Copper-Catalyzed Vicinal Oxyazidation and Diazidation of Styrenes under Mild Conditions: Access to Alkyl Azides

Article abstract of DOI:10.1021/acs.orglett.5b03130

A novel and efficient copper-catalyzed oxyazidation and diazidation of styrenes is described. The stable azidoiodine(III) reagent is used as an efficient azide radical source in this reaction. A variety of synthetically useful functional groups are compat

Full text of DOI:10.1021/acs.orglett.5b03130

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Vicinal Oxyazidation and Diazidation of Styrenes
under Mild Conditions: Access to Alkyl Azides
Ming-Zhu Lu,† Cheng-Qiang Wang,† and Teck-Peng Loh*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: A novel and efficient copper-catalyzed oxy-
azidation and diazidation of styrenes is described. The stable
azidoiodine(III) reagent is used as an efficient azide radical source
in this reaction. A variety of synthetically useful functional groups
are compatible with the mild reaction conditions. This protocol
enables the straightforward synthesis of various functionalized
azides in good-to-excellent yields.
rganic azides have been recognized as important
intermediates and building blocks in organic synthesis
Scheme 1. Representative Azido-Substituted Bioactive
Compounds and Copper-Catalyzed Oxyazidation and
Diazidation of Styrenes
O
due to their synthetic versatility, in particular, as powerful
precursors of nitrogen-containing reactive species and nitrogen-
rich heterocycles.1 For instance, organic azides can be easily
transformed into amines, isocyanates, and pharmaceutically
important heterocycles. Organic azides have shown wide
applications in materials science, polymer synthesis, and drug
discovery.2 Within the concept of “Click” chemistry, organic
azides have enjoyed a renaissance in recent years because of
their ever-increasing applications in copper-catalyzed azide−
alkyne cycloaddition (CuAAC) reactions.3 More importantly,
many azido-substituted compounds exhibit valuable biological
activities, such as antiviral activity and enzyme inhibition
(Scheme 1).4 Accordingly, the development of efficient and
practical methods for the incorporation of an azide group into
organic molecules, to construct functionalized azides in a highly
chemo- and regioselective manner, has inspired considerable
interest in past decades.5
maximal increase in molecular complexity. Elegant work
involving aminoazidation,9 carboazidation,10 azidocyanation,11
azidofluorination,12 and trifluoromethylazidation13 of alkenes
using different azide reagents (NaN3, TfN3, or TMSN3) has
been realized. Recently, the groups of Shi, Wang, and Xia
independently reported the oxyazidation reaction of alke-
nes.9c,14 In these reactions, the azide group was incorporated by
the addition of oxygen radicals to the CC bond followed by
trapping with a suitable azide reagent. In this context, the
strategy of direct generation of a stable azidyl radical followed
by an oxygen-trapping pathway is highly appealing yet more
challenging. To the best of our knowledge, such reactions have
With regard to the synthesis of aliphatic azides, conventional
methods are mainly based on nucleophilic substitution
reactions of electrophilic substrates with inorganic azides.1a,6
However, these methods often suffer from limited substrate
scope because of the need for harsh reaction conditions. The
direct azidation of aliphatic C−H bonds using azidoiodine(III)
reagent 1, reported by the groups of Zhdankin, Groves and
Hartwig, provides a straightforward approach to the synthesis
of alkyl azides.7 Another efficient method to alkyl azides is to
carry out hydroazidation of alkenes since they are readily
available chemical feedstocks.8 Despite the value of these
methods, it is highly attractive to take advantage of the more
effective synthetic strategy of metal-catalyzed difunctionaliza-
tion of alkenes that enables direct installation of two functional
groups in one step to afford substituted organic azides with a
Received: October 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03130
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Organic Letters
Letter
been scarcely investigated.15 Inspired by recent advances and
our continuing interest in difunctionalization of alkenes,16 we
report herein a novel copper-catalyzed oxyazidation and
diazidation of styrenes that takes advantage of the stable
azidoiodine(III) reagent 1 under mild conditions (Scheme 1).
It is worth mentioning that azidoiodine(III) reagent 1 plays a
dual role as an azidyl radical source and also as a coupling
partner for the oxyazidation of styrenes.
delivered the desired product in only a trace amount, and the
styrene substrate was recovered (Table 1, entry 18).
