A novel ruthenium-catalyzed dehydrogenative synthesis of 2-arylquinazolines from 2-aminoaryl methanols and benzonitriles

Article abstract of DOI:10.1021/ol503052s

By employing a commercially available Ru₃(CO)₁₂/Xantphos/t-BuOK catalyst system, a novel and straightforward ruthenium-catalyzed dehydrogenative synthesis of 2-arylquinazolines has been demonstrated. A series of 2-aminoaryl methanols were efficiently converted in combination with different types of benzonitriles into various desired products in moderate to good yields upon isolation. The synthetic protocol proceeds with the advantages of operational simplicity, high atom efficiency, broad substrate scope, and no need for the use of less environmentally benign halogenated reagents, offering an important basis for accessing 2-arylquinazolines.

Full text of DOI:10.1021/ol503052s

Letter
pubs.acs.org/OrgLett
A Novel Ruthenium-Catalyzed Dehydrogenative Synthesis of
2‑Arylquinazolines from 2‑Aminoaryl Methanols and Benzonitriles
Mengmeng Chen,†,‡ Min Zhang,*,† Biao Xiong,† Zhenda Tan,† Wan Lv,† and Huanfeng Jiang†
†School of Chemistry & Chemical Engineering, South China University of Technology, Guangzhou 510641,
People’s Republic of China
‡School of Chemical & Material Engineering, Jiangnan University, Wuxi 214122, People’s Republic of China
S
* Supporting Information
ABSTRACT: By employing a commercially available Ru3(CO)12/Xantphos/t-BuOK catalyst system, a novel and straight-
forward ruthenium-catalyzed dehydrogenative synthesis of 2-arylquinazolines has been demonstrated. A series of 2-aminoaryl
methanols were efficiently converted in combination with different types of benzonitriles into various desired products in moderate
to good yields upon isolation. The synthetic protocol proceeds with the advantages of operational simplicity, high atom
efficiency, broad substrate scope, and no need for the use of less environmentally benign halogenated reagents, offering an
important basis for accessing 2-arylquinazolines.
Scheme 1. Representative Methods for Accessing
Quinazolines
he quinazoline moiety is the core structure of numerous
alkaloids and functional molecules that exhibit diverse
T
biological and therapeutic activities such as antibacterial,1
antiviral,2 anticonvulsant,3 and anticancer4 and are potent
inhibitors of the epidermal growth factor receptors of tyro-
sine kinase.5 For example, erlotinib and gefitinib are well-
known drugs used for the treatment of lung cancer. Moreover,
quinazolines could serve as valuable intermediates for various
synthetic purposes including the preparation of functionalized
materials.6
The first example for the synthesis of quinazolines was re-
ported by Griess in 1869 through the reaction of cyanogen with
anthranilic acid. Due to the increasing importance of quinazo-
line derivatives, much attention has been focused on the
development of alternative approaches for accessing this type
of compound in the past decade, which mainly involve (1)
oxidative condensation of 2-aminobenzylamine with benzalde-
hydes or benzyl alcohols (Scheme 1, approach A),7 o-carbonyl
anilines with benzyl amines (approach B),8a,b or ammonia and
different carbon sources8c−e (approaches C and D); (2) con-
densation of oxime derivatives with aldehydes (approach E);9
(3) oxidative coupling of o-carbonyl halobenzenes with ammonia
and aldehydes (approach F);10 (4) Ullmann or Buchwald−
Hartwig amination-involved cyclization of amidines with
o-carbonyl halobenzenes11a (approach G), 2-halobenzyl halides11b
or 2-halobenzyl tosylates (approach H),11c and 2-halobenzyl
amines (approach I);11d (5) oxidative coupling of amidines with
benzyl alcohols or bezaldehyes (approach J)11e and hypervalent
iodine-substituted alkynes (approach K);11f and (6) intra-
molecular oxidative cyclization of N-alkylated arylamidines
(approach L).12 Despite these contributions, many of them
require the addition of excess oxidants and the use of special
prefunctionalized or less environmentally benign halogenated
reagents, which could result in preparation difficulties or a
detrimental influence on the environment. From the viewpoint of
green synthesis concerns, development of environmentally
friendly shortcuts for accessing quinazolines from stable and easily
available substrates still remains a demanding goal.
