N-(1-Oxy-2-picolyl)oxalamic acids as a new type of O,O-ligands for the Cu-catalyzed N-arylation of azoles with aryl halides in water or organic solvent

Article abstract of DOI:10.1039/c5ob00045a

N-(1-Oxy-pyridin-2-ylmethyl)oxalamic acids (L3-L5) were identified as novel efficient ligands for copper-catalyzed C-N cross-coupling of azoles and aryl halides in water. The N-arylation of imidazoles, indoles and pyrazoles proceeded with moderate to excellent yields and complete selectivity over aromatic amines and phenols. Moreover, L5, which is also efficient in organic solvent with low catalyst loading, can be used to promote the N-arylation reactions with water-sensitive materials. The catalytic mechanism was proposed based on the results of several verification experiments which indicated that the ligands as new-type chelators may coordinate to Cu(i) with two oxygen atoms of N-oxide and amide in the coupling process. This journal is

Full text of DOI:10.1039/c5ob00045a

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N-(1-Oxy-2-picolyl)oxalamic Acids as New Type of O,O-Ligands
for the Cu-Catalyzed N-Arylation of Azoles with Aryl Halides in
Water or Organic Solvent
Yongbin Wang,a Yu Zhang,b Beibei Yang,a Ao Zhang,*,c Qizheng Yao*,a
aSchool of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009,
China,
qz_yao@163.com;
bAllist Pharmaceuticals, Inc., 1118 Halei Road, Shanghai, China;
cShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200000, China,
aozhang@simm.ac.cn.
Abstract
Nꢀ(1ꢀOxyꢀpyridinꢀ2ꢀylmethyl)oxalamic acids (L3-L5) were identified as novel efficient ligands
for copperꢀcatalyzed CꢀN crossꢀcoupling of azoles and aryl halides in water. The Nꢀarylation of
imidazoles, indoles and pyrazoles proceeded with moderate to excellent yields and complete
selectivity over aromatic amines and phenols. Moreover, L5, which is also efficient in organic
solvent with low catalyst loading, can be used to promote the Nꢀarylation reactions with
waterꢀsensitive materials. The catalytic mechanism was proposed based on the results of several
verification experiments which indicated that the ligands as newꢀtype chelators may coordinate to

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Cu(I) with two oxygen atoms of Nꢀoxide and amide in the coupling process.
Introduction
Nꢀarylazoles are found in many bioactive compounds, natural products and chemical
materials for the synthesis of ionic liquids or Nꢀheterocyclic carbenes.1 Conventional preparation
protocols of these moieties, including nucleophilic substitution of activated aryl halides with
azoles and traditional Cuꢀcatalyzed Ullmann CꢀN cross couplings, have several apparent
drawbacks which limited their applications. Strongly electronicꢀwithdrawing substitutes are
necessary to activate the aryl halides in the former case. However, both of them suffer from harsh
conditions and narrow functional group tolerance.2 So far, great effort has been made to overcome
these problems. For example, Nꢀarylation of azoles can be accomplished using aryllead triacetate,
arylboronic acid, triarylbismuth, diaryl iodonium salt, and arylstannane reagents with low loading
of copper salt under mild conditions, but these methods generally require toxic, expensive or
unusual reagents which are difficult to obtain.3
The most attractive and efficient methods for the preparation of Nꢀaryl azoles involve
copperꢀcatalyzed Ullmannꢀtype coupling reactions. The coupling can be catalyzed by ligandꢀfree
or ligandꢀassisted copper catalyst while Cuꢀligands were applied to decrease the amount of
catalyst, increase the functional group tolerance and avoid harsh conditions.4 Since several
N,Nꢀand N,Oꢀbased chelators were developed as efficient Cuꢀligands used to facilitate the
Nꢀarylation of azoles by Buchwald et al.5 and Ma et al.6 respectively, a series of novel
copper/ligand systems have been reported.3f,7 Ecoꢀfriendly Cu/ligand systems, performed with low
loading of catalysts, at mild conditions and/or in water, appeared in recent years.8 Aqueousꢀphase

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reaction is particularly attractive owing to the fact that water is the most economic and
ecoꢀfriendly material.8c,d
.
In our previous report, Nꢀ(2,6ꢀdimethylphenyl)oxalamic acid (DMAPO) was shown to be a
powerful ligand to enable copperꢀcatalyzed reactions of aryl halides with primary/secondary
amines to take place under relatively mild conditions.9 We found that DMAPO can also slightly
facilitate the Cuꢀcatalyzed Nꢀarylation of azoles in water. On this basis, we designed and
synthesized a series of oxalamic acidꢀtype ligands (L1ꢀL7). These ligands were reconstructed
from DMAPO with Nꢀoxide strategy which has been used in the design of Cuꢀligand for Ullmann
reaction.10 Intensive research of the substituent effect on the catalytic efficiencies of the ligands
furnished several new and efficient Cuꢀligands. Herein, we describe a full account of our recent
work about novel O,Oꢀligands which can efficiently promote the copperꢀcatalyzed coupling of
azoles with aryl halides in aqueousꢀphase and organic solvent.
Results and Discussion
Figure 1. Structures of DMAPO and the designed Ligands
The structures of DMAPO and the designed ligands were shown in figure 1. L1ꢀL7 with
Nꢀoxide groups are stable and easily synthesized from different materials in high yields. Firstly,

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we obtained substituted 2ꢀpicolylamines/arylamines (L1a-L7a) through different methods.11
Treatment of amines with tertꢀbutyl oxalyl monochloride afforded L1b-L7b, followed by
treatment with 3ꢀchloroperbenzoic acid to yield pyridine Nꢀoxides (L1c-L7c). Finally, the ligands
(L1ꢀL7) were obtained after the tertꢀbutyl groups were removed by trifluoroacetic acid (Scheme
1).
Scheme 1. Synthesis of the Designed Ligands Containing Pyridine N-Oxide Groups
(L1-L7)
4ꢀBromoanisole and imidazole were chosen as model substrates to screen the efficiencies of
these ligands in the Nꢀarylation reactions in water. The standardized protocol was carried out with
4ꢀbromoanisole (1.0 mmol), imidazole (1.4 mmol), CuI (5.0 mol %), Ligand (10 mol %) and
TBAB (0.2 eq) at 100 °C in water (1 mL). As shown in table 1, DMAPO can slightly promote the
model reaction while L1 and L2, which were directly reconstructed from DMAPO with pyridine
Oꢀoxide strategy, showed better activities (entries 1ꢀ3). L2 was reasonably simplified through
removing an aromatic ring to afford L3 which efficiently promote the coupling with excellent
yield (entry 4). L4ꢀL7 as analogues of L3 were equipped with different substitutes on the pyridine
rings to examine the effect of the substitutes to their activities. The results showed that the

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efficiencies of the ligands were maintained when the substitutes were added to the 4ꢀposition of
the pyridine ring (entries 5ꢀ8).
By using L5 as the ligand, the coupling of 4ꢀbromoanisole and imidazole was selected as the
model reaction to optimize the catalytic conditions in water, including optimization of the bases,
copper sources, additives and temperature. Reactions employing different bases, including K3PO4,
Cs2CO3 and KOH, at 90 °C were explored. The efforts showed that three inorganic bases provided
almost the same yield (entries 9ꢀ11); however, KOH was the cheapest one and of practical
application in this coupling reaction. The reactions with different copper sources showed that CuI
promote the highest yielding reaction (70%) although other copper salts can be utilized in this
coupling (entries 12ꢀ14). TBAB as phase transfer catalyst was found to be the most favorable
additive for the catalytic reaction and the amount can be reduced to 0.1 equiv without significant
decrease in yield (entries 15ꢀ19). The isolated yield of the coupling with 0.1 eq TBAB increased to
95% when the temperature was raised to 100 °C (entry 20). However, the optimal conditions for
the coupling of 4ꢀbromoanisole and imidazole in water involves the application of 5 mol % of CuI,
10 mol % of L5, 0.1 equiv of TBAB and 2.0 equiv KOH at 100 °C. Under the optimized
conditions, 4ꢀiodoanisole furnished the same product in satisfactory yield (90 %) when performed
with imidazole at 70 °C (entry 21).
Table 1. DMAPO and Designed Ligands for Copper-catalyzed N-Arylation of Imidazole
with 4-Bromoanisole in Watera

