Thiazepine derivatives

Concerning the mechanism of O/H insertion, direct carbenoid insertion, oxonium ylide and proton transfer processes have been discussed 7). A recent contribution to this issue is furnished by the Cu(acac)2- or Rh2(OAc)4-catalyzed reaction of benz-hydryl 6-diazopenicillanate 237) with various alcohols, from which 6a-alkoxypenicil-lanates 339 and tetrahydro-l,4-thiazepines 340 resulted324. Formation of 340 is rationalized best by assuming an oxonium ylide intermediate 338 which then rearranges as shown in the formula scheme. Such an assumption is justified by the observation of thiazepine derivatives in reactions which involved deprotonation at C-6 of 6p-aminopenicillanates 325,326). It is possible that the oxonium ylide is the common intermediate for both 339 and 340. 

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... 

An intramolecular free radical addition was used to prepare the 1,2-thiazepine derivatives 30 and 31 from 29 (Equation 6). A further elegant intramolecular radical cyclization was then used to convert 30 to a new aza-bicyclic system with a bridgehead nitrogen <2001JOC3564>. 

Compared with azepine derivatives, considerable scope still exists for innovative exploration of ring-closing metathesis methodology to access multisubstituted 1,2-oxazepine and 1,3-thiazepine derivatives and benz-fused analogues. Also, the full synthetic potential of the Meisenheimer rearrangement to afford various 1,2-oxazepine derivatives with different types of functionality present is still to be realized. 

A review on tianeptine, a dibenzo[. While a number of bis-fused 1,2-thiazepine systems are known, they were outside the scope of this chapter. 

Considerable synthetic scope exists for the application of diene-based and ene-yne-based ring-closing metathesis reactions to the synthesis of 1,3-oxazepine and 1,3-thiazepine derivatives. Particular emphasis on type e reactions is likely to be very fruitful. 

Obviously most papers on the title heterocycles also list NMR data as part of the characterization. We will mention only a few articles that are partially or completely dedicated to NMR studies of 1,4-oxazepine and 1,4-thiazepine derivatives. 

In general, 1,4-oxazepines and 1,4-thiazepine derivatives are stable compounds. Many of the (di)benzo derivatives are crystalline, while some of the more flexible monocyclic derivatives may be liquids. Conjugated (benzo)thiazepine derivatives can lose sulfur on heating, forming (fused) pyridines. This aspect of their reactivity is treated in Section 13.09.5. The completely or partially reduced derivatives of the title heterocycles and the benzo analogues may adapt different conformations, which has already been discussed in Section 13.09.2. The study of the tautomerism of lactams 9 has also been mentioned in Section 13.09.2. 

Tricyclic thiazepine derivatives were analogously prepared via an intramolecular Mannich-type reaction <1995JME2145, 2000JOC4269>. 

In this case, the seven-membered ring is formed from the reaction of an electrophilic carbon atom with an electron-rich component, such as an aromatic ring to afford di- or tricyclic benzo-l,4-thiazepine derivatives. 

Reduction of nitro compound 269 with stannous chloride did not give the expected amino compound but rather the tricyclic 1,4-thiazepine derivative 270 after a semi-pinacol-type rearrangement (Equation 22) <2002JOC8662>. 

Compounds 128 were prepared in high yields either by thermal [1 Ire-arrangement of sulfonium ylides 126 to intermediates 127 which were then converted into the thiazepine derivatives (128) by ring expansion on photolysis in methanol, or directly from the ylides 126 by ultraviolet irradiation, which causes a photo[l,2]rearrangement followed by ring expansion (Scheme 39) (77CPB292). 

There have been a number of reports on the preparation and chemistry of fused thiazepine derivatives. Toda el al. have noted the stereocontrolled synthesis of tetrahydro-1,5-benzothiazepines, trans- and c/s-263, on reaction of o-aminothiophenol with the epoxide 262 in the presence of magnesium perchlorate the overall yield of 263 was 94% and the trans.cis ratio was 24 76 and the factors controlling the stereochemical outcome were discussed [01H1451 ]. 

