Synthesis of pyrazolo[1,5- c ]quinazoline derivatives through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1 H -pyrazoles with carbonyl compounds and aqueous ammonia

Article abstract of DOI:10.1021/jo4001756

A practical and efficient synthesis of pyrazolo[1,5-c]quinazolines and 5,6-dihydropyrazolo[1,5-c]quinazolines, including several spiro compounds, through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with carbonyl compounds and aqueous ammonia under air has been developed. Compared with literature methods toward pyrazolo[1,5-c]quinazoline derivatives, the synthetic method reported in this paper has the advantages of readily available and inexpensive starting materials and reagents, broad scope of substrates, and mild reaction conditions.

Full text of DOI:10.1021/jo4001756

Article
pubs.acs.org/joc
Synthesis of Pyrazolo[1,5‑c]quinazoline Derivatives through Copper-
Catalyzed Tandem Reaction of 5‑(2-Bromoaryl)‑1H‑pyrazoles with
Carbonyl Compounds and Aqueous Ammonia
Shenghai Guo,* Jiliang Wang, Xuesen Fan,* Xinying Zhang, and Dongqiang Guo
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, People’s Republic
of China
S
* Supporting Information
ABSTRACT: A practical and efficient synthesis of pyrazolo[1,5-c]quinazolines and 5,6-dihydropyrazolo[1,5-c]quinazolines,
including several spiro compounds, through copper-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with carbonyl
compounds and aqueous ammonia under air has been developed. Compared with literature methods toward pyrazolo[1,5-
c]quinazoline derivatives, the synthetic method reported in this paper has the advantages of readily available and inexpensive
starting materials and reagents, broad scope of substrates, and mild reaction conditions.
regard to pyrazole derivatives,8 we found that copper-catalyzed
INTRODUCTION
■
tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with carbon-
N-Fused heterocycles have attracted considerable interest since
yl compounds and aqueous ammonia provided a straightfor-
they are widely present in naturally occurring alkaloids with a
ward route to pyrazolo[1,5-c]quinazolines as well as 5,6-
broad range of biological activities.1 In addition, they are also
dihydropyrazolo[1,5-c]quinazolines. Herein, we would like to
valuable building blocks of potential drug molecules such as
disclose the details of our research work.
Belotecan hydrochloride (CKD-602), Sitagliptin phosphate
(MK-0431), and FK-453.2 Among those N-fused heterocycles,
RESULTS AND DISCUSSION
■
pyrazolo[1,5-c]quinazoline derivatives have been used as Gly/
NMDA receptor and excitatory amino acid antagonists,3 potent
Initially, we chose 5-(2-bromophenyl)-3-methyl-1H-pyrazole
(1a), benzaldehyde (2a), and aqueous ammonia as model
substrates to optimize the reaction conditions with regard to
copper catalysts, solvents, and reaction temperature. After some
trials, we were able to find that treatment of a mixture of 1a, 2a,
and aqueous ammonia with CuCl (10 mol %) in DMSO at 100
°C in a sealed tube under air for 24 h could afford 2-methyl-5-
phenylpyrazolo[1,5-c]quinazoline (3a) in 58% yield (Table 1,
entry 1). It is noted that this Cu(I)-catalyzed tandem reaction
could be realized in the absence of additional ligand and base.
In this process, aqueous ammonia served not only as a reactant
but also as a base to neutralize the in situ formed hydrobromic
acid. Subsequently, several copper catalysts, including copper(I)
and copper(II) salts, were screened by employing DMSO as the
solvent. Among them, CuI emerged as the most efficient
(compare entries 1−5). Then, the effect of solvent on this
tandem reaction was also investigated by using CuI as the
catalyst (compare entries 3 and 6−8), and a highest yield of
88% was obtained with DMF as the reaction medium (entry 6).
It was also observed that reaction temperatures higher or lower
phosphodiesterase 10A and Eg5 ATPase, and potential vaccinia
virus inhibitors.4 To date, the most frequently used synthetic
routes toward pyrazolo[1,5-c]quinazoline derivatives involve
the condensation of 5-(o-aminophenyl) pyrazoles with acyl
chlorides, aldehydes, or ketones under the promotion of strong
acid or base.3−5 While these synthetic methods are generally
efficient, they usually suffer from difficult to obtain starting
materials, harsh reaction conditions, or multistep processes.
Therefore, a more practical and general pathway toward
pyrazolo[1,5-c]quinazoline skeleton starting from simple and
easy to obtain starting materials is highly desirable.
Meanwhile, the development of novel copper-catalyzed
coupling reactions to construct complex organic molecules
has been one of the hottest research fields in organic synthesis.
This is mainly due to the fact that, compared with other
transition-metal catalysts, copper catalysts are efficient,
inexpensive, less toxic, and easy to handle. Recently, copper-
catalyzed coupling reactions have been extensively utilized in
carbon−carbon and carbon−heteroatom bond formation
reactions.6 Through this kind of reaction, various N-fused
heterocyclic compounds have been prepared.7 On the basis of
the above facts and as a continuation of our recent studies with
Received: January 25, 2013
© XXXX American Chemical Society
A
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Table 1. Optimization of Reaction Conditions for the
Synthesis of 3a
Table 2. Scope of the Synthesis of Pyrazolo[1,5-
c]quinazolines (3)
a
a
b
b
entry
catalyst
CuCl
solvent
T (°C)
yield (%)
entry
R1
R2
R3
product yield (%)
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
iPrOH
toluene
DMF
100
100
100
100
100
100
100
100
120
80
58
65
84
81
75
88
27
0
1
2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
3a
3b
3c
3d
3e
3f
88
80
61
65
75
73
40
60
63
64
58
71
54
35
40
82
75
72
65
57
79
73
81
82
48
78
CuBr
CuI
4-CH3C6H4
4-FC6H4
3
3
4
Cu(OAc)2
CuCl2
CuI
4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-CF3C6H4
3,4-(CH3O)2C6H3
1-naphthyl
4-pyridyl
5
5
6
6
7
CuI
7
3g
3h
3i
8
CuI
8
9
CuI
70
47
61
9
10
CuI
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
c
11
CuI
DMF
100
3k
3l
a
2-thienyl
Unless otherwise noted, the reactions were run with 0.4 mmol of 1a,
0.48 mmol of 2a, 0.04 mmol of catalyst, and 0.4 mL of 26% aqueous
ammonia in 1.5 mL of solvent in a sealed tube under air for 24 h.
Isolated yield. CH3COONH4 (6 mmol) was used to replace aqueous
styryl
3m
3n
3o
3p
3q
3r
n-propyl
b
c
c
H
ammonia.
Ph
Ph
4-CH3C6H4
4-ClC6H4
1-naphthyl
n-propyl
Ph
Ph
Ph
3s
3t
than 100 °C resulted in decreased yields of 3a (entries 9 and
10). When ammonium acetate was used to replace aqueous
ammonia as the source of ammonia, lower yield of 3a was
observed (entry 11).
