Cobalt-Catalyzed Regioselective Ortho C(sp2)-H Bond Nitration of Aromatics through Proton-Coupled Electron Transfer Assistance

Article abstract of DOI:10.1021/acs.joc.7b00808

A cobalt-catalyzed proton-coupled electron transfer (PCET) mediated regioselective ortho-specific nitration of aromatic C(sp²)-H bonds using chelation-assisted removable vicinal diamine directing groups was developed. The reaction proceeded under mild conditions in the presence of Co(OAc)₂·4H₂O as the catalyst with AgNO₂ utilized as the nitro source as well as terminal oxidant in the presence of O₂ as an external oxidant. No external base or additives were required for this process. Controlled experiments and mechanistic investigations with DFT calculations revealed that the reaction proceeds through a PCET promoted nitro functional group transfer pathway. Moreover, the produced compounds are valuable and pharmaceutically quite relevant.

Full text of DOI:10.1021/acs.joc.7b00808

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Article
Cobalt-Catalyzed Regioselective Ortho C(sp2)-H Bond Nitration of
Aromatics Through Proton-Coupled Electron Transfer (PCET) Assistance
Desaboini Nageswar Rao, Sk Rasheed, Gaurav Raina, Qazi Naveed Ahmed,
Chaitanya Kumar Jaladanki, Prasad V. Bharatam, and Parthasarathi Das
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Jun 2017
Downloaded from http://pubs.acs.org on June 21, 2017
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The Journal of Organic Chemistry
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CobaltꢀCatalyzed Regioselective Ortho C(sp2)ꢀH Bond
Nitration of Aromatics Through ProtonꢀCoupled
Electron Transfer (PCET) Assistance
Desaboini Nageswar Rao,a Sk. Rasheed,a Gaurav Raina,a Qazi Naveed Ahmed,a Chaitanya Kumar
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Jaladanki,b Prasad V. Bharatam b and Parthasarathi Das a,*
a Medicinal Chemistry Division, Indian Institute of Integrative Medicine(CSIR), Jammu 180001, India.
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Sector 67, S.A.S. Nagar –160 062, Punjab, India.
Eꢀmail: partha@iiim.ac.in
TOC Graphic
Co(OAc)2.4H2O
(10 mol %)
31 examples
up to 92% yield
Ar
Ar
AgNO2
THF, O2, 80 oC, 6 h
N
N
N
N
H
H
H
NO2
Co-catalysis
DG
DG: 2-aminopyridine/
Base, additive free conditions
31 examples, high yielding
Removable directing groups
Regioselective
Functional group tolerable
Involves PCET reaction
followed by NO2 migration
N
N
pyrimidine/ pyrazine/
pyridazine/ quinoline/
isoquinoline/
III
H
NO2
O
Co
O
O
O
benzothiazole
ABSTRACT
A cobaltꢀcatalyzed protonꢀcoupled electron transfer (PCET) mediated regioselective orthoꢀspecific
nitration of aromatic C(sp2)ꢀH bonds using chelation assisted removable vicinal diamine directing
groups has been developed. The reaction proceeded under mild conditions in the presence of
Co(OAc)2·4H2O as the catalyst and AgNO2 utilized as nitro source as well as terminal oxidant in the
presence of O2 as a external oxidant, no external base and additives were required for this process. By
doing controlled experiments and mechanistic investigations with DFT calculations revealed that the
reaction proceeds through PCET promoted nitro functional group transfer pathway. Moreover the
produced compounds are valuable and pharmaceutically quite relevant.
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INTRODUCTION
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Cobaltꢀcatalyzed crossꢀcoupling reactions received significant attention in past few decades from the
synthetic community as a way to construct carbon–carbon or carbon–heteroatom bonds, because cobalt
catalysts are less expensive, environmentally benign, and possess unique reactivity.1 Thus, the use of a
cobalt catalyst in C–C bondꢀforming reactions has attracted significant attention, mostly leading to
alkylations, alkenylations, and arylations. In recent days, the research groups of Daugulis2, Yoshikai3,
Nakamura4, Kanai5, Ackermann6, Glorius7, Song8, Chang9 and others10 devised cobaltꢀcatalyzed
methods for chelationꢀassisted C−C/C–X bond formation by using different directing groups (DGs) via
C–H bond activation. In comparison with the well established chelationꢀassisted, cobaltꢀcatalyzed C–C
bond formation via direct functionalization of C–H bonds, there are limited examples for direct C–N
bond formation. In this context direct amination/ amidation of CꢀH bonds catalyzed by Co(II)/Co(III)
systems have been studied.11 However, to the best of our knowledge a cobaltꢀcatalyzed direct orthoꢀ
specific CꢀH nitration of arenes is unprecedented.
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Nitroarenes are important building blocks in organic synthesis and very often are essential constituents
of therapeutic and pharmaceutically relevant molecules, as well as being important in the chemical
industry.12 Numerous useful methods for their preparation have been developed, but regioselective
nitration still remains a challenge.13 Recently, transition metalꢀcatalyzed, chelationꢀassisted orthoꢀ
nitrations of aromatic CꢀH bonds have been accomplished.14 Despite these advances, these C–H
nitrations are mostly dominated by expensive secondꢀrow transitionꢀmetal catalysts such as Pd, Rh and
Ru. In particular, two different groups recently established palladium catalyzed ortho nitrations using
AgNO2 as nitro source and K2S2O8 as external oxidant.14fꢀg In these reactions, as anticipated Pd catalyst
requires additives, which is not synthetically efficient and advantageous from an ecological point of
view and no regioselectivity was observed in case of metaꢀsubstituted substrates. Therefore, an
economic, efficient and environmentally benign regioselective orthoꢀspecific nitration method is highly
desirable. As a part of our continuing interest15 in the development of CꢀH activation/functionalization,
we became interested in the cobaltꢀcatalyzed regioselective orthoꢀspecific nitration of arenes. Herein,
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The Journal of Organic Chemistry
we describe the development of a novel cobaltꢀcatalyzed, orthoꢀspecific C–H nitration of synthetically
useful aromatic derivatives. Notable features of our general strategy includes a) 2ꢀaminopyridine can be
used as an unusual ligand, with the design based on a vicinal diamine diꢀcoordinate removable directing
group b) a protonꢀ coupled electron transfer (PCET) reaction followed by a AcOHꢀAcO ion exchange
and nitro functional group transfer. Added advantages of our strategy are; predictable regiocontrol,
challenging C–H/C–N functionalizations with unactivated arenes, a reaction that is normally very
difficult to achieve via traditional approaches (Scheme 1).
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Scheme 1.
Summary of this work
Literature reports
Pd(OAc)2,
K2S2O8, AcOH
N
N
Ar
Ar
ref 14f
ref 14g
AgNO2
AgNO2
DCE, 90 oC, 6 h
N
N
N
N
H
H
H
NO2
Pd(OAc)2, K2S2O8
DCE, 110 oC, 48 h
Ar
O
H
Ar
N
O
N
NO2
Cobalt-catalyzed regioselective ortho-specific nitration (this work)
Co(OAc)2.4H2O
(10 mol %)
31 examples
up to 92% yield
Ar
Ar
AgNO2
THF, O2, 80 oC, 6 h
N
H
N
N
N
H
H
NO2
Co-catalysis
DG
Base, additive free conditions
31 examples, high yielding
Removable directing groups
Regioselective
Functional group tolerable
Involves PCET reaction
followed by NO2 migration
DG: 2-aminopyridine/
N
N
pyrimidine/ pyrazine/
pyridazine/ quinoline/
isoquinoline/
III
H
NO2
O
Co
O
O
O
benzothiazole
RESULTS AND DISCUSSION
To probe the feasibility of this approach, a study was initiated with the reaction between NaNO2 (1.1
equiv) and Nꢀphenyl pyridinꢀ2ꢀamine (1a) by using Co(OAc)2 (10 mol %) in the presence of AgOAc (1
equiv) as oxidant and NaOAc (2 equiv) as base, THF as solvent in O2 atm, at 80 oC for 6 h. Under these
conditions, 2a was isolated in 5% yield (Table 1, entry 1). By changing different nitro sources it was
noted that, with AgNO2 as nitro source, the desired product (2a) obtained in 63% yield (Table 1, entries
2ꢀ3). By changing different external oxidants, no improvement of the isolated yield was observed (Table
1, entries 4ꢀ8). Interestingly, in the absence of NaOAc as the base, the product yield increased to 85%
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(Table 1, entry 9). When the reaction was performed without adding any external oxidant, the desired
product was isolated in 70% yield (Table 1, entry 10). This indicates that AgNO2 was acting as nitro
source as well as an oxidant. When the AgNO2 conc. is increased to 1.5 equiv the ortho nitration
product was obtained with 92% yield (Table 1, entry 11). By decreasing the reaction temperature, a
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o
reduction in the yield was observed (Table 1, entries 12–13), indicating that 80 C is optimal
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temperature for this transformation. Under openꢀair conditions, the yield dropped to 60% and
incomplete conversion noticed. A poor yield (30%) was observed under N2 atm (Table 1, entries 14–
15), suggesting that O2 atm is necessary for this reaction. There is no reaction in the absence of
Co(OAc)2.4H2O (Table 1, entry 16). Using different solvents (DMF/toluene) instead of THF did not
improve the yield (Table 1 entries 17ꢀ18). The C–H nitration of arenes using different directing groups
(Fig. 1, A–M), was inefficient under the same optimized reaction conditions. However, reactions with
substrates having vicinal diamine system (3a-g) were found compatible to reaction conditions. This
establishes the unique property of vicinal diamines as removable directing groups for the selective
orthoꢀnitration of aromatics with interesting biological properties16 under described reaction conditions.
