Counterion Control of t-BuO-Mediated Single Electron Transfer to Nitrostilbenes to Construct N-Hydroxyindoles or Oxindoles

Article abstract of DOI:10.1002/anie.202104319

tert-Butoxide unlocks new reactivity patterns embedded in nitroarenes. Exposure of nitrostilbenes to sodium tert-butoxide was found to produce N-hydroxyindoles at room temperature without an additive. Changing the counterion to potassium changed the reaction outcome to yield solely oxindoles through an unprecedented dioxygen-transfer reaction followed by a 1,2-phenyl migration. Mechanistic experiments established that these reactions proceed via radical intermediates and suggest that counterion coordination controls whether an oxindole or N-hydroxyindole product is formed.

Full text of DOI:10.1002/anie.202104319

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Counterion Control of t-BuO-Mediated Single Electron Transfer to
Nitrostilbenes Constructs N-Hydroxyindoles or Oxindoles
Authors: Yingwei Zhao, Haoran Zhu, Donald J. Wink, Siyoung Sung,
Joseph M. Zadrozny, and Tom G Driver
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104319
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
Counterion Control of t-BuO-Mediated Single Electron Transfer to
Nitrostilbenes Constructs N-Hydroxyindoles or Oxindoles
Yingwei Zhao,†[a,b] Haoran Zhu,†[a] Siyoung Sung,[c] Donald J. Wink,[a] Joseph M. Zadrozny*[c] and Tom
G. Driver*[a]
Y. Zhao,† H. Zhu,† S. Sung, D. J. Wink, J. M. Zadrozny and T. G. Driver
† These authors contributed equally.
[a]
[c]
Department of Chemistry
[b]
College of Chemical Engineering
Huaqiao University, Xiamen
668 Jimei Boulevard, Xiamen, Fujian, 361021 P.R. China
University of Illinois at Chicago
845 W Taylor St. MC 111, Chicago, IL 60607, USA
E-mail: tgd@uic.edu
Department of Chemistry
Colorado State University
Fort Collins, CO 80523
Supporting information for this article is given via a link at the end of the document.
Abstract: tert-Butoxide unlocks new reactivity patterns embedded in
nitroarenes. Exposure of nitrostilbenes to sodium tert-butoxide was
found to produce N-hydroxyindoles at room temperature without an
additive. Changing the counterion to potassium changed the reaction
outcome to yield solely oxindoles through an unprecedented
workers established that electron-transfer to the iodoarene
occurred from the in situ-generated phenanthroline dianion 1.[9d]
Inspired by these reports, we were curious if exposure of a
nitrostilbene to an alkoxide would generate a nitrosoarene
intermediate that might be intercepted intramolecularly to afford
an N-heterocycle (Scheme 1). In contrast to our expectations, we
found that nitrostilbene 2 could be converted to N-hydroxyindole
5 using simply NaOt-Bu at room temperature without an additive.
Strikingly, changing the counterion to potassium triggered an
unprecedented dioxygen transfer and [1,2] aryl migration tandem
reaction to afford oxindole 6 as the only N-heterocycle from
nitrostilbene 2.
dioxygen-transfer reaction followed by
a 1,2-phenyl migration.
Mechanistic experiments established that these reactions proceed via
radical intermediates and suggest that counterion coordination
controls whether an oxindole or N-hydroxyindole product is formed.
