Synthesis of Tetracyclic Quinazolinones Using a Visible-Light-Promoted Radical Cascade Approach

Article abstract of DOI:10.1021/acs.joc.6b00869

A practical approach for the synthesis of tetracyclic pyrroloquinazolines using photoredox strategy has been developed. The visible-light-promoted intramolecular single-electron-transfer process between photocatalyst and N-(2-iodobenzyl)-N-acylcyanamides

Full text of DOI:10.1021/acs.joc.6b00869

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Note
Synthesis of Tetracyclic Quinazolinones Using a
Visible-Light-Promoted Radical Cascade Approach
Yue-Yue Han, Heng Jiang, Ruzhi Wang, and Shouyun Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00869 • Publication Date (Web): 03 Jun 2016
Downloaded from http://pubs.acs.org on June 3, 2016
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Synthesis of Tetracyclic Quinazolinones Using a
Visible-Light-Promoted Radical Cascade Approach
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Yue-Yue Han, Heng Jiang, Ruzhi Wang and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210023, China.
*E-mail: yushouyun@nju.edu.cn
ABSTRACT:
A
practical approach for the synthesis of tetracyclic
pyrroloquinazolines using photoredox strategy has been developed. The
visible-light-promoted intramolecular single-electron-transfer (SET) process between
photocatalyst and N-(2-iodobenzyl)-N-acylcyanamides is considered to be involved in
this transformation. Targeted pyrroloquinazoline derivatives (15 examples) are
presented in good isolated yields (30%-88%).
Tetracyclic pyrroloquinazoline occurs as a key structural entity in dozens of natural
products, such as luotonins A and E, mackinazolinone, rutaecarpine and
deoxyvasicinone (Scheme 1).1 This type of natural products disclose a wide range of
biological activities including the specific cytotoxicity and potent inhibition to
proteases, which would be applicable in the discovery of pharmaceutical candidates.2
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Therefore, the synthesis of heterocyclic compounds bearing the tetracyclic
pyrroloquinazoline scaffold has drawn intensive attention to synthetic chemists.
Previously, the construction of tetracyclic pyrroloquinazoline scaffold commonly
focused on the Pd-catalyzed cyclizations.3 For example, Li and co-workers reported a
Pd-catalyzed approach to prepare tetracyclic pyrroloquinazolines from
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2-bromo-N-(2-iodobenzyl)benzamides,
which
underwent
cyanation/N-addition/N-arylation reaction sequence in a two-stage and one-pot
manner (Scheme 2a).3a The Wu group also reported a decent method to prepare
tetracyclic pyrroloquinazolines through palladium-catalyzed carbonylation of
2-bromobenzylamines with 2-bromoanilines (Scheme 2b).3b In addition, tetracyclic
pyrroloquinazolines could also be prepared through radical approach.4,5 Malacria and
co-workers described the AIBN/n-Bu3SnH-mediated radical cascade cyclization of
N-(2-iodobenzyl)-N-acylcyanamides to prepare pyrroloquinazoline-type polycyclic
compounds (Scheme 2c).4a A concise total synthesis of luotonin A was achieved using
this strategy. The aforementioned methods are normally conducted at elevated
temperature or proceed in the presence of toxic reagents (e. g. n-Bu3SnH). These
limitations considerably restrict not only the operational simplicity towards the
preparation of this pyrroloquinazoline-type tetracyclic compounds, but also the
pharmaceutical availability of compounds bearing this characteristic scaffold.
