Dearomatization of Electron-Deficient Phenols to ortho-Quinones: Bidentate Nitrogen-Ligated Iodine(V) Reagents

Article abstract of DOI:10.1002/anie.201909868

Despite their broad utility, the synthesis of ortho-quinones remains a significant challenge, in particular, access to electron-deficient derivatives remains an unsolved problem. Reported here is the first general method for the synthesis of electron-deficient ortho-quinones by direct oxidation of phenols. The reaction is enabled by a novel bidentate nitrogen-ligated iodine(V) reagent, a previously unexplored class of compounds which we have termed Bi(N)-HVIs. The reaction is extremely general and proceeds with excellent regioselectivity for the ortho over para isomer. Functionalization of the ortho-quinone products was examined, resulting in a facile one-pot synthesis of catechols, as well as the incorporation of a variety of heteroatom nucleophiles. This method represents the first synthetic application of Bi(N)-HVIs and demonstrates their potential as a platform for the further development of highly reactive, but also highly tunable, I(V) reagents.

Full text of DOI:10.1002/anie.201909868

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Dearomatization of Electron-Deficient Phenols to ortho-Quinones
Enabled by Bidentate Nitrogen-Ligated I(V) Reagents
Authors: Xiao Xiao, Nathaniel S Greenwood, and Sarah E. Wengryniuk
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909868
Angew. Chem. 10.1002/ange.201909868
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10.1002/anie.201909868
Angewandte Chemie International Edition
COMMUNICATION
Dearomatization of Electron-Deficient Phenols to ortho-Quinones
Enabled by Bidentate Nitrogen-Ligated I(V) Reagents
Dr. Xiao Xiao[a], Nathaniel S. Greenwood[a][b], and Sarah E. Wengryniuk[a]*
Dedicated to Professor Viktor V. Zhdankin, in honor of his transformative contributions to the field of hypervalent iodine chemistry.
Abstract: Ortho-quinones are versatile functional groups found in
nature, materials science, and total synthesis. Despite their broad
utility, the synthesis of o-quinones remains a significant challenge,
and in particular, access to electron-deficient derivatives remains an
unsolved problem. Herein, we report the first general method for the
synthesis of electron-deficient o-quinones via the direct oxidation of
phenols. The reaction is enabled by a novel bidentate nitrogen-ligated
I(V) reagent, a previously unexplored class of compounds which we
have termed Bi(N)-HVIs. The reaction is extremely general and
proceeds with excellent regioselectivity for the ortho over para isomer.
Functionalization of the o-quinone products was examined, resulting
in a facile one-pot synthesis of the catechols as well as the
incorporation of a variety of heteroatom nucleophiles. This represents
the first synthetic application of Bi(N)-HVIs and demonstrates their
potential as a platform for the further development of highly reactive,
but also highly tunable, I(V) reagents.
o-quinones, through intramolecular transfer of an oxygen
atom.[11,12] A general and notable limitation to the aforementioned
methods is the requirement for electron-rich phenols as
substrates to achieve high reactivity.[13-15] As a result, examples
of diverse o-quinones possessing electron-withdrawing groups
are scarce and thus the subsequent chemistry of these species is
essentially unexplored. Given the diverse applications of o-
quinones across synthesis, biology, and materials chemistry the
ability to explore a broader range of electronic effects could reveal
novel properties and unlock previously inaccessible reactivity. To
this end, the development of novel reagent systems capable of
effecting the controlled oxidation of electron-deficient phenols is
of central importance.
