Iodine Catalyzed Oxidative Synthesis of Quinazolin-4(3H)-ones and Pyrazolo[4,3-d]pyrimidin-7(6H)-ones via Amination of sp3 C-H Bond

Article abstract of DOI:10.1021/acs.joc.5b00989

Molecular iodine catalyzed oxidative coupling of 2-aminobenzamides with aryl methyl ketones produced 2-aryl quinazolin-4(3H)-ones. The reaction performed well in the absence of any metal or ligand. The quantity of iodine played a very crucial role in this transformation in order to selectively get 2-aryl quinazolin-4(3H)-ones. The utility of this protocol for synthesis of pyrazolo[4,3-d]pyrimidin-7(6H)-ones including a key intermediate involved in sildenafil synthesis has also been demonstrated.

Full text of DOI:10.1021/acs.joc.5b00989

Subscriber access provided by NEW YORK UNIV
Note
Iodine catalyzed oxidative synthesis of quinazolin-4(3H)-ones and
pyrazolo[4,3-d]pyrimidin-7(6H)-ones via amination of sp3 C-H bond
Shabber Mohammed, Ram A. Vishwakarma, and Sandip Bibishan Bharate
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00989 • Publication Date (Web): 12 Jun 2015
Downloaded from http://pubs.acs.org on June 15, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Iodine catalyzed oxidative synthesis of quinazolinꢀ
4(3H)ꢀones and pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones
via amination of sp3 CꢀH bond
Shabber Mohammed, †‡ Ram A. Vishwakarma,†‡* Sandip B. Bharate†‡*
†Medicinal Chemistry Division, CSIRꢀIndian Institute of Integrative Medicine, Canal Road, Jammuꢀ
180001, India
‡
Academy of Scientific & Innovative Research, CSIRꢀIndian Institute of Integrative Medicine, Canal
Road, Jammuꢀ180001, India
TOC
o New method for 2ꢀaryl quinazolinꢀ4(3H)ꢀones
o No use of metal or ligand
o
o
Catalytic quantity of molecular iodine
Synthesis key intermediate of sildenafil
ABSTRACT. Molecular iodine catalyzed oxidative coupling of 2ꢀaminobenzamides with aryl ketones
produced 2ꢀaryl quinazolinꢀ4(3H)ꢀones. The reaction performed well in the absence of any metal or
ligand. The quantity of iodine played very crucial role in this transformation in order to selectively get 2ꢀ
aryl quinazolinꢀ4(3H)ꢀones. The utility of this protocol for synthesis of pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀ
ones including a key intermediate involved in sildenafil synthesis has also been demonstrated.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
KEYWORDS. quinazolinꢀ4(3H)ꢀones, pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones, sp3 CꢀH bond
1
2
3
functionalization, molecular iodine, oxidative coupling
4
5
6
7
8
9
Quinazolinꢀ4(3H)ꢀones are an important class of fused heterocycles having wide occurrence among
natural products1ꢀ6 and bioactive compounds.7,8 Especially, 2ꢀaryl substituted quinazolinones have been
reported as potent kinase inhibitors (e.g. idelalisib).9ꢀ11 Similarly, the pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀ
one is another important class of fused heterocycles possessing promising biological activities.12,13 The
blockbuster drug sildenafil (Viagra®)13 which is used to treat erectile dysfunction contains a
pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀone pharmacophore. Because of their medicinal importance,
synthetically, these scaffolds have been extensively explored.14ꢀ16 Among various transformations
reported for synthesis of quinazolinones, the condensation of 2ꢀaminobenzamide with various simple
aryl precursors using metal or metalꢀfree conditions is one of the most elegant and widely studied
approach. Various reports on this approach (summarized in Figure 1) includes: (a) the condensation of
2ꢀaminobenzamide with aryl aldehyde,15,17 aryl carboxylic acid,18 aryl acid chloride19; (b) Pd,20 Ir,21
Zn22 or I2/DMSO23 catalyzed benzylic C−H amidation with benzyl alcohols; or condensation with
benzyl amine,24 or benzyl halides;25 (c) Pd(OAc)2/BuPAd2/CO catalyzed condensation with aryl
bromides;26 (d) PdCl2/DPPP/CaCl2 mediated condensation with aryl halides and via palladium catalyzed
isocyanide insertion;27 (e) metalꢀfree (tBuO)2 (DTBP)/ TsOH mediated condensation with methylarenes
or methylhetarenes;28 (f) CuCl catalyzed condensation with methylhetarenes;29 and (g) TFA catalyzed
condensation with ketoalkynes.30 Many of these protocols have certain disadvantages. The condensation
with carbonyl compounds (aldehydes, acids or acid chlorides) requires use of stoichiometric quantities
of toxic oxidants (such as DDQ)17 or coupling agents (such as EDCI)/ bases.18 Furthermore, the
condensation with benzyl alcohols20ꢀ22 and aryl halides26,27 requires metal catalysts. The present work
describes the use of aromatic ketones as a coupling partner which are cheap, commercially available and
relatively stable. Furthermore, the protocol is metalꢀfree and requires catalytic amount of iodine and
molecular oxygen as an oxidant.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
Figure 1. Literature reports (paths aꢀg and h2)
and the present work (path h1) for synthesis of
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
quinazolinꢀ4(3H)ꢀones.
The use of molecular iodine as a catalyst is a promising strategy in organic synthesis which
substitutes many transition metals. Especially, the amidation of C(sp3)ꢀH bonds using molecular iodine
is very attractive and it finds utility in synthesis of wide range of Nꢀheterocycles. Recently, Wu and
coworkers31 reported I2/DMSO catalyzed condensation of 2ꢀaminobenzamide with acetophenone to
produce 2ꢀbenzoyl substituted quinazolinone 3a (path h2 of Figure 1). Wu’s protocol involved the use of
stoichiometric quantity of molecular iodine (110 mol%), which led to the formation of 2ꢀbenzoyl
substituted quinazolinone 3a via formation of glyoxal 7a as a key intermediate (Figure 2). Interestingly,
during our investigations, it was observed that on the use of catalytic amounts of iodine (10 mol%), the
acetophenone 6a forms Schiff’s base 4a as a key intermediate, which then undergoes cyclization
followed by formaldehyde loss to produce 2ꢀaryl quinazolinone product 2a (path h1 in Figure 1, and
Figure 2) instead of 2ꢀbenzoyl quinazolinone 3a. Thus, herein we report an efficient metalꢀfree approach
for synthesis of 2ꢀaryl quinazolinꢀ4(3H)ꢀones 2 and pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones 9 via
condensation of 2ꢀaminobenzamides 1 with aryl ketones 6 using molecular iodine as a catalyst and
molecular oxygen as an oxidant.
