Copper-catalyzed oxoazidation and alkoxyazidation of indoles

Article abstract of DOI:10.1021/ol500793c

Copper-catalyzed oxoazidation and alkoxyazidation of indoles has been developed. The dearomatization reaction which leads to versatile 3-azido indolenine and oxindole derivatives in moderate to good yields could be used in a further transformation.

Full text of DOI:10.1021/ol500793c

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxoazidation and Alkoxyazidation of Indoles
Hang Yin,† Teng Wang,† and Ning Jiao*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Road 38, Beijing 100191, China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Copper-catalyzed oxoazidation and alkoxyazidation
of indoles has been developed. The dearomatization reaction
which leads to versatile 3-azido indolenine and oxindole derivatives
in moderate to good yields could be used in a further
transformation.
he dearomatization1 of indoles has been an attractive topic
we report an efficient azidation and dearomatization of indoles
Tin organic synthesis due to the importance of the using azidoiodinane and alcohol.
Our research started with the model reaction with substrates
derivatives of dearomatization products such as indolenines
and 2-oxindoles, which are common structural motifs in various
natural products and synthetic bioactivity molecules.2 In the
past decades, many efficient approaches have been developed to
modify and dearomatize indoles.3 Among the corresponding
products, 3-nitrogen-containing derivatives are very important
cores in many useful molecules, including SSR-14945, a
vasopressin VIb receptor antagonist, and a gastrin/CCK-B
receptor antagonist AG-041R (Figure 1).4
3-methylindole (1a) and azidoiodinane (2a) under an argon
atmosphere, using methanol as the solvent (Table 1). None of
the desired product was observed in the absence of any
transitional metal catalyst (entry 1). Various transition metal
salts such as iron, cobalt, palladium, and manganese were
investigated. However, nothing optimal appeared among the
results (entries 2−5). To our delight, a 43% yield of 3a was
observed when CuBr was employed as the catalyst (entry 6),
which indicates that copper salt might benefit the formation of
the desired product 3a. It is noteworthy that 3a was obtained
highly regioselectively as the sole product. Thus, a broad scope
of copper salts was investigated. The dearomatization of 1a in
the presence of CuCN or Cu(acac)2 (10 mol %) proceeded
well and afforded 3a in 46% and 50% yield (entries 7 and 11).
Since CuCN and Cu(acac)2 afforded similar yields of product, a
rate order experiment was investigated (see Figure S8,
Supporting Information), which indicated that both Cu(I)-
and Cu(II)-catalyzed alkoxyazidation are not a first-order
reaction. As the catalyst Cu(acac)2 was identified, we shortened
the reaction time to 1.5 h. Surprisingly, the reaction yield
increased to 77% (entry 12). Subsequently, different atmos-
pheres were tested. The results indicate that the presence of air
and O2 could decrease the yield of 3a (entries 14−15). A lower
temperature did not improve the yield. Only a 20% yield of 3a
was obtained when the reaction was carried out at room
temperature (entry 13). In addition, when 2.0 equiv of 2a were
employed, the yield of 3a showed not only no improvement
but also a slight decrease (entry 16). We also investigated
different kinds of N3 sources, including NaN3, TMSN3
(azidotrimethylsilane), TsN3 (p-toluenesulfonyl azide), and
DPPA (diphenylphosphoryl azide) with the same amount of
PIDA (iodobenzene diacetate). However, only a trace amount
of 3a was observed by GC-MS when NaN3 and PIDA were
used instead of 2a (entry 17). Other azides did not afford 3a in
Figure 1. Representative 3-nitrogen-containing oxindoles.
As an effective and easy converting unit, azide was widely
used in constructing a C−N bond.5 Our group has been
focused on concise and efficient nitrogenation reactions using
azides and other N-reagents as the nitrogen source.6 In the
reported methodologies, azides were rarely employed in the
dearomatization of indoles, especially the intermolecular
reactions with azides and other nucleophiles.7 In 1976, Ikeda
and co-workers reported an interesting azidation and
dearomatization of some indoles employing iodine azide
reagents.8 Nevertheless, iodine azides are very unstable and
should be prepared on site and used in situ. Thus, milder and
more efficient approaches are still attractive to accomplish this
reaction.
Azidoiodinane9 (2a), first reported by Zhdankin and co-
workers, was used for direct azidation of many organic
substrates, which confirmed its stability and efficiency.10 This
solid azide reagent remains active for a very long time. Herein
Received: January 3, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Table 1. Optimization of the Methoxyazidation of 3-Methyl
a
Indole 1a to Indolenines 3a
b
N3 source
(equiv)
temp
(°C)
time
(h)
yield of 3a
entry
cat.
(%)
1
−
FeCl2
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (1.5)
2a (2.0)
NaN3 (1.5)
TMSN3 (1.5)
TsN3 (1.5)
DPPA (1.5)
60
60
60
60
60
60
60
60
60
60
60
60
rt
10
10
10
10
10
10
10
10
10
10
10
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
N.R.
N.R.
N.R.
N.R.
N.R.
43
2
3
Co(OAc)2
PdCl2
4
5
Mn(OAc)2
CuBr
6
7
CuCN
46
8
CuI
10
9
CuOAc
29
10
11
12
13
CuF2
26
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
