Letter pubs.acs.org/OrgLett
Highly Selective Synthesis of Dihydrobenzo[d]isoxazoles and Dihydrobenzo[d]oxazoles from Oximes and Arynes via in Situ Generation of Nitrones Tuanli Yao,* Beige Ren, Bo Wang, and Yanna Zhao College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, 6 Xuefu Road, Weiyang District, Xi’an, Shaanxi 710021, China S Supporting Information *
ABSTRACT: An efficient method for the synthesis of dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles bearing a quaternary carbon center has been developed. The reaction involves generation of a ketonitrone intermediate in situ from a ketoxime and an aryne. A novel thermal rearrangement of the dihydrobenzo[d]isoxazole products to the corresponding dihydrobenzo[d]oxazoles has been observed. These transformations tolerate a variety of functional groups and offer a rapid and efficient way to diverse dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles under mild transition-metal-free conditions.
Scheme 1. Synthesis of Dihydrobenzo[d]isoxazoles and Dihydrobenzo[d]oxazoles
1,3-Dipolar cycloaddition reaction (1,3-DC) is a powerful route for the synthesis of heterocycles.1 Nitrones are valuable synthetic intermediates since their 1,3-DC reactions with alkenes and alkynes afford versatile isoxazolidine and isoxazoline products.2 The most common methods for the preparation of nitrones include condensation of aldehydes/ketones with N-substituted hydroxylamines,3 oxidation of N,N-disubstituted amines,4 hydroxylamines5 and imines,6 fragmentation of N-hydroxyamino sulfonates,7 N-alkylation of O-trimethylsilyl oximes,8 and addition of N-benzylhydroxyl amine to dialkyl acetylenedicarboxylates.9 Arynes generated from o-silylaryl triflates10a and hexadehydro Diels−Alder reactoins10b have been employed extensively in recent years for the construction of a wide range of heterocycles.11 The 1,3-DC reaction of arynes with nitrones has been reported, which afforded dihydrobenzo[d]isoxazoles.12 In these previous studies, aldehyde nitrones prepared by the aforementioned methods were applied, and very few ketonitrones have been examined (Scheme 1). To continue with our interest in aryne chemistry,13 we envisioned that a nitrone intermediate might be generated in situ from an oxime and an aryne, and a subsequent [3 + 2] cycloaddition with a second equivalent of the aryne would produce the dihydrobenzo[d]isoxazole product (Scheme 1). Aryne serves as both an electrophile11b and a proton acceptor for the oxime during the generation of the nitrone. The overall reaction involves a one-pot, two-step procedure for the synthesis of dihydrobenzo[d]isoxazoles. This strategy is pretty challenging since oximes can be both O-nucleophiles14 and N-nucleophiles.15 O-Arylation of oximes could be a potential competing reaction.16 Dihydrobenzo[d]isoxazoles are not only an important subunit in pharmaceuticals with various biological activities17 but also an important intermediate for the synthesis of complex mole© 2017 American Chemical Society
cules.12b Herein, we report a novel method for the synthesis of dihydrobenzo[d]isoxazoles bearing a quaternary carbon center under mild transition-metal-free conditions, which involves generation of a ketonitrone intermediate in situ from a ketoxime and an aryne. The observation of a novel thermal rearrangement of the dihydrobenzo[d]isoxazole products led to the development of a one-pot synthesis of dihydrobenzo[d]oxazoles from ketoximes and arynes. We commenced our study by briefly optimizing this aryneinduced one-pot reaction using (E)-1-phenylethan-1-one oxime (1a) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) (Supporting Information, Table 1). The “optimized Received: April 26, 2017 Published: May 31, 2017 3135
DOI: 10.1021/acs.orglett.7b01260 Org. Lett. 2017, 19, 3135−3138
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Organic Letters
