Sequential Oxidative Fragmentation and Skeletal Rearrangement of Peroxides for the Synthesis of Quinazolinone Derivatives

Article abstract of DOI:10.1021/acs.joc.1c00889

For the first time, the sequential reaction of peroxyoxindole that involves base-promoted oxidative fragmentation to isocyanate formation and primary amine or amino alcohol accelerated skeletal rearrangement to synthesize exo-olefinic-substituted quinazolinone or oxazoloquinazolinone is reported. The advantages of this new reaction include a broad substrate scope and transition-metal-free and room-temperature conditions. The formation of the isocyanate as a key intermediate that accelerates oxidative skeletal rearrangement has been confirmed by trapping experiments and spectroscopic evidence.

Full text of DOI:10.1021/acs.joc.1c00889

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Article
Sequential Oxidative Fragmentation and Skeletal Rearrangement of
Peroxides for the Synthesis of Quinazolinone Derivatives
Akash S. Ubale, Moseen A. Shaikh, and Boopathy Gnanaprakasam*
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ABSTRACT: For the first time, the sequential reaction of peroxyoxindole that involves base-promoted oxidative fragmentation to
isocyanate formation and primary amine or amino alcohol accelerated skeletal rearrangement to synthesize exo-olefinic-substituted
quinazolinone or oxazoloquinazolinone is reported. The advantages of this new reaction include a broad substrate scope and
transition-metal-free and room-temperature conditions. The formation of the isocyanate as a key intermediate that accelerates
oxidative skeletal rearrangement has been confirmed by trapping experiments and spectroscopic evidence.
other research groups by using different heterocyclic perox-
ides.7e−g
INTRODUCTION
■
Heterocycles are the most essential and important chemical
entity in pharmaceuticals and agricultural applications.1 A large
number of alkaloids contain diverse heterocycles in the scaffold.
Peroxide-functionalized heterocycles emerge as a vital inter-
mediate in diverse oxidative transformations.2 Moreover, the
incorporation of peroxide functionality on the oxindole or
substituted-2-oxindole derivatives makes them fascinating
precursors for structurally distinct rearrangement reactions.3
In general, peroxides are known to perform Baeyer−Villiger
oxidation,4 and the Hock process5 to produce phenol from
cumene hydroperoxide involving the migration of an aryl/alkyl
group to an electron-deficient oxygen atom has been broadly
studied under an acid source. Synthetically, the Kornblum−
DeLaMare rearrangement6 is an important rearrangement in
organic peroxide for the production of ketones and alcohols
under basic conditions (Scheme 1A).6 On the basis of these
rearrangements, the skeletal rearrangement of the peroxides to
access biologically important intermediates is an attractive
paradigm in organic synthesis. Recently, pioneering work on
direct C−H peroxidation of 2-oxindole by a Cu catalyst and
subsequent base-mediated fragmentation has been reported by
Stoltz and co-workers (Scheme 1B).7a Subsequently, our group
reported the rearrangement of C3-substituted 2-oxindole
peroxide using a Lewis acid as well as a Brønsted acid (Scheme
1C).7b−d A few other rearrangements have also been reported by
Nitrogen-containing heterocyclic compounds such as C4-
substituted quinazolinone8 and quinazolinediones9 exhibit a
wide range of biological properties such as Na+/Ca2+ exchange
inhibitor,10 anti-inflammatory,11 anticancer,12 antimalarial,13
antidiabetic,14 and antihypertensive15 activities (Figure 1).
Hence, it has a central role in drug development, medicinal
chemistry, and corresponding drug-target relationships super-
intended for specific biological activity and drug action. In the
literature, few pioneering methods have been reported for the
synthesis of 4-methylene-3,4-dihydroquinazolin-2-ones.16a,b
Gimeno et al. reported the Au(I)-complex-catalyzed synthesis
of 4-methylene-3,4-dihydroquinazolin-2-ones from 1-(o-alkyny-
laryl) urea.16c−e Afterward, Barba and co-workers described the
synthesis of 3-substituted 2-quinazolinones from the reaction of
2-aminoacetophenone and an electrogenerated cyanomethyl
anion from acetonitrile reduction at a graphite electrode.16f
Recently, to overcome the use of expensive catalysts or ligands,
Received: April 17, 2021
Published: July 7, 2021
https://doi.org/10.1021/acs.joc.1c00889
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 9621−9636
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Scheme 1. State of the Art in a Rearrangement of Peroxide
Figure 1. Pharmacologically active quinazolinone framework.
Ma and co-workers reported a variant protocol for the synthesis
of 4-alkenylquinazolinons and 4-alkenylquinazolinthione by
using catalytic amounts of NaOH under reflux.17 Although there
are pros and cons of the reported method for the quinazolinone
derivatives, designing an attractive and newer approach for these
heterocycles is an evergrowing paradigm in chemical synthesis.
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From the literature, it is evident that no peroxide rearrangement
has been used for the construction of the quinazolinone
derivatives. As a part of our research on the rearrangement of
peroxides toward the synthesis of heterocycles (Scheme
1C),7b−d herein we report the transition-metal-free oxidative
fragmentation of peroxyoxindole derivatives to synthesize
bioactive quinazolinone derivatives in the presence of various
amine nucleophiles. The present work includes the following
features: (i) first report on quinazolinone using a peroxide via
oxidative fragmentation and skeletal rearrangement; (ii)
transition-metal-free and room-temperature reaction condi-
tions; and (iii) efficient, broad substrate scope and high yield.
our survey of bases, KOH is found to be the best base for this
transformation. Furthermore, by decreasing the KOH quantity,
a decrease in yield was observed (Table 1, entries 10 and 11).
Next, varieties of solvents were tested to enhance the product
yield of 3a, but no improvement was detected (Table 1, entries
12−17). In the case of water, there was no detection of desired
product 3a. From this experimental study, THF is established to
be the best solvent for this conversion to provide 3a in 87% yield
after 3 h (Table 1, entry 7). Product 3a was characterized by
spectroscopic techniques and single-crystal XRD (Figure 2).
Next, we started our studies to generalize the substrate scope
for quinazolinone derivatives. Initially, electron-rich benzyl
amines such as 2-Me, 4-Me, 4-OMe, 3,4-OMe, 2,3,4-OMe, and
4-Ph afforded a 64−90% yield of products 3b−3g (Scheme 2).
Afterward, in the presence of an electron-withdrawing
substituent such as 4-F, 3-Br, or 4-CF3 on benzyl amines,
moderate to good yields of corresponding products 3h−3j were
provided (Scheme 2). Gratifyingly, heteroaryl amines were well
tolerated under optimized experimental conditions. 2-Picolyl-
amine, tryptamine, and furfuryl amine were successfully
converted to 3k, 3l, and 3m in 58, 61, and 67% yields,
respectively. Furthermore, the scope of the reaction was
analyzed with primary aliphatic amines. When cyclopropyl,
methyl, ethyl, hexyl, and octyl amines were used under standard
optimized conditions, products 3n−3r were isolated in
moderate to good yields (Scheme 2). Additionally, propargyl-
amine and allylamine provided corresponding products 3s and
3t in 65 and 61% yields, respectively. Notably, 3-methoxy-
phenethylamine provided quinazolinone product 3u in 65%
yield. Similarly, the reaction of 3-butyl-3-(tert-butylperoxy)-
indolin-2-one 1c with 2a afforded product 3v as an exclusive E
isomer in 21% yield. Furthermore, the reaction of peroxide 1d
with 4-methoxybenzylamine 2d afforded 3w as an E/Z mixture
in 50% yield. A reaction of peroxide 1b with 2d led to product 3x
in 63% yield. Furthermore, this reaction with primaquine
bisphosphate amine afforded the respective product 3y in 45%
yield. However, the reaction of 1a with aniline, 4-methoxy
aniline, or tryptophan led to a complicated reaction mixture that
could not be separated by column chromatography. Remark-
ably, the reaction of 1a′ with amines preceded instinctively to
give the desired derivatives of the 4-methylene-3-substituted
quinazolinone in 58−85% yields (Scheme 3). To our delight, a
gram-scale reaction was also successfully performed with 1a (1.0
g, 4.25 mmol) and 2a under optimized conditions to afford a
65% yield of product 3a.
RESULTS AND DISCUSSION
■
To establish a base-mediated oxidative fragment and skeletal
rearrangement to 4-methylene-3-substituted quinazolinone,
initial optimization was performed with peroxides 1a and 2a.
Control experiments 1a and 2a in the absence of base at room
temperature or 60 °C in THF solvent did not produce the
desired product 3a (Table 1, entries 1 and 2). Hence, base has a
a
Table 1. Optimization of Reaction Conditions
entry
1
2
base
solvent
yield (%) of 3a
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
EtOH
t-BuOH
H2O
no reaction
no reaction
25
no reaction
74
77
87
75
82
27
55
67
78
55
b
3
4
5
6
7
8
9
Na2CO3
K2CO3
Cs2CO3
NaOH
KOH
t-BuOK
t-BuOLi
KOH
KOH
KOH
KOH
KOH
c
10
11
d
12
13
14
15
16
17
KOH
KOH
KOH
no reaction
76
80
EtOAc
ACN
In contrast to primary amines, the reaction of peroxyoxindole
with secondary amine-based nucleophiles generates a variety of
urea derivatives (Scheme 4). Thus, the reaction of 1a and
secondary amine having different substitutions such as −N-
(Me)2, −N(iPr)2, and −N(iBu)2 under the above standard
reaction condition by using KOH (1 equiv) for 2 h afforded urea
derivatives 6a−6c in moderate to good yields (Scheme 4).
Moreover, pyrrolidine and morpholine afforded 80 and 71%
yields of products 6d and 6e, respectively.
Next, we have extended this concept to the molecular
reconstruction of the peroxyoxindole by using amino alcohols.
For instance, the reaction of peroxyoxindole 1a with 1.5 equiv of
KOH and ethanolamine 8a at room temperature afforded
tricyclic compound 9a in 81% isolated yield. To outspread the
substrate scope, this reaction was performed with other amino
alcohols to afford products 9b−9g in moderate to good yields
(Scheme 5).
a
Reaction conditions: base (0.35 mmol), compound 1a (0.35 mmol),
compound 2a (0.42 mmol), and solvent (2 mL) were stirred at room
b
c
d
temperature for 3 h. At 60 °C. 0.2 equiv of base used. 0.5 equiv of
base used. The mentioned yields are isolated yields.
decisive role in the oxidative fragmentation of the peroxide.
When this reaction was performed in the presence of Na2CO3,
product 3a was obtained in 25% yield (Table 1, entry 3). Next,
K2CO3 failed to give 3a (Table 1, entry 4). Interestingly, the
reaction works well in the presence of Cs2CO3 and provided
product 3a in 74% yield. Furthermore, we screened a variety of
bases for this reaction. Notably, the addition of NaOH results in
a slight improvement in the yield of product 3a to 77% yield
(Table 1, entry 6). An excellent yield was obtained for 3a in the
case of KOH as a base (Table 1, entry 7). Other bases such as
KOtBu and LiOtBu are also efficient to form the product 3a in
75 and 82% yields, respectively (Table 1, entries 8 and 9). From
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Figure 2. ORTEP crystal structure of 3a showing thermal ellipsoids at the 50% probability level.
Likewise, the formation of other tricyclic compounds from
peroxyoxindole derivatives also progressed well in the presence
of chiral amino alcohols to afford as a diastereomeric mixture
[9h (de = 97%):9h′ (de = 90%, dr = 3.4:1), [9i (de = 94%):9i′
(de = 95%, dr = 2.4:1), and [(9j (de 94%):9j′ (de = 84%, dr =
1.3:1] in good yields. The stereochemistry and structure of
compound 9h was confirmed using single-crystal XRD (Figure
3). Moreover, the stereochemistry of all of the other tricyclic
compounds (9h, 9h′, 9i, 9i′, and 9j, 9j′) was comparatively
dispensed on the basis of the crystal structure of 9h.
