3.4- Diethyl-2-methylpyrrole

Cold, aqueous sodium hydroxide brings about the collapse of diethyl 2,7-dimelhyl-4//-azepine-3,6-dicarboxylate (3) to the 1-substituted pyrrole 4,29 whereas with aqueous ethanolic ammonia solution ring contraction is accompanied by loss of the butenoic acid side chain and formation of ethyl 2-methylpyrrole-3-carboxylate (94% mp 77-78cC). 

In a deceivingly simple process apparently involving a butatriene intermediate, a one-pot preparation of ethyl 5-methylpyrrole-2-carboxylate (6) from diethyl acetamidomalonate (4) and l,4-dichloro-2-butyne (5) has been described <96JOC9068>. 

Krapcho and Vivelo have described a new formal total synthesis of tropinone (124) and ( )-cocaine (98) (94). Cycloaddition of IV-methylpyrrole (182) and acetylenedicarboxylic acid leads to 183, which is hydrogenated to 184. The diacid mixture 184 is refluxed in MeOH/HCl to yield the diester mixture 185. Addition of this to an excess of metallic sodium in liquid ammonia at — 78°C leads to the N-methylpyrrolidine derivative 186 (cf. 95), whose diethyl analog 147 has earlier been converted to tropinone (124) and (+)-cocaine (98) (78-80) (Scheme 13). 

In addition to the parent heterocycle, both AT,N-diethyl-l-methylpyr-role-3-carboxamide and l-methylpyrrole-3-carboxaldehyde have been selectively a-lithiated in the 2-position (85TL6213 87JOC104), the latter compound via the intermediacy of an a-(Af-methylpiperazino) alkoxide (Scheme 6). The a-amino alkoxide is formed in situ, via the addition of... 

American workers needed to prepare the bis-amino acid 1 and adopted a literature procedure in which two equivalents of diethyl acetamidomalonate were to be alkylated with one equivalent of l,4-dichloro-2-butyne using two equivalents of sodium ethoxide in hot ethanol. Hydrolysis and decarboxylation of the dialkylated malonate would then give 1. This alkylation reaction was carried out, but ten equivalents of sodium ethoxide were used rather than two. This resulted in formation of ethyl 5-methylpyrrole-2-carboxylate in ca. 40% yield. Further study showed that the reaction to produce the pyrrole required equimolar amounts of the acetamidomalonate and the dichlorobutyne, excess of sodium ethoxide, and heating. No pyrrole was formed at room temperature. 

A solution of 0.8 g of diethyl N-[l-methyl-3-(2-nitro-3-chlorophenyl)-3-oxopropylidene]aminomalonate in 4 ml of absolute tetrahydrofuran was added dropwise with stirring to a solution prepared with 8 ml of absolute ethanol and 100 mg of metallic sodium. After the reaction mixture was refluxed for 4.5 hours, the solvents were distilled off under reduced pressure. The residue was added with an ice-water and the solution was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, after which ether was distilled off. The residue was recrystallized from benzene to obtain ethyl 3-(2-nitro-3-chlorophenyl)-5-methylpyrrole-2-carboxylate as colorless needles having MP 220°-223°C. 

The addition sequence may determine the primary reaction course or influence impurity formation. For example, condensation of diethyl 3-oxoglutarate 33 with chloroacetone and methylamine is expected to give the 5-methylpyrrole 34, the Hantzch pyrrole product (Figure 5.14). The isomeric 4-methylpyrrole 35 (a precursor to zomepirac sodium) was prepared in good yield by first treating 33 with methylamine, then adding chloroacetone [22]. The addition sequence was also important for the chlorination of the sulfinate anion 36 The dimer 37 was produced when N-chlorosuccinimide was added to the reaction, but when 36 was added slowly to excess Cl2, the desired sulfonyl chloride 38 was produced (Figure 5.14) [23], The course of these reactions may be predicted if one takes a mental snapshot of them. 

