One-pot synthesis of triazoloquinazolinones via copper- catalyzed tandem click and intramolecular C-H amidation

Article abstract of DOI:10.1002/adsc.201301013

A novel and highly efficient copper-catalyzed tandem synthesis of triazoloquinazolinones is explored. The synthetic strategy involves a sequential one-pot click reaction followed by aerobic intramolecular C-H amidation. Two distinct and important transfor

Full text of DOI:10.1002/adsc.201301013

FULL PAPERS
DOI: 10.1002/adsc.201301013
One-Pot Synthesis of Triazoloquinazolinones via Copper-
À
Catalyzed Tandem Click and Intramolecular C H Amidation
Manikandan Selvarajua and Chung-Ming Suna,*
a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan
E-mail: cmsun@mail.nctu.edu.tw
Received: November 14, 2013; Revised: January 21, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301013.
Abstract: A novel and highly efficient copper-cata- milder, rapid and ligand-free reaction conditions as
lyzed tandem synthesis of triazoloquinazolinones is well as a broader substrate scope are the salient fea-
explored. The synthetic strategy involves a sequential tures of this novel protocol.
one-pot click reaction followed by aerobic intramo-
À
À
lecular C H amidation. Two distinct and important Keywords: C H amidation; copper-catalyzed reac-
transformations were carried out in one-pot by em- tion; one-pot protocol; tandem reactions; triazolo-
ploying a single cost-effective copper catalyst. The quinazolinones
Introduction
stoichiometric copper catalysts and excess of trapping
agents.[3–5] In the current study, we have contemplated
The copper-catalyzed azide–alkyne cycloaddition and explored the notion that it is possible to couple
À
À
(CuAAC) reaction fusing organic azides and terminal the triazole formation with C H amidation for C N
alkynes is one of the most powerful synthetic tools to bond formation by intramolecular trapping of the nu-
[8]
À
synthesize triazoles by virtue of simple reaction condi- cleophilic amidic N H bond at ambient temperature
tions, broader substrate scope and exceptional atom (Scheme 1).
economy. This transformation has a wide range of ap-
Metal-catalyzed cross-coupling reactions are one of
plications in the fields of organic chemistry, medicinal the most powerful methods available for the construc-
chemistry, chemical biology and materials science.[1] It tion of carbon-carbon and carbon-heteroatom bonds.
À
is known that this copper-catalyzed cycloaddition pro- Most C H bond activations have been demonstrated
ceeds with the formation of a copper-triazole adduct on expensive palladium, rhodium and ruthenium com-
as a reactive intermediate which undergoes rapid pro- plexes.[9] Currently copper-catalyzed C H functionali-
À
tonation to furnish the triazole product.[2] Recently zation is receiving much attention because of the
this organo-copper adduct was employed as an inter- harmless and inexpensive copper catalysts. For in-
À
mediate for the in-situ functionalization of the triazole stance, many copper-catalyzed C H amidation/amina-
by trapping with an excess of electrophiles such as tion reactions were developed for the functionaliza-
ICl, alkyl, aryl and acyl halides.[3] Jeng et al. utilized tion of various heterocycles such as azoles, benzimida-
ICl as a trapping agent for the formation of 5-iodo- zoles and imidazoles.[10]
triazole as a suitable substrate for the various cross-
Triazoloquinazolinones are an important class of ni-
coupling reactions.[4] In addition, cuprated tri
AHCTUNGTRENNUNG
were caught successfully with excess allyl iodides by range of biological applications such as anticancer
Zhang et al.[5] Very recently, Ding and co-workers and antihypertensive agents. These tricyclic heterocy-
demonstrated the intramolecular interception of 5- cles show moderate affinity towards benzodiazepine
cuprated 1,2,3-triazoles with aryl iodides for the Ull- receptors, A1 and A2A adenosine receptors and they
mann coupling reaction.[6] Van der Eyckenꢀs group can act as ligands against GABAA receptors.[11–14] Ad-
also carried out a post-Ugi modification with the or- ditionally, the 1,2,3-triazole core is a prominent struc-
[7]
À
ganocopper intermediate for C N bond formation.
