Synthesis of 2,4-diaminoquinazolines and tricyclic quinazolines by cascade reductive cyclization of methyl N -cyano-2-nitrobenzimidates

Article abstract of DOI:10.1021/jo2023697

An efficient route to N⁴-substituted 2,4-diaminoquinazolines has been developed by employing tandem condensation of cyanoimidate-amine and reductive cyclization in iron-HCl system. This method is tolerant of a following intramolecular N-alkylation and produces two fused heterocycles in a one-pot procedure. This protocol is a facile two-step synthesis of tricyclic quinazolines, which is effected by potent cyanoimidation and tandem reductive cyclization from 2-nitrobenzaldehydes. Moreover, the forming process of tricyclic quinazolines has been investigated from the ring-opening/ring-closing cascade point of view. It is found that the preparation of tricyclic quinazolinones in good yields relies on the selective hydrolysis of tricyclic quinazolines in base or acid system.

Full text of DOI:10.1021/jo2023697

Article
pubs.acs.org/joc
Synthesis of 2,4-Diaminoquinazolines and Tricyclic
Quinazolines by Cascade Reductive Cyclization of Methyl
N-Cyano-2-nitrobenzimidates
Ping Yin,† Nan Liu,† Yu-Xing Deng,† Yue Chen,‡ Yong Deng,*,† and Ling He*,†
†Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
‡Department of Nuclear Medicine Affiliated Hospital, Luzhou Medical College, No. 25 Taiping Street, Luzhou, Sichuan, 646000,
P. R. China
S
* Supporting Information
ABSTRACT: An efficient route to N4-substituted 2,4-diaminoquinazolines has been developed by employing tandem condensa-
tion of cyanoimidate−amine and reductive cyclization in iron−HCl system. This method is tolerant of a following intramolecular
N-alkylation and produces two fused heterocycles in a one-pot procedure. This protocol is a facile two-step synthesis of tricyclic
quinazolines, which is effected by potent cyanoimidation and tandem reductive cyclization from 2-nitrobenzaldehydes. Moreover,
the forming process of tricyclic quinazolines has been investigated from the ring-opening/ring-closing cascade point of view. It is
found that the preparation of tricyclic quinazolinones in good yields relies on the selective hydrolysis of tricyclic quinazolines in
base or acid system.
trypanosomal and leishmanial dihydrofolate reductase.8
INTRODUCTION
The development of efficient N-heterocycle formation by cas-
■
Apart from the research above, some N4-monosubstituted
quinazolineamines serve as a key intermediate in the synthesis
cade reaction is significant for both natural product synthesis
of opioid receptor like-1 (ORL1) antagonists.9 Likewise, 2,3-
and medical chemistry studies. Quinazolines and quinazolones
occur in various natural products1 and listed drugs as the core
dihydroimidazo[1,2-c]quinazolin-5-amine, containing a quinazo-
linediamine structure, is an important scaffold in a series of kinase
inhibitors. They are effective for treatment of angiogenesis-
mediated and hyper-proliferative diseases, including cancer, in-
flammation, and other kinase-associated disorders.10
structure, and many of them are identified for their noticeable
biological activities.2 Among the quinazolines libraries, the class
of 2,4-diaminoquinazolines are very important pharmacophores
presented in numerous marketed drugs. For example, prazosin,
a selective α1 adrenoceptor antagonist drug,3 has a wide applica-
tion in clinical therapy due to its prominent antihypertensive
effect. As the new analogues of dihydrofolate reductase inhibitor
methotrexate, trimetrexate and piritrexim4 provide alternative
antineoplastic protocols. Moreover, their prominent anticancer
effects are extremely vital for the widespread drug resistance of
methotrexate.5 In addition, these lipophilic drugs play a new role
in the treatment of Pneumocystis carinii pneumonia (PCP).6
Other studies have shown that the quinazolinediamine deriva-
tives have not only been applied as the well-known anticancer
agent, but also exhibited some other remarkable functions,
including SMN2 promoter activators7 and selective inhibitors of
Such versatility of 2,4-diaminoquinazolines is very attractive
for organic synthesis, and distinct methods to achieve them have
been developed. Traditional synthetic strategies mainly include
the use of 2-aminobenzonitriles or 2-fluorobenzonitriles as
the starting materials. Although the cyclization of substituted
2-aminobenzonitriles can react with various agents, such as gua-
nidine, dicyandiamide, or chloroformamidine hydrochloride, the
yields of these preparations are modest in most cases.11 In com-
parison with previous results, the reaction of 2-fluorobenzonitrile
Received: November 24, 2011
Published: January 27, 2012
© 2012 American Chemical Society
2649
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
with guanidine carbonate gives an excellent yield, but it still
needs a high temperature to promote cyclization.12 N-Substituted
2,4-diaminoquinazolines are commonly obtained by 2,4-
dichloroquinazolines that can be efficiently prepared from
quinazoline-2,4-diones by refluxing in phosphorus oxychlor-
ide.13 Despite its general universality, several disadvantages exist
in this method; respectively, vigorous reagent POCl3 has to be
used in chlorination, and elevated temperature cannot be avoid-
ed in the coupling with amine at the 2-position. Furthermore,
in the synthesis of N4-monosubstituted 2,4-diaminoquinazoline,
low yield is produced because of the poor coupling with
ammonia.9 Accordingly, there might be considerable benefits to
developing various paths for the synthesis of diaminoquinazo-
line. Recently, solid-phase method has been employed to effect
combinatorial libraries of 2,4-diaminoquinazolines in good yield
and purity.14 Another novel approach to 2,4-diaminoquinazolines
is also facilitated by Cu-catalyzed Ullmann-type N-arylation
from 2-bromobenzonitriles with guanidine.15 To develop a more
practical and economic methodology for the synthesis of 2,4-
diaminoquinazolines, we have attempted to utilize the cyanoimi-
dation of aldehydes as the initial architectonic strategy. Oxidative
imidation of aldehydes has emerged as an attractive route to
nitrogen-containing heterocycles.16 Our previous work17 has
reported that cyanoimidation serves as a facile formation of
cyanoimidate, which is an important intermediate for the syn-
thesis of N-heterocyclic compounds.18 To the best of our
knowledge, the synthesis of diaminoquinazoline starting from
N-cyano-2-nitrobenzimidate and amine has remained undevel-
oped. Herein, we demonstrate a one-pot procedure to prepare
N4-substituted 2,4-diaminoquinazolines and their polycyclic
derivatives via reduction and intramolecular cyclization.
yielded trace product (Table 1, entry 5). However, a dramatic
increase was observed while the reductive iron was activated
by a small amount of concentrate hydrochloride (Table 1,
entry 6). Moreover, Fe/AcOH led to little decrease of yield
(Table 1, entry 7). In the comparison of different acids, we
concluded that strong acid was beneficial for effecting higher
product yield (Table 1, entries 5, 6, and 7). Additionally, further
optimization demonstrated that 4 equiv of iron elevated the
yield (Table 1, entry 8), but prolongation of reaction time with
more reductive agent did not give the better results (Table 1,
entry 9).
In our previous report, the optimization of cyanoimidation
was processed. We thus decided to follow the same
procedure, and several substrates with different substituted
groups were used to test the universality in cyanoimidation
of nitrobenzaldehydes. Parallel tests indicated that the
addition of 4 Å MS promoted the conversion of aldehyde
and reduced the generation of carboxylic ester. Presumably
in this process, the molecular sieve acted as a dehydrating
agent that promoted the condensation of aldehydes with
cyanamide. We found that substrates with electron-with-
drawing or electron-donating groups gave good results uni-
formly on a 0.06 mol scale. As shown in Table 2 (entries 1, 2, 5
and 6), 2-nitrobenzaldehyde and electron-poor aldehydes are
converted to cyanoimidates in good yield. Meanwhile, cyano-
imidation of nitrobenzaldehydes with electron-donating groups
on the aryl rings also provided desired products in good yields
(Table 2, entry 3 and 4).
After the preparation of cyanoimidates, we focused on the
synthesis of different substituted diaminoquinazolines. Having
established the optimal conditions, we then wished to combine
the condensation and reductive cyclization into a one-pot re-
action. Gratifyingly, the cascade process of different cyanoimi-
dates with amines output good yield in most instances (Table 3).
Treated with methyl N-cyano-2-nitrobenzimidate (2a), simple
primary amines substituted with aliphatic chains or rings were
easily converted to diaminoquinazolines by Fe/HCl (Table 3,
entries 1, 3, 9, and 10), and substitution containing aryl groups
also yielded good results (Table 3, entries 4, 11). From several
examples, we excitedly found that the reaction bore hydroxyl
radical by using aminoalcohols (Table 3, entries 6, 12, 13, 15,
and 19). The investigation of secondary amines also gave good
yields in presence of more amines and reductive agents. Not-
ably, unsubstituted diaminoquinazoline was accessed in nearly
quantitative yield by using ammonia−water (Table 3, entry 18).
