Brian Iddon

2H-benzimidazoles (isobenzimidazoles). Part 10. Synthesis of polysubstituted o-phenylenediamines and their conversion into heterocycles, particularly 2-substituted benzimidazoles with known or potential anthelminthic activity

Abstract Polysubstiluted o -phenylenediamines were syathesised in moderate to high yield by reductive cleavage of the corresponding 2 H -benzimidazole-2-spirocyclohexane with sodium dithionite in aqueous ethanol and converted into methyl benzimidazole-2-carbamates and 2-methylthio-and 2-trifluoromethylbenzimidazoles with known or potential anthelminthic activity. 5-(Pyrimidin-2-ylthio)-benzimidazole and 1 l-(pyridin-2-ylthio)dioenzo[ a,c ]phenazine were synthesised too. Attempts to oxidise 1,3-dihydro-2 H -4,9-diazanaphth[2,3- d ]imidazole, prepared by condensation of 2,3-diaminoquinoxaline with cyclohexanone, to an analogue of the title system failed.

Synthesis and Reactions of Lithiated Monocyclic Azoles Containing Two or More Hetero-Atoms. Part III: Pyrazoles

The metallation and halogen → metal exchange reactions of isoxazoles (1,2-oxazoles) and the reactions of the resulting organometallic derivatives, particularly lithiated derivatives, are reviewed comprehensively

Use of the vinyl group as an efficient protecting group for azole N- atoms: Synthesis of polyfunctionalized imidazoles and thieno[2,3-d] ⇌ [3,2-d]imidazole

Abstract 2,4,5-Tribromo-1-vinylimidazole was prepared from 2,4,5-tribromoimidazole and 1,2-dibromoethane and its Br-atoms were replaced regioselectively in the order 2 → 5 → 4 via Br → MgBr and other exchange reactions. Efficient removal of the vinyl groups from the resulting polyfunctionalized imidazoles was achieved with ozone or potassium permanganate. An extension of this methodology has allowed the first synthesis of thieno[2,3- d ] ⇌ [3,2- d ]-imidazole.

Metal–halogen exchange reactions of mono- and poly-halogenoimidazoles

4(5)-Bromoimidazole gave a mixture of 4- and 5-bromo-1-methylimidazole on treatment with 1 or 2 mol equiv. of n-butyl-lithium in ether or THF under various reaction conditions followed by addition of dimethyl sulphate. 5-lodo- and 2,4,5-tribromo-1-methylimidazole were prepared similarly. Attempts to exchange the bromine atoms for lithium in 5-bromo- or 2,4,5-tribromo-1-methylimidazole with n-butyllithium failed. 2,4,5-Tribromo-1-ethoxymethylimidazole was prepared by N-1-alkylation of tribromoimidazole with chloromethyl ethyl ether in benzene in the presence of triethylamine. Corresponding alkylation of 2,4,5-tri-iodoimidazole required the use of sodium methoxide in dioxan and gave mainly 1-ethoxymethyl-4,5-di-iodoimidazole. Successive treatment of 2,4,5-tribromo-1-ethoxymethylimidazole with n-butyl-lithium and diphenyl disulphide gave 4,5-dibromo-1-ethoxymethyl-2-phenylthioimidazole which, on further reaction with n-butyl-lithium followed by addition of dimethyl disulphide, gave 4-bromo-1-ethoxymethyl-5-methylthio-2-phenylthioimidazole. 1-Ethoxymethyl-4,5-di-iodoimidazole reacted successively with n-butyl-lithium and diphenyl disulphide to give a mixture of 1-ethoxymethyl-4-iodo-2-phenylthioimidazole (major product) and 1-ethoxymethyl-4-iodo-2,5-bisphenylthioimidazole.

Synthesis of thieno-[2,3-b]-, -[3,2-b]- and -[3,4-b]-thiophenes and thieno-[3′,2′:4,5]-, -[2′,3′:4,5]- and -[3′,4′:4,5]-thieno[3,2-d]pyrimidin-7(6H)-ones starting from thiophene

3-Bromo-, 3,5-dibromo- and 3,4,5-tribromo-2-thienyllithium have been prepared by bromine → lithium exchange and converted into a number of thiophene derivatives, including the corresponding 2-carbaldehydes. The aldehydes have been converted into the corresponding thiophene 2-carbonitriles. Metallation of 2,5-dibromo- or 2,4,5-tribromo-thiophene with LDA occurred at a vacant 3-position but the resulting 3-lithiated thiophenes rearranged (mechanism discussed) to 3,5-dibromo- and 3,4,5-tribromo-2-thienyllithium, which were quenched with various electrophiles. Attempts to dilithiate 2,5-dibromothiophene with LDA were unsuccessful. 3,4-Dibromo-2,5-dilithiothiophene was prepared from 2,3,4,5-tetrabromothiophene but it failed to yield the 2,5-dicarbaldehyde with N,N-dimethylformamide. The title thienothiophenes were prepared by reaction of a 3-bromothiophene-2-carbaldehyde, a 2-bromothiophene-3-carbaldehyde (prepared by bromination of a thiophene-3-carbaldehyde) or a 4-bromothiophene-3-carbaldehyde, or a corresponding nitrile, with ethyl 2-sulfanylacetate or 2-sulfanylacetamide. Thienothiophenes carrying an o-aminocarboxamide substitution pattern gave the title thienothieno[3,2-d]pyrimidinones with triethyl orthoformate.

