Catalyst-free cyclization of anthranils and cyclic amines: One-step synthesis of rutaecarpine

Article abstract of DOI:10.1039/c9cc06160f

An efficient synthesis of a variety of quinazolinone derivatives via a direct cyclization reaction between commercially available anthranils and cyclic amines is described. The developed transformation proceeds with the merits of high step- and atom-efficiency, a broad substrate scope, and good to excellent yields, without additional catalysts, and offers a practical way for the preparation of rutaecarpine and its derivatives with structural diversity.

Full text of DOI:10.1039/c9cc06160f

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DOI: 10.1039/C9CC06160F
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Catalyst-Free Cyclization of Anthranils and Cyclic
Amines: One-step Synthesis of Rutaecarpine
Jian Li,* Zheng-Bing Wang, Yue Xu, Xue-Chen Lu, Shang-Rong Zhu, Li Liu
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
derivatives. Bowman and Weaver’s group developed a radical
cyclization starting from 2-(1H-indol-3-yl)ethan-1-ol in four steps to
afford Rutaecarpine in only 1.2% yield.14 Bannister’s group reported
three steps reaction for the synthesis of Rutaecarpine through
tandem Sonagashira reaction / Lorock indole synthesis reaction /
intramolecular substitution in 61% yield in more than 168 hours.15 In
2008, Seidel’s group published a new redox-neutral condensation
reaction of aminobenzaldehyde with commercially available 2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole to access ring B and selective
oxidation of the coupling product provided the aimed structural
motif in 40% yield.16 Despite the significant utility of these
achievements, most of them suffer from one or more drawbacks
such as harsh reaction conditions, long reaction time and multistep
synthesis, which limited the expansion in the preparation of
compound libraries. Thus, the development of novel and efficient
strategy to access Rutaecarpine scaffolds from easily available
reagents remains highly desirable. Herein, we report a straight
approach to Rutaecarpine following one step cyclization by using
An efficient synthesis of a variety of quinazolinone derivatives via a
direct cyclization reaction between commercially available
anthranils and cyclic amines is described. The developed
transformation proceeds with the merits of high step- and atom-
efficiency, broad substrate scope, good to excellent yield, without
additional catalyst, which offers a practical way for the preparation
of Rutaecarpine and its derivatives with structural diversity.
Nitrogen-containing heterocycles are important structural motif in
many natural products and biologically active compounds.1 Among
them, quinazolinones have been demonstrated to possess a wide
range of biological and therapeutic activities, and the related units
extensively exist in numerous natural products, bioactive molecules,
pharmaceuticals and agrochemicals.2 In particular, quinazolinone-
containing Rutaecarpine and its derivatives have attracted
considerable interest due to their biological activities,3 such as
vasorelaxing,4 cytotoxity,5 antiobesity,6 antiplatelet aggregation7
(Scheme 1). For example, Rutaecarpine has been applied as a
vasodilator agent,8 compound HL-60 has been found to have
cytotoxity,9 valeric acid-Rutaecarpine has been investigated as an
antiplatelet inhibiton.10 Luotonin A, which carries both quinoline and
quinazoline rings, is a cyctotoxic alkaloid first isolated in 1997 from
the plant Peganum nigellastrum and it has been widely used for
treatment of rheumatism and inflammation.11 In 2003, Luotonin A
has been found to display useful cytotoxity in vitro against the
murine leukemia P-338 cell with an IC50 value of 6.3 μM.12 Therefore,
numerous approaches have been nicely explored to access the
related scaffolds in recent years.13 The core scaffold of Rutaecarpine
contains A, B, C, D and E rings, and a variety of synthetic endeavors
have devoted to construct the skeleton from two strategies (Scheme
1): 1) formation of ring C; 2) formation of ring B. The construction of
ring C is the general method which usually started from indole
Representtive Rutaecarpine Derivatives
O
N
O
N
O
O
N
N
N
N
N
N
N
N
HN
HN
HOOC(H2C)4
Cl
Luotonins A
Rutaecarpin
Cl
e
HL-60
Antiplatelet Inhibition
previous work
strategy 1
C
: formation of ring
Bowman and Waver, 2007 [ref. 13]
O
O
N
OH
N
(Me3Sn)2
3 steps
N
B
N
C
A
t-BuPh, hv
15% yield
N
D
8% yield
Br
N
H
HN
E
H
Bannister et al. 2014, [ref. 14]
OMe
O
OH
OMe
N
N
H+ , 120 o
168 h
C
A
B
N
C
2 steps
N
D
O
N
81% yield
HN
E
N
Cl 75% yield
HN
B,
Siedel et al., 2008 [ref.15]
strategy 2
: formation of ring
CHO
N
140 o
C
N
KMnO4, acetone
A
B
C
HN
EtOH, 72h
66% yield
61% yield
N
N
NH2
D
N
H
HN
E
H
HN
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School
of Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou,
213164, China. E-mail: lijianchem@cczu.edu.cn
†Electronic Supplementary Information (ESI) available: [synthetic details, additional
spectroscopic data, and characterization of the new compounds. CCDC1940471
and 1943441 contain the supplementary crystallographic data for this paper.
