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The carbomethylation of arylacrylamides leading to 3-ethyl-3-substituted indolin-2-one by cascade radical addition/cyclization†
Received 22nd January 2014, Accepted 12th February 2014
Qiang Dai,a Jintao Yu,a Yan Jiang,a Songjin Guo,a Haitao Yanga and Jiang Cheng*ab
DOI: 10.1039/c4cc01053a www.rsc.org/chemcomm
An FeCl2-promoted carbomethylation of arylacrylamides by di-tertbutyl peroxide (DTBP) is achieved, leading to 3-ethyl-3-substituted indolin-2-one in high yield. The reaction tolerates a series of functional groups, such as cyano, nitro, ethyloxy carbonyl, bromo, chloro, and trifluoromethyl groups. The radical methylation and arylation of the alkenyl group are involved in this reaction.
Methylation is a fundamental transformation in organic chemistry because of the ubiquitousness of methyl groups in organic compounds and its importance in biologically active molecules.1 Undoubtedly, the introduction of methyl along with other functionalizations in one step would be beneficial for the diversity and complexity of the final product. The oxidative difunctionalization of alkenes is a powerful strategy which enables the bond formation at the vicinal positions.2 Like the well-developed metal-catalyzed oxidative aminooxygenation,3 diamination,4 and dioxygenation of alkenes,5 the oxidative dicarbonation of alkenes has attracted increasing attention from chemists.6 Meanwhile, the radical coupling was well developed in the methylation of the C–H bond,7 amides8 and carboxylic acid (Scheme 1).9 These elegant examples spurred us to test the feasibility of difunctionalization of alkenes involving radical methylation. To achieve such a transformation, the choice of a suitable substrate is essential. Recently, much attention has been paid to the difunctionalization of arylacrylamides as activated alkenes,10 leading to indolin-2-one as a useful scaffold in a wide range of natural products and biologically active drugs.11 With respect to the dicarbonation of arylacrylamides, arylalkylation,12 trifluoromethylarylation,13 diarylation14 and arylcyanation15 were well developed. Zhu developed the cascade decarboxylation/C–H a
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, and Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China. E-mail: [email protected] b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210093, P. R. China † Electronic supplementary information (ESI) available: Detailed synthetic procedures and characterization of new compounds. See DOI: 10.1039/c4cc01053a
This journal is © The Royal Society of Chemistry 2014
Scheme 1
The radical methylation reaction.
functionalization using visible-light photoredox catalysis toward 3,3-dialkyl substituted indolin-2-one.16 Liu demonstrated the coppercatalyzed alkylarylation of arylacrylamides by simple alkanes.17 Herein, we report our study onthe radical carbomethylation of arylacrylamides, involving the addition of the methyl radical and cyclization. Initially, the reaction of phenylacrylamide with DTBP was chosen as the model reaction in CH3CN at 135 1C. The desired product was isolated in 25% yield, along with 49% of the product via the addition of the cyanoethyl radical followed by cyclization (Table 1, entry 1). To our delight, the sequential methylation/cyclization product was formed in 38% yield in DMSO (Table 1, entry 2). By replacing DMSO with benzene or chlorobenzene, the desired product was isolated in 55% and 50% yields, respectively (Table 1, entries 3 and 4). The reaction did not work in toluene. The yield was further increased to 72% in the presence of 20 mol% FeCl2, indicating that FeCl2 acts as a promoter rather than a catalyst in this procedure (Table 1, entry 6). However, the employment of CuCl (20 mol%) had little effect on the reaction (Table 1, entry 7). The reaction temperature is crucial for this transformation, as the reaction efficiency did not increase at 150 1C but sharply decreased at 120 1C (Table 1, entries 8 and 9). With the optimized conditions in hand, the scope of substrates was investigated as shown in Fig. 1. Firstly, the effect of substituted groups on the aryl ring was probed. The reaction was not sensitive to the electronic nature of the phenylacrylamide as both electronwithdrawing and donating substituted substrates worked well to deliver the desired product in good to excellent yields. The reaction tolerated a series of functional groups, such as cyano,
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Table 1
ChemComm
Selected results for optimal reaction conditionsa
reaction efficiency was found between 3q and 3r. Importantly, the applicable scope was not limited to 3-ethyl-3-methyl indolinone, as the 3-acetoxymethyl, methoxymethyl and chloromethyl analogues (3s, 3t and 3u) were efficiently prepared in 76%, 62% and 72% yields, respectively.
