Pyrrolo benzothiazepines

Treatment of substituted pyrrole 171a (R = pyrrol-2-yl) with triphosgene and triethylamine leads to pyrrolo-benzothiazepine 172 in 35% yield (Scheme 34 (1994M1283)). Similarly, substituted pyrrole 171b (R = N-Me-pyrrol-3-yl) produces pyrrolo-benzothiazepine 175. 

I.2 Pyrrolo-benzothiazepines with other fusion modes. Thiazepine with fused pyrrole ring 250b can be prepared by condensing ortho-amino thiophenol with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4... 

Formylation of 5H-benzo[/]pyrrolo[l,2-d][l,4]diazepin-6(7H)-one 180 pyrrole ring with POCI3/DMF is known (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). Formyation of pyrrolo-benzothiazepine can be accomplished using POCI3/ PhNMeCHO (Scheme 76 (2004JMC143)). The monoaldehyde 375 (R = H) is... 

Syntheses of a series of pyrrolo-benzazepine acetic acids 381 have been reported (Scheme 77 (1994MI385)). They include acylation of the core heterocycle with ethoxy oxalyl chloride in the first step to afford ketoesters 380. This sequence can also be successfully applied to a pyrrolo-benzothiazepine ring system. 

Similarly, methylation of pyrrolo-benzothiazepines 172 (Scheme 34, Section 2.3.1 (1994MI283)) and 307 (Scheme 66, Section 3.3.1.2 (2005FES385)) with methyl iodide in acetone in the presence of potassium carbonate proceeds regioselectively and produces N-methyl pyrrole derivatives as sole products. Methylation on the thiazepine ring nitrogen requires stronger base, i.e. potassium ferf-butoxide, to give dimethyl 174 and 311, respectively. 

Oxidation on the sulfur atom of pyrrolo-benzothiazepine 175 (Scheme 34, Section 2.3.1 (1994MI283)), indolo benzothiazepine (Scheme 65, Section 3.3.1.2 (1998MI139)) and pyrrolo-benzothiadiazepine (Scheme 74, Section 4.2 (1994SC2685)) proceeds smoothly with hydrogen peroxide in acetic acid or with MCPBA to afford cyclic sulfones in good yields. 

Reduction of the keto group in naphtho derivative 115 with sodium borohydride results in 69% of the alcohol 116 (Scheme 23, Section 2.1.3.3 (1999PHA645)). Further triethylsilane reduction gives 117 in 67% yield. Synthesis of a series of pyrrolo-benzazepine and pyrrolo-benzothiazepine acetic acids (Scheme 77, Section 5.1.1 (1994MI385)) includes reduction of ketoesters 380 into corresponding hydroxyl esters, subsequent deoxygenation with iodine/PPhs and hydrolysis. 

The 1-isopropoxymethyl derivative of pyrrolo-benzothiazepine 376 can be obtained from aldehyde 375 through the tosyl hydrazone followed by reduction with sodium borohydride in 2-propanol. 1-Methyl substituted 378 is available from aldehyde 375 and hydrazine monohydrate followed by potassium tert-butoxide (Scheme 76, Section 5.1.1 (2004JMC143)). 

Benzo[e]thieno[3,2- ]thiepin-10(5Ef)-one 388 can be smoothly reduced with sodium borohydride to the corresponding alcohol, which forms the chloro substituted compound under standard treatment with thionyl chloride (1991CPB2564). Dihydro derivatives of pyrrolo-benzothiazepine 377 have been reported starting from ketone 373 by a carbonyl reduction, bromination and amination sequence (Scheme 76, Section 5.1.1 (1998JMC3763, 2002JMC344, 2004JMC143)). 

Intramolecular electrophilic cyclization of an A -benzylpyrrole (76) can be achieved by treatment of the sulfoxide with acetic anhydride <92H(34)51> the product (77) is an interesting pyrrolo-benzothiazepine derivative (Equation (18)). 

