Efficient construction of 3-substituted-quinazolin-4(3H)-ones and theoretical investigation on the reaction pathways

Article abstract of DOI:10.1080/10426507.2017.1322085

A highly efficient and convenient method was developed to synthesize 2,7-dimethyl-3- phenyl- quinazolin-4(3H)-ones from 2-acetamidobenzoic acid, arylamines, arylhydrazines and arylacylhydrazines. Quinazolin-4(3H)-ones were obtained in good to excellent yields (85–98%) using dropwise POCl₃ as a condensing agent in acetonitrile. Theoretical calculations were performed to explore the competition reaction pathways and the corresponding free energy profiles for the reaction of 2-acetamido-4-methyl-benzoic acid with aniline. The calculations show that the reaction proceeds through three different stages, including the formation of benzoxazin-4-one, diamide and quinazolin-4(3H)-one. The formation of benzoxazin-4-one follows a Vilsmeier-Haack mechanism, in which the POCl₃ transfers the 2-acetamido-benzoic acid into an imidoyl chloride, followed by intramolecular attack of the carboxyl oxygen involving addition-elimination sequence. The formation of diamide is initialized by the nucleophilic attack of the aniline nitrogen atom on the carbonyl carbon of benzoxazin-4-one, accompanied by aniline-assisted proton transferring. The formation of quinazolin-4(3H)-one follows an intramolecular nucleophilic addition-elimination mechanism, where the POCl₃ helps the elimination of water. The present studies provide insight into the mechanism for the formation reactions of quinazolin-4(3H)-ones in the presence of POCl₃.

Full text of DOI:10.1080/10426507.2017.1322085

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Efficient Construction of 3-Substituted-
Quinazolin-4(3H)-Ones and Theoretical
Investigation on the Reaction Pathways
Xinyun Zhao, Juanfeng Lu, Lamei Wu & Xi Chen
To cite this article: Xinyun Zhao, Juanfeng Lu, Lamei Wu & Xi Chen (2017): Efficient Construction
of 3-Substituted-Quinazolin-4(3H)-Ones and Theoretical Investigation on the Reaction Pathways,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1322085
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1322085
Accepted author version posted online: 28
Apr 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20
Download by: [The UC San Diego Library]
Date: 30 April 2017, At: 11:40

ACCEPTED MANUSCRIPT
Efficient Construction of 3-Substituted-Quinazolin-4(3H)-Ones and Theoretical
Investigation on the Reaction Pathways
*
Xinyun Zhao, Juanfeng Lu, Lamei Wu, Xi Chen
College of Chemistry and Materials Science, South-Central University for Nationalities, Wuhan,
4
30074, P. R. China
*
Correspondence Xi Chen, College of Chemistry and Materials Science, South-Central
University for Nationalities, Wuhan, 430074, P. R. China E-mail: ccnuchen@yahoo.com
Abstract
A highly efficient and convenient method was developed to synthesize 2,7-dimethyl-3-
phenyl- quinazolin-4(3H)-ones from 2-acetamidobenzoic acid, arylamines, arylhydrazines and
arylacylhydrazines. Quinazolin-4(3H)-ones were obtained in good to excellent yields (85 ~ 98%)
using dropwise POCl as a condensing agent in acetonitrile. Theoretical calculations were
3
performed to explore the competition reaction pathways and the corresponding free energy
profiles for the reaction of 2-acetamido-4-methyl-benzoic acid with aniline. The calculations
show that the reaction proceeds through three different stages, including the formation of
benzoxazin-4-one, diamide and quinazolin-4(3H)-one. The formation of benzoxazin-4-one
follows a Vilsmeier-Haack mechanism, in which the POCl transfers the 2-acetamido-benzoic
3
acid into an imidoyl chloride, followed by intramolecular attack of the carboxyl oxygen
involving addition-elimination sequence. The formation of diamide is initialized by the
nucleophilic attack of the aniline nitrogen atom on the carbonyl carbon of benzoxazin-4-one,
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
accompanied by aniline-assisted proton transferring. The formation of quinazolin-4(3H)-one
follows an intramolecular nucleophilic addition-elimination mechanism, where the POCl helps
3
the elimination of water. The present studies provide insight into the mechanism for the
formation reactions of quinazolin-4(3H)-ones in the presence of POCl3.
Key words
One-pot synthesis; 3-substituted-quinazolin-4(3H)-ones; Phosphoryl trichloride; Reaction
mechanism.
