Palladium and Lewis-Acid-Catalyzed Intramolecular Aminocyanation

Feb 21, 2018 - Other palladium sources, such as Pd(OAc)2 and Pd2dba3 were less effective paired with Xantphos when compared with CpPd(1-phenylallyl) (...
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Cite This: J. Am. Chem. Soc. 2018, 140, 3331−3338

Palladium and Lewis-Acid-Catalyzed Intramolecular Aminocyanation of Alkenes: Scope, Mechanism, and Stereoselective Alkene Difunctionalizations Zhongda Pan,† Shengyang Wang,† Jason T. Brethorst, and Christopher J. Douglas* Department of Chemistry, University of MinnesotaTwin Cities, 207 Pleasant St. SE, Minneapolis, Minnesota 55455, United States S Supporting Information *

ABSTRACT: An expansion of methodologies aimed at the formation of versatile organonitriles, via the intramolecular aminocyanation of unactivated alkenes, is herein reported. Importantly, the need for a rigid tether in these reactions has been obviated. The ease-of-synthesis and viability of substrates bearing flexible backbones has permitted for diastereoselective variants as well. We demonstrated the utility of this methodology with the formation of pyrrolidones, piperidinones, isoindolinones, and sultams. Furthermore, subsequent transformation of these motifs into medicinally relevant molecules is also demonstrated. A double crossover 13C-labeling experiment is consistent with a fully intramolecular cyclization mechanism. Deuterium labeling experiments support a mechanism involving syn-addition across the alkene.

1. INTRODUCTION Nitriles are versatile building blocks in organic chemistry found in pharmaceuticals, cosmetics, and organic materials.1 Recent advances in cyanation reactions using nonmetallic cyanating agents hold promise for minimizing the environmental concerns associated with metal cyanides.2 The DuPont adiponitrile process represents a classic industrial application of the catalytic hydrocyanation reaction of alkenes.3 However, compared with the well-established cyanide addition reactions to polar functional groups,4 cyanide addition reactions to nonpolar C−C multiple bonds, such as alkenes and alkynes, are substantially more challenging.5 Recently, new catalytic approaches for accessing functionalized nitriles by cyanofunctionalization reactions of alkenes (or alkynes) have been discovered. The addition of a C−CN or heteroatom−CN σ-bond across a nonpolar C−C π-bond installs new C−CN bonds in conjunction with vicinal C−C,6 C−B,7 C−Si,8 C−Ge,9 C−Sn,10 C−Br,11 C−S,12 C−O,13 or C−N14,15 bonds in a single operation. Nakao’s group reported palladium/Lewis-acid-catalyzed intramolecular oxycyanation13a and aminocyanation14a of alkenes through the activation of O− CN bonds of cyanates and N−CN bonds of cyanamides, respectively. These transformations, including a preliminary enantioselective variant, enable rapid construction of substituted dihydrobenzofuranes, indolines, and pyrrolidines. We independently discovered Rh(I)/BPh3-catalyzed and B(C6F5)3catalyzed aminocyanation of alkenes to access indolines and tetrahydroquinolines (Scheme 1, part a).14b For our metal free process, a recent computational study postulated a concerted asynchronous alkene addition mechanism.14c Very recently, Shi and co-workers demonstrated an oxycyanation of methylenecyclopropanes triggered by N−CN bond cleavage, leading to the formation of benzo[d][1,3]oxazines.13b © 2018 American Chemical Society

Scheme 1. Synthesis of Lactams and Sultams by N−CN Bond Activation and Aminocyanation of Alkenes

Despite these advances, current aminocyanation methods are typically restricted to constructing heterocycles containing rigid aromatic backbones (e.g., indolines and tetrahydroquinolines) or requiring activated alkenes (e.g., methylenecyclopropanes). Received: February 2, 2018 Published: February 21, 2018 3331

DOI: 10.1021/jacs.8b01330 J. Am. Chem. Soc. 2018, 140, 3331−3338

Article

Journal of the American Chemical Society Table 1. Optimization of Aminocyanation Conditions

