One-pot three-component selective synthesis of isoindolo[2,1-: A] quinazoline derivatives via a palladium-catalyzed cascade cyclocondensation/cyclocarbonylation sequence

Article abstract of DOI:10.1039/c7ob00256d

A practical and highly efficient procedure for the selective preparation of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones through a palladium-catalyzed one-pot three-component cascade reaction of 2-aminobenzamides with 2-bromobenzaldehydes and carbon monoxide under atmospheric pressure has been developed. This cascade reaction, in which four new C-C/C-N bonds and two new rings are simultaneously constructed, is triggered by a cyclocondensation of 2-aminobenzamides with 2-bromobenzaldehydes, followed by a Pd-catalyzed cyclocarbonylation of the in situ formed 2,3-dihydroquinazolin-4(1H)-ones with CO (1 atm). Compared with the existing methods, the present protocol has the advantages of readily available starting materials, broad substrate scope, structural diversity of products, and free of high-pressure equipment.

Full text of DOI:10.1039/c7ob00256d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00256D
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ARTICLE
One‐pot three‐component selective synthesis of isoindolo[2,1‐
a]quinazoline derivatives via palladium‐catalyzed cascade cyclo‐
condensation/cyclocarbonylation sequence
Received 00th January 20xx,
Accepted 00th January 20xx
Shenghai Guo,* Jianhui Zhai, Fang Wang, and Xuesen Fan*
DOI: 10.1039/x0xx00000x
A practical and highly efficient procedure for the selective preparation of 6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
diones through palladium‐catalyzed one‐pot three‐component cascade reaction of 2‐aminobenzamides with 2‐
bromobenzaldehydes and carbon monoxide under atmospheric pressure has been developed. This cascade reaction, in
which four new C‐C/C‐N bonds and two new rings are simultaneously constructed, is triggered by a cyclocondensation of
2‐aminobenzamides with 2‐bromobenzaldehydes, followed by a Pd‐catalyzed cyclocarbonylation of the in situ formed 2,3‐
dihydroquinazolin‐4(1H)‐ones with CO (1 atm). Compared with the existing methods, the present protocol has the
advantages of readily available starting materials, broad substrate scope, structural diversity of products, and free of high‐
pressure equipment.
www.rsc.org/
component domino reaction of 2‐formylbenzoic acid with
isatoic anhydride and amines under different reaction
conditions (Scheme 1).2,7 While the above‐mentioned
Introduction
Isoindoloquinazoline derivatives, as an important class of
quinazoline‐containing heterocyclic compounds, are attracting
increasing interest as they are frequently encountered in
natural products and synthetic compounds with a wide range
of bioactivities.1 Among them, isoindolo[2,1‐a]quinazoline
derivatives have been utilized as not only potent inhibitors of
TNF‐α2 and cancer cell proliferation,3 but also efficient
stabilizer of organic materials against degradation caused by
heat, light and/or oxidation.4 In general, isoindolo[2,1‐
a]quinazoline derivatives could be obtained through
annulation of 2‐formylbenzoic acid derivatives with the
corresponding nucleophiles. For instance, Wang and other
groups reported an efficient synthesis of isoindolo[2,1‐
a]quinazoline derivatives through cascade reaction of 2‐
formylbenzoic acid with 2‐aminobenzamides or 2‐
aminobenzohydrazides in different solvents (Scheme 1).5
Foroumadi and Bunce independently disclosed a synthesis of
synthetic routes are generally effective and reliable, all of
them require the use of 2‐formylbenzoic acid derivatives,
which are unfortunately difficult‐to‐obtain from commercial
sources and very expensive, especially for the substituted ones.
Therefore, the development of novel and general synthetic
approaches toward isoindolo[2,1‐a]quinazoline derivatives
from commercially available and inexpensive starting materials
remains in high demand for both organic and medicinal
chemists.
Meanwhile,
palladium‐catalyzed
carbonylative
multicomponent reaction turns out to be one of the most
powerful tools for the construction of various carbonyl‐
containing acyclic and cyclic organic compounds with a
substantial increase in molecular complexity.8 Among these
reactions, palladium‐catalyzed three‐component carbonylative
cyclizations of aromatic halides with carbon monoxide and
organic nucleophiles have been proven to be highly effective in
the synthesis of various quinazoline derivatives.9 However, to
the best of our knowledge, an efficient synthesis of
isoindolo[2,1‐a]quinazoline‐5,11‐diones
via
one‐pot
reduction/cyclization cascade reaction of 2‐nitrobenzamides
with 2‐formylbenzoic acid in the presence of reductants (such
as: SnCl2 or Fe) (Scheme 1).6 Pal and other groups
demonstrated that 6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐
5,11‐diones could be efficiently synthesized by a three‐
isoindolo[2,1‐a]quinazoline
derivatives
by
employing
palladium‐catalyzed three‐component cyclocarbonylation has
not been reported yet until now. In a continuation of our
efforts to explore novel synthetic apporaches toward valuable
quinazoline‐containing heterocyclic compounds,10 we disclose
herein a practical synthesis of 6,6a‐dihydroisoindolo[2,1‐
a]quinazoline‐5,11‐diones from inexpensive commercial
reagents 2‐aminobenzamides, 2‐bromobenzaldehydes, and
carbon monoxide (1 atm) (Scheme 1). Now, we would like to
report our results in this regard.
Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug
Innovation, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, China. E‐mail: shguo@htu.cn;
xuesen.fan@htu.cn.
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra of
compounds 3a‐3u, 4, and 5. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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Table 1. Optimization of reaction conditions for the synthesis of 3aa
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DOI: 10.1039/C7OB00256D
Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd2(dba)3
PdCl2
Ligand
Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield(%)b
46
BuPAd2
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
Scheme 1. Synthetic routes toward isoindolo[2,1‐a]quinazoline derivatives.
2
X-Phos
32
3
TFP
48
Results and discussion
Initially, 2‐aminobenzamide (1a) and 2‐bromobenzaldehyde
4
TCHP
44
5
PPh3
39
(
2a) were chosen as model substrates to optimize the reaction
conditions with regard to ligands, Pd catalysts, bases, and
solvents (Table 1). To our delight, treatment of 1a (0.4 mmol)
and 2a (0.4 mmol) with CO (1 atm) in the presence of Pd(OAc)2
(5 mol %), n‐butyl di(1‐adamantyl)phosphine (BuPAd2) (15
mol %), and DABCO (3.0 equiv.) in DMSO (2 mL) at 120 oC for
10 h could afford the expected 6,6a‐dihydroisoindolo[2,1‐
a]quinazoline‐5,11‐dione (3a) in 46% isolated yield (entry 1).
Next, with Pd(OAc)2 as catalyst, other ligands including 2‐
dicyclohexylphosphino‐2',4',6'‐triisopropylbiphenyl (X‐Phos),
tris(2‐furanyl)phosphine (TFP), tricyclohexylphosphine (TCHP),
triphenylphosphine (PPh3), and tri‐(tert‐butyl) phosphonium
tetrafluoroborate ([(t‐Bu)3PH]BF4) were screened (entries 2‐6).
Among them, [(t‐Bu)3PH]BF4 gave the best result (63%). Then,
the effect of different Pd catalysts such as Pd(PPh3)2Cl2,
Pd2(dba)3, and PdCl2 on this reaction was also investigated
(entries 7‐9). Of these catalysts, PdCl2 exhibited the highest
catalytic activity. In addition, five other bases including DBU,
Et3N, morpholine, piperidine, and K2CO3 were also tried,
however, all of them were less effective than DABCO (entries
10‐14 vs 9). In following studies, we found that when DMF,
NMP, and EtOH were used to replace DMSO as the reaction
medium, lower yields of 3a were observed (entries 15‐17).
Decreasing or increasing the reaction temperature from 120 oC
resulted in decreased yields of 3a (entries 18‐19). Moreover, it
was also observed that reducing the loadings of Pd catalyst
and ligand gave 3a in a lower yield of 32% (entry 20). Finally,
PdCl2, [(t‐Bu)3PH]BF4, and DABCO were proved to be essential
for the formation of 3a (entries 21‐23).
6
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
[(t-Bu)3PH]BF4
-
63
7
48
8
56
9
82
10
11
12
13
14
15
16
17c
18d
19e
20f
21
22
23
PdCl2
nd
PdCl2
Et3N
18
PdCl2
morpholine
piperidine
K2CO3
nd
PdCl2
32
PdCl2
nd
PdCl2
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
-
60
PdCl2
NMP
68
PdCl2
EtOH
nd
PdCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
54
PdCl2
62
PdCl2
32
-
nd
PdCl2
nd
PdCl2
[(t-Bu)3PH]BF4
nd
a The reactions were run with: 1a (0.4 mmol), 2a (0.4 mmol), CO (1 atm), catalyst
(0.02 mmol), ligand (0.06 mmol), base (1.2 mmol), solvent (2 mL), 120 oC, 10 h. b
Isolated yield; nd = not detected. c The reaction was run at 80 C. The reaction
o
d
With the optimized reaction conditions (Table 1, entry 9) in
hand, the scope and limitation of this novel cascade reaction
was run at 100 oC. The reaction was run at 130 oC. With the use of catalyst
e
f
(0.008 mmol) and ligand (0.024 mmol).
leading to isoindolo[2,1‐a]quinazolines (
and the results are shown in Table 2. First, the reactions of three other aldehydes (
several 2‐bromobenzaldehyde derivatives with 2‐ 2‐bromothiophene‐3‐carbaldehyde, and 2‐chlorobenzaldehyde,
aminobenzamide (1a) and carbon monoxide (1 atm) were with 2‐aminobenzamide (1a) under atmospheric CO pressure.
