Efficient copper-catalyzed synthesis of 2-amino-4(3h)-quinazolinone and 2-aminoquinazoline derivatives

Article abstract of DOI:10.1055/s-0029-1216871

We have developed a versatile and efficient method for copper-catalyzed synthesis of both 2-amino-4(3H)-quinazolinone and 2-aminoquinazoline derivatives. The protocol uses readily available substituted 2-halobenzoic acids, 2-bromobenzaldehyde, 2-bromophen

Full text of DOI:10.1055/s-0029-1216871

PAPER
2679
Efficient Copper-Catalyzed Synthesis of 2-Amino-4(3H)-quinazolinone and
2-Aminoquinazoline Derivatives
C
atalyze
d
Synthes
u
is of
Q
uinazo
h
linone
a
nd Q
u
uinazoline
D
eriva
H
tives uang,a,b Haijun Yang,a Hua Fu,*a Renzhong Qiao,*b Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
b
State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering,
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, P. R. of China
E-mail: qiaorz@mail.buct.edu.cn
Received 10 March 2009; revised 27 April 2009
the onset of diabetic complications, and compound B
shows antihypertensive activity (Figure 1).7 Compound C
displays potent inhibitors of tRNA-guanine transglycosy-
lase,8 and compound D was used as a 2¢-deoxynucleotide
Abstract: We have developed a versatile and efficient method for
copper-catalyzed synthesis of both 2-amino-4(3H)-quinazolinone
and 2-aminoquinazoline derivatives. The protocol uses readily
available substituted 2-halobenzoic acids, 2-bromobenzaldehyde,
2-bromophenyl ketones and guanidines as the starting materials, in- analogue.9 The 2-aminoquinazolines have been shown to
be potential histamine H2 antagonists,10 thymidylate syn-
expensive copper(I) iodide as the catalyst, and the method has im-
thase inhibitors,11 cognition enhancement agents,12 and
portant application values for construction of N-heterocycles in
organic chemistry and medicinal chemistry.
inhibitors of tumor necrosis factor.13 For example, it is re-
Key words: copper-catalyzed, cross-coupling, 2-amino-4(3H)-
ported that E is used as potent H4R (the human histamine
H4 receptor) ligands,14 arylaminoquinazoline pyridones F
quinazolinone, 2-aminoquinazoline, synthetic method
as potent, selective, and orally efficacious inhibitors of re-
ceptor tyrosine kinase c-Kit,15 and G as a 2¢-deoxynucle-
otide analogue (Figure 1).16 Although some methods have
been reported for the synthesis of 2-amino-4(3H)-
quinazolinone17 and 2-aminoquinazoline derivatives,15,16
the routes used are often troublesome and some starting
materials are not readily available or are difficult to pre-
pare, so it is highly desirable to develop a more conve-
nient and efficient method. Recently, great progress for
copper-catalyzed N-arylations have been made,18 and we
have also developed some copper-catalyst systems that
were used in N-arylations.19 Some N-heterocycles have
been constructed via the Ullmann coupling by us20 and
other research groups.21 Herein, we report a simple, prac-
tical and efficient strategy for copper-catalyzed synthesis
of 2-amino-4(3H)-quinazolinone and 2-aminoquinazoline
derivatives.
The quinazoline skeleton is found to be an important class
of molecules with physiological significance and pharma-
ceutical utility.1 The quinazoline derivatives with differ-
ent substituent groups show different biological and
medicinal activity. 2-Amino-4(3H)-quinazolinone deriva-
tives display a large range of biological properties such as
antitumor (thymidylate synthase inhibition), antibacterial
and antifungal activities,2 antihypertensive effects,3 or
dopamine agonist activity.4 They have also been shown to
interfere with insulin secretion and smooth muscle con-
tractile activity by targeting KATP channel activity,5 and
such molecules were used as analgesic and anti-inflam-
matory agents.6
For example, 2-(arylamino)-4(3H)-quinazolinone A is an
inhibitor of the enzyme aldose reductase,6 which prevents
O
O
H
N
O
NH
NH
COOH
N
HN
NH
N
N
NH2
N
N
H
N
N
H
O
OH
C
A
B
O
N
NH2
H2N
N
N
NH
N
N
O
N
antiTA
N
HO
N
NH2
N
N
O
HO
N
D
E
F
G
O
N
Me
HO
Ar
HO
Figure 1 Several examples of 2-amino-4(3H)-quinazolinone and 2-aminoquinazoline derivatives with biological and medicinal activity
SYNTHESIS 2009, No. 16, pp 2679–2688
x
x.
x
x
.
2
0
0
9
Advanced online publication: 26.06.2009
DOI: 10.1055/s-0029-1216871; Art ID: F05409SS
© Georg Thieme Verlag Stuttgart · New York

2680
X. Huang et al.
PAPER
Initially, 2-bromobenzoic acid and pyrrolidine-1-carbox- trogen atmosphere at 110 °C (entries 1–6), and copper io-
amidine sulfate were chosen as the model substrates to op- dide showed the best activity (entry 1). The effect of
timize reaction conditions including optimization of solvents was investigated (compare entries 1, 7 and 8),
catalysts, solvents and bases. As shown in Table 1, several and N,N-dimethylformamide was the best choice (entry
copper catalysts were tested using cesium carbonate as the 1). Other bases, potassium carbonate and tripotassium
base and N,N-dimethylformamide as the solvent under ni- phosphate, were also screened, and cesium carbonate
Table 1 Copper-Catalyzed Coupling of Pyrrolidine-1-carboxamidine Sulfate with 2-Bromobenzoic Acid or 2-Bromobenzaldehyde: Optimi-
zation of Conditionsa
O
O
NH
OH
N
N
N
catalyst, ligand
base, solvent
Br
NH
3c
1a
+
•H2SO4
N
NH2
CHO
Br
N
2
2c
N
4a
5c
HO
COOH
COOH Me NH HN Me
COOH
N
H
N
H
N
H
COOH
L4
Me
N
L1
L2
L3
L5
Me
Entry
1
Catalyst
CuI
Ligand
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Yield (%)b
85
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
2
Cu
–
67
3
CuSO4
CuBr
Cu2O
Cu(OAc)2·H2O
CuI
–
80
4
–
75
5
–
83
6
–
77
7
–
78
8
CuI
–
trace
70
9
CuI
–
10
11
12
13
14
15
16
17
18
19
CuI
–
K3PO4
73
–
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
CuI
L1
–
78
CuI
21c
67c
41c
65c
32c
38c
53
CuI
L1
L2
L3
L4
L5
L1
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: using 1a as the substrate for entries 1–12; using 4a as the substrate for entries 13–19. 2-Bromobenzoic acid or 2-bro-
mobenzaldehyde (0.5 mmol), pyrrolidine-1-carboxamidine sulfate (2c) (1 mmol), catalyst (0.1 mmol), ligand (0.2 mmol), base (2 mmol), sol-
vent (3 mL for entries 1–12, 5 mL for entries 13–19) under N2. Reaction temperature (110 °C for entries 1–12, 120 °C for entries 13–19).