To understand the reaction pathway for the formation of 4-
methylene-3-substituted quinazolinone, we have performed
several experiments using peroxyoxindole (Scheme 6). The
reaction of N-methylated peroxyoxindole 1aa has been proven
to be chemically inactive under optimized reaction conditions
(Scheme 6,(i)). This experiment suggests that the abstraction of
proton from oxindole nitrogen was a crucial step for this
transformation. To identify the intermediate in this reaction, a
trapping experiment was performed with other nucleophiles.
Hence, we reacted peroxyoxindole 1a with alcohol 2aa, which
gave carbamate 6g in 53% yield (Scheme 6,(ii)). This reaction
confirmed the generation of isocyanate intermediate B, and this
in-situ-generated isocyanate intermediate was trapped by
alcohol 2aa. From this experimental observation, we hypothe-
sized that after deprotonation at oxindole nitrogen, an
isocyanate intermediate was formed. Furthermore, in the
absence of an external nucleophile, peroxyoxindole 1a under-
goes intramolecular cyclization to afford 4-hydroxyquinolinone
7a (Scheme 6,(iii)).7a
On the basis of experimental observations and literature
precedents,7a we have proposed the two possible pathways
shown in Scheme 7. In pathway (a), we envision the complete
elimination of t-BuOOH from peroxyoxindole 1a that would
lead to N-alkylated product 4a via intermediate A (Scheme 7,
pathway a). But pathway (a) failed to deliver product 4a.
However, in pathway (b), peroxyoxindole 1a is followed by
Kornblum−DeLaMare rearrangement,6 similar to 4-oxa-Grob
fragmentation,18 and Stoltz’s group reported oxidative fragmen-
tation.7a Pathway (b) allowed the fragmentation of the C2−C3
bond and elimination of tert-butyl alcohol to the simultaneous
formation of ketone, and isocyanate is an intermediate (B)
generated in situ (Scheme 7, pathway (b)). The B intermediate
was highly unstable even in the absence of amine and was not
able to be isolated from the reaction, which immediately gave
cyclized product 3a. To confirm the isocyanate as the
intermediate, we have performed the reaction of 2-amino
acetophenone and benzylisocyanate in the presence or absence
of KOH, resulting in product 3a (Scheme 6, entry (vi)).
Furthermore, this intermediate (B) was also confirmed by a
trapping experiment with different secondary amine/oxygen-
based nucleophiles (Schemes 4 and 6, entry (ii)). The
isocyanate formation in the reaction was also confirmed by the
in situ analysis of IR and HRMS (SI Figures S3 and S1). In the
case of product 9, intermediate B undergoes a reaction with a
primary amine/amino alcohol to obtain urea derivative C/C′.
Furthermore, intermediate C containing a nitrogen atom is
highly unstable (not able to isolate from the reaction mixture),
undergoing a rapid intramolecular reaction with ketone to form
the D/D′ hemiaminol intermediate. Interestingly, intermediate
C′ was isolated from the reaction of peroxide 1a and 3-amino-1-
propanol and performed the cyclization in the presence of KOH
to give product 9a (Scheme 6, entry (v)). Finally, the
dehydration of D afforded product 3a. Afterward, iminium
cation E formed upon dehydration of D′ to facilitate another
intramolecular addition reaction (i.e., oxygen attack over the
iminium cation to generate 9a (Scheme 7).
Next, the application of a 4-methylene-3-substituted
quinazolinone derivative has been investigated for the synthesis
of 3-substituted quinazoline-2,4-diones by an oxidation reaction.
This oxidation has been performed using 3a and 3p with CuCl2
and TBHP.19 After the reaction was complete, corresponding
products 10a and 10b were isolated in 78 and 69% yields
(Scheme 8). Moreover, the synthesized quinazoline-2,4-diones
can be employed as valuable precursors in the synthesis of
various bioactive molecules.9
CONCLUSIONS
■
We have developed a novel transition-metal-free sequential
oxidative fragmentation and rearrangement of peroxyoxindole
for the synthesis of 4-methylene-3-substituted quinazolinone
derivatives in the presence of a varieties of amine and hydroxyl
nucleophiles. This reaction was easily achieved by inexpensive
benchtop KOH base under ambient condition and synthesized a
large number of quinazolinone derivatives in good to excellent
yields. A plausible mechanism has been proposed on the basis of
the experimental results, and previous literature studies involved
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a
Scheme 2. Substrate Scope for Quinazolinone Derivatives
a
Reaction conditions: KOH (19 mg, 0.35 mmol, 1 equiv), peroxy compound 1 (0.35 mmol, 1 equiv), and amines 2 (0.42 mmol, 1.2 equiv) in THF
b
(2 mL) were stirred at room temperature for 3 h. 2 equiv of base was used. The mentioned yields are isolated yields. For product 3v, 3-butyl-3-
(tert-butylperoxy)indolin-2-one has been used. For product 3w, 3-benzyl-3-(tert-butylperoxy)indolin-2-one has been used. For 3x, 3-phenyl-3-(tert-
butylperoxy)indolin-2-one has been used.
the fragmentation of peroxyoxindole via deprotanation to form
isocyanate as the key step in the formation of quinazolinone
derivatives.
EXPERIMENTAL SECTION
■
General Information and Data Collection. The amines, 2-
oxindole, amino alcohols, KOH, cupric chloride, and tert-butyl
hydroperoxide (TBHP) 5.0−6.0 M in decane solution were purchased
from Sigma-Aldrich. All of the solvents used in the reactions were dry
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a
Scheme 3. Substrate Scope for Quinazolinone Derivatives
a
Reaction conditions: KOH (19 mg, 0.35 mmol, 1 equiv), peroxy compound 1a′ (0.35 mmol, 1 equiv), and amine 2a (0.42 mmol, 1.2 equiv) in
THF (2 mL) were stirred at room temperature for 3 h. The mentioned yields are isolated yields.
a
Scheme 4. Synthesis of Urea Derivatives
a
Reaction conditions: KOH (0.35 mmol), compound 1 (0.35 mmol), compound 5 (0.42 mmol), and THF (2 mL) were stirred at room
temperature for 2 h. The mentioned yields are isolated yields.
grade. The column chromatographic separation separations were
achieved over 100−200 mesh size silica gel. Visualization completed
with UV light, PMA, and CAM staining go along with the heating
method. By using a Bruker or JEOL spectrometer, the 1H and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively. The following
information was used in NMR follow-up experiments: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; b, broad; ddd, doublet of
doublets of doublets. High-resolution mass spectra were recorded via a
Waters Synapt G2 applying electrospray ionization (ESI). Infrared
(ATR) spectra were obtained with a Bruker Alpha-E infrared
spectrometer. HPLC analysis was performed using an Agilent 1200
infinity series HPLC system with a diode array detector. Diastereomeric
excess values were determined by HPLC analysis on a Chiralpak IA (4.6
mm × 250 mm) column in comparison with authentic racemic material
using n-heptane and isopropanol as eluents. Data were analyzed using
Agilent OpenLAB software. The melting point was measured using the
BUCHI M-560 melting-point instrument. All melting points were
measured in an open glass capillary tube. Single-crystal diffraction
analysis data were collected at 100 K with a Bruker Kappa Apex III CCD
Duo diffractometer (operated at 1500 W power: 50 kV, 30 mA) using
graphite monochromatic Mo Kα radiation and Cu Kα radiation. More
information on crystal structures can also be obtained from the
Cambridge Crystallographic Data Centre (CCDC) via deposition
numbers 2053446 (3a) and 2053447 (9h).
were added to THF (2 mL). Then the tube was sealed with a rubber
septum, and the reaction mixture was kept at room temperature with
stirring for 3 h. After the completion of the reaction, water was added,
and the resulting mixture was extracted with ethyl acetate two times
using 10 mL of solvent each time. The organic layers were combined
and dried over Na2SO4. After removing the solvent under reduced
pressure, the residue was purified by using column chromatography
(EtOAc:n-hexane = 30:70 to 70:30).
(B) Experimental Procedure for the Gram-Scale Synthesis of 3a. In
a 20 mL resealable vial, KOH (238 mg, 4.25 mmol, 1 equiv), compound
1a (1000 mg, 4.25 mmol, 1 equiv), and benzyl amine 2a (546 mg, 5.1
mmol, 1.2 equiv) were added to THF (10 mL). Then the tube was
sealed with a rubber septum, and the reaction mixture was kept at room
temperature with stirring for 3 h. After the completion of the reaction,
water was added, and the resulting mixture was extracted with ethyl
acetate two times using 20 mL of solvent each time. The organic layers
were combined and dried over Na2SO4. After removing the solvent
under reduced pressure, the residue was purified by using column
chromatography (EtOAc:n-hexane = 30:70) to afford 3-benzyl-4-
methylene-3,4-dihydroquinazolin-2(1H)-one 3a (694 mg, 65%) as a
white solid.
(C) General Experimental Procedure for the Synthesis of Urea
Derivatives. In a 20 mL resealable vial, KOH (19 mg, 0.35 mmol, 1
equiv), compound 1a (0.35 mmol, 1 equiv), and amine 5a (0.42 mmol,
1.2 equiv) were added to THF (2 mL). Then the tube was sealed with a
rubber septum, and the reaction mixture was kept at room temperature
with stirring for 2 h. After the completion of the reaction, water was
added, and the resulting mixture was extracted with ethyl acetate two
(A) General Experimental Procedure for the Synthesis 4-
Methylene-3-Substituted Quinazolinone Derivatives (3). In a 20
mL resealable vial, KOH (19 mg, 0.35 mmol, 1 equiv), peroxy
compound (0.35 mmol, 1 equiv), and amine (0.42 mmol, 1.2 equiv)
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a
Scheme 5. Synthesis of a Polyheterocycle Scaffold
a
Reaction conditions: KOH (1.5 eq, 0.525 mmol), compound 1 (0.35 mmol), compound 8 (1.2 eq 0.42 mmol), and solvent (2 mL) were stirred at
room temperature for 3 h. The mentioned yields are isolated yields.
Figure 3. ORTEP crystal structure of 9h showing thermal ellipsoids at the 50% probability level.
times using 10 mL of solvent each time. The organic layers were
combined and dried over Na2SO4. After removing the solvent under
reduced pressure, the residue was purified by using column
chromatography (EtOAc:n-hexane = 20:80 to 50:50).
(D) Experimental Procedure for the Synthesis Carbamates (6g). In
a 20 mL resealable vial, KOH (19 mg, 0.35 mmol, 1 equiv), compound
1a (82 mg, 0.35 mmol, 1 equiv), and 2-methoxybenzyl alcohol 2aa (58
mg, 0.42 mmol, 1.2 equiv) were added to THF (2 mL). Then the tube
was sealed with a rubber septum, and the reaction mixture was kept at
room temperature with stirring for 3 h. After the completion of the
reaction, water was added, and the resulting mixture was extracted with
ethyl acetate two times using 10 mL of solvent each time. The organic
layers were combined and dried over Na2SO4. After removing the
solvent under reduced pressure, the residue was purified by using
column chromatography (EtOAc:n-hexane = 10:90).
(E) Experimental Procedure for the Synthesis of 1-(2-Acetylphen-
yl)-3-(3-hydroxypropyl)urea (6i). In a 20 mL resealable vial, KOH
(29.5 mg, 0.52 mmol, 1.5 equiv), peroxy compound 1a (0.35 mmol, 1
equiv), and 3-aminopropan-1-ol (0.42 mmol, 1.2 equiv) were added to
THF (2 mL). Then the tube was sealed with a rubber septum, and the
reaction mixture was kept at room temperature with stirring for 20−30
min. Water was added to the reaction mixture, and the resulting mixture
was extracted with ethyl acetate two times using 10 mL of solvent each
time. The organic layers were combined and dried over Na2SO4. After
removing the solvent under reduced pressure, the residue was purified
by using column chromatography (EtOAc:n-hexane = 30:70 to 70:30).
