Three-component domino synthesis of 2-arylquinazoline-4-amines in one pot by activating an sp3 C-H bond in a nonmetal catalytic oxidation system

Article abstract of DOI:10.1002/ejoc.201101315

The nonmetal catalytic oxidation system I₂/tert-butyl hydroperoxide (TBHP) has been unprecedentedly applied to a three-component domino reaction and simultaneously a simple and efficient protocol has been developed to newly synthesize 2-aryl-N-substitutied quinazoline-4-amines in one pot from isatoic anhydride, aromatic amine, and another amine containing methylene adjacent to nitrogen. This protocol is new and practical because both the electron-donating and -withdrawing groups substituted on amines 2 or 3 can survive and provide the corresponding products in reasonable yields. Iodine is essential to the three-component, one-pot reaction unlike the step-wise procedure. The nonmetal catalytic oxidation system I₂/tert-butyl hydroperoxide (TBHP) has been successfully applied to a three-component domino reaction, and a new, simple, efficient protocol has been developed to synthesize 2-aryl-N-substitutied quinazoline-4-amines in one pot from isatoic anhydride, aromatic amine, and another amine containing methylene adjacent to nitrogen. Copyright

Full text of DOI:10.1002/ejoc.201101315

FULL PAPER
DOI: 10.1002/ejoc.201101315
Three-Component Domino Synthesis of 2-Arylquinazoline-4-amines in One Pot
by Activating an sp3 C–H Bond in a Nonmetal Catalytic Oxidation System
Li-Yan Zeng,[a] Wen-Bin Yi,[a] and Chun Cai*[a]
Keywords: Nitrogen heterocycles / Multicomponent reactions / C–H activation / Iodine / Oxidation
The nonmetal catalytic oxidation system I2/tert-butyl hydro- amine containing methylene adjacent to nitrogen. This pro-
peroxide (TBHP) has been unprecedentedly applied to a
three-component domino reaction and simultaneously a sim-
ple and efficient protocol has been developed to newly syn-
thesize 2-aryl-N-substitutied quinazoline-4-amines in one
pot from isatoic anhydride, aromatic amine, and another
tocol is new and practical because both the electron-donat-
ing and -withdrawing groups substituted on amines 2 or 3
can survive and provide the corresponding products in rea-
sonable yields. Iodine is essential to the three-component,
one-pot reaction unlike the step-wise procedure.
operation, special setups, and low yields.[3–6] Current classi-
cal protocol mainly depends on the availability of the indis-
pensable 2-amino-NЈ-substituted benzamidine precursor,
which was subsequently treated with various aldehydes,[7,8]
moreover, the prerequisite intermediate, 2-amino-NЈ-substi-
tuted benzamidine, had to be prepared from 2-aminobenzo-
nitrile and amine (Scheme 1) required high temperature and
stepwise workup procedures.[8] Nevertheless, quinazolin-4-
amines have been bioevaluated as AP-1 and NF-κB inhibi-
tors (Figure 1b),[4] nitric oxide synthase (NOS) inhibitors,
and aurora A and B inhibitors (Figure 1c);[5] tricyclic quin-
azolinimines were described to possess cholinesterase in-
hibitory activity.[6] Their wide range of bioactivities accen-
tuated the need to develop a milder and more general pro-
cedure for scaffold manipulation of quinazoline-4-amines.
Introduction
The ubiquitous quinazolinone ring, regarded as a “privi-
leged structure”, features in natural products and synthetic
compounds that exhibit a broad spectrum of biological and
pharmaceutical activities.[1] Although a number of well-es-
tablished methods directed toward preparing structural mo-
tifs containing the quinalinone moiety have been devel-
oped,[2] its derived structure, quinazolin-4-amine substi-
tuted at C2 and/or NЈ- (at C-4; Figure 1a), was scarcely con-
structed in a convenient manner. A detailed literature sur-
vey implied that most of the routes described for the synthe-
sis of quinazolin-4-amines were scattered, multistep, suf-
fered from long reaction periods, involved cumbersome
Scheme 1. Commonly used method for the synthesis of quinazolin-
4-amine.
Among the currently used strategies applied to find new
biologically active compounds, multicomponent reactions
(MCRs) are used to increase molecular complexity and di-
versity with minimum time, labor, cost, and waste pro-
duction,[9] especially for multicomponent domino reactions,
which involve preforming an intermediate in situ for subse-
quent transformations with a strategically positioned reac-
tive site in the given compound in the same reaction mix-
ture.[10] Accordingly, we tried to design a practical and ef-
ficient multicomponent domino protocol for the production
of quinazoline-4-amines. In recent years, continued research
into C–C or C–N bond formation concluded that the sp3
Figure 1. Substituted quinazolin-4-amines.
[a] Chemical Engineering College, Nanjing University of Science &
Technology,
Nanjing 210094, China
Fax: +86-25-84315030
E-mail: c.cai@mail.njust.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101315 or from
the author.
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L.-Y. Zeng, W.-B. Yi, C. Cai
FULL PAPER
C–H bond α to nitrogen in amines could be readily acti-
vated to generate iminium ions through single-electron-
transfer processes under oxidative conditions, especially
tert-butyl hydroperoxide (TBHP), and thus, to anticipate
various newer reactions.[11–13] Collectively, copper-catalyzed
oxidative sp3 C–H bond activation was prevalent, whereas
metal-free conditions were limited. Additionally, iodine,
which possesses both Lewis acid and oxidation abilities, has
been explored by the groups of Jiang, Zhang, and Fan to
promote sp3 C–H bond activation in the presence of TBHP
or PhI(OAc)2.[12,13] To the best of our knowledge, no report
has focused on the multicomponent domino reaction pro-
moted by activating the sp3 C–H bond α to nitrogen in
amines without using a transition-metal catalyst. From this
viewpoint, we employed isatoic anhydride (1a), amine, and
another amine containing methylene adjacent to nitrogen
as starting materials with the aim of producing the quinaz-
oline-4-amine structure. Herein, we describe an unprece-
dented protocol for the synthesis of quinazolin-4-amines by
applying iodine oxidative conditions to a three-component
Scheme 3. Preparation of 4aaa in one pot.
Table 1. Optimization of the conditions for the synthesis of 2-
phenyl-N-(p-tolyl)-1,2-dihydroquinazolin-4-amine (4aaa) from in-
termediate M1.[a]
domino reaction from facile starting materials with signifi- Entry I2 [mol-%] Oxidant Solvent (mL) t [h] Yield [%][b]
cant advantages over conventional linear-type syntheses.
