Catalyzed Intramolecular Hydroamination of Unactivated Terminal and

Letter pubs.acs.org/OrgLett

Gold(I)-Catalyzed Intramolecular Hydroamination of Unactivated Terminal and Internal Alkenes with 2‑Pyridones Jacob C. Timmerman, Sébastien Laulhé,† and Ross A. Widenhoefer* French Family Science Center, Duke University, Durham, North Carolina 27708, United States S Supporting Information *

ABSTRACT: The cationic gold phosphine complex [(P1)Au(NCMe)]+SbF6− [P1 = P(t-Bu)2o-biphenyl; 2] catalyzes the intramolecular hydroamination of 6-alkenyl-2-pyridones to form 1,6carboannulated 2-pyridones in high yield. The hydroamination of 6(γ-alkenyl)-2-pyridones was effective for monosubstituted and 1,1- and 1,2-disubstituted aliphatic alkenes, and the method was likewise effective for the hydroamination of 6-(δ-alkenyl)-2-pyridones. Spectroscopic analysis of mixtures of 6-(3-butenyl)-2-pyridone, (P1)AuCl, and AgSbF6 established the N-bound 2-hydroxypyridine complex [(P1)Au(NC6H3-2-OH-6-CH2CH2CHCH2)]+ SbF6− as the catalyst resting state.

T

similar complexes catalyze both the hydroamination of unactivated alkenes with ureas and related nucleophiles19,20 and the hydroamination of methylenecyclopropanes with 2pyridones.18 Indeed, treatment of 6-(3-butenyl)-2-pyridone (1a) with a catalytic amount of [(P1)Au(NCMe)]+SbF6− [P1 = P(t-Bu)2-o-biphenyl; 2] in dioxane at 80 °C for 4 h led to isolation of the 2,3-dihydroindolizin-5-one 3a in 95% yield (eq 1). The gold NHC complex (IPr)AuOTf likewise catalyzed the

he intramolecular addition of the N−H bond of an amine or carboxamide derivative across the CC bond of an electronically unactivated alkene (hydroamination) has received considerable attention as an attractive and atom-economical approach to the synthesis of nitrogen heterocycles.1 However, whereas numerous systems catalyze the intramolecular hydroamination of terminal alkenes, the intramolecular hydroamination of aliphatic 1,2-disubstituted alkenes remains problematic.1 Extant approaches catalyzed by early transition metal complexes,2 lanthanide metallocene complexes,3 late transition metal complexes,4 or Brønsted or Lewis acids5 as well as uncatalyzed Cope-type hydroamination6 suffer from a number of limitations including narrow substrate scope, poor functional group compatibility, and the necessity of sterically biasing gem-2,2-disubstitution. Recently, the intramolecular hydroamination of aliphatic 1,2-disubstituted alkenes has been realized via proton-coupled electron transfer7 or electrocatalytic8 generation of amidyl radicals, but these methods are restricted to N-arylcarboxamide derivatives.9−11 Herein, we report a gold(I)-catalyzed method for the intramolecular hydroamination of 6-alkenyl-2-pyridones that is effective for aliphatic 1,2-disubstituted alkenes. 1,6-Carboannulated 2-pyridones are structural components of a number of naturally occurring and biologically active molecules12 and are potential synthetic precursors to the indolizidine and quinolizidine alkaloids.13 Unfortunately, synthetic approaches to 1,6-carboannulated 2-pyridones, particularly those containing a saturated 1,6-linkage, are limited and typically rely on C6 cyclization of a N-derivatized 2pyridone14 or assembly of the 2-pyridone moiety on a preexisting cyclic template.15 In this context, we envisioned the intramolecular hydroamination of 6-alkenyl-2-pyridones as a potentially expedient approach to 1,6-annulated 2-pyridones.16−18 Toward the hydroamination of 6-alkenyl-2-pyridones, we targeted cationic gold(I) complexes containing sterically hindered, electron-rich supporting ligands as catalysts because © XXXX American Chemical Society

