N2,N2′-disubstituted oxalic acid bishydrazides: Novel ligands for copper-catalyzed Ci￡N coupling reactions in water

Article abstract of DOI:10.1002/aoc.1765

A series of N²,N²′-disubstituted oxalic acid bishydrazides were synthesized. Some, for example, N²,N ²′-di-1-(4-methoxyphenyl)-ethanyloxylic-(bishydrazide), are novel and effective ligands for copper-catalyzed Ullmann-type Ci￡N coupling reaction in water. A variety of amines could be effectively N-arylated with aryl halides under both microwave irradiation and conventional heating (even at 30 °C) with good to excellent yields.

Full text of DOI:10.1002/aoc.1765

Full Paper
Received: 9 August 2010
Revised: 29 October 2010
Accepted: 7 November 2010
Published online in Wiley Online Library: 9 February 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1765
ꢀ
N2,N2 -disubstituted oxalic acid bishydrazides:
novel ligands for copper-catalyzed C–N
coupling reactions in water
Fei Meng, Chenxia Wang, Jianwei Xie, Xinhai Zhu and Yiqian Wan∗
A series of N2,N2ꢀ-disubstituted oxalic acid bishydrazides were synthesized. Some, for example, N2,N2ꢀ-di-1-(4-methoxyphenyl)-
ethanyloxylic-(bishydrazide), are novel and effective ligands for copper-catalyzed Ullmann-type C–N coupling reaction in
water. A variety of a◦mines could be effectively N-arylated with aryl halides under both microwave irradiation and conventional
c
heating (even at 30 C) with good to excellent yields. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: amination; cross-coupling; copper; microwave chemistry; water chemistry
Introduction
vided a general means for amination of aryl bromides and aryl
iodides with a variety of amines at room temperature.[17] How-
ever, the large amount of BCO (50 mol%) or oxalyldihydrazide
(50 mol%) and ketones (100 mol%) that were required, and a lack
of understanding of why ketones are necessary in the oxalyl-
dihydrazide–ketone–CuO system, persuaded us to improve our
protocols. Moreover, we have found pyrrole-2-carbohydrazides to
be novel ligands for Cu-catalyzed Ullmann C–N coupling reac-
tions in pure water.[18] The broad substrate range, low catalyst
loading, short reaction times, and availability of various copper
sources encouraged us to explore in detail oxalyldihydrazides as
ligands. Furthermore, based on the intriguing work by Efetova
and coworkers,[19] we postulated that N2,N2ꢁ-disubstituted oxalic
acid bishydrazides may be a class of effective ligands for copper
catalylzed C–N coupling. Here, we report the syntheses of various
N2,N2ꢁ-disubstituted oxalic acid bishydrazides and their applica-
tion as novel ligands for copper-catalyzed C–N coupling reaction
in water.
C–N bond formation catalyzed by transition metals (such as
palladium and copper) has received extensive attention for its
essential role in synthesis of numerous important pharmaceutics
and materials.[1] However, the traditional Cu-mediated C–N cross-
coupling, such as Ullmann and Goldberg reactions, has limited
practical application due to the requirement for stoichiomeric
amounts of copper reagents and harsh reaction conditions.
Recently, the process of copper catalyzed C–N coupling has been
invigorated by cleverly designed ligands (such as diamines,[2]
amino acids,[3] diols,[4] triols,[5] β-diketones,[6] imines,[7] amino
alcohols,[8] diazaphospholane[9] and others[10]), and also by the
development of sustainable protocols that avoid toxic and/or high
boiling point organic solvents. Several groups have successfully
performed the Ullmann-type C–N reactions in pure water or
aqueousmedia.[11] Forexample,pyridineN-oxides[12] andthiazolyl
phosphine compounds[13] were found to be effective ligands for
Cu-catalyzed arylations with aryl bromides and iodides in aqueous
media, and primary aryl amines were prepared in aqueous DMSO
withCuI/proline-catalyzedaminationofarylhalides.[14] Inaddition,
Larhed and co-workers showed that the copper-catalyzed N-
arylation of free and protected amino acids could be carried
out in the KI aqueous solution under microwave irradiation.[15]
Moreover, ligand-free CuI-catalyzed C–N bond formation was
accomplished in 40% n-Bu4N+ OH− under argon atmosphere.[16]
However, since reactions in water or aqueous media often require
harsh conditions (such as high temperature, long reaction times),
a general and mild procedure for copper-catalyzed amination
of aryl halides in water still needs to be established. Recently,
strong microwave heating has become a helpful tool because
of its rapid and convenient superheating and excellent reaction
control.[15] Thus, the combination of ‘water’ and ‘microwave’ may
be a promising approach to improve the water-based reaction of
C–N bond formation.
Results and Discussion
To determine if the hydrogen atoms on the non-amide ni-
trogen atoms of oxalic acid bishydrazides play a key role
in copper-catalyzed C–N coupling in water, L1 and L2 were
synthesized (Fig. 1, Scheme 1). BCO was initially reduced to
N2,N2ꢁ-dicyclohexyloxylic-bishydrazide (Scheme 1, method A, L1),
which was further methylated to produce N2,N2ꢁ-dicyclohexyl-
N2,N2ꢁ-dimethyloxalicbishydrazide (Scheme 1, method C, L2). The
activities of all three ligands (Fig. 1, L0,L1 and L2) in promot-
ing the CuO catalyzed C–N coupling, utilizing 4-bromoanisole
∗
Correspondenceto:Yiqian Wan,SchoolofChemistryandChemicalEngineering,
Sun Yat-sen University, Guangzhou 510275, People’s Republic of China.
