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Reaction of the chiral azirine 1a with nucleophiles and dienes is described. Thiols, heteroaromatic nitrogen compounds and phenylmagnesium bromide add to the azirine 1a to give functionalised aziridines 2/3a–h. X-Ray crystal structures for the products 3e and 3g have been obtained. Diastereodifferentiation of the two faces of the azirine 1a is observed in most cases, but only thiophenol gives a single diastereomer (2a). Most mixtures of diastereomers were separated by dry flash chromatography. Benzylamine produced a dimer of the original azirine 1a, compound 9. Representative conjugated dienes (cyclopentadiene, furan and open chain dienes) were added to the chiral azirine 1a. Only poor selectivities were observed. The selectivity was not significantly enhanced in the cycloaddition of cyclopentadiene to the more bulky azirine 1b.

Methyl cis -deisopropyldehydroabietate was selectively nitrated at the 12-position by reaction with ‘claycop’, a montmorillonite clay impregnated with copper(II) nitrate. The 12-nitro compound was reduced to the corresponding amine and this was subjected to a combined acylation and ortho nitration. The compounds so produced were further converted into octahydro-1 H -phenanthro[2,3- d ]imidazoles by reductive cyclization. The same acylation- ortho nitration methodology was shown to provide a short synthesis of 2-substituted benzimidazoles from aniline.

The transient 1-azafulvenium methides 24, 26 and 28 generated by thermal extrusion of sulfur dioxide from pyrrolo[1,2-c][1,3]thiazole 2,2-dioxide 20 (R = Me), 22 and 23 undergo sigmatropic [1,8]H shifts and the 1-acyl derivatives 30 electrocyclise to give novel pyrrolo[1,2-c][1,3]oxazines 32. The analogous 1,2-diazafulvenium methide 36 has been intercepted in [8π + 2π] cycloadditions with electron-rich silylated acetylenes to give adducts 37–40. This behaviour is partially explained by Frontier MO theory.

The pyrrolo[1,2-c]thiazole generated by dehydration of dimethyl 5-methyl-1H,3H-pyrrolo[1,2-c]thiazole-6,7-dicarboxylate 2-oxide acts as a thiocarbonyl ylide in its cycloaddition to electron deficient alkenes but as an azomethine ylide with electron deficient alkynes. The analogous pyrazolo[1,5-c]thiazole, generated similarly, acts as a thiocarbonyl ylide with both types of dipolarophile. This behaviour is partially explained by Frontier MO theory.

Four 2-azidoacrylamides 5 have been prepared from the corresponding acrylamides 3 by reaction with bromine then with sodium azide. From three of these azides, compounds 5b–5d, 2H-azirine3-carboxamides 2 were produced by pyrolysis in toluene. These azirines reacted with conjugated dienes at room temperature to give cycloadducts. The reaction of the chiral azirine amide 2d with cyclopentadiene showed no selectivity.

Reactions of the methyl 2-aryl-2H-azirine-3-carboxylates 1a and 1b with nucleophiles are described. Thiols add to the CN bond to give aziridines 4–6. Propargyl alcohol similarly gives the aziridine 7. Primary and secondary aliphatic amines react with the azirines to give methyl 3-aminoacrylates 8–12. 4-Cyclohexen-1-ylmorpholine and 1-cyclopenten-1-ylpyrrolidine react with the azirine 1a to give products formulated as the aziridine 13 and the vinylidenecyclopentanone 14, respectively, in contrast to previously reported reactions of enamines with azirines from which pyrroles were isolated. Acetylacetone gives a pyrrole-3-carboxylate 15 in low yield with the azirine 1a. All these products have been rationalised by invoking initial addition of the nucleophile to the CN bond of the azirine. The tetrahydrofuran-2-yl radical also adds to the CN bond of the azirine 1a, giving the aziridine 16 as a single diastereoisomer. X-Ray crystal structures of methyl (E)-3-amino-3-(2,6-dichlorophenyl)-2-morpholin-4-ylpropenoate 8 and of methyl 3-(2,6-dichlorophenyl)-2-(tetrahydrofuran-2-yl)aziridine-2-carboxylate 16 are reported.

