A-Alkylpyrroles

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. 

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). ... 

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>. 

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. 

A significant fragmentation mode of the A-alkylpyrroles produces an ion of mass 67 which is almost homogeneous and corresponds to C4H5N+. Deuterium labeling has established that this ion arises predominantly by hydrogen migration either from C-4 of the alkyl... 

The fragmentation of A-f-butylpyrroles322 appears to be contrary to that observed for other A-alkylpyrroles. The formation of an immonium ion from the molecular ion would require elimination of a methyl radical. This cleavage is not observed but a fragment ion resulting from loss of isobutene is formed instead. The exact mechanism of this cleavage is not known. 

Carbenoid addition of diazocarbonyl compounds to pyrrole, A -alkylpyrroles, indole, N-alkylindoles, imidazole, and benzimidazole does not result in cyclopropanation, but leads to the formal products of carbene insertion into a heterocyclic C-H bond (see Houben-Weyl, Vol.E19b, ppll58 and 1334). However, Af-acylpyrroles, and Af-acylindoles - " have successfully been converted into 2-azabicyclo[3.1.0]hex-3-ene-exo-6-carboxylates and alkyl-1,la,2,6b-tetrahydrocyclopropa[ ]indole-exo-l-carboxylate, respectively (for an experimental procedure, see Houben-Weyl, Vol.E19b, pll60). 

Alkylamino-l-deoxy-D-fructoses (32, R = n-C4H9, CHaCOjCaHs, CHaCeHs) react with the same dicarbonyl compounds giving the corresponding A-alkylpyrroles (33, R = ri-C4H(, (ilHaCOaCsHs, CHaCeHa R = OCaHa, Similarly, 1-arylamino-l-deoxy-D-fructoses (32,... 

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