Entry
Metal
Solvent
T/1C
Yieldb (%)
1c 2 3 4 5d 6 7 8 9
— — — — — FeCl2 CuCl FeCl2 FeCl2
MeCN DMSO Benzene Chlorobenzene Toluene Benzene Benzene Benzene Benzene
135 135 135 135 135 135 135 120 150
25 38 55 50 Trace 72 62 54 73
a
Reaction conditions: phenylacrylamide (0.2 mmol), metal (20 mol%), DTBP (2.5 equiv.), solvent (1.5 mL) in a sealed tube, N2. b Isolated yield. c 3-Cyanoethyl-3-methyl indolinone was isolated in 49% yield. d 3-Benzyl3-methyl indolinone. DTBP = di-tert-butyl peroxide.
(1) Next, the developed procedure was applied to the synthesis of 3w, which is a progesterone receptor antagonist.18 Using the standard procedure, 3w was isolated in 73% yield (eqn (1)). More experiments were conducted to get some insight into this reaction (Scheme 2). Firstly, adding 2.5 equivalents of 2,2,6,6tetramethyl-1-piperidinyloxyl (TEMPO) inhibited the reaction and the radical coupling product between the methyl radical and TEMPO was confirmed by GC-MS (eqn (2)). Moreover, a trace amount of toluene, which was derived from the radical methylation of benzene, was also detected by GC-MS. These results strongly indicated that a methyl radical was involved in this reaction. Secondly, the inter- and intramolecular isotopic kinetic experiments were conducted, and the kH/kD was found to be nearly 1.0 and 1.0, respectively (eqn (3) and (4)), indicating that the cleavage of the arene C–H bond is not the ratedetermining step.19 Moreover, these results implied that either an electrophilic aromatic substitution or a free-radical substitution was involved in the cyclization step.20 However, the substituent effect on the reaction rate was observed in the competitive experiment, where the electron-withdrawing substituent was beneficial for the reaction. This result is not consistent with the electrophilic aromatic substitution and supports the radical aromatic pathway (eqn (5)). Based on the aforementioned experimental results, a proposed mechanism is outlined in Scheme 3. Initially, the homolytic cleavage of DTBP produces a tert-butoxy radical, which is converted to a methyl radical by the loss of one equivalent of acetone. In the
Fig. 1 FeCl2-promoted carbomethylation of an arylacryamide. All reactions were carried out with arylacrylamide 1 (0.2 mmol), DTBP (0.5 mmol, 2.5 equiv.), FeCl2 (20 mol%), in benzene (1.5 mL) at 135 1C under N2 for 12 h. Isolated yield. Mixture of 6- and 4-Me products, the ratio is determined by 1H NMR spectroscopy. The 6-Br isomer was isolated in 21% yield.
nitro, ethoxycarbonyl, bromo, chloro, and trifluoromethyl groups. Notably, bromo and chloro groups survived well under the reaction conditions, which were suitable for further potential functionalization (3j–3l). The steric hindrance had little effect on this transformation, as evidenced by the comparable yields between 3f and 3g. Importantly, the hetero-aryl analogue was also a good reaction partner in this transformation. For example, 3p was isolated in 73% yield. For the meta-substituted substrates, cyclization at the more hindered site is preferred to form the 4-substituted indolinones as the major products (3h and 3j). Secondly, the effect of the protecting group on the nitrogen atom was studied. No difference in the
3866 | Chem. Commun., 2014, 50, 3865--3867
Scheme 2
Preliminary mechanism study.
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Scheme 3
Proposed mechanism.
presence of FeCl2, the formation of the tert-butoxy radical may be accelerated by the single electron transfer (SET) reaction, along with an Fe(III) species. Subsequently, the addition of the methyl radical to the arylacrylamide forms a new radical species 4. Then, the cyclization takes place to form the radical intermediate 5. Finally, the single electron transfer reaction between intermediate 5 and the tert-butoxy radical or Fe(III) species delivers the indolinone, along with one equivalent of tert-butanol. For the meta-substituted substrate, the cyclization at the more crowded 4-position is preferred because the resonance structure of the intermediate 5 is more stable than that of the 6-position. In conclusion, we developed an FeCl2-promoted carbomethylation of arylacrylamides, which provided a facile pathway leading to ethyl-3-substituted indolin-2-one. The procedure tolerates cyano, nitro, ethyloxy carbonyl, bromo, chloro and trifluoromethyl groups. A sequential methyl radical addition and cyclization is involved in this reaction. We thank the National Natural Science Foundation of China (no. 21272028 and 21202013), the ‘‘Innovation & Entrepreneurship Talents’’ Introduction Plan of Jiangsu Province, the Natural Science Foundation of Zhejiang Province (no. R4110294), the Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology and the State Key Laboratory of Coordination Chemistry at Nanjing University for financial support.
