Palladium-catalyzed cyanation of quinazoline-4-tosylates for access to 4-cn-functionalized quinazolines

Article abstract of DOI:10.1055/s-0033-1339918

A highly efficient palladium-catalyzed cyanation of quinazoline-4-tosylates is disclosed. The method is successfully developed for the direct access to various 4-CN-functionalized quinazolines, which are potentially useful as biologically and pharmaceutically active compounds. The reactions were performed under mild conditions using inexpensive copper(I) cyanide as cyano source in good to excellent yields and great functional group diversities. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339918

PAPER
▌3245
paper
Palladium-Catalyzed Cyanation of Quinazoline-4-tosylates for Access to
4-CN-Functionalized Quinazolines
Synthesis of 4-CN Functionalized Quinazolines
Xu Zhao,a Yirong Zhou,b Qin Yang,b Yepeng Xie,a Qiuping Ding,a Zhihong Deng,a Ming Zhang,a Jingshi Xu,a
Yiyuan Peng*a,b
a
Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022,
P. R. of China
b
Key Laboratory of Small Functional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. of China
Fax +86(791)88120396; E-mail: yypeng@jxnu.edu.cn; E-mail: yiyuanpeng@yahoo.com
Received: 28.07.2013; Accepted after revision: 16.09.2013
efficient palladium-catalyzed cyanation of quinazoline-4-
tosylates using copper(I) cyanide as the cyano source for
direct access toward various 4-CN functionalized quinaz-
olines.
Abstract: A highly efficient palladium-catalyzed cyanation of
quinazoline-4-tosylates is disclosed. The method is successfully de-
veloped for the direct access to various 4-CN-functionalized quin-
azolines, which are potentially useful as biologically and
pharmaceutically active compounds. The reactions were performed
under mild conditions using inexpensive copper(I) cyanide as cyano
source in good to excellent yields and great functional group diver-
sities.
Initially, 2-(p-tolylquinazolin-4-yl)-4-(4-methylbenzene)-
sulfonate (1a) was chosen as a model substrate to opti-
mize the reaction conditions. To our delight, the first
glimpse of success was revealed upon using copper(I) cy-
anide as the cyano source in the presence of a combination
of Pd(OAc)2, Ph3P, and Cs2CO3 in 1,2-dichloroethane
(DCE) at 80 °C for 10 hours, where the desired product 2a
was isolated in 56% yield (Table 1, entry 1). Then, sys-
tematic optimization was carried out through evaluation
of metal catalyst, base additive, ligand, and solvent. At
first, a group of palladium sources, including PdCl2,
Pd(PPh3)2Cl2, Pd(MeCN)Cl2, and Pd2(dba)3, as well as
some copper sources such as CuI and Cu(OTf)2 were test-
ed (entries 1–7). Among all these cases, only Pd2(dba)3
could generate a comparable result (entry 5). Next, a vari-
ety of bases were tested as additives (entries 8–16). It was
found that neither weak inorganic bases nor organic bases
could facilitate the transformation, while stronger inor-
ganic bases, such as t-BuOK, KOH, and NaOH provided
much lower yield. Different ligands were examined for an
optimization of the reaction (entries 17–21), and DPPF
showed the highest efficiency providing 87% yield of the
product (entry 20). Finally, DPPF was selected as the op-
timal ligand to investigate the effect of solvents (entries
23–28). Aromatic solvent toluene furnished the highest
yield of 96% among all the tested solvents (entry 24).
Moreover, water and air were found to be unfavorable for
the process (entries 29, 30). Furthermore, control experi-
ments proved that in the absence of any one of the reaction
parameters [Pd(OAc)2, DPPF, Cs2CO3], no conversion
was observed.
