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Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated

Derivatives from Epoxides toward the Synthesis of Aza Heterocycles
Alageswaran Jayaram, Karthick Govindan, Vijaya Raghavan Kannan, Vijay Thavasianandam Seenivasan,
Nian-Qi Chen, and Wei-Yu Lin*
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ABSTRACT: A new method for directly synthesizing acylated and

alkylated quinazoline derivatives by the epoxide ring-opening
Downloaded via UNIV OF SAO PAULO on February 6, 2023 at 15:52:59 (UTC).

reaction in the presence of I2/DMSO with 2-aminobenzamide is

described herein. The developed mild protocol is efficient and
displays a wide variety of functional group tolerance and substrate-
controlled high selectivity, and the application of a continuous flow
technique allows for faster reaction time and higher yields.
Moreover, the robustness of the method is applicable in gram-
scale synthesis.

■ INTRODUCTION
Aza heterocycles exhibit engrossing biological activity,
Considering the synthetic importance, the evolution of a
simple, transition-metal-free, and single protocol for diverse
methods allowing effective access to this class of aza
especially for quinazoline scaffolds which are found in a wide
heterocycles would be highly desirable. Recently, our group
range of natural products and pharmaceuticals. Indeed, various
reported a technique using DMSO that serves as the −CH2
molecules based on quinazoline structural motifs were
and −CH synthon to produce quinazoline derivatives (Figure
investigated widely, which showed miscellaneous therapeutic
1c).18 As a continuation of our efforts toward the construction
potentials such as anti-inflammatory, anti-cancer, anti-tumor,
of N-heterocycles,19 we herein developed a fast and efficient
5-HT3 receptor antagonistic, and glucagon receptor antago- method for producing biologically active diverse N-hetero-
nistic activities.1 Due to their impressive properties in the cycles such as 2-benzoylquinazolin-4(3H)-one and phenyl-
medicinal field, several methods have been developed. One of (pyrrolo[1,2-a] quinoxalin-4-yl) methanone derivatives using
the most artistic and well-studied transformations toward epoxides as acyl precursors (Figure 1d). In addition, the same
quinazolines was the condensation of 2-aminobenzamide with approach could also be used to successfully synthesize a range
various simple aryl-functionalized sources under metal or of novel 1-methyl-dihydroquinazolin-4(1H)-ones in batch, and
metal-free conditions. For example, 2-aminobenzamide was the use of continuous flow reaction conditions allowed the
treated with various precursors such as benzyl alcohols,2 reduction of the reaction time, made it operationally safe, and
benzylamine,3 phenylacetic acid,4 aldehyde,2e,5 ketone,6 improved the reaction yields over the batch technique.20 To
amide,7 α-keto acids,8 potassium-2-oxo-2-phenylacetate,9 β- the best of our knowledge, no reports have identified that
ketoester,10 toluene,11 benzonitrile,12 alkene,13 and alkyne13b epoxides can serve as acyl and alkyl precursors using the same
to afford the aryl group-incorporated quinazoline derivatives methodology.
that have been reported (Figure 1a). Regrettably, all these
methods are certain to provide only arylated derivatives,
though there are also few specific examples known for
■ RESULTS AND DISCUSSION
To endorse our hypothesis, we have performed a reaction
introducing acyl groups on a quinazoline scaffold and are
between 2-aminobenzamide (1a) and styrene oxide (2a) as
mainly based on the reaction of acetophenone with 2-
aminobenzamide under different conditions.14 Despite these
developments, certain flaws exist, such as requiring high iodine Received: November 22, 2022
doses, external oxidants, excess sulfur loading, longer reaction Published: January 17, 2023
times, and lack of selectivity. Recently, researchers disclosed
the cyclization of quinoline derivatives by incorporating
sulfoxonium ylide/ruthenium,15 terminal alkyne/iodine,16 and
α-hydroxy acids/tert-butyl hydroperoxide17 (Figure 1b).

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.2c02802

1749 J. Org. Chem. 2023, 88, 1749−1761
The Journal of Organic Chemistry pubs.acs.org/joc Article

Figure 1. Previous and our approaches.