We began our efforts by examining the condensation reaction of 2ꢀaminobenzamide (1a) with
acetophenone (6a) under various conditions as shown in Table 1. Based on the recent report on the
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 18
condensation of acetophenone with 2ꢀaminobenzenethiol,32 we investigated the reaction of 1a with 6a in
DMSO and PhCl (1:1) as a solvent in an open air atmosphere (or molecular oxygen) at 140 °C, however
reaction does not proceed at all (entries 1ꢀ3); and even the Schiff’s base 4a was also not formed. Then,
we used 10 mol% I2 in DMSO at room temperature (entry 4) or under heating (entries 5ꢀ6) in air
atmosphere (entries 4ꢀ6) or using molecular oxygen (entry 7), which led to formation of desired product
2ꢀaryl quinazolinone 2a upto 30% yield along with Schiff’s base 4a (entries 4ꢀ7). This indicated that
iodine acts as a Lewis acid to form Schiff’s base 4a. On the use of 100 and 150 mol% of I2 in the
presence of molecular oxygen, the benzoyl substituted product 3a was formed in 50% yield, whereas
yield of 2a remained 20% (entries 8ꢀ9). Further, when the mol% of I2 was decreased from 100 to 50, the
yield of 2a was increased up to 35% (entry 10). Further decrease in the iodine quantity to 10 mol%
resulted in further improvement in 2a yield (entry 11). As seen in the entry 7, longer reaction time and
10 mol% I2 produces only desired product 2a along with Schiff’s base 4a without formation of
undesired product 3a; therefore we further intended to use smaller equivalents of iodine and a longer
reaction time. These efforts indicated that 10 mol% I2 in DMSO in the presence of molecular oxygen for
16 h, results in formation of 73% of the desired 2ꢀaryl quinazolinone 2a (entry 12).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the reaction conditions
O
O
O
O
O
N
O
I
NH
NH2
NH
Ph
NH2
+
NH
Ph
+
+
+
Ph
H3C
Ph
N
N
N
NH2
1a
Ph
O
6a
2a
3a
4a
5a
Entry Iodine (mol
%)
oxidant solvent
Temp.
(oC)
140
Time (h)
10
Yield (%)a
2a
0
3a
0
4a
0
5a
0
1
0
air
DMSO +
PhClb
2
3
4
5
6
7
8
9
0
0
air
O2
air
air
air
O2
O2
O2
O2
O2
O2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
140
140
rt
110
140
rt
110
110
110
110
110
10
10
10
10
10
20
4
4
4
10
16
0
0
0
0
0
0
0
0
50
50
40
0
0
0
0
0
0
0
0
10
10
10
10
100
150
50
10
10
10
30
30
20
20
20
35
50
73
20
20
20
20
0
traces
10
traces
traces
traces
0
0
10
11
12c
traces
traces
traces
traces
aisolated yield. b DMSO: PhCl (1: 1). c optimized reaction condition.
4
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
These results concluded that the catalyst loading played a crucial role in selective formation of 2ꢀaryl
1
2
2a versus 2ꢀbenzoyl product 3a, as depicted in Figure 2. When iodine was used in stochiometric
equivalent, acetophenone 6a immediately gets converted to glyoxal 7a which further reacts with 2ꢀ
aminobenzamide (1a) to produce 3a as a major product. However, on the use of catalytic amount of
iodine (10 mol%), preferentially the Schiff’s base 4a gets formed which on cyclization yields 2ꢀaryl
quinazolinone 2a as a major product.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
100 mol% I2
DMSO, 110 oC, O2
O
NH
+ 1a
O
Ph
Ph
N
3a
O
7a
O
O
O
H3C
Ph
6a
+
1a
NH2
NH
Ph
10 mol% I2
N
N
DMSO, 110 oC, O2
Ph
2a
4a
Figure 2. Catalyst loading as a key determinant
factor for formation of 2a versus 3a
Under the optimized reaction conditions, the scope and generality of the oxidative condensation
reaction was then explored (Scheme 1). The condensation with nonꢀsubstituted acetophenone gave
slightly lower yields in comparison to substituted acetophenones. The reactions with aryl ketones
bearing electronꢀdonating groups on the aromatic ring proceeded smoothly to give the desired products
in good yields (entries 2b, 2c, 2d, and 2e). Electronꢀwithdrawing functional groups bearing aryl ketones
also gave good yields (entries 2f and 2g). These findings indicated that there is no effect of the type of
substituents on the yield of desired product. Mild EWGs such as fluoro, bromo were also well tolerated
under optimized reaction conditions (entries 2h-j) while orthoꢀbromo substitution produced slightly
lower yield (entry 2j). Similarly, the 3ꢀacetamido aryl ketone yielded lesser yield (entry 2k). It is
noteworthy to mention that biphenyl (e.g. 2l), heteroaryl (e.g. 2m-o) and fused aryl (e.g. 2p) ketones
were also well tolerated in this reaction, producing corresponding products in good yields. Like aryl
ketones, a series of haloꢀsubstituted 2ꢀaminobenzamides such as chloro and iodo were also well
tolerated (2q-t) in this reaction. Further, in case of 2ꢀaminoꢀNꢀethylbenzamide, reaction does not
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
proceed (e.g. 2u). For 3ꢀchloro and 3,4ꢀdichloro substituted phenyl ketones, the desired 2ꢀaryl products
were not obtained; instead benzoyl substituted products 3b and 3c were obtained. This could be due to
the fact that the Schiff’s base is not getting formed for these ketones under our optimized reaction
conditions. Unfortunately, aliphatic ketones are also not suitable for this kind of transformations.
The pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones are putative building blocks for synthesis of PDE5
inhibitors and kinase inhibitors. Therefore, we investigated the utility of this protocol for preparation of
key building blocks for biologically important pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀone class of compounds.
