Article Cite This: J. Org. Chem. 2018, 83, 8183−8192
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Diverse Transformation of Vinyl Azides with 2,2,6,6Tetramethyl‑N‑oxopiperidinium Jia-Li Liu,†,§ Shu-Wei Wu,†,§ Qing-Yan Wu,† and Feng Liu*,†,‡ †
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Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China ‡ Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China S Supporting Information *
ABSTRACT: A 2,2,6,6-tetramethyl-N-oxopiperidinium (TEMPO+)-mediated three-component diverse transformation of vinyl azides under metal-free conditions is described. The reaction protocols are operationally simple and conducted at ambient temperature, allowing to access various TEMPO-trapped ketones, amides, and α-alkoxyalkyl azides. Preliminary mechanistic studies indicate that an alkene radical cation-mediated radical−radical cross-coupling C−O bond formation could be involved.
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INTRODUCTION The association of an electron-rich (a donor) with an electrondeficient (an acceptor) molecule yields an electron donor− acceptor (EDA) complex, which can bring about an electron transfer event without the need of any photocatalyst.1 Although the physicochemical properties of EDA complexes have been extensively studied since the 1950s,2 their use in chemical synthesis is still under-explored. In recent years, a variety of novel methods involving EDA complexes have been developed for useful transformations.3 These remarkable achievements show possibilities for new reaction design through EDA complex in organic synthesis. As a demonstration of this potential, we report herein a facile, roomtemperature, diverse transformation of vinyl azides using 2,2,6,6-tetramethyl-N-oxopiperidinium (TEMPO+) as the electron acceptor. Recently, vinyl azides,4 a class of functionalized alkenes with unique intrinsic reactivity, have emerged as important synthons for developing novel synthetic methods.5 As an electron-rich enamine-type molecule, vinyl azide 1 is liable to react with an electrophile to form an iminodiazonium ion intermediate 7.6 The subsequent step is either the Schmidt-type rearrangement to give a nitrilium ion 8 that could be intercepted by water to produce an amide 10 or interruption of the rearrangement by an alcohol to yield an α-alkoxy-β- haloalkyl azide 9 (Scheme 1).6a On the other hand, we found that vinyl azide 1 could interact with an electron-poor molecule, such as Selectfluor (1chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), to form an EDA complex.7 A single electron transfer (SET) process took place subsequently, generating an alkene radical cation 11, followed by fluorine atom transfer and nucleophilic addition with water to give αfluoroketone 12 (Scheme 2).7a © 2018 American Chemical Society
Scheme 1. Electrophilic Transformation of Vinyl Azides
Within the realm of open-shell chemistry, the alkene radical cations show a combination of free radical and cation chemistry that confers an interesting manner of reactivity on them.8 As excellent oxidants, TEMPO+ and its analogues are widely used for the oxidation of alcohols.9 Recently, a chargetransfer (CT) complex TEMPO−ClO2 was identified by Yamamoto and co-workers.10 Our very recent report also demonstrated that TEMPO+ could interact with vinyl ether to form an EDA complex.11 Thus, we wondered if we might be able to access the reactive open shell radical cation via a thermal-activated electron transfer from vinyl azide to TEMPO+ as Selectfluor did.7 In the present study, we further advance the concept of EDA complex and aim to diversely convert vinyl azides into TEMPO-trapped ketones 2, amides 3, and α-alkoxyalkyl azides 4 (Scheme 2). Received: April 16, 2018 Published: June 6, 2018 8183
DOI: 10.1021/acs.joc.8b00954 J. Org. Chem. 2018, 83, 8183−8192
Article
The Journal of Organic Chemistry Scheme 2. EDA Complex-Enabled Transformation of Vinyl Azides
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RESULTS AND DISCUSSION
noted that around 40% yield of amide 3a was detected in the examples of DCE and DCM (entries 8 and 10). Subsequently, examination of the amount of external water showed that 2 equiv of water could give the highest chemical yield of 2a (entries 11−13). In order to neutralize the byproduct HClO4, inorganic base (NaHCO3 or Na2CO3) was added, but the chemical yields dropped (entries 14−15). The reaction proceeded smoothly in the dark as well though the yield shrank a little (entry 16 vs entry 12). With the optimized reaction conditions in hand (Table 1, entry 12), we aimed to survey the scope and limitations of this protocol. As depicted in Table 2, various α-aryl vinyl azides were treated with TEMPO+ClO4−, providing the corresponding TEMPO-trapped ketones in moderate to excellent isolated yields (2a−t, except 2n). Modulation of the aryl ring with a variety of substituents was well-tolerated, regardless of the
At the outset, we used 4-(1-azidovinyl)biphenyl as the model substrate to screen the reaction conditions (Table 1). To our delight, we observed the TEMPO-trapped ketone 2a in 89% NMR yield and only trace amount of 3a and 5a were found when using THF as the solvent (entry 1). Other organic solvents were also examined (entries 2−10), identifying THF as the best one in terms of chemical yield of 2a. It should be Table 1. Optimization of the Reaction Conditions for Synthesis of TEMPO-Trapped Ketonesa
Table 2. Scope for Synthesis of TEMPO-Trapped Ketones
yield (%)c entry
solventb
H2O (equiv)
T (h)
2a
3a
5a
1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e 16f
THF acetone 1,4-dioxane DMF DMSO EtOAc CH3CN DCE PhCl DCM THF THF THF THF THF THF
− − − − − − − − − − 1 2 4 2 2 2
6 0.5 6 4.5 6 6 0.5 4.5 6 1 6 6 6 6 6 12
89 85 77 74 0 63 59 33 25 16 88 97 76 51 51 71
