Transition metal-free synthesis of quinazolinones using dimethyl sulfoxide as a synthon

Article abstract of DOI:10.1039/c9ob01629e

Biologically important quinazolinones have been synthesized from 2-aminobenzamides and DMSO. The key feature of the reaction is the utilization of DMSO as a methine source for intramolecular oxidative annulation. The CNS depressant drug methaqualone has also been synthesized by our methodology. The present method involves the synthesis of quinazolinones with a broad substrate scope and a good yield.

Full text of DOI:10.1039/c9ob01629e

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10.1039/C9OB01629E.
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DOI: 10.1039/C9OB01629E
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Transition Metal-Free Synthesis of Quinazolinones Using Dimethyl
Sulfoxide as a Synthon.
Seohoo Lee a§, Jaeuk Sima§, Hyeju Joa, Mayavan Vijia, Lanka Srinua, Kiho Leeb, Heesoon Leea,
Received 00th January 20xx,
Accepted 00th January 20xx
Manjunatha Vishwanatha,* and Jae-Kyung Junga,* .
DOI: 10.1039/x0xx00000x
Biologically important quinazolinones have been synthesized transformations such as methylation (-CH3), methylenation (–
from 2-aminobenzamides and DMSO. The key feature of the
reaction is utilization of DMSO as methine source for
intramolecular oxidative annulation. CNS depressant drug
Methaqualone has been also synthesized by our methodology. The
present method involves the synthesis of quinazolinones with
broad substrate scope and good yield.
C
H
–)
,
2
O
O
O
NH
CHO
N
N
N
N
N
N
H
N
HN
Rutaecarpine
COX-2 inhibitor
Luotonin A
Antitumor agent
Bouchardatine
Adipogenesis inhibitor
F
Aza-heterocycles occupy principle position in drug discovery
and development. Quinazolinone is one such ubiquitous aza-
heterocyclic core which is found in more than 200 natural
products such as Rutaecarpine, Luotonin A, and Bouchardatine,
which are biologically important.1 Several FDA approved drugs
having this core structure are currently in the market or in
clinical trials (Figure 1) for the treatment of depression, cancer
and obesity etc.2 Recent studies proved that quinazolinones can
bind effectively to various druggable targets, thus acting as an
indispensable molecular tool to understand complex biological
processes.3 Owing to its potential, quinazolinone motifs are
widely explored for biological and medicinal activity, hence they
are classified as privileged scaffolds.4
H
O
N
N
Cl
N
Cl
N
F
H2N
NH
N
S
O
OH
O
O
O
N
N
N
Methaqualone
CNS depressant
Quinethazone
Diuretic agent
Albaconazole
Antifungal agent
Figure
1 Representative natural products and drugs bearing quinazolinone
pharmacophore.
annulation (=CH–), formylation (–CHO) and cyanation (–CN)
etc.9 Currently, exploration of DMSO as formaldehyde
surrogate to synthesize heterocyclic moieties like quinolines
and chromanones are hot topics in synthetic chemistry.10 As a
part of our quest for the synthesis of biologically important
molecules,11 herein we report transition metal-free, microwave
assisted synthesis of quinazolinones by using DMSO as a carbon
source. Our protocol involves the rapid synthetic route to
synthesize these privileged scaffolds from commercially
available starting materials.
Initially the model reaction was performed using 2-
aminobenzamide 1, DMSO as substrates and K2S2O8, DABCO as
additive and base, respectively. Complete conversion of the
starting material was observed after 20 hours, although isolated
yield was 45% (Table 1, entry 1). Encouraged by the above
preliminary result, we focused our attention towards improving
the yield by varying additive and base. Various additives were
screened (Table 1, entries 2-4), among which K2S2O8 proved to
be the best additive in terms of yield and conversion. Screening
bases like DBU and TEA (Table 1, entries 5-6) did not yield
fruitful results. Attempts to optimize the reaction by varying
additive, base loading and temperature failed to improve the
isolated yield (Table 1, entries 7-8). Interestingly, when the
reaction was carried out in microwave reactor at 160 °C,
Synthetic chemists dedicated enormous efforts to develop
greener route for the synthesis of quinazolinones.5
Conventional synthesis of quinazolinones has several
limitations such as use of formaldehyde as a carbon source
and harsh reaction conditions involving transition metals and
inorganic acids.6 Despite the development of vast number of
synthetic protocols for synthesis of quinazolinones, a facile
synthetic route replacing toxic formaldehyde as a carbon
source and mild catalyst would be highly desirable for bulk
synthesis.7
Dimethyl sulfoxide (DMSO) is one of the widely
used solvent in organic synthesis because of low toxicity, high
solubilizing capacity, stability and low cost.8 Over the last
decade, DMSO is used as a synthon in wide number of key
a. College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of
Korea. E mail: orgjkjung@chungbuk.ac.kr, 16vishwanath@gmail.com.