1
2
3
4
5
6
7
8
10
20
30
0
300
10
10
10
10
10
10
10
TBHP
TBHP
TBHP
TBHP
–
H2O2
TBHP
TBHP
TBHP
TBHP
DDQ
Air
–
–
–
–
–
–
4
4
4
10
24
6
16
16
6
70
67
32
77
n.r.[c]
51
Results and Discussion
EtOH (2)
H2O (1)
DMF (1)
DMSO (1)
DMSO (1)
–
trace
43
64
With this consideration, we initially prepared 2-amino-
N-p-tolylbenzamide (M1) from 1a and p-toluidine (2a) in
EtOH at reflux with a yield of 89% in the presence of
5 mol-% of iodine (Scheme 2), and thus, heating intermedi-
ate M1 and an excess of benzylamine (3a) under I2/TBHP
oxidative conditions. Fortunately, the desired product, 2-
9
10
11
12
4
10
24
67
53
n.r.[c]
[a] Reaction conditions: intermediate M1 (1 mmol), 3a (2.5 mmol),
oxidant, and iodine were added to a tube. The tube was sealed with
a screw cap and stirred at 90 °C. The reaction was terminated when
the reaction was complete according to TLC analysis. [b] Isolated
yield. [c] n.r.: no reaction.
phenyl-N-p-tolyl-1,2-dihydroquinazolin-4-amine
(4aaa),
structurally identified by NMR spectroscopy and MS, was
formed in 4 h with 70% yield when the reaction mixture
was sealed with a screw cap in a tube at 90 °C (Scheme 3).
Thereafter, the reaction solvent, oxidant, and the amount
of iodine were primarily evaluated; the results (Table 1)
indicated that oxidant was essential (TBHP was favored),
solvent-free was optimum, and the transformation provided
77% yield of the product without iodine, but required a
prolonged reaction time of10 h (Table 1, entry 4).
influence on the reaction. Therefore, the reactants were
added in two portions, various solvents (EtOH, AcOEt,
DMSO, DMF, H2O, MeCN) were tested, and trace
amounts of product could be detected, but were difficult to
isolate. After a series of attempts, we occasionally found
that the reaction mixture containing 1a, 2a, and iodine, ex-
posed to air at 90 °C gradually melted into a homophasic
solution, but solidified in 2 min; the solid was isolated and
was proven to be M1 by means of NMR spectroscopy.
Thereupon, we added excess 3a and TBHP to the solidified
mixture containing the in situ formed intermediate M1 and
sealed the tube with a screw cap. Continued stirring for 10 h
afforded the expected product 4aaa in 34% yield. This re-
sult once again demonstrated the efficiency of solvent-free
conditions for the reaction.
Scheme 2. Preparation of intermediate 2-amino-N-(p-tolyl)benz-
amide (M1).
Encouraged by initial success with condensing 1a, 2a,
Subsequently, we tried to combine the two unit reactions and 3a in two steps, but one pot, avoiding the isolation of
into one MCR. Treatment of the three reactants 1a, 2a, and intermediate M1, we carried out further optimization of
3a under similar reaction conditions gave a poor yield of conditions. As denoted in Table 2, the amounts of iodine,
product 4aaa (Scheme 3) and modulating the reaction tem- TBHP, and 3a were evaluated. Conducting the transforma-
perature, time, or the ratio of substrates had no positive tion in the presence of 10 mol-% of iodine and 1.5 equiv. of
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Three-Component Domino Reaction
TBHP and 3a for 8 h (Table 2, entry 8) increased the yield
In a comprehensive study, various representative aro-
up to 52%. Interestingly, no 4aaa was detected from the matic amines 2 and amines 3 with an sp3 C–H bond adja-
reaction mixture without iodine, whereas heating intermedi- cent to nitrogen were then subjected to the optimized condi-
ate M1 and 3a under similar reaction conditions without tions (Table 2, entry 8). Generally, both electron-donating
iodine (Table 1, entry 4) afforded the product in 77% yield. and -withdrawing groups substituted on amines 2 and 3
Confused by the result, we heated 1a and 2a in EtOH at were tolerated and smoothly provided the corresponding
reflux without iodine (Scheme 4) to obtain intermediate M1 products in moderate to good yield. For aromatic amines
in 6 h with 71% yield, compared with the reaction catalyzed 2, the electron-donating groups facilitated the reaction from
by 5 mol-% iodine, giving 89% yield of M1 in 2 h. On all the viewpoint of reaction times t1 and t2, whereas the elec-
accounts, for the synthesis of product 4aaa, iodine only ac- tron-withdrawing groups slightly attenuated the reaction
celerated the two-unit reaction in step-wise procedure, but rate. Comparatively, for amines 3, electron-withdrawing
was necessary for in the three-component domino reaction. groups were more beneficial for the transformation in terms
The reason for this result is uncertain.
of total yields and reaction times (Table 3, entries 5–8), es-
pecially for (4-fluorophenyl)methanamine (3b), which was
reacted with 2a and transformed into the corresponding
product 4aab in 6 h in 74% yield (Table 3, entry 5). Disap-
pointingly, steric hindrance had an adverse influence on the
reaction, which was verified with the failure of the reaction
with o-substituted amines 2 and 3.
Table 2. Optimization of conditions for the synthesis of 4aaa in one
pot.[a]
In addition, we further explored the potential of this pro-
tocol with 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (1b).
A prolonged reaction time, t1, of 150 min was needed to
generate the intermediate in EtOH at reflux in air; amine 3
and TBHP were added after the solvent was evaporated. As
depicted in Table 3, entries 15–17, when compound 2a was
examined as a typical aromatic amine 2, we successfully ob-
tained the corresponding products 4baa and 4bad from 3a
and (4-methoxyphenyl)methanamine (3d), respectively, in
reasonable yields. Unexpectedly, electron-withdrawing 3b
failed to generate the corresponding product 4bab, even af-
ter prolonged reaction times.
Entry I2 [mol-%] TBHP [equiv.] 3a [equiv.] t2 [h] Yield [%][b]
In addition, it is noteworthy that when AcONH4 was em-
ployed to replace the aromatic amine for the synthesis of 2-
aryl-1,2-dihydroquinazolin-4-amine under standard condi-
tions, a rather complicated structure was formed, ac-
companied by the isolation of a complicated intermediate.