For ESI or other electronic formatSee DOI: 10.1039/x0xx00000x
O
N
Our work
130 o
C
B
A
O
C
NH
toluene
80% yield
N
N
N
H
D
HN
E
Scheme 1. Rutaecarpine and its derivatives and the synthetic
strategies
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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reaction to synthesize 5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-
View Article Online
8-ones 3. For anthranils, aromatic ring bearing electron-withdrawing
DOI: 10.1039/C9CC06160F
one step cyclization by using readily available substrates including of
anthranils and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole using the
strategy of formation of ring B.
Inspired by Seidel’s work, one ring-fused aminal was obtained
from the thermally promoted reaction between an
aminobenzaldehyde and a cyclic amine.16 In view of our interest in
the preparation of nitrogen-containing polycyclic products via
tandem reaction,17 we thought that developing the cascade coupling
reaction between anthranils and cyclic amines would offer a direct
method for the synthesis of quinazolinone compounds. On the other
or electron-donating substituents were tolerated in this
transformation. Generally, the electronic properties of the
substituents had an effect on the reaction rate, as the reactions of
the substrates bearing electron-donating groups proceeded
effectively, 5,6-Dimethoxybenzo[c]isoxazole and 6,7-dihydro-
[1,4]dioxino[2',3':4,5]benzo[1,2-c]isoxazole worked well to give 3g
and 3h in 80% and 81% yields, respectively. Next, a range of THIQs
were examined to modify the substituents at 2-, 3- and 4-positions
of the quinazolinone products, and the reaction was compatible with
fluoro, chloro, bromo, methyl and methoxy functional group as
summarized in Table 2. Substitutions at the 5-, 6- and 7- positions of
THIQs were all well tolerated. When 6-position substituted THIQ was
used as substrate, the desired product 3l with the best yield (96%)
was observed. In addition, two substituted reaction substrates could
also be subjected to the reaction conditions, with 3r and 3s obtained
hand, anthranil has been investigated as
a new type of
multifunctional synthesis agent for its ability to deliver a nucleophilic
amino group and an electrophilic formyl group simultaneously.18 To
explore the possibility of the proposed annulation process, we began
our preliminary investigation by using anthranil 1a and equal
equivalent of 1,2,3,4-tetrahydroisoquinoline (THIQ) 2a in 1,2-
in
good
yields
by
employing
and
6,7-dichloro-1,2,3,4-
6,7-dimethoxy-1,2,3,4-
o
dichloroethane (DCE) in a sealed tube at 130 C in the absence of
tetrahydroisoquinoline
catalyst (Table 1, entry 1). Gratifyingly, target product 5,6-dihydro-
8H-isoquinolino[1,2-b]quinazolin-8-one 3a was obtained in 30% yield
tetrahydroisoquinoline as the substrates.
after 1 hour. Subsequently, a survey of other solvents, such as DMSO, Table 2. Anthranils and THIQ scopea,b
DMF, EtOH and Toluene, was carried out. We found that a change in
O
130 o
C
N
the solvent has a significant effect on the reaction outcome. Among
R1
R1
O
R2
NH
N
the solvents screening, Toluene appeared to be the most suitable
reaction media, thus giving the product 3a in 80% yield (Table 1,
entry 5). Since both reaction substrates are liquid, we tried the
reaction without solvent at 130 oC. Surprisingly, the yield (92%) of the
desired product 3a was significantly improved at the same
temperature. These results prompted us to optimize the yield of the
reaction. To a large extent, the temperature affected the reaction
N
R2
2
1
3
O
N
O
O
Cl
N
N
N
N
N
N
3a,
3b, 88%
92%
O
3c, 65%
O
O
O
MeO
MeO
N
3d, X = Cl, 85%
3e,
N
N
N
o
rate. The yield of 3a was only 45% at 100 C and the product was
X =NO2, 75%
O
N
N
X
3f, X = CO2Me, 85%
difficult to produce at lower temperature.
