Room-Temperature, Water-Promoted, Radical-Coupling Reactions of Phenols with tert -Butyl Nitrite

Article abstract of DOI:10.1055/s-0036-1589038

A radical-radical cross-coupling reaction of phenols with tert -butyl nitrite has been developed with the use of water as an additive. This method allows the construction of C-N bonds under an air atmosphere at room temperature, providing the ortho -nitrated phenol derivative in moderate to good yields.

Full text of DOI:10.1055/s-0036-1589038

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
W.-T. Wei et al.
Letter
Synlett
Room-Temperature, Water-Promoted, Radical-Coupling Reactions
of Phenols with tert-Butyl Nitrite
Wen-Ting Wei*
Wen-Ming Zhu
Weida Liang
Yi Wu
NO2
H
OH
OH
H2O
R1
t-BuONO
+
R1
THF, r.t.
R2
R2
R1 = H, Br
Mild reaction condition
Radical coupling
Hui-Yan Huang
Yi-Ling Huang
Junfei Luo
R2 = H, OMe, Me, t-Bu
F, Cl, Br, I
14 examples, up to 83% yield
Hongze Liang*
School of Materials Science and Chemical Engineering,
Ningbo University, Ningbo 315211, P. R. of China
weiwenting@nbu.edu.cn
lianghongze@nbu.edu.cn
Received: 09.04.2017
Accepted after revision: 04.05.2017
Published online: 21.06.2017
catalyzed radical-coupling reaction for the synthesis of N-
alkyl-substituted aminophenols through direct alkylamina-
tion of phenols under mild conditions was reported
(Scheme 1; Path c).6 Other methods for ortho-amination of
phenol derivatives through radical reactions were reported
too.7 However, all of the above-mentioned radical-coupling
reactions were limited to anilines, and the coupling of nitro
radicals to phenols has rarely been reported.
DOI: 10.1055/s-0036-1589038; Art ID: st-2017-w0241-l
Abstract A radical–radical cross-coupling reaction of phenols with
tert-butyl nitrite has been developed with the use of water as an addi-
tive. This method allows the construction of C–N bonds under an air at-
mosphere at room temperature, providing the ortho-nitrated phenol
derivative in moderate to good yields.
Nitro compounds are widely used as key intermediates
and building blocks in organic chemistry, material sciences,
and the pharmaceutical industry.8 As part of our continuing
interest in radical chemistry, we envisioned that nitro radi-
Key words radical reaction, cross-coupling, phenols, butyl nitrite,
C–N bond formation, nitrophenols
The formation of C–C or C–X (X = N, O, S, etc.) bonds
through a C–H oxidative radical-coupling reaction has re-
ceived much attention due to the appearance of the con-
cepts of atom economy and green chemistry.1 Recently, the
radical-coupling reaction between two C–H/C–H and X–H
centers has emerged as a highly attractive strategy for cre-
ating complex molecules.2 Such cross-coupling reactions
provide a direct synthetic route that avoids prior function-
alization of the C–H or X–H bond. Among the various radi-
cal-coupling reactions, the construction of C–N bonds is of
high interest due to its considerable importance in modern
organic chemistry.
It is well known that phenols are important motifs for
the food, materials, and pharmaceutical industries.3 Conse-
quently, the construction of C–N bonds to phenols through
radical reactions has long been a hot topic in organic chem-
istry. One efficient example was reported by Patureau and
co-workers, who disclosed a dioxygen-mediated dehydro-
genative amination of phenols with phenothiazine in the
presence of cumene (Scheme 1; Path a).4 Recently, with
some excellent work, Xia’s group developed a practical
strategy for constructing C–N bonds by using phenols and
anilines through a radical–radical cross-coupling promoted
by visible light (Scheme 1; Path b).5 Subsequently, an iron-
X
R2
(a)
H
X
OH
R2
N
cumene, O2
+
OH
N
H
AcOH, 130–150 °C
R1
X = O, S
R1
H
R3
N
R4
OR2
K2S2O8, air
R3
(b)
+ HN
R4
OH
MeCN, r.t., blue LED
R1
H
R1
R3
R2
N
OH
R3
R2
FeCl3
OH
R1
BzO
N
+
(c)
(d)
toluene, r.t.
