2-Methyl-diphenyl, cyclization

Methyl-diphenyl, cyclization, 30 65 2-Methyl-2,4-diphenylpentane, hydrogenolysis, 35 330... 

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

Methyl-8-(2-chlorophenyl)-3,4-dihydro-177,877-pyrido[2,l-f][l,4]oxazine-7,9-carboxylate was obtained by cyclization of l,4-dihydropyridine-3,5-dicarboxylate 338 in the presence of 3M HC1 <1997CAP2188071>. Mild catalytic hydrogenation of oxazinone 339 over 5% Pd/C catalyst afforded 3,4-diphenyl-9-hydroxyperhydropyrido[2,l-f][l,4]oxazin-l-one via sequential iV-carbobenzyloxy (fV-Cbz) deprotection and reductive amination <1998TL3659>. 

The Jacobs-Gould intramolecular cyclization of diethyl N-(6-methyl-2-pyridyl)amino-methylenemalonate to 3-ethoxycarbonyl-7-methyl-l,8-naphthyrid-4-one is another reaction ideally suited to microwave heating, although conductively heated equipment was employed for laboratory-scale experiments [45]. The product is a key intermediate in the synthesis of nalidixic acid, the first of the quinolone antibacterials. The process usually is conducted at temperatures of 200-250 °C and in high dilution, with heat transfer oils such as the eutectic mixture of diphenyl ether and biphenyl. However, it proceeded rapidly, predictably and controllably under solvent-free conditions. 

Later it was shown in reactions of aromatic aldehyde methylhydrazones 137a-f with benzonitrile oxide that the initially formed Z-adduct 138, depending on the reaction procedure and the substituents, undergoes either isomerization to the thermodynamically stable E-adduct 139, tautomerization to an oxatriazine 140 or irreversible cyclization to a triazole 141 (Scheme 1.28). The structure of 4-methyl-3.6-diphenyl-5,6-dihydro-4//-1,2.4,5-oxatriazinesl40a was confirmed by an X-ray study (308). 

Itahara has also found that the phenylation of A-aroylpyrroles can be achieved using Pd(OAc>2 [30, 31]. Although A-benzoylpyrrole (22) yields a mixture of diphenylpyrrole 23, cyclized pyrrole 24, and bipyrrolyl 25 as shown, l-(2,6-dichlorobenzoyl)pyrrole 26 gives the diphenylated pyrrole 27 in excellent yield. The IV-aroyl groups are readily cleaved with aqueous alkali and the arylation reaction also proceeds with p-xylene and p-dichlorobenzene. Unfortunately, N-methyl-, iV-acetyl-, and A-(phenoxycarbonyl)pyrroles give complex mixtures of products. 

It was later claimed that the thermal cyclization of bis(aminomethylene-malonates) (601, R = H, Me, Cl, N02, R1 = Et) by heating in refluxing diphenyl ether for 15-30 min under nitrogen afforded 8-(substituted amino)quinoline-3-carboxylates (603) in 31-75% yields (78USP4123536). In the cases of the methyl and chloro derivatives (601, R = Me, Cl, R1 = Et), l,10-phenanthroline-3,8-dicarboxylates (602, R = Me, Cl, R1 = Et) could also be isolated as byproducts in 3-4% yields. 

The thermal cyclization of m-phenylenediamine derivatives (799) by heating in diphenyl ether afforded angular l,7-phenanthroline-3,9-dicarboxylate (800), if a substituent was not present at position 2 of the phenyl ring of 799 (R = H), but the linear pyrido[3,2-g]quinolinecarbox-ylate (801, R = Me, R1 = R2 = H) was prepared from the 2-methyl-substituted derivative (799, R = Me, R1 = R2 = H) (72GEP2220294). 

The cyclization of /V-(6-methyl-2-pyridyl)aminomethylenemalonate (1001, R = Me, R1 = H), labeled on one of the carboxyl groups with l4C, gave labeled 1,8-naphthyridine (1003, R = Me, R1 = H) in boiling diphenyl ether and labeled pyrido[l,2-a]pyrimidine (1002, R = Me, R1 = H) in a mixture of phosphoryl chloride and polyphosphoric acid in 77% and 85% yields, respectively (73MI2 75MI2). 

N-( l-Acetyl-3-methyl-5-pyrazolyl)aminomethylenemalonate (1103) was cyclized to pyrazolo[l,5-a]pyrimidine-6-carboxylate (1102, R = 2-Me) in 82% yield by heating in boiling diphenyl ether for 10 min (74AP177). 

Reactions.—Nucleophilic Attack at Carbon. (/) Carbonyls. Methyl arylglyoxylates react with trisdimethylaminophosphine (TDAP) to form m-a/S-dimethoxycarbonyl-stilbene oxides.63 The initially formed zwitterion (61) reacts with a second molecule of the ester to form a fra/ -diphenyl-1,4,2-dioxaphospholan intermediate, which undergoes a concerted symmetry-allowed retrograde n2s + 4 cycloaddition to give a carbonyl ylide, conrotatory cyclization of which leads to the cw-oxirans (62) (Scheme 3). 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). lodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative... 

