Synthesis of {2,3-dihydro-7-halopyrrolo-[(2,1-b)]-quinazolin-9-(1h)-one and 2,3-dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazolin-9-(1h)-one}: New analogs of deoxyvasicinone

Article abstract of DOI:10.1080/00397911.2010.534228

A series of novel halogen-substituted deoxyvasicinone f2,3-dihydro-7- halopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-dihydro-5,7-dihalopyrrolo- [(2,1-b)]-quinazolin-9-(1H)-oneg derivatives was synthesized by condensation of halogenated anthranilic acids (2, 3, 4, 5) with 4-aminobutyric acid (6) in refluxing m-xylene over phosphorus pentoxide for 3 h to give the desired compounds (7a-7d). Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.534228

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Synthesis of {2,3-Dihydro-7-halopyrrolo-
[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-
Dihydro-5,7-dihalopyrrolo-[(2,1-b)]-
quinazolin-9-(1H)-one}: New Analogs of
Deoxyvasicinone
Babatunde Ojo a & Bejoy K. Chowdhury b
a Department of Chemistry, Fort Valley State University, Fort Valley,
Georgia, USA
b Department of Chemistry, School of Tropical Medicine, Calcutta,
India
Accepted author version posted online: 06 Sep 2011.Version of
record first published: 16 Dec 2011.
To cite this article: Babatunde Ojo & Bejoy K. Chowdhury (2012): Synthesis of {2,3-Dihydro-7-
halopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-Dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazolin-9-
(1H)-one}: New Analogs of Deoxyvasicinone, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:7, 1002-1009
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Synthetic Communications1, 42: 1002–1009, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.534228
SYNTHESIS OF {2,3-DIHYDRO-7-HALOPYRROLO-
[(2,1-b)]-QUINAZOLIN-9-(1H)-ONE AND
2,3-DIHYDRO-5,7-DIHALOPYRROLO-[(2,1-b)]-
QUINAZOLIN-9-(1H)-ONE}: NEW ANALOGS OF
DEOXYVASICINONE
Babatunde Ojo1 and Bejoy K. Chowdhury2
1Department of Chemistry, Fort Valley State University, Fort Valley,
Georgia, USA
2Department of Chemistry, School of Tropical Medicine, Calcutta, India
GRAPHICAL ABSTRACT
Abstract A series of novel halogen-substituted deoxyvasicinone f2,3-dihydro-7-halopyrrolo-
[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazolin-
9-(1H)-oneg derivatives was synthesized by condensation of halogenated anthranilic acids
(2, 3, 4, 5) with 4-aminobutyric acid (6) in refluxing m-xylene over phosphorus pentoxide
for 3 h to give the desired compounds (7a–7d).
Keywords Adhatoda vasica; deoxyvasicinone; vasicine; vasicinone
INTRODUCTION
Two quinazoline alkaloids, vasisine and vasicinone, have been isolated from the
Indian medicinal plant Adhatoda vasica Nees[1] and from the grassy part of Galena
officinalis.[2] Extracts containing these quinazoline alkaloids have been used in tra-
ditional medicine[3] as a remedy for cold, cough, bronchitis, asthma, and related
airway disorders. Quinazolinone-based natural products have interesting pharmaco-
logical activities and have been extensively studied for pharmaceutical activities.
Many methods were developed for the synthesis of vasicine, vasicinone, and related
Received June 21, 2010.
Address correspondence to Babatunde Ojo, Department of Chemistry, Fort Valley State
University, 1005 State University Drive, Fort Valley, GA 31030, USA. E-mail: ojob@fvsu.edu
1002