tural motif in medicinal chemistry and is frequently
Predominantly, these transformations involve the in- found in medicinally important compounds.[15] Given
sertion of the intermediate into the electrophilic the prevalence of this privileged core in biologically
carbon-halide bond of electrophiles which requires active molecules, it has received relatively less atten-
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Manikandan Selvaraju and Chung-Ming Sun
À
Scheme 1. Synthetic strategy for the formation of triazoloquinazolinones via one-pot CuAAC C H amidation.
tion so far and the direct synthetic methods available (25%) and CuCl (30%) (Table 1, entries 2 and 3). No
in the literature are very limited. The only common reaction was observed with CuACHTNUTGRNEUNG(OAc)2 and
approach available for the synthesis of 1,2,3-triazolo- CuSO4·5H2O in the presence of sodium ascorbate as
quinazolines is the reaction of azidobenzoic acid with an additive (Table 1, entries 4 and 5). Also, the reac-
substituted acetonitriles.[16] Prerequisite starting mate- tion did not proceed at all in the absence of either
rials, longer reaction times, harsh reaction conditions copper catalyst or base (Table 1, entries 6 and 7). It
are some of the setbacks associated with this method. was found that employing DIPEA as the base showed
Hence there is a demand for an elegant and alternate best transformation (entry 1, 80%) and a relatively
strategy to access this attractive scaffold. We demon- lower yield (52%) was obtained when Et3N was used
strate here that triazole synthesis can be coupled with as base (entry 8). The various inorganic bases such as
À
intramolecular C N bond formation for the rapid as- K2CO3, Cs2CO3 and NaOAc were less effective. From
sembly of biologically important triazoloquinazoli- the brief survey of various solvents, THF was chosen
nones. Notably, there is no example of constructing as the optimal solvent. Other solvents such as ace-
N-heterocycles via sequential click reaction with aero- tone, DCM and DMF gave the products in poor
À
bic oxidative C H amidation. This unprecedented yields under the same conditions (Table 1, entries 12,
transformation uses air rather than metal salts as the 13 and 15). However, when methanol was used as the
oxidant and proceeds under very mild conditions solvent, the reaction ceased with the non-cyclized
without the use of any ligands or additives.
product (4aa in Scheme 4) and only traces of the
fused product were observed (Table 1, entry 14).
From this observation, it is inferred that, in the
presence of a protic solvent, the triazole-copper
adduct undergoes rapid protonation rather than cycli-
Results and Discussion
To explore the idea of trapping the organo-copper in- zation. An attempt to utilize oxygen as an oxidant
termediate in the copper-catalyzed click reaction, we and an increase in temperature did not improve the
commenced our study with the reaction of various reaction yield. Only a trace amount of product was
benzamides and phenylacetylene. Benzamide and N- observed when the reaction was performed under a ni-
butyl-/N-arylbenzamides did not yield the desired trogen atmosphere and the large amount of uncy-
products in this transformation but furnished only the
ACHTUNGTRENcNGNU lized triazole product 4aa was isolated. (Table 1,
uncyclized triazoles. Interestingly N-methoxybenz- entry 16) This anticipated result confirmed that the
À
amide 1a (1 equiv.) with phenyl acetylene 2a oxygen in the air acts as a primary oxidant for this C
(1 equiv.)
and
diisoproylethylamine
(DIPEA) H amidation. Finally the most favorable conditions
(1.2 equiv.) in the presence of CuI (10 mol%) in THF were identified as 10 mol% CuI, 1.2 equivalents of
under air at room temperature for 1 h delivered the DIPEA as a base in THF at room temperature for
cyclized product 3aa in 80% yield (Table 1, entry 1). one hour.