b Isolated yield.
c In the presence of 200 mg of 4 Å MS.
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

PAPER
Catalyzed Synthesis of Quinazolinone and Quinazoline Derivatives
2681
proved to be the most effective base (compare entries 1, 9 ter the optimization process for catalysts, ligands, solvents
and 10). No target product was observed in the absence of and bases, the various 2-amino-4(3H)-quinazolinone and
catalyst (entry 11). Reaction yield decreased when L-pro- 2-aminoquinazoline derivatives were synthesized under
line was used as the ligand (entry 12). Reaction tempera- our standard conditions: 20 mol% copper(I) iodide as the
ture was also investigated, the yield of the target product catalyst, 4 equivalents cesium carbonate as the base (rela-
reached a maximum when temperature was gradually tive to 2-halobenzoic acids, 2-bromobenzaldehydes or 2-
raised to 110 °C. However, reaction of 2-bromobenzalde- bromophenyl ketones) and N,N-dimethylformamide as
hyde with pyrrolidine-1-carboxamidine sulfate did not the solvent at 110 °C or 120 °C under a nitrogen atmo-
perform well (entry 13) under the optimized conditions in sphere. 40 mol% L-proline as the ligand was required us-
entry 1. Various ligands L1–L5 were screened in the pres- ing 2-bromobenzaldehyde or 2-bromophenyl ketones as
ence of 200 mg of 4 Å MS (entries 14–18), and L-proline the substrates, and 4 Å MS was added for 2-bromobenzal-
showed highest efficiency (entry 14). The coupling pro- dehyde.
vided lower yield in the absence of 4 Å MS (entry 19). Af-
Table 2 Copper-Catalyzed Synthesis of 2-Amino-4(3H)-quinazolinoe Derivativesa
O
O
CuI, Cs2CO3
DMF, 110 °C
2•HY
NH
HN
R2
OH
NH
R1
R1
+
R3
N
R3
X
N
N
R2
1
2
3
O
O
O
Cl
OH
OH
OH
Br
Br
Cl
1a
1b
1c
Entry
1
1
2
Product, Yieldb
O
NH
NH
•H2SO4
O
N
1a
NH2
N
N
2
O
2a
2b
2c
3a (81%)
O
NH
NH
•H2SO4
N
2
3
1a
N
N
NH2
2
3b (80%)
O
NH
NH2
NH
•H2SO4
N
1a
N
N
2
3c (85%)
O
NH
NH
•H2SO4
N
N
4
5
1a
1a
NH2
N
N
2
N
2d
Me
3d (84%)
O
NH•HCl
H2N
NH
NH2
N
NH2
2e
3e (64%)
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

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PAPER
Table 2 Copper-Catalyzed Synthesis of 2-Amino-4(3H)-quinazolinoe Derivativesa (continued)
O
O
CuI, Cs2CO3
DMF, 110 °C
2•HY
NH
HN
R2
OH
NH
R1
R1
+
R3
N
R3
X
N
N
R2
1
2
3
O
O
O
Cl
OH
OH
OH
Br
Br
Cl
1a
1b
1c
Entry
1
2
Product, Yieldb
3a (74%)
6
7
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
3b (77%)
3c (78%)
8
9
3d (75%)
3e (50%)
10
O
Cl
NH
11
12
13
14
1c
1c
1c
1c
2a
2b
2d
2c
N
N
O
3f (90%)
O
Cl
NH
N
N
3g (94%)
O
Cl
NH
N
N
N
Me
3h (93%)
O
Cl
NH
N
N
3i (95%)
a Reaction conditions: under N2, substituted 2-halobenzoic acid (0.5 mmol), guanidine sulfate (1 mmol) or guanidine hydrochloride (1 mmol),
CuI (0.1 mmol), Cs2CO3 (2 mmol), DMF (3 mL), reaction temperature (110 °C), reaction time (20 h for entries 1–4; 40 h for others).
b Isolated yield.
The scope of copper-catalyzed couplings of the substitut- yields (entries 6–10). Aryl chlorides are weak substrates
ed 2-halobenzoic acids with guanidine salt derivatives in the previous copper-catalyzed N-arylations,18,19 and the
was investigated under our optimized conditions. As results showed the ortho-effect of carboxyl during N-ary-
shown in Table 2, all the examined substrates gave the lations (see the reaction mechanism). In addition, N-ary-
corresponding 2-amino-4(3H)-quinazolinone derivatives lation for 2-bromo-5-chlorobenzoic acid selectively
in good to excellent yields. The substituted guanidines occurred at the ortho-site C–Br bond of carboxyl 1c, and
displayed higher reactivity than free guanidine. Interest- C–Cl bond at the 5-site remained which also exhibited the
ingly, 2-chlorobenzoic acid (1b) also provided good ortho-effect of carboxyl (entries 11–14). 2-Bromo-5-
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

PAPER
Catalyzed Synthesis of Quinazolinone and Quinazoline Derivatives
2683
Table 3 Copper-Catalyzed Synthesis of 2-Aminoquinazoline De-
chlorobenzoic acid (entries 11–14) provided higher yields
than the other 2-halobenzoic acids. We also attempted
cascade reactions of 2-bromobenzaldehyde or 2-bro-
mophenyl ketones with guanidine salt derivatives to syn-
thesize various 2-aminoquinazoline derivatives under our
optimized conditions. As shown in Table 3, the tested
substrates provided moderate to good yields. In general,
the order of reactivity is 1-(2-bromophenyl)ethanone > 2-
bromobenzaldehyde > (2-bromophenyl)(phenyl)metha-
none, and the substituted guanidines showed higher reac-
tivity than free guanidine which are similar to the results
shown in Table 2.
