Palladium Catalyzed Cross-Dehydrogenative Coupling/Annulation Reaction: A Practical and Efficient Approach to Hydroxyisoindolo[1,2-b]quinazolinone

Article abstract of DOI:10.1002/ejoc.201900417

The palladium-catalyzed cross-dehydrogenative coupling (CDC) followed by an intramolecular cyclization between arylquinazolinones and aldehydes has been described. This viable transformation provides a variety of novel substituted hydroxyisoindolo[1,2-b]quinazolinone compounds in moderate to good yields. Additionally, the reaction is performed with toluene in place of benzaldehyde by using an excess amount of tert-butyl hydroperoxide (TBHP) as the oxidant in good yield.

Full text of DOI:10.1002/ejoc.201900417

A Journal of
Accepted Article
Title: Palladium Catalyzed Cross-Dehydrogenative Coupling/
Annulation Reaction: A Practical and Efficient Approach to
Hydroxyisoindolo[1,2-b]quinazolinone
Authors: Minoo Dabiri, Noushin Farajinia Lehi, Siyavash Kazemi
Movahed, and Hamid Reza Khavasi
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900417
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900417
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10.1002/ejoc.201900417
European Journal of Organic Chemistry
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Palladium Catalyzed Cross-Dehydrogenative Coupling/Annulation
Reaction: Practical and Efficient Approach to
Hydroxyisoindolo[1,2-b]quinazolinone
A
Minoo Dabiri,*[a] Noushin Farajinia Lehi,[a] Siyavash Kazemi Movahed[a] and Hamid Reza Khavasi[a]
Abstract: The palladium-catalyzed cross-dehydrogenative coupling
(CDC) followed by an intramolecular cyclization between
arylquinazolinones and aldehydes has been described. This viable
Several recent reports have utilized aldehydes in directed
transition metal-catalyzed CDC/annulation reaction for the
preparation of heterocyclic compounds. Sharma et al. have
described the first efficient synthetic route to 3-hydroxyisoindolin-
1-ones via tandem Rh-catalyzed CDC of secondary benzamides
with aldehydes and intramolecular cyclization (Scheme 1a).[9] Lian
et al. have shown an efficient, one-step, and highly functional
group-compatible synthesis of substituted N-aryl-2H-indazoles
via the Rh-catalyzed CDC reaction between azobenzenes and
aldehydes with subsequent cyclization and aromatization
(Scheme 1b).[10] Duan et al. have reported a Pd-catalyzed
CDC/annulation pathway for N-phenoxyacetamides with
aldehydes to form 1,2-benzisoxazoles (Scheme 1c).[11]
transformation provides
a
variety of novel substituted
hydroxyisoindolo[1,2-b]quinazolinone compounds in moderate to
good yields. Additionally, the reaction is performed with toluene in
place of benzaldehyde by using an excess amount of tert-butyl
hydroperoxide (TBHP) as the oxidant in good yield.
Introduction
Development of selective and efficient C-C bond-forming
reactions is of paramount importance in organic chemistry since
they provide reliable access to the key steps that are required for
building complex molecules from simple precursors. Transition-
metal-catalyzed cross-coupling reactions based on using two pre-
functionalized substrates belong to one of the most effective
processes that are used for C-C bond formation. Transition-metal-
catalyzed C-H bond activation and subsequent C-C bond
formation has attracted considerable interest in recent years as
they prevent the needs for multi-step preparation of pre-activated
starting materials and production of stoichiometric metallic
waste.[1,2] However, in these cases, one coupling partner still has
to be pre-functionalized.[3,4] As one of the most important C−H
activation processes, cross dehydrogenative-coupling (CDC)
reactions have emerged in recent years and provided a viable
alternative to conventional methods of C–C bond-forming
reactions. Regarding the atom economy, this synthetic method
offers one of the ideal synthetic procedures for selective C-C
bond-forming reactions. Compared with traditional cross-coupling
reactions, which usually involve pre-functionalized starting
materials (e.g., such as -Hal, -OTf, -BR2, -SnR3, -SiR3, -ZnHal, -
MgHal and, thus, lead to stoichiometric amounts of waste), the
direct dehydrogenative functionalization of C-H bonds has been
proven to be as a more eco-friendly option.[5–8]
Scheme 1. Representative approaches for the CDC reaction of aldehyde and
arenes and followed by intramolecular cyclization.
The pyrrolo[2,1-b]quinazolinone structural motif is gaining
prominence in medicinal and organic chemistry.[12] They have
been found in a broad spectrum of pharmacologically and
biologically active compounds, such as luotonin A, cruciferane,
vasicinone, tryptanthrin, nigellastrine, phaitanthrins, and
[a]
Prof. Dr. M. Dabiri, N. F. Lehi, Dr. S. K. Movahed, Prof. Dr. H. R.
Khavasi,
Faculty of Chemistry and Petroleum Sciences
Shahid Beheshti University
peharmaline, while
defined as
a
notable class of
pharmacologically active compounds exhibiting anticancer,
antiviral, anti-Alzheimer's disease, anti-inflammatory, and anti-
allergic characteristics (Figure 1).[13–17] In spite of their biological
importance, the number of studies on the synthesis of these fused
heterocyclic structures have rarely been reported. Thus, the
Tehran Province, Tehran, District 1, Daneshjou Boulevard,
1983969411
E-mail: m-dabiri@sbu.ac.ir
Homepage: http://facultymembers.sbu.ac.ir/dabiri
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201900417
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development of effective and more economical approaches for
the construction of these compounds is highly promising and can
further develop their applications in organic and medicinal
chemistry.
be presumed that the increase in TBHP equivalents would lead to
the further oxidation of the aldehydes and, therefore, reduce the
reaction yield. In the absence of either Pd(OAc)2 or TBHP, no
product was observed, indicating that Pd(OAc)2 and TBHP are
indispensable ingredients for the CDC/annulation reaction (Table
1, entries 6 and 14). Other catalysts including Cu(OAc)2, PdCl2 ,
Ru(p-cymene)Cl2, Ru(COD)Cl2, and Co(OAc)2 were also
ineffective under the present conditions (Table 1, entries 15-19).