model substrates (Table 1). To our delight, the desired yields (entries 6 and 7). Decreasing or increasing the reaction
product 3a could be obtained in 71% yield in the presence of temperature did not improve the yield (entries 8−10). Further,
20 mol % iodine in DMSO solvent at 110 °C under an O2 the loading of iodine dosage was evaluated (entries 11−14),
atmosphere (entry 1). Encouraged by this result, several and it was confirmed that 20 mol % of iodine gave the
optimizations were evolved. Surprisingly, the reaction maximum yield of 3a (92%). Finally, different solvents were
proceeded well under a N2 atmosphere with a 92% yield used in place of DMSO such as DMF, MeCN, MeOH, H2O,
(entry 2). No reaction occurred at ambient temperature (entry toluene, and 1,4-dioxane, leading to trace or no conversion
3). The resultant product was formed in 60 and 42% yields (entries 15−20). As a result, the ideal reaction condition was
when the reaction was performed without adding iodine under determined to be 2-aminobenzamide (1a) (0.20 mmol), 2-
O2 and N2 atmospheres, respectively (entries 4 and 5). When phenyloxirane (2a) (0.24 mmol), and iodine (20 mol %) in
the reaction was performed in atmospheric air or with a longer DMSO (1.0 mL) for 2 h at 110 °C under an N2 atmosphere
reaction time, there may be a slight decrease in the reaction (Table 1, entry 2).
1750 https://doi.org/10.1021/acs.joc.2c02802
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Table 1. Studies on the Reaction Parametersa desired product 5f was isolated in 49% (66% in flow) yield by
changing the pyrrole ring moiety to 3,4-dimethylpyrrole (4f).
After gaining encouraging results, we extended our strategy
to use 2-(methylamino)-N-phenylbenzamide (6a) and 2-
phenyloxirane (2a) as model substrates under standard
conditions in batch as well as in continuous flow methods.
As illustrated in Table 4, unexpected cyclization occurred to
iodine temperature yield produce (benzyl)alkylated derivatives (7) in good yields
entry (mol %) solvent (°C) atmosphere (%)b
effectively (7a, 68% batch and 77% flow). The R1 group
1 20 DMSO 110 O2 71 bearing both electron-donating (Me and OMe) and electron-
2 20 DMSO 110 N2 92 withdrawing (Cl and F) groups showed good reactivity,
3 20 DMSO RT O2 traces leading to the corresponding product in good and excellent
4 DMSO 110 O2 60 yields (7b, 62% batch and 87% flow; 7c, 69% batch; 7d, 78%
5 DMSO 110 N2 42 batch and 86% flow; and 7e, 70% batch). Subsequently,
6 20 DMSO 110 open air 87 aliphatic substrates in the R1 group also operated well and
7 20 DMSO 110 open air 88c yielded 7f−i (7f, 45% batch and 61% flow; 7g, 57% batch and
8 20 DMSO 70 N2 traces 70% flow; 7h, 77% batch; and 7i, 56% batch and 65% flow).
9 20 DMSO 100 N2 43 To further highlight our methodology, we showcased diverse
10 20 DMSO 120 N2 77 substrates in the R4 group, such as benzyl, phenyl, allyl, and
11 10 DMSO 110 N2 85 propargyl, which showed great potential for the cyclization
12 30 DMSO 110 N2 82
process 7j−m, and good yields were observed under
13 50 DMSO 110 N2 67
continuous flow conditions.
14 100 DMSO 110 N2 60
Next, to check the scalability of the transformation, a
15 20 DMF 110 N2 N.R.
reaction was performed with 5.0 mmol of 1a, and the
16 20 MeCN 80 N2 N.R.
corresponding product 3a was obtained with a good yield of
17 20 MeOH 50 N2 N.R.
85% (Scheme 1a). The stable key intermediates (3ab and 3ad)
18 20 H2O 90 N2 N.R.
were successfully achieved in the presence of iodine using an
19 20 toluene 100 N2 traces
external oxidant at a lower temperature with a good yield
20 20 1,4-dioxane 90 N2 traces
a
(Scheme 1b).
Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), and solvent To elucidate the reaction mechanism, a series of experiments
(1.0 mL). bIsolated yield. cReaction was performed up to 16 h; N.R. = were performed (Scheme 2). When radical scavengers [2,2,6,6-
no reaction.
tetramethylpiperidinyloxy (TEMPO) and butylated hydrox-
ytoluene (BHT)] were used with 1a or 4a under standard
conditions, the desired product was obtained. In addition, the
Having established the optimal reaction conditions, we reaction of 6d with TEMPO was significantly inhibited, and
explored the reaction scope with different 2-aminobenzamides BHT gave the desired product. Iodine and TEMPO have a
and various epoxides (Table 2). When styrene epoxide reacts known interaction;22 therefore, these findings provide a piece
with 2-aminobenzamide bearing electron-withdrawing sub- of evidence that a non-radical channel may be involved in the
stituents (I, Br, and NO2) and an electron-donating substituent formation of acylation and alkylation (Scheme 2a−c). When
(OMe) on the aryl ring, the reaction occurred smoothly with 1a reacted with 2-oxo-2-phenylethyl-4-methylbenzenesulfonate
good to excellent yields in 55−83% (3b−e). Next, we turned (2ab), 2-iodoacetophenone (2ac), or 2-hydroxyacetophenone
our attention to elucidate further scope in various epoxides, (2ad), the desired product 3a was obtained in 56, 72, and 69%
When the styrene oxides were tethered with electron-deficient yields, respectively (Scheme 2d). These results suggest that
groups (Br), as anticipated, the desired reaction was smoothly during the reaction, 2,3-phenyl migration may occur through
furnished (3f). It is noteworthy that the aliphatic oxirane also elimination of the leaving group (X = OTs, I, and OH).6,13b,14b
worked well and gave moderate to good yields (3g−i). Moreover, when the reaction temperature was decreased to 80
Unfortunately, with R1 group substituents containing aryl or °C or the reaction was performed with cyclohexa-1,4-diene, the
alkyl moieties, the reaction was inefficient and decomposed resulting 3ab was predominantly observed (Scheme 2e−f),
under these conditions (3j−k). which indicates that 3ab was involved in the transformations,
Recently, our laboratory have developed efficiently and and it would serve as the key intermediate in this reaction. As
convenient for the synthesis of pyrazole, internal alkynes, and shown in Scheme 2g, the observed results further confirm that
primary amides using a continuous flow system.21 After the formation of 3a occurred through 3ab. Additionally, it
successfully establishing the scope of 2-benzoylquinazolin- implies that the lower temperature (80 °C) was inefficient for
4(3H)-one derivative, we expanded our strategy with further oxidation. Next, 7d was not formed without an iodine
optimized standard conditions to the synthesis of the acylated source, unveiling the crucial role of iodine. The lower
cyclized product of phenyl(pyrrolo[1,2-a] quinoxalin-4-yl) temperature did not affect the yield of the formation of
methanone (5a) from 2-(1H-pyrrol-1-yl) aniline (4a) and 2- alkylation (Scheme 2h−i).
phenyloxirane (2a) as substrates in good and excellent yields Based on the control experiment results and literature
(Table 3) under batch and flow conditions (5a, 72% in batch reports,23 a plausible mechanism for the representative reaction
and 85% in flow). In addition, electron-donating substituents between 2-aminobenzamide 1a or the substrate (6) and
(Me and OMe) and electron-withdrawing substituents (F and styrene oxide (2a) to furnish the desired products 3a and 7 is
CF3) on the phenyl ring in the pyrrole moieties delivered the proposed in Scheme 3. Initially, styrene oxide 2a was oxidized
respective products in 55−75% yield (5b−e). Significantly, the with I2/DMSO to form 2ac via the ring-opening reaction. A
1751 https://doi.org/10.1021/acs.joc.2c02802
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Table 2. Substrates Scope for 2-Benzoylquinazolin-4(3H)-one Derivativesa

a
Reaction conditions: 1 (0.20 mmol), 2 (0.24 mmol), I2 (20 mol %), DMSO (1.0 mL), reaction time (2−4 h). bIsolated yield. cReaction was
performed in a sealed tube; N.R = no reaction.

