Metal-free oxidative synthesis of quinazolinones via dual amination of sp3 C-H bonds

Article abstract of DOI:10.1039/c4cc02648a

A novel metal-free synthesis of quinazolinones via dual amination of sp³ C-H bonds was developed. The sp³ carbon in methylarenes or adjacent to a heteroatom in DMSO, DMF or DMA was used as the one carbon synthon. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02648a

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Metal-free oxidative synthesis of quinazolinones via
dual amination of sp3 C–H bonds
Cite this: DOI: 10.1039/x0xx00000x
Dan Zhao, Teng Wang and JianꢀXin Li*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
especially in preparations of pharmaceutical agents due to the
presence of heavy transition metal impurities in the final products.
Therefore, a more environmentally friendly route for the synthesis of
quinazolinones under metalꢀfree conditions remains highly desirable.
A novel metal-free synthesis of quinazolinones via dual
amination of sp3 C–H bonds was developed. The sp3 carbon
in methylarenes or adjacent to a heteroatom in DMSO, DMF
or DMA was used as the one carbon synthon.
Quinazolinone heterocycle, widely presented in natural
products and synthetic pharmaceuticals, has been extensively
studied for its biological and therapeutic activities.1 Many
synthetic efforts have been made for its construction starting
from a variety of substrates,2 among which, 2ꢀamino benzamide
is probably the most typical one. Quinazolinones have
commonly been prepared via condensation of 2ꢀamino
benzamides with either carboxylic acid derivatives under harsh
conditions,3 or aldehydes with subsequent oxidation using
strong oxidants (Scheme 1, path a).4 To overcome these
drawbacks, recent reports gave improved methods using
benzylic methylene sp3 carbon as the one carbon synthon,
developing a more environmentally friendly process (Scheme 1,
path b). Benzyl alcohols were used for preparation of
quinazolinones under metal or iodine catalytic systems.5 Very
recently, selective autoxidation of benzyl amines were also
applied in this field, which possessed a highly valuable
advantage.6 Under Cuꢀcatalyzed aerobic oxidative system,
benzyl halides could be also served as starting materials.7
Considering that carbon monoxide can be used as a cheap carbon
source, palladiumꢀcatalyzed carbonylation reaction might become a
promising strategy for heterocyclic compounds preparation. Very
recently, an interesting work demonstrated that in the presence of a
palladium catalyst, carbonylative synthesis of quinazolinones could
be achieved starting from 2ꢀamino benzamides and bromobenzenes
(Scheme 1, path c).8 Notably, all synthetic routes mentioned above
depended on the use of functional group in substrate, which showed
less atomꢀefficient compared with the attractive crossꢀ
dehydrogenativeꢀcoupling (CDC) reactions9. Besides, most of the
cases were restricted to the transition metal assisted approach, which
Scheme 1. Different pathways for the synthesis of quinazolinones.
In recent years, a great progress has been made in C–N bond
formation via C–H/N–H crossꢀcoupling but challenges still
remained.10 For example, methodologies for the amination of
primary benzylic C–H bonds in toluene derivates are relatively
scarce.11 Notable examples included transition metal
a
,
b
c
catalyzed,11 iodide salt catalyzed11 and hypervalent iodine
mediated benzylic C–H amination via C–H/N–H crossꢀ
d,e
coupling,11
and the nitrogen sources were limited to
sulphonamide, carboxamide and azole derivatives. Besides,
there are few examples of the introduction of methylarenes or
methylhetarenes to construct nitrogenꢀcontaining heterocycles
via C–N bond formations.12 Encouraged by above results, and
in the continuation of our research on
herein report direct approach for the synthesis of
N
ꢀheterocycles,13 we
a
quinazolinones from 2ꢀamino benzamides and methylarenes
(Scheme 1, path d). The transformation could be carried out via
(tBuO)2 (DTBP) mediated domino reactions in which dual
oxidative C–N couplings were involved, and quite different
from the mentioned heterocycle construction reactions starting
from methylarenes or methylhetarenes, transition metals were
not essential.
