Strategy for Catalytic Chemoselective Cross-Enolate Coupling

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Strategy for Catalytic Chemoselective Cross-Enolate Coupling Reaction via a Transient Homocoupling Dimer Takafumi Tanaka, Tsukushi Tanaka, Taro Tsuji, Ryo Yazaki,* and Takashi Ohshima* Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan S Supporting Information *

ABSTRACT: A new strategy, a transient homocoupling dimer strategy, for direct catalytic oxidative cross-enolate coupling reactions is developed. Cross-enolate coupling products bearing a (contiguous) tetrasubstituted carbon center were obtained chemoselectively without the need for stoichiometric amounts of strong bases/metal oxidants, and thus, the present catalysis provides a general method for the synthesis of unnatural α,α-disubstituted amino acid motifs. The distinct transformation of azlactone and 2-acylimidazole units highlighted the synthetic utility of the present catalysis.

O

Scheme 1. Oxidative Cross-Enolate Coupling

xidative coupling of two distinct nucleophiles offers direct and expeditious access to unique molecular architectures.1 Among them, oxidative cross-enolate coupling reactions of two different types of carbonyl compounds are highly straightforward methodologies for the synthesis of synthetically useful unsymmetrical 1,4-dicarbonyl compounds.2 Oxidative cross-enolate coupling reactions using two different carbonyls comprise an extremely formidable challenge, however, due to the concomitant formation of undesired homocoupling dimers, resulting in low chemical yields of the cross-enolate coupling products.2 Thus, extensive efforts over the past several decades have been dedicated to the development of methodologies for the chemoselective formation of cross-enolate coupling products. In early works, excess amounts of one enolate precursor were used to obtain a synthetically satisfactory yield of the cross-coupling product over an undesired homocoupling product.3 A combination of in situ generated distinct lithium enolates4 or boron-enolates with silicon-enolates5,6 was recently used to distinguish the two enolate intermediates, followed by treatment with metal oxidants (Scheme 1, eq 1). A chiral amine-catalyzed enantioselective reaction of aldehyde with silicon-enolates was also achieved (Scheme 1, eq 2).7 Although cross-enolate coupling products were chemoselectively obtained in synthetically useful yields, they included in situ or preformation of metal enolates followed by oxidative coupling.8 Moreover, construction of the tetrasubstituted carbon center in oxidative cross-enolate coupling reactions is quite challenging. Herein, we developed an iron-catalyzed oxidative cross-enolate © XXXX American Chemical Society

coupling reaction of distinct pronucleophiles for the construction of a tetrasubstituted carbon center using a transient homocoupling dimer strategy (Scheme 1, eq 3). Received: April 25, 2018

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DOI: 10.1021/acs.orglett.8b01313 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(Table 1, entry 8). Other metals, such as copper, nickel, and cobalt, did not promote the reaction (Table 1, entries 9−11).14 Next, we explored the scope of the catalytic oxidative crossenolate coupling reaction (Scheme 2). A range of azlactones

We planned to use a homocoupling dimer, which is commonly recognized as an undesired product in cross-enolate coupling reactions, as a transient intermediate and allow the homocoupling dimer to engage in the catalytic chemoselective cross-enolate coupling reaction. For this purpose, azlactone9 was selected as a pronucleophile because the corresponding homocoupling dimer is rapidly formed even under mildly oxidative conditions, leading to the construction of a highly congested contiguous tetrasubstituted carbon center.10 We hypothesized that the highly congested carbon−carbon bond of the homocoupling dimer could be activated through a radical or oxidative addition process using the appropriate metal catalyst.10e,f Subsequent coupling with another catalytically in situ generated enolate furnished the desired cross-enolate coupling product: an α,α-disubstituted aspartic acid motif (Scheme 1, eq 3). We began our investigation using azlactone 1a and 2acylimidazole 2a, which could be activated by a Lewis acid catalyst, as model substrates.11,12 Our reaction design first seemed quite difficult because homodimerization with subsequent formation of the cross-coupling product through highly congested C−C bond activation should be promoted by a single catalytic action (Table S1).13 We initially used stoichiometric amounts of metal salts for proof of concept and found that the combined use of readily available iron(III) chloride with DMAP delivered the desired product 3aa (Table 1, entry 1). These results led us to investigate further

