Synthesis of Cu-catalysed quinazolinones using a Csp3-H functionalisation/cyclisation strategy

Article abstract of DOI:10.1039/c7ob01723e

A series of 2,3-disubstituted-4(3H)-quinazolinones were synthesised via a copper-catalysed C_sp3-H functionalisation/cyclisation of 2-amino-N,N-dialkylbenzamides. In comparison to the reported methods this strategy allows an easy access to diversely substituted quinazolinones under mild conditions in air. The reaction also exhibits good functional group tolerance and would be of value to heterocyclic researchers as well as pharmaceutical process chemists. The reaction is proposed to proceed through a double SET type radical mechanism.

Full text of DOI:10.1039/c7ob01723e

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Synthesis of Cu-catalysed quinazolinones using a
Csp3–H functionalisation/cyclisation strategy†
Cite this: DOI: 10.1039/c7ob01723e
Aniket V. A. Gholap,a Soham Maity,b Carola Schulzke, c Debabrata Maiti *b and
a
Anant R. Kapdi
*
A series of 2,3-disubstituted-4(3H)-quinazolinones were synthesised via a copper-catalysed Csp3–H func-
tionalisation/cyclisation of 2-amino-N,N-dialkylbenzamides. In comparison to the reported methods this
strategy allows an easy access to diversely substituted quinazolinones under mild conditions in air. The
reaction also exhibits good functional group tolerance and would be of value to heterocyclic researchers
as well as pharmaceutical process chemists. The reaction is proposed to proceed through a double SET
type radical mechanism.
Received 13th July 2017,
Accepted 4th August 2017
DOI: 10.1039/c7ob01723e
rsc.li/obc
1. Introduction
The structural motif of quinazolinone (also known as 4(3H)-
quinazolinone) has attracted considerable attention in the past
few decades due to the promising bio-activity of its derivatives
ranging from antimalarial, antimicrobial, anti-inflammatory,
anticonvulsant, antihypertensive, and antidiabetic, to antitumor
activities.1 Its occurrence as a major building block of a large
number of alkaloids2 further elevates its case for synthetic
evaluation. 2,3-Disubstituted-4(3H)-quinazolinones amongst
other derivatives of quinazolinones have gained commercial
relevance in the form of drugs such as rutaecarpine, (+)-febrifu-
gine, afloqualone and raltitrexed. Due to this inherent impor-
tance, there is considerable interest and need to investigate and
optimise the synthesis of quinazolinones and their derivatives.
General synthetic strategies for obtaining substituted quina-
zolinones are well-known3 and the introduction of transition-
metal catalysed4–7 processes has contributed immensely in
making the procedures synthetically attractive. Recent studies
have focussed on the employment of two types of metal-cata-
lysed cyclisation processes for an efficient and economical con-
struction of the quinazolinone structural motif (Scheme 1).
Following path A, the C–N bond forming ring closure between
b and c positions could be achieved using Ru, Cu and Ir based
Scheme 1 Cyclisation strategies for the construction of the quinazoli-
none structural motif.
catalytic systems,8 while path B constitutes an efficient palla-
dium catalysed cyclocarbonylation connecting positions c and
d.9 A third pathway (path C) has also been reported which
includes an intra-molecular aza-Wittig reaction linking a and
b,3c–e although a metal-mediated protocol is yet to be explored.
We report herein, our investigations into the synthesis of 2,3-
disubstituted-4(3H)-quinazolinone through pathway C via a
copper-catalysed
Csp3–H functionalisation/cyclisation of
2-amino-N,N-dialkylbenzamides.
2. Results and discussion
C–H bond functionalisation10 in recent years has emerged as a
powerful synthetic strategy for the direct functionalisation of
substrates without the requirement of pre-functionalization (a
pre-requisite for cross-coupling reactions). Amongst the
various C–H bonds available for functionalisation, Csp3–H
bond functionalisation remained a major synthetic challenge.
