Synthesis of sterically encumbered and functionalized diaryl-diazenes by formal [3+3] cyclization of 2-aryldiazenyl-3-silyloxy-2-en-1-ones with 1,3-bis(silyloxy)-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2008.02.026

Functionalized diaryl-diazenes (azo-dyes) were regioselectively prepared by formal [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 2-aryldiazenyl-3-silyloxy-2-en-1-ones.

Full text of DOI:10.1016/j.tetlet.2008.02.026

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2262–2264
Synthesis of sterically encumbered and functionalized diaryl-diazenes
by formal [3+3] cyclization of 2-aryldiazenyl-3-silyloxy-2-en-1-ones
with 1,3-bis(silyloxy)-1,3-butadienes
Jennifer Hefner a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 10 January 2008; revised 3 February 2008; accepted 5 February 2008
Available online 9 February 2008
Abstract
Functionalized diaryl-diazenes (azo-dyes) were regioselectively prepared by formal [3+3] cyclization of 1,3-bis(silyloxy)-1,3-buta-
dienes with 2-aryldiazenyl-3-silyloxy-2-en-1-ones.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Azo-dyes; Cyclizations; Diazenes; Silyl enol ethers
Diaryl-diazenes (azo-dyes) are of outstanding impor-
tance as dyes in the field of material sciences, analytical
biochemistry, analytical chemistry, and food chemistry.1
In recent years, it has been shown that functionalized
diaryl-diazenes are of increasing relevance in the field of
medicinal chemistry, due to their wide range of pharmaco-
logical activity. For example, salicylic acid-derived diazene
A (Fig. 1) has been reported to show anticancer, cytotoxic,
apoptosis-inducing, antiallergic, antihistaminic, and pro-
tein-binding activity. It shows interesting transport proper-
ties in vivo and inhibits the release of leukotriene B4,
thromboxane B2, and prostaglandin.2 Alizarin yellow R
(B) has been reported to act as an inhibitor of amyloid
fibril formation.3
The classic approach to diaryl-diazenes relies on the
reaction of benzene derivatives with aryldiazonium salts
which involves the formation of a carbon–nitrogen bond.
Although this method has been widely applied, the synthe-
sis of more complex, heavily substituted and functionalized
derivatives is difficult or not possible at all, due to steric
and electronic effects. The formation of regioisomeric mix-
tures or undesired regioisomers is a severe problem. In
addition, the synthesis of the required starting materials,
substituted benzene derivatives, can be a difficult task.
An alternative strategy for the synthesis of azo-dyes
relies on cyclization reactions of synthetic building blocks
which already contain a diazene moiety. For example,
heterocyclic azo-dyes have been prepared by the reaction
of 2-aryldiazenyl-1,3-diones with guanidine,4a sulfuryl di-
amide,4b hydroxylamine,4c hydrazines,4d,e hydrazides,4f
and anilines.4g The synthesis of diaryl-diazenes (arene-
based azo-dyes) by a building block strategy has, to the
OH
O
H
N
N
HO
N
N
S
O2
A
OH
O
HO
N
N
CO2H
B
Fig. 1. Pharmacologically important diaryl-diazenes.
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.026

