Oxidative synthesis of quinazolinones and benzothiadiazine 1,1-dioxides from 2-aminobenzamide and 2-aminobenzenesulfonamide with benzyl alcohols and aldehydes

Article abstract of DOI:10.1039/c3ra45765f

An interesting procedure for the zinc-catalyzed oxidative transformation of ready available 2-aminobenzamide, 2-aminobenzenesulfonamide with benzyl alcohols has been developed. Various quinazolinones and benzothiadiazine 1,1-dioxides were prepared in moderate to good yields under identical conditions. The reactions of both aromatic aldehydes and aliphatic aldehydes with 2-aminobenzamide under catalyst free conditions were described as well. In water media, the products were formed in good yields.

Full text of DOI:10.1039/c3ra45765f

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PAPER
Oxidative synthesis of quinazolinones and
benzothiadiazine 1,1-dioxides from 2-amino-
benzamide and 2-aminobenzenesulfonamide with
benzyl alcohols and aldehydes†
Cite this: RSC Adv., 2014, 4, 8
Muhammad Sharif,bd Julita Opalach,bc Peter Langer,bc Matthias Bellerb
ab
*
and Xiao-Feng Wu
An interesting procedure for the zinc-catalyzed oxidative transformation of ready available
2-aminobenzamide, 2-aminobenzenesulfonamide with benzyl alcohols has been developed. Various
quinazolinones and benzothiadiazine 1,1-dioxides were prepared in moderate to good yields under
identical conditions. The reactions of both aromatic aldehydes and aliphatic aldehydes with
2-aminobenzamide under catalyst free conditions were described as well. In water media, the products
were formed in good yields.
Received 26th July 2013
Accepted 30th October 2013
DOI: 10.1039/c3ra45765f
www.rsc.org/advances
Heterocyclic compounds synthesis is one of the main branches and benzothiadiazine 1,1-dioxides are attractive frameworks
of organic synthesis, due to the recognized importance of because of their reported anticancer, antiviral, anti-inamma-
heterocycles in natural products, advanced materials, crop tory, as well as anti-microbial activity properties.2 Moreover,
protecting agents, and pharmaceuticals.1 Among the numerous quinazolinones are used as ligands for benzodiazepine and
known heterocyclic compounds, quinazolinones (Scheme 1) AMPA receptors in the CNS system or as DNA binders as well.3
Regarding their prevalence, plentiful methodologies have been
developed for heterocycles preparation, cascade reaction,
domino reaction, multicomponent reaction are representative
examples. For the synthesis of quinazolinones and benzothia-
diazine 1,1-dioxides,4 the reaction of carboxylic acid derivatives
(such as benzoic acids, benzoyl chlorides and etc.) with 2-ami-
nobenzamide and 2-aminobenzenesulfonamide are the typical
procedures.5 The oxidation of 2-amido benzonitriles are also
known and some other methodologies were developed as well.6
More recently, the reaction of 2-aminobenzamide or 2-amino-
benzenesulfonamide with benzyl alcohols come into the view of
synthetic chemists and Pd, Ru or Ir are the usual applied cata-
lysts.7 Remarkably, in 2013, an iodine-catalyzed one-pot two-
step oxidative synthesis of quinazolinones from alcohols and
2-aminobenzamide was reported.7d The reaction using DMSO as
oxidant, using DMC as solvent at 100 C, the reaction via the
ꢀ
Scheme 1 Selected examples of biological active quinazolines.
oxidation of alcohols to aldehydes as the key step and then
followed by cyclization to give quinazolinones.
aDepartment of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou,
We recently reported a zinc-catalyzed oxidative amidation of
benzyl alcohols, numbers of amides were prepared by using
TBHP as oxidant.8 In view of copious advantages of zinc catal-
ysis9 and our incessant research interests in developing zinc-
catalyzed oxidation reactions,10 we became interested in
applying our procedure in the direct oxidative synthesis of
quinazolinones and benzothiadiazine 1,1-dioxides from 2-ami-
nobenzamide and 2-aminobenzenesulfonamide with benzyl
alcohols. As we expected, various desired products were
Zhejiang Province, People’s Republic of China, 310018. E-mail: xiao-feng.wu@
catalysis.de
b
¨
¨
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Strasse
29a, 18059 Rostock, Germany
c
¨
¨
Universitat Rostock, Institut fur Chemie, Albert-Einstein-Str. 3a, 18059 Rostock,
Germany
dDepartment of Chemistry, Comsats Institute of Information Technology, 22060,
Abbottabad, Pakistan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra45765f
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Table 1 Zinc-catalyzed oxidative synthesis of quinazolinonesa
Table 1 (Contd.)
Yieldb
76
Entry
1
Substrate
Product
Yieldb
90
Entry
11
Substrate
Product
2
3
85
80
12
13
75
68
4
5
6
7
73
69
71
76
14
15
16
60
67
72
17
85
a
ZnI2 (10 mol%), 2-aminobenzamide (1 mmol), benzyl alcohols (1
8
63
75
70
mmol), DMSO (2 mL), TBHP (70% in H2O; 4 eq.), 110 ꢀC, 16 h.
b
Isolated yields.
9
prepared in good to excellent yields under our conditions in
one-pot one-step manner.
Based on our previous report,8 the initial experiment was
carried out in H2O (2 mL) at 110 ꢀC. But no product was
produced with 23% conversion of benzyl alcohol in the pres-
ence of ZnI2 (10 mol%) and TBHP (70% in H2O; 4 eq.). 10% of
quinazolinone was formed in toluene with 41% of benzyl
alcohol converted under the same conditions, while only 5%
10
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Table 2 Zinc-catalyzed oxidative synthesis of benzothiadiazine 1,1- Table 2 (Contd.)
dioxidesa
Entry
11
Substrate
Product
Yieldb
76
Entry
1
Substrate
Product
Yieldb
86
12
64
58
2
3
88
89
13
a
ZnI2 (10 mol%), 2-aminobenzenesulfonamide (1 mmol), benzyl
alcohols (1 mmol), DMSO (2 mL), TBHP (70% in H2O; 4 eq.), 110 ꢀC,
16 h. Isolated yields.
