Giese Addition

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

pubs.acs.org/OrgLett

Cobalt-Catalyzed Diastereoselective Difluoroalkylation/Giese Addition Domino Reactions Shengnan Han,§,† Shaodong Liu,§,† Lei Liu,† Lutz Ackermann,*,‡ and Jie Li*,† †

School of Pharmaceutical Sciences, Jiangnan University, Lihu Road 1800, 214122 Wuxi, Jiangsu, China Institut für Organische und Biomolekulare Chemie Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany

‡

Org. Lett. Downloaded from pubs.acs.org by UNIV OF SOUTHERN INDIANA on 05/13/19. For personal use only.

S Supporting Information *

ABSTRACT: An efficient cobalt-catalyzed difluoroalkylation/ Giese radical conjugate cyclization manifold with various alkyne-tethered cyclohexadienones and halogenated fluorinating reagents was accomplished under remarkable mild reaction conditions, thus providing an expedient route to valuable fluorinated chromens. The utility of this transformation was demonstrated by high site selectivity as well as chemo- and diastereoselectivity, broad substrate scope, excellent functional group tolerance, and facile late-stage modification.

T

he functionalization of cyclohexadienones via cyclizations has been recognized as an increasingly powerful strategy for the construction of decorated bicyclic frameworks,1 and these structural motifs are widely found in bioactive natural products (Figure 1).2 In this context, a two-step reaction

Figure 2. Transition-metal-catalyzed desymmetrization of alkynetethered cyclohexadienones.

addition and protonolysis with water (Figure 2b). 15 Furthermore, a photoredox-catalyzed sulfonylative cyclization with sulfonyl azides was recently reported by Lam.16 In addition to these remarkable advances in the transition-metalcatalyzed desymmetrization of alkyne-tethered cyclohexadienones, versatile cobalt catalysts12d,17 have been utilized for several cross-couplings between alkyl halides and alkenes.18 However, cyclative functionalization of alkynyl cyclohexadienones promoted by a low-valent cobalt catalysis has as of yet unfortunately proven elusive. Recently, transition-metal-catalyzed fluoroalkylation has emerged as a powerful tool and experienced remarkable progress19 for the installation of fluorine-containing motifs into organic molecules, which played a vital role in the synthesis of many compounds with various acitivities of relevance to biology or medicinal chemistry.20 Easily accessible and userfriendly halogenated difluoroacetates (XCF2CO2Et, X = Br or

Figure 1. Representative examples of biologically active compounds and natural products.

sequence consisting of the oxidative dearomatization, along with an intramolecular Michael addition through organocatalysis, has been successfully applied for the preparation of these building blocks, as was reported by Hayashi,3 Rovis,4 Gaunt,5 You,6 and Sasai,7 among others.8 Since Feringa and co-workers developed the intramolecular asymmetric Heckreaction with cyclohexadienone in 2002,9 alkyne-tethered cyclohexadienones have been used as reaction partners for the synthesis of cis-hydrobenzofuranones using Ni,10 Cu,11 Rh,12 Pd,13 and Au14 catalysis (Figure 2a). In sharp contrast, the preparation of 6,6-biscyclic products, such as hydrochromenes, continues to be challenging. Thus, the only example was thus far realized through nickel-catalyzed crosscouplings between alkyne-tethered cyclohexadienones and arylboronic acids, along with subsequent intramolecular © XXXX American Chemical Society

Received: April 22, 2019

A

DOI: 10.1021/acs.orglett.9b01400 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters I) have hence been utilized for the installation of fluorinebased structural motifs.21 Additionally, an efficient halofluoroalkylation with alkynes and halo-fluoroalkanes using cobalt catalysis was recently developed by Jacobi von Wangelin in a stereoconvergent fashion.22 Given these findings, we became intrigued by establishing novel difluoroalkylative cyclizations in a diastereoselective fashion. As a result, we herein report a stereoselective cobalt-catalyzed difluoroalkylation/Giese addition23 domino reaction24 manifold with easily accessible bromodifluoroalkanes and alkyne-tethered cyclohexadienones (Figure 2c). We initiated our studies by optimizing the reaction conditions for the envisioned cobalt-catalyzed cascade difluoroalkylation and reductive cyclization of 1 with bromodifluoroacetate (2). Preliminary experiments identified CoBr2, dppbz, and Zn dust as a suitable catalytic system at ambient temperature. Among various solvents, MeCN displayed a beneficial effect leading to 3 in 33% yield (Table 1, entries 1−3). Further, we were pleased to find that the

