Total synthesis of rutaecarpine and analogues by tandem azido reductive cyclization assisted by microwave irradiation

Article abstract of DOI:10.1055/s-0030-1259095

The total synthesis of rutaecarpine and several analogues has been developed by using an azido reductive cyclization process starting from substituted azido benzoic acids. The intramolecular azido reductive cyclization step was performed with triphenylphosphine or Ni₂B in HCl-MeOH (1 M) using microwave irradiation. This synthetic route is amenable for the generation of a library of quinazolinone compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259095

LETTER
61
Total Synthesis of Rutaecarpine and Analogues by Tandem Azido Reductive
Cyclization Assisted by Microwave Irradiation
Total
S
yntheses of
h
R
utaecarpin
m
e
andAnalogues ed Kamal,*a M. Kashi Reddy,a T. Srinivasa Reddy,b Leonardo Silva Santos,c Nagula Shankaraiah*b
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27193189; E-mail: ahmedkamal@iict.res.in
b
c
National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca,
P.O. Box 747, Talca, Chile
Fax +56(71)200448; E-mail: lssantos@utalca.cl
Received 13 August 2010
merous methods have been reported for the construction
of the D ring and/or for building the connection between
the D and B rings starting from tryptamine derivatives.24
Recently, Lee and co-workers developed a versatile syn-
Abstract: The total synthesis of rutaecarpine and several analogues
has been developed by using an azido reductive cyclization process
starting from substituted azido benzoic acids. The intramolecular
azido reductive cyclization step was performed with triphenylphos-
phine or Ni2B in HCl–MeOH (1 M) using microwave irradiation. thetic strategy to rutaecarpine by nitro reductive cycliza-
tion with SnCl2·2H2O.25 In spite of the advantages of tin
This synthetic route is amenable for the generation of a library of
quinazolinone compounds.
reduction, there are instances in the literature wherein
Key words: quinazolinones, b-carbolines, azido-reductive cycliza-
tion, Ni2B, microwave irradiation
substantial quantities of tin by-products are formed. Fur-
thermore, most of the cell lines that have been biologically
screened have proven to be intolerant of tin even at very
low levels. We have been involved in the synthesis of bio-
The quinazolinone skeleton is an important building block active fused quinazolinone natural products, such as (–)-
for a large number of naturally occurring alkaloids1 and vasicinone and its deoxy derivatives, by employing azido
their synthetic analogues. Such compounds possess a va- reductive cyclization approaches26 using lactams and sub-
riety of biological properties, such as antimalarial,2 anti- stituted azido benzoic acids as precursors. In this context,
convulsant,3 antibacterial,4 antidiabetic,5 and anticancer we became interested in the total synthesis of rutaecarpine
activity.6 Thus, due to the diverse range of the pharmaco- (1a) and its analogues 1b–h by employing azido reductive
logical activities of quinazolinones and their derivatives, cyclization assisted by microwave irradiation.