rivativesa (continued)
O
R4
N
CuI, L-proline
Cs2CO3, DMF
HN
NH
2 •HY
R4
N
+
R3
N
120 °C
R2
O
Br
R3
N
R2
4
2
5
O
O
H
Ph
Br
Br
Br
4a
4b
4c
Entry
7
4
2
Product/Yieldb
Table 3 Copper-Catalyzed Synthesis of 2-Aminoquinazoline
Derivativesa
O
R4
N
N
CuI, L-proline
Cs2CO3, DMF
HN
NH
2 •HY
R4
4b
2b
N
+
N
N
R3
N
120 °C
R2
O
Br
R3
N
R2
4
2
5
5g (81%)
O
O
H
Ph
N
8
4b
2c
Br
Br
Br
N
N
4a
4b
4c
5h (83%)
Entry
1
4
2
Product/Yieldb
N
N
9
10
11
4b
4b
4c
2d
2e
2a
4a
4a
4a
2a
N
N
N
N
O
N
Me
5a (64%)
5i (81%)
N
N
N
2
3
2b
2c
N
N
N
N
N
N
N
NH2
5b (60%)
5j (48%)
Ph
N
N
N
5c (67%)
O
5k (55%)
Ph
4
5
4a
4a
2d
2e
N
N
N
Me
12
13
4c
2b
5d (48%)
N
N
N
5l (50%)
N
NH2
Ph
5e (51%)
N
4c
2c
N
N
N
6
4b
2a
N
N
O
5m (56%)
5f (67%)
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2684
X. Huang et al.
PAPER
Table 3 Copper-Catalyzed Synthesis of 2-Aminoquinazoline De-
of the carboxyl and amino groups in 8 affords the target
product 3 leaving water.
rivativesa (continued)
O
R4
N
In summary, we have developed a versatile and efficient
method for the copper-catalyzed synthesis of both 2-ami-
no-4(3H)-quinazolinone and 2-aminoquinazoline deriva-
tives. The couplings were performed using readily
available starting materials (substituted 2-halobenzoic
acids, 2-bromobenzaldehyde, 2-bromophenyl ketones and
guanidines) and inexpensive catalyst (CuI). The present
method shows simple, economical and practical advan-
tages over the previous methods, so it will provide an op-
portunity for construction of diverse and useful molecules
in biological chemistry and medicinal chemistry.
CuI, L-proline
Cs2CO3, DMF
HN
NH
2 •HY
R4
N
+
R3
N
120 °C
R2
O
Br
R3
N
R2
4
2
5
O
O
H
Ph
Br
Br
Br
4a
4b
4c
Entry
14
4
2
Product/Yieldb
Ph
N
All reactions were carried out under N2. NMR spectra were record-
ed on a Jeol JNM-ECA 300 spectrometer in CDCl3 using TMS as
the internal standard (1H NMR: TMS at 0.00 ppm, CDCl3 at 7.24
ppm; 13C NMR: CDCl3 at 77.0 ppm) or in DMSO-d6 using TMS as
the internal standard (1H NMR: TMS at 0.00 ppm, DMSO at 2.50
ppm; 13C NMR: DMSO at 40.0 ppm). Low-resolution ESI-MS were
carried out on a Bruker ESQYIRE-LC spectrometer, and high-res-
olution mass spectra were recorded on a Waters Q-TOF Premier
spectrometer. PE = petroleum ether (bp 60–90 °C).
4c
4c
2d
N
N
N
Me
5n (48%)
Ph
N
15
2e
Compounds 3a–i; General Procedure
N
NH2
A two-neck round bottom flask was charged with a magnetic stirrer,
evacuated and backfilled with N2. Substituted 2-halobenzoic acid
(0.5 mmol), guanidine sulfate (1 mmol) or guanidine hydrochloride
(1 mmol), Cs2CO3 (2 mmol, 652 mg) and DMF (3 mL) were added.
After stirring for 20 min under N2, CuI (0.1 mmol) was added to the
flask. The reaction temperature was raised to 110 °C. After 20 h (for
entries 1–4 in Table 2) or 40 h (for entries 5–14 in Table 2), the re-
sulting solution was cooled to r.t. and filtered, and the solid was
washed with DMF (3 mL). The combined filtrate was concentrated
with the aid of a rotary evaporator, and the residue was purified by
column chromatography on silica gel to provide the desired prod-
uct.
5o (45%)
a Reaction conditions: under N2, reaction temperature (120 °C), reac-
tion time (40 h), aldehyde or ketone (0.5 mmol), guanidine sulfate (1
mmol) or guanidine hydrochloride (1 mmol), CuI (0.1 mmol), L-pro-
line (0.2 mmol), Cs2CO3 (2 mmol), DMF (5 mL). 200 mg of 4 Å MS
was added for aldehyde.
b Isolated yield.
A possible formation mechanism of 2-amino-4(3H)-
quinazolinone derivatives was proposed in Scheme 1 ac-
cording to the results shown in Table 2 and the ortho-sub-
stituent effect.22 Coordination of substituted 2-
halobenzoic acid with copper(I) iodide first forms 6 in the
presence of base (Cs2CO3). Oxidative addition of 6 and a
complex of copper with guanidine provides coordinate 7,
reductive elimination of 7 gives the N-arylation product
(8) of guanidine, releasing copper catalyst, and coupling
2-(Morpholin-1-yl)quinazolin-4(3H)-one (3a)23
Eluent: PE–EtOAc (2:1). Yield: 93 mg (81% using 2-bromobenzoic
acid as the substrate); 85 mg (74% using 2-chlorobenzoic acid as the
substrate). White solid; mp > 250 °C.