In this regard, dehydrogenative or oxidative functionalisation
strategies for the Csp3–H bond11 are known and have proved
useful towards the construction of various structural motifs. The
aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road,
Matunga, Mumbai-400019, India. E-mail: ar.kapdi@ictmumbai.edu.in
bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai 400076, India. E-mail: dmaiti@chem.iitb.ac.in
cInstitute fur Biochemie, Ernst-Moritz-Arndt Universität Greifswald,
Felix-Hausdorff- Straße 4, D-17487 Greifswald, Germany
†Electronic supplementary information (ESI) available. CCDC 1548639. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7ob01723e
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utilisation of mild and green oxidants coupled with the appli- choice of solvent greatly impacts the selectivity with the exclu-
cation of labile reagents contributes largely to the synthetic sive formation of quinazolin-4(3H)-one (2A) observed in DMF
appeal of this strategy. We therefore envisaged a commercially (entry 11, Table 1). Other nitrogen based ligands that have
available tetrakis(pyridine)copper(II) triflate-catalysed dehydro- shown promising results in copper-catalysed couplings such as
genative Csp3–H bond functionalisation/cyclisation strategy under L-proline, 1,10-phenanthroline, and DMAP failed to further
aerobic conditions as a practical and efficient approach for the improve either yield or selectivity. Interestingly, the employ-
construction of the quinazolinone moiety. A recent report by ment of an easily synthesised13 and commercially available
Maiti and co-workers12 in 2014 involving the cyclization of Cu(Py)4(OTf)2 provided the desired quinazolinone in competi-
o-hydroxy-N,N-dialkylbenzamides was envisaged as the possible tive yield (entry 20, Table 1).
starting point. Although, in comparison to phenols, aniline
derivatives would provide an interesting challenge in terms of of the dehydrogenative coupling reaction was further explored.
reactivity while their biological significance is immense.
Variation in the alkyl groups R1 and R2 on the backbone of
With an active catalytic system identified, the substrate scope
In the first attempt, 2-amino-N,N-dibenzylbenzamide under 2-amino-N,N-dialkylbenzamides would allow the synthesis of a
the dehydrogenative coupling conditions with CuCl2·2H2O (no diverse range of 2,3-disubstituted quinazolinones (Scheme 2).
ligand added) in air as an oxidant and m-xylene as the solvent Initial observations revealed the more efficient functionalisation
at 130 °C provided a mixture of 3-benzyl-2-phenylquinazolin-4 of N-benzyl Csp3–H compared to N-alkyl Csp3–H bonds.
(3H)-one (2A) and 3-benzyl-2-phenyl-2,3-dihydroquinazolin-4
(1H)-one (2B) in poor yields (entry 1, Table 1).
The selectivity obtained was nearly exclusive providing
2-arylsubstituted quinazolinones in good yields. Next, substitu-
Adding pyridine as a ligand helped improve the yield as ent effects were explored providing an insight into the reaction
well as the selectivity of the dehydrogenative coupling reaction mechanism. An electronic influence on the aryl substituent R2
(entry 2, Table 1). On further screening of different copper affects the catalytic efficiency adversely with the unsubstituted
catalyst precursors, Cu(OTf)2 in combination with pyridine benzamides furnishing the cyclised product in competitive
was found to provide the best selectivity (entry 8, Table 1). The yields as do those with only mildly electron-releasing 4-Me
substituents. The introduction of strongly electron-releasing
substituents (3- or 4-MeO) brought about a slight reduction in
Table 1 Optimization study for copper-catalysed Csp3–H functionalisa-
tion/cyclisation strategy for quinazolinone synthesis
% Yield
(2A/2B)
No
Copper precursor Ligand
Solvent
Copper precursor screening
1
2
3
4
5
6
7
8
CuCl2·2H2O
CuCl2·2H2O
Cu(OAc)2·H2O
Cu(OAc)2
CuOAc
CuCl2 (anhyd)
Cu(acac)2
—
m-Xylene 20/16
m-Xylene 46/11
m-Xylene 65/18
m-Xylene 75/11
m-Xylene 67/22
m-Xylene 57/13
m-Xylene 47/18
m-Xylene 58/2
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Cu(OTf)2
Solvent screening
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
PhMe
MeCN
DMF
THF
DCE
MeOH
H2O
45/0
8/0
62/0
9/0
—
10
11
12
13
14
15
—
—
Ligand screening
16
17
18
19
20
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
L-Proline
1,10-Phenanthroline DMF
DMAP
2-NH2-pyridine
—
—
—
DMF
32/0
20/0
60/0
32/0
74/0
30/0
42/0
DMF
DMF
DMF
DMF
DMF
Cu(Py)4(OTf)2
21a Cu(Py)4(OTf)2
22
Cu(DMF)4(OTf)2
a Pyridine is replaced by 4-N,N-dimethylamino pyridine.