nucleophilic addition reaction of 1a with reactive 2ac followed advantages. Moreover, iodine-promoted synthetic develop-
by intramolecular cyclization led to II. Then, an effective 2,3- ments are underway in our laboratory.
phenyl shift occurred to form intermediate 3ab. Further, it gets
oxidation in the presence of I2/DMSO by the elimination of
hydrogen iodide and dimethyl sulfide to form the desired
product 3a. Similarly, the substrate 6 reacts with 2ac to form V
■ EXPERIMENTAL SECTION
Experimental Procedure for 2-Benzoylquinazolin-4(3H)-one
Derivatives (3a−j). A 10 mL vial was charged with 1a−j (0.2 mmol,
followed by VI with the elimination of water. Then, 2,3-phenyl 1.0 equiv), 2-phenyloxirane (0.24 mmol), iodine (20 mol %), and
migration occurred to form cationic intermediate VII. Finally, DMSO (1 mL) in a nitrogen atmosphere. The reaction mixture was
by the oxidation process, the desired product 7 was formed. stirred at 110 °C in an oil bath for about 2−4 h, then it was allowed to
reach room temperature, and quenched with a saturated solution of
■ CONCLUSIONS
In summary, we have developed a novel method for
Na2S2O3. After diluting with 5 mL of water, the aqueous layer was
extracted with ethyl acetate (3 × 10 mL), and the combined ethyl
acetate layer was washed with a brine solution (1 × 5 mL). The final
controllable oxidative cyclization of acylated and alkylated ethyl acetate layer was then dried over MgSO4 and concentrated
quinazoline derivatives by the epoxide ring-opening reaction in under reduced pressure to get the crude product. The obtained crude
the presence of the I2/DMSO system. This efficient single product was purified using column chromatography by eluting with
methodology helps to synthesize divergent N-heterocycles ethyl acetate/hexane (3:7) to afford pure 2-benzoylquinazolin-4(3H)-
without any metal or oxidants. This method also successfully one derivatives 3a−j up to 51−92% yields.
Experimental Procedure for Phenyl(pyrrolo[1,2-a]-
and efficiently applied in continuous flow conditions with good quinoxalin-4-yl)methanone Derivatives (5a−f). A 10 mL vial
yields. We anticipate that the results of our research will was charged with (4a−f) (0.2 mmol, 1.0 equiv), 2-phenyloxirane
encourage the repurposing of other heterocyclic skeletons as (0.24 mmol), iodine (20 mol %), and DMSO (1 mL) in a nitrogen
valuable synthetic building blocks for developing elaborately atmosphere. The reaction mixture was stirred at 110 °C in an oil bath
decorated derivatives of the scaffolds with therapeutic for about 2−6 h, then it was allowed to reach room temperature, and

1752 https://doi.org/10.1021/acs.joc.2c02802
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Table 3. Substrate Scope for Phenyl(pyrrolo[1,2-a] Quinoxalin-4-yl) Methanone Derivativesa

a
Reactions were performed in batch and flow conditions. Reaction conditions in batch: 4 (0.20 mmol), 2a (0.24 mmol), I2 (20 mol %), DMSO
(1.0 mL), and reaction time (2−6 h). bReaction conditions in flow: 4 (0.20 mmol), 2a (0.26 mmol), I2 (30 mol %), and DMSO (2.0 mL) with the
residence time of 13 min. cIsolated yields.

quenched with a saturated solution of Na2S2O3. After diluting with 5 product. The obtained crude product was purified using column
mL of water, the aqueous layer was extracted with ethyl acetate (3 × chromatography by eluting with ethyl acetate/hexane (2:8) to afford
10 mL), and the combined ethyl acetate layer was washed with brine the desired product, and the final product was analyzed by 1H NMR.
solution (1 × 5 mL). The final ethyl acetate layer was then dried over Flow Method for the Synthesis of Derivatives (7a, 7b, 7d,
MgSO4 and concentrated under reduced pressure to get the crude 7f, 7g, 7i, and 7m). The flow microreactor system consists of one T-
product. The obtained crude product was purified using column shaped micromixer (M1 500 μm), one microtube reactor (R1), and
chromatography by eluting with ethyl acetate/hexane (2:8) to afford two reagent delivering units P1 (inner diameter = 800 μm; length L =
pure 2-benzoylquinazolin-4(3H)-one derivatives 5a−f up to 49−75% 25 cm) and P2 (inner diameter = 800 μm; length L = 25 cm). A
yields. solution of 6 (0.1 M in DMSO, flow rate = 0.1 mL/min) and a
Experimental Procedure for 2-Benzyl-1-methyl-3-phenyl- solution of I2 and 2a (0.02 M and 0.13 M, respectively, in DMSO,
2,3-dihydroquinazolin-4(1H)-one Derivatives (7a−m). A 10 mL flow rate = 0.1 mL/min) were introduced to M1 (M1 Φ = 500 μm)
vial was charged with (6a−m) (0.2 mmol, 1.0 equiv), 2-phenyloxirane using syringe pumps. The resulting solution was passed through R1
(0.24 mmol), iodine (20 mol %), and DMSO (1 mL) in a nitrogen (Φ = 800 μm; L = 500 cm) through a BPR (2.8 bar) at 110 °C
atmosphere. The reaction mixture was stirred at 110 °C in an oil bath temperature. After the steady state was reached (after 1 min), the final
for about 2−6 h, then it was allowed to reach room temperature, and product solution was collected for 18 min in a vial. After diluting with
quenched with a saturated solution of Na2S2O3. After diluting with 5 5 mL of water, the aqueous layer was extracted with ethyl acetate (3 ×
mL of water, the aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined ethyl acetate layer was washed with brine
10 mL), and the combined ethyl acetate layer was washed with brine solution (1 × 5 mL). The final ethyl acetate layer was then dried over
solution (1 × 5 mL). The final ethyl acetate layer was then dried over MgSO4 and concentrated under reduced pressure to get the crude
MgSO4 and concentrated under reduced pressure to get the crude product. The obtained crude product was purified using column
product. The obtained crude product was purified using column chromatography by eluting with ethyl acetate/hexane (2:8) to afford
chromatography by eluting with ethyl acetate/hexane (2:8) to afford the desired product, and the final product was analyzed by 1H NMR.
pure 2-benzoylquinazolin-4(3H)-one derivatives 7a−m up to 45− Experimental Procedure for Gram-Scale Synthesis of 2-
78% yields. Benzoylquinazolin-4(3H)-one (3a). A 100 mL round-bottom flask
Flow Method for the Synthesis of Derivatives (5a, 5b, and was charged with 1a (5.0 mmol, 1.0 equiv), 2-phenyloxirane (6.0
5f). The flow microreactor system consists of one T-shaped mmol, 1.2 equiv), iodine (20 mol %), and DMSO (30 mL) in a
micromixer (M1 500 μm), one microtube reactor (R1), and two nitrogen atmosphere. The reaction mixture was stirred at 110 °C in an
reagent delivering units P1 (inner diameter = 800 μm; length L = 25 oil bath for about 4 h, then it was allowed to reach room temperature,
cm) and P2 (inner diameter = 800 μm; length L = 25 cm). A solution and quenched with a saturated solution of Na2S2O3. After diluting
of 4 (0.1 M in DMSO, flow rate = 0.1 mL/min) and a solution of I2 with 100 mL of water, the aqueous layer was extracted with ethyl
and 2a (0.02 M, 0.13 M in DMSO, flow rate = 0.1 mL/min) were acetate (3 × 100 mL), and the combined ethyl acetate layer was
introduced into M1 (M1 Φ = 500 μm) using syringe pumps. The washed with the brine solution (1 × 100 mL). The final ethyl acetate
resulting solution was passed through R1 (Φ = 800 μm, L = 500 cm) layer was then dried over MgSO4 and concentrated under reduced
and fitted with a backpressure regulator (BPR; 2.8 bar) at 110 °C pressure to get the crude product. The obtained crude product was
temperature. After the steady state was reached (after 1 min), the final purified using column chromatography by eluting with ethyl acetate/
product solution was collected for 18 min in a vial. After diluting with hexane (3:7) to afford pure 2-benzoylquinazolin-4(3H)-one (3a) as a
5 mL of water, the aqueous layer was extracted with ethyl acetate (3 × white solid (1.06 g, 85%).
10 mL), and the combined ethyl acetate layer was washed with brine Characterization Data. 2-Benzoylquinazolin-4(3H)-one (3a).14b
solution (1 × 5 mL). The final ethyl acetate layer was then dried over The title compound was synthesized according to the general
MgSO4 and concentrated under reduced pressure to get the crude procedure. The crude mixture was purified using column chromatog-