R1
X
X = CH, N
X
this work
NO2
H
OH
OH
H2O
t-BuONO
R1
R1
+
THF, r.t.
R2
R2
Scheme 1 C–N bond formation by using phenols as partners in radi-
cal-coupling reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
W.-T. Wei et al.
Letter
Synlett
cals might be generated from t-BuONO, promoted by H2O,
and that these radicals might undergo radical–radical cou-
pling with phenoxyl radicals to give nitrophenols. Here, we
report a H2O-promoted radical-coupling reaction of phe-
nols with t-BuONO at room temperature (Scheme 1; Path
d).
Table 1 Optimization of the Reaction Conditionsa
H
NO2
OH
OH
additive
t-BuONO
+
solvent, r.t.
2a
1a
3aa
To verify our hypothesis, we chose the reaction of naph-
thol (1a) with t-BuONO (2a) as a model reaction to opti-
mize the reaction by the use of various additives or sol-
vents. The results are summarized in Table 1. Initially,
naphthol (1a) was treated with t-BuONO (2a) in THF at
room temperature for 2.5 hours to give the desired 1-nitro-
2-naphthol (3aa) in 7% isolated yield (Table 1, entry 1). Con-
sequently, a preliminary study was implemented with the
aim of identifying an appropriate additive that would pro-
mote the reaction between 1a and 2a. Several additives, in-
cluding tetrabutylammonium bromide (TBAB), metal cata-
lysts, and H2O were chosen on the basis of reports that
these promoted similar radical-coupling reactions. When a
solution of 1a and 2a in THF was stirred in the presence of a
catalytic amount of TBAB, CuCl2, FeCl3, Pd(OAc)2, or H2O as
an additive (entries 2–6, respectively), H2O provided the
desired 1-nitro-2-naphthol (3aa) in 51% isolated yield (en-
try 6), the best yield among the additives examined. With
regard to the optimal amount of the additive, the reaction
in the presence of 2.0 equivalents of H2O provided the best
results (entries 6–10). Next, the reaction conditions were
further investigated and the influence of various solvents
on the outcome of the model reaction was screened. We es-
tablished that the reaction can be run in a number of sol-
vents (entries 8 and 11–15). We found that THF was the
best solvent (entry 8). Moreover, an attempt to increase the
yield by raising the reaction temperature to 40 °C failed
(entry 16). We were pleased to find with a 1 g scale of sub-
strate 1a, the product was successfully prepared in good
yield by prolonging the reaction time to 12 hours, but with-
out other optimization (entry 17). Thus, the optimized re-
action conditions were as follows: 1a (0.3 mmol), 2a (0.6
mmol), and H2O (2.0 equiv), in THF (2 mL) under an air at-
mosphere at room temperature for 2.5 hours.
Entry
Additive (equiv)
Solvent
Yieldb (%)
1
2
–
THF
7
20
19
20
41
51
72
75
32
75
56
27
62
17
54
59
71
TBAB (0.1)
CuCl2 (0.1)
FeCl3 (0.1)
Pd(OAc)2 (0.1)
H2O (0.1)
H2O (1.2)
H2O (2.0)
H2O (4.0)
THF
3
THF
4
THF
5
THF
6
THF
7
THF
8
THF
9
THF
10
11
12
13
14
15
16c
17d
Pd(OAc)2 (0.1) + H2O (2.0)
H2O (2.0)
THF
1,4-dioxane
MeCN
EtOAc
DMSO
toluene
THF
H2O (2.0)
H2O (2.0)
H2O (2.0)
H2O (2.0)
H2O (2.0)
H2O (2.0)
THF
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), additive, solvent (2
mL), air atmosphere, r.t., 2.5 h.
b Isolated yield.
c At 40 °C.
d 1a (6.94 mmol, 1 g), 12 h.