3h,
81%
3g, 80%
O
O
N
Table 1. Optimization of the reaction conditionsa
O
N
N
3k,
X = F, 82%
N
F
Cl
O
3l, X =Cl, 96%
N
N
3m, X =OMe, 87%
3j,
91%
3i, 80%
N
solvent
temp.
X
O
NH
O
N
N
N
O
O
N
2a
1a
N
N
N
3a
3n, X = F, 82%
X =Cl, 91%
X = Br, 90%
X = Me, 90%
3o,
3p,
3q,
N
Entry
Solvent
Temperature (oC)
Yield (%) b
3r, 86%
OMe
Cl
3s,
84%
X
OMe
Cl
1
2
3
4
5
6
7
8
9
DCE
DMSO
DMF
EtOH
Toluene
--
130
130
130
130
130
130
50
30
55
50
--
a Reaction condition: 1 (0.5 mmol), 2 (0.5 mmol), 130 oC, 1 h. b Isolated
yield of pure product.
Next, a range of 3-aryl benzo[c]isoxazole were examined to
modify the substituents with THIQs under the optimized reaction
conditions (Table 3). As the good tolerance of substrate-bearing Cl
and I provides a convenient platform for further elaboration via
conventional Pd(0)-catalyzed cross-coupling reaction, 5-chloro-3-
arylbenzo[c]isoxazole and 5-iodo-3-arylbenzo[c]isoxazole were
employed to explore the scope of isoxazole. 3-Position aromatic ring
of benzo[c]isoxazole could be decorated with different substituents
in para positions, thus affording corresponding products in 65-91%
yields. The structure of 4o was confirmed by single-crystal X-ray
diffraction. When 3-phenyl-5-(phenylethynyl) benzo[c]isoxazole was
used as substrate, the product 4q was produced in 75% yield, it
revealed that the alkynyl group was also tolerated in this
transformation.
80
92
--
--
--
80
--
--
100
45
a Reaction condition: 1a (0.5 mmol), 2a (0.5 mmol) in solvent (2.0
mL), 1 h. b Isolated yield of pure product.
Having identified optimal reaction conditions for the cyclization
reaction, we next turned our attention to the scope of the reaction
by reacting various anthranils with THIQs. The results are
summarized in Table 2. Firstly, a variety of anthranils 1 with a range
of substituents at 5,6-position, including substituted halogen,
piperidine, methoxyl, ester and nitro groups were evaluated in the
To demonstrate the synthetic application of this protocol, we
carried out the reaction with anthranil 1a and 2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole 5 in toluene at 130 C for the preparation of
o
2 | J. Name., 2012, 00, 1-3
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Rutaecarpine (Scheme 2). Gratifyingly, the desired product between secondary amine and carbonyl groups to foVrimewNAr,tOicl-eaOcenltinael
Rutaecarpine could be obtained in 80% yield. Thus, this method C, and subsequent dehydration would happen to produce D.
DOI: 10.1039/C9CC06160F
provides a convenient approach to these quinazolinone-containing Complex D could be transformed into the target compound 4 by 1,5-
compounds, the synthesis of which otherwise required several steps H migration. When the R group was hydrogen, compound 3 was
from known starting materials.
obtained under air atmosphere by oxidation reaction.21
Table 3. Benzo[c]isoxazoles and THIQs scopea,b
Table 4. 3-Substituted benzo[c]isoxazoles scopea,b
R2
R2
R2
R1
R2
N
R1
130 o
C
N
R1
R3
R1
O
130 o
C
NH
NH
N
N
R3
O
N
1
2
N
H
4
N
HN
X
N
X
1
5
6
4f,
4g
,
x = H 91%
4a,
4b
X = H, 87%
, X= Cl, 90%
, X= Br, 86%
, X= OMe, 80%
, X= Cl, 88%
X
X
4h
, X= Br, 86%
, X= OMe, 81%
, X= Me, 80%
6a,
6b,
6c,
6d,
6e,
6f,
X = H, 70%
X = Cl, 71%
X = Br, 68%
X = Me, 58%
X = t-Bu, 56%
X = OMe, 55%
4c
4d
4i
4j
I
Cl
N
N
4e,
X= C4H9, 70%
6g,
6h,
6i,
X = Cl, 56%
X = Br, 68%
X = t-Bu, 53%
N
N
4k
, X= C4H9, 77%
Cl
I
N
N
X
Br
N
N
HN
HN
4l
, X= Me, 83%
4m, X= OMe, 71%
4n,
I
Cl
N
X= C4H9, 65%
N
N
p-OMe-C6H4
OMe
Cl
OMe
4o,
79%
N
OMe
Ph
OMe
Ph
Ph
N
Ph
HN
N
N
6j,
52%
N
N
4p,
70%
4q,
75%
a Reaction condition: 1 (0.5 mmol), 5 (0.6 mmol) in toluene (0.5 mL),
130 oC, 1 h. b Isolated yield of pure product.