J. Hefner, P. Langer / Tetrahedron Letters 49 (2008) 2262–2264
2263
Table 1
Synthesis of 4a–g
best of our knowledge, not been reported to date. Herein,
we report an efficient and regioselective synthesis of diaryl-
diazenes by formal [3+3] cyclizations5,6 of novel 2-aryl-
diazenyl-3-silyloxy-2-en-1-ones with 1,3-bis(silyloxy)-1,3-
butadienes.7 This strategy relies on the assembly of one
of the arene moieties and formation of two carbon–carbon
bonds. The sterically encumbered and functionalized
diaryl-diazenes reported herein are not readily available
by other methods.
1
2
3, 4
R1
R2
R3
% (3)a
% (4)a
a
a
a
a
a
a
b
a
b
c
d
e
f
a
b
c
d
e
f
H
H
H
H
H
H
Me
H
Me
Me
Me
Me
Me
Me
Ph
88
98
96
64
59
81
96
93
91
88
92
91
85
86
Cl
Br
iBu
iPr
H
a
g
H
a
2-Aryldiazenyl-1,3-diones 3a–g were prepared by the
reaction of 1,3-diketones 1a,b with anilines 2a–e (Scheme
1, Table 1).4h The silylation of 3a–g afforded the 2-aryl-
diazenyl-3-silyloxy-2-en-1-ones 4a–g. The TiCl4-mediated
reaction of 4a–g with 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes 5a–f, readily available from the corresponding 1,3-
dicarbonyl compounds,5 afforded the functionalized diaryl-
diazenes 6a–t (Scheme 2, Table 2). The best yields were
obtained when the reaction was carried out in a highly con-
centrated solution.8 In addition, the quality of the starting
materials, and the stoichiometry played an important role.
The formation of 6a–t can be explained by TiCl4-mediated
conjugate addition of the terminal carbon atom of 5 onto
4, cyclization by attack of the central carbon atom of the
1,3-bis(trimethylsilyloxy)-1,3-butadiene onto the carbonyl
group, and subsequent aromatization upon aqueous
work-up. The moderate yields can be explained by an
incomplete conversion (isolation of the hydrolyzed starting
materials), TiCl4-mediated oxidative dimerization of 5,9
and decomposition. In addition, the handling of each indi-
vidual experiment and the chromatographic separation
play an important role.
Yields of isolated products.
Me3SiO OSiMe3
R4
O
OH
R5
R4
Me
R5
5a-f
+
R3
Me3SiO
Me
O
N
N
i
N
R3
N
R2
R2
R1
R2
R2
6a-t
R1
4a-g
Scheme 2. Synthesis of diaryl-diazenes 6a–t. Reagents and conditions: (i)
TiCl4, CH2Cl2, À78?20 °C, 12 h.
Table 2
Synthesis of 6a–t
a
4
5
6
R1
R2
R3
R4
R5
%
a
a
a
a
a
b
b
b
b
b
c
d
d
d
e
e
e
e
f
a
b
c
d
e
a
c
e
b
d
a
a
c
b
a
c
f
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
OMe
OEt
66
60
30
51
41
44
35
32
40
47
20
41
30
37
32
31
33
41
31
30
In conclusion, we reported the synthesis of diaryl-di-
azenes by [3+3] cyclization of 2-aryldiazenyl-3-silyloxy-
2-en-1-ones with 1,3-bis(silyloxy)-1,3-butadienes. The
Me
Et
OMe
H
Me
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OMe
OMe
OMe
OEt
OMe
OMe
tBu
OEt
OMe
OMe
H
Cl
Cl
Cl
Cl
Cl
Br
iBu
iBu
iBu
iPr
iPr
iPr
iPr
H
O
g
h
i
O
O
O
N
Me
R2
R3
R3
1a,b
Me
j
Et
H
H
+
N
i
k
l
NH2
m
n
o
p
q
r
Me
H
R2
R2
R2
R1
H
R1
2a-f
Me
H
3a-g
ii
b
a
a
H
H
H
Me3SiO
Me
s
O
g
t
H
R3
a
Yields of isolated products.
N
N
sterically encumbered and functionalized products
reported herein are not readily available by other methods.
R2
R2
R1
4a-g
Acknowledgment
Scheme 1. Synthesis of 2-aryldiazenyl-3-silyloxy-2-en-1-ones 4a–g.
Reagents and conditions: (i) (1) NaNO2, HCl, 0 °C, 10 min; (2) NaOAc,
H2O, EtOH, 0 °C, 3 h; (ii) Me3SiCl, NEt3, benzene, 20 °C, 48 h.
Financial support by the State of Mecklenburg-Vor-
pommern is gratefully acknowledged.

2264
J. Hefner, P. Langer / Tetrahedron Letters 49 (2008) 2262–2264
P.; Rane, N. Indian J. Chem., Sect. B 2004, 43, 1320; (h) Narayana, B.;
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8. Typical experimental procedure: To a CH2Cl2 solution (2.5 mL) of 4a
(553 mg, 1.0 mmol) and 5a (391 mg, 1.5 mmol) was added TiCl4
(209 mg, 1.1 mmol) at À78 °C. The temperature of the solution was
allowed to warm to 20 °C within 18 h. To the mixture was added
hydrochloric acid (10%) and the organic and the aqueous layer were
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combined organic layers were dried (Na2SO4), filtered, and the filtrate
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solid (186 mg, 66%), mp = 82 °C; Rf = 0.56 (heptanes/EtOAc = 3:1).
1H NMR (300 MHz, CDCl3): d 2.31 (s, 3H, CH3), 2.61 (s, 3H, CH3),
3.99 (s, 3H, OCH3), 6.78 (s, 1H, Ar), 7.50 (m, 3H, N@NAr), 7.86 (d,
1H, N@NAr), 7.89 (d, 1H, N@NAr), 11.23 (s, 1H, OH). 13C NMR
(75.5 MHz, CDCl3): d 17.3, 20.5 (CH3), 52.2 (OCH3), 111.4 (CAr),
118.3 (CHAr), 122.4, 129.1, 130.9 (CHAr) 136.8, 137.3 (CArCH3), 145.4,
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m/z (%) = 284 (M+, 99), 179 (100), 147 (91), 77 (59). HRMS (EI): calcd
for C16H16N2O3 ([M]+): 284.11554, found: 284.11567.
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