1-naphthol also gave the ortho-nitrated product 3da in 39%
yield. We then turned our attention to an investigation of
the scope of the phenol in this radical-coupling reaction. In
this regard, two regioisomers were obtained when phenol
(1e) was used as a starting material, giving 2-nitrophenol
(3ea) and 4-nitrophenol (3ea′) in 41 and 20% yield, respec-
tively. It can be seen from the ratio of 3ea and 3ea′ that the
ortho-radical is more easily generated than the para-radi-
cal. Screening showed that several substituents such as al-
kyl, methoxy, fluoro, chloro, bromo, or iodo groups, were
well tolerated under the optimal conditions. For example,
phenols with an electron-donating methoxy, methyl, or
tert-butyl group in the para-position showed high reactivi-
ty in the radical-coupling reaction with 2a, providing the
corresponding products 3fa, 3ga, and 3ha in good yields.
Gratifyingly, halogens were also well tolerated, which
should prove instrumental for further late-stage diversifi-
cation by, inter alia, cross-coupling reactions (3ia, 3ja, 3ka,
and 3la). Phenols bearing two substituents on the aromatic
ring reacted smoothly with 2a, providing the desired prod-
ucts. These results indicated that an electronic effect on the
With the optimized reaction conditions in hand, we
turned our attention to an investigation of the scope of this
radical-coupling reaction (Table 2).9 A variety of different
phenol derivatives were smoothly converted into the corre-
sponding products in moderate yields. First of all, the radi-
cal coupling of naphthols and t-BuONO (2a) were investi-
gated, and the treatment of 6-bromo-2-naphthol under the
optimized conditions gave the corresponding product 3ba
in 81% yield. Interestingly, ortho-nitration did not take place
when 1-bromo-2-naphthol was used as the starting mate-
rial. Instead, cleavage of the C–Br bond occurred to give the
nitrated product 3aa in moderate yield. This revealed that
the reaction might proceed by a radical process. Moreover,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
W.-T. Wei et al.
Letter
Synlett
substituted group played no role in the reaction, which pre-
cludes the possibility of an electrophilic substitution reac-
tion.
We then studied the effects of the reaction time on the
yields under the optimized reaction conditions. As can be
seen in Figure 1, the curve showed a rapid rise, eventually
flattening with increasing time. We also found that a yield
of 75% was actually reached at 2.5 hours. Further prolonga-
tion of the reaction time did not show any marked effect on
the yield.
Table 2 Examples of Radical-Coupling Reactionsa
NO2
OH
H
OH
H2O (2.0 equiv)
THF, r.t.
t-BuONO
+
R1
R1
2a
R2
R2
3
1
Entry
1
Phenol
Product
Yield (%)
75
NO2
OH
OH
1a
3aa
NO2
OH
OH
2
3
4
81
Br
Br
1b
3ba
Br
Br
OH
OH
traceb
NO2
1c
3ca
3da
OH
OH
NO2
39
1d
OH
OH
OH
NO2
and
5
6
7
41/20
NO2
1e
3ea/3ea'
OH
OH
NO2
62
OMe
OMe
1f
3fa
OH
OH
NO2
82
Me
Me
3ga
1g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
W.-T. Wei et al.
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Synlett
Table 2 (continued)
Entry
Phenol
Product
Yield (%)
83
OH
OH
NO2
NO2
NO2
NO2
NO2
8
9
t-Bu
t-Bu
1h
3ha
OH
OH
65
F
F
1i
3ia
OH
OH
10
11
12
13
14
62
Cl
Cl
1j
3ja
OH
OH
60
Br
Br
1k
3ka
OH
OH
71
I
I
1l
3la
OH
OH
Me
OH
Me
O2N
Me
NO2
and
44/38
Me
Me
Me
OH
1m
3ma/3ma'
OH
Cl
Cl
NO2
75
Cl
Cl
1n
3na
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), H2O (0.6 mmol), THF (2 mL), air atmosphere, r.t., 2.5 h.
b 3aa was formed in 67% yield by radical coupling of 1-bromo-2-naphthol with t-BuONO, and accompanying cleavage of the C–Br bond.
