Synthesis of 4-alkynylquinazolines: Pd-Cu-cocatalyzed coupling of quinazoline-4-tosylates with terminal alkynes using N-heterocyclic carbenes as ligands

Article abstract of DOI:10.1039/c4ob00700j

A Pd-Cu-cocatalyzed coupling reaction of quinazoline-4-tosylates with terminal alkynes using N-heterocyclic carbenes (NHC) as ligands is described, providing 4-alkynylquinazolines in good to excellent yields. This transformation proceeds under mild conditions with high efficiency, which is attractive for focused compound library construction. This journal is the Partner Organisations 2014.

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ARTICLE TYPE
Synthesis of 4-Alkynylquinazolines: Pd-Cu-cocatalyzed Coupling of
Quinazoline-4-tosylates with Terminal Alkynes Using N-Heterocyclic
Carbenes as Ligands
Yiyuan peng,*a,b Ping Huang,a Yu Wang,a Yirong Zhou, a JianJun Yuan,a
Qin Yang,b Xin Jiang,a Zhihong Deng a and Jingshi Xu,a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A Pd-Cu-cocatalyzed coupling reaction of quinazoline-4-tosylates with terminal alkynes using N-
heterocyclic carbenes (NHC) as ligands is described, which providing 4-alkynylquinazolines in good to
10 excellent yields. This transformation proceeds under mild conditions with high efficiency, which is
attractive for focused compound library construction.
Cl
N
Introduction
N
(1) chlorination
Nu-
Nu
N
O
During the last decade, N-Heterocyclic carbenes (NHCs)
have been widely used as strong electronic donating
N
NH
N
P
N
Nu-
15 ancillary ligands for organometallic chemistry and
II
I
N
homogeneous catalysis.1 Especially they serve as ligands
or coupling with
boronic acids
(2 )Phosphonium salt
in many catalytic coupling reactions,2a such as Suzuki,2b-d
Heck,2e and Sonogashira reactions.3 Sonogashira coupling
PF6
PF6
PF6
PF6
N
N
N
PF6
N
N
P
N
N
N
P
N
N
N
P
N
O
N
N
N
N
P
is a classic method for the formation of a new C-C bond
20 between aryl alkynes and aryl halides.4 Recently, the
reaction substrates have been expanded to aryl triflates,5
aryl chlorides,6 and aryl tosylates.6g, 7,8,9
On the other hand, quinazoline derivatives have been
shown to be important in organic synthesis as well as in
25 medicinal chemistry.10 They exhibit remarkable biological
N
Br
N
O
N
N
Br
O
P
N
N
N
BrOP
PyBrOP
PyBOP
BOP
PyAOP
45
Scheme 1. protocols for the synthesis of 4-functionalized
quinazolines
However most of these methods can only be applied to
the preparation of quinazolines with 4-position
heteroatoms (N, O, S) group. Relatively few examples
activities,
such
as
anticonvulsant,
antibacterial,
antidiabetic, and anticancer activities.11 Among this class
of molecules, the 4-functionalized quinazolines have been
demonstrated as effective fungicides, anti-inflammatory,
50 concerning preparation for 4-C substituted quinazolines
have been reported. To the best of our knowledge, there
are only three examples concerning introduction of C–
group at the 4-position of quinazoline core. Guiry
described Pd-enhanced coupling reactions for synthesis of
55 4-arylquinazolines starting from arylboronic acid and 4-
chloroquinazolines.17a Kitano reported that the 4-
alkynylquinazolines were synthesized by a Sonogashira
coupling reaction of 4-chloroquinazolines with terminal
alkynes.17b Recently, we investigated the feasibility of one-
60 pot palladium-catalyzed synthesis of 4-arylquinazolines
from the reaction of 4-quinazolinones and arylboronic acid
in the presence of TsCl.17c For 4-alkynylquinazolines could
serve as potent EGFR tyrosine kinase inhibitors,17b the
development of efficient routes for rapid access to 4-
65 alkynylquinazolines under mild conditions is of high
demand.