The Azirine ester 2 bearing Oppolzer’s N,N-diethyl-(1R)-isobornyl-10-sulfonamide chiral auxilliary shows moderate diastereoselectivity in its Diels-Alder reaction with cyclo-pentadiene whereas the addition of thiophenol is highly diastereoselective; X-ray crystal structures of the aziridine esters 6 and 7 are reported.

The azirinyl ester 2 (R = Bu t ) has been generated by thermolysis of t-butyl 2-azidoacrylate. It is too unstable to allow its full characterisation but it has been intercepted by Diels-Alder cycloaddition to several dienes. Addition to a chiral diene 8 is highly diastereoselective.

The azetidinones 1, 2 and 3 have been prepared from simple quinoline derivatives. 2,2a,3,4-Tetrahydro-1H-azeto[1,2-a]quinolin-1-one 1 has been synthesised from quinoline N-oxide and, more efficiently, in three steps from 2-methylquinoline. In both routes 1,2,3,4-tetrahydroquinoline-2-acetic acid 7 is prepared as an intermediate and this is then cyclised to the azetidinone 1. The 8-hydroxyazetidinone 3 has been synthesised by analogous routes, the hydroxy group being protected as an isopropyl ether during the intermediate steps. An X-ray crystal structure of compound 3 has been obtained and this reveals intramolecular hydrogen bonding between the hydroxy and carbonyl groups. The unsaturated azetidinone 2 has been prepared from 1 by stereoselective radical bromination at C-4 followed by dehydrobromination with DBU.

Diels–Alder reactions of the methyl 2-aryl-2H-azirine-3-carboxylates 1a and 1b have been investigated in order to determine the stereoselectivity and regioselectivity of the reaction. The azirines react with a range of electron rich dienes at room temperature to give Diels–Alder adducts. The reaction leads to the formation of endo-cycloadducts with both cyclic and acyclic dienes; furan is exceptional in giving an exo-adduct 7. X-Ray crystallography has established the structure 9 of the Diels–Alder adduct formed from the azirine 1a and 1-acetoxybutadiene. The same regioselectivity, in which the more nucleophilic terminus of the diene combines with the carbon atom of the CN bond, is found in the adducts from several other 1- and 2-substituted dienes. Only isoprene, among the dienes examined, gives a mixture containing the opposite regioisomer 14 as a minor component.

The 8,8a-dihydroazeto[1,2-a]indol-2(1H)-ones (benzocarbapenems) 1a, 16, 17, 22, 27, 35 and 36 have been prepared by cyclodehydration of the corresponding β-amino acids, these amino acids being obtained by reduction of the analogous 2-substituted or 2,7-disubstituted indoles. The hydroxy group of compound 36 is designed to mimic the carboxylic acid function of the carbapenems on the basis of molecular modelling. The azetidinones 1a and 27, which are unsubstituted at the methylene group of the four-membered ring, are unstable and highly susceptible to ring opening by nucleophiles but the compounds 22, 35 and 36 with two methyl substituents at this position are much more stable. The carbonyl stretching frequency in the IR is close to 1770 cm–1 for all the azetidinones except the phenol 36 for which the absorption is at 1735 cm–1. An X-ray crystal structure of compound 36 is reported.

Covering March 1999 to February 2001. Previous review: J. Chem. Soc., Perkin Trans. 1, 1999, 2849

Derivatives of indole-3-carbaldehyde oxime have been prepared that bear a carbon-carbon double bond at C-2 and a five- or six-membered ring linking the α-carbon artom of the vinyl group and the indole nitrogen atom. Compound 9, with a five-membered ring linking the two atoms, failed to undergo a cyclisation reaction on heating. However the oximes 16 and 22, with a six-memberd ring linking the two atoms, cyclised in boiling toluene. The cyclisation led to the formation of the pyrido-indoles 17 and 18, respectively.

The rhodium catalysed hydrogenation of a range of N-t-butoxycarbonylindoles has been investigated. In most cases the hydrogenation proceeded smoothly at 200 psi in the presence of acetic acid to give the corresonding N-t-butoxycarbonyl-cis-2,3-dihydroindoles in high yield. Some indoles, in particular those bearing an acyl substituent at C2 or C3, were not selectively reduced at the C2–C3 bond.

