Richard M. Scrowston

7-Substituted benzo[b]thiophenes and 1,2-benzisothiazoles. Part 1. Hydroxy- or methoxy-derivatives

Readily available 2-hydroxy-3-methoxybenzaldehyde (orthovanillin) is converted, via thermal rearrangement (Newman–Kwart) of the O-aryl-NNdimethylthiocarbamate, into 2-mercapto-3-methoxybenzaldehyde (3). This thiol undergoes base-catalysed condensation with compounds of the type ClCH2X (e.g. X = CO2H, Ac, or CN), to give the appropriate 2-(X-substituted)-7-methoxybenzo[b]thiophene. Successive demethylation and decarboxylation of 7-methoxybenzo[b]thiophene-2-carboxylic acid provides a convenient route to 7-hydroxybenzo[b]thiophene. 7-Methoxybenzo[b]thiophene undergoes bromination and nitration at the 4-position; the structure of the 4-bromo compound is confirmed by an unambiguous synthesis. 2-Mercapto-3-methoxybenzaldehyde (3) reacts with chloramine to provide a simple synthesis of 7-methoxy-1,2-benzisothiazole. 2-Mercapto-3-methoxybenzonitrile, obtained as above from the corresponding 2-hydroxy compound, gives 2-acetyl-3-amino-7-methoxybenzo[b]thiophene when treated with chloropropanone, and 3-amino-7-methoxy-1,2-benzisothiazole when treated with chloramine.

Tricyclic heteroaromatic systems containing a bridgehead nitrogen atom. Part 3. [1,2,4]Triazolo[3′,4′ : 3,2]pyrazolo[3,4-d]pyrimidines, tetrazolo[1′,5′ : 1,5]pyrazolo[3,4-d]pyrimidines and pyrimido-[5′,4′ : 4,5]pyrazolo[3,2-c][1,2,4]triazines

6-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one 16 has been prepared and converted into its 3-chloro 6, 3-thioxo 17 and 3-methylthio derivatives 9. Each of these could be converted into the 3-hydrazino derivative 3, cyclisation of which with carbon disulfide or triethyl orthoformate generated the fused 1,2,4-triazoles 23 and 20, respectively. Alternatively, the hydrazino derivative 3 gave a substituted hydrazide 26 or thiosemicarbazide 25, from which the 1,2,4-triazoles 21 and 22 respectively were obtained. The equilibrium between 3-azido-6-phenyl-1H-pyrazolo[3,4-d]-pyrimidine 5 and 2-phenyl-9H-tetrazolo[1′5′ : 1,5]pyrazolo[3,4-d]pyrimidine 27 was studied.3-Diazo-4-methyl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidine 29 was prepared by diazotisation of the corresponding amine 1 and converted into the 3-azido compound 4, which could not be cyclised to form a tetrazole. Finally, the diazo compound 29 readily formed the pyrimido[5′4′ : 4,5]pyrazolo-[3,2-c][1,2,4]triazine derivatives 32 and 33, when treated with pentane-2,4-dione and ethyl acetoacetate respectively.

7-Substituted benzo[b]thiophenes and 1,2-benzisothiazoles. Part 2. Chloro and nitro derivatives

The 7-chloro and 7-nitro derivatives of benzo[b]thiophene and 1,2-benzisothiazole have been prepared from readily available precursors, which for each substituent are common to both ring systems. 7-Chloro-benzo[b]thiophene has been obtained from 3-chloro-2-mercaptobenzoic acid via 7-chlorobenzo[b]-thiophen-3(2H)-one, or from 2,3-dichlorobenzaldehyde, either viaβ-(2,3-dichlorophenyl)-α-mercapto-acrylic acid (16) or, preferably, via 7-chlorobenzo[b]thiophene-2-carboxylic acid. Hexamethylphos-phoric triamide is a particularly useful solvent in which to effect the selective nucleophilic replacement of the 2-chloro substituent in 2,3-dichlorobenzaldehyde. 7-Chloro-1,2-benzisothiazole is available by treatment of 3-chloro-2-mercaptobenzaldehyde with chloramine (57%), or by heating 2,3-dichlorobenzaldehyde with sulphur and aqueous ammonia (46%).7-Nitrobenzo[b]thiophene has been obtained by treatment of 2-bromo-3-nitrobenzaldehyde with mercaptoacetic acid under alkaline conditions, followed by decarboxylation of the resulting 2-carboxylic acid. Cyclisation of 2-(n- or t-butylthio)-3-nitrobenzaldoxime with polyphosphoric acid gives 7-nitro-1,2-benzisothiazole in high yield. 3-Nitro-2-t-butylthiobenzaldehyde behaves unexpectedly with chloramine, to give what is believed to be 7-nitro-2-t-butyl-1,2-benzisothiazolium chloride (24)(73%).