1753 https://doi.org/10.1021/acs.joc.2c02802
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Table 4. Substrate Scope for 2-Benzyl-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one Derivativesa

a
Reactions were performed in batch and flow conditions. Reaction conditions in batch: 6 (0.20 mmol), 2a (0.24 mmol), I2 (20 mol %), DMSO
(1.0 mL), and reaction time (2−6 h). bReaction conditions in flow: 6 (0.20 mmol), 2a (0.26 mmol), I2 (30 mol %), and DMSO (2.0 mL) with the
residence time of 15 min. cIsolated yields.

raphy by eluting with ethyl acetate/hexane (3:7) and obtained as a with ethyl acetate/hexane (3:7) and obtained as a white solid (48 mg,
white solid (46 mg, 92%); 1H NMR (400 MHz, DMSO-d6) δ 12.68 74%); mp 258−259 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s,
(s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2.0 Hz, 2H), 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.16−8.14 (m, 2H), 8.03 (dd, J = 8.0
7.91−7.87 (m, 1H), 7.79−7.73 (m, 2H), 7.68−7.64 (m, 1H), 7.60 (t, Hz, 4.0 Hz, 1H), 7.75−7.74 (m, 1H), 7.60 (t, J = 8.0 Hz, 2H), 7.50−
J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.7, 160.9, 7.35 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 187.5, 160.5,
147.6, 146.0, 134.9, 134.4, 134.0, 131.9, 129.6, 129.5, 128.5, 127.0, 150.0, 138.0, 134.8, 134.4, 131.3, 129.0, 128.9, 128.7, 126.1, 125.0,
123.4. 121.6. HRMS (EI+) m/z: [M]+ calcd for C15H9BrN2O2, 327.9847;
2-Benzoyl-6-iodoquinazolin-4(3H)-one (3b).14b The title com- found, 327.9848.
pound was synthesized according to the general procedure. The crude 2-Benzoyl-6-nitroquinazolin-4(3H)-one (3d).14b The title com-
mixture was purified using column chromatography by eluting with pound was synthesized according to the general procedure. The crude
ethyl acetate/hexane (3:7) and obtained as a white solid (62 mg, mixture was purified using column chromatography by eluting with
83%); 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.48 (d, J = ethyl acetate/hexane (3:7) and obtained as a white solid (36 mg,
4.0 Hz, 1H), 8.18−8.13 (m, 3H), 7.75 (tt, J = 7.2 Hz, 1.6 Hz, 1H), 62%); 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.87 (d, J =
7.61−7.54 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.4, 2.8 Hz, 1H), 8.60 (dd, J = 8.8 Hz, 2.8 Hz, 1H),8.13−8.16 (m, 2H),
159.4, 147.0, 146.3, 144.0, 136.0, 134.6, 133.9, 132.0, 131.1, 128.6, 7.97 (d, J = 9.2 Hz, 1H), 7.78 (tt, J = 7.6 Hz, 1.2 Hz, 1H), 7.63−7.59
124.8, 95.2. (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 187.5, 161., 152.7,
2-Benzoyl-6-bromoquinazolin-4(3H)-one (3c). The title com- 152.0, 146.5, 135.2, 134.2, 131.4, 130.5, 129.3, 129.1, 123.8, 122.4.
pound was synthesized according to the general procedure. The 2-Benzoyl-6-methoxyquinazolin-4(3H)-one (3e).14c The title
crude mixture was purified using column chromatography by eluting compound was synthesized according to the general procedure. The

1754 https://doi.org/10.1021/acs.joc.2c02802
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 1. Application in Gram Scale Synthesis of 2-Benzylquinazolin-4(3H)-one Derivatives