1H NMR (CDCl3, 300 MHz): d = 11.83 (br s, 1 H), 8.02 (d, J = 7.9
Hz, 1 H), 7.62 (t, J = 8.2 Hz, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 7.19 (t,
J = 7.2 Hz, 1 H), 7.81–7.87 (m, 8 H).
HN
R2
NH2
R3
O
O
N
2
CuI, Cs2CO3
OH
O
R1
R1
Cu
1
X
HI
X
6
O
O
O
N
Cs2CO3
CuX
O
OH
NH2
NH
R1
R1
R1
R3
Cu
X
N
N
H2O
R2
8
HN
R2
NH2
3
N
7
R2
R3
N
R3
Scheme 1 Possible formation mechanism of 2-amino-4(3H)-quinazolinone derivatives
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

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Catalyzed Synthesis of Quinazolinone and Quinazoline Derivatives
2685
13C NMR (CDCl3, 75 MHz): d = 165.6, 151.1, 150.4, 135.1, 126.2,
6-Chloro-2-(piperidin-1-yl)quinazolin-4(3H)-one (3g)17c
125.5, 123.0, 116.9, 66.7, 45.6.
MS: m/z [M + H]+ = 232.2.
Eluent: CHCl3–MeOH (from 100:1 to 60:1). Yield: 124 mg (94%).
White solid; mp > 250 °C.
1H NMR (DMSO-d6, 600 MHz): d = 11.44 (br s, 1 H), 7.81 (s, 1 H),
7.58 (dd, J = 8.5, 2.8 Hz, 1 H), 7.25 (d, J = 9.0 Hz, 1 H), 3.61 (t,
J = 5.5 Hz, 4 H), 1.53–1.59 (m, 6 H).
13C NMR (DMSO-d6, 150 MHz): d = 162.7, 151.2, 150.1, 134.8,
127.4, 126.0, 125.2, 118.2, 46.2, 25.6, 24.5.
2-(Piperidin-1-yl)quinazolin-4(3H)-one (3b)24
Eluent: PE–EtOAc (2:1). Yield: 92 mg (80% using 2-bromobenzoic
acid as the substrate); 89 mg (77% using 2-chlorobenzoic acid as the
substrate). White solid; mp 225–228 °C.
1H NMR (CDCl3, 300 MHz): d = 11.55 (br s, 1 H), 8.04 (dd, J = 7.9,
1.4 Hz, 1 H), 7.57 (dt, J = 7.6, 1.4 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1
H), 7.12 (t, J = 7.9 Hz, 1 H), 3.77 (m, 4 H), 1.72 (m, 6 H).
MS: m/z [M + H]+ = 264.1.
6-Chloro-(4-methylpiperazin-1-yl)quinazolin-4(3H)-one (3h)26
Eluent: CHCl3–MeOH (from 100:1 to 30:1). Yield: 129 mg (93%).
White solid; mp > 250 °C (Lit.26 > 250 °C).
13C NMR (CDCl3, 75 MHz): d = 165.7, 151.6, 150.5, 134.8, 126.3,
125.2, 122.2, 116.6, 46.4, 25.8, 24.6.
MS: m/z [M + H]+ = 230.3.
1H NMR (DMSO-d6, 600 MHz): d = 11.50 (br s, 1 H), 7.82 (s, 1 H),
7.60 (dd, J = 8.6, 2.1 Hz, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 3.62 (t,
J = 4.8 Hz, 4 H), 2.37 (t, J = 4.8 Hz, 4 H), 2.20 (s, 3 H).
2-(Pyrrolidin-1-yl)quinazolin-4(3H)-one (3c)
Eluent: PE–EtOAc (2:1). Yield: 91 mg (85% using 2-bromobenzoic
acid as the substrate); 84 mg (78% using 2-chlorobenzoic acid as the
substrate). White solid; mp 232–235 °C.
1H NMR (CDCl3, 300 MHz): d = 11.00 (br s, 1 H), 8.05 (d, J = 7.6
Hz, 1 H), 7.57 (t, J = 8.3 Hz, 1 H), 7.38 (d, J = 8.3 Hz, 1 H), 7.10 (t,
J = 7.2 Hz, 1 H), 3.71 (t, J = 6.2 Hz, 4 H), 2.06 (t, J = 6.5 Hz, 4 H).
13C NMR (DMSO-d6, 150 MHz) (small amount of D2SO4 was add-
ed to promote dissolving power of sample in DMSO-d6): d = 162.7,
157.6, 151.1, 146.0, 135.3, 128.1, 125.5, 118.5, 52.2, 43.0, 42.7.
MS: m/z [M + H]+ = 279.1.
6-Chloro-2-(pyrrolidin-1-yl)quinazolin-4(3H)-one (3i)26
Eluent: CHCl3–MeOH (from 100:1 to 60:1). Yield: 118 mg (95%).
White solid; mp > 250 °C (Lit.26 >250 °C).
13C NMR (CDCl3, 75 MHz): d = 165.0, 151.7, 148.9, 134.6, 126.3,
124.6, 121.5, 116.2, 46.7, 25.4.
HRMS: m/z [M + H]+ calcd for C12H14N3O: 216.1137; found:
216.1141.
1H NMR (DMSO-d6, 600 MHz): d = 11.28 (br s, 1 H), 7.81 (s, 1 H),
7.54 (dd, J = 8.6, 2.8 Hz, 1 H), 7.23 (d, J = 8.9 Hz, 1 H), 3.49 (t,
J = 6.2 Hz, 4 H), 1.90 (t, J = 6.2 Hz, 4 H).
13C NMR (DMSO-d6, 150 MHz) (small amount of D2SO4 was add-
ed to promote dissolving power of sample in DMSO-d6): d = 159.7,
147.2, 138.2, 136.5, 129.7, 126.3, 119.9, 116.6, 49.6, 25.1.
2-(4-Methylpiperazin-1-yl)quinazolin-4(3H)-one (3d)23a
Eluent: CHCl3–MeOH (30:1). Yield: 103 mg (84% using 2-bro-
mobenzoic acid as the substrate); 91 mg (75% using 2-chlorobenzo-
ic acid as the substrate). White solid; mp 225–228 °C.