It was found that the yield could be remarkably improved by
increasing the catalyst loading as an isolated yield of 71% for the
product was obtained in the presence of 10 mol% of Pd(OAc)2
(Table 1, entry 20). The increase in the loading of Pd(OAc)2 to 15
mol% has not rendered any effect on the yield (Table 1, entry 21).
Finally, the optimal reaction temperature was evaluated as it has
a well-known and considerable influence on the reaction rate.
Accordingly, the reduction of temperature could not improve the
yield of the reaction (Table 1, entry 22). Also, There was no
significant change in the yield when the temperature was
increased to 100 °C (Table 1, entry 23). Thus, for all the
subsequent reactions, we used the optimized reaction conditions,
which were determined to be the combination of Pd(OAc)2 (10
mol%), TBHP (4 eq.) in DCE solvent at 80 °C for 16 h under N2
atmosphere, as shown in entry 20.
Figure
1 Biological active compounds with a pyrrolo[2,1-b]quinazolinone
skeleton.
Based on above introduction and also as part of our ongoing
research studies on the C-H activation reactions and organic
synthesis,[18–23] herein we present the tandem palladium-
catalyzed CDC reaction followed by an intramolecular cyclization
between arylquinazolinones and aldehydes under tert-butyl
Table 1. Optimization of the reaction conditions[a]
hydroperoxide (TBHP) as
a convenient oxidant to afford
hydroxyisoindolo[1,2-b]quinazolinone. To the best of our
knowledge, this is the first report of CDC/annulation reaction for
the
formation
of
hydroxyisoindolo[1,2-b]quinazolinone
polyheterocyclic frameworks (Scheme 1d).
Entry
Cat. (mol %)
Solvent
Oxidant
(equiv.)
Yield[b]
(%)
Results and Discussion
In our initial study, 2-phenylquinazolin-4(3H)-one (1a) and
benzaldehyde (2a) were chosen as the model substrates for
optimizing the reaction conditions. The results are summarized in
Table 1. It is noteworthy that the combination of Pd(OAc)2 (5
mol%) and two equivalents of TBHP as the oxidant in
dichloroethane (DCE) under N2 atmosphere at 80 °C for 16 h
promoted the reaction of 1a and 2a to produce our target product
3aa with 43% yield (Table 1, entry 1). Solvent screening has
demonstrated that the choice of solvent is crucial for this
transformation. When acetonitrile, dioxane, toluene and
tetrahydrofuran (THF) were employed as the solvent, the product
was formed in only trace amounts (Table 1, entries 2–5). It can be
seen that the DCE was chosen as the best solvent. DCE would
enhance the reactivity of catalytic species and stabilize activated
complexes in the reaction.[24] Other oxidants such as K2S2O8,
H2O2, AgOAc and Cu(OAc)2 did not promote the desired reaction
(Table 1, entries 7–10). O2, the ideal oxidant, was also tested
under these conditions, but the chemical yield was not improved
(Table 1, entry 11). Additionally, the increase in the mount of
TBHP to four equivalents has resulted in a yield increase of up to
52% (Table 1, entry 12). In contrast, the further addition of TBHP
equivalents failed to enhance the yield (Table 1, entry 13). It can
1
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
DCE
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
-
43
2
Acetonitrile
Dioxane
Toluene
THF
36
3
12
4
27
5
Trace
Trace
11
6
DCE
7
DCE
K2S2O8 (2)
H2O2 (2)
AgOAc (2)
Cu(OAc)2 (2)
O2
8
DCE
17
9
DCE
Trace
Trace
13
10
11
12
13
DCE
DCE
DCE
TBHP (4)
TBHP (6)
52
DCE
49
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14
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
n.r
15
Cu(OAc)2 (5)
PdCl2 (5)
trace
29
16
17
Ru(p-cymene)Cl2
Ru(COD)Cl2
Co(OAc)2
Trace
9
18
19
trace
71
20
Pd(OAc)2 (10)
Pd(OAc)2 (15)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
21
74
22[c]
23[d]
41
73
[a] 2-Phenylquinazolin-4(3H)-one (1a) (1 mmol), benzaldehyde (2a) (1.2
mmol), catalyst (X mol %), oxidant (X eq.), solvent (3 mL), temp. = 80 °C,
time = 16 h, sealed tube, N2 [b] Isolated yield. [c] Temp. = 50 °C. [d] Temp.
= 100 °C.
The scope of the method was investigated by synthesizing
a broad range of hydroxyisoindolo[1,2-b]quinazolinones by using
a variety of aldehydes and 2-arylquinazolin-4(3H)-one derivatives
under the optimized reaction conditions. First, we used 2-
phenylquinazolin-4(3H)-one to react with different aldehydes, as
shown in Table 2.