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Scheme 1. Quinazolinone-Containing Biologically Active Natural Products
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Inspired by these beautiful works, as well as our previous work with respect to the
photoredox-catalyzed radical triple bond insertions to construct various heterocycles,6
we envisioned that the tetracyclic pyrroloquinazolinanes could be prepared by
photoredox-catalyzed
intramolecular
radical
cyanide
insertion
of
N-(2-iodobenzyl)-N-acylcyanamides (Scheme 2d). Several challenges associated with
this approach have to be pointed out, including (1) the inertia of aryl iodides 7 for the
generation of aryl radical species upon photoredox conditions compared with other
active aryl radical precursors such as aryl diazonium salts8 and diaryliodonium salts,9
(2) the inertia of the cyano group as the radical acceptor in photoredox catalysis.10
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Scheme 2. Synthesis of Tetracyclic Quinazolinones
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With
these
considerations
in
mind,
we
initially
used
N-acyl-N-(2-iodobenzyl)-cyanamide (1a)4a as the model substrate to explore this
transformation. To our delight, 30% yield of the desired pyrroloquinazoline 2a based
1
on H NMR analysis was obtained when a solution of 1a, TEA and fac-Ir(ppy)3 (2.0
mol%) in MeCN was irradiated by white LED strips for 12 h at room temperature
(Table 1, entry 1). The use of inorganic bases such as Na2HPO4 and KOtBu instead of
TEA couldn’t give any desired product (entries 2-3). This phenomenon suggests that
TEA was not only used as a base, but also played as a quencher of photo-excited
catalyst (fac-Ir(ppy)3*) in the catalytic cycle. We further screened a range of organic
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bases including Ph3N, DIPEA, DBU, DMAP, NMM and TMEDA (entries 4-9).
DIPEA was proved to be the optimal organic base affording 2a in 69% yield (entry 5).
The employment of other commonly used photocatalysts (Ir(ppy)2(dtbbpy)PF6,
Ir(dFCF3ppy)2(dtbbpy)PF6, Ru(bpy)3Cl2 and Ru(Phen)3(PF6)2) couldn’t give any
improvement of the yield (entries 10-13). Other solvents, such as DMF, MeOH,
DMSO and CH2Cl2, were not superior to MeCN in this transformation (entries 14-17).
The use of 3.0 equivalent of DIPEA gave comparable yield of 2a (entry 18).
Satisfactorily, the NMR yield of 2a could be increased to 87% (83% isolated yield) by
diluting the reaction system to 0.02 M (entry 19). The reaction couldn’t proceed
without photocatalyst or visible light irradiation (entries 20-21).
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Table 1. Reaction Condition Optimizationa
entry
photocatalyst
Ir(ppy)3
base
TEA
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
2a/%b
1
2
3
4
5
30
0
Ir(ppy)3
Na2HPO4
KOtBu
Ph3N
Ir(ppy)3
0
Ir(ppy)3
0
Ir(ppy)3
DIPEA
69
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Ir(ppy)3
Ir(ppy)3
DBU
DMAP
NMM
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
trace
trace
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8
Ir(ppy)3
9
Ir(ppy)3
TMEDA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
38
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18c
19d
20f
21
Ir(ppy)2(dtbbpy)PF6
Ir(dFCF3ppy)2(dtbbpy)PF6
Ru(bpy)3Cl2
Ru(Phen)(PF6)2
Ir(ppy)3
66
18
20
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29
Ir(ppy)3
MeOH
DMSO
CH2Cl2
MeCN
MeCN
MeCN
MeCN
0
Ir(ppy)3Cl2
Ir(ppy)3
64
35
Ir(ppy)3
70
Ir(ppy)3
87 (83e)
0
Ir(ppy)3
none
0
aReaction conditions: a solution of 1a (0.1 mmol), base (0.2 mmol) and photocatalyst
(0.002 mmol, 2.0 mol %) in the indicated solvent (1.0 mL) was irradiated by white
b
1
c
LED strips at rt for 12 h. The yields are based on HNMR analysis. 0.3 mmol of
d
e
f
DIPEA was used. 5.0 mL of MeCN was used. Isolated yield. Reaction was
conducted in the dark.
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With the optimized conditions in hand, we then intended to explore the scope of
this transformation. In general, the desired cyclization products 2 with 6/5/6/6 ring
system were achieved in acceptable to excellent yields (Scheme 3). The substituents
on the aryl of benzoyl motif could be a range of electronic donating or withdrawing
functional groups (-OMe, -Me, -F, -Cl, -CF3, -CN, CO2Me), affording desired
products 2a-2h in 68%-88% yields. The aryl of benzoyl motif could also be 1- or
2-naphthalene (2i, 67% and 2j, 83%) and 1-thiophene (2k, 33%). In addition,
N-acylcyanamide derived from 2-iodophenylethanamine was also compatible in this
transformation to give 2l with 6/6/6/6 ring system in 30% yield. Cinnamic
acid-derived cyanamides were also be suitable in this transformation to give tricyclic
products 2m-2o in 50%-86% yields, which were not achieved in
AIBN/n-Bu3SnH-mediated radical cascade cyclization.4 The reaction could be scaled
up to gram scale. When 3 mmol (1.09 g) of 1a was subjected to standard conditions
with 1.0 mol% of photocatalyst, the product 2a could be isolated in 85% yield.
