carbazone (160).133 At higher pH, the open-chain isomer (160) can be isolated, whereas the major product in acidic media is the triazolidinone (161). Recent observations 34 of the tautomerism between semicarbazones and triazolidi- nones have also been described in terms of a similar, reversible cyclisation.

Me / NH2 f O N— NH `J'H (160)

• /H~

(161)

Substitution of the dimethylamino group by a methoxy group was expected to eliminate the possibility of preferential chlorination of the urea substituent, yet still promote the required stabilisation of the incipient positive charge in (134). The methoxyureas were prepared by the two routes shown in Scheme 10 and the addition of an O-alkylhydroxyl- 148

amine to an isocyanate (route A) was adopted as the preferred method.

Scheme 10

+ArNCO NH 2 OH HONH.CO.NHAr (162)

A B

+ArNCO NH 2 OMe MeONH.CO.NHAr (163)

For route B, the alkylation of the hydroxamic acid

(162), prepared by the addition of hydroxylamine to the requisite isocyanate, is reported 735 to be selective using dimethyl sulphate under controlled conditions of pH, but in our hands, products from competing N-alkylation were always observed. Another side reaction that detracted from the use of 1-hydroxy-3-phenylurea (162a)is a facile rearrangement to give an 0-carbamylhydroxylamir_e (164), which has been reported to occur by dissociation into the isocyanate and hydroxylamine (Equation 21)136

PhNH.CO.NH OH PhNCO + NH2OH — PhNHCO2.NH2 [21]

(162a) (164) 149

PhN~ C H~ / NH

Ph NH. CO2 .NH, [221

(165) Ph N'• H~

C2H2j

One product obtained via such a rearrangement is considered to be the oxadiazolidinone (165), probably resulting from condensation of (164) with acetone, used

in the work-up procedures (Equation 22). The i.r. spec-

trum contains a carbonyl absorption at 1710 cm (solid

phase) and 1730 cm-1 (solution) suggesting the urethane system, rather than a urea and the n.m.r. spectrum contains

two non-equivalent C-methyl groups, consistent with an

acetone-derived addend in a ring structure. The mass

spectroscopic data also corroborate the structure of

(165), for the major decomposition pathway, giving the

We 119 or We 73 ions, can readily be accomodated by the oxadiazolidinone assignment, as outlined in Scheme 11. 150

Scheme 11

0 —Co Ph N PhN % Me „ NH NHH Me Me Me

PhNCO mle 119 (CH3 )2 C=N-O ~ mle 73

CH2

PhN+. mle 91 CH3 N mle 56

C6 H5 mle 77 C3H5 mle 42

During the attempted oxidation and cycloaddition reactions with 1-methoxy-3-phenylurea, the major reaction product, using tert-butyl hypochlorite as oxidant, was the corresponding p-chlorophenyl derivative. Excess of the chlorinating reagent did not afford further substitution of the ring. This reaction closely resembles the Orton rearrangement 137 of N-chloro anilides to give p-chlor- anilides (Equation 23), whereby the halogenating species is regarded to be free chlorine, generated by the reaction of the N-chloroaryl (166) with adventitious hydrogen chloride; present in the tert-butyl hypochlorite.

151

R N—Cl

+ HCL [23]

(166) CL

Silver (I) and base catalysed reactions of para- substituted aryl ureas did not afford the requisite cyclo- adducts with various trapping agents; instead, conversion into alkyl or aryl urethanes (169) occurred via formation of the corresponding isocyanate (168). Subsequent reaction with methanol or ethanol, arising from the work-up procedure, afforded the observed products.

/OMe R NH.CO.N gA — RNCO ~H RNH.CO2 R' [24] \Cr.

_ (167) (168) (169)

Monitoring the silver (I) catalysed reaction (Equation 24; R = p-C1C5H4 ) in chloroform solution by i.r. spectroscopy showed the disappearance of the N- -1 chlorourea (167) (carbonyl absorption at 1740 cm ) after 50 mins. and formation of a new isocyanate absorption at

2267 cm-1 . p-Chlorophenylisocyanate was isolated by direct vacuum distillation from the reaction medium

(b.p. 75-80°C/8 mm) and had identical spectroscopic properties to authentic material.

152

4. Carbamylsulphilimines

An alternative approach to N-chlorination for

generating the positively-charged nitrogen in the dipolar diaziridinone tautomer (134) has been the incorporation of a sulphilimine function into the urea (170), thereby

providing the powerful leaving group R 2ST.

HO N-.-S R 2

R NH RN (170) (171)

An example of sulphilimines being used to produce an electrophilic nitrogen in a pyridine ring has been

described by Rees et a/.,138 in which the sulphilimine

(172) was shown to react with diphenylnitrilimine (173)

to give the tetrazine (174), by the proposed mechanism

shown in Scheme 12.

Scheme 12

Me2S .Ph

Ph / I

.-...... „.„.N 1 N

Ph Ph

(172) (173) (174) 153

By comparison to the reactions of the pyridylsul- philimine (172), trapping of the N-carbamylsulphilimine (170), or its tautomer (171), with the reactive 1,3-dipoles diphenylnitrilimine and diazomethane has been attempted. The S,S-diarylsulphilimine (177) was synthesised

from the free diarylsulphilimine (175)139 by deriviti- sation with the corresponding isocyanate (Equation 25). The preparation of the N-carbamyl-S,S-dialkylsulphilimine (178), however, was attempted by a different route for free dialkylsulphilimines are thermally unstable at 14o ambient temperatures By comparison with the synthesis of N-aryldialkylsulphilimines (172) from dimethylsulphoxide and the primary amines in the presence of phosphorus pentoxide 1 41 or trifluoroacetic anhydride, '42 the corresponding reactions with phenylurea afforded the relatively unstable dialkylsulphilimine (178) in very low yield.

Ph Ph Ph j5 -.- - jS-•-NH /S+-N. CO NHR [2 5] Ph Ph Ph

(175) R= Me (176) R= Ph (177)

Me O Me P 2 s /S~O + PhNHCONH2 \S-~,N.CONHPh [26] / Me Mes (178) 154

The attempted reactions of the sulphilimines (176)

- (178) with diphenylnitrilimine (173) and diazomethane showed no evidence of addition products analogous to the tetrazines reported by Rees et a /. 138 The stable diaryl- sulphilimines (176) and (177) were recovered in very high yield, whereas the major product, other than by nitrilimine decomposition, from the reaction with the dialkylsulphilimine was phenylurea, resulting from hydrolysis. At this point, attempts to achieve our objective were suspended. 155

EXPERIMENTAL

Melting points were determined on a Kofler hot- stage apparatus. Infrared spectra were recorded on a Perkin-Elmer 137 spectrophotometer and data are given in -1 wave numbers (cm ); samples were prepared as Nujol mulls or in chloroform solution. 'H Nuclear magnetic resonance spectra were recorded on either a Varian T-60 instrument or a Jeol MH-100 instrument. d-Chloroform was used as solvent, unless stated otherwise, and data are given in ppm (T) from tetramethylsilane (THIS) as internal standard. Ultraviolet measurements were taken on a Pye-Unicam SP 800 spectrophotometer and A maX values are given in nanometers and refer to solutions in ethanol. Mass spectra were recorded on an A.E.I. MS 9 or were obtained from the Physico-chemical Measurements Unit, Harwell.

3C FT N.m.r. spectra were recorded on a Jeol FX-60 instrument at 32°C, using TMS as internal standard, or CDC13 for the silylated substrates. Free-induction decays (FID) over a 4 kHz spectral width were collected in 4096 data points, with a computer resolution of 1.95 Hz per data point. For the noise-decoupled spectra (complete 156 carbon-hydrogen decoupling) a pulse width of 8 ps (equivalent to a 45 ° flip angle), a pulse interval of 1 s, and a pulse repetition time of 5 s were used, and the spectra were averaged over 1000-4000 scans, or 200-400 scans for concentrated sample solutions. Integrations were measured using a gated carbon-hydrogen decoupling mode, operating with an extended repetition time of 25 s, a reduced spectral width of 0.5 kHz and increased FID accumulations of greater than 10,000 scans.

Samples were prepared as 20-25% w/v solutions in d-chloroform, and also as 90% w/v solutions in d5-acetone or d5-pyridine, wherever specified. The silylamides were distilled directly into the 10 mm n.m.r. tubes by means of an adapted vacuum distillation apparatus.

Since silyl reagents and compounds require strictly anhydrous conditions, manipulative techniques were of a special nature ( cf. Ref. 35) involving, in addition to syringes and a dry box with a nitrogen atmosphere, speci- fically designed apparatus akin to the Schlenk apparatus. Further to general methods of purification, as outlined

by Perrin et al., 143 solvents were fractionated from chlorotrimethylsilane or hexamethyldisilazane, wherever appli-

cable.

Cerium(VI) analysis of molybdenum pentoxide complexes (5)

Mo0 5.L (150 200 mg) was dissolved in 1:1 isopropa- nol - water (50 ml) and the solution was acidified with 6N sulphuric acid (2 ml). The active oxygen content was determined by titration with approximately 0.1M ceric 157 sulphate in 1.5N sulphuric acid (standardised against arsenious oxide66 ), using ferroin as indicator.

(N,N-Dimethylformamido)oxodiperoxomolybdenum(VI) (5d) Molybdic acid (20 g, 0.15 mol) was dissolved in 30% hydrogen peroxide (100 ml) at 35°C. The yellow solution was cooled to 15°C and dimethylformamide (10.95 g, 0.15 mol) added. The aqueous solution was partially evaporated under reduced pressure, maintaining the temperature below 35°C. The resultant yellow crystals were collected by filtration and washed thoroughly with ether and a small volume of methanol (2x 25 ml) to remove all traces of hydrogen peroxide. The hydrated complex was dried in vacuo over phosphorus pentoxide to yield Mo05. D?1F as a yellow powder (29.8 g, 75%) ; m.p. 102° C (decomp) ; Vmax (Nujol) 1665, 1350, 975, 885, 875, 720 cm-1 ; T

7.1 (3H, s), 7.0 (3H, s), 2.1 (1H, bs); Amax (EtOH) 335 nm (log e 3.9) ; (Found: active C0] , 25.4. C3H7MoN06 requires active M, 25.70%).

Bis(N,N- dimethvlformamido)oxodiperoxomolybdenum(VI) (5e) Dimethylformamide (102 g, 1.4 mol) was added to a cooled solution of molybdic acid (90 g, 0.68 mol) in 30% hydrogen peroxide (360 ml). The solution was partially evaporated under reduced pressure and low temperature (< 35°C) until yellow crystals appeared. The crystals were collected, washed with ether (4x 150 ml) and a minimum volume of methanol, and dried to yield Mo05 . 2DMF (110 g,

65%); m.p. 100-102°C; Vmax (Nujol) 1660, 1640, 1350, 945, 875, 860, 680, 655 cm-' (lit.37 Vmax 1650, 945, 855, 680, 655 cm-1 ); T 7.1 (3H, s), 7.0 (3H, s), 2.1 (1H, bs); 158

Found: active [0] , 19.67. Calc. for C6Hu, MoN202 active [0] , 19.87%) .

N-Trimethylsilylcaprolactam (16) E-Caprolactam (2.26 g, 20 mmol) and dry triethylamine (2.12 g, 21 mmol) were dissolved in dry benzene (20 ml) and chlorotrimethylsilane (2.7 g, 25 mmol) was added over 15 min. to the vigorously stirred solution. Immediate precipitation of triethylamine hydrochloride occurred. The mixture was heated under reflux for 1 h, then filtered under dry nitrogen and the solvent evaporated. Vacuum distillation of the residual oil gave the silylamide (16) as a colourless oil.(2.63 g, 71%); b.p. 112-114°C / 5.5 mm (lit.,14 b.p. 111-111.5°C / 6 mm); vmax (film) 1640 cm-1 ; 9.85 (9H, s) , 8.2 (6H, m), 7.3 (211, m) , 6.8 (2H, m) .

Dioxobis-(N- oxycaprolactamato)molybdenum(VI) (20) N-Trimethylsilylcaprolactam (450 mg, 2.4 mmol) and Mo0 5.DMF (320 mg, 1.2 mmol) were dissolved in dry dichloromethane (15 ml) and stirred at room temperature for 45 h. Evaporation of the solvent gave a red-brown oil, which was chromatographed on silica (3% methanol:chloroform). Crystallisation from benzene-petroleum ether afforded the pale yellow molybdenum hydroxamate (20) (390 mg, 42%);

m.p. 192-193°C (decomp.); vmax (Nujol) 1570, 930, 900 cm-I ; T 8.2 (6H, m), 7.1 (2H, m), 6.7 (2H, m).

N-Hydroxy-E-caprolactam (24) The molybdenum hydroxamate complex (20) (100 mg, 0.26 mmol) was dissolved in warm 1M EDTA.Na4 solution

(15 ml) and left to stand for 4 h. The basic solution was 159 acidified with dilute hydrochloric acid to pH 7.5 and continuously extracted with dichloromethane for 24 h. After evaporation of the solvent., N-hydroxy-E-caprolactam was crystallised from ether-petroleum ether (59 mg, 88%); m.p. 78-79°C (lit.,145 80°C); Vmax (Nujol) 3200-2700, -1 1645 cm ; T 8.2 (6H, m), 7.0 (2H, m), 6.7 (2H, m), 3.4 (1H, bs) .

N-Trimethylsilyl-2-pyrrolidone (14) Chiorotrimethylsilane (5.77 g, 53 mmol) was added dropwise over 20 min. to a boiling solution of 2-pyrrolidone (4.25 g, 50 samol) and triethylamine (5.12 g, 51 mmol)• in dry benzene (35 ml) and reflux continued for 1 h. Triethylamine hydrochloride was removed by filtration under dry nitrogen, washed with dry benzene and the filtrate was evaporated under reduced pressure. The residual oil was distilled under vacuum to yield N-trimethylsilyl- 2-pyrrolidone (5.53 g, 70%); b.p. 51-52°C / 2 mm

77-81°C / 6 mm); Jmax (film) 1670 cm-1 ; T (neat) 9.7 (9H, s), 7.8 (4H, m), 6.6 (2H, m).

