A concise and cascade synthesis of batracylin and substituted isoindolo-[1,2- b ]quinazolin-12(10 H)-ones

Article abstract of DOI:10.1055/s-0030-1259921

A concise, highly convergent, and practical synthesis of the clinical-phase anticancer agent batracylin in a two-stage process in excellent yield is described. The B and C rings of this tetracyclic heterocycle are constructed by cascade cyclization of 5-nitro-2-aminobenzyl alcohol with 2-cyanomethyl benzoate in trifluoroacetic acid in good yield in a single-pot reaction. A plausible mechanism for the cascade reaction is also proposed. As part of these studies, a range of batracylin derivatives with different substituents on the C and D rings are synthesized. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259921

844
LETTER
A Concise and Cascade Synthesis of Batracylin and Substituted Isoindolo-
[1,2-b]quinazolin-12(10H)-ones
S
ynthesisof Batr
.
acylin Shankar,a Manoj Balu Wagh,a M. V. Madhubabu,a N. Vembu,b U. K. Syam Kumar*a
a
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad, 500049, India
Fax +91(40)23045439; fax +91(40)23045438; E-mail: syam_kmr@yahoo.com
b
Urumu Dhanalakshmi College, Tiruchirappalli 620019, India
Received 28 October 2010
This paper is dedicated to Prof. H. Ila on the occasion of her 67th birthday
O
10
9
Abstract: A concise, highly convergent, and practical synthesis of
H2N
8
N
N
the clinical-phase anticancer agent batracylin in a two-stage process
in excellent yield is described. The B and C rings of this tetracyclic
heterocycle are constructed by cascade cyclization of 5-nitro-2-ami-
nobenzyl alcohol with 2-cyanomethyl benzoate in trifluoroacetic
acid in good yield in a single-pot reaction. A plausible mechanism
for the cascade reaction is also proposed. As part of these studies, a
range of batracylin derivatives with different substituents on the C
and D rings are synthesized.
D
C
N
B
7
A
N
6
OH
1 batracylin
2 (–)-vasicine
R
O
N
N
O
N
N
Key words: batracylin, antineoplastic agents, cascade cyclization,
5-nitro-2-aminobenzyl alcohol
N
O
3 tryptanthrin
4a R = H, luotonin A
4b R = OH, luotonin B
4c R = OMe, luotonin E
Batracylin (8-aminoisoindolo[1,2-b]quinazolin-12(10H)-
one); NSC320846, 1) is an anticancer agent synthesized
by Kabbe in 1978.1 It is currently undergoing clinical
evaluation as an anticancer agent at the National Cancer
Institute.2 Batracylin exhibits in vivo antineoplastic activ-
ity against murine leukemia P-388, and is shown to inhibit
tumor growth completely in 80–100% of mice with early-
stage colon adenocarcinoma.3 Animal studies have also
shown that batracylin has effective oral activity against
solid tumors (implanted colon adenocarcinomas, pancre-
atic ductal carcinomas, hepatoma 129) and adriamycin,
cisplatin, and methotrexate-resistant P388 leukemia.4
Structurally batracylin is a quinazoline fused onto an
isoindolone moiety. Similar structures are present in sev-
eral natural products of great pharmacological interest in-
cluding (–)-vasicine (2)5 and tryptanthrin (3)6 which have
anti-inflammatory activity, and lutonins 4a–c7 which has
antitumoural activity (Figure 1). The major limitations to
the chemotherapeutic potential of batracylin (1) are the
high level of dose required for its antineoplastic activity
and its systemic toxicity, especially in rats.
Figure 1
halides or benzyl amine 7. This intermediate 2-(2,5-di-
aminobenzyl)isoindoline-1,3-dione (5) upon cyclodehy-
dration under different reaction conditions results in
batracylin in varying yields.9 Malacria et al. utilized an
amide-iminyl radical 8 cyclization protocol in their ap-
proach to the batracylin framework10 (Figure 2).
