One-pot synthesis of quinazoline derivatives via [2+2+2] cascade annulation of diaryliodonium salts and two nitriles

Article abstract of DOI:10.1039/c3cc43216e

An efficient one-pot approach to multiple substituted quinazolines with diaryliodonium salt 1, and two nitriles 2 has been presented. The reaction enables great flexibility of the substitution patterns on quinazolines and is applicable to two different nitriles to give a regio-selective product.

Full text of DOI:10.1039/c3cc43216e

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One-pot synthesis of quinazoline derivatives via
[2+2+2] cascade annulation of diaryliodonium
Cite this: DOI: 10.1039/c3cc43216e
salts and two nitriles†
Xiang Su,ab Chao Chen,*a Yong Wang,ac Junjie Chen,a Zhenbang Louac and
Ming Lic
Received 1st May 2013,
Accepted 6th June 2013
DOI: 10.1039/c3cc43216e
www.rsc.org/chemcomm
An efficient one-pot approach to multiple substituted quinazolines with
diaryliodonium salt 1, and two nitriles 2 has been presented. The reaction
enables great flexibility of the substitution patterns on quinazolines and
is applicable to two different nitriles to give a regio-selective product.
Scheme 1 One-pot synthesis of quinazoline derivatives through cascade annu-
Quinazolines are one of the most important nitrogen hetero-arenes
commonly found in lots of natural products, pharmaceutical mole-
cules, pesticides and functional organic materials. As main building
lation of diaryliodonium salts and two nitriles.
blocks, quinazolines widely occur in many natural alkaloids isolated quinazolines (especially those with poly-substituents), it is highly
from plants, animals and various microorganisms.1 Quinazoline desired to develop synthetic methods with a new strategy. Herein, we
derivatives have also shown diverse biological and therapeutic prop- would like to report a novel one-pot synthesis of quinazoline
erties such as anticancer, antitubercular, antibacterial, and antiviral derivatives through cascade annulation of diaryliodonium salts and
agents.2 The approval of quinazoline-based drugs – gefitinib (Iressa) two nitriles. The reactions are catalyzed by Cu(OTf)2 in the [2+2+2]
and erlotinib hydrochloride (Tarceva) for the treatment of non-small- cyclization mode with three molecules, in which the diaryliodoniums
cell lung cancer,3 has renewed the passion of developing new provide aryl groups serving as the C2-building block (Scheme 1).
synthetic strategies to prepare quinazolines.4 Traditionally, numerous
As part of our ongoing project of efficiently and ecologically
named reactions, including Niementowski synthesis, Bischler syn- synthesizing nitrogeneous hetero-arenes with diaryliodonium salts, we
thesis, Riedel synthesis and modified Duff synthesis,5 are known for recently reported a novel method to prepare quinolines with diaryl-
the synthesis of quinazolines. These methods generally proceed via iodonium salts, nitriles and alkynes catalyzed by Cu(OTf)2.7 The
classic condensation, addition and substitution reactions, often reaction proceeded via a series of electrophilic reactions and a key
suffering from a limited source of starting materials and low intermediate was the N-aryl nitrilium cation generated in situ by the
tolerance of functional groups. Recently, the synthesis of quinazoline reaction of nitrile and iodonium salt in the presence of Cu(OTf)2. So we
derivatives based on C–H-bond activation has been realized and envisioned that if the alkyne molecule is replaced by a second molecule
received much attention due to step-economy and a lower require- of nitrile, a quinazoline product would be obtained alternatively. Thus,
ment of functionality.6 However, the new synthesis requires much we examined a simple [A + 2B] annulation: the reaction of diphenyl-
work on the optimization of catalysts, ligands, oxidants and other iodonium 1a with 2 eq. of benzonitriles 2a at the same condition as
reaction conditions and is still at the infant stage of being well used in the previous study. To our delight, the expected 2,4-diphenyl
understood. To meet the high demand of the efficient synthesis of quinazoline 3a was isolated in 64% yield. When 3 eq. of benzonitrile
were used, the yield was increased to 84% (Table 1, entry 1).
a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
Next, a range of aromatic nitriles, including 1-naphthyl and
2-thienyl nitriles were examined and in all cases 2,4-diaryl
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084,
China. E-mail: chenchao01@mails.tsinghua.edu.cn; Tel: +86-10-62773684
b College of Chemistry and Biological Engineering, Beijing University of Science and
quinazolines were obtained in good isolated yields (Table 1,
entries 2–8). Aliphatic nitriles were also fit for the reaction to give
2,4-dialkyl quinazolines, albeit in lower yields (entries 9 and 10).
However, ethyl cyanoformate (NCCO2Et) and diethyl cyanphosphate
(NCPO(OEt)2) didn’t undergo the quinazoline annulation presum-
ably because of their electron-deficiency (entries 11 and 12).
The above results have shown the facile construction of quinazo-
lines with substituents on the pyrimidine ring. Encouraged by this,
Technology, Beijing, 100083, China
c College of Chemistry and Molecular Engineering, Qingdao University of Science
and Technology, Qingdao, 266042, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, full characterization including 1H NMR, 13C NMR, ESI-MS and HRMS data
