Synthesis of 1,2-Dihydropyridines Catalyzed by Well-Defined Low

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Synthesis of 1,2-Dihydropyridines Catalyzed by Well-Defined LowValent Cobalt Complexes: C−H Activation Made Simple Brendan J. Fallon, Jean-Baptiste Garsi, Etienne Derat, Muriel Amatore, Corinne Aubert, and Marc Petit* Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, Paris 75252 CEDEX 05, France S Supporting Information *

ABSTRACT: A convenient one-pot system has been developed, allowing the synthesis of highly substituted dihydropyridines via a C−H activation/6π-electrocyclization pathway. The reaction proceeds with high regioselectivity, and we disclose the first example of isolated dihydropyridines lacking substitution in the 2 position. Moreover, the use of a simple well-defined low-valent cobalt complex without the need for reducing agents or additives in combination with computational studies provides a clearer insight into the C−H activation pathway than was previously reported. KEYWORDS: C−H activation, cobalt, 1,2-dihydropyridine, 6π-electrocylization, well-defined catalyst, mechanistic investigation Scheme 1. Annulation of α,β-Unsaturated Imines and Alkynes via a C−H Activation/6π-Electrocyclization Pathway

−H bond functionalization has become an incredibly powerful tool for the synthesis of elaborate scaffolds from relatively cheap and easily accessible starting materials.1 Indeed, having convenient routes to access densely functionalized Nheterocycles is of particular interest due to the prevalence of which they are found in natural products and drugs.2 An increasingly common approach to access diverse heterocyclic structures is via a C−H alkenylation/cyclization pathway based predominately on the use of a second-row transition metal such as rhodium and ruthenium.3−5 However, more recently, there has been a surge in interest to develop the catalytic potential of first-row transition metals.6 Cobalt, in particular, has been the subject of much development in this area.7 In the early 1950s, Murahashi demonstrated the ability of cobalt to participate in C− H functionalization.8 Other notable contributors include Klein, who studied the activity of stoichiometric electron-rich cobalt(I) species.9 More recently, the group of Yoshikai has developed elegant bimetallic cobalt systems capable of a range of C−H bond functionalization.7k The approach of chelation-assisted olefinic C−H bond alkenylation/cyclization has been extensively explored by the groups of Bergman and Ellman who have exploited the use of a rhodium(I)-catalyzed olefinic C−H alkenylation of α,β-unsaturated imines in the presence of alkynes followed by a subsequent 6π-electrocyclization to yield substituted dihydropyridines (Scheme 1a).3a−e The group of Yoshikai demonstrated that the generation of an in situ lowvalent cobalt species was capable of promoting the same reaction in good yields (Scheme 1b).10 Both these approaches provide access to 1,2-dihydropyridines, which are difficult to synthesize by other means and also have the value of being easily converted to pyridines and tetrahydropyridines.11 However, despite the advantages, both catalytic systems have certain undesirable features: the use of an expensive noble metal in the case of rhodium; a bimetallic cobalt system which utilizes an excess of

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reducing agents. Excess reducing agents, in this case Grignard derivatives, increases the complexity of any mechanistic study and also has the potential to limit substrate scope. In addition, both cases require the use of tailored phosphine ligands. To address some of these issues, our group recently reported a chelation-assisted hydroarylation of alkynes using a well-defined low valent cobalt complex Co(PMe3)4, which proceeded without the need for additives or reducing agents.12,13 As a continuing effort to demonstrate the utility of these complexes and their broad applicability to catalytic C−H functionalization, we began to explore their application in the synthesis of dihydropyridines (Scheme 1c). The previously optimized reaction conditions disclosed by our group for the hydoarylation of alkynes allowed us to isolate dihydropyridines 3aa in near quantitative yield (see Received: September 24, 2015 Revised: November 9, 2015

