Practical and Large Scale Procedures for the Synthesis of Achiral and Chiral Benzoxaboroles Subash C. Jonnalagadda, 1 Dinara S. Gunasekera, 1 Josyula V. B. Kanth, 2 Paul Kiprof, 1 and Venkatram R. Mereddy 1 1 Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812 2 New Product Research & Development, Aldrich Chemical Company, 6000 N. Teutonia Ave, Milwaukee, WI 53209

Benzoxaboroles S. J. Benkovic, S. J. Baker, M. R. K. Alley, Y. H. Woo, Y. K. Zhang, T. Akama, W. Mao,J. Baboval, P. T. R. Rajagopalan, M. Wall,L. S. Kahng, A. Tavassoli, L. Shapiro, J. Med. Chem., 2005 , 48 , 7468. S. J. Baker, Y. K. Zhang, T. Akama, A. Lau, H. Zhou, V. Hernandez, W. Mao, M. R. K. Alley, V. Sanders, J. J. Plattner, J. Med. Chem., 2006 , 49 , 4447. Aryl boronic acids and boronates are highly useful synthetic intermediates especially for the transition metal catalyzed cross coupling with aryl and vinyl halides. One such class of cyclic boronic acids are the benzoxaboroles. They have been utilized in wide variety of applications in medicinal and materials chemistry. For example, some of these cyclic boronic acids, exhibit excellent anti-fungal activity 1 and recently, a fluoro-substituted benzoxaborole, AN2690 has been identified for clinical trials for onychomycosis (an infection of toes, and finger nails). 2

S. J. Benkovic, S. J. Baker, M. R. K. Alley, Y. H. Woo, Y. K. Zhang, T. Akama, W. Mao,J. Baboval, P. T. R. Rajagopalan, M. Wall,L. S. Kahng, A. Tavassoli, L. Shapiro, J. Med. Chem., 2005 , 48 , 7468.

S. J. Baker, Y. K. Zhang, T. Akama, A. Lau, H. Zhou, V. Hernandez, W. Mao, M. R. K. Alley, V. Sanders, J. J. Plattner, J. Med. Chem., 2006 , 49 , 4447.

Aryl boronic acids and boronates are highly useful synthetic intermediates especially for the transition metal catalyzed cross coupling with aryl and vinyl halides.

One such class of cyclic boronic acids are the benzoxaboroles. They have been utilized in wide variety of applications in medicinal and materials chemistry.

For example, some of these cyclic boronic acids, exhibit excellent anti-fungal activity 1 and recently, a fluoro-substituted benzoxaborole, AN2690 has been identified for clinical trials for onychomycosis (an infection of toes, and finger nails). 2

Applications of Benzoxaboroles Some of the benzoxaboroles have also been found to selectively complex with naturally occuring oligosaccharides to affect direct glycosidation of the sugars. 1 They have also been used for the selective recognition of cell-surface glycoconjugates. 2 The other applications of these molecules include their use as cross-coupling synthons in the organic chemistry, 3 steroid conjugates for molecular imprinting, dyes, 4 biosensors of α-hydroxycarboxylic acids, and biocides for plastic biodegradatation. 5 1. K. Oshima, Y. Aoyama, J. Am. Chem. Soc. 1999 , 121 , 2315. 2. M. Dowlut, D. G. Hall, J. Am. Chem. Soc. 2006 , 128 , 4226. 3. K. C. Nicolaou, S. Natarajan, H. Li, N. F. Jain, R. Hughes, M. E. Solomon, J. M. Ramanjulu, C. N. C. Boody, M. Takayanagi, Angew. Chem. Int. Ed., 1998 , 37 , 2708; 4. A. P. Russell, C. W. Zepp, U. S. Patent, 1996 , US5512246. 5. P. W. Austin, C. J. Kneale, P. J. Crowley, J. M. Clough, P. C. T. Int. Appl., 1995 , WO9533754

Some of the benzoxaboroles have also been found to selectively complex with naturally occuring oligosaccharides to affect direct glycosidation of the sugars. 1 They have also been used for the selective recognition of cell-surface glycoconjugates. 2

The other applications of these molecules include their use as cross-coupling synthons in the organic chemistry, 3 steroid conjugates for molecular imprinting, dyes, 4 biosensors of α-hydroxycarboxylic acids, and biocides for plastic biodegradatation. 5

Preparation of Benzoxaboroles Our preliminary synthesis of benzoxaboroles involved the dilithiation of o -bromobenzyl alcohol followed by the treatment with trialkylborate and acidic hydrolysis. V. V. Zhdankin, P. J. Persichini, L. Zhang, S. Fix, P. Kiprof, Tetrahedron Lett., 1999 , 40 , 6705