Ph
4-ClC6H4
3u
3v
3w
3x
3y
3z
4-CH3C6H4
Ph
Ph
Ph
Ph
Ph
Cl
Ph
With the optimized reaction conditions (Table 1, entry 6) in
hand, the scope and generality of this copper-catalyzed tandem
reaction leading to pyrazolo[1,5-c]quinazolines was studied.
First, it was observed that while aryl-, heteroaryl-, alkenyl-, and
alkyl-substituted aldehydes were all compatible with the
reaction conditions to provide the desired products in
moderate to good yields, aromatic aldehydes generally gave
the corresponding products in yields higher than those of
aliphatic aldehydes (Table 2, entries 14, 15, 20, and 25). It was
also found that aryl-substituted aldehydes with various
substituents on the aryl ring underwent this tandem reaction
smoothly, and various functional groups, from the electron-rich
methoxy to the electron-deficient trifluoromethyl, were well
tolerated with the reaction conditions. With 1-naphthaldehyde
and heteroaryl aldehydes, the corresponding products 3j−3l
were obtained in 58−71% yields (entries 10−12). Moreover,
the reaction of cinnamaldehyde with 1a and aqueous ammonia
proceeded smoothly to give 3m in 54% yield (entry 13). The
effect of different R1 and R2 groups in 5-(2-bromoaryl)-1H-
pyrazoles (1) on this reaction was also studied. It turned out
that the electronic effect and steric hindrance of R1 and R2 did
not show obvious effect on the output of the reactions.
To elucidate the mechanism of the copper-catalyzed tandem
reaction, several control experiments were carried out. First, we
found that, although copper-catalyzed direct amination of aryl
halides with aqueous ammonia has been previously reported,9
treatment of 1a with aqueous ammonia in the presence of CuI
(10 mol %) at 100 °C for 24 h resulted in a complex mixture,
and the expected 5-(2-aminophenyl)-3-methyl-1H-pyrazole (4)
was not observed by LCMS analysis (Scheme 1). This result
might rule out the possibility of compound 4 as an intermediate
for the formation of 3a.
Cl
4-CH3C6H4
n-propyl
Ph
Cl
CH3O
a
The reactions were performed with 1 (0.4 mmol), 2 (0.48 mmol),
CuI (0.04 mmol), 26% aqueous ammonia (0.4 mL), and DMF (1.5
mL) at 100 °C in a sealed tube under air for 24 h. Isolated yield.
b
c
(CHO)n (2.0 equiv) was used.
Scheme 1. Attempted Amination of 1a with Aqueous
Ammonia
Second, it was observed that treating a mixture of 1a, 2a, and
aqueous ammonia with CuI at 100 °C for 12 h under nitrogen
atmosphere could afford 2-methyl-5-phenyl-5,6-dihydro-
pyrazolo[1,5-c]quinazoline (5a) in a yield of 77%. Subse-
quently, stirring the solution of 5a in DMF in the presence of
CuI (10 mol %) at 100 °C under air for 5 h could afford 3a in
96% yield (Scheme 2). These results suggested that 5a should
be a key intermediate of the above-described tandem process
leading to 3a.
Based on the above observations, a plausible mechanism for
the formation of 3a is illustrated in Scheme 3. Initially,
condensation of benzaldehyde (2a) with aqueous ammonia
affords phenylmethanimine (I). N-Arylation of I with 5-(2-
bromophenyl)-3-methyl-1H-pyrazole (1a) under the catalysis
B
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Scheme 2. Formation of 5a under Nitrogen and Its Transformation into 3a under Air
Scheme 3. Plausible Mechanism for the Formation of 3a
of CuI10 gives rise to intermediate II. Intramolecular
nucleophilic cyclization of II affords the key intermediate 5a.
Subsequent oxidative aromatization of 5a by air in the presence
of CuI gives 3a as the final product.
atmosphere is required in Fu’s protocol, while our procedure
is accomplished under air.
To further simplify the operation, we have tried a four-
component protocol for the synthesis of pyrazolo[1,5-c]-
quinazoline derivatives by using 1-(2-bromophenyl)-1,3-diones
8, hydrazine hydrate, carbonyl compounds, and aqueous
ammonia as the starting materials. Thus, 1-(2-bromophenyl)-
butane-1,3-dione (8a) was treated with hydrazine hydrate (1.1
equiv) in DMF at room temperature for 2 h. Then,
benzaldehyde (1.5 equiv), CuI (10 mol %), and aqueous
ammonia were added. The mixture was then stirred at 100 °C
for 24 h. To our delight, 3a could be isolated from the resulting
mixture in a total yield of 74% (Scheme 4).
The substrate scope of the above-described one-pot, two-
step, four-component reaction was then studied. It showed that
different combinations of 1-(2-bromophenyl)-1,3-diones with
hydrazine hydrate, carbonyl compounds, and aqueous ammonia
were proved to be suitable for this tandem process to provide
the corresponding pyrazolo[1,5-c]quinazoline derivatives in
reasonably good yields (Table 4, entries 1−6).
Having established an efficient protocol for the preparation
of pyrazolo[1,5-c]quinazolines via the tandem reaction of 5-(2-
bromoaryl)-1H-pyrazoles with aldehydes and aqueous ammo-
nia, we were then interested in whether this protocol was also
compatible with ketones as the carbonyl component. Thus, 1a
(0.4 mmol) was treated with acetone (0.8 mmol) and aqueous
ammonia under the optimized conditions for the preparation of
3 (Table 1, entry 6). We were pleased to find that the
envisioned tandem reaction proceeded smoothly with acetone
to generate the desired 2,5,5-trimethyl-5,6-dihydropyrazolo-
[1,5-c]quinazoline (7a) in 44% yield. Furthermore, increasing
the amount of acetone from 2 to 4 equiv could improve the
yield of 7a to 54% (Table 3, entry 1). Interestingly, with
cyclopentanone (2 equiv) as the carbonyl component, 2′-
methyl-6′H-spiro[cyclopentane-1,5′-pyrazolo[1,5-c]-
quinazoline] (7d) could be obtained in a yield of 51% (Table 3,
entry 4). Increasing the amount of cyclopentanone from 2 to 4
equiv did not improve the yield. Based on the above results, the
scope of the reaction leading to 5,6-dihydropyrazolo[1,5-
c]quinazolines 7 was explored by using 5-(2-bromoaryl)-1H-
pyrazoles 1 (0.4 mmol), aqueous ammonia (0.4 mL), and
acyclic ketones (1.6 mmol) or cyclic ketones (0.8 mmol) as
reactants and CuI (0.04 mmol) as catalyst in DMF under air
atmosphere (Table 3). It was found that various aliphatic
ketones, including acyclic and cyclic ketones, were suitable
substrates for this reaction and afforded the corresponding
products in modest to good yields. Moreover, acetophenone,
an aryl-substituted ketone, was also tried for this copper-
catalyzed tandem reaction, but it failed to provide the desired
product.