Scheme 2. Substrate Generalitiesa

Table 1. Effect of Reaction Parametersa

entry

variation from the standard conditions

1

FeCl3 (200 mol %) and DMAP (200 mol %) without DTBP none without FeCl3 and DMAP without DTBP without DMAP pyridine instead of DMAP N,N-dimethylaniline instead of DMAP FeCl2 instead of FeCl3 CuCl instead of FeCl3 NiCl2 instead of FeCl3 CoCl2 instead of FeCl3

2 3 4 5 6 7 8 9 10 11

yield (%) 55 72 (74)b N.D. trace N.D. (55)c N.D. N.D. 11 N.D. N.D. N.D.

a

Conditions: 1a (0.1 mmol), 2a (0.2 mmol), MS 4 Å (50.0 mg), PhCl (0.2 mL). Yields were determined by NMR analysis. bIsolated yield (0.2 mmol scale). cReaction time was 24 h. PMP = p-methoxyphenyl, DTBP = di-tert-butyl peroxide, N.D. = not detected.

a

Conditions: 1 (0.2 mmol), 2 (0.4 mmol), PhCl (0.4 mL), MS 4 Å (100 mg). Isolated yields are shown. b1.0 equiv of 2b was used.

could be used (3aa−3ga). Valine-derived azlactone 1h afforded the product 3hb in 18% yield as a single diastereomer. Several substituents on the imidazole ring were applicable (3ac and 3ad). When α-methyl substituted substrates of 2 were used, cross-coupling products 3ab, 3ae, and 3af were obtained in higher yield with high to moderate diastereoselectivity. The stereochemistry of the major isomer was determined by X-ray crystallographic analysis of product 3af. It is particularly noteworthy that 3ab was obtained in high yield even when using only 1 equiv of 2b. Various substituents of 2, such as a long alkyl chain, benzyl group, terminal alkene, protected hydroxy group, and cyclopropyl ring, did not affect the

optimization using iron(III) chloride as a catalyst. Extensive investigation revealed that DTBP was a competent oxidant in the presence of 10 mol % of iron(III) chloride and DMAP, and cross-enolate coupling product 3aa was isolated in 74% yield (Table 1, entry 2). No desired product 3aa was detected without the use of iron chloride and DMAP (Table 1, entry 3). When DTBP was omitted, trace amounts of product 3aa were produced (Table 1, entry 4). The addition of 10 mol % of DMAP substantially facilitated the reaction (Table 1, entries 5− 7). Iron(II) chloride exhibited poor catalytic performance B

DOI: 10.1021/acs.orglett.8b01313 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters chemical yield (3ag−3ak). Sterically congested cyclohexyl and isopropyl groups were incorporated (3al and 3am). An αphenyl-substituted substrate was also applicable (3an). Chemoselective cross-enolate coupling of the 2-acylimidazole functionality was achieved even in the presence of an aryl ketone functionality (3ao). It is also noteworthy that the present cross-coupling reaction constructed contiguous tetrasubstituted carbon centers (3ap). To the best of our knowledge, this is the first example of a contiguous tetrasubstituted carbon center construction through oxidative cross-enolate coupling. Our mild reaction conditions, without any external bases, enabled late-stage oxidative cross-enolate coupling reaction using functionalized 2-acylimidazoles. Indomethacin- and febuxostat-attached 2-acylimidazoles were efficiently coupled with 1a in good yield (3aq, 3ar). To demonstrate the chemoselective nature of the present oxidative cross-enolate coupling, we selected a substrate with a malonate diester as a more acidic and bidentate coordinative functionality (Scheme 3). Malonate diester is quite high in acidity (diethylmalonate:

