Hydroamination

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

pubs.acs.org/OrgLett

Enantioselective Decarboxylative Propargylation/Hydroamination Enabled by Organo/Metal Cooperative Catalysis Yu-Chen Zhang, Zi-Jing Zhang, Lian-Feng Fan, and Jin Song* Department of Chemistry, University of Science and Technology of China, Hefei 230026, China S Supporting Information *

ABSTRACT: The first catalytic enantioselective decarboxylative propargylation/hydroamination reaction of ethynyl benzoxazinanones with malononitriles enabled by organo/ copper cooperative catalysis was established. Various 3-indolinmalononitrile derivatives, displaying a high tolerance for functional groups, could be obtained in good yields with high levels of enantioselectivity (up to 85% yield, 96:4 er). More importantly, this organo/metal cooperative catalytic system will provide a powerful synthetic strategy for new reaction development.

T

Over the past decades, Cu- and Ru-catalyzed propargylic substitution reactions via metal-allenylidene complexes have emerged as the most powerful strategy for the construction of complex molecules.5,6 As shown in the pioneering works by Lu, Xiao7 and You,8 under the catalysis of a copper complex, ethynyl benzoxazinanone 1a is considered to be an efficient precursor for the construction of indol/indoline derivatives (Scheme 2a). As part of recent advances and our ongoing efforts toward the development of cooperative catalysis systems,9 we speculated that a cooperatively catalytic copper/amine system10 could be developed for the construction of indoline scaffolds. As proposed in Scheme 2b, an electrophilic copper-allenylidene intermediate I is generated upon Cu-mediated decarboxylation of ethynyl benzoxazinanone 1a. Meanwhile, the combination of malononitrile 2 and a chiral amine catalyst would lead to the nucleophilic intermediate II; the subsequently asymmetric propargylic addition of I led to intermediate III. The final hydroamination step would access enantioenriched indoline malononitrile derivatives 3a. However, there are still some challenges: (i) the compatibility of copper and chiral amine catalytic systems; (ii) control of the regioselectivity in the propargylation step;11 and (iii) control of the chemoselectivity between the alkynyl group and the cyano group in the hydroamination step.12 Herein, we describe the development of such a cooperative catalytic decarboxylative propargylation/hydroamination reaction of ethynyl benzoxazinanones with malononitriles. The initial attempts to validate the proposed reaction were examined by the reaction of ethynyl benzoxazinanone 1a and 2benzylmalononitrile 2a in the cooperative catalysis of chiral ureacinchona alkaloid 4a and an achiral copper complex, which is in situ generated from CuBr and pyridine bis(oxazoline) ligand (pybox ligand) L1 (Table 1, entry 1). To our great delight, the

he indoline scaffold has been prevalently encountered as a privileged core structure in naturally bioactive alkaloids,1 constituting a large family of biological molecules as exemplified by (−)-Physostigmine, Benzastatin E, and Pentopril (Scheme 1a). Due to its structural complexity as well as bioactive diversity, Scheme 1. Representative Biologically Active Molecules with Indoline and Malononitrile Scaffolds

the enantioselective construction of an indoline skeleton has emerged as one of the most practical strategies in drug discovery.2 However, malononitrile compounds have been considered to be useful organic intermediates in medicinal synthesis,3 presenting a broad range of biological activities (Scheme 1b).4 Stimulated by the unique biological activities of indoline and malononitrile scaffolds, the synthesis of optical active 3-indolin-malononitrile scaffold has a high value in synthetic and pharmaceutical chemistry (Scheme 1c). © XXXX American Chemical Society

