Diversification of quinazolinones by Pd-catalyzed C(sp3)-acetoxylation

Article abstract of DOI:10.1021/acs.joc.7b01934

The quinazolinone ring has been exploited as a directing group for C(sp³)-H functionalization for the first time. The proximal C-γ(sp³)-H bonds have been oxidized by palladium-catalyzed acetoxylation reaction. Various functional grou

Full text of DOI:10.1021/acs.joc.7b01934

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Article
Diversification of Quinazolinones by Pd-Catalyzed C(sp3)-Acetoxylation
Dnyaneshwar Nilkanth Garad, and Santosh B. Mhaske
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01934 • Publication Date (Web): 28 Aug 2017
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Diversification of Quinazolinones by Pd-Catalyzed C(sp3)-Acetoxylation
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Dnyaneshwar N. Garad and Santosh B. Mhaske*
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Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
ABSTRACT: The quinazolinone ring has been exploited as a directing group for C(sp3)-H
functionalization for the first time. The proximal C-(sp3)-H bonds have been oxidized by
palladium-catalyzed acetoxylation reaction. Various functional groups on the quinazolinone
scaffold were tolerated to provide novel quinazolinone derivatives. The use of base was found to
be crucial for the monoselective acetoxylations.
INRODUCTION
Quinazolinones is one of the significant classes of heterocyclic compounds, which are
commonly found in many natural products and pharmaceuticals.1 The several biological
activities such as antimalarial, antidiabetic, antihypertensive, anticonvulsant, diuretic, anticancer,
hypnotic, antitussive, anti-inflammatory, among others possessed by the quinazolinone alkaloids
have gained considerable attention in synthetic as well as medicinal chemistry. Many of the
quinazolinone natural products having good therapeutic assets commonly encompass β or  sp3-
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oxidized carbons (Figure 1),1c,e which could be potentially accessed by selective oxidation using
metal catalyzed directed C-H activation process.
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Figure 1. Selected quinazolinone natural products containing β or  sp3-oxidized carbons.
Such C-H bond activation process would assist to eliminate the number of steps and avoid pre-
functionalization of starting materials. The major challenge associated with C-H bond activation
is regio-selectivity because organic compounds contain a wide variety of C-H bonds. One of the
best ways to overcome the regio-selectivity issue is to use a directing-group, which can bring a
metal catalyst into close proximity of precise C-H bond by chelation with a metal catalyst. The
major development in the area of C-H bond activation mainly focuses on the C(sp2)-H bond
functionalization. The C(sp2)-H bonds are comparatively easy to activate because of
arene’s/olefin’s π-stabilizing interaction with a metal catalyst to form strong olefin/aryl-metal
bond. In contrast, activation of C(sp3)-H bonds is underdeveloped and challenging because of
the absence of π-stabilizing interaction with metal center similar to arenes/olefins.2 Nevertheless,
notable development has been done in the area of C(sp3)-H bond activation where various
directing groups (including mono as well as bidentate) have been exploited in the C(sp3)-H bond
functionalization.2,3 Several metal catalysts like Pd, Rh, Ir, Ru, Co, Cu, and Fe have been used
for introducing various functional groups on the sp3 carbons. Arylation, alkylation, olefination,
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alkynylation, alkoxylation, acetoxylation, hydroxylation, amination, and halogenation are some
of the functionalizations, which are often used for C(sp3)-H diversification by transition metal
catalysis (Scheme 1a).2-6
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Scheme 1. Transition Metal-Catalyzed C(sp3)−H Functionalizations
Albeit, the quinazolinone scaffolds have been synthesized by several advanced strategies1b and
few metal-catalyzed C(sp2)-H activation approaches,7 nevertheless, to the best of our knowledge,
quinazolinone-directed C(sp3)-H functionalization was not known until now. Recently our
laboratory introduced a new protocol for C(sp2)-arylations of quinazolinone directed by
quinazolinone scaffold.8 In continuation of our interest in the functionalization of quinazolinone
alkaloids by C-H activation, we anticipated that quinazolinone scaffold could be used as an
intrinsic directing group for the C(sp3)-H functionalizations. In this context, herein we report
quinazolinone directed diverse C(sp3)-acetoxylations (Scheme 1b).
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RESULTS AND DISCUSSION
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The optimization of the desired protocol was carried out on the substrate 1a (Table 1).
We first attempted the commonly used C(sp3)-acetoxylation reaction condition using Pd-catalyst
and diacetoxy iodobenzene (PIDA) in acetic acid, but we observed the expected product 2a
formation in moderate yields (entries 1, 2). Interestingly, we did not observe any C(sp2)-
acetoxylated product for this substrate.7f Increase in the oxidant mole ratio showed a little
improvement in the yield (entry 3).
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Table 1. Optimization Studies
entrya
catalyst (x mol%)
oxidant (equiv)
solvent/temp ºC
yield (%)b
1
Pd(OAc)2 (10)
PhI(OAc)2 (1)
AcOH/100
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3
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
PhI(OAc)2 (1.1)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (2)
AcOH/120
AcOH/120
AcOH/120
AcOH/120
toluene/120
AcOH/120
AcOH/120
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4
80
5
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
--
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PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
N.R.
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7c
8
N.R.
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Cu(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PhI(OAc)2 (1.5)
K2S2O8 (1.5)
oxone (1.5)
AcOH/120
AcOH/120
AcOH/120
N.R.
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aReaction conditions: 1a (0.2 mmol), AcOH (1 mL) in glass tube with screw cap for 24 h. bIsolated yield. N.R. =
No reaction. cAdditive: 1.5 equiv Na2CO3
To our delight, when the catalyst loading was doubled, the expected product 2a was obtained in
very good yield (entry 4). Further increase in the oxidant did not improve the yield substantially
(entry 5). Many other deviations from the standard condition (entry 4) including solvent,
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additive, without metal, other metal-catalyst and oxidants resulted in either no reaction or
inferior yields (entries 6-11). It is interesting to note that the optimized reaction condition (entry
4) could furnish acetoxylated product 2a in good yield without using acetic anhydride as a co-
solvent, which is generally used for such acetoxylation reactions.