1H NMR (CDCl3, 300 MHz): d = 11.78 (br s, 1 H), 8.04 (d, J = 7.6
Hz, 1 H), 7.60 (t, J = 6.9 Hz, 1 H), 7.39 (d, J = 7.9 Hz, 1 H) 7.17 (t,
J = 7.6 Hz, 1 H), 3.85 (t, J = 4.5 Hz, 4 H), 2.59 (t, J = 4.5 Hz, 4 H),
2.38 (s, 3 H).
13C NMR (CDCl3, 75MHz): d = 165.5, 151.3, 150.3, 134.9, 126.1,
125.3, 122.6, 116.7, 54.7, 46.1, 45.0.
MS: m/z [M + H]+ = 245.2.
MS: m/z [M + H]+ = 250.1.
Compounds 5a–o; General Procedure
A two-neck round bottom flask was charged with a magnetic stirrer,
evacuated and backfilled with N2. 2-Bromobenzaldehyde or 2-bro-
mophenyl ketone (0.5 mmol), guanidine sulfate (1 mmol) or guani-
dine hydrochloride (1 mmol), L-proline (0.2 mmol), Cs2CO3 (2
mmol, 652 mg) and DMF (5 mL) were added (200 mg of 4 Å MS
was added for 2-bromobenzaldehyde). After stirring for 20 min un-
der N2, CuI (0.1 mmol) was added to the flask, and then the reaction
temperature was raised to 120 °C. After 40 h, the resulting solution
was cooled to r.t. and filtered, and the solid was washed with DMF
(3 mL). The combined filtrate was concentrated with the aid of a ro-
tary evaporator, and the residue was purified by column chromatog-
raphy on silica gel to provide the desired product.
2-Aminoquinazolin-4(3H)-one (3e)25
Eluent: CHCl3–MeOH (from 100:1 to 20:1). Yield: 52 mg (64% us-
ing 2-bromobenzoic acid as the substrate); 41 mg (50% using 2-
chlorobenzoic acid as the substrate). White solid; mp > 250 °C.
1H NMR (DMSO-d6, 300 MHz): d = 11.18 (br s, 1 H), 7.87 (dd, J =
7.9, 1.4 Hz, 1 H), 7.55 (dt, J = 7.4, 1.7 Hz, 1 H), 7.19 (d, J = 8.3 Hz,
1 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.50 (br s, 2 H).
2-(Morpholin-1-yl)quinazoline (5a)
Eluent: PE–EtOAc (40:1). Yield: 68 mg (64%). Yellow solid; mp
112–115 °C.
13C NMR (DMSO-d6, 75 MHz): d = 163.5, 152.7, 134.6, 126.5,
123.7, 122.1, 117.6.
1H NMR (CDCl3, 300 MHz): d = 9.00 (s, 1 H), 7.68–7.63 (m, 2 H),
7.58 (d, J = 8.6 Hz, 1 H), 7.22 (t, J = 7.9 Hz, 1 H), 3.95 (t, J = 4.5
Hz, 4 H), 3.81 (t, J = 5.4 Hz, 4 H).
13C NMR (CDCl3, 75 MHz): d = 161.5, 159.3, 152.2, 134.2, 127.5,
125.8, 122.8, 119.8, 67.0, 44.6.
MS: m/z [M + H]+ = 162.2.
6-Chloro-2-(morpholin-1-yl)quinazolin-4(3H)-one (3f)
Eluent: CHCl3–MeOH (from 100:1 to 60:1). Yield: 119 mg (90%).
White solid; mp > 250 °C.
1H NMR (DMSO-d6, 600 MHz): d = 11.58 (br s, 1 H), 7.84 (s, 1 H)
7.62 (dd, J = 8.4, 2.8 Hz, 1 H), 7.29 (d, J = 9.0 Hz, 1 H), 3.69–3.59
(m, 8 H),
13C NMR (DMSO-d6, 150 MHz): d = 162.6, 151.6, 149.6, 134.9,
127.6, 126.6, 125.3, 118.7, 66.2, 45.9.
HRMS: m/z [M + H]+ calcd for C12H13ClN3O2: 266.0696; found:
266.0702.
HRMS: m/z [M + H]+ calcd for C12H14N3O: 216.1137; found:
216.1142.
2-(Piperidin-1-yl)quinazoline (5b)27
Eluent: PE–EtOAc (40:1). Yield: 63 mg (60%). Yellow solid; mp
148–150 °C.
1H NMR (CDCl3, 300 MHz): d = 8.96 (s, 1 H), 7.64–7.52 (m, 3 H),
7.17–7.12 (m, 1 H), 3.92 (t, J = 6.0 Hz, 4 H), 1.64 (m, 6 H).
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X. Huang et al.
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13C NMR (CDCl3, 75 MHz): d = 161.4, 159.4, 152.6, 133.9, 127.4,
125.6, 122.1, 119.4, 45.2, 26.0, 25.1.
MS: m/z [M + H]+ = 214.4.
1H NMR (CDCl3, 300 MHz): d = 7.79 (d, J = 7.9 Hz, 1 H), 7.58–
7.69 (m, 2 H), 7.11 (m, 1 H), 3.70 (t, J = 6.8 Hz, 4 H), 2.76 (s, 3 H),
2.00 (m, 4 H).
13C NMR (CDCl3, 75 MHz): d = 168.7, 157.6, 152.4, 133.4, 126.0,
2-(Pyrrolidin-1-yl)quinazoline (5c)
Eluent: PE–EtOAc (40:1). Yield: 67 mg (67%). Yellow solid; mp
90–93 °C.
1H NMR (CDCl3, 300 MHz): d = 8.98 (s, 1 H), 7.66–7.57 (m, 3 H),
125.4, 121.4, 118.8, 46.8, 25.7, 21.9.
HRMS: m/z [M + H]+ calcd for C13H16N3: 214.1344; found:
214.1351.
7.15 (td, J = 6.3, 1.5 Hz, 1 H), 3.70 (t, J = 6.6 Hz, 4 H), 2.03 (m, 4
H).