With the optimal conditions in hand (Table 1, entry 16), we
next investigated the substrate scope of this reaction, and the
results are summarized in Scheme 2. A variety of styrenes
Scheme 2. Scope of the Copper-Catalyzed Oxyazidation of
a b
,
Styrenes
To identify reaction conditions for the oxyazidation of
styrenes, we began our studies with 2-vinylnaphthalene (2a) as
a model substrate with azidoiodine(III) reagent 1, in the
presence of Cu(MeCN)4PF6 as catalyst, in DCE at 40 °C. We
were rather pleased to find that the oxyazidation product 3a
was obtained in 14% yield (Table 1, entry 1). However,
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
time (h)
yield (%)
1
Cu(MeCN)4PF6
CuCl
DCE
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
14
0
2
DCE
3
CuBr
DCE
0
4
CuI
DCE
0
5
Cu(OAc)2
Cu(OTFA)2
CuOTf·toluene
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DCE
0
6
DCE
11
27
53
10
43
59
trace
trace
67
64
71
52
trace
7
DCE
8
DCE
9
THF
10
11
dioxane
DCM
DMSO
DMF
DCM
DCM
DCM
DCM
DCM
c
12
13
14
d
15
e
a
16
Reaction conditions: 2 (0.2 mmol), 1 (0.3 mmol), Cu(OTf)2 (10
f
b
17
mol %), DCM (2 mL), stirred at 40 °C for 4 h under N2. Isolated
yields.
18
a
Reaction conditions: 2a (0.2 mmol), 1 (0.24 mmol, 1.2 equiv),
catalyst (0.02 mmol, 10 mol %), solvent (2 mL), 40 °C, under N2.
b
c
Isolated yields. The diazidation product was isolated in 30% yield.
bearing both electron-donating and electron-withdrawing
substituents on the aromatic ring reacted smoothly to provide
the desired products in moderate-to-excellent yields (3b−m). It
is worth noting that many synthetically relevant functional
groups such as fluoro, chloro, and bromo were compatible with
the conditions, revealing the possibility of further trans-
formations by the well-established cross-coupling reactions.
Styrenes with a di- and trisubstituted phenyl ring proved to be
favorable substrates, affording the desired products in good
yields (3n and 3o). Reaction of 1-vinylnaphthalene with
azidoiodine(III) reagent 1 afforded the product 3p in 46%
yield. The heterocyclic substrate 2-vinylthiophene exhibited
slightly lower reactivity, and the product 3q was isolated in 43%
yield. The cyclic substrates gave the products 3r and 3s in 75%
and 58% yields, respectively. However, 1,1-disubstituted
substrate 2t successfully delivered the corresponding product
3t, albeit with lower efficiency.
d
e
f
At 50 °C. 1.5 equiv of 1 was used. 5 mol % of Cu(OTf)2 was used.
catalysts such as CuCl, CuBr, CuI, or Cu(OAc)2 turned out to
be ineffective for this transformation (Table 1, entries 2−5).
Cu(OTf)2 was found to be the optimal catalyst, delivering the
desired product in 53% yield (Table 1, entry 8). Dichloro-
methane (DCM) was the best solvent (Table 1, entry 11). It
should be noted that only trace amounts of the oxyazidation
product were detected in DMSO, whereas a diazidation
product 4a was isolated as a side product in 30% yield
(Table 1, entry 12). The yield of 3a was further improved to
67% with a prolonged reaction time (Table 1, entry 14).