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Scheme 3. Substrate Scopea
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aReaction conditions: a solution of 1a (0.2 mmol), DIPEA (0.4 mmol) and
fac-Ir(ppy)3 (0.004 mmol, 2.0 mol %) in MeCN (10.0 mL) was irradiated by white
b
LED strips at rt for 12 h. Yields are for the isolated products. The reaction was
running in 5 mmol scale for 24 h, and the loading of fac-Ir(ppy)3 was reduced from
2.0 mol % to 1.0 mol %.
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To investigate the mechanism of this reaction, a series of emission quenching
experiments were performed to acquire further insight into the photoredox catalytic
cycle. The experiments revealed that it was DIPEA to quench the excited state of
fac-Ir(ppy)3 (for details, see the Supporting Information). This result suggests that the
reaction might undergo a reductive quenching mechanism. On the basis of the
experimental observations, a plausible mechanism is proposed in Scheme 4. The
catalytic cycle starts from the photo-excitation of fac-Ir(ppy)3 upon visible light
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*
irradiation to generate the excited-state photocatalyst (fac-Ir(ppy)3 ). The reductive
*
-
quenching of fac-Ir(ppy)3 by DIPEA gives fac-Ir(ppy)3 and N-centered radical cation
species 7.11 Afterwards, single electron transfer (SET) between N-acylcyanamide 1a
-
and fac-Ir(ppy)3 can afford an aryl radical intermediate 3,7 which undergoes
intramolecular radical cyclization to give radical intermediate 5.12 Subsequently, one
electron oxidation of 5 can generate aryl cation intermediate 6, following the
aromatization to give tetracyclic pyrroloquinazoline 2a.6
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Scheme 4. Proposed Mechanism
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In summary, we have described a practical approach to construct polycyclic
pyrroloquinazolines using photoredox-catalyzed intramolecular radical cyanide
insertion. This photoredox neutral strategy proceeds under visible light irradiation at
room temperature and the experiments are easy to carry out. The hazardous radical
initiator AIBN and toxic n-Bu3SnH can be avoided, which renders this protocol
particularly valuable in terms of green synthetic chemistry aspect.
Experimental Section
General Information. All reagents and solvents were used without further
purification. Thin layer chromatography (TLC) was performed on EMD precoated
plates (silica gel 60 F254, Art 5715) and visualized by fluorescence quenching under
UV light and by staining with phosphomolybdic acid or potassium permanganate,
respectively. Column chromatography was performed on EMD Silica Gel 60 (300–
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400 Mesh) using a forced flow of 0.5–1.0 bar. H NMR (400 MHz), 13C NMR
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(100MHz) and 19F (376MHz) were measured on a 400 M NMR spectrometer.
Chemical shifts are expressed in parts per million (ppm) with respect to the residual
solvent peak. Coupling constants are reported as Hertz (Hz), signal shapes and
splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. Infrared (IR) spectra were recorded on a IR spectrophotometer and are
reported as wavenumber (cm–1).
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General Procedure for Preparation of N-acyl-N-(2-iodobenzyl)-cyanamides.4a
KOH (326 mg, 5.8 mmol) was added to a solution of N-(2-iodobenzyl)-cyanamide
(1.5 g, 5.8 mmol)4a in THF/H2O (15 mL, v:v = 1:1). The mixture was stirred at
ambient temperature for 30 min and concentrated under reduced pressure. Toluene (7
mL) was added to the residue. After cooling to 0 °C, acyl chloride (11 mmol) was
added slowly. The mixture was then warmed to 25 °C and stirred for another 2 h.
After the reaction was complete (as judged by TLC analysis), the reaction mixture
was poured into a separatory funnel containing 20 mL of H2O and 20 mL of CH2Cl2.
The layers were separated and the organic layers were extracted with H2O (2 × 20
mL). The organic layers were dried over Na2SO4 and concentrated under reduced
pressure after filtration. The crude product was purified by flash chromatography on
silica gel to afford the desired product.
The N-acyl-N-(2-iodobenzyl)-cyanamides derivatives 1a, 1b, 1f, 1g, 1h and 1k are
known compounds and were synthetized according to the literature.4a
N-cyano-N-(2-iodobenzyl)-4-methylbenzamide
(1c).