Attempted oxidation of N-trimethylsilyl-2-pyrrolidone The silylamide (232 mg, 1.48 mmol) was treated with Mo05.2DMF (184 mg, 0.74 mmol) in dry dichloromethane (5 ml) at 25°C and at 40°C. Analysis of the reaction mixture by t.l.c. indicated a trace of hydroxamic acid from the reaction at the lower temperature, however, isolation of the products in the usual manner gave only 2-pyrrolidone, the hydrolysis product. 160

N-t-Butylacetamide (8) Acetic anhydride (20.4 g, 0.2 mol) in dry ether (150 ml) was added over 30 min. to a cooled solution of t-butylamine (14.6 g, 0.2 mol) in ether (50 ml) and the mixture stirred at room temperature for 16 h. Evaporation of the solvent and excess reagents afforded the amide (8) as a white crystalline solid, which was recrystallised from aqueous ethanol (20.0 g, 88%); m.p. 100-101°C (lit.16

98°C); vmax (Nujol) 3420, 1675 cm ; 'f 8.70 (9H, s), 8.15 (3H, s).

N-t-Butyl-0-trim'thylsilylacetimidate (13) To a solution of N-t-butylacetamide (4.6 g, 40 mmol) in dry triethylamine (40 ml), chlorotrimethylsilane (6 g, 50 mmol) was added over 15 min. and the mixture heated under reflux for 2 h. After cooling, the amine hydrochloride was filtered off and triethylamine removed by distillation at atmospheric pressure. Vacuum distillation of the residue :ave the silylamide (13) (4.6 g, 62%); b.p

88-90°C / 150 mm;T 9.85 (9H, s), 8.85 (9H, s), 8.15 (3H, s).

N-Hydroxy-N-t-butylacetamide (22) A solution of the silylated amide (13) (110 mg, 0.63 mmol) in dry dichloromethane (1 ml) was stirred with Mo05.2DMF (110 mg, 0.34 mmol) for 24 h. at room temperature. The solvent was evaporated and the product taken up in 1M EDTA (25 ml) and the solution stirred for 3 h. The solution was acidified to pH 7.5 and continuously extracted with dichloromethane giving a yellow oil which was separated by preparative t.l.c. (Silica - 2% methanol: chloroform). N-t-Butyl-N-hydroxyacetamide was isolated as 161 a colourless oil (13 mg, 16%). The hydroxamic acid was further purified by micro-distillation under reduced pressure: b.p. 90°C / 0.35 mm (lit.,47 93°C / 0.5 mm); Vmax (film) 3160, 1620, 1270, 1200, 1170 cm 1 ; 'r (CC14) 8.60 (9H, s), 7.95 (3H, s), 3.0 (1H, bs);rn/e 131 (10%),

115 (10), 100 (7), 74 (45), 57 (100), 43 (49); (Found: M+ 131 .0946. Cale. for C 6H 13 NO2 : M+ 131.0946).

(Hexamethylphosphoramido)oxodiperoxomolybdenum(VI) (5b) In accordance with the method of Mimoun, 37 molybdenum trioxide (25 g, 0.17 mol) was stirred with 30% hydrogen peroxide (130 ml) (for 4 h) at 40.1 C and the mixture filtered. The yellow solution was cooled to 15°C and hexamethyiphosphoramide (HMPA) .(30 g, 0.168 mol) was added forming a pale yellow precipitate. The precipitate was filtered off, washed with ether (5x 50 ml) and recrystallised from ethanol at 35°C to yield the hydrated diperoxomolybdenuri complex (5a) (35.8 g, 62%).

M 05.HMPA.H20 was dried in vacuo over phosphorus pentoxide for 5 days, giving the molybdenum complex (5b) (34.0 g, 100% from the hydrated complex); m.p. 101-102°C

(decomp); vmax (Nujol) 1300, 1190, 1165, 1095, 995, 970, 875, 865, 765, 670 cm-1 ; T 7.17 (9H, s), 7.05 (9H, s); (Found: C, 20.46; H, 5.00; N, 11.84; active [0], 17.8. Calc. for C6H18 MoN306P: C, 20.28; H, 5.07; N, 11.83; active M, 18.02 %). (N.B. Mo05.HMPA is unstable and gradually loses its active oxygen over one month.) 162

(Hexamethylphosphoramido)oxodiperoxopyridinomolybdenum(VI) (5f)

By the method of Vedejs,38 Mo05.HMPA (5b) (4.07g, 11.5 mmol) was dissolved in dry THF (15 ml) and pyridine (0.905 g, 11.5 mmol) added slowly with vigorous stirring. The resulting precipitate was collected, washed with ether and dried (4.88 g, 80%); vmax (Nujol) 1600, 1310, 1190, 1100, 1000, 950, 880, 870, 770, 715 cm-'; T 7.38 (9H, s), 7.22 (9H, s), 2.2 (2H, m), 1.8 (1H, m), 1.0 (2H, m); (Found: active [o] , 14.45. C11 1123MoN406P requires active M, 14.74 %).

Dipyridinium p-oxo-bis- [oxodiperoxomolybdate (VI )' dihydrate (6)

By the method of Mimoun,3? molybdenum trioxide- (2.5 g, 18 mmol) was dissolved in 30% hydrogen peroxide (50 ml) at 40°C. Pyridine 1.4 g, 18 mmol) was added giving an initial red solution which afforded a yellow precipitate on acidification with 5N sulphuric acid. The precipitate was filtered off, washed with ether and alcohol, and crystallised from methanol, giving the hydrated complex

(4.18 g, 90%); (Found: active [o] , 22.29. C10 1112 Mo2N2013 requires active [0], 22.69 %). This complex was dried in vacuo over phosphorus pentoxide; vmax (Nujol) 3100, 3000- 2800, 1640, 1615, 1540, 1340, 1250, 1200, 950, 870, 850, -1 750 cm .

N,0-Bis-(trimethylsilyl)acetamide (50) By the method of Klebe,148 acetamide (19.7 g, 0.33 mol) was dissolved in dry triethylamine (180 ml) and chlorotrimethylsilane (90 g, 0.84 mol) added over 15 min. 163

The reaction mixture was .boiled gently for 15 h, cooled and filtered under nitrogen. The excess of triethylamine was removed by evaporation and bis-(trimethylsilyl)acetamide was collected by vacuum distillation (45 g, 67%); b.p. 56-8°C / 17 mm (lit.,1{a 71-73°C / 35 mm); z' (CC14) 9.95 (18H, s), 8.10 (3H, s). Continued vacuum distillation also gave mono-(trimethylsilyl)acetamide (48) as a white crystalline solid; b.p. 90-2°C / 17 mm (lit.,14S b.p.

105-7°C / 35 mm); T 9.75 (9H, s), 8.05 (3H, s), 2.95 (1H, s).

Trimethylsilylacetanilide (29) a) Chlorotrimethylsilane (16.0 g, 0.148 mol) was added dropwise to a solution of acetanilide (16.6 g, 0.123 mol) and triethylamine (18.4 g, 0.184 mol) in dry benzene (100 ml) and the mixture heated under reflux for a further 1 h. On cooling the triethylamine hydrochloride was filtered off under nitrogen, washed with dry benzene and the filtrate was distilled at atmospheric pressure to remove the solvent. The residual oil was distilled under vacuum to yield (N/19)-trimethylsilylacetanilide as a colourless oil (14.24 g, 56%); b.p. 105-106°C / 15 mm (lit.," b.p. 105°C / 13 mm); vmax (film) 1650, 1590, 1375, 1250, 840, 755, 700 cm-1 ;

T 9.75 (9H, s), 8.20 (3H, s), 3.2-2.6 (5H, m). b) Acetanilide (1.35 g, 10 mmol) was dissolved in dry tetrahydrofuran (10 ml) in a centrifuge tube and sodium hydride (50% dispersion in oil; 480 mg, 10 mmol) added under nitrogen. After 1 h, the amide anion was quenched with chlorotrimethylsilane (1.2 g, 11 mmol). The reaction mixture was centrifuged and the supernatant liquid removed 164

via a syringe. Vacuum distillation of the solution afforded trimethylsilylacetanilide (1.66 g, 850: The yield could be increased by further extraction of the sodium chloride residue with dry THF). c) To a solution of acetanilide (540 mg, 4 mmol) in dry pyridine (1 ml), bis-(trimethylsilyl)acetamide (1 g,

5 mmol) and a trace of chlorotrimethylsilane were added and the solution boiled under reflux for 10 min. The trimethylsilylamide (29) was collected by fractionation under reduced pressure (0.70 g, 850).

Dioxobis-(N-phenylacetohydroxamato)molybdenum(VI) (33) Trimethylsilylacetanilide (3.12 g, 15 mmol) was added to a solution of Mo0 5 .HMPA (2.66 g, 7.5 mmol) in dry dichloromethane (20 ml) and the solution stirred at room temperature for 4.5 h. The resulting dark red solution was evaporated under reduced pressure and the residue-was triturated with ether and crystallised from methanol to give the pale yellow molybdenum hydroxamate (33) (1.44 g,

450); m.p. 188 C (decomp.); ° Vmax (Nujol)-1570, 1010, 940, 900, 780, 695 cm ; T 7.75 (3H, s), 2.5 (5H, m); Amox(Et0H)

251 nm (log E 4.26); (Found: C, 44.92; H, 3.95; N, 6.49.

C t6 H~5MoN206 requires C, 44.87; H, 3.77; N, 6.54 0).

N-Hydroxyacetanilide (34)

a) From the molybdenum dihydroxamate (33)

The molybdenum complex (33) (150 mg, 0.3 mmol) was stirred with 1M EDTA.Na4 (30 ml) for 2 h. at 50°C. The aqueous solution was acidified to pH 7.5 and continuously extracted with dichloromethane, giving the hydroxamic acid

(34) as a white crystalline product (80 mg, 89%); m.p. 49 65-66°C (from benzene-petroleum ether) (lit.," 67-67.5°C); 165

Vmax (Nujol) 3200, 1635 cm ; 'r 7.81 (3H, s), 2.51 (5H, m), 0.6 (1H, bs). b) Without isolation of the intermediate Mo complex Trimethylsilylacetanilide (482 mg, 2.3 mmol) was stirred with Mo05.2DMF (375 mg, 1.15 mmol) in dry dichloromethane (10 ml) for 15 h. The solvent was evaporated and the residue was dissolved in 1M EDTA.Na4 solution (30 ml) and the basic solution (pH 9-10) was washed with dichloromethane (2x 10 ml) to remove unreacted amide. After acidification to pH 7.5 and continuous extraction of the aqueous phase with dichloromethane, the crude hydroxamic acid was purified by preparative t.l.c. (Silica-4% methanol:chloroform) (168 mg, 48%). The results from the use of alternative oxidants and solvents in the above oxidation are given in Table 3. c) In situ preparation of N-hydroxyacetanilide from acetanilide A solution of acetanilide (270 mg, 2 mmol) in hexamethyldisilazane (7 ml) was heated under reflux with a trace of chlorotrimethylsilane for 18 h. Evaporation of the excess of reagent left the silylamide (29) as a colourless oil (416 mg, 100%); Vmax (film) no NH absorption, 1650, 1590, 1375, 1250, 840, 755, 700 cm-1; T 9.80 (9H, s), 8.25 (3H, s), 3.1-2.6 (5H, m). Without further purificaton the product (29) was dissolved in dry dichloromethane (8 ml) and treated with Mo 05. DMF (273 mg, 1.1 mmol) for 6 h. After removal of the solvent the resulting red oil was dissolved in 1M EDTA.Na4 solution (25 ml), washed with dichloromethane (2x 10 ml) and the pH of the solution adjusted to 7.5. Continuous extraction 166 with dichloromethane, followed by preparative t.l.c. afforded the hydroxamic acid (34) (162 mg, 47%).

Attempted oxidation of trimethylsilylacetanilide (29) with trimethylsilyl m-chloroperbenzoate A solution of trimethylsilylacetanilide (29) (200 mg, 1 mmol) and trimethylsilyl m-chloroperbenzoate (prepared from sodium m-chloroperbenzoate and chlorotrimethylsilane) (215 mg, 1 mmol) in dry benzene was heated under reflux for 8 h. T.l.c. and ferric chloride analyses indicated no reaction other than hydrolysis of the silylated components.

N-(4'-Nitronhenyl)-0-trimethylsilylacetimidate (32) 4 -Nitroacetanilide (3.60 g, 20 mmol) was dissolved in dry tetrahydrofuran (25 ml) and sodium hydride (50% dispersion in oil; 1.0 g, 21 mmol) added under nitrogen. After complete formation of the anion, chlorotrimethylsilane (2.2 g, 22 mmol) was added and the mixture stirred for 1 h. at room temperature. Removal of the sodium chloride by filtration under nitrogen and evaporation of the filtrate afforded a low-melting yellow solid which was distilled under vacuum, giving the silylanilide (32) (4.0 g, 80%); m.p. 60°C; b.p. 135-140°C / 1.0 mm (lit.,48 b.p. 88-90°C / 0.2 mm); r 9.85 (9I-I, s), 7.85 (3H, s), 2.9 (4H, m).

N-(4'-Nitrophenyl)acetohydroxamic acid (37) A solution of Mo05.2DMF (708 mg, 2.2 mmol) and the trimethylsilylanilide (32) (360 mg, 2 mmol) was stirred for 15 h. at room temperature. The hydroxamic acid was isolated in the usual manner, yielding pale yellow crystals 167

(188 mg, 4870; m.p. 175-176°C; vmax (Nujol) 3200, 1640 cm-1 ; T (CD30D) 7.62 (3H, s), 2.10 (2H, d J 10 Hz), 1.90 (2H, d J 10 Hz); (Found: C, 48.81; H, 4.21; N, 13.95. C8H8N204 requires C, 48.95; H, 4.11; N, 14.33 %)

41 -Methoxy-N-trimethylsilylacetanilide (31) 4 -Methoxyacetanilide (4.6 g, 28 mmol) was suspended in hexamethyldisilazane (10 ml) and heated under reflux with a trace of chlorotrimethylsilane for 48 h. The reaction products were distilled under reduced pressure giving the excess of the disilazane reagent and the silylamide (31) as a colourless oil (5.50 g, 83%); b.p. 112-

115°C / 1.5 mm (lit.,148 75-6°C / 0.2 mm); 'r (neat) 9.80 (9H, s), 8.21 (3H, s), 6.19 (3H, s), 3.09 (4H, bs).

