Synthesis and characterization of Bis-quinazolines from linear tetra-amines involving 2-(aminomethyl)benzenamine with aldehydes

Article abstract of DOI:10.1002/jhet.807

Three tetra-amine compounds 2-((2-(2-aminobenzylamino)ethylamino)methyl) benzenamine (L₁), 2-((3-(2-aminobenzylamino)propylamino)methyl) benzenamine (L₂), and 2-((4-(2-aminobenzylamino)butylamino)methyl) benzenamine (L₃) were synthesized and then their reaction with 2-hydroxybenzaldehyde, 2-nitrobenzaldehyde, and 2-hydroxy-3-methoxybenzaldehyde were investigated. Treatment of L₁, L₂, and L₃ with the former aldehydes gave derivatives of quinazolines in a good yield. The products have been studied with IR, ¹H NMR, ¹³C NMR, COSY, HMQC, and microanalysis.

Full text of DOI:10.1002/jhet.807

July 2013
Synthesis and Characterization of Bis‐quinazolines from Linear
Tetra-amines Involving 2‐(Aminomethyl)benzenamine
with Aldehydes
979
a
a
b
*
Reza Azadbakht, Maryame Khodabandeh, Hassan Keypour,
Reza Haji Hosseini Baghdad Abadi,a and Hadi Amiri Rudbaric
aDepartment of Chemistry, Payame Noor University (PNU), Iran
bFaculty of Chemistry, Bu Ali Sina university, Hamedan, Iran
cDipartimento di Chimica Inorganica, Universitá di Messina, Italy
*
E-mail: r_azadbakht@yahoo.com
Received July 25, 2010
DOI 10.1002/jhet.807
Published online 2 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
Three tetra‐amine compounds 2‐((2‐(2‐aminobenzylamino)ethylamino)methyl)benzenamine (L1),
2‐((3‐(2‐aminobenzylamino)propylamino)methyl)benzenamine (L2), and 2‐((4‐(2‐aminobenzylamino)
butylamino)methyl)benzenamine (L3) were synthesized and then their reaction with 2‐hydroxybenzaldehyde,
2‐nitrobenzaldehyde, and 2‐hydroxy‐3‐methoxybenzaldehyde were investigated. Treatment of L1, L2, and
L3 with the former aldehydes gave derivatives of quinazolines in a good yield. The products have been
1
studied with IR, H NMR, 13C NMR, COSY, HMQC, and microanalysis.
J. Heterocyclic Chem., 50, 979 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Ring‐closing reactions continue to emerge as a useful
approach for the construction of various heterocyclic
compounds. Quinazolines have been widely studied in recent
years due to their wide range of chemotherapeutic activities
including antiviral [1], antibacterial [2, 3], antifungal [4, 5],
antimalarial [6], antitumorals [7–9], antihypertensive [10],
diuretic [11, 12], inhibitors of cyclin‐dependent kinases [13],
anticonvulsant [14], ghrelin receptor antagonists [15], anti‐
inflammatory, analgesic, and COX‐II inhibitors [16, 17].
Hence, the synthesis and research of new quinazolines is of
great interest. We report the synthesis and characterization of
seven derivatives of diastereoisomers of Bis‐quinazolines (1,
2, 3, 4, 5, 6, and 7) derived of L1, L2, and L3 with 2‐
nitrobenzaldehyde, 2‐hydroxy‐3‐methoxybenzaldehyde, and
2‐hydroxybenzaldehyde. The linear tetra‐amines, L1, L2, and
L3, were synthesized by condensation of 1,2‐diaminoethane,
1,3‐diaminopropane, and/or 1,4‐diaminobutane with 2‐
nitrobenzaldehyde followed by reduction of imine bonds of
the resulting products with NaBH4 and then reduction of the
nitro groups using zinc and ammonium chloride (Scheme 1).