numerous methods have been developed for their synthe-
sis.7 Rutaecarpine is the major alkaloid component of Wu-
O
C
A
N
Chu-Yu, a Chinese herbal drug, and the rutaecarpine scaf-
fold has been found to act by suppressing platelet plug for-
mation in mesenteric venules and increasing intracellular
Ca2+ in endothelial cells.8 Recently, Don and co-workers9
reported that rutaecarpine derivatives selectively inhibited
human CYP1A1, CYP1A2, and CYP2B1, and exhibit
cytotoxicity10 as well as inhibitory effects on COX-2.11
Rutaecarpine (1a; Figure 1)12 was originally isolated from
the dried fruits of Evodia rutaecarpa and callus tissue cul-
tured from the stem of Phellodendron amurense.13–16 It
has been extensively used as a remedy for headache,
dysentery, cholera, worm infections, and postpartum.17
Moreover, the analogues, euxylophoricine A (1b) and eu-
xylophoricine C (1c), have also been found to possess
anti-stomachic, antiemetic, anti-nociceptive, anti-inflam-
matory, anti-pyretic, analgesic, astringent, anti-hyperten-
sive, uterotonic, and TCDD-receptor agonist activities.18
Robinson and co-workers19 reported the first total synthe-
sis of rutaecarpine and, since then, several routes to 1a and
its derivatives have been developed.20–23 In addition, nu-
B
D
N
H
N
E
R3
R1
R2
R1 = R2 = R3 = H, rutaecarpine (1a)
R
R
R
R
R
R
R
1 = H, R2 = R3 = OMe (1b)
1 = H, R2–R3 = -OCH2O- (1c)
1 = H, R2 = OMe, R3 = H (1d)
1 = H, R2 = OBn, R3 = OMe (1e)
1 = H, R2 = Cl, R3 = H (1f)
1 = H = R2 = H, R3 = Br (1g)
1 = OBn, R2 = R3 = H (1h)
Figure 1 Representative chemical structure of rutaecarpine (1a)
and its analogues 1b–h
Microwave-assisted (MWA) organic synthesis has played
a pivotal role in the preparation of N-heterocyclic com-
pounds.27 In contrast to conventional heating, application
of microwave energy has the major advantage of shorter
reaction times because of the rapid core heating associated
with microwaves. Therefore, reactions frequently exhibit
cleaner product profiles and use minimal amounts of sol-
vent. This prompted us to synthesize these quinazolinones
using a CEM Discovery microwave reactor with nickel
boride (Ni2B) as a reducing reagent.26b As expected, the
SYNLETT 2011, No. 1, pp 0061–0064
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.12.2010
DOI: 10.1055/s-0030-1259095; Art ID: D22210ST
© Georg Thieme Verlag Stuttgart · New York

62
A. Kamal et al.
LETTER
reaction time was reduced dramatically. The mild reaction 3H-b-carboline (3) was prepared from the commercially
conditions, as well as the high yield of this reaction, en- available tryptamine (2) by treatment with acetic anhy-
couraged us to apply this methodology to its derivatives. dride in anhydrous CH2Cl2 at room temperature for two
During the course of this synthesis, we noted that Ni2B hours to give the N-acetylated amide; subsequent Bis-
was the reagent of choice to obtain such heterocyclic com- chler–Napieralsky cyclization with POCl3 in anhydrous
pounds.
benzene at reflux for one hour gave imine 3 in good yield
(85%) as shown in Scheme 2.
The retrosynthetic analysis of the central framework of ru-
taecarpine (1a) and analogues is depicted in Scheme 1.
The synthetic features include isomerization of the en-
docyclic imine double bond into an exocyclic olefin by
benzoylation, oxidation of the terminal double bond to
form a cyclic amide, and azido reductive cyclization, as
key steps. Imine 3 was obtained from tryptamine (2) by
treatment with Ac2O followed by Bischler–Napieralsky
cyclization.28 Having prepared imine 3, the stage was set
for an important coupling reaction with suitably substitut-
ed azido benzoyl chlorides, which were prepared from a
variety of azido benzoic acids by treatment with COCl2.
Next, the key intermediates 5a–h were oxidized with
KMnO4 to convert the exocyclic double bond into cyclic
amides 6a–h. We also attempted an intramolecular aza-
Wittig reductive cyclization approach to the synthesis of
5a using TPP followed by treatment with aqueous ammo-
nia under heating; however, this approach afforded the
quinazolinone natural product 1a in lower yield (62%).