4
5
6
7
60
60
75
69
b
yield was resulted in DMF. To our delight, 95% of our desired
product was formed by using DMSO as solvent. With decreased
temperature (80 ꢀC) in DMSO, the yield of quinazolinone drops
dramatically and lot of N-(2-carbamoylphenyl)benzamide was
isolated.
With the best reaction conditions in hand, we carried out the
generality of this methodology with different benzyl alcohols
(Table 1 and 2). Methyl-, methoxy-, methylthio-substituted
benzyl alcohols were successfully converted and gave the cor-
responding products in 73–85% yields (Table 1, entries 2–4).
Naphthyl substituted quinazolinones were produced in 69–71%
yield under the same conditions (Table 1, entries 5 and 6).
Additionally, halogen-substituted and electron-withdrawing
group-substituted benzyl alcohols can be reacted as well and the
desired products were isolated in 63–76% yields (Table 1,
entries 7–12). Notably, moderate to good yields of heterocycle
decorated quinazolinones were prepared under identical
conditions as well (Table 1, entries 13–17). 2-Aminobenzyl-
amine was tested as substrate as well, but only traces of desired
quinazolinone was detected and together with diverse by-
products.
Besides quinazolinones, benzothiadiazine 1,1-dioxides can
be produced by simply replacing 2-aminobenzamide with 2-
aminobenzenesulfonamide. 13 examples of benzothiadiazine
1,1-dioxides with different substituents were isolated in good
yields (Table 2). Both electron-donating and electron-with-
drawing functional groups were tolerable, as well as heterocyclic
compounds.
8
83
79
67
9
10
Regarding the reaction pathway, we believe N-(2-carbamoyl-
phenyl)benzamide or N-(2-sulfamoylphenyl)benzamide should
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Table 3 Oxidative synthesis of quinazolinonesa
Table 3 (Contd.)
Yieldb[%]
73%
Entry
1
Aldehyde
Product
Yieldb[%]
90%
Entry
10
Aldehyde
Product
2
3
60%
75%
11
12
13
77%
71%
55%
4
5
78%
83%
14
68%
6
7
8
9
70%
74%
76%
88%
15
16
17
18
68%
80%
70%
69%
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Table 3 (Contd.)
Entry
19
Aldehyde
Product
Yieldb[%]
69%
Scheme 2 Oxidative synthesis of benzothiadiazine 1,1-dioxides.
Several halogen and electron-withdrawing functional groups are
tolerable as well and gave the desired products in good to excel-
lent yields (Table 3, entries 9–14).
20
65%
Several heterocyclic aldehydes were applied as substrates
because of the interesting biological activities of heterocycles,
the corresponding 2-heterocyclic substituted quinazolinones
were synthesized straightforward in good yields (Table 3, entries
15–20). Remarkably, even 5-(hydroxymethyl)furan-3-carbalde-
hyde can be applied as starting material as the hydroxymethyl
group is potentially reactive under oxidative conditions (Table 3,
entry 18). Additionally, aliphatic aldehydes were reacted with
2-aminobenzamide as well and gave the corresponding alkyl-
substituted products in good yields (62–88%; Table 3, entries
21–24) which are difficult in previous methodology.
Besides the preparation of quinazolinone derivatives, this
green methodology can also be applied in the synthesis of
benzothiadiazine 1,1-dioxides (Scheme 2). Three examples of
benzothiadiazine 1,1-dioxides were produced in good yields
under the same conditions. Here, the cyclization step may
responsible for the need of relative high temperature, which
could be decreased by the assistant of Lewis acid.
21
22
23
88%
83%
80%
24
62%
In conclusion, an interesting methodology for quinazoli-
nones and benzothiadiazine 1,1-dioxides preparation has been
developed. Under the assistant of ZnI2/TBHP, various of the
desired heterocycles were isolated in good to excellent yields. By
using aldehydes instead of benzyl alcohols as substrates, the
reactions can be carried out under catalyst free conditions in
water. All the products were prepared in good yields.
a
2-Aminobenzamide (1 mmol), aldehydes (1 mmol), H2O (2 mL), TBHP
b
(70% in water, 4 mmol), 110 ꢀC, 16 h. Isolated yields.
be the key intermediate which could also be prepared by the
reaction of 2-aminobenzamide with aldehydes under even
catalyst free conditions. Here, notably,
a InCl3-catalyzed
condensation of aromatic aldehydes with 2-aminobenzamides
to quinazolinones was reported in 2012.11 The reaction works at
room temperature, but need MeCN as the organic solvent. As
Experimental section
General comments
the demands of sustainable development, we think it’s inter- All reactions were carried out under air. Reactions were moni-
esting and necessary to develop a more general catalyst free tored by TLC analysis (pre-coated silica gel plates with uores-
system for the quinazolinones synthesis.12,13
cent indicator UV254, 0.2 mm) and visualized with 254 nm UV
By simply changing the solvent from DMSO to water, excellent light or iodine. Chemicals were purchased from Aldrich, Alfa
yield of quinazolinone was isolated under a catalyst free condi- Asar and unless otherwise noted were used without further
tion. As shown in Table 3, ortho-, para-, andmeta-alkylsubstituted purication. All compounds were characterized by 1H NMR, 13
C
1
benzaldehydes were successfully reacted with 2-amino- NMR, GC-MS and HRMS spectroscopy. H spectra were recor-
benzamide and gave the corresponding products in good yields ded on Bruker AV 300 and AV 400 spectrometers. 13C NMR
(Table 3, entries 2–4). Methoxyl and methylthio can be tolerated spectra were recorded at 282 MHz. EI (70 eV) mass spectra were
as well (Table 3, entries 5 and 6). 2-Naphthyl substituted quina- recorded on MAT 95XP (Thermo ELECTRON CORPORATION).