in the absence of the reductant completely inhibited the transformation (entries 15−17). With these optimized reaction conditions in hand, we next began exploring the substrate scope of the reaction with various alkyne-tethered cyclohexadienones (1) as the reaction partner (Scheme 1). First, this transformation could be easily Scheme 1. Cobalt-Catalyzed Difluoroalkylative Reductive Cyclization Cascade of Alkyne-Tethered with Bromodifluoroacetate

Table 1. Optimization of the Cobalt-Catalyzed Difluoroalkylative Giese Reactiona

entry

ligand

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

dppbz dppbz dppbz dppbz dppbz dppbz dppf dppp Xantphos IMesHCl IPrHCl bpy TMEDA dppbz dppbz − dppbz

Acetone DCE MeCN Acetone MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN

25 28 33 32c 41c 51c,d 0c Tracec 0c 0c 0c 0c 0c 63c,e 0c,f 0c 0c,g

a 1.0 mmol scale. The dr ratio in parentheses was determined by 1H NMR spectroscopy (dr > 20:1 unless otherwise mentioned).

scaled up, with only a slightly reduced yield (51% vs 63%). Both electron-donating and electron-withdrawing substituents at the para-, meta-, and ortho-positions of the ethynylphenyl ring were identified as viable substrates for the difluoroalkylation and reductive cyclization cascade reaction, thus providing the fluorinated chromen derivatives 4−9 with high levels of stereoselectivity. Moreover, an ethyl substituent at the quaternary carbon center, and a thiophen substituent also smoothly led to the desired products 10−11. Importantly, as for the C-link alkyne-tethered cyclohexadienone, the desired cis-hydronaphthalen product 12 was generated in 68% yield. The versatility of the cobalt-catayzed reductive coupling was further explored with various functionalized alkyne-tethered cyclohexadienones and different bromodifluoroacetamides (Scheme 2). Similarly, a wide range of electrophilic functional groups were well tolerated by our robust cobalt catalyst. Substituted ethynylphenyl ring bearing methyl, methyloxy, fluoro, chloro, ester, nitrile, and trifluoromethyl substituents, as well as a thiophen, efficiently delivered the corresponding fluorinated chromens 13−22 in 44−88% yields. However, more sterically hindered substrates provided the desired products 23−24 with slightly reduced diasteroselectivities. We thereafter evaluated the influence of ethyl or n-butyl groups at the quaternary carbon center, while highly stereoselective chromen derivatives 25−26 were obtained in 48−61% yields. Remarkably, a variety of decorated bromodifluoroacetamides were proven to be viable substrates as well. The ring size of amides had only a slight influence. Indeed, five-, six-, and seven-membered amides afforded the products 27−32 in 46−66% yields. Similar observations were

a

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), CoBr2 (10 mol %), dppbz (10 mol %), Zn (2.0 equiv), H2O (10.0 equiv), 23 °C, 16 h. bIsolated yield. cH2O (10 equiv). d60 °C. eCoBr2 (20 mol %), dppbz (20 mol %), 60 °C, 8 h. fWithout CoBr2. gWithout Zn. The dr ratio in parentheses was determined by 1H NMR spectroscopy (dr > 20:1 unless otherwise mentioned).

efficacy of our cobalt catalysis was remarkably improved by the use of H2O (10 equiv) as the cosolvent and performing the reaction at 60 °C (entries 4−6). Interestingly, no reaction was observed when employing other phosphine ligands, such as dppf, dppp, and XantPhos, as well as N-heterocyclic carbenes, 2,2′-bipyridine, and TMEDA (entries 7−13). It is worth noting that 20 mol % of CoBr2 and dppbz led to an increased isolated yield of 63% with high diastereoselectivity (dr > 20:1; entry 14). Omission of either of the catalyst’s components or B


Letter

Organic Letters Scheme 3. Mechanistic Studiesa

Scheme 2. Versatility of the Cobalt-Catalyzed Difluoroalkylative Giese Addition Domino Reactiona

a

a

The dr ratio in parentheses was determined by spectroscopy (dr > 20:1 unless otherwise mentioned).

