A short synthesis of quinazolinocarboline alkaloids rutaecarpine, hortiacine, euxylophoricine A and euxylophoricine D from methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates

Article abstract of DOI:10.1016/S0040-4039(02)00711-6

Reactions of methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates with tryptamine at room temperature produced 2-cyano-3-[2-(indol-3-yl)ethyl]-4(3H)-quinazolinones, which underwent cyclization on heating with TFAA/HCl(g) to afford quinazolinocarboline alkaloids rutaecarpine (1a), hortiacine (1b), euxylophoricine A (1c) and euxylophoricine D (1d) in excellent yields.

Full text of DOI:10.1016/S0040-4039(02)00711-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3993–3996
A short synthesis of quinazolinocarboline alkaloids rutaecarpine,
hortiacine, euxylophoricine A and euxylophoricine D from
methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates
Pramod K. Mohanta and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 9 April 2002; accepted 11 April 2002
Abstract—Reactions of methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates with tryptamine at room temperature
produced 2-cyano-3-[2-(indol-3-yl)ethyl]-4(3H)-quinazolinones, which underwent cyclization on heating with TFAA/HCl(g) to
afford quinazolinocarboline alkaloids rutaecarpine (1a), hortiacine (1b), euxylophoricine A (1c) and euxylophoricine D (1d) in
excellent yields. © 2002 Elsevier Science Ltd. All rights reserved.
O
O
The dried fruit of Evodia rutaecarpa has been used in
traditional Chinese medicine under the name Wu-Chu-
Yu1 and Shih-Hu2 against e.g. headache, dysentery,
cholera, worm infections and postpartum disturbances.3
Extracts of the drug contain quinazolinocarboline alka-
loids rutaecarpine (1a) and evodiamine (2). Recently,
callus tissue cultured from the stem of Phellodendron
amurense has been shown to produce 1a along with a
variety of other alkaloids.4 In modern literature 1a and
its derivatives have been reported to display strong
cycloxygenase (COX-2) inhibitory activity.5 It was also
found to suppress platelet plug formation in mesenteric
venules and increase intracellular Ca2+ in endothelial
cells.6 Asahina isolated 1a first around 1915 and more
than a decade later the first total synthesis was
reported7 by Asahina, Manske and Robinson. Since
then several routes8 have been developed for the synthe-
sis of 1a. Some of the problems involved in these
syntheses are the low yield (44%) in the final cyclization
step coupled with unavoidable side products9 and
longer reaction time (166 h).10 All these problems
prompted us to develop a new efficient methodology.
R1
R2
N
N
B
N
A
C
N
D
R3
N
N
E
Me
1
H
H
2
1a, R1= R2= R3= H, Rutaecarpine
Evodiamine
b, R1= R2= H, R3= OMe, Hortiacine
O
c, R1= R2= OMe, R3= H, Euxylophoricine A
S
N
N
d, R1= R2= R3= OMe, Euxylophoricine D
e, R1= Br, R2= R3= H
f, R1= H, R2= Cl, R3= H
N
1g
H
starting materials methyl N-(4-chloro-5H-1,2,3-dithia-
zol-5-ylidene)anthranilates (4) in the context of natural
product synthesis and in this paper we report the total
synthesis of quinazolinocarboline alkaloids 1a, hor-
tiacine (1b),12a euxylophoricine
A
(1c),12b euxy-
lophoricine
respectively, from 4a–e.
D
(1d)12c and their analogues 1e–g,
Our synthetic strategy for quinazolinocarboline alka-
loids 1 is to construct B ring and build the connection
between the B and D rings starting from 4 and
tryptamine (5) (Scheme 1).
