Organic Letters
Letter
Figure 1. Evolution of synthetic strategies over the past century to access nitroarenes and nitroheteroarenes via ipso-substitution of arylboronic
acids using various sources of the nitro group.
transfer (SET) process initiated by exogenous,26 visible-light
sensitized catalyst, similar reaction conditions were first
examined. Our investigation focused on the reaction of
nonsubstituted phenylboronic acid 1a and NO2-transfer
reagents (I−IV) as model substrates. After a systematic
screening of different reaction parameters, photocatalysts,
solvents, concentrations, and reagents, it was found that 1a
(1.0 equiv), II (2.0 equiv) and [Ru(bpy)3](PF6)2 (2.5 mol %)
in acetonitrile (0.5 M) at 23 °C under irradiation from a 350
W blue LED light for 19 h afforded the desired product 2a in
89% (Table 1; for complete details, see the Supporting
of 2a can be obtained if hexafluoroisopropanol (HFIP) is used
as a solvent at 60 °C. Other phenylboronic derivatives under
both methodologies gave low or trace amounts of the desired
With the optimized reaction conditions in hand, the
generality of these protocols was examined with respect to a
wide array of readily available arylboronic and heteroarylbor-
onic acids. As shown in Scheme 1, our ipso-nitration
methodologies tolerate various functional groups, substitution
patterns, and electronics. It is noteworthy that halogen
substituents (2c, 2j, 2n−2p), as well as hydroxyl (2f) and
ester (2r) groups, remain untouched under the reaction
conditions of both methodologies, allowing further structural
elaboration. Compared to the previously reported methods,
enhanced reactivity was observed, especially for arylboronic
acids bearing fluorinated functionalities.16,19 Electron-rich (2b,
2g, 2k−2m, 2ab) and electron-deficient (2d, 2e, 2h−2j, 2q−
2t) arylboronic acids with ortho-, meta-, and para-substituents
are all viable substrates, affording exclusively mononitrated
arenes in good to excellent yields. Also, similar reaction
efficiencies were achieved with disubstituted and polysub-
stituted arylboronic acids (2u−2z, 2ae). Furthermore,
structurally complex boronic acid 1af can be efficiently
converted to the desired product in 68% yield. Encouraged
by such functional group tolerance, we then examined the ipso-
nitration of heteroarylboronic acids, which are generally
challenging to functionalize via previously reported method-
ologies.19,20 We were pleased to observe that both electron-
rich (2ah−2aj) and electron-deficient (2ag, 2am) substituents
were tolerated, furnishing the desired nitro-derivatives in
moderate to good yields. In addition, a range of other five-
membered heteroaryl rings such 3-nitrothiophene (2al), 3,5-
dimethyl-4-nitroisoxazole (2ak), and 4-nitrodibenzo[b,d]-
thiophene (2an), were also synthesized by the same protocols.
In all cases, we did not observe polynitration under established
conditions.19 Overall, comparative results of two method-
ologies show the suitability of the photocatalytic protocol
toward electron-poor aryl(hetero)boronic acids, whereas the
HFIP-promoted strategy was found to be more efficient for
ipso-nitration of electron-rich substrates.
a
Table 1. Reaction Design and Optimization Studies
b
entry catalyst (mol %) [NO2] solvent conditions [°C/h] 2a [%]
1
2
3
4
5
6
7
8
9
[Ru(bpy3)2+]
I
II
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
HFIP
HFIP
HFIP
HFIP
HFIP
23/19
23/19
23/19
23/19
85/19
85/19
85/19
60/19
60/24
60/24
60/24
60/24
0
89
55
<5
39
96
93
95
0
[Ru(bpy3)2+]
[Ru(bpy3)2+]
[Ru(bpy3)2+]
−
Mg(ClO4)2
Zn(NTf2)2
−
−
−
−
−
III
IV
IV
IV
IV
IV
II
III
IV
IV
10
11
12
<5
21
trace
c
d
a
Condition (a): [Ru] (2.5 mol %), 1a (1.0 equiv), reagent (2.0
equiv), MeCN (0.5 M), blue LEDs, rt, 19 h. Condition (b): catalysts
(10 mol %), HFIP (0.5 M), 60 °C, 19 h. Yields are determined by
b
GC-MS using n-decane as an internal standard. 1a was used.
c
d
PhBF3K was used. PhB(pin) was used.
To gain insight into the reaction mechanism, a series of
mechanistic studies for both methodologies were performed
and are discussed separately. A plausible mechanism for visible-
light-regulated radical nitration is proposed in Figure 2.27 After
initial excitation of the photocatalyst, the resulting excited
[Ru(bpy)3]2+* undergoes oxidative quenching with II,
promoting rapid and irreversible formation of a NO2 radical
species via mesolytic N−N bond fragmentation.28 Upon
addition of the nitryl radical to the ipso-carbon of the
phenylboronic acid, the subsequent oxidation and deborony-
strated poor reactivity under photocatalytic conditions,
because of its decomposition in solution. However, we were
pleased to observe that ipso-nitration with IV proceeded in
39% yield in acetonitrile at 85 °C (see Table 1, entry 5).
The yield of the reaction was dramatically improved to 96%
by adding catalytic amounts of Lewis acids (Table 1, entries 6
Further screening of the solvent revealed that the catalyst can
be omitted from the reaction mixture and a quantitative yield
B
Org. Lett. XXXX, XXX, XXX−XXX