A diversity oriented synthesis of 2,10-dioxo-10H-1,2,3,4,4a,5-hexahydropyridazino[3,2-b]quinazolines

Article abstract of DOI:10.3987/com-05-s(t)9

A parallel method for the synthesis of the title compounds is described. Thus, methyl anthranilates (5) are transformed into 2-aminobenzohydrazides (3) which were treated with 4-oxo acids (4) to afford in high yields and acceptable purity of piridazino[3,2-b]quinazolines (1). Compounds (1) present four diversity centers (R₁, R₂, R₃, and R₄). The range of chemically acceptable substituents at each center has been evaluated. The isolation of a possible intermediate in the formation of 1, which presents an amino structure (10), has allowed proposing a complete mechanistic rationalization for the formation of structures (1).

Full text of DOI:10.3987/com-05-s(t)9

HETEROCYCLES, Vol. 67, No. 1, 2006
161
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 161 - 173. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd March, 2005, Accepted, 13th May, 2005, Published online, 13th May, 2005. COM-05-S(T)9
A
DIVERSITY ORIENTED SYNTHESIS OF 2,10-DIOXO-10H-
1,2,3,4,4a,5-HEXAHYDROPYRIDAZINO[3,2-b]QUINAZOLINES
Elisabeth Schuler,a,c Nacho Juanico,a Jordi Teixidó,a Enrique L. Michelotti,b
and José I. Borrella,*
aMolecular Engineering Group, Chemical Institute of Sarrià, Ramon Llull
University, Via Augusta, 390, E-08017 Barcelona, Spain *corresponding author:
j.i.borrell@iqs.url.edu
bRohm and Haas Company, 727 Norristown Road, Spring House, PA,
19477-0904, USA. Current address: Locus Pharmaceuticals, Inc. Four Valley
Square, 512 Township Line Rd., Blue Bell, PA 19422, USA
cCurrent address: Medichem, Barcelona Science Park, Josep Samitier 1-5,
E-08028 Barcelona, Spain
Abstract – A parallel method for the synthesis of the title compounds is
described.
Thus, methyl anthranilates (5) are transformed into
2-aminobenzohydrazides (3) which were treated with 4-oxo acids (4) to afford in
high yields and acceptable purity of piridazino[3,2-b]quinazolines (1).
Compounds (1) present four diversity centers (R1, R2, R3, and R4). The range of
chemically acceptable substituents at each center has been evaluated. The
isolation of a possible intermediate in the formation of 1, which presents an
aminol structure (10), has allowed proposing a complete mechanistic
rationalization for the formation of structures (1).
INTRODUCTION
2,10-Dioxo-10H-1,2,3,4,4a,5-hexahydropiridazino[3,2-b]quinazolines (1) have attracted little attention as
scaffolds for library production although they present four possible diversity centers (Figure 1) and have
been reported in literature to present broad range of biological activities such as anti-inflammatory and
analgesic,1 anti-insomnia, anticonvulsant, and mental illness.2,3 The corresponding dehydro derivatives
(2) have been claimed for the treatment of neurodegenerative diseases of the central nervous system
(Alzheimer, Parkinson, and Huntington),4 for treatment of prostatic hyperplasia5 and osteoporosis6 and as
very potent herbicides.7

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HETEROCYCLES, Vol. 67, No. 1, 2006
O
O
R4
N
9
N
G
O
9a
5a
N
8
7
N
2
3
4a
N
N
R1
R1
4
6
R3
2
R2
1
Figure 1
As a part of our work in the area of combinatorial chemistry focused on the preparation of random
libraries for agrochemical screening,8 we decided to prepare small sized libraries of
pyrazolo[3,2-b]quinazolines (1) using a solution-phase parallel synthesis approach. The present paper
reports the results of such study.
RESULTS AND DISCUSSION
Compounds (1) are usually prepared by condensation of anthranilic hydrazides (3) with 4-oxo acids (4)
(Scheme 1) in moderate to good yields,1-3,9 a procedure which in most cases is amenable to parallelization.
Anthranilic hydrazides (3) can also, in principle, be prepared in parallel by treatment of N-substituted
methyl anthranilates (5) with substituted hydrazines (6) in refluxing EtOH.8,10,11 Eleven methyl
anthranilates (5{1-11}) were selected on the basis of price, commercial availability, and diversity (Figure
2), six, esters (5{1-6}), were purchased and five, esters (5{7-11}), were prepared from the corresponding
acids (7{6-11}) in almost quantitative yields by treatment with CH2N2 in Et2O. Building blocks
(5{1-11}) are responsible for the diversity in R1 and R2.
O
O
O
O
R4
N
OH
H
R3
N
NH2NHR4
O
N
R4
OR
4
N
O
6
H
b
c
NH
R2
NH
R2
N
R1
R1
R1
R3
3
7 R= H
5 R= Me
R2
1
a
Reagents and conditions: a) CH2N2 in Et2O; b) EtOH, 60-70ºC; c) benzene, TsOH, reflux
Scheme 1. Chemset numbering of compounds (1) is standardized as follows: 1{building block 5, building
block 6, building block 4}. Chemset numbering of intermediates follows the same standardization.
Three hydrazines (6{1-3}) (Figure 3) were selected to introduce diversity in R4: hydrazine (6{1}) (R4=H),
methylhydrazine (6{2}) (R4=Me), and phenylhydrazine (6{3}) (R4=Ph). Treatment in parallel of methyl
anthranilates (5{1-11}) with 15 equivalents of hydrazine (6{1}) in EtOH at 60-70ºC for 15-24 h afforded
the corresponding hydrazides (3{x,1}) (x=1-7,9-11) in 43-92% yields.
Methyl 2-amino-
6-methylbenzoate (5{8}) did not yield the expected hydrazide (3{8,1}), possible because of steric

