Expedious and practical synthesis of the bioactive alkaloids rutaecarpine, euxylophoricine A, deoxyvasicinone and their heterocyclic homologues

Article abstract of DOI:10.1016/j.tetlet.2006.01.031

Efficient assembly of pyrimido-β-carbolines 1 and 2, including the bioactive alkaloids rutaecarpine, euxylophoricine A, and deoxyvasicinone (3), is reported from suitable aromatic amino acids 7 or corresponding aromatic amino esters 8 and imino-thioethers 5 or 6 in a one-step sequence in moderate to good yields. The key step of this methodology is based on an intramolecular aza-displacement of a methylthio group followed by spontaneous cyclodehydration. Furthermore, when aromatic amino esters 8 were used instead of amino acids, a tandem amino-methylthio displacement/amino ester cyclization takes place.

Full text of DOI:10.1016/j.tetlet.2006.01.031

Tetrahedron Letters 47 (2006) 1777–1781
Expedious and practical synthesis of the bioactive alkaloids
rutaecarpine, euxylophoricine A, deoxyvasicinone
and their heterocyclic homologues
Abdulkareem Hamid,a Abdelhakim Elomrib and Adam Daıcha,*
¨
aLaboratoire de Chimie, URCOM, EA 3221, UFR des Sciences and Techniques de l’Universite´ du Havre, BP 540,
25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
bLaboratoire de Pharmacognosie, UFR Me´decine-Pharmacie, 22 Boulevard Gambetta, F-76183 Rouen Cedex, France
Received 4 October 2005; revised 6 January 2006; accepted 11 January 2006
Available online 30 January 2006
Abstract—Efficient assembly of pyrimido-b-carbolines 1 and 2, including the bioactive alkaloids rutaecarpine, euxylophoricine A,
and deoxyvasicinone (3), is reported from suitable aromatic amino acids 7 or corresponding aromatic amino esters 8 and imino-thio-
ethers 5 or 6 in a one-step sequence in moderate to good yields. The key step of this methodology is based on an intramolecular
aza-displacement of a methylthio group followed by spontaneous cyclodehydration. Furthermore, when aromatic amino esters 8
were used instead of amino acids, a tandem amino-methylthio displacement/amino ester cyclization takes place.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Among the products isolated and structurally identified
from these extracts, rutaecarpine (1a) isolated from the
dried fruit of Evodia rutaecarpa3 showed remarkable
activities against headache, cholera, dysentery, worm
infestations and post partum disturbances.2,4 Recent
investigations have shown that rutaecarpine (1a) and/
or the quinazoline–carboline alkaloids are present in
numerous plants,5–9 all members of the Rutaceae family.
Besides, further biological investigations revealed that,
in addition to its strong anti-inflammatory activity,10
rutaecarpine (1a) possess numerous other interesting
medicinal profiles such as analgesic,11 astringent, anti-
emetic, anti-hypertensive,11b,c uterotonic,12 anti-platelet
aggregation,13 and vasorelaxing14 activities. Moreover,
rutaecarpine (1a) and/or its derivatives possess a strong
and selective inhibitory activity on cyclooxygenase-2
(COX-2),10b,11c on human CYP1A1, CYP1A2, and
CYP1B1.15
The indolopyridoquinazolinone framework constitutes
an important class of heterocycles belonging to quinazo-
line-type alkaloids isolated from both the heartwood and
the fruit of rutaceous plants and rutaceae trees as well as
animals and microorganisms.1 Their extracts have long
been used as important remedies in Chinese traditional
medicine for the treatment of various diseases.2
O
E
O
E
A
C
N
N
B
N
H
D
N
N
N
R1
R2
R3
(2) E: aromatic ring
(1a) R2=H, R3=H
Rutaecarpine
(1b) R2=MeO, R3=MeO
Euxylophoricine A
(1c) R2=Cl, R2=H
O
N
N
Their anti-tumor activity16 is less important than the
one exhibited by luotonins A and B17 and camptothe-
cin.18 In these cases, 10-bromo-, 11-methoxy-, and
10,11-methylenedioxyrutaecarpines are the most active
derivatives in the series. More recently, numerous
thiophene analogues of rutaecarpine (1a) have shown
good anti-cancer activity in vitro but no activity
in vivo.16c
(3) Deoxyvasicinone
Keywords: Bioactive product; Alkaloid; Thioether; Imino-thioether;
Heterocycle; Peptedic coupling; Lawesson’s; Thionation; One-pot
procedure.