investigated. We found that substituted 2‐ Unfortunately, all of them could not afford the desired
bromobenzaldehydes ( ) bearing either electron‐donating isoindolo[2,1‐a]quinazolines (
). Next, the substrate scope of
groups (‐Me and ‐OMe) or electron‐withdrawing groups (‐F, ‐Cl, 2‐aminobenzamide derivatives (
) were examined. The results
and –CF3) on the phenyl ring at different positions were all indicated that 2‐aminobenzamides (
) having a methyl,
compatible with the reaction conditions to afford the methoxyl, or chloro group on the phenyl moiety could take
corresponding isoindolo[2,1‐a]quinazoline derivatives 3b 3f in part in this reaction smoothly to deliver the desired products
60%‐85% isolated yields and no obvious electronic effect was 3g
3r in modest to good yields. Meanwhile, substrates ( ) with
observed. In addition, we also studied the cascade reactions of electron‐donating substituents (R2) generally gave the desired
3) were then explored
2), including 2‐bromonicotinaldehyde,
(2)
2
3
1
1
‐
‐
1
2 | J. Name., 2012, 00, 1‐3
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base under nitrogen atmosphere afforded compound
4 (88%)
Table 2. Scope for the synthesis of isoindolo[2,1‐a]quinazoline derivatives (3)a,b
View Article Online
(8%) (Scheme 2, eq 1). SDecOoI:n1d0,.10t3h9e/Cp7aOlBla0d0i2u5m6D‐
along with
5
catalyzed cyclocarbonylation of
4 with CO (1 atm) by using [(t‐
Bu)3PH]BF4 as ligand and DABCO as base provided 3a in 86%
isolated yield (Scheme 2, eq 2).
3c, 72%
3a, 82%
3d, 85%
3g, 80%
3b, 72%
3f, 60%
3i, 63%
3e, 77%
3h, 63%
3k, 70%
3n, 69%
Scheme 2. Control experiments.
On the basis of the above results and previous reports,8i,11
a
possible mechanism for the formation of 3a is demonstrated in
Scheme 3. Initially, the oxidative addition of Pd (0) to
compound
of 2‐aminobenzamide (1a) with 2‐bromobenzaldehyde (2a
under basic conditions, gives rise to a palladium complex (I).
Next, the insertion of CO into the C‐Pd bond of complex (
4, which is formed in situ via the cyclocondensation
)
I
)
3j, 69%
3l, 66%
3o, 63%
affords an acylpalladium complex (II), which then eliminates
hydrogen bromide regioselectively to yield intermediate III
under the promotion of base. Finally, reductive elimination of
III delivers 3a and regenerates the Pd(0) species. In addition, it
is also possible that the intramolecular nucleophilic attack of
NH on the carbonyl group of acylpalladium complex (II) gives
the product (3a) and the active Pd(0) species.
3m, 64%
3p, 64%
3s, 83%
3r, 60%
3u, 32%
3q, 62%
3t, 70%
a Reaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), CO (1 atm), PdCl2 (0.02 mmol),
b
[(t‐Bu)3PH]BF4 (0.06 mmol), DABCO (1.2 mmol), DMSO (2 mL), 120 oC, 10 h.
Isolated yields are shown.
products in yields higher than those with electron‐withdrawing
substituents (3g and 3k vs 3p). To further extend the scope of
Scheme 3. Possible mechanism for the formation of 3a.
amide substrates (1), we also studied the reactions of N‐Bn
and N‐NHPh substituted 2‐aminobenzamides with 2‐
bromobenzaldehyde (2a) and CO (1 atm) under the optimized
reaction conditions. It turned out that the reactions
underwent smoothly to yield the corresponding isoindolo[2,1‐
a]quinazoline derivatives 3s and 3t in 83% and 70% yields,
respectively. Finally, the palladium‐catalyzed three‐component
reaction of 2‐aminoquinoline‐3‐carboxamide with 2a and CO
(1 atm) was also tried under the optimized reaction conditions.
To our delight, the desired product 3u could be obtained in 32%
isolated yield.
Conclusions
In conclusion, we have successfully developed a facile and
efficient protocol for the selective synthesis of isoindolo[2,1‐
a]quinazoline derivatives via palladium‐catalyzed three‐
component carbonylative cyclization of 2‐aminobenzamides
with 2‐bromobenzaldehydes under atmospheric pressure of
carbon monoxide. Compared with the existing procedures, the
present synthetic route exhibits good functional group
tolerance, commercially available starting materials, high
regioselectivity, and operational simplicity. Further
development of novel palladium‐catalyzed three‐component
carbonylative cyclization reactions for the construction of
To gain some insights into the mechanism for the formation
of products 3, the following control experiments were carried
out, and the results are demonstrated in Scheme 2. First,
treatment of a mixture of 1a and 2a with the use of DABCO as
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other quinazoline‐fused heterocyclic compounds is currently 67.1, 109.6, 117.1, 119.9, 120.3, 123.7, 124.9, 125.9, 128.6,
View Article Online
DOI: 10.1039/C7OB00256D
C16H13N2O3 [M + H]+ 281.0921, found 281.0918.
underway in our laboratory.
134.0, 137.8, 143.7, 163.9, 164.1, 164.8. HRMS (ESI) calcd for
8‐Fluoro‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
Experimental Section
dione (3d). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (91 mg, 85%), mp 235‐237 oC. 1H NMR (DMSO, 400
MHz) δ 6.59 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.78 (t, J = 6.8 Hz,
1H), 7.94‐7.99 (m, 3H), 8.02‐8.05 (m, 1H), 8.13 (d, J = 8.0 Hz,
1H), 9.52 (s, 1H); 13C NMR (DMSO, 150 MHz) δ 67.1, 112.3 (d, J
= 25.2 Hz, 1C), 118.3 (d, J = 24.2 Hz, 1C), 119.9, 120.3, 125.3,
127.0 (d, J = 9.9 Hz, 1C), 128.1, 128.7, 134.1, 137.5, 143.8 (d, J
= 9.8 Hz, 1C), 163.9, 164.0, 165.4 (d, J = 249.3 Hz, 1C). HRMS
(ESI) calcd for C15H9FN2NaO2 [M + Na]+ 291.0540, found
291.0541.
