An Expedient Synthesis of Benzo[h]quinazolin-4(3H)-one: Structure of Samoquasine A Revisited

Article abstract of DOI:10.1055/s-2003-42409

An expedient four-step synthesis of benzo[h]quinazolin-4(3H)-one (1) starting from 1-tetralone is reported. The claimed identity of samoquasine A with perlolidine (4) has been discussed in the light of the present synthesis.

Full text of DOI:10.1055/s-2003-42409

2
292
SHORT PAPER
An Expedient Synthesis of Benzo[h]quinazolin-4(3H)-one: Structure of
Samoquasine A Revisited
a
a
b
S
M
ynthesisof Benzo[
h
]q
a
uinazolin-
4
n
(3
H
)-one
:
S
a
tructure of
sS amoquasine
AC
Revisited hakrabarty,* Sandipan Sarkar, Yoshihiro Harigaya
a
Department of Chemistry, Bose Institute, 93/1, A.P.C. Road, Kolkata 700009, India
Fax +91(33)23506790; E-mail: chakmanas@yahoo.co.in
b
School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan
Received 24 June 2003
In view of this structural controversy and the reported5
low overall yield (34%) of synthetic 1, we have developed
a new and expedient synthesis of 1 in a higher overall
yield, which we report herein.
Abstract: An expedient four-step synthesis of benzo[h]quinazolin-
4
(3H)-one (1) starting from 1-tetralone is reported. The claimed
identity of samoquasine A with perlolidine (4) has been discussed
in the light of the present synthesis.
Keywords: thiourea, condensation, heterocycles, natural products, Since the most general pyrimidine ring synthesis involves
sulfur, dehydrogenations
the reaction of a 1,3-dicarbonyl compound with a suitable
N–C–N fragment, we planned to condense an appropriate
7
-
keto ester with thiourea and desulphurise the resulting
Benzo[h]quinazolines, their 5,6-dihydro derivatives and 2-mercapto-4-pyrimidinone. Following Krapcho’s meth-
8
the corresponding quinazolin-4(3H)-ones constitute a od of -ethoxycarbonylation of cycloheptanone, 1-tetra-
small group of heterocycles which are important either lone was converted to its 2-methoxycarbonyl derivative
1
a–e
9
from the synthetic viewpoint,
e.g. for the preparation (6) in excellent yield by treatment with sodium hydride
1
b
1
of the triazasteroidal skeleton, or as bioactive com- and dimethyl carbonate. Compound 6 was found from H
pounds, e.g. antitumor or antidepressive agents and in- NMR data to exist as an equimolar mixture of the keto and
hibitors of platelet aggregation. A new cytotoxic enol tautomers (see Experimental). Condensation of 6
2
a,b
3
alkaloid, designated samoquasine A, was isolated by a with thiourea efficiently provided 1,2,5,6-tetrahydro-2-
Japanese group from the seeds of custard apple (Annona thioxobenzo[h]quinazolin-4(3H)-one (7). Desulfurisation
squamosa) and was identified as ‘3,4-dihydroben- of 7 by Raney nickel (W2) produced the 5,6-dihydro de-
zo[h]quinazolin-4-one’ (1) (Figure 1) from detailed spec- rivative of 1, i.e. 5,6-dihydrobenzo[h]quinazolin-4(3H)-
4
troscopic analysis. Although the 2-methyl (2) and 2-ethyl one (8) in very good yield. Subsequent dehydrogenation
1
d
(
3) derivatives of 1 are known synthetically, the parent of 8 by 10% palladised charcoal in refluxing ortho-dichlo-
molecule 1 appeared not to have been synthesised until robenzene furnished the target molecule (1) in an overall
then, which prompted a Taiwanese group to report a new yield of 43.5% starting from 1-tetralone (Scheme 1). The
5
1
13
synthesis of 1–3. They concluded in this report that
H and C NMR spectral data of our final product agreed
samoquasine A was definitely different from 1 and also quite well with those reported for 1 by the Taiwanese
from perlolidine (4), isolated earlier from rye grass and group.5
6a,b
5
this time from A. squamosa. They further suggested the
Our work reaffirms the non-identity of samoquasine A
with 1, in agreement with the Taiwanese observation. Per-
tinently, the original Japanese workers have published in
benzo[f]phthalazin-4(3H)-one structure (5) for samo-
quasine A.