zolinones were prepared in good yields (Table 3, entries 7 and 8). GC was performed on Agilent 6890 chromatograph with a 30 m
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HP5 column. HRMS was performed on MAT 95XP (EI) and
Agilent 6210 Time-of-Flight LC/MS (ESI). GC-MS was performed
on Agilent 5973 chromatograph Mass Selective Detector. All
yields reported refer to isolated yields.
2-(m-Tolyl)quinazolin-4(3H)-one
Yield: (200 mg, 85%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.45 (s,
3H, CH3), 7.44–7.59 (m, 3H), 7.76–7.79 (m, 1H), 7.81–7.90 (m,
1H), 7.99–8.03 (m, 1H), 8.06 (s, 1H), 8.17–8.21 (m, 1H), 12.6 (s,
1H, NH). 13C NMR (DMSO-d6): d ¼ 20.9 (CH3), 120.9 (C), 124.8
(CH), 125.8 (CH), 126.5 (CH), 127.4 (CH), 128.2 (CH), 128.5 (CH),
131.9 (CH), 132.6 (C), 134.6 (CH), 137.9 (C), 148.7 (C), 152.3 (C),
162.2 (CO).GC-MS (EI, 70 eV): m/z (%) [M+] 236 (80), 119 (100), 92
(13), 90 (15). HRMS (ESI): calc. for C15H12N2O1: 236.09441;
found: 236.09433.
General procedure for the oxidative synthesis of
quinazolinone
ZnI2 (10 mol%) and a stirring bar were added to a 50 mL pres-
sure tube. Then, DMSO (2 mL), benzyl alcohol (1 mmol), and 2-
aminobenzamide (1 mmol) were added. At the end, TBHP (70%
in H2O; 4 eq.) was added and the nal solution was kept at 110
ꢀC temperature for 16 h. The mixture was cooled to room and
solvent was removed under vacuum. The pure product can be
isolated by either washed with water, ethyl acetate and nally
hexane or recrystallized from MeOH.
2-(4-Fluorophenyl)quinazolin-4(3H)-one
1
Yield: (190 mg, 79%); H NMR (300 MHz, DMSO-d6): d ¼ 7.38–
7.76 (m, 2H), 7.52–7.58 (m, 1H), 7.74–7.78 (m, 1H), 7.84–7.89
(m, 1H), 8.16–8.19 (m, 1H), 8.25–8.32 (m, 1H), 12.6 (s, 1H, NH).
13C NMR (DMSO-d6): d ¼ 120.3 (2CH), 120.8 (2CH), 125.8 (CH),
130.8 (C), 131.5 (C), 132.2 (CH), 134.2 (CH), 135.4 (C), 139.5
(CH), 156.3 (C), 167.3 (CO), 168 (d, J ¼ 249.8 Hz, CF3). GC-MS
(EI, 70 eV): m/z (%) [M+] 240 (100), 122 (13), 120 (12), 119 (93), 95
(18), 92 (15), 90 (14). HRMS (ESI): calc. for C14H9N2O1F1:
240.06934; found: 240.06911.
General procedure for the catalyst free synthesis of
quinazolinone
In a 25 mL pressure tube equipped with a stirring bar, aldehyde
(1 mmol), 2-aminobenzamide (1 mmol), H2O (2 mL), and
tert-butyl peroxide (70% in H2O; 4 mmol) were injected by
ꢀ
syringe. Then tube was closed and heated up to 110 C for 16
hours. When the reaction completed, cool the reaction mixture
to room temperature. The pure product can be isolated by either
simply ltration or recrystallized from MeOH.
2-(4-Chlorophenyl)quinazolin-4(3H)-one
1
Yield: (161 mg, 63%); H NMR (300 MHz, DMSO-d6): d ¼ 7.35–
7.43 (m, 1H), 7.54–7.60 (m, 1H), 7.64–7.69 (m, 2H), 8.18–8.27
(m, 2H), 12.6 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 115.1 (C),
116.1 (CH), 123.4 (CH), 128.4 (CH), 129.7 (2CH), 131.9 (2CH),
133.6 (C), 135.6 (C), 136.1 (CH), 140.7 (C), 150.9 (C), 163.0 (CO).
GC-MS (EI, 70 eV): m/z (%) [M+] 256 (73), 119 (100), 111 (11), 92
(14), 90 (14), 75 (12). HRMS (ESI): calc. for C15H9N2O1Cl:
256.03979; found: 256.03921.
2-Phenylquinazolin-4(3H)-one
1
Yield: (200 mg, 91%); H NMR (300 MHz, DMSO-d6): d ¼ 7.53–
7.64 (m, 4H), 7.76–7.90 (m, 2H), 8.17–8.23 (m, 3H), 12.6 (s, 1H,
NH). 13C NMR (DMSO-d6): d ¼ 121.9 (C), 126.8 (CH), 127.5 (CH),
128.4 (C), 128.7 (2CH), 129.5 (2CH), 132.3 (CH), 133.6 (C), 135.5
(CH), 149.6 (C), 153.3 (C), 163.2 (CO). GC-MS (EI, 70 eV): m/z (%)
[M+] 222 (85), 119 (100), 104 (10), 92 (13), 90 (13), 77 (20). HRMS
(ESI): calc. for C14H10N2O1: 222.07876; found: 222.07887.
