Substituted pyrroles methyl

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

Replacement of the ethanolamine head group is also well tolerated. Substitution with a cyclopropyl (243) [37], allyl (244) or propargyl group (245) [164] all led to an increase in binding affinity compared to AEA. Replacement of the head group with aromatics is also allowed. The phenyl derivative (246) retains affinity at the CBi receptor [37], whereas the 2-substituted A-methyl pyrrole (247) has a 2-fold improved affinity compared to AEA [167]. Interestingly, the 3-substituted furan derivative (23) that has micromolar affinity for the AEA transporter (see above) does not bind to the CBi receptor, but has good affinity for the CB2 receptor [167]. These results are summarised in Table 6.20. 

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

The protonation of acetyl- and formyl-pyrroles occurs on the carbonyl group (Skylar et al., 1966). So, for example, in the nmr spectrum of 2,4-dimethyl-3-acetyl-pyrrole in concentrated acid the vinyl (C-5) proton resonance is retained, although there is exchange in deuteriated acid (Melent eva et al., 1971). The behaviour of carbethoxy-substituted pyrroles is more complicated, however. While 3-carbethoxy derivatives [168] and the 2-carbethoxy derivatives unsubstituted at the 5-position [169] protonate at the a-position of the ring and are not exceptional, the 2-carbethoxy derivatives with a methyl group at the 5-position [170] give evidence in the nmr... 

Gly-OEt was also added to ethyl 3-perfluoroalkylpropynoates which were transformed in several steps into 5-perfluoroalkyl-substituted l-methyl-2-ethoxycarbonylpyrrolidin-3-ones (90X6705). 3-Propyl- and 4-propylpro-lines and 4- -pentylproline were synthesized from diethyl acetamidomalo-nate and an unsaturated aldehyde (67JA2459 72JMC1255). Ethyl benzyli-denecyanoacetate reacts with hippuric acid to give the pyrrole 8 (87H2323). 

High diastereoselectivity (ds >10 1) has been achieved when the substituted pyrrole 589 was reacted with lithium and a catalytic amount (8%) of naphthalene in THF at —78 °C, being methylated with methyl iodide hence trani-product 590 was obtained (Scheme 155) . 

In methanolic cyanide, N-substituted pyrroles193 are substituted in the 2-position by a cyano group on anodic oxidation. Methoxylation, which is often observed as a side reaction in the anodic oxidation in methanolic cyanide, was suppressed completely. When N-substituted pyrroles carry a methyl group in the 2- and 5-positions, a side-chain cyanation occurs.193,194... 

Side chains Different porphyrins vary in the nature of the side chains that are attached to each of the four pyrrole rings. For example, uroporphyrin contains acetate (-CH2-COO-) and propionate (-CH2-CH2-COO-) side chains, whereas coproporphyrin, is substituted with methyl (-CH3) and propionate groups. 

The solution spectrum of pyrrole displays a strong band at ca. 210 nm (Table 23). The weak band at ca. 240 nm reported in the older literature is now generally accepted as arising from autoxidation products. Substitution of methyl for hydrogen generally leads to... 

In an extensive ab initio study, the preferred conformers for substituted pyrroles are predicted to be, inter alia NCCH trans and C(2)CCH cis for 2- and 3-methylpyrroles [i.e. a methyl C—H bond eclipsing the pyrrole C(2)—C(3) bond) NCCO cis and C(2)CCO cis for 2- and 3-hydroxymethylpyrroles pyramidal at nitrogen for aminopyrroles planar OH trans for hydroxypyrroles planar trans for vinylpyrroles, and planar cis (syn) for formylpyr-roles. In agreement with experiment the energy difference between the two rotamers for 3-formylpyrrole is much smaller than for the 2-isomer (79NJC473). 

Substituted pyrroles do not react with Grignard reagents or alkali metals, but 1-methyl and 1-phenylpyrrole have been reported to react with w-butyllithium to give the a-lithio derivative.218... 

Extention of the reaction of ketoximes with acetylene to oximes of hydroxyalkyl ketones can lead to the synthesis of inaccessible, functionally substituted pyrroles and A-vinyl derivatives. However, the methyl a- and /3-hydroxyalkyl ketoximes used by Trofimov et al. (80ZOR410) appeared to react with acetylene in the KOH/DMSO system in an abnormal way. 

Later, French scientists (74BCF1147) made good progress by using methylhydrazones (74) and methyl esters of propiolic and acetylenedicar-boxylic acids instead of acetylene. They obtained mixtures of the corresponding 4- and 4,5-methoxycarbonyl substituted pyrroles (76) and their N-methyl derivatives (77) in 5-45% yield (Scheme 36). The reaction involves the intermediate N-vinylhydrazones (75). 

A synthetic route to substituted a-methyl pyrroles (141) from ketoximes and 1,2-dibromopropane has been developed (Scheme 69) (88IZV2175). 

A substituted pyrrole (Fig. 7c) was electropolymerised across the pores of an alumina membrane [83] and the resultant polymer film then acted as a permselective membrane across which anions could cross. This was then used to separate an analyte solution from an internal sensing solution containing nitrate reductase enzyme and methyl viologen. 

We still have to make the pyrrole with the alkyl side chain for this acylation reaction. Friedel-Crafts alkylation is not an option but pyrroles are reactive enough to do the Mannich reaction. Formaldehyde and an amine combine to give another iminium salt 107 that reacts with A-methyl pyrrole to give, after rearomatisation 109 the substituted pyrrole 110. 

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