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Cite this: Chem. Commun., 2014, 50, 4115

Iron-catalyzed aerobic difunctionalization of alkenes: a highly efficient approach to construct oxindoles by C–S and C–C bond formation†

Received 17th January 2014, Accepted 26th February 2014

Tao Shen,a Yizhi Yuan,a Song Songa and Ning Jiao*ab

DOI: 10.1039/c4cc00401a www.rsc.org/chemcomm

A novel iron-catalyzed efficient approach to construct sulfonecontaining oxindoles, which play important roles in the structural library design and drug discovery, has been developed. The use of readily available benzenesulfinic acids, an inexpensive iron salt as the catalyst, and air as the oxidant makes this sulfur incorporation protocol very efficient and practical.

Sulfone-containing molecules exhibit important functions in materials, synthetic intermediates, and pharmaceuticals.1 The significance of organosulfur compounds has inspired chemists to develop efficient C–S bond-formation transformations.2 In the past few decades, through a radical process, the addition of sulfonyl radicals to carbon–carbon unsaturated bonds represents a particularly useful strategy for sulfone synthesis.3,4 Despite the significances of these methods,4 some precursors such as sulfonyl halides, cyanides, selenides, azides, and hydrazides are employed to generate the sulfonyl radicals by treatment with radical initiators or photolysis. They cause atom transfer radical additions to multiple bonds in the presence of a stoichiometric amount of oxidants such as copper(II), TBHP, and cerium(IV) salts. Nevertheless, these processes are limited to the scope of substrates which are sometimes unstable in the presence of the oxidants. Recently, the group of Lei developed oxysulfonylation of alkenes by employing simple and readily available benzenesulfinic acids as the sulfonyl radical precursor using dioxygen as the oxidant5 (a, Scheme 1). 3-Substituted oxindoles play important roles in the structural library design and drug discovery.6 Therefore, the sulfone-containing oxindoles should be in high demand due to the potential unique biological activity of the products. Herein we report a novel and direct Fe catalyzed aerobic difunctionalization of activated alkenes via a

State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Rd. 38, Beijing 100191, People’s Republic of China. E-mail: [email protected]; Fax: +86-010-8280-5297 b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China † Electronic supplementary information (ESI) available. CCDC 981556. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc00401a

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Scheme 1

Difunctionalization of alkenes with benzenesulfinic acids.

cascade C–S and C–C bond formation for rapid building of sulfone-containing oxindoles (b, Scheme 1). To the best of our knowledge, this is a novel aerobic oxidative sulfonyl-carbocyclization of activated alkenes to construct sulfonyl substituted oxindoles. Molecular oxygen is employed as a green oxidant and plays a very important role in initiating this transformation, which makes this protocol very easy to handle. An inexpensive iron salt is employed as the catalyst. This observation represents an efficient approach to construct sulfonecontaining oxindoles by employing simple and readily available sulfinic acid as the sulfur source. We began our study by examining the reaction of N-methylN-arylacrylamide 1a and benzenesulfinic acid 2a for the direct sulfonylation and cyclization. Interestingly, 3aa was obtained in 77% yield by using 10% Fe(NO3)39H2O as a catalyst in MeCN (entry 1, Table 1). To our delight, when the loading of PhSO2H 2a was reduced to 1.5 eq., the yield of 3aa increased to 94% (entry 2, Table 1). When the reaction was performed under Ar, only 38% yield of 3aa was obtained (entry 3), which indicates that O2 may be an oxidant involved in this sulfon-carbocyclization process. Other solvents such as DCE, CHCl3 and THF did not perform well (see ESI†). Other transition metal catalysts such as FeCl3, AgNO3, Cu(NO3)2, Pd(OAc)2, and AuCl3 showed low efficiencies, respectively (entry 4, Table 1, and ESI†). Notably, some organic radical catalysts such as TEMPO and NHPI did not work (entries 5 and 6, Table 1). 3aa was obtained only in 16% yield in the absence of any catalyst (entry 7, Table 1).

