Copper-catalyzed N-arylation of carbamate-protected hydrazones with organobismuthanes

Article abstract of DOI:10.1016/j.tetlet.2006.12.071

Efficient copper(II) acetate-catalyzed N-arylation of carbamate-protected hydrazones was achieved under mild reaction conditions with organobismuthanes.

Full text of DOI:10.1016/j.tetlet.2006.12.071

Tetrahedron Letters 48 (2007) 1155–1157
Copper-catalyzed N-arylation of carbamate-protected
hydrazones with organobismuthanes
a
a
b
a
a,
*
Pavel Starkov, Ivan Zemskov, Rannar Sillard, Olga T sˇ ubrik and Uno M a¨ eorg
a
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171-77 Stockholm, Sweden
b
Received 23 October 2006; revised 5 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—Efficient copper(II) acetate-catalyzed N-arylation of carbamate-protected hydrazones was achieved under mild reaction
conditions with organobismuthanes.
Ó 2006 Elsevier Ltd. All rights reserved.
Carbon–nitrogen bond formation remains one of the
most extensively reviewed areas in organic chemistry,
R
1
2
3
with palladium, nickel and copper-catalyzed N-aryl-
ations playing an important role in the toolbox of orga-
NH2
N
R'
H
R
1
nic synthesis. However, some of these methods have
4
drawbacks. Palladium salts are expensive, toxic and
N
require the use of phosphines, N-heterocyclic carbenes
or other ligands. Nickel catalysts have been reported
H
1
to show low tolerance to functional groups and to be
highly toxic. At the same time, copper-mediated reac-
R'
R
R
5
R
tions have gained popularity due to mild reaction condi-
tions and the applicability to a variety of aryl donors.3
N
N
N
H
N
N
Substituted hydrazines are important in a diverse array
6
of fields, including agrochemicals and pharmaceuticals.
NH2
O
R'
Recently, several aspects of copper-catalyzed N-aryla-
7
8
tion of hydrazines and azo compounds were studied
within our group. In the present study we focused on
hydrazones, since they are appealing precursors to
monoarylated and 1,1-disubstituted hydrazines as well
as to a number of azaheterocycles, inorganic hetero-
Figure 1.
R2
R2
R1
N NH2
a
R1
N N
R3
b
R1
R3
9
cycles and indoles (Fig. 1). Previously, to allow the
N N
synthesis of such compounds, only palladium catalysis
H
H
Ar
1
0
was employed.
1
2
3
Scheme 1. Preparation of arylated hydrazones. Reaction conditions:
The hydrazones of interest were prepared by condensa-
tion of hydrazines with the corresponding aldehyde or
ketone as described previously (Scheme 1). In the
+
(
2 3
a) ketone/aldehyde, H , reflux; (b) arylating agent, Cu(OAc) , Et N.
1
1
presence of copper(II) acetate benzophenone hydra-
zone with a free amino moiety underwent rapid oxida-
tion to afford the symmetric azine Ph C@NN@CPh
Keywords: N-Arylation; Hydrazines; Organobismuthanes.
*
Corresponding author. Tel.: +372 7375 243; fax: +372 7375 245;
e-mail: uno.maeorg@ut.ee
2
2
(92%), the carbamate-protected hydrazone derivatives
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.071