Naphtho[1,2-b]thiophen. Part I. Preparation and electrophilic substitution

Naphtho[1,2-b]thiophen was prepared from 3,4-dihydronaphthalen-1 (2H)-one by a five-stage process. Bromination, formylation, acetylation, and lithiation of naphtho[1,2-b] thiophen occurred at the 2-position. Nitration gave a mixture of the 2- and 5-nitro-derivatives; the structure of the latter was confirmed by transforming it into the 5-bromo-compound, which could be prepared unambiguously. Bromination and nitration of ethyl naphtho[1,2-b]thiophen-2-carboxylate gave mainly the 5-substituted compound in each case.

Preparation of some thiopyranopyridine derivatives

In the first systematic study of thiopyranopyridines in which the sulphur atom is separated from the pyridine ring by one carbon atom, the four isomeric enol esters, ethyl 5-hydroxy-8H-thiopyrano[3,4-b]-pyridine-6-carboxylate (4b), ethyl 8-hydroxy-5H-thiopyrano[4,3-b]pyridine-7-carboxylate (5b), and ethyl 4-hydroxy-1H-thiopyrano[3,4-c]- and [4,3-c]pyridine-3-carboxylate (6b) and (7b), have been synthesised. Improved methods for the preparation of their pyridine precursors are described. With phenylhydrazine, the enol esters (4b)–(7b) give condensed pyrazole derivatives (15)–(18), which have dipolar structures; with hot mineral acid they undergo decarboxylative hydrolysis, to give the corresponding oxothiopyranopyridines (4a)–(7a).

Addition reactions of benzo[b]thiophen. Part 1. Self-addition and addition of simple aromatic hydrocarbons

Benzo[b]thiophen undergoes facile addition reactions across the 2,3-bond when treated with aluminium chloride in an appropriate solvent at 0 or 20 °C. In carbon disulphide or dichloromethane, it undergoes self-addition to give two or more of the four possible 2- or 3-(2- or 3-benzo[b]thienyl)2,3-dihydrobenzo[b]thiophens (3)–(6). In the presence of an aromatic solvent, the dimerisation reaction just mentioned predominates at low temperatures (0 °C or below), or at room temperature if the solvent is benzene, chlorobenzene, t-butylbenzene, isopropylbenzene, or 1,3,5-trimethylbenzene. At room temperature, in toluene, ethylbenzene, and 1,2- or 1,4-dimethylbenzene, solvent addition occurs to give a mixture of the corresponding 2- and 3-aryl-2,3-dihydrobenzene[b]thiophens. At 80 °C, benzene and toluene give the fully aromatic 2-arylbenzo[b]thiophen. The reactions are discussed in terms of an ionic mechanism involving protonation of benzo[b]thiophen by moist aluminium chloride and reaction of the resulting electrophile with benzo[b]thiophen or with an aromatic substrate.

Substitution reactions of benzo[b]thiophen derivatives. Part VII. Reactions of 4-hydroxybenzo[b]thiophen, its 3-methyl derivative, and related compounds

Die Formylierung der Benzothiophene (I) nach Gatterrnann und die Bromierung mit N-Brom-succinimid fuhren als elektrophile Substitutionsreaktionen zu den 5-substituierten Derivaten (IIa).

A Regiospecific and Stereoselective Rearrangement of a 1-β-D-Ribofuranosyl-5-aminoimidazole to a 4-β-D-Ribofuranosylaminoimidazole

Abstract Ethyl 1-methyl-4-(β-D-ribofuranosylamino)imidazole-5-carboxylate 8 was synthesized from ethyl 5-amino-1-(5-O-trityl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carboxylate 4 by quaternization and subsequent base-catalysed ring-opening and closure.

