I(III)-catalyzed oxidative cyclization - Migration tandem reactions of unactivated anilines

Article abstract of DOI:10.1021/acs.orglett.0c03497

An I(III)-catalyzed oxidative cyclization-migration tandem reaction using Selectfluor as the oxidant was developed that converts unactivated anilines into 3H-indoles is reported herein. The reaction requires as little as 1 mol % of the iodocatalyst and is mild, tolerating pyridine and thiophene functional groups, and the dependence of the diastereoselectivity of the process on the identity of the iodoarene or iodoalkane precatalyst suggests that the catalyst is present for the stereochemical determining C-N bond forming step.

Full text of DOI:10.1021/acs.orglett.0c03497

pubs.acs.org/OrgLett
Letter
I(III)-Catalyzed Oxidative Cyclization−Migration Tandem Reactions
of Unactivated Anilines
Tianning Deng, Emily Shi, Elana Thomas, and Tom G. Driver*
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ABSTRACT: An I(III)-catalyzed oxidative cyclization−migration tandem
reaction using Selectfluor as the oxidant was developed that converts
unactivated anilines into 3H-indoles is reported herein. The reaction requires
as little as 1 mol % of the iodocatalyst and is mild, tolerating pyridine and
thiophene functional groups, and the dependence of the diastereoselectivity of
the process on the identity of the iodoarene or iodoalkane precatalyst suggests
that the catalyst is present for the stereochemical determining C−N bond
forming step.
Scheme 1. Development of I(III)-Catalyzed C−N Bond
he ubiquitous nature of C−N bonds in nonplanar N-
Theterocycles and materials continues to spur the
development of efficient processes that generate electrophilic
nitrogen catalytic intermediates to trigger C−N bond
formation.1,2 While this intermediate can be accessed by
oxidation, most methods require the presence of a strong
electron-withdrawing N-substituent for a successful reaction
outcome.3 In contrast, catalytic reactions that construct C−
NAr bonds employ an aryl azide or nitroarene as the N atom
source require heat or superstoichiometric quantities of
reductant to access the electrophilic N-aryl nitrogen inter-
mediate.4,5 Oxidative methods that generate the electrophilic
N-aryl intermediate are less common6 and require an N-
electron-withdrawing substituent on the aniline. We discovered
that electrophilic N-aryl nitrenoids could be generated from
I(III)-mediated oxidation of unactivated 2-substituted anilines
and trapped to afford benzazepinones or 3H-indoles.7 At the
conclusion of our study, we were curious if catalysis could be
achieved by pairing iodobenzene with a superstoichiometric
oxidant. Oxidative catalytic processes using an iodine catalyst
have emerged recently as a powerful way to create new bonds
through the dearomatization of electron-rich arenes.8,9 While
phenols and aromatic ethers are common substrates, the
development of I(III)-catalyzed oxidative methods of anilines
remains nascent and requires a strong electron-withdrawing
group on nitrogen for C−N bond formation.6 In 2011,
Antonchick and co-workers reported that biaryl acetimides
could be transformed into N-acetyl carbazoles using a
diiodobiaryl catalyst and acetic peroxide as the oxidant
(Scheme 1).6a Herein, we report that unactivated anilines
can be converted into 3H-indoles, important bioactive
scaffolds,10 through an I(III)-catalyzed oxidative cascade
reaction using Selectfluor as the terminal oxidant.
Forming Reactions
To investigate if catalysis of an oxidative cyclization-
migration reaction could be achieved, the reactivity of 2-
aminostyrene 11a toward a substoichiometric amount of
iodobenzene and a terminal oxidant was examined (Table 1).8h
This substrate is readily available from the cross-coupling of 2-
aminophenylboronic acid and the vinyl triflate of derived from
2-phenylcyclohexanone. While we had only moderate success
Received: October 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03497
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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Table 1. Optimization of the I(III)-Catalyzed Oxidative
Cyclization−Migration Reaction
Table 2. Effect of Changing the Electronic Nature of the
Aniline
a
entry
#
R1
R2
R3
yield (%)
b
1
2
3
4
5
6
7
8
a
H
H
H
H
H
H
H
OMe
Me
Cl
F
CF3
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Me
F
98 (94)
99
99
85
97
b
c
d
e
f
g
h
i
j
k
l
m
n
OMe
Me
Cl
a
entry
RI
mol %
solvent
yield, %
1
2
3
4
5
6
7
8
9
PhI
PhI
PhI
PhI
PhI
PhI
7
13
14
15
n-BuI
I2
20
20
20
20
5
HFIP
42
77
100
90
99
99
91
30
73
F
HFIP/H2O (100:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
HFIP/H2O (10:1)
OCF3
H
H
H
H
H
H
H
H
91
50
88
82
c
c
c
c
9
b
c
1
10
11
12
13
14
76
20
20
20
20
20
20
91
86
92
90
H
H
10
11
12
70
100
n.r.
a
b
Isolated after silica gel chromatography. Reaction performed at 1.0
c
mmol scale with 20 mol % of PhI. Reaction performed with 5 mol %
a
1
of PhI.
