Multifunctionalization of Unactivated Cyclic Ketones via Synergistic

Letter Cite This: Org. Lett. 2018, 20, 1207−1211

pubs.acs.org/OrgLett

Multifunctionalization of Unactivated Cyclic Ketones via Synergistic Catalysis of Copper and Diarylamine: Access to Cyclic α‑Enaminone Yang Li,† Ran Zhang,† Xihe Bi,*,†,‡ and Junkai Fu*,†,§ †

Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024, China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China § Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China S Supporting Information *

ABSTRACT: A multifunctionalization of unactivated cyclic ketones via synergistic catalysis of copper and diarylamine for the direct synthesis of cyclic α-enaminone is reported for the first time. This reaction goes through oxidative α-amination, followed by a desaturation, and features mild reaction conditions, a broad substrate scope, and great functional group tolerance.

I

n the past few years, cooperative catalysis of combining transition metals with organocatalysts has attracted increasing attention. In this synthetic strategy, separate catalytic cycles are simultaneously promoted by two different catalysts to achieve an overall transformation.1 This concept has greatly pushed the innovation in functionalization of unactivated cyclic ketones, and a series of practical or enantioselective methods have emerged to afford different types of functionalized ketones in strong basefree or environmentally friendly pathways (Figure 1a). Dong and co-workers successively utilized synergistic catalysis of Rh(I) and bifunctional arylamine to realize the α-alkylation, α-alkenylation, and α-arylation of cyclopentanone.2 α-Allylic alkylation of cyclic ketones has been achieved by several groups employing cooperative Pd/secondary amine catalysis.3 Later, Wang’s group4 and Wu’s group5 designed elegant combinations of metal Lewis acids and bifunctional amines to promote the asymmetric aldol reaction of cyclic ketones. Recently, Jia and Dixon independently developed highly enantioselective palladium or silver/amine-co-catalyzed intramolecular desymmetrization of cyclohexanones.6 In addition, significant breakthroughs have been achieved recently in β-functionalization of unactivated cyclic ketones by the MacMillan’s group using cooperative organocatalysis and photoredox catalysis through a β-enaminyl radical intermediate.7 Despite these great achievements in monofunctionalization of unactivated cyclic ketones,8 direct multifunctionalization via synergistic catalysis, which means the introdution of several functional groups into simple cyclic ketones in one single step, has been rarely studied. Such investigations, if realized, would allow for rapid construction of synthetically significant and structurally complex motifs. O-Benzoylhydroxylamines, which are the most widely used electrophilic aminating reagents, have attracted much attention in recent years.9 These reagents are easily prepared, fairly stable, and compatible with a series of metals including Pd, Cu, Rh, Ru, Ni, and Fe complexes (Figure 1b). Hirano and Miura reported © 2018 American Chemical Society

Figure 1. Different strategies for the functionalization of carbonyl compounds.

Cu(I)-promoted electrophilic amination of ketene silyl acetals with O-benzoylhydroxylamines to obtain α-amino esters.10a Later, Wang and co-workers described α-amination of esters and amides through the reaction of zinc enolates and hydroxylamines, which was ineffective for α-substituted esters and amides.10b However, the direct α-amination of carbonyl Received: January 11, 2018 Published: February 8, 2018 1207

DOI: 10.1021/acs.orglett.8b00125 Org. Lett. 2018, 20, 1207−1211

Letter

Organic Letters compounds using O-benzoylhydroxylamines as nitrogen sources has not yet been explored.11 Herein, we report the first multifunctionalization of unactivated cyclic ketones by employing O-benzoylhydroxylamines as both amination reagents and oxidants via cooperative Cu and organocatalyst to generate αenaminone, which is a type of versatile synthon showing “dual electronic attitude”,12 but is not easily obtained13 (Figure 1c). To realize this strategy, a few challenges would need to be overcome: (1) the nucleophilic amine should be compatible with electrophilic hydroxylamines in the presence of metal; and (2) the reaction of Cu catalyst with hydroxylamines would generate high valent Cu complex, and this intermediate should not be inhibited by the aminocatalyst. Our work was initiated by the reaction of cyclopentanone 1a with O-benzoylhydroxylamine 2a in the presence of CuCl and TsOH (see Table 1). Various aliphatic amines, including