CONCLUSION
■
In summary, we have developed a facile methodology for the
synthesis of pyrazolo[1,5-c]quinazolines or 5,6-dihydro-
pyrazolo[1,5-c]quinazolines via copper-catalyzed tandem re-
action of 5-(2-bromoaryl)-1H-pyrazoles with carbonyl com-
pounds and aqueous ammonia under air atmosphere.
Interestingly, with cyclic ketones, the corresponding spiro-5,6-
dihydropyrazolo[1,5-c]quinazolines were successfully synthe-
sized in modest yields. Moreover, we found that the tandem
reaction could also be carried out in a one-pot, four-component
manner by starting with 1-(2-bromophenyl)-1,3-diones,
hydrazine hydrate, carbonyl compounds, and aqueous
ammonia. Compared with literature procedures, advantages of
the present protocol include readily available starting materials,
diversity of products, good functional group tolerance, and
simple operation process. Further application of this catalytic
system to the synthesis of other N-fused heterocycles is
currently underway in our laboratory.
It is noted that, during our studies on this work, Fu and co-
workers described an efficient copper-catalyzed one-pot, two-
step synthesis of pyrazolo[1,5-c]quinazolines starting from 1-
(2-halophenyl)-3-alkylprop-2-yn-1-ones, hydrazine, and ami-
dines under the promotion of Cs2CO3.11 Compared with Fu’s
synthesis of pyrazolo[1,5-c]quinazolines, our method has the
following notable features. First, both pyrazolo[1,5-c]-
quinazolines and 5,6-dihydropyrazolo[1,5-c]quinazolines, in-
cluding the synthetically attractive spiro scaffolds, can be
prepared with our method, while Fu’s method is limited to the
preparation of pyrazolo[1,5-c]quinazolines. Second, inert
EXPERIMENTAL SECTION
■
General Methods. Unless noted, all commercial reagents and
solvents were used without further purification. 1-(2-Bromoaryl)-1,3-
diones 8 were prepared according to the published methods.12 5-(2-
Bromoaryl)-1H-pyrazoles 1 were prepared though the condensation of
C
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a
Table 3. Synthesis of 5,6-Dihydropyrazolo[1,5-c]quinazolines 7
a
The reactions were carried out with 1 (0.4 mmol), acyclic ketone (1.6 mmol) or cyclic ketone (0.8 mmol), CuI (0.04 mmol), 26% aqueous
b
ammonia (0.4 mL), and DMF (1.5 mL) at 100 °C in a sealed tube under air for the indicated time. Isolated yield.
Scheme 4. One-Pot, Four-Component Reaction Leading to 3a
1-(2-bromoaryl)-1,3-diones 8 with hydrazine hydrate according to the
General Procedure for the Preparation of Pyrazolo[1,5-
c]quinazolines 3. To a tube containing 5-(2-bromoaryl)-1H-pyrazole
1 (0.4 mmol), aldehyde 2 (0.48 mmol), and CuI (0.04 mmol) in DMF
(1.5 mL) was added 26% aqueous ammonia (0.4 mL). Then, the tube
was sealed, and the mixture was stirred at 100 °C under air atmosphere
for 12 h. After being cooled to room temperature, the tube was open
to air for 1 min and then sealed again. Upon being stirred at 100 °C for
another 12 h, the reaction was quenched with NH4Cl solution and
extracted with ethyl acetate two times. The combined organic layer
literature procedures.13 Melting points were recorded with a micro
1
melting point apparatus and uncorrected. H and 13C NMR spectra
were recorded at 400 and 100 MHz, respectively. High-resolution
mass spectra (HRMS) were obtained by using a MicrOTOF mass
spectrometer. All reactions were monitored by thin-layer chromatog-
raphy (TLC) using silica gel plates (silica gel 60 F254 0.25 mm), and
components were visualized by observation under UV light (254 and
365 nm).
D
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a
Table 4. One-Pot, Four-Component Synthesis of Pyrazolo[1,5-c]quinazoline Derivatives
a
Reaction conditions: 8 (0.5 mmol), hydrazine hydrate (0.55 mmol), DMF (2 mL), 2 h, room temperature for R1 = Me; 80 °C for R1 = Ph, and then
b
CuI (0.05 mmol), aqueous ammonia (0.5 mL), aldehyde (0.75 mmol) or ketone (1.0 mmol), 100 °C, air, 24 h for aldehyde, 5 h for ketone. Isolated
yield.
was washed with H2O and brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum, and the crude
product was purified by chromatography on silica gel to afford the
desired pyrazolo[1,5-c]quinazoline 3.
(CDCl3, 100 MHz) δ 14.3, 98.3, 115.2 (d, J = 22.1 Hz, 2C), 119.3,
122.9, 127.4, 128.5, 129.0 (d, J = 3.1 Hz, 1C), 129.6, 132.7 (d, J = 8.3
Hz, 2C), 139.9, 141.4. 146.3, 153.5, 164.4 (d, J = 250.0 Hz, 1C);
HRMS (ESI) calcd for C17H13FN3 [M + H]+ 278.1088, found
278.1108.
2-Methyl-5-phenylpyrazolo[1,5-c]quinazoline (3a): Petroleum
ether/ethyl acetate (8:1) as eluent; white solid (91 mg, 88%), mp 68−
5-(4-Bromophenyl)-2-methylpyrazolo[1,5-c]quinazoline
1
(3d): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (88
70 °C; H NMR (CDCl3, 400 MHz) δ 2.55 (s, 3H), 6.83 (s, 1H),
1
7.54−7.65 (m, 5H), 7.96−8.00 (m, 2H), 8.39 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 14.3, 98.2, 119.3, 122.9, 127.3, 128.2, 128.5,
129.5, 130.3, 130.9, 132.9, 140.0, 141.3, 147.5, 153.4; HRMS (ESI)
calcd for C17H14N3 [M + H]+ 260.1182, found 260.1166.
mg, 65%), mp 176−178 °C; H NMR (CDCl3, 400 MHz) δ 2.54 (s,
3H), 6.82 (s, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H),
7.69 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 8.33 (d, J = 8.4 Hz,
2H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 98.4, 119.4, 123.0, 125.6,
127.6, 128.6, 129.7, 131.4, 131.8, 132.0, 139.8, 141.4, 146.3, 153.6;
HRMS (ESI) calcd for C17H13BrN3 [M + H]+ 338.0287, found
338.0315.
2-Methyl-5-p-tolylpyrazolo[1,5-c]quinazoline (3b): Petroleum
ether/ethyl acetate (8:1) as eluent; white solid (87 mg, 80%), mp 76−
78 °C; 1H NMR (CDCl3, 400 MHz) δ 2.46 (s, 3H), 2.55 (s, 3H), 6.81
(s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.59−7.64
(m, 1H), 7.96 (t, J = 8.0 Hz, 2H), 8.31 (d, J = 7.6 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 14.3, 21.6, 98.1, 119.3, 122.9, 127.1, 128.5,
128.9, 129.5, 130.1, 130.3, 140.1, 141.2, 141.3, 147.6, 153.3; HRMS
(ESI) calcd for C18H16N3 [M + H]+ 274.1339, found 274.1326.
