Letter pubs.acs.org/OrgLett
Bromoallylation of Alkenes Leading to 4‑Alkenyl Bromides Based on Trapping of β‑Bromoalkyl Radicals Takashi Kippo,† Kanako Hamaoka,† Mitsuhiro Ueda,† Takahide Fukuyama,† and Ilhyong Ryu*,†,‡ †
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, 599-8531, Japan Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
‡
S Supporting Information *
ABSTRACT: A radical-chain addition of allyl bromides to aryl alkenes, vinyl ester, and vinyl phthalimide was studied in which elusive β-bromoalkyl radicals were trapped efficiently to give 5-bromo-1-pentenes in good to high yields (16 examples). A subsequent carbonylative radical cyclization with AIBN/Bu3SnH/CO was successful in giving the corresponding 3,5disubstituted cyclohexanone derivatives in moderate yields. Synthesis of a piperidine ring was also successful by subsequent reaction with primary amine. Scheme 1. Concept: C−C Bond Formation via β-BrSubstituted Alkyl Radicals A
T
he functionalization of carbon−carbon multiple bonds is of the utmost importance in the synthesis of a wide variety of organic molecules, and free-radical-mediated addition/fragmentation reactions could be powerful tools for this purpose.1,2 We recently developed the bromine-radicalmediated bromoallylation reactions of alkynes,3 allenes,4,5 and alkylidenecyclopropanes,6 which afforded bromine-substituted 1,4-, 1,5-, 1,6-, and 1,7-dienes, respectively.7 These Br−C bonds are subject to further functionalization. In these allylation reactions, bromine radicals work as chain-transfer species, and allyl bromides serve as allylating agents and as a source of bromine radicals.8 Traditional radical hydrobromination of alkenes with HBr involves the reversible addition of a bromine radical to a least hindered end of the alkenes to form βbromoalkyl radical A as the key step (Scheme 1, eq 1).9 Radical A abstracts hydrogen from HBr to give anti-Markovnikov products with the liberation of a bromine radical. For bromoallylation of alkenes to occur, key radical A must be trapped by allylic bromides in preference to a backward βfragmentation reaction (Scheme 1, eq 2). Unlike the case of alkynes, this step seems rather difficult to achieve, since the βcleavage of the C(sp3)−Br bond is quite fast. We speculated that the use of aryl-substituted alkenes, in which radical A would be stabilized by π-conjugation to retard the βfragmentation (thermodynamic key), would allow bromoallylation of the alkenes to occur. We also thought that the process combined with electron-deficient allyl bromides, supposed to work as efficient radical trap (kinetic key), would facilitate the formation of B. Herein, we report that the radical-based bromoallylation of arylalkenes, a vinyl ester, and a vinyl phthalimide, proceeded well to give good to high yields of 5© 2017 American Chemical Society
bromoalkenes. We also confirmed that the products obtained were converted to 3,5-disubstituted cyclohexanones and a piperidine by a carbonylative radical cyclization and reaction with primary amine, respectively, which represents a formal [2 + 2 + 1]cycloaddition. Received: August 9, 2017 Published: September 25, 2017 5198
DOI: 10.1021/acs.orglett.7b02471 Org. Lett. 2017, 19, 5198−5200
Letter
Organic Letters First, we carried out the bromoallylation reaction of styrene (1a) with ethyl 2-(bromomethyl)acrylate (2a) using AIBN (2,2′-azobisisobutylonitrile) as a radical initiator at 80 °C for 1 h (Scheme 2). We were pleased to find that the envisaged
Table 1. Bromoallylation of Alkenes 1 with Allyl Bromides 2a
Scheme 2. Bromoallylation of Styrene (1a) with 2a
bromoallylation of 1a proceeded well to give the expected ethyl 5-bromo-2-methylene-4-phenylpentanoate (3a) in good yields (eq 3). The higher the concentration of 2a, the better the yields of 3a (for example, 83% isolated yield with [2a] = 3.6 M). Encouraged by the results of eq 3 with 1a, we then examined the generality of the bromoallylation of a variety of aryl alkenes 1 leading to 5-bromoalkenes 3 (Table 1). The reaction of palkyl- or phenyl-substituted styrenes 1b−d bearing Me, t-Bu, and Ph substituents with 2a proceeded well to give the corresponding 4-aryl-5-bromo-1-pentenes 3b−d in high yields (entries 2−4). p-Chlorostyrene 1e also gave the corresponding 5-bromoalkene 3e in an 80% yield (entry 5). Electron-poor aryl alkenes 1f, 1g, and 1h could participate