NNN pincer Ru(II)-catalyzed dehydrogenative coupling of 2-aminoarylmethanols with nitriles for the construction of quinazolines

Article abstract of DOI:10.1016/j.tet.2019.03.046

An efficient NNN pincer Ru(II)-catalyzed preparation of quinazolines via acceptorless dehydrogenative strategy has been developed. Under the optimized conditions, a broad range of substituted o-aminobenzyl alcohols and (hetero)aryl or alkyl nitriles were well tolerated to afford various 2-substituted quinazolines in high yields. Subsequently, a set of control experiments have been performed to elucidate the reaction mechanism, which underwent alcohol oxidation, nitrile hydration, and cyclocondensation steps. The current protocol is featured with several advantages, such as environmental benignity, operational simplicity, broad substrate scope (compatible with aliphatic nitriles, up to 87% yield), and short reaction time (mostly in 2 h).

Full text of DOI:10.1016/j.tet.2019.03.046

Accepted Manuscript
NNN pincer Ru(II)-catalyzed dehydrogenative coupling of 2-aminoarylmethanols with
nitriles for the construction of quinazolines
Xiao-Min Wan, Zi-Lin Liu, Wan-Qing Liu, Xiao-Niu Cao, Xinju Zhu, Xue-Mei Zhao,
Bing Song, Xin-Qi Hao, Guoji Liu
PII:
S0040-4020(19)30348-5
https://doi.org/10.1016/j.tet.2019.03.046
TET 30232
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 January 2019
Revised Date: 22 March 2019
Accepted Date: 25 March 2019
Please cite this article as: Wan X-M, Liu Z-L, Liu W-Q, Cao X-N, Zhu X, Zhao X-M, Song B, Hao X-Q,
Liu G, NNN pincer Ru(II)-catalyzed dehydrogenative coupling of 2-aminoarylmethanols with nitriles for
the construction of quinazolines, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.03.046.
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ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
NNN pincer Ru(II)-catalyzed dehydrogenative coupling of 2-aminoarylmethanols
with nitriles for the construction of quinazolines
Xiao-Min Wan‡, Zi-Lin Liu‡, Wan-Qing Liu, Xiao-Niu Cao, Xinju Zhu, Xue-Mei Zhao, Bing Song, Xin-
Qi Hao, and Guoji Liu
College of Chemistry and Molecular Engineering, School of Life Sciences, School of Chemical Engineering and Energy, Zhengzhou University, No. 100 of
Science Road, Zhengzhou, Henan 450001, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient NNN pincer Ru(II)-catalyzed preparation of quinazolines via acceptorless
dehydrogenative strategy has been developed. Under the optimized conditions, a broad range of
substituted o-aminobenzyl alcohols and (hetero)aryl or alkyl nitriles were well tolerated to
afford various 2-substituted quinazolines in high yields. Subsequently, a set of control
experiments have been performed to elucidate the reaction mechanism, which underwent alcohol
oxidation, nitrile hydration, and cyclocondensation steps. The current protocol is featured with
several advantages, such as environmental benignity, operational simplicity, broad substrate
scope (compatible with aliphatic nitriles, up to 87% yield), and short reaction time (mostly in 2
h).
Available online
Keywords:
Pincer Ru(II) complexes
Acceptorless dehydrogenation
Quinazolines
2009 Elsevier Ltd. All rights reserved.
Homogeneous reaction
1. Introduction
benign and atom economic. Hence, it is highly desirable to
develop green and sustainable methodologies for the synthesis of
As an important class of N-heterocycles, quinazoline
derivatives are prevalent in many nature products and synthetic
drugs with wide therapeutic and pharmacological applications
[1]. Due to the importance of quinazoline as medicinal agents, a
variety of synthetic strategies have been developed (Scheme 1)
[2]. Classic preparation of substituted quinazolines can be
achieved via condensation of o-aminobenzyl amines with
carbonyl equivalents, such as alcohols [3a], aldehydes [3b,c],
ketones [3d], amines [3e], nitriles [3f], and others [3g,h]. Also,
reaction of o-carbonyl anilines [4] or halides [5] with benzyl
amines [4a,b,5a], oximes [4c], amidines [5b,c], and ammonia
equivalents [4d-g,5d] in the presence of C1 building blocks is an
alternative to access quinazolines. Additionally, the same
skeletons can be prepared using o-halobenzyl [6] or o-
aminobenzyl [7] halides with amidines [6,7a-b] and amides [7c].
Moreover, intramolecular oxidative annulation of amidines via
C-C bond formation [8] or oxidative coupling of amidines with
various carbon sources [9] could be utilized to synthesize
quinazolines. Recently, transition-metal-catalyzed C-H activation
of benzimidates with dioxazolones [10a-d] or azides [10e] was
also reported. Despite the above advancements, many existing
strategies require equivalent oxidants, prefunctionalized
quinazolines.
Scheme 1. Strategies for the construction of quinazoline
skeletons
substrates, and external additives, which is not environmental
———
‡ X.-M.W. and Z.-L.L. contributed equally.
 Corresponding author. E-mail address: bingsong@zzu.edu.edu (B. Song); xqhao@zzu.edu.cn (X.-Q. Hao).

2
Tetrahedron
In recent years, transition-metal-catalyzed transfer
ACCEPTED MANUSCRIPT
Entry
Ru Cat.
Solvent
Base
KOtBu
KOtBu
KOtBu
KOtBu
KOH
Yield [%]
39
hydrogenations and acceptorless dehydrogenations have emerged
as a facile and efficient strategy to construct heterocyclic
scaffolds [11]. Specially, the utilization of abundant and
sustainable alcohols to accomplish N-heterocycles such as
pyridines, quinolines, pyrroles, imides, benzimidazoles,
pyrimidines, quinoxalines, quinazolinones, have been well
developed by Milstein [12], Kemp [13], Beller [14], Zhang [15],
Li [16], and others [17]. However, the employment of same
strategy to access quinazolines has only sporadic reports
catalyzed by Ru, Pd, Au and Ni salts [18]. Meanwhile, long
reaction time (16 – 24 h) was usually required to achieve
satisfactory yields in previous literatures. Moreover, the
1
a
b
c
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
toluene
2
69
3
56
4
d
b
b
b
b
b
b
b
b
b
b
-
58
5
48
6
KHMDS
K2CO3
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
-
56
7
NR
61
employment
of
aliphatic
nitriles
and
substituted
8
aminophenylmethanols were less explored.
9
6
Pincer-type complexes are a class of well-defined structures
with superior performance in catalytic (de)hydrogenation and
transfer (de)hydrogenation via fine modifications of steric and
electronic effects [19]. Recently, we have prepared a series of
NNN pincer Ru(II) complexes, which exhibited high efficiency
in transfer hydrogenation of ketones, N-monoalkylation of
amines, and α-alkylation of methylene ketones [20]. As a
continue of our previous work, we herein firstly reported
synthesis of quinazolines catalyzed by NNN pincer Ru
complexes a-d (Figure 1). Compared with previous reports, the
current methodology exhibits superior activity, such as low
catalytic loading (1-2 mol%), broad substrate scopes, no external
ligands, and short reaction time (mostly in 2 h).
10
13
14b
15b
16b
17b
dioxane
30
tbutyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
tamyl alcohol
57
82
37c, 47d
57e, 82f
38
18b
a
b
NR
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), Ru Cat.
(1 mol%), base (0.5 equiv), tamyl alcohol (1 mL), 2 h, 130 C,
o
under air. Isolated yields. b 1a (0.425 mmol). c Under Ar. d Under
O2. e 1 h. f 4 h.