The cascade reactions were also performed with various sub-
stitutes to study the electronic effect of the cyanoimidates, and
satisfactory results were observed (Table 3, entries 14−17, 19,
and 20). However, the optimal condition was not fit for
arylamine, and no desired product was obtained.
Inspired by the synthetic potential of the efficient reduction
and cyclization, we wished to expand the research to the
construction of tricyclic quinazolines derivatives. A continuous
3-N-alkylation of quinazoline core was adopted to achieve another
heterocyclic ring by using chloroalkylamines. The one-pot re-
action employed by additional K2CO3 provided excellent results
in tandem transformations involving neutralization and N-alkyla-
tion. Moreover, the tricyclic quinazolines (5) could undergo a
ring-opening/ring-closing cascade with NaOH or HCl/NaHCO3
to achieve the formation of quinazolinone. Simultaneously, the
tandem intramolecular reaction afforded the framework of tri-
cyclic guanidine, whose functional groups embedded into poly-
cyclic architecture are very significant for total synthesis19 and
RESULTS AND DISCUSSION
■
Our proposed route to diaminoquinazolines used 2-nitrobenzalde-
hydes as the starting materials (Scheme 1). Initial investigation
Scheme 1. Proposed Route to Diaminoquinazolines
indicated the oxidative cyanoimidation of 2-nitrobenzaldehydes
and the condensation with amine both performed in excellent
yields. Hence, our following studies focused on the reductive
conversion from 2-nitrobenzimidamides (3) to diaminoquina-
zolines (4).
We began the optimization with N′-cyano-N-(2-(dimethyl-
amino)ethyl)-2-nitrobenzimidamide as the model substrate
(Table 1). In preliminary hydrogen reduction catalyzed
by 10 mmol % Pd/C, there was only trace product obtained
(Table 1, entry 1). In contrast, Raney Ni (10 mmol %) catalytic
hydrogenation gave a moderate yield (Table 1, entry 2).
Reaction executed with sodium dithionite was observed with a
similar result, but using SnCl2 in EtOH did not obtain any of
the desired products (Table 1, entries 3, 4). We also had at-
tempted to choose Fe/NH4Cl as the reductive agent and only
2650
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
a
Table 1. Reduction of 2-Nitrobenzimidamide (3b)
b
entry
reductive agent
temp/time
solvent
MeOH
yield (%)
1
2
3
4
5
6
7
Pd/C (10 mmol %), H2
Ni (10 mmol %), H2
Na2S2O4
rt/6 h
rt/24 h
trace
52
MeOH
EtOH/H2O
EtOH
35 °C/2 h
80 °C/3 h
95 °C/3 h
64 °C/3 h
64 °C/3 h
64 °C/3 h
64 °C/10 h
41
SnCl2
0
Fe/NH4Cl
Fe/HCl
H2O
trace
83
MeOH
MeOH
MeOH
MeOH
Fe/AcOH
79
c
8
d
Fe/HCl
88
9
Fe/HCl
86
a
Conditions: reactions were conducted on a 0.2 mmol scale using 1 equiv of substrate (3b), 2 equiv of reductive agents (except catalytic
b
c
d
hydrogenation), and 3 mL of solvents. Isolated yield. The reaction was carried out with 4 equiv of iron (1.8 mmol). The reaction was carried out
with 6 equiv of iron (2.7 mmol).
a
Table 2. Cyanoimidation of 2-Nitrobenzaldehydes
ring of cyanoimidates (Table 4, entries 2−6). Performed with
3-chloropropan-1-amine, various derivatives of 3,4-dihydro-
2H-pyrimido[1,2-c]quinazolin-6-amines were provided in good
yields as well (Table 4, entries 7−12).
Further studies of tricyclic quinazolines had shown that
cleavage of 2H-pyrimidine ring proceeded readily in the pre-
sence of sodium hydrate22 and gave quinazolinones in good yield
(Table 4, entries 7−12). Nevertheless, this method was not suit-
able for 2H-imidazole series and only produced trace product.
Because of the disappointing ring-opening results of base, we
adopted the use of diluted hydrochloric acid to advance the
hydrolysis,23 which was proven to be effective after neutralization
using sodium bicarbonate in further cyclization. The intramol-
ecular cascade of methyl N-cyano-2-nitrobenzimidate (5a) af-
forded 2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (6a) in
good yield (Table 4, entry 1). Therefore, efforts to transform
the tricyclic substrates are focused on other substituents, and
moderate yields are obtained (Table 4, entries 2−6). The effect
of acid hydrolysis was carried out into 2H-pyrimidine derivatives,
which only generated inferior results (Table 4, entries 7−9). In
addition, two selected compounds 5h and 6g were further
verified by X-ray crystallography.24
Finally, we attempted to study the tentative mechanism and
the formation of side products in the ring-opening/ring-closing
cascade reaction. Hydrolysis of 2H-pyrimidine derivatives had
been chosen as the model reaction (Scheme 2), which led to
the formation of ring-opening products 2-aminoquinazolinones
(7), along with unexpected coproduct (8). Actually, ring-open-
ing intermediates were generated as a hydrochloride form that
hindered the coming cyclization. Once the aminoquinazolinone
hydrochlorides were neutralized with base, they afforded tri-
cyclic guanidine product (6) via smooth intramolecular cycliza-
tion in refluxing ethanol and water. Besides, monoacetylation of
the unstable intermediates were readily achieved in acetic an-
hydride−triethylamine system, which provided another avail-
able framework of 2-aminoquinazolin-4(3H)-ones. Several
aspects of the findings uncovered that there may be a selective
hydrolysis in the ring-opening process of tricyclic quinazolines.
Hydrolysis of 2H-pyrimidine series deduced by base selectively
gave desired products uniquely, which was superior to the
acidolysis. However, acid allowed a more powerful hydrolysis
a
Conditions: substrate (0.06 mol), NH2CN (0.24 mol), t-BuONa
(0.24 mol), and 4 Å molecular sieve (10 g), MeOH (500 mL), rt for
0.5 h; then NBS (0.24 mol), 50 °C, 12 h. The isolated yields were
obtained by the average of two parallel tests and based on the
b
c
recovered aldehydes. Control test without 4 Å MS.
organocatalysis.20 Accordingly, these characteristics have
attracted considerable attention in their synthetic method
research.21
To explore the utility of these cascade reactions, the scope of
various cyanoimidates was studied. As illustrated in Table 4,
2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (5a) was ob-
tained in excellent yield from methyl N-cyano-2-nitrobenzimi-
date (2a) and 2-chloroethanamine (Table 4, entry 1). The tan-
dem reaction could also tolerate different substitutes at benzene
2651
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
a b
,
Table 3. Synthesis of Diaminoquinazolines
a
Conditions: (1) cyanoimidates (1 mmol) and amines (1.5 mmol, 1.5 equiv), MeOH (2 mL), rt for 3 h. (2) iron (9 mmol, 4 equiv), concentrated
b
c
hydrochloric acid (0.6 mL), reflux for 3 h. Isolated yield after silica gel chromatography. 25% aqueous methylamine was used with the
corresponding molar ratio. 3 mmol amines (3 equiv), 13.5 mmol iron (6 equiv) and 1 mL of concentrated hydrochloric acid were used. 25%
d
e
ammonia−water was used with the corresponding molar ratio.
for the 2H-imidazole series than base because of the stability
of five-membered rings. These two complementary routes
exhibited an efficacious hydrolysis in executing the ring-
opening/ring-closing cascade and furnished a practical
preparation of tricyclic quinazolinones.
CONCLUSIONS
■
Potent cyanoimdiation and reductive cyclization serve as a
uniquely effective synthesis to N4-monosubstituted diamino-
quinazoline from ortho-nitroaldehydes, and they can also
2652
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
Table 4. Scope of Cascade Reactions
a
Conditions: (1) chloroalkylamines hydrochloride (1 mmol, 2 equiv) and NaHCO3 (1 mmol, 2 equiv), rt for 0.5 h; then cyanoimidates (0.5 mmol),
50 °C, 6 h. (2) iron (4.5 mmol, 4 equiv), concentrated hydrochloric acid (0.4 mL), reflux for 3 h; then potassium carbonate (5 mmol), reflux for
b
c
additional 6 h. Isolated yield after silica gel chromatography. Conditions: For 2H-imidazole series, 5 (0.2 mmol), HCl (0.5 mol/L)/EtOH (5:1)
30 mL, reflux for 6 h; then NaHCO3 (20 mmol), reflux for additional 72 h. For 2H-pyrimidine series, 5 (0.2 mmol), 0.01 N NaOH/EtOH (5:1)
d
e
30 mL, reflux for 72 h. The reaction time of acidolysis was 12 h. Conditions of 2H-imidazole series (acidolysis) were used for contrast tests.
provide tricyclic quinazolines via the similar facile route. What
deserved to be mentioned was the formation of two hetero-
cycles accomplished in a one-pot procedure. Subsequently, the
significant ring-opening/ring-closing cascade of tricyclic
quinazolines was demonstrated to afford quinazolinones
including cyclic guanidine. Continued efforts to explore the
2653
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
13C NMR (100 MHz, CDCl3) δ 177.1, 152.6, 150.4, 122.3, 112.6,
107.7, 105.8, 104.2, 58.1; HRMS (M + Na+) calcd for C10H7N3NaO5
272.0283, found 272.0283.