Likewise, RCM was utilized to access 1,2-thiazepine derivatives 192 and 193 (Scheme 93) <2005S1421, 1999TL4761>. The cyclic sulfonamide 194 can be prepared by heating 5-aminopentanesulfonyl chloride. The ketone HCCC(0)CH=CHSCN reacts with amines to give the l,2-thiazepin-5-one system 195 <1961CB1606>. 

Hydrolytic cleavage of the C-O bond of bicyclic, tetracyclic, and steroidal enolates with HF-SbFs induces their isomerization to the corresponding ketones (Scheme 14.41) [104]. Rearrangement of dienones to aromatic compounds is also promoted by HF-SbFs (Scheme 14.42) [105]. Ring expansion of methyl penicilli-nates is achieved by SbCls to give thiazepine derivatives [106]. 1,3-Dithianes derived from ketones and aldehydes are deprotected with SbCls by means of a single-electron-transfer mechanism [107]. 

Initial 1,3-dipolar cycloaddition of the mesoionic compound (87) to (86), followed by extrusion of carbon dioxide, leads to the 1,2-thiazepine derivatives (88) and (89) in low yields (Equation (13)) <85MI 907-01>. 

Oxidation of the exocyclic sulfur atom in the 1,3-thiazepine derivatives (33 R = Ph, CH2Ph, Et) with MCPBA gave the thione S -oxides (34). The sulfine structure was confirmed by oxidation to the 0X0 derivatives (35) (Scheme 4). Yields and melting points for (34) and (35) are given in Table... 

A series of selective D2 dopamine receptor agonists were discovered and optimized to obtain benzothiazepine amide 161, a lead compound that possessed good in vitro physical properties, metaboHc stabihty, and in vivo pharmacokinetics (14JME3450). A number of 8-alkoxy-4,5-dihydrobenzo[l)] [l,2,4]triazolo[4,3-(/][l,4]thiazepine derivatives were synthesized, with compound 162 showing potent anticonvulsant activity (14JEIM272). 

A series of 5-dialkylaminoethyl-benzo-l,5-thiazepin-4-ones (36) has been obtained by reaction of the known benzo-l,5-thiazepin-4-ones (35) with dialkylaminoethyl chlorides and sodium hydride in dioxan or, better, DMSO. The acetoxy-compounds (37) are converted by standard procedures into benzo-l,5-thiazepine derivatives such as (38) and (39). 

There were examples of reactions of tetrahydropyrimidine—thione derivatives with 1,4-dielectrophiles affording pyrimido-fused 1,3-thiazepine derivatives (13JHC838). 

More recently, a simple and efficient reaction for the synthesis of steroid/nonsteroid fused benzo[fe][l,4]thiazepines and 2-aiylsubstituted benzo[Z)][l,4]thiazepines was developed. using Pd(OAc)2 as the catalyst in DMF solvent with heating, a wide variety of steroidal/nonsteroidal p-bromovinyl aldehydes and 2-aminothiophenols undergo this reaction to give good yields of benzo[Z>][l,4]thiazepine derivatives (Scheme 4.17). A palladium catalyst was explored in benzoxazocine synthesis via intramolecular C-N coupling as well. ... 

Furthermore, highly substituted furan-fused 1,4-thiazepine derivatives 14 can be prepared by a three-component reaction (3CR) involving thiazoUum salts 12, DMAD, and ketenes or acid derivatives [15] (Scheme 5.9). 

SCHEME 5.9 Synthesis of polysubstituted furan-fused 1,4-thiazepine derivatives 14. 

In the case of an N-alkyl residue with a terminal leaving group, for example, R=CH2-CH2-CH2-I, intramolecular S-alkylation of the ring-opening product 7 is observed, which in the example given leads to the thiazepine derivative 6 [340]. 

Ethyleneacetals from cyclic 1,1-chlorothioethers. Startg. perhydro-1,4-thiazepine deriv. refluxed 1 hr. with Ag20 in methanol -> product. Y 92%. 

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