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PhI(OAc)2-Mediated functionalisation of unactivated alkenes for synthesis of pyrazoline and isoxazoline derivatives Xiao-Qiang Hu, Guoqiang Feng, Jia-Rong Chen,* Dong-Mei Yan, Quan-Qing Zhao, Qiang Wei and Wen-Jing Xiao*
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A PhI(OAc)2-promoted radical cyclization of β,γ-unsaturated hydrazones and oximes have been developed for efficient synthesis of various valuable pyrazoline and isoxazoline derivatives with satisfactory yields (up to 96%) under mild conditions.
Introduction
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The functionalisation of unactivated alkenes represents one of the most powerful approaches for carbon–carbon and carbon– heteroatom bonds formation. Not surprisingly, over the past decades, considerable research efforts have been devoted into this field. Particularly, remarkable advances have been achieved in transition-metal-mediated (Pd, Ni, Cu, Au, Ti, Pt etc.) hydroamination, hydroxygenation, oxyamination, diamination and dioxygenation of alkenes.1 However, either the high cost or toxicity of the transition metals or the harsh reaction conditions largely restricted their applications in practical synthesis. The commercially available hypervalent iodine (III) reagents represent a type of powerful oxidants and have recently been widely used in various oxidation and metal-catalyzed coupling reactions.2 In this context, the hypervalent iodine (III) reagents have also been commonly used in difunctionalisation of unactivated carbon-carbon double bond via an iodonium ion intermidiate, which are directly generated by an alkene oxidation process (Scheme 1a).3 To our knowledge, exploration of hypervalent iodine (III) reagents in radical hydroamination and hydroxygenation of unactivated alkenes is still rare.4 Pyrazolines and isoxazolines represent two classes of biologically important five-membered nitrogen-containing heterocycles, which widely exist in many natural products, biologically active compounds and pharmaceuticals.5 These ring systems have often been utilised as chiral ligands in asymmetric catalysis.6 Typically, these heterocyclic scaffolds can be efficiently prepared via 1,3-dipolar cycloaddition reactions of nitrile oxides or nitrile imines with alkenes.7 However, there are still certain limitations associated with these methodologies, such as poor regioselectivity and limited substrate scope. Recently, β,γ-unsaturated hydrazones and oximes have been established as a family of versatile building blocks for assembly of diversely substituted pyrazoline and isoxazoline derivatives. Representative strategies include transition-metal salts (e.g., Co(III), Cu(II), Pd(II), etc.) catalyzed cyclization of β,γ-unsaturated oximes and hydrazones.8 On the other hand, developing metal-free variants This journal is © The Royal Society of Chemistry [year]
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has also recently attracted extensive attention. Mosher,9 Mukherjee10 and our group11 have independently reported the halocyclization reactions of β,γ-unsaturated oximes and hydrazones through a bromonium or iodonium ion intermediate to construct the corresponding pyrazoline and isoxazoline derivatives with high efficiency under mild reaction conditions. In addition, metal-free radical cyclization provided a potential platform for the transformation of β,γ-unsaturated hydrazones and oximes into valuable heterocycles. For instance, Han’s group has recently reported several elegant examples of radical cyclization of hydrazonyl or oxime radicals using stoichiometric amount of TEMPO or azodicarboxylates, providing the corresponding oxyamination, dioxygenation and diamination products (e.g., isoxazolines, pyrazolines and azomethine imines) in good yields.12 Very recently, our group developed a visible-lightinduced photocatalytic hydroamination and oxyamination of β,γunsaturated hydrazones 1 via a N-centered radical intermediate.13 In the process, however, the β,γ-unsaturated oximes proved to be not suitable probably due to the higher oxidation potential of oximes. Given the strong oxidizing potential of hypervalent iodine (III) reagents, we envisaged that the intramolecular radical cyclization of β,γ-unsaturated hydrazones 1 and oximes 3 via Nand O-centered radical intermediates might be achieved using such oxidants, such as PhI(OAc)2 (Scheme 1b). Herein, we wish to communicate our preliminary results.
Scheme 1. PhI(OAc)2-mediated alkene functionalisation.