2-(4-(Triuoromethyl)phenyl)quinazolin-4(3H)-one
2-(4-Methoxyphenyl)quinazolin-4(3H)-one
1
Yield: (203 mg, 70%); H NMR (300 MHz, DMSO-d6): d ¼ 7.57–
1
Yield: (201 mg, 80%); H NMR (300 MHz, CDCl3): d ¼ 3.76 (s,
7.63 (m, 1H), 7.80–7.98 (m, 4H), 8.19–8.23 (m, 1H), 8.39–8.42
(m, 2H), 12.8 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 122.2 (C),
123.0 (C), 126.4 (2CH), 126.9 (CH), 128.1 (CH), 128.6 (CH), 129.7
(2CH), 131.8 (C), 135.7 (CH), 137.5 (C), 149.3 (C), 152.2 (C), 163.1
(CO). GC-MS (EI, 70 eV): m/z (%) [M+] 290 (100), 145 (23), 119
(99), 92 (17), 90 (16). HRMS (ESI): calc. for C15H9N2O1F3:
290.06615; found: 290.06587.
3H), 8.26–8.30 (m, 1H), 8.60–8.72 (m, 2H), 8.91–9.02 (m, 1H),
9.07–9.10 (m, 1H), 9.44–9.49 (1H), 12.5 (s, 1H, NH2). 13C NMR
(CDCl3): d ¼ 56.3 (OCH3), 113.4 (CH), 118.5 (CH), 121.6 (CH),
126.7 (CH), 127.5 (CH), 129.1 (CH), 130.6 (C), 130.8 (C), 134.9
(CH), 135.5 (C), 138.1 (C), 149.1 (CH), 160.2 (C), 163.1 (CO). GC-
MS (EI, 70 eV): m/z (%) [M+] 252 (100), 251 (93), 223 (19), 222
(40), 221 (18), 119 (31), 91 (18), 90 (16). HRMS (EI): calc. for
C
15H12N2O2: 252.08933; found: 252.08895.
2-(4-(Triuoromethoxy)phenyl)quinazolin-4(3H)-one
Yield: (232 mg, 70%); 1H NMR (300 MHz, DMSO-d6): d ¼
2-(4-(Methylthio)phenyl)quinazolin-4(3H)-one
Yield: (195 mg, 73%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.56 (s, 7.55–7.60 (m, 3H), 7.76–7.79 (m, 1H), 7.86–7.91 (m, 1H), 8.18–
3H), 7.35–7.40 (m, 2H), 7.81–7.92 (m, 5H), 8.31–8.42 (m, 1H), 8.22 (m, 1H), 8.32–8.36 (m, 2H), 12.7 (s, 1H, NH). 13C NMR
12.8 (s, 1H, NH).13C NMR (CDCl3): d ¼ 15.4 (SCH3), 124.8 (2CH), (DMSO-d6): d ¼ 121.7 (2CH), 121.9 (C), 122.6 (C), 126.8 (CH),
126.0 (CH), 126.8 (CH), 127.9 (CH), 128.6 (CH), 129.0 (2CH), 126.5 (d, J ¼ 259.7 Hz, OCF3), 128.4 (CH), 131.0 (2CH), 132.9
129.5 (C), 135.7 (C), 149.5 (CH), 150.6 (C), 152.5 (C), 163.1 (CO). (C), 135.6 (CH), 149.5 (C), 151.3 (C), 152.3 (C), 163.2 (CO). GC-
GC-MS (EI, 70 eV): m/z (%) [M+] 268 (100), 119 (78), 92 (10), 90 MS (EI, 70 eV): m/z (%) [M+] 306 (100), 119 (92), 92 (17), 90
(11). HRMS (ESI): calc. for C15H12N2O1S: 268.06649; found: (14). HRMS (ESI): calc. for C15H9N2O2F3: 306.06106; found:
268.06631.
306.06090.
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70 eV): m/z (%) [M+] 272 (92), 153 (14), 127 (27), 119 (100), 92
(15), 90 (10). HRMS (ESI): calc. for C18H12N2O1: 272.09441;
found: 272.09424.
2-(Pyridin-3-yl)quinazolin-4(3H)-one
1
Yield: (150 mg, 68%); H NMR (300 MHz, DMSO-d6): d ¼ 7.56–
7.66 (m, 2H), 7.79–7.83 (m, 1H), 7.87–7.93 (m, 1H), 8.19–8.23
(m, 1H), 8.51–8.56 (m, 1H), 8.78 (d, J ¼ 4.95 Hz, 1H), 9.34 (s, 1H),
12.8 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 121.9 (C), 124.2 (CH),
126.6 (CH), 127.6 (CH), 128.3 (C), 129.5 (C), 135.4 (CH), 136.1
(CH), 149.2 (CH), 151.4 (CH), 152.5 (C), 162.9 (CO). GC-MS (EI,
70 eV): m/z (%) [M+] 223 (90), 119 (100), 92 (18), 90 (13), 78 (11).
HRMS (ESI): calc. for C13H9N3O1: 223.07401; found: 223.07411.
2-(Naphthalen-2-yl)quinazolin-4(3H)-one
1
Yield: (194 mg, 75%); H NMR (300 MHz, DMSO-d6): d ¼ 7.42–
7.92 (m, 7H), 7.96–8.51 (m, 4H), 12.7 (s, 1H, NH). 13C NMR
(DMSO-d6): d ¼ 121.2 (C), 125.0 (CH), 125.2 (CH), 125.8 (CH),
125.9 (CH), 126.3 (CH), 126.8 (CH), 127.0 (CH), 127.4 (CH), 127.6
(CH), 128.3 (CH), 130.2 (C), 130.3 (C), 133.7 (C), 133.1 (C), 134.5
(CH), 148.7 (C), 153.6 (C), 161.9 (CO). GC-MS (EI, 70 eV): m/z (%)
[M+] 272 (53), 272 (100).