We reasoned that a polymerization reaction occurred and
suppressed the anticipated reaction. To obtain the target
structure, 2-aminobenzamide (N) was employed directly to
react with an excess amount of amine 3. The results out-
lined in Scheme 5 show that, fortunately, both electron-do-
1
2
3
4
5
6
7
8
9
10
10
0
2
2
2
2
2
2
2
1.5
1.5
1.0
2.5
2.5
2.5
2
1.5
1.2
1
1.5
2.5
1.5
10
24
24
10
8
8
16
8
34
0
20
10
10
10
10
10
10
10
32
35
45
42
30
52
41
18
16
12
[a] Reaction conditions: 1a (2 mmol), 2a (2 mmol), and iodine were
added to a tube exposed to air and stirred at 90 °C. After the reac-
tion mixture solidified, compounds 3a and TBHP were added. The
tube was sealed and stirred at 90 °C. The reaction was terminated
after analysis by TLC. [b] Isolated yield.
Scheme 4. Preparation of intermediate M1.
Scheme 5. Preparation of 2-aryl-1,2-dihydroquinazolin-4-amine.
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L.-Y. Zeng, W.-B. Yi, C. Cai
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Table 3. The three-component domino reaction for the synthesis of 2-aryl-N-substituted quinazoline-4-amines in one pot.[a]
[a] Reaction conditions: 1a (2 mmol), 2a (2 mmol), and iodine (0.2 mmol) were added to a tube exposed to air and stirred at 90 °C. After
the reaction mixture solidified, compounds 3a (3 mmol) and TBHP (3 mmol) were added. The tube was sealed and stirred at 90 °C. The
reaction was terminated after analysis by TLC. [b] Isolated yield.
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Three-Component Domino Reaction
cap. Mass spectra were recorded on a Finnigan TSQ Quantum-LC/
MS/MS instrument in electrospray ionization (negative) mode. H
nating and -withdrawing amines 3 work well with N and
provide good yields of the corresponding products up to
84%.
1
NMR, 13C NMR, COSY, and HSQC spectra were recorded on a
AVANCE 500 Bruker spectrometer operating at 500 and 125 MHz
in CDCl3 or [D6]DMSO, respectively, and chemical shifts are re-
ported in ppm. Elemental analyses were performed on a Yanagim-
oto MT3CHN recorder.
A tentative mechanism is proposed in Scheme 6. Accord-
ing to our previous investigation into 1a,[2b] intermediate
M1 was formed by the elimination of CO2 from ring-
opened 1a and the presence of CO2 was confirmed when
precipitate appeared in the clarified saturated solution of
calcium hydroxide. Intermediate imine A was readily gener-
ated from M1 when amine 3 was added in the presence
of iodine, subsequently, the sp3 C–H bond in imine A was
activated by single-electron transfer under these reaction
conditions, and thus, iminium ions were generated and in-
termediate B was formed[11–14] by intramolecular cycliza-
tion and the final product 4 was generated from B.
Typical Stepwise Procedure for the Synthesis of 2-Phenyl-N-(p-
tolyl)-1,2-dihydroquinazolin-4-amine (4aaa)
Synthetic Procedure for Intermediate M1: Compounds 1a (0.815 g,
5 mmol), 2a (0.535 g, 5 mmol), and iodine (0.126 g, 1 mmol) were
added to EtOH (5 mL) and the mixture was heated at reflux in air.
The reaction mixture gradually turned into a homophasic solution
and 2 h later the reaction was terminated and cooled to room tem-
perature. The solid was precipitated and isolated by filtration, after
drying, to give the off-white product M1 (0.95 g, 84%).
Synthetic Procedure for 4aaa from Intermediate M1: Intermediate
M1 (1 mmol, 0.226 g), 3a (2.5 mmol, 0.268 g), TBHP (0.257 g of
70% aqueous solution, 2.0 mmol), and iodine (0.1 mmol, 0.025 g)
were added in a tube and sealed with a screw cap. The tube contain-
ing the reaction mixture was heated and stirred in oil bath at 90 °C.
The intermediate was monitored by TLC (4:3 petroleum ether/Ac-
OEt, v/v) and was consumed in 4 h. The reaction was terminated
and cooled to room temperature before the solid was gradually
precipitated and isolated, followed by washing with ice-cold EtOH
and a solution of sodium thiosulfate. A white powder was obtained
after drying. The product was collected as a white solid after
recrystallization from EtOH (0.22 g, 70%).
Typical One-Pot Procedure for the Synthesis of 4aaa: Compounds
1a (1 mmol, 0.163 g), 2a (1 mmol, 0.107 g), and iodine (0.1 mmol,
0.025 g) were added to a tube. Heating the tube in air at 90 °C in
an oil bath, resulted in a homophasic reaction mixture, which was
stirred for 2 min, and the mixture solidified. Compound 3a
(1.5 mmol, 0.16 g) and TBHP (0.193 g of 70% aqueous solution,
1.5 mmol) were added and the tube was sealed with a screw cap.
Stirring and heating of the solution at 90 °C for 8 h was continued
before the reaction was terminated and cooled to room tempera-
ture. Solid gradually precipitated from the reaction mixture and
was isolated followed by washing with ice-cold EtOH and a solu-
tion of sodium thiosulfate. White powder was obtained after dry-
ing. The product was collected as a white solid after recrystalli-
zation from EtOH (0.16 g, 52%).
Scheme 6. Tentative reaction mechanism.
Conclusions
We have successfully applied the nonmetal catalytic oxi-
dation system I2/TBHP to a three-component domino reac-
tion and simultaneously developed a new and efficient pro-
tocol to synthesize N-substituted 2-arylquinazoline-4-
amines in one pot from 1a, aromatic amine, and another
amine containing methylene adjacent to nitrogen. Both
electron-donating and -withdrawing groups substituted on
aromatic amines 2 or 3 can survive the reaction and provide
the correspondent products. Compared with the stepwise
General Procedure for the Synthesis of 2-Aryl-1,2-dihydroquinazolin-
4-amines from N: Compound N (1 mmol, 0.136 g), substituted 3
(1.5 mmol), TBHP (0.193 g of 70% aqueous solution, 1.5 mmol),
and iodine (0.1 mmol, 0.025 g) were added to a tube and sealed by
a screw cap. The tube containing reaction mixture was heated and
procedure, iodine played a key role in the three-component, stirred in oil bath at 90 °C. The reaction was terminated several
hours later and the reaction mixture was cooled to room tempera-
ture, solid gradually precipitated, and was isolated followed by
washing with ice-cold EtOH and a solution of sodium thiosulfate.
An off-white powder was obtained after drying.
one-pot reaction. 2-Aryl-1,2-dihydroquinazolin-4-amines
were also prepared through a similar procedure. The new
method provides a promising alternative for the synthesis of
2-arylquinazoline-4-amines, owing to its ease of execution;
flexibility; ready availability of starting materials; and sub-
stantial minimization of waste, labor, time, and cost.
2-Amino-N-(p-tolyl)benzamide (M1): Recrystallized from EtOH.