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,... 

The valence tautomerism 251 257 has been proposed to account for the formation of iV-methylthiobenzamide by irradiation (2537 A) in methyl cyanide solution. The valence tautomer 257, R = Me, = Ph, has been detected spectroscopically (p , 2060 cm —N=C=S) either during photolysis at 25° or by heating at 160°. Photochemical oxidative cyclization of 4,5-diaryl derivatives (251, R = R = Ar) analogous to the formation of phenanthrene from stilbene has been reported. Thus, irradiation of the 4,5-diphenyl derivative 251, R = R = Ph, yields the tetracyclic meso-ionic compound (258). ... 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Applications of the Conrad-Limpach reaction to the synthesis of 1-hydroxy-4,7-phenanthrolines or, more correctly, l-oxo-l,4-dihydro-4,7-phenanthrolines, from p-phenylenediamine or 6-aminoquinolines continue to be reported. l,10-Dihydroxy-3,8-dimethyl-4,7-phenanthroline has again been prepared from p-phenylenediamine,234 hot diphenyl ether being used to effect the cyclization. Other examples include the new or improved preparations of l-hydroxy-3-methyl-, 10-amino-l-hydroxy-3-methyl-,232 2-(y-chlorocrotonyl)- l,10-dihydroxy-3,8-dimethyl-, and 2,9-bis (y- chlorocrotonyl)-1,10- dihydroxy - 3,8 - dimethyl - 4,7 - phenanthro-lines.235 Compounds prepared in this way have been patented as antiasthmatic agents.178 A closely related synthesis employing poly-phosphoric acid as cyclizing agent has yielded l-hydroxy-3-phenyl-4,7-phenanthroline.236... 

The sequence for the synthesis of l,3,6-triazacycl[3,3,3]azines (58) is based on the reaction of 2,6-diaminopyridine with ethoxymethylene-malononitrile or ethyl ethoxymethylenecyanoacetate, leading to compounds 56. These on acylation gave 57, which after cyclodehydration yielded the desired cyclazines (58). Small amounts of the unsubstituted parent triazacyclazine (58a) were observed when the cyclization of 57 was carried out in a refluxing mixture of biphenyl and diphenyl ether. Decyanation of 4-cyano-2-methyl-l,3,6-triazacycl[3,3,3]azine (58f) with polyphosphoric acid at 200° yields 2-methyl-l,3,6-triazacycl-[3,3,3]azine (58b).18-80 The synthesis of 58d was carried out by a closely related route.74... 

Quinoxaline 1-oxide (209) reacts with phenyl isocyanate to give 2-anilinoquinoxaline (210) together with 1,3-diphenyl-l-(2-quinoxalinyl)-urea (211) and cyclized oxidation product of the urea 212.215 2-Quinoxalinone 4-oxide (205) and its 1-methyl derivative undergo addition reactions, e.g., with phenyl isocyanate and benzyne to give compounds 214 and 216, respectively.216 These reactions are formulated as proceeding via the intermediate cycloadducts 213 and 215. Compound 216 has also been obtained by photolysis of 3-(o-hydroxy-phenyl)quinoxaline 1-oxide.51 1,3-Dipolar cycloaddition of quinoxaline... 

Heating diethyl (l-isoquinolylamino)methylenemalonates in diphenyl ether gave ethyl 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylates (97) (78USP4127720). Cyclization of diethyl[(4-amino-l-isoquinolyl)amino] methylenemalonate in a mixture of acetic anhydride and pyridine in methylene chloride at ambient temperature afforded ethyl 7-acetylamino-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylate [84JAP(K)84/172472]. The 7-nitro derivative was prepared similarly. Cyclization of diethyl [(7-methoxy-3-methyl-l-isoquinolyl)amino]methylenemalonate in polyphos-phoric acid at 130°C for 6 h gave 10-methoxy-6-methyl-4//-pyrimido[2,l-a]isoquinolin-4-one in 29% yield [94IJC(B)795]. 

Under these strong acid conditions, products from other rearrangements and acid cleavage reactions are sometimes found. For example, a mixture of 5-r-butyl-3-methyl-benzo[6]thiophene (the expected product), 6-f-butyl-3-methyIbenzo[6]thiophene and 3-methy benzo[6]thiophene was obtained on cyclization of p-t- butylphenylthioacetone with phosphorus pentoxide. During the cyclization of phenyl phenacyl sulfide to give a mixture of 2- and/or 3-phenylbenzo[Z ]thiophenes, small amounts of diphenyl disulfide and 5-pheny thio-3-phenylbenzo[6]thiophene were also formed (70AHC(11)177). 

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