Upon a thorough literature investigation, it is understandable
that the synthesis of quinazolines from 2-aminobenzaldehydes
and benzonitriles is less likely due to the 2-aminobenzaldehydes
tending to undergo a homocondensation. Inspired by our
recent work on ruthenium-catalyzed transformation of abun-
dant and sustainable alcohols into value-added products,13
Received: October 18, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503052s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
we believe such a synthetic goal could be realized by replacing
2-aminobenzaldehydes with 2-aminobenzyl alcohols 1 in the
presence of a suitable ruthenium catalyst system. Through an
acceptorless dehydrogenative coupling process,14 the reaction
might undergo the following tandem sequences: (1) The
nucleophilic addition of the amino group of 1 to the benzonitrile
2 forms an amidine intermediate A. (2) Then, the ruthenium-
catalyzed dehydrogenation of the alcohol unit of A gives an
o-carbonyl amidine B. (3) Finally, the thermodynamically
favorable intramolecular condensation of B would afford the
desired quinazoline product 3 (Scheme 2).
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
ligand
base
3a, yield %
1
2
cat. 1
cat. 2
cat. 3
cat. 4
cat. 5
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
38
trace
40
3
4
53
5
48
6
7
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
cat. 4
31
trace
34
Scheme 2. Possible Pathway for Accessing Quinazolines
8
9
10
11
12
13
14
15
16
17
20
15
10
K2CO3, Cs2CO3 or NaOMe
trace
50
CsOH
c
t-BuOK
t-BuOK
t-BuOK
78
d
e
78, 69
f
a
Unless otherwise stated, all reactions were carried out under nitrogen
With the above-described idea in mind, we initiated our
investigations by choosing the synthesis of 2-phenylquinazoline
3a from (2-aminophenyl)methanol 1a and benzonitrile 2a as a
model reaction to determine an efficient reaction system. First,
five ruthenium catalysts were tested by performing the reaction at
130 °C for 16 h using t-BuOK as the base, Xantphos (L1) as a
ligand in t-amyl alcohol (Figure 1; see cat. 1−cat. 5 and L1).
atmosphere by using 1a (0.5 mmol), 2a (0.7 mmol), catalyst (cat. 1,
cat. 2, and cat. 5: 3 mol %; cat. 3: 1.5 mol %; cat. 4: 1 mol %), ligand
(3 mol %), base (20 mol %), t-amyl alcohol (1.5 mL), temperature
b
(130 °C), reaction time (16 h). GC yield using hexadecane as an
c
d
e
internal standard. Base loading: 50 or 60 mol %. 140 °C. 120 °C.
f
Under air atmosphere.
even a trace of desired product (Table 1, entry 17). Hence, the
optimal reaction condition is indicated in entry 15 of Table 1.
With the optimal reaction conditions in hand, we examined the
generality and the limitations of the synthetic protocol. The
reactions of 1a in combination with a variety of benzonitriles,
including the heteroaryl 2j, were tested. As shown in Table 2, all
the reactions proceeded smoothly and furnished the desired
products in moderate to good yields upon isolation (Table 2,
entries 1−10). It was found that the substituents on the aryl ring
of the benzonitriles have a certain influence on the formation of
products. Specifically, the nitriles bearing an electron-with-
drawing group (i.e., F−, Cl−, Br−, and −CF3) (Scheme 2,
3b−3e) afforded the products in relatively higher yields than the
electron-rich ones (i.e., −Me, −OMe, −SMe, and −N(Me)2)
(Scheme 2, 3f−3i); this phenomenon can be rationalized as the
electron-deficient benzonitriles benefit from the nucleophilic
addition of the amino group of 1a to the cyano center, which is in
agreement with the possible mechanism proposed in Scheme 1.