1

ND = not detected.

involves an initial single electron transfer (SET) from Co(I)Ln to 2. A subsequent anti-addition of the radical ·CF2(EWG) (B) into the alkyne of 1 forms an alkenyl radical C, which undergoes an intramolecular Giese radical conjugate addition to generate the key intermediate D. Finally, the stoichiometric reductant Zn, along with hydrolysis, liberates the desired products and regenerates the active Co(I)Ln complex A (Scheme 4). Finally, we further illustrated the synthetic utility of this cobalt-catalyzed difluoroalkylation/reductive cyclization manifold by hydrolyzing the ester of product 3, thus furnishing the

H NMR

made when employing NH-free bromodifluoroacetates as the fluorinating reagents. Interestingly, secondary amides underwent the difluoroalkylation/Giese conjugate addition with substrate 1a to generate the desired products 33−35 with good diastereoselectivities, albeit in moderate yields. Engaged by the unique regioselectivity and outstanding activity of the cobalt catalysis, we sought to unravel the catalyst’s mode of action. To this end, a series of control experiments with representative radical scavengers were performed (Scheme 3). Importantly, the desired transformation was completely inhibited when employing 20 mol % of TEMPO as a typical radical scavenger. The adduct 36 derived from the difluoroalkyl radical and TEMPO was accordingly detected. Similar observations were made in the presence of stoichiometric quantities of BHT (Scheme 3a). Furthermore, a significant deuteration (60% D) at the αposition of ketone was noted when using isotopically labeled D2O as the additive (Scheme 3b). Remarkably, no desired product was detected when H2O was omitted in the reaction (Scheme 3c). Based on our mechanistic studies and previous mechanistic insights,16,21b,22 we propose a plausible catalytic cycle which

Scheme 4. Proposed Catalytic Cycle

C


Letter

Organic Letters corresponding carboxylic acid 37 in 96% yield.21d Meanwhile, a palladium-catalyzed hydrogenation of 12 provided the desired hexahydronaphthalenone 38 in 97% yield (Scheme 5).12b

