Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron(III)-Catalyzed Ortho-Preferred Radical Nucleophilic Alkylation of Electron-Deficient Arenes Fei Yu,†,§ Ting Wang,‡,§ Huan Zhou,† Yajun Li,† Xinhao Zhang,‡ and Hongli Bao*,† †
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, People’s Republic of China ‡ Lab of Computational Chemistry and Drug Design, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, People’s Republic of China S Supporting Information *
ABSTRACT: The untraditional iron-catalyzed, ortho-preferred, radical alkylation of electron-deficient (hetero)arenes is reported. A variety of electron-deficient arenes were shown to react with various primary alkyl sources, producing the alkylated (hetero)arenes in good yields. This reaction might be an alkyl radical, nucleophilic aromatic substitution reaction, rather than the traditional electrophilic Friedel−Crafts reaction. HOMO−LUMO analysis and DFT studies on the key transition states underlying the regioselectivity are consistent with the observed reactions and the conclusions.
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electron-deficient arenes7 and transition-metal-catalyzed direct C−H alkylation of electron-deficient arenes that has since emerged as an interesting alternative. However, transition-metalcatalyzed C−H alkylation of electron-deficient arenes often requires proximal chelate-assisting directing groups, along with the ortho-selective alkylation products (Scheme 1, eq 2). Recently, Zhang’s group8 and Miura’s group9 independently reported intermolecular C−H alkylation of highly electrondeficient polyfluoroarenes based on their unique electronic properties. These achievements overcame some of the limitations associated with the traditional routes, but the success of such reactions still depends on the use of special arenes. A significant advance in para-selective radical alkylation of electrondeficient arenes with only cycloalkanes as the secondary alkylating reagent10 was made by Li et al. In this case, di-tertbutyl peroxide11 was used as the radical initiator and a range of electron-deficient arenes were used as substrates. Inspired by Li et al., we speculated whether alkyl peroxides,12 which have been developed as alkyl radical resources, could be applied to the catalytic C−H alkylation of electron-deficient arenes. In this paper, we report our recent discoveries concerning radical nucleophilic alkylation of electron-deficient arenes with unbiased C−H bonds, in an ortho-preferred fashion. Here, primary alkyl groups were introduced to the electron-deficient aryl rings (Scheme 1, eq 3), in contrast to Friedel−Crafts alkylation and Li et al. Initial studies of the model reaction between the electrondeficient chlorobenzene (1a) and lauroyl peroxide (LPO) 2a suggested the following optimal reaction conditions: catalyzed by
lkylated aromatic compounds are seen widely as the fundamental motifs of pesticides, medicines, dyes, conductive polymer materials, and fine chemicals.1 Many strategies have been developed to synthesize such compounds, but direct alkylation of aromatic C−H bonds is one of the most appealing approaches, owing to its atom-efficient ability to form carbon− carbon bonds.2 Traditionally, Friedel−Crafts alkylation of arenes is a powerful and frequently used method to construct alkylated arenes since various alkyl halides,3 olefins,4 and alcohols5 can be used as the electrophilic alkylating reagents (Scheme 1, eq 1). Scheme 1. General Methods for C−H Alkylation of Arenes
However, despite the progress that has been achieved, the utility of this reaction is often compromised by the restricted scope of functional groups, polyalkylation, harsh conditions, and other limitations.6 Due to the nature of the electrophilic aromatic substitution in this reaction, the requirement of electron-rich arenes is the key to a successful Friedel−Crafts alkylation reaction. The development of a synthetic strategy for C−H alkylation of poorly reactive, electron-deficient arenes is an ongoing challenge. In 2009, Bandini and co-workers reported a Lewis acid catalyzed direct intramolecular C−H alkylation of moderately © XXXX American Chemical Society
Received: October 17, 2017
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DOI: 10.1021/acs.orglett.7b03244 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 2.5 mol % of Fe(OTs)3, the mixture of LPO and chlorobenzene was heated under N2 atmosphere. The alkylated product 3a was produced in as high as 80% yield with the regioisomer ratio as o/ p/m = 7:1:2 (Scheme 2, eq 1; for more details, see Supporting Information).13
Table 1. Iron-Catalyzed Radical Alkylation of Different Electron-Deficient Arenesa,b,c
Scheme 2. Rationalization of Regioselectivity with Theoretical Calculations and Experimental Results
a
Reaction conditions: LPO (0.5 mmol) and Fe(OTs)3 (2.5 mol %) in arene at 100 °C under N2. bThe yield of isolated product. cThe ratio of isomers was determined by GC−MS.