Introduction
Zenin 1845 and Klinger 1882
The ubiquitous nature of N-heterocycles in pharmaceuticals and
organic materials has inspired the discovery of new reactivity
patterns to facilitate their construction.[1],[2] The development of
reductive methods to access these privileged scaffolds by
constructing C–N bonds using nitroarenes has received
significant attention because of the ready availability and robust
nature of nitroarenes. While traditional C–N bond formation
methods were developed using a superstoichiometric quantity of
a reductant to deoxygenate the nitro-group,[3] recent efforts have
focused on the development of catalytic processes that use the
combination of a transition metal-[4] a base-metal-[5] or a
phosphine[6] catalyst and a stoichiometric reductant. In contrast to
these approaches, 175 years ago,[7] sodium methoxide was
reported to reduce nitrobenzene to azoxybenzene in boiling
methanol (Scheme 1). Subsequent mechanistic investigations in
1962 by Ogata and Mibae suggested that electron-transfer from
alkoxide triggered deoxygenation to produce an ArNO
intermediate which reacted with an N-hydroxybenzene to produce
the azoxy product.[8] After these mechanistic studies, interest in
exploiting electron-transfer from alkoxides waned, until a recent
resurgence in the use of potassium tert-butoxide as a single-
electron reductant.[9] In 2010, the Hayashi and Shi groups
reported that tert-butoxide mediated the transition metal-free
couplings of iodoarenes.[9a, 9b] Investigations by Murphy and co-
Ph
Ph
+
H
O
Ph
O
O
NaOMe
N
O
N
N
N
+
H
+
+ H2O
2 PhNO2
+ NaOH
MeOH
70 °C
OH
H
H
ONa
Ph
Murphy 2014
Me
Me
I
KOt-Bu (4 equiv)
phen (0.2 equiv)
N
Ph
N
N
2 K+
PhH, 130 °C
Me
Me
1
N
N
Possible to intramolecularly trap the nitrosoarene intermediate?
Ar
Ar
Ar
OR
Ar
O
additive
?
N
O
NO2
N
O
OH
2
3
4
5
This work
HO
Ar
Ar
MOt-Bu (2 equiv)
Ar
O
THF, 25 °C
N
N
NO2
OH
H
2
5
or
6
only product using
NaOt-Bu
KOt-Bu
Scheme 1. tert-Butoxide-mediated N-heterocycle formation from nitroarenes.
1
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
Results and Discussion
cyclization was explored by developing conditions to alkylate the
N-hydroxyl group as well examining the effect of changing the
electronic- and steric environment of the nitrostilbenes (Table 2).
The substrates for this study were either commercially available
or readily prepared in one-step from 2-bromonitroarenes and
styrene using a Heck reaction.[14] Because N-alkoxy- or N-
acetoxyheterocycles are more stable,[15] we explored telescoping
the reaction by adding an electrophile to determine if the sensitive
N-hydroxy functionality could be alkylated or acetylated. We
found that a methyl-, benzyl-, or benzoate group could be easily
added to the initially formed N-hydroxyindole to improve the
reproducibility of the reaction sequence and ease purification. Our
investigation of a series of nitrostilbenes that varied their
electronic- and steric nature revealed that higher yields were
obtained in the presence of electron-donating groups positioned
Investigation of the scope and limitations of N-heterocycle
formation. To test our hypothesis that nitrosoarene intermediates
could be accessed using an alkoxide and trapped to afford an N-
heterocycle, the reactivity of nitrostilbene 2a was examined
(Table 1). While no reaction was observed upon exposure of 2a
to sodium methoxide in boiling methanol, changing the solvent to
tetrahydrofuran resulted in the formation of N-hydroxyindole 5a at
room temperature (entries 1 and 2). The yield of 5a was improved
by changing the identity of the alkoxide with the best outcome
obtained when tert-butoxide was used (entries 2 – 4). Increasing
the temperature or the reaction time, however, did not further
increase the yield (entries 5 and 6). The reaction was not light-
dependent:[10] performing the reaction in a foil-covered vessel
provided N-hydroxyindole 5a in 55% yield (entry 7). A solvent
screen revealed that N-hydroxyindole formation occurred
smoothly in ethereal solvents, but was attenuated in tert-butanol
(entries 7 – 10).[11] To our surprise, the identity of the counterion
was critical to the reaction outcome: while no reaction was
observed when lithium- or magnesium tert-butoxide was
employed, 3-phenyl-3-hydroxy-2-oxindole 6a was obtained as the
only product using potassium tert-butoxide irrespective of
exposure to light (entries 11 – 13). The formation of 6a, whose
structure confirmed by X-ray crystallography,[12] involves not only
oxygen transfer to the ortho-alkenyl substituent but also a [1,2]-
phenyl shift. While oxygen transfer from nitroarenes to pendant
acetylenes has been reported to afford N-heterocycles,[13] this
oxidation-migration tandem reaction of ortho-alkenyl substituents
is unprecedented.
Table 2. Scope of NaOt-Bu-mediated N-hydroxindole formation.