(c) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenter. Chem. Rev. 2016, 116, 7330−7396. (2) (a) Yoder, B. J.; Cao, S.; Norris, A.; Miller, J. S.; Ratovoson, F.; Razafitsalama, J.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. Antiproliferative prenylated stilbenes and flavonoids from Macaranga alnifolia from the madagascar rainforest. J. Nat. Prod. 2007, 70, 342−346. (b) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. A. Cytotoxic geranyl stilbenes from Macaranga schweinfurthii. J. Nat. Prod. 1998, 61, 1509−1512. (c) Zhang, J.-T.; Cao, X.-P. Total Synthesis of Malyngamides K, L, and 5′’-epi-C and Absolute Configuration of Malyngamide L. J. Org. Chem. 2011, 76, 3946−3959. (d) Malloy, K. L.; Gerwick, W. H. Malyngamide 2, an Oxidized Lipopeptide with Nitric Oxide Inhibiting Activity from a Papua New Guinea Marine Cyanobacterium. J. Nat. Prod. 2011, 74, 95−98. (3) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. Cysteine-Derived Organocatalyst in a Highly Enantioselective Intramolecular Michael Reaction. J. Am. Chem. Soc. 2005, 127, 16028−16029. (4) Liu, Q.; Rovis, T. Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones Using the Intramolecular Stetter Reaction. J. Am. Chem. Soc. 2006, 128, 2552−2553. (5) (a) Vo, N. T.; Pace, R. D. M.; O’Har, F.; Gaunt, M. J. An Enantioselective Organocatalytic Oxidative Dearomatization Strategy. J. Am. Chem. Soc. 2008, 130, 404−405. (b) Leon, R.; Jawalekar, A.; Redert, T.; Gaunt, M. J. Catalytic enantioselective assembly of complex molecules containing embedded quaternary stereogenic centres from simple anisidine derivatives. Chem. Sci. 2011, 2, 1487− 1490. (6) (a) Gu, Q.; You, S.-L. Desymmetrization of cyclohexadienones viacinchonine derived thiourea-catalyzed enantioselective aza-Michael reaction and total synthesis of (−)-Mesembrine. Chem. Sci. 2011, 2, 1519−1522. (b) Jia, M.-Q.; You, S.-L. Desymmetrization of cyclohexadienones via D-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction. Chem. Commun. 2012, 48, 6363− 6365. (7) Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.; Sasai, H. Enantioselective Synthesis of α-Alkylidene-γ-Butyrolactones: Intramolecular Rauhut-Currier Reaction Promoted by Acid/Base Organocatalysts. Angew. Chem., Int. Ed. 2012, 51, 5423−5426. (8) (a) Wu, W.; Li, X.; Huang, H.; Yuan, X.; Lu, J.; Zhu, K.; Ye, J. Asymmetric Intramolecular Oxa-Michael Reactions of Cyclohexadienones Catalyzed by a Primary Amine Salt. Angew. Chem., Int. Ed. 2013, 52, 1743−1747. (b) Martín-Santos, C.; Jarava-Barrera, C.; del Pozo, S.; Parra, A.; Díaz-Tendero, S.; Mas-Ballesté, R.; Cabrera, S.; Alemán, J. Highly Enantioselective Construction of Tricyclic Derivatives by the Desymmetrization of Cyclohexadienones. Angew. Chem., Int. Ed. 2014, 53, 8184−8189. (c) Yao, W.; Dou, X.; Wen, S.; Wu, J.; Vittal, J. J.; Lu, Y. Enantioselective desymmetrization of cyclohexadienones via an intramolecular Rauhut−Currier reaction of allenoates. Nat. Commun. 2016, 7, 13024−13031. (9) Imbos, R.; Minnaard, A. J.; Feringa, B. L. A Highly Enantioselective Intramolecular Heck Reaction with a Monodentate Ligand. J. Am. Chem. Soc. 2002, 124, 184−185. (10) Kumar, R.; Hoshimoto, Y.; Tamai, E.; Ohashi, M.; Ogoshi, S. Two-step synthesis of chiral fused tricyclic scaffolds from phenols via desymmetrization on nickel. Nat. Commun. 2017, 8, 32−38. (11) (a) Yang, W.-L.; Sun, Z.-T.; Zhang, J.; Li, Z.; Deng, W.-P. Enantioselective synthesis of 3-amino-hydrobenzofuran-2,5-diones via Cu(I)-catalyzed intramolecular conjugate addition of imino esters. Org. Chem. Front. 2019, 6, 579−583. (b) Shu, T.; Zhao, L.; Li, S.; Chen, X.-Y.; von Essen, C.; Rissanen, K.; Enders, D. Asymmetric Synthesis of Spirocyclic β-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions. Angew. Chem., Int. Ed. 2018, 57, 10985−10988. (c) Liu, P.; Fukui, Y.; Tian, P.; He, Z. T.; Sun, C.Y.; Wu, N.-Y.; Lin, G.-Q. Cu-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Enynes. J. Am.

Scheme 5. Late-Stage Modification

In conclusion, we have reported on an in situ formed Co(I)Ln catalyst that enabled difluoroalkylative Giese addition domino reactions between various alkyne-tethered cyclohexadienones and bromodifluoroalkanes under exceedingly mild reaction conditions, providing a practical access to CF2containing 6,6-bicyclic scaffolds. This tandem desymmetrization displayed excellent selectivity in terms of an initial antidifluoroalkylation of the alkyne and a subsequent 6-exo-trig cyclization of the thus generated alkenyl radical with high diastereoselectivity, and featured a broad substrate scope. Preliminary mechanistic studies provided support for a radical pathway. Further extensions of the method are currently underway in our laboratory.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01400. Experimental procedures, characterization data, and 1H, 13 C, and 19NMR spectra for new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Lutz Ackermann: 0000-0001-7034-8772 Jie Li: 0000-0002-6912-3346 Author Contributions §

S.H. and S.L contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant No. 21602083), Natural Science Foundation of Jiangsu Province (Grant No. BK20160160). We also thank the Fundamental Research Funds for the Central Universities (JUSRP51703A).

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REFERENCES

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Giese Addition

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