E-mail: ceswyq@mail.sysu.edu.cn
We recently described BCO [bis(cyclohexanone) oxalyldihy-
drazone]–CuO and oxalyldihydrazide–ketone–CuO systems to
carry out amination of aryl halides in water. Both protocols pro-
School of Chemistry and Chemical Engineering, Sun Yat-sen University,
Guangzhou 510275, People’s Republic of China
c
Appl. Organometal. Chem. 2011, 25, 341–347
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

F. Meng et al.
O
O
O
H
H
N
H
N
H
N
N
NH2
N
N
N
H2N
N
H
N
H
N
H
H
O
O
O
BCO
L0
L I
O
O
H
N
H
O
H
H
N
H
N
N
N
N
N
N
N
N
N
H
N
H
H
H
H
O
O
O
L3
L4
L2
O
H
N
H
N
O
O
H
N
H
N
H
N
H
N
O
H
N
H
N
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
O
H
O
O
L8
O
L7
L5
L6
O
O
O
H
N
H
N
H
N
H
H
H
N
N
N
N
N
H
N
H
N
H
N
N
H
H
H
O
O
O
L9
L10
L11
NO2
O
H
H
N
O
O
N
H
H
N
H
N
H
N
N
N
H
N
H
O
O2N
L13
O
O
L12
Figure 1. Structures of oxalic acid bishydrazides.
O
O
O
R
C
H
H
+
H
R'
N
N
H2N
N
R
R'
N
H
NH2
C
R
N
H
N
R'
CH3OH
O
O
O
R
O
R
H
H
H
N
Method C R'
N
N
R'
N
Method A
Method B
N
H
N
R'
N
N
R'
H
H
R
O
R
O
Method A: NaBH4/CH3OH for ligands L1, L3-L4, L7-L10, and L12
Method B: Et3SiH/CF3COOH for ligands L11, and L13
Method C: CH3I/Pyr./DMF for ligand L2
O
H
H
N
H
N
Method D
N
R''
R''
NH2
R'
N
N
H
H
O
Method D: diethyl oxalate/CH3OH/H+ for ligands L5, and L6
Scheme 1. Synthetic routes of the ligands.
structure–activity relationship. Most oxalic acid bishydrazides
were prepared readily by reduction of the corresponding
oxalyldihydrazone with metal hydrides or by transesterification
of hydrazines with diethyl oxalate (Scheme 1, methods A and
D) according to published methods with minor modifications
as needed. For example, a mixture of DCM (dichloromethane)
and methanol (v/v, 5 : 1) can be used effectively as a solvent to
obtain L12 (Fig. 1) with an acceptable yield from reduction of
corresponding oxalyldihydrazone with NaBH4. On the other hand,
triethylsilane–TFA was a more effective reducatant than NaBH4
when synthesizing L11 and L13 (Scheme 1, method B) from its
oxalyldihydrazone precursors.
AsillustratedinFig. 2, mostoxalicacidbishydrazides(butL0and
L2), were potential ligands to promote the model reaction, and
neither electronic nor steric effects of substituents on non-amide
nitrogen atoms had any influence on their efficiency. However,
electron-rich N2,N2ꢁ-diaralkyl oxalic acid bishydrazides (such as
H
CuO 5 mol %
Br
NH2
N
L 20 mol %
KOH/TBAB
H2O,MW
130°C 5 min
O
O
Scheme 2. The model reaction to test effect of oxalic acid bishydrazides as
ligands for copper catalytic C–N cross coupling reaction in water.
reacting with aniline as the model reaction (Scheme 2), were ex-
plored. As shown in Fig. 2, the difference between their yields
of 4-methoxy-N-phenylbenzenamine in the model reaction when
L1,L0 andL2 were applied as ligands (48%, L1; trace,L0; trace,L2)
indicated that methyl group and the free hydrogen atoms on non-
amide nitrogen atoms were necessary for L1 to be an effective
ligand, although the mechanism remains unknown.
A series of oxalic acid bishydrazides (Fig. 1) was synthesized
(Scheme 2) to obtain more effective ligands and to explore their
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 341–347

ꢁ
N2,N2 -disubstituted oxalic acid bishydrazides
catalyst, Cu-sources and the proportions of the starting materials,
catalyst and ligands in the model reaction (Table 1).
To assess the application capacity of the CuO–L12 catalyst
system, a variety of functionalized aryl halides animated with
anilines, benzylamine and aliphatic amines in the optimized
conditions was tested [Table 1 entry 23: amine (500 mol%), CuO
(5 mol%), L12 (25 mol%), TBAB (50 mol%), KOH (200 mol%), H2O
(2 ml), 130 ◦C, MW]. The data are tabulated in Tables 2 and 3.