Scheme 2 Synthesis of 2,3-disubstituted-4(3H)-quinazolinones.
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yield whereas electron-withdrawing substituents (Cl, Br, and F)
a
SET (single electron transfer) mechanism15 with an
provided poorer results. These studies point strongly towards iminium-type intermediate involved in the rate-limiting step.
the involvement of a radical mechanism that is significantly To test this hypothesis, we first performed the catalytic dehy-
influenced by electronic effects of the substituents.
drogenative coupling reaction with a radical scavenger
Of the synthesised quinazolinones, compound 2a was crys- (TEMPO, 2,2,6,6-tetramethylpiperidine 1-oxyl) added at the
tallized from dichloromethane in the monoclinic space group initial stage of the reaction (Scheme 4). As expected the cata-
P21/n with eight molecules in the unit cell and two molecules lytic reaction failed to furnish the cyclised product supporting
in the asymmetric unit (Fig. 1).14 These two independent the envisaged intermediacy of radical species.
molecules can be distinguished by the torsion angle between
The role of molecular oxygen (previously present in the
their backbones and the phenyl substituents which is 79.7° for form of air or pure O2 supplied via a balloon) in promoting the
molecule 1 and 69.4° for molecule 2, clearly verifying that the cyclisation reaction was next investigated with the catalytic
presence of two independent molecules is not due to over- reaction performed under a nitrogen atmosphere. The reaction
looked symmetry. The orientation of the benzyl substituent is proceeded sluggishly with a poor yield of the product, confirm-
further slightly different in the two molecules although this ing the requirement of molecular oxygen for an effective cycli-
difference is not as much pronounced.
sation (Scheme 5).
We next turned our attention to the possibility of synthesis-
ing 2,3-dihydroquinazolin-4(1H)-ones using the developed pro-
tocol with N,N-dibenzyl-2-(propylamino)benzamide as a start-
ing material. To test the feasibility of the catalytic procedure,
N,N-dibenzyl-2-(propylamino)benzamide (3a) was subjected to
dehydrogenative coupling which provided the corresponding
dihydroquinazolin-4(1H)-one (4a) in good yield (Scheme 3).
Other alkyl substituents (such as butyl) when employed unfor-
tunately did not furnish the desired dihydroquinazolinones as
the preferential cyclisation failed to occur.
Scheme 4 Dehydrogenative coupling with TEMPO as
scavenger.
a radical
3. Mechanistic studies
The dehydrogenative coupling reaction giving access to 2,3-di-
substituted-4(3H)-quinazolinones is most likely going through
Scheme 5 Catalytic reaction performed under an inert N2 atmosphere.
Fig. 1 Single crystal X-ray structure of molecule 1 of compound 2a.
Ellipsoids are shown with 50% probability. H atoms are omitted for
clarity reasons.
Scheme 3 Synthesis of dihydroquinazolinones via copper-catalysed
C–H functionalisation/cyclisation.
Fig. 2 Plausible SET-type mechanism for the synthesis of
quinazolinones.
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Table 2 Crystal data and structure refinement for 3-benzyl-2-phenyl-
quinazolin-4(3H)-one (2a)
Based on these observations a plausible mechanistic propo-
sal involving a SET mechanism11a,15 is being put forth (Fig. 2).
The reaction initiates through a loss of proton from the di-
substituted benzamide resulting in a substrate bound Cu(II)
center (A). This further undergoes a single electron transfer to
oxidise the amide-nitrogen resulting in the formation of inter-
mediate B.16 The generation of a Cu(II)-superoxo species could
then be envisaged via Cu(I) (B) functionalisation of a molecule
of O2.17 The abstraction of the H atom from the N-benzylic C–H
bond by intermediate C would then lead to the formation of a
Cu(II)hydroperoxo complex D as well as an active iminium ion
intermediate. In the final step, a nucleophilic attack of the
iminium carbon atom by the anilide ion and loss of the H
atom leads to the formation of the cyclised 2B product which
would then undergo a second SET mechanism leading to the
formation of 2,3-disubstituted-4(3H)-quinazolinones.
