Copper(I)-picolinic acid catalyzed N-arylation of hydrazides

Article abstract of DOI:10.1016/j.tetlet.2008.08.050

An efficient copper-catalyzed carbon-nitrogen bond formation is described. The copper(I) complex with commercially available 2-picolinic acid ligand was found to be effective in N-arylation of N-Boc-hydrazine. This methodology offers a regioselective N-ar

Full text of DOI:10.1016/j.tetlet.2008.08.050

Tetrahedron Letters 49 (2008) 6192–6194
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(I)-picolinic acid catalyzed N-arylation of hydrazides
*
Miu Suen Lam, Hang Wai Lee, Albert S. C. Chan, Fuk Yee Kwong
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis, Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper-catalyzed carbon–nitrogen bond formation is described. The copper(I) complex with
commercially available 2-picolinic acid ligand was found to be effective in N-arylation of N-Boc-hydr-
azine. This methodology offers a regioselective N-arylation of hydrazides using a variety of substituted
aryl iodides.
Received 5 June 2008
Revised 22 July 2008
Accepted 12 August 2008
Available online 19 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
experiment revealed that nearly no conversion of aryl iodide was
observed in the absence of ligand (entry 1). Copper bronze
Transition metal catalyzed cross-coupling methodology is one
of the most powerful tools for bond construction between organo-
metallic nucleophiles and electrophiles.1 Palladium complex with
phosphine ligand is always an effective catalyst system in these
reactions.2 However, the expensiveness of the precious metal
source as well as the supporting ligands sometimes limits their
versatility and applicability in industrial processes. In view of this
shortcoming, considerable efforts in searching inexpensive cata-
lytic system are continuing. Recently, significant advances have
been made on the evolution of relatively less expensive copper-
catalyzed Ullmann-type reactions.3 With the application of
structurally appropriate ligands (such as N,N,N,O, or O,O-bidentate
ligands), numerous Cu-catalyzed C–N,4 C–O,5 C–S,6 and C–C7
coupling reactions could be carried out under relatively mild reac-
tion conditions.
essentially gave no conversion of aryl iodides while CuCl, CuOTf
and Cu(MeCN)4ClO4 complexes were not as efficient as the CuI
(entries 2–6). In addition to the metal sources, we examined the
coordination efficiency of the 2-picolinic acid scaffold to the copper
metal sphere. Ligand L2 with a substituted methyl group on the
6-position presumably hindered the coordination of the nitrogen
Table 1
Initial screening of copper source and picolinic acid ligand derivatives in Cu-catalyzed
N-arylation of hydrazidea
Me
Me
Boc
5 mol% Cu source/L1-L4
+
HN
Boc
Cs2CO3, DMF
80 °C
N
NH2
Me
Me
I
NH2
We recently reported an effective copper catalyst system for the
arylation of malonates.8 This versatile copper(I)-picolinic acid
complex showed effective C–C coupling even at room temperature
reaction conditions. There are a number of successful Cu-catalyzed
N-arylations that have been reported, however, the examples on
regioselective N-arylation of hydrazine derivatives are rare.9 In
2001, Buchwald and co-workers reported Cu–phen complex cata-
lyzed N-arylation of hydrazides.9a They also briefly showed the
application of Cu–picolinic acid system in some selected examples.
Nevertheless, room for exploration of efficient catalytic system
remains. Herein, we report our Cu–picolinic acid system to the
relatively unexplored Cu-catalyzed N-arylation of hydrazides.
Initial screenings of the C–N bond formation between N-Boc-
hydrazide and aryl iodide were triggered as a function of copper
source and picolinic acid ligand derivatives (Table 1). Control
Entry
Copper source
Ligand
Yieldb
1
2
3
4
5
6
7
8
9
CuI
CuI
CuCl
No ligand
Trace
65
51
Trace
63
53
31
34
39
L1
L1
L1
L1
L1
L2
L3
L4
Cu powder (bronze)
CuOTf
Cu(MeCN)4ClO4
CuI
CuI
CuI
OMe
O
Me
O
O
O
N
Me
N
N
N
OH
OH
OH
OH
L1
L2
L3
L4
a
5-Iodo-m-xylene (1.0 mmol), tert-butylcarbazate (1.2 mmol), Cu source
(5 mol %), ligands L1–L4 (10 mol %), Cs2CO3 (3.0 mmol), and DMF (1.0 mL) under N2
at 80 °C for 24 h.
* Corresponding author.
E-mail address: bcfyk@inet.polyu.edu.hk (F. Y. Kwong).
b
Isolated yields were reported.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.050