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Initially, β,γ-unsaturated hydrazone 1a was selected as the model substrate with the use of K2CO3 as the base and PhI(OAc)2 (1.5 equiv) as the oxidant in CH2Cl2 to examine the feasibility of intramolecular hydroamination reaction. To our delight, the reaction proceeded smoothly without addition of any metal salts and the expected hydroamination product 2a was obtained in 11% yield (Table 1, entry 1). To further improve the reaction efficiency, the reaction media has been extensively investigated. As shown in Table 1, the yield of 2a can be increased to 26% by using PhMe as the solvent (Table 1, entry 2). Other solvents such as EtOAc, CH3CN and DMSO substantially decreased the reaction efficiency (Table 1, entries 4-6), while THF gave the best result with 2a being obtained in 48% yield (Table 1, entry 6). Then, a brief screen of organic bases identified the organic base DABCO to be the best base for this transformation, delivering 2a in 65% GC yield (Table 1, entries 10-14). A simple survey of commonly used oxidants showed that PhI(OAc)2 is still the best of choice. For example, PhI(CO2CF3)2 largely decreased the yield of 2a to 32% (Table 1, entry 15), while other strong oxidants such as MnO2, mCPBA and tBuO2H leading to decomposition of 1a or complex mixture (Table 1, entries 15-18).
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the aliphatic β,γ-unsaturated hydrazones also proved to be suitable for this reaction. A wide range of alkyl groups, such as View Article Online tert-butyl, isopropyl and cyclohexyl wereDOI: found to be well 10.1039/C5OB00029G accomodated, affording the desired products 2j-2l in 53-76% yields. In addition, phenylethyl group substituted hydrazone 1m also underwent this hydroamination process smoothly to give the desired product 2m in 61% yield with 1:1 dr. Moreover, the reactin with hydrazone 1n bearing germinal methyl groups at αposition also proceeded well to furnish the corresponding hydroamination product 2n in 32% yield. Gratifyingly, the reaction efficiency can be dramatically increased by changing the Ts group into Ms group. As a result, the desired products 2o-2q were obtained in satisfactory yields (Table 2, 73-92%). It should be noted that these products were only obtained in very low yields under our previously develped photocatalytic conditions (Table 2, 32-43%).13 Encouraged by these results, we surmised that such PhI(OAc)2-mediated hydroamination strategy might be also extended to other radical precursors, such as β,γ-unsaturated oximes. Table 2 Substrate scope of the hydroamination reaction of hydrazones a, b
Table 1 Optimization studies a
Ts HN
Entry 1
Oxidant PhI(OAc)2
Solvent CH2Cl2
Yield b (%) 11
toluene
Base K2CO3 K2CO3
2
PhI(OAc)2
3
PhI(OAc)2
EtOAc
K2CO3
11
4
PhI(OAc)2
DMSO
K2CO3
6
5
PhI(OAc)2
CH3CN
K2CO3
15
6
PhI(OAc)2
THF
K2CO3
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7
PhI(OAc)2
THF
Na2CO3
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8
PhI(OAc)2
THF
Cs2CO3
59
9
PhI(OAc)2
THF
Et3N
10 11
PhI(OAc)2
THF
DABCO
PhI(OAc)2
THF
DBU
R
26
Ts
Ts
Ts
N N
Ts
N N
N N
N N Ph
2j, 76%
2k, 64% Ts
N N
2l, 53% Ms
2m, 61% (dr = 1:1) Ms
Ms
N N
N N
N N
47 65 (61)
c
Cl
51 2n, 32%
53
2o, 79% PC: 32%
2p, 73% PC: 43%
2q, 92% PC: 42%
PhI(OAc)2
THF
TMG
13
PhI(OAc)2
THF
DMAP
trace
a
14
PhI(OAc)2
N-methylimidazole DABCO
trace 32
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2
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PhI(CO2CF3)2
THF THF
16
MnO2
THF
DABCO
trace
17
mCPBA
THF
DABCO
trace
18
t
BuOOH
THF
DABCO
trace b
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Determined by GC using biphenyl as internal standard. c Isolated yield.
With the optimal reaction conditions established, we firstly investigated the generality of the metal-free hydroamination reaction of β,γ-unsaturated hydrazones. As shown in Table 2, various electron-rich (Me, MeO) and electron-poor (F, Cl, Br, CF3) substituents at 2-, 3- or 4-positions of aromatic ring were well tolerated to give the corresponding products 2b-2i in moderate to good yields (Table 2, 54-65%). More importantly, 2 | Journal Name, [year], [vol], 00–00
Unless otherwise noted, reactions were carried out with 1 (0.3 mmol),
h. b Isolated yield. PC = photoredox catalysis. 13
Unless otherwise noted, reactions were carried out with 1a (0.2 mmol),
oxidant (0.3 mmol), base (0.4 mmol) in the solvent (2.0 mL) at 25 oC.