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Introduction
Quinazolin-4(3H)-ones are important heterocyclic compounds due to their versatile
1
2
3
4
biological activities including antibacterial, antifungal, antimicrobial, antitumor,
5
6
anticonvulsant, and anti-inflammatory properties. They can be also used as inhibitors of the
7
PARP-1 and histone deacetylase-6. Quinazolin-4(3H)-ones can be synthesized through various
8
9
reactions using a wide variety of reagents. However, some of the reported synthetic methods
often suffer from some drawbacks, such as complicated workup, high temperature, long reaction
time, expensive and hazardous reagents and low yields. Demonstrated in Scheme 1 are the
1
0
typical synthetic routes from 2-acetamidobenzoic acid, the most common raw material. As
shown in this Scheme, 2-acetamidobenzoic acid can react with amines in the presence of
8
11
5 ,
condensing agents such as PO(C H ) /pyridine, acetic anhydride , P O bis(trichloromethyl)
6
5 3
2
1
0b
11-12
3.
carbonate , PCl and POCl
The yields are usually in the range of 18~88%. In addition to
3
8
the experimental studies mentioned, mechanisms of these reactions were also proposed.
8
Pyrimidine and acetic anhydride were suggested acting as proton shuttle and esterifying agent ,
respectively. Condensing agents such as PCl , POCl and P O do not seem to be suitable for
3
3
2
5
proton shuttle. Thus, mechanisms of reactions using these condensing agents may be different
from the ones using pyrimidine or acetic anhydride. It is necessary to investigate the general
mechanism to explain the roles of these condensing agents.
In this work we attempted to explore improved method to prepare quinazolin-4(3H)-ones
using 2-acetylamino-4-methylbenzoic acid as a raw material. Herein, we report an efficient
one-pot synthesis of a series of new 2,7-dimethyl-3-substituted quinazoline-4(3H)-ones using
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
POCl as a condensing agent. Good to excellent yields (85 ~ 98%) of the target compounds were
3
obtained. In order to explore the reaction mechanisms, quantum chemistry calculations were
performed to study the competing reaction pathways and the corresponding free energy profiles
of the reactions were obtained.
Results and Discussion
The model reaction of 2-acetylamino-4-methyl benzoic acid (1) and aniline (2) was firstly
carried out under different conditions. The structures of target compounds 5a-i have not been
reported before. The yields of 5a under these conditions are summarized in Table 1. As
displayed by this Table, yields of 5a were very low when pyridine or P O was used as a
2
5
condensing agent alone, or with other compounds. Yield of 5a varied from 20% to 92% when
POCl was used as a condensing agent in different solvents (CH Cl , THF, toluene and
3
2
2
acetonitrile). These results show that POCl and acetonitrile are the best combination for the
3
formation of 5a. Based on these observations, we continued to study the effect of the amounts of
POCl . Related results are collected in Table 2. The highest yield (92%) was obtained when 2
3
mmol POCl was used. Using less or more (0.5, 1 and 2.5 mmol) POCl led to relatively lower
3
3
yields. It is worth noting that a diamide 6 (Scheme 2) was observed when 0.5 mmol POCl was
3
used at 55°C. This intermediate disappeared when additional POCl were added. From this
3
phenomenon, it was speculated that 1) the POCl participated in the conversion of reactant 1 to
3
intermediate 6 and the conversion of 6 to 5a, and 2) the rate of the latter step should be slower
than the former step. Based on these assumptions, the routes for the formation of
3
-arylquinazolin-4(3H)-one were proposed (Scheme 2). To testify these assumptions, reaction
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
coordinates calculations were performed, and the results will be discussed in the calculation
section.
The model reaction mentioned above provides optimal reaction conditions for synthesis of 5a,
i.e. 2 mmol POCl in 10 mL of CH CN and 82°C reaction temperature. These conditions were
3
3
applied to the synthesis of other quinazolin-4(3H)-ones using arylamines, or arylhydrazines,
aralkylamines and arylacylhydrazines as raw materials. Yields of the corresponding products
were collected in Scheme 3. Good to excellent yields (85-98%) of quinazolin-4(3H)-ones were
achieved for reactions with arylamines, arylhydrazines and arylacylhydrazines. When
aralkylamine was used, the yield of 5g decreased to 62%. The quinazolin-4(3H)-ones yields in
1
1, 12c
our hands are significantly higher than the reported (39-57%) results.
The yield
1
1, 12c
enhancement may be ascribed to the way of raw materials feeding. In those work
all raw
materials were added in one portion, whereas in our work the condensing agent POCl was added
3
in a dropwise manner.
As mentioned in the introduction section, the reaction mechanism when the condensing agent
POCl used should be different from the ones when pyrimidine or acetic anhydride used. Thus, it
3
is necessary to investigate the role of POCl . We take the reaction of 2-acetamido-benzoic acid
3
with aniline as an example to study the competition reaction pathways and corresponding free
energy profiles. These calculations demonstrate that the reaction proceeds via three different
stages (Scheme 4), i.e. the formations of benzoxazin-4-one, diamide and quinazolin-4(3H)-one.
For these reactions, different competitive pathways were found and will be discussed below.