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With our previously optimized conditions (10 mol % of catalyst at 170 °C in a sealed tube using thermal of microwave heating in toluene)14 in hand, we began to explore the scope and limitations of the current annulation reaction (Table 1). Initially, various α,β-unsaturated imines were examined in the presence of diphenylacetylene 2a. A variety of benzylidenacetones imines were smoothly converted to the desired dihydropyridine products, 3aa−3ma. Electron-donating groups (e.g., Me, t-Bu and MeO) and electron-withdrawing groups (e.g., Cl, F, CF3, CN, CO2Me) were well tolerated. It is worth highlighting that an ester substituent is compatible with our reaction conditions (no Grignard or reducing reagent) leading to the desired dihydropyridine 3ia without side reactions. Interestingly the sterically hindered product 3ja could be isolated in 62% yield under our reaction conditions, which is in contrast to the similar reaction reported by Yoshikai where the cyclized product was not obtained but rather just the dienone product. We can speculate the elevated reaction temperature in our case is sufficient to overcome the steric repulsion between the 1-naphthyl and the neighboring phenyl groups facilitating the 6π-electrocyclization.15 The robustness of our catalytic system was also demonstrated by performing the reaction on gram scale in the case of product 3aa without any decrease in yield. Using the phenyl-ketimine 1l or the aldimine 1m, almost quantitative yields were obtained. Next, we examined the reactivity of a variety of symmetrical and unsymmetrical alkynes, commencing with TMS-substituted alkynes 2b−2h. All TMS-substituted alkynes examined exhibited excellent reactivity and in all but one case furnished the dihydropyridine product as a single regioisomer with the TMS substituent proximal to the dihydropyridine’s nitrogen. The same trends in regioselectivity have been previously reported by our group for the cobalt-catalyzed C−H alkenylation.12 In addition to the excellent regioselectivity observed chemical susceptible alkynes bearing heteroatoms which often suppress the activity of transition metal-catalyzed processes participated in the annulation reaction without issue to furnish compounds 3ag−3ai.16 1-Phenyl-1-pentyne reacted with imine 1a to afford product 3aj in good yield and regioselectivity (75%, r.r 95/5). To gain a better understanding of the factors governing the regioselectivity, 1-phenyl-propyne 2l and 1phenyl-butyne 2k were also examined. We observed a decrease in the regioselectivity for product 3ak (r.r. 80/20) and 3al (r.r. 52/48). These results strongly suggest that regioselectivity is under steric control. Finally for the present scope, dihydropyridines 3am and 3km were obtained from the reaction of oct-4yne 2m with the corresponding imines in excellent yields. As demonstrated, the present annulation reaction is broadly applicable to a range of α,β-unsaturated imines and alkynes. However, in the presence of terminal alkynes, a commonly encountered limitation of cobalt- and rhodium-catalyzed processes are a competitive dimerization reaction.13,17 We could circumvent this problem by developing a simple one-pot annulation/desilylation sequence of TMS-substituted alkynes. This simple approach allowed us to benefit from the highly regioselective annulation of TMS-substituted alkynes to access to the best of our knowledge the first example of 1,2dihydropyridines lacking substitution in the 2 position 4ab− 4af (See Scheme 2). To begin our mechanistic investigation and eliminate a possibility of a pathway through thermal [4 + 2] cycloaddition, compounds 1a and 2a were subjected to the reaction condition in absence of catalyst, and no dihydropyridine product was observed. Then imine 1n was subjected to our reaction

Table 1). Using HCo(PMe3)4 as a catalyst, we could also isolate 3aa with slightly lower yield. This result was in contrast to the Table 1. Scope of the Annulation Reaction between α,βUnsaturated Imines and Alkynesa

a

Unless otherwise stated, reaction performed on 0.5 mmol scale using 10 mol % Co(PMe3)4. bReaction performed on 1 g of 1a. c94% yield was obtained using HCo(PMe3)4 as catalyst. dNo formation of 3aa was observed in absence of catalyst. eSame yields were obtained under thermal or microwave heating. f Regioisomeric ratio (91/9). g Regioisomeric ratio

previously reported catalytic systems from the groups of Bergman, Ellman, and Yoshikai, where screening of ligands, reducing agents, and sometimes additives are required. In addition to being a very general catalyst for C−H functionalization, Co(PMe3)4 is easily and cheaply synthesized on a large scale, and the simplistic nature of the ligand coupled with a welldefined oxidation state allow for facile mechanistic or computational studies. 7494

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were possible depending on the number of coordinating phoshines. The reductive elimination was not studied by DFT due to the nonambiguous nature of this step. It appears that the mechanism is similar in the case of α,β-unsaturated imines to the one previously reported for aromatic imines. A barrier of 16.85 kcal/mol (11.17 kcal/mol with entropy included) was found for the C−H activation leading to product 3aa. The C−H activation is concomitant with a direct hydrogen transfer to the alkyne, the transition state being late because the C−H bond broken distance is found to be 1.73 Å (See Figure 1).19 The alkyne is