Cysteine methyl ester has been converted into a series of 2-substituted methyl thiazolidine-4-carboxylates by reaction with carbonyl compounds including aromatic aldehydes and a- and P-oxoesters. These thiazolidines react with silver carbonate with the elimination of the elements of H2S and with the formation of transient 1 -substituted 2-azadiene carboxylate esters. The Diels-Alder reactions of these azadienes have been shown to take place with both electron rich dienophiles (enamines) and with electron deficient dienophiles (enones). The cycloaddition reactions are regioselective but not stereoselective. Exceptionally, the intermediates act as dienophiles when reacted with cyclopentadiene. Some of the 2-azadienes derived from oxoesters tautomerise to isolable enamines. A new example of intramolecular 1,3-dipolar cycloaddition of a Schiff base of a S-allylcysteine methyl ester derivative is described.

The 2-azadiene 5 was generated from the Schiff bases of serine methyl ester and cysteine methyl ester and 2-allyloxybenzaldehyde 1 . Compound 5 failed to undergo an intramolecular Diels-Alder reaction. When it was generated in the presence of aluminium trichloride the pyridine 6a was isolated; the structure of this pyridine indicates that the catalyst has reversed the regiochemistry of the dimersiation of 5 . The reaction of the activated allyloxybenzaldehyde 2 with cysteine methyl ester follows a different course from that of 1. The allylic function is transferred to sulfur and the Schiff base 9 is formed. This undergoes a rapid internal 13-dipolar cycloaddition at room temperature to give the thienopyrrole 10 the structure of which has been established by X-ray crystallography.

The benzocarbapenem 1 has been prepared trom ethyl indole-2-acetate by reduction, hydrolysis ol the ester and cyclisation. The methyl substituted carbapenems 12, 13 and 14 have also been prepared. The hydrogenation of ethyl N-BOC-indole-2-proparioate 5 is diastereoselective.

The palladium(0) catalysed coupling of 2-bromocyclopentene-1-carboxaldehyde N , N -dimethylhydrazone 1 with vinylzinc halides and with 2-furyl- and 2-thicnylzinc halides provides a route to the corresponding 2-vinyl- and 2-heteroaryl-cyclopentene-1-carboxaldehyde dimethylhydrazones. These cyclise thermally to 6,7-dihydro-5 H -2-pyrindines ( e.g. , 3).

The Diels-Alder reactions of N-benzylidenedehydroalanine methyl ester 1a with but-3-en-2-one and with other electron deficient dienophiles have been found to give new dihydro- and tetrahydropyridines. The cycloaddition reactions are regioselective but not stereoselective. Cycloaddition reactions between 1a and enamines have also been observed. The [4 + 2] cycloaddition reactions of other N-arylidenedehydroalanine methyl esters are also reported. Two new types of azadiene were prepared, namely N-(benzoylmethylene)dehydroalanine methyl ester 1e and N-(ethoxycarbonylmethylene)dehydroalanine methyl ester 1f. Their reactions with N-cyclohexen-1-ylpyrrolidine and with N-cyclopenten-1-ylpyrrolidine have led to the isolation of the dihydropyridine and pyridine esters.

The Diels-Alder reaction of 1,2,4-triazines with cyclic vinyl ethers leads to a range of substituted pyridines with hydroxyalkyl and oxoalkyl side chains. With dihydrofuran the aromatization of the 1:1 adduct is inhibited by conformational factors and this allows 2:1 adducts to be isolated. Different regioselectivity is observed in the 2:1 adducts formed from ethyl 5-phenyl-1,2,4-triazine-3-carboxylate 1f and from ethyl 5,6-diphenyl-1,2,4-triazine-3-carboxylate 1b. An X-ray crystal structure of the 2:1 adduct 5 formed from 2,3-dihydrofuran and 1b is reported.

The thiazolidines 2 , derived from L-cysteine methyl ester and aromatic aldehydes, react with silver carbonate and DBU to give methyl 2-(arylideneamino)acrylates 1 .these 2-azadienes undergo Diels-Alder reactions with both electron rich dienophiles and electron deficient dienophiles.