5-(4-Fluorophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3c):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (68 mg,
61%), mp 119−121 °C; 1H NMR (CDCl3, 400 MHz) δ 2.55 (s, 3H),
6.84 (s, 1H), 7.24 (t, J = 8.4 Hz, 2H), 7.52−7.56 (m, 1H), 7.61−7.65
(m, 1H), 7.96−7.98 (m, 2H), 8.48 (t, J = 6.8 Hz, 2H); 13C NMR
5-(4-Chlorophenyl)-2-methylpyrazolo[1,5-c]quinazoline
(3e): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (88
1
mg, 75%), mp 174−176 °C; H NMR (CDCl3, 400 MHz) δ 2.55 (s,
3H), 6.83 (s, 1H), 7.52−7.56 (m, 3H), 7.63 (t, J = 7.6 Hz, 1H), 7.96
(d, J = 8.0 Hz, 2H), 8.41 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 14.3, 98.3, 119.3, 122.9, 127.5, 128.4, 128.6, 129.6, 131.3,
131.8, 137.0, 139.9, 141.4, 146.2, 153.5; HRMS (ESI) calcd for
C17H13ClN3 [M + H]+ 294.0793, found 294.0819.
5-(3-Chlorophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3f):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (86 mg,
E
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73%), mp 140−142 °C; 1H NMR (CDCl3, 400 MHz) δ 2.54 (s, 3H),
6.79 (s, 1H), 7.46−7.54 (m, 3H), 7.59−7.63 (m, 1H), 7.92−7.96 (m,
2H), 8.34−8.35 (m, 1H), 8.43 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 14.3, 98.4, 119.3, 122.9, 127.6, 128.58, 128.62, 129.4, 129.7, 130.4,
130.9, 134.1, 134.5, 139.7, 141.3, 145.8, 153.6; HRMS (ESI) calcd for
C17H13ClN3 [M + H]+ 294.0793, found 294.0811.
2-Methyl-5-propylpyrazolo[1,5-c]quinazoline (3n): Petroleum
ether/ethyl acetate (5:1) as eluent; white solid (32 mg, 35%), mp 84−
86 °C; 1H NMR (CDCl3, 400 MHz) δ 1.11 (t, J = 7.2 Hz, 3H), 1.98−
2.08 (m, 2H), 2.54 (s, 3H), 3.30 (t, J = 8.0 Hz, 2H), 6.74 (s, 1H), 7.48
(t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),
7.92 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.0, 14.3,
19.7, 34.7, 98.2, 119.3, 123.0, 126.8, 127.9, 129.4, 139.7, 140.1, 151.1,
153.1; HRMS (ESI) calcd for C14H16N3 [M + H]+ 226.1339, found
226.1334.
5-(2-Chlorophenyl)-2-methylpyrazolo[1,5-c]quinazoline
(3g): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (47
1
mg, 40%), mp 139−141 °C; H NMR (CDCl3, 400 MHz) δ 2.49 (s,
2-Methylpyrazolo[1,5-c]quinazoline (3o): Petroleum ether/
ethyl acetate (5:1) as eluent; white solid (29 mg, 40%), mp 71−73
°C; 1H NMR (CDCl3, 400 MHz) δ 2.55 (s,3H), 6.77 (s, 1H), 7.57 (t,
J = 8.0 Hz, 1H), 7.62−7.66 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.98 (d,
J = 7.6 Hz, 1H), 9.01 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.1,
98.2, 119.8, 123.2, 127.9, 128.5, 129.6, 139.0, 139.5, 139.7, 154.4;
HRMS (ESI) calcd for C11H10N3 [M + H]+ 184.0869, found 184.0858.
2,5-Diphenylpyrazolo[1,5-c]quinazoline (3p) (ref 11): Petro-
leum ether/ethyl acetate (5:1) as eluent; white solid (105 mg, 82%),
mp 107−109 °C; 1H NMR (CDCl3, 400 MHz) δ 7.32 (s, 1H), 7.40−
7.50 (m, 3H), 7.54−7.67 (m, 5H), 8.01−8.06 (m, 4H), 8.53−8.55 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 95.2, 119.5, 123.0, 126.8, 127.5,
128.1, 128.7, 128.8, 129.1, 129.8, 130.6, 131.0, 132.4, 132.7, 140.0,
141.8, 147.5, 154.7; MS (ESI) m/z 322.4 [M + H]+.
2-Phenyl-5-p-tolylpyrazolo[1,5-c]quinazoline (3q) (ref 11):
Petroleum ether/ethyl acetate (5:1) as eluent; white solid (101 mg,
75%), mp 132−134 °C; 1H NMR (CDCl3, 400 MHz) δ 2.51 (s, 3H),
7.29 (s, 1H), 7.41−7.43 (m, 3H), 7.46−7.54 (m, 3H), 7.63 (t, J = 8.0
Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 7.2 Hz, 2H), 8.49 (d, J
= 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.7, 95.1, 119.4,
122.9, 126.8, 127.3, 128.6, 128.75, 128.82, 129.0, 129.7, 129.9, 130.6,
132.5, 140.1, 141.3, 141.8, 147.5, 154.5; MS (ESI) m/z 336.4 [M +
H]+.
3H), 6.84 (s, 1H), 7.45−7.52 (m, 2H), 7.55−7.61 (m, 2H), 7.64−7.68
(m, 2H), 8.01 (t, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ
14.5, 98.7, 119.7, 123.2, 127.1, 127.9, 128.7, 129.7, 130.0, 130.8, 131.3,
133.1, 133.6, 139.7, 140.4, 146.5, 154.1; HRMS (ESI) calcd for
C17H13ClN3 [M + H]+ 294.0793, found 294.0783.
2-Methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-c]-
quinazoline (3h). Petroleum ether/ethyl acetate (8:1) as eluent;
1
white solid (79 mg, 60%), mp 104−106 °C; H NMR (CDCl3, 400
MHz) δ 2.55 (s, 3H), 6.83 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.62−7.66
(m, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 8.54 (d, J
= 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 98.4, 119.4,
123.0, 123.9 (q, J = 270.5 Hz, CF3), 125.1 (q, J = 3.8 Hz, 2C), 127.8,
128.7, 129.7, 130.8, 132.4 (q, J = 32.0 Hz, 1C), 136.2, 139.7, 141.3,
145.9, 153.7; HRMS (ESI) calcd for C18H13F3N3 [M + H]+ 328.1056,
found 328.1086.