30 anti-cancer,
anti-microbial
and
anti-hypertensive
agents.12,13 Consequently, considerable progress in
synthetic methodology for 4-functionalized quinazoline
derivatives have been made during the past decade.14,15
Generally, two protocols have been developed for the
35 synthesis of 4-functionalized quinazolines starting from
3H-quinazolin-4-one(4-quinazolinone)
Chlorination of 4-quinazolinone with reagents such as
SOCl2, POCl3, and PCl5, and then substitution with
nucleophiles to afford the corresponding 4-functionalized
40 quinazolines
phosphonium salts (such as PyBroP, PyBOP, BroP, BOP),
then substitution with nucleophiles or coupling with
boronic acids to yield 4-functionalized quinazolines
(Scheme 1): (1)
13a-j,15b
.
(2) Activation of C-OH group with
16
.
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On basis of our recent work,17c we here reported that Pd-
Cu-cocatalyzed coupling of quinazoline-4-tosylates with
terminal alkynes for synthesis of 4-alkynylquinazolines
using NHC as ligand.
Gratifyingly, when 5 mol % NHC A was added, the yield
of 3a increased to 18%. Then, a series of NHCs ligand
were screened, and NHC-D turned out to be the best one
with the highest yield of 35%. Next, we examined the base
20 effect on the reaction (Table 1, entries 8-13) and found that
no better results were generated. Further screening of
solvents revealed that the yield could be improved to 55%
when the reaction was carried out in CH3CN (entry 19). No
better results were obtained when the reaction was
25 performed at 80 °C or 100 °C. Finally, the catalyst
screening results indicated that the output of the reaction
could be raised to 75% when Pd(PPh3)2Cl2 was used (entry
22). Further test indicated that added CuI as a co-catalyst
could improve the yield, and Pd(PPh3)2Cl2–CuI was the
5
Results and discussion
At the outset, 2-phenyl-quinazolin-4-tosylate 1a and
phenyl acetylene 2a were employed as the substrates for
reaction development. Firstly, the reaction was performed
in the presence of 1.5 eq. DABCO and 5 mol% Pd(OAc)2
10 in DCE at 60℃. Only trace amount of desired product 2-
phenyl-4-(phenylethynyl)quinazoline 3a was detected.
Table 1. Generation of 4-alkynylquinazolines via Pd-Cu-co-
catalyzed coupling reactions of quinazoline-4-tosylates with
terminal alkynes using NHC as a ligand
30 best combination ( entry 27, yield 89%). The result is
contrast to Buchwald, where in the presence of a copper
cocatalyst has a deleterious effect on the coupling
reaction.6g Control experiment showed that no reaction
occurred use CuI as the catalyst (Table 1, entry 28).
OTs
[M] 5 mol %/ L(NHC) 10 mol %
N
+
N
35
With this promising result in hands, we started to
explore the generality of this NHC-bimetal-co-catalyzed
reactions of quinazoline-4-tosylates with alkynes under the
optimized conditions highlighted above [5 mol%
Pd(PPh3)2Cl2 5 mol% CuI, 10 mol% NHC, 1.5eq.
Base, Solvent, N2,Temp
N
N
Bn
+
N
+
+
N
N
Br
N
N
N
Cl
Bn
40 DABCO, in CH3CN at 60 °C]. The results are summarized
in Table 2. To assess the impact of the structural and
functional motifs on the reaction of 1a, we tested a range
of alkynes 2. For all cases, compounds 1a reacted with 2
Cl
C
A
B
OH
Bn
N
Bn
+
N
+
Br
I
S
N
S
Bn
leading
to
the
corresponding
2-phenyl-4-
N
Cl
Bn
45 alkynylqunazolines 3 in good to excellent yields (3a-3h).
Both aryl and alkyl substituted acetylenes were
demonstrated as good compatible in the transformation.
Moreover, it was found that substrates with electron-
withdrawing groups on R3 were less reactive to some
50 extent than those with the electron-donating groups when
the R3 group is phenyl. For example, the reactions of
electron-withdrawing substituted substrates such as p-
chloro or m-fluoro phenylacetylene gave the corresponding
product 3b or 3c in 74% or 65% yield. While the reactions
55 of electron-donating substituted substrates such as p-
methoxyl, p-ethoxyl or p-ethylphenylacetylene afforded
the corresponding product in 92%, 92% or 75% yields. We
next examined the reactivity of quinazolinic tosylates 1
with different substituents on 2-position. As expected, the
60 corresponding products were obtained in good to excellent
yields when R1 is aryl group (3i-3o). The reactions only
gave moderate yields when R1 is alkyl group (3p).