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Depicted in Figure 1 are competitive pathways of the reaction stage 1. Figure 1A depicts two
pathways for intramolecular nucleophilic addition-elimination reactions between the carboxyl
and amide moiety. For the pathway without the POCl the total free energy barrier is as high as
3
,
4
8.33 kcal/mol, proving that carboxyl group is weak for nucleophilic attacking. When the POCl3
molecule is involved in, the total free energy barrier is reduced to 31.56 kcal/mol. From the
structures in this Figure, it can also be found that the POCl plays two different roles in the two
3
reaction steps. In the intramolecular nucleophilic step, the POCl forms hydrogen bonding
3
interaction with the amide group and induces the accumulation of positive charge on the amide
carbon, which will enhance the electrophilicity of amide carbon and facilitate the nucleophilic
attacking of carboxyl oxygen. In the water-eliminating step, the POCl acts as dehydrater which
3
takes a water from INT1 to form INT2. Figure1B depicts a pathway that follows the
Vilsmeier-Haack mechanism, in which the POCl transfers the 2-acetamido-benzoic acid into an
3
imidoyl chloride via two steps, followed by an intramolecular nucleophilic addition-elimination
reaction between the carboxyl and imidoyl chloride moiety. The total free energy barrier for this
pathway is only 24.15 kcal/mol, indicating that this pathway is more favorable than the ones
depicted in Figure 1A.
There are two competitive reaction pathways for reaction stage 2 (Figure 2). Figure 2A
describes a direct nucleophilic addition-elimination reaction between the benzoxazin-4-one and
aniline. As can be seen from this Figure, direct nucleophilic attacking of aniline on the
benzoxazin-4-one is difficult, due to the high free energy barrier of 52.33 kcal/mol. The
accumulation of negative charges on the carbonyl oxygen in the nucleophilic process should be
1
3
responsible for the high free energy barrier . Thus, adding a number of hydrogen bond donors to
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
the carbonyl oxygen will benefit the dispersion of these negative charges and reducing the free
energy barrier of the nucleophilic step. As can be seen from Figure 2B, when more anilines were
involved, the free energy barrier for the nucleophilic attacking was reduce to 31.61 kcal/mol. The
aniline-assisted nucleophilic addition mechanism presented in Figure 2B was not reported in the
literature, despite its similarity to the well-known catalytic triad mechanism of some hydrolases
1
3
14
such as cocaine esterase and butyrylcholinesterase .
Depicted in Figure 3 are competitive pathways for reaction stage 3. Similar to Figure 1A,
Figure 3A describes two pathways for intramolecular nucleophilic addition-elimination reactions
between the--NHC H and --COCH moiety of the diamine 6. For the pathway without the
6
5
3
POCl the total free energy barrier is as high as 48.01 kcal/mol. When the POCl molecule
3
3
participates in the elimination step, the total free energy barrier is reduced to 41.66 kcal/mol.
Different from the mechanisms described in Figure 1A, free energy calculations show that
presence of the POCl (not shown in Figure 3A) hardly affects the nucleophilic addition of the
3
-
-NH-C H moiety to the --COCH moiety. Figure 3B depicts a Vilsmeier-Haack pathway which
6 5 3
is similar to the one in Figure 1B, i.e. imidoyl chloride formation followed by intramolecular
nucleophilic addition-elimination. However, the free energy barrier for the intramolecular
nucleophilic addition-elimination step in Figure 3B is as high as 53.62 kcal/mol, which is about
2
9.47 kcal/mol higher than the counterpart in Figure 1B. The reason could be attributed that the
proton from the phenyl amide group is more difficult to remove than the proton from the
carboxyl group. Hence, for formation stage of the quinazolin-4(3H)-one, the Vilsmeier-Haack
pathway is less favorable than the POCl -assisted intramolecular nucleophilic
3
addition-elimination pathway.
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
It should be noted that part of the phosphorus-containing transition states (i.e. TS1B_1 and
1
5
TS3B_1) described in Figures 1B and 3B have been proposed. Other phosphorus-containing
transition states described in Figures 1 and 3 were not reported.
Through the theoretical calculations mentioned above, we determined the fundamental
reaction pathways for the reaction of 2-acetamido-benzoic acid with aniline in the present of
POCl . The free energy calculations show that the free energy barrier for the third reaction stage
3
is the highest among the three reaction stages, demonstrating that conversion of the diamide 6 to
the quinazolin-4(3H)-one 5a determines the rate of the quinazolin-4(3H)-one formation reaction.
This conclusion was consistent with aforementioned experimental speculation, indicating that the
present theoretical calculations are reasonable.
The present studies also indicate that the POCl serves as a dehydrating agent that exerts its
3
role in the first and third reaction stages. It has been argued that the POCl may serve as an
3
acylation agent which converts the 2-acetamido-benzoic acid into an acid chloride. To clarify
this issue, we also theoretically studied the acylation of 2-acetamido-benzoic acid by POCl . The
3
calculation results indicate that the Gibbs free energy barrier value for the acylation of
2
-acetamido-benzoic acid by POCl is as high as 62.70 kcal/mol, suggesting that the POCl is
3 3
improper for the acylation of 2-acetamido-benzoic acid.
