Radical-Mediated Heck-Type Alkylation: Stereoconvergent

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Radical-Mediated Heck-Type Alkylation: Stereoconvergent Synthesis of Functionalized Polyenes Hong Zhang,† Xinxin Wu,† Yunlong Wei,† and Chen Zhu*,†,‡ †

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Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, China ‡ Key Laboratory of Synthesis Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032, China S Supporting Information *

ABSTRACT: The stereospecific synthesis of polyenes is of great synthetic value. Disclosed herein is a new, efficient, stereoconvergent approach for the synthesis of functionalized polyenes via a radical-mediated Heck-type alkylation. The easily accessed Z- and E-mixed alkenes are harnessed as starting material, leading to a unique stereoisomer of polyenes. In addition, the transformation features mild reaction conditions and broad functional group compatibility. A variety of valuable 1,3-dienes and 1,3,5-trienes are afforded in useful yields.

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a stereoconvergent pathway, in which the Z- and E-alkene mixture readily accessed from the Wittig reactions is employed as starting material, leading to a single stereoisomer of polyenes. The transformation is performed under mild conditions, manifesting a broad functional group tolerance. A variety of valuable 1,3-dienes and 1,3,5-trienes are furnished in useful yields. At the outset, the reaction of a mixture of Z- and E-1a with the multifunctionalized tertiary alkyl bromide 2a was investigated to optimize the reaction conditions (Table 1; for details see the Supporting Information (SI)). With copper salt as catalyst, the use of dimethylacetamide (DMA) delivered a better yield than other solvents (entries 1−6). The desired alkylated 1,3-diene 3a was exclusively obtained in E,Econfiguration. The use of Na2HPO4 as base significantly improved the yield to 94% (entries 7−11). Using less expensive CuCl instead of Cu(OTf)2 afforded an identical yield (entry 12). Variation of bpy to other ligands decreased the yield (entries 13−15). The reaction outcome was not compromised when reducing the amount of 2a to 1.5 equiv and the reaction temperature to 40 °C (entry 16). The reaction also proceeded with other metal catalysts, but afforded

onjugated polyenes are extensively present in natural products which usually demonstrate unique biological activities.1 For instance, Stellettin C is a cytotoxic triterpene isolated from a marine sponge, Stelletta sp.;2 Inthomycin A is a specific inhibitor of cellulose biosynthesis and displays in vitro inhibitory activity against human prostate cancer growth;3 Vitamin A and D2 play a far greater role in health and protect against numerous diseases (Scheme 1a).4 Furthermore, conjugated polyenes often serve as versatile feedstocks in synthetic chemistry, e.g. in the Diels−Alder cycloaddition reactions as a 4π-component.5 For industrial use, the polymerization of 1,3-dienes and other polyenes via Ziegler− Natta catalysis affords the high-value polymerized materials.6 Therefore, development of practical approaches to produce conjugated polyenes is in high demand.7 The conventional preparation of conjugated polyenes mainly relies on two pathways: the Wittig reaction and the Heck− Mizoroki cross-coupling (Scheme 1b). The former generally results in a mixture of Z- and E-olefinic isomers;8 the latter offers a solution for the stereocontrol problem, but sometimes the vinyl iodide precursor is not easily obtained.9 As for an efficient polyene synthesis, the accessibility of starting materials should also be fully considered along with the aim of gaining a unique stereoselectivity. Herein, we disclose a new approach for the synthesis of functionalized polyenes via a radicalmediated Heck-type alkylation (Scheme 1c).10 Notably, this is © XXXX American Chemical Society

Received: August 10, 2019

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DOI: 10.1021/acs.orglett.9b02838 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

lead to a mixture of stereoisomeric 1,3-dienes in about a 1:1 ratio (entry 20). With the optimized reaction conditions in hand, we set about assessing the generality of this protocol (Scheme 2).

