Copper-catalyzed oxyazidation of unactivated alkenes: A facile synthesis of isoxazolines featuring an azido substituent

Article abstract of DOI:10.1021/ol403687k

A novel and efficient Cu(OAc)₂-catalyzed oxyazidation of unactivated alkenes was developed. The reactions are easy to conduct, occur under mild conditions, and form azido-substituted isoxazolines in good yields.

Full text of DOI:10.1021/ol403687k

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxyazidation of Unactivated Alkenes: A Facile
Synthesis of Isoxazolines Featuring an Azido Substituent
Liping Zhu, Hongmei Yu, Zhaoqing Xu,* Xianxing Jiang, Li Lin, and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University,
Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A novel and efficient Cu(OAc)2-catalyzed oxyazidation of
unactivated alkenes was developed. The reactions are easy to conduct, occur
under mild conditions, and form azido-substituted isoxazolines in good yields.
rganic azides are important intermediates and building
blocks that can be easily converted to N-containing
trapped by a suitable azido radical reagent. In this way, the
oxyazidation of alkene could be achieved in an alkene
difunctionalization. Isoxazolines are an important class of
heterocycles found in several biologically active agents and
versatile intermediates in organic synthesis. Importantly, by
using the above-mentioned oxyazidation protocol, isoxazolines
featuring an azido substituent can be easily synthesized through
oxime radical intramolecular alkene cyclization and an azido-
trapping pathway. As part of our research interests on copper-
catalyzed synthesis of heterocycles,19 we disclose here a novel
Cu(II)-catalyzed oxyazidation of unactivated alkenes for the
synthesis of azido-substituted isoxazolines. Notably, in our
system, the more reliable and commercially available TMSN3 is
employed as the azide reagent, which avoids the preparation of
the azido iodine(III) reagents as a separate process. Moreover,
neither hypervalent iodine(III) reagents nor other oxidants
were required in the reaction. We found that inorganic bases,
such as NaOAc and Na2CO3, are able to promote the
formation of oxime radical. By using this method, the oxime
radicals were very efficiently generated and subsequently added
to alkenes at room temperature, which provide a simple and
mild method for oxime radical generation and could be further
applied in the synthetic application of oxime radicals.
O
structural motifs, especially pharmaceutically important hetero-
cycles.1 The Cu-catalyzed cycloaddition of azide and alkyne
(Huisgen 1,3-dipolar cycloaddition2) has been intensively
studied in the past decade and broadly used in polymer
synthesis,3 peptide chemistry,4 material science,5 and drug
discovery.6 Many azido-substituted compounds show interest-
ing biological activities.7 More interestingly, organic azides are
used as photoaffinity labeling agents for biomolecules.8
A traditional method for the preparation of organic azides is
the Sandmeyer reaction, which suffers from the formation of
equal amounts of potentially hazardous byproducts.9 In the past
years, Cu-catalyzed cross coupling reactions of aromatic halides
or boronic acids with azide reagents (TfN3, NaN3, or TMSN3
(Me3SiN3)) have been well documented.10 Recently, a more
economical and efficient method for the synthesis of aryl azides
has been developed by a transition-metal-catalyzed C−H
azidation. In the reactions, the hypervalent iodine reagents or
peroxides were essentially required.11 Aliphatic azides are
usually obtained via substitutions of alkyl halides by inorganic
azides,12 transition-metal-catalyzed hydroazidation of alkenes,13
radical azidation,14 and electrophilic substitution with azido
iodine(III) reagents.15
At the beginning, we chose oxime 1a as substrate, 1.5 equiv
of TMSN3 as azide reagent, and 20 mol % of Cu(OTf)2 as
catalyst. The reaction was carried out in dry DMF under an
argon atmosphere at room temperature. After 24 h, only 10% of
the desired oxyazidation product 3a was obtained (Table 1,
entry 1). To our delight, the basic additives dramatically
increased the product’s yield. A stoichiometric amount of
NaOAc, K2CO3, or Cs2CO3 gave quantitative conversions in
which use of NaOAc led to the cleanest reaction with 83%
isolated yield (entries 2−4).20 We then tested the catalytic
activities of other copper salts, such as Cu(OAc)2, CuCl2·2H2O,
CuI, CuBr, and CuCl. The results indicated that all Cu salts
were effective for this transformation regardless of the different
Difunctionalization of unactivated alkenes attracts more and
more attention in organic synthesis. Compared with previously
