Synthesis and reactions of some new benzylphthalazin-1-ylaminophenols, 2H-chromene and 5h-chromeno[2,3-d]pyrimidine derivatives with promising antimicrobial activities

Article abstract of DOI:10.2174/157017812801264737

A series of (4-benzylphthalazin-1-ylamino)phenols 4-6 were prepared. Bromination of (4-benzylphthalazin-1- ylamino)phenol (1) with bromine afforded the bromophenol derivative 7, while condensation of the isomeric (4- benzylphthalazin-1-ylamino)phenol (2)

Full text of DOI:10.2174/157017812801264737

360
Letters in Organic Chemistry, 2012, 9, 360-367
Synthesis and Reactions of Some New Benzylphthalazin-1-ylaminophenols,
2H-Chromene and 5H-Chromeno[2,3-d]pyrimidine Derivatives with
Promising Antimicrobial Activities
Ashraf H.F. Abd El-Wahab*,1,2, Hany M. Mohamed1,3, Ahmed M. El-Agrody4,
Mohammed A. El-Nassag1 and Ahmed H. Bedair1
1Chemistry Department, Faculty of Science, Al-Azhar University, 11884, Nasr City, Cairo, Egypt
2Chemistry Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi Arabia
3Chemistry Department, Faculty of Medicine, Jazan University, 82621, Jazan, Saudi Arabia
4Chemistry Department, Faculty of Science, King Khalid University, 9004, Abha, Saudi Arabia
Received January 09, 2012: Revised February 20, 2012: Accepted March 15, 2012
Abstract: A series of (4-benzylphthalazin-1-ylamino)phenols 4-6 were prepared. Bromination of (4-benzylphthalazin-1-
ylamino)phenol (1) with bromine afforded the bromophenol derivative 7, while condensation of the isomeric (4-
benzylphthalazin-1-ylamino)phenol (2) or 7-(4-benzylphthalazin-1-ylamino)naphthalene-2-ol (3) with arylidenema-
lononitriles 8a-c in ethanol/piperidine solution afforded chromene derivatives 9a-c and 10a,b. Treatment of 7-(4-
benzylphthalazin-1-ylamino)-4-(p-methoxyphenyl)-4H-chromene-3-carbonitrile (9a) with triethyl orthoformate/Ac2O
afforded ethoxymethyleneamino derivative 11. Condensation of 9a with DMFDMA/xylene gave chromenopyrimidine
derivative 13, while treatment of 9a with Ac2O afforded the N-acetylimino derivative 14. The structures of the newly
synthesized derivatives were confirmed by their elemental analysis and spectral data. The antimicrobial activities of some
selected compounds were also studied and some of them were found to exhibit promising effects against Gram-positive
and Gram-negative bacteria and fungi.
Keywords: Arylidenemalononitriles, antimicrobial activity, benzylphthalazin-1-ylaminophenols, bromine, chromene
derivatives.
1. INTRODUCTION
mentioned above, we report here facile synthesis of the title
compounds using benzylphthalazin-1-ylaminophenols as
starting materials. Such compounds could possess interesting
and useful biological properties.
Several reports have been recently published on the
chemistry of pthalazine-1(H)-one derivatives [1-9]. In
addition phthalazine derivatives are important heterocycles
known to possess multiple biological activities such as
antimicrobial, anticonvulsant, cardiotonic, vasorelaxant,
antifungal, anticancer, antitumor, anti-anxiety and anti-
inflammatory activities [10-19].