General
Unless noted, all commercial reagents and solvents were used
without further purification. Melting points were recorded
with a micro melting point apparatus and uncorrected. The 1H
NMR spectra were recorded at 400 or 600 MHz. The 13C NMR
spectra were recorded at 150 MHz. High‐resolution mass spec‐
tra (HRMS) were collected in ESI mode by using a MicrOTOF
mass spectrometer. All reactions were monitored by thin‐layer
chromatography (TLC) using silica gel plates (silica gel 60 F254
0.25 mm) and components were visualized by observation
under UV light (254 and 365 nm)
9‐Chloro‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
dione (3e). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (88 mg, 77%), mp 242‐244 oC. 1H NMR (DMSO, 400
MHz) δ 6.52 (s, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.51‐7.55 (m, 1H),
7.69‐7.72 (m, 2H), 7.93‐7.98 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H),
9.38 (s, 1H); 13C NMR (DMSO, 150 MHz) δ 67.3, 120.0, 120.5,
124.1, 125.5, 126.5, 128.7, 133.6, 133.8, 134.1, 135.6, 137.3,
139.8, 163.6, 164.0. HRMS (ESI) calcd for C15H10ClN2O2 [M + H]+
285.0425, found 285.0429.
General procedure for the preparation of isoindolo[2,1‐
a]quinazoline derivatives (3).
To a schlenk tube (15 mL) containing a solution of 2‐
aminobenzamide
bromobenzaldehyde
1
(0.4 mmol) in DMSO (2 mL) were added 2‐
(0.4 mmol), PdCl2 (0.02 mmol), [(t‐
2
Bu)3PH]BF4 (0.06 mmol), DABCO (1.2 mmol) under CO (1 atm)
atmosphere. Then, the mixture was stirred at 120 oC for 10 h.
After being cooled to room temperature, the reaction was
quenched with NH4Cl and extracted with ethyl acetate. The
combined organic layer was washed with H2O and brine, and
then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by col‐
umn chromatography on silica gel to afford the corresponding
8‐(Trifluoromethyl)‐6,6a‐dihydroisoindolo[2,1‐
]quinazoline‐5,11‐dione (3f). Petroleum ether/ethyl acetate
a
o
1
(2:1) as eluent; white solid (76 mg, 60%), mp 245‐247 C. H
NMR (DMSO, 400 MHz) δ 6.60 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H),
7.71‐7.75 (m, 1H), 7.99 (dd, J = 0.8, 7.6 Hz, 1H), 8.04‐8.11 (m,
3H), 8.31 (s, 1H), 9.45 (s, 1H); 13C NMR (DMSO, 150 MHz) δ
67.5, 120.1, 120.5, 122.2 (q, J = 3.3 Hz, 1C), 124.2 (q, J = 271.4
Hz, 1C), 125.1, 125.5, 127.9 (q, J = 4.4 Hz, 1C), 128.7, 133.2 (q, J
= 31.7 Hz, 1C), 134.1, 135.5, 137.2, 141.8, 163.6, 163.8. HRMS
(ESI) calcd for C16H9F3N2NaO2 [M + Na]+ 341.0508, found
341.0512.
6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐dione
3.
6,6a‐Dihydroisoindolo[2,1‐
a
]quinazoline‐5,11‐dione (3a)2.
Petroleum ether/ethyl acetate (1:1) as eluent; white solid (82
mg, 82%), mp 256‐258 oC. 1H NMR (DMSO, 400 MHz) δ 6.52 (s,
1H), 7.35 (t, J = 8.0 Hz, 1H), 7.66‐7.73 (m, 2H), 7.80 (t, J = 7.2 Hz,
1H), 7.88‐7.90 (m, 2H), 7.97‐7.98 (m, 1H), 8.08 (d, J = 8.0 Hz,
1H), 9.41(s, 1H); 13C NMR (DMSO, 150 MHz) δ 67.5, 120.0,
120.5, 124.3, 124.6, 125.3, 128.7, 130.7, 131.6, 133.7, 134.0,
137.6, 141.2, 164.1, 165.0. MS (ESI) m/z 251 [M + H]+.
3‐Methyl‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
dione (3g). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (84 mg, 80%), mp 243‐245 oC. 1H NMR (DMSO, 400
MHz) δ 2.38 (s, 3H), 6.48 (s, 1H), 7.52 (dd, J = 2.0, 8.4 Hz, 1H),
7.67 (t, J = 8.0 Hz, 1H), 7.77‐7.81 (m, 2H), 7.87‐7.89 (m, 2H),
7.96 (d, J = 8.0 Hz, 1H), 9.39 (s, 1H); 13C NMR (DMSO, 150 MHz)
δ 21.0, 67.5, 120.0, 120.3, 124.2, 124.6, 128.7, 130.6, 131.8,
133.6, 134.5, 134.6, 135.2, 141.2, 164.2, 164.8. HRMS (ESI)
calcd for C16H12N2NaO2 [M + Na]+ 287.0791, found 287.0794.
