Z-Selective Hydroalkylation of Ynone

Publication Date (Web): July 17, 2018 ... Exclusively α- and highly E/Z-selective hydroalkylation of ynone, ynoate, and ynamide was achieved via phot...
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Letter Cite This: Org. Lett. 2018, 20, 4691−4694

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Highly Regioselective and E/Z‑Selective Hydroalkylation of Ynone, Ynoate, and Ynamide via Photoredox Mediated Ni/Ir Dual Catalysis Su Yong Go, Geun Seok Lee, and Soon Hyeok Hong* Department of Chemistry, College of Natural Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea

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ABSTRACT: Exclusively α- and highly E/Z-selective hydroalkylation of ynone, ynoate, and ynamide was achieved via photoredox mediated Ni/Ir dual catalysis with high atom and step economy, producing trisubstituted enones, which are versatile synthetic building blocks. The developed reaction selectively delivered the α/Z isomer, which is complementary to the previously reported β-alkylation processes. The trisubstituted enones could be transformed to more valuable compounds via post-functionalization.

T

Scheme 1. Synthesis of Trisubstituted Enones through Hydroalkylation of Activated Alkynes with C(sp3)−H Bonds

risubstituted enones are versatile synthetic building blocks for the preparation of natural products and biologically active compounds. A variety of methods such as aldol reactions,1 olefination,2 cross-coupling,3,4 Heck reactions,5 C−H activation,6 and the addition of organometallic reagents7 have been developed to synthesize trisubstituted enones. However, these approaches are less efficient in the aspects of atom and step economy. The direct, regioselective addition of C−H bonds across activated alkynes can serve as a highly atom- and stepeconomical reaction to yield multisubstituted olefinic structures. In 2014, Kang et al. developed the Co-catalyzed βalkylation of terminal alkynes with THF.8 In the case of activated internal alkynes, the reaction resulted in the formation of α-alkylated products. Hilt and co-workers reported a Zn-mediated α-selective addition of THF across aryl-propiolates.9 However, both these reactions suffered from low E/Z selectivity and limited substrate scope, as only terminal alkynes or propiolate derivatives could be applied. Wang et al. reported a visible-light-promoted β-selective alkenylation of THF with propiolate derivatives.10 However, this method was also unable to overcome the low E/Z selectivity and limited substrate scope, as only propiolate derivatives could be employed. Wu and co-workers recently demonstrated the highly regioselective and E/Z-selective hydroalkylation of nonactivated alkynes with ethers via a metallaphotoredox strategy.11 However, for an activated alkyne, ethyl 3-phenylpropiolate (one example), their method failed to control the regioselectivity and produced α- and βalkylated mixtures (1:1.5). Therefore, it is still challenging to generate highly α- and E/Z-selective trisubstituted enones by the direct addition of C−H bonds to activated alkynes (Scheme 1). To achieve a highly α- and E/Z-selective, atom-economical C−H addition, two fundamental strategies were devised. First, a silyl group, which can provide steric and electronic effects to control the reaction selectivity with extensive opportunities for post-functionalization, was introduced as a directing group into © 2018 American Chemical Society

the activated alkynes. Second, to avoid the use of a stoichiometric amount of additives as employed in the previously reported C−H additions to alkynes, the recent photoredox-mediated Ni catalytic method, which enables the generation of catalytically active alkyl radicals without external radical sources, was adopted.11,12 By implementing these strategies, a silyl-group-assisted C(sp3)−H bond addition reaction across activated alkynes was achieved via visiblelight-mediated Ni/Ir dual catalysis to afford trisubstituted enones with exclusive α- and high E/Z-selectivity. This methodology is complementary to the traditional and previously reported β-alkylation processes.10 The initial investigations were performed with the reaction of ynones 1 with THF (Table 1). Various silyl groups in compound 1 were evaluated to find the best silyl directing group inducing the desired selectivity. Silyl groups such as trimethylsilyl (TMS) and dimethylphenylsilyl (DMPS) groups generated various unidentified products (entries 1 and 4). Slightly more stable silyl groups such as tert-butyldimethylsilyl Received: June 28, 2018 Published: July 17, 2018 4691

DOI: 10.1021/acs.orglett.8b02017 Org. Lett. 2018, 20, 4691−4694

Letter

Organic Letters Table 1. Optimization of THF Alkenylationa

deviation

Scheme 2. Scope of Ynone, Ynoate, and Ynamidea

yield (%)b (2:2′), (Z/E of 2)c

entry

R

1 2 3 4 5

TMS TBDMS TES DMPS TIPS

none none none none none

6

TIPS

7

TIPS

8

TIPS

9

TIPS

10

TIPS

NiBr2·glyme instead of NiCl2· glyme NiBr2·glyme + LiCl (1 equiv) instead of NiCl2·glyme Ni(acac)2 or Ni(cod)2 instead of NiCl2·glyme no cooling (60 °C) instead of 18 (only 2), 23 °C (>20:1) without NiCl2 or dtbbpy or [Ir] or 0 light

complex mixture 52 (−), (1.6:1) 48 (−), (3:1) complex mixture 83 (78d) (only 2), (>20:1) 18 (only 2), (>20:1) 41 (only 2), (>20:1) 0

