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Diverse Transformation of Vinyl Azides with 2,2,6,6-Tetramethyl-N-oxopiperidinium Jia-Li Liu, Shu-Wei Wu, Qing-Yan Wu, and Feng Liu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00954 • Publication Date (Web): 06 Jun 2018 Downloaded from http://pubs.acs.org on June 6, 2018
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The Journal of Organic Chemistry
Diverse Transformation of Vinyl Azides with 2,2,6,6-Tetramethyl-N-oxopiperidinium Jia-Li Liu,†,# Shu-Wei Wu,†,# Qing-Yan Wu,† and Feng Liu*,†,§ †
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 #
These authors contributed equally to this work
O
O O
R1 N3 R2
R1
R1
N
or
R2
N O
N H
O
N
R2
(R = H)
ROH
RO
N3
or R 1
O
N
R2 (R = Alkyl)
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 -alkoxyalkyl azides.
Preliminary
mechanistic
studies
indicate
that
an
alkene
radical
cation-mediated radical-radical cross-coupling C–O bond formation could be
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involved. INTRODUCTION The association of an electron-rich (a donor) with an electron-deficient (an acceptor) molecule, yields an electron donor-acceptor (EDA) complex, that 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, room-temperature, diverse transformation of vinyl azides using 2,2,6,6-tetramethyl-N-oxopiperidinium (TEMPO+) as the electron acceptor. Scheme 1. Electrophilic Transformation of Vinyl Azides
N3 R2
R1 1
N
E
N2
-N 2 R2
R1
R2 R1 N E
8
7E ROH RO N 3 R1 9
O E
R2
R1
E
N H
R2 10
Recently, vinyl azides,4 a class of functionalized alkenes with unique intrinsic reactivity, have emerged as important synthons for developing novel synthetic
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The Journal of Organic Chemistry
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
(1-chloromethyl-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 -fluoroketone 12 (Scheme 2).7a Scheme 2. EDA Complex-Enabled Transformation of Vinyl Azides N Previous work:
N F
Cl 2BF4
SelectFluor
O R1
N3 F
N N
SET, H 2 O
Cl
R2
R2 N3
12
N3
EDA complex R2
R1
V ia:
R2
R1 11
1
R1
O
R1
O N This study:
O
O
N3 R2
F
R1
EDA
R1
N
or
R2
SET, ROH
2
N O ClO 4
O
R1
O
N
N
R2
(R = H)
RO N 3
(TEMPO ClO4 )
N H
3
(R = Alkyl)
R2 4
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 analogs are widely used for the oxidation of alcohols.9 Recently, a charge-transfer (CT) complex
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TEMPO–ClO2 was identified by Yamamoto and coworkers.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 -alkoxyalkyl azides 4 (Scheme 2).
RESULTS AND DISCUSSION 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 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 equivalents 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).
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The Journal of Organic Chemistry
Table
1.
Optimization
of
the
Reaction
Conditions
for Synthesis
of
TEMPO-trapped Ketones a O O N3 TEMPO ClO 4 (1.5 equiv) Ph
solvent, rt
= TMP
Ph 2a + H N
1a
N
OTMP
OTMP O
Ph
N3 N3 Ph
3a
a
Entry
Solventb
H2O (equiv)
T (h)
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
5a
Yield (%)c 2a
3a
5a
89 85 77 74 0 63 59 33 25 16 88 97 76 51 51 71