9‐Methyl‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
dione (3b). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (76 mg, 72%), mp 255‐257 oC. 1H NMR (DMSO, 400
MHz) δ 2.45 (s, 3H), 6.47 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.59 (d,
J = 7.6 Hz, 1H), 7.67‐7.71 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.96
(d, J = 7.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 9.38 (s, 1H); 13C NMR
(DMSO, 150 MHz) δ 21.4, 67.4, 120.0, 120.5, 124.3, 124.4,
125.2, 128.7, 131.8, 134.0, 134.5, 137.7, 138.6, 140.6, 164.1,
165.1. HRMS (ESI) calcd for C16H13N2O2 [M + H]+ 265.0972,
found 265.0976.
3,9‐Dimethyl‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
dione (3h). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (70 mg, 63%), mp 265‐267 oC. 1H NMR (DMSO, 400
MHz) δ 2.37 (s, 3H), 2.45 (s, 3H), 6.42 (s, 1H), 7.49‐7.52 (m, 1H),
7.58 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.73‐7.76 (m, 2H), 7.94 (d,
J = 8.4 Hz, 1H), 9.33 (s, 1H); 13C NMR (DMSO, 150 MHz) δ 21.0,
21.4, 67.4, 120.0, 120.3, 124.29, 124.31, 128.7, 131.9, 134.3,
134.50, 134.54, 135.3, 138.6, 140.5, 164.2, 164.9. HRMS (ESI)
calcd for C17H15N2O2 [M + H]+ 279.1128, found 279.1142.
8‐Methoxy‐3‐methyl‐6,6a‐dihydroisoindolo[2,1‐
8‐Methoxy‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐5,11‐
dione (3c). Petroleum ether/ethyl acetate (1:1) as eluent;
white solid (81 mg, 72%), mp 258‐260 oC. 1H NMR (DMSO, 400
MHz) δ 3.89 (s, 3H), 6.46 (s, 1H), 7.19 (dd, J = 2.0, 8.4 Hz, 1H),
7.32 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.66‐7.70 (m,
1H), 7.79 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 6.4 Hz, 1H), 8.04 (d, J =
7.6 Hz, 1H), 9.30 (s, 1H); 13C NMR (DMSO, 150 MHz) δ 56.4,
a
]quinazoline‐5,11‐dione (3i). Petroleum ether/ethyl acetate
o
1
(1:1) as eluent; white solid (74 mg, 63%), mp 257‐259 C. H
NMR (DMSO, 400 MHz) δ 2.36 (s, 3H), 3.89 (s, 3H), 6.40 (s, 1H),
7.18 (dd, J = 2.0, 8.4 Hz, 1H), 7.45‐7.50 (m, 2H), 7.75‐7.79 (m,
4 | J. Name., 2012, 00, 1‐3
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2H), 7.92 (d, J = 8.4 Hz, 1H), 9.26 (s, 1H); 13C NMR (DMSO, 150
MHz) δ 21.0, 56.3, 67.1, 109.6, 117.0, 119.8, 120.1, 123.8,
9‐Chloro‐3‐methoxy‐6,6a‐dihydroisoindolo[2,1V‐iew Article Online
DOI: 10.1039/C7OB00256D
a
]quinazoline‐5,11‐dion (3o). Petroleum ether/ethyl acetate
o
1
125.8, 128.7, 134.2, 134.5, 135.5, 143.7, 163.8, 164.2, 164.7. (1:1) as eluent; white solid (79 mg, 63%), mp 249‐251 C. H
HRMS (ESI) calcd for C17H14N2NaO3 [M + Na]+ 317.0897, found NMR (DMSO, 400 MHz) δ 3.83 (s, 3H), 6.47 (s, 1H), 7.31 (dd, J =
317.0899.
3.2, 8.8 Hz, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.86‐7.89 (m, 3H), 7.97
(d, J = 8.8 Hz, 1H), 9.50 (s, 1H); 13C NMR (DMSO, 150 MHz) δ
8‐Fluoro‐3‐methyl‐6,6a‐dihydroisoindolo[2,1‐
a
]quinazoline‐5,11‐dione (3j). Petroleum ether/ethyl acetate 56.1, 67.3, 112.1, 120.6, 121.65, 121.69, 123.9, 126.5, 130.7,
o
1
(2:1) as eluent; white solid (78 mg, 69%), mp 251‐253 C. H 133.4, 134.0, 135.5, 139.7, 156.9, 163.4, 163.8. HRMS (ESI)
NMR (DMSO, 400 MHz) δ 2.38 (s, 3H), 6.48 (s, 1H), 7.50‐7.55 calcd for C16H11ClN2NaO3 [M + Na]+ 337.0350, found 337.0361.