when Sc(OTf)3 was employed as the additive, the desired product 3aa could be isolated in 68% yield. The frequently used ligands (for instance, 1,10-phenanthroline) would slightly decrease the yield (see entry 13). Later, control experiments were carried out (entries 14 and 15). Without an organocatalyst, only 9% yield of 3aa was obtained, while no desired product could be detected in the absence of CuCl, showing the important roles of organocatalyst and transition metal. It was noteworthy that when 1.0 equiv hydroxylamine was used, 3aa was isolated in only 20% yield, together with some unidentified impurities. With the optimized reaction conditions secured, we explored the substrate scope with various cyclic ketones. As shown in Scheme 1, the cyclopentanones with methyl or isopropyl group Scheme 1. Substrate Scope of Cyclic Ketonesa

Table 1. Optimization of the Reaction Conditionsa

entry

metal salt

amine

1 2 3 4 5 6 7 8 9 10

CuCl CuCl CuCl CuI CuCN CuCl2 FeCl2 Pd(OAc)2 CuCl CuCl

11

CuCl

12

CuCl

c

CuCl

14 15

CuCl none

pyrrolidine piperidine diphenylamine diphenylamine diphenylamine diphenylamine diphenylamine diphenylamine aniline bis(4-bromophenyl) amine bis(4-bromophenyl) amine bis(4-bromophenyl) amine bis(4-bromophenyl) amine none bis(4-bromophenyl) amine

13

additive

yieldb (%)

TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH TsOH

0 0 48 13 0 26 0 0 42 56

Zn(OTf)2

31

Sc(OTf)3

68

Sc(OTf)3 + 1,10phenanthroline Sc(OTf)3 Sc(OTf)3

57 9 0

a All reactions were carried out in 0.1 M CH3CN with 10 mol % metal salt, 30 mol % amine, 10 mol % additive, and 2.5 equiv Obenzoylhydroxylamine under N2 atmosphere. bIsolated yields. cWith 10 mol % 1,10-phenanthroline.

a Reaction conditions: 1 (0.20 mmol), 2a (0.50 mmol), CuCl (10 mol %), bis(4-bromophenyl)amine (30 mol %), and Sc(OTf)3 (10 mol %) in CH3CN (2.0 mL) at room temperature (25 °C) for 36 h. b The reaction was run at 50 °C for 12 h. cCu(NO3)2·3H2O (10 mol %) was used as a metal salt.

pyrrolidine and piperidine, all failed to give any desired product (entries 1 and 2). Arylamines are softer aminocatalysts, compared to aliphatic amines, and prove to be ideal partners when combined with a hard metal catalyst.14 On the other hand, we speculate that the low nucleophilicity of arylamines would enable the compatibility with electrophilic hydroxylamines. Luckily, when diphenylamine was utilized as an aminocatalyst, the reaction smoothly produced α-enaminone 3aa in 48% yield (entry 3). Other metal salts either gave unsatisfied yields or made no effects on the desired reaction (entries 4−8). We then tested different aryl amines. The aniline gave a similar result as diphenylamine (entry 9), while bis(4-bromophenyl)amine could improve the yield up to 56% (entry 10). The Lewis acids could also efficiently promote the condensation of amines and ketone substrates to generate enamine intermediates.15 So we tried several different Lewis acids (entries 11 and 12). To our delight,

at the C3 position could all be converted to corresponding αenaminone 3ba and 3ca with excellent chemoselectivity and regioselectivity at the ketone C5 position. A wide range of different functional groups were tolerated under the oxidative amination conditions. Nitro, amine, and tert-butyldimethyl silyl (TBS) ether all proved to be compatible to give 3da−3fa in good yields. Carbonyl groups, such as ethyl or benzyl ester, could all be well-tolerated (3ga, 3ha). Moreover, the reactive terminal alkene could survive to give 3ia, which would allow for further manipulations. Delightedly, the cyclopentanones bearing quaternary carbon centers could be smoothly transformed to the corresponding products 3ja−3la in good yields. Later, the 1208