1 (0.06 mmol), NiCl2·glyme (20 mol %), dtbbpy (30 mol %), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), and THF (6.0 mL) irradiated with a 34 W blue LED. bNMR yields calculated using 2,4,6-triiodophenol as the internal standard. cSelectivity ratios were determined by the crude 1H NMR spectra. dIsolated yield. a

1 (0.06 mmol), NiCl2·glyme (20 mol %), dtbbpy (30 mol %), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), and THF (6.0 mL) irradiated with a 34 W blue LED. Z/E = >20:1, unless otherwise noted. Isolated yields of the Z isomer. bZ/E = 10:1. a

(TBDMS) and triethylsilyl (TES) groups exhibited better yields and selectivities (entries 2 and 3). Use of the triisopropylsilyl (TIPS) group resulted in the highest yield (83%) with remarkable selectivities (entry 5). In particular, the Z-selective, α-addition product was favored over the generally favored E-isomer. Compound 2 was characterized by nuclear Overhauser effect (NOE) experiments (Figures S1−S5). Substituting TIPS with other alkyl or aryl groups resulted in either poor selectivity or low yield (Table S1). For example, in the case of linear alkyl groups, a mixture of all four isomers was obtained (entry 2, Table S1). Replacing TIPS with aryl groups or less sterically hindered alkyl groups resulted in poor yields with low selectivity (Table S1). It was reasoned that the bulkier TIPS group could make the reaction more sensitive to the steric environment, providing enough stability to generate the desired products.13 The role of chloride was essential, as replacement of NiCl2 with other Ni(II) or Ni(0) precatalysts resulted in significantly lower yields (entries 6 and 8). The addition of LiCl to NiBr2·glyme improved the reactivity, confirming the critical role of the chloride ligand (entries 7). Conducting the reaction without a cooling fan (about 60 °C) resulted in significantly lower yields (entry 9). Control experiments highlighted the essential roles of the Ni catalyst, ligand, photocatalyst, and light (entry 10). After optimization of the reaction conditions, we next investigated the scope of the reaction. The reactions proceeded efficiently with various kinds of activated alkynes such as ynone, ynoate, and ynamide with exclusive α-functionalization and high E/Z selectivity (Scheme 2), overcoming the limitations of the previously reported methods.8−11 In all cases, highly Z-selective (mostly >20:1, Z/E) and exclusive αaddition products were observed by 1H NMR spectroscopy.14 The reactions with various aliphatic TIPS-protected ynones (2a−2e) proceeded smoothly. Compared to aliphatic ynones, the aromatic ynones exhibited lower yields. The reaction was

facile with an electron-rich aromatic ynone (2f), while electron-poor aromatic ynones resulted in poor yields. The yield of benzyl ynone (2g) was increased by 30% compared to the phenyl analogue. To our delight, a ynoate (2h), which can serve as a good precursor for various trisubstituted enones (Scheme 4), was highly reactive (98%). The reaction also proceeded well with other functional groups such as bulkier ynoates and an ynamide (2i−2l). Next, different C−H coupling partners were investigated. In addition to THF, other cyclic and acyclic ethers, and even an amide, performed well under the modified reaction conditions. The use of cosolvent (benzene) with a decreased amount of C−H coupling partners (20 equiv) was necessary, due to the solubility issue of the catalyst mixture (Scheme 3). In the cases of 2o and 2q, the yields were improved by increasing the reaction temperature (50 °C). For 1,3-dioxolane, lower efficiency as compared to the reaction with THF was observed, likely owing to the decomposition of the product (2p). Interestingly, benzylic C(sp3)−H bond functionalization was possible with an increased amount (80 mol %) of the Ni complex (2r). This reaction also proceeded in an efficient manner with α-amino C(sp3)−H bonds in dimethylacetamide (DMA), leading to a high yield (2s). Taking advantage of the TIPS group, further transformations of 2h were performed (Scheme 4). The silyl group was successfully transformed to halogen functionalities under the halogenative desilylation conditions previously reported for nonactivated vinyl silanes.15 The iodinated and brominated products (3a, 3b) were produced in moderate yields, providing ample scope for additional transformations involving vinyl halides. For example, the produced vinyl iodide 3a was arylated maintaining E/Z-stereochemistry (4a) (Figure S6). Further utilization of the carbonyl group or the ester group was also 4692

