Molecular Catalysis
Palladium-catalyzed carbonylative synthesis of quinazolines: Silane act as
better nucleophile than amidine
,
,c,*
Jia-Ming Lua, Yong-Wang Huoa, Xinxin Qia *, Xiao-Feng Wub
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, PR China
b Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, PR China
c
¨
Leibniz-Institut für Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords:
A palladium-catalyzed reductive carbonylation reaction has been developed for the synthesis of quinazolines.
With N-(2-iodophenyl)benzimidamide as starting materials, a series of quinazolines were obtained through the
aromatic aldehyde intermediates in moderate to good yields with good functional group compatibilities. In this
system, silane act as better nucleophile than amidine.
Quinazoline
Palladium catalyst
Carbonylation
Aromatic aldehyde
N-(2-iodophenyl)benzimidamide
During the past decades, transition-metal-catalyzed carbonylation
reactions have proven to be one of the powerful methods for the con-
struction of carbonyl-containing compounds and have attracted lots of
attentions for their widely application in both academic and industrial
fields. [1] Among all the carbonylation reactions, the synthesis of aro-
matic aldehyde by reductive carbonylation is considered to be unique
and interesting. One representative example was developed by Beller’s
group, [2] a general and practical palladium-catalyzed reductive
carbonylation of aryl and heteroaryl bromides in the presence of syngas.
Furthermore, several other methods have been reported for the prepa-
ration of aromatic aldehydes by different research groups as well. [3]
Recently, we also explored a few reductive carbonylation reactions for
the synthesis of aromatic aldehydes. [4] Additionally, the synthesis of
bis(indolyl)methanes, [5] and chalcone [6] have also been developed
via the aldehyde-mediate palladium-catalyzed reductive carbonylation
reactions.
mediate quinazolines synthesis came to our mind (Scheme 1, eq a). In
our approach, it is noteworthy that the reaction could potentially un-
dergo another competitive pathway (Scheme 1, eq b). [18] We reasoned
that this pathway may be suppressed by the selection of hydrogen
source. Under these backgrounds, we wish to disclose here a
palladium-catalyzed quinazolines synthesis via a reductive carbonyla-
tion process with aromatic aldehydes as the key intermediates.
Initially, we carried out this reductive carbonylation reaction with
N-(2-iodophenyl)benzimidamide 1a (prepared from o-iodoaniline and
benzonitrile) as model substrate, Pd(OAc)2 as the catalyst, PPh3 as the
ligand, Mo(CO)6 as the CO source, Et3SiH as the hydrogen source, Et3N
as the base in DMF at 120 ◦C for 16 h, the target product 2a was ob-
tained in 5% yield (Table 1, entry 1). Next, different silanes were
studied (Table 1, entry 2–4), 19% yield of 2a was observed with
Ph2SiH2 as the hydrogen source (Table 1, entry 2). Delightly, when
using 3 equivalent of Mo(CO)6, the quinazoline product was detected in
47% yield (Table 1, entry 5). Palladium catalysts, such as Pd(TFA)2,
PdCl2, PdBr2, and Pd(acac)2 were then examed, resulting the desired
quinazoline in lower yields (Table 1, entry 6–9). Subsequently, various
mono- and bidentate phosphine ligands were examined, PCy3 and
Xphos resulted the corresponding product in 18% and 26% yields
(Table 1, entry 10–11), while BuPAd2 gave a comparable yield as PPh3
(Table 1, entry 12). Gratifyingly, P(C6F5)3 appeared to be the best
ligand in this reaction, producing the corresponding product in 56%
(Table 1, entry 13). Compare to monodentate ligands, the use of
bidentate ligands decreased the product yield (Table 1, entry 14–15).
Quinazolines, a valuable class of nitrogen-containing compounds
which play an important role in pharmaceutical industry due to their
wide range biological and medicinal activities such as antibacterial, [7]
anticancer, [8] anticonvulsant, [9] anti-inflammatory, [10] antima-
larial, [11] antitubercular, [12] and antiviral properties. [13] Therefore,
numerous protocols for the preparation of quinazolines has been
developed during these years. [14] Although much efforts have been put
on this area, [15–17] the exploration of novel catalytic system remains
an active field of research. Considering the straightforward and effective
utilization of palladium-catalyzed reductive carbonylation, an aldehyde
* Corresponding authors.
Received 9 April 2021; Received in revised form 3 May 2021; Accepted 4 May 2021
Available online 26 May 2021
2468-8231/© 2021 Elsevier B.V. All rights reserved.
Lu, Jia-Ming