1-Bromo-3,4-dihydronaphthalene-2-carboxaldehyde 2 has been converted by three methods, each involving halogen-metal exchange and palladium(0) catalysed cross coupling, into N,N-dimethylhydrazones of 1-aryl- and 1-vinyl-3,4-dihydronaphthalene-2- carboxaldehydes. The N,N-dimethylhydrazone 10 of the aldehyde 2 undergoes efficient bromine-lithium exchange with butyllithium, as does 2-bromobenzaldehyde N,N-dimethylhydrazone 17. The dimethylhydrazones of 1-vinyl-3,4-dihydronaphthalene-2-carboxaldehydes were not isolated by underwent electrocyclic ring closure followed by loss of dimethylamine in solution to give 5,6-dihydrobenz[f]isoquinolines. 1-Aryl-3,4-dihydronaphthalene-2- carboxaldehyde N,N-dimethylhydrazones also cyclised in the same way when subjected to vapour phase pyrolysis.

Three 1-phenyl-1,2,3-triazoles 1a–c bearing substituents at the 4-position have been converted into the corresponding 5-lithio compounds. These undergo fragmentation and loss of nitrogen at room temperature. The N-phenylalkynamide salts 3 so produced have been intercepted in [2 + 2] cycloadditions. The salt derived from the triazole-4-carboxamide 1b reacts with cyclohexanone and with 4-chlorobenzaldehyde by cycloaddition to the CO bond; the cycloadducts then undergo ring-opening and the amides 5 and 7 are isolated. Analogous reactions are observed with the 4-(dihydroloxazol-2-yl)triazole 1c: in this case the lithium salt also reacts with a Schiff base, 4-chloro-α-phenyliminotoluene, and with an electrophilic alkene, dimethyl fumarate. A cyclobutene diester, compound 12, has been isolated from this last reaction. The lithium salt 3a derived from 1,4-diphenyltriazole 1a has similarly been intercepted by dimethyl fumarate and by nitrostyrenes. Structures 13 and 14 have been assigned to the products of these reactions.

Three hydrazones of ethyl bromopyruvate, the dinitrophenylhydrazone 2a, the toluene-4-sulphonylhydrazone 2b and the t-butoxycarbonylhydrazone 2c, have been reacted with a series of nucleophilic alkenes and heterocycles in the presence of sodium carbonate. Azoalkenes 3 are presumed as intermediates and adducts have been isolated. The azoalkenes derived from hydrazones 2a and 2c are found to be useful electrophiles and electrophilic dienes.

The cyclic disulfides 2,3-dithiabicyclo[2.2.2]oct-5-ene 5, 1,4-dihydro-2,3-benzodithiin 6 and hexa-hydro-5,8-epoxy-2,3-benzodithiin 7 have been prepared by oxidation of the corresponding dithiols. Each of these compounds has been subjected to vapour phase pyrolysis in order to determine whether a retro Diels–Alder reaction occurs, leading to the formation of diatomic sulfur (S2) and a diene. Compounds 5 and 7 both appeared to decompose in this way; in each case the expected diene was detected in the pyrolysate together with sulfur (S8). Attempts to intercept S2 and thus to obtain direct evidence for its formation were not successful. The benzodithiin 6 underwent an analogous loss of sulfur on vapour phase pyrolysis, but only as a minor reaction pathway, and this decomposition pathway was not detectable in solution pyrolyses. Solution pyrolysis of 6 in the presence of N-phenylmaleimide gave N-phenyl-2,3-naphthalimide 21 in low yield. cis-Cyclopentene-3,5-dithiol 9 has also been prepared but no evidence could be obtained for the formation of the disulfide 4 on oxidation. Reaction of the dithiol 9 with aldehydes and ketones in the presence of acids led to the formation of adducts (such as 12 and 13 from acetone) which were rapidly interconverted in acidic media.