As shown in Table 2, the N-arylation of anilines with most aryl
bromides, whether they were electron-rich, electron-neutral or
electron-poor, provided the desired products with good yields
(Table 2, entries 1–4, 6 and 7). It was intriguing that N-arylation of
aniline with 1-bromo-4-(trifluoromethyl)-benzene (Table 2, entry
5) afforded only a 45% yield due to the extremely low reactivity
of 1-bromo-4-(trifluoromethyl)benzene (about 21% unreacted,
measured by GC analysis). In contrast, N-arylation of aniline with
1-bromo-4-nitrobenzene (Table 2, entry 8) gave a 43% yield due
to the high reactivity of 1-bromo-4-nitrobenzene, which often
caused some side-reactions (for example, hydroxylation) in water.
All aryl bromides and iodides reacted readily with benzylamine
(Table 3), similar to the arylation of anilines. It should be noted that
68% yield for N-benzyl-2-methylaniline demonstrated no obvious
steric ortho-effect (Table 3, entry 4). The liner and cyclic aliphatic
primary amines were arylated smoothly under the experimental
conditions. In addition, these reactions exhibited good selectivity
Figure 2. Effect of various N2,N2ꢁ-disubstituted oxalic acid bishydrazides
as ligands to promote CuO-catalyzed C–N coupling of 4-bromoanisole
reacting with aniline. Reaction conditions: 0.5 mmol of 4-bromoanisole,
5 mol%CuO, 20 mol%ligands, 400 mol%amine, 200 mol%KOH, 100 mol%
TBAB, 1 ml H2O, 5 min at 130 ◦C under microwave irradiation.
L10–L12 in Fig. 2) exhibited higher efficiency than that of their
electron-poor cousins (L13, Fig. 2).
EncouragedbytheseresultsandthefactthatL12(Fig. 2)wasthe
most effective ligand for the CuO catalytic system, we optimized
the conditions of the base, time, temperature, phasetransfer
Table 1. Effect of catalyst, base, temperature, PTC (phase transfer catalyst) and time on the coupling reaction of 4-bromoanisole with anilinea
H
N
Br
NH2
Cu-source,base
PTC,Ligand
H2O,MW
O
O
3
1
2
Catalyst
(%mol)
Ligand
(%mol)
Temperature
(◦C)
Time
(min)
Conversion
(%)
Yield
(%)b
Entry
2 : 1
Base (%mol)
PTC (%mol)
1
CuO(5)
CuO(5)
CuO(5)
CuCl2(5)
CuCl(5)
CuI(5)
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
15
25
25
25
25
25
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(100)
KOH(300)
KOH(200)
KOH(200)
KOH(200)
K3PO4(200)
K2CO3(200)
Cs2CO3(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
KOH(200)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
SDS-Na(100)
PEG400(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(100)
TBAB(50)
130
140
120
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
7
5
92
63
85
84
89
74
80
77
63
64
93
60
89
94
47
35
54
90
98
97
90
95
99
74
51
69
68
70
60
66
52
45
57
66
48
70
75
42
33
47
72
77
82
77
83
93
2
3
4
5
6
7
Cu2O(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
Cu(5)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuO(3)
CuO(10)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
CuO(5)
a Reaction conditions: 0.5 mmol of 4-bromoanisole, aniline, catalyst, ligand (L12), base, PTC, H2O (1.0 ml), microwave (100 W).
b Calculated by GC/MS.
c
Appl. Organometal. Chem. 2011, 25, 341–347
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F. Meng et al.
Table 2. Microwave-assisted
coupling ꢁ reactions
of
aryl
Table 3. microwave-assisted coupling reactions of aryl halides
halides with anilines using N2,N2 -di-1-(4-methoxyphenyl)-
ꢁ
with aliphatic amines using N2,N2 -di-1-(4-methoxyphenyl)-
ethanyloxylicbishydrazide (L12) as the ligand in watera
ethanyloxylicbishydrazide (L12) as the ligand in watera
H
N
CuO 5 mol %
NH2
L12 25 mol %
CuO 5 mol %
L12 25 mol %
X
X
Aliphatic amines
Arylamine
3
R
R'
ArX
1a
R
R
R'
KOH/TBAB
KOH/TBAB
H2O, MW
3
H O, MW
1
2
2
2
1
Yield (%)b
83
Entry
1
ArX
Amine
Product
Yield (%)b
87
Entry
1
Amine
Product
N
NH2
Br
Br
Br
NH2
H
N
2c
O
O
O
3a
2a
1a
O
75c
79d
80
3i
81c
82d
84
2
3
H
N
NH2
Br
Br
2
3
4
5
NH2
NH2
NH2
H
O
N
1a
1b
2c
2c
2c
2b
O
3b
1b
3j
76d
79
73d
83
H
N
NH2
2a
Br
1c
H
N
3c
3k
3l
74d
80
81d
68
H
N
4
5
Br
1c
NH2
2a
Br
H
N
3d
1i
74d
45
66d
72
NH2
2a
Br
H
N
Br
NH2
H
N
F C
2c
1d
3
F3C
F3C
1d
3e
F3C
49d
84
3m
67d
85
H
N
6
7
NH2
2a
Br
Br
6
7
Br
NH2
NH2
H
CI
N
1e
1f
2c
2c
CI
Cl
3f
1e
81d
85
Cl
3n
79d
86
H
N
NH2
2a
Br
Br
H
N
3g
O
O
1f
O
3e
76d
43
O
78d
46
8
9
Br
NH2
2a
H
N
8
NH2
O N
H
1g
2
O2N
N
3h
2c
O N
1g
44d
68
2
O2N
3p
I
H
N
NH2
2a
43d
85
1h
9
NH2
NH2
l
3d
H
N
72d
2c
2c
1h
3k
a Reaction conditions: ArX (1.0 mmol), anilines (5.0 mmol), CuO
(0.05 mmol), L12 (0.25 mmol), KOH (2 mmol), TBAB (0.5 mmol), H2O
(2.0 ml), 130 ◦C, 5 min, microwave (100 W).