Corresponding author. Tel.: +33 02 32 74 44 03; fax: +33 02 32 74 43
91; e-mail: adam.daich@univ-lehavre.fr
*
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.031

1778
A. Hamid et al. / Tetrahedron Letters 47 (2006) 1777–1781
Due to their interesting biological profile, a number of
reliable preparative methods are known in the literature.
Thus, Fischer indole synthesis under harsh conditions of
temperature can yield the quinazolinocarboline systems
in several forms.17 Also, treatment of aromatic amino
acids or the corresponding amino esters with lactam
derivatives such as chloro-imine18 and amino-imine19
has been applied successfully and resulted in the forma-
tion of D ring. The iminoketenes, derived from the latter
amino acids, with amides or the corresponding imino-
ethers under cycloaddition conditions, furnished the
suitable quinazolone systems via the formation of C
ring.20 Furthermore, other ring-closure protocols which
consist in the protonation of the 4(3H)-quinazolinone
moiety followed by electrophilic attack on the indole
ring,21 or the simple condensation of Appel’s salt with
amino esters followed by successive treatment with
tryptamine derivatives and TFAA/HCl(g) combination
on heating,22 and finally the aryl–aryl coupling reaction
of 2-bromoaromatic derivatives with the quinazolinone
heterocycle with Pd reagents, have also been explored.23
In all these methods, the synthetic strategy is to con-
struct the D ring and/or to build the connection between
the D and B rings starting from tryptamine derivatives.
N
S
N
H
5
NH
S
MeI, 2% NaOHaq
EtOH, rt, 24 h
and/or
N
H
4
quantitative
N
S
N
6
Scheme 1. Scheme leading to triheterocyclic imino-thioethers 5 and 6.
O
CO H
2
R
R
2
N
S
7a-c
N
NH
3
2
R2
R3
N
N
R1
5 or 6
AcOH
N
R1
Reflux, 24 h
1a-c and 2a
O
CO2H
NH2
N
85%
79%
N
N
H
7a
7b
7c
(1a) Rutaecarpine
O
N
Cl
CO2H
NH2
2. Results and discussion
Cl
N
N
As part of a long-term project dealing with the search
for a simple synthetic route to rutaecarpine (1a) as well
as its homologues, we report herein a concise and facile
synthesis of these derivatives. Our synthetic strategy is
based on the simple condensation of amino acids or
the corresponding amino esters with the more accessible
imino-thioether function in a one-pot fashion using two
procedures.
H
(1b) Chlororutaecarpine
O
N
MeO
CO2H
81%
75%
OMe
OMe
N
N
H
Me
O
NH2
(1c) Euxylophoricine A
O
N
CO2H
NH2
7a
As the starting point of our study, the requisite tri-
heterocyclic imino-thioether 5 (Scheme 1) was obtai-
ned in one step in quantitative yield by S-alkylation
of 2,3,4,9-tetrahydro-b-carboline-1-thione (4)24 with
1 equiv of methyl iodide in ethanol at room temperature
for 24 h in the presence of 2% aqueous NaOH. In a
similar manner, but with an excess of methyl iodide
(>1.2 equiv), the S-alkylated product 5 was accompa-
nied with the N,S-dialkylated product 6. These two
components were formed in 4/1 ratio and were easily
separated by chromatography on a silica gel column
using a mixture of ethyl acetate/cyclohexane (1/1) as
eluent.
N
N
(2a) N-Methylrutaecarpine
Scheme 2. Condensation of aromatic amino acids 7a–c with trihetero-
cyclic imino-thioethers 5 and 6.
Having established the effectiveness of this route for the
preparation of the indolopyridoquinazoline derivatives
1a–c and 2a including the rutaecarpine (1a) and the
euxylophoricine A (1c) alkaloids, we decided to explore
aromatic or heteroaromatic amino esters instead of the
corresponding amino acids. The amino ester functional-
ity was chosen for the following reasons: 1°—some het-
erocyclic amino acids are not commercially available;
2°—the amino ester function could be manipulated
without specific precautions instead of the correspond-
ing amino acid; and finally 3°—various methods for
the synthesis of heterocyclic amino esters are available
in the literature, which are short and involve the use
of cheap reagents as well as mild conditions.