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16g 17g

palladium

CpPd(1-phenylallyl) Pd(PPh3)4 Pd(OAc)2 Pd2dba3 CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl) CpPd(1-phenylallyl)

ligand

Xantphos Xantphos Xantphos dpped dppp dppb DPEphos Xantphos Nixantphos DBFphos Xantphos Xantphos Xantphos

Lewis acid (equiv)

T (°C)

yield of 2a (%)a

BPh3 (0.5) B(C6F5)3 (0.5) AlCl3 (0.5) BPh3 (0.5) BPh3 (0.5) BPh3 (0.5) BPh3 (0.5) BPh3 (0.4) BPh3 (0.4) BPh3 (0.4) BPh3 (0.4) BPh3 (0.4) BPh3 (0.4) BPh3 (0.4)

100 80 80 90 90 90 90 80 80 80 80 80 80 80 80 80 80

0b 0b 0c 87 81 67 69 0b 23 49 72 93 81 0b 20:1 d.r.). Encouraged by these results, we further extended the scope of diastereoselective aminocyanation reactions to access functionalized lactams bearing an all-carbon stereocenter (2an), an N-phthalimide group (2ao), or a benzyloxy group (2ap) α to the carbonyl, resulting in generally good yield. The d.r. was excellent when one of the α-substituents was large, as in 2an (19:1 d.r.) and 2ao (20:1 d.r.), but lower when both were small (2ap, 3.2:1). Furthermore, cyclization of an alkene with an allylic stereogenic center proceeded cleanly to provide densely substituted lactam 2aq in 92% yield and 4.4:1 d.r. To gain the further insight into the diastereoselectivity of the aminocyanation reactions, we studied the stereochemistry of the alkene addition step. We designed a terminal monodeuterated substrate (trans-1ad-d1) to examine how the N−Pd bond inserts into the alkene. The possible outcomes are synaddition, anti-addition, or a mixture of the two. A possible mode for anti-addition is through ionization of N−Pd bond to form an alkene complex, followed by attack of nitrogen on the alkene. This would be consistent with our null observation on cyano group crossover, if it occurred by the formation of a tight ion pair. The structures of the possible products (2ad-d1-I and 2ad-d1-II) are shown in Scheme 5.

Figure 1. Optimal geometry of 2ad and nOe results.30

product as 2ad-d1-I, assuming a conformation where the methyl and nitrile groups are anti. This assumption seemed reasonable, but we sought additional data to confirm our assignment. To bolster our assignment of 2ad-d1, we utilized computational methods29 to predict the chemical shifts of the diastereotopic protons in 2ad. Conformational minimization in silico confirmed our assumptions about the anti-orientation of the nitrile and methyl group in the dominant conformers. The diastereotopic protons (labeled as 31 and 13 in Figure 1) were respectively predicted at δ = 2.80 and 2.62 ppm (Δδ = 0.18 ppm), while the experimental chemical shifts are δ = 2.89, 2.70 ppm (Δδ = 0.19 ppm) in the 1H NMR of 2ad. Compared with the spectrum of 2ad-d1, the more upfield peak around 2.70 ppm is not observed, confirming that proton 13 is the one labeled as deuterium. Combined with nOe results, we assign 2ad-d1-I as the diastereomer produced by of aminocyanation of trans-1ad-d1. These results are consistent with the alkene addition proceeding via a syn-addition pathway. Based on syn-aminopalladation, we proposed a model (shown in Scheme 6) to elucidate the origin of the

Scheme 5. Mechanistic Study of Alkene Addition Step

Scheme 6. Proposed Model for the Diastereoselectivity

Aminocyanation of trans-1ad-d1 yielded a single diastereomer, however, assigning the position of deuterium in 2ad-d1 was challenging due to the exocyclic stereogenic center. The 1H NMR spectrum of unlabeled 2ad showed the diastereotopic protons (atom 13 and 31 in Figure 1) as well-resolved signals (δ = 2.89, 2.70 ppm), showing that the two protons are in distinct electronic environments. Thus, we hypothesized that the two diastereotopic protons could be assigned by nOe experiments. As expected, the downfield diastereotopic proton in 2ad shows the through-space interactions with aromatic proton 24 on the isoindoline and 32/35 on the paramethoxyphenyl group. The upfield diastereotopic proton is only observed to enhance the signal of proton 32/35 on the para-methoxyphenyl group. We also ran an nOe experiment for the only proton alpha to the nitrile (δ = 2.88 ppm) in the 1H NMR of 2ad-d1, and we observed nOe for aromatic proton 24 and 32/35. These data support the assignment of our labeled

diastereoselectivity. During the ring-forming step, the molecule may adopt a chairlike conformation. Meanwhile, the larger substituent adjacent to the carbonyl prefers to be oriented in a pseudoaxial position to minimize strain between the R-group and the carbonyl. Hence, the cyclization reactions afforded the diastereomers we observed (2al−2ap).

