Enantioselective Phosphine-Catalyzed Allylic Alkylations of mix

Oct 27, 2017 - The first enantioenriched synthesis of 1,1,3-trisubstituted (trifluoromethyl)indene derivatives, bearing a quaternary stereogenic carbo...
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Letter Cite This: Org. Lett. 2017, 19, 6080-6083

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Enantioselective Phosphine-Catalyzed Allylic Alkylations of mixIndene with MBH Carbonates Junyou Zhang, Hai-Hong Wu,* and Junliang Zhang* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China S Supporting Information *

ABSTRACT: The first enantioenriched synthesis of 1,1,3trisubstituted (trifluoromethyl)indene derivatives, bearing a quaternary stereogenic carbon center, is reported using a simple chiral sulfinamide phosphine-catalyzed asymmetric allylic alkylation of a mixture of indenes with Morita−Baylis− Hillman carbonates. The resulting derivatives can serve as a valuable synthetic building block for some drugs and natural products. Broad substrate scope and high regio- and enantioselectivity of this reaction were particularly remarkable.

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afford tertiary 1H-indene-1-amine compounds (Scheme 1a). In 2016, Jørgensen first realized a formal [4 + 2] cycloaddition of benzofulvenes with 2,4-dienals through trienamine catalysis, providing a facile method to spiroindene derivatives5a (Scheme 1b-left). The same group also demonstrated an asymmetric cyclopropanation of benzofulvenes with dimethyl bromomalonate to construct cyclopropane spiroindenes by the employing chiral phase-transfer catalysis (PTC)5b (Scheme 1b-right). Undoubtedly, asymmetric hydrogenation is also a powerful tool to obtain chiral indene derivatives catalyzed by Co,6b Ir,6c Rh,6d and Zr6e complexes. Due to its salient strong electron-acceptor characteristics, the CF3 group can enhance robustness against metabolic oxidation. Therefore, the construction of organic compounds bearing a trifluoromethyl group has attracted much attention.7 However, to the best of our knowledge, the synthesis of optically active (trifluoromethyl)indene derivatives, especially with all carbon C1-quaternary carbon stereocenters, has not so far been reported. The asymmetric allylic alkylation is an effective method for controlling the facial access of nucleophiles to double bonds and allows carbon−carbon and carbon−heteroatom bonds to often be formed rapidly. Morita−Baylis−Hillman (MBH) carbonates have been developed to react with a range of nucleophiles via this reaction mode, especially under the catalysis of chiral phosphines.8 Very recently, our group has devised an umpolung addition of trifluoromethyl ketimines to MBH carbonates catalyzed by Peng-Phos to produce valuable α-methylene-γlactams.8k Inspired by this work, we became interested in defining whether chiral indenes with a trifluoromethylated quaternary stereocenter could be efficiently constructed by the phosphine-catalyzed asymmetric allylic alkylation of mixindenes. However, this method poses considerable challenges

he indene core is a privileged framework in numerous natural products.1 Chiral, nonracemic indenes that bear a stereogenic center are valuable in pharmaceutical research.2 However, methods for enantioselective syntheses of these compounds are limited, particularly for indene molecules enantioenriched with a quaternary center. Few efforts have been made for building different chiral indene derivatives over the years. Among the methods that are available, there are two typical efficient strategies based on intra-3 and intermolecular4,5 cyclization. Representative intramolecular methods focus on C− H activation via Pd(II)3a,b catalysis. Cramer4a et al. developed an enantioselective Rh(I)-catalyzed intermolecular tandem cyclization of unsaturated aromatic ketimines with internal alkynes to Scheme 1. Synthesis of Indene Derivatives and MBH Carbonates Utilized in Asymmetric Allylic Alkylation Reactions

Received: September 15, 2017 Published: October 27, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b02895 Org. Lett. 2017, 19, 6080−6083

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope of the Aryl Ring of Indenesa

3a entry

1

cat.*

solvent

yield [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d 17e 18f 19 20g

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a′ 1a+1a′

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P8 P8 P8 P8 P8 P8 P8 P8 P8 P8

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DCM DCE THF Et2O CH3CN toluene toluene toluene toluene toluene