oxazoles on the basis of their 1H NMR spectra. The methyl group on the quaternary carbon of dihydrobenzo[d]isoxazoles exhibits a single peak at 1.57−1.70 ppm, while in dihydrobenzo[d]oxazoles the peak of methyl group is observed at 1.98−2.04 ppm. Only trace of 3a was observed when changing the solvent to toluene, DMF, or THF, and most of 1a was recovered. The generality and efficiency of this method were studied (Table 1). Oxime 1a possessing a p-methylphenyl group afforded dihydrobenzo[d]isoxazole 3a in a good yield and selectivity. The structure of 3a was confirmed by X-ray crystallography. This reaction is very sensitive to electronic effects. Without the paramethyl on the phenyl group, 3b was produced along with dihydrobenzo[d]oxazole 3b′ in a less selective 13:1 ratio, and the reaction was not completed after 5 h (entry 2). Replacing the pmethyl with an electron-withdrawing ester group or an electrondonating methoxyl group led to lower yields and selectivity (entries 3 and 4). The selectivity was improved when performing the reaction at 0 °C, which also slowed down the reaction rate (entry 5). Interestingly, when an iodide is on the ortho position of the phenyl, this chemistry showed excellent selectivity (entry 7). The steric effect of bulky o-iodide on the phenyl group prevented the thermal rearrangement of 3f, thus improving the selectivity of the reaction (see Scheme 3). Oximes bearing a thienyl (3h) or a naphthyl (3i) group also worked in this chemistry (entries 9 and 10). The steric effect of substituents on the carbon of the oxime double bond is not significant since congested 3,3-diaryl dihydrobenzo[b]isoxazoles can be efficiently prepared by this method, and better selectivity could be achieved when performing the reaction at 10 °C (entries 11−16). 3,3-Dialkyl dihydrobenzo[b]isoxazole 3n was prepared in a moderate yield with excellent selectivity (entry 17). Unfortunately, phenyl aldehyde oxime did not work in this chemistry, and the reaction was messy. The “optimized conditions” for the one-pot synthesis of dihydrobenzo[d]oxazoles 3′ from ketoximes and arynes employed 0.25 mmol of ketoxime 1, 2.2 equiv of silylaryl triflate 2, and 3.0 equiv of CsF in 5 mL of MeCN at 80 °C for 1 h, which produced 97% of 3a′ as the only product (Supporting Information, Table 1). Oximes with a variety of functional groups such as ester, amide, methoxy, halogen, and nitro group are all well tolerated (Table 2, entries 1−13). The structure of 3a′ and 3i′ was confirmed by X-ray crystallography. All reactions showed good to excellent selectivity except entry 10 in which the bulky o-iodide on the phenyl group slowed down the thermal rearrangement of 3f (see Scheme 3). The oxime with a thienyl group produced a 0.8:1 mixture of 3h′ and 3h in a moderate overall yield (entry 14). No known [4 + 2] cyclization reaction between aryne and thiophene occurred under these reaction conditions.18 Oximes bearing a naphthyl or ethyl group also worked well in this chemistry (entries 15 and 16). 2,2-Diphenyldihydrobenzo[b]oxazoles were prepared as the only product in good to excellent yield (entries 17− 20). The reaction of unsymmetrical 3-methoxy benzyne showed excellent selectivity, and only product 3u′ was obtained in an 83% yield (entry 21). Unfortunately, aldehyde oximes such as phenyl aldehyde oxime did not work in this method, and only the Oarylation product of the oxime was observed (not shown). The thermal rearrangement of 3,3-disubstituted dihydrobenzo[b]isoxazole 3a to dihydrobenzo[b]oxazole 3a′ was examined by 1H NMR (Scheme 2). Compound 3a was converted to 3a′ almost quantitatively at 40 °C over 5 h. The same rearrangement can occur in other solvents such as MeCN and THF. To the best of our knowledge, this structural rearrangement is unprecedented.
Table 1. Synthesis of Dihydrobenzo[d]isoxazolesa
a All reactions were run using 1 (0.25 mmol), 2 (0.75 mmol), and CsF (1.0 mmol) in 5 mL of acetonitrile for 5 h. bThe ratio of 3 to 3′ was determined by H NMR. cIsolated overall yield. d36% of oxime 1b was recovered. e45% of oxime 1h was recovered. f46% of oxime 1i was recovered. gThe ratio of 3j to 3j′ could not be determined by 1H NMR. h54% of oxime 1k was recovered.