80d
83
l
10
H
N
b Isolated yield.
O
1j
3i
O
c Reaction conditions: 90 ◦◦C, 8 h, heated in oil bath.
80d
18
d Reaction conditions: 30 C, 48h, sealed vial in oil bath.
Cl
11
NH2
H
N
2c
F3C
1k
F3C
3m
Traced
73
for primary amines over secondary amines (Table 3, entries 14
and 15). We also examined the benzylamination for less-reactive
1-chloro-4-(trifluoromethyl)benzene (Table 3, entry 11) under the
optimized reaction conditions, whereby the targeted compound
was obtained with only 18% yield. This experiment will benefit the
future study of copper-catalyzed aminations of aryl chlorides in
water.
For industrial scale synthesis, it is necessary to extend
the CuO–L12 catalyst system from microwave heating to a
conventional heating mode. We conducted the corresponding
H
12
13
Br
Br
NH2
2d
N
O
O
1a
1a
O
3q
69d
87
H
N
NH2
2e
O
3r
77d
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 341–347

ꢁ
N2,N2 -disubstituted oxalic acid bishydrazides
was carried out with Merck silica gel 60F254 plates. 1H NMR spectra
were recorded at room temperature on a Varian Mercury-Plus
300 or 400 instrument with TMS as an internal reference. Liquid
chromatography–mass spectra were recorded on a Shimadzu
LCMS-2010A instrument, GC–MS spectra were recorded on a
Finnegan Voyager GC/MS instrument with an electron impact
(70 eV) mass selective detector, EI mass spectra were recorded on
the Thermo DSQ mass spectrometer and FAB mass spectra was
run on the VGA-ZAB-HS. Element analyses were carried out on
an Element Vario EL series element analyzer. Melting points were
determined on a WRS-1B digital melting point apparatus. Ligands
L3, L5, L6, L7, L8, L10 and all products of amination of aryl halides
Table 3. (Continued)
CuO 5 mol %
L12 25 mol %
X
Aliphatic amines
Arylamine
3
R
KOH/TBAB
H2O, MW
2
1
Entry
14
ArX
Amine
Product
Yield (%)b
Br
43
O
H
N
N
O
O
1a
1a
O
O
2f
3s
49d
25
1
15
Br
were known compounds and identified by comparison their H
and 13C spectra data with those reported in the literature.
NH
2g
N
O
3t
27d
General Procedure A for the Synthesis of Ligands
a Reaction conditions: ArX (1.0 mmol), amines (5.0 mmol), CuO
(0.05 mmol), L12 (0.25 mmol), KOH (2.0 mmol), TBAB (0.5 mmol), H2O
(2.0 ml), 130 ◦C, 5 min, microwave (100 W).
Synthesis of L1
b Isolated yield.
To a 100 ml round bottom flask were added N2,N2ꢁ-dicyclo-
hexylideneoxalohydrazide (1.39 g, 5.0 mmol) and methanol
(30 ml); NaBH4 (0.46 g, 12.0 mmol) was then added to the mix-
ture in an ice bath under a nitrogen atmosphere. After removal of
the ice bath the mixture was stirred at room temperature for 1.5 h
andfiltered, thesolidwaswashedwithwater(20 ml)andmethanol
(15 ml), and purified by flash column chromatography on silica gel
(dichloromethane as elu◦ent) to yield L1 (1.13 g, white solid, 80%
yield). M.p.: 224.3–225.9 C. 1H NMR (300 MHz, CDCl3) δ: 2.77–2.85
(m, 2H, CH–N), 1.15–1.90 (m, 20H, CH2). 13C NMR (75 MHz, CDCl3)
δ: 157.8 (C O), 59.1 (CH–N), 31.2 (CH2 –CH), 25.8 (CH2 –CH2),
24.4(CH2 –CH2 –CH). IR (KBr, cm−1): ν(N–H): 3203, ν(C O): 1663.
ESI-MS: m/z = 283 [M + H]+. Anal. calcd for C14H26N4O2 = C,
59.55; H, 9.28; N, 19.84. Found: C, 59.35; H, 9.133; N, 19.58.
c Reaction conditions: 90 ◦◦C, 8 h, heated in oil bath.
d Reaction conditions: 30 C, 48 h, sealed vial in oil bath.
reactions at 30 ◦C in an oil bath. Good-to-excellent isolated yields
of desired products were obtained only with prolonged reaction
time (48 h, tabulated in Tables 2 and 3). Additionally, two typical
example reactions (Tables 2 and 3, entry 1) performed well and
also gave excellent yields within 8 h at 90 ◦C. These results would
benefit organic chemists in developing a practical C–N coupling
reaction in water.