Using this protocol, the pyrazoloꢀpyrimidinones 9a-c were prepared in 50ꢀ60% yield. In this case,
comparatively lesser yields were obtained because reaction does not went to completion under the
optimized reaction condition. The pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀone 9a is a key intermediate in
synthesis of a top selling drug sildenafil, whereas 9b could be utilized towards synthesis of potent
mTOR inhibitors (Scheme 1). This approach for synthesis of 9a allows further modifications (for further
SAR studies) on the phenolic OH, whereas reported approaches of sildenafil synthesis has these
limitations (which always involves alkylated phenolic OH right from the first step).13,33
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
O
O
O
10 mol% I2, O2
NH
Ar1
NH2
1
2
+
Ar1
DMSO, 110 o
C
H3C
O
Ar2
N
Ar2
NH2
1: Ar1 = Ph
8: Ar1 = pyrazole
16 h
6
2: Ar1 = Ph
9: Ar1 = pyrazole
3
4
5
6
O
N
O
N
O
NH
NH
NH
NH OH
N
N
OMe
2b (78%)
7
8
9
2a (73%)
2c (76%)
2d (80%)
O
O
O
O
NH
N
NH
NH
NH
N
NO2
N
N
10
11
12
13
14
15
16
17
18
19
20
F
NO2
OH
2h (76%)
2e (70%)
O
2f (77%)
2g (82%)
O
O
O
NH
N
NH Br
NH
N
NH Ph
H
N
N
N
Br
O
2i (77%)
2j (65%)
2k (50%)
2l (72%)
O
O
O
O
NH
N
NH
N
NH
N
NH
N
N
S
O
OMe
OMe
2o (50%)
2n (62%)
2m (65%)
2p (72%)
O
O
O
O
21
22
Cl
I
I
I
NH
N
NH
NH
NH
N
N
N
23
24
25
26
27
28
2t (76%)
2r (80%)
2s (82%)
2q (80%)
O
OMe
Cl
NO2
OMe
O
N
Cl
O
Cl
N
N
NH
NH
N
O
O
2u (0%)
O
3b (68%)
3c (77%)
O
O
N
N
N
29
NH OH
NH
NH
N
N
N
30
31
32
33
N
N
N
NO2
9c (60%)
9b (50%)
9a (55%)
Scheme 1. Scope of the reaction for synthesis of
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
various
quinazolinꢀ4(3H)ꢀones
2
and
pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones
9.
Reagents and conditions: 2ꢀaminobenzamide (1,
1.0 equiv.) or 4ꢀaminoꢀ1ꢀmethylꢀ3ꢀpropylꢀ1Hꢀ
pyrazoleꢀ5ꢀcarboxamide (8, 1.0 equiv.), aryl
ketone (6, 1.0 equiv.), 10 mol% I2, DMSO, 110
°C, O2 atmosphere, 16 h, 50ꢀ82%.
To elucidate the reaction mechanism, we conducted a series of control experiments. Under the
molecular oxygen, the reaction of αꢀiodo phenyl ketone 10 with 2ꢀaminobenzamide 1a produced product
3a in good yield, both with I2 (10 mol%) as well as without I2 (Scheme S1a of supporting information).
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
The αꢀiodo phenyl ketone 10 gets immediately converted to glyoxal 7a which then produces 3a. Another
experiment of phenyl glyoxal 7a with 2ꢀaminobenzamide 1a proceeded smoothly to form 3a as a major
product (Scheme S1b). These two experiments indicated that the formation of our desired product 2a
does not involve αꢀiodo ketone 10 and glyoxal 7a as intermediates. Once these intermediates (10 and/or
7a) gets formed, preferentially 3a gets formed with no opportunity to form 2a. Next, in order know the
possible reaction intermediates; we performed MS analysis of the reaction mixtures at different time
intervals. The MS spectrum after 1 h reaction time showed masses for Schiff’s base 4a or possibly its
cyclized intermediate I (m/z 238) along with product 2a (m/z 222), and m/z 364 (for iodinated
intermediate II). Interestingly, after 4 h, we observed a mass m/z 146 for formaldehyde condensed
byproduct quinazolinꢀ4(3H)ꢀone 11. Additionally, we also observed the mass for iodinated byproduct 5a
(m/z 347). The MS analysis details are provided in section S2 of supporting information. To prove the
formation of formaldehyde adduct 11, we conducted control reaction of 2ꢀaminobenzamide 1a with
formaldehyde, wherein we observed formation of quinazolinꢀ4(3H)ꢀone 11 in 55% yield (Scheme S1c of
supporting information). Thus, accordingly, we proposed a plausible reaction mechanism for formation
of 2a from 1a and 6a as depicted in Figure 3. In this reaction, iodine activates acetophenone 6a leading
to the formation of Schiff’s base 4a, which on cyclization produces intermediate I. Intermediate I
undergoes iodination to produce II. The intermediate II on coupling with DMSO forms III. Elimination
of dimethyl sulfide and formaldehyde from III leads to the formation of intermediate IV, which finally
on oxidation by molecular oxygen produces product 2a.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Figure 3. Proposed mechanism for synthesis of
quinazolinꢀ4(3H)ꢀones
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have developed a new iodineꢀcatalyzed synthesis of 2ꢀaryl quinazolinꢀ4(3H)ꢀones
via condensation of 2ꢀaminobenzamide with aryl ketones using molecular oxygen as an oxidant. The
utility of this protocol for preparation of pyrazolo[4,3ꢀd]pyrimidinꢀ7(6H)ꢀones has also been
demonstrated.
EXPERIMENTAL SECTION
1
13
General information. H, C and DEPT NMR spectra were recorded on FTꢀNMR 500 and 400
MHz instruments. Chemical data for protons are reported in parts per million (ppm) downfield from
tetramethylsilane and are referenced to the residual proton in the NMR solvent (CDCl3: 7.26, CD3OD:
3.28 and DMSOꢀd6: 2.5 ppm). Carbon nuclear magnetic resonance spectra (13C NMR) were recorded at
125 MHz or 100 MHz: chemical data for carbons are reported in parts per million (ppm, δ scale)
downfield from tetramethylsilane and are referenced to the carbon resonance of the solvent (CDCl3: 77,
CD3OD: 49 and DMSOꢀd6: 39.5 ppm). IR spectra were recorded on IR spectrophotometer. Melting
points were recorded on digital melting point apparatus.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
Optimized procedure for preparation of 2-aryl quinazolin-4(3H)-ones (2) and pyrazolo[4,3-
d]pyrimidin-7(6H)-ones (9). To the preheated mixture of 2ꢀaminobenzamides 1 or 4ꢀaminoꢀ1ꢀmethylꢀ
3ꢀpropylꢀ1Hꢀpyrazoleꢀ5ꢀcarboxamide 8 (100 mg, 1 equiv.) and corresponding acetophenone 6 (1 equiv.)