Empirical formula
Formula weight
Temperature
C21H16N2O
312.36
170(2) K
Wavelength
Crystal system, space group
Unit cell dimensions
0.71073 Å
Monoclinic, P21/n
a = 9.933(2) Å, alpha = 90 deg
b = 29.454(6) Å, beta = 112.40(3) deg
c = 11.470(2) Å, gamma = 90 deg
3102.5(12) Å3
Volume
Z, calculated density
Absorption coefficient
F(000)
8, 1.337 Mg m−3
0.083 mm−1
1312
Crystal size
0.292 × 0.081 × 0.060 mm
Theta range for data collection 3.109 to 20.818 deg
Limiting indices
−9 ≤ h ≤ 9, −29 ≤ k ≤ 29, −11 ≤ l ≤ 11
Reflections collected/unique
Completeness to theta
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
10 622/3231 [R(int) = 0.1280]
= 25.242, 57.6%
None
Full-matrix least-squares on F2
3231/0/433
0.794
R1 = 0.0448, wR2 = 0.0723
R1 = 0.1464, wR2 = 0.0960
n/a
4. Conclusion
Extinction coefficient
Largest diff. peak and hole
We have reported herein a simple and highly practical protocol
for the synthesis of 2,3-disubstituted-4(3H)-quinazolinones via
copper-catalysed dehydrogenative Csp3–H functionalisation/
cyclisation of 2-amino-N,N-dialkylbenzamides. The catalytic
conditions were also found to be useful towards the synthesis
of dihydroquinazolinones. A SET-type mechanism involving an
iminium radical cation as the possible intermediate has been
found to be operational in the catalytic reaction.
0.159 and −0.202 e Å−3
atoms were refined anisotropically. Hydrogen atoms were
refined isotropically on calculated positions using a riding
model with their Uiso values constrained to 1.2Ueq of their pivot
atoms. All calculations were carried out using SHELX-201319
and WinGX GUI, Ver2013.2.20,21 Crystallographic data are
summarized in Table 2.
6. Experimental section
6.2 Synthesis of Cu(Py)4(OTf)2
6.1 General remark
Tetrakis(pyridine)bis(trifluoromethanesulfonato-O)copper(II) was
synthesized by a reported method.22 The commercially available
chemicals were purchased from Aldrich Chemical Co. or Alfa
Aesar and were used without further purification. All the reaction
solvents were dried by standard methods before use.
All the catalytic reactions were conducted in open air in
Schlenk tubes. TLC analysis was performed on a Merck 5554
aluminium backed silica gel plate and the compound was visu-
alized by ultraviolet light (254 nm). All yields refer to isolated
yields obtained by column chromatography. NMR spectro-
scopic data of compounds (1H, 13C) were recorded on an
Agilent 400 MHz spectrometer in CDCl3 and DMSO-d6. In
6.3 General procedure for synthesis of quinazolinone
a
dry Schlenk tube, 2-amino-N-benzylbenzamide
Chemical shifts are reported in parts per million downfield (0.5 mmol), 2 ml of DMF, and tetrakis(pyridine)copper(II)
from an internal standard tetramethylsilane. Coupling con- triflate (5 mol%) were added. The resulting solution was stirred
stant J values are reported in hertz (Hz). Elemental analysis at 130 °C in open air for 12 h. After 12 h, the reaction was moni-
was performed using an Elementar Vario Micro cube. All the tored by TLC for completion and on cooling the reaction mixture
chemicals were obtained from commercial sources.
the solvent was removed by using a rotary evaporator under
X-ray structural analysis. A suitable single crystal of 2a was reduced pressure. The residue thus obtained was further purified
mounted on a thin glass fibre coated with paraffin oil. X-ray by column chromatography (15% ethyl acetate in petroleum
single-crystal structural data were collected at low temperature ether) to provide the cyclised quinazolinone as a white solid.