A wide range of benzaldehydes with
substituents on the benzene rings was investigated. In general,
the reaction of 1a with benzaldehydes derivatives bearing
electron-releasing groups such as (p-Me, p-i-Pr, p-OMe, and p-
OBn) gave good yields (3ab-3ae). In contrast, electron-deficient
benzaldehydes were relatively less reactive under these reaction
conditions. Halogen-substituted aldehydes (p-F, p-Cl, and p-Br)
were moderately converted to the corresponding products (3af-
3ah), respectively. However, the reaction was completely
hampered in the presence of the strongly electron-withdrawing
group (p-NO2) (3ai). A slightly steric effect was observed when
meta-substituted (m-OMe, m-Br, and m-F) and ortho-substituted
(o-F) benzaldehyde reacted with 1a, and inferior yields of the
[a] 2-Phenylquinazolin-4(3H)-one (1a) (1 mmol), aldehyde (2) (1.2 mmol),
Pd(OAc)2 (10 mol%), TBHP (4 eq.), DCE (3 mL), temp. = 80 °C, time = 16
h, sealed tube, N2, [b] Isolated yield.
products
(3aj-3am)
were
obtained.
Polysubstituted
benzaldehydes such as 2,5-dimethoxy, 2,3-dimethoxy, 2,4-
dichloro and 2,4,6-trimethyl groups gave moderate yields of the
corresponding products (3an-3aq), respectively. The moderate
yield obtained in the case of the polysubstituted benzaldehydes
could be, in part, because of the instability of intermediate acyl
radical, a steric factor, or a combination of both.[25] Furfural as an
electron-rich heteroaromatic aldehyde was used, and the desired
product (3ar) was obtained in good yield (59%). The
heteroaromatic aldehyde (4-pyridinecarboxaldehyde) was found
to be unreactive and did not afford the corresponding product 3as.
The aliphatic aldehyde (n-butyraldehyde) was used, and the
product 3at was isolated in 43% yield. Additionally, the α-β
unsaturated aldehyde (cinnamaldehyde) was used but failed to
provide the desired product 3au.
Furthermore, the scope of 2-arylquinazolin-4(3H)-one
substrate was also screened (Table 3). The para-substituted
arylquinazolinones with the electron-releasing group (p-Me) on
the benzene rings were favored in the reaction and able to form
the desired product in good yield (3ba). By contrast, electron-
withdrawing groups (p-Cl and p-NO2) were relatively less reactive
in these reaction conditions (3ca and 3da). Notably, the reaction
of meta-substituted arylquinazolinone derivatives preferentially
occurred at the more sterically accessible position to give the
corresponding products (3ea and 3fa) since the steric effects
would seemingly prevent either the formation of the
cyclopalladated intermediate or the access of the aldehyde to the
cyclopalladated intermediate. Nevertheless, the ortho-substituted
arylquinazolinones showed relatively less reactivity since
Table 2. Scope of aldehydes for Pd-catalyzed CDC/annulation reaction[a]
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coplanar conformation between the aromatic ring and the
quinazolinone moiety was not accessible (3ga and 3ha).
Encouraged by the recent reports of C-H bond acylation with
toluene derivatives,[26,27] we further explored the compatibility of
this protocol with toluene instead of benzaldehyde. In this respect,
we optimized the reaction conditions by varying only the
concentration of TBHP to achieve better product yields.
Accordingly, the best results were obtained when 2-
phenylquinazolin-4(3H)-one (1a, 1 mmol) was treated with
toluene (2 mmol) in the presence of Pd(OAc)2 (10 mol%) and
TBHP (8 eq.) at 80 °C for 16 h, which produced the target
compound 3aa with 59% yield (Scheme 2).
Table 3. Scope of 2-arylquinazolin-4(3H)-ones for Pd-catalyzed
CDC/annulation reaction[a]
Scheme 2. Pd catalyzed CDC/annulation reaction between 2-phenylquinazolin-
4(3H)-one and toluene
On the basis of the previous reports,[11,28,29]
a plausible
mechanism pathway is proposed and depicted in Scheme 3. The
reaction is probably initiated by chelate-assisted ortho-selective
cyclometalation of 2-phenylquinazolin-4(3H)-one (1a) by
Pd(OAc)2 and generates
a
five-membered cyclopalladated
intermediate (A). Then,
a “rollover” cyclometalation of
intermediate (A) affords the intermediate (B).[30,31] The
palladacycle (B) undergoes oxidation with acyl radical, generated
in situ by hydrogen abstraction, to produce the highly active
Pd(IV) species or dimeric Pd(III) (C) intermediates.[32] After
reductive elimination, a new C-C bond can be formed with Pd
attached to an amide nitrogen atom of phenylquinazolinone. The
intramolecular nucleophilic attack occurs to form a palladium
alkoxide (E), which is protonated by acetic acid to give our desired
product (3aa).
[a] 2-Arylquinazolin-4(3H)-one (1) (1 mmol), benzaldehyde (2a) (1.2 mmol),
Pd(OAc)2 (10 mol%), TBHP (4 eq.), DCE (3 mL), temp. = 80 °C, time = 16
h, sealed tube, N2, [b] Isolated yield.
Finally, the structure of product 3ac was confirmed
unambiguously by single crystal X-ray analysis (Figure 2).
Figure 2. Single crystal X-ray structure of compound 3ac (CCDC: 1875974)
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Anthranilamide (15 mmol) and an aldehyde (18 mmol) were dissolved in
DMSO (40 mL). Then, the reaction mixture was stirred at 100 °C in an
open flask and monitored by TLC. After complete consumption of the
starting materials, the reaction mixture was cooled to room temperature.