crude mixture was purified using column chromatography by eluting (39 mg, 72%); 1H NMR (400 MHz, DMSO-d6) δ 8.64 (t, J = 1.4 Hz,
with ethyl acetate/hexane (3:7) and obtained as a yellowish white 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.95 (d, J =
solid (30 mg, 55%); 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.1 Hz, 1H), 7.76−7.71 (m, 2H), 7.60−7.54 (m, 3H), 7.11−7.04 (m,
8.16 (d, J = 8.0 Hz, 2H), 7.76−7.71 (m, 2H), 7.61−7.57 (m, 3H), 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.5, 150.1, 136.0, 134.9,
7.49 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 3.92 (s, 3H); 13C{1H} NMR (100 133.7, 131.3, 131.2, 129.6, 128.5, 128.1, 125.6, 124.5, 115.1, 114.9,
MHz, DMSO-d6) δ 187.1, 161.0, 159.3, 147.0, 141.4, 134.4, 134.0, 114.0, 109.1.
130.9, 130.3, 128.5, 124.1, 124.0, 106.4, 55.9. (7-Methylpyrrolo[1,2-a]quinoxalin-4-yl)(phenyl)methanone
2-(4-Bromobenzoyl)quinazolin-4(3H)-one (3f).1c The title com- (5b).15a The title compound was synthesized according to the general
pound was synthesized according to the general procedure. The crude procedure. The crude mixture was purified using column chromatog-
mixture was purified using column chromatography by eluting with raphy by eluting with ethyl acetate/hexane (1:9) and obtained as a
ethyl acetate/hexane (3:7) and obtained as a white solid (46 mg, bright yellow solid (32 mg, 56%); 1H NMR (400 MHz, DMSO-d6) δ
70%); 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.23−8.11 8.58 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 8.26 (s, 1H), 8.04 (dd, J = 8.4 Hz,
(m, 3H), 7.90−7.73 (m, 4H), 7.56−7.52 (m, 1H); 13C{1H} NMR 1.2 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.71 (tt, J = 8.0 Hz, 1.2 Hz,
(100 MHz, DMSO-d6) δ 187.7, 161.3, 152.9, 152.1, 146.7, 135.4, 1H), 7.60−7.56 (m, 2H), 7.40−7.37 (m, 1H), 7.10 (dd, J = 4.0 Hz,
134.3, 131.6, 130.6, 129.4, 129.3, 123.9, 122.5. 1.2 Hz, 1H), 7.03 (dd, J = 4.0 Hz, 2.2 Hz 1H), 2.57 (s, 3H); 13C{1H}
2-Acetylquinazolin-4(3H)-one (3g).24 The title compound was NMR (100 MHz, DMSO-d6) δ 192.7, 165.0, 148.9, 141.0, 136.2,
synthesized according to the general procedure. The crude mixture 134.2, 132.5, 131.0, 130.6, 129.0, 127.8, 127.5, 123.9, 116.9, 115.4,
was purified using column chromatography by eluting with ethyl 108.5, 22.0.
acetate/hexane (3:7) and obtained as a white solid (25 mg, 67%); 1H (8-Methoxypyrrolo[1,2-a]quinoxalin-4-yl)(phenyl)methanone
(5c).15a The title compound was synthesized according to the general
NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.36 (dd, J = 8.0 Hz, 1.6
procedure. The crude mixture was purified using column chromatog-
Hz, 1H), 7.90−7.86 (m, 2H), 7.63 (m, 1H), 2.77 (s, 3H); 13C{1H}
raphy by eluting with ethyl acetate/hexane (3:17) and obtained as a
NMR (100 MHz, CDCl3) δ 194.2, 160.6, 147.8, 145.4, 135.0, 129.5,
dark yellow solid (33 mg, 55%); 1H NMR (400 MHz, DMSO-d6) δ
129.3, 127.0, 123.6, 24.1.
8.57 (s, 1H), 8.02−7.93 (m, 2H), 7.87−7.79 (m, 2H), 7.67 (t, J = 6.0
2-Propionylquinazolin-4(3H)-one (3h). The title compound was
Hz, 1H), 7.57−7.54 (m, 2H), 7.14−6.98 (m, 3H), 3.96 (s, 3H);
synthesized according to the general procedure. The crude mixture 13
C{1H} NMR (100 MHz, DMSO-d6) δ 192.2, 160.9, 159.3, 146.23
was purified using column chromatography by eluting with ethyl
136.0, 133.4, 131.9, 130.5, 128.4, 124.5, 123.4, 116.4, 114.9, 114.3,
acetate/hexane (3:7) and obtained as a white solid (25 mg, 62%); mp
107.7, 98.3, 56.3.
204−206 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H),
(7-Fluoropyrrolo[1,2-a]quinoxalin-4-yl)(phenyl)methanone
8.20−8.17 (m, 1H), 7.92−7.88 (m, 1H), 7.85−7.82 (m, 1H), 7.67− (5d).15a The title compound was synthesized according to the general
7.63 (m, 1H), 3.18 (q, J = 12.0 Hz, 4.0 Hz, 2H), 1.10 (t, J = 8.0 Hz, procedure. The crude mixture was purified using column chromatog-
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 196.6, 160.9, 147.2, raphy by eluting with ethyl acetate/hexane (1:9) and obtained as a
134.8, 128.8, 128.5, 126.2, 126.2, 123.2, 29.8, 7.5. HRMS (EI+) m/z: greenish yellow solid (41 mg, 72%); 1H NMR (400 MHz, DMSO-d6)
[M]+ calcd for C11H10N2O2, 202.0742; found, 202.0745. δ 8.62 (dd, J = 2.4 Hz, 1.2 Hz, 1H), 8.39 (dd, J = 10 Hz, 2.8 Hz, 1H),
2-Butyrylquinazolin-4(3H)-one (3i). The title compound was 8.01−8.00 (m, 3H), 7.75−7.71 (m, 1H), 7.58 (t, J = 8.0 Hz, 2H),
synthesized according to the general procedure. The crude mixture 7.43 (td, J = 8.0 Hz, 4.0 Hz, 1H), 7.13 (dd, J = 6.8 Hz, 1.2 Hz, 1H),
was purified using column chromatography by eluting with ethyl 7.07 (dd, J = 4.0 Hz, 2.8 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-
acetate/hexane (3:7) and obtained as a white solid (22 mg, 51%); mp d6) δ 192.6, 163.9 (d, JC‑F = 247.0 Hz), 149.3, 136.0, 134.4, 133.3,
222−224 °C; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.37−8.35 131.5, 131.0, 129.2 (d, JC‑F = 11.0 Hz), 123.6, 117.9, 115.8, 114.5 (d,
(m, 1H), 7.89−7.82 (m, 2H), 7.64−7.60 (m, 1H), 3.22 (t, J = 8.0 Hz, JC‑F = 24.0 Hz), 109.1, 102.6; 19F{1H} NMR (376 MHz, DMSO-d6) δ
2H), 1.81 (sextet, J = 8.0 Hz, 2H), 1.04 (t, J = 8.0 Hz, 3H); 13C{1H} −108.2.
NMR (100 MHz, CDCl3) δ 196.5, 160.7, 147.9, 145.2, 134.9, 129.4, Phenyl(7-(trifluoromethyl)pyrrolo[1,2-a]quinoxalin-4-yl)-
129.2, 127.0, 123.7, 38.2, 17.4, 13.8. HRMS (EI+) m/z: [M]+ calcd for methanone (5e).15a The title compound was synthesized according
C12H12N2O2, 216.0899; found, 216.0893. to the general procedure. The crude mixture was purified using
Phenyl(pyrrolo[1,2-a]quinoxalin-4-yl)methanone (5a).15a The column chromatography by eluting with ethyl acetate/hexane (1:9)
title compound was synthesized according to the general procedure. and obtained as a dark yellow solid (51 mg, 75%); 1H NMR (400
The crude mixture was purified using column chromatography by MHz, DMSO-d6) δ 8.89 (d, J = 12.0 Hz, 2H), 8.12 (d, J = 8.0 Hz,
eluting with ethyl acetate/hexane (2:8) and obtained as a yellow solid 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0

1755 https://doi.org/10.1021/acs.joc.2c02802
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 2. Control Experiments

1756 https://doi.org/10.1021/acs.joc.2c02802
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 3. Plausible Mechanism