Taking into account that the alkylthio group in the imino-
thioether function could be extruded easily by nucleo-
philic displacement,25 the S-methyl derivatives 5 and 6
would constitute valuable platforms to access molecules
1 and 2 (Scheme 2). At the outset, condensation of
indolodihydropyridine 5 with anthranilic acid (7a) in
refluxing dry acetic acid for 24 h allowed an easy access
to the expected rutaecarpine alkaloid (1a) after recrystal-
lization from anhydrous ethanol (85% yield). Similarly,
chlororutaecarpine (1b), euxylophoricine A (1c), and
N-methylrutaecarpine (2a) were also obtained cleanly
and easily in yields ranging from 75% to 81%.26
Thus, methyl anthranilate (8a) was treated with 1 equiv
of imino-thioether 5 (Scheme 3) in glacial acetic acid at

A. Hamid et al. / Tetrahedron Letters 47 (2006) 1777–1781
1779
O
3 equiv. NaH
DMF
amino-esters
N
N
N
S
N
(8a-f)
CO2R
- RO
Ar
CO2R
Ar
N
H
N
H
AcOH
Reflux
4 h
N
H
5
N
0°C to rt
12 h
N
H
H
Ar
9a-f
1a,2b-f
10a-f
R=Me, Et
O
O
N
CO2Me
NH2
NH2
N
H
N
55%
51%
47%
48%
48%
39%
N
N
H
N
N
H
N
H
CO2Et
8d
2d
8a
(1a) Rutaecarpine
O
O
O
NH2
NH2
N
N
S
O
S
S
N
O
S
N
N
H
N
H
CO2Me
CO2Et
8e
8b
2e
2b
2c
O
Ph
CO2Me
NH2
NH2
N
N
Ph
N
S
N
N
N
H
N
H
CO2Et
S
N
2f
8c
8f
Scheme 3. Fused b-carboline derivatives 1a and 2b–f by condensation of aromatic amino esters 8a–f with triheterocyclic imino-thioether 5 in a two-
step procedure under successive acid and base treatment.
reflux for 4 h. After cooling and evaporation of the sol-
vent, analysis of the residue indicated the formation of
the amino-imine derivative 9a as the sole reaction prod-
uct. This compound was isolated in pure form after
recrystallization from dry ethanol in 95% yield.27 Fur-
thermore, although a variety of reaction times and tem-
peratures were explored the formation of the desired
cyclized product 1a was not observed. This is due prob-
ably to the relatively low electrophilicity of the ester
function under acidic conditions.
anta and Kim.22 Similarly, with the known methyl 2-
amino-4-phenylthiophene-3-carboxylate (8c),28 the
reaction resulted in the formation of the expected and
new thienopyrimido-b-carboline 2c in moderate yield
(47%). This is due to the low reactivity of the 2-amino
group as compared with the one at the 3-position of
the thiophene ring in 8b. In an effort to further delineate
the scope of the cyclization process, the elaboration of
other amino ester models, substituted by indolyl, benzo-
furyl or pyridothienyl groups on the aromatic moiety
was explored. Thus, ring closure of the known ethyl 3-
amino-1H-indole-2-carboxylate (8d)29 to the corre-
sponding indolopyrimido-b-carboline 2d was performed
in 48% yield. The use of the known ethyl 3-amino-
benzo[b]furane-2-carboxylate (8e)30 and ethyl 3-amino-
Consistent with the above remark, when amino-imine
derivative 9a was treated with 3 equiv of NaH in dry
DMF at 0 °C, then at room temperature for 12 h, the
isolated product, after the usual work up and recrystal-
lization of the resulting solid from dry ethanol afforded
rutaecarpine (1a) in 58% yield. This results from the
peptidic coupling process via the intermediate anion
10a. Interestingly when the reaction was conducted in
a one-step procedure starting from the cyclic imino-thio-
ether 5, evaporation of AcOH and its replacement with
dry DMF after 4 h of reaction gave the expected alkal-
oid 1a in 55% yield. This is identical to the overall yield
reported above for the two separate steps.
thieno[2,3-b]pyridine-2-carboxylate
(8f),30b,31
also
demonstrate the effectiveness of this protocol since the
cyclized benzofuropyrimido-b-carboline 2e and pyrido-
thienopyrimido-b-carboline 2f were isolated in 48%
and 39% yield, respectively. An additional demonstra-
tion of the utility of this methodology was made by
the synthesis of a new complex N-polyheterocyclic
system containing pyridopyrimido-b-carboline. For
instance, either methyl or ethyl 6-amino[1,3]dioxolo-
[4,5-g]quinoline-7-carboxylate (8g) (obtained by the
modified classical procedure32 from the commercially
available 6-nitrobenzo[1,3]dioxole-5-carbaldehyde (11)),
were converted successfully into the expected dioxolo-
benzopyridopyrimido-b-carboline 2g (Scheme 4). This
compound was isolated by chromatography followed
by recrystallization from ethanol in 41% yield, which
is comparable to that reported for related structures.
