Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Photocatalytic Reductive Fluoroalkylation of Nitrones Vyacheslav I. Supranovich, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman* N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation S Supporting Information *
ABSTRACT: A method for the addition of fluorinated groups to nitrones using an iridium photocatalyst and ascorbic acid as a stoichiometric reducing agent is described. The reaction proceeds through the generation of fluorinated radicals by single-electron reduction of fluorinated alkyl iodides with an iridium complex mediated by visible light. Besides perfluorinated reagents, partially fluorinated alkyl iodides can also be effectively used leading to the products, which cannot be obtained by conventional nucleophilic addition reactions. The resulting hydroxylamines can be readily converted to valuable fluorinated amines by reduction with zinc.
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described. To this end, herein we report a general method for the synthesis of fluorinated hydroxylamines. Mild conditions of the method provide notably wider scope compared to nucleophilic addition reactions.12 Furthermore, products 3 can be considered as precursors of pharmacophoric amines bearing a fluorinated substituent at the α-position.13 Our concept for the reductive fluoroalkylation of nitrones is shown in Scheme 2. First, fluorinated alkyl iodide 2 is reduced
ue to the importance of organofluorine compounds in medicinal chemistry and related fields,1 novel methods for the introduction of a fluorinated fragment into a specific position of organic molecules are highly desirable.2 A methodology of nucleophilic fluoroalkylation has dominated in this area for a long time, relying, primarily, on silicon reagents.3 At the same time, over the past decade, processes of radical fluoroalkylation have come to the forefront of organofluorine chemistry.4 Indeed, the major benefit of radical reactions is that they can allow for the introduction of fluorinated groups, for which corresponding carbanionic reagents do not exist or are unavailable. Moreover, the advent of photoredox catalysis5 has offered very mild methods for the generation of fluorine-containing radicals.6 The addition of fluorinated radicals at the CN double bond has been poorly investigated.7 Only hydrazones were successfully utilized as acceptors of the trifluoromethyl radical in a series of oxidative C−H functionalization reactions (Scheme 1).8,9 Nitrones are known to behave as efficient radical traps,10 and have occasionally been used to intercept fluorinated radicals leading to observable nitroxyl species.11 However, despite the facile radical addition step, no protocols for the reductive fluoroalkylation of nitrones have been
Scheme 2. Reductive Fluoroalkylation of Nitrones
Scheme 1. Fluoroalkylation of Azomethines
by a catalyst to generate the corresponding free radical, which adds at the nitrone double bond. Subsequent single-electron reduction of nitroxyl radical 4 and protonation of nitroxide species affords hydroxylamine 3. As a stoichiometric reductant we used readily available ascorbic acid.14 Two distinct pathways Received: December 22, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b03987 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Fluoroalkylation of Nitronesa,b
can work with the use of the same photocatalyst. In mode A, the light-activated catalyst serves as a source of electrons (oxidative quenching), and its reduced state is regenerated with the aid of ascorbate. In mode B, the catalyst is first reduced by ascorbate (reductive quenching) leading to a strongly reductive species, which activates the alkyl iodide. Besides reducing the catalyst, ascorbate anion can also serve as a source of hydrogen atom toward nitroxyl radical 4.15 Difluorinated iodide 2a16,17 and trifluoromethyl iodide18 were originally selected as model substrates (Table 1). First, the Table 1. Optimization Studies
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cat.
red.
solvent
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b
eosin Yb eosin Yb,c Cu(dap)2PF6 Ru(bpy)3(BF4)2 Ru(bpy)3(BF4)2 Ru(bpy)3(BF4)2 Ru(phen)3(BF4)2 Ru(bpy)3(BF4)2 Ir(ppy)3 Ir[dF(CF3)ppy]2PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6
Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-Nad Asc-H, NEt3 Asc-H, NEt3 Asc-H Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-H, NEt3 Asc-H, coll.f
MeOH MeOH MeOH MeOH MeOH MeOH MeCN MeOH MeOH MeOH MeOH MeOH DMSO DMSO DMSO
yielda (%) 4 4 67 30 21 70 48 40 71 77 86e 63e 91e
a
Determined by 19F NMR with internal standard. bDisodium salt was used. cGreen LED was used. dSodium ascorbate. eIsolated yield. f2,4,6Collidine.