HETEROCYCLES, Vol. 67, No. 1, 2006
163
hindrance at the carbonyl group. Compounds (3{x,1}) (x=1-7,9-11) were isolated by simple filtration
from the reaction mixture and used in the step without further purification.
The reaction of methyl anthranilates with phenyl hydrazine (6{3}) under the same reaction conditions
used for 6{1} yielded only the unwanted regioisomer (8) (Figure 3). Thus, treatment of methyl
N-methylanthranilate (5{2}) with phenylhydrazine (6{3}) in EtOH at reflux gave only hydrazide (8{2,3}).
The alternative treatment of N-methylanthranilic acid (7{2}) with phenylhydrazine (6{3}) using DCC as
coupling agent in CH2Cl2 at room temperature for 4 h afforded 3{2,3} in 25% yield after separation from
the unwanted regioisomer (8{2,3}) by column chromatography (Figure 3). Using the same reaction
conditions
anthranilic
acid
(7{1})
and
N-phenylanthranilic
acid
(7{11})
yielded
2-amino-N'-phenylbenzohydrazide (3{1,3}) and 2-phenylamino-N'-phenylbenzohydrazide (3{11,3}) in
16% and 25% yields after separation from 8{1,3}and 8{11,3} respectively.
We could not overcome regiochemical problems when methylhydrazine (6{2}) was used as building
block. Treatment of either methyl anthranilate (5{1}) or the corresponding anthranilic acid (7{1}) with
methylhydrazine (6{2}) yielded only N-methyl derivative (8{1,2}). Diversity in R4 will be consequently
limited to hydrogen or aryl groups.
O
O
O
O
Cl
OMe
OMe
O
OMe
NH2
OMe
NH2
O
NH
Me
Cl
NH2
O
1
2
3
4
O
Me
MeO
MeO
MeO
Me
O
OMe
OMe
OH
NH2
OH
NH2
MeO
O
NH2
NH2
OMe
7
8
6
5
O
F
OH
OH
NH2
OH
NH2
NH
Ph
9
OMe
11
10
Figure 2: Methyl anthranilates (5{1-6}) and anthranilic acids (7{7-11}) used as building blocks
Three commercially available 4-oxo acids (4{1-3}) (Figure 3) were selected to introduce diversity in R3.
Treatment in parallel of previously prepared hydrazides (3) with 1.5 equivalents of 4-oxo acids (4{1-3})
using TsOH as catalyst in refluxing benzene yielded the expected pyrridazino[3,2-b]quinazolines (1) in
good yields. Isolation was carried out either by filtration, if the product precipitates out of solution, or

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HETEROCYCLES, Vol. 67, No. 1, 2006
the reaction mixture was concentrated in vacuo and fractionated in AcOEt/water, to afford
pyridazino[3,2-b]quinazolines (1).
O
O
NH2
N
6{1}: R4=H
6{2}: R4=Me
6{3}: R4=Ph
OH
4{1}: R3=H
4{2}: R3=Me
4{3}: R3=Ph
NH2NHR4
R3
R4
NH
R2
R1
O
8
Figure 3: Hydrazines and oxo acids used.
Reactions proceed quite well with 4-oxobutyric acid (4{1}) and levulinic acid (4{2}). In general the latter
gave better yields. On the contrary, all attempts carried out with 3-benzoylpropionic acid (4{3}) failed,
probably due to the steric hindrance introduced by the phenyl group. Consequently, diversity at R3 will
be limited to hydrogen or alkyl groups. Table 1 summarizes the demonstrative library of
1
pyridazino[3,2-b]quinazolines (1) prepared. Each compound was characterized by IR, H-NMR,
13C-NMR, and MS spectral data (Table 2).
Table 1. Compounds (1) prepared.
Com-
pound
R1
R2 R3 R4 Yield mp (ºC) Elemental Analysis (%): Found (Calculated)
(%)
C
H
N
1{1,1,2}a
1{1,3,2}a
1{2,1,1}
1{2,1,2}
1{2,3,2}
H
H
H
H
H
H
H
Me H 70
Me Ph 22
33
183-185 62.10 (62.33) 5.42 (5.67) 18.00 (18.17)
202-204 70.17 (70.34) 5.63 (5.58) 13.53 (13.67)
192-195 62.55 (62.33) 5.83 (5.67) 18.03 (18.17)
133-135 63.72 (63.66) 6.24 (6.16) 17.42 (17.13)
166-168 70.89 (71.01) 5.89 (5.96) 13.35 (13.08)
183-185 54.12(54.25) 4.76 (4.55) 15.54 (15.82)
188-190 53.85 (54.25) 4.81 (4.55) 15.49 (15.82)
198-200 57.90 (57.72) 5.94 (5.88) 14.15 (14.42)
164-166 56.23 (56.07) 5.81 (5.96) 13.15 (13.08)
182-185 63.35 (63.66) 6.25 (6.16) 17.06 (17.13)
150-155 59.43 (59.76) 5.82 (5.79) 15.96 (16.08)
169-171 57.53 (57.83) 4.62 (4.85) 16.54 (16.86)
195-197 69.76 (69.61) 5.35 (5.15) 14.10 (14.33)
187-188 70.49 (70.34) 5.79 (5.58) 13.81 (13.67)
208-210 75.21 (75.18) 5.22 (5.52) 10.67 (10.96)
Me H
H
Me Me H 77
Me Me Ph 38
1{3,1,2} 8-Cl
1{4,1,2} 7-Cl
1{5,1,2} 7,8-OMe
H
H
H
Me H 73
Me H 77
Me H 92
Me H 38
Me H 25
Me H 29
Me H 53
1{6,1,2} 6,7,8-OMe H
1{7,1.2} 8-Me
1{9,1,2} 6-OMe
1{10,1,2} 8-F
1{11,1,1} H
H
H
H
Ph
H
H
17
1{11,1,2} H
Ph Me H 20
1{11,3,2} H
Ph Me Ph 29
aIncluded in reference 1 but without elemental analysis or spectral data
The formation of compounds (1) has been previously reported but the mechanism by which the tricyclic
system is formed has not been rationalized. In the preparation of compound (1{5,1,2}) (Scheme 2) we

