Visible-Light-Mediated Synthesis of Rutaecarpine Alkaloids through C-N Cross-Coupling Reaction

Article abstract of DOI:10.1055/a-1468-6231

A visible-light-initiated cross-dehydrogenative-coupling amination is described, featuring metal- and photocatalyst-free, at room temperature, and using air as an oxidant. The reaction provides a facile approach for the synthesis of rutaecarpine and its derivatives. The substrates with electron-withdrawing groups give higher yields than those with electron-donating groups, but the substituent position has a negligible influence on the yield. Using binaphthyl-diyl hydrogen phosphate and dibenzyl phosphate as catalysts both deliver satisfying yields. This straightforward light-driven strategy might be applicable to the synthesis of quinazolinone derivatives.

Full text of DOI:10.1055/a-1468-6231

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–F
letter
A
en
D. Chen et al.
Letter
Synlett
Visible-Light-Mediated Synthesis of Rutaecarpine Alkaloids
through C–N Cross-Coupling Reaction
Dong Chena
Shiqing Lia
O
O
N
N
R1
Jinhua Wangb
Tiantian Goua
Linfeng Zhanga
Guixia Wang*a
Xiangfei Kong*a
R1
purple LED, rt, air
NH2
N
RO
RO
O
(0.1 equiv)
dioxane
HN
HN
up to 92% yield
P
OH
mild reaction conditions (rt, air)
metal- and photocatalyst-free
wide substrate scope (21 examples)
H2O and H2O2 release
a College of Chemistry and Bioengineering, Guangxi Key Laboratory of Elec-
trochemical and Magnetochemical Functional Materials, Guilin University
of Technology, 12 Jian Gan Road, Guilin 541004, P. R. of China
2010033@glut.edu.cn
xiangfei.kong@glut.edu.cn
b State Key laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China, School of Chem-
istry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai
Road, Guilin, 541004, P. R. of China
wang.jin.hua.821@163.com
Corresponding Authors
O
Received: 28.02.2021
Accepted after revision: 27.03.2021
Published online: 27.03.2021
O
N
O
N
R
N
N
O
N
DOI: 10.1055/a-1468-6231; Art ID: st-2021-l0073-l
N
O
N
HN
HO
O
Me
Abstract
A visible-light-initiated cross-dehydrogenative-coupling
camptothecin
luotonin A (R = H)
luotonin B (R = OH)
luotonin E (R = OMe)
tryptanthrin
amination is described, featuring metal- and photocatalyst-free, at
room temperature, and using air as an oxidant. The reaction provides a
facile approach for the synthesis of rutaecarpine and its derivatives. The
substrates with electron-withdrawing groups give higher yields than
those with electron-donating groups, but the substituent position has a
negligible influence on the yield. Using binaphthyl-diyl hydrogen phos-
phate and dibenzyl phosphate as catalysts both deliver satisfying yields.
This straightforward light-driven strategy might be applicable to the
synthesis of quinazolinone derivatives.
O
O
N
O
N
N
C
N
D
N
E
N
B
OH
HN
A
Me HN
rutaecarpine (1a)
vasicinone
evodiamine
Figure 1 Natural quinazolinones and related alkaloids
Key words cross-dehydrogenation coupling, C–H amination, photo-
chemistry, air oxidant, rutaecarpine, quinazolinone alkaloids
idemic effects,7 anti-inflammatory effects,8 antidiabetic
effects,9 antioxidative effects,10 and 15-lipoxygenase inhibi-
tory activity.11
Quinazolinone framework is one of the privileged struc-
tures possessing diverse biological and medicinal activities,
which is widely present in natural products and synthetic
materials.1 Polycyclic quinazolinones such as luotonins,
camptothecin, tryptanthrin, vasicinone, evodiamine, and
rutaecarpine (Figure 1) have attracted considerable atten-
tion because of their interesting biological activities, such
as vasorelaxing, cytotoxity, antiobesity, and antiplatelet ag-
gregation.2,3
In 1915 Asahina and Kashiwaki isolated rutaecarpine
(1a) for the first time from Evodia rutaecarpa,4 which has
long been used in traditional Chinese medicine as a herbal
remedy to treat gastrointestinal disorders, headache, post-
partum hemorrhage, etc.5 Since then, accumulating re-
search has proven new useful biological properties of ru-
taecarpine and its analogues, such as anticancer,6 hypolip-
Due to its multiple biological activities, many efforts
have been made on the synthesis of 1a and its ana-
logues.3f,12 Rutaecarpine (1a) was traditionally obtained
through building the D ring or C and D rings simultaneously
at the final stage, using anthranilic acid, tryptamine and
their derivatives as the starting materials.13 Recently, some
impressive protocols were reported by Su’s and Pan’s
groups to give 1a and its derivatives, respectively, as shown
in Scheme 1a,b.13d,e The Fischer indole synthesis was also
adopted to afford 1a by constructing the B ring, as depicted
in Scheme 1c.14 Although quite a few synthetic methodolo-
gies of 1a have been provided, most of which are multistep
synthetic projects or require special starting materials
and/or excess oxidant or reductant or harsh reaction condi-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Chen et al.
