CuCl-catalyzed one-pot synthesis of 5,6-dihydropyrazolo[1,5-c]quinazolines

Article abstract of DOI:10.1016/j.tet.2014.02.027

A simple and efficient procedure for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines via CuCl-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with aldehydes and aqueous ammonia under nitrogen atmosphere has been developed. The usefulne

Full text of DOI:10.1016/j.tet.2014.02.027

Tetrahedron 70 (2014) 2383e2388
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CuCl-catalyzed one-pot synthesis of 5,6-dihydropyrazolo[1,5-c]
quinazolines
*
*
Shenghai Guo , Jiliang Wang, Yan Li, Xuesen Fan
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Normal
University, Xinxiang, Henan 453007, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines via CuCl-
catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with aldehydes and aqueous ammonia
under nitrogen atmosphere has been developed. The usefulness of this novel methodology was show-
cased by its successful application in the preparation of a potential Eg5 inhibitor.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 16 December 2013
Received in revised form 28 January 2014
Accepted 13 February 2014
Available online 19 February 2014
Keywords:
Copper-catalyzed
Tandem reaction
One-pot synthesis
5,6-Dihydropyrazolo[1,5-c]quinazoline
Potential Eg5 inhibitor
1. Introduction
In recent years, copper-catalyzed tandem reactions have
attracted much attention due to their high efficiency in carbon-
ecarbon and carboneheteroatom bond formation reactions as well
as in the construction of various heterocyclic skeletons.1,2 As part of
our research in this regard,3,4 we have disclosed a copper-catalyzed
synthesis of pyrazolo[1,5-c]quinazolines through the tandem re-
action of 5-(2-bromoaryl)-1H-pyrazoles with aldehydes and
aqueous ammonia under air atmosphere.4 In studying the mecha-
nism of this tandem process, we found that when the reaction was
carried out under nitrogen atmosphere, 5,6-dihydropyrazolo[1,5-c]
quinazoline, other than pyrazolo[1,5-c]quinazoline, was exclusively
obtained (Scheme 1). Literature searching revealed that 5,6-
dihydropyrazolo[1,5-c]quinazolines appear promising as excit-
atory amino acid and adenosine receptor and Gly/NMDA receptor
antagonists,5 and potential vaccinia virus and Eg5 ATPase in-
hibitors.6 Notwithstanding their importance, protocols for the
preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines are very
limited and usually suffer from multistep sequence, limited sub-
strate scope, and poor overall yield.5e7 Therefore, it is highly de-
sirable to develop a more efficient and practical synthetic method
Scheme 1.
for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazoline de-
rivatives. Based on the above facts, we decided to study the copper-
catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with
aldehydes and aqueous ammonia under nitrogen atmosphere in
detail, thereby providing a straightforward and efficient route to-
ward 5,6-dihydropyrazolo[1,5-c]quinazolines. In this paper, we
wish to disclose our research results in this aspect.
2. Results and discussion
Initially, 5-(2-bromophenyl)-3-methyl-1H-pyrazole (1a), benz-
aldehyde (2a), and aqueous ammonia were used as model sub-
strates to optimize the reaction conditions including catalysts,
solvents, and reaction temperature (Table 1). It turned out that
treatment of a mixture of 1a (0.4 mmol), 2a (0.8 mmol), and
aqueous ammonia (0.4 mL) with CuI (10 mol %) in DMF (1.5 mL) at
100 ꢀC in a sealed tube under nitrogen atmosphere for 12 h could
give rise to the desired 2-methyl-5-phenyl-5,6-dihydropyrazolo
[1,5-c]quinazoline (3a) in 82% yield (Table 1, entry 1). Reducing
the amount of 2a from 2.0 to 1.2 equiv (relative to 1a) resulted in
* Corresponding authors. Tel.: þ86 373 3329261; fax: þ86 373 3326336; e-mail
addresses: shguo@htu.cn, guo_shenghai@yahoo.com (S. Guo), xuesen.fan@htu.cn
(X. Fan).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.027

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S. Guo et al. / Tetrahedron 70 (2014) 2383e2388
a lower yield of 75%.4 Next, other copper catalysts were in-
Table 1
Optimization for the synthesis of 3aa
vestigated, and the highest yield of 86% was obtained with CuCl as
the catalyst (Table 1, entry 3). When DMSO was used to replace
DMF as the reaction medium, the yield of 3a decreased (Table 1,
entry 3 vs 6). Moreover, the reaction temperature was also screened
by using CuCl as catalyst and DMF as solvent, and 100 ꢀC proved to
be optimal (Table 1, entry 3 vs 7e8).