2. RESULTS AND DISCUSSION
2.1. Chemistry
Treatment of 4-benzyl-1-chlorophthalazine with m-, p-
aminophenols and/or 7-amino-2-naphthol afforded (4-
benzylphthalazin-1-ylamino)phenols 1, 2 and/or 7-(4-benzyl-
phthalazin-1-ylamino)naphthalene-2-ol (3) [25]. Aminome-
thylation of 1 with formaldehyde and piperidine afforded 4-
(4-benzylphthalazin-1-ylamino)-2,6-bis(piperidin-1-ylmethyl)
phenol (4a). Similarly, treatment of 1 with morpholine gave
the corresponding 4-(4-benzylphthalazin-1-ylamino)-2,6-
bis(morpholinomethyl)phenol (4b), Also, treatment of 1 with
formaldehyde and diethylamine gave the corresponding 4-(4-
benzylphthalazin-1-ylamino)-2,6-bis((diethylamino)me-
thyl)phenol (5). Hydroxymethylation of 1 with methanolic
formaldehyde gave an orange material insoluble in most
organic solvents which was formulated as 6,6'-methylenebis
(4-(4-benzylphthalazin-1-ylamino)-2-(hydroxymethyl)phenol)
(6). No proton NMR data was recorded and its mass
spectrum gave no molecular ion peak. Bromination of 1 with
bromine gave the corresponding 4-(4-benzylphthalazin-1-
ylamino)-2-bromophenol (7), in which one bromine atom
In clinical trials, it was reported that changrolin [20] (I,
Fig. 1) was effective as an antiarrhythmic agent [21]. Stout et
al. [22] searched for 1,2-diazine analogs of changrolin and it
was found that while the bis(pyrrolidinylmethyl)phenol
pattern of changrolin appeared to be optimal in this series
(IIa, Fig. 1), a wide latitude existed for the heteroaryl
substituent for maintaining good antiarrhythmic and
parasympatholytic activities. Moreover, some pyran and
fused 4H-pyran derivatives have found application in clinical
medicine. Zanamivir (III, Fig. 1) has been shown to be
effective in treating influenza [23] and epicatechin
(epigallocatechin) gallates IVa,b (Fig. 1) demonstrate strong
effects against Plasmodium falciparum, the mosquito-borne
organism responsible for malaria [24]. Due to the results
*Address correspondence to this author at the Chemistry Department,
Faculty of Science, Al-Azhar University, 11884, Nasr City, Cairo, Egypt;
Tel: +201008199893; Fax: +20222629358;
E-mail: ash_abdelwahab@hotmail.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis and Reactions of Some New Benzylphthalazin-1-ylaminophenols
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
361
R
N
OH
R`
OH
X
a;= H
b;= Cl
c;= Cl
R
R`
H2CN
H2CN
HN
X
N
HN
H2CN
H2CN
H2CN
H
N
N
N
N
d;= H CH2NMe2 CH2NMe2
X
I
II
OH
OH
HO
O
OH
COOH
NH2
O
HN
III
HO
O
OH
HN
OH
OH
O
a; X= H
b; X= OH
O
OH
NH
OH
IV
Fig. (1). Structures of changrolin, phenols, zanamivir and catechins.
CH2Ph
CH2Ph
CH2Ph
N
N
N
N
N
N
OH
NH
HN
HN
1
2
3
OH
OH
CH2Ph
CH2Ph
CH2Ph
N
N
N
N
N
X
NH / CH2O
X
N
CH2O / CH3OH
HN
NH
NH
1
(
C
X
2
H
5
)
N
N
2
N
H
B
r
/
2
/
A
OH
C
HO
O
O
OH
H
c
O
H
H
2
H
O
6
4a; X= CH2
b; X= O
CH2Ph
CH2Ph
N
N
N
N
HN
HN
7
N
N
OH
Br
OH
5
Scheme 1. Synthesis of 4-benzylphthalazin-1-ylaminophenol derivatives.

362 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
El-Wahab et al.
H
H
+
+
CH2Ph
CN
51 (100)
+
N
N
CH2Ph
+
CH2Ph
N
N
NH2
+
m/z; 103 (31.8)
N
2C4H6
HN
N
N
NH
HN
(41)
N
N
+
+
H
HN
NH
C
H
OH
5; m/z=497 (10.5)
=
N
C
H
H
=
(
2
N
OH
m/z; 381 (13.6)
8
H
)
(
2
9
)
O
CH2Ph
CH2Ph
m/z; 89 (18.1)
+
N
N
N
N
N
N
PhH2C
PhH2C
CH2Ph
NH
NH
N
N
N
N
219 (0)
438 (0)
H
H
O
HO
+
O
OH
H
H
HN
NH
OH
91 (50.6)
CN
6; m/z: 726 (0)
OH
OH
OH
CN
- H
m/z: 288 (0)
128 (25.3)
H
H
HN
NH
+
NH
)
5
H
H
N
H
H
N
2
(
N
H
H
C 2
53 (76.8)
CH2OH
H3C
CH2OH
C
OH
O
CH2=C=O
(42)
OH
OH
m/z: 287 (16.1)
CH2OH
(31)
N
78 (6.9)
H
H
O
(
109 (52.9)
2
6
)
m/z: 151 (0)
- H
H
H
52 (27.6)
HN
NH
NH
NH
CH2 (14)
OH
OH
O
O
OH
CH2OH
m/z: 286 (29.9)
O
O
m/z: 122 (100)
m/z: 136 (41.4)
Scheme 2. Mass spectral interpretation for compounds 5 and 6.