Conclusion
In this work we developed the efficient synthesis of quinazolin-4(3H)-ones from
2
-acetylamino-4-methylbenzoic acid and a series of arylamines, arylhydrazine and
arylacylhydrazines in the presence of POCl . The optimal reaction conditions were as follows: 1)
3
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
running the reaction at 82°C; 2) using POCl as a condensing agent; 3) keeping the molar ratio of
3
POCl to 2-acetylamino-4-methylbenzoic acid ratio as 2:1; 4) using acetonitrile as solvent. These
3
conditions do not apply to the reaction of 2-acetylamino-4-methylbenzoic acid with
aralkylamine, heterocyclic amine (e.g., 1,3,4-thiadiazol-2-amine), aliphatic amine (e.g., isobutyl
amine), sulfonamide (e.g.,Toluene-4-sulfonamide) and alicyclic amine (e.g. cyclohexyl amine)
amine.
The theoretical mechanism studies demonstrate that these reactions proceeded via three
different stages, i.e. the formation of benzoxazin-4-one, diamide and quinazolin-4(3H)-one. The
calculations indicate that the last reaction stage determines the rate of the formation of
quinazolin-4(3H)-one, which is consistent with the experimental observation. The free energy
computations also show that the POCl acts as a dehydrating agent, rather than an acylation
3
reagent during the reaction process. Our present calculations provide insight into the mechanism
of the quinazolin-4(3H)-one formation reactions.
Experimental
1
13
H NMR and C NMR spectra were recorded on a Varian NMR 400 MHz instrument and the
chemical shifts, δ, are in ppm and tetramethylsilane as internal standard. High-resolution mass
spectrometry (HRMS) was recorded on a Agilent LC-Q-TOF-MS-6520 instrument. Melting
points were recorded on an X-6 digital melting point apparatus. All reagents were purchased
from commercial suppliers and used without further purification. And CH CN was dried by 4A
3
molecular sieves before use. The progress of the reaction was monitored by thin layer
chromatography (TLC). The reaction mechanism studies were carried out by performing a series
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
quantum mechanical calculations in order to explore the fundamental reaction pathways and to
estimate the corresponding Gibbs free energy barrier. Details of these computations could be
1
found at the computational details section. The Supplemental Materials contains sample H and
1
3
C NMR for products 5a -- 5i (Figures S 1 -- S 21).
Procedure for the preparation of 2-amino-4-methylbenzoic acid (3) and N-acetylaniline (4):
Aniline (0.18g, 2 mmol) was added into a solution of 2-acetylamino-4-methylbenzoic acid
(0.19g, 1 mmol) in toluene (10 mL) at room temperature. The mixture was stirred and refluxed
for 10 h at 110°C. The solvent was evaporated under reduced pressure. The mixture was
separated by column chromatography to give 2-amino-4-methylbenzoic acid (3, 0.10 g) and
N-acetylaniline (4, 0.12 g).
1
6
1
2
-amino-4-methylbenzoic acid (3) : Mp: 188.2-189.6°C. H NMR (400 MHz, CDCl ) δ 7.81(d,
3
1
J = 8.0Hz), 6.51- 6.48(m, 2H), 2.28(s, 3H). Its H NMR data and melting point were consistent
with those of standard sample.
1
7
1
N-acetylaniline (4) : Mp: 117.8-118.8°C. H NMR (400 MHz, CDCl ) δ 7.65 (br, 1H, NH),
3
1
7
.50(d, 2H, J = 8.0Hz), 7.30(t, 2H, J = 8.0Hz), 7.09(t, 1H, J = 7.4Hz), 2.15(s, 3H). Its H NMR
data and melting point were consistent with those of standard sample.
General Procedure for the synthesis of 2,7-dimethyl-3-substituted- quinazoline-4(3H)-one
derivatives (5a-g)：
Aniline (0.18 g, 2 mmol) was added into a solution of 2-acetylamino-4-methylbenzoic acid
(
0.19g, 1 mmol) in CH CN (5 mL) at room temperature. The mixture was stirred and treated
3
1
0
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
dropwise with a solution of POCl (0.31g, 2 mmol) in CH CN (5 mL) over a period of ten
3
3
minutes via dropping funnel. The resulting mixture was heated to 82°C and stirred for an
additional 3-20 h. The solvent was evaporated. The mixture was cooled to room temperature and
water (20 mL)was added into the residue and neutralized using 10% of NaHCO Then was
3
.
extracted using CH Cl (2 × 10 mL). The organic layer was separated and dried and the desired
2
2
product was obtained by column chromatography.