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Scheme 6. Experiments for Mechanistic Studies
(F) Experimental Procedure for the Synthesis 4-Hydroxyquinolin-
2(1H)-one (7a). Compound 7a was prepared according to the reported
procedure by the Stoltz group.7a In a 20 mL resealable vial, KOH (19
mg, 0.35 mmol, 1 equiv) and compound 1a (82 mg, 0.35 mmol, 1
equiv) were added to DMF (2 mL). Then the tube was sealed with a
rubber septum, and the reaction mixture was kept at room temperature
with stirring for 2 h. After the completion of the reaction, the resulting
mixture was filtered through a plug of Celite and the filtrate was
concentrated under reduced pressure. Finally, the residue was purified
by using column chromatography (DCM:MeOH = 90:10).
(G) General Experimental Procedure for the Synthesis of a
Polyheterocycle Scaffold (9). In a 20 mL resealable vial, KOH (29.5
mg, 0.52 mmol, 1.5 equiv), peroxy compound (0.35 mmol, 1 equiv),
and amino alcohols (0.42 mmol, 1.2 equiv) were added to THF (2 mL).
Then the tube was sealed with a rubber septum, and the reaction
mixture was kept at room temperature with stirring for 3 h. After the
completion of the reaction, water was added, and the resulting mixture
was extracted with ethyl acetate two times using 10 mL of solvent each
time. The organic layers were combined and dried over Na2SO4. After
removing the solvent under reduced pressure, the residue was purified
by using column chromatography (EtOAc:n-hexane = 30:70 to 70:30).
(H) Experimental Procedure for the Oxidation of the 4-
Methylene-3-Substituted Quinazolinone Derivative (10). In a 50
mL round-bottomed flask, compound 3a (0.25 mmol, 1 equiv), CuCl2
(5 mol %), 2,2′-bipyridine (5 mol %), and 5.0−6.0 M tert-butyl
hydroperoxide (TBHP) in decane solution (0.50 mmol, 2 equiv) were
added to acetonitrile (2 mL). Then the round-bottomed flask was
sealed using a rubber septum without maintaining any special
conditions such as an inert atmosphere. The reaction mixture was
kept at room temperature for 12 h. After the completion of the reaction,
a volatile component was evaporated under vacuum. The residue was
directly purified by silica gel chromatography (EtOAc:n-hexane =
30:70).
(I) Experimental Procedure for the Detection of the Isocyanate
Intermediate Using HRMS Analysis. In a 20 mL resealable vial,
compound 1b (104 mg, 0.35 mmol, 1 equiv) and KOH (20 mg, 0.35
mmol, 1 equiv) were added at 0 °C in dry THF (2 mL). Then the tube
was sealed with a rubber septum, and the reaction was performed under
a nitrogen atmosphere. After 5 min, the reaction mixture was subjected
to HRMS analysis. The presence of m/z = 224.0716 corresponds to
isocyanate intermediate B (SI, Figure S1).
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Scheme 7. Plausible Mechanism for Products 3a and 9a
evaporation. A needle-shaped single crystal was mounted on a loop by
applying a small amount of paraffin oil. Crystal data for compound 3a:
C16H15N2O, M = 249.28, monoclinic, space group P21/n with a =
10.4745(5) Å, b = 5.5284(2) Å, c = 21.446(1) Å, α = 90°, β =
101.990(1)°, γ = 90°, V = 1214.79(9) Å3, T = 296(2) K, R1 = 0.0490,
wR2 = 0.1282 on observed data, z = 4, Dcalcd = 1.363 g cm−3, F(000) =
524, absorption coefficient = 0.127 mm−1, λ = 0.71073 Å, 3014
reflections collected on a Bruker APEX-II CCD single-crystal
diffractometer, and 2362 observed reflections (I ≥ 2σ(I)). The largest
difference peak and hole are 0.875 and −0.267 eÅ−3, respectively
3-(2-Methylbenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3b). Prepared according to general procedure A, using 2-
methylbenzylamine (51 mg, 0.42 mmol) to afford 3-(2-methylbenzyl)-
4-methylene-3,4-dihydroquinazolin-2(1H)-one (3b) (65 mg, 70%
yield) as a yellow solid after purification using silica gel column
Scheme 8. Oxidation of 4-Methylene-3-Substituted
Quinazolinone Derivative
a
a
Reaction conditions: compound 3a/3p (0.25 mmol, 1 equiv), CuCl2
(5 mol %), 2,2′-bipyridine (5 mol %), and TBHP (2 equiv) in 2 mL
of acetonitrile were stirred at room temperature for 12 h.
(J) Experimental Procedure for the Observation of the Isocyanate
Intermediate Using IR Analysis. In a 20 mL resealable vial, compound
1b (104 mg, 0.35 mmol, 1 equiv) and KOH (20 mg, 0.35 mmol, 1
equiv) were added at 0 °C to dry THF (2 mL). Then the tube was
sealed with a rubber septum, and the reaction was performed under a
nitrogen atmosphere. After 5 min, the IR spectrum was recorded for the
reaction mixture (Figure S3). Then 4-methoxybenzylamine 2d (48 mg,
0.35 mmol, 1 equiv) was added to the reaction mixture, and the IR
spectrum was recorded after 10 min (Figure S4). The IR spectra
indicate the disappearance of the isocyanate peak. Interestingly, after 2
h the complete disappearance of the isocyanate peak was noticed
(Figure S5).
(K) Analytical Data for the Product. 3-Benzyl-4-methylene-3,4-
dihydroquinazolin-2(1H)-one (3a). Prepared according to general
procedure A, using benzylamine (45 mg, 0.42 mmol) to afford 3-benzyl-
4-methylene-3,4-dihydroquinazolin-2(1H)-one (3a) (76 mg, 87%
yield) as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 249−252 °C. H
NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.56 (d, J = 7.4 Hz, 1H),
7.25−7.20 (m, 1H), 7.16−7.12 (m, 1H), 7.09−7.01 (m, 2H), 6.94−
6.86 (m, 3H), 4.88 (s, 2H), 4.73 (d, J = 2.4 Hz, 1H), 3.87 (d, J = 2.4 Hz,
1H), 2.29 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 149.9,
139.9, 135.6, 134.7, 133.8, 130.0, 126.3, 125.7, 124.1, 123.8, 122.0,
115.9, 114.6, 84.8, 44.3, 18.6. IR (neat): 1502, 1694, 2919, 3358 cm−1.
HRMS (ESI-TOF) m/z calculated for C17H17N2O (M + H)+ 265.1341,
found 265.1349.
3-(4-Methylbenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3c). Prepared according to general procedure A, using 4-
methylbenzylamine (59 mg, 0.42 mmol) to afford 3-(4-methylbenzyl)-
4-methylene-3,4-dihydroquinazolin-2(1H)-one (3c) (71 mg, 77%
yield) as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 183−186 °C. H
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H),
7.24−7.19 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.7 Hz, 1H),
6.77 (d, J = 7.9 Hz, 1H), 5.08 (s, 2H), 4.78 (d, J = 2.6 Hz, 1H), 4.24 (d, J
= 2.6 Hz, 1H), 2.32 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
140.2, 136.7, 134.9, 133.5, 130.2, 129.4, 126.5, 124.1, 122.9, 117.1,
114.7, 86.5, 47.1, 21.2. IR (neat): 1508, 1630, 1979, 2921, 3204 cm−1.
HRMS (ESI-TOF) m/z calculated for C17H17N2O (M + H)+ 265.1341,
found 265.1339.
1
chromatography (EtOAc:n-hexane = 30:70). MP = 198−201 °C. H
NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H),
7.35−7.20 (m, 6H), 6.99−6.91 (m, 2H), 5.00 (s, 2H), 4.81 (d, J = 2.3
Hz, 1H), 4.12 (d, J = 2.3 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-
d6) δ 150.1, 139.7, 137.0, 135.6, 130.1, 128.4, 126.7, 126.3, 123.9, 122.1,
115.9, 114.6, 85.2, 45.8. IR (neat): 1453, 1685, 2919, 3207 cm−1.
HRMS (ESI-TOF) m/z calculated for C16H15N2O (M + H)+ 251.1184,
found 251.1184. Crystals of compound 3a were grown using
dichloromethane and petroleum ether (2:1) as a solvent by slow
3-(4-Methoxybenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3d). Prepared according to general procedure A, using 4-
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methoxybenzylamine (58 mg, 0.42 mmol) to afford 3-(4-methoxy-
benzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3d) (70 mg,
71% yield) as a white solid after purification using silica gel column
bromobenzylamine (78 mg, 0.42 mmol) to afford 3-(3-bromo-
benzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3i) (71 mg,
62% yield) as a white solid after purification using silica gel column
1
1
chromatography (EtOAc:n-hexane = 30:70). MP = 175−185 °C. H
chromatography (EtOAc:n-hexane = 30:70). MP = 196−198 °C. H
NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H),
7.24−7.21 (m, 3H), 7.00−6.95 (m, 1H), 6.89−6.84 (m, 2H), 6.80 (d, J
= 8.0 Hz, 1H), 5.06 (s, 2H), 4.79 (d, J = 2.6 Hz, 1H), 4.26 (d, J = 2.6 Hz,
1H), 3.78 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 151.8,
140.2, 135.0, 130.2, 128.7, 127.9, 124.0, 122.8, 117.1, 114.9, 114.2, 86.2,
55.4, 46.7. IR (neat): 1464, 1521, 1696, 2917, 3131 cm−1. HRMS (ESI-
TOF) m/z calculated for C17H17N2O2 (M + H)+ 281.1290, found
281.1297.
3-(3,4-Dimethoxybenzyl)-4-methylene-3,4-dihydroquinazolin-
2(1H)-one (3e). Prepared according to general procedure A, using 3,4-
dimethoxybenzylamine (70 mg, 0.42 mmol) to afford 3-(3,4-
dimethoxybenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one
(3e) (70 mg, 64% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 209−211
°C. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.25−7.22 (m, 1H), 7.01−6.96 (m, 1H), 6.89−6.79 (m, 4H), 5.06
(s, 2H), 4.80 (d, J = 2.6 Hz, 1H), 4.29 (d, J = 2.6 Hz, 1H), 3.85 (d, J =
2.7 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.8, 151.8, 149.3,
148.2, 140.3, 135.0, 130.2, 129.2, 124.0, 122.9, 118.8, 117.0, 114.8,
111.2, 110.0, 86.3, 56.0, 47.2. IR (neat): 1513, 1632, 1679, 2954, 3441
cm−1. HRMS (ESI-TOF) m/z calculated for C18H19N2O3 (M + H)+
311.1395, found 311.1388.
NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45
(s, 1H), 7.38 (dt, J = 7.5, 1.6 Hz, 1H), 7.28−7.167 (m, 4H), 7.03−6.99
(m, 1H), 6.80 (dd, J = 8.0, 0.9 Hz, 1H), 5.08 (s, 2H), 4.80 (d, J = 2.8 Hz,
1H), 4.17 (d, J = 2.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
151.6, 140.2, 139.1, 134.9, 130.4, 130.4, 130.3, 129.6, 125.2, 124.1,
123.0, 123.0, 116.9, 114.9, 86.5, 46.9. IR (neat): 1521, 1695, 2847, 3260
cm−1. HRMS (ESI-TOF) m/z calculated for C16H14BrN2O (M + H)+
329.0289, found 329.0294.
4-Methylene-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazo-
lin-2(1H)-one (3j). Prepared according to general procedure A, using 4-
(trifluoromethyl)benzylamine (74 mg, 0.42 mmol) to afford 4-
methylene-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-
2(1H)-one (3j) (75 mg, 67% yield) as a yellow solid after purification
using silica gel column chromatography (EtOAc:n-hexane = 30:70).