Key words: copper, palladium catalysis, quinazoline-4-tosylate
Transition-metal-catalyzed functional group transforma-
tions maintain always the central position in modern or-
ganic synthesis.1 The nitrile moiety serves as pivotal
precursor for multitude of conversions into a great number
of other functional groups, such as hydrolysis into carbox-
yl, hydration into amide, reduction into amine or alde-
hyde, cycloaddition into tetrazole, etc.2 Moreover,
benzonitriles themselves are also of significant interest,
and have broad applications in material science, agro-
chemicals, and pharmaceuticals.3 Consequently, tremen-
dous efforts have been devoted into this area and various
catalytic systems were established by using different cat-
alysts, cyanating agents, and substrates.4 Although steady
progress has been achieved, there is still great room to in-
spire chemists for development of novel systems includ-
ing the following characters: inexpensive agents, easily
practicable operations, and mild reaction conditions. Ex-
cept for the mostly studied classic examples of palladium-
catalyzed cyanation of aryl halides,5 other proper sub-
strates like pseudohalides,6 arylboronic acids,7 alkene,8 al-
kyne,9 and aromatic hydrocarbon10 have also been
successfully used in this transformation. Among them,
OTf as a good leaving group has shown excellent re-
sults.11 Based on our previous work,12 we envisioned that
the OTs group may be nucleophilically substituted by a
cyano group to provide 4-CN substituted quinazolines,
which are potentially useful as biologically and pharma-
ceutically active compounds. Herein, we disclose a highly
With the optimized reaction conditions in hand, the sub-
strate scope was explored and the results are summarized
in Scheme 1. Different substituents on the 2-position of
aromatic ring were first evaluated. In general, the
electron-rich substrates provided a little higher yield than
electron-deficient ones. In addition, steric hindrance did
exert some influence on the transformation; thus bulkier
substrates provided lower yield of the desired products
SYNTHESIS 2013, 45, 3245–3250
Advanced online publication: 14.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339918; Art ID: SS-2013-H0525-OP
© Georg Thieme Verlag Stuttgart · New York

3246
X. Zhao et al.
PAPER
Table 1 Optimization of Reaction Parametersa
(2a vs 2b vs 2c). Even heterocycles like pyridine and fu-
ran were also tolerated well in this catalytic system and
pretty satisfying results were obtained (2g and 2h). When
substrates containing halo atom were employed, the reac-
tion occurred regioselectively at the 4-position of the
quinazoline core structure and no reaction occurred at the
Cl or F atom sites (2i, 2j, 2k, and 2l).
OTs
metal source (5 mol%)
CN
N
ligand (10 mol%)
N
CuCN
+
N
base (2 equiv)
solvent
N
1a
2a
Furthermore, the reactants bearing aliphatic chain substit-
uents at the 2-position could also furnish the expected
products in moderate to good yields (2m and 2n). Finally,
the influence of the substituents on the quinazoline core
rings was investigated. Neither F atom or methyl group
had an obvious influence on the catalytic process (2o, 2p,
2q, and 2r).
Entry Metal source
Base
Ligand
Solvent
Yield
(%)b
1
2
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
56
<5
<5
5
3
Pd(PPh3)2 Cl2 Cs2CO3
Pd(MeCN)Cl2 Cs2CO3
In order to collect more information about this unique cat-
alytic process, substrate 3 containing both OTs group and
an aryl bromide moiety was utilized under the identical
conditions. We were glad to find that both the OTs and
aryl bromide groups can be displaced by the cyano group
in one-pot at the same time by treatment with four equiv-
alents of copper(I) cyanide (Scheme 2). Additionally,
control experiments were carried out to examine the leav-
ing ability of different leaving groups including OTs, OTf,
and Cl. The results indicated that the substrates 5 and 6
bearing OTs and OTf, respectively, have almost the same
reactivity, and similar yields were obtained. The chlori-
nated substrate 7 gave only 11% yield of the correspond-
ing cyano product due to its much lower reactivity
(Scheme 3).