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2f, R = 4-Br, 58% 2g, R = 4-Cl, 54% 2h, R = 4-CF3, 56% 2i, R = 3-Br, 54%
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2a, R = H, 65% 2b, R = 4-Me, 61% 2c, R = 3-MeO, 59% 2d, R = 2-Cl, 60% 2e, R = 4-Cl, 54%
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Gratifyingly, the β,γ-unsaturated oximes also proved to be suitable for this transformation, while these substrates can’t be tolerated under our previously reported photocatalytic condition probably due to the higher oxidation potential of these oximes (Table 3). Under the standard reaction conditions, a wide range of oximes 3a-3i bearing electron-donating (Me, tBu, MeO) or electron-withdrawing (Cl, Br, F, CF3) groups at the phenyl ring proceeded smoothly to afford the corresponding isoxazolines 4a4i in generally good yields (Table 3, 57-94%). Thus, such metalfree hydroxygenation reaction provided a facile and alternative access to diverse biologically and synthetically valuable isoxazoline derivatives. This journal is © The Royal Society of Chemistry [year]
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Table 3 Substrate scope of the hydroxygenation reaction of oximes a, b 30
yields under the metal-free conditions. Furthermore, this methodology can be applied to the hydroxygenation and View Article Online dioxygenation of β,γ-unsaturated oximes DOI: for synthesis of various 10.1039/C5OB00029G biologically important isoxazolines. This reaction provides an alternative platform for the functionalisation of unactivated alkenes under metal-free conditions. Further studies toward the mechanism as well as enantioselective versions are ongoing in our laboratory.15
Experimental
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Unless otherwise noted, reactions were carried out with 3 (0.3 mmol),
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2 h. b Isolated yield.
Based on the proposed radical pathway (Scheme 1), N- and O-centered radical intermediates might be involved in the above processes. As such, this oxidative system might enable intermolecular oxyamination and dioxygenation of β,γunsaturated hydrazones and oximes (Table 4). As a proof of this concept, TEMPO was added as the oxygen radical source under the standard reaction conditions. To our delight, the oxyamination reaction of hydrazones 1 proceeded smoothly to give the desired products 5a and 5b in 52% and 46% yield, respectively. Moreover, the dioxygenation of β,γ-unsaturated oximes 3 also reacted smoothly to furnish the dioxygenation products 6a-6c with excellent yields (94-96%).14 It is worth noting that the N-O bond of products can be easily cleaved to afford the biologically important alcohols under the reductive condition.13
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Table 4 Substrate scope of the oxyamination and dioxygenation a, b
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Ts
Ms
N N t
Bu
O N
5a, 52% a
N O
N N Ph
R O N
5b, 46%
General procedure for preparation of β,γ-unsaturated oxime 3a To a stirred solution of 1-(p-tolyl)but-3-en-1-one (10 mmol, 1.0 eq.) in EtOH (10 mL), hydroxylammonium chloride (50 mmol, 5.0 eq.) and sodium acetate trihydrate (70 mmol, 7.0 eq.) were added at 0 oC. Then, the mixture was stirred at room temperature until the reaction was completed as monitored by TLC analysis. Then, the solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate 10:1~5:1) to give compound 3a as a white solid in 67% yield. General procedure for hydroamination of β,γ-unsaturated hydrazones β,γ-Unsaturated hydrazone 1a (98.5 mg, 0.3 mmol) and DABCO (67.3 mg, 0.6 mmol) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 10:1~5:1) directly to give the desired product 2a in 61% yield as a white solid.
O N
6a, R = 4-MePh, 95% 6b, R = 4-t BuPh, 94% 6c, R = 3-FPh, 96%
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Unless otherwise noted, reactions were carried out with 1 or 3 (0.3 mmol),
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) and TEMPO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2 h. b Isolated yield.
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Conclusion
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General procedure for preparation of β,γ-unsaturated hydrazone 1a To a stirred solution of 1-(p-tolyl)but-3-en-1-one (20 mmol, 1.0 eq.) in MeOH (10 mL), p-toluenesulfonyl hydrazide (30 mmol, 1.5 eq.) was added at 0 oC. The mixture was stirred at the same temperature until the reaction was completed as monitored by TLC analysis. Then, the solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate 5:1~3:1) to give compound 1a as a white solid in 49% yield.