A. Current methods of dearomatization of phenols to o-quinones
[O]= tyrosinase,
O2/Cu(I), I(V)
OH
OH
O
H
OH
O
[O]
R= –XR, –alkyl, –H
–2e–
–2e–
examples of R=EWG
are limited
R
R
R
Ortho-quinones[1] represent
a valuable and versatile
1
3
2
functional group; they are common in Nature[2] and have found
applications in materials science,[3] catalysis,[4] and as
intermediates in complex molecule synthesis[5]. Despite this utility,
the synthesis of structurally and electronically diverse o-quinones
B. (Bis)cationic nitrogen-ligated hypervalent iodine reagents
R
2+
N
I
N
N
N
O
2OTf–
R
I
remains challenging and is
a limitation in their further
2OTf–
I(III) N-HVIs (4)
development. An appealing strategy is the direct conversion of
readily available phenols (1) via a net 4e– oxidation, first to the
corresponding catechols (2), and subsequent dearomatization to
give o-quinone 3 (Scheme 1A).[6] Challenges to this approach
include controlling the regioselectivity of the initial oxygenation
(ortho vs. para) as well as finding suitable oxidant systems that
are compatible with the sensitive o-quinone products. Oxidants
I(V) Bi(bipy)-HVI (5a)
unexplored reactivity as
novel I(V) oxidant scaffold
– enhanced redox potentials
– novel reactivity
C. This work: Bi(N)-HVI synthesis of electron-deficient o-quinones
O
OH
OH
O
OH
Nu
Bi(N)-HVI (5b)
NuH
[9]
such as Fremy’s salt,[7] dimethyldioxirane,[8] or MeReO3–H2O2
R
R
R
in situ
either lack regioselectivity or favor generation of the p-quinone
unless this position is blocked with a substituent. Recently, the
Lumb group has developed an elegant solution to this challenge
through the use of biomimetic aerobic copper catalysis, inspired
by the mechanism of the tyrosinase enzyme.[10] Hypervalent
iodine reagents in the I(V) oxidation state, namely IBX and its
analogues, have also been found to give high regioselectivity for
30 examples
In situ generation of Bi(N)-HVI
R= H, –EWGs
CO2Et
2+
O
OAc
OAc
CO2Et
2OTf–
I
N
O
TMSOTf (2.0 equiv.)
4-CO2Etbipy (1.0 equiv.)
13 ligands screened
N
I
in situ
Bi(N)-HVI 5b
6
[a]
Dr. X. Xiao, N. S. Greenwood, Prof. Dr. S. E. Wengryniuk
Department of Chemistry
– General approach to e-deficient o-quinones and catechols
– First ligand study and synthetic application Bi(N)-HVIs
Temple University
1901 N. 13th St. Philadelphia, PA 19122
E-mail: sarahw@temple.edu; wengryniuklab.weebly.com
Scheme 1. Dearomatization of phenols to o-quinones. Current state of the art
and reported strategy.
[b]
Present Contact: N. S. Greenwood
Department of Chemistry
Yale University
225 Prospect St., New Haven, CT 06520
In recent years, our laboratory has reported on the unique
reactivity and synthetic applications of (bis)cationic nitrogen-
ligated I(III) reagents, or N-HVIs (4, Scheme 1B).[16] We, and
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201909868
Angewandte Chemie International Edition
COMMUNICATION
others, have found that I(III) N-HVIs of the type [PhI(het)2]2OTf,
which possess to datively bound nitrogen ligands, possess
dramatically enhanced and novel reactivity over their neutral
counterparts.[17] We were therefore intrigued by a 2002 report by
the Zhdankin laboratory disclosing the synthesis and
characterization of bidentate nitrogen-ligated I(V)-species with a
2,2’-bipyridine ligand (5a), for which no studies on its reactivity or
synthetic applications have been reported.[18] We hypothesized
that these bidentate I(V)-scaffolds, or Bi(N)-HVIs, could unlock
novel reactivity for I(V) reagents, analogous to their I(III) N-HVI
counterparts, and potentially enable oxidation of challenging,
previously unreactive electron-deficient phenols to o-quinones.
Furthermore, the presence of the bidentate nitrogen ligands could
provide advantages for reagent design, including (1) a functional
platform to allow facile tuning of the redox potentials and (2)
address practical issues common to I(V) reagents[12] through
generation of a more monomeric reagent composition.
6 was completely inactive, the highly reactive PhI(O)(OTf)2 gave
a maximum yield of 59% after just 20 mins, however the yield then
steadily diminished, reaching just 27% at 4.0 h. This result
emphasizes the need to carefully control the oxidant properties in
order to avoid degradation of the sensitive o-quinone products.