N-(4'-Methoxyphenyl)acetohydroxamic acid (36) The silylamide (31) (240 mg, 1 mmol) was stirred with Moo 5.2DMF (163 mg, 0.5 mmol) in dry dichloromethane (2 ml) at ambient temperature for 15 h. The solvent was removed under reduced pressure and the residue dissolved in warm 1M EDTA solution (25 ml). Continuous extraction of the neutralised aqueous solution (pH 7.5) with dichloromethane and purification by preparative t.l.c. (Silica- 5% methanol:chloroform) gave the hydroxamic acid (36) (74 mg,

41%); m.p. 98-101°C; VmQX (Nujol) 3220, 1645 cm-1 ; T 7.8 (3H, s), 6.2 (3H, s), 2.9 (4H, m), 2.0 (1H, bs); (Found: C, 59.54; H, 6.14; N, 7.53. C9H11 NO3 requires C, 59.66; H, 6.12; N, 7.73 %).

Trimethylsilyl-4'-chloroacetanilide (30) 4 -Chloroacetanilide (3.39 g, 20 mmol) was dissolved

in hexamethyldisilazane (15 ml) and heated under reflux 168 with a trace of concentrated sulphuric acid for 36 h. Distillation of the products yielded the requisite trimethylsilylanilide (30) (3.62 g, 75%); b.p. 98°C / 2 mm

(lit.,148 b.p. 61-2 C°/ 0.2 mm); Y 9.85 (9H, s), 8.05 (3H, s), 3.0 (4H, s).

N-(4'-Chiorophenvi)acetohydroxamic acid (35) The trimethylsilylanilide (30) (240 mg, 1 mmol) and

Mo05.2DMF (320 mg, 1 mmol) were dissolved in dry dichloromethane (10 ml) and stirred at room temperature for 15 h. Isolation by treatment with EDTA in the usual manner and purification by preparative t.l.c. (Silica - 5% methanol: chloroform) gave N-(4'-chlorophenyl)acetohydroxamic acid (78 mg, 42%); m.p. 111-112°C (lit.,148 113°C) ; Vmax (Nujol) 3200, 1640 cm-1 ; 1" 7.78 (3H, s), 2.78 (2H, d J 8 Hz), 2.51 (2H, d J 8Hz) .

Trimethylsilyl-N-propylbenzamide (39) N-Propylbenzamide (4.0 g, 25 mmol) and dry triethylamine (3.1 g, 32 mmol) were dissolved in dry toluene (40 ml). Chlorotrimethylsilane (4.0 g, 37 mmol) was added over 15 min. to the stirred solution and then the reaction mixture was gently boiled under reflux for 2 h. The silylamide (39) was isolated by filtering off the by-products under nitrogen and distillation under reduced pressure (3.0 g,.

50%); b.p. 90-92°C / 0.5 mm; -L' 9.80 (9H, s), 9.1 (3H, m), 8.4 (2H, m), 6.8 (2H, m), 2.75 (5H, m).

N-Propylbenzohydroxamic acid (40) • Trimethylsilyl-N-propylbenzamide (470 mg, 2 mmol) in dry dichloromethane (5 ml) was stirred with Mo05.2DMF

(325 mg, 1 mmol) for 15 h. The crude product after evapo- 169 ration of the solvent was treated with 1M EDTA solution (35 ml) at pH 9-10, the resulting basic solution washed with dichloromethane (2x 10 ml), and then the aqueous phase was acidified to pH 7.5 and continuously extracted with dichloromethane. Preparative t.l.c. (Silica - 1% methanol:chloroform) gave the hydroxamic acid (40) (80 mg, 34%); m.p. 69-70°C; vmax(CHC13) 3450, 1640, 1520, 1250 cm ; T 9.0 (3H, t), 8.3 (2H, m), 6.5 (2H, t), 3.0 (1H, bs), 2.6-2.0 (5H, m); (Found: C, 67.32; H, 7.56; N, 7.98. C;0H73NO2 requires C, 67.02; H, 7.31; N, 7.82 %).

N,2',4',6'-Tetrar. thyl-N-trimethylsi1ylbenzamide (46) N,2',4',6'-Tetramethylbenzamide (300 mg, 2.5 mmol) was suspended in hexamethyldisilazane (5 ml) with a trace of acid and the mixture was boiled under reflux for 16 h. Vacuum distillation of the products afforded the unreacted hexamethyldisilazane and the silylamide (46) (250 mg, 40%); b.p. 80-85°C / 1.0 mm; T 9.63 (9H, s), 7.85, 7.75 and 7.50 (12H, singlets), 3.20 (2H, s).

Attempted oxidation of N,2',4',6'-tetramethyl-N-trimethylsilylbenzamide (46) The silylamide (46) (100 mg, 0.4 mmol) and Moo 5 .2DMF (100 mg, 0.3 mmol) were stirred together in dry dichloromethane (2 ml) for 120 h. at room temperature. A small extent of oxidation was indicated by a weak colouration with ferric chloride, although isolation of the hydroxamic acid was not able to be achieved.

Attempted oxidation of N,0-bis-(trimethylsilyl)acetamide (50) On addition of a bis-(trimethylsilyl)acetamide

(400 mg, 2 mmol) to a solution of Mo05.DMF (250 mg, 1 mmol) 170 in dry dichloromethane (4 ml), a rapid exothermic reaction occurred giving a deep red solution. Although the presence of a hydroxamate function was indicated by ferric chloride, only isolation of acetamide, but not the hydroxamic acid, was achieved after work-up.

Trimethylsilylbenzamide (49) Benzamide (2.41 g, 20 mmol) was suspended in hexamethyldisilazane (10 ml) and heated under reflux with a trace of concentrated sulphuric acid for 48 h. and then the excess of the disilazane was evaporated in vacuo. Sublimation of the residue gave benzamide (30%) at 100-2°C / 0.005 mm and the mono-(trimethylsilyl)amide (49) (2.50 g,

65%) at 63-5°C / 0.005 mm (lit.,78 142-3°C / 0.54 mm); m.p. 100-1°C (lit.78 118-20°C); Vmnx (CHC13) 3350, 1660 -1 cm ; T 9.6 (9H, s), 4.0 (1H, bs), 2.6-2.0 (5H, m).

Attempted oxidation of trimethylsilylbenzamide Trimethylsilylbenzamide (960 mg, 5 :pmol) was added to a solution of Moo S.HMPA_ (1.07 g, 3 mmol) in dry dichloromethane (10 ml) and stirred at room temperature for 24 h. Chromatographic separation of the reaction mixture on silica (5% rnethanol;.dichlormethane) yielded the parent benzamide and bis-(benzohydroxamato)dioxomolybdenum (VI) (51) (estimated yield of 3%), which was compatible with an authentic sample prepared from benzohydroxamic acid and molybdic acid in concentrated hydrochloric acid; m.p. 189-90°C (decomp.); VmQx (Nujol) 3400, 3200, 1530, 940, 930, 885, 690 cm ; -r ( d6 -DMSO) 2.3 (3H, m) , 1.8 (2H, m) . 171

2-(2',2'-Dichloroacetamido)phenol (61) The amide (61) was prepared according to the method of Virtanen 49 by the dropwise addition of freshly distilled dichloroacetyl chloride 150 (5.0 g, 34 mmol) to a suspension of 2-aminophenol (7.4 g, 68 mmol) in dry ether (100 ml). The reaction mixture was stirred for 1 h. at room temperature and the amine hydrochloride by-product was removed by filtration. Evaporation of the solvent and recrystallisation of the residue from benzene gave 2-dichloroacetamidophenol (61) (7.1 g, 95%); m.p. 135.5-6°C

(lit.,49 134-5°C); vmax (KBr) 3430, 3230, 1670, 1540, -± 1455, 1340, 1285, 1190, 1100, 860, 800, 750, 730, 650 cm ; T ( dō-DMSO) 2.95 (4H, bs), 1.95 (1H, d J 7 Hz), 0.05 (1H, bs, exchanges in D20), -0.30 (1H, bs, exchanges in D20) .

2-Hydroxy-4-(H)-1,4-benzoxazine-3-one (62) By the method- of Virtanen, 49 2- (dichloroacetamido)- phenol (2.2 g, 10 mmol) was added to a boiling solution of sodium bicarbonate (1.68 g, 10 mmol) in water (80 ml) and boiling continued for 30 min. The reaction mixture was cooled, acidified with dilute hydrochloric acid and then extracted with ether (6x 50 ml). The combined extracts were washed with dilute hydrochloric acid (2x 10 ml), dried and evaporated to give the benzoxazinone (62) (1.50 g, 49 91%); m.p. 202-3°C (lit., 201-3°C); vmax (Nujol) 3400, -1 3180, 1685, 1075, 1030, 1010, 830, 750 cm ; T (d5 -DMSO) 4.31 (1H, s), 2.9 (4H, m), 0.7 (1H, bs); Amax 250 nm

(log F 3.84), 280 (3.59), 287 (3.56); m/e 165 (25%), 136 (100), 109 (13), 108 (19), 80 (30), 65 (9), 52 (11);

(Found: M 165.0420. Cale. for C9H7NO3 : A4+ 165.0426). 172

2,4-Dihydroxy-4(H)-benzoxazin-3-one (65) The lactam (62) (4.95 g, 30 mmol) was heated in BSA (20 g, 100 mmol) under reflux for 1 h. Removal of the excess of BSA in vacuo left 4-trimethylsilyl-2-trimethylsilyloxy-4(H)-benzoxazin-3-one (63) as a brown oil (9.3 g, 100%); Y 9.88 (9H, s), 9.66 (9H, s), 4.58 (1H, s), 3.15 (3H, m), 3.0 (1H, m). The silylated benzoxaxinone (63) was dissolved in dry dichloromethane (20 ml) and stirred with Mo05.2DMF (14.5 g, 45 mmol) for 8 h. at room temperature. The solvent was removed and the residue dissolved in 1M EDTA.Na4 (100 ml). The basic solution was extracted with ether to recover the original benzoxazinone (62). After acidification to pH 7.0, the aqueous phase was continuously extracted with ether for 2 days and the crude product purified on a polyamide column (SC 6 - 50% acetone:toluene) yielding the requisite hydroxamic acid (65) as white needles (1.75 g, 33%); m.p. 153-4°C (lit.,49 153°C); sublimes

50-55°C / 0.005 mm; vmax (Nujol) 3400, 3360, 1650, 1040, 980, 830, 750 cm-1 ; T (d6 -DMSO) 4.27 (1H, s), 3.2-1.5 (1H, bs, exchanges in D20), 3.00 (3H, m), 2.70 (1H, m); A max (EtOH) 254 nm (log E 3.6), 283 (3.5), 288 (3.5); We 181 (10%), 165 (10), 163 (7), 136 (41), 135 (100), 91 (26), 79 (57), 64 (21), 52 (38), 18 (30); (Found: C, 52.89; H, 4.06; N, 7.68 %; M + 181.0375. Caic. for C8H7N04 : C, 53.05; H, 3.88; N, 7.74 %; M+ 181.0375).

2-Amino-4-methylphenol 4-Methyl-2-nitrophenol (7.7 g, 50 mmol) in 95% ethanol (60 ml) was hydrogenated over 5% palladium on 173 carbon at room temperature and atmospheric pressure till 3 moles of hydrogen were consumed (4 h). The catalyst was filtered off and the solution evaporated to give the ,151 1 aminophenol (6.1 g, 98%); m.p. 135-7°C (lit. 35°C); umax (Nujol) 3460, 3390, 3200-2500, 1280, 1220, 880, 800, -1 715 cm ;1' 7.93 (3H, s), 6.0 (2H, bs, exchanges in D20), 3.5 (3H, m), 2.0 (1H, bs, exchanges in D20).

2-(2',2'-Dichloroacetamido)-4-methylphenol (66) 2-Amino-4-methylphenol (3.86 g, 31 mmol) was suspended in dry ether (50 ml) and dichloroacetyl chloride (2.2R g, 15.5 mmol) in dry ether was added dropwise over 20 min. The mixture was stirred for 1 h. further and the precipitated amine hydrochloride filtered off. Evaporation of the solvent gave the amidophenol (66) (3.54 g, 97%); m.p. 136-7°C; umax (Nujol) 3340, 3180, 1660, 1595, 1540, 1200, 1115, 805, 625 cm-1 ; T (d5-DMSO) 7.75 (3H, s), 3.45 (1H, s), 3.20 (2H, s), 2.20 (1H, s), 0.65 (2H, bs, exchanges in D20); m/e 237 (2%), 235 (9.5), 233 (M, 15), 150 (100), 122 (37), 94 (22), 77 (•14), 32 (54); (Found: M+ 233.0013. C9 H 9 N0235C12 requires M + 233.0010) .

2-Hydroxy-6-methy1-4(H)-benzoxaxin-3-one (67) 2-(Dichloroacetamido)-4-methylphenol (2.34 g, 10 mmol) was added to a boiling solution of 0.4M sodium bicarbonate (50 ml, 20 mmol) and reflux continued for 45 min. On cooling the benzoxazinone crystallised and was collected by filtration. Further product was obtained by acidification of the aqueous filtrate and extraction with ether. Recrystallisation from acetone-petroleum ether afforded the requisite benzoxazinone (67) (1.70 g, 95%); m.p. 207-

211°C; sublimes 100°C / 4 x 10-5 mm; umax (Nujol) 3220, 1680, 174

1610, 1210, 1070, 1020, 865, 805 cm-1 ; T (d5-acetone)

7.75 (3H, s), 4.40 (1H, s), 3.10 (3H, m); m/e 179 (60%),

150 (100), 122 (60), 94 (35), 77 (32), 39 (32); (Found:

C, 60.30; H, 5.36; N, 7.02%;/14+ 179.0588. C9 H9NO3 requires C, 60.33; H, 5.06; N, 7.82 %; 114 4- 179.0583 ).

