Co(Dmgh)2Py

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OF ALKYLCOBALOXIMES

A thesis presented

noi P." PAGONA (FOTIOU) ROUSSI

In Partial Fulfilment of the Requirements •

for the Degree of

DOCTOR OF PHILOSOPHY

THE UNIVERSITY OF LONDON

HOFFMAN LABORATORY, Department of Chemistry, Imperial College, London, SW7 2AY. August, 1980. 2.

ABSTRACT

The synthesis of alkylcobaloximes and alkylcobalamins, and their reactions with metals are reviewed in detail. Only the reactions, where the cobalt-carbon bond is cleaved, are examined. Reactions where the metal complexes with the ligands are not mentioned.

The limitations of the preparation of alkylcobaloximes from hydridocobaloxime and olefins are described.

The development of the reaction of cobaloxime(II) with electron deficient alkyl halides as a useful synthetic route to alkylcobaloximes is reported.

A study of the reaction of alkylcobaloximes with copper(II) halides is presented. A mechanism is proposed.

The enzymic reactions of coenzyme 312 are briefly mentioned.

The theories of the mechanism of the carbon-skeleton rearrangements, catalysed by coenzyme B12 are reviewed. The preparation of some model compounds is described. 3.

ACKNOWLEDGEMENTS

I would like to thank:

Dr. D.A. Widdowson for his supervision, encouragement and friendship throughout these studies.

Professsor W.J. Albery and Mr. J.P. Davies for the preliminary electrochemical studies. Dr. D.J. Williams for the

X-ray analysis; Mr. D.Neuhaus for the 250 MHz spectra and

Mr. K.I. Jones for the microanalytical service.

My parents for supporting me financially throughout my

B.Sc. and Ph.D. degrees.

Miss M.C. Alpoim for her friendship and Mr. P. Quayle for his kindness, friendship and for all his help in writing this thesis.

Finally, Miss M. Shanahan for typing the manuscript. 4.

CONTENTS

PAGE:

REVIEW

1. Synthesis of alkylcobaloximes and

alkylcobalamins. 5.

2. Dealkylation reactions of alkylcobaloximes and

alkylcobalamins by metal species. 41.

3. Summary. 76.

4. References. 78.

RESULTS AND DISCUSSION

1. Synthesis of alkylcobaloximes. 85.

2. Reactions of alkylcobaloximes with a-bromonitroalkanes. 109.

3. Reactions of alkylcobaloximes with copper(II) salts. 112.

4. Synthesis of coenzyme B12 model compounds. 133.

5. Summary. 166.

EXPERIMENTAL 175.

REFERENCES 228.

APPENDIX 234. 5.

REVIEW

CHAPTER 1.

SYNTHESIS OF ALKYLCOBALOXIMES AND ALKYLCOBALAMINS

Introduction.

The cobalt atom in both cobaloximes and cobalamins can exist as a cobalt(I) anion, cobalt(II) (neutral), and cobalt(III) cation. As a result, cobalt(I) react's with electrophilic reagents, cobalt(II) with radicals, and cobalt(III) with nucleophilic reagents, to form alkylcobalt(III) complexes. Cobalt(I) and cobalt(II) species are generally heat and oxygen sensitive. Their formation from the stable cobalt(III) compounds is shown in 1-9 Scheme 1.

Zn [ Co (dmgH) 2B ]+ ? Co (dmgH) 2B HO ) [ Co (dmgH) 2B ]+ +

J,NaBH4 1H2 2[Co(dmgH)2B] _ H30 [ Co (dmgH) 2B ] ~ — \ HCo (dmgH) B -H3 2 0+

+, Zn, AcOH - Cr2 HO B12s B12a NaBHr, - Zn, NH4Cl 1'ieCH (OH) COMe Cr2+, pH = 5 V(OH)3, NaOH Zn/Hg, HC?04 H3 0+ -H30+ V(III),pH:7

2 113 HB12 B12r Pt or PtO, pH < 9.9

SCHEME 1*

Abbreviations used for ligands and complexes are explained in the Appendix. 6.

The methods of preparation of alkylcobaloximes and alkylcobalamins are classified according to whether the effective cobalt-containing reagent is formally cobalt(III), cobalt(II), cobalt(I) or a hydridocobalt species.

Preparation from Cobalt(III) Reagents.

The reaction of cobalt(III) compounds with alkylmetals was used in the earlier preparations of alkylcobalt compounds. Aryl and alkyl Grignard reagents were reacted with ralocobaloximes in ethereal solvents to form alkyl- or arylcobaloximes 10 (Equation

1). Analogous reactions were observed with other anionic alkylating agents such as lithium, sodium, aluminium, boron, and mercury alkyls.2

XCo(dmgH)2B + RMgX —p RCo(dmgH)2B + MgX2 1

Similarly, it was reported that when excess of methylmagnesium iodide reacted with dicyano-cobyrinic acid heptamethyl ester, a methyl group was placed on the cobalt and the ester side-chains were converted into tertiary hydroxy groups. Direct alkylation of the 11 cobalt atom was also observed by the use of lithium alkyls.

Cobalt(III) compounds have been reacted with other reagents than alkyl metals to form alkylcobaloximes or alkylcobalamins.

However, these methods are applicable only to the synthesis of specific alkylcobaloximes and alkylcobalamins.

Dolphin and Silverman observed that bromopyridinato-

cobaloxime and hydroxocobalamin reacted with vinyl ethers to

form alkylpyridinatocobaloximes and alkylcobalamins respectively, 12-14 (Scheme 2). The formation of a n-complex intermediate was

proposed to be followed by nucleophilic attack of the solvent to

form the alkylcobalt(III) complexes. Analogous reactions were 15 observed by other workers. CH2=CHOEt H~ 0E1 ROH C H CH(OE) BrCo(dmgH)2py ›) 2 CH2=CHOCH2CH2OH Co(dmgH)2py Cō dmgH) PY- AcOH,H2O H2CH

CH2CH(ON2 H2CH0 CH2=CHOEt C B a pH=9 12 H2O CH2=CH0(CH)20H BZ] Bz 1 2 ~+ O(CH2)20H ĪH2CH(OEt)OH H+7H>_,:+, C H Co] Bz CH2CH

S CHEME 2

The reaction seems to be very sensitive to the conditions

employed. As a result, other workers had difficulty in obtaining

the same results.16 Dolphin stated that on hydrolysis of

2,2-diethoxyethylcobalamin (1),formylmethylcobalamin (2) was

obtained. This compound was unstable below pH 9. Schrauzer

prepared formy]methylcobalamin from bromo-or chloroacetaldehyde. 17,18

3-Hydroxybutan-2-one was used as the reducing agent because of the

reactivity of haloacetaldehydes. The two compounds had different

nmr spectra, stability and rates for acid hydrolysis. The acid

hydrolysis of 2,2-diethoxyethylcobalamin, prepared from the

corresponding alkyl halide showed that only traces of compound (2)

were formed. The main products of the hydrolysis were acetaldehyde

and aquocobalamin.17 However, an intermediate in the hydrolysis was

the hemiacetal of formylmethylcobalamin. The rate of hydrolysis of this

compound was similar to the rate observed by Dolphin for what he believed

to be compound (2). Schrauzer also disputed the existence of 7-complexes

and he proposed a simple nucleophilic attack on cobalt(III) (Scheme 3).17

Pathway (b) is unlikely. Nucleophilic attack at vinyl ethers is unknown.

CH2= CHOEt -.1L114 B12CH2CHOEt Et )'B12CH2CH(0Et)2 a 1

b EtO

1312a -CH2CH(OEt)2 7 312CH2CH(0Et)2 1

SCHEME 3 9.

However, a report published recently, on the hydroxide- promoted reduction of the corrole complexes of cobalt(III) in the presence of olefin, supports the formation of a Tr-complex (Scheme

4).19 Spectroscopic evidence indicated the absence of any stable intermediate having a carbon-cobalt bond, in contrast with reactions of cobalt corrinoid complexes. Et0 III] + CH [Co 2=CHOEt tom— EtOCH(OH)CH2 + [Co III] H [Co McCO2Et

Me Et Et

[co]

Et- Me

SCHEME 4 Malononitrile and related substances also react with aquo- cobalamin20 or cobaloxime(III) ion21 (Scheme 5). It would appear that the authors assumed that it was the 'base-on' cobalamin that was formed. However, secondary alkylcobalamins are known to exist mainly in the 'base-off' form. 10.

CHICN)2 1;1i2e0OH 4c10 1PhCH2CN —.gZ PhCHCN Cō] z

+ CH2(CN)2 Co(dmgW2 P2› [CofdmgHl2] >(NCI2CHCo(dmgH)2

SCHEME 5 The authors proposed the formation of a carbanion which reacted with the cobalt(III) complex. However, they stated that the observed reaction rates were very fast which would require a fast deprotonation step, i.e., base catalysis. The mechanism of the reaction was not examined.

The reaction of the anion of 2-ethoxycarbonylacetonitrile with hydroxocobaloxime has been reported to yield l-ethoxycarbonyl-l- 22 cyanomethylcobaloxime.

Also methoxymethylpyridinatocobaloxime was prepared by the reaction of sodium methoxide on halomethylpyridinatocobaloximes.23

Although the starting cobalt-containing species is a cobalt(III) complex, the actual reactive species involved in the formation of the cobalt-carbon bond is the cobalt(I) ion (Equation 2). 11.

NaONe XCH 2Co(dmgH) zpy ---~ [Co(dmgH) z py]OCH + Ne 2X—>

McOCH2Co(dmgH)2py + X 2

Preparation from Cobalt(II) Reagents.

Both cobaloximes(II) and cobalamin(II) couple with alkyl radicals 8 24'25 to form alkylcobalt(III) complexes (Scheme 6). ' Cobaloxime(II) reacts also with alkyl halides to give alkylcobaloximes. This reaction will be discussed later. hy McCo(dmgH)zpy ; Me + Co(dmgH)zpy `B12r MeB12

2Co(dm0)2py + RMe2COOH —4 RCo(dmgH)zpy + HOCo(dmgH)zpy + Me2CO

Blzr Me9C00H >Me3CO' + 'OH Me2CO + B12a + Mē B12r> McB12

SCHEME 6

The reaction of hydroperoxides with cobalt(II) has been

employed in the synthesis of cobalt(III) complexes containing

equatorial ligands other than dimethylglyoxime.

The reaction of tributylboride with cobaloxime(II)to give

butylcobaloxime has also been mentioned2 but the reaction was not

examined further. 12,

An interesting reaction was observed when methylcobalamin and carboxymethylcobalamin were obtained from an acetate buffered solution of cobalamin(II) and vanadium(III) in the presence of limiting concentrations of oxygen.7 Oxygen radicals, generated from oxygen and the reducing metal ions (vanadium(III)), reacted with acetic acid to form alkyl radicals, which subsequently reacted with cobalamin(II) to give alkylcobalamins. Under the reaction conditions cobalamin(II) was not irreversibly oxidised or degraded even though oxygen radicals were generated. At high pH the carboxymethylcobalamin was mainly formed while methylcobalamin was the main product at low pH (Scheme 7).

= 4.75~ H20 + MeCO2H pKa McCO2 + H30+

30 pKa = 4.88, 02 + V3+ 1-1 } H02. 02 f--- 02 + V02+(aq.)

1MeCO2H jMeCO2

202 + H20 + McCO 'CH2CO2 + HO + 202

312r, H 30 l / McB12 B12r Me + CO2 B12CH2CO2H

SCHEME 7 13.

A wide range of alkyl and w-carboxyalkylcobalamins were prepared by this method. Best yields of alkylcobalamins were obtained using Fenton's reagent (Fe2+, H202) in place of molecular oxygen, while for w-carboxyalkylcobalamins, best yieldswere obtained from the electrochemical generation of the oxygen radicals. However, the yields dropped as the alkyl chain increased.

Preparation from Cobalt(I) Reagents.

The preparation of the cobalt(I) ion from cobalt(II) or

cobalt(III) has already been discussed. Both cobaloxime(I) ion 26 and cobalamin(I) ion have been described as supernucleophiles.

Their nucleophilicity (n) was defined according to Pearson as:

log (17.-- - where k and are the second order specific nTfeI - 2 ), ,,IeOH -MeOH rate constants for attack, by a nucleophile Y and methanol

respectively, on the substrate methyl iodide, at 25°C in methanolic

solution. The values calculated were 14.4 for cobalamin(I) ion and

14.3 for cobaloxime(I) ion. This property of the cobalt(I) ion

in planar ligand environments may a consequence of the shape

and antibonding energy of the 3d22 orbital, the highest occupied

orbital in these systems. Axial bases accepting charge via a

Tr-electron back donation from the cobalt atom have the effect

of reducing the cobaloxime(I) nucleophilicity, whereas strong hard

bases in the axial position increase it.

As a result of their nucleophilicity cobalamin(I) ion and

cobaloxime(I) ion react with most alkylating agents, i.e„ halides, 3'27-32 sulphates, sulphonates,phosphates.2' Methyl oxalate also

14.

reacts slowly with cobalamin(I) ion to form methylcobalamin

(Scheme 8).6

312s RX } RB12

RO Ts RB12

RCOC€ > RCOB12

(RCO) 20 ) RCOB12

McCo(dmngH) 2py), McB1 2

Me 2SO4 McB12

CH2N2 MeB 1 2

S-adenos ylmethionine > NeB12

CHE=CHBr > CH2CHB12

>HC=CB1 2 +BrCH=CHB12

HC=CH )CH2=CHB12 0 CH 2 ___2 >B12CH 2CH2OH

CH2(CH2 CH 2 i 312CH2 (CH2)1'CH2OH

CH2=CHCN i'B12C112CH2CN 15.

[Co(dmgH) 2B) `RCo(dmgH) 2B

Me2SO4 j McCo (dmgH) 2B

X(CH2)nOH HO(CH2)nCo(dmgH) 2B CH2=CHX } CH 2=CHCo(dmgH) 2B jj0 01 2CH2 )HOCH 2CH2Co(dmgH) 2B

CH2C112C112 i HOCH2CH2CH2Co(dmgH) 2B 0

CH 2 (CH 2) 2CL2 no reaction

HC-CH --21 CH2=CHCo (dmgH) 2B

PhCECH PhCH=CHCo (dmgH) 2B

Ne2NCH2Ph 1 PhCH2Co(dmgH)2B Me02CCECCO 2Me + _ Me 3NCH2PhI ) PhCH2Co (dmgH) 2B

S-adenosylmethionine McCo(dmgH)2B

CH2=CHCN )NCCH2CH2Co(dmgH)2B •

SCHEME 8

As it can be seen from Scheme 8, a wide variety of alkylcobaloximes

and alkylcobalamins can be prepared by this method.

(a) Displacement Reactions.

The reaction of cobalt(I) ion with alkyl halides or tosylates

has been used for the synthesis of most alkylcobaloximes and

alkylcobalamins. The yields fOr simple alkylcobaloximes are

often quantitative. As a result the mechanism of the reaction 16.

has been studied in detail.33 The rate of the reaction was of

first order in both the alkyl halide and the cobalt(I) ion.

Two mechanisms are possible for the reaction (Equations 3,4).

S- S- [Co(dmgH)2B]_ + RX—'r B (dmgH) 2Co... R... X--) RCo (dmgH) 2B + X_ 3

[Co(dmgH)2B] + RX-=,>X- + Co(dmgH)2B + R' RCo(dmgH)2B 4

Both a bimolecular nucleophilic displacement and an electron

transfer mechanism would show a dependence on the halogen, i.e.,

I > Br > C? . The cobalt(I) ion reactions were in general more

sensitive to the leaving group by a factor of ten compared to

a typical SN2 reaction. The authors argued that since the reaction

of pentacyanocobaltate(II) ion with alkyl halides is a hundred

times more sensitive to the nature of the leaving group34 than are

the cobalt(I) reactions then the reaction described by Equation 4

can be excluded. However, the reaction of pentacyanocobaltate(II)

ion with alkyl halides (atom abstraction) is different than that

of Equation 4 (electron transfer) and therefore cannot be compared.

In fact, an electron transfer mechanism has been observed in the

reaction of [N,N'-bis(salicylidene) ethylenediamino]-1-methylimidazole-

cobalt(II) with p —nitrobenzyl bromide.35 The ratio kI/kBr was 35 less than ten.

The nucleophilic character of the reaction was apparent from

the variation of the rates of reaction with the alkyl group of the

organic halide. The order of reactivity: PhCH2 > CH9 > CH2CH3 >

(CH2)3CH3 ' CH2CH2CH9 > CH(CH9)2 » CH2C(CH3)333 is found with 17.

the cobaloxime(I) ions, with cobalamin(I) ion and conventional nucleophiles such as methoxide ions. The rate of the reactions of cobaloxime(I) ion with different cycloalkyl halides was also

studied. Again, the relative rates, cyclopentyl ti cyclobutyl >

cyclohexyl > cyclopropyl, were consistent with a nucleophilic

substitution.33 Further evidence was provided by the calculation

of entropy of activation (-20to-30eu). Its negative value 33 indicated an increased order in the transition state.

The effect of the axial base on the reaction rates of

cobaloxime(I) ions with ethyl bromide was studied.33 The results

are shown in Table 1. They were explained by the authors on the

basis that the coordination of a strong electron donor to the

planar tetracoordinate cobalt(I) ion would increase its nucleophilicity.

The coordination of a Tr-acceptor base would decrease the nucleophilicity

of the cobalt(I) ion. The reduction of the rate in the presence

of some bases, e.g„ phosphines, isocyanides,is in agreement with

this assumption but some rate variations seem to be anomalous.

When a base is added,both four and five coordinate cobalt(I)

species are present, which may have different reactivities. The

observed rate constant is therefore dependent on the rate of

association of the fifth ligand, the relative rate coefficients

associated with the four and five coordinate species and the

concentration of added ligands in solution. TABLE 1

Base Ration K Base Ratio K o obsd c-1 (M-1 sec-1) m-1 se

None 10 4-cyanopyridine 500 5.3

water 1100 11 4-cyanopyridine 10 5.4

pyridine 500 5.9 triphenylphosphine 10 0.3

pyridine 20 7.2 triphenylarsine 10 1.3

pyridine 10 7.8 triphenylstilbene 10 1.9

pyridine 5 8.3 tributylphosphine 10 1.7

2-picoline 500 6.0 tributylphosphine 1 1.6

2-picoline 10 12 tributylphosphine 0.5 2.0

2,6-lutidine 500 4.8 dimethylsulphide 500 3.5

2,6-lutidine 10 11 dimethylsulphide 10 3.0

aniline 10 5.9 cyanide 1 11

cyclohexylamine 500 10 cyclohexylisonitrile 10 0.54 cyclohexylamine 10 8.1 a [base]: [cobaloxime] 19.

The effect of added bases was also studied in the reaction 33 of cobalamin(I) ion and cobinamide(I) ion with alkyl halides.

A slight inhibiting effect was observed in the reactivity of cobinamide(I) ion, while there was no effect observed in the cobalamin(I) ion reactions. Presumably, 5,6-dimethylbenzimidazole is not replaced by other bases. Interestingly, 5,6-dimethylbenzimidazole seems to have no effect on the nucleophilicity of cobalamin(I) ion, since both the cobinamide(I) ion and cobalamin(I) ion reacted at approximately the same rate with propyl chloride. The rate dependence on the equatorial ligand seems to be in agreement with the nucleophilicity of the different cobalt(I) complexes33 i.e., [Co(salen)] > [Co(dmgH)2] > [Co(c-hgH)2] > [Co(c-pgH)2] >

[Co(dpgH)2] > [Co(dotnH)].

The nature of the alkyl group is limited by steric effects.

Cobalamin(I) reacts with secondary alkyl halides but the products are unstable under the reaction conditions33 Surprisingly, the reactions of cobalamin(I) ion with alkylating agents are not subject to greater steric hindrance than those of cobaloxime(I) ion. The relative rates of reactions of cobalt(I) nucleophiles of both cobalamin(I) ion and cobaloxime(I) ion with secondary alkyl halides were quite similar. This indicates that the maximum of the potential energy profile for the S112 transition state is largely dominated by contributions due to bond breaking. Steric effects of the corrin ligand evidently become important only after the passage of the energy maximum. Secondary alkylcobaloximes are usually stable under the reaction conditions. Tertiary alkylcobaloximes are generally unstable and only three examples have so far been isolated. In each case, (3-elimination of hydrogen was inhibited. 20.

Milder conditions are obtained if the cobalt(I) ion is prepared by the disproportionation of cobalt(II) in base. The preparation of cobalt(I) ion by the elimination of acrylonitrile from a-cyanoethylpyridinatocobaloxime was also reported to have some advantages.

Also the micelle effect on the reaction rate was examined.

The reaction was catalysed by cetyltrimethylammonium bromide micelles. However, anionic micelles, such as lauryl sulphate inhibited or did not have any effect on the rate.36

Finally, the stereochemistry of the reaction was examined using 2- or 4-substituted cyclohexylpyridinatocobaloximes(Scheme 9)37 and 1,2-dideuterio -4,4-dimethylbutylpyridinatocobaloxime (Scheme 10).3839 '

The observed inversion of configuration in both cases confirmed the

SN2 character of the reaction (Equation 3).

The nmr spectra of 2- and 4-substituted cyclohexylpyridinatocobaloximes showed no temperature dependence indicating that the pyridinatocobaloxime group always occupies the equatorial position.

This is not surprising considering its bulkiness. The magnitude of the coupling constants of the hydrogens on carbons2-and 4-in compounds

(3), (4) and (5), (6) respectively defines their conformation and thereforethe stereochemistry of compounds (3), (4), (5) and (6).

Similarly, 1,2-dideuterio-4,4-dimethylbutylpyridinatocobaloxime

(7) was prepared from threo-1,2-dideuterio-4,4-dimethylbutyl-p- toluenesulphonate or trifluorometh:anesulphonate. 39 The observed coupling constant of the product (A,2 = 13.2 Hz), confirmed that the reaction takes place with inversion of configuration. 21.

Co(dmgH)2py McOH [co(dmgH)2pyr 25°C H ~~ OH 3

r Co(dmgH)2py .H McOH_ [CoCcimgH)2pyr H 25°C OMe •.OMe

H [Co(dmgH)2py] X McOH _ ( Co(dmgH)2py 0°C H~

H [Co(dmgH)2pyr Y ~ {o(dmgH)2PY 0°C H~

a. X= Br, Y=Br b.X =OTs,Y=OH

SCHEME 9 22.

CMe3 H1 [Co(dmgH)2pyf

OR Co(dmgH)zPY

threo erythro . R =p-BrC6H4S02 7 R = CF3S02

SCHEME 10 In the reaction with allylic halides, both SN2 and SN2' 4041 mechanisms occurred. However, unlike the reactions of the

same halides with conventional nucleophiles, the preference of

the cobalt(I) nucleophile for primary carbon seemed to be

sufficiently pronounced, that only one of the two possible isomers

was usually obtained from both a-and y-substituted allyl halides

(Scheme 11). This discrimination of the cobalt(I) ion for the

primary or unhindered unsaturated carbon atom was shown strongly

in the displacement of pyridinatocobaloxime(I) ion by bis(cyclo-

hexanedionedioximato)pyridinecobalt(I) ion from y-methylallyl-

pyridinatocobaloxime. The reaction took place exclusively by 41 an SN2 mechanism. 23.

CHCH Cl + [ Co (dmgH) py ]- MICH= 2 2 S__2 NeCH=CHCH2Co (dmgH) 2py

NeCHC€CH=CH2 + [Co(dmgH)2py]-

Me C=CHCH Ct + [Co(dmgH)2py] 2 2 S_.2 Me 2C=CHCH 2Co (dmgH) 2py

Me2CtCCH=CH2 + [Co(dmgH)2py] N

MICH=CHCH2Co (dmgH) 2py + [Co (c hgH) 2py] MICH=CHCH2Co (c-hgH) 2py +

[ Co (dmgH) 2py ]

SCHEME 11

Alk-2-yn-1-yl halides reacted with the cobalt(I) ion under the usual basic conditions to give the 1-allenylcobaloximes (SN2v).40,41 However, when the reaction was performed under carefully controlled conditions (low temperature-pH ti 7),only the

SN2 reaction was observed in some cases.41 Presumably, the alk-2- yn-l-ylcobaloxime was formed initially, if there was no steric hindrance, and then under basic conditions and prolonged reaction time the unreacted cobalt(I) ion reacted with the alk-2-yn-1-ylcobaloxime at the 3-carbon (Scheme 12).

pH 'L 10 HC=CCH 2Ce + [ Co (dmgH) 2py ] HZC=C=CHCo (dmg)H 2py

HC-CCH2Ci + (Co(dmgH)2PY] lowptemperature HC=CCH2Co(dmgH)2py

ti 9 HC=CCH 2Co (dmgH) 2 p + [ Co (dmgH) 2py] pH y HZC=C=CHCo (dmgH) 2p37

CH2 (CH 2 ) 4C(Cf) C-CH + [Co (dmgH) 2py] —)&H 2 (CH2) J=C=CHCo (dmgH)2py

McCECCH 2Cf + [ Co (dmgH) 2py ] --mai MeC=CCH2Co (dmgH) 2py

SCHEME 12 24.

When alk-2-yn-1-yl halide was mixed with pyridinatocobaloxime(II) in non-polar solvents no reaction occurred. This observation makes an electron transfer mechanism in neutral medium unlikely.

Allenyl halides were also reported to react with the cobalt(I) 40 '4I ion by both the SN2 and SN2' mechanisms (Scheme 13).

H2C=C=CHBr + [ Co (dmgH) 2py] --4 HC-CCH2Co (dmgH) 2py + H2C=C=CHCo (dmgH)2 py

1 1 [Co(dmgH) 2py] + C€CH=C=CR1R2--> py(dmgH)2 CoCH=C=CR1R2

SCHEME 13

Alkenyl halides reacted with both pyridinatocobaloxime(I) ion and cobalamin(I) ion to form alkenylcobalt(III) compounds, usually 42-44 with retention of configuration. Exceptions to this generalisation have been found.45 The products from p-chlorostyrenes showed some isomerisation but that is probably a result of a radical reaction during the extended time required for the reaction, Two pathways are possible. Hydrogen halide could be eliminated, followed by addition of the cobalt(I) ion to the triple bond. Alternatively, the cobalt(I) ion could add to the double bond and the elimination of a halide ion could follow. The elimination-addition mechanism seems improbable since a mixture of a- and 0-cobaloximes would be expected with 2-halostyrenes undernuidlybasic conditions.42 The addition of cobalt(I) ion to the triple bond was shown to be trans.43 Finally,

25.

the reaction was conducted in deuteriated solvent and sodium borodeuteriide was used to prepare the anion from chloropyridinatocobaloxime. There was no exchange of the a-hydrogen which would be expected if phenylacetylene was an intermediate.43 Therefore, the addition of the nucleophile followed by elimination is more probable. The order of reactivityfor different 2-halostyrenēs was: I >. Br » Cl > F.42 The alkenyl fluorides were rather unreactive. This order of reactivity was the opposite to that observed generally for the reactions of nucleophiles with 2-halo - < 46,47 styrenes, i.e., Br < Cl < F, This indicates that with pyridinatocobaloxime(I) ion as the nucleophile the cleavage of the carbon-halogen bond is involved in the rate determining step.

An initial coordination of the anion to the olefin cannot be ruled out. However, intermediates of open-structure' such as (8a, b)

(Scheme 14) cannot be present. Nu

8a 11,

8b SCHEME 14

26.

The reaction has been used extensively for the preparation

of model compounds in studies of the reactions of the coenzyme B12

in nature. The actual coenzyme and some of its analogues have 6,48,49 also been prepared by this method (Scheme 15).

N HO HO 2,.6125. z.H30+ NAN

Me CH2 ~ M 0

p 0 [cocImgH)2p (CH2)4 (CH ) (C"~Z 24 HON= =NOH HON= ^NOH Me Me

SCHEME 15 The reaction between cobalamin(I) ion and cyclodecyl halide was 50 shown to take place via an electron transfer mechanism (Scheme 16). 27.

+512r -->

SCHEME 16 Cyclodecyl toluenesulphonate did not react with cobalamin(I) ion indicating that an SN2 mechanism was not operative. 1-Deuterio-

1-iodocyclodecane reacted with cobalamin(I) ion and the alkylcobalamin formed reacted with bromine. Scrambling of the deuterium was observed in bromocyclodecane in accord with a radical intermediate.

Experiments showed that part of the scrambling took place in the actual formation of the alkylcobalamin. Similarly, the reaction of cobalamin(I) ion with the bromoester (9) probably involved an electron transfer mechanism since the sulphonate (10) did not 51 react with cobalamin(I) ion (Scheme 17),

CO2Et CO2Et B12s + COSEt COSEt Br B12 9 CO2Et B12s + COSEt OTs B12 10

SCHEME 17 28.

11 N „:~ 11 H FI H Br [co(cimqH)2py] [Co(dmgH)2py]

d H H Fi 12+ Co(dmgH)2py 12 HH Co(dmgH)2py

Br Co(dmgH)2py

,g;1 + [codmgH 2pI --*

+[Co(dmg1-02PYT Co(dmgH)2py

3■2Br+[Co(dmg1-1)2pI--> Co(dmgH)2py g:IBr Co(dmgH)2py 4C0(dmgH) PYT

Ph A43r+ [Co(dmgH)2PY] --~ Ph Me Ph! e Ph/ Co(dmgH)2py

SCHEME 18 29.

A number of alkylcobaloximes have been prepared, where an 5-54 electron transfer mechanism cannot be ruled out (Scheme 18).

An electron transfer mechanism was proposed for the preparation of compound (12).52 The observed retention of configuration was expected because of the shielding by the dihydrophenanthrene moiety. A similar type of substitution cannot take place in the endo-bromide (11) due to steric hindrance.

1-Adamantyl bromide and 1 -norIornyl bromide reacted with pyridinatocobaloxime(I) ion at approximately the same rate.

Usually, the reactivities of the two bromides differ by a factor 53 of 1010 for SN1 reactions and by a factor of 103 for radical processes.

In the light of this evidence the authors ruled out the possibility of an electron transfer mechanism. Similarly, the authors discounted an electron transfer mechanism for the preparation of 1-methyl-2,2- diphenylcyclopropylpyridinatocobaloxime because 1-methyl-2,2-diphenyl- 54 cyclopropyl bromide did not react with pyridinatocobaloxime(II).

However, this is not proof against an electron transfer mechanism and further investigation is required, A report was published recently where evidence was given that at least in certain cases the reaction of pyridinatocobaloxime(I) ion with alkyl bromides or iodides 55 occurs via an electron transfer mechanism (Scheme 19),

CpldmgH)2py R~~ ~ R2 X R Co(dmgH) 2py R 13 14 30.

Product R1 R2 X (13) (14)

H H OTs 100 0

H H Br 71 29

H H I 35 65

Ph H I 0 100

SCHEME 19

An interesting reaction was observed in a study of the possible cobalt-alkyl species produced in the biological reactions of DDT 56,57 (Scheme 20). 1-Chloro-2-di-(g-chlorophenyl)ethylenylpyridinato - cobaloxime was produced by elimination of hydrogen chloride from the first formed product of SN2 attack by cobalt(I) ion. A similar reaction was observed with 1,1,2,3-tetrabromopropane in methanol

(Scheme 20).58

(L-CIC6H4") 2CHCCC3 + [Co(dmgH) 2py] --->(L -C?C6H4)2 C=CC?Co(dmgH) 2PY

McOH [Co(dmgH)2py] + CHBr2CHBrCH2Br McOCH2CH=CHCo(dmgH)2py

SCHEME 20 31.

b) Reactions with Olefins and Acetylenes.

As shown in Scheme 8, both cobalamin(I) ion6 and pyridinatocobaloxime(I) ion2'3 reacted with olefins and acetylenes to form organocobalt(III) complexes. Cobalamin(I) ion reacted with acetylenic compounds provided that only a small group (H, Me) was on the

carbon that would subsequently be linked to the cobalt.6 Ethylenic

compounds were only reactive if the group was terminal and

activated by an adjacent electron withdrawing group.6

Pyridinatocobaloxime(I) ion was also only found to react with

olefins that were activated by an electron withdrawing group.2,3 The products were sometimes unstable under the reaction conditions. Only

with}iighly reactive olefins was reduction of the organocobalt products

negligible (Equation 5). R-Elimination to form the starting olefin

or reductive cleavage of the cobalt-carbon bond to form the substituted

alkane were the main side reactions . The sensitivity of the

reaction to both electronic and steric effects is illustrated in the

examples given in Equations 6 - 9.

H2O RCo(dmgH)2py + [Co(dmgH)2py] > 2Co(dmgH)2py + RH + HO 5

CH2==CHCN + [Co(dmgH) 2py]- -=> NCCH2CH2Co(dmgH) 2py 6

CH 2=C (Me) CN + [ Co (dmgH) 2py ] /` > "7

MICH=CHCN + 2[ Co (dmgH) 2PY] -0> McCH2CH 2CN + 2 Co (dmgH) 2py + HO 8

CH2= C(Me)CO2Me + [Co(dmgH)2py]-- py(dmgH)2CoCH2CH(Me)CO2Me + Me2CHCO2Me

very low yield 9 32.

It was shown that,initially, a Tr-complex was formed between the

double bond and the cobalt(I) ion.59 At high pH where the

alkylcobaloximes could not be formed, a red complex was observed

which was unstable. On addition of excess of pyridine the pyridinato-

cobaloxime(I) ion was reformed. Also, when an alkyl halide was 59 added the corresponding alkylcobaloxime was formed (Scheme 21).

RX CH2=CHCO2Me + [ Co (dmgH) Zpy ] ' CHZ T CHCO2Me ---=-~ R Co (dmgH) Zpy +

[Co(dmgH)2py] CH2=CHCO2Me

1,PY CH2=CHCO2Me + [Co(dmgH) Zpy]

SCHEME 21

The rates of alkylation of these complexes were significantly

diminished as compared to those of the free pyridinatocobaloxime(I)

ion and became very slow in the presence of excess of olefinic

ligand. This indicates that the n-complexes themselves are not

reactive and that the alkylation occurs only via the equilibrium

amounts of the free cobalt(I) ion present. In contrast to the

behaviour of the free cobalt(I) ion,the rates of alkylation of the

7-complexes were found to increase with decreasing nucleophilicity of

the cobalt(I) ions. This is probably because the less nucleophilic

cobalt(I) complexes form the less stable Ti-complexes, The inability

of triphenylphosphinatocobaloxime(I) ion to form a 7i-complex confirms

this assumption. 33.

59 A similar 7r-complex was observed with cobalamin(I) ion.

However, such compounds were formed only on addition of an excess of strong ii-complexing agents such as fumaronitrile. The existence of an equilibrium was indicated by the dimunition. in the rate of alkylation of cobalamin(I) ion in the presence of acrylonitrile and fumaronitrile.59 A a-donor, Tr-acceptor bonding model was proposed by the authors. The a-donor interaction is restricted to the ligand and the 4s, 4pz metal orbitals. The

3d 2 orbital is filled and therefore could not interact. The z d orbital is involved in the ir-backbonding. xz The cobalt(I) ion is usually added at the position of normal nucleophilic attack.2'3 However, some exceptions to this generalisation 60-63 have been found with both olefins and some epoxides (Scheme 22). PhCH(OH)C5 2ColdmgH)2py

h+ [Co] \ h H00H2CH(PFJCo(dmgH)Zpy PhCH=CH2 + [Co] ---> PhCH(Me)Co(dmgH)2py CH2=C(Me)CN+ Me2C(CN)Co(dmgM2py [cof o(dmgH)2py

OH [Cor H H Co(dmgH)2py [Co] _ [codmgH 2pyf

SCHEME 22 34.

