Formal [4+2] cycloaddition of 3-ethoxycyclobutanones with azo compounds

Article abstract of DOI:10.1016/j.tetlet.2016.07.087

Azobenzenes reacted with 3-ethoxycyclobutanoes to give 2,3-dihydro-pyridazin-4(1H)-ones by using EtAlCl₂as a Lewis acid. Thus, ring cleavage of 3-ethoxycyclobutanones took place to form a zwitterionic intermediate by activation with EtAlCl₂, and intermolecular formal [4+2] cycloaddition of the zwitterionic intermediate proceeded with azobenzenes to give 2,3-dihydro-pyridazin-4(1H)-ones after elimination of ethanol. Regioselectivity for cycloaddition of unsymmetrical azobenzenes, ring contraction and chemoselective reduction of 2,3-dihydro-pyridazin-4(1H)-ones, and [4+2] cycloaddition to 4-phenyl-1,2,4-triazolin-3,5-dione are also described.

Full text of DOI:10.1016/j.tetlet.2016.07.087

Accepted Manuscript
Formal [4+2] cycloaddition of 3-ethoxycyclobutanones with azo compounds
Yusuke Shima, Jun-ichi Matsuo
PII:
S0040-4039(16)30953-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.087
TETL 47949
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 May 2016
19 July 2016
28 July 2016
Please cite this article as: Shima, Y., Matsuo, J-i., Formal [4+2] cycloaddition of 3-ethoxycyclobutanones with azo
compounds, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.087
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1
Tetrahedron Letters
Formal [4+2] cycloaddition of 3-ethoxycyclobutanones with azo compounds
Yusuke Shima and Jun-ichi Matsuo*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Azobenzenes reacted with 3-ethoxycyclobutanoes to give 2,3-dihydro-pyridazin-4(1H)-ones by
using EtAlCl as a Lewis acid. Thus, ring cleavage of 3-ethoxycyclobutanones took place to
form a zwitterionic intermediate by activation with EtAlCl , and intermolecular formal [4+2]
cycloaddition of the zwitterionic intermediate proceeded with azobenzenes to give 2,3-dihydro-
pyridazin-4(1H)-ones after elimination of ethanol. Regioselectivity for cycloaddition of
unsymmetrical azobenzenes, ring contraction and chemoselective reduction of 2,3-dihydro-
pyridazin-4(1H)-ones, and [4+2] cycloaddition to 4-phenyl-1,2,4-triazolin-3,5-dione are also
described.
2
2
Available online
Keywords:
Cycloaddition
Cyclobutanone
Azobenzene
2
009 Elsevier Ltd. All rights reserved.
Regioselectivity
Hydropyridazine
8
f
Hydropyridazines are seen in key structural cores of bioactive
compounds such as piperazimycin A and 1-azafagomine, and
4+2] cycloaddition to the N=N bond of azo compounds is
corresponding six-membered compounds.
In this paper, we
1
2
describe
a
new formal [4+2] cycloaddition of 3-
ethoxycyclobutanones with the N=N bonds of azobenzenes and
[
considered to be one of the most powerful methods for synthesis
of multiply substituted hydropyridazines (Figure 1). Hetero-
4-phenyl-1,2,4-triazolin-3,5-dione.
3,4
Reaction conditions for formal [4+2] cycloaddition of
cyclobutanone 1a and azobenzene were screened, and it was
found that cycloadduct 2a was obtained most efficiently in 73%
Diels-Alder reactions of acyldiazenes have been reported for
5
synthesis of hydropyridazine derivatives, but those of
6
azobenzenes have not been reported probably because the
2
yield when EtAlCl was used as a Lewis acid (Table 1, entry 1).
LUMO energy of azobenzenes is not low enough for hetero-
A variety of cyclobutanones1b‒i reacted with azobenzene to
afford the corresponding cycloadducts 2b‒i. 2,2-Dialkyl- and 2-
monoalkylcyclobutanones that had bulky alkyl groups such as t-
butyl and i-propyl groups at the 2-position gave the desired
products in high yields (entries 2‒7). On the other hand, 2-
monoalkylcyclobutanones with primary alkyl groups such as
benzy and methyl groups and 2-nonsubsituted 3-
ethoxycyclobutanone (1i) gave the corresponding products in
Diels-Alder reactions.
component is required for [4+2] cycloaddition of azobenzenes.
Therefore, another reactive C4
7
27‒49% yields (entries 8‒10).
Table 1.
Formal [4+2] cycloaddition between 3-ethoxycyclobutanones
a
1a‒i and azobenzene
Figure 1. Bioactive compounds having a hydropyridazine structure.
Cyclobutanones have been utilized as useful building blocks
8
in organic synthesis, and 3-ethoxycyclobutanones have unique
and characteristic reactivities that are not observed in other
cyclobutanones. Thus, four-membered ring cleavage takes place
regioselectively at the more substituted C2‒C3 bond to form a
zwitterionic intermediate by activation with an appropriate Lewis
1
2
b
entry
1
2
3
4
1
R
R
2
Yield (%)
c
1a
1b
1c
1d
Me
Me
2a
2b
2c
2d
73
70
97
87
9
acid. The zwitterionic intermediate reacted as a C4 component
–(CH
–(CH
–(CH
2
2
2
)
)
)
6
5
4
–
–
–
9
10
11
with various C=O, C=C,
C=N
bonds to give the