HETEROCYCLES, Vol. 67, No. 1, 2006
165
isolated a possible reaction intermediate that we assigned to structure (10) based on the following spectral
data: IR ν (cm-1): 3332, 3274, 3213 (NH, OH), 1703 (C=O); 1H-NMR (CDCl3) δ (ppm): 7.84 and 7,50 (s,
1H, H-Ph), 4.23 (br, 4H, NH and OH), 3.97 and 3.94 (s, 3H, OMe), 2.60-2.20 (m, 4H, CH2CH2), 1.48 (s,
13
3H, Me); C-NMR (CDCl3) δ (ppm): 171.9 (C=O), 163.5 (C=O), 153.2 (C7), 146.3 (C8), 130.4 (C5a),
111.1 (C9a), 109.5 (C9), 103 (C6), 81.0 (C4a, quaternary carbon), 56.3 (OMe), 56.2 (OMe), 31.7 (CH2),
30.1 (CH2), 20.9 (Me). Particularly important to this assignment is the presence in the 13C-NMR spectrum
of a quaternary carbon at 81.0 ppm. Aminol (10) would be the result of the dehydration of salt 9 followed
(or preceded) by condensation without dehydration of the 2-aminophenyl group onto the 4-oxo group.
Dehydration of aminol (10) to imines (11a) or (11b) would be disfavored because either the methyl or
methylene groups would be necessarily inside the macrocyclic ring with the consequent high steric
hindrance (Scheme 2). Aminols (10) would lead to the final pyridazino[3,2-b]quinazolines (1) by
nucleophilic displacement of the hydroxyl group by the nitrogen atom bonded to the C10 carbonyl group
with subsequent loss of water.
The complete characterization of aminol (10) (R1=7,8-OMe, R2=H, R3=Me, R4=H) by means of MS
spectrum was not possible because in the registering conditions (10) underwent loss of water to the final
pyridazino[3,2-b]quinazoline (1{5,1,2}).
O
O
O
O
MeO
MeO
NH2
OH
MeO
MeO
NH3
N
O
N
H
H
4{2}
O
NH2
NH2
3{5,1}
O
9
O
H
N
O
H
N
9
MeO
MeO
O
..
H
9a
O
MeO
8
N
N
2
OH
- H2O
3
N
H
7
5a
MeO
N
H
4a
4
Me
6
Me
10
1{5,1,2}
O
O
H
H
H
H
N
N
O
MeO
MeO
MeO
N
N
O
Me
11a
11b
MeO
N
N
Me
Scheme 2: Rationalization of compound (1{5,1,2}) formation
Compounds (1) were inactive in assays for herbicidal, fungicidal or insecticidal activities.