We have developed an efficient and practical PhI(OAc)2mediated intramolecular radical hydroamination and oxyamination of β,γ-unsaturated hydrazones, and a wide range of dihydropyrazole derivatives can be obtained in good to excellent This journal is © The Royal Society of Chemistry [year]
General procedure hydroxygenation of β,γ-unsaturated oximes β,γ-Unsaturated oxime 3a (52.5 mg, 0.3 mmol) and DABCO (67.3 mg, 0.6 mmol) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the desired product 4a in 67% yield as a white solid.
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β,γ-Unsaturated hydrazone 1j (88.2 mg, 0.3 mmol), DABCO (0.6 mmol, 67.3 mg), TEMPO (2.0 eq.) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the corresponding product 5a in 52% yield as yellow oil.
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General procedure for dioxygenation of β,γ-unsaturated oximes β,γ-Unsaturated oxime 3a (52.5 mg, 0.3 mmol), DABCO (67.3 mg, 0.6 mmol), TEMPO (2.0 eq.) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the corresponding product 6a in 95% yield as yellow oil.
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Acknowledgements 25
We are grateful to the National Natural Science Foundation of China (NO. 21272087, 21472058, 21232003, and 21202053) and the National Basic Research Program of China (2011CB808603) for support of this research.
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Key Laboratory of Pesticide & Chemical Biology, Ministry of Education; College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China. Fax: +86 27 67862041; Tel: +86 27 67862041; E-mail:[email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Experimental procedures and compound characterisation data. For ESI and other electronic format See DOI: 10.1039/b000000x/ 1 For selected reviews on the transition-metal mediated functionalisation of alkenes, see: (a) T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795; (b) S. R. Chemler, Org. Biomol. Chem., 2009, 7, 3009; (c) R. I. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011, 111, 2981; (d) F. Cardona and A. Goti, Nat. Chem., 2009, 1, 269; (e) T. J. Donohoe, C. K. Callens, A. Flores, A. R. Lacy and A. H. Rathi, Chem. Eur. J., 2011, 17, 58; (f) T. A. Ramirez, B. Zhao and Y. Shi, Chem. Soc. Rev., 2012, 41, 931; (g) R. M. de Figueiredo, Angew. Chem. Int. Ed., 2009, 48, 1190; (h) S. Hong and T. J. Marks, Acc. Chem. Res., 2004, 37, 673; (i) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94, 2483; (j) K. Muniz, Chem. Soc. Rev., 2004, 33, 166; (k) D. Nilov and O. Reiser, Adv. Synth. Catal., 2002, 344, 1169. 2 For selected reviews on chemistry of hypervalent iodine (III) reagents, see: (a) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2002, 102, 2523; (b) T. Wirth, Angew. Chem. Int. Ed., 2005, 44, 3656; (c) R. D. Richardson and T. Wirth, Angew. Chem. Int. Ed., 2006, 45, 4402; (d) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108, 5299; (e) U. Farooq, A. U. Shah and T. Wirth, Angew. Chem. Int. Ed., 2009, 48, 1018; (f) H. Liang and M. A. Ciufolini, Angew. Chem. Int. Ed., 2011, 50, 11849; (g) V. V. Zhdankin, J. Org. Chem., 2011, 76, 1185; (h) F. V. Singh and T. Wirth, Chem. Asian J., 2014, 9, 950. 3 For representative examples on hypervalent iodine (III) reagentsmediated functionalisation of alkenes, see: (a) H. M. Lovick and F. E. Michael, J. Am. Chem. Soc., 2010, 132, 1249; (b) D. J. Wardrop, E. G. Bowen, R. E. Forslund, A. D. Sussman and S. L. Weerasekera, J.
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Yang, R. Fang, X.-X. Peng, W. Yu and B. Han, J. Org. Chem., 2013, 78, 10692; (c) X.-Y. Duan, N.-N. Zhou, R. Fang, X.-L. Yang, W. Yu and B. Han, Angew. Chem. Int. Ed., 2014, 53, 3158. 13 X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M. Beauchemin and W.-J. Xiao, Angew. Chem. Int. Ed., 2014, 53, 12163. 14 In sharp contrast to Han’s work, it was found that this type of oxygenation of β,γ-unsaturated oximes can proceed smoothly at room temperature about 2 h. Control experiments suggested that the oxime radicals were directly generated from the oxidation of β,γ-unsaturated oximes by PhI(OAc)2 under basic condition. 15 Please see the Supporting Information for more details.