Table 1. Optimization of Co-catalyzed aromatic C(sp2)-H nitration reaction of substrate 1a.a
H
H
N
Co(OAc)2.4H2O (10 mol %)
oxidant (1 equiv)
N
[NO2]
source
N
N
base (2 equiv)
THF, 80 oC, 6 h
O2 atm
NO2
H
1a
2a
entry
[NO2] source
oxidant
base
yieldb (%) 2a
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3
4
5
6
7
8
9
NaNO2
AgNO3
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgOAc
AgOAc
AgOAc
Ag2O
Ag2CO3
BQ
AgOTf
K2S2O8
AgOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
--
5
40
63
61
50
40
60
30
85
10
11c
12d
13e
14f
15g
16h
17i
18j
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
--
--
--
--
--
--
--
-
--
--
--
--
--
--
--
-
70
92
75
20
60
30
n.r.
30
15
-
-
a Reaction conditions: 1a (0.29 mmol), [NO2] source (1.1 equiv), Co(OAc)2.4H2O (10 mol%), oxidant (1 equiv), base (2.0 equiv), solvent
(1.5 mL), 80 oC, in O2 atm, 6 h; bisolated yield; cAgNO2 (1.5 equiv); dAgNO2 (1.5 equiv), reaction at 60 oC; eAgNO2 (1.5 equiv), reaction at
f
g
i
j
rt; AgNO2 (1.5 equiv), reaction in air; AgNO2 (1.5 equiv), reaction in N2 atm; h without cobaltꢀcatalyst, DMF used as solvent; toluene
used as solvent.
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The Journal of Organic Chemistry
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OCH3
N
N
H
H
4
N
CH3
N
X
5
6
O
O
7
8
X = N: D, 0%
X = C: E, 0%
B: dec.
A: 0%
C: 0%
9
N
H
O
S
H
N
N
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N
N
N
O
O
OCH3
I: trace
F: 0%
G: 0%
H: 0%
O
O
O
O
OMe
N
H
N
N
H
N
O
N
H
N
H
N
M
: trace
J: 0%
K: 0%
L: 0%
H
H
N
H
N
N
N
N
N
N
N
R
H3C
NO2
3a
NO2
NO2
R = H: , 88%
3d, 78%
3c, 88%
3b
R = CH3: , 92%
H
N
H
N
H
N
S
N
N
N
N
H3C
H3C
Cl
NO2
NO2
NO2
3e, 75%
3f,85%
3g, 70%
Figure 1. Screening of different directing groups for the aromatic C(sp2)-H nitration reaction. dec.=
decomposed.
With these optimized reaction conditions in hand, we probed the substrate scope for the nitration of Nꢀ
phenylpyridinꢀ2ꢀamines (1a–x). As shown in Scheme 2, a wide variety of functionalized aromatic
amines bearing both electronꢀrich (2b–2d) and electronꢀdeficient (2e–2i) functional groups in the paraꢀ
position afforded coupling products in good yields (73–90%), indicating that the electronic nature of the
aromatics have no influence on the reaction. For metaꢀsubstituted substrates, the reactions proceeded
with complete selectivity for the less hindered orthoꢀposition with good yields (2j–m; 70–77%).
Notably, the fluoro, chloro, and bromo functional groups are well tolerated under this reaction
conditions. The functional group at the orthoꢀposition did not inhibit the transformation, as the desired
nitro product was obtained in good yield (2n, 88%). A similar orthoꢀproduct was obtained for the
methylenedioxy compound (2o, 80%). Disubstituted substrates bearing methyl, methoxy, and nitro
groups at the 3, 4-positions provided the orthoꢀproducts (2p and 2q) in good yields 70–72%. Similarly,
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disubstituted substrates bearing fluoro, chloro, and bromo groups at different positions provided the
orthoꢀnitrated products in good yields (2rꢀt; 70ꢀ78%). In case of the naphthyl group, the mono nitration
product (2u) was obtained in 74% yield. In this context substituted pyridines also tested. In the case of
methylꢀsubstitution the yield is 92% (2w), while the bromo derivative gave the orthoꢀproduct (2v) with
decreased yield (78%). The heterocyclic substrate also underwent smooth nitration and afforded the
product (2x) in 68% yield.
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In continuation to nitration, we tried to extend the concept for C–H methoxylation of aromatics. For this
reason, we tested the reaction of 1a with Co(OAc)2.4H2O (10 mol %) and Ag2O (1.5 equiv) in MeOH
(1.5 mL)in O2 atm for 6 h, and the orthoꢀmethoxylated product 4 was isolated in 82% yield (Scheme 3).
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Scheme 3.
Ortho-methoxylation of aromatic C-H bond
H
N
H
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Co(OAc)2.4H2O (10 mol %)
Ag2O (1.5 equiv)
N
N
N
MeOH (1.5 mL)
80 oC, 6 h, O2 atm
OMe
H
4
, 82%
1a
Next, we applied our transformations in the rapid synthesis of biologically active compounds (Scheme
4). Selective reduction of 2a and 3a, carried out by the treatment with Zn dust/NH4Cl in MeOH at 80 oC
for 4 h, gave reduced compounds 5 and 6 in 75% and 70% yields, respectively. Using 10% Pd/C, at 1
atm of H2 in MeOH for 2 hours at room temperature gave a 95% yield. These reduced amines (5 or 6)
could be used for the rapid synthesis of biologically active compounds COX–II inhibitors17 and
monoamine reuptake inhibitors.18
Scheme 4.
Synthesis of bioactive compounds
X = N
condition A
X = CH
condition A
N
Zn (3 equiv)
Zn (3 equiv)
N
N
NH4Cl (3 equiv), MeOH
80 oC, 4 h, 75%
NH4Cl (3 equiv), MeOH
80 oC, 4 h, 70%
NH
X
NH
N
NH
NH2
NO2
NH2
condition B
10% Pd/C, H2, MeOH
rt, 2h, 95%
condition B
10% Pd/C, H2, MeOH
rt, 2h, 95%
5
6
X = CH or N
2a 3a
or
O
N
N
Cl
X
N
(NH2)2SO2
X
O
X
NH
(MeOCH2CH2)2O
N
N
O
S
NH2 PhMe, 13 h
10 min reflux
then cooled
N
NH
rt - reflux
ref 17
ref 18
X = CH or N
X = N or CH
X = CH or N
(monoamine reuptake inhibitors)
(COX-II inhibitors)
5
6
or
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The removal of the directing groups was necessary to emphasize the efficiency of the method. The
cleavage of pyrimidine and pyridine rings was performed in two steps; first reduction by triethylsilane
in TFA at 50 °C for 4 h, then treatment with N2H4/AcOH in MeOH at rt for 15 h, which produced oꢀ
nitro aniline 7 in 72% yield. In another study, the reductive cleavage of pyrimidine and pyridine rings
produced benzeneꢀ1,2ꢀ diamine 8 in 75% yield, reduced by Pd/C, H2 1atm, and HCl in isopropanol at rt
for 16 h, followed by treatment with N2H4/AcOH in EtOH at 120 oC for 30 min (Scheme 5).
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Scheme 5.
Removal of the pyridine and pyrimidine directing groups
N
(i) Et3SiH, TFA
50 oC, 4 h
(i) Pd/C, H2 (1 atm), HCl
iPrOH, rt, 16 h
NH2
NH2
NH2
X
NH
NO2
(ii) N2H4H2O, AcOH
MeOH, rt, 15 h
NO2
(ii) NH2NH2.H2O, AcOH
o
EtOH, 120 C, 30 min
7, 72%
8,75%
X = CH or N
2a 3a
or
To gain insight into the mechanism of the C−H nitration reactions, a series of control experiments were
conducted (Scheme 6). In experiment (eq1), the addition of TEMPO (2 equiv) as a radical quencher
completely inhibit the reaction. This indicates the reaction may involve a radical process.19 To explore
further the electronic effect on the rate of the reaction, we performed intermolecular competition
experiments between 1b and 1h under the optimized conditions, which somewhat favors the electronꢀ
rich arene in a 1.1:1 ratio of 2b and 2h (eq 2). This suggested that direct cobaltation of arene C–H bonds
is not happening. In another set of reactions, with different substrates 9, 10, 11 and 12 under standard
conditions, no product formation was observed (eq 3ꢀ6), that confirmed that a free NH group is
essential. The kinetic isotope effect was also determined. A 1:1 mixture of [D3]-1a and 1a was treated
with AgNO2. No kinetic isotope effect (KIE; KH /KD=1) was obtained (eq 7), indicating that C-H bond
cleavage of the arenes is not the rate limiting step.
