A Catalytic Enantioselective Iodocyclization Route to Dihydrooxazines

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Catalytic Enantioselective Iodocyclization Route to Dihydrooxazines Rahul Suresh,⊥ Amit Kumar Simlandy,⊥ and Santanu Mukherjee* Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India S Supporting Information *

ABSTRACT: The first catalytic enantioselective synthesis of 5,6-dihydro-4H-1,2-oxazines bearing an oxygen-containing quaternary stereogenic center has been developed through iodoetherification of γ,δ-unsaturated oximes. This operationally straightforward reaction is catalyzed by Cinchona alkaloids-based bifunctional tertiary aminothiourea derivatives and furnishes the products generally in good to excellent yields and with moderate to high enantioselectivities (up to 97:3 er).

E

Scheme 1. Synthesis of 5,6-Dihydro-4H-1,2-oxazines

nantioselective construction of nitrogenous heterocycles containing a quaternary stereogenic center has always been appealing to synthetic chemists, because of their presence in natural products and bioactive targets.1 In addition, such heterocycles are often used as intermediates to highly functionalized building blocks.2 In this regard, tremendous progress has been made toward the synthesis of five-membered nitrogenous heterocycles such as isoxazolines.3 In contrast, its congener 5,6dihydro-4H-1,2-oxazines (Scheme 1A) are largely overlooked, because of the nonavailability of convenient synthetic methods. This six-membered cyclic oxime ether is of great synthetic importance as it can easily be transformed to pyrrolidines, pyrroles, 1,4-amino alcohols, 1,4-diketones, and furan derivatives, which, in turn, found applications in the synthesis of unnatural amino acids, amino sugars, pheromones, complex natural products, and pharmaceutically active agents.4 Strategies allowing access to this heterocycle are limited. [4 + 2]-Cycloaddition reaction between nitrosoalkenes and electronrich alkenes constitutes a seemingly simple route to 5,6-dihydro4H-1,2-oxazines (Scheme 1A).5 Jørgensen et al. developed the first catalytic inverse-electron demand hetero-Diels−Alder reaction of nitrosoalkenes using pyrrolidine and its derivative as catalysts.6 Besides low enantioselectivity, the instability of nitrosoalkenes, as well as regioselectivity issues, are some of the limitations of this approach. Intramolecular cyclization of γelectrophilic oximes is a relatively less-explored strategy to 5,6dihydro-4H-1,2-oxazines (Scheme 1A)7 and has not been applied for their enantioselective synthesis. Consequently, catalytic enantioselective synthesis of this heterocycle bearing an oxygen-containing quaternary stereocenter remain unknown to date. In order to address this issue, we thought of exploiting the intramolecular cyclization strategy with γ,δ-unsaturated oximes through the in situ generation of a γ-electrophilic center using an electrophilic halogenating agent (Scheme 1B). Electrophilic © XXXX American Chemical Society

halogen-induced reactions of this type have been established as a reliable method for enantioselective trans-heterodifunctionalization of unactivated alkenes during the past few years.8,9 Development of a wide range of catalytic strategies has enabled the control of absolute stereochemistry in such reactions. We recognized that successful implementation of this strategy would deliver 5,6-dihydro-4H-1,2-oxazines having an oxygen-containing quaternary stereocenter and an additional halogen handle for further manipulation. The purpose of this report is to present the first catalytic enantioselective synthesis of 5,6-dihydro-4H-1,2-oxazines bearing an oxygen-containing quaternary stereogenic center.10,11a Building on our previous works,11 we relied on the use of bifunctional tertiary aminothiourea derivative12 as a catalyst for the proposed iodoetherification of γ,δ-unsaturated oximes. A combination of Lewis basic sulfur and Brønsted basic tertiary Received: January 1, 2018

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DOI: 10.1021/acs.orglett.8b00002 Org. Lett. XXXX, XXX, XXX−XXX