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HETEROCYCLES, Vol. 67, No. 1, 2006
EXPERIMENTAL
All melting points were determined with a Büchi 530 capillary apparatus and are uncorrected. IR spectra
1
were recorded in a Nicolet Magna 560 FTIR spectrophotometer. H- and 13C-NMR spectra were
determined in a Varian Gemini-300 operating in a field strength of 300 and 75.5 MHz, respectively.
Chemical shifts are reported in parts per million (δ) and coupling constants (J) in Hz, using in the case of
1H-NMR, tetramethylsilane (TMS) or sodium 2,2,3,3-tetradeuteriotrimethylsilylpropionate (TSPNa) as
13
internal standards and setting, in the case of C-NMR, the references at the signal of the solvent (77.0
ppm for CDCl3, 39.5 ppm and for DMSO-d6). . Elemental microanalyses were obtained in a Carlo-Erba
CHNS-O/EA 1108 analyzer and gave results for the elements stated with ±0.4% of the theoretical values.
Methyl N-phenylanthranilate (5{11}) (R1=H, R2=Ph) was obtained according to a reported procedure.12
Analytical samples of compounds (5), (3), and (1) were obtained by preparative HPLC using a Gilson
HPLC provided with a Gilson 215 Liquid Handler and UV detector at 220 and 254 nm. Columns used
were a YMC-Pack SIL (150 x 10 mm, 5 µm) for the normal phase and a YMC-Pack ODS-AQ (100 x 10
mm, 5 µm) for the reverse phase.
General procedure for the synthesis of methyl anthranilates (5{7-10}). Methyl 5-methylanthranilate
(5{7}) (R1=5-Me, R2=H): A ethereal solution of diazomethane prepared according to the procedure and
apparatus of Hudlicky13 using 2.8 g (13.2 mmol) of Diazald® (N-methyl-N-nitroso-p-toluenesulfonamide)
in 132 mL of Et2O, 0.8 g (13.2 mmol) of KOH in 1.3 mL of water, 4.7 mL of Carbitol and 1.3 mL of
Et2O, was added dropwise to a suspension of 1.0 g (6.6 mmol) of 5-methylanthranilic acid (7{7}) in 50
mL of Et2O. The resulting mixture was stirred for 1 h, concentrated in vacuo to afford 1.1 g (99%) of
methyl 5-methylanthranilate (5{7}) as a pale yellow liquid. IR (CHCl3) ν (cm-1): 3477, 3370 (N-H), 1690
(C=O), 1582, 1562, 1502, 1456, 1440; 1H-NMR (CDCl3) δ (ppm): 7.66 (d, 4JHH= 2 Hz, 1H, H6), 7.10 (dd,
4
3
3JHH= 8 Hz, JHH= 2 Hz, 1H, H4), 6.59 (d, JHH= 8 Hz, 1H, H3), 5.55 (br, 2H, NH2), 3.86 (s, 3H,
13
-COOCH3), 2.23 (s, 3H, C5-CH3); C-NMR (CDCl3) δ (ppm): 168.6 (C=O), 148.2 (C2), 135.2 (C4),
130.8 (C6), 125.4 (C5), 116.8 (C3), 110.7 (C1), 51.5 (-COOCH3), 20.2 (C5-CH3); MS, m/z (%):165 (80)
[M+], 133 (100), 104 (25), 84 (31), 69 (61), 49 (38); Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N,
8.48. Found: C, 65.03; H, 6.93; N, 8.15.
Methyl 6-methylanthranilate (5{8}) (R1=6-Me, R2=H): As above but using 1.0 g (6.6 mmol) of
6-methylanthranilic acid (7{8}). Yield: 98%; IR (CHCl3) ν (cm-1): 3483, 3378 (N-H), 1696 (C=O), 1607,
1588, 1465, 1441; 1H-NMR (CDCl3) δ (ppm): 7.08 (dd, 3JHH= 7 Hz, 3JHH= 7 Hz, 1H, H4), 6.54-6.52 (m,
13
2H, H5, H3), 5.11 (br, 2H, NH2), 3.89 (s, 3H, -COOCH3), 2.43 (s, 3H, C6-CH3); C-NMR (CDCl3) δ
(ppm): 166.1 (C=O), 150.7 (C2), 140.5.8 (C6), 133.8 (C4), 119.2 (C5), 117.5 (C1), 113.0 (C3), 51.5