Notes and references ¨herr and T. Cernak, Angew. Chem., Int. Ed., 1 For reviews, see: (a) H. Scho ¨mmerle and C. A. M. Fraga, 2013, 52, 12256; (b) E. J. Barreiro, A. E. Ku Chem. Rev., 2011, 111, 5215; For recent a-methylation of ketone, see: (c) L. K. M. Chan, D. L. Poole, D. Shen, M. P. Healy and T. J. Donohoe, Angew. Chem., Int. Ed., 2014, 53, 761; (d) Y. Li, D. Xue, W. Lu, C. Wang, Z.-T. Liu and J. Xiao, Org. Lett., 2014, 16, 66. 2 For some recent reviews on the difunctionalization of alkenes, see: (a) K. H. Jensen and M. S. Sigman, Org. Biomol. Chem., 2008, 6, 4083; (b) V. Kotov, C. C. Scarborough and S. S. Stahl, Inorg. Chem., 2007, 46, 1910; (c) B. Jacques and K. Muinz, in Catalyzed CarbonHeteroatom Bond Formation, ed. A. K. Yudin, Wiley VCH, 2010, pp. 119–135; (d) S. R. Chemler, Org. Biomol. Chem., 2009, 7, 3009; (e) S. Shylesh, M. Jia and W. R. Thiel, Eur. J. Inorg. Chem., 2010, 4395; ( f ) S.-X. Huang and K. Ding, Angew. Chem., Int. Ed., 2011, 50, 7734; ( g) K. Muniz and C. Martinez, J. Org. Chem., 2013, 78, 2168; (h) S. R. Chemler and M. T. Bovino, ACS Catal., 2013, 3, 1076. ˜ iz, Chem. Soc. Rev., 2004, 33, 166; (b) G. Liu and S. S. Stahl, 3 (a) K. Mun J. Am. Chem. Soc., 2006, 128, 7179; (c) L. V. Desai and M. S. Sanford, Angew. Chem., Int. Ed., 2007, 46, 5737; (d) G. Li, H.-T. Chang and K. B. Sharpless, Angew. Chem., Int. Ed. Engl., 1996, 35, 451. ¨velmann, M. Nieger and K. Mun ˜iz, J. Am. 4 (a) J. Streuff, C. H. Ho ˜iz, J. Am. Chem. Soc., 2007, Chem. Soc., 2005, 127, 14586; (b) K. Mun 129, 14542; (c) P. A. Sibbald and F. E. Michael, Org. Lett., 2009, ´rez and K. Mun ˜iz, Angew. Chem., Int. 11, 1147; (d) A. Iglesias, E. Pe
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˜iz and C. Martı´nez, J. Org. Chem., Ed., 2010, 49, 8109; (e) K. Mun 2013, 78, 2168. (a) A. Wang, H. Jiang and H. Chen, J. Am. Chem. Soc., 2009, 131, 3846; (b) Y. Li, D. Song and V. M. Dong, J. Am. Chem. Soc., 2008, 130, 2962; (c) M. J. Rawling and N. C. O. Tomkinson, Org. Biomol. Chem., 2013, 11, 1434; (d) B. C. Giglio, V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011, 133, 13320; (e) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94, 2483; ( f ) C. J. R. Bataille and T. J. Donohoe, Chem. Soc. Rev., 2011, 40, 114. (a) X. Tong, M. Beller and M. K. Tse, J. Am. Chem. Soc., 2007, 129, 4906; (b) L. L. Welbes, T. W. Lyons, K. A. Cychosz and M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 5836; (c) Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu and Y.-M. Liang, Org. Lett., 2014, 16, 270 and references therein; (d) K. B. Urkalan and M. S. Sigman, Angew. Chem., Int. Ed., 2009, 48, 3146 and references therein. (a) S. R. Neufeldt, C. K. Seigerman and M. S. Sanford, Org. Lett., 2013, 15, 2302; (b) Y. Zhang, J. Feng and C.-J. Li, J. Am. Chem. Soc., 2008, 130, 2900; (c) X. Chen, J.