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Entry Copper salt Ligand
Base
PTC(mol%) Temp(°C) Yield[%]b
1
2
CuI
CuI
DMAPO KOH
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TBAB(20)
TEBA(20)
TEAC(20)
100
100
100
100
100
100
100
100
90
18
36
78
97
96
98
85
82
70
71
73
54
58
55
10
Trace
6
L1
L2
L3
L4
L5
L6
L7
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K3PO4
Cs2CO3
KOH
KOH
KOH
KOH
KOH
3
CuI
4
CuI
5
CuI
6
CuI
7
CuI
8
CuI
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
CuI
90
CuI
90
Cu2Oc
CuBr2
CuSO4
CuI
90
90
90
90
CuI
90
CuI
KOH PEGꢀ400(20)
90
CuI
KOH
KOH
KOH
KOH
TBAB(10)
ꢀꢀ
90
67
4
CuI
90
CuI
TBAB(10)
TBAB(10)
100
70
95
90d
CuI
aUnless otherwise noted, the reactions were carried out with 4ꢀbromoanisole (1.00 mmol), imidazole (1.40 mmol),
Copper salt (5.0 mol %), Ligand (10 mol %), base (2.00 mmol), PTC and H2O (1.0 mL) under N2ꢀatmosphere for
48 h in schlenk tube; bIsolated yield; c2.5 mol % Cu2O was applied; d4ꢀiodoanisole instead of 4ꢀbromoanisole.
TEBA: Benzyltriethylamonium·Chloride; TEAC: Tetraethylammonium chloride.
When the temperature dropped to 90 °C and the solvent was changed into organic solvent
(DMSO), only L5 afforded satisfactory yield (96%) with low loading of catalyst (2.5 mol % CuI
and 5.0 mol % L) as shown in table 2. This result indicated that strong electronicꢀwithdrawing
group at the 4ꢀposition of the pyridine drastically increase the activity of the catalyst. Finally, L5
was chosen as the ligand to examine the robustness of the reaction due to the applicability of L5 to
aqueous and organic solvent.

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Table 2. DMAPO and Designed Ligands for Copper-catalyzed N-Arylation of Pyrazole
with 4-Iodoanisole in DMSOa
Ligand
Yield[%]b
None DMAPO
14 26
L1
L2
L3
L4
L5
96
L6
L7
30
45
54
61
41
20
aUnless otherwise noted, the reactions were carried out with 4ꢀiodoanisole (1.00 mmol), pyrazole (1.40 mmol), CuI
°
(2.5 mol %), L (5.0 mol %), K3PO4 (2.00 mmol) and DMSO (1.0 mL) at 90 C for 48 h in reaction tube under N2
atmosphere; bIsolated yield.
In DMSO, a wide variety of functional azoles successfully coupled with aryl iodides when
the reactions were operated with low loading of catalysts (2.5 mol % CuI and 5.0 mol % L5) and
K3PO4 (2.0 eq) at 90 °C for 48 h (table 2). Imidazole, pyrazole, pyrrole, indole and benzimidazoles
exclusively provided the corresponding products with excellent isolated yields even performed
with aryl iodides possess electronꢀdonating groups.
Table 3. CuI-Catalyzed Couplings of Azoles with Aryl Iodides in DMSOa,b
aUnless otherwise noted, the reactions were carried out with aryl iodides (1.00 mmol), azole (1.40 mmol), CuI

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°
(2.5% mmol), L5 (5.0% mmol), K3PO4(2.00 mmol) and DMSO (1.0 mL) at 90 C for 48 h in reaction tube under
N2 atmosphere; bIsolated yield.
In water, the scope of aryl halides was investigated by using CuI/L5 system under the optimal
conditions. As summarized in table 3, various functionalized aryl iodides, bromides and chlorides
were subjected to this protocol at 70 °C, 100 °C and 120 °C, respectively. It was found that the
reactions worked well in almost all cases. Aryl halides, including electronꢀrich, electronꢀneutral
aryl iodides and bromides, afforded corresponding products in excellent isolated yields for 48 h
(entries 1ꢀ3, 6ꢀ11) while less time was required to electronꢀdeficient halides (entries 4, 12ꢀ16). The
conditions of the Nꢀarylation of imidazole promoted by Cu/L5 are comparable with that of several
reported Cu/ligand systems which are comparatively efficient in water.8bꢀd,12 2ꢀBromoanisole
afforded relatively lower yield (61%) than its paraꢀ and metaꢀ isomers and the yield was increased
to 82% when the temperature was raised to 110 °C (entry 17). This phenomenon about steric
hindrance effect is coherent with previous studies.7g,8d,10c Furthermore, various functional groups,
such as ketones, free amines and free hydroxyls, were well tolerated with excellent yields under
optimal conditions (entries 9, 10, 12). In the case of ethyl 4ꢀiodobenzoate, only a trace of desired
product was determined due to the hydrolysis of the ester. However, the Nꢀaryl imidazole was
isolated with satisfactory yield when performed in DMSO (entry 5). Finally, 4ꢀnitrochlorobenzene
was successfully coupled with imidazole in moderate yield (67 %) at 120 °C (entry 18).
Table 4. CuI-Catalyzed N-Arylation of Imidazole with Aryl Halides in Watera

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Entry
Product
TimeYieldb Entry
(h) [%]
90
Product
TimeYieldb
(h) [%]
98f
1
(ArI)
48
10
48 92c,f
97d,f
99c
90d
(ArBr)
2
48 99
48 97
40 99
48 76e
48 95
48 99
48 99
48 99
11
(ArBr)
48 99
30 85
36 92
36 99
(ArI)
3
12
(ArBr)
(ArI)
4
13
(ArBr)
(ArI)
5
14
(ArBr)
(ArI)
6
15
(ArBr)
6
99
(ArBr)
7
16
(ArBr)
40 99
(ArBr)
8
17
(ArBr)
48 61
82g
(ArBr)
9
18
48 67
(ArBr)
(ArCl)

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aUnless otherwise noted, the reactions were carried out with aryl halides (1.00 mmol), imidazole (1.40 mmol), CuI
(5.0 mol %), L5 (10 mol %), KOH (2.00 mmol), TBAB (0.10 mmol) and H2O (1.0 mL) in schlenk tube under N2
atmosphere; bIsolated yield; cThe reaction was performed with L3 instead of L5; dThe reaction was performed with
e
f
g
L4 instead of L5; The reaction was performed under the conditions given in Table 2; KOH (3.00 mmol); At
110 °C.
To further expand the substrate scope of this methodology, the CuI/L5 system was explored
with other Nꢀcontaining heterocycles. As shown in table 4, a variety of azoles such as substituted
imidazoles, pyrazoles, pyrroles indazoles and indoles were applied with varies aryl halides to give
the corresponding Nꢀarylazoles in moderate to excellent isolated yields under the optimized
conditions but different temperature. 4ꢀMethyl imidazole was found to be effective nucleophilic
azole as well as imidazole when performed with 4ꢀiodoanisole and 4ꢀbromoanisole at 70 °C and
100 °C respectively. A mixture of N1ꢀand N3ꢀarylation isomers was obtained with good yields and
moderate regioselectivity. The ratios of the isomers are shown in the parentheses while
N1ꢀsubstituted product is the major product (entries 1, 11). 2ꢀMethylimidazole and 2ꢀacetylpyrrole
as less nucleophilic partners with steric hindrance successfully coupled with iodobenzene in good
yield at 110 and 100 °C (entries 2, 3). Notably, 2ꢀbromopyridine could be conducted smoothly to
provide 2ꢀsubstituted pyridines with azoles examined here in excellent yields even the temperature
was decreased to 90 °C (entries 10, 12, 13, 20). Indazole, indoles and pyrazole proceeded with
aryl iodides to exclusively furnish the coupling products with good to excellent yield at 100 °C,
90 °C and 110 °C respectively while aryl bromides gave rise to moderate to excellent yield at
120 °C (entries 4ꢀ9, 14ꢀ20).