When water (100 mL) was added to the reaction mixture, the precipitate
was formed and collected by filtration. Recrystallization in ethanol afforded
quinazolinone.[33]
General
procedure
for
the
Synthesis
of
hydroxyisoindolo[1,2-b]quinazolinone compounds:
A sealed tube (10 mL) that contained 2-arylquinazolinone 1 (1.0 mmol),
aldehyde (1.2 mmol), Pd(OAc)2 (10 mol%), TBHP (4 mmol) and DCE as a
solvent (3.0 mL) was purged with nitrogen gas and the reaction was stirred
at 80 ℃ for 16h. At the end of the reaction, the reaction mixture was cooled
to room temperature, concentrated under reduced pressure, water was
added, and then extracted with EtOAc (2 x 15 mL). The organic layer was
further washed with brine solution. Afterward, the organic layer was
separated and dried over anhydrous Na2SO4 and concentrated under
reduced pressure using a rotary evaporator. Finally, purification was
accomplished by thin layer chromatography to afford the desired pure
product.
2-phenylquinazolin-4(3H)-one: White solid, Yield: 84%, mp: 234-236 °C
(lit.[34] mp: 237-238 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.56 (br s, 1H),
8.20 – 8.15 (m, 3H), 7.88 – 7.74 (m, 2H), 7.63 – 7.50 (m, 4H).
Scheme 3. A plausible mechanism.
2-(p-tolyl)quinazolin-4(3H)-one: White solid, Yield: 78%, mp: 239-241 °C
(lit.[35] mp: 245-247 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.47 (br s, 1H),
8.16 – 8.09 (m, 3H), 7.83 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.51
(t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 2.39 (s, 3H).
Conclusions
We have described a highly efficient method for palladium-
catalyzed CDC/annulation reaction of arylquinazolinones with
aldehydes. These transformations have been applied to a wide
range of substrates, and typically proceeded with high levels of
regio- and chemoselectivity. Additionally, the reaction is
performed with toluene in place of benzaldehyde by using an
excess amount of TBHP in good yield. This method provides an
alternative approach for the synthesis of biologically important
hydroxyisoindolo[1,2-b]quinazolinones. Further investigations
into the biological properties, scopes, and synthetic of these
hydroxyisoindolo[1,2-b]quinazolinone derivatives and the studies
of the reaction mechanism are currently in progress.
2-(4-chlorophenyl)quinazolin-4(3H)-one: White solid, Yield: 65%, mp:
304-306°C (lit.[34] mp: 300-308 °C);1H NMR (300 MHz, DMSO-d6) δ 12.61
(br s, 1H), 8.22– 8.14 (m, 3H), 7.87 – 7.73 (m, 2H), 7.64 – 7.51 (m, 3H).
2-(4-nitrophenyl)quinazolin-4(3H)-one: White solid, Yield: 52%, mp:
359-361 °C (lit. [34] mp: 362-364 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.78
(br s, 1H), 8.48 – 8.35 (m, 4H), 8.18 (d, J = 8.0 Hz, 1H), 7.90 – 7.73 (m,
2H), 7.58 (t, J = 7.7 Hz, 1H).
2-(3-chlorophenyl)quinazolin-4(3H)-one: White solid, Yield: 56%, mp:
292-294 °C (lit. [34] mp: 296-298 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.53
(br s, 1H), 8.24 (s, 1H), 8.18 – 8.15 (m, 2H), 7.88 – 7.75 (m, 2H), 7.66 –
7.58 (m, 2H), 7.54 – 7.51 (m, 1H).
Experimental Section
2-(3-bromophenyl)quinazolin-4(3H)-one: White solid, Yield: 52%, mp:
293-291 °C (lit.[35] mp: 300 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.63 (br
s, 1H), 8.38 (s, 1H), 8.17 (t, J = 8.3 Hz, 2H), 7.92 – 7.75 (m, 3H), 7.53 (q,
J = 7.8 Hz, 2H).
General Information. All solvents and starting materials were purchased
from Merck and Sigma. Analytical thin layer chromatography (TLC) was
performed on pre-coated silica gel 60 F254 plates. The products were
purified by thin layer chromatography (MERCK Silica Gel 60). 1H and 13C-
NMR Spectra: were recorded on Bruker DRX 300 and 75 MHz and INOVA
500 and 126 MHz, respectively. Mass spectra were recorded on an Agilent
Technology (HP) 5973 Network Mass Selective Detector operating at an
ionization potential of 70 eV. Elemental analysis of products was
performed using an Elementar Analysensysteme GmbH VarioEL CHNS.
2-(2-fluorophenyl)quinazolin-4(3H)-one: White solid, Yield: 52%, mp:
160-162 °C (lit.[36] mp: 162-163 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.61
(br s, 1H), 8.19 – 8.16 (m, 1H), 7.89 – 7.72 (m, 3H), 7.66 – 7.55 (m, 2H),
7.46 – 7.35 (m, 2H).
2-(2-methoxyphenyl)quinazolin-4(3H)-one: White solid, Yield: 52%, mp:
199-201 °C (lit.[35] mp: 201-203 °C); 1H NMR (300 MHz, DMSO-d6) δ 12.12
(br s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8
Hz, 2H), 7.56 – 7.50 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.5 Hz,
1H), 3.86 (s, 3H).