Screening of the various copper sources revealed that
Subsequently, we probed into the scope and gener-
CuI is the most suitable catalyst for this transforma- ality of this domino process under the optimized con-
tion. Among the other copper sources tested, a rela- ditions. As shown in Scheme 2, various substituted 2-
tively lower yield was observed in the case of CuBr azido-N-methoxybenzamides could be converted into
2
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One-Pot Synthesis of Triazoloquinazolinones
Table 1. Optimization of the conditions for the reaction of 2-azido-N-methoxybenzamide1a and phenylacetylene 2a.[a]
Entry
Catalyst
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
CuI
CuBr
CuCl
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
–
THF
THF
THF
THF
EtOH/H2O
THF
THF
80
30
25
5[c]
0[c]
0
Cu
N
CuSO4·5H2O
–
CuI
0
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Et3N
THF
THF
THF
THF
acetone
DCM
MeOH
DMF
THF
52
35
22
20
41
36
5[d]
43
8[e]
K2CO3
Cs2CO3
NaOAc
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
10
11
12
13
14
15
16
CuI
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10 mol%), base (0.36 mmol), solvent (2 mL) under air at
room temperature.
Isolated yield.
Added sodium ascorbate as an additive.
Large amount of non-cyclized product (4aa) isolated.
Under nitrogen.
[b]
[c]
[d]
[e]
Scheme 2. Substrate scope for the reaction of 2-azido-N-methoxybenzamides 1 and phenylacetylene 2a.
their corresponding products in good to excellent sitions could react with phenylacetylene in good
yields. Results showed that 2-azido-N-methoxybenz- yields (Scheme 3, 3fa, 3ga and 3ha). The substitution
ACHTUNGTRENNUNGamides substituted with a methyl group at various po- at an ortho position retards the reaction with a longer
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Scheme 3. Substrate scope for the reaction of 2-azido-N-methoxybenzamide 1a and terminal alkynes 2.
reaction time (6 h) and diminished yield (57%) possi- position provided better yields and those with elec-
bly due to its steric hindrance (Scheme 3, 3ha). tron-withdrawing groups furnished the products in di-
Electron-withdrawing substrates such as those with minished yields. It is possible that the electron-with-
chloro, and fluoro substituents at the aromatic ring of drawing groups may weaken the stability of the inter-
2-azido-N-methoxybenzamides were all well tolerated mediate during the cyclization process. The reaction
with moderate yields which provided the possibility scope with respect to the alkyne coupling partner was
for further derivatization (Scheme 3, 3ca, 3da, 3ea). also investigated and it was found to be compatible
Interestingly substrates with electron-donating me- with a variety of different terminal alkynes, including
thoxy substitutents and naphthyl-substituted azido- alkyl-, aryl-, and heterocyclic alkynes. For some of the
ACHTUNGTRENNUNGamides furnished the desired products in good yields aromatic alkynes, we observed the homocoupling
(Scheme 2, 3ba, 3ia and 3ja). Thus, the electronic diyne as a side product with the very minimum yields
nature of the substituent on the aromatic ring exerted (1–5%) under these conditions.
a considerable influence on the reactivity. The sub-
Both electron-rich and electron-deficient terminal
strates containing electron-donating groups at various alkynes react smoothly to furnish the desired prod-
ucts. Many valuable functional groups such as methyl,
methoxy, chloro, bromo, and CF3 (Scheme 3, 3ab, 3ac,
3ad, 3ag, 3ah, 3ai) were well tolerated to provide
ample opportunity for further functionalization of the
products. Importantly terminal alkynes containing the
heterocyclic thiophene moiety smoothly reacted to
furnish the corresponding triazoloquinazolinones in
74% yields. It is worthy of mention that aliphatic
linear as well as cyclic terminal alkynes, e.g., pent-1-
yne, methyl propiolate and ethynylcyclohexane, could
also be converted into the target compound which
broadens the substrate scope (Scheme 3, 3ai, 3aj,
3ak).
Control experiments were performed to elucidate
Scheme 4. Control experiments for the formation of 3aa.
the reaction mechanism for the synthesis of quinazoli-
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One-Pot Synthesis of Triazoloquinazolinones
Scheme 5. Plausible mechanism for the formation of 3.