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Several reactions with different azoles and aryl halides were carried out under the optimized
conditions to examine the substrate scope of L3 and L4 (entries 1, 10 of Table 4 and entry 9 of
Table 5). The outcomes pointed that the activity of these two ligands is comparable and sometimes
even better than that of L5. L3, which can be synthesized easily due to its simple structure, is
applicable in facilitating the Nꢀarylation reactions in water.
Table 5. CuI-Catalyzed N-Arylation of Azoles with Aryl Halidesa
Entry
Product
Temp Yield Entry
(°C) [%]
Product
Temp Yield
(°C) [%]
1
70
110
100
100
90
88c
（4:1）(ArBr)
11
100 89c
(ArI)
（3:1）
2
82
80
92
87
12
(ArBr)
90
90
98
82
69
61
(ArI)
3
13
(ArBr)
(ArI)
4
14
(ArBr)
120
120
(ArI)
5
15
(ArI)
(ArBr)

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6
90
90
83
90
16
(ArBr)
120
120
73
(ArI)
7
17
69
(ArI)
(ArBr)
8
110
94
74
18
(ArBr)
120 70f
(ArI)
9
110 86d
19
120
90
89
99
(ArI)
80e (ArBr)
10
90
99
20
(ArBr)
(ArBr)
aUnless otherwise noted, the reactions were carried out with aryl halides (1.00 mmol), imidazole (1.40 mmol), CuI
(5.0% mmol), L5 (10% mmol), KOH (2.00 mmol), TBAB(0.10 mmol) and H2O (1.0 mL) in schlenk tube under N2
atmosphere for 48 h; bIsolated yield; c4ꢀMe:5ꢀMe selectivity is reported in parentheses was determined by 1H NMR
d
e
spectra of the pure products; The reaction was performed with L3 instead of L5; The reaction was performed
with L4 instead of L5. fKOH (3.0 mmol).
Mechanistic Study
The efficiencies of catalyst systems applied in copperꢀcatalyzed CꢀN couplings are governed
by several factors while ligands that coordinate to Cu play an important role in this process.4b,10b
Most of the ligands used in Ullmann reactions are bidentate or multidentate chelators.8d,9,13 L3, L4
and L5 as efficient ligands contain three functional groups which may coordinate to Cu, namely
Nꢀoxide14a, amide14bꢀhand carbonyl groups14h,i. L11 as bidentate ligand without carboxyl group

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could efficiently promote the coupling of imidazole and 4ꢀbromoanisole in water to provide the
desired product with slightly lower yield than L3. L9 and L10 showed poor activity in this
reaction perhaps due to the absence of Nꢀoxide or amide group in the ligands. These results
indicated that the Nꢀoxide and amide groups play important roles and the carboxyl group was not
absolutely necessary in the catalytic process. Pyridine Nꢀoxides and amides are efficient
Cuꢀligands which have been widely utilized in coordination and catalytic chemistry.10b,c,14bꢀi
Therefore, the Nꢀ(1ꢀoxyꢀ2ꢀpicolyl)oxalamic acids may act as bidentate ligands and the two
coordinated sites may be the Nꢀoxide and amide groups. Meanwhile, the carboxyl groups should
increase the efficiency of the ligands through changing the properties of the ligands. For example,
they can elevate the solubility of the ligands in water which is favorable to aqueous phase
reaction8b,10c
.
The amide group of oxalamic acid can efficiently coordinate to copper with nitrogen14f,g,i or
oxygen atom14e,h,i of the amide. Structural feature analysis of previously reported Cuꢀoxalamic
acid complexes reveals that the NꢀCu coordinated form generally requires the deprotonation of the
amide.14f,g,i The amide might directly coordinate to the Cu(I) with the oxygen atom without
deprotonation since L10 as similar ligand of L3 without hydrogen on the amide was as effective
as L3 in promoting the coupling. In summary, we presumed that the effective ligands may act as
O,Oꢀligand (the oxygen atoms of the Nꢀoxide and amide) in the Cuꢀcatalyzed process. As shown
in Scheme 2, eightꢀmember reactive species A formed by the chelating Cu(I) with the ligand
participated the catalytic cycle with oxidative addition and reductive elimination to generate
Nꢀarylazoles and regenerate the complex A.8d,9,10b,15

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Figure 1. The Presumed Catalytic Mechanism of Cu/L in Promoting the N-Arylation of
Azoles.
aIsolated yield when promoted the Nꢀarylation of imidazole with 4ꢀbromoanisole under the conditions of table 4.
Conclusion
In summary, we have developed an useful copper catalyzed system for the Nꢀarylation of
azoles with Nꢀ(1ꢀoxyꢀpyridinꢀ2ꢀylmethyl)oxalamic acids as ligands in water under relatively mild
conditions. This process avoids the use of toxic organic solvents, expensive bases and harsh
conditions. Moreover, the Cu/L5 system, which is also efficient in organic solvent with low
catalyst loading, can be used to promote the Nꢀarylation reactions of azoles with waterꢀsensitive
materials. The presumed catalytic mechanism of CuI/L was verified by several experiments. The
novel coordinate pattern and the applicability of L5 to both aqueousꢀphase and organic solvent
may lead to the development of new Cu/ligand systems. Applications of this type of ligands to
other coupling reactions are being explored in our laboratory.

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Experimental Section
Synthesis of the Ligands. L1ꢀL8 and L10 was synthesized from amines (L1aꢀL8a) and L9 was
commercial available. The amines (L1aꢀL8a) were obtained through different methods. L1a, L2a,
L3a, and 2ꢀchlorobenzyamine (L8a) were purchased from commercial sources and used without
further purification. L6a and L7a were synthesized according the literature but under normal
atmosphere press11a while L4a and L5a were synthesized from 4ꢀmethoxyꢀ2ꢀpyridylmethol and
4ꢀnitroꢀ2ꢀpyridylmethol respectively.
tert-Butyl N-(3-methyl-pyridin-2-yl)oxamate (L1b): To a magnetically stirred solution of
2ꢀaminoꢀ3ꢀmethylpyridine (320 mg, 3.0 mmol) and triethylamine (610 mg, 6 mmol) in CH2Cl2 (20
mL) was added, dropwise, a solution of tertꢀButyl oxalyl chloride (600 mg, 3.64 mmol) in CH2Cl2
(6 mL). After it was stirred for 2 h, the mixture was diluted with CH2Cl2 (30 mL) and then washed
with water and brine. The organic layer was dried over Na2SO4 and evaporated. The crude product
was purified with silica gel chromatography to give the L1b (576 mg, 2.44 mmol, 81.3%). White
1
solid; m.p. 123ꢀ125 °C; H NMR (300 MHz, CDCl3) δ 9.38 (br, 1H), 8.29 (d, J = 3.6 Hz, 1H),
7.58 (d, J = 8.0 Hz, 1H), 7.14 (dd, J1 = 7.4 Hz, J2 = 4.9 Hz, 1H), 2.29 (s, 3H), 1.59 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 159.3, 155.3, 148.1, 146.0, 140.0, 128.6, 122.3, 85.0, 27.7, 18.1; HRMS
calcd for C12H17N2O3 (M + H)+, 237.1234, found 237.1233.
tert-Butyl N-(3-methyl-1-oxy-pyridin-2-yl)oxamate (L1c): T To a magnetically stirred
solution of L1b (500 g, 2.12 mmol) in CH2Cl2 (20 mL) was added 75% 3ꢀChloroperbenzoic acid
(580 mg, 2.52 mmol) slowly. After 12 h, K2CO3 (600 mg, 4.34 mmol) was added into the mixture.
It was stirred additional 6 h. The reaction mixture was filtered and eluted with CH2Cl2 (30 mL).
The filtrate was concentrated, and the crude product was purified through recrystallization from