White prisms, 84% yield (0.95 g); m.p. 140–142 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.36 (s, 3 H, CH3), 5.51 (s, 2 H, NH2),
6.72–6.75 (m, 2 H, aromatic), 7.19 (d, J = 9.0 MHz, 2 H, aromatic),
7.26–7.29 (m, 1 H, aromatic), 7.46–7.49 (m, 3 H, aromatic), 7.72
(s, 1 H, NH) ppm. MS (ES–): m/z = 225 [M – H].
Experimental Section
General: All of the reagents were obtained from commercial suppli-
ers and used without further purification. The reaction vessel used
was a thick-wall pressure glass tube (capacity 15 mL) with a screw
2-Phenyl-N-(p-tolyl)-1,2-dihydroquinazolin-4-amine (4aaa): White
prisms, 52% yield (0.16 g); m.p. 188–190 °C. H NMR (500 MHz,
CDCl3): δ = 2.31 (s, 3 H, CH3), 4.72 (s, 1 H, NH), 6.01 (d, J =
1
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L.-Y. Zeng, W.-B. Yi, C. Cai
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9.0 MHz, 1 H, aromatic), 6.89–6.92 (m, 1 H, aromatic), 7.07–7.11 2.0 MHz, 1 H, aromatic), 6.68 (d, J = 8.0 MHz, 1 H, aromatic),
(m, 4 H, aromatic), 7.29–7.30 (m, 4 H, aromatic and NH), 7.32– 6.94–7.00 (m, 3 H, aromatic), 7.10–7.11 (dd, J = 7.0 MHz, 2 H,
7.34 (m, 1 H, aromatic), 7.37–7.39 (m, 2 H, aromatic), 8.04 (d, J =
aromatic), 7.26–7.27 (m, 1 H, aromatic), 7.28 (s, 1 H, NH), 7.34–
7.5 MHz, 1 H) ppm. 1H NMR (500 MHz, [D6]DMSO): δ = 2.26 7.37 (m, 3 H, aromatic), 8.02–8.03 (dd, J = 7.5 MHz, 1 H) ppm.
(s, 3 H, CH3), 6.23 (d, J = 2.5 MHz, NH), 6.71–6.76 (m, 2 H,
aromatic), 7.12–7.13 (m, 4 H, aromatic), 7.25–7.31 and 7.36–7.37
(m, 7 H, aromatic), 7.59 (d, J = 7.5 MHz, NH), 7.71 (d, J =
13C NMR (125 MHz, CDCl3): δ = 73.1, 113.9, 114.6, 114.8, 116.0,
118.9, 125.9, 126.1, 127.8, 127.8, 128.0, 128.1, 133.0, 134.7, 139.4,
144.2, 160.9, 162.1, 162.9 ppm. MS (ES–): m/z = 350 [M – H].
8.0 MHz, 1 H, aromatic), 8.04 (d, J = 7.5 MHz, 1 H) ppm. 13C C20H15ClFN3 (351.81): calcd. C 68.28, H 4.30, N 11.94; found C
NMR (125 MHz, CDCl3): δ = 21.0, 74.8, 114.8, 116.9, 119.5, 126.8,
126.9, 128.7, 128.9, 129.0, 129.6, 133.8, 136.6, 138.0, 140.0, 145.3,
163.1 ppm. MS (ES–): m/z = 312 [M – H]. C21H19N3 (313.40):
calcd. C 80.48, H 6.11, N 13.41; found C 80.41, H 6.03, N 13.54.
68.34, H 4.33, N 11.97.
2-(4-Fluorophenyl)-N-phenyl-1,2-dihydroquinazolin-4-amine (4acb):
White prisms, 58 % yield (0.19 g); m.p. 222–225 °C. 1H NMR
(500 MHz, CDCl3): δ = 4.75 (s, 1 H, NH), 6.14 (s, 1 H, aromatic),
N-(4-Chlorophenyl)-2-phenyl-1,2-dihydroquinazolin-4-amine (4aba): 6.67 (d, J = 7.5 MHz, 1 H, aromatic), 6.93–6.98 (m, 3 H, aromatic),
White prisms, 56% yield (0.19 g); m.p. 196–198 °C. 1H NMR
7.17–7.22 (m, 3 H, aromatic), 7.28 (s, 1 H, NH), 7.29–7.37 (m, 5
(500 MHz, CDCl3): δ = 4.77 (s, 1 H, NH), 6.10 (d, J = 1.5 MHz, H, aromatic), 8.03–8.04 (dd, J = 8.0 MHz, 1 H) ppm. 13C NMR
1 H, aromatic), 6.66 (d, J = 8.0 MHz, 1 H, aromatic), 6.91–6.94 (125 MHz, CDCl3): δ = 74.7, 114.8, 117.0, 119.7, 126.8, 126.8,
(m, 1 H, aromatic), 7.13 (d, J = 8.5 MHz, 2 H, aromatic), 7.25 (d, 127.0, 128.7, 128.9, 129.0, 129.1, 133.9, 139.9, 140.6, 145.3, 163.1
J = 9.0 MHz, 2 H, aromatic), 7.30–7.31 (m, 3 H, aromatic), 7.34–
7.37 (m, 3 H, aromatic), 8.03 (d, J = 7.5 MHz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 74.7, 114.9, 116.6, 119.7, 121.7,
126.9, 127.2, 127.49, 128.2, 128.4, 128.9, 129.0, 129.1, 129.2, 130.4,
132.4, 134.1, 139.0, 139.4, 145.4, 163.2 ppm. MS (ES–): m/z = 332
[M – H]. C20H16ClN3 (333.82): calcd. C 71.96, H 4.83, N 12.59;
found C 71.87, H 4.89, N 12.63.
ppm. MS (ES–): m/z = 316 [M – H]. C20H16FN3 (317.36): calcd. C
75.69, H 5.08, N 13.24; found C 75.67, H 5.03, N 13.31.
N-(4-Bromophenyl)-2-(4-fluorophenyl)-1,2-dihydroquinazolin-4-
amine (4adb): White prisms, 52% yield (0.21 g); m.p. 234–236 °C.
1H NMR (500 MHz, CDCl3): δ = 4.72 (s, 1 H, NH), 6.12 (d, J =
1.5 MHz, 1 H, aromatic), 6.68 (d, J = 8.0 MHz, 1 H, aromatic),
6.94–7.00 (m, 3 H, aromatic), 7.05–7.06 (dd, J = 6.5 MHz, 2 H,
aromatic), 7.28 (s, 1 H, NH), 7.34–7.37 (m, 3 H, aromatic), 7.42–
7.44 (m, 2 H, aromatic), 8.02–8.04 (dd, J = 8.0 MHz, 1 H) ppm.