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significantly, depending on the method of purification. In addition, the er of the unpurified (crude) product was found to be different from various fractions obtained from column chromatography on silica gel, especially using a less-polar eluent. For example, the crude product 3a with 93:7 er, when subjected to gravity-driven silica gel column chromatography, furnished an enantiomerically depleted sample (with 83:17 er) of 3a in the first fractions and an enantiomerically enriched sample (with 97:3 er) of 3a in the last fractions. However, combination of all these fractions led to the isolation of pure 3a with er identical to that of crude 3a (93:7 er). These observations clearly indicate that the self-disproportionation of enantiomers (SDE)14 is the reason behind this anomalous behavior. Fortunately, this anomaly could be avoided with rapid chromatographic purification, using a more-polar eluent, and consistent er was observed during various stages of purification. Sublimation is another technique often employed for testing SDE.14 In our case, prolonged exposure of the product under vacuum showed neither any enrichment nor depletion of its er. Equipped with the SDE-free purification protocol, optimization of reaction conditions was continued. The introduction of a catalytic amount (1 mol %) of molecular iodine was found to have a small yet positive effect on the outcome of the reaction (Table 1, entry 4).9l Similarly, molecular sieves proved to be beneficial and 4 Å MS afforded the product with excellent yield and enantioselectivity (Table 1, entry 6). Further enhancement of the er was possible by changing the reaction medium to 1:1 tert-butylbenzene (t-BuPh) and CH2Cl2 (Table 1, entry 8). The efficiency of other thiourea derivatives II−IV was also tested. While catalysts II and III were found to be equally effective as I, our previously developed catalyst IV11a did not provide any additional benefit (Table 1, entries 9−11). Eventually, cinchonidine-derived thiourea II was selected for subsequent studies, considering its lower molecular weight and ease of preparation. Conducting the reaction at higher dilution did not offer any improvement in er (Table 1, entry 12). Interestingly, the reaction with the model substrate 1a, when performed in CH2Cl2 under otherwise standard reaction conditions, afforded the product 3a with the same level of yield and enantioselectivity (Table 1, entry 13). This late-stage development opened up the possibility of applying these modified reaction conditions to substrates that are less soluble and/or fared inefficiently in 1:1 tBuPh/CH2Cl2 (vide infra). Having identified the optimum catalyst and reaction conditions (Table 1, entry 9 or 13), we subjected various 1,4disubstituted γ,δ-unsaturated (E)-oximes to explore the generality of our newly developed protocol for the enantioselective synthesis of 5,6-dihydro-4H-1,2-oxazines. As depicted in Table 2, para- and meta-substituted aryl groups on the olefin were welltolerated and the products (3b−3d) were formed in high yields and generally with good to excellent enantioselectivities. Several γ,δ-unsaturated oximes bearing sterically and electronically modified aryl substituents on the oxime carbon were tested and furnished the products (3f−3n) usually in excellent yields with moderate to good er. Similarly, the product (3o) containing a heteroaryl group on the oxime carbon could be synthesized in near quantitative yield with 95:5 er. Although oximes bearing an aliphatic substituent on olefin (1p and 1q) underwent smooth iodocyclization, the products (3p and 3q) were obtained with moderate er. However, er of 3p could be significantly enriched through a single recrystallization. In addition to 3p, in most cases, a single recrystallization furnished the products with highly enantioenriched, if not in virtually enantiopure, form. Please

Table 1. Catalyst Evaluation and Reaction Conditions Optimizationa

a

Reactions were performed using 1.0 equiv of 1a and 1.6 equiv of 2 on a 0.05 mmol scale. bYields correspond to the isolated yield. cEnantiomeric ratio (er), as determined by HPLC analysis using a stationary phase chiral column (see the Supporting Information). dReaction with 1.0 mol % I2. eReaction with 50 mg molecular sieves (MS). f Reaction at an initial concentration of 0.01 M.

amine was reasoned to activate the electrophilic iodinating agent and the hydroxyl group of oxime, respectively, while anionbinding catalysis13 by thiourea was surmised to be crucial in discriminating the two equilibriating enantiomeric iodiranium cations (Scheme 1B). Accordingly, our initial attempts to effect this iodocyclization reaction were focused on using thioureas derived from Cinchona alkaloids (I−IV) as the catalyst (Table 1). For the purpose of optimizing the reaction conditions, we chose 1,4-diphenylsubstituted γ,δ-unsaturated (E)-oxime 1a as the model substrate and commercially available N-iodosuccinimide (NIS, 2) as the electrophilic iodine source. Our earlier studies11 revealed the polarity of the reaction medium as an important parameter for obtaining a high level of enantioselectivities in iodocyclization reactions, and a mixture of solvents proved to be the best. Fortunately, no product formation was observed when the reaction was conducted in a 4:1 mixture of toluene and CH2Cl2 at −80 °C in the absence of any catalyst (Table 1, entry 1). Under the same conditions, 10 mol % of quinine-derived thiourea I furnished the desired 5,6-dihydro-4H-1,2-oxazine derivative 3a in near quantitative yield and with moderate enantiomeric ratio (er) (Table 1, entry 2). To our delight, a drastic enhancement in enantioselectivity was observed upon changing the reaction medium to 1:1 toluene/CH2Cl2 and 3a was formed with 93:7 er (Table 1, entry 3). Here, it must be mentioned that, during the initial stage of reaction optimization, we found the product er to vary B

