3-Alkylperoxy-3-cyano-oxindoles from 2-Cyano-2-diazo-N-phenyl-acetamides via Cyclizing Carbene Insertion and Subsequent Radical Oxidation

Article abstract of DOI:10.1021/acs.orglett.6b00367

A transition-metal-free one-pot sequence for the synthesis of 3-peroxy-substituted oxindoles from readily prepared 2-cyano-2-diazo-acetamides is reported. The two-step tandem process includes a highly efficient thermal intramolecular C-H-carbene insertion

Full text of DOI:10.1021/acs.orglett.6b00367

Letter
pubs.acs.org/OrgLett
3‑Alkylperoxy-3-cyano-oxindoles from 2‑Cyano-2-diazo‑N‑phenyl-
acetamides via Cyclizing Carbene Insertion and Subsequent Radical
Oxidation
Marvin Kischkewitz, Constantin-Gabriel Daniliuc, and Armido Studer*
Institute of Organic Chemistry, Westfalische Wilhelms-Universitat, Corrensstraße 40, 48149 Munster, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: A transition-metal-free one-pot sequence for
the synthesis of 3-peroxy-substituted oxindoles from readily
prepared 2-cyano-2-diazo-acetamides is reported. The two-step
tandem process includes a highly efficient thermal intra-
molecular C−H-carbene insertion followed by a tetrabutyl-
ammonium iodide (TBAI) catalyzed radical C3-peroxy-
functionalization. The protocol provides easy access to a new
class of 3-cyano-3-peroxy-disubstituted oxindoles. Useful
transformations to amides and alcohols are demonstrated.
Scheme 1. Approaches to C3-Disubstituted Oxindoles
he oxindole core is an important substructure that can be
T
found in various indoline alkaloids.1 In particular C3-
substituted oxindoles show unique biological activity, and they
can be identified as a recurring motif in many natural products2
and pharmaceutical compounds.3 Therefore, several methods
for the synthesis of C3-functionalized oxindoles have been
developed over the years.4 However, peroxy-substituted
oxindoles have not been well investigated to date. This is
surprising since the peroxo entity is also observed in natural
products5 and has gained interest in pharmaceutical research.6
Therefore, the development of efficient methods for the
synthesis of peroxy-substituted oxindoles is important in order
to fully exploit their biological potential.
3-Peroxy-oxindoles have been prepared by organo7- or Ni8-
catalyzed addition of alkyl hydroperoxides to isatin-derived
ketimines to give the corresponding 3-amino-3-peroxy-
oxindoles. Furthermore, hydroperoxide intermediates are
generated during pentanidium catalyzed α-hydroxylation of α-
substituted oxindoles.9 In all these processes the synthesis starts
with preformed oxindole core structures. Recently, Xiao and co-
workers reported the synthesis of 3-hydroxy-oxindoles from α-
diazoamides via a photoredox-catalyzed tandem process
(Scheme 1).10 This sequence comprises C−C bond formation
to give intermediate oxindoles which in turn become oxidized
to 3-hydroperoxy-oxindoles. Reductive O−O bond cleavage
eventually leads to 3-hydroxy-oxindoles (Scheme 1). However,
methods allowing for direct preparation of 3-peroxy-substituted
oxindoles from α-diazoamides are currently unknown. Also
considering the growing importance of step economy11 in
synthesis we report herein a transition-metal-free method for
direct preparation of 3-peroxy-oxindoles from readily accessible
α-cyano-α-diazo-amides.