Having established the capacity of cyclic imino-thio-
ether 5 to undergo a tandem amino-methylthio displace-
ment/amino ester cyclization to produce rutaecarpine
alkaloids, we sought to determine if this mechanism
might be extended to heteroaromatic amino esters.
Thus, under our optimized conditions (Scheme 3), reac-
tion of the commercial methyl 3-aminothiophene-2-car-
boxylate (8b) with imino-thioether 5 (1 equiv) afforded
the fused thieno[3,2-d]pyrimidone component 2b in
51% yield. Its spectroscopic data (NMR, IR, etc.) were
in good agreement with those reported earlier by Moh-
We then, finally, tested the behavior of 5-methylsulfa-
nyl-3,4-dihydro-2H-pyrrole (13) as starting material in
our protocol (Scheme 5).

1780
A. Hamid et al. / Tetrahedron Letters 47 (2006) 1777–1781
Hamid. We are also grateful for many fruitful discus-
sions throughout the course of this work with Professor
B. Decroix.
CO2R
CN
NO2
12
CHO
NO2
O
O
O
O
CO2R
NC
Piperidine
ROH
11
85%
Fe
References and notes
51%
AcOH
CO2R
NH2
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O
O
N
S
+
N
8g
N
H
5
41%
R=Me, Et
O
N
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N
N
H
O
O
N
2g
Scheme 4. Scheme leading to complex N-polyheterocyclic system 2g.
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O
CO2Me
NH2
N
N
+
86%
(14) Deoxyvasicinone
S
N
8a
13
Scheme 5. Scheme leading to the deoxyvasicinone alkaloid 14.
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3. Conclusion
We have performed successfully in this letter two short
and new syntheses of the rutaecarpine and euxylophor-
icine A alkaloids. Our strategy uses, in a one-pot proce-
dure, the cyclocondensation of aromatic amino acids or
the corresponding amino esters with imino-thioethers
derived from various thiolactams. This approach was
extended to the synthesis of other alkaloid analogues
in which the benzene moiety of rutaecarpine and euxylo-
phoricine A is replaced by various substituted benzene
rings as well as heterocyclic systems. The extension of
the reaction to the synthesis of deoxyvasicinone, starting
from pyrrolidin-2-thione was also accomplished effi-
ciently. Furthermore, the friendly reaction conditions,
the cheap and readily available reagents used in all the
steps make both methods suitable for the large-scale
production of these targets. Consequently, they allow
an easy and rapid access to original heterocycles of
potential pharmaceutical value.
Acknowledgements
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The authors are grateful to the Libyan Government for
a Graduate Fellowship (2002–2005) attributed to A.

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thioether 5 or 6 (0.15 mol) was refluxed in glacial acetic
acid (60 mL) under stirring for 24 h. After cooling,
evaporation of the solvent gave a solid which was
recrystallized from EtOH to furnish rutaecarpine (1a)
and its derivatives 1b,c and 2a in yields ranging from 75%
to 85%. Selected data for chlororutaecarpine (1b): yellow-
orange crystals (EtOH); mp > 300 °C (decomposition); IR
(KBr) 3042 (CH), 2975 (CH), 1651 (C@O), 1595 (C@N)
ꢀ
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cmÀ1
; d 3.12 (t,
1H NMR (300 MHz, DMSO-d6):
J = 6.26 Hz, 2H, CH2–CH2), 4.41 (t, J = 6.26 Hz, 2H,
CH2–CH2), 5.25 (br s, 1H, NH), 7.07 (t, J = 7.04 Hz, 1H,
Har), 7.21 (t, J = 7.04 Hz, 1H, Har), 7.41–7.52 (m, 3H,
Har), 7.64 (d, J = 7.83 Hz, 1H, Har), 8.13 (d, J = 7.83 Hz,
1H, Har); 13C NMR (75 MHz, DMSO-d6): d 18.8, 41.1,
112.6, 118.6, 119.5, 119.8, 120.1, 124.8, 125.0, 125.3, 126.1,
126.7, 128.7, 138.8, 138.9, 146.6, 148.5, 160.1. Anal. Calcd
for C18H12ClN3O: C, 67.19; H, 3.76; N, 13.06. Found: C,
67.03; H, 3.54; N, 12.96.