50
77
20
c
14
60
60
60
60
60
60
60
61
d
15
12
16
75
e
17
trace
N.R.
N.R.
N.R.
e
18
e
19
Figure 2. Cu-catalyzed dearomatization of 3-methylindoles 1 to
indolenines and 2-oxindoles 3. Reaction conditions unless specified
otherwise: 1 (0.3 mmol), 2a (0.45 mmol), Cu(acac)2 (0.03 mmol) in
corresponding R2OH (1.0 mL) at 60 °C under Ar, 1.5 h. Isolated
yields. Conditions for 3j: 1a (0.3 mmol), 2a (0.45 mmol), Cu(acac)2
(0.03 mmol), PEG 6000 (74.0 mg) in H2O (0.5 mL), and ethyl acetate
(0.5 mL) at 60 °C under Ar, 10 h. Isolated yield.
e
20
a
Reaction conditions: 1a (0.3 mmol), catalyst (10 mol %), and N3
source in dry MeOH (1.0 mL), stirred under Ar for corresponding
b
c
d
time. Isolated yields. The reaction was carried out under air. The
reaction was carried out under O2. 1.5 equiv of PIDA was added.
e
their cases (entries 18−20), which indicate the particularity of
the azidoiodinane 2a.
boxylic acid decomposed by 2a did not participate in the
reaction (see eqs S1−2 and Figure S5, Supporting Informa-
tion).
The structure of 3a shows that another nucleophile methanol
is involved in this transformation, which demonstrates the
potential with various other nucleophiles. Interestingly,
methanol highly regioselectively attacked the 2-position of
indole followed by the formation of C−N bond at the 3-
position. No other substitutions were observed in this reaction.
Under the optimal reaction conditions (Table 1, entry 12),
dearomatization of different substituted indoles with different
kinds of alcohols was investigated (Figure 2). 3-Methylindoles
with 5-Me and 5-OMe substituted offered good yields with the
methanol nucleophile (3b and 3c), respectively. Although 3-
arylindoles did not work under these conditions, 3-alkylindoles
such 3-ethyl-indole, 3-propyl-indole, and 3-butyl-indole worked
well producing the desired products 3d, 3e, and 3f in
moderated yields, respectively. Ethanol also worked well with
the substrate 1a affording 3g. When different alcohols were
used, moderate yields of corresponding products were
obtained. Isopropanol and n-propanol gave the same 56%
yield of 3h and 3i, respectively, which indicated that the steric
effects of the alcohols might not affect the reaction too much.
Phenethyl alcohol also afforded the corresponding product 3k
but in a lower yield. To our delight, water could participate this
reaction well and afforded 2-oxindole 3j in 81% yield. The
structure of 3j was further confirmed by single-crystal X-ray
analysis. Other nucleophiles such as CH3NO2, TsNH2 (p-
toluenesulfon amide) have also been investigated. However, no
desired corresponding products were obtained. The iodocar-
Intramolecular reactions of substituted tryptophols were also
investigated in DMSO (Figure 3). The desired tricyclic
dearomatization products were obtained in moderate to good
yields. The substituted tryptophols bearing either an electron-
withdrawing group (5-F) or an electron-donating group (5-Me)
were tolerant in this transformation. A longer chain of 3-
Figure 3. Substrate scope for Cu-catalyzed dearomatization of indoles.
Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), Cu(acac)2 (0.03
mmol) in DMSO (2.0 mL) at 60 °C under Ar, 1.5 h. All isolated yield.
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substituted tryptophols and a large steric group such as 2-Ph
also afforded the corresponding six-membered ring product and
2-phenyl substituted product in moderate yields, respectively
(3o, 3p).
Scheme 1. Proposed Mechanism of the Direct
Intramolecular Transformation
The obtained 3-azido oxindole 3j could be converted into
various derivatives. Reacting with phenyl acetylene (4) afforded
a 95% yield of the triazole product 5 (eq 1). In addition, the 3-
azido group could be easily converted into an amino group in
76% yield (eq 2), which indicates further transformations of
this product.11
In summary, we have developed a novel and efficient Cu-
catalyzed dearomatization of 3-substituted indoles. 3-Azido
indolenine and oxindole derivatives are easily constructed
which could be used for further transformation by this
oxoazidation and alkoxyazidation. An intramolecular reaction
also performs well in this transformation to afford azido
tricyclic molecules. Further mechanistic study and applications
of this reaction are ongoing in our group.
To investigate the mechanism, a series of reactions were
investigated. In order to trap the possible radical intermediates,
1.5 equiv of 2,6-di-tert-butyl-4-methylphenol (BHT) and
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) were respec-
tively added as the radical scavenger in the reaction of 1a (eqs 3
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full characterization of new products,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jiaoning@bjmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Science Foundation of China
(Nos. 21325206, 21172006), National Young Top-notch
Talent Support Program, and the Ph.D. Programs Foundation
of the Ministry of Education of China (No. 20120001110013)
is greatly appreciated. We thank Miancheng Zou in this group
for reproducing the results of 3g and 3l.
and 4). Neither of the reactions afforded the corresponding
product 3a. Although 3-methylindolin-2-one (7) afforded 3j in
a 76% yield under the optimal conditions (eq 5),10i 7 was not
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