2
-Acetylamino-4-methyl-N-phenyl-benzamide (6)
1
White solid. Mp >300.0°C. H NMR (400 MHz, DMSO-d ) δ 10.59(s, 1H),10.36(s, 1H),
6
8
.07(s, 1H), 7.71(d, 3H, J = 7.6Hz), 7.36(t, 2H, J = 7.6Hz), 7.12(t, 1H, J = 7.2Hz), 7.04(d, 1H, J
=
7.6Hz), 2.35(s, 3H), 2.06(s, 3H).
2
,7-Dimethyl-3-phenyl-quinazolin-4(3H)-one (5a):
1
Yellow solid. Mp: 191.2-192.5°C; H NMR (400 MHz, CDCl ) δ 8.15(1H, d, J = 8.0Hz),
3
1
3
7
.58-7.49(m, 3H), 7.48(s, 1H), 7.30- 7.25(m, 3H), 2.52(s, 3H), 2.23(s, 3H). C NMR (400 MHz,
DMSO-d ) δ 21.9, 24.5, 118.6, 126.6, 126.8, 128.3, 128.95, 129.3, 130.0, 138.4, 145.5, 147.9,
6
+
+
1
54.8, 161.7(C = O). HRMS (ESI): Calcd. for C H N O [M+H] : 251.1179; Found: 251.1191.
16 15 2
2
,7-Dimethyl-3-(4-nitrophenyl)- quinazoline-4(3H)-one(5b):
1
Yellow solid. Mp: 187.1-188.9°C. H NMR (400 MHz, DMSO-d ) δ 8.42(d, 2H, J = 8.4Hz),
6
7
2
.99(d, 1H, J = 8.0Hz), 7.82(d, 2H, J = 8.4Hz), 7.49(s, 1H), 7.36(d, 1H, J = 8.0Hz), 2.49(s, 3H),
1
3
.13(s, 3H). C NMR (101 MHz, DMSO-d ) δ 161.5, 153.8, 148.1, 147.9, 145.8, 144.2, 130.9,
6
1
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
+
+
1
2
28.5, 126.8, 126.6, 125.2, 118.4, 24.5, 21.9. HRMS (ESI): Calcd. for C H N O [M+H] :
16 14 3 3
96.1030; Found: 296.1030.
2
,7-Dimethyl-3-p-tolyl-3H-quinazolin-4-one (5c):
1
Yellow solid. Mp：192.6-193.8°C. H NMR (400 MHz, DMSO-d ) δ 7.97(d, 1H, J = 8.4Hz),
6
1
3
7
.46(s, 1H), 7.37-7.28(m, 5H), 2.47(s, 3H), 2.40(s, 3H), 2.11(s, 3H). C NMR (101 MHz,
DMSO-d ) δ 161.7, 155.1, 147.9, 145.4, 138.8, 135.8, 130.5, 128.6, 128.2, 126.7, 126.6, 118.6,
6
+
+
2
4.5, 21.9, 21.2. HRMS (ESI): Calcd. for C H N O [M+H] : 265.1335; Found: 265.1340.
17 17 2
2
,7-Dimethyl-3-phenylamino-3H-quinazolin-4-one (5d):
1
Yellow solid. Mp：149.8-151.0°C. H NMR (400 MHz, DMSO-d ) δ 9.10(s,1H), 7.96(d, 1H,
6
J = 8.0Hz), 7.49(s,1H), 7.34(d, 1H, J = 8.0Hz), 7.20(t, 2H, J = 7.6Hz), 6.84(t, 1H, J = 7.2Hz),
1
3
6
1
.64(d, 2H, J = 8.0Hz), 2.49(s, 3H), 2.48(s, 3H). C NMR (101 MHz, DMSO-d ) δ 160.5, 158.1,
6
47.37, 147.35, 145.8, 129.7, 128.3, 127.0, 126.5, 120.7, 119.2, 112.8, 21.9, 21.8. HRMS (ESI):
+
+
Calcd. for C H N O [M+H] : 266.1288; Found: 266.1292.
1
6
16
3
2
,7-Dimethyl-3-benzoylamino-3H-quinazolin-4-one (5e):
1
Yellow solid. Mp：186.0-187.8°C. H NMR (400 MHz, DMSO-d ) δ 11.6(s, 1H), 8.02(t, 3H,
6
J = 6.4Hz), 7.70(t, 1H, J = 7.2Hz), 7.61(t, 2H, J = 7.2Hz), 7.50(s, 1H), 7.39(d, 1H, J = 8.0Hz),
1
3
2
1
.49(s, 3H), 2.46(s, 3H). C NMR (101 MHz, DMSO-d ) δ 166.4, 159.4, 156.6, 147.2, 146.2,
6
33.2, 131.8, 129.3, 128.7, 128.2, 127.1, 126.8, 118.7, 21.8, 21.6. HRMS (ESI): Calcd. for
+
+
C H N O [M+H] : 294.1237; Found: 294.1243.