These results prompted us to explore MWA reactions to
improve the yields in the final step of the azido-reductive
cyclization of the key intermediates 6a–h by using Ni2B
as a reducing reagent.
i) Ac2O, CH2Cl2
r.t., 2 h
NH2
N
ii) POCl3
N
N
H
dry benzene
reflux, 1 h, 85%
H
2
3
Scheme 2 Synthesis of b-carboline 3 by employing Bischler–
Napieralsky cyclization
The key intermediates 5a–h (77–84%)30 were obtained by
mixing tricyclic b-carboline 3 and a variety of substituted
2-azidobenzoyl chlorides in CH2Cl2 at room temperature
for two hours (Scheme 3). After isomerization of the en-
docyclic double bond to the exocyclic double bond, an ox-
idative cleavage step was carried out by using KMnO4 to
give the requisite 2,3,4,9-tetrahydro-b-carbolin-1-one de-
rivatives 6a–h25,30 in moderate yields (58–67%). Then, we
explored an intramolecular aza-Wittig reductive-cycliza-
tion with 5a using TPP in THF for 12 hours to give phos-
phine intermediate 7a, although a considerable amount of
the azido starting material remained (indicated by TLC).
To this reaction mixture was added 1–2 mL of ammonia
solution, and the mixture was heated at 60–70 °C for two
hours to afford the quinazolinone natural product 1a in
moderate yield (62%).
O
O
N
N
N
N
R3
R2
H
H
N
O
Based on the results of this study we decided to explore
the reduction of azido functionality with Ni2B/HCl–
MeOH (1 M) using microwave irradiation (70 W)26b to af-
ford the final products (1a–h)31 in excellent yields (80–
90%) as shown in Scheme 3.
R3
N3
1a–h
6a–h
R1
R1
R2
R1
O
In conclusion, we have developed a simple and efficient
synthetic strategy to rutaecarpine and its derivatives by
employing an azido reductive tandem-cyclization ap-
N
R2
R3
N3
N
R3
R2
H
proach.29–31
A successful microwave-assisted reaction
COOH
N3
4a–h
5a–h
with nickel boride as a reducing reagent has been used in
the final cyclization step of the synthesis. The reaction
conditions are particularly attractive and mild, and the
synthetic route allows easy access to the quinazolinone al-
kaloids.
R1
NH2
N
N
H
N
H
Acknowledgment
2
3
M.K.R. thanks CSIR New Delhi for the award of a research fel-
lowship. L.S.S. thanks Fondecyt (1085308) for support.
Scheme 1 Retrosynthetic analysis of rutaecarpine (1a) and its ana-
logues 1b–h
References and Notes
Our synthetic work began with substituted azido benzoic
acids 4a–h, which were prepared by reported methods.26a
The acids 4a–h were converted into their acid chlorides
by employing COCl2 in anhydrous CH2Cl2 at 0 °C to
room temperature for six hours. 1-Methyl-4,9-dihydro-
(1) Mhaske, S. B.; Argade, P. Tetrahedron 2005, 62, 9787.
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Kim, H.-S.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima,
Y. J. Med. Chem. 1999, 42, 3163.
Synlett 2011, No. 1, 61–64 © Thieme Stuttgart · New York

LETTER
Total Syntheses of Rutaecarpine and Analogues
63
R1
O
R2
R3
N3
i) (COCl)2, CH2Cl2
0 °C to r.t., 6 h
N
N
R3
H
ii) 3, Et3N, Ch2Cl2
r.t., 2 h
(77–84%)
COOH
N3
5a–h
4a–h
R2
R1
KMnO4
dry acetone
r.t., 12 h (58–67%)
O
O
N
TPP, THF
r.t., 12 h
N
N
H
O
N
R3
H
O
N
7a
N3
6a–h
PPh3
R2
R1
aq NH3, Δ
2 h, 62%
Ni2B, HCl–MeOH (1 M)
MW (70 W)
2 min, 80–90%
O
N
O
N
N
H
N
N
H
N
R3
1a–h
R1
rutaecarpine (1a)
R2
Scheme 3 An intramolecular tandem azido reduction cyclization approach to rutaecarpine (1a) and analogues 1b–h
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Synlett 2011, No. 1, 61–64 © Thieme Stuttgart · New York

64
A. Kamal et al.
LETTER
H.; Kim, S. I.; Park, J. G.; Lee, E. S.; Jahng, Y. Heterocycles
2001, 55, 1555. (d) Chang, H. W.; Kim, S. I.; Jung, H.;
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119.0, 118.4, 112.0, 111.1, 101.8, 41.1, 29.6; HRMS (ESI):
m/z [M + Na]+ calcd for C19H15N5O: 352.1174; found:
352.1182.