reported reactions between alkenes and azide reagents,
difunctionalization of an alkene with an azido group and
another functional group has not been well explored.16 In 2010,
Chemler and co-workers reported a stoichiometric copper(II)-
promoted intramolecular azidoamination and oxyazidation of
alkenes.17a,b Very recently, Zhang and Studer disclosed a radical
oxyazidation of alkenes. In the reaction, a freshly prepared
TEMPONa solution was used as the radical precursor, which
needs to be injected to the system via a syringe pump. The
separately prepared azido iodine(III) reagent is also essentially
required to facilitate the transformation.17c
Arxime radical was isolated 50 years ago, whereas its
applications in organic synthesis are very few.18 We envisioned
that a proper catalyst could promote the formation of oxime
radical, which could add to an alkene and subsequently be
Received: December 20, 2013
Revised: March 1, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope Study
b
entry
catalyst
additive
solvent
yield (%)
1
2
3
4
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
THF
10
NaOAc
K2CO3
Cs2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
83
71
76
89
c
6
51
d
7
70
8
19
9
CHCl3
toluene
DMF
DMF
DMF
DMF
DMF
10
10
trace
79
e
11
f
12
70
13
trace
90
g
14
Cu(OAc)2
Cu(OAc)2
h
15
75
a
All reactions were carried out by using 1 (0.2 mmol), compound 2
a
(1.5 equiv), anhydrous basic additive (1.2 equiv), catalyst (20 mol %),
All reactions were carried out by using 0.2 mmol of 1, 1.5 equiv of 2,
b
c
and solvent (2 mL) under argon and stirred at room temperature for
and 2 mL of DMF. Yields refer to isolated yields. 80 °C, 2 h. relative
configuration was not assigned.
b
c
24 h, except as noted. Isolated yield. 0.2 equiv of NaOAc, 50 °C.
d
e
Dry solvents were used in all cases. 22 mol % of 2,2′-bipyridine was
used. 22 mol % of 1,10-phenanthroline was used. 1.5 equiv of 4, 0.5
h. 1.5 equiv of 5, 0.5 h.
f
g
h
(75%) and 3f (79%), respectively. The 2-, 3-, 4-, and 2,4-
dichlorophenyl substituted oximes were suitable and exhibited
good reactivities (3g−j). The substrates with other types of
electron-withdrawing substituents, such as −NO2 and −F, also
reacted well under standard conditions (3k and 3l). Copper
was reported as an effective catalyst for the cross coupling of
aryl bromide with an azide reagent under basic conditions.10b
Interestingly, we noticed that 3-bromophenyl oxime reacted
with TMSN3 efficiently and formed 3m (70%) with the highly
reactive bromo substituent untouched under such copper
catalytic conditions, which render the azidation products good
opportunities for further transformations, e.g., transition-metal-
catalyzed functionalization of the C−Br bond. The oxime
bearing a naphthyl group was a compatible substrate and gave
the product in good yield (3n). The azidation with
heteroarene-substituted oximes were achieved, furnishing the
corresponding biheteroarenes in moderate to good yields (3o
and 3p), respectively. We were pleased to find that under the
stated conditions the aliphatic oximes provided good
conversion to the desired products as well (3q and 3r). Then
the present method was successfully applied to construct an
azido-substituted isoxazoline containing a quaternary carbon
center (3s). In addition, the reaction gave 3t with a moderate
diastereselectivity (dr = 11:1).23 Interestingly, 3u was formed
under standard conditions instead of azido-substituted isoxazo-
lines.
valencies of the metal catalysts (see the Supporting
Information). The highest yield was obtained when 20 mol %
of Cu(OAc)2 was employed (entry 5). Although a catalytic
amount of NaOAc can promote the reaction by raising the
temperature to 50 °C, the yield was low (51%, entry 6). The
yield heavily relied on the choice of solvent: CH3CN, THF, or
CHCl3 provided moderate to low yield whereas toluene only
gave a trace amount of the oxyazidation product (entries 7−
10). The use of ligands, namely 2,2′-bipyridine and 1,10-
phenanthroline, deteriorated the reaction (entries 11 and 12).
It should be noted that the reaction did not occur in the
absence of Cu(OAc)2, which revealed that the copper catalyst
was crucial to this transformation (entry 13). Other transition-
metal catalysts were examined: FeCl3, Yb(OTf)3, and Al(OTf)3
led to lower yield; Ni(OAc)2·4H2O, Zn(OTf)2, Sc(OTf)3, or
In(OTf)3 were completely ineffective in this reaction (see the
Supporting Information). Finally, azido iodine(III) reagents 4
and 5 were also tested in this reaction.21 To our astonishment,
the reaction was complete within 30 min and gave the desired
product with 90% and 75% yield, respectively (entries 14 and
15).