Purification
by
chromatography (petroleum ether/EtOAc = 15:1) afforded 1c as a white solid (1.7 g,
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79% yield). m.p.: 84—86 °C; IR (film, cm-1): 2989, 2896, 2230, 1702, 1608, 1567,
1510, 1453, 1435, 835, 756, 742, 725 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95–7.90
(m, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.45–7.37 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.12–
7.05 (m, 1H), 4.93 (s, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 144.4,
140.2, 135.9, 130.9, 130.7, 129.3, 129.0, 128.8, 127.8, 110.7, 99.3, 55.3, 21.7;
HRMS-DART m/z calcd for C16H14ON2I+ [M+H+] 377.0145, found 377.0143.
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N-cyano-4-fluoro-N-(2-iodobenzyl)benzamide
(1d):
Purification
by
chromatography (petroleum ether/EtOAc = 15:1) afforded 1d as a white solid (1.5 g,
67% yield). m.p.: 87—89 °C ; IR (film, cm-1): 2989, 2895, 2226, 1707, 1603, 1507,
1
1440, 844, 752, 745 cm-1; H NMR (400 MHz, CDCl3) δ 7.96–7.88 (m, 3H), 7.45–
7.37 (m, 2H), 7.21–7.13 (m, 2H), 7.13–7.07 (m, 1H), 4.94 (s, 2H); 13C NMR (100
MHz, CDCl3) δ167.1, 165.7 (d, J = 256.8 Hz) , 140.2, 135.7, 131.7 (d, J = 9.4 Hz),
131.1, 130.9, 128.9, 126.8 (d, J = 3.3 Hz), 116.1 (d, J = 22.3 Hz), 110.4, 99.4, 55.5;
19F NMR (376 MHz, CDCl3) δ –103.55; HRMS-DART m/z calcd for C15H11ON2FI+
[M+H+] 380.9895, found 380.9893.
4-chloro-N-cyano-N-(2-iodobenzyl)benzamide
(1e):
Purification
by
chromatography (petroleum ether/EtOAc = 15:1) afforded 1e as a white solid (1.7 g,
74% yield). m.p.: 88—89 °C ; IR (film, cm-1): 3090, 2975, 2231, 1702, 1590, 1569,
1489, 845, 744 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.96–7.90 (m, 1H), 7.84–7.79 (m,
2H), 7.49–7.45 (m, 2H), 7.44–7.39 (m, 2H), 7.14–7.06 (m, 1H), 4.93 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ167.2, 140.3, 140.0, 135.6, 131.2, 130.9, 130.3, 129.1,
129.0, 128.9, 110.2, 99.4, 55.4; HRMS-DART m/z calcd for C15H11ON2ClI+ [M+H+]
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396.9599, found 396.9599.
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N-cyano-N-(2-iodobenzyl)-1-naphthamide (1i): Purification by chromatography
(petroleum ether/EtOAc = 20:1) afforded 1i as a white solid (1.7 g, 72% yield). m.p.:
132—134 °C ; IR (film, cm-1): 2989, 2898, 2231, 1723, 1698, 1688, 1558, 1467, 801,
779, 765, 742 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 8.03 (d, J
= 8.3 Hz, 1H), 7.95 (dd, J = 7.9, 0.8 Hz, 1H), 7.92–7.88 (m, 1H), 7.86 (dd, J = 7.1, 0.8
Hz, 1H), 7.64–7.58 (m, 1H), 7.58–7.55 (m, 1H), 7.55–7.50 (m, 1H), 7.49 (dd, J = 7.7,
1.6 Hz, 1H), 7.42 (td, J = 7.5, 0.9 Hz, 1H), 7.10 (td, J = 7.7, 1.7 Hz, 1H), 5.06 (s, 2H);
13C NMR (100 MHz, CDCl3) δ168.4, 140.2, 135.8, 133.6, 132.8, 130.84, 130.82,
129.98, 128.9, 128.7, 128.5, 128.0, 127.0, 126.9, 124.4, 124.3, 109.7, 99.4, 54.9;
HRMS-DART m/z calcd for C19H14ON2I+ [M+H+] 413.0145, found 413.0141.