4
5
Pd2(dba)3
CuI
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
KOH
47
6
NR
NR
21
7
Cu(OTf)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
9
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
NaOH
10
Na2CO3
K3PO4
NR
NR
NR
NR
NR
NR
51
K2HPO4
DBU
DABCO
Et3N
In conclusion, we have developed an effective palladium-
catalyzed cyanation reaction using quinazoline-4-tosyl-
ates as reactants, which furnished a rapid and straightfor-
ward method to prepare 4-CN functionalized quinazolines
that are potential biologically and medically useful com-
pounds. This catalytic system has several advantages:
mild and practical reaction conditions, inexpensive cop-
per(I) cyanide as the cyano source, good to excellent
yields, and great functional group tolerance. Further ef-
forts are under way to explore the usage of this novel cat-
alytic strategy.
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Xant-phos DCE
X-phos DCE
10
S-phos
DPPF
Cy3P
DCE
<5
87
DCE
DCE
NR
<5
40
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
CH2Cl2
THF
toluene
MeCN
DMF
96
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using
silica gel (60 Å pore size, 32–63 μm, standard grade). Analytical
TLC analyses were performed using glass plates precoated with
0.25 mm 230–400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). TLC plates were visualized by exposure to ul-
traviolet light. Organic solutions were concentrated on rotary evap-
orator at 25–35 °C and ~20 Torr. NMR spectra are recorded in parts
per million from internal TMS on the δ scale. 1H and 13C NMR spec-
tra were recorded in CDCl3 on a Bruker DRX-400 spectrometer op-
erating at 400 MHz and 100 MHz, respectively. All chemical shift
values are quoted in ppm and coupling constants quoted in Hz.
High-resolution mass spectra (HRMS) were obtained on a
micrOTOF II Instrument.
<5
NR
NR
NR
DMSO
DMA
toluene/H2O NR
(1:1)
30c
Pd(OAc)2
Cs2CO3
DPPF
toluene
NR
a All reactions were performed in 0.2 mmol scale, standard condi-
tions: quinazoline-4-tosylate (0.2 mmol, 1 equiv), CuCN (0.4 mmol,
2 equiv), Pd sources (0.0l mmol, 5 mmol%), ligand (0.02 mmol, 10
mmol%), base (0.4 mmol, 2 equiv), solvent (2 mL); 80 °C, 10 h, inert
atmosphere.
b Isolated yield. NR = no reaction.
Palladium-Catalyzed Cyanation of Quinazoline-4-tosylates;
General Procedure
A mixture of quinazoline-4-tosylate 1 (0.20 mmol), Pd(OAc)2 (5
mol%), DPPF (10 mol%), and Cs2CO3 (0.40 mmol, 2.0 equiv) in
c The reaction was carried out under an air atmosphere.
Synthesis 2013, 45, 3245–3250
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 4-CN Functionalized Quinazolines
3247
CN
OTs
Pd(OAc)2 (5 mol%)
DPPF (10 mol%)
N
N
CuCN
(2 equiv)
R1
+
R1
Cs2CO3 (2 equiv), toluene
N2, 80 °C
R2
N
R2
N
2
1
CN
N
CN
N
CN
N
CN
N
N
N
N
N
2a, 96% (8 h)
2b, 90% (8 h)
2c, 82% (8 h)
2d, 82% (8 h)
CN
N
CN
N
CN
CN
N
N
O
O
N
N
O
N
N
N
N
2e, 84% (8 h)
2f, 89% (8 h)
2g, 98% (8 h)
2h, 90% (8 h)
CN
CN
N
CN
N
CN
N
N
Cl
Cl
N
N
N
N
Cl
F
Cl
2i, 74% (12 h)
2j, 68% (13 h)
2k, 66% (12 h)
2l, 57% (16 h)
CN
N
CN
N
CN
N
CN
N
N
N
N
N
F
2m, 68% (9 h)
2n, 75% (8 h)
2o, 84% (8 h)
2p, 89% (12 h)
CN
F
CN
N
N
N
N
N
N
2q, 94% (8 h)
2r, 95% (8 h)
Scheme 1 Substrate scope
CN
CN
N
X
N
identical
conditions
OTs
N
N
identical
conditions
N
CuCN
+
CuCN
+
2 equiv
N
N
4 equiv
N
OMe
CN
8
OMe
3
4, 57%
Br
5 X = OTs, 59%
6 X = OTf, 61%
7 X = Cl, 11%
Scheme 2 Double cyanation of 3
Scheme 3 Cyanation of 5, 6, and 7
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3245–3250

3248
X. Zhao et al.
PAPER
toluene (3.0 mL) was stirred at 80 °C for 8–16 h. After completion
of the reaction as indicated by TLC (eluent: PE–EtOAc, 10:1 to
4:1), evaporation of the solvent followed by purification by chroma-
tography on silica gel (eluent: PE–EtOAc, 10:1 to 4:1) provided the
corresponding product 2.