was introduced on the o-position with respect to OH group
(Scheme 1).
compound 5 the characteristic bands were at 3438–3220
cm−1 (OH and NH), 2980-2922 cm−1 ( aliphatic C-H) and
1
1646 cm−1 (C=N), respectively. The H-NMR of compound
The structure of compounds 4-7 were confirmed by IR,
1H-NMR and MS. The IR spectrum of compound 4a showed
absorptions at 3402–3258 cm−1 (for OH and NH), while for
4a showed characteristic signals at δ 9.05 ppm (br, 1H, OH)
and 8.26 ppm (s, 1H, NH), while 4b was characterized by

Synthesis and Reactions of Some New Benzylphthalazin-1-ylaminophenols
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
363
broadened singlets at 8.90 ppm and 6.55 ppm (OH and NH,
respectively). The mass spectra of compounds 5 and 7
showed the corresponding molecular ion peaks at m/z 497
(M+, 10.25) and m/z 405 (M+, 18.9), (M+2), respectively.
The fragmentation patterns of compounds 5, 6 are illustrated
in Scheme 2.
Treatment of 2 with the arylidenemalononitriles 8a-c [26,
27] in ethanol/piperidine solution afforded the corresponding
CH2Ph
N
CN
N
Ar
NH2
HN
O
10a,b
t
a
e
H
3
CH2Ph
;
CH2Ph
CH2Ph
.
p
i
P
/
N
N
N
N
H
N
N
O
t
E
CN
HN
HN
HN
EtOH/ Pip.
Heat
- 2H
2
+
Cl
Ar
CN
H
Ar
H
8a; Ar= C6H4-OCH3-p
b; Ar= C6H4-CH3-p
c; Ar= C6H4-Cl-p
Ar
CN
O
O
OH
CN
CN
9c
C
N
NH
NH
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
N
N
N
N
N
N
N
N
N
N
Ac2O
Heat
+ 2H
DMFDMA
Xylene; heat
HN
HN
HN
Me
HN
HN
H
Ar
Ar
Ar
Ar
Ar
O
O
H
O
O
O
O
O
CH
CN
CN
CN
CN
N
N
Me
NH2
9a,b
N
N
N
H
H
H
H
N
N
Me
Me
Me
Me
[O]
(EtO)3CH/ Ac2O
Heat
12
CH2Ph
CH2Ph
- Me2NH
N
N
N
N
CH2Ph
HN
CH2Ph
OCH3
N
N
N
OCH3
Me
N
O
NH
O
O
HN
N
O
OCH3
OCH3
CN
N
CN
Me
N
OEt
14
O
H
O
N
11
N
13
N
N
Scheme 3. Synthesis of chromene and chromenopyrimidine derivatives.

364 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
El-Wahab et al.
7-(4-benzylphthalazin-1-ylamino)-4-(p-methoxyphenyl or p-
2.2. Antibacterial Activities
tolyl)-4H-chromene-3-carbonitriles
benzylphthalazin-1-ylamino)-2-imino-4-(p-chlorophenyl)-
4H-chromene-3-carbonitrile (9c).
9a,b
and
7-(4-
The inhibition zones were measured in millimeters at the
end of an incubation period of 48 hours at 28 °C. N,N-
dimethylformamide (DMF) showed no inhibition zone. Test
results from one measurement are shown in Table 1.
In a similar manner, reaction of 3 with arylidenemalo-
nonitriles 8a,b afforded the corresponding chromene-2-
carbonitrile derivatives 10a,b. Treatment of 9a with triethyl
orthoformate/Ac2O afforded [7-(4-benzylphthalazin-1-yl-N-
acetylamino)-3-ethoxymethyleneamino-4-(p-methoxyphenyl]-
4H-chromene-3-carbonitrile (11). Condensation of 9a with
dimethylformamide dimethylacetal (DMFDMA)/xylene
gave an abnormal reaction product which was formulated as
(Z)-N-(4-benzylphthalazin-1(2H)-ylidene)-5-(p-methoxyphe-
nyl)-5H-chromeno[2,3-d]pyrimidin-8-amine (13) rather than
the expected 2-dimethylaminomethyleneamino-4H-chro-
mene-3-carbonitrile derivative 12. The formation of 13
indicates that the carbonitrile group of a non-isolable
intermediate product undergoes partial reduction under the
reaction conditions followed by intramolecular cyclization to
13 with the elimination of a dimethylamine moiety.