2,4-Dihydroxy-6-methyl-4(H)-benzoxazin-3-one (70) The benzoxazinone (67) (1.0 g, 5.6 mmol) was dissolved in hexamethyldisilazane (5 ml) and heated under reflux with a trace of chlorotrimethylsilane for 12 h. The solvent was removed under vacuum and a solution of the residual bis-(trimethylsilyl)benzoxazinone (68) in dry dichloromethane (6 ml) was stirred with Mo05.2DMF (1.80 g, 5.6 mmol) for 4 h. at ambient temperature. The dichloromethane was evaporated and the resulting red oil was treated with lM EDTA solution (30 ml). The basic solution was washed with ether (2x 25 ml) giving the benzoxazinone (67) (38%). The aqueous solution was acidified to pH 7.0, continuously extracted with ether for 24 h. and the crude product was purified by column chromatography (polyamide SC 6 - 50% acetone:toluene), yielding the dihydroxybenzōxa- zinone (70) (340 mg, 31%); m.p. 160-1°C; Vmax (Nujol) 3300, 3200-2500, 1655, 1610, 1215, 1050, 870, 795 cm-1 ; T 7.70 (3H, s),.4.27 (1H, s), 3.7 (2H, bs, exchanges in D20), 3.20 (2H, s), 2.84 (1H, s); m/e 195 (10%), 179 (11), 173 (22), 149 (100), 104 (16), 93 (28), 78 (23), 47 (34), 44 (52); (Found: C, 55.44; H, 4.69; N, 6.86 %; M 195.0530. C9H9N04 requires C, 55.39; H, 4.65; N, 7.18 %; M + 195.0532 ) 175

Attempted oxidation of penicillin G S-oxide Penicillin G S-oxide (50 mg, 0.14 mmol) was dissolved in BSA (2 ml) and stored at room temperature for 14 days. Evaporation of the excess of reagent and the by products gave tris-(trimethylsilyl)penicillin GS-oxide (58) (80 mg). The trisilyl penicillin (58) was dissolved in dry dichloromethane (1 ml) and stirred with MoO 5.2DMF (45 mg, 0.14 mmol) for 7 days. By further reaction with EDTA and separation in the usual manner, the parent penicillin G S-oxide (56) (20%) and its isomer, containing a configu- ration about positions 5,6, was isolated (20 mg, 40%); m.p. 120-4°C (decamp.) (lit., 47 123-5°C) ; Vmax (Nujol) 3400, 3220, 1775, 1735, 1675 cm-1 ; T (d5-DMSO) 8.75 (3H, s), 8.40 (3H, s), 6.45 (2H, s), 5.73 (1H, s), 4.90 (1H, dd J 2,8 Hz), 4.65 (1H, d J 2 Hz), 2.68 (5H, s), 1.92 (1H, bs).

Ethyl 3-rie thyl-3- (trimethylsilvlacPtamido) acrylate (55) Ethyl 3-acetamido-3-methylacrylate (5.13 g, 30 mmol) was dissolved in dry triethylamine (12 ml) and chlorotrimethylsilane (5.0 g, 36 mmol) added over 10 min. to the vigorously stirred solution. The mixture was boiled under reflux for 3 h, cooled and filtered under nitrogen. Distillation of the filtrate yielded the silylamide (55) as a colourless oil (1.13 g, 16%); b.p. 80-2°C ; T 9.62 (9H, s), 8.7 (3H, m), 8.1 (3H, s), 7.72 (3H, s), 5.90 (2H, m), 5.0 (1H, s). 176

Attempted oxidation of ethyl 3-methyl-3-(trimethylsilyl- acetamido)acrylate (55) The oxidation of the silylamide (55) (510 mg, 2.1 mmol) with Mo05.2mtF (320 mg, 1 mmol) in dichloromethane and isolation of the products in the usual manner gave no indication of hydroxamic acid formation, affording ethyl 3-acetamido-3-methylacrylate (54) from hydrolysis.

2-Trimethylsi1yloxy2yridine (73) Chlorotrimethylsilane (15 g, 0.14 mol) was added over 20 min. to a solution of 2-pyridone (9.5 g, 0.1 mol) and triethylamine (13 g, 0.13 mol) in dry acetonitrile (120 ml). The reaction mixture was boiled under reflux for 2 h, cooled and filtered under nitrogen. Evaporation of the solvent left a red oil which was distilled under vacuum yielding the silyloxypyridine (73) as a colourless oil (7 g, 4250; b.p. 77-80°C / 20 mm (lit.,79 63°C / 12 mm); -r 9.67 (9H, s), 3.20 (2H, m), 2.60 (lii, m), 2.00 (1H, m).

2-Hydroxypyridine-l-oxide (74) 2-Trimethylsilyloxypyridine (167 mg, 1 mmol) was added to a solution of Mo05.2DMF (360 mg, 1.14 mmol) in dry dichloromethane (2 ml) and the solution stirred for 2 h. at room temperature. Removal of the solvent produced an orange oil which was dissolved in 1M EDTA.Na4 solution (25 ml). The basic solution (pH 9) was washed with dichloromethane (2x 10 ml), acidified to pH 7.5 and then continuously extracted with dichloromethane. Purification of the extract by preparative t.l.c. afforded the hydroxamic acid 151 (74) (100 mg, 91%); m.p. 148-9°C (lit. , m.p. 149 °C); —1 1max (Nujol) 3320, 1265 cm ; T 3.2 (2H, m), 2. 6 (2H, m ). 177

The product had compatible properties with an authentic sample prepared by the method of Wagner.151

1,3-Diphenyl-l-trimethylsilylurea (79) a) Phenylisocyanate (4.76 g, 40 mmol) and hexamethyldisilazane (3.22 g, 20 mmol) were heated in dry ether (20 ml) under reflux for 24 h. Evaporation of the solvent afforded a viscous oil which crystallised on standing. The mono-(trimethylsilyl)urea (79) was recrystallised from dry, Analar petroleum ether; m.p. 77-9°C (sealed tube)

(lit., 52 m.p. 77-9°C); Vmcx (CC14) 330, 1650 cm-1 ; 'r 9.77 (9H, s), 2.90 (1H, bs), 2.9-2.3 (10H, m). On heating a sample of (79) in a sealed tube at 150°C, a new crystalline material was formed; m.p. 168- 70°C, corresponding to diphenylcarbodiimide, m.p. 168°C.146 b) A suspension of 1,3-diphenylurea (125 mg, 0.59 mmol) in hexamethyldisilazane (5 ml) was heated under reflux with chlorotrimethylsilane (0.5 ml) for 5 h. After removal of the excess of the reagents by evaporation, the. spectroscopic properties of the residual oil indicated a 50% mixture of the mono-(trimethyisilyl)urea (79) and diphenylcarbodiimide.

Attempted oxidation of 1,3-diphenyl-1-trimethylsilylurea (79) The silyl urea (79) (180 mg, 0.63 mol) was stirred with a suspension of Moo 5.DMF (84 mg, 0.34 mmol) in dry dichloromethane (5 ml) for 16 h. at room temperature. Analysis of the reaction mixture by ferric chloride indicated no formation of the corresponding hydroxamic acid. 178

1,1-Diethyl-3-phenylurea (81) A solution of phenylisocyanate (7.70 g, 64.5 mmol) in dry ether (15 ml) was added dropwise over 30 min. to a cooled solution of diethylamine (4.70 g, 64.5 mmol) in dry ether (30 ml) The solvent was evaporated and the residual white solid crystallised from ethyl acetate giving 1, 1-diethyl-3-phenylurea (12.0 g, 9470) ; m.p. 85-6° C (lit 1;z

84-5°C); Vmax (Nujol) 3300, 1640 cm-1 ; 8.76 (6H, t), 6.60 (4H, q), 3.61 (1H, bs), 2.6 (5H, m).

Attempted oxidation of l,1-diethyl-3-phenyl-3-trimethylsilylurea (82) A solution of diethylphenylurea (81) (1.92. g, 10 mmol) in dry THF (15 ml) was added to a suspension of sodium hydride (60% dispersion in oil; 740 mg, 18 mmol) in dry THF (5 ml). The reaction mixture was stirred for 30 min. at room temperature and then chlorotrimethylsilane (2.3 ml, 1.9 g, 18 mmol) was added and the solution heated under reflux for 30 min. The resulting gelatinous white. precipitate was centrifuged and the clear supernatant solution evaporated to give the silylurea (82) as a colourless oi153(2 .27 g, 86%); T 9.80 (9H, s) , 8.7 (6H, t), 6.5 (4H, q), 2.6 (5I, m). Without further purification the silylurea (86 mg, 0.33 mmol) was stirred with a suspension of Mo0 5.DMF (57 mg, 0.16 mmol) in dry dichloromethane (2 ml) at ambient temperature for 72 h. No hydroxamic acid formation was apparent by t.l.c. analysis (with detection by ferric chloride), and the parent urea (81) was isolated as the sole product. 179

Methyl N-phenyl-N-trimethylsilylcarbamate (84) To a solution of methyl N-phenylcarbamate (15.1 g, 0.1 mol) and triethylamine (12.5 g, 0.125 mol) in dry toluene (50 ml), chlorotrimethylsilane (15.0 g, 0.14 mol) was added slowly with vigorous stirring and the mixture was boiled for 45 min. under reflux. The dense white precipitate of triethylamine hydrochloride was filtered off under nitrogen and the red filtrate distilled under reduced pressure to yield the silylurethane (84) (5.7 g, 36%); b.p. 85-90°C / 2.5 mm; T 9.70 (9H, s), 6.22 (3H, s) , 2.8 (5H, m)

Attempted oxidation of methyl N-phenyl-N-trimethylsilylcarbamate (84) The silylurethane (84) (446 mg, 2 mmol) was added to a suspension of Mo05.DMF (250 mg, 1 mmol) in dry dichloromethane (2 ml) and stirred at room temperature for 18 h. No hydroxamic acid function was detected by ferric chloride, the p~'o?uct from hydrolysis, methyl N-phenyl carbamate (83), being the major product.

N-Trimethylsilvlsuccinimide (88) Chlorotrimethylsilane (13 ml, 10.9 g, 0.102 mol) was added dropwise over 10 min. to a boiling, stirred solution of succinimide (9.9 g, 0.1 mol) in dry triethylamine (25 ml). The reaction mixture was allowed to stand for 1 h, then filtered rapidly and washed with cold triethylamine. The volatile materials in the filtrate were removed by distillation and the residue was vacuum distilled to give N-trimethylsilylsuccinimide (6.0 g,'38%); b.p. 68°C / 1.5 mm; T 9.58 (9H, s ), 7.30 (4H, s). 180

Attempted oxidation of N-trimethylsilylsuccinimide (88) N-Trimethylsuccinimide (682 mg, 4 mmol) and Mo05. DMF (498 mg, 2 mmol) were stirred together in dry dichloromethane (10 ml) for 15 h. at ambient temperature. T.l.c. and ferric chloride analyses of the reaction mixture indicated no hydroxamic acid formation. After quenching with water succinimide, the hydrolysis product, could be recovered as the sole product.

N-Hydroxysuccinimide By the method of Wunsch and Jaeger, 153 succinic anhydride (1.5 g, 15 mmol) was added to a stirred solution of hydroxylamine hydrochloride (1.04 g, 15 mmol) in water (1.5 ml), dioxan (1 ml), and 5N sodium hydroxide (3 ml). The reaction mixture was heated at 60°C for 2 h. and the solvents evaporated under vacuum. The residue was extracted and crystallised from ethyl acetate giving N-hydroxysuccinimide (870 mg, 50,o); m.p. 100°C (lit.,153

98-99°C); Vmax (Nujol) 3400-2000,'1705, 1660, 1290, 1215, 1100 cm .

Attempted preparation of (N-oxysuccinimido)oxodiperoxomolybdenum(VI) A solution of N-hydroxysuccinimide (50 mg, 0.43 mmol) in hot water (1 ml) was added dropwise to a solution of molybdenum trioxide (31 mg, 0.22 mmol) in hot concentrated hydrochloric acid (0.5 ml). A white crystalline precipitate was formed, the spectroscopic and physical properties of which were identical to succinic acid; m.p. 182-4°C (lit., 146 184°C); V max (Nujol) 3500-2000, 1700, 1200, -1 920 cm . 181

Thioacetanilide (89) A solution of phenylisothiocyanate (13.5 g, 0.1 mol) in dry ether was added over 15 min. to freshly prepared methylmagnesium iodide (0.1 mol). The reaction mixture was quenched with water (300 ml) and extracted with ether (4x 50 ml), giving thioacetanilide which was recrystallised from hot .water (13.82 g, 92%); m.p. 75-7°C (lit., 146 75-6° C); T 7.50 (1.5H, s), 7.30 (1.5H, s), 2.6 (3H, m), 2.4 (2H, m), 1.2 (1H, bs).

Trimethylsilylthioacetanilide (90) Thioacetanilide (640 mg, 4.2 mmol) was dissolved in dry ether (12 ml) and n-butyl-lithium (1.7M, 2.5 ml, 4.2 mmol) was added under nitrogen giving a red solution. On addition of chlorotrimethylsilane (550 mg, 5 mmol), a pale yellow suspension formed. After 30 min. at room temperature, the reaction mixture was centrifuged and the supernatant solution distilled under vacuum to yield the silylthioamide (90) (450 mg, 4770; 8O-5°C / 4 mm T 9.70 (9H, s), 7.75 (3H, s), 3.6-2.4 (5H, m), (1it36 T 9.70 (9H, s), 7.70 (3H, s), 3.03-2.5 (5H, m)).