O
O
H2N
H2N
H+
N
N
O
H2O
NH2
N
1 batracylin
5
O
X
O
R3
R1
N
R2
N
O
6a X = O
7a R1 = OH, R2 = NO2, R3 = NO2
8
6b X = NH 7b R1 = Cl, R2 = NO2, R3 = NH2
7c R1 = Cl, R2 = NO2, R3 = NO2
Batracyclin (1) is known to undergo reversible hydrolytic
cleavage to produce ring-opened 2-(2,5-diaminoben-
zyl)isoindoline-1,3-dione (5) under acidic hydrolytic con-
ditions.8 Most of the reported synthetic approaches to
batracylin thus utilize 2-(2,5-diaminobenzyl)isoindoline-
1,3-dione (5) as the key intermediate, which is synthe-
sized by the reaction of either phthalic anhydride (6a) or
phthalimide (6b) with appropriately substituted benzyl
Figure 2
Herein we report a highly concise and convergent cascade
synthesis of batracylin (1) in a two-step process in very
high isolated yield. The methodology employed in our to-
tal synthesis of batracylin and its derivatives is depicted in
the retrosynthetic scheme (Scheme 1). The reduction of
nitro group in 9 to an amine functionality would yield
batracylin (1). The (8-nitro-isoindolo[1,2-b]quinazolin-
SYNLETT 2011, No. 6, pp 0844–0848
x
x.
x
x.
2
0
1
1
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259921; Art ID: D29010ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Batracylin
845
12(10H)-one (9) could be synthesized via the reaction of was confirmed by means of IR and NMR spectroscopy
2-methyl cyanobenzoate (10) with 2-amino-5-nitrophenyl and mass spectroscopy.13
methanol (11) under acidic conditions.
OH
O
O
O
TFA
O
N
OMe
N
70–75 °C
O2N
H2N
+
N
N
10–12 h
NH2
N
N
N
10
11
12
(62%)
1 batracylin
9
Scheme 2
O
O2N
The intermediate methyl 2-{N-[2-(hydroxymethyl)phe-
nyl]carbamimidoyl}benzoate (13) is assumed to be
formed by nucleophilic attack of amine 11 on the nitrile
functionality of 10 under acidic reaction conditions
(Scheme 3). In path a, the cycloamidation of the interme-
diate 13 via the elimination of methanol results in the for-
mation of iminoisoindolinone derivative 14. Intermediate
14 on loss of water yields the triene 15, which on electro-
cyclization under thermal conditions can lead to the for-
mation of isoindolo[1,2-b]quinazolin-12(10H)-one (12).
Conversely, iminoamine 13 (path b) under SN1 reaction
conditions results in carbocation 16, which further leads
to the formation of methyl 2-(3,4-dihydroquinazolin-2-
yl)benzoate (17). The cycloamidation of 17 along with
concomitant elimination of methanol gives 12. In path c,
the triene 13a is assumed to be the key intermediate,
which on electrocyclization under thermal reaction condi-
tions results in methyl 2-(3,4-dihydroquinazolin-2-
yl)benzoate (17). The cycloamidation of 17 with loss of
methanol yields 12.
OH
OMe
+
NH2
CN
11
10
Scheme 1
To test the validity of our disconnection approach, the cas-
cade cyclization reaction was attempted for the synthesis
of de-amino batracylin, isoindolo[1,2-b]quinazolin-
12(10H)-one (12, Scheme 2). 2-Methyl cyanobenzoate 10
was prepared by cyanation of commercially available me-
thyl iodobenzoate with Cu(I)CN in acetonitrile as report-
ed in the literature.11 The cascade cyclization was
attempted initially in various organic acids such as formic
and acetic acid, under neat conditions, and also in combi-
nation with other solvents at elevate temperatures, but
these attempts did not furnish the desired product. The re-
action was also performed in PTSA/toluene combina-
tions, and in various Lewis acids such as BF3·OEt2, SnCl4,
and TiCl4 in suitable solvents or under solvent-free condi-
tions, but resulted in either unidentifiable product mix-
tures or unreacted or hydrolyzed starting materials.
However, when the reaction was carried out in anhydrous
trifluoroacetic acid at 70–75 °C, complete disappearance
of starting materials was observed within 10–12 hours
along with formation of a single major product and work-
up and isolation gave pure product 12 in 62% yield.12 The
structure of isoindolo[1,2-b]quinazolin-12(10H)-one (12)
Encouraged by these results, batracylin derivatives 24–29
were synthesized (Table 1).14 All the reactions are per-
formed in a single-pot operation in trifluoroacetic acid at
70–75 °C over a period of 10–16 hours.
