Abstract
An efficient methodology for the preparation of α-hydroxyamides via boric acid mediated addition of isonitriles on to aldehydes has been developed. The reaction of isonitriles with α-boronobenzaldehyde takes place under intramolecular catalysis conditions to provide functionalized benzoxaboroles.
Keywords: Multicomponent reactions, Isonitriles, Boric acid, Benzoxaboroles
Introduction
Boric acid is an inexpensive, non-toxic compound and it is generally considered a green material.1 It is an excellent precursor for the preparation of various types of organoboranes and is also used as a mild Lewis acid catalyst for several organic transformations.2 α-Hydroxyamides are important synthetic intermediates in organic synthesis and also serve as valuable agents in medicinal chemistry.3 The use of isonitriles in three or four component multicomponent coupling reactions such as Passerini and Ugi is well documented in the literature.4 The addition of isonitriles on to carbonyl compounds is usually catalyzed by strong protic acids or Lewis acids to provide α-hydroxyamides.5
Results and Discussion
Owing to the aforementioned advantages, we envisaged the utility of boric acid for the direct α-addition of isonitriles on to aldehydes to synthesize α-hydroxyamides. For the current study, we chose benzyl, cyclohexyl and t-butyl isonitriles (2a-c) and various types of aldehydes 1a-g. We initiated the optimization of the reaction conditions with propionaldehyde 1a with benzyl isonitrile 2a. The reaction was studied in various solvents such as THF, CH2Cl2, EtOAc, DMF, DMSO, Dioxane, MeOH and water with varying amounts of boric acid (10 mol% to one equivalent). DMF as a solvent and one equivalent of boric acid were found to be optimal in obtaining cleaner reaction with good yields. Aliphatic isonitriles 2b, 2c and aliphatic aldehydes were in general found to be more reactive and the reactions were completed in 24 hours of stirring at room temperature. Aromatic aldehydes reacted slowly and required almost 48 hours of reaction time. Upon completion, the reaction mixture was washed with water, worked up with diethyl ether and pure products were obtained after silica gel column chromatography.
We also explored the reaction with the ketones 3-pentanone and acetophenone as representative examples. However, the reactions were found to be very sluggish even with two equivalents of boric acid and elevated temperature (80°C).
We then applied the methodology for intramolecular version of the reaction starting with o-formyl phenylboronic acid 5. We envisaged that the proximity of the boronic acid to the formyl group in 5 could lead to a facile reaction with isonitrile under self catalysis mode without any additional boric acid catalysis. This reaction should provide direct access to functionalized cyclic boronic acids (benzoxaboroles) 6. Indeed, the reaction of boronoaldehyde 5 with isonitrile 2a in DMF at room temperature took place smoothly with out boric acid to provide the product benzoxaborole in 81% yield. Similarly, isonitriles 2b and 2c upon reaction with 5 provided the corresponding benzoxaboroles 6b and 6c respectively (Scheme 1). This class of boron compounds have extensive applications in materials chemistry and synthetic chemistry as excellent intermediates for Suzuki cross coupling reactions.6 Several of these compounds have also been found to exhibit important antibacterial and antifungal properties.7
Scheme 1.
Synthesis of α-Amido Benzoxaboroles
Representative procedure for the preparation of hydroxyamide 4a
To a stirred solution of propionaldehyde 1a (0.14 mL, 2.0 mmol) in 2mL DMF was added benzyl isonitrile 2a (0.24 mL, 2.0 mmol), and boric acid (0.12 g, 2.0 mmol) and stirred overnight at room temperature. Upon completion (TLC), the reaction mixture was worked up with water and diethyl ether (3 × 25 mL). The combined organic layers were dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel, hexane:acetone, 4:1) to obtain 0.30 g (78%) of hydroxy amide 4a. 1H NMR (500 MHz, CDCl3): 7.22-7.32 (m, 5H), 7.18 (bs, 1H), 4.47 (t, J = 4.5 Hz, 1H), 4.42 (dd, J = 4.0, 15.0 Hz, 1H), 4.36 (dd, J = 4.0, 15.0 Hz, 1H),4.05-4.08 (m, 1H), 1.78-1.90 (m, 1H), 1,62-1.72 (m, 1H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): 174.5, 138.2, 128.9, 127.9, 127.7, 73.2, 43.3, 28.1, 9.4; ESI-MS: 216 [(M+Na)+, 100%], 194 (M+H)+.