3. CONCLUSION In summary, we developed an intramolecular aminocyanation of alkenes by N−CN bond activation of N-acyl and N-sulfonyl cyanamides, accessing a broad range of nitrogen-containing heterocycles, including pyrrolidones, piperidinones, isoindolinones, and sultams. The synthetic utility of the method was 3336

DOI: 10.1021/jacs.8b01330 J. Am. Chem. Soc. 2018, 140, 3331−3338

Article

Journal of the American Chemical Society

transfer hydrocyanation: Fang, X.; Yu, P.; Morandi, B. Science 2016, 351, 832. (6) Recent reviews: (a) Wen, Q.; Lu, P.; Wang, Y. RSC Adv. 2014, 4, 47806. (b) Nakao, Y. Catalytic C−CN Bond Activation. In C−C Bond Activation; Dong, G., Ed.; Springer: Berlin, 2014; pp 33−58. (c) Nakao, Y. Bull. Chem. Soc. Jpn. 2012, 85, 731. (7) (a) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem. Soc. 2003, 125, 6358. (b) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44, 2380. (c) Suginome, M.; Yamamoto, A.; Sasaki, T.; Murakami, M. Organometallics 2006, 25, 2911. (8) (a) Chatani, N.; Hanafusa, T. J. Chem. Soc., Chem. Commun. 1985, 838. (b) Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1988, 53, 3539. (c) Suginome, M.; Kinugasa, H.; Ito, Y. Tetrahedron Lett. 1994, 35, 8635. (9) (a) Chatani, N.; Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1990, 55, 3393. (b) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Organomet. Chem. 1994, 473, 335. (10) Obora, Y.; Baleta, A. S.; Tokunaga, M.; Tsuji, Y. J. Organomet. Chem. 2002, 660, 173. (11) Murai, M.; Hatano, R.; Kitabata, S.; Ohe, K. Chem. Commun. 2011, 47, 2375. (12) (a) Kamiya, I.; Kawakami, J.; Yano, S.; Nomoto, A.; Ogawa, A. Organometallics 2006, 25, 3562. (b) Lee, Y. T.; Choi, S. Y.; Chung, Y. K. Tetrahedron Lett. 2007, 48, 5673. (c) Pawliczek, M.; Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 1716. (13) (a) Koester, D. C.; Kobayashi, M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134, 6544. (b) Yuan, Y.; Yang, H.; Tang, X.; Wei, Y.; Shi, M. Chem. - Eur. J. 2016, 22, 5146. (14) (a) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732. (b) Pan, Z.; Pound, S. M.; Rondla, N. R.; Douglas, C. J. Angew. Chem., Int. Ed. 2014, 53, 5170. (c) Zhao, J.; Wang, G.; Li, S. Chem. Commun. 2015, 51, 15450. (d) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314. (15) Formal aminocyanation reactions of alkenes: (a) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu, Q.; Zhang, Q. Angew. Chem., Int. Ed. 2013, 52, 2529. (b) Sun, C.; O’Connor, M. J.; Lee, D.; Wink, D. J.; Milligan, R. D. Angew. Chem., Int. Ed. 2014, 53, 3197. (c) Jiang, H.; Gao, H.; Liu, B.; Wu, W. Chem. Commun. 2014, 50, 15348. (16) Reviews: (a) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953. (b) Martelli, G.; Orena, M.; Rinaldi, S. Curr. Org. Chem. 2014, 18, 1373. (c) Martelli, G.; Orena, M.; Rinaldi, S. Curr. Org. Chem. 2014, 18, 1539. (17) (a) Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsujimoto, H.; Soga, M. Chem. Pharm. Bull. 2007, 55, 1682. (b) Baldwin, J. J.; Cacatian, S.; Claremon, D. A.; Dillard, L. W.; Flaherty, P. T.; Ishchenko, A. V.; Jia, L.; Mcgeehan, G.; Simpson, R. D.; Singh, S. B.; Tice, C. M.; Xu, Z.; Yuan, J.; Zhao, W.; Zhuang, L. Patent WO2008156816 A2, December 24, 2008. (c) Jirgensons, A.; Leitis, G.; Kalvinsh, I.; Robinson, D.; Finn, P.; Khan, N. Patent WO2008142376 A1, November 27, 2008. (18) See the Supporting Information for details. (19) 1a′ was independently synthesized from 4-methyl-2,2diphenylpent-4-enoic acid and p-toluidine. (20) Similar to CpPd(allyl), CpPd(1-phenylallyl) is known to undergo facile reductive elimination upon reacting with phosphine ligands, enabling a rapid and quantitative formation of palladium(0) species, which presumably accounts for its superior reactivity toward the oxidative addition of N−CN bonds: Norton, D. M.; Mitchell, E. A.; Botros, N. R.; Jessop, P. G.; Baird, M. C. J. Org. Chem. 2009, 74, 6674. (21) (a) Dierkes, P.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton Trans. 1999, 1519. (b) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev. 2000, 100, 2741. (c) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895. (22) Begnell, L.; Jeffery, E. A.; Meisters, A.; Mole, T. Aust. J. Chem. 1974, 27, 2577.