conversion of 1a to 3a in 86% yield. Conversely, treatment of 1a with a catalytic 1:1 mixture of Ph3PAuCl and AgSbF6 (5 mol %) at 80 °C for 18 h led to no detectable consumption of 1a. Similarly, treatment of 1a with a catalytic amount of HOTf (5 mol %) at 80 °C for 6 h led to no detectable consumption of 1a, which argues against a Brønsted acid catalyzed pathway for hydroamination. In addition to 1a, 6-(γ-alkenyl)-2-pyridones 1b and 1c containing a 1,1-disubstituted alkene moiety underwent efficient gold-catalyzed intramolecular hydroamination at 80 °C to give 3b and 3c, respectively, containing an α-amino quaternary carbon atom (Table 1, entries 1 and 2). More significantly, 6-(γ-alkenyl)-2-pyridones containing an (E)terminal methyl (1d and 1e), n-propyl (1f), or benzyl (1g) group, a homoallylic silyloxy (1h), formate (1i), or phthalimide (1j) group, or both (E)-terminal and allylic methyl groups (1k) underwent intramolecular hydroamination at 120 °C to give the corresponding 2,3-dihydroindolizin-5-ones 3d−k in good Received: February 14, 2017

A

DOI: 10.1021/acs.orglett.7b00450 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Hydroamination of 6-Alkenyl-2-pyridones and 6Alkenyldihydropyrimidin-2-ones Catalyzed by 2 (5 mol %) in Dioxane (60−100 °C) or Diglyme (120 °C)

Figure 1. Unreactive substrates for gold-catalyzed intramolecular hydroamination.

1p and 1q, available in one step via the Biginelli annulation,21 underwent gold-catalyzed intramolecular hydroamination to form the 1,6-annulated 3,4-dihydropyrimidin-2-ones 3p and 3q (Table 1, entries 15 and 16). Drawing upon our previous efforts in the area of gold(I)catalyzed enantioselective alkene hydroamination,20,22 we sought to evaluate the potential for the enantioselective hydroamination of 6-alkenyl-2-pyridones. A preliminary screen of enantiomerically pure bis(gold) phosphine complexes, silver salts, and reaction conditions was encouraging, and reaction of 1a with a catalytic 1:2 mixture of (P2)Au2Cl2 [P2 = (S)DTBM-MeOBIPHEP] and AgOTf at 24 °C for 48 h led to the isolation of 3a in 93% yield with 80% ee (eq 2).23

A number of experiments were performed to probe the mechanism and energetics of the gold(I)-catalyzed hydroamination of 6-alkenyl-2-pyridones. In one experiment, reaction of an equimolar mixture of 1a, (P1)AuCl, and AgSbF6 in CD2Cl2 at −80 °C generated the N-bound 2-hydroxypyridine gold complex 5 as the exclusive product without detectable coordination of the alkene moiety to gold (Scheme 1).24−26 Scheme 1

a

Complex 5 was thermally unstable and when warmed at 23 °C underwent first-order decay through three half-lives (kobs = 1.19 ± 0.3 × 10−3 s−1; ΔG⧧ = 21.3 kcal/mol) to form the gold 2,3dihydroindolizin-5-one complex 6 without formation of any detectable intermediates (Scheme 1); 6 was likewise formed as the exclusive product from reaction of 3a, (P1)AuCl, and AgSbF6 at −80 °C. Analysis of the temperature dependence of kobs for the conversion of 5 to 6 from 3 to 23 °C established the activation parameters: ΔH⧧ = 19.3 ± 0.8 kcal/mol and ΔS⧧ = −6.2 ± 0.8 e.u. Conversion of the O-deuterated isotopomer 5d1, generated from 1a-N-d (90% d), to 6-d1 at 18 °C displayed no significant deuterium KIE [kH/kD = 0.96 ± 0.05] and goldcatalyzed cyclization of 1a-N-d formed 3a-d1 with exclusive

Isolated yield. bNMR yield. c10 mol % of 2 used.