The isolated yields of these products provide some insight
into the reaction mechanism, indicating that the reaction
might have proceeded preferentially via path b. The ami-
no alcohols 22 and 23 forms stable carbocations under
H+
path a
H+
MeO
O
O
O
OH
OH
••
NH
NH
N
– H2O
– H+
– MeOH
– H+
N
HN
13
N
15
MeO
14
MeO
MeO
O
– H+
N
MeO
O
O
O
O
path b
TFA
+
OH2
– MeOH
NH
NH
N
HN
70–75 °C
– H+
– H2O
– H+
H2N
10
••
•
N
HN
N
HN
OH
16
17
12
13
11
MeO
MeO
MeO
– MeOH
O
O
O
+
path c
OH2
HN
NH
NH
– H2O
– H+
••
N
HN
N
17
13
13a
Scheme 3
Synlett 2011, No. 6, 844–848 © Thieme Stuttgart · New York

846
R. Shankar et al.
LETTER
Table 1 Synthesis of Isoindolo[1,2-b]quinazolin-12(10H)-one
Entry
1
Aminobenzyl alcohol
Cyanomethyl benzoate Batracylin derivative
Yield (%)
63
Mp (°C)
O
O
Br
Br
HO
N
OMe
214
213
243
278
H2N
N
CN
18
10
10
24
25
26
27
O
O
O
HO
N
N
N
2
3
4
57
54
53
H2N
F
N
N
N
F
19
HO
H2N
10
10
20
F
F
F
F
HO
H2N
21
O
O
5
6
10
10
72
70
210
123
N
N
HO
N
N
H2N
22
28
29
HO
H2N
23
NO2
O
MeO
SN1 reaction conditions, and this is consistent with the for-
mation of isoindolo[1,2-b]quinazoline 28 and 29 in higher
yields. The electron-withdrawing effect of the fluoro sub-
stituents would destabilize the carbocations derived from
amino alcohols 21 and 19 and the isoindolo[1,2-
b]quinazolines 27 and 25 are formed from these starting
materials in comparatively lower yields.
NO2
N
LAH
+
H2N
H2N
THF, 0–10 °C
60%
O
OMe
OH
30
11
10
TFA, 70–75 °C
10–12 h
47%
For the synthesis of batracylin (Scheme 4), the required 2-
aminonitrophenyl methanol (11) was synthesized by the
reduction of corresponding benzoic acid methyl ester
30.15 The cascade reaction of 11 with 2-methyl cyanoben-
zoate (10) in the presence of trifluoroacetic acid at 70–
75 °C resulted in 8-nitroisoindolo[1,2-b]quinazolin-
12(10H)-one (9) in 47% yield of analytically pure product
within 13–15 hours. Reduction of the nitro functionality
in 9 was carried out with ammonium formate–Pd/C and
afforded batracylin (1) in 90% yield as a yellow solid (mp
280–282 °C; lit. 287–288 °C9b)16 with spectroscopic and
analytical data in agreement with the literature.17
O
O
H2N
O2N
Pd/C
N
N
N
N
NH4OAC, MeOH
90%
1
9
Scheme 4
In summary, a highly convergent cascade process has
been developed for the synthesis of batracylin and its an-
alogues in excellent yield. The novel synthetic approach
Synlett 2011, No. 6, 844–848 © Thieme Stuttgart · New York

LETTER
Synthesis of Batracylin
847
(11) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7,
95.
involves assembly of the B and C rings of batracylin under
acidic conditions. Compared with the known methods of
batracylin synthesis, the present synthesis provides a new
unique cascade route to batracylin and its substituted
isoindolo[1,2-b]quinazolin-12(10H)-one derivatives from
easily accessible precursors. This novel methodology ap-
pears to be well suited for preparation of simple congeners
and several analogues that may prove useful in defining a
pharmacological profile of this class of batracylin and its
derivatives. We are further exploring the application of
this cascade reaction sequence for the synthesis of other
naturally occurring compounds having the isoindolo[1,2-
b]quinazoline frame work.
(12) A solution of methyl 2-cyanobenzoate (0.5 g, 0.003 mol), 2-
aminophenylmethanol (0.57 g, 0.0047 mol) in TFA (10 mL)
was refluxed for 10–12 h, and the progress of the reaction
was monitored by TLC. After complete disappearance of the
starting material, the reaction was quenched with ice water
and the aqueous layer extracted with CH2Cl2 (2 × 10 mL).