Scheme 1. Importance of Conjugated Polyenes and the Synthesis

Scheme 2. Scope of Dienesa

Table 1. Reaction Conditions Surveya

entry

catalyst

base

ligand

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16b 17 18 19 20c

Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 CuCl CuCl CuCl CuCl CuCl CuI CuBr2 FeCl2 Ir(ppy)3

K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K2HPO4 CsF K2CO3 Na2CO3 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 Na2HPO4 TTMSS

bpy bpy bpy bpy bpy bpy bpy bpy bpy bpy bpy bpy phen PPh3 dppe bpy bpy bpy bpy −

DCE DCM acetone CH3CN DMF DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMA DMF

29 36 30 50 30 61 84 89 60 43 94 94 87 77 80 94 85 83 48 68

a

Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), CuCl (10 mol %), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL) under N2, 40 °C. b80 °C.

First, a variety of aryl dienes bearing diverse functional groups were investigated. Notably, performing the reaction on a 1.0 mmol scale did not compromise the reaction outcome (3a). Both electron-rich (e.g., alkyl, aryl, OMe) and -deficient (e.g., halide, OCF3, CF3, CO2Me) groups were tolerated in the reaction, readily affording the corresponding alkylated E,Edienes (3b−3l). Despite the sensitivity of alkynes to radical reaction conditions, the radical alkylation proceeded exclusively at the diene part (3m). The presence of aryl bromide was useful, as it reserved a platform for product elaboration by cross-couplings (3h and 3s). The change of substitution from the para- to meta- or ortho-position did not impede the transformation (3n−3q). In addition to phenyl and naphthyl (3r) dienes, the analogous heteroaryl (e.g., thienyl, benzothienyl, pyridyl, quinolyl) dienes could also be prepared by this method (3t−3w). The alkylation of multiply substituted dienes, in particular the less reactive internal dienes, also

a

Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), catalyst (10 mol %), ligand (10 mol %), and base (1.1 equiv) in solvent (2 mL) under N2 for 9 h, 80 °C. Yields of isolated products are given. b2a (1.5 equiv), 40 °C. cfac-Ir(ppy)3 (2 mol %), TTMSS (2.0 equiv), irradiated with 14 W blue LEDs for 3 h. bpy = bipyridine. TTMSS = (i-Pr)3SiSH.

lower yields (entries 17−19). This radical transformation could be promoted by photocatalytic conditions; however, this B

DOI: 10.1021/acs.orglett.9b02838 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Variation of Alkylating Reagentsa

occurred in a stereospecific manner, which was determined by NOE experiments (3x−3z). Moreover, in the case of 3y, the addition of an alkyl radical adjacent to the methyl side was verified by HMBC experiment. Remarkably, the protocol could also be applied to the intricate scaffolds based on natural products and drug molecules, for instance, febuxostat, lithocholic acid, and Ibuprofen (3aa−3ac). The case of 3ac was intriguing, in which the racemization of chirality at the αposition of carbonyl did not take place under the mild reaction conditions (for details, see the SI). It should be noted that the sole stereoisomer of diene products was stereoconvergently furnished from the Z,E-mixture of precursors, indicating supreme stereocontrol in the reaction. The alkylation of 1,3,5-trienes was subsequently studied. A series of representative examples were tested under the previous conditions (Scheme 3). Likewise, the reaction readily Scheme 3. Scope of Trienesa

a

Reaction conditions: 1 or 4 (0.2 mmol), 2b-d (1.5 equiv), CuCl (10 mol %), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL) under N2, 40 °C. b80 °C.

Scheme 5. Proposed Mechanism

a

Reaction conditions: 4 (0.2 mmol), 2a (1.5 equiv), CuCl (10 mol %), bpy (10 mol %), and Na2HPO4 (1.1 equiv) in DMA (2 mL) under N2, 40 °C.

the radical chain process (path b), to convert the intermediate c to the final product 3. First, SET from c to the Cu(II) species affords the allylic cation d that then reacts with bromide to generate the allylbromide e. Alternatively, intermediate c could abstract a bromine atom from compound 2 to afford the allylbromide e. Meanwhile, the alkyl radical a is regenerated and perpetuates the radical chain process. Eventually, dehydrobromination of e promoted by a base results in the product 3.11 This is also the key step to offering exclusive stereoselectivity as well as the thermodynamically favored E,Ediene product. Another possible approach to afford the product 3 might directly go through the direct deprotonation of cation d. In addition to the well-known function of dienes, serving as an important 4π-component in the Diels−Alder cycloaddition,5 the products could also be transformed into other valuable molecules. For example, treating 3a with tBuOK in wet ethanol led to a new diene product 7 via decarboxylation (Scheme 6a). While direct reduction of 3a by a strong reducing agent such as LiAlH4 led to a messy reaction, the same expected product 8 was obtained through the tBuOKmediated decarboxylative hydroxymethylation approach (Scheme 6b). In conclusion, we have disclosed a novel protocol for stereoconvergent synthesis of conjugated polyenes via a