Hz, 1H), 7.58 (t, J = 8.0 Hz, 2H), 7.12 (dd, J = 16.0 Hz, 4.0 Hz, 2H); raphy by eluting with ethyl acetate/hexane (3:17) and obtained as
13
C{1H} NMR (100 MHz, DMSO-d6) δ 191.9, 151.8, 137.2 (d, JC‑F = brownish yellow gum (44 mg, 68%); 1H NMR (400 MHz, DMSO-d6)
242.0 Hz), 135.4, 134.8, 131.7, 131.0, 129.2 (d, JC‑F = 51.0 Hz), δ 7.79 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.49 (m, 1H), 7.35−7.31 (m,
128.3, 125.7, 124.0, 123.0, 122.4 (d, JC‑F = 4.0 Hz), 119.1, 116.0, 2H), 7.28−7.25 (m, 2H), 7.23−7.15 (m, 4H), 7.02 (dd, J = 7.6 Hz,
113.6 (d, JC‑F = 4.0 Hz), 110.0; 19F{1H} NMR (376 MHz, DMSO-d6) 2.0 Hz, 2H), 6.84 (td, J = 7.6 Hz, 1.0 Hz, 1H), 6.74 (d, J = 8.0 Hz,
δ −60.3. 1H), 5.46 (t, J = 8.0 Hz, 1H), 3.03 (qd, J = 14.0 Hz, 7.0 Hz, 2H), 2.84
(1,3-Dimethylpyrrolo[1,2-a]quinoxalin-4-yl)(phenyl)methanone
(5f).15a The title compound was synthesized according to the general (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.8, 146.7, 140.9,
procedure. The crude mixture was purified using column chromatog- 136.0, 134.0, 129.6, 128.5, 128.3, 128.2, 126., 126.50, 126.0, 117.6,
raphy by eluting with ethyl acetate/hexane (3:17) and obtained as 116.9, 112.9, 78.8, 36.8, 36.8.
greenish brown gum (29 mg, 49%); 1H NMR (400 MHz, DMSO-d6) 2-Benzyl-1-methyl-3-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one
δ 8.76 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 8.31 (d, J = 4.0 Hz, 1H), 8.05− (7b). The title compound was synthesized according to the general
8.04 (m, 1H), 8.03−8.02 (m, 1H), 7.89−7.86 (m, 1H), 7.74−7.69 procedure. The crude mixture was purified using column chromatog-
(m, 1H), 7.61−7.58 (m, 1H), 7.56 (m, 1H), 7.1 (dd, J = 8.0 Hz, 4.0 raphy by eluting with ethyl acetate/hexane (1:9) and obtained as an
Hz, 1H), 7.03 (dd, J = 4.0 Hz, 2.8 Hz, 1H), 1.44 (s, 6H); 13C{1H} off-white solid (42 mg, 62%); mp 143−145 °C; 1H NMR (400 MHz,
NMR (100 MHz, DMSO-d6) δ 192.8, 154.1, 149.3, 136.2, 134.3, DMSO-d6) δ 7.76 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.47−7.43 (m, 1H),
132.6, 131.0, 130.4, 129.1, 127.7, 124.0, 123.8, 117.4, 115.2, 112.0, 7.20−7.13 (m, 7H), 7.02 (dd, J = 8.0 Hz, 4.0 Hz, 2H), 6.83 (td, J =
108.6, 35.9, 31.7. HRMS (ESI) m/z: [M + H]+ calcd for C20H17N2O,
7.6 Hz, 0.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.40−5.36 (m, 1H),
301.1341; found, 301.1693.
2-Benzyl-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one 3.02 (qd, J = 14.0 Hz, 7.8 Hz, 2H), 2.81 (s, 3H), 2.29 (s, 3H);
13
(7a).25 The title compound was synthesized according to the general C{1H} NMR (100 MHz, DMSO-d6) δ 160.8, 146.6, 138.4, 136.1,
procedure. The crude mixture was purified using column chromatog- 135.3, 133.9, 129.6, 129.1, 128.2, 128.2, 126.5, 126.5, 117.5, 116.9,

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The Journal of Organic Chemistry pubs.acs.org/joc Article