Addition reactions of benzo[b]thiophen. Part 4. Reactions of some acetoxy- and hydroxy-benzo[b]thiophens with benzene or toluene

Heating acetoxybenzo[b]thiophens with AICl3–benzene can give the normal Fries-rearranged products (for the 4-OAc and 7-OAc isomers); these sometimes react further to give their 2,3-dihydro-(for 4-OAc and 7-OAc) or 2-phenyl derivatives (for 6-OAc). Alternatively, benzene can add across the 2,3-double bond of the acetoxycompound, to give the 2-(for 6-OAc) or 3-phenyl-2,3-dihydrobenzo[b]thiophens (for 7-OAc). With AICl3 in dichloromethane, 6-acetoxybenzo[b]thiophen undergoes intermolecular transfer of an acetyl group to give a mixture of 6-acetoxy-2- and 3-acetylbenzo[b]thiophens and 6-hydroxybenzo[b]thiophen. With AICl3 in benzene at room temperature, 4-acetoxybenzo[b]thiophen gives a rearranged product, 4,5-dihydro-2,4-diphenylbenzo[b]thiophen-7(6H)-one (3a)(17%).In the presence of AICl3 for 0.5 h, 4-, 5-, 6-, and 7-hydroxybenzo[b]thiophens undergo addition of benzene or toluene, to give the appropriate 2-aryl-2,3-dihydrohydroxybenzo[b]thiophens (1). Yields are high for the 4- and 6-hydroxy-isomers (80–-85%), but lower for the 5-(55%) and 7-isomers (10%). In each of these reactions the starting hydroxybenzo[b]thiophen is partly converted into its 2,3-dihydro-derivative. 5- and 7-Hydroxybenzo-[b]thiophen also each give the same 4,5-dihydro-2,4-diarylbenzo[b]thiophen-7(6H)-one (3)(25%) in this reaction. When the reaction period with benzene or toluene is extended to 5 days, the amount of solvent addition product (1) decreases, but all four hydroxy-isomers now give the same rearranged product (3). The mechanism of of this unusual rearrangement is discussed in terms of a spiro-intermediate.

Condensed isothiazoles. Part 5. Thieno[2,3-d]isothiazoles and thieno[3,2-d]isothiazoles

2,3-Disubstituted thiophens containing a sulphur function (SH, SMe, or SCN) and a carbonyl group (CHO or Ac) have been prepared and converted into thieno[2,3-d or 3,2-d]isothiazoles. Methods used to prepare 1,2-benzisothiazoles are often inapplicable in the thiophen series. For example, an (E)-methyl (2-methylthio-3-thienyl)O-p-nitrobenzoylketoxime (6) in hot diethylene glycol or acetic acid gave the corresponding 3-acetamido-2-methylthiothiophen (15); in concentrated sulphuric acid at –5 °C, it gave the Beckmann rearranged product (15) and a thieno[3,2-d]thiazole (19). Similarly, (E)-methyl (3-methylthio-2-thienyl)O-p-nitrobenzoylketoxime (42) gave 2-methylthieno[2,3-d]thiazole with concentrated sulphuric acid, but with acetic acid it gave the thieno[2,3-d]isothiazole (43) and 2-acetamido-3-methylthiothiophen. Heating the (E)-2-mercaptothiophen-3-carbaldoxime (27) in an inert solvent gave the corresponding thieno[3,2-d]isothiazole (14); the (E)-3-mercaptothiophen-2-carbaldoxime (47) cyclised in hot AcOH–Ac2O, to give the thieno[2,3-d]isothiazole (44). Thieno[3,2-d]isothiazoles were also prepared by treating a methyl (2-mercapto-3-thienyl) ketone (21) with chloramine and by heating a 2-iminothieno[3,2-d]-3,1,4-oxathiazepine (29) in an inert solvent. The products obtained by selective S-alkylation of 3,5-bis(sodiomercapto)isothiazole-4-carbonitrile with ethyl bromoacetate and iodomethane were cyclised, to give 4-aminothieno[3,2-d or 2,3-c]isothiazole derivatives (34) and (36).