It is evident from the topography of the tetra‐amines that
they possess two 2‐(aminomethyl)benzenamines in which it
is highly prone to form of Bis‐quinazolines. There are two
probable optical isomers for this ring‐formation reaction. Reac-
tion with aldehydes produces Bis‐quinazolines that precipitated
out of solution in the beginning of the reactions. The IR spectra
of all derivatives of Bis‐quinazolines are similar. The absence
of bands characteristic of the carbonyl and primary amine
groups of the starting materials in the infrared spectra, and the
absence of a Schiff‐base ν(C N) vibration and the presence of
secondary amine vibrations were evidence of formation of
the Bis‐quinazolines. The NMR studies of the compound of
1, 2, 3, 4, 5, 6, and 7 also provide strong evidence for the for-
mation of the derivatives of Bis‐quinazolines. The absence of
signals characteristic of the imine carbons and protons, the
existence of a signal at ≈5.2–5.8 with intensity 2, attributed
to CH methine were evidence of formation of the Bis‐
quinazolines. The 13CNMR spectra of Bis‐quinazolines clearly
show that diastereoisomers are synthesized. In the aliphatic
region of the 13CNMR spectra, the signals appeared as binary.
© 2013 HeteroCorporation

980
R. Azadbakht, M. Khodabandeh, H. Keypour, R. H. H. B. Abadi, and H. A. Rudbari
Vol 50
N1,N3‐Bis(2‐nitrobenzyl)propane‐1,3‐diamine (I2). Yield: (93%),
IR (Nujol, cm−1): 3319 m (NH); 1340 and 1541 s(NO2); 1H NMR δH
(300 MHz, CDCl3, ppm): 1.55 (t, 2H, C CH2 C), 2.22 (br, 2H, NH),
2.55 (t, 4H, CH2 N), 3.84 (s, 4H, CH2 benzyl), 7.11–7.91 (m, 8H, Ar).
13C NMR δC (300 MHz, CDCl3, ppm): 29.45, 47.29, 50.07, 123.94,
127.27, 130.49, 132.59, 136.16, 148.46. Anal. Calcd for
C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 59.12; H,
5.80; N, 16.31.
Scheme 1
N1,N4‐Bis(2‐nitrobenzyl)butane‐1,4‐diamine (I3). Yield: (81%),
IR (Nujol, cm−1): 3320 m (NH); 1344 and 1524 s (NO2); 1H NMR
δH (300 MHz, CDCl3, ppm): 1.55 (br, 6H, C CH2 CH2 C and NH),
2.63 (4H, CH2 N), 3.91 (s, 4H, CH2 benzyl), 7.10–7.94 (m, 8H,
Ar). 13C NMR δC (300 MHz, CDCl3, ppm): 28.43, 48.27, 50.17,
123.84, 127.267, 130.69, 132.32, 135.12, 148.86. Anal. Calcd for
C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.12; H,
6.23; N, 15.59.
General procedure for synthesis of 2‐((2‐(2‐aminobenzy-
lamino)ethylamino)methyl)benzenamine (L1), 2‐((3‐(2‐ami-
nobenzylamino)propylamino)methyl)benzenamine (L2) and
2‐((4‐(2‐aminobenzylamino)butylamino)methyl)benzenamine
(L3). A mixture of I1, I2, and/or I3 (10 mmol), ammonium chloride
(40 mmol), and water (10 mL) in methanol (100 mL) was heated
to boiling, and then zinc dust (2 g, 30 mmol) was added. After 4
h, the solution was filtered, and then more water was added, and
the solution was adjusted to pH 11 with NaOH. The solution
was extracted with chloroform (×3). The chloroform extracts
were combined and dried over anhydrous sodium sulfate. The
dried extracts were then reduced to a small volume on a rotary
evaporator. The products formed as yellow oil.
2‐((2‐(2‐Aminobenzylamino)ethylamino)methyl)benzenamine
(L1). Yield: (75%), IR (Nujol, cm−1): 3310 and 3420 m(NH2). 1H
NMR δH (300 MHz, CDCl3, ppm): 2.87 (4H, CH2), 3.41 (br, 6H,
NH), 3.70 (s, 4H, CH2 benzyl), 6.37–7.09 (m, 8H, Ar). 13C
NMR δC (300 MHz, CDCl3, ppm): 48.30, 52.27, 115.31, 117.23,
123.67, 127.97, 129.48, 146.42. Anal. Calcd for C16H22N4: C,
71.08; H, 8.20; N, 20.72. Found: C, 71.18; H, 8.23; N, 20.78.