113.9, 78.0, 36.9, 36.8, 20.6. HRMS (ESI) m/z: [M + H]+ calcd for 3-Allyl-2-benzyl-1-methyl-2,3-dihydroquinazolin-4(1H)-one (7h).
C23H23N2O, 343.1805; found, 343.1808. The title compound was synthesized according to the general
2-Benzyl-3-(4-methoxyphenyl)-1-methyl-2,3-dihydroquinazolin- procedure. The crude mixture was purified using column chromatog-
4(1H)-one (7c). The title compound was synthesized according to the raphy by eluting with ethyl acetate/hexane (2:8) and obtained as a
general procedure. The crude mixture was purified using column white solid (45 mg, 77%); mp 90−95 °C; 1H NMR (400 MHz,
chromatography by eluting with ethyl acetate/hexane (1:9) and DMSO-d6) δ 7.69 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H), 7.42−7.37 (m,
obtained as a white solid (49 mg, 69%); mp 140−142 °C; 1H NMR 1H), 7.27−7.20 (m, 3H), 7.12−7.10 (m, 2H), 6.79−6.76 (m, 1H),
(400 MHz, DMSO-d6) δ 7.75 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.47−7.42 6.67 (d, J = 8.0 Hz, 1H), 5.74 (ddd, J = 12.0 Hz, 8.0 Hz, 4.0 Hz, 1H),
(m, 1H), 7.20−7.13 (m, 5H), 7.01 (dd, J = 7.6 Hz, 1.6 Hz, 2H), 6.88 5.15−5.11 (m, 2H), 4.85 (t, J = 6.4 Hz, 1H), 4.46 (m, 1H), 2.99−
(dt, J = 8.0 Hz, 4.0 Hz, 2H), 6.84−6.80 (m, 1H), 6.72 (d, J = 8.0 Hz, 2.83 (m, 3H), 2.79 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
1H), 5.34 (dd, J = 6.8 Hz, 5.6 Hz, 1H), 3.75 (s, 3H), 3.01 (qd, J = 161.5, 147.0, 136.9, 134.9, 134.0, 130.2, 128.8, 128.3, 127.1, 117.8,
14.0 Hz, 7.2 Hz, 2H), 2.80 (s, 3H); 13C{1H} NMR (100 MHz, 117.2, 117.1, 112.9, 76.1, 47.3, 36.8. HRMS (ESI) m/z: [M + Na]+
DMSO-d6) δ 160.9, 157.3, 146.7, 136.1, 133.9, 133.7, 129.6, 128.6, calcd for C19H20N2ONa, 315.1468; found, 315.1463.
128.2, 128.1, 126.5, 117.5, 116.9, 113.8, 112.9, 79.2, 55.3, 36.9, 36.8. 2-Benzyl-3-dodecyl-1-methyl-2,3-dihydroquinazolin-4(1H)-one
HRMS (ESI) m/z: [M + H]+ calcd for C23H23N2O2, 359.1754; found, (7i). The title compound was synthesized according to the general
359.1758. procedure. The crude mixture was purified using column chromatog-
2-Benzyl-3-(4-chlorophenyl)-1-methyl-2,3-dihydroquinazolin- raphy by eluting with ethyl acetate/hexane (1:19) and obtained as off-
4(1H)-one (7d). The title compound was synthesized according to the white gum (47 mg, 56%); 1H NMR (400 MHz, DMSO-d6) δ 7.67
general procedure. The crude mixture was purified using column (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.39−7.35 (m, 1H), 7.26−7.18 (m, 3H),
chromatography by eluting with ethyl acetate/hexane (2:8) and 7.12−7.10 (m, 2H), 6.76 (td, J = 7.6 Hz, 0.8 Hz, 1H), 6.64 (d, J = 8
obtained as a pale yellow solid (56 mg, 78%); mp 158−160 °C; 1H Hz, 1H), 4.94 (t, J = 6.4 Hz, 1H), 3.71 (ddd, J = 14.8 Hz, 8.4 Hz, 6.8
NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.0 Hz, 4.0 Hz, 1H), Hz, 1H), 2.92 (dd, J = 12.8 Hz, 6 Hz, 1H), 2.82 (d, J = 6.8 Hz, 1H),
7.48 (m, 1H), 7.37−7.33 (m, 2H), 7.30−7.26 (m, 2H), 7.19−7.13 2.8 (s, 3H), 2.32−2.25 (m, 1H), 1.49−1.35 (m, 2H), 1.29−1.15 (m,
(m, 3H), 7.03 (dd, J = 8.0 Hz, 4.0 Hz, 2H), 6.85 (m, 1H), 6.76 (d, J = 18H), 0.84 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
8.0 Hz, 1H), 5.50 (t, J = 6.8 Hz, 1H), 3.01 (qd, J = 14.0 Hz, 7.0 Hz, δ 161.6, 147.0, 137.0, 133.8, 130.2, 128.8, 128.2, 127.0, 117.7, 117.5,
2H), 2.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0, 146.5, 112.8, 76.5, 45.5, 36.9, 36.7, 31.8, 29.5, 29.5, 29.4, 29.2, 29.2, 28.1,
139, 136.2, 134.4, 132.2, 129.6, 129.5, 129.3, 128.8, 128.0, 127.1, 26.7, 22.6, 14.5. HRMS (ESI) m/z: [M + H]+ calcd for C28H41N2O,
118.8, 117.7, 113.5, 81.2, 38.5, 38.0. HRMS (ESI) m/z: [M + H]+ 421.3213; found, 421.3209.
calcd for C22H20N2OCl, 363.1259; found, 363.1253. 1,2,3-Tribenzyl-2,3-dihydroquinazolin-4(1H)-one (7j). The title
2-Benzyl-3-(4-fluorophenyl)-1-methyl-2,3-dihydroquinazolin- compound was synthesized according to the general procedure. The
4(1H)-one (7e). The title compound was synthesized according to the crude mixture was purified using column chromatography by eluting
general procedure. The crude mixture was purified using column with ethyl acetate/hexane (3:17) and obtained as off-white gum (42
chromatography by eluting with ethyl acetate/hexane (1:9) and mg, 51%); 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J = 8.0 Hz,
obtained as a white solid (48 mg, 70%); mp 163−165 °C; 1H NMR 4.0 Hz, 1H), 7.36−7.25 (m, 8H), 7.20−7.10 (m, 6H), 6.96−6.94 (m,
(400 MHz, DMSO-d6) δ 7.77 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.47 (m, 2H), 6.81 (td, J = 8.0 Hz, 4.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.13
1H), 7.27 (dd, J = 8.0 Hz, 4.0 Hz, 2H), 7.19−7.11 (m, 5H), 7.03− (d, J = 16.0 Hz, 1H), 4.87 (t, J = 6.4 Hz, 1H), 4.38 (d, J = 16.0 Hz,
7.01 (m, 2H), 6.84 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.45 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.51 (d, J = 16.0 Hz, 1H), 2.97 (qd, J
(t, J = 6.4 Hz, 1H), 3.01 (qd, J = 14.0 Hz, 7.0 Hz, 2H), 2.86 (s, 3H); = 13.0 Hz, 7.0 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ
13
C{1H} NMR (100 MHz, DMSO-d6) δ 160.9, 158.6 (d, JC‑F = 242.0 161.4, 145.5, 137.4, 137.1, 136.3, 133.4, 129.6, 128.5, 128.4, 128.3,
Hz), 146.8, 137.2, 136.0, 134.1, 129.6, 128.8 (d, JC‑F = 86.0 Hz), 127.8, 127.2, 117.9, 117.4, 113.9, 74.4, 52.3, 47.5, 37.1. HRMS (ESI)
128.3, 128.2, 126.6, 117.6, 116.6, 115.3 (d, JC‑F = 22.0 Hz), 113.0, m/z: [M + Na]+ calcd for C29H26N2ONa, 441.1937; found, 441.1938.
78.9, 36.7, 36.6; 19F{1H} NMR (376 MHz, DMSO-d6) δ −115.8. 2-Benzyl-3-(4-chlorophenyl)-1-phenyl-2,3-dihydroquinazolin-
HRMS (ESI) m/z: [M + H]+ calcd for C22H20N2OF, 347.1554; 4(1H)-one (7k). The title compound was synthesized according to the
found, 347.1550. general procedure. The crude mixture was purified using column
2-Benzyl-1-methyl-3-(thiophen-2-ylmethyl)-2,3-dihydroquinazo- chromatography by eluting with ethyl acetate/hexane (3:97) and
lin-4(1H)-one (7f). The title compound was synthesized according to obtained as a brownish white solid (23 mg, 36%); mp 180−183 °C;
1
the general procedure. The crude mixture was purified using column H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J = 8.0 Hz, 4.0 Hz, 1H),
chromatography by eluting with ethyl acetate/hexane (2:8) and 7.773 (d, J = 8.0 Hz, 1H), 7.61−7.57 (m, 1H), 7.42−7.38 (m, 2H),
obtained as white sticky liquid (31 mg, 45%); 1H NMR (400 MHz, 7.32−7.27 (m, 3H), 7.25−7.19 (m, 3H), 7.15−7.12 (m, 3H), 7.07−
CDCl3) δ 8.19 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.60−7.56 (m, 1H), 6.98 (m, 2H), 6.67 (dd, J = 8.0 Hz, 4.0 Hz, 2H), 5.54 (t, J = 8.0 Hz,
7.48−7.38 (m, 4H), 7.26−7.24 (m, 2H), 7.12−7.04 (m, 3H), 6.77 (d, 1H), 3.19 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6)
J = 8.0 Hz, 1H), 5.58 (dd, J = 16.0 Hz, 1.0 Hz, 1H), 4.85 (t, J = 6.8 δ 160.7, 147.1, 143.2, 139.8, 138.28, 136.67, 134.32, 131.18, 130.21,
Hz, 1H), 3.88 (d, J = 15.6 Hz, 1H), 3.11 (qd, J = 14.0 Hz, 7.0 Hz, 130.07, 129.49, 129.0, 128.3, 127.5, 124.5, 123.2, 122.7, 122.3, 122.0,
2H), 2.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 146.5, 80.9, 39.4. HRMS (ESI) m/z: [M + H]+ calcd for C27H22N2OCl,
139.9, 136.4, 133.9, 129.6, 129.1, 128.9, 127.1, 126.9, 126.8, 125.7, 425.1415; found, 425.1419.
118.5, 117.3, 113.1, 76.6, 43.5, 37.7, 37.5. HRMS (ESI) m/z: [M + 1-Allyl-2,3-dibenzyl-2,3-dihydroquinazolin-4(1H)-one (7l). The
Na]+ calcd for C21H20N2ONaS, 371.1194; found, 371.1188. title compound was synthesized according to the general procedure.
2-Benzyl-3-isopropyl-1-methyl-2,3-dihydroquinazolin-4(1H)-one The crude mixture was purified using column chromatography by
(7g). The title compound was synthesized according to the general eluting with ethyl acetate/hexane (7:93) and obtained as off-white
procedure. The crude mixture was purified using column chromatog- gum (39 mg, 54%); 1H NMR (400 MHz, DMSO-d6) δ 7.77 (dd, J =
raphy by eluting with ethyl acetate/hexane (3:17) and obtained as 7.6 Hz, 1.6 Hz, 1H), 7.42−7.38 (m, 1H), 7.34−7.23 (m, 7H), 7.22
yellowish white gum (33 mg, 57%); 1H NMR (400 MHz, DMSO-d6) (m, 1H), 7.10−7.07 (m, 2H), 6.83 (td, J = 7.2 Hz, 0.8 Hz, 1H), 6.8
δ 7.71 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.41−7.37 (m, 1H), 7.27−7.18 (d, J = 8.0 Hz, 1H), 5.42 (ddd, J = 10.0 Hz, 6.0 Hz, 3.0 Hz, 1H), 5.11
(m, 3H), 7.09−7.07 (m, 2H), 6.80 (td, J = 8.0 Hz, 4.0 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 4.93 (d, J = 0.8 Hz, 1H), 4.91−4.88 (m, 1H),
(d, J = 8.0 Hz, 1H), 5.00 (dd, J = 8.4 Hz, 5.2 Hz, 1H), 4.45 (septet, J 4.78 (t, J = 6.8 Hz, 1H), 3.83 (dd, J = 15.6 Hz, 5.6 Hz, 1H), 3.65 (d, J
= 8.0 Hz, 1H), 3.00−2.76 (qd, J = 13.5 Hz, 8.4 Hz, 2H), 2.61 (s, 3H), = 16.0 Hz, 1H), 3.38−3.36 (m, 1H), 2.95−2.84 (m, 2H); 13C{1H}
1.17 (8.0, 3H), 1.13 (8.0, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) NMR (100 MHz, DMSO-d6) δ 161.4, 145.5, 137.5, 136.4, 133.4,
δ 161.1, 146.0, 136.8, 133.3, 129.6, 128.3, 127.9, 126.6, 118.2, 117.4, 133.4, 129.6, 128.5, 128.3, 128., 127.7 127.3, 126.6, 117.9, 117.4,
112.9, 72.2, 45.9, 37.2, 20.7, 20.2. HRMS (ESI) m/z: [M + Na]+ calcd 117.3, 114.1, 73.5, 51.7, 47.5, 37.1. HRMS (ESI) m/z: [M + Na]+
for C19H22N2ONa, 317.1624; found, 317.1625. calcd for C25H24N2ONa, 391.1780; found, 391.1773.