for all new compounds and X-ray crystal structure of 4f, and X-ray data for 5a.
CCDC 934862 and 935164. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc43216e
c
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Table 1 Quinazoline 3 formed from the reaction of diphenyliodonium 1a with
various nitriles 2
Entry
R
Product, isolated yield
Fig. 1 Crystal structure of 4f (left) and 5a (right).
1
2
3
4
5
6
7
8
Ph
3a, 84%
3b, 59%
3c, 66%
3d, 90%
3e, 88%
3f, 82%
3g, 71%
3h, 80%
3i, 52%
3j, 54%
NP
4-Br-Ph
4-CF3-Ph
4-MeO-Ph
4-CH3-Ph
2-CH3-Ph
1-Naphthyl
2-Thienyl
Bn
Table 2 Quinazoline 5 formed from the reaction of 1a and 2d with various
second nitriles 2
9
10
11
12
Bu
CO2Et
PO(OEt)2
NP
Entry
R
Product, isolated yield
1
2
3
4
5
6
7
Bu
Bn
5a, 69%
5b, 50%
5c, 72%
5d, 55%
5e, 65%
5f, 57%
5g, 60%
we introduced substituents on the phenyl ring, by the use of
functionalized diaryliodonium salts. Various diaryliodonium tri-
flates were readily prepared by known methods.8,9 Diaryliodoniums
with a range of substituents involving 4-bromo, 4-trifluoromethyl,
2,4- and 2,5-dimethyl, 2- and 4-methyl, 2- and 4-fluoro, 4-chloro and
benzo groups all worked well with 3.0 eq. of benzonitrile 2a to give
the desired products 4 (Scheme 2). The structure of 4f was further
confirmed by XRD of its single crystal (Fig. 1, CCDC 934862).
These successful examples are actually realized with two compo-
nents via the [A + 2B] cyclization mode and provide quinazolines
with identical substituents at the 2- and 4-positions. Consequently,
we attempted to prepare quinazolines by the use of two different
nitriles, which are obviously more useful but challenging due to the
close reactivity. To avoid the formation of regio-isomers, the diary-
liodonium salt and the first nitrile (1.1 : 1) were allowed to react for a
while converting all of the first nitrile into the N-aryl nitrilium salt
discretely before the second nitrile was added. With the first nitrile
4-CF3-Ph (1 eq. 100 1C)
BrCH2
Br
ClCH2
CO2Et
exemplified as 4-methoxy benzonitrile 2d, the optimized procedure
was: diphenyliodonium 1a (1.1 eq.) and 4-methoxybenzonitrile 2d
(1.0 eq.) were reacted at 120 1C for 0.5 h and then a second nitrile
was added to continue reacting for 12 h to produce quinazoline 5
respectively (Table 2). The second nitriles with Bu, Bn or 4-trifluoro-
methyl phenyl groups gave the desired product in synthetically
useful yields. The structure of 5a was unequivocally confirmed by
XRD analysis (Fig. 1, CCDC 935164).
To our delight, the second nitriles with bromo, bromomethyl,
chloromethyl, or ester groups also worked well to give functionalized
quinazolines which were not readily accessible via traditional
quinazoline synthesis methods. The reaction of 1a and 2d with
diethyl cyanophosphate (NCPO(OEt)2) afforded protonated product
5h instead of 5i (Scheme 3). The protonated product was already
formed before the reaction was quenched. The deuteration reaction
proved the H-atom at the 4-position came from diphenyliodonium 1a
and the mechanism for this specific reaction is not clear at present.
In this [A + B + C] cyclization, the first nitrile is possibly alter-
nated to other aromatic nitriles under re-optimized conditions and
selected examples with isolated yield are shown in Scheme 4 (the
second nitrile was exemplified as valeronitrile 2j). Unfortunately,
the use of alkyl nitrile as the first nitrile was unsuccessful (around
10% yield whatever the second nitrile was).
Scheme 2 The synthesis of quinazolines 4 from various diaryliodonium triflates
1 with benzonitrile 2a.
Scheme 3 The investigation of 5h formed in the reaction of 1, 2d and diethyl
cyanophosphate (NCPO(OEt)2).
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and elimination chemistry. The facile construction of the
quinazoline skeleton and simple manipulation might be useful
for the design and generation of a quinazolines’ library.
This work was supported by the National Natural Science
Foundation of China (21102080) and the Tsinghua University
Initiative Scientific Research Program (2011Z02150).
Notes and references
Scheme 4 Quinazoline 6 formed from the reaction of 1a and aromatic nitrile
with valeronitrile 2j as the second nitrile (see ESI† for details).
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In the preparation of these quinazolines, we often observed
N-aryl amide as a byproduct by GC-MS (around 10% yield). This
phenomena was attributed to the hydrolysis of the N-aryl nitrilium
salt formed during the reaction.7,10 Actually, Ph2IPF6 1a and
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(1)
Based on the above findings and previous report, we proposed
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Cu(I) via reduction or disproportion and then oxidative addition
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group to the nitrile to give N-phenylnitrilium intermediate I.
Intermediate I would produce the anilide by hydrolysis.
N-phenylnitrilium species I is quickly attacked by the second
nitrile to give intermediate II, which undergoes an electrophilic
substitution on the aryl ring to give the quinazoline product.
In summary, an efficient one-pot approach to multiple sub-
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nitriles to give a regio-selective product. This strategy of electro-
philic annulations enables great flexibility of the substitution
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Scheme 5 Proposed mechanism.
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