Figure 1
Scheme 1 Reagents and conditions: i) NaH, Me CO , 115 °C, 5 h;
2
3
HCl (3 M); ii) NaOMe, MeOH, SC(NH ) , reflux, 10 h; glacial HO-
2
2
SYNTHESIS 2003, No. 15, pp 2292–2294
x
x.
x
x
.
2
0
0
3
Ac; iii) Raney Ni (W2), EtOH, reflux, 4 h; iv) 10% Pd–C, o-C H Cl ,
6
4
2
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42409; Art ID: P05403SS
Georg Thieme Verlag Stuttgart · New York
reflux, 48 h
©

SHORT PAPER
Synthesis of Benzo[h]quinazolin-4(3H)-one: Structure of Samoquasine A Revisited
2293
the meantime a brief statement (in ‘Additions and Correc- 2.2 mmol) was added to the above solution and refluxed for 10 h.
1
0
The solvent was distilled off and the residue was dissolved in hot
tions’ of a journal) that they identified samoquasine A as
perlolidine (4) and, therefore, withdrew this trivial name
samoquasine A. This identity remains highly doubtful to
us particularly on the following grounds: (a) samoquasine
A was reported not to melt up to 300 °C whereas perloli-
dine had a melting point of 280–282°C, (b) samoquasine
A was freely soluble in chloroform, but the NMR data of
H O (50 mL). Glacial HOAc (5 mL) was added dropwise to make
2
the solution acidic when a white fluffy solid was formed. It was fil-
tered, washed successively with sat. aq NaHCO (3 × 10 mL) and
3
H O, dried (Na SO ) and crystallised from EtOAc to afford 7.
2
2
4
Yield: 0.303 g (66%); white needles; mp 260–262 °C.
–
1
IR (Nujol): 3429, 1666, 1566, 1228, 1149, 764 cm .
perlolidine could not be measured in CDCl and had to be 1H NMR (DMSO-d
recorded in pyridine-d , and (c) samoquasine A displayed
C NMR signal at = 101.6 but perlolidine did not
record any signal in this region.
): = 12.479 (s, 1 H, NH), 12.233 (s, 1 H, NH),
3
6
5
7.973 (d, 1 H, J = 7.5 Hz, H-10), 7.405 (t, 1 H, J = 7 Hz, H-8),
5
1
3
7.270–7.36 (m, 2 H, H-7, 9), 2.775 (t, 2 H, J = 7 Hz, CH -6), 2.459
2
a
(
t, 2 H, J = 7 Hz, CH -5).
2
1
3
C NMR (DMSO-d ): = 176.0 (C-2), 161.6 (C-4), 145.2 (C-10b),
6
To conclude, we have developed a new, expedient and
more efficient synthesis of 1, which sheds some light on
the existing structural controversy about samoquasine A
and can also be utilised for the preparation of 4-amino- or
alkylaminobenzo[h]quinazolines and benzo[h]-quinazo-
lin-2,4-diones.
1
1
39.8 (C-6a), 131.8 (CH-8), 129.1 (CH-7), 127.5 (CH-9), 126.7 (C-
0a), 125.7 (CH-10), 112.5 (C-4a), 27.5 (CH -6), 19.4 (CH -5).
2
2
+
MS: m/z (%) = 230 (M , 100), 229 (100), 212 (90), 201 (22), 186
23), 170 (21), 169 (17), 143 (43), 128 (34), 115 (70).
(
HRMS: m/z calcd for C H ON S: 230.0514; found: 230.0498
1
2
10
2
+
(
M ).