Entry
Catalyst
Solvent
T (ꢀC)
Yield (%)b
With the optimized reaction conditions (Table 1, entry 3) in
hand, we were then interested in exploring the scope of aldehydes
and 5-(2-bromoaryl)-1H-pyrazoles in the 5,6-dihydropyrazolo[1,5-
c]quinazoline formation reaction. As shown in Table 2, aromatic
aldehydes with a variety of substituents on the aryl ring (including:
Me, MeO, Cl, Br, and F) reacted very well with 1a and aqueous
ammonia to afford the desired products 3aeh in 65e86% yields
(Table 2, entries 1e8). 1-Naphthaldehyde and thiophene-2-
carbaldehyde also underwent the tandem reactions smoothly,
thus generating the corresponding products 3i and 3j in 85% and
65% yields, respectively (Table 2, entries 9 and 10). In addition,
alkyl-substituted aldehydes were found to be compatible with the
reaction conditions to provide 3k and 3l in yields of 51% and 76%
(Table 2, entries 11 and 12). Next, pyrazoles 1 with different
1
2
3
4
5
6
7
8
CuI
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
100
100
100
100
100
100
80
82
81
86
47
53
74
49
71
CuBr
CuCl
Cu(OAc)2
CuCl2
CuCl
CuCl
CuCl
120
The bold in the entry signifies the best reaction conditions.
a
All the reactions were performed with 1a (0.4 mmol), 2a (0.8 mmol), catalyst
(0.04 mmol), 26% aqueous ammonia (0.4 mL), and solvent (1.5 mL) in a sealed tube
(15 mL) under nitrogen atmosphere for 12 h.
b
Isolated yield.
Table 2
Synthesis of 5,6-dihydropyrazolo[1,5-c]quinazolines 3a,b

S. Guo et al. / Tetrahedron 70 (2014) 2383e2388
2385
substitution patterns were examined, and it was found that the
electronic effect and steric hindrance of R1 and R2 groups on pyr-
azoles 1 did not influence the formation of products 3mev obvi-
ously (Table 2, entries 13e22).
apparatus and uncorrected.1H 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 chromatography (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).
On the basis of the above results and our previous observations,4
a possible mechanism for the formation of 3 is illustrated in
Scheme 2. Initially, CuCl-catalyzed cross-coupling of pyrazole 1
with the in situ generated imine A affords intermediate B. Sub-
sequent intramolecular nucleophilic cyclization of B gives rise to
the final product 3 under nitrogen atmosphere.
4.2. General procedure for the preparation of products 3aev
To a mixture of 5-(2-bromoaryl)-1H-pyrazole 1 (0.4 mmol), al-
dehyde 2 (0.8 mmol), CuCl (0.04 mmol), and DMF (1.5 mL) in
a sealed tube (15 mL) was added 26% aqueous ammonia (0.4 mL)
under nitrogen atmosphere. Then, the tube was sealed and the
resulting solution was stirred at 100 ꢀC until the reaction was
completed as monitored by TLC (ca. 12 h for R1¼Me; 18 h for
R1¼Aryl). After being cooled to room temperature, 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 removed
under reduced pressure and the residue was purified by chroma-
tography on silica gel, eluting with petroleum ether/ethyl acetate
(3:1), to afford the corresponding product 3.
Scheme 2. Possible mechanism for the formation of 3.
As mentioned above, compounds containing the 5,6-dihydro-
pyrazolo[1,5-c]quinazoline scaffold often exhibit significant
biological activities.5,6 In particular, 5-(2-fluorophenyl)-2,9-
dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (3w) was re-
cently identified as a potential Eg5/Kinesin spindle protein in-
hibitor by Pae et al. through virtual screening.6b To the best of our
knowledge, synthetic method for the preparation of 3w has not
been reported yet.
4.2.1. 2-Methyl-5-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline
(3a). White solid; yield: 89.9 mg (86%); 1H and 13C NMR of com-
pound 3a are the same as the previously reported ones.4
In our following studies, we were gratified to find that by
employing the synthetic strategy developed in this paper, 3w could
be conveniently synthesized in 69% yield through the tandem re-
action of 5-(2-bromo-5-methylphenyl)-3-methyl-1H-pyrazole
(1g), which could be prepared from 2-bromo-5-methylbenzoic acid
(4), with 2-fluorobenzaldehyde (2h), and aqueous ammonia under
nitrogen atmosphere (Scheme 3).