Table 1. Optimization of dearomatization of p-NO2-phenol 7
O
OH
R
N
O
O
Oxidant (1.2 equiv.)
CDCl3, rt
N
I
R
2OTf–
NO2
NO2
7
7a
5a–5n
Ligands Screened for in situ Bi(N)-HVIs
8f, R = 5-Me
8g, R = 6-Me
8h, R = 4-tBu
8i, R = 5-Br
8a, R = H
R
R
8b, R = 4-CO2Et
8c, R = 4-NO2
8d, R = 4-MeO
8e, R = 4-Me
N
N
N
Herein, we report the development of the first general strategy
for the synthesis of electron-deficient o-quinones directly from
phenols through oxidation with a novel Bi(N)-HVI reagent, Bi(4-
CO2Etbipy)-HVI (5b) (Scheme 1C). The required Bi(N)-HVIs
could be generated in situ and a library of 13 sterically and
electronically diverse scaffolds were explored. The scope of the
oxidation is extremely broad, with 30 electron-deficient phenols or
naphthols undergoing oxidation to the corresponding o-quinones
in good to excellent yield. The reactivity of the resulting electron-
deficient o-quinones was found to be dramatically altered from
their electron-rich counterparts and several efficient strategies for
their derivatization, including one-pot reduction to the
corresponding catechols are reported. In addition to the synthetic
utility of the resulting o-quinones and catechols, this study
provides the first synthetic application of Bi(N)-HVIs and
establishes their potential as a novel platform for I(V)-reagent
development.
8n
8k, R = H
8l, R = Cl
8m, R = Me
N
N
N
R
N
R
8j
Entry[a]
HVI
Time
Yield/%[b]
1
2
3
4
DMP
IBX
PhIO2
24 h
24 h
24 h
24 h
1.5 h
30 min
24 h
20 min
4.0 h
30 (27)[e]
12(86)
0
0
o-tBuSO2PhIO2
5
Bi(bipy)HVI 5a (isolated)
Bi(bipy)HVI 5a (in situ)
PhI(O)(OAc)2 (6)
71(23)[e]
6[c]
7
94
0
59
27
0
99
91
8[d]
PhI(O)(OTf)2 (9)
9[c]
10[c]
8n
40 min
30 min
4.0 h
To begin our investigation, p-NO2-phenol (7) was selected as
an electron-deficient model substrate for the dearomatization
(Table 1); due to the relative instability of the resulting o-quinone
(7a), yields were determined by 1H-NMR using 1,2-
dibromoethane as an internal standard.[11a] We began by
screening a panel of widely used I(V) oxidants including DMP, IBX,
iodosylbenzene, and [(o-tBuSO2)Ph]IO2 (entries 1-4) and, as
anticipated,[11] these reagents gave low or no conversion to o-
quinone 7a, even after 24 h. Then turning to the Bi(N)-HVIs of
interest, reported 2,2’-bipy reagent 5a was prepared from
PhI(O)(OAc)2 (6) by treatment with TMSOTf according to
Zhdankin’s procedure[18] and isolated as a white solid (see
Supporting Information for details). Upon treatment of 7 with
Bi(bipy)-HVI 5a, p-NO2-quinone 7a was observed in 71% NMR
yield after just 1.5 h (entry 5). With this promising result in hand,
the oxidation was then attempted via the in situ generation of 5a
(see Scheme 1C, inset) in order to avoid any potential issues of
reagent stability during isolation and we were pleased to see an
improved 94% yield of 7a after just 30 min (entry 6). In order to
confirm that 5a was indeed the active oxidant under these in situ
conditions, both the starting oxidant PhI(O)(OAc)2 (6) and
PhI(O)(OTf)2, the activated intermediate generated upon