(30) Oxidation reaction procedure for 2-(2-azidobenzoyl)-
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (6a): To a
stirred solution of 5a (0.400 g, 1.13 mmol) in anhydrous
acetone (20 mL) was added KMnO4 (0.264 g, 1. 70 mmol) at
r.t. and the mixture was stirred for 12 h. The solvent was
evaporated under reduced pressure and the reaction mixture
was diluted with EtOAc (40 mL) and filtered through Celite.
The organic layer was washed with aqueous NaHCO3
followed by brine and dried over anhydrous Na2SO4. After
filtration and evaporation, the crude product was purified by
column chromatography, eluting with EtOAc–hexane (7:3)
to afford 6a in 67% yield as a white solid; mp 87–90 °C. IR
(KBr): 3421, 2111, 1697, 1634 cm–1; 1H NMR (400 MHz,
CDCl3): d = 8.18 (br s, 1 H), 7.84 (d, J = 7.84 Hz, 1 H),
7.63–7.59 (m, 2 H), 7.38–7.32 (m, 1 H), 7.23–7.20 (m, 2 H),
7.18 (d, J = 7.55 Hz, 1 H), 7.16–7.19 (m, 1 H), 4.43 (br,
2 H), 3.24 (t, J = 8.10 Hz, 2 H); 13C NMR (100 MHz,
CDCl3): d = 167.9, 161.2, 142.6, 137.8, 132.6, 130.1, 129.5,
128.1, 126.5, 124.8, 124.6, 123.4, 119.8, 118.9, 118.0,
101.9, 41.9, 21.7; HRMS (ESI): m/z [M]+ calcd for
C18H13N5O2Na: 354.3186; found: 354.3207.
(31) Typical procedure for preparation of rutaecarpine (1a): A
mixture of 6a (0.100 g, 0.302 mmol) in MeOH (2.0 mL) and
Ni2B (0.114 g, 0.906 mmol) and 1.0 M HCl (1.0 mL) in a
glass tube was placed in a microwave reactor (CEM
Discovery LabMate) and irradiated at 70 W for 2 min,
during which time the temperature was kept at 52 °C with
cooling. The reaction mixture was brought to ambient
temperature and the solvent was evaporated, the residue was
neutralized with saturated aqueous 5% NaHCO3 solution,
and then extracted with EtOAc (3 × 25 mL). The combined
organic phases were washed with brine, dried over Na2SO4,
filtered and evaporated under reduced pressure. The crude
product thus obtained was purified by column chroma-
tography on silica (60–120 mesh) to afford the final
compound 1a (0.072 g, 90%); mp 254–255 °C. 1H NMR
(400 MHz, CDCl3): d = 9.25 (br s, 1 H), 8.33 (dd, J = 1.23,
7.85 Hz, 1 H), 7.62–7.74 (m, 3 H), 7.43–7.69 (m, 2 H), 7.35
(dt, J = 1.22, 6.85 Hz, 1 H), 7.20 (t, J = 8.44 Hz, 1 H), 4.57
(t, J = 6.96 Hz, 2 H), 3.25 (t, J = 6.95 Hz, 2 H); 13C NMR
(100 MHz, CDCl3): d = 161.6, 147.5, 144.9, 138.2, 134.3,
127.2, 126.6, 126.1, 125.6, 125.5, 121.3, 120.6, 120.1,
118.3, 112.1, 19.6, 41.1, 20.2; HRMS (ESI): m/z [M + H]+·
calcd for C18H13N3O: 287.1054; found: 287.1057.