Treatment of 9a with Ac2O afforded 7-(4-benzylphthalozin-
1-ylamino)-2-N-acetylimino-4-(p-methoxyphenyl)-2H-
chromene-3-carbonitrile (14). A plausible mechanism for the
formation of 14 is a nucleophilic substitution to give the
acylamino chromenes 9a,b, followed by interconversion into
the tautomeric imino form 11 and oxidation to afford the
final product (Scheme 3).
The results from (Table 1) indicated that compounds 4a,
4b, 5,6 and 7 exhibit high inhibitory effects against all tested
Gram-negative and Gram-positive bacteria, while com-
pounds 9a-c, 10a,b exhibit moderate effects against all tested
Gram-negative and Gram-positive bacteria and compounds
11, 13 and 14 show weak activity.
Compounds 4b, 4a and 6 exhibit high inhibitory effects
against Aspergillus ochraceus Wilhelm (AOW) fungus and
moderate inhibitory effects against Penicillium chrysogenum
Thom (PCT).
The remaining compounds show weak activities against
the tested fungi.
2.3. Structure-Activity Relationship (SAR) Studies
The structure activity relationship (SAR) studies of 1 and
its analogues revealed that compounds 4b, 4a, 6, 5 and 7 has
the higher inhibitory effects against all tested bacteria than
the compound 1. These data indicate that the activity of
compounds 4b, 4a, 6, 5 and 7 are considerably attributed to
the presence of morpholinomethyl, piperidinylmethyl,
diethylamino groups (more decreasing in size) at 2,6-postion
of the phenyl ring, suggesting that there might be a size
Table 1. Antimicrobial Activity of the New Compounds
Inhibition zone diameter in mm
Compd.
Fungi
Gram-positive bacteria
Gram-negative bacteria
No. a
PCT
AOW
SC
BSP
BS
BC
EC
PA
17
14
19
15
17
18
19
18
1b
18
17
19
17
17
19
20
18
20
18
26
27
26
26
20
28
25
26
27
25
27
28
24
28
26
26
25
27
27
28
24
26
25
27
24
27
28
26
25
27
4a
4b
5
6
7
15
12
15
14
15
17
10
13
10
-
17
14
13
12
10
14
12
11
13
-
16
18
17
21
18
19
14
15
16
22
20
25
-
15
20
20
19
22
15
17
17
16
22
20
25
-
15
19
22
20
23
17
15
19
14
22
20
25
-
14
18
19
22
18
18
14
16
14
22
20
25
-
15
20
21
19
20
19
16
17
15
22
20
25
-
16
18
20
22
19
18
16
15
14
22
20
25
-
2b
9a
9b
9c
10a
10b
11
13
14
Ampicillin
Tetracycline
Norfloxacin
Mycostatin
-
-
-
-
20
20
a: conc. = 1 mg mL−1 of new compounds in DMF. Microorganisms: Pseudomonas aeruginosa (PA) (MTCC 741); Escherichia coli (EC) (NCTC-10410); Bacillus cereus (BC)
(ATGG 14579); Bacillus subtilis (BS) (MTCC 441); Bacillus sphaericus (BSP) (MTCC 11); Staphylococcus (SC) (MTCC 96); Aspergillus ochraceus Wilhelm (AOW) (AUCC-230);
Penicillium chrysogenum Thom (PCT) (AUCC-530). b: [25].

Synthesis and Reactions of Some New Benzylphthalazin-1-ylaminophenols
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
365
limited pocket at position C-2,6 or to the presence of the
bromine atom or the hydroxymethyl group (more decreasing
in size) at position C-2 of the phenyl ring, while for
compound 2 and its analogues revealed that compounds 9c,
4b, 9a, 10a, 10b, 11,13 and 14 has the higher inhibitory
effects against all tested bacteria than the compound 2. These
data indicate that the activity of compounds 9c, 4b, 9a, 10a,
10b, 11,13 and 14 are considerably attributed to the
4-(4-Benzylphthalazin-1-ylamino)-2,6-bis(piperidin-1-yl-
methyl)phenol (4a)
Yellow crystals, 70%, mp 280–282 °C; ethanol/benzene;
IR (νmax, cm−1): 3402–3258 (OH and NH), 3060, 3022 (C-H
1
aromatic) and 2956 (C-H aliphatic). H-NMR: δH 9.05 (br,
1H, OH, exchangeable by D2O), 8.26 (s, 1H, NH,
exchangeable by D2O), 7.88 (s, 1H, Ar-H), 7.21–7.39 (m,
10H, Ar-H), 4.38 (s, 2H, CH2Ph), 3.36 (s, 4H, 2CH2N), 2.95
(overlapping signals, 8H, 4CH2(a)), 1.65 [overlapping
signals, 8H, 4CH2(b)], 1.49 (m, 4H, 2CH2(c). Anal. Calcd for
C33H39N5O (521): C, 75.97; H, 7.53; N, 13.42%. Found: C,
75.83; H, 7.40; N, 13.33%.