How might one prepare (i) diethyl 4-methylpyrrole-2,3-dicarboxylate, (ii) ethyl 2,4,5-trimethylpyrrole-3-carboxylate (iii) ethyl 4-amino-2-methylpyrrole-3-carboxylate (iv) ethyl 3,4,5-trimethylpyrrole-2-carboxylate ... 

Aromatic /-amines can act as carbon nucleophiles in reaction with perfluorinated 1,3,5-triazines. Amines used are 1-methylpyrrole, 1-methylindole, l,8-bis(dimethylamino)naphthalene (proton sponge), A,A-dimethyl- and JV,7V-diethyl-aniline. All the amines reacted at the expected position in the ring except A,7V-diethylaniline which also gave some or//io-product not seen with N,N-dimethylaniline (Equation (8)) <92T7939>. 

Likewise, the major product (amongst many), from the addition of diethyl azodicarboxylate with 1-methyl-2-vinylpyrrole has been shown, mainly on the basis of H and C NMR spectral evidence, to be the 2-ethoxy-6-(l-methylpyrrol-2-yl)-5,6-dihydro-4//-l,3,4-oxadiazine (263) <85JCR(S)12>,... 

Ludwig. This compound has an empirical formula corresponding to structure (1) and shows the ultraviolet and infrared" absorptions of a pyrrole-3-carboxylic ester. Its acetylation gives a tetra-O-acetyl derivative." Oxidation with lead tetraacetate yields ethyl 5-formyl-2-methyl-pyrrole-3-carboxylate (4), identical with the compound prepared in a different way. Oxidation with potassium permanganate in alkaline solution at low temperature yields 3-(ethoxycarbonyl)-2-methylpyrrole-5-carboxylic acid (7) which can be transformed " into the diethyl ester (8), identical... 

Selective reduction. NaBH4 added with stirring at 5° under Ng to a soln. of ethyl 3-ethyl-4-acetyl-5-methylpyrrole-2-carboxylate in tetrahydrofuran, then BFg-etherate added dropwise at a rate to keep the temp, near 10°, warmed to 25°, and stirred 1 hr. at this temp. ethyl 3,4-diethyl-5-methylpyrrole-2-carboxylate. Y ca. 100%. H. W. Whitlock and R. Hanauer, J. Org. Chem. 33, 2169 (1968) also with reduction of carbalkoxyl groups, azulenes, s. A. G. Anderson, Jr., and R. D. Breazeale, Am. Soc. 91, 2375 (1969). 

Jones RA, Rustidge DC, Cushman SM (1984) Pyrrole studies XXX A critical evaluation of the Knorr synthesis of trifluoromethylpyrroles and the reactivity of diethyl 4-trifluoromethyl-2-methylpyrrole-3,5-dicarboxylate. Synth Commun 14 575-584... 

In the pyrrole series h ogenated azides can be prepared by direct halogenation. 2,4r-Dimethyl-3-ethylpyiTole-5-carbonyl azide has been brominated to 2-bromomethyl-3-ethyl-4-methylpyrrol n5-car-bonyl azide and 2-methyl-3,4-diethylpyrrole-5-carbonyl azide (XXIX) has been chlorinated with sulfuryl chloride to 2-trichloro-methyl-3,4-diethylpyrrole-5-carbonyl azide, which on treatment with methanol yields 3,4-diethyl-2-carbomethoxy-5-carbomethoxyaminopyr-role (XXX). Dichlorination is also successful 2,4-dimethyl-3-bromo-... 

It is not true, as commonly stated, that all pyrroles with a free a-position give an intense red colour in this test in the cold. In fact, performance in the colour test parallels roughly the ability to couple with diazonium salts (p. 76). Thus, of the four compounds ethyl pyrrole-1-carboxylate, ethyl 4-nitropyrrole-2-carboxylate, diethyl 3-methylpyrrole-2-4- and diethyl 2-methylpyrrole-3,5-dicarboxylate, none of which undergoes coupling, the... 

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