Furthermore, increasing the reaction temperature to 50 °C
afforded the desired product in a slightly lower yield (Table 1,
entry 15). The best yield of 3a was obtained when 1.5 equiv of
azidoiodine(III) reagent was employed (Table 1, entry 16). It
was also observed that a lower catalyst loading failed to improve
the efficiency of this transformation (Table 1, entry 17). Finally,
reaction of 2a with 1 in the absence of the copper catalyst
We next focused on the diazidation of styrenes to obtain
vicinal diazides which were particularly useful precursors for the
synthesis of 1,2-diamines.17 This important structural motif is
found in a wide range of bioactive natural products,
B
DOI: 10.1021/acs.orglett.5b03130
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Organic Letters
Letter
pharmaceutical molecules, as well as ligands or catalysts used in
asymmetric catalytic reactions.18 Therefore, practical and
convenient methods for the synthesis of vicinal diazides are
highly desirable.19 As noted above, the diazidation product 4a
was isolated in 30% yield when the reaction was performed in
DMSO. Encouraged by this promising result, we attempted to
investigate a novel method for direct 1,2-diazidation of styrenes
to afford vicinal diazides. Gratifyingly, treating 2a with 1 in the
presence of CuI as catalyst in DMSO gave the diazidation
product 4a in 82% yield (Scheme 3).20 Various substrates
biologically relevant complex moleclues. When estrone-derived
substrate 5 was subjected to the corresponding reaction
conditions, the desired products 6 and 7 were obtained in
64% and 69% yields, respectively (Scheme 4).
Scheme 4. Vicinal Oxyazidation and Diazidation of an
Estrone Derivative
Scheme 3. Scope of the Copper-Catalyzed Diazidation of
a,b
Styrenes
Considering the synthetic utility of these products, we further
investigated the diverse transformations of the oxyazidation
product 3a (Scheme 5). A click reaction of 3a with
Scheme 5. Transformations of Oxyazidation Product 3a
phenylacetylene readily afforded the corresponding triazole 8
in 93% yield. Reaction of 3a with benzyne generated in situ
proceeded smoothly to provide benzotriazole 9 in 81% yield.
Moreover, the amine 10 was obtained in 78% yield by the
Staudinger reduction of 3a. Importantly, the iodobenzoate
group can be easily removed by treatment of 3a with K2CO3 in
MeOH, providing the valuable 2-azido alcohol product 11 in
excellent yield. It is worth noting that 2-azido alcohol product
11 is a highly important intermediate in organic synthesis which
could be readily transformed into 1,2-amino alcohols, aziridines,
and other azaheterocycles.22
To investigate the mechanism of this reaction, a series of
trapping reactions were conducted. When we added 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) to the reaction
mixture, the oxyazidation product 3a was isolated only in 8%
yield. Addition of 2,6-di-tert-butyl-4-methylphenol (BHT)
resulted in complete inhibition of the oxyazidation reaction
(eq 1, Scheme 6). Moreover, the diazidation reaction was
strongly inhibited by addition of TEMPO or BHT (eq 2,
Scheme 6). Furthermore, when the radical clock 12 was
employed, the cyclization product 13 were obtained in 26%
yield (eq 3, Scheme 6). These observations suggest the general
features of radical mechanism of this process.
a
Reaction conditions: 2 (0.2 mmol), 1 (0.5 mmol, 2.5 equiv), CuI (10
b
mol %), DMSO (2 mL), stirred at 40 °C for 4 h under N2. Isolated
yields.
bearing a wide range of functional groups at the ortho position
were well compatible with the conditions to furnish the
diazidation products in good-to-excellent yields (4b−m).
Importantly, substituents such as CF3, NO2, and CN were
well tolerated in this reaction without any compromise.
Styrenes with substituents at the ortho or meta position of
phenyl ring did not affect the efficiency of this process, and
excellent yields were achieved (4n−t). Moreover, styrene with a
disubstituted phenyl ring was also suitable and afforded 4u in
70% yield. Reactions of 1-vinylnaphthalene and 2-vinyl-
thiophene with azidoiodine(III) reagent 1 gave products 4v
and 4w in moderate yields. Finally, the cyclic styrene afforded
4x in 45% yield with moderate diastereoselectivity (5:1).21
To illustrate the synthetic potential of this reaction, we
applied this protocol to the late-stage modification of
In summary, we have developed a novel copper-catalyzed
vicinal oxyazidation and diazidation of styrenes that takes
advantage of the azidoiodine(III) reagent 1 as a azide source
under mild conditions. This protocol tolerates a wide range of
functional groups and enables the convenient synthesis of alkyl
azides in good-to-excellent yields. The synthetic potential of
C
DOI: 10.1021/acs.orglett.5b03130
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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this protocol is also demonstrated by a variety of synthetically
useful transformations.
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.5b03130.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, HRMS) (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21372210) and the State
Key Program of National Natural Science Foundation of China
(21432009) for the funding of this research.
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