(m, 2H), 7.70 (dd, J = 2.0, 8.0 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H),
7.93 (t, J = 2.8 Hz, 1H), 7.95 (t, J = 2.8 Hz, 1H), 9.34 (s, 1H); 13
2‐Chloro‐6,6a‐dihydroisoindolo[2,1‐
dione (3p). Petroleum ether/ethyl acetate (1:1) as eluent;
a]quinazoline‐5,11‐
C
NMR (DMSO, 150 MHz) δ 21.0, 67.1 (d, J = 2.1 Hz, 1C), 112.3 (d, white solid (73 mg, 64%), mp 253‐255 oC. 1H NMR (DMSO, 600
J = 25.1 Hz, 1C), 118.3 (d, J = 23.0 Hz, 1C), 119.9, 120.1, 126.9 MHz) δ 6.54 (s, 1H), 7.42 (dd, J = 1.8, 8.4 Hz, 1H), 7.69 (t, J = 7.8
(d, J = 9.9 Hz, 1C), 128.2, 128.7, 134.6, 134.7, 135.1, 143.8 (d, J Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.90 (t, J = 6.6 Hz, 2H), 7.97 (d, J
= 11.0 Hz, 1C), 163.8, 164.1, 165.3 (d, J = 249.3 Hz, 1C). HRMS = 8.4 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 9.51 (s, 1H); 13C NMR
(ESI) calcd for C16H12FN2O2 [M + H]+ 283.0877, found 283.0865.
(DMSO, 150 MHz) δ 67.7, 119.3, 119.4, 124.5, 124.7, 125.3,
3‐Methoxy‐6,6a‐dihydroisoindolo[2,1‐
a
]quinazoline‐5,11‐
130.6, 130.8, 131.2, 134.0, 138.3, 138.5, 141.2, 163.4, 165.0.
dione (3k). Petroleum ether/ethyl acetate (1:1) as eluent; HRMS (ESI) calcd for C15H10ClN2O2 [M + H]+ 285.0425, found
white solid (78 mg, 70%), mp 236‐238 oC. 1H NMR (DMSO, 600 285.0432.
MHz) δ 3.83 (s, 3H), 6.47 (s, 1H), 7.30 (dd, J = 2.0, 6.0 Hz, 1H),
7.46 (d, J = 2.0 Hz, 1H), 7.67 (t, J = 5.2 Hz, 1H), 7.77 (t, J = 5.2 Hz,
2‐Chloro‐9‐methyl‐6,6a‐dihydroisoindolo[2,1‐
]quinazoline‐5,11‐dione (3q). Petroleum ether/ethyl acetate
(1:1) as eluent; white solid (74 mg, 62%), mp 262‐264 C. H
a
o
1
1H), 7.86‐7.88 (m, 2H), 7.98 (d, J = 6.0 Hz, 1H), 9.44 (s, 1H); 13
C
NMR (DMSO, 150 MHz) δ 56.0, 67.5, 112.0, 120.6, 121.6, 121.7, NMR (DMSO, 400 MHz) δ 2.46 (s, 3H), 6.49 (s, 1H), 7.41 (dd, J =
124.2, 124.6, 130.6, 131.0, 131.8, 133.5, 141.1, 156.7, 163.9, 2.0, 8.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.76 (d, J =
164.8. HRMS (ESI) calcd for C16H13N2O3 [M + H]+ 281.0921, 7.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 9.46
found 281.0932.
(s, 1H); 13C NMR (DMSO, 150 MHz) δ 21.4, 67.5, 119.3, 119.4,
3‐Methoxy‐9‐methyl‐6,6a‐dihydroisoindolo[2,1‐
124.4, 124.5, 125.2, 130.6, 131.4, 134.8, 138.3, 138.57, 138.60,
a
]quinazoline‐5,11‐dione (3l). Petroleum ether/ethyl acetate 140.8, 163.4, 165.1. HRMS (ESI) calcd for C16H11ClN2NaO2 [M +
o
1
(1:1) as eluent; white solid (78 mg, 66%), mp 264‐266 C. H Na]+ 321.0401, found 321.0399.
NMR (DMSO, 600 MHz) δ 2.45 (s, 3H), 3.83 (s, 3H), 6.42 (s, 1H), 2,9‐Dichloro‐6,6a‐dihydroisoindolo[2,1‐
a
]quinazoline‐5,11‐
7.29 (dd, J = 2.4, 8.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.58 (d, J = dione (3r). Petroleum ether/ethyl acetate (1:1) as eluent; white
7.8 Hz, 1H), 7.67 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 9.0 solid (76 mg, 60%), mp 235‐237 oC. 1H NMR (DMSO, 600 MHz)
Hz, 1H), 9.40 (s, 1H); 13C NMR (DMSO, 150 MHz) δ 21.4, 56.0, δ 6.54 (s, 1H), 7.44 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (m, 2H), 7.94
67.4, 112.0, 120.5, 121.6, 121.7, 124.2, 124.3, 131.1, 132.0, (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 9.53 (s,
134.2, 138.5, 140.5, 156.6, 163.9, 164.9. HRMS (ESI) calcd for 1H); 13C NMR (DMSO, 150 MHz) δ 67.5, 119.3, 119.5, 124.2,
C17H15N2O3 [M + H]+ 295.1077, found 295.1082.
