Cu(I) mediated one-pot synthesis of azobenzenes from bis-Boc aryl hydrazines and aryl halides

Article abstract of DOI:10.1016/j.tetlet.2003.10.091

N,N′-bis-Boc aryl hydrazines underwent Cu(I) catalyzed couplings with aryl halides to provide N,N′-bis-Boc diaryl hydrazines. The resulting N,N′-bis-Boc diaryl hydrazines are readily oxidized to the azobenzenes in the presence of Cu(I) and a base. A prolo

Full text of DOI:10.1016/j.tetlet.2003.10.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 117–120
Cu(I) mediated one-pot synthesis of azobenzenes from
bis-Boc aryl hydrazines and aryl halides
Kyu-Young Kim, Jeong-Taek Shin, Kang-Sang Lee and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul 133-791, South Korea
Received 18 September2003; revised 11 October2003; accepted 20 October2003
Abstract—N,N0-bis-Boc aryl hydrazines underwent Cu(I) catalyzed couplings with aryl halides to provide N,N0-bis-Boc diaryl
hydrazines. The resulting N,N0-bis-Boc diaryl hydrazines are readily oxidized to the azobenzenes in the presence of Cu(I) and a base.
A prolonged heating of the initial coupling reactions directly provides the corresponding azobenzenes in one pot.
Ó 2003 Elsevier Ltd. All rights reserved.
Azobenzenes have a wide variety of potential applica-
tions toward organic non-linear optics, optical storage
media, chemosensors, and photochemical switches, be-
cause of their characteristic color and photoresponsive
properties.1 Despite the current interests, the structures
of the azobenzenes appeared in the literature are rather
limited. We are interested in the synthesis of highly
functionalized azobenzenes with multiple diazo linkages
forthe development of novel photochemical sensing
devices. With conventional methods,2 however, they are
not trivial tasks.
dppf system showed the similarlack of eractivity with
electron rich aryl halides. The CuI/phen system turned
out to be completely inactive. The catalyst system
Pd(OAc)2/P(t-Bu)3 was found to be effective forthe
couplings of N-Boc aryl hydrazides with both electron
poor and rich aryl halides.
In this account, we wish to present one-pot synthesis of
azobenzenes via Cu(I) catalyzed couplings of N,N0-bis-
Boc aryl hydrazines with aryl halides and concomitant
in situ oxidations.
Recently, we have reported a new synthetic method for
azobenzenes starting from N-Boc aryl hydrazines via
Pd-catalyzed coupling reactions with various aryl ha-
lides followed by direct oxidations with NBS/pyridine in
Realizing the BuchwaldÕs CuI/phen catalyst system is for
a formal carbamation reaction (couplings onto –NHBoc
side), we decided to investigate the Cu(I) catalyzed
couplings of N0-Boc aryl hydrazines in lieu of N-Boc aryl
hydrazines with various aryl halides. Simple treatment
of phenyl hydrazine with Boc2O provided N0-Boc phenyl
hydrazine, which readily undergo coupling reactions
with various aryl halides to produce the N0-Boc diaryl
hydrazines in good yields (Table 1).
CH2Cl2 into azobenzenes.3 The requisite N-Boc aryl
5
hydrazines were prepared via Pd4 orCu
couplings of tert-butyl carbazate with aryl halides.
catalyzed
While the BuchwaldÕs CuI/phen system is effective for
the couplings with both electron rich and deficient aryl
halides, the SkerljÕs Pd2(dba)3/dppf system is effective
only with the aryl halides bearing electron withdrawing
group.4 When employed forthe couplings of N-Boc aryl
hydrazines (couplings onto –NH2 side), the Pd2(dba)3/
Although the coupling reactions themselves proceeded
reasonably well, the starting N0-Boc aryl hydrazines are
not readily available. If not commercial, they need to be
prepared through the process involving the coupling of
Boc–NHNH2 with aryl halides followed by unmasking
and remasking steps.
Use of bis-Boc aryl hydrazines could possibly circum-
vent the above tedious sequential deprotection and
reprotection process. Arterburn et al. reported effi-
cient synthesis of bis-Boc pyridyl hydrazines via
Keywords: azobenzene; Cu(I); one-pot synthesis.