As a part of our ongoing research program, we have
already been involved in exploiting the potential syn-
thetic applications of 5-arylimino 4-chloro-5H-1,2,3-
dithiazoles and recently reported the synthesis of
various heterocyclic and spiroheterocyclic com-
pounds.11 We wished to utilize the easily accessible
Starting materials 4a–d can be prepared from the
respective anthranilates 6a–d and 4,5-dichloro-1,2,3-
dithiazolium chloride (Appel’s salt)13 in good yields
(67–78%) according to the literature14 procedure
(Scheme 2). Reaction of 4a (287 mg, 1 mmol) with
tryptamine 5a (R3=H, 160 mg, 1 mmol) in dry CH2Cl2
at rt for 29 h afforded 2-cyano-3-[2-(indol-3-yl)ethyl]-
Keywords: alkaloids; dithiazoles; quinazolinones.
* Corresponding author. Tel.: +82-2-883-6636; fax: +82-2-874-8858;
e-mail: kkim@plaza.snu.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00711-6

3994
P. K. Mohanta, K. Kim / Tetrahedron Letters 43 (2002) 3993–3996
1a. In a typical experiment, 3a (150 mg, 0.47 mmol) was
R3
heated (120–130°C) with TFAA (3.4 mL, 23.8 mmol)/
HCl(g) for 3.5 h. The solid separated out on pouring
the reaction mixture onto ice-cold water was filtered
and on recrystallization from ethanol afforded 1a in
pure form (130 mg, 95%, mp 257°C, lit.8a 258°C)
(Scheme 2). Hortiacine (1b), isolated from the plant
Hortia arborea12a was obtained in 93% yield from 3b
under the same conditions. Similarly the other quina-
zolinocarboline alkaloids euxylophoricine A (1c)12b and
euxylophoricine D (1d)12c extracted from the bark of
the Euxylophora paraensis Hub were also synthesized
from 3c and 3d in 91% and 90% yields, respectively,
under similar conditions. A comparison of spectro-
scopic data (NMR, MS) of 1a–d showed good agree-
ment with the reported data. Bromo-3e and chloro-3f
derivatives of quinazolin-4-ones on heating with
TFAA/HCl(g) gave bromo-1e and chlororutaecarpine
O
N
R3
R1
R2
O
OMe
R1
H2N
+
N
N
H
1
N
H
5
Cl
R2
N
3
CN
S
N
S
4
Scheme 1.
4(3H)-quinazolin-4-one (3a) in (195 mg) 62% yield with
sulfur and unreacted starting materials 4a (60 mg, 21%)
and 5a (Scheme 2). To improve yield of 3a, the reaction
mixture was stirred at rt for longer time (72 h) to give
a mixture of cyanothioformamide 8a14 (19%) and 3a
(62%) along with starting materials 4a and 5a. Similarly
4b–d reacted with 5a at rt for 24–31 h to afford 3c, 3e
and 3f in 59–68% yields. Compounds 3b and 3d were
also obtained in 63% and 60% yields, respectively, when
5-methoxytryptamine (5b) was reacted with 4a and 4b
under the similar conditions. Similarly, thienopyrimi-
done 3g was obtained from the reaction of 4e, prepared
from methyl 3-amino-2-thiophenecarboxylate (6e) and
7 under the same conditions as for 4, with 5a in 61%
yield. Compounds 3a–g were characterized from their
spectroscopic (1H, 13C NMR, IR, and MS) and analyt-
ical data.15
15
1f in 96% and 97% yields, respectively. When 2-cyan-
othieno[3,2-d]-pyrimidone 3g was treated with TFFA/
HCl(g) at 120°C, 1g15 was obtained in 89% yield.
The plausible mechanism for the formation of 1 can be
rationalized as the protonation of 2-cyano-3-trypto-
phylquinazolin-4-one 3 to form an aza-stabilized9 car-
bocation, which suffers nucleophilic attack by the
enaminocarbon of the pyrrole moiety of 9B leading to
a spiro intermediate 10 (Scheme 3). The intermediate 10
undergoes rearrangement to more stable pentacyclic
structure 12 (Path a) via 11. Extrusion of HCN from 12
2-Cyano-3-[2-(indol-3-yl)ethyl]-4(3H)-quinazolinone 3a
served as an excellent intermediate for the synthesis of
Scheme 2. Reagents and conditions: (i) CH2Cl2/pyridine/rt/2–3 h; (ii) 5/CH2Cl2/rt/24–31 h; (iii) TFAA/HCl(g)/ 120–130°C/3–4 h.