Scheme 2. Study of Ring-Opening Process
Methyl 4-Bromo-N-cyano-2-nitrobenzimidate (2e; Table 2; Entry 5).
Eluent petroleum ether/chloroform/ethyl acetate (100:10:10 to
100:20:10). Yield, 12.64 g, 78% (based on the recovered aldehyde).
1
White solid: mp 131−132 °C; H NMR (400 MHz, CDCl3) δ 8.39
(d, J = 1.6 Hz, 1H), 7.97 (dd, J = 8.0, 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz,
1H), 4.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.1, 149.0,
137.5, 130.2, 128.5, 126.7, 124.8, 112.3, 58.2; HRMS (M + Na+) calcd
for C9H6BrN3NaO3 305.9490, found 305.9492.
Methyl 5-Bromo-N-cyano-2-nitrobenzimidate (2f; Table 2; Entry 6).
Eluent petroleum ether/chloroform/ethyl acetate (100:10:10 to
100:20:10). Yield, 13.72 g, 83% (based on the recovered aldehyde).
1
White solid: mp 145−147 °C; H NMR (400 MHz, CDCl3) δ 8.15
(d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.8, 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz,
1H), 4.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.5, 149.4,
135.6, 131.8, 129.7, 127.7, 126.5, 112.0, 58.2; HRMS (M + Na+) calcd
for C9H6BrN3NaO3 305.9490, found 305.9496.
bioactivities of these heterocycles will be made in the further
studies.
EXPERIMENTAL SECTION
General Procedure for Synthesis of N4-Substitued 2,4-
Diaminoquinazolines. Cyanoimidates (2, 1 mmol) and amines
(1.5 mmol, 1.5 equiv) were dissolved in MeOH (4 mL), and the mix-
ture was stirred at room temperature for 3 h and diluted with addi-
tional MeOH (25 mL), followed by the addition of iron (9 mmol,
502 mg, 4 equiv) and concentrated hydrochloric acid (0.6 mL). The
final temperature was elevated to reflux for 3 h. Excess sodium bicarbo-
nate (15 mmol, 1.26 g) was added to neutralize the diaminoquinazo-
line and percitipate remnant ferri iron. The reaction was kept refluxing
for an additional 2 h and operated by kieselguhr filteration. The filtrate
solution was evaporated by vacuum distillation, and the residue was
purfied by flash column chromatography to afford product 4.
N4-Butylquinazoline-2,4-diamine (4a; Table 3; Entry 1). Eluent
dichloromethane/methanol (100:15). Yield, 199 mg, 92%. White
solid: mp 165−166 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.08−8.06
(m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J =
7.6 Hz, 1H), 6.39 (s, 2H), 3.51−3.47 (m, 2H), 1.66−1.58 (m, 2H),
1.41−1.31 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 160.5, 159.8, 150.0, 132.7, 123.2, 123.1, 120.7, 111.0,
40.3, 30.9, 20.0, 14.0; HRMS (M + H+) calcd for C12H17N4 217.1453,
found 217.1458.
■
1H NMR experiments were recorded on a 400 MHz spectrometer, and
13C NMR experiments were recorded on a 100 MHz spectrometer.
The mass spectra (ESI/HRMS) were recorded on mass spectrometer.
4 Å molecular sieves were dried at 200 °C under vacuum for 12 h and
grinded before use. Methanol was predried over 4 Å molecular sieves.
Flash chromatography on silica gel (300−400 mesh) was performed.
General Procedure for Cyanoimidation. To a 1 L oven-dried
flask with a solution of aldehydes (1, 0.06 mol), NH2CN (0.24 mol,
10.09 g), and 4 Å molecular sieve (10.0 g) in MeOH (500 mL) was
added t-BuONa (0.24 mol, 23.06 g) in portions (the temperature was
controlled by an ice bath and not allowed to exceed 35 °C), and the
mixture was stirred at 25 °C for 0.5 h. Then, NBS (0.24 mol, 42.72 g)
was added to the reaction mixture, which cooled in an ice bath. Then,
the reaction mixture was allowed to warm up and stirred at 50 °C for
12 h. The solvent was removed by vacuum distillation, and then
CHCl3 (400 mL)/saturated aqueous Na2S2O3 (300 mL) were added
to the residue and stirred for 10 min. The mixture was filtered, and the
filtrate was extracted with another CHCl3 (2 × 200 mL). The organic
layer was combined, washed with brine, and dried over anhydrous
Na2SO4. The solvent was removed, and the crude product was purified
by flash column chromatography to afford the product.
N4-(2-(Dimethylamino)ethyl)quinazoline-2,4-diamine (4b; Table 3;
Entry 2). Eluent dichloromethane/methanol/triethylamine
(100:15:0.5). Yield, 198 mg, 86%. Light yellow solid: mp 139−140 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.0 Hz, 1H), 7.91 (s,
1H), 7.49 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.6
Hz), 6.26 (s, 2H), 3.60 (m, 2H), 2.56 (t, J = 6.8 Hz, 2H), 2.24
(s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 160.9, 160.5, 151.4, 133.1,
124.3, 123.2, 121.1, 111.3, 58.1, 45.5, 38.5; HRMS (M + H+) calcd for
C12H18N5 232.1562, found 232.1566.
Methyl N-Cyano-2-nitrobenzimidate (2a; Table 2; Entry 1).
Eluent petroleum ether/chloroform/ethyl acetate (100:20:10 to
100:40:10). Yield, 9.65 g, 80% (based on the recovered aldehyde).
1
White solid: mp 120−122 °C; H NMR (400 MHz, CDCl3) δ 8.25
(d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H),
7.63 (d, J = 8.0 Hz, 1H), 4.09 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 177.2, 150.4, 134.6, 132.7, 129.2, 126.3, 125.2, 112.6, 58.0; HRMS
(M + H+) calcd for C9H8N3O3 206.0566, found 206.0565.
N4-Methylquinazoline-2,4-diamine (4c; Table 3; Entry 3). Eluent
dichloromethane/methanol (100:20). Yield, 163 mg, 94%. White
solid: mp 209−211 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.05
(s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.22 (d, J =
8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.29 (s, 2H), 2.96 (d, J = 4.4 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ 161.0, 160.2, 150.6, 132.6,
123.7, 123.0, 120.6, 111.1, 27.9; HRMS (M + H+) calcd for C9H11N4
175.0984, found 175.0983.
Methyl 5-Chloro-N-cyano-2-nitrobenzimidate (2b; Table 2;
Entry 2). Eluent petroleum ether/chloroform/ethyl acetate
(100:10:10 to 100:20:10). Yield, 11.51 g, 85% (based on the re-
covered aldehyde). White solid: mp 136−138 °C; 1H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.8, 2.4 Hz, 1H), 7.58
(d, J = 2.4 Hz, 1H), 4.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
174.5, 151.8, 141.6, 132.6, 129.1, 127.8, 126.7, 112.1, 58.3; HRMS (M +
Na+) calcd for C9H6ClN3NaO3 261.9995, found 261.9993.
N4-Benzylquinazoline-2,4-diamine (4d; Table 3; Entry 4). Eluent
dichloromethane/methanol (100:8). Yield, 218 mg, 87%. White solid:
Methyl N-Cyano-4,5-dimethoxy-2-nitrobenzimidate (2c; Table 2;
Entry 3). Eluent petroleum ether/chloroform/ethyl acetate (100:15:10
to 100:40:10). Yield, 10.88 g, 78% (based on the recovered aldehyde).
1
mp 115−118 °C; H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H),
1
8.06 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38−7.23 (m, 6H),
7.06 (t, J = 7.6 Hz, 1H), 6.24 (s, 2H), 4.75 (d, J = 5.2 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 160.6, 160.3, 151.4, 134.0, 132.8,
128.5, 127.6, 127.0, 124.0, 123.1, 120.6, 110.9, 43.5; HRMS (M + H+)
calcd for C15H15N4 251.1297, found 251.1294.
Yellow solid: mp 151−153 °C; H NMR (400 MHz, CDCl3) δ 7.71
(s, 1H), 6.92 (s, 1H), 4.07 (s, 3H), 4.00 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 177.5, 153.6, 150.9, 139.0, 120.1, 112.8, 109.9, 107.7, 57.9,
56.9, 56.7; HRMS (M + Na+) calcd for C11H11N3NaO5 288.0596,
found 288.0612.
4-(Piperidin-1-yl)quinazolin-2-amine (4e; Table 3; Entry 5).
Eluent dichloromethane/methanol (100:8). Yield, 194 mg, 85%.