Received: April 8, 2018

A

DOI: 10.1021/acs.orglett.8b01101 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

of chiral ligands L2−L5 were evaluated (entries 2−5), and L3 was identified to be the optimum one (entry 3). Reaction conditions and other parameters were studied (see SI, Table S2), and the standard conditions were obtained as CuBr (10 mol %), pybox ligand L3 (20 mol %), chiral urea-cinchona catalyst 4a (10 mol %), ethynyl benzoxazinanone 1a (0.1 mmol), 2benzylmalononitrile 2a (0.4 mmol), MgSO4 (50 mg) in DCM (1.0 mL) at 10 °C with stirring for 12 h (entry 6). In order to gain more insight into the cooperative catalytic system, we carried out some control experiments (Table 1, entries 7−11). No background reaction was observed with an individual catalytic system (entries 7 and 8). These results supported the synergistic feature of this reaction system that the chiral copper complex and organocatalyst, respectively, play a crucial role. The enantioselectivity was dramatically decreased to 85:15 er when ent-L3 was used (entry 9). Furthermore, the use of an achiral pybox ligand L1 or 4-dimethylaminopyridine (DMAP) would dramatically affect both the efficiency and selectivity of this reaction (entries 10 and 11), thus implying that the matched chirality of ligand and amine catalyst plays a key role in the cooperative decarboxylative propargylation/hydroamination reaction. With the optimal conditions in hand, the scope of this reaction with respect to the substitution of 2-benzylmalononitriles 2 was explored (Table 2). We were pleased to find that a wide range of

Scheme 2. Design of Cooperative Decarboxylative Propargylation/Hydroamination Reaction

Table 2. Substrate Scope of Malononitriles 2a Table 1. Optimization of Reaction Conditionsa

entry

[Cu]

1 2 3 4 5 6d 7d 8d 9d 10d 11d

CuBr CuBr CuBr CuBr CuBr CuBr

L1 L2 L3 L4 L5 L3

CuBr CuBr CuBr CuBr

L3 ent-L3 L1 L3

L

4a 4a 4a 4a 4a 4a 4a 4a 4a 4a DMAP

yield (%)b

er (%)c

30 52 51 50 55 72 n.d. n.d. 35 50 43

90:10 92:8 94:6 75:25 91:9 95:5

entry

3

R (2)

yield (%)b

er (%)c

1 2 3 4 5 6 7 8 9 10 11 12

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak 3al

C6H5 (2a) 2−Cl-C6H4 (2b) 3−Cl-C6H4 (2c) 3-Me-C6H4 (2d) 3-OMe-C6H4 (2e) 4−F-C6H4 (2f) 4−Cl-C6H4 (2g) 4−Br-C6H4 (2h) 4-OMe-C6H4 (2i) 1-naphthyl (2j) 2-thiophenyl (2k) H (2l)

72 57 72 69 82 85 67 64 80 68 50 39

95:5 91:9 95:5 93:7 95:5 95:5 96:4 96:4 92:8 90:10 90:10 86:14

a

Reaction conditions: 1a (0.1 mmol), 2 (0.4 mmol), CuBr (10 mol %), L3 (20 mol %), 4a (10 mol %), MgSO4 (50 mg) in DCM (1.0 mL) at 10 °C for 12 h. bIsolated yield. cThe er value was determined by HPLC.

85:15 89:11 55:45

malononitriles 2 bearing either electron-withdrawing or donating substituents on the benzene ring were tolerated in this protocol (entries 1−9), delivering chiral 3-indolin-malononitrile derivatives 3 in generally high yields (up to 85%) and good enantioselectivities (up to 96:4 er). The reaction of naphthyland hetereoaryl-substituted malononitriles 2j and 2k also proceeded successfully to afford the desired products 3aj and 3ak in good enantioselectivities (entries 10 and 11). Nevertheless, this method can also be extended to aliphatic substituted malononitrile 2l affording product 3al with moderate stereoselectivity (entry 12). The absolute configuration of 3ah (>99.5:0.5 er after recrystallization) was assigned by singlecrystal X-ray diffraction analysis (see SI).

a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), CuX (10 mol %), L (12 mol %), 4a (20 mol %) in DCM (2.0 mL) at 25 °C for 12 h. b Isolated yield. cThe er value was determined by HPLC. dWith 1a (0.1 mmol), 2a (0.4 mmol), CuBr (10 mol %), L3 (20 mol %), 4a (10 mol %), MgSO4 (50 mg) in DCM (1.0 mL) at 10 °C for 12 h.