Furthermore, when R1 is hydrogen, no desired product was
obtained (result is not list in the table), because the reactant
65 was decomposed to the corresponding quinazoline under
reaction conditions. It is noteworthy that substrates with
electron-donating groups on the R1 were more reactive to
some extent than those with electron-withdrawing groups
when the R1 group was phenyl. For example, the reaction
70 of 2-(p-methyl)phenyl quinazolin-4-tosylate or 2-
D
F
E
15
Entry
[M]
NHC
Base
Sovent
T
yield
(%)b
Trace
18
Trace
30
35
Trace
26
25
18
15
trace
3
(oC)
60
60
60
60
60
60
60
60
60
60
60
60
60
60
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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
-
DABCO DCE
DABCO DCE
DABCO DCE
DABCO DCE
DABCO DCE
DABCO DCE
DABCO DCE
Cs2CO3
K2CO3
K3PO4
Et3N
A
B
C
D
E
F
D
D
D
D
D
D
D
D
DCE
DCE
DCE
DCE
DCE
DCE
DBU
t-BuOK
DABCO THF
trace
35
Trace
DABCO Toluene 60
1,4-
Pd(OAc)2
D
DABCO
60
38
dioxane
17
18
19
20
21
22
23
24
25
26
27
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
Pd2(dba)3
PdCl2
D
D
D
D
D
D
D
D
D
D
DABCO DMF
DABCO H2O
60
60
60
80
32
Trace
55
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
DABCO CH3CN
50
100 30
60
60
60
60
60
75
65
30
65
82
Pd(OAc)2+CuI
Pd(PPh3)2Cl2
+CuI
D
DABCO CH3CN
60
60
89
-
28
CuI
D
DABCO CH3CN
a Isolated yield based on quinazoline-4-tosylate 1a.
benzo[1,3]dioxol-5-yl-quinazolin-4-tosylate
with
2
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phenylacetylene gave rise to the desired product 3m or 3n
in 78% or 83% yield, respectively. While for the reaction
of 2-(4-chlorophenyl)quinazolin-4-tosylate with 2a gave
the corresponding yield of 72%. Vinyl substituted alkynes
In conclusion, we have developed an efficient reaction for
synthesis of 4-alkynylquinazolines. The coupling reactions of
quinazoline-4-tosylates with terminal alkynes cocatalyzed by
Pd(PPh3)2Cl2 and CuI with NHC as a ligand, affording 4-
5
such as cyclohexenylacetylene was also studied, and gave 20 alkynylquinazolines in good to excellent yields. The
the product 3q in a yield of 76%. Finally, 6-chloro-
quinazolin-4-tosylate was also assessed, and the results
indicated that electron-withdrawing substituted on
quinazoline core would suppress the reaction, however
transformation proceeded under mild conditions with high
efficiency, which is attractive for further library construction.
Experimental Section
10 moderate to good yields were also obtained (3r, 3s).
General experimental procedure for synthesis of 3. A mixture
25 of 2-Aryl-p-methylbenzenesulfonatequinazoline 1 (0.20 mmol)
and Pd(PPh3)2Cl2 (5 mol %), NHC (D) (10 mol %), CuI (5
mol %), DABCO (0.3 mmol, 1.5 equiv) with alkyne 2 (0.3 mmol,
1.5 equiv) in CH3CN (2.0 mL) were added subsequently. The
mixture was stirred at 60 °C for 4 hours. After completion of the
30 reaction as indicated by TLC, the solvent was evaporated. The
residue was diluted with EtOAc (10 mL), washed with H2O (10
mL), dried over anhydrous MgSO4. Evaporation of the solvent
followed by purification on silica gel provided the corresponding
product 3.