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(29) Coupling reaction procedure for {2-azidophenyl)-(1-
methylene-3,4-dihydro-1H-pyrido[3,4-b]indol-2 (9H)-
yl}methanone (5a): To a stirred solution of 3 (0.250 g, 1.53
mmol) in CH2Cl2 (10 mL) was added Et3N (0.22 mL, 1.63
mmol) dropwise at 0 °C over 10 min, then 2-azidobenzoyl
chloride (0.295 g, 1.62 mmol) dissolved in CH2Cl2 (5 mL)
was added at the same temperature. The reaction was
brought to r.t. and stirred for another 2 h. After completion
of the reaction, the solvent was evaporated and extracted
with CH2Cl2 (3 × 20 mL), washed with aqueous NaHCO3
followed by brine, separated, and dried over anhydrous
Na2SO4. The combined organic extracts were evaporated
under reduced pressure and further purified by column
chromatography with EtOAc–hexane (1:1) as eluent to
afford 5a in 84% yield as a white solid; mp 86–88 °C. IR
(KBr): 3381, 2105, 1638, 1415 cm–1; 1H NMR (300 MHz,
CDCl3): d = 8.12 (br s, 1 H), 7.53 (d, J = 7.55 Hz, 1 H),
7.36–7.43 (m, 2 H), 7.32 (d, J = 7.55 Hz, 1 H), 7.20–7.25
(m, 1 H), 7.11–7.16 (m, 3 H), 4.93 (s, 1 H), 4.07 (s, 1 H),
4.00 (t, J = 8.58, 9.09 Hz, 2 H), 3.24 (t, J = 8.08 Hz, 2 H);
13C NMR (75 MHz, CDCl3): d = 167.6, 136.9, 132.3, 132.1,
130.3, 129.1, 128.2, 126.7, 125.1, 124.7, 123.5, 119.9,
Euxylophoricine A (1b): Yield: 0.043 g (82%); mp 293–
295 °C; 1H NMR (300 MHz, CDCl3): d = 9.25 (br s, 1 H),
7.65 (s, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.44 (d, J = 8.1 Hz,
1 H), 7.35 (dd, J = 7.8, 8.1 Hz, 1 H), 7.20 (t, J = 7.8 Hz,
1 H), 7.06 (s, 1 H), 4.60 (t, J = 7.0 Hz, 2 H), 4.01 (s, 3 H),
3.99 (s, 3 H), 3.24 (t, J = 7.0 Hz, 2 H); 13C NMR (75 MHz,
CDCl3): d = 161.1, 155.1, 148.7, 143.9, 143.6, 138.2, 127.3,
125.7, 125.3, 120.6, 119.9, 117.6, 114.5, 111.9, 107.1,
106.4, 56.3, 56.2, 41.1, 19.6; HRMS: m/z [M + H]+· calcd for
C20H17N3O3: 347.1263; found: 347.1266.
Euxylophoricine C (1c): Yield: 0.041 g (80%); mp 307–
309 °C; 1H NMR (300 MHz, CDCl3): d = 9.10 (br s, 1 H),
7.65 (s, 1 H), 7.64 (d, J = 6.95 Hz, 1 H), 7.44 (d,
J = 6.92 Hz, 1 H), 7.36 (t, J = 6.95 Hz, 1 H), 7.20 (t,
J = 6.9 Hz, 1 H), 7.06 (s, 1 H), 6.10 (s, 2 H), 4.57 (t,
J = 6.9 Hz, 2 H), 3.27 (t, J = 6.9 Hz, 2 H); 13C NMR (75
MHz, CDCl3): d = 160.9, 153.5, 147.1, 143.9, 143.8, 138.1,
127.2, 125.7, 125.4, 120.6, 120.0, 117.6, 116.1, 111.9,
105.9, 104.2, 102.5, 41.8, 19.8; HRMS: m/z [M + H]+· calcd
for C19H13N3O3: 331.0955; found: 331.0961.
Synlett 2011, No. 1, 61–64 © Thieme Stuttgart · New York

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