first copper-mediated directed ortho CÀH nitration of
(hetero)arenes using 1,2,3-trichloropropane (1,2,3-TCP) as
solvent and dioxygen as terminal oxidant (Figure 1, path b).
One of the novel findings is the necessity of 1,2,3-TCP as
solvent to achieve high conversion in the nitration. In this
paper, a mechanism involving a four-centered transition state
based on results of the kinetic isotope effect (KIE) studies
and designed experiments is proposed to interpret the ortho
regioselectivity and the source of nitro group. This finding
represents a new approach to regioselective aromatic
nitration.
Initially, a survey on the reaction parameters, including
catalyst, nitrating agent, and solvent, was conducted under
dioxygen atmosphere at fixed temperature (130 °C) and
reaction time (24 h), using the nitration of 2-phenylpyr-
idine 1a1 as a model (Table 1). Metal catalysts were first
screened using AgNO3 as a nitrating agent and 1,2,3-TCP
as solvent. With Cu(OAc)2 as catalyst, at least 50 mol %
Cu(OAc)2 was found to be essential for an efficient con-
version affording 2a1 in 85% yield within 17 h (entries
1À3). Also worthy of note is the cuprous salt CuOAc,
which, like Cu(OAc)2, is similarly effective, albeit with the
need for slightly longer reaction time (24 h) (entry 4). As a
control, no reaction occurred without Cu(OAc)2 under
otherwise identical conditions (entry 5). Instead of Cu-
(OAc)2, other cupric salts such as Cu(OTf)2 and CuF2
resulted in only a slight conversion with the recovery of a
bulk of substrate 1a1 (entries 6 and 7), thus asserting the
importance of the acetate ion. Under similar conditions as
for Cu(OAc)2, Pd(OAc)2 (10 mol %) also demonstrated
comparable efficiency but with a lower conversion (entry
8). Other metal salts such as Mn(OAc)3 (a single-electron
oxidant) and Sc(OTf)3 (a strong Lewis acid) proved in-
effective for this reaction (entries 9 and 10). Furthermore,
investigations on the nitrating agents disclosed that except
for AgNO2, which produced 2a1 with almost identical
Table 1. Condition Screeninga
amt
yieldb (%)
entry
cat.
(mol %)
MNO3
solvent
of 2a1
1c
2c
3d
4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuOAc
10
30
50
50
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO2
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
1,2,3-TCP
7.5 (92.5)
45 (55)
85
67
5
0
6c
7c
8c
9
Cu(OTf)2
CuF2
50
50
10
50
50
50
50
50
50
50
50
50
50
18 (82)
17 (83)
Pd(OAc)2
Mn(OAc)3
Sc(OTf)3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
23 (77)
0
10
11
12e
13
0
75
Fe(NO3)3 1,2,3-TCP
0
NaNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
1,2,3-TCP
DCPf
2aÀOH 62
2a-Cl 78
0
14g Cu(OAc)2
15
16
17
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
1,4-dioxane
DMSO
trace
pentanediol Di2a 15
1,2,3-TCP
1:1:1i
18h Cu(OAc)2
a Reactions were performed on 1.0 mmol scale, at 0.5 M (with respect to
2-phenylpyridine 1a1). b Isolated yields. c Ratio of 2a1 to the recovered 1a1 (in
parentheses) was determined by 1H NMR analysis of crude product. d Reaction
was complete in 17 h. e Fe(NO3)3 9H2O was used. f 1,3-Dichloropropane.
3
g Trace amount of 2a1 was detected by TLC. h Under nitrogen atmosphere. i The
ratio of 2a1/2a-OH/1a1 was determined by 1H NMR analysis of crude product.
As summarized in Scheme 1, substrates 1b with different
directing groups were subjected to the optimal conditions
(Table 1, entry 3). The chelating group appeared to be
essential for the nitration because no reaction was observed
for 3- and 4-phenylpyridine (2b1 and 2b2). Clearly, a
suitable directing group was necessary to achieve both high
reaction efficiency and high yields for ortho CÀH nitration
of arenes. For instance, other common directing groups,
including pyrimidine, thiazole, and pyrazole, could be
equally employed to direct ortho CÀH nitration, but
relatively lower yields and longer reaction times are ex-
pected in comparison with the 2-pyridyl group (2b3À2b5).
In addition, o-methyloxime completely failed as a directing
group (2b6). These results are consistent with the capability
of coordination of these directing groups.9 Using quinoline
as the directing group, it was found that benzo[h]quinoline
exclusively gave the desired product 2b7 in 75% yield,
whereas 8-methylquinoline was unreactive (2b8).
efficiency as AgNO3, no reaction occurred with Fe(NO3)3
3
9H2O (entries 11, 12). WithNaNO3, anorthohydroxylated
2a-OH was obtained as the major product7 (entry 13).
Eventually, different solvents were screened, and among
them 1,2,3-TCP exhibited unmatched efficacy for the
nitration. The halogenated alkanes with high boiling point
such as 1,3-dichloropropane (DCP) gave 2a-Cl as the
major product along with a trace amount of 2a1 (entry
14). In addition, 1,4-dioxane, DMSO, and pentanediol all
proved to be unsuitable solvents (entries 15À17). The
importance of dioxygen for a clean and single conversion
was confirmed, since a mixture of 1a1, 2a1, and 2a-OH was
obtained in nearly equal amount under nitrogen atmo-
sphere (entry 18). Consequently, the reaction conditions in
entry 3 were endorsed as optimal and subjected to further
investigations. Obviously, 1,2,3-TCP played a crucial role
in the reaction.8
With a reliable protocol in hand, the scope of the direct
ortho nitration of 2-(hetero)arylpyridines 1a was investi-
gated (Table 2). Under the optimal conditions (Table 1,
entry 3), a variety of 2-(2-nitroaryl)pyridines, bearing either
an electron-donating or electron-withdrawing group at the
2-position (2a2À2a5), 4-position (2a6À2a13), or 3-position
(7) For ortho-hydroxylation of 2-arylpyridines, see: Kim, S. H.; Lee,
H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 5863.
(8) 1,2,3-TCP may act as an oxidant or proton donor like other
chlorinated alkanes: (a) Jin, L.; Xin, J.; Huang, Z.; He, J.; Lei, A. J. Am.
Chem. Soc. 2010, 132, 9607. (b) Ilies, L.; Asako, S.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 7672.
(9) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc.
2008, 130, 13285.
Org. Lett., Vol. 13, No. 24, 2011
6537