Scheme 4. Transformation of the Products

homocoupling dimer under standard conditions (Scheme 5).20 While homocoupling dimer 10a derived from azlactone Scheme 5. Homocoupling Dimer Formation

Scheme 3. Application of Homocoupling Dimer Strategy

pKa = 16.4).15 In addition, the bidentate coordinative nature of the malonate makes chemoselective enolization of a less reactive functionality such as ketone extremely difficult. When substrate 2s was subjected to standard benzylation conditions using t-BuOK and benzyl bromide, malonate diester was exclusively benzylated, indicating high acidity of α-proton of the malonate functionality.14 In contrast, exclusive formation of product 3as was observed under standard oxidative crossenolate coupling reaction. The present transient homocoupling dimer strategy could be applicable to the cross coupling of other carbonyls instead of azlactone (Scheme 3). Oxindoles and benzofuranones provide a homocoupling dimer rapidly, and the homolysis of the corresponding homocoupling dimer also occurs to afford stable α-radical species.16−18 When substrates 4a and 4b were subjected to the standard conditions without any modification, cross-coupling products 5ab and 5bb, bearing an all-carbon quaternary center, were obtained, clearly demonstrating the utility of the present transient homocoupling dimer strategy. The distinct transformation of azlactone and 2-acylimidaozle units in the coupling product 3aa was achieved (Scheme 4).19 A selective azlactone ring-opening reaction proceeded under acidic conditions (6aa). Transformations of 2-acylimidazole groups to carboxylic acid and amide were achieved through MeOTf activation (7aa and 8aa). Dual transformation of both functionalities to methyl esters also succeeded upon treatment with MeOTf, followed by DBU in MeOH (9aa). During the course of the reaction, we detected the homocoupling dimer 10a derived from azlactone 1a by TLC and 1H NMR analysis. Thus, we tried to isolate the

1a was isolated in high yield, no homocoupling dimer 11a derived from 2-acylimidazole 2a was detected. Furthermore, when homocoupling dimer 10a was used as the starting material, the cross-coupling product 3aa was obtained in high yield, suggesting that cross-coupling product 3aa formed through transient homocoupling dimer 10a. In conclusion, we developed a new strategy for catalytic chemoselective oxidative cross-enolate coupling reactions without the need for stoichiometric amounts of metal oxidants and bases. Late-stage oxidative cross-enolate coupling and chemoselective activation of 2-acylimidazoles over more acidic and bidentate coordinative malonate diester were achieved. The present oxidative cross-coupling reaction constructed contiguous tetrasubstituted carbon centers for the first time. In addition, the applicability of the present transient homocoupling dimer strategy was demonstrated. Further studies are in progress in our laboratory to expand the application of the present strategy for chemoselective oxidative cross-coupling reaction.

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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/acs.orglett.8b01313. Experimental details, characterizations, and NMR spectra of all products (PDF) C

DOI: 10.1021/acs.orglett.8b01313 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Accession Codes