Yellow solid: mp 201−203 °C; 1H NMR (400 MHz, DMSO-d6)
δ 7.75 (d, J = 8.4 Hz, 1H), 7.62−7.59 (m, 1H), 7.37 (d, J = 8.4 Hz,
1H), 7.18 (t, J = 7.6 Hz, 1H), 6.99 (s, 2H), 3.68 (m, 4H), 1.68
Methyl N-Cyano-6-nitrobenzo[d][1,3]dioxole-5-carbimidate (2d;
Table 2; Entry 4). Eluent petroleum ether/chloroform/ethyl acetate
(100:10:10 to 100:20:10). Yield, 11.16 g, 84% (based on the recovered
aldehyde). Yellow solid: mp 142−143 °C; 1H NMR (400 MHz,
CDCl3) δ 7.66 (s, 1H), 6.92 (s, 1H), 6.24 (s, 2H), 4.07 (s, 3H);
2654
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
(m, 6H); 13C NMR (100 MHz, DMSO-d6) δ 164.9, 157.5, 149.2,
133.4, 126.3, 122.1, 121.5, 111.2, 50.5, 25.8, 24.3; HRMS (M + H+)
calcd for C13H17N4 229.1453, found 229.1458.
2-(2-Aminoquinazolin-4-ylamino)ethanol (4f; Table 3; Entry 6).
Eluent dichloromethane/methanol (100:15). Yield, 185 mg, 91%.
White solid: Decomp 268 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.98
(d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.18 (d, J =
8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.02 (s, 2H), 4.90 (s, 1H), 3.61−
3.53 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 160.7, 160.7, 152.3,
132.4, 124.5, 123.1, 120.0, 111.1, 59.8, 43.3; HRMS (M + H+) calcd
for C10H13N4O 205.1089, found 205.1081.
4-(Pyrrolidin-1-yl)quinazolin-2-amine (4g; Table 3; Entry 7).
Eluent dichloromethane/methanol (100:10). Yield, 167 mg, 78%.
Light yellow solid: Decomp 272 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.06 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz,
1H), 7.06 (t, J = 8.0 Hz, 1H), 6.27 (s, 2H), 3.82 (t, J = 6.0 Hz, 4H),
1.94 (t, J = 6.0 Hz, 4H); 13C NMR (100 MHz, DMSO-d6) δ 160.1,
157.2, 145.5, 132.9, 126.6, 121.5, 121.1, 111.7, 51.1, 25.3; HRMS
(M + H+) calcd for C12H15N4 215.1297, found 215.1290.
(m, 1H), 3.44−3.38 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 160.8, 160.2, 151.3, 144.4, 132.7, 128.3, 127.3, 126.3, 124.0, 123.3,
120.6, 111.1, 70.9, 49.5; HRMS (M + H+) calcd for C16H17N4O
281.1402, found 281.1395.
6-Chloro-N4-methylquinazoline-2,4-diamine (4n; Table 3; Entry 14).
Eluent dichloromethane/methanol (100:8). Yield, 181 mg, 87%.
White solid: mp 205−208 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.13−8.07 (m, 2H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J =
8.8 Hz, 1H), 6.46 (s, 2H), 2.94 (d, J = 4.4 Hz, 3H); 13C NMR (100
MHz, DMSO-d6) δ 160.4, 160.2, 149.6, 132.6, 125.7, 124.1, 122.3,
111.8, 27.9; HRMS (M + H+) calcd for C9H10ClN4 209.0594, found
209.0587.
2-(2-Amino-6-chloroquinazolin-4-ylamino)ethanol (4o; Table 3;
Entry 15). Eluent dichloromethane/methanol (100:10). Yield, 220 mg,
1
92%. White solid: mp 202−205 °C; H NMR (400 MHz, DMSO-d6)
δ 8.16 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H),
7.20 (d, J = 8.8 Hz, 1H), 6.32 (s, 2H), 4.78 (t, J = 4.8 Hz, 1H), 3.61−
3.60 (m, 2H), 3.53 (q, J = 5.2 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 160.7, 160.0, 150.4, 132.7, 126.1, 124.0, 122.5, 111.9, 59.6, 43.5;
HRMS (M + H+) calcd for C10H12ClN4O 239.0700, found 239.0704.
N4-Benzyl-6-chloroquinazoline-2,4-diamine (4p; Table 3; Entry 16).
Eluent dichloromethane/methanol (100:5). Yield, 236 mg, 83%.
White solid: mp 189−191 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.83(s, 1H), 8.26 (s, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.39−7.24
(m, 6H), 6.63 (s, 2H), 4.73 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 159.7, 157.0, 142.7, 138.6, 134.3, 128.6, 128.2, 127.4,
126.9, 123.7, 121.8, 111.5, 45.7; HRMS (M + H+) calcd for
C15H14ClN4 285.0907, found 285.0903.
4-Morpholinoquinazolin-2-amine (4h; Table 3; Entry 8). Eluent
dichloromethane/methanol (100:8). Yield, 189 mg, 82%. Yellow solid:
1
mp 162−164 °C; H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J =
8.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.09 (t,
J = 7.6 Hz, 1H), 6.45 (s, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.55 (t, J =
4.4 Hz, 4H); 13C NMR (100 MHz, DMSO-d6) δ 166.1, 159.8, 154.3,
132.7, 125.6, 125.3, 120.5, 111.8, 66.3, 50.3; HRMS (M + H+) calcd
for C12H15N4O 231.1246, found 231.1245.
N4-Propylquinazoline-2,4-diamine (4i; Table 3; Entry 9). Eluent
dichloromethane/methanol (100:8). Yield, 190 mg, 94%. White solid:
N4-Cyclohexyl-6,7-dimethoxyquinazoline-2,4-diamine (4q; Table 3;
Entry 17). Eluent dichloromethane/methanol (100:10). Yield, 274 mg,
91%. Light yellow solid: mp 206−207 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.86 (s, 1H), 7.59 (s, 1H), 6.76 (s, 1H), 6.56 (s, 2H),
4.23−4.15 (m, 1H), 3.84 (s, 6H), 1.94−1.92 (m, 2H), 1.82−1.79
(m, 2H), 1.69−1.66 (m, 1H), 1.46−1.12 (m, 5H); 13C NMR
(100 MHz, DMSO-d6) δ 158.8, 158.0, 158.0, 154.3, 145.4, 104.2,
103.2, 102.6, 56.5, 55.7, 49.3, 32.6, 25.6, 25.5; HRMS (M + H+) calcd
for C16H23N4O2 303.1821, found 303.1831.
1
mp 163−167 °C; H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J =
8.0 Hz, 1H), 7.87 (t, J = 8.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.19
(d, J = 8.4 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.12 (s, 2H), 3.42 (q, J =
6.0 Hz, 2H), 1.68−1.61 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 160.5, 160.4, 151.4, 132.5, 124.0, 123.1,
120.3, 111.0, 42.3, 22.1, 11.8; HRMS (M + H+) calcd for C11H15N4
203.1297, found 203.1301.
N4-Cyclohexylquinazoline-2,4-diamine (4j; Table 3; Entry 10).
Eluent dichloromethane/methanol (100:10). Yield, 207 mg, 85%.
White solid: Decomp 261 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.07
(d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H),
7.20 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.20 (s, 2H), 4.17−
4.12 (m, 1H), 1.92−1.90 (m, 2H), 1.79−1.76 (m, 2H), 1.67−1.63
(m, 1H), 1.43−1.27 (m, 4H), 1.20−1.11 (m, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 160.2, 159.7, 150.8, 132.6, 123.5, 123.4,
120.3, 111.0, 49.1, 32.4, 25.6, 25.4; HRMS (M + H+) calcd for
C14H19N4 243.1610, found 243.1606.
Quinazoline-2,4-diamine (4r; Table 3; Entry 18). Eluent dichloro-
methane/methanol (100:20). Yield, 152 mg, 95%. White solid: mp
246−248 °C; (lit.12 mp 254−258 °C); H NMR (400 MHz, DMSO-
1
d6) δ 7.95 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.29 (s, 2H),
7.19 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.02 (s, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 167.7, 165.9, 157.4, 137.6, 129.2,
128.8, 125.1, 115.5; HRMS (M + H+) calcd for C8H9N4 161.0827,
found 161.0825.
2-(2-Amino-6,7-dimethoxyquinazolin-4-ylamino)ethanol (4s;
N4-Phenethylquinazoline-2,4-diamine (4k; Table 3; Entry 11).
Eluent dichloromethane/methanol (100:8). Yield, 220 mg, 83%.
White solid: mp 187−189 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.69
(s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.31−7.15
(m, 7H), 6.89 (s, 2H), 3.75−3.70 (m, 2H), 2.97 (t, J = 7.6 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 160.4, 158.3, 146.8, 139.7, 133.5,
Table 3; Entry 19). Eluent dichloromethane/methanol (100:20).
1
Yield, 217 mg, 82%. Light yellow solid: mp 264−265 °C; H NMR
(400 MHz, D2O) δ 6.72 (s, 1H), 6.14 (s, 1H), 3.82 (m, 2H), 3.76
(s, 3H), 3.72 (s, 3H), 3.58 (m, 2H); 13C NMR (100 MHz, D2O)
δ 156.8, 156.8, 151.5, 151.0, 143.2, 99.4, 98.9, 95.0, 57.0, 53.5, 53.3, 40.7;
HRMS (M + H+) calcd for C12H17N4O3 265.1301, found 265.1303.