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3
Scheme 6. Control and kinetic experiments
4
5
6
7
8
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
H
H
N
N
(eq 1)
THF, 80 oC, 6 h, O2 atm
N
N
NO2
H
TEMPO
9
TEMPO (2 equiv) = 2a, 0%
1a
10
11
12
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H
H
N
N
N
N
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
H3C
H
H3C
NO2
1b
1h
(0.5 equiv)
(eq 2)
THF, 80 oC, 6 h, O2 atm
H
N
H
N
N
H
N
F3C
F3C
NO2
2b:2h = 1.1:1
(0.5 equiv)
CH3
N
CH3
N
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
(eq 3)
(eq 4)
THF, 80 oC, 6 h, O2 atm
N
N
H
9
NO2
No reaction
H3C
O
H3C
O
N
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
N
N
N
THF, 80 oC, 6 h, O2 atm
NO2
H
10
No reaction
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
(eq 5)
(eq 6)
N
N
THF, 80 oC, 6 h, O2 atm
H
NO2
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No reaction
O
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
O
THF, 80 oC, 6 h, O2 atm
N
N
NO2
H
No reaction
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D
H
D
Co(OAc)2.4H2O (10 mol %)
AgNO2 (1.5 equiv)
H
N
N
(eq 7)
1a
(0.5 equiv)
2a
THF, 80 oC, 3 h, O2 atm;60%
N
N
D
NO2
D
D
kH/kD = 1.0
[D2]-2a
[D3]-1a
(0.5 equiv)
By considering all these observations, and to elucidate the mechanism of reaction outlined below,
quantum chemical (Density Functional Theory, DFT) calculations were employed (Scheme 7). The
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entire reaction mechanism study was performed using a model compound Nꢀphenylꢀ2ꢀaminopyridine
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(NPA). The entire reaction is classified into four steps (i) an initial PCET reaction, (ii) AcOHꢀAcO ion
exchange, (iii) nitro functional group transfer and (iv) final Hꢀabstraction to form a nitro product,1,20
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Initially, precatalyst Co(II)(OAc)2 gets convert to the Co(III)(OAc)2(NO2) in the presence of AgNO2.
The catalyst Co(III)(OAc)2(NO2) forms an initial reactant complex (RC) by the coꢀordination with Nꢀ
arylꢀ2ꢀaminopyridine, which is more stable by ~3.49 kcal/mol. The RC is characterized by a Co(III)
center in an octahedral arrangement (one bidentate acetate, one monodentate acetate, nitro and reactant
A (bidentate)); it is also characterized by an AcOꢀꢀꢀHꢀN hydrogen bond which facilitates the hydrogen
radical abstraction process (See Supporting Information for the 3D structures). The energy barrier for
the hydrogen radical abstraction reaction is 1.13 kcal/mol via TS1, the resultant complex (I1) is
marginally endergonic (0.35 kcal/mol). The molecular orbital analysis of the transition state showed that
the abstraction of hydrogen follows a protonꢀcoupled electron transfer (PCET) mechanism. This is
evident from the fact that the molecular orbital’s are localized on the lone pair of nitrogen rather than
the breaking NꢀH bond, such mechanism was reported for Hꢀabstraction reaction from NꢀH bond.1 In
PCET reaction the proton transfer to acetate and the electron delocalized to the cobalt metal (Co (III)
reduced to Co (II)). To verify whether an SET (Single Electron Transfer) process is involved, TDꢀDFT
(B3LYP) calculations were performed, such mechanism has been reported in the cobalt catalysis.1 The
energy barrier required for the transfer of electron is ~35 kcal/mol; this value is much larger than the
energy barrier for Hydrogen transfer process by a PCET (1.13 kcal/mol) reaction. Thus, the molecular
orbital analysis, as well as the energy profile of the reaction, confirmed that the Hꢀabstraction reaction
follows a PCET process rather than an SET mechanism. The energy barrier for the transfer of nitro
group from cobalt center (Co(II)) to phenyl group is found to be very high (~45 kcal/mol) from I1, thus,
it is found worth to consider Co(III) center. Hence, the possibility of acetic acid group exchange with
an acetate ion [forms a complex I2 (a Co(III) species with the octahedral arrangement)] is considered,
and this is an endergonic process by ~12.55 kcal/mol. I2 is characterized by an Ar–HꢀꢀꢀOAc interaction
and the 3D arrangement of atoms is suitable for NO2 group transfer. The radical is delocalized on the
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The Journal of Organic Chemistry
aniline ring, which has been confirmed by spin density calculations (the total spin density at the aniline
ring is 1.2, which indicates that the aniline ring is adapting radical character). The transfer of nitro
functional group from I2 is only about 13.11 kcal/mol via TS2 (which is much lesser than from I1),
leads to the generation of an intermediate complex I3, giving a square planar arrangement at Co(II)
center. This is an exergonic process by ~5.07 kcal/mol. This is a rate limiting step for the nitration
reaction. In I3, the reactive ortho carbon (of aryl group) adopts sp3 hybridization (tetrahedral carbon)
and the outgoing hydrogen atom is oriented towards an acetate ligand, which facilitates Hꢀtransfer
process. This Hꢀtransfer reaction leading to the formation nitro intermediate I4 (which is an exergonic
process by 22.35 kcal/mol), the energy barrier required for the Hꢀtransfer is 5.06 kcal/mol. In the I3 →
I4 reaction, no change in the radical character at the metal center is observed (the spin density at Co
center is 1 in both the intermediates I3 and I4). Further, the proton transfers (via a PCET process) to the
iminoꢀfunctional group from AcOH (requires a small barrier of 0.68 kcal/mol via TS4) leads to the
formation of I5, this is a slightly exergonic process (ꢀ1.53 kcal/mol). Intermediate I5 does not carries
any radical (during PCET process, the proton moves to nitrogen atom and electron moves to Co center
so radical gets neutralized). Finally, the complex I5 dissociate to nitro product and Co(OAc)2, which is
an exergonic process (10.48 kcal/mol). Overall, this cobalt cycle is an exergonic process ~30.02
kcal/mol, all the intermediate steps can be explained in terms of least motion pathways, supporting the
proposed mechanism and 3D structures of intermediate complexes are provided in Supporting
Information.
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Scheme 7.
Plausible reaction mechanism with DFT calculations (the energy values are in kcal/mol).
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CONCLUSIONS
In conclusion, we have developed the first cobaltꢀcatalyzed orthoꢀspecific nitration of aromatic C(sp2)ꢀ
H bonds using 2ꢀaminopyridine as the vicinal diamine, removable directing group. In this process,
AgNO2, acts as a nitro source as well as an oxidant. This rare Coꢀcatalyzed protocol showed broad
substrate scope, excellent functional group tolerance, and high regioselectivity, thus providing an
appealing approach to the synthesis of orthoꢀnitro derivatives with challenging substitution patterns.
The detailed studies on controlled experiments and mechanistic investigations with DFT calculations
revealed that the reaction proceeds through protonꢀcoupled electron transfer (PCET) promoted nitro
functional group transfer pathway. Finally, we believe this finding will contribute to the expansion of
the repertoire of cobalt catalysis.
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The Journal of Organic Chemistry
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EXPERIMENTAL SECTION
General Information:
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All purchased chemicals were used without further purification. All the starting substrates were
prepared according to literature reported methods. Microwave reactions were carried out under CEM
discover monomode microwave synthesizer (method of monitoring the reaction mixture temperature is
external surface sensor). All reactions were performed under oxygen balloon atmosphere. THF was
distillated with sodium metal. Analytical thin layer chromatography was performed using TLC preꢀ
coated silica gel 60 F254 MERCK (20x20 cm). TLC plates were visualized by exposing UV light or by
iodine vapors. Organic solutions were concentrated by rotatory evaporation on BUCHIꢀSwitzerland; Rꢀ
120 rotatory evaporator and vacuum pump Vꢀ710. Flash column chromatography was performed on
Merck flash silica gel 100ꢀ200 mesh size. Melting points of solid compounds were determined on
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BUCHIꢀBꢀ545ꢀSwitzerland melting point apparatus. H and 13C NMR spectra were recorded with
BRUKER 500 and 400 MHz NMR instruments. Proton and carbon magnetic resonance spectra (1H
NMR and 13C NMR) were recorded using tetramethylsilane (TMS) in the solvent of CDCl3 as the
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internal standard (1H NMR: TMS at 0.00 ppm, CHCl3 at 7.24 ppm; C NMR: CDCl3 at 77.0 ppm) or
were recorded using tetramethylsilane (TMS) in the solvent of DMSOꢀd6 as the internal standard (1H
NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm;13C NMR: DMSO at 40.0 ppm) or were recorded using
tetramethylsilane (TMS) in the solvent of Acetoneꢀd6 as the internal standard (1H NMR: TMS at 0.00
ppm, Acetone at 2.09 ppm;13C NMR: Acetone at 29.9 ppm, 206.7 ppm). All the NMR spectra were
processed in MestReNova. HRMS spectra were recorded with LCMSꢀQTOF Module No. G6540 A
(UHD) instrument.
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General Procedure for the Co-catalyzed C(sp2)-H bond nitration of aromatics
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To an oven dried 25 mL twoꢀnecked round bottomed flask with refluxing condenser connected with an
oxygen balloon. To this flask a solution of Nꢀarylꢀ2ꢀaminoheterocycles (1.0 equiv) in THF (1.5 mL) was
added, Co(OAc)2.4H2O (0.1 equiv) and AgNO2 (1.5 equiv), were also added sequentially at room
temperature with stirring. The flask was evacuated with oxygen balloon after it was closed with septa,
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o
and the reaction mixture was stirred at 80 C temperature under an oxygen balloon atmosphere for 6 h.