in this transformation (entries 6−8). The reactions of electron-rich alkenes also worked well. For example, the reaction of p-acetoxystyrene 1i with 2a provided the desired bromoallylated products 3i in an 84% yield (entry 9). Similarly, bromoallylation of o-, m-, and pmethoxystyrenes 1j, 1k, and 1l all worked well to give the corresponding 5-bromoalkenes 3j, 3k, and 3l in 94, 78, and 93% yields, respectively (entries 10, 11, and 12). The reaction of 1-vinylnaphthalene 1m showed modest reactivity and gave product 3m in a 50% yield (entry 13). The reaction of 1l with α-bromomethylacrylonitrile 2b also proceeded to give the corresponding cyano-substituted bromoalkene 3n in a 71% yield (entry 14). Aliphatic terminal alkenes are not suitable for the present bromoallylation due to competitive allyl C−H abstraction; however, we found that O- and N-substituted alkenes worked quite well. The reaction of vinyl benzoate (1o) with 2a gave the desired bromoallylation product 3o in a 78% yield (entry 15). In a similar manner, the reaction of Nvinylphthalimide (1p) with 2a gave 3p in a 71% yield (entry 16). The present bromoallylation reaction can be scaled into gram-scale synthesis of the 5-bromoalkene (eq 4).
Since the products 3 contain a bromoalkyl substructure, we envisaged that formal [3 + 2 + 1] cycloaddition could be attained with a combination of the bromoallylation of alkenes and a subsequent carbonylative radical cyclization (Scheme 3, eq 5).10 Indeed, tributyltin hydride mediated reaction of 3a with CO proceeded to give 3,5-disubstituted cyclohexanone 4a in a 58% yield, in which acyl radical formation and a subsequent
a
Conditions: 1 (1.0 mmol), 2 (4.0 mmol), AIBN (20 mol %), C6H6 (0.5 mL), 80 °C, 1 h. bIsolated yield after column chromatography on SiO2 and preparative HPLC. 5199
DOI: 10.1021/acs.orglett.7b02471 Org. Lett. 2017, 19, 5198−5200
Organic Letters
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ACKNOWLEDGMENTS This work was supported by Grants-in-Aid for Scientific Research (A) (26248031) from JSPS and Scientific Research on Innovative Areas 2707 Middle Molecular Strategy (15H05850) from MEXT. T.K. acknowledges the Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.
Scheme 3. Formal [3 + 2 + 1] Reaction Leading to Cyclohexanones and Piperidine
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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.7b02471. Detailed experimental procedures and spectroscopic data (PDF)
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REFERENCES
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6-endo acyl radical cyclization proceed. In a similar manner, 5bromoalkenes 3d and 3l were converted to the corresponding 3,5-disubstituted cyclohexanones 4b and 4c in 53 and 47% yields, respectively. Since products 3 have two distal electrophilic centers, the terminal bromide and the electron deficient alkene, another formal [3 + 2 + 1] cycloaddition was also achieved by subsequent reaction with primary amine, which provides a new method to construct piperidine ring. Thus, the reaction of 3a with n-butylamine in the presence of Et3N gave 3,5-disubstituted piperidene 5a, via Michael addition and SN2 reaction at the resulting amine nitrogen (Scheme 3, eq 6). Unlike the anti-Markovnikov hydrobromination of alkenes, due to the elusive nature of β-bromoalkyl radicals, bromineradical-addition-based C−C bond formation of alkenes has been considered difficult. However, the results of this study demonstrate that aryl-, oxygen-, and nitrogen-substituted alkenes would produce the stabilized β-bromoalkyl radical intermediates, which allow the next C−C bond-forming reactions. By the present bromoallylation protocol, a variety of 5-bromo-1-pentenes were prepared in good to high yields. Products bearing a Br−C moiety could be successfully functionalized, and we demonstrated the conversion of the products to 3,5-disubstituted cyclohexanones and a piperidine by a carbonylative radical cyclization and Michael addition/SN2 reaction, respectively.
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Letter
AUTHOR INFORMATION
Corresponding Author
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[email protected]. ORCID
Takahide Fukuyama: 0000-0002-3098-2987 Notes
The authors declare no competing financial interest. 5200
DOI: 10.1021/acs.orglett.7b02471 Org. Lett. 2017, 19, 5198−5200