3,8‐Dimethoxy‐6,6a‐dihydroisoindolo[2,1‐ ]quinazoline‐
125.6, 126.6, 130.6, 133.4, 133.9, 135.7, 138.2, 138.4, 139.7,
a
163.2, 163.7. HRMS (ESI) calcd for C15H8Cl2N2NaO2 [M + Na]+
5,11‐dione (3m). Petroleum ether/ethyl acetate (1:1) as eluent; 340.9855, found 340.9851.
white solid (79 mg, 64%), mp 267‐269 oC. 1H NMR (DMSO, 400
6‐Benzyl‐6,6a‐dihydroisoindolo[2,1‐
a
]quinazoline‐5,11‐
MHz) δ 3.82 (s, 3H), 3.88 (s, 3H), 6.40 (s, 1H), 7.18 (d, J = 8.4 Hz, dione (3s)2. Petroleum ether/ethyl acetate (2:1) as eluent;
1H), 7.27 (dd, J = 2.8, 8.8 Hz, 1H), 7.43‐7.44 (m, 2H), 7.77 (d, J = white solid (113 mg, 83%), mp 153‐155 oC. 1H NMR (CDCl3, 400
8.4 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 9.34 (s, 1H); 13C NMR MHz) δ 4.63 (d, J = 16.8 Hz, 1H), 5.51 (d, J = 16.8 Hz, 1H), 6.36
(DMSO, 150 MHz) δ 56.0, 56.4, 67.2, 109.8, 111.9, 117.0, 120.6, (s, 1H), 7.20‐7.26 (m, 3H), 7.32‐7.43 (m, 4H), 7.53‐7.61 (m, 2H),
121.4, 121.5, 123.8, 125.7, 131.2, 143.6, 156.5, 163.7, 163.9, 7.64‐7.69 (m, 1H), 7.96‐7.98 (m, 1H), 8.12‐8.14 (m, 1H), 8.23
164.7. HRMS (ESI) calcd for C17H14N2NaO4 [M + Na]+ 333.0846, (dd, J = 1.2, 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 46.7, 70.7,
found 333.0842.
120.3, 125.0, 125.4, 125.5, 126.3, 127.3, 129.1, 129.5, 130.6,
8‐Fluoro‐3‐methoxy‐6,6a‐dihydroisoindolo[2,1‐
132.6, 132.7, 133.8, 136.2, 137.0, 137.8, 164.1, 164.9 (one 13
C
a
]quinazoline‐5,11‐dione (3n). Petroleum ether/ethyl acetate signal was not observed). MS (ESI) m/z 341 [M + H]+.
o
1
(1:1) as eluent; white solid (83 mg, 69%), mp 237‐239 C. H
6‐(Phenylamino)‐6,6a‐dihydroisoindolo[2,1‐a]quinazoline‐
NMR (DMSO, 400 MHz) δ 3.83 (s, 3H), 6.46 (s, 1H), 7.31 (dd, J = 5,11‐dione (3t)5b. Petroleum ether/ethyl acetate (2:1) as eluent;
3.2, 8.8 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.63‐7.70 (m, 2H), white solid (95 mg, 70%), mp 181‐183 oC. 1H NMR (DMSO, 600
7.88‐7.91 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 9.49 (s, 1H); 13C NMR MHz) δ 6.50 (d, J = 7.8 Hz, 2H), 6.64 (t, J = 7.2 Hz, 1H), 6.65 (s,
(DMSO, 150 MHz) δ 56.0, 67.2, 110.5 (d, J = 23.0 Hz, 1C), 112.1, 1H), 6.97 (t, J = 7.8 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.57 (t, J =
120.6, 120.8 (d, J = 23.0 Hz, 1C), 121.6, 121.7, 126.8 (d, J = 8.7 7.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.81
Hz, 1C), 130.8, 134.3 (d, J = 8.7 Hz, 1C), 137.1, 156.8, 163.62 (d, (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.2 Hz,
J = 3.3 Hz, 1C), 163.65 (d, J = 246.0 Hz, 1C), 163.8. HRMS (ESI) 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H); 13C NMR (DMSO, 150
calcd for C16H11FN2NaO3 [M + Na]+ 321.0646, found 321.0645.
MHz) δ 72.7, 113.1, 119.7, 120.0, 120.6, 124.2, 125.7, 127.1,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
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ARTICLE
Journal Name
4
5
W. Hölzl and B. Rotzinger, Isoindolo[2,1‐a]quinazoline deriv‐
atives for stabilization of organic materials.
View ArticPleaOtnelinnet
129.0, 129.1, 130.8, 132.0, 133.6, 134.5, 137.5, 139.7, 148.8,
165.2, 165.6. MS (ESI) m/z 342 [M + H]+.
DOI: 10.1039/C7OB00256D
WO2013/139799 A1, 2013.
4b,5‐dihydroisoindolo[1',2':2,3]pyrimido[4,5‐b]quinoline‐
(a) L. Lu, K. Yang, M.‐M. Zhang and X.‐S. Wang, J. Heterocycl.
Chem., 2014, 51, 630‐634; (b) R.‐Z. Jin, W.‐T. Zhang, Y.‐J.
Zhou and X.‐S. Wang, Tetrahedron Lett., 2016, 57, 2515‐2519;
(c) K. V. Sashidhara, L. R. Singh, G. R. Palnati, S. R. Avula and
R. Kant, Synlett, 2016, 27, 2384‐2390; (d) R. V. Devi, A. M.
Garande and P. M. Bhate, Synlett, 2016, 27, 2807‐2810.
(a) M. Mahdavi, R. Najafi, M. Saeedi, E. Alipour, A. Shafiee
and A. Foroumadi, Helv. Chim. Acta, 2013, 96, 419‐423; (b) R.
