Cyclizations sodium hydride

In the case of a 2,3,4-triaminopyridine, diazotization of the 3-amino group gives a mixture of the two possible cyclized products. 111 and 112, intercon-verted by sodium hydride (98MIP42706). 

Low yields of 5-acyl-2,3-dihydropyrrolo[2,l-Z ]oxazoles (37) were obtained by treatment of 2-acyl-5-nitropyrrole (35) with ethylene oxide. Better yields are reported starting from hydroxy derivative 36a or its acetate 36b using sodium hydride in THE The presence of an acyl group at the position 2 was found necessary for the cyclization (Scheme 5) (71JCS(C)2554). 

Reaction of 2-methoxytetrahydropyrrole with dioxalane-2,4-dione in presence of Et3N in benzene followed by treatment with MeONa in methanol afforded the monocyclic intermediate 185. Its treatment with BuLi followed by perfluorobenzoyl chloride gave 186 whose hydrolysis gave 187 which possess low or no antibacterial activity (96PHA805). Regiospecific intramolecular cyclization of 188 with sodium hydride yielded 189 as ester whose hydrolysis gave the respective acid (87JHC1537) (Scheme 35). 

The preparation of several medium- and large-sized 2-carbo-methoxycycloalkanones has been accomplished by treatment of the cycloalkanone with sodium triphenylmethyl, followed by carbonation with dry ice, and esterification with diazomethane. 1 The yields are good but the procedure is laborious. The synthesis of 2-carbomethoxycycIooctanone via the Dieckmann cyclization of dimethyl azelate with sodium hydride yields 48% of this product when the procedure is carried out over a 9-day period.3... 

It will be recalled that one of the key operations in the synthesis of IJK ring system 86 is the intramolecular conjugate addition reaction (see 90—>89, Scheme 17b) to form ring J. In the context of compound 90, the electrophilic a,/ -unsaturated ester moiety and the potentially nucleophilic tertiary hydroxyl group reside in proximal regions of space, a circumstance that would seem to favor the desired cyclization evept (see Scheme 19). Indeed, exposure of a solution of 90 in THFto sodium hydride (1 equiv.) for one hour at 25 °C results in the formation of compound 89 in 92% yield. In... 

Pyrrolo[l,2-a]azepin-5-one (11), prepared by cyclization of methyl 5-(pyrrol-2-yl)penta-2,4-dienoate (10) with sodium hydride in toluene, in trifluoroacetic acid solution forms the diatropic 5-hydroxypyrrolo[1,2-a]azepinium ion 12.216 6-Methyl-5//-pyrrolo[l,2-tf]azepin-5-one(mp41 -43 C), formed in low yield (20%) by the action of [(ethoxycarbonyl)methylene]triphenylphos-phorane on 4-(pyrrol-2-yl)but-3-en-2-one, behaves similarly. 

The addition of a-(acylamino) esters to 3-aryl-2-propenoates, with sodium ethoxide in ethanol or sodium hydride in benzene as base, is a frequently ultilized procedure9-" A The initial Michael adducts cyclize to 3-aryl-5-oxo-2-pyrrolidinecarboxylic acids with modest to high trans diastereoselectivities 10°. 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

In order to synthesize quinolizidine compounds, some authors have used the Parsons method (Bu3SnH/AIBN) to cleave the iV-tosyl group of 2-piperidones such as 144 (AIBN = 2,2 -azobisisobutyronitrile). After detosylation to 145, the intramolecular cyclization of the lactam promoted by sodium hydride gave quinolizidinone 146. T reatment of this compound with Raney nickel both cleaved the C-S bond and reduced the C=C bond to give quinazolinone 147, while the lactam carbonyl was reduced with LiAlH4 to give 148 (Scheme 23) <2005TL8551>. 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

Hydroxy-3,4-dihydro-2,l-benzothiazine 2,2-dioxide 15 can be synthesized in a convenient manner <94TL2911>. Blondet and co-workers used a cyclization of an ortho-(chloromethyl or carboxaldehyde) A-protected sulfonanilide 13 or 16 with sodium hydride in DMF to give the benzothiazine dioxide 14 or 17 in 35% and 47% yields, respectively (Scheme 4). Finally, removal of the methoxy group and hydrogenation led to the formation of 5-hydroxy-3,4-dihydro-2,l-benzothiazine 2,2-dioxide 15 in good yield over two steps. 

Treatment of a methanolic solution of the nitrile derivatives (81 R1 = CH2CN, R2 = CONH2) [prepared in two steps from the calcium antagonist compound (81 R1 = R2 = H)] with sodium hydride resulted in facile cyclization, giving the 4-aminoimidazol-2-one derivative (82) (53%) (90JMC1805). 