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Table 1 Optimization for the direct sulfon-carbocyclization of activated alkenesa

Entry

Cat. (mol%)

Yield of 3aab (%)

1 2 3 4 5 6 7

Fe(NO3)39H2O (10) Fe(NO3)39H2O (10) Fe(NO3)39H2O (10) FeCl3 (10) TEMPO (10) NHPI (10) None

77 94c 38d Trace Trace Trace 16

a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), solvent (2 mL), and stirred at 100 1C under air for 12 h. b Isolated yields. c 0.3 mmol PhSO2H (2a) was used. d The reaction was carried out under Ar.

With the optimized reaction conditions in hand, the substrate scope of this aerobic sulfon-carbocyclization of alkenes was investigated. Various N-arylacrylamides were subjected to the optimized reaction conditions (Scheme 2). N-arylacrylamides containing both electron-donating and electron-withdrawing groups at the aryl ring executed smoothly to produce the corresponding products in good to excellent yields. Generally, substrates with an electron-withdrawing group could afford higher yields. It is noteworthy that the N-methyl-N-phenylmethacrylamides with halo-substituents (F, Cl, Br, and I) were tolerated under these mild reaction conditions leading to the corresponding halo-substituted oxindoles in excellent yields (88–96%, 3ca–3fa). N-protected N-phenylmethacrylamides could be smoothly converted into the desired oxindoles in excellent yields (3ma–3oa, Scheme 2). Interestingly, the N-arylacrylamide substrate with substituents at the meta position, highly regioselective, provided oxindoles

Scheme 3 Iron-catalyzed aerobic sulfon-carbocyclization of activated alkenes. These reactions were carried out at 100 1C under air for 12 h. Isolated yields. a 0.6 mmol of MeSO2H was used. b 0.4 mmol of EtSO2H was used. c 0.3 mmol of 2 was used.

in high yield (3ra, Scheme 2). Various protected a-hydroxymethyl derivatives provided the oxysulfonylation products in moderate yields (3sa and 3ta, Scheme 2). When N-methyl-N-(naphthalen1-yl)-methacrylamide was employed, the desired two isomers were obtained in 55% and 21% yields (3wa and 3wa0 , Scheme 2). Interestingly, various substituted sulfinic acids could be smoothly converted into expected sulfonated oxindoles in moderate to excellent yields (Scheme 3). Substrates with a highly unstable group such as cyclopropyl could also smoothly produce the desired product in excellent yield (3ad, Scheme 3). Besides, various benzene sulfinates with different substituents (e.g., Me, Cl, NHAc) were well tolerated (3ae–3ag, Scheme 3). Furthermore, this chemistry was applied in the synthesis of more complicated rings. Notably, the current protocol allows the formation of aza-2-oxindole derivatives in good yield (eqn (1)). When 1y was employed as a substrate, the six-memberedring product 3ya was obtained in 81% yield (eqn (2)). Tetrahydroisoquinoline and dibenzazepine structural motifs are commonly encountered in many biologically active compounds. Interestingly, tricyclic sulfonated oxindole derivative 3za was obtained in 74% yield from the corresponding tetrahydroquinoline substrate (eqn (3)). Notably, a larger tetracyclic oxindole derivative was successfully prepared in 68% yield using this protocol (eqn (4)).

(1)

(2)

Scheme 2 Iron-catalyzed aerobic sulfon-carbocyclization of activated alkenes. Reaction conditions: see entry 2, Table 1. a 0.3 mmol PhSO2H was used. b The reaction mixture was stirred for 24 h.

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(3)

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Fe(II) could be easily oxidized to Fe(III) to complete the catalytic cycle. (5)

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(6)

(7) Scheme 4

Range of reactions of the sulfonated oxindoles.