DOI: 10.1021/acs.orglett.8b00125 Org. Lett. 2018, 20, 1207−1211

Letter

Organic Letters

Scheme 3. Representative Derivatizations of α-Enaminone

transformation was found to proceed efficiently with a variety of aryl groups at the C3 position, including phenyl, naphthyl, thienyl, and various substituted phenyl groups (3ma−3sa). The cyclohexanone could also undergo the desired reaction pathway to offer α-enaminone 3ta, albeit in a low yield of 31%, probably due to the overoxidation of the formed α-enaminone.16 When 3,3- or 4,4-dimethylcyclohexanone were empolyed as the substrates, 3ua and 3va were obtained in acceptable yields. Unfortunately, the cyclopentanones bearing substituents at the C2 position, such as methyl or n-butyl groups, failed under the optimized reaction conditions. Next, various hydroxylamines were subjected to the oxidative amination reaction of cyclopentanone (Scheme 2). The numbers Scheme 2. Substrate Scope of Hydroxylaminesa

simple hydrolysis into corresponding 2-hydroxy cyclopentenone 4 from 3ma in an acidic medium, the α-enaminone 3aa could react with N-bromosuccinimide to install a bromo atom on the β position to produce α-amino-β-bromocyclopentenone (5).17 The vinyl bromide moiety allows for further Suzuki coupling reactions of 5 with different aryl boric acids to deliver a sequence of complex cyclopentenone derivatives 6a−6c. Finally, we performed extensive experiments to elucidate the reaction mechanism (Scheme 4). The addition of TEMPO or Scheme 4. Mechanistic Investigations

butylated hydroxytoluene (BHT) into the reaction mixture would totally suppress the desired reaction. Treatment of known α-amino cyclopentanone 7 with the standard reaction conditions generated α-enaminone 3aa in 79% yield, which indicates that the reaction goes through α-amino intermediate. When hydroxylamine 8 was employed as the partner, aminooxygenation products (10) were obtained, along with a trace amount of the desired product (9), suggesting that the aminyl radical might be generated in the reaction process.18 On the basis of above experimental results, a plausible mechanism is illustrated in Figure 2. Initially, the condensation of organocatalyst with ketone in the presence of Lewis acid would produce enamine A. The enamine intermediate A then underwent single electron transfer (SET) with Cu(III) species B, which was generated from the oxidative addition of Obenzoylhydroxylamine (2) and Cu(I), to deliver radical cation C and Cu(II) species D.19 Recombination of radical cation C and Cu(II) D would give the iminium ion E and regenerate Cu(I) catalyst through either radical coupling or reductive elimination of Cu(III) complex.9e,18b Hydrolysis of iminium E into ketone, followed by further oxidation with O-benzoylhydroxylamine, resulted in the formation of α-enaminone 3aa.20 In summary, a multifunctionalization of unactivated cyclic ketones by simultaneously introducing double bond and αamino group is developed via synergistic catalysis of copper and diarylamine. The O-benzoylhydroxylamines are employed as

a Reaction conditions: 1a (0.20 mmol), 2 (0.50 mmol), CuCl (10 mol %), bis(4-bromophenyl)amine (30 mol %), and Sc(OTf)3 (10 mol %) in CH3CN (2.0 mL) at room temperature (25 °C) for 36 h.

of O-benzoylhydroxylamines, derived from cyclic amines such as morpholine, N-protected piperazines, and functionalized piperidines, could all be transformed to corresponding α-enaminones 3ab−3ak in good yields. Later, acyclic hydroxylamines were proven to be suitable partners for the reaction. Hydroxylamines prepared from N-benzyl-N-methyl and N,N-dibenzyl amine could provide products 3al and 3an in 71% and 75% yields, respectively, while N-benzyl-N-butyl amine-based hydroxylamine just resulted in the formation of 3am in a yield of 60%. Functionalized O-benzoylhydroxylamines bearing a fluorine atom or allyl, propargyl, or naphthyl moieties all readily participated in the reaction to generate 3ao−3ar, which offered opportunities for further transformations. Furthermore, the reaction was compatible with O-benzoylhydroxylamines derived from primary amines, and α-enaminones 3as−3au were isolated in moderate yields, showing the broad scope of hydroxylamines. The α-enaminones are versatile building blocks and could be further utilitied in various transformations (Scheme 3). Besides 1209