R2
NaOt-Bu
(2 equiv)
R3–X
R1
R1
R2
R1
R2
OR3
N
N
NO2
THF, 25 °C
40 h
OH
2
5a
entry
1
#
nitroarene 2
N-heterocycle 5
R3
yield, %a
H
60
67 (63)b
60
Ph
Ph
N
OR3
Me
Bn
Bz
a
NO2
59
Ph
Ph
N
H
Me
58
62
2
3
4
5
6
b
c
e
g
h
MeO
MeO
F
NO2
Ph
OR3
Ph
OR3
H
Me
53
42
N
F
The scope and limitations of the NaOt-Bu-mediated reductive
NO2
Ph
H
Me
24 (38)c
22 (44)c
Ph
OR3
Ph
OR3
N
CF3O
CF3O
NO2
Ph
Table 1. Development of reductive and divergent N-heterocycle formation.
HO
O
O
Ph
O
O
Ph
RO
M
Me
Me
63
44
N
Ph
O
NO2
conditions
N
N
NO2
MeO
OH
H
6a
2a
5a
or
MeO
Ph
Ph
OR3
N
MOR
NO2
entry
(2 equiv)
solvent
h
T (°C)
yield, %a
5a:6a
F
F
1
2
NaOMe
NaOMe
NaOEt
MeOH
THF
16
16
16
16
16
40
40
40
40
40
16
16
16
70
25
25
25
60
25
25
25
25
25
25
25
25
n.r.
14
26
55
57
60
55
53
55
38
0
…
Ph
H
Me
25 (60)c
17 (63)c
7
i
Ph
OR3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
…
N
NO2
3
THF
4-MeOC6H4
4-MeOC6H4
H
Me
46
60
4
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
LiOt-Bu
THF
8
9
l
N
OR3
NO2
5
THF
p-Tol
6
THF
p-Tol
H
Me
68
75
m
n
N
OR3
7b
8
THF
NO2
dioxane
2-MeTHF
t-BuOH
THF
4-FC6H4
4-FC6H4
H
Me
67
59
10
11
N
9
NO2
OR3
10
11
12
4-ClC6H4
25 (53)c
28 (55)c
4-ClC6H4
H
Me
o
N
NO2
OR3
Mg(Ot-Bu)2
KOt-Bu
THF
0
…
Ph
13c,d
THF
62
<1:20
Ph
N
OR3
12
q
Me
52
NO2
a
b
Isolated after silica gel chromatography. Reaction performed in a foil-
c
covered vessel. The outcome of the reaction did not change if light was
excluded. The X-Ray structure of 6a was deposited in the Cambridge
a
b
d
Isolated after silica gel chromatography. Reaction performed on 2 mmol
scale. c The tert-BuO-mediated reduction was performed at 100 °C for 16 h.
Crystallographic Database (CCDC 198003). THF = tetrahydrofuran.
2
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
para to the styryl group (entries 2 and 5). In contrast, the presence
of electron-withdrawing groups severely attenuated the reaction
yield. Gratifyingly, the yield of N-hydroxyindole could be rescued
if the reaction was heated to 100 °C (entries 4 and 7). Changing
the electronic nature of the β-aryl group had less of an overt effect
on the reaction outcome: while higher yields were observed for
electron-rich aryl groups, the presence of a fluorine did not
diminish the yield as substitution on the nitroarene moiety (entries
8 – 11). While adding a stronger electron-withdrawing Cl did
reduce the yield, increasing the temperature of the reaction
increased the yield of 5o. The reactivity of naphthalene-derived
2q illustrated that N-hydroxyindole formation was relatively
insensitive to steric constraints (entry 12).
After our initial investigation into the scope of using NaOt-Bu as
the reductant, we turned our attention to exploring the reactivity of
nitrostilbenes towards KOt-Bu (Table 3). Analysis of the reactivity
patterns revealed several differences in comparison to N-
hydroxyindole formation. First, the success of the oxygen-
transfer-migration reaction was less dependent on the electronic
nature of the nitrostilbene with chloro-, bromo- and even
trifluoromethyl groups tolerated (entries 2 – 10). Further, the
opposite electronic trend was observed for β-aryl groups: more
electron-deficient groups led to higher oxindole yields (entries 11
– 15). Naphthalene 2q demonstrated that oxindole formation
tolerated an increased steric environment around the nitro-group
to afford 6q albeit in diminished yield relative to 6a (entry 16). In
contrast to N-hydroxyindole formation, the yield was not improved
when the reaction temperature was increased.