incorporating
benzo[f]chromene,
a
2H-chromene, 4H-chromene, 1H-
ethoxymethyleneamino-4H-chromene,
chromenopyrimidine or acetylimino-2H-chromene nuclei
(more increasing in size) at nitrogen atom, suggesting that
there might be a size limited pocket at nitrogen atom.
4-(4-Benzylphthalazin-1-ylamino)-2,6-bis(morpholino-
methyl)phenol (4b)
Compounds 4a, 4b and 6 exhibit high inhibitory effects
against Aspergillus ochraceus Wilhelm (AOW) fungus and
moderate inhibitory effects against Penicillium chrysogenum
Thom (PCT). These data indicate that the activity of
compounds 4b, 4a and 6 are considerably attributed to the
presence of morpholinomethyl, piperidinylmethyl groups
(more decreasing in size) at 2,6-postion of the phenyl ring,
suggesting that there might be a size limited pocket at
position C-2,6 or the hydroxymethyl group at position C-2 of
the phenyl ring, while the other compounds showed weak
activity.
Yellow crystals, 65%, mp 288–282 °C; ethanol/benzene;
IR (νmax, cm−1): 3386–3220 (OH and NH), 3050, 3035 (C-H
1
aromatic) 2920-2852 (C-H aliphatic). H-NMR: δH 8.90 (br,
1H, OH, cancelled by D2O), 8.55(d, J = 7.80 Hz, 1H, Ar-H),
8.05 (d, J = 7.80 Hz, 1H, Ar-H) , 7.61 (s, 1H, Ar-H), 7.15–
7.41, 7.82–7.86 (2 sets of multiplets, 9H, Ar-H and NH),
4.49 (s, 2H, CH2Ph), 3.63 (s, 4H, 2CH2N), 3.54 (complex
pattern, 8H,4CH2O), 3.07 (complex pattern, 8H, 4CH2N).
Anal. Calcd for C31H35N5O3 (525): C, 70.83; H, 6.71; N,
13.32%. Found: C, 70.65; H, 6.65; N, 13.33%.
4-(4-Benzylphthalazin-1-ylamino)-2,6-bis((diethylamino)
methyl)phenol (5)
3. CONCLUSIONS
A number of Mannich reaction products (4-ben-
zylphthalazin-1-ylamino)-2,6-bis(piperidin-1-yl-(methyl),
(morpholinomethyl)
(compounds 4a,b and 5), 6,6'-methylenebis(4-(4-benzyl-
phthalazin-1-ylamino)-2-(hydroxymethyl) phenol) (6) and
(4-(4-benzylphthalazin-1-ylamino)-2-bromophenol (7) were
synthesized and evaluated for preliminary biological
activities. The results of the antimicrobial activities of these
products were promising.
Deep red crystals, 60%, mp >340 °C; (AcOH); IR (νmax
,
cm−1): 3438–3220 (OH and NH), 3055, 3030 (C-H
aromatic), 2980–2922 (C-H aliphatic), 1646 (C=N). MS m/z
(%) = 497 (M+, 10.25), 381 (13.6), [M-2(CH3CH2CH2CH3)],
235(59.1), 103 (31.8), 89 (18.2), 91 (100). Anal. Calcd for
C31H39N5O (497): C, 74.81; H, 7.90; N, 14.07%. Found: C,
74.81; H, 7.75; N, 13.97%.