With the optimized conditions in hand (Table 1, entry 14), the
substrate scope of nitriles was investigated (Scheme 2). Initially,
a series of para-, meta-, and ortho-substituted aromatic nitriles
were employed, which gave the desired quinazolines 3a- o in 56-
87% yields. It was found that both electron-donating (OMe, Me)
and electron-withdrawing (F, Cl, Br, I, and CF3) groups are well-
tolerated under the current catalytic system. However, strong
electron deficient (NO2) and electron rich (OH, NMe2) benzo-
nitriles either gave low yield (14%) or remain unreactive (not
shown). Meanwhile, for ortho-substituted nitriles, longer reaction
time or/and higher Ru and base loading were adopted in order to
obtain satisfactory results (3n and 3o). Subsequently, both β- and
α-naphthyl nitriles were tested, which provided quinazolines 3p-
q in 67% and 73% yields, respectively, with extended time
required for bulky α-substituted nitrile. Next, heteroaryl nitriles,
including 4-pyridyl nitrile, 2-furonitrile, and 2-thenonitrile, were
examined. Compared with aromatic nitriles, products 3r-t were
isolated in slightly decreased yields (57-78%). Moreover,
synthetically more challenging alkyl-substituted quinazolines
could also be accessed in 47-86% yields using less reactive
aliphatic nitriles including cyclopropanecarbonitrile 2u,
isobutyronitrile 2v, pentanenitrile 2w, 3-methylbutanenitrile 2x,
pivalonitrile 2y, and cyclohexanecarbonitrile 2z. However,
acrylonitrile and acetonitrile were proved to be unreactive
substrates.
Figure 1. Pincer Ru(II) complexes a-d
2. Results and discussion
The Ru(II) complexes a-d were prepared according to
previous reports.[20] Initially, 2-aminophenylmethanol 1a and
benzonitrile 2a were utilized as the model substrates to optimize
the reaction conditions (Table 1). To our delight, the target 2-
phenyl quinazoline 3a was obtained in 69% yield in the presence
of Ru Cat. b (1 mol%) and KOtBu (0.5 equiv) in tamyl alcohol (1
o
mL) at 130 C for 2 h under air (Table 1, entry 2). Subsequently,
the effects of various bases were investigated, indicating KOtBu
was the optimal choice (Table 1, entries 5-8). Replacement tamyl
alcohol with other solvents all led to decreased yields (Table 1,
entries 9-13). Meanwhile, it was found that increased temp-
perature and base loading had little influence on reaction
efficiency, and lowered temperature and base loading both led to
inferior results (See the SI). Next, the ratio of 1a and 2a was
systematically modified and 3a could be isolated in 82% yield
(Table 1, entry 14). When the reaction was carried out under
argon or oxygen, decreased efficiency was observed (Table 1,
entry 15). Similarly, shortening the reaction time to 2 h led to
reduced yield, and extending the reaction time to 4 h had little
effect on reaction yield (Table 1, entry 16). Finally, a substantial
drop in yield was observed in the absence of either Ru Cat. b or
KOtBu, suggesting the necessity for both Ru catalyst and base.
Encouraged by the above results, the substrate scope of
substituted 2-aminoaryl alcohols with nitriles was also explored
(Scheme 3). Initially, methyl- and chloro-containing 2-aminoaryl
alcohols were examined with benzonitrile, which delivered the
product 4a-e in 65-84% yields. Subsequently, substituted 2-
aminoaryl alcohols reacted with a series of aromatic nitriles to
afford the corresponding disubstituted quinazolines 4f-w in 38-
83% yields. It is noted that most reactions proceeded smoothly
Table 1. Optimization of reaction conditionsa

under the optimized conditions irrespective of electronic effect.
ACCEPTED MANUSCRIPT
Meanwhile, the aromatic halides were well tolerated, which give
opportunity for further functionalization. Next, satisfactory yields
(41-76%) were able to be obtained for naphthyl and heteroaryl
nitriles. In an attempt to obtain 4z, the product was isolated in
45% yield, with 34% of starting material left. We also tried to
extend the reaction time to 10 h, however, no improved yield was
obtained, which is probably attributed to the low reactivity of
isonicotinonitrile [3f,18e]. Finally, the current methodology
exhibited great applicability for aliphatic nitriles to afford the
desired products 4ad-ai in 37-87% yields. Specially, 3-methyl
substituted aminoaryl alcohol could be efficiently converted to
quinazolines 4ae and 4af in high yields in 2 h.
a
Scheme 2. Substrate scope of nitriles. Reaction conditions: 1a
(0.425 mmol), 2 (0.25 mmol), Ru Cat. b (1 mol%), KOtBu (0.5
t
o
equiv), amyl alcohol (1 mL), 2 h, 130 C, under air. Isolated
yields. b 10 h. c Ru Cat b. (2 mol %), KOtBu (1 equiv), 10 h. d 4 h.
e KOtBu (1 equiv), 4h.
Scheme 3. Substrate scope of aminoaryl alcohols and nitriles.a
Reaction conditions: 1 (0.425 mmol), 2 (0.25 mmol), Ru Cat. b
t
o
(1 mol%), KOtBu (0.5 equiv), amyl alcohol (1 mL), 2 h, 130 C,
To explore the reaction mechanism, a set of control
experiments were conducted (Scheme 4). In an attempt to isolate
reaction intermediates, the reaction of 1a and 2a was interrupted
after 30 min, which gave product 3a in 28% yield accompanied
with carbonyl intermediate 5 in 6% yield, indicating alcohol
oxidation is involved in the dehydrogenation synthesis of
quinazoline (Scheme 4, eq 1). When 1a was subject to the
standard conditions, 2-aminobenzaldehyde 5 was isolated in 20%
yield. Meanwhile, without Ru b, carbonyl intermediate 5 was
obtained in 9% yields (Scheme 4, eq 2), suggesting both Ru Cat.
c
d
e
under air. Isolated yields. b 10 h. 4 h. KOtBu (1 equiv), 10 h.
34% of starting material 1 was retrieved.
b and KOtBu are indispensable for alcohol oxidation. According
to previous literatures,[3f,19e,21] KOtBu and other bases have
been reported to induce nitrile hydration. In our case, benzonitrile
2a was converted to benzamide 6 in 72% yield under the
standard conditions. Also, benzamide 6 could still be isolated in
70% yield without Ru cat. b, while no benzamide 6 was detected

4
Tetrahedron
ACCEPTED MANUSCRIPT
without KOtBu, suggesting KOtBu itself plays an important role
in nitrile hydration process (Scheme 4, eq 3). With above results,
the coupling reactions between 1a and 6, 5 and 2a, as well as 5
and 6 were performed under the standard conditions, which
provided product 3a in 68%, 93%, and 97% yields, respectively
(Scheme 4, eqs 4-6), which implies that 2-aminobenzaldehyde 5
and benzamide 6 are the key intermediates during the mechanism.
Moreover, without Ru Cat. b, only 35% yield was obtained for
3a in eq 4, and the yield of 3a remained almost unchanged in eqs
5 and 6, which again demonstrates importance of KOtBu in
nitrile hydration and subsequent cyclocondensation steps. Finally,
the Hg poisoning experiment was carried out under the optimized
conditions (Scheme 4, eq 7). The desired product 3a could still
be obtained in 76% yield, indicating the formation of Ru(0)
nanoparticles might not be involved.
