Pyrroles sodium hydride

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. 

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 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,... 

Although pyrrole is a weak acid, it can be depro-tonated by using a strong base, e.g. sodium hydride, and the anion can be used in typical nucleophilic reactions. This allows simple transformations such as... 

Another approach leading to pyrroles from enaminoketones was demonstrated [94H(37)487]. An enamine with the thiophene ring (15) was converted into an imido chloride vinylog, which interacts with esters of amino acids in the presence of sodium hydride in dimethylformamide and affords... 

Three l-hydroxy-3-phenylpyrroles (46) were formed (72JOC1561) in 26-44% yields, instead of the anticipated 6//-oxazines, when the corresponding E-oximes (44) were treated successively with one equivalent of sodium hydride in dimethylformamide (DMF) followed by triphenylvinylphosphonium bromide Z-benzil oxime gave no pyrrole. The cyclization probably proceeds via cyclization to the N-oxide 45 and tautomerism to the 1-hydroxypyrrole. 

Yet another method has been described (162) (Scheme 50) for the preparation of the tricyclic enamine (225). /V-Alkylation of ethyl pyrrole-2-carbox-ylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156) but contrasting with the report of Dolby et al. (160). 

The pyrrolylthioacetate (105) undergoes Dieckmann ring closure when treated with sodium hydride to give the thieno[2,3-6]pyrrole-2,4-dicarboxylate (106) (65JOC184). 

A mixture of l,2-dimethyl-3-acetyl-4-isopropyl-5-phenyl pyrrole (12.75 g, 0.05 mol) and diethyl isopropylidene succinate (10.7 g, 0.05 mol) in dry toluene (70 ml) was added to a stirred solution of sodium hydride (80% dispersion in oil, 3.8 g, 0.125 mol) suspended in dry toluene (10 ml) under nitrogen atmosphere. A few drops of absolute ethanol were added to initiate the exothermic reaction. The reaction mixture was stirred for about 40 h at ambient temperature until no hydrogen was formed, and finally the reaction mixture was poured into crashed ice-water (100 ml). The organic layer was separated and extracted with saturated sodium carbonate solution (2 x 50 ml). The combined aqueous layer was extracted with toluene (50 ml), and then the aqueous phase was acidified slowly with 5 M hydrochloric acid and washed with toluene (3 x 100 ml). The toluene solution was dried with MgSO 4 and the solvent was removed the half-ester was obtained as a gum. 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

MO-Acetals afford robust protection for indoles and pyrroles with SEM and BOM ethers being particular favourites. A SEM group has also been used to protect imidazole.534 They are introduced in much the same way as already discussed for amines and amides in section 8.6. L Hence treatment of Indolelactam derivative 274.1 with SEMC and sodium hydride in THF at —15 °C afforded the M 0-acetal 274 in >80% yield 535... 

Azaindoles are readily acylated on the pyrrole nitrogen by warming on a water bath with acid anhydrides or with acid chlorides in the presence of carbonate or pyridine. Good yields were obtained by this procedure for the following compounds l-acetyl-7-azaindole, 1-benzoyl- and l-benzenesulfonyl-7-azaindole, l-benzoyl-2-methyl-7-azaindole, 1-ethoxycarbonyl- and l-chloroacetyl-7-azaindole, l-acetyl-3-cyano-7-azaindole, 1-benzoyl-4-azindole, and 1-acetyl- and l-benzoyl-2,5-dimethyl-4-azaindole. The only reported failure was with 5-methyl-2-phenyl-4-azaindole, which failed to react with acetic anhydride or benzoyl chloride. 2-Methyl-7-azaindole-3-acetic acid was acylated by treatment of its ierGbutyl ester with sodium hydride in dimethylformamide, followed by p-chlorobenzoyl chloride. ... 

The Michael addition /ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCOs to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respeetively. 

A further example is the synthesis of 3H-pyrrolizine from the reagent and pyrrole-2-aldehyde (Eastman) in ether with sodium hydride as condensing agent. 

Similarly, the reaction of l,2,3-tris(ter/-butylsulfanyl)cyclopropenylium ion 5 with amines in the presence of sodium hydride afforded the pyrrole derivatives 6 with elimination of one equivalent of fer -butylthiol. ... 

Tris(isopropylsulfanyl)cyclopropenylium ion 9 also reacted with pyrrole in the presence of sodium hydride in dimethyl sulfoxide to give the pyrrolizine derivatives 10 and... 

Carboxylic ester and activated N-methylene groups react under strongly basic conditions at room temperature to form a pyrrole ring, but attempts to cyclize the V-tosyl analogue of (70.1) under Dieckmann reaction conditions were unsuccessful when the -acetyl amine (70.1) was treated with sodium hydride, cyclization was achieved in good yield. 

As in pyrroles, the A-hydrogen in indoles is much more acidic (pK 16.2) than that of an aromatic amine (aniline has pK 30.7). Any very strong base will effect complete conversion of an A-unsubstituted indole into the corresponding indolyl anion, amongst the most convenient being sodium hydride, n-butyUithium or an alkyl Grignard reagent. 

The pA a for loss of the A -hydrogen of imidazole is 14.2 it is thus an appreciably stronger acid than pyrrole (pATa 17.5) because of the enhanced delocalisation of charge, involving both nitrogens in the imidazolyl anion. Salts of imidazoles can be alkylated or acylated on nitrogen. One convenient method is to use the dry sodium/potassium salt obtained by evaporation of an aqueous alkaline solution sodium hydride in dimethylformamide also serves very well for this purpose. 

Hydrazonium salts (117) with sodium hydride in DMSO give azirines (118), which react further with ketones to give 2f/-pyrroles (119) benzyl cyanide similarly gives 120 (Scheme 43).114-116 This reaction is claimed to be the most convenient general route to 2H-pyrroles (yields 20-80%).114... 

By analogy with secondary amines, pyrrole proves to be an NH acid, pXa = 17.51. For this reason, pyrrole reacts with sodium, sodium hydride or potassium in inert solvents, and with sodium amide in liquid ammonia, to give saltlike compounds ... 

With a Ka value of 16.97, indole possesses an NH-acidity similar to that of pyrrole. Indole reacts, therefore, with sodamide in liquid ammonia, with sodium hydride in organic solvents, with Grignard reagents and with -butyllithium to give 1-metalated indoles. 

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