Table 2. Generation of 4-Alkynylquinazolines 3 via Pd-Cu-co-
Catalyzed Coupling Reactions of Quinazoline-4-tosylates with
Terminal Alkynes Using NHC as A Ligand a
R3
OTs
Pd(PPh3)2Cl2 -CuI-NHC
R3
N
+
R2
N
R2
DABCO-CH3CN, N2,60
N
R1
N
R1
OMe
Cl
F
35
2-Phenyl-4-(phenylethynyl)quinazoline (3a). white solid, mp:
112-113 ; 1H NMR (400 MHz, CDCl3) δ 7.44-7.54 (m, 6H),
7.61 (t, J = 7.2 Hz, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.89 (t, J = 7.1
Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.64
(d, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 85.7, 97.8,
N
N
N
N
N
Ph
N
Ph
N
Ph
N
Ph
3a, 89%
3b, 74%
3c, 65%
3d, 92%
OC2H5
C2H5
40 121.4, 124.0, 126.5, 127.7, 128.6, 128.7, 129.1, 130.1, 130.7,
132.6, 134.2, 137.9, 151.0, 152.9, 160.9; HRMS calcd. for
C22H14N2(M+H)+ ,307.1235; Found 307.1264.
C4H9-n
2-Phenyl-4-((4-chlorophenyl)ethynyl)quinazoline (3b). White
solid, mp: 118-119 ; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J =
45 8.4 Hz, 2H), 7.50-7.55 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.68 (d,
J = 8.4 Hz, 2H), 7.89 (t, J = 7.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H),
8.32 (d, J = 8.2 Hz, 1H), 8.63 (d, J = 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) 86.5, 96.3, 119.8, 123.8, 126.3, 127.7, 128.6,
128.7, 129.1, 130.7, 133.8, 134.3, 136.4, 137.7, 151.0, 152.5,
50 160.9; HRMS calcd. for C22H13ClN2(M+H)+, 341.0846; Found
341.0858.
N
N
N
N
N
Ph
N
Ph
N
Ph
N
Ph
3e, 92%
3f, 75%
3g, 92%
3h, 89%
N
N
N
N
N
N
N
N
Me
OMe
OM
O
2-Phenyl-4-((3-fluorophenyl)ethynyl)quinazoline (3c). White
3i, 92%
3j, 89%
3k, 79%
O
3l, 95%
OMe
1
solid, mp: 123-124 ; H NMR (400 MHz, CDCl3) δ 7.20 (t, J =
8.0 Hz, 1H), 7.4-7.58 (m, 6H), 7.68 (t, J = 7.6 Hz, 1H), 7.94 (t, J
55 = 7.3 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H),
8.64 (d, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 86.2,
2
2
N
N
N
N
95.9, 117.5 (d, JCF = 21.2 Hz), 119.3 (d, JCF = 23.1 Hz), 123.1
3
4
N
N
N
N
(d, JCF = 9.4 Hz), 123.9, 126.3, 127.8, 128.5 (d, JCF = 3.0 Hz),
C3H7-n
Me
Cl
O
3
128.6, 128.7, 129.1, 130.4 (d, JCF =8.5Hz), 130.7, 134.3, 137.7,
O
3m, 78%
3n, 83%
3o, 72%
3p, 63%
60 151.1, 152.4, 160.9, 161.2 (d, 1JCF = 246.1 Hz); HRMS calcd. for
C22H13FN2(M+H)+, 325.1141; Found: 325.1140.
2-Phenyl-4-((4-methoxyphenyl)ethynyl)quinazoline
(3d).
1
Cl
White solid, mp: 178-179 ; H NMR (400 MHz, CDCl3) δ 3.88
(s, 3H), 6.97 (d, J = 7.6 Hz, 2H), 7.49-7.58 (m, 3H), 7.61-7.67
65 (m, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.88-7.93 (m, 1H), 8.09 (d, J =
8.4 Hz, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.64 (d, J = 6.8 Hz, 2H ) ;
13C NMR (100 MHz, CDCl3) δ 55.4, 85.1, 98.7, 113.3, 114.4,
123.9, 126.5, 127.5, 128.6, 128.7, 129.0, 130.6, 134.1, 134.4,
N
Cl
N
N
N
N
N
OCH3
OCH3
3q, 76%
3r, 58%
3s, 83%
aIsolated yields based on quinazoline-4-tosylate 1.
15 Conclusions
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137.9, 150.9, 153.2, 160.9, 161.1; HRMS calcd. for
C23H16N2O(M+H)+, 337.1341; Found 337.1335.