(170 K) using a STOE-IPDS 2T diffractometer equipped with a
3-Benzyl-2-phenylquinazolin-4(3H)-one (2a).23 1H NMR
normal-focus, 2.4 kW, sealed-tube X-ray source with graphite- (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.9 Hz, 1H), 7.86 (t, J =
monochromated MoKα radiation (λ = 0.71073 Å). The program 7.7 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H),
XArea was used for the integration of diffraction profiles; 7.51–7.37 (m, 5H), 7.18 (t, J = 6.1 Hz, 3H), 6.89 (d, J = 6.5 Hz, 2H),
numerical absorption correction was made with the programs 5.16 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.9, 156.6, 147.3,
X-shape and X-red32; all from STOE© 2010. The structure was 137.0, 135.4, 135.3, 130.2, 128.9, 128.7, 128.4, 127.8, 127.7, 127.6,
solved by SHELXT-201418 and refined by full-matrix least- 126.8, 126.6, 120.7, 48.6. Anal. calcd for C21H16N2O: C, 80.75; H,
squares methods using SHELXL-2013.19 The non-hydrogen 5.16; N, 8.19. Found: C, 80.68; H, 5.11; N, 8.14.
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3-Ethyl-2-phenylquinazolin-4(3H)-one (2b).23 1H NMR 7.05 (ddd, J = 10.7, 10.0, 5.2 Hz, 3H), 3.84 (s, 3H), 3.47 (s, 3H).
(400 MHz, CDCl3) δ 8.34 (d, J = 8.2 Hz, 1H), 7.79–7.71 (m, 2H), 13C NMR (101 MHz, CDCl3) δ 162.6, 159.8, 155.9, 147.2, 136.4,
7.55–7.48 (m, 6H), 4.04 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 134.3, 130.0, 127.4, 127.0, 126.6, 120.5, 120.0, 115.8, 113.4,
3H). 13C NMR (101 MHz, CDCl3) δ 162.0, 156.1, 147.1, 135.5, 55.4, 34.1. Anal. calcd for C16H14N2O2: C, 72.16; H, 5.30; N,
134.3, 129.7, 128.8, 127.6, 127.4, 126.9, 126.6, 120.9, 41.1, 14.1. 10.52. Found: C, 72.18; H, 5.35; N, 10.43.
Anal. calcd for C16H14N2O: C, 77.40; H, 4.87; N, 11.28. Found:
C, 77.24; H, 5.06; N, 11.33.
2-(4-Methoxyphenyl)-3-methylquinazolin-4(3H)-one
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.5 Hz, 1H), 7.76–7.69
(2j).24
3-Methyl-2-phenylquinazolin-4(3H)-one (2c).23 1H NMR (m, 2H), 7.54–7.44 (m, 3H), 7.01 (d, J = 8.7 Hz, 2H), 3.86 (s,
(400 MHz, CDCl3) δ 8.36–8.32 (m, 1H), 7.80–7.73 (m, 2H), 7.54 3H), 3.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.9, 160.9,
(dtt, J = 9.6, 7.3, 2.1 Hz, 6H), 3.50 (s, 3H). 13C NMR (101 MHz, 156.0, 147.3, 134.2, 129.7, 127.7, 127.3, 126.7, 126.6, 120.3,
CDCl3) δ 162.7, 156.1, 147.2, 135.3, 134.3, 130.0, 128.8, 127.9, 114.1, 55.4, 34.4. Anal. calcd for C16H14N2O2: C, 72.16; H, 5.30;
127.4, 126.9, 126.6, 120.4, 34.2. Anal. calcd for C15H12N2O: C, N, 10.52. Found: C, 72.31; H, 5.36; N, 10.40.
76.25; H, 5.12; N, 11.86. Found: C, 76.39; H, 5.18; N, 11.60.
3-Butyl-2-(4-methoxyphenyl)quinazolin-4(3H)-one
(2k).25
5H-Isoquinolino[1,2-b]quinazolin-8(6H)-one (2d).26 1H NMR 1H NMR (400 MHz, CDCl3) δ 8.29 (ddd, J = 8.0, 1.2, 0.6 Hz,
(400 MHz, DMSO d6) δ 8.34 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 1H), 7.73–7.67 (m, 2H), 7.46 (dt, J = 4.1, 2.0 Hz, 2H), 7.44 (d,
7.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), J = 2.0 Hz, 1H), 7.02–6.97 (m, 2H), 4.02–3.96 (m, 2H), 3.85 (s,
7.55–7.35 (m, 4H), 4.27 (t, J = 6.3 Hz, 2H), 3.08 (t, J = 6.1 Hz, 3H), 1.61–1.52 (m, 2H), 1.17 (dt, J = 14.9, 7.5 Hz, 2H), 0.76 (t,
2H). 13C NMR (101 MHz, DMSO-d6) δ 161.0, 149.7, 147.7, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.3, 160.5,
138.1, 134.8, 132.1, 129.4, 128.2, 127.8, 127.7, 127.6, 126.9, 156.1, 147.1, 134.1, 129.4, 127.9, 127.3, 126.7, 126.6, 120.7,
126.7, 120.8, 39.6, 26.8. Anal. calcd for C16H12N2O: C, 77.40; H, 114.0, 55.4, 45.7, 30.7, 19.9, 13.4. Anal. calcd for C19H20N2O2:
4.87; N, 11.28. Found: C, 77.27; H, 4.72; N, 11.41.