Scheme 5. Proposed plausible mechanism
3. Conclusion
In conclusion, we have successfully developed an efficient
methodology to access quinazolines via acceptorless de-
hydrogenation process catalyzed by well-defined NNN pincer
Ru(II) complexes. The protocol exhibited wide functional groups
compatibility irrespectively of electronic effects. In special,
various heteroaromatic and aliphatic nitriles were well tolerated
to deliver the corresponding 2-substituted quinazolines in
moderate to high yields. Finally, control experiments were
conducted, which demonstrates that both Ru complex and KOtBu
are necessary for alcohol oxidation, and KOtBu dominates nitrile
hydration and subsequent cyclocondensation steps.
4. Experimental section
4.1. General Information
Unless otherwise indicated, all the starting materials and reagents
were commercially available and used without further
purification. All reactions were carried out in oven-dried 15 mL
sealed tubes under an air atmosphere. Melting points were
determined on an XT4A melting point apparatus and are
uncorrected. Flash column chromatography was performed using
200−300 mesh silica gel. Analytical and preparative thin-layer
chromatography (TLC) plates coated with commercial silica gel
GF254 were used to monitor the reactions and purify products.
1H, 13C and 19F NMR spectra were recorded on Bruker DPX 400
or Bruker DPX 600 instruments using TMS as an internal
standard. HRMS were determined on a Q-Tof Micro MS/MS
System ESI spectrometer.
Scheme 4. Control experiments
On the basis of above results and our previous reports, a
plausible mechanism was proposed (Scheme 5). Initially, 1a
reacted with Ru complex b in the presence of KOtBu gave Ru-
alkoxide intermediate I, which underwent β-elimination to afford
Ru-H intermediate II[22] and carbonyl intermediate 5. Reaction
between Ru-H II and 1a would regenerate intermediate I
accompanied with release of hydrogen gas. On the other hand,
KOtBu promoted hydration of benzonitrile 2a produced amide
intermediate 6, followed by subsequent cyclocondensation with
intermediate 5 to provide the desired product quinazoline 3a.
4.2 General Procedure for Preparation of Quinazolines 3 or 4
To an oven-dried 15 mL sealed tube were added 2-
aminophenylmethanol 1 (0.425 mmol), benzonitrile 2 (0.25
mmol), Ru cat. b (1.94 mg, 1 mol%), and KOtBu (14.02 mg, 0.5
t
equiv) in amyl alcohol (1 mL) under an air atmosphere. The
sealed tube was capped and heated at 130 oC for 2 h. The reaction
mixture was cooled down to room temperature and directly

MHz, CDCl3) δ 160.7, 158.9, 150.7, 149.3, 143.9, 134.6, 129.4,
concentrated under vacuum. The crude mixture was purified by
preparative thin-layer-chromatography (petroleum ether/ethyl
acetate = 20/1) to give the desired product 3 or 4.
ACCEPTED MANUSCRIPT
128.9, 128.3, 127.2, 123.9, 123.8.
4.4.9 2-(3-Methoxyphenyl)quinazoline (3i) [3f]: Yellow solid
(51.3 mg, 87% yield); m.p. 71−72 °C. 1H NMR (400 MHz,
CDCl3) δ 9.43 (d, J = 0.4 Hz, 1H), 8.25–8.15(m, 2H), 8.10–8.03
(m, 1H), 7.93–7.84 (m, 2H), 7.61–7.54 (m, 1H), 7.44 (t, J = 8.0
Hz, 1H), 7.07–7.05 (m, 1H), 3.94 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 160.8, 160.4, 160.1, 150.7, 139.5, 134.1, 129.6, 128.7,
127.3, 127.1, 123.7, 121.2, 117.2, 113.1, 55.5.
4.3 Hg(0) Poisoning Test
The experiment was performed using 2-aminophenylmethanol 1a
(0.425 mmol), benzonitrile 2a (0.25 mmol), KOtBu (14.02 mg,
0.5 equiv), Ru cat. b (1.94 mg, 1 mol%), and an excess (500
equiv to the Ru cat. b) of Hg(0) in amyl alcohol (1 mL). Hg(0)
was added into the reaction mixture at the beginning.
t
4.4.10 2-(m-Tolyl)quinazoline (3j) [3f]: Yellow solid (47.2 mg,
4.4 Characterization of Quinazolines 3 and 4
1
86% yield); m.p. 94−95 °C. H NMR (400 MHz, CDCl3) δ 9.44
4.4.1 2-Phenylquinazoline (3a) [18a]: Yellow solid (42.2 mg,
82% yield); m.p. 99−100 °C. 1H NMR (400 MHz, CDCl3) δ 9.44
(s, 1H), 8.64–8.60 (m, 2H), 8.09–8.04 (m, 1H), 7.91–7.84 (m,
2H), 7.61–7.47 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 161.1,
160.5, 150.8, 138.1, 134.1, 130.6, 128.7, 128.6, 127.3, 127.1,
123.6.
(s, 1H), 8.45–8.38 (m, 2H), 8.15–8.02 (m, 1H), 7.97–7.82 (m,
2H), 7.67–7.52 (m, 1H), 7.43 (t, J = 7.6, 1H), 7.32 (d, J = 7.4,
1H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.2, 160.5,
150.8, 138.3, 138.0, 134.1, 131.5, 129.2, 128.6, 128.6, 127.2,
127.1, 125.8, 123.6, 21.6.
4.4.11 2-(3-Fluorophenyl)quinazoline (3k) [18a]: Light yellow
1
4.4.2 2-(4-Methoxyphenyl)quinazoline (3b) [18a]: Yellow solid
(46.2 mg, 78% yield); m.p. 84−86 °C. 1H NMR (600 MHz,
CDCl3) δ 9.39 (s, 1H), 8.57 (d, J = 7.7 Hz, 2H), 8.02 (d, J = 7.6
Hz, 1H), 7.85 (d, J = 6.9 Hz, 2H), 7.53 (s, 1H), 7.04 (d, J = 7.5
Hz, 2H), 3.88 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 161.9,
160.9, 160.4, 150.9, 134.0, 130.8, 130.2, 128.4, 127.1, 126.8,
123.3, 114.0, 55.4.
solid (40.0 mg, 63% yield); m.p. 92−93 °C. H NMR (400 MHz,
CDCl3) δ 9.45 (s, 1H), 8.46–8.39 (m, 1H), 8.36–8.31 (m, 1H),
8.11–8.06 (m, 1H), 7.95–7.89 (m, 2H), 7.63–7.60 (m, 1H), 7.53–
7.45 (m, 1H), 7.22–7.17 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
163.3 (JC-F = 246.0 Hz), 160.5, 159.9 (JC-F = 3.1 Hz), 150.7,
140.5 (JC-F = 7.8 Hz), 134.3, 130.1 (JC-F = 8.0 Hz), 128.7 127.6,
127.1, 124.2 (JC-F = 2.8 Hz), 123.8, 117.5 (JC-F = 21.6 Hz), 115.4
(JC-F = 23.5 Hz). 19F NMR (376 MHz, CDCl3) δ -113.18.
4.4.3 2-(p-Tolyl)quinazoline (3c) [18a]: Yellow solid (46.2 mg,
1
82% yield); m.p. 100−101 °C. H NMR (400 MHz, CDCl3) δ
4.4.12 2-(3-Chlorophenyl)quinazoline (3l)[3f]: White solid (50.5
mg, 84% yield); m.p. 145−147 °C. 1H NMR (400 MHz, CDCl3) δ
9.46 (d, J = 0.6 Hz, 1H), 8.66−8.61 (m, 1H), 8.58–8.45 (m, 1H),
8.12–8.06 (m, 1H), 8.01–7.85 (m, 2H), 7.72–7.59 (m, 1H), 7.51–
7.41 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 160.6, 159.7, 150.7,
139.9, 134.8, 134.3, 130.6, 129.9, 128.7, 128.7, 127.7, 127.2,
126.7, 123.8.