Letter
Synlett
tions, such as at high temperature. The concise and envi-
ronment-friendly methods never fail to fascinate organic
chemists. Recently, the synthesis of rutaecarpine alkaloids
via an electrochemical cross-dehydrogenative coupling at
the final stage was reported by Pan’s group (Scheme 1d)15
and Sun’s group (Scheme 1e).16 These are novel, straightfor-
ward, and step-economical synthetic approaches to obtain
1a.
tion of the synthesis and bioactivity of quinazolinone alka-
loids,24 and this article reports the use of the light-driven
intramolecular C–N cross-coupling reaction to synthesize
rutaecarpine and its derivatives as depicted in Scheme 1e.
Initially, 2-aminobenzamide (2a) was chosen as the
model substrate to investigate C–N cross-coupling reactions
under irradiation with 220 W m–2 and light with  = 395 nm
(Table 1). It was reported the phosphate catalysts worked
well in this visible-light-driven C–N cross-coupling reaction
based on 2-amino-benzamide derivatives by Zheng's
group.23 We first tried methyl phosphate as a catalyst. Using
10 mol% of it, the desired product 1a was generated only in
trace amounts (Table 1, entry 1). While using diphenyl
phosphate, the reaction proceeded smoothly to give 1a in
55% yield (entry 2). When dibenzyl phosphate was exam-
ined, the yield was improved to 66% (entry 3). The yield was
promoted to 70% when (R)-(–)-1,1′-binaphthyl-2,2′- diyl
hydrogenphosphate ((R)-BPA) was used (entry 4). Altering
the reaction time resulted in diminished yields (entries 5
and 6). Similarly, the yield of compound 1a was reduced
when 5 mol% of (R)-BPA were used (entry 7). The solvents
had a dominant influence on the reaction yields, and diox-
ane had been identified as the optimal solvent for this reac-
tion (entry 4). The replacement of dioxane with DMF, EtO-
Ac, THF, and MeOH as solvent did not improve the yield (en-
tries 8–11). Without the irradiation, the product 1a was not
obtained, and the starting material was recovered in diox-
ane, DMF, EtOAc, THF, and MeOH (entries 12–16). The pho-
tocatalyst R-(BRA) did not work under the nitrogen atmo-
sphere in dioxane, DMF, EtOAc, THF, and MeOH (entries 17–
21). The reaction also did not proceed in the absence of the
photocatalyst R-(BRA) (entry 22). These control experi-
ments indicated that light irradiation, O2, and the phos-
phate (R)-BPA were crucial for this reaction (entries 12–22).