N,2-Diphenyl-1,2-dihydroquinazolin-4-amine (4aca): White prisms,
71% yield (0.21 g); m.p. 192–194 °C. 1H NMR (500 MHz, CDCl3):
δ = 4.79 (s, 1 H, NH), 6.13 (d, J = 2.5 MHz, 1 H, aromatic), 6.65– 13C NMR (125 MHz, CDCl3): δ = 74.0, 114.9, 115.8, 116.0, 116.7,
6.66 (dd, J = 8.0 MHz, 1 H, aromatic), 6.90–6.93 (m, 1 H, aro-
120.0, 120.5, 128.8, 128.8, 128.9, 129.2, 132.1, 134.2, 135.2, 135.2,
matic), 7.2–7.22 (m, 1 H, aromatic), 7.29–7.30 (m, 4 H, aromatic 139.3, 145.2, 162.0, 163.0, 164.0 ppm. MS (ES–): m/z = 394 [M –
and NH), 7.31–7.32 (m, 1 H, aromatic), 7.32–7.33 (m, 1 H, aro-
matic), 7.38–7.39 (m, 2 H, aromatic), 8.04–8.05 (dd, J = 8.0 MHz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 74.7, 114.8, 117.0,
119.7, 126.8, 126.8, 127.0, 128.7, 128.9, 129.0, 129.1, 133.9, 139.9,
140.6, 145.3, 163.1 ppm; MS (ES–): m/z = 298 [M – H]. C20H17N3
(299.37): calcd. C 80.24, H 5.72, N 14.04; found C 80.21, H 5.78,
N 14.16.
H]. C20H15BrFN3 (396.26): calcd. C 60.62, H 3.82, N 10.60; found
C 60.57, H 3.85, N 10.69.
N,2-Di-tolyl-1,2-dihydroquinazolin-4-amine (4aac): White prisms,
49% yield (0.16 g); m.p. 218–220 °C. 1H NMR (500 MHz, CDCl3):
δ = 2.31 (s, 6 H, CH3), 4.69 (s, 1 H, NH), 6.05 (d, J = 1.5 MHz, 1
H, aromatic), 6.62 (d, J = 8.0 MHz, 1 H, aromatic), 6.88–6.91 (m,
1 H, aromatic), 7.08–7.11 (m, 6 H, aromatic), 7.24–7.26 (d, J =
8.0 MHz, 2 H, aromatic), 7.28–7.32 (m, 2 H, aromatic and NH),
8.03–8.04 (dd, J = 8.0 MHz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.0, 21.1, 74.6, 114.7, 117.0, 119.5, 126.7, 126.8,
N-(4-Bromophenyl)-2-phenyl-1,2-dihydroquinazolin-4-amine (4ada):
White prisms, 44% yield (0.17 g); m.p. 217–219 °C. 1H NMR
(500 MHz, CDCl3): δ = 4.75 (s, NH, 1 H), 6.11 (s, aromatic, 1 H),
6.66 (d, J = 8.0 MHz, aromatic, 1 H), 6.92–6.94 (m, aromatic, 1 129.0, 129.4, 129.5, 133.7, 136.5, 137.1, 138.0, 138.8, 145.3, 163.1
H), 7.07–7.09 (m, aromatic, 2 H), 7.30–7.33 (m, aromatic, 4 H), ppm. MS (ES–): m/z = 326 [M – H]. C22H21N3 (327.43): calcd. C
7.34–7.37 (m, aromatic and NH, 3 H), 7.40–7.42 (m, aromatic, 2
H), 8.03 (d, J = 8.0 MHz, 1 H). 13C NMR (125 MHz, CDCl3): δ
= 74.7, 114.9, 116.7, 119.8, 120.4, 126.8, 128.7, 128.9, 129.1, 129.3,
132.0, 134.1, 139.4, 139.5, 145.3 ppm. MS (ES–): m/z = 376 [M –
H]. C20H16BrN3 (378.27): calcd. C 63.50, H 4.26, N 11.11; found
C 63.55, H 4.23, N 11.21.
80.70, H 6.46, N 12.83; found C 80.76, H 6.43, N 12.75.
N-(4-Chlorophenyl)-2-(p-tolyl)-1,2-dihydroquinazolin-4-amine
(4abc): White prisms, 47 % yield (0.16 g); m.p. 240–242 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 4.71 (s, 1 H,
NH), 6.07 (d, J = 1.5 MHz, 1 H, aromatic), 6.64 (d, J = 8.0 MHz,
1 H, aromatic), 6.90–6.93 (m, 1 H, aromatic), 7.09 (d, J = 8.0 MHz,
1 H, aromatic), 7.13–7.14 (dd, J = 7.0 MHz, 2 H, aromatic), 7.23–
7.28 (m, 5 H, aromatic and NH), 7.32–7.33 (m, 1 H, aromatic),
8.02–8.03 (dd, J = 8.0 MHz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.1, 74.6, 114.8, 116.6, 116.7, 119.7, 126.8, 127.1,
127.8, 128.4, 129.0, 129.1, 129.5, 129.5, 132.3, 132.4, 134.0, 136.4,
2-(4-Fluorophenyl)-N-p-tolyl-1,2-dihydroquinazolin-4-amine (4aab):
White prisms, 74% yield (0.25 g); m.p. 217–220 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 4.73 (d, J = 9.5 MHz,
1 H, NH), 6.10 (s, 1 H, aromatic), 6.66 (d, J = 8.0 MHz, 2 H,
aromatic and NH), 6.90–6.98 (m, 3 H, aromatic), 7.04 (d, J =
8.5 MHz, 2 H, aromatic), 7.10 (d, J = 8.5 MHz, 2 H, aromatic), 139.0, 139.2, 145.4, 163.2 ppm. MS (ES–): m/z = 346 [M – H].
7.28 (s, 1 H, NH), 7.32–7.37 (m, 3 H, aromatic), 8.03 (d, J = C21H18ClN3 (347.85): calcd. C 72.51, H 5.22, N 12.08; found C
7.5 MHz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.0, 74.2,
114.8, 115.6, 115.7, 116.9, 119.8, 126.9, 128.8, 128.8, 129.1, 129.7,
133.9, 135.8, 136.8, 137.7, 145.2, 163.1 ppm. MS (ES–): m/z = 330
[M – H]. C21H18FN3 (331.39): calcd. C 76.11, H 5.45, N 12.68;
found C 76.03, H 5.42, N 12.79.
72.47, H 5.21, N 12.13.