a Reaction condition: 1 (0.5 mmol), 2 (0.5 mmol), 130 oC, 1 h. b Isolated
yield of pure product.
O
N
Further investigation with respect to the scope of 3-aryl
benzo[c]isoxazole 1 was conducted with 2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole 5 in toluene (Table 4). It was exciting to find that
3-aryl benzo[c]isoxazole 1 bearing halogen, methyl, tert-butyl and
methoxy groups all gave the desired products smoothly. The
formation of 6j was confirmed by X-ray crystallography.
130 o
C
O
NH
N
toluene
80% yield
N
N
H
5
HN
Rutaecarpine
1a
O
NaH(60%,1.5 equiv.)
DMF, reflux
O
Br
2 equiv.
7
O
N
O
N
O
N
130 o
C
N
N
O
NH
NaOH
THF/H2O, reflux
95% yield
toluene
80% yield
N
N
N
H
N
O
HN
Rutaecarpine
N
1a
HOOC(H2C)4
5
O
8
Antiplatelet Inhibition
9
Scheme 2. Synthesis of Rutaecarpine.
Scheme 3. Synthesis of Antiplatelet inhibition.
As a utility of our method, we provided a concise route for the
formal synthesis of valeric acid-Rutaecarpine 9,10 which was
investigated as an antiplatelet inhibition, as shown in Scheme 3.
Firstly, Rutaecarpine was generated under the standard reaction
conditions. Treatment of Rutaecarpine with benzyl 5-
R
R
HO
R
O
ND
R
HN
N
O
2
D
D
O
D
N
N
D
N
NH
D
1
A
bromopentanoate
7 afforded compound 8, which can be
C
B
subsequently converted to target compound 9. This strategy made a
significant progress in the synthesis of 9 and provided the final
compound in 76% yield totally.
O
R
D
R
D
O2
N
1,5-H migration
N
N
In order to figure out the reaction mechanism, we conducted a
series of control experiments (Scheme S3). Base on the results and
related literature,19 a plausible reaction mechanism is depicted for
the formation of compounds 3 (path a) and 4 (path b) in Scheme 4.
Anthranil is regarded as a heteroaromatic 10-π-electron system and
its dipole moment (3.06 D) indicates a considerable degree of
polarity, which may be attributed to contributions from canonical
forms. Firstly, THIQ was attacked by the resonance A generated from
anthranil 1 to afford intermediate B.20 Then intramolecular addition
R = H
N
N
N
D
D
3
4
Scheme 4. Possible mechanistic pathways.
In conclusion, we have developed a concise and general strategy
for the construction of a quinazolinones by a direct cyclization
reaction between anthranils and cyclic amines in the absence of a
This journal is © The Royal Society of Chemistry 20xx
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transition-metal catalyst without the use of an additional (11) (a) Z. Ma, Y. Hano, T. Nomura, Heterocycles 2005, 65, 2203;
View Article Online
initiator/oxidant. This transformation produced a broad range of
DOI: 10.1039/C9CC06160F
(b) J. L. Liang, H. C. Cha, Y. Jahng, Molecules 2011, 16, 4861.
quinazolinones as well as fused quinazolinones in good to excellent
yields under simple reaction conditions. Applying this strategy, a
concise synthesis of Rutaecarpine and its derivatives has been
accomplished without muti-steps process. Further studies to
understand the mechanism for the reaction are currently underway
in our laboratory.
We thank Jiangsu Key Laboratory of Advanced Catalytic Materials
and Technology (BM2012110), Advanced Catalysis and Green
Manufacturing Collaborative Innovation Center in Changzhou
University.
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