1-Phenyl-2-hydroxyethylpyridinatocobaloxime was initially

reported to be the isomer (15)64 but the assignment was later 60,61 reversed, 1-Cyano-l-methylethylpyridinatocobaloxime was

prepared under both neutral and basic conditions.62 However,

mild conditions are necessary since some workers were unable to

obtain the product in alkaline medium.3

As described above, the cobalt(I) ion adds to both substituted

and unsubstituted acetylenes.3'6 In the addition reactions of the

cobalt(I) ion to substituted acetylenes both the a- and 5-isomers were observed, or even mixtures of both (Scheme 23).

c PhCECH + [ Co (dmgH) 2py] ---~ PhCH=CHCo (dmgH) 2py

c HC-CCO2R + [Co(dmgH)2py] -)- R02CCH CHCo(dmgH)2py

c HC-CCH2OH + [Co(dmgH)2py] ---) Py(dmgH)2CoCH=CHCH2OH +

CH2=C (CH2OH) Co (dmgH) 2py

HC-CCH, + [ Co (dmgH) 2py ] -> CH2=C(Me) Co (dmgH) 2py

CF3-C=CH + [ Co (dmgH) 2py ] , > py(dmgH) 2CoCH=CHCF3

SCHEME 23 35.

c) Reactions of Hydridocobalt Species.

The preparations of both hydridocobalamin and hydridopyridinatocobaloxime have been described. Initially, it was thought that all the reactions of cobalamin(I) ion involved the hydridocobalamin.29 This confusion arose from the reactions with diazomethane and olefins. Subsequently, the cobalamin(I) ion was established as the reactive species for the preparation of alkylcobalamins in alkaline medium.65 The existence of hydridocobalamin itself was disputed until Schrauzer reported a preparation which involved the reduction of aquocobalamin with zinc in acetic acid.9 The presence of excess of zinc in the reaction mixture was necessary for the existence of hydridocobalamin. In the absence of zinc it is unstable and decomposes easily to hydrogen and cobalamin(II).

Noble metal compounds (platinum oxide, palladium(II) acetate) catalyse its decomposition to cobalamin(II) even at pH ti 9.9.

Hydridopyridinatocobaloxime is usually prepared from hydrogen and the cobalt(II) complex.66 The mechanism of the hydrogenation of pyridinatocobaloximehas been studied (Scheme 24).66 The presence of base accelerated its formation. 67,68

Co(dmgH)2 py + HOT— ' [Co(dmgH) (dmg)py] + H2O H?a [H2Co(dmgH) (dmg)py]

[ Co (dmgH) (dmg) py ] > 2 [ HCo (dmgH) (dmg) py ] OH 2 [Co (dmgH) (dmg) py ] 2 + 2H20 slow

Co(dmgH)2 H2 + Co(dmgH) 2 t-- H2C0(dmgH)2 ` 2HCo(dmgH)2

SCHEME 24 36.

Hydridopyridinatocobaloxime is also unstable. It decomposes with heat or in the presence of air. When strong Tr-acceptor axial ligands are present the complex is more stable. Hydridotributylphosphinato- cobaloxime has been characterised.69 It is stable under nitrogen.

It is soluble in non-polar solvents indicating the covalent

character of the cobalt-hydrogen bond. In non-polar solvents such

as hexane, it is unreactive towards olefins. In aqueous methanol it 69 reacts with substituted olefins to form a-substituted alkylcobaloximes.

Again, hydridocobaloximes add to double bonds cnly if there is an 3'62 electron-withdrawing group present (Scheme 25). The only

exception is the addition of hydridocobaloxime to propene to form

isopropylpyridinatocobaloxime.3 Addition to epoxides has also

been observed (Scheme 25).64

0 HCo(dmgH) 2py + CH2 CH2-3 HOCH2CH2Co(dmgH)2py

HCo (dmgH) 2py + CH2=CHCH20H-4 HOCH2CH2CH2Co (dmgH) 2py

HCo(dmgH)2py + CH2=CHMe —>Me2CH2 + Me2CHCo(dmgH)2py

HCo(dmgH)2py + CH2=C(Me) CN----) Ne2C (CN) Co (dmgH) 2py

HCo(dmgH) 2py + EtO2CCHI= CHCOZEt-- ) EtO2CCH=CHCO2Et + Et02CCH2CH2CO2Et

SCHEME 25 37.

As shown in Scheme 25, the alkylcobaloximes formed under these conditions can be hydrogenated further to give the saturated compound. Both the electronic and steric effects involved in the 62 formation and cleavage of alkylcobaloximes have been studied.

Electron withdrawing substituents accelerate both the formation and the reductive cleavage of the alkylcobaloximes. Steric compression prevents the formation of alkylcobaloximes and accelerates their cleavage. Generally, it was observed that the electronic effects outweighed the steric factor. This is illustrated by the relative rate of hydrogenation of some alkylcobaloximes, i.e., Me2C(CN)Co(dmgH)2 py >

McCH(CO2Me)Co(dmgH)2py > NeCH(CN)Co(dmgH)2 py > PhCHMeCo(dmgl)2 py. 70 The hydrogenation of unsaturated esters was studied in detail.

Using deuteriated solvents or deuteriopyridinatocobaloxime it was shown that the a-alkylcobaloxime is initially formed. The alkylcobaloxime is cleaved reductively to form a carbanion which is protonated by the solvent, as summarised in Scheme 26.

Hydridopyridinatocobaloxime adds also to acetylenes. Its existence in this reaction has been confirmed by cleaving 2,2-dideuterio-

2-hydroxy-l-phenylethylpyridinatocobaloxime in the presence of phenylacetylene, S-Deuterio -a-styrylcobaloxime was formed. The stereochemistry of the addition to phenylacetylene has been studied and shown 61 to be cis (Scheme 27).

However, this is not general. Trans addition was observed when 61 other substituents than phenyl were present, (Scheme 28).

38.

HCo(dmgH)2py + R1R2C=CR3CO2Me . R1R2CHCR3(CO2Me)Co(dmgH)2py

f Co(dmgH 2py)2

R~R2CHCR3CO2Me ~H3 ~R R ~tHCHR3COZMe HZO

SCHEME 26

Ph H Ph H

C€Co(dmgH) 2py + NaBD4 + PhCECH 11-eL34. 1 / + ` I I / py(dmgH) 2Co D py(dmgH) 2 Co H 45% 55%

Ph H Ph H MeO Co(dmgH) 2py + D2 + PhCECH

py(dmgH) 2 Co D py(dmgH) 2 Co H 90% 10%

SCHEME 27 R H HCo(dmgH) 2B + R10ECR —> B(dmgH) 2Co R1

R = H R1 = CO2Me B = pyridine Me CO 2Et aniline CO2Me CO 2Me pyridine H CF3 pyridine

SCHEME 28 39.

Although with 1-substituted olefins, it is the 1,2- disubstituted

isomer that is usually formed, no such generalisations can be made with 42 the acetylenes (Scheme 29).

PhC-CH + HCo(dmgH) Z py --) H2C=CPhCo(dmgH) 2py

HC=CCH2OH + HCo(dmgH) 2py —) CH2=C(CH2OH)Co(dmgH)2py + HOCH2CH=CHCo- (dmgH)2Py MeC-CH + HCo (dmgH) Zpy ---) CH 2=C (CH3) Co (dmgH) Zpy

RO2CCECH + HCo(dmgH) 2py ---) R02CCH=CHCo(dmgH) 2py

F,CC-CH + HCo(dmgH) 2PY —) CF3CH=CHCo(dmgH) 2py

SCHEME 29

'72 Hydridocobalamin is more reactive than hydridocobaloxime,9'71

and reacts with unactivated olefins, alkyl halides, acid halides

and acetylenes (Scheme 30).43

HB12 MeI McB12

HC-CH CH2=CHB12

McCOCI • McCOB12

cyclohexene >CH2(CH2)4CHB1 2

CH2=CH2 )MeCH2B12

CH2=CHMey , „n In

SCHEME 30 40.

A wide variety of both primary and secondary alkylcobalamins, previously inaccessible were subsequently prepared. The secondary alkylcobalamins were mostly in the'base-off'form. 41.

CHAPTER 2

DEALKYLATION REACTIONS OF ALKYLCOBALOXIMES AND ALKYLCOBALAMINS BY

METAL SPECIES

Electrophilic Cleavage

Mercury(II), thallium(III), and palladium(IV) salts are known to dealkylate alkylcobalamins and alkylcobaloximes by electrophilic attack of the metal species at the carbon-cobalt bond. The products observed in each case were an alkylmetal complex, together with an aquocobalt(III) complex.

The reaction of mercury with organocobalt complexes has been studied extensively because methylcobalamin is believed to be responsible for the formation of methylmercury(II) ion (a neurotoxin), 73,74 in nature.

(a) Mercury(II)

In 1964, it was reported that methylpentacyanocobaltate(III) ion reacted with mercury(II) chloride to give methylmercury(II) chloride.75 76 More recently, a similar reaction was observed with alkylcobaloximes 77,78 and the mechanism was studied in detail by two different groups.

Kinetic studies indicated that the reaction was of first order in both

the mercury(II) salt and the alkylcobaloxime. The rate of the reaction decreased as the pH was decreased. Two different reactions were observed in acidic media [high pH could not be employed because mercury(II) oxide was deposited] as shown in Equations 10 and 11, from which the rate Equation 12 can be derived, 42.

K RCo(dmgH)20H2 + H30+ ~_~ [RCo(dmgH2) (dmgH)0H2]+ + H20 10

k1 RCo(dmgH) 20H2 + Hg2+ > [Co(dmgH) 2(0H2) 2]+ + RHg 11 H20

- k2[Hg2+][RC0(dMgH)20H2]; k2 = k1 12 d[dtR] + 1 + K [H ] A

It should be noted, that the protonated cobaloxime and the boron difluoride derivative of the alkylcobaloxime (16), were both shown to be unreactive towards mercury(II). In both cases, the cobalt- carbon bond would be expected to be poorer in electron density compared to alkylcobaloximes.77

.Me

Co • • •

• • •

~ OH2

16 43.

The rates of the reaction were calculated under pseudo first order conditions, i.e., where a large excess of mercury(II) salt was employed, and the rate constant, kl, was calculated for different cobaloximes.

The observed order of reactivity, CH3 > CH2CH3 % CH2CH2CH3 > 76-78 CH 2CH 2CH(CH3) 2 > CH 2CH (CH3) 2 > CH 2C (CH3) 3 > CH(CH3)21 indicates that a-substitu ents and to a lesser extent R-substituents inhibit the reaction. Secondary alkylcobaloximes were found to react very slowly.

Kinetic studies on the rates of reactions of aryl- and benzylcobaloximes revealed that arylcobaloximes.reactedfaster than alkylcobaloximes, whereas the analogous benzylcobaloximes were of comparable reactivity to the alkylcobaloximes. The nature of the p—substituent in the case of the arylcobaloximes had a marked effect on the reaction rate, as indicated by the Hammett p value (-6.3). This is close to the value reported79 for the reaction of mercury(II) iodide with diarylmercury(II) (Equation 13). The high value (p = -5.9), for this was interpreted in terms of the weak electrophilicity of mercury(II).

(P-ZC6H4) 2Hg + Hg_ .°2-4 2 p-ZC6H4HgI 13

In contrast, the reactions of R-substituted benzylcobaloximes were found to be less sensitive to the nature of the p-substituent as reflected by a p value of =1,2, This is close to that found for the exchange reaction of n-substituted benzylmercury(II) bromide with mercury(II) bromide (p % -1.0).80 It should be noted however, that the reactivity sequence for the reactions of the alkylcobaloximes with 44.

mercury(II) [i.e., CH3 > CH 2CH3 > CH 2CH 2CH3 » CH(CH3)2] differs from that for Equation 13 [i.e., CH3 < CH 2CH3 ti CH 2CH 2CH3 ti CH(CH3)2].

The significance of this difference is unclear.

From the electronic and steric effects described above, it can be inferred that these reactions go via an SE2 mechanism.

Generally, it has been found that mercury(II) electrophilic substitutions take place with retention of configuration. Adin and 77 Espenson tentatively suggested that mercury(II) should therefore, attack from the same side of the a-carbon as the cobalt atom.

Later studies showed, however, that the reaction takes place with inversion of configuration. 81,82,83

Initial studies were carried out on 2- and 4-substituted 81'82 cyclohexylcobaloximes. As reported earlier, secondary alkylcobaloximes react very slowly, so the authors had to employ drastic conditions, which caused side reactions such as elimination to take place. Consequently, the preliminary (erroneous) findings were 82 misleading.81 A correction was published (Scheme 31).

The organomercurials, so formed in the reaction, were then converted to the corresponding bromides using bromine in pyridine. 83 This transformation is known to go with retention of configuration,

so it follows, that, by comparison with authentic samples of the alkyl

bromides, the configuration of the intermediate mercurials could

be established. 45.

Both cis-2-methoxycyclohexylpyridinato cobaloxime (17) and trans-2-hydroxycyclohexylpyridinatocobaloxime (20) can undergo thermal elimination to give cyclohexene. Nercuration of cyclohexene in ethanol or methanol can give rise to trans-2-ethoxy- cyclohexylmercury(II) chloride (19) and trans-2-methoxycyclohexyl- mercury(II) chloride (18) respectively.

Trans-4-t-butylcyclohexylpyridinatocobaloxime (21) gave, after bromination , a mixture of both cis and trans bromides in a ratio of 3:2. It was claimed, however, by these workers that cis-4-t-hutylcyclohexylmercury(II) chloride was the only intermediate present. This suggestion could not be completely substantiated because the intermediate organomercurial was converted back to alkylcobaloxime (21) when sodium chloride was added to the reaction mixture. Hence, only small quantities of the intermediates could be isolated, which led to difficulties in their characterisation.

The fact that a mixture of bromides was obtained was attributed to the bromination. The bromination of an authentic sample of cis-4-t-butylcyclohexylmercury(II) chloride to confirm this suggestion was not attemtped. Only cis-4-t-butylcyclohexylpyridinatocobaloxime (22) gave one product, indicating that the reaction takes place with inversion of configuration. However, again, only the final bromide was characterised and not the intermediate organomercurial. The above results show that 2- and 4-substituted cyclohexylcobaloximes are not the ideal systems to study the stereochemistry of the reaction. 46.

Co(dmgH)2py 1.Hg(OAc)2,EtOH,A gCl ~HgCI OMe 2.NaCl ' + .0Me v`*.-0Et 17 18 19 jBr2ipy Br ,'Br + .-0Me v OEt ratio: 3 2 r-yCoCcimgli2pY 1. Hg (OAd2, Me0H HgCI 2.NaCl •OH OMe 20 18 CMe3 CMe3 CMe3

1. Hg(NO3)2,Et0H, A~ 2.NaCL3.Br2,py

Co(dmgH)2py Br

21 ratio: 2 3

Mea

1.Hg(NO3)2,Me0H 2. NaCl, 3.Br2,py o((dmdmg H)2py 22

SCHEME 31 47.

A more elegant approach towards the elucidation of the

stereochemical course of the reaction was conducted on 1,2-dideuterio-

3, 3-dimethylbutylpyridinatocobaloxime (23) (Scheme 32).38

CMe3 CMe3 H1 [co(dmg H)2py] ,

OR Co(dmgH)2py erythro 1.R=H 23 2.R=D-02SC6H4Br 1.Hg2+

SCHEME 32 48.

The coupling constants between the vicinal hydrogens H1 and

H2 are different for the threo (5-7 Hz) and the erythro (11-14 Hz) diastereoisomers. Alkylcobaloxime (23) was expected to be in the erythro form since the formation of alkylcobaloximes from the cobalt(I) ion is known to proceed with inversion. In agreement with this observation, it was found in this case that the coupling constant J was 13.2 Hz. The coupling constant for 1 , 2 1,2-dideuterio-3,3-dimethylbutylmercury(II) chloride (24) was

5.3 Hz showing that the reaction proceeds with inversion of configuration.

This exceptional reaction for mercury(II) may be due to the presence of the macrocyclic ligand of the cobaloxime which prevents a sufficiently close approach to the alkyl group.

An 'open' SE2 reaction was therefore proposed, the transition state of which is shown in Scheme 33. Hg2+

0:1-1 - 0 Me N ,N Me \C~ / \C

Me N 8 NAMe

SCHEME 33 49.

The stereochemistry of the reaction of several unsaturated alkylcobaloximes, such as 1-octenyl and (i-styrylcobaloximes, 42,84-86 with mercury(II) salts, has also been studied. It was found that 3-styrylcobaloxime (either the cis or the trans isomer) reacted with retention of configuration in acetic acid and

DMF,42,85 A mixture of products was obtained when impure solvents were used.*84 Interestingly, when a-styrylcobaloxime was mixed with mercury(II) acetate, only mercury(0) was deposited, indicating 42 that it reacted as an oxidant and not as an electrophile.

However, in the case of octenylcobaloximes, a mixture of products was obtained which varied with the solvent (Table 2).85

TABLE 2

Cobaloxime Solvent cis % trans

DMF 74 24

C6H1s Co (dmgH) 2p y AcOH 35 65

37 C6H13 H DMF 63 t\ H Co(dmgH)2py AcOH 31 69

* Impurities in solvent may initiate a radical reaction. 50.

A mechanism was postulated (Scheme 34).

H H 2+ 1 / Hg2+ ,H. J:15, :H a-~ H -- --H R/ 25 R CC°lL' J R ÌicO 1 R=C6H13 bAcO- R=Ph J- 1 R Hg+ + + [Col H H y H Co H Hg R \---/ + [Cor+ Ac0— r Ac H R H [Co] = Co(dmgH)2py

SCHEME 34

Attack of acetate ion* on intermediate (25) is more likely for

R = C6H13 and in acetic acid, so a considerable amount of inversion

is observed. On the contrary, stabilisation of the positive charge by

the adjacent phenyl group would make pathway (a) (Scheme 34) the more

favoured process.

The reaction of other cobalt complexes with mercury(II) salts also

exhibits an SE2 type mechanism.87'88 In agreement with this, the order

of reactivity observed for different chelates is: McCo(salphen)0H2>

MeCo(salen)0H2 > McCo(Me2salen)0H2 > McCo(dmgH)20H2 > McCo(dotnH)0H2.

* Mercury(II) acetate was used for the reactions.

51.

Similar to this reaction is the reaction of alkylcobinamides

with mercury(II) salts.89 These reactions can also be considered

as electrophilic substitution reactions. The rate of reaction for

different cobinamides is largely dependent on the substitution of

the a-carbon. The order of reactivity was found to be:

CH3 > CH(CH3)2 > CH2CH3 ti CH2CH2CH3. The isopropylcobinamide would

appear to be very labile. This may be due to steric compression

between the secondary alkyl ligand and the corrin ring which would

lead to a weakening of the cobalt-carbon bond.

The reaction of the alkylcobalamins, and particularly of methyl-

cobalamin is more complicated. Contradictory reports about the 73,90,91 76,92,93,94 products and the mechanism of the reaction have

been published. The reason for this is that the mercury(II) ion

complexes with 5,6-dimethylbenzimidazole to form a 'base-off' complex

(11) which reacts very slowly with mercury(II) at the alkyl group.

Most of the higher alkylcobalamins form the 'base-off' complex

easily and react by two different pathways (Scheme 35), from which

the rate Equation 14 Can be derived.92

R R I _i -_ Co]H g(OAd2 ` Co]A + 2 c0^ 1:13z k~ 1 2+ 26 Bz-H9 a H2O b3 H20 k2 Hg(OAc 2 RHg++ 2Ac0-+ B12a RHg + HgOAc++ Ac0-+ B12a

SCHEME 35 52.

R = k3[Hg(OAc)2][RB12] + k2[Hg(0Ac)2][RB12-Hg2+] =

= T [k3[Hg(0Ac) 2] 1 + k2[Hg(0Ac) 2](1- 131 2 K1[Hg(0Ac)2] + 1 K1[Hg(0Ac)2] + 1)]

total concentration of cobalamin TB12 =

K1 = ratio k1/k-1 14

Methylcobalamin forms the 'base-off' complex with more difficulty because the base is more tightly bound to cobalt.

The extent to which it is formed depends very much on the mercury(II) salt used, i.e., on the dissociation constant,and on the medium of the reaction (pH, ionic strength, anions present). Hence, methylcobalamin reacts faster than alkylcobaloximes and alkylcobinamides because it is the 'base-on' complex that reacts more rapidly with the mercury(II) salt (trans-effect). It is faster than the higher alkylcobalamins because of the steric, as well as the trans-effect. The order of reactivity is: CH3 > CH2CH3 > CH2CH2CH3.

The reactions can be classified into two categories depending on the mercury(II) salt.

1, Reactions with mercury salts that dissociate entirely to give the

mercury(II) ion (e,g., mercury(II) nitrate).

2. Reactions with mercury salts where the mercury-ligand bond is

very strong and dissociation occurs to a very small extent

(e,g•, mercury(II) chloride) . 53.

The mercury(II) ion (Hg2+) has been shown to be the main species that complexes with methylcobalamin. So when methylcobalamin reacts with mercury(II) nitrate in water a yellow 'base-off' complex (26), is formed. The ratio of the two complexes 'base-on' and 'base-off' depends on the concentration of mercury(II) nitrate.

At high concentrations the methylcobalamin is mainly in the

'base-off' form and the reaction takes place mainly via pathway (a),

(Scheme 35). At low concentrations the dominant pathway is (b).

The dissociation constant of mercury(II) chloride is low and the main species in solution is the neutral molecule. So the main reaction can be depicted as in Equation 15. The equilibria

16 and 17 also exist to a very small extent.95

ki McB12 + HgCe2 + H20 B12a + MeHg+ + 2Cl 15

HgC'2 ~? Hg 2+ 2Ct- 16

McB12 + Hg2+ K3 McB12-Hg2+ 17

Total concentration of methylcobalamin

= [MeB12]T = [MeB12] + [MeB12-Hg2 ]

Total concentration of mercury(II) chloride

= [HgCe2]T = [HgC€2] + [Hg2+] +][Cp ]2 [MeB12-Hg2+] ICs = [lig2 K3 - [HgC€2]T [MeB12][Hg2+J

The rate of the reaction is given by Equation 18.

Rate = k l[Me B12][HgCi2] 18 54.

For pseudo first order conditions where [HgCt2] » [MeB12], the rate can be expressed as in Equation 19.

Rate = k 19 obs[NeB12]

Taking into account the two equilibria 16 and 17 then it can be shown that:

1 + 1) 20 3 [C ( ?]2 kobs k1[Ct]2 + (lk [HgC(21T) t

If K2/[C€ ]2 is much smaller than 1 and K3K2/k1[Ct ]2 is smaller than k1 [HgCt2]T-1 then it follows that Equation 20 can be simplified to Equation 21.

1 1 21 kobs k1[HgCt2]T

In actuality, a plot of k -1 versus 'kl-1[HgCt2] -1 gave a obs T straight line, which is in accord with the assumptions that it is the mercury(II) cation (Hg2+) that complexes with methylcobalamin and also that both equilibria 16 and 17 are well to the left. It was found that mercury(II) chloride reacted slower than mercury(II) nitrate, when the latter was in low concentrations. This is in accord with the expected effect of a strong mercury-chlorine bond.

The products of the reaction were aquocobalamin and methylmercury(II) 73'91 chloride and not dimethylmercury as reported earlier. This is not surprising since methylmercury(II) chloride was found to react very slowly with methylcobalamin;to yield dimethylmercury.96 55.

Dimethylmercury may be an artefact from methylmercury(II) chloride (Equation 22).

2MeHg+ + 2Cl ' HgC?2 + HgMe2 22

This equilibrium may be pushed to the right in the in vivo system for reasons which are not, as yet apparent.84

Finally, the reaction of mercury(II) acetate with methylcobalamin 76,92-94 has been studied extensively by many workers. Their reports are conflicting, as it would appear that the reaction is extremely sensitive to the exact reaction conditions employed (pH, ionic

strength, and anions present). De Simone and his coworkers,92 for example, found that when mercury(II) acetate is added to an acetate buffered solution of methylcobalamin a yellow 'base-off' complex is formed immediately. In contrast , Chu and Gruenwedel,94 and

Schrauzer6 did not observe the formation of the yellow complex.

More recent investigations however, have confirmed De Simone's original observations.93 The rate constants calculated by all the groups were in good agreement. All found that the reaction with mercury(II) acetate is faster than that with either mercur.y(II) nitrate or mercury(II) chloride.

Chu and Gruenwedel94 stated that the actual reactive species

is the 'base-on' complex. It was also found that the reaction

was first order in both total mercury(II) species and methylcobalamin.

These observations are consistent with a reaction such as depicted in

Equation 23.

kl McB12 + Hg(0Ac)2 McHg+ + 2Ac0 + B12a 23 H20

56.

Such a reaction would lead to a rate equation of the form:

Rate = kl[Hg(OAc)2][MeB12], the observed rate constant for this -1 -1. equation being 349 + 21 M sec

De Simone stated that a pre-equilibrium is first established

(Equation 24), which could be followed by one of three different

reactions (Equations 25,26,27).

McB12 + Hg(OAc)2 K1 - McB12-Hg2+ + 2AcO 24

2+ k2 + - + NeB 12-Hg + Hg(OAc)2 H20 )B12a + McHg + Ac0 + HgOAc 25

2+ k3 + MeB lz-Hg n '> 1312a + McHg 26 n2,-,

4 + Mal, + Hg(0Ac)2 + H20 -3 B12a + MeHg + 2AcO 27

If Equation 25 was correct then under pseudo first order

conditions, it follows that:

- K1k2[Hg(OAc)2]2 R = k [MeB12]; where k obs obs 1 + K1[Hg(0Ac)2] k2[Hg (OAc) 2 ]2 Hence, [H g (OAc ) 2 ] _ _ 1 K1 kobs

A plot of [Hg(0Ac)2] versus [Hg(OAc)2] 2kobs-1 revealed that K1 would have a negative value, and therefore, the process described

by reaction 25 was ruled out.

Reactions 26 and 27 cannot be distinguished kinetically since

the observed rate constants are given by Equations28 and 29 respectively. 57.

K1k3[Hg(OAc)2] k - 28 obs 1 + K1[Hg(OAc)2]

k4[Hg(0Ac)2] kobs - 29 1 + K1[Hg(0Ac)2]

Assuming that reaction 27 was correct, the authors calculated -1 K1 and k4 from a plot of versus [Hg(0Ac)2] . The K1 kobs -1 value found was in good agreement with that calculated independently. -1 The value for ka was 370 M-1 sec which was also in good agreement with that found by other workers.

Reaction 26 was discarded by the authors on the basis of the argument that both methylcobinamide and the 'base-off' complex react slower than methylcobalamin. It should be pointed out that this argument differentiates reactions 25 and 27 but not 26 from 27.

Reaction 26 is indeed unlikely because, as the authors state later, the cobalt-carbon bond is strengthened, as electron density is removed from the cobalt atom.

Also, an intramolecular reaction is difficult to envisage as the corrin ring is between the mercury atom and the methyl group.

The kinetic studies of De Simone though, cannot rule out such a reaction.

Further study of the reaction of mercury(II) acetate with methylcobalamin under controlled conditions is necessary in order to clarify whether

the 'base-off' complex is formed easily and the reasons for the high 93 reactivity of mercury(II) acetate. The suggestion by some workers

that the reactive species, for the demethylation of methylcobalamin,

is the mercury(II) ion (Hg2+), is premature. Also the explanation put 58.

forward that mercury(II) acetate is more reactive than mercury(II) chloride simply because of its lower stability is still without 93 proof.

The effect of micelles on the reaction has been studied.93'97

Anionic micelles seem to increase the rate of reaction for alkylcobaloximes, although the effect is partly diminished because they increase its basicity.97 A decrease in the rate of reaction of alkylcobalamins was observed. Again, the basicity of 5,6-dimethylbenzimidazole increased.93

(b) Thallium(III)

The reaction between thallium(III) salts and cobalt complexes was initially described by Johnson and his coworkers.98 Thallium(III) chloride reacted rapidly with 2-, 3- and 4-pyridylmethylpentacyano-

cobalt(III) ion, in aqueous solution, to give the corresponding monopyridylmethylthallium(III) chloride ion. As with mercury(II)

salts the reaction was of first order in both the pyridylmethyl-

pentacyanocobalt(III) ion, and in total thalliūm(III) chloride.

The thallium(III) dichloride ion was found to be the most reactive 98 species.

The reaction of alkylcobaloximes with thallium(III) chloride

was also examined in some detail.78 It was found to be very

similar to the reaction observed with mercury(II) salts, but

slower (Equations 30, 31, 32).

2+ RCo(dmgH)20H2 + 2+ k10 RT.( + [Co(dmgH)2(0H2)2] T? H20 > 59.

+` K RCo (dmgH) 20H 2 + H3O A [RCo (dmgH2) (dmgH) 0H2 ]+ + H20 31

][T?3+] d[T?R21 kl[RCo(dmgH) 20H2 32 dt 1 + KA[H+]

Both k1 and KA were calculated but the values were inaccurate because the hydrolysis of thallium(III) ion was appreciable in the pH range of the kinetic experiments.

The reaction of thallium(III) salts with methylcobalamin have been briefly mentioned.99 Transmethylation with thallium(III) chloride takes place in an analogous manner to that observed with mercury(II) chloride. Methylcobalamin also reacted with dimethyl- thallium(III) acetate.96 The reaction was slower than that with thallium(III) chloride which is to be expected for an electrophilic attack at the methyl group.

(c) Palladium(II) 100 Palladium(II) salts were reported to react with alkylcobaloximes in the presence of olefins (Equation 33). The other products of

the reaction were not mentioned. , 113 R 1 R3 H Pd 2+ R1Co(chel)B + > 33 R R` R2 R4

It was suggested that an organopalladium(II) intermediate

is formed which subsequently reacts with the olefin. This theory

was confirmed by the isolation of the stable bis(ir-allylpalladium(II)

chloride) complex when allylcobaloxime reacted with palladium(II)

chloride. The other reactions attempted gave rise to unstable

60.

organopalladium(II) complexes which reacted immediately with

the olefin present.

1,4-Benzoquinone and 1,4-naphthoquinone were also methylated 101,102 with methylcobaloximes in the presence of palladium(II) salts.

It has been found that methylation also takes place in the absence

of palladium(II) salts, but the yields are very low. The

electrophilic attack of palladium(II) chloride on methylcobaloxime

to form methylpalladium(II) chloride was proposed. The organo-

palladium(II) compound adds to 1,4-quinones to form the methylated

compound (Scheme 36). The yields varied from 3 to 43%.

McCo(chel) OH2 PdCl2 McPdCI + [Co(chel) (OH2)21+ + Cr. H20 0 0

McPdCI +

Me (ch el )= (d m g H)2, (dotn H) + Pd° + HCl H

SCHEME 36

However, methylcobalamin has been found to methylate 1,4-naphtho- 102 quinone in very low yield only in the presence of palladium(II).

61.

The reaction of palladium(II) chloride with methylcobalamin, 103 in the presence of chloride ions, was examined in detail. The reaction was found to be similar to that described by De Simone with mercury(II) acetate, although in this case the rate of the reaction was considerably slower (Scheme 37).

McB12 + PdGer McB12-PdCt3 + Ct k l -1 27

McB12 + PdCt4 McPdCe r + Ct k20 B12a +

McCt + Pd° + 2Ct-

SCHEME 37

The formation of a 'base-off' complex (27) with palladium(II) 104 tetrachloride ion has been confirmed by independent work. On the basis of kinetic studies, it has also been possible to rule out the other plausible mechanistic pathways (Equations 34,35).

McB1 2-PdCi3 B12a + McPdCi3 - McCt + Pd° + 2C€ 34

McB12-PdCt3 + *PdCt4 -212-4 B12a + Me*PdCt3 + PdCt4 35 I, MeC? + Pd° + 2Ct 62.

The observation that the reactions of palladium(II) tetrachloride ion were slower than the analogous reactions of mercury(II) salts can be explained in terms of the higher electrophilicity of the mercury(II) over the palladium(II) salts.

Redox Reactions

Platinum(IV) hexachloride and gold(III) tetrachloride ions react rapidly with methylcobalamin in the presence of equimolar amounts of platinum(II) tetrachloride and gold(I) dichloride ions.99

Even in the presence of catalytic amounts of platinum(II) salts and gold(I) salts, the reaction is fast. Platinum(IV) tetrachloride reacted with methylcobalamin after an induction period. The reaction proceeded slowly but went to completion. Presumably small amounts of platinum(II) ions are generated from platinum(IV) which slowly 105 catalyse the reaction.

The products of the reaction were aquocobalamin and a methylplatinum(IV) complex which decomposes to platinum(II) and methyl chloride in the presence of excess of chloride ion. The nmr spectrum of the methylplatinum(IV) complex indicated that the methyl group was 105,106 bound directly to platinum, Labelling experiments in the reaction of methylcobalamin in which quantitative transfer of the labelled methyl group from cobalt to platinum was observed, also

supports this view. The reactivity of various alkylcobalamins was

found to be in the order:CH3 > CH2CH3 > CH2CH2CH3i it was also

reported that alkylcobinamides reacted slower than the. analogous

63.

alkylcobalamins. The reaction exhibited a pH dependence. The

optimum conditions for the reaction appeared to be at pH 2, while

at pH 7 the reaction was entirely stopped.

Platinum(II) tetrachloride ion has been found to form a 'base- 107 on' complex with methylcobalamin. The complexation appears to

take place with groups which project above the ccrrin ring,

probably with the acetamide chains on rings A and D. When the 108 B ring of the corrin ligand was converted to the s-lactam derivative

the reaction still took place but at a lower r«te. The basicity of

5,6-dimethylbenzimidazole towards the cobalt atom was stronger than

in free methylcobalamin. This indicates that the electron density

along the cobalt-carbon bond in the complex (28) is less than for

free methylcobalamin. A two electron I redox switch' mechanism

was proposed which was in agreement with the kinetic data (Scheme 38).

e Me Me I _Co] -[Coi -1Co] Bz --Bz BzH+

Me PtCI~ 2 PtCl2 +B -_ To~ k- > McPtCl 4 12a+ Cl Bz PtCl6, I-0 5 28

SCHEME 38

64.

The reaction pathway in Scheme 38 leads to the rate Equation 36.

kK2K3[PtCt4 ][PtCt6 ][MeB12] [tot d B12a] _ 36 dt K2 + K1K2 + Kl[H+] + K2K3[PtCt4 ]

109 The factor K1K2 is very small and therefore the rate

Equation 36 can be modified to Equation 37.

kK2K3[PtCf 4 ][PtCe ][MeB12] d[B12a] tot

dt Kz + K1[11 ] + K2K3[PtGe ] 37

This rate law implies a first order dependence on methylcobalamin and platinum(IV) hexachloride ion, under all reaction conditions, as well as a first order dependence on platinum(II) tetrachloride ion when it is present at low concentrations or at low pH. This was confirmed experimentally.

An electrophilic attack of the platinum(IV) hexachloride ion at

the cobalt-carbon bond, weakened by the platinum(II) complexation,

cannot be ruled out, but it would seem unlikely. Most of the

platinum(II) - platinum(IV) reactions are known to proceed by a

two electron 'redox switch' mechanism.

Nucleophilic Substitution.