4.2.2. 2-Methyl-5-p-tolyl-5,6-dihydropyrazolo[1,5-c]quinazoline
(3b). White solid; yield: 91.4 mg (83%); mp 146e148 ꢀC. 1H NMR
(CDCl3, 400 MHz)
d 2.28 (s, 3H), 2.31 (s, 3H), 4.63 (br s, 1H), 6.36
(s, 1H), 6.44 (s, 1H), 6.65 (d, J¼8.0 Hz, 1H), 6.86 (t, J¼8.0 Hz, 1H),
7.09e7.13 (m, 3H), 7.19 (d, J¼8.0 Hz, 2H), 7.46 (dd, J¼1.2, 7.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz)
d 13.8, 21.2, 72.2, 99.4, 114.2, 114.9, 119.6,
124.0, 126.6, 129.2, 129.5, 137.0, 138.2, 139.0, 139.4, 149.5. HRMS
(ESI) calcd for C18H18N3 [MþH]þ: 276.1495, found: 276.1504.
4.2.3. 5-(4-Methoxyphenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]
quinazoline (3c). White solid; yield: 80.4 mg (69%); mp 101e103 ꢀC.
1H NMR (CDCl3, 400 MHz)
d 2.27 (s, 3H), 3.74 (s, 3H), 4.67 (br s, 1H),
6.35 (s, 1H), 6.39 (s, 1H), 6.64 (d, J¼8.0 Hz, 1H), 6.82e6.88 (m, 3H),
7.11 (dt, J¼1.6, 7.6 Hz, 1H), 7.22e7.24 (m, 2H), 7.45 (dd, J¼1.6, 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz)
d 13.8, 55.3, 72.0, 99.4, 114.2, 114.8,
119.6, 124.0, 128.2, 129.2, 132.0, 138.2, 139.5, 149.5, 160.2 (one 13C
signal was not observed). HRMS (ESI) calcd for C18H18N3O [MþH]þ:
292.1444, found: 292.1462.
Scheme 3. The synthesis of potential Eg5 inhibitor (3w).
4.2.4. 5-(4-Chlorophenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]-qui-
nazoline (3d). Light yellow solid; yield: 91.0 mg (77%); mp
3. Conclusion
107e109 ꢀC. 1H NMR (CDCl3, 400 MHz)
d 2.27 (s, 3H), 4.69 (br s, 1H),
6.36 (s, 1H), 6.46 (s, 1H), 6.68 (d, J¼8.0 Hz, 1H), 6.88 (t, J¼7.2 Hz, 1H),
In summary, we have developed an efficient synthetic approach
toward 5,6-dihydropyrazolo[1,5-c]quinazolines via the copper-
catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with
aldehydes and aqueous ammonia under nitrogen atmosphere
without using any additional ligand and base. As an application,
this methodology offers a straightforward route toward a potential
Eg5 inhibitor (3w). The present protocol displays broad substrate
scope, good yields, and mild reaction conditions.
7.13 (t, J¼8.0 Hz,1H), 7.20 (d, J¼8.4 Hz, 2H), 7.27 (d, J¼8.0 Hz, 2H), 7.45
(d, J¼7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 13.8, 71.5, 99.7, 114.2,
115.1, 120.0, 124.1, 128.1, 129.0, 129.4, 135.0, 138.2, 138.4, 138.9, 149.8.
HRMS (ESI) calcd for C17H15ClN3 [MþH]þ: 296.0949, found: 296.0969.
4.2.5. 5-(4-Bromophenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]-qui-
nazoline (3e). Yellow oil; yield: 98.0 mg (72%). 1H NMR (CDCl3,
400 MHz) d 2.27 (s, 3H), 4.76 (br s, 1H), 6.36 (s, 1H), 6.41 (s, 1H), 6.66
(d, J¼8.0 Hz, 1H), 6.88 (t, J¼7.6 Hz, 1H), 7.10e7.13 (m, 3H), 7.41
4. Experimental section
4.1. General
(d, J¼8.4 Hz, 2H), 7.45 (d, J¼7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.8, 71.6, 99.7, 114.2, 115.1, 120.0, 123.2, 124.1, 128.4, 129.4, 132.0,
138.2, 138.9, 139.0, 149.9. HRMS (ESI) calcd for C17H15BrN3 [MþH]þ:
340.0444, found: 340.0423.
Unless noted, all commercial reagents and solvents were used
without further purification. THF was distilled from sodium/benzo-
phenone. Melting points were recorded with a micro melting point
4.2.6. 5-(4-Fluorophenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]-qui-
nazoline (3f). Light yellow solid; yield: 78.2 mg (70%); mp

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S. Guo et al. / Tetrahedron 70 (2014) 2383e2388
158e160 ꢀC. 1H NMR (CDCl3, 400 MHz)
d
2.27 (s, 3H), 4.64 (br s, 1H),
139.5, 148.8. HRMS (ESI) calcd for C14H18N3 [MþH]þ: 228.1495,
6.36 (s, 1H), 6.47 (s, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.86e6.90 (m, 1H),
found: 228.1500.