The progress of the reaction was monitored by TLC and after completion of the reaction. THF was
evaporated in vacuo and then 10 mL of water was added to the reaction mixture at room temperature.
The mixture was extracted with EtOAc (10 mL) further extracted two times with EtOAc (2 x 10 mL)
and the combined organic phase was washed with sat. aq. NaHCO3 dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by column chromatography to give pure ortho specific nitrated
Nꢀarylꢀ2ꢀamino heterocycles (2a–x, 3a-g).
N-(2-Nitrophenyl)pyridin-2-amine (2a)23: Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 58 mg
o
1
(92%). Yellow solid, m.p. 157ꢀ159 C; H NMR (400 MHz, Acetone–d6) δ = 9.04 (s, 1H), 8.18 (d,
J=4.2, 1H), 8.02 (d, J=7.1, 2H), 7.88 (d, J=9.1, 2H), 7.55 (t, J=7.3, 1H), 6.86 (d, J=8.3, 1H), 6.84 – 6.78
(m, 1H);13C NMR (125 MHz, Acetone–d6) δ = 166.1, 155.7, 149.2, 148.3, 141.1, 138.6, 130.3, 125.8,
117.5, 117.4, 113.1; HRMS(ESI): calcd. for C11H10N3O2[M+H]+, 216.0768; found: 216.0770.
N-(4-Methyl-2-nitrophenyl)pyridin-2-amine (2b): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
55 mg (88%). Yellow solid, m.p. 88ꢀ90 oC; 1H NMR (400 MHz, CDCl3) δ = 8.15 (d, J=3.9, 1H), 7.51 –
7.42 (m, 1H), 7.31 (S, 1H), 7.23 (d, J=1.7, 1H), 7.20 (d, J=8.4, 1H), 7.14 (d, J=8.3, 1H), 6.82 (d, J=8.5,
1H), 6.70 (t, J=6.4, 1H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 156.4, 148.0, 146.8, 137.9,
133.3, 130.2, 129.9, 123.2, 121.3, 114.5, 107.8, 20.8; HRMS(ESI): calcd. for C12H12N3O2[M+H]+,
230.0924; found:230.0925.
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N-(4-Methoxy-2-nitrophenyl)pyridin-2-amine (2c): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
52 mg (87%). Yellow solid, m.p. 74ꢀ76 oC; 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.69 (d, J = 9.4
Hz, 1H), 8.36 – 8.21 (m, 1H), 7.67 (d, J = 3.1 Hz, 1H), 7.60 (td, J = 8.2, 1.9 Hz, 1H), 7.22 (dd, J = 9.4,
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3.1 Hz, 1H), 6.90 (t, J = 7.0 Hz, 2H), 3.85 (s, 3H); C NMR (125 MHz, CDCl3) δ = 157.1, 156.4,
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147.6, 138.0, 132.9, 128.03, 124.3, 114.9, 114.6, 114.1, 107.3, 55.5; HRMS(ESI): calcd. for
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C12H12N3O3[M+H]+, 246.0873; found: 246.0870.
N-(4-Ethoxy-2-nitrophenyl)pyridin-2-amine (2d): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
o
52 mg (85%). Yellow solid, m.p. 112ꢀ114 C; 1H NMR (400 MHz, CDCl3) δ = 11.76 (s,1H), 8.58 (dd,
J=8.3, 1.8, 1H), 8.47 (dd, J=4.5, 1.8, 1H), 8.37 (d, J=9.3, 1H), 7.66 (d, J=3.0, 1H), 7.25 – 7.19 (m, 1H),
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7.01 – 6.81 (m, 2H), 4.11 (q, J=7.0, 2H), 1.46 (t, J=7.0, 3H); C NMR (125 MHz, CDCl3) δ = 155.6,
147.9, 145.9, 137.6, 127.9, 122.9, 121.7, 117.6, 114.8, 111.3, 110.3, 55.6, 22.5; HRMS(ESI): calcd. for
C13H14N3O3[M+H]+, 260.1030; found:260.1035.
N-(4-Bromo-2-nitrophenyl)pyridin-2-amine (2e): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
42 mg (73%). Yellow solid, m.p. 168ꢀ170 oC; 1H NMR (400 MHz, CDCl3) δ = 8.24 (d, J=3.7, 1H), 8.13
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(d, J=8.7, 2H), 7.52 (d, J=8.4, 2H), 7.27 (d, J=7.8, 1H), 6.88 (d, J=7.6, 2H); C NMR (125 MHz,
CDCl3) δ = 153.6, 147.6, 141.3, 138.5, 133.3, 132.6, 125.6, 123.6, 117.2, 117.0, 111.3; HRMS(ESI):
calcd. for C11H9BrN3O2[M+H]+, 293.9873; found: 293.9875.
N-(4-Chloro-2-nitrophenyl)pyridin-2-amine (2f): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
o
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48 mg (78%). Yellow solid, m.p. 150ꢀ152 C; H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1H), 8.20 (d,
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J=9.3, 1H), 7.43 (s, 1H), 7.31 (br, 4H), 6.69 (d, J=9.2, 1H); C NMR (100 MHz, CDCl3) δ = 170.1,
158.0, 145.3, 137.3, 136.3, 135.6, 132.4, 129.5, 128.6, 122.4, 106.0; HRMS(ESI): calcd. for
C11H9ClN3O2[M+H]+, 250.0378; found:250.0376.
N-(4-Fluoro-2-nitrophenyl)pyridin-2-amine (2g): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
o
45 mg (76%). Yellow solid, m.p. 182ꢀ184 C; 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.90 (dd, J
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= 9.6, 5.1 Hz, 1H), 8.32 (dd, J = 5.0, 1.2 Hz, 1H), 7.92 (dd, J = 8.9, 3.1 Hz, 1H), 7.63 (ddd, J = 8.2, 7.4,
1.9 Hz, 1H), 7.34 (ddd, J = 9.8, 7.1, 3.1 Hz, 1H), 6.95 (ddd, J = 7.3, 5.0, 0.8 Hz, 1H), 6.90 (d, J = 8.3
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Hz, 1H); C NMR (125 MHz, CDCl3) δ = 161.4, 159.6, 159.5 (d, J=12.9),151.9, 146.2, 144.4, 137.0,
133.6, 125.1 (d, J=8.3), 116.6 (d, J=22.8), 106.4; HRMS(ESI): calcd. for C11H9FN3O2[M+H]+,
234.0674; found:234.0675. 159.5 (d, J = 12.9 Hz).
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N-(2-Nitro-4-(trifluoromethyl)phenyl)pyridin-2-amine (2h): Eluent: Petroleum ether/ethyl acetate
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(7:3). Yield: 45 mg (75%). Yellow solid, m.p. 130ꢀ132 C; H NMR (400 MHz, CDCl3) δ = 9.14 (d,
J=2.5, 1H), 8.32 (dd, J=9.2, 2.6, 1H), 7.67 – 7.60 (m, 4H), 7.43 (s, 1H), 6.85 (d, J=9.2, 1H); 13C NMR
(125 MHz, CDCl3) δ = 158.8, 145.9, 142.6, 137.1(d, J=2.5), 132.4, 127.4 (q, J=5.6), 126.1 (d, J=3.2),
125.3, 123.1, 119.7, 117.0, 110.0 (d, J=1.7); HRMS(ESI): calcd. for C12H9F3N3O2[M+H]+, 284.0643;
found:284.0648.
N-(2-Nitro-4-(trifluoromethoxy)phenyl)pyridin-2-amine (2i): Eluent: Petroleum ether/ethyl acetate
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(7:3). Yield: 47 mg (80%). Yellow solid, m.p. 110ꢀ112 C; H NMR (400 MHz, CDCl3) δ 10.18 (s,
1H), 8.97 (d, J = 9.5 Hz, 1H), 8.34 (dd, J = 4.9, 1.2 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.67 (ddd, J = 9.2,
8.3, 4.1 Hz, 1H), 7.44 (dd, J = 9.5, 2.7 Hz, 1H), 6.99 (ddd, J = 7.2, 5.0, 0.7 Hz, 1H), 6.94 (d, J = 8.2 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ = 159.1, 146.4, 146.0, 137.3, 136.7, 133.5, 128.8 (q, J=7.5), 123.3,
122.3, 121.5, 119.4, 107.2; 19F NMR (376 MHz, CDCl3) δ ꢀ58.51; HRMS(ESI): calcd. for
C12H9F3N3O3[M+H]+, 300.0590; found:300.0611.
N-(2,5-Dinitrophenyl)pyridin-2-amine (2j): Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 47 mg
(77%). Yellow solid, m.p. 216ꢀ218 oC; 1H NMR (400 MHz, Acetone–d6) δ = 9.63 (s, 1H), 9.02 (s, 1H),
8.75 (s, 1H), 8.25 (dd, J=9.2, 2.1, 1H), 8.02 (d, J=8.1, 1H), 7.80 (d, J=8.1, 1H), 7.52 (d, J=8.1, 1H), 6.95
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(d, J=9.2, 1H); C NMR (125 MHz, Acetone–d6) δ = 159.6, 149.6, 146.2, 142.0, 138.6, 133.6, 130.8,
126.2, 118.0, 114.7, 111.8; HRMS(ESI): calcd. for C11H9N4O4[M+H]+, 261.0619; found:261.0620.