The combined extracts washed with aq NaHCO3 (10%, 25
mL) dried over anhyd Na2SO4, filtered, and concentrated
under vacuum. The crude product was then purified by
column chromatography using CH2Cl2 as an eluent; yield
0.43 g (62%).
(13) Isoindolo [1,2-b]Quinazolin-12(10H)-one (12)
Yield 62%; mp 186 °C (lit. 175–177 °C);8 IR (KBr): 1724,
1650 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.08 (d, J = 7.6
Hz, 1 H, ArH), 7.90 (d, J = 6.7 Hz, 1 H, ArH), 7.74–7.63 (m,
2 H, ArH), 7.51 (d, J = 8.0 Hz, 1 H, ArH), 7.34–7.18 (m, 3
H, ArH), 5.00 (s, 2 H, CH2) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 166.2, 148.7, 140.0, 134.0, 133.2, 132.4,
130.1, 128.4, 127.4, 127.3, 127.2, 122.8, 121.9, 121.2, 40.2
ppm. MS: m/z (%) = 235.2 [M + H]+. Anal. Calcd for
C15H10N2O (234.2): C, 76.91; H, 4.30; N, 11.96; O, 6.83.
Found: C, 76.83; H, 4.25, N, 4.26, O, 6.70.
(14) 8-Bromoisoindolo[1,2-b]quinazolin-12(10H)-one (24)
Yield 63%; mp 214 °C. IR (KBr): 1731, 1645 cm–1. 1H NMR
(500 MHz, DMSO-d6): d = 8.02 (d, J = 7 Hz, 1 H, ArH), 7.90
(d, J = 7 Hz, 1 H, ArH), 7.84–7.77 (m, 2 H, ArH), 7.57 (s, 1
H, ArH), 7.51 (dd, J = 8.2, 1.5 Hz, 1 H, ArH), 7.34 (d,
J = 8.5 Hz, 1 H, ArH), 4.93 (s, 2 H, CH2) ppm. 13C NMR
(100 MHz, CDCl3): d = 165.9, 149.2, 139.3, 133.7, 133.1,
132.4, 131.1, 129.8, 128.8, 124.4, 122.7, 121.9, 119.5, 40.7
ppm. MS: m/z (%) = 313.1 [M + H]+. Anal. Calcd for
C15H9BrN2O (311.99): C, 57.53; H, 2.90; N, 8.95; O, 5.11.
Found: C, 57.48; H, 2.85; N, 8.85; O, 5.1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors would like to thank Dr. Vilas H. Dahanukar for his con-
stant encouragement and support. We also thank the analytical de-
partment, Dr. Reddy’s Laboratories, for providing the analytical
support.
References and Notes
(1) Kabbe, H. J. Justus Liebigs Ann. Chem. 1978, 398.
(2) (a) Plowman, J.; Paul, K. D.; Atassi, G.; Harrison, S. D.;
Dykes, D. J.; Kabbe, H. J.; Narayanan, V. L.; Yoder, O. C.
Invest. New Drugs 1988, 6, 147. (b) Dzierzbicka, K.;
Trzonkowski, P.; Sewerynek, P. L.; Mysliwski, A. J. Med.
Chem. 2003, 46, 978. (c) Guillaumel, J.; Léonce, S.; Pierre,
A.; Renard, P.; Pfeiffer, B.; Arimondo, P. B.; Monneret, C.
Eur. J. Med. Chem. 2006, 379. (d) Yilin, R.; Yun Feng, C.;
Ting, C.; Chen, A. Y.; Yu, C.; Liu, L. F.; Cheng, C. C.
Pharm. Res. 1993, 10, 918.
(3) Waud, W. R.; Hamson, S. D.; Gilbert, K. S.; Laster, W. R.;
Griswold, D. P. Cancer Chemother. Pharmacol. 1991, 27,
456.
(4) Mucci-LoRusso, P.; Polin, L.; Bissery, M. A.; Valeriote, F.;
Plowman, J.; Luk, G. D.; Corbett, T. H. Invest. New Drugs
1989, 7, 295.