Kuroda and Suzuki used reaction of 267a with 2-bromoaniline leading to anilide 312 as the first step of their sequence in the preparation of 1H-imidazo[4,5-c]quinolin-4(5//)-ones (Scheme 77) (91TL6915). Reaction of 267a with amines usually does not require any catalyst and/or base, but in this case use of sodium hydride was reported. The anilide 312 was sequentially alkylated, first with methyl iodide in ethanol with potassium hydroxide at room temperature and then with different alkyl iodides in acetone at reflux to provide intermediate 313. This compound was then cyclized via palladium catalyzed reaction leading to product 314. This reaction provides a new entry to l//-imidazo[4,5-c]quinolin-4(5//)-ones that are of current interest as antiasthmatic agents. 

New tri- and tetracyclic compounds containing the pyridazine moiety were synthesized in a multistep reaction sequence from commercially available pyridazine 173 <00AP231>. Acid chloride 173 reacted- readily with 174 to yield 175. Cyclized product 176 was then produced by treatment of tethered pyridazine 175 with sodium hydride in an intramolecular SNAr displacement. 

The key step in Hu s synthesis of 51 was cyclization of 50 by heating with copper(I) iodide and sodium hydride in DME, followed by a 10% aqueous ammonia work-up. Intermediate 50 was prepared via Michael addition of ethyl acetamidocyano acetate to the appropriate chalcone followed by acid-catalyzed ring closure [42,43]. 

Dehydrative condensation of pyrrole-2-carboxaldehyde 77 and ethyl carbazate afforded carbethoxyhydrazone 78 in quantitative yield. Cyclization of 78 in the presence of a catalytic amount of sodium hydride (10mol%) in dimethyl-formamide (DMF) at 100°C led to the formation of pyrrolo[l,2-tf][l,2,4]triazin-4-one 27 in 75% yield (Scheme 8) <1999T13703>. 

The earliest synthetic method for 1-benzazepine derivatives was a ring closure of -substituted anilines by C-N bond formation. Cyclization of 4-(2-aminophenyl butanoic acid and the corresponding butyl chloride gave the lactam (1, R1 = R2 = H) [1] and the 2-deoxo analogue [93], respectively. Thermal cyclization of (41, R1 = R2 = Me R3 = OH) gives 2,5-dioxo-benzazepines (38, R1 = R2 = Me R3 = R4 = R5 = H) [94]. Treatment of analogous esters with sodium hydride gives the derivatives of (38) [9, 95],... 

The Dieckmann cyclization of aminomethylenemalonates (1308) in boiling ethanol for 45 min, by the action of alkoxide, gave pyrrole-2,4-dicar-boxylates (1309) in 24-86% yields (77HI821 78CPB2224). Pyrrole-2,4-dicarboxylate (1309, R = H,R = Et) was also prepared in 71% yield from 1308 (R = H, R1 = Et) by reaction with sodium hydride in boiling benzene for 4 hr (78CPB2224). The 1-phenyl derivative (1309, R = Ph, R1 = Et) was prepared in 52% yield in an exothermic reaction of 1308 (R = Ph,... 

Imidoyl chlorides (1679) were reacted with dimethyl malonate in THF in the presence of sodium hydride at room temperature to give aminometh-ylenemalonates (1680) in 67-82% yields (89TL4821). The 4-methylphenyl derivative of 1680 (R = 4-MeC6H4) was cyclized by heating in cumene at 200°C to afford 4-hydroxy-2-trifluromethylquinoline-3-carboxylate (1681) in 66% yield. 

These findings did encourage us to examine further the biological properties of the imidazoisoindoles, particularly since their physical properties were also quite different from their phthalimide precursors. The first requirement was an improved procedure for the synthesis of the imidazoisoindoles. A number of reagents, both acidic and basic, were found that would effect cyclization of these phthalimides. One o the most consistent methods utilized sodium hydride in hot toluene or xylene. Some large-scale preparations, e.g. of were successfully run using sodium hydroxide pels in xylene. 

Cyclization of quinoline derivatives 185 in DMSO on the action of cesium carboxate at 85°C afforded diesters 186 [95T11125]. No cyclization product could be obtained when a piperazono group was present in 185 (R = piperazino). Cyclization in the presence of sodium hydride gave lower yield. When the potassium salt of 185 was applied in the presence of 20 mol%... 

Similarly, 3-oxo-6-nitrobenzoxazine, which is also a lactam, has been N-arylated using sodium hydride and 4-nitrochlorobenzene in dimethylformamide (DMF) <1985IJB1263>. The reaction is a nucleophilic aromatic substitution assisted by the 4-nitro group and is therefore not general to all aryl halides. However, there is a route to N-arylated benzoxazines 148-151 through a catalyzed tandem cyclization-arylation reaction of 147, shown in Scheme 9 <2004S2527>. 

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