treatment of 6 with TMSOTf, were screened (entries 7, 8). While
Bi(4-CO2Etbipy)HVI 5b
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
17[c]
Bi(4-NO2bipy)HVI 5c
Bi(4-OMebipy)HVI 5d
Bi(4-Mebipy)HVI 5e
Bi(5-Mebipy)HVI 5f
Bi(6-Mebipy)HVI 5g
Bi(4-tBubipy)HVI 5h
Bi(5-Brbipy)HVI 5i
30 min
40 min
40 min
30 min
40 min
30 min
30 min
4.0 h
30 min
4.0 h
1.0 h
30 min
1.0 h
63
38(44)[e]
64(17)[e]
94
59(39)[e]
12(46)[e]
98
83
99
18[c]
Bi(biquin)HVI 5j
81
19[c]
20[c]
21[c]
80(12)[e]
70
Bi(1,10-phen)HVI 5k
Bi(2-Cl-1,10-phen)HVI 5l
Bi(2-Me-1,10-phen)HVI 5m
83(17)[e]
[a] All the reactions were carried out with 7 (0.1 mmol) and oxidant (0.12 mmol)
in 3.0 mL CDCl3; [b] 1H-NMR yields, using 1,2-dibromoethane as internal
standard [c] In situ Bi(N)-HVIs prepared from PhI(O)(OAc)2 (0.12 mmol),
TMSOTf (0.24 mmol), and ligands 8a-8m (0.12 mmol) or 8n (0.24 mmol) in
CDCl3 followed by addition of 7 in CDCl3 [d] PhI(O)(OTf)2 was prepared in situ
from PhI(O)(OAc)2 and TMSOTf [e] Value in parentheses is 1H-NMR yield of 7
remaining.
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10.1002/anie.201909868
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COMMUNICATION
Table 2. Dearomatization substrate scopes[a]
CO2Et
2OTf–
CO2Et
PhIO(OAc)2 (1.2 equiv.)
TMSOTf (2.4 equiv.)
4-CO2Etbipy (8b) (1.2 equiv)
OH
O
N
O
N
O
I
[In situ Bi(N)HVI]
CDCl3, rt
R
R
5b
Entry
phenol
OH
quinone
yield (%)[b]
Entry
phenol
quinone
yield (%)[b]
OH
O
O
O
O
R
R
R
R
R
R
1
2
3
4
5
6
7
8
R = NO2 (7)
7a
9a
99
87
96
93
99
99
91
59
70
84
71
70
60
59
23
24
R = Cl (30)
CF3 (31)
OH
30a
31a
O
77
99
CO2Me (9)
CN (10)
SO2Me (11)
CF3(12)
CHO (13)
COCH3 (14)
F (15)
Cl (16)
Br (17)
I (18)
H (19)
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
O
O
F
F
F
F
F
F
25
26
32
32a
O
80
OH
9
O
10
11
12
13
14
NO2
NO2
CH3 (20)
Ph (21)
OH
33
34
33a
68
O
O
OH
48[h]
O
15
OH
O
22a
O
Br
O
Br
22
27
34a
34a’
65
OH
R
a:a’ (4.9:1)
R
O
O
O
OH
O
16
17
R = CO2Me (23)
CN (24)
OH
23a (54)
24a (83)
54
83
O
O
O
O
O
R
28[e]
35
36
35a
34a’
68
R
R
a:a’ (1.5:1)
18[c]
19[c]
20
R = NO2 (25)
25a
26a
27a
25a’
26a’
27a’
28a’
49 a:a’ (6:1)
66 a:a’(1.5:1)
76 a:a’ (2:1)
78 a:a’ (2.9:1)
O
CO2Et (26)
CN (27)
Br (28)
O
OH
29[e]
35a
60 [53][f]
21
28a
OH
Cl
O
O
OH
O
O
Cl
O
CO2H
O
O
22
66[d]
29a:7a (1:2.3)
NO2
NO2
NO2
Br
Br
29
29a
7a
30[g]
37
37a
92 [90][f][h]
[a] Unless otherwise noted, all the reactions were carried out with phenol (0.1 mmol), PhI(O)(OAc)2 (0.12 mmol), TMSOTf (0.24 mmol) and 5b (0.12 mmol) in 3.0
mL CDCl3 for 15 mins; [b] Yields were determined by crude 1H NMR using 1,2-dibromoethane as internal standard; [c] 1H NMR yield after 5 mins; [d] along with
24% 1HNMR yield of remaining 29; [e] 8d was used instead of 8b; [f] isolated yield; [g] 8k was used instead of 8b and the reaction time was 1 h. [h] Oxidation of 22
and 37 are examples of 2e– oxidations that can also be achieved using I(III) oxidants. Oxidation of 22 with only 0.6 equiv. of 8b gave a similar result (50% yield of
22a), however 0.6 equiv. gave a decreased 62% yield in the case of 37a.