and/(diethylamino)methyl)phenols
Synthesis of 6,6'-methylenebis(4-(4-benzylphthalazin-1-
ylamino)-2-(hydroxymethyl) phenol) (6)
A mixture of compound 1 (0.32 g, 1.0 mmol) in methanol
(30 mL) and 37% formaldehyde solution (2 mL) and 2 drops
of Et3N was refluxed for 1/2 hour. The separated solid was
filtered off, washed with water and methanol, then boiled
with methanol, filtered off and dried. The solid obtained was
recrystallized from acetic acid. Brown crystals, 45%, mp
>340 °C; IR (νmax, cm−1): 3400–3225 (OH and NH), 3065,
3027 (C-H aromatic), 2922 (C-H aliphatic), 1600 (C=N). MS
m/z (%) = 726 (M+, 0.00), 287 (16.1), 286 (29.9), 136 (41.4),
128 (25.3), 122 (100), 109 (52.9), 91 (50.6). Anal. Calcd for
C45H38N6O4 (726): C, 74.36; H, 5.27; N, 11.56%. Found: C,
74.22; H, 5.20; N, 11.43%.
4. EXPERIMENTAL
4.1. General
Melting points were determined on a Stuart melting point
apparatus and are uncorrected. IR spectra were recorded in
KBr using a FT-IR 5300 spectrometer and Perkin Elmer
spectrum RXIFT-IR system (ν, cm−1). The H-NMR spectra
1
(300 MHz) were recorded in DMSO-d6 on a Varian Mercury
VX-300 NMR spectrometer. Chemical shifts (δ) are related
to that of the solvent. Mass spectra were measured on a
Shimadzu GMMS-QP-1000 EX mass spectrometer at 70 eV.
The elemental analyses were performed at the Micro-
analytical Center, Cairo University. Cairo (Egypt).
Synthesis of 4-(4-benzylphthalazin-1-ylamino)-2-bromo-
phenol (7)
4.2. General Procedure for the Synthesis of 4-
Benzylphthalazin-1-ylamino Derivatives 4-5
To a stirring solution of compound 1 (0.32 g, 1.0 mmol)
in acetic acid (30 mL) bromine (10 mmol) was added
dropwise with constant stirring. After completion of the
addition the reaction will left for 2 hours, then the reaction
mixture was poured into cold water (50 mL). The solid
obtained was filtered off and recrystallized from ethanol.
Brown crystals, 75%, mp 180–182 °C; IR (νmax, cm−1):
3166–3072 (OH and NH), 3044, 3027 (C-H aromatic), 2958,
2922, 2906 (C-H aliphatic), 1658 (C=N). MS, m/z (%) = 405
A mixture of compound 1 (0.32 g, 1.0 mmol), 37%
formaldehyde solution (6.5 mL) and piperidine, morpholine
or diethylamine (55 mmol) in ethanol (5 mL) was stirred
with warming for 3 hours. The solvent was removed by
rotatory evaporation; the product was dissolved in dioxane
and saturated with dry hydrogen chloride. The solid obtained
was filtered off to give crude products.

366 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
El-Wahab et al.
(M+, 18.9), M+2 (15.1), 404 (M-H, 22.6), 325 (M-HBr,
18.9), 234 (9.4), 129 (20.8), 103 (18.9), 91 (100), 77 (13.2).
Anal. Calcd for C21H16BrN3O (405): C, 62.08; H, 3.97; N,
10.34%. Found: C, 61.87; H, 3.88; N, 10.15%.
9.32, 9.02 (3s, 3H, NH), exchangeable by D2O), 8.60 (d, J =
2.0 Hz, 1H, Ar-H), 8.20 (d, J = 1.6 Hz, 1H, Ar-H), 7.94–7.81
(m, 5H, Ar-H), 7.42–6.95 (m, 11H, Ar-H),5.05 (s, 1H, H-4),
4.65 (s, 2H, CH2Ph), 2.13 (s, 3H, ArCH3). MS, m/z (%) =
545 (M+,67.1), 478 (8.1), 454 (100), 376 (99.2), 326 (3.2),
92 (6.6), 66 (18.9). Anal. Calcd for C36H27N5O (545): C,
79.24; H, 4.99, N, 12.84%. Found: C, 79.08; H, 4.83; N,
12.59%.
3.3. General Procedure for the Synthesis of Chromene
Derivatives 9a-c and 10a,b
A mixture of compound 1 or 2 (0.32 g or 0.37 g, 1.0
mmol) and arylidinemalononitrile (8a-c) (1.0 mmol) in
absolute ethanol (30 mL) and two drops of piperidine was
refluxed for 3 hours. The mixture was then cooled and the
separated solid was filtered off, washed with ethanol and
recrystallized from the appropriate solvent.