Figure 1. ORTEP diagram of compound 3aa.
none derivatives as shown in Scheme 4. When the re- Conclusions
action was carried out under a nitrogen atmosphere
(exclusion of air), the target product was formed only An unprecedented one-pot protocol for the synthesis
in a trace amount and the reaction furnished the non- of triazoloquinazolinones by the reaction of azidoa-
cyclized compound 4aa as the major product. This in- mides and terminal alkynes was successfully discov-
À
dicates that the subsequent intramolecular C H ami- ered. The overall domino process comprising the for-
dation requires oxygen as the oxidant. Furthermore, mation of a C N bond and two new rings involves an
À
the reaction of compound 4aa under the optimized initial intramolecular trapping of the organocopper
conditions did not progress to the final product which intermediate with amide and subsequent C H amida-
À
suggests that the transformation is concerted and ex- tion. This protocol features air as the oxidant, ligand-
cludes the two-step sequential pathway.[1f] Although free reaction conditions, impressive substrate scope
À
the mechanism of copper-catalyzed C N bond forma- for both coupling partners and excellent functional
tion has been proposed, the details remain uncertain group tolerance. The accessibility and generality of
where the possibility of both Cu2+ and Cu3+ inter- this process make it highly valuable and it will open
mediates was discussed.[17] Based on the aforemen- a new window to many other useful transformations
tioned observations and earlier literature evidence, in organic synthesis.
a putative mechanism for the one-pot synthesis of tri-
azoloquinazolinones by this novel copper-catalyzed
domino reaction is proposed in Scheme 5.[4–8]
Initially, the reactive C Cu intermediate (I) was
formed during the copper-catalyzed azide–alkyne cy-
Experimental Section
À
Typical Procedure for the Synthesis of 3aa
À
loaddition which then inserted into the amidic N H
To 2-azidobenzoic amide 1a (0.1 g, 0.52 mmol) in THF was
added CuI (0.019 g, 10 mol%), DIPEA (0.08 g, 0.62 mmol)
followed by phenylacetylene (0.053 g, 0.52 mmol) at room
temperature and the resulting reaction mixture was allowed
to stir at room temperature for one hour under the open air
bond in the presence of base to furnish the cyclized
intermediate (II). Upon reductive elimination, the in-
termediate (II) provided the desired product under an
aerobic atmosphere. An alternative pathway could be
the initial formation of a base-promoted copper-ben- atmosphere. After the completion of the reaction, the mix-
ture was filtered through a pad of celite and washed with di-
chloromethane. The filtrate was concentrated and the resi-
due was purified by silica-gel column chromatography (30%
ethyl acetate/hexane) to afford the desired product 3aa;
yield: 80%.
zamidato complex which would then catalyze the cy-
cloaddition followed by C N bond formation. How-
À
ever, the isolation of uncyclized triazole product
during the control experiments and the major forma-
tion of this product in a protic solvent (Table 1,
entry 14) exclude this possible pathway. Finally, the
structure of the newly synthesized triazoloquinazoli-
nones was unambigously ascertained by single crystal
X-ray diffraction studies[18] (Figure 1).
4-Methoxy-3-phenylACTHUNRGTENNUG[1,2,3]triazoloHCATUNGTRENN[UGN 1,5-a]quinazolin-
5(4H)-one (3aa): 1H NMR (300 MHz, CDCl3): d=8.50 (d,
J=8.2 Hz, 1H), 8.43 (d, J=7.9 Hz, 1H), 7.93 (t, J=7.95 Hz,
1H), 7.80 (dd, J=7.8, 1.2 Hz, 2H), 7.66 (t, J=7.7 Hz, 1H),
7.56–7.41 (m, 3H), 3.70 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=155.6, 135.4, 134.2, 130.4, 129.6, 129.2, 129.0,
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128.4, 128.2, 128.1, 116.5, 115.8, 64.2; MS (ESI): m/z=293
(MH+); HR-MS (ESI): m/z=293.1026 (M+H), calcd. for
C16H12N4O2 [MH+]: 293.1033; IR (KBr): n=2915, 2850,
1695, 1606, 1571 cmÀ1.
m/z=327.0645 (M+H), calcd. for C16H11ClN4O2 [MH+]:
327.0643; IR (KBr): n=2915, 2848, 1689, 1619, 1567 cmÀ1.