5-(3,4-Dimethoxyphenyl)-2-methylpyrazolo[1,5-c]-
quinazoline (3i): Petroleum ether/ethyl acetate (5:1) as eluent; white
solid (80 mg, 63%), mp 106−107 °C; 1H NMR (CDCl3, 400 MHz) δ
2.54 (s, 3H), 3.97 (s, 3H), 4.01 (s, 3H), 6.81 (s, 1H), 7.03 (d, J = 8.8
Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.94−7.97
(m, 2H), 8.02 (d, J = 1.6 Hz, 1H), 8.17 (dd, J = 2.0, 8.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.4, 56.0, 56.1, 98.2, 110.4, 113.4, 119.2,
122.9, 124.2, 125.3, 127.1, 128.4, 129.6, 140.0, 141.5, 147.0, 148.5,
151.4, 153.3; HRMS (ESI) calcd for C19H18N3O2 [M + H]+ 320.1394,
found 320.1416.
2-Methyl-5-(naphthalen-1-yl)pyrazolo[1,5-c]quinazoline (3j):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (79 mg,
64%), mp 163−165 °C; 1H NMR (CDCl3, 400 MHz) δ 2.44 (s, 3H),
6.88 (s, 1H), 7.41−7.45 (m, 1H), 7.50−7.54 (m, 1H), 7.59−7.73 (m,
4H), 7.94−7.96 (m, 2H), 8.06 (t, J = 8.0 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 14.4, 98.6, 119.6, 123.1, 125.1, 125.3, 126.2, 126.8, 127.7,
128.1, 128.5, 128.7, 129.7, 130.7, 131.3, 133.8, 139.9, 140.8, 148.0,
153.9 (one 13C signal was not observed); HRMS (ESI) calcd for
C21H16N3 [M + H]+ 310.1339, found 310.1330.
2-Methyl-5-(pyridin-4-yl)pyrazolo[1,5-c]quinazoline (3k): Pe-
troleum ether/ethyl acetate (5:1) as eluent; white solid (60 mg, 58%),
mp 149−150 °C; 1H NMR (CDCl3, 400 MHz) δ 2.56 (s, 3H), 6.87 (s,
1H), 7.59 (t, J = 7.6 Hz, 1H), 7.64−7.68 (m, 1H), 7.98−8.01 (m, 2H),
8.39 (d, J = 3.6 Hz, 2H), 8.86 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 14.3, 98.5, 119.6, 123.0, 124.3, 128.2, 128.9, 129.9, 139.6, 140.5,
141.3, 144.7, 149.7, 153.9; HRMS (ESI) calcd for C16H13N4 [M + H]+
261.1135, found 261.1119.
2-Methyl-5-(thiophen-2-yl)pyrazolo[1,5-c]quinazoline (3l):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (75 mg,
71%), mp 105−107 °C; 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3H),
6.79 (s, 1H), 7.25−7.27 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.60 (t, J =
7.6 Hz, 1H), 7.65 (d, J = 4.8 Hz, 1H), 7.93 (t, J = 8.0 Hz, 2H), 8.88 (d,
J = 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 98.1, 118.8,
122.9, 126.9, 127.8, 128.1, 129.6, 131.7, 133.7, 135.6, 139.9, 141.2,
141.8, 153.3; HRMS (ESI) calcd for C15H12N3S [M + H]+ 266.0746,
found 266.0770.
5-(4-Chlorophenyl)-2-phenylpyrazolo[1,5-c]quinazoline (3r):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (103 mg,
72%), mp 170−172 °C; 1H NMR (CDCl3, 400 MHz) δ 7.32 (s, 1H),
7.42−7.50 (m, 3H), 7.57 (t, J = 8.8 Hz, 3H), 7.66 (t, J = 7.2 Hz, 1H),
7.99−8.06 (m, 4H), 8.54 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 95.3, 119.4, 123.0, 126.8, 127.7, 128.3, 128.7, 128.8, 129.2,
129.9, 131.0, 132.1, 132.2, 137.2, 139.8, 141.9, 146.3, 154.8; HRMS
(ESI) calcd for C22H15ClN3 [M + H]+ 356.0949, found 356.0974.
5-(Naphthalen-1-yl)-2-phenylpyrazolo[1,5-c]quinazoline
(3s): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (97
1
mg, 65%), mp 220−222 °C; H NMR (CDCl3, 400 MHz) δ 7.34−
7.45 (m, 5H), 7.53 (t, J = 7.6 Hz, 1H), 7.64−7.74 (m, 3H), 7.80−7.86
(m, 3H), 7.97 (d, J = 8.4 Hz, 1H), 8.03−8.10 (m, 3H), 8.16 (d, J = 7.6
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 95.6, 119.8, 123.2, 125.0,
125.5, 126.1, 126.7, 126.8, 127.9, 128.4, 128.57, 128.65, 128.8, 129.0,
129.9, 130.4, 130.8, 131.4, 132.3, 133.8, 139.9, 141.4, 148.2, 155.1;
HRMS (ESI) calcd for C26H18N3 [M + H]+ 372.1495, found 372.1486.
2-Phenyl-5-propylpyrazolo[1,5-c]quinazoline (3t) (ref 11):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (65 mg,
1
57%), mp 76−78 °C; H NMR (CDCl3, 400 MHz) δ 1.16 (t, J = 7.2
Hz, 3H), 2.10 (m, 2H), 3.40 (t, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.40−
7.44 (m, 1H), 7.48−7.53 (m, 3H), 7.59−7.64 (m, 1H), 7.90 (d, J = 8.4
Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.04−8.06 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 14.2, 19.8, 34.8, 95.3, 119.4, 123.0, 126.8, 127.0,
128.1, 128.8, 129.0, 129.6, 132.7, 139.8, 140.5, 151.5, 154.5; MS (ESI)
m/z 288.4 [M + H]+.
2-(4-Chlorophenyl)-5-phenylpyrazolo[1,5-c]quinazoline
(3u): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (113
1
mg, 79%), mp 166−168 °C; H NMR (CDCl3, 400 MHz) δ 7.25 (s,
(E)-2-Methyl-5-styrylpyrazolo[1,5-c]quinazoline (3m): Petro-
leum ether/ethyl acetate (8:1) as eluent; yellow solid (62 mg, 54%),
mp 113−115 °C; 1H NMR (CDCl3, 400 MHz) δ 2.57 (s, 3H), 6.74 (s,
1H), 7.38−7.48 (m, 4H), 7.60 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.2 Hz,
2H), 7.91 (t, J = 8.8 Hz, 2H), 8.10 (d, J = 15.6 Hz, 1H), 8.28 (d, J =
16.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 98.3, 117.5, 119.3,
123.1, 126.8, 128.1, 128.3, 128.8, 129.6, 129.7, 135.8, 140.0, 140.3,
140.4, 145.4, 153.1; HRMS (ESI) calcd for C19H16N3 [M + H]+
286.1339, found 286.1352.