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PE/EA to give the L1c (460 mg, 1.82 mmol, 86.6%). Colorlessꢀcrystalline solid; m.p. 130ꢀ133 °C;
1H NMR (300 MHz, CDCl3) δ 10.19 (br, 1H), 8.19 (d, J = 6.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H),
7.11 (t, J = 6.5 Hz, 1H), 2.36 (s, 3H), 1.62 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.9, 155.3,
142.0, 135.8, 131.4, 129.6, 121.6, 85.6, 27.7, 19.2; HRMS calcd for C12H17N2O4 (M + H)+,
253.1183, found 253.1186.
N-(3-Methyl-1-oxy-pyridin-2-yl)oxalamic acid (L1): To a magnetically stirred solution of
L1c (400 mg, 1.58) in CH2Cl2 (20 mL), trifluoroacetic acid (6 ml) was added dropwise. After it
was stirred for 24 h, the reaction solution was concentrated and the resulting residue was purified
through recrystallization from PE/EA to give L1 (238 mg, 1.21 mmol, 76.8%). White solid; m.p.
139ꢀ142 °C; 1H NMR (300 MHz, DMSOꢀd6) δ 16.50ꢀ11.30 (br, 1H), 10.58 (br, 1H), 8.22 (s, 1H),
7.28 (s, 1H), 2.21 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δ 160.9, 157.5, 141.6, 136.5, 132.9,
127.5, 123.2, 17.4; HRMS calcd for C8H9N2O4 (M + H)+, 197.0557, found 197.0558.
tert-Butyl N-(7-methyl-quinolin-8-yl)oxamate (L2b): The procedure was the same as
1
described above for the synthesis of L1b. White solid; m.p. 125ꢀ127 °C; H NMR (300 MHz,
CDCl3) δ 10.16 (br, 1H), 8.87 (dd, J1 = 4.2 Hz, J1 = 1.5 Hz, 1H), 8.12 (dd, J1 = 8.2 Hz, J1 = 1.4 Hz,
1H), 7.64 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.2 Hz, J = 4.2 Hz, 1H), 2.50
(s, 3H), 1.66 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.8, 155.1, 149.6, 142.6, 135.8, 133.9, 130.4,
130.3, 126.5, 125.2, 120.9, 84.8, 27.9, 20.6; HRMS calcd for C16H19N2O3 (M + H)+, 287.1390,
found 287.1393.
tert-Butyl N-(7-methyl-1-oxy-quinolin-8-yl)oxamate (L2c): The procedure was the same as
1
described above for the synthesis of L1c. Light brown solid; m.p. 141ꢀ143 °C; H NMR (300
MHz, CDCl3) δ 13.9 (s, 1H), 8.44 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.4

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Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 6.1 Hz, J = 2.1 Hz, 1H), 2.42 (s, 3H), 1.64 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 159.2, 155.0, 137.9, 136.1, 134.5, 132.6, 130.4, 128.5, 127.7 124.8,
120.2, 84.5, 27.9, 21.2; HRMS calcd for C16H19N2O4 (M + H)+, 303.1339, found 303.1345.
N-(7-Methyl-1-oxy-quinolin-8-yl)oxalamic acid (L2): The procedure was the same as
described above for the synthesis of L1. Light brownꢀflaky solid; m.p. 180ꢀ182 °C; 1H NMR (300
MHz, DMSOꢀd6) δ 14.33 (br, 1H), 13.62 (s, 1H), 8.58 (s, J = 5.9 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H),
7.88 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 2.30 (s, 3H); 13C NMR
(75 MHz, DMSOꢀd6) δ 161.4, 155.0, 138.2, 135.0, 133.5, 131.9, 130.2, 127.62, 127.59, 125.5,
121.4, 20.3; HRMS calcd for C12H11N2O4 (M + H)+, 247.0713, found 247.0718.
tert-Butyl N-(pyridin-2-ylmethyl)oxamate (L3b): To a magnetically stirred solution of
2ꢀpicolyamine (1.84 g, 17.0 mmol) and triethylamine (3.40 g, 33.7 mmol) in CH2Cl2 (60 mL) was
added, dropwise, a solution of tertꢀButyl oxalyl chloride (3.10 g, 18.8 mmol) in CH2Cl2 (10 mL).
After it was stirred for 2 h, the mixture was diluted with CH2Cl2 (30 mL) and then washed with
water and brine. The organic layer was dried over Na2SO4 and evaporated. The crude product was
purified with silica gel chromatography to give the L3b (3.52 g, 14.2 mmol, 83.5%). Yellowish
oil; 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 4.5 Hz, 1H), 8.25 (br, 1H), 7.69 (td, J1 =7.7 Hz, J2
= 1.7 Hz, 1H), 7.29 (t, J = 3.5 Hz, 1H), 7.27ꢀ7.20 (m, 1H), 4.62 (d, J = 4.3 Hz, 2H), 1.57 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 159.4, 157.6, 155.2, 149.2, 136.9, 122.7, 122.2, 84.4, 44.7, 27.7;
HRMS calcd for C12H17N2O3 (M + H)+, 237.1234, found 237.1234.
tert-Butyl N-((1-oxy-pyridin-2-yl)methyl)oxamate (L3c): To a magnetically stirred solution
of L3b (2.30 g, 9.75 mmol) in CH2Cl2 (40 mL) was added 75% 3ꢀChloroperbenzoic acid (2.70 g,
11.7 mmol) slowly. After 12 h, K2CO3 (2.70 g, 19.6 mmol) was added into the mixture. It was

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stirred additional 6 h. The reaction mixture was filtered and eluted with CH2Cl2 (60 mL). The
filtrate was concentrated, and the crude product was purified through recrystallization from PE/EA
1
to give the L3c (2.13 g, 8.44 mmol, 86.6%). Whiteꢀcrystalline solid; m.p. 126ꢀ127 °C; H NMR
(300 MHz, CDCl3) δ 8.36 (br, 1H), 8.26 (t, J = 4.2 Hz, 1H), 7.46 (t, J2 = 5.2 Hz, 1H), 7.32ꢀ7.23 (m,
2H), 4.69 (d, J = 6.1 Hz, 2H), 1.54 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.9, 158.0, 146.5,
139.6, 126.5, 126.2, 125.4, 84.6, 39.7, 27.7; HRMS calcd for C12H17N2O4 (M ꢀ H)+, 253.1183,
found 253.1187.
N-((1-Oxy-pyridin-2-yl)methyl)oxalamic acid (L3): To a magnetically stirred solution of
L3b (1.00 g, 3.96 mmol) in CH2Cl2 (30 mL), trifluoroacetic acid (12 ml) was added dropwise.
After it was stirred for 24 h, the reaction solution was concentrated and the resulting residue was
purified through recrystallization from EA to give L3 (0.730 g, 3.72 mmol, 94.0%). White solid;
m.p. 185ꢀ187 °C; 1H NMR (300 MHz, DMSOꢀd6) δ 16.00ꢀ12.00 (br, 1H), 9.33 (t, J = 5.9 Hz, 1H),
8.32 (t, J2 = 2.5 Hz, 1H), 7.44ꢀ7.30 (m, 3H), 4.43 (d, J = 6.2 Hz, 2H); 13C NMR (75 MHz,
DMSOꢀd6) δ 161.6, 158.8, 147.0, 139.0, 125.4, 124.8, 123.7, 38.5; HRMS calcd for C8H9N2O4 (M
+ H)+, 197.0557, found 197.0559.
2-Bromomethyl-4-methoxypyridine (L4a-1): To a magnetically stirred solution of
4ꢀmethoxyꢀ 2ꢀ(hydroxymethyl)pyridine (1.00 g, 7.19 mmol) in CH2Cl2 (40 mL) was added PBr3
(2.54 g, 9.38 mmol) slowly in iceꢀwater bath. After addition, the mixture was brought to reflux for
3 h. The reaction mixture was allowed to cool to room temperature and then added into water (30
ml) slowly. After the mixture was stirred for 5 min, 30 mL K2CO3 (1 M) was added to basify the
mixture. The organic layer was separated and the aqueous layer was extracted by 2*30 ml CH2Cl2.
The organic layer was combined, washed with brine, dried over Na2SO4 and then evaporated. The