* Corresponding author. Tel.: +82-2-2290-0936; fax: +82-2-2299-
0762; e-mail: ccho@hanyang.ac.kr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.091

118
K.-Y. Kim et al. / Tetrahedron Letters 45 (2004) 117–120
Table 1. Cu-catalyzed N-arylation of N0-Boc aryl hydrazine
Entry Halides
Time
(h)
Product
Yield
(%)
Scheme 2. Separate syntheses of N- and N0-Boc diaryl hydrazines.
1
2
3
4
5
R ¼ H, X ¼ I
22
11
5
3a (R ¼ H)
87
81
51
45
R ¼ OMe, X ¼ I
3b (R ¼ OMe)
3c (R ¼ NO2)
3d (R ¼ CO2Et)
R ¼ NO2, X ¼ I
R ¼ CO2Et, X ¼ Br48
R ¼ CN, X ¼ Br47
The oxidations of the resulting 6a–6j to the azobenzenes
were troublesome as they are not reactive under the
conditions that we used previously for the oxidation of
mono-Boc diaryl hydrazines to the azobenzenes.3;8 Re-
moval of one or both Boc groups prior to the oxidations
would be the next option, which also turned out to be
problematic. Attempted removal of the Boc group(s)
underthe usual conditions ersulted in the cleavage of
N–N bond, to give rise to the corresponding aryl
amines. We have found, aftera numberof failures, that
bis-Boc diphenyl hydrazines can be directly oxidized
into the azobenzenes when heated with NaOH in EtOH,
in reasonable yields.7 The intrinsic incompatibility with
the base sensitive group, however, is a serious drawback.
Later we have found that bis-Boc diaryl hydrazines are
readily oxidized to the azobenzenes under the reaction
conditions, identical to those used forthe couplings of
Boc aryl hydrazines with aryl iodides. Further study
using 6a as a model has revealed that the oxidation
reaction is best conducted when heated with stoichio-
metric amounts of CuI and Cs2CO3 at 110 °C in
DMF. Under these conditions, we were able to prepare
an array of azobenzenes, directly from N,N0-bis-Boc
diaryl hydrazines bearing various otherwise incompati-
ble functional groups, in fair to good isolation yields
(Table 3).8 The hydrazide with free hydroxyl group gave
only trace of the product (entry 5).
3w (R ¼ CO2Me) 56
Scheme 1. Syntheses of bis-Boc aryl hydrazines.
Pd-catalyzed couplings of N,N0-bis-Boc hydrazine with
2-halo-pyridines.6 Using their conditions, we prepared
various N,N0-bis-Boc aryl hydrazines 5 in good isolation
yields (Scheme 1).
The resulting bis-Boc aryl hydrazines 5 underwent
coupling reactions with aryl halides under the Buch-
waldÕs conditions (CuI/phen), but in only moderate
isolated yields. No coupling reactions were observed
with Pd catalysts. We laterfound that the stoichiometric
use of CuI dramatically increases the reaction rate and
chemical yield. Both electron rich and deficient aryl
halides were well coupled, to furnish the corresponding
bis-Boc diaryl hydrazines in almost quantitative yields
(Table 2).
In entry 1, the isolated product 6a0 was found to be
mono-Boc diaryl hydrazine, resulting from the slow
removal of one Boc group during the coupling process.
The structure of 6a0 was assigned by separate syntheses
of both regio-isomers as shown below (Scheme 2).