HALOGEN-SUBSTITUTED ANALOGS OF DEOXYVASICINONE
1003
analogs,[4–12] but there has been no literature report of 2,3-dihydro-7-halopyrrolo-
[(2,1-b)]-quinazolin-9-(1H)-one and 2,3-dihydro-5,7-dihalopyrrolo-[(2,1-b)]-quinazo-
lin-9-(1H)-one derivatives from anthranilic acid. Our synthetic efforts focused on the
design of new analogs of deoxyvasicinone, which allowed substitution of halogens
(at positions 7 and 5, respectively) on the quinazolin-9-(1H)-one ring. In preparation
for this effort, we have investigated a new synthetic strategy to deoxyvasicinone that
proceeds through the commercially available anthranilic acid as the starting point
for the syntheses. These compounds were synthesized to aid in establishing further
structure–activity relationships within the quinazolin-9-(1H)-one class of compounds.
We now report the efficient synthesis of four new analogs of deoxyvasicinone.
Anthranilic acid (1) was brominated below the freezing point (16 ꢀC) of glacial
acetic acid[13] to give abundant precipitates of 5-bromoanthranilic acid (2) and in
boiling glacial acetic acid[13] to furnish 3,5-dibromoanthranilic acid (3). Anthranilic
acid was chlorinated[14a] in a mixture of well-cooled sulfuryl chloride and ether under
reflux, followed by the removal of the ether and sulfuryl chloride at reduced pressure.
Aqueous acidification of the residue gave precipitates of 5-chloroanthranilic acid (4).
Anthranilic acid was chlorinated in a mixture of concentrated hydrochloric acid and
water[14b] to furnish 3,5-dichloroanthranilic acid (5) (Scheme 1).
The 5-bromo- and 3,5-dibromoanthranilic acid analogs were subsequently
reacted with 4-aminobutyric acid (6) in refluxing m-xylene over phosphorus pen-
toxide for 3 h to give their crude products, respectively. In a similar fashion, the
5-chloro- and 3,5-dichloroanthranilic acid analogs were reacted with 4-aminobutyric
Scheme 1. Halogenation of anthranilic acid. Reagents and conditions: (a) bromine, glacial acetic acid,
below 16 ꢀC; (b) wash with benzene; (c) aqueous concentrated hydrochloric acid; (d) extract with hot
water; (e) bromine, glacial acetic acid; (f) reflux; (g) wash with glacial acetic acid and benzene; (f) hot
water; (h) recrystallize from ethanol; (i) sulfuryl chloride (SO2Cl2), ether, cool to room temperature; (j)
reflux and evaporation of ether; (k) aqueous 8% hydrochloric acid; (l) aqueous 6M NaOH; (m) saturated
sodium acetate; (n) hot 95% ethanol, hot water; (o) aqueous concentrated hydrochloric acid, cool below
30 ꢀC; (p) water, benzene, reflux; and (q) recrystallize from ethanol.

1004
B. OJO AND B. K. CHOWDHURY
Scheme 2. General scheme for synthesis of deoxyvasicinone derivatives. Reagents and conditions: (a)
m-xylene, phosphorus pentoxide (P2O5); (b) reflux (3 h); (c) extract with aqueous acid; (d) basify with
ammonia; (e) extract base with ether; and (f) recrystallize from benzene and petroleum ether.
acid (6) in refluxing m-xylene over phosphorus pentoxide for 3 h by a method essen-
tially similar to that described for bromo- analogs to give their crude products,
respectively.
For each series, the crude product was isolated from the reaction mixture by
extraction with acid followed by basification with aqueous ammonia and subsequent
extraction of the base with diethyl ether. The resulting residue from the ether extract
was recrystallized from a mixture of benzene and petroleum ether to give pure crys-
tals of compounds 7a–7d, in good yield. The synthesis of the parent compound,
deoxyvasicinone (8), has previously been reported in the literature.[15] However,
our synthetic strategy was employed to synthesize this compound in a much better
yield by a procedure similar to that described for compounds 7a–7d (see Scheme 2).
RESULTS AND DISCUSSION
The results of the condensation of anthranilic acid derivatives with 4-aminobu-
tyric acid in refluxing m-xylene to deoxyvasicinone derivatives are summarized in
Table 1. These compounds were synthesized in good yields (80% and above), and
pure crystals of each compound were obtained. Several solvents were attempted
for the condensation process, and m-xylene was the best solvent because the
products were obtained in relatively pure form (single spot on thin-layer chromato-
graphy, TLC). Several solvent systems were attempted for the recrystallization
process, but a mixture of benzene and petroleum ether gave the purest form of these
compounds, supported by spectra data. The chemical structure of these compounds