b. College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
§ These authors contributed equally to the work.
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COMMUNICATION
Journal Name
drastically reduced the reaction time to 2 hours and yield was
improved to 68% (Table 1, entry 9). The conditions in entry 9
View Article Online
DOI: 10.1039/C9OB01629E
O
O
Table 1. Optimization of reaction conditions.a
K2S2O8 (2.0 equiv),
DABCO (2.0 equiv)
R2
R2
N
N
R1
H
R1
DMSO, 160 o
MW, 2 hours
C
O
O
NH2
N
H
Additive
Base
DMSO, Temp
1a-p
2a-o
NH2
NH2
NH
N
2a
H
O
N
O
N
O
N
O
1a
NH
N
N
N
H
H
H
N
H
Entry
Additive
Base
Temp
(°C)
140
140
140
140
140
140
140
160
160
Time
(h)
20
24
24
24
24
24
48
8
Yieldb
(%)
45
26
12
-
28
-
36c
54
68d
2a,
2b,
2c,
2d,
68%
61%
59%
52%
N
1
2
3
4
5
6
7
8
9
K2S2O8
AcOH
TFA
DABCO
-
O
N
N
O
O
O
Bn
H
CF3
N
N
-
-
N
H
N
H
N
H
PTSA
2h,
47%
2e,
61%
2f,
53%
2g,
63%
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
DBU
TEA
DABCO
DABCO
DABCO
O
O
O
O
N
N
N
N
N
H
H
N
H
N
H
N
2
2i,
2j,
2k,
2l,
72%
65%
61%
O
59%
O
a Reaction conditions: 2-aminobenzamide 1 (1.0 mmol), additive (2.0 equiv), base
(2.0 equiv), DMSO 2.0 mL. b Isolated yield. c 1.0 equiv K2S2O8 and 1.0 equiv DABCO
were used.d Reaction was carried out in microwave condition.
O
O
O
F
Cl
H
N
O
O
N
NH
H
NH
N
H
N
N
H
N
H
2m,
64%
2n,
49%
2o,
2p,
53%
62%
were chosen as optimal reaction condition for further studies.
With the optimized reaction conditions in hand, we set out
to explore the substrate scope of our methodology. 2-
Aminobenzamides bearing various functional groups (1a-1p)
were tested, gratifyingly most of the substrates afforded the
desired product in moderate to good yields. Aliphatic
substituents at the amide nitrogen atom (2b-2g) were well
tolerated. Electron releasing substituents significantly
increased the yield due to increase in the nucleophilicity of the
amide, thus favoring annulation, whereas trifluoroethyl
substituted amide 1h also afforded the product 2h smoothly but
with moderate yield of 47%. With N-phenyl substituted amide
the reaction proceeded smoothly when compared to
unsubstituted 2- aminobenzamide 1a due to electron releasing
effect, furnishing the product with 72% yield. Substrates with
various aromatic substitutions on amides were tested and the
products (2i-2m) were isolated with good to moderate yield of
65-59%, whereas substrates with electron withdrawing groups
like NO2 and CN groups on aromatic substitution decomposed
in the optimized conditions. Consequently, we focused our
attention on the effect of substituents on the aromatic ring of
2-aminobenzamide. Substrates bearing F, Cl, dimethoxy groups
were employed and the desired products (2m–2p) were
isolated with 49 to 62% yield.
