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Letter Cite This: Org. Lett. 2018, 20, 6298−6301

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Organocatalytic Enantioselective Addition of α‑Aminoalkyl Radicals to Isoquinolines Xiangyuan Liu,†,∥ Yang Liu,†,∥ Guobi Chai,§ Baokun Qiao,† Xiaowei Zhao,† and Zhiyong Jiang*,†,‡ †

Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, P. R. China School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China § Key Laboratory of Tobacco Flavor Basic Research of CNTC, Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou, Henan 450001, P. R. China Downloaded via UNIV OF SUNDERLAND on October 5, 2018 at 17:41:40 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: With a dual organocatalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and under the irradiation with visible light, an enantioselective Minisci-type addition of αamino acid-derived redox-active esters (RAEs) to isoquinolines has been developed. A variety of prochiral α-aminoalkyl radicals generated from RAEs were successfully introduced on isoquinolines, providing a range of valuable α-isoquinoline-substituted chiral secondary amines in high yields with good to excellent enantioselectivities. tion of N-aryl glycines to α-branched 2-vinylazaarenes,7e we were pleased to find that chiral phosphoric acid (CPA) as Brønsted acid catalyst was capable of providing an effective stereochemical control to the formation of α-stereocenters for azaarenes. In this context, we were intrigued to explore the feasibility of this catalytic scenario to the enantioselective manifold of Minisci addition of α-aminoalkyl radicals to azaarenes, to furnish an array of inconveniently accessible chiral azaarene-containing secondary amines. When we had gained some satisfactory results, unfortunately Phipps and coworkers7z preceded us to report a similar work (Scheme 1A). Nevertheless, we still wished to complete this work for two

D

ue to the potential capability of allowing unconventional bond cleavages and formations with high functional group tolerance, radical-based transformations have long been appreciated as a powerful tool in organic synthesis.1 For example, the addition of free radicals to protonated azaarenes, termed Minisci-type reactions, has been widely accepted to furnish diverse significant functionalized azaarene derivatives.2,3 In the past few years, several Minisci reactions have been successfully established by using visible-light-driven photoredox catalysis,4 thus opening up a new and promising avenue for the synthesis of those essentially challenging-tosynthesize but valuable azaarenes in a sustainable manner.3 As a paradigm, Shang, Fu, and co-workers reported a decarboxylative α-aminoalkylation of α-amino acid-derived redox-active esters (RAEs) with various electron-deficient azaarenes. The method provides a direct and convenient approach to access a vast array of important α-azaarene-substituted secondary amines.3e Remarkably, this elegant work revealed the viability of a racemic phosphoric acid catalyst to promote the transformations via H-bonding interaction with the N atom of azaarenes. In recent years, we have become interested in the development of visible-light-mediated asymmetric reactions through devising dual catalytic systems5−7 involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and a chiral organocatalyst.7 When in the progress of investigating a conjugate addition−enantioselective protona© 2018 American Chemical Society

Scheme 1. Enantioselective Minisci-Type Reactions between α-Amino Acid-Derived RAEs and Azaarenes

Received: August 31, 2018 Published: September 26, 2018 6298

DOI: 10.1021/acs.orglett.8b02791 Org. Lett. 2018, 20, 6298−6301

Letter

Organic Letters major reasons (Scheme 1B). First, our established cooperative catalytic system is transition-metal free as both the photoredox catalyst and chiral catalyst are organic, which would be a more sustainable synthetic protocol. Second and more importantly, our work is focused on the addition of α-aminoalkyl radicals to isoquinolines. The corresponding products are α-isoquinolinesubstituted secondary amines, which are significant molecular architectures of many bioactive compounds8 and ligands9 in transition-metal catalysis. In the Phipps work, however, no relative example has been reported. Herein, we would like to communicate the results. We began our investigations by selecting isoquinoline 1a and N-ethoxycarbonyl-L-phenylalanine-derived RAE 2a as the model substrates (Table 1). On the basis of a single-

Scheme 2. Mechanistic Considerations

Table 1. Optimization of the Reaction Conditionsa

entry

variation from standard conditions

yield (%)b

eec

1 2 3 4 5 6 7 8 9 10

none C2 instead of C1 C3 instead of C1 without 4 Å MS Ir[(dF(CF3)ppy)2(dtbpy)]PF6 instead of DPZ [Ru(bpy)3]Cl2 instead of DPZ no DPZ no C1 no light under air

95 0 70 90 88 trace trace N.R. 0 N.A.

