Selective deprotection of N - Boc -imidazoles and pyrazoles by NaBH 4 in EtOH

Herein, a novel method for the selective N-Boc deprotection of imidazoles, benzimidazoles and pyrazoles in good to excellent yield (75-98%), using NaBH 4 in EtOH at room temperature is reported. Under these conditions, the primary Boc -protected amines and a number of N-Boc-protected aromatic heterocycles such as pyrrole and indole remain completely intact.


Introduction
The N-Βοc methodology is widely used in organic synthesis to prepare various functionalized heterocycles as well as in the field of peptide chemistry for the preparation of very interesting bioactive products.The Nprotected amines being acid labile and inert towards catalytic hydrogenation and basic reagents, 1,2 are compatible with many other protecting groups (N-Cbz, N-Fmoc, benzylester etc) and therefore ideal partners for orthogonal protective protocols.
Nevertheless, several heterocycles of nitrogen including imidazoles, benzimidazoles, pyrazoles, pyrroles, indoles etc., protected with N-Boc group, can also be deprotected under basic conditions.In almost all cases the deprotection is selective only for some heterocycles under certain conditions.
Specifically, the N-Boc-imidazole is deprotected with H 2 NNH 2 or NH 3 /MeOH, 3 the selective cleavage of Boc group from N-Boc imidazoles and indoles is achieved with Cs 2 CO 3 , imidazole at 70 °C 4 and N-Boc-2-lithiated pyrroles are deprotected with NaOMe/MeOH/THF. 5Furthermore, deprotection of N-Boc-indoles with TBAF in refluxing THF has been reported, 6 while removal of Boc protecting group from the aromatic ring of indole as well as the pyrrolidine ring of S-proline and of pyroglutamic acid was achieved with Sn(OTf) 2 in dry CH 2 Cl 2 . 7hermolytic removal of the Boc-protecting group of indoles and pyrroles at 180 °C has also been reported 8 and hydrolysis at 100 °C 9 was used for the deprotection of N-Boc-imidazole, benzimidazole, pyrazole, 1Hpyrrolo [2,3-b]pyridine, 1H-benzo[d] [1,2,3] triazole as well as other N-protected aliphatic amines.Cleavage of the N-Boc group of imidazole moiety can be achieved with K 2 CO 3 /MeOH 10a, b under heating, and the same deprotection can be carried out from the heterocycles of indole, indazole, azaindole, indazole, pyrazole, indolone, quinolinone, oxazolone with Νa 2 CO 3 in refluxing DME. 11In addition to the aforementioned methods, hydrolytic cleavage of N-Boc group from primary aromatic amines, imidazole and benzimidazoles moiety with protic ionic liquids 12 has been reported.Furthermore, the primary N-Boc group can be deprotected by excess of t-butoxide in slightly wet THF or MeTHF. 13uring a multistep synthesis of a certain compound, we attempted to reduce a methyl ester with NaBH 4 in dry EtOH.Unexpectedly, we obtained deprotection of the N-Boc-benzimidazole moiety, present in the substrate structure.Because of this complication, we found it interesting and relevant to investigate the reaction in detail.

Mechanism
The proposed mechanism explaining the observed reactivity of NaBH 4 on Boc protected substrates of imidazole, benzimidazole and pyrazole is presented in Scheme 1.In both cases, the Na + can be stabilized by the lone pairs of oxygen and nitrogen forming a type of favored 6-membered and 5-membered ring respectively.The hydride anion from the B-H bond of BH

Conclusions
The selective cleavage of N-Boc-protecting group of imidazole, benzimidazole and pyrazole in good to excellent yields can be achieved by using NaBH 4 in EtOH (95% or dry).Under the same conditions, other aromatic heterocycles like pyrrole and indole but also the primary N-Boc-protected amines remain completely intact.Therefore, this study is highly relevant for researchers engaged in multistep synthesis of substrates containing these entities, such as peptides containing histidine and tryptophan which possess the side chain of imidazole and indole, respectively.Furthermore, if a reduction is attempted with NaBH 4 , at a later stage in the synthetic process of a compound with a variety of orthogonally protected functional groups, the deprotection of the aforementioned rings can cause undesirable complications.Moreover, this study substantially complements the standard acidic or basic deprotections of tert-butyl carbamates already known in literature.

Experimental Section
General.All chemicals and solvents were reagent grade and used without purification.Dry EtOH was purchased from Merck and compounds 11, 13, 14, 18, 19, pyrrole, indole, histamine, (S)-histidine and its methylester were also commercially available.Chromatographic purification of products was accomplished using Merck Silica Gel 60 (70−230 or 230−400 mesh).Thin layer chromatography (TLC) was performed on Silica Gel 60 F254 aluminum plates.TLC spots were visualized with UV light or phosphomolybdic acid in EtOH.
Melting points were determined on a Büchi 530 apparatus and are uncorrected.

Synthesis of Boc-protected substrates 1-12 tert-Butyl 1H-imidazole-1-carboxylate (1).
To a stirred solution of imidazole (13) (681 mg, 10.0 mmol) in MeOH (40 mL), Et 3 N (1.40 mL, 1 equiv., 10.0 mmol) and Boc 2 O (2.40 g, 1.1 equiv., 11.0 mmol) were added.The reaction mixture was continuously stirred at room temperature overnight, the solvent was evaporated under reduced pressure and the residue, dissolved in AcOEt, was washed with brine, 5% NaHCO 3 and H 2 O.The organic phase was dried with Na 2 SO 4 , the solvent was evaporated and purification of the product was achieved by column chromatography eluting with AcOEt-petroleum ether (8:2).The product was isolated as white solid; yield 1.6 g (92%).The analytical data were in accordance to the literature.

General procedure of the reaction of the substrates with NaBH 4 in dry or 95% EtOH (Table 1)
To a stirring solution of the organic substrate (1 mmol) in dry EtOH or 95% EtOH (3 mL), NaBH 4 [57.0 mg, 1.5 eq, 1.5 mmol, (in case of compound 2, 114.0 mg, 3 eq, 3 mmol)] was added in small portions and the reaction mixture was left stirring at rt.The reaction was followed by TLC (or mass spectroscopy) and upon completion, it was quenched by the dropwise addition of a 3N solution of HCl at 0 °C, until gas production ceased (pH ~7).The organic solvent was evaporated in high vacuo and the residue was dissolved in CHCl 3 (3 mL) and dried with Na 2 SO 4 .After evaporation of the solvent, the product was isolated and appropriately purified.Imidazole (13) was isolated as white solid.Mp 90-91 °C (mp 25

Table 1 .
Cleavage of N-protected heterocycles with NaBH 4 4  -, attacks like a nucleophile on the carbonyl of tertbutoxycarbonyl group, and the tetrahedral intermediate can evolve by considering the N-heterocyclic anions as the leaving groups, well stabilized by resonance.The anions in the protic solvent generate the heterocycles, and tert butyl formate is also produced.Scheme 1. Possible mechanism for the cleavage of Boc-group from imidazole and pyrazole with NaBH 4 .AUTHOR(S)

Table 1 .
Continued a Yields are given in isolated products; all compounds were either compared with known data in the literature, whereas new compounds (2, 12, 17) were fully characterized by 1 H NMR,13C NMR, MS and HRMS; b Use of 1.5 eq NaH (60% in mineral oil) in dry THF; c Dry THF was used as solvent; d 3 eq of NaBH 4 were used (instead of 1.5 eq).