Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins in

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Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones Prakash Basnet,† Roshan K. Dhungana,† Surendra Thapa,† Bijay Shrestha,† Shekhar KC,† Jeremiah M. Sears,§ and Ramesh Giri*,† †

Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, New Mexico 87131, United States Sandia National Laboratories, Advanced Materials Laboratory, 1001 University Boulevard SE, Albuquerque, New Mexico 87106, United States

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S Supporting Information *

nterception of in situ-generated Heck C(sp 3 )−MX intermediates by organometallic reagents is a powerful method to difunctionalize unactivated olefins (Scheme 1).1

furnish 1,2- or 1,4-difunctionalized products (Scheme 1B).5 In some cases, olefins that lack intrinsic stabilizing factors follow a Heck carbometalation, β-H elimination and [M]−H reinsertion steps prior to transmetalation to give 1,1-difunctionalized products (Scheme 1C).6 Unactivated olefins on aliphatic backbones also readily undergo isomerization7 by redox relay that involves a series of C(sp3)−MX species generated through sequential β-H elimination/M−H migratory insertion steps.8 In some cases, such isomerization can be harnessed for remote functionalization.9 In a recent report, Sigman and co-workers demonstrated that unactivated olefins tethered to carbonyl compounds would undergo such a process involving a Pd-catalyzed Heck reaction10 until the C(sp3)−PdX species result in β-H elimination from α-position to furnish terminally arylated α,β-unsaturated carbonyl compounds (Scheme 2).11 Herein,

Scheme 1. Strategies for Olefins Dicarbofunctionalization and the Complication by β-H Elimination

Scheme 2. Pd Redox Relay and Interception of C(sp3)−NiX Species during 1,3-Diarylation of Unactivated Olefins

ABSTRACT: We disclose a [(PhO)3P]/NiBr2-catalyzed regioselective β,δ-diarylation of unactivated olefins in ketimines with aryl halides and arylzinc reagents. This diarylation proceeds at remote locations to the carbonyl group to afford, after simple H+ workup, diversely substituted β,δ-diarylketones that are otherwise difficult to access readily with existing methods. Deuteriumlabeling and crossover experiments indicate that diarylation proceeds by ligand-enabled contraction of transient nickellacycles.

I

This process creates two new carbon−carbon (C−C) bonds across an olefin with new stereocenters2 and enables to build complex molecules rapidly,3 the access for which would otherwise require multiple steps from readily available chemicals with the known methods. However, development of such a method for acyclic alkenes remains incredibly challenging primarily due to the flexible alkyl chain and the high propensity of the Heck C(sp3)−MX species to undergo βhydride (β-H) elimination that leads to the formation of Heck products (Scheme 1A). Because of these complications, regioselective olefin dicarbofunctionalization has generally remained successful with dienes and styrenes,4 a class of substrates that tender internal stabilization of Heck C(sp3)− MX species by generating π-allyl/π-benzyl complexation and © 2018 American Chemical Society

we demonstrate that one of such redox-relay Heck C(sp3)− MX species generated at the β-position of carbonyl derivatives can be intercepted with arylzinc reagents to furnish β,δdiarylketones (Scheme 2). This process was rendered successful by utilizing (PhO)3P/NiBr2 as a new catalyst and modifying the carbonyl group to an imine for intercepting the redox-relay Heck C(sp3)−NiX species by coordination-assisted formation of transient nickellacycles.12 Preliminary studies by deuterium-labeling and crossover experiments indicate that the Received: March 21, 2018 Published: June 12, 2018 7782

DOI: 10.1021/jacs.8b03163 J. Am. Chem. Soc. 2018, 140, 7782−7786

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Journal of the American Chemical Society

Table 1. Optimization of Reaction Conditionsa

reaction proceeds by a (PhO)3P-promoted contraction of sixmembered transient nickellacycles to five-membered nickellacycles. In our continued efforts to expand the scope of coordination-assisted olefin difunctionalization to synthetically important carbonyl compounds,13 we examined olefins in simple aliphatic ketone-derived imines.14 Unfortunately, our preliminary examination of diarylation of imine 1 derived from 5-hexenone and aniline under our previously reported conditions13 either did not form any product or only produced the Heck product 2 in 74% yield (Scheme 3).15 We reasoned Scheme 3. Formation of Heck Product via a Fluxional SixMembered Transient Metallacycle