MP = 180−182 °C. 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.61
(d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H),
7.28−7.24 (m, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H),
5.20 (s, 2H), 4.82 (d, J = 2.8 Hz, 1H), 4.15 (d, J = 2.8 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 152.0, 140.9, 140.2, 134.9, 130.4, 129.5 (q,
J = 32.0 Hz), 127.9 (q, J = 42.6 Hz), 125.7 (q, J = 3.4 Hz), 124.2 (q, J =
271.5 Hz), 124.0, 123.1, 116.7, 115.1, 86.3, 47.0. IR (neat): 1325, 1496,
1680, 2923 cm−1. HRMS (ESI-TOF) m/z calculated for C17H14F3N2O
(M + H)+ 319.1058, found 319.1050.
4-Methylene-3-(2,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-
2(1H)-one (3f). Prepared according to general procedure A, using 3,4,5-
trimethoxybenzylamine (83 mg, 0.42 mmol) to afford 4-methylene-3-
(2,4,5-trimethoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (3f) (107
mg, 90% yield) as a yellow solid after purification using silica gel column
4-Methylene-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazolin-
2(1H)-one (3k). Prepared according to general procedure A, using 2-
picolylamine (45 mg, 0.42 mmol) to afford 4-methylene-3-(pyridin-2-
ylmethyl)-3,4-dihydroquinazolin-2(1H)-one (3k) (51 mg, 58% yield)
as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 225−227 °C. H
1
NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H),
7.27−7.21 (m, 1H), 7.02−6.97 (m, 1H), 6.83−6.77 (m, 1H), 6.51 (s,
2H), 5.03 (s, 2H), 4.81 (d, J = 2.6 Hz, 1H), 4.28 (d, J = 2.7 Hz, 1H),
3.81 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 151.7, 140.4,
137.0, 134.9, 132.5, 130.3, 124.1, 123.0, 117.0, 114.8, 103.4, 86.7, 61.0,
56.2, 47.8. IR (neat): 1460, 1519, 1651, 2925, 3273 cm−1. HRMS (ESI-
TOF) m/z calculated for C19H20N2O4 (M + H)+ 341.1501, found
341.1505.
chromatography (EtOAc:n-hexane = 30:70). MP = 173−176 °C. H
NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.58 (ddd, J = 4.9, 1.7, 0.9 Hz,
1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.29−7.22
(m, 2H), 7.17 (dd, J = 6.9, 5.4 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.80 (d,
J = 8.0 Hz, 1H), 5.24 (s, 2H), 4.78 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.0, 151.6, 149.4,
140.2, 137.0, 134.9, 130.3, 124.0, 123.0, 122.2, 120.7, 117.0, 114.9, 86.7,
49.5. IR (neat): 1439, 1676, 2922, 3213 cm−1. HRMS (ESI-TOF)m/z
calculated for C15H14N3O (M + H)+ 252.1137, found 252.1138.
14b-Methyl-8,9,14,14b-tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]-
quinazolin-6(5H)-one (3l). Prepared according to general procedure A,
using tryptamine (67 mg, 0.42 mmol) to afford 14b-methyl-8,9,14,14b-
tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]quinazolin-6(5H)-one (3l)
(65 mg, 61% yield) as a yellow solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 50:50). MP = 175−178
°C. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.55 (d, J = 7.8 Hz,
1H), 7.45−7.41 (m, 2H), 7.25−7.21 (m, 3H), 7.16 (t, J = 7.4 Hz, 1H),
7.00 (t, J = 7.6 Hz, 1H), 6.80 (dd, J = 7.7, 3.4 Hz, 1H), 4.82−4.75 (m,
1H), 3.26 (ddd, J = 12.9, 10.9, 4.7 Hz, 1H), 2.93−2.79 (m, 2H), 1.85 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 136.2, 136.0, 134.3,
128.7, 126.9, 125.3, 123.9, 122.6, 122.5, 120.1, 118.8, 114.7, 111.1,
110.7, 58.8, 38.6, 26.8, 21.1. IR (neat): 1520, 1657, 2900 cm−1. HRMS
(ESI-TOF) m/z calculated for C19H18N3O (M + H)+ 304.1450, found
304.1457.
3-([1,1′-Biphenyl]-4-ylmethyl)-4-methylene-3,4-dihydroquinazo-
lin-2(1H)-one (3g). Prepared according to general procedure A, using
4-phenylbenzylamine (77 mg, 0.42 mmol) to afford 3-([1,1′-biphenyl]-
4-ylmethyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3g) (95
mg, 83% yield) as a faint yellow solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 228−231
°C. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.62 (t, J = 7.2 Hz,
5H), 7.45 (t, J = 7.6 Hz, 2H), 7.38−7.26 (m, 4H), 6.96 (dd, J = 14.1, 7.7
Hz, 2H), 5.05 (s, 2H), 4.85 (d, J = 2.0 Hz, 1H), 4.18 (d, J = 2.1 Hz, 1H).
13C{1H} NMR (100 MHz, DMSO-d6) δ 150.1, 139.9, 139.7, 138.7,
136.3, 135.6, 130.2, 128.9, 127.3, 127.0, 126.8, 126.5, 123.9, 122.1,
115.9, 114.6, 85.3, 45.5. IR (neat): 1514, 1696, 1743 cm−1. HRMS
(ESI-TOF) m/z calculated for C22H19N2O (M + H)+ 327.1497, found
327.1490.
3-(4-Fluorobenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3h). Prepared according to general procedure A, using 4-
fluorobenzylamine (53 mg, 0.42 mmol) to afford 3-(4-fluorobenzyl)-4-
methylene-3,4-dihydroquinazolin-2(1H)-one (3h) (65 mg, 69% yield)
as a white solid after purification using silica gel column
3-(Furan-2-ylmethyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3m). Prepared according to general procedure A, using
furfurylamine (41 mg, 0.42 mmol) to afford 3-(furan-2-ylmethyl)-4-
methylene-3,4-dihydroquinazolin-2(1H)-one (3m) (57 mg, 67% yield)
as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 180−183 °C. H
NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29
(dd, J = 8.3, 5.2 Hz, 2H), 7.24 (t, J = 7.7 Hz, 1H), 7.05−6.97 (m, 3H),
6.83−6.79 (m, 1H), 5.09 (s, 2H), 4.79 (d, J = 2.8 Hz, 1H), 4.20 (d, J =
2.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, (d, J = 243.5
Hz), 151.9 (d, J = 6.5 Hz), 140.2, 135.0, 132.3 (d, J = 2.5 Hz), 130.3,
128.2 (d, J = 7.9 Hz), 124.0, 122.9, 116.9, 115.7, 115.5, 115.0 (d, J = 1.3
Hz), 86.2, 46.7. IR (neat): 1507, 1678, 2921 cm−1. HRMS (ESI-TOF)
m/z calculated for C16H14FN2O (M + H)+ 269.1090, found 269.1084.
3-(3-Bromobenzyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3i). Prepared according to general procedure A, using 3-
1
chromatography (EtOAc:n-hexane = 30:70). MP = 180−183 °C. H
NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.36−7.30 (m, 1H), 7.22 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H),
6.86 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 1.7 Hz, 2H), 5.07 (s, 2H), 4.84 (d, J
= 2.7 Hz, 1H), 4.49 (d, J = 2.7 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 151.7, 150.3, 141.7, 140.2, 134.9, 130.1, 123.8, 122.7, 116.9,
115.0, 110.4, 108.0, 85.4, 40.5. IR (neat): 1520, 1696, 3612 cm−1.
HRMS (ESI-TOF) m/z calculated for C14H13N2O2 (M + H)+
241.0977, found 241.0981.
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3-Cyclopropyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one
(3n). Prepared according to general procedure A, using cyclopropyl-
amine (24 mg, 0.42 mmol) to afford 3-cyclopropyl-4-methylene-3,4-
dihydroquinazolin-2(1H)-one (3n) (40 mg, 58% yield) as a black solid
after purification using silica gel column chromatography (EtOAc:n-
hexane = 30:70). MP = 145−147 °C. 1H NMR (400 MHz, CDCl3) δ
9.21 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.25−7.20 (m, 1H), 7.00−6.95
(m, 1H), 6.86−6.83 (m, 1H), 4.89 (d, J = 1.6 Hz, 1H), 4.72 (d, J = 1.6
Hz, 1H), 2.66−2.60 (m, 1H), 1.16−1.09 (m, 2H), 0.79−0.74 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 153.0, 141.8, 135.2, 129.8, 123.9,
yield) as a white solid after purification using silica gel column
chromatography (EtOAc:n-hexane = 30:70). MP = 170−172 °C. H
1
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H),
7.28−7.25 (m, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H),
4.96 (d, J = 3.0 Hz, 1H), 4.65 (d, J = 2.4 Hz, 2H), 4.54 (d, J = 3.0 Hz,
1H), 2.24 (t, J = 2.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
150.4, 139.6, 134.6, 130.3, 124.1, 123.1, 117.0, 114.8, 86.1, 78.1, 77.1,
71.7, 33.2. IR (neat): 1462, 1521, 1686, 3284 cm−1. HRMS (ESI-TOF)
m/z calculated for C12H11N2O (M + H)+ 199.0871, found 199.0873.
3-Allyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3t). Pre-
pared according to general procedure A, using allylamine (28 mg, 0.42
mmol) to afford 3-allyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one
(3t) (42 mg, 61% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 127−130
°C. 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.54 (d, J = 8.0 Hz,
1H), 7.26−7.22 (m, 1H), 6.99 (dd, J = 7.9, 7.4 Hz, 1H), 6.84 (d, J = 7.8
Hz, 1H), 5.93−5.84 (m, 1H), 5.30−5.21 (m, 2H), 4.83 (d, J = 2.5 Hz,
1H), 4.52−4.51 (m, 2H), 4.32 (d, J = 2.3 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 151.5, 140.4, 135.1, 132.0, 130.1, 123.9, 122.7, 117.0,
116.7, 115.0, 85.5, 46.1. IR (neat): 1496, 1654, 2923, 3242 cm−1.
HRMS (ESI-TOF) m/z calculated for C12H13N2O (M + H)+ 201.1028,
found 201.1027.
122.6, 118.2, 114.7, 88.4, 26.1, 10.3. IR (neat): 1415, 1517, 1683, 2922,
3214, cm−1. HRMS (ESI-TOF) m/z calculated for C12H13N2O (M +
H)+ 201.1028, found 201.1033.
3-Methyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3o).
Prepared according to general procedure A, using methylamine (13
mg, 0.42 mmol) to afford 3-methyl-4-methylene-3,4-dihydro-
quinazolin-2(1H)-one (3o) (28 mg, 46% yield) as a yellow solid after
purification using silica gel column chromatography (EtOAc:n-hexane
= 30:70). MP = 155−157 °C. 1H NMR (400 MHz, CDCl3) δ 9.05 (s,
1H), 7.57 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.3
Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.82 (d, J = 2.3 Hz, 1H), 4.26 (d, J =
2.3 Hz, 1H), 3.29 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.5,
141.8, 135.0, 130.2, 123.9, 122.7, 116.8, 114.9, 84.3, 30.6. IR (neat):
1454, 1559, 1637, 2924, 3344 cm−1. HRMS (ESI-TOF) m/z calculated
for C10H11N2O (M + H)+ 175.0871, found 175.0878.
3-Ethyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3p). Pre-
pared according to general procedure A, using ethylamine (19 mg, 0.42
mmol) to afford 3-ethyl-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3p) (45 mg, 69% yield) as a white solid after purification using
silica gel column chromatography (EtOAc:n-hexane = 30:70). MP =
159−162 °C. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.55 (d, J =
8.0 Hz, 1H), 7.27−7.22 (m, 1H), 7.01−6.95 (m, 1H), 6.81 (d, J = 8.0
Hz, 1H), 4.83 (d, J = 2.5 Hz, 1H), 4.32 (d, J = 2.5 Hz, 1H), 3.93 (q, J =
7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 151.2, 140.1, 135.3, 130.1, 124.0, 122.6, 117.1, 114.8, 84.0,
38.4, 11.3. IR (neat): 1441, 1495, 1654, 2924, 3204 cm−1. HRMS (ESI-
TOF) m/z calculated for C11H13N2O (M + H)+ 189.1028, found
189.1030.