P. K. Mohanta, K. Kim / Tetrahedron Letters 43 (2002) 3993–3996
3995
J. Haematol. 2000, 110, 110–115; (c) Wang, G. J.; Shan,
J.; Pang, P. K. T.; Yang, M. C. M.; Chou, C. J.; Chen, C.
F. J. Pharmacol. Exp. Therap. 1996, 270, 1016–1021.
7. Asahina, Y.; Manske, R. H. F.; Robinson, R. J. Chem.
Soc. 1927, 1708–1710.
8. (a) Bergman, J. In The Alkaloids; Brossi, A. R., Ed. The
Quinazolino-carboline alkaloids; Academic Press: New
York, 1983; Vol. 21, pp. 29–54; (b) Kokosi, J.; Szasz, G.;
Hermecz, I. Tetrahedron Lett. 1992, 33, 2995–2998.
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1985, 6, 1385–1390.
10. Kametani, T.; Loc, C. V.; Higa, T.; Ihara, M.; Koizumi,
M.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99, 2306–
2308.
11. (a) Jeon, M.-K.; Kim, K.; Park, Y. J. J. Chem. Soc.,
Chem. Commun. 2001, 1412–1413; (b) Jeon, M.-K.; Kim,
K. Tetrahedron 1999, 55, 9651–9667.
12. (a) Pachter, I. J.; Raffauf, R. F.; Ullyot, G. E.; Ribeiro,
O. J. Am. Chem. Soc. 1960, 82, 5187–5193; (b) Canonica,
L.; Danieli, B.; Manitto, P.; Russo, G.; Ferrari, G.
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2525.
Scheme 3.
13. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber.
1985, 118, 1632–1643.
finally gives 1. Alternatively, one may envisage that
elimination of HCN from 10 (Path b) to give 13,
followed by 1,2-migration leading to 14 and subsequent
deprotonation would give 1. To our knowledge the
nitrile elimination from 2-position of quinazolin-4-one
is not known in the literature. However, a-aminotriles
are reported16 to liberate cyanide ion under acidic
conditions and this strategy has been utilized for the
synthesis of various indole alkaloids.
14. Lee, H.-S.; Chang, Y.-G.; Kim, K. J. Heterocycl. Chem.
1998, 35, 659–668.
15. 3e: Crystals (CHCl3-n-hexane), mp 232–233°C; IR (KBr)
3408, 1664, 1568, 1452 cm−1 1H NMR (300 MHz,
;
DMSO-d6) l 3.18 (t, J=7.41 Hz, 2H), 4.36 (t, J=7.43
Hz, 2H), 6.91 (t, J=7.47 Hz, 1H), 7.06 (t, J=7.53 Hz,
1H), 7.19 (d, J=2.10 Hz, 1H), 7.36 (d, J=8.09 Hz, 1H),
7.51 (d, J=7.85 Hz, 1H), 7.74 (d, J=8.68 Hz, 1H), 8.10
(dd, J=2.90, 8.67 Hz, 1H), 8.34 (d, J=2.24 Hz, 1H),
10.96 (brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6) l
24.55, 48.84, 110.35, 112.43, 112.49, 118.61, 119.40,
122.03, 123.58, 124.65, 124.81, 127.88, 129.47, 131.01,
133.49, 137.11, 138.99, 145.82, 159.29; MS m/z (%) 394
(M++1); 393 (M+); 392 (M+−1), 144, 143 (100%). Anal.
calcd for C19H13BrN4O: C, 58.03; H, 3.33; N, 14.25.