Both cobalamin(I) and cobaloxime(I) are known to be strong

nucleophiles. Cobaloxime(I) was also shown to be readily displaced by 110 nucleophiles from saturated carbon (Equation 38).

RCo(chel)B + [Co(chel')B] --kll RCo(chel')B + [Co(chel)B] 38 65.

The reaction was studied for alkylpyridinatocobaloxime and bis(cyclohexanedionedioximato)pyridinecobalt(I) ion. For primary alkylcobaloximes the reaction was fast, but no reaction was observed over long periods of time with secondary alkylcobaloximes.

The position of equilibrium varied with the alkyl group.

The reaction of 1-octylpyridinatocobaloxime was studied since the rate of the reaction was slow enough to allow accurate measurements.

The reaction was of first order in each reactant. The entropy of activation was negative indicating a strong compression on the alkyl group between the two large metal-containing groups in the transition state. This is in agreement with the observed order of reactivity, i.e., CH3 » CH2CH3 > CH2CH2CH3 > CH2CH2CH2CH3 > PhCH2CH2 > n-C8H17.

The rate of the reaction is given by McKay's Equation (39), where a is the fraction of new equatorial ligand in the total organocobalt product after time, t,

a [Ao][Bo] _ R -R = ln(7 k - 39 0.5 )( LAo] + [Bo])t obs [Ao][Bo]

When the reaction.of methylcobalt complex (29) was examined, the nmr spectrum indicated that a third methylcobalt complex (31), with a mixed ligand, was present (Scheme 39).

McCo (c-hgH) 2py + [ Co (dmgH) 2py ]- . ` McCo (dmgH)2 py + [ Co (c-hgH) 2py ]

29 e 30 MeCo(dmgH)(c-hgH)py 31

SCHEME 39 66.

The compounds 29, 30 and 31 were present in a ratio of

1:1:2 respectively, i.e., complete randomisation took place

at equilibrium. The experimental evidence indicated that the

equatorial ligand exchanged rapidly between the original cobalt(I)

ion and the newly displaced cobalt(I) ion. Similar randomisation

occurs with higher alkylcobaloximes. This randomisation takes

place under alkyl transfer conditions only, but the two processes 111 are not concerted. The precise mechanism is unclear.

McKay`s Equation (39) holds for the rate of exchange even

in those cases where all or partial randomisation of equatorial

ligands occurs, provided that the dimethylglyoximato and cyclo-

hexanedionedioximato ligands have an equal influence on the rates

of reaction of the several species in which they are contained.

Cobalt(II)species also react with alkylcobaloximes and with

a faster rate than the cobalt(I) ion.42 The possibility that the reactive

species are traces of cobalt(II) was ruled out as there was no

signal arising from cobalt(II) observed when the esr spectrum of the

reaction mixture was recorded, Also in the presence of a variable

excess of sodium borohydride there was no change in the reaction

rate.

The stereochemistry of the reaction was examined. Erythro-

1,2-dideuterio-2-phenylethylbis(cyclohexanedionedioximato)pyridinecobalt(III) reacted with the bis(cyclohexanedionedioximato)pyridine-

cobalt(I) ion. A mixture of erythro and threo-alkylcobalt, complex

was obtained indicating inversion of configuration at the a-carbon.

All the experimental evidence is in agreement with a nucleophilic

substitution (SN2) mechanism. 67.

Homolytic Substitution.

(a) Cobalt(II)

Pyridinatocobaloxime(II) reacts with alkylbis(cyclohexane- 112 dionedioximato)pyridinecobalt(III) in neutral media. Equal concentrations of the two cobalt(II) complexes were obtained when equilibrium was reached (Equation 40).

Co (dmgH) 2py + RCo (c-hgH) 2py 21'1-1 RCo (dmgH) 2py + Co(c-hgH) 2py 40 k-1

The rate of the reaction is first order in both cobalt complexes.

A disproportionation of cobalt(II) to cobalt(I) and cobalt(III) was ruled out since the cobalt(II) complexes react faster than the cobalt(I) species. If disproportionation was taking place the opposite would be true. Also the rate was only twelve times Aowzc- in dichloromethane than in methanol, indicating that there is no charge separation in the transition state. Cobalt(I) anion is also known to react with dichloromethane. No chloromethylpyridinatocobaloxime was observed. Finally, the reaction was conducted in acetic acid in the presence of phenylacetylene but a-styrylpyridinato- cobaloxime was not detected. If cobalt(I) species were present in acetic acid, then addition of hydridopyridinatocobaloxime to phenylacetylene would have taken place.

Similarly, a free radical mechanism was discounted by a study of the variation in rate of reaction of different alkylcobaloximes.

The value of kl for n-propylpyridinatocobaloxime, was 1.2 x 10-1 f mol-1 sec-1, while that for the isopropylpyridinatocobaloxime was

68.

5.9 x 10-3 t mol-1 sec-1. Furthermore, 5-hexenylpyridinatocobaloxime

did not produce any cyclohexyl- or cyclopentylpyridinatocobaloxime

excluding the presence of either free radicals or carbonium ions.

The rate of the reaction is given by Equation 39, as in

the case of the reactions of the cobalt(I) anion. The same

randomisation of equatorial ligands was also observed. Again the

exchange took place between the original cobaloxime(II) and the 111 newly displaced cobalt(II) complex. 111,112 The stereochemistry of the reaction was e-camined. In'

the reaction of erythro-1,2-dideuterio-2-phenylethylbis(cyclohexane-

dionedioximato)pyridinecobalt(III) with bis(cyclohexanedione-

dioximato)pyridinecobalt(II), a mixture of erythro and threo- alkyl-

cobalt complexes was obtained. This indicates inversion of

configuration at the a-carbon. The order of reactivity is also in

agreement with the inversion of configuration at the a-carbon, i.e.,

CH3 » CH2CH3 'k, CH 2CH2CH3 > CH2CH2CH2CH3 > C6H5CH2CH2 > n-C8H17 >

CH(CH3)2 > CH2CH(CH3)2. The mechanism is best described as a

bimolecular homolytic substitution at a saturated carbon (Scheme 40 ).

PY PY

SCHEME 40

69.

Reaction between cobaloxime(II) and allylcobaloximes has

been observed. The experimental evidence is in favour of an SH2' 113 mechanism, i.e., attack at the y-carbon (Equation 41). The

rearrangement of 1-methylbut-3-enylpyridinatocobaloxime to

2-methylbut-3-enylpyridinatocobaloxime probably involves a

bimolecular homolytic displacement. Cyclopropylcarbinyl intermediates 114 have been proposed.

Co(dmgH)2L + CH2=CR*CH2Co(dmgH)2L L(dmgH'P 2CoCH2CR=*CH2 + Co(dmgH)2L 41

(b) Chromium(II)

A very similar,but slower reaction takes place with an aqueous F115 solution of chromium(II) cation. An essentially quantitative

transfer of the alkyl group takes place (Scheme 41).

K RCo(dmgH) 20H 2 + H30H [RCo(dmgH2)(dmgH)OH 2]+ + H 2O

Cr2+\k B kA / Cr2+

(H20)5CrR2+

SCHEME 41

Some of the organochromium complexes were stable enough to be

isolated, Others were characterised by reacting them with acid

or bromine to form the corresponding alkane or alkyl bromide respectively.

i' The reaction was studied at low pH because of the instability of

the chromium(II) ion at high pH. 70.

The order of reactivity for different alkylcobaloximes was

CH3 > C6H5CH2 » CH2CH3 > CH2CH2CH3 > CH(CH3)2 > CH2C(CH3)3.

The reaction was first order in both the alkylcobaloxime and the chromium(II) ion. The rate constant,kA was found to be larger than kB (Scheme 41). A bimolecular homolytic substitution mechanism, SH2, was proposed. The stereochemistry of the reaction should be studied in order to confirm this point.

Alkylcobalamins reacted in a similar way with aqueous chromium(II) ion. (Equation 42). 116

2+ - RB12 + Cr2+aq k + B12r; d[RB12] - k[Cr > (H20)5CrR dt 2+aq][RB12] 42

Again, a 1:1 stoicheiometry was observed as with the alkylcobaloximes. Under the reaction conditions, low pH, the alkylcobalamins were protonated and it was the `base-off' complex that reacted with the chromium(II) ion.

A negative entropy of activation indicates a highly ordered transition state. The bulky corrin ring is expected to cause some strain on the cobalt-carbon bond and therefore make it more labile compared to the cobalt-carbon bond in the alkylcobaloximes.

As a consequence, alkylcobalamins were found to react faster than alkylcobaloximes. All the evidence is again in agreement with an homolytic substitution (SH2), 71.

The possibility of a cobalt(III)-chromium(II) redox process, accompanied or followed by the transfer of a carbanion to the coordination sphere of chromium(III)(a redox SE2 sequence) cannot be ruled out. The order of reactivity of both alkylcobaloximes and alkylcobalamins would support this mechanism. However, the quantitative transfer of the alkyl group would require an extremely site-specific redox process. Also, formation of alkane would be expected to compete with the alkyl transfer if there was any carbanionic character at the alkyl group during the transfer.

This was not observed indicating that a redox SE2 mechanism is rather improbable.

Tin

Methylcobalamin was found to react with tin(II) ions (Equation 43) 117 in hydrochloric acid (pH 1) in the presence of sodium chloride.

-x SnCfx2 + McB12 + B12a klu McSnC~y3 y + 2B12r + H20 43

No reaction takes place in the absence of aquocobalamin (B12a).

Iron(III) chloride can be used instead of aquocobalamin but excesses of both tin(II) and iron(III) are necessary. Under pseudo first order conditions the rate of the reaction is given by Equation 44.

_ d[R1312] _ [ 2+]n s [R1312]][R = kl Sn 44 dt - k ob 12 ' obsk 72.

A plot of k obs versus [Sn2+] gave a straight line whose intercept was zero, therefore, Equation 44 can be written as:

d[RB12] - kl[Sn dt 2+][RB12]

Methylcobalamin reacts faster than ethylcobalamin. As a control experiment iron(II) or tin(IV) complexes were mixed with methylcobalamin. The cobalt-carbon bond was not cleaved. In addition, no reaction was observed when tin(II) was mixed with methylcobalamin in the presence of tin(IV).

When sulphuric acid and sodium sulphate or perchloric acid and sodium perchlorate were used as the reaction media, the reaction did not take place, although the pH of the medium was 1. In aqueous sodium tartate and tartaric acid (pH 3-5), methylcobalamin was again cleaved. This is because chloride or tartate ions 117 stabilise the intermediate tin(III) species (Scheme 42).

2 Sn2+ + Fe3+(B12a) • Sn3+ + Fe2+(B12r)

Sn3+ + RB12 k3) RSn3+ + B12r

Sn3+ + Fe k°> Sn + Fe2+

SCHEME 42

The mechanism proposed in Scheme 42 is in agreement with the observation that vast excesses of iron(III) and the tin(II) salt were required. The mode of cleavage appears to be either SH2 or a site-specific reduction of the alkylcobalamin at the alkyl group with concurrent carbanion transfer to tin. 73.

The reactions of all cobalt(II), chromium(II) and tin(III) are similar. The order of reactivity is Co(II) > Cr(II) > Sn(III).

Although a redox process cannot be ruled out, homolytic substitution

(SH2) would be the more probable mechanism.

Alkylcobaloximes react with stannite in alkaline solution 118 in a different way to alkylcobalamins. The reaction is very sensitive to the nature of the axial base, as is evident from the lack of reactivity of alkylcobaloximes containing Tr-acceptor axial bases such as tri-n-butylphosphine. The reaction was slow, particularly so with the higher- alkylcobaloximes [CH3 » CH2CH3 ti CH2CH2CH3 '

CH(CH3)2].

The products of the reaction were alkanes or olefins, obtained from the higher alkylcobaloximes, presumably by a 0-elimination reaction (Scheme 43). Also, a purple 'stannito-cobaloxime' was observed. This probably is a charge transfer complex of cobaloxime(I) with stannite. The complex must be rather labile because when methyl iodide was added, methylcobaloxime was formed rapidly.

A displacement of the base by stannite followed by a reductive cleavage of the cobalt-carbon bond was proposed as the mechanism of the reaction

(Scheme 43).

-B RCo(dmgH)2B + Sn(OH)4 [RCo(dm H )2- Sn(OH) ]- +B g 3

H IHO olefin + H20 + [ Co (dmgH) 2B ] [ Co (dmgH) 2B ] + Sn(OH) 4 + R ~"" RH

SCHEME 43 74.

Lead

The demethylation of methylcobalamin by lead(IV) to give .119 volatile organolead compounds has been mentioned The mechanism of the reaction, however, has not been studied. Lead(II) was unreactive towards methylcobalamin in- vitro. However, the methylation of lead(II) acetate by microorganisms isolated from an aerated aquarium has been reported.120 There was no mention of the methylating species but the possibility that methylcobalamin is involved in the reaction cannot be ruled out.

Arsenic 121 122 Finally, both the biological and chemical 'methylation of arsenic(V) have been reported. Schrauzer methylated arsenic(III) and arsenic(V) with both methylcobaloxime and methylcobalamin under reducing conditions (DTE or zn/NH4Ce). A reductive cleavage of the cobalt-carbon bond was again proposed.

The biological methylation of arsenic(V) also required methylcobalamin. However, there was no proof that methylcobalamin was the methyl donor and on further investigation of the mechanism 123 of the reaction this possibility was discounted.

Miscellaneous.

Copper(II) also demethylates methylcobalamin. This reaction will be discussed later. The methylation of trimethyllead(IV) acetate, 75.

trimethyltin(IV) acetate, trimethyltellurium(IV) iodide, tetra- methylantimony(V) iodide, and tetramethylarsenic(V) iodide by methylcobalamin has been mentioned.96 The mechanism of the reaction was not examined. 76.

SUMMARY

Most of the alkylcobalt complexes are formed from cobalt(I) and an alkylating agent. The cobalamin(I) ion has been described as a supernucleophile. Although the nucleophilicity of other cobalt(I) complexes is lower, it is sufficient for them to react with most unhindered alkylating agents. However, the conditions employed to generate the anion are basic and often the alkyl product is unstable.

The mechanism of the reaction is in some cases ambiguous.

With most alkylating agents a nucleophilic substitution is operative but an electron transfer mechanism with some alkyl bromides and iodides has been shown to occur.

The cobalt(II) and cobalt(III) are used in some syntheses but only for the preparation of specific alkylcobaloximes. Their utility in the synthesis of alkylcobaloximes has not been explored.

The reaction of alkylcobalamins with metals has been studied in detail because of its importance in the formation of toxic organometallics in the environment. It now seems certain that methylcobalamin is responsible for the formation of the methylmercury(II) ion which caused the Minamata disease. 77.

The mechanism of the reaction is under dispute. It has not yet been settled as to whether it is the 'base-on' complex that is methylating mercury or the 'base-off' complex. Further study of the reaction under carefully controlled conditions is necessary.

The reaction of alkylcobaloximes with chromium(II), cobalt(II), and cobalt(I) complexes has been studied. The mechanism of the reactions has been elucidated.

The importance of the methylation of other metals by methylcobalamin in the environment is now being studied. Alkylation of many metals has been observed but the mechanism of the reactions has been studied only briefly. 78.

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and J.W. Sibert, Bioinorg. Chem., 1972, 2, 93.

123. W.R. Cullen, C.L. Froese, A. Lui, B.C. McBride, D.J. Patmore,

and M. Reimer, J. Organomet. Chem., 1977, 139, 61. 85.

RESULTS AND DISCUSSION

1. Synthesis of Alkylcobaloximes.

(a) From Hydridopyridinatocobaloxime.

The preparation of alkylcobaloximes from hydridopyridinato- cobaloximes has already been discussed. The reaction usually takes place if there is an electron withdrawing group present such as a nitrile, or an ester.1 However, propene reacts with hydridopyridinatocobaloxime to give isopropylpyridinatocobaloxime in low yield.2 Also, norbornadiene and indene were found to react with

the, hydride to give a mixture of 2-norborn-5-enyl and 3-nortricyclenyl- pyridinatocobaloxime,3 and 2-indanylpyridinatocobaloxime respectively

In order to examine the limitations of the reactivity of the hydridocobalt(I) species, reactions with other substituted or cyclic olefins were attempted. Ethyl prop-2-enylimidate (1) and prop-2-enamidine (2) were prepared as shown in Equation 1.5

, HCI NH3, EtOH CHz=CHCN EtOH > CH2=CHC(0Et)=,NH.HCI ) CHz=CHC(NHz)=NH •HCl 1 I 2

The hydrogen chloride salts were unreactive. Hydrogen was absorbed slowly, presumably because of the decomposition of hydridopyridinatocobaloxime to give 3-aminobutan-2-one oxime.6 The organic substrate reacted with the solvent to give ethyl 3-methoxypropionate.

Problems arose because of the sensitivity of the organic substrate

to the conditions under which the hydridocobalt(I) species are generated (aqueous base). Milder conditions were employed and these are summarised in Table 1. However, absolutely anhydrous conditions could not be used since cobalt(II) chloride itself contains 86.

water (hexahydrate). The free imines were generated with base

(Table 1) and reacted with the hydridocobalt(I) species. In these

examples only the 0-isomer was isolated and not the a-isomer, as is

usually the case.2 This may be because the substituents on the

olefin were sufficiently basic to remove the proton from the

cobalt atom and generate the pyridinatocobaloxime(I) ion (Scheme 1).

This subsequently reacted with the olefin to give the 0-substituted

alkylpyridinatocobaloxime.7

HCo(dmgH) 2py~ CH 2=CHC(OEt)=NH.HC-C --- CH2=CHC(OEt)=NH

McOH py(dmgH) 2CoCH2CH2C(OEt)=NH -~ py(dmgH)2CoCH2CH2CO2Me

2 3 IH 0 EtO2CCH2CH2Co(dmgH) 2py

SCHEME 1

As the wrong mode of addition was observed and the hydrolysis of

the carbon nitrogen bond under the reaction conditions could not

be stopped, these reactions were abandoned.

The reactions of hydridopyridinatocobaloxime with some cyclic

olefins are summarised in Table 2. TABLE 1

1 Olefin Solvent Base Product j Ratea Ī }

CH2=CFk(OEt)NH.HC? McOH NaOH McOCH2CH2CO2Et 1 0.71

CH2=CHc(0Et)NH NeOH NaOH, Et 3Nb decomposition products -

CH2=CHc(OEt)NH McOH NaOH, Et 3Nb decomposition products -

CH2=CH.(OEt)NH Me0H NaOH, NaOAcb Me02CCH2CH2Co(dmgH) 2py 6.00

CH2=CHc(OEt)NH THF NaH, NaOAcb EtO2CCH2CH2Co(dmgH) 2py 0.15

CH 2=CHi(OEt')NH c THF NaH, NaOAcb EtO2CCH2CH2Co (dmgH) 2py 1.18

CH2=CHtOEt)NH THF NaH, NaOAcb H2NCOCH2CH2Co(dmgH) 2py very slow a The rate of the reaction of acrylonitrile with the hydridopyridinatocobaloxime was used as reference. The initial rates of hydrogen absorption were compared. b Base used to generate the free imine from the salts (1) and (2). c In the presence of acetic acid, TABLE 2

Olefin Observations Yield Rel.Ratea (%)

Coumarin hydridopyridinatocobaloxime decomposed, - - coumarin recovered Santonin hydridopyridinatocobaloxime decomposed, santonin - - recovered Indene 2-indanylpyridinatocobaloxime 88 6.6 Acenaphthylene 1-acenaphthenylpyridinatocobaloxime 83 - Norbornadiene 2-norborn-5-enylpyridinatocobaloxime + 3-nortri- 78 6.9 cyclenylpyridinatocobaloxime (7:3) Norbornene 2-norbornylpyridinatocobaloxime 19 0.6 Dicyclopentadieneb unknownc 8 0.6 Cyclopentadiene cyclopentene 92 6.6 Cyclopentene hydridopyridinatocobaloxime decomposed,cyclopentene - - recovered Diethyl maleate diethyl succinate 14 very slow Maleic anhydride hydridopyridinatocobaloxime decomposed,maleic - - anhydride recovered y-crotonolactone8 hydridopyridinatocobaloxime decomposed, y-crotono- - - lactone recovered cyclopent-2-enone cyclopentanone - - cyclopropylbenzene9 hydridopyridinatocobaloxime decomposed, cyclopropyl- - - benzene recovered 89.

Footnotes to Table 2.

a The rate of the reaction of acrylonitrile with hydrido-

pyridinatocobaloxime was used as reference. The initial

rates of hydrogen absorption were compared.

b In the presence of acetic acid.

c See discussion below. 90.

Table 2 shows that reaction can take place with strained olefins as well as those connected to activating substituents.

Surprisingly, there is no reaction with maleic anhydride, y-crotonolactone, coumarin and santonin. Both the electronic effects of the substituents present and/or the strain of the ring should favour their reaction with the hydride.

In all the cases where the reaction did not take place, acetic acid was added in an attempt to catalyse the reaction. In the absence of acetic acid the alkylcobaloxime was not formed with dicyclopentadiene.

The hydrogen uptake was fast initially, but after a short time it became slow, Presumably, the alkylcobaloxime is formed initially (8%). and then it stops, the reasons for this behaviour remain obscure. 10 Acetic acid itself catalyses the decomposition of the hydride, and it is this decomposition which is probably responsible for the continuation of hydrogen absorption (Scheme 2). The cobalt(II) complex in acid decomposes further to aqueous cobalt(II) ion and dimethylglyoxime,

2HCo(dmgH)2B — 2Co(dmgH)2B + 1-1- 2 in acid:

HCo(dmgH)2B 30H 0H 2OCo(dmgH)2B]+ + H2

[H2OCo(dmgH)2B1+ + HCo(dmgH) 2B 2Co(dmgH) 2B + H2O+

SCHEME 2

91.

The orientation of the cobaloxime group in norbornane,

nortricyclene,norbornene and dicyclopentene could not be determined.

However, considering the bulkiness of the group it would be

reasonable to suggest that it is in the exo position, as shown in

compounds (5), (6), (7) and (8). With dicyclopentadiene, the more

strained double bond would be expected to react. The nmr spectrum

of the alkylcobaloxime is in agreement with this assumption, but

not sufficiently unambiguous to be definitive.

Co(dmgH)2py

5 Co(dmgH)2py

H py(dmgH)2Co H or py(dmgN)2Co

11 At the time of this work the reactions of cyclopent-2-enone

and cyclopentadiene12 with hydridopyridinatocobaloxime were reported.

Again, total hydrogenation of the double bond was observed. 92.

(b) From Pyridinatocobaloxime(II).

As mentioned before, Schrauzer's method is good for the preparation of simple alkylcobaloximes. Problems arise when there are certain substituents present, particularly electron withdrawing ones.

It had been observed that chloropyridinatocobaloxime reacted with ethylbromoacetate or ethyl 2-bromopropionate, in the presence of zinc, to form ethoxycarbonylmethylpyridinatocobaloxime and

1-ethoxycarbonylethylpyridinatocobaloxime in 21 and 36% yield 13 respectively.

A study of the reaction was undertaken to examine its utility in the synthesis of substituted alkylcobaloximes. Difficulty was experienced in repeating the experiments, particularly the reaction with ethyl bromoacetate. The yields of the reactions were variable.

Higher temperatures (the reactants were heated to reflux in toluene) did not have any effect on the yields of the alkylcobaloximes.

The use of activated zinc, made by treating it with sulphuric and nitric acid, did not change the yields. Reactions with other cr-substituted alkyl halides were attempted, The results are

summarised in Table 3.

Again, in cases where there was no alkylcobaloxime formation,

the conditions were varied (high temperature, activated zinc) but

there was no difference observed in the products of the reaction.. TABLE 3

RX Product Yield Solvent T (°C) (%)

BrCH2CO2Et EtO2CCH2Co(dmgH)2py 20 benzene 75

McCHBrCO2Et EtO2CCH(Me)Co(dmgH)2py 54 benzene 70

EtCHBrCO2Et EtO2CCH(Et)Co(dmgH)2py 30 benzene 70

PhCHBrCO2Et = - benzene 70 tBuCHBrCO2Et - - benzene 70

Me2CBrCO2Et - - benzene 70

PhCOCH2Br - - benzene 70

PhCOCH2Br - - dimethoxyethane 82

PhCOCMe2Br - - benzene 70 94.

Other complexes such as bromopyridinatocobaloxime and bromotriphenylphosphinatocobaloxime were prepared.14 The first reacted with alkyl halides to give alkylcobaloximes in low yield, but from the reaction of the second halocobaloxime, starting material was recovered (Table 4). Attempts to prepare bromotributylphosphinatocobaloxime resulted in the formation of the 15 protonated dibromocobaloxime ion (9).

Br2Co(dmgH)(dmgH2)H20

Attempts to prepare fluoropyridinatocobaloxime, so that the effect of the halogen on the reaction could be studied, also failed.

TABLE 4

Alkyl Halide XCo(dmgH)2B Product Yield (%)

BrCH2CO 2Et BrCo(dmgH)2py EtO 2CCH2Co(dmgH)2py 16

McCHBrCO2Et BrCo(dmgH)2py EtO2CCH(Me)Co(dmgH)2py 30

EtCHBrCO 2Et BrCo(dmgH)2py EtO 2CCH(Et)Co(dmgH)2py 4

McCHBrCO2Et BrCo(dmgH)2PPh3 - -

Me2CBrCO2Et BrCo(dmgH)2PPh3 - -

95.

Initially, it was thought that the reaction takes place via

the Reformatski reagent (10).

RI ,0 ZnX+

R2 OEt

If this was the case, other more reactive metal enolates should

react with chloropyridinatocobaloxime to form the alkylcobaloxime.

Ethyl propionate reacted with potassium hydride to form enolate 16 (11). The anion was initially quenched with deuterium oxide.

Ethyl 2-deuteriopropionate was formed (70% deuterium incorporation)

confirming the formation of the anion. When chloropyridinato-

cobaloxime was added to the anion (11), a rapid reaction took place.

There was no alkylcobaloxime formed, Presumably, the anion reacted

with the equatorial ligands of the complex and this led to its

decomposition, The same occurred with enolate (12)17 prepared from

isopropenyl acetate and methyl lithium.

Me 0-K+ H 0 Li+ /,----\\_/ \_._/ /-\ H OEt H CH3

11 12

When the reaction was performed in the presence of p-dinitrobenzene

or styrene the yield of the alkylcobaloxime formed was zero. Control

experiments to ensure that there was no reaction between styrene or

p-dinitrobenzene and chloropyridinatocobaloxime were performed.

96.

When zinc initially reacted in benzene at 70°C with ethyl

2-bromopropionate alone and chloropyridinatocobaloxime was added, the yields of the alkylcobaloxime dropped considerably. On the contrary, the best yields were obtained when zinc and chloropyridinatocobaloxime were mixed and then the bromoester was added.

This suggested the formation of a radical intermediate, rather than anionic species, as originally postulated. The reaction of benzyl bromide with chloropyridinatocobaloxime in the presence of zinc gave benzylpyridinatocobaloxime in 21% yield. This indicated that zinc may reduce chloropyridinatocobaloxime to pyridinatocobaloxime(II) which then reacted with the alkyl halides to give the alkylcobaloximes

(Scheme 3).

2C?Co (dmgH) Zpy + Zn ----3 2Co (dmgH)Z py + ZnCt2

Zn 2RX

2Co(dmgH)2pY XCo(dmgH)2py + 2R' 2RCo(dmgH)2py

SCHEME 3

Cobaloximes(II) are known to react with benzyl bromide to yield benzylcobaloximes. This reaction has been studied in detail 18,19 byy Halp ern, (Scheme 4),

RX + Co(dmgH)2B R'+ XCo (dmgH) 2B slow

ast4 R. + Co(dmgH) 2Bf— RCo(dmgH)2 B

SCHEME 4 97.

The stoicheiometry of the reaction was found to be, cobalt(II) complex to alkyl halide, 2:1 and the rate is given by Equation 2.

d[Co(dmgH) 2B] 2k[Co(dmgH)2B][R X] 2 dt

The rate determining step was the abstraction of the halogen by the cobalt(II) complex. The effect of both the equatorial ligands and the axial base on the reaction has been studied.19 The equatorial ligands had negligible effect but the axial bases had a strong effect on the rate of the reaction (Table 5). Cobalt(II) complexes containing different p-substituted triphenylphosphines reacted with benzyl bromides. Hammett plot gave a value of p -1.4.

The enhancement of the rate by electron donating substituents is

consistent with a transition state where electron transfer takes

place to a certain extent (Equation 3), d- d+

RX + Co(dmgH)2B ---. R X Co(dmgH)2B 3

For the other bases, although there was some indication that

the rate increased with their basicity, the correlation was far

from perfect. In particular, complexes of the most bulky ligands

such as tricyclohexylpho spline exhibited rates that were significantly

lower than expected on the basis of the ligand basicities, suggesting

that steric factors were more important than electronic factors. 98.

TABLE 5

)a,b Base pKa k(M-1 sec-1

-1 1. pyridine 5.2 (1.5 + 0.1) x 10 -1 2. 4-picoline 6.1 (2.1 + 0.2) x 10 3. 1-methylimidazole 7.0 (5.5 + 0.2) x 10-1 -1 4. piperidine 11.1 (1.0 + 0.1) x 10 -1 5. (Me0)3P (1.5 + 0.1) x 10 6. (p-CtC6H4)3P (9.7 + 0.2) x 10-3 7. Ph3P 2.73 (2.1 + 0.1) x 10-2 8. (P-McC6H4)3P (3.4 + 0.1) x 10-2 9. (p-Me0C6H4)3P 4.46 (4.8 + 0.1) x 10-2 10. (n-Bu)3P 8.43 1.6 + 0.1

11. .Et 3P 8.69 1.1 + 0.1

12. Me3P 8.65 7.1 + 0.1

13. (c-C61111) 3P 9.7 (4.4 + 0.2) x 10-3

a k is the rate constant for the reaction of cobaloxime(II) with benzyl bromide.

b All the reactions were conducted in benzene except when

the base was tricyclohexylphosphine; the reaction was conducted in acetone. 99.

The reasons may be because the effective basicity of a large ligand is lowered due to its inability to approach the cobalt as closely assmaller-ligands. Also steric resistance in going from the initial five-coordinate cobalt(II) configuration to six coordinate cobalt(III) would lower the rate of the reaction. The latter effect is likely to be important only if the initial five coordinate complexes are significantly stabilised by distortion from a square-pyramidal configuration.

The importance of the electronic effect was also shown by the enhancement in reactivity of the substituted benzyl bromides by electron withdrawing substituents. This is in agreement with a transition state shown in Equation 3.

The possibility of an electron transfer mechanism operating,which had previously been observed in the reaction of [N,N'-bis(salicylidene)- ethylenediamino)-l-inethylimidazolecobalt(II) with p-nitrobenzyl bromide (Scheme 5)20 was ruled out.

Co(saloph)B'2 + P-O2NC6H4CH2Br [Co(saloph)B 2]+ + Br + a-02NC6H4CH2

Co(saloph)B + p-02NC6H4CH2 —a p-02NC6H4CH2Co(saloph)B

B = 1-methylimidazole

SCHEME 5 100.

This mechanism was operative only if a strong electron withdrawing substituent• was present in the alkyl halide as in the above case.

Also a base was required to stabilise the positive charge developed on the cobalt atom. When the base was pyridine the alternative mechanism, atom abstraction, was operative.20 For an electron transfer mechanism a six-coordinate complex was required. In the reaction of cobaloxime(II) with the alkyl halides, the five coordinate complex was shown to be the reactive species.19 The two mechanisms were clearly distinguished by their dependence on the halogen atom. The rate of an atom transfer reaction is expected to be more dependent on the halogen atom rather than the rate of an electron transfer reaction. For [N,N!-bis(salicylidene)ethylenediamino)-l-inethylimidazolecobalt(II) the ratiokI/kBr < 10. For cobaloxime(II) the ratio kI/kBr varied between 102 and 103. In both cases the sequence RC? < RBr < RI was found.

Another possibility would be the disproportionation of the cobalt(II) complex to cobalt(I) ion and cobalt(III) ion and the subsequent reaction of cobalt(I) ion with the alkyl halide. This reaction has been previously used for the preparation of alkylcobaloximes, However, the disproportionation usually occurs under basic conditions. Also, if this was the case, an enhancement of the rate would be expected on changing the solvent of the reaction from benzene to acetone, There was no significant change observed.19

Finally, the fact that 1-bromo-l-phenylethane reacted about five times faster than benzyl bromide is a direct evidence against :an SN2 reaction.18 101.

This reaction was originally observed with pentacyanocobalt(III) 21 22 ion and benzyl bromide. ' It was also observed with other cobalt. 23'24 complexes but has not been explored synthetically. This may be in part due to the low theoretical yield (50%) of the reaction.

The yields of the alkylcobaloximes would improve if the halocobāloxime could be reduced to cobalt(II) with a suitable reagent such as zinc.

Indeed, the yields improved considerably when cobaloxime(II) was used as the starting material (Table 6).

Zinc-copper, aluminium powder and aluminium amalgam were also tried as reducing agents (Table 7). Aluminium powder was totally inactive. Zinc was found to be superior in most of the cases.

A disadvantage of the reaction was the preparation of pyridinatocobaloxime(II) complex. The complex is oxygen sensitive and has to be handled with care, particularly so when in solution28 Once dry and under nitrogen, it decomposes very slowly. Higher yields would be expected if the cobalt(II) complex were to be prepared in situ,

To this end, the complex was prepared in acetone from cobalt(II) acetate, dimethylglyoxime and pyridine and then ethyl 2-bromopropionate and zinc were added at 50°C, The alkylcobaloxime was formed, but only in 38% yield. The reaction was repeated in benzene at 70°C and the alkylcobaloxime was formed in 93% yield. The same method

was applied to other alkyl halides (Table 8), The alkylcobaloximes

were also prepared by Schrauzerl s method (from cobalt(I)ion and the

alkyl halide) so that the two methods could be compared (Table 8). TABLE 6

Co(dmgH) 2B RX Product Yield (%)

Co(dmgH)2py McCHBrCO2Et EtO 2CCH(1`,1e)Co(dmgH) 2Py 63 Co(dmgH)2PPh3 McCHBrCO 2Et - - Co(dmgH) 2py2 BrCH2CO 2Et EtO 2CCH2Co(dmgH) 2py 56 Co(dmgH) 2Py 2 McCHBrCO2Et EtO 2CCH(Me)Co(dmgH) 2py 60

Co(dmgH) Zpy 2 McCHC?CO 2Et EtO 2CCH(Me)Co(dmgH)2Py 35 Co(dmgH) 2py2 EtCHBrCO2Et EtO2CCH(Et)Co(dmgH) 2py 60 Co(dmgH) 2py 2 PrCHBrCO2Et BrCo(dmgH) 2py - Co(dmgH) 2py2 i-PrCHBrCO 2Et BrCo(dmgH) 2py - Co(dmgH) 2py2 Me 3CCHBrCO 2Et25 BrCo(dmgH) 2py - Co (dmgH) 2PY 2 PhCHBrCO 2Et EtO2CCH (Ph) Co (dmgH) 2PY 8

Co(dmgH) 2PY 2 McCOC? - - Co (dmgH) 2py2 PhCOC? - - Co(dmgH) 2py 2 Ph 2CBrCOBr - -

Co(dmgH) 2py 2 ClCH2CN NCCH2Co(dmgH) 2py 89 Co(dmgH)2py2 McCHC(CN NCCH(Me) Co (dmgH) 2PY 65 Co (dmgH) 2Py 2 Me3CCHBrCN BrCo(dmgH) 2py - 26 Co(dmgH) 2PY 2 BrCH 2NO 2 O 2NCH 2Go (dmgR) 2pt' 8

Co(dmgH) 2pY2 Me 2C(NO 2)Br27 BrCo(dmgH) 2py + (Me 2CNO 2) 2 - Co(dmgH) 2PY2 PhCOCH 2Br PhCOCH 2Co (dmgH) 2py traces TABLE 7 .