that the fluxional characteristics of the six-membered transient nickellacycle 3 could be responsible for the Heck reaction by making it harder to stabilize the C(sp3)−NiX species and prompting them to undergo rapid β-H elimination. We then hypothesized that such transient nickellacycles could be stabilized in situ by intercepting them with exogenous ligands that could create a comparatively rigid, higher coordinate organonickel species. Examination of a variety of ligands with NiBr2 indeed revealed that (PhO)3P was an excellent ligand to promote diarylation of unactivated olefins in ketimines with aryl iodides and arylzinc reagents (Table 1, entry 1). Surprisingly, the unactivated olefin underwent 1,3-diarylation, rather than 1,2-diarylation, furnishing β,δ-diarylketone 5 along with the Heck product 2 in 54% and 12% yields, respectively. No product arising from β-H elimination from the α-position of the carbonyl group was observed. Further examination of other solvents (entries 2−5) showed that the diarylated product 5 was formed in best yield in MeCN (entry 2). The results with triarylphosphines, trialkylphosphines, triarylphosphites and trialkylphosphites (entries 6−10) indicate that the 1,3-diarylation reaction requires an electrondeficient ligand. The reaction does not form the diarylated product 5 without NiBr2 and generates only Heck product 2 in 18% yield in the absence of (PhO)3P (entries 11 and 12). Altering the phenyl group in imine electronically with p-F and p-Me substituents or replacing it with nBu group also formed the diarylated product 5 in lower yields (entries 13−15). Shorter reaction time decreased the yield of the product 5 (entry 16). Other catalysts based on Pd, Fe, Co and Cu did not catalyze the diarylation reaction (entry 17). Control experiments with the parent ketone as a substrate both with and without (PhO)3P formed neither the diarylated nor the Heck product (entries 18 and 19). These experiments highlight the critical roles played by (PhO)3P and the imine group in promoting Heck carbometalation and nickellacycle contraction, and stabilizing the resultant transient nickellacycles. After optimizing the reaction conditions, we examined the scope of the current reaction for β,δ-diarylation of imine 1 with 4-(trifluoromethyl)phenylzinc iodide and different aryl iodides (Table 2). The reaction proceeds with both electron-rich and electron-poor aryl iodides16 and tolerates substituents such as alkyl, OMe, Cl, F, CO2Me and CF3 on aryl iodides. In

a 0.1 mmol scale reactions in 0.5 mL solvent. b1H NMR yields using pyrene as an internal standard. Value in parentheses is the isolated yield from 0.5 mmol. c80% remaining starting material. dPd(OAc)2, CoCl2, FeCl2 or CuI.

Table 2. Scope with Aryl Iodidesa

a

Isolated from 0.5 mmol. 5−10% Heck products observed.

addition, the reaction also tolerates ortho-substitution on aryl iodides as demonstrated by ortho-Me and 1-naphthyl (31 and 37). We further examined the scope of the current β,δ-diarylation reaction with respect to different ketimines, aryl iodides and arylzinc reagents (Table 3).17 The reaction typically works well with electron-deficient arylzinc reagents.16 The reaction 7783

DOI: 10.1021/jacs.8b03163 J. Am. Chem. Soc. 2018, 140, 7782−7786

Communication

Journal of the American Chemical Society Table 3. Scope with Ketone Derivatives, Aryl Iodides and Arylzinc Reagentsa

Isolated from 0.5 mmol. 5−10% Heck products observed. b50 °C.

a

tolerates functional groups such as Me, F, Cl and CF3 on arylzinc reagents and alkyl, OMe, F, Cl, CN and CF3 on aryl iodides. The aryl iodides and arylzinc reagents can be used in different combinations with several ketimines to furnish variously substituted β,δ-diarylketones. The reaction also proceeds well with ketimines derived from ketones with substitutions at α-carbons both at distal (51−53) and proximal (54−64) locations to the unactivated olefins. The diarylation reactions with these substituted ketones gave products in nearly 1:1 diastereomeric ratios (54−64). We further conducted deuterium-labeling and crossover experiments in order to understand the process of metallacycle contraction, and propose a catalytic cycle (Scheme 6). We subjected the imine 1-d2 labeled with deuterium (86% D) at the allylic position (β-d2) to our standard reaction condition for diarylation (Scheme 4). Analysis of the diarylated product

Scheme 5. Crossover Experiment

remains mostly bound to the substrate (Scheme 6).11e Such ring contraction to the five-membered nickellacycle 71 proceeds by β-H elimination from a β-carbon followed by H−NiX reinsertion to olefin prior to transmetalation/reductive elimination to furnish β,δ-diarylketones.18 Because no product is observed without (PhO)3P, we postulate that the ligand Scheme 6. Proposed Catalytic Cycle