2-(Benzo[d][1,3]dioxol-5-yl)-4-(cyclopropylethynyl)quinazoline
1
(3k). White solid, mp: 125-126 ; H NMR (400 MHz, CDCl3) δ
2-Phenyl-4-((4-ethoxyphenyl)ethynyl)quinazoline (3e). Light
1.02-1.14 (m, 4H), 1.64-1.71 (m, 1H), 6.02 (s, 2H), 6.92 (d, J =
yellow solid, mp: 132-133 ; 1H NMR (400 MHz, CDCl3) δ 1.43 60 8.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H),
5
(t, J = 7.0 Hz, 3H), 4.06 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.50-
7.56 (m, 3H), 7.61 (t, J = 7.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H),
7.87 (t, J = 7.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.2
Hz, 1H), 8.64 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
7.97 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.19 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 0.5, 9.5, 72.9, 101.3, 103.9, 108.0, 108.6,
123.5, 123.6, 126.4, 126.9, 128.5, 132.2, 133.8, 148.0, 149.7,
150.6, 152.9, 160.0; HRMS calcd. for C20H14N2O2 (M+Na)+,
14.7, 63.7, 85.1, 98.9, 113.1, 114.8, 123.9, 126.5, 127.5, 128.6, 65 337.0953; Found 337.0976.
10 128.7, 129.0, 130.6, 134.1, 134.4, 138.0, 150.9, 153.2, 160.6,
160.9; HRMS calcd. for C24H18N2O (M+H)+, 351.1497; Found
351.1518.
2-(3,4-Dimethoxyphenyl)-4-(cyclopropylethynyl)quinazoline
1
(3l). White solid, mp: 128-129 ; H NMR (400 MHz, CDCl3) δ
1.04-1.08 (m, 4H), 1.64-1.71 (m, 1H), 3.95 (s, 3H), 4.06 (s, 3H),
2-Phenyl-4-((4-ethylphenyl)ethynyl)quinazoline (3f). White
6.98 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.81 (t, J = 7.6
solid, mp: 136-137 ; 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 70 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.1 Hz, 2H), 8.24
15 7.6 Hz, 3H), 2.73 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.51-7.56 (m,
3H), 7.64-7.78 (m, 3H), 7.91 (t, J = 7.2 Hz, 1H), 8.11 (d, J = 8.3
Hz, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.64 (d, J = 7.4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 15.3, 29.0, 85.3, 98.6, 118.5, 124.0,
126.6, 127.6, 128.3, 128.6, 128.7, 129.0, 130.7, 132.7, 134.2
20 137.8, 146.9, 150.9, 153.1, 160.9; HRMS calcd. for
C24H18N2(M+H)+, 335.1548; Found 335.1553.
(d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 0.2, 9.2, 55.5,
55.6, 72.7, 103.6, 110.4, 110.8, 121.8, 123.3, 126.1, 126.5, 128.2,
130.3, 133.5, 148.5, 150.3, 150.9, 152.6, 159.9; HRMS calcd. for
C21H18N2O2 (M+H)+, 331.1447; Found 331.1476.
75
2-(p-Tolyl)-4-(phenylethynyl)quinazoline (3m). White solid,
mp: 125-126 ; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 7.34
(d, J = 7.6 Hz, 2H), 7.45 (m, 3H), 7.61 (t, J = 7.4 Hz, 1H), 7.77
(d, J = 6.5 Hz, 2H), 7.88 (t, J = 7.3 Hz, 1H), 8.07 (d, J = 8.3 Hz,
1H), 8.36 (d, J = 8.1 Hz, 1H), 8.54 (d, J = 7.6 Hz, 2H); 13C NMR
2-Phenyl-4-(cyclopropylethynyl)quinazoline (3g). White
solid, mp: 108-109 ; 1H NMR (400 MHz, CDCl3) δ 1.01-1.15
(m, 4H), 1.68-1.70 (m, 1H), 7.45-7.60 (m, 4H), 7.85 (d, J = 7.5 80 (100 MHz, CDCl3) δ 21.6, 85.8, 97.7, 121.4, 123.9, 124.8, 126.4,
25 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.59-
8.66 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 0.7, 9.6, 73.1,
104.3, 124.0, 126.6, 127.4, 128.5, 128.7, 128.9, 130.5, 134.0,
137.9, 150.8, 153.3, 160.8; HRMS calcd. for C19H14N2 (M+Na)+,
293.1055; Found 293.1075.