Co(dmgH)2BX RX Metal Product Yield (%)

Co(dmgH)2py2 McCHBrCO2Et Zn/Cu Et02CCH(Me)Co(dmgH)2py 48 Co(dmgH)2PPh3 McCHBrCO2Et Zn/Cu - - Co(dmgH)2py2 BrCH2CO2Et At/Hg Et02CCH2Co(dmgH)2py 52 Co(dmgH)2py2 McCHBrCO2Et At/Hg EtO2CCH(Me)Co(dmgH)2py 65 Co(dmgH)2py2 EtCHBrCO2Et At/Hg Et02CCH(Et)Co(dmgH)zpy 45 Co(dmgH)2py2 PrCHBrCO2Et At/Hg Et02CCH(Pr)Co(dmgH)2py 33 Co(dmgH)2py2 i-PrCHBrCO2Et At/Hg Et02CCH(i-Pr)Co(dmgH)2py 3 Co(dmgH)2py2 Me3CCHBrCO2Et At/Hg BrCo(dmgH)zpy - Co(dmgH)2py2 PhCHBrCO2Et At/Hg BrCo(dmgH)zpy - Co(dmgH)2py2 CtCH2CN At/Hg- NCCH2Co(dmgH)2py 59 Co(dmgH)2py2 BrCH2NO2 At/Hg O2NCH2Co(dm u) zPY traces Co(dmgH)zpy2 Me2C(Br)NO2 At/Hg BrCo(dmgH)zpy - Co(dmgH)2py2 PhCOCH2Br At/Hg PhCOCH2Co(dmgH)2py I 20 TABLE 8 r ' RX Product Yield (%) Reference Yield (%)

BrCH2CO2Et EtO2CCH2Co(dmgH)2py 90 18 McCHBrCO2Et EtO2CCH(Me)Co(dmgH) 2py 93 18 EtCHBrCO2Et EtO2CCH(Et)Co(dmgH) 2py 85 38 PrCHBrCO2Et EtO2CCH(Pr)Co(dmgH)2py 90 45 i-PrCHBrCO2Et EtO2CCH(i-Pr)Co(dmgH) 2py 70 28 Me3CCHBrCO2Et BrCo(dmgH)2py - - PhCHBrCO2Et EtO2CCH(Ph)Co(dmgH) 2py traces 36a CtCH2CN NCCH2Co(dmgH) 2py 64 36 NeCH(C?)CN NCCH(Me)Co(dmgH) 2py 69 20 BrCH2NO2 02NCH2Co(dmgH)2py 24 19 BrCMe2NO2 BrCo(dmgH) 2py - - PhCOCH2Br PhCOCH2Co(dmgH) 2py 31 17 Me2CHBr Me2CHCo(dmgH) 2py tracesb 33 Met McCo(dmgH)2py 95 77c

a Literature yield 40%.29 b Isopropyl iodide gave 57% yield in the absence of a reducing agent. c Methylpyridinatocobaloxime has been prepared by Schrauzer's method in 99% yield using dimethylsulphate as an alkylating agent.J° 105.

The fact that zinc was acting as a reducing agent for halocobaloxime was shown from the high yield of cyanomethylpyridinatocobaloxime (89%) (Table 6). Zinc and chloroacetonitrile were heated in benzene at 70°C but there was no reaction observed.

The reduction of haloesters31 by zinc is a competitive reaction which lowers the yields of cobaloximes. This is shown in Table 8.

When the reduction by zinc is fast the yields of the alkylcobaloximes are low. This may explain the low yields of the alkylcobaloximes in acetone.

The lower yields obtained from the chlorides are in agreement with the slow abstraction of chlorine by cobalt(II) as compared with

the abstraction of bromine. Analogously, the yield of isopropyl-

pyridinatocobaloxime was low (only traces) when isopropyl bromide

was the starting material, From isopropyl iodide the alkylcobaloxime

was obtained in 57% yield,2 Methyl iodide reacted to give methyl-

pyridinatocobaloxime in high yield even though there were no electron

withdrawing groups present, an indication of the ease with which the

iodine atom is abstracted,

The fact that the electron deficient alkyl bromides react in

higher yields than the analogous unsubstituted compounds is also

in agreement with the mechanism described by Halpern.

The presence of a radical intermediate was apparent from

the isolation of 2,3-dimethyl-2,3-dinitrobutane from the reaction

of 2-bromo-2-nitropropane with cobalt(II), The bromine abstraction

evidently took place but the alkyl radical formed was too bulky

to react with the cobalt(II) complex. Hence, coupling of the

radicals gave 2,3-dimethyl-2,3-dinitrobutane. 106.

Triphenylphosphinatocobaloxime(II) reacted with alkyl halides but failed to give alkylcobaloximes. Presumably the bulkiness of the base inhibits the coupling of the cobalt(II) complex with the radical (cf. Table 5, entries 12,13). In addition, the basicity of triphenylphosphine is lower than that of pyridine (Table 5).

This is reflected in the observation that triphenylphosphinatocobaloxime(II) reacts with benzyl bromides about ten times more slowly than pyridinatocobaloxirae(II).19

The possibility of the formation of cobaloxime(I) ion had also to be ruled out, since the reduction of cobaloxime(II) by zinc in ethanol and sodium hydroxide to give cobaloxime(I) is knōwn.32

Ethyl 2-bromopropionate reacted with pyridinatocobaloxime(II) and zinc, under nitrous oxide, to yield 1-ethoxycarbonylethylpyridinatocobaloxime in 907. yield. It is known that nitrous oxide 33 34 rapidly destroys the cobalt(I) complexes. ' Therefore, the

possibility that under the reaction conditions cobalt(II) is reduced to cobalt(I) and that reacts further with the alkyl halides was ruled out, since the yield of the alkylcobaloxime in the presence of nitrous oxide would be considerably reduced. Furthermore, when zinc and pyridinatocobaloxime(II) were heated in benzene at 70°C for three hours only the starting materials were isolated. There was no blue colour developed, characteristic of the cobalt(I) ion.

There are three limitations for the method described here.

Firstly, good yields are obtained only with electron deficient alkyl

halides. Simple alkyl halides give comparable (or worse) yields 107.

to those of the Schrauzer method. Simple alkyl iodides give good yields but they are generally less accessible. Secondly, bulky alkyl halides react with the cobalt(II) complex but the alkylcobaloximes are not formed. This is a common limitation to all the methods used for the synthesis of alkylcobaloximes.

Finally, the a-haloesters that are rapidly reduced by zinc give low yields of the alkylcobaloximes.

However, the method has several advantages compared with the other methods known in the literature. As mentioned before,

Schrauzer's method is not successful for many substituted alkyl halides or olefins.7 Under the basic conditions employed, elimination can occur easily to form the olefin. Reduction of the alkylcobaloxime by cobaloxime(I) ion to form the saturated hydrocarbon is another undesirable side reaction. The synthesis from hydridocobaloxime is very sensitive to the bulkiness of the substituents present in the olefins, and can be applied only to very few olefins which contain an electron withdrawing group.

The new methodology offers excellent scope for non-aqueous, non-nucleophilic cobaloxime synthesis under mild conditions.

The method has been successfully applied in the synthesis of alkylcobaloximes as possible models for coenzyme Ba2 action.

This will be discussed later.

The preparation of nitromethylpyridinatocobaloxime deserves a special mention. The yields were low and the purification was tedious, The yields were low with Schrauzer's method also. The

108.

reasons for this are not clear, particularly since there are no bulky substituents present in the alkyl halide, but probably lies in the nature of the nitronate radical produced. It was impossible to obtain an analytically pure sample of the alkyl -

cobaloxime. Presumably, during the preparation of bromonitro-

methane (13) some dibromonitromethane (14) was also formed (Scheme 6). It was impossible to remove all the impurity from the

main product by distillation. Both the compounds (13) and (14)

could react with pyridinatocobaloxime(II) to form nitromethyl-

pyridinatocobaloxime (15) and bromonitromethylpyridinatocobaloxime

(16) respectively (Scheme 6).

Br2 CH3NO KOH> CH2NO2 02NCH2Br + Br

13 1KOH 0 N CHBr B-2>r 02NCHBr2 + Br 14 +///0- 02NCH2Br + Co(dmgH)2 py --j- BrCo(dmgH)2 py + CH2=N/ \0'

CH2NO + Co(dmgH)2py --4 O2NCH2Co(dmgH)2py

Br2CHNO 2 + Co(dmgH) 2p BrCo (dmgH) 2py + C.HBrNO2

HBrNO2 + Co(dmgH)2py 02NCH(Br)Co(dmgH)2py

SCHEME 6 109.

A mixture of the two alkylcobaloximes (15) and (16) in a

ratio of 3.3:1 would account for the elemental analysis obtained.

2. Reactions of Alkylcobaloximes with a-Bromonitroalkanes.

Many attempts have been made to form carbon-carbon bonds using

alkylcobaloximes, few have proved successful. Usually, the

homolytic displacement of cobaloxime(II) from a a-bonded allyl, 35-38 allenyl or benzylcobaloxime has been employed, (Scheme 7).

RI R3 + BrCC C3 CC?3CR1R2CR3=CH2 + BrCo(dmgH) 2B R2 CH2Co(dmgH)2B

R1 ~--~ + BrCCt3 --~ CCt3CR'R2C=CH + BrCo(dmgH)2B R2' 'Co(dmgH)2B

ArCH2Co(dmgH) 2B + BrCC(3 --> ArCH2Br + ArCH2CCC3

R1 R3

BrCH(CO 2Et) 2 CH2=CR3CR1R2CH(CO2Et) 2 R2 CH2Co (dmgH) 2B

SCHEME 7

RCo(dmgH)2B ---> R' + Co(dmgH)2B

Co(dmgH) 2B + BrCH(CO2Et) 2 >BrCo (dmgH) 2B + CH(CO2Et) 2

' CH(CO2Et) 2 + RCo(dmgH) 2B -- > RCH(CO2Et) 2 + Co(dmgH) 2B

R1 R3 RE `--~ R 2r— CH 2

SCHEME 8 110.

The mechanism of the reaction is shown in Scheme 8. The

reactions have always been regiospecific.

A possible route to the formation of a carbon-carbon bond

would involve the oxidation of the alkylcobaloxime to a cobalt(IVY

complex, the cobalt-carbon bond of which is labile. Both homolytic

and heterolytic cleavage are possible in principle. In the case

of an homolytic cleavage, the alkyl radical could couple easily

with another radical present. A reaction, where a carbon-carbon

bond was formed, which may involve a cobalt(IV) complex has been 39 reported, (Scheme 9). However, in this particular example

the cobalt-carbon bond was not cleaved.

PhH CN N / \ ~CNE NC> ~CN H CHz[Co] Ph TCNE~ f [Co] \ + TCNE- / NC CN H CHZ[Co~~] Phh H Co] TCNE = (NC12C=C(CN)2 [Co]=[Co(cimgH2B] B= imidazole

SCHEME 9 2-Bromo-2-nitropropane is known to act as an electron acceptor (Scheme 10).40 The possibility of a reaction between

2-bromo-2-nitropropane and methylpyridinatocobaloxime as shown in Scheme 11 was examined.

(CH3) 2C=NO2 + BrC(CH3)2NO2 ----. (CH3) 2C-NO2 + BrC(CH3)2 N0z

BrC(CH3)2 NO2 --. Br + 02NC(CH3) 2

SCHEME 10

(CH3)2C(Br)NO z+ CH3 Co(dm H) zPY [CH Co(dm H) z PY + + (CH3)2 CN02 + Br

Q,r [MeCo(dmgH)zpy)+ + (CH3)2CNO2 —). (CH3)3CNO2 + BrCo(dmgH)2py

SCHEME 11

Methylpyridinatocobalo*ime and 2-bromo-2-nitropropane were heated to reflux in acetonitrile for four days. Only polar compounds were formed which were uncharacterised. Because the expected product, t-butyl nitrite was volatile, another reaction with methylpyridinatocobaloxime and 2-bromo-2-nitrocamphāne was attempted. The mixture was heated in dimethylacetamide for three days. Again:, only a very polar white solid was isolāted. The product was not characterised.

Presumably, the complex decomposed slowly with the heat and the

compounds formed were from the reaction of dimethylglyoxime with the

alkyl bromides, 112.

3. Reaction of Alkylcobaloximeswith Copper(II) Salts.

INTRODUCTION

The cleavage of methylcobalamin by copper(II) chloride has been

reported.41 The reaction took place in water, but only in the

presence of chloride ions; methyl chloride was the sole product.

In ethanol the reaction was retarded by the presence of chloride

ion. The products in this case were methylethyl ether and methyl

chloride, in a ratio of 1:1. Methane was not detected in any of

the reactions. The stoicheiometry of the reactants was 1:1.

The authors proposed a transfer of the methyl group as a

carbanion, followed by nucleophilic attack on the methyl group of

the methyl copper intermediate to give metallic copper (Equation 4).

McB12 + CuCt2 H B12a + NeCuCt Ct > MeC? + Cu + Ct 4

13 An analogous reaction was observed with alkylcobaloximes.

Copper(II) chloride, copper(II) bromide, and copper(II) acetate

cleaved the alkylcobaloximes, while copper(II) fluoride, copper(II)

sulphate, copper(II) tetraphenylborate, and bis(acetylacetonato)-

copper(II) were -unreactive. A wide variety of alkylcobaloximes were 13 cleaved (Scheme 12),

RCo(dmgH) 2py + CuX2 -- > Co(dmgH)2 py + RCuX2 ---> CuX + RX 17 R = Bu, McCHCO2Me, C6H13CHMe, NeCHCN, CH2(CH2)4CH2

SCHEME 12 113.

The transfer of the alkyl group to copper(II) as a formal radical

was proposed by the author (Scheme 12). In this case a copperKI) compound

would be the product of nucleophilic attack on the alkylcopper intermediate

(17). Compound (17) was analogous to that proposed for the oxidation of 42 alkyl radicals by copper(II) halides (Scheme 13).

R' + CuX2 -4 RCuX 2 RCuX+X —> R+CuX2 _ . RX + CuX

17 SCHEME 13

The stereochemistry of the reaction was examined by treating R-1-methyl-

heptylpyridinatocobaloxime with copper(II) chloride. The 2-chlorooctane 22 13 isolated was mostly racemic, [o] = 0.64. D RESULTS

The reaction of copper(II) salts with alkylcobaloximes was found to

be much slower than reported by other workers.13 These workers used only

a small excess of the copper(II) salt over the alkylcobaloxime.

Pentylpyridinatocobaloxime reacted with different amounts of copper(II)

bromide(1, 1.5, 2.0, 2.5 molar equivalents). The yields of pentyl

bromide in each case were 6, 9, 43 and 50% respectively (glc). Although

these values cannot be accurate, because of the volatility of the product,

there is a clear indication that two equivalents of copper(II) bromide are

required.

The order of reactivity of the three copper(II) salts was found to be

copper(II) bromide > copper(II) chloride > copper(II) acetate. The

observed order of reactivity of the alkylcobaloximesasmeasured crudely

by tic monitoring was p-Me0C6H4CH2 > C6H5CHMe ti C6H5CH2 > Me2CH > Me1 Et >

CH2CO2Et rt, 02NC6H3CH2. Although the method is inaccurate an indication

of the effect of substituents in the alkyl group, on the rate of reaction

is given.

Qualitative analysis of the reaction mixture for both copper(II)

and copper(0) was negative,43 A test with an ethanolic solution of

114.

diquinoline44 though, was positive for copper(I).

Initially, it was thought that the only product of the reaction was the alkyl halide. More careful examination of the reaction mixture of copper(II) bromide with isopropylcobaloxime revealed the presence of 0-Isopropyl dimethylglyoxime (18). An authentic sample of compound (18) was prepared as shown in Scheme 14.

/ 1 + NaH + Me2CHBr + NaBr HON NOH HON NOCHMe2 18 SCHEME 14

The dependence of the product distribution on the amount of copper(II) salt used was examined. Benzylpyridinatocobaloxime was reacted with 1,2 and 5 equivalents of copper(II) bromide. The

products were isolated by plc. The results are summarised in Table

9. The effect of lithium bromide on the product distribution was

also examined (entry 3) ,

TABLE 9

Products (7)

RCo(dmgH)2py : CuBr : LiBr 2 PhCH2Br (19)a (20)a

1, 1 : 1 : 0 traces 10 14

2, 1.: 2 : 0 78 3 14

3. 1.; 2 : 1 77 - -

4. 1 ; 5 :0 60 - -

a Compounds (19) and (20) are 0-benzyl dimethylglyoxime and

00-dibenzyl dimethylglyoxime respectively. 115.

The possibility of external nucleophilic attack was examined.

The results are summarised in Table 10. Although there is an indication of external nucleophilic attack (entry 11) the evidence is not conclusive. A reaction of the nucleophile with the copper(II) salt before it reacts with the alkylcobaloxime cannot be ruled out. Blank experiments have been performed in some cases to check whether or not the reaction of the nucleophile with the alkyl halide, formed initially, was the source of nucleophile substituted product. All the products were identified by ms and glc (authentic samples were prepared in all cases and the retention times were compared). The ratios were estimated by glc.

The stereochemistry of the reaction was examined.. R-1-Methyl- heptylpyridinatocobaloxime reacted with copper(II) bromide in acetonitrile to give 2-bromooctane with 24% inversion.* In the presence of lithium bromide 22% inversion was observed.

The solvent appeared to have a strong effect on the reaction.

The reaction of benzylpyridinatocobaloxime with copper(II) bromide in acetonitrile went to completion in half an hour at room temperature, At the same period of time in benzene only a small amount of alkylcobaloxime had reacted.

* Different values have been reported in the literature for

the optical rotation of 2-bromooctane.45 The highest, -41.60 , 46 has been used for these calculations. TABLE 10

R RX(blank) CuX2 Nu Products

1. Me2CH CuCt2 LiBr Me2CHBr : Me2CHCt 1:1.4

2. Me2CH CuBr2 LiOMe Me2CHBr : Me2CHOMe 7.5:1

Me2CHBr LiOMe Me2CHBr : Me2CHOMe 6.6:1

3. Me2CH CuCt2 KOAc Me2CHCt + Me2CHOAc (traces)

4. Me2CH CuCt2 LICN Me2CHCt

5. Me2CH CuCt2 KCN Me2CHCt + Me2CHCN (traces)

6. PhCH 2 CuCt2 LiBr PhCH2Ct : PhCH2Br 5:1

7. PhCH 2 CuCt2 LiOMe PhCH2Ct : PhCH2OMe 2.7:1

8. PhCH2 CuCt2 LiCN PhCH2Ct

9. PhCHMe CuCt2 PhCHCtMe

10. PhCHMe CuCt2 LiBr PhCHCtMe : PhCHBrMe 1:2.7

11. PhCHMe CuCt2 LiOMe PhCHCtMe : PhCH(OMe)Me 1:28.5 PhCHCtMe LiOMe PhCHCtMe : PhCH(OMe)Me 1:12.8

12. PhCHMe KOAc PhCHCtMe : PhCH(OAc)Me 1:2.3.

13. PhCH2CH2 CuCt2 LiBr PhCH2CH2Ct + PhCH2CH2Br

117.

Finally, the possibility of free carbonium ions or radicals being generated during the reaction was examined.

1,I-Dideuterio-2-phenylethylpyridinatocobaloxime (prepared as shown in Scheme 15) reacted with copper(II) bromide. Less

than 4% deuterium scrambling was observed.

LAH PhCH2CO2Et > PhCH2CH2OH PBr9 > PhCH2CH2Br

BsC? LAD PhCH2CH2OBs

PhCH2CD20H ,, Co(dmH) 2py] J 1BsC? PhCH2CH2Co(dmgH)2py

PhCH2CD2OBs ICuBr2 .

,[Co(dmH) 2PY] PhCH2CH2Br j CuBr2 PhCH2CD2Co(dmgH)2py > PhCH2CD2Br + PhCD2CH2Br

> 96% < 4%

SCHEME 15

47 The phenethyl carbonium ion is known to have structure (21).

If this was an intermediate in the reaction then scrambling of the

deuterium in 1-bromo-2-phenylethane would be expected. 2-Phenylethyl

radical rearranges only slightly, 2-5% at 145-175°C.48 So the

experiment rules out the formation of free carbonium ions during the

course of the reaction, but not of free radicals.

HZC-CHZ 21 1.18.

Radicals such as 1-cyclopropylethyl(22) have been shown to 49 rearrange rapidly to the open chain unsaturated radical (23),

while the analogous carbonium ion (24) exhibits a greater stability 50 (Scheme 16). ix 114°C,/ 22 23 24

SCHEME 16 In the light of these facts, it was attempted to prepare

1-cyclopropylethylpyridinatocobaloxime and examine its reaction

with copper(II) bromide. Initially, the preparation of 1 -bromo-

1-3cyclopropylethane was attempted, The preparation of this

compound from the reaction of alcohol (25) with hydrogen bromide

in ether has been reported.S1 Ring opening even at -78°C was

observed, The same difficulties were experiencedin the preparation

pg the iodide from the alcohol and phosphorus/iodine. Attempts to

use milder brominating reagents52 also resulted in ring opening

(Scheme 17). The alcohol was unreactive towards 2.-toluenesulphonyl

chloride but 1-cyclopropyl-1-methanesulphonatoethane (26) was

formed from the reaction of alcohol (25) with methanesulphonyl chloride

(Scheme 17),53

119.

HO HB8a~ CH3CH=CHCH2CH2Br

25 DMF, RT ) CH3CH=CHCH2CH2Br Ph3P.Br2

DMF, -60°C) CH3CH=CHCH2CH2Br Ph3P.Br 2

12 py' > CH3CH=CHCH2CH2I 0°C

MsCe, Et3N CH2Ct2f 25°C OMS

SCHEME 17

When compound (26) was treated with pyridinatocobaloxime(I) ion, only pent-3-enylpyridinatocobaloxime was detectable (Scheme

18), Cycloprōpylmethylpyridinatocobaloxime is known to rearrange to but--3-enylpyridinatocobaloxime at room temperature.54 It is not known whether the ring opening occurred before or after the reaction with cobalt(I) ion.

IV• ( [col- CH3CH=CHCH2CH2[CoJ OMs [co] [co]=Co(dmgH)2pj;

SCHEME 18 120.

In any case, the difficulty experienced in preparing

1-bromo-l-cyclopropylethane indicated that even the carbonium ion undergoes facile ring opening, and so in this case a carbonium ion intermediate could not be distinguished from a radical one.'

Hex-5-enyl radical is known to cyclise rapidly to cyclopentylmethyl radical55 while hex-5-enyl carbonium ion forms the cyclohexyl 56 carbonium ion (Scheme 19).

SCHEME 19 Hex-5-enylpyridinatocobaloxime was prepared from cobalt(I)

ion and hex-5-enyl bromide. The complex reacted with copper(II)

bromide to give a mixture of hex-5-enyl and cyclopentylmethyl

bromide in a ratio 2,7:1 (Scheme 20). The products were

identified by glc and ms. An authentic sample of cyclopentylmethyl

bromide was also prepared for comparison (Scheme 21).

Br CuBr2 Co(dmgH)2py 27 SCHEME 20

(30H Br Ph3P•Br2~ DMF SCHEME 21 121.

The presence of radicals or carbonium ions in the cleavage

of secondary alkylcobaloximes was checked by the reaction of

1-methylhex-5-enylpyridinatocobaloxime. The different routes

to prepare the alkylcobaloxime are shown in Schemes22 and 23.

CH2=CH(CH2)3CH2OH «r2 0/ «5H5NH12 MHZ—cH(GH2)3cH0 CHZCl2 71eMgI CH2—CH(CH2)3CH(BrHe SPB r3 -PY CH2=CH(CH2)3CH(OH)Me iTsapy decomposed unknown products SCHEME 22

~—\ OH sOG2 Cl 2s_1la,› ~ H ph3P.Br2 OH ~1.Mg r 2.MeCHO PBr3,PY 1 Br [cod_ [co]

[Co] --=--[CoCcimgH)2pA SCHEME 23 122.

The oxidation of hex-5-en-1-al proved problematic.57 Long

reaction time and excess of the oxidant were necessary. The

bromination of hept-6-en-2-ol gave a low yield of the bromide

(47%, lit.,58 67.5%). The bromide decomposed during its distillation.

In order to overcome these problems, a different route was

employed starting from tetrahydrofurfuryl alcohol, so that large

amounts of 2-bromohept-6-ene would be obtained. Again, the

bromination of pent-4-en-1-ol took place in low yield (23%).

I-Methylhex-5-enylpyridinatocobaloxime reacted with copper(II)

bromide to give 2-bromohept-6-ene and one of the cyclic isomers

in a ratio of 2.15:1 (Equation 5). The products were identified

by glc - ms. As 1-bromomethyl-2-methylcyclopentane ('27) was not

available, 3-methylcyclohexanyl bromide(28) was prepared in order

to differentiate between the two compounds. The ms of the

rearranged material and of compound (28) were identical. However,

this does not necessarily exclude compound (27). The possibility of

a rearrangement of compound (27) to (28) in the mass spectrometer

cannot be excluded. It was not possible to characterise the

rearranged product unambiguously. Both hex-5-enyl and 1-methylhex-

5--enylcobaloxime were heated in benzene at the same temperature

and for the same period as in their reactions with copper(II) bromide.

In both cases, only a small amount of decomposition was observed.

There were no rearrangement products.

[co]

27 28 [Co] Co(dmgH)2py 215 123.

The Mechanism of the Reaction.

Three mechanisms are possible for this reaction.

(a) Electrophilic Substitution.

As mentioned before, this mechanism was proposed for the 41 reaction of methylcobalamin with copper(II) chloride (Equation 4) and is analogous to the reaction of alkylcobalt(III) complexes with mercury(II) salts.S9 However, nearly all the evidence is against such a mechanism.

An electrophilic substitution would require the formation 13 of copper(0), This was not observed. Metallic copper was not observed in the reaction of methylcobalamin with'copper(II) 41 bromide either.

The alkyl group effect is opposite to that expected for an

SE2 mechanism (Table 11).3

Table 11. Rate constants for the reaction of mercury(II) salts with

alkyl aquocobaloximes,

R Me Et Pr Me2CH

k(if-1 s-1) 65 + 2 0.121 + 0.007 0.092 + 0.003 < 7 x 10-6

R PhCH2 p-Me0C6H4CH2 p.-FC6H4CH2 12-02NC6H4CH2 -3 -2 k(Ns) 7.5 x 10-2 11.3 x 10 2.8 x 10 6.5 x 10-3 124.

The formation of compounds (18), (19) and (20) or of rearranged products cannot be explained by an SE2 mechanism.

Probably the strongest evidence against this mechanism is the stereochemistry of the reaction. High percentage of inversion would be expected if an SE2 mechanism was operative.

On the light of this evidence an SE2 mechanism was ruled out.

(b) Homolytic Substitution.

A second possible mechanism would be the transfer of the alkyl group to copper(II) as a formal radical (Scheme 7). This mechanism has already been proposed for the cleavage of the alkylcobaloximes by copper(II) halides.13 Homolytic substitution has been proposed for the reaction of alkylcobaloximes with cobalt(II)60 and chromium(II) complexes,61

The fact that copper(II) chloride, copper(II) bromide and copper(II) acetate were reactive, while copper(II) sulphate, copper(II) fluoride, copper(II) tetraphenylborate and bis(acetylacetonato)copper(II) were unreactive is in support of an SH2 mechanism. The formation of copper(I) is also consistent with this mechanism.

However, there are a number of observations that cannot be explained by this mechanism. The alkyl group effect is opposite to 61 that expected for a bimolecular process (Table 12).

Table 12, Rate constants for the reaction of chromium(II) salts with

alkylaquocobaloximes,

R Me Et Pr Me 2CH 1 k(M1 s_ ) 230 1.4 x 10-2 1.3 x 10-3 1.08 x 10-4 125.

The analogous reaction with cobalt(II)60 took place with inversion of configuration, which was not observed with the copper(II) halide reaction. This was attributed by some workers to the presence of the alkylcopper intermediate (17). However, these intermediates are usually cleaved without the formation of free carbonium ions or radicals.42 Similarly, the rearrangement of the alkyl group cannot be explained.

Based on this evidence an SH2 mechanism appeared improbable.

Another possibility would be the oxidation of the alkylcobaloxime to cobalt(IV). Hocoolytic or heterolytic cleavage would then be possible (Scheme 24).

IV + RCo (dmgH) 2py + CuBr2 [ RCo (dmgH) 2py ] + CuBr + Br_

d Br-

RBr + Co(dmgH)2py R. + Co(dmgH)2pyl CuBr2 RBr + [Co(dmgH)2py]+ j CuBr2 BrCo(dmgH)2py + CuBr RCuBr2

31 RON NOH RON NOR 1 29 30 RBr + CuBr

+ Co2+ + dmgH2

SCHEME 24 126.

The oxidation of alkylcobaloximes by ammonium cerium(IV) nitrate 62-65 and iridium(IV) hexachloride ion has been observed. The reaction is summarised in Scheme 25.

For R = secondary alkyl group or benzyl:

H RCo(dmgH)20H2 —÷[RCo(dmgH)20H2]+ Co 2+ 2dmgH2 + ROH

. icr 2+ RC€ + CO + 2dmgH2 Z+ + dmgH2 + olefin + H2O

For R = primary alkyl group:

IV V RCo(dmgH) 20H2 [RCo(dmgH) 20H2]~-= [RCo(dmgH)20H2]2+ + RCo(dmgH)20H2

V [RCo(dmgH)20H2]2+ -H+ > [Co(dmgH)20H2]+ + olefin

SCHEME 25

There is some controversy about the products of the reaction.

The benzyl alcohol, that was reported as the product of the reaction

in the absence of an external nucleophile63 was not observed by 13 other workers.

In the presence of an external nucleophile 90% inversion was 66 observed (Equation 6).

HCt, HC€04 C8H Co(dmgH) 0H2 + (N114)2 Ce(NO3)6 C 8H17Ct + 17 2 H20, McOH 16%

C8H16 + Co2+ + 2dmgH2

50% 6 127.

When only one equivalent of the oxidant was used, 0-alkyl dimethylglyoximes were formed in nearly quantitative yield 62 (Equation 7).

PhCH2Co(dmgH) 20H2 + IrC?6 ----4 + Co 2+ + dmgH2 7 NOH \ NOCH2Ph

Most of the observations made can be explained by this mechanism. The formation of copper(I) and the order of reactivity of the copper(II) salts are in agreement with the reduction of copper(II) to copper(I).

The high reactivity of copper(II) bromide in acetonitrile is consistent with its reduction to copper(I). Acetonitrile is known to stabilise the copper(I) ion and copper(II) salts in acetonitrile 67 solution have been described as powerful oxidising agents.

Copper(II) bromide in acetonitrile was present as copper(II)

tetrabromide ion (32), 10%, copper(II) tribromide ion (33), 50%, and copper(II) ion (34), 401,68 Copper(II) tetrabromide ion is the

predominant species in the presence of bromide ion.

2+ [CuBr,.] 2 [CuBr3 (MeCN) 2 ] [ Cu(MeCN) 6 ]

32 33 34

The alkyl group effect on the rate of the reaction is in

agreement with the oxidation of cobalt(III) to cobalt(IV). The rates of oxidation of alkylcobaloximes by iridium(IV) hexachioride ion 63 are given in Table 13, 128 .

Table 13

R Me Et Pr Me2CH PhCH2 p-Me0C6H4CH2 4 6 k.(rīls-1) 1 2 2 8 x 10 8xl03 4 x 10

R p-McC6H4CH2 p-FC6H4CH2 R-02NC6H4CH2 ls 1(04 -i) 2 x 105 1.5 x 104 ti 2

Also, cyclic voltametry has been employed in some cases to measure the reversible oxidation potentials of alkylcobaloximes

(Table 14).69 Again, a similar trend in the reactivity of alkyl-

cobaloximes was observed.

Table 14

R Me Et Me2CH PhCH2

El (V) 0.902 0.878 0.856 0.859 2

The organic products of the reaction are also consistent with

the oxidation of cobalt(III). The formation of compounds (29) and

(30), pathway (c), when only one equivalent of copper(II) bromide

was used, is analogous to that when one molar equivalent of iridium(IV) 62,63 hexachloride ion was• used. 129.

The homolytic cleavage of the cobalt(IV) complex is consistent with the observations. Rapid trapping by copper(II) bromide would give rise to rearranged alkyl bromides.

Homolytic substitution on the cobalt(IV) complex cannot be excluded. It is not clear whether the inversion observed arises from an SH2 attack on the cobalt(IV)complex or from an SN2 attack.

The nucleophilic attack observed in certain reactions (Table 10) is in agreement with pathway (d). However, nucleophilic attack on intermediate (31) cannot be excluded. In fact, all three processes

(a, b and d) may be operative. Heterolytic cleavage of the cobalt(IV) complex to form free carbonium ions, at least with primary alkylcobaloximes, has been dismissed.

An argument against this mechanism would be the low percentage of inversion of configuration compared with that observed from the alkylcobaloximes by cerium(IV). The high temperature employed as well as the different rates of oxidation may favour pathway (a) rather than (b) or (d). Indeed, totally racemised 2- brōmooctane • was isolated when the reaction was conducted in benzene where the oxidation rate is very slow,

An unaccountable fact is the difference in the reaction with one or two molar equivalents of copper(II) bromide. When two equivalents of copper(II) bromide in acetonitrile were used, the reaction was fast and went to completion, When one molar equivalent was used all the alkylcobaloxime was consumed, but at a much 130.

slower rate. If a mechanism, as shown in Scheme 24 was operative, then the reaction would be expected to go only to 50% completion.

It is not clear whether the alkylcobaloxime reacts slowly with one equivalent of copper(II) bromide or whether it undergoes slow thermal decomposition.

Attempts to confirm the presence of cobalt(IV) species by esr.70 failed due to the absorption of copper(II) in the same region.

Only the disappearance of copper(II) species was observed.

In order to examine whether the oxidation of cobalt(III) by copper(II) is a feasible process, their oxidation potentials were measured.

The current-voltage curve on a Rotating Disc Electrode (Pt) for the reaction of cobalt(III) to cobalt(IV) is shown in Figure 1.

The wave is quasi-reversible, which is described by Equation 8.

_ D - (1 8 1limdlim _ 1 + e -8 + k e -a) 8 z j - ko

(E-Ea)F where 8 = k D (Levich equation) RT D zD k' is the electrochemical rate constant at E = Ems: kD is the heterogeneous rate constant describing mass transport, a is the observed gradient of Tafel law for reduction.

8 is the normalised variable describing potential.

D is the diffusion coefficient. zD is the thickness of the diffusion layer.

Figure 2 shows the current-voltage curve analysed. The limiting current is not too well defined but a reasonable fit is obtained when a=0.45,

40uA, kD ilim /kō=1.14, El=Ee=0.815V(wrt, saturated calomel electrode). 131.

From the gradient of the Levich plot, Figure 3, the value of

D (diffusion coefficient) can be calculated.