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N-(5-Chloro-2-nitrophenyl)pyridin-2-amine (2k): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
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46 mg (75%). Yellow solid, m.p. 146ꢀ148 C; H NMR (400 MHz, DMSO–d6) δ = 9.48 (s, 1H), 8.21
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(d, J=3.9, 1H), 8.09 (d, J=2.0, 1H), 7.92 (d, J=9.2, 1H), 7.70 – 7.62 (m, 1H), 7.58 – 7.51 (m, 1H), 6.87
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(d, J=8.3, 1H), 6.85 – 6.79 (m, 1H); C NMR (125 MHz, DMSO–d6) δ = 153.9, 146.7, 146.7, 137.8,
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137.2, 128.5, 127.2, 118.4, 116.2, 114.9, 112.1; HRMS (ESI): calcd. for C11H9ClN3O2[M+H]+,
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250.0378; found:250.0372.
N-(5-Fluoro-2-nitrophenyl)pyridin-2-amine (2l): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
42 mg (70%). Yellow solid, m.p. 178ꢀ180 oC; 1H NMR (400 MHz, CDCl3) δ = 8.34 (d, J=4.3, 1H), 8.08
(t, J=8.8, 1H), 7.80 (dd, J=14.1, 2.3, 1H), 7.69 – 7.63 (m, 1H), 7.26 (s, 1H), 7.12 (dd, J=9.3, 1.9, 1H),
6.97 (dd, J=7.0, 5.1, 1H), 6.90 (d, J=8.3, 1H); 13C NMR (125 MHz, CDCl3) δ = 158.5, 156.4, 154.2,
149.3, 147.5, 137.6, 128.0, 127.2(d, J=1.0 ), 117.0, 112.6(d, J=3.8), 104.8 (d, J=26.8); HRMS(ESI):
calcd. for C11H9FN3O2[M+H]+, 234.0673; found:234.0670.
N-(2-Nitro-5-(trifluoromethyl)phenyl)pyridin-2-amine (2m): Eluent: Petroleum ether/ethyl acetate
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(7:3). Yield: 42 mg (70%). Yellow solid, m.p. 144ꢀ146 C; H NMR (400 MHz, MeOD) δ = 8.99 (d,
J=2.5, 1H), 8.21 (dd, J=9.3, 2.7, 1H), 8.08 (s, 1H), 7.81 (d, J=7.8, 1H), 7.41 (t, J=8.0, 1H), 7.23 (d,
J=7.7, 1H), 6.78 (d, J=9.3, 1H); 13C NMR (125 MHz, CDCl3) δ = 155.0, 149.5, 140.8 (d, J=2.5), 138.3,
132.4, 130.9, 128.7, 127.4 (dd, J=6.7, 1.8), 123.1, 117.0, 114.6 (d, J=5.6), 111.1 (d, J=2.8);
HRMS(ESI): calcd. for C12H9F3N3O2[M+H]+, 284.0641; found:284.0645.
N-(2-Methyl-6-nitrophenyl)pyridin-2-amine (2n): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
o
1
55 mg (88%). Yellow solid, m.p. 126ꢀ128 C; H NMR (400 MHz, CDCl3) δ = 8.41 – 8.28 (m, 1H),
8.10 (s, 1H), 8.08 (d, J=2.6, 1H), 8.03 – 7.96 (m, 1H), 7.64 (ddd, J=8.3, 7.3, 1.9, 1H), 6.99 (d, J=8.3,
1H), 6.94 (ddd, J=7.3, 5.0, 0.8, 1H), 6.66 (s, 1H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ = 153.8,
148.5, 145.3, 138.2, 126.3, 125.9, 123.4, 117.4, 116.0, 115.1, 111.3, 17.9; HRMS(ESI): calcd. for
C12H12N3O2[M+H]+, 230.0924; found: 230.0920.
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N-(6-Nitrobenzo[d][1,3]dioxol-5-yl)pyridin-2-amine (2o): Eluent: Petroleum ether/ethyl acetate (7:3).
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o
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Yield: 49 mg (80%). Yellow solid, m.p. 142ꢀ144 C; H NMR (400 MHz, CDCl3) δ = 8.18 (dd, J=5.0,
1.2, 1H), 7.45 – 7.38 (m, 1H), 6.75 (s, 1H), 6.72 (d, J=2.1, 1H), 6.67 (d, J=2.1, 1H), 6.65 (d, J=2.2, 1H),
6.63 (s, 1H), 5.96 (s, 2H); 13C NMR (125 MHz, CDCl3) δ = 148.3, 148.0, 145.0, 140.0, 137.3, 120.1,
115.1, 112.1, 108.7, 108.3, 101.4, 79.3; HRMS(ESI): calcd. for C12H10N3O4[M+H]+, 260.0666; found:
260.0660.
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N-(4-Methoxy-5-methyl-2-nitrophenyl)pyridin-2-amine (2p): Eluent: Petroleum ether/ethyl acetate
(7:3). Yield: 42 mg (71%). Yellow solid, m.p. 160ꢀ162 oC; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H),
8.59 (d, J = 9.5 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 3.1 Hz, 1H), 7.42 (dd, J = 8.3, 2.3 Hz,
1H), 7.19 (dd, J = 9.5, 3.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.82 (s, 3H), 2.27 (s, 3H); 13C NMR (125
MHz, CDCl3) δ = 153.4, 148.1, 138.2, 132.6, 129.9, 125.2, 121.8, 117.8, 113.1, 110.6, 108.0, 56.3, 17.3;
HRMS(ESI): calcd. for C13H14N3O3[M+H]+, 260.1030; found: 260.1035.
N-(5-Methyl-2,4-dinitrophenyl)pyridin-2-amine (2q): Eluent: Petroleum ether/ethyl acetate (7:3).
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1
Yield: 42 mg (70%). Yellow solid, m.p. 132ꢀ134 C; H NMR (400 MHz, CDCl3) δ = 9.14 (d, J=2.4,
1H), 8.32 (d, J=6.5, 1H), 8.21 (s, 1H), 7.66 (d, J=8.2, 1H), 7.37 (d, J=8.2, 1H), 7.31 (s, 1H), 6.78 (d,
13
J=9.2, 1H), 2.05 (s, 3H); C NMR (125 MHz, CDCl3) δ = 158.8, 151.0, 146.0, 144.0, 136.1, 133.0,
132.3, 124.6, 122.5, 121.7, 115.8, 17.0; HRMS(ESI): calcd. for C12H11N4O4[M+H]+, 275.0774;
found:275.0772.
N-(4,5-Dichloro-2-nitrophenyl)pyridin-2-amine (2r): Eluent: Petroleum ether/ethyl acetate (7:3).
o
Yield: 45 mg (77%). Yellow solid, m.p. 196ꢀ198 C; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 9.29
(s, 1H), 8.39 (dd, J = 5.0, 1.3 Hz, 1H), 8.35 (s, 1H), 7.73 – 7.56 (m, 1H), 7.01 (ddd, J = 7.3, 5.0, 0.7 Hz,
1H), 6.93 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, Acetone–d6) δ = 159.5, 146.2, 140.7, 133.4, 132.7,
131.3, 125.8, 121.8, 120.4, 118.1, 111.6; HRMS(ESI): calcd. for C11H8Cl2N3O2[M+H]+, 283.9988;
found:283.9985.
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N-(5-Chloro-4-fluoro-2-nitrophenyl)pyridin-2-amine (2s): Eluent: Petroleum ether/ethyl acetate
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o
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(7:3). Yield: 43 mg (72%). Yellow solid, m.p. 186ꢀ188 C; H NMR (400 MHz, MeOD) δ = 8.96 (d,
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J=2.5, 1H), 8.19 (dd, J=9.3, 2.8, 1H), 7.92 (dd, J=6.7, 2.7, 1H), 7.48 – 7.38 (m, 1H), 7.11 (t, J=9.0, 1H),
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6.75 – 6.67 (m, 1H); C NMR (125 MHz, CDCl3) δ = 156.3, 154.3, 151.9, 148.6 (d, J=28.2), 144.4,
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138.8, 137.0, 135.1, 128.4 (d, J=7.2), 120.1 (d, J=20.5), 106.4; HRMS(ESI): calcd. for
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C11H8ClFN3O2[M+H]+, 268.0284; found: 268.0285.
N-(2,4-Dibromo-6-nitrophenyl)pyridin-2-amine (2t): Eluent: Petroleum ether/ethyl acetate (7:3).
Yield: 39 mg (70%). Yellow solid, m.p. 150ꢀ152 oC; 1H NMR (400 MHz, CDCl3) δ = 9.07 (s, 1H), 8.26
(d, J=7.0, 1H), 7.58 (s, 1H), 7.40 (d, J=7.4, 1H), 7.25 (s, 1H), 7.03 (s, 1H), 6.74 (d, J=9.3, 1H); 13C
NMR (125 MHz, CDCl3) δ = 154.3, 147.2, 144.8, 143.5, 137.4, 120.0, 119.9, 119.4, 116.4, 113.6,
112.1; HRMS(ESI): calcd. for C11H8Br2N3O2[M+H]+, 371.8977; found:371.8974.