N-cyano-N-(2-iodobenzyl)-2-naphthamide (1j): Purification by chromatography
(petroleum ether/EtOAc = 20:1) afforded 1j as a white solid (1.8 g, 75% yield). m.p.:
82—84 °C ; IR (film, cm-1): 3055, 2986, 2901, 2235, 1703, 1684, 1628, 1558, 1466,
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833, 752, 734 cm-1; H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.92 (t, J =7.4 Hz,
3H), 7.85 (d, J = 8.4 Hz, 2H), 7.62–7.50 (m, 2H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H), 7.39
(t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.98 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ168.3, 140.2, 135.9, 135.5, 132.1, 131.0, 130.8, 130.4, 129.4, 128.88, 128.89, 128.8,
127.9, 127.8, 127.3, 124.4, 110.6, 99.5, 55.5; HRMS-DART m/z calcd for
C19H14ON2I+ [M+H+] 413.0145, found: 413.0145.
N-cyano-N-(2-iodophenethyl)benzamide (1l): Purification by chromatography
(petroleum ether/EtOAc = 20:1) afforded 1l as a white solid (1.6 g, 76% yield). IR
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(film, cm-1): 3085, 3055, 2980, 2230, 1702, 1591, 1568, 1489, 1472, 845, 744 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.76–7.70 (m, 2H) 7.61–7.54
(m, 1H), 7.50–7.42 (m, 2H), 7.36–7.28 (m, 2H), 7.70–6.93 (m, 1H), 4.02 (t, J = 7.4
Hz, 2H), 3.24 (t, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ168.2, 140.0, 139.4,
133.2, 130.9, 130.3, 129.1, 128.7, 128.62, 128.59, 110.9, 100.4, 47.5, 38.6;
HRMS-DART m/z calcd for C16H14ON2I+ [M+H+] 377.0145, found: 377.0145.
N-cyano-N-(2-iodobenzyl)cinnamamide (1m): Purification by chromatography
(petroleum ether/EtOAc = 40:1) afforded 1m as a white solid (1.2 g, 53% yield). m.p.:
112—114 ℃; IR (film, cm-1): 2975, 2930, 2227, 1680, 1617, 1598, 1570, 1468, 745,
748, 687 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.98–7.99 (m, 2H), 7.64–7.58 (m, 2H),
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7.47–7.36 (m, 5H), 7.16 (d, J = 15.4 Hz, 1H), 7.10–7.05 (m, 1H), 4.91 (s, 2H); C
NMR (100 MHz, CDCl3) δ164.5, 149.1, 140.1, 135.9, 133.5, 131.5, 130.6, 130.2,
129.1, 128.83, 128.79, 113.6, 110.1, 99.2, 54.2; HRMS-DART m/z calcd for
C17H14ON2I+ [M+H+] 389.0145, found: 389.0145.
(E)-N-cyano-N-(2-iodobenzyl)-3-(p-tolyl)acrylamide
(1n):
Purification
by
chromatography (petroleum ether/EtOAc = 40:1) afforded 1n as a white solid (1.4 g,
60% yield). m.p.: 129—131 °C ; IR (film, cm-1): 2968, 2920, 2228, 1695, 1619, 1604,
1
1568, 1456, 1330, 813, 747, 718 cm-1; H NMR (400 MHz, CDCl3) δ7.91 (dd, J =
11.6, 3.6 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.42 – 7.32 (m, 2H), 7.23 (d, J = 7.9 Hz,
2H), 7.15 –7.02 (m, 2H), 4.91 (s, 2H), 2.40 (s, 3H)； 13C NMR (100 MHz, CDCl3) δ
164.7, 149.2, 142.3, 140.1, 136.0, 130.9, 130.6, 130.1, 129.8, 128.9, 128.8, 112.5,
110.2, 99.9, 54.1, 21.6; HRMS-DART m/z calcd for C18H16ON2I+ [M+H+] 403.0302,
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(E)-N-cyano-N-(2-iodobenzyl)-3-(4-methoxyphenyl)acrylamide (1o): Purification
by chromatography (petroleum ether/EtOAc = 20:1) afforded 1o as a white solid (1.6
g, 67% yield). m.p.: 135—137 °C ; IR (film, cm-1): 2996, 2928, 2228, 1688, 1616,
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1599, 1571, 1508, 1458, 1344, 1289, 821, 745 cm-1; H NMR (400 MHz, CDCl3) δ
7.93–7.84 (m, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.43–7.31 (m, 2H), 7.09–7.04 (m, 1H),
13
7.01 (d, J = 15.3 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 4.89 (s, 2H), 3.85 (s, 3H); C
NMR (100 MHz, CDCl3) δ164.8, 162.4, 148.8, 140.1, 136.1, 130.7, 130.5, 130.0,
128.8, 126.3, 114.6, 110.9, 110.3, 99.2, 55.5, 54.1; HRMS-DART m/z calcd for
C18H16O2N2I+ [M+H+] 419.0251, found 419.0251.