3-Hexyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one (3q). Pre-
pared according to general procedure A, using hexylamine (43 mg, 0.42
mmol) to afford 3-hexyl-4-methylene-3,4-dihydroquinazolin-2(1H)-
one (3q) (63 mg, 73% yield) as a white solid after purification using
silica gel column chromatography (EtOAc:n-hexane = 30:70). MP =
108−110 °C. 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.55 (d, J =
7.8 Hz, 1H), 7.26−7.22 (m, 1H), 7.00−6.96 (m, 1H), 6.84 (dd, J = 8.1,
0.9 Hz, 1H), 4.82 (d, J = 2.4 Hz, 1H), 4.28 (d, J = 2.5 Hz, 1H), 3.85 (t, J
= 7.7 Hz, 2H), 1.74−1.67 (m, 2H), 1.43−1.31 (m, 6H), 0.90 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.6, 140.3, 135.4,
130.0, 123.9, 122.5, 117.0, 114.9, 84.0, 43.4, 31.7, 26.8, 25.6, 22.7, 14.2.
IR (neat): 1424, 1497, 1629, 1684, 2929, 3202 cm−1. HRMS (ESI-
TOF) m/z calculated for C15H21N2O (M + H)+ 245.1654, found
245.1651.
4-Methylene-3-octyl-3,4-dihydroquinazolin-2(1H)-one (3r). Pre-
pared according to general procedure A, using octylamine (54 mg, 0.42
mmol) to afford 4-methylene-3-octyl-3,4-dihydroquinazolin-2(1H)-
one (3r) (71 mg, 75% yield) as a yellow solid after purification using
silica gel column chromatography (EtOAc:n-hexane = 30:70). MP =
108−110 °C. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 7.54 (dd, J =
8.1, 1.1 Hz, 1H), 7.25−7.20 (m, 1H), 7.00−6.95 (m, 1H), 6.83 (dd, J =
7.9, 0.8 Hz, 1H), 4.82 (d, J = 2.5 Hz, 1H), 4.28 (d, J = 2.5 Hz, 1H),
3.87−3.80 (m, 2H), 1.74−1.66 (m, 2H), 1.33−1.25 (m, 10H), 0.86 (t, J
= 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.4, 140.3,
135.3, 130.0, 123.9, 122.5, 117.0, 114.8, 84.1, 43.5, 31.9, 29.4, 29.4,
27.1, 25.6, 22.7, 14.2. IR (neat): 1433, 1679, 2921, 3204 cm−1. HRMS
(ESI-TOF) m/z calculated for C17H25N2O (M + H)+ 273.1967, found
273.1971.
3-(3-Methoxyphenethyl)-4-methylene-3,4-dihydroquinazolin-
2(1H)-one (3u). Prepared according to general procedure A, using 3-
methoxyphenethylamine (52.92 mg, 0.42 mmol) to afford 3-(3-
methoxyphenethyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one
(3u) (67 mg, 65% yield) as a yellow solid after purification using silica
gel column chromatography (EtOAc:n-hexane = 30:70). MP = 128−
130 °C. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.58 (d, J = 7.3 Hz,
1H), 7.28−7.22 (m, 2H), 7.03−6.99 (m, 1H), 6.93−6.85 (m, 2H), 6.78
(dd, J = 8.2, 1.7 Hz, 2H), 4.90 (d, J = 2.6 Hz, 1H), 4.43 (d, J = 2.7 Hz,
1H), 4.10−4.04 (m, 2H), 3.80 (s, 3H), 3.01−2.97 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 159.9, 150.9, 140.6, 140.2, 135.1, 130.2,
129.7, 124.1, 122.8, 121.2, 117.0, 114.7, 114.6, 112.0, 84.6, 55.3, 44.9,
32.0. IR (neat): 1517, 1680, 2927, 3616 cm−1. HRMS (ESI-TOF) m/z
calculated for C18H19N2O2 (M + H)+ 295.1446, found 295.1456.
(E)-3-Benzyl-4-butylidene-3,4-dihydroquinazolin-2(1H)-one (3v).
Prepared according to general procedure A, using benzylamine (45 mg,
0.42 mmol) to afford (E)-3-benzyl-4-butylidene-3,4-dihydro-
quinazolin-2(1H)-one (3v) (22 mg, 21% yield) as a yellow solid after
purification using silica gel column chromatography (EtOAc:n-hexane
= 30:70). MP = 122−124 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (s,
1H), 7.39 (d, J = 7.9 Hz, 1H), 7.31−7.28 (m, 4H), 7.24−7.21 (m, 2H),
7.01−6.97 (m, 1H), 6.79 (dd, J = 7.9, 0.8 Hz, 1H), 5.04 (s, 2H), 4.99 (t,
J = 7.1 Hz, 1H), 2.28 (q, J = 7.2 Hz, 2H), 1.38−1.29 (m, 2H), 0.80 (t, J =
7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.5, 137.5, 136.8,
133.0, 129.1, 128.6, 127.1, 126.9, 126.6, 121.7, 118.4, 114.1, 112.7, 48.2,
30.6, 23.9, 13.7. IR (neat): 1448, 1500, 1669, 2922, 3211 cm−1. HRMS
(ESI-TOF) m/z calculated for C19H21N2O (M + H)+ 293.1654, found
293.1660.
(E/Z)-4-Benzylidene-3-(4-methoxybenzyl)-3,4-dihydroquinazo-
lin-2(1H)-one (3w). Prepared according to general procedure A, using
4-methoxybenzylamine (58 mg, 0.42 mmol) to afford (E/Z)-4-
benzylidene-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one
(3w) (62 mg, 50% yield) as a white solid after purification using silica
gel column chromatography (EtOAc:n-hexane = 30:70). MP = 236−
238 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.21 (s, 1H), 7.49
(d, J = 7.4 Hz, 1H), 7.39−7.35 (m, 4H), 7.29−7.27 (m, 3H), 7.24−7.20
(m, 3H), 7.14−7.10 (m, 3H), 7.04−7.00 (m, 2H), 6.89−6.83 (m, 5H),
6.77 (t, J = 7.2 Hz, 2H), 6.67−6.62 (m, 3H), 6.31 (s, 1H), 6.08 (s, 1H),
5.13 (s, 2H), 4.70 (s, 2H), 3.79 (s, 3H), 3.70 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 158.7, 154.4, 152.9, 137.3, 136.6, 136.2, 135.3,
134.3, 134.1, 129.9, 129.8, 129.4, 129.2, 128.9, 128.8, 128.8, 128.6,
128.5, 128.4, 127.9, 127.2, 126.7, 123.0, 122.8, 121.8, 121.6, 117.0,
114.4, 114.4, 114.2, 113.8, 113.6, 111.8, 109.7, 55.4, 55.2, 49.5, 47.4. IR
(neat): 1454, 1509, 1678, 2918 cm−1. HRMS (ESI-TOF) m/z
calculated for C23H21N2O2 (M + H)+ 357.1603, found 357.1604.
4-Hydroxy-3-(4-methoxybenzyl)-4-phenyl-3,4-dihydroquinazo-
lin-2(1H)-one (3x). Prepared according to general procedure A, using 4-
methoxybenzylamine (48 mg, 0.35 mmol) to afford 4-hydroxy-3-(4-
4-Methylene-3-(prop-2-yn-1-yl)-3,4-dihydroquinazolin-2(1H)-
one (3s). Prepared according to general procedure A, using
propargylamine (23.13 mg, 0.42 mmol) to afford 4-methylene-3-
(prop-2-yn-1-yl)-3,4-dihydroquinazolin-2(1H)-one (3s) (45 mg, 65%
9631
https://doi.org/10.1021/acs.joc.1c00889
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The Journal of Organic Chemistry
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Article
methoxybenzyl)-4-phenyl-3,4-dihydroquinazolin-2(1H)-one (3x) (80
mg, 63% yield) as a white solid after purification using silica gel column
chromatography (EtOAc:n-hexane = 70:30). MP = 140−143 °C. H
(EtOAc:n-hexane = 20:80). 1H NMR (400 MHz, CDCl3) δ 11.39 (s,
1H), 8.68 (dd, J = 8.6, 0.8 Hz, 1H), 7.82 (dd, J = 8.0, 1.4 Hz, 1H), 7.48−
7.44 (m, 1H), 6.95−6.91 (m, 1H), 3.23 (s, 2H), 3.21 (s, 2H), 2.62 (s,
3H), 2.13−2.02 (m, 2H), 0.94 (s, 6H), 0.93 (s, 6H). 13C{1H} NMR
(100 MHz, CDCl3) δ 202.7, 155.5, 143.4, 135.1, 131.6, 120.8, 120.1,
119.7, 55.9, 28.4, 27.7, 20.2. IR (neat): 1240, 1449, 1527, 1647, 1735
cm−1. HRMS (ESI-TOF) m/z calculated for C17H27N2O2 (M + H)+
291.2072, found 291.2072.
1
NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.40−7.38 (m, 1H), 7.28
(t, J = 7.5 Hz, 2H), 7.23−7.19 (m, 2H), 7.16−7.11 (m, 1H), 7.08 (d, J =
8.6 Hz, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.86−6.79 (m, 2H), 6.70 (d, J =
8.7 Hz, 2H), 4.30 (d, J = 15.1 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 3.67
(s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 157.5, 152.0, 145.6,
134.8, 132.0, 128.9, 128.6, 128.0, 127.7, 127.5, 125.8, 124.9, 120.9,
113.3, 112.8, 87.6, 54.9, 45.2. IR (neat): 1456, 1540, 1607, 1656, 2922,
2853 cm−1. HRMS (ESI-TOF) m/z calculated for C22H20N2O3Na (M
+ Na)+ 383.1372, found 383.1382.
N-(2-Acetylphenyl)pyrrolidine-1-carboxamide (6d). Prepared ac-
cording to general procedure C, using pyrrolidine (30 mg, 0.42 mmol)
to afford N-(2-acetylphenyl)pyrrolidine-1-carboxamide (6d) (65 mg,
80% yield) as a yellow solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 20:80). MP = 96−98 °C. H
3-(4-((6-Methoxyquinolin-8-yl)amino)pentyl)-4-methylene-3,4-
dihydroquinazolin-2(1H)-one (3y). Prepared according to general
procedure A, using primaquine (109 mg, 0.42 mmol) to afford 3-(4-
((6-methoxyquinolin-8-yl)amino)pentyl)-4-methylene-3,4-dihydro-
quinazolin-2(1H)-one (3y) (64 mg, 45% yield) as a white solid after
purification using silica gel column chromatography (EtOAc:n-hexane
NMR (400 MHz, CDCl3) δ 11.24 (s, 1H), 8.68 (dd, J = 8.6, 1.0 Hz,
1H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.48 (ddd, J = 8.7, 7.3, 1.5 Hz, 1H),
6.94 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 3.53−3.50 (m, 4H), 2.62 (s, 3H),
1.95 (s, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 202.9, 154.1, 143.4,
135.2, 131.7, 120.6, 120.1, 119.6, 45.8, 28.5. IR (neat): 1525, 1648,
1735, 2930, 3615 cm−1. HRMS (ESI-TOF) m/z calculated for
C13H17N2O2 (M + H)+ 233.1290, found 233.1297.