DOI: 10.1021/acs.orglett.8b02017 Org. Lett. 2018, 20, 4691−4694

Letter

Organic Letters Scheme 3. Scope of C(sp3)−H Partners in Hydroalkylationa

Scheme 5. Experimental Investigations for Determining the Reaction Mechanism

Alkyne (0.10 mmol), NiCl2·glyme (20 mol %), dtbbpy (30 mol %), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), and C−H donor (20 equiv), benzene (1.0 mL) irradiated with a 34 W blue LED. Z/E = >20:1. Isolated yields of the Z isomer. b50 °C. cNiCl2·glyme (80 mol %), dtbbpy (90 mol %). a

Scheme 4. Post-functionalization of TIPS Enones

Figure 1. Proposed mechanism.

catalytic cycle. Such a stepwise process is consistent with deuterium labeling studies, showing that the vinyl hydrogen did not originate from THF (Figures S8−S10). Based on two control experiments, we believe that our reaction proceeds through a Ni−alkyl pathway, not a Nihydride pathway. First, less sterically bulky n-butyl ynoate was used to check the trend in regioselectivity depending on the C−H coupling partners, as silyl ynoates exhibited exceedingly high selectivity (Scheme 3 and Table S3). The regioselectivity is increased with sterically bulkier C−H coupling partners consistent with a Ni−alkyl pathway (Scheme 5b). If the Ni−H pathway would be operative, the regioselectivity should not be changed depending on the sterics of the C−H coupling partners.12d Second, the reactivity was maintained in reasonably good yields (50%−60%) even with the addition of many different bases, although a base can shut down the generation of a nickel hydride intermediate by abstracting HCl (Table S4). In summary, a TIPS-group-induced highly regioselective and E/Z-selective hydroalkylation of activated alkynes was developed for the synthesis of trisubstituted enones via photoredox mediated Ni/Ir dual catalysis. The reaction delivered the α-selective Z isomer with highly controlled selectivity that was endowed by the distinguished steric properties of the TIPS group, which is complementary to the

demonstrated by the synthesis of allylic alcohol (3c) and the corresponding ynone (2b) through a Weinreb amide.16 Notably, the Z geometry was perfectly preserved throughout the synthetic operations. A plausible mechanism was proposed based on control experiments (Scheme 5) and previously reported studies (Figure 1).11,12 As shown in Table 1, chloride proved to be an essential component of the Ni/Ir dual system (entries 5−8). Doyle and co-workers have suggested that the photolysis of Ni(III)Cl2 B could generate the chlorine radical, which could then abstract a hydrogen atom from THF.12a,b Similarly, the formation of the THF−TEMPO adduct in a radical quenching study supported the hypothesis that the reaction also proceeds via a THF radical intermediate generated by a hydrogen atom transfer (HAT) process with the chlorine atom (Scheme 5a). The THF radical generated by this process may rebound to Ni(II) species C and form the THF-bound Ni(III) complex D. The alkyl−Ni(III) complex D could be reduced to alkyl− Ni(II) species E. This nucleophilic alkyl−Ni(II) E can undergo migratory insertion with 1 to furnish vinyl Ni complex F, as proposed by the MacMillan group.12d The innate selectivity of the insertion process, as reported by the Bergman group,17 and the sterics of the silyl group endow the high selectivity. The protodenickelation of F would deliver the desired product with regeneration of the initial Ni(II) complex A, completing the 4693

DOI: 10.1021/acs.orglett.8b02017 Org. Lett. 2018, 20, 4691−4694

Letter

Organic Letters β-alkylation process via nucleophilic Giese processes and other formal hydroalkylation reactions of alkynes. Further transformation of the products could provide diverse functionalized trisubstituted alkenes. A mechanism involving the catalytic generation of alkyl radicals and insertion of an alkyl−nickel intermediate into alkynes, which sequentially underwent protodemetalation to enable the resulting hydroalkylation reaction, was proposed.

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Chem. Soc. 2018, 140, 5701. (e) Kang, B.; Hong, S. H. Chem. Sci. 2017, 8, 6613. (f) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 0052. (13) Ruecker, C. Chem. Rev. 1995, 95, 1009. (14) Reduced alkenes were the major side products. (15) (a) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10, 1727. (b) Sidera, M.; Costa, A. M.; Vilarrasa, J. Org. Lett. 2011, 13, 4934. (16) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b) Singh, J. J. Prakt. Chem. 2000, 342, 340. (c) Balasubramaniam, S.; Aidhen, I. Synthesis 2008, 2008, 3707. (17) Huggins, J. M.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 3002.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02017. Experimental procedures and full spectroscopic data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Soon Hyeok Hong: 0000-0003-0605-9735 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Samsung Science and Technology Foundation under Project Number SSTFBA1601-12.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02017 Org. Lett. 2018, 20, 4691−4694