A facile synthesis of simple alkaloids - Synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids

Article abstract of DOI:10.1016/S0040-4039(03)00080-7

An efficient procedure for preparation of the simple alkaloids, 2,3-polymethylene-4(3H)-quinazolinones, luotonin A, tryptanthrin, and rutaecarpine has been established by the reaction of lactam-HCl salts with POCl₃ followed by cyclization with methyl anthranilate.

Full text of DOI:10.1016/S0040-4039(03)00080-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1883–1886
A facile synthesis of simple alkaloids—synthesis of
2,3-polymethylene-4(3H)-quinazolinones and related alkaloids
Eung Seok Lee, Jae-Gyu Park and Yurngdong Jahng*
College of Pharmacy, Yeungnam University, Kyongsan 712-749, South Korea
Received 6 December 2002; revised 8 January 2003; accepted 8 January 2003
Abstract—An efficient procedure for preparation of the simple alkaloids, 2,3-polymethylene-4(3H)-quinazolinones, luotonin A,
tryptanthrin, and rutaecarpine has been established by the reaction of lactam-HCl salts with POCl3 followed by cyclization with
methyl anthranilate. © 2003 Published by Elsevier Science Ltd.
quinazolinones have been pursued.8 Although most of
The 2,3-polymethylene-4(3H)-quinazolinones (1a,b) are
not the only alkaloids isolated from plants,1 but are the
part of a family of intriguing alkaloids including the
bronchodilator vasicinone (2a),2 antiendotoxic isaindig-
otone (2b),3 cytotoxic luotonins (3),4 antibiotic tryptan-
thrin (4),5 and antiinflammatory rutacearpine (3)6 and
related alkaloids.6f
these are applicable to acyclic amides, methods for
cyclic amides, especially without aryl group as a part,
are somewhat limited.8 These limitations have led to the
continuous development of new procedures for cyclic
amides, such as cyclocondensation of isatoic anhydride
and lactams,1c metal catalyzed reductive N-heterocy-
clization of N-(2-nitrobenzoyl)lactams in the presence
of CO,1d,g intramolecular aza-Wittig reaction of N-(2-
azidobenzoyl)lactams,1f,h condensation of anthranilic
acid with O-alkyllactims,1i,k and reaction of anthranilic
Since Niementowski’s preparation of 4(3H)-quinazoli-
none by fusing anthranilic acid with formamide,7 sev-
eral methods aimed toward the synthesis of modified
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(03)00080-7

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E. S. Lee et al. / Tetrahedron Letters 44 (2003) 1883–1886
acid with SOCl2 followed by cyclization with lactams.1j
Nevertheless, up to this point the development of sim-
ple procedures for modified quinazolinone synthesis
relied on the use of rather toxic or expensive reagents.
yield6d while the present procedure afforded 1.4 times
higher yield.
The generality of the scheme was examined with 2-
indolinone (9) to provide the corresponding quinazoli-
none derivative 10 in 82% yield. Two-step conversion of
10 gives the known alkaloid 4 in 76% yield.13
As a part of our research on biologically important
natural products, we herein describe a modified proce-
dure for the efficient preparation of 1 as well as alka-
loids 3a, 4 and 5.
In conclusion, a simple procedure for the preparation
of 2,3-polymethylene-4(3H)-quinazolinones has been
established by reacting lactam-HCl salts with POCl3
followed by cyclization with methyl anthranilate. The
described procedure was applied to the preparation of
two simple alkaloids, luotonin A and rutaecarpine, as
well as indolo[2,1-b]quinoazolin-12(6H)-one, a key
intermediate for the preparation of tryptanthrin.
The synthetic strategy stems from the reactivity of
N-arylbenziminochlorides9 which are known to con-
dense with anthranilic acid and its derivatives to yield
corresponding quinazolinones. We have exploited this
reactivity by employing cyclic iminochlorides (7) as
active intermediates in the synthesis of a series of
modified quinazolinones.
General Procedure: Into a solution of 2-azacyclo-
nonanone (14.1 g, 0.1 mole) in CHCl3 (100 mL) was
passed dry HCl gas. The lactam-HCl salt precipitated
was collected and suspended in POCl3 (30 mL). The
suspension was warmed to 40°C and stirred for 2 h to
give a clear solution. Removal of excess POCl3 in vacuo
afforded an oil, which was neither isolated nor charac-
terized, but instead was dissolved in dry THF (100 mL).
Into this solution was added methyl anthranilate (22.7
g, 0.15 mole). The mixture was stirred for 12 h at room
temperature and diluted with water (80 mL). The reac-
tion mixture was made basic with NH4OH (100 mL)
and extracted with CH2Cl2 (100 mL×3). The organic
layers were combined and dried over MgSO4. Evapora-
tion of the solvent gave a solid which was crystallized
from EtOH to yield 20.56 g (85%) of 7,8,9,10,11,12-
Attempts to directly condense the simple lactams (6) or
their HCl salts with methyl anthranilate or chlorination
of 6 with POCl3 followed by reaction with methyl
anthranilate yielded unsatisfactory results.10 Pretreat-
ment of 6 with either 37.5% HCl or dry HCl, however,
dramatically improved formation of the desired prod-
ucts (Table 1).
Following our reaction scheme with known lactams,
3-oxo-1H-pyrrolo[3,4-b]quinoline11 (entry 6) and 1-
oxo-1,2,3,4-tetrahydropyrido[3,4-b]indole12 (entry 7)
smoothly led to the production of the corresponding
alkaloids, luotonin A (3a) and rutaecarpine (5) in the
yield of 88% and 92%, respectively. It is worthwhile to
note that the early synthesis of 5 utilizing lactam 8 and
methyl anthranilate in the presence of POCl3 gave 66%