To further explore the substrate scope, we next turned
our attention to examine the reactions of different substituted
2-aminoaryl alcohols with various benzonitriles. Gratifyingly, all
the substrates underwent efficient cyclization to afford the
desired products in moderate to good isolated yields (Table 2,
entries 11−25). Except for the substituent influence of
benzonitriles, it was found that the electron-donating group
containing 2-aminoaryl methanol 1b afforded the desired
product in higher yields (Table 2, entries 11−16) than the
relatively electron-poor 1c (Table 2, entries 19−25), which can
be ascribed to the electron-rich substituents that could enhance
the nucleophilicity of the amino group of 1b, thus favoring
the nucleophilic addition to the benzonitriles. Moreover, the
reaction of 1a with pentanenitrile 2k led to an inseparable
Figure 1. Catalysts and ligands tested for the optimization of reaction
conditions.
Ru3(CO)12 (cat. 4) exhibited the highest activity in the
formation of product 3a along with a small portion of 1a
decomposing to aniline (Table 1, entries 1−5). The absence of
catalyst failed to give any desired product (Table 1, entry 6).
Then, cat. 4 in combination with the other six diphosphine
ligands was tested, and the results show that these ligands were
less effective than Xantphos (Figure 1 L2−L7 and Table 1,
entries 7−12). Further, several other bases were proven to be
totally ineffective or inferior to t-BuOK (Table 1, entries 13 and
14). Hence, we chose cat. 4/L1/t-BuOK as the preferred
combination. An increase of base loading resulted in an improved
yield, and 50 mol % was sufficient to result in a desirable yield
(Table 1, entry 15). However, both increase and decrease of re-
action temperature could not afford an improved yield (Table 1,
entry 16). Finally, the reaction under air atmosphere failed to give
B
dx.doi.org/10.1021/ol503052s | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 2. Convenient Synthesis of 2-Arylquinazolines
a
Unless otherwise stated, all reactions were carried out under nitrogen atmosphere by using 1a (0.5 mmol), 2a (0.7 mmol), catalyst (1 mol %),
b
c
ligand (3 mol %), base (50 mol %), t-amyl alcohol (1.5 mL), temperature (130 °C), reaction time (16 h). Isolated yield. GC yield.
mixture, and the expected product 2-alkylquinazoline 3z was
detected in 18% GC yield (Table 2, entry 26). Noteworthy, all
the obtained products possess a nonsubstituted C−H unit at
position 4, which offers a potential for further elaboration of
complex molecules via direct C−H bond functionalization.15
Moreover, because the aryl groups are ortho to the nitrogen atom,
the products have the potential to be utilized as the C∧N ligands
for the preparation of organometallic complexes or materials.16
To gain insight into the possible information on the
quinazoline forming process, the reaction of 1a and 2a was
interrupted after 3 h to analyze the reaction intermediates (eq 1).
Except for the generation of product 3a and amidine 3a1 in 6 and
C
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Letter
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In summary, we have developed a novel method for the
convenient synthesis of 2-arylquinazolines. By employing a
commercially available Ru3(CO)12/Xantphos/t-BuOK catalyst
system, a series of 2-aminoaryl methanols were efficiently
converted in combination with a different type of benzonitriles
into various desired products in moderate to good yields upon
isolation. The synthetic protocol proceeds with the advantages
of operational simplicity, high atom efficiency, broad sub-
strate scope, and no need for the use of less environmentally
benign halogenated reagents, offering an important basis for
accessing 2-arylquinazolines. Considering the importance of
2-arylquinazolines in biological, medicinal, and synthetic organic
chemistry, the presented method has the potential to be frequently
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures including spectroscopic and
analytical data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(14) Representative examples on the application of acceptorless
dehydrogenation of alcohols: (a) Khusnutdinova, J. R.; Ben-David, Y.;
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■
*E-mail: minzhang@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the funds of the National Natural
Science Foundation of China (21472052 and 21101080),
Fundamental Research Funds for the Central Universities of
China (2014ZZ0047), and Distinguished talent program of
SCUT.
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