in DMSO in a roundꢀbottom flask in presence of oxygen (supplied using oxygen balloon), was added
iodine (10 mol%). Oxygen gas was continuously passed using oxygen balloon and reaction mixture was
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
heated at 110 C for 16 h. After completion of the reaction, water (20 ml) was added to the reaction
mixture. A saturated Na2S2O3 solution was then added until the brown colour disappeared. Product was
extracted with EtOAc (3 × 10 ml). The organic layer was collected, dried on anhydrous sodium sulphate
and solvent was evaporated on rotary evaporator to get the crude product. The crude product was
purified by silica gel (#100ꢀ200) column chromatography using 2ꢀ20% EtOAc: nꢀhexane to get pure
quinazolinone products. Most of the compounds were purified without column chromatography. MeOH
was added to the crude product and the resulting suspension was filtered. Obtained residue was washed
with MeOH 2ꢀ3 times and dried. To get good yield of the product, on addition of methanol, the product
was allowed to settle down for 2ꢀ3 days, which resulted in formation of a crystalline pure product.
2ꢀPhenylquinazolinꢀ4(3H)ꢀone (2a, SSꢀ730).28 White solid; yield: 73% (119 mg); m.p. 232ꢀ235 °C;
1H NMR (400 MHz, DMSOꢀd6, ppm): δ 11.57 (s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.26ꢀ8.24 (m, 2H),
13
7.86ꢀ7.80 (m, 2H), 7.60ꢀ7.50 (m, 3H), 7.52 (t, J = 7.2 Hz, 1H); C NMR (101 MHz, CDCl3, ppm): δ
163.8, 151.9, 149.4, 134.9, 132.8, 131.6, 129.0, 127.9, 127.43, 126.8, 126.3, 120.8; IR (CHCl3): νmax
3436, 2926, 1666, 1481, 1297, 1144 cmꢀ1; ESIꢀMS: m/z 223.08 [M+H]+; HRꢀESIMS: m/z 223.0869
calcd for C14H10N2O+H+ (223.0871).
2ꢀ(pꢀTolyl)quinazolinꢀ4(3H)ꢀone (2b, SSꢀ524).28 White solid; yield: 78% (135 mg); m.p. 239ꢀ242 °C;
1H NMR (400 MHz, CDCl3, ppm): δ 8.16ꢀ8.09 (m, 3H), 7.84 (t, J = 8.2 Hz, 1H), 7.74 (d, J = 7.8 Hz,
1H), 7.52 (t, J = 8.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H). IR (CHCl3): νmax 3436, 2918, 1667,
1600, 1486, 1241, 768 cmꢀ1; ESIꢀMS: m/z 237.10 [M+H]+; HRꢀESIMS: m/z 237.1029 calcd for
C15H12N2O+H+ (237.1028).
10
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
2ꢀ(4ꢀMethoxyphenyl)quinazolinꢀ4(3H)ꢀone (2c, SSꢀ743).28 White solid; yield: 76% (140 mg); m.p.
1
2
3
1
247ꢀ249 °C; H NMR (400 MHz, CDCl3, ppm): δ 8.27 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 8.7 Hz, 2H),
4
5
6
7
8
9
7.79 (d, J = 4.0 Hz, 2H), 7.49 (dd, J = 3.9, 8.0 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 3.91 (s, 3H); 13C NMR
(126 MHz, DMSOꢀd6, ppm): δ 162.2, 161.8, 151.8, 148.8 134.5, 129.4, 127.2, 126.1, 125.8, 124.7,
120.6, 113.9, 55.4; IR (CHCl3): νmax 3436, 2920, 1678, 1600, 1484, 1031, 765 cmꢀ1; ESIꢀMS: m/z
253.09 [M+H]+; HRꢀESIMS: m/z 253.0967 calcd for C15H12N2O2+H+ (253.0977).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(2ꢀHydroxyphenyl)quinazolinꢀ4(3H)ꢀone (2d, SSꢀ571).34 White solid; yield: 80% (140 mg); m.p.
1
252ꢀ255 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 8.24ꢀ8.16 (m, 2H), 7.87 (t, J = 8.2 Hz, 1H), 7.78
(d, J = 8.1 Hz, 1H), 7.59ꢀ7.54 (m, 1H), 7.49ꢀ7.44 (m, 1H), 7.03ꢀ6.95 (m, 2H); IR (CHCl3): νmax 3578,
3204, 2346, 1667, 1440, 1226 cmꢀ1; ESIꢀMS: m/z 239.07 [M+H] +; HRꢀESIMS: m/z 239.0811 calcd for
C14H10N2O2+H+ (239.0821).
2ꢀ(4ꢀHydroxyphenyl)quinazolinꢀ4(3H)ꢀone (2e, SSꢀ761).35 Yellow solid; yield: 70% (140 mg); m.p.
>280 oC; 1H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.61 (s, 1H), 10.79 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H),
8.09 (d, J = 8.7 Hz, 2H), 7.90 (t, J = 7.1 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 6.93
13
(d, J = 8.7 Hz, 2H); C NMR (126 MHz, DMSOꢀd6, ppm): δ 185.1, 163.5, 161.1, 149.8, 134.7, 133.7,
128.1, 125.9, 125.1, 122.5, 115.4; IR (CHCl3): νmax 3585, 3047, 2923, 1658, 1450, 1353, 1095, 640 cmꢀ
1; ESIꢀMS: m/z 237.07 [MꢀH] –.
2ꢀ(3ꢀNitrophenyl)quinazolinꢀ4(3H)ꢀone (2f, SSꢀ754).36 Yellow solid; yield: 77% (151 mg); m.p. 220ꢀ
1
222 °C; H NMR (400 MHz, CD3OD, ppm): δ 8.43 (s, 1H), 8.08 (dd, J = 1.5, 8.1 Hz, 1H), 7.90 (d, J =
7.9 Hz, 1H), 7.65 (dd, J = 1.4, 7.7 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.29 (dd, J = 4.2, 11.2 Hz, 1H),
13
6.82 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H); C NMR (126 MHz, CDCl3 + CD3OD, ppm): δ
167.1, 150.4, 149.6, 147.7, 135.8, 132.8, 130.8, 129.3, 124.0, 121.6, 120.0, 116.3; IR (CHCl3): νmax
3393, 2923, 1649, 1529, 1271, 1020 cmꢀ1; ESIꢀMS: m/z 266.0 [MꢀH]ꢀ.