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resulting residue as extremely unstable oil was directly used in next step without further
purification. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 5.8 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.73
(dd, J1 = 5.7 Hz, J1 = 2.3 Hz, 1H), 4.50 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4,
158.3, 150.8, 109.5, 109.1, 55.3, 33.9.
2-((4-Methoxy-pyridin-2-yl)methyl)isoindoline-1,3-dione (L4a-2): To a magnetically
stirred solution of the above product in DMF (20 ml) was added Phthalimide K (1.86 g, 10.0
mmol). After it was stirred for 24 h, the reaction mixture was diluted with water (60 mL) and the
aqueous layer was extracted with 3*20 ml ethyl acetate. The organic layer was combined and then
washed with water and brine, dried over Na2SO4 and evaporated. The crude product was purified
through recrystallization from PE/EA to give L4a-2 (1.47g, 5.48 mmol, combined yield of two
1
steps was 76.2%). White solid; m.p. 116ꢀ118 °C; H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 5.7
Hz, 1H), 7.91ꢀ7.83 (m, 2H), 7.76ꢀ7.66 (m, 2H), 6.79 (d, J = 2.1 Hz, 1H), 6.69 (dd, J1 = 5.7 Hz, J2
= 2.3 Hz, 1H), 4.96 (s, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.1, 166.3, 157.0, 150.9,
134.0, 132.2, 123.5, 108.5, 107.7, 55.2, 42.9; HRMS calcd for C15H13N2O3 (M + H)+, 269.0921,
found 269.0918.
(4-Methoxy-pyridin-2-yl)methylamine (L4a):16 To a magnetically stirred solution of L4a-2
(1.07 g, 3.99 mmol) in MeOH (40 ml) was added H2NNH2•H2O (1.25 g, 80%, 20.0 mmol). The
reaction mixture was heated to reflux for 4 h after the addition. The reaction solution was allowed
to cool to room temperature, filtered and then eluted with MeOH (10 mL). The filtrate was
concentrated, added 40 ml H2O and basified by adding 10 mL KOH (1 M). The aqueous layer was
extracted by 4*20 ml DCM. The organic layer was combined, dried over Na2SO4 and evaporated
to give L4a (460 mg, 3.33 mmol) as yellowish oil. 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 4.4

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Hz, 1H), 6.73 (s, 1H), 6.59 (d, J = 3.2 Hz, 1H), 3.82 (s, 2H), 3.74 (s, 3H), 1.99 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 166.2, 163.6, 150.3, 108.1, 106.8, 55.0, 47.7; HRMS calcd for C7H11N2O (M
+ H)+, 139.0866, found 139.0868.
tert-Butyl N-((4-methoxy-pyridin-2-yl)methyl)oxamate (L4b): The procedure was the
1
same as described above for the synthesis of L3b. Colorless oil; H NMR (300 MHz, CDCl3) δ
8.29 (br, 1H), 8.25 (d, J = 5.8 Hz, 1H), 6.70 (s, 1H), 6.65 (dd, J1 = 5.7 Hz, J1 = 2.2 Hz, 1H), 4.45
(d, J = 5.4 Hz, 2H), 3.74 (s, 3H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 166.3, 159.3, 157.5,
157.1, 150.3, 109.0, 107.8, 84.2, 55.1, 44.7, 27.6; HRMS calcd for C13H19N2O4 (M + H)+,
267.1339, found 267.1340.
tert-Butyl N-((4-methoxy-1-oxy-pyridin-2-yl)methyl)oxamate (L4c): The procedure was
the same as described above for the synthesis of L3c. Colorless oil; 1H NMR (300 MHz, CDCl3) δ
8.80 (d, J = 5.7 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.83 (d, J1 = 7.2 Hz, J2
= 3.4 Hz, 1H), 4.67 (d, J = 6.3 Hz, 2H), 3.87 (s, 3H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
158.9, 158.3, 158.1, 147.3, 140.2, 111.6, 111.4, 84.4, 56.2, 39.8, 27.6; HRMS calcd for
C13H19N2O5 (M + H)+, 283.1288, found 283.1296.
N-((4-Methoxy-1-oxy-pyridin-2-yl)methyl)oxalamic acid (L4): The procedure was the
1
same as described above for the synthesis of L3. White solid; m.p. 188ꢀ189 °C; H NMR (300
MHz, DMSOꢀd6) δ 14.0 (br, 1H), 9.27 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.02 (dd, J1 =
7.2 Hz, J2 = 3.5 Hz, 1H), 6.91 (d, J = 3.4 Hz, 1H), 4.42 (d, J = 6.1 Hz, 2H), 3.82 (s, 2H); 13C NMR
(75 MHz, DMSOꢀd6) δ 161.6, 158.9, 157.3, 148.0, 114.0, 110.6, 109.8, 56.3, 38.7; HRMS calcd
for C9H11N2O5 (M + H)+, 227.0662, found 227.0666.
2-Bromomethyl-4-nitropyridine (L5a-1):17 The procedure was the same as described above

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1
for the synthesis of L4a-1. Unstable colorless oil; H NMR (300 MHz, CDCl3) δ 8.89 (d, J = 5.4
Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.97 (dd, J1 = 5.3 Hz, J1 = 2.0 Hz, 1H), 4.67 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 160.1, 154.6, 151.8, 116.2, 115.6, 32.2.
2-((4-Nitro-pyridin-2-yl)methyl)isoindoline-1,3-dione(L5a-2): The procedure was the
same as described above for the synthesis of L4a-2. White solid; m.p. 194ꢀ195 °C; 1H NMR (300
MHz, DMSOꢀd6) δ 8.82 (d, J = 5.4 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 3.7 Hz, 1H), 7.98ꢀ7.84 (m,
4H), 5.12 (s, 2H); 13C NMR (75 MHz, DMSOꢀd6) δ 168.1, 159.1, 154.7, 152.2, 135.1, 132.2,
123.8, 115.8, 114.9, 42.5; HRMS calcd for C14H10N3O4 (M + H)+, 284.0666, found 284.0670.
(4-Nitro-pyridin-2-yl)methylamine (L5a): The procedure was the same as described above
for the synthesis of L4a. Extremely unstable erythrine oil; 1H NMR (300 MHz, CDCl3) δ 8.86 (d,
J = 5. Hz, 1H), 8.10 (s, 1H), 7.89 (d, J1 = 3.6 Hz, 1H), 4.16 (s, 2H), 1.71 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 151.4, 114.3, 113.7, 47.6.
tert-Butyl N-((4-nitro-pyridin-2-yl)methyl)oxamate (L5b): The procedure was the same as
described above for the synthesis of L3b. White solid; m.p. 91ꢀ93 °C; 1H NMR (300 MHz, CDCl3)
δ 8.88 (d, J = 5.3 Hz, 1H), 8.09 (br, 1H), 8.02 (s, J = 1.5 Hz, 1H), 7.96 (dd, J1 = 5.3 Hz, J2 = 1.8
Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.5, 159.2, 157.9,
154.4, 151.6, 115.2, 114.6, 84.8, 44.8, 27.6; HRMS calcd for C12H16N3O5 (M + H)+, 282.1084,
found 282.1086.
tert-Butyl N-((4-nitro-1-oxy-pyridin-2-yl)methyl)oxamate (L5c): The procedure was the
1
same as described above for the synthesis of L3c. Yellowish solid; m.p. 148ꢀ150 °C; H NMR
(300 MHz, CDCl3) δ 8.37 (d, J = 7.1 Hz, 1H), 8.34ꢀ8.26 (m, 2H), 8.11 (dd, J1 = 6.9 Hz, J2 = 2. 9
Hz, 1H), 4.71 (d, J = 6.2 Hz, 2H), 1.54 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.7, 158.3, 1148.3,