M. S. Lam et al. / Tetrahedron Letters 49 (2008) 6192–6194
6193
Table 3
R
O
Copper-catalyzed coupling of aryl iodides with N-Boc-hydrazinea
N
N
Cu
O
Cu
5 mol% CuI,
O
Boc
NH2
10 mol% L1
O
R
Boc
+
R
HN
N
R = Me, OMe; L3, L4
L1
Cs2CO3, DMF
80 ºC
I
NH2
Figure 1. Suggested binding modes for the picolinic acid ligands.
Entry
Arl
Product
Isolated yield
73
Me
Me
atom to the metal center, and hence catalytic efficacy was lowered
(entry 7). Upon placing either a methyl or a methoxy group to the
3-position of the ligand (i.e., L3 and L4), lower catalytic activities
were observed (entries 8–9). It is suggested that the 2-picolinic
acid L1 could offer a suitable planar N,O coordination, while the
L3 and L4 might not provide effective binding templates (Fig. 1).
Several types of bases were investigated in order to seek the
best reaction conditions (Table 2). Cesium carbonate gave the de-
sired product in the highest yield among other commonly used
inorganic bases (entries 1 vs 4–8). Moreover, 3 equivalents of the
base was found to be optimal (entries 1–3). Apart from the base
screening, solvent parameter was examined. DMF provided the
highest efficiency while dioxane, THF, tert-amyl alcohol, and tolu-
ene gave moderate yields (entries 1, 9–12).
In order to probe the effectiveness of this Cu-catalyzed protocol,
a series of aryl iodides were examined (Table 3). A variety of para-
and meta-substituted aryl iodides with functional groups such as
chloro, methoxy, trifluoromethyl, amino, cyano, and hydroxyl were
compatible under our reaction conditions (entries 3–10). Interest-
ingly, there was no competitive N-arylation of aniline in this reac-
tion when 4-iodoaniline was used (entry 7). No significant
electronic effect to the rate or yield of the reaction was observed.
Heterocycle such as 3-iodopyridine furnished the desired product
in moderate yield (entry 11). Presumably, the nitrogen atom from
this electrophile exerts competitive coordination to the copper
sphere, and renders the complex coordinatively saturated.
Although some functionalized aryl iodides could tolerate the
present reaction conditions, the phenolic, ester, nitro and thienyl
groups were found to be inferior (Fig. 2).
1
Boc
N
Me
Me
Me
Me
I
NH2
Boc
2
3
67
65
65
61
67
62
52
70
30
52
28
N
I
NH2
F
F
Boc
N
I
NH2
Cl
Cl
Boc
4
N
I
NH2
MeO
F3C
H2N
MeO
F3C
H2N
Boc
5
N
I
NH2
Boc
6
N
I
NH2
Boc
7
N
I
NH2
Boc
8
N
NC
NC
I
I
NH2
In summary, coupling with our previous investigation using
Cu–picolinic acid catalyst, we have extended the scope of this sim-
ple system to the underdeveloped N-arylation of hydrazine deriv-
atives. The inexpensiveness and commercial availability of the Cu
source as well as the 2-picolinic acid ligand offer attractive features
Boc
9
N
Me
HO
Me
HO
NH2
Boc
10
11
N
I
NH2
Table 2
Base and solvent optimization for Cu-catalyzed N-arylation of hydrazidea
Boc
N
N
NH2
N
Me
I
Me
I
Me
5 mol% CuI
Boc
10 mol% L1
+
HN
Boc
base, solvent
80 ºC
Boc
N
NH2
Me
12
Me
I
N
NH2
NH2
Me
Entry
Base (equiv)
Solvent
Yieldb
a
Aryl iodide (1.0 mmol), tert-butylcarbazate (1.2 mmol), CuI (5 mol %), ligand L1
(10 mol %), Cs2CO3 (3.0 mmol), and DMF (1.0 mL) under N2 at 80 °C for 24 h.
1
2
3
4
5
6
7
8
9
Cs2CO3 (3.0)
Cs2CO3 (1.5)
Cs2CO3 (6.0)
Li2CO3 (3.0)
K2CO3 (3.0)
Na2CO3 (3.0)
K3PO4 (3.0)
NaOt-Bu (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
70
12
48
15
11
Trace
Trace
Trace
40
58
43
HO
S
I
EtO
O2N
I
I
I
O
10
11
12
t-Amyl alcohol
THF
Toluene
Figure 2. Unsuccessful examples for the Cu-catalyzed N-arylation of hydrazine
49
derivative.
a
5-Iodo-m-xylene (1.0 mmol), tert-butylcarbazate (1.2 mmol), CuI (5 mol %),
ligand L1 (10 mol %), base (1.5–6.0 mmol), and solvent (1.0 mL) under N2 at 80 °C
for 24 h.
to this protocol. Further investigations of this versatile catalytic
system will be reported in due course.
b
Isolated yields were reported.

6194
M. S. Lam et al. / Tetrahedron Letters 49 (2008) 6192–6194
Metals for Organic Synthesis, Building Blocks and Fine Chemicals, 2nd ed.; Wiley-
2. Experimental
2.1. General consideration
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4622.
Unless otherwise noted, all reagents were purchased from com-
mercial suppliers and used without purification. DMF was pre-
dried by calcium hydride, and distillated under reduced pressure.
Toluene was distilled from sodium benzophenone ketyl under
nitrogen. Commercially available aryl iodides (liquid form only)
2. (a) Handbook of Organopalladium for Organic Synthesis; Nigeshi, E., Ed.; Wiley
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were purified by passing through
a
short plug (0.5 cm
width  4 cm height) of neutral alumina or by distillation under
reduced pressure. GC analysis was conducted on a HP G1800C
GCD system using a HP5MS column (30 m  0.25 mm). Known
products were characterized by NMR and mass spectroscopy and
compared to the literature data or authentic sample analysis.
2.2. General procedure
An oven-dried resealable vial was charged with CuI (9.5 mg,
0.05 mmol, 5 mol %), 2-picolinic acid (13.5 mg, 0.10 mmol,
10 mol %), and Cs2CO3 (977 mg, 3.0 mmol). The flask was evacu-
ated and backfilled with nitrogen (3 cycles). tert-Butylcarbazate
(159 mg, 1.2 mmol), aryl iodide (1.0 mmol), and DMF (1.0 mL)
were added under nitrogen. The vial was sealed, and the reaction
mixture was stirred at 80 °C for 24 h. The resulting suspension
was cooled to room temperature, and filtered through
a
0.5 Â 1 cm silica pad. The crude mixture was purified by column
chromatography on silica gel (230–400 mesh).
Acknowledgments
We thank the Research Grants Council of Hong Kong (CERG:
PolyU 5008/06P), The Hong Kong Polytechnic University Internal
Research Grant (A-PH51), and Areas of Excellence AoE for the
financial support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.050.
8. Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.
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References and notes
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