2ꢀ(4ꢀNitrophenyl)quinazolinꢀ4(3H)ꢀone (2g, SSꢀ769).34 Yellow solid; yield: 82% (160 mg); m.p. >300
1
°C; H NMR (400 MHz, CD3OD, ppm): δ 8.04 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.50 (dd,
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
J = 1.3, 7.8 Hz, 1H), 7.18 (dd, J = 4.2 11.2, Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.58 (t, J = 7.5 Hz, 1H);
13C NMR (126 MHz, DMSOꢀd6, ppm): δ 163.6, 155.3, 146.6, 133.5, 127.3, 126.5, 123.3, 117.3, 114.8,
114.3; IR (CHCl3): νmax 3410, 2921, 1681, 1517, 1470, 1351, 1020 cmꢀ1; ESIꢀMS: m/z 266.05 [MꢀH]ꢀ;
HRꢀESIMS: m/z 266.0580 calcd for C14H9N3O3ꢀH– (266.0571).
1
2
3
4
5
6
7
8
9
2ꢀ(4ꢀFluorophenyl)quinazolinꢀ4(3H)ꢀone (2h, SSꢀ744).28 White solid; yield: 76% (134 mg); m.p. 240ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
242 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.59 (s, 1H), 8.26 (dd, J = 5.5, 8.8 Hz, 2H), 8.16 (d, J
= 7.2 Hz, 1H), 7.88ꢀ7.83 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 8.8 Hz,
2H); IR (CHCl3): νmax 3424, 2922, 2852, 2853, 1672, 1466, 1288, 1095 cmꢀ1; ESIꢀMS: m/z 241.07
[M+H]+; HRꢀESIMS: m/z 241.0782 calcd for C14H9FN2O+H+ (241.0777).
2ꢀ(4ꢀBromophenyl)quinazolinꢀ4(3H)ꢀone (2i, SSꢀ531).23 White solid; yield: 77% (169 mg); m.p. 292ꢀ
1
295 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.66 (s, 1H), 8.19 (m, 3H), 7.83 (m, 4H), 7.58 (t, J =
7.3 Hz, 1H); IR (CHCl3): νmax 3428, 2919, 1659, 1633, 1335, 1179, 768 cmꢀ1; ESIꢀMS: m/z 300.98
[M+H]+; HRꢀESIMS: m/z 302.9945 calcd for C14H9 BrN2O+H+ (302.9955).
81
2ꢀ(2ꢀBromophenyl)quinazolinꢀ4(3H)ꢀone (2j, SSꢀ802).37 White solid; yield: 65% (143 mg); m.p. 204ꢀ
1
206 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.91 (s, 1H), 8.23 (m, 3H), 8.05 (dd, J = 2.3, 8.7 Hz,
1H), 7.75 (t, J = 3.7 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H); IR (CHCl3): νmax 3301, 2922, 1595, 1580, 1441,
1106, 1019 cmꢀ1; ESIꢀMS: m/z 300.99 [M+H]+; HRꢀESIMS: m/z 300.9962 calcd for C14H9 BrN2O+H+
79
(300.9976).
Nꢀ(3ꢀ(4ꢀOxoꢀ3,4ꢀdihydroquinazolinꢀ2ꢀyl)phenyl)acetamide (2k, SSꢀ778). White solid; yield: 50%
1
(102 mg); m.p. >300 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.54 (s, 1H), 10.21 (s, 1H), 8.34 (s,
1H), 8.16 (d, J = 7.0 Hz, 1H), 7.85 (m, 2H), 7.76 (m, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz,
13
1H), 2.09 (s, 3H); C NMR (126 MHz, DMSOꢀd6, ppm): δ 168.6, 139.5, 134.6, 133.3, 128.9, 127.3,
126.6, 125.8, 122.1, 121.8, 120.9, 118.5, 23.9; IR (CHCl3): νmax 3585, 2923, 1658, 1405, 1255, 843 cmꢀ
1; ESIꢀMS: m/z 280.10 [M+H]+; HRꢀESIMS: m/z 280.1076 calcd for C16H13N3O2+H+ (280.1086).
12
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
2ꢀ([1,1'ꢀBiphenyl]ꢀ2ꢀyl)quinazolinꢀ4(3H)ꢀone (2l, SSꢀ777). White solid; yield: 72% (157 mg); m.p.
1
2
3
1
226ꢀ228 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.58 (s, 1H), 8.20ꢀ8.17 (m, 4H), 7.90ꢀ7.71 (m,
4
5
6
7
8
9
3H), 7.66ꢀ7.49 (m, 6H); 13C NMR (126 MHz, DMSOꢀd6, ppm): δ 171.2, 162.2, 152.2, 150.1, 148.7,
134.6, 132.6, 131.3, 128.5, 127.9, 127.8, 127.6, 126.5, 125.8, 120.9, 116.3, 114.3; IR (CHCl3): νmax
3195, 1667, 1558, 1452, 1296, 1144 cmꢀ1; ESIꢀMS: m/z 299.11 [M+H]+; HRꢀESIMS: m/z 299.1174
calcd for C20H14N2O+H+ (299.1184).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(5ꢀMethylthiophenꢀ2ꢀyl)quinazolinꢀ4(3H)ꢀone (2m, SSꢀ755).38 White solid; yield: 65% (115 mg);
1
m.p. 204ꢀ206 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 8.33ꢀ8.27 (m, 2H), 8.22 (d, J = 7.8 Hz, 1H),
13
7.94.7.90 (m, 2H), 7.72ꢀ7.66 (m, 1H), 7.09 (d, J = 3.8 Hz, 1H), 2.61 (s, 3H); C NMR (101 MHz,
DMSOꢀd6, ppm): δ 177.1, 161.4, 154.8, 148.3, 139.2, 136.1, 135.4, 129.4, 128.9, 128.2, 126.6, 123.5,
16.15; IR (CHCl3): νmax 3410, 2921, 1657, 1505, 1332, 1132, 1015 cmꢀ1; ESIꢀMS: m/z 243.05 [M+H]+;
HRꢀESIMS: m/z 243.0597 calcd for C13H10N2OS+H+ (243.0592).