Scheme 2. One-Pot Desilylation at 2 Position of the Dihydropyridines

conditions. We did not observe the dihydropyridine product rather almost quantitative conversion to product 5na as a result of C2-alkenylation (Scheme 3).18 We can surmise that the Scheme 3. C−H Alkenylation of Imine 1n

thermodynamic penalty incurred to facilitate the 6π-electrocyclization through loss of aromaticity is too great in this case, and thus, the reaction is arrested at the C−H alkenylation step. From this result, we can postulate that the present annulation reaction proceeds in a two-step fashion (i.e, olefinic C−H alkenylation to form an azatriene derivative followed by 6πelectrocyclization). To examine the relative reactivity between olefinic C−H alkenylation versus aromatic sp2-hydroarylation, an intermolecular competition experiment was carried out between imines 1o and 1a (Scheme 4). In the presence of a limiting amount of

Figure 1. DFT calculated transition state structure for the C−H activation. Spin density isosurface is also shown in yellow (localized on the cobalt atom).

mandatory in this process, because without it, the reaction was calculated to be endothermic (by 5.10 kcal/mol or by 4.97 kcal/ mol with entropy included). Inclusion of solvent effect (by using the implicit COSMO scheme) did not modify theses conclusions. Thus, it is necessary to exchange three phosphines with an imine and an alkyne before the C−H activation step. This C−H activation pattern can be designated as a metal-assisted σ bond metathesis as we previously disclosed, which is also termed ligand-to-ligand hydrogen transfer (LLHT).20 Combining our experimental data from this study and our previous work on the use of well-defined cobalt species for C−H functionalization, we can propose the following catalytic cycle (Scheme 5). Ligand exchange between three trimethylphosphines, the α,βunsaturated imine, and alkyne leads to the generation of intermediate (I). A concerted hydrogen transfer via an oxidative pathway furnishes intermediate (II). Intermediate (II) undergoes reductive elimination leading to the formation of intermediate (III). Exchange with the starting materials liberates the intermediate (IV), which readily undergoes a subsequent 6πelectrocyclization to yield the desired dihydropyridine product 3. It is worth noting that due to the elevated temperature, at which the present reaction is carried out, we never managed to isolate or observe the expected azatriene intermediates with the exception of product 5na as previously discussed. In conclusion, we have developed a cobalt-catalyzed C−H bond activation/alkenylation/6π−electrocyclization cascade to provide access to a diverse range of dihydropyridines up to gram scale in excellent yields. The addition of a desilylation step has allowed us unprecedented access to 2-unsubstituted 1,2

Scheme 4. Competition Experiment

diphenylacetylene, a ratio of 80/20 in favor of the dihydropyridine compound 3aa was observed, suggesting that the activation of olefinic C−H bond is favorable compared to the aromatic C− H bond. Having in hand a simple well-defined catalytic species, we turned to DFT calculations to aid with elucidation of the reaction mechanism, a technique we already demonstrated in our previous studies.12,13 Using Turbomole (v6.4), at the B3LYPD3/def2-SV(P) level, investigations on the key step (namely, the C−H activation) were undertaken because several pathways 7495