HETEROCYCLES, Vol. 67, No. 1, 2006
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(-COOCH3), 18.3 (C6-CH3); Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.70; H,
6.80; N, 8.27.
Methyl 3-methoxyanthranilate (5{9}) (R1=3-OMe, R2=H): As above but using 1.0 g (6.0 mmol) of
3-methoxyanthranilic acid (7{9}).Yield: 96%; IR (CHCl3) ν (cm-1): 3496, 3377 (N-H), 1693 (C=O), 1615,
1589, 1552, 1478, 1462; 1H-NMR (CDCl3) δ (ppm): 7.47 (dd, 3JHH= 8 Hz, 4JHH= 1 Hz, 1H, H6), 6.85 (dd,
3JHH= 8 Hz, 4JHH= 1 Hz, 1H, H4), 6.56 (dd, 3JHH= 8 Hz, 3JHH= 8 Hz, 1H, H5), 6.00 (br, 2H, NH2), 3.87 (s,
6H, -COOCH3, C3-OCH3); 13C-NMR (CDCl3) δ (ppm): 168.7 (C=O), 147.0 (C3), 141.7 (C2), 122.5 (C6),
114.6, 112.9 (C5, C4), 110.1 (C1), 55.7 (C3-OCH3), 51.5 (-COOCH3); Anal. Calcd for C9H11NO3: C,
59.66; H, 6.12; N, 7.73. Found: C, 59.73; H, 6.28; N, 7.45.
Methyl 5-fluoroanthranilate (5{10}) (R1=5-F, R2=H): As above but using 1.0 g (6.5 mmol) of
5-fluoroyanthranilic acid (7{10}). Yield: 99%; IR (CHCl3) ν (cm-1): 3483, 3375 (N-H), 1700 (C=O),
1
4
1602, 1592, 1567, 1496; H-NMR (CDCl3) δ (ppm): 7.54 (dd, 3JHF= 10 Hz, JHH = 3 Hz, 1H, H6 ), 7.04
3
(ddd, 3JHF= 9 Hz, JHH= 8 Hz, 4JHH= 3 Hz, 1H, H4), 6.62 (dd, 3JHH = 9 Hz, 4JHH= 5 Hz, 1H, H3), 5.58 (br,
13
2H, NH2), 3.88 (s, 3H, -COOCH3); C-NMR (CDCl3) δ (ppm): 167.3 (C=O), 152.80 (C5), 146.2 (C2),
121.2 (C4), 117.5, 115.4 (C3, C6), 111.7 (C1), 51.5 (-COOCH3); Anal. Calcd for C8H8NO2F: C, 56.80; H,
4.77; N, 8.28. Found: C, 56.75; H, 4.93; N, 8.12.
General procedure for the synthesis of anthranilic hydrazides (3{x,1}). N-Methyl anthranilic
hydrazide (3{2,1}) (R1=H, R2=Me, R4=H): A mixture of
1.0 mL (6.7 mmol) of methyl
N-methylanthranilate (5{2}), 3.2 mL (0.10 mol) of hydrazine (6{1}), and 15 mL of EtOH was heated at
reflux for 24 h. The resulting precipitate was filtered, sequentially washed with water and EtOH, and
dried over P2O5 to afford 0.9 g (85%) of 3{2,1}as a white solid, mp 137-138ºC (mp10a 141-142ºC); IR
1
(KBr) ν (cm-1): 3331, 3305 (N-H), 1629 (C=O), 1573, 1532, 1514; H-NMR (CDCl3) δ (ppm): 7.47 (br,
2H, -CONHNH2, -NH-CH3), 7.36-7.29 (m, 2H, H4, H6), 6.67 (d, 3JHH= 8 Hz, 1H, H3), 6.58 (ddd, 3JHH= 8
Hz, 3JHH= 7 Hz, 4JHH= 1 Hz, 1H, H5), 4.80-3.20 (br, 2H, -CONHNH2), 2.86 (s, 3H, -NH-CH3); 13C-NMR
(CDCl3) δ (ppm): 170.8 (-CONHNH2), 150.4 (C2), 133.2 (C4), 127.0 (C6), 114.6 (C5), 113.1 (C1), 111.1
(C3), 29.6 (-NHCH3); MS, m/z (%): 165 (46) [M+], 134 (100), 77 (35); Anal. Calcd for C8H11N3O: C,
58.17; H, 6.71; N, 25.43. Found: C, 58.49; H, 6.51; N, 25.10.
Anthranilic hydrazide (3{1,1}) (R1=H, R2=H, R4=H): As above but using 1.0 g (6.7 mmol) of methyl
anthranilate (5{1}) at 70ºC for 21 h. Yield: 47%, mp 119-121ºC (mp14 120-121ºC); IR (KBr) ν (cm-1):
1
3444, 3326, 3177 (N-H), 1620 (C=O), 1578, 1562, 1506, 1483, 1450; H-NMR (CDCl3) δ (ppm):
7.30-7.20 (m, 3H, -CONHNH2, H4, H6), 6.80-6.56 (m, 2H, H3, H5), 5.45 (br, 2H, C2-NH2), 4.04 (br, 2H,
13
-CONHNH2); C-NMR (DMSO-d6) δ (ppm): 168.5 (CONHNH2), 149.3 (C2), 131.5 (C4), 127.6 (C6),

