Cis -Specific cyanofluorination of vinyl azides enabled by electron-donor-acceptor complexes: Synthesis of α-azido-β-fluoronitriles

Article abstract of DOI:10.1039/c7cc07165e

Here we report a novel electron-donor-acceptor (EDA) complex-enabled three-component cyanofluorination of vinyl azides under metal-free conditions in a cis-specific manner. This reaction protocol is operationally simple without exclusion of either moisture or oxygen, allowing access to a wide range of highly-functionalized α-azido-β-fluoronitriles bearing quaternary carbons that are difficult to obtain by existing methods.

Full text of DOI:10.1039/c7cc07165e

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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cis-Specific cyanofluorination of vinyl azides enabled by electron-
donor-acceptor complexes: synthesis of -azido-β-fluoronitriles
Shu-Wei Wu,a Jia-Li Liua and Feng Liu*a,b
α
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here we report a novel electron-donor-acceptor (EDA) complex-
enabled three-component cyanofluorination of vinyl azides under
is relatively underdeveloped owing to the challenges in the
achievement of satisfactory regioselectivity.9 In addition to the
benzylic10 and allylic fluorination,11 the fluorination via olefin
functionalization provides a practical approach for the precise
installation of a fluorine atom on alkanes.12 Recently, radical
fluorination of alkenes via iron or silver catalysis has received
significant attention (Scheme 1).13 However, the lack of stereo-
control was often encountered in the fluorination of alkenes.
metal-free conditions in
a cis-specific manner. This reaction
protocol is operationally simple without exclusion of either
moisture or oxygen, allowing to access a wide range of highly-
functionalized
α-azido-β-fluoronitriles that bearing quaternary
carbons are difficult to be obtained by existing methods.
The electron-donor-acceptor (EDA) complex-enabled organic
synthesis is a mild and sustainable approach, emerging as a valuable
platform for access to a range of products from relatively simple
feedstocks under transition-metal-free conditions.1 Although the
physicochemical properties of EDA complexes have been
extensively studied since the 1950s,2 their use in synthetic
Previous work:
free radical-mediated fluorination of alkenes (ref. 13)
X
X
R2
F
R1
R1
SelectFluor
R2
E2
O
O
O
O
X = H or
R
chemistry
achievements involving EDA complexes3 include, for instance,
radical asymmetric
perfluoroalkylation,3a-d alkylation,3e-g
remains
underexplored.1
Recently,
synthetic
E1
(EtO) P
or
or
2
Ar
,
N3
,
OH
,
Ar
N
This study:
radical cation-mediated cyanofluorination of alkenes
intramolecular cyclization,3h and biaryl coupling.3i-j For the
continued advancement of this field, the design and development
of novel and efficient strategies to prepare useful organic
molecules, such as fluorinated compounds, is highly desirable.
N3
N3
NC
SelectFluor
R2
R2
R1
R1
TMSCN
cis-specific
F
H
N3
Via:
R2
We have an intense interest in the transformation of alkenes into
fluorine-containing compounds4 due to the great utility of
organofluorine compounds as pharmaceuticals, agrochemicals, and
materials.5 In the past ten years, the development of efficient and
direct fluorination protocols has been of considerable significance.6
In spite of the great progress made in the transition-metal catalysed
construction of Csp2-F bond via C-H activation7 and cross-coupling
reactions,8 the techniques for direct access to aliphatic Csp3-F bond
R1
Scheme 1 Fluorination of alkenes for access to aliphatic Csp3-F bond.
Within the realm of open-shell chemistry, alkene radical cations
display a combination of free radical and cation chemistry that
confers a fascinating manner of reactivity and selectivity on them.14
Inspired by this concept, we questioned whether the fluorination of
olefins via alkene radical cation intermediates might be rerouted to
deliver fluorinated products in good regio- and stereo-selectivity.
Thus, we describe herein a metal-free and mild protocol for regio-
and stereo-selective cyanofluorination of vinyl azides with
Selectfluor as a fluorine source and TMSCN as a cyanating reagent,
a.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. E-mail: fliu2@suda.edu.cn
b.Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China.
affording
α-azido-β-fluoronitriles that bearing quaternary α-
carbons are difficult to access by existing methods (Scheme 1). To
the best of our knowledge, this reaction represents the first
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: Experimental details,
characterization data, and copies of 1H and 13C NMR spectra for all compounds. See
DOI: 10.1039/x0xx00000x
example
of
synthesis
of
α-azido-β-fluoronitriles
via
cyanofluorination of vinyl azides.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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acetonitrile solution of 1a (Figure 1a, see ESI†). Moreover, the
optical absorption spectrum showed a bathochromic shift to the
visible spectral region, above 450 nm, where neither the substrate
nor Selectfluor absorbs (Figure 1b, see ESI†). It is no doubt that an
EDA complex formed between vinyl azide 1a and Selectfluor in
acetonitrile.