E. S. Lee et al. / Tetrahedron Letters 44 (2003) 1883–1886
1885
Table 1. Synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids
hexahydroazonino[2,1-b]quinazolin-14(6H)-one (1e) as
white needles: mp 101–102°C. IR (thin film) w 1675,
References
1610, 1580, 1565, 1410, 1350, 1310 cm−1. 1H NMR
(CDCl3, 300 MHz) l 8.27 (dd, J=8.2, 1.8 Hz, 1H), 7.73
(ddd, J=8.2, 7.2, 1.2 Hz, 1H), 7.66 (dd, J=8.2, 1.5 Hz,
1H), 7.44 (ddd, J=8.2, 7.2, 1.5 Hz, 1H), 4.34 (br s, 2H),
3.09–3.02 (m, 2H), 2.10–1.67 (m, 4H), 1.62–1.34 (m,
6H). Anal. calcd for C15H18N2O: C, 74.35; H, 7.49; N,
11.56. Found: C, 74.63; H, 7.58; N, 11.43.
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Acknowledgements
Financial support by Korea Research Foundation
Grant
(KRF-2002-005-E00019)
is
gratefully
acknowledged.

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13. Indolo[2,1-b]quinazolin-12(6H)-one (10): mp 215–216°C
(lit.14 mp 215–216°C). IR (KBr) w 1680, 1640, 1605, 1560,
1465, 1360, 1330, 1310 cm−1 1H NMR (CDCl3, 300
.
MHz) l 8.53 (dd, J=8.4, 1.8 Hz, 1H), 8.46 (dd, J=8.4,
1.2 Hz, 1H), 8.02 (ddd, J=8.2, 1.5, 0.5 Hz, 1H), 7.68 (td,
J=8.2, 1.5 Hz, 1H), 7.54–7.44 (m, 2H), 7.08 (t, J=8.2
Hz, 1H), 6.98 (t, J=8.4 Hz, 1H), 4.22 (s, 2H). 6-Benzyl-
idenindolo[2,1-b]quinoazolin-12(6H)-one (11): A mixture
of 11.7 g (0.05 mol) of 10 and 31.8 g (0.30 mol) of
benzaldehyde in 80 mL of Ac2O was refluxed for 48 h.
Excess benzaldehyde and Ac2O were removed under
reduced pressure. The resulting mixture was carefully
poured into 100 mL of 50% NaOH and extracted with
CH2Cl2 (50 mL×3). Organic layers were combined and
dried over MgSO4. Evaporation of the solvent gave a
yellow solid (14.4 g, 89%) whose 1H NMR spectrum
showed presence of two regioisomers (E- and Z- through
the benzylidene double bond). Thus, compound 11 was
not fully characterized, but instead carried to the next
step. Trypthanthrin (4): A solution of 3.22 g (0.01 mol) of
11 in 200 mL of CH2Cl2 was cooled in an acetone–dry ice
bath and O3 was bubbled through the solution. Excess O3
was purged and 20 mL of (CH3)2S was added to the
mixture. Evaporation of the solvent afforded 2.48 g of
semi-solid, which was chromatographed on silica gel,
eluting with CH2Cl2:EtOAc (1:1). The latter fractions
gave 2.06 g (83%) of yellow needles after recrystallization
from the eluent: mp 265–266°C (lit.5b mp 267–268°C,
1
lit.5g mp 261°C). IR (KBr) v 1725, 1675 cm−1. H NMR
(400 MHz, CDCl3) d 8.68 (dm, J=8.0 Hz, H10), 8.48
(ddd, J=8.2, 1.5, 0.8 Hz, H1), 8.10 (ddd, J=8.0, 1.2, 0.6
Hz, H4), 7.96 (ddd, J=7.8, 1.4, 0.6 Hz, H7), 7.91 (ddd,
J=8.2, 7.5, 1.5 Hz, H3), 7.85 (ddd, J=8.0, 7.8, 1.3 Hz,
H9), 7.72 (ddd, J=8.2, 7.8, 1.5 Hz, H2), 7.45 (ddd,
J=8.0, 7.5, 1.2 Hz, H8).
14. Bergman, J.; Tilstam, U.; Toernroos, K. W. J. Chem.
Soc., Perkin Trans. 1 1987, 519.