General procedure for the Synthesis of substituted
quinazolin-4(3H)-one substrates:
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12-hydroxy-12-phenylisoindolo[1,2-b]quinazolin-10(12H)-one (3aa):
White solid, Yield: 71%, mp: 269-270°C, IR (KBr) (νmax /cm-1): 3422, 1690,
1579, 1424; 1H NMR (300 MHz, DMSO-d6) δ 8.22 – 8.15 (m, 2H), 7.96 (s,
2H), 7.86 – 7.73 (m, 2H), 7.61 – 7.49 (m, 4H), 7.38 – 7.34 (m, 4H); ); 13C
NMR (126 MHz, DMSO-d6) δ 162.0, 156.2, 149.1, 145.6, 142.6, 134.7,
133.9, 129.2, 128.7, 126.6, 125.9, 125.1, 120.9; MS (m/z): 326 (M+); Anal.
Calcd for C21H14N2O2: C, 77.29; H, 4.32; N, 8.58. Found: C, 77.36; H, 4.41;
N, 8.64.
159.2, 149.2, 146.4, 141.0, 139.0, 134.0, 133.4, 130.6, 130.6, 130.2, 128.7,
128.7, 128.6, 128.6, 128.1, 126.7, 122.4; MS (m/z): 360 (M+); Anal. Calcd
for C21H13ClN2O2: C, 69.91; H, 3.63; N, 7.76. Found: C, 70.06; H, 3.69; N,
7.67.
12-(4-fluorophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3ah): White solid, Yield: 57%, mp: 228-231 °C; IR (KBr) (νmax /cm-1):
3450, 1693, 1565, 1416; 1H NMR (300 MHz, DMSO-d6) δ 8.16 – 8.04 (m,
2H), 7.82 – 7.68 (m, 2H), 7.63 – 7.61 (m, 2H), 7.49 – 7.45 (m, 3H), 7.35 –
7.32 (m, 1H), 7.15 – 7.10 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ 162.8,
152.8, 149.1, 148.5, 147.9, 135.1, 133.2, 131.8, 129.1, 128.2, 128.0, 127.0,
126.3, 121.4; MS (m/z): 344 (M+); Anal. Calcd for C21H13FN2O2: C, 73.25;
H, 3.81; N, 8.14. Found: C, 73.46; H, 3.85; N, 8.11.
12-hydroxy-12-(p-tolyl)isoindolo[1,2-b]quinazolin-10(12H)-one (3ab):
White solid, Yield: 73%, mp: 246-248 °C; IR (KBr) (νmax /cm-1): 3448, 1698,
1619, 1468;1H NMR (300 MHz, DMSO-d6) δ 8.09 – 8.06 (m, 2H), 7.86 –
7.76 (m, 3H), 7.65 – 7.59 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.36 – 7.28 (m,
3H), 7.12 (d, J = 7.9 Hz, 2H), 2.26 (s, 3H); 13C NMR (126 MHz, DMSO-d6)
δ 165.2, 159.5, 148.4, 139.2, 136.9, 134.8, 133.1, 130.5, 129.3, 127.1,
126.6, 126.3, 125.8, 122.5, 21.1; MS (m/z): 340 (M+); Anal. Calcd for
C22H16N2O2: C, 77.63; H, 4.74; N, 8.23. Found: C, 77.82; H, 4.80; N, 8.14.
12-hydroxy-12-(3-methoxyphenyl)isoindolo[1,2-b]quinazolin-
10(12H)-one (3aj): White solid, Yield: 72%, mp: 217-219 °C; IR (KBr) (νmax
1
/cm-1): 3437, 1690, 1608, 1500; H NMR (300 MHz, DMSO-d6) δ 8.09 (d,
J = 7.6 Hz, 2H), 7.91 – 7.75 (m, 2H), 7.63 (d, J = 4.7 Hz, 2H), 7.52 (t, J =
7.2 Hz, 1H), 7.39 – 7.36 (m, 1H), 7.21 – 7.14 (m, 2H), 6.88 – 6.85 (m, 1H),
6.77 (d, J = 7.6 Hz, 1H), 3.74 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ
159.7, 141.5, 134.9, 133.7, 133.4, 130.6, 130.0, 127.7, 127.2, 126.6, 124.2,
122.5, 117.7, 115.7, 113.6, 112.1, 55.6; MS (m/z): 356 (M+); Anal. Calcd
for C22H16N2O2: C, 74.15; H, 4.53; N, 7.86. Found: C, 74.33; H, 4.47; N,
7.71.
12-hydroxy-12-(4-isopropylphenyl)isoindolo[1,2-b]quinazolin-
10(12H)-one (3ac): White solid, Yield: 76%, mp: 236-238 °C; IR (KBr)
(νmax /cm-1): 3214, 1696, 1622, 1422; 1H NMR (300 MHz, DMSO-d6) δ 8.12
– 8.07 (m, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.62 – 7.59 (m, 2H), 7.51 (t, J =
7.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 3H), 7.18 (d, J = 7.7 Hz, 2H), 2.88 – 2.78
(m, 1H), 1.16 (s, 3H), 1.13 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 154.1,
149.0, 148.7, 137.2, 134.9, 133.7, 130.5, 130.1, 127.6, 127.2, 126.7, 126.6,
125.8, 124.3, 123.4, 122.5, 33.5, 24.2; MS (m/z): 368 (M+); Anal. Calcd for
C24H20N2O2: C, 78.24; H, 5.47; N, 7.60. Found: C, 78.41; H, 5.55; N, 7.71.