-J. Li, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 78; (d) X. Chen, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 12634; For reviews for radical, see: (e) H. Togo, Advanced free radical reactions for organic synthesis, Elsevier, 2004; ( f ) S. Z. Zard, Radical reaction in organic synthesis, Oxford, 2003. Q. Xia, X. Liu, Y. Zhang, C. Chen and W. Chen, Org. Lett., 2013, 15, 3326. Y. Zhu, H. Yan, L. Lu, D. Liu, G. Rong and J. Mao, J. Org. Chem., 2013, 78, 9898. (a) S. Jaegli, J. Dufour, H. Wei, T. Piou, X. Duan, J. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498; (b) Y. Meng, L.-N. Guo, H. Wang and X.-H. Duan, Chem. Commun., 2013, 49, 7540; (c) T. Shen, Y. Yuan and N. Jiao, Chem. Commun., 2014, 50, 554; (d) Y.-M. Li, X.-H. Wei, X.-A. Li and S.-D. Yang, Chem. Commun., 2013, 49, 11701; (e) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian and S.-D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; ( f ) X.-H. Wei, Y.-M. Li, A.-X. Zhou, T.-T. Yang and S.-D. Yang, Org. Lett., 2013, 15, 4158; (g) H. Wang, L.-N. Guo and X.-H. Duan, Adv. Synth. Catal., 2013, 355, 2222; (h) D. C. Fabry, M. Stodulski, S. Hoerner and T. Gulder, Chem.–Eur. J., 2012, 18, 10834; (i) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng and J.-H. Li, Chem. Sci., 2013, 4, 2690; ( j) H.-L. Wei, T. Piou, J. Dufour, L. Neuville and J. Zhu, Org. Lett., 2011, 13, 2244; (k) S. Jaegli, J. Dufour, H.-l. Wei, T. Piou, X.-H. Duan, J.-P. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498. (a) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (c) B. S. Jensen, CNS Drug Rev., 2002, 8, 353; (d) A. Millemaggi and R. J. K. Taylor, Eur. J. Org. Chem., 2010, 4527. (a) T. Wu, X. Mu and G. Liu, Angew. Chem., Int. Ed., 2011, 50, 12578; (b) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and J.-H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638; (c) W.-P. Mai, J.-T. Wang, L.-R. Yang, J.-W. Yuan, Y.-M. Xiao, P. Mao and L.-B. Qu, Org. Lett., 2014, 16, 204. (a) H. Egami, R. Shimizu, S. Kawamura and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52, 4000; (b) W. Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem., Int. Ed., 2013, 52, 13086; (c) X. Mu, T. Wu, H. Wang, Y. Guo and G. Liu, J. Am. Chem. Soc., 2012, 134, 878; (d) F. Yang, P. Klumpthu, Y.-M. Liang and B. H. Lipshutz, Chem. Commun., 2014, 50, 936. W. Fu, F. Xu, Y. Fu, M. Zhu, J. Yu, C. Xu and D. Zou, J. Org. Chem., 2013, 78, 12202. A. Pinto, Y. Jia, L. Neuville and J. Zhu, Chem.–Eur. J., 2007, 13, 961. J. Xie, P. Xu, H. Li, Q. Xue, M. Jin, Y. Cheng and C. Zhu, Chem. Commun., 2013, 49, 5672. Z. Li, Y. Zhang, L. Zhang and Z.-Q. Liu, Org. Lett., 2014, 16, 382. S. Alluri, H. Feng, M. Livings, L. Samp, D. Biswas, T. W. Lam, E. Lobkovsky and A. K. Ganguly, Tetrahedron Lett., 2011, 52, 3945. (a) T. Wu, H. Zhang and G. Liu, Tetrahedron, 2012, 68, 5229; (b) X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 6790; (c) W. D. Jones and F. J. Feher, J. Am. Chem. Soc., 1986, 108, 4814; (d) W. D. Jones, Acc. Chem. Res., 2003, 36, 140; (e) A. Pinto, L. Neuville, P. Retailleau and J. Zhu, Org. Lett., 2006, 8, 4927. (a) J. A. Tunge and L. N. Foresee, Organometallics, 2005, 24, 6440; (b) R. Taylor, Electrophilic Aromatic Substitution, Wiley, New York, 1990, pp. 25–27.