proceeded regardless of the steric and electronic effects, leading to the corresponding functionalized E,E,E-trienes with exclusive stereoselectivity (5a−5f). Multisubstituted trienes were also apt to afford the products that are otherwise hard to make (5g and 5h). Then we focused attention toward varying the alkylating reagent 2a in order to evaluate the necessity of each functional group in 2a (Scheme 4). The reaction of 2b, in which another alkyl group such as ethyl was employed in lieu of methyl, with either diene or triene afforded the desired products (6a and 6b). Moreover, the methyl group could also be replaced with an aryl group, leading to the similar alkylated diene and triene products (6c and 6d). The reaction using 2d readily proceeded, indicating that the cyano group was dispensable to the alkylation reaction (6e and 6f). However, it was found that the ester group was crucial, as the transformation did not occur in the absence of ester under the current conditions. A proposed mechanism is depicted in Scheme 5. The interaction between a Cu(I) salt and compound 2 generates the electrophilic alkyl radical a and Cu(II) species. The addition of intermediate a to diene 1 leads to an allyl radical represented by resonance structures b and c. There are three pathways: the Cu-catalyzed SET process (path a and c) and C

DOI: 10.1021/acs.orglett.9b02838 Org. Lett. XXXX, XXX, XXX−XXX

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(2) (a) McCormick, J. L.; McKee, T. C.; Cardellina, J. H., II; Leid, M.; Boyd, M. R. Cytotoxic Triterpenes from a Marine Sponge, Stelletta sp. J. Nat. Prod. 1996, 59, 1047. (b) McKee, T. C.; Bokesch, H. R.; McCormick, J. L.; Rashid, M. A.; Spielvogel, D.; Gustafson, K. R.; Alavanja, M. M.; Cardellina, J. H.; Boyd, M. R. Isolation and Characterization of New Anti-HIV and Cytotoxic Leads from Plants, Marine, and Microbial Organisms. J. Nat. Prod. 1997, 60, 431. (3) (a) Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. The Syntheses of Rac-Inthomycin A, (+)-Inthomycin B and (+)-Inthomycin C Using a Unified Synthetic Approach. Tetrahedron 2008, 64, 4778. (b) Kumar, M.; Bromhead, L.; Anderson, Z.; Overy, A.; Burton, J. W. Short, Tin-Free Synthesis of All Three Inthomycins. Chem. - Eur. J. 2018, 24, 16753. (c) Yoshino, M.; Eto, K.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Organocatalytic Asymmetric Syntheses of Inthomycins A, B and C. Org. Biomol. Chem. 2012, 10, 8164. (4) (a) Cox, B. D.; Muccio, D. D.; Hamilton, T. P. Conformational Analysis of Retinoic Acids: Effects of Steric Interactions on Nonplanar Conjugated Polyenes. Comput. Theor. Chem. 2013, 1011, 11. (b) He, M.-C.; Shi, Z.; Sha, N.-N.; Chen, N.; Peng, S.-Y.; Liao, D.-F.; Wong, M.-S.; Dong, X.-L.; Wang, Y.-J.; Yuan, T.-F.; Zhang, Y. Paricalcitol Alleviates Lipopolysaccharide-Induced Depressive-Like Behavior by Suppressing Hypothalamic Microglia Activation and Neuroinflammation. Biochem. Pharmacol. 2019, 163, 1. (5) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction. J. Am. Chem. Soc. 2000, 122, 4243. (b) Teo, Y.-C.; Loh, T.