N8-Benzyl-[1,3]dioxolo[4,5-g]quinazoline-6,8-diamine (4t; Table 3;
Entry 20). Eluent dichloromethane/methanol (100:15). Yield, 255 mg,
87%. Light yellow solid: mp 258−260 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.57 (s, 1H), 7.66 (s, 1H), 7.37−7.30 (m, 4H), 7.23
(t, J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.48 (s, 2H), 6.10 (s, 2H), 4.72
(d, J = 5.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.9, 158.2,
152.4, 146.3, 143.7, 139.7, 128.5, 127.6, 127.0, 104.1, 102.0, 100.5,
43.6; HRMS (M + H+) calcd for C16H15N4O2 295.1195, found
295.1196.
129.0, 128.6, 126.4, 123.5, 121.9, 121.5, 110.7, 42.6, 34.6; HRMS (M +
H+) calcd for C16H17N4 265.1453, found 265.1452.
2-(2-Aminoquinazolin-4-ylamino)-3-(1H-indol-3-yl)propan-1-ol
(4l; Table 3; Entry 12). Eluent dichloromethane/methanol (100:10).
Yield, 269 mg, 81%. Yellow solid: mp 153−155 °C; 1H NMR
(400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.99
(d, J = 6.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.55 (t, J = 6.4 Hz, 1H),
7.32−6.97 (m, 6H), 6.58 (s, 2H), 4.90 (br, 1H), 4.62 (m, 1H), 3.62
(m, 2H), 3.09 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 160.5,
158.9, 148.3, 136.3, 133.2, 127.8, 123.7, 123.5, 122.2, 121.3, 121.0,
118.7, 118.5, 111.7, 111.6, 110.9, 62.6, 53.8, 26.3; HRMS (M + H+)
calcd for C19H20N5O 334.1668, found 334.1660.
General Procedure for Synthesis of Tricyclic Quinazolines
(5). Chloroalkylamines hydrochloride (1 mmol, 2 equiv) and NaHCO3
(1 mmol, 84 mg, 2 equiv) were stirred in 2 mL of MeOH at rt for 30
min, and then cyanoimidates (2, 0.5 mmol) were added and stirred at
50 °C for 6 h. Then, iron (4.5 mmol, 251 mg, and 4 equiv), con-
centrated hydrochloric acid (0.4 mL), and additional MeOH (25 mL)
were added, and the reaction was performed to reflux. After 3 h,
potassium carbonate (5 mmol, 691 mg) was added, and the reaction
was stirred for additional 6 h in refluxing methanol. The final mixture
2-(2-Aminoquinazolin-4-ylamino)-1-phenylethanol (4m; Table 3;
Entry 13). Eluent dichloromethane/methanol (100:8). Yield, 247 mg,
1
88%. White solid: mp 127−129 °C; H NMR (400 MHz, DMSO-d6)
δ 8.11 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.51−7.46 (m, 3H), 7.35
(t, J = 7.6 Hz, 2H), 7.27−7.21 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.28
(s, 2H), 5.63 (s, 1H), 4.99 (dd, J = 8.0, 3.2 Hz, 1H), 3.79−3.73
2655
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
was filtered through Celite. The filtrate was evaporated by vacuum
distillation, and the residue was purified by flash column chromatog-
raphy to afford product 5.
triethylamine (100:20:0.5). Yield, 110 mg, 85%. Light yellow solid:
Decomp 263 °C; 1H NMR (400 MHz, D2O/5% TFA) δ 7.44 (s, 1H),
6.83 (s, 1H), 4.03 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.63
(t, J = 5.6 Hz, 2H), 2.22 (t, J = 5.6 Hz, 2H); HRMS (M + H+) calcd
for C13H17N4O2 261.1352, found 261.1357.
3,4-Dihydro-2H-[1,3]dioxolo[4,5-g]pyrimido[1,2-c]quinazolin-6-
amine (5j; Table 4; Entry 10). Eluent dichloromethane/methanol/
triethylamine (100:20:0.5). Yield, 94 mg, 77%. Light yellow solid:
Decomp 253 °C; 1H NMR (400 MHz, D2O/5% TFA) δ 7.32 (s, 1H),
6.84 (s, 1H), 6.10 (s, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 5.2 Hz,
2H), 2.22 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, D2O/5% TFA)
δ 159.3, 154.8, 151.0, 150.3, 136.6, 106.6, 104.8, 103.2,103.1, 99.4,
99.3, 47.6, 41.4, 19.7; HRMS (M + H+) calcd for C12H13N4O2
245.1039, found 245.1045.
2,3-Dihydroimidazo[1,2-c]quinazolin-5-amine (5a; Table 4; Entry 1).
Eluent dichloromethane/methanol/triethylamine (100:10:0.5). Yield,
1
83 mg, 89%. White solid: mp 261−264 °C; H NMR (400 MHz,
D2O/5% TFA) δ 8.06−7.97 (m, 2H), 7.55−7.51(m, 2H), 4.58−4.56
(m, 2H), 4.39 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz, D2O/5%
TFA) δ 155.3, 145.2, 137.4, 135.8, 124.6, 124.3, 115.1, 102.7, 44.0,
42.9; HRMS (M + H+) calcd for C10H11N4 187.0984, found 187.0987.
9-Chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (5b;
Table 4; Entry 2). Eluent dichloromethane/methanol/triethylamine
1
(100:10:0.5). Yield, 101 mg, 92%. White solid: Decomp 283 °C; H
NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 2.4 Hz, 1H), 7.36 (dd, J =
8.4, 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.74 (s, 2H), 3.98−3.86
(m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 154.0, 151.0, 149.1,
133.0, 125.6, 124.6, 124.1, 115.1, 52.6, 45.8; HRMS (M + H+) calcd
for C10H10ClN4 221.0594, found 221.0589.
8,9-Dimethoxy-2,3-dihydroimidazo[1, 2-c]quinazolin-5-amine
(5c; Table 4; Entry 3). Eluent dichloromethane/methanol/triethyl-
amine (100:20:0.5). Yield, 103 mg, 84%. White solid: Decomp 291 °C;
1H NMR (400 MHz, D2O/5% TFA) δ 7.41 (s, 1H), 6.90 (s, 1H), 4.51
9-Bromo-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-amine (5k;
Table 4; Entry 11). Eluent dichloromethane/methanol/triethylamine
1
(100:10:0.5). Yield, 118 mg, 85%. White solid: Decomp 274 °C; H
NMR (400 MHz, DMSO-d6) δ 7.78 (t, J = 8.4 Hz, 1H), 7.09−7.03
(m, 2H), 6.82 (s, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.43 (t, J = 5.2 Hz,
2H), 1.86 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
δ 152.7, 148.8, 145.8, 126.6, 125.1, 125.0, 123.7, 117.6, 43.2, 42.8,
20.0; HRMS (M + H+) calcd for C11H12BrN4 279.0245, found
279.0248.
10-Bromo-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-amine
(5l; Table 4; Entry 12). Eluent dichloromethane/methanol/triethyl-
amine (100:10:0.5). Yield, 110 mg, 79%. White solid: Decomp 261 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 2.4 Hz, 1H), 7.42 (dd,
J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.70 (s, 2H), 3.69 (t, J =
6.0 Hz, 2H), 3.44 (t, J = 5.6 Hz, 2H), 1.87−1.81(m, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 152.3, 146.3, 144.9, 134.1, 126.7, 125.4,
120.6, 112.5, 43.1, 43.1, 20.1; HRMS (M + H+) calcd for C11H12BrN4
279.0245, found 279.0252.
General Procedure A for Synthesis of Tricyclic Quinazoli-
nones (6a−6f). Tricyclic quinazolines (5, 0.2 mmol) were dissolved
in 25 mL of HCl (0.5 mol/L) and 5 mL of EtOH, and then the re-
action was heated to refluxing vigorously. After 6 h, excess NaHCO3
(20 mmol, 1.68 g) was added and kept refluxing for additional 72 h.
Then, the solvent was removed under reduced pressure, and the
residue was purfied by flash column chromatography.
(t, J = 9.2 Hz, 2H), 4.31 (t, J = 9.2 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H);
13C NMR (100 MHz, D2O/5% TFA) δ 156.3, 153.6, 145.5, 144.6,
133.3, 103.0, 103.0, 96.7,96.6, 95.0, 54.3, 53.6, 43.9, 42.3; HRMS (M +
H+) calcd for C12H15N4O2 247.1195, found 247.1193.