9.42 (s, 1H), 8.55 (d, J = 8.2, 2H), 8.14–7.99 (m, 1H), 7.9–7.8 (m,
2H), 7.56 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.44 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 161.2, 160.4, 150.8, 140.9,
135.4, 134.0, 129.4, 128.6, 127.1, 127.0, 123.5, 21.5.
4.4.4 2-(4-Chlorophenyl)quinazoline (3d) [18a]: White solid
1
(49.5 mg, 82% yield); m.p. 129−131 °C. H NMR (600 MHz,
CDCl3) δ 9.44 (s, 1H), 8.57 (d, J = 7.3 Hz, 2H), 8.06 (d, J = 7.7
Hz, 1H), 7.92 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 6.0 Hz, 1H), 7.49
(d, J = 7.3 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 160.5, 160.0,
150.7, 136.9, 136.6, 134.3, 129.9, 128.8, 128.6, 127.5, 127.2,
123.6.
4.4.13 2-(3-Bromophenyl)quinazoline (3m) [3f]: Light yellow
1
solid (53.6 mg, 76% yield); m.p. 144−146 °C. H NMR (400
MHz, CDCl3) δ 9.45 (d, J = 0.6 Hz, 1H), 8.79 (t, J = 1.8 Hz, 1H),
8.55 (dt, J = 7.8, 1.2 Hz, 1H), 8.10–8.05 (m, 1H), 7.96–7.87 (m,
2H), 7.70–7.56 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 160.6, 159.6, 150.7, 140.1, 134.3, 133.5, 131.6,
130.1, 128.7, 127.7, 127.2, 127.1, 123.8, 122.9.
4.4.5 2-(4-Bromophenyl)quinazoline (3e) [18a]: Yellow solid
1
(59.2 mg, 83% yield); m.p. 138−140 °C. H NMR (400 MHz,
CDCl3) δ 9.41 (d, J = 0.6 Hz, 1H), 8.64–8.38 (m, 2H), 8.05 (d, J
= 8.9 Hz, 1H), 7.99–7.82 (m, 2H), 7.74–7.52 (m, 3H). 13C NMR
(101 MHz, CDCl3) δ 160.5, 160.1, 150.7, 137.0, 134.3, 131.8,
130.2, 128.6, 127.5, 127.2, 125.4, 123.7.
4.4.14 2-(2-Chlorophenyl)quinazoline (3n) [3f]: Yellow liquid
(33.5 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J =
0.5 Hz, 1H), 8.13 (dd, J = 8.5, 0.6 Hz, 1H), 8.03–7.92 (m, 2H),
7.86–7.81 (m, 1H), 7.73–7.66 (m, 1H), 7.57–7.51 (m, 1H), 7.44–
7.38 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 162.0, 160.3, 150.4,
138.3, 134.4, 132.9, 131.8, 130.6, 130.3, 128.7, 128.1, 127.2,
126.9, 123.3.
4.4.6 2-(4-Iodophenyl)quinazoline (3f) [3f]: Yellow solid (57.8
1
mg, 74% yield); m.p. 126−127°C. H NMR (400 MHz, CDCl3) δ
9.43 (d, J = 0.4 Hz, 1H), 8.38–8.31 (m, 2H), 8.08–8.03 (m, 1H),
7.95–7.79 (m, 4H), 7.65–7.59 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 160.5, 160.3, 150.7, 137.8, 137.6, 134.3, 130.3, 128.6,
127.5, 127.2, 123.7, 97.8.
4.4.15 2-(o-Tolyl)quinazoline (3o) [3f]: Yellow liquid (35.2 mg,
1
64% yield). H NMR (600 MHz, CDCl3) δ 9.49 (s, 1H), 8.09 (d,
J = 8.4 Hz, 1H), 7.98–7.88 (m, 3H), 7.64 (t, J = 7.4 Hz, 1H),
7.41–7.30 (m, 3H), 2.61 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
164.1, 160.1, 150.4, 138.6, 137.4, 134.1, 131.3, 130.7, 129.3,
128.6, 127.5, 127.1, 126.0, 122.9, 21.1.
4.4.7 2-(4-(Trifluoromethyl)phenyl)quinazoline (3g) [18a]:
1
Yellow solid (54.6 mg, 80% yield); m.p. 183−185 °C. H NMR
(400 MHz, CDCl3) δ 9.47 (d, J = 0.4 Hz, 1H), 8.73 (d, J = 8.1 Hz,
2H), 8.12–8.07 (m, 1H), 8.01–7.88 (m, 2H), 7.77 (d, J = 8.2 Hz,
2H), 7.71–7.60 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 160.6,
159.6, 150.7, 141.3, 134.4, 132.1 (JC-F = 68.6 Hz), 128.77, 128.83,
127.9, 127.2, 125.5 (JC-F = 3.8 Hz), 124.2 (JC-F = 273.3 Hz), 123.9.
19F NMR (376 MHz, CDCl3) δ -62.66.
4.4.16 2-(Naphthalen-2-yl)quinazoline (3p) [3f]: Yellow solid
1
(40.0 mg, 67% yield); m.p. 132−134 °C. H NMR (400 MHz,
CDCl3) δ 9.46 (d, J = 0.4 Hz, 1H), 9.14 (d, J = 0.4 Hz, 1H), 8.72
(dd, J = 8.6, 1,7 Hz, 1H), 8.10 (d, J = 8.8, 1H), 8.06–8.00 (m,
1H), 7.97 (d, J = 8.8 Hz, 1H), 7.92–7.85 (m, 3H), 7.60–7.48 (m,
3H), 13C NMR (101 MHz, CDCl3) δ 161.0, 160.5, 150.8, 135.4,
134.7, 134.2, 133.5, 129.3, 129.0, 128.7, 128.3, 127.8, 127.3,
127.2, 127.1, 126.3, 125.5, 123.6.
4.4.8 2-(4-nitrophenyl)quinazoline (3h) [3b]: Yellow solid (9.2
mg, 14% yield); m.p. 174−176 °C. 1H NMR (400 MHz, CDCl3) δ
9.52 (s, 1H), 8.87–8.77 (m, 2H), 8.43–8.34 (m, 2H), 8.18–8.11
(m, 1H), 8.02–7.94 (m, 2H), 7.76–7.66 (m, 1H). 13C NMR (151
4.4.17 2-(Naphthalen-1-yl)quinazoline (3q) [3f]: Yellow solid
1
(46.7 mg, 73% yield); m.p. 118−121 °C. H NMR (400 MHz,

6
Tetrahedron
CDCl3) δ 9.59 (d, J = 0.4 Hz, 1H), 8.72–8.66 (m, 1H), 8.26–
4.4.27 6-Chloro-2-phenylquinazoline (4a) [18a]: Yellow solid
ACCEPTED MANUSCRIPT
1
8.12 (m, 2H), 8.07–7.89 (m, 4H), 7.74–7.60 (m, 2H), 7.59–7.50
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 163.5, 160.4, 150.6,
136.3, 134.3, 134.2, 131.3, 130.4, 129.7, 128.7, 128.5, 127.8,
127.2, 126.9, 126.0, 125.9, 125.3, 123.2.