As determined using H NMR spectroscopy using CH2Br2 as the
b
internal standard. 98% isolated yield after silica gel chromatography.
c
Me3SiO2CCF3 used instead of TFA.
omethyl group resulted in a significantly greater yield of the
3H-indole with the latter requiring only 1 mol % of PhI
(entries 8−11). In contrast to our earlier reports using aryl
azides or nitrostyrenes,4b,5h the steric environment around the
N atom precursor can be increased with an additional ortho-
substituent: high yields of 3H-indole was observed from
anilines bearing an R3-methoxy, methyl, or fluoro group using
only 1 mol % of PhI (entries 12−14).
using the combination of 20 mol % of PhI with mCPBA as the
oxidant,11 using Selectfluor as the oxidant resulted in 42% of
3H-indole 12a (entry 1).12,13 We found that a quantitative
yield of 12a could be obtained if water was added as a
cosolvent (entries 2 and 3); increasing the amount of water
over 50%, however, led to lower yields.14 Our investigations
also determined that trifluoracetic acid additive could be
replaced with trimethylsilyltrifluoroacetate (entry 4).15 To our
delight, we found that the catalyst loading of PhI could be
decreased to as little as 1 mol % without adversely affecting the
yield (entries 5 and 6). The effect of changing the identity of
the catalyst was also surveyed (entries 7−12). Biaryl 7
demonstrated that increasing the steric environment of the
catalyst did not attenuate the yield of the oxidative cyclization
process (entry 7). In contrast, changing the electronic nature
of the ArI catalyst had a detrimental effect on the reaction
outcome (entries 8−10): only 30% of 12a was formed using 4-
nitroiodobenzene as the catalyst. The yield rebounded using
either 4-CO2Me or 4-MeO iodoarene but was lower than when
using iodobenzene. While alkyl iodine(III) species are
established to decompose to I2 or I−OH upon exposure to
an oxidant,16 we found 1-iodobutane afforded a quantitative
yield of 12a (entry 11), and no reaction was observed when I2
was examined as a catalyst (entry 12).
Using the combination of 1 mol % of PhI and Selectfluor as
the stoichiometric oxidant, we surveyed the effect of changing
the electronic and steric nature of aniline 11 (Table 2).
Irrespective of whether the para-R1-substituent was an
electron-releasing or electron-withdrawing group, nearly a
quantitative yield of 3H-indole 12 was observed (entries 1−6).
In contrast, the identity of the meta-R2- substituent impacted
the efficiency of the oxidative cyclization-migration reaction
requiring 5 mol % of PhI for conversion to 3H-indole. While a
moderate yield of 12g (R2 = OMe) was obtained (entry 7),
changing its identity to a methyl, halide, or even trifluor-
The reaction scope was further explored using N-
heteroaromatic substrates and by varying the identity of the
ortho-alkenyl substituent using 20 mol % of PhI because lower
catalyst loadings led to incomplete conversion unless otherwise
noted (Scheme 2). We found that 2-, 3-, or 4-aminopyridines
were smoothly transformed into 3H-indoles 17a−17c. While
thiophenes were incompatible in our stoichiometric reaction,7
they were tolerated using the catalytic conditions. Surprisingly,
neither ring contraction nor phenyl migration was observed
from these electron-rich heteroarenes; instead cyclization only
occurred to give 18d and 18e as the sole products.17 Next, the
effect of modifying the structure of the ortho-alkenyl
substituent was investigated. While no diastereoselectivity
was observed in 17f with a homoallylic tert-butyl substituent
using 1 mol % of PhI, substrates containing an ortho-
heterocycle group could be transformed into spirocycles 17g
and 17h although a higher catalyst loading was required; the
latter showed that this reaction can access a structural motif
prevalent in biologically active molecules and alkaloids.2c
Aniline 16i revealed that substrates bearing α-aryl substituents
were effectively converted to 17i using only 1 mol % of PhI.