93 N.A. 40 86 86 N.A. N.A. N.A. N.A. N.A.

interaction with 1a (entry 2). Ligand C3, featuring a smaller 2naphthyl, presented a decreased enantioselectivity (entry 3). Molecular sieves were found to present a slightly positive effect on enantioselectivity. When in the absence of them, 3a was accessed with a decreased ee (86%, entry 4). Ir[(dF(CF3)ppy)2(dtbpy)]PF6, the photoredox catalyst used by Shang and Fu in the racemic Minisci reaction and by Phipps in the enantioselective manifold, was also evaluated. As entry 5 shows, 3a was obtained in 88% yield with 86% ee, which was a bit poorer than the results of employing DPZ catalyst (entry 1). [Ru(bpy)3]Cl2 was detected to be ineffective in the transformation because no reaction was observed (entry 6). The control experiments confirmed that DPZ, C1, visible light, and an oxygen-free environment are indispensable for the transformation to occur (entries 7−10). With the optimal reaction conditions in hand, the scope of this asymmetric Minisci-type addition toward constructing diverse chiral α-isoquinoline-substituted secondary amines was examined (Scheme 3). The reactions of isoquinoline 1a with a variety of amino acid-derived RAEs 2 furnished products 3a− 3s in 77−95% yields with 17 to 93 ee within 60 h. For the αaryl-alanine-derived RAEs (3b−3o), electron-deficient (3b− 3i) or electron-donating (3j−3o) substituents at the para-, meta-, and ortho-positions of the aryl ring presented similar reactivities and enantioselectivities. Tryptophan-derived RAE was also compatible to the reaction conditions, and product 3p, which contains two important azaarenes such as isoquinoline and indole, was obtained in 85% yield with 82% ee. The use of valine-based RAE (3q) introduced an alkyl group, i.e., isopropyl, at the stereocenter of the secondary amine with 83% ee; of note, C3 was used as the chiral catalyst in this reaction to achieve better enantioselectivity. However, the reaction conditions were not compatible to leucine- (3r) and alanine (3s)-derived RAEs due to the decreased enantioselectivity especially for 3s (17% ee). With respect to isoquinolines 1, the reaction tolerated distinct aryl substituents regardless of their electronic properties and substitution patterns, and the corresponding products 3t−w were obtained in 81 to 93% yields with 82 to 90% ee. The reaction to furnish 3a was attempted on a 1.0 mmol scale, and the same enantioselectivity with slightly decreased yield was obtained after 96 h (footnote b). It is worth mentioning that no reaction was found when quinoline and pyridine, which were evaluated in the Phipps work,7z were used as the starting substrates. The stereochemistry of these adducts was assigned based on the structure of 3e, as solved by single-crystal X-ray diffraction.11

a

Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol). bYield of isolated product. cDetermined by HPLC analysis on a chiral stationary phase.

electron-transfer reductive quenching mechanism described by Shang and Fu wherein RAE (A, E1/2 = −1.26 to −1.37 V)10 was an oxidant and the radical B generated from addition of αaminoalkyl radical (E1/2 = −1.03 V) to isoquinoline was determined as a preferential reductant, we suggested that our DPZ (for *DPZ, Et(S*/S•−) = +0.91 V, for DPZ•−, E1/2 = −1.45 V) would be a viable photoredox catalyst (Scheme 2). As an initial attempt, the reaction was performed using 0.5 mol % DPZ and 10 mol % diphenyl phosphoric acid in CH2Cl2 at 25 °C and irradiated by a 3 W blue LED, and the desired racemic product 3a could be obtained in 82% yield [see entry 3, Table S1 in the Supporting Information (SI)]. The result encouraged us to examine a variety of chiral CPAs and reaction parameters (see Table S1 in SI). We observed that transformations conducted in 1,2-dimethoxyethane (DME) as solvent at −10 °C for 60 h in the presence of 1.0 mol % DPZ and 15 mol % chiral SPINOL-CPA C1 with 15 mg of 4 Å molecular sieves (MS) as an additive and under irradiation with two 3 W blue LEDs furnished the desired chiral product 3a in 95% yield with 93% ee (entry 1). Using C2 with 9anthryl instead of 6-(1-naphthyl)-9-anthryl as the substituent at the 6,6′-positions, no reaction was observed, likely due to its slightly modified spatial structure hindering the H-bonding 6299