yield as single regio- and diastereomers (Table 1, entries 3−10). In contrast, 6-(γ-alkenyl)-2-pyridones containing a (Z)-terminal methyl group or a phenyl group at either the internal or (E)terminal positions failed to undergo gold(I)-catalyzed intramolecular hydroamination (Figure 1), which further argues against a Brønsted acid-catalyzed pathway for hydroamination. In addition to 6-(γ-alkenyl)-2-pyridones, the 6-(δ-alkenyl)-2pyridones 1l-o underwent gold-catalyzed 6-exo hydroamination to form the tetrahydroquinolizin-4-ones 3l-o (Table 1, entries 11−14). Likewise, the 6-(γ-alkenyl)-dihydropyrimidin-2-ones B

DOI: 10.1021/acs.orglett.7b00450 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

■

incorporation of deuterium into the exocyclic methyl group with ∼90% retention of deuterium (eq 3).

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ross A. Widenhoefer: 0000-0002-5349-8477 Present Address †

(S.L.) Department of Chemistry & Chemical Biology, IUPUI, Indianapolis, IN 46202.

When a solution of 1a and a catalytic amount of 2 in dioxane-d8 was analyzed periodically by 31P NMR spectroscopy at 60 °C, the resonance corresponding to 5 was observed as the sole phosphine-containing species throughout ∼90% conversion and then broadened and disappeared at higher conversion with the appearance of the resonance corresponding to 6, which established 5 as the catalyst resting state. On the basis of these experiments and literature precendents, we propose a mechanism for the gold-catalyzed conversion of 1a to 3a involving endergonic, intramolecular displacement of the 2-hydroxypyridine ligand of 5 with the pendant alkene moiety to form π-alkene complex I27 followed by outer-sphere C−N bond formation28 and protodeauration of the resulting gold β-pyridinium alkyl complex II29 to release 3a and regenerate 5 and/or 6 (Scheme 2). The modest entropy of

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge the NSF (CHE-1213957) for support of this research. J.C.T. thanks Duke University for the C. R. Hauser Memorial Fellowship.

■

Scheme 2

activation argues against turnover-limiting associative30 or dissociative ligand exchange while the absence of a significant KIE for the conversion of 5-d1 to 6-d1 argues against turnoverlimiting protodeauration of II. Rather, these data, and also the observed dependence of the rate of hydroamination on alkene substitution and tether length, are consistent with a mechanism involving rapid and reversible conversion of 5 to I followed by turnover-limiting C−N bond formation (I → II). In summary, we have developed an effective gold(I)catalyzed procedure for the intramolecular hydroamination of unactivated alkenes, including aliphatic 1,2-disubstituted alkenes, with 2-pyridones to form 1,6-carboannulated 2pyridones. Additionally, we have identified the gold N-2hydroxypyridine complex 5 as the catalyst resting state, and we have demonstrated the feasibility of the enantioselective hydroamination of 6-alkenyl-2-pyridones.

