Electrosynthesis of polycyclic quinazolinones and rutaecarpine from isatoic anhydrides and cyclic amines

Article abstract of DOI:10.1039/d0ra09382c

A direct decarboxylative cyclization between readily available isatoic anhydrides and cyclic amines was established to construct polycyclic fused quinazolinones employing electrochemical methods. This procedure was performed in an undivided cell without the use of a transition-metal-catalyst and external oxidant. A broad scope of polycyclic fused quinazolinones were obtained in moderate to good yields. Additionally, rutaecarpine was also prepared through our method in one step in good yield. This journal is

Full text of DOI:10.1039/d0ra09382c

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Electrosynthesis of polycyclic quinazolinones and
rutaecarpine from isatoic anhydrides and cyclic
amines†
Cite this: RSC Adv., 2020, 10, 44382
*
Xingyu Chen,‡ Xing Zhang,‡ Sixian Lu and Peng Sun
A direct decarboxylative cyclization between readily available isatoic anhydrides and cyclic amines was
established to construct polycyclic fused quinazolinones employing electrochemical methods. This
procedure was performed in an undivided cell without the use of a transition-metal-catalyst and external
oxidant. A broad scope of polycyclic fused quinazolinones were obtained in moderate to good yields.
Additionally, rutaecarpine was also prepared through our method in one step in good yield.
Received 4th November 2020
Accepted 30th November 2020
DOI: 10.1039/d0ra09382c
rsc.li/rsc-advances
Quinazolinones represent a class of important nitrogen con- quinazolinones from readily available materials are still in
taining heterocyclic compounds which are widely distributed in need. Intermolecular oxidative annulation reaction using cyclic
natural products and synthetic materials. Over the last few amines were reported by Zhang11 and Li12 to offer polycyclic
decades, hundreds of quinazolinone alkaloids with a polycyclic fused quinazolinones employing oxygen as oxidant (Scheme
structural motif have been discovered and studied for various 2c). Very recently, TBHP (t-butyl hydroperoxide) mediated
purposes.1 Representatively, rutaecarpine and its derivatives reaction between isatins and tetrahydroisoquinolines via
attracted considerable attention of pharmaceutical scientists cascade Baeyer–Villiger oxidation rearrangement and cycliza-
due to their broad biological activities including antiobesity,2 tion were achieved by us13 and Hu14 respectively. In the last few
anti-tumor,3 and cardiovascular protection.4 Owing to their years, the prosperity of electrochemistry provided us green and
wide applications, tremendous efforts have been devoted to the economy instrument for organic synthesis.15 Isatoic anhydrides
construction of this privileged skeleton. The classical synthetic are versatile bulk chemical materials which have been used to
approaches5 to quinazolinones depend on the condensation synthesis a large variety of compound especially N-heterocy-
between 2-aminobenzoic acid derivatives and other synthons, cles.16 Herein, as our continuous interests in the construction of
which suffered from tedious steps, hash conditions, limited bioactive heterocycles,17 we reported a direct electrochemical
scope and poor yields. To overcome these shortcomings, intermolecular [4 + 2] cycloaddition between readily available
a number of methodologies were established to synthesis isatoic anhydrides and cyclic amines leading to polycyclic qui-
polycyclic quinazolinones. Thanks to the rapid development of nazolinones and rutaecarpine (Scheme 2d). This protocol
transition-metal catalyzed C–H activation reactions, Pd,6 Ru,7 exhibited mild conditions, excellent yield and good functional
and Rh8 catalyzed intermolecular cyclization reactions between group tolerance. No additional oxidant and transition-metal-
pre-synthesized quinazolinones and alkynes, vinyl/allyl catalyst was need in the overall process (Scheme 1).