NO2
H
As shown in Scheme 2, when the two radical inhibitors
OH
OH
H2O (2.0 equiv)
THF, r.t.
t-BuONO
+
TEMPO and 2,6-di-tert-butyl-4-methylphenol (BHT) were
separately added to the radical-coupling reaction, a stoi-
chiometric amount of the radical inhibitor (2.4 equiv) re-
sulted in no conversion of 1-naphthol (1a). These results
confirm that the coupling reaction proceeds through a radi-
cal mechanism.
2a
1a
3aa
Additive
Yield of 3aa
0%
TEMPO (2.4 equiv)
BHT (2.4 equiv)
trace
Scheme 2 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
W.-T. Wei et al.
Letter
Synlett
Funding Information
research funds of NBU, Grant / Award Number: 'No. ZX2016000706'
reseacrh
uf
n
ds
of
N
B
U
Acknowledgment
This research is sponsored by research funds of NBU (No.
ZX2016000706) and the K. C. Wong Magna Fund in Ningbo Universi-
ty.
Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589038.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Figure 1 Time-dependence curves for the transformation of 1a into
3aa. Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), H2O (0.6
mmol), THF (2 mL), air atmosphere, r.t.
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(Scheme 3). Initially, t-BuONO is split into t-BuOH and
HNO2 in the presence of H2O. HNO2 is not stable and quickly
converts into an NO2 radical, an NO radical, and H2O. Subse-
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2HNO2
NO2 + NO + H2O
t-BuO
NO
air
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t-BuOH
NO2
t-BuONO
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OH
O
NO2
NO2
NO2
R
R
R
radical-radical
cross cupling
3
B
A
Scheme 3 Plausible mechanism
In summary, we have developed a simple method for
the synthesis of nitrophenols by a water-promoted radical-
coupling reaction of phenols with t-BuONO. In this reac-
tion, C–N bonds are formed through radical–radical cross-
coupling. In addition, no metals or bases are required, and
the reaction can be performed under an air atmosphere at
room temperature. Efforts to extend the applications of the
radical-coupling reaction in synthetic chemistry are cur-
rently underway in our laboratory.
(9) Nitration of Phenols 1; General Procedure
To a Schlenk tube were added phenol 1 (0.3 mmol), tert-BuONO
(2a; 0.6 mmol), H2O (0.6 mmol), and THF (2 mL), and the
mixture was stirred at 25 °C under air atmosphere for the indi-
cated time until the starting material was completely consumed
(TLC). The mixture was extracted with EtOAc (3 × 10 mL), and
the organic extracts were dried (Na2SO4) and concentrated
under vacuum to give a crude product that was purified by
column chromatography (silica gel, hexane/EtOAc, 5/1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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W.-T. Wei et al.
Letter
Synlett
1-Nitro-2-naphthol (3aa)
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Synth. Catal. 2015, 357, 1161.
(12) Yang, X.-H.; Song, R.-J.; Li, J.-H. Adv. Synth. Catal. 2015, 357,
3849.
Yellow solid; yield: 0.0427 g (75%); mp 102.7–103.4 °C. 1H NMR
(300 MHz, CDCl3): δ = 12.19 (s, 1 H), 8.88 (d, J = 8.7 Hz, 1 H),
7.97 (d, J = 9.0 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 7.8 Hz,
1 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 9.0 Hz, 1 H). 13C NMR (75
MHz, CDCl3): δ = 158.9, 139.3, 131.0, 129.4, 128.7, 126.9, 125.7,
123.2, 119.4, 119.3. LRMS (EI, 70 eV): m/z (%): 189 (M+, 100),
115 (77), 89 (39).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F