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10.1002/anie.201909868
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COMMUNICATION
With a practical in situ protocol in hand, a small library of
bidentate nitrogen ligands (8b-8m), as well as pyridine (8n) as a
monodentate control, were then screened to examine the effect
of ligand sterics and electronics on reactivity on Bi(N)-HVI
reactivity. The importance of bidentate chelation was clearly
demonstrated as switching to pyridine (8n) resulted in a complete
loss of activity and full starting material recovery (entry 9).
Electron-deficient ligands (8b, 8i, entries 10, 17) both gave
excellent yields and showed minimal product degradation, with
Bi(4-CO2Etbipy)HVI 5b providing near quantitative yield of 7a
after just 30 min with only a small drop in yield after prolonged
reaction time. A lower yield was obtained with 4-NO2-bipy ligand
5c, however this is due to its poor solubility of the resulting
Bi(N)HVI in organic solvents (entry 11). In contrast, the presence
of a strongly electron-donating 4-OMe group (8d) led to a
significant decrease in conversion (entry 12). The presence of
alkyl substitution had minimal effect on reaction efficiency (entries
13-15), with the exception of a t-Bu group at the 4-position (8h,
entry 16) which led to a significant drop in yield, possibly due to
decreased reagent stability. The use of 2,2’-biquinoline ligand 8j
gave 99% yield of 7a after 30 mins however also facilitated
product degradation upon continued exposure (entry 18). Finally,
the role of bite angle and ligand rigidity was examined with 1,10-
phenanthroline derivatives 8k-8m, which were all found to be
competent oxidants, producing 7a in yields equivalent to or
slightly less than the best bipyridine derivatives. It is worth noting
that despite its excellent reactivity in the dearomatization,
attempts to isolate Bi(1,10-phen)HVI 5k revealed a low bench
stability, indicating a pronounced effect on reagent stability. After
considering both the efficiency and robustness of the reaction,
Bi(4-CO2Etbipy)HVI 5b was selected as the optimal reagent for
further examination of the reaction scope.
found to give high yields of the quinone products but with
decreased levels of ortho/para selectivity in the case of 34 and 35.
Finally, oxidation of 37 possessing an intramolecular trapping
nucleophile gave monooxidized spirocyclic product 37a in an
excellent 90% yield.[19] It is of note that in the cases of more
electron-rich naphthols 35-37, either the Bi(4-OMebipy)HVI 5d or
the more rigid Bi(1,10-phen)HVI 5k were found to give higher
yields. These results demonstrate the power of the highly modular
Bi(N)HVI platform which allows facile tuning of the oxidant system
to a target substrate, an element of control that is not possible
using typical I(V) oxidant systems.
Due to the previous lack of general methods to access
electron-deficient o-quinones, little is known about the
subsequent reactivity and how it may differ from their more
common electron-rich counterparts. To begin, we found that a
one-pot reduction with NaBH4 gave facile access to the
corresponding catechols (Scheme 2). Interestingly, while all the
reactions proceeded in high yields, reduction of 4-NO2 quinone 7a
and 6-CO2Me quinone 9a instead gave major products derived
from addition of MeOH to the polarized double bonds adjacent to
the electron-withdrawing groups (38a, 41a). This is particularly
interesting as there were no products arising from 1,4-addition to
either carbonyl of the o-quinone and the structure of 41a was
unambiguously confirmed by X-ray crystallography (Scheme 2,
inset). These reactions provide access to monoprotected
pyrogallols that would otherwise be challenging to access.