■

REFERENCES

(1) (a) Nishina, N.; Yamamoto, Y. Top. Organomet. Chem. 2012, 43, 115. (b) Reznichenko, A. L.; Nawara-Hultzsch, A. J.; Hultzsch, K. C. Top. Curr. Chem. 2013, 343, 191. (c) Bernoud, E.; Lepori, C.; Mellah, M.; Schulz, E.; Hannedouche, J. Catal. Sci. Technol. 2015, 5, 2017. (d) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. Chem. Rev. 2015, 115, 2596. (e) Gupta, A. K.; Hull, K. L. Synlett 2015, 26, 1779. (f) Coman, S. M.; Parvulescu, V. I. Org. Process Res. Dev. 2015, 19, 1327. (2) (a) Stanlake, L. J. E.; Schafer, L. L. Organometallics 2009, 28, 3990. (b) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 18246. (c) Bexrud, J. A.; Schafer, L. L. Dalton Trans. 2010, 39, 361. (d) Chapurina, Y.; Ibrahim, H.; Guillot, R.; Kolodziej, E.; Collin, J.; Trifonov, A.; Schulz, E.; Hannedouche, J. J. Org. Chem. 2011, 76, 10163. (e) Manna, K.; Everett, W. C.; Schoendorff, G.; Ellern, A.; WIndus, T. L.; Sadow, A. D. J. Am. Chem. Soc. 2013, 135, 7235. (3) (a) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett. 2001, 3, 3091. (b) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. J. Org. Chem. 2004, 69, 1038. (c) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 6149. (4) (a) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570. (b) Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449. (c) Julian, L. D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 13813. (d) Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 413. (e) Liu, Z.; Yamamichi, H.; Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2772. (5) (a) Haskins, C. M.; Knight, D. W. Chem. Commun. 2002, 2724. (b) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (c) Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938. (d) McKinney Brooner, R. E.; Widenhoefer, R. A. Chem. - Eur. J. 2011, 17, 6170. (6) (a) Black, D. St. C.; Doyle, J. E. Aust. J. Chem. 1978, 31, 2317. (b) Ciganek, E. J. Org. Chem. 1995, 60, 5803. (c) Ciganek, E.; Read, J. M.; Calabrese, J. C. J. Org. Chem. 1995, 60, 5795. (d) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243. (7) Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 13492. (8) Zhu, L.; Xiong, P.; Mao, Z.-Y.; Wang, Y.-H.; Yan, X.; Lu, X.; Xu, H.-C. Angew. Chem., Int. Ed. 2016, 55, 2226. (9) Nicewicz has demonstrated the intramolecular hydroamination of trisubstituted aliphatic alkenes with sulfonamides catalyzed by an organic photoredox system, but this method was not applicable to aliphatic 1,2-disubstituted alkenes: Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588. (10) Engle has recently reported the palladium-catalyzed regioselective intermolecular hydroamination of 1,2-disubstituted alkenes tethered to a metal-binding auxiliary: Gurak, J. A., Jr; Yang, K. S.; Liu, Z.; Engle, K. M. J. Am. Chem. Soc. 2016, 138, 5805.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00450. Experimental procedures; kinetic and spectroscopic data (PDF) C

DOI: 10.1021/acs.orglett.7b00450 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

1978, 100, 7055. (c) Boga, C.; Bonamartini, A. C.; Forlani, L.; Modarelli, V.; Righi, L.; Sgarabotto, P.; Todesco, P. E. Eur. J. Org. Chem. 2001, 2001, 1175. (27) (a) Brooner, R. E. M.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2013, 52, 11714. (b) Jones, A. C. Top. Curr. Chem. 2014, 357, 133. (28) (a) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b) Akana, J. A.; Bhattacharyya, K. X.; Müller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2007, 129, 7736. (c) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (d) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148. (e) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079. (f) LaLonde, R. L.; Brenzovich, J.; Benitez, D.; Tkatchouk, E.; Kelley, K.; Goddard, W. A., III; Toste, F. D. Chem. Sci. 2010, 1, 226. (29) Kovács, G.; Ujaque, G.; Lledós, A. J. Am. Chem. Soc. 2008, 130, 853. (30) Bender, C. F.; Brown, T. J.; Widenhoefer, R. A. Organometallics 2016, 35, 113.