6.98e7.02 (m, 2H), 7.11e7.15 (m, 1H), 7.26e7.30 (m, 2H), 7.45e7.47
(m, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.8, 71.6, 99.6, 114.2, 115.0,
4.2.13. 2,5-Diphenyl-5,6-dihydropyrazolo[1,5-c]quinazoline
115.8 (d, J¼21.9 Hz, 2C), 120.0, 124.1, 128.6 (d, J¼8.0 Hz, 2C), 129.3,
135.8 (d, J¼2.2 Hz, 1C), 138.2, 139.1, 149.7, 163.1 (d, J¼245.8 Hz, 1C).
HRMS (ESI) calcd for C17H15FN3 [MþH]þ: 280.1245, found: 280.1258.
(3m). White solid; yield: 112.5 mg (87%); mp 83e85 ꢀC. 1H NMR
(CDCl3, 400 MHz)
d
4.75 (br s, 1H), 6.62 (s, 1H), 6.69 (d, J¼8.4 Hz,
1H), 6.90e6.94 (m, 2H), 7.15 (dt, J¼1.2, 7.6 Hz, 1H), 7.31e7.34
(m, 6H), 7.38e7.42 (m, 2H), 7.57 (dd, J¼1.2, 7.6 Hz, 1H), 7.84e7.87
4.2.7. 5-(3-Fluorophenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]-qui-
(m, 2H); 13C NMR (CDCl3, 100 MHz)
d 72.2, 96.9, 114.3, 115.3, 120.0,
nazoline (3g). Light yellow solid; yield: 79.3 mg (71%); mp
124.1, 125.8, 126.6, 127.9, 128.6, 128.8, 129.0, 129.5, 133.4, 138.7,
76e77 ꢀC. 1H NMR (CDCl3, 400 MHz)
d
2.29 (s, 3H), 4.69 (br s, 1H),
139.2, 139.9, 152.1. HRMS (ESI) calcd for
324.1495, found: 324.1517.
C
22H18N3 [MþH]þ:
6.37 (s, 1H), 6.51 (s, 1H), 6.69 (d, J¼8.0 Hz, 1H), 6.86e7.01 (m, 3H),
7.04e7.06 (m,1H), 7.13 (dt, J¼1.2, 7.6 Hz,1H), 7.24e7.30 (m,1H), 7.46
(dd, J¼1.6, 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.8, 71.5, 99.7,
4.2.14. 2-Phenyl-5-p-tolyl-5,6-dihydropyrazolo[1,5-c]quinazoline
113.6 (d, J¼22.5 Hz, 1C), 114.2, 115.2, 116.1 (d, J¼21.1 Hz, 1C), 120.1,
122.2 (d, J¼2.9 Hz, 1C), 124.1, 129.4, 130.5 (d, J¼8.0 Hz, 1C), 138.1,
138.7, 142.5 (d, J¼6.6 Hz, 1C), 149.9, 162.9 (d, J¼245.8 Hz, 1C). HRMS
(ESI) calcd for C17H15FN3 [MþH]þ: 280.1245, found: 280.1251.
(3n). White solid; yield: 124.1 mg (92%); mp 106e108 ꢀC. 1H NMR
(CDCl3, 400 MHz)
d 2.31 (s, 3H), 4.69 (br s, 1H), 6.58 (s, 1H), 6.69
(d, J¼8.0 Hz,1H), 6.89 (s,1H), 6.91 (t, J¼8.0 Hz,1H), 7.10e7.21 (m, 5H),
7.29e7.33 (m, 1H), 7.39 (t, J¼8.0 Hz, 2H), 7.56 (dd, J¼1.2, 8.0 Hz, 1H),
7.83e7.86 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 21.2, 72.1, 96.8, 114.3,
4.2.8. 5-(2-Fluorophenyl)-2-methyl-5,6-dihydropyrazolo[1,5-c]-qui-
115.3, 119.9, 124.1, 125.8, 126.5, 127.8, 128.6, 129.4, 133.4, 137.0, 138.6,
138.9, 139.3, 152.0 (one 13C signal was not observed). HRMS (ESI)
calcd for C23H20N3 [MþH]þ: 338.1652, found: 338.1659.