2
Tetrahedron Letters
t
t
i
5
6
7
8
9
trans-1e
cis-1e
Bu
Bu
Pr
H
H
H
H
H
H
2e
2e
2f
2g
2h
2i
84
81
78
49
27
27
d
1f
1g
1h
Table 2.
d
Bn
Me
H
d
Formal [4+2] cycloaddition between cyclobutanone 1a and
symmetrical azobenzenes 3a-j
a
1
0
1i
a
Reaction conditions: cyclobutanone 1 (4.0 equiv), azobenzene (1.0 equiv),
2
and EtAlCl (2.2 equiv) were used.
b
Isolated yield.
c
Reaction time: 1 h.
d
A mixture of diastereomers of 1 was used.
Next, the formal [4+2] cycloaddition of 1a with various
b
entry
1
2
3
4
5
6
7
X (3)
p-NO
yield of 4 (%)
0
azobenzene derivatives 3a‒j was investigated (Table 2).
Azobenzene having a nitro group or a dimethylamino group on
the phenyl ring did not give the cycloadduct (entries 1 and 7). p-
Chloro or p-bromo substitution resulted in lowering yields of
cycloadducts 4b,c. p- or m-Alkyl substitution of the phenyl ring
of azobenzene did not affect the yield for the cycloadduct (entries
, 5, and 8), but o-alkyl substitution influenced the cycloaddition
and it proceeded very slowly probably due to its steric influence
entries 9 and 10).
2
(3a)
p-Cl (3b)
p-Br (3c)
p-Me (3d)
26
15
58
67
30
0
72
5
6
t
p- Bu (3e)
p-OMe (3f)
p-NMe (3g)
2
4
8
9
10
m-Me(3h)
o-Me(3i)
2
(
o,p-Me (3j)
a
b
For reaction conditions, see Table 1.
Isolated yield.
Furthermore, unsymmetrical azobenzenes were used in the
cycloaddition reaction in order to investigate its regioselectivity
1
2
(
Table 3). It was found that regioselectivity was not observed
when a halogen was introduced on the aromatic ring of
azobenzene (entries 1 and 2), while obvious regioselectivity was
observed when a methoxy group and a nitro group were
introduced on the aromatic ring (entries 3‒5).
a
Table 3. Reaction with unsymmetrical azobenzenes
b
entry
1
Azobenzene 5
Product 6
yield (%)
45
2
50

3
3
60
4
25
5
25
a
For reaction conditions, see Table 1.
b
Isolated yield.
c
The structures of products were deduced from the results of entry 5.
The structures of 6e,e’ were determined by treatment of the
Scheme 2. A proposed mechanism.
1
3
isolated major regioisomer 6e with zinc in acetic acid.
The
compound 7 was obtained quantitatively and this result suggests
that p-anisidine bound at the -position of the carbonyl group of
6e (Scheme 1). Therefore, it was assumed that the more
electron-rich aromatic ring was attached to the -position of the
carbonyl group of 2,3-dihydro-pyridazin-4(1H)-ones 6 when
unsymmetrial azobenzene derivatives 5 were used (entries 3 and
4).
Scheme 1. Transformation of 6e and 2c to 7.
A proposed reaction mechanism is shown in Scheme 2. 3-
Ethoxycyclobutanone 8 was activated with EtAlCl
2
to form a
2,3-Dihydro-pyridazin-4(1H)-ones consist of a new class of
compounds and their transformation is shown in Scheme 3. The
C=C bond of 2a was reduced chemoselectively by using L-
zwitterionic intermediate 9 by cleaving the more substituted
9
C2‒C3 bond. The more nucleophilic nitrogen of azobenzene
14
attacked the part of oxonium cation to form 10.
The
Selectride and 12 was obtained in 72% yield.
regioselectivity in unsymmetrical azobenzenes was controlled by
the difference in nucleophilicity of two nitrogens of azobenzenes.
Cyclization of 10 and elimination of ethanol gave the product 11.