To assess the impact of the ortho-styryl substituent on the
reaction outcome, substrates 2s, Z-2a and 2r were investigated
(Scheme 2). The position of the phenyl substituent was found to
control which N-heterocycle was formed: exposure of α-
phenylnitrostyrene 2s to tert-butoxide afforded only N-
methoxyindole 5sa using either KOt-Bu or NaOt-Bu after
telescoping the reaction with MeI, although an increased reaction
temperature was required using NaOt-Bu. The stereochemistry of
the 2-nitrostilbene was also critical to the reaction outcome. While
E-nitrostilbene formed either N-hydroxyindole 5a or oxindole 6a
depending on identity of the tert-butoxide counterion, the reaction
of Z-2a afforded only oxindole 6a irrespective of whether sodium-
or potassium tert-butoxide was used. Similar reactivity was
observed when nitrostilbene 2r was exposed to NaOt-Bu, which
produced only oxindole 6r where one of the oxygen atoms was
transferred to the ortho-alkenyl substituent.[16] These results
suggest that steric interactions between the β-phenyl substituent
and a reactive intermediate or stabilization of a radical- or charged
intermediate by the α-phenyl substituent can override the
counterion effect.
Ph
H
Ph
HO
Table 3. Scope of KOt-Bu-mediated oxindole formation.
Ph
MOt-Bu
(2 equiv)
MOt-Bu
(2 equiv)
Ph
HO
Ar
O
R2
R1
R2
R1
H
Ar
KOt-Bu (2 equiv)
then MeI
N
N
O
NO2
NO2
H
OMe
THF, 25 °C, 16 h
N
5sa
6a
NO2
55%, NaOt-Bu
71%, KOt-Bu
62%, NaOt-Bu
71%, KOt-Bu
H
2s
Z-2a
2
6
O
entry
#
a
R1
H
R2
H
Ar
yield, %a
62 (55)b
Ph
Ph
NaOt-Bu
(2 equiv)
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NO2
Ph
OH
6r, 53%
N
b
c
d
e
f
MeO
F
H
H
H
H
H
43
43
48
57
38
41
49
74
49
41
38
56
50
66
2r
3
Scheme 2. Effect of phenyl substituent position on the reaction outcome.
4
Cl
5
F3CO
F3C
Mechanistic EPR investigations. To investigate if the tert-
butoxide-mediated N-heterocycle formation involved the
formation of radical intermediates, the reaction was analyzed
using X-band, solution-phase EPR spectroscopy (Figures 1 and
2). At room temperature, reaction mixtures from addition of KOtBu
and NaOtBu exhibit EPR spectra near g = 2.00. The additional
most-common feature of the spectra is the existence of a three-
line pattern, typical for a radical interacting with a 14N (I = 1)
nucleus. We attribute these peaks to radical intermediates of an
electron transfer from tert-butoxide (Eox = +0.10 V vs SCE)[17] to
nitrostilbene (Ered = –1.13 V vs SCE).[4g, 18] The high potential gap
of ΔE = 1.03 V between the oxidation peak potential of t-BuO– and
the reduction peak potential of nitrostilbene suggests that
coordination of the counterion occurs to facilitate the transfer.[19]
This hypothesis is supported by the simulation of the X-band EPR
spectrum from the NaOt-Bu-mediated reaction, which afforded
the best match with experiment when a nitro radical anion was
assumed coordinated to the sodium counterion (Figure 1a).[20]
The foregoing outcome suggests that counterion identity is
critical to directing the radical formation pathway. For example,
the EPR spectrum obtained from the NaOt-Bu-mediated reaction
displays only three well-resolved peaks and no further couplings
to 1H in Figure 1a. The absence of additional peaks from the latter
6
7
g
h
j
O–CH2–O
8
H
H
H
H
H
H
H
H
MeO
F
9
10
11
12
13
14
15
k
l
Br
H
4-MeOC6H4
p-Tol
m
n
o
p
H
H
4-FC6H4
4-ClC6H4
4-CF3C6H4
H
H
HO
Ph
Ph
O
16
q
41
NO2
N
H
a
b
Isolated after silica gel chromatography. Reaction performed on 2 mmol
scale.