HALOGEN-SUBSTITUTED ANALOGS OF DEOXYVASICINONE
1005
Table 1. Physical and analytical data of 2,3-dihydropyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one derivatives
(7a–7d)
Elemental analysis (%)
(Calc.=found)
Compound
X
Y
H
Mp (ꢀC) Yield (%)
Molecular formula (M)
C
H
N
7a
Br
176–178
181–183
201–203
233–235
196–197
83
81
82
85
82
C
C
11H9N2OBr (264.102)
11H8N2OBr2 (344.006)
50.00
50.03
38.37
38.36
60.15
60.17
51.76
51.75
70.95
70.94
3.44
3.44
2.33
2.31
4.13
4.16
3.14
3.13
5.41
5.39
10.61
10.63
8.14
7b
7c
7d
8
Br Br
8.14
Cl
Cl
H
H
Cl
H
C11H9N2OCl (219.651)
11H8N2OCl2 (255.104)
C11H10N2O (186.213)
12.75
12.78
10.98
10.98
15.04
15.07
C
was established based on the infrared (IR), mass spectrometry (MS), 1H NMR, and
13C NMR spectral data. All compounds synthesized in this study gave satisfactory
elemental analysis data and were within 0.4% of calculated values.
CONCLUSION
In conclusion, cyclization of a mixture of mono- and dihalogenated anthranilic
acid with 4-aminobutyric acid and phosphorus pentoxide in refluxing xylene, fol-
lowed by an aqueous workup procedure, gave the desired target compound in good
yield. This route may serve as an excellent synthetic methodology for synthesis of
deoxyvasicinone derivatives in good yields.
EXPERIMENTAL
Compounds were synthesized utilizing reagents commercially available from
Aldrich Chemical Co. and Fisher Scientific without further purification. Melting
points were determined in open capillary tubes on a Meltemp melting-point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded with
a Bruker Avance (AV) 400 spectrometer at 400 MHz. Chemical shifts are quoted in
parts per million (ppm) from internal standard tetramethylsilane (TMS). IR spectra
were recorded with an ATI Mattson RS-1 FTIR spectrometer using KBr pellets. All
solvents and chemicals were of research grade and were obtained from Merck and