HRMS (ESI): m/z [M + H]+ calcd for C16H10N3O2: 276.0773; found:
276.0794.
2-[4-(Dimethylamino)phenyl]quinazoline-4-carbonitrile (2f)
Yield: 48.8 mg (89%); red solid; mp 194–195 °C.
IR (KBr): 2919, 2236, 1606, 1371, 1187, 824, 776 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 8.8 Hz, 2 H), 8.15 (d,
J = 8.0 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.93 (t, J = 7.8 Hz, 1 H),
7.64 (t, J = 7.6 Hz, 1 H), 6.81 (d, J = 9.2 Hz, 2 H), 3.09 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 161.5, 152.7, 152.0, 143.3, 135.3,
130.2, 129.0, 128.0, 124.9, 123.9, 122.4, 114.7, 111.7, 40.2.
2-p-Tolylquinazoline-4-carbonitrile (2a)
Yield: 47.0 mg (96%); yellow solid; mp 160–162 °C.
IR (KBr): 2923, 2237, 1608, 1394, 847 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.51 (d, J = 8.4 Hz, 2 H), 8.23 (d,
J = 8.4 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.01 (dd, J = 7.2, 1.2 Hz,
1 H), 7.75 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 2.46 (s, 3
H).
HRMS (ESI): m/z [M + H]+ calcd for C17H15N4: 275.1297; found:
275.1274.
13C NMR (100 MHz, CDCl3): δ = 161.1, 151.8, 143.4, 142.0, 135.6,
133.7, 129.6, 129.4, 129.1, 128.7, 124.9, 122.9, 114.5, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3: 246.1031; found:
246.1042.
2-(Pyridin-4-yl)quinazoline-4-carbonitrile (2g)
Yield: 45.8 mg (98%); yellow solid; mp 177–178 °C.
IR (KBr): 2919, 2241, 1613, 1394, 847, 774, 538 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.91 (br s, 2 H), 8.48 (s, 2 H), 8.31
(d, J = 8.4 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 8.11 (t, J = 7.8 Hz, 1
H), 7.88 (t, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 151.6, 150.8, 143.7, 143.5,
136.2, 130.6, 129.8, 125.1, 123.6, 122.3, 114.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H9N4: 233.0827; found:
233.0805.
2-m-Tolylquinazoline-4-carbonitrile (2b)
Yield: 44.1 mg (90%); yellow solid; mp 154–156 °C.
IR (KBr): 2922, 2237, 1616, 1546, 1462, 789, 768, 726 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.29–8.28 (m, 2 H), 8.15 (d,
J = 8.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.92 (dd, J = 8.0, 7.2 Hz,
1 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.25 (d,
J = 7.6 Hz, 1 H), 2.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.0, 151.7, 143.4, 138.6, 136.2,
135.7, 132.4, 129.4, 129.3, 129.2, 128.8, 125.9, 124.9, 122.9, 114.5,
21.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3: 246.1031; found:
246.1046.
2-(Furan-2-yl)quinazoline-4-carbonitrile (2h)
Yield: 39.8 mg (90%); yellow solid; mp 192–194 °C.
IR (KBr): 2924, 2853, 2239, 1591, 1463, 1414, 1384, 845, 768, 750
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.4 Hz, 2 H), 8.05–
8.00 (m, 1 H), 7.78–7.72 (m, 2 H), 7.54–7.53 (m, 1 H), 6.65 (t,
J = 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 153.8, 151.5, 151.2, 146.3, 143.7,
136.2, 129.3, 129.2, 125.2, 122.7, 116.0, 114.1, 112.7.