C, 74.00; H, 6.54; N, 9.08. Found: C, 74.03; H, 6.50; N, 9.02.
3-Butyl-2-phenylquinazolin-4(3H)-one (2e).25 1H NMR
3-Butyl-2-(4-chlorophenyl)quinazolin-4(3H)-one (2l).25 1H
(400 MHz, CDCl3) δ 8.31 (dd, J = 7.8, 0.8 Hz, 1H), 7.76–7.69 (m, NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 1H), 7.64–7.53 (m,
2H), 7.52–7.45 (m, 6H), 3.98–3.92 (m, 2H), 1.56 (dt, J = 15.3, 2H), 7.39–7.31 (m, 5H), 3.85–3.78 (m, 2H), 1.43 (dt, J = 15.3,
7.6 Hz, 2H), 1.20–1.09 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H). 7.7 Hz, 2H), 1.09–0.99 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 162.1, 156.2, 147.1, 135.5, 134.2, 13C NMR (101 MHz, CDCl3) δ 162.0, 155.1, 146.9, 136.0, 134.3,
129.7, 128.7, 127.7, 127.3, 126.9, 126.7, 120.8, 45.6, 30.6, 19.8, 133.9, 129.2, 129.0, 127.3, 127.1, 126.7, 120.8, 45.7, 30.7, 19.8,
13.3. Anal. calcd for C18H18N2O: C, 77.06; H, 6.52; N, 10.06. 13.4. Anal. calcd for C18H17ClN2O: C, 69.12; H, 5.48; N, 8.96.
Found: C, 77.14; H, 6.51; N, 9.79.
Found: C, 69.24; H, 5.57; N, 8.78.
2-(4-Chlorophenyl)-3-methylquinazolin-4(3H)-one
3-Butyl-2-(p-tolyl)quinazolin-4(3H)-one (2f).25 1H NMR
(2m).24
(400 MHz, CDCl3) δ 8.30 (d, J = 7.6 Hz, 1H), 7.75–7.68 (m, 2H), 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.2 Hz, 1H), 7.70 (ddd,
7.46 (ddd, J = 8.1, 6.3, 2.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.29 J = 15.6, 11.3, 4.2 Hz, 2H), 7.50–7.43 (m, 5H), 3.44 (s, 3H).
(d, J = 8.0 Hz, 2H), 4.00–3.94 (m, 2H), 2.41 (s, 3H), 1.57 (dt, J = 13C NMR (101 MHz, CDCl3) δ 162.5, 154.9, 147.1, 136.3, 134.4,
15.4, 7.6 Hz, 2H), 1.16 (dq, J = 14.8, 7.4 Hz, 2H), 0.75 (t, J = 133.7, 129.5, 129.1, 127.4, 127.2, 126.7, 120.4, 34.2. Anal. calcd
7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.2, 156.4, 147.1, for C15H11ClN2O: C, 66.55; H, 4.13; N, 10.38. Found: C, 66.64;
139.8, 134.2, 132.6, 129.3, 127.6, 127.3, 126.8, 126.6, 120.8, H, 4.17; N, 10.24.
45.7, 30.7, 21.4, 19.9, 13.4. Anal. calcd for C19H20N2O: C, 78.05;
H, 6.89; N, 9.58. Found: C, 78.11; H, 6.68; N, 9.41.