OH
OH
O
In situ
Bi(N)-HVI 5b
OH
O
NaBH4
CH2Cl2, rt
MeOH:CH2Cl2
R
R
R
38-45
OH
OH
OH
Using in situ Bi(4-CO2Etbipy)HVI 5b as the oxidant, the scope
of the dearomatization was examined with a wide range of
electron-deficient phenols and found to be extremely general
(Table 2). p-Substituted phenols with electron-withdrawing groups
(7, 9-14, entries 1-7) and halogens (15-18, entries 8-11) all gave
the corresponding o-quinones in good to excellent yields. The use
of more prototypical electron-rich substrates, including phenol
(19), p-Me (20), and p-Ph (21) all underwent oxidation (entries 12-
14), albeit in slightly lower yields, again emphasizing the
importance of matching oxidant to substrate in these
transformations. Oxidation of 1,4-dihydroquinone (22) gave 1,4-
benzoquinone in moderate yield (entry 15), indicating that
performing the second dearomatization step from the higher I(V)
oxidation state may be detrimental. Electron-withdrawing o-
substituents were well tolerated, giving o-quinones 23a and 24a
in good yields (entries 16, 17). m-Substituted phenols 25-28
proceeded in good yields to give a mixture of regioisomeric o-
quinones with low to moderate selectivity for oxidation at the
sterically more accessible position (entries 18-21). The oxidation
of disubstituted phenols was then examined and found to also be
highly efficient. 2-Cl-4-NO2-phenol (29) gave good yield but as a
1:2.3 ratio of desired product 29a and 7a resulting from
regioisomeric oxidation and loss of chloride (entry 22). 3,5-di-
chloro (30), 3,5-diCF3- (31), and 3,4,5-trifluoro-phenol (32) all
proceeded in excellent yields (entries 23-25). Finally, several
naphthol derivatives (33-36) were examined (entries 25-29) and
OH
R’
OH
OH
38 R’ = H
NO2
CO2Me
CN
40, 81%
38a R’ = OMe
66% (38:38a= 1:6.3)
39, 72%
OH
OH
OH
OH
OH
MeO2C
R'
OH
41 R’ = H
41a R’ = OMe
CF3
SO2Me
60% (41:41a = 1:4)
42, 88%
43, 68%
OCO2Et
OCO2Et
OH
OH
Cl
F
F
Cl
F
41a
45, 63%[b]
44, 75%
Scheme 2. One-pot synthesis of electron-deficient catechols from phenols.[a] [a]
All reactions performed on 0.5 mmol scale. Yields are isolated yields over two
steps. [b] Free catechol product was unstable to isolation and was therefore
protected in situ with ethyl chloroformate. Yield reported is over 3 steps.
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10.1002/anie.201909868
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COMMUNICATION
Inspired by the addition of MeOH to the nitroolefin of 7a, we
decided to further probe the scope of nucleophiles that could be
added to this highly polarized o-quinone (Scheme 3). Revisiting
the mixture of products obtained in the attempted NaBH4
reduction, conditions to efficiently access both 38 and 38a were
established. Catechol 38 could be achieved in 81% yield via redox
exchange with 4-methoxyphenol and the 3-methylated pyrogallol
38a could be obtained in improved yield simply by stirring 7a in
MeOH. Thiols were found to be highly efficient nucleophiles, with
EtSH giving 46 in 95% yield and PhSH giving 47 in 60% yield.
Finally, addition of N-Me-aniline gave 48 in good yield. Facile
access to such diverse, densely functionalized catechols
including O, S, N groups from commercial p-nitrophenol 7,
demonstrates the power of the reported methodology to expand
the scope of o-quinones and catechols that are accessible for
both chemical and biological applications.
phenol dearomatization reactions (Scheme 4). Initial ligand
exchange between in situ generated Bi(N)-HVI and phenol
substrate likely results in an equilibrium between monodentate 49
and bidentate 50, both of which could engage in intramolecular
delivery of an oxygen atom to the ortho-position, giving I(III)-
ligated catechol 51 after rearomatization. Intermediate 51 then
undergoes a second oxidation to give the o-quinone, along with
fully reduced phenyliodide (52) and protonated diamine ligand
(53); both 52 and 53 can be observed in the NMR spectra of the
crude reactions. The coordination environment at the iodine
center after initial phenol attack, either 49 or 50, is not currently
known but would be important to the potential development of
asymmetric variants of Bi(N)-HVI reagents, studies that are
currently of interest to our laboratory.