Conclusion
General Procedure B for the Synthesis of Ligands
In conclusion, a series of N2,N2ꢁ-disubstituted oxalic acid bishy-
drazides have been synthesized and demonstrated to be novel
and effective ligands for copper-catalyzed Ullmann-type C–N
coupling reaction in water. Moreover, we have established a
novel, practical and economic catalytic system, CuO–N2,N2ꢁ-di-1-
(4-methoxyphenyl)-ethanyloxylicbishydrazide (L12), which effec-
tively catalyzes N-arylations of various amines with aryl bromides
and aryl iodides in water without N2 protection under microwave
irradiation or conventional heating. Given the usefulness of oxalic
acid bishydrazides in Ullmann-type C–N coupling in water, we
believe, therefore, that the procedure presented herein may be
of great applicability in C–N bond formation in water or aqueous
media for academic or industrial formations.
Synthesis of L2
To a 100 ml round-bottom flask were added N2,N2ꢁ-dicyclo-
hexyloxalohydrazide (0.7 g, 2.5 mmol), pyridine (0.79, 10.0 mmol),
iodomethane (1.42g, 10.0 mmol) and DMF (20 ml). After stirring
at 60 ◦C for 3 h, the mixture was added to water (30 ml), and
filtered. The solid was collected, washed with methanol (20 ml),
and purified by flash column chromatography on silica gel eluting
with a mixture of dichloromethane–methanol (60 : 1) to yield
L2 (0.47g, white solid, 60% yield). M.p.: 223.7–224.3 C. H NMR
(300 MHz, CDCl3) δ: 8.12 (s, 2H, NH), 2.6 (s, 6H, CH3 –N), 2.58–2.56
(m, 2H, CH–N), 1.93–1.18 (m, 20H, CH2). 13C NMR (75 MHz, CDCl3)
δ: 157.6(C O), 65.1 (CH–N), 42.3 (CH3 –N), 28.78 (CH2 –CH), 25.63
(CH2 –CH2), 24.94 (CH2 –CH2 –CH). IR (KBr, cm−1): ν(N–H): 3203,
ν(C O): 1659. ESI-MS: m/z = 311 [M + H]+. Anal. calcd for
C16H30N4O2 = C, 61.9; H, 9.74; N, 18.05. Found: C, 61.99; H, 9.597;
N, 17.93.
◦
1
Experimental
General Methods and Materials
Unless otherwise noted, all chemicals were commercially available
and used as received. All microwave assisted C–N coupling
reactions were carried out on the CEM discover system (model no.
908010, manufactured by CEM Company in USA, with vertically
focused IR temperature control system, maximum microwave
power 300 W, frequency 2.455 GHz) in 10 ml vials sealed with
a septum with a stirring option. Flash column chromatography
was performed with silica gel (200–300 mesh) purchased from
Qingdao Haiyang Chemical Co. Ltd. Thin-layer chromatography
General Procedure C for the Synthesis of Ligands
Synthesis of L3[20]
To a 100 ml of three-necked round bottom flask were added
oxalohydrazide (1.18 g, 10.0 mmol), cyclopentanone (1.85 g,
22.0 mmol), methanol (50 ml) and glacial acetic acid (0.1 ml), and
the mixture was refluxed for 3 h. After cooling to room temper-
ature, NaBH4 (0.91 g, 24.0 mmol) was added in ice bath under a
c
Appl. Organometal. Chem. 2011, 25, 341–347
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F. Meng et al.
nitrogen atmosphere. Then the mixture was stirred at room tem-
perature for another 1 h and filtered, the solid was washed with
water (20 ml) and methanol (15 ml), and purified by flash column
chromatography on silica gel using dichloromethane–methanol
(40 : 1) as eluent to yield L3 (1.91 g, white solid,75% yield).
Synthesis of L12
Oxalohydrazide (1.18 g, 10.0 mmol), 1-(4-methoxyphenyl)
ethanone (3.30 g, 22.0 mmol), methanol (30 ml), glacial
acetic acid (0.1 ml), NaBH4 (0.91 g, 24.0 mmol) and
dichloromethane–methanol(v/v,5 : 1,50 ml)wereused.Thecrude
productwaspurifiedbyflashcolumnchromatographyonsilicagel
eluting with a mixture of dichloromethane–methanol (40◦: 1) to
yield L12 (2.32g, white solid, 60% yield). M.p.: 174.7–175.1 C. 1H
NMR (300 MHz, CDCl3) δ: 7.25(d, J = 8.4 Hz, 4H, CH arom), 6.87(d,
J = 8.4 Hz, 4H, CH arom), 4.05(q, J = 6.3 Hz, 2H, CH–N), 3.81 (s, 6H,
CH3 –O), 1.38(d, J = 6.3 Hz, 6H, CH3 –CH). 13C NMR(75 MHz, CDCl3)
δ: 159.1 (C O), 157.3 (C–O arom), 133.8 (C–CH arom), 128.0 (C
arom), 114.0 (C arom), 59.5 (CH–N), 55.3 (CH3 –O), 21.2 (CH3 –CH).
IR (KBr, cm−1): ν(N–H): 3318, ν(C O): 1651. FAB+-MS: m/z = 387
[M + H]+. Anal. calcd for C20H26N4O4· 1/5H2O = C, 61.59; H, 6.82;
N, 14.36. Found: C, 61.86; H, 6.714; N, 14.28.