2-(Thiophen-2-yl)quinazolin-4(3H)-one
1
Yield: (164 mg, 72%); H NMR (300 MHz, DMSO-d6): d ¼ 7.49–
7.56 (m, 1H), 7.71–7.76 (m, 2H), 7.82–7.93 (m, 2H), 8.15–8.19
(m, 1H), 8.64–8.65 (m, 1H), 12.5 (s, 1H, NH). 13C NMR (DMSO-
d6): d ¼ 120.9 (C), 125.8 (CH), 126.3 (CH), 127.0 (CH), 127.2
(CH), 127.3 (CH), 128.6 (CH), 134.5 (CH), 135.3 (C), 148.2 (C),
148.8 (C), 162.0 (CO). GC-MS (EI, 70 eV): m/z (%) [M+] 228 (100),
119 (59), 92 (11), 90 (12). HRMS (ESI): calc. for C12H8N2OS1:
228.03519; found: 228.03515.
N-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenyl)acetamide
Yield: (209 mg, 75%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.13 (s,
3H, CH3), 7.49–7.56 (m, 1H), 7.76–7.89 (m, 4H), 8.14–8.22 (m,
3H), 10.3 (s, 1H, NH), 12.4 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼
24.1, 118.3, 120.7, 125.8, 126.2, 126.7, 127.2, 128.5, 134.5, 142.1,
143.9, 151.8, 162.5 (CO), 168.7 (CO). GC-MS (EI, 70 eV): m/z (%)
[M+] 279 (92), 237 (100), 119 (81), 92 (15), 90 (10), 43 (28). HRMS
(ESI): calc. for C16H13N3O2: 279.10023; found: 279.10026.
2-(Furan-2-yl)quinazolin-4(3H)-one
1
Yield: (127 mg, 60%); H NMR (300 MHz, DMSO-d6): d ¼ 6.67–
3-Phenyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
6.80 (m, 1H), 7.49–7.56 (m, 1H), 7.65–7.68 (m, 1H), 7.70–7.74
(m, 1H), 7.81–7.87 (m, 1H), 8.02–8.04 (m, 1H), 8.14–8.18 (m,
1H), 12.4 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 112.5 (CH), 114.4
(CH), 121.0 (C), 125.9 (CH), 126.4 (CH), 127.1 (CH), 134.6 (CH),
144.0 (C), 146.0 (CH), 146.5 (C), 154.5 (C), 161.6 (CO). GC-MS (EI,
70 eV): m/z (%) [M+] 212 (100), 211 (17), 90 (10). HRMS (ESI):
calc. for C12H8N2O2: 212.05803; found: 212.05760.
1
Yield: (222 mg, 86%); H NMR (300 MHz, DMSO-d6): d ¼ 7.35–
7.93 (m, 7H), 8.02–8.15 (m, 2H), 12.2 (s, 1H, NH). 13C NMR
(DMSO-d6): d ¼ 119.0 (CH), 122.0 (C), 123.7 (CH), 127.1 (CH),
128.7 (2CH), 129.3 (2CH), 132.3 (C), 133.3 (CH), 135.9 (C), 155.2
(C). GC-MS (EI, 70 eV): m/z (%) [M+] 258 (58), 194 (12), 155 (100),
91 (62), 64 (22). HRMS (ESI): calc. for C13H10N2OS1: 258.04575;
found: 258.04581.
2-(Furan-3-yl)quinazolin-4(3H)-one
3-(3-Methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-
dioxide
1
Yield: (142 mg, 67%); H NMR (300 MHz, DMSO-d6): d ¼ 7.54–
7.59 (m, 2H), 7.69–7.73 (m, 1H), 7.83–7.89 (m, 1H), 8.09–8.19
(m, 3H), 12.3 (s, 1H, NH). GC-MS (EI, 70 eV): m/z (%) [M+] 212
(100), 211 (17), 90 (10). HRMS (ESI): calc. for C12H8N2O2:
212.05803; found: 212.05760.
Yield: (256 mg, 89%); 1H NMR (300 MHz, DMSO-d6): d ¼ 3.91 (s,
3H, OCH3), 7.29–7.38 (m, 1H), 7.45–7.54 (m, 1H), 7.56–7.61 (m,
2H), 7.74–7.92 (m, 2H), 12.2 (s, 1H, NH). 13C NMR (DMSO-d6):
d ¼ 56.6 (OCH3), 114.3, 118.4, 119.4, 119.5, 121.4, 122.4, 124.3,
124.6, 127.7, 131.0, 134.1, 136.4, 155.5, 160.3. GC-MS (EI, 70 eV):
m/z (%) [M+] 288 (74), 287 (17), 155 (100), 91 (58), 63 (17). HRMS
(ESI): calc. for C14H12N2O3S1: 288.05631; found: 288.05583.
2-(Benzo[b]thiophen-2-yl)quinazolin-4(3H)-one
1
Yield: (195 mg, 70%); H NMR (300 MHz, DMSO-d6): d ¼ 7.17–
7.25 (m, 1H), 7.44–7.61 (m, 4H), 7.74–7.78 (1H), 7.86–7.97 (2H),
8.08–8.10 (1H), 8.18–8.23 (1H), 12.9 (s, 1H, NH). 13C NMR
(DMSO-d6) d ¼ 114.9, 115.5, 117.7, 123.9, 124.9, 125.0, 125.6,
127.1, 127.9, 133.7, 135.1, 135.8, 140.8, 148.5, 164.3 (CO). GC-
MS (EI, 70 eV): m/z (%) [M+] 278 (100), 159 (12), 119 (38), 89 (14).