7-Fluoroisoindolo[1,2-b]quinazolin-12(10H)-one (25)
Yield 57%; mp 213 °C. IR (KBr): 1729, 1646 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.06 (d, J = 7.2 Hz, 1 H, ArH), 7.92
(d, J = 6.8 Hz, 1 H, ArH), 7.75–7.69 (m, 2 H, ArH), 7.22 (dd,
J = 2.4, 9.6 Hz, 1 H, ArH), 7.19–7.12 (m, 1 H, ArH), 6.98–
6.93 (m, 1 H, ArH), 4.95 (s, 2 H, CH2) ppm. 13C NMR (100
MHz, CDCl3): d = 166.8, 149.9, 142.1, 133.0, 132.6, 132.3,
131.6, 131.1, 130.4, 127.8, 127.7, 123.5, 123.2, 122.3, 40.3
ppm. MS: m/z (%) = 253.2 [M + H]+. Anal. Calcd for
C15H9FN2O (252.07): C, 71.42; H, 3.60; N, 11.11; O, 6.34.
Found: C, 71.34; H, 3.50; N, 11.01; O, 6.29.
(5) (a) Amin, A. H.; Mehta, D. R.; Samarth, S. S. Prog. Drug
Res. 1970, 14, 218. (b) Gupta, O. P.; Anand, K. K.;
Ghattak Ray, B. J.; Atal, C. K. Indian J. Exp. Biol. 1978, 16,
1075.
9-Methylisoindolo[1,2-b]quinazolin-12(10H)-one (26)
Yield 54% mp 243 °C. IR (KBr): 1721, 1650 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 8.04 (d, J = 6.8 Hz, 1 H, ArH),
7.92–7.78 (m, 3 H, ArH), 7.26–7.24 (m, 2 H, ArH), 7.14–
7.10 (m, 1 H, ArH), 4.85 (s, 2 H, CH2), 2.49 (s, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): d = 166.8, 148.4, 139.8,
135.4, 134.1, 132.8, 132.0, 130.4, 129.3, 128.3, 125.7,
123.1, 122.3, 119.8, 39.4, 18.1 ppm. MS: m/z (%) = 249.2
[M + H]+. Anal. Calcd for C16H12N2O (248.09): C, 77.40; H,
4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.78; N, 11.19;
O, 6.35.
7,8-Difluoroisoindolo[1,2-b]quinazolin-12(10H)-one (27)
Yield 53%; mp 278 °C. IR (KBr): 1729, 1647 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.04 (d, J = 7.6 Hz, 1 H, ArH), 7.9
(d, J = 6.8 Hz, 1 H, ArH), 7.75–7.68 (m, 2 H, ArH), 7.34 (m,
1 H, ArH), 7.00 (t, 8.8 Hz, 1 H, ArH), 4.90 (s, 2 H, CH2)
ppm. 13C NMR (100 MHz, CDCl3): d = 180.0, 158.5, 141.2,
133.2, 132.5, 130.3, 123.4, 122.4, 116.9, 115.4, 110.0, 40.3
ppm. MS: m/z (%) = 271.2 [M + H]+. Anal. Calcd for
C15H8F2N2O (270.06): C, 66.67; H, 2.98; N, 10.37; O, 5.92.
Found: C, 66.58; H, 2.87; N, 10.29; O, 5.83.
(6) (a) Mitscher, L. A.; Wong, W.-C.; DeMeulenaere, T.;
SulkoT, ; Drake, S. Heterocycle 1981, 15, 1017.
(b) Mitscher, L. A.; Baker, W. Med. Res. Rev. 1998, 18, 363.
(7) (a) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J.
Heterocycles 1997, 46, 541. (b) Ma, Z. Z.; Hano, Y.;
Nomura, T.; Chen, Y. J. Heterocycles 1999, 51, 1883.
(8) Ames, M. M.; Mathiesen, D. J. Chromatogr. 1989, 491, 488.
(9) (a) Meegalla, S. K.; Stevens, G. J.; McQueen, C. A.; Chen,
A. Y.; Yu, C.; Liu, L. F.; Barrows, L. R.; LaVoie, E. J.
J. Med. Chem. 1994, 37, 3434. (b) Rosevear, J.; Wilshire,
J. F. K. Aust. J. Chem. 1990, 43, 339. (c) Martínez-Viturro,
C. M.; Domínguez, D. Tetrahedron Lett. 2007, 48, 1023.
(10) (a) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.;
Malacria, M. Angew. Chem. Int. Ed. 2007, 46, 576.