Found: C, 58.17; H, 3.41; N, 13.92.
In conclusion, we have achieved total synthesis of
quinazolinocarboline alkaloids 1a–d and their ana-
logues 1e–g in good yields requiring only two steps
from dithiazoles 4a–e.
Acknowledgements
Financial support from BK-21 is highly acknowledged.
References
3f: Crystals (CHCl3-n-hexane), mp 210–211°C; IR (KBr)
3403, 1670, 1574, 1449 cm−1 1H NMR (300 MHz,
;
DMSO-d6) l 3.19 (t, J=7.38 Hz, 2H), 4.37 (t, J=7.34
Hz, 2H), 6.91 (t, J=7.44 Hz, 1H), 7.06 (t, J=7.51 Hz,
1H), 7.18 (d, J=2.10 Hz, 1H), 7.35 (d, J=6.48 Hz, 1H),
7.49 (d, J=7.87 Hz, 1H), 7.77 (dd, J=1.96, 8.57 Hz, 1H),
7.90 (d, J=1.87 Hz, 1H), 8.28 (d, J=8.56 Hz, 1H), 10.95
(brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6) l 22.03,
46.06, 107.57, 109.49, 109.68, 115.87, 116.69, 119.28,
119.38, 121.74, 125.17, 125.22, 126.61, 128.12, 131.45,
134.43, 138.19, 145.14, 157.05; MS m/z (%) 348 (M+), 143
(100%). Anal. calcd for C19H13ClN4O: C, 65.43; H, 3.76;
N, 16.06. Found C, 65.18; H, 3.81; N, 15.90.
1. Chu, J. H. Sci. Rec. (China) 1951, 4, 279–284; Chem.
Abstr. 1952, 46, 11589b.
2. Li, M.-T.; Hung, H.-I. Yao Hsueh Pao 1966, 13, 265–272;
Chem. Abstr. 1966, 65, 3922c.
3. (a) Chen, A. L.; Chen, K. K. J. Am. Pharm. Assoc. 1933,
22, 716–719; (b) Hsu, H. Y.; Chen, Y. P.; Sheu, S. J.;
Hsu, C. H.; Chen, C. C.; Chang, H. C. Chinese Material
Medica—A Concise Guide; Modern Drug Press: Taipei,
1985; p. 288.
4. Michael, J. P. Nat. Prod. Rep. 1999, 16, 697–709.
5. Hibino, S.; Choshi, T. Nat. Prod. Rep. 2001, 18, 66–87.
6. (a) Wu, S.-N.; Lo, Y.-K.; Chen, H.; Li, H.-F.; Chiang,
H.-T. Neuropharmacology 2001, 41, 834–843; (b) Sheu, J.
R.; Hung, W. C.; Wu, C. H.; Lee, Y. M.; Yen, M. H. Br.
3g: Colorless solid (CHCl3-n-hexane), mp 219–220°C; IR
1
(KBr) 3344, 1661, 1580, 1453 cm−1; H NMR (300 MHz,
DMSO-d6) l 3.19 (t, J=7.47 Hz, 2H), 4.41 (t, J=7.50
Hz, 2H), 6.91 (t, J=7.41 Hz, 1H), 7.06 (t, J=7.50 Hz,
1H), 7.19 (d, J=2.27 Hz, 1H), 7.35 (d, J=8.12 Hz, 1H),
7.49 (d, J=7.87 Hz, 1H), 7.53 (d, J=5.28 Hz, 1H), 8.35
(d, J=5.27 Hz, 1H), 10.97 (brs, 1H, NH); 13C NMR (75
MHz, DMSO-d6) l 24.79, 48.58, 110.30, 112.41, 112.77,
118.58, 119.35, 122.02, 124.62, 126.07, 126.67, 127.90,