4
Tetrahedron
Scheme 3. Chemoselective reduction of 2a.
Org. Chem. 2007, 72, 7504. (b) Graziano, M. L.; Iesce, M. R.;
Cermola, F. J. Chem. Res., Synop. 1996, 82.
8
.
.
(a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem.,
Int. Ed. 2011, 50, 7740. (b) Namyslo, J. C.; Kaufmann, D. E.
Chem. Rev. 2003, 103, 1485. (c) Lee-Ruff, E.; Mladenova, G.
Chem. Rev. 2003, 103, 1449. (d) Bellus, D.; Ernst, B. Angew.
Chem., Int. Ed. Engl. 1988, 27, 797. (e) Conia, J. M.; Robson, M.
J. Angew. Chem., Int. Ed. Engl. 1975, 14, 473. (f) Matsuo, J.
Tetrahedron Lett. 2014, 55, 2589.
9
1
Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc.
2
008, 130, 11600.
0. (a) Matsuo, J. I.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org.
Lett. 2009, 11, 3822. (b) Matsuo, J.; Sasaki, S.; Hoshikawa, T.;
Ishibashi, H. Chem. Comm. 2010, 46, 934. (c) Matsuo, J.;
Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 5831. (d)
Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.;
Matsuo, J.; Ishibashi, H. Angew. Chem. Int. Ed. 2013, 52, 906.
1. Matsuo, J.; Okado, R.; Ishibashi, H. Org. Lett. 2010, 12, 3266.
2. Jia, X.; Han, J. J. Org. Chem. 2014, 79, 4180.
The reaction of cyclobutanone 1a and 4-phenyl-1,2,4-
triazolin-3,5-dione (PTAD, 13) gave the [4+2] adduct 14 in 35%
yield by using TiCl as a Lewis acid (Scheme 4). The same
reaction by the activation with EtAlCl gave 14 in 22% yield.
Diethyl azodicarboxylate did not react with 1a by using EtAlCl
or TiCl
4
2
2
1
1
1
4
.
3. Comins, D. L.; Brooks, C. A.; Ingalls, C. L. J. Org. Chem. 2001,
6
6, 2181.
4. Donohoe, T. J.; Connolly, M. J.; Walton, L. Org. Lett. 2009, 11,
562.
5. Kato, T.; Sato, M. J. Org. Chem. 1974, 39, 3205.
1
1
Scheme 4. Reaction of 1a and PTAD (13).
5
Supplementary Material
Supplementary data associated with this article can be found
in the online version, at __.
In conclusion, we have developed formal [4+2] cycloaddition
of 3-ethoxycyclobutanones with azobenzenes and 4-phenyl-
1,2,4-triazolin-3,5-dione to 2,3-dihydro-pyridazin-4(1H)-ones.
Regioselectivity for the cycloaddition of unsymmetrical
azobenzenes was clarified and some transformations of
cycloadducts were developed. 1,2,3,6-Tetrahydropyridazin-3-
ones, which are isomers of the above-mentioned products, were
prepared by the reaction of diketene and azobenzenes followed
15
by reduction and elimination. Therefore, the present method
provides unique method for preparation of
a
teterahydropyridazins.
Acknowledgments
Financial support from JSPS KAKENHI Grant Number
5K07855 is greatly appreciated.
1
References and notes
1
2
3
.
.
.
Miller, E. D.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Org.
Chem. 2007, 72, 323.
Bols, M.; Hazell, R. G.; Thomsen, I. B. Chem. Eur. J. 1997, 3,
9
40.
For a general review of hetero-Diels-Alder reactions, see (a) The
Diels-Alder reactions: Selected Practical Methods: Fringuelli, F.,
Taticchi, A., Eds.; John Wiley & Sons: New York, 2002. (b)
Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Heidari, B.; Hamidi, H.
RSC Adv. 2015, 5, 101999. (c) Ishihara, K.; Sakakura, A.
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Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006,
4
5
.
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8
, 6023. (b) Vidyacharan, S.; Sagar, A.; Sharada, D. S. Org. Bio.
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(a) Vartanyan, R. S.; Gyul'budagyan, A. L.; Khanamiryan, A. K.;
Mkrtumyan, E. N.; Kazaryan, Z. V. Khimiya Geterotsiklicheskikh
Soedinenii 1991, 783. (b) Liu, B.; Li, K.-N.; Luo, S.-W.; Huang,
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6482.
6
7
.
.
Lazraq, M.; Escudie, J.; Couret, C.; Satge, J.; Soufiaoui, M.
Organometallics 1991, 10, 1140.
Formal [3+2] cycloaddition of donor-acceptor cyclopropanes with
diazene derivatives was reported. See: (a) Korotkov Vadim, S.;
Larionov Oleg, V.; Hofmeister, A.; Magull, J.; de Meijere, A. J.

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Formal [4+2] cycloaddition of 3-
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ethoxycyclobutanones with azo compounds
Yusuke Shima and Jun-ichi Matsuo*

5
Highlights
Formal [4+2] cycloaddition of azobenzenes with 3-ethoxycyclobutanoes to 2,3-dihydro-pyridazin-4(1H)-
ones was developed.
Regioselectivity for cycloaddition of unsymmetrical azobenzenes was clarified.
Ring contraction and chemoselective reduction of 2,3-dihydro-pyridazin-4(1H)-ones were developed.