Alkylpyrroles

Alkylphenols Alkyl polyglycosides N-Alkylpyrroles Alkyl thiophenes Alkyltins Alkynes... 

V- Alkylpyrroles react with maleic anhydride to give the electrophilic substitution product (7) and not the Diels-Alder addition product found for... 

N-Alkylpyrroles may be obtained by the Knorr synthesis or by the reaction of the pyrrolyl metallates, ie, Na, K, and Tl, with alkyl haUdes such as iodomethane, eg, 1-methylpyrrole [96-54-8]. Alkylation of pyrroles at the other ring positions can be carried out under mild conditions with allyhc or hensylic hahdes or under more stringent conditions (100—150°C) with CH I. However, unless most of the other ring positions are blocked, poly alkylation and polymerisation tend to occur. N-Alkylation of pyrroles is favored by polar solvents and weakly coordinating cations (Na", K" ). More strongly coordinating cations (Li", Mg " ) lead to more C-alkylation. 

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

Alkyl substituents. The steric effect of 1-alkyl substituents in the pyrrole series has been demonstrated in, for example, Vilsmeier formylation reactions. Thus as the bulk of the alkyl substituent on nitrogen is increased e.g. from Me to Bu ) so does the proportion of /3 substitution (70JCS(C)2573). A similar trend has been observed in a series of experiments on the trifiuoroacetylation of A-alkylpyrroles with trifluoroacetic anhydride (80JCR(S)42). 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

Pyrrole and alkylpyrroles can be acylated by heating with acid anhydrides at temperatures above 100 °C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacetyl-pyrrole on heating with acetic anhydride at 150-200 °C. iV-Acylpyrroles are obtained by reaction of the alkali-metal salts of pyrrole with an acyl halide. AC-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

The nitrosation of pyrroles and indoles is not a simple process. The 3-nitroso derivatives (84) obtained from indoles exist largely in oximino forms (85) (80IJC(B)767). Nitrosation of pyrrole or alkylpyrroles may result in ring opening or oxidation of the ring and removal of the alkyl groups. This is illustrated by the formation of the maleimide (86) from 2,3,4 -trime thylpyrrole. 

A wide vanety of nucleophiles, such as 1-alkylpyrroles, furans, thiophenls [51], phenols [52], anilmes [55, 54], indoles [55], CH-acidic compounds [56, 57], as well as organolithium [56], Gngnard [57, 59], organocadmiura, and organozmc compounds [56], undergo C-hydroxyalkylation with trifluoropynivates to yield derivatives of a-trifluoromethyi a-hydroxy acids. 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

Cyclotrithiazyl chloride is also a useful reagent in organic chemistry in the fusion of 1,2,5-thiadiazoles to quinones as well as the synthesis of (a) isothiazoles from 2,5-disubstituted furans and (b) bis-1,2,5-thiadiazoles from A-alkylpyrroles (Scheme 8.4). Alkenes and alkynes react readily with (NSC1)3 to give 1,2,5-thiadiazoles, while 1,4-diphenyl-1,3-butadiene gives a variety of heterocyclic products including a bis(l, 2,5-thiadiazole). ... 

Carbon tetrachloride was also found to react with pyrryl potassium to give 3-chloropyridine, however the mechanism is obscure and would justify further investigation. In a preparatively useful reaction, pyrrole and chloroform in the vapor phase at 500-550° gave 3-chloro-pyridine (33%) and a little 2-chloropyridine (2-5%). No interconversion of the isomers occurred under these conditions, though pyrolytic rearrangement of N-alkylpyrrole to 3-substituted pyridines is considered to involve 2-alkylpyrroles as intermediates. There is some independent evidence that dichlorocarbene is formed in the vapor phase decomposition of chloroform. ... 