Oxidation of trimethylsilylthioacetanilide (90) The silyl thioanilide (90) (250 mg, 1.12 mmol) was stirred with Moo 5 .2DMF (365 mg, 1.13 mmol) in dry dichloromethane (1 ml) for 30 min. T.l.c. indicated complete conversion into a polar product. Evaporation of the solvent and crystallisation of the residue from methanol gave acetanilide (129 mg, 85%); m.p. 115-6°C (lit.,146 115-6°C); (Found: M} 135 .0679. Ca.ic. for C8H9 NO M+ 135 .0684 ) 182

N-Trimethylsilylbenzenesulphonamide (92) Benzenesulphonamide (1.57 g, 10 mmol) was heated in hexamethyldisilazane (5 ml) under reflux with a trace of acid for 48 h. Vacuum distillation of the reaction mixture afforded mono-(trimethylsilyl)benzenesulphonamide (90) as a white solid (1.57 g, 69%); m.p. 60-5°C (lit., 154 63-5°C); b.p. 120°C / 0.1 mm (lit.,154 128-30°C / 0.013 mm); T 9.8 (9H, s) , 3.90 (1H, bs), 2.7-2.0 (5H, m) .

Attempted oxidation of N-trimethylsilylbenzenesulphonamide (90) The silylated sulphonamide (90) (37 mg, 1.6 mmol) and Mo05.DMF (200 mg, 0.8 mmol) were dissolved in dry dichloromethane (5 ml) and stirred for 48 h. at room temperature. Only the product of hydrolysis, benzenesulphonamide was formed.

Oxidation of trimethylstannylacetanilide (98) A solution of acetanilide (270 mg, 2 mmol) in dry THF (10 ml) was added to a suspension of sodium hydride (50% dispersion; 100 mg, 2 mmol) in dry THF. Chlorotri methylstannane (440 mg, 2.2 mmol) was added to the resulting clear solution and the reaction mixture left to stand for 2 h. at room temperature. Evaporation of the supernatant solution after removal of the sodium chloride by centrifuge, afforded trimethylstannylacetanilide as a strong smelling oil; r 9.42 (9H, s), 8.25 (3H, s), 3.2- 2.6 (5H, m). Without further purification, the stannyl anilide (2 mmol) was reacted with Mo05.2DMF (650 mg, 2 mmol) in dry dichloromethane (2 ml) for 20 h. at room temperature. After evaporation of the solvent, the residue 183 was dissolved in warm 20% aqueous EDTA.Na4 solution (50 ml) and the solution acidified to pH 7. Continuous extraction with dichloromethane and separation of the products by preparative t.l.c. gave acetanilide (73%) and N-hydroxyacetanilide (25 mg, S%). The physical and spectroscopic properties of the products were in accord with those of authentic materials.

Oxidation of triphenylsilylacetanilide (97) By the method for trimethylstannylacetanilide, sodium acetanilide (2 mmol) was reacted with chlorotri- phenylsilane (590 mg, 2 mmol) to give triphenylsilylacetanilide (97) as a white crystalline solid (75%); T 7.75 (3H, s), 3.0 (20H, m). Subsequent oxidation of the silylamide (97) with Mo05 .2DMF (650 mg, 2 mmol) yielded N-hydroxyacetanilide (23 mg, 8%) after isolation in the usual manner.

Attempted oxidation of N-iodomagnesiumacetanilide (95) Phenylisocyanate (3.85 g, 33 mmol) in dry ether (20 ml) was added dropwise under nitrogen to a freshly prepared solution of methylmagnesium iodide (33 mmol) in dry ether (40 ml) at 0°C. Evaporation of the solvent gave N-iodomagnesiumacetanilide (95) as a white solid. A solution of (95) (1.90 g, 8 mmol) in dry dichloromethane (20 ml) was treated in situ with Mo05.DMF (1.0 g, 4 mmol) . No hydroxamic acid formation was indicated by ferric chloride tests, and the separation of the products by preparative t.l.c. gave acetanilide as the sole product.

Ethyl N-(4-chlorophenyl)acetimidate (103)

4-Chloroacetanilide (1.02 g, 6 mmol) was added to a 184 solution of freshly prepared triethyloxonium tetrafluoroborate (60 mmol) in dry dichloromethane (20 ml) and stirred at room temperature for 4 h. The reaction mixture was poured slowly into 20% sodium hydroxide solution at 0°C. The basic aqueous phase was separated, extracted with dichloromethane (2x 10 ml) and the combined organic fractions dried over sodium sulphate. Evaporation of the solvent and distillation of the residual oil under vacuum afforded the imino-ether (103), as a colourless oil (800 mg, 680); b.p. 90-5°C / 1.5 mm (lit.,155 123-4°C / 11.8 mm);

t 8.72 (3H, t), 8.25 (3H, s), 5.85 (2H, q), 3.40 (2H, d J 9 Hz), 2.83 (2H, d J 9 Hz).

Ethyl N-(4-methoxyphenyl)acetimidate (104) Prepared from 4-methoxyacetanilide (6 mmol) and triethyloxonium tetrafluoroborate (60 mmol) in the usual manner (62%); b.p. 90°C / 1.0 mm; T 8.74 (3H, t J 8 Hz), 8.22 (3H, s), 6.30 (3H, s), 5.83 (2H, q J 8 Hz), 3.30 (414; dd ,' 9,16 Hz).

Ethyl N-(4-nitrophenyl)acetimidate (105) By the method for ethyl (4-chlorophenyl)acetimidate (103), 4-nitroacetanilide (8 mmol) was O-alkylated with Meerwein's salt (56 mmol) to give the imine-ether (105)

(52%); b.p. 90-105°C / 0.8 mm; T 8.70 (3H, t), 8.16 (3H, s), 5.80 (2H, q), 3.18 (2H, d J 10 Hz), 1.87 (2H, d J 10 Hz).

2-Ethoxy-l-pyrroline (106) By the method of Aue and Thomas, 23 the imino-ether (106) was prepared by alkylation of 2-pyrrolidone (63%); b.p. 55-65°C / 35 mm (lit.,23 137-142°C); T 8.70 (3H, t), 185

8.00 (2H, m), 7.70 (2H, m), 6.35 (2H, m), 5.80 (2H, q); m/e 113 (30%), 98 (10), 85 (65), 84 (65), 69 (31), 58

(42), 57 (37), 42 (58), 41 (100).

1-Aza-2-ethoxycyclohept-1-ene (107) E-Caprolactam (1.7 g, 15 mmol) and freshly prepared triethyloxoniu.*n tetrafluoroborate (46 mmol) in dry dichloromethane (20 ml) was left to stand for 16 h. at room temperature. The reaction mixture was poured into saturated sodium bicarbonate and then extracted with dichloromethane (3x 25 ml). Vacuum distillation afforded the imino- ether (107) (1.20 g, 57%); b.p. 67-70°C / 10 mm (lit.;55 81-2°C / 26 mm); 8.80 (3H, t), 8.4 (6H, m), 7.6 (2H, m), 6.4 (2H, m), 6.1 (2H, q).

Trimethylsilylbenzimidazole (117) Benzimidazole (2.36 g, 2 mmol) in hexamethyldisilazane (4 ml) was heated under reflux with a trace of acid for 18 h. Trimethylsilylbenzimidazole was isolated as a white solid by vacuum distillation of the reaction mixture, (3.52 g, 92%); b.p. 105-110°C / 0.35 mm (lit.,t03 112°C / 0.3 mm); T (CC14 ), 9.95 (9H, s), 3.05 (2H, m), 2.85 (1H, m), 2.50 (2H, m).

Benzimidazole- 1-oxide (118) Trimethylsilylbenzimidazole (500 mg, 2.65 mmol) in dry dichloromethane (4 ml) was stirred with Mo05.2DMF (460 mg, 1.42 mmol) for 15 h. at room temperature. Separa- tion of the crude reaction products by preparative t.l.c. (Silica - 2% methanol:chloroform) afforded benzimidazole

(85%) and benzimidazole-1-oxide (35 mg, 10%); m.p. 211-4°C

(lit., 105 213-5°C); V m.x (Nujol) 3500-2000, 1300, 1220, 186

1100, 800 cm-1 ; 7 ( d5-DMSO) 2.70 (2H, m), 2.35 (2H, m), 2.10 (1H, bs, exchanges in Dz0); m/e 134 (8%); 118 (100), + 91 (27), 73 (19), 64 (15), 63 (14), 32 (19); (Found h11-

134.0474. C7 H5 N2 0 requires M+ 134 .0480 ) .

Adenine-1-oxide (125) Adenine (108 mg, 0.9 mmol) was heated in hexamethyldisilazane (1 ml) under reflux with a trace of acid for 16 h. Evaporation of the excess of reagent left bis-(trimethylsilyl)adenine (120) as a colourless oi1. 157 A solution of Mo05.2DMF (480 mg, 0.9 mmol) in dry dichloromethane (1 ml) was stirred with the £ilylatcd adenine (120) at room temperature for 48 h. The reaction mixture was chromatographed on silica (15% methanol:chloroform) to yield adenine and a more polar component corresponding to adenine-1-oxide (7 mg, 5%); m.p. ca. 300°C (slow decomp.)

(lit.,158 297-307°C); Amax (EtOH) 235 nm (log E _4.15)

(lit.158 A max 231, 262 nm at pH 7); (Found: M + 151.0491. C5H5 N50 requires MT 151.0494 ).

4-Quinolone-1-oxide (123) •4-Quinolone (78 mg, 0.5 mmol) was suspended in hexamethyldisilazane (2 ml) and heated under reflux with a trace of acid of 5 h. giving a colourless solution. The excess of the disilazane was removed in vacuo and the residual white solid dissolved in dry dichloromethane (1 ml). Mo05.2DMF (200 mg, 0.6 mmol) was added and the solution stirred for 16 h. The N-oxide (123) was isolated by preparative t.l.c. (Silica - 8% methanol:chloroform) (45 mg,

55%); m.p. 235-7°C (lit.,159 238°C); VmCZ (Nujol) 3400, 1620 cm-1 ; m/e 161 (30%), 160 (8), 145 (100), 117 (57), 187

116 (31), 90 (33), 89 (30), 44 (22), 18 (88), 17 (19);

(Found: M+ 161.0479. C9H7NO2 requires M + 161.0477).

Hydrolysis of N,N-dimethylhexanamide N,N-Dimethylhexanamide (148 mg, 1.04 mmol), molybdenum trioxide (144 mg, 1 mmol) and t-bu.tylhydroperoxide (450 mg, 5 mmol) in acetonitrile (5 ml) were heated under reflux for 15 h. Separation of the products by preparative t.l.c. (Silica - 1.5% methanol:dichloromethane) afforded unreacted amide (15%) and hexanoic acid(84 mg, 70%), iden-

tical to an authentic sample; V max (film) 3500-2400, 1710, 1420, 1300, 1250, 1100, 940 cm-1 ; T 9.20 CAH, t); 8.9-8.0 (6H, m), 7.63 (2H, t), -1.20 (1H, s).

Oxidation of allylethylsulphide (128) Allylethylsulphide (102 mg, 1 mmol) and Mo05.HMPA. (180 mg, 0.5 mmol) were stirred together in dry chloroform for 2 h. Separation of the products by preparative t..1 . c . gave allylethylsulphoxide (129) (113 mg, 98%), having identical spectroscopic properties to an authentic

sample; Vmax (film) 3070, 1635, 1460, 1420, 1040, 1015,. 925 cm-t ; T 8.66 (3H, t), 7.35 (2H, q), 6.52 (2H, d J 7 Hz), 4.65 (2Hi, m), 4.20 (1H, m) Further oxidation of allylethylsulphoxide (55 mg,

0.5 mmol) with Mo05.DMF (193 mg, 0.75 mmol) in dry dichloromethane (5 ml) afforded allylethylsulphine (130) (58 mg, 92%), idendical to an authentic sample; Vmax (film)

3050, 1310, 1140, 935 cm-1 ; -r 8.66 (3H, t), 7.10 (2H, q), 6.35 (2H, d J 7 Hz), 4.5 (2H, m), 4.3 (1H, m).

4-Trimethylsilyloxyphenol (179) Chlorotrimethylsilane (3 g, 27 mmol) was added drop- 188

wise to a vigorously stirred solution of p-cresol (2.70 g, 25 mmol) and triethylamine (2.50 g, 25 mmol) in dry ether (50 ml), and the mixture left to stand for 30 min. The triethylamine hydrochloride was filtered off, and the solvent evaporated. Vacuum distillation yielded 4-tri-

methylsilyloxytoluene (3.60 g, 80%); b.p. 100-5°C / 30 mm (lit.,160 85.3°C / 12 mm); T 9.81 (9H, s), 7.79 (3H, s), 3.4 (2H, d), 3.05 (2H, d).

Attempted oxidation of 4-trimethylsilyloxyphenol (179) The silylether (179) (180 mg, 1 mmol) was stirred with MoOS.DMF (150 mg, 0.5 mmol) in dry dichioromethaLa

(10 ml) for 48 h. at -70°, 0°, and 25°C. Separation of the products by t.l.c. gave the parent p-cresol as the sole product (95%).

1,3-Di-t-butylurea (140) Phosgene (10 g, 0.1 mol) in dry dichloromethane (200 ml) was added over 1 h. to a cooled solution of t-butylamine (45 g, 0.6 mol) in dichloromethane (200 ml) and the mixture stirred for 2 h. at room temperature. The solvent was evaporated and the product washed with dilute hydrochloric acid and water, and then crystallised from chloroform to give the urea (140) (16.9 g, 95%); m.p.

(sealed tube) 263-4°C (lit.,116 m.p. (sealed tube) 243-4°C;

vmox (Nujol) 3350, 1635 cm-1 ; T 8.67 (18H, s) , 5.25 (2H, s, exchanges in D20)

Di-t-butyldiaziridinone (131) By the method of Greene and Stowell,116 a freshly prepared solution of t-butylhypochlorite 161 (970 mg,

8.94 mmol) was added under nitrogen to a suspension of 189 di-t-butylurea (1.50 g, 8.7 mmol) in sodium-dried t-butanol (7 ml) in a flask, protected from the light. To the pale yellow solution of the chlorourea, a freshly prepared solution of potassium t-butoxide in t-butanol (1.035M, 10 ml, 1.035 mmol) was added over 10 min. with rapid stirring. The reaction mixture was poured into water and extracted with hexane (4x 15 ml). The diaziridinone (131) was collected by vacuum distillation, as a colourless oil; b.p. 60-3°C / 10 mm (lit., 116 58-9°C / 8 mm);

vmax (film) 1930, 1880, 1860, 1800 cm-1 ; T 8.80 (18H, s).