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After having the identified optimal condition, we next evaluated the scope of the reaction
with respect to the substituent variation at various positions of quinazolinones (Scheme 2).
Scheme 2. Palladium Catalyzed Benzylic-Acetoxylations of Various Quinazolinonesa,b
o
aReaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2 (0.3 mmol), AcOH (1 mL), 8-24 h, 120 C.
bIsolated yield. cInstead other isomer (scheme 4, 2p) formed as a major product. ND = not detected.
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The N-H free quinazolinone, when subjected under the developed protocol, ended up in the
complex reaction mixture, and no expected product 2b was detected. Hence, initially N- Me
substitution was kept constant and the effect of variation at the second position of quinazolinone
ring was studied.As mentioned above, quinazolinone with the phenyl ring substituent at the
second position provided product 2a in very good yield, however with electron-
donating/withdrawing and halo- substituents on the phenyl ring the expected products 2c-e were
observed in moderate to good yields. The steric hindrance of the aromatic ring at the second
position might be affecting the metal coordination and thus resulting in the moderate yields.
Pleasingly, the quinazolinones with heterocyclic substituents at the second position produced
expected products 2f and 2g in good to excellent yields. Probably the heteroatoms of these
substituents coordinate with the metal catalyst more effectively, and substrates behave like a
bidentate directing group and hence enhance the reaction. Surprisingly, when alkyl substituted
quinazolinone was subjected under the developed protocol, the expected product 2h was formed
in a trace amount along with the formation of other C(sp3)-acetoxylation product. The
quinazolinone without substitution at the second position provided product 2i in very good yield.
Furthermore, the scope of the reaction with respect to N-substituent variation was studied.
Various N-substitutions were well tolerated and furnished the corresponding products such as
primary alkyl 2j, cyclohexyl 2k, benzyl 2l and phenyl 2m in very good to excellent yields.
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The result obtained in the scheme 2 with substrate 1h, prompted us to investigate the
scope of the C(sp3)-acetoxylation reaction on 2-tert-butyl substituted quinazolinones. We
prepared substrate 1n for this study (Scheme 3).
Application of our standard condition on 1n
provided the monoacetoxylated product 2n and diacetoxylated product 2na in the almost
equivalent ratio (Condition A).
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Scheme 3. The Effect of a Base on Palladium Catalyzed C(sp3)-Acetoxylations
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To improve the selectivity, we tried few additives, and gratifyingly addition of sodium carbonate
furnished selectively the monoacetoxylated product 2n in very good yield (Condition B). The
crucial effect of a base on the outcome of a reaction was previously observed for C(sp2)/C(sp3)-
arylation.8,9 Further increase in the oxidant and additive showed enhancement in the
diacetoxylated product 2na along with substantial amount of monoacetoxylated product 2n
(Condition C, D). However, in the absence of the base, we observed the exclusive formation of
diacetoxylated product 2na in moderate yield (Condition E). We did not observe the formation
of the corresponding triacetoxylated product 2nb in any of these reactions. With the optimized
condition (scheme 3) for selective monoacetoxylation of 2-tert-butyl quinazolinones in hand, we
planned to study the scope of the reaction (Scheme 4). The quinazolinone substrate without any
substitution at aromatic ring afforded the product 2n in good yield.
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Scheme 4. Palladium-Catalyzed C(sp3)-Acetoxylations of Various Quinazolinonesa-c
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aReaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2 (0.22 mmol), Na2CO3 (0.22 mmol), AcOH (1
b
mL), 24 h, 120 oC. Isolated yield. cTrace amount of diacetoxylated products were observed in all the cases.
The methyl substituted quinazolinones 2o and 2p were obtained in good and moderate yields
respectively. The 6-methoxy substituted quinazolinone under the developed protocol conceded
product 2q formation in good yield. The reaction scope could be further extended to obtain iodo
2r and fluoro 2s quinazolinones. The electron deficient quinazolinone with a nitro substituent
was also tolerated and furnished the product 2t in very good yield.
Scheme 5. Reaction with Catalytic Iodobenzene and Oxone
Having developed a wide substrate scope of the reaction, we decided to study a catalytic version
of our protocol, which may be useful for practical applications. The reagent PIDA could be
regenerated in situ in the reaction from iodobenzene (20 mol%) and oxone in the acetic acid,
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which would eventually act as an oxidant for the metal catalyst (Scheme 5). The product 2i was
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synthesized in good yield by using this catalytic process.
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Figure 2. Plausible Mechanism.
A plausible mechanism for the developed C(sp3)-H activation protocol is depicted in
figure 2. According to the literature analogy,5i we believe that in the first step, Pd(II) chelates
with the imine nitrogen of quinazolinone 1 and activates the C(sp3)-H bond to form a five-
membered palladacycle A. PIDA oxidatively adds to the palladacycle A to form the palladacycle
B [Pd(IV)]. The final step involves C-O bond forming reductive elimination to afford the product
2. It may proceed either by an intramolecular elimination from the metal center or SN2 attack by
an external acetate ion.5i
CONCLUSION
In summary, quinazolinone scaffold has been successfully used as an inherent directing group for
Pd-catalyzed C(sp3)-H functionalization. Diverse novel quinazolinone derivatives have been
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synthesized. The developed acetoxylation protocol could be used for the synthesis of natural
products and derivatization of bioactive quinazolinones for SAR studies. A base controlled
monoselective acetoxylation demonstrated herein may find important applications in the area of
C-H activation. Currently, the work towards the development of quinazolinone directed
asymmetric C-H activation processes for the synthesis of bioactive natural products and their
congeners is underway in our laboratory.