CCDC: 1875974
12-(3-fluorophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3ak): White solid, Yield: 53%, mp: 274-276 °C; IR (KBr) (νmax /cm-1):
3435, 1672, 1565, 1415;1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J = 6.9
Hz, 1H), 7.87 – 7.75 (m, 2H), 7.63- 7.58 (m, 2H), 7.53 – 7.27 (m, 5H), 7.20
– 7.07 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.9, (d, J = 242.2 Hz),
149.0, 147.8, 135.0, 133.9, 130.8, 127.7, 127.3, 126.6, 124.1, 123.3, 122.4,
121.7, 115.3 (d, J= 20.3 Hz), 113.1 (d, J = 23.3 Hz). MS (m/z): 344 (M+);
Anal. Calcd for C21H13FN2O2: C, 73.25; H, 3.81; N, 8.14. Found: C, 73.42;
H, 3.90; N, 8.12.
12-hydroxy-12-(4-methoxyphenyl)isoindolo[1,2-b]quinazolin-
10(12H)-one (3ad): White solid, Yield: 68%, mp: 177-180 °C; IR (KBr)
(νmax /cm-1): 3394, 1677, 1604, 1466; 1H NMR (300 MHz, DMSO-d6) δ 8.25
(d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.75 – 7.61 (m, 2H), 7.52 –
7.42 (m, 2H), 7.35 – 7.21 (m, 3H), 7.02 - 6.84 (m, 3H), 3.71 (s, 3H); 13
C
NMR (126 MHz, DMSO-d6) δ 159.4, 157.5, 148.4, 139.3, 135.0, 134.2,
133.1, 129.1, 127.5, 127.1, 126.8, 126.5, 126.1, 121.8, 114.7, 114.1, 55.6;
MS (m/z): 356 (M+); Anal. Calcd for C22H16N2O3: C, 74.15; H, 4.53; N, 7.86.
Found: C, 74.30; H, 4.63; N, 7.80.
12-(3-bromophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3al): White solid, Yield: 61%, mp: 234-236 °C; IR (KBr) (νmax /cm-1):
3426, 1702, 1567, 1417; 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J = 7.0
Hz, 2H), 7.90 – 7.79 (m, 3H), 7.63 (s, 2H), 7.51 – 7.49 (m, 2H), 7.36 (s,
2H), 7.24 – 7.18 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 153.7, 149.0,
142.6, 135.0, 133.9, 131.3, 131.0, 130.8, 128.7, 127.7, 127.3, 126.6, 124.8,
124.1, 123.4, 122.4, 122.1. MS (m/z): 249 (M+ - 155); Anal. Calcd for
C21H13BrN2O2: C, 62.24; H, 3.23; N, 6.91. Found: C, 62.41; H, 3.32; N,
6.82.
12-(4-(benzyloxy)phenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-
10(12H)-one (3ae): White solid, Yield: 70%, mp: 198-200 °C; IR (KBr)
(νmax /cm-1): 3414, 1644, 1572, 1415; 1H NMR (300 MHz, DMSO-d6) δ 8.09
– 8.04 (m, 2H), 7.83 – 7.79 (m, 2H), 7.64 – 7.61 (m, 2H), 7.53 – 7.30 (m,
10H), 6.96 – 6.93 (m, 2H), 5.06 (s, 2H); 13C NMR (126 MHz, DMSO-d6) δ
162.6, 157.4, 156.1, 147.5, 146.8, 138.6, 137.4, 134.9, 134.4, 134.1, 130.5,
128.9, 128.3, 128.1, 127.7, 127.6, 126.6, 118.1, 115.7, 114.9, 69.7; MS
(m/z): 313 (M+ - 119); Anal. Calcd for C28H20N2O3: C, 77.76; H, 4.66; N,
6.48. Found: C, 78.01; H, 4.89; N, 6.23.
12-(2-fluorophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3am): White solid, Yield: 48%, mp: 256-258 °C; IR (KBr) (νmax /cm-1):
3445, 1688, 1571, 1411; 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H),
8.07 – 7.99 (m, 2H), 7.87 – 7.74 (m, 2H), 7.63 – 7.49 (m, 3H), 7.37 – 7. 24
(m, 3H), 6.97 – 6.90 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 164.7, 161.9
(d, J= 256.5 Hz), 158.6, 148.9, 146.9, 135.1, 133.8, 131.0, 130.8, 129.6,
127.7, 127.3, 126.9, 126.6, 125.5, 124.9, 123.0, 116.0 (d, J= 23.2 Hz); MS
(m/z): 344 (M+); Anal. Calcd for C21H13FN2O2: C, 73.25; H, 3.81; N, 8.14.
Found: C, 73.42; H, 3.89; N, 8.09.
12-(4-bromophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3af): White solid, Yield: 64%, mp: 281-283 °C; IR (KBr) (νmax /cm-1):
3428, 1696, 1568, 1416; 1H NMR (300 MHz, DMSO-d6) δ 8.13 -8.02 (m,
2H), 7.77 – 7.61 (m, 5H), 7.52 – 7.49 (m, 2H), 7.40 – 7.32 (m, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 149.1, 139.4, 134.9, 133.7, 131.6, 130.7,
128.3, 127.6, 127.1, 126.6, 124.3, 123.6, 122.4, 121.9. MS (m/z): 404 (M+);
Anal. Calcd for C21H13BrN2O2: C, 62.24; H, 3.23; N, 6.91. Found: C, 62.47;
H, 3.32; N, 6.88.