1H), 7.42 (d, J = 8.0 Hz, 2H), 7.54−7.67 (m, 5H), 7.93 (d, J = 8.4 Hz,
2H), 8.01 (d, J = 8.4 Hz, 2H), 8.48−8.51 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 95.2, 119.4, 123.0, 127.7, 128.0, 128.2, 128.8, 129.0,
129.9, 130.6, 130.9, 131.1, 132.6, 135.0, 140.0, 142.0, 147.4, 153.5;
HRMS (ESI) calcd for C22H15ClN3 [M + H]+ 356.0949, found
356.0975.
5-Phenyl-2-p-tolylpyrazolo[1,5-c]quinazoline (3v): Petroleum
ether/ethyl acetate (8:1) as eluent; white solid (98 mg, 73%), mp
140−142 °C; 1H NMR (CDCl3, 400 MHz) δ 2.42 (s, 3H), 7.27−7.29
F
dx.doi.org/10.1021/jo4001756 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 3H), 7.54−7.67 (m, 5H), 7.93 (d, J = 7.6 Hz, 2H), 8.03 (t, J = 7.6
Hz, 2H), 8.54−8.56 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.5,
95.1, 119.5, 123.0, 126.7, 127.5, 128.1, 128.7, 129.5, 129.6, 129.7,
130.7, 131.0, 132.8, 139.1, 140.0, 141.8, 147.5, 154.8; HRMS (ESI)
calcd for C23H18N3 [M + H]+ 336.1495, found 336.1488.
1 (0.4 mmol), acyclic ketone (1.6 mmol) or cyclic ketone (0.8 mmol),
and CuI (0.04 mmol) in DMF (1.5 mL) was added 26% aqueous
ammonia (0.4 mL) in a sealed tube (15 mL) under air atmosphere,
and the mixture was stirred at 100 °C for the time indicated in Table 3.
Upon completion as monitored by TLC, the reaction was quenched
with NH4Cl solution and extracted with ethyl acetate two times. The
combined organic layer was washed with H2O and brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by chromatography on
silica gel to afford the desired 5,6-dihydropyrazolo[1,5-c]quinazoline 7.
2,5,5-Trimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (7a):
Petroleum ether/ethyl acetate (5:1) as eluent; white solid (46 mg,
54%), mp 105−106 °C; 1H NMR (CDCl3, 400 MHz) δ 1.72 (s, 6H),
2.34 (s, 3H), 4.20 (br s, 1H), 6.28 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H),
6.85 (t, J = 7.6 Hz, 1H), 7.11−7.15 (m, 1H), 7.39−7.41 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 13.8, 28.0, 71.9, 99.5, 114.8, 115.3, 119.7,
123.9, 129.1, 137.3, 139.2, 148.6; HRMS (ESI) calcd for C13H16N3 [M
+ H]+ 214.1339, found 214.1319.
5,5-Diethyl-2-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline
(7b). Petroleum ether/ethyl acetate (5:1) as eluent; white solid (32
mg, 33%), mp 73−75 °C; 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, J =
7.2 Hz, 6H), 1.75−1.84 (m, 2H), 2.29−2.38 (m, 2H), 2.32 (s, 3H),
3.91 (br s, 1H), 6.23 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 7.6
Hz, 1H), 7.06−7.10 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 7.8, 13.9, 33.7, 77.7, 98.4, 112.9, 113.7, 118.3,
123.7, 129.2, 138.4, 140.2, 148.7; HRMS (ESI) calcd for C15H20N3 [M
+ H]+ 242.1652, found 242.1637.
9-Chloro-2,5-diphenylpyrazolo[1,5-c]quinazoline (3w) (ref
11): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (115
1
mg, 81%), mp 148−150 °C; H NMR (CDCl3, 400 MHz) δ 7.21 (s,
1H), 7.40−7.48 (m, 3H), 7.52−7.60 (m, 4H), 7.87 (d, J = 8.8 Hz,
1H), 7.93 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 8.50−8.53 (m,
2H); 13C NMR (CDCl3, 100 MHz) δ 95.6, 120.4, 122.3, 126.7, 128.1,
128.8, 129.2, 130.09, 130.14, 130.6, 131.1, 132.1, 132.4, 133.0, 138.3,
140.7, 147.4, 154.7; MS (ESI) m/z 356.8 [M + H]+.
9-Chloro-2-phenyl-5-p-tolylpyrazolo[1,5-c]quinazoline (3x):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (121 mg,
82%), mp 178−180 °C; 1H NMR (CDCl3, 400 MHz) δ 2.49 (s, 3H),
7.29 (s, 1H), 7.38−7.49 (m, 5H), 7.56 (dd, J = 2.0, 8.8 Hz, 1H), 7.91
(d, J = 8.8 Hz, 1H), 8.00−8.03 (m, 3H), 8.44−8.46 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 21.7, 95.7, 120.4, 122.4, 126.8, 128.8,
128.9, 129.2, 129.6, 130.1, 130.7, 132.2, 132.9, 138.5, 140.8, 141.6,
147.7, 154.8 (one 13C signal was not observed); HRMS (ESI) calcd for
C23H17ClN3 [M + H]+ 370.1106, found 370.1093.
9-Chloro-2-phenyl-5-propylpyrazolo[1,5-c]quinazoline (3y):
Petroleum ether/ethyl acetate (8:1) as eluent; white solid (62 mg,
48%), mp 98−100 °C; 1H NMR (CDCl3, 400 MHz) δ 1.14 (t, J = 7.6
Hz, 3H), 2.06 (m, 2H), 3.35 (t, J = 7.6 Hz, 2H), 7.17 (s, 1H), 7.40−
7.53 (m, 4H), 7.79 (d, J = 8.8 Hz, 1H), 7.91−7.92 (m, 1H), 8.00−8.02
(m, 2H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 19.7, 34.6, 95.7, 120.4,
122.4, 126.7, 128.9, 129.2, 129.6, 129.9, 132.3, 132.5, 138.2, 139.4,
151.7, 154.6; HRMS (ESI) calcd for C19H17ClN3 [M + H]+ 322.1106,
found 322.1098.
5-Ethyl-2,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline
(7c): Petroleum ether/ethyl acetate (5:1) as eluent; white solid (49
mg, 54%), mp 67−69 °C; 1H NMR (CDCl3, 400 MHz) δ 0.90 (t, J =
7.6 Hz, 3H), 1.74 (s, 3H), 1.80−1.86 (m, 1H), 2.14−2.20 (m, 1H),
2.32 (s, 3H), 4.13 (br s, 1H), 6.26 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H),
6.81 (t, J = 8.0 Hz, 1H), 7.09−7.13 (m, 1H), 7.36−7.38 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 8.2, 13.8, 26.3, 33.7, 74.6, 99.1, 114.3,
114.8, 119.2, 123.8, 129.1, 137.5, 139.5, 148.6; HRMS (ESI) calcd for
C14H18N3 [M + H]+ 228.1495, found 228.1501.