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EXPERIMENTAL SECTION
General Information: All reagents and solvents were used as received from commercial sources
unless otherwise noted. All experiments were carried out under an argon atmosphere in a sealed
tube. Precoated plates (silica gel 60 PF254, 0.25 mm or 0.5 mm) were utilized for thin-layer
chromatography (TLC). Column chromatographic purifications were carried out on flash silica
gel (240−400 mesh) using petroleum ether and ethyl acetate as the eluents. The 1H and 13C NMR
spectra were recorded on 200/400/500 MHz and 50/100/125 MHz NMR spectrometer,
respectively, in CDCl3. Chemical shifts were reported as δ values from standard peaks. The
melting points were recorded on a Buchi instrument. The mass spectra were taken on an LC−MS
(ESI) mass spectrometer. High-resolution mass spectrometry (HRMS) was performed on a
TOF/Q-TOF mass spectrometer. All quinazolinone starting materials were prepared according to
modified literature procedures.10,11
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Experimental Procedures for the Synthesis of Starting Materials:
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Step i: General Procedure for the Synthesis of Anthranilamides:
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To a solution of substituted anthranilic acid (1 mmol) in THF (5 mL) was added 1,1'-
carbonyldiimidazole (CDI) (1 mmol) under argon atmosphere and the resulting reaction mixture
was stirred at room temperature (RT) for 12 h. The corresponding amine (1.1 mmol) [or 40%
aqueous solution in case of methyl amine (5 mmol)] was added to the above reaction mixture at
RT and stirred for another 4 h. It was diluted with ethyl acetate (50 mL), and the organic layer
was washed with water and brine followed by drying over anhydrous sodium sulfate and
concentration in vacuo. The crude anthranilamide product was used further without purification.
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Step ii: General Procedures for the Synthesis of Quinazolinones from Anthranilamides:
Method A:
The N-substituted anthranilamides from step (i) (1.0 mmol; 1.0 equiv) and the corresponding
aldehydes (1.1 mmol; 1.1 equiv) [or 40% aqueous solution in the case of formaldehyde (1.5
o
mmol; 1.5 equiv)] were dissolved in DMSO (5 mL). The reaction mixture was stirred at 120 C
in an open flask and the progress was monitored by TLC. After complete consumption (24 h) of
the starting materials, the reaction mixture was poured onto water and extracted with DCM. The
organic layer was combined, dried over anhydrous sodium sulfate, and concentrated in vacuo.
The crude mixture was purified by silica gel column chromatography using petroleum ether /
EtOAc (5-10:1) as eluents to afford quinazolinone 1.
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Method B:
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a) To the solution of N-substituted anthranilamides from step (i) (1.0 mmol; 1.0 equiv) in DCM
(10 mL) was added pyridine (3 mmol; 3 equiv). After 5 minutes pivaloyl chloride (1.1 mmol; 1.1
equiv) was added slowly at RT and the resulting mixture was stirred for another 6 h. The reaction
mixture was then diluted with DCM (50 mL) and washed with HCl (aqueous, 1M), saturated
aqueous NaHCO3 and brine. The organic phase was dried over sodium sulfate and concentrated
in vacuo. The crude product was used further without purification.
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b) Iodine (4 mmol; 4 equiv) was added to the solution of crude product from step (a) (1.0 mmol;
1.0 equiv) in benzene (10 mL). Subsequently HMDS (5 mmol; 5 equiv) was added slowly and
o
the reaction mixture was heated to 80 C for 12 h. It was allowed to cool to RT and diluted with
DCM (50 mL). The organic layer was washed with aqueous Na2SO3, brine and water. The
organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude
product was purified by silica gel column chromatography using petroleum ether / EtOAc (5-
10:1) as eluents to afford quinazolinone 1.
3,8-Dimethyl-2-phenylquinazolin-4(3H)-one (1a)
Following the Method A procedure, 1a was obtained as a colorless solid
o
1
(153 mg; 61% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); mp 121-124 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.19 (d, J = 7.9 Hz, 1H), 7.65-7.58 (m,
3H), 7.56-7.50 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 3.52 (s, 3H), 2.61 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 163.3, 154.6, 146, 136.1, 135.8, 134.8, 129.9, 128.6, 128.4, 126.5, 124.3, 120.4,
34.4, 17.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H15ON2 251.1179, found 251.1177.
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2-(4-Methoxyphenyl)-3,8-dimethylquinazolin-4(3H)-one (1c)
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Following the Method A procedure, 1c was obtained as a colorless
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solid (118 mg; 42% yield). Rf: 0.4 (1:4 EtOAc: Pet. ether); mp 161-
163 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.17 (d, J = 7.9 Hz, 1H),
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7.64-7.52 (m, 3H), 7.37 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 3.90 (s, 3H), 3.56 (s, 3H),
2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.5, 160.9, 154.5, 146.1, 135.9, 134.7,
130.2, 128.2, 126.2, 124.3, 120.3, 114, 55.4, 34.6, 17.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C17H17O2N2 281.1285, found 281.1284.
3,8-Dimethyl-2-(4-nitrophenyl)quinazolin-4(3H)-one (1d)
Following the Method A procedure, 1d was obtained as a pale yellow
solid (148 mg; 50% yield). Rf: 0.5 (1:3 EtOAc: Pet. ether); mp 221-
223 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.41 (d, J = 8.5 Hz, 2H),
7.19 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 6.7 Hz,
13
1H), 7.43 (d, J = 7.4 Hz, 1H), 3.52 (s, 3H), 2.59 (s, 3H); C NMR (100 MHz, CDCl3) δ (ppm)
162.8, 152.3, 148.5, 145.6, 141.5, 136.3, 135.1, 129.7, 127.3, 124.4, 124, 120.6, 34.2, 17.2;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14O3N3 296.1030, found 296.1030.
