Oxidative Fluorocyclization of Vinyl Azides Leading to 5-Azido,5-fluoro-1,3-oxolan-2-one

Article abstract of DOI:10.1002/ejoc.201901699

Vinyl azides have become versatile building blocks in organic synthesis. Most of their transformations usually undergo a fast release of molecular N₂ to generate 2H-aziridine and vinyl nitrene intermediates. However, retaining the azides group

Full text of DOI:10.1002/ejoc.201901699

A Journal of
Accepted Article
Title: Oxidation Fluoroxidation of Vinyl Azides Leading to 5-Azido, 5-
Fluoro-1,3-oxolan-2-one
Authors: lin li, Shanshan Cao, Fanyi lin, Peiqiu Liao, and Yongquan
Ning
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901699
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901699
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European Journal of Organic Chemistry
10.1002/ejoc.201901699
COMMUNICATION
Oxidative Fluorocyclization of Vinyl Azides Leading to 5-Azido, 5-
Fluoro-1,3-oxolan-2-one
#
#
Lin Li, Shanshan Cao, Fanyi Lin, Peiqiu Liao* and Yongquan Ning.*
Abstract: Vinyl azides have become versatile building blocks in
moiety acts as an in situ formed leaving group. Building from our
long understanding efforts in the chemistry of α-vinyl azides, we
8
organic synthesis. Most of their transformations usually undergo a
fast release of molecular N
2
to generate 2H-aziridine and vinyl
here report an oxidative fluorocyclization of vinyl azides with in
situ generated difluoroiodobenzene from PIDA and Py•HF. It is
7
nitrene intermediates. However, retaining the azides group in the
final product is quite rare and great challenging. Here we design and
validate a new alkene difunctionalization strategy that involves an
oxidative fluorocyclization of vinyl azides for the synthesis of a
variety of 5-azido, 5-fluoro-1,3-oxolan-2-ones with broad substrate
scope and good functional group tolerance in good to excellent
yields. The in situ introduction of a removal leaving group in this
difunctionalization reaction is a key to retain azide moiety in the final
product.
the first example of intermolecular oxyfluorination of vinyl azides.
Moreover, azides group retained in the final products as a useful
handle. Furthermore, all of these 5-azido, 5-fluoro-1,3-oxolan-2-
one are novel compounds, which may have potential application
value in organic and medicinal chemistry research.
Introduction
Since the vinyl azides are easily prepared via the hydroazidation
1
of alkynes, which are employed as versatile building blocks in
organic synthesis as witnessed from the reported literature.2,3
Most of the transformations based on vinyl azides usually
2
undergo a fast release of molecular N to generate 2H-aziridine
and vinyl nitrene intermediates, providing diverse, structurally
distinct molecular skeletons. Mechanistically, vinyl azide usually
acts as an important C-C-N synthons for synthesis of various N-
containing molecules. Although retaining the azides group in the
final product is quite rare and a great challenge. To date only a
few reports available in the literature. For example, in 2017,
López et al. reported a Cu-catalysed [3+2] cycloaddition/allylic
azide rearrangement of vinyl carbene precursors with vinyl azide
to form azidocyclopentenes (Fig 1a).4 Very recently, Xu group
reported Cu-catalyzed asymmetric [4+2]-cycloaddition of vinyl
azides with unsaturated ketone esters to build various chiral
Fig 1. The reaction of vinyl azides with azide retention
We first investigated the reaction of vinyl azide 1a with in situ
generated PhIF •HF (pyridine•HF as fluorine source, PIDA as
2
oxidant) in DCM at 25 °C as a model reaction, affording the
desired fluoroxidation product 2a in 96% yield (Table 1, entry 1).
When changing oxidant to PhIO and PIFA, a very low yield was
obtained (entry 2, 3), and the reaction failed to provide the
desired product when PIDA was replaced with K
2
S
2
O
8
2 2
or H O
(
Et
entry 4, 5). Switching to other potential fluorine sources (e.g.