Represenative procedure for the preparation of benzoxaborole 6b
To a stirred solution of boronoaldehyde 5 (0.3 g, 2.0 mmol) in 2mL DMF was added tert-butyl isonitrile 2a (0.23 mL, 2.0 mmol), and stirred overnight at room temperature. Upon completion (TLC), the reaction mixture was worked up with water and ethyl acetate (3 × 25 mL). The combined organic layers were dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel, hexane:ethyl acetate, 3:1) to obtain 0.30 g (65%) of benzoxaborole 6b. (Found: C, 61.53; H, 8.10; N, 6.02 %; C12H16BNO3 requires: C, 61.84; H, 6.92; N, 6.01%); 1H NMR (500 MHz, DMSO-d6): 9.33 (bs, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.52 (s, 1H), 5.27 (s, 1H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3): 169.4, 152.3, 131.3, 130.8, 128.1, 122.9, 80.2, 51.1, 28.9; ESI-MS: 232 [(M-H)+, 100%].
Conclusions
In conclusion, we have developed an efficient protocol for the preparation of α-hydroxyamides via boric acid mediated addition of isonitriles on to aldehydes. The reaction in general provides good yields of the products under very mild reaction conditions. We have applied the methodology for intramolecular version to synthesize functionalized benzoxaboroles. Owing to the importance of hydroxyamides and benzoxaboroles as synthetic intermediates and also as medicinal agents, we believe that the current methodology will find applications in organic and medicinal chemistry.
Table 1.
Boric acid mediated addition of isonitriles and aldehydes for the synthesis of α-hydroxyamides.
 | ||||
|---|---|---|---|---|
| Entry | Aldehyde | Isonitrile | Product | Yield |
| 1 |  |
 |
 |
78% |
| 2 | ” |  |
 |
74% |
| 3 | ” |  |
 |
75% |
| 4 |  |
 |
 |
70% |
| 5 | ” |  |
 |
71% |
| 6 | ” |  |
 |
74% |
| 7 |  |
 |
 |
61% |
| 8 | ” |  |
 |
64% |
| 9 | ” |  |
 |
72% |
| 10 |  |
 |
 |
78% |
| 11 | ” |  |
 |
74% |
| 12 | ” |  |
 |
72% |
| 13 |  |
 |
 |
82% |
| 14 |  |
 |
 |
76% |
| 15 | ” |  |
 |
80% |
| 16 |  |
 |
 |
65% |
| 17 | ” |  |
 |
68% |
| 18 | ” |  |
 |
67% |
| 19 |  |
 |
 |
75% |
| 20 | ” |  |
 |
72% |
| 21 | ” |  |
 |
78% |
Acknowledgements
We thank the Departments of Chemistry and Biochemistry, Rowan University, and University of Minnesota Duluth for the funding. Partial support for this work was provided by research grants from the National Institutes of Health (CA129993) (VRM) and Whiteside Institute for Clinical Research (VRM).
Footnotes
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References
- 1.Boric Acid General Fact Sheet-National Pestidice Information Center http://npic.orst.edu/factsheets/boricgen.pdf.