2‐((3‐(2‐Aminobenzylamino)propylamino)methyl)benzenamine
1
(L2). Yield: (68%), IR (Nujol, cm−1): 3321 and 3425 m(NH2). H
EXPERIMENTAL
NMR δH (300 MHz, CDCl3, ppm): 1.64 (q, H, C CH2 C), 2.68
(4H, CH2 N), 3.36 (br, 6H, NH), 3.77 (s, 4H, CH2 benzyl),
6.40–7.11 (m, 8H, Ar). 13C NMR δC (300 MHz, CDCl3, ppm):
29.40, 46.91, 52.21, 115.26, 117.12, 123.45, 127.86, 129.43,
146.35. Anal. Calcd for C17H24N4: C, 71.79; H, 8.51; N, 19.70.
Found: C, 71.85; H, 8.48; N, 19.72.
2‐((4‐(2‐Aminobenzylamino)butylamino)methyl)benzenamine
(L3). Yield: (71%), IR (Nujol, cm−1): 3302 and 3414 m (NH2). 1H
NMR δH (300 MHz, CDCl3, ppm): 1.52 (q, 4H, C CH2 CH2 C),
2.61 (4H, CH2 N), 3.4 (br, 6H, NH), 3.78 (s, 4H, CH2 benzyl),
6.41–7.11 (m, 8H, Ar). 13C NMR δC (300 MHz, CDCl3, ppm):
27.14, 48.49, 52.20, 115.14, 116.97, 123.61, 127.70, 129.27,
146.41. Anal. Calcd for C18H26N4: C, 72.44; H, 8.78; N, 18.77.
Found: C, 72.45; H, 8.81; N, 18.72.
General procedure for synthesis of N1,N2‐bis(2‐nitrobenzyl)
ethane‐1,2‐diamine (I1), N1,N3‐bis(2‐nitrobenzyl)propane‐1,3‐
diamine (I2), and N1,N4‐bis(2‐nitrobenzyl)butane‐1,4‐diamine
(I3). To a stirred solution of 1,3‐propandiamine, 1,2‐ethandiamine,
or 1,4‐butandiamine (10 mmol) in methanol (100 mL), 2‐
nitrobenzaldehyde (20 mmol) was added in methanol (60 mL). The
mixture was refluxed for 5 h. The solution was then allowed to cool
to room temperature after which sodium borohydride (1.5 g) was
added in small portions to the stirred solution over 50 min. The
volume was then reduced to 20 mL by rotary evaporation. Excess
water was added to the mixture, and the pH was adjusted to 12 with
sodium hydroxide. The solution was extracted with chloroform (×3).
The chloroform extracts were combined and dried over anhydrous
sodium sulfate. The dried extracts were then reduced to a small
volume on a rotary evaporator. The products formed as yellow oil.
N1,N2‐Bis(2‐nitrobenzyl)ethane‐1,2‐diamine (I1). Yield: (95%),
General procedure for synthesis of derivatives of quinazolines.
To nitrobenzaldehyde, 2‐hydroxy‐3‐methoxybenzaldehyde and/or 2‐
hydroxybenzaldehyde (10 mmol) dissolved in hot ethanol (30 mL)
was added to solution of L2 or L3 (5 mmol). The reaction mixture
was stirred while refluxing for 1 h. The compounds, which
precipitated during refluxing were filtered off and washed several
times with hot ethanol, and dried in air at room temperature (Scheme 1).