A reaction of alkylpyrroles with hot aqueous sulfuric acid leading to indoles almost certainly involves the dimers as intermediates, thus 2-methylpyrrole gives 2,4-dimethylindole and 2-isopropyl-, 3-methyl-, and 2,3-dimethylpyrrole lead to indoles the structures of which have not yet been established. 

A convenient and general method has been developed for the synthesis of alkylpyrroles starting from ketones and nitroalkenes via reduction of the intermediate acetic nitronic anhydride as shown in Eq. 10.1. Ketone enolates react with a variety of nitroalkenes to yield the Michael adducts, lithium nitronates, which are trapped with acetic anhydride to give the corresponding acetic nitronic anhydrides. The acetic nitronic anhydrides are easily converted into alkylpyrroles by reduction with Zn(Cu).3... 

Various types of alkylpyrroles are prepared under mild conditions by reacting nitroalkenes with imines in the presence of Sm(Oi-Pr)3 (Eq. 10.11).13 Thus, the Grob-Camenish type reaction is accelerated by samarium catalysts. 

Reaction of ketocarbenoids with pyrrole and N-alkylpyrroles yields the product of formal insertion into the a-C—H bond (256) in many cases the -insertion product 257 is formed concomitantly, but generally in lower yield 238-241 >. The regioselectivity varies according to the catalyst, the diazo compound and the N-alkyl substituent. Some examples concerning the former two variables are given in Table 18 239 240). 

Efficient synthesis of highly substituted alkylpyrroles and fused pyrroles has been achieved by three-component coupling of ... 

A-Alkylpyrroles undergo cycloaddition reactions with trithiazyl trichloride (NSC1)3 to afford, depending on the substituents R1, R2, and R3, thiadiazoles 216-218. The reactions are proposed to proceed by addition of the N-S(C1)-N fragment across the 2,3- and the 4,5-bonds of the A-alkylpyrrole, followed by a series of eliminations to give the observed products (Equation 49) <1997CC1493, 1997J(P 1)3189>. 

A range of alkylating agents have been used for the preparation of 1 -alkylpyrroles (Table 5.30). However, in contrast with the corresponding reaction of the indoles, no alkylation of the ring carbon atoms occurs with saturated haloalkanes, but there is... 

The trifluoroacetyl and acetyl groups show the same qualitative conformational preference, at least when bonded to N-alkylpyrrole (80JCR(S)42) and benzo[h]furan (840MR197). 

Pyrroles are found in the volatiles of most heated foods [29], although they have received less attention than some other classes of aroma volatiles. Some pyrroles may contribute desirable aromas, e.g. 2-acetylpyrrole has a caramel-like aroma, and pyrrole-2-carboxaldehyde is sweet and corn-like, but alkylpyrroles and ac-ylpyrroles have been reported to have unfavourable odours [22]. Many more volatile pyrroles have been found in coffee than in other foods [30], and they are common products of amino acid-sugar model systems. Pyrroles are closely related in structure to the furans, and they are probably formed in a related manner from the reaction of a 3-deoxyketose with ammonia or an amino compound followed by dehydration and ring closure (cf Scheme 12.2). 

The sulfur-nitrogen halide (NSC1)3 is also a useful reagent in organic chemistry. For example, alkenes or alkynes react readily with (NSC1)3 to produce 1,2,5-thiadiazoles and the reaction with A-alkylpyrroles gives bis-1,2,5-thiadiazoles. 

Large 1-alkyl substituents increase 3-substitution in the Vilsmeier formylation of pyrroles (70JCS(C)2573). A similar trend occurs in trifluoroacetylation of W-alkylpyrroles (80JCR(S)42). The trifluoroacetylation, formylation and bromination of 1-tritylpyrrole occur regioselectively at the 3-position in high yield (83JCS(P1)93). 

Electron donor 2-substituents orient substitution in furan, thiophene and selenophene into the 5-position. In pyrrole, although the ratio of a to (3 reactivity is much smaller than in the other five-membered rings, 5-substituted 2-alkylpyrroles still appear to be the major products. 

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