3-(4-Bromophenyl)-4-methoxyACHTNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3ah): H NMR (300 MHz, CDCl3): d=8.41
(d, J=8.4, 1H), 8.36 (dd, J=8.1, 1.4 Hz, 1H), 7.90 (td, J=
8.7, 1.4 Hz, 1H) 7.74–7.66 (m, 2H), 7.64–7.54 (m, 3H), 3.72
(s, 3H); 13C NMR (75 MHz, CDCl3): d=155.4, 135.5, 134.1,
131.4, 131.0, 130.5, 129.2, 128.21, 128.0, 122.7, 116.5, 115.7,
64.2; MS (ESI): m/z=371 (MH+); HR-MS (ESI): m/z=
371.0137 (M+H), calcd. for C16H11BrN4O2 [MH+]: 371.0138;
IR (KBr): n=3068, 2994, 1693, 1619,1571 cmÀ1.
4-Methoxy-3-(para-tolyl)ACTHNUTRGNENG[U 1,2,3]triazoloCAHTUNGTRENN[UGN 1,5-a]quinazolin-
5(4H)-one (3ab): 1H NMR (300 MHz, CDCl3): d=8.48 (d,
J=8.5 Hz, 1H), 8.41 (dd, J=8.0, 1.3 Hz, 1H), 7.92 (td, 8.7,
1.3 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.62 (td, J=8.1,
1.3 Hz, 1H), 7.29 (d, J=7.7 Hz, 2H), 3.70 (s, 3H), 2.44 (s,
3H); 13C NMR (75 MHz, CDCl3): d=155.6, 138.3, 135.4,
134.2, 130.5, 130.2, 129.4, 129.2, 128.9, 128.0, 126.1, 116.5,
115.7, 64.2, 21.3; MS (ESI): m/z=307 (MH+); HR-MS
(ESI): m/z=307.1187, calcd. for C17H14N4O2 [MH+]:
307.1190; IR (KBr): n=2915, 2850, 1695, 1617, 1598 cmÀ1.
4,7-Dimethoxy-3-phenylACTHNUTRGENNU[G 1,2,3]triazoloHCATUNGTRENN[UGN 1,5-a]quinazolin-
1
5(4H)-one (3ai): H NMR (300 MHz, CDCl3): d=8.37 (t, J=
7.8 Hz, 2H), 7.87 (t, J=7.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H),
4.17 (s, 3H), 2.93 (t, J=7.5 Hz, 2H), 1.86 (t, J=7.5 Hz, 2H),
1.04 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
155.6, 135.2, 134.3, 130.7, 129.7, 129.1,127.7, 116., 115.6, 64.5,
26.9, 23.1, 13.8; MS (ESI): m/z=259 (MH+); HR-MS (ESI):
m/z=259.1189 (MH+), calcd. for C13H14N4O2 [MH+]:
259.1190; IR (KBr): n=2962, 2937, 2871, 1693, 1619,
1577 cmÀ1.
4-Methoxy-3-(4-methoxyphenyl)ACTHNUGTRNENUG[1,2,3]triazoloHCATUNGTRENN[GUN 1,5-a]qui-
nazolin-5(4H)-one (3ac): 1H NMR (300 MHz, CDCl3): d=
8.42 (d, J=8.4 Hz, 1H), 8.36 (d, J=7.8 Hz, 1H), 7.89 (t, J=
8.4 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.61 (t, J=7.7 Hz,
1H), 6.99 (d, J=8.7 Hz, 2H), 3.87 (s, 3H), 3.69 (s, 3H);
13C NMR (75 MHz, CDCl3): d=159.7, 155.5, 135.3, 134.2,
130.9, 130.2, 130.0, 129.2, 128.0, 121.4, 116.5, 115.7, 113.6,
64.2, 55.3; MS (ESI): m/z=323 (MH+); HR-MS (ESI):
m/z=323.1145 (MH+), calcd. for C17H14N4O3 [MH+]:
323.1139; IR (KBr): n=2937, 2836, 1695, 1573 cmÀ1.