nazoline (3h). Light yellow solid; yield: 72.6 mg (65%); mp
118e120 ꢀC. 1H NMR (CDCl3, 400 MHz)
d 2.33 (s, 3H), 4.78 (br s, 1H),
6.41e6.45 (m, 2H), 6.64 (d, J¼8.0 Hz, 1H), 6.85 (dt, J¼0.8, 7.2 Hz,1H),
6.91e6.95 (m, 2H), 7.03e7.10 (m, 2H), 7.20e7.25 (m, 1H), 7.46e7.48
4.2.15. 5-(4-Bromophenyl)-2-phenyl-5,6-dihydropyrazolo[1,5-c]-qui-
(m, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.8, 66.3 (d, J¼4.3 Hz, 1C),
nazoline (3o). Yellow oil; yield: 130.3 mg (81%). 1H NMR (CDCl3,
99.4, 114.0, 115.2, 115.6 (d, J¼21.1 Hz, 1C), 119.8, 124.0, 124.5 (d,
J¼3.6 Hz, 1C), 127.0 (d, J¼2.9 Hz, 1C), 127.6 (d, J¼12.4 Hz, 1C), 129.3,
130.4 (d, J¼8.7 Hz, 1C), 138.6, 138.9, 149.8, 159.6 (d, J¼244.4 Hz, 1C).
400 MHz)
d
4.79 (br s, 1H), 6.52 (s, 1H), 6.69 (d, J¼7.6 Hz, 1H), 6.88
(s, 1H), 6.93 (t, J¼8.0 Hz, 1H), 7.12e7.18 (m, 3H), 7.30e7.34 (m, 1H),
7.38e7.42 (m, 4H), 7.55 (dd, J¼1.2, 7.6 Hz, 1H), 7.82e7.84 (m, 2H);
HRMS (ESI) calcd for
280.1237.
C
17H15FN3 [MþH]þ: 280.1245, found:
13C NMR (CDCl3, 100 MHz)
d 71.6, 97.0, 114.3, 115.5, 120.3, 123.1,
124.2, 125.8, 128.0, 128.4, 128.7, 129.6, 131.9, 133.2, 138.6, 138.8,
138.9, 152.3. HRMS (ESI) calcd for C22H17BrN3 [MþH]þ: 402.0600,
found: 402.0589.
4.2.9. 2-Methyl-5-(naphthalen-1-yl)-5,6-dihydropyrazolo[1,5-c]-
quinazoline (3i). White solid; yield: 105.9 mg (85%); mp 88e90 ꢀC.
1H NMR (CDCl3, 400 MHz)
d
2.24 (s, 3H), 4.76 (br s, 1H), 6.44 (s, 1H),
4.2.16. 2-Phenyl-5-(thiophen-2-yl)-5,6-dihydropyrazolo[1,5-c]-qui-
6.49 (d, J¼7.6 Hz, 1H), 6.86 (t, J¼8.0 Hz, 1H), 6.93 (d, J¼6.8 Hz, 1H),
7.04 (t, J¼8.0 Hz, 1H), 7.14 (s, 1H), 7.30 (t, J¼8.4 Hz, 1H), 7.47e7.53
(m, 3H), 7.80 (d, J¼8.4 Hz,1H), 7.86e7.89 (m,1H), 8.10e8.12 (m,1H);
nazoline (3p). Yellow oil; yield: 101.4 mg (77%). 1H NMR (CDCl3,
400 MHz)
d
4.87 (br s, 1H), 6.78 (d, J¼7.6 Hz, 1H), 6.86 (s, 1H),
6.87e6.89 (m, 1H), 6.92 (s, 1H), 6.94e6.98 (m, 1H), 7.02 (d, J¼3.2 Hz,
1H), 7.17e7.21 (m, 2H), 7.30e7.35 (m, 1H), 7.39e7.43 (m, 2H), 7.55
(dd, J¼1.2, 7.6 Hz, 1H), 7.86e7.88 (m, 2H); 13C NMR (CDCl3,
13C NMR (CDCl3,100 MHz)
d 13.8, 70.6, 99.4,114.0,115.1,119.6, 123.1,
124.0, 125.31, 125.35, 125.8, 126.7, 129.1, 129.2, 129.8, 130.3, 134.1,
134.3, 138.9, 139.4, 149.8. HRMS (ESI) calcd for C21H18N3 [MþH]þ:
312.1495, found: 312.1480.
100 MHz)
d 68.3, 97.2, 114.6, 115.9, 120.6, 124.2, 125.8, 125.9, 126.3,
126.7,127.9,128.7,129.6,133.3,138.0,138.6,143.3,152.3. HRMS (ESI)
calcd for C20H16N3S [MþH]þ: 330.1059, found: 330.1080.