2-o-Tolylquinazoline-4-carbonitrile (2c)
Yield: 40.1 mg (82%); yellow solid; mp 156–157 °C.
IR (KBr): 2925, 2238, 1615, 1543, 1392, 1075, 891, 771, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 8.4 Hz, 1 H), 8.20 (d,
J = 8.8 Hz, 1 H), 8.06 (t, J = 7.6 Hz, 1 H), 8.02 (d, J = 7.6 Hz, 1 H),
7.84 (t, J = 7.6 Hz, 1 H), 7.44–7.35 (m, 3 H), 2.66 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.7, 151.4, 143.1, 138.1, 136.6,
135.8, 131.7, 131.2, 130.2, 129.8, 129.5, 126.2, 124.9, 122.4, 114.5,
21.5.
HRMS (ESI): m/z [M + H]+ calcd for 222.0667; found: 222.0668.
2-(4-Chlorophenyl)quinazoline-4-carbonitrile (2i)
Yield: 39.2 mg (74%); yellow solid; mp 182–183 °C.
IR (KBr): 2919, 2849, 2237, 1596, 1545, 1406, 1097, 841, 769, 737
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.56 (d, J = 8.4 Hz, 2 H), 8.25 (d,
J = 8.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 8.04 (t, J = 7.8 Hz, 1 H),
7.79 (t, J = 7.6 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 151.7, 143.5, 137.9, 135.9,
134.8, 130.1, 129.6, 129.5, 129.1, 125.0, 123.0, 114.34.
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3: 246.1031; found:
246.1042.
2-Phenylquinazoline-4-carbonitrile (2d)
Yield: 37.9 mg (82%); yellow solid; mp 171–172 °C.
IR (KBr): 2924, 2236, 1599, 1485, 767, 704 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.63–8.62 (m, 2 H), 8.26 (d,
J = 8.4 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 8.04 (t, J = 7.8 Hz, 1 H),
7.78 (t, J = 7.8 Hz, 1 H), 7.57–7.53 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.0, 151.8, 143.5, 136.4, 135.7,
131.6, 129.5, 129.4, 128.8, 128.8, 125.0, 123.1, 114.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H9ClN3: 266.0485; found:
266.0504.
2-(4-Fluorophenyl)quinazoline-4-carbonitrile (2j)
Yield: 33.9 mg (68%); yellow solid; mp 171–172 °C.
IR (KBr): 2919, 2238, 1602, 1406, 1235, 845, 800, 766, 531 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.64 (dd, J = 8.4, 6.0 Hz, 2 H),
8.25 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 8.04 (t, J = 7.8
Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.23 (t, J = 8.8 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H10N3: 232.0875; found:
232.0880.
2-(Benzo[d][1,3]dioxol-5-yl)quinazoline-4-carbonitrile (2e)
Yield: 46.2 mg (84%); yellow solid; mp 229–230 °C.
IR (KBr): 3072, 2925, 2235, 1598, 1274, 1026, 875, 769, 574 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.25–8.20 (m, 2 H), 8.13–8.09 (m,
2 H), 8.01 (d, J = 7.2 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 6.96 (d,
J = 8.4 Hz, 1 H), 6.08 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 165.2 (d, 1JC,F = 251 Hz), 160.1,
3
151.7, 143.5, 135.9, 132.6, 131.0 (d, JC,F = 9 Hz), 129.5, 129.4,
125.0, 123.0, 115.9 (d, 2JC,F = 22 Hz), 114.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H9FN3: 250.0781; found:
250.0763.
13C NMR (100 MHz, CDCl3): δ = 160.5, 151.8, 150.7, 148.5, 143.3,
135.7, 130.9, 130.8, 129.3, 129.0, 128.8, 124.9, 124.1, 122.8, 114.5,
101.7.
2-(3-Chlorophenyl)quinazolone-4-carbonitrile (2k)
Yield: 35.0 mg (66%); white solid; mp 187–188 °C.