12-(2,5-dimethoxyphenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-
10(12H)-one (3an): White solid, Yield: 61%, mp: 272-274 °C; IR (KBr)
(νmax /cm-1): 3410, 1690, 1600, 1467; 1H NMR (300 MHz, DMSO-d6) δ 8.07
– 8.00 (m, 2H), 7.81 (d, J = 7.3 Hz, 2H), 7.69 (d, J = 3.2 Hz, 1H), 7.64 –
7.43 (m, 4H), 7.27 – 7.25 (m, 1H), 6.88 – 6.84 (m, 1H), 6.72 (d, J = 9.0 Hz,
1H), 3.81 (s, 3H), 2.95 (s, 3H);. 13C NMR (75 MHz, DMSO-d6 + 1%
CF3COOH) δ 161.2, 158.1, 142.6, 135.9, 129.3, 129.1, 128.3, 126.8,
123.1, 122.2, 121.1, 120.4, 118.6, 117.3, 115.8, 114.2, 113.5, 109.7, 56.4,
12-(4-chlorophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-
one (3ag): White solid, Yield: 67%, mp: 265-268 °C; IR (KBr) (νmax /cm-1):
3429, 1693, 1561, 1435; 1H NMR (500 MHz, DMSO-d6) δ 8.11 – 8.03 (m,
2H), 7.78 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.63 – 7.61 (m, 2H), 7.46 – 7.44
(m, 3H), 7.37 – 7.32 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ 161.3,
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10.1002/ejoc.201900417
European Journal of Organic Chemistry
FULL PAPER
55.6; MS (m/z): 356 (M+ - 30); Anal. Calcd for C23H18N2O4: C, 71.49; H,
4.70; N, 7.25. Found: C, 71.64; H, 4.76; N, 7.15.
2H), 7.85 – 7.73 (m, 4H), 7.52 – 7.39 (m, 4H), 7.33 - 7.31 (m, 2H); 13C
NMR (126 MHz, DMSO-d6) δ 159.1, 149.8, 148.9, 143.9, 139.2, 130.1,
128.9, 128.4, 127.9, 127.6, 127.3, 126.7, 125.9, 124.3, 122.4; MS (m/z):
360 (M+); Anal. Calcd for C21H13ClN2O2: C, 69.91; H, 3.63; N, 7.76. Found:
C, 70.14; H, 3.70; N, 7.83.
12-(2,3-dimethoxyphenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-
10(12H)-one (3ao): White solid, Yield: 55%, mp: 230-233 °C; IR (KBr)
(νmax /cm-1): 3196, 1693, 1626, 1473; 1H NMR (300 MHz, DMSO-d6) δ 8.11
– 8.04 (m, 2H), 7.86 – 7.74 (m, 4H), 7.65 – 7.60 (m, 2H), 7.51 – 7.49 (m,
1H), 7.27 – 7.18 (m, 2H), 7.04 (d, J = 7.9 Hz, 1H), 3.66 (s, 3H), 2.69 (s,
3H); 13C NMR (126 MHz, DMSO-d6) δ 154.5, 152.5, 148.2, 145.1, 134.8,
133.3, 132.8, 131.5, 130.3, 127.7, 127.0, 126.5, 123.6, 123.4, 122.8, 122.6,
120.5, 115.7, 113.7, 59.0, 56.0; MS (m/z): 386 (M+); Anal. Calcd for
C23H18N2O4: C, 71.49; H, 4.70; N, 7.25. Found: C, 71.69; H, 4.75; N, 7.16.
3-chloro-12-hydroxy-12-phenylisoindolo[1,2-b]quinazolin-10(12H)-
one (3ea): White solid, Yield: 64%, mp: 231-233 °C, IR (KBr) (νmax /cm-1):
3463, 1670, 1580, 1421;1H NMR (300 MHz, DMSO-d6) δ 8.11 – 8.04 (m,
2H), 7.81 – 7.62 (m, 4H), 7.50 – 7.43 (m, 4H), 7.36 – 7.30 (m, 5H); 13
C
NMR (126 MHz, DMSO-d6) δ 161.3, 158.5, 150.3, 144.0, 141.1, 135.1,
133.4, 131.1, 130.3, 129.7, 128.7, 128.0, 126.9, 126.8, 126.2, 118.7; MS
(m/z): 360; Anal. Calcd for C21H13ClN2O2: C, 69.91; H, 3.63; N, 7.76.
Found: C, 70.02; H, 3.67; N, 7.72.
12-(2,4-dichlorophenyl)-12-hydroxyisoindolo[1,2-b]quinazolin-
10(12H)-one (3ap): White solid, Yield: 53%, mp: 251-253 °C; IR (KBr)
(νmax /cm-1): 3439, 1693, 1577, 1430; 1H NMR (300 MHz, DMSO-d6) δ 8.44
– 8.38 (m, 1H), 8.06 (d, J = 7.7 Hz, 2H), 7.88 – 7.90 (m, , 2H), 7.67 – 7.63
(m, 2H), 7.55 – 7.39 (m, 3H), 7.24 (s, 1H); 13C NMR (126 MHz, DMSO-d6)
δ 162.1, 158.7, 145.7, 143.2, 138.4, 135.4, 135.1, 134.3, 133.8, 132.0,
130.9, 130.2, 128.8, 127.9, 127.4, 126.7, 123.6, 121.9, 106.5; MS (m/z):
394 (M+); Anal. Calcd for C21H12Cl2N2O2: C, 63.82; H, 3.06; N, 7.09. Found:
C, 63.99; H, 3.10; N, 7.07.