13C NMR (CDCl3, 75 MHz): d = 161.2, 158.1, 152.7, 134.1, 127.6,
125.5, 121.8, 119.4, 47.0, 25.7.
HRMS: m/z [M + H]+ calcd for C12H14N3: 200.1188; found:
200.1185.
4-Methyl-2-(4-methylpiperazin-1-yl)quinazoline (5i)
Eluent: CHCl3–MeOH (30:1). Yield: 99 mg (81%). Yellow solid;
mp 38–39 °C.
1H NMR (CDCl3, 300 MHz): d = 7.76 (d, J = 7.9 Hz, 1 H), 7.61–
7.53 (m, 2 H), 7.14 (m, 1 H), 4.00 (t, J = 4.8 Hz, 4 H), 2.73 (s, 3 H),
2.50 (t, J = 4.8 Hz, 4 H), 2.33 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 168.8, 158.5, 152.0, 133.5, 126.3,
125.2, 122.1, 119.0, 55.2, 46.3, 43.9, 21.9.
2-(4-methylpiperazin-1-yl)quinazoline (5d)14
Eluent: CHCl3–MeOH (from 100:1 to 30:1). Yield 55 mg (48%).
HRMS: m/z [M + H]+ calcd for C14H19N4: 243.1610. found:
243.1612.
Yellow solid; mp 55–58 °C (Lit.14 74–76 °C).
1H NMR (CDCl3, 300 MHz): d = 8.99 (s, 1 H), 7.65 (m, 2 H), 7.56
(d, J = 8.4 Hz, 1 H), 7.21 (t, J = 6.9 Hz, 1 H), 4.03 (m, 4 H), 2.57
(m, 4 H), 2.39 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 161.5, 159.2, 152.3, 134.2, 127.5,
125.7, 122.6, 119.7, 55.1, 46.2, 43.9.
4-Methyl-2-aminoquinazoline (5j)
Eluent: CHCl3–MeOH (100:1). Yield: 38 mg (48%). Yellow solid;
mp 137–139 °C.
1H NMR (CDCl3, 300 MHz): d = 7.85 (d, J = 8.2 Hz, 1 H), 7.64 (t,
J = 6.9 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H),
5.85 (br s, 2 H), 2, 77 (s, 3 H).
MS: m/z [M + H]+ = 229.2.
2-Aminoquinazoline (5e)27b,28
13C NMR (CDCl3, 75 MHz): d = 170.3, 159.7, 151.6, 133.9, 125.7,
Eluent: CHCl3–MeOH (from 100:1 to 50:1). Yield: 37 mg (51%).
125.4, 122.8, 119.6, 21.6.
HRMS: m/z [M + H]+ calcd for C9H11N3: 160.0875; found:
160.0873.
Yellow solid; mp 196–199 °C (Lit.28 204 °C).
1H NMR (DMSO-d6, 300 MHz): d = 9.10 (s, 1 H), 7.77 (d, J = 7.9
Hz, 1 H), 7.66 (t, J = 6.8 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.20 (t,
J = 6.9 Hz, 1 H), 6.91 (br s, 2 H).
13C NMR (DMSO-d6, 75 MHz): d = 162.8, 161.4, 152.3, 134.5,
128.4, 125.0, 122.4, 120.0.
4-Phenyl-2-(morpholin-1-yl)quinazoline (5k)29
Eluent: PE–EtOAc (50:1). Yield: 80 mg (55%). Yellow solid; mp
118–120 °C.
1H NMR (CDCl3, 300 MHz): d = 7.84 (d, J = 8.3 Hz, 1 H), 7.76–
7.73 (m, 2 H), 7.66–7.65 (m, 2 H), 7.54–7.52 (m, 3 H), 7.19–7.14
(m, 1 H), 4.00 (t, J = 4.5 Hz, 4 H), 3.82 (t, J = 5.2 Hz, 4 H).
MS: m/z [M + H]+ = 146.2.
4-Methyl-2-(morpholin-1-yl)quinazoline (5f)29
Eluent: PE–EtOAc (40:1). Yield: 77 mg (67%). Yellow solid; mp
62–64 °C.
13C NMR (CDCl3, 75 MHz): d = 169.4, 158.7, 153.5, 137.9, 133.7,
129.9, 129.8, 128.5, 127.4, 126.4, 122.6, 118.0, 67.1, 44.6.
1H NMR (CDCl3, 300 MHz): d = 7.84 (d, J = 8.3 Hz, 1 H), 7.64–
7.59 (m, 2 H), 7.20 (td, J = 7.5, 1.8 Hz, 1 H), 3.96 (t, J = 4.5 Hz, 4
H), 3.81 (t, J = 4.6 Hz, 4 H), 2.78 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 169.1, 158.5, 151.9, 133.6, 126.4,
125.3, 122.4, 119.3, 67.1, 44.6, 21.9.
MS: m/z [M + H]+ = 292.1.
4-Phenyl-2-(piperidin-1-yl)quinazoline (5l)29
Eluent: PE–EtOAc (50:1). Yield: 72 mg (50%). Yellow solid; mp
96–98 °C.
1H NMR (CDCl3, 300 MHz): d = 7.77 (d, J = 8.6 Hz, 1 H), 7.74–
7.69 (m, 2 H), 7.63–7.53 (m, 2 H), 7.49–7.45 (m, 3 H), 7.06 (dt,
J = 7.2, 1.4 Hz, 1 H), 3.97 (t, J = 5.5 Hz, 4 H), 1.65 (m, 6 H).
MS: m/z [M + H]+ = 230.2.
4-Methyl-2-(piperidin-1-yl)quinazoline (5g)
Eluent: PE–EtOAc (40:1). Yield 92 mg (81%). Yellow solid, mp
69–71 °C.
13C NMR (CDCl3, 75 MHz): d = 169.1, 158.8, 154.0, 138.2, 133.5,
130.0, 129.6, 128.4, 127.4, 126.3, 121.9, 117.6, 45.1, 26.2, 25.2.