General Procedure for the Synthesis of Tetracycle Quinazolinones. A 10 mL
round bottom flask equipped with a rubber septum and magnetic stir bar was charged
with N-cyano-N-(2-iodobenzyl)benzamide 1a (0.2 mmol, 1.0 equiv), DIPEA (0.4
mmol, 2.0 equiv) and Ir(ppy)3 (0.004 mmol, 0.02 equiv). The flask was evacuated and
backfilled with nitrogen for 3 times. MeCN (10.0 mL) was added with a syringe under
nitrogen. The mixture was then irradiated by white LED strips. After the reaction was
complete (as judged by TLC analysis), the mixture was concentrated under reduced
pressure after filtration. The crude product was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 10:1).
Isoindolo[1,2-b]quinazolin-10(12H)-one (2a).4a Purification by chromatography
(petroleum ether/EtOAc = 10:1) afforded 2a as a yellow solid (38.8 mg, 83% yield).
1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H),
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7.86–7.74 (m, 2H), 7.65–7.54 (m, 3H), 7.49 (t, J = 7.4 Hz, 1H), 5.14 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ160.7, 155.0, 149.5, 139.6, 134.3, 132.7, 132.4, 128.9,
127.4, 126.5, 126.4, 123.54, 123.51, 120.6, 49.8.
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7-methoxyisoindolo[1,2-b]quinazolin-10(12H)-one
(2b).4c
Purification
by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2b as a yellow solid (38.6
mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 8.17 (d, J =
7.6 Hz, 1H), 7.66–7.11 (m, 2H), 7.61–7.55 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.06 (dd,
J = 8.8, 2.4 Hz, 1H), 5.13 (s, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ164.6,
160.3, 155.6, 151.8, 139.9, 132.7, 132.3, 128.9, 127.9, 123.5, 123.4, 116.6, 114.2,
108.0, 55.7, 49.7.
7-methylisoindolo[1,2-b]quinazolin-10(12H)-one
(2c).3b
Purification
by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2c as a yellow solid (36.7
mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 7.6 Hz,
1H), 7.66–7.60 (m, 3H), 7.59–7.54 (m, 1H), 7.31 (dd, J = 8.1, 0.9 Hz, 1H), 5.13 (s,
13
2H), 2.52 (s, 3H); C NMR (100 MHz, CDCl3) δ160.5, 155.1, 149.3, 145.4, 139.7,
132.6, 132.4, 128.9, 128.1, 127.0, 126.3, 123.7, 123.5, 118.1, 49.8, 21.9.
7-fluoroisoindolo[1,2-b]quinazolin-10(12H)-one
(2d).3b
Purification
by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2d as a yellow solid (37.8
mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.39 (t, J = 7.3 Hz, 1H), 8.18 (d, J = 7.3 Hz,
1H), 7.73–7.56 (m, 3H), 7.48 (d, J = 9.5 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 5.16 (s,
2H); 13C NMR (100 MHz, CDCl3) δ166.5 (d, J = 253.5 Hz), 160.0, 156.2, 151.7 (d, J
= 13.3 Hz), 139.8, 132.7, 132.4, 129.1 (d, J = 11.0 Hz), 129.0, 123.8, 123.6, 117.3,
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115.1 (d, J = 23.5 Hz), 112.7 (d, J = 22.2 Hz), 49.9. 19F NMR (376 MHz, CDCl3) δ –
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103.62;
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7-chloroisoindolo[1,2-b]quinazolin-10(12H)-one
(2e).