Although the yield was quite good by using 4 (Table 1, entry
14),22 considering the availability of the azide reagents, we
finally chose entry 5 as the optimal conditions for the substrate
scope investigations (Scheme 1). The oximes with an electron-
donating substituent at the o-, m-, or p-position on the aryl ring
underwent the oxyazidation smoothly and provided the desired
products with good yields (3b−d). The monomethyl- or
dimethyl-substituted substrates efficiently proceeded to form 3e
Organic azides are versatile intermediates and building blocks
in organic synthesis. Considering the abundance of isoxazoline
in biologically active agents, the synthetic utility of the
oxyazidation product was further demonstrated for the
synthesis of isoxazoline analogues. Under the typical click
reaction conditions, 3a was treated with phenylacetylene in the
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Letter
presence of CuI to give the corresponding triazole 6 in 91%
yield (Scheme 2). Compound 3a could easily convert to 7
stoichiometric amount of TEMPO can serve as an initiator and
trapping reagent for the oxime radical cyclization. In the
reaction, a relatively long time (48 h) and high temperature (80
°C) were essentially required.24a According to Han’s report, we
carried out a reaction by using oxime 1a and TEMPO (1 equiv)
as the substrates. After 24 h at rt, no reaction occurred,
suggesting that the oxime radical is not able to form at low
temperature by this procedure. We then tested the activities of
the copper catalyst and basic additives for this transformation.
To our delight, a catalytic amount of NaOAc (20 mol %)
promoted the reaction very efficiently and gave the cyclization
product in 40% yield after 30 min. The moderate outcome
might be attributed to the formation of TEMPO-H, which was
detected by the ESI-HRMS study of the reaction mixture.25
The control experiments proved that both Na2CO3 and
Cu(OAc)2 are effective for this reaction and gave the desired
product in 39% and 18% yield, respectively. Although the
mechanism of the oxyazidation reaction is not completely clear
yet, the experimental results indicated that, in the reaction, the
basic additive served as a catalyst for the generation of oxime
radical,26 whereas Cu(OAc)2 catalyzed the formation of azido
radical11c (for a detailed discussion, see the Supporting
Information).
Scheme 2. Synthetic Utility of Current Method
through a Staudinger reduction and in situ protection sequence
with excellent yield. It is worth noting that under slightly
modified conditions with the azido iodine(III) reagent 4, the
alcohol 8 was readily cyclized to give the corresponding
oxyazidation product 9 in moderate yield.7b
To shed light on the reaction mechanism, several experi-
ments were conducted (Scheme 3). When 2,2,6,6-tetramethyl-
In conclusion, we have developed a novel process for the
intramolecular radical oxyazidation of alkenes. The reactions
are easy to conduct, occur under mild conditions, and form the
azido-substituted isoxazolines in good yields. In the trans-
formation, the cheap and commercially available TMSN3 is
employed as the azide reagent instead of the widely used azido
iodine(III) reagents (or the combination of organic azides and
hypervalent iodine reagents).11,17c The preliminary mechanistic
study demonstrates that the inorganic base, such as NaOAc and
Na2CO3, can efficiently catalyze the formation of oxime
radicals. The process is an important complement to the
previously reported methods for oxime radical generation,
which is effective for both alkene radical oxyazidation and
alkene radical dioxygenation. The synthetic utility of the
current method is demonstrated with a couple of synthetically
useful transformations. Further studies for a clearer under-
standing of the reaction mechanism and the asymmetric version
of the reaction are ongoing in our laboratory.
Scheme 3. Mechanistic Studies
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
piperidin-1-oxyl (TEMPO, 1.5 equiv) was added to the reaction
under standard conditions, the oxyazidation reaction was
completely shut down and gave the TEMPO-trapped product
10 in 84% yield (eq 1). The result suggested that a radical
pathway might be involved in the reaction. Using 2,6-di-tert-
butyl-4-methylphenol (BHT, 1.5 equiv) as additive, the yield of
desired product was lowered to 42% (eq 2). Interestingly, the
BHT−oxime adduct was detected by ESI-HRMS measurement
of the crude reaction mixture, which indicated that the oxime
radical was generated in the system and served as a radical
reagent for this transformation. A careful literature survey
revealed that the generation of oxime radicals usually requires a
radical initiator (e.g., TEMPO), oxidant (e.g., Ag2O, DEAD), or
photolyzing.24 However, in our reaction, none of these factors
were introduced to the system, except for a copper catalyst and
basic additive. To probe the possibility for the generation of
oxime radical by Cu(II) salt and/or NaOAc, we performed
several reactions (eq 3). Han and co-workers reported that a
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zqxu@lzu.edu.cn.
*E-mail: wangrui@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the grants from the NSFC (Nos. 21272107,
21102141, and 21202072), the National S&T Major Project of
China, and the Fundamental Research Funds for the Central
Universities (Nos. 860976 and 861188).
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