2-(4-Bromophenyl)-3-methylquinazolin-4(3H)-one (2n).24 1H
NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 8.0, 0.9 Hz, 1H),
3-Methyl-2-(p-tolyl)quinazolin-4(3H)-one (2g).23 1H NMR 7.79–7.63 (m, 4H), 7.47 (ddt, J = 8.8, 4.0, 1.8 Hz, 3H), 3.48 (s,
(400 MHz, CDCl3) δ 8.30 (d, J = 8.5 Hz, 1H), 7.75–7.69 (m, 2H), 3H). 13C NMR (101 MHz, CDCl3) δ 162.6, 155.0, 147.1, 134.4,
7.49–7.42 (m, 3H), 7.30 (d, J = 7.9 Hz, 2H), 3.48 (s, 3H), 2.41 (s, 134.1, 132.1, 129.7, 127.4, 127.2, 126.7, 124.6, 120.4, 34.2.
3H). 13C NMR (101 MHz, CDCl3) δ 162.8, 156.2, 147.3, 140.2, Anal. calcd for C15H11BrN2O: C, 57.16; H, 3.52; N, 8.89. Found:
134.2, 132.4, 129.4, 127.9, 127.4, 126.8, 126.6, 120.4, 34.3, 21.4. C, 57.03; H, 3.36; N, 8.95.
Anal. calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found:
C, 76.85; H, 5.78; N, 11.36.
2-(4-Bromophenyl)-3-butylquinazolin-4(3H)-one
1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.76–7.62
(2o).25
2-([1,1′-Biphenyl]-4-yl)-3-methylquinazolin-4(3H)-one (2h). (m, 4H), 7.49 (t, J = 7.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H),
1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 7.9 Hz, 1H), 7.76–7.70 3.98–3.91 (m, 2H), 1.55 (dt, J = 15.3, 7.7 Hz, 2H), 1.16 (dt, J =
(m, 4H), 7.62 (dd, J = 8.9, 7.8 Hz, 4H), 7.48 (ddd, J = 9.4, 5.2 14.8, 7.4 Hz, 2H), 0.77 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
Hz, 3H), 7.41–7.35 (m, 1H), 3.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.0, 155.1, 146.9, 134.4, 134.3, 131.9, 129.5, 127.3,
CDCl3) δ 162.7, 155.9, 147.3, 143.0, 140.0, 134.3, 134.1, 128.9, 127.1, 126.7, 124.2, 120.8, 45.7, 30.7, 19.9, 13.4. Anal. calcd for
128.5, 127.9, 127.5, 127.5, 127.1, 127.0, 126.6, 120.4, 34.3. C18H17BrN2O: C, 60.52; H, 4.80; N, 7.84. Found: C, 60.29; H,
Anal. calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 4.65; N, 7.75.
1
80.62; H, 5.12; N, 8.71.
3-Butyl-2-(4-fluorophenyl)quinazolin-4(3H)-one (2p). H NMR
2-(3-Methoxyphenyl)-3-methylquinazolin-4(3H)-one
(2i). (400 MHz, CDCl3) δ 8.32–8.28 (m, 1H), 7.77–7.67 (m, 2H),
1H NMR (400 MHz, CDCl3) δ 8.32–8.27 (m, 1H), 7.76–7.69 (m, 7.55–7.46 (m, 3H), 7.20 (t, J = 8.6 Hz, 2H), 3.99–3.91 (m, 2H),
2H), 7.47 (ddd, J = 8.2, 5.9, 2.3 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 1.55 (dt, J = 15.3, 7.6 Hz, 2H), 1.16 (dt, J = 14.8, 7.4 Hz, 2H),
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0.76 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.5,
162.0, 155.2, 146.9, 134.3, 131.6, 130.0, 129.9, 127.3, 127.1,
126.7, 120.8, 116.0, 115.8, 45.7, 30.7, 19.8, 13.4. Anal. calcd for
C18H17FN2O: C, 72.95; H, 5.78; N, 9.45. Found: C, 72.75; H,
5.90; N, 9.41.