Synthesis of L4
Oxalohydrazide (1.18 g, 10.0 mmol), 2-adamantanone (3.3 g,
22.0 mmol), methanol (50 ml), glacial acetic acid (0.1 ml) and
NaBH4 (0.91 g, 24.0 mmol) were used. The crude product was
purified by flash column chromatography on silica gel eluting
with a mixture of dichloromethane–methanol, (40 : 1) to yield
L4 (1.91 g, white solid, 75% yield). M.p.: 263.0–263.7 ◦C. 1H NMR
(300 MHz, CDCl3) δ: 3.12–3.06 (m, 2H, CH–N), 2.14–1.51 (m, 28H,
CH2 –CH). 13C NMR (75 MHz, CDCl3) δ: 157.7 (C O), 64.0 (CH–N),
37.7 (CH–CH–CH2), 37.0 (CH–CH–CH2), 31.2 (CH–CH2 –CH), 30.9
(CH–CH2 –CH), 27.6 (CH2 –CH–CH2). IR (KBr, cm−1): ν(N–H): 3281,
ν(C O): 1659. ESI-MS: m/z = 387 [M + H]+. Anal. calcd for
C22H34N4O2 = C, 68.36; H, 8.87; N, 14.49. Found: C, 68.18; H, 8.727;
N, 14.38.
General Procedure D for the Synthesis of Ligands
Synthesis of L5[20]
To a 100 ml round bottom-flask were added phenylhydrazine
(1.19 g, 11.0 mmol), diethyl oxalate (0.73 g, 5.0 mmol), methanol
(50 ml) and glacial acetic acid (0.1 ml). The mixture was refluxed
for 5 h and then cooled to room temperature, and the resulting
solid was collected and washed with water (20 ml) and methanol
(15 ml), and purified by flash column chromatography on silica gel
eluting with a mixture of dichloromethane–methanol (40 : 1) to
afford L5 (1.15g, white solid, 85% yield).
Synthesis of L7[20]
Oxalohydrazide (1.18 g, 10.0 mmol), propan-2-one (1.28 g,
22.0 mmol), methanol (50 ml), glacial acetic acid (0.1 ml) and
NaBH4 (0.91 g, 24.0 mmol) were used. The crude product was
purified by flash column chromatography on silica gel eluting
with a mixture of dichloromethane–methanol, (40 : 1) to yield L7
(1.54g, white solid, 76% yield).
Synthesis of L6[21]
Synthesis of L8[20]
Methylhydrazine(1.02 g, 8.8 mmol), diethyl oxalate (0.58 g,
4.0 mmol), methanol (50 ml) and acetic acid glacial (0.1 ml) were
used. The crude product was purified by recrystallization (DCM
50 ml) to yield L6 (0.28 g, white solid, 48%).
Oxalohydrazide (1.18 g, 10.0 mmol), butan-2-one (1.58 g,
22.0 mmol), methanol (50 ml), glacial acetic acid (0.1 ml) and
NaBH4 (0.91 g, 24.0 mmol) were used. The crude product was
purified by flash column chromatography on silica gel eluting with
a mixture of dichloromethane–methanol (40 : 1) to yield L8 (1.5g,
white solid, 65% yield).
General Procedure E for the Synthesis of Ligands
Synthesis of L11
Synthesis of L9[20]
To a 100 ml three-necked round bottom flask were added oxalo-
hydrazide (1.18 g, 10.0 mmol), acetophenone (2.64 g, 22.0 mmol),
methanol (30 ml) and glacial acetic acid (0.1 ml), then the mixture
wasrefluxedfor3 h. Afteroxalohydrazidehadbeenconsumed, the
reaction mixture was filtered. After washing with water (20 ml) and
methanol (20 ml), the crude product was not futher purified. The
crude product (1.0 mmol) was dissolved in CF3COOH (20.0 mmol)
and triethylsilane (2.0 mmol) was added. The resulting solution
was stirred at 0 ◦C for 2 h. The mixture was acidified with 15 ml HCl
(10% aq.) and washed with hexane (15 ml). The pH of the aqueous
layer was slowly basified with KOH pellets to 7–8 and extracted
with dichloromethane (20 ml × 3). The combined organic extracts
were dried by Na2SO4 and evaporated to give a crude product
which was purified by flash column chromatography on silica
gel eluting with a mixture of dichloromethane–methanol (40 : 1)
to yield L11 (2.00g, white solid, 62% yield). M.p. : 142.1–142.5 ◦C.
1H NMR (300 MHz, CDCl3) δ: 7.38–7.27 (m, 10H, CH arom), 4.11
(q, J = 6.6 Hz, 2H, CH–CH3), 1.42 (d, J = 6.6 Hz, 6H, CH3 –CH).
13C NMR (75 MHz, CDCl3) δ: 157.5 (C O), 141.6 (CH–CH arom),
128.7 (C arom), 128.0 (C arom), 127.0 (C arom), 60.1 (CH–CH3),
20.8 (CH3 –CH). IR (KBr, cm−1): ν(N–H): 3304, ν(C O): 1640. MS
(EI, m/z): 326 (4) [M+ ], 105 (100). Anal. calcd for C18H22N4O2 = C,
66.48; H, 6.973; N, 17.17. Found: C, 66.48; H, 6.973; N, 17.17.