Metallation and metal–halogen exchange reactions of imidazoles

Some reactions (reagents in parentheses) are reported of 1-ethoxymethyl-2-phenylthioimidazol-5-yl-lithium {Me2S2, Ph2S2, [(EtO)2CHCH2]2S2}, 1-ethoxymethyl-5-methylthio-2-phenylthioimidazol-4-yl-lithium (Me2S2, HCONMe2, CO2), 4, 5-dibromo-1-ethoxymethyl-imidazol-2-yl-lithium (Me2S2, Ph2S2), and 2-substituted derivatives of 4-bromo-1-ethoxymethylimidazol-5-yl-lithium (e.g. with Me2S2), prepared by metallation or metal halogen exchange reactions.

Azoles. Part 10. Thiazolo[4′,5′,4,5]thieno[3,2-d]pyrimidine, a New Heterocyclic Ring System

Abstract Thieno[2,3-d]thiazoles were prepared by reaction of 4-chlorothiazole-5-carbaldehydes or 4-chlorothiazole-5-carbonitriles with either ethyl 2-mercaptoacetate or 2-mercaptoacetamide. The 6-minothieno[2,3-d]thiazole-5-carboxamides obtained were converted into the corresponding thiazolo[4′,5′;4,5]thieno[3,2-d]pyrimidin-5(6H)-one by treatment with triethyl orthoformate in acetic anhydride. With phosphoryl chloride these gave the 5-chloro-derivative, which underwent displacement of the chlorine-atom when allowed to react with various amines. Reductive dechlorination of 5-chlorothiazolo[4′,5′;4,5]thieno[3,2-d]-pyrimidine gave the parent heterocycle.

2H-benzimidazoles (isobenzimidazoles). Part 9. Synthesis and reactions of 4,6-dibromo-2H-benzimidazole-2-spirocyclohexane

Abstract The title compound 1 was prepared by condensation of 3,5-dibromo- o -phenylenediamine 10 with cyclohexanone and oxidation of the resulting 4,6-dibromo-1,3-dihydro-2 H -benzimidazole-2-spirocyclohexane 5 with manganese dioxide. With sodium 2,3-dichlorophenoxide, sodium benzenesulfinate, or piperidine it reacts by loss of bromine, to give the 6-substituted derivatives 2 , 3 , and 4 , respectively. Morpholine, however, gives 5,7-dibromo-4-morpholino-2 H -benzimidazole-2-spirocyclohexane 15 whilst pyrid-2(1 H )-thione and pyrimidin-2(1 H )-thione give 4-bromo-1,3-dihydro-6-(pyridin-2-ylthio)-2 H -benzimidazole-2-spirocyclohexane 6 and 5,7-dibromo-1,3-dihydro-4-(pyrimidin-2-ylthio)-2 H -benzimidazole-2-spirocyclohexane 14 , respectively. In the presence of 1 or 2 mol equiv. of sodium methoxide an aryne mechanism appears to operate, leading to the formation of either a mixture of 5-bromo-6-methoxy- 11 and 6-bromo-4-methoxy-2 H -benzimidazole-2-spirocyclohexane 12 or 5,6-dimethoxy-2 H -benzimidazole-2-spirocyclohexane 13 , respectively. Oxidation of the title compound 1 with m -chloroperoxybenzoic acid yields the 1-oxide 7 exclusively, which reacts with piperidine and morpholine by loss of the 4-bromine atom, to give compounds 16 and 17 , respectively, in the latter case with concomitant loss of oxygen.

A new synthesis of isocyanates

The isocyanates (3)–(7) were prepared from the corresponding amine, carbonyl sulphide, and S-ethyl chlorothioformate by a procedure analogous to the Andreasch–Kaluza synthesis of isothiocyanates.

A convenient synthesis of 4(5)-mono-, 4,5-di-, and 2,4,5-tri-substituted imidazoles☆

Abstract A procedure is described for the stepwise introduction of substituents (hydrogen included) into the imidazole ring by FGI of the bromine atoms in 1-protected 2,4,5-tribromoimidazoles in the order 2 → 5 → 4 using halogen-metal exchange techniques.