Furthermore, we tested various dialkyl sulfoxides to
synthesize 2-substituted quinazolinones (Scheme 2). Diethyl,
dibenzyl, dibutyl and dioctyl sulfoxides furnished the desired
quinazolinones (2q–2t) with moderate yields (up to 68%).
Having successfully synthesized wide range of quinazolinones,
we demonstrated synthetic utility of the method by
synthesizing the CNS depressant drug Methaqualone 2u
(Scheme 3). 2-amino-N-(o-tolyl)benzamide 1k and diethyl
sulfoxide (5.0 equiv) were used as substrate under optimized
reaction condition, the desired Methaqualone 2u was isolated
with 57% yield.
Scheme 1. Substrate scope of 2-aminobenzamides. All the reactions were performed in
1.0 mmol scale, Yields mentioned are isolated yields.
Deuterium-labelling experiment with DMSO-d6 was
performed under the optimized reaction condition to gain
insight into the reaction mechanism (Scheme 4). DMSO-d6
furnished the deuterated product 2v with 61% yield. The above
result confirmed that the DMSO acts as a source of methine unit
in the product. The plausible reaction pathway for the reaction
is depicted in Scheme 5. DMSO reacts with K2S2O8 to generate
sulfenium ion A. The sulfenium ion was condensed with 2-
aminobenzamide to afford B, which undergoes the elimination
of methanethiol forming imine intermediate C. Under basic
environment, intramolecular annulation of C furnished the
intermediate D, followed by autooxidation to afford the desired
quinazolinone 2.
O
O
K2S2O8 (2.0 equiv),
O
DABCO (2.0 equiv)
NH2
NH2
NH
R'
R'
S
R'
Xylene,160 o
MW, 2 hours
C
N
R'= CH3,C3H7,
Ph, C7H15
1a
2q-2t
O
O
O
O
NH
NH
C7H15
61%
NH
NH
N
N
N
N
2q,
2r,
2s,
2t,
48%
57%
68%
Scheme 2. Substrate scope of various sulfoxides. All the reactions were performed in 1.0
mmol scale.
O
O
K2S2O8 (2.0 equiv),
DABCO (2.0 equiv)
N
N
H
S
Xylene, 2 hours
O
N
NH2
1k
MW, 160 o
C
5.0 equiv
2u,
57%
Methaqualone
Scheme 3. Synthesis of Methaqualone by transition metal-free synthesis.
2 | J. Name., 2012, 00, 1-3
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K2S2O8 (2.0 equiv),
DABCO (2.0 equiv)
NH2
NH2
NH
DMSO-d6, 160oC
D
1a
2v
61%
Scheme 4. Deuterium-labelling experiment with DMSO-d6.
2
3
O
K2S2O8
S
S
A
O
O
NH2
NH2
NH
K2S2O8, DABCO
DMSO, MW, 160 o
C
S
N
H
O
1a
2a
A
O
N
O
N
O
H
N
NH2
S
NH
H
H
H
N
CH3SH
H
B
H
D
C
Scheme 5. Plausible mechanistic pathway.
Conclusion
In conclusion, an efficient, metal-free synthesis of
quinazolinones have been developed via K2S2O8-mediated
oxidative annulation reaction. Commercially available 2-
aminobenzamides and DMSO were used as the starting
materials to synthesize a broad spectrum of biologically
important quinazolinones with moderate to good yields. In this
method, K2S2O8 reacts with DMSO to afford in situ generation
of sulfenium ion, which acts as one carbon source for oxidative
annulation, use of deuterated DMSO proved that the DMSO is
source of methine unit. We believe, the new methodology
offers several advantages like greener reaction condition, wide
substrate scope and simplicity of operation.
4
5
6
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
7
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This work was supported by the National Research Foundation
of Korea grants funded by the Korea Government (MSIP) (MRC
2017R1A5A2015541, and Basic Science Research Program
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9OB01629E
Transition
Metal
Highlightes of the methodology
Transition metal - free synthesis
DMSO as a synthon
Biologically important quinazolinones
Broad substrate scope
O
O
N
R2
K2S2O8 (2.0 equiv),
DABCO (2.0 equiv)
O
S
R2
R3
N
N
R1
H
R3
R3
R1
NH2
MW,160oC
up to 72% yield
22 substrates