Some Reactions of Benzoxaboroles V. V. Zhdankin, P. J. Persichini, L. Zhang, S. Fix, P. Kiprof, Tetrahedron Lett., 1999 , 40 , 6705

Modified Procedure for the Preparation of Benzoxaboroles We further extended the protocol with the purpose of developing an inexpensive and practical procedure for the large scale synthesis of benzoxaboroles. We employed NaH for the initial deprotonation of hydroxyl group followed by treatment with n BuLi to affect debromination. The dianion thus generated was treated with triisopropylborate yielding the intermediate boronate. Acidic hydrolysis of the boronate ester with 10% sulfuric acid followed by column chromatography produced the required benzoxaborole.

X-Ray Crystal Structure of Vinylbenzoxaborole

Applications of Benzoxaboroles In order to demonstrate the applicability of these compounds, we performed the Suzuki-Miyaura cross coupling of the benzoxaboroles with 2-bromopyridine in the presence of Pd(PPh 3 ) 4 and Na 2 CO 3 to afford the 2-pyrimidinyl benzyl alcohols in high yields (89-95%).

Preparation of Chiral Benzoxaboroles With an aim to expand the scope and robustness of the current protocol, chiral benzoxaboroles were synthesized starting from o -bromobenzaldehyde. The enantioselective allylboration of aldehyde with Ipc 2 BAllyl furnished the homoallylic alcohol in 94% ee. Sequential addition of NaH, BuLi, and B(O i Pr) 3 to the alcohol followed by hydrolysis provided the chiral benzoxaborole in high yield. Similarly the saturated benzoxaborole was synthesized under similar conditions in two steps starting from the homoallylic alcohol.

Preparation of Chiral Benzoxaboroles

Preparation of Fluorobenzoxaboroles We have also applied the methodology for synthesis of 5-fluorobenzoxaborole (AN2690). This molecule has recently been identified as a lead molecule for the treatment of onychomycosis. Reduction of the commercially available 5-fluoro-2-bromobenzaldehyde with NaBH 4 , and the one-pot reaction with NaH, n BuLi, and B(O i Pr) 3 , followed by acid treatment provided AN2690 in 65% overall yield

Preparation of Fluorobenzoxaboroles

Large Scale Synthesis of Benzoxaboroles We were successful in synthesizing multigram quantities (>200g) of benzoxaborole utilizing our modified protocol. During the process we were able to further simplify the procedure by avoiding the column chromatography. The crude benzoxaborole was treated with 6N NaOH to affect the formation of water soluble boron "ate" complex. Washing the aqueous layer with pentane removed any organic byproducts. Acidification of the aqueous layer to pH 1 and recrystallization from water afforded essentially pure benzoxaborole in >80% yield.

Conclusions We have developed a convenient procedure for the synthesis of benzoxaboroles starting from o -bromobenzyl alcohols in a single pot transformation. The product benzoxaboroles were utilized for cross-coupling under Suzuki-Miyaura conditions with 2-bromopyridine yielding the pyridinyl benzyl alcohols in high yield. The reaction protocol is highly tunable and it has been extended to prepare optically pure benzoxaboroles. We also synthesized AN2690 a potential agent for topical treatment of onychomycosis in multigram quanatities. The present protocol is highly scalable and we were able to obtain multigram (~200 gram) quantities of all the boroles with utmost ease. These compounds are highly stable and the efforts are underway towards the commercialization of these molecules. Owing to the importance of benzoxaboroles in organic, bio-organic, materials, and medicinal chemistry, we believe the present methodology would find wide range of applications.

We have developed a convenient procedure for the synthesis of benzoxaboroles starting from o -bromobenzyl alcohols in a single pot transformation.

The product benzoxaboroles were utilized for cross-coupling under Suzuki-Miyaura conditions with 2-bromopyridine yielding the pyridinyl benzyl alcohols in high yield.

The reaction protocol is highly tunable and it has been extended to prepare optically pure benzoxaboroles.

We also synthesized AN2690 a potential agent for topical treatment of onychomycosis in multigram quanatities.

The present protocol is highly scalable and we were able to obtain multigram (~200 gram) quantities of all the boroles with utmost ease.

These compounds are highly stable and the efforts are underway towards the commercialization of these molecules. Owing to the importance of benzoxaboroles in organic, bio-organic, materials, and medicinal chemistry, we believe the present methodology would find wide range of applications.

Acknowledgements Department of Chemistry and Biochemistry College of Pharmacy, University of Minnesota Duluth