Although the exact reaction mechanism is unclear at the
moment, the oxidation may proceed through the elimi-
nation of the Boc group as described in Scheme 3. The
Table 2. Cu-catalyzed arylation of bis-Boc aryl hydrazine
Table 3. Direct oxidations to azobenzenes with CuI/Cs2CO3
Entry
R–ArI
Timea (h)
Product
Yielda (%)
Entry
6
Time
(days)
Azo-
benzene
Yield (%)
1
2
R ¼ p-NO2
R ¼ p-CO2Me
R ¼ p-CN
R ¼ p-OMe
R ¼ p-CH2OH
R ¼ H
3 (48)
3 (48)
3 (24)
18 (72)
4 (48)
3 (48)
3 (48)
3 (48)
48 (96)
3 (48)
6a (6a0)
6b
6c
99 (33)
99 (43)
99 (92)
86 (25)
95 (35)
99 (43)
99 (43)
99 (93)
90 (71)
99 (43)
3
1
2
6a (R ¼ p-NO2)
6b (R ¼ m-CN)
6c (R ¼ p-CO2Me)
6d (R ¼ p-COMe)
6e (R ¼ p-CH2OH)
6f (R ¼ H)
1
1
1
1
3
3
3
3
2
3
7a
7b
7c
7d
7e
7f
54
63
4
6d
6e
5
3
72
45
6
6f
6g
4
7
R ¼ p-Me
R ¼ p-OMe
R ¼ p-Ph
5
Trace
97
64
8
6h
6i
6jb
6
9
10
7
6g (R ¼ p-Me)
7g
7h
7i
R ¼ p-I
8
6h (R ¼ p-OMe)
6i (R ¼ p-Ph)
47
83
9
10
a The values in ( ) are the results when 0.1 equiv of CuI was used.
b bis-Hydrazide.
6j (R ¼ p-N@N–Ph)
7j
51

K.-Y. Kim et al. / Tetrahedron Letters 45 (2004) 117–120
119
Acknowledgements
tBuO
N
O
O2N
CuI
Cu
Ph-p-NO2
This work was supported by Nuclear R&D Program of
the Ministry of Science and Technology (MOST).
K.K.Y. and S.J.T. thank the financial support from the
BK21 Program.
N
OtBu
N
Cs CO
2
3
N
O
O
Cu
8a
O
base
H
6a
workup
NBoc
HN
NO2
7a
6a'
Scheme 3. Proposed mechanism for the oxidation of bis-Boc diaryl
hydrazine to azobenzene.
References and Notes
1. (a) Ichimura, K. In Photochromism: Molecules and
Systems; Durr, H., Bouas-Laurent, H., Eds.; Elsevier:
Amsterdam, The Netherlands, 1990; p 903; (b) Willner, I.;
Willner, B. In Bioorganic Photochemistry: Biological
Applications of Photochemical Switches; Morrison, H.,
Ed.; Wiley: New York, 1993; Vol. 2, pp 1–110; (c) Kumar,
G. S.; Neckers, D. C. Chem. Rev. 1989, 89, 1915; (d)
Kanis, D. R.; Ratner, M. A.; Marks, T. J. Chem. Rev.
1994, 94, 195; (e) Burland, D. M.; Miller, R. D.; Walsh, C.
A. Chem. Rev. 1994, 94, 31; (f) Schlingmann, G.; Milne,
L.; Carter, G. T. Tetrahedron 1998, 54, 13013; (g) Harvey,
A. J.; Abell, A. D. Tetrahedron 2000, 56, 9763; (h) Wang,
S.; Advincula, R. C. Org. Lett. 2001, 3, 3831; (i) DiCesare,
N.; Lakowicz, J. R. Org. Lett. 2001, 3, 3891; (j) Sunazuka,
T.; Handa, M.; Nagai, K.; Shirahata, T.; Harigaya, Y.;
Otoguro, K.; Kuwajima, I.; Omura, S. Org. Lett. 2002, 4,
367; (k) Jousselme, B.; Blanchard, P.; Gallego-Planas, N.;
Delaunay, J.; Allain, M.; Richomme, P.; Levillain, E.;
Roncali, J. J. Am. Chem. Soc. 2003, 125, 2888; (l)
Muraoka, T.; Kinbara, K.; Kobayashi, Y.; Aida, T. J.
Am. Chem. Soc. 2003, 125, 5612; (m) Saiki, Y.; Sugiura,
H.; Nakamura, K.; Yamaguchi, M.; Hoshi, T.; Anzai, J.