3
N•HF, AgF, CsF ), led to no reaction (entries 6-8). A brief
9
10
11
5
cyclic azides (Fig 1b). Considering the widespread importance
survey of other solvents revealed poor or no conversion in DMF,
DMSO and CHCl (entries 9-11); similarly, lowering the reaction
of azides group in organic synthesis, exploring new strategies of
for the synthesis of organic azides from vinyl azides would be
3
temperature to -40 or -20 °C led to reduced yields (entries 12-14)
6
highly desirable.
Table 1. Optimization of the Reaction Conditions.[a,b]
In this context, we targeted to develop a new strategy via
alkene difunctionalization that enables the in situ introduction of
a leaving group and intact the N group in the transformations.
3
The idea was inspired by recent works from the group of
Jacobsen and others.7 In their works, the interaction of the
PhIF
2
•HF (generated in situ from reaction of PIDA with Py•HF)
Entry
oxidant
PIDA
PhIO
‘F’ source
Py·HF
Py·HF
Py·HF
Py·HF
Py·HF
solvent
DCM
T (°C)
25
yield (%)
b
with the double bond of styrenyl triggered a sequential fluoride
addition and cyclization process, in which a hypervalent iodine
1
2
3
4
5
6
7
8
9
96
70
86
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DMSO
DMF
25
25
25
25
25
25
25
25
25
25
PIFA
[
a]
Northeast Normal University, Dr. Lin Li; Dr.Shanshan Cao, Dr. Fanyi
Lin, Dr. Peiqiu Liao, Dr. Yongquan Ning.
Department of Chemistry,
Jilin Province Key Laboratory of Organic Functional Molecular
Design & Synthesis
2 2 8
K S O
H
O
2 2
0
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
3
Et N·HF
0
AgF
CsF
0
Renmin Street, No. 5268, Changchun, 130024, China.
E-mail: Liaopq774@nenu.edu.cn
0
E-mail: ningyq508@nenu.edu.cn
Py·HF
Py·HF
Py·HF
0
#
#
LinLi and Shanshan Cao contributed equally.
1
0
1
0
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under https://xxxxx.
1
CHCl
3
57
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European Journal of Organic Chemistry
10.1002/ejoc.201901699
COMMUNICATION
12
PIDA
Py·HF
DCM
DCM
-20
0
60
84
intermediate D with releasing 2-methylpropene. Finally, the
13
PIDA
Py·HF
products
2 are formed by losing hydrogen cation from
intermediate D.
14
PIDA
Py·HF
DCM
40
78
The practicality of the method was evaluated by the gram-
scale synthesis of 2a under identical reaction conditions, and
produced in nearly similar yields in a 10 mmol scale reaction
[
a] Reaction conditions: 1 (0.5 mmol), PIDA (1.5 mmol), and Py·HF (5.0 mmol)
in 3 mL of DCM at 25 °C for 1 min. Yields are of isolated products.
(
Scheme 3). Next, the synthetic utility of the product was
investigated. For example, the azide group in 2a easily
converted to 1,2,3-triazoles through base-mediated 1,3-dipolar
cycloaddition with alkynes,13 affording the corresponding triazole
products 3 and 4 93% and 89% yields, respectively.
Scheme 3. Gram-scale synthesis and further reactions of 2a. Reaction
conditions: (a). 2a. (0.5 mmol) and DMAD (0.6 mmol) in 8.0 mL of water at
70 °C for 8 h. (b). 2a. (0.5 mmol), CsF (2 mmol) and 2-(trimethylsilyl)phenyl
triflate (1.2 mmol) in 2.0 mL of MeCN at 25 °C for 24 h.
Scheme 1. Synthesis of 5-azido, 5-fluoro-1,3-oxolan-2-one
Next, the optimal reaction conditions were adopted on a
variety of vinyl azides to investigate the generality of the protocol.