(47.0 mg, 78% yield); m.p. 131−134 °C. H NMR (400 MHz,
CDCl3) δ 9.37 (d, J = 0.5 Hz, 1H), 8.64–8.55 (m, 2H), 8.0 (d, J =
8.0 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.83–7.77 (m, 1H), 7.60–
7.48 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 159.5, 149.3,
137.6, 135.1, 132.8, 130.9, 130.4, 128.7, 128.6, 125.8, 124.0.
4.4.18 2-(Pyridin-4-yl)quinazoline (3r) [3c]: White solid (40.5
mg, 78% yield); m.p. 123−124 °C. eluent, petroleum ether/ethyl
acetate=3/1; 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.80 (d,
J = 6.0, 2H), 8.46 (dd, J = 4.5, 1.6 Hz, 2H), 8.18–8.05 (m, 1H),
8.02–7.88 (m, 2H), 7.78–7.59 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 160.7, 158.9, 150.6, 150.5, 145.3, 134.5, 128.9, 128.3,
127.2, 124.2, 122.4.
4.4.28 6-Methyl-2-phenylquinazoline (4b) [18a]: White solid
1
(44.4 mg, 81% yield); m.p. 128−129 °C. H NMR (400 MHz,
CDCl3) δ 9.35 (s, 1H), 8.65–8.53 (m, 2H), 7.96 (d, J = 8.6 Hz,
1H), 7.70 (dd, J = 8.6, 1.9 Hz, 1H), 7.64 (s, 1H), 7.57–7.45 (m,
3H), 2.53 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.4, 159.7,
149.4, 138.2, 137.4, 136.4, 130.4, 128.6, 128.5, 128.3, 125.8,
123.6, 21.6.
4.4.19 2-(Furan-2-yl)quinazoline (3s) [4e]: Yellow solid (34.6
mg, 71% yield); m.p. 127 °C. 1H NMR (600 MHz, CDCl3) δ 9.37
(s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.89 (t, J = 8.0 Hz, 2H), 7.69 (s,
1H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 6.67–6.57
(m, 1H). 13C NMR (101 MHz, CDCl3) δ 160.7, 154.1, 152.5,
150.4, 145.3, 134.5, 128.4, 127.3, 123.4, 114.1, 112.3.
4.4.29 8-Methyl-2-phenylquinazoline (4c) [9c]: Yellow liquid
(46.1 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H),
8.69–8.60 (m, 2H), 7.73–7.64 (m, 2H), 7.57–7.39 (m, 4H), 2.83
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.6, 159.9, 149.7,
138.4, 137.1, 133.8, 130.5, 128.6, 128.6, 126.9, 124.8, 123.5,
16.9.
4.4.20 2-(Thiophen-2-yl)quinazoline (3t) [3f]: Yellow solid (40.2
mg, 76% yield); m.p. 130−132 °C. 1H NMR (400 MHz, CDCl3) δ
9.34 (d, J = 0.4 Hz, 1H), 8.15 (dd, J = 3.7, 1.2 Hz, 1H), 8.0 (d, J
= 8.9 Hz, 1H), 7.91–7.81 (m, 2H), 7.58–7.48 (m, 2H), 7.20–7.15
(m, 1H). 13C NMR (101 MHz, CDCl3) δ 160.5, 157.9, 150.6,
143.9, 134.4, 130.0, 129.3, 128.4, 128.2, 127.3, 127.0, 123.4.
4.4.30 7-Chloro-2-phenylquinazoline (4d) [3h]: Yellow solid
(39.1 mg, 65% yield); m.p. 135−136 °C. H NMR (400 MHz,
CDCl3) δ 9.41 (s, 1H), 8.65–8.53 (m, 2H), 8.08 (d, J = 1.7.Hz,
1H), 7.84 (d, J = 8.6 Hz, 1H), 7.59–7.45 (m, 4H). 13C NMR (101
MHz, CDCl3) δ 161.9, 160.2, 151.3, 140.3, 137.6, 131.0, 128.7,
128.7, 128.4, 128.4, 127.8, 121.9.
1
4.4.21 2-Cyclopropylquinazoline (3u) [3f]: Yellow liquid (24.4
mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 7.90
(d, J = 8.9 Hz, 1H), 7.86–7.78 (m, 2H), 7.56–7.47 (m, 1H), 2.44–
2.36 (m, 1H), 1.31–1.24 (m, 2H), 1.17–1.10 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.4, 160.3, 150.4, 133.9, 127.5, 127.1,
126.3, 123.2, 18.6, 10.6.
4.4.31 5-Chloro-2-phenylquinazoline (4e) [26]: Yellow solid
(40.0 mg, 67% yield); m.p. 99−101 °C. H NMR (400 MHz,
CDCl3) δ 9.82 (s, 1H), 8.67–8.57 (m, 2H), 7.98 (d, J = 8.5 Hz,
1H), 7.77 (t, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.5, 0.7 Hz, 1H),
7.58–7.45 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 161.6, 157.8,
151.8, 137.5, 133.9, 131.9, 131.0, 128.8, 128.7, 127.8, 127.2,
121.4.
1
4.4.22 2-Isopropylquinazoline (3v) [23]: Yellow liquid (28.0 mg,
1
65% yield). H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.05–
7.97 (m, 1H), 7.91–7.83 (m, 2H), 7.61–7.55 (m, 1H), 3.39 (hept,
J = 6.9 Hz, 1H), 1.46 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 171.8, 160.5, 150.4, 133.9, 128.0, 127.0, 126.9, 123.3,
38.0, 21.8.
4.4.32 6-Chloro-2-(4-methoxyphenyl)quinazoline (4f) [3d]:
Yellow solid (48.7 mg, 72% yield); m.p. 165 °C. H NMR (400
MHz, CDCl3) δ 9.32 (d, J = 0.5 Hz, 1H), 8.57–8.51 (m, 2H), 7.96
(d, J = 9.0 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 9.0,
2.3 Hz, 1H), 7.06–7.00 (m, 2H), 3.89 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 162.1, 161.1, 159.4, 149.3, 134.9, 132.2, 130.3,
130.2, 125.8, 123.7, 114.0, 55.4.
1
4.4.23 2-Butylquinazoline (3w) [8a]: Yellow liquid (26.1 mg,
1
56% yield). H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.02–
7.95 (m, 1H), 7.92–7.85 (m, 2H), 7.59 (td, J = 7.6, 0.9 Hz, 1H),
3.13 (t, J =7.8 Hz, 2H), 1.97–1.85 (m, 2H), 1.54–1.41 (m, 2H),
1.02–0.94 (t, J =7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
167.9, 160.4, 150.4, 134.0, 127.9, 127.1, 126.9, 123.1, 39.8, 31.2,
22.7, 14.0.
4.4.33 6-Chloro-2-(p-tolyl)quinazoline (4g) [18a]: Yellow solid
1
(46.8 mg, 74% yield); m.p. 164−166 °C. H NMR (400 MHz,
CDCl3) δ 9.34 (d, J = 0.4 Hz, 1H), 8.47 (d, J = 8.2 Hz, 2H), 7.98
(d, J = 9.0 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 9.0,
2.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 161.4, 159.4, 149.3, 141.2, 135.0, 134.9,
132.5, 130.3, 129.5, 128.6, 125.8, 123.9, 21.5.
4.4.24 2-isobutylquinazoline (3x) [24]: Yellow liquid (22.0 mg,
1
47% yield). H NMR (300 MHz, CDCl3) δ 9.33 (d, J = 3.5 Hz,
1H), 7.97 (d, J = 8.56 Hz, 1H), 7.91-7.78 (m, 2H), 7.62–7.52 (m,
1H), 2.98 (dd, J = 7.3, 2.9 Hz, 2H), 2.47–2.29 (m, 1H), 1.05–0.91
(m, 6H). 13C NMR (75 MHz, CDCl3) δ 167.1, 160.2, 150.2, 134.0,
127.9, 127.0, 126.9, 123.0, 48.8, 28.8, 22.5.