2ꢀ(5,6ꢀDimethoxybenzofuranꢀ2ꢀyl)quinazolinꢀ4(3H)ꢀone (2n, SSꢀ760). Yellow solid; yield: 62% (146
mg); m.p. 231ꢀ233 °C; 1H NMR (400 MHz, CDCl3, ppm): δ 10.29 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H),
13
7.82ꢀ7.72 (m, 3H), 7.53ꢀ7.47 (m, 1H), 7.11 (d, J = 6.8 Hz, 2H), 3.99 (s, 3H), 3.97 (s, 3H); C NMR
(126 MHz, DMSOꢀd6, ppm): δ 161.5, 150.3, 150.1, 148.5, 147.1, 146.3, 144.2, 134.6, 127.3, 126.6,
125.9, 121.1, 119.1, 110.8, 102.9, 95.43, 55.9, 55.8; IR (CHCl3): νmax 3417, 2917, 1650, 1474, 1304,
1497, 1102, 1024 cmꢀ1; HRꢀESIMS: m/z 322.0980 calcd for C18H14N2O4 (322.0954).
+
2ꢀ(Pyridinꢀ3ꢀyl)quinazolinꢀ4(3H)ꢀone (2o, SSꢀ758).39 White solid; yield: 50% (81 mg); m.p. 272ꢀ275
1
°C; H NMR (400 MHz, CD3OD, ppm): δ 9.26 (d, J = 1.9 Hz, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.51 – 8.47
(m, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.86ꢀ7.83 (m, 2H), 7.60ꢀ7.54 (m, 2H); IR (CHCl3): νmax 3585, 2921,
1673, 1467, 1169 cmꢀ1; ESIꢀMS: m/z 224.07 [M+H]+; HRꢀESIMS: m/z 224.0790 calcd for
C13H9N3O+H+ (224.0824).
2ꢀ(Naphthalenꢀ2ꢀyl)quinazolinꢀ4(3H)ꢀone (2p, SSꢀ753).28 White solid; yield: 72% (144 mg); m.p.
1
247ꢀ249 °C; H NMR (500 MHz, DMSOꢀd6, ppm): δ 12.88 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.29ꢀ8.24
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
(m, 2H), 8.16ꢀ8.11 (m, 2H), 7.91ꢀ7.81 (m, 1H), 7.69ꢀ7.65 (m, 5H); IR (CHCl3): νmax 3356, 2920, 1666,
1574, 1443, 1292, 1022, 773 cmꢀ1; ESIꢀMS: m/z 273.10 [M+H]+; HRꢀESIMS: m/z 273.1040 calcd for
C18H12N2O+H+ (273.1028).
1
2
3
4
5
6
7
8
9
6ꢀIodoꢀ2ꢀphenylquinazolinꢀ4(3H)ꢀone (2q, SSꢀ795). White solid; yield: 80% (106 mg); m.p. > 260
°C; 1H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.87 (s, 1H), 8.49ꢀ8.15 (m, 4H), 7.76 (t, J = 7.4 Hz, 1H),
7.62ꢀ7.53 (m, 3H); 13C NMR (125.7 MHz, DMSOꢀd6, ppm): δ 187.0, 143.1, 142.9, 134.3, 134.1, 133.9,
131.6, 130.8, 128.6, 128.5, 127.8, 124.5; IR (CHCl3): νmax 3397, 2921, 1662, 1591, 1285, 1173, 843,
776 cmꢀ1; ESIꢀMS: m/z 348.98 [M+H]+; HRꢀESIMS: m/z 348.9822 calcd for C14H9IN2O+H+
(348.9838).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6ꢀChloroꢀ2ꢀ(4ꢀmethoxyphenyl)quinazolinꢀ4(3H)ꢀone (2r, SSꢀ748).39 White solid; yield: 80% (134
1
mg); m.p. 286ꢀ288 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.83 (s, 1H), 8.20ꢀ8.14 (m, 3H), 7.92
(dd, J = 2.2, 8.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); IR (CHCl3):
νmax 3418, 2924, 1682, 1651, 1460, 1263, 1127 cmꢀ1; ESIꢀMS: m/z 287.05 [M+H]+; HRꢀESIMS: m/z
287.0583 calcd for C15H11ClN2O2+H+ (287.0587).
6ꢀIodoꢀ2ꢀ(4ꢀmethoxyphenyl)quinazolinꢀ4(3H)ꢀone (2s, SSꢀ796). White solid; yield: 82% (118 mg);
1
m.p. 220ꢀ222°C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.81 (s, 1H), 8.52ꢀ8.13 (m, 4H), 7.56 (d, J =
8.5 Hz, 1H), 7.13 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H);13C NMR (125.7 MHz, DMSOꢀd6, ppm): δ 185.6,
164.8, 160.4, 150.5, 146.9, 143.5, 134.8, 133.9, 126.9, 124.9, 114.5, 56.2; IR CHCl3): νmax 3418, 2920,
1658, 1457, 1313, 1167 cmꢀ1; ESIꢀMS: m/z 378.99 [M+H]+; HRꢀESIMS: m/z 378.9928 calcd for
C15H11IN2O2+H+ (378.9943).
6ꢀIodoꢀ2ꢀ(4ꢀnitrophenyl)quinazolinꢀ4(3H)ꢀone (2t, SSꢀ798). White solid; yield: 76% (114 mg); m.p. >
1
260 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.92 (s, 1H), 8.50 (s, 1H), 8.48ꢀ8.38 (m, 4H), 8.20
13
(dd, J = 1.9, 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl3 + DMSOꢀd6, ppm): δ
185.8, 159.9, 150.0, 148.2, 146.1, 143.2, 139.2, 134.3, 132.2, 130.5, 124.5, 123.1; IR (CHCl3): νmax
14
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
3426, 2918, 1666, 1519, 1342, 1160, 1016 cmꢀ1; HRꢀESIMS: m/z 391.9521 calcd for C14H8N3O3IꢀHꢀ
1
2
3
(391.9538).
4
5
6
7
8
2ꢀBenzoylquinazolinꢀ4(3H)ꢀone (3a, SSꢀ789).31 White solid; yield: 50% (91 mg); m.p. 179ꢀ182 °C;
1H NMR (400 MHz, CDCl3, ppm): δ 10.18 (s, 1H), 8.58ꢀ8.48 (m, 2H), 8.41 (dd, J = 1.0, 7.9 Hz, 1H),
9
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.98ꢀ7.84 (m, 2H), 7.72ꢀ7.64 (m, 2H), 7.56 (t, J = 7.8 Hz, 2H); C NMR (126 MHz, CDCl3, ppm): δ
185.6, 161.0, 147.9, 145.9, 134.9, 134.3, 134.0, 133.9, 131.8, 129.5, 129.4, 128.4, 126.9, 123.2; IR
(CHCl3): νmax 3436, 2926, 1666, 1481, 1297, 1144 cmꢀ1; ESIꢀMS: m/z 251.08 [M+H]+; HRꢀESIMS: m/z
251.0812 calcd for C15H10N2O2+H+ (251.0821).