2,3-Dihydro-[1,3]dioxolo[4,5-g]imidazo[1,2-c]quinazolin-5-
amine (5d; Table 4; Entry 4). Eluent dichloromethane/methanol/
triethylamine (100:20:0.5). Yield, 94 mg, 82%. Light yellow solid:
Decomp 310 °C; 1H NMR (400 MHz, D2O/5% TFA) δ 7.22 (s, 1H),
6.88 (s, 1H), 6.12 (s, 2H), 4.45 (t, J = 9.6 Hz, 2H), 4.24 (t, J = 9.6 Hz,
2H); 13C NMR (100 MHz, D2O/5% TFA) δ 155.8, 153.8, 145.2,
144.6, 135.2, 101.9, 100.0, 99.8, 96.3, 94.9, 94.8, 43.9, 42.3; HRMS
(M + H+) calcd for C11H11N4O2 231.0882, found 231.0879.
8-Bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (5e;
Table 4; Entry 5). Eluent dichloromethane/methanol/triethylamine
1
(100:10:0.5). Yield, 101 mg, 76%. White solid: Decomp 271 °C; H
NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.4 Hz, 1H), 7.16 (d, J =
1.6 Hz, 1H), 7.08 (dd, J = 8.4, 1.6 Hz, 1H), 6.88 (s, 2H), 3.98−3.88
(m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 154.3, 151.8, 151.4,
127.1, 126.5, 125.5, 123.7, 113.0, 52.6, 45.7; HRMS (M + H+) calcd
for C10H10BrN4 265.0089, found 265.0071.
2,3-Dihydroimidazo[2,1-b]quinazolin-5(1H)-one (6a; Table 4;
Entry 1). Eluent dichloromethane/methanol (100:2). Yield, 27.1 mg,
72%. White solid: mp 264−268 °C; (lit.26 263−265 °C); H NMR
1
(400 MHz, DMSO-d6) δ 7.91 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.55
(t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H),
4.11 (t, J = 8.4 Hz, 2H), 3.62 (t, J = 8.4 Hz, 2H); 13C NMR (100
MHz, DMSO-d6) δ 160.4, 154.9, 151.4, 134.1, 126.0, 124.5, 121.8,
117.4, 42.4, 39.5; HRMS (M + H+) calcd for C10H10N3O 188.0824,
found 188.0825.
9-Bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (5f;
Table 4; Entry 6). Eluent dichloromethane/methanol/triethylamine
(100:10:0.5). Yield, 109 mg, 82%. White solid: Decomp 279 °C; (lit.25
mp > 260 °C); 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 2.4 Hz,
1H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.77
(s, 2H), 3.99−3.85 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 153.6,
151.2, 149.3, 135.3, 127.1, 125.8, 116.1, 112.0, 53.3, 45.7; HRMS (M + H+)
calcd for C10H10BrN4 265.0089, found 265.0081.
7-Chloro-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-one (6b;
Table 4; Entry 2). Eluent dichloromethane/methanol (100:3). Yield,
1
30.2 mg, 68%. White solid: mp 277−279 °C; H NMR (400 MHz,
3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-6-amine (5g; Table 4;
DMSO-d6) δ 7.96 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 8.8,
2.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.11 (t, J = 8.4 Hz, 2H), 3.63 (t,
J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 159.4, 155.1,
150.3, 134.1, 126.6, 125.6, 124.9, 118.5, 42.5, 39.5; HRMS (M + H+)
calcd for C10H9ClN3O 222.0434, found 222.0434.
Entry 7). Eluent dichloromethane/methanol/triethylamine
1
(100:10:0.5). Yield, 81 mg, 81%. White solid: mp 266−267 °C; H
NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.2 Hz, 1H), 7.36−7.32
(m, 1H), 6.99−6.92 (m, 2H), 6.67 (s, 2H), 3.73 (t, J = 6.0 Hz, 2H),
3.45 (t, J = 5.6 Hz, 2H), 1.87 (t, J = 5.6 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 151.7, 146.9, 146.9, 132.1, 124.6, 123.1,
121.4, 117.8, 43.3, 42.5, 20.0; HRMS (M + H+) calcd for C11H13N4
201.1140, found 201.1142.
7,8-Dimethoxy-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-one
(6c; Table 4; Entry 3). Eluent dichloromethane/methanol (100:3).
Yield, 26.2 mg, 53%. Yellow solid: Decomp 269 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.56 (s, 1H), 7.26 (s, 1H), 6.71 (s, 1H), 4.08
(t, J = 8.4 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.60 (t, J = 8.4 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 159.9, 154.7, 154.4, 147.4, 145.3,
10-Chloro-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-amine
(5h; Table 4; Entry 8). Eluent dichloromethane/methanol/triethyl-
amine (100:10:0.5). Yield, 97 mg, 83%. White solid: mp 271−273 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 2.4 Hz, 1H), 7.30 (dd,
J = 8.8, 2.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.68 (s, 2H), 3.69 (t, J =
5.6 Hz, 2H), 3.44 (t, J = 5.2 Hz, 2H), 1.83 (t, J = 5.2 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 152.3, 145.9, 144.9, 131.3, 125.0,
124.7, 123.7, 120.4, 43.2, 43.1, 20.1; HRMS (M + H+) calcd for
C11H12ClN4 235.0750, found 235.0746.
109.6, 105.9, 105.8, 55.8, 55.8, 42.5, 39.6; HRMS (M + H+) calcd for
C12H14N3O3 248.1035, found 248.1031.
7,8-Dihydro-[1,3]dioxolo[4,5-g]imidazo[2,1-b]quinazolin-10(6H)-
one (6d; Table 4; Entry 4). Eluent dichloromethane/methanol (100:3).
Yield, 29.6 mg, 64%. Yellow solid: Decomp 303 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.22 (s, 1H), 6.69 (s, 1H), 6.07
(s, 2H), 4.07 (t, J = 8.4 Hz, 2H), 3.59 (t, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 159.8, 154.5, 153.1, 149.2, 143.7, 110.9, 103.4,
9,10-Dimethoxy-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6-
amine (5i; Table 4; Entry 9). Eluent dichloromethane/methanol/
2656
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
102.8, 102.0, 42.5, 39.7; HRMS (M + H+) calcd for C11H10N3O3
232.0722, found 232.0721.
3.28 (t, J = 5.6 Hz, 2H), 1.98−1.92 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 161.1, 150.9, 149.9, 137.2, 128.7, 126.5, 117.9, 112.4,
40.4, 20.3; HRMS (M + H+) calcd for C11H11BrN3O 280.0085, found
280.0088.
8-Bromo-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-one (6e;
Table 4; Entry 5). Eluent dichloromethane/methanol (100:3). Yield,
1
32.3 mg, 61%. White solid: Decomp 284 °C; H NMR (400 MHz,
General Procedure for Ring-Opening Acidolysis. Tricyclic
quinazolines (0.5 mmol) was added to 25 mL of HCl (0.5 mol/L), and
then the reaction was kept refluxing for 6 h. When the completion of
acidolysis was verified by TLC monitoring, the reaction was allowed to
cool to room temperature and neutralized by NaHCO3 (20 mmol).
The mixture was extracted with CHCl3/MeOH (30:1), and then the
organic phase was concentrated and purified by flash column chro-
matography to afford the major product (7) and the coproduct (8).
2-Amino-3-(3-aminopropyl)quinazolin-4(3H)-one (7a; Scheme 2).
Eluent dichloromethane/methanol/triethylamine (100:5:0.5 to
DMSO-d6) δ 8.05 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 1.2 Hz,
1H), 7.24 (dd, J = 8.4, 1.2 Hz, 1H), 4.10 (t, J = 8.4 Hz, 2H), 3.64
(t, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 159.9, 155.6,
152.8, 127.9, 127.7, 126.5, 124.5, 124.6, 116.5, 42.4, 39.6; HRMS (M +
H+) calcd for C10H9BrN3O 265.9929, found 265.9938.
7-Bromo-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-one (6f;
Table 4; Entry 6). Eluent dichloromethane/methanol (100:3). Yield,
1
33.7 mg, 63%. White solid: Decomp 323 °C; H NMR (400 MHz,
DMSO-d6) δ 7.97 (s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.67−7.65
(m, 1H), 7.15 (d, J = 8.8 Hz, 2H), 4.11 (t, J = 8.4 Hz, 2H), 3.63 (t, J =
8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 159.3, 155.2, 150.6,
136.8, 128.0, 126.9, 119.1, 113.4, 42.6, 39.6; HRMS (M + H+) calcd
for C10H9BrN3O 265.9929, found 265.9943.
1
100:20:0.5). Yield, 63.1 mg, 58%. White solid: Decomp 226 °C; H
NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.0 Hz, 1H), 7.55 (t, J =
7.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.05
(t, J = 6.4 Hz, 2H), 2.59 (t, J = 6.4 Hz, 2H), 1.76 (t, J = 6.4 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 162.3, 152.9, 150.1, 134.3, 126.7,
General Procedure B for Synthesis of Tricyclic Quinazoli-
nones (6g−6l). Tricyclic quinazolines (5, 0.2 mmol) were added to
25 mL of NaOH (0.01 mol/L) and 5 mL of EtOH. Then, the mixture
was heated to refluxing vigorously for 72 h. Then, the solvent was re-
moved under reduced pressure, and the residue was purfied by flash
column chromatography.