desired 3-indolin-malononitrile product 3aa was obtained in moderate yield and enantioselectivity (30% yield, 90:10 er, entry 1). Screening of chiral urea-cinchona catalysts showed that 4a was the best chiral amine catalyst (see Supporting Information (SI), Table S1). Encouraged by these promising results, a series B

DOI: 10.1021/acs.orglett.8b01101 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters As shown in Table 3, this protocol was also available to a wide range of ethynyl benzoxazinanones 1 bearing various sub-

preliminary derivations were carried out. As shown in Scheme 3, we treated enantioenriched 3aa with a 10-fold molar excess of

Table 3. Substrate Scope of Ethynyl Benzoxazinanone 1a

Scheme 3. Synthetic Applications

entry

3

R (1)

yield (%)b

er (%)c

1 2d 3 4 5d 6 7 8

3af 3bf 3cf 3df 3ef 3ff 3gf 3hf

H (1a) 5-F (1b) 6-Cl (1c) 6-Br (1d) 6-Me (1e) 7-F (1f) 7-CF3 (1j) 7-Me (1h)

85 65 68 50 61 55 50 56

95:5 94:6 92:8 90:10 95:5 90:10 94:6 93:7

30% aqueous H2O2 in THF at room temperature, and the desired indoline diol 5 was obtained in 75% yield without loss of optical purity. The hydrogenation of 3hf gave the cis-diastereoisomer 6 in moderate yield and excellent diastereoselectivity with maintained enantioselectivity.5n Furthermore, the hydrolysis of 6 occurred to afford the corresponding diamide 7 with excellent stereoselectivity. In summary, we have established the first catalytic asymmetric approach to construct 3-indolin-malononitrile scaffold in good yields and enantioselectivities (up to 85% yield, 96:4 er). It turned out that copper complexes and the chiral urea-cinchona organocatalyst, respectively, play a crucial role to exhibit high enantioselectivity of this cascade decarboxylative propargylation/hydroamination reaction. The future study will focus on the comprehensive exploration of the reaction mechanism and other propargylic substitution reactions initiated with ogano/metal cooperative catalysis.

a

Reaction conditions: 1 (0.1 mmol), 2f (0.4 mmol), CuBr (10 mol %), L3 (20 mol %), 4a (10 mol %), MgSO4 (50 mg) in DCM (1.0 mL) at 10 °C for 12 h. bIsolated yield. cThe er value was determined by HPLC. dCompound 4a (20 mol %) in DCM (0.5 mL).

stituents at different positions on the benzene ring, affording 3indolin-malononitrile derivatives 3 with structural diversity in generally good yields (up to 85%) and enantioselectivities (up to 95:5 er). Ethynyl benzoxazinanones 1b−1d and 1f with halogen substituents at the 5-, 6-, and 7-positions, all participated in the transformation smoothly (entries 2−4 and 6). Furthermore, electron-donating substituents, such as methyl, in different positions on the aromatic ring (1e and 1h) were also employed in the reaction successfully, affording the products in moderate yields and good enantioselectivities (entries 5 and 8). On the basis of our experimental results, a hypothetical transition state was proposed (Figure 1). As depicted, the chiral

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01101. Experimental details and characterization data (PDF) Accession Codes

CCDC 1569457 contains 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 1. Proposed catalytic transition state.

bis(oxazoline)copper(II) complexes undergo the decarboxylation with 1a to generate copper−allenylidene complex. However, the urea part of organocatalyst 4a might serve as an activator of the tosyl group of the copper-allenylidene intermediate by a dual hydrogen-bond interaction;13 the tertiary amine part of the quinine unit acted as a Brønsted base to deprotonate and activate malononitriles 2 via a strong hydrogen bond with a nitrogen atom of malononitriles 2.14 These two catalysts, respectively, played their important roles on the reactivity and enantioselectivity control in the cooperative decarboxylative propargylation/hydroamination reaction. As part of our aim at demonstrating the practicability of the current reaction, 0.5 mmol scale and gram-scale reactions of ethynyl benzoxazinanones 1 and malononitriles 2 were performed successfully (see SI, Tables S3 and S4). To demonstrate the synthetic versatility of this reaction, some