4.4.34 6-Chloro-2-(4-chlorophenyl)quinazoline (4h) [3f]: Yellow
solid (43.0 mg, 63% yield); m.p. 191−193 °C. H NMR (400
MHz, CDCl3) δ 9.37 (d, J = 0.4 Hz, 1H), 8.59–8.47 (m, 2H), 8.01
(d, J = 9.0 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 9.0,
2.3 Hz, 1H), 7.54–7.43 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
160.3, 159.6, 149.2, 137.2, 136.1, 135.3, 133.0, 130.4, 129.9,
128.9, 125.9, 124.0.
1
4.4.25 2-(tert-butyl)quinazoline (3y) [3c]: Yellow liquid (26.2 mg,
1
56% yield). H NMR (300 MHz, CDCl3) δ 9.37 (s, 1H), 8.00 (d,
J = 8.8 Hz, 1H), 7.91–7.81 (m, 2H), 7.61–7.50 (m, 1H), 1.52 (s,
9H). 13C NMR (75 MHz, CDCl3) δ 173.5, 159.9, 150.1, 133.6,
128.4, 126.9, 126.8, 122.8, 39.6, 29.7.
4.4.35 2-(4-Methoxyphenyl)-6-methylquinazoline (4i) [3b]: White
1
solid (37.2 mg, 60% yield); m.p. 114−116 °C. H NMR (600
MHz, CDCl3) δ 9.31 (s, 1H), 8.55 (d, J = 8.4 Hz, 2H), 7.92 (d, J
= 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.03 (d, J =
8.4 Hz, 2H), 3.88 (s, 3H), 2.53 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 161.7, 160.2, 159.7, 149.4, 136.9, 136.3, 130.9, 130.0,
128.1, 125.8, 123.3, 114.0, 55.4, 21.6.
4.4.26 2-cyclohexylquinazoline (3z) [25]: Yellow liquid (34.1mg,
64% yield). 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 7.93(d, J
= 8.9, 1H), 7.85–7.75 (m, 2H), 7.55-7.47 (m, 1H), 3.01 (tt, J =
11.6, 3.4 Hz, 1H), 2.04 (d, J = 13.3 Hz, 2H), 1.91–1.64 (m, 5H),
1.52–1.26 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 170.0, 160. 3,
150.3, 133.8, 128.0, 127.0, 126.8, 123.2, 47.9, 31.9,26.3, 26.0.
4.4.36 6-Methyl-2-(p-tolyl)quinazoline (4j) [18a]: Yellow solid
1
(43.5 mg, 74% yield); m.p. 154−156 °C. H NMR (400 MHz,

CDCl3) δ 9.34 (s, 1H), 8.48 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.6
MHz, CDCl3) δ 9.38 (d, J = 0.6 Hz, 1H), 8.39 (dd, J = 9.0, 2.3 Hz,
1H), 8.30–8.26 (m, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 2.2
Hz, 1H), 7.86–7.80 (m, 1H), 7.53–7.44 (m, 1H), 7.23–7.19 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 163.3 (JC-F = 244.96 Hz),
162.1, 160.1 (JC-F = 3.1 Hz), 159.5, 149.1, 140.0 (JC-F = 7.8 Hz),
ACCEPTED MANUSCRIPT
Hz, 1H), 7.70 (dd, J = 8.6, 1.9 Hz, 1H), 7.64 (d, J = 0.7 Hz, 1H),
7.33 (d, J = 8.0 Hz, 2H), 2.54 (s, 3H), 2.43 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 160.5, 159.7, 149.4, 140.6, 137.2, 136.3,
135.5, 129.4, 128.4, 128.2, 125.8, 123.5, 21.6, 21.5.
135.3, 133.2, 130.4, 130.1 (JC-F = 8.0 Hz), 125.8, 124.2 (JC-F
=
2.8 Hz), 117.7 (JC-F = 21.7 Hz), 115.4 (JC-F = 23.4 Hz). 19F NMR
(376 MHz, CDCl3) δ -112.99.
4.4.37 2-(4-Bromophenyl)-6-methylquinazoline (4k) [18a]: White
1
solid (41.8 mg, 56% yield); m.p. 182−183 °C. H NMR (600
MHz, CDCl3) δ 9.33 (s, 1H), 8.46 (d, J = 8.1 Hz, 2H), 7.94 (d, J
= 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 8.1 Hz, 3H),
2.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.8, 159.4, 149.3,
137.7, 137.1, 136.6, 131.7, 130.0, 128.3, 125.8, 125.1, 123.7,
21.7.
4.4.45 2-(3-Methoxyphenyl)-6-methylquinazoline (4s): White
solid (38.4 mg, 61% yield); m.p. 109−110 °C. H NMR (400
1
MHz, CDCl3) δ 9.34 (s, 1H), 8.23–8.10 (m, 2H), 7.97 (d, J = 8.6
Hz, 1H), 7.70 (dd, J = 8.6, 1.9 Hz, 1H), 7.64 (d, J = 0.7 Hz, 1H),
7.43 (t, J = 8.0 Hz, 1H), 7.06–7.03 (m, 1H), 3.94 (s, 3H), 2.54 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 160.2, 160.0, 159.7, 149.3,
139.7, 137.5, 136.4, 129.6, 128.3, 125.8, 123.7, 121.0, 117.0,
112.9, 55.4, 21.6. HRMS (positive ESI) m/z [M + H+] Calcd. For
C16H15N2O (251.1179), Found 251.1181.
4.4.38 6-Methyl-2-(4-(trifluoromethyl)phenyl)quinazoline (4l)
1
[18a]: White solid (32.7 mg, 45% yield); m.p. 149−151 °C. H
NMR (600 MHz, CDCl3) δ 9.38 (s, 1H), 8.71 (d, J = 7.9 Hz, 2H),
7.99 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 7.3 Hz, 3H), 7.69 (s, 1H),
2.58 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 158.9, 149.3,
141.5, 138.2, 136.7, 131.9 (JC-F = 32.40 Hz), 128.7, 125.8, 125.5
(JC-F = 3.74 Hz), 124.3 (JC-F = 273.31 Hz), 123.8, 21.7. 19F NMR
(376 MHz, CDCl3) δ -62.62.
4.4.46 2-(3-Fluorophenyl)-6-methylquinazoline (4t) [18a]: Light
1
yel-low solid (29.8 mg, 50% yield); m.p. 126−128 °C. H NMR
(400 MHz, CDCl3) δ 9.35 (d, J = 0.3 Hz, 1H), 8.38 (dt, J = 7.8,
1.3 Hz, 1H), 8.33–8.26 (m, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.73
(dd, J = 8.6, 1.9 Hz, 1H), 7.67 (d, J = 0.7 Hz, 1H), 7.56–7.39 (m,
1H), 7.20–7.15 (m, 1H), 2.56 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 163.3 (JC-F = 244.4 Hz), 159.8, 159.2 (JC-F = 3.3 Hz),
149.3, 140.6 (JC-F = 8.0 Hz), 137.8, 136.6, 130.0 (JC-F = 8.0 Hz),
128.3, 125.8, 124.0 (JC-F = 2.8 Hz), 123.8, 117.2 (JC-F = 21.6 Hz),
115.3 (JC-F = 23.3 Hz), 21.7. 19F NMR (376 MHz, CDCl3) δ -
113.28.