124.0, 121.6, 116.4, 39.4, 37.9, 30.2; HRMS (M + H+) calcd for
C11H15N4O 219.1246, found 219.1250.
3,4-Dihydro-2H-pyrimido[1,2-c]quinazolin-6(7H)-one (8a;
Scheme 2).21 Yield, 22.7 mg, 22%. White solid: mp 242−244 °C;
(lit.28 mp 250−251 °C); H NMR (400 MHz, CDCl3) δ 9.87 (br,
1
3,4-Dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one (6g; Table 4;
1H), 8.06 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.10 (d, J =
7.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.67(t,
J = 5.6 Hz, 2H), 1.98 (t, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 150.9, 145.8, 136.4, 132.2, 125.9, 123.2, 116.6, 114.5, 44.6, 40.9, 20.4.
2-Amino-3-(3-aminopropyl)-6-chloroquinazolin-4(3H)-one (7b;
Scheme 2). Eluent dichloromethane/methanol/triethylamine
(100:5:0.5 to 100:25:0.5). Yield, 63.8 mg, 51%. White solid: Decomp
Entry 7). Eluent dichloromethane/methanol (100:5). Yield, 32.5 mg,
81%. White solid: mp 237−238 °C; (lit.27 237 °C); H NMR (400
1
MHz, DMSO-d6) δ 7.87 (dd, J = 8.0, 1.2 Hz, 1H), 7.70 (s, 1H), 7.54−
7.50 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 3.94
(t, J = 5.6 Hz, 2H), 3.29 (t, J = 5.6 Hz, 2H), 1.96 (t, J = 5.6 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 161.7, 150.4, 150.2, 134.3, 126.5,
123.6, 120.9, 116.1, 39.9, 38.7, 20.2; HRMS (M + H+) calcd for
C11H12N3O 202.0980, found 202.0984.
1
261 °C; H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 2.4 Hz, 1H),
7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.03 (t, J =
6.8 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 1.76 (t, J = 6.8 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 161.3, 153.0, 148.8, 134.3, 126.1,
125.4, 125.2, 117.2, 39.5, 37.7, 29.6; HRMS (M + H+) calcd for
C11H14ClN4O 253.0856, found 253.0861.
10-Chloro-3,4-dihydro-2H-pyrimido[1,2-c]quinazolin-6(7H)-one
(8b; Scheme 2). Yield, 42.3 mg, 36%. White solid: mp 257−261 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.84 (d, J = 2.4 Hz,
1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.73 (t,
J = 5.6 Hz, 2H), 3.49 (t, J = 5.6 Hz, 2H), 1.81 (t, J = 5.6 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 149.4, 144.1, 136.4, 131.8, 126.1,
124.5, 117.6, 116.7, 44.0, 40.2, 20.1; HRMS (M + H+) calcd for
C11H11ClN3O 236.0591, found 236.0588.
General Procedure for Acetylation of Intermediate Quina-
zolinones. To a solution of quinazolinones (7, 0.2 mmol) in dichloro-
methane (20 mL) were added acetic anhydride (0.6 mmol, 61.3 mg)
and triethylamine (0.6 mmol, 60.7 mg), and the reaction was stirred at
room temperature for 2 h. After completion of the reaction as in-
dicated by TLC, The reaction mixture was washed by aqueous K2CO3
and dried over anhydrous MgSO4. The organic phase was concen-
trated by vacuum distillation, and the residue was purfied by flash
column chromatography to afford product 9.
N-(3-(2-Amino-4-oxoquinazolin-3(4H)-yl)propyl)acetamide (9a;
Scheme 2). Eluent dichloromethane/methanol (100:5). Yield, 37.5
mg, 72%. White solid: mp 218−220 °C; 1H NMR (400 MHz, DMSO-
d6) δ 7.89 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.55 (t, J = 8.4 Hz, 1H),
7.17 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 7.03 (s, 2H), 3.99
(t, J = 7.6 Hz, 2H), 3.11−3.09 (m, 2H), 1.80 (s, 3H), 1.72 (t, J =
7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.5, 161.1, 152.4,
148.9, 134.4, 126.2, 125.5, 125.3, 117.3, 39.8, 36.6, 27.7, 23.0; HRMS
(M + H+) calcd for C13H17N4O2 261.1352, found 261.1345.
N-(3-(2-Amino-6-chloro-4-oxoquinazolin-3(4H)-yl)propyl)-
acetamide (9b; Scheme 2). Eluent dichloromethane/methanol
(100:5). Yield, 44.0 mg, 75%. White solid: mp 225−226 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.81 (d, J = 2.0 Hz, 1H),
7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.19−7.17 (m, 3H), 3.98 (t, J = 7.2 Hz,
2H), 3.12−3.07 (m, 2H), 1.80 (s, 3H), 1.71 (t, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 169.4, 161.0, 152.3, 148.8, 134.3,
8-Chloro-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one
(6h; Table 4; Entry 8). Eluent dichloromethane/methanol (100:5).
Yield, 37.0 mg, 78%. White solid: mp 261−264 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.52
(dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.93 (t, J = 6.0 Hz,
2H), 3.30−3.27 (m, 2H), 1.95 (t, J = 5.6 Hz, 2H); 13C NMR (100
MHz, DMSO-d6) δ 161.3, 150.8, 149.4, 134.8, 126.2, 125.6, 125.0,
117.2, 40.5, 39.0, 20.2; HRMS (M + H+) calcd for C11H11ClN3O
236.0591, found 236.0588.
8,9-Dimethoxy-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-
one (6i; Table 4; Entry 9). Eluent dichloromethane/methanol (100:5).
1
Yield, 43.2 mg, 81%. Yellow solid: Decomp 263 °C; H NMR (400
MHz, DMSO-d6) δ 7.41 (s, 1H), 7.22 (s, 1H), 6.59 (s, 1H), 3.91 (t,
J = 5.6 Hz, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.27 (m, 2H), 1.94 (t, J =
5.6 Hz, 2H); HRMS (M + H+) calcd for C13H16N3O3 262.1192, found
262.1189.
8,9-Dihydro-6H-[1,3]dioxolo[4, 5-g]pyrimido[2,1-b]quinazolin-
11(7H)-one (6j; Table 4; Entry 10). Eluent dichloromethane/methanol
(100:5). Yield, 36.6 mg, 75%. Light yellow solid: Decomp 268 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.17 (s, 1H), 6.57
(s, 1H), 6.04 (s, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.26−3.24 (m, 2H),
1.92 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.2,
153.6, 149.9, 148.6, 143.4, 109.8, 103.2, 102.5, 102.0, 40.1, 39.0, 20.6;
HRMS (M + H+) calcd for C12H12N3O3 246.0879, found 246.0875.
9-Bromo-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one
(6k; Table 4; Entry 11). Eluent dichloromethane/methanol (100:5).
Yield, 44.9 mg, 80%. White solid: Decomp 271 °C; 1H NMR
(400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.26
(s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 3.90 (t, J = 5.2 Hz, 2H), 3.28 (t, J =
5.2 Hz, 2H), 1.95 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 161.1, 151.6, 150.9, 128.6, 127.9, 125.5, 123.6 115.1, 39.8, 38.6,
19.8; HRMS (M + H+) calcd for C11H11BrN3O 280.0085, found
280.0099.
8-Bromo-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one
(6l; Table 4; Entry 12). Eluent dichloromethane/methanol (100:5).
Yield, 41.1 mg, 73%. White solid: Decomp 276 °C; (lit.21b mp > 206 °C);
1H NMR (400 MHz, DMSO-d6) δ 7.92−7.90 (m, 1H), 7.62 (dd, J =
8.8, 2.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.92 (t, J = 5.6 Hz, 2H),
2657
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658

The Journal of Organic Chemistry
Article
126.1, 125.5, 125.2, 117.2, 39.6, 36.5, 27.6, 22.9, 22.8; HRMS (M +
H+) calcd for C13H16ClN4O2 295.0962, found 295.0963.
(9) Okano, M.; Mito, J.; Maruyama, Y.; Masuda, H.; Niwa, T.;
Nakagawa, S.; Nakamura, Y.; Matsuura, A. Bioorg. Med. Chem. 2009,
17, 119−132.
(10) (a) Haddach, M.; Pierre, F. PCT Int. Appl., WO 2011035019,
2011. (b) Henteman, M. F.; Scott, W.; Wood, J.; Johnson, J.; Redman,
A.; Bullion, A.; Guernon, L. PCT Int. Appl., WO 2009091550, 2009.
(c) Hentemann, M.; Wood, J.; Scott, W.; Michels, M.; Campbell, A.;
Bullion, A.; Rowley, R. B.; Redman, A. PCT Int. Appl., WO
2008070150, 2008.
(11) (a) Rosowsky, A.; Marini, J. L.; Nadel, M. E.; Modest, E. J.
J. Med. Chem. 1970, 13, 882−886. (b) Rosowsky, A.; Chen, H. J. Org.
Chem. 2001, 66, 7522−7526.