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jin Song: 0000-0003-0449-1727 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21702199) and the China Postdoctoral Science Foundation (No. 2017M612075). C

DOI: 10.1021/acs.orglett.8b01101 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

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Chem., Int. Ed. 2017, 56, 5212. (m) Lu, X.; Ge, L.; Cheng, C.; Chen, J.; Cao, W.; Wu, X. Chem. - Eur. J. 2017, 23, 7689. (10) (a) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140. (b) Sladojevich, F.; Fuentes de Arriba, Á . L.; Ortín, I.; Yang, T.; Ferrali, A.; Paton, R. S.; Dixon, D. J. Chem. - Eur. J. 2013, 19, 14286. (11) (a) Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed. 2007, 46, 1650. (b) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774. (c) Vyas, D. J.; Hazra, C. K.; Oestreich, M. Org. Lett. 2011, 13, 4462. (d) Uehling, M. R.; Marionni, S. T.; Lalic, G. Org. Lett. 2012, 14, 362. (e) Hazra, C. K.; Oestreich, M. Org. Lett. 2012, 14, 4010. (f) Shen, R.; Luo, B.; Yang, J.; Zhang, L.; Han, L.-B. Chem. Commun. 2016, 52, 6451. (12) (a) Benati, L.; Bencivenni, G.; Leardini, R.; Minozzi, M.; Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G.; Rizzoli, C. Org. Lett. 2004, 6, 417. (b) Feng, X.; Wang, J.-J.; Zhang, J.-J.; Cao, C.-P.; Huang, Z.-B.; Shi, D.-Q. Green Chem. 2015, 17, 973. (13) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (14) (a) Li, X.; Cun, L.; Lian, C.; Zhong, L.; Chen, Y.; Liao, J.; Zhu, J.; Deng. Org. Biomol. Chem. 2008, 6, 349. (b) Shi, J.; Wang, M.; He, L.; Zheng, K.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 4711. (c) Russo, A.; Capobianco, A.; Perfetto, A.; Lattanzi, A.; Peluso, A. Eur. J. Org. Chem. 2011, 2011, 1922. (d) Yang, W.; Jia, Y.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 332.