Table 1 Optimization of reaction conditions a
N3
NC
SelectFluor (1.5 equiv)
N3
F
"
"
CN source (2 equiv)
solvent, rt
Ph
Ph
1a
2a
SelectFluor (1.5 equiv)
N3
TMSCN (2 equiv)
entry
1
solvent
DCM
“-CN“ source
TMSCN
t (h)
yield (%)b
< 5
< 5
37
NC
R1
N3
R2
R2
R1
24
24
0.5
0.5
1
CH3CN/DCM (1:2)
rt, 1.5-24 h
F
2
H
1
2
DMF
TMSCN
NC
R = H, 2b, 75% (1.5 h)
R = F, 2c, 78% (2 h)
R = Cl, 2d, 86% (2 h)
R = Br, 2e, 80% (2 h)
R = Me, 2f, 73% (1.5 h)
R = OMe, 2g, 55% (1.5 h)
R = NO2, 2h, 70% (8 h)
N3
F
3
MeCN
MeCN
TMSCN
4c
5
TMSCN
< 5
65
R = C(O)OMe, 2i, 63% (8 h)
R
MeCN/DCM (1:1)
MeCN/DCM (1:2)
MeCN/DCM (1:3)
MeCN/DCM (1:4)
MeCN/DCM (1:2)
MeCN/DCM (1:2)
MeCN/DCM (1:2)
MeCN/DCM (1:2)
TMSCN
TMSCN
TMSCN
TMSCN
TBSCN
NC
NC
N3
F
N3
F
NC
N3
F
6
1.5
3
78
N
7
77
O
Ph
2l
, 65% (3 h)
2j
2k
, 79% (1.5 h)
, 69% (8 h)
8
8
77
NC
NC
NC
N3
NC
N3
N3
F
N3
F
H
N
9
24
24
24
1.5
< 5
< 5
< 5
75
R
O
F
F
10
11
12d
nBu4NCN
CuCN
Br
2q
, 89% (1.5 h)
2p
, 26% (12 h)
2o
R = Br, 2m, 71% (2 h)
R = Me, 2n, 77% (1.5 h)
, 43% (12 h)
N3
N3
N3
NC
TMSCN
NC
NC
NC
N3
a1a (0.2 mmol), Selectfluor (0.3 mmol) and “–CN” source (0.4 mmol) in organic
solvent or co-solvent (2 mL). bIsolated yield. cCsF (0.4 mmol). dIn the dark.
F
H
F
H
F
H
Me
Ph
MeO
F
S
2t
, 89%
2u
, 52%
(4 h, d.r. = 13:1[a]
2s
, 72%
(3 h, d.r. > 20:1[a]
NC
)
)
2r
(1.5 h, d.r. > 20:1[a]
)
, 67% (3 h)
NC
N3
N3
N3
F
N3
NC
NC
O
F
Initially, examination and optimization of the reaction
parameters were carried out under natural light using vinyl azide 1a
as the model substrate, Selectfluor as the source of atomic fluorine
and TMSCN as the source of nucleophilic cyanation reagent (Table
1). A brief screening of organic solvents revealed that a co-solvent
system was critical to furnishing the desired product in good yields
(entries 5–8) since each solvent alone turned out to be inferior
(entries 1–3). We were delighted to identify the solvent mixture
CH3CN/DCM (1:2) as the best one in terms of chemical yield (entry
6). It should be noted that a prolonged reaction time was needed to
consume 1a when increasing the ratio of DCM (entries 5–8).
Employing CsF as the “TMS+” scavenger, to our surprise, the
reaction was inhibited (entry 4). An evaluation of other nucleophilic
cyanogen sources showed that TMSCN was the most effective one
compared to TBSCN, tetrabutylammonium cyanide, and copper(I)
cyanide (entry 6 vs. entries 9–11). The reaction also proceeded
smoothly in the dark (entry 12), which reveals that light is not
essential for this transformation. Additionally, the reaction was
surprisingly insensitive to air, so all the reactions were run under an
aerobic atmosphere.
H
F
F
H
Ph
2y, 24% (24 h)
2w, 52%
(3 h, d.r. > 20:1[a]
2x, 37% (8 h)
2v
, 32%
)
(24 h, d.r. > 20:1[a]
)
Scheme 2 Scope for cyanofluorination of vinyl azides. [a] The d.r. value was
determined by 19F NMR spectroscopy of the product.