1758 https://doi.org/10.1021/acs.joc.2c02802
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2,3-Dibenzyl-1-(prop-2-yn-1-yl)-2,3-dihydroquinazolin-4(1H)- Vijay Thavasianandam Seenivasan − Department of

one (7m). The title compound was synthesized according to the Medicinal and Applied Chemistry, Kaohsiung Medical
general procedure. The crude mixture was purified using column University, Kaohsiung 80708, Taiwan, ROC
chromatography by eluting with ethyl acetate/hexane (3:17) and
obtained as off-white gum (41 mg, 56%); 1H NMR (400 MHz,
Nian-Qi Chen − Department of Medicinal and Applied
DMSO-d6) δ 7.74 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.47−7.42 (m, 1H), Chemistry, Kaohsiung Medical University, Kaohsiung 80708,
7.32−7.20 (m, 8H), 7.13−7.11 (m, 2H), 6.91−6.85 (m, 2H), 5.13 (t, Taiwan, ROC
J = 6.4 Hz, 1H), 5 (d, J = 12.0 Hz, 1H), 4.16 (dd, J = 16.0 Hz, 4.0 Hz, Complete contact information is available at:
1H), 3.89 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 3.56 (d, J = 16.0 Hz, 1H), https://pubs.acs.org/10.1021/acs.joc.2c02802
3.22 (t, J = 2.4 Hz, 1H), 2.95 (qd, J = 16.0 Hz, 8.0 Hz, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 161.2, 144.8, 137.4, 136.1, 129.7,
128.5, 128.3, 127.8, 127.4, 127.3, 126.7. 118.5, 117.7, 114.0, 79.3, Notes
75.7, 74.5, 48.2, 38.6, 37.5. HRMS (ESI) m/z: [M + Na]+ calcd for The authors declare no competing financial interest.
C25H22N2ONa, 389.1624; found, 389.1624.
2-Benzylquinazolin-4(3H)-one (3ab).2c The title compound was
synthesized according to the general procedure. The crude mixture
was purified using column chromatography by eluting with ethyl
■ ACKNOWLEDGMENTS
The authors gratefully acknowledge funding from the National
acetate/hexane (3:7) and obtained as a white solid (36.4 mg, 77%); Science and Technology Council (MOST 111-2113-M-037-
1
H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.07 (dd, J = 8 Hz, 016-), Taiwan, and the Centre for Research Resources and
1.2 Hz, 1H), 7.79−7.75 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48−7.44 Development of Kaohsiung Medical University for mass and
(m, 1H), 7.38 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.24 (m, 400 MHz NMR analyses.
1H), 3.94 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.3,
156.5, 149.4, 137.0, 134.9, 129.4, 129.0, 127.4, 127.3, 126.7, 126.2,
121.2, 41.3.
2-Benzyl-6-nitroquinazolin-4(3H)-one (3ad).26 The title com-
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Corresponding Author
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