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169

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HETEROCYCLES, Vol. 67, No. 1, 2006
116.2 (C5), 114.7 (C3), 113.7 (C1); Anal. Calcd for C7H9N3O: C, 55.62; H, 6.00; N, 27.80. Found: C,
55.47; H, 5.85; N, 27.51.
5-Chloroanthranilic hydrazide (3{3,1}) (R1=5-Cl, R2=H, R4=H): As above but using 1.0 g (5.4 mmol)
of methyl 5-chloroanthranilate (5{3}) at 60ºC for 21 h. Yield: 58%, mp136-139ºC (mp14 129-134ºC); IR
1
(KBr) ν (cm-1): 3452, 3429, 3354, 3327, 3288 (N-H), 1651 (C=O), 1580, 1564, 1515, 1483; H-NMR
(CDCl3) δ (ppm): 7.29-7.25 (m, 2H, H6, -CONHNH2 ), 7.18 (dd, 3JHH= 9 Hz, 4JHH= 2 Hz, 1H, H4), 6.64
(d, 3JHH= 9 Hz, 1H, H3), 5.60-3.00 (br, 4H, C2-NH2, -CONHNH2); 13C-NMR (DMSO-d6) δ (ppm): 167.2
(CONHNH2), 148.2 (C2), 131.3 (C4), 127.0 (C6), 117.8 (C5, C3), 114.6 (C1); MS, m/z (%): 187 (9)
[M++2], 185 (25) [M+], 156 (31), 154 (100), 126 (31); Anal. Calcd for C7H8N3OCl: C, 45.30; H, 4.34; N,
22.64. Found: C, 45.12; H, 4.56; N, 22.97.
4-Chloroanthranilic hydrazide (3{4,1}) (R1=4-Cl, R2=H, R4=H): As above but using 1.0 g (5.4 mmol)
of methyl 4-chloroanthranilate (5{4}) at 60ºC for 21 h. Yield: 83%, mp 149-151ºC; IR (KBr) ν (cm-1):
3485, 3355, 3315 (N-H), 1656 (C=O), 1577, 1526, 1479; 1H-NMR (CDCl3) δ (ppm): 7.21 (d, 3JHH= 8 Hz,
1H, H6), 7.20 (br, 1H, -CONHNH2), 6.69 (d, 4JHH= 2 Hz, 1H, H3), 6.62 (dd, 3JHH= 8 Hz, 4JHH= 2 Hz, 1H,
H5), 5.58 (br, 2H, C2-NH2), 4.03 (br, 2H, -CONHNH2); 13C-NMR (DMSO-d6) δ (ppm): 167.7
(CONHNH2), 150.7 (C2), 136.0 (C4), 129.4 (C6), 115.0 (C5), 114.3 (C3), 112.4 (C1); MS,: m/z (%): 187
(8) [M++2], 185 (27) [M+], 156 (32), 154 (100), 126 (18); Anal. Calcd for C7H8N3OCl: C, 45.30; H, 4.34;
N, 22.64, Found: C, 45.46; H, 4.04; N, 22.30.
4,5-Dimethoxyanthranilic hydrazide (3{5,1}) (R1=4,5-OMe, R2=H, R4=H): As above but using 1.0 g
(4.7 mmol) of methyl 4,5-dimethoxyanthranilate (5{5}) at 60ºC for 21 h. Yield: 77%, mp 178-179ºC; IR
(KBr) ν (cm-1): 3415, 3329, 3306, 3273, 3216 (N-H), 1634 (C=O), 1595, 1577, 1511; 1H-NMR (CDCl3) δ
(ppm): 7.16 (br, 1H, -CONHNH2), 6.79 (s,1H, H6), 6.21 (s, 1H, H3), 5.40-4.00 (br, 4H, C2-NH2,
13
-CONHNH2), 3.86 (s, 3H, C4-OCH3), 3.81 (s, 3H, C5-OCH3); C-NMR (DMSO-d6) δ (ppm): 168.5
(-CONHNH2), 152.6 (C4), 145.8 (C2), 139.1 (C5), 111.5 (C6), 103.8 (C1), 99.8 (C3), 56.3, 55.1
(C4-OCH3, C5-OCH3); MS, m/z (%): 211 (31) [M+], 180 (100), 152 (12); Anal. Calcd for C9H13N3O3: C,
51.18; H, 6.20; N, 19.89. Found: C, 51.25; H, 6.18; N, 19.57.
3,4,5-Trimethoxyanthranilic hydrazide (3{6,1}) (R1=3,4,5-OMe, R2=H, R4=H): As above but using
1.0 g (4.2 mmol) of methyl 3,4,5-trimethoxyanthranilate (5{6}) at 60ºC for 21 h. Yield: 43%, mp
105-107ºC; IR (KBr) ν (cm-1): 3475, 3361, 3306, 3330 (N-H), 1625 (C=O), 1578, 1542, 1522, 1487;
1H-NMR (CDCl3) δ (ppm): 7.39 (br, 1H, -CONHNH2), 6.66 (s, 1H, H6), 5.70-4.00 (br, 4H, C2-NH2,
-CONHNH2), 3.93 (s, 3H, C5-OCH3), 3.87 (s, 3H, C4-OCH3), 3.79 (s, 3H, C3-OCH3); 13C-NMR
(DMSO-d6) δ (ppm): 168.1 (-CONHNH2), 145.1, 142.6, 140.2, 138.5 (C5, C4, C3, C2), 108.0 (C1), 106.9