HRMS (ESI): calc. for C16H10N2O1S1: 278.05084; found:
278.05082.
3-(4-(Methylthio)phenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-
dioxide
Yield: (160 mg, 60%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.55 (s,
3H, CH3), 7.34–7.38 (m, 1H), 7.47–7.55 (m, 2H), 7.67–7.77 (m,
1H), 7.83–7.91 (m, 2H), 8.02–8.03 (m, 2H), 12.3 (s, 1H, NH). 13
C
NMR (DMSO-d6): d ¼ 117.4, 122.4, 123.6, 124.8, 125.0, 126.6,
128.5, 129.6, 133.1, 134.6, 147.6, 154.2.
2-(Naphthalen-1-yl)quinazolin-4(3H)-one
1
3-(m-Tolyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
Yield: (188 mg, 69%); H NMR (300 MHz, DMSO-d6): d ¼ 7.60–
7.72 (m, 4H), 7.77–7.95 (m, 3H), 8.07–8.11 (m, 1H), 8.19–8.29 Yield: (240 mg, 88%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.44 (s,
(m, 3H), 12.7 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 121.2 (C), 3H, CH3), 7.48–7.54 (m, 3H), 7.62–7.66 (m, 1H), 7.71–7.77 (m,
125.0 (CH), 125.2 (CH), 125.8 (CH), 126.3 (CH), 126.7 (CH), 127.0 1H), 7.82–7.88 (m, 3H), 12.2 (s, 1H, NH). 13C NMR (DMSO-d6):
(CH), 127.4 (CH), 127.6 (CH), 128.3 (CH), 130.0 (CH), 130.4 (C), d ¼ 21.8 (CH3), 119.3, 122.4, 124.2, 126.3, 127.6, 129.4, 132.7,
133.1 (C), 134.5 (CH), 135.3 (C), 148.7 (C), 161.8 (CO). GC-MS (EI, 134.0, 134.4, 136.4, 139.4, 155.8. GC-MS (EI, 70 eV): m/z (%) [M+]
14 | RSC Adv., 2014, 4, 8–17
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262 (62), 208 (11), 155 (100), 91 (57), 64 (17). HRMS (ESI): calc. Hz), 127.8 (dd, J ¼ 90.3 Hz), 130.2, 131.7, 132.6, 134.1, 136.3,
for C14H12N2O2S1: 272.06140; found: 272.06137.
153.3 (d, J ¼ 170.4 Hz), 154.5. GC-MS (EI, 70 eV): m/z (%) [M+]
342 (39), 326 (24), 155 (100), 138 (10), 91 (77), 64 (26). HRMS
(ESI): calc. for C14H9N2O3S1F3: 342.02805; found: 342.02803.
3-(4-Fluorophenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
1
Yield: (207 mg, 75%); H NMR (300 MHz, DMSO-d6): d ¼ 7.39–
3-(Thiophen-2-yl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
7.58 (m, 3H), 7.64–7.68 (m, 1H), 7.74–7.81 (m, 1H), 7.88–7.92
(m, 1H), 12.2 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 116.5 (d, J ¼ Yield: (169 mg, 64%); H NMR (300 MHz, DMSO-d6): d ¼ 7.24–
24.5 Hz), 116.8, 122.5, 124.9 (d, J ¼ 33.9 Hz), 128.3, 129.8, 132.9, 7.27 (m, 1H), 7.49–7.55 (m, 1H), 7.60–7.65 (m, 1H), 7.73–7.78
(d, J ¼ 24.5 Hz), 133.4, 134.4, 165.7, (d, J ¼ 250.3 Hz), 167.3. GC- (m, 1H), 7.81–7.82 (m, 1H), 7.86–7.89 (m, 1H), 8.60–8.62 (m,
MS (EI, 70 eV): m/z (%) [M+] 276 (57), 212 (15), 155 (100), 91 (69), 1H), 12.0 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 119.1, 122.5,
64 (26). HRMS (ESI): calc. for C13H9N2O3S1F1: 276.03633; found: 124.3, 127.1, 127.7, 128.5, 129.1, 132.8, 134.1, 136.3, 151.0. GC-
1
276.03625.
MS (EI, 70 eV): m/z (%) [M+] 264 (79), 207 (20), 155 (100), 138
(11), 91 (64), 64 (30). HRMS (ESI): calc. for C11H8N2O2S2:
264.00217; found: 264.00211.
3-(Furan-3-yl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
1
Yield: (188 mg, 76%); H NMR (300 MHz, DMSO-d6): d ¼ 7.13–
2-(4-(tert-Butyl)phenyl)quinazolin-4(3H)-one
7.15 (m, 1H), 7.48–7.59 (m, 2H), 7.73–7.79 (m, 1H), 7.84–7.88
(m, 1H), 7.95–7.96 (m, 1H), 11.9 (s, 1H, NH). 13C NMR (DMSO- Yield: (216 mg, 78%); 1H NMR (300 MHz, DMSO-d6): d ¼ 1.35 (s,
d6): d ¼ 109.1, 118.1, 120.6, 121.8, 123.5, 126.7, 133.3, 135.4, 9H), 7.50–7.61 (m, 3H), 7.73–7.88 (m, 2H), 8.14–8.21 (m, 2H),
145.4, 147.2, 149.6, 153.1. GC-MS (EI, 70 eV): m/z (%) [M+] 248 8.46 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 31.7 (3CH3), 35.35
(71), 155 (100), 91 (61), 64 (31).