9-Methoxy-2,5-diphenylpyrazolo[1,5-c]quinazoline (3z) (ref
11): Petroleum ether/ethyl acetate (8:1) as eluent; white solid (110
1
mg, 78%), mp 141−143 °C; H NMR (CDCl3, 400 MHz) δ 3.93 (s,
3H), 7.21−7.24 (m, 2H), 7.33 (m, 1H), 7.41−7.49 (m, 3H), 7.59−
7.60 (m, 3H), 7.91 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 7.2 Hz, 2H), 8.52−
8.53 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 55.7, 95.0, 103.9,
119.1, 120.3, 126.7, 128.1, 128.7, 129.0, 130.2, 130.5, 130.6, 132.5,
132.9, 134.6, 141.6, 145.4, 154.2, 158.7; MS (ESI) m/z 352.4 [M +
H]+.
2′-Methyl-6′H-spiro[cyclopentane-1,5′-pyrazolo[1,5-c]-
quinazoline] (7d): Petroleum ether/ethyl acetate (8:1) as eluent;
1
white solid (49 mg, 51%), mp 131−133 °C; H NMR (CDCl3, 400
MHz) δ 1.78−1.81 (m, 2H), 1.92−1.95 (m, 4H), 2.33 (s, 3H), 2.44−
2.49 (m, 2H), 4.32 (br s, 1H), 6.30 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H),
6.87 (t, J = 7.6 Hz, 1H), 7.10−7.14 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 13.9, 23.7, 38.0, 82.0, 99.8, 115.6,
Typical Procedure for the Preparation of Compound 5a. To
a mixture of pyrazole 1a (94.8 mg, 0.4 mmol), benzaldehyde 2a (48.7
μL, 0.48 mmol), and CuI (7.6 mg, 0.04 mmol) in DMF (1.5 mL) was
added 26% aqueous ammonia (0.4 mL) in a sealed tube (15 mL)
under nitrogen atmosphere, and the mixture was stirred at 100 °C for
12 h. The reaction was quenched with NH4Cl solution and extracted
with ethyl acetate two times. The combined organic layer was washed
with H2O and brine and then dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum, and the crude product was
purified by chromatography on silica gel, eluting with petroleum
ether/ethyl acetate (3:1), to afford 5a (80 mg) as white solid in 77%
isolated yield (mp 158−160 °C): 1H NMR (CDCl3, 400 MHz) δ 2.27
(s, 3H), 4.82 (br s, 1H), 6.37 (s, 1H), 6.44 (s, 1H), 6.62 (d, J = 7.6 Hz,
1H), 6.85−6.88 (m, 1H), 7.09−7.13 (m, 1H), 7.24−7.26 (m, 2H),
7.30−7.31 (m, 3H), 7.46−7.48 (m, 1H); 13C NMR (CDCl3, 100
MHz) δ 13.6, 72.1, 99.3, 113.9, 114.8, 119.4, 123.8, 126.4, 128.7,
129.0, 129.1, 138.0, 139.1, 139.9, 149.5; HRMS (ESI) calcd for
C17H16N3 [M + H]+ 262.1339, found 262.1364.
115.7, 119.9, 123.9, 128.9, 138.0, 139.5, 148.5; HRMS (ESI) calcd for
C15H18N3 [M + H]+ 240.1495, found 240.1506.
2′-Methyl-6′H-spiro[cyclohexane-1,5′-pyrazolo[1,5-c]-
quinazoline] (7e): Petroleum ether/ethyl acetate (8:1) as eluent;
1
white solid (70 mg, 69%), mp 110−112 °C; H NMR (CDCl3, 400
MHz) δ 1.27−1.37 (m, 2H), 1.43−1.53 (m, 2H), 1.70−1.81 (m, 2H),
2.00−2.03 (m, 2H), 2.19 (dt, J = 4.0, 13,2 Hz, 2H), 2.34 (s, 3H), 4.60
(br s, 1H), 6.28 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.2 Hz,
1H), 7.10−7.14 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 13.9, 22.3, 24.6, 34.6, 72.9, 99.5, 115.4, 115.8, 119.7,
123.8, 129.0, 137.4, 138.7, 148.4; HRMS (ESI) calcd for C16H20N3 [M
+ H]+ 254.1652, found 254.1636.
2′-Methyl-6′H-spiro[cycloheptane-1,5′-pyrazolo[1,5-c]-
quinazoline] (7f): Petroleum ether/ethyl acetate (5:1) as eluent;
1
white solid (34 mg, 32%), mp 116−118 °C; H NMR (CDCl3, 400
MHz) δ 1.57−1.65 (m, 6H), 1.80 (s, 2H), 1.96−2.01 (m, 2H), 2.33 (s,
3H), 2.37−2.43 (m, 2H), 4.41 (br s, 1H), 6.27 (s, 1H), 6.74 (d, J = 8.0
Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.39 (d, J =
7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.0, 22.6, 29.7, 39.5,
76.9, 99.3, 115.4, 115.7, 119.7, 123.7, 128.9, 137.1, 139.0, 148.4;
HRMS (ESI) calcd for C17H22N3 [M + H]+ 268.1808, found 268.1826.
5,5-Dimethyl-2-phenyl-5,6-dihydropyrazolo[1,5-c]-
quinazoline (7g): Petroleum ether/ethyl acetate (8:1) as eluent;
Typical Procedure for the Preparation of 3a via Copper-
Catalyzed Aerobic Oxidation of 5a. To a solution of compound 5a
(64.3 mg, 0.246 mmol) in DMF (2 mL) was added CuI (4.7 mg,
0.0246 mmol), and then the mixture was stirred at 100 °C for 5 h
under air atmosphere. The resultant mixture was poured into water
and extracted with ethyl acetate two times. The combined organic
layer was washed with H2O and brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum and the crude
product was purified by chromatography on silica gel to afford
compound 3a (62 mg) as white solid in 96% isolated yield.
1
white solid (61 mg, 55%), mp 172−174 °C; H NMR (CDCl3, 400
MHz) δ 1.80 (s, 6H), 4.13 (br s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.80 (s,
1H), 6.91 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 7.2
Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.88 (d, J =
General Procedure for the Preparation of 5,6-
Dihydropyrazolo[1,5-c]quinazolines 7. To a mixture of pyrazole
G
dx.doi.org/10.1021/jo4001756 | J. Org. Chem. XXXX, XXX, XXX−XXX

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7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 28.0, 72.3, 96.9, 114.8,
115.5, 119.9, 124.0, 125.8, 127.6, 128.6, 129.2, 133.7, 137.6, 139.2,
151.3; HRMS (ESI) calcd for C18H18N3 [M + H]+ 276.1495, found
276.1506.
