Synthesis Of Five-membered Nitrogen-containing Heterocyclic Boronic Acid and Its Ester

Synthesis Of Five-membered Nitrogen-containing Heterocyclic Boronic Acid and Its Ester

In the past few decades, coupling reactions have been widely used in the synthesis of novel alkyl compounds or aromatic heterocyclic compounds.

In these transition metal catalyzed coupling reactions, Suzuki coupling reactions are favored due to their mild reaction conditions, suitability for multiple functional groups, relative stability in air, and relatively low toxicity [1]. Therefore, chemists have been interested in the synthesis and activity of new boronic acid derivatives. These compounds, especially nitrogen-containing heterocyclic boronic acids, can be used in the establishment of combinatorial compound libraries in medicinal chemistry research.

1. Synthesis of five-membered nitrogen-containing heterocyclic boronic acid and its ester

1. 1 Synthesis of pyrrole borate and its esters
As early as 1991, research on the synthesis of pyrrole borate derivatives began. However, at present, there are still few reports published at home and abroad. Pyrrole boric acid can be prepared by direct lithiumation of pyrrole or metal-halogen displacement and re-boronation, but this generally requires a protecting group on the nitrogen atom. Heretofore, the protecting groups for the nitrogen atom on the pyrrole ring are mainly: tert-butoxycarbonyl protecting group [2], triisopropylsilyl protecting group [3], phenylsulfonyl protecting group [4].

1.1.1 Synthesis of 2-pyrroleboronic acid and its ester

In 1991, Schluter et al. [2] reported the synthesis of N-tert-butoxycarbonyl-2-pyrroleboronic acid, which was prepared using N-tert-butoxycarbonylpyrrole as starting material at -78 °C. The solution of 2,2,6,6-tetramethylpiperidine in tetrahydrofuran is reacted with n-butyl lithium, followed by reaction with trimethyl borate to form the corresponding borate compound, and then hydrolyzed under acidic conditions to obtain the target. The product, in a yield of about 40%, is shown below.

In 1993, Kelly et al. [5] prepared N-tert-butoxycarbonyl-2-pyrroleboronic acid in the same manner in 82% yield. In recent years, other research groups have used N-tert-butoxycarbonylpyrrole as a substrate, reacted with LDA or LiTMP in tetrahydrofuran solution at -78 °C, and obtained N-un via boronylation reaction and hydrolysis reaction. Butoxycarbonyl-2-pyrroleboric acid, the yield was 58%, 72%, respectively. It has been found that a major problem in the application of the boronic acid compound in the Suzuki coupling reaction is that heating is prone to deborolation, in addition to a certain amount of dimer formation, as shown below.

In order to reduce the deboronation reaction and the dimerization reaction of N-tert-butoxycarbonyl-2-pyrroleboronic acid in the Suzuki coupling reaction, Ketcha et al. [6] used a benzenesulfonyl group as a protecting group for the nitrogen atom. However, the desulfonylation reaction occurs competitively while the lithium group of the 1-phenylsulfonylpyrrole 2 carbon atom occurs, and the corresponding pyrrole boric acid is finally obtained in only 8% yield. In 2004, Dinsmore et al. [7] prepared the same compound as a substrate in the presence of diisopropylamine, followed by Grignard reaction with isopropylmagnesium bromide, followed by boronation and hydrolysis. The corresponding target compound, but the yield was only 13%.

In 2002, the Miyaura research team [8] reported for the first time the synthesis of 2-pyrroleboronic acid pinacol esters, which are based on pyrrole, in the rhodium catalyst dichloro-chloro-1,5-cyclooctadienyl ruthenium complex and In the presence of the ligand 4,4'-di-tert-butyl-2,2'-dipyridine, the corresponding target product was produced in 67% yield with pinacol diborate, as shown below. In this reaction, a pinacol ester of boronic acid was used in place of pinacol diborate to form 2-pyrroloboronic acid pinacol ester, but the yield was reduced to 42%. Studies have found that the main problem with this reaction is the need to consume a large excess of substrate to avoid the formation of diboronated products.

1.1.2 Synthesis of 3-pyrroleboronic acid and its ester
In 1992, Muchowski et al. [3] synthesized 1-triisopropylsilyl-3-pyrroleboronic acid. The method is carried out by a two-step reaction starting from triisopropylsilylpyrrole, firstly using NIS at the 3-position selective iodine of pyrrole, followed by trimethylborate under the action of tert-butyllithium. The reaction is further hydrolyzed in an aqueous methanol solution to give the desired product which can be further purified by recrystallization as shown below.

In 2001, Smith et al. [9] reported the direct synthesis of N-triisopropylsilyl-3 by reacting triisopropylsilylpyrrole with boronic acid pinacol ester in a cyclohexane solvent under the action of a ruthenium catalyst. - Pyrrole borate method, yield 81%. The synthetic reaction ruthenium catalyst uses CpRh(η4-C6Me6) (wherein Cp is pentamethylcyclopentene). N-triisopropylsilyl-3-pyrroleboronic acid pinacol ester can also be formed by substituting pinacol diborate for the boronic acid ester in the reaction, but the yield is 79%.

In recent years, the Buchwald research group [10] reported the catalytic coupling of metal palladium to prepare 1-triisopropylsilyl-3-pyrroleboronic acid pinacol ester, which is 3-bromo-N-triisopropylsilyl. Pyrrole is a substrate which is produced by the action of pinacol ester of boric acid in the presence of S-Phos and triethylamine as shown below. Thereafter, the same reaction was carried out by replacing the protecting group on the nitrogen atom with a tert-butoxycarbonyl group or a benzyl group, but the result was not satisfactory, and the yield was only 30% and 24%.