(C), 121.8 (C), 126.3 (2CH), 126.7 (CH), 127.2 (CH), 128.2 (CH),
128.4 (2CH), 130.8 (C), 135.4 (CH), 149.6 (C), 153.1 (C), 155.2 (C),
163.2 (CO). GC-MS (EI, 70 eV): m/z (%) [M+] 278 (85), 263 (100).
N-(4-(1,1-dioxido-2H-benzo[e][1,2,4]thiadiazin-3-yl)phenyl)-
acetamide
2-(2,6-Dimethylphenyl)quinazolin-4(3H)-one
Yield: (211 mg, 67%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.06 (s,
3H, CH3), 7.23–7.27 (m, 1H), 7.34–7.38 (m, 1H), 7.47–7.57 (m, Yield: (125 mg, 60%); 1H NMR (300 MHz, DMSO-d6): d ¼ 2.19 (s,
3H), 7.68–7.75 (m, 1H), 7.83–7.88 (m, 1H), 8.01–8.03 (m, 1H), 6H, 2CH3), 7.63 (d, J ¼ 7.63 Hz, 1H); 7.18–7.24 (m, 1H), 7.34 (t,
9.91 (s, 1H, NH), 12.3 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼ 24.7, J ¼ 7.35 Hz, 1H); 7.59 (d, J ¼ 7.63 Hz, 1H); , 7.72 (d, J ¼ 7.91 Hz,
118.3, 119.4, 123.3, 124.4, 127.4, 127.6, 133.9, 135.4, 137.8, 1H); 7.88 (d, J ¼ 7.35 Hz, 1H), 8.21 (d, J ¼ 7.63 Hz, 2H); 12.5 (s,
138.7, 148.4, 156.8 (CO), 168.9 (CO).
1H, NH). 13C NMR (DMSO-d6): d ¼ 19.8 (2CH3), 121.9 (C), 126.6
(CH), 127.5 (CH), 128.2 (2CH), 129.4 (CH), 129.9 (CH), 135.3
(CH), 135.4 (C), 136.2 (C), 141.9 (C), 149.6 (C), 151.8 (C),
162.5 (CO).
3-(4-Chlorophenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
1
Yield: (201 mg, 69%); H NMR (300 MHz, DMSO-d6): d ¼ 7.16-
7.59 (m, 3H), 7.70–7.92 (m, 3H), 8.03–8.15 (m, 2H), 12.3 (s, 1H,
NH). 13C NMR (DMSO-d6): d ¼ 118.4, 121.4, 123.3, 123.6, 126.8,
2-(4-Nitrophenyl)quinazolin-4(3H)-one
128.9, 130.1, 133.1, 135.4, 137.7, 147.6, 153.6. GC-MS (EI, 70 eV): Yield: (173 mg, 65%); 1H NMR (300 MHz, DMSO-d6): d ¼ 6.72 (t,
m/z (%) [M+] 292 (44), 228 (11), 155 (100), 91 (57), 64 (22), 63 (16). J ¼ 7.63 Hz, 1H), 6.80 (d, J ¼ 8.52 Hz, 1H), 7.27–7.33 (m, 1H),
HRMS (ESI): calc. for
292.00741.
C
13H9N2O2S1Cl: 292.00733; found: 7.37 (s, 1H), 7.63–7.66 (m, 1H), 7.78 (dt, J ¼ 8.62 Hz, 1H), 8.29
(dt, J ¼ 8.62 Hz, 2H), 8.56 (s, 1H, NH). 13C NMR (DMSO-d6): d ¼
115.5, 115.8, 118.4, 124.5, 128.3, 128.9, 134.5, 148.2, 148.3,
3-(4-(Triuoromethyl)phenyl)-2H-benzo[e][1,2,4]thiadiazine
150.3, 164.3(CO). GC-MS (EI, 70 eV): m/z (%) [M+] 267 (100), 221
1,1-dioxide
(32), 192 (13), 119 (36), 92 (8), 90 (11).
1
Yield: (270 mg, 79%); H NMR (300 MHz, DMSO-d6): d ¼ 7.13–
2-(5-(Hydroxymethyl)furan-3-yl)quinazolin-4(3H)-one
7.34 (m, 1H), 7.53–7.67 (m, 2H), 7.76–7.82 (m, 1H), 8.05 (d, J ¼
7.98 Hz, 2H), 8.29 (d, J ¼ 7.98 Hz, 2H), 12.4 (s, 1H, NH). 13C NMR Yield: (166 mg, 69%); 1H NMR (300 MHz, DMSO-d6): d ¼ 4.55 (s,
(DMSO-d6): d ¼ 115.8, (d, J ¼ 12.3 Hz), 118.5, 121.4, 123.4, 123.7, 2H, OCH2), 5.52 (s, 1H, OH), 6.61 (d, J ¼ 3.43 Hz, 1H), 7.49–7.55
125.1 (d, J ¼ 270.1 Hz), 127.0, 129.2, 132.7, 133.2, 135.3, 153.4. (m, 1H), 7.63 (d, J ¼ 3–52 Hz, 1H), 7.71–7.76 (m, 1H), 7.81–7.87
GC-MS (EI, 70 eV): m/z (%) [M+] 326 (55), 307 (10), 262 (10), 155 (m, 1H), 8.13.8.17 (m, 1H), 12.5 (s, 1H, NH). 13C NMR (DMSO-
(100), 91 (79), 64 (22). HRMS (ESI): calc. for C14H9N2O2S1F3: d6): d ¼ 56.7 (OCH2), 110.3 (CH), 115.3 (CH), 122.2 (C), 126.8
326.03313; found: 326.03281.
(CH), 127.3 (CH), 128.1 (CH), 135.6 (CH), 144.9 (C), 145.9 (C),
149.7 (C), 160.3 (C), 162.5 (CO).