conditions” for the synthesis of dihydrobenzo[b]isoxazoles employed 0.25 mmol of ketoxime 1a, 3.0 equiv of silylaryl triflate 2a, 4.0 equiv of CsF in 5 mL of MeCN at 10 °C for 5 h, which afforded an 85% isolated yield of 3-methyl-2,3-diphenyl-2,3dihydrobenzo[d]isoxazole (3a). A small amount of a side-product was observed in 1H NMR, which later was identified as dihydrobenzo[d]oxazole 3a′. The dihydrobenzo[d]isoxazoles can be distinguished from the corresponding dihydrobenzo[d]3136
DOI: 10.1021/acs.orglett.7b01260 Org. Lett. 2017, 19, 3135−3138
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a
All reactions were run using 1 (0.25 mmol), 2 (0.55 mmol), and CsF (0.75 mmol) in 5 mL of MeCN for 1 h. bThe ratio was determined by 1H NMR. cIsolated yield. dThe reaction time was 5 h.
Scheme 2. Thermal Rearrangement of 3a to 3a′ Monitored by 1 H NMR
Scheme 3. Proposed Mechanism
When the reaction was carried out in the presence of 10 equiv of D2O, 70% of deuteration on the ortho position of N-phenyl group was observed in 1H NMR, which supports the nucleophilic attack of nitrogen atom of oxime to aryne (eq 1). We propose a mechanism for this process, which is illustrated in Scheme 3. Aryne I, which is generated by the 1,2-elimination of silylphenyl triflate 2a, reacts as an electrophile16,19 with nitrogen
atom of oxime 1. Then the carbanionic center in the intermediate II abstracts a proton from the hydroxyl group to form nitrone III. [3 + 2] Cycloaddition between nitrone III and a second 3137
DOI: 10.1021/acs.orglett.7b01260 Org. Lett. 2017, 19, 3135−3138
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(4) (a) Zajac, W. W., Jr.; Walters, T. R.; Darcy, M. G. J. Org. Chem. 1988, 53, 5856. (b) Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954. (c) Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 2003, 70, 265. (d) Goti, A.; Cardona, F.; Soldaini, G. Org. Synth. 2005, 81, 204. (5) (a) Cicchi, S.; Corsi, M.; Goti, A. J. Org. Chem. 1999, 64, 7243. (b) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42, 6503. (6) Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473. (7) Van Hijfte, L.; Little, R. D. J. Org. Chem. 1985, 50, 3940. (8) LeBel, N. A.; Balasubramanian, N. Tetrahedron Lett. 1985, 26, 4331. (9) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10, 4493. (10) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211. (b) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208. (11) For reviews of aryne chemistry, see: (a) Chen, Y.; Larock, R. C. In Modern Arylation Methods; Ackerman, J., Ed.; Wiley/VCH: New York, 2009; pp 401−473. (b) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (c) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (d) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (e) Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199. (f) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (g) Wu, C.-R.; Shi, F. Asian J. Org. Chem. 2013, 2, 116. (h) Gampe, C. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3766. (i) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (j) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed. 2006, 45, 3579. (k) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725. (12) (a) Wu, Q.; Li, B.; Lin, W.; Shi, C.; Chen, Y.; Chen, Y. Hecheng Huaxue 2007, 15, 292. (b) Dai, M.; Wang, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6613. (c) Wu, K.; Chen, Y.; Lin, Y.; Cao, W.; Zhang, M.; Chen, J.; Lee, A. W. M. Tetrahedron 2010, 66, 578. (d) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77, 2279. (e) Okuma, K.; Hirano, K.; Shioga, C.; Nagahora, N.; Shioji, K. Bull. Chem. Soc. Jpn. 2013, 86, 615. (f) Khangarot, R. K.; Kaliappan, K. P. Eur. J. Org. Chem. 2012, 2012, 5844. (g) Li, P.; Wu, C.; Zhao, J.; Li, Y.; Xue, W.; Shi, F. Can. J. Chem. 2013, 91, 43. (13) (a) Yao, T. Tetrahedron Lett. 2015, 56, 4623. (b) Yao, T.; Zhang, H.; Zhao, Y. Org. Lett. 2016, 18, 2532. (c) Yao, T.; He, D. Org. Lett. 2017, 19, 842. (14) Selected examples for oximes as O-nucleophiles, see: (a) Kontokosta, D.; Mueller, D. S.; Wang, H. Y.; Anderson, L. L. Org. Lett. 2013, 15, 4830. (b) Cao, Z. P.; Liu, Z. Q.; Liu, Y. L.; Du, H. F. J. Org. Chem. 2011, 76, 6401. (c) Ngwerume, S.; Lewis, W.; Camp, J. E. J. Org. Chem. 2013, 78, 920. (15) Selected examples for oximes as N-nucleophiles, see (a) Peng, X. G.; Tong, B. M. K.; Hirao, H. J.