88 85 87 43 85 85 82 85 88 78 87 86 71 53 46 71 47 35 84 87

b

ee [%]c 96 95 95 66 92 89 45 97 89 8 94 96 94 97 93 96 96 96 96 95

a Unless otherwise specified, all reactions were carried out with 1 (0.1 mmol), 2a (0.15 mmol), chiral phosphine catalyst (10 mol %) in solvent (2 mL), rt, 3a/3a′ > 49:1 (see Supporting Information for details). bIsolated yield. cDetermined by HPLC analysis using a chiral stationary phase. d7.5 mol % P8 used. e5 mol % P8 used. f2.5 mol % P8 used. g1a/1a′ = 1:1.

a Unless otherwise specified, all reactions were performed with 1 (0.1 mmol), 2 (0.15 mmol), and P8 (10 mol %) in toluene (2 mL) under argon, rt; isolated yields were reported; ee was determined by chiral HPLC analysis. bIsomer ratio of starting material (see SI for details). c 15 mol % P8 used.

derived from aliphatic sulfinimines were then investigated. Disappointingly, low enantioselectivity of the product arose with the P7 with a bulky tert-butyl group, even though the reaction gave rise to a good yield (Table 1, entry 7). To our delight, P8 with a less sterically demanding isopropyl proved to be a promising catalyst, incredibly furnishing an 85% yield with 97% ee. Further simplification of the skeleton from isopropyl to methyl led to a slightly lower ee (Table 1, entry 9). Next, the influence of solvent was also evaluated, and no solvents were better than toluene (Table 1, entries 11−15). Further investigations into lowering the catalyst loading from 10% to 7.5%, 5%, and 2.5% did not adversely affect the enantioselectivity, but the yield declined significantly (Table 1, entries 16−18). Interestingly, 3-phenyl-1-(trifluoromethyl)-1H-indene 1a′, the isomer of 1a, also reacted smoothly to give product in 84% yield with 96% ee (Table 1, entry 19), proving that a mixture of 1a and 1a′ could be used directly (Table 1, entry 20). With the optimal reaction conditions in hand, we next examined the substrate scope of this highly regio- and enantioselective allylic alkylation. In general, the aryl ring of indenes bearing electron-donating or electron-withdrawing groups at the 5-position were well tolerated. For instance, 5Me-substituted 3b and 5-MeO-substituted 3c were exclusively formed in good yields and with excellent enantioselectivity (Scheme 2; 3b, 88% yield, 94% ee, and 3c, 83% yield, 94% ee). In particular, a strong electron-withdrawing substituent CF3 at the

Figure 1. Screened chiral phosphine catalysts.

due to the easy fluoride elimination9 of indene carbanion intermediates. With this in mind, the reaction of 1-phenyl-3-(trifluoromethyl)-1H-indene 1a and carbonate 2a in toluene was investigated in the presence of a series of (R)-tert-butylsulfinamide derived chiral phosphine catalysts (Figure 1) at room temperature. Gratifyingly, the product 3a was obtained in 88% yield with 96% ee with less than a 2% NMR yield of a byproduct 3a′ when P1 was used (Table 1, entry 1). Motivated by this result, a systematic screening of related catalysts was conducted. Whether with an aryl substituent at the ortho-position of the phenyl ring, such as P2, P3, and P6, good enantioselectivities and high yields were obtained. Wei-Phos P5 also gave a favorable result, but XiaoPhos P4 delivered only moderate ee. Several simpler catalysts 6081

DOI: 10.1021/acs.orglett.7b02895 Org. Lett. 2017, 19, 6080−6083

Letter

Organic Letters Scheme 3. Substrate Scope of Indenes Functionalized at the 3Positiona

Scheme 4. Gram-Scale Synthesis of 3g and Transformations

a Unless otherwise specified, all reactions were performed with 1 (0.1 mmol), 2 (0.15 mmol), and P8 (10 mol %) in toluene (2 mL) under argon, rt; isolated yields were reported; ee was determined by chiral HPLC analysis. bIsomer ratio of starting material (see SI for details).

high yields with excellent enantioselectivities (3w−3z). Nevertheless, ether substituted carbonates derived from acrylatebenzaldehyde (2f) or acetaldehyde (2g) were not compatible in this catalysis mode (eq 1; see SI for details). Finally, it is noteworthy that when the CF3 group was functionalized with an ester, for instance, this delivered the corresponding asymmetric allylic alkylation product in 97% yield and 90% ee (eq 2).