Methyl
4-methoxy-5-oxo-4,5-dihydroACTHNGUTREN[UNG 1,2,3]triazoloACHTUNGTRENNUNG[1,5-
a]quinazoline-3-carboxylate (3aj): 1H NMR (300 MHz,
CDCl3): d=8.49 (d, J=8.2 Hz, 1H), 8.42 (d, J=7.8 Hz, 1H),
7.96 (t, J=7.5 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 4.28 (s, 3H),
4.04 (s, 3H); 13C NMR (75 MHz, CDCl3): d=159.8, 156.1,
135.8, 135.6, 133.8, 129.2, 128.8, 122.5, 116.4, 116.1, 65.7,
52.6; MS (ESI): m/z=275 (MH+); HR-MS (ESI): m/z=
297.0594 (M+Na), calcd. for C12H10N4O4 [MNa+]: 297.0594;
IR (KBr): n=2911, 2850, 1733, 1697, 1558 cmÀ1.
4-Methoxy-3-[4-(trifluoromethyl)phenyl]
ACHTUNGTREN[NUGN 1,2,3]triazolo-
ACHTUNGTRENNUNG
CDCl3): d=8.41 (d, J=8.4 Hz, 1H), 8.37(d, J=8.1 Hz, 1H),
7.96–7.88 (m, 3H), 7.72 (d, J=7.5 Hz, 2H), 7.63 (t, J=
7.5 Hz, 1H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
155.4, 135.5, 134.0, 132.7, 130.9, 130.4, 130.0, 129.7, 129.2,
128.9, 128.3, 125.9, 125.1, 122.2, 116.4, 115.7, 64.2; MS (ESI):
m/z=361 (MH+); HR-MS (ESI): m/z=361.0910 (M+H),
calcd. for C17H11F3N4O2 [MH+]: 361.0907; IR (KBr): n=
2938, 2917, 1698, 1617, 1508 cmÀ1.
3-Cyclohexyl-4-methoxyACTHNUTRGENNU[G 1,2,3]triazoloHCATUNGTRENN[UGN 1,5-a]quinazolin-
5(4H)-one (3ak): 1H NMR (300 MHz, CDCl3): d=8.42 (d,
J=8.3 Hz, 1H), 8.38 (d, 8.3 Hz, 1H) 7.88 (t, J=7.7 Hz, 1H),
7.60 (t, J=7.7 Hz, 1H), 4.19 (s, 3H), 3.11–2.93 (m, 1H),
2.10–1.85 (m, 6H), 1.54–1.31 (m, 4H); 13C NMR (75 MHz,
CDCl3): d=155.8, 135.2, 134.7, 134.3, 129.5, 129.1, 127.7,
116.6, 115.6, 64.5, 34.8, 33.2, 26.6, 25.8; MS (ESI): m/z= 299
(MH+); HR-MS (ESI): m/z=299.1499 (M+H), calcd. for
C16H18N4O2 [MH+]: 299.1503; IR (KBr): n=2929, 2852,
1697, 1617, 1509 cmÀ1.
4-Methoxy-3-(thiophen-3-yl)ACTHNUGTRENNUG[1,2,3]triazoloACHTUNGTERN[NUGN 1,5-a]quinazo-
lin-5(4H)-one (3ae): 1H NMR (300 MHz, CDCl3): d=8.39
(d, J=8.7 Hz, 1H), 8.35 (dd, J=8.7, 1.5 Hz, 1H), 7.88 (td,
J=8.7, 1.5 Hz, 1H), 7.73–7.72 (m, 1H), 7.65–7.55 (m, 2H),
7.42–7.39 (m, 1H), 3.83 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=155.4, 135.4, 134.1, 129.8, 129.3, 129.1, 128.5,
128.0, 126.3, 125.4, 124.3, 116.4, 115.7, 64.5; MS (ESI): m/z=
299 (MH+); HR-MS (ESI): m/z=299.0601 (M+H), calcd.
for C14H10N4O2S [MH+]: 299.0597; IR (KBr): n=3106, 2938,
1695, 1606, 1508 cmÀ1.
4,7,8-Trimethoxy-3-phenylACTHNUTRGNENG[U 1,2,3]triazoloCAHTUNGTRENN[UGN 1,5-a]quinazolin-
1
5(4H)-one (3ba): H NMR (300 MHz, CDCl3): d=7.85–7.81
(m, 3H), 7.79 (s, 1H), 7.67 (s, 1H), 7.54–7.38 (m, 3H), 4.11
(s, 3H), 4.02 (s, 3H), 3.68 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=155.4, 149.4, 130.2, 130.2, 129.6, 129.1, 128.3,
128.1, 109.1, 108.4, 97.6, 64.2, 56.97, 56.5; MS (ESI): m/z=
353 (MH+); HR-MS (ESI): m/z=353.1247 (M+H), calcd.
for C18H16N4O4 [MH+]: 353.1244; IR (KBr): n=2913, 2848,
1677, 1621, 1517 cmÀ1.