and Ag15 as catalysts. We therefore decided to use 2-cyano-2-
diazoacetamides as starting materials and t-BuOOH (TBHP) in
combination with Bu4NI (TBAI)16 for peroxidation and
attempted to develop a sequence comprising a transition-
metal-free carbene insertion reaction17 with subsequent metal-
free oxidation.18
2-Cyano-2-diazo-N-methyl-N-(p-tolyl)acetamide (1a) was
chosen as a model substrate for optimization studies (Table
1). Amide 1a and all other 2-cyano-2-diazo-acetamides were
readily accessed in two steps by Steglich esterification19 and
subsequent Regitz diazotransfer.20 Reactions were conducted
with TBHP (5.0 equiv) in the presence of TBAI (5.0 mol %) at
60 °C for 48 h, and commonly used solvents were screened first
(Table 1, entries 1−3). Pleasingly, 56% of the targeted 2a was
obtained upon running the cascade in benzene (Table 1, entry
1). In dioxane a complex reaction mixture resulted and only a
trace amount of 2a was identified (Table 1, entry 2). The best
The oxindole framework is often constructed via intra-
molecular C−H-carbene insertion reactions of α-diazo
compouds12 by using transition metals such as Rh,13 Ru,14
Received: February 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00367
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Optimization with 1a as a Substrate
Scheme 2. Preparation of Various 2-Cyano-2-alkylperoxy-
Substituted Oxindoles 2a−p (Isolated Yields)
TBHP
(equiv)
TBAI
(mol %)
temp
(°C)
time
(h)
yield
(%)
entry
solvent
c
1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
10.0
2.5
5.0
5.0
5.0
5.0
5.0
10.0
1.0
−
benzene
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
60
60
60
90
80
80
80
80
80
80
48
48
48
24
12
12
12
12
12
12
56
2
trace
b
3
70
c
4
70
b
5
6
80
b
66
b
7
67
b
8
39
b
9
5.0
74
b
10
5.0
61
a
b
Reactions were conducted with 1a (0.25 mmol, 0.25 M). Isolated
c
1
yield. Yields determined by H NMR using CH2Br2 as an internal
standard.
result in this series was obtained in MeCN, and 2a was
obtained in 70% isolated yield (Table 1, entry 3). The reaction
time could be decreased to 24 h by increasing the temperature
to 90 °C without diminishing the yield (Table 1, entry 4). The
ideal reaction temperature was found to be 80 °C (12 h), and
oxindole 2a was isolated in 80% yield (Table 1, entry 5).
Varying the amount of TBAI did not lead to any further
improvement of the yield (Table 1, entries 6 and 7). Notably,
conducting the reaction in the absence of TBAI provided 2a in
39% yield (Table 1, entry 8).21 Increasing or lowering the
amount of oxidant led to lower yields (Table 1, entries 9 and
10).
To document the substrate scope, various 2-cyano-2-diazo-
acetamides 1a−o were reacted under optimized conditions
(Table 1, entry 5) to the corresponding peroxy-substituted
oxindoles 2a−o (Scheme 2). The effect of the para-substituent
in the 2-cyano-2-diazo-acetamide was investigated first (2a−g).
Electronic effects are small, and no real trend was noted. Both
electron-donating and -withdrawing substituents were tolerated,
and oxindoles 2a−g were isolated in moderate to good yields
(56−84%). We further examined the effect of the N-substituent
and tested the ethyl-, cyclohexyl-, allyl-, benzyl-, and phenyl-
substituted diazoacetamides 1h−m along these lines. Except for
the N-allylated system 1k, where oxindole 2k was isolated in
low yield (30%), all other congeners provided the correspond-
ing products 2h−j, 2l, and 2m in good yields. The structure of
the N-phenyl-substituted-oxindole 2m was confirmed by X-ray
analysis (Figure 1). The meta-substituted amide 1n afforded the
cylization/oxidation product as an isomeric mixture (2n/2n′ =
1.0:1.3) in 76% combined yield. However, the naphthyl
derivate 1o provided the five-membered-ring oxindole 2o
with complete regiocontrol in 66% yield. The six-membered
ring product was not observed. Finally, the method was shown
to work well with cumyl hydroperoxide in place of TBHP as
documented by the successful preparation of oxindole 2p
(71%). Notably, with 2-acetyl-2-diazo-N-methyl-N-phenyl-
acetamide as a substrate, reaction under the optimized
conditions delivered N-methylisatin in 52% yield.
To shed light on the mechanism of the novel cascade,
mechanistic experiments were conducted. Upon heating 1a in
MeCN to 80 °C in the absence of TBHP/TBAI, 2-cyano-
oxindole 3a was obtained in 98% yield (Scheme 3). If 3a gets
exposed to the applied reaction conditions product 2a was
formed in 51% yield. These two experiments indicate that our
cascade proceed via initial cyclization to form compounds of
type 3 as intermediates followed by TBHP/TBAI-mediated
oxidation. We assumed that cyclization occurs via carbene C−
B
DOI: 10.1021/acs.orglett.6b00367
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Proposed Mechanism
Figure 1. X-ray structure of oxindole 2m (thermal ellipsoids are shown
with 30% probability).