3-bromo-12-hydroxy-12-phenylisoindolo[1,2-b]quinazolin-10(12H)-
one (3fa): White solid, Yield: 62%, mp: 245-247 °C; IR (KBr) (νmax /cm-1):
3448, 1689, 1562, 1464;1H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.08
(s, 1H), 7.83 – 7.82 (m, 2H), 7.73 – 7.65 (m 3H), 7.47 (s, 2H), 7.34 (s, 4H);
13C NMR (126 MHz, DMSO-d6) δ 152.4, 149.0, 144.4, 142.7, 139.3, 134.8,
133.0, 130.7, 127.8, 127.6, 127.2, 126.6, 126.0, 123.5; MS (m/z): 404 (M+);
Anal. Calcd for C21H13BrN2O2: C, 62.24; H, 3.23; N, 6.91. Found: C, 62.35;
H, 3.28; N, 6.87.
12-hydroxy-12-mesitylisoindolo[1,2-b]quinazolin-10(12H)-one (3aq):
White solid, Yield: 62%, mp: 236-238 °C; IR (KBr) (νmax /cm-1): 3422, 1676,
1609, 1416; 1H NMR (300 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.73 – 7.48 (m,
6H), 6.69 – 6.64 (m, 3H), 2.10 (s, 3H), 2.06 (s, 6H); 13C NMR (126 MHz,
DMSO-d6) δ 162.0, 155.3, 151.6, 142.2, 139.1, 138.6, 136.4, 135.4, 134.3,
132.7, 130.6, 130.3, 127.4, 126.5, 126.1, 121.4; MS (m/z): 368 (M+); Anal.
Calcd for C24H20N2O2: C, 78.24; H, 5.47; N, 7.60. Found: C, 78.30; H, 5.56;
N, 7.51.
4-fluoro-12-hydroxy-12-phenylisoindolo[1,2-b]quinazolin-10(12H)-
one (3ga): White solid, Yield: 37%, mp: 201-203 °C; IR (KBr) (νmax /cm-1):
3440, 1689, 1588, 1413; 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H),
7.72 – 7.68 (m, 4H), 7.61 – 7.53 (m, 4H), 7.41 (s, 2H), 7.35 – 7.33 (m, 1H);
13C NMR (126 MHz, DMSO-d6) δ 159.2, 158.2 (d, J= 248.2 Hz), 149.1,
147.6, 142.8, 134.3, 133.3, 133.0, 132.7, 129.4, 127.5, 127.1, 126.0, 125.6,
122.6, 121.7, 119.4 (d, J= 26.46 Hz), 113.7 (d, J= 32.76 Hz); MS (m/z):
344 (M+); Anal. Calcd for C21H13FN2O2: C, 73.25; H, 3.81; N, 8.14. Found:
C, 73.43; H, 3.86; N, 8.17
12-(furan-2-yl)-12-hydroxyisoindolo[1,2-b]quinazolin-10(12H)-one
(3ar): White solid, Yield: 59%, mp: 175-177 °C; IR (KBr) (νmax /cm-1): 3140,
1691, 1566, 1468; 1H NMR (300 MHz, DMSO-d6) δ 8.16 – 8.05 (m, 3H),
7.87 – 7.80 (m, 2H), 7.72 – 7.67 (m, 2H), 7.58 – 7.44 (m, 3H), 6.81 (m, 1H),
6.48 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 162.7, 159.6, 148.7, 146.5,
135.0, 133.7, 130.7, 129.0, 128.2, 126.7, 123.4, 122.3, 96.6; MS (m/z):
316 (M+); Anal. Calcd for C19H12N2O3: C, 72.15; H, 3.82; N, 8.86. Found:
C, 72.40; H, 3.88; N, 8.82.
Acknowledgments
We gratefully acknowledge Research Council of Shahid Beheshti
University for their financial support.
12-hydroxy-12-propylisoindolo[1,2-b]quinazolin-10(12H)-one (3at):
White solid, Yield: 43%, mp: 151-153 °C; IR (KBr) (νmax /cm-1): 3076, 1682,
1565, 1489; 1H NMR (300 MHz, DMSO-d6) δ 8.20 (t, J = 7.1 Hz, 2H), 8.01
(d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.75 – 7.70 (m, 2H), 7.58 –
7.51 (m, 2H), 7.30 (s, 1H), 3.07 – 2.95 (m, 1H), 2.34 – 2.26 (m, 1H), 0.90
– 0.73 (m, 2H), 0.71 – 0.64 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.7,
159.6, 149.0, 146.5, 135.0, 133.7, 130.7, 129.0, 128.2, 126.7, 123.4, 122.3,
96.6, 38.0, 17.3, 14.0; MS (m/z): 292 (M+); Anal. Calcd for C18H16N2O3: C,
73.95; H, 5.52; N, 9.58. Found: C, 74.10; H, 5.62; N, 9.52.
Keywords: C-H activation • Palladium • Acylation • Annulation •
Aldehyde
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10.1002/ejoc.201900417
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
CDC Annulation
Noushin Farajinia Lehi, Siyavash
Kazemi Movahed, Hamid Reza Khavasi
and Minoo Dabiri*
Page No. – Page No.
The palladium-catalyzed cross-dehydrogenative coupling followed by an
intramolecular cyclization between arylquinazolinones and aldehydes is reported.
Palladium Catalyzed Oxidative Cross-
Dehydrogenative
This viable transformation provides
hydroxyisoindolo[1,2-b]quinazolinone compounds in moderate to good yields.
a
variety of novel substituted
Coupling/Annulation Reactions: A
Practical and Efficient Approach to
hydroxyisoindolo[1,2-b]quinazolinone
This article is protected by copyright. All rights reserved.