998
S. P. Chavan, R. Sivappa / Tetrahedron Letters 45 (2004) 997–999
1OOC
R
EtOOC
A
B
C
PhNH
N
O
N
N
D
O
O
2OOC
R
N
N
O
O
N
N
O
O
H
N
N
N
N
N
E
6
4
5
3
Scheme 1.
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
H
O
O
O
O
N
iv
HN
ii
HN
iii
i
O
O
N
O
N
HN
2
HN
N
6
7
8
9
EtOOC
v
N
O
O
vi
N
vii
O
O
O
O
N
PhNHN
N
H
N
N
N
N
5
4
1
3
Scheme 2. Reagents and conditions: (i) Ethyl c-aminobutyrate hydrochloride, DMF, Et3N, DMAP (cat), 96%; (ii) ethyl oxalyl chloride, DCM,
K2CO3, 98%; (iii) PCl3, xylene, reflux, 2 h, 80%; (or) (a) Ph3P, I2, Et3N, DCM, 70%; (b) piperidine, DCM; (c) CH3CN, reflux, 1.5 h, 75%; (iv) NaH,
DMF, 80%; (v) 6 N HCl, 81%, reflux; (iv) PhNHNH2, 98%; (vii) PPA, 180 °C, 95%.
amide 9 to the quinazolinone diester 6 was best achieved
with PCl3 in refluxing xylene. Alternatively, treatment of
amide 9 with PPh3/I2/Et3N12 followed by refluxing the
amidine so formed with piperidine in acetonitrile fur-
nished the quinazolinone diester 6. Having obtained the
diester 6 with suitable functionality the stage was set to
investigate the proposed strategy that is, the Dieckmann
condensation for the construction of the b-keto ester.
Among the various bases and conditions tried, NaH/
DMF afforded the b-keto ester 5 in 80% yield. b-Keto
ester 5, which existed in its enol form, was decarboxy-
lated to afford 9,10,11,12-tetrahydro-4H-pyrido[2,1-b]-
quinazoline-4,9-dione 4 under refluxing conditions with
aqueous 6 N HCl. The dione 4 was treated with phen-
ylhydrazine under acidic conditions to form hydrazone 3
in almost quantitative yield. Hydrazone 3 was subjected
to the Fischer indole synthesis as reported earlier.7f Thus
heating the hydrazone in freshly prepared PPA at 180 °C
for 0.5 h furnished rutaecarpine 1 in 95% yield (Scheme
2).
References and notes
1. (a) Asahima, Y.; Kashiwaki, K. J. Pharm. Soc. Jpn. 1915,
35, 1293; (b) Bergman, J. In The Alkaloids; Brossi, A. R.,
Ed.; Academic: NewYork, 1983; Vol. 21, p 29; (c) Ikuta,
A.; Urabe, H.; Nakamura, T. J. Nat. Prod. 1998, 61, 1012.
2. Chu, J. H. Sci. Record 1951, 4, 279; Chem. Abstr. 1952, 46,
11589b.
3. Li, H.-T.; Houng, H.-I. Yao Hsueh Hsueh Pao 1966, 13,
265; Chem. Abstr. 1966, 65, 3922c.
4. (a) Amin, A. H.; Mehta, D. R.; Samarth, S. G. Prog.
Drug. Res. 1970, 14, 218; (b) Johne, S. Prog. Drug. Res.
1982, 26, 259.
5. Kiss, A.; Kokosi, J.; Rotter, R.; Hemecz, I. Tetrahedron
2000, 56, 7987, and references cited therein.
6. (a) Yang, L. M.; Lin, S.-J.; Lin, L.-C.; Kuo, Y.-H. Chin.
Pharm. J. 1999, 51, 219; (b) Yang, L. M.; Chen, C.-F.;
Kuo, H.-L. Bioorg. Med. Lett. 1995, 5, 465.
7. (a) Kametani, T.; Loc, C. V.; Higa, T.; Koizumi, M.;
Ihara, M.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99,
2306; (b) Bergman, J.; Bergman, S. Heterocycles 1981, 16,
2347; (c) Bergman, J.; Bergman, S. J. Org. Chem. 1985, 50,
1246; (d) Eguchi, S.; Takeuchi, H.; Matsushita, Y.
Heterocycles 1992, 33, 153; (e) Kaneko, C.; Chiba, T.;
Kasaki, K.; Miwa, C. Heterocycles 1985, 23, 1385; (f)
Kokosi, J.; Hermecz, I.; Szasz, G.; Meszaros, Z. Tetrahe-
dron Lett. 1981, 22, 4861; (g) Mohanta, P. K.; Kim, K.
Tetrahedron Lett. 2002, 43, 3993; (h) Lee, E. S.; Park, J.
G.; Jahng, Y. Tetrahedron Lett. 2003, 44, 1883, and
references cited therein.
In summary, we have developed a novel, concise and
efficient entry to pyridoquinazolinone alkaloids, which
is amenable to access analogues.
Acknowledgements
8. For a recent review on the Fischer indole synthesis, see:
Hughes, D. L. Org. Prep. Proced. Int. 1993, 5, 607.
9. (a) Kokosi, J.; Hermecz, I.; Podanyi, B.; Szasz, G.;
Meszaros, Z. J. Heterocycl. Chem. 1985, 22, 1373; (b)
R.S. thanks CSIR for a fellowship and funding from
CSIR (New Delhi) under YSA (SPC) scheme is grate-
fully acknowledged.