4.2.10. 2-Methyl-5-(thiophen-2-yl)-5,6-dihydropyrazolo[1,5-c]-qui-
nazoline (3j). Light yellow solid; yield: 69.5 mg (65%); mp
4.2.17. 2-Phenyl-5-propyl-5,6-dihydropyrazolo[1,5-c]quinazoline
114e116 ꢀC. 1H NMR (CDCl3, 400 MHz)
d
2.29 (s, 3H), 4.85 (br s, 1H),
(3q). Colorless oil; yield: 88.0 mg (76%). 1H NMR (CDCl3, 400 MHz)
6.34 (s, 1H), 6.74 (d, J¼8.4 Hz, 1H), 6.78 (s, 1H), 6.87e6.92 (m, 2H),
d
0.96 (t, J¼7.6 Hz, 3H), 1.44e1.54 (m, 2H), 1.93e2.03 (m, 1H),
7.01 (d, J¼2.4 Hz, 1H), 7.13e7.20 (m, 2H), 7.45 (dd, J¼0.8, 7.6 Hz, 1H);
2.06e2.14 (m, 1H), 4.44 (br s, 1H), 5.59e5.62 (m, 1H), 6.75
(d, J¼8.0 Hz, 1H), 6.79 (s, 1H), 6.89 (dt, J¼0.8, 7.6 Hz, 1H), 7.16
(dt, J¼1.2, 8.0 Hz, 1H), 7.31e7.35 (m, 1H), 7.41e7.45 (m, 2H), 7.50
(dd, J¼1.6, 8.0 Hz, 1H), 7.87e7.89 (m, 2H); 13C NMR (CDCl3,
13C NMR (CDCl3, 100 MHz)
d 13.8, 68.1, 99.8, 114.5, 115.6, 120.3,
124.1, 125.8, 126.4, 126.6, 129.3, 137.6, 138.6, 143.4, 149.8. HRMS
(ESI) calcd for C15H14N3S [MþH]þ: 268.0903, found: 268.0912.
100 MHz) d 13.8, 17.8, 37.4, 70.0, 96.6,114.7, 115.4, 119.8, 124.0, 125.7,
4.2.11. 2-Methyl-5,6-dihydropyrazolo[1,5-c]quinazoline (3k). White
solid; yield: 37.8 mg (51%); mp 94e96 ꢀC. 1H NMR (CDCl3, 400 MHz)
127.7, 128.7, 129.3, 133.7, 138.0, 139.5, 151.5. HRMS (ESI) calcd for
C
19H20N3 [MþH]þ: 290.1652, found: 290.1649.
d
2.32 (s, 3H), 4.45 (br s, 1H), 5.35 (s, 2H), 6.28 (s, 1H), 6.75
(d, J¼8.4 Hz, 1H), 6.88 (t, J¼8.0 Hz, 1H), 7.13 (t, J¼8.0 Hz, 1H), 7.41
4.2.18. 5-Phenyl-2-p-tolyl-5,6-dihydropyrazolo[1,5-c]quinazoline
(d, J¼8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.6, 59.6, 99.4, 115.4,
(3r). White solid; yield: 112.0 mg (83%); mp 102e104 ꢀC. 1H NMR
115.7, 120.3, 124.2, 129.0, 138.1, 140.4, 149.2. HRMS (ESI) calcd for
(CDCl3, 400 MHz) d 2.38 (s, 3H), 4.75 (br s, 1H), 6.61 (s, 1H), 6.69
C
11H12N3 [MþH]þ: 186.1026, found: 186.1040.
(d, J¼7.6 Hz, 1H), 6.87 (s, 1H), 6.91 (t, J¼7.2 Hz, 1H), 7.12e7.17 (m,
1H), 7.20 (d, J¼8.4 Hz, 2H), 7.28e7.31 (m, 5H), 7.56 (d, J¼7.2 Hz, 1H),
4.2.12. 2-Methyl-5-propyl-5,6-dihydropyrazolo[1,5-c]quinazoline
7.74 (d, J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 21.3, 72.2, 96.7,
(3l). Colorless oil; yield: 69.1 mg (76%). 1H NMR (CDCl3,
114.4, 115.3, 119.9, 124.1, 125.7, 126.5, 128.8, 129.0, 129.3, 129.4,
130.6,137.6,138.6,139.1,140.0,152.2. HRMS (ESI) calcd for C23H20N3
[MþH]þ: 338.1652, found: 338.1674.
400 MHz)
d
0.94 (t, J¼8.0 Hz, 3H), 1.38e1.48 (m, 2H), 1.86e2.06
(m, 2H), 2.32 (s, 3H), 4.42 (br s, 1H), 5.47e5.50 (m, 1H), 6.26
(s, 1H), 6.71 (d, J¼8.4 Hz, 1H), 6.81e6.85 (m, 1H), 7.09e7.13
(m, 1H), 7.37e7.39 (m, 1H); 13C NMR (CDCl3, 100 MHz)
d
13.7,
4.2.19. 2-(4-Chlorophenyl)-5-phenyl-5,6-dihydropyrazolo[1,5-c]-qui-
nazoline (3s). White solid; yield: 114.5 mg (80%); mp 119e120 ꢀC.