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PhI(OAc)2-Mediated functionalisation of unactivated alkenes for synthesis of pyrazoline and isoxazoline derivatives Xiao-Qiang Hu, Guoqiang Feng, Jia-Rong Chen,* Dong-Mei Yan, Quan-Qing Zhao, Qiang Wei and Wen-Jing Xiao*
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A PhI(OAc)2-promoted radical cyclization of β,γ-unsaturated hydrazones and oximes have been developed for efficient synthesis of various valuable pyrazoline and isoxazoline derivatives with satisfactory yields (up to 96%) under mild conditions.
Introduction
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The functionalisation of unactivated alkenes represents one of the most powerful approaches for carbon–carbon and carbon– heteroatom bonds formation. Not surprisingly, over the past decades, considerable research efforts have been devoted into this field. Particularly, remarkable advances have been achieved in transition-metal-mediated (Pd, Ni, Cu, Au, Ti, Pt etc.) hydroamination, hydroxygenation, oxyamination, diamination and dioxygenation of alkenes.1 However, either the high cost or toxicity of the transition metals or the harsh reaction conditions largely restricted their applications in practical synthesis. The commercially available hypervalent iodine (III) reagents represent a type of powerful oxidants and have recently been widely used in various oxidation and metal-catalyzed coupling reactions.2 In this context, the hypervalent iodine (III) reagents have also been commonly used in difunctionalisation of unactivated carbon-carbon double bond via an iodonium ion intermidiate, which are directly generated by an alkene oxidation process (Scheme 1a).3 To our knowledge, exploration of hypervalent iodine (III) reagents in radical hydroamination and hydroxygenation of unactivated alkenes is still rare.4 Pyrazolines and isoxazolines represent two classes of biologically important five-membered nitrogen-containing heterocycles, which widely exist in many natural products, biologically active compounds and pharmaceuticals.5 These ring systems have often been utilised as chiral ligands in asymmetric catalysis.6 Typically, these heterocyclic scaffolds can be efficiently prepared via 1,3-dipolar cycloaddition reactions of nitrile oxides or nitrile imines with alkenes.7 However, there are still certain limitations associated with these methodologies, such as poor regioselectivity and limited substrate scope. Recently, β,γ-unsaturated hydrazones and oximes have been established as a family of versatile building blocks for assembly of diversely substituted pyrazoline and isoxazoline derivatives. Representative strategies include transition-metal salts (e.g., Co(III), Cu(II), Pd(II), etc.) catalyzed cyclization of β,γ-unsaturated oximes and hydrazones.8 On the other hand, developing metal-free variants This journal is © The Royal Society of Chemistry [year]
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has also recently attracted extensive attention. Mosher,9 Mukherjee10 and our group11 have independently reported the halocyclization reactions of β,γ-unsaturated oximes and hydrazones through a bromonium or iodonium ion intermediate to construct the corresponding pyrazoline and isoxazoline derivatives with high efficiency under mild reaction conditions. In addition, metal-free radical cyclization provided a potential platform for the transformation of β,γ-unsaturated hydrazones and oximes into valuable heterocycles. For instance, Han’s group has recently reported several elegant examples of radical cyclization of hydrazonyl or oxime radicals using stoichiometric amount of TEMPO or azodicarboxylates, providing the corresponding oxyamination, dioxygenation and diamination products (e.g., isoxazolines, pyrazolines and azomethine imines) in good yields.12 Very recently, our group developed a visible-lightinduced photocatalytic hydroamination and oxyamination of β,γunsaturated hydrazones 1 via a N-centered radical intermediate.13 In the process, however, the β,γ-unsaturated oximes proved to be not suitable probably due to the higher oxidation potential of oximes. Given the strong oxidizing potential of hypervalent iodine (III) reagents, we envisaged that the intramolecular radical cyclization of β,γ-unsaturated hydrazones 1 and oximes 3 via Nand O-centered radical intermediates might be achieved using such oxidants, such as PhI(OAc)2 (Scheme 1b). Herein, we wish to communicate our preliminary results.
Scheme 1. PhI(OAc)2-mediated alkene functionalisation.