2-(2-Fluorophenyl)-3,8-dimethylquinazolin-4(3H)-one (1e)
Following the Method A procedure, 1e was obtained as a colorless solid
o
1
(161 mg; 60% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); mp 129-131 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.20 (d, J = 7.9 Hz, 1H), 7.66-7.49 (m,
3H), 7.41 (t, J = 7.9 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.22 (t, J = 9.2 Hz, 1H), 3.48 (s, 3H), 2.61
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.7, 159.4 (d, J = 248.9 Hz), 150.4, 146, 136.2,
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134.8, 132 (d, J = 8.5 Hz), 130.7 (d, J = 3.1 Hz), 126.8, 124.9 (d, J = 3.1 Hz), 124.3, 124 (d, J =
15.4 Hz), 120.7, 115 (d, J = 20.8 Hz), 32.8 (d, J = 3.9 Hz), 17.3; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C16H14ON2F 269.1085, found 269.1084.
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3,8-Dimethyl-2-(pyridin-2-yl)quinazolin-4(3H)-one (1f)
Following the Method A procedure, 1f was obtained as a colorless solid
(138 mg; 55% yield). Rf: 0.5 (1:2.3 EtOAc: Pet. ether); mp 165-167 oC; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.72 (d, J = 4.3 Hz, 1H), 8.20 (d, J = 7.9
Hz, 1H), 7.96-7.88 (m, 2H), 7.61 (d, J = 7.3 Hz, 1H), 7.48-7.37 (m, 2H), 3.65 (s, 3H), 2.63 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.1, 154.1, 152.3, 148.5, 145.8, 137.2, 136.1,
134.7, 126.8, 124.9, 124.5, 124.4, 120.9, 33.6, 17.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C15H14ON3 252.1131, found 252.1129.
3,8-Dimethyl-2-(quinolin-2-yl)quinazolin-4(3H)-one (1g)
Following the Method A procedure, 1g was obtained as a colorless solid
(157 mg; 52% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); mp 198-200 oC; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.38 (d, J = 8.5 Hz, 1H), 8.23 (d, J =
7.9 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.93 (d, J
= 7.9 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.42 (t,
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J = 7.9 Hz, 1H), 3.78 (s, 3H), 2.65 (s, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 163.2, 153.6,
152.4, 146.7, 145.8, 137.3, 136.2, 134.7, 130.2, 129.7, 128, 127.8, 127.6, 127, 124.5, 121.9, 121,
33.7, 17.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H16ON3 302.1288, found 302.1284.
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2-(tert-Butyl)-3,8-dimethylquinazolin-4(3H)-one (1h)
Following the Method B procedure, 1h was obtained as a beige solid (124
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9
o
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mg; 54% yield). Rf: 0.5 (1:6 EtOAc: Pet. ether); mp 56-58 C; H NMR (400
MHz, CDCl3) δ (ppm) 8.09 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.32
(t, J = 7.9 Hz, 1H), 3.76 (s, 3H), 2.60 (s, 3H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm)
164.4, 159.9, 145.1, 136.1, 134.3, 126, 123.9, 119.7, 39.6, 33.4, 29.6, 17; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C14H19ON2 231.1492, found 231.1491.
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3,8-Dimethylquinazolin-4(3H)-one (1i)
Following the Method A procedure, 1i was obtained as a colorless solid (139
o
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mg; 80% yield). Rf: 0.5 (1:2 EtOAc: Pet. ether); mp 81-84 C; H NMR (400
MHz, CDCl3) δ (ppm) 8.16 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H), 7.59 (d, J = 7.3 Hz,
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1H), 7.38 (t, J = 7.9 Hz, 1H), 3.59 (s, 3H), 2.61 (s, 3H); C NMR (100 MHz, CDCl3) δ (ppm)
161.9, 146.9, 145.5, 135.8, 134.8, 126.8, 124.2, 121.9, 34, 17.4; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C10H11ON2 175.0866, found 175.0865.
8-Methyl-3-propylquinazolin-4(3H)-one (1j)
Following the Method A procedure, 1j was obtained as a colorless solid
o
1
(136 mg; 67% yield). Rf: 0.4 (1:4 EtOAc: Pet. ether); mp 100-102 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 8.05 (s, 1H),
7.59 (d, J = 7.3 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 3.97 (t, J = 6.7 Hz, 2H), 2.61 (s, 3H), 1.89-1.80
13
(m, 2H), 1.00 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 161.4, 146.7, 145.4,
135.7, 134.7, 126.7, 124.4, 122.2, 48.5, 22.6, 17.4, 11.1; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C12H15ON2 203.1179, found 203.1176.
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3-Cyclohexyl-8-methylquinazolin-4(3H)-one (1k)
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Following the Method A procedure, 1k was obtained as a colorless solid
(109 mg; 45% yield). Rf: 0.5 (1:6 EtOAc: Pet. ether); mp 162-164 oC; 1H
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NMR (500 MHz, CDCl3) δ (ppm) 8.17 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H),
7.59 (d, J = 6.9 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 4.86-4.76 (m, 1H), 2.61 (s, 3H), 2.01 (d, J =
11.4 Hz, 2H), 1.94 (d, J = 13.3 Hz, 2H), 1.79 (d, J = 13.7 Hz, 1H), 1.69-1.58 (m, 2H), 1.58-1.46
(m, 2H), 1.32-1.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ (ppm) 161, 146.1, 142.7, 135.5,
134.7, 126.7, 124.6, 121.9, 53.2, 32.6, 25.9, 25.3, 17.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C15H19ON2 243.1492, found 243.1490.
