Synthesis of α-Fluoroketones from Vinyl Azides and Mechanism Interrogation

Article abstract of DOI:10.1021/acs.orglett.6b01691

An efficient and mild fluorination of vinyl azides for the synthesis of α-fluoroketones is described. The mechanistic studies indicated that a single-electron transfer (SET) and a subsequent fluorine atom transfer process could be involved in the reaction.

Full text of DOI:10.1021/acs.orglett.6b01691

Letter
pubs.acs.org/OrgLett
Synthesis of α‑Fluoroketones from Vinyl Azides and Mechanism
Interrogation
Shu-Wei Wu and Feng Liu*
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Department of Medicinal Chemistry,
College of Pharmaceutical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient and mild fluorination of vinyl azides for the synthesis
of α-fluoroketones is described. The mechanistic studies indicated that a single-
electron transfer (SET) and a subsequent fluorine atom transfer process could be
involved in the reaction.
Scheme 1. Reactions of Vinyl Azides
luorine atoms prevail in pharmaceuticals, agrochemicals,
Fand materials due to their unique biological, chemical, and
physical properties.1 Moreover, radiotracers labeled with 18F are
extensively used as positron emission tomography (PET)
agents.2 As a result, the development of new methods for
efficient, selective, and mild incorporation of a fluorine atom
into diverse molecules has received significant attention in
organic synthesis. In particular, the emergence of bench-stable,
safe, and easily accessible fluorinating reagents, such as 1-
(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate) (Selectfluor), N-fluorobenzenesulfonimide
(NFSI), 1-fluoropyridiniums, etc., has substantially advanced
the progress of C−F bond formation.1−3 α-Fluoroketones are
versatile building blocks for the synthesis of a wide variety of
fluorine-containing compounds.4 Generally, ketones,5 phenyl-
ethylenes,6 and phenylacetylenes7 were used as feedstocks for
the preparation of α-fluoroketones. However, despite significant
advances, these methodologies generally remain limited due to
complicated procedures, harsh reaction conditions, limited
substrate scope, and/or the requirement of expensive noble
metals.
association of an electron-rich substrate with an electron-
deficient reagent to form an aggregate was referred to as an
electron donor−acceptor (EDA) complex.13 Herein, we report
an efficient and mild method for the synthesis of various α-
fluoroketones from the corresponding vinyl azides using
Selectfluor as fluorine source as well as investigations on the
fluorinating mechanism (Scheme 1).
We began our investigation on the reaction of the substrate
1a with Selectfluor using acetonitrile as the solvent. To our
delight, we observed the desired α-fluoroketone 2a in 12% yield
(Table 1, entry 1). As might be expected, we identified that the
use of an inorganic base (e.g., NaHCO3) and water was
essential for the desired product formation in satisfactory yield.
The screening of organic solvents showed acetonitrile was the
best choice in terms of chemical yield and reaction time
(entries 2−7). We next examined the influence of water in this
fluorine incorporation protocol. The results showed that 2
Vinyl azides,8 a class of unique functionalized alkenes with
high intrinsic reactivity, have served as versatile synthons for
numerous transformations.9 As an enamine-type nucleophile,
vinyl azide was readily subjected to the electrophile to generate
an iminodiazonium ion A, followed by Schmidt-type rearrange-
ment to form nitrilium ion B, which could be intercepted by
water to yield the amide (Scheme 1).10 Very recently, alcohols
successfully interrupted the migration to produce α-alkoxy-β-
haloalkyl azides (Scheme 1).11 We were drawn to the possibility
that replacing alcohol with water could provide an approach to
synthesis of α-fluoroketones.
Although the traditional electrophilic addition process has
been extensively accepted as the mechanism for these
transformations of vinyl azides (Scheme 1),10,11 we could not
exclude the possibility that a charge transfer12 between an
electron donor (vinyl azide) and an electron acceptor
(Selectfluor) took place in the reaction. Accordingly, the
Received: June 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01691
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Control Experiments
b
entry
solvent
base
H2O (equiv) time (h) yield (%)
1
CH3CN
CH3CN
acetone
DMF
0.5
0.5
3
12
53
44
30
<5
<5
<5
82
77
41
53
81
75
37
28
2
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
3
4
3
5
THF
3
6
DCM
3
7
AcOEt
3
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
0.5
0.5
0.5
0.5
0.5
0.5
3
9
5
c
10
11
12
13
excess
2
2
2
2
2
KHCO3
Na2HPO4
NaHCO3
NaHCO3
d
14
e
15
3
a
1a (0.20 mmol), Selectfluor (0.30 mmol), base (0.40 mmol), H2O
b
c
(0.40 mmol), and solvent (2 mL). Isolated yield. Cosolvent
CH3CN/H2O (2:1). NFSI (0.30 mmol). 2,4,6-Trimethyl-N-
fluoropyridinium (0.30 mmol).
d
e
equiv of water gave the highest chemical yield and employing
an excess amount of water diminished the reaction yields
(entries 8−10). Furthermore, replacing NaHCO3 with other