REFERENCES
■
(1) (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
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2′-Phenyl-6′H-spiro[cyclopentane-1,5′-pyrazolo[1,5-c]-
quinazoline] (7h): Petroleum ether/ethyl acetate (8:1) as eluent;
1
white solid (53 mg, 44%), mp 150−152 °C; H NMR (CDCl3, 400
MHz) δ 1.83 (s, 2H), 1.99 (s, 4H), 2.61 (s, 2H), 4.23 (br s, 1H), 6.77
(d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.93 (t, J = 8.0 Hz, 1H), 7.15−7.19
(m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.51−7.53
(m, 1H), 7.91 (d, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ
23.9, 38.4, 82.4, 97.1, 115.6, 115.8, 120.1, 124.0, 125.7, 127.6, 128.6,
129.1, 133.8, 138.3, 139.6, 151.0; HRMS (ESI) calcd for C20H20N3 [M
+ H]+ 302.1652, found 302.1661.
9′-Chloro-2′-methyl-6′H-spiro[cyclopentane-1,5′-pyrazolo-
[1,5-c]quinazoline] (7i): Petroleum ether/ethyl acetate (8:1) as
1
eluent; white solid (59 mg, 54%); H NMR (CDCl3, 400 MHz) δ
(3) (a) Varano, F.; Catarzi, D.; Colotta, V.; Calabri, F. R.; Lenzi, O.;
Filacchioni, G.; Galli, A.; Costagli, C.; Deflorian, F.; Moro, S. Bioorg.
Med. Chem. 2005, 13, 5536. (b) Varano, F.; Catarzi, D.; Colotta, V.;
Poli, D.; Filacchioni, G.; Galli, A.; Costagli, C. Chem. Pharm. Bull.
2009, 57, 826. (c) Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.;
1.75−1.78 (m, 2H), 1.88−1.95 (m, 4H), 2.31 (s, 3H), 2.41−2.46 (m,
2H), 4.34 (br s, 1H), 6.27(s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 7.05 (dd, J
= 2.4, 8.8 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 13.8, 23.7, 38.1, 82.0, 100.3, 117.0, 123.5, 124.7, 128.5, 136.9,
138.0, 148.7 (one 13C signal was not observed); HRMS (ESI) calcd for
C15H17ClN3 [M + H]+ 274.1106, found 274.1126.
̀
Galli, A.; Costagli, C.; Carla, V. J. Med. Chem. 2002, 45, 1035.
9′-Methoxy-2′-methyl-6′H-spiro[cyclohexane-1,5′-pyrazolo-
[1,5-c]quinazoline] (7j): Petroleum ether/ethyl acetate (8:1) as
eluent; white solid (68 mg, 60%), mp 104−106 °C; 1H NMR (CDCl3,
400 MHz) δ 1.28−1.35 (m, 2H), 1.47−1.57 (m, 2H), 1.70−1.77 (m,
2H), 1.95−1.98 (m, 2H), 2.10−2.17 (m, 2H), 2.33 (s, 3H), 3.79 (s,
3H), 4.17 (br s, 1H), 6.27 (s, 1H), 6.73−6.79 (m, 2H), 6.95 (d, J = 2.4
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.8, 22.3, 24.8, 34.3, 55.7,
73.0, 99.8, 108.5, 115.2, 117.7, 118.6, 132.1, 137.2, 148.2, 154.1;
HRMS (ESI) calcd for C17H22N3O [M + H]+ 284.1757, found
284.1744.
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M.; Prebil, R.; Grose
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D.; Malavasic, C.; Golobic, A.; Stare, K.; Dahmann, G.; Stanovnik, B.;
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lj, U.; Kralj,
Svete, J. Helv. Chim. Acta 2011, 94, 1703.
General Procedure for the Preparation of Pyrazolo[1,5-
c]quinazoline Derivatives 3 or 7 via Copper-Catalyzed One-
Pot, Four-Component Reaction. A mixture of compound 8 (0.5
mmol) and hydrazine hydrate (0.55 mmol) in DMF (2 mL) was
stirred at room temperature or 80 °C for 2 h in a sealed tube. Then
CuI (0.05 mmol), aldehyde (0.75 mmol) or aliphatic ketone (1.0
mmol), and 26% aqueous ammonia (0.5 mL) were successively added
into the reaction system at room temperature, and the mixture was
stirred at 100 °C for 24 h (for aldehyde) or 5 h (for ketone) in the
same sealed tube under air atmosphere. The reaction was quenched
with NH4Cl solution and extracted with ethyl acetate two times. The
combined organic layer was washed with H2O and brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by chromatography on
silica gel to afford the desired product 3 or 7.
(6) For selected reviews, see: (a) Ma, D.; Cai, Q. Acc. Chem. Res.
2008, 41, 1450. (b) Rao, H.; Fu, H. Synlett 2011, 745. (c) Evano, G.;
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H.; Jiang, Y.; Fu, H. Eur. J. Org. Chem. 2012, 6798. (e) Sang, P.; Yu,
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2012, 68, 7768. (b) Guo, S.; Wang, J.; Guo, D.; Zhang, X.; Fan, X.
RSC Adv. 2012, 2, 3772.
(9) For copper-catalyzed direct aminations of aryl halides with
aqueous ammonia, see: (a) Kim, J.; Chang, S. Chem. Commun. 2008,
3052. (b) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337.
(c) Wang, D.; Cai, Q.; Ding, K. Adv. Synth. Catal. 2009, 351, 1722.
(d) Xu, H.; Wolf, C. Chem. Commun. 2009, 3035. (e) Meng, F.; Zhu,
X.; Li, Y.; Xie, J.; Wang, B.; Yao, J.; Wan, Y. Eur. J. Org. Chem. 2010,
6149. (f) Tao, C.; Liu, W.; Lv, A.; Sun, M.; Tian, Y.; Wang, Q.; Zhao,
J. Synlett 2010, 1355. (g) Thakur, K. G.; Ganapathy, D.; Sekar, G.
Chem. Commun. 2011, 47, 5076. (h) Zeng, X.; Huang, W.; Qiu, Y.;
Jiang, S. Org. Biomol. Chem. 2011, 9, 8224. (i) Li, Y.; Zhu, X.; Meng,
F.; Wan, Y. Tetrahedron 2011, 67, 5450. (j) Ji, P.; Atherton, J. H.; Page,
M. I. J. Org. Chem. 2012, 77, 7471. (k) Diao, X.; Wang, Y.; Jiang, Y.;
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Tetrahedron 2012, 68, 9364.
Compounds 3a, 3e, 3l, 3p, 7d, and 7e were prepared through the
above procedure, and the structure of these compounds was confirmed
1
by H NMR and TLC analysis.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR and 13C NMR spectra of 3a−3z, 5a, and
7a−7j. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: shguo@htu.cn, xuesen.fan@htu.cn.
■
Notes
(10) To the best of our knowledge, the copper-catalyzed N-arylation
of imines with aryl halides has not been reported yet. For the
palladium-catalyzed couplings of imines with aryl halides, see:
(a) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367. (b) Mann, G.; Hartwig, J. F.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grants 21172057 and
21202040) and PCSIRT (IRT1061).
́
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H
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