3-Benzyl-8-methylquinazolin-4(3H)-one (1l)
Following the Method A procedure, 1l was obtained as a colorless solid
(163 mg; 65% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); mp 143-144 oC; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.19 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H),
7.61 (d, J = 7.3 Hz, 1H), 7.44-7.28 (m, 6H), 5.21 (s, 2H), 2.61 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 161.4, 146.6, 145.1, 135.9, 135.8, 134.9, 129, 128.3, 128, 126.9, 124.6, 122.2,
49.5, 17.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H15ON2 251.1179, found 251.1175.
8-Methyl-3-phenylquinazolin-4(3H)-one (1m)
Following the Method A procedure, 1m was obtained as a colorless solid
o
1
(85 mg; 36% yield). Rf: 0.4 (1:9 EtOAc: Pet. ether); mp 117-119 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.23 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H),
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7.66 (d, J = 7.3 Hz, 1H), 7.56 (t, J = 7.3 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.47-7.41 (m, 3H),
2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 161.1, 146.4, 144.8, 137.6, 136, 135.2, 129.6,
129, 127.2, 127, 124.9, 122.4, 17.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H13ON2
237.1022, found 237.1019.
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2-(tert-Butyl)-3-methylquinazolin-4(3H)-one (1n)
Following the Method B procedure, 1n was obtained as a colorless solid (119
mg; 55% yield). Rf: 0.5 (1:6 EtOAc: Pet. ether); mp 63-65 oC; H NMR (400
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MHz, CDCl3) δ (ppm) 8.25 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.64
13
(d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 3.76 (s, 3H), 1.55 (s, 9H); C NMR (100 MHz,
CDCl3) δ (ppm) 164, 161.3, 146.7, 133.8, 127.4, 126.4, 126.3, 119.8, 39.2, 33.6, 29.6; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C13H17ON2 217.1335, found 217.1335.
2-(tert-Butyl)-3,6-dimethylquinazolin-4(3H)-one (1o)
Following the Method B procedure, 1o was obtained as a colorless solid
o
1
(104 mg; 45% yield). Rf: 0.5 (1:9 EtOAc: Pet. ether); mp 104-106 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.04 (s, 1H), 7.53 (t, J = 9.2 Hz, 2H),
3.75 (s, 3H), 2.48 (s, 3H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 164.1, 160.4,
144.8, 136.5, 135.4, 127.3, 125.7, 119.6, 39.1, 33.6, 29.7, 21.3; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C14H19ON2 231.1492, found 231.1490.
2-(tert-Butyl)-6-methoxy-3-methylquinazolin-4(3H)-one (1q)
Following the Method B procedure, 1q was obtained as a thick oil (99
1
mg; 40% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); H NMR (400 MHz,
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CDCl3) δ (ppm) 7.61 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.4 Hz, 1H),
3.92 (s, 3H), 3.77 (s, 3H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 163.9, 159.1,
158.1, 141.5, 129.1, 124.4, 120.5, 105.4, 55.8, 39, 33.7, 29.7; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C14H19O2N2 247.1441, found 247.1439.
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2-(tert-Butyl)-6-iodo-3-methylquinazolin-4(3H)-one (1r)
Following the Method B procedure, 1r was obtained as a colorless solid
o
1
(120 mg; 35% yield). Rf: 0.5 (1:9 EtOAc: Pet. ether); mp 109-111 C; H
NMR (400 MHz, CDCl3) δ (ppm) 8.58 (d, J = 1.8 Hz, 1H), 7.95 (dd, J =
8.6, 1.8 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 3.74 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 162.6, 162.1, 146, 142.6, 135.2, 129.4, 121.5, 90.6, 39.4, 33.8, 29.6; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C13H16ON2I 343.0302, found 343.0299.
2-(tert-Butyl)-6-fluoro-3-methylquinazolin-4(3H)-one (1s)
Following the Method B procedure, 1s was obtained as a colorless solid
o
1
(112 mg; 48% yield). Rf: 0.5 (1:9 EtOAc: Pet. ether); mp 69-71 C; H
NMR (400 MHz, CDCl3) δ (ppm) 7.87 (dd, J = 8.6, 2.4 Hz, 1H), 7.65 (dd,
13
J = 9.2, 4.9 Hz, 1H), 7.42 (dt, J = 8.6, 2.4 Hz, 1H), 3.76 (s, 3H), 1.55 (s, 9H); C NMR (100
MHz, CDCl3) δ (ppm) 163.4 (d, J = 3.1 Hz), 160.7 (d, J = 247.4 Hz), 160.6 (d, J = 1.5 Hz),
143.4, 129.9 (d, J = 8.5 Hz), 122.5 (d, J = 23.9 Hz), 120.9 (d, J = 8.5 Hz), 110.9 (d, J = 23.9 Hz),
39.2, 33.7, 29.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H16ON2F 235.1241, found
235.1240.
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2-(tert-Butyl)-3-methyl-7-nitroquinazolin-4(3H)-one (1t)
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Following the Method B procedure, 1t was obtained as a pale yellow
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solid (86 mg; 33% yield). Rf: 0.5 (1:4 EtOAc: Pet. ether); mp 152-154
oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.49 (d, J = 1.8 Hz, 1H), 8.39
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(d, J = 8.6 Hz, 1H), 8.18 (dd, J = 8.6, 1.8 Hz, 1H), 3.79 (s, 3H), 1.57 (s, 9H); C NMR (100
MHz, CDCl3) δ (ppm) 163.9, 162.8, 151.4, 147.2, 128.3, 123.8, 123.2, 120, 39.6, 33.9, 29.5;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H16O3N3 262.1186, found 262.1185.