Purification
by
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chromatography (petroleum ether/EtOAc = 10:1) afforded 2e as a yellow solid (47.3
mg, 88%). m.p.: 236—238 °C ; IR (film, cm-1): 2974, 2920, 1668, 1619, 1597, 1549,
1454, 878, 773 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.5 Hz, 1H), 8.16 (d,
J = 7.6 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.69–7.56 (m, 3H), 7.43 (dd, J = 8.5, 1.9 Hz,
13
1H), 5.14 (s, 2H); C NMR (100 MHz, CDCl3) δ160.1, 156.1, 150.5, 140.5, 139.8,
132.7, 132.4, 129.0, 127.9, 127.0, 126.9, 123.7, 123.5, 119.0, 49.9; HRMS-DART m/z
calcd for C15H10ON2Cl+ [M+H+] 269.0476, found: 269.0476.
7-(trifluoromethyl)isoindolo[1,2-b]quinazolin-10(12H)-one (2f).3b Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2f as a yellow solid (42.3
mg, 70%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 7.6 Hz,
1H), 8.11 (s, 1H), 7.74–7.56 (m, 4H), 5.17 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ159.8, 156.2, 149.5, 139.7, 135.8 (q, J = 32.9 Hz), 132.9, 132.2 , 129.2, 127.6, 124.9
(q, J = 4.0 Hz), 123.8, 123.6, 123.5 (q, J = 273.7 Hz), 122.8, 122.3 (q, J = 4.1 Hz),
50.0. 19F NMR (376 MHz, CDCl3) δ –63.11.
10-oxo-10,12-dihydroisoindolo[1,2-b]quinazoline-7-carbonitrile
(2g).4a
Purification by chromatography (petroleum ether/EtOAc = 10:1) afforded 2g as a
yillow solid (35.3 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.1 Hz, 1H),
8.20 (d, J = 7.5 Hz, 1H), 8.15 (s, 1H), 7.72–7.63 (m, 4H), 5.19 (s, 2H); 13C NMR (100
MHz, CDCl3) δ159.6, 156.6, 149.6, 139.8, 133.2, 132.3, 132.2, 129.3, 128.1, 127.8,
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Methyl 10-oxo-10,12-dihydroisoindolo[1,2-b]quinazoline-7-carboxylate (2h).4a
Purification by chromatography (petroleum ether/EtOAc = 10:1) afforded 2h as a
yillow solid (43.8 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.43 (d, J =
8.3 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.72–7.56 (m, 3H),
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5.18 (s, 2H), 4.00 (s, 3H); C NMR (100 MHz, CDCl3) δ166.2, 160.2, 155.7, 149.5,
139.7, 135.4, 132.7, 132.5, 129.3, 129.1, 126.8, 126.4, 123.7, 123.6, 123.5, 52.6, 49.9.
Benzo[f]isoindolo[1,2-b]quinazolin-14(12H)-one
(2i).
Purification
by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2i as a yillow solid (38.1
mg, 67%). m.p.: 247—249 °C ; IR (film, cm-1): 2989, 2920, 1656, 1621, 1609, 1592,
1
1552, 1470, 836, 784, 724 cm-1; H NMR (400 MHz, DMSO) δ 9.99 (d, J = 8.6 Hz,
1H), 8.34 (d, J = 8.9 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.86
13
(dd, J = 8.2, 5.1 Hz, 2H), 7.83–7.74 (m, 2H), 7.71–7.64 (m, 2H), 5.31 (s, 2H); C
NMR (100 MHz, DMSO) δ160.6, 156.1, 152.0, 141.4, 135.9, 132.9, 132.7, 131.8,
131.2, 129.2, 129.01, 128.96, 126.9, 126.8, 126.7, 124.7, 123.3, 113.6, 51.1;
+
HRMS-DART m/z calcd for C19H13ON2 [M+H+] 285.1022, found: 285.1022.
Benzo[h]isoindolo[1,2-b]quinazolin-7(9H)-one
(2j).
Purification
by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2j as a yellow solid (47.2
mg, 83%). m.p.: 223—225 °C ; IR (film, cm-1): 2919, 2850, 1654, 1651, 1610, 1556,
1
1469, 763, 735, 721 cm-1; H NMR (400 MHz, CDCl3) δ 9.51–8.94 (m, 1H), 8.33–
8.21 (m, 2H), 7.92–7.86 (m, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.73–7.66 (m, 2H), 7.65–
7.53 (m, 3H), 5.15 (s, 2H); 13C NMR (100 MHz, CDCl3) δ160.7, 154.9, 148.4, 139.7,
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+
121.8, 116.8, 50.0; HRMS-DART m/z calcd for C19H13ON2 [M+H+] 285.1022, found:
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285.1023.