acetates, sulfoxonium ylides were developed successively to
We start our investigation with isatoic anhydride (1a) and
prepare poly-cyclic quinazolinones (Scheme 2a). Alternatively, tetrahydroisoquinoline (2a) as the model substrates. The reac-
Zheng and co-workers explored light9 or (NH4)2S2O8 (ref. 10) tion was conducted in an undivided cell equipped with two
induced intramolecular cyclization of 2-aminobenzamide and
2-nitrobenzamide derivatives, the products were synthesized
under metal-free conditions (Scheme 2b). These brilliant works
provide us efficient routes to polycyclic quinazolinones,
however, the highly-functionalized substrates they used need to
be synthesized in advance in several steps. More convenient and
straightforward synthetic methods to produce polycyclic
Institute of Chinese Meteria Medica, Artermisinin Research Center, Academy of
Chinese Medical Sciences, Beijing, 100700, P. R. China. E-mail: psun@icmm.ac.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra09382c
Scheme 1 Bioactive polycyclic quinazolinones.
‡ These author contributed equal to this paper.
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Table 1 Optimization of reaction conditionsa
Entry
Solvent
Electrolyte
Temperature
Yield (3a)b
1
2
3
4
5
6
7
8
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
MeOH
EtOH
TFE
NaClO4
LiClO4
nBn4NBF4
nBn4NPF6
KI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
75 ꢀ
75 ꢀ
75 ꢀ
75 ꢀ
75 ꢀ
75 ꢀ
75 ꢀ
75 ꢀ
C
C
C
C
C
C
C
C
0%
0%
0%
0%
33%
66%
72%
80%
88%
85%
82%
32%
45%
0%
9
75 ꢀC
10
11
12
13
14
75 ꢀ
75 ꢀ
75 ꢀ
50 ꢀ
25 ꢀ
C
C
C
C
C
HFIP
H2O
EtOH
EtOH
TBAI
a
Reaction conditions: 1a (1.2 mmol, 1.2 equiv.), 2a (1.0 mmol, 1.0
equiv.), electrolyte (1.0 M), solvent (10 mL), in an undivided cell
equipped with two graphite electrodes, constant voltage (6.0 V) for 6
b
hours under air atmosphere. Isolated yields.
Scheme 2 Synthesis of polycyclic quinazolinones.
(90% and 92%, respectively). When 6-triuoromethoxy isatoic
anhydride was tested, the expected product 3g was also ob-
tained in the yield of 88%. Additionally, a battery of halogen-
substituted isatoic anhydrides at the C-6 position of benzene
ring were also proved to be favorable for this electrochemical
transformation, and the corresponding products (3h–3j) were
synthesized in the yield over 75%. According to our previous
research, the product with iodine at the benzene ring could be
transformed to structural diverse compounds through Pd
catalyzed cross coupling reaction with alkyne, aryl-boronic acid
and amines. Isatoic anhydride with strong electron withdrawing
NO2 failed to give corresponding products. Then, products with
substituent group at C-5 position of the benzene ring were also
generated in the yields of 79% to 81% (3k–3l). We also examined
the multi-substituted isatoic anhydrides to provided structural
diverse products in the yield of 69% (3m). We then turned our
attention to the reaction with respect to the amines. A series of
tetrahydroisoquinoline was loaded to the reaction system and
desired products were generated in good yields. Either electron
donating methoxyl group (3o) or electron withdrawing nitro
group (3q) was proved to be tolerable for the process. These
results indicated that the electronic characters of the benzene
ring of tetrahydroisoquinoline has no obvious inuence on the
reaction outcomes. We are pleased to nd that di-substituted
quinazolinones 3r was generated in 89% yield. Apart from tet-
rahydroisoquinolines, isoindoline with ve-membered cyclic
amines was also examined to generate 3s in 81% yield.
graphite electrodes. At rst, a series of commonly used elec-
trolytes including perchlorate and ammonium were evaluated.