Scheme 4. Deuterium-Labeling Experiment

5-d2 revealed that one of two allylic deuteriums migrated quantitatively (85% D) to γ-position of the carbonyl group. We then conducted a crossover experiment between the imine 1 and the styryl imine 65 (Scheme 5), a Heck product that serves as an intermediate during redox relay. Analysis of the products showed that the product 35 arising from the imine 1 was generated predominantly along with traces of the product 32. These results, along with the observation of 5−10% Heck products in all reactions, indicate that the contraction of the six-membered transient nickellacycle 68 proceeds while Ni 7784

DOI: 10.1021/jacs.8b03163 J. Am. Chem. Soc. 2018, 140, 7782−7786

Communication

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Savage, N. A.; Dong, G. J. Am. Chem. Soc. 2012, 134, 20005. (o) Logan, K. M.; Sardini, S. R.; White, S. D.; Brown, M. K. J. Am. Chem. Soc. 2018, 140, 159. (3) For reviews on olefin difunctionalization to form C−C/C−O, N bonds, see: (a) Chemler, S. R.; Karyakarte, S. D.; Khoder, Z. M. J. Org. Chem. 2017, 82, 11311. (b) Gockel, S. N.; Buchanan, T. L.; Hull, K. L. J. Am. Chem. Soc. 2018, 140, 58. (c) Wolfe, J. P. Synlett 2008, 2008, 2913. (4) (a) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 5784. (b) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137, 13476. (c) Kuang, Z.; Yang, K.; Song, Q. Org. Lett. 2017, 19, 2702. (d) Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe, N. Adv. Synth. Catal. 2004, 346, 905. (e) Mizutani, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 3959. (f) McCammant, M. S.; Liao, L.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 4167. (g) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355. (h) McCammant, M. S.; Shigeta, T.; Sigman, M. S. Org. Lett. 2016, 18, 1792. (5) For olefin dicarbofunctionalization by a radical process, see: (a) García-Domínguez, A.; Li, Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835. (b) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. Org. Lett. 2014, 16, 4666. (c) Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 10202. (d) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (e) Ilchenko, N. O.; Janson, P. G.; Szabó, K. J. J. Org. Chem. 2013, 78, 11087. (f) Liang, Z.; Wang, F.; Chen, P.; Liu, G. J. Fluorine Chem. 2014, 167, 55. (g) He, Y.-T.; Li, L.-H.; Yang, Y.-F.; Zhou, Z.-Z.; Hua, H.-L.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2014, 16, 270. (h) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2016, 138, 15547. (6) (a) Saini, V.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11372. (b) Werner, E. W.; Urkalan, K. B.; Sigman, M. S. Org. Lett. 2010, 12, 2848. (c) Saini, V.; Liao, L.; Wang, Q.; Jana, R.; Sigman, M. S. Org. Lett. 2013, 15, 5008. (d) Urkalan, K. B.; Sigman, M. S. Angew. Chem., Int. Ed. 2009, 48, 3146. (7) (a) Kocen, A. L.; Klimovica, K.; Brookhart, M.; Daugulis, O. Organometallics 2017, 36, 787. (b) Kita, M. R.; Miller, A. J. M. Angew. Chem., Int. Ed. 2017, 56, 5498. (c) Crossley, S. W. M.; Barabé, F.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 16788. (d) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134, 10357. (e) Chen, C.; Dugan, T. R.; Brennessel, W. W.; Weix, D. J.; Holland, P. L. J. Am. Chem. Soc. 2014, 136, 945. (f) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998. (g) Larionov, E.; Li, H.; Mazet, C. Chem. Commun. 2014, 50, 9816. (8) (a) Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59. (b) Weinstein, A. B.; Stahl, S. S. Angew. Chem., Int. Ed. 2012, 51, 11505. (c) Aspin, S.; Goutierre, A.-S.; Larini, P.; Jazzar, R.; Baudoin, O. Angew. Chem., Int. Ed. 2012, 51, 10808. (d) Kohler, D. G.; Gockel, S. N.; Kennemur, J. L.; Waller, P. J.; Hull, K. L. Nat. Chem. 2018, 10, 333. (e) Park, J.-W.; Kou, K. G. M.; Kim, D. K.; Dong, V. M. Chem. Sci. 2015, 6, 4479. (9) For a review, see: (a) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8, 209 For selected examples, see:. (b) Chinkov, N.; Majumdar, S.; Marek, I. J. Am. Chem. Soc. 2003, 125, 13258. (c) He, Y.; Cai, Y.; Zhu, S. J. Am. Chem. Soc. 2017, 139, 1061. (10) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 7290. (11) For redox relay Heck arylation of olefin-tethered alcohols, see: (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455. (b) Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960. (c) Patel, H. H.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 14226. (d) Chen, Z.-M.; Hilton, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 11461. (e) Hilton, M. J.; Xu, L.-P.; Norrby, P.-O.; Wu, Y.-D.; Wiest, O.; Sigman, M. S. J. Org. Chem. 2014, 79, 11841. (f) Dang, Y.; Qu, S.; Wang, Z.-X.; Wang, X. J. Am. Chem. Soc. 2014, 136, 986.