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(2) (a) Alkaloids Cordell, G. A., Ed.; Elsevier: Amsterdam, 2010; Vol. 69. (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed; John Wiley & Sons: Hoboken, NJ, 2010. (3) For rhodium(I) catalysis, see: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645−3651. (b) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064−4067. (c) Duttwyler, S.; Chen, S.; Takase, M. K.; Wiberg, K. B.; Bergman, R. G.; Ellman, J. A. Science 2013, 339, 678−682. (d) Ischay, M. A.; Takase, M. K.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 2478−2481. (e) Duttwyler, S.; Chen, S.; Lu, C.; Mercado, B. Q.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2014, 53, 3877−3880. (4) For rhodium(III) catalysis, see: (a) Zhang, X.; Si, W.; Bao, M.; Asao, N.; Yamamoto, Y.; Jin, T. Org. Lett. 2014, 16, 4830−4833. (b) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326−18339. (c) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462−5465. (d) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585−9587. (e) Hyster, T. K.; Rovis, T. Chem. Sci. 2011, 2, 1606−1610. (f) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846−11848. (5) For ruthenium catalysis, see: (a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281−295. (b) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 9489−9496. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278−3281. (6) Kulkarni, A.; Daugulis, O. Synthesis 2009, 4087−4109. (7) For reviews and selected references on cobalt C−H activation, see: (a) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490−498. (b) Hummel, J. R.; Ellman, J. A. Org. Lett. 2015, 17, 2400−2403. (c) Lee, P.-S.; Yoshikai, N. Org. Lett. 2015, 17, 22−25. (d) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010, 132, 12249−12251. (e) Ding, Z.; Yoshikai, N. Org. Lett. 2010, 12, 4180−4183. (f) Ding, Z.; Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51, 4698−4701. (g) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53, 10209−10212. (h) Wu, B.; Santra, M.; Yoshikai, N. Angew. Chem., Int. Ed. 2014, 53, 7543−7546. (i) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136, 5424−5431. (j) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M. Adv. Synth. Catal. 2014, 356, 1491−1495. (k) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208−1219. (l) Tilly, D.; Dayaker, G.; Bachu, P. Catal. Sci. Technol. 2014, 4, 2756−2777. (m) Ackermann, L. J. Org. Chem. 2014, 79, 8948−8954. (n) Xu, W.; Yoshikai, N. Angew. Chem., Int. Ed. 2014, 53, 14166−14170. (o) Yu, D.-G.; Gensch, T.; de Azambuja, F.; Vasquez-Céspedes, S.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722−17725. (8) (a) Murahashi, S. J. Am. Chem. Soc. 1955, 77, 6403−6404. (b) Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816−4817. (9) (a) Klein, H.-F.; Beck, R.; Flörke, U.; Haupt, H.-J. Eur. J. Inorg. Chem. 2002, 3305−3312. (b) Klein, H.-F.; Camadanli, S.; Beck, R.; Leukel, D.; Flörke, U. Angew. Chem., Int. Ed. 2005, 44, 975−977. (c) Beck, R.; Sun, H.; Li, X.; Camadanli, S.; Klein, H.-F. Eur. J. Inorg. Chem. 2008, 3253−3257. (d) Beck, R.; Frey, M.; Camadanli, S.; Klein, H.-F. Dalton Trans. 2008, 4981−4983. (e) Camadanli, S.; Beck, R.; Flörke, U.; Klein, H.-F. Dalton Trans. 2008, 5701−5704. (10) Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196−199. (11) For other synthesis of 1,2-dihydropyridines, see: (a) Mizoguchi, H.; Oikawa, H.; Oguri, H. Nat. Chem. 2014, 6, 57−64. (b) Chau, S. T.; Lutz, J. P.; Wu, K.; Doyle, A. G. Angew. Chem., Int. Ed. 2013, 52, 9153− 9156. (c) Amatore, M.; Lebœuf, D.; Malacria, M.; Gandon, V.; Aubert, C. J. Am. Chem. Soc. 2013, 135, 4576−4579. (d) Oshima, K.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2012, 134, 3699−3702. (e) Nadeau, C.; Aly, S.; Belyk, K. J. Am. Chem. Soc. 2011, 133, 2878−2880. (f) Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830−3833. (g) Adak, L.; Chan, W.-C.; Yoshikai, N. Chem. - Asian J. 2011, 6, 359−362. (h) Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem. Commun. 2010, 46, 312−314. (i) Motamed, M.; Bunnelle, E. M.; Singaram, S. W.; Sarpong, R. Org. Lett. 2007, 9, 2167−2170. (j) Brunner, B.; Stogaitis, N.; Lautens, M. Org. Lett. 2006, 8, 3473−3476. (12) Fallon, B. J.; Derat, E.; Amatore, M.; Aubert, C.; Chemla, F.; Ferreira, F.; Pérez-Luna, A.; Petit, M. J. Am. Chem. Soc. 2015, 137, 2448− 2451.

Scheme 5. Proposed Catalytic Cycle

dihydropyridines in a one-pot manner. Through a combination of computational and experimental studies, we have been able to decipher the C−H activation mechanism. This work represents our continuing efforts to demonstrate the catalytic potential of well-defined low-valent cobalt complexes, which we believe have the potential to become credible alternatives to expensive rhodium catalysis and complicated bimetallic cobalt systems.

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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/acscatal.5b02138. Experimental procedures and physical properties of compounds (PDF) Crystallographic data (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by CNRS, MRES, UPMC, and ANR (ANR-12-BS07-0031- 01COCACOLIGHT), which we gratefully acknowledge.

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REFERENCES

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