1006
B. OJO AND B. K. CHOWDHURY
Lancaster. The progress of the reaction was monitored by TLC. Mass spectra were
obtained using a Micromass LCT mass spectrometer operating at 20 eV. Elemental
analyses were performed on a Perkin-Elmer 2400 CHN analyzer instrument, and
were within 0.4% of calculated values.
2,3-Dihydro-7-bromopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one (7a)
A mixture of 5-dibromoanthranilic acid (2.0 g, 0.0093 mol), 4-aminobutyric
acid (1.5 g, 0.0145 mol) and phosphorus pentoxide (6.0 g, 0.0423 mol) in xylene
(200 ml) (previously dried over P2O5) was refluxed for 3 h. The reaction mixture
was cooled, and xylene was decanted off. Crushed ice and distilled water were added
to the solid substance formed in the reaction flask, and this was shaken thoroughly
and transferred into a separatory funnel. The aqueous acidic layer was extracted
with chloroform (3 ꢁ 100 ml). The chloroform extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated off when a pale-yellow residue (X)
was obtained. The residue X gave positive alkaloid test with Dragendroff’s spray
reagent. The residue (X) was dissolved in ether (250 ml) and extracted with 5%
hydrochloric acid (3 ꢁ 100 ml). The aqueous acid layer was extracted with ether
(1 ꢁ 100 ml) to remove any nonalkaloid impurity. The acid extract was then basified
with ammonia. The resulting solution was extracted with ether (3 ꢁ 100 ml), and the
ether extract was dried over anhydrous sodium sulfate. Removal of solvent in vacuo
gave an off-white solid (980 mg), which on recrystallization from benzene and pet-
roleum ether provided 850 mg (83%) of 7a as a light yellow solid: mp 176–178 ꢀC;
1
d H NMR (CDCl3): d 2.21–2.36 (m, J ¼ 7.94, 7.21 Hz, 2H, NCH2CH2CH2), 3.18
(t, J ¼ 7.94 Hz, 2H, NCH2CH2CH2), 4.21 (t, J ¼ 7.21 Hz, 2H, NCH2CH2CH2),
7.40–7.48 (m, 1H, ArH), 7.70–7.73 (d, J ¼ 2.00 Hz, 1H, ArH), 8.41–8.43 (d,
J ¼ 2.00 Hz, 1H, ArH). 13C NMR (CDCl3, 50 MHz) d 19.4, 32.4, 46.4, 120.4,
126.2, 126.3, 126.7, 134.1, 149.0, 159.4, 160.9. MS-CI m=z 265.102 calcd. for
C11H9N2 OBr (MHþ). IR (KBr): 2931, 2855, 1679, 1600, 1556, 1455. Anal. calcd.
for C11H9N2 OBr: C, 50.0; H, 3.44; N, 10.61; Br, 30.25. Found: C, 50.03; H, 3.44;
N, 10.63; Br, 30.25.
2,3-Dihydro-5,7-dibromopyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one (7b)
A mixture of 3,5-dibromoanthranilic acid (2.0 g, 0.0068 mol), 4-aminobutyric
acid (1.5 g, 0.0145 mol), and phosphorus pentoxide (6.0 g, 0.0423 mol) in xylene
(200 ml) (previously dried over P2O5) was cyclized by a method virtually identical
to that employed to synthesize 7a. The resulting solution was extracted with ether
(3 ꢁ 100 ml), and the ether extract was dried over anhydrous sodium sulfate.
Removal of solvent in vacuo gave a pale yellow solid (850 mg), which on recrystalli-
zation from benzene and petroleum ether yielded 735 mg (81%) of 7b as a light
1
yellow solid: mp 181–183 ꢀC; H NMR (CDCl3): d 2.21–2.36 (m, J ¼ 7.94, 7.21 Hz,
2H, NCH2CH2CH2), 3.18 (t, J ¼ 7.94 Hz, 2H, NCH2CH2CH2), 4.21 (t, J ¼ 7.21 Hz,
Hz, 2H NCH2CH2CH2), 8.15–8.16 (d, J ¼ 2.12 Hz, 1H, ArH), 8.40–8.41 (d, 1H,
J ¼ 2.12 Hz, ArH). 13C NMR (CDCl3, 50 MHz) d 19.4, 32.4, 46.4, 120.4, 126.2,
126.3, 126.7, 134.1, 149.0, 159.4, 160.9. MS-CI m=z 345.006 calcd. C11H8N2OBr2
(MHþ). IR (KBr): 2931, 2855, 1679, 1600, 1556, 1455. Anal. calcd. for

