Cyclization reactions phosgene

Quite recently, novel cyclization reactions involving CO to give carbocydic and heterocyclic compounds, which are characteristic for mthenium catalysts, have been developed. Ruthenium complexes provide new avenues for cydization reactions. In addition, CO is often used as a reducing agent, and reductive carbonylations of nitro compounds catalyzed by mthenium complexes are very attractive reactions that provide phosgene-free processes [3]. 

The cyclization reactions of phosgene are described in detail in Chapter 10 these transformations represent important routes to many intermediates in the food, pharmaceutical and agricultural industries. For example, iV-carboxyanhydride, of type (4.21), are formed from the reaction of phosgene with 1-amino acids ... 

Tryptamine undergoes a straightforward cyclization reaction with phosgene [856a] ... 

Because of the ease with which this cyclization reaction occurs, phosgene has been used as a reagent for the enantiomeric resolution of 1,2- and 1,3-diols [1151,1152] ... 

Perimidinones are available from 1,8-naphthalenediamines in cyclization reactions with potassium cyanate, carbonate, and chlorocarbonate esters, phosgene, and urea all methods give satisfactory results. 2-Alkoxy- and aryloxyperimidines are readily available by nucleophilic substitution reactions in the 2-position <81RCR8I6>. 

Suitable substituted triazole derivatives can be cyclized with phosgene or some of its substitutes (e.g., diphosgene, triphosgene, carbonyl diimidazole) to form the corresponding triazolotriazole derivatives. This approach can be demonstrated by reactions in Scheme 81 <77CB1691,84JOC1703>. 

A large-scale cyclization reaction of carbamates with functionalized butenoates, starting from carbamates prepared without phosgene, for the efEdent preparation of 3-(substituted phenyl)-5-isopropylidene-l,3-oxazolidine-2,4-dione derivatives (azaladones) having potent herbicidal adivity, has been described in a patent application [240]. By reacting an N-(substituted phenyl)carbamate 312 with a 2-hydroxy-3-alkenoic acid ester (for example, ethyl 2-hydroxy-3-methyl-3-butenoate) or a 3-alkoxy-2-hydroxyalkanoic add ester, at 210 °C for 15 h, azaladone 313 was formed in 71.5% yield. 

Cyclization of the hydrazone derivatives of 4-benzoyl[ 1,2,3]triazole 695 by reaction with one carbon inserting agent such as an orthoester, an aldehyde, a ketone, or a phosgene afforded triazolotriazine 696 or 697 (88JHC743). The newly created C—N bond displays particular sensitivity due to the electron-attracting effect of the triazole ring (Scheme 147). 

Alternatively, two phosgene equivalents were studied, methyl chloroformate and p-nitrophenyl chloroformate. When methyl chloroformate was used for the end game, N-carbamate 54 was obtained smoothly but subsequent cyclization to ben-zoxazinone 1 was sluggish. Furthermore, removal of the unreacted intermediate methyl carbamate 54 from Efavirenz was not trivial, thus we did not pursue this method. On the other hand, reaction of 53 and p-nitrophenyl chloroformate initially provided the corresponding p-nitrophenyl carbamate 55 under mild basic conditions (KHC03). Carbamate 55 was smoothly cyclized to 1 upon increasing... 

N-benzylaniline with phosgene, and then with sodium azide to produce carbonyl azide 52. On heating, nitrogen is evolved and a separable mixture of nitrene insertion product 53 and the desired ketoindazole 54 results. The latter reaction appears to be a Curtius-type rearrangement to produce an N-isocyanate (54a), which then cyclizes. Alkylation of the enol of 54... 

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 12), which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype, in the synthesis of 146, reaction of the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141). Cyclization of the ortho nitrourea function by means of sodium hydroxide leads to the N-oxide (142) this last reaction represents... 

A number of general methods for the synthesis of meso-ionic 1,2,4-triazol-3-ones are available. Sodium ethoxide-catalyzed cyclization of 1-benzoyl-l,4-diphenylsemicarbazide (201, R = R = R = Ph, X = O) yielded anhydro-3-hydroxy-1,4,5-triphenyl-1,2,4-triazolium hydroxide (200, R = R = R = Ph). A general route to meso-ionic 1,2,4-triazol-3-ones (200) is exemplified by the formation of the 1,4,5-triphenyl derivative (200, R = R = R = Ph) from A-amino-MA -diphenylbenzamidine (202, R = R = R = Ph) and phosgene. In contrast with this ready meso-ionic compound formation, the corresponding reaction of the iV-methylbenzamidine (202, R = Me, R = R = Ph) did not yield the meso-ionic 1,2,4-triazol-3-one (200, R = Me, R = R = Ph). The product was in fact 3,4-diphenyl-2-methyl-l,2,4-triazol-5-onium chloride (203), which on heating gave 3,4-diphenyl-1,2,4-triazol-5-one (204, R = Ph). The formation of the A-methyl derivative (200, R = Me, R = R = Ph, yield 79%) by heating the 7V-thiobenzoyl semicarbazide (201, R = Me, R = R = Ph, X = S) with potassium carbonate in methyl cyanide has been reported. Another synthesis of A-methyl derivatives (200, R = Me) involves methylation of 3-methyl-4-phenyl-l,2,4-triazol-5-one (204,... 

When phosgene is used, the carbonic ester derivative formed in the reaction cyclizes by regenerating one molecule of amidoxime 115). 

Reaction of isatoic anhydride with a-aminoalkynes gave 209, which cyclized to a mixture of the oxazolo[3,2-b]quinazolines (210) and 2-aminophenyloxazoles (211) upon treatment with phosgene (89JHC1495). 

The y-amino-p-hydroxy acid derived oxazolidinones 55 are prepared from the corresponding N-unprotected y-amino-p-hydroxy ester derivatives by reaction with phosgene,1119,391 carbonyl diimidazole,[41] or benzyl chloroformate.[86] Alternatively, cyclization is obtained from the N-carbamate protected derivatives, i.e. from the TV-isopropenyloxycarbonyl derivatives under heating,[381 or from the TV-Boc or N-Z derivatives under basic conditions. [68 81 87] By analogy, the p,y-diamino acid analogue is converted into the imidazolidinone 57 by treatment of the unprotected compound with phosgene.[83 88]... 

The cyclization of a-hydrazinohydrazones (653) with ketones has been used for the synthesis of 4-amino-2,3,4,5-tetrahydro-l,2,4-triazines (654), and their reaction with phosgene affords 4-amino-4,5-dihydro-1,2,4-triazin-3-ones (655) (78HC(33)189, pp. 608, 656). 3-Thioxo-l,2,4-triazine-5,6-dione (657) was obtained when oxamohydrazide (656) reacted with thiophosgene (76ACS(B)7l). 

The electrophilic one-carbon species can be an aldehyde, ketone, carboxylic acid, phosgene, thiophosgene, carbonyl diimidazole (CDI), etc., and the reaction essentially involves condensation with a 1,5-dinucleophile. The 1,5-dinucleophile invariably contains at least one heteroatom at a terminus, and more often than not two, so that the cyclization always involves the formation of at least one bond between carbon and a heteroatom. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

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