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142.2, 140.4, 120.6, 119.6, 85.0, 39.5, 27.6; HRMS calcd for C12H15N3NaO6 (M + H)+, 320.0853,
found 320.0859.
N-((4-Nitro-1-oxy-pyridin-2-yl)methyl)oxalamic acid (L5): The procedure was the same as
1
described above for the synthesis of L3. White solid; m.p. 193ꢀ195 °C; H NMR (300 MHz,
DMSOꢀd6) δ 14.2 (br, 1H), 9.45 (t, J = 5.7 Hz, 1H), 8.53 (d, J = 7.1 Hz, 1H), 8.19 (dd, J1 = 7.2 Hz,
J2 = 3.1 Hz, 1H), 8.11 (d, J = 2.9 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6)
δ 161.5, 159.0, 148.9, 141.8, 140.5, 119.3, 118.3, 38.4; HRMS calcd for C8H7N3NaO6 (M + H)+,
264.0227, found 264.0231.
tert-Butyl N-((5-fluoro-pyridin-2-yl)methyl)oxamate (L6b): The procedure was the same
as described above for the synthesis of L3b. Yellowish oil; 1H NMR (300 MHz, CDCl3) δ 8.41 (d,
J = 2.5 Hz, 1H), 8.17 (br, 1H), 7.41 (td, J1 = 8.5 Hz, J2 = 2.8 Hz, 1H), 7.37ꢀ7.29 (m, 1H), 4.60 (d,
1
J = 5.6 Hz, 2H), 1.57 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.3, 158.8 (d, JCF = 254.1 Hz),
157.6, 151.6 (d, 4JCF = 3.6 Hz), 137.3 (d, 2JCF = 23.9 Hz), 123.7 (d, 2JCF = 18.5 Hz), 123.1 (d, 3JCF
= 4.3 Hz), 84.5, 44.2, 27.7; HRMS calcd for C12H16FN2O3 (M + H)+, 255.1139, found 255.1144.
tert-Butyl N-((5-fluoro-1-oxy-pyridin-2-yl)methyl)oxamate (L6c): The procedure was the
1
same as described above for the synthesis of L3c. Yellowish oil; H NMR (300 MHz, CDCl3) δ
8.44 (br, 1H), 8.24 (dd, J1 = 6.3 Hz, J2 = 2.3 Hz, 1H), 7.49 (t, J = 8.6 Hz, 1H), 7.10 (td, J1 = 7.0 Hz,
J2 = 2.2 Hz, 1H), 4.65 (d, J = 6.4 Hz, 2H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 161.4,
158.9, 158.1, 143.6 (d, 4JCF = 4.0 Hz), 129.6 (d, 2JCF = 35.5 Hz), 126.3 (d, 3JCF = 9.2 Hz), 113.9 (d,
2JCF = 19.6 Hz), 84.5, 38.9, 27.6; HRMS calcd for C12H14FN2O4 (M ꢀ H)ꢀ, 269.0943, found
269.0946.
N-((5-Fluoro-1-oxy-pyridin-2-yl)methyl)oxalamic acid (L6): The procedure was the same

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1
as described above for the synthesis of L3. White solid; m.p. 184ꢀ186 °C; H NMR (300 MHz,
DMSOꢀd6) δ 13.99 (br, 1H), 9.30 (t, J = 5.8 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 7.39 (d, J = 7.4 Hz,
2H), 4.39 (d, J = 5.9 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6) δ 161.5, 159.0 (d, 1JCF = 246.5 Hz),
158.8, 144.3 (d, 4JCF = 3.9 Hz), 129.0 (d, 2JCF = 35.7 Hz), 124.1 (d, 3JCF = 9.7 Hz), 113.3 (d, 2JCF
=
19.9 Hz), 38.1; HRMS calcd for C8H8FN2O4 (M + H)+, 215.0463, found 215.0464.
tert-Butyl N-((3, 5-difluoro-pyridin-2-yl)methyl)oxamate (L7b): The procedure was the
1
same as described above for the synthesis of L3b. Yellowish oil; H NMR (300 MHz, CDCl3) δ
8.32 (d, J = 2.1 Hz, 1H), 8.22 (br, 1H), 7.27 (td, J1 = 9.1 Hz, J2 = 2.3 Hz, 1H), 4.66 (d, J = 5.1 Hz,
2H), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.3, 158.7 (dd, 1JCF = 259.5 Hz, 3JCF = 5.1 Hz),
157.5, 156.2 (dd, 1JCF = 262.4 Hz, 3JCF = 6.1 Hz), 139.6 (dd, 2JCF = 15.8 Hz, 4JCF = 3.7 Hz), 133.1
2
4
2
(dd, JCF = 23.2 Hz, JCF = 4.8 Hz), 111.6 (t, JCF = 21.2 Hz), 84.5, 38.9, 27.7; HRMS calcd for
C12H14F2N2NaO3 (M + Na)+, 295.0865, found 295.0871.
tert-butyl N-((3, 5-difluoro-1-oxy-pyridin-2-yl)methyl)oxamate (L7c): The procedure was
the same as described above for the synthesis of L3c. Colorless oil; 1H NMR (300 MHz, CDCl3) δ
8.27 (br, 1H), 8.11 (t, J = 1.8 Hz, 1H), 7.00 (td, J1 = 7.8 Hz, J2 = 1.9 Hz, 1H), 4.71 (d, J = 5.7 Hz,
1
3
2H), 1.52 (d, J = 1.2 Hz, 9H); 13C NMR (75 MHz, CDCl3) δ 159.2 (dd, JCF = 251. 9 Hz, JCF
=
15.5 Hz), 158.8, 158.1 (dd, 1JCF = 253.4 Hz, 3JCF = 15.0 Hz), 157.7, 134.8 (dd, 2JCF = 36.5 Hz, 4JCF
2
4
2
= 9.4 Hz), 126.7 (dd, JCF = 36.0 Hz, JCF = 5.0 Hz), 103.9 (t, JCF = 24.2 Hz), 84.5, 32.7, 27.6;
HRMS calcd for C12H15F2N2O4 (M + H)+, 289.0994, found 289.1002.
N-((3, 5-Difluoro-1-oxy-pyridin-2-yl)methyl)oxalamic acid (L7): The procedure was the
1
same as described above for the synthesis of L3. White solid; m.p. 183ꢀ184 °C; H NMR (300
MHz, DMSOꢀd6) δ 13.99 (br, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 7.69 (t, J = 8.8 Hz, 1H), 4.48 (d, J =