3996
P. K. Mohanta, K. Kim / Tetrahedron Letters 43 (2002) 3993–3996
134.04, 137.09, 138.04, 155.63, 156.58; MS m/z (%) 320
8.16 (d, J=8.51 Hz, 1H), 11.90 (s, 1H, NH); 13C NMR
(75 MHz, DMSO-d6) l 19.72, 41.77, 113.50, 119.49,
120.36, 120.73, 120.97, 125.67, 125.92, 126.20, 126.97,
127.61, 129.57, 139.67, 139.79, 147.41, 149.41, 160.96; MS
m/z (%) 322 (M++2), 321 (M++1), 320 (M+, 100%), 292,
257. Anal. calcd for C18H12ClN3O: C, 67.19; H, 3.76; N,
13.06. Found: C, 66.84; H, 3.79; N, 12.88.
(M+), 164, 143 (100%). Anal. calcd for C17H12N4OS: C,
63.73; H, 3.78; N, 17.49; S, 10.01. Found: C, 63.44; H,
3.70; N, 17.18; S, 10.08.
1e: Crystals (EtOH), mp 276–278°C; IR (KBr) 3368,
1670, 1568, 1436 cm−1; 1H NMR (300 MHz, DMSO-d6) l
3.20 (t, J=6.87 Hz, 2H), 4.44 (t, J=6.85 Hz, 2H), 7.10 (t,
J=7.5 Hz, 1H), 7.28 (t, J=7.62 Hz, 1H), 7.49 (d, J=8.25
Hz, 1H), 7.62 (d, J=9.62 Hz, 1H), 7.65 (d, J=8.58 Hz,
1H), 7.95 (dd, J=2.13, 8.70 Hz, 1H), 8.22 (d, J=1.88 Hz,
1H), 11.89 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
l 19.71, 41.92, 113.46, 119.01, 119.24, 120.73, 120.94,
123.09, 125.70, 125.87, 127.69, 129.47, 129.73, 138.13,
139.62, 146.59, 147.30, 160.48; MS m/z (%) 367 (M++2),
365 (M+, 100%), 338, 285. Anal. Calcd for C18H12BrN3O:
C, 59.03; H, 3.30; N, 11.47; Found: C, 59.39; H, 3.47; N,
11.65.
1g: Colorless solid (EtOH), mp 279–280°C, IR (KBr)
3424, 1648, 1584, 1488 cm−1 1H NMR (300 MHz,
;
DMSO-d6) l 3.17 (t, J=6.96 Hz, 2H), 4.46 (t, J=6.95
Hz, 2H), 7.09 (t, J=7.43 Hz, 1H), 7.26 (t, J=7.53 Hz,
1H), 7.40 (d, J=2.24 Hz, 1H), 7.46 (d, J=8.25 Hz, 1H),
7.64 (d, J=7.95 Hz, 1H), 8.19 (d, J=5.24 Hz, 1H), 11.92
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) l 19.83,
41.48, 113.38, 118.45, 120.64, 120.81, 121.35, 125.50,
125.57, 125.72, 127.96, 136.37, 139.45, 147.91, 156.76,
157.93; MS m/z (%) 294 (M++1), 293 (M+), 292 (M+−1,
100%), 265. Anal. calcd for C16H11N3OS: C, 65.51; H,
3.78; N, 14.32; S, 10.93. Found: C, 65.29; H, 3.49; N,
14.21; S, 10.62.
1f: Crystals (EtOH), mp 290–293°C; IR (KBr) 3344,
1648, 1587, 1444 cm−1; 1H NMR (300 MHz, DMSO-d6) l
3.20 (t, J=6.8 Hz, 2H), 4.46 (t, J=6.77 Hz, 2H), 7.12 (t,
J=7.40 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.52 (brd,
J=8.25 Hz, 2H), 7.65 (s, 1H), 7.69 (d, J=9.76 Hz, 1H),
16. Goes, A. D. S.; Ferroud, C.; Santamaria, J. Tetrahedron
Lett. 1995, 36, 2235–2238.