Scheme 3. Mechanistic Studies
natively, the tert-butoxyl radical might react with TBHP via H-
abstraction to give t-BuOH and the tert-butylperoxyl radical,
which itself can abstract the α-H atom in 3h to give B. Iodine
(I2), formed upon iodine radical dimerization, gets reductively
cleaved by the TBHP anion, thereby generating a longer lived
tert-butylperoxyl radical, an iodine radical, and iodide anion.
Hence, we assume that iodide acts as a catalyst in this oxidation
process, as suggested before.16b Steered by the persistent radical
effect,26 the longer lived tert-butylperoxyl radical eventually
undergoes selective cross-coupling with radical B to give the
isolated product 2h.
Finally, to document the potential of the method for the
preparation of α-substituted-α-hydroxy-oxindoles, we planned
to reduce the O−O bond in 2h. However, all of our attempts
failed. Upon reduction of 2h the intermediate α-cyano-α-
hydroxy-indole underwent, under the tested conditions, fast
HCN elimination to give N-methyl isatin. Depending on the
reduction conditions isatin was then further reduced to α-
hydroxy-N-methyl-oxindole lacking the α-cyano substituent.
Therefore, 2h was first converted to the primary amide 7 by
treatment with H2O2 under basic conditions (76%, Scheme 5).
Reduction of the peroxide with H2 in the presence of Pd on
charcoal as a catalyst gave 3-hydroxy-oxindole 8 in excellent
yield (98%).
H-insertion into the arene and that the carbene is generated
thermally from the corresponding α-diazoamide. However, we
were surprised that carbene generation in the absence of any
transition metal occurs that efficiently at 80 °C.22 To prove
generation of a free carbene under the reaction conditions, we
tested dibenzyl substituted diazo amide 4 as a substrate and
isolated cycloheptatriene 5 in 52% yield as the major product.
Cyclization/oxidation compound 6 was identified in trace
Scheme 5. Preparation of an α-Hydroxyoxindole
amounts. The formation of 5 is the result of a Buchner ring
̈
expansion reaction23 providing strong evidence for the
formation of a free carbene under the applied conditions. We
therefore disregard C−C bond formation to occur via a
homolytic aromatic substitution.24
Based on these studies the following mechanism is proposed
for the synthesis of peroxy-substituted oxindoles from α-
diazoacetamides (Scheme 4). In the first step, carbene A,
thermally generated from 1h, undergoes a concerted C−H-
carbene insertion to the neighboring arene to give 2-cyano-
oxindole 3h. For the second step we suggest a TBAI catalyzed
oxidation process.25 Electron transfer (ET) from iodide to
TBHP generates via a reductive O−O bond cleavage an iodine
radical, a tert-butoxyl radical, and the hydoxyl anion. The tert-
butoxyl radical then abstracts the α-carbonyl H atom of
intermediate 3h forming t-BuOH and C-radical B. Alter-
In summary, a novel class of α-peroxy-substituted oxindoles
has been synthesized via a transition-metal-free one-pot
sequence starting from readily accessible 2-cyano-2-diazo-
acetamides. Reactions proceeded via initial carbene C−H
insertion to construct the oxindole core, followed by a radical
α-peroxidation with alkyl hydroperoxides and TBAI as a
catalyst. The nitrile functionality in the α-peroxy-substituted
oxindoles can be hydrolyzed to give the corresponding peroxy-
C
DOI: 10.1021/acs.orglett.6b00367
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00367.
Experimental details, characterization data for the
products (PDF)
Supplementary crystallographic data (CCDC 1451727)
(CIF)
(15) Wang, H.-L.; Li, Z.; Wang, G.-W.; Yang, S.-D. Chem. Commun.
2011, 47, 11336−11338.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: studer@uni-muenster.de.
Notes
(17) Liu, Z.; Tan, H.; Wang, L.; Fu, T.; Xia, Y.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2015, 54, 3056−3060.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Westfalische Wilhelms-University for supporting
̈
our work.
(21) Traces of transition metals might mediate/catalyze the oxidation
step: Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
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DOI: 10.1021/acs.orglett.6b00367
Org. Lett. XXXX, XXX, XXX−XXX