If A is the area of the electrode, v is the kinematic viscocity, c is the concentration in bulk solution, W is the rotation speed of

R.D.E. in Hz then:

1 1 2 1 1 2 vS lim lim = 1.554nFAD3v- cmW3 ==4> 1213 i = 1.554nFAc~(W)

D = 5.81x10-6cm2s-1

2 1 1 D 1 1 1 k _ zD = 0.643W-7 v.61)7 4> kD D - zD D0.643s -3 = 3.72x10 when W = 9Hz. -3 k 3.1?140 - 3.26x10-3cros-1

The current-voltage curve for the copper(II) to copper(I) reaction is shown in Figure 4. The oxidation of bromide to bromine is responsible for the lower part of the curve. The higher part 2+ e + (Cu —> Cu ) is quasi-reversible and the oxidation potential

E4is 0.51V. Hence LE = 0.30V.

For [Co(III)] = 5mM and [Cu(II)] = 5mM, the concentration of cobalt(IV) species can be calculated from the Nernst Equation:

-3)2e-0.3/0.025 [Co(IV)]2 = (5x10 [Co(IV)] = 1.2x10-5M, which indicates that the process is feasible. 132.

It is noteworthy that a similar mechanism has been proposed for the cleavage of alkylcobaloximes by halogens.13 However, direct evidence for the existence of cobalt(IV) species is necessary. More studies to distinguish between an SN2 and SH2 mechanism are also required. 133.

4. Synthesis of Coenzyme B12 Model Compounds.

(a) INTRODUCTION

Coenzyme B12 and methylcobalamin are involved in many enzymatic reactions. The reactions are classified into two categories.

Methylcobalamin is involved in the first group of reaction and the coenzyme B12 is involved in the second (Table 15).71

Table 15

(a) 1. Synthesis of methionine

2. Synthesis of methane

3. Synthesis of acetate

(b) 4. Dioldehydrase, e.g., HOCH2CH(OH)CH3 --4 CH3CH2CHO + H2O

5. Ethanolamine ammonia lyase,e.g., HOCH2CH2NH2 ---CH3CHO + NH3

6. Aminomutase utilising either:

(i) (S)-3,6-diaminohexanoate

(ii) (R)-2,6-diaminohexanoate e.g., 3S-H2NCH2CH2CH2CH(NH2)CH2CO2H

(iii) (R)-2,5-diaminopentanoate 3S5SCH3CH(NH2)CH2CH(NH2)CH2CO2H (iv) a-or R-leucine

7. Methylmalonyl-CoA mutase

8, Glutamate mutase

9, a-Methylene glutarate mutase

10, Ribonucleotide reductase 134.

The reactions 4 to 9 can be generally described as:

H X X H

C C 1.-1 ----C----C I I

In all cases it was found that the hydrogen atom that was

transferred was equilibrated with the two hydrogens of the 5' carbon atom of deoxyadenosine connected to cobalt. Esr

experiments have shown the presence of cobalt(II) as an intermediate

in these reactions. The sequence of transformations shown in

Scheme 26 has generally been accepted.71

CHZ A 'CH2 A S' + A—CH3 s 4. I Co] --> -[Co] ---- -co] ---- 10 -1- Bz Bz Bz

CH2 A CH2—A p

o] ~ PH + --Co] ~ -[Co] ? [120z Bz Bz J SH= Substrate , PH=Product A-CH2 = 5-Deoxyadenosyl.

SCHEME 26 135.

However, the mechanism of the rearrangement itself has not yet been settled. Different theories have been developed including a free radical mechanism. In this there was no requirement for the formation of a cobalamin-substrate, carbon-cobalt bond, neither was the possibility excluded. Reactions of chemical models have 72 supported this mechanism (Scheme 27).

OH AcOH / hv ColdmgH2 0 py OH A

Y nH OH

OH OH

SCHEME 27 Another theory supported the presence of cobalt(III) 7-complexes

(35), Equation 9, particularly as intermediates in 312 mediated dioldehydrase reactions. This theory was supported by studies on 73 the alcoholysis of acetoethylcobaloximes. 136.

SOH CH2 _ _ _CH(OH) CH2CH(OH)2 9 _ f oi 4co] Bz Bz 35

Schrauzer suggested that the cobalt-carbon bond of the coenzyme is cleaved heterolytically.74 However, this mechanism does not explain many currently accepted facts and may be disregarded.

An entirely novel interpretation was described by

Corey and Green.75 This involves cleavage of the equatorial corrin ring of the Ba2 coenzyme and is thus not susceptible to testing by simple chemical models. Although the mechanism accounts for many observations, it does not explain the esr observations of organic radicals and cobalamin(II) during the enzymatic reactions.

The enzyme reactions, 7, 8 and 9 of Table 15 are of interest because they involve a carbon-skeleton rearrangement (Equations

10, 11, and 12),

The first reaction involves the 1,2-shift of the thiolester

group. The rearrangement is intramolecular and takes place with retention of configuration. The second reaction involves the migration of the acrylic acid group. The third involves the intramolecular migration of the glycyl group with inversion of configuration.

Model compounds have been prepared in attempts to emulate the first 76-81 two reactions.

137.

/CO2H ~ 10 Coscoa I COSCoACO2"

COH L02H CO2H

N~H2 ~H2 c u 12 2H

The rearrangement of methylmalonyl-coenzyme A to succinyl-

coenzyme A has been studied in detail. A very simple chemical

model was prepared initially. On cleavage some rearrangement

was observed but in very low yield (Scheme 28).76 CO2Me ~COZMe /CO2H CO2H + CO2H _[Co] CO2H CO2H CO2H Bz 13.6% 37% 18%

SCHEME 28

A theory was developed which suggested that the yield of the

rearrangement product is low due to the homolytic cleavage of the

cobalt-carbon bond. The malonic ester 'substrate' loses contact

with the central cobalt atom and thus, deprived of that atom's 138.

77,78 effect, is no longer able to rearrange. A more sophisticated model was prepared in which the substrate was bound to the equatorial ligand (36). Photolysis of the cobaloxime followed by hydrolysis gave methylsuccinic acid in 82% yield. A mechanism for the rearrangement was postulated (Scheme 29). Experiments with deuterium labelling have indicated that the hydrogen is 78 abstracted from the methylene group next to the oxime.

Another model containing a thiolester function was prepared 79 and exclusive migration of the thiolester group was observed.

It is possible that the rearrangement takes place at the intermediate 80 radical stage (37) to (38), Scheme 30. However, the role of cobalamin in the rearrangement is not established.

0----H----- lC N2 ~ (CH 1ti

MeVN~ âNMe 0----H----O B=MeOH 36 139.

(

SCHEME 29

ca2Et CO2Et •XCOSEt COZEt —~ Co + B12s COSEt B~~ 37 BZ '~pCOSEt J / )p Br CO2Et COzEt COSEt COSEt -CTQ] _H Bz - Co] Bz Y ,CO2Et CO2Et XCOSEt —COSEt 33-44% SCHEME 30 140.

Model compounds have been prepared for the second reaction

also. Alkylcobalamin (39) was photolysed in water. Three

acids,3-methylitaconic acid, butadiene-2,3-dicarboxylic acid 81 and a-methyleneglutaric acid were isolated (Equation 13).

CO2THP ~ COZTHP,/COH ZH -COzH yCO2H H20 Co] __> + + 13 6z ~CO2H ~COZH TCO2H 39 15% 7% 3.5%

When experiments were conducted in deuterium oxide, deuterium incorporation was observed in both a-methyleneglutaric . acid and

S--methylitaconic acid. The deuterium was found to be at the 81 1-position indicating the acrylic group had migrated. 82 The third reaction has been ) studied only enzymatically.

Again, the hydrogen which migrates became equivalent with two

other hydrogens of the coenzyme.82 A primary kinetic effect was 82 observed, The mechanism proposed is- shown in Scheme 31.

There was no evidence for the formation of glycine during the

reaction . The attack of cobalamin(I) ion at the a-carbon is

contrary to the usual mode of addition df cobalainin(I) ion to

substituted olefins. 141.

N CH2A CH2H~ ~~ A + -[C°] Co] z T ū_ Bz CO2 NH Bz

N CO2+ ACH21H +z CH-NH3 CH2A HZN~ C' CH2= CHCO2 2 2 -[C01 L-)cDC\I+ 05] Col 1 T Bz Bz z AC H2=5-D eoxyadenosyl

SCHEME 31 Retey's work indicated that rearrangement can take place in high yield with model compounds, if the substrate remains in proximity to cobalt so that it catalyses the rearrangement.

_+ o Et

HOHi ŌOHs~ ' 0 Me CO2Et ,N/Me

Co I CF3CO2 CO2Et Me INPY \N ~Me o(dmgH)2py 40 41 142.

The nmr spectrum of compound (40) in trifluoroacetic acid

showed that the four methyl groups of the equatorial ligand are non-equivalent.83 This suggests that the alkyl group is not free

to rotate about the cobalt-carbon bond. The formation of a hydrogen

bond between the carbonyl group and the protonated dimethyl-

glyoxime to form the salt (41) is possible. This would inhibit

any rotation making the four methyl groups non-equivalent. The

X-ray analysis of compound (40) indicated that in the non-protonated

cobaloxime there is no interaction between the carbonyl group and

the hydrogen of the planar ligand (Figure 5). A similar effect

was observed with other esters, The hydrogen bonding would be

possible in neutral medium if the alkyl group contained a carboxyl

R-substituent (42), Even if the cobalt-carbon bond is cleaved, it

is possible that the hydrogen bond will facilitate retention of

the alkyl group close to cobalt and rearrangement may be induced.

C Me_ HO 0 Me N C"

Me- N ' N e 0------H------0 42 143.

The observation that the carbonyl groups at the two position in alkylcobaloximes absorb at low frequency in the it may be connected with this interaction. However, it has not been clarified whether this is due to an inductive effect of the cobaloxime group or an interaction between the equatorial ligand and the carbonyl group.

The preparation and study of the structure of the alkylcobaloximes (43), (44) and (45) was therefore undertaken.

[Co] NRIR2 [Co] PhCONH [Co]

/ Et CO2Et ~244 C OZEt CO2Ne 43 45 [Co] = Co Cd mgH)2py

(b) Synthesis of 2,3-Diethoxycarbonylpropylpyridinatocobaloxime (43).

.Alkylcobaloxime (43) was prepared from itaconic acid as shown in Scheme 32. 4 [Co] / Et0H,H2502 no reaction 24h C/OzH OZH CO2Et CO2Et J,HBrAcOH

(—T_Co] [Cof Br CO2Et CO2Et CO2Et CO2Et 43 [Co] = [co(cimgH 2py]

SCHEME 32 144.

- In the nmr of compound(43), the four methyl groups of the dimethylglyoxime ligand appeared as two singlets in deuteriochloroform and as

four singlets in trifluoroacetic acid. Evidently, a hydrogen bonding

analogous to that observed in compound(40) was present.

It was attempted to prepare 2,3-dicarboxypropylpyridinato

cobaloxime, in order to compare its spectra with those of compound

(43). Hydrolysis of ester groups close to the cobalt atom are

difficult and requires drastic conditions because they are

sterically hindered. Therefore, the more facile hydrolysis of

the cyclic anhydride analogue was attempted (Scheme 33).

Br HBr,AcOH, 0 ~ [coT no reaction KI,Me2C0

no reaction < [Co] [co] anhydrous I ' I[Co] conditions 0 [co]=[cocimgH2py]

SCHEME 33 Cobaloxime(II) abstracted the iodine atom but it did not react

with the radical to form the alkylcobaloxime. It is not clear why

cobaloxime(I) ion did not react with the iodide. As the preparation

of the other two esters (44) and (45) was necessary, the formation

of the acid was not pursued any further.

145.

cobaloxime (44).

The alkylcobaloximes (44) and (45) were of particular interest

since chemical models for the aspartate-glutamate rearrangement

have not as yet been reported.

The first route to compound (44) is shown in Scheme 34.

Diethyl N-formylaspartate was treated with two equivalents of

lithium diisopropylamide and the resulting anion was quenched

with formaldehyde or ethyl formate. Starting material was always

recovered together with other products. In some cases there was

an indication that the desired compounds (46), (47) were formed

but the reactions were not reproducible.

NH3Cl- 1.KH HNCHO 1.LDA unidentified } \ 2.HCO2Et / \ 2.H—CHS( products CO2Et CO2Et CO2EtCO2Et 1.LDA 2.HCO2Et ~3.Ac20 unidentified products SCHEME 34.

HNCHO H2OH HNCH 0 ~Ac ( COZEt CO2Et COZEt CO2Et 46 47 146.

Another route was attempted starting from diethyl N,N-dimethylaspartate (48), Scheme 35. This compound was best prepared from hydrogen and formaldehyde85 rather than formic acid and 86 formaldehyde. The anion was generated by treating compound (48) with potassium hydride. On addition of methyl iodide diethyl

N,N-dimethyl-3-methylaspartate was formed in 43% yield. When ethyl formate or formaldehyde was used to quench the anion, mainly starting material was recovered. Changing the temperature of the reaction or the amount of potassium hydride used had little or no effect. Only in one case was it possible to isolate a compound having the spectral data expected for the desired product (49).

Again, the yield was low and the reaction was irreproducible.

NMe2 NMe2 H 1.KH,18-crown-6> 1

COZEt CO2Et2.HCH0 COZEt CO2Et

48 KKH 2.HCO2Et 49 3.Ac20

starting material recovered

SCHEME 35 The alcohol (49) appeared to have all the required spectral data, However, it decomposed on attempted purification by plc. The alcohol did not give a molecular ion in the mass spectrum, although a fragment from elimination of water and of the ethoxycarbonyl group at m/e 156 (50) 147.

was observed. The analogous fragment (51) was observed from the starting material. Accurate mass measurement confirmed that the formula of the fragment (50) was CBH14NO2.

\ tNMe tNMe2 „ 2

51 CO2Et 50 CO2Et

Attempts to eliminate the alcohol group or to form an ether, without the isolation of the alcohol 49, also failed. Elimination of the amino group appeared to be preferred (Scheme 36).

NMez iNMe3I- 1.KH,18-crown-6~N Me Me 2.HCH0 CO2Et 1..02Et CO2Et CO2Et CO2Et CO2Et

CO2Et

SCHEME 36 This route seemed initially to be most straight forward because all the functional groups were already present and only the addition of a carbon unit was required. However, the necessity for an oxygen function on the additional carbon unit seemed to create problems.

148.

An analogous route was attempted by treating the anion with

diiodomethane (Scheme 37). The advantages• of this method were

that the alkylcobaloxine would be obtained easily from compound

(52), if formed. Also the complications from the alcohol

functionality would be avoided. The products of the reaction

were unidentified. NMe2 NMe Me2 j KH 2 CH IZ 18-crown-6> X' r ~Et COZEt 02Et CO2Et CO2Et Et 52

SCHEME 37 It has been mentioned that halomethylpyridinatocobaloximes 87 are base unstable (Equation.14).

CeCH2Co (dmgH) 2py MeO > NeOCH2C( + [ Co (dmgH) 2py] --.~

NeOCH2Co(dmgH)2py + Cr - 14

The possibility that this reaction would take place with the

anion of diethyl N,N-dimethylaspartate (Scheme 38) was examined.

Only starting materials were recovered. Probably, the reagent was

too bulky. 11+9.

NMe2 NMe2 ci ClCH Co] + C [Co] QzEt C42Et CO2Et CO Et

[co]CHI NMe2 ( COZEt COZEt [Co]= [co(dmgH2py]

SCHEME 38 As the functionalisation of the 3-position of diethyl aspartate proved unfruitful, a different approach was attempted. This is outlined in Scheme 39.

Z X=N Z

CO2Me CO2R CDZMe

SCHEME 39 This methodology involved a masked glycine unit which could be easily deprotected after the reaction. The reactions attempted are shown in Schemes 40-42. 150.

~-0 CH2BrCHBrCO2Me> Ph/ u Ph 53 Br CO Me CH 2=C ( Br)CO 2 Me+ N 0 + N + 55 Pht--0 Ph)--O 54 SCHEME 40

MeO—COZMe

N 1 .KH , N~0 + PhCO2Me+ 2.CH2(0Me)CHBrCO2Me Phi-0 Ph 1 0 53 3.Me0H 56 • Me0 Me PhCONHCH2CO2Me+CH-C(Br)CO2Me +55+ Br CO2Me CO2Me 57 SCHEME 41

Me0--0O2Me 1.110Et N > N 0 + 2.CH2(OM&CHXCO2Me Ph 0 Ph) 0 53 56 traces PhCONHCH2CO2Et + 55 X=Br,I SCHEME 42 151.

2-Phenyl-2-oxazolin — 5-one (53)88 has been used often for the synthesis of substituted aminoacids. Upon reaction with methyl

2,3-dibromopropionate89 elimination of hydrogen bromide instead of displacement at the 2-carbon took place. Whether 4-(2-bromo-2- methoxycarbonylethyl)-2-phenyl-2-oxazolin-5-one (54) was formed 89 by the Michael addition of the anion to methyl 2-bromoacrylate

or by direct displacement at the 3-carbon is not clear. The structure

of compound (54) was assigned on the basis of nmr, ms and by the

fact that it eliminated easily to give methyl 2-bromoacrylate and

2-phenyl-2-oxazolin-5-one. In all these reactions another compound

(55) was formed, which appeared to be a dimer of 2-phenyl-2-oxazolin-

5-one. As the reaction did not give the expected products it was

not pursued any further.

The anion of compound (53) was treated with methyl 2-bromo-3-

methoxypropionate.40 Elimination in this case should be more

difficult, Some of the desired compound 4-(1-methoxycarbonyl-2-

methoxyethyl)-2-phenyl-2-oxazolin-5-one (56) was probably formed,

but only in 0,5% yield. Elimination of hydrogen bromide did not

take place but the ce-hydrogen was abstracted. This led to the formation

of dimethyl 2-bromo -2,3 -di-(methoxymethyl )butan-1,4-dioate (57)

as shown in Scheme 43.

Thecounterion, potassium, was replaced by thallium in an

effort to assist the displacement reaction. 152.

N ~p Me0CH2CHIBr)COZMe )— 0 N~0 KH, N Ph ~ —OMe Ph/~ Ph~0 Me MgtH C.He'lC3 r Me0 OMe CO2Me Br CO2Me CO2Me 57

SCHEME 43 The reaction was very slow. Only the starting materials were

recovered and the presence of the expected product was only

detected by mass spectrometry. Stork and his coworkers have

reported the use of ethyl*N-benzylideneglycinate (58) in the synthesis 91 of e-aminoacids as shown in Scheme 44,

PhCH=NCH2CO2Et ICO2Et ----- ) H2NCHR1CO2R

1 PhCH=NCRSR2CO2Et --3 H2NCR1R2CO2R R = H, Et.

SCHEME 44 153.

The anion of compound (58) can be alkylated with alkyl halides 91 but it can also undergo facile conjugate addition.

Initially, a reaction between compound (58) and methyl 2- bromo-3-methoxypropionate was attempted (Schemes 45-47). Because of the instability of the imines, the product,without purification, was treated with benzoyl chloride to form the amide (Equation 15).92

HO- COCt RICH=NR2 R3 R iCH=N(R 2)COR3C? - —H R1CHO + R3CONHR2 15 20

When the reaction was conducted at low temperature ethyl hippurate and 1-benzoyl-3-bromo-5-ethoxycarbonyl-3-methoxycarbonyl-

2-phenylpyrrolidine(59) were isolated, Scheme 45. A mechanism for the preparation of compound (59) is shown in Scheme 46. It is of interest that the formation of compound (59) goes via a formal

5 -endo-trig cyclisation which is a disfavoured process according

to Baldwin's rules.93 Compound (59) was fully characterised.

The nmr, it and 33C spectra were in agreement with the structure

shown above. In agreement with-this mechanism is the immediate

decoloration of the solution on the addition of methyl 2-bromo-

3-methoxypropionate to the anion, When the reaction was performed

at higher temperatures the desired compound (60) was formed but in

low yields (5%), Again, compound (59) and ethyl hippurate were

the main compounds isolated. 154.

PhCH=NCH2CO2Et 1.LDA,HMPATHF, 78°C , PhCOCl 58 2.MeOCH2CHBrCO2Me, 78°C,7h Et2O COPh + EtO2C Ph PhCONHCH CO Et 2 2 CO2Me Br 59 SCHEME 45

PhCH=NCHCO2Et + McOCH2CHBrCO2Me CH2=C(Br)CO2Me + 58 PhCH=NCHCO2Et + CH2C(Br)CO2Me---> COPh EtO2C N Ph EtO 2C NY Ph 1H30+ Br _> ~ CO2Me~hCOC~ 4CO2Me Br (O2Et LO2Me Br 59

SCHEME 46

PhCH=NCH2CO2Et 1. LDA,HMP4,1HF,-78°C PhCOCI~ 58 2.MeOCH2CHBrCO2Me,-20°C,12h Et2O

COPh PhCONH ~OMe + EtO 2C~N ph + PhcONNGH2CO2Ft CO2Me COZEt CO2Me 60 59 Br

SCHEME 47

155.

Methyl 2-bromo-3-N,N-diethylpropionate (61)94 was used in

place of methyl 2-bromo-3-methoxypropionate. Elimination of

compound (61) to methyl 2-bromoacrylate should in this case be

less favoured. Compound (61) was prepared from diethylamine and

methyl 2-bromoacrylate'.. The compound was unstable in air, so

usually it was prepared in situ and immediately reacted with the

anion (Scheme 48).

L121 "4L1 121-I 11UI 11.V21 "lt PhCH=NCHCOEt PhCH=N r--NEt2 61 _ CO2Et C O2 e \PhCOCI PhCONH 1 PhCONH çNEt2PhCO3H PhCONHM t2 CO2Et CO2Me Et20 C e 64 CO2Et~2Me 63 62 Et2NOH

SCHEME 48 Initially, the desired compound ethyl 2-benzamido-3-methoxy-

carbonyl-4-N,N-diethylaminobutanoate (62) was formed. Treatment

with perbenzoic acid resulted in the formation of the N-oxide (63),

which eliminated immediately diethylhydroxylamine. The spectral data

(nmr, ir, ms) of the product isolated, was in agreement with ethyl

2-benzamido-3-methoxycarbonylbut-3--enoate (64). However, attempts

to repeat the reaction failed. Attempts to form salts (65), (66),

and (67) and then eliminate to the olefin (64) also failed. 156.

COPh COMe Et2 PhONH PhCONH (_$Et2Me I- PhONH NEt2 Cr k Cr CO2Et CO2Me CO2Et CO2Me CO2Et CO2Me 65 66 67

Difficulty was also observed in the formation of amide (62).

Hydrolysis of the benzylidene group led to the formation of ethyl

2-amino-3-methoxycarbonyl-4-N,N-diethylaminobutanoate (68) as well

as (62). The reactions were generally irreproducible and mixtures

of many compounds were obtained.

A similar method, but using sulphur substituents in place

of nitrogen was tried. Methyl 2-bromo-3-thiophenylpropionate (69)

was prepared from methyl 2-bromoacrylate and thiophenol. The product

was "slightly unstable because of its tendency to eliminate hydrogen

bromide, presumably through an episulphonium ion intermediate (70)

(Equation 16).

SPh CO2Me Ph CH2 C(Br)CO2Me+PhSH —÷1 --> S ---> CH2=C(SPh)CO2Me 16 Br 69 70 CO2Me

The anion of compound (58) was added slowly to compound (69).

After the usual work up and treatment with benzoyl chloride, ethyl

2-benzamido-4--methoxycarbonyl-4-thiophenylbutanoate (71) and 1-benzoyl

5-ethoxycarbonyl-3-methoxycarbonyl-2-phenyl-3-thiophenylpyrrolidine (72) 157.

were isolated in 20 and 40% yield respectively. The reaction was

repeated but the anion was added at a much slower rate. Compound

(71) was isolated in 45% yield. Only traces of compound (72)

were formed. Both compounds were characterised by nmr, ir, ms,

and accurate mass measurement. The 250 MHz proton nmr and proton

decoupled spectra were in agreement with the structure assigned to

compound (71). A possible mechanism for the preparation of the

two compounds is shown in Scheme 50.

PhCH=NCH CO Et KOtBu,THF 78°C , PhCOCI 2 2 PhSCH2CH(Br)CO2Me PhCONH SPh NOPh + Et02C~' Ph + PhCONHCH2CO2Et COZEt CO2Me ~ ~SPh 72 CO2Me 71 SCHEME 49

Ph PhCH=N SPh S\ PhCH=NCHCO2Et+ / -->71 + CO2Me CO2Et CO2Me iPhCH=NCHCO2Et CHPh EtOZC-- -Ph Ho N% 72E- SPh SPh CO2Me tÍO2Me SCHEME 50 158.

At the same time of this work, a communication for the synthesis of an analogous compound was published.95 The route is shown in

Scheme 51.

0 %~HZHCIB NH2 H~ COZEt 2NH ~ COZEt CO2Et ~ COZEt OzEt CO2H CO2H

HZ ~ CO2H CO2H 73

SCHEME 51 Addition of hydrogen bromide to the double bond of 2-amino-3-

carboxybut-3-enoic acid (73) would give 2-amino-4-bromo-3-carboxy=-

butanoic acid (74) from which alkylcobaloxime (44, R1 = R2 = R3 = R` = H)

could be easily prepared.. In the light of this work the efforts

to prepare alkylcobaloxime (44) were set aside and attention concentrated

on the glutamate analogue (vide infra).

NH2 Br CO2H [02H 74 159.

(d) Preparation of 3-Benzamido-l-methoxycarbonnl-3-ethoxycarbonyl

propylpyridinatocobaloxime (45).

For the preparation of alkylcobaloxime (45) a precursor of the

general structure (75) was required.

X= Cl, Br, I, OTs

Analogues of this compound have already been prepared in the

literature. These are shown in Schemes 5296 and 53.97

Me2C=CH2 McCONHCH(CO2Et)2' CtCH2CH(OH)CO2Et CilCH2CH(OtBu)CO2Et

McCONHC(CO2Et)2CH2CH(OtBu)CO 2Et H~ t H2NCH(CO.2H)CH2CH(Ce)CO2H

SCHEME 52

HOZCCHzCH2CH(CO2H)NH3Cl- SOCl2 > +Cl Cl2,hv ClS03H ~p ClS03H Cl Cl H N Cl Cr N + 3 ~~ 0 0 0 82% 8%

SCHEME 53 The first method (Scheme 52) is long and tedious since the starting

material, ethyl 3-chloropropionate is not readily available. 160.

The preparation of 4-chloroglutamic anhydride is shorter.

However, chlorination of both 3- and 4-carbons is possible, so the conditions of the reaction have to be controlled carefully.

A disadvantage of both methods is that the alkyl chloride is obtained. The yields of alkylcobaloximes drop in the order

I > Br > CC independently of the oxidation state of the starting cobalt complex (cobalt(I) or cobalt(II)).

However, when it was attempted to prepare 4-chloroglutamic anhydride, by the above route, only a black tar was obtained from which it was impossible to isolate the anhydride. Attempts to isolate the free acid, which would be more stable also failed.

It is noteworthy that the yield reported in the literature (82%) is based on glc.

Different approaches to compound (75) were attempted. The methodology adopted was to couple the two parts of the molecule

together as shown in Scheme 54. rii RireN R2N1 ~Br ±o2r+ CH2C(Br)CO2Me 3 CO2R3 CO2Me

SCHEME 54 The first methods attempted are shown in Schemes 55 and 56.

No reaction took place between compound (53) and methyl 2-bromo-

acrylate. This indicates that compound (54) was formed by direct

displacement of the bromide ion. The yield of compound (54) from

methyl 2,3-dibromopropionate was too low to be of synthetic use.

No reaction took place between diethyl acetamidomalonate and methyl

2-bromoacrylate. 161.

Br CO2Me + CH2=C(Br)CO2Me N~ N 0 THF 54 SCHEME 55

McCONHCH(CO2Et)2 + CH2=C(Br)CO2Me! > no reaction THF SCHEME 56

Compound (58) was also used (Scheme 57). The addition

appeared to take place at -78°C. Compound (59) was obtained in

25% yield, together with another product, tentatively assigned as

compound (76) in 20% yield, when an equimolar amount of compound

(58) and methyl 2-bromoacrylate were used. When the anion of

compound (58) (1 equivalent) was added to a solution of methyl

2-bromoacrylate (1.5 equivalent) in THF at -78°C, a mixture of

compounds (59) and (77) were obtained in 24 and 23% yield respectively.

The reaction was repeated at -110°C but the same products were formed.

A possible mechanism for the formation of these compounds is shown

in Schemes57, 58.

The structure of compounds (76) and (77) was assigned only on

the basis of nmr, it and ms. Since they were of no special interest,

these reactions were not pursued any further. When a catalytic

amount of potassium t-butoxide in the presence of t-butanol was

used as a base at 0°C, only compound(59) was obtained. At -20°C 162.

PhCH=N PhCH-NCH2CO2Et 1.LDATHF,2 78°C CH2 =C(Br ) CO 2 Mē CO2Et C0 M H30+

PhCH=N Br EtO2C--cN~Ph Br PhCH=N~_/COZEt tO2Me CO2Me EtOZC COPh ~N=CHPh PhCH=N Et02C~(N Ph CO2Et \ r CO2Et CO2Me OZMe 59 PhCONH NHCOPh CO2Et CO2Et CO2Me 76 SCHEME 57

PhCH=N PhCH=NCHCO2Et+CH2=C(Br)CO2Me(excess)- CO2Et CO2Me CH2 C(Br)CO2M 1 4 PhCH=N 1 gO;Me COPh N~ ~ CO2Et CO2Me Et02C Ph 1-Br PhCONLH CO2Me CO2Me B Br 59 CO2Et CO2Me 77 SCHEME 58 163.

a mixture of compound (59) and ethyl 2-benzamido-4-bromo-4-methoxy-

carbonylbutanoate (78) was obtained in 38 and-14% yield respectively.

The structure of compound (78) was assigned on the evidence of

nmr (250 MHz), ir, ms and elemental analysis. The yield of compound

(78) was improved to 56% when catalytic amount of sodium ethoxide

in ethanol-THF was used as a base (Scheme 60).

PhCH=NCH2CO2Et+ CH =C(Br)CO Me THFtBuOH, PhCOG, 2 KOtBu Et20 COPh PhCONH Br Et02C N Ph + Br CO2Et CO2Me CO2Me 59(38%) 78(14%) SCHEME 59

PhCH=NCH2CO2Et + CH2 C(Br)CO2Me THFEtOH, PhCOCI, NaOEt Et20 Ph PhCONH Br + N 0 02Et CO2Me Et02C CO2Me 78(56%) 79(9%) SCHEME 60

The structure of compound (79) was assigned on the basis of

its nmr (250 MHz), ir, ms and elemental analysis. A possible

mechanism for its formation is shown in Scheme 61. The three protons

H1, H2, Ha appeared as double doublets. The coupling constants

J = 9,0 Hz and J = 4.5 Hz accounted for the axial-axial and axial-

equatorial couplings respectively, The proton H4 appears at 8 = 6.89 ppm

164.

and is broad. The isomeric structure (80) cannot account for the

chemical shift of proton H4. H41 would be expected at higher field.

A coupling between the protons H4 1 , H2 and H3 would also be

expected. Ph Ph H Ph~H4 CO Me + r Ne0 H1 ---~ N ÇJ H1 CO Et02C 2 CO2Me EtO2C 3 2 O2Me 2Et Br H~ H H H 80 79

SCHEME 61 The alkylcobaloxime (45) was prepared from compound (78) as

shown in Equation 17.

PhCONH pr PhCONH [Co] -Z ~-~ 17 CO2Et tO2Me C6 H6 CO2Et 02Me [Co]cocdmgH)2py 45(43%)

The structure of 3-benzamido-3-ethoxycarbonyl-1-•methoxy-

carbonylpropylpyridinatocobaloxime was assigned on the evidence

of nmr, it and elemental analysis.

The structure (45) was confirmed by single crystal X-ray analysis.

This is shown in Figures 6 and 7. The X-ray photograph is that of

the R,R-, S,S-alkylcobaloxime racemate. 0-5 is above the oxygen-

hydrogen-oxygen bond. There does not seem to be any interaction since

their distance is equal to the sum of the Van der Waal's radii. 165.

The nmr spectrum of compound (45) in trifluoroacetic acid was recorded. There was no difference from that using deuterfo- chloroform as solvent. Presumably, the size of the ring formed is important. Interaction between the alkyl group and the equatorial ligand seems to occur when there is a 0-carbonyl group and an eight-membered ring is formed. The formation of a seven- membered ring, when an a-carbonyl group is present, seems to be unfavoured. 166.

SUMMARY

The reaction of hydridocobaloxime with substituted or cyclic olefins was studied. In both cases it was observed that the reaction cannot be of wide applicability in the synthesis of alkylcobaloximes. Reaction often did not take place or even if it did, the fully hydrogenated product was obtained.

Cobaloxime(II) was found to be a useful precursor for the preparation of substituted alkylcobaloximes. Reductive cleavage or 0-elimination, which are observed with cobaloxime(I) ion, are avoided. The method has already been applied in the preparation of a model compound for the methyleneaspartate-glutamate rearrangement, catalysed by coenzyme B,2.

The mechanism of the cleavage of alkylcobaloximes by copper(II) halides was studied. In particular, the reaction intermediates, the product distribution, the solvent effect and the stereochemistry of

the reaction were examined. The reaction was compared with the other known reactions of alkylcobaloximes with metal species. Best agreement was observed with the reaction with iridium(IV) hexachloride ion, i.e., oxidation of the alkylcobaloxime to the cobalt(IV) complex.

The electrochemical study of the reaction was in agreement with this

proposal. However, more detailed kinetic study of the reaction is necessary. 167.

It was suggested that hydrogen bonding between a (3-carbonyl group of the alkyl substrate and the equatorial ligand of cobaloximes may be of help in mimicking the enzyme effect in the carbon-skeleton rearrangements catalysed by coenzyme B12. The hydrogen bonding could help to hold the alkyl group close to cobalt so that the rearrangement would take place. Some model compounds were prepared. Hydrogen bonding was observed only when the alkyl group contained a R-carbonyl and not with an a-carbonyl. This is of importance since in all cases with methylmalonate, methylitaconate and - R-merhylaspartate, if a carbon-cobalt bond is formed the carboxy groups will be at the 2- position. Preparation of more model compounds and study of the significance of a hydrogen bonding on the rearrangement is necessary. lO 09 0.8 07 0.6 05 ~------~------~------~~======~------~O E/V

30 1.1 1.0 0.9 08 07 06 05

-10

40 r ON I/PA 170. Figure 3 A AA 'lim 6

44-

40 ~

36 -

32 ~

28~

0 1 2 4 5 6 W1/2/s1l2 i/pA

, 25 -n_. / La , , c-, EIV '" ro ..,. ..- ,- 0 +- 12 10 I 08 06 Oir 02 -02 -04 -06 -08 172. Figure 5 173.

Figure 6

o °,1>o-ftu-cc,m_ta,0° ft'f

~ll,l~ 174. Figure 7 175.

EXPERIMENTAL

GENERAL PROCEDURES

Melting points were determined using a Kofler hot stage.

Nmr spectra were recorded on a Varian T60, Varian XL 100,

Perkin-Elmer R32 90 MHz or Bruker WM 250 MHz. spectrometer. Infrared spectra were recorded on a Perkin-Elmer 257 or 298, spectrometer. Optical rotations were recorded on a Perkin-Elmer 141 polarimeter. Mass spectra were recorded on a V.G. 7070 instrument.