2‐(3‐(2‐(2‐(2‐Hydroxy‐3‐methoxyphenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)ethyl)‐1,2,3,4‐tetrahydroquinazolin‐2‐yl)‐6‐methoxyphenol
1
IR (Nujol, cm−1): 3320 m (NH); 1342 and 1540 s (NO2); H
NMR δH (300 MHz, CDCl3, ppm): 2.46 (br, 2H, NH), 2.62
(t, 4H, CH2 N), 3.88 (s, 4H, CH2 benzyl), 7.11–7.91 (m, 8H,
Ar) 13C NMR δC (300 MHz, CDCl3, ppm): 48.34, 49.93,
123.99, 127.33, 130.46, 132.55, 135.24, 148.60. Anal. Calcd
for C16H18N4O4: C, 58.17; H, 5.49; N, 16.96. Found: C,
58.23; H, 5.55; N, 16.93.
1
(1). Yield: (79%), IR (KBr, cm−1): 3406s (NH). H NMR δH (300
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Synthesis and Characterization of Bis-quinazolines from Linear Tetraamines
Involving 2-(Aminomethyl)benzenamine with Aldehydes
981
MHz, DMSO‐d6, ppm): 2.74 and 2.94 (4H, CH2 N), 3.74 (s, 10H,
CH2 benzyl and OCH3), 5.27 and 5.32 (s, 2H, methine), 6.51–7.01
(m, 14H, Ar), 10.29 (br, 2H, OH). 13C NMR δC (300 MHz, DMSO‐
d6, ppm): 48.20, 48.42, 49.54, 50.01, 56.02, 56.05, 68.86, 69.19,
112.36, 114.09, 116.62, 116.78, 118.59, 120.25, 127.38, 127.68,
142.49, 142.72, 145.43, 147.93, 147.99. Anal. Calcd for
C32H34N4O4: C, 71.35; H, 6.36; N, 10.40. Found: C, 71.40; H, 6.32;
N, 10.42.
2‐(2‐Nitrophenyl)‐3‐(2‐(2‐(2‐nitrophenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)ethyl)‐1,2,3,4‐tetrahydroquinazoline (2). Yield: (75%), IR
(KBr, cm−1): 3421 s (NH), 1361 and 1520 (NO2). 1H NMR δH (300
MHz, CDCl3, ppm): 2.67 (4H, CH2 N), 3.32 (d, 4H, CH2 benzyl),
4.61(br, 2H, NH), 5.87 (s, 2H, methine), 6.41–7.71 (m, 16H, Ar).
13C NMR δC (300 MHz, DMSO‐d6, ppm): 46.31, 50.73, 68.87,
114.16, 117.63, 124.49, 127.76, 128.25, 129.44, 129.53, 132.22,
137.04, 142.28, 149.23. Anal. Calcd for C30H28N6O4: C, 67.15; H,
5.26; N, 15.66. Found: C, 67.15; H, 5.23; N, 15.71.
2‐(3‐(4‐(2‐(2‐Hydroxyphenyl)‐1,2‐dihydroquinazolin‐3(4H)‐
yl)butyl)‐1,2,3,4‐tetrahydroquinazolin‐2‐yl)phenol (7). Yield:
1
(80%), IR (KBr, cm−1): 3423 s (NH). H NMR δH (300 MHz,
DMSO‐d6, ppm): 1.61 (4H, C‐CH2 CH2 C), 2.49 and 2.72 (4H,
CH2 N), 3.20 (NH ), 3.54 and 3.72(d, 4H, CH2 benzyl), 5.21 (s,
2H, methine) 6.22–7.27 (m, 16H, Ar), 11.09 (s, 2H, OH). 13C
NMR δC (300 MHz, DMSO‐d6, ppm): 25.32, 47.08,
47.20,51.12, 69.68, 69.79, 114.29, 116.27, 116.31, 116.35,
117.02, 119.11, 126.57, 127.78, 128.44, 129.42, 142.20,
156.61. Anal. Calcd for C32H34N4O2: C, 75.86; H, 6.76; N,
11.06. Found: C, 75.86; H, 6.76; N, 11.06.
Acknowledgments. The authors are thankful to Payame Noor
University (PNU) for financial support.