L-Proline also reacts with 2-hydroxy-6-methylacetophenones in boiling DMF to give racemic pyrrolo[2,l-h][l,3]benzoxazines 138 (79JOC4005). For the synthesis of pyrrolo[2,l-c][l,4]benzothiazepines 139, three different syntheses from L-Pro and 2-methylthiobenzoic acid or the disulfide of o-mercaptobenzoyl chloride have been described (88JHC1007). 

Pyrrolo[l,2]thiazepines. Hydroxy lactam 280a (n — m — 1), upon treatment with neat TFA at room temperature gives a 20 1 mixture of benzothiazepines 283 and 284 in overall 94% yield. In contrast, 280b (n — 2,m — 0) produces... 

A new method for the preparation of pyrrolo[2,l-c][l,4]benzothiazepine 292 starting from aldehyde 291 with an intramolecular Mitsunobu cyclization in the last step has been reported (Scheme 63 (1999T1479)). A disadvantage of this procedure is the redox nature of the Mitsunobu reaction, which is responsible for a side oxidation of the thiol group and poor isolated yields of the product. 

Pyrrolo[2,l-c][l,4]benzothiazepine 297 (R=Ph) has been prepared by an intramolecular nucleophilic displacement of acetyl derivative 296 (Scheme 64 (1992H51)). The same compound and its aryl (R = Ar (1992H51)) and carboethoxy or cyano (R = C(30Et or CN (1990H1291)) analogs can also be obtained by a Pummerer rearrangement-cyclization of sulfinyl precursor 298. 

Pyrrolo[3,4-c][l,5]-benzothiazepin-3-ones 300 are available from ketoester 299 by a three-step sequence which includes hydrolysis and decarboxylation, aldol condensation and cyclization with o-aminothiophenol (Equation (35) (1993CE773)). 

Reaction of phenyl-5H,llH-pyrrolo[2,l-c][l,4]benzothiazepine 297 (R = Ph) with paraformaldehyde and 1-methylpiperazine dihydrochloride in methanol occurs on the 2-pyrrole position and affords Mannich product 372 (Equation (41) (1999JMC3334)). 

The lactam carbonyl of 2H-pyrrolo[3,4- 7][l,5]benzothiazepinone 310 undergoes an O-S exchange with Lewasson s reagent to afford benzothiazepine thiones 311 (Scheme 66, Section 3.3.1.2 (2005FES385)). 

As is the case with other five-membered rings condensed to 1,5-benzo-thiazepines, pyrrolo derivatives have received intensive study and several synthetic routes have appeared. Although it would be possible to obtain several pyrrolo-l,5-benzothiazepines, only two types of fusion have been reported. 

Dimethyl-2,3,4,10-tetrahydro-l//-pyrrolo[3,4-c][l,5]benzothiazepin-1-ones (10) were prepared by a reaction between 2-aminothiophenol (5) and 3-arylmethylene-5,5-dimethyltetramic acids (9) in 81-%% yields (Scheme 4) (84YZ1004). 

Analogously, 4,10-dihydro-l//-pyrrolo[3,4-c][l,5]benzothiazepine-l,3 (2/7)-diones (12) were easily obtained in 47-94% yields by acid-catalyzed cyclocondensation of 4-arylmethylenepyrrolidine-2,3,5-triones (11) with 2-aminothiophenol (5) (Scheme 5) (87S937). 

Some pyrrolo[2,l-Vilsmeier-Haack formylation and successive base-catalyzed intramolecular cyclization (Scheme 6) (72FES1003 73FES494 80FES279). 

Pyrrolo[2,1 -d][ 1,5]benzothiazepine-6-carboxylic acid (27) was obtained via base-catalyzed cyclization of pyrrole-2-carboxaldehydes 26 and 28, each synthesized by Vilsmeier-Haack formylation of their respective pyrroles 24 and 25, prepared in turn by condensation of 18, respectively, with ethyl bromoacetate and chloroacetonitrile in the presence of sodium ethylate at room temperature. When treated with piperidine in refluxing benzene for 48 hours, 26 and 28 afforded ester 29 and nitrile 31 from which, in an alkaline medium, acid 27 could be obtained. Under similar experimental conditions, acid 27 was also formed from amide 30 (Scheme... 

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