J. Am. Chem. Soc. 2003, 125, 9268.
Table 4. Cu(I) mediated one-pot synthesis of azobenzenes starting
from the couplings with aryl iodides
Entry
R–ArI
Time
(days)
7
Yield (%)
1
2
3
4
5
6
7
8
9
10
R ¼ p-NO2
R ¼ m-CN
R ¼ p-CO2Me
R ¼ p-COMe
R ¼ p-CH2OH
R ¼ H
2
7a
7b
7c
7d
7e
7f
50
60
3
2
69
50
4
7
Trace
60
46
6.5
6.5
4
R ¼ p-Me
7g
7h
7i
R ¼ p-OMe
R ¼ p-Ph
43
67
3
R ¼ p-I
3
7j
45
2. (a) The Chemistry of Synthetic Dyes; Venkataraman, K.,
Ed.; Academic: New York, 1970; Vols. 1–7; (b) Hegarty,
A. F. In The Chemistry of Diazonium andDiazo Groups,
Part 2; Wiley: New York, 1978; p 545; (c) Gordon, P. F.;
Gregory, P. Organic Chemistry in Colour; Springer: New
York, 1983; p 95; (d) Szele, I.; Zollinger, H. Top Curr.
Chem. 1983, 112, 1; (e) Zollinger, H. Color Chemistry;
VCH: New York, 1987; p 85; (f) Davey, M. H.; Lee, V.
Y.; Miller, R. D.; Marks, T. J. J. Org. Chem. 1999, 64,
4976.
TLC monitoring showed that all the starting bis-Boc
diaryl hydrazine 6a is first converted into the low run-
ning spot, presumed to be 8a based on the isolation of
mono-Boc diaryl hydrazine 6a0 upon workup, before
subsequent transformation to the high running azo-
benzene 7a. A similarelimination of Boc gor up on 8a
would provide 7a.
3. Lim, Y.-K.; Lee, K.-S.; Cho, C.-G. Org. Lett. 2003, 5,
979.
4. Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett.
1999, 40, 3543.
5. Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
3, 3803.
We next studied the one-pot synthesis of azobenzenes
from bis-Boc aryl hydrazines and aryl halides. Table 4
summarizes our results under the optimized reaction
conditions.9
6. Arterburn, J. B.; Rao, K. V.; Ramdas, R.; Dible, B. R.
Org. Lett. 2001, 4, 1351.
The one-pot syntheses starting with aryl bromides
were also feasible, providing the corresponding azo-
benzenes, somewhat lower yields, compared to aryl
iodides.10
7. When R ¼ OMe, H, Me, COPh, COMe, we obtained the
corresponding azobenzenes in 30–50% isolated yields.
8. Representative procedure: To a sealed tube were charged
with 5a (54.8 mg, 0.128 mmol), copper(I) iodide (24.3 mg,
1.0 equiv), Cs2CO3 (49.9 mg, 1.2 equiv), and DMF
(1.0 mL). After1 day at 110 °C, the reaction mixture was
cooled to rt, filtered through a plug of silica gel and
washed with ethyl acetate. The filtrate was concentrated in
vacuo and purified by silica-gel chromatography (hex-
anes/EtOAc ¼ 8:1) to provide 15.6 mg (54% yield) of the
product 7a.
In summary, we have found that N,N0-bis-Boc aryl
hydrazines undergo Cu(I) mediated coupling reac-
tions with aryl halides bearing either electron with-
drawing or donating substituents. The resulting
N,N0-bis-Boc diaryl hydrazines were directly oxidized to
the azobenzenes when heated in DMF with CuI/
Cs2CO3. The above coupling and oxidation can be
performed in one pot to give the corresponding azo-
benzenes.
9. Representative procedure: To a sealed tube were charged
with p-nitro-phenyl iodide (55.1 mg, 0.221 mmol), bis-Boc
aryl hydrazine (81.9 mg, 1.2 equiv), copper(I) iodide

120
K.-Y. Kim et al. / Tetrahedron Letters 45 (2004) 117–120
(42.1 mg, 0.221 mmol, 1.0 equiv), 1,10-phenanthroline
tography (hexanes/EtOAc ¼ 8:1) to provide 25.3 mg (50%
yield) of the product 7a.
10. The reaction of 5a with p-cyano-phenyl bromide and p-
tert-butyl-phenyl bromide provided the corresponding
azobenzenes 7k and 7l in 53% and 5% isolated yields,
respectively.
(4.0 mg, 0.1 equiv), Cs2CO3 (86.5 mg, 1.2 equiv), and
DMF (3.0 mL). Ater2 days at 110 °C, the reaction
mixture was cooled to rt, filtered through a plug of silica
gel and washed with ethyl acetate. The filtrate was
concentrated in vacuo and purified by silica-gel chroma-