Armed with the optimized conditions, we then system-
atically studied the scope of this reaction. We are pleased to
find that the procedure exhibited highly functional group
tolerance, as shown in Scheme 2. First, the substrates 2b
and 2c, bearing electron-neutral and electron-donating
groups at the C-3 position (3-Me and 3-OMe), afforded 1b
and 1c in 74% and 56% yields, respectively. While with halo-
gen substituents (3-F, 3-Cl, and 3-Br) the products 1d, 1e,
and 1f could be obtained in 92%, 76% and 77% yields, re-
spectively. Second, 2-aminobenzamide bearing methyl and
methoxy groups at C-4 position (2g and 2h) delivered 1g
and 1h in 82% and 57% yields, respectively. While with hal-
ogen substituents (4-F, 4-Cl, and 4-Br), the products 1i–k
could be given with moderate yields, too. Third, 2-amino-
benzamide bearing methyl and methoxy groups at C-5 po-
sition provided 1l and 1m in 54% and 59% yields, respec-
tively, while 2-aminobenzamide with halogen substituents
gave the products in 62% (1n), 83% (1o), and 65% yield (1p),
respectively. Finally, 2-aminobenzamide bearing methyl
and methoxy groups at C-6 position provided 1q and 1r in
90% and 52% yields, respectively. While from halogenated
a) Su's work13d
O
O
R1
EDCl (1.1–1.5 equiv)
DMF, air, 25–80 °C
N
OH
R1
N
+
R2
N
NH2
N
H
HN
R2
42–89% yield
b) Pan's work13e
O
O
N
N
N H
NC
R1
R1
DBU (3 equiv), DMA
150 °C, 20–36 h
F
HN
HN
R2
43–92% yield
R2
c) Chavan's work14
O
O
O
N
N
PhNHNH2
PPA
180 °C, 0.5 h
N
N
N
N
HN
NNHPh
O
95% yield
d) Pan's work15
O
O
N
N
n-Bu4NPF6 (0.2 equiv)
N
NH2
MeCN, air, 70 °C, 4 h
HN
HN
80% yield
O
e) Sun's work16
O
N
HN
O
+
N
CV = 6 V, TBAI (0.1 M)
EtOH, air, 75 °C, 6 h
HN
O
O
N
H
HN
80% yield
f) This work
O
R1
N
N
R1
purple LED
N
NH2
RO
RO
O
HN
(0.1 equiv)
P
HN
OH
Scheme 1 Various approaches towards rutaecarpine and its deriva-
tives
Photocatalysis has been proven to be a forceful and en-
vironment-friendly tool to initiate all kinds of organic reac-
tions. In photocatalytic processes, photoredox catalysts
normally play a crucial role.17 Some photoredox photocata-
lysts, such as Ru complexes,18 Ir complexes,19 organic dyes,20
and other photosensitizers,21 have been extensively investi-
gated in recent years. The visible-light-catalyzed cross-de-
hydrogenative coupling amination was developed by Pand-
ey’s group.22 Recently, a visible-light-driven intramolecular
C–N cross-coupling reaction was used to prepare the N-
substituted polycyclic quinazolinone derivatives by Zheng’s
group.23 In this reaction a long-lived photoactive photoiso-
mer complex was formed, and no metal- or photocatalysts
were used. Our research interest remains in the investiga-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

C
D. Chen et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditionsa
O
N
O
N
(R)-BPA
R1
N
R1
O
N
O
N
10 W LED, dioxane, rt, air, 12 h
NH2
N
HN
HN
10 W LED (395 nm)
NH2
catalyst, solvent, air, rt
2a–u, R1 = F, Cl, Br, Me or OMe
HN
1a–u
HN
1a
2a
O
N
N
O
O
N
N
O
N
N
HN
HO
O
O
O
P
HN
Me
P
OMe
HN
O
O
OMe
OH
O
O
HO
methyl
phosphate
1a, 74%
O
1b, 74%
1c, 56%
P
P
OH
OH
O
O
O
O
diphenyl
phosphate
dibenzyl
phosphate
(R)-BPA
N
N
N
N
N
N
HN
N
F
Cl
HN
1e, 76%
Br
HN
1f, 77%
1a (%)b
1d, 92%
Entry
Catalyst
Solvent
Time (h)
O
O
O
1
2
methyl phosphate
diphenyl phosphate
dibenzyl phosphate
(R)-BPA
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
12
12
12
12
18
6
trace
55
N
N
N
MeO
F
N
Me
N
HN
HN
HN
3
66
1g, 82%
1h, 57%
1i, 77%
O
O
O
N
4
70
Me
N
N
N
N
5
(R)-BPA
68
Cl
N
Br
F
6
(R)-BPA
53
HN
N
HN
HN
HN
HN
1j, 64%
1k, 62%
1l, 54%
7c
(R)-BPA
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
50
O
O
N
N
O
8
(R)-BPA
52
MeO
Cl
N
N
9
(R)-BPA
EtOAc
THF
51
N
10
11
12d
13d
14d
15d
16d
17e
18e
19e
20e
21e
22f
(R)-BPA
43
HN
HN
1m, 59%
1n, 62%
1o, 83%
(R)-BPA
MeOH
dioxane
DMF
39
Me
O
O
OMe
O
NRg
NR
NR
NR
NR
NR
trace
NR
NR
NR
NR
Br
(R)-BPA
N
N
N
N
N
(R)-BPA
N
HN
HN
(R)-BPA
EtOAc
THF
1p, 65%
1q, 90%
1r, 52%
(R)-BPA
F
Br
O
O
Cl
O
N
N
(R)-BPA
MeOH
dioxane
DMF
N
N
N
N
(R)-BPA
HN
1u, 75%
HN
HN
1s, 83%
1t, 63%
(R)-BPA
(R)-BPA
EtOAc
THF
Scheme 2 Substrate scope for the synthesis of rutaecarpine deriva-
tives
(R)-BPA
(R)-BPA
MeOH
dioxane
–
zamide with electron-withdrawing groups gave better
yields than those with electron-donating groups (such as
1d vs. 1c, 1i vs. 1h, 1n vs. 1m, and 1s vs. 1r).