reaction of N-methyl-C-phenyl nitrone 1a with iodide 2a (1.5 equiv) in the presence of a photocatalyst (0.5 mol %) under irradiation with blue light was evaluated. As a reducing system a combination of ascorbic acid and triethylamine (1.5 equiv of each) was used. The reaction proceeded with various ruthenium and iridium catalysts, among which a cationic iridium complex, Ir(ppy)2(dtbbpy)PF6, provided the optimal result. Though methanol was used as solvent in the initial experiments, the reaction in dimethyl sulfoxide gave superior results, affording product 3a in 86% isolated yield. When these conditions were applied to trifluoromethyl iodide 2b, the product was formed in a decreased yield of 63%. Finally, when triethylamine was substituted by 2,4,6-trimethylpyridine (collidine), trifluoromethylation product 3b was isolated in 91% yield. Under the optimized conditions, a series of nitrones were fluoroalkylated (Scheme 3). The reaction worked well with nitrones bearing alkyl, benzyl, aryl, and heteroaryl groups. Nitrones derived from enolizable aliphatic aldehydes also furnished the expected products (3h,u,v) in good yields. At the same time, for the substrates bearing a bulky tert-butyl group either at nitrogen or at carbon of the CN bond decreased yields were noted (products 3z,π). Similarly, a nitrone derived from acetophenone was less efficient (product 3σ), likely, because of steric effects. For nitrones having aromatic groups,
a c
1.5 equiv of RfI was used unless mentioned otherwise. bIsolated yield. 1.0 equiv of RfI was used. dNEt3 was used as base.
some byproducts were observed, which were tentatively ascribed to the attack of fluorinated radicals onto the benzene ring. This side reaction was especially noticeable for substrates with an electron-rich 4-methoxyphenyl group. The ring fluoroalkylation may not only be competitive with the desired process, but it can also take place with the product, that is, after the nitrone consumption. Fortunately, the use of a precisely stoichiometric amount of fluoroalkyl iodide in these cases allowed isolation of the target hydroxylamines (3q,t−y) in good yields. Partially fluorinated iodides (RfCH2I) are also important building blocks for the synthesis of organofluorine compounds. However, these iodides cannot be converted into the corresponding carbanionic reagents owing to facile βelimination. As a result, nucleophilic trifluoroethylation of any electrophiles still has not been reported! On the other hand, generation of 2,2,2-trifluoroethyl radical is known,19 although B
DOI: 10.1021/acs.orglett.7b03987 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters 2,2,2-trifluoro-1-iodoethane (CF3CH2I) is noticeably more difficult to reduce compared to perfluorinated iodides.20,21 A combination of ascorbic acid and a photocatalyst provides an opportunity for the generation of strongly reducing species by the reductive quenching (Scheme 2, mode B). It was rewarding to find that our conditions worked well for the addition of partially fluorinated iodides 5 to nitrones (Scheme 4). In this case, morpholine (2.5 equiv) proved to be the optimal base.
Scheme 5. Synthesis of Fluorinated Amines
Scheme 4. Reactions of Partially Fluorinated Iodidesa
fluoroalkyl groups. The method can be used to access partially fluorinated secondary amines by the reduction of N−O bond of the hydroxylamines.
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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.7b03987. Experimental procedures, compound characterization data, and NMR spectra for all compounds (PDF)
a
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AUTHOR INFORMATION
Corresponding Author
Isolated yield. b1.0 equiv of CF3CH2I was used.
*E-mail:
[email protected]. ORCID
To verify the radical character of the fluoroalkylation process, the reaction of nitrone 1a with CF3I was performed in the presence of TEMPO (1.5 equiv). However, a compound resulting from the trapping of the CF3 radical (TEMPO−CF3) was formed only in 15% yield along with the expected nitrone addition product 3b (76%, according to 19F NMR). This result is associated with the ability of ascorbate to reduce TEMPO to give TEMPO-H,15a and the latter compound was indeed observed by GC−MS. Concerning the reaction mechanism, the reduction potential of the catalyst excited state [Ir(ppy)2(dtbbpy)PF6, Ir(III)*/ Ir(IV), −0.96 V vs SCE]5a is not strong enough to reduce fluoroalkyl iodides with potentials varying from −1.22 to −1.70 V.20,21 Therefore, the mode B involving the reductive quenching of the photocatalyst by ascorbic acid affording an Ir(II) species [Ir(II)/Ir(III), −1.51 V]5a is more likely (Scheme 2). Nitrones are reduced at potentials around −2 V,22suggestsuggesting that they are notably less prone to reduction than fluorinated alkyl iodides. Hydroxylamines 3 and 6 obtained from the fluoroalkylation reaction can be easily converted into amines 7 (Scheme 5). Thus, the reduction of the N−O bond can be effected by zinc under acidic conditions furnishing amines 7 in almost quantitative yields. It is worthy of note that fluorinated amines 7a−c cannot be accessed by conventional nucleophilic addition to imines due to inaccessibility of the suitable nucleophilic reagents. In summary, a convenient method for the reductive radical fluoroalkylation of nitrones affording hydroxylamines is described. The addition reaction is promoted by visible-light irradiation, with an iridium photocatalyst being recycled by stoichiometric amounts of a reducing agent. Various fluorinated iodides serve as suitable components for the transfer of the
Alexander D. Dilman: 0000-0001-8048-7223 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Russian Science Foundation (Project 14-50-00126). REFERENCES
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DOI: 10.1021/acs.orglett.7b03987 Org. Lett. XXXX, XXX, XXX−XXX