1H NMR (CDCl3, 300 MHz): d = 7.70 (d, J = 8.3 Hz, 1 H), 7.60–
7.52 (m, 2 H), 7.12 (m, 1 H), 3.93 (m, 4 H), 2.74 (s, 3 H), 1.63 (m,
6 H).
13C NMR (CDCl3, 75 MHz): d = 168.7, 158.7, 152.3, 133.4, 126.2,
125.2, 121.7, 118.8, 45.0, 26.0, 25.1, 21.9.
HRMS: m/z [M + H]+ calcd for C14H18N3: 228.1501; found:
228.1504.
MS: m/z [M + H]+ = 290.2.
4-Phenyl-2-(pyrrolidin-1-yl)quinazoline (5m)
Eluent: PE–EtOAc (50:1). Yield: 77 mg (56%). Yellow solid; mp
146–149 °C.
1H NMR (CDCl3, 300 MHz): d = 7.81–7.72 (m, 3 H), 7.68–7.58 (m,
2 H), 7.52–7.50 (m, 3 H), 7.08 (dt, J = 7.4, 1.7 Hz, 1 H), 3.76 (t, J =
6.9 Hz, 4 H), 2.02 (m, 4 H).
4-Methyl-2-(pyrrolidin-1-yl)quinazoline (5h)
Eluent: PE–EtOAc (40:1). Yield: 89 mg (83%). Yellow solid; mp
69–72 °C.
13C NMR (CDCl3, 75 MHz): d = 169.2, 157.7, 153.9, 138.2, 133.5,
129.9, 129.6, 128.4, 127.5, 126.0, 121.5, 117.6, 46.9, 25.7.
HRMS: m/z [M + H]+ calcd for C18H18N3: 276.1501; found:
276.1504.
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

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Catalyzed Synthesis of Quinazolinone and Quinazoline Derivatives
2687
4-Phenyl-2-(4-methylpiperazin-1-yl)quinazoline (5n)29
Eluent: CHCl3–MeOH (30:1). Yield: 71 mg (48%). Yellow solid;
mp 96–98 °C (Lit.29 97–98 °C).
1H NMR (CDCl3, 300 MHz): d = 7.82 (d, J = 8.2 Hz, 1 H), 7.75–
7.72 (m, 2 H), 7.64–7.62 (m, 2 H), 7.52–7.50 (m, 3 H), 7.12 (dt, J =
6.8, 2.7 Hz, 1 H), 4.06 (m, 4 H), 2.54 (m, 4 H), 2.37 (s, 3 H).
13C NMR (CDCl3, 75 MHz): d = 169.2, 158.7, 153.7, 138.0, 133.6,
129.9, 129.7, 128.4, 127.4, 126.3, 122.3, 117.8, 55.2, 46.3, 44.0.
MS: m/z [M + H]+ = 305.2.
(11) McNamara, D. J.; Berman, E. M.; Fry, D. W.; Werbel, L. M.
J. Med. Chem. 1990, 33, 2045.
(12) Levin, J. I.; Fanshawe, W. J.; Epstein, J. W.; Beer, B.;
Bartus, R. T.; Dean, R. L. Bioorg. Med. Chem. Lett. 1992, 2,
349.
(13) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.;
Carson, D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860.
(14) Smits, R. A.; Lim, H. D.; Hanzer, A.; Zuiderveld, O. P.;
Guaita, E.; Adami, M.; Coruzzi, G.; Leurs, R.; de Esch, I. J.
P. J. Med. Chem. 2008, 51, 2457.
(15) Hu, E.; Tasker, A.; White, R. D.; Kunz, R. K.; Human, J.;
Chen, N.; Bürli, R.; Hungate, R.; Novak, P.; Itano, A.;
Zhang, X.; Yu, V.; Nguyen, Y.; Tudor, Y.; Plant, M.; Flynn,
S.; Xu, Y.; Meagher, K. L.; Whittington, D. A.; Ng, G. Y.
J. Med. Chem. 2008, 51, 3065.
2-Amino-4-phenylquinazoline (5o)30
Eluent: PE–EtOAc (from 20:1 to 2:1). Yield: 50 mg (45%). Yellow
solid; mp 125–128 °C.
1H NMR (CDCl3, 300 MHz): d = 7.82 (d, J = 8.6 Hz, 1 H), 7.69–
7.60 (m, 4 H), 7.54–7.51 (m, 3 H), 7.19 (t, J = 7.9 Hz, 1 H), 5.94 (br
s, 2 H).
(16) Li, J.-S.; Fan, Y.-H.; Zhang, Y.; Marky, L. A.; Gold, B.
J. Am. Chem. Soc. 2003, 125, 2084.
(17) (a) For a recent review, see: Vögtle, M. M.; Marzinzik, A.
L. QSAR Comb. Sci. 2004, 23, 440. (b) Kundu, B.; Partani,
P.; Duggineni, S.; Sawant, D. J. Comb. Chem. 2005, 7, 909.
(c) Wéber, C.; Demeter, A.; Szendrei, G. I.; Greiner, I.
Tetrahedron Lett. 2003, 44, 7533. (d) Yang, R.-Y.; Kaplan,
A. Tetrahedron Lett. 2000, 41, 7005. (e) Gopalsamy, A.;
Yang, H. J. Comb. Chem. 2000, 2, 378. (f) Yu, Y.; Ostresh,
J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 5831.
(g) Wilson, L. J. Org. Lett. 2001, 3, 585. (h) Villalgordo, J.
M.; Obrecht, D.; Chucholowsky, A. Synlett 1998, 1405.
(i) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron 1989, 45,
4263. (j) Zhang, W.; Mayer, J. P.; Hall, S. E.; Weigel, J. A.
J. Comb. Chem. 2001, 3, 255. (k) Larksarp, C.; Alper, H.
J. Org. Chem. 2000, 65, 2773. (l) Fray, M. J.; Mathias, J. P.;
Nichols, C. L.; Po-Ba, Y. M.; Snow, H. Tetrahedron Lett.
2006, 47, 6365. (m) Zeghida, W.; Debray, J.; Chierici, S.;
Dumy, P.; Demeunynck, M. J. Org. Chem. 2008, 73, 2473.