3
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
NaOt-Bu
(2 equiv)
KOt-Bu
(2 equiv)
Ph
Ph
Analysis of the reaction using EPR spectroscopy reveals a
substantial change in spectral shape when the crown ether is
present, potentially suggesting changes in spin identity via crown-
ether binding to the counterion.[26] Together, these experiments
suggest that coordination of the counterion controls whether N-
hydroxyindole 5 or oxindole 6 is produced.
Ph
2a
O
O
N
O
N
O
THF, 25 °C
1h
THF, 25 °C
1h
N
O
O
Na
7
8
9
93:7
a. NaOt-Bu
b. KOt-Bu
experimental
simulated
experimental
simulated
HO
NaOt-Bu
(2 equiv)
NaOt-Bu
(2 equiv)
Ph
Ph
R
Ph
R
R
O
N
15-crown-5
(2 equiv)
N
NO2
OH
H
6a, 44%; 6c, 30%;
6g, 38%; 6l, 25%
2a, 2c, 2g, 2l
5a, 60%; 5c, 53%
325
330
335
Magnetic Field (mT)
340
345
325
330
335
340
345
5g, 63% (NOMe); 5l, 46%
Magnetic Field (mT)
Na coordination to nitro-group
Ph
Ph
Ph
Figure 1. Experimental (black) and simulated (red) X-band EPR spectra of tert-
butoxide-mediated reduction of nitrostilbene 2a (THF, 298 K, 1 h) (a, result of
NaOt-Bu reaction, b, result of KOt-Bu reaction) Data collection parameters:
Frequency = 9.4306 GHz, Power = 0.2 mW, Modulation = 0.1 G; a. Fitting
parameters for 7 are giso = 2.005, Aiso = 29 MHz, and an line width for isotropic
broadening, lw =[0.81 0.53] in mT (the first Gaussian and the latter Lorentzian
broadening); b. Fitting parameters for 8 are giso = 2.009, A = [22.1 18.2] MHz,
lw = 1.09 mT, τcorr = 5 ns, and weight = 0.85; and fitting parameters for 9 are giso
= [2.007], A = [21.2 14.7 11.9 8.7], and lw = 0.2 mT, relative contributions to
spectral intensity are 93% 8 and 7% 9.
Ph
e–
O
O
Na+
N
N
O
O
N
NO2
8
O
7
Na
10
O
2a
oxindole 6
N-hydroxyindole 5
Scheme 3. Effect of 15-crown-5 on the reaction outcome.
Reactivity of 18O-labeled reagents. To determine if the C2- and
C3 oxygens in oxindole originated from an intra- or
6
intermolecular reaction, the reactivity of 18O-labeled potassium
tert-butoxide and 18O-labeled nitrostilbene 2g was investigated
(Scheme 4). When K18Ot-Bu was used, no 18O-incorporation into
6a was observed to suggest that both oxygens were transferred
from the nitro-group. To test if oxygen transfer occurred
intermolecularly, a mixture of 2a and 2g-18O were submitted to
reaction conditions and double crossover of the labeled- and
unlabeled oxygens to the oxindole product was observed to afford
16% of 6a and 6a-18O and 64% of 6g-18O2 and 6g-18O. Analysis
of the mass spectrum showed an increase of the [M + 2]+ signal
for 6a and [M – 2]+ signal for 6g-18O to suggest that only one of
the oxygen atoms is transferred, and the parent ion [(M) – OH]+
revealed that intermolecular O-transfer occurred only to the C2-
position of the oxindole.
couplings strongly suggests that the spin density is localized only
in the nitro group, not delocalized onto the aromatic ring. We
propose that the small size as well as strong Lewis acidity of Na+
allows for effective binding to the nitro group and prevention of
spin density delocalizing on the aryl ring. In contrast, a spectrum
displaying significantly more complicated hyperfine interactions
was observed when KOt-Bu was employed (Figure 1b).[21],[22]
Simulation of the spectra with a variety of possible radicals
revealed a best match when assuming a mixture of 93% of 8 and
7% of 9. We interpret these data to suggest that the nitro radical
is less effective in coordinating the larger potassium counterion.