2ꢀ(3ꢀChlorobenzoyl)quinazolinꢀ4(3H)ꢀone (3b, SSꢀ801). White solid; yield: 68% (142 mg); m.p. 231ꢀ
233 °C; 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 7.82ꢀ7.78 (m, 2H), 7.71ꢀ
7.63 (m, 2H), 7.58ꢀ7.50 (m, 2H), 7.44 (t, J = 8.2 Hz, 1H); 13C NMR (126 MHz, CDCl3+ CD3OD, ppm):
δ 188.8, 161.7, 147.4, 146.1, 134.9, 132.6, 130.8, 130.2, 129.5, 129.2, 126.6, 126.4, 123.0; IR (CHCl3):
νmax 3439, 2923, 2853, 1456, 1430, 1238 cmꢀ1; ESIꢀMS: m/z 285.04 [M+H]+; HRꢀESIMS: m/z 285.0419
calcd for C15H9ClN2O2+H+ (285.0431).
2ꢀ(3,4ꢀDichlorobenzoyl)quinazolinꢀ4(3H)ꢀone (3c, SSꢀ792). White solid; yield: 77% (180 mg); m.p.
258ꢀ260 °C; 1H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.92 (s, 1H), 8.27ꢀ8.20 (m, 1H), 7.92ꢀ7.82 (m,
13
3H), 7.72ꢀ7.64 (m, 3H); C NMR (101 MHz, CDCl3+CD3OD, ppm): δ 185.1, 159.1, 144.8, 135.6,
132.3, 131.0, 130.7, 129.2, 127.4, 126.9, 126.5, 124.2, 123.8; IR (CHCl3): νmax 3417, 2918, 1683, 1586,
1382, 1238, 1102 cmꢀ1; ESIꢀMS: m/z 319.00 [M+H]+; HRꢀESIMS: m/z 319.0039 calcd for
C15H8Cl2N2O2+H+ (319.0041).
5ꢀ(2ꢀHydroxyphenyl)ꢀ1ꢀmethylꢀ3ꢀpropylꢀ1,6ꢀdihydroꢀ7Hꢀpyrazolo[4,3ꢀd]pyrimidinꢀ7ꢀone (9a, SSꢀ
1
756). White solid; yield: 55% (85 mg); m.p. 234ꢀ236 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 8.13
(dd, J = 1.3, 8.0 Hz, 1H), 7.44ꢀ7.37 (m, 1H), 7.03ꢀ6.91 (m, 2H), 4.16 (s, 3H), 2.80 (t, J = 7.4 Hz, 2H),
1.81ꢀ1.72 (m, 2H), 0.98ꢀ0.92 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3, ppm): δ 158.5, 153.9,
151.0, 143.7, 135.3, 132.7, 127.7, 124.3, 118.9, 117.5, 114.8, 27.1, 21.5, 13.7; IR (CHCl3): νmax 3418,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
2960, 1687, 1500, 1433, 1237, 1097 cmꢀ1; ESIꢀMS: m/z 285.13 [M+H]+; HRꢀESIMS: m/z 285.1380
1
2
3
calcd for C15H16N4O2+H+ (285.1352).
4
5
6
1ꢀMethylꢀ5ꢀ(4ꢀnitrophenyl)ꢀ3ꢀpropylꢀ1,6ꢀdihydroꢀ7Hꢀpyrazolo[4,3ꢀd]pyrimidinꢀ7ꢀone (9b, SSꢀ821).40
7
8
9
1
Yellow solid; yield: 50% (85 mg); m.p. 229ꢀ231 °C; H NMR (400 MHz, DMSOꢀd6, ppm): δ 12.69 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H), 8.38ꢀ8.33 (m, 4H), 4.19 (s, 3H), 2.84ꢀ2.74 (m, 2H), 1.82ꢀ1.71 (m, 2H), 0.98ꢀ0.92 (m, 3H); IR
(CHCl3): νmax 3410, 2920, 2837, 1681, 1517, 1351, 1110 cmꢀ1; ESIꢀMS: m/z 314.12 [M+H]+; HRꢀ
ESIMS: m/z 314.1211 calcd for C15H15N5O3+H+ (314.1253).
1ꢀMethylꢀ5ꢀphenylꢀ3ꢀpropylꢀ1,6ꢀdihydroꢀ7Hꢀpyrazolo[4,3ꢀd]pyrimidinꢀ7ꢀone (9c, SSꢀ808).26 White
1
solid; yield: 60% (88 mg); m.p. 194ꢀ197 °C; H NMR (400 MHz, CDCl3, ppm): δ 10.91 (s, 1H), 8.11
(dd, J = 3.1, 6.5 Hz, 2H), 7.54 (d, J = 2.0 Hz, 3H), 4.30 (s, 3H), 2.98ꢀ2.92 (m, 2H), 1.91ꢀ1.85 ( m, 2H),
1.04 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 155.3, 149.0, 146.4, 138.8, 132.4, 130.5,
128.3, 126.6, 124.0, 37.6, 27.2, 21.8, 13.5; IR (CHCl3): νmax 3440, 2931, 1688, 1633, 1490, 1100 cmꢀ1;
ESIꢀMS: m/z 269.14 [M+H]+; HRꢀESIMS: m/z 269.1389 calcd for C15H16N4O+H+ (269.1402).
1
Quinazolinꢀ4(3H)ꢀone (11).41 Light pink solid; yield: 55% (59 mg); m.p. 218ꢀ220 °C; H NMR (400
MHz, DMSOꢀd6, ppm): δ 12.25 (s, 1H), 8.17ꢀ 8.07 (m, 2H), 7.82 (t, J = 7.2 Hz, 1H), 7.67 (d, J = 8.1 Hz,
1H), 7.53 (t, J = 7.4 Hz, 1H); IR (CHCl3): νmax 3417, 2921, 1675, 1517, 1453, 1110 cmꢀ1; ESIꢀMS: m/z
147.04 [M+H]+; HRꢀESIMS: m/z 147.0570 calcd for C8H6N2O+H+ (147.0558).