6,14‐dione (3u). DCM/MeOH (20:1) as eluent; light yellow solid
(38 mg, 32%), mp > 300 oC. 1H NMR (DMSO, 600 MHz) δ 6.70 (s,
1H), 7.65 (t, J = 7.8 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.85 (t, J =
7.8 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.93‐7.95 (m, 2H), 8.03 (d, J
= 8.4 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 9.02 (s, 1H), 9.69 (s, 1H);
13C NMR (DMSO, 150 MHz) δ 67.2, 116.6, 124.7, 124.9, 126.2,
127.0, 128.3, 130.1, 130.9, 131.5, 133.0, 134.0, 139.6, 141.0,
148.0, 148.6, 163.4, 164.0. HRMS (ESI) calcd for C18H12N3O2 [M
+ H]+ 302.0924, found 302.0911.
6
7
A. Bunce and B. Nammalwar, J. Heterocycl. Chem., 2011, 48
,
991‐997.
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S. C. Joseph, S. Mukherjee and M. Pal, Tetrahedron Lett.,
2013, 54, 6744‐6746; (b) K. V. Sashidhara, G. R. Palnati, R. P.
Dodda, S. R. Avula and P. Swami, Synlett., 2013, 24, 105‐113;
(c) F. Esmaeili‐Marandi, M. Saeedi, I. Yavari, M. Mahdavi and
A. Shafiee, Helv. Chim. Acta, 2016, 99, 37‐40.
2‐(2‐Bromophenyl)‐2,3‐dihydroquinazolin‐4(1H
)‐one (4)12.
Petroleum ether/ethyl acetate (2:1) as eluent; white solid (107
mg, 88%), mp 173‐175 oC. 1H NMR (DMSO, 600 MHz) δ 6.09 (s,
1H), 6.72 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.99 (s, 1H),
7.25‐7.28 (m, 1H), 7.32‐7.34 (m, 1H), 7.45 (t, J = 7.2 Hz, 1H),
7.65‐7.69 (m, 3H), 8.19 (s, 1H); 13C NMR (DMSO, 150 MHz) δ
66.9, 115.1, 115.2, 118.0, 122.7, 127.9, 128.6, 129.6, 131.2,
133.3, 133.9, 139.6, 148.2, 164.1. MS (ESI) m/z 304 [M + H]+.
8
For selected examples, see: (a) A. Brennführer, H. Neumann
and M. Beller, Angew. Chem., Int. Ed., 2009, 48, 4114‐4133;
(b) X.‐F. Wu, H. Neumann and M. Beller, Chem. Soc. Rev.,
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L. He, H. Li, H. Neumann, M. Beller and X.‐F. Wu, Angew.
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Chen, W. Wu and H. Jiang, Chem. Commun., 2014, 50, 2488‐
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Org. Chem., 2015, 80, 8189‐8197; (h) Y. He, X. Zhang and X.
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Shen, A. Spannenberg and X.‐F. Wu, Angew. Chem., Int. Ed.,
2‐(2‐Bromophenyl)quinazolin‐4(3H
)‐one (5)13. Petroleum
ether/ethyl acetate (2:1) as eluent; white solid (9.5 mg, 8%),
mp 160‐162 oC. 1H NMR (CDCl3, 600 MHz) δ 7.40 (t, J = 7.8 Hz,
1H), 7.49 (t, J = 7.8 Hz, 1H), 7.52‐7.55 (m, 1H), 7.71‐7.74 (m,
2H), 7.82 (m, 2H), 8.27 (d, J = 7.8 Hz, 1H), 10.49 (brs, 1H); 13C
NMR (CDCl3, 150 MHz) δ 120.9, 121.1, 126.5, 127.4, 127.97,
128.0, 131.3, 132.0, 133.7, 134.9, 135.0, 148.9, 152.1, 162.2.
MS (ESI) m/z 302 [M + H]+.
Acknowledgements
2016, 55, 5067‐5070; (l) X.‐F. Wu, Chem. Eur. J., 2015, 21
12252‐12265; (m) J.‐B. Peng, X. Qi and X.‐F. Wu, ChemSus‐
Chem, 2016, , 2279‐2283; (n) X.‐F. Wu, RSC Adv., 2016, 6,
,
We thank the National Natural Science Foundation of China
(Grants 21202040 and 21572047), Project Funded by China
Postdoctoral Science Foundation (2014M552007 and
2015T80771), and the Program for Innovative Research Team
in Science and Technology in University of Henan Province
(15IRTSTHN003) for financial support.
9
83831‐83837; (o) J.‐B. Peng, X. Qi and X.‐F. Wu, Synlett, 2017,
28, 175‐194.
9
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6 | J. Name., 2012, 00, 1‐3
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12 S. K. Ghosh and R. Nagarajan, RSC Adv., 2016, 6, 27378‐
View Article Online
DOI: 10.1039/C7OB00256D
27387.
13 J. K. Laha, K. V. Patel, K. S. S. Tummalapalli and N. Dayal,
Chem. Commun., 2016, 52, 10245‐10248.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB00256D
Graphical Abstract
An efficient route to 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones via
Pd-catalyzed carbonylative cyclization of 2-aminobenzamides with
2-bromobenzaldehydes under atmospheric CO pressure is reported.