N-Phenyl-2-(p-tolyl)-1,2-dihydroquinazolin-4-amine (4acc): White
prisms, 59% yield (0.19 g); m.p. 200–204 °C. H NMR (500 MHz,
CDCl3): δ = 2.30 (s, 3 H, CH3), 4.77 (s, 1 H, NH), 6.08 (d, J =
1.5 MHz, 1 H, aromatic), 6.63 (d, J = 8.0 MHz, 1 H, aromatic),
1
N-(4-Chlorophenyl)-2-(4-fluorophenyl)-1,2-dihydroquinazolin-4- 6.88–6.92 (m, 1 H, aromatic), 7.08 (d, J = 8.0 MHz, 2 H, aromatic),
amine (4abb): White prisms, 60% yield (0.21 g); m.p. 228–230 °C.
7.18 (s, 1 H, NH), 7.20–7.22 (d, J = 8.5 MHz, 2 H, aromatic), 7.26
(d, J = 8.5 MHz, 2 H, aromatic), 7.28–7.33 (m, 4 H, aromatic),
1H NMR (500 MHz, CDCl3): δ = 4.72 (s, 1 H, NH), 6.12 (d, J =
564
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 559–566

Three-Component Domino Reaction
8.03–8.05 (dd, J = 7.5 MHz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 21.1, 74.5, 114.8, 117.0, 119.6, 126.7, 127.0, 128.9,
129.0, 129.4, 133.8, 137.0, 138.8, 140.7, 145.3, 163.1 ppm. MS
(ES–): m/z = 312 [M – H]. C21H19N3 (313.40): calcd. C 80.48, H
6.11, N 13.41; found C 80.39, H 6.08, N 13.47.
135.4, 135.9, 136.7, 138.7, 143.1, 160.8, 161.0 ppm. MS (ES–): m/z
= 390 [M – H]. C21H18BrN3 (392.30): calcd. C 64.30, H 4.62, N
10.71; found C 64.34, H 4.75, N 10.52.
2-Phenyl-1,2-dihydroquinazolin-4-amine (4aga): Off-white prisms,
75% yield (0.17 g); m.p. 198–200 °C. 1H NMR (500 MHz, CDCl3):
δ = 4.42 (s, 1 H, NH), 5.80 (s, 1 H, NH), 5.92 (s, 1 H, aromatic),
6.69 (d, J = 8.0 MHz, 1 H, aromatic), 6.91–6.94 (m, 1 H, aromatic),
7.34–7.37 (m, 1 H, aromatic), 7.46–7.48 (m, 3 H, aromatic), 7.60–
7.62 (m, 2 H, aromatic), 7.96–7.97 (m, 1 H, aromatic) ppm. 1H
NMR (500 MHz, [D6]DMSO): δ = 5.75 (s, 1 H, aromatic), 6.66–
6.69 (m, 1 H, aromatic), 6.74 (d, J = 8.0 MHz, 1 H, aromatic), 7.10
(s, 1 H, NH), 7.22–7.26 (m, 1 H, aromatic), 7.33–7.41 (m, 3 H,
aromatic), 7.49 (d, J = 7.0 MHz, 2 H, aromatic), 8.29 (s, 1 H, NH)
ppm. 13C NMR (125 MHz, CDCl3): δ = 68.1, 113.6, 114.7, 118.7,
126.4, 127.8, 128.2, 129.2, 133.0, 137.6, 146.2, 163.7 ppm. MS
(ES–): m/z = 222 [M – H]. C14H13N3 (223.28): calcd. C 75.31, H
5.87, N 18.82; found C 75.34, H 5.81, N 18.76.
2-(4-Methoxyphenyl)-N-(p-tolyl)-1,2-dihydroquinazolin-4-amine
(4aad): White prisms, 62 % yield (0.22 g); m.p. 228–230 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3), 3.77 (s, 3 H,
CH3), 4.68 (s, 1 H, NH), 6.05 (d, J = 0.5 MHz, 1 H, aromatic),
6.64 (d, J = 8.0 MHz, 1 H, aromatic), 6.78–6.80 (dd, J = 6.5 MHz,
2 H, aromatic), 6.90–6.92 (m, 1 H, aromatic), 7.05–7.10 (m, 4 H,
aromatic), 7.28 (s, 1 H, NH), 7.29–7.34 (m, 3 H, aromatic), 8.02–
8.03 (dd, J = 7.5 MHz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 21.0, 55.2, 74.5, 114.0, 114.7, 116.9, 119.5, 127.0, 128.2, 129.1,
129.6, 132.1, 133.7, 136.6, 137.9, 145.4, 160.0, 163.2 ppm. MS
(ES–): m/z = 342 [M – H]. C22H21N3O (343.43): calcd. C 76.94, H
6.16, N 12.24; found C 76.98, H 6.11, N 12.35.
N-(4-Chlorophenyl)-2-(4-methoxyphenyl)-1,2-dihydroquinazolin-4-
amine (4abd): White prisms, 46% yield (0.16 g); m.p. 238–239 °C.
1H NMR (500 MHz, CDCl3): δ = 3.78 (s, 3 H, CH3), 4.68 (s, 1 H,
NH), 6.07 (s, 1 H, aromatic), 6.66 (d, J = 8.0 MHz, 1 H, aromatic),
6.80 (d, J = 9.0 MHz, 2 H, aromatic), 6.90–6.94 (m, 1 H, aromatic),
7.11 (d, J = 9.0 MHz, 2 H, aromatic), 7.25–7.27 (m, 4 H, aromatic),
7.28 (m, 2 H, aromatic and NH), 7.33–7.36 (m, 1 H, aromatic),
8.02–8.04 (dd, J = 8.0 MHz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 55.3, 74.4, 114.1, 114.7, 116.6, 119.7, 128.3, 128.6,
129.0, 129.1, 131.3, 132.4, 134.0, 138.9, 145.5, 160.2, 163.3 ppm.
MS (ES–): m/z = 362 [M – H]. C21H18ClN3O (363.85): calcd. C
69.32, H 4.99, N 11.55; found C 69.28, H 5.07, N 11.51.
2-(4-Fluorophenyl)-1,2-dihydroquinazolin-4-amine (4agb): Off-white
prisms, 69% yield (0.17 g); m.p. 168–170 °C. H NMR (500 MHz,
1
CDCl3): δ = 4.37 (s, 1 H, NH), 5.79 (s, 1 H, NH), 5.93 (s, 1 H,
aromatic), 6.69 (d, J = 8.0 MHz, 1 H, aromatic), 6.92–6.95 (m, 1
H, aromatic), 7.14–7.17 (m, 2 H, aromatic), 7.35–7.38 (m, 1 H,
aromatic), 7.60–7.63 (m, 2 H, aromatic), 7.95–7.97 (m, 1 H, aro-
matic) ppm. 13C NMR (125 MHz, CDCl3): δ = 67.5, 113.6, 114.7,
115.1, 115.2, 118.9, 127.8, 128.4, 133.1, 133.6, 146.1, 163.6 ppm.