3-(3-Chlorophenyl)-4-methoxyACTHNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3af): H NMR (300 MHz, CDCl3): d=8.45
(d, J=8.4, 1H), 8.39 (dd, J=8.1, 1.4 Hz), 7.92 (td, J=7.2,
1.4 Hz), 7.83- 7.80 (m, 1H), 7.75–7.60 (m, 2H), 7.47–7.37 (m,
2H), 3.74 (s, 1H); 13C NMR (75 MHz, CDCl3): d=155.5,
135.5, 134.1, 130.8, 130.6, 129.4, 129.2, 129.0, 128.4, 128.2,
127.6, 116.5, 115.8, 64.2; MS (ESI): m/z=327 (MH+); HR-
MS (ESI): m/z=327.0644 (M+H), calcd. for C16H11ClN4O2
[MH+]: 327.0643; IR (KBr): n=3070, 2938, 1697, 1604,
1571 cmÀ1.
8-Chloro-4-methoxy-3-phenylACHTNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3ca): H NMR (300 MHz, CDCl3): d=8.48
(d, J=2.1 Hz, 1H), 8.34 (d, J=8.6 Hz, 1H), 7.80 (dd, J=7.9,
2.1 Hz, 2H), 7.60 (dd, J=8.6, 2.o Hz, 1H), 7.56–7.39 (m,
3H), 3.69 (s, 3H); 13C NMR (75 MHz, CDCl3): d=155.0,
142.2, 134.8, 130.7, 129.6, 128.7, 128.6, 128.2, 115.9, 114.9;
MS (ESI): m/z=327 (MH+); HR-MS (ESI): m/z=327.0643
(M+H), calcd. for C16H11ClN4O2 [MH+]: 327.0643; IR
(KBr): n=3056, 2938, 1693, 1608, 1571, 1504 cmÀ1.
3-(4-Chlorophenyl)-4-methoxyACTHNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3ag): H NMR (300 MHz, CDCl3): d=8.47
(d, J=8.4, 1H), 8.41 (d, J=8.1 Hz, 1H), 7.94 (t, J=7.8 Hz,
1H), 7.77 (d, J=8.6 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.47
(d, J=8.6 Hz, 2H), 3.74 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=155.5, 146.5, 135.5, 134.5, 134.2, 133.7, 133.6,
130.8, 130.5, 129.3, 128.8, 128.4, 128.2, 127.5, 124.9, 116.5,
115.8, 64.4; MS (ESI): m/z=327 (MH+); HR-MS (ESI):
7-Chloro-4-methoxy-3-phenylACHTNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3da): H NMR (300 MHz, CDCl3): d=8.43
(d, J=8.8 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 7.88 (dd, J=8.8,
2.2 Hz, 1H), 7.79 (dd, J=7.9, 1.5 Hz, 2H), 7.56–7.43 (m,
6
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FULL PAPERS
One-Pot Synthesis of Triazoloquinazolinones
3H), 3.69 (s, 3H); 13C NMR (75 MHz, CDCl3): d=154.6,
135.6, 134.2, 132.6, 130.6, 130.2, 129.6, 128.8, 128.7, 128.6,
128.2, 117.8, 117.4, 64.3; MS (ESI): m/z=327 (MH+); HR-
MS (ESI): m/z=327.0644 (M+H), calcd. for C16H11ClN4O2
[MH+]: 327.0643; IR (KBr): n=3052, 2937, 1695, 1608 cmÀ1.
HR-MS (ESI): m/z=323.1141 (MH+), calcd. for C17H14N4O3
[MH+]: 323.1139; IR (KBr): n=3357, 2989, 2931, 1677, 1608,
1567 cmÀ1.
