A synthetic route to 1-(4-boronobenzyl)-1H-pyrrole

The synthesis of 1-(4-boronobenzyl)-1H-pyrrole was investigated using three different routes. Two key routes that involved the introduction of the boronate group protected as the pinacol ester, failed, due to deprotection problems. The route involving the introduction of the boronate group as the final step of the reaction yielded 1-(4-boronobenzyl)-1H-pyrrole (10).

In an attempt to combine the thin film forming properties of pyrroles 25 with our interest in boronates 35,36 as receptors and sensors, 37,38 we now report strategies directed to the synthesis of 1-(4-boronobenzyl)-1H-pyrrole (10).

Results and discussion
The synthesis of pyrrole/boronate compounds is problematic due to the sensitivity of the pyrrole group to undergo oxidation under acidic conditions leading to uncontrolled polymerisation and decomposition 39 and the aqueous solubility of the boronate group which may necessitate its protection, to facilitate isolation and characterisation.
Our strategy to the synthesis of 1-(4-boronobenzyl)-1H-pyrrole (10) is outlined in Scheme 2, and involved the introduction of the boronate group early in the reaction, protected as a pinacol ester due to stability problems associated with the ethylene glycol group. 35 4-Carboxybenzeneboronic acid (1) was converted to the pinacol ester in refluxing toluene (Dean-Stark apparatus) in quantitative yields to give the cyclic boronate ester 2 in high yield (98%). The attempted conversion of the pinacol protected acid 2, to the acid chloride (3) using thionyl chloride or oxalyl chloride failed to yield the desired product due to the stability of the pinacol protecting group. The milder procedure of Lee 40 using triphenylphosphine/carbon tetrachloride yielded the crude acid chloride 3 on solvent evaporation as a mixture contaminated with the pinacol protected acid 2 and triphenylphosphine. Due to the moisture sensitivity of 3, the compound was used as isolated and reacted with pyrrole, using dimethylaminopyridine (DMAP) as an acylation catalyst to yield the N-acylpyrrole 4, in low yield (24%). The N-acylpyrrole 4 was successfully reduced to 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) benzyl)-1H-pyrrole (5) using BF 3 /OEt 2 / NaBH 4 . 31 Cleavage of the cyclic boronate ester 5 was attempted using 4M HCl, RT, 18 h, 35 BBr 3 /CH 2 Cl 2 41 and MeOH/TsOH/reflux, but all methods failed to yield the desired product 10, due to decomposition of the pyrrole group. Milder methods SiO 2 /CH 2 Cl 2 /(COOH) 2 , 42 basic hydrolysis (dioxane/NaOH(aq)) and oxidative cleavage (NaIO 4 /Me 2 CO/aq. NH 4 OAc) 43 also failed to yield 10.
The inability of the synthetic routes depicted in Schemes 2 and 3 to produce 1-(4-boronobenzyl)-1H-pyrrole (10) led to the investigation of an alternative approach to the product, in which the boronate group was introduced late in the reaction, as shown in Scheme 4. In this approach, 4-bromobenzylamine was condensed with DMT under neutral conditions in an aqueous mixture of AcOH/pyr to give 1-(4-bromobenzyl)-1H-pyrrole (9). 32 Lithiation of 9 with t-butyllithium, quenching with trimethylborate followed by acid hydrolysis finally yielded 1-(4-boronobenzyl)-1H-pyrrole (10) (52%) in moderate yield. Confirmation of the structure of (10) using mass spectroscopic techniques proved inconclusive as the molecular ion was not directly observed based on the technique used, due to the elimination of H 2 O from the -B(OH) 2 group. 35 In EIMS, a distinct peak was observed at 182 for (M + -H 2 O+1) and in negative ion ESMS peaks at 437 for (2M + +Cl) and 236 (M + +Cl). Definitive confirmation of the structure of compound 10 was finally achieved by its conversion to the pinacol ester 5 (69%) in high yield.
In conclusion, a variety of methods have been investigated to synthesise 1-(4-boronobenzyl)-1H-pyrrole (10). It is clear based on the results reported here that the introduction of the boronate group, late in the reaction, is the most effective method for the preparation of this compound (Scheme 4) due to the lack of an adequate method for the removal of the pinacol protecting group from 5 (Schemes 2 and 3). Review of the literature identified that the carbazole analogue of 10, 4-((9H-carbazol-9-yl)methyl)phenylboronic acid 44 had been prepared from the corresponding carbazole analogue of 9, 9-(4-bromobenzyl)-9H-carbazole  using a similar procedure to Scheme 4, but n-butyllithium(n-BuLi) replaced t-butyllithium(t-BuLi).