a Reaction conditions: 2a (0.15 mmol), 10 mol% catalyst, solvent (1 mL, an-
alytical reagents), under air, at rt, irradiation with 10 W purple LED (395
nm), the glass tube is 6.0 cm away from the light source; (R)-BPA=(R)-(–)-
Based on the above experimental results and previous
literature,23,25 a possible reaction mechanism is depicted in
Scheme 3. This photocatalyzed C–N cross-coupling reaction
is initiated by the photoisomerization of 2a on irradiation
with visible light, hence giving the short-lived photoisomer
I. The long-lived photoenolization complex II is obtained by
the coordination of (R)-BPA through the hydrogen-bonding
interaction.23 Then the radical pair III is generated by a SET
process induced by irradiation of visible light. Then the su-
1,1′-binaphthyl-2,2′-diyl hydrogenphosphate.
b Isolated yield.
c (R)-BPA (5 mol%).
d Without light.
e Under N2.
f Without (R)-BPA.
g NR = no reaction.
substituents (6-F, 6-Cl, and 6-Br), the corresponding prod-
ucts could be prepared in moderate yields, too. As discussed
above, the reactions proceeded smoothly in all cases de-
spite of the electronic and steric properties of the substitu-
ents. Regardless of substituent positions, 2-aminoben-
peroxide radical anion O2 abstracts a H+ from the amino
•–
radical cation to generate the amino radical IV,25a followed
by an intramolecular 1,6-HAT process,25b thereby affording
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

D
D. Chen et al.
Letter
Synlett
the carbon-centered radical V. Next, the radical recombina-
easily converted into the iminium ion XI under acidic con-
ditions. The deprotonation of XI by the anion HO2– delivers
H2O2 and the target compound 1a.
•
tion of V and HO2 gives the crucial intermediate VI, an ac-
tive hydroperoxide species.23
The following reactions could be accomplished in two
paths. In path A, the ketone intermediate VII is produced via
the elimination of one water molecule from VI.23 Then in-
tramolecular addition between primary amine and carbon-
yl groups and subsequent dehydration would produce the
final product 1a. Alternatively, intermediate VI is trans-
formed into the iminium ion VIII via reversible heterolytic
bond cleavage and catalyzed by the Brønsted acid (R)-BPA
(path B).25c
In order to confirm the reaction mechanism, the LC–MS
of the crude reaction mixture was performed.26 The mass
spectrum contained a base ion at m/z 290.1297 (Supporting
Information), matching the protonated molecular ion of IX,
the m/z calculated for [M + H]+ was 290.1288 (Scheme 3). In
addition, there was a minor ion at m/z 291.1350 in the mass
spectrum (Supporting Information ), one mass unit higher
than that of IX, corresponding to [M + H]+ of IV and V.
In summary, a visible-light-driven cross-dehydrogena-
tion coupling was demonstrated to construct C–N bonds in
this work.27 Both (R)-BPA and dibenzyl phosphate gave sat-
isfying yields in this metal- and photocatalyst-free reaction.