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2.8 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6) δ 161.5, 158.8 (dd, 1JCF = 246.5 Hz, 3JCF = 17.7 Hz),
1
3
2
4
158.4 (dd, JCF = 248.9 Hz, JCF = 15.6 Hz), 158.3, 134.7 (dd, JCF = 26.8 Hz, JCF = 5.1 Hz),
2
4
2
126.6 (dd, JCF = 36.8 Hz, JCF = 5.0 Hz), 103.5 (t, JCF = 25.2 Hz), 32.5; HRMS calcd for
C8H7F2N2O4 (M + H)+, 233.0368, found 233.0378.
Ethyl N-(2-chlorobenzyl)oxamate (L8b): To a magnetically stirred solution of the
2ꢀchlorobenzylamine (2.40 g, 17.0 mmol) and triethylamine (2.63 g, 26.0 mmol) in CH2Cl2 (60
mL) was added, dropwise, a solution of ethyl oxalyl monochloride (2.32 g, 17.0 mmol) in CH2Cl2
(10 mL). After it was stirred for 2 h, the mixture was diluted with 30 ml CH2Cl2 and then washed
with water and brine。The organic phase was dried over Na2SO4 and evaporated. The crude
product was purified by silica gel chromatography and then recrystallized from PE/EA to give the
amide as white solid (3.36 g, 13.9 mmol, 81.8%). White solid; m.p. 55ꢀ57 °C; 1H NMR (300 MHz,
CDCl3) δ 7.54 (br, 1H), 7.43ꢀ7.34 (m, 2H), 7.30ꢀ7.21 (m, 2H), δ 4.62 (d, J = 6.3 Hz, 2H), 4.34 (q,
J = 7.1 Hz, 2H), δ 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 160.5, 156.5, 134.2,
133.8, 130.4, 129.7, 129.4, 127.2, 63.3, 41.8, 14.0; HRMS calcd for C11H11ClNO3 (M ꢀ H)ꢀ,
240.0433, found 240.0439.
N-(2-Chlorobenzyl)oxalamic acid (L8): To a magnetically stirred solution of the above
product (2.80 g, 11.6 mmol) in a mixture of THF (15 ml) and water (15 ml) was added NaOH (974
mg 17.4 mmol) slowly. After it was stirred for 2 h at room temperature, the mixture was diluted
with water (40 ml) and then washed with ethyl acetate (20 ml). The aqueous layer was extracted
with ethyl acetate after acidified by adding conc. HCl (4 mL). The organic layer was washed with
water and brine, dried over Na2SO4 and evaporated. The crude product was recrystallized from
1
PE/EA to give L8 as white solid (2.20 g, 10.3 mmol, 88.8%). White solid; m.p. 136ꢀ138 °C; H

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NMR (300 MHz, DMSOꢀd6) δ 16.00ꢀ12.00 (br, 1H), 9.37 (d, J = 5.9 Hz, 1H), 7.50ꢀ7.40 (m, 1H),
7.38ꢀ7.24 (m, 3H), δ 4.42 (d, J = 6.2 Hz, 2H); 13C NMR (75 MHz, DMSOꢀd6) δ 161.9, 158.7,
135.2, 131.8, 129.1, 128.7, 128.5, 127.1, 40.3; HRMS calcd for C9H9ClNO3 (M + H)+, 214.0265,
found 214.0272.
tert-Butyl N-methyl-N-(pyridin-2-ylmethyl)oxamate (L10b): An oven dried twoꢀnecked
flask was charged with L11 (944 mg, 4.0 mmol) and a magnetic stir bar, and the flask was fitted
with a rubber septum. The vessel was evacuated and back filled with nitrogen, and this sequence
was repeated additional two times. Anhydrous THF (30 mL) and MeI (1.14 g, 8.0 mmol) were
then added successively. NaH (65%, 220 mg, 6.0 mmol) was added slowly in iceꢀwater bath and
the reaction mixture was stirred at room temperature for 12 h. Saturated NaHCO3 solution was
added very slowly to quench the reaction and 20 mL DCM and 20 mL H2O was then added to the
mixture. Organic layer was separated, washed with brine, dried over Na2SO4 and then
concentrated. The crude product was purified with silica gel chromatography to give L10b (690
mg, 2.74 mmol, 68.4%). Yellowish solid; m.p. 75ꢀ78 °C; the product was analyzed as a about 1:1
mixture of rotamers (25°C); 1H NMR (300 MHz, CDCl3) for the major rotamer: δ 8.56 (t, J = 6.2
Hz, 1H), 7.69 (td, J1 = 7.7 Hz, J2 = 1.6 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H),
4.70 (s, 2H), 3.04 (s, 3H), 1.58 (s, 9H); 1H NMR (300 MHz, CDCl3) for the major rotamer: δ 8.56
(t, J = 6.2 Hz, 1H), 7.73 (td, J1 = 7.7 Hz, J2 = 1.6 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.22 (d, J =
7.5 Hz, 1H), 4.61 (s, 2H), 2.96 (s, 3H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 162.7, 162.42,
162.37, 162.32, 155.9, 155.8, 149.5, 149.2, 137.1, 137.0, 122.8, 122.7, 122.3, 121.3, 84.52, 84.45,
55.4, 51.7, 35.3, 32.3, 27.9, 27.8; HRMS calcd for C13H19N2O3 (M ꢀ H)ꢀ, 251.1390, found
251.1395.

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tert-Butyl N-methyl-N-((1-oxy-pyridin-2-yl)methyl)oxamate (L10c): The procedure was
the same as described above for the synthesis of L3c. White solid; m.p. 117ꢀ119 °C; the product
1
was analyzed as a 5:4 mixture of rotamers (25°C). H NMR (300 MHz, CDCl3) for the major
rotamer: δ 8.29 (t, J = 5.9 Hz, 1H), 7.40ꢀ7.21 (m, 3H), 4.81 (s, 2H), 3.21 (s, 3H), 1.59 (s, 9H); 1H
NMR (300 MHz, CDCl3) for the minor rotamer: δ 8.29 (t, J = 5.9 Hz, 1H), 7.40ꢀ7.21 (m, 3H),
4.77 (s, 2H), 3.04 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 163.0, 162.9, 162.0, 161.6,
146.7, 146.3, 139.6, 126.0, 125.8, 125.4, 124.8, 124.7, 123.7, 84.9, 84.8, 49.1, 45.9, 36.8, 33.2,
27.9, 27.8; HRMS calcd for C13H19N2O4 (M + H)+, 267.1339, found 267.1341.
N-methyl-N-((1-Oxy-pyridin-2-yl)methyl)oxalamic acid (L10): The procedure was the
same as described above for the synthesis of L3. White solid; m.p. 156ꢀ158 °C; the product was
1
analyzed as a 7:5 mixture of rotamers (25°C). H NMR (300 MHz, DMSOꢀd6) for the major
rotamer: δ 14.4 (br, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.60ꢀ7.36 (m, 2H), 7.18 (t, J = 4.6 Hz, 1H), 4.60
(s, 2H), 3.10 (s, 3H); 1H NMR (300 MHz, DMSOꢀd6) for the minor rotamer: 14.4 (br, 1H), 8.34 (d,
J = 2.8 Hz, 1H), 7.60ꢀ7.36 (m, 2H), 7.33 (t, J = 5.0 Hz, 1H), 4.68 (s, 2H), 2.91 (s, 3H); 13C NMR
(75 MHz, DMSOꢀd6) δ 164.5, 164.1, 163.5, 163.4, 145.9, 145.5, 139.3, 139.2, 125.6, 125.4, 125.3,
125.0, 124.3, 123.6, 48.5, 45.3, 36.0, 32.3; HRMS calcd for C9H10N2NaO4 (M + Na)+, 233.0533,
found 233.0538.
N-(pyridin-2-ylmethyl)acetmide (L11a): The procedure was the same as described above
for the synthesis of L3b. 1H NMR (300 MHz, CDCl3) 8.52 (d, J = 4.5 Hz, 1H), 7.67 (td, J1 = 7.7
Hz, J2 = 1.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.20 (dd, J1 = 7.0 Hz, J2 = 5.5 Hz, 1H), 7.11 (br,
1H), 4.55 (d, J = 5.0 Hz, 2H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 156.5, 148.9,
136.9, 122.4, 122.2, 44.5, 23.1; ESIꢀMS m/z 173.1 (M + Na)+.