Oxalohydrazide (1.18 g, 10.0 mmol), hexan-2-one (2.20 g,
22.0 mmol), methanol (50 ml), glacial acetic acid (0.1 ml) and
NaBH4 (0.91 g, 24.0 mmol) were used. The crude product was
purified by flash column chromatography on silica gel eluting
with a mixture of dichloromethane–methanol (40 : 1) to yield L9
(2.00 g, white solid, 70% yield). M.p.: 128.7–129.1 ◦C. 1H NMR
(300 MHz, CDCl3) δ: 3.01–2.94 (m, 2H, CH–NH), 1.51–0.92 (m, 24H,
CH2 –CH3). 13CNMR(75 MHz, CDCl3)δ:157.8(C O), 50.1(CH–NH),
34.5 (CH–CH2 –CH2), 28.0 (CH2 –CH2 –CH2), 22.8(CH2 –CH2 –CH3),
18.5 (CH3 –CH), 14.0 (CH3 –CH2). IR (KBr, cm−1): ν(N–H): 3288,
ν(C O): 1650. ESI-MS: m/z = 287 [M + H]+. Anal. calcd for
C14H30N4O2 = C, 58.71; H, 10.56; N, 19.56. Found: C, 58.95; H,
10.47; N, 19.47.
Synthesis of L10[20]
Oxalohydrazide (1.18 g, 10.0 mmol), benzaldehyde (2.33 g,
22.0 mmol), methanol (50 ml), glacial acetic acid (0.1 ml), and
NaBH4 (0.91 g, 24.0 mmol) were used. The crude product
was purified by flash column chromatography on silica gel
(dichloromethane–methanol, 40 : 1) to yield L10 (1.79g, white
solid, 60% yield).
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 341–347

ꢁ
N2,N2 -disubstituted oxalic acid bishydrazides
Synthesis of L13
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (ethyl acetate–petroleum ether as
eluent) to yield 3a–t (Tables 2 and 3).
Oxalohydrazide (1.18 g, 10.0 mmol), 1-(4-nitrophenyl)ethanone
(3.63 g, 22.0 mmol), methanol (50 ml) and glacial acetic acid
(0.1 ml) were used. The crude product was purified by flash
column chromatography on silica gel eluting with a mixture
of dichloromethane–methanol (40 :◦1) to yield L13 (0.21 g, white
solid, 50% yield). M.p.: 198.4–199.8 C. 1H NMR (300 MHz, CDCl3)
δ: 8.37 (br s, 2H, NH–C), 8.21 (d, J = 8.4 Hz, 4H, CH arom), 7.53
(d, J = 8.4 Hz, 4H, CH arom), 4.24 (q, J = 6.6 Hz, 2H, CH–CH3),
1.41 (d, J = 6.6 Hz, 6H, CH3 –CH). 13C NMR (75 MHz, pyridine-d5)
δ: 160.3 (C O), 151.8 (C–CH arom), 147.4 (C–NO2 arom), 128.5
(C arom), 123.7 (C arom), 59.6 (CH–CH3), 21.6 (CH3 –CH). IR (KBr,
cm−1): ν(N–H): 3339, ν(C O): 1674. MS (EI, m/z): 416 (9) [M+ ],
150 (100). Anal. calcd for C18H20N6O6 = C, 51.92; H, 4.84; N, 20.18.
Found: C, 51.83; H, 4.950; N, 20.01.
Acknowledgment
This work was supported financially by grants from the National
Natural Science Foundation of China (20872182, 20802095) and
by the National High Technology Research and Development
Program of China (863 Program), no. 2006AA09Z446. We would
like to thank professor Hengming Ke (University of North Carolina
at Chapel Hill) for helpful discussions and suggestions during this
work, and thank Dr H.M. Fried at UNC Chapel Hill for proofreading
the manuscript. We also wish to thank the CEM Corporation for
providing the microwave Discover.
Supporting information
General Procedure F for the Microwave-assisted Coupling
Reaction under the Optimized Condition
Supporting information may be found in the online version of this
article.
To a 10 ml of microwave vessel were added CuO (0.004 g,
0.05 mmol),L12(0.097 g,0.25 mmol),arylhalide(1.0 mmol),amine
(5.0 mmol), KOH (0.056 g, 1.0 mmol), TBAB (0.161 g, 0.5 mmol),
H2O (2.0 ml) and a magnetic stir bar. The vessel was sealed with a
septum and placed into the single mode microwave cavity. It took
1 mintorampthereactiontemperaturefromroomtemperatureto
130 ◦C, then the reaction mixture was held at this temperature for
5 minutes. After allowing the mixture to cool to room temperature,
the reaction mixture was added with water (30 ml) and extracted
with ethyl acetate (3 × 30 ml). The organic phases were combined
and washed with water and brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (ethyl acetate–petroleum
ether as eluent) to yield 3a–t (Tables 2 and 3).