demonstrated in a variety of transformations of the resulting lactam heterocycles, including those leading to medicinally relevant intermediates. Additionally, diastereoselective aminocyanation reactions, previously underdeveloped, were successfully applied to the formation of densely substituted pyrrolidones. We have shown through isotope labeling experiments that the reaction proceeds via a syn-addition pathway and that the cyclization is intramolecular due to the lack of crossover in cyanide labeled experiments. These data add clarity to the mechanistic picture for the N−CN bond activation and functionalization promoted by palladium and Lewis acid catalysts.

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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/jacs.8b01330. Experimental details for the preparation of new compounds, tabulated characterization data (1H NMR, 13 C NMR, melting points, MS, and IR), and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Christopher J. Douglas: 0000-0002-1904-6135 Author Contributions †

Z.P. and S.W. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank National Institutes of Health for funding this work (R01 GM095559). We thank Dr. Letitia Yao (UMN) for assistance with nOe experiments. We thank Mr. Xiao Xiao (UMN) for discussions regarding NMR chemical shift prediction.

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REFERENCES

(1) (a) Three Carbon−Heteroatom Bonds: Nitriles, Isocyanides, and Derivatives. In Science of Synthesis; Murahashi, S.; Ed.; Georg Thieme Verlag: Stuttgart, 2004; Vol. 19. (b) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations; Wiley-VCH: New York, 1989. (c) Fatiadi, A. In Preparation and Synthetic Application of Cyano Compounds; Patai, P., Rappaport, Z.; Eds.; Wiley: New York, 1983. (2) Reviews: (a) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049. (b) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 11948. (c) Ping, Y.; Ding, Q.; Peng, Y. ACS Catal. 2016, 6, 5989. (3) Recent reviews: (a) Rajanbabu, T. V. Org. React. 2011, 75, 1. (b) Bini, L.; Müller, C.; Vogt, D. ChemCatChem 2010, 2, 590. (c) van Leeuwen, P. W. N. M. In Homogeneous Catalysis: Understanding of the Art; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2004; pp 229−237. (4) Kurono, N.; Ohkuma, T. ACS Catal. 2016, 6, 989. and references cited therein. (5) (a) Podlech, J. Introduction of the Cyano Group by Addition to Alkenes. In Three CarbonHeteroatom Bonds: Nitriles, Isocyanides, and Derivatives; Georg Thieme Verlag: Stuttgart, 2004; Vol. 19; pp 333− 344, and references cited therein. (b) A recent report on catalytic 3337

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DOI: 10.1021/jacs.8b01330 J. Am. Chem. Soc. 2018, 140, 3331−3338