17
16
3
2
1
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
2
,7-Dimethyl-3-(4-methoxycarbonylphenyl)-3H-quinazolin-4-one (5f):
1
Yellow solid. Mp：210.7-212.1°C. H NMR (400 MHz, DMSO-d ) δ 8.13(d, 2H, J = 8.0Hz),
6
7
2
1
.99(d, 1H, J = 8.0Hz), 7.63(d, 2H, J = 8.0Hz), 7.48(s, 1H), 7.35(d, 2H, J = 8.0Hz), 3.91(s, 3H),
1
3
.48(s, 3H), 2.11(s, 3H). C NMR (101 MHz, DMSO-d ) δ 166.1, 161.5, 154.2, 147.9, 145.7,
6
42.6, 130.9, 130.6, 129.7, 128.4, 126.8, 126.6, 118.4, 52.9, 24.4, 21.9. HRMS (ESI): Calcd. for
+
+
C H N O [M+H] : 309.1234; Found: 309.1228.
18
17
2
3
2
,7-dimethyl-3-(3-phenylpropyl)quinazolin-4(3H)-one (5g):
1
Yellow solid. Mp：173.5-175.1°C. H NMR (400 MHz, DMSO-d ) δ 7.97(d, 2H, J = 8.0Hz),
6
7
3
1
.36(s, 1H), 7.19-7.31(m, 6H), 4.01(t, 3H, J = 7.6Hz), 2.70(t, 3H, J = 7.6Hz), 2.52(s, 3H), 2.43(s,
1
3
H), 1.92-1.99(m, 2H). C NMR (101 MHz, DMSO-d ) δ 161.4, 155.3, 147.7, 145.0, 141.5,
6
28.8, 128.7, 128.0, 126.5, 126.43, 126.37, 118.1, 43.97, 32.9, 29.7, 23.1, 21.8. HRMS (ESI):
+
+
Calcd. for C H N O [M+H] : 293.1648; Found: 293.1654.
1
9
21
2
3
-(4-Hydroxy-phenyl)-2,7-dimethyl-3H-quinazolin-4-one(5h):
1
Yellow solid. Mp： 272.5-274.2C. H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.97(d,
1
8
1
H, J = 8.0Hz), 7.44(s, 1H),7.32(d, 2H, J = 8.0Hz), 7.17(d, 2H, J = 8.4Hz), 6.90(d,1H, J =
1
3
.4Hz), 2.47(s,3H), 2.12(s, 3H). C NMR (101 MHz, DMSO-d ) δ 161.9, 158.1, 155.6, 147.9,
6
+
45.3, 129.8, 129.4, 128.2, 126.7, 126.6, 24.5, 21.8. HRMS (ESI): Calcd. for C H N O
2
1
6
15
2
+
[
M+H] : 267.1128; Found: 267.1132.
1
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
3
-(4-Chloro-phenyl)-2,7-dimethyl-3H-quinazolin-4-one (5i)
1
White solid. Mp: 221.5-222.4C. H NMR (400 MHz, DMSO-d ) δ, 7.98 (d, 1H, J = 8.0Hz),
6
7
2
1
2
.63 (d, 2H, J = 8.0Hz), 7.50(d, 2H, J = 8.0Hz), 7.47(s, 1H), 7.34(d, 1H, J = 8.0Hz), 2.47(s,3H),
1
3
.12(s, 3H). C NMR (101 MHz, DMSO-d ) δ 161.7, 154.6, 147.9, 145.6, 137.3, 134.1, 131.0,
6
+
+
30.1, 128.3, 126.8, 126.6, 118.5, 24.5, 21.9. HRMS (ESI): Calcd. for C H ClN O [M+H] :
1
6
14
2
85.0789; Found:285.0793.
Computational details
Density functional theory (DFT) with Becke’s three-parameter hybrid exchange functional
1
8
and the Lee-Yang-Parr correlation functional (B3LYP) in combination with the 6-31+G* basis
set was used to fully optimize the geometries of reactants and products, and also were used to
search for all possible geometries of transition states and intermediates. Vibrational frequency
analysis were carried out to ensure the geometries were indeed local minimal or saddle points on
the potential energy surfaces and to determine the zero-point vibrational frequency calculations.
Intrinsic reaction coordinate (IRC) calculations were then performed to confirm the correct
connections between reactants, transition states, intermediates and products on the potential
energy surfaces. In addition, the effect of solvent, e.g. acetonitrile, was accounted for by using
IEFPCM solvation model and geometries parameters optimized in the gas phase. In order to save
computation times, in some computations the geometries of anilines were truncated to
methylamine.
1
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Acknowledgement
The research was supported in part by National Natural Science Foundation of China (grants
2
1273089) and the Special Fund for Basic Scientific Research of Central Colleges,
South-Central University for Nationalities (CZY11004).
1
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
References
1
. Wang, X.; Yin, J.; Shi, L.; Zhang, G.; Song, B. Eur. J. Med. Chem. 2014, 77, 65-74.