5-position had no negative influence on the yield and ee (3d). Halogen-substituents were also compatible with the reaction to give high ee values and moderate to excellent yields (3e−3h). When the 7-position of the indene was bearing a methyl group, the corresponding 3i could be also produced in 77% yield with 96% ee. Additionally, a disubstituted indene ring could be used, such as 4,6-dimethyl, 5,6-dimethoxy, and 5,6-dioxole, with the corresponding (trifluoromethyl)indenes products being exclusively obtained in high yield (82%−94%) with high enantioselectivities (90%−94% ee) (3j−3l). To our delight, a naphthalene ring could be used instead of the benzene ring of indene, leading to the corresponding products in good yields with excellent enantioselectivity (3m−3n). We next investigated the scope of different substituents at the 3-position of indenes under the standard reaction conditions. Indenes containing electron-rich (3o), electron deficient (3p− 3r), or electron-neutral (3u−3v) substituents all proved to be suitable reaction partners with favorable yields and excellent ee values (Scheme 3). Moreover, bromo-compounds were welltolerated, furnishing the corresponding products in similar enantioselectivities and yields (3s, 3t). Additionally, when the ester group of the MBH carbonate was replaced by other substituents, the corresponding products were still obtained in

To illustrate the practical applicability of this protocol, a Gramscale reaction under the standard conditions was conducted without loss of efficiency and enantioselectivity (3g: 91% yield, 96% ee). Besides, several transformations of these chiral allylic alkylation products were carried out (Scheme 4). For example, 6082