N-(1-Nitronaphthalen-2-yl)pyridin-2-amine (2u): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
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43 mg (74%). Yellow solid, m.p. 122ꢀ124 C; H NMR (400 MHz, CDCl3) δ = 8.11 (dd, J=20.6, 9.4,
2H), 7.93 (d, J=9.0, 1H), 7.74 (d, J=8.2, 1H), 7.60 (d, J=8.5, 1H), 7.58 – 7.52 (m, 1H), 7.34 (d, J=4.2,
1H), 7.12 (dd, J=8.6, 2.3, 1H), 6.92 (d, J=9.0, 1H), 6.80 (d, J=9.1, 1H); 13C NMR (100 MHz, DMSO–
d6) δ = 156.5, 147.1, 145.1, 131.8, 129.6, 122.7, 122.5, 121.5, 121.4, 121.2, 120.1, 115.9, 111.2, 109.7,
109.0; HRMS(ESI): calcd. for C15H12N3O2[M+H]+, 266.0924; found:266.0920.
5-Bromo-N-(2-nitrophenyl)pyridin-2-amine (2v): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
46 mg (78%). Yellow solid, m.p. 170ꢀ172 oC; 1H NMR (400 MHz, CDCl3) δ = 8.36 (d, J=2.2, 1H), 8.24
13
– 8.18 (m, 2H), 7.71 (dd, J=8.7, 2.5, 1H), 7.61 – 7.55 (m, 2H), 6.92 (s, 1H), 6.82 (d, J=8.7, 1H); C
NMR (100 MHz, CDCl3) δ = 161.4, 152.3, 148.9, 146.3, 140.5, 126.2, 125.6, 117.0, 115.6, 112.5,
112.0; HRMS(ESI): calcd. for C11H9BrN3O2[M+H]+, 293.9872; found:293.9880.
5-Methyl-N-(2-nitrophenyl)pyridin-2-amine (2w): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
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1
57 mg (92%). Yellow solid, m.p. 158ꢀ160 C; H NMR (400 MHz, CDCl3) δ = 8.16 (dt, J=5.0, 3.1,
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3H), 7.52 – 7.47 (m, 2H), 7.45 (dd, J=8.4, 1.9, 1H), 7.23 (s, 1H), 6.87 (d, J=8.4, 1H), 2.29 (s, 3H); C
NMR (100 MHz, CDCl3) δ = 151.5, 147.9, 147.4, 140.7, 138.9, 126.8, 125.7, 116.1, 111.3, 17.7;
HRMS(ESI): calcd. for C12H12N3O2[M+H]+, 230.0923; found:230.0920.
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N-(4-Nitrothiophen-3-yl)pyridin-2-amine (2x): Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 43
mg (68%). Yellow solid, m.p. 160ꢀ162 oC; 1H NMR (400 MHz, CDCl3) δ = 9.73 (s, 1H), 9.09 (d, J=6.9,
1H), 7.96 – 7.90 (m, 1H), 7.78 (d, J=8.8, 1H), 7.34 (d, J=6.8, 1H), 7.20 – 7.07 (m, 1H), 6.80 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ = 151.7, 143.6, 133.6, 122.7, 122.1, 115.9, 112.7, 111.2, 104.1;
HRMS(ESI): calcd. for C9H8N3O2S[M+H]+, 222.0332; found: 222.0335.
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N-(2-Nitrophenyl)pyrimidin-2-amine (3a)14f: Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 56
o
1
mg (88%). Yellow solid, m.p. 134ꢀ136 C; H NMR (500 MHz, CDCl3) δ = 10.49 (s, 1H), 8.98 (d,
J=8.7, 1H), 8.54 (d, J=4.8, 2H), 8.24 (dd, J=8.5, 1.5, 1H), 7.69 – 7.60 (m, 1H), 7.05 (ddd, J=8.4, 7.2,
1.3, 1H), 6.91 (t, J=4.8, 1H); 13C NMR (125 MHz, CDCl3) δ = 159.3, 158.0, 136.9, 135.7, 135.5, 126.1,
120.9, 120.8, 114.6; HRMS(ESI): calcd. for C10H9N4O2[M+H]+, 217.0720; found:217.0718.
N-(4-Methyl-2-nitrophenyl)pyrimidin-2-amine (3b)14f: Eluent: Petroleum ether/ethyl acetate (7:3).
o
1
Yield: 57 mg (92%). Yellow solid, m.p. 142ꢀ144 C; H NMR (400 MHz, CDCl3) δ = 10.26 (s, 1H),
8.75 (d, J=8.7, 1H), 8.45 (d, J=4.8, 2H), 7.97 (s, 1H), 7.38 (dd, J=8.7, 1.6, 1H), 6.80 (t, J=4.8, 1H), 2.31
(s, 3H); 13C NMR (125 MHz, CDCl3) δ = 159.4, 158.0, 136.5, 135.7, 134.5, 131.1, 125.7, 121.0, 114.4,
20.4; HRMS(ESI): calcd. for C11H11N4O2[M+H]+, 231.0877; found:231.0880.
N-(2-Nitrophenyl)quinolin-2-amine(3c): Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 53 mg
o
1
(88%). Yellow solid, m.p. 220ꢀ222 C; H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 9.43 (d, J = 8.2
Hz, 1H), 8.26 (dd, J = 8.5, 1.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71 (d, J =
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8.0 Hz, 1H), 7.67 (ddd, J = 8.7, 4.9, 1.7 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.08 – 6.90 (m, 2H); C
NMR (125 MHz, CDCl3) δ = 151.8, 150.71, 144.5, 141.7, 133.5, 132.8, 131.2, 130.7, 129.8, 128.9,
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128.5, 127.8, 121.1, 119.2, 117.8;
found:266.0931.
HRMS(ESI): calcd. for C15H12N3O2[M+H]+, 266.0923;
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N-(4-Methyl-2-nitrophenyl)pyrazin-2-amine (3d): Eluent: Petroleum ether/ethyl acetate (7:3). Yield:
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49 mg (78%). Yellow solid, m.p. 116ꢀ118 C; H NMR (400 MHz, CDCl3) δ = 10.18 (s, 1H), 8.67 (d,
J=8.7, 1H), 8.34 (d, J=1.2, 1H), 8.23 (dd, J=2.5, 1.4, 1H), 8.15 (d, J=2.7, 1H), 8.07 (d, J=1.0, 1H), 7.44
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(dd, J=8.7, 2.0, 1H), 2.38 (s, 3H); C NMR (125 MHz, CDCl3) δ = 150.6, 141.3, 136.9, 136.9, 136.5,
135.4, 135.2, 131.1, 125.9, 120.0, 20.4; HRMS(ESI): calcd. for C11H11N4O2[M+H]+, 231.0876;
found:231.0879.
6-Chloro-N-(4-methyl-2-nitrophenyl)pyridazin-3-amine (3e): Eluent: Petroleum ether/ethyl acetate
o
1
(7:3). Yield: 45 mg (75%). Yellow solid, m.p. 196ꢀ198 C; H NMR (400 MHz, CDCl3) δ = 10.19 (s,
1H), 8.83 (d, J=8.7, 1H), 8.07 (s, 1H), 7.48 (d, J=8.4, 1H), 7.41 (d, J=9.2, 1H), 7.10 (d, J=9.2, 1H), 2.40
(s, 3H); 13C NMR (125 MHz, CDCl3) δ = 155.3, 150.4, 137.3, 135.5, 134.6, 131.8, 130.3, 129.8, 125.9,
121.0, 20.5; HRMS(ESI): calcd. for C11H10ClN4O2[M+H]+, 265.0487; found:265.0489.
N-(2-Nitrophenyl)isoquinolin-1-amine(3f): Eluent: Petroleum ether/ethyl acetate (7:3). Yield: 51 mg
o
1
(85%). Yellow solid, m.p. 128ꢀ130 C; H NMR (400 MHz, CDCl3) δ = 9.13 (s, 1H), 8.93 (d, J=8.6,
1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=9.0, 1H), 8.03 (d, J=8.3, 1H), 7.89 (dd, J=18.3, 8.6, 1H), 7.72 (d,
J=7.7, 2H), 7.45 (t, J=7.8, 2H), 6.87 (d, J=9.0, 1H); 13C NMR (125 MHz, CDCl3) δ = 157.0, 144.7,
140.3, 132.8, 130.0, 128.8, 127.3, 126.0, 125.0, 123.6, 123.4, 123.1, 118.1, 117.5, 115.6; HRMS(ESI):
calcd. for C15H12N3O2[M+H]+, 266.0923; found:266.0920.
N-(4-Methyl-2-nitrophenyl)benzo[d]thiazol-2-amine (3g): Eluent: Petroleum ether/ethyl acetate (7:3).
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1
Yield: 42 mg (70%). Yellow solid, m.p. 198ꢀ200 C; H NMR (400 MHz, CDCl3) δ = 8.33 (d, J=7.4,
1H), 8.12 (s, 1H), 7.47 (d, J=7.7, 1H), 7.33 (dd, J=16.3, 8.0, 1H), 7.00 (m, 2H), 6.94 (m, 2H), 2.23 (s,
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3H); C NMR (125 MHz, CDCl3) δ = 153.0, 145.1, 143.6, 133.6, 133.5, 122.7, 122.1, 121.5, 121.2,
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113.6, 111.2, 109.0, 104.1, 19.7; HRMS(ESI): calcd. for C14H12N3O2S[M+H]+, 286.0645; found:
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286.0640.