- 2 (a).Shteinberg LY. Russ. J. Appl. Chem. 2009;82:613–617. [Google Scholar]; (b) Kondaiah GCM, Reddy LA, Babu KS, Gurav VM, Huge KM, Bandichhor R, Reddy PP, Bhattacharya A, Anand RV. Tetrahedron Lett. 2008;49:106–109. [Google Scholar]; (c) Nath J, Chaudhuri MK. Green Chemistry Letters and Reviews. 2008;1:223–230. [Google Scholar]; (d) Tu S-J, Zhu XT, Fang F, Zhang X-J, Zhu S-L, Li T-J, Shi D-Q, Wang X-S, Ji S-J. Chin. J. Chem. 2005;23:596–598. [Google Scholar]; (e) Chaudhuri MK, Hussain S, Kantam ML, Neelima B. Tetrahedron Lett. 2005;46:8329–8331. [Google Scholar]; (f) Maki T, Ishihara K, Yamamoto H. Org. Lett. 2005;7:5047–5050. doi: 10.1021/ol052061d. [DOI] [PubMed] [Google Scholar]; (g) Stapp PR. J. Org. Chem. 1973;38:1433–1434. [Google Scholar]
- 3.Schenck HA, Lenkowski PW, Mukherjee IC, Kob SH, Stables JP, Patel MK, Brown ML. Bioorg. Med. Chem. 2004;12:979–993. doi: 10.1016/j.bmc.2003.12.011. [DOI] [PubMed] [Google Scholar]; (b) Kuduk SD, Chang RK, DiPardo RM, Di Marco CN, Murphy KL, Ransom RW, Reiss DR, Tang C, Prueksaritanont T, Pettibone DJ, Bock MG. Bioorg. Med. Chem. Lett. 2008;18:5107–5110. doi: 10.1016/j.bmcl.2008.07.126. [DOI] [PubMed] [Google Scholar]
- 4 (a).Banfi L, Riva R. Organic Reactions. 2005;65:1–141. [Google Scholar]; (b) Domling A, Ugi I. Angew Chem. Int. Ed. 2000;39:3168–3210. doi: 10.1002/1521-3773(20000915)39:18<3168::aid-anie3168>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
- 5 (a).Yue T, Wang M-X, Wang D-X, Masson G, Zhu J. Angew. Chem. Intl. Ed. 2009;48:6717–21. doi: 10.1002/anie.200902385. [DOI] [PubMed] [Google Scholar]; (b) Yue T, Wang MX, Wang DX, Masson G, Zhu J. J. Org. Chem. 2009;74:8396–8399. doi: 10.1021/jo9017765. [DOI] [PubMed] [Google Scholar]; (c) Mihara H, Xu Yingjie, Shepherd NE, Matsunaga S, Shibasaki M. J. Am. Chem. Soc. 2009;131:8384–8385. doi: 10.1021/ja903158x. [DOI] [PubMed] [Google Scholar]; (d) Wang S, Wang M-X, Wang D-X, Zhu J. Eur. J. Org. Chem. 2007;24:4076–4080. [Google Scholar]; (e) Wang S-X, Wang M-X, Wang D-X, Zhu J. Org. Lett. 2007;9:3615–3618. doi: 10.1021/ol7014658. [DOI] [PubMed] [Google Scholar]; (f) Denmark SE, Bui T. J. Org. Chem. 2005;70:10190–10193. doi: 10.1021/jo0517500. [DOI] [PubMed] [Google Scholar]; (g) Denmark SE, Fan Y. J. Am. Chem. Soc. 2003;125:7825–7827. doi: 10.1021/ja035410c. [DOI] [PubMed] [Google Scholar]; (h) Seebach D, Adam G, Gees T, Schiess M, Weigand W. Chem. Ber. 1988;121:507–17. [Google Scholar]; (i) Hagedorn I, Eholzer U. Chem. Ber. 1965;98:936–940. doi: 10.1002/cber.19650980125. (i) [DOI] [PubMed] [Google Scholar]
- 6 (a).Nicolaou KC, Natarajan S, Li H, Jain NF, Hughes R, Solomon ME, Ramanjulu JM, Boody CNC, Takayanagi M. Angew. Chem. Int. Ed. 1998;37:2708. doi: 10.1002/(SICI)1521-3773(19981016)37:19<2708::AID-ANIE2708>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]; (b) Nicolaou KC, Li H, Boody CNC, Ramanjulu JM, Yue TY, Natarajan S, Chu XJ, Brase S, Rubsam F. Chem. Eur. J. 1999;5:2584. [Google Scholar]; (c) Tan YL, White AJP, Widdowson DA, Wilhelm R, Williams DJ. J. Chem. Soc. Perkin Trans 1. 2001:3269. [Google Scholar]
- 7 (a).Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. Bioorg. Med. Chem. Lett. 2009;19:2129–2132. doi: 10.1016/j.bmcl.2009.03.007. [DOI] [PubMed] [Google Scholar]; (b) Wozniack AA, Cyranski MK, Zubrowska A, Sporzynski A. J. Organomet. Chem. 2009;694:3533–3541. [Google Scholar]; (c) Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MRK, Sanders V, Plattner JJ. J. Med. Chem. 2006;49:4447–4450. doi: 10.1021/jm0603724. [DOI] [PubMed] [Google Scholar]