As described in scheme 1, we first examined a variety of cyclic
alcohols. 3-Phenylcyclobutanol and cyclopentyl alcohol were
successfully subjected to this transformation with 70% and 85%
yield (2b, 2d), respectively. Cyclohexyl alcohols tethered with
different functional groups also suitable to give the desired
fluorocyclization products (2, 4-11,) with good to excellent yields
Conclusions
In conclusion, we have developed a general and practical
strategy to synthesize 5-azido, 5-fluoro-1,3-oxolan-2-one via
oxidative fluorocyclization of vinyl azides. The practicality of this
method was highlighted by its mild reaction conditions, broad
substrate scope, good functional group tolerance, and moderate
to good yields. The azide group retained in the final product
provides many synthetic opportunities for the preparation of
valuable nitrogen-containing cyclic carbonate skeleton.
(
80-93%). Also, the use of tetrahydropyran derivative leading to
the desired product 2n in an 94% yield. Furthermore, 7-15
membered macrocyclic compounds were also efficiently
converted into the corresponding 5-azido, 5-fluoro cyclic
carbonate (2o-2r, 56%-85%). Remarkably, anthrone derivative
also participated in this transformation to give the consistent
cyclic carbonate in good yields (2s, 56% yield). Dialkyl alcohols
was also smoothly transferred into cyclic carbonates (2t) with 67%
yield.
Experimental Section
Typical synthetic procedure (with 2a as an example): To a stirred
solution of vinyl azides 1a (0.5 mmol, 1.0 equiv), PhI(OAc)
2
(0.6 mmol,
1.2 equiv) in DCM (3.0 mL) in a 15 mL of Schlenk tube under air was
added Py•HF (2.5 mmol, 5 equiv) in one portion. The reaction was
o
allowed to stir at 25 C until the complete consumption of vinyl azides as
monitored by TLC analysis (typically
1 min). Then the resulting
heterogeneous mixture was transferred carefully into a vigorously stirred
suspension of silica (15 g per 1 mmol of the substrate) in ethyl acetate at
-
78 °C. The resulting suspension was allowed to warm to room
temperature. Then the resulting suspension was filtered, extract with
DCM (3×15 mL), washed with brine (3 ×40 mL). Then combined organic
2 4
layer was dried over Na SO . After removal of the solvent under reducd
pressure, rhe residue was separated by flash column chromatography to
give 2a in 90% yield as a colorless oil.
Scheme 2. Proposed Mechanism
Based on the literature precedence, a plausible mechanism
is proposed in Scheme 2. At first, the 1,2-iodofluorination of the
vinyl azide with PhIF
2
•2HF (generated in situ from reaction of
2
Keywords: Vinyl azides • PhIF •HF • Azide retention • 5-azido,
PIDA with Py•HF),7,13 occurs to form intermediate B through the
activated intermediate A. Then the subsequent intermolecular
nucleophilic attack of the carbonyl oxygen to the C-I bond in
fluorinated intermediate B generates an intermediate C. After
nucleophilic attack of the oxygen atom to hydrogen atom and
electron transfers of hydrogen atom, intermediate C transfer to
5-fluoro-1,3-oxolan-2-one
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European Journal of Organic Chemistry
10.1002/ejoc.201901699
COMMUNICATION
COMMUNICATION
Here we design and validate a new
strategy via alkene difunctionalization
that enable the in situ introduction of a
Oxidation Fluoroxidation of Vinyl
Azides Leading to 5-Azido, 5-Fluoro-
1,3-oxolan-2-one
3
leaving group, keeping the N group
#
#
intact in the transformations, access
to a variety of 5-azido, 5-fluoro- 1,3-
oxolan-2-one derivatives with broad
substrate scope and good functional
group tolerance in good to excellent
yields.
Lin Li, Fanyi Lin, Peiqiu Liao* and
Yongquan Ning*
Page No. 1– Page No.3
*one or two words that highlight the emphasis of the paper or the field of the study
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