2
2
2
. (a) Liu, G.; Liu, C. P.; Ji, C. N.; Sun, L.; Liu, X. G.; Wen, Q. W.; Xu, S. G. Asian J. Chem.
013, 25, 9853-9856; (b) Monirah, A.-A.; Danah, A.-S.; Fatima, E.-B. Res. J. Chem. Environ.
013, 17, 48-52.
3
4
5
. Hurmath, U. S.; Gayam, K. R. Curr. Pharma Res. 2012, 3, 690-696.
. Unnissa S, H.; Reddy, G. K.; Aravazhi, T. J. Appl. Pharm. Sci. 2013, 3, 136-140.
. (a) Amir, M.; Ali, I.; Hassan, M. Z. Arch. Pharmacal Res. 2013, 36, 61-68; (b) Gupta, D.;
Kumar, R.; Roy, R. K.; Sharma, A.; Ali, I.; Shamsuzzaman, M. Med. Chem. Res. 2013, 22,
3
282-3288.
6
5
. Sheorey, R. V.; Thangathiruppathy, A.; Alagarsamy, V. Trop. J. Pharm. Res. 2013, 12,
83-589.
7
. (a) Giannini, G.; Battistuzzi, G.; Vesci, L.; Milazzo, F. M.; De Paolis, F.; Barbarino, M.;
Guglielmi, M. B.; Carollo, V.; Gallo, G.; Artali, R.; Dallavalle, S. Bioorg. Med. Chem. Lett.
2
014, 24, 462-466; (b) Yu, C.-W.; Chang, P.-T.; Hsin, L.-W.; Chern, J.-W. J. Med. Chem. 2013,
5
6, 6775-6791.
8
2
. Noolvi, M. N.; Patel, H. M.; Bhardwaj, V.; Chauhan, A. Eur. J. Med. Chem. 2011, 46,
327-2346.
1
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
9
. (a) Reisch, J.; Usifoh, C. O.; Oluwadiya, J. O. J. Heterocycl. Chem. 1990, 27, 1953-1956; (b)
Kulkarni, S. S.; Singh, S.; Shah, J. R.; Low, W.-K.; Talele, T. T. Eur. J. Med. Chem. 2012, 50,
2
1
64-273; (c) Luo, H.; Yang, S.; Zhao, Q.; Xiang, H. Med. Chem. Res. 2014, 23, 2584-2595.
0. (a) Rabilloud, G.; Sillion, B. J. Heterocycl. Chem. 1980, 17, 1065-1068; (b) Su, W. K.; Wu,
D. Z.; Xie, Y. Y.; Li, J. J. Org. Prep. Proced. Int. 2006, 38, 89-94; (c) Storelli, S.; Verdijk, P.;
Verzijl, D.; Timmerman, H.; van de Stolpe, A. C.; Tensen, C. P.; Smit, M. J.; De Esch, I. J. P.;
Leurs, R. Bioorg. Med. Chem. Lett. 2005, 15, 2910-2913.
1
1
1. Zeng, G.; Sun, F. Huaxue Shijie 2005, 46, 732-733.
2. (a) Afsah, S. A.; Ahmad, J.; Purbey, R.; Kumar, A. Asian J. Chem. 2003, 15, 552-554; (b)
Meyyanathan, S. N.; Ramu, M.; Suresh, B. Med. Chem. Res. 2010, 19, 993-999; (c) Schroeder,
C. E.; Yao, T.; Sotsky, J.; Smith, R. A.; Roy, S.; Chu, Y.-K.; Guo, H.; Tower, N. A.; Noah, J.
W.; McKellip, S.; Sosa, M.; Rasmussen, L.; Smith, L. H.; White, E. L.; Aube, J.; Jonsson, C. B.;
Chung, D.; Golden, J. E. J. Med. Chem. 2014, 57, 8608-8621.
1
1
1
3. Liu, J.; Zhao, X.; Yang, W.; Zhan, C. G. J. Phys. Chem. B 2011, 115, 5017-5025.
4. Chen, X.; Fang, L.; Liu, J.; Zhan, C. G. Biochemistry 2012, 51, 1297-1305.
5. Li, J. J. Vilsmeier-Haack reaction. Name Reactions: A Collection of Detailed Reaction
Mechanisms, 3rd ed.; Springer: Berlin, Heidelberg, 2006; pp 603-604.
1
1
6. Tsukamoto, H.; Suzuki, R.; Kondo, Y. J. Comb. Chem. 2006, 8, 289-292.
7. Grob, C. A. Helv. Chim. Acta 1950, 33, 1787-1796.
1
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1
8. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652; (b) Lee, C.; Yang, W.; Parr, R. G.
Phys. Rev. B 1988, 37, 785-789; (c) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M.