The intramolecular Diels-Alder reactions of hydrazones derived from methacrolein or ethylacrolein and terminally unsaturated N-acyl-N-methylhydrazines have been investigated. The hydrazones 7b and 7c derived from N-methyl-N-pent-4-enoylhydrazine 3b were found to undergo intramolecular [4 + 2] cycloaddition above 140 °C and the pyridopyridazines 12 were isolated. The corresponding hydrazones 8b and 8c from N-methyl N-pent-4-ynoylhydrazone 4a reacted similarly and gave as the final products the pyridines 13. The scope of the reaction is limited, as was shown by the failure of several other terminally unsaturated hydrazones of αβ-unsaturated aldehydes to undergo intramolecular cycloaddition. These hydrazones did, however, undergo intermolecular [4 + 2] cyctoaddition to N-phenylmaleimide. Other hydraiones 15 of methacrolein. including the benzoylhydrazone and the phenylhydrazone, also reacted with N-phenylmaleimide to give the pyridine 14b by way of an isolable dihydropyridine 16.

The pyrrolizidin-3-ones 5, 7 and 10 have been prepared from pyrrole by making use of its reaction with ethyl bromopyruvate oxime in the presence of sodium carbonate to introduce the side chain. The 5-substituents were introduced into the pyrrole ester 2 before hydrolysis and dehydrative cyclization. The X-ray crystal structure of compound 10 has been determined and this shows that the C3 to N4 bond is no longer than in normal tertiary amides, as has been obsered with other N-acylated azoles.

2,3-Dithiabicyclo[2.2.1]hept-5-ene has been prepared at room temperature by the oxidation of cis-cyclopentene-3,5-dithiol and decomposes in solution at 130–160 °C to cyclopentadiene and diatomic sulfur, which has been intercepted.

1-Bromo-3,4-dihydronaphthalene-2-carboxaldehyde 2 has been converted by three methods, each involving halogen-metal exchange and palladium(0) catalysed cross coupling, into N,N-dimethylhydrazones of 1-aryl- and 1-vinyl-3,4-dihydronaphthalene-2- carboxaldehydes. The N,N-dimethylhydrazone 10 of the aldehyde 2 undergoes efficient bromine-lithium exchange with butyllithium, as does 2-bromobenzaldehyde N,N-dimethylhydrazone 17. The dimethylhydrazones of 1-vinyl-3,4-dihydronaphthalene-2-carboxaldehydes were not isolated by underwent electrocyclic ring closure followed by loss of dimethylamine in solution to give 5,6-dihydrobenz[f]isoquinolines. 1-Aryl-3,4-dihydronaphthalene-2- carboxaldehyde N,N-dimethylhydrazones also cyclised in the same way when subjected to vapour phase pyrolysis.

The reaction of ethyl 2-nitrosopropenoate 2a with 1-methylpyrrole, 2,5-dimethylpyrrole and 2,5-diphenylpyrrole has been investigated. In every case the products result from highly regioselective attack at C-2 of the pyrrole by the electrophile. The azopropenoate esters 2b and 2c react similarly with pyrroles, to the extent that even 1 -(triisopropylsilyl)pyrrole is attacked exclusively at the 2-position by the azo ester 2b. In contrast, the nitrile oxide ethyl cyanoformate N-oxide 12 reacts at the 3-position of 2,5-dimethyl- and of 2,5-diphenyl-pyrrole. The reactions of the nitroso and azo esters with pyrroles are interpreted as Diels–Alder cycloadditions with inverse electron demand.

t-Methods of annelation of indole across the 1- and 2-positions have been explored using both the intramolecular Heck reaction and Dieck- mann cyclisation. Two examples (5) and (7) of the title ring system have been produced by the thermal cyclisation of indole-3-carboxal- dehyde oximes with an alkenyl substituent at C-2

The palladium(0) catalysed coupling of 2-bromocyclopentene-1-carboxaldehyde N , N -dimethylhydrazone 1 with vinylzinc halides and with 2-furyl- and 2-thicnylzinc halides provides a route to the corresponding 2-vinyl- and 2-heteroaryl-cyclopentene-1-carboxaldehyde dimethylhydrazones. These cyclise thermally to 6,7-dihydro-5 H -2-pyrindines ( e.g. , 3).