K.; Murakami, M. Chem. Lett. 1992, 21, 2099. (d) Yasu, Y.; Koike, T.; Akita, M. Chem. Commun. 2012, 48, 5355. (8) For a metal-free oxidative enolate coupling reaction, see: (a) Kato, T.; Yasui, K.; Odagi, M.; Nagasawa, K. Adv. Synth. Catal. 2017, 359, 2881. (b) Saito, M.; Kobayashi, Y.; Tsuzuki, S.; Takemoto, Y. Angew. Chem., Int. Ed. 2017, 56, 7653. (c) Kaiser, D.; Teskey, C. J.; Adler, P.; Maulide, N. J. Am. Chem. Soc. 2017, 139, 16040. (9) For a review on azlactone, see: de Castro, P. P.; Carpanez, A. G.; Amarante, G. W. Chem. - Eur. J. 2016, 22, 10294. (10) (a) Dixit, V. M.; Bhat, V.; Trozzolo, A. M.; George, M. V. J. Org. Chem. 1979, 44, 4169. (b) Kato, H.; Tani, K.; Kurumisawa, H.; Tamura, Y. Chem. Lett. 1980, 9, 717. (c) Rodriguez, H.; Marquez, A.; Chuaqui, C. A.; Gomez, B. Tetrahedron 1991, 47, 5681. (d) Marquez, A.; Chuaqui, C. A.; Rodriguez, H.; Zagal, L. Tetrahedron 1985, 41, 2341. (e) Andersen, K. K.; Gloster, D. F.; Bray, D. D.; Shoja, M.; Kjær, A. J. Heterocycl. Chem. 1998, 35, 317. (f) Curto, J. M.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 18. (11) No desired product was observed using acylpyrazoles. For our recent results, see: (a) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016, 138, 2664. (b) Taninokuchi, S.; Yazaki, R.; Ohshima, T. Org. Lett. 2017, 19, 3187. (12) For utility of 2-acylimidazoles, see: (a) Ohta, S.; Hayakawa, S.; Nishimura, K.; Okamoto, M. Chem. Pharm. Bull. 1987, 35, 1058. (b) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (13) For recent reviews on C−C bond activation, see: (a) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613. (b) Murakami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759. (14) See Supporting Information for details. (15) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295. (c) Bordwell, F. G.; Harrelson, J. A., Jr. Can. J. Chem. 1990, 68, 1714. (16) For dimerization of oxindoles, see: (a) Hendrickson, J. B.; Göschke, R.; Rees, R. Tetrahedron 1964, 20, 565. (b) Inada, A.; Morita, Y. Heterocycles 1982, 19, 2139. (c) Fang, C.-L.; Horne, S.; Taylor, N.; Rodrigo, R. J. Am. Chem. Soc. 1994, 116, 9480. (d) Ghosh, S.; Chaudhuri, S.; Bisai, A. Org. Lett. 2015, 17, 1373. (e) Wu, H.-R.; Huang, H.-Y.; Ren, C.-L.; Liu, L.; Wang, D.; Li, C.-J. Chem. - Eur. J. 2015, 21, 16744. (f) Wu, H.-R.; Cheng, L.; Kong, D.-L.; Huang, H.-Y.; Gu, C.-L.; Liu, L.; Wang, D.; Li, C.-J. Org. Lett. 2016, 18, 1382. (g) Bleith, T.; Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Angew. Chem., Int. Ed. 2016, 55, 7852. (h) Uraguchi, D.; Torii, M.; Ooi, T. ACS Catal. 2017, 7, 2765. (17) For dimerization and homolysis of benzofuranones, see: (a) Scaiano, J. C.; Martin, A.; Yap, G. P. A.; Ingold, K. U. Org. Lett. 2000, 2, 899. (b) Frenette, M.; Aliaga, C.; Font-Sanchis, E.; Scaiano, J. C. Org. Lett. 2004, 6, 2579. (c) Frenette, M.; MacLean, P. D.; Barclay, L. R. C.; Scaiano, J. C. J. Am. Chem. Soc. 2006, 128, 16432. (18) For homolysis of oxindole, see: Sohtome, Y.; Sugawara, M.; Hashizume, D.; Hojo, D.; Sawamura, M.; Muranaka, A.; Uchiyama, M.; Sodeoka, M. Heterocycles 2017, 95, 1030. (19) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249. (20) We found that iron and copper catalysts promoted dimerization of azlactone under aerobic conditions. Detailed studies will be reported in due course.

CCDC 1839704 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ryo Yazaki: 0000-0001-9405-1383 Takashi Ohshima: 0000-0001-9817-6984 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant Number JP15H05846 in Middle Molecular Strategy, JP16H01032 in Precisely Designed Catalysts with Customized Scaffolding, Grant-in-Aid for Scientific Research (C) (#16K08166), and Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP17am0101091. R.Y. thanks Yoshida Foundation for Promotion of Learning and Education and the Tokyo Biochemical Research Foundation. We thank Dr. Kazuteru Usui and Rikiya Horikawa at Kyushu University for assistance with X-ray crystallography.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01313 Org. Lett. XXXX, XXX, XXX−XXX