127.4, 128.6, 128.7, 129.4, 130.1, 132.6, 134.2, 135.1, 140.9,
151.0, 152.8, 161.0; HRMS calcd. for C23H16N2 (M+H)+,
321.1392; Found 321.1394.
2-(Benzo[d][1,3]dioxol-5-yl)-4-(phenylethynyl)quinazoline
1
85 (3n). White solid, mp: 153-154 ; H NMR (400 MHz, CDCl3) δ
30
2-Phenyl-4-(butyl-ethynyl)quinazoline (3h). White solid, mp:
6.05 (s, 2H), 6.95 (d, J = 8.2 Hz, 1H), 7.43-7.46 (m, 3H), 7.60 (t,
J = 7.5 Hz, 1H), 7.77 (d, J = 6.0 Hz, 2H), 7.87 (t, J = 7.6 Hz, 1H),
8.03 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H),
8.35 (d, J = 8.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 85.7,
1
98-99 ; H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H),
1.44-1.53 (m, 2H), 1.64-1.70 (m, 2H), 2.55 (t, J = 7.2 Hz, 2H),
7.39-7.51 (m, 4H), 7.49 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.7 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.52 (d, J 90 97.6, 101.4, 108.3, 108.8, 121.4, 123.7, 126.4, 127.3, 128.6,
35 = 6.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 12.6, 18.5, 21.2,
29.2, 76.6, 99.7, 123.0, 125.5, 126.4, 127.5, 127.6, 127.8, 129.5,
133.0, 136.8, 149.8, 152.3, 159.7; HRMS calcd. for C20H18N2
(M+Na)+, 309.1348; Found 309.1368.
128.8, 130.1, 132.3, 132.6, 134.2, 148.2, 150.0, 151.0, 152.7,
160.3; HRMS calcd. for C23H14N2O2 (M+H)+, 351.1134; Found
351.1140.
2-(4-Chlorophenyl)-4-(phenylethynyl)quinazoline (3o). White
1
2-(4-Methoxyphenyl)-4-(cyclopropylethynyl)quinazoline (3i). 95 solid, mp: 145-146 ; H NMR (400 MHz, CDCl3) δ 7.46-7.51
1
40 White solid, mp: 112-113 ; H NMR (400 MHz, CDCl3) δ 0.90-
1.05 (m, 4H), 1.54-1.60 (m, 1H), 3.77 (s, 3H), 6.92 (d, J = 8.6 Hz,
2H), 7.43 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.89 (d, J =
8.3 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 8.6 Hz, 2H);
(m, 5H), 7.66 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.92 (t,
J = 7.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.0 Hz,
1H), 8.60 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
85.5, 98.1, 121.3, 123.9, 126.5, 127.8, 128.7, 128.8, 129.0, 130.1,
13C NMR (100 MHz, CDCl3) δ 0.9, 9.8, 55.6, 73.4, 104.2, 114.1, 100 130.2, 132.6, 134.4, 136.3, 136.9, 150.9, 152.9, 159.9; HRMS
45 123.9, 126.8, 127.2, 128.9, 130.5, 130.8, 134.2, 151.1, 153.4,
160.8, 162.1; HRMS calcd. for C20H16N2O (M+H)+, 301.1341;
Found 301.1334.
calcd. for C22H13ClN2 (M+H)+, 341.0846; Found 341.0858.
2-Propyl-4-(phenylethynyl)quinazoline (3p). White solid, mp:
1
91-92 ; H NMR (400 MHz, CDCl3) δ 1.06 (t, J = 7.3 Hz, 3H),
2-(p-Tolyl)-4-(cyclopropylethynyl)quinazoline (3j). White
1.93-2.03 (m, 2H), 3.11 (t, J = 7.8 Hz, 2H), 7.42-7.47 (m, 3H),
1
solid, mp: 97-98 ; H NMR (400 MHz, CDCl3) δ 0.98-1.14 (m, 105 7.64 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.89 (t, J = 7.6
50 4H), 1.62-1.68 (m, 1H), 2.42 (s, 3H), 7.31 (d, J = 7.3 Hz, 2H),
7.54 (t, J = 6.9 Hz, 1H), 7.82 (t, J = 6.5 Hz, 1H), 8.01 (d, J = 8.1
Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 14.0, 22.4, 41.9, 85.4, 97.9, 121.3,
123.4, 126.3, 127.3, 128.3, 128.6, 130.1, 132.5, 134.1, 150.5,
152.7, 167.4; HRMS calcd. for C19H16N2 (M+H)+, 273.1392;
Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.49 (d, J = 7.5 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 0.6, 9.5, 21.5, 73.1, 104.0, 123.8,
126.5, 127.1, 128.6, 128.7, 129.2, 133.9, 135.1, 140.7, 150.7, 110 Found 273.1391.