HALOGEN-SUBSTITUTED ANALOGS OF DEOXYVASICINONE
1007
C11H8N2OBr2: C, 38.37; H, 2.33; N, 8.14; Br, 46.51. Found: C, 38.36; H, 2.31; N,
8.14; Br, 46.50.
2,3-Dihydro-7-chloropyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one
A mixture of 5-chloroanthranilic acid (0.95 g, 0.0055 mol), 4-aminobutyric acid
(1.0 g, 0.0097 mol), and phosphorus pentoxide (6.0 g, 0.0423 mol) in xylene (200 ml)
(previously dried over P2O5) was cyclized by a method virtually identical to that
employed to synthesize 7a. The resulting solution was extracted with ether (3 ꢁ
100 ml), and the ether extract was dried over anhydrous sodium sulfate. Removal
of solvent in vacuo gave a white solid (910 mg), which on recrystallization from ben-
zene and petroleum ether provided 750 mg (82%) of 7c as a white solid: mp
201–203 ꢀC; 1H NMR (CDCl3):
d
2.21–2.36 (m, J ¼ 7.94, 7.21 Hz, 2H,
NCH2CH2CH2, 3.18 (t, J ¼ 7.94 Hz, 2H, NCH2CH2CH2), 4.21 (t, J ¼ 7.21 Hz, 2H,
NCH2CH2CH2), 7.42–7.49 (m, 1H, ArH), 7.73–7.75 (d, J ¼ 2.12 Hz, 1H, ArH),
8.45–8.47 (d, J ¼ 2.12 Hz, 1H, ArH). 13C NMR (CDCl3, 50 MHz) d 19.4, 32.4,
46.4, 120.4, 126.2, 126.3, 126.7, 134.1, 149.0, 159.4, 160.9. MS-CI m=z 220.651 calcd.
for C11H9N2OCl (MHþ). IR (KBr): 2931, 2855, 1679, 1600, 1556, 1455. Anal. calcd.
for C11H9N2OCl: C, 60.15; H, 4.13; N, 12.75; Cl, 16.14. Found: C, 60.17; H, 4.16; N,
12.78; Cl, 16.14.
2,3-Dihydro-5,7-dichloropyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one (7d)
A mixture of 3,5-dichloroanthranilic acid (0.95 g, 0.0046 mol), 4-aminobutyric
acid (1.0 g, 0.0097 mol) and phosphorus pentoxide (6.0 g, 0.0423 mol) in xylene
(200 ml) (previously dried over P2O5) was cyclized by a method virtually identical
to that employed to synthesize 7a. The ether extract was dried over anhydrous
sodium sulfate, and the solvent evaporated off completely to furnish a whitish solid
(992 mg), which on recrystallization from benzene and petroleum ether provided
892 mg (85%) of 7d as a white solid: mp 233–235 ꢀC; 1H NMR (CDCl3): d
2.21–2.36 (m, J ¼ 7.94, 7.21 Hz, 2H, NCH2CH2CH2), 3.18 (t, J ¼ 7.94 Hz, 2H,
NCH2CH2CH2), 4.21 (t, J ¼ 7.21 Hz, 2H, NCH2CH2CH2), 7.82–7.83 (d, 1H,
J ¼ 2.12 Hz, ArH), 8.22–8.23 (d, 1H, J ¼ 2.12 Hz, ArH). 13C NMR (CDCl3,
50 MHz) d 19.4, 32.4, 46.4, 120.4, 126.2, 126.3, 126.7, 134.1, 149.0, 159.4, 160.9.
MS-CI m=z 256.104 calcd. for C11H8N2OCl2 (MHþ). IR (KBr): 2931, 2855, 1679,
1600, 1556, 1455. Anal. calcd. for C11H8N2OCl2: C, 51.76; H, 3.14; N, 10.98; Cl,
27.85. Found: C, 51. 75; H, 3.13; N, 10.98; Cl, 27.84.
2,3-Dihydropyrrolo-[(2,1-b)]-quinazolin-9-(1H)-one (8)
A mixture of anthranilic acid (2.0 g, 0.0146 mol), 4-aminobutyric acid (1.5 g,
0.0145 mol), and phosphorus pentoxide (6.0 g, 0.0423 mol) in xylene (200 ml)
(previously dried over P2O5) was cyclized by a method similar to that described
for compounds 7a. The resulting solution was extracted with ether (3 ꢁ 100 ml),
and the ether extract was dried over anhydrous sodium sulfate. Removal of solvent
in vacuo gave a white solid (980 mg), which on crystallization from benzene and pet-
roleum ether provided 857 mg (82%) of 8 as a white solid: mp 196–197 ꢀC. Anal.

1008
B. OJO AND B. K. CHOWDHURY
calcd. for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C, 70.94; H, 5.39; N,
1
15.07. H NMR (CDCl3): d 2.21–2.36 (m, J ¼ 7.94, 7.21 Hz, 2H, NCH2CH2CH2),
3.18 (t, J ¼ 7.94 Hz, 2H, NCH2CH2CH2), 4.21 (t, J ¼ 7.21 Hz, 2H, NCH2CH2CH2),
7.40–7.48 (m, 1H, ArH), 7.62–7.77 (m, 2H, ArH), 8.26 (dd, J ¼ 8.00, 1.14 Hz, 1H,
ArH). 13C NMR (CDCl3, 50 MHz) d 19.4, 32.4, 46.4, 120.4, 126.2, 126.3, 126.7,
134.1, 149.0, 159.4, 160.9. MS-CI m=z 187.213 calcd. for C11H10N2O (M þ 1). IR
(KBr): 2931, 2855, 1679, 1600, 1556, 1455. Anal. calcd. for C11H10N2O: C, 70.95;
H, 5.41; N, 15.04%. Found: C, 70.94; H, 5.39; N, 15.07%.
ACKNOWLEDGMENTS
The authors thank Gabrielle Jones and Octavia Felton for their assistance
during the preparation of this manuscript and the National Institutes of Health
(NIH=NIGMS) for support of this work.
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