Experimental Procedures for Pd-Catalyzed C(sp3)-Acetoxylation:
General Procedure-1:
A glass tube with screw cap was charged with quinazolinone 1a-m (0.2 mmol), Pd(OAc)2 (0.02
mmol) and diacetoxy iodobenzene (PIDA) (0.3 mmol). To this mixture, AcOH (1 mL; 0.2M)
was added and the tube was flushed twice with argon gas. It was sealed with a Teflon screw cap
and placed in a preheated oil bath at 120 °C. The progress of the reaction was monitored by TLC.
The reaction mixture was cooled to RT after 8-24 h, diluted with ethyl acetate, and evaporated
under vacuo to dryness. The residue was purified by column chromatography to afford pure
quinazolinone 2a-m.
General Procedure-2:
A glass tube with screw cap was charged with quinazolinone 1n-t (0.2 mmol), Pd(OAc)2 (0.02
mmol), diacetoxy iodobenzene (PIDA) (0.22 mmol) and sodium carbonate (0.22 mmol). To this
mixture, AcOH (1 mL; 0.2M) was added and the tube was flushed twice with argon gas. It was
sealed with a teflon screw cap and placed in a preheated oil bath at 120 °C. The progress of the
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reaction was monitored by TLC. The reaction mixture was cooled to RT after 24 h, diluted with
ethyl acetate, and evaporated under vacuo to dryness. The residue was purified by column
chromatography to afford pure quinazolinone 2n-t.
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Experimental Procedure-3: (Catalytic PIDA)
A glass tube with screw cap was charged with quinazolinone 1i (35 mg; 0.2 mmol), Pd(OAc)2
(4.5 mg; 0.02 mmol), iodobenzene (5 µL; 0.04 mmol) and oxone (185 mg; 0.6 mmol). To this
mixture, AcOH (1 mL; 0.2M) was added and the tube was flushed twice with argon gas. It was
sealed with a teflon screw cap and placed in a preheated oil bath at 120 °C. The progress of the
reaction was monitored by TLC. The reaction mixture was cooled to RT after 12 h, diluted with
ethyl acetate, and evaporated under vacuo to dryness. The residue was purified by column
chromatography to afford pure quinazolinone 2i (35 mg; 76%).
(3-Methyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)methyl acetate (2a)
According to the general procedure-1, the title compound 2a was obtained
as a colorless solid (49 mg; 80% yield); reaction time: 24 h; Rf: 0.4 (1:4
o
1
EtOAc: Pet. ether); mp 137-139 C; H NMR (400 MHz, CDCl3) δ (ppm)
8.31 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.65-7.58 (m, 2H), 7.57-7.46 (m, 4H), 5.62 (s,
2H), 3.54 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.9, 162.9, 155.5, 145.2,
135.4, 133.2, 133, 130.1, 128.6, 128.4, 126.6, 126.5, 120.5, 62, 34.5, 21; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C18H17O3N2 309.1234, found 309.1230.
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(2-(4-Methoxyphenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2c)
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According to the general procedure-1, the title compound 2c was
obtained as a colorless solid (41 mg; 60% yield); reaction time: 24 h;
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Rf: 0.5 (1:3 EtOAc: Pet. ether); mp 117-119 oC; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.29 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.47
(d, J = 7.3 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 5.62 (s, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 2.14 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.9, 163.1, 161.1, 155.3, 145.3, 133, 130.2, 127.7,
126.5, 126.3, 120.3, 113.9, 62, 55.5, 34.7, 21.1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C19H19O4N2 339.1339, found 339.1335.
(3-Methyl-2-(4-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2d)
According to the general procedure-1, the title compound 2d was
obtained as a pale yellow solid (32 mg; 45% yield); reaction time: 24
o
1
h; Rf: 0.4 (1:3 EtOAc: Pet. ether); mp 201-203 C; H NMR (400
MHz, CDCl3) δ (ppm) 8.41 (d, J = 8.5 Hz, 2H), 8.32 (d, J = 7.9 Hz, 1H), 7.88-7.77 (m, 3H), 7.55
(t, J = 7.9 Hz, 1H), 5.58 (s, 2H), 3.53 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
170.8, 162.4, 153.3, 148.6, 144.8, 141, 133.4, 129.7, 127.4, 126.6, 124, 120.6, 61.7, 34.3, 21;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H16O5N3 354.1084, found 354.1077.
(2-(2-Fluorophenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2e)
According to the general procedure-1, the title compound 2e was obtained
as a colorless solid (44 mg; 68% yield); reaction time: 24 h; Rf: 0.4 (1:3
EtOAc: Pet. ether); mp 89-91 oC; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.32
(d, J = 8 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.60-7.49 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.23 (t, J
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= 8.8 Hz, 1H), 5.60 (s, 2H), 3.50 (d, J = 1.5 Hz, 3H), 2.14 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ (ppm) 170.9, 162.3, 159.3 (d, J = 248.9 Hz), 151.4, 145.2, 133.3, 133, 132.2 (d, J = 8.6 Hz),
130.7 (d, J = 1.9 Hz), 126.9, 126.6, 124.9 (d, J = 2.9 Hz), 123.7 (d, J = 15.3 Hz), 120.8, 115.9 (d,
J = 21 Hz), 61.9, 32.9, (d, J = 3.8 Hz), 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C18H16O3N2F 327.1139, found 327.1135.
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(3-Methyl-4-oxo-2-(pyridin-2-yl)-3,4-dihydroquinazolin-8-yl)methyl acetate (2f)
According to the general procedure-1, the title compound 2f was obtained
as a colorless solid (50 mg; 80% yield); reaction time: 12 h; Rf: 0.4 (1:2
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EtOAc: Pet. ether); mp 164-166 C; H NMR (400 MHz, CDCl3) δ (ppm)
8.72 (d, J = 4.3 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 3.7 Hz, 2H), 7.81 (d, J = 7.3 Hz,
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1H), 7.52 (t, J = 7.3 Hz, 1H), 7.46 (m, 1H), 5.63 (s, 2H), 3.68 (s, 3H), 2.14 (s, 3H); C NMR
(100 MHz, CDCl3) δ (ppm) 170.9, 162.7, 153.8, 153.2, 148.4, 145, 137.3, 133.2, 133.1, 126.9,
126.7, 125.1, 124.7, 121, 61.9, 33.7, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H16O3N3
310.1186, found 310.1181.