Synthesis 2013, 45, 3245–3250
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-CN Functionalized Quinazolines
3249
IR (KBr): 2924, 2236, 1614, 1545, 1430, 890, 786, 766, 724 cm–1.
13C NMR (100 MHz, CDCl3): δ = 165.1 (d, 1JC,F = 251 Hz), 160.0,
3
151.9, 147.5, 142.8, 132.7, 131.9, 130.8 (d, JC,F = 8 Hz), 128.1,
1H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H), 8.50 (d, J = 6.4 Hz,
1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 8.06 (t,
J = 7.8 Hz, 1 H), 7.82 (t, J = 7.8 Hz, 1 H), 7.50–7.48 (m, 2 H).
124.6, 121.3, 115.8 (d, 2JC,F = 22 Hz), 114.5, 22.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H11FN3: 264.0937; found:
264.0949.
13C NMR (100 MHz, CDCl3): δ = 159.1, 151.1, 143.0, 137.6, 135.5,
134.6, 131.0, 129.6, 129.3, 129.0, 128.2, 126.3, 124.5, 122.7, 113.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H9ClN3: 266.0485; found:
7-Methyl-2-(pyridin-4-yl)quinazoline-4-carbonitrile (2q)
Yield: 46.3 mg (94%); yellow solid; mp 174–175 °C.
IR (KBr): 3061, 2923, 2234, 1600, 1394, 847, 774, 538 cm–1.
266.0506.
1H NMR (400 MHz, CDCl3): δ = 8.83 (br s, 2 H), 8.40 (s, 2 H), 8.13
(d, J = 8.4 Hz, 1 H), 7.96 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 2.67 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 158.8, 151.7, 150.7, 148.1, 143.6,
142.9, 132.9, 128.4, 124.6, 122.2, 121.9, 114.3, 22.5.
2-(2,5-Dichlorophenyl)quinazoline-4-carbonitrile (2l)
Yield: 34.1 mg (57%); white solid; mp 190–191 °C.
IR (KBr): 2924, 2237, 1613, 1542, 1338, 1048, 889, 814, 769 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 8.0 Hz, 1 H), 8.25 (d,
J = 8.4 Hz, 1 H), 8.13 (t, J = 7.8 Hz, 1 H), 7.95–7.87 (m, 2 H), 7.50
(d, J = 8.8 Hz, 1 H), 7.43 (dd, J = 8.4, 2.4 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H11N4: 247.0984; found:
247.0975.
13C NMR (100 MHz, DMSO-d6): δ = 160.4, 151.4, 143.3, 137.7,
136.2, 133.0, 132.1, 132.0, 131.7, 131.1, 130.7, 129.6, 125.0, 122.9,
114.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H8Cl2N3: 300.0095; found:
300.0118.
5-Fluoro-2-(pyridin-4-yl)quinazoline-4-carbonitrile (2r)
Yield: 47.5 mg (95%); brown solid; mp 166–168 °C.
IR (KBr): 2924, 2201, 1624, 1563, 1413, 824, 701, 557 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.90 (br s, 2 H), 8.48 (s, 2 H),
8.08–8.03 (m, 2 H), 7.54–7.49 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.6, 156.1 (d, 1JC,F = 262 Hz),
2-Styrylquinazoline-4-carbonitrile (2m)
Yield: 35.0 mg (68%); yellow solid; mp 151–153 °C.
IR (KBr): 2922, 2236, 1613, 1543, 1366, 755, 685 cm–1.
152.6, 150.5, 142.6, 138.9, 136.3 (d, JC,F = 9 Hz), 125.9 (d,
2
3JC,F = 4 Hz), 115.2, 114.6 (d, 2JC,F = 19 Hz), 114.5, 114.3.