Initially, as usual, transition metal catalysts were employed
in the reaction of 2ꢀamino benzamide (1a) and toluene (2a) in
the presence of DTBP as oxidant (Table 1). As expected, the
desired reaction took place, leading to the formation of the
was
a major problem regarding their practical applicability,
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product 3a in moderate yield under iron or palladium catalysis
(entries 1–3). To our surprise, a control experiment confirmed
Table 1. Optimization of the reaction conditionsa
Entry
1
2
3
4
5
6
7
8
Cat.
FeCl3
CuCl2
Pd(OAc)2
—
—
—
—
—
—
—
—
—
—
—
—
—
Oxidantb
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
BPO
Additive
—
—
—
—
TsOH
K2CO3
TsOH
TsOH
TsOH
TsOH
TsOH
KH2PO4
BF3ꢁEt2O
CH3COOH
CF3COOH
Yieldc (%)
52
trace
57
36
81
trace
trace
45
36
0
0
16
19
31
61
57
60
42
a
Reaction conditions:
1
(0.3 mmol),
2
(2 mL), DTBP (0.9 mmol),
TsOH (0.6 mmol), DMSO (2 mL), 110 oC, 20 h. Isolated yield.
9
TBPB
DDQ
Then, a wide range of 2ꢀamino benzamides were employed
for annulation with methylarenes under the optimized
conditions (Table 2). Most of toluenes with electronꢀdonating
and withdrawing substituents could be converted to the desired
10
11
12
13
14
15
16
17
18
19
20
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
products in moderate to good yields (3b
steric hindrance had little influence on the reaction (3b
Methyl substituted naphthalene and heteroarene also proved
applicable (3k ). The substituents at the phenyl ring of 2ꢀ
amino benzamides did not affect the efficiency of this
transformation (3m 3o ). This strategy was also available to
the synthesis of quinazolinones bearing ꢀphenyl and ꢀalkyl
substituents from corresponding 2ꢀamino ꢀsubstituted
benzamide with toluenes (3n ). Surprisingly, when 2ꢀaminoꢀ
ꢀ(secꢀbutyl)benzamide were subjected to identical conditions,
–
j
). Remarkably, the
–
d
).
tBuCOOH
–
l
—
—
—
—
CH3SO3H
CF3SO3H
TsOHd
34
73
51
,
–p
TsOHe
N
N
21
—
TsOHf
N
a
Reaction conditions: 1a (0.3 mmol), 2a (2 mL), cat. (10 mol%),
–
v
oxidant (0.9 mmol), additive (0.6 mmol), DMSO (2 mL), 110 oC, 20
b
N
h.
TBHP: 70%
Bu. c Isolated yield. d 0.5 equiv. e 1 equiv. f 3 equiv.
that the reaction occurred in the absence of the transition metal
catalyst (entry 4). Interestingly, ꢀtoluenesulfonic acid (TsOH)
tBuOOH in water, BPO: (PhCOO)2, TBPB:
the expected products 3u was observed in 30% yield along with
3u' in 41% yield. The low yield of 3u was most probably
attributed to steric effect of the secꢀbutyl group on the substrate.
Moreover, a Dꢀlabeling experiment proved that the additional
carbon atom in 3u' was derived from DMSO (see ESI), which
strongly suggested the methyl carbon of DMSO could be
introduced as the one carbon synthon, although its reactivity
was lower than that of toluene in current conditions. Because of
the structural similarity, 2ꢀamino benzenesulfonamide was
PhCOOO
t
p
improved the yield significantly (entry 5). Among the various
oxidants examined, we observed that DTBP was the most
efficient one (entries 7–11). At this stage, other types of organic
and inorganic acids were also tested, but not as efficient as
TsOH (entries 12–18). The yields dropped after varying the
amount of TsOH (entries 19–21), we deduced that TsOH could
promote the reaction by adjusting the pH value of reaction
solution.
tested and 3ꢀphenylꢀ3,4ꢀdihydroꢀ(2
H
)ꢀ1,2,4ꢀbenzothiadiazineꢀ
). The yields were
1,1ꢀdioxides were obtained as products (3w
–
x
lower than those of quinazolinones, presumably due to the
poorer nitrogen nucleophilicity of sulfonamides. Besides the
intermolecular annulations using the above substrates, other
potential substrates were tested (See ESI). We also tried
intramolecular reaction to construct fused fourꢀmembered rings
but failed (See ESI).