3-(4-(Triuoromethoxy)phenyl)-2H-benzo[e][1,2,4]thiadiazine
1,1-dioxide
2-Hexylquinazolin-4(3H)-one
1
Yield: (284 mg, 83%); H NMR (300 MHz, DMSO-d6): d ¼ 7.43– Yield: (202 mg, 88%); 1H NMR (300 MHz, DMSO-d6): d ¼ 0.87 (t,
7.7.69 (m, 4H), 8.08–8.22 (m, 4H), 13.2 (s, 1H, NH). 13C NMR J ¼ 7.30 Hz, 3H), 1.23–1.39 (m, 6H), 1.74 (Pent. 2H), 2.61 (t, J ¼
(DMSO-d6): d ¼ 119.4, 121.9, 122.4, 124.3, 126.2 (d, J ¼ 263.3 7.63 Hz, 2H), 7.44–7.49 (m, 1H), 7.60–7.63 (m, 1H), 7.78–7.81
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(m, 1H), 8.09–8.13 (m, 1H), 12.2 (s, 1H, NH). 13C NMR (DMSO-
d6): d ¼ 14.8 (CH3), 22.9 (CH2), 27.7 (CH2), 29.1 (CH2), 31.8
(CH2), 35.4 (CH2), 121.7 (C), 126.6 (CH), 126.8 (CH), 127.7 (CH),
135.1 (CH), 149.9 (C), 158.4 (C), 162.8 (CO). GC-MS (EI, 70 eV):
m/z (%) [M+] 230 (5), 187 (11), 160 (100). HRMS (ESI): calc. for
Chem., 2002, 9, 1167–1185; (i) S. Khelili, N. Kihal,
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N. Vicker, Synth. Commun., 1993, 23, 2833–2837; (b)
B. P. Bandgar, Synth. Commun., 1997, 27, 2065–2068; (c)
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D. H. Panday, J. A. Sharma, V. Sudarsanam and K. K. Vasu,
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and D. Ma, Org. Lett., 2012, 14, 1150–1153; (f) A. V. Lygin
and A. de Meijere, Org. Lett., 2009, 11, 389–392; (g) B. Ma,
Y. Wang, J. Peng and Q. Zhu, J. Org. Chem., 2011, 76, 6362–
6366; (h) J. E. R. Sadig, R. Foster, F. Wakenhut and
M. C. Willis, J. Org. Chem., 2012, 77, 9473–9486.
7 (a) A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, Org.
Biomol. Chem., 2012, 12, 240–243; (b) J. Zhou and J. Fang,
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10817–10822.
C
14H18N2O1: 230.14136; found: 230.14113.
2-Heptylquinazolin-4(3H)-one
1
Yield: (202 mg, 83%); H NMR (300 MHz, DMSO-d6): d ¼ 0.87
(t, J ¼ 7.30 Hz, 3H), 1.23–1.39 (m, 8H), 1.74 (Pent. 2H),
2.61 (t, J ¼ ,7.63 Hz, 2H), 7.44–7.49 (m, 1H), 7.60–7.63 (m, 1H),
7.78–7.81 (m, 1H), 8.09–8.13 (m, 1H), 12.2 (s, 1H, NH). 13C NMR
(DMSO-d6): d ¼ 14.8 (CH3), 23.0 (CH2), 27.8 (CH2), 29.3 (CH2),
29.5 (CH2), 32.1 (CH2), 35.5 (CH2), 121.7 (C), 126.6 (CH), 126.8
(CH), 127.7 (CH), 135.1 (CH), 149.9 (C), 158.8 (C), 163.1 (CO).
GC-MS (EI, 70 eV): m/z (%) [M+] 244 (5), 187 (10), 160 (100).
HRMS (ESI): calc. for C15H20N2O1: 244.15701; found: 244.15698.
2-Cyclohexylquinazolin-4(3H)-one
1
Yield: (141 mg, 62%); H NMR (300 MHz, DMSO-d6): d ¼ 1.21–
1.40 (m, 3H), 1.54–1.73 (3H), 1.79–1.96 (4H), 7.47 (t, J ¼ 7.45 Hz,
1H), 7.63 (d, J ¼ 8.40 Hz, 1H), 7.79 (d, J ¼ 7.45 Hz, 1H), 8.11 (d,
J ¼ 8.40 Hz, 1H), 12.1 (s, 1H, NH). 3C NMR (DMSO-d6): d ¼ 26.3
(CH2), 26.5 (2CH2), 31.2 (2CH2), 43.8 (CH), 121.9 (C), 126.6 (CH),
126.8 (CH), 127.9 (CH), 135.1 (CH), 149.9 (C), 161.7 (C),
162.9 (CO).
Notes and references
1 For selected reviews on this topic, see: (a) D. M. D’Souza and
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T. J. J. Muller, Chem. Soc. Rev., 2007, 36, 1095–1108; (b)
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B. Willy and T. J. J. Muller, Curr. Org. Chem., 2009, 13,
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Weinheim, Germany, 2011; (g) B. Heller and M. Hapke,
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R. Rossi, Tetrahedron, 2009, 65, 10269–10310.
2 (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62,
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1994, 43, 143–238; (c) S. E. de Laszlo, C. S. Quagliato,
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T. S. Schorn, G. J. Zingaro and P. K. S. Siegl, J. Med. Chem.,
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8 X.-F. Wu, M. Sharif, A. Pews-Davtyan, P. Langer, K. Ayub and
M. Beller, Eur. J. Org. Chem., 2013, 2783–2787.
9 For reviews on zinc-catalyzed organic reactions, see: (a)
X.-F. Wu, Chem. Asian J., 2012, 7, 2502–2509; (b) X.-F. Wu
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and H. Neumann, Adv. Synth. Catal., 2012, 354, 3141–3160;
RSC Advances
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