1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 8.18 (d, J = 8.4 Hz,
1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.99 (t, J = 7.6 Hz, 1 H), 7.73 (t,
J = 7.6 Hz, 1 H), 7.67 (d, J = 7.2 Hz, 2 H), 7.44–7.35 (m, 3 H), 7.35
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.3, 151.6, 143.3, 140.5, 135.8
135.7, 129.6, 129.2, 129.0, 128.9, 127.9, 126.3, 125.1, 122.7, 114.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H8FN4: 251.0733; found:
251.0725.
2-(4-Cyanophenyl)quinazoline-4-carbonitrile (4)
Yield: 29.2 mg (57%); yellow solid; mp 226–227 °C.
IR (KBr): 2923, 2225, 1610, 1453, 1263, 855, 801, 768, 552 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.76 (d, J = 8.4 Hz, 2 H), 8.31 (d,
J = 8.0 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 8.10 (t, J = 7.8 Hz, 1 H),
7.89–7.84 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.0, 151.6, 143.7, 140.3, 136.2,
132.6, 130.4, 129.7, 129.2, 125.1, 123.3, 118.5, 114.8, 114.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H12N3: 258.1031; found:
258.1044.
2-Propylquinazoline-4-carbonitrile (2n)
Yield: 29.6 mg (75%); yellow solid; mp 67–68 °C.
IR (KBr): 3035, 2925, 2872, 2234, 779 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 8.4 Hz, 1 H), 8.09 (d,
J = 8.8 Hz, 1 H), 8.02 (t, J = 7.6 Hz, 1 H), 7.77 (t, J = 7.6 Hz, 1 H),
3.15 (t, J = 7.6 Hz, 2 H), 2.17–1.87 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 167.4, 150.8, 142.8, 135.1, 128.7,
128.3, 124.4, 122.2, 113.9, 40.9, 21.5, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H9N4: 257.0827; found:
257.0841.
2-(4-Methoxyphenyl)quinazoline-4-carbonitrile (8)
Yield: 30.8 mg (59%); yellow solid; mp 192–193 °C.
IR (KBr): 3066, 2926, 2838, 2041, 1606, 1585, 1254, 1028, 840,
534 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.51 (d, J = 8.4 Hz, 2 H), 8.14 (d,
J = 8.0 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.95–7.90 (m, 1 H), 7.66
(t, J = 7.6 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.6, 159.8, 150.8, 142.4, 134.6,
129.5, 128.2, 128.1, 127.8, 123.9, 121.7, 113.5, 113.2, 54.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H12N3: 198.1031; found:
198.1046.
7-Methyl-2-phenylquinazoline-4-carbonitrile (2o)
Yield: 41.2 mg (84%); white solid; mp 194–195 °C.
IR (KBr): 3058, 1600, 1487, 825, 771, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 2 H), 8.09 (d, J = 8.4 Hz,
HRMS (ESI): m/z [M + Na]+ calcd for C16H11N3NaO: 284.0800;
1 H), 7.92 (s, 1 H), 7.58–7.54 (m, 4 H).
found: 284.0791.
13C NMR (100 MHz, CDCl3): δ = 161.0, 152.0, 147.3, 142.8, 136.5,
131.8, 131.4, 128.8, 128.7, 128.2, 124.5, 121.4, 114.6, 22.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H12N3: 246.1031; found:
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (grant No. 20962010 and 21162012), Jiangxi Provincial Depart-
ment of Science and Technology (for Jiangxi’s Key Laboratory of
Green Chemistry, and No. 20122BAB203007), and the Science
Foundation of Education Department of Jiangxi province (grant No.
GJJ10386) for their financial support.
246.1028.
2-(4-Fluorophenyl)-7-methylquinazoline-4-carbonitrile (2p)
Yield: 46.8 mg (89%); white solid; mp 214–215 °C.
IR (KBr): 3067, 2927, 2239, 1601, 1452, 1225, 848, 788, 504 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.59 (t, J = 8.0 Hz, 2 H), 8.10 (d,
J = 8.4 Hz, 1 H), 7.91 (s, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.21 (t,
J = 8.0 Hz, 2 H), 2.65 (s, 3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3245–3250

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X. Zhao et al.
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Synthesis 2013, 45, 3245–3250
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