(b) Beaume, A.; Courillon, C.; Derat, E.; Malacria, M.
Chem. Eur. J. 2008, 16, 1228.
Synlett 2011, No. 6, 844–848 © Thieme Stuttgart · New York

848
R. Shankar et al.
LETTER
10-Phenylisoindolo[1,2-b]quinazolin-12(10H)-one (28)
Yield 72%; mp 210 °C. IR (KBr): 1732, 1646 cm–1. 1H NMR
(500 MHz, DMSO-d6): d = 8.10 (d, J = 7.5 Hz, 1 H, ArH),
7.88–7.78 (m, 3 H, ArH), 7.49 (d, J = 7.0 Hz, 1 H, ArH),
7.35–7.21 (m, 8 H, ArH), 6.47 (s, 1 H, CH) ppm. 13C NMR
(100 MHz, DMSO-d6): d = 174.8, 165.9, 153.2, 143.1,
138.9, 133.9, 133.8, 132.8, 129.7, 128.8, 128.7, 128.1,
127.8, 127.8, 127.3, 126.4, 126.2, 123.2, 122.3, 54.5 ppm.
MS: m/z (%) = 311.2 [M + H]+. Anal. Calcd for C21H14N2O
(310.11): C, 81.27; H, 4.55; N, 9.03; O, 5.16. Found: C,
81.20; H, 4.50; N, 8.92; O, 5.10.
10-Methylisoindolo[1,2-b]quinazolin-12(10H)-one (29)
Yield 70%; mp 123 °C. IR (KBr): 2925, 1728, 1648 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.98 (d, J = 7.6 Hz, 1 H, ArH),
7.81 (d, J = 7.2 Hz, 1 H, ArH), 7.64–7.57 (m, 2 H, ArH),
7.40 (d, J = 8.0 Hz, 1 H, ArH), 7.26–7.21 (m, 1 H, ArH),
7.18–7.15 (m, 1 H, ArH), 7.12 (d, J = 6.8 Hz, 1 H, ArH),
5.41 (q, J = 6.4 Hz, 1 H, CH), 1.51 (d, J = 6.4 Hz, 3 H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): d = 167.0, 149.9, 139.8,
134.5, 132.9, 132.0, 130.6, 128.6, 127.8, 127.7, 127.7,
127.5, 123.2, 122.1, 47.9, 23.6 ppm. MS: m/z (%) = 249.2
[M + H]+. Anal. Calcd for C16H12N2O (248.09): C, 77.40; H,
4.87; N, 11.28; O, 6.44. Found: C, 77.32; H, 4.81; N, 11.20;
O, 6.36.
(15) Kato, T.; Kawamura, K.; Morita, M.; Uchida, C. WO 2005/
049608 A1, 2005.
(16) Eguchi, S.; Goto, S. Heterocycl. Commun. 1999, 1, 1.
(17) 8-Aminoisoindolo[1,2-b]quinazolin-12(10H)-one (1)
Mp 280–282 °C (recrystallized from CH2Cl2). IR (KBr):
3474, 1688, 1645 cm–1. 1H NMR (400 MHz, DMSO-d6): d =
7.95 (d, J = 8.0 Hz, 1 H, ArH), 7.86 (d, J = 6.8 Hz, 1 H,
ArH), 7.78–7.68 (m, 2 H, ArH), 7.13 (d, J = 8.4 Hz, 1 H,
ArH), 6.52 (dd, J = 2.4, 8.2 Hz, 1 H, ArH), 6.46 (s, 1 H,
ArH), 5.54 (s, 2 H, NH2), 4.80 (s, 2 H, CH2) ppm. 13C NMR
(100 MHz, DMSO-d6): d = 165.9, 148.8, 143.8, 134.2,
132.8, 131.3, 129.7, 129.4, 128.8, 122.8, 122.6, 121.2,
113.2, 111.7, 40.3 ppm. MS: m/z (%) = 250.2 [M + H]+.
Anal. Calcd for C15H11N3O (249.09): C, 72.28; H, 4.45; N,
16.86; O, 6.42. Found: C, 72.19; H, 4.38; N, 16.80; O, 6.35.
Synlett 2011, No. 6, 844–848 © Thieme Stuttgart · New York

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