(12) Hynes, J. B.; Pathak, A.; Panos, C. H.; Okeke, C. C. J. Heterocycl.
Chem. 1988, 25, 1173−1177.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of products. X-ray data of
compounds (5h and 6g) are provided in CIF format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lhe2001@sina.com (L.H.); dengyongy@sohu.com (Y.D.).
(13) (a) Dehnhardt, C. M.; Venkatesan, A. M.; Chen, Z.; Ayral−
Kaloustian, S.; Dos Santos, O.; Delos Santos, E.; Curran, K.; Follettie,
M. T.; Diesl, V.; Lucas, J.; Geng, Y.; DeJoy, S. Q.; Petersen, R.;
Chaudhary, I.; Brooijmans, N.; Mansour, T. S.; Arndt, K.; Chen, L.
J. Med. Chem. 2010, 53, 897−910. (b) Millen, J.; Riley, T. N.; Waters,
I. W.; Hamrick, M. E. J. Med. Chem. 1985, 28, 12−17.
(14) (a) Wilson, L. J. Org. Lett. 2001, 3, 585−588. (b) Dener, J. M.;
Lease, T. G.; Novack, A. R.; Plunkett, M. J.; Hocker, M. D.; Fantauzzi,
P. P. J. Comb. Chem. 2001, 3, 590−597.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Science
Foundation of China (No. 21072131).
(15) Yang, X.-B.; Liu, H.-X.; Fu, H.; Qiao, R.-Z.; Jiang, Y.-Y; Zhao, Y.-
F. Synlett 2010, 101−106.
(16) (a) Ishihara, M.; Togo, H. Tetrahedron 2007, 63, 1474−1480.
(b) Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Tetrahedron
2007, 63, 638−643. (c) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu,
A.; Kita, Y. Tetrahedron Lett. 2005, 46, 2197−2199.
REFERENCES
■
(1) For selected reviews, see: (a) D’yakonov, A. L.; Telezhenetskaya,
M. V. Chem. Nat. Comput. 1997, 33, 221−267. (b) Michael, J. P. Nat.
Prod. Rep. 2008, 25, 166−187. (c) Mhaske, S. B.; Argade, N. P.
Tetrahedron 2006, 62, 9787−9826.
(2) For selected reviews, see: (a) He, N.-Q.; Yan, S.-J; Lin, J. Huaxue
Tongbao 2010, 73, 314−325. (b) Salagierski, M.; Sosnowski, M. Cent.
Eur. J. Urol. 2009, 62, 228−232. (c) Kaur, P.; Kaur, A.; Kaur, R.; Kaur,
K. J. Global Pharma Technol. 2010, 2, 35−39.
(3) Campbell, S. F.; Davey, M. J.; Hardstone, J. D.; Lewis, B. N.;
Palmer, M. J. J. Med. Chem. 1987, 30, 49−57.
(4) (a) Graffner-Nordberg, M.; Fyfe, M.; Brattsand, R.; Mellgard, B.;
(17) Yin, P.; Ma, W.-B.; Chen, Y.; Huang, W.-C.; Deng, Y.; He, L.
Org. Lett. 2009, 11, 5482−5485.
(18) (a) M’Hamed, M. O.; M’Rabet, H.; Efrit, M. L. C. R. Chim.
2007, 10, 1147−1156. (b) Zarguil, A.; Boukhris, S.; El Efrit, M. L.
Tetrahedron Lett. 2008, 49, 5883−5886. (c) He, R. J.; Ching, S. M.;
Lam, Y. L. J. Comb. Chem. 2006, 8, 923−928. (d) Che, J.;
Raghavendra, M. S.; Lam, Y. L. J. Comb. Chem. 2009, 11, 378−384.
(e) Huffman, K. R.; Schaefer, F. C. J. Org. Chem. 1963, 28, 1816−
1821.
̊
Hallberg, A. J. Med. Chem. 2003, 46, 3455−3462. (b) Graffner-
Nordberg, M.; Kolmodin, K.; Åqvist, J.; Queener, S. F.; Hallberg, A.
J. Med. Chem. 2001, 44, 2391−2402. (c) Graffner-Nordberg, M.;
Marelius, J.; Ohlsson, S.; Persson, A.; Swedberg, G.; Andersson, P.;
Andersson, S. E.; Åqvist, J.; Hallberg, A. J. Med. Chem. 2000, 43,
3852−3861.
(5) Pineda, P.; Kanter, A.; McIvor, R. S.; Benkovic, S. J.; Rosowsky,
A.; Wagner, C. R. J. Med. Chem. 2003, 46, 2816−2818.
(6) (a) Am. J. Hosp. Pharm. 1994, 51, 591−592. (b) Fulton, B.;
Wagstaff, A. J.; McTavish, D. Drugs 1995, 49, 563−576. (c) Takimoto,
C. H.; Allegra, C. J. Oncology 1995, 9, 645−656.
(7) (a) Singh, J. Abstracts of Papers, 239th ACS National Meeting,
San Francisco, CA, March 21−25, 2010; American Chemical Society:
Washington, D.C., 2010; MEDI. (b) Butchbach, M. E. R.; Singh, J.;
Thorsteinsdottir, M.; Saieva, L.; Slominski, E.; Thurmond, J.;
Andresson, T.; Zhang, J.; Edwards, J. D.; Simard, L. R.; Pellizzoni,
L.; Jarecki, J.; Burghes, A. H. M.; Gurney, M. E. Hum. Mol. Genet.
2010, 19, 454−467. (c) Thurmond, J.; Butchbach, M. E. R.; Palomo,
M.; Pease, B.; Rao, M.; Bedell, L.; Keyvan, M.; Pai, G.; Mishra, R.;
Haraldsson, M.; Andresson, T.; Bragason, G.; Thosteinsdottir, M.;
Bjornsson, J. M.; Coovert, D. D.; Burghes, A. H. M.; Gurney, M. E.;
Singh, J. J. Med. Chem. 2008, 51, 449−469. (d) Singh, J.; Thurmond,
J.; Pease, B.; Rao, M.; Palomo, M.; Pai, G.; Bedell, L.; Keyvan, M.;
Mishra, R.; Zhang, J.; Onua, E.; Bjarnadottir, E.; Haraldsson, M.;
Andresson, T.; Gunnseinsdottir, T.; Atlason, P.; Sigthorsson, G.;
Bragason, G.; Thorsteinsdottir, M.; Gurney, M. Abstracts of Papers,
230th ACS National Meeting, Washington, D.C., Aug 28−Sept 1,
2005; American Chemical Society: Washington, D.C., 2005; MEDI.
(8) (a) Berman, J. D.; King, M.; Edwards, N. Antimicrob. Agents
Chemother. 1989, 33, 1860−1863. (b) Khabnadideh, S.; Pez, D.;
Musso, A.; Brun, R.; Perez, L. M. R.; Gonzalez−Pacanowska, D.;
Gilbert, I. H. Bioorg. Med. Chem. 2005, 13, 2637−2649.
(19) (a) Evans, P. A.; Qin, J.; Robinson, J. E.; Bazin, B. Angew. Chem.,
́
Int. Ed. 2007, 46, 7417−7419. (b) Arnold, M. A.; Day, K. A.; Duron,
S. G.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 13255−13260.
(c) Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782−
10783.
(20) (a) Leow, D.; Lin, S.-S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H.
Angew. Chem. 2008, 120, 5723−5727. (b) Corey, E. J.; Grogan, M. J.
Org. Lett. 1999, 1, 157−160.
(21) (a) Larraufie, M.-H.; Ollivier, C.; Fensterbank, L.; Malacria, M.;
Laco
M.-F.; Thier
̂
te, E. Angew. Chem., Int. Ed. 2010, 49, 2178−2181. (b) Pereira,
́
y, V.; Besson, T. Tetrahedron 2007, 63, 847−854.
(c) Clews, J.; Curtis, A. D. M.; Malkin, H. Tetrahedron 2000, 56,
8735−8746.
(22) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50,
1105−1109.
(23) (a) Zielinski, W.; Kudelko, A. J. Heterocycl. Chem. 2002, 39,
1289−1292. (b) Hynes, J. B.; Singh, S. K.; Fetzer, O.; Shane, B. J. Med.
Chem. 1992, 35, 4078−4085. (c) Gangjee, A.; Kothare, M.; Kisliuk,
R. L. J. Heterocycl. Chem. 2000, 37, 1097−1102.
(24) For single crystal X-ray structure data of compounds 5h and 6g,
see the Supporting Information.
(25) Pereira, M. -F.; Alexandre, F. R.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2004, 45, 3097−3099.
(26) Wagner, G.; Bunk, E. Pharmazie 1979, 34, 209−213.
(27) Dean, W. D.; Papadopoulos, E. P. J. Heterocycl. Chem. 1982, 19,
1117−1124.
(28) Mizuhara, T.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Chem.
Commun. 2009, 45, 3413−3415.
2658
dx.doi.org/10.1021/jo2023697 | J. Org. Chem. 2012, 77, 2649−2658