DOI: 10.1021/acs.orglett.8b00002 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. (A) Large-Scale Experiment and (B) Synthesis of Enantiomeric Dihydrooxazine

Scheme 3. Synthetic Transformations Involving 3a

a

Unless stated otherwise, reactions were carried out on a 0.1 mmol scale. Yields correspond to the isolated yield. b Enantiomeric ratio (er) was determined by HPLC analysis using a stationary phase chiral column (see the Supporting Information). Values in parenthesis indicate er of the product after a single recrystallization.cReaction in CH2Cl2. dReaction on a 0.05 mmol scale.eYield based on reactive oxime isomer.

note that, in cases where the standard reaction conditions (Table 1, entry 9) failed to deliver the products with reasonable yield and/or er, the reactions were carried out in CH2Cl2. Absolute configuration of 3a was unambiguously determined by single-crystal X-ray diffraction analysis and found to be R (Scheme 2A). The configurations of the remaining examples were tentatively assigned by analogy as the same. To showcase the scalability and practicality of our protocol, the iodocyclization of 1a was carried out at a scale 10 times greater than that used for studying the substrate scope (Scheme 2A). The product 3a was obtained in near quantitative yield without any chromatographic purification15 with slightly diminished enantioselectivity, compared to small-scale experiments. For reactions catalyzed by Cinchona alkaloids or their derivatives, accessing both the product enantiomers with the same level of enantioselectivity remains a challenge due to the nonavailability of the respective enantiomeric alkaloids.16 We were pleased to find that, using cinchonine-derived thiourea V as the catalyst, the enantiomeric 5,6-dihydro-4H-1,2-oxazine derivative ent-3a could be obtained in 82% yield and with 95.5:4.5 er (Scheme 2B). With access to both product antipodes and scale-up feasibility tested, we turned our attention to the elaboration of this synthetically useful nitrogenous heterocycle. Appended with an excellent leaving group, these dihydrooxazine derivatives are obvious targets for nucleophilic displacement reactions. For example, treatment of 3a with thiophenol and sodium azide in DMF resulted in the corresponding thioether 4 and azide derivative 5, respectively, in good yields (Scheme 3). The azide 5 was transformed to Boc-protected amine 6 through a one-pot two-step reaction sequence. Reductive deiodination of 3a under hydrogenation conditions furnished 7 in excellent yield. Global

reduction of 7 with LiAlH4 generated 1,4-amino alcohol, which was isolated after Boc-protection in 56% overall yield. The modest diastereoselectivity of the reduction step notwithstanding, this and all other transformations proceeded without any loss of enantiopurity. Encouraged by the successful implementation of the iodocyclization strategy for the synthesis of six-membered nitrogenous heterocycle 5,6-dihydro-4H-1,2-oxazine, we wondered whether the seven-membered rings can be constructed under similar conditions.17 Exposure of related 1,5-diphenyl substituted δ,ε-unsaturated (E)-oxime 9 to similar reaction conditions indeed furnished the desired seven-membered heterocycle 4,5,6,7-tetrahydro-1,2-oxazepine 10 in high yield, albeit with poor er (Scheme 4). Scheme 4. Synthesis of Tetrahydrooxazepine

In summary, the first catalytic enantioselective synthesis of dihydrooxazines bearing an oxygen-containing quaternary stereogenic center has been developed. This operationally straightforward approach feeds on easily accessible γ,δunsaturated oximes and makes use of electrophilic iodineinduced cyclization reaction to deliver 5,6-dihydro-4H-1,2oxazines generally in good to excellent yields and with moderate C