-P. Catalytic Enantioselective DielsAlder Reaction via a Chiral Indium(III) Complex. Org. Lett. 2005, 7, 2539. (c) Wilson, R. M.; Danishefsky, S. J. Pattern Recognition in Retrosynthetic Analysis: Snapshots in Total Synthesis. J. Org. Chem. 2007, 72, 4293. (d) Dai, M.; Sarlah, D.; Yu, M.; Danishefsky, S. J.; Jones, G. O.; Houk, K. N. Highly Selective Diels-Alder Reactions of Directly Connected Enyne Dienophiles. J. Am. Chem. Soc. 2007, 129, 645. (e) Hayashi, Y.; Samanta, S.; Gotoh, H.; Ishikawa, H. Asymmetric Diels-Alder Reactions of α,β-Unsaturated Aldehydes Catalyzed by a Diarylprolinol Silyl Ether Salt in the Presence of Water. Angew. Chem., Int. Ed. 2008, 47, 6634. (6) (a) Pragliola, S.; Cipriano, M.; Boccia, A. C.; Longo, P. Macromol. Polymerization of Phenyl-1,3-butadienes in the Presence of Ziegler-Natta Catalysts. Macromol. Rapid Commun. 2002, 23, 356. (b) Ren, Y.; Miller, J. T.; Polderman, S. T.; Vo, T. D.; Wallace, A. C. M.; Cue, J. M. O.; Tran, S. T.; Biewer, M. C.; Stefan, M. C. Halidefree Neodymium Phosphate Based Catalyst for Highly Cis-1,4 Selective Polymerization of Dienes. RSC Adv. 2019, 9, 3345. (c) He, J.-Y.; Cui, L.; Qi, Y.-L.; Dai, Q.-Q.; Bai, C.-X. Neodymium Organic Sulfonate Complexes: Tunable Electronegativity/Steric Hindrance and Application in Controlled Cis-1,4-polymerization of Butadiene. Chin. J. Polym. Sci. 2019, 37, 208. (d) Liu, X.; Li, W.; Niu, Q.; Wang, R.; He, A. Trans-1,4- Stereospecific Polymerization of Isoprene With MgCl2-Supported Ziegler-Natta Catalyst I. Initial Polymerization Kinetic and Polymerization Mechanism. Polymer 2018, 140, 255. (7) For reviews of polyene synthesis, see: (a) Mehta, G.; Prakash, H. S. R. Synthesis of Conjugated Dienes and Polyenes. In Patai’s Chemistry of Functional Groups; Rappoport, Z., Ed.; John Wiley & Sons, Ltd.: Chichester, U.K., 1997. (b) De Paolis, M.; Chataigner, I.; Maddaluno, J. Recent Advances in Stereoselective Synthesis of 1,3Dienes. Top. Curr. Chem. 2012, 327, 87. For selected examples of synthesis of conjugated dienes, see: (c) Hu, X.-H.; Zhang, J.; Yang, X.F.; Xu, Y. H.; Loh, T.-P. Stereo- and Chemoselective Cross-Coupling between Two Electron-Deficient Acrylates: An Efficient Route to (Z, E)-Muconate Derivatives. J. Am. Chem. Soc. 2015, 137, 3169. (d) Olivares, A. M.; Weix, D. J. Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling to form Highly Substituted 1,3-Dienes. J. Am. Chem. Soc. 2018, 140, 2446. (e) Liu, M.; Yang, P.; Karunananda, M. K.; Wang, Y.; Liu, P.; Engle, K. M. C(alkenyl)-H Activation via Six-Membered Palladacycles: Catalytic 1,3-Diene Synthesis. J. Am. Chem. Soc. 2018, 140, 5805.

Scheme 6. Product Transformations

radical-mediated Heck-type alkylation. The Z- and E-alkene mixtures, which are readily obtained from the Wittig reactions, are employed as starting material, leading to the single stereoisomers of polyenes. The transformation features mild reaction conditions and broad functional group tolerance. A vast array of valuable 1,3-E,E-dienes and 1,3,5-E,E,E-trienes are furnished in useful yields.

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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.9b02838. Experimental details, compound characterization data, and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chen Zhu: 0000-0002-4548-047X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.Z. is grateful for the financial support from the National Natural Science Foundation of China (21722205), the Project of Scientific and Technologic Infrastructure of Suzhou (SZS201708), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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REFERENCES

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DOI: 10.1021/acs.orglett.9b02838 Org. Lett. XXXX, XXX, XXX−XXX