HETEROCYCLES, Vol. 67, No. 1, 2006
171
(C6), 60.4, 59.9, 56.3 (C5-OCH3, C4-OCH3, C3-OCH3); MS, m/z (%): 241 (39) [M+], 210 (100); Anal.
Calcd for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42. Found: C, 49.30; H, 6.28; N, 17.74.
5-Methylanthranilic hydrazide (3{7,1}) (R1=5-Me, R2=H, R4=H): As above but using 1.2 g (7.0 mmol)
of methyl 5-methylanthranilate (5{7}) at 60ºC for 15 h. Yield: 61%, mp 133-135ºC; IR (KBr) ν (cm-1):
1
3453, 3366, 3352, 3297, 3182 (N-H), 1624 (C=O), 1582, 1569, 1530, 1497; H-NMR (CDCl3) δ (ppm):
7.29 (br, 1H, -CONHNH2), 7.09 (s, 1H, H6), 7.06 (dd, 3JHH= 8 Hz, 4JHH= 2 Hz, 1H, H4), 6.63 (d, 3JHH= 8
Hz, 1H, H3), 5.24 (br, 2H, C2-NH2), 4.03 (br, 2H, -CONHNH2), 2.23 (s, 3H, C5-CH3); MS, m/z (%): 165
(32) [M+], 134 (100), 106 (30); Anal. Calcd for C8H11N3O: C, 58.17; H, 6.71; N, 25.44. Found: C, 57.95;
H, 6.83; N, 25.20.
3-Methoxyanthranilic hydrazide (3{9,1}) (R1=3-OMe, R2=H, R4=H): As above but using 1.1 g (6.1
mmol) of methyl 3-methoxyanthranilate (5{9}) at 60ºC for 15 h. Yield: 80%, mp 147-149ºC; IR (KBr) ν
(cm-1): 3442, 3334, 3316 (N-H), 1638 (C=O), 1610, 1591, 1551, 1518, 1474; 1H-NMR (CDCl3) δ (ppm):
7.33 (br, 1H, -CONHNH2), 6.92 (dd, 3JHH= 8 Hz, 4JHH= 1 Hz, 1H, H6), 6.83 (dd, 3JHH= 8 Hz, 4JHH= 1 Hz,
1H, H4), 6.60 (dd, 3JHH= 8 Hz, 3JHH= 8 Hz, 1H, H5), 5.74 (br, 2H, C2-NH2), 4.04 (br, 2H, -CONHNH2),
13
3.87 (s, 3H, C3-OCH3); C-NMR (DMSO-d6) δ (ppm): 168.4 (-CONHNH2), 146.9 (C3), 139.3 (C2),
119.3 (C6), 114.1 (C5), 113.3 (C1), 111.8 (C4), 55.5 (C3-OCH3); MS, m/z (%): 181 (45) [M+], 150 (100);
Anal. Calcd for C8H11N3O2: C, 53.03, H, 6.12; N, 23.19). Found: C, 53.06; H, 6.09; N, 22.83.
5-Fluoroanthranilic hydrazide (3{10,1}) (R1=5-F, R2=H, R4=H): As above but using 1.1 g (6.7 mmol)
of methyl 5-fluoroanthranilate (5{10}) at 60ºC for 15 h. Yield: 58%, mp 128-130ºC; IR (KBr) ν (cm-1):
3443, 3327, 3191 (N-H), 1647 (C=O), 1592, 1572, 1512, 1486; 1H-NMR (CDCl3) δ (ppm): 7.26 (br, 1H,
3
4
-CONHNH2), 7.05-6.95 (m, 2H, H4, H6), 6.66 (ddd, JHH= 8 Hz, JHF= 5 Hz, 5JHH= 1 Hz, 1H, H3),
4
6.00-3.00 (br, 4H, C2-NH2, -CONHNH2); 13C-NMR (DMSO-d6) δ (ppm): 167.4 (d, JCF= 2 Hz,
1
CONHNH2), 152.7 (d, JCF= 230 Hz, C5), 146.1 (C2), 118.9 (d, 2JCF= 22 Hz, C4), 117.4 (d, 3JCF= 7 Hz,
2
C3), 113.4 (C1), 113.2 (d, JCF= 23 Hz, C6); MS, m/z (%): 169 (38) [M+], 138 (100), 110 (37); Anal.
Calcd for C7H8N3OF: C, 49.70, H, 4.77; N, 24.84. Found: C, 49.63; H, 4.45; N, 24.46.
N-Phenylanthranilic hydrazide (3{11,1}) (R1=H, R2=H, R4=H): As above but using 1.0 g (4.5 mmol)
of methyl N-phenylanthranilate (5{11}) at 70ºC for 21 h. Yield: 92%, mp 185-187ºC; IR (CHCl3) ν
(cm-1): 3320, 3298, 3274 (N-H), 1638 (C=O), 1599, 1574, 1520; 1H-NMR (CDCl3) δ (ppm): 9.06 (br, 1H,
-NHPh), 7.53 (br, 1H, -CONHNH2), 7.44-7.10 (m, 7H, H6, H3, H4, H2’, H3’), 7.06-6.98 (m, 1H, H4’),
3
3
4
13
6.76 (ddd, JHH= 9 Hz, JHH= 8 Hz, JHH= 2 Hz, 1H, H5), 4.8-2.5 (br, 2H, -CONHNH2); C-NMR
(DMSO-d6) δ (ppm): 168.1 (-CONHNH2), 143.9 (C2), 141.6 (C1’), 131.7 (C4), 129.4 (C3’), 128.4 (C6),
121.7 (C4’), 119.2 (C2'), 118.2 (C5), 118.03 (C1), 115.0 (C3); MS, m/z (%): 227 (38) [M+], 196 (100),
167 (25); Anal. Calcd for C13H13N3O: C, 68.70; H, 5.77; N, 18.49. Found: C, 68.45 H, 5.93; N, 18.50.