Attempted trapping of di-t-butyldiaziridinone (131) The diaziridinone (131) (50 mg) was dissolved in freshly distilled cyclopentadiene (3 ml) and sealed under vacuum in a pyrex tube. The contents were heated at temperatures ranging from 20°C to 200°C for 15 h. The reaction mixture was diluted with water and extracted with hexane. Evaporation of the solvent afforded the unreacted di-t-butyldiaziridinone (reaction temperature below 80°C) or,for reaction temperatures greater than 80°C, di-t-butylurea (140); m.p. (sealed tube) 262-4°C;Vmax (Nujol) -1 3300, 1640 cm ; T 8.70 .(18H, s), 5.30 (2H, s) ; m/e 172 (23%), 157 (35), 84 (10), 72 (11), 58 (100), 57 (51), 41 (44), 32 (50), 29 (26); (Found: C, 61.53; H, 11.31; N, 15.95. Calc. for C9H 20 N20 : C, 62.73; H, 11.70; N, 16.26 70).

1,1-Dimethyl-4-phenylsemicarbazide (158) A solution of phenylisocyanate (11.9 g, 0.1 mol) in ether (40 ml) was added over 20 min. to a solution of anhydrous 1,1-dimethylhydrazine (6.80 g, 0.11 mol) in dry 190

ether (90 ml) and the mixture was stirred for 1 h. further. The solvent was evaporated giving the semicarbazide as a white solid (17.80 g, 99%), which was crystallised from ether; m.p. 108-9°C (lit. ,162 109-110°C); vmQx (CHC13)

3350, 1680 cm 1 ; i 7.42 (6H, s), 3.84 (1H, bs), 3.1-2.3 (5H, m), 180 (1H, bs).

Attempted trapping of 1,1-dimethyl-4-phenylsemicarbazide (158) Freshly prepared t-butylhypochlorite (365 mg, 3.37 mmol) was added under nitrogen to a suspension of the semicarbazide (158) (590 mg, 3.3 mmol) in t-butanol (3 ml) and in the absence of light. After 5 min. at room temperature a clear yellow solution was observed. Potassium t-butoxide in t-butanol (3.42 mmol) and excess of•;freshly distilled cyclopentadiene were added. The reaction mixture was stirred for 1 h. at ambient temperature, filtered and washed with t-butanol. Separation of the products by preparative t.1.c. (Silica - 1% methanol:dichloromethane) gave the parent semicarbazide (60%) and 1-methyl-4-phenyl- -1,2,4-triazolidin-3-one (159) (105 mg, 18%); m.p. 200- 10°C (decomp.) ;sublimes 150°C/ lx 10-4 mm; vmQx (CC14) 3600,

3065, 3030, 1685 cm-1 ; T (CC14) 7.25 (3H, s), 5.40 (1H, d J 14 Hz), 4.97 (1H, d J 14 Hz), 2.6 (5H, m), 1.75 (1H, bs); m/e 177 (75%), 119 (15), 106 (48), 91 (19), 85 (31), 77 (21), 71 (100), 59 (30), 57 (35); (Found: C, 60.92; H, 6.04; N, 23.37. C9H11 N30 requires C, 61.00; H, 6.26; N, 23.71 %).

1-Hydroxy-3-phenylurea (163) Phenylisocyanate (120 mg, 1 mmol) was added to a solution of hydroxylamine hydrochloride (280 mg, 4 mmol) 191 in methanol (2 ml) containing sodium hydroxide (160 mg, 4 mmol), and the reaction mixture was stirred for 1 h. at room temperature. After evaporation of the solvent, the residue was washed with water (4x 15 ml) and then dried giving 1-hydroxy-3-phenylurea (130 mg, 86%); m.p. 142-4°C

(lit., 135 143-4°C); Vmax (Nujol) 3500, 3240, 1650, 1240, 1190, 770, 700 cm 1.

3,3-Dimethyl-4-phenyl-1,2,4-oxadiazolidin-5-one (165) A solution of 1-hydroxy-3-phenylurea in acetone was left to stand for 10 h. at room temperature. Separa- tion of the reaction mixture by preparative t.l.c. (Silica - 2% methanol:chloroform) and crystallisation of the major component from chloroform gave the oxadiazolidinone (165), (71%); m.p. 109-110°C;vmaX (Nujol) 3240, 3120, 1710, 1650, 1535, 1320, 1305, 1225, 1025, 750, -1 700 cm ; T 7.97 (3H, s), 7.95 (3H, s), 2.6 (5H, m), 1.73 (1H, bs); We 192 (26%), 120 (22), 119 (100), 93 (69), 91 (74); 73 (91), 56 (44), 42 (62); (Found: C, 62.91;

H, 6.36; N, 14.45. C10 H11 N202 requires C, 62.48; H, 6.29; N, 14.58 %) .

1-Methoxy-3-phenylurea (163a) By the method of Scherer et a 1., 135 phenylisocyanate (270 mg, 2.28 mmol) was added over 5 min. to a rapidly stirred solution of 0-methylhydroxylamine hydrochloride (prepared by the method of Hjeds 7fi3 ) (194 mg, 2.28 mmol) and sodium hydroxide (91 mg, 2.28 mmol) in methanol (4 ml). The sodium chloride was filtered off and the crude product purified by preparative t.l.c. (Silica - 0.5% methanol: chloroform) to give 1-methoxy-3-phenylurea (182 mg, 50%);

192

m.p. 113-5°C (lit.,135 114-5°C); T 6.20 (3H, s), 3.0-2.3 (6H, m, 1H exchanges in D20);/77/6 166 (30%), 119 (56), 92 (49), 77 (46), 47 (100), 39 (32).

Attempted trapping of 1-methoxy-3-phenylurea (163a) The urea (133 mg, 0.8 mmol) was suspended in t-butanol (1 ml) and t-butylhypochlorite (0.1 ml, 0.85 mmol) was added under nitrogen and in the absence of light. To the resulting pale green solution, potassium t-butoxide in t-butanol (0.96 mmol) and freshly distilled cyclopentadiene (1 ml) were added. After 1. h. the potassium chloride was filtered off, the solvent evaporated and the residual brown oil separated by preparative t.l.c. (Silica - dichloromethane). Methyl /V-(4-chlorophenyl)- carbamate (169a) was isolated as the single major product (37 mg, 25%); m.p. 115°C (lit., 164 115°C); vmax (CC14 ) 3440, 1745, 830, 690 cm-1 ; (Nujol) 3340, 1695 cm 1 ;

t 6.22 (3H, s), 3.25 (1H, bs, exchanges in D20), 2.70 (4H, s) ; We 187 (33%), 185 (M, 100), 155 (15), 153 (45), 142 (15), 140 (45), 128 (13), 126 (26), 101 (7.5), 99 (22), 63 (13), 59 (26), 32 (15). The spectroscopic data, m.p. and mixed m.p. were compatible with those of an authentic sample prepared by the methanolysis of 4-chlorophenylisocyanate (168a)264

4-Chlorophenylisocyanate (168a) Based on a method by Schriner et a I. , 165 a solution of 4-chloroaniline (13.95 g, 109 mmol) in ethyl acetate (150 ml) was added slowly to a saturated solution of phosgene in ethyl acetate (50 ml). Evaporation of the solvent afforded 4-chlorophenyicarbamyl chloride, which was,distilled under vacuum, during which thermolysis 193 occurred giving 4-chlorophenylisocyanate (14.6 g, 87%); b.p. 62-4°C / 4 mm (lit.,164 115-7°C / 45 mm); umax (Cd 4) 2265, 1595, 1500, 1450, 1110, 1090, 1010 cm-1 ; r 3.03 (2H, d J 9 Hz), 2.74 (2H, d J 9 Hz)

1-(4'-Chlorophenyl)-3-methoxyurea (163b) O-Methylhydroxylamine hydrochloride (170 mg, 2 mmol) was dissolved in dichloromethane (20 ml) containing a strong base ion-exchange resin (Dowex 1-8X), previously washed with methanol. After stirring for 15 min. the resin was filtered off and 4-chlorophenylisocyanate (310 mg, 2 mmol) added. Purification of the products by preparative t.l.c. gave the methoxyurea (163b) (372 mg, 9370; 135 m.p. 141-2°C (lit., 140-2°C) ; umax (Nujol) 3310,

3200, 1650, 860, 700 cm-1 ; r 5.80 (3H, s), 2.30 (4H, m), 2.1 (2H, bs, exchanges in D20).

Rearrangement of 1-(4'-chlorophenyl)-3-methoxyurea (163b) a) The methoxyarylurea (163b) (400 mg, 2 mmol) was suspended in dichloromethane (10 ml) in a flask protected from the light and t-butylhypochlorite (220 mg, 2 mmol). was added under nitrogen. Silver nitrate (100 mg) was added and the mixture stirred at room temperature for 2 h. After filtration of the silver salts, separation of the products by preparative t.l.c. (Silica - 2% ethanol: chloroform) gave ethyl N-(4-chlorophenyl)carbamate (169b)

(256 mg, 69%); m.p. 68-9°C (lit. , 156 68°C); umax (Nujol) -1 -1 3300, 3100, 1693 cm ; (CC14) 1740 cm ; T 8.30 (3H, t), 5.40 (2H, q), 2.8 (1H, bs), 2.3 (4H, s). A minor product (7%) corresponded to methyl N-(4-chlorophenyl)carbamate (169a); m.p. 115-6°C (lit. 164 194

115°C); V max (Nujol) 3340, 1695, 1550, 1240, 830 cm-1 ; T 6.26 (3H, s), 2.75 (5H, m). Both products were identical to authentic samples of the ethyl and methyl urethanes. b) Isolation of the intermediate isocyanate (168a) The reaction between the N-chlorourea (1.5 mmol) prepared as in (a) and silver oxide (300 mg) was monitored by i.r. spectroscopy. The initial absorption at 1740 cm-1 corresponding to the chlorourea disappeared within 50 min. with the formation of a new, strong isocyanate absorption (2267 cm-' ). The reaction mixture was filtered and vacuum distillation gave 4-chlorophenylisocyanate; b.p.

80°C / 9 mm (lit.,164 115-7°C / 45 mm). The spectroscopic properties were in accord with those of an authentic sample (168a).

1-Methoxy-3-methylurea (163c) 0-Methylhydroxylamine hydrochloride (2.78 g, 33 mmol) was disso'_vid in a solution of sodium hydroxide (1.5 g, 35 mmol) in water (15 ml) and the free hydroxylamine was extracted with ethanol-free chloroform (3x 30 ml). Methylisocyanate (2.2 ml, 38 mmol) in chloroform (10 ml) was added over 5 min. to the hydroxylamine and the mixture stirred for 30 min. at room temperature. The solvent was evaporated and the residual white solid was crystallised from toluene to give 1-methoxy-3-methylurea (2.78 g, 81%); m.p. 86-8°C (lit., 167 84-6°C); Vmax (CHC13) 3450, 3340, 3200, 2820, 1680, 1545 cm-1 ; (Nujol) 1655 cm-1 ; -r 7.15 (3H, d J 4.5 Hz), 6.30 (3H, s), 4.25 (1H, bs), 2.2 (1H, bs). 195

Attempted trapping of 1-methoxy-3-methylurea (163c) The N-chlorourea was prepared by the addition of t-butylhypochlorite (250 mg, 2 mmol) to the methoxyurea (163c) (208 mg, 2 mmol) in ethanol-free chloroform (5 ml) under nitrogen and in the absence of light. Cyclohexene (2 ml) and silver oxide (500 mg) were added and the reaction mixture stirred for 3 h. at room temperature. The major component from preparative t.l.c. (Silica - 0.5% methanol:dichloromethane) corresponded to methyl N-methyl- carbamate (169c) (53 mg, 30%); Vmax (CHC13) 3450, 1720, 1510, 1230 cm-1 ; -r 7.17 (3H, d. J 5 Hz), 6.2 (3H, s), 3.8 (1H, bs). Spectroscopic data were identical to those of an authentic sample, prepared from methanolysis of methylisocyanate.

1,3-Dimethyl-4,,6,7-tetrahvidrobenzimidazolin-2-one t-Butyihypochlorite (0.5 ml, 4.5 mmol) was added to a solution ol 1,3-dimethylurea (370 mg, 4.2 mmol) in dichloromethane (20 ml) at 0°C, under nitrogen and in the dark. Freshly prepared 1-pyrrolidinylcyclohex-1-ene X68 (2 ml) was added, followed by sodium hydride (225 mg, 9 mmol) and the solution was stirred for 4 h. at room temperature. The reaction mixture was filtered through Celite and the solvent evaporated. Trituration with light petroleum removed the excess of the enamine and cyclohexanone, and separation of the residual oil by preparative t.l.c. (Silica - 2% methanol:dichloromethane) gave, amongst many other products, the cyclic adduct (151)

(118 mg, 17%); vmax (Nujol) 2790, 1680, 1630 cm ; T 8.2 (4H, m), 7.6 (4H, m), 6.8 (6H, s); We 166 (6%), 138 196

(9), 110 (9.5), 82 (64), 58 (50), 30 (100), 15 (23); (Found: M 166 .1104. C9H14N20 requires M 116.1106 ) .