Thin layer chromatography, both preparative and analytical, was carried out under an atmosphere of carbon dioxide using GF25, silica plates unless stated to the contrary. Column chromatography was carried out on silica H (type 60) unless stated otherwise. A mixture of chloroform, ethyl acetate and methanol (2:2:1 v/v/v) was used for the alkylcobaloximes for both column chromatography and thin layer chromatography.

All the solvents were purified and dried as described in

P.D. Perrin, W.L.F. Armarego and D.R. Perrin, 'Purification of

Laboratory Chemicals', Pergamon Press, Oxford, 1966. 176.

1. Synthesis of Alkylcobaloximes

(a) From Hydridopyridinatocobaloxime

Reaction with 1-ethoxy-l-imino-2-propene hydrochloride.

Cobalt(II) bromide hexahydrate (13.1 g, 40 mmoles) and dimethylglyoxime (9.28 g, 80 mmoles) were stirred in degassed methanol (150 ml) under nitrogen in subdued light, until the

cobalt(II) bromide dissolved. Sodium hydroxide (3.2 g,

80 mmoles) in water (10 ml) was added, followed by pyridine

(3.2 g, 40 mmoles). The brown solution was stirred and cooled

to room temperature. 1-Ethoxy-1-imino -2-propene hydrochloride

(6.78 g, 50 mmoles) was added and the mixture shaken under an

atmosphere of hydrogen. When the hydrogen uptake (321 ml, 14.3

mmoles in 345 min) stopped, the mixture was poured into water

(200 ml) and left for 2 h at 4°C. The precipitate was filtered

and the filtrate extracted with chloroform (3 x 100 ml). The

combined extracts were dried (MgSO4) and the solvent was removed

under reduced pressure, The residue was distilled to give ethyl

3-methoxypropionate (2.64 g, 407),6 1.27 (3H, t, J = 7 Hz), (CDCC3) 2.8 (2H, t, J = 6 Hz), 3.70 (5H, m), 4.18 (2H, q, J = 7 Hz),

vmax(film) 2860, 1730, 1375, 1230, 1200, 1150, 1025 cm-1.

2-Methoxycarbonylethylpyridinatocobaloxime (3).

The same procedure as above was adopted to generate cobaloxime(II)

(20 mmoles). A mixture of 1-ethoxy-l-imino-2-propene hydrochloride

(3,39 g, 25 mmoles) and sodium acetate (2.05 g, 25 mmoles) was added 177.

and the solution stirred under an atmosphere of hydrogen. When the hydrogen uptake (236 ml, 10 mmoles in 69 min) stopped, water

(100 ml) was added and the mixture cooled to 4°C for 2 h. The precipitate was filtered and dried in vacuo to give compound (3)

(5.5 g, 60%),6(CDC-(3) 1.6-1.9 (2H, m, -CH2-CO2Me), 2.12 (14H, s, -CH2-CH2CO2Me and CH3-C=N-), 3.55 (3H, s, CH3-000), 7.2-8.7 (5H, m, 'max (Nujol) 1720, 1602, 1550, 1380, 1320, 1220 cm-1 py), (Found: C, 44.85; H, 5.73; N, 15.38. Calc. for C17H26N506Co:

C, 44.84; H, 5.71; N, 15.38%).

2-Ethoxycarbonylethylpyridinatocobaloxime (4).

Cobalt(II) bromide hexahydrate (3.27 g, 10 mmoles) and dimethylglyoxime (2.32 g, 20 mmoles) were stirred in degassed THF

(100 ml) at room temperature under nitrogen in subdued light until most of the cobalt(II) bromide had dissolved. Sodium hydride (0.48 g,

20 mmoles) was added followed by pyridine (0.79 g, 10 mmoles). The brown solution was stirred and cooled to room temperature. 1-Ethoxy- l-imino-2-propene hydrochloride (1.69 g, 12.5 mmoles) and sodium acetate (1.025 g, 12.5 mmoles) were added and the mixture was stirred under an atmosphere of hydrogen. When the hydrogen uptake

(56 ml, 2.5 mmoles in 134 min) stopped, the precipitate was filtered and the mother liquor concentrated under reduced pressure. Column chromatography gave compound (4) (1.17 g, 25%), 1.25 (3H, t, 6(CDCe3) J = 7Hz, CH3-CH2000), 1.75 (2H, m, CH2-CO2Et), 2.15 (14H, s, CH2-CH2-

CO2Et and CH3-C=N-), 4.1 (2H, q, J = 7 Hz, CHs-CH2-000-), 7.2-8.7

(5H, m, py), vmax (Nujol) 1725, 1605, 1565, 1380, 1300, 1245, 1120,

1095, 770, 705 cm-1. 178.

2-Indanylpyridinatocobaloxime.

Cobaloxime(II) (40 mmoles) was prepared in methanol (150 ml)

as before. Indene (5.8 g, 50 mmoles) was added and the mixture

stirred under an atmosphere of hydrogen. When the hydrogen uptake

(412 ml, 18 mmoles in 250 min) was complete, water (200 ml) added

and the solution cooled to 4°C for 2 h. The precipitate was

filtered and dried in vacuo to give the cobaloxime (17.1 g, 88%),

t3) 0.75-1.78 (2H, m, -CH2-CHCo-), 1.9 (6H, s, CH3-C=N-), a(CDC 2.05 (6H, s, CH3-C=N-), 2.40 (2H, m, CH2-Ar), 3.70 (IH, d, J = 7 Hz,

-CSI--Co-), 6.4-8.6 (9H, m, py and Ar), (Nujol) 3620, 3200, 1605, vmax -1 1565, 1385, 1240, 760, 710 cm .

2-Norborn-5enylpyridinatocobaloxime (7) and 3-nortricyclenylpyridinato=

cobaloxime (6).

Cobaloxime(II) (20 mmoles) in methanol (75 ml) was prepared

as before. Norbornadiene (2.3 g, 25 mmoles) was added and the mixture

stirred under an atmosphere of hydrogen. When the hydrogen uptake

(228 ml, 10 mmoles in 42 min) stopped, water (100 ml) was added and

the mixture cooled to 4°C for 2 h. The precipitate was filtered and

recrystallised from methanol to give a mixture of compounds (7) and

(6) (7,2 g, 78%, ratio 7:3 respectively),6(CDCI3) 0.67-1.1 (4H, m),

2,1 (13H, s, CH3-C=N- and -CH-Co), 2.6-2.7 (2H, m, -CH-CH=CH),

5.87 (2H, m, -CH-CH=CH-CH), 7.1-8.7 (5H, m, py), umax (Nujol) 3040,

1605, 1555, 1375, 1235, 770, 715 cm-1 (Found: C, 52.08; H, 6.05;

N, 15,15. C2oH28N504Co requires C, 52.06; H, 6.07; N, 15.18%). 179.

Reaction with diethyl maleate.

Cobaloxime(II)(10 mmoles) was prepared in methanol (35 ml) as before. Diethyl.maleate (2.15 g, 12.5 mmoles) was added and the mixture

stirred under an atmosphere of hydrogen. When the hydrogen uptake

(224 ml, 10 mmoles in 6 h) stopped, water (50 ml) was added and the

precipitate filtered. The filtrate was extracted with petroleum,

30-40°C (3 x 50 ml) and the combined extracts were dried (Na2SO4).

The solvent was removed under reduced pressure and the residue

distilled to give diethyl succinate (0.25 g, 1L.%), b.p. 110°C at

20 mmHg (lit.,98 105 at 15 mmHg),6(CDCt3) 1.26 (6H, t, J = 7 Hz,

CH3-CH2OCO), 2.55 (4H, s,.-CH2-CH2-CO2Et), 4.20 (4H, q, J = 7 Hz,

CH3-CH2 -000 -).

Reaction with cyclopentadiene.

Cobaloxime(II) (10 mmoles) was prepared as before. Cyclopenta-

diene (0.825 g, 12.5 mmoles) was added and the mixture stirred under

an atmosphere of hydrogen. When the hydrogen uptake (207 ml, 9.2

mmoles in 43 min) stopped, water (50 ml) was added and the mixture

extracted with benzene (3 x 50 ml). Cyclopentene was identified

as the sole volatile product by glc comparison with authentic

material. The yield based on hydrogen uptake was 92%.

Reaction with dicyclopentadiene.

Cobaloxime(II) (10 mmoles) was prepared as before. Dicyclopenta-

diene (1.65 g, 12.5 mmoles) and glacial acetic acid (1 ml) were

added. When the hydrogen uptake (336 ml, 15 mmoles in 12h) stopped, 180.

water (100 ml) was added and the solution cooled to 4°C for 2h.

The precipitate was filtered and dried in vacuo. Column chromatography, followed by recrystallisation from methanol gave compound (8)

(0.4 g, 8%), 0.8-2.16 (10H, m), 2.10 (12H, s, CH3-C=N-), 6(CDCt3) 2.6-2.8 (1H, m, -CH=CH-CH-), 5.6 (2H, m, -CH=CH-), 7.2-8.6 (5H, m,

3120, 3040, 1605, 1560, 1495, 1300, 1230, 820, 765, py), vmax (Nujol) 700 cm 1, .i3C nmr: 115.4, 115.2, 114.8, 104.9, 101.6, 735, d(CDCt3) 98.92, 94.68, 55.8, 54.8, 53.6, 33.9, 30.2, 27.2, 24.6, 23.2, 21.0

16.8 (Found: C, 55.03; H, 6.51; N, 14.13. C231.332N504C0 requires

C, 55.09; H, 6.39; N, 13.97%).

2-Norbornylpyridinatocobaloxime (').

Cobaloxime(II) (10 mmoles) was prepared as before. Norbornene

(1,17 g, 12.5 mmoles) was added and the mixture stirred under an atmosphere of hydrogen. Water (50 ml) was added after the hydrogen

uptake (112 ml, 5 mmoles) stopped. The mixture was cooled to 4°C for

2 h and filtered. The precipitate was dried in vacuo; column

chromatography, followed by recrystallisation from methanol gave

compound (5) (0.9 g, 19%), 0.65-1.8 (11H, m), 2.12 (12H, 'S(CDCt3) s, CH -C=N-), 7.02-8.73 (5H, m, py), (Nujol) 3120, 3050, 1620, 3 vmax 1565, 1498, 1232, 1071, 980, 783, 765 cm-1 (Found: C, 51.63; H, 6.47;

N, 15.07. .C2OHaoN504Co requires C, 51.84; H, 6.48; N, 15.12%). 181.

1-Acenaphthenylpyridinatocobaloxime.

The experiment was repeated with acenaphthylene (1.9 g,

12.5 mmoles). The precipitate (4.3 g, 83%) was unstable to purification by column chromatography or recrystallisation,

(CDC-t3) 1.68 (3H, s, CH3-C=N-), 1.78 (3H, s, CH3-C=N-), 2.2

(3H, s, CH3-C=N-), 2.23 (3H, s, CH3-C=N-), 2.9-3.4 (3H, m,

Ar-CH2-CH-Co), 7.25-8.5 (11H, m, py and Ar), max (Nujol) 1605, 1560, 1235, 1090, 1070, 1040, 1000, 975, 920, 875, 835, 815, -1 785, 765, 730, 705 cm .

(b) From Fyridinatocobaloxime(II)

Bromopyridinatocobaloxime.

Cobalt (II) bromide hexahydrate (13.734 g, 42 nnnoles) and

dimethylglyoxime (11 g, 95 moles) were dissolved in boiling

ethanol (400 ml, 95%). The hot solution was filtered and pyridine

(6.8 g, 86 imnoles) added. The solution was left to stand overnight

at room temperature and then filtered. The precipitate was washed

successively with water (100 ml), ethanol (100 ml), and diethyl

ether (100 ml) and recrystallised from nitromethane to yield the

bromocobaloxime (11.7 g, 62%) (CDCe9) 2.38 (12H, s, CH3-C=N-), ,6 7.25-8.40 (5H, m, py), vmax (Nujol) 3120, 3050, 1620, 1560, 1500, 1240,

1090, 975, 880, 770, 700 cm-1, m.p. > 231°C (decomp.) (Found:

C, 35.09; H, 4,19; N, 15.59; Br,17.82. C13H19BrN504Co requires

C, 34.82; H, 4.24; N, 15.62; Br, 17.86%). 182.

Bromotriphenylphosphinatocobaloxime.

The above method was employed but triphenylphosphine (22.532 g,

86 mmoles) was used instead of pyridine. Recrystallisation from nitromethane gave the title compound (17 g, 647.), m.p. 217-218°C, a(CDC.(3) 2.02 (12H, d, J = 1.5 Hz, CH3-C=N-), 7.22-7.42 (15H, m,

Ph) , v max (Nujol) 3460, 3050, 1560, 1440, 1245, 1195, 980, 755, -1 695 cm (Found: C, 49.59; H, 4.68; N, 8.66; P, 4.7. C 26H 2 9Br N4 0 4 PCo requires C, 49.45; H, 4.6; N, 8,87; P, 4.91%).

Attempted preparation of bromotributylphosphinatocobaloxime.

Cobalt(II) bromide hexahydrate (13.7 g, 42 mmoles) and dimethylglyoxime (11 g, 95 mmoles) were dissolved in 'ethanol (400 ml,

95%). The hot solution was filtered and tributylphosphine (16.968 g,

84 mmoles)added, The solution was left to stand for 12 h at 25°C and then filtered. The precipitate was washed successively with water (100 ml), ethanol (100 ml) and diethyl ether (100 ml). The green crystals were dried in vacuo to give dibromohydrocobaloxime monohydrate (15.2 g, 77%), iS(db-DMSO) 2.47 (12H, s, cH3-C=N-), 4.4

(2H, br, H20), v (Nujol) 3580, 3500, 3150, 1620, 1555, 1230, max -1 735, 720 cm (Found: C, 20.51; H, 3.23; N, 11.68. C8H17Br2N405Co requires C, 20.51; H, 3.63; N, 11.96%).

Ethoxycarbonylmethylpyridinatocobaloxime.

Chloropyridinatocobaloxime (1 g, 2.48 mmoles) and zinc wool

(0.2 g, 3 mmoles) were stirred in benzene (3 ml) under nitrogen at

75°C. Ethyl bromoacetate (0.5 g, 3 mmoles) was added together with

a small crystal of iodine, The mixture was heated at 80°C for 2 h 183.

and then poured into 10% sulphuric acid (10 ml). The two layers were separated and the aqueous phase was extracted with chloroform

(3 x 20 ml). The combined extracts were washed with water (30 ml), dried (MgSO4) and the solvent was removed under reduced pressure.

Column chromatography gave the title compound (0.23 g, 20%),

(CDCi3) 1.2 (3H, t, J = 7 Hz, CH3-CH2000-), 1.68 (2H, s,-CH2-CO2Et), 2.22 (12H, s, CH3-C=N-), 3.9 (2H, q, J = 7 Hz, CH3-CH2-000-),

7.3-8.8 (5H, m, py), vmax (Nujol) 3240, 1690, 1650, 1610, 1565, 1365, 1270, 1235, 1090, 770, 745, 700 cm-1.

1-Ethoxycarbonylethylpyridinatocobaloxime.

Chloropyridinatocobaloxime (2.0 g, 4.95 mmoles) and zinc wool

(0.4 g, 6 mmoles) were stirred in benzene (10 ml), at 70°C under

nitrogen, Ethyl 2-bromopropionate (1.15 g, 6.35 mmoles) and a small

crystal of iodine were added. The mixture was heated at 85°C for

1 h and then poured into 10% sulphuric acid (20 ml). The two phases

were separated and the aqueous phase was extracted with chloroform

(3 x 40 ml). The combined extracts were washed with water (60 ml),

dried(MgSO4) and the solvent was removed under reduced pressure.

Column chromatography gave the title compound (1.2541 g, 54%), s (CDC?3) 0,4 (3H, d, J = 7 Hz, CH3-CHCo-), 1.2 (3H, t, J = 7 Hz, CH3-CH2000-),

2,22 (13H, s, CH3-C=N- and -CH-Co-), 3.90 (2H, q, J = 7Hz,CH3CH2-000-),

7.22-8.7 (5H, m, py), vmax (Nujol) 3560-3400, 3100, 1685, 1605,

1560, 1340, 1240, 1190, 1155, 1110, 775, 735, 705 cm-1. 184.

1-Ethoxycarbonylpropylpyridinatocobaloxime.

The procedure for the preparation of 1-ethoxycarbonylethylpyridinatocobaloxime was adopted using ethyl 2-bromobutyrate as an alkylating agent . Column chromatography gave the alkylcobaloxime (30%),6(CDCt3) 0.72 (3H, t, J = 6 Hz, CH3-CH2CHCo-),

1.25 (5H, m, CH3-CH2000- and CH3CH2-CHCo-), 2.2 (13H, s, CH3-C=N- and -CH-Co-), 4.0 (2H, q, J = 8 Hz, CH3CH2-000-), 7.35-8.70 (5H, m,

(Nujol) 3100, 3050, 1690, py), vmax 1602, 1560, 1270, 1240, 1180, 1120, 770, 730, 705 cm 1 (Found: C, 47.14; H, 6.62; N, 14.42.

Calc, for C19H30N506Co: C, 47.20; H, 6.2; N, 14.49%).

Ethoxycarbonylmethylpyridinatocobaloxime.

Bromopyridinatocobaloxime (1.11 g, 2.48 mmoles) and zinc wool

(0.2 g, 3 mmoles) were suspended in benzene (3 ml) under nitrogen and warmed to 75°C. Ethyl bromoacetate (0.5 g, 3 mmoles) was added together with a small crystal of iodine. The mixture was heated at

80°C for 2 h. After the usual work up and column chromatography the title compound (0.18 g, 16%) was obtained, identical (ir, nmr) with that obtained from chloropyridinatocobaloxime.

Reaction of chloropyridinatocobaloxime with ethyl 2-bromopropionate in the presence of p-dinitrobenzene.

Zinc wool (0.4 g, 6 mmoles) and chloropyridinatocobaloxime

(2.0 g, 4.95 mmoles) were stirred in benzene (7 ml) at 75°C under nitrogen. Ethyl 2-bromopropionate (1.15 g, 6.4 mmoles) and p-dinitrobenzene (0.504 g, 3 mmoles) together with a small crystal of 185.

iodine were added and the mixture was stirred at 75°C until all the zinc

was. consumed. Only traces of alkylcobaloxime were present in

the mixture (tic).

Reaction of chloropyridinatocobaloxime with ethyl 2-bromopropionate

in the presence of styrene.

The experiment was repeated as above except that styrene used

instead of 2.- dinitrobenzene. The alkylcobaloxime was not formed

(tic) ,

Reaction of chloropyridinatocobaloxime with the zinc enolate of

ethyl 2-bromopropionate.

Ethyl 2-bromopropionate (1.18 g, 6.5 mmoles) and zinc wool (0.4 g,

6.mmoles) were stirred in benzene (7 ml) at 80°C under nitrogen

until all the zinc dissolved, Chloropyridinatocobaloxime (2.0 g,

4,95 mmoles) was added and the mixture heated for 2 h. The alkyl-

cobaloxime was not formed (tic).

Reaction of chloropyridinatocobaloxime with the lithium enolate

of acetone.

Isopropenyl acetate (0.230 g, 2.3 mmoles) was added to a solution

of methyl.lithium(4.6 mmoles) in 1,2-dimethoxyethane (4.6 ml) under

nitrogen at -78°C. After 45 min a suspension of chloropyridinato-

cobaloxime (1.0 g, 2.48 mmoles) in 1,2-dimethoxyethane (20 ml) was

added. The mixture was stirred at 40°C for 12 h, then cooled and

poured into 10% sulphuric acid (20 ml). The two layers were separated and the aqueous phase was extracted with chloroform (2 x 20 ml).

The combined extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The residue did not contain an alkylcobaloxime (nmr, tic).

Reaction of chloropyridinatocobaloxime with the potassium enolate of ethyl propionate.

Ethyl propionate (0.255 g, 2.5 mmoles) was added to a suspension of potassium hydride (0.1 g, 2.5 mmoles, oil free) in THF (10 ml) under nitrogen. Chloropyridinatocobaloxime (1.009 g, 2.5 mmoles) in

THF (10 ml) was added. The solution turned red and then slowly brown.

The mixture was stirred overnight at room temperature. After the usual work up the nmr and tic analysis showed the absence of an alkylcobaloxime.

Benzylpyridinatocobaloxime,

Zinc wool (0.1 g, 1,5 mmoles), chloropyridinatocobaloxime (0.5 g,

1,239 mmoles) and benzyl bromide (0.28 g, 1.63 mmoles) were stirred

in benzene at 75°C under nitrogen. The mixture was stirred for 12 h,

then poured into 10% sulphuric acid (5 ml) and the two layers were

separated. The aqueous phase was extracted with chloroform (3 x 10 ml)

and the combined extracts were washed with water (20 m1). The

chloroform solution was dried (Na2SO4) and the solvent removed under

reduced pressure. Column chromatography gave the alkylcobaloxime 187.

(0.1124 g, 21%),6(CDCi3) 1.93 (12H, s, CHs-C=N-), 2.81(2H, s,

-CH2-Ph), 6.8-8.83 (10H, m, py and Ph),.9max (Nujol) 3400, 1600,

1560, 1490, 975, 915, 765, 690 cm-1.

Reaction of pyridinatocobaloxime(II) with zinc.

Zinc wool (0.1 g, 1.5 mmoles) and pyridinatocobaloxime(II)

(0.5 g, 1.359 mmoles) were mixed in benzene (3 ml) at 80°C under

nitrogen. After 3 h the starting materials were detectable.

1-Ethoxycarbonylethylpyridinatocobaloxime.

Zinc wool (0.2 g, 3 mmoles) and pyridinatocobaloxime(II) (1.104 g,

3 n❑Moles) were mixed in benzene (10 ml) and heated to' 80°C under nitrogen, Ethyl 2-bromopropionate (0.63 g, 2.95 mmoles) together

with a small crystal of iodine were added and the mixture stirred at

80°C for 1 h. 10% Sulphuric acid (10 ml) was added to the cooled

mixture, and the two phases were separated. The aqueous phase was

extracted with chloroform (3 x 20 ml). The combined extracts were

washed with water (30 ml), dried (Na2SO4) and the solvent was removed

under reduced pressure, Column chromatography gave the title compound

(0.87 g, 63%), identical (ir, nmr) with that obtained from chloropyridinato-

cobaloxime.

Reaction of trans-dipyridinatocobaloxime(II) with alkyl halides.

In a typical experiment trans-dipyridinatocobaloxime(0.5 g, 1.2

mmoles), zinc wool (0.1 g, 1.5 mmoles) and the alkyl halide (1.5 mmoles)

were stirred in benzene (3 ml), under nitrogen at 70-75°C for 3 h. 188.

The mixture was cooled, added to 10% sulphuric acid (5 ml) and the two phases were separated. The aqueous phase was extracted with chloroform (3 x 10 ml), the combined extracts were washed with water

(20 ml) and dried (MgSO4). The solvent was removed under reduced pressure; column chromatography gave the alkylcobaloxime (Table 6).

The same procedure was adopted using zinc-copper, aluminium powder or aluminium amalgam instead of zinc wool (Table 7).

1-Ethoxycarbonylbutylpyridinatocobaloxime.

The procedure described above was adopted using ethyl

2-bromobutyrate as the alkylating agent and aluminium amalgam as the reducing agent. The title compound (0.197 g, 33%) was obtained,

) 0.72-1.42 (10H, m, CH -CH2-CH2-CHCo- and CH3-CH2000-), 2.2 S(CDCt3 3 (13H, s, CH3-C=N- and -CH-Co-), 3.92 (2H, q, J = 7 Hz, CH3CH2-000-),

7,2-8.65 (5H, m, py), vmax (Nujol) 3100, 3080, 1685, 1602, 1555, 1490, -1 1390, 1260-1230, 1170, 1145, 1120, 770, 735, 705, 635 cm (Found:

C, 48,28; H, 6.47; N, 14.12. C20H32N506Co requires C, 48.25;

H, 6,48; N, 14.08%),

1-Ethoxycarbonyl-2-methylpropylpyridinatocobaloxime.

Trans-dipyridinatocobaloxime(II) (0.5 g, 1.12 moles), aluminium

amalgam (0.1 g, 1.5 mmoles)and ethyl 2-bromo-3-methylbutyrate

(0.332 g, 1.5 mmoles) were heated to 40°C in benzene (3 ml) under

nitrogen for 1 h. The cooled mixture was added to 10% sulphuric

acid (5 ml) and the two phases were separated. The aqueous phase

was extracted with chloroform (3 x 10 ml). The combined extracts

were washed with water (20 ml) and dried (Na2SO4). The solvent was 189.

removed under reduced pressure; column chromatography, followed by plc and recrystallisation from methanol-water gave the alkylcobaloxime (0.017 g, 3%),6(CDCt3) 0.8 (3H, d, J = 6 Hz, CH3-CH-), 0.9 (3H, d, J = 5 Hz, CH3-CH-), 1.2 (4H, t, J = 7 Hz, CH3-CH2000- and CH3-CH-CHCo-), 2.22 (13H, s, CH3-C=N- and -CH-Co-), 3.95 (2H, q, J = 7 Hz, CH3CH2-000-), 7.22-8.7 (5H, m, py), v (Nujol) 3120, max -1 3050, 1685, 1620, 1565, 1500, 1245, 770, 700 cm (Found: C, 47.98;

H, 6.50; N, 13.87. C2QH32N504Co requires C, 48.25; H, 6.48; N, 14.08%).

Nitromethylpyridinatocobaloxime (15).

Bromonitromethane (3.14 g, 22.4 moles) was added slowly to a

suspension of zinc wool (1.0 g, 15 moles) and trans-dipyridinato-

cobaloxime(II) (4.917 g, 11 moles) in benzene (20 ml) at 70°C under

nitrogen. 10% Sulphuric acid (30 ml) was added to the cooled mixture,

the two phases were separated and the aqueous phase was extracted

with chloroform (3 x 40 ml). The combined extracts were washed with

water (50 m1) and dried (Na2SO4). The solvent was removed under

reduced pressure; column chromatography yielded compound (15) (0.38 g, CH 4.1 (2H, s, -CH 8%), d (CDCi'3) 2.26 (12H, s, 3-C=N-), 2-NO2), 7.33-8.7 (5H, m, py), vmax (Nujol) 1615, 1560, 1455, 1355, 1320, 980, 890 cm 1.

1-Ethoxycarbonylethylpyridinatocobaloxime.

a. Cobalt(II) acetate tetrahydrate (1.25 g, 5 moles), dimethyl-

glyoxime (1,16 g, 10 mmoles) and pyridine (1.6 g, 20 moles) were

dissolved in acetone (10 ml) at 50°C under nitrogen. Ethyl 2-bromo- 190.

propionate (1.81 g, 10 mmoles) and zinc (excess) were added and the mixture was heated for 1 h. The solvent was removed under reduced pressure; column chromatography gave the alkylcobaloxime (0.89 g,

38%), identical (ir, nmr) with that obtained from chloropyridinatocobaloxime.

b. Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 „uuoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 70°C under nitrogen for 2 h.

Ethyl 2-bromopropionate (0.724 g, 4 mmoles) and zinc wool (excess) were added and the mixture was heated for 1 h. The solvent was removed under reduced pressure and the residue chromatographed on a cblumn. The product, dissolved in chloroform (20 ml), was washed with water (2 x 10 ml) to remove pyridinium salts. The chloroform solution was dried (Na2SO4) and the solvent removed under reduced pressure to leave the title compound (0.872 g, 93%), identical (nmr, ir) with that obtained from chloropyridinatocobaloxime.

Ethoxycarbonylmethylpyridinatocobaloxime.

Cobalt(II)`acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 70°C under nitrogen for 2 min.

Ethyl bromoacetate (0.668 g, 4 mmoles) and zinc wool (excess) were added and the mixture was heated at 70°C for 2 h. The solvent was removed under reduced pressure and the residue, dissolved in chloroform 191.

(20 ml), washed with water (2 x 10 ml). The chloroform solution was dried (Na2SO4) and the solvent removed under reduced pressure.

Column chromatography afforded the title compound (0.819 g, 90%), identical (nmr, ir) with that obtained from chloropyridinatocobaloxime.

1-Ethoxycarbonylpropylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles),dimethylglyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 60°C under nitrogen for 2 min.

Ethyl 2-bromobutyrate (0.78 g, 4 mmoles) and zinc wool (excess) were added and the mixture was heated for 1 h. The solvent was removed under reduced pressure and the residue, dissolved in chloroform (20 ml), washed with water (2 x 10 ml). The solution was dried (Na2SO4) and the solvent removed under reduced pressure. Column chromatography gave the title compound (0.821 g, 85%), identical (nmr, ir) with that obtained from chloropyridinatocobaloxime.

1-Ethoxycarbonylbutylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 50°C under nitrogen for 2 min.

Ethyl 2-bromovalerate(0.836 g, 4 mmoles) and zinc wool (excess) were added and the mixture was heated for 1 h. After the usual work up and column chromatography, the alkylcobaloxime (0.895 g, 90%) was obtained, identical (nmr, ir) with that obtained from trans-dipyridinatocobaloxime(II), 192.

1-Ethoxycarbonyl-2-methylpropylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 'moles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 40°C under nitrogen for 2 min.

Ethyl 2-bromo-3-methylbutyrate (1.254 g, 6 'moles) and zinc wool (excess) were added and the mixture was heated at 40°C for 1.5 h. After the usual work up and column chromatography, the title compound

(0.696 g, 70%) was obtained, identical (nmr, ir) with that obtained from trans-dipyridinatocobaloxime(II).

Cyanomethylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 70°C under nitrogen for 2 min.

Chloroacetonitrile (0.302 g, 4 mmoles) and zinc wool (excess) were added and the mixture was heated for 1 h. After the usual work up and column chromatography, the alkylcobaloxime (0.522 g, 64%), was obtained 1.33 (2H, s, -CH2-CN), 2.28 (12H, s, CH3-C=N-), ,s(CDC?3) 7.3-8.65 (5H, m, py), vmax (Nujol) 3380, 3160, 3110, 2200, 1600, 1555,

1235, 1220, 975, 770, 700, 610 cm1.

1-Cyanoethylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethyl-

glyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were

stirred in degassed benzene (10 ml) at 60°C under nitrogen for 2 min.

1-Chloro-l-methylacetonitrile (0.36 g, 4 mmoles) and zinc wool (excess)

were added and the mixture was heated for 1 h. After the usual work

up and column chromatography the title compound (0.58 g, 69%) was 193.

obtained,6(CDCr3) 0.57 (3H, d, J = 8 Hz, CH3-CHCN), 2.27 (6H, s, CH3- C=N-), 2.28 (6H, s, CH3-C=N-), 2.07-2.47 (1H, m, -CH-CH3), 7.25-8.7

(5H, m, py), v (Nujol) 3100, 2230, 1620, 1575, 1245, 995, 780, max 715 cm-1.

Benzoylmethylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred in degassed benzene (10 ml) at 45°C under nitrogen for 2 min. a-Bromoacetophenone (1,194 g, 6 mmoles) and zinc wool (excess) were added and the mixture was heated for 1 h. After the usual work up and column chromatography, the title compound (0.302 g, 31%), was

obtained, 2.07 (12H, s, CH,-C=N-), 2.44 (2H, s, -CH2-COPh), d(CDCl3) 7.18-8.6 (10H, m, py and Ph),max (CHC?3) 3090, 1615, 1564, 1370,

1320, 1090, 1070, 1015 cm-1.

1-Ethoxycarbonyl-1-phenylmethylpyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethyl-

glyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were

stirred in degassed benzene (10 ml) at 34°C under nitrogen for 2 min.

Ethyl 2-bromo-2-phenylacetate (1.458 g, 6 mmoles) and zinc wool (excess)

were added and the mixture was heated at 34°C for 2 h. After the

usual work up and column chromatography, the alkylcobaloxime (traces)

was obtained, 1.22 (3H, t, J = 7 Hz, CH3-CH2000-), 1.94 6(CDCi3) 194.

(6H, s, CH3-C=N-), 1.96 (6H, s, CH3-C=N-), 3.59 (1H, s, Ph-CH-CO2Et),

3.85 (2H, q, J = 7 Hz , CH3-CH2-000-), 7.15-8.45 (10H, m, py and Ph).

Nitromethylpyridinatocobaloxime (15).

Cobalt(II) acetate tetrahydrate (0.498, 2 mmoles), dimethylglyoxime

(0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were stirred

in degassed benzene (10 ml) at 45°C under nitrogen for 2 min. Bromo-

nitromethane (1.12 g, 8 mmoles) and zinc wool (excess) were added

and the mixture was heated up to 60°C for 1 h. After the usual work

up and column chromatography, the alkylcobaloxime (0.205 g, 24%) was

obtained, identical (nmr, ir) with that obtained from trans-dipyridinato-

cobaloxime(II),

Methy1pyridinatocobaloxime.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethyl-

glyoxime (0.464 g, 4 mmoles) and pyridine (0.474 g, 6 mmoles) were

stirred in degassed benzene (10 ml) at 40°C under nitrogen for 2 min.

Iodomethane (0.852 g, 6 mmoles) and zinc wool (excess) were added and

the mixture was heated at 40°C for 24 h. The solvent was removed

under reduced pressure and the residue, dissolved in chloroform (20 ml),

washed with water (2 x 10 ml). The solution was dried (Na2SO4) and

the solvent removed under reduced pressure to leave the alkylcobaloxime

(0.73 g, 957), 6(CDCt3) 0,7 (3H, s, CH3-Co-), 2.0 (12H, s, CHs-C=N-),

7,2-8.6 (5H, m, py), Vmax (Nujol) 3110, 3040, 1605, 1555, 1480, 1235, 970,

880, 770, 700 cm.-1 195.

Preparation of 1-Ethoxycarbonylethylpyridinatocobaloxime in the presence of nitrous oxide.

Cobalt(II) acetate tetrahydrate (0.498 g, 2 mmoles), dimethylglyoxime

(0.464 g, 4 mmoles), pyridine (0.474 g, 6 mmoles) and zinc wool

(excess) were stirred in degassed benzene (10 ml) under nitrous oxide at 70°C for 10 min. Ethyl 2-bromopropionate (0.724 g, 3 mmoles) was added and the mixture heated for 1 h. The solvent was removed

under reduced pressure and the residue, dissolved in chloroform (20 ml),

washed with water (2 x 10 ml). The solution was dried (Na2SO4) and

the solvent removed under reduced pressure. Column chromatography

afforded the title compound (0.844 g, 90%), identical (nmr, ir)

with that obtained from chloropyridinatocobaloxime.

Preparation of Alkylpyridinatocobaloximes from pyridinatocobaloxime(I) ion.

In a typical experiment, cobalt(II) chloride hexahydrate (2.38 g,

10 mmoles) and dimethylglyoxime (2.32 g, 20 mmoles) were stirred in

degassed methanol (35 ml), under nitrogen, until cobalt(II) chloride

was dissolved. Sodium hydroxide (0.8 g, 20 mmoles) in water (2.5 ml)

was added, followed by pyridine (0.8 g, 10 mmoles). The mixture was

cooled to -10°C and stirred at that temperature for 15 min. Sodium

hydroxide (0.4 g, 10 mmoles) in water (1 ml) was added, followed by

saturated aqueous palladium(II) chloride (two drops) and sodium

borohydride (0.05 g, 1.3 mmoles). The mixture was protected from the

light and an alkyl halide (12.5 mmoles) added. The mixture was stirred

overnight at room temperature under nitrogen and water (80 ml) added.