1156
P. Starkov et al. / Tetrahedron Letters 48 (2007) 1155–1157
a
Table 1. Optimization of the N-arylation of Boc-protected acetophenone hydrazone 2a
Entry
Bi reagent
Cu salt
Solvent
Temperature
Time (d)
Yield 3aa (%)
1
2
3
4
5
Ph
3
Ph
3
Ph
3
Ph
3
Ph
3
Ph
3
Bi
Bi
Bi(OAc)
Bi
Bi
Bi
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
CuCl
2
2
2
2
DCM
DCE
DCM
DCM
DCM
MeOH
rt
Reflux
rt
rt
rt
rt
3
1
3
1
1
1
92
97
89
72
20
2
b
c
6
Cu(OAc)
2
n.r.
a
b
c
Reaction conditions: hydrazone 2a (0.427 mmol), Bi reagent (1.5 equiv), Cu salt (1.5 equiv), Et
Without Et N.
No product formation was detected by TLC.
3
N (1.5 equiv), solvent (3 mL).
3
a
Table 2. Copper(II) acetate-catalyzed N-arylation of hydrazones 2 with triarylbismuthanes
1
2
3
Entry
R
R
R
Ar
2
3
Conditions
Time (d)
Yield (%)
1
2
3
4
5
6
7
Boc
Boc
Boc
Boc
Boc
Boc
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
H
Ph
2a
2a
2a
2a
2b
2c
2d
3aa
3ab
3ac
3ad
3ba
3ca
3db
A
B
B
B
B
A
A
1
3
3
3
3
1
1
97
90
10
96
72
p-Tol
o-Tol
p-An
Ph
Ph
p-Tol
CH@CHPh
Ph
Ph
b
44
98
Ph
a
Reaction conditions: hydrazone (1 equiv), Ar
condition B: DCM, rt.
Partially decomposed on the silica column.
3 2 3
Bi (1.5 equiv), Cu(OAc) (1.5 equiv), Et N (1.5 equiv); condition A: DCE, heating under reflux;
b
were found to be stable against oxidation. However,
carbamate protection increases the amidic nature of
the hydrazones, which compared to amines, show a
poorer reactivity towards arylation.
over three days gave only a 10% yield. Arylation with
both 1-Np Bi and 1-Np Bi(OAc) yielded no product.
Raising the temperature and using different promoters
3
3
2
(t-BuOK, Py, Et N, DBU, DMAP) did not lead to
3
an increase in reactivity and only the formation of
1-NpOAc was detected by TLC. Thus, as has been
previously reported, introduction of sterically congested
aryl substituents with bismuth reagents is somewhat
Primarily, optimization of the reaction with triaryl-
bismuthane and its diacetate with Et N serving as a pro-
3
1
2
moter showed that the former reagent gave slightly
1
3
12
improved results (Table 1). When the reaction was car-
ried out at ambient temperature in dichloromethane, the
yield of 3aa approached 70% over 24 h and 90% over
three days. When the reaction mixture was heated under
reflux in DCE, the starting material 2a was consumed
within 24 h. Copper(II) acetate gave superior results
compared to copper(I) chloride, which is in accordance
complicated.
As a comparison, arylation with arylboronic acids,16
which are less sterically hindered and more ‘aryl-
economic’, was attempted. Reaction of hydrazone 2a
with PhB(OH) in DCM over three days yielded 4%
2
and 7% of the product in the presence of Et N and
3
1
a
with mechanistic considerations. Previously, N-aryla-
tion using arylboronic acids as aryl donors carried out
in methanol was shown to be successful even with the
pyridine, respectively. No reaction was detected with
1-NpB(OH) . Reaction of 2a with PhB(OH) in metha-
2
2
nol with heating under reflux for three days afforded
only 15% of the product.
1
4
catalytic loadings of the copper(II) salt. However,
when we used organobismuthanes in methanol, no reac-
tion was detected even upon heating under reflux.
In summary, we have demonstrated the applicability of
organobismuth reagents rather than arylboronic acids in
the copper-catalyzed N-arylation of amidic nitrogen.
The carbamate-protected hydrazones used as model
substrates generally give good to excellent yields under
mild reaction conditions. Taken together, this method
represents a useful alternative to Buchwald–Goldberg
amidation and can be successfully applied to the synthe-
sis of trisubstituted amides and hydrazides.
In general, N-arylation of carbamate-protected hydr-
azones takes place under mild reaction conditions
(
Table 2), and can be employed as a convenient alter-
1
5
native to Buchwald–Goldberg amidation. The yield
of the phenylated product of Boc-protected benzalde-
hyde hydrazone, 3ca, was 44% due to partial decompo-
sition during purification on silica gel. Arylation of the
aminic nitrogen in 2-phenyl benzophenone hydrazone
2
d with p-Tol Bi proceeded in 24 h to afford the corre-
3
sponding product 3db in a 98% isolated yield.
Acknowledgements
The only limitation is in the introduction of sterically
This work was financially supported by the Estonian
Science Foundation (Grant No. 6706).
hindered aryls. The reaction of 2a with o-Tol Bi
3

P. Starkov et al. / Tetrahedron Letters 48 (2007) 1155–1157
1157
Supplementary data
8. (a) Kisseljova, K.; T sˇ ubrik, O.; Sillard, R.; M a¨ eorg, U.
Org. Lett. 2006, 8, 43–45; (b) T sˇ ubrik, O.; Kisseljova, K.;
M a¨ eorg, U. Synlett 2006, 2391–2394.
Analytical data for new compounds 2b and 3ab–db.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2006.12.071.
9
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À1
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; H NMR (200 MHz, CDCl ) d
13
1
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