We have successfully synthesized the rutaecarpine and its
derivatives under mild conditions. A broad scope of sub-
strates and several functional groups were well tolerated in
this protocol in moderate to excellent yields. The substrates
–
Then, the deprotonation of VIII by the anion HO2 , fol-
lowed by the intramolecular nucleophilic cyclization, gives
cyclized intermediate IX, the rutaecarpine hydride. Then IX
proceeds through the same transformations (steps A–F) to
generate another active hydroperoxide species X. And X is
*
O
O
H
O
OH
NH
*
P
H
O
N
N
N
O
O
hν
O
H
O
P
NH2
A
O
HN
HN
HO
N
B
HN
I
2a
SET: Single-electron tranfer
HAT: Hydrogen-atom transfer
II
*
O
N
O
O
hν
O2
– OOH
D
N
N
1,6-HAT
E
+
NH
SET
C
NH
H
H
N
N
HN
H
HN
H
–
O2
H
[M + H]+ = 291.1366
[M + H]+ = 291.1366
IV
V
III
O
N
O
O
P
O
O
N
O
– H2O
path A
HO
N
OOH
F
N
H
– H2O
O
NH2
HN
N
OOH
H
NH
HN
1a
H
VII
VI
path B
O
O
O
P
HO
O
O
+
N
N
– H2O2
A, B, C, D, E and F
N
H
–
OOH
N
N
HN
H
H
H
[M + H]+ = 290.1288
VIII
IX
O
O
O
O
N
N
P
+
N
– H2O2
O
HO
N
1a
H
H
OOH
HN
HN
OOH
–
XI
X
Scheme 3 The proposed mechanism
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

E
D. Chen et al.
Letter
Synlett
with electron-withdrawing groups gave higher yields than
those with electron-donating groups, but the substituent
position has a negligible influence on the yield. This
straightforward light-driven strategy might be applicable to
the synthesis of quinazolinone derivatives.
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Conflict of Interest
The authors declare no conflict of interest.
Funding Information
This work was supported by the Natural Science Foundation of
Guangxi Province (2020GXNSFAA297251), the National Natural Sci-
ence Foundation of China (22001049) and the Key Laboratory of Elec-
trochemical and Magnetochemical Function Materials.
N
ati
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(26) Mass spectra were obtained by using a LCMS-9030 quadrupole
mass spectrometer (SHIMADZU, Japan) equipped with an APCI
source operated in positive/negative ion mode and an Agilent
SB C18 column (150 mm × 2.1 mm, I.D., particle size 5 m) with
ultraviolet detection at 344 nm. The mobile phase was acetoni-
trile–water (51:49, v/v) at a flow rate of 0.2 mL/min at room
temperature.
References and Notes
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Eur. J. Med. Chem. 2015, 94, 87. (b) Schepetkin, I. A.; Khlebnikov,
A. I.; Potapov, A. S.; Kovrizhina, A. R.; Matveevskaya, V. V.;
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2019, 161, 179. (c) Wang, M.-X.; Lin, L.; Chen, Y.-D.; Zhong, Y.-P.;
Lin, Y.-X.; Li, P.; Tian, X.; Han, B.; Xie, Z.-Y.; Liao, Q.-F. Pharmacol.
Res. 2020, 159, 104978. (d) Surbala, L.; Singh, C. B.; Devi, R. V.;
Singh, O. J. J. Pharmacol. Sci. 2020, 143, 307. (e) Ma, J.; Chen, L.;
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(27) Typical Procedures
A glass tube (10 mL) was charged with 2a (0.022 g, 0.075
mmol), (R)-BPA (0.0025 g, 0.0075 mmol), and 1,4-dioxane (0.5
mL), then closed under air. The reaction was put on the photore-
actor which is cooled by 25 °C water, irradiated for 12 h. After
the reaction was completed (monitored by TLC), the solvent was
removed under reduced pressure, and the crude product was
purified by flash chromatography to give 1a in 70% yield; mp
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

F
D. Chen et al.
Letter
Synlett
1
259–261 °C. H NMR (500 MHz, CDCl3):  = 9.51 (s, 1 H), 8.33–
8.31 (m, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.66–7.61 (m, 2 H), 7.42 (t,
J = 7.5 Hz, 1 H), 7.36 (d, J = 5.0 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H),
7.17 (t, J = 7.5 Hz, 1 H), 4.59 (t, J = 5.0 Hz, 2 H), 3.23 (t, J = 5.0 Hz,
2 H). 13C NMR (126 MHz, CDCl3):  = 161.62, 147.50, 145.03,
138.31, 134.36, 127.26, 127.18, 126.60, 126.23, 125.64, 125.59,
121.18, 120.63, 120.10, 118.39, 112.10, 41.14, 19.68.
According to the procedures reported previously, 2a was readily
prepared form 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-indole (3)
and 2-aminobenzoic acid in the presence of HATU and Et3N,23
and tryptamine reacted with paraformaldehyde in the mixed
solvent of acetic acid and methanol to give 3.28
(28) Cochrane, E. J.; Hassall, L. A.; Coldham, I. J. Org. Chem. 2015, 80,
5964.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F