(3-Methyl-4-oxo-2-(quinolin-2-yl)-3,4-dihydroquinazolin-8-yl)methyl acetate (2g)
According to the general procedure-1, the title compound 2g was
obtained as a colorless solid (65 mg; 91% yield); reaction time: 12 h; Rf:
0.5 (1:3 EtOAc: Pet. ether); mp 175-177 oC; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.41-8.32 (m, 2H), 8.15 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.6 Hz,
1H), 7.94 (d, J = 7.9 Hz, 1H), 7.86-7.77 (m, 2H), 7.67 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.3 Hz,
1H), 5.65 (s, 2H), 3.81 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.9, 162.8,
153.2, 146.6, 144.9, 137.3, 133.2, 133.1, 130.3, 129.7, 128, 127.97, 127.7, 127, 126.8, 121.9,
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121, 61.9, 33.8, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H18O3N3 360.1343, found
360.1338.
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(3-Methyl-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2i)
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According to the general procedure-1, the title compound 2i was obtained as a
colorless solid (39 mg; 85% yield); reaction time: 12 h; Rf: 0.4 (1:2 EtOAc: Pet.
ether); mp 128-130 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (d, J = 7.9 Hz,
1H), 8.08 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 5.58 (s, 2H), 3.60 (s, 3H),
2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.8, 161.5, 146.4, 146.37, 133.8, 133,
126.9, 126.7, 122.1, 61.9, 34.1, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H13O3N2
233.0921, found 233.0918.
(4-Oxo-3-propyl-3,4-dihydroquinazolin-8-yl)methyl acetate (2j)
According to the general procedure-1, the title compound 2j was obtained
as a colorless solid (43 mg; 82% yield); reaction time: 18 h; Rf: 0.3 (1:4
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EtOAc: Pet. ether); mp 97-100 C; H NMR (400 MHz, CDCl3) δ (ppm)
8.29 (d, J = 7.9 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 5.58 (s,
2H), 3.97 (t, J = 7.3 Hz, 2H), 2.13 (s, 3H), 1.89-1.77 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 170.8, 160.9, 146.3, 146.2, 133.8, 132.9, 126.8, 122.2, 61.9, 48.5,
22.6, 21, 11.1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H17O3N2 261.1234, found 261.1231.
(3-Cyclohexyl-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2k)
According to the general procedure-1, the title compound 2k was
obtained as a colorless solid (51 mg; 85% yield); reaction time: 11 h; Rf:
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0.4 (1:6 EtOAc: Pet. ether); mp 115-117 C; H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (d, J =
7.9 Hz, 1H), 8.18 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 5.58 (s, 2H), 4.81 (t,
J = 11 Hz, 1H), 2.14 (s, 3H), 2.05-1.89 (m, 4H), 1.80 (d, J = 12.8 Hz, 1H), 1.70-1.45 (m, 4H),
1.35-1.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.9, 160.6, 145.6, 143.7, 133.9,
132.7, 127.2, 126.7, 122, 61.9, 53.4, 32.6, 25.9, 25.2, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C17H21O3N2 301.1547, found 301.1543.
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(3-Benzyl-4-oxo-3,4-dihydroquinazolin-8-yl)methyl acetate (2l)
According to the general procedure-1, the title compound 2l was
obtained as a colorless solid (55 mg; 89% yield); reaction time: 8 h; Rf:
0.4 (1:4 EtOAc: Pet. ether); mp 124-126 oC; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.32 (d, J = 7.9 Hz, 1H), 8.15 (s, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H),
7.41-7.29 (m, 5H), 5.58 (s, 2H), 5.21 (s, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
170.8, 161, 146.1, 146, 135.6, 134, 133.1, 129, 128.4, 128.1, 127, 122.3, 61.8, 49.6, 21; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C18H17O3N2 309.1234, found 309.1230.
(4-Oxo-3-phenyl-3,4-dihydroquinazolin-8-yl)methyl acetate (2m)
According to the general procedure-1, the title compound 2m was
obtained as a colorless solid (56 mg; 95% yield); reaction time: 12 h; Rf:
0.3 (1:6 EtOAc: Pet. ether); mp 141-143 oC; 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.36 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.61-7.47 (m, 4H), 7.45-
7.39 (m, 2H), 5.63 (s, 2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 170.8, 160.6, 146,
145.7, 137.4, 134.3, 133.2, 129.6, 129.1, 127.3, 126.9, 122.5, 61.9, 21; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C17H15O3N2 295.1077, found 295.1074.
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2-Methyl-2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl acetate (2n)
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According to the general procedure-2, the title compound 2n was
obtained as a beige solid (47 mg; 85% yield); reaction time: 24 h; Rf: 0.5
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(1:3 EtOAc: Pet. ether); mp 75-77 C; H NMR (400 MHz, CDCl3) δ
(ppm) 8.25 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.9
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Hz, 1H), 4.52 (s, 2H), 3.75 (s, 3H), 2.06 (s, 3H), 1.56 (s, 6H); C NMR (100 MHz, CDCl3) δ
(ppm) 171.1, 163.8, 158.2, 146.4, 134, 127.5, 126.8, 126.4, 119.9, 72.1, 42.4, 33, 23.6, 21;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H19O3N2 275.1390, found 275.1385.