J. J. Phys. Chem. 1994, 98, 11623-11627.
1
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
a
Table 1. Yields of 2,7-dimethyl -3-phenyl-quinazoline-4(3H)-one(5a) under different conditions
b
Entry
Temperature(°C)
Condensing Agents
Solvent
Toluene
Toluene
Toluene
Toluene
Yield (%)
none
34
1
2
3
4
5
6
7
8
9
110
110
110
110
82
none
d
PPh /Pyridine
3
POCl3
Pyridine
Pyridine
POCl3
84
trace
trace
20
CH CN
3
40
CH Cl2
2
66
POCl3
THF
68
c
82
POCl3
CH CN
92
3
82
P2O5
CH CN
28
3
d
1
0
82
PPh /Pyridine
CH CN
trace
3
3
a
Reaction conditions: 2-acetylamino-4-methylbenzoic acid (1 mmol), aniline (2 mmol),
condensing agents (2 mmol) in 10 mL of different solvents at refluxing temperature. The
reaction progress was monitored by TLC according to disappearing of
2
-acetylamino-4-methylbenzoic acid.
b
Isolated yields by column chromatography.
c
The reaction was carried out for 3h.
d
Molar ratio 1:1 as compared with 1
1
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 2. Yield of 2,7-dimethyl-3-phenyl-quinazolin-4(3H)-one (5a) using different amounts of
a
POCl at different temperatures (°C)
3
b
c
Entry
Temperature(°C)
POCl3
2
Yield (%)
d
1
1
1
1
1
2
3
4
55
82
82
82
92
0.5
1
60
60
84
2.5
a
Reaction conditions: 2-acetylamino-4-methylbenzoic acid (1mmol) and aniline (2mmol) in 10
mL of CH CN. The reaction time is 3h.
3
b
The molar ratios of POCl /2-acetylamino-4-methylbenzoic acid.
3
c
Isolated yield by column chromatography
d
The reaction was carried out for 10h.
2
0
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
N
O
A
OH
TS1A_2
H
O
O
H
O
HN
TS1A_1
O
H
O
O
NH
O
INT1A
O
O
O
O
N
1
N
H
INT2
OH
Cl
P
Cl
Cl
TS1A_3
TS1A_4
Reaction coordinate
B
Reaction coordinate
Figure 1. Competitive pathways in reaction Stage 1. (A) Intramolecular nucleophilic
addition-elimination pathways and (B) Vilsmeier-Haack reaction pathway. The molecular
geometries were optimized at B3LYP/6-31+G* level. IEFPCM solvation model was used to
account for the effects of the solvent acetonitrile.
2
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
O
H
NH
NH
A
N
O
H
O
N
HN
O
N
OH
O
N
H
N
O
N
OH
O
H2N
+
INT2
R e a c t i o n c o o r d i n a t e
B
H
N
N
N H
H
H
H
O
N
O
H
O
N
H
N
H
N
H
O
O
H2N
+
OH
N
INT2
Reaction coordinate
Figure 2. Competitive pathways in reaction Stage 2. (A) Direct nucleophilic attacking
pathways and (B) Aniline-assisted nucleophilic attacking. The CH NH appears in this Figure is
3
2
a model structure of the aniline. Computational details are described in Figure 1.
2
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A
O
N
N
O
N
H
5a
NH
O
6
Reaction coordinate
B
Reaction coordinate
Figure 3. Competitive pathways in reaction Stage 3. (A) Intramolecular nucleophilic
addition-elimination pathways and (B) Vilsmeier-Haack reaction pathway. Computational details
are described in Figure1.
2
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 1. Reported synthetic routes of quinazolin-4(3H)-ones from 2-acetamidobenzoic acid
and arylamines under different conditions.
2
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
H
O
O
O
POCl3
NH2
POCl3
H O
N
N
H
NH
-
NH
2
N
O
O
1
6
5a
Scheme 2. Proposed routes for the formation of 2,7-dimethyl-3-phenyl-quinazoline-4(3H)-one
2
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
O
H
O
POCl3/CH3CN
R
N
+
R NH2
o
NH
82 C
N
O
5a-i
NO2
CH3
O
N
O
N
O
N
N
N
N
5
c: 91%
5
a: 92%
5b: 95%
O
COOCH3
O
N
O
H
H
N
N
N
N
N
O
N
N
5
d: 91%
5e: 90%
5f: 85%
O
OH
Cl
O
O
N
N
N
N
N
N
5
g: 62%
5h: 89%
5i: 98%
Scheme 3. Yields of different quinazolin-4-ones. Reagents and conditions:
-acetylamino-4-methylbenzoic acid (1 mmol), amines (2mmol) and POCl (2 mmol) in 10 mL
2
3
of CH CN at 82°C. All yields are obtained by column chromatography.
3
2
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Stage 1
Stage 2
Stage 3
NH2
O
O
N
H
O
POCl3
O
O
NH
O
POCl3
NH
N
O
NH
N
O
1
INT2
6
5a
Scheme 4. Different stages for the formation of compound 5a.
2
7
ACCEPTED MANUSCRIPT