(18) For recent reviews on copper-catalyzed N-arylation, see:
(a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337. (d) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054; and references cited
therein.
13C NMR (CDCl3, 75 MHz): d = 170.8, 159.8, 153.1, 137.2, 134.1,
129.9, 129.5, 128.6, 127.6, 125.7, 123.0, 118.5.
MS: m/z [M + H]+ = 222.2.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065, 20732004, 20872010), Chinese
863 Project (Grant No. 2007AA02Z160, 2006DFA43030). Pro-
grams for New Century Excellent Talents in University (NCET-05-
0062) and Changjiang Scholars and innovative Research Team in
University (PCSIRT) (No. IRT0404) in China and the Key Subject
Foundation
from
Beijing
Department
of
Education
(XK100030514).
References
(1) (a) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L.
A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges,
A. J. Science 1994, 265, 1093. (b) de Laszlo, S. E.; Chang,
R. S.; Cheng, T. B.; Faust, K. A.; Greenlee, W. J.; Kivlighn,
S. D.; Lotti, V. J.; O’Malley, S. S.; Schorn, T. W.; Siegl, P.
K.; Tran, J.; Zingaro, G. J. Bioorg. Med. Chem. Lett. 1995,
5, 1359. (c) Johne, S. Pharmazie 1981, 36, 583.
(2) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.;
Duch, D. S.; Ferone, R.; Hall, W. R.; Humphrey, J.; Kelly, J.
M.; Wilson, D. C. J. Med. Chem. 1993, 36, 2279.
(3) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.; Gutcait, A.; Liu, S.-
W.; Yen, M.-H.; Chien, S.-L.; Rong, J.-K. J. Med. Chem.
1998, 41, 3128.
(4) Grosso, J. A.; Nichols, E. D.; Kohli, J. D.; Glock, D. J. Med.
Chem. 1982, 25, 703.
(5) Somers, F.; Ouedraogo, R.; Antoine, M.-H.; de Tullio, P.;
Becker, B.; Fontaine, J.; Damas, J.; Dupont, L.; Rigo, B.;
Delarge, J.; Lebrun, P.; Pirotte, B. J. Med. Chem. 2001, 44,
2575.
(19) (a) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005,
70, 8107. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem. Eur. J. 2006, 12, 3636. (c) Jiang, D.; Fu, H.; Jiang,
Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672. (d) Jiang, Q.;
Jiang, D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007, 1836.
(e) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth.
Catal. 2006, 348, 2197.
(20) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem. Int. Ed.
2009, 48, 348. (b) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.;
Zhao, Y. Chem. Commun. 2008, 6333. (c) Yang, D.; Fu, H.;
Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 7841.
(21) For recent studies on the synthesis of N-heterocycles
through Ullmann-type couplings, see: (a) Martin, R.;
Rodríguez, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006,
45, 7079. (b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006,
71, 1802. (c) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org.
Lett. 2006, 8, 4351. (d) Zou, B.; Yuan, Q.; Ma, D. Angew.
Chem. Int. Ed. 2007, 46, 2598. (e) Yuan, X.; Xu, X.; Zhou,
X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72, 1510.
(22) (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajar, S.; Yue, T.-
Y.; Li, H.; Bräse, S.; Ramanjulu, J. M. J. Am. Chem. Soc.
1997, 119, 3421. (b) Lindley, J. Tetrahedron 1984, 40,
1433. (c) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus,
V. J. Org. Chem. 1999, 64, 2986. (d) Cai, Q.; Zou, B.; Ma,
D. Angew. Chem. Int. Ed. 2006, 45, 1276.
(6) Alagarsamy, V.; Dhanabal, K.; Parthiban, P.; Anjana, G.;
Deepa, G.; Murugesan, B.; Rajkumar, S.; Beevi, A. J.
J. Pharm. Pharmacol. 2007, 59, 669.
(7) (a) Hess, H.-J.; Cronin, T. H.; Scriabine, A. J. Med. Chem.
1968, 11, 130. (b) Hussain, M. A.; Chiu, A. T.; Price, W. A.;
Timmermans, P. B.; Shefter, E. Pharm. Res. 1988, 5, 242.
(8) Hrtner, S. R.; Ritschel, T.; Stengl, B.; Kramer, C.;
Schweizer, W. B.; Wagner, B.; Kansy, M.; Klebe, G.;
Diederich, F. Angew. Chem. Int. Ed. 2007, 46, 8266.
(9) Liu, H.; Gao, J.; Kool, E. T. J. Org. Chem. 2005, 70, 639.
(10) Ogawa, N.; Yoshida, T.; Aratani, T.; Koshinaha, E.; Kato,
H.; Ito, Y. Chem. Pharm. Bull. 1988, 36, 2955.
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York

2688
X. Huang et al.
PAPER
(23) (a) Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.
Synthesis 2008, 1069. (b) Dean, W. D.; Papadopoulos, E. P.
J. Heterocycl. Chem. 1982, 19, 1117.
(24) Weber, C.; Szendrei, G. I.; Greiner, I. Pharma. Chem. 2003,
2, 25.
(25) (a) George, B. J.; Dib, H. H. Tetrahedron 2006, 62, 1182.
(b) Leonard, N. J.; Kazmierczak, F.; Rykowski, A. Z. J. Org.
Chem. 1987, 52, 2933.
(26) Ram, V. J.; Farhanullah; Tripathi, B. K.; Srivastava, A. K.
Bioorg. Med. Chem. 2003, 11, 2439.
(27) (a) Henriksen, S. T.; Sorensen, U. S. Tetrahedron Lett. 2006,
47, 8251. (b) Sasse, K. Synthesis 1978, 379.
(28) Kvaskoff, D.; Bednarek, P.; George, L.; Waich, K.;
Wentrup, C. J. Org. Chem. 2006, 71, 4049.
(29) Gomez, P. V.; Madronero, R.; Vega, S. Synthesis 1977, 345.
(30) Kamal, A.; Rao, M. V.; Sattur, P. B. Heterocycles 1986, 24,
3075.
Synthesis 2009, No. 16, 2679–2688 © Thieme Stuttgart · New York