After cooling to 4°C for 2 h, the precipitate was filtered and dried

in vacuo. Column chromatography yielded the alkylcobaloximes (Table 8). 196.

2. Reaction of Alkylcobaloximes with a-Bromonitroalkanes

Reaction of methylpyridinatocobaloxime with 2-bromo-2-nitropropane.

2-Bromo-2-nitropropane (0.5527 g, 3.29 mmoles) was added slowly to a solution of methylpyridinatocobaloxime (1.111 g, 2.9 mmoles) in acetonitrile (15 ml) at room temperature under nitrogen. The

temperature was raised slowly to 80°C and the mixture heated to reflux for four days. Water (10 ml) was added and the mixture

extracted with ether (3 x 40 ml). Most of the solvent was removed

at atmospheric pressure. Glc analysis showed the absence of nitro-t-

butane. The tic analysis showed only the presence of very polar

compounds.

Reaction of methylpyridinatocobaloxime with 2-bromo-2-nitrocamphane.

2-Bromo-2-nitrocamphane (0.5 g, 1.91 mmoles) was added to a

solution of methylpyridinatocobaloxime (0.73 g, 1.91 mmoles) in

dimethylācetamide (20 ml) under nitrogen. The mixture was

heated at 135°C for three days, The solvent was removed under

reduced pressure and the residue extracted thoroughly with ether.

The tic analysis showed the presence of very polar compounds only.

3. Reaction of Alkylcobaloximes with Copper(II) Salts

Reaction of copper(II) chloride with n-butylpyridinatocobaloxime.

Anhydrous copper(II) chloride (0.072 g, 0.535 mmoles) and

n-butylpyridinatocobaloxime (0.09 g, 0.211 mmoles) were heated at

60°C in THF (4 ml) for 10 min. The solvent was removed under reduced

pressure. Column chromatography gave n-butylpyridinatocobaloxime

(0.06 g, 67%) . 197.

Reaction of copper(II) bromide with n-butylpyridinatocobāloxime.

Anhydrous copper(II) bromide (0.109 g, 0.49 mmoles) and n-butylpyridinatocobaloxime (0.208 g, 0.49 mmoles) were heated at

60°C in THF (4 ml) under nitrogen for 3 h. The glc analysis of the mixture showed the presence of a substance with the same retention time as bromobutane by comparison with an authentic sample. The solvent was removed under reduced pressure. Column chromatography gave n-butylpyridinatocobaloxime (0.024 g, 12%) and bromopyridinatocobaloxime (0.011 g, 5%), identical (nmr, ir) with that of an authentic sample (Found: C, 34.99; H, 4.21; N, 15.53. Calc. for C13H19BrN504Co:

C, 34.82; H, 4.24; N, 15.62%).

Reaction of copper(II) acetate with ethylpyridinatocobaloxime.

Copper(II) acetate monohydrate (0.056 g, 0.28 uuuoles) and ethylpyridinatocobaloxime (0.1 g, 0.251 mmoles) were heated at

30°C in ether (2 ml) for 24 h. The gic analysis indicated the formation of ethyl acetate,

Reaction of copper(II) bromide with isopropylpyridinatocobaloxime. a. Copper(II) bromide (0.054 g, 0.24 mmoles) and isopropylpyridinatocobaloxime (0.05 g, 0.12 mmoles) were heated in isopropanol (3 ml) at 60°C under nitrogen, for 6 h. A pale yellow solid precipitated from isopropanol during the reaction. The glc analysis indicated the presence of 2-bromopropane. The tic analysis showed total consumption of isopropylpyridinatocobaloxime. The precipitate formed was filtered and part of it treated with aqueous ammonia. There was no colour 198.

change observed. Another part of it was dissolved in ethanol and a solution of diquinoline in ethanol added. A pink colour developed.

The precipitate had the same R value on tic as copper(I) bromide. F b. Isopropylpyridinatocobaloxime (0.05 g, 0.12 mmoles) was heated in isopropanol (3 ml) at 60°C under nitrogen. After 12 h the alkylcobaloxime was unreacted (tic).

Reaction of copper(II) bromide with pentylpyric.inatocobaloxime.

Fentylpyridinatocobaloxime (0.1 g, 0.228 mmoles) and copper(II) bromide (1, 1.5, 2,0, 2.5 molar equivalents) were heated at 60°C in isopropanol (4 ml), under nitrogen, until all the alkylcobaloxime was consumed (tic). The glc analysis indicated the presence of bromopentane (6, 9, 43, 50%), The yields were estimated by comparison with standard solutions of bromopentane in isopropanol.

Reaction of copper(II) chloride with alkylpyridinatocobaloxime in the presence of nucleophiles.

Copper(II) chloride (0.323 g, 2.4 mmoles), isopropylpyridinatocobaloxime (0.5 g, 1.2 mmoles) and a nucleophile (1.2 mmoles) were heated in ether (5 ml) at 30°C, under nitrogen, for 24 h. The products of the reaction were examined by glc, ms. In all the cases authentic samples were prepared and the glc results confirmed. The results are summarised in Table 10. Similar experiments were performed with benzylpyridinatocobaloxime and 1-phenylethylpyridinatocobaloxime.

The results are also summarised in Table 10. 199.

Reaction of copper(II) bromide with isopropylpyridinātocobaloxime.

Copper(II) bromide (0.543 g, 2.43 mmoles) and isopropylpyridinatocobaloxime (0.5 g, 1.2 mmoles) were heated in isopropanol (10 ml) at 60°C under nitrogen. When all the alkylcobaloxime was consumed

(tic), the solvent removed under reduced pressure and the residue dissolved in the minimum amount of chloroform. Plc gave bromopyridinatocobaloxime (0.074 g, 14%), identical (nmr, ir) with an authentic sample and 0-isopropyl dimethylglyoxime (18) (0.05 g, 26%),

1.24 (6H, d, J = 6 Hz, CH3CH(CH3)0-), 1.98 (3H, s, CH3-C=N-), (CDCe3) 3 3)2CH0-), v 2.0 (3H, s, CH -C=N-), 4.1-4.6 (1H, m (CH max (CC" 3600, 3500-3100, 2980, 1470, 1450, 1385, 1375, 1370, 1330, 1315, 1160,

1135, 1120, 980, 935, 910, 670 cm-1, m/e 158 (M+).

0-Isopropyl dimethylglyoxime (18).

Dimethylglyoxime (0.3 g, 2.59 mmoles) and sodium hydride (0.062 g,

2.59 mmoles) were mixed in DMA (5 ml).2-Bromopropane (0.32 g, 2.59 mmoles)

was added when the hydrogen evolution stopped. The mixture was heated up to 60°C for 24 h. Water (10 ml) was added and the mixture extracted

with ether (4 x 20 ml). The combined extracts were washed with

water and dried (Na2SO4). The solvent was removed under reduced pressure,

plc (petroleum, 40-60°C - ether, 8:2 v/v) gave compound (18) (0.1 g,

25i), identical (nmr, ir, m/e) with that obtained from the reaction

of isopropylpyridinatocobaloxime with copper(II) bromide. 200.

1,1-Dideuterio-2-phenylethanol.

Lithium aluminium deuteriide(1.2 g, 28.6 mmoles) was suspended in ether (300 ml) at 30°C. Ethyl phenylacetate (8.6 g, 52.4 mmoles) in ether (50 ml) was added at such a rate so that the solvent was just refluxing. At the end of the addition, the mixture was stirred at room temperature for 1 h, then cooled to 0°C and ethyl. acetate

(10 ml) added. 4N Hydrochloric acid (30 ml) was added slowly. The two phases were separated and the aqueous phase was extracted with ether (30 m1). The combined extracts were washed with water (100 ml) and dried (Na2SO4). The solvent was removed under reduced pressure; column chromatography (petroleum, 40-60°C - ether, 1:1 v/v) gave the alcohol (0.69 g, 11%).., S(CM) 2.67 (2H, s, PhCH2-CD2OH), 7.03 (5H, s, Ph), m/e 124 (M+), for 2-phenylethanol S(CDCt3) 2.67 (2H, t, J = 6 Hz, PhCH2-CH2OH), 3.33-3.9 (3H, m, PhCH2CH2OH), 7.0 (5H, s, Ph), m/e

122 (M+) , 93, 92, 77.

1,1-Dideuterio-2-phenylethyl-p-bromophenylsulphonate.

1,1-Dideuterio -2-phenylethanol (0.6 g, 4.84 mmoles) was dissolved

in pyridine (10 ml) and cooled to 4°C. p-Bromophenylsulphonyl

chloride (1.967 g, 7.7 mmoles) was added and the solution left to

stand at 4°C for 24 h. The mixture was poured into ice-water (60 g)

with stirring and the crystals formed were filtered, washed with

water and dried in vacuo to yield the sulphonate (0.81 g, 49%),

(CC/4) 2.92 (2H, s, PhCH2-CD2-), 7.03-7.33 (5H, m, Ph), 7.6 (4H,

s, 2.-BrC6H4-0502-), for 2-phenylethyl p-bromophenylsulphonate, 201.

2.93 (2H, t,J = 6 Hz, PhCH2-CH2-), 4.23 (2H, t, J = 6 Hz, d(CDC{3) -CH2-0S02-), 6.9-7.3 (5H, m, Ph), 7.57 (4H, s, p-BrC6H4-0S02-).

1,1-Dideuterio-2-phenylethylpyridinatocobaloxime.

Cobalt(II) chloride hexahydrate (0.476 g, 2 mmoles) and dimethylglyoxime (0.464 g, 4 mmoles) were stirred in degassed methanol

(10 ml), under nitrogen, until cobalt(II) chloride was dissolved.

Sodium hydroxide (0.16 g, 4 mmoles) in water (1 ml) was added, followed by pyridine (0.16 g, 2 mmoles). The mixture was cooled to

-10°C and stirred at that temperature for 15 min. Sodium hydroxide

(0.08 g, 2 mmoles) in water (0.5 ml) was added, followed by saturated aqueous palladium(II) chloride (one drop) and sodium borohydride

(0.01 g, 0.26 mmoles). The mixture was protected from light and

1,1-dideuterio-2-phenylethyl p-bromophenylsulphonate (0.8 g, 2.33 mmoles) added. The mixture was stirred overnight at room temperature under nitrogen and water (20 ml) added. After cooling to 4°C for 2 h the precipitate was filtered and recrystallised from methanol to give the title compound (0.9 g, 81%), 2.11 (14H, s, CH5-C=N- and 8(CDC4) - PhCH2-CD2-), 7.09-8.73 (10H, m, py and Ph), (Nujol) 2100, 1600, vmax 1555, 1275, 1230, 1175, 960, 880, 750, 720, 690, 630 cm-1, for

2-phenylethylpyridinatocobaloxime S 2.11 (14H, s, CH3-C=N- (CDC-(3) — and PhCH2CH2-), 2.2 (2H, m, PhCH2CH2-), 7.07-8.73 (10H, m, py and Ph), -1 v (Nujol) 3400, 1600, 1560, 1490, 1280, 1230, 975, 950, 755, 685 cm. max 202.

Reaction of copper(II) bromide with 1,1-dideuterio-2-phenylethylpyridinatocobaloxime.

Copper(II) bromide (0.47 g, 2.1 mmoles) and l,1-dideuterio-2- phenylethylpyridinatocobaloxime (0.5 g, 1.05 mmoles) were stirred in benzene (2 ml), under nitrogen, at 70°C. After eight days all the alkylcobaloxime was consumed (tic) and the solvent removed under reduced pressure, followed by plc (petroleum, 40-60°C - ether,

8:2 v/v) to give 1,1-dideuterio-2-phenylethyl bromide (0.1 g, 51%),

(CDC-(3) 3.07 (2H, s, PhCH2-CD2-), 7.0-7.4 (5H, m, Ph), for 1-bromo-

2-phenylethane S (CDCl3) 2.83-3.65 (4H, m, PhCH2CH2-Br), 7.0-7.4 (5H, m, Ph).

Hex-5-enylpyridinatocobaloxime.

Pyridinatocobaloxime(I) ion (9.35 mmoles) was prepared as

before at -10°C. 1-Bromohex-5-ene (2.04 g, 12.5 mmoles) was added

and the mixture stirred at room temperature, under nitrogen, for

12 h in subdued light. Water (80 ml) was added and the mixture

cooled to 4°C for 4 h. The precipitate was filtered and recrystallised

from methanol to give the cobaloxime (3.16 g, 75%),S(CDC-(3) 0.97-2.2 (8H, m, CH2=CHCH2CH2CH2CH2-), 2.1 (12H, s, CH3-C=N-), 4.67-5.05

(2H, m, CH2=CH-), 5.56-6.04 (1H, m, CH2=CH-), 7.13-8.67 (5H, m, py),

(CHC-(3 vmax ) 3400, 3050, 2850, 1635, 1600, 1555, 1445, 1370, 1200, 970, 910, 875 cm-1 (Found: C, 50.50; H, 6.74; N, 15.51. Calc. for

C19H30N04Co: C, 50.55; H, 6.65; N, 15.52%). 203.

Reaction of copper(II) bromide with hex-5-enylpyridinatocobaloxime.

Copper(II) bromide (0.447 g, 2 moles) and hex-5-enylpyridinatocobaloxime (0.451 g, 1 mole) were stirred in benzene (10 ml)

70°C under nitrogen. When all the alkylcobaloxime was consumed (tic) six days, petroleum, 40-60°C added and the solution filtered. The solvent was slowly removed at atmospheric pressure to leave a mixture of 1-bromohex-5-ene (identical nmr, glc with an authentic sample) and bromocyclopentylmethane, 1.19-1.96 (11H, m, CH3 6(CDCi3) CH(CH2)3CH-CH2Br), 3.38 (2H, d, J = 7 Hz, CH-CH2-Br), m/e 162,4 (M+).

The ratio of the two compounds was 2.7:1, estimated by gic analysis.

An authentic sample of bromocyclopentylmethane was prepared and was used for comparison.

Bromocyclopentylmethane.

Cyclopentylmethanol (2 g, 20 moles) and triphenylphosphine

(5.764 g, 22 moles) were dissolved in DMF (20 ml) at 0°C. Bromine was added slowly until the orange coloration persisted. The solution was stirred for 1 h at room temperature and the volatile products

were distilled at room temperature at 1 mm Hg. On addition of water, a heavy oil separated which was dissolved in ether and dried

(Na2SO4). The solvent was distilled at atmospheric pressure to

leave the bromide (2.0 g, 61%), identical (nmr, ms, glc) with that formed from the reaction of copper.(II) bromide with hex-5-enylpyridinato-

cobaloxime. 204.

Decomposition of hex-5-enylpyridinatocobaloxime.

Hex-5-enylpyridinatocobaloxime (0.451 g, 1 mmole) was suspended in benzene (10 ml) at 70°C under nitrogen for six days.

The solvent was removed under reduced pressure. The residue contained mainly hex-5-enylpyridinatocobaloxime. The alkylcobaloxime was partly decomposed but there was no cyclopentylmethylpyridinato- cobaloxime present (nmr).

Hex-5-enal.

Pyridinium dichromate (3.76 g, 10 mmoles) and hex-5-enol (0.2 g,

2 mmoles) were mixed in dichloromethane (50 ml). The solution was stirred at room temperature for 36 h. and ether (50 ml) added. The mixture was filtered and the solvent removed under reduced pressure.

Ether (30 ml) was added to the residue and filtered through silica H

(type 60). The solvent was removed under reduced pressure and the residue distilled to yield hex-5-enal (0.05 g, 25%), b.p. 120°C 99,100 (lit,, 118, 120°C),S 1.35-2.65 (6H, m, CH2=CH-(CH2)3-CH0), (CDC a) - 4,75-5,17 (2H, m, CH2=CH-CH2-), 5.33-6.12 (1H, m, CH2=CH-CH2-), 9.73

(1H, t, J = 2 Hz, -CHO), ymax (film) 3080, 2940, 2860, 2720, 1720,

1640, 1595, 1580, 990, 915, 750, 705 cm-1. Part of the aldehyde was

treated with a hot solution of 2,4-dinitrophenylhydrazine (0.1 g, 0.5 mmoles) in ethanol (2 ml) and conc. sulphuric acid (two drops). A yellow precipitate was formed, filtered and recrystallised from methanol to give hex-5-enal 2,4-dinitrophenylhydrazone, m.p. 93-94°C 99-101 (lit., 101-101.5, 93-94, 96°C), m/e 278 (M+) 260, 232, 206, 149,

122, 81. 205.

Hept-6-en-2-ol.

Methyl iodide (1.136 g, 8 mmoles) in ether (5 ml) was added

slowly to magnesium turnings (0.218 g, 9 mmoles). At the end of the

addition, the solution was heated to reflux for 15 min, cooled to

0°C and hex-5-enal (0.45 g, 4.6 mmoles) in ether (5 ml) added slowly.

The mixture was stirred at room temperature for 1 h and 5% hydrochloric

acid (10 ml) added slowly at 0°C. The two layers were separated

and the aqueous phase was extracted with ether (2 x 20 ml). The

combined extracts were thoroughly washed with water, dried (Na2SO4)

and the solvent was removed under reduced pressure to leave hept-6-en-

2-ol (0.42 g, 80%),6 1.17 (3H, d, J = 6 Hz, CH CH-OH), (CDCt3) s- 1.12-2.3 (7H, m, CH2=CH-(CH2)3- and-OH), 3.6-4.0 (1H, m, -CHOH),

4.77-5.2 (2H, m, CH2=CH-), .5.47-6.17 '-( 1H, m,CH2=CH-), vmax (film)

3360, 3080, 2975, 2930, 2880, 1640, 1460, 1315, 1120, 1085, 1000, 940,

910, 820 cm-1, m/e 114 (M+), 113, 99, 97, 96, 81, 71, 55,54, 45.

2-Bromohept-6-ene.

Hept-6-en-2-ol (1.05 g, 9.2 mmoles) in pyridine (0.8 g, 10 mmoles)

and petroleum, 30--40°C (5 ml) was added slowly to a solution of

phosphorus tribromide (1.08 g, 3.98 mmoles) in petroleum, 40-60°C (5 ml)

at -10°C under nitrogen. The mixture was stirred at room temperature

for 12 h. Ice-water (20 g) was added and the aqueous phase extracted

with ether (3 x 20 ml). The combined extracts were washed with water

(30 ml), 5% aqueous sodium bicarbonate (30 ml),saturated brine (30 ml)

and dried (K2CO3). The solvent was removed under reduced pressure to 206.

leave the bromide (1.4 g, 47%),6(CDC-(3) 1.12-2.38 (9H, m,

CH2 CH'(CH2)3CHBrCH3), 3.95-4.42 (1H, m, -CHBr-), 4.73-5.23 (2H, m,

CH2=CH-), 5.47-6.23 (1H, m, CH2=CH-), v (film) 3080, 2980, — — max 2860, 1640, 1455, 990, 910, 730 cm 1, m/e 176, 178 (M+), 134,

136, 97, 96, 81.

102 Tetrahydrofurfuryl chloride.

Thionyl chloride (50 g, 420 mmoles) was added to a vigorously stirred solution of tetrahydrofurfuryl alcohol (40.8 g, 400 mmoles) in pyridine (34.8 g, 440 mmoles). When necessary the mixture was cooled in an ice-bath, so that the temperature did not exceed 60°C during the addition. At the end of the addition, the solution was stirred at room temperature for 4 h and at .50°C for 2 h. The cooled mixture was poured in a beaker and extracted thoroughly with ether.

The extracts were combined and the solution was concentrated under reduced pressure, The residue was washed with water (3 x 10 ml) and dried (Na2SO4). Distillation gave the title compound (34 g, 71%), 102 b,p. 41-42°C at 11 mmHg (lit., 47-48°C at 15 mmHg), 6(CDC?3) 1.7-2.25 (4H, m), 3.5 (2H, d, J = 6 Hz), 3.6-4.23 (3H, m), (film) vmax 2950, 2860, 1440, 1280, 1250, 1180, 1055, 960, 920, 870, 815, 740 cm-l.

1-Bromopent-4-ene.

Pent-4-en-1-ol (8.6 g, 100 mmoles) and triphenylphosphine (28.82 g,

110 mmoles) were dissolved in DMF (120 ml) at 0°C. Bromine (16.0 g,

100 mmoles) was added slowly and the solution stirred at room temperature for 1 h. The volatile products were distilled at room temperature at 207.

1 mmHg. On addition of water (20 ml) a heavy oil separated which was dried (Na2SO4) to give the title compound (3.4 g, 23%), S(CCtr,)

1.73-2.4 (4H, m, CH2=CH(CH2)2-), 3.35 (2H, t, J = 6 Hz, -CH20H),

=CH-), 5.38-6.13, (1H, m, CH2=CH-), (film) 4.77-5.22 (2H, m, CH2 vmax 3090, 2990, 2840, 1645, 1250, 995, 915, 760 cm-1.

Hept-6-en-2-ol.

1-Bromopent-4-ene (3.4 g, 22.8 mmoles) in ether (10 ml) was added slowly to magnesium turnings (0.73 g, 30 mmoles). At the end of the addition, the mixture was heated to reflux for 30 min, then cooled to 0°C and acetaldehyde (1.32 g, 30 mmoles) in ether (10 ml) added slowly. The solution was stirred at room temperature for 2 h and ice-cold 5% hydrochloric acid (5 ml) added. The two layers were separated and the aqueous phase was extracted with ether (2 x 20 ml)

The combined extracts were washed with water and dried (Na2804).

The solvent was removed under reduced pressure to leave the alcohol

(1.9 g, 73%), identical (nmr, ir) with that obtained from the reaction

of hex-5-enal with methylmagnesium iodide.

1-Methylhex-5-enylpyridinatocobaloxime.

Pyridinatocobaloxime(I) ion (5 mmoles) was prepared in the usual

way in methanol (20 ml) at -10°C. 2-Brotuohept-6-ene (1 g, 7.25 mmoles)

was added and the mixture stirred under nitrogen and subdued light,

at room temperature for 12 h. Water (50 ml) was added and the solution

extracted with chloroform (3 x 40 ml). The combined extracts were 208.

dried (Na2SO4) and the solvent was removed under reduced pressure.

Column chromatography gave the cobaloxime (0.3 g, 13%), 6(CDCe3) 0.4 (3H, d, J = 7 Hz, CH3-CHCo-), 1.11-1.7 (6H, m, -CHCo-(CH2)s-),

1.82-2.2 (2H, m, CH2=CH-CH2-), 2.12 (13H, s, CH3-C=N- and-CHCo-),

4.83-5.2 (2H, m, CH2=CH-), 5.59-6.1 (1H, m, CH2=CH-), 7.19-8.67

(5H, m, py), vmax(CHCt3) 3420, 2980,..2840, 1640, 1608, 1560, 1330,

1070, 970, 910 cm-1 (Found: C, 51.33; H, 6.86; N, 14.74.

C20H32N504Co.requires C, 51.61; H, 6.88; N, 15.05%).

Reaction of copper(II) bromide with hept-6-en-2-ylpyridinatocobaloxime.

Copper(II) bromide (0.29 g, 1.3 mmoles) and hept-6-en-2-ylpyridinato-

cobaloxime (0.3 g, 0.645 mmoles) were stirred in degassed benzene

at 70°C, under nitrogen, for seven days. Petroleum, 40-60°C was

added, the solution filtered and the solvent removed at atmospheric

pressure. The glc-ms analysis of the residue showed the presence of

2-bromohept-6-ene and a rearranged product in a ratio 2.15:1 (gic).

Reaction of copper(II) bromide with R-1-methylheptylpyridinatocobaloxime.

a Copper(II) bromide (0.894 g, 4 mmoles) and R-1-methylheptylpyridinato-

cobaloxime (0.962 g, 2 mmoles) were stirred in acetonitrile (10 ml) at

70°C, under nitrogen, for 5 min. The solvent was removed under reduced

pressure and the residue extracted thoroughly with ether. The

combined extracts were concentrated under reduced pressure and an

ethereal solution of the residue was filtered through silica H (type 60).

Concentration of the solution under reduced pressure gave 2-bromooctane 209.

(16H, 4.02-4.37 (0.139 g, 36%), S(CDCt3) 0.9-1.92 m), (1H, m), [a ]D20 m/e 192, 194 (M+), 113, 111, = _9.2° (ether).

b. The same experiment was performed in the presence of lithium D20 = - bromide.Again, 2-bromooctane (0.13 g, 34%), [a ] 8.2° (ether) was isolated.

Reactions of copper(II) bromide with benzylpyridinatocobaloxime.

a. Benzylpyridinatocobaloxime (0.69 g, 1.5 mmoles) and copper(II)

bromide (0.67 g, 3 mmoles) were stirred in acetonitrile (20 ml) at

50°C, under nitrogen, for 10 min. The solvent was removed under

reduced pressure. Column chromatography (petroleum, 40-60°C) yielded (CDC?3) 4.4 (2H, s) , 7.28 benzyl bromide (0.2 g, 78%) , S (5H, s) , (film) 3020, 2920, 1700, 1500, 1450, 810, 750, 690 cm-1, m/e 170, vmax 172 (M) and compound (19) (0.01 g, 3%), m.p. 95°C (lit.,63 85°C), 2,04 (3H, s, CH =N-), 2.08 (3H-, s, CH (CDCe3) - 3-C 3-C=N-), 5.2 (2H, (5H, 3600, 3500-3130, s, PhCH2-), 7.33 s, Ph), vmax (CC-C4) 3090, 3070, 3040, 1500, 1455, 975, 920, 895, 695 cm-1, m/e 206 (M+), 189, 115, 91, 77.

b. The above experiment was repeated using equimolar amounts of

copper(II) bromide and benzylpyridinatocobaloxime. Column chromatography

(petroleum, 40-60°C - ether, 8:2 v/v) gave traces of benzyl bromide,

compound (19) (10%) and compound (20) (14%),6(CDCf3) 2.03 (6H, s, CH3-C=N-), 5.2 (4H, s, PhCH2), 7.34 (10H, s ), v (CCl4) 3095, 3070, max 210.

3040, 2930, 2860, 1500, 1370, 1225, 1120, 1015, 690 cm-1, m/e 296

(M+), 91.

c. The experiment was repeated using a 5 molar excess of copper(II) bromide over the alkylcobaloxime. Only benzyl bromide (60%) was isolated.

d. The experiment was repeated in the presence of lithium bromide.

Only benzyl bromide (77%) was isolated after the usual work up.

4. Synthesis of Coenzyme Ba2 Model Compounds

b Compound (43) .

2-Bromomethylsuccinic anhydride. 45% Hydrogen bromide in acetic acid (9 ml, 50 mmoles) was added

slowly to a solution Of itaconic anhydride (5.6 g, 50 mmoles) in

ether (50 ml). The mixture was stirred for 1 h at room temperature

and acetic acid removed under reduced pressure. The residue was

recrystallised from ether-petroleum,. 40-60°C to give the title compound

(4 g, 41%), m.p. 53-55°C, d(CDC-(3) 2.97-3.3 (2H, m, -CH2Br), 3.62-3.98

(3H, m, 0=C-CH2-CH-00-), max (Nujol) 3050, 2990, 1875, 1795, 1410, 1380, 1320, 1290, 1145, 1080, 990, 930, 890, 850, 815, 740, 670 cm-1,

m/e 195, 193 (194, 192) (M+), 120, 122, 113 (Found: C, 31.2; H, 2.57;

Br, 41.25. C5H5Br03 requires C, 31.1; H, 2.59; Br, 41.45%). 211.

Diethyl 2-bromomethylsuccinate.

A similar reaction of diethyl itaconate with hydrogen bromide gave the bromide (80%),6(CDCi3) 1.27 (6H, t, J = 7 Hz, CH3CH2-000-), 2.67-2.83 (2H, dd, -CH2-CO2Et), 3.05-3.53 (1H, m, CH-CO2Et), 3.65

(2H, d, J = 4 Hz, -CH2Br), 4.12 (2H, q, J = 7 Hz, CH3CH2-000-),

4.17 (2H, q, J = 7 Hz, CH3CH2-000-).

2-Ethoxycarbony1-3-ethoxycarbonylpropylpyridinatocobaloxime (43).

Pyridinatocobaloxime(I) ion (10 mmoles) was prepared the usual way at -10°C under nitrogen in methanol (15 ml). Diethyl 2-bromomethylsuccinate (3.2 g, 12 mmoles) was added and the mixture stirred at room temperature for 12 h. Water (50 ml) was added and the solution cooled at 4°C for 2 h. The precipitate was filtered and dried in vacuo. Column chromatography, followed by recrystallisation

1.2 from methanol-water gave compound (43) (1.11 g, 20%),6(CDCl3) (6H, t, J = 7 Hz, CH3CH2-000-), 2.1 (6H, s, CHs-C=N-), 2.13 (6H, s, CH3-C=N-), 1.9-2.63 (5H, m, CH2-CH-CH2Co-), 4.03 (4H, q, J = 7 Hz, CH3CH2-000-), 7.07-8.63 (5H, m, py), 6(TFAA) 1.2 (6H, t, J = 7 Hz),

2.2 (3H, s, CH3-C=N-), 2.37 (3H, s, CHs-C=N-), 2.51 (3H, s, CH3-C=N-),

2.57 (3H, s, CH3-C=N-), 2.32 (2H, m, CH2-CO2Et), 3.0 (3H, m, -CH-CH2-Co),

4.23 (4H, q, J = 7 Hz), 7.87-8.78 (5H, (Nujol) 3430, 2960, m), 'max 1720, 1603, 1560, 1430, 1250, 1170, 1085, 1070, 975, 920, 875, cm-1

(Found: C, 47.67; H, 6.20; N, 12.25. C22H34N508Co requires C, 47.57; H, 6,13; N, 12.61%). 212.

2-Iodomethylsuccinic anhydride.

2-Bromomethylsuccinic anhydride (2.9 g, 15 mmoles) and potassium iodide (5.15 g, 31 mmoles) were mixed in acetone (10 ml) and heated to reflux for 24 h. Dry ether (70 ml) was added and the solution filtered. The solvent was removed under reduced pressure and the residue recrystallised from ether-petroleum, 40-60°C to give the title compound (2.88 g, 80%),d 2.93-3.18 (2H, m, -CH2 (CDCC3) -00-), 3.47-3.73 (3H, m, I-CH2-CH-00-), v (Nujol) 3020, 1865, 1785, 1410, 1365, 1290, — max 1230, 1090, 1045, 1005, 975, 930, 890, 840, 805, 775, 740 cm-1, m/e 240 (M+) 128, 127. c. Compound (44).

Diethyl N-formylaspartate.

Sodium (0.92 g, 40 mmoles) was dissolved in ethanol (30 ml) under nitrogen. The solution was cooled in an ice-bath and diethyl aspartate

(7.56 g, 40 mmoles) added followed by ethyl formate (2.96 g, 40 mmoles)

The mixture was warmed slowly to 50°C and stirred at that temperature forz h. Acetic acid (2.4 g, 40 mmoles) was added and the solvent removed under reduced pressure. The residue was extracted thoroughly with ether and the combined extracts were concentrated under reduced pressure. Column chromatography on neutral alumina (ether) gave the title compound (7.9 g, 91%),6 27 (6H, t, J = 7 Hz, CH3CH2-000-), ,CDCt3) 1. 2.9 (2H, d, J = 5 Hz, CH2-CO2Et), 3.92-4,43 (4H, m, CH3CH2-000-), 4.90

(1H, m, -CH-NCOH), 7.53 (1H, br, HCONH-), 8.17 (1H, s, H-CON-), (film) 'max 3350, 2990, 2940, 2755, 1740, 1680, 1520, 1470, 1100, 1050, 970, 860,

820, 780 cm 1. 213.

Diethyl N,N-dimethylaspartate (48).

Diethyl aspartate hydrochloride (10 g, 44 mmoles), formaldehyde

(7.8 g, 260 mmoles), magnesium sulphate (3.6 g) and 10% palladium on carbon (3.8 g) were stirred in ethanol (60 ml) under hydrogen- When the hydrogen absorption stopped, the solution was filtered and the precipitate washed thoroughly with ether. The solvent was removed under reduced pressure to leave compound (48) (8.59 g, 90%), d(CDC-(,)

1.23 (3H, t, J = 7 Hz, CH3CH2-000-), 1.28 (3H, t, J = 7 Hz,CH3CH2-000-),

2.37 (6H, s, -N(CH3)2), 2.6 -2.8 (2H, dd, CH2-CO2Et), 3.62-3.85 (1H, dd, -CH-NMe2), 4.17 (2H, q, J = 7 Hz, -CH2-000-), 4.27 (2H, q, J = 7 Hz,

-CH2-000-), umax (film) 2990, 2865, 2830, 2780, 1730, 1455, 850, 795,

760 cm-1. Diethyl N,N-dimethyl-3-methylaspartate.

Diethyl N,N-dimethylaspartate (0.217 g, 1 mole) and methyl iodide

(0.16 g, 1.05 mmoles) were added to a suspension of potassium hydride

(0.08 g, 2 mmoles) in THF (40 ml) under nitrogen. The mixture was stirred at room temperature for 1 h and the solvent removed under reduced pressure.

Plc (ether-petroleum , 40-60°C, 7;3 /v) gave compound (48) (0.043 g,

20%) and diethyl N,N-dimethyl-3 methylaspartate (0.1 g, 43%), 6(CDCr3) 1.23 (3H, t, J = 8 Hz, CH3CH2-000-), 1.27 (3H, t, J = 8 Hz, CH3-CH2-000-),

1.63 (3H, d, J = 4 Hz, CH3-CH-CO2Et), 2.32 (6H, s, (CH3)2N-), 2.65-3.0

(1H, m, -CH-Me), 4.16 (5H, m, CH3CH2-000- and Me2N-CH-), m/e 231 (M+), 172, 159, 158, 131, 130, 102. 214.

Reaction of diethyl N,N-dimethylaspartate with formaldehyde.

Diethyl N,N-dimethylaspartate (0.868 g, 4 mmoles) and paraformaldehyde

(0.15 g, 5 mmoles) were added to a suspension of potassium hydride

(0.2 g, 5 mmoles) and 18-crown-6 (catalytic amount) in THF (40 ml) at

-20°C under nitrogen. The mixture was stirred at that temperature

for 3 h and water (10 ml) added. The solution was extracted with

ether (4 x 40 ml) and the combined extracts were dried (Na2SO4). The

solvent was removed under reduced pressure; plc (ethanol-ethyl acetate

85:15 v/v) gave compound (48) (0.35 g, 40%), and diethyl 3-hydroxy-

methyl-N,N-dimethylaspartate (49) (0.081 g, 8%), s(CDC(3) 1.06-1.52 (6H, m, CH3CH2-000-), 2.32 (6H, s, (CH3)2N-), 3-3.8 (4H, m, H0-CH2-CH-CH-

N(CH3)2), 3.8-4.66 (4H, m, CH3CH2-000-), vmax (film) 3550, 3430-3090,

2840, 2800, 1725, 1155, 1095, 910, 855 cm-1, m/e 216, 156.1027

(C8H14NO2 requires 156.1025).

Chloromethylpyridinatocobaloxime.