13.8, 17.7, 37.3, 69.6, 99.2, 114.7, 115.2, 119.6, 123.9, 129.1, 137.5,

S. Guo et al. / Tetrahedron 70 (2014) 2383e2388
2387
1H NMR (CDCl3, 400 MHz)
d
4.67 (br s, 1H), 6.62 (s, 1H), 6.72
(20 mL), and brine (10 mL), and then dried over anhydrous Na2SO4
and concentrated. The crude product was purified by chromatog-
raphy on silica gel, eluting with petroleum ether/ethyl acetate
(10:1), to afford compound 6 (1.49 g) as yellow oil in 65% isolated
(d, J¼8.0 Hz, 1H), 6.84 (s, 1H), 6.92 (t, J¼8.0 Hz, 1H), 7.16 (t, J¼8.0 Hz,
1H), 7.32e7.35 (m, 7H), 7.54 (d, J¼7.6 Hz, 1H), 7.74 (d, J¼8.8 Hz, 2H);
13C NMR (CDCl3, 100 MHz)
d 72.3, 96.8, 114.2, 115.3, 120.1, 124.1,
126.6,127.1, 128.7, 128.8,129.1, 129.6,131.9, 133.5,138.8,139.2,139.7,
151.0. HRMS (ESI) calcd for C22H17ClN3 [MþH]þ: 358.1106, found:
358.1116.
yield. 1H NMR (CDCl3, 400 MHz)
d 2.16 (s, 3H), 2.31 (s, 3H), 5.94 (s,
1H), 7.07 (dd, J¼2.0, 8.4 Hz, 1H), 7.29 (d, J¼2.0 Hz, 1H), 7.47 (d,
J¼8.4 Hz, 1H), 15.63 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
d 20.8,
25.3, 101.7, 116.6, 130.5, 132.5, 133.6, 137.49, 137.52, 186.6, 192.1.
4.2.20. 9-Chloro-2,5-diphenyl-5,6-dihydropyrazolo[1,5-c]quinazoline
HRMS (ESI) calcd for
255.0031.
C
11H12BrO2 [MþH]þ: 255.0015, found:
(3t). White solid; yield: 128.8 mg (90%); mp 143e145 ꢀC. 1H NMR
(CDCl3, 400 MHz)
d
4.72 (br s, 1H), 6.62 (s, 1H), 6.64 (d, J¼8.0 Hz,
1H), 6.87 (s, 1H), 7.09 (dd, J¼2.4, 8.0 Hz, 1H), 7.25e7.32 (m, 6H), 7.38
4.3.3. 5-(2-Bromo-5-methylphenyl)-3-methyl-1H-pyrazole (1g). To
a solution of compound 6 (1.02 g, 4 mmol) in EtOH (5 mL) was
added hydrazine hydrate (6 mmol) and the reaction mixture was
stirred at 80 ꢀC for 2 h. The solvent was removed under reduced
pressure and the crude product was purified by chromatography on
silica gel, eluting with petroleum ether/ethyl acetate (3:1), to afford
compound 1g (0.8 g) as yellow oil in 80% isolated yield. 1H NMR
(t, J¼7.6 Hz, 2H), 7.52 (d, J¼2.4 Hz, 1H), 7.80e7.82 (m, 2H); 13C NMR
(CDCl3, 100 MHz)
d 72.1, 97.3, 115.7, 116.6, 123.7, 124.9, 125.8, 126.4,
128.0, 128.6, 128.9, 129.15, 129.17, 133.1, 137.47, 137.53, 139.5, 152.3.
HRMS (ESI) calcd for C22H16ClN3Na [MþNa]þ: 380.0925, found:
380.0954.
4.2.21. 9-Chloro-2-phenyl-5-p-tolyl-5,6-dihydropyrazolo[1,5-c]-qui-
(CDCl3, 400 MHz)
(dd, J¼2.0, 8.4 Hz, 1H), 7.40 (d, J¼1.6 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H),
11.30 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
11.3, 20.8, 105.7, 118.8,
d 2.17 (s, 3H), 2.25 (s, 3H), 6.45 (s, 1H), 6.96
nazoline (3u). Colorless oil; yield: 129.4 mg (87%). 1H NMR (CDCl3,
400 MHz)
d
2.30 (s, 3H), 4.75 (br s, 1H), 6.53 (s, 1H), 6.59
d
(d, J¼8.4 Hz, 1H), 6.85 (s, 1H), 7.06e7.16 (m, 5H), 7.28e7.32 (m, 1H),
130.1, 131.8, 133.2, 133.6, 137.2, 141.9, 148.6. HRMS (ESI) calcd for
C
7.36e7.40 (m, 2H), 7.51 (d, J¼2.0 Hz, 1H), 7.80e7.82 (m, 2H); 13C
11H12BrN2 [MþH]þ: 251.0178, found: 251.0185.