DOI: 10.1021/acs.orglett.7b02895 Org. Lett. 2017, 19, 6080−6083

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Organic Letters

9559. (c) Egi, M.; Shimizu, K.; Kamiya, M.; Ota, Y.; Akai, S. Chem. Commun. 2015, 51, 380. (4) For selected examples of synthesis indene skeleton via intermolecular cyclization, see: (a) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 11098. (b) Zhou, F.; Yang, M.; Lu, X. Org. Lett. 2009, 11, 1405. (c) Yang, L.; Zheng, H.; Luo, L.; Nan, J.; Liu, J.; Wang, Y.; Luan, X. J. Am. Chem. Soc. 2015, 137, 4876. (d) Reddy Chidipudi, S.; Burns, D. J.; Khan, I.; Lam, H. W. Angew. Chem., Int. Ed. 2015, 54, 13975. (e) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 4880. (f) Pham, M. V.; Cramer, N. Chem. - Eur. J. 2016, 22, 2270. (5) (a) Donslund, B. S.; Nielsen, R. P.; Monsted, S. M. N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 11124. (b) Donslund, B. S.; Jessen, N. I.; Jakobsen, J. B.; Monleón, A.; Nielsen, R. P.; Jørgensen, K. A. Chem. Commun. 2016, 52, 12474. (6) (a) Kraft, S.; Ryan, K.; Kargbo, R. B. J. Am. Chem. Soc. 2017, 139, 11630. (b) Friedfeld, M. R.; Shevlin, M.; Margulieux, G. W.; Campeau, L.-C.; Chirik, P. J. J. Am. Chem. Soc. 2016, 138, 3314. (c) Schrems, M. G.; Neumann, E.; Pfaltz, A. Angew. Chem., Int. Ed. 2007, 46, 8274. (d) Zhang, Z.; Wang, J.; Li, J.; Yang, F.; Liu, G.; Tang, W.; He, W.; Fu, J.J.; Shen, Y.-H.; Li, A.; Zhang, W.-D. J. Am. Chem. Soc. 2017, 139, 5558. (e) Troutman, M. V.; Appella, D. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4916. (7) For selected examples, see: (a) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Criscione, K. R. J. Med. Chem. 1999, 42, 3315. (b) Dal Pozzo, A.; Ni, M.; Muzi, L.; de Castiglione, R. D.; Mondelli, R.; Mazzini, S.; Penco, S.; Pisano, C.; Castorina, M.; Giannini, G. J. Med. Chem. 2006, 49, 1808. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (d) O’Shea, P. D.; Chen, C.-Y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Volante, R. P. J. Org. Chem. 2009, 74, 1605. (8) For reviews of asymmetric phosphine catalysis, see: (a) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (b) Li, W.; Zhang, J. Chem. Soc. Rev. 2016, 45, 1657. (c) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (d) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. For selected examples of AAA reactions utilizing MBH adducts under the chiral phosphine catalyst, see: (e) Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed. 2004, 43, 6689. (f) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (g) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011, 2011, 1956. (h) Zhong, F.; Luo, J.; Chen, G.-Y.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2012, 134, 10222. (i) Zhao, S.; Zhao, Y.-Y.; Lin, J.-B.; Xie, T.; Liang, Y.-M.; Xu, P.-F. Org. Lett. 2015, 17, 3206. (j) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Angew. Chem., Int. Ed. 2016, 55, 2147. (k) Chen, P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 13316. (9) For reviews, see: (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Chelucci, G. Chem. Rev. 2012, 112, 1344. For selected examples about fluoride elimination of the carbanion intermediate of αCF3 compounds, see: (c) Kitazume, T.; Ohnogi, T.; Miyauchi, H.; Yamazaki, T.; Watanabe, S. J. Org. Chem. 1989, 54, 5630. (d) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 2002, 1917. (e) Yang, J.; Mao, A.; Yue, Z.; Zhu, W.; Luo, X.; Zhu, C.; Xiao, Y.; Zhang, J. Chem. Commun. 2015, 51, 8326. (f) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J. Chem. Commun. 2016, 52, 4922. (10) (a) Zhou, W.; Su, X.; Tao, M.; Zhu, C.; Zhao, Q.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 14853. (b) Zhou, W.; Chen, P.; Tao, M.; Su, X.; Zhao, Q.; Zhang, J. Chem. Commun. 2016, 52, 7612. (11) (a) Compagnone, R. S.; Avila, R.; Suárez, A. I.; Abrams, O. V.; Rangel, H. R.; Arvelo, F.; Piña, I. C.; Merentes, E. J. Nat. Prod. 1999, 62, 1443. (b) Sammelson, R. E.; Gurusinghe, C. D.; Kurth, J. M.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2002, 67, 876. (12) CCDC 1574639 for compound 8; see the SI for details.

hydrolysis of ester 3g provided efficient access to the carboxylic acid 6. Treatment of 3g with DIBAL-H delivered chiral allyl alcohol product 7 smoothly. The highly efficient and stereoselective palladium-catalyzed Heck reaction of 3g with iodobenzene generated alternative access to multiple valuable and optically active alkenyl compounds.10 Cycloaddition of 3g with α-chlorobenzaldoxime could provide isoxazoline-containing natural products.11 The hydroxyl of 7 could easily undergo oxidation to acrolein, and the phenyl hydrazine 10 was obtained via condensation with phenylhydrazine. The absolute stereochemistry of 8 was determined via single-crystal X-ray diffraction, and the configurations of the remaining products was assigned by analogy (see the SI for details).12 In summary, we have developed a mild, highly efficient, and regio-/enanotioselective allylic alkylation that provides optically enriched 1,1,3-trisubstituted (trifluoromethyl)indene derivatives, which employ a simple chiral sulfinamide phosphine catalyst. Further efforts toward the transformation of these optically active trifluoromethylindene compounds are currently in progress in our laboratory, and these results will be reported in due course.

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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.7b02895. Experimental procedures; spectroscopic date for catalyst, substrates, and products (PDF) X-ray data for (R)-8 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hai-Hong Wu: 0000-0001-6266-8290 Junliang Zhang: 0000-0002-4636-2846 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the 973 Program (2015CB856600), the National Natural Science Foundation of China (21373088, 21425205, 21672067), and the Changjiang Scholars and Innovative Research Team in University (PCSIRT) for financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b02895 Org. Lett. 2017, 19, 6080−6083