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 1959. (b) Shi, Z. Z.; Koester, D. C.; Boultadakis-Arapinis, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 12204. (c) Yeom, H. S.; Lee, Y.; Lee, J. E.; Shin, S. Org. Biomol. Chem. 2009, 7, 4744. (d) Flores, M. A.; Bode, J. W. Org. Lett. 2010, 12, 1924. (e) Mo, D. L.; Wink, D. A.; Anderson, L. L. Org. Lett. 2012, 14, 5180. (f) Peacock, L. R.; Chapman, R. S. L.; Sedgwick, A. C.; Mahon, M. F.; Amans, D.; Bull, S. D. Org. Lett. 2015, 17, 994. (16) (a) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99. (b) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198. (17) (a) Raut, A. W.; Doshi, A. G.; Raghuwanshi, R. B. Orient. J. Chem. 1998, 14, 363 and references therein. (18) Reinecke, M. G.; Del Mazza, D.; Obeng, M. J. Org. Chem. 2003, 68, 70. (19) Swain, S. P.; Shih, Y.-C.; Tsay, S.-C.; Jacob, J.; Lin, C.-C.; Hwang, K. C.; Horng, J.-C.; Hwu, J. R. Angew. Chem., Int. Ed. 2015, 54, 9926. (20) For rearrangement of 2,3-dihydroisoxazoles involving an aziridine intermediate, see: (a) Freeman, J. P. Chem. Rev. 1983, 83, 241. (b) Liguori, A.; Ottana, R.; Romeo, G.; Sindona, G.; Uccella, N. Tetrahedron 1988, 44, 1255. (c) Mullen, G. B.; Bennett, G. A.; Georgiev, V. S. Liebigs Ann. Chem. 1990, 1990, 109. (d) Tsuge, O.; Torii, A. Bull. Chem. Soc. Jpn. 1976, 49, 1138. (e) Friebolin, W.; Eberbach, W. Tetrahedron 2001, 57, 4349.
equivalent of the aryne I produces dihydrobenzo[d]isoxazole 3. The rearrangement of 3 is initiated by thermal NO-cleavage, and subsequent rebonding affords spiral aziridine V.20 The NOcleavage can be either a radical fission (pathway a) or an ionic fission (pathway b). V reacts further by ring opening to generate iminium VI. Intramolecular insertion of phenoxide into iminium generates dihydrobenzo[d]oxazole 3′. The thermal rearrangement of 3a has been carried out in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, 15.0 equiv). Compound 3a′ was still formed in a good yield, and no TEMPO-radical adduct was detected. Thus, pathway b is favored at the time being. We could not exclude the possibility of pathway a since the intramolecular free radical reaction might proceed very fast. In conclusion, a new and efficient method for the synthesis of various dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles from oximes and 2-(trimethylsilyl)aryl triflates has been developed, which involves in situ generation of nitrones from ketoximes and arynes. The dihydrobenzo[d]isoxazole products can be converted to corresponding dihydrobenzo[d]oxazoles through a novel thermal rearrangement. These tandem transformations offer a diverse dihydrobenzo[d]isoxazoles and dihydrobenzo[d]oxazoles scaffolds under mild transition-metalfree conditions in good to excellent yields.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01260. Detailed experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for all previously unknown products (PDF) Crystallographic data for 3a (CIF), 3j (CIF), 3a′ (CIF), and 3i′ (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Tuanli Yao: 0000-0003-2905-6596 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Shaanxi University of Science and Technology for financial support of this research (BJ15-33). REFERENCES
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DOI: 10.1021/acs.orglett.7b01260 Org. Lett. 2017, 19, 3135−3138