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Initially, β,γ-unsaturated hydrazone 1a was selected as the model substrate with the use of K2CO3 as the base and PhI(OAc)2 (1.5 equiv) as the oxidant in CH2Cl2 to examine the feasibility of intramolecular hydroamination reaction. To our delight, the reaction proceeded smoothly without addition of any metal salts and the expected hydroamination product 2a was obtained in 11% yield (Table 1, entry 1). To further improve the reaction efficiency, the reaction media has been extensively investigated. As shown in Table 1, the yield of 2a can be increased to 26% by using PhMe as the solvent (Table 1, entry 2). Other solvents such as EtOAc, CH3CN and DMSO substantially decreased the reaction efficiency (Table 1, entries 4-6), while THF gave the best result with 2a being obtained in 48% yield (Table 1, entry 6). Then, a brief screen of organic bases identified the organic base DABCO to be the best base for this transformation, delivering 2a in 65% GC yield (Table 1, entries 10-14). A simple survey of commonly used oxidants showed that PhI(OAc)2 is still the best of choice. For example, PhI(CO2CF3)2 largely decreased the yield of 2a to 32% (Table 1, entry 15), while other strong oxidants such as MnO2, mCPBA and tBuO2H leading to decomposition of 1a or complex mixture (Table 1, entries 15-18).
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the aliphatic β,γ-unsaturated hydrazones also proved to be suitable for this reaction. A wide range of alkyl groups, such as View Article Online tert-butyl, isopropyl and cyclohexyl wereDOI: found to be well 10.1039/C5OB00029G accomodated, affording the desired products 2j-2l in 53-76% yields. In addition, phenylethyl group substituted hydrazone 1m also underwent this hydroamination process smoothly to give the desired product 2m in 61% yield with 1:1 dr. Moreover, the reactin with hydrazone 1n bearing germinal methyl groups at αposition also proceeded well to furnish the corresponding hydroamination product 2n in 32% yield. Gratifyingly, the reaction efficiency can be dramatically increased by changing the Ts group into Ms group. As a result, the desired products 2o-2q were obtained in satisfactory yields (Table 2, 73-92%). It should be noted that these products were only obtained in very low yields under our previously develped photocatalytic conditions (Table 2, 32-43%).13 Encouraged by these results, we surmised that such PhI(OAc)2-mediated hydroamination strategy might be also extended to other radical precursors, such as β,γ-unsaturated oximes. Table 2 Substrate scope of the hydroamination reaction of hydrazones a, b
Table 1 Optimization studies a
Ts HN
Entry 1
Oxidant PhI(OAc)2
Solvent CH2Cl2
Yield b (%) 11
toluene
Base K2CO3 K2CO3
2
PhI(OAc)2
3
PhI(OAc)2
EtOAc
K2CO3
11
4
PhI(OAc)2
DMSO
K2CO3
6
5
PhI(OAc)2
CH3CN
K2CO3
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6
PhI(OAc)2
THF
K2CO3
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7
PhI(OAc)2
THF
Na2CO3
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8
PhI(OAc)2
THF
Cs2CO3
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9
PhI(OAc)2
THF
Et3N
10 11
PhI(OAc)2
THF
DABCO
PhI(OAc)2
THF
DBU
R
26
Ts
Ts
Ts
N N
Ts
N N
N N
N N Ph
2j, 76%
2k, 64% Ts
N N
2l, 53% Ms
2m, 61% (dr = 1:1) Ms
Ms
N N
N N
N N
47 65 (61)
c
Cl
51 2n, 32%
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2o, 79% PC: 32%
2p, 73% PC: 43%
2q, 92% PC: 42%
PhI(OAc)2
THF
TMG
13
PhI(OAc)2
THF
DMAP
trace
a
14
PhI(OAc)2
N-methylimidazole DABCO
trace 32
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2
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PhI(CO2CF3)2
THF THF
16
MnO2
THF
DABCO
trace
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mCPBA
THF
DABCO
trace
18
t
BuOOH
THF
DABCO
trace b
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Determined by GC using biphenyl as internal standard. c Isolated yield.
With the optimal reaction conditions established, we firstly investigated the generality of the metal-free hydroamination reaction of β,γ-unsaturated hydrazones. As shown in Table 2, various electron-rich (Me, MeO) and electron-poor (F, Cl, Br, CF3) substituents at 2-, 3- or 4-positions of aromatic ring were well tolerated to give the corresponding products 2b-2i in moderate to good yields (Table 2, 54-65%). More importantly, 2 | Journal Name, [year], [vol], 00–00
Unless otherwise noted, reactions were carried out with 1 (0.3 mmol),
h. b Isolated yield. PC = photoredox catalysis. 13
Unless otherwise noted, reactions were carried out with 1a (0.2 mmol),
oxidant (0.3 mmol), base (0.4 mmol) in the solvent (2.0 mL) at 25 oC.