172
HETEROCYCLES, Vol. 67, No. 1, 2006
General
procedure
for
the
synthesis
of
N'-phenylbenzohydrazides
(3{x,3}).
2-Methylamino-N'-phenylbenzohydrazide (3{2,3}) (R1=H, R2=Me, R4=Ph): A mixture of 3.0 g (19.8
mmol) of N-methylanthranilic acid (7{2}), 3.0 mL (29.8 mmol) of phenylhydrazine (6{3}), 4.1 g (19.8
mmol) of DCC in 60 mL of CH2Cl2 was stirred for 4 h at rt. The resulting solution was concentrated in
vacuo, the residue was extracted with CH2Cl2, and the extract was washed with 5% NaHCO3 solution,
dried (MgSO4), and concentrated in vacuo to give a 14:86 mixture of 3{2,3} and the N-phenyl derivative
(8{2,3}). The two isomers were separated by column chromatography (AcOEt:hexane, 1:4) to give 0.72 g
(16%) of 3{2,3}, mp 127-129ºC; IR (CHCl3) ν (cm-1): 3406, 3296 (N-H), 1640 (C=O), 1602,1579,1519,
1
1495; H-NMR (CDCl3) δ (ppm): 7.91 (br, 1H, -NHCH3), 7.50-7.30 (br, 1H, -CONHNHPh), 7.47 (dd,
3JHH= 8 Hz, 4JHH= 2Hz, 1H, H6), 7.37 (ddd, 3JHH= 8 Hz, 3JHH= 8 Hz, 4JHH= 2 Hz, 1H, H4), 7.26-7.23 (m,
2H, H3’), 7.78-7.00 (m, 3H, H2’, H4'), 6.68 (d, 3JHH= 8 Hz, 1H, H3), 6.61 (ddd, 3JHH= 8 Hz, 3JHH= 8 Hz,
13
4JHH= 1 Hz, 1H, H5), 6.26 (br, 1H, -CONHNHPh), 2.81 (s, 3H, -NHCH3); C-NMR (CDCl3) δ (ppm):
170.0 (CONH), 150.9 (C2), 148.3 (C1’), 133.8 (C4), 129.2 (C3’), 127.1 (C6), 121.3 (C4’), 114.5 (C5),
113.6 (C2’), 112.0 (C6), 111.4 (C3), 29.6 (NHCH3); MS, m/z (%): 241 (37) [M+], 134 (100); Anal. Calcd
for C14H15N3O: C, 69.69; H, 6.27; N, 17.41, Found: C, 69.37; H, 6.57; N 17.22.
2-Amino-N'-phenylbenzohydrazide (3{1,3}) (R1=H, R2=H, R4=Ph): As above but using 2.9 g (21.4
mmol) of anthranilic acid (7{1}). Yield: 25%, 169-171ºC (mp10b 168-170ºC); IR (KBr) ν (cm-1): 3428,
3334, 3242 (N-H), 1644 (C=O), 1615, 1587, 1571, 1547, 1494, 1444; 1H-NMR (CDCl3) δ (ppm): 7.75 (br,
1H, -CONHNHPh), 7.49 (dd, 3JHH= 8 Hz, 4JHH= 1Hz, 1H, H6), 7.40-7.20 (m, 3H, H4, H3’), 7.04-6.84 (m,
13
3H, H2’, H4’), 6.78-6.60 (m, 2H, H3, H5), 6.27 (br, 1H, -CONHNHPh), 5.52 (br, 2H, NH2); C-NMR
(DMSO-d6) δ (ppm): 168.8 (CONH), 149.9, 149.8 (C2, C1’), 132.2 (C4), 128.7 (C3’), 128.0 (C6), 118.5
(C4’), 116.4 (C5), 114.7 (C3), 112.8 (C1), 112.3 (C2’); Anal. Calcd for C13H13N3O: C, 68.71; H, 5.77; N,
18.49. Found: C, 68.75; H, 5.71; N, 18.06.
2-Phenylamino-N'-phenylbenzohydrazide (3{11,3}) (R1=H, R2=Ph, R4=Ph): As above but using 2.9 g
(13.8 mmol) of N-phenylanthranilic acid (7{11}). Yield: 25%, 118-120ºC; IR (CHCl3) ν (cm-1): 3310
(N-H), 1644 (C=O), 1591, 1577, 1516, 1495; 1H-NMR (CDCl3) δ (ppm): 9.14 (br, 1H, -NHPh), 8.05 (br,
3
4
1H, -CONHNHPh), 7.52 (dd, JHH= 8 Hz, JHH= 1Hz, 1H, H6), 7.44-7.18 (m, 6H, H3, H4, H3’, H3”),
3
4
7.18-7.08 (m, 2H, H2”), 7.03-6.99 (m, JHH= 8 Hz, JHH= 1 Hz, 1H, H4”), 6.96-6.84 (m, 3H, H2’, H4’),
3
3
4
13
6.75 (ddd, JHH= 8 Hz, JHH= 7 Hz, JHH= 2 Hz, 1H, H5), 6.30 (br, 1H, -CONHNHPh); C-NMR
(CDCl3): δ (ppm): 169.7 (CONHNHPh), 148.0 (C1”), 146.2 (C1’), 141.0 (C2), 133.1 (C4), 129.3 (C3”,
C3’), 127.5 (C6), 123.7 (C1), 122.9 (C4”), 121.5 (C4’), 121.2 (C2”), 117.9 (C5), 115.5 (C3), 113.6 (C2’);
MS, m/z (%): 303 (28) [M+], 196 (100), 167 (19); Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N 13.85.
Found: C, 75.48; H, 5.56; N, 13.44.

HETEROCYCLES, Vol. 67, No. 1, 2006
173
General
procedure
for
the
synthesis
of
2,10-dioxo-10H-1,2,3,4,4a,5-hexahydro-
piridazino[3,2-b]quinazolines (1)
A mixture of the corresponding hydrazide (2) (1.1 mmol), the 4-oxo acid (4) (1.65 mmol), and one crystal
of TsOH in 4.0 mL of benzene was heated at reflux for 2 h. In most cases the expected compound
precipitates, in which case the reaction mixture was filtered and washed with Et2O. In remaining cases the
reaction mixture was concentrated in vacuo, the residue suspended in water and extracted with AcOEt.
The combined organic extracts were washed with 5% NaHCO3 solution, dried (MgSO4), and concentrated
in vacuo. Crude 1 were purified by column chromatography using AcOEt or hexane:AcOEt (1:1) as
eluent.
ACKNOWLEDGEMENTS
Financial support by Rohm and Haas Company is gratefully acknowledged. One of us (E. S.) wants to
thank Rohm and Haas Company for a PhD grant.
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