In summary, the first general method for the synthesis of
electron-deficient o-quinones has been developed, starting from
readily available phenol starting materials. The dearomatization is
enabled by the unique reactivity of a bidentate nitrogen-ligated I(V)
reagent, Bi(4-CO2Etbipy)-HVI 5b, which can be generated in situ.
This report represents the first demonstration of the synthetic
utility of the I(V) Bi(N)-HVI reagent class and indicates their
potential as a new platform for the design of highly tunable I(V)
reagents. The subsequent derivatization of the electron-deficient
o-quinones was demonstrated with a practical one-pot sequence
to the corresponding catechols as well as the addition of O, N,
and S nucleophiles to 4-nitro o-quinone, which add with complete
regioselectively into the vinyl nitro functionality. Further synthetic
applications of electron-deficient o-quinones as well as the
continued development of Bi(N)-HVIs are ongoing in our
laboratory and will be reported in due course.
HO
NO2
7
OH
OH
OH
in situ
OH
Bi(N)-HVI 5b
MeO
H
OMe
NO2
MeOH
OH
NO2
38a, 60%[a]
O
O
38, 81%
Me
NH
7a
OH
EtSH
OH
OH
NO2
OH
Ph
PhSH
N
NO2 Me
48, 49%[c]
S
NO2
OH
OH
Me
46, 95%
SPh
Acknowledgements
NO2
47, 62%[b]
The authors are grateful to the National Institutes of Health (NIH
R01 GM123098) for financial support of this work and the authors
would like to acknowledge the Donors of the American Chemical
Society Petroleum Research Fund for partial support of this
research (DNI-56603). We are thankful to Jessica M. Roth, MS
who conducted preliminary experiments with the Bi(N)HVI
reagents, including stability studies. We thank Dr. Charles
DeBrosse (Temple University) for NMR spectroscopic assistance
and Dr. Charles W. Ross III, Director: Automated Synthesis and
Characterization at University of Pennsylvania Chemistry for
providing high-resolution mass spectral data.
Scheme 3. Derivatizations of 4-NO2 quinone 7a with nucleophiles. Isolated
yields are reported over two steps from phenol 7. [a] Along with 4% yield of 38
[b] Along with 30% yield of 38 [c] Along with 18% yield of 38
R
OH
2+
Ph
Ph
N
N
O
N
R
R
I
N
I
O
O
I
N
OH
HN+
O
2OTf-
R
R
2OTf-
2OTf-
49
50
Ph
O
N
H
I
R’
Keywords: ortho-quinone • phenol • hypervalent iodine •
I
O
HN
N
O
O
dearomatization
H
2OTf-
2OTf-
R’
R
R
+
+
HN
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52
53
51, I(III)
Scheme 4. Proposed mechanism of Bi(N)-HVI mediated dearomatization
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proceeds analogously to previously reported I(V)-mediated
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10.1002/anie.201909868
Angewandte Chemie International Edition
COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/anie.201909868
Angewandte Chemie International Edition
COMMUNICATION
This article is protected by copyright. All rights reserved.

10.1002/anie.201909868
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Dr. Xiao Xiao, Nathaniel S. Greenwood,
Dr. Prof. Sarah E. Wengryniuk*
OH
OH
CO2Et
OH
OH
OH
O
BH4
in situ
a
CO2Et
N
N
O
I(V) Bi(N)HVI
R
Page No. – Page No.
N
O
I
2OTf–
In situ
NuH
R
R
30 examples
R= –H,
Dearomatization of Electron-Deficient
Phenols to ortho-Quinones Enabled
by Bidentate Nitrogen-Ligated I(V)
Reagents
Herein, we report the first general method for the dearomatization of electron-
deficient phenols to ortho-quinones, enabled by a novel bidentate nitrogen-ligated
I(V) reagent; this represents the first synthetic application of this reagent class. The
o-quinones can be converted directly to novel, densely functionalized catechols in a
one-pot fashion.
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