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2f, R = 4-Br, 58% 2g, R = 4-Cl, 54% 2h, R = 4-CF3, 56% 2i, R = 3-Br, 54%
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2a, R = H, 65% 2b, R = 4-Me, 61% 2c, R = 3-MeO, 59% 2d, R = 2-Cl, 60% 2e, R = 4-Cl, 54%
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Gratifyingly, the β,γ-unsaturated oximes also proved to be suitable for this transformation, while these substrates can’t be tolerated under our previously reported photocatalytic condition probably due to the higher oxidation potential of these oximes (Table 3). Under the standard reaction conditions, a wide range of oximes 3a-3i bearing electron-donating (Me, tBu, MeO) or electron-withdrawing (Cl, Br, F, CF3) groups at the phenyl ring proceeded smoothly to afford the corresponding isoxazolines 4a4i in generally good yields (Table 3, 57-94%). Thus, such metalfree hydroxygenation reaction provided a facile and alternative access to diverse biologically and synthetically valuable isoxazoline derivatives. This journal is © The Royal Society of Chemistry [year]
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Table 3 Substrate scope of the hydroxygenation reaction of oximes a, b 30
yields under the metal-free conditions. Furthermore, this methodology can be applied to the hydroxygenation and View Article Online dioxygenation of β,γ-unsaturated oximes DOI: for synthesis of various 10.1039/C5OB00029G biologically important isoxazolines. This reaction provides an alternative platform for the functionalisation of unactivated alkenes under metal-free conditions. Further studies toward the mechanism as well as enantioselective versions are ongoing in our laboratory.15
Experimental
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Unless otherwise noted, reactions were carried out with 3 (0.3 mmol),
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2 h. b Isolated yield.
Based on the proposed radical pathway (Scheme 1), N- and O-centered radical intermediates might be involved in the above processes. As such, this oxidative system might enable intermolecular oxyamination and dioxygenation of β,γunsaturated hydrazones and oximes (Table 4). As a proof of this concept, TEMPO was added as the oxygen radical source under the standard reaction conditions. To our delight, the oxyamination reaction of hydrazones 1 proceeded smoothly to give the desired products 5a and 5b in 52% and 46% yield, respectively. Moreover, the dioxygenation of β,γ-unsaturated oximes 3 also reacted smoothly to furnish the dioxygenation products 6a-6c with excellent yields (94-96%).14 It is worth noting that the N-O bond of products can be easily cleaved to afford the biologically important alcohols under the reductive condition.13
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Table 4 Substrate scope of the oxyamination and dioxygenation a, b
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Ts
Ms
N N t
Bu
O N
5a, 52% a
N O
N N Ph
R O N
5b, 46%
General procedure for preparation of β,γ-unsaturated oxime 3a To a stirred solution of 1-(p-tolyl)but-3-en-1-one (10 mmol, 1.0 eq.) in EtOH (10 mL), hydroxylammonium chloride (50 mmol, 5.0 eq.) and sodium acetate trihydrate (70 mmol, 7.0 eq.) were added at 0 oC. Then, the mixture was stirred at room temperature until the reaction was completed as monitored by TLC analysis. Then, the solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate 10:1~5:1) to give compound 3a as a white solid in 67% yield. General procedure for hydroamination of β,γ-unsaturated hydrazones β,γ-Unsaturated hydrazone 1a (98.5 mg, 0.3 mmol) and DABCO (67.3 mg, 0.6 mmol) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 10:1~5:1) directly to give the desired product 2a in 61% yield as a white solid.
O N
6a, R = 4-MePh, 95% 6b, R = 4-t BuPh, 94% 6c, R = 3-FPh, 96%
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Unless otherwise noted, reactions were carried out with 1 or 3 (0.3 mmol),
PhI(OAc)2 (0.45 mmol), DABCO (0.6 mmol) and TEMPO (0.6 mmol) in THF (6.0 mL) at 25 oC for 2 h. b Isolated yield.
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Conclusion
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General procedure for preparation of β,γ-unsaturated hydrazone 1a To a stirred solution of 1-(p-tolyl)but-3-en-1-one (20 mmol, 1.0 eq.) in MeOH (10 mL), p-toluenesulfonyl hydrazide (30 mmol, 1.5 eq.) was added at 0 oC. The mixture was stirred at the same temperature until the reaction was completed as monitored by TLC analysis. Then, the solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate 5:1~3:1) to give compound 1a as a white solid in 49% yield.
We have developed an efficient and practical PhI(OAc)2mediated intramolecular radical hydroamination and oxyamination of β,γ-unsaturated hydrazones, and a wide range of dihydropyrazole derivatives can be obtained in good to excellent This journal is © The Royal Society of Chemistry [year]
General procedure hydroxygenation of β,γ-unsaturated oximes β,γ-Unsaturated oxime 3a (52.5 mg, 0.3 mmol) and DABCO (67.3 mg, 0.6 mmol) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the desired product 4a in 67% yield as a white solid.