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N-((1-oxy-pyridin-2-yl)methyl)acetmide (L11): The procedure was the same as described
1
above for the synthesis of L3c. H NMR (300 MHz, CDCl3) 8.25 (dd, J1 = 5.4 Hz, J1 = 1.7 Hz,
1H), 7.51ꢀ7.36 (m, 2H), 7.34ꢀ7.22 (m, 2H), 4.61 (d, J = 6.2 Hz, 2H), 2.00 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.0, 147.2, 138.9, 125.9, 124.5, 38.9, 22.6; HRMS calcd for C8H11N2O3 (M +
H)+, 167.0815, found 167.0816.
General Procedure for the reactions in DMSO. A reaction tube was charged with CuI (2ꢀ2.5
mol %), Ligand (4ꢀ5 mol %), azole (solid, 1.4 equiv), aryl iodide (solid, 1 mmol), K3PO4 (2 mmol)
and a magnetic stir bar, and the reaction tube was fitted with a rubber septum. The vessel was
evacuated and back filled with nitrogen, and this sequence was repeated additional two times.
Azole (liquid, 1.4 equiv), aryl iodide (liquid, 1 mmol) and DMSO (1 mL) were then added
successively. The reaction tube was sealed and stirred in an oil bath at 90 °C for 48 h. The reaction
mixture was cooled to room temperature, diluted with 20 ml water, and extracted with 2*20 ml EA.
The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated. The
resulting residue was purified by silica gel chromatograph using a mixture of PE and EA to give
the desired product. Representative examples are as follows.
1-(4-Methoxyphenyl)-1H-imidazole (1a, 3a, 4a):18 Yellowish solid; 1H NMR (300 MHz,
CDCl3) δ 7.75 (s, 1H), 7.28 (d, J = 8.9 Hz, 2H), 7.19 (s, 1H), 7.17 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H),
3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 135.8, 130.6, 130.0, 123.1, 118.7, 114.8, 55.5;
ESIꢀMS m/z 175.1 (M + H)+.
1
1-(4-Methoxyphenyl)-1H-pyrazole (2a, 5i):10b,18a,b Light brown solid; H NMR (300 MHz,
CDCl3) δ 7.80 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.57 (d, J = 9.0 Hz, 2H), 6.95 (d, J =

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9.0 Hz, 2H), 6.41 (t, J = 2.1 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.2, 140.6,
134.0, 126.8, 120.8, 114.5, 107.2, 55.5; ESIꢀMS m/z 175.1 (M + H)+.
1
1-(4-Methoxyphenyl)-1H-pyrrole (3b):19 White solid; H NMR (300 MHz, CDCl3) δ 7.29
(d, J = 8.9 Hz, 2H), 6.98 (t, J = 1.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.31 (t, J = 1.9 Hz, 2H), 3.80
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.7, 134.5, 122.2, 119.7, 114.7, 109.9, 55.6; ESIꢀMS m/z
174.1 (M + H)+.
1
1-(4-Methoxyphenyl)-1H-indole (3c):12a Yellowish oil; H NMR (300 MHz, CDCl3) δ 7.67
(dd, J1 = 7.0 Hz, J2 = 1.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.24 (d, J =
3.2 Hz , 1H), 7.22ꢀ7.10 (m, 2H), 6.98 (d, J = 8.9 Hz , 2H), 6.45 (d, J = 2.9 Hz , 1H), 3.82 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 158.3, 136.4, 132.9, 129.0, 128.4, 126.0, 122.2, 121.1, 120.2, 114.8,
110.4, 103.0, 55.6; ESIꢀMS m/z 224.1 (M + H)+.
1
1-Phenylꢀ1H-benzimidazole (3d):18b Yellowish oil; H NMR (300 MHz, CDCl3) δ 8.10 (s,
1H), 7.92ꢀ7.84 (m, 1H), 7.60ꢀ7.40 (m, 6H), 7.37ꢀ7.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
144.0, 142.3, 136.3, 133.7, 130.1, 128.0, 124.0, 123.7, 122.8, 120.6, 110.5; ESIꢀMS m/z 217.1 (M
+ Na)+.
1
2-Amino-1-phenylꢀ1H-benzimidazole (3e):8c White solid; H NMR (300 MHz, CDCl3) δ
7.58ꢀ7.48 (m, 2H), 7.48ꢀ7.34 (m, 4H), 7.15ꢀ7.05 (m, 1H), 7.01ꢀ6.92 (m, 2H), 5.84 (br, 2H); 13C
NMR (75 MHz, CDCl3) δ 153.8, 142.3, 135.0, 134.9, 130.3, 128.7, 126.7, 122.0, 119.9, 116.1,
108.3; ESIꢀMS m/z 210.1 (M + H)+.
General Procedure for the reactions in water. A schlenk tube was charged with CuI (5 mol %),
Ligand (10 mol %), azole (solid, 1.4 equiv), aryl halide (solid, 1 mmol), base (2 mol), additive

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(0.1ꢀ0.2 equvi) and a magnetic stir bar, and the reaction tube was fitted with a rubber septum. The
vessel was evacuated and back filled with nitrogen, and this sequence was repeated additional two
times. Aryl halide (liquid, 1 mol), azole (liquid, 1.4 equiv) and solvent (1 mL) were then added
successively. The reaction tube was sealed and stirred in an oil bath for 6ꢀ48 hours. The reaction
mixture was then cooled to room temperature, diluted with 20 ml water, and extracted with 2*20
ml. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated. The
resulting residue was purified by silica gel chromatograph using a mixture of PE and EA to give
the desired product. Representative examples are as follows.
1-Phenyl-1H-imidazole (4b):3f,12a,18,19 Yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.86 (s,
1H), 7.47 (t, J = 7.8 Hz, 2H), 7.42ꢀ7.32 (m, 3H), 7.28 (s, 1H), 7.20 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 137.3, 135.5, 130.3, 129.9, 127.5, 121.4, 118.2; ESIꢀMS m/z 145.0 (M + H)+.
1-(4-Methylphenyl)-1H-imidazole (4c):18a,b,20 Yellowish oil; 1H NMR (300 MHz, CDCl3) δ
7.72 (s, 1H), 7.19ꢀ7.12 (m, 5H), 7.09 (s, 1H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.4,
135.6, 134.9, 130.3, 130.1, 121.4, 118.3, 20.9; ESIꢀMS m/z 159.1 (M + H)+.
1-(4-Fluorophenyl)-1H-imidazole (4d):21 Yellowish oil; 1H NMR (300 MHz, CDCl3) δ 7.80
(s, 1H), 7.42ꢀ7.31 (m, 2H), 7.23 (s, 1H), 7.21ꢀ7.11 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 161.5
(d, 1JCF = 245.8 Hz), 135.6, 133.5, 130.3, 123.3 (d, 3JCF = 8.5 Hz), 118.5, 116.6 (d, 2JCF = 22.8 Hz);
ESIꢀMS m/z 163.1 (M + H)+.
1
Ethyl 4-(imidazol-1-yl)benzoate (4e):3f,18a,20c White solid. H NMR (300 MHz, CDCl3) δ
8.17 (d, J = 8.5 Hz, 2H), 7.97 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.25 (s, 1H), 4.41 (q,
J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.5, 140.6, 135.4, 131.4,