2‐(3‐(3‐(2‐(2‐Hydroxy‐3‐methoxyphenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)propyl)‐1,2,3,4‐tetrahydroquinazolin‐2‐yl)‐6‐methoxyphenol
REFERENCES AND NOTES
1
(3). Yield: (75%), IR (KBr, cm−1): 3409 s (NH). H NMR δH
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(300 MHz, CDCl3, ppm): 1.86 (2H, C CH2 C), 2.71 (4H,
CH2 N), 3.84 (s, 10H, CH2 benzyl and OCH3),4.51(br, 2H,
NH), 5.17 (s, 2H, methine) 6.41–7.21 (m, 14H, Ar). 13C NMR
δC (300 MHz, DMSO‐d6, ppm): 25.37, 46.81, 47.17, 49.17,
56.05, 69.31, 69.71, 112.46, 114.09, 116.28, 116.90, 118.56,
120.22, 127.20, 127.76, 142.28, 145.61, 147.92. Anal. Calcd
for C33H36N4O4: C, 71.72; H, 6.57; N, 10.14. Found: C, 71.81;
H, 6.62; N, 10.13.
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2‐(2‐Nitrophenyl)‐3‐(3‐(2‐(2‐nitrophenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)propyl)‐1,2,3,4‐tetrahydroquinazoline (4). Yield: (77%), IR
1
(KBr, cm−1): 3422 s (NH). H NMR δH (300 MHz, CDCl3, ppm):
1.61 (2H, C CH2 C), 2.51 (4H, CH2 N), 3.47 (s, 4H, CH2 benzyl),
4.52(br, 2H, NH), 5.76 (s, 2H, methine) 6.39–7.63 (m, 14H, Ar) 13C
NMR δC (300 MHz, CDCl3, ppm): 25.43, 45.82, 50.23, 114.04,
117.68, 124.41, 127.53, 128.24, 129.33, 129.60, 131.67, 134.22,
137.06, 141.28, 148.92. Anal. Calcd for C31H30N6O4: C, 67.62; H,
5.49; N, 15.26. Found: C, 67.60; H, 5.43; N, 15.20.
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2‐(3‐(4‐(2‐(2‐Hydroxy‐3‐methoxyphenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)butyl)‐1,2,3,4‐tetrahydroquinazolin‐2‐yl)‐6‐methoxyphenol
1
(5). Yield: (80%), IR (KBr, cm−1): 3404 s (NH). H NMR δH (300
MHz, DMSO‐d6, ppm): 1.69 (4H, C CH2 CH2 C), 2.75 (4H,
CH2 N), 3.82 (s, 10H, CH2 benzyl and OCH3), 4.49 (br, 2H, NH),
5.21 (s, 2H, methine) 6.54–7.16 (m, 14H, Ar). 13C NMR δC (300
MHz, DMSO‐d6, ppm): 25.28, 47.16, 51.16, 56.07, 112.55, 114.17,
116.28, 116.96, 118.56, 120.23, 127.08, 127.79, 142.27, 145.78,
147.97. Anal. Calcd for C34H38N4O4: C, 72.06; H, 6.76; N, 9.89.
Found: C, 72.11; H, 6.77; N, 9.89.
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2‐(2‐Nitrophenyl)‐3‐(4‐(2‐(2‐nitrophenyl)‐1,2‐dihydroquinazolin‐
3(4H)‐yl)butyl)‐1,2,3,4‐tetrahydroquinazoline (6). Yield: (81%), IR
1
(KBr, cm−1): 3423 s (NH). H NMR δH (300 MHz, CDCl3, ppm):
1.44 (4H, C CH2 CH2 C), 2.49 (4H, CH2 N), 3.38 (s, 4H, CH2
benzyl), 4.53 (br, 2H, NH), 5.83 (s, 2H, methine), 6.54–7.8 (m, 16H,
Ar) 13C NMR δC (300 MHz, DMSO‐d6, ppm): 25.04, 45.89, 52.16,
52.53, 68.32, 113.70, 116.69, 117.17, 124.85, 127.75, 127.82,
129.14, 129.33, 132.22, 136.97, 142.27, 149.15. Anal. Calcd for
C32H32N6O4: C, 68.07; H, 5.71; N, 14.88. Found: C, 68.02; H, 5.74;
N, 14.92.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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