Our survey showed that the identity of the β-substituent
controlled the reaction outcome. While ring contraction was
observed with the β-methyl substituent to afford 17j, when
either a β-sulfone or β-carboxylate group was present, only a
[1,2] shift of the electron-poor group was observed to afford
18k and 18l. To further probe this phenomenon, the electronic
nature of the β-aryl substituent of the ortho-cyclohexenyl
substituent was varied in 16m and 16n: while the electron-
B
https://dx.doi.org/10.1021/acs.orglett.0c03497
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Scheme 2. Effect of Heteroarenes and ortho-Substituent
Identity on the Reaction Outcome
Scheme 3. Investigation of the Relationship between
Diastereoselectivity and the Identity of the Iodine Catalyst
MeI, the yield of the transformation was significantly
reduced.19 To determine if the lowered yield was a result of
the acidic reaction conditions, trimethylsilyl trifluoroacetate
was examined as the additive, and the yield of 17t was
significantly improved without attenuation of the diastereose-
lectivity. Reducing the temperature of the reaction to 0 °C
further improved the stereoselectivity to 88:12 using MeI and
Me3SiO2CCF3. Together these results suggest that the catalyst
is present for the stereochemical defining C−N bond forming
step (TS-19), and the inverse correlation of the steric nature
with the selectivity implies that a shortened N−I bond is
critical for achieving a selective reaction.
We discovered an oxidative catalytic process for generating
electrophilic N-aryl nitrenoids from unactivated indoles to
produce nonplanar N-heterocycles using the combination of an
iodoarene or iodoalkane catalyst and Selectfluor as the oxidant.
The compatibility of pyridine and thiofuran functionalities in
this oxidative cyclization−migration reaction underscores the
mildness of these conditions. The dependence of the
diastereoselectivity with the identity of the catalyst indicates
that it is present for the stereochemical defining C−N bond
forming step. Our future studies will build on these results to
probe the details of both the C−N and C−C bond forming
steps as well as develop I(III)-catalyzed stereoselective
oxidative reactions.
deficient 16m required a higher catalyst loading, only ring
contraction was observed. Increasing the size of the ortho-
cycloalkenyl substituent in 16o or acyclic 16p, however,
triggered a [1,2] phenyl shift to afford only 18o or 18p.
The reversal in the migration aptitude that was observed for
anilines 11a and 16o spurred us to investigate this
phenomenon further with o-cycloheptenyl-substituted sub-
strates (Scheme 2).
Submission of 16q to reaction conditions produced a 31:69
mixture of ring-contraction and aryl migration products. While
reducing the electronic nature of the β-aryl group did not
change the reaction outcome, only [1,2] aryl migration
occurred with the electron-rich 16s.
In an attempt to gain more insight into the potential
stereoselectivity of the process, the reactivity of allylic-
substituted 16t was investigated (Scheme 3). Exposure of
16t to 20 mol % of PhI and 1.3 equiv of Selectfluor produced
17t as a 79:21 mixture of diastereomers. We were curious if
changing the identity of the catalyst impacted the diaster-
eoselectivity of the process. If the stereoselectivity of the
process was affected, that would suggest the catalyst was
present for the stereodetermining step.8e,18 Contrary to our
expectations, increasing the steric nature of the aryl iodide by
adding ortho-methyl or ortho-isopropyl groups reduced the
diastereoselectivity. This trend continued when the bulkier
diodobiarene 7 was assayed to afford a nearly 1:1 mixture of
diastereomers. The electronic nature of the iodoarene also
affected the reaction outcome: a moderate improvement in the
diastereoselectivity was observed using 4-MeO-iodoarene,
whereas employing the electron-deficient 4-CO2Me-iodoarene
resulted in a reduced stereoselectivity and yield of 3H-indole
17t. Iodoalkanes were also examined, and the diastereose-
lectivity inversely depended on the size and length of the alkyl
chain.11 While the best diastereoselectivity was obtained using
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03497.
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Experimental details and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tom G. Driver − Department of Chemistry, University of
Illinois at Chicago, Chicago, Illinois 60607-7061, United
States; orcid.org/0000-0001-7001-342X; Email: tgd@
uic.edu
Authors
Tianning Deng − Department of Chemistry, University of
Illinois at Chicago, Chicago, Illinois 60607-7061, United States
Emily Shi − Department of Chemistry, University of Illinois at
Chicago, Chicago, Illinois 60607-7061, United States
C
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Letter
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Elana Thomas − Department of Chemistry, University of Illinois
at Chicago, Chicago, Illinois 60607-7061, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03497
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation CHE-
1564959 and the National Institutes of Health (NIGMS)
GM138388 for their generous financial support. We thank Mr.
Furong Sun (UIUC) for high resolution mass spectrometry
data.
DEDICATION
Dedicated to the memory of Professor Kilian Mun
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iz.
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E
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