(8) (4)

Oxindoles with an appended sulfonyl group obtained by the presented methodology can be used to create a focused compound library. After obtaining the model product 3aa in 76% yield on a gram scale under standard conditions (eqn (5)), we embarked upon exploring the diverse synthetic transformations of sulfonyl oxindoles (Scheme 4). 3aa could be reduced by LiAlH4 to give 2H-indole 6 in 81% yield. Moreover, the synthetic utility of the sulfonated oxindoles was exemplified by the alkylation reaction to produce 7, 8, and 9 in good to excellent yields. In addition, the halogenation of 3aa with CBr4 and CCl4 provided oxazoline 10 and 11, respectively (Scheme 4). The reaction was completely suppressed in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) (eqn (6)). Moreover, the intramolecular and intermolecular kinetic isotope effects (KIE) were investigated (the intramolecular kH/kD = 1.3 and intermolecular kH/kD = 1.1) (eqn (7) and (8)), which indicates that C–H bond cleavage may not be the rate-determining step.7 Based on the above results, a possible mechanism is proposed (Scheme 5). Initially, the sulfonyl radical could be easily initiated by O2.5 Subsequent radical addition to activated alkene 1a generates radical intermediate A. Then the intramolecular carbocyclization of radical intermediate A affords radical intermediate B,8 which is oxidized by Fe(III) to form cationic intermediate C via a SET process. Intermediate C finally produces terminal product 2a via a deprotonation step. In the presence of O2,

Scheme 5

Proposed mechanism.

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In summary, we have developed a novel iron-catalyzed aerobic difunctionalization of alkenes for the construction of C–S and C–C bonds. This protocol provides an efficient approach to form sulfone-containing oxindoles, which play important roles in the structural library design and drug discovery. The use of readily available benzenesulfinic acids, an inexpensive iron salt as the catalyst, and air as the oxidant makes this sulfone incorporation protocol environmentally benign and practical. Further studies on the synthetic application of this chemistry are underway. Financial support from the National Science Foundation of China (No. 21325206, 21172006), the National Young Top-notch Talent Support Program, and the PhD Programs Foundation of the Ministry of Education of China (No. 20120001110013) are greatly appreciated. We thank Miancheng Zou in this group for reproducing the results of 3ma and 3ae.

Notes and references 1 P. Metzner and A. Thuillier, ed. A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Sulfur Reagents in Organic Synthesis, Academic Press, London, 1994. 2 M. Fontecave, S. Ollagnier-de-Choudens and E. Mulliez, Chem. Rev., 2003, 103, 2149. 3 M. P. Bertrand and C. Ferreri, in Radicals in Organic Synthesis, ed. P. Renaud and M. Sibi, Wiley-VCH, Weinheim, 2001, vol. 2, pp. 485–504. 4 For some examples for sulfonyl radical addition to a carbon–carbon double bond, see: (a) R. A. Gancarz and J. L. Kice, J. Org. Chem., 1981, 46, 4899; (b) I. D. Riggi, J.-M. Surzur and M. P. Bertrand, Tetrahedron, 1988, 44, 7119; (c) W. E. Truce and C. T. Goralski, J. Org. Chem., 1971, 36, 2536; (d) D. C. Craig, G. L. Edwards and C. A. Muldoon, Tetrahedron, 1997, 53, 6171; (e) N. Mantrand and P. Renaud, Tetrahedron, 2008, 64, 11860; ( f ) T. Taniguchi, A. Idota and H. Ishibashi, Org. Biomol. Chem., 2011, 9, 3151; ( g) X. Li, X.-S. Xu, P.-Z. Hu, X.-Q. Xiao and C. Zhou, J. Org. Chem., 2013, 78, 7343. 5 Q. Lu, J. Zhang, Y. Qi, H. Wang, Z. Liu and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 7156. 6 (a) J. E. M. N. Klein and R. J. K. Taylor, Eur. J. Org. Chem., 2011, 6821; (b) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (c) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003; (d) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (e) C. Marti and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209. 7 E. M. Simmons and J. F. Hartwig, Angew. Chem., Int. Ed., 2012, 51, 3066. 8 For selected recent radical synthesis of oxindoles, see: (a) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and

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4118 | Chem. Commun., 2014, 50, 4115--4118

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Iron-catalyzed aerobic difunctionalization of alkenes: a highly efficient approach to construct oxindoles by C-S and C-C bond formation.

A novel iron-catalyzed efficient approach to construct sulfone-containing oxindoles, which play important roles in the structural library design and d...
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