base or Selectfluor with other fluorinating reagent did not
improve the chemical yield (entries 11−13 and 14, 15).
First, to gain more insight about the mechanism of this
reaction, a series of control experiments was conducted
(Scheme 2, eqs 1−4). In the presence of radical scavenger
TEMPO, no fluorine-containing products were obtained, but
the TEMPO adducts 3a and 3b were found in the reaction
mixture. To rule out the possibility that TEMPO could be
involved in the initiation step, the reaction of 1a without
Selectfluor was carried out. As might be expected, TEMPO
only acted as the radical scavenger (Scheme 2, eqs 1 and 2). On
the other hand, when the reaction of 1a was conducted under
standard conditions in the presence of radical scavenger 1,1-
diphenylethene, we did not find any adduct products except 2a
(Scheme 2, eq 3). To exclude the influence of natural light, we
also conducted the reaction of 1a under the standard reaction
conditions in the dark. The reaction proceeded smoothly to
afford the desired α-fluoroketone 2a in 85% yield (Scheme 2,
eq 4). To provide further evidence, (Z)-4-(1-azido-2-cyclo-
propylvinyl)-1,1′-biphenyl (1z) was prepared as a radical
probe.14 However, the reaction of 1z only gave α-fluoroketone
2z in 80% yield, without the formation of ring-opening product
(Scheme 2, eq 5).
Scheme 3. Further Experiments
Having established above optimal reaction conditions, we
aimed to define the scope of this new C−F bond forming
protocol. As shown in Figure 1, a series of differentially
substituted α-fluoroketones were readily obtained in moderate
to good yields. Although we found that o-bromide (2k) was
provided only in 41% yield accompanied by α-fluoroamide as
the competitive product15 probably due to steric hindrance, this
protocol could accommodate a wide range of substituents on
arenes regardless of their electronic properties (2a−m). For
example, both the electron-rich p-methoxyl group (2f) and the
electron-deficient p-nitro group (2h) gave the corresponding
products in good yields. It is of note that vinyl azides containing
alkynyl (2n) or alkenyl (2o) groups were compatible with the
reaction conditions, providing the desired products in useful
yields. This protocol could also be extended to nonterminal
vinyl azides (2p−r), including cyclic substrate (2p), quickly
generating the desired α-fluoroketones in high yields (less than
10 min). Not only aryl but alkyl substrates could be subject to
In order to confirm the fact that the oxygen of α-
fluoroketones was from H2O, an isotopic-labeling experiment
using H2O18 was performed (Scheme 3, eqs 1 and 2). As
expected, the results indicated that water could catch the
iminodiazonium ion D before migration (Schemes 1, 3, and 4).
In addition, because of the generation of H2O from the reaction
of the released HN3 with NaHCO3, we also detected 23% of
the 16O product under the standard reaction conditions
(Scheme 3, eq 1).
B
DOI: 10.1021/acs.orglett.6b01691
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Letter
the fluorination, furnishing the corresponding α-fluoroketones
in satisfactory yields (2s−y). Moreover, the chemical yields
were not compromised when a series of functionalized groups
were installed (2s−x vs 2y). In particular, in the examples of 2t
and 2u, the formyl group and the benzyl alcohol unit were not
affected in the process of fluorination.
Scheme 4. Proposed Mechanism
On the basis of the above results, we can deduce that direct
electrophilic fluorination of vinyl azide10 is disfavored in this
case. Thus, a plausible radical mechanism for this fluorine-
incorporated reaction is proposed in Scheme 4. The initial step
involves a single-electron transfer (SET) process,11,12 convert-
ing the vinyl azide 1 into the radical cation C. The subsequent
step is a fluorine atom transfer to generate the intermediate D,
followed by a reaction with H2O to give the intermediate E,
which undergoes an elimination of HN3 to furnish α-
fluoroketone 2.
In conclusion, we have developed a transition-metal-free and
efficient protocol for the synthesis of α-fluoroketones from
vinyl azides under mild reaction conditions. The mechanistic
studies indicated that a fluorine atom transfer process could be
involved. This protocol, in the presence of commercially
available Selectfluor, readily provided a variety of desired
products in moderate to good yields. Moreover, this trans-
formation showed excellent functional group tolerance and
demonstrated its potential for further applications in medicinal
and agrochemical research. Further applications of radical
cation of vinyl azides in organic synthesis are ongoing in our
group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01691.
1
Experimental details, characterization data, and H, 19F,
and 13C NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fliu2@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Grant No. 21302134), the Natural
Science Foundation of Jiangsu (Grant No. BK20130338), and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).
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D
DOI: 10.1021/acs.orglett.6b01691
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