There was no de-sired product generated until potassium iodide
was employed as electrolyte (entries 1–5). When potassium
iodide was replaced with tetra-butyl ammonium iodide (TBAI),
a moderate yield of 66% was obtained (entry 6). Later, DMF was
examined to maintain the yield to 72% (entry 7). The yield was
promoted to over 80% when protic solvent such as MeOH,
EtOH, TFE and HFIP were used (entries 8–11). It was worth
mentioning that an excellent yield of 88% was obtained when
the reaction was performed in EtOH (entry 9). Only 32% product
was generated in H2O may be attributed to the poor solubility of
the reactant (entry 12). The yield was obviously decreased to
ꢀ
45% with the reduction of the temperature to 50 C (entry 13).
The reaction did not occur at room temperature (entry 14)
(Table 1).
Based on the optimized conditions, we turned to explore the
scope of the reaction. We are pleased to nd that this procedure
exhibited excellent functional group tolerance, as shown in
Table 2. Firstly, a wide range of isatoic anhydride derivatives
were investigated to be compatible with the reaction conditions.
Isatoic anhydride with methyl at C-8 position delivered prod-
ucts 3b in the yield of 81%. Substrate with methoxyl and
bromine at C-7 position were also proper for the optimized
conditions and corresponding product 3c and 3d was prepared
in 92% and 79% yields. Next, a series of isatoic anhydride with
different electronic effect groups at C6-position of the benzene
ring were tested. Electron neutral and donating groups (6-Me
and 6-OMe) performed well to yield 3e and 3f in high yields
Aer the substrates scope exploration, the reaction was
amplied to 10 mmol scales to illustrate the synthetic
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Table 2 Scope of the reactiona,b
Scheme 3 Synthetic application of the reaction.
tetramethylpiperidine-1-oxyl) and BHT (butylated hydrox-
ytoluene) (Scheme 4) were loaded to the reaction system, the
yield were reduced to less than 30%. When 2a was treated with
the standard conditions for two hours, 3,4-dihydroisoquinoline
(4) was obtained in the yield of 81%. The combination of 1a and
4 offer 3a in the yield of 98% under standard conditions. When
1a and 2a were heated at 75 ꢀC for 12 hours, 5 was generated in
95% yield. We treated 5 under standard conditions for 12 hours,
27% 3a was obtained with 70% starting material recovered.
The cyclic voltammetry experiments have been conducted to
determine the redox potential of the starting material (for
details see ESI†). Based on these results and previous reports,
we proposed the plausible reaction pathway as shown in
Scheme 5. The reaction could be accomplished in two paths.
Firstly, the iodine anion was oxidized at anode to generate
iodine radical which subsequently offered iodine. Next,
a
Reaction conditions: 1a (1.2 mmol, 1.2 equiv.), 2a (1.0 mmol, 1.0
equiv.), TBAI (1.0 M), EtOH (10 mL), in an undivided cell equipped
with two graphite electrodes, constant voltage (6.0 V) for 6 hours
under air atmosphere. b Isolated yields.
applications of the process. To our delight, this electrochemical
procedure performed smoothly at gram scale to afford the
product in 69% yield (Scheme 3a). Rutaecarpine is an inter-
esting natural product with polycyclic quinazolinone skeleton.
The convenient and environmental benign synthetic method
for bioactive natural products is one of the most pursued issues
for chemists. Herein, rutaecarpine was synthesised through our
method from commercially available starting materials in the
yield of 80% (Scheme 3b).
In the course of condition screening we found that only
iodine anion electrolyte could generate the desired product.
Molecular iodine and iodine reagents-mediated reactions have
been well explored as powerful instruments for organic
synthesis due to their characters of cheap, green, and easily
available.18 When we replaced the electrochemical conditions
with iodine, 80% yield was also obtained (Scheme 4). When
radical
scavengers
such
as
TEMPO
(2,2,6,6-
Scheme 4 Mechanism study.
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Conclusions
In summary, we have developed a straightforward electro-
chemical approach to construct polycyclic quinazolinones
from readily available isatoic anhydrides and cyclic amines in
one step. A broad scope of fused quinazolinones were prepared
in moderate to good yield in the absence of transition-metal
catalyst and external oxidant. This method also provided effi-
cient route to rutaecarpine.
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