1
= 60:40). MP = 90−93 °C. H NMR (400 MHz, CDCl3) δ 9.20 (s,
1H), 8.50 (dd, J = 4.2, 1.6 Hz, 1H), 7.90 (dd, J = 8.3, 1.6 Hz, 1H), 7.49
(d, J = 8.0 Hz, 1H), 7.29−7.25 (m, 1H), 7.21−7.17 (m, 1H), 6.95−6.91
(m, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.31 (q, J = 2.5 Hz, 2H), 6.03 (s, 1H),
4.76 (d, J = 2.5 Hz, 1H), 4.24 (d, J = 2.6 Hz, 1H), 3.86 (s, 3H), 3.73−
3.60 (m, 2H), 1.92−1.81 (m, 4H), 1.72−1.67 (m, 1H), 1.30 (d, J = 6.3
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.5, 151.5, 145.1,
144.3, 140.1, 135.5, 135.2, 134.8, 130.1, 130.0, 123.9, 122.6, 121.9,
116.9, 114.8, 96.8, 91.7, 84.4, 55.3, 48.0, 43.2, 34.0, 22.4, 20.6. IR
(neat): 1453, 1519, 1661, 2956 cm−1. HRMS (ESI-TOF) m/z
calculated for C24H27N4O2 (M + H)+ 403.2134, found 403.2134.
3-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-methylene-3,4-dihydroqui-
nazolin-2(1H)-one (3z). Prepared according to general procedure A,
using piperonylamine (64 mg, 0.42 mmol) to afford 3-(benzo[d][1,3]-
dioxol-5-ylmethyl)-4-methylene-3,4-dihydroquinazolin-2(1H)-one
(3z) (60 mg, 58% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 173−175
°C. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.61 (d, J = 7.8
Hz, 1H), 7.31−7.25 (m, 1H), 6.98−6.91 (m, 2H), 6.83 (dd, J = 9.0, 4.7
Hz, 2H), 6.74 (dd, J = 8.0, 1.4 Hz, 1H), 5.97 (s, 2H), 4.90 (s, 2H), 4.82
(d, J = 2.3 Hz, 1H), 4.17 (d, J = 2.4 Hz, 1H). 13C{1H} NMR (100 MHz,
DMSO-d6) δ 150.1, 147.4, 146.0, 139.6, 135.5, 130.9, 130.1, 123.9,
122.1, 119.6, 116.0, 114.6, 108.2, 107.0, 100.8, 85.3, 45.5. IR (neat):
1440, 1546, 1626, 1681, 3062 cm−1. HRMS (ESI-TOF) m/z calculated
for C17H15N2O3 (M + H)+ 295.1083, found 295.1093.
N-(2-Acetylphenyl)morpholine-4-carboxamide (6e). Prepared
according to general procedure C, using morpholine (37 mg, 0.42
mmol) to afford N-(2-acetylphenyl)morpholine-4-carboxamide (6e)
(62 mg, 71% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 20:80). MP = 133−135
°C. 1H NMR (400 MHz, CDCl3) δ 11.52 (s, 1H), 8.58 (dd, J = 8.6, 0.8
Hz, 1H), 7.84 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (ddd, J = 8.7, 7.4, 1.5 Hz,
1H), 7.00−6.96 (m, 1H), 3.73 (t, J = 4.64 Hz, 4H), 3.56 (t, J = 5.12 Hz,
4H), 2.63 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 203.3, 154.9,
143.0, 135.3, 131.8, 120.9, 120.7, 119.8, 66.6, 44.0, 28.5. IR (neat):
1243, 1528, 1644, 1734, 2922 cm−1. HRMS (ESI-TOF) m/z calculated
for C13H17N2O3 (M + H)+ 249.1239, found 249.1248.
N-(2-Acetylphenyl)-2-amino-6-oxocyclohex-1-ene-1-carboxa-
mide (6f). Prepared according to general procedure C, using 3-amino-
2-cyclohexen-1-one (47 mg, 0.42 mmol) to afford N-(2-acetylphenyl)-
2-amino-6-oxocyclohex-1-ene-1-carboxamide (6f) (15 mg, 16% yield)
as a yellow solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 20:80). MP = 120−123 °C. H
NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 8.6, 0.8 Hz, 1H), 8.01 (dd, J =
8.5, 0.7 Hz, 1H), 7.77 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.56 (ddd, J = 8.3,
6.8, 1.3 Hz, 1H), 3.27 (t, J = 6.04 Hz 1H), 3.05 (s, 3H), 2.80 (t, J = 6.36
Hz, 2H), 2.24−2.16 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ
200.8, 162.2, 150.1, 148.0, 131.6, 129.3, 127.8, 126.5, 125.6, 125.5, 41.2,
34.9, 21.4, 16.2. IR (neat): 1524, 1695, 1739, 3616 cm−1. HRMS (ESI-
TOF) m/z calculated for C15H17N2O3 (M + H)+ 273.1239, found
273.1237.
3-(2-Acetylphenyl)-1,1-dimethylurea (6a). Prepared according to
general procedure C, using dimethylamine (19 mg, 0.42 mmol) to
afford 3-(2-acetylphenyl)-1,1-dimethylurea (6a) (43 mg, 60% yield) as
a yellow solid after purification using silica gel column chromatography
2-Methoxybenzyl (2-Acetylphenyl)carbamate (6g). Prepared
according to general procedure D, using 2-methoxybenzyl alcohol
(58 mg, 0.42 mmol) to afford 2-methoxybenzyl (2-acetylphenyl)-
carbamate (6g) (51 mg, 53% yield) as a faint green solid after
purification using silica gel column chromatography (EtOAc:n-hexane
= 10:90). MP = 108−110 °C. 1H NMR (400 MHz, CDCl3) δ 11.22 (s,
1H), 8.52 (dd, J = 8.6, 0.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.54
(ddd, J = 8.6, 7.4, 1.4 Hz, 1H), 7.41 (dd, J = 7.5, 1.6 Hz, 1H), 7.31 (td, J
= 8.1, 1.7 Hz, 1H), 7.06 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 6.96 (td, J = 7.5,
0.9 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.28 (s, 2H), 3.86 (s, 3H), 2.64 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 202.3, 157.5, 154.0, 141.5,
135.1, 131.7, 129.6, 129.5, 124.6, 121.6, 121.4, 120.5, 119.4, 110.5, 62.4,
55.5, 28.6. IR (neat): 1522, 1650, 1732, 3615 cm−1. HRMS (ESI-TOF)
m/z calculated for C17H17NO4Na (M + Na)+ 322.1055, found
322.1060.
3-(2-Acetylphenyl)-1-(2-hydroxyethyl)-1-methylurea (6h). Pre-
pared according to general procedure C, using 2-(methylamino)-
ethanol (31 mg, 0.42 mmol) to afford 3-(2-acetylphenyl)-1-(2-
hydroxyethyl)-1-methylurea (6h) (71 mg, 86% yield) as a white solid
after purification using silica gel column chromatography (EtOAc:n-
hexane = 30:70). MP = 112−115 °C. 1H NMR (400 MHz, CDCl3) δ
11.46 (s, 1H), 8.58 (dd, J = 8.6, 1.1 Hz, 1H), 7.87−7.84 (m, 1H), 7.53−
7.48 (m, 1H), 7.02−6.98 (m, 1H), 3.83 (s, 3H), 3.60−3.57 (m, 2H),
3.18−3.17 (m, 10H), 2.66−2.65 (m, 3H), 1.82 (s, 1H). 13C{1H} NMR
1
(EtOAc:n-hexane = 20:80). MP = 85−88 °C. H NMR (400 MHz,
CDCl3) δ 11.40 (s, 1H), 8.63 (dd, J = 8.6, 0.9 Hz, 1H), 7.84 (dd, J = 8.0,
1.5 Hz, 1H), 7.49 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 6.98−6.94 (m, 1H),
3.07 (s, 6H), 2.63 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 203.0,
155.8, 143.4, 135.2, 131.7, 120.9, 120.3, 119.7, 36.4, 28.5. IR (neat):
1524, 1738, 2921, 3616 cm−1. HRMS (ESI-TOF) m/z calculated for
C11H15N2O2 (M + H)+ 207.1134, found 207.1141.
3-(2-Acetylphenyl)-1,1-diisopropylurea (6b). Prepared according
to general procedure C, using diisopropylamine (25 mg, 0.42 mmol) to
afford 3-(2-acetylphenyl)-1,1-diisopropylurea (6b) (71 mg, 77% yield)
as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 20:80). MP = 199−102 °C. H
NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 8.48 (dd, J = 8.6, 1.0 Hz,
1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (ddd, J = 8.7, 7.2, 1.6 Hz, 1H),
6.96−6.92 (m, 1H), 3.98−3.88 (m, 2H), 2.64 (s, 3H), 1.38 (s, 6H),
1.37 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 202.9, 154.5, 143.7,
135.0, 131.7, 121.2, 120.5, 120.0, 46.5, 28.5, 21.2. IR (neat): 1309,
1521, 1645, 1734, 3264 cm−1. HRMS (ESI-TOF) m/z calculated for
C15H23N2O2 (M + H)+ 263.1759, found 263.1759.
3-(2-Acetylphenyl)-1,1-diisobutylurea (6c). Prepared according to
general procedure C, using diisobutylamine (54 mg, 0.42 mmol) to
afford 3-(2-acetylphenyl)-1,1-diisobutylurea (6c) (78 mg, 76% yield)
as a red liquid after purification using silica gel column chromatography
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J. Org. Chem. 2021, 86, 9621−9636

The Journal of Organic Chemistry
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Article
(100 MHz, CDCl3) δ 203.2, 157.1, 143.0, 135.3, 131.8, 121.2, 120.8,
120.0, 61.8, 52.1, 35.9, 28.6. IR (neat): 1203, 1452, 1644, 2923 cm−1.
HRMS (ESI-TOF) m/z calculated for C12H16N2O3Na (M + Na)+
259.1059, found 259.1059.
Hz, 1H), 3.16 (m, 1H), 3.01 3.05 (d, J = 13.5 Hz, 1H), 2.97 (d, J = 13.5
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.7, 135.1, 134.9,
130.7, 129.3, 128.1, 126.9, 124.8, 122.5, 122.1, 113.9, 94.1, 64.3, 47.0,
44.1. IR (neat): 1438, 1671, 2912, 3212 cm−1. HRMS (ESI-TOF) m/z
calculated for C17H17N2O2 (M + H)+ 281.1290, found 281.1289.
11b-Methyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]-
quinazolin-6-one (9d). Prepared according to general procedure G,
using 3-aminopropan-1-ol (32 mg, 0.42 mmol) to afford 11b-methyl-
3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]quinazolin-6-one
(9d) (58 mg, 76% yield) as a yellow solid after purification using silica
gel column chromatography (EtOAc:n-hexane = 30:70). MP = 140−
142 °C. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.37 (dd, J = 7.8,
1.4 Hz, 1H), 7.24−7.20 (m, 1H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.72
(dd, J = 8.0, 0.8 Hz, 1H), 4.48−4.43 (m, 1H), 4.09 (td, J = 11.4, 3.6 Hz,
1H), 3.98−3.94 (m, 1H), 3.29 (td, J = 13.2, 4.0 Hz, 1H), 2.10−1.88 (m,
2H), 1.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.0, 134.0,
129.3, 124.9, 124.2, 122.6, 113.6, 86.3, 60.6, 35.8, 25.1, 23.0. IR (neat):
1520, 1657, 1716, 3615 cm−1. HRMS (ESI-TOF) m/z calculated for
C12H15N2O2 (M + H)+ 219.1133, found 219.1136.