4.4.39 2-(4-Methoxyphenyl)-8-methylquinazoline (4m): White
1
solid (54.7 mg, 87% yield); m.p. 87−88 °C. H NMR (600 MHz,
CDCl3) δ 9.34 (s, 1H), 8.61 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 7.7
Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 2H), 3.89 (s,
3H), 2.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.7, 160.5,
159.8, 149.8, 136.8, 133.8, 131.2, 130.1, 126.4, 124.8, 123.2,
113.9, 55.4, 16.9. HRMS (positive ESI) m/z [M + H+] Calcd. For
C16H15N2O (251.1179), Found 251.1183.
4.4.47 2-(3-Bromophenyl)-8-methylquinazoline (4u): White solid
1
(57.4 mg, 78% yield); m.p. 131 °C. H NMR (400 MHz, CDCl3)
4.4.40 8-Methyl-2-(4-(trifluoromethyl)phenyl)quinazoline (4n):
White solid (27.2 mg, 38% yield); m.p. 95−96 °C. 1H NMR (400
MHz, CDCl3) δ 9.41 (s, 1H), 8.76 (d, J = 8.1 Hz, 2H), 7.80–7.69
(m, 4H), 7.52 (t, J = 7.6 Hz, 1H), 2.85 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 160.7, 158.5, 149.6, 141.6, 137.3, 134.1, 131.9
(JC-F = 32.33 Hz), 128.7, 127.5, 125.4 (JC-F = 3.73 Hz), 124.8,
124.3 (JC-F = 288.3 Hz), 123.8, 16.9. 19F NMR (376 MHz,
CDCl3) δ -62.63. HRMS (positive ESI) m/z [M + H+] Calcd. For
C16H12F3N2 (289.0947), Found 289.0951.
δ 9.38 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.58 (dt, J = 7.8, 1.3 Hz,
1H), 7.76–7.68 (m, 2H), 7.63–7.58 (m, 1H), 7.50 (t, J = 7.8 Hz,
1H), 7.39 (t, J = 7.6 Hz, 1H), 2.84 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 160.6, 158.5, 149.6, 140.5, 137.2, 134.1, 133.3, 131.5,
130.1, 127.3, 127.1, 124.8, 123.7, 122.9, 17.0. HRMS (positive
ESI) m/z [M + H+] Calcd. For C15H12BrN2 (299.0178), Found
299.0179.
4.4.48 7-Chloro-2-(3-chlorophenyl)quinazoline (4v): Yellow
1
solid (54.9 mg, 80% yield); m.p. 180−184 °C. H NMR (400
4.4.41 7-Chloro-2-(p-tolyl)quinazoline (4o): Yellow solid (47.2
mg, 74% yield); m.p. 150−151 °C. 1H NMR (400 MHz, CDCl3) δ
9.38 (d, J = 0.6 Hz, 1H), 8.49 (d, J = 8.1 Hz, 2H), 8.05 (t, J =
1.84 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 8.6, 2.0 Hz,
1H), 7.33 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 162.0, 160.1, 151.4, 141.3, 140.2, 134.9, 129.5, 128.7,
128.4, 128.2, 127.7, 121.8, 21.6. HRMS (positive ESI) m/z [M +
H+] Calcd. For C15H12ClN2 (255.0684), Found 255.0685.
MHz, CDCl3) δ 9.43 (d, J = 0.6 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H),
8.50 (dt, J = 7.0, 1.7 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.88 (d, J
= 8.6 Hz, 1H), 7.59 (dd, J = 8.6, 1.9 Hz, 1H), 7.52–7.42 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 160.6, 160.3, 151.2, 140.6, 139.4,
134.9, 130.9, 129.9, 128.9, 128.8, 128.4, 127.8, 126.8, 122.1.
HRMS (positive ESI) m/z [M + H+] Calcd. For C14H9Cl2N2
(275.0137), Found 275.0139.
4.4.49 5-Chloro-2-(m-tolyl)quinazoline (4w): White solid (39.0
mg, 61% yield); m.p. 121−122 °C. 1H NMR (400 MHz, CDCl3) δ
9.83 (d, J = 0.4 Hz, 1H), 8.47–8.37 (m, 2H), 8.00 (d, J = 8.6 Hz,
1H), 7.83–7.75 (m, 1H), 7.60 (dd, J = 7.6, 0.8 Hz, 1H), 7.44 (t, J
= 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 2.49 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 161.8, 157.8, 151.9, 138.4, 137.4, 133.9,
131.9, 131.9, 129.3, 128.7, 127.8, 127.2, 126.0, 121.4, 21.5.
HRMS (positive ESI) m/z [M + H+] Calcd. For C15H12ClN2
(255.0684), Found 255.0685.
4.4.42 5-Chloro-2-(4-methoxyphenyl)quinazoline (4p): White
1
solid (46.0 mg, 68% yield); m.p. 139−141 °C. H NMR (400
MHz, CDCl3) δ 9.78 (d, J = 0.6 Hz, 1H), 8.62–8.54 (m, 2H), 7.94
(d, J = 8.6 Hz, 1H), 7.81–7.72 (m, 1H), 7.57 (dd, J = 7.5, 0.8 Hz,
1H), 7.09–7.00 (m, 2H), 3.91 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 162.2, 161.4, 157.7, 151.9, 133.8, 131.9, 130.5, 130.1,
127.6, 126.7, 121.1, 114.1, 55.4. HRMS (positive ESI) m/z [M +
H+] Calcd. For C15H12ClN2O (271.0633), Found 271.0635.
4.4.43 5-Chloro-2-(4-iodophenyl)quinazoline (4q): White solid
(51.3 mg, 56% yield); m.p. 194−195 °C. H NMR (400 MHz,
1
4.4.50 6-Chloro-2-(naphthalen-2-yl)quinazoline (4x): Yellow
1
solid (50.9 mg, 70% yield); m.p. 179−181 °C. H NMR (400
CDCl3) δ 9.81 (d, J = 0.6 Hz, 1H), 8.40–8.30 (m, 2H), 8.02–7.96
(m, 1H), 7.91–7.85 (m, 2H), 7.81 (dd, J = 8.5, 7.6 Hz, 1H), 7.63
(dd, J = 7.6, 0.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.9,
157.9, 151.8, 137.9, 137.0, 134.1, 132.0, 130.4, 127.8, 127.5,
121.5, 98.3. HRMS (positive ESI) m/z [M + H+] Calcd. For
C14H9ClIN2 (366.9493), Found 366.9495.
MHz, CDCl3) δ 9.45 (d, J = 0.4 Hz, 1H), 9.15 (s, 1H), 8.70 (dd, J
= 8.7, 1.7 Hz, 1H), 8.10–8.01 (m, 2H), 7.98 (d, J = 8.7 Hz, 1H),
7.92–7.87 (m, 2H), 7.86 (dd, J = 9.0, 2.3 Hz, 1H), 7.59–7.50 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 161.3, 159.5, 149.3, 135.2,
134.9, 134.8, 133.4, 132.8, 130.4, 129.3, 129.1, 128.4, 127.8,
127.3, 126.3, 125.9, 125.3, 124.0. HRMS (positive ESI) m/z [M +
H+] Calcd. For C18H12ClN2 (291.0684), Found 291.0683.
4.4.44 6-Chloro-2-(3-fluorophenyl)quinazoline (4r) [18a]: White
1
solid (50.6 mg, 78% yield); m.p. 144−146 °C. H NMR (400

8
Tetrahedron
4.4.51 7-Chloro-2-(naphthalen-1-yl)quinazoline (4y): White
123.1, 37.9, 21.9, 16.8. HRMS (positive ESI) m/z [M + H+] Calcd.