DOI: 10.1021/acs.orglett.8b00002 Org. Lett. XXXX, XXX, XXX−XXX

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(4) (a) Sukhorukov, A. Y.; Ioffe, S. L. Chem. Rev. 2011, 111, 5004. (b) Tsoungas, P. G. Heterocycles 2002, 57, 915. (5) (a) Gaonkar, S. L.; Rai, K. M. L. J. Heterocycl. Chem. 2005, 42, 877. (b) Zimmer, R.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1988, 27, 1518. (c) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Chem. Commun. 1976, 581. (6) Wabnitz, T. C.; Saaby, S.; Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 828. (7) (a) Karapetyan, V.; Mkrtchyan, S.; Dang, T. T.; Villinger, A.; Reinke, H.; Langer, P. Tetrahedron 2008, 64, 8010. (b) Chaminade, X.; Chiba, S.; Narasaka, K.; Dunach, E. Tetrahedron Lett. 2008, 49, 2384. (c) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Purgatorio, V.; Temperini, A.; Marini, F.; Santi, C. Tetrahedron: Asymmetry 2001, 12, 3297. (d) Ali Dondas, H.; Grigg, R.; Hadjisoteriou, M.; Markandu, J.; Kennewell, P.; Thornton-Pett, M. Tetrahedron 2001, 57, 1119. (8) For reviews, see: (a) Wolstenhulme, J. R.; Gouverneur, V. Acc. Chem. Res. 2014, 47, 3560. (b) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. Org. Biomol. Chem. 2014, 12, 2333. (c) Tripathi, C. B.; Mukherjee, S. Synlett 2014, 25, 163. (d) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938. (e) Hennecke, U. Chem. - Asian J. 2012, 7, 456. (f) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 2011, 1335. (9) For selected examples, see: (a) Arai, T.; Watanabe, O.; Yabe, S.; Yamanaka, M. Angew. Chem., Int. Ed. 2015, 54, 12767. (b) Shen, Z.; Pan, X.; Lai, Y.; Hu, J.; Wan, X.; Li, X.; Zhang, H.; Xie, W. Chem. Sci. 2015, 6, 6986. (c) Hu, D. X.; Seidl, F. J.; Bucher, C.; Burns, N. Z. J. Am. Chem. Soc. 2015, 137, 3795. (d) Toda, Y.; Pink, M.; Johnston, J. N. J. Am. Chem. Soc. 2014, 136, 14734. (e) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.; Ishihara, K. Angew. Chem., Int. Ed. 2014, 53, 6974. (f) Tripathi, C. B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52, 8450. (g) Huang, D.; Liu, X.; Li, L.; Cai, Y.; Liu, W.; Shi, Y. J. Am. Chem. Soc. 2013, 135, 8101. (h) Brindle, C. S.; Yeung, C. S.; Jacobsen, E. N. Chem. Sci. 2013, 4, 2100. (i) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch, P. M.; Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134. (j) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681. (k) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174. (l) Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 7332. (m) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474. (n) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298. (10) For selected examples of enantioselective construction of oxygencontaining quaternary stereogenic center, see: (a) Zeng, X.-P.; Zhou, J. J. Am. Chem. Soc. 2016, 138, 8730. (b) Simlandy, A. K.; Mukherjee, S. Org. Biomol. Chem. 2016, 14, 5659. (c) Kumar, V.; Mukherjee, S. Chem. Commun. 2013, 49, 11203. (d) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964. Also see refs 8 and 9f. (11) (a) Tripathi, C. B.; Mukherjee, S. Org. Lett. 2015, 17, 4424. (b) Tripathi, C. B.; Mukherjee, S. Org. Lett. 2014, 16, 3368. Also see ref 9f. (12) For a pioneering contribution, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. For selected reviews, see: (b) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298. (c) Connon, S. J. Chem. Commun. 2008, 2499. (13) (a) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534. (b) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518. (14) (a) Soloshonok, V. A.; Roussel, C.; Kitagawa, O.; Sorochinsky, A. E. Chem. Soc. Rev. 2012, 41, 4180. (b) Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766. (15) For details, see the Supporting Information. (16) For representative examples, see: (a) Ray Choudhury, A.; Mukherjee, S. Org. Biomol. Chem. 2012, 10, 7313. (b) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166. (17) (a) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492. (b) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.

to high enantioselectivities. Catalyzed by Cinchona alkaloidsbased bifunctional tertiary aminothiourea derivatives, both the product enantiomers can be synthesized with a similar level of er. Besides providing a facile enantioselective route to this longawaited six-membered heterocycle, preliminary experiments hold promise for the enantioselective synthesis of 4,5,6,7tetrahydro-1,2-oxazepines, which is a seven-membered cyclic oxime ether.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00002. Experimental details, characterization data, and crystallographic data (PDF) NMR spectra and HPLC chromatograms (PDF) Accession Codes

CCDC 1813636 and 1813637 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Rahul Suresh: 0000-0003-3423-713X Amit Kumar Simlandy: 0000-0002-8792-4825 Santanu Mukherjee: 0000-0001-9651-6228 Author Contributions ⊥

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is funded by SERB [Grant No. SB/S1/OC-63/ 2013]. A.K.S. thanks the CSIR for a doctoral fellowship. We wish to thank Mr. Rupak Saha (IPC, IISc, Bangalore) for his help with the X-ray structure analysis.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00002 Org. Lett. XXXX, XXX, XXX−XXX