5
,6-Dihydrobenzo[h]quinazolin-4(3H)-one (8)
Mps were determined on a Toshniwal apparatus and are uncorrect-
ed. IR spectra were recorded on a Nicolet Impact 410 spectropho-
tometer, LR EI-MS in AEI MS 30 and JEOL JMS-AX505HA, HR
FAB-MS (using m-nitrobenzyl alcohol as liquid matrix) in JEOL
1
1
Raney Ni (W2) (two spatulas) was added to a solution of 6 (0.460
g, 2 mmol) in dehydrated EtOH (20 mL) and the mixture was re-
fluxed for 4 h. The mixture was filtered hot through a Celite bed and
washed with hot EtOAc (2 × 10 mL). The solvent was distilled off
to furnish a white fluffy solid. After purification by column chroma-
tography (PE–EtOAc, 1:4), the product was crystallised from
EtOAc to give 8.
1
13
JMS-700 MStation mass spectrometers, H (500 MHz) and C (125
MHz) NMR spectra, both 1D and 2D, including DEPT 135, in a
1
13
Bruker DRX 500 NMR spectrometer. Individual H and C NMR
assignments, wherever made, are based on HMQC and HMBC
spectral analyses. Column chromatography was performed on silica
gel (60–120 mesh, Qualigens, India) and TLC was carried out on
silica gel G (Merck, India) plates. PE refers to petroleum ether boil-
ing at 60–80°C.
Yield: 0.336 g (85%); white needles; mp 234°C.
IR (Nujol): 3314, 1652, 1559, 1222, 1149, 751 cm–1.
1H NMR (DMSO-d6): = 12.426 (s, 1 H, NH), 8.144 (s, 1 H, H-2),
8
.032 (d, 1 H, J = 7 Hz, H-10), 7.344 (t, 1 H, J = 6.5 Hz, H-8), 7.311
t, 1 H, J = 8.5 Hz, H-9), 7.261 (d, 1 H, J = 6.5 Hz, H-7), 2.825 (t, 2
H, J = 7.5 Hz, CH -6), 2.646 (t, 2 H, J = 7.5 Hz, CH -5).
(
Methyl 1-Oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6)
Sodium hydride (2.76 g, 60% suspension in mineral oil) was freed
from the oil by washing with anhyd benzene (3 × 10 mL), and
2
2
13
C NMR (DMSO-d ): = 161.9 (C-4), 154.3 (C-10b), 148.3 (CH-
6
Me CO (10 mL) was added to it. A solution of 1-tetralone (4.38 g,
2
3
2), 139.0 (C-6a), 133.1 (C-10a), 130.9 (CH-8), 128.8 (CH-7), 127.6
(CH-9), 125.8 (CH-10), 120.8 (C-4a), 27.1 (CH -6), 19.9 (CH -5).
3
0 mmol) in Me CO (10 mL) was added dropwise to the above so-
2 3
2
2
lution at 90 °C. The resulting cake was heated at 115°C for 5 h. The
mixture was cooled in ice and treated successively with MeOH (2
+
MS: m/z (%) = 198 (M , 71), 197 (100), 169 (16), 154 (15), 129
24), 115 (16).
(
mL) and HCl (3 M; 100 mL), and extracted with Et O (3 × 20 mL).
2
The organic phase was washed successively with sat. aq NaHCO3,
brine and H O. It was dried (Na SO ), filtered, and the Et O was dis-
HRMS: m/z calcd for C H ON : 198.0793; found: 198.0795 (M+).
12 10 2
2
2
4
2
tilled off from the filtrate. The crude product was purified by col-
Benzo[h]quinazolin-4(3H)-one (1)
umn chromatography (PE–EtOAc, 9:1) to furnish 6.
A solution of 8 (0.198 g, 1 mmol) in hot o-C H Cl (7 mL) contain-
6
4
2
ing 10% Pd/C (0.60 g) was refluxed for 48 h when 8 was consumed
TLC). The mixture was filtered hot through a Celite bed and
washed with hot EtOAc (2 × 10 mL). The solvent was distilled off
from the pooled filtrates under reduced pressure to furnish a yellow-
ish fluffy solid, which was crystallised from EtOAc to give 1.