eq 3). This iron(III)-catalyzed reaction preferred the electrondeficient substrate, and the ratio of the products 3b and 3c was 3.7:1. The calculated free energy of transition state 3b_TS is about 3.1 kcal/mol lower than that of 3c_TS (Scheme 2, eq 4-i), which is qualitatively consistent with the experimental data. Friedel−Crafts alkylation generally prefers electron-rich arene, but this reaction exhibits the opposite result. Further, HOMO− LUMO analysis was introduced to address the origin of the competition between 1,4-dichlorobenzene and benzene (Scheme 2, eq 4-ii), and it was found that the LUMO energy of 1,4-dichlorobenzene is 0.68 eV lower than that of benzene. This indicates that this iron(III)-catalyzed radical reaction probably is an alkyl radical nucleophilic aromatic substitution reaction, rather than a typical electrophilic aromatic substitution reaction. These results are consistent with the experimental observation that electron-deficient arenes are preferred over electron-rich arenes. Our hypothesis was further verified by the behavior of 1,4-dichlorobenzene, benzene, and anisole (Scheme 2, eq 5). The electron density of the benzene ring increases in the order anisole > benzene > 1,4-dichlorobenzene, but the yields for the radical alkylations decrease from 1,4-dichlorobenzene to anisole, which strongly supports the view that this radical alkylation is a type of alkyl radical nucleophilic aromatic substitution reaction. With the optimized reaction conditions in hand, the scope of electron-deficient arenes was studied, and the results are shown in Table 1. As expected, in the radical nucleophilic aromatic substitution reaction product 3e, the radical alkyl group prefers to attack the position ortho to chlorine, rather the position ortho to methyl group. Because of the electron-donating methyl group, the yield was low. Other halogen substituted arenes, such as 1f− 1k, underwent the radical alkylation smoothly and delivered the corresponding products with good to high yields. For substrate 1j, the radical alkyl group preferred to attack the position ortho to chlorine, rather than the position ortho to fluorine. Other electron-withdrawing groups, such as formyl (1l), cyano (1m), and carbonyl (1n) were also examined, and all were tolerated under the reaction conditions, affording the corresponding products 3l−3n in moderate to good yields. The compatibility of these electron-withdrawing groups in this reaction can greatly
The chlorine atom is a deactivating substituent in Friedel− Crafts alkylations, making the benzene ring less reactive. Moreover, a primary carbocation is not a good alkyl source for Friedel−Crafts alkylation because of the possibility of concomitant carbocation rearrangements. A question is why this radical alkylation of deactivated chlorobenzene with primary alkyl group happens? In order to understand these unusual results, computational studies were carried out.14 For the sake of simplicity, the model used for density functional theory (DFT) calculations employed a propyl radical (•C3H7), instead of the undecyl radical (•C11H23) from the homolytic cleavage of LPO, as the alkyl substituent. This propyl radical could then attack the benzene ring destroying its aromaticity, in what is commonly proposed to be the rate-determining step. The corresponding transition states of a radical attacking different positions of chlorobenzene, 3a_TS-1, 3a_TS-2, and 3a_TS-3, are shown in Scheme 2, eq 2. We found that the relative free energy of 3a_TS1 is 0.9 and 1.3 kcal/mol lower compared to that of 3a_TS-2 and 3a_TS-3, respectively, which is consistent with the experimentally observed 7:2:1 ratio of o-, m-, and p-alkylated products. Scheme S1 in the SI presents the regioselectivity transition states of different substrates by DFT calculations.15 For almost all the substrates in Table 1, the computational regioselectivity agrees well with the experimental results. A competitive radical reaction of 1,4-dichlorobenzene and benzene was carried out (Scheme 2, B
DOI: 10.1021/acs.orglett.7b03244 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Table 3. Iron-Catalyzed Radical Alkylation of Heteroarenesa
broaden the substrate scope of various electron-deficient arenes, and the tolerated functional group can be used as an anchor for further transformations. Next, the scope of alkyl radical sources from alkyl carboxylic acids12 was studied as shown in Table 2. In order to highlight the Table 2. Iron-Catalyzed Radical Alkylation with Various Alkyl Diacyl Peroxidesa
a
Reaction conditions: LPO (0.5 mmol), Fe(OTs)3 (2.5 mol %), in heteroarene (5 mL), under N2. The yield of isolated product. The ratio of regioisomers was determined by GC−MS.