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The carbomethylation of arylacrylamides leading to 3-ethyl-3-substituted indolin-2-one by cascade radical addition/cyclization†
Received 22nd January 2014, Accepted 12th February 2014
Qiang Dai,a Jintao Yu,a Yan Jiang,a Songjin Guo,a Haitao Yanga and Jiang Cheng*ab
DOI: 10.1039/c4cc01053a www.rsc.org/chemcomm
An FeCl2-promoted carbomethylation of arylacrylamides by di-tertbutyl peroxide (DTBP) is achieved, leading to 3-ethyl-3-substituted indolin-2-one in high yield. The reaction tolerates a series of functional groups, such as cyano, nitro, ethyloxy carbonyl, bromo, chloro, and trifluoromethyl groups. The radical methylation and arylation of the alkenyl group are involved in this reaction.
Methylation is a fundamental transformation in organic chemistry because of the ubiquitousness of methyl groups in organic compounds and its importance in biologically active molecules.1 Undoubtedly, the introduction of methyl along with other functionalizations in one step would be beneficial for the diversity and complexity of the final product. The oxidative difunctionalization of alkenes is a powerful strategy which enables the bond formation at the vicinal positions.2 Like the well-developed metal-catalyzed oxidative aminooxygenation,3 diamination,4 and dioxygenation of alkenes,5 the oxidative dicarbonation of alkenes has attracted increasing attention from chemists.6 Meanwhile, the radical coupling was well developed in the methylation of the C–H bond,7 amides8 and carboxylic acid (Scheme 1).9 These elegant examples spurred us to test the feasibility of difunctionalization of alkenes involving radical methylation. To achieve such a transformation, the choice of a suitable substrate is essential. Recently, much attention has been paid to the difunctionalization of arylacrylamides as activated alkenes,10 leading to indolin-2-one as a useful scaffold in a wide range of natural products and biologically active drugs.11 With respect to the dicarbonation of arylacrylamides, arylalkylation,12 trifluoromethylarylation,13 diarylation14 and arylcyanation15 were well developed. Zhu developed the cascade decarboxylation/C–H a
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, and Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China. E-mail: [email protected] b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210093, P. R. China † Electronic supplementary information (ESI) available: Detailed synthetic procedures and characterization of new compounds. See DOI: 10.1039/c4cc01053a
This journal is © The Royal Society of Chemistry 2014
Scheme 1
The radical methylation reaction.
functionalization using visible-light photoredox catalysis toward 3,3-dialkyl substituted indolin-2-one.16 Liu demonstrated the coppercatalyzed alkylarylation of arylacrylamides by simple alkanes.17 Herein, we report our study onthe radical carbomethylation of arylacrylamides, involving the addition of the methyl radical and cyclization. Initially, the reaction of phenylacrylamide with DTBP was chosen as the model reaction in CH3CN at 135 1C. The desired product was isolated in 25% yield, along with 49% of the product via the addition of the cyanoethyl radical followed by cyclization (Table 1, entry 1). To our delight, the sequential methylation/cyclization product was formed in 38% yield in DMSO (Table 1, entry 2). By replacing DMSO with benzene or chlorobenzene, the desired product was isolated in 55% and 50% yields, respectively (Table 1, entries 3 and 4). The reaction did not work in toluene. The yield was further increased to 72% in the presence of 20 mol% FeCl2, indicating that FeCl2 acts as a promoter rather than a catalyst in this procedure (Table 1, entry 6). However, the employment of CuCl (20 mol%) had little effect on the reaction (Table 1, entry 7). The reaction temperature is crucial for this transformation, as the reaction efficiency did not increase at 150 1C but sharply decreased at 120 1C (Table 1, entries 8 and 9). With the optimized conditions in hand, the scope of substrates was investigated as shown in Fig. 1. Firstly, the effect of substituted groups on the aryl ring was probed. The reaction was not sensitive to the electronic nature of the phenylacrylamide as both electronwithdrawing and donating substituted substrates worked well to deliver the desired product in good to excellent yields. The reaction tolerated a series of functional groups, such as cyano,
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Table 1
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Selected results for optimal reaction conditionsa
reaction efficiency was found between 3q and 3r. Importantly, the applicable scope was not limited to 3-ethyl-3-methyl indolinone, as the 3-acetoxymethyl, methoxymethyl and chloromethyl analogues (3s, 3t and 3u) were efficiently prepared in 76%, 62% and 72% yields, respectively.