8-Fluoro-4-methoxy-3-phenylACTHNUGTRENNUG[1,2,3]triazoloACHTUNGTERN[NUGN 1,5-a]quinazo-
lin-5(4H)-one (3ea): 1H NMR (300 MHz, CDCl3): d=8.44
(dd, J=8.9, 5.5 Hz, 1H), 8.16 (dd, J=8.6, 2.4 Hz, 1H), 7.81
(dd, J=7.9, 1.5 Hz, 2H), 7.50–7.43 (m, 3H), 7.35 (td, 8.7,
2.4 Hz, 1H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
Acknowledgements
The authors thank the National Science Council of Taiwan
for the financial assistance and the authorities of the National
Chiao Tung University for providing the laboratory facilities.
This paper is particularly supported by “Aim for the Top
University Plan” of the National Chiao Tung University and
Ministry of Education, Taiwan.
168.4, 165.0, 155.0, 135.8 (d, JC,F =50.1 Hz), 132.4, (d, JC,F
=
41.7 Hz), 130.7, (d, JC,F =60.9 Hz) 129.6, 128.7, 128.5, 128.2,
116.4, (d, JC,F =116.4 Hz) 113.0, 103.2, (d, JC,F =109.8 Hz)
64.3; MS (ESI): m/z=311 (MH+); HR-MS (ESI): m/z=
311.0941 (M+H), calcd. for C16H11FN4O2 [MH+]: 311.0939;
IR (KBr): n=3056, 2938, 1681, 1619 cmÀ1.
4-Methoxy-7-methyl-3-phenylACHTNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
References
1
zolin-5(4H)-one (3fa): H NMR (300 MHz, CDCl3): d=8.16
(d, J=8.1 Hz, 2H), 7.76 (d, J=6.9 Hz, 2H), 7.50–7.31 (m,
4H), 3.64 (s, 3H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=155.5, 147.1, 134.0, 130.4, 130.2, 129.5, 129.2, 129.1, 128.9,
128.3, 128.1, 115.57, 113.97, 64.16, 22.16; MS (ESI): m/z=
307 (MH+); HR-MS (ESI): m/z=C17H14N4O2 (M+H),
calcd. for C31H33N6O4 [MH+]: 307.1190; IR (KBr): n=3056,
2937, 1695, 1625 cmÀ1.
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zolin-5(4H)-one (3ga): H NMR (300 MHz, CDCl3): d=8.30
(d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J=8.0, 1.4 Hz,
2H), 7.69 (dd, J=8.4, 1.4 Hz, 1H), 7.53–7.37 (m, 3H), 3.67
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4-Methoxy-8-methyl-3-phenylACHTNUTRGENN[UG 1,2,3]triazoloACHTUGNTREN[NUGN 1,5-a]quina-
1
zolin-5(4H)-one (3ha): H NMR (300 MHz, CDCl3): d=8.48
(d, J=8.5 Hz, 1H), 8.40 (dd, J=8.0, 1.4 Hz, 1H), 7.91 (td,
8.7, 1.4 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.62 (td, J=8.1,
1.4 Hz, 1H), 7.29–7.25 (m, 2H), 3.70 (s, 3H), 2.44 (s, 3H);
13C NMR (75 MHz, CDCl3): d=155.6, 138.3, 135.4, 134.2,
130.5, 130.2, 129.4, 129.2, 128.9, 128.0, 126.1, 116.56, 115.78,
64.2, 21.3; MS (ESI): m/z=307 (MH+); HR-MS (ESI):
m/z=307.1188 (M+H), calcd. for C17H14N4O2 [MH+]:
307.1190; IR (KBr): n=2921, 2852, 1693, 1608, 1508 cmÀ1.
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lin-5(4H)-one (3ia): H NMR (300 MHz, CDCl3): d=8.84 (s,
1H), 8.68 (s, 1H), 7.98 (dd, J=8.2, 2.4 Hz, 2H), 7.82 (d, J=
7.3 Hz, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H),
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One-Pot Synthesis of Triazoloquinazolinones via Copper-
9
À
Catalyzed Tandem Click and Intramolecular C H
Amidation
Adv. Synth. Catal. 2014, 356, 1 – 9
Manikandan Selvaraju, Chung-Ming Sun*
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These are not the final page numbers!