ACCEPTED MANUSCRIPT
1
solid (32.4 mg, 45% yield); m.p. 148−150 °C. H NMR (400
MHz, CDCl3) δ 9.54 (d, J = 0.6 Hz, 1H), 8.77–8.69 (m, 1H),
8.23–8.15 (m, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.97–7.89 (m, 2H),
7.68–7.49 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 164.4, 160.1,
151.1, 140.6, 135.8, 134.2, 131.2, 130.8, 130.0, 129.0, 128.6,
128.4, 127.8, 127.0, 126.0, 125.8, 125.3, 121.5. HRMS (positive
ESI) m/z [M + H+] Calcd. For C18H12ClN2 (291.0684), Found
291.0685.
For C12H15N2 (187.1230), Found 187.1229.
4.4.59 2-Butyl-8-methylquinazoline (4ag): Yellow liquid (32.4
mg, 65% yield). 1H NMR (600 MHz, CDCl3) δ 9.28 (s, 1H), 7.69
(d, J = 7.0 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H), 3.14 (t, J = 7.6 Hz,
2H), 2.76 (s, 3H), 1.97–1.89 (m, 2H), 1.52–1.43 (m, 2H), 0.99 (t,
J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.8, 160.3,
149.5, 136.4, 133.6, 126.4, 124.8, 122.9, 39.6, 30.8, 22.6, 16.9,
14.0. HRMS (positive ESI) m/z [M + H+] Calcd. For C13H17N2
(201.1386), Found 201.1388.
4.4.52 6-Chloro-2-(pyridin-4-yl)quinazoline (4z): Yellow solid
(27.2 mg, 45% yield); m.p. 165−167 °C; eluent, petroleum
ether/ethyl acetate=3/1. H NMR (400 MHz, CDCl3) δ 9.44 (d, J
= 0.4 Hz, 1H), 8.81 (dd, J = 4.6, 1.5 Hz, 2H), 8.44 (dd, J = 4.6,
1.5 Hz, 2H), 8.08 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H),
7.89 (dd, J = 9.0, 2.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
159.8, 159.2, 150.5, 149.1, 144.9, 135.6, 134.0, 130.6, 125.9,
124.6, 122.3. HRMS (positive ESI) m/z [M + H+] Calcd. For
C13H9ClN3 (242.0480), Found 242.0479.
1
4.4.60 2-Butyl-7-chloroquinazoline (4ah): Yellow liquid (20.4
mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 7.98
(d, J = 1.9 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 8.6,
1.9 Hz, 1H), 3.11 (t, J = 7.7 Hz, 2H), 1.96–1.84 (m, 2H), 1.53–
1.39 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 169.0, 160.0, 150.9, 140.2, 128.3, 128.2, 127.2, 121.4,
39.7, 30.9, 22.6, 13.9. HRMS (positive ESI) m/z [M + H+] Calcd.
For C12H14ClN2 (221.0840), Found 221.0841.
4.4.53 6-Methyl-2-(pyridin-4-yl)quinazoline (4aa): Light yellow
solid (22.7 mg, 41% yield); m.p. 149−151 °C; eluent, petroleum
ether/ethyl acetate=3/1. H NMR (400 MHz, CDCl3) δ 9.42 (s,
4.4.61 5-Chloro-2-cyclopropylquinazoline (4ai): Yellow liquid
(26.4 mg, 52% yield). H NMR (400 MHz, CDCl3) δ 9.60 (s,
1
1
1H), 8.80 (dd, J = 4.5, 1.6 Hz, 2H), 8.44 (dd, J = 4.5, 1.6 Hz, 2H),
8.03 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.6, 1.9 Hz, 1H), 7.74 (s,
1H), 2.60 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 158.3,
150.4, 149.2, 145.5, 138.7, 136.8, 128.5, 125.9, 124.2, 122.2,
21.8. HRMS (positive ESI) m/z [M + H+] Calcd. For C14H12N3
(222.1026), Found 222.1027.
1H), 7.80 (d, J = 8.4, 1H), 7.75–7.67 (m, 1H), 7.52 (dd, J = 7.4,
1.0 Hz, 1H), 2.45–2.36 (m, 1H), 1.32–1.26 (m, 2H), 1.20–1.13
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 169.3, 157.6, 151.4,
133.7, 131.8, 126.7, 126.3, 121.0, 18.6, 11.0. HRMS (positive
ESI) m/z [M + H+] Calcd. For C11H10ClN2 (205.0527), Found
205.0526.
4.4.54 6-Chloro-2-(thiophen-2-yl)quinazoline (4ab): Yellow
solid (47.0 mg, 76% yield); m.p.180−181 °C. 1H NMR (400
MHz, CDCl3) δ 9.28 (d, J = 0.5 Hz, 1H), 8.14 (dd, J = 3.7, 1.2 Hz,
1H), 7.95 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.80 (dd,
J = 9.0, 2.3 Hz, 1H), 7.53 (dd, J = 5.0, 1.2 Hz, 1H), 7.21−7.16 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 159.6, 158.1, 149.1, 143.4,
135.3, 132.5, 130.4, 129.9, 129.6, 128.5, 126.0, 123.7. HRMS
(positive ESI) m/z [M + H+] Calcd. For C12H8ClN2S (247.0091),
Found 247.0092.
Acknowledgments
Financial support from the National Natural Science
Foundation of China (Grant Nos. 21672192 and 21803059), the
China Postdoctoral Science Foundation (Grant Nos.
2016M602254 and 2016M600582), the Program for Science &
Technology Innovation Talents in Universities of Henan
Province (Grant No. 17HASTIT004), the Aid Project for the
Leading Young Teachers in Henan Provincial Institutions (Grant
No. 2015GGJS-157), and the Natural Science Foundation of
Henan Province (Grant No. 182300410255) is gratefully
appreciated. is gratefully appreciated.
4.4.55 2-(Furan-2-yl)-6-methylquinazoline (4ac): Yellow solid
1
(31.2 mg, 60% yield); m.p. 140−142 °C. H NMR (600 MHz,
CDCl3) δ 9.29 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.6
Hz, 1H), 7.66 (d, J = 16.6 Hz, 2H), 7.42 (s, 1H), 6.61 (s, 1H),
2.56 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 153.6, 152.6,
149.0, 145.1, 137.5, 136.8, 128.1, 126.0, 123.4, 113.6, 112.3,
21.6. HRMS (positive ESI) m/z [M + H+] Calcd. For C13H11N2O
(211.0866), Found 211.0867.
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Supplementary Material
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Graphical Abstract
An efficient NNN pincer Ru(II)-catalyzed preparation of
NNN Pincer Ru(II)-Catalyzed
quinazolines via acceptorless dehydrogenative strategy
has been developed, which is featured with several
advantages, such as environmental benignity, operational
simplicity, broad substrate scope, and short reaction time.
Dehydrogenative Coupling of
2-Aminoarylmethanols with Nitriles for the
Construction of Quinazolines
Xiao-Min Wan,‡ Zi-Lin Liu,‡ Wan-Qing Liu, Xiao-Niu Cao, Xinju Zhu, Xue-Mei Zhao, Bing Song*, Xin-Qi
Hao*, and Guoji Liu
College of Chemistry and Molecular Engineering, School of Life Sciences, School of Chemical Engineering and
Energy, Zhengzhou University, No. 100 of Science Road, Zhengzhou, Henan 450001, P. R. China