Table 2. Intermolecular annulation of 1
with methylarenes 2a
2 | J. Name., 2012, 00, 1-3
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Table 3. Intermolecular annulation of 1
with DMAa
a
Reaction conditions:
1 (0.3 mmol), DTBP (0.9 mmol), TsOH (0.6
o b
mmol), DMA (2 mL), 110 C, 20 h. Isolated yield. DMF (2 mL)
instead of DMA was used. c DMSO (2 mL) instead of DMA was used.
After success in the elaboration of 2ꢀsubstituted
quinazolinones, we moved our focus back to investigating the
possibility of DMSO as an efficient carbon source. Based on
some related research,16 we hypothesize that, nucleophilic
attack of αꢀtertꢀbutoxylated intermediate and a sequential C–S
bond cleavage were involved, and the following domino
process occurred similarly to those in Scheme 3. Then, further
optimizations were carried out by testing the annulation of 2ꢀ
Scheme 2. Investigation into the reaction mechanism.
To obtain insights into the mechanism, some control
experiments have been performed (Scheme 2). We first ruled
out the possibility of benzaldehyde as the reaction intermediate
and indeed didn't detect it in reaction mixture. The competitive
annulations involving toluene and tolueneꢀd8 were performed,
aminoꢀN
ꢀphenylbenzamide with similar sp3 carbons adjacent to
and a large intermolecular kinetic isotope effect (KIE, kH/kD =
6.1) was observed (Scheme 2a), thus indicating that the
cleavage of benzyl C–H bond was involved in the rateꢀ
determining step. A negative influence on the yield was
observed when BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) or
TEMPO (2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl) was added to
the reaction system (Scheme 2b), which suggested that the
reaction probably proceeded via a free radical process. We next
heteroatoms in some other solvents, and DMA was the best one
considering the availability (see ESI). As described in Table 3,
starting from substrates with
Nꢀaryl, Nꢀalkyl or phenyl
substituents, the desired products were obtained with moderate
to excellent yields. Notably, functional groups such as F, Cl or
Br remained intact, allowing for further functionalization of the
products.
In conclusion, we have developed a novel, metalꢀfree
approach for the synthesis of 2ꢀaryl quinazolinones via dual
benzylic C–H bonds amination, using 2ꢀamino benzamides and
methylarenes as the accessible starting materials. The possible
radical mechanistic pathway is also proposed on the basis of
control experiments. In addition, the commonly used solvents,
such as DMSO, DMF or DMA were also effective in the
similar annulation reactions via sp3 C–S or C–N bond cleavage
and C–N bond formations. Further application of the
investigated whether 2ꢀ(benzylamino)benzamide
6 or 2ꢀamino
Nꢀbenzylbenzamide 1p was the reaction intermediate, and the
results indicated that amino group instead of amide group
played an important role in intermolecular amination (Scheme
2c). Considering that tertꢀbutoxy intermediate was reported
involved in C–N bond formation via nucleophilic reaction
assisted by Lewis acid,14 we speculated this intermediate could
also be attacked by 1a to give
amination/oxidation would form the product 3a. Expectedly,
the reaction of 1a and afforded the product 3a (Scheme 2d).
6, and subsequent intramolecular
5
methodology in other
Nꢀheterocycles synthesis is currently
underway in our laboratory.
Financial support from National Natural Science Foundation of
China (21272114, 91313303), and the National Natural Science
Fund for Creative Research Groups (21121091) is gratefully
acknowledged.
Notes and references
State Key Lab of Analytical Chemistry for Life Science, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, 210093, P. R.
China. E-mail: lijxnju@nju.edu.cn; Fax: +86-25-83686419; Tel: +86-25-
83686419
Scheme 3. Possible mechanism.
Therefore, a possible mechanism is proposed as shown in
Scheme 3. Initially, the homolysis of DTBP gave tertꢀbutoxy
radicals.15 Benzyl radical was then generated by abstraction of
H from toluene, and subsequent coupling of these two radicals
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/c000000x/
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