DOI: 10.1021/acs.orglett.8b00125 Org. Lett. 2018, 20, 1207−1211

Letter

Organic Letters

(3) (a) Ibrahem, I.; Córdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952. (b) Usui, I.; Schmidt, S.; Breit, B. Org. Lett. 2009, 11, 1453. (c) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 19354. (d) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014, 53, 6776. (e) Tang, S.; Wu, X.; Liao, W.; Liu, K.; Liu, C.; Luo, S.; Lei, A. Org. Lett. 2014, 16, 3584. (f) Yang, C.; Zhang, K.; Wu, Z.; Yao, H.; Lin, A. Org. Lett. 2016, 18, 5332. (4) (a) Xu, Z.; Daka, P.; Wang, H. Chem. Commun. 2009, 45, 6825. (b) Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Chem. Commun. 2011, 47, 224. (c) Serra-Pont, A.; Alfonso, I.; Solà, J.; Jimeno, C. Org. Biomol. Chem. 2017, 15, 6584. (5) Zhang, Q.; Cui, X.; Zhang, L.; Luo, S.; Wang, H.; Wu, Y. Angew. Chem., Int. Ed. 2015, 54, 5210. (6) (a) Liu, R.-R.; Li, B.-L.; Lu, J.; Shen, C.; Gao, J.-R.; Jia, Y.-X. J. Am. Chem. Soc. 2016, 138, 5198. (b) Manzano, R.; Datta, S.; Paton, R. S.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 5834. (7) (a) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science 2013, 339, 1593. (b) Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 18323. (c) Jeffrey, J. L.; Petronijević, F. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 8404. For some other examples for direct β-functionalization of cyclic ketones, see: (d) Huang, Z.; Dong, G. J. Am. Chem. Soc. 2013, 135, 17747. (e) Okada, M.; Fukuyama, T.; Yamada, K.; Ryu, I.; Ravelli, D.; Fagnoni, M. Chem. Sci. 2014, 5, 2893. (8) For some other examples, see: (a) Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010, 49, 10181. (b) Xu, Z.; Liu, L.; Wheeler, K.; Wang, H. Angew. Chem., Int. Ed. 2011, 50, 3484. (c) Liu, L.; Sarkisian, R.; Xu, Z.; Wang, H. J. Org. Chem. 2012, 77, 7693. (9) For selected reviews, see: (a) Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947. (b) Barker, T. J.; Jarvo, E. R. Synthesis 2011, 2011, 3954. (c) Corpet, M.; Gosmini, C. Synthesis 2014, 46, 2258. (d) Yan, X.; Yang, X.; Xi, C. Catal. Sci. Technol. 2014, 4, 4169. (e) Dong, X.; Liu, Q.; Dong, Y.; Liu, H. Chem.Eur. J. 2017, 23, 2481. For selected examples, see: (f) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680. (g) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (h) Dong, Z.; Dong, G. J. Am. Chem. Soc. 2013, 135, 18350. (10) (a) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 11827. (b) McDonald, S. L.; Wang, Q. Chem. Commun. 2014, 50, 2535. (11) For selected reviews on α-amination of carbonyl compounds, see: (a) Erdik, E. Tetrahedron 2004, 60, 8747. (b) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (c) Guillena, G.; Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465. (d) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 42, 2001. (e) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637. (f) Maji, B.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2015, 88, 753. (g) de la Torre, A.; Tona, V.; Maulide, N. Angew. Chem., Int. Ed. 2017, 56, 12416. (12) (a) Lankri, D.; Albarghouti, G.; Mahameed, M.; Tsvelikhovsky, D. J. Org. Chem. 2017, 82, 7101. (b) Dounay, A.; Overman, L.; Wrobleski, A. J. Am. Chem. Soc. 2005, 127, 10186. (c) Rueping, M.; Parra, A. Org. Lett. 2010, 12, 5281. (d) Figueroa, R.; Froese, R.; He, Y.; Klosin, J.; Theriault, C.; Abboud, K. A. Organometallics 2011, 30, 1695. (13) Despite many reports on the preparation of cyclic β-enaminone, the methods to cyclic α-enaminone are limited; for a review, see: (a) Negri, G.; Kascheres, C.; Kascheres, A. J. Heterocycl. Chem. 2004, 41, 461. For selected examples, see: (b) Tobias, M. A.; Strong, J. G.; Napier, R. P. J. Org. Chem. 1970, 35, 1709. (c) Sato, K.; Kojima, Y.; Sato, H. J. Org. Chem. 1970, 35, 2374. (d) Sato, K.; Inoue, S.; Kitagawa, T.; Takahashi, T. J. Org. Chem. 1973, 38, 551. (e) Ho, C.-M.; Lau, T.-C. New J. Chem. 2000, 24, 859. (f) Nunes, J. P. M.; Afonso, C. A. M.; Caddick, S. RSC Adv. 2013, 3, 14975. (g) Wang, Z.; Reinus, B. J.; Dong, G. Chem. Commun. 2014, 50, 5230. (14) Deng, Y.; Liu, L.; Sarkisian, R. G.; Wheeler, K.; Wang, H.; Xu, Z. Angew. Chem., Int. Ed. 2013, 52, 3663. (15) Gualandi, A.; Mengozzi, L.; Wilson, C. M.; Cozzi, P. G. Chem. Asian J. 2014, 9, 984. (16) (a) Bautista, R.; Jerezano, A. V.; Tamariz, J. Synthesis 2012, 44, 3327. (b) Lei, Z.-Q.; Ye, J.-H.; Sun, J.; Shi, Z.-J. Org. Chem. Front. 2014,