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Thieno[3',2':4,5]pyrimido[2,1-a]isoindol-11(9H)-one (2k).4a Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2k as a yellow solid (15.8
mg, 33%). 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 5.3 Hz,
1H), 7.67–7.63 (m, 2H), 7.62–7.56 (m, 1H), 7.48 (d, J = 5.3 Hz, 1H), 5.16 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ157.3, 157.0, 156.6, 139.7, 134.6, 132.6, 131.8, 129.1,
124.7, 123.7, 123.6, 121.3, 50.0.
5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (2l).4b Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2l as a yellow solid (14.9
1
mg, 30%). H NMR (400 MHz, CDCl3) δ 8.54–8.46 (m, 1H), 8.36–8.27 (m, 1H),
7.94–7.72 (m, 2H), 7.55–7.39 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 4.42 (t, J = 6.5 Hz,
2H), 3.11 (t, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ161.7, 149.5, 147.6,
137.1, 134.3, 131.8, 129.4, 128.1, 127.7, 127.53, 127.50, 126.9, 126.6, 120.7, 39.6,
27.4.
2-phenyl-2,6-dihydropyrimido[2,1-a]isoindol-4(3H)-one (2m).13 Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2m as a yellow solid (34.1
mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 7.9, 1.1 Hz, 1H), 7.44–7.35 (m,
3H), 7.35–7.27 (m, 2H), 7.26–7.22 (m, 1H), 7.04–6.92 (m, 2H), 4.92 (s, 2H), 4.18 (dd,
J = 9.8, 6.0 Hz, 1H), 3.25 (dd, J = 18.2, 9.8 Hz, 1H), 2.84 (dd, J = 18.2, 5.9 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ175.0, 169.6, 139.7, 138.2, 137.3, 129.5, 129.0, 128.3,
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2-(p-tolyl)-2,6-dihydropyrimido[2,1-a]isoindol-4(3H)-one (2n). Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 2n as a yellow solid (47.5
mg, 86%). IR (film, cm-1): 3288, 2973, 2920, 1743, 1648, 1514, 1430, 1399, 1346,
818, 733 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 7.9, 1.0 Hz, 1H), 7.29 (td,
J = 7.7, 1.0 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.03–6.91 (m,
2H), 4.87 (s, 2H), 4.07 (dd, J = 9.8, 6.2 Hz, 1H), 3.20 (dd, J = 18.2, 9.9 Hz, 1H), 2.80
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(dd, J = 18.2, 6.2 Hz, 1H), 2.36 (s, 3H); C NMR (100 MHz, CDCl3) δ175.1, 147.1,
139.7, 138.1, 137.5, 130.1, 129.9, 129.0, 128.3, 127.7, 126.3, 97.9, 48.2, 44.9, 38.3,
+
21.1; HRMS-DART m/z calcd for C18H17ON2 [M+H+] 277.1335, found: 277.1335.
2-(4-methoxyphenyl)-2,6-dihydropyrimido[2,1-a]isoindol-4(3H)-one
(2o).
Purification by chromatography (petroleum ether/EtOAc = 10:1) afforded 2o as a
yillow solid (29.2 mg, 50%). IR (film, cm-1): 3289, 2966, 2918, 1734, 1648, 1609,
1583, 1512, 1430, 1348, 1249, 832, 745 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 (d,
J = 7.7 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 7.2 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 4.87 (s, 2H), 4.07 (dd, J = 9.9, 6.4 Hz, 1H), 3.82 (s, 3H),
3.20 (dd, J = 18.2, 9.9 Hz, 1H), 2.79 (dd, J = 18.2, 6.4 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ174.9, 170.6, 159.5, 139.7, 137.1, 129.8, 129.1, 129.0, 128.4, 126.6, 114.8,
+
97.9, 55.4, 48.6, 44.1, 38.2. HRMS-DART m/z calcd for C18H17O2N2 [M+H+]
293.1285, found: 293.1284.
Acknowledgments
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Financial support from the National Natural Science Foundation of China (21472084
and 81421091), the Qing Lan Project of Jiangsu Province and Shanghai Institute of
Organic Chemistry, CAS is acknowledged.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publication
website at DOI:
Characterization of products (copies of 1H, 13C, and 19F NMR spectra)
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