2-Methyl-2-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propane-1,3-diyl diacetate (2na)
According to the general procedure-2 with PIDA (3 equiv or 5 equiv)
and Na2CO3 (3 equiv or 5 equiv), the title compound 2na was obtained
as a beige solid (37 mg; 55% yield or 49 mg; 73% yield respectively);
with 5 equiv of PIDA without base (30 mg; 45% yield), reaction time: 24 h; Rf: 0.3 (1:3 EtOAc:
Pet. ether); mp 114-116 C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.26 (d, J = 7.9 Hz, 1H), 7.73
o
(t, J = 7.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 4.67 (d, J = 11.6 Hz, 2H),
4.57 (d, J = 11.6 Hz, 2H), 3.75 (s, 3H), 2.03 (s, 6H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 170.7, 163.5, 155, 146.1, 134.1, 127.6, 127.1, 126.5, 120, 66.4, 46, 32.1, 20.8, 18.7;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H21O5N2 333.1445, found 333.1440.
2-(3,6-Dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl acetate (2o)
According to the general procedure-2, the title compound 2o was
obtained as a colorless solid (46 mg; 80% yield); reaction time: 24 h;
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Rf: 0.3 (1:6 EtOAc: Pet. ether); mp 100-102 C; H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (s,
1H), 7.52 (apparent s, 2H), 4.51 (s, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 2.05 (s, 3H), 1.55 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 171.1, 163.8, 157.3, 144.5, 136.9, 135.5, 127.3, 125.7, 119.7,
72.1, 42.3, 32.9, 23.7, 21.3, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H21O3N2 289.1547,
found 289.1545.
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2-(3,8-Dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl acetate (2p)
According to the general procedure-2, the title compound 2p was
obtained as a beige solid (26 mg; 45% yield); reaction time: 24 h; Rf: 0.5
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(1:4 EtOAc: Pet. ether); mp 81-82 C; H NMR (400 MHz, CDCl3) δ
(ppm) 8.10 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 4.54 (s, 2H),
3.75 (s, 3H), 2.56 (s, 3H), 2.07 (s, 3H), 1.57 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
171.1, 164.2, 156.9, 144.9, 136.1, 134.5, 126.4, 124.1, 119.9, 72.2, 42.7, 32.9, 23.7, 21.3, 21;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H21O3N2 289.1547, found 289.1541.
2-(6-Methoxy-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl acetate (2q)
According to the general procedure-2, the title compound 2q was
obtained as a colorless solid (46 mg; 75% yield); reaction time: 24
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h; Rf: 0.3 (1:4 EtOAc: Pet. ether); mp 118-120 C; H NMR (400
MHz, CDCl3) δ (ppm) 7.60 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 9 Hz, 1H), 7.30 (dd, J = 9, 2.4 Hz,
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1H), 4.50 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 2.05 (s, 3H), 1.54 (s, 6H); C NMR (100 MHz,
CDCl3) δ (ppm) 171.1, 163.7, 158.4, 155.9, 141.2, 129.1, 124.5, 120.6, 105.5, 72.1, 55.8, 42.2,
33, 23.7, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H21O4N2 305.1496, found 305.1493.
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2-(6-Iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl acetate (2r)
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According to the general procedure-2, the title compound 2r was
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Rf: 0.3 (1:6 EtOAc: Pet. ether); mp 131-133 C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.58 (s, 1H), 7.96 (dd, J = 8.5, 1.8 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 4.49 (s,
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2H), 3.74 (s, 3H), 2.05 (s, 3H), 1.55 (s, 6H); C NMR (100 MHz, CDCl3) δ (ppm) 171, 162.4,
159, 145.7, 142.8, 135.2, 129.4, 121.6, 91, 71.9, 42.6, 33.1, 23.6, 21; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C15H18O3N2I 401.0357, found 401.0363.
2-(6-Fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl acetate (2s)
According to the general procedure-2, the title compound 2s was
obtained as a colorless solid (37 mg; 64% yield); reaction time: 24 h;
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Rf: 0.3 (1:6 EtOAc: Pet. ether); mp 106-108 C; H NMR (400 MHz,
CDCl3) δ (ppm) 7.87 (dd, J = 7.9, 2.4 Hz, 1H), 7.63 (dd, J = 9.2, 4.9 Hz, 1H), 7.43 (dt, J = 8.5,
2.4 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 2.06 (s, 3H), 1.55 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 171, 163.1 (d, J = 3.1 Hz), 160.9 (d, J = 247.4 Hz), 157.5 (d, J = 1.5 Hz), 143.1, 130 (d, J
= 8.5 Hz), 122.7 (d, J = 23.9 Hz), 121.1 (d, J = 9.3 Hz), 111.1 (d, J = 23.1 Hz), 72, 42.4, 33.1,
23.7, 21; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H18O3N2F 293.1296, found 293.1293.
2-Methyl-2-(3-methyl-7-nitro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl acetate (2t)
According to the general procedure-2, the title compound 2t was
obtained as a colorless solid (45 mg; 70% yield); reaction time: 24 h;
Rf: 0.3 (1:4 EtOAc: Pet. ether); mp 117-119 oC; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.47 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.20 (dd, J = 8.6, 1.8 Hz, 1H),
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4.52 (s, 2H), 3.78 (s, 3H), 2.06 (s, 3H), 1.58 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
170.9, 162.6, 160.9, 151.5, 146.8, 128.4, 123.9, 123.2, 120.4, 71.6, 42.9, 33.4, 23.8, 20.9; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C15H18O5N3 320.1241, found 320.1239.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Spectroscopic data (1H, 13C and HRMS spectra) of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
D.N.G. thanks UGC-New Delhi for research fellowship, and S.B.M. gratefully acknowledges
generous financial support from DST-SERB, New Delhi.
REFERENCES
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(c) Kshirsagar, U. A. Org. Biomol. Chem. 2015, 13, 9336. (d) Kahn, I.; Ibrar, A.; Ahmed, W.;
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M. Org. Lett. 2014, 16, 4790. (c) Li, Q.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Adv.
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