Synthesis of [7-(4-benzylphthalazin-1-yl-N-acetylamino)-3-
ethoxymethyleneamino-4-(4-methoxy-phenyl]-4H-
chromene-3-carbonitrile (11)
A mixture of 9a (0.51 g, 1.0 mmol) and triethyl
orthoformate (2 mL) in acetic anhydride (10 mL) was
refluxed for 5 h. After cooling, the precipitated product was
filtered off and washed several times with cold ethanol and
recrystallized from benzene. Yellow crystals, 50%, mp 180–
182 °C; IR (νmax, cm−1): 3062 (C-H ethylenic), 2926, 2852
2-Amino-7-(4-benzylphthalazin-1-ylamino)-4-(p-metho-
xyphenyl)-4H-chromene-3-carbonitrile (9a)
Yellow crystals, 75%, mp 298–300 °C; (dioxane); IR
(νmax, cm−1): 3416, 3352 (NH2), 3065, 3024 (C-H aromatic),
2936, 2898 (C-H aliphatic), 2230 (CN). 1H- NMR: δH 10.48,
9.84, 8.47 (3brs, 3H, 3NH), exchangeable by D2O), 8.68,
8.65 (d, J = 8.1 Hz, 1H, Ar-H), 7.53, 7.50, 7.47 ( dd, J = 8.1
and 7.8 Hz, 1H, Ar-H), 7.36–7.08 (m, 10H, Ar-H), 7.07, 7.05
(d, J = 7.8 Hz, 2H, Ar-H), 6.89, 6.86 (d, J = 7.8 Hz, 2H, Ar-
H), 6.76–6.70 (d, J = 0.9 Hz), 1H, H-4), 3.73 (s, 2H,
CH2Ph),3.34 (s, 3H, OCH3). MS, m/z (%) = 511 (M+, 4.3),
509 (16.4), 482 (55.7), 402 (100), 371 (19.5). Anal. Calcd
for C32H25N5O2 (511): C, 75.13; H, 4.93 N, 13.69%. Found:
C, 75.08; H, 4.79; N, 13.55%.
1
(C-H aliphatic), 2228 (CN). H-NMR: δH 8.61 (s, 1H,
CH=N), 7.18–7.98 (m, 14H, Ar-H), 7.02 (s, 1H, 4H-
pyran),6.88, 6.86 (d, J = 7.8 Hz, 2H, Ar-H), 4.00 (q, J = 7.2
Hz, 2H, CH2), 3.73 (s, 2H, CH2Ph), 3.72 (s, 3H, OCH3), 2.25
(s, 3H, CH3CON), 0.87 (t, J = 7.2, 3H, CH2CH3). MS, m/z
(%) = 609 (M+, 10.2), 474 (M+-(C6H4OCH3 and CO), 35.1),
401(M-(C6H4OCH3 + 2CO + C2H5O), 100).478 (8.1), 454
(100). Anal. Calcd for C37H31N5O4 (609): C, 72.09; H, 5.13,
N, 11.49%. Found: C, 72.77; H, 5.04; N, 11.30%.
Synthesis
of
3-(4-benzylphthalazin-1-ylamino)-10-(p-
methoxyphen-yl)-10H-5-oxa-6,7-diaza-anthracene (13)
2-Amino-7-(4-benzylphthalazin-1-ylamino)-4-(p-tolyl)-4H-
chromene-3-carbonitrile (9b)
A mixture of 9a (0.51 g, 1.0 mmol) and N,N-
dimethylformamide dimethylacetal (1.0 mmol) in xylene (20
mL) was refluxed for 3 hours. The solvent was removed
under reduced pressure, and the residue was collected,
washed with ethanol and recrystallized from benzene. Brown
crystals, 65 %, mp 280–282 °C; IR (νmax, cm−1): 3428 (NH),
Yellow crystals, 70 %, mp 288–290 °C; (dioxane); IR
(νmax, cm−1): 3414, 3350 (NH2), 3089, 3045 (C-H aromatic),
2975, 2937 (C-H aliphatic), 2228 (CN). MS, m/z (%) = 495
(M+, 7.2), 434 (17.4), 402 (33.3), 356 (5.8), 176 (11.6), 109
(94.2), 53 (100). Anal. Calcd for C32H25N5O (495): C, 77.56;
H, 5.08, N, 14.13%. Found: C, 77.09; H, 4.87; N, 14.05%.