11b-Phenyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]-
quinazolin-6-one (9e). Prepared according to general procedure G,
using 3-aminopropan-1-ol (32 mg, 0.42 mmol) to afford 11b-phenyl-
3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]quinazolin-6-one (9e)
(75 mg, 76% yield) as a faint yellow solid after purification using silica
gel column chromatography (EtOAc:n-hexane = 30:70). MP = 189−
192 °C. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 7.48 (d, J = 7.5 Hz,
2H), 7.41−7.36 (m, 3H), 7.28 (t, J = 7.3 Hz, 1H), 7.13 (td, J = 7.9, 1.3
Hz, 1H), 6.94−6.89 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.61 (dd, J =
13.4, 3.2 Hz, 1H), 4.09−4.01 (m, 2H), 3.04 (td, J = 13.2, 3.1 Hz, 1H),
2.17−2.03 (m, 1H), 1.50 (d, J = 13.1 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 153.0, 140.9, 133.5, 129.3, 129.2, 128.2, 126.2, 123.1,
122.5, 114.1, 89.9, 62.6, 37.8, 25.3. IR (neat): 1425, 1605, 1666, 2922,
3204 cm−1. HRMS (ESI-TOF) m/z calculated for C17H17N2O2 (M +
H)+ 281.1290, found 281.1297
11b-Benzyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]-
quinazolin-6-one (9f). Prepared according to general procedure G,
using 3-aminopropan-1-ol (32 mg, 0.42 mmol) to afford 11b-benzyl-
3,4,7,11b-tetrahydro-2H,6H-[1,3]oxazino[3,2-c]quinazolin-6-one (9f)
(73 mg, 71% yield) as a yellow solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 156−158
°C. 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.23 (d, J = 6.7 Hz,
1H), 7.18−7.14 (m, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.07 (t, J = 7.2 Hz,
2H), 6.96 (t, J = 7.6 Hz, 1H), 6.76−6.69 (m, 2H), 6.52−6.46 (m, 1H),
4.53 (dd, J = 13.6, 5.9 Hz, 1H), 4.27−4.20 (m, 1H), 4.01−3.96 (m,
1H), 3.66 (d, J = 13.3 Hz, 1H), 3.38 (td, J = 13.0, 4.4 Hz, 1H), 3.00 (d, J
= 13.3 Hz, 1H), 2.06−1.94 (m, 1H), 1.86−1.81 (m, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 152.1, 135.1, 134.6, 130.4, 129.4, 127.9,
126.8, 125.6, 122.0, 121.5, 113.2, 89.2, 60.4, 41.8, 35.7, 24.9. IR (neat):
1437, 1664, 2920 cm−1. HRMS (ESI-TOF) m/z calculated for
C18H19N2O2 (M + H)+ 295.1446, found 295.1452
12b-Benzyl-2,3,4,5,8,12b-hexahydro-7H-[1,3]oxazepino[3,2-c]-
quinazolin-7-one (9g). Prepared according to general procedure G,
using 4-amino-1-butanol (37 mg, 0.42 mmol) to afford 12b-benzyl-
2,3,4,5,8,12b-hexahydro-7H-[1,3]oxazepino[3,2-c]quinazolin-7-one
(9g) (67 mg, 62% yield) as a yellow solid after purification using silica
gel column chromatography (EtOAc:n-hexane = 30:70). MP = 195−
198 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.29 (dd, J = 7.7,
1.3 Hz, 1H), 7.20−7.15 (m, 1H), 7.09−6.97 (m, 4H), 6.71−6.68 (m,
2H), 6.54 (dd, J = 8.0, 0.8 Hz, 1H), 4.39 (d, J = 13.3 Hz, 1H), 3.78 (d, J
= 13.8 Hz, 1H), 3.60 (td, J = 12.2, 1.3 Hz, 1H), 3.30 (t, J = 12.5 Hz, 1H),
3.18 (d, J = 13.2 Hz, 1H), 2.98 (d, J = 13.2 Hz, 1H), 1.84−1.71 (m, 2H),
1.65−1.44 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.8, 136.5,
134.7, 130.4, 129.4, 127.7, 126.7, 125.7, 121.8, 120.6, 113.2, 92.8, 64.6,
47.3, 40.3, 29.2, 27.3. IR (neat): 1448, 1495, 1603, 1658, 2923, 3202
cm−1. HRMS (ESI-TOF) m/z calculated for C18H19N2O2 (M + H)+
309.1603, found 309.1596
1-(2-Acetylphenyl)-3-(3-hydroxypropyl)urea (6i). Prepared ac-
cording to general procedure E, using 3-aminopropan-1-ol (32 mg,
0.42 mmol) to afford 1-(2-acetylphenyl)-3-(3-hydroxypropyl)urea (6i)
(25 mg, 31% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70). MP = 111−113
°C. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.12 (dd, J = 8.0, 1.3
Hz, 1H), 7.61 (m, 1H), 7.25−7.21 (m, 1H), 7.12 (d, J = 8.1 Hz, 1H),
4.19 (m, 4H), 2.06 (m, 2H), 2.02 (s, 3H), 1.82 (bs, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 192.6, 171.3, 162.5, 152.1, 138.7, 135.2, 128.5,
123.5, 115.1, 114.6, 62.5, 38.3, 27.2, 21.0. IR (neat): 1243, 1660, 1715,
1733, 2921 cm−1. HRMS (ESI-TOF) m/z calculated for C12H17N2O3
(M + H)+ 237.1239, found 237.1240.
1-(2-Acetylphenyl)-3-(tert-butyl)urea (6j). Prepared according to
general procedure C, using tert-butylamine (31 mg, 0.42 mmol) to
afford 1-(2-acetylphenyl)-3-(tert-butyl)urea (6j) (53 mg, 65% yield) as
a yellow liquid after purification using silica gel column chromatography
(EtOAc:n-hexane = 30:70). 1H NMR (400 MHz, CDCl3) δ 10.95 (s,
1H), 8.52 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.9
Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 2.63 (s, 3H), 1.39 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 203.0, 154.2, 143.4, 135.1, 131.7, 120.7,
120.2, 120.1, 119.9, 51.1, 29.3. IR (neat): 1014, 1539, 1649, 1715, 3350
cm−1. HRMS (ESI-TOF) m/z calculated for C13H18N2O2Na (M +
Na)+ 257.1265, found 257.1247.
4-Hydroxyquinolin-2(1H)-one (7a).7a,20 Prepared according to
general procedure F, using 3-(tert-butylperoxy)-3-methylindolin-2-
one (82 mg, 0.35 mmol) to afford 4-hydroxyquinolin-2(1H)-one (7a)
(45 mg, 80% yield) as a white solid after purification using silica gel
column chromatography (DCM:MeOH = 90:10). The data for this
compound and for the reported compound are in agreement.
10b-Methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-
5-one (9a). Prepared according to general procedure G, using
ethanolamine (26 mg, 0.42 mmol) to afford 10b-methyl-2,3,6,10b-
tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one (9a) (58 mg, 81%
yield) as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 161−163 °C. H
NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H),
7.25−7.22 (m, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.86−6.84 (m, 1H), 4.18−
4.10 (m, 2H), 3.94 (dd, J = 14.3, 7.1 Hz, 1H), 3.66 (dt, J = 10.4, 7.0 Hz,
1H), 1.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.6, 134.5,
129.3, 124.5, 123.1, 122.7, 114.2, 91.9, 63.5, 43.4, 27.6. IR (neat): 1517,
1673, 3061, 3616 cm−1. HRMS (ESI-TOF) m/z calculated for
C11H13N2O2 (M + H)+ 205.0977, found 205.0978.
10b-Phenyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-
5-one (9b). Prepared according to general procedure G, using
ethanolamine (26 mg, 0.42 mmol) to afford 10b-phenyl-2,3,6,10b-
tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one (9b) (75 mg, 78%
yield) as a white solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 170−173 °C. H
NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.51 (m, 2H), 7.38−7.30 (m,
3H), 7.30−7.27 (m, 1H), 7.19 (m, 1H), 6.97 (td, J = 7.7, 1.1 Hz, 1H),
6.82 (dd, J = 8.0, 0.7 Hz, 1H), 4.26 (ddd, J = 10.7, 8.2, 5.9 Hz, 1H), 4.08
(td, J = 8.2, 5.9 Hz, 1H), 3.95 (td, J = 8.3, 5.9 Hz, 1H) 3.36 (ddd, J =
10.7, 8.4, 5.9 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.7,
143.0, 134.0, 129.5, 128.8, 128.4, 126.6, 125.1, 122.9, 121.4, 114.4, 94.2,
62.8, 43.4. IR (neat): 1434, 1602, 1670, 2920, 3212 cm−1. HRMS (ESI-
TOF) m/z calculated for C16H15N2O2 (M + H)+ 267.1134, found
267.1131.
10b-Benzyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-
5-one (9c). Prepared according to general procedure G, using
ethanolamine (26 mg, 0.42 mmol) to afford 10b-benzyl-2,3,6,10b-
tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one 9c (71 mg, 72% yield)
as a yellow solid after purification using silica gel column
1
chromatography (EtOAc:n-hexane = 30:70). MP = 154−156 °C. H
(3S,10bR)-3-Ethyl-10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo-
[3,2-c]quinazolin-5-one (9h) and (3S,10bS)-3-Ethyl-10b-methyl-
2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one (9h′). Pre-
pared according to general procedure G, using (S)-(+)-2-amino-1-
NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23
(dd, J = 7.5, 1.4 Hz, 1H), 7.20−7.16 (m, 3H), 7.05−6.98 (m, 3H),
6.75−6.73 (m, 1H), 4.11−4.06 (m, 1H), 4.00 (m, 1H), 3.84 (q, J = 7.7
9633
https://doi.org/10.1021/acs.joc.1c00889
J. Org. Chem. 2021, 86, 9621−9636

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
propanol (37 mg, 0.42 mmol) to afford (3S,10bR)-3-ethyl-10b-methyl-
2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one 9h (45 mg,
55% yield) as a faint pink solid after purification using silica gel column
chromatography (EtOAc:n-hexane = 30:70) with MP = 185−187 °C
and (3S,10bS)-3-ethyl-10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo-
[3,2-c]quinazolin-5-one 9h′ (13 mg, 16% yield) as a white solid after
purification using silica gel column chromatography (EtOAc:n-hexane
= 70:30) with MP = 184−186 °C. Diastereomers 9h and 9h′ are
present in a ratio of 3.4:1. HPLC for 9h (CHIRALPAK IA column, n-
heptane/isopropanol = 80/20, flow rate = 0.7 mL/min, l = 254 nm): tR
= 9.62 min (major), tR= 7.23 min (minor), 97% de. HPLC for 9h′
(CHIRALPAK IA column, n-heptane/isopropanol = 80/20, flow rate =
0.7 mL/min, l = 254 nm): tR= 9.88 min (major), tR = 9.61 min
(minor), 90% de. (3S,10bR)-3-Ethyl-10b-methyl-2,3,6,10b-tetrahydro-
5H-oxazolo[3,2-c]quinazolin-5-one (9h): 1H NMR (400 MHz,
CDCl3) δ 7.87 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.22 (td, J = 8.1,
1.3 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.79 (t, J = 7.1 Hz, 1H), 4.10 (td, J
= 10.5, 5.5 Hz, 1H), 4.01 (dd, J = 8.4, 6.6 Hz, 1H), 3.91 (dd, J = 8.5, 4.6
Hz, 1H), 2.23−2.12 (m, 1H), 1.74−1.63 (m, 1H), 1.56 (s, 3H), 1.03 (t,
J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.4, 134.8,
129.1, 124.0, 122.7, 114.0, 113.9, 92.4, 69.1, 59.1, 29.5, 28.0, 10.7. IR
(neat): 1524, 1690, 1739, 3616 cm−1. HRMS (ESI-TOF) m/z
calculated for C13H17N2O2 (M + H)+ 233.1290, found 233.1295.
