1.3- Thiazepine ring

The process scheme (Fig. 12.7-7) starts from the N-protected dipeptide dimer [l-lys-L-homocys]2 disulfide which, after reduction of the S - S bond, is oxidized enzymatically to N-Cbz-L-homo-cys-L-lys-e-aldehyde. Under acidic conditions, the aldehyde group is present as a gem-diol, attacks the a-N and closes the ring to the aminol. After nucleophilic attack of the S - H group, the hydroxyl group acts as a leaving group and affords closure of the 1,3-thiazepine ring. 

A further neat example of multicomponent reactions in heterocyclic synthesis was reported by Ma et al. <06AG(E)7793>. They prepared the furan-fused 1,4-thiazepine 140 in good yield using the three components 137, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised. 

Analogous dimethylamino derivatives of this ring with different substitution patterns on the thiazepine ring have been reported (1996X7745). 

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. 

As is the case with furo derivatives, the fusion of a thiophene ring can occur only at edges b and c of the thiazepine ring otherwise, a heterocyclic ring with two heteroatoms will be obtained. Much work has appeared on the thienobenzothiazepine system and its neuropharmacological activity since its first synthesis was reported in 1968. 

The examples reported for this system obviously concern the only possible fusion of a tetrazole nucleus on the d edge of the 1,5-thiazepine ring with a nitrogen bridgehead. 

Three benzopyranobenzothiazepine systems, depending on the different annelation of the benzopyrano nucleus to the thiazepine ring, are known. The synthesis was generally achieved by condensation reaction of amino-thiophenol with chromone or coumarin derivatives. 

Scheme 59 Inhibition of class C /3-lactamase via the formation of dihydro-1,4-thiazepine ring.

When the method described in Section III.l is a Iied to either 2-aminodiphenyl ether (53.10, X - O) or thio ether (53.10, X = S), a new oxazepine or thiazepine ring is formed. 

A single crystal x-ray structure determination has been reported on the benzothiazepinone derivative (24). The thiazepine ring was shown to have a boat conformation <86AX(C)l58i>. 

There have been no papers dealing with the reactivity of the fully unsaturated 1,2-oxazepine or 1,2-thiazepine rings or their benzo or dibenzo derivatives, apart from rearrangements of the dibenzo[c/][l,2]oxazepines (81) as outlined in Section 9.07.7.1. The Src-electron, 1,2-oxazepinium perchlorate salts (61) (see Section 9.07.7.1) are stable, consistent with the charge delocalized seven-membered ring structure proposed, and do not undergo a Diels-Alder reaction with maleic anhydride <81ZOR881>. 

Ring transformation of the thiazepine ring in compound 81 bearing fluorine atom and perfluoroalkyl substituent into the pyridine one enabled to obtain the corresponding 3-fluoroquinoline derivative 82 (Scheme 32) [52],... 

Scheme 43 Formation of thiazepine ring system from CNiND 3.

When 6-diazopenicillanates are irradiated in the presence of sulfur nucleophiles, predominantly 6/3-substitution products are obtained (77JOC2224). When BFs-EtiO is used to catalyze the reaction with nucleophiles, however, the products are primarily the 6a-isomers (78TL995). The use of rhodium or copper catalysis led primarily to ring-opened thiazepine products, presumably by way of the intermediate (56 Scheme 39) (80CC798). 

The synthesis of new thiazepinobenzimidazoles has been described by Chimirri and co-workers <00H(53)613>. The ring contraction of the 1,4-thiazepine derivatives 135 and 136... 

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... 

The formation of thiazine systems by ring contractions of 2,3-dihydro-l,4-thiazepine 303 (Equation 108) <1971CC698>, 2,3>4,7-tetrahydro-l,4,5-thiadiazepin-3-one 3, 3 -dioxide 304 (Equation 109) <1972T2307>, 2,3-dihy-drobenzo[ ][l,4]thiazepin-4(57/)-ones 305 and 306 (Scheme 78) <1992LA403>, and 6,7-dihydro-1,4-thiazepin-5(477)-one. -oxide 307 (Equation 110) <1999H(51)1639> has been published. 

Alkynylthiazoles 130 undergo unique cyclohydrocarbonylation, involving ring expansion, catalyzed by [Rh(l,5-COD)] [(7] -C6FlsBPh3)] to give 2-(Z)-6-(A)-4/7-[l,4]thiazepin-5-ones 136 (Equation (9)). ... 

Thioxanthen-9-one 10,10-dioxides with sodamide undergo ring expansion to dibenzo [/>,/]-[l,4]thiazepin-l 1-one 5,5-dioxides (75JHC1211). 

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