S,S-Diphenyl-N-(N'-phenylcarbamyl)sulphilimine (178) a) (Adapted from the method of Swern.142 ) Dimethyl- sulphoxide (140 mg, 1.8 mmol) in dry dichloromethane (1 ml) was cooled to -70°C under a nitrogen atmosphere. Trifluoroacetic anhydride (198 mg, 1 mmol) was added slowly, maintaining the temperature below -50°C. A suspension of phenylurea (136 mg, 1 mmol) in dry dichloromethane (2 ml) was added and the mixture stirred at -40°C for 3 h. The solution was quenched with water and allowed to reach room temperature, then separated and the aqueous phase washed with dichloromethane. The combined organic fractions were washed with water and dried (magnesium sulphate). Purification of the crude material by preparative t.i.c. (Silica -. dichloromethane) gave the dialkylsulphilimine (178) as an unstable oil (6 mg, 3%); vmax

(film) 1615 cm T 7.4 (6H, s), 6.2 (1H, bs), 3.4 (5H, m). b) (From the method of Claus and yycudilik.141 ) Phenyl- urea (1.36 g, 10 mmol) and phosphorus pentoxide (2.5 g) were suspended in ethanol-free chloroform (15 ml) under nitrogen. Dimethylsuiphoxide (2.5 ml) and triethylamine (2.0 g) were added simultaneously over 10 min. at room temperature. After 1 h. the solvent was removed in vacfio and the products separated by preparative t.l.c. (Silica - ethyl acetate), giving the dimethylsulphilimine (178) (60 mg, 3%). 197

Attempted addition of diazomethane to S,S-dimethyl- N-(N'-phenylcarbamyl)sulphilimine (178) A solution of the dimethylsulphilimine (178) and diazomethane in dry ether-dichloromethane (1:1, 5 ml) was stirred for 24 h. at room temperature. T.l.c. indicated no reaction other than complete decomposition of the dialkylsulphilimine.

S,S-Diphenyl-N-(4-toluen_esulphonyl)sulphilimine (180). By the reported method,169 diphenylsulphide (1.86 g, 10 mmol) and chloramine T (2.50 g, 11 mmol) were dissolved in methanol (30 ml) and acetic acid (1 ml) in methanol (5 ml) added. The mixture was heated at 60°C for 1.5 h, then poured into cold, 2N sodium hydroxide solution and the resulting precipitate filtered, washed with water and dried. Crystallisation from acetone- petroleum ether gave the tosylsulphilimine (180) (3.05 g, 173 86%); m.p. 110-1°C (lit., 111-2°C); Vmax (Nujol) 1300, 1140, 1085, 955, 760 cm-1 ; ? 7.70 (3H, s), 2.86 (2H, d J 8 Hz), 2.5 (10H, m), 2.20 (2H, d J 8 Hz);

Amax (MeOH) 228 nm (log E 4.59) .

S,S-Diphenylsulphilimine hydrate (175) The sulphilimine (175) was prepared according to

the method of Oae et al. 133 by Jdissolving dissolving the tos Ylsul- philimine (180) (1 g, 2.8 mmol) in concentrated sulphuric acid (1 ml). After 10 min. the solution was poured onto ice and extracted with dichloromethane (3x 20 ml) giving an intermediate tosylate salt, which was taken up in dichloromethane and washed with 20% sodium hydroxide (3x 15 ml). The solvent was evaporated and the residue 198 was crystallised from benzene-petroleum ether to give diphenylsulphilimine hydrate (175) (480 mg, 7870; m.p. 70-1°C (lit.,i39 71°C); Vmax (Nujol) 3400, 3100, 1630, 1075, 1060, 930, 750, 730 cm-1 ; 'r 7.7 (2H, bs, exchanges in D20), 3.6 (1H, bs, exchanges in D20), 2.5 (10H, m).

S, S-Diphenyl-N-(N'-phenylcarbamyl)sulphilimine (177) Phenylisocyanate (120 mg, 1 mmol) was added to a solution of diphenylsulphilimine (175) (230 mg, 1 mmol) in dichloromethane and left to stand for 15 min. Evapo- ration of the solvent and crystallisation of the residue from chloroform gave the carbamylsulphilimine (177) (300 mg, 94%); m.p. 132-4°C (lit., 139a 133.5-5°C); Vmax (Nujol) 3400, 3280, 1620, 1220, 750, 690 cm 1; T 3.2-2.2 (15H, m) . Spectroscopic data were identical to those of an authentic sample.

Attempted addition of diphenylnitrilimine (173) to 3,3- diphenyl-N-(N'-phenylcarbamyl)sulphilimine (177) The nitrilimine precursor, 3-chloro-1,3-diphenyl- hydrazone (181) was prepared by the method of Pechmann 170 ; m.p. 130-2°C (lit.,170 131°C); vmax (Nujol) 3300, 3100, 1600, 1570, 760, 690 cm-1 . The diphenylsulphilimine (177) (66 mg, 0.21 mmol) and the chlorohydrazone (181) (50 mg, 0.22 mmol) were dissolved in acetonitrile (5 ml) and triethylamine (0.25 ml) was added under nitrogen. The solution was stirred for 48 h. at ambient temperature under nitrogen. T.l.c. indicated only complete decomposition of the nitrilimine, 199 whereas the sulphilimine (177) could be recovered by preparative t.l.c. (Silica - ethyl acetate) (60 mg,

90ō). 200

References to Part II

1. H.L. Yale, Chem.Rev., 1943, 33, 209. 2. L. Bauer and O. Exner, Angew . Chem . I nternet. Edn., 1974 13, 376. 3. R.T. Coutts, Canad.J.Pharm.Sci., 1967, 1, 1; 27. 4. H. Henecka in 'Methoden der Organischen Chemie,' Verlag, Stuttgart, 1952, Vol. 8, part III, p.500. 5. G. Anderegg, F. L'Eplattenier and G. Schwarzenbach, Helv.Chim.Acta, 1963, 46, 1390; 1400; 1409. 6. S.C. Shome, Analyst, 1950, 75, 27. 7. J.S. Neilands, Science, 1967, 156, 1443; Struct. Bonding (Berlin), 1966, 1, 59. 8. M.J. Perkins and P. Ward, J.C.S. Chem.Comm., 1973, 883. 9. J.B. Bapat, D. St.C. Black and R.F.C. Brown, Adv. Heterocyclic Chem., 1969, 10, 199. 10. G.A. Zentmyer, Science, 1944, 100, 294. 11. R.J.G. Searle, P. Kirby and P. ten Haken, Chem.Ztg., 1973, 97, 417. 12. C.W. Young, G.S. Schochetman, S. Hodas and M.E. Balis, Cancer Res., 1967, 27, 535. 13.a) W. Keller-Schierlein, V. Prelog and H. Milner, Fortschr.Chem.Org.Naturstoffe; 1964, 22, 279; b) A. Chimiak, Wiadomosci.,Chem, 1965, 19, 803; H. Mahr, , Pure Appl .Chem . , 1971, 28, 603; O. Mikes and J. Turkova, Chem.Listy, 1964, 58, 65; F. Mathis, Bull.Soc.chim.France, 1953, D9; D. Davidson, J.Chem.Educ., 1940, 17, 81; J. Falecki, Wiadomosci Chem., 1955, 9, 265. 14. C.W. Muth, J.R. Elkins, P.I.L. De Matte and S.T. Chiang, J.Org.Chem., 1967, 32, 1106. 15. J.T. Edward and P.F. Morand, Canad.J.Chem., 1960, 38, 1317. 16. H.O. Larson and E.K.W. Wat, J.Amer.Chem.Soc., 1963, 85, 827. 17. B. Ganen, Tetrahedron Letters, 1976, 1951. 18. E. Ochiai and A. Ohta, Chem.Pharm.Bull., 1962, 10, 1260. 19. J.F. Elsworth and M. Lamchen, J.Chem.Soc.(C), 1966, 1477. 201

20. G. Wagner and H. Pischel, Arch.Pharm., 1962, 295, 897. 21. G.T. Newbold and F.S. Spring, J.Chem.Soc., 1949, S133; L.A. Paquette, Tetrahedron, 1966, 22, 25. 22. D.St.C. Black, R.F.C. Brown and A.M. Wade, Tetra- hedron Letters, 1971,. 4519. 23. D.H. Aue and D. Thomas, J.Org.Chem., 1974, 39, 3855.

24. S.A. Matlin and P.G. Sammes, J.C.S. Chem.Comm ., 1972, 1222. 25. J.A. Hinson, J.R. Mitchell and D.J. Jollow, Mol. Pharmacol., 1975, 11, 462; I.C. Calder, M.J. Creek, P.J. Williams, C.C. Funder, C.R. Green, K.N. Ham and J.D. Tange, J.Med.Chem., 1973, 16, 499. 26. J.C. McDonald, J.Biol.Chem., 1961, 236, 512. 27. A.J. Birch and H. Smith, Ciba Found.Symp., Amino Acids Peptides Antimetab.Activity, 1958, p. 247 (Chem.Abs., 1959, 53, 14171 e). 28. J.E. Reimann and R.U. Bjerrum, Biochem., 1964, 3, 847; C.L. Tipton, M.C. Wang, F.H.C. Tsao, C.C.L. Tu and R.R. Husted, Phytochem, 1973, 12, 347. 29. R. Nery, Biochem.J., 1971, 122, 317; A. Goldstein, L. Aronov and S.M. Kalman, 'Principles of Drug Action,' Harper & Row, New York, 1969, p. 691; K P. BUtcke, B.J. Gough and T.E. Shellenberger, Biochem.Pharmacol., 1974, 23, 1745. 30(a) L.Birkofer and A. Ritter, Newer Methods of Prep .Ora . Chem., 1968, 5, 211; (b) J.F. Klebe, Adv.Org.Chem:, 1972, 8, 97. 31. L.H. Sommer, 'Stereochemistry Mechanism & Silicon,' McGraw-Hili, New York., 1965. 32. 'Protective Groups in Organic Chemistry,' ed. J.F.W. McOmie, Plenum, London, 1973 33. A.D. Pierce, 'Silylation of Organic Compounds,' Pierce Chemical Co., Illinois, 1968. 34(a) J.F. Klebe and J.B. Bush, Internat.Symp.Organosilicon Chem., Sci.Comm. Prague, 1965 (Chem.Abs., 1966, 65, 8731 g); B. Boe, J.Organometallic Chem., 1976, 107, 139; (b) C. Eaborn, 'Organosilicon Compounds,' Butterworths, London,1960. 35. D.A. Schriver, 'The Manipulation of Air Sensitive 202

Compounds' McGraw-Hill, New York, 1969. 36. W. Walter, H.W. Luke and J. Voss, Annalen, 1975, 1808; W. Walter and H.W. LUke, Angew.Chem.Internat. Edn., 1975, 14, 427. 37. H. Mimoun, I.S. de Roche and L. Sajus, Bull.Soc. chim.France, 1969, 1482. 38. E. Vedejs, J.Amer.Chem.Soc., 1974, 96, 5944. 39. H. Mimoun, I.S. de Roche and L. Sajus, Tetrahedron, 1970, 26, 37. 40. R.L. Dutta and B. Chatterjee, J.Indian Chem.Soc., 1969, 46, 268. 41(a) S.A. Matlin, P.G. Sammes and R.M. Upton, submitted for publication; (b) S.A. Matlin, Ph.D. Thesis, University of London, 1972. 42. L. Holleck and H.J. Exner, Z.Electrochem., 1952, 56, 677; A. Tallec and D. Pettier, Compt.rend., 1964, 259, 400. 43. W.E. Bull, S.K. Madan and J.E. Willis, Inorg.Chem., 1963, 2, 303; S.K. Madan and H.H. Denk, J.Inorg. Nuclear Chem., 1967, 29, 1669; R.J. Niedzielski and G. Znider, Canad.J.Chem., 1965, 43, 2618. 44(a) E. Fraimet, A. Bazonin and R. Calas, Compt.rend., 1963, 1304; (b) C. Kruger, E.G. Rochow and U. Wannagat, Chem.Ber., 1963, 96, 2138; (c) J. Pump and E.G. Rochow, ibid., 1964, 97, 627; (d) G. Schirawski and U. Wannagat, Monatsh., 1969, 100, 1901; (e) C.H. Yoder and D. Bonelli, Inorg.Nuclear Chem.Lett., 1972, 8, 1027; (f) W.Kantlehner, W. Kugel and H. Brederek, Chem.Ber., 1972, 105, 2264. 45. C.H. Yoder, W. Copenhafer and B. DuBeshter, J.Amer. Chem.Soc., 1974, 96, 4283. 46. T.S. Chou, Tetrahedron Letters, 1974, 725. 47. P. Claus, A. Vlietinck, E.R. Roets, H. Vanderhaeghe and S. Toppett, J.C.S. Perkin I, 1973, 932. 48. G.E. Gutowski, Tetrahedron Letters, 1970, 1779. 49. E. Honkanen & A.I. Virtanen, Acta Chem.Scand., 1960; 14, 504; 1961, 15, 221. 50. J.N.T. Gilbert, P.T.J. Nelmes and J.W. Powell, J.Pharm.Pharmacol., 1978, 30, 173. 51. H. Shindo, Chem.Pharm.Bull., 1960, 8, 845. 203

52. J.F. Klebe, J.B. Bush and J.E. Lyons, J.Amer.Chem. Soc., 1964, 86, 4400. 53. D.Y. Zhinkin, M.M. Morgunova, K.K. Popkov and K.A. Andrianov, Bull.Acad.Sci. (U:S.S.R.), Div. Chem.Sci., 1966, 818. 54. C. Eaborn, R.A. Jackson and R.W. Wallingham, J.Chem.Soc.(C), 1967, 2188. 55. W.P. Neumann and G.N. Neumann, J.Organometallic Chem., 1970, 25, C59. 56. W. Walter and H.W. Like, Angew.Chem.Internat.Edn., 1977, 16, 535. 57. K. Itoh, K. Matsuzaki and Y. Ishii, J.Chem.Soc.(C), 1968, 2709. 58. W. Walter in 'Organosulphur Chemistry,' ed. M.J. Janssen, Wiley, New York, 1967, p. 241. 59. K.A. Petrov and L.N. Andreev, Russ.Chem.Rev., 1971, 40, 505. 60. H. Ulrich, 'Cycloaddition Reactions of Heterocumulenes,' Academic Press, London, 1967, p. 179. 61. E. Vedejs and J.E. Telschow, J.Org.Chem., 1976, 41, 740. 62. S.L. Regen and G.M. Whitesides, J.Organometallic Chem., 1973, 59, 293. 63. F.A. Cotton and G. Wilkinson, 'Advanced Inorganic Chemistry,' Wiley-Interscience, New York, 1967, p. 460. 64. R.G. Sauer, J.Amer.Chem.Soc., 1944, 66, 1707. 65. R.G. Beiles, R.A. Safina and E.M. Beiles, Russ.J. Inorg.Chem., 1961, 6, 825. 66. A.I. Vogel, 'Quantitative Inorganic Analysis,' Longmans, London, 1961, p. 318. 67. W.D. Emmons, J.Amer.Chem.Soc., 1956, 78, 6208; 1957, 79, 5739;V. Madau and L.B. Clapp, ibid., 1969, 91, 6078. 68. K.B. Sharpless, J.M. Townsend and D.R. Williams, J.Amer.Chem.Soc., 1972, 94, 295; A.A. Achrem, T.A. Timoschutsch and D.I. Metelitza, Tetrahedron, 1974, 30, 3165. 69. R.A. Sheldon, Rec.Tray.chim., 1973, 92, 253. 70. E.S. Gould, R.R. Hiatt and L.K.C. Irwin, J.Amer. Chem.Soc., 1968, 90, 4573.