Entry
Metal
Solvent
T/1C
Yieldb (%)
1c 2 3 4 5d 6 7 8 9
— — — — — FeCl2 CuCl FeCl2 FeCl2
MeCN DMSO Benzene Chlorobenzene Toluene Benzene Benzene Benzene Benzene
135 135 135 135 135 135 135 120 150
25 38 55 50 Trace 72 62 54 73
a
Reaction conditions: phenylacrylamide (0.2 mmol), metal (20 mol%), DTBP (2.5 equiv.), solvent (1.5 mL) in a sealed tube, N2. b Isolated yield. c 3-Cyanoethyl-3-methyl indolinone was isolated in 49% yield. d 3-Benzyl3-methyl indolinone. DTBP = di-tert-butyl peroxide.
(1) Next, the developed procedure was applied to the synthesis of 3w, which is a progesterone receptor antagonist.18 Using the standard procedure, 3w was isolated in 73% yield (eqn (1)). More experiments were conducted to get some insight into this reaction (Scheme 2). Firstly, adding 2.5 equivalents of 2,2,6,6tetramethyl-1-piperidinyloxyl (TEMPO) inhibited the reaction and the radical coupling product between the methyl radical and TEMPO was confirmed by GC-MS (eqn (2)). Moreover, a trace amount of toluene, which was derived from the radical methylation of benzene, was also detected by GC-MS. These results strongly indicated that a methyl radical was involved in this reaction. Secondly, the inter- and intramolecular isotopic kinetic experiments were conducted, and the kH/kD was found to be nearly 1.0 and 1.0, respectively (eqn (3) and (4)), indicating that the cleavage of the arene C–H bond is not the ratedetermining step.19 Moreover, these results implied that either an electrophilic aromatic substitution or a free-radical substitution was involved in the cyclization step.20 However, the substituent effect on the reaction rate was observed in the competitive experiment, where the electron-withdrawing substituent was beneficial for the reaction. This result is not consistent with the electrophilic aromatic substitution and supports the radical aromatic pathway (eqn (5)). Based on the aforementioned experimental results, a proposed mechanism is outlined in Scheme 3. Initially, the homolytic cleavage of DTBP produces a tert-butoxy radical, which is converted to a methyl radical by the loss of one equivalent of acetone. In the
Fig. 1 FeCl2-promoted carbomethylation of an arylacryamide. All reactions were carried out with arylacrylamide 1 (0.2 mmol), DTBP (0.5 mmol, 2.5 equiv.), FeCl2 (20 mol%), in benzene (1.5 mL) at 135 1C under N2 for 12 h. Isolated yield. Mixture of 6- and 4-Me products, the ratio is determined by 1H NMR spectroscopy. The 6-Br isomer was isolated in 21% yield.
nitro, ethoxycarbonyl, bromo, chloro, and trifluoromethyl groups. Notably, bromo and chloro groups survived well under the reaction conditions, which were suitable for further potential functionalization (3j–3l). The steric hindrance had little effect on this transformation, as evidenced by the comparable yields between 3f and 3g. Importantly, the hetero-aryl analogue was also a good reaction partner in this transformation. For example, 3p was isolated in 73% yield. For the meta-substituted substrates, cyclization at the more hindered site is preferred to form the 4-substituted indolinones as the major products (3h and 3j). Secondly, the effect of the protecting group on the nitrogen atom was studied. No difference in the
3866 | Chem. Commun., 2014, 50, 3865--3867
Scheme 2
Preliminary mechanism study.
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Scheme 3
Proposed mechanism.
presence of FeCl2, the formation of the tert-butoxy radical may be accelerated by the single electron transfer (SET) reaction, along with an Fe(III) species. Subsequently, the addition of the methyl radical to the arylacrylamide forms a new radical species 4. Then, the cyclization takes place to form the radical intermediate 5. Finally, the single electron transfer reaction between intermediate 5 and the tert-butoxy radical or Fe(III) species delivers the indolinone, along with one equivalent of tert-butanol. For the meta-substituted substrate, the cyclization at the more crowded 4-position is preferred because the resonance structure of the intermediate 5 is more stable than that of the 6-position. In conclusion, we developed an FeCl2-promoted carbomethylation of arylacrylamides, which provided a facile pathway leading to ethyl-3-substituted indolin-2-one. The procedure tolerates cyano, nitro, ethyloxy carbonyl, bromo, chloro and trifluoromethyl groups. A sequential methyl radical addition and cyclization is involved in this reaction. We thank the National Natural Science Foundation of China (no. 21272028 and 21202013), the ‘‘Innovation & Entrepreneurship Talents’’ Introduction Plan of Jiangsu Province, the Natural Science Foundation of Zhejiang Province (no. R4110294), the Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology and the State Key Laboratory of Coordination Chemistry at Nanjing University for financial support.
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