ACKNOWLEDGEMENT. Authors are thankful to analytical division IIIM for analytical support. S.
Mohammed is thankful to CSIR for research fellowship. The financial support from DSTꢀSERB is
gratefully acknowledged (grant no. SR/FT/CSꢀ168/2011).
AUTHOR INFORMATION.
Corresponding Author
*Tel: +91ꢀ191ꢀ2586333; Tel: +91ꢀ191ꢀ2585006 (Extn. 345). Eꢀmail: sbharate@iiim.ac.in. (S.B.B.)
*Tel: +91ꢀ191ꢀ2586333; Tel: +91ꢀ191ꢀ2585222. Eꢀmail: ram@iiim.ac.in. (R.A.V.)
16
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
Notes
The authors declare no competing financial interest.
1
2
3
4
5
6
IIIM Communication number. IIIM/xxxx/2015
7
8
9
SUPPORTING INFORMATION AVAILABLE: Experimental procedures, characterization data,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR spectra scans. This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
Michael, J. P. Nat. Prod. Rep. 2007, 24, 223.
Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
Michael, J. P. Nat. Prod. Rep. 2003, 20, 476.
Michael, J. P. Nat. Prod. Rep. 2002, 19, 742.
Demeunynck, M.; Baussanne, I. Curr. Med. Chem. 2013, 20, 794.
Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur. J. Med. Chem. 2014, 76, 193.
Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.; Ohta,
M.; Tsukamoto, S.; Parker, P.; Workman, P.; Waterfield, M. Bioorg. Med. Chem. 2006, 14, 6847.
(10) Smith, R. A.; Thompson, S. K.; Hosahalli, S.; Bejugam, M.; Nanduri, S.; Panigrahi, S.
K.; Mahalingam, N. US20140073782 A1 (Endo Pharmaceuticals Inc.).
(11) Garber, K. Nature Rev. Drug. Discov. 2014, 13, 162.
(12) Lee, W.; Ortwine, D. F.; Bergeron, P.; Lau, K.; Lin, L.; Malek, S.; Nonomiya, J.; Pei, Z.;
Robarge, K. D.; Schmidt, S.; Sideris, S.; Lyssikatos, J. P. Bioorg. Med. Chem. Lett. 2013, 23, 5097.
(13) Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6, 1819.
(14) He, L.; Li, H.; Chen, J.; Wu, X.ꢀF. RSC Adv. 2014, 4, 12065.
(15) Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
(16) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
(17) Mitobe, Y.; Ito, S.; Mizutani, T.; Nagase, T.; Sato, N.; Tokita, S. Bioorg. Med. Chem.
Lett. 2009, 19, 4075.
(18) Purandare, A. V.; Gao, A.; Wan, H.; Somerville, J.; Burke, C.; Seachord, C.; Vaccaro,
W.; Wityak, J.; Poss, M. A. Bioorg. Med. Chem. Lett. 2005, 15, 2669.
(19) Potewar., T. M.; Nadaf., R. N.; Daniel., T.; Lahoti, R. J.; Srinivasan, K. V. Synth.
Commun. 2005, 35, 231.
(20) Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y. J. Org. Chem. 2012, 77.
(21) Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730.
(22) Sharif, M.; Opalach, J.; Langer, P.; Beller, M.; Wu, X.ꢀF. RSC Adv. 2014, 4, 8.
(23) Ge, W.; Zhu, X.; Wei, Y. RSC Adv. 2013, 3, 10817.
(24) Nguyen, T. B.; Ermolenko, L.; AlꢀMourabit, A. Green Chem. 2013, 15, 2713.
(25) Wei, H.; Li, T.; Zhou, Y.; Zhou, L.; Zeng, Q. Synthesis 2013, 45, 3349.
(26) Wu, X.ꢀF.; He, L.; Neumann, H.; Beller, M. Chem. Eur. J. 2013, 19, 12635.
(27) Jiang, X.; Tang, T.; Wang, J.ꢀM.; Chen, Z.; Zhu, Y.ꢀM.; Ji, S.ꢀJ. J. Org. Chem. 2014, 79,
5082.
(28) Zhao, D.; Wang, T.; Li, J. X. Chem. Commun. 2014, 50, 6471.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
(29) Li, Q.; Huang, Y.; Chen, T.; Zhou, Y.; Xu, Q.; Yin, S.ꢀF.; Han, L.ꢀB. Org. Lett. 2014, 16,
1
2
3672.
(30) Yang, X.; Cheng, G.; Shen, J.; Kuai, C.; Cui, X. Org. Chem. Front. 2015, 2, 366.
(31) Zhu, Y. P.; Fei, Z.; Liu, M. C.; Jia, F. C.; Wu, A. X. Org. Lett. 2013, 15, 378.
(32) Liao, Y.; Qi, H.; Chen, S.; Jiang, P.; Zhou, W.; Deng, G. J. Org. Lett. 2012, 14, 6004.
(33) Dunn, P. J. Org. Proc. Res. Develop. 2005, 9, 88.
(34) Zhang, J.; Ren, D.; Ma, Y.; Wang, W.; Wu, H. Tetrahedron 2014, 70, 5274.
(35) Laclef, S.; Harari, M.; Godeau, J.; SchmitzꢀAfonso, I.; Bischoff, L.; Hoarau, C.;
3
4
5
6
7
8
9
Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17, 1700.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(36) Khan, K. M.; Saad, S. M.; Shaikh, N. N.; Hussain, S.; Fakhri, M. I.; Perveen, S.; Taha,
M.; Choudhary, M. I. Bioorg. Med. Chem. 2014, 22, 3449.
(37) Zhao, D.; Zhou, Y.ꢀR.; Shen, Q.; Li, J.ꢀX. RSC Adv. 2014, 4, 6486.
(38) Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H.ꢀK.; Lee, K.ꢀH.; D. Paull, K. Biochem.
Pharmacol. 1996, 51, 53.
(39) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 1274.
(40) Khan, K. M.; Maharvi, G. M.; Choudhary, M. I.; Rahman, A.ꢀu.; Perveen, S. J.
Heterocycl. Chem. 2005, 42, 1085.
(41) Kim, N. Y.; Cheon, C. H. Tetrahedron Lett. 2014, 55, 2340.
18
ACS Paragon Plus Environment