MS (ES–): m/z = 240 [M – H]. C14H12FN3 (241.27): calcd. C 69.70,
H 5.01, N 17.42; found C 69.61, H 5.13, N 17.48.
2-(p-Tolyl)-1,2-dihydroquinazolin-4-amine (4agc): Off-white prisms,
81% yield (0.19 g); m.p. 178–180 °C. 1H NMR (500 MHz, CDCl3):
δ = 2.41 (s, 3 H, CH3), 4.39 (s, 1 H, NH), 5.81 (s, 1 H, NH), 5.88
(s, 1 H, aromatic), 6.68 (d, J = 8.0 MHz, 1 H, aromatic), 6.90–6.93
(m, 1 H, aromatic), 7.26–7.28 (m, 2 H, aromatic), 7.33–7.37 (m, 1
H, aromatic), 7.49 (d, J = 8.0 MHz, 2 H, aromatic), 7.94–7.96 (m,
1 H, aromatic) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.3, 67.9,
113.6, 114.7, 118.6, 125.9, 126.3, 127.7, 128.8, 133.0, 134.7, 139.2,
146.3, 163.8 ppm. MS (ES–): m/z = 236 [M – H]. C15H15N3
(237.30): calcd. C 75.92, H 6.37, N 17.71; found C 75.97, H 6.32,
N 17.65.
2-(4-Methoxyphenyl)-N-phenyl-1,2-dihydroquinazolin-4-amine
(4acd): White prisms, 44 % yield (0.15 g); m.p. 206–209 °C. 1H
NMR (500 MHz, CDCl3): δ = 3.77 (s, 3 H, CH3), 4.74 (s, 1 H,
NH), 6.09 (s, 1 H, aromatic), 6.65 (d, J = 8.0 MHz, 1 H, aromatic),
6.78 (d, J = 9.0 MHz, 2 H, aromatic), 6.89–6.92 (m, 1 H, aromatic),
7.18–7.21 (m, 3 H, aromatic), 7.28–7.34 (m, 5 H, aromatic), 8.03–
8.05 (dd, J = 7.5 MHz, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 55.2, 74.4, 114.0, 114.8, 116.9, 119.6, 126.8, 127.2, 128.2, 128.9,
129.1, 131.9, 133.8, 140.5, 145.5, 160.0, 163.2 ppm. MS (ES–): m/z
= 328 [M – H]. C21H19N3O (329.40): calcd. C 76.57, H 5.81, N
12.76; found C 76.54, H 5.88, N 12.79.
2-(4-Methoxyphenyl)-1,2-dihydroquinazolin-4-amine (4agd): Off-
white prisms, 84 % yield (0.22 g); m.p. 158–160 °C. 1H NMR
(500 MHz, CDCl3): δ = 3.84 (s, 3 H, CH3), 4.38 (s, 1 H, NH), 5.84
(d, J = 7.5 MHz, 1 H, NH), 5.87 (s, 1 H, aromatic), 6.68 (d, J =
8.0 MHz, 1 H, aromatic), 6.90–6.93 (m, 1 H, aromatic), 6.97 (d, J
= 8.0 MHz, 2 H, aromatic), 7.33–7.37 (m, 1 H, aromatic), 7.53 (d,
J = 8.5 MHz, 2 H, aromatic), 7.96 (d, J = 7.5 MHz, 1 H, aromatic)
ppm. 13C NMR (125 MHz, CDCl3): δ = 54.5, 67.7, 113.4, 113.6,
118.7, 119.7, 124.1, 125.5, 126.8, 127.7, 133.1, 134.9, 148.6, 150.1,
161.5, 162.1 ppm. MS (ES–): m/z = 252 [M – H]. C15H15N3O
(253.30): calcd. C 71.13, H 5.97, N 16.59; found C 71.15, H 5.94,
N 16.56.
6-Bromo-2-(4-methoxyphenyl)-N-(p-tolyl)-1,2-dihydroquinazolin-4-
amine (4bad): Light-brown prisms, 46% yield (0.19 g); m.p. 174–
1
176 °C. H NMR (500 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 3.78
(s, 3 H, CH3), 4.72 (s, 1 H, NH), 6.03 (d, J = 1.0 MHz, 1 H, aro-
matic), 6.54 (d, J = 8.5 MHz, 1 H, aromatic), 6.79–6.81 (dd, J =
7.0 MHz, 2 H, aromatic), 7.03–7.05 (m, 2 H, aromatic), 7.10 (d, J
= 7.0 MHz, 2 H, aromatic), 7.25 (d, J = 9.0 MHz, 2 H, aromatic),
7.28 (s, 1 H, NH), 7.38–7.40 (dd, J = 8.5 MHz, 1 H, aromatic),
8.14 (d, J = 2.0 MHz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 20.1, 54.3, 73.3, 110.4, 113.1, 115.6, 117.4, 125.8, 127.1, 128.7,
130.5, 130.7, 135.4, 135.9, 136.6, 143.3, 159.1, 161.0 ppm. MS
(ES–): m/z = 420 [M – H]. C22H20BrN3O (422.32): calcd. C 62.57,
H 4.77, N 9.95; found C 62.59, H 4.71, N 9.87.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1D NMR spectra for all compounds 4 and the 2D
NMR spectrum for compound 4aaa.
6-Bromo-2-phenyl-N-(p-tolyl)-1,2-dihydroquinazolin-4-amine (4baa):
Grey powder, 51 % yield (0.20 g); m.p. 164–166 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3), 4.88 (s, 1 H, NH), 6.05
(d, J = 2.5 MHz, 1 H, aromatic), 6.52 (d, J = 8.5 MHz, 1 H, aro-
matic), 7.05–7.07 (d, J = 8.0 MHz, 2 H, aromatic), 7.09–7.11 (d, J
Acknowledgments
= 8.0 MHz, 2 H, aromatic), 7.29–7.30 (m, 3 H, aromatic and NH), We thank financial supported by the Nanjing University of Science
7.33–7.38 (m, 4 H, aromatic), 8.13 (d, J = 2.0 MHz, 1 H) ppm. 13
NMR (125 MHz, CDCl3): δ = 20.0, 73.7, 110.6, 115.6, 117.5, 125.7,
126.0, 127.0, 127.3, 127.5, 127.6, 127.8, 128.1, 128.7, 129.8, 130.5,
C
and Technology (2010ZDJH14). We also acknowledge the Analysis
and Testing Center Nanjing University of Science and Technology
for NMR analysis of this work.