As a result of the weaker coordination, the formation of two spin
isomers is allowed, one featuring an NO2 radical and one with spin
density delocalized onto the aryl ring. We note that this
preliminary interpretation requires that the radical is not
delocalized across both moieties. This outcome could occur if
interactions with K+ drive the nitro-groups away from planarity with
the stilbene.[23] Extension of this interpretation could explain the
less complex EPR spectrum for the Na+ system: stronger binding
of the nitro radical anion to Na+ produces only one, NO2-localized
isomer. We tentatively interpret the difference in coordination in
these simulated spectra to account for the difference in reaction
outcome: the lack of coordination to the counterion could enable
oxygen-atom transfer from 8 to the ortho-styryl substituent to
afford oxindole 6a, which would not be possible when it is bound
to the sodium ion.[24]
HO
Ph
Ph
K18Ot-Bu (2 equiv)
no incorporation of 18
into oxindole 6a
O
O
THF, 25 °C, 16 h
N
NO2
H
2a
6a
18O-Crossover experiment
HO
H18
O
KOt-Bu
(2 equiv)
Ph
18O
Ph
Ph
O
O
O
+
+
O
2a
+
THF, 25 °C
16 h
N18O2
O
O
N
N
2g-18
(50% N18O, 28% N18O2)
6a-18
O
6g-18
6g-18
O
H
H
6a
O
Scheme 4. Investigation of an intra- or intermolecular mechanism for oxygen
These EPR experiments spurred us to examine the effect of a
crown ether on the reaction outcome (Scheme 3). When 15-
crown-5 was added in combination with NaOt-Bu, we found that
N-hydroxyindole 5a was no longer formed, and oxindole 6a was
produced as the only N-heterocyclic product. This phenomenon
proved to be general: exposure of 2-nitrostilbenes 2c, 2g, or 2l
produced only oxindoles 6c, 6g, or 6l albeit in lower yield than
using KOt-Bu.[25] In contrast, the addition of 18-crown-6 to the
KOt-Bu-mediated reaction resulted in no change to the
outcome—oxindole 6a was the only N-heterocycle formed.
transfer.
Potential mechanisms for N-heterocycle formation. Our data
suggests
dependence of the reaction outcome on the identity of the
counterion (Scheme 5). Electron transfer from tert-butoxide to
nitrostilbene produces radical anion 8 and tert-butoxy radical,[27]
which fragments to produce acetone and methyl radical.
a
possible mechanism that accounts for the
4
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
Mesomer 10 traps sodium ion to produce 7, which accepts a
second electron to form 11. Fragmentation of 11 produces
nitrosostilbene 12, which undergoes a 6π-electron-five atom
electrocyclization to form 13 that isomerizes to produce N-
hydroxyindole 5a.[28]
examined as a substrate. In line with our mechanistic hypothesis,
treatment of 15 with KOt-Bu resulted in the formation of oxindole
6a. Conversion of 2-nitrostilbene oxide to oxindole supports that
the intermolecular reaction occurs between a nitroarene radical
anion and a neutral nitroarene.
Single-electron reduction
Conclusion
Ph
Ph
Ph
Na+
Ph
t-BuO
O
O
O
N
O
O
N
O
N
O
N
O
In conclusion, we have discovered a novel tert-butoxide-mediated
reaction of 2-nitrostilbenes that produces either
t-BuO
7
Na
8
10
2a
a
N-
O
fragmentation
+ Me
hydroxyindole or an oxindole depending on the identity of the
counterion. The reactivity patterns exhibited by the 2-
nitrostilbenes suggest that the N-heterocyclic products are formed
by either an intra- or intermolecular reaction, where the degree of
coordination of the counterion to the radical anion dictate which
mechanism occurs. Our findings illustrate that nitrosoarene
reactive intermediates can not only be generated at room
temperature from nitroarenes but that unprecedented reactivity
patterns can be triggered divergently to produce functionalized N-
heterocycles. In addition to leveraging this novel reactivity to
construct different sized N-heterocycles, future studies are also
aimed at obtaining a deeper understanding of the spin dynamics
and spin Hamiltonian parameters of the observed radical
intermediates to conclusively assign their identity.