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General procedure for the cobalt catalyzed C(sp2-H) methoxylation of aromatics:
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To an oven dried 25 mL twoꢀnecked round bottomed flask with refluxing condenser connected with an
oxygen balloon. To this flask a stirred solution of N–phenylpyridin–2–amine (0.294 mmol, 1.0 equiv) in
MeOH (1.5 mL) was added Co(OAc)2.4H2O (0.0294 mmol, 0.1 equiv) and Ag2O (0.44 mmol, 1.5
equiv), were also added sequentially at room temperature with stirring. The flask was evacuated with
oxygen balloon after it was closed with septa, and the reaction mixture was stirred at 80 oC temperature
under an oxygen balloon atmosphere for 6 h. The progress of the reaction was monitored by TLC and
after completion of the reaction, MeOH was evaporated in vacuo and then 10 mL of water was added to
the reaction mixture at room temperature. The mixture was extracted with EtOAc (10 mL) further
extracted two times with EtOAc (2 x 10 mL) and the combined organic phase was washed with sat. aq.
NaHCO3 dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography (Hexanes/EtOAc, 7:3) to give pure ortho specific methoxylated N–(2–
methoxyphenyl)pyridin–2–amine24 (4) as a brown colour thick liquid (48 mg, 82%).1H NMR (500
MHz, CDCl3) δ = 8.22 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 6.97 (s, 2H), 6.91 (s, 1H), 6.86
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(d, J=7.5, 1H), 6.73 (s, 1H), 3.89 (s, 3H); C NMR (125 MHz, CDCl3) δ = 155.6, 148.9, 147.7, 137.6,
130.0, 121.8, 120.8, 118.5, 114.8, 110.4, 109.5, 55.6; LC-MS (ESI) m/z: 201.10 [M+H].
General procedures for the selective reduction of nitro groups:
Zn/NH4Cl mediated synthesis of N1–(pyrimidin–2–yl)benzene–1,2–diamine (5):
To a stirred solution of N–(2–nitrophenyl) pyrimidin–2–amine (0.231 mmol, 1.0 equiv) in MeOH (2
mL) was added Zn dust (1.388 mmol, 3 equiv) and NH4Cl (1.388 mmol, 3 equiv), at room temperature.
o
The reaction mixture was stirred at 80 C temperature for 4 h. The progress of the reaction was
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monitored by TLC and after completion of the reaction, MeOH was evaporated in vacuo and then 10 ml
of water was added to the reaction mixture at room temperature. The mixture was extracted with EtOAc
(20 mL) further extracted two times with EtOAc (2 x 20 mL) and the combined organic phase was
washed with sat. aq. NaHCO3 dried over Na2SO4 and concentrated in vacuo. The crude product was
purified by column chromatography (Hexanes/EtOAc, 2:3) to give pure N1–(pyrimidin–2–yl)benzene–
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1,2–diamine23 (5) (33 mg, 75%) as light brown colour solid, mp 176–178 °C. H NMR (400 MHz,
CDCl3) δ = 8.37 (d, J=4.8, 2H), 7.40 – 7.33 (m, 1H), 7.08 (td, J=7.8, 1.4, 1H), 7.00 (s, 1H), 6.84 (d,
13
J=7.6, 2H), 6.67 (t, J=4.8, 1H), 3.98 (s, 2H); C NMR (125 MHz, CDCl3) δ = 161.4, 158.4, 141.7,
126.8, 126.1, 125.3, 119.2, 117.0, 111.9; HRMS(ESI): calcd. For C10H11N4[M+H]+, 187.0978;
found:187.0980.
Pd/C mediated synthesis of N1–(pyrimidin–2–yl)benzene–1,2–diamine (5):
To a stirred solution of N–(2–nitrophenyl) pyrimidin–2–amine (0.231 mmol, 1.0 equiv) in MeOH (2
mL) was added 10% Pd/C (0.0231 mmol, 0.1 equiv) at room temperature. The reaction mixture was
stirred at room temperature under H2 balloon atmosphere pressure for 2 h. The progress of the reaction
was monitored by TLC and after completion of the reaction, the solution was filtered through celite pad,
and then MeOH was evaporated in vacuo. The crude product was purified by column chromatography
(Hexanes/EtOAc, 2:3) to give pure N1–(pyrimidin–2–yl)benzene–1,2–diamine (5) (40 mg, 95%) as light
brown colour solid.
Zn/NH4Cl mediated synthesis of N1–(pyridin–2–yl)benzene–1,2–diamine (6):
To a stirred solution of N–(2–nitrophenyl)pyridin–2–amine (0.231 mmol, 1.0 equiv) in MeOH (2 mL)
was added Zn dust (1.388 mmol, 3 equiv) and NH4Cl (1.388 mmol, 3 equiv), at room temperature. The
reaction mixture was stirred at 80 oC temperature for 4 h. The progress of the reaction was monitored by
TLC and after completion of the reaction, MeOH was evaporated in vacuo and then 10 ml of water was
added to the reaction mixture at room temperature. The mixture was extracted with EtOAc (20 mL)
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further extracted two times with EtOAc (2 x 20 mL) and the combined organic phase was washed with
sat. aq. NaHCO3 dried over Na2SO4 and concentrated in vacuo. The crude product was purified by
column chromatography (Hexanes/EtOAc, 2:3) to give pure N1–(pyridin–2–yl)benzene–1,2–diamine
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23(6) (30 mg, 70%) as brown solid, mp 120–122 °C. H NMR (400 MHz, CDCl3) δ = 8.14 – 8.10 (m,
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1H), 7.41 (ddd, J=9.1, 7.5, 1.9, 1H), 7.11 – 7.07 (m, 2H), 6.71 – 6.67 (m, 2H), 6.65 – 6.60 (m, 2H), 6.48
(s, 1H), 3.50 (s, 2H); 13C NMR (125 MHz, CDCl3) δ = 157.8, 148.1, 143.3, 137.7, 131.2, 125.0, 115.9,
113.8, 106.8; HRMS(ESI): calcd. For C11H12N3 [M+H]+, 186.1026; found: 186.1029.
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Pd/C mediated synthesis of N1–(pyridin–2–yl)benzene–1,2–diamine (6):
To a stirred solution of N–(2–nitrophenyl)pyridin–2–amine (0.231 mmol, 1.0 equiv) in MeOH (2 mL)
was added 10% Pd/C (0.0231 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at
room temperature under H2 balloon atmosphere pressure for 2 h. The progress of the reaction was
monitored by TLC and after completion of the reaction, the solution was filtered through celite pad, and
then MeOH was evaporated in vacuo. The crude product was purified by column chromatography
(Hexanes/EtOAc, 2:3) to give pure N1–(pyridin–2–yl)benzene–1,2–diamine (6) (40 mg, 95%) as a
brown colour solid.
General procedures for the deprotection of directing groups:
Deprotection of pyridine or pyrimidine rings for the synthesis of ortho-nitro anilines:
N–(2–nitrophenyl)pyridine–2–amine or N–(2–nitrophenyl)pyrimidine–2–amine(0.231 mmol, 1 equiv)
was dissolved in TFA (1 mL) in a round bottomed flask. Et3SiH (0.693 mmol, 3 equiv) was added and
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the mixture stirred at 50 C under argon for 4 h. On completion of reaction, the solvent was removed
under reduced pressure and N2H4.H2O (1 mL), acetic acid (0.5 mL) and methanol (1 mL) were added
and the mixture stirred under argon at room temperature for 15 h. On completion of the reaction, the
solvents were removed under reduced pressure. After addition of 1N NaOH solution (2 mL), the
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mixture was extracted with Et2O (3 x10 mL). The combined organic layers were dried over Na2SO4,
filtered, and evaporated in vacuo. The product was purified by silica gel column chromatography
(Hexanes/EtOAc, 7:3) to give the pure 2ꢀnitro aniline 7 as a yellow solid (23 mg, 72%), mp 72–74 °C.
1H NMR (500 MHz, CDCl3) δ = 8.12 (d, J=8.6, 1H), 7.42 – 7.32 (m, 1H), 6.81 (d, J=8.4, 1H), 6.75 –
6.68 (m, 1H), 6.08 (s, 2H); 13C NMR (125 MHz, CDCl3) δ = 144.6, 135.7, 126.2, 118.7, 116.9;
HRMS(ESI): calcd. For C6H7N2O2[M+H]+, 139.0502; found: 139.0510.
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Deprotection of pyridine or pyrimidine rings for the synthesis of ortho diamino benzene:
A round bottomed flask was charged with Pd/C (10% Pdꢀbasis) and iPrOH (1 mL) and the mixture was
stirred for 5 min under N2 atmosphere. Afterwards, 2a or 3a (0.231 mmol, 1 equiv), which was
dissolved in iPrOH (1 mL), and 2N HCl (300 µL, 1.386 mmol, 6 equiv.) were added to the solution. The
resulting mixture was flushed with H2 three times and then stirred under H2 (1 atm) at 50oC for 16 h.
Then, the solids were removed by filtration through Celite, and the solution was evaporated to dryness.
Afterwards, 1N NaOH solution (1 mL) was added, and the reaction mixture was extracted with DCM
(3x10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness.
The crude product was dissolved in 1 mL NH2NH2·H2O, and 0.5 mL AcOH, and EtOH (1 mL) in a
microwave vial and flushed with argon. The vial was heated up to 120oC for 30 min in microwave. The
reaction mixture was allowed to cool to ambient temperature and the volatiles were removed under
reduced pressure. After addition of 1N NaOH solution (1 mL), the mixture was extracted with Et2O
(3x10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness.