Yield: 5.9 g (96%); straw-yellow coloured oil.
(
–
1
IR (film): 1745, 1686, 1646, 771 cm .
1H NMR (CDCl3): = 12.401 (s, 1 H, enolic OH), 8.035 (d, 1 H,
J = 8 Hz, H-8/5), 7.791 (d, 1 H, J = 7 Hz, H-8/5), 7.234 (d, 1 H,
J = 8 Hz, H-8/5), 7.157 (d, 1 H, J = 8 Hz, H-8/5), 7.479 (td, 1 H,
J = 7.5, 1 Hz, H-6/7), and 7.312 (t, 1 H, J = 7 Hz, H-6/7), 7.308 (t,
5
Yield: 0.156 g (80%); pale yellow flakes; mp 304–306°C (lit. mp
2
44–245 °C).
1
3
H each, J = 7 Hz, H-6/7), 7.266 (t, 1 H, J = 7 Hz, H-6/7), 3.811 (s,
H, CO Me), 3.769 (s, 3 H, CO Me), 3.613 (dd, 1 H, J = 10, 5 Hz,
–
1
IR (KBr): 1662, 1610, 1624, 1232, 771 cm .
2
2
1
H-2 of keto form), 3.1–2.9 (m, 2 H, CH -4 of keto form), 2.796 (t,
H NMR (DMSO-d ): = 12.473 (s, 1 H, NH), 8.893 (d, 1 H, J = 8
2
6
2
H, J = 7.5 Hz, CH -4 of enol form) and 2.556 (t, 2 H, J = 7.5 Hz,
Hz, H-10), 8.347 (s, 1 H, H-2), 8.05 (d, 1 H, J = 8.5 Hz, H-5), 8.025
(d, 1 H, J = 8 Hz, H-7), 7.922 (d, 1 H, J = 8.5 Hz, H-6), 7.751 (t, 1
H, J = 7 Hz, H-9), 7.708 (t, 1 H, J = 7.5 Hz, H-8).
13
2
CH -3 of enol form), 2.53–2.44 (m, 1 H, CH -3 of keto form), 2.38–
2
2
2
.30 (m, 1 H, CH -3 of keto form).
2
+
MS: m/z (%) = 204 (M , 78), 173 (72), 145 (100), 117 (94), 115
C NMR (DMSO-d ): = 161.7 (C-4), 148.0 (C-10b), 147.1 (CH-
6
(
64), 114 (90).
2), 136.4 (C-6a), 130.2 (C-10a), 130.0 (CH-8), 128.8 (CH-7), 127.9
(CH-9), 127.5 (CH-6), 125.4 (CH-10), 122.0 (CH-5), 119.8 (C-4a).
1
,2,5,6-Tetrahydro-2-thioxobenzo[h]quinazolin-4(3H)-one (7)
+
MS: m/z (%) = 196 (M , 100), 169 (20), 140 (24), 114 (12).
A solution of 6 (0.408 g, 2 mmol) in anhyd MeOH (5 mL) was add-
ed to NaOMe (0.115 g sodium in 2 mL MeOH). Thiourea (0.167 g,
Synthesis 2003, No. 15, 2292–2294 © Thieme Stuttgart · New York

2
294
M. Chakrabarty et al.
SHORT PAPER
Acknowledgements
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The authors express their sincere thanks to the Director, Bose Insti-
tute for providing laboratory facilities, to Mr. B. Majumdar, NMR
Facilities, B. I. for recording the spectra and to the C.S.I.R., Govt.
of India for providing a Senior Research fellowship (S.S.).
(
(
(
4) Morita, H.; Sato, Y.; Chan, K.-L.; Choo, C. Y.; Itokawa, H.;
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6) (a) Reifer, I.; White, E. P. N. Z. J. Sci. Technol., Sect. B
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1
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Synthesis 2003, No. 15, 2292–2294 © Thieme Stuttgart · New York