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β,γ-Unsaturated hydrazone 1j (88.2 mg, 0.3 mmol), DABCO (0.6 mmol, 67.3 mg), TEMPO (2.0 eq.) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the corresponding product 5a in 52% yield as yellow oil.
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General procedure for dioxygenation of β,γ-unsaturated oximes β,γ-Unsaturated oxime 3a (52.5 mg, 0.3 mmol), DABCO (67.3 mg, 0.6 mmol), TEMPO (2.0 eq.) were dissolved in freshly distilled THF (4.5 mL) under Ar. Then, PhI(OAc)2 (144.9 mg, 0.45 mmol) was added to the mixture. After that, the solution was stirred at room temperature about 2 h until the reaction was completed as monitored by TLC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 20:1~10:1) directly to give the corresponding product 6a in 95% yield as yellow oil.
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Acknowledgements 25
We are grateful to the National Natural Science Foundation of China (NO. 21272087, 21472058, 21232003, and 21202053) and the National Basic Research Program of China (2011CB808603) for support of this research.
Notes and references 30
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Key Laboratory of Pesticide & Chemical Biology, Ministry of Education; College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China. Fax: +86 27 67862041; Tel: +86 27 67862041; E-mail:[email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Experimental procedures and compound characterisation data. For ESI and other electronic format See DOI: 10.1039/b000000x/ 1 For selected reviews on the transition-metal mediated functionalisation of alkenes, see: (a) T. E. Muller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795; (b) S. R. Chemler, Org. Biomol. Chem., 2009, 7, 3009; (c) R. I. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011, 111, 2981; (d) F. Cardona and A. Goti, Nat. Chem., 2009, 1, 269; (e) T. J. Donohoe, C. K. Callens, A. Flores, A. R. Lacy and A. H. Rathi, Chem. Eur. J., 2011, 17, 58; (f) T. A. Ramirez, B. Zhao and Y. Shi, Chem. Soc. Rev., 2012, 41, 931; (g) R. M. de Figueiredo, Angew. Chem. Int. Ed., 2009, 48, 1190; (h) S. Hong and T. J. Marks, Acc. Chem. Res., 2004, 37, 673; (i) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94, 2483; (j) K. Muniz, Chem. Soc. Rev., 2004, 33, 166; (k) D. Nilov and O. Reiser, Adv. Synth. Catal., 2002, 344, 1169. 2 For selected reviews on chemistry of hypervalent iodine (III) reagents, see: (a) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2002, 102, 2523; (b) T. Wirth, Angew. Chem. Int. Ed., 2005, 44, 3656; (c) R. D. Richardson and T. Wirth, Angew. Chem. Int. Ed., 2006, 45, 4402; (d) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108, 5299; (e) U. Farooq, A. U. Shah and T. Wirth, Angew. Chem. Int. Ed., 2009, 48, 1018; (f) H. Liang and M. A. Ciufolini, Angew. Chem. Int. Ed., 2011, 50, 11849; (g) V. V. Zhdankin, J. Org. Chem., 2011, 76, 1185; (h) F. V. Singh and T. Wirth, Chem. Asian J., 2014, 9, 950. 3 For representative examples on hypervalent iodine (III) reagentsmediated functionalisation of alkenes, see: (a) H. M. Lovick and F. E. Michael, J. Am. Chem. Soc., 2010, 132, 1249; (b) D. J. Wardrop, E. G. Bowen, R. E. Forslund, A. D. Sussman and S. L. Weerasekera, J.
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Yang, R. Fang, X.-X. Peng, W. Yu and B. Han, J. Org. Chem., 2013, 78, 10692; (c) X.-Y. Duan, N.-N. Zhou, R. Fang, X.-L. Yang, W. Yu and B. Han, Angew. Chem. Int. Ed., 2014, 53, 3158. 13 X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M. Beauchemin and W.-J. Xiao, Angew. Chem. Int. Ed., 2014, 53, 12163. 14 In sharp contrast to Han’s work, it was found that this type of oxygenation of β,γ-unsaturated oximes can proceed smoothly at room temperature about 2 h. Control experiments suggested that the oxime radicals were directly generated from the oxidation of β,γ-unsaturated oximes by PhI(OAc)2 under basic condition. 15 Please see the Supporting Information for more details.
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