1.3.4- Thiadiazepine ring 6-

Syntheses of this class of compounds usually involve 1,2,5-thiadiazepine ring 333 (Figure 6) which is stable in the S-oxidized form and structurally represents cyclic pyrrole N-sulfonyl derivatives. Most of the synthetic strategies include formation of an S-Npyrroie bond in the early stages. A final cyclization step typically includes (i) intramolecular cyclization by creation of an N-X bond from a suitable pyrrole precursor or (ii) a 6 + 1 type cyclization that involves dielectrophilic species to form linker X and utilizes the nucleophilicity of the phenyl amino group and of the pyrrole ring at C2. Intramolecular processes with the formation... 

Fusion of the imidazole ring to pyrrolo-benzothiadiazepine 340 can be achieved by straightforward TosMIC cycloaddition approach (Scheme 72, Section 4.2 (1994JHC1033)). An alternative sequence starts with the addition of nitromethane to the C-N double bond on the thiadiazepine ring, nitro group reduction and manganese oxide oxidation of the intermediate dihydroimidazole derived from amine 342 and tiiethyl ortho formate. 

A similar regiospecific [2 -I- 2] cycloaddition across a C=S group occurred when benzoyl isothiocyanate (436) and 2,3-diphenyl-1-azirine were heated in refiuxing benzene for 12 hours. The product obtained was shown to be (438) and an intermediate such as (437) could also be involved in this cycloaddition (74JOC3763). In contrast, thiobenzoyl isocyanate added in a [4-1-2] fashion, and after ring expansion gave a thiadiazepine derivative. 

Diester 352 (Scheme 74, Section 4.2 (1994SC2685)) after the sulfur atom oxidation undergoes hydrolysis and intramolecular acylation to the pyrrolo-thiadiazepine 353 with a fused lactam ring. 

Structurally similar seven-membered dihydro-l,2,7-thiadiazepine 69 and l,2,7-thiadiazepan-3,6-dione 70 were obtained by an unexpected dimerization of acetoxime 71 (1997BSB605) and a ring closure of dicarboxamide 72 (1995CC1449). Curiously, the reaction of sulfur monochloride containing two sulfur atoms in both cases led to the insertion of one sulfur atom to the seven-membered ling or three sulfur atoms to the by-product 73 in the second reaction, but not two sulfurs (Scheme 36). 

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. 

Yet a further variation of this theme consists in the replacement of the bridging methylene group by sulfur to give a thiadiazepine as the central ring. The starting thiophene ether (26-3) is obtained by the nucleophilic aromatic displacement of fluorine in nitrobenzene (26-1) by the anion from imidazole-2-thiol (26-2). The nitro... 

As stated in CHEC(1984) and CHEC(1996), both possible thiadiazepines systems 20 and 21 have been synthesized. The synthesis of 1,2,3-thiadiazepines, described in CHEC(1996), remains to be the only, to the best of our knowledge, publication available on this ring system. In contrast, however, the respective 1,2,7-thiadiazepines attracted significant interest due to their biological activity, particularly as HIV-1 protease inhibitors. This section is dedicated to the discussion of this 1,2,7-thiadiazepine template. 

In contrast to benzothiadiazepines 40 (see Scheme 4), the nucleophilic attack of -BuLi on bis(triazolo)thiadiazepine 77 (R = H) (Scheme 14) occurred both at the sulfur atom and at the proton of the seven-membered ring resulting in formation of two ring-opened products <2002MC131>. Carbanion formation at the bridgehead of 78 (R1 = R2 = H) (Scheme 15) is easily achieved by treatment with -BuLi or lithium diisopropylamide (LDA) subsequent alkylation with Mel afforded the monomethylated product 78 (R1 =Me R2 = H) in 54% yield <1981T2045>. 

Type cycloadduct 24 (Scheme 1) was obtained as the major product on cycloaddition of n-chloranil with l-ethoxycarbonyl-l/7-azepine <1982H(19)1197>. Treatment of 4-ethoxycarbonyl-5-chloro-l,2,3-thiadiazole with ethylenediamine under basic conditions occurs with heterocyclic ring opening/recyclization to form bis(triazole)-fused thiadiazepine 77 (R = COOEt) (Scheme 14). The benzo-fused analog was prepared by the similar reaction with o-phenylenediamine <1999CC2273>. 

Dinitrobiphenyl [101-104] is thus in alkaline solution at a suitable potential, reducible to benzo[c]cinnoline-7V-oxide in acid solution the reduction proceeds to 4,5-dihydrobenzo[c]cinnoline, which is very easily (e.g., by air) oxidized to benzo[c]cinnoline. A similar ring closure during the reduction of 2,2, 6,6 -tetranitrobiphenyl yields A-oxides of 4,5,9,10-tetraazapyrene [105-107]. Reduction of 2,2 -dinitrodiphenylsulfide yields via 2,2 -(bishydroxylamino)diphenylsulfide in strongly acidic or in alkaline solution dibenzo[Z)/]-l,4,5-thiadiazepine and its iV-oxide [108] under slightly different conditions the formation of 3-hydroxyphenothiazine has been reported [109]. 

Both of the two possible ring systems, 1,2,3- (27) and 1,2,7-thiadiazepines (28), have been reported. 

The structural identity of (38 R = OMe, R = H, R = C02Et) has been verified by conversion of this adduct to the A,7V -dimethyl derivative, of which x-ray crystallographical analysis confirmed the proposed benzo-annelated thiadiazepine structure. In the crystal structure, the ring adopts a seven-membered chair-like conformation, and significant delocalization of the electron pairs on both nitrogens is indicated by the sum of the torsion angles (346-350°) around each of these atoms. 

This chapter is organized in a manner similar to Chapter 9.13. Of the ten possible 1,2,4-triheteroepine ting systems, the following five systems, triazepine, oxadiazepine, thiadiazepine, dioxa-zepine, and oxathiazepine ring systems, have been prepared and the other five systems are still unknown. 

A variety of 1,2,4- and 1,3,4-thiadiazepines has been prepared however, the monocyclic rings are still unknown. 

Amino-3-thiol-1,2,4-triazole derivatives have been extensively utilized for the synthesis of 1,3,4-thiadiazepines, condensed with a 1,2,4-triazine ring. 

This chapter is organized in a manner similar to Chapters 9.13 and 9.14. Of the ten theoretically possible 1,2,5-triheteroepine ring systems, the following six have been prepared triazepine, oxa-diazepine, thiadiazepine, dithiazepine, oxathiazepine, and trithiepine. 

Pyrrolo[l,2- >]-l,2,5-benzothiadiazepine 1,1-dioxide (105) has been obtained by cyclization of the A(-formamide derivative (104), derived from l-(2-aminobenzenesulfonyl)pyrrole (103) and acetic formic anhydride, with phosphorus oxychloride via a Bischler-Napieralski reaction in 47% yield, or by iron powder-acetic acid reduction of the nitro-aldehyde derivative (106) and subsequent ring closure of the resulting aminoaldehyde intermediate in 92% yield <94JHC1033>. The reaction of (103) with ethyl glyoxylate hemiacetal via a Pictet-Spengler type condensation afforded the benzo-thiadiazepine (107) in a high yield (94%) <94JHC867> (Scheme 17). 

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