REFERENCES

(1) (a) Southon, I. W.; Buckingham, J. Dictionary of Alkaloids; Chapman and Hall: New York, 1989. (b) Gueritte, F.; Fahy, J. In Anticancer Agents from Natural Products; Cragg, G. M., Kingstom, D. G. I., Newman, D. J., Eds.; CRC Press: Boca Raton, FL, 2005; p 123. (c) Modern Alkaloids; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim, 2008. (d) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (2) (a) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (b) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 2010, 3975. (c) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447. (d) Zi, W.; Zuo, Z.; Ma, D. Acc. Chem. Res. 2015, 48, 702. (3) (a) Masesane, I. B.; Desta, Z. Y. Beilstein J. Org. Chem. 2012, 8, 2166. (b) Dandia, A.; Singh, R.; Maheshwari, S. Curr. Org. Chem. 2014, 18, 2513. (c) Nayak, S.; Chakroborty, S.; Bhakta, S.; Panda, P.; Mohapatra, S. Res. Chem. Intermed. 2016, 42, 2731. (4) (a) Edwards, J. D.; Pianka, M. J. J. Sci. Food Agric. 1963, 14, 55. (b) Horiuchi, F.; Fujimoto, K.; Ozaki, T.; Nishizawa, Y. Agric. Biol. Chem. 1971, 35, 2003. (c) Hofmann, M.; Bastiaans, H. M. M.; Langewald, J.; Oloumi-Sadeghi, H.; Culbertson, D. L. PCT Int. Appl. WO 2007017414A1 20070215, 2007. (d) Pohlman, M.; Hofmann, M.; Bastiaans, H. M. M.; Rack, M.; Culbertson, D. L.; Oloumi-Sadeghi, H.; Hokama, T.; Palmer, C.; Langewald, J. PCT Int. Appl. WO 2007071609A1 20070628, 2007. (5) For selected examples of Cu-catalyzed propargylic substitution reactions, see: (a) Bruneau, C.; Dixneuf, P. Metal Vinylidenes and Allenylidenes in Catalysis; Wiley-VCH: Weinheim, 2008. (b) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (c) Hattori, G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2008, 47, 3781. (d) Detz, R. J.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 2009, 6263. (e) Fang, P.; Hou, X.-L. Org. Lett. 2009, 11, 4612. (f) Ljungdahl, N.; Kann, N. Angew. Chem., Int. Ed. 2009, 48, 642. (g) Ding, C.-H.; Hou, X.L. Chem. Rev. 2011, 111, 1914. (h) Nishibayashi, Y. Synthesis 2012, 44, 489. (i) Zhang, C.; Hu, X.-H.; Wang, Y.-H.; Zheng, Z.; Xu, J.; Hu, X.-P. J. Am. Chem. Soc. 2012, 134, 9585. (j) Zhang, D.-Y.; Hu, X.-P. Tetrahedron Lett. 2015, 56, 283. (k) Zhu, F.-L.; Zou, Y.; Zhang, D.-Y.; Wang, Y.-H.; Hu, X.-H.; Chen, S.; Xu, J.; Hu, X.-P. Angew. Chem., Int. Ed. 2014, 53, 1410. (l) Cheng, L.-J.; Cordier, C. J. Angew. Chem., Int. Ed. 2015, 54, 13734. (m) Tsuchida, K.; Senda, Y.; Nakajima, K.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2016, 55, 9728. (n) Shao, L.; Wang, Y.-H.; Zhang, D.-Y.; Xu, J.; Hu, X.-P. Angew. Chem., Int. Ed. 2016, 55, 5014. (o) Li, R.Z.; Tang, H.; Yang, K. R.; Wan, L.-Q.; Zhang, X.; Liu, J.; Fu, Z.; Niu, D. Angew. Chem., Int. Ed. 2017, 56, 7213. (p) Cheng, L.-J.; Brown, A. P. N.; Cordier, C. J. Chem. Sci. 2017, 8, 4299. (6) For selected examples of Ru-catalyzed propargylic substitution reactions, see: (a) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed. 2005, 44, 7715. (b) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498. (c) Senda, Y.; Nakajima, K.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2015, 54, 4060. (7) (a) Wang, Q.; Li, T.-R.; Lu, L.-Q.; Li, M.-M.; Zhang, K.; Xiao, W.-J. J. Am. Chem. Soc. 2016, 138, 8360. (b) Li, T.-R.; Cheng, B.-Y.; Wang, Y.N.; Zhang, M.-M.; Lu, L.-Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2016, 55, 12422. (c) Li, T.-R.; Lu, L.-Q.; Wang, Y.-N.; Wang, B.-C.; Xiao, W.-J. Org. Lett. 2017, 19, 4098. (8) Shao, W.; You, S.-L. Chem. - Eur. J. 2017, 23, 12489. (9) (a) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567. (b) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 3329. (c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302. (d) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222. (e) Shao, Z.-H.; Zhang, H.-B. Chem. Soc. Rev. 2009, 38, 2745. (f) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (g) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272. (h) Chen, D.-F.; Han, Z.Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (i) Yang, Z.P.; Zhang, W.; You, S.-L. J. Org. Chem. 2014, 79, 7785. (j) Afewerki, S.; Córdova, A. Chem. Rev. 2016, 116, 13512. (k) Meazza, M.; Rios, R. Synthesis 2016, 48, 960. (l) Song, J.; Zhang, Z.-J.; Gong, L.-Z. Angew. D

DOI: 10.1021/acs.orglett.8b01101 Org. Lett. XXXX, XXX, XXX−XXX