References
[1] a) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400;
b) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248,
2337; c) J. F. Hartwig, Synlett 2006, 1283; d) M. Kienle, S. Dubbaka,
K. Brade, P. Knochel, Eur. J. Org. Chem. 2007, 4166; e) G. Evano,
N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054; f) F. Monnier,
M. Taillefer, Angew. Chem. Int. Ed. 2008, 47, 3096; g) F. Monnier,
M. Taillefer, Angew. Chem. Int. Ed. 2009, 48, 6954.
[2] a) J. C. Antilla, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2002,
124, 11684; b) A. Klapars, X. Huang, S. L. Buchwald, J Am. Chem. Soc.
2002, 124, 7421.
[3] a) D. Ma, C. Xia, Org. Lett. 2001, 3, 2583; b) D. Ma, Q. Cai, Acc. Chem.
Res. 2008, 41, 1450.
[4] a) D. Jiang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2007, 72, 672; b)
F. Y. Kwogn, A. Klapars, S. L. Buchwald, Org. Lett. 2002, 4, 581.
[5] Y. Chen, H. Chen, Org. Lett. 2006, 8, 5609.
General Procedure G for the Coupling Reaction in Oil Bath
[6] a) N. Xia, M. Taillefer, Angew.Chem.Int.Ed. 2009, 48, 337; b) A. Shafir,
S. L. Buchwald, J Am. Chem. Soc. 2006, 128, 8742.
[7] a) H. -J. Cristau, P. P. Cellier, J.-F. Spindler, M. Taillefer, Chem. Eur. J.
2004, 10, 5607; b) Y.-H. Liu, C. Chen, L.-M. Yang, Tetrahedron Lett.
2006, 47, 9275.
To a 25 ml of round-bottom flask were added CuO (0.004 g,
0.05 mmol), L12 (0.097 g, 0.25 mmol), 4-bromoanisole (0.186 g,
1.0 mmol), amine (5 mmol), KOH (0.112 g, 2.0 mmol), TBAB
(0.161 g, 0.5 mmol), H2O (8.0 ml) and a magnetic stir bar. The
reaction mixture reacted for 8 h at 90 ◦C in an oil bath. After
4-bromoanisole was consumed, the reaction mixture was cooled
to room temperature, the reaction mixture was added with water
(30 ml) and extracted with ethyl acetate (3 × 30 ml). The organic
phases were combined and washed with water and brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel eluting
with a mixture of ethyl acetate–petroleum ether (1 : 20) to yield
3a (Table 2, entry 1) and 3i (Table 3, entry 1).
[8] Z. Lu, R. Twieg, Tetrahedron Lett. 2005, 46, 2997.
[9] M. Yang, F. Liu, J. Org. Chem. 2007, 72, 8969.
[10] a) H. Rao, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2005, 70, 8107; b)
J. Mao, J. Guo, H. Song, S. Ji, Tetrahedron 2008, 64, 1383.
[11] a) M. Carril, R. Sanmartin, E. Dominguez, Chem. Soc. Rev. 2008, 37,
639; b) D. Dallinger, C. O. Kappe, Chem. Rev. 2007, 107, 2563.
[12] L. Liang, Z. Li, X. Zhou, Org. Lett. 2009, 11, 3294.
[13] G. V. Oshovsky,A. Ouali,N. Xia,M. Zablocka,R. T. Boere,C. Duhayon,
M. Taillefer, J. P. Majoral, Organometallics 2008, 27, 5733.
[14] J. Kim, S. Chang, Chem. Commun. 2008, 3052.
[15] S. Rottger, Per. J. R. Sjoberg, M. Larhed, J. Comb. Chem. 2007, 9, 204.
[16] H. Xu, F. Zheng, Y. Liang, Z. Cai, Y. Feng, D. Che, Tetrahedron Lett.
2010, 51, 669.
[17] a) X. Zhu, Y. Ma, L. Su, H. Song, G. Chen, D. Liang, Y. Wan, Synthesis
2006, 3955; b) X. Zhu, L. Su, L. Huang, G. Chen, J. Wang, H. Song,
Y. Wan, Eur. J. Org. Chem. 2009, 635.
General Procedure H for the Coupling Reaction in Oil Bath
To a 10 ml of microwave vessel were added CuO (0.004 g,
0.05 mmol),L12(0.097 g,0.25 mmol),arylhalide(1.0 mmol),amine
(5.0 mmol),KOH(0.112 g,2.0 mmol),TBAB(0.161 g,0.5 mmol),H2O
(2.0 ml) and a magnetic stir bar. The reaction mixture reacted for
48 h at 30 ◦C. After 4-bromoanisole was consumed, the reaction
mixture was added with water (30 ml) and extracted with ethyl
acetate (3 × 30 ml). The organic phases were combined and
washed with water and brine, dried over anhydrous Na2SO4, and
[18] J. Xie, X. Zhu, M. Huang, F. Meng, W. Chen, Y. Wan, Eur. J. Org. Chem.
2010, 3219.
[19] O. P. Efetova,
T. Y. Slyva,
I. O. Fryts’kyi,
M. M. Dudarenko,
V. O. Kalibabchuk, P. Kraemer, Dopovidi Natsional’noi Akademii
Nauk Ukraini 2002, 161.
[20] J. Szmuszkovicz, M. Greig, J. Med. &Pharmacent. Chem. 1961, 4, 259.
[21] Y. Wan, X. Zhu, F. Meng, C. Wang, J. Xie, H. Song, CN 101691318,
2010.
c
Appl. Organometal. Chem. 2011, 25, 341–347
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc