Recyclization of hydrazides of 2-carboxyphenyldifurylmethanes: Synthesis of novel 4,10-dihydro-3H-pyridazino[1,6-b]isoquinolin-10-one system

Article abstract of DOI:10.1055/s-2006-958419

A novel heterocyclic system of 4,10-dihydro-3H-pyridazino[1,6-b] isoquinolin-10-one has been synthesized via acid-catalyzed recyclization of hydrazides of 2-carboxyphenyldifurylmethanes as well as by alternative synthesis by interaction of the correspondi

Full text of DOI:10.1055/s-2006-958419

LETTER
3431
Recyclization of Hydrazides of 2-Carboxyphenyldifurylmethanes: Synthesis of
Novel 4,10-Dihydro-3H-pyridazino[1,6-b]isoquinolin-10-one System
S
ynthesis of 4,10-D
l
ihydro
e
-3
H
-pyrida
x
zino[1,6-
b
]i
a
soquinolin-
n
10-one Syste
d
m
er V. Butin,*a Artem S. Dmitriev,a Vladimir T. Abaev,b Valery E. Zavodnikc
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology,
Moskovskaya st. 2, Krasnodar 350072, Russian Federation
Fax +7(861)2596592; E-mail: alexander_butin@mail.ru
b
c
North-Ossetian State University, Vatutina st. 46, Vladikavkaz 362025, Russian Federation
Karpov Institute of Physical Chemistry, Vorontsovo pole st. 10, Moscow 103064, Russian Federation
Received 27 July 2006
position of the benzylfuran, derivatives of benzofuran,3
indole,4 isocoumarine,5 isoquinolone6 and isochromenes7
can be obtained (Scheme 1). In this case the furan ring can
be considered as a formal equivalent of a 1,4-dicarbonyl
compound.
Abstract: A novel heterocyclic system of 4,10-dihydro-3H-pyr-
idazino[1,6-b]isoquinolin-10-one has been synthesized via acid-
catalyzed recyclization of hydrazides of 2-carboxyphenyldifuryl-
methanes as well as by alternative synthesis by interaction of the
corresponding isocoumarine ketones with hydrazine hydrate.
Key words: furans, ring opening, ring closure, fused-ring systems,
pyridazino[1,6-b]isoquinolin-10-one
Another feature of the mentioned transformation is that
the furan ring, on reacting with the ortho-substituent, sup-
plies only one carbon atom into the newly formed hetero-
cycle and liberates the second carbonyl group into a free
form. Usually in the case of intermolecular reactions of
furan derivatives with nucleophiles both carbonyl groups
are involved in the recyclization process.8 In our condi-
tions, if the benzylfuran 3 bears a second furan ring, recy-
clization is accompanied with a secondary intramolecular
carbocyclization leading to tetracyclic derivatives 5
(Scheme 2).5b,6,7,9
It is well known that alkylfurans can undergo ring cleav-
age in hydrolytic acid-catalyzed conditions giving rise to
1,4-dicarbonyl compounds that often participate in subse-
quent reactions. This property of furan derivatives to
serve as 1,4-diketone precursors has been extensively
used in organic synthesis.1 It is worthy to note that trans-
formation of the furan ring does not necessarily need for-
mation of the free 1,4-diketone. In particular, we have
developed a new general approach to benzannulated het-
erocycles 2, based on recyclization of ortho-substituted
benzylfurans 1.2 By varying the substituents in the ortho-
To broaden the scope of our method for the synthesis of
fused-ring heterocyclic compounds we tried to take ad-
vantage of the free keto group in further heterocycliza-
tions. We reasoned that the introduction of the second
XH
XH
X
H
H+
O
+
O
– H+
O
R1
R1
R1
R2
R2
R2
1
2
X = O, NTs, COO, CONAlk, CH2O
Scheme 1 Benzannulated heterocycles from ortho-substituted benzylfurans
XH
X
X
H+
O
– H3O+
R
R
R
O
O
O
O
+
H
4
5
3
X = O, NAc, COO, CONAlk, CH2O
Scheme 2 Cascade recyclization–cyclization reaction of ortho-substituted aryldifurylmethanes
SYNLETT 2006, No. 20, pp 3431–3434
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-958419; Art ID: D22406ST
© Georg Thieme Verlag Stuttgart · New York

3432
A. V. Butin et al.
LETTER
Table 1 Yields of Esters 9 and Hydrazides 10
nucleophilic center into a molecule of the starting com-
pound 6 would allow us to redirect the secondary cycliza-
tion towards tricyclic compounds 7 according to
Scheme 3.
Entry R1
R2
Compound Yield of 9 Compound Yieldof10
(%)
86
80
83
87
85
82
(%)
72
70
65
71
60
68
1
2
3
4
5
6
H
Cl
Br
I
H
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
YH
Y
H
XH
R2
X
H+
H
O
R1
H
R1
R2
6
H
H
Cl
Br
7
Scheme 3 Tricyclic fused-ring heterocyclic compounds from
ortho-substituted benzylfurans
of pyridazino[1,6-b]isoquinolinone 13a–f12 were isolated
as sole products (Method A, Scheme 5).
To check this assumption we chose hydrazides of the cor-
responding 2-carboxybenzylfurans that formally met this
structural requirement. We started with readily available
compounds 8a–f.5b We failed to obtain acid chlorides of
the compounds 8a–f as possible precursors of the corre-
sponding hydrazides. Interaction of phosphorus pen-
tachloride, thionyl chloride or oxalyl chloride with 8a–f
resulted in a strong tarrification of the reaction mixture
that was attributed to the acid sensitivity of the furan
rings. For this reason esters 9a–f were chosen as precur-
sors to the hydrazides. It should be noted that the classical
method of their synthesis by refluxing carbonic acids in
alcohols in the presence of mineral acids is not applicable
in our case as compounds 8a–f undergo recyclization into
isocoumarine derivatives under these conditions.5b Finally
esters 9a–f were obtained in good yields by methylation
of the corresponding acids with methyl iodide in the pres-
ence of potassium hydroxide in dimethyl sulfoxide.10 Sub-
sequently esters 9a–f were transformed into hydrazides
10a–f11 by interaction with hydrazine monohydrate
(NH2NH2·H2O) in refluxing n-butanol (Scheme 4,
Table 1).
Unfortunately, this reaction was insufficiently clean, thus
the isolation of the target compounds was complicated.
Hence the alternative synthesis of pyridazino[1,6-b]iso-
quinolinones 13a–f was probed. Our alternative approach
was based on the ready replacement of oxygen in isocou-
marine derivatives by nitrogen atom with nitrogen-con-
taining nucleophiles like amines,13 hydroxylamine14 or
hydrazine.15 Within this approach we also started with
compounds 8a–f that were transformed with good yields
into ketones 14a–f according to the procedure reported by
us earlier.5b Compounds 14a–f afforded corresponding
hydrazones 15a–f upon treatment with NH2NH2·H2O in
ethylene glycol at room temperature. Subsequent reflux-
ing of the resultant solutions without isolation of hydra-
zones within 15 minutes smoothly gave rise to the desired
pyridazino[1,6-b]isoquinolinone 13a–f (Method B,
Scheme 5).16 In the Table 2 are cited overall yields of
13a–f from starting compounds 8a–f. As can be seen from
the table method B is preferable over method A in term of
the yields. Moreover method B is easier from a prepara-
tive point of view.
Recyclization of hydrazides 10a–f was accomplished by
boiling the hydrazides in an anhydrous solution of p-tolu-
enesulfonic acid in benzene. Evidently, the first step of the
transformation included intermediate ketones 11a–f. As
expected, the presence of the more nucleophilic amino
group altered the course of the secondary reaction. The
cyclization in that case proceeded affecting the nitrogen
atom of hydrazine group rather than b-carbon atom of
furan ring. As a result, tetracyclic compounds 12a–f
were not detected in the reaction mixture and derivatives
Pyridazino[1,6-b]isoquinolinone derivatives 13a–f were
fully characterized by spectral methods. For unambiguous
proof of structure X-ray analysis was performed on the
monocrystal of compound 13f (Figure 1).17
In summary, we have developed two synthetic protocols
to the novel heterocyclic system of 4,10-dihydro-3H-
pyridazino[1,6-b]isoquinolin-10-one starting from ortho-
carboxybenzylfurans. To the best of our knowledge only
two benzannulated analogues of this system have been
O
O
O
R1
R2
OH
MeI, KOH,
DMSO, r.t.,
20 min
R1
R2
NHNH2
O
OMe
R1
R2
N2H4, n-BuOH,
reflux, 20 min
O
O
O
O
O
8a–f
9a–f
10a–f
Scheme 4 Synthesis of esters 9a–f and hydrazides 10a–f
Synlett 2006, No. 20, 3431–3434 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 4,10-Dihydro-3H-pyridazino[1,6-b]isoquinolin-10-one System
3433
Method A
10a–f
p-TsOH, C6H6
(15% weight),
reflux, 10 min
O
R1
R2
O
O
N
N
R1
R2
NH2
N
R1
R2
NH2
N
O
O
O
O
13a–f
11a–f
12a–f
ethylene glycol,
reflux 15 min
O
O
NH2NH2,
ethylene glycol,
r.t., 30 min
HCl, EtOH
(8 % weight)
reflux, 40 min
R1
R2
R1
R2
O
O
8a–f
Method B
O
N
H2N
O
O
14a–f
15a–f
Scheme 5 Synthesis of pyridazino[1,6-b]isoquinolinones 13a–f
Table 2 Yields of Pyridazino[1,6-b]isoquinolinones 13a–f
reported.15,18 Pyridazines and isoquinolones constitute an
important pharmacophoric moiety present in many drugs
and from this point of view derivatives of 4,10-dihydro-
3H-pyridazino[1,6-b]isoquinolin-10-one are of interest to
medicinal chemists. Besides, we believe that the proposed
approach to the cascade recyclization–cyclization reac-
tions in the ortho-substituted benzylfurans bearing addi-
tional nucleophilic substituents in suitable positions will
be a versatile tool for the design of polycyclic heterocyclic
compounds and further work in this field is in progress.
Entry
Compound R1
R2
Method A, Method B,
yield (%) yield (%)
1
2
3
4
5
6
13a
13b
13c
13d
13e
13f
H
Cl
Br
I
H
25
30
32
31
35
33
38
35
38
37
35
38
H
H
H
H
H
Cl
Br
Acknowledgment
Financial support was provided by Bayer HealthCare AG (Germa-
ny) and the Russian Foundation of Basic Research (grant 03-03-
32759).
References and Notes
(1) For reviews, see: (a) Dean, F. M. Adv. Heterocycl. Chem.
1982, 30, 167. (b) Dean, F. M. Adv. Heterocycl. Chem.
1982, 31, 237. (c) Piancatelli, G.; D’Auria, M.; D’Onofrio,
F. Synthesis 1994, 867.
(2) For a review, see: Butin, A. V.; Abaev, V. T. Izv. Akad. Nauk
Ser. Khim. 2001, 1436.
(3) (a) Butin, A. V.; Krapivin, G. D.; Zavodnik, V. E.;
Kul’nevich, V. G. Khim. Geterotsikl. Soedin. 1993, 616.
(b) Abaev, V. T.; Gutnov, A. V.; Butin, A. V. Khim.
Geterotsikl. Soedin. 1998, 603. (c) Gutnov, A. V.; Butin, A.
V.; Abaev, V. T.; Krapivin, G. D.; Zavodnik, V. E.
Molecules 1999, 4, 204.
(4) Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G.
D. Tetrahedron Lett. 2001, 42, 2031.
(5) (a) Dmitriev, A. S.; Podelyakin, S. A.; Abaev, V. T.; Butin,
A. V. Khim. Geterotsikl. Soedin. 2005, 1400. (b) Abaev, V.
T.; Dmitriev, A. S.; Gutnov, A. V.; Podelyakin, S. A.; Butin,
A. V. J. Heterocycl. Chem. 2006, 43, 1195.
Figure 1 ORTEP diagram of 13f
Synlett 2006, No. 20, 3431–3434 © Thieme Stuttgart · New York

3434
A. V. Butin et al.
LETTER
(6) Abaev, V. T.; Osipova, A. A.; Butin, A. V. Khim.
Geterotsikl. Soedin. 2001, 849.
(7) Butin, A. V.; Abaev, V. T.; Mel’chin, V. V.; Dmitriev, A. S.
Tetrahedron Lett. 2005, 46, 8439.
(8) See for example: (a) Bezoari, M. D.; Paudler, W. W. J. Org.
Chem. 1980, 45, 4584. (b) Haley, J. F.; Rosenfeld, S. M.;
Keehn, P. M. J. Org. Chem. 1977, 42, 1379.
(CO) cm–1. 1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H,
CH3), 2.33 (t, J = 7.5 Hz, 2 H, CH2), 2.38 (s, 3 H, CH3), 2.84
(t, J = 7.5 Hz, 2 H, CH2), 6.15 (d, J = 3.1 Hz, 1 H, 4-HFur),
6.31 (d, J = 3.1 Hz, 1 H, 3-Hfur), 7.33 (d, J = 8.7 Hz, 1 H,
HAr), 7.51 (dd, J = 2.2, 8.7 Hz, 1 H, HAr), 8.52 (d, J = 2.2 Hz,
1 H, HAr). 13C NMR (50 MHz, CDCl3): d = 13.82, 22.54,
24.43, 24.65, 105.25, 106.95, 113.16, 126.36, 126.80,
128.09, 132.69, 133.04, 134.63, 135.08, 145.49, 152.92,
158.27, 163.19. MS: m/z (%) = 329, 327 (5, 15) [M+ + 1],
328, 326 (28, 83) [M+], 293 (28), 292 (100), 249 (18), 208
(15), 43 (20). Anal. Calcd for C18H15ClN2O2: C, 66.16; H,
4.63. Found: C, 66.08; H, 4.69.
(c) Kharchenko, V. G.; Markushina, I. A.; Voronin, S. P.
Khim. Geterotsikl. Soedin. 1982, 418. (d) Kharchenko, V.
G.; Gubina, T. I.; Voronin, S. P.; Markushina, I. A. Khim.
Geterotsikl. Soedin. 1986, 1453. (e) Voronin, S. P.; Gubina,
T. I.; Markushina, I. A.; Kharchenko, V. G. Khim.
Geterotsikl. Soedin. 1989, 1333.
(13) (a) Ferrer, S.; Naughton, D. P.; Parveen, I.; Threadgill, M. D.
J. Chem. Soc., Perkin Trans. 1 2002, 335. (b) Ukita, T.;
Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Moritani, Y.;
Saruta, K.; Higashijima, T.; Kotera, J.; Takagi, M.;
Kikkawa, K.; Omori, K. J. Med. Chem. 2001, 44, 2204.
(c) Kowalczyk, B. A. Synthesis 2000, 1113.
(9) (a) Butin, A. V.; Gutnov, A. V.; Abaev, V. T.; Krapivin, G.
D. Khim. Geterotsikl. Soedin. 1998, 883. (b) Butin, A. V.;
Smirnov, S. K.; Stroganova, T. A. J. Heterocycl. Chem.
2006, 43, 623. (c) Gutnov, A. V.; Abaev, V. T.; Butin, A. V.;
Dmitriev, A. S. J. Org. Chem. 2001, 66, 8685.
(10) For a typical procedure, see: Johnstone, R. W. A.; Rose, M.
E. Tetrahedron 1979, 35, 2169.
(d) Yamaguchi, S.; Uchiuzoh, Y.; Sanada, K. J. Heterocycl.
Chem. 1995, 32, 419. (e) Bhide, B. H.; Akolkar, V. D.;
Brahmbhatt, D. I. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1993, 32, 675.
Preparation of Compounds 9a–f; General Procedure
To a suspension of finely powdered KOH (2 g) in anhyd
DMSO (40 mL) were added compound 8 (6.76 mmol) and
MeI (2 mL, 12.12 mmol) and the mixture was stirred at r.t.
for 20 min. The suspension was filtered off and the filtrate
was poured into H2O (500 mL). The resulting emulsion was
brought to pH 5–6 with dilute HCl and extracted with
CH2Cl2 (4 × 30 mL). The combined extract was dried over
anhyd Na2SO4 and evaporated to dryness. The residue was
purified by flash chromatography on silica gel (hexane–
CH2Cl2, 10:1). Eluate containing the target compound was
reduced in volume to 10–20 mL and left for crystallization at
temperature below 0 °C.
(14) Cushman, M.; Jayaraman, M.; Vroman, J. A.; Fukunaga, A.
K.; Fox, B. M.; Kohlhagen, G.; Strumberg, D.; Pommier, Y.
J. Med. Chem. 2000, 43, 3688.
(15) Dusemund, J. Arch. Pharm. (Weinheim, Ger.) 1982, 315,
925.
(16) Preparation of Compounds 13a–f (Method B); General
Procedure
A suspension of compound 14 (3.37 mmol) in ethylene
glycol (50 mL) with NH2NH2·H2O (1 mL) was stirred at r.t.
until complete dissolution of the starting material was
observed (30 min, TLC monitoring). The resulting solution
was refluxed for 15 min, poured into H2O (300 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined extract
was washed with H2O, dried over anhyd Na2SO4 and
evaporated to dryness. The residue was purified by column
chromatography on silica gel (hexane–EtOAc, 4:1). The
solvent was stripped off of the eluate and the residue was
recrystallized from hexane–EtOAc (10:1) at temperature
below 0 °C.
Selected analytical data of 9b: mp 57–58 °C. 1H NMR (300
MHz, CDCl3): d = 2.24 (s, 6 H, CH3), 3.87 (s, 3 H, OCH3),
5.85 (d, J = 3.3 Hz, 2 H, 4-HFur), 5.88 (d, J = 3.1 Hz, 2 H, 3-
Hfur), 6.48 (s, 1 H, CH), 7.24 (d, J = 8.5 Hz, 1 H, HAr), 7.41
(dd, J = 2.2, 8.5 Hz, 1 H, HAr), 7.90 (d, J = 2.2 Hz, 1 H, HAr).
Anal. Calcd for C19H17ClO4: C, 66.19; H, 4.97. Found: C,
66.01; H, 5.09.
(11) Preparation of Compounds 10a–f; General Procedure
A mixture of compound 9 (5.81 mmol), NH2NH2·H2O (9
mL) and n-BuOH (9 mL) was refluxed for 20 min. Then it
was poured into H2O (300 mL). The resulting precipitate
was filtered off, air-dried and used in the next step as such.
(12) Preparation of Compounds 13a–f (Method A); General
Procedure
(17) Crystal data of compound 13f: C18H15BrN2O2, monoclinic,
space group C2/c; a = 32.028(6) Å, b = 11.022(2) Å, c =
9.016(2) Å, a = 90°, b = 90.48(3)°, g = 90°, V = 3182.6(11)
Å3, Z = 8, Dcalcd = 1.550 Mg/m3, F(000) = 1504; 3330
reflections collected, 3116 unique (Rint = 0.0269); final R
indices (3116 observed collections I >2sI): R1 = 0.0331,
wR2 = 0.0818; final R indices (all data): R1 = 0.1677, wR2 =
0.0945. Crystallographic data (excluding structure factors)
for the structure in this article have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 614755. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or E-mail: deposit@ccdc.cam.ac.uk]. Each
request should be accompanied by the complete citation of
this paper.
To a 15% solution of p-TsOH in benzene (20 mL), prepared
by refluxing p-TsOH·H2O in benzene with azeotropic
removal of H2O, compound 10 (4.19 mmol) was added and
the mixture was refluxed for 10 min. The resulting solution
was poured into H2O (300 mL). The slurry was extracted
with CH2Cl2 (3 × 50 mL). The combined extract was washed
with H2O, dried over anhyd Na2SO4 and evaporated to
dryness. The residue was purified by column
chromatography on silica gel (hexane–EtOAc, 4:1). Solvent
was stripped off of the eluate and the residue was
recrystallized from hexane–EtOAc (10:1) at temperature
below 0 °C.
(18) Veeraraghavan, S.; Popp, F. D. J. Heterocycl. Chem. 1981,
18, 71.
Selected analytical data of 13b: mp 173–174 °C. IR: 1667
Synlett 2006, No. 20, 3431–3434 © Thieme Stuttgart · New York