The product was dried under high vacuum to give the pure oꢀphenylenediamine 8 as a off white solid
(19 mg, 75%), mp 102–104 °C. 1H NMR (500 MHz, CDCl3) δ = 6.76 (d, J=7.4, 1H), 6.67 (s, 2H), 6.56
(s, 1H), 3.82 (s, 2H), 3.00 (s, 2H); 13C NMR (125 MHz, CDCl3) δ = 121.3, 119.7, 116.8,
116.3;HRMS(ESI): calcd. For C6H9N2[M+H]+, 109.0760; found:109.0765.
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Controlled experiments:
Reaction in the presence of radical quencher TEMPO (eq 1):
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To a stirred solution of N–phenylpyridin–2–amine (0.294 mmol, 1 equiv) in THF (1.5 mL) was added
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Co(OAc)2.4H2O (0.0294 mmol, 0.1 equiv) and AgNO2 (0.441 mmol, 1.5 equiv), and TEMPO ( 0.588
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mmol, 2 equiv) at room temperature. The reaction mixture was stirred at 80 C temperature under an
oxygen atmosphere for 6 h, and cooled to room temperature. The reaction mixture was diluted with
10mL of CH2Cl2, and filtered through a celite pad, then detected by TLC. The result showed that 2a was
not obtained.
Intermolecular competition reaction between 1b and 1h (eq 2):
To
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stirred solution of [N–(p–tolyl)pyridin–2–amine (1b) (0.5 equiv) andN–(4–
(trifluoromethyl)phenyl)pyridin–2–amine(1h) (0.5 equiv)] (0.120 mmol, 1 equiv) in THF (1.5 mL) was
added Co(OAc)2.4H2O (0.012 mmol, 0.1 equiv) and AgNO2 (0.18 mmol, 1.5 equiv), at room
temperature. The reaction mixture was stirred at 80 oC temperature under an oxygen atmosphere for 6 h.
The progress of the reaction was monitored by TLC and after completion of the reaction. THF was
evaporated in vacuo and then 10 mL of water was added to the reaction mixture at room temperature.
The mixture was extracted with EtOAc (10 mL) further extracted two times with EtOAc (2 x 10 mL)
and the combined organic phase was washed with sat. aq. NaHCO3 dried over Na2SO4 and concentrated
in vacuo. The crude products were purified by column chromatography on silica gel.N–(4–methyl–2–
nitrophenyl)pyridin–2–amine (2b, 40%) and N–(2–nitro–4–(trifluoromethyl)phenyl)pyridin–2–amine
(2h, 35%) were isolated in 1.1:1 ratio.
Reaction with N-methyl-N-phenylpyridin-2-amine (eq 3):
To a stirred solution of N–methyl–N–phenylpyridin–2–amine(0.271 mmol, 1 equiv) in THF (1.5 mL)
was added Co(OAc)2.4H2O (0.0271 mmol, 0.1 equiv) and AgNO2 (0.406 mmol, 1.5 equiv), at room
temperature. The reaction mixture was stirred at 80 oC temperature under an oxygen atmosphere for 6 h,
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and cooled to room temperature. The reaction mixture was diluted with 10mL of CH2Cl2, and filtered
through a celite pad, then detected by TLC. The result showed that the corresponding ortho nitrated
product was not formed.
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Reaction with N-phenyl-N-(pyridin-2-yl)acetamide (eq 4):
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To a stirred solution of N–phenyl–N–(pyridin–2–yl)acetamide(0.235 mmol, 1 equiv) in THF (1.5 mL)
was added Co(OAc)2.4H2O (0.0235 mmol, 0.1 equiv) and AgNO2 (0.353 mmol, 1.5 equiv), at room
temperature. The reaction mixture was stirred at 80 oC temperature under an oxygen atmosphere for 6 h,
and cooled to room temperature. The reaction mixture was diluted with 10mL of CH2Cl2, and filtered
through a celite pad, then detected by TLC. The result revealed that the corresponding ortho nitrated
product was not formed.
Reaction with 2-benzylpyridine (eq 5):
To a stirred solution of 2–benzylpyridine (0.295 mmol, 1 equiv) in THF (1.5 mL) was added
Co(OAc)2.4H2O (0.0295 mmol, 0.1 equiv) and AgNO2 (0.442 mmol, 1.5 equiv), at room temperature.
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The reaction mixture was stirred at 80 C temperature under an oxygen atmosphere for 6 h, and cooled
to room temperature. The reaction mixture was diluted with 10mL of CH2Cl2, and filtered through a
celite pad, then detected by TLC. The result revealed that the corresponding ortho nitrated product was
not formed.
Reaction with 2-phenoxy pyridine (eq 6):
To a stirred solution of 2–phenoxy pyridine (0.294 mmol, 1 equiv) in THF (1.5 mL) was added
Co(OAc)2.4H2O (0.0294 mmol, 0.1 equiv) and AgNO2 (0.442 mmol, 1.5 equiv), at room temperature.
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The reaction mixture was stirred at 80 C temperature under an oxygen atmosphere for 6 h, and cooled
to room temperature. The reaction mixture was diluted with 10 mL of CH2Cl2, and filtered through a
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celite pad, then detected by TLC. The result revealed that the corresponding ortho nitrated product was
not formed.
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Kinetic Experiemnts:
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Synthesis of benzen-2,4,6-d3-amine:
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In a microwave reaction vial with a magnetic stir bar, aniline (2.15 mmol, 1 equiv) was added, followed
by Conc. HCl (260 µL, 1 equiv) in 5 mL of D2O. The vial was capped and sealed and heated in the
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microwave synthesis apparatus for 30 minutes at a temperature of 180 C. The reaction mixture can be
directly concentrated to afford the DCl salt of the aniline. Alternatively, basic aqueous workup (via
addition of 10 mL 3M NaOH, 6 mL brine and 20 mL Et2O, separation of phases, and washing the
organic phase with brine) can be used to afford the benzeneꢀ2,4,6ꢀd3ꢀaniline as light brown colour liquid
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(186 mg, 90%).1H NMR (400 MHz, CDCl3) δ = 7.13 (s, 1H), 3.57 (s, 1H); C NMR (125 MHz,
CDCl3) δ = 145.5, 128.2, 128.1; LC-MS (ESI) m/z: 97.10 [M+H].
Synthesis of N-(phenyl-2,4,6-d3)pyridin-2-amine:
To an oven dried round–bottomed flask were added palladium diacetate (0.0318 mmol, 5mol %), (±)–
2,2'–bis(diphenylphosphino)–1,1'–binaphthyl [(±)–BINAP] (0.0318 mmol, 5 mol%) and toluene
(anhydrous, 5 mL), and the resulting mixture then stirred under a stream of argon for 10 minutes. After
this time 2ꢀbromo pyridine (0.636 mmol, 1 equiv) and 2,4,6– deuterated aniline (0.763 mmol, 1.2 equiv)
were added with caesium carbonate (1.908 mmol, 3 equiv), the reaction was fitted with a condenser, and
heated to reflux with vigorous stirring under argon for 14 h. After this time the solids were removed by
filtration through celite, the pad washed with DCM (2 x 20 mL) and the volatiles removed under
reduced pressure. The resulting residue was purified by columnar chromatography on silica gel, to give
pure N–(phenyl–2,4,6–d3)pyridin–2–amine as white solid (77 mg, 70%).1H NMR (400 MHz, CDCl3) δ
= 8.24 – 8.19 (m, 1H), 7.54 – 7.46 (m, 1H), 7.34 (s, 2H), 6.88 (d, J=8.4, 1H), 6.77 – 6.71 (m, 1H), 6.61
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(s, 1H). 13C NMR (125 MHz, CDCl3) δ = 155.1, 147.3, 139.3, 136.6, 128.1, 128.0, 113.93, 107.1; LC-
MS (ESI) m/z: 174.10 [M+H].
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Determination of kinetic isotopic effect:
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amine (0.5 equiv) in THF (1.5 mL) was added Co(OAc)2.4H2O (0.1 equiv) and AgNO2 (1.5 equiv), at
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room temperature. The reaction mixture was stirred at 80 C temperature under an oxygen atmosphere
for 3h. THF was evaporated in vacuo and then 10 mL of water was added to the reaction mixture at
room temperature. The mixture was extracted with EtOAc (10 mL) further extracted two times with
EtOAc (2 x 10 mL) and the combined organic phase was washed with sat. aq. NaHCO3 dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography and the
kinetic isotopic effect (KIE) value was calculated as kH/kD = 1.0. 1H NMR (400 MHz, CDCl3) δ = 8.28
– 8.22 (m, 2H), 8.17– 8.08 (m, 4H), 7.56 (td, J=8.0, 1.9, 2H), 7.53 – 7.48 (m, 2H), 7.04 (s, 2H), 6.89 –
6.83 (m, 4H).
ASSOCIATED CONTENT
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Supporting Information Available: Copies of H and C NMR spectra, and mechanistic studies as a
separate file. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author *Eꢀmail: partha@iiim.ac.in. Notes The authors declare no competing financial
interest.
ACKNOWLEDGEMENTS
D. N. R., G. R. and Sk. R., thanks UGCꢀNew Delhi and CSIR for their research fellowship. This
research work financially supported by CSIRꢀNew Delhi (BSC0108). IIIM communication no
IIIM/1930/2016.
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