facilitates ring contraction. In addition, (PhO)3P, an electrondeficient ligand, could also facilitate reductive elimination.19 In summary, we have developed a new (PhO)3P/NiBr2 catalyst for regioselective 1,3-diarylation of unactivated olefins in ketimines with aryl iodides and arylzinc reagents to furnish variously substituted β,δ-diarylketones. This remote diarylation was made feasible by the combination of (PhO)3P as a ligand and imine as a coordinating group that enabled to intercept transient Heck C(sp3)−NiX intermediates. Deuterium-labeling and crossover experiments indicate that the reaction proceeds by the contraction of six-membered nickellacycles to fivemembered nickellacycles enabled by the presence of (PhO)3P.

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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.8b03163. Experimental procedures, characterization data for all compounds, and crystallographic data (PDF) Data for C24H23F6O2 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Ramesh Giri: 0000-0002-8993-9131 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the University of New Mexico (UNM) and the National Science Foundation (NSF CHE-1554299) for financial support, and upgrades to the NMR (NSF grants CHE08-40523 and CHE09-46690) and MS Facilities. The Bruker X-ray diffractometer was purchased via an NSF CRIF:MU award to UNM (CHE04-43580), Sandia National Laboratories (see the SI).

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REFERENCES

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Journal of the American Chemical Society (12) For selected examples of coordination-assisted Ni-catalyzed Negishi coupling, see: (a) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11908. (b) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154. (c) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 5794. (d) Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011, 13, 1218. (13) (a) Shrestha, B.; Basnet, P.; Dhungana, R. K.; Kc, S.; Thapa, S.; Sears, J. M.; Giri, R. J. Am. Chem. Soc. 2017, 139, 10653. (b) Thapa, S.; Dhungana, R. K.; Magar, R. T.; Shrestha, B.; Kc, S.; Giri, R. Chem. Sci. 2018, 9, 904. (14) For other examples of olefin dicarbofunctionalization using a coordinating group, see: (a) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.; Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 12270. (b) Li, W.; Boon, J. K.; Zhao, Y. Chem. Sci. 2018, 9, 600. (c) Yahiaoui, S.; Fardost, A.; Trejos, A.; Larhed, M. J. Org. Chem. 2011, 76, 2433. (d) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K. M. J. Am. Chem. Soc. 2017, 139, 10657. (e) Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M. J. Am. Chem. Soc. 2016, 138, 15122. For fluoroarylation and dioxygenation of olefins using a coordinating group, see: (f) Talbot, E. P. A.; Fernandes, T. d. A.; McKenna, J. M.; Toste, F. D. J. Am. Chem. Soc. 2014, 136, 4101. (g) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2013, 15, 46. (15) For directed Heck reaction, see: (a) Oestreich, M. In Directed Metallation; Chatani, N., Ed.; Springer: Berlin, Heidelberg, 2007; p 169. (b) Maity, S.; Dolui, P.; Kancherla, R.; Maiti, D. Chem. Sci. 2017, 8, 5181 For examples of Ni-catalyzed Heck reactions, see:. (c) Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem. Soc. 2011, 133, 19020. (d) Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 1858. (e) Harris, M. R.; Konev, M. O.; Jarvo, E. R. J. Am. Chem. Soc. 2014, 136, 7825. (f) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 3638. (g) Gøgsig, T. M.; Kleimark, J.; Nilsson Lill, S. O.; Korsager, S.; Lindhardt, A. T.; Norrby, P.-O.; Skrydstrup, T. J. Am. Chem. Soc. 2012, 134, 443. (h) Desrosiers, J.-N.; Hie, L.; Biswas, S.; Zatolochnaya, O. V.; Rodriguez, S.; Lee, H.; Grinberg, N.; Haddad, N.; Yee, N. K.; Garg, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed. 2016, 55, 11921. (i) Huihui, K. M. M.; Shrestha, R.; Weix, D. J. Org. Lett. 2017, 19, 340. (16) Because the reaction is strongly influenced by electronic changes on ArZnI but not on ArI and only 1,3-diarylated products are formed without 1,2-diarylation, we postulate that either the transmetalation or the reductive elimination could be rate-limiting. (17) Heteroaryl iodides formed products in