(11) Copper(I) complexes catalyze the intermolecular formal hydroamination of aliphatic 1,2-disubstituted alkenes with hydroxylamine esters and hydrosilanes. (a) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62. (b) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem., Int. Ed. 2016, 55, 776. (12) (a) Morita, H.; Hirasawa, Y.; Kobayashi, J. Heterocycles 2009, 77, 679. (b) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752. (c) Atta-urRahman, A.; Choudhary, M. I.; Parvez, K.; Ahmed, A.; Akhtar, F.; Nure-Alam, M.; Hassan, N. M. J. Nat. Prod. 2000, 63, 190. (d) Gan, C.-Y.; Low, Y.-Y.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2009, 72, 2098. (e) Li, S.; Tian, X.; Niu, S.; Zhang, W.; Chen, Y.; Zhang, H.; Yang, X.; Zhang, W.; Li, W.; Zhang, S.; Ju, J.; Zhang, C. Mar. Drugs 2011, 9, 1428. (f) Boschin, G.; Resta, G. Alkaloids Derived from Lysine: Quinolizidine (a Focus on Lupin Alkaloids) in Natural Products; Ramawat, K. G., Merillon, J. M., Eds.; Springer Verlag: Berlin, 2013; p 38. (13) (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. (c) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (14) (a) Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40, 4073. (b) Menes-Arzate, M.; Martínez, R.; Cruz-Almanza, R.; Muchowski, J. M.; Osornio, Y. M.; Miranda, L. D. J. Org. Chem. 2004, 69, 4001. (c) Osornio, Y. M.; Miranda, L. D.; Cruz-Almanza, R.; Muchowski, J. M. Tetrahedron Lett. 2004, 45, 2855. (d) Miranda, L. D.; Muchowski, J. M.; Osornio, Y. M. Rev. Soc. Quim. Mex. 2004, 283. (e) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419; Angew. Chem. 2006, 118, 2479. (f) West, A.; Bisai, S. P.; Lim, A. D.; Narayan, R. R.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187. (g) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996. (h) Gallagher, T.; Derrick, I.; Durkin, P. M.; Haseler, C. A.; Hirschhäuser, C.; Magrone, P. J. Org. Chem. 2010, 75, 3766. (i) Durkin, P.; Magrone, P.; Matthews, S.; Dallanoce, C.; Gallagher, T. Synlett 2010, 2010, 2789. (j) Donets, P. A.; Cramer, N. Angew. Chem., Int. Ed. 2015, 54, 633. (15) (a) Beshore, D. C.; Smith, A. B., III. J. Am. Chem. Soc. 2007, 129, 4148. (b) Imase, H.; Tanaka, K. Chem. Lett. 2009, 38, 1152. (c) Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 418. (d) Cheng, X.; Waters, S. P. Org. Lett. 2013, 15, 4226. (16) Hydroamination employing 2-pyridones as nucleophiles has been realized only with allenes17 and methylenecyclopropanes.18 (17) Li, C.; Kähny, M.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 13780. (18) (a) Timmerman, J. C.; Robertson, B. D.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2015, 54, 2251. (b) Timmerman, J. C.; Widenhoefer, R. A. Adv. Synth. Catal. 2015, 357, 3703. (19) (a) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (b) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143. (c) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747. (d) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2008, 2741. (e) Li, H.; Widenhoefer, R. A. Org. Lett. 2009, 11, 2671. (f) Li, H.; Song, F.; Widenhoefer, R. A. Adv. Synth. Catal. 2011, 353, 955. (20) Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. (21) Kappe, C. O. Tetrahedron 1993, 49, 6937. (22) (a) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2007, 9, 2887. (b) Lee, S. D.; Timmerman, J. C.; Widenhoefer, R. Adv. Synth. Catal. 2014, 356, 3187. (23) For a recent review of enantioselective hydroamination, see: Hannedouche, J.; Schulz, E. Chem. - Eur. J. 2013, 19, 4972. (24) A single example of a cationic gold(I) N-2-hydroxypyridine complex has been reported: Thwaite, S. E.; Schier, A.; Schmidbaur, H. Inorg. Chim. Acta 2004, 357, 1549. (25) In nonpolar solvents, 2-pyridones exist as rapidly equilibrating mixtures of monomeric and dimeric 2-pyridone and 2-hydroxypyridine tautomers with modest preference for the former (KT = 6−12 in THF).26 (26) (a) Hammes, G. G.; Spivey, H. O. J. Am. Chem. Soc. 1966, 88, 1621. (b) Bensaude, O.; Chevrier, M.; Dubois, J. E. J. Am. Chem. Soc. D

DOI: 10.1021/acs.orglett.7b00450 Org. Lett. XXXX, XXX, XXX−XXX