1
3016 (C-H aromatic), 1600 (C=N). H-NMR: δH 9.28 (s, 1H,
NH, exchangeable by D2O), 8.96 (s, 1H, NH, exchangeable
by D2O), 8.57 (d, J = 7.5 Hz, 1H, Ar-H), 8.09 (d, J = 1.8 Hz,
1H, Ar-H), 7.90, 7.89, 7.87 (dd, J = 7.5&1.5 Hz, 1H, Ar-
H),7.60 (t, J = 2.1 Hz, 1H, Ar-H), 7.34, 7.33 (d, J = 1.5 Hz,
1H, Ar-H), 7.31–7.11 (m, 13H, Ar-H), 6.45 (d, J = 2.1 Hz,
1H, H-4), 4.54 (s, 2H, CH2Ph), 3.76 (s, 3H, OCH3). MS, m/z
(%) = 522 (M+-H, 3), 521(M+-2H, 36), 327 (79), 326 (100),
128 (6.6), 91 (65.9). Anal. Calcd for C33H25N5O2 (523): C,
75.70; H, 4.81, N, 13.38%. Found: C, 75.34; H, 4.64; N,
13.29%.
7-(4-Benzylphthalazin-1-ylamino)-2-imino-4-(p-chloro-
phenyl)-2H-chromene-3-carbonitrile (9c)
Yellow crystals, 70 %, mp 308–310 °C; (dioxane); IR
(νmax, cm−1): 3416, 3356 (NH2), 3079, 3024 (C-H aromatic),
2930, 2915 (C-H aliphatic), 2234 (CN). MS, m/z (%); 513
(M+, 40), 486 (M+-HCN, 56.7), together with base peak at
m/z 406 (M+-PhCH2O). Anal. Calcd for C31H20ClN5O (513):
C, 72.44; H, 3.92, N, 13. 63%. Found: C, 72.15; H, 3.80; N,
13.55%.
Synthesis of 7-(4-benzylphthalozin-1-ylamino)-2-N-acetyli-
mino-4-(p-methoxyphenyl)-2H-chromene-3-carbonitrile
(14)
3-Amino-9-(4-benzylphthalazin-1-ylamino)-1-(p-metho-
xyphenyl)-1H-benzo[f]chromene-2-carbonitrile (10a)
Green crystals, 60 %, mp 294–296 °C; (dioxane); IR
(νmax, cm−1): 3459, 3379 (NH2), 2182 (CN). MS, m/z (%) =
561 (M+, 6.7), 494 (6.0), 454 (6.0), 376 (34.3), 326 (35.8),
91 (91), 66 (100). Anal. Calcd for C36H27N5O2 (561): C,
76.99; H, 4.85, N, 12.47%. Found: C, 76.83; H, 4.75; N,
12.35%.
A mixture of 9a (0.51 g, 1.0 mmol) and acetic anhydride
(20 mL) was refluxed for 3 hours, then allowed to cool at
room temperature and diluted with water (30 mL). The solid
product so formed was collected by filtration, washed with
dil. ethanol and dried. The crude solid thus obtained was
recrystallized from ethanol. Yellow crystals 60 %, mp 150–
152 °C; IR (νmax, cm−1): 3425 (NH), 3070 (C-H aromatic),
2928 (CH aliphatic), 2226 (CN), 1640 (CO). 1H-NMR: δH
7.96–6.83 (m, 16H, Ar-H), 4.68 (s, 2H, CH2Ph), 3.72 (s, 3H,
OCH3), 2.38 (s, 3H, N-acetyl). MS, m/z (%) = 551 (M+,
47.7), 460 (21.7), 443 (100), 400 (8.9). Anal. Calcd for
3-Amino-9-(4-benzylphthalazin-1-ylamino)-1-p-tolyl-1H-
benzo[f]chromene-2-carbonitrile (10b)
Green crystals, 65%, mp 306–308 °C; (dioxane); IR
(νmax, cm−1): 3462, 3382 (NH2), 3061, 3020 (C-H aromatic),
2970, 2915 (C-H aliphatic), 2180 (CN). 1H- NMR: δH 9.53,

Synthesis and Reactions of Some New Benzylphthalazin-1-ylaminophenols
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
367
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73.88; H, 4.48; N, 12.66%.
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CONFLICT OF INTEREST
[18]
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Declared none.
Dogruer, D.S.; Sahin, M.F.; Kupeli, E.; Yesilada, E. Synthesis of
new
2-[1(2H)-phthalazinon-2-yl]acetamide
and
3-[1(2H)-
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