With the optimized reaction conditions established (Table 1,
entry 6), we next investigated the scope of this protocol (Scheme
2). A number of vinyl azides bearing a variety of substituents were
examined, showing that a wide range of substrates and functional
groups are tolerated (2a–y). In most cases, a high conversion of
vinyl azide occurred within 8 h. Substrates bearing electron-
donating and electron-withdrawing groups at the para or meta
positions on the phenyl rings provided the corresponding α-azido-β-
fluoropropanenitriles in good yields (2b–o), although the highly
electron-rich substrates with a methoxyl group or an acetamido
group gave relatively low yields (2g and 2o). This cyanofluorination
appears to be sensitive to steric effects and prolonged reaction time
was required, producing the desired o-bromide only in 26% yield
(2p). Notably, the cyanofluorination of vinyl azides with alkenyl (2k)
and alkynyl (2l) groups on phenyl rings was readily proceeded
without compromising the chemical yields. Besides phenyl rings,
the naphthyl (2q) and thienyl (2r) moieties were also well
compatible with the reaction conditions. This protocol was
subsequently applied to non-terminal (Z)-vinyl azides (2s–w) and
tetrasubstituted alkene (2x), furnishing the desired products in
Typically, EDA complex exhibits a new absorption band, the
charge-transfer (CT) band, which is shifted to longer wavelength
compared to the UV-vis absorption spectra of its individual
components.2 In many cases, this band lies within the visible region,
thus showing
a distinctive coloration. In early stage of our
investigations, we did observe that a noticeable yellow colour
appeared immediately when adding white solid Selectfluor into an
2 | J. Name., 2012, 00, 1-3
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acceptable yields with excellent stereoselectivities, albeit with some contrast to recent synthetic achievements involving the
stereochemical erosion in the example of 2u. The stereochemical intermediacy of a photoactive EDA complex,1 the subsequent single
outcome of these reactions could be determined by the reactive electron transfer (SET) is activated thermally, leading to the
conformation of the carbocation intermediate D (Scheme 4). generation of an alkene radical cation (C) within B, followed by a
Despite the good reactivity of aryl vinyl azides, we found that alkyl fast fluorine atom transfer in cage to yield the carbocation
vinyl azide (2y) performed poorly. It was reasoned that the intermediate D. The final step is a nucleophilic cyanation, furnishing
conjugated π-system with aryl moiety might be crucial to the the desired cyanofluorination product in
a stereo-controlled
formation of EDA complex and following electron transfer
.
fashion. On the other hand, out-of-cage diffusion and following
atomic fluorine transfer, as an alternative pathway, cannot be
excluded at the present stage.
PMP
N
N3
NC
CuSO4•5H2O (5 mol %)
sodium L-ascorbate (10 mol %)
OMe
F
N
N
F
H
NC
+
(1)
Cl
tBuOH/H2O (2:1)
R1
N3
N
N3
R2
N
N
H
rt, 4h
N
Cl
R2
+
F
2w
R1
F
2BF4
1
3, 81%
SelectFluor
white solid
colorless
colored EDA complex
SET
A
N3
N3
NC
HOOC
F
H
F
aq. NaOH
(2)
H
100 °C, 12 h
2w
N3
4
, 90%
CN
F
in cage
F-atom transfer
N3
Cl
N3
N
N
H
H
N
R2
standard conditions
TEMPO (2 equiv)
R2
N
R1
2a
not detected
(3)
(4)
+
O
R1
R1
N3
F
F
H
B
Ph
O
Ph
D
1a
5, 12%
R2
F
HO
leaves the cage
F
SelectFluor (1.5 equiv)
H2O (2 equiv)
-
a
Ph
Ph
t
o
m
Ph
t
r
a
N3
Ph
n
s
NaHCO3 (2 equiv)
CH3CN, rt, 0.5 h
N3
f
e
r
N3
7, 70%
N3
6
NC
R1
R2
R1
R2
C
F-atom transfer
H2O
SET
SelectFluor
F
H
2
Scheme 4 Proposed mechanism.
Ph
Ph
Ph
Ph
N3
N3
Scheme 3 Further transformations and control experiments.
In summary, we have developed an operationally simple and
unprecedented protocol for the synthesis of -azido-β-
α
fluoronitriles from vinyl azides under mild reaction conditions.
The investigations indicated that an EDA complex-enabled
generation of alkene radical cation and subsequent fluorine
atom transfer could be involved in the reaction. Moreover, this
transformation showed excellent regio- and stereo-selectivity,
as well as tolerance of a broad range of functional groups.
Other applications of EDA complex as an efficient strategy for
the development of novel and useful synthetic methods are
underway in our lab.
Overall, access to highly-functionalized fluorine-containing
products by cyanofluorination of vinyl azides provides an
opportunity to rapidly generate useful synthons for further
transformations. To illustrate this point, we conducted copper-
catalysed click reaction and hydrolysis reaction, converting 2w into
the desired fluorinated 1,2,3-triazole (3) (Scheme 3, eq 1) and
carboxylic acid (4) (eq 2) in 81% and 90% yields respectively.
Meanwhile, the cis-cyanofluorination can be unambiguously
confirmed by the crystal structures of 3 and 8 (see ESI†).15
Furthermore, control experiments were performed to gain more
insights into the reaction pathway. In the presence of radical
scavenger TEMPO, no fluorine-incorporated products were found,
but the TEMPO adduct 5 was obtained (eq 3). As might be
expected, the reaction of cyclopropyl vinyl azide 6, a radical probe,
with Selectfluor and water gave the ring-opening product 7 in 70%
yield (eq 4).4b,16 It is of note that ring opening of the reporter group
in the radical cation intermediate could be ultrafast (k > 1 × 1011 s–
1).16 These results strongly support the involvement of a radical
process in the EDA complex-enabled cyanofluorination.
Acknowledgements
Grateful for the financial support from the National Natural
Science Foundation of China (Grant No. 21302134).
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