Me
Me
N-Hydroxyindole formation
Ph
Ph
Ph
Ph
H
e–
5a
N
O
O
N
O
O
N
O
13
N
NaO–
Na
7
11
Na
12
O
Scheme 5. Potential mechanism for N-hydroxyindole formation.
Our data suggests that oxindole 6 is formed through an
intermolecular mechanism when the counterion is not coordinated
to the nitrostilbene radical anion (Scheme 6).[29] The
intermolecular oxygen-atom transfer could occur by attack of
radical anion 8 onto the nitrostilbene 2 at the β-position to afford
nitrite 14,[30] which undergoes a 3-exo-tet radical cyclization to
produce epoxide 15.[31],[32],[33] Ring-opening by the proximal nitro
group could produce 16.[34],[35],[36] tert-Butoxide-mediated single
electron reduction followed by fragmentation produces 18.
Hydrogen-atom abstraction by tert-butoxy radical or methyl
radical produces ketone 19.[37],[38] Isomerization forms enol 20,[39]
Acknowledgments
TGD, YZ, and HZ are grateful to the National Science Foundation
CHE-1564959 and the National Institutes of Health (NIGMS)
R01GM138388 for their generous financial support. We thank
Professor Leslie Fung and Dr. Daniel McElheny for assistance
with the EPR spectrometer and Mr. Furong Sun (UIUC) for high
resolution mass spectrometry data.
Ph
Oxindole formation
Ph
Ph
ArNO
O
Ph
Ph
O
+
O
N
O
18O
18
NO2
N
O
Keywords: tert-butoxide • single electron transfer • nitroarene
3-exo-tet
N
8
2-18
O
O18
14
15
N18O2
5-exo-tet
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Ph
H
18O
O
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Ph
H
Ph
H
e–
18O
N
18 O
18O
N
O
O
N
N
H-atom
18O
19 18O
abstraction 18
17
16
18O
18O
18 O
18O
Ph
[2]
[3]
Ph
Ph
O
6a
O
OH
N
18 OH
N
N
18O
18 OH
20
21
22
Reactivity of 2-nitrostilbene oxide
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O
Ph
Ph
KOt-Bu (2 equiv)
O
THF, 25 °C, 16 h
N
NO2
15%
H
15
6a
Scheme 6. Potential intermolecular mechanism for oxindole formation.
which attacks the nitroso group to produce N-heterocycle 21. A
subsequent 1,2 phenyl shift affords N-hydroxyoxindole 22,[40]
which is reduced to oxindole 6a. To test if oxygen-transfer
occurred via an epoxide intermediate, 2-nitrostilbene oxide was
5
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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in the reaction.
[25]
[26]
Oxindole formation was accompanied by azoxy by-product.
The effect of the addition of 15-crown-5 to NaOt-Bu-mediated reduction
of 4-nitrostilbene was also investigated using EPR spectroscopy.
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or radicals responsible for the signals. However, we did notice significant
changes in the EPR spectral shape, which is likely attributable to
interaction with the crown ether. For more details, refer to the Supporting
Information.
[27]
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6
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10.1002/anie.202104319
Angewandte Chemie International Edition
RESEARCH ARTICLE
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For
related
intramolecular
ring-opening
of
ortho-
nitrophenylcyclopropane to form 1-oxo-1,2-benzoxazolium- or 1-oxo-
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[40]
Alternatively, ketone 19 could be formed from 17 through an H-atom-
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alkoxy radical 18.
While formation of a ketyl radical could start a chain process, this
appears unlikely because an excess of the tert-butoxide reductant is
required for a positive reaction outcome.
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
Ph
Ar
N
N
O
O
MOt-Bu
(2 equiv)
Ar
OH
Na
or
or
THF, 25 °C
HO
NO2
Ph
Ar
O
O
N
N
O
K
H
tert-Butoxide unlocks divergent reactivity embedded in nitrostilbenes to construct N-hydroxyindoles or oxindoles depending on
whether sodium or potassium is the counterion.
Institute and/or researcher Twitter usernames: ((optional))
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