Figure 2. Proposed reaction mechanism.

both amination reagents and oxidants, and the choice of diarylamine as aminocatalyst proves crucial for the reaction. This established protocol provides efficient access to cyclic αenaminone with mild reaction conditions, broad substrate scope and great functional group tolerance. Further mechanistic investigations indicate a radical process.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00125. Experimental procedures and spectra copies (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (X. Bi). *E-mail: [email protected] (J. Fu). ORCID

Xihe Bi: 0000-0002-6694-6742 Junkai Fu: 0000-0002-7714-8818 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We gratefully acknowledge the NSFC (Nos. 21502017, 21522202, 21702027), the Ministry of Education of the People’s Republic of China (No. NCET-13-0714), and Fundamental Research Funds for the Central Universities (No. 2412017QD010).

■

REFERENCES

(1) For selected reviews on metal/organo catalysis, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999. (c) Stegbauer, L.; Sladojevich, F.; Dixon, D. J. Chem. Sci. 2012, 3, 942. (d) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (e) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (f) Yang, Z.-P.; Zhang, W.; You, S.-L. J. Org. Chem. 2014, 79, 7785. (g) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272. (h) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116. (i) Afewerki, S.; Córdova, A. Chem. Rev. 2016, 116, 13512. (2) (a) Wang, Z.; Reinus, B.; Dong, G. J. Am. Chem. Soc. 2012, 134, 13954. (b) Mo, F.; Dong, G. Science 2014, 345, 68. (c) Lim, H. N.; Dong, G. Angew. Chem., Int. Ed. 2015, 54, 15294. (d) Mo, F.; Lim, H. N.; Dong, G. J. Am. Chem. Soc. 2015, 137, 15518. (e) Xu, Y.; Su, T.; Huang, Z.; Dong, G. Angew. Chem., Int. Ed. 2016, 55, 2559. 1210

DOI: 10.1021/acs.orglett.8b00125 Org. Lett. 2018, 20, 1207−1211

Letter

Organic Letters 1, 634. (c) Liu, X.-L.; Zhang, X.-L.; Xia, A.-B.; Guo, Y.-J.; Meng, C.-H.; Xu, D.-Q. Org. Biomol. Chem. 2017, 15, 5126. (17) Lee, H. I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 5067. (18) (a) Noack, M.; Göttlich, R. Chem. Commun. 2002, 38, 536. (b) Shen, K.; Wang, Q. Chem. Sci. 2015, 6, 4279. (c) Nishikawa, D.; Hirano, K.; Miura, M. J. Am. Chem. Soc. 2015, 137, 15620. (19) (a) Cossy, J.; Bouzide, A. J. Chem. Soc., Chem. Commun. 1993, 1218. (b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027. (c) Cecere, G.; König, C. M.; Alleva, J. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 11521. (20) (a) Hassner, A.; Catsoulacos, P. J. Org. Chem. 1967, 32, 549. (b) Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135, 12964.

1211

DOI: 10.1021/acs.orglett.8b00125 Org. Lett. 2018, 20, 1207−1211