DOI: 10.1021/acs.orglett.8b02791 Org. Lett. 2018, 20, 6298−6301

Letter

Organic Letters Scheme 3. Substrate Scopea

Accession Codes

CCDC 1863502 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

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

Zhiyong Jiang: 0000-0002-6350-7429 Author Contributions ∥

X.L. and Y.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Grants from the NSFC (21402239, 21672052), Henan Province (14IRTSTHN006, 162300410002), and Young Elite Scientists Sponsorship Program by CAST (2017QNRC001) are gratefully acknowledged.

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(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001. (b) Togo, H. In Advanced Free Radical Reactions for Organic Synthesis; Elsevier Science: Amsterdam, 2004. (2) For selected reviews, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. (b) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27, 79. (c) Duncton, M. A. MedChemComm 2011, 2, 1135. (d) Tauber, J.; Imbri, D.; Opatz, T. Molecules 2014, 19, 16190. For selected examples, see: (e) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M. J. Org. Chem. 1987, 52, 730. (f) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194. (g) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. P. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14411. (h) Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13, 1852. (i) Correia, C. A.; Yang, L.; Li, C.-J. Org. Lett. 2011, 13, 4581. (j) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (k) Biaco, J. L.; Jones, S. L.; Barker, T. J. Heterocycles 2016, 92, 1687. (3) (a) Jin, J.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54, 1565. (b) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87. (c) Huff, C. A.; Cohen, R. D.; Dykstra, K. D.; Streckfuss, E.; DiRocco, D. A.; Krska, S. W. J. Org. Chem. 2016, 81, 6980. (d) Li, G.-X.; MoralesRivera, C. A.; Wang, Y.; Gao, F.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2016, 7, 6407. (e) Cheng, W.-M.; Shang, R.; Fu, Y. ACS Catal. 2017, 7, 907. (f) Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. ACS Catal. 2017, 7, 4057. (g) Cheng, W.-M.; Shang, R.; Fu, M.-C.; Fu, Y. Chem. - Eur. J. 2017, 23, 2537. (h) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem. Sci. 2017, 8, 3512. (i) Wu, X.; Zhang, H.; Tang, N.; Wu, Z.; Wang, D.; Ji, M.; Xu, Y.; Wang, M.; Zhu, C. Nat. Commun. 2018, 9, 3343. (4) For selected reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (b) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 985. (c) Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48, 1474. (d) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. (e) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (5) For selected reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (b) Schultz, D. M.;

a

Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), DPZ (1.0 mol %), C1 (15 mol %), 4 Å MS (30 mg), DME (2.0 mL), −10 °C, 2 × 3 W blue LEDs. Yield of isolated product. er was determined by HPLC analysis on a chiral stationary phase. bOn a 1.0 mmol scale, 96 h, yield of 3a = 60%, ee of 3a = 93%. c15 mol % C3 was used as catalyst. dt = 96 h.

In conclusion, we developed enantioselective Minsci-type addition reactions of α-amino acid-derived RAEs to isoquinolines via visible-light-driven cooperative photoredox and chiral Brønsted acid catalysis. By using DPZ as a photosensitizer and CPA as a chiral catalyst, a variety of α-aminoalkyl radicals generated from RAEs efficiently reacted with various isoquinolines, resulting in a number of valuable α-isoquinolinesubstituted secondary amines in high yields with good to excellent enantioselectivities. The satisfactory results encourage us to pursue further novel radical addition reactions to diverse azaarenes through such a dual organocatalysis platform.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02791. General information, optimization, procedures, characterization data, determination of the absolute configuration, and NMR spectra (PDF) 6300

DOI: 10.1021/acs.orglett.8b02791 Org. Lett. 2018, 20, 6298−6301

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DOI: 10.1021/acs.orglett.8b02791 Org. Lett. 2018, 20, 6298−6301