55 153.1, 160.7; HRMS calcd. for C20H16N2 (M+Na)+, 307.1211;
Found 307.1198.
2-(4-Methoxyphenyl)-4-(Cyclohex-1-
enylethynyl)quinazoline (3q). Yellow white solid, mp: 123-125℃
4
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DOI: 10.1039/C4OB00700J
; 1H NMR (400 MHz, CDCl3) δ 8.62 – 8.48 (m, 2H), 8.24 (d, J =
8.2 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.90 – 7.67 (m, 1H), 7.60 –
7.42 (m, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.65- 6.46 (m, 1H), 3.89
(s, 3H), 2.53-2.26 (m, 2H), 2.25 -2.23 (m, 2H),, 2.06-1.63 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 161.8, 160.6, 153.2, 150.9,
140.1, 133.9, 130.6, 130.3, 128.7, 126.9, 126.5, 123.6, 119.9,
113.8, 100.1, 83.6, 55.3, 28.8, 26.1, 22.1, 21.3. HRMS calcd. For
C23H20N2O (M+Na)+, 363.1473; Found 363.1478.
3
Using NHCs as
a
ligand in Sonogashira reaction (a) M.
Sreenivasulu, K. S. Kumar, P. R. Kumar, K. B. Chandrasekhar, M.
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65
70
5
2-Phenyl-4-(cyclopropylethynyl)-6-chloro-quinazoline (3r).
4
5
10 White solid, mp: 142-143 ; 1H NMR (400 MHz, CDCl3) δ 1.09-
1.11 (m, 4H), 1.68-1.73 (m, 1H), 7.49-7.51 (m, 3H), 7.77 (d, J =
8.9 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 8.17 (s, 1H), 8.57 (d, J =
7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 0.2, 9.3, 72.3, 104.6,
124.0, 124.9, 128.1, 128.2, 130.1, 130.3, 132.6, 134.4, 137.0,
15 148.8, 151.9, 160.5; HRMS calcd. for C19H13ClN2 (M+Na)+,
327.0665; Found 327.0678.
75
80
6
2-(4-Methoxyphenyl)-4-(cyclopropylethynyl)-6-chloro-
1
85
quinazoline (3s). White solid, mp: 119-120 ; H NMR (400
MHz, CDCl3) δ 1.04-1.15 (m, 4H), 1.68-1.75 (m, 1H), 3.88 (s,
20 3H), 7.01 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 9.1 Hz, 1H), 7.93 (d, J
= 8.7 Hz, 1H), 8.15 (s, 1H), 8.53 (d, J = 8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 0.4, 9.4, 55.1, 72.4, 104.4, 113.6, 123.9,
125.1, 129.8, 130.0, 130.1, 132.2, 134.5, 149.1, 152.0, 160.5,
161.7; HRMS calcd. for C20H15ClN2O (M+H)+, 335.0951; Found
25 335.0972.
90
7
8
95
Activated vinyl tosylates for Sonogashira reaction: (a) X. Fu, S.
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Acknowlledgements
100
105
110
115
Financial support from National Natural Science Foudation of
China (No. 21162012, 81261120413, and 21362014), Jiangxi
Provincial Department of Science and Technoloy (for Jiangxi`s
30 Key Laboratory of Green Chemistry, nos. 20122BAB203007 and
20132BAB213006), Jiangxi Educational Committee (GJJ10386),
and Foundation for Young People (Yang Qin) of Jiangxi Normal
University is gratefully acknowledged.
9
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yiyuanpeng@yahoo.com
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