Scheme 3. Possible Mechanism
elevated temperature, homolytic cleavage of the alkyl diacyl peroxide generates an alkyl-free radical by releasing a molecule of CO2. Meanwhile, single-electron transfer (SET) from the iron(II) species A produces the iron(III) species B. The generated alkyl free radical C nucleophilic attacks the arene substrate to form the delocalized radical intermediate D, which is then oxidized by the iron(III) species B to produce the delocalized carbocation intermediate E. Finally, an active iron(II) species A is regenerated together with the formation of an alkyl carboxylate anion, which can abstract a proton from the intermediate E to form the desired alkylated product. Since it is unlikely that iron can coordinate to the electron-deficient substrates and affect the selectivity, the ortho-selectivity might come from the stability of delocalized arene radical intermediates. In summary, we have developed an iron-catalyzed orthopreferred radical alkylation of electron-deficient (hetero)arenes and alkyl diacyl peroxides. This reaction might be an alkyl radical nucleophilic aromatic substitution reaction. DFT studies and HOMO−LUMO analysis support this hypothesis.
a
Reaction conditions: alkyl diacyl peroxide (0.5 mmol) and Fe(OTs)3 (2.5 mol %) in o-dichlorobenzene or p-dichlorobenzene (5 mL or 6 g) at 100 °C under N2. bReaction was performed at 80 °C. cReaction was performed at 70 °C.
generality, substrates 1b and 1g with two chlorine atoms were tested, affording the corresponding products 4 and 5, respectively. Under the optimized conditions, the diacyl peroxides that contain long chain alkyl groups afforded the corresponding alkylated products 4a−4d and 5a−5e in good yields. Alkyl diacyl peroxides with a phenyl group could also deliver the corresponding alkylated products 4e, 4f and 5f, 5g, along with the unchanged benzylic C−H bond. The alkyl chain of peroxides with a functional group, such as chloride or ester, produced the alkylated products 4g, 4h and 5h, 5i respectively, with good yields. Further study showed that the substrate scope was not limited to alkyl diacyl peroxides: aryl diacyl peroxides could also be applied to the radical nucleophilic aromatic substitution reaction. For example, benzoyl peroxide (BPO) delivered the biphenyl products (4i and 5j) with good yields.16 Heteroarenes can also undergo radical alkylation with good to excellent yields (Table 3). For thiophene (6a) and furan (6b), only monoalkylated products were identified with the alkyl group attaching to the ortho-position of the heteroatom. Furfural 6c delivered the corresponding product 7c with a tolerated aldehyde group, while benzofuran 6d produced an alkylated product 7d in moderate yield. When pyridine (6e) was used as the substrate, good yields but low regioselectivity were achieved. In this reaction, no acid additive was needed, which was different from the Minisci reaction conditions.17,18 A hypothetical mechanism for the iron-catalyzed alkyl radical nucleophilic aromatic substitution reaction is proposed in Scheme 3.10,12 With the assistance of the iron-catalyst and/or
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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.7b03244. Experimental details, data, DFT studies, and spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xinhao Zhang: 0000-0002-8210-2531 Hongli Bao: 0000-0003-1030-5089 C
DOI: 10.1021/acs.orglett.7b03244 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Author Contributions
(12) (a) Li, Y.; Han, Y.; Xiong, H.; Zhu, N.; Qian, B.; Ye, C.; Kantchev, E. A. B.; Bao, H. Org. Lett. 2016, 18, 392. (b) Jian, W.; Ge, L.; Jiao, Y.; Qian, B.; Bao, H. Angew. Chem., Int. Ed. 2017, 56, 3650. (c) Qian, B.; Chen, S.; Wang, T.; Zhang, X.; Bao, H. J. Am. Chem. Soc. 2017, 139, 13076. (13) For more details on the optimization of the radical alkylation reaction, please see Supporting Information, Table S1. (14) Computational details are given in the Supporting Information. (15) Theoretical regio-selectivity studies for substrates 1d, 1e, 1f, 1g, 1h, 1j, 1l, 1m, and 1n have been conducted as shown in Supporting Information, Scheme S1. (16) Secondary alkyl diacyl peroxides afforded only trace amount of the corresponding products. (17) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Tetrahedron 1971, 27, 3575. (18) Hasebe, M.; Tsuchiya, T. Tetrahedron Lett. 1986, 28, 3239.
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F.Y. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank NSFC (Grant Nos. 21502191, 21672213, 21232001), Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), The 100 Talents Program, “The 1000 Youth Talents Program”, Haixi Institute of CAS (CXZX-2017-P01), and the Shenzhen STIC (JCYJ20170412150343516) for financial support.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03244 Org. Lett. XXXX, XXX, XXX−XXX