NMR (CDCl3, 100 MHz)
d 21.2, 72.0, 97.3, 115.6, 116.5, 123.7, 124.7,
125.8,126.4, 128.0, 128.6, 129.1, 129.5,133.1, 136.6, 137.5, 137.7, 139.1,
152.2. HRMS (ESI) calcd for C23H19ClN3 [MþH]þ: 372.1262, found:
372.1249.
4.3.4. Potential Eg5 inhibitor (3w). Colorless oil; yield: 81.0 mg
(69%). 1H NMR (CDCl3, 400 MHz)
2.28 (s, 3H), 2.33 (s, 3H), 4.71 (br
d
s, 1H), 6.39 (s, 1H), 6.42e6.46 (m, 1H), 6.55 (d, J¼7.6 Hz, 1H),
6.88e6.94 (m, 3H), 7.02e7.07 (m, 1H), 7.18e7.22 (m, 1H), 7.28
4.2.22. 9-Methoxy-2,5-diphenyl-5,6-dihydropyrazolo[1,5-c]quin-
(s,1H); 13C NMR (CDCl3,100 MHz)
d
13.8, 20.6, 66.4 (d, J¼4.3 Hz,1C),
azoline (3v). Light yellow solid; yield: 100.4 mg (71%); mp
99.3, 114.1, 115.3, 115.5 (d, J¼21.1 Hz, 1C), 124.2, 124.4 (d, J¼2.9 Hz,
1C), 127.1 (d, J¼3.0 Hz, 1C), 127.6 (d, J¼12.3 Hz, 1C), 129.2, 130.0,
130.3 (d, J¼8.0 Hz, 1C), 136.3, 139.0, 149.7, 159.7 (d, J¼244.4 Hz, 1C).
HRMS (ESI) calcd for C18H17FN3 [MþH]þ: 294.1401, found: 294.1413.
105e107 ꢀC. 1H NMR (CDCl3, 400 MHz)
d 3.82 (s, 3H), 4.52 (br s, 1H),
6.57 (s, 1H), 6.71e6.78 (m, 2H), 6.89 (s, 1H), 7.10 (d, J¼2.4 Hz, 1H),
7.29e7.34 (m, 6H), 7.38e7.42 (m, 2H), 7.85e7.87 (m, 2H); 13C NMR
(CDCl3, 100 MHz)
d 55.8, 72.2, 97.1, 108.7, 115.9, 116.6, 118.0, 125.8,
126.6, 127.8, 128.6, 128.7, 128.8, 132.7, 133.4, 138.5, 139.7, 151.9,
154.2. HRMS (ESI) calcd for C23H20N3O [MþH]þ: 354.1601, found:
354.1611.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grants 21202040 and 21272058) and PCSIRT (IRT1061) for finan-
cial support.
4.3. Typical procedure for the preparation of potential Eg5
inhibitor 3w
4.3.1. Methyl 2-bromo-5-methylbenzoate (5).8 To a suspension of
compound 4 (2.15 g, 10 mmol) in dry DCM (40 mL) and DMF
(0.2 mL) at 0 ꢀC was slowly added oxalyl chloride (1.3 mL, 15 mmol).
After being stirred for 1 h at room temperature, the reaction mix-
ture was treated with MeOH (20 mL) and then stirred for 3 h. The
resulting solution was neutralized with saturated aqueous Na2CO3
(100 mL) and extracted with DCM (70 mLꢁ2). The combined or-
ganic layer was washed with water (50 mL) and brine (50 mL),
dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure and the residue was purified by chromatography on
silica gel, eluting with petroleum ether/ethyl acetate (30:1), to af-
ford compound 5 (2.27 g) as colorless oil in 99% isolated yield. 1H
Supplementary data
Copies of 1H NMR and 13C NMR spectra of 3aev, 5, 6, 1g, and 3w.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.027.
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d
2.30 (s, 3H), 3.90 (s, 3H), 7.10 (dd, J¼2.4,
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hydride (18 mmol) in dry THF (30 mL) was slowly added acetone
(10 mmol) under nitrogen atmosphere. After being stirred for 2 h at
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