The crystals of compound 9h were grown using dichloromethane and
petroleum ether (2:1) as a solvent by slow evaporation. A needle-
shaped single crystal was mounted on a loop by applying a small amount
of paraffin oil. Crystal data for compound 9h: C13H15N2O2, M = 231.27,
orthorhombic, space group P 21 21 21 with a = 7.5792(3) Å, b =
7.7672(3) Å, c = 19.9951(7) Å, α = 90°, β = 90°, γ = 90°, V =
1177.09(8) Å3, T = 296(2) K, R1 = 0.0306, wR2 = 0.0814 for observed
data, z = 4, Dcalcd = 1.305 g cm−3, F(000) = 492, absorption coefficient =
0.725 mm−1, λ = 1.54178 Å, 1999 reflections collected on a Bruker
APEX-II CCD single-crystal diffractometer, and 1964 observed
reflections (I ≥ 2σ(I)). The largest difference peak and hole are
0.510 and −0.142 eÅ−3, respectively
(3S,10bS)-3-Ethyl-10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo-
[3,2-c]quinazolin-5-one (9h′). 1H NMR (400 MHz, CDCl3) δ 7.80 (s,
1H), 7.32 (dd, J = 7.6, 1.1 Hz, 1H), 7.22 (td, J = 7.8, 1.4 Hz, 1H), 7.04
(td, J = 7.5, 0.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.37 (dd, J = 8.8, 7.0
Hz, 1H), 4.14−4.08 (m, 1H), 3.99 (dd, J = 8.9, 2.7 Hz, 1H), 2.07−1.96
(m, 1H), 1.67−1.60 (m, 1H), 1.45 (s, 3H), 0.80 (t, J = 7.5 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 151.2, 134.8, 128.8, 125.5, 123.0,
122.8, 114.0, 92.4, 69.0, 56.4, 25.5, 24.1, 9.3. IR (neat): 1520, 1674,
3615 cm−1. HRMS (ESI-TOF) m/z calculated for C13H17N2O2 (M +
H)+ 233.1290, found 233.1295.
(3S,10bR)-3-Isopropyl-10b-methyl-2,3,6,10b-tetrahydro-5H-
oxazolo[3,2-c]quinazolin-5-one (9i) and (3S,10bS)-3-Isopropyl-10b-
methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one
(9i′). Prepared according to general procedure G, using (S)-(+)-2-
amino-3-methyl-1-butanol (43 mg, 0.42 mmol) to afford (3S,10bR)-3-
isopropyl-10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]-
quinazolin-5-one (9i) (41 mg, 48% yield) as a gray solid after
purification using silica gel column chromatography (EtOAc:n-hexane
= 30:70) with MP = 205−208 °C and (3S,10bS)-3-isopropyl-10b-
methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one 9i′
(17 mg, 20% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 70:30) with MP = 204−
207 °C. Diastereomers 9i and 9i′ are present in a ratio of 2.4:1. HPLC
for 9i (CHIRALPAK IA column, n-heptane/isopropanol = 80/20, flow
rate = 0.7 mL/min, l = 254 nm): tR= 8.03 min (major), tR = 6.82 min
(minor), 94% de. HPLC for 9i′ (CHIRALPAK IA column, n-heptane/
isopropanol = 80/20, flow rate = 0.7 mL/min, l = 254 nm): tR = 13.63
min (major), tR = 8.12 min (minor), 95% de. (3S,10bR)-3-isopropyl-
10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one
(9i): 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.38−7.34 (m, 1H),
7.22 (td, J = 7.7, 1.5 Hz, 1H), 7.03 (td, J = 7.5, 1.1 Hz, 1H), 6.77 (dd, J =
8.0, 0.7 Hz, 1H), 3.98 (dd, J = 8.4, 2.9 Hz, 1H), 3.93−3.88 (m, 1H),
3.76 (dd, J = 8.4, 5.9 Hz, 1H), 2.17−2.04 (m, 1H), 1.56 (s, 3H), 1.15 (d,
J = 6.9 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 153.2, 135.0, 129.1, 124.3, 124.0, 122.6, 113.8, 92.5, 67.7,
64.2, 31.8, 30.0, 19.9, 19.6. IR (neat): 1524, 1693, 1739, 3616 cm−1.
HRMS (ESI-TOF) m/z calculated for C14H19N2O2 (M + H)+
247.1446, found 247.1444.
(3S,10bS)-3-Isopropyl-10b-methyl-2,3,6,10b-tetrahydro-5H-
oxazolo[3,2-c]quinazolin-5-one (9i′). 1H NMR (400 MHz, CDCl3) δ
7.31 (d, J = 7.0 Hz, 1H), 7.23 (td, J = 7.8, 1.4 Hz, 1H), 7.05 (td, J = 7.5,
0.9 Hz, 1H), 6.98 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.26−4.21 (m, 1H),
4.13−4.09 (m, 2H), 2.69−2.59 (m, 1H), 1.45 (s, 3H), 0.89 (d, J = 7.1
Hz, 3H), 0.58 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
150.7, 128.7, 125.6, 125.5, 123.1, 122.9, 113.7, 92.4, 64.8, 60.0, 26.2,
25.2, 19.5, 14.7.IR (neat): 1511, 1605, 1670, 3062, 3613 cm−1. HRMS
(ESI-TOF) m/z calculated for C14H19N2O2 (M + H)+ 247.1446, found
247.1451.
(3S,10bR)-3-Benzyl-10b-methyl-2,3,6,10b-tetrahydro-5H-
oxazolo[3,2-c]quinazolin-5-one (9j) and (3S,10bS)-3-Benzyl-10b-
methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one
(9j′). Prepared according to general procedure G, using (S)-2-amino-3-
phenylpropan-1-ol (64 mg, 0.42 mmol) to afford (3S,10bR)-3-benzyl-
10b-methyl-2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one
(9j) (47 mg, 45% yield) as a white solid after purification using silica gel
column chromatography (EtOAc:n-hexane = 30:70) with MP = 122−
125 °C and (3S,10bS)-3-benzyl-10b-methyl-2,3,6,10b-tetrahydro-5H-
oxazolo[3,2-c]quinazolin-5-one (9j′) (36 mg, 35% yield) as a white
solid after purification using silica gel column chromatography
(EtOAc:n-hexane = 70:30) with MP = 92−95 °C. Diastereomers 9j
and 9j′ are present in a ratio of 1.3:1. HPLC for 9j (CHIRALPAK IA
column, n-heptane/isopropanol = 80/20, flow rate = 0.7 mL/min, l =
254 nm): tR = 11.84 min (major), tR = 4.72 min (minor), 94% de.
HPLC for 9j′ (CHIRALPAK IA column, n-heptane/isopropanol = 80/
20, flow rate = 0.7 mL/min, l = 254 nm): tR = 13.47 min (major), tR =
11.81 min (minor), 84% de. (3S,10bR)-3-Benzyl-10b-methyl-
2,3,6,10b-tetrahydro-5H-oxazolo[3,2-c]quinazolin-5-one (9j): 1H
NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.38−7.33 (m, 5H), 7.30−
7.22 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.90−6.89 (m, 1H), 4.47−4.43
(m, 1H), 4.00 (dd, J = 8.8, 5.4 Hz, 1H), 3.90 (t, J = 7.8 Hz, 1H), 3.54 (d,
J = 13.2 Hz, 1H), 3.06−2.99 (m, 1H), 1.48 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 152.9, 137.6, 134.9, 129.7, 129.1, 128.7, 126.8,
124.0, 123.9, 122.6, 114.2, 92.7, 68.2, 58.7, 40.4, 29.2. IR (neat): 1524,
1685, 3617 cm−1. HRMS (ESI-TOF) m/z calculated for C18H19N2O2
(M + H)+ 295.1446, found 295.1444.
(3S,10bS)-3-Benzyl-10b-methyl-2,3,6,10b-tetrahydro-5H-
oxazolo[3,2-c]quinazolin-5-one (9j′). 1H NMR (400 MHz, CDCl3) δ
9.01 (s, 1H), 7.34−7.17 (m, 8H), 7.02 (td, J = 7.5, 1.0 Hz, 1H), 6.91 (d,
J = 8.0 Hz, 1H), 4.41−4.36 (m, 1H), 4.18 (dd, J = 8.9, 6.9 Hz, 1H), 4.03
(dd, J = 9.3, 2.4 Hz, 1H), 3.66 (dd, J = 13.2, 2.7 Hz, 1H), 2.51 (dd, J =
13.2, 10.3 Hz, 1H), 1.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
151.9, 138.0, 135.0, 129.4, 128.8, 128.7, 126.6, 125.5, 122.8, 122.7,
114.2, 92.6, 68.5, 56.8, 37.7, 25.6. IR (neat): 1523, 1685, 3615 cm−1.
HRMS (ESI-TOF) m/z calculated for C18H19N2O2 (M + H)+
295.1446, found 295.1443.
3-Benzylquinazoline-2,4(1H,3H)-dione (10a). Prepared according
to general procedure H, using 3-benzyl-4-methylene-3,4-dihydro-
quinazolin-2(1H)-one 3a (63 mg, 0.25 mmol) to afford 3-benzyl-
quinazoline-2,4(1H,3H)-dione 10a (49 mg, 78% yield) as a white solid
after purification using silica gel column chromatography (EtOAc:n-
hexane = 30:70). MP = 203−205 °C. 1H NMR (400 MHz, CDCl3) δ
9.93 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.54−
7.52 (m, 2H), 7.33−7.29 (m, 2H), 7.25−7.20 (m, 2H), 7.04 (d, J = 8.1
Hz, 1H), 5.27 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.4,
152.0, 138.6, 137.0, 135.2, 129.0, 128.7, 128.6, 127.8, 123.5, 115.0,
114.7, 44.3. IR (neat): 1459, 1645, 1735, 2922, 3282 cm−1. HRMS
(ESI-TOF) m/z calculated for C15H13N2O2 (M + H)+ 253.0977, found
253.0968.
3-Ethylquinazoline-2,4(1H,3H)-dione (10b). Prepared according to
general procedure H, using 3-ethyl-4-methylene-3,4-dihydro-
quinazolin-2(1H)-one 3p (47 mg, 0.25 mmol) to afford 3-ethyl-
quinazoline-2,4(1H,3H)-dione 10b (33 mg, 69% yield) as a white solid
after purification using silica gel column chromatography (EtOAc:n-
hexane = 30:70). MP = 190−192 °C. 1H NMR (400 MHz, CDCl3) δ
10.35 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.61 (ddd, J = 8.2, 7.3, 1.5 Hz,
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1H), 7.25−7.21 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 4.17 (q, J = 7.1 Hz,
2H), 1.32 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
162.3, 52.1, 138.7, 135.0, 128.4, 123.4, 115.1, 114.8, 36.3, 13.3. IR
(neat): 1455, 1659, 1715, 2919, 3058 cm−1. HRMS (ESI-TOF) m/z
calculated for C10H11N2O2 (M + H)+ 191.0820, found 191.0824.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00889.
■
sı
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Copies of 1H and 13C NMR spectra and crystallographic
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FAIR data, including the primary NMR FID files, for
compounds 3a−z, 6a−j, 7a, 9a−h, 9h′, 9i, 9i′, 9j, 9j′, 10a,
and 10b (ZIP)
Accession Codes
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CCDC 2053446−2053447 contain the supplementary crystallo-
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ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
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AUTHOR INFORMATION
Corresponding Author
Boopathy Gnanaprakasam − Department of Chemistry, Indian
Institute of Science Education and Research, Pune 411008,
India; orcid.org/0000-0002-3047-9636;
Email: gnanaprakasam@iiserpune.ac.in
■
Authors
Akash S. Ubale − Department of Chemistry, Indian Institute of
Science Education and Research, Pune 411008, India;
orcid.org/0000-0001-6893-1192
Moseen A. Shaikh − Department of Chemistry, Indian Institute
of Science Education and Research, Pune 411008, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00889
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the SERB (CRG/2018/
003935), India. A.S.U. thanks UGC-India, and M.A.S. thanks
DST for the INSPIRE fellowship. B.G. thanks SERB and IISER-
Pune for the research support.
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