Pyridinatocobaloxime(I) ion (20 mmoles) was prepared as before

in methanil(70 ml) at -10°C. Dichloromethane (3.4 g, 40 mmoles) was

added and the solution stirred under nitrogen at room temperature for

12 h, Water (120 ml) was added and the mixture cooled to 4°C for 2 h

The precipitate formed was filtered and recrystallised from methanol

to give the cobaloxime (5.51 g, 66%), 2.18 (12H, s, CH -C=N-), a(CDCi3) 3 3.68 (2H, s, CH2-Co-), 7.15-8.26 (5H, m, py), max (Nujol) 1600, 1555,

1230, 1175, 970, 765, 700, 690, 670 cm-1. 215.

Reaction of compound (48) with chloromethylpyridinatocobaloxime.

Compound (48) (0.85 g, 3.9 mmoles) was added to a suspension of potassium hydride (0.3168 g, 7.9 mmoles) and 18-crown-6 (catalytic amount) in THF (10 ml) at -20°C under nitrogen. The mixture was stirred at -20°C for 1 h and then chloromethylpyridinatocobaloxime

(1.2525 g, 3 mmoles) added. The mixture was stirred for 12 h at room temperature, water (10 ml) added and the mixture extracted with chloroform (4 x 30 ml). The combined extracts were dried (Na2SO4) and the solvent was removed under reduced pressure. Column chromatography gave compound (48) (0.68 g, 80%) and chloromethylpyridinatocobaloxime

(0.783 g, 63%).

Reactions of 2-phenyl-2-oxazolin-5-one (53) with methyl 2,3-dibromopropionate. a. 2-Phenyl-2-oxazolin-5 -one (0.483 g, 3 mmoles) was added to a suspension of potassium hydride (0.14 g, 3.5 mmoles) and 18-crown-6

(catalytic amount) in THF (30 ml) at -5°C under nitrogen. After 5 min, methyl 2,3-dibromopropionate (0.738 g, 3 mmoles) was added and the mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure; plc (ether) gave methyl 2,3-dibromopropionate (0.5535 g, 75%), compound (54) (0.1 g, 10%), m/e 327, 325

(M+), 246, 245, 213, 167, 165, 161, 105 and an uncharacterised compound (55), m.p. 135-137°C,6(CDCf3) 4.5 (1H, s), 7.3-7.6 (5H, m), m/e 322, 217, 161, 134, 122, 105, 77. 216.

b. Compound (53) (0.7728 g, 4.8 mmoles) was added to a suspension of potassium hydride (0.1933 g, 4.82 mmoles) and 18-crown-6 (catalytic amount) in THF (50 ml) at -20°C under nitrogen. After s h, methyl 2,3-dibromopropionate (1.11 g, 4.5 mmoles) was added and the mixture stirred at -20°C for 3 h and at room temperature for 2 h. Methanol

(20 ml) was added and the solution stirred at room temperature for

12 h. The solvent was removed under reduded pressure; column chromatography

(ether-petroleum, 40-60°C, 1:1 v/v) gave methyl 2-bromoacrylate (0.50 g,

3.83 (3H, 6.25 (1H, d, J = 2 Hz), 6.95 (1H, d, J = 2 Hz) 67%), 6(CDCt3) s), (identical with an authentic sample), (film) 3115, 3025, 3000, 2950, ''max 1730, 1610, 1260, 1190, 1106, 990, 937, 862, 792, 715, 660 cm 1 and compound (55) (0.29 g).

Reaction of compound (53) with methyl 2-bromo-3-methoxypropionate.

Compound (53) (1.175 g, 7.3 mmoles) was added to a suspension of

potassium hydride (0.293 g, 7.3 mmoles) and 18-crown-6 (catalytic amount)

in THF (60 ml) at room temperature under nitrogen. After 5 min, methyl

2-bromo-3-methoxypropionate (1.438 g, 7.3 mmoles) was added and the

mixture heated at 50°C for 12 h. Methanol (10 ml) was added and the

solution heated for another 2 h. The solvent was removed under reduced pressure and the residue extracted thoroughly with ether. Column

chromatography (ether-petroleum,40-60°C, 8:2 v/v) gave methyl benzoate

(0.245 g, 25%),6(cDCt3) 3.87 (3H, s), 7.12-8.18 (5H, m), methyl 2-bromo-

3-methoxypropionate (0.55 g, 38%), compound (57) (0.1g, 4%), s (CDCi3) 2.25-2.45 (1H, m, CH-CO2Me), 3.25 (3H, s, CH3-0-CH2), 3.37 (3H, s, CH3-0-CH2),

3.67 (3H, s, CH3-000-), 3.7 (3H, s, CH3-000-), 3.65-3.88 (4H, m, CH2-0CH3),

m/e 312, 314 (M}), 280, 282, 251, 250, 249, 248, 217, 192, 194, 117, 217.

compound (56) (0.01 g, 0.5%), m/e 277 (M+), 164, 161, 134, 117, 106,

105, 86, methyl hippurate (0.3 g, 21%), m.p. 84-85°C (lit., 45 85°C) and the uncharacterised compound (55) (0.2 g).

Methyl 2-iodo-3-methoxypropionate.

Methyl 2-bromo-3-methoxypropionate (3.94 g, 2 mmoles) and potassium iodide (excess) were mixed in acetone (40 ml). The solution was heated to reflux for 24 h, and the solvent removed under reduced pressure.

The residue was extracted thoroughly with ether, the combined extracts were washed with water and dried (Na2SO4), The solvent was removed under reduced pressure to leave the iodide (4.88 g, 100%), 6(CDCl3) 3.40 (3H, s, CH3-0CH2), 3.75 (3H, s, CH3-000-), 3.65-3.85 (2H, m, CH2-

OMe), 4.33-4.53 (1H, dd, -CH-I), v (film) 3000, 2835, 1740, 1350, max 1255, 1210, 1195, 1180, 1125, 1110, 1085, 965, 950, 910, 855, 730, 720,

675 cm-1, m/e 244 (M+), 213, 185, 117, 86, 85.

Reactions of compound (58) with methyl 2-bromo-3-methoxypropionate. a. Butyl lithium (3.0 ml, 4 mmoles) was added to a solution of diisopropylamine (0.404 g, 4 mmoles) in THF (40 ml) at -50°C under nitrogen. The solution was cooled at -78°C and HMPA (1 ml) followed

by compound (58) (0.764 g, 4 mmoles) in THF (1 ml) added. Methyl 2-bromo-

3-methoxypropionate (0.788 g, 4 mmoles) was added. The mixture was

stirred at -78°C for 7 h and at -50°C for 2 h. Ammonium chloride

(3 g) was added and the solution let to warm to 0°C. Ice-cold aqueous

ammonium chloride (30 ml) was added and the solution extracted with ether 218.

(4 x 50 ml). The combined extracts were washed with ice-water (50 ml), dried (Na2SO4) and the solvent was removed under reduced pressure at room temperature. The residue was dissolved in ether (5 ml) and added slowly under nitrogen to a solution of benzoyl chloride (0.562 g,

4 mmoles) in ether (10 ml) at 0°C. The mixture was stirred at 4°C for 12 h and 5% sodium bicarbonate (20 ml) added. The two layers were separated and the aqueous phase was extracted with ether (4 x 20 ml).

The combined extracts were washed with water, dried(Na2SO4) and concentrated

under reduced pressure. Plc (ether-petroleum , 40-60°C, 6.6:3.4 v/v)

gave ethyl hippurate (0.31 g, 37%), m.p. 65-66°C (lit.,45 67.5°C) and

°C (from ether), d compound (59) (0.23 g, 25%), m.p. 130-132 (CDC?3) 1.37 (3H, t, J = 7 Hz, CH3CH2-000-), 2.61-3.23 (2H, m,'CH-CH2-C(Br)CO2Me-),

3.46 (3H, s, CH3-000-), 4.38 (2H, q, J = 7 Hz, CH3CH2-000-), 5.07-5.27

(Nujol) (2H, m, -CH-0O2Et and -CH-NCOPh), 7.1-7.7 (10H, m, Ph), vmax 1730, 1630, 1575, 1440, 1370, 1345, 1292, 1260, 1240, 1190, 1155, 1108,

1025, 930, 865, 820, 790, 775, 760, 730, 705, 670, 625 cm-1, m/e 460,

462 (M+ + 1), 430, 428, 416, 414, 380, 306, 244, 170, 106, 105, 77,

13C nmr: S 11.5 (CH3CH2-000), 40 (CH -C(Br)CO2Me), 44 (CH3-000), (CDCi3) 2 49.6 (-C-CO2Et), 51.6 (CH2CH3), 55.2 (C(Br)CO2Me), 63 (C-Ph), 106.4, 107.4, 107.8, 109.2, 113.6, 115.6, 139.8, 143.4 (Found: C, 57.48;

H, 4.76; N, 2.94. C22H22BrN05 requires C, 57.39; H, 4.78; N, 3.04%).

b. The experiment was repeated but after the addition of methyl

2-bromo-3-methoxypropionate (0.394 g, 2 mmoles ) in HMPA (5 ml), the mixture was let to warm to -20°C and stirred at that temperature for 12 h.

After the usual work up and treatment with benzoyl chloride, plc, (ether- 219.

petroleum, 40-60°C, 7:3 v/v) gave compound (59) and compound (60)

(0.0323 g, 5%),6(CDCt3) 1.27 (3H, t, J = 8 Hz, CH3-CH2000-), 3.32 (3H, s, CH3-0CH2), 3.73 (3H, s, CH3-000-), 3.57-3.93 (4H, m, Me0-

CH2-CH-CH-NHCOPh), 4.23 (2H, q, J = 8 Hz), 6.87-7.53 (5H, m), m/e 323 (M+), 292, 278, 264, 250, 207, 117, 105, 91.

Methyl 2-bromo-3-E,E-diethylaminopropionate (61).

Diethylamine (1.88 g, 25.8 mmoles) in ether (5 ml) was added

slowly to a solution of methyl 2-bromoacrylate (4.257 g, 25.8 mmoles)

in ether (10 ml) at 0°C under nitrogen. The mixture was stirred for

1 h at room temperature, then washed with 5% aqueous sodium bicarbonate

(20 ml) and water (20 ml). The organic phase was dried (Na2S01.),

the solvent removed under reduced pressure and the residue distilled

to give compound (61) (4.3 g, 70%), b.p. 105°C at 15 mmHg (lit.,94 91-3°C

mmHg), 0.97 (6H, t, J = 6.5 Hz, CH CH2N-), 2.53 (4H, at 9 6(CDCl3) 3 q , J = 6.5 Hz, CH3CH2N-), 3.1 (2H, m, -CH2NEt2), 3.73 (3H, s, -CO2CH3),

4.2 (1H, dd, J = 10 Hz, J = 5 Hz, -CHBrCO2Me), vmax (film) 2975, 2880, 2810, 1750, 1440, 1390, 1265, 1225, 1160, 1150, 1110, 970, 850,

795, 760, 715 cm 1.

Reaction of compound (58) with compound (61).

Compound (58) (0.382 g, 2 mmoles) in THF (2 ml) was added to

a solution of lithium diisopropylamide (2 mmoles) prepared as before,

in THF (40 ml) and HMPA (4 ml) at -78°C under nitrogen. The anion

formed was added dropwise to a solution of compound (61) (0.476 g,

2 mmoles) in THF (20 ml) at -78°C. The mixture was let to warm to

room temperature slowly and stirred for 12 h. The solution was 220.

partitioned between ice-water (40 ml) and ether (100 ml); the aqueous phase was extracted with ether (3 x 40 ml) and the combined extracts were washed with ice-cold aqueous ammonium chloride (2 x 50 ml), then with ice-water (50 ml) and dried (Na2SO4). The solvent was removed under reduced pressure at room temperature. The residue was dissolved in ether (10 ml) and added slowly to a solution of benzoyl chloride (0.281 g, 2 moles) in ether (20 ml) at 0°C under nitrogen. 5% Aqueous sodium bicarbonate (20 ml) was added and the solution stirred for 1 h at room temperature. The two layers were separated and the aqueous phase was extracted with ether (2 x 20 ml).

The combined extracts were washed with water (20 ml),dried (Na2SO4) and the solvent was removed under reduced pressure. The residue was dissolved in ether (30 ml) and dry hydrogen chloride bubbled through the solution. The precipitate was filtered, washed with ether and dissolved in 5% aqueous sodium bicarbonate (20 ml). The aqueous

solution was extracted with ether (4 x 20 ml), the combined extracts

were dried (Na2SO4) and the solvent was removed under reduced pressure.

Part of the residue (0.25g) was dissolved in ether at 0°C. m-Chloroper

benzoic acid in ether (10 ml) was added until the potassium iodide

paper indicated that the peracid was not reacting. The solvent was

removed under reduced pressure and plc (petroleum,40-60°C-ether, 2:8 v/v)

gave compound (64) (0.089 g, 16%), (5 1.23 (3H, t, J = 7 Hz, (CDCt3) CH3-CH2-000-), 3.75 (3H, s, CH3-000-), 4.22 (2H, q, J = 7 Hz, CH3CH2-000-),

5.57 (1H, d, J = 8 Hz, -CH-NHCOPh), 6.1 (1H, s, HCH=C-CO2Me), 6.4

(1H, s, HCH=C-), 6.93-8.12 (6H, m, Ph and -NHCOPh), (film) 'max 221.

3300, 3070, 1715, 1660, 1600, 1575, 920, 900, 850, 810, 750, cm-1, m/e 291 (M+), 232, 218, 177, 156, 139, 111, 105.

Methyl 2-bromo-3-thiophenylpropionate (69).

Methyl 1-bromoacrylate (0.55 g, 3.3 mmoles) was added slowly to a solution of thiophenol (0.363 g, 3.3 mmoles) and potassium t- butoxide (0.037 g, 0.33 mmoles) in THF (10 ml) at 0°C under nitrogen.

The mixture was stirred at room temperature overnight and the solvent removed under reduced pressure. The residue was extracted thoroughly with ether and the combined extracts were concentrated under reduced pressure. Column chromatography (ether-petroleum, 40-60°C, 5:95 v/v) gave compound (69) (0.33 g, 36%),S 3.38-3.62 (2H, dd, J = 9.5 Hz, (CDC(, 3) J = 6 Hz, -CH2-SPh), 3.8 (3H, s, -CO2CH3), 4.17-4.42 (1H, dd, J = 9 Hz,

J = 6 Hz, -CH(Br)CO2Me), 7.3-7.63 (5H, m, Ph), v (film) 3050, 3040, max 2810, 1730, 1570, J465, 1265, 1200, 1135, 1040, 1010, 875, 820, 730,

680, 650 cm-1 (Found: C, 44.07; H, 4.14; Br, 28.84. C10H11BrO2S requires C, 43.65; H, 4.00; Br, 29.1%), m/e 273.9666 (M+ requires

273.9664).

Reactions of compound (58) with compound (69). a. Compound (58) (0.166 g, 0.87 mmoles) in THF (1 ml) was added to a solution of potassium t-butoxide (0.098 g, 0.87 mmoles) in THF

(40 ml) at -78°C under nitrogen. The anion was added dropwise to a solution of compound (69) (0.24 g, 0.87 mmoles) in THF (10 ml) at -78°C.

The mixture was allowed to warm slowly to room temperature and stirred for 4 h. The solvent was removed under reduced pressure at room temperature 222.

and the residue dissolved in ether (100 ml). The solution was washed with ice-cold aqueous ammonium chloride (2 x 30 ml) and water (30 ml), dried (Na2SO4) and concentrated under reduced pressure at room temperature.

The residue was treated as before with benzoyl chloride. Plc (ether- petroleum, 40-60°C, 6:4 v/v) gave compound (72) (0.12 g, 40%), m.p.

C (from dichloromethane-ether), d 1.37 (3H, t, J = 7 Hz, 173-174° (CDCt3) CH3CH2-000-), 2.26-3.08 (2H, m, CH2-C(SPh)CO2Me), 3.36 (3H, s, -CO2CH3),

4.4 (2H, q, J = 7 Hz, CH3CH2-OCO-), 4.8 (1H, br, -CH(CO2Et)NCOPh), m, -CH(Ph)NCOPh),6.92-7.5 (15H, n:, Ph), (CHCe3) 5.06-5.36 (1H, vmax 3050, 2990, 2950, 2840, 1730, 1635, 1600, 1585, 1370, 1095, 1020, 970,

940, 905, 890, 820, 635 cm-1, m/e 489.1610 (M+ requires 489.1610), 416,

380, 306, 207, 190, 161, 105, 77 and compound (71) (0.05 g, 20%),

(CDCC3) 1.27 (3H, t, J = 7 Hz, CH3CH2-000-), 2.09-2.9 (211, m, CH2CH- (SPh)CO2Me), 3.51 (3H, s, -CO2CH3), 3.62 (3H, s, -CO2CH3), 3.7-3.87

(1H, m, -CH-SPh), 4.18 (2H, q, J = 7 Hz, CH3CH2-000-), 4.81-5.2 (1H, m,

- (film) 3350, 3070, 2880, CH-NHCOPh), 6.92-7.96 (6H, m, -NHCOPh), vmax 1745, 1665, 1600, 1585, 1535, 1270, 1200, 1160, 1110, 1070, 860, 750,

735, 695 cm 1, m/e 401.13 (M+ requires 401.1297) 369, 291, 207, 161,

105, 77.

b. The experiment was repeated in a larger scale (7 moles) and the anion added very slowly (5 h) to compound (69). The work up and reaction with benzoyl chloride were performed as before. Plc (ether-petroleum,

40-60°C, 6:4 v/v) gave only traces of compound (72) and compound (71)

(1.25 g, 45%). 223.

d. Compound (45).

Reactions of compound (58) with methyl 2-bromoacrylate. a. Compound (58) (0.955 g, 5 mmoles), in THF (2 ml) was added slowly to a solution of lithium diisopropylamide (5 mmoles) in THF (30 ml) at -78°C under nitrogen. Methyl 2-bromoacrylate (0.99 g, 6 mmoles) in THF (2 ml) was added and the temperature raised slowly to 0°C.

Ice-cold aqueous ammonium chloride (20 ml) was added and the solution extracted with ether (3 x 40 ml). The combined extracts were washed with ice-water (40 ml), dried (Na2SO4) and concentrated under reduced pressure at room temperature. Treatment of the product with benzoyl chloride (0.7 g, 5 mmoles) gave a mixture of products; plc of a part of the residue afforded compound (59) (0.58 g, 25%), m.p. 130-132°C

(from ether) and compound (76) (0.25 g, 20%), d(CDC-(3) 1.28 (6H, t, J = 7 Hz, CH3CH2-000-), 1.85-3.1 (3H, m, CH2-CH(CO2Me)-), 3.57 (3H, s,

-CO2CH3), 3.62 (3H, s, -CO2CH3), 3.93-4.42 (5H, m, CH3CH2-000 - and

-CH-NHCOPh), 4.75-5.18 (1H, m, -CH-NHCOPh), 6.52-7.1 (2H, br, -NHCOPh),

7.16-7.93 (10H, m, Ph), vmax (film) 3320, 3070, 2990, 1745, 1655, 1608, -1 1585, 1535, 1380, 1310, 1250, 1205, 1165, 1110, 1025, 910, 800, 730 cm , m/e 498 (M+), 497, 291, 207, 161, 105, 77.

b. Compound (58) (0.955 g, 5 mmoles) in THF (2 ml) was added slowly to a solution of diisopropylamide (5 mmoles) in THF (30 ml) at -78°C under nitrogen. The anion was added to a solution of methyl 2-bromoacrylate

(1.24 g, 7.5 mmoles) in THF (10 ml) at -78°C for 2 h and ammonium chloride (3 g) added. The mixture was warmed to 0°C, ice-water (30 ml) added and the solution extracted with ether (4 x 30 ml). The combined 224.

extracts were washed with aqueous ammonium chloride (2 x 30 ml), with ice-water (30 ml) and dried (Na2SO4). The solvent was removed under reduced pressure at room temperature. The product was treated the usual way with benzoyl chloride (0.7 g, 5 mmoles). Column chromatography (ether-petroleum, 40-60°C, 1:1 v/v) yielded compound

(59) (0.54 g, 24%) and compound (77) (0.47 g, 23%),S 1.25 (CDC-(3) (3H, t, J = 7 Hz, CH3CH2-OCO-), 1.92-3.07 (4H, m, CH2-C(Br)CO2Me),

3.52 (3H, s, -CO2CH3), 3.57 (3H, s, -CO2CH3), 4.13 (2H, q, J = 7 Hz,

CH3CH2-000-), 4.72-5.17 (2H, m, CH2CH(Br)CO2Me and CH-NHCOPh), 7.17-

7.83 (5H, m, Ph), m/e 456, 458 (M+ - Br), 457, 455, 384, 382, 352, 350,

105, 77.

c. Compound (58) (0.955 g, 5 mmoles) in THF (2 ml) was added slowly to a solution of potassium t-butoxide (0.065 g, 0.577 mmoles) in t-butanol (0.4 g, 5.4 mmoles) and THF (50 ml) at -20°C. Methyl

2-bromoacrylate (0.825 g, 5 mmoles) was added and the mixture stirred for 2 h at -20°C. Ammonium chloride (3 g) was added, the mixture warmed to 0°C followed by addition of ice-cold aqueous ammonium chloride (20 ml).

The solution was extracted with ether (4 x 50 ml) and the combined extracts were washed with ice-water (2 x 50 ml), dried (Na2SO4) and concentrated under reduced pressure at room temperature. The product was treated with

benzoyl chloride as before. Column chromatography (petroleum, 40-60°C- ether, 1:1 v/v) gave compound (59) (0.87 g, 38%) and compound (78)

(0.26 g, 14%),m.p. 97-98°C (from ether), two diastereoisomers (1) d(CDC-1'3) (250 MHz) 1.30 (3H, t, J = 6.6 Hz, CH3CH2-000-), 2.41-2.91

(2H, m, -CH2-CHBrCO2Me), 3.68 (3H, s, -CO2CH3), 4.25 (2H, q, J = 6.6 Hz,

CH3CH2-000), 4.44 (1H, t, J = 7.4 Hz, -CH2-CHBrCO2Me), 4.99 (1H, ddd,

-CH-NHCOPh), 6.94 (111, d, J = 7.6 Hz, -CH-NH-COPh), 7.38-7.86 (5H, m, Ph) 225.

and (2) S(CDC-C3) (250 MHz) 1.32 (3H, t, J = 6.6 Hz, CH3CH2-000-) ,

2.41-2.91 (2H, m, -CH2-CHBrCO2Me), 3.79 (3H, s, -CO2CH3),4.25 (2H, q,

J = 6.6 Hz, CH3CH2-000-), 4.43 (1H, dd, J = 6.6 Hz, -CH2-CHBrCO211e),

4.89 (1H, ddd, -CH-NHCOPh), 7.09 (1H, d, J = 7.6 Hz, -CH-NHCOPh), 7.38-

7.86 (5H, m, Ph), u (film) 3330, 3060, 2980, 1735, 1650, 1600, max 1580, 1525, 1330, 1280, 1210, 1155, 1100, 1025, 910, 730, 645 cm-1, m/e 371, 373 (M+), 300, 298, 292, 291, 232, 218, 207, 176, 178, 158, 105,

77 (Found: C, 48.39; H, 4.89 ; N, 3.74; Br, 21.62. C15H18BrN05 requires

C, 48.4; H, 4.84; N, 3.76; Br, 21.5%).

Ethyl 2-benzamido-4-bromo-4-methoxycarbonylbutyrate (78).

Sodium (0.0115 g, 0.5 mmoles) was dissolved in dry ethanol (20 ml) and THF (20 ml) under nitrogen. The solution was cooled to -20°C and compound (58) (0.955 g, 5 mmoles) in THF (2 ml) added, followed by methyl 2-bromoacrylate (0.825 g, 5 mmoles) in THF (2 ml). The solution

was stirred at -20°C for 2 h, ammonium chloride (3 g) added, the mixture

warmed to 0°C, treated with ice-cold aqueous ammonium chloride,

extracted with ether (3 x 40 ml) and washed with water (40 ml). The

combined extracts were dried (Na2SO4) and concentrated under reduced

pressure at room temperature to leave ethyl 2-N-benzylideneamino=4-

bromo-4-methoxycarbonylbutyrate (1.424 g, 80%),6(CDCl3) 1.26 (3H, t,

J = 7 Hz, CH3CH2-000-), 2.47-3.07 (2H, m, -CH2-CHBrCO2Me), 3.72 (3H, s,

-CO2CH3), 4.23 (3H, m, CH3CH2-000- and -CH2-CHBrCO2Me), 4.49 (1H, dd, -CH-NHCOPh), 7.42-7.92 (5H, m, Ph), 8.33 (1H, s, -N=CHPh). The product

was dissolved in ether (10 ml) and added to a solution of benzoyl chloride 226.

(0.7025 g, 5 mmoles) in ether (10 ml) at 0°C under nitrogen. The mixture was washed with 5% aqueous sodium bicarbonate (20 ml) and the aqueous phase extracted with ether (2 x 20 ml). The combined extracts were washed with water (30 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (petroleum,

40-60°C, - ether, 2:8 v/v) gave compound (78) (1.04 g, 70%), m.p.

97-98°C (from ether) and compound (79), (0.1 g, 9%), m.p. 158-159°C

(from ether),6(CDCC3)(250 MHz) 1.24 (3H, t, J = 7.5 Hz), 1.8 (1H, dd,

J = 4.5 Hz, J = 7.5 Hz), 2.0 (1H, dd, J = 4.5 H;:, J = 9.0 Hz), 2.82

(1H, dd, J = 7.5 Hz, J = 9.0 Hz), 3.72 (3H, s), 4.22 (2H, q, J = 7.5 Hz),

6.89 (1H, br), 7.39-7.82 (5H, m), "max (film) 2950, 1720, 1650, 1600, 1580, 1370, 1325, 1270, 1210, 1160, 1060, 1035, 1025, 950, 880, 855, 845,

780, 695, 610 cm-1, m/e 291 (M+) 260, 245, 232, 218, 207, 186, 170, 105,

77 (Found: C, 61.82; H, 6.18; N, 4.79. C15H17N05 requires C, 61.85;

H, 5.93; N, 4.81%).

3-Benzamido-3-ethoxycarbonyl-1-methoxycarbonylpropylpyridinato- cobaloxime (45).

Cobalt(II) acetate tetrahydrate (0.996 g, 4 mmoles),dimethylglyoxime (0.928 g, 8 mmoles) and pyridine (0.948 g, 12 mmoles) were stirred in degassed benzene (15 ml) at 65°C for 2 min. Zinc wool

(excess) and compound (78) (1.8 g, 4.8 mmoles) were added and the mixture was stirred at 65°C under nitrogen for 2 h. The solvent was removed under reduced pressure. Column chromatography, followed

by recrystallisation from methanol-water gave compound (45) (1.19 g,

45%), 1.27 (3H, t, J = 7.25 Hz, CH CH2-000-), 1.73-2.3 (3H, 6(CDCe9) 9 227.

m, -CH 2-CH-Co), 2.2 (12H, s, CH3-C=N-), 3.47 (3H, s, CO2CH3), 4.18

(2H, q, J = 7.25 Hz, CH3CH 2-000-), 4.39-4.66 (1H, m, -CH-NHCOPh), 6.91 (1H, d, J = 7 Hz, -CH-NHCOPh), 7.19-8.53 (10H, m, py and Ph),

vmax (Nujol) 3340, 2920, 2860, 1730, 1695, 1660, 1605, 1535, 1280, 1240, 1230, 1205, 1115, 1090, 1080, 775, 725, 700 cm-1 (Found:

C, 50.80; H, 5.68; N, 12.68. C28H32N609Co requires C, 50.91;

H, 5.61; N, 12.73%). 228.

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APPENDIX

ABBREVIATIONS AND SYMBOLS

Cobaloxime (dmgH): Bis(dimethylglyoximato)cobalt.

The oxidation state of cobalt is shown only when different from +3. c-hgH : Cyclohexanedionedioximato. c-pgH : Cyclopentanedionedioximato. dpgH : Diphenylglyoximato dotnH

/(CH2)3\ N/

\N N~ OH O-

salen R=H X=(CH2)2

Me2salen R=Me X=(CH2)2

salphen R=H X=o-phenylene

The 'base-on' or 'base-off' forms of the cobalamins are shown in the

Schemes as: -6;01 -[Co]

Z —Bz

B12a : Aquo- or hydroxocobalamin(III).

B12r : Aquo- or hydroxocobalamin(II).

B12s : Aquo- or hydroxocobalamin(I).

HB12 : Hydridocobalamin. Alkylcobaloxime Synthesis for Reactive Alkyl Halides

By PAGONA F. Roussi and DAVID A. WrnDOwsoN* (Department of Chemistry, Imperial College, London SW7 2AY)

Reprinted from Journal of The Chemical Society Chemical Communications 1979

The Chemical Society, Burlington House, London W1V OBN

810 J.C.S. CHEM. COMM., 1979

Alkylcobaloxime Synthesis for Reactive Alkyl Halides

By PAGONA F. Rouss2 and DAVID A. WIDDOWSON* (Department of Chemistry, Imperial College, London SW7 2AY)

Summary The reaction of bisdimethylglyoximatocobalt- oximes, for which a mechanism is proposed; the yields are (n) with a-halogenoesters and related compounds in the generally superior to those of conventional syntheses for presence of zinc in non-aqueous solvent gives alkylcobal- the title compounds.

J.C.S. CHEM. COMM., 1979 811

P.LKYLCOBALOXIMMES are of particular interest because of In order to define the reaction more precisely, a number their use as simple models for the reactions of cobalamin of control experiments were carried out. Firstly, the role dependent enzymes.' Alkylcobaloxime synthesis is domin- of zinc in the process could be either as a reductant for the ated by two approaches: the addition of hydridocobaloxime halogenocobaloxime or as a reductant for the a-halogeno- to olefins' and the alkylation of bis(dimethylglyoximato- ester.' When preformed zinc enolates5 were used, no pyridinato)cobalt(I) anions, the Schrauzer method.3 The cobaloxime was produced. Furthermore, lithium and latter is the more frequently used technique and involves the potassium enolates were equally ineffective. The reduction in situ generation of the cobalt(i) anion in aqueous meth- of the a-halogenoester by zinc is therefore a competitive anolic solution at high pH. Although yields are high for side reaction. This is not important in the simple a-halo- simple alkyl halides, the method is less successful with genoesters, but may be the predominant reason for the reactive halides such as a-halogenoesters. We report here lower yields of the more substituted compounds. This a synthesis which is technically simple, particularly effective interpretation is confirmed by the reaction of chloroaceto- for x-bromoesters, and which complements the Schrauzer nitrile with chloropyridinatocobaloxime in the presence of method. zinc to give cyanomethylcobaloxime in 89% yield. Chloro- acetonitrile is inert to zinc under the conditions of this 2Co(dmgH)_py2 -;- RX -3 RCo(dmgH)2py 1- XCo(dmgH),py reaction. The reduction of vitamin Bj,a with zinc gives vitamin SCHEME 1. dmgH = dimethylglyoximato. py = pyridinato. B1256 at the cobalt(I) oxidation level. The question arises, therefore, of the exact oxidation state of cobalt in the The reaction of bisglyoximatocobalt(II) complexes with cobaloxime synthesis. Treatment of cobaloxime(H) with alkyl halides has been studied mechanistically' (overall zinc alone did not generate the cobalt(i) anion. It appears process as Scheme 1) but not further developed presumably therefore that cobaloxime(II) is the intermediate in the because of the adverse stoicheiometry and the tedious recycling of the halogenocobaloxime and the overall separation of the mixed cobalt(III) complexes resulting. mechanism is plausibly expressed in Scheme 2. These reactions can be conducted in a non-nucleophilic medium and therefore offer potential for alkylcobaloxime Co(dmgH)2py2 -}- RX -+ XCo(dmgH)3py + R• -1- py synthesis from highly electrophilic halides provided that the R• Co(dmgH)2py2 -> RCo(dmgH),py -}- py halogenocobaloxime can be recycled. 2XCo(dmgH)2py Zn -. 2Co(dmgH)2py -1- 2X- + Zn2+ Of the reducing agents which will selectively reduce halogenocobaloxime in the presence of a-halogenoesters SCHEME 2 (aluminium powder, aluminium amalgam, and zinc), we have found zinc wool to be the most effective. In a typical The scope for the synthesis is defined by the examples in experiment, cobalt acetate (2 mmol), dimethylglyoxime the Table. Simple alkyl halides (nos. 1 and 2) give com-

TABLE. Cobaloxime syntheses Reaction Reference No. RX T/°C time/h Yield/ % yields/ % 1 McI 40 24 95 74b 2 Me2CHBr 60 72 Tracee 33 3 BrCH2CO2Et 70 2 90 18 4 McCHBrCO2Et 70 90 18 5 EtCHBrCO,Et 60 1 85 38 6 PraCHBrCO2Et 50 1 90 45 7 Pr'CHBrCO2Et 40-45 1.5 70 28 8 PhCHBrCO0Et 35 2 Trace 36d 9 Mc2CCHBrCO2Et 40 1.5 0 10 PhCOCH,Br 45 1 31 17 11 CICH..CN 70 1 64 36 12 McCHCICX 60-70 1 69 20 13 BrCH \O, 45-60 1 24 19 14 BrCMe2NO, 40 2 Oe a As they are rarely reported in the literature, yields by the Schrauzer method in our hands are given for comparison. b Literature yield 99% using dimethyl sulphate (see G. N. Schrauzer, Inorg. Synth., 1968, 11, 61). C Isopropyl iodide gave a 57% yield for the unrecycled reaction (see G. N. Schrauzer and R. J. \Vindgassen, J. Amer. Chem. Soc., 1966, 88, 3738). d Literature yield 40% (see M. N. Ricroch and A. Gaudemer, J. Organometallic Chem., 1974, 67, 119). e Product: 2,3-dimethyl-2,3-dinitrobutane.

(4 mmol), and pyridine (6 mmol) in degassed benzene (10 ml) parable (or worse) yields to those of the Schrauzer method. at 60 `C under nitrogen were mixed with the alkyl halide The elusive tertiary alkylcobaloximes7 are not produced by (4 mmol) and an excess of zinc wool. After 1 h, work up this approach (e.g. no. 14) presumably because of steric via column chromatography on silica gel generally gave congestion. The only a-halogenoesters which do not give moderate to good yields of the alkylcobaloxime (Table). high yields are those rapidly reduced by zinc& (no. 8) or 812 J.C.S. CHEM. COMM., 1979 prohibited by steric congestion (no. 9). Iodides react alkylcobaloxime synthesis under mild conditions. faster than bromides (see no. 2 footnote c) but are generally less accessible. Within these limitations, the method offers excellent scope for non-aqueous, non-nucleophilic (Received, 25th May 1979; Com. 551.)

G. N. Schrauzer, Angew. Chem. Internat. Edn., 1976, 15, 417. 2 For detailed accounts see: D. Dodd and M. D. Johnson, J. Organometallic Chem., 1973, 52, 1; J. M. Pratt and P. J. Craig, Adv. Organometallic Chem., 1973, 11, 331. 8 G. N. Schrauzer and R. J. Windgassen, J. Amer. Chem. Soc., 1967, 89, 1999. J. Halpern, and P. F. Phelan, J. Amer. Chem. Soc., 1972, 94, 1881; P. W. Schneider, P. F. Phelan, and J. Halpern, ibid., 1969, 91, 77. 6 M. W. Rathke, Org. Reactions, 1974, 22, 423 and references cited therein. e A. W. Johnson, L. Mervyn, N. Shaw, and E. Lester Smith, J. Chem. Soc., 1963, 4146. 9 H. Eckert, D. Lenoir, and I. Ugi, J. Organometallic Chem., 1977, 141, C23.