Eur. J. Org. Chem. 2012, 559–566
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
565

L.-Y. Zeng, W.-B. Yi, C. Cai
FULL PAPER
Roberts, T. Johnson, C. Dousson, G. B. Hill, A. A. Mortlock,
N. Heron, R. W. Wilkinson, S. R. Wedge, S. P. Heaton, R. Ode-
dra, N. J. Keen, S. Green, E. Brown, K. Thompson, S.
Brightwell, J. Med. Chem. 2006, 49, 955–970.
a) M. Decker, F. Krauth, J. Lehmann, Bioorg. Med. Chem.
2006, 14, 1966–1977; b) M. Decker, J. Med. Chem. 2006, 49,
5411–5413; c) R. Abderrahim, K. Boujlel, Phosphorus Sulfur
Silicon Relat. Elem. 2005, 180, 79–84; d) M. Decker, Eur. J.
Med. Chem. 2005, 40, 305–313.
a) K. M. El-Shaieb, H. Hopf, P. G. Jones, Z. Naturforsch. B
2009, 64, 858–864; b) K. M. El-Shaieb, H. Hopf, P. G. Jones,
ARKIVOC 2009, x, 146–160; c) K. M. El-Shaieb, P. G. Jones,
Z. Naturforsch. B 2009, 64, 945–951; d) K. M. El-Shaieb, J.
Chem. Res. 2010, 3, 137–139.
W. Szczepankiewicz, J. Suwin´ski, R. Bujok, Tetrahedron 2000,
56, 9343–9349.
a) J. Zhu, H. Bienaymé, Multicomponent Reaction, Wiley-VCH,
Weinheim, 2005; b) L. Weber, Curr. Med. Chem. 2002, 9, 2085–
2093; c) C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10, 51–
80; d) J. D. Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15,
1300–1308; e) A. Domling, Chem. Rev. 2006, 106, 17–89.
a) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
2006, 118, 7292; Angew. Chem. Int. Ed. 2006, 45, 7134–7186;
b) L. F. Tietze, Chem. Rev. 1996, 96, 115–136.
[1] For selected examples, see: a) S. Zhu, J. Wang, G. Chandra-
shekar, E. Smith, X. Liu, Y. Zhang, Eur. J. Med. Chem. 2010,
45, 3864–3869; b) R. S. Giri, H. M. Thaker, T. Giordano, J.
Williams, D. Rogers, V. Sudersanam, K. K. Vasu, Eur. J. Med.
Chem. 2009, 44, 2184–2189; c) M. A. Cinelli, A. Morrell, T. S.
Dexheimer, E. S. Scher, Y. Pommier, M. Cushman, J. Med.
Chem. 2008, 51, 4609–4619; d) H. Kubota, A. Kakefuda, T.
Watanabe, N. Ishii, K. Wada, N. Masuda, S. Sakamoto, S.-I.
Tsukamoto, J. Med. Chem. 2003, 46, 4728–4740; e) M. Hour,
L. Huang, S. Kuo, Y. Xia, K. Bastow, Y. Nakanishi, E. Hamel,
K. Lee, J. Med. Chem. 2000, 43, 4479–4487.
[2] For selected examples, see: a) J. R. Li, X. Chen, D. Shi, S. L.
Ma, Q. Li, Q. Zhang, J. H. Tang, Org. Lett. 2009, 11, 1193–
1196; b) L. Y. Zeng, C. Cai, J. Heterocycl. Chem. 2010, 47,
1035–1039; c) J. X. Chen, W. K. Su, H. Y. Wu, M. C. Liu, C.
Jin, Green Chem. 2007, 9, 972–975; d) C. L. Yoo, J. C. Fettinger,
M. J. Kurth, J. Org. Chem. 2005, 70, 6941–6943; e) J. W.
Corbett, S. S. Ko, J. D. Rodgers, J. Med. Chem. 2000, 43, 2019–
2030.
[3] a) M. B. Vovk, Russ. J. Org. Chem. 2007, 43, 312–314; b) F. Li,
Q. Meng, W. Li, Z. Li, Q. Wang, F. Tao, ARKIVOC 2007, i,
40–50; c) R. Anderskewitz, R. Bauer, G. Bodenbach, D. Gester,
B. Gramlich, G. Morschhaeuser, F. W. Birke, Bioorg. Med.
Chem. Lett. 2005, 15, 669–673; d) S. A. Rocco, J. E. Barbarini,
R. Rittner, Synthesis 2004, 429–435; e) A. Bodtke, P. Langer,
Tetrahedron Lett. 2004, 45, 8741–8743; f) P. Langer, A. Bodtke,
Tetrahedron Lett. 2003, 44, 5965–5967; g) H. Divisova, H. Hav-
lisova, P. Borek, P. Pazdera, Molecules 2000, 5, 1166–1174; h)
J. W. Chern, P. L. Tao, M. H. Yen, G. Y. Lu, C. Y. Shiau, Y. J.
Lai, S. L. Chien, C. H. Chan, J. Med. Chem. 1993, 36, 2196–
2207.
[6]
[7]
[8]
[9]
[10]
[11] a) C. J. Li, Acc. Chem. Res. 2009, 42, 335–455, and references
cited therein; b) C. F. Wan, J. T. Zhang, S. J. Wang, J. M. Fan,
Z. Y. Wang, Org. Lett. 2010, 12, 2338–2341.
[12] a) H. F. Jiang, H. W. Huang, H. Cao, C. R. Qi, Org. Lett. 2010,
12, 5561–5563; b) J. T. Zhang, D. P. Zhu, C. M. Yu, C. F. Wan,
Z. Y. Wang, Org. Lett. 2010, 12, 2841–2843.
[13] R. H. Fan, W. X. Li, D. M. Pu, L. Zhang, Org. Lett. 2009, 11,
1425–1428.
[4] M. S. S. Palanki, P. E. Erdman, M. H. Ren, M. Suto, B. L.
Bennett, A. Manning, L. Ransone, C. Spooner, S. Desai, A.
Ow, R. Totsuka, P. Tsao, W. Toriumi, Bioorg. Med. Chem. Lett.
2003, 13, 4077–4080.
[5] F. H. Jung, G. Pasquet, C. L. Van der Brempt, J.-J. M.
Lohmann, N. Warin, F. Renaud, H. Germain, C. De Savi, N.
[14] a) Z. P. Li, C. J. Li, J. Am. Chem. Soc. 2004, 126, 11810–11811;
b) Z. P. Li, C. J. Li, J. Am. Chem. Soc. 2005, 127, 3672–3673.
Received: September 9, 2011
Published Online: November 22, 2011
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