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279–281 °C (decomposition); IR (KBr) 3263 (NH broad),
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1704 (C@O), 1645 (C@N) cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 2.49 (s, 3H, CH3), 3.20 (t, J = 6.78 Hz, 2H,
CH2–CH2), 4.43 (t, J = 6.78 Hz, 2H, CH2–CH2), 5.40 (br
s, 1H, NH), 7.10 (t, J = 7.72 Hz, 1H, Har), 7.29 (t,
J = 8.62 Hz, 1H, Har), 7.45–7.53 (m, 2H, Har), 7.69 (dd,
J = 7.91 Hz, 2H, Har), 7.82 (dt, J = 0.94 and 7.62 Hz, 1H,
Har), 8.18 (dd, J = 0.75 and 7.81 Hz, 1H, Har), 11.95 (s,
1H, NH); 13C NMR (75 MHz, CDCl3): d 19.3, 40.3, 41.2,
113.0, 118.9, 120.3, 120.5, 120.9, 125.2, 125.4, 126.3, 126.6,
127.1, 135.0, 139.2, 145.8, 147.1, 160.9, 167.5. Anal. Calcd
for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C,
71.31; H, 5.21; N, 13.09.
23. Harayama, T.; Hori, A.; Serban, G.; Morikami, Y.;
Matsumoto, T.; Abe, H.; Takeuchi, Y. Tetrahedron
2004, 60, 10645–10649.
24. For the synthesis of the triheterocyclic thiolactam 4, see:
(a) Benovskyf, P.; Stille, J. R. Tetrahedron Lett. 1997, 38,
8475–8478; (b) Gittos, M. W.; Robinson, M. R.; Verge, J.
P.; Davies, R. V.; Iddon, B.; Suschitzky, H. J. Chem. Soc.,
Perkin Trans. 1 1976, 33–38.
25. For heteroannulation using this concept and leading to
imidazolo-, thiazolo-, and thiazinopyrimidones, see: (a)
Sauter, F.; Fro¨hlich, J.; Blasl, K.; Gewald, K. Heterocycles
1995, 40, 851–866; (b) Sauter, F.; Fro¨hlich, J.; Chow-
dhury, A. Z. M. S.; Hametner, C. Monatsh .Chem. 1997,
128, 503–508; (c) Sauter, F.; Fro¨hlich, J.; Chowdhury, A.
Z. M. S.; Hametner, C. Sci. Pharm. 1997, 65, 83–85; (d)
Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.; Bes-
son, T. Tetrahedron 2003, 59, 1413–1419; (e) Bock, M. G.;
DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.;
Springer, J. P.; Freidinger, R. M. J. Org. Chem. 1987, 52,
1646–1647; See also the use of this protocol in dihydro-
isoquinoline series: (f) Shklyaev, Y. V.; Glushkov, V. A.;
Belogub, N. B.; Misyura, N. B. Chem. Heterocycl. Compd.
1996, 32, 689–695.
28. Perrisin, M.; Luu, D. C.; Narcisse, G.; Bakri-Logeais, F.;
Huguet, F. J. Med. Chem. Chim. Ther. 1980, 15, 563–565.
29. See, for example, the following reference: Unangst, P. C.
J. Heterocycl. Chem. 1983, 20, 495–499.
30. (a) Sangapure, S. S.; Agasimundin, Y. S. Ind. J. Chem.
1976, 14B, 686–691; (b) Showalter, H. D. H.; Bridges, A.
J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J.
Med. Chem. Ch. 1999, 42, 5464–5474.
31. Schneller, S. W.; Clough, F. W. J. Heterocycl. Chem. 1974,
11, 975–977.
32. The reductive cyclization of the nitro derivative 12 to the
corresponding bicyclic amino ester 8g (8g with R = Et is
already described in the literature, 8g with R = Me
was unknown before this report) was achieved by using
TiCl4/Zn, TiCl4/Sm, or SmI2; in our case we used a
combination AcOH/Zn as a cheaper reagent for this
purpose.
33. Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.;
Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Org. Lett. 2005, 7,
3363–3366, and references cited therein.
26. General procedure: The suspension of an equimolecular
amount of amino acids 7a–c (0.15 mol) and imino-