204

71. J.F. Klebe, Acc.Chem.Res., 1970, 3, 299. 72. v.W. Hahn and L Metzinger, Makromol.Chem., 1956, 21, 113. 73. D. Brandes and A. Blaschette, J.Organometallic Chem., 1973, 49, C6. 74. G. Greber and H.R. Kirchedorf, Chem.Ber., 1971, 104, 3131. 75. L. Birkofer and H. Dickopp, Angew.Chem., 1964, 76, 648; L.Birkofer and H. Dickopp, Chem.Ber., 1968, 101, 3579. 76. L. Birkofer and H. Dickopp, Chem.Ber., 1969, 102, 14 77. L. Birkofer, H. Dickopp and S.K. Majlis, Chem.Ber., 1969, 102, 3094. 78. M.J. Hurwitz and P.L. De Benneville, U.S.P. 2,876,234 (Chem.Abs., 1959, 53, 12238 d). 79. L. Birkofer, A. Ritter and H.P. KUlthau, Chem.Ber., 1964, 97, 934. 80. L. Birkofer, H.P. KUlthau and A. Ritter, Chem.Ber., 1960, 93, 2810. 81. R.J.P. Corriu and G.F. Larmeau, J.Organometallic Chem., 1974, 67, 243; R.J.P. Corriu and B.J.L. Hemmer, ibid. , 1975, 102, 407. 82. A. Komoriya and C.H. Yoder, J.Amer.Chem. Soc., 1972 94, 5285. - 83. A.L Smith, Spectrochim.Acta, 1960, 16, 87. 84. K. Itoh, M. Katsuda and Y. Ishii, J.Chem.Soc.(B), 1970, 302. 85. M. Fukui, K. Itoh and Y. Ishii, J.C.S. Perkin II, 1972, 1043. 86. I. Matsuda, K. Itoh and Y. Ishii, J.Organometallic Chem., 1974, 69, 353; V.N. Torocheshnikov, N.M. Sergeyev, N.A. Viktorov, G.S. Goldin, Y.G. Poddubny and A.Y. Koltsova, J.Organometallic Chem., 1974, 70, 347. 87. H.J. Reich and D.A. Murcia, J.Amer.Chem.Soc., 1973, 95, 3418. 88. Y.K. Grishin, N.M. Sergeyery and Y.A. Ustynyuk, Org.Magn.Resonance, 1972, 4, 377; N.M. Sergeyev, Y.K. Grishin, Y.N. Luzikov and Y.A. Ustynyuk, 205

J.Organometallic Chem., 1972, 38, Cl. 89. N.K. Wilson and J.B. Stothers, Topics in Stereochem., 1974, 8, 1. 90. L.M. Jackman and S. Sternhell, 'Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry,' Pergamon, Oxford, 1969. 91. G.C. Levy and.G.L. Nelson, 'Carbon-13 N.M.R. for Organic Chemists,' Wiley, New York, 1972. 92. J.H. Noggle and R.E. Schirmer, 'The Nuclear Over- hauser Effect,' Academic Press, London, 1971; R.A. Bell & J.K. Saunders, Topics in Stereochem., 1973, 7, 1. 93. G.C. Levy and U. Edlund, J.Amer.Chem.Soc., 1975, 97, 4482. 94. T.H. Marec-_ and K.N. Scott, Analyt.Chem., 1977, 49, 2130. 95. R. Freeman, H.D.W. Hill and R. Kaptein, J.Magn. Resonance, 1972, 7, 327. 96. G.N. LaMar, J.Amer.Chem.Soc., 1971, 93, 1040; G.C. Levy and J.D. Cargioli, J.Magn.Resonance, 1973, 10, 231. 97. I.K. O'Neill and M.A. Pringeur, Org.Magn.Resonance, 1974, 6, 398. 98. J.B. Stothers, 'Carbon-13 N.M.R. Spectroscopy, 'Academic Press, New York, 1972; F.W. Wehrli and T. Wirthlin, 'Interpretation of Carbon-13 N.M.R. Spectra,' Heydon, London 1976. 99. L.F. Johnson and W.C. Jankowski, 'Carbon-13 N.M.R. Spectra, ' Wiley, New York, 1972. 100. H.L. Retcofsky and R.A. Friedel, J.Phys.Chem., 1968, 72, 2619. 101. P.A. Claret & A.G. Osborne, Spectroscopy Lett., 1977, 10, 35. 102. U. Vdgeli and W. v.Philipsborn, Org.Magn.Resonance, 1973, 5, 551. 103. L. Birkofer, P. Richter and A. Ritter, Chem.Ber., 1960, 93, 2804; T.J. Pullukat and G. Urry, Tetra- hedron Letters, 1967, 1953; K. Rilhlmann, Chem.Ber., 1961, 94, 2311. 104. K. RUhlma nn, A. Reiche and M. Becker, Chem.Ber., 206

1965, 98, 184. 105. S. Chua, M.J. Cook and A.R. Katritsky, J.Chem.Soc. (B), 1971, 2350. 106. A.R. Katritsky and J.M. Lagowski, 'The Chemistry of Heteroaromatic N-Oxides,' Academic Press, 1971. 107. I.L. Finar and M.D. Rackham, J.Chem.Soc.(B), 1968, 211. 108. G.W. Stacy, T.E. Wollner and T.R. Oakes, J.Hetero- cyclic Chem., 1966, 3, 51. 109. M.A. Stevens, D.I. Magrath, H.W. Smith and G.B. Brown, J.Amer.Chem.Soc., 1958, 80. 2755. 110. J.H. Lister in 'The Chemistry of Heterocyclic Compounds. Fused Pyrimidines: Part II. Purines, ed. D.J. Brown, Wiley-Interscience, New York, 1971 p. 410. 111. R.J. Sundberg, 'The Chemistry of Indoles,' Academic Press, New York, 1970, (a) p. 293-5; (b) 372-7. 112. G.A. Tolstikov, U.M. Dzhemilev, Y.P. Yur'ev, F.B. Gershanov and S.R. Rastikov, Tetrahedron Letters, 1971, 2807. 113. G.A. Tolstikov, Y.P. Yur'ev and U.M. Dzhemilev, Russ.Chem.Rev., 1975, 44, 319. 114. D.A. Buckingham, J. MacB.Harrowfield and A.M. Sargeson, J.Amer.Chem.Soc., 1974, 96, 1726; A. ZukerbUhler and T. Kaden, Helv.Chim.Acta, 1972, 55, 623. 115. H.L. Vaughn and M.D. Robbins, J.Org.Chem., 1975, 40, 1187; J. San Philippo, L.J. Romano, C.I. Chern and J.S. Valentine, J.Org.Chem., 1976, 41, 586. 116. F.D. Greene, J.C.Stowell and W.R. Bergmark, J.Org. Chem., 1969, 34, 2254. 117. F.D. Greene, W.R. Bergmark and J.G. Pacifici, J.Org. Chem., 1969, 34, 2263. 118. I. Lengyet and J.C. Sheehan, Angew.Chem.Internat.Edn., 1968, 7, 25. 119. F.D. Greene and J.F. Pazos, J.Org.Chem., 1969, 34, 2269; C.J. Wilkerson and F.D. Greene, ibid., 1975 40, 3112. 120. H. Quast and L. Bieber, Angew.Chem.Internat.Edn. 1975, 14, 428. 207

121. C.A. Renner and F.D. Greene, J.Org.Chem., 1976, 41, 2813. 122. T. Agawa, Y. Ohshiro and K. Takagi, Jap.P., 75, 117, 774 (Chem.Abs., 1976, 84, 59486 a). 123. K.L. Mok and M.J. Nye, J.C.S. Chem.Comm., 1974, 608. 124. J.F. Liebman and A. Greenberg, J.Org.Chem., 1974, 39, 123. 125. H. Quast and E. Spiegel, Angew.Chem., 1977, 89, 112. 126. G. L'abbē, G. Verheist, C.C. Yu and S. Toppett, J.Org.Chem., 1975, 40, 1728. 127. D.M. Revitt, J.C.S. Chem.Comm., 1975, 24; E. Van Loock, J.M. Vandensavel, G. L'abbē and G. Smets, J.Org.Chem., 1973, 38, 2916. 128. G. Stork and I. Borowitz, J.Amer.Chem.Soc., 1960, 82, 4307. 129. D. Pocar and R. Stradi, Tetrahedron, 1976, 1839. 130. H. Budzikiewicz, C. Djerassi and D.H. Williams, 'Mass Spectrometry of Organic Compounds,' Holden- Day, San Francisco, 1967, p. 503. 131. L.F. Fieser and M. Fieser, 'Reagents for Organic Synthesis,' Wiley, New York, 1967, p. 1002-19; and references therein. 132. R. Taydoni, L. Lacrampe, A. Hiimann, R. Furstoss and B. Wagell, Tetrahedron Letters, 1975, 735. 133. M. Anteunis, F. Borremans, W. Tadros, A.H.A. Zaher and S.S. Gliobrial, J.C.S. Perkin I, 1972, 616. 134. H. Schildknecht and G. Hatzmann, Annalen, 1969, 724, 226. 135. 0. Scherer, G. Hbrlein and K. Hertel, Angew.Chem., 1963, 75, 851. 136. H.G. Aurich and H.G. Scharpenberg, Chem.Ber., 1973, 106, 1881. 137. K.P. Orton and A.E. Bradfield, J.Chem.Soc., 1927, 986. 138. T.L. Gilchrist, C.J. Harris and C.W. Rees, J.C.S. Chem.Comm., 1974, 485; T.L. Gilchrist, C.J. Harris, C.J. Moody and C.W. Rees, ibid. , 1974, 486. 139(a) Y. Tamura, K. Sumoto, H. Matsushima, H. Taniguchi and H. Taniguchi, J.Org.Chem., 1973, 38, 4324; (b) N. Furukawa, T. Omata, T. Yashimura, T. Aida and S. Oae, Tetrahedron Letters, 1972, 1619. 208

140. T.L. Gilchrist and C.J. Moody, Chem.Rev., 1977, 77 409 141. P. Claus and W. Vycudilik, Monatsh., 1970, 101, 396. 142. A.K. Sharma and D. Swern, Tetrahedron Letters, 1974, 1503. 143. D.D. Perrin, W.L.F. Amarego and D.R. Perrin, rPurification of Laboratory Chemicals,' Pergamon, Oxford, 1966. 144. K. Ruhlmann and B. Rupprich, Annalen, 1965, 686, 226. 145. L.D'.Abberio, G.DiMaio, L. Panizzi and P.A. Tardella, Ricerca Sci., 1961, 1, 312. 146. I.M. Heilbron, 'Dictionary of Organic Compounds,' Eyre and Spottiswoode, London, 1965, 4th edn. 147. H.G. Aurich and J. Tr6sken, Chem.Ber., 1973, 106, 3483. 148. J.F. K1ebe, H. Finkbeiner and D.M. White, J.Amer. Chem.Soc., 1966, 88, 3390. 149. H.E. Baumgarten, A. Staklis and E.M. Miller, J.Org. Chem., 1965, 30, 1203: 150. H.C. Brown, J.Amer.Chem.Soc., 1938, 60, 1325. 151. G. Wagner and H. Pischel, Arch.Pharm., 1962, 295, 897. 152. I.B. Romanova, U. Katlukova and L.V. Penskaya, J.Gen.Chem. (U.S.S.R.), 1969, 39, 1884. 153. G. Wunsch and E. Jager, Z.fiir Physiol.Chem., 1966, 346, 301. 154. N.Y. Derkach and N.P. Smetankina, J.Gen.Chem. (U.S.S.R.), 1964, 34, 3660. 155. R.H. Dewolfe, J.Org.Chem., 1962, 27, 490. 156. R.E. Benson and T.L. Cairns, J.Amer.Chem.Soc., 1948, 70, 2117. 157. T. Nishimura and I. Iwai, Chem.Pharm.Bull., 1964, 12, 352. 158. M.A. Stevens, D.I. Magrath, H.W. Smith and G.B. Brown J.Amer.Chem.Soc., 1958, 80, 2735. 159. E. Ochiai and T. Naito, J.Pharm.Soc.Japan, 1947, 67, 154. 160. A.P. Kreshkov, V.A. Drozdov and V.N. Kryazev, J.Gen.Chem. (U.S.S.R.), 1967, 37, 2017. 161. M.J. Mintz and C. Walling, Org.Synth.Coll.Vol.V, 1973, 184. 209

162. S. Wawzonek, T.H. Plaisance and D.P. Boaz, Tetra- hedron, 1972, 28, 3669. 163. H. Hjeds, Acta Chem.Scand.,1963, 75, 851. 164. W. Siefken, Annalen, 1949, 562, 75. 165. R.L. Shriner, Y.H. Horne and R.F.B. Cox, Org.Synth. Coll.Vol.II, 1943, 453. 166. H. Vittenet, Bull.Soc.chim.France, 1899, 21, 954. 167. T.P. Johnston, G.S. McCaleb, P.S. Opliger, W.R. Laster and J.A. Montgomery, J.Med.Chem., 1971, 14 600. 168. S. Hiinig, E. Lucke and W. Brenninger; Org.Synth., 1961, 41, 65. 169. K. Tsujihara, N. Furukawa, K. Oae and S. Oae, Bull.Chem.Soc.Japan, 1969, 42, 2631. 170. H. v.Pechmann and L. Seeberger, Ber, 1894, 27, 2122.