3-Benzyl-2-phenyl-1-propyl-2,3-dihydroquinazolin-4(1H)-one
(4a).26 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 7.7, 1.5 Hz,
1H), 7.49–7.05 (m, 11H), 6.87–6.78 (m, 1H), 6.57 (d, J = 8.3 Hz,
1H), 5.76 (d, J = 15.2 Hz, 1H), 5.31 (s, 1H), 3.58 (d, J = 15.2 Hz,
1H), 3.18 (ddd, J = 13.9, 8.2, 5.3 Hz, 1H), 2.90–2.79 (m, 1H),
1.37 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 162.5, 145.9, 138.4, 136.5, 133.7, 129.0, 128.9, 128.7,
128.7, 128.1, 127.64, 126.4, 117.9, 116.6, 112.7, 75.0, 50.8, 46.6,
20.3, 11.1. Anal. calcd for C24H24N2O: C, 80.87; H, 6.79; N,
7.86. Found: C, 80.59; H, 6.89; N, 7.64.
(c) S. Guo, Y. Li, L. Tao, W. Zhang and X. Fan, RSC Adv.,
2014, 4, 59289; (d) T. Songsichan, J. Promsuk,
V. Rukachaisirikul and J. Kaeobamrung, Org. Biomol. Chem.,
2014, 12, 4571; (e) S. Laclef, M. Harari, J. Godeau, I. Schmitz-
Afonso, L. Bischoff, C. Hoarau, V. Levacher, C. Fruit and
T. Besson, Org. Lett., 2015, 17, 1700; (f) Y. Bao, Y. Tan, K. Xu,
J. Su, Z. Zha and Z. Wang, J. Org. Chem., 2015, 80, 4736;
(g) T. Kotipalli, V. Kavala, D. Janreddy, V. Bandi, C.-W. Kuo
and C.-F. Yao, Eur. J. Org. Chem., 2016, 1182.
5 Palladium-catalysed substituted quinazolinone synthesis
via carbonylation: (a) J. E. R. Sadig, R. Foster, F. Wakenhurt
and M. C. Willis, J. Org. Chem., 2012, 77, 9473; (b) C. Shen,
N. Y. T. Man, S. Stewart and X.-F. Wu, Org. Biomol. Chem.,
2015, 13, 4422; (c) L. He, M. Sharif, H. Neumann, M. Beller
and X.-F. Wu, Green Chem., 2014, 16, 3763.. Palladium-cata-
lysed substituted quinazolinone synthesis via isocyanide
insertion: X. Jiang, T. Tang, J.-W. Wang, Z. Chen, Y.-M. Zhu
and S.-J. Ji, J. Org. Chem., 2014, 79, 5082.
6 Rhodium-catalysed substituted quinazolinone synthesis:
R. Lingayya, M. Vellakkaran, K. Naggaiah and
J. B. Nanubolu, Adv. Synth. Catal., 2016, 358, 81.
7 Vanadium-catalysed substituted quinazolinone synthesis:
D. Zhan, T. Li, X. Zhang, C. Dai, H. Wei, Y. Zhang and
Q. Zeng, Synth. Commun., 2013, 43, 2493.
8 Path A cyclisation process: copper-catalysed: (a) W. Xu,
Y. Jin, H. Liu, Y. Jiang and H. Fu, Org. Lett., 2011, 13, 1274;
(b) W. Xu and H. Fu, J. Org. Chem., 2011, 76, 3846;
(c) D. Yang, Y. Wang, H. Yang, T. Liu and H. Fu, Adv. Synth.
Catal., 2012, 354, 477; (d) L. Xu, Y. Jiang and D. Ma, Org.
Lett., 2012, 14, 1150.. Ruthenium-catalysed: A. J. A. Watson,
A. C. Maxwell and J. M. J. Williams, Org. Biomol. Chem.,
2012, 10, 240. Iridium-catalysed: J. Fang and J. Zhou, Org.
Biomol. Chem., 2012, 10, 2389.
Acknowledgements
A. R. K. would like to acknowledge the Department of Science
and Technology for the DST FIST for infrastructural support to
the Department of Chemistry. Alexander von Humboldt
Foundation is also acknowledged for the equipment grant to
A. R. K. The authors also would like to thank University Grants
Commission India for the UGC-FRP faculty award for A. R. K.
References
1 (a) E. Jafari, M. R. Khajouei, F. Hassanzadeh,
G. H. Hakimelahi and G. A. Khodarahmi, Results Pharma
Sci., 2016, 11, 1; (b) K. Chen, K. Wang, A. M. Kirichian,
A. F. Al Aowad, L. K. Iyer, S. J. Adelstein and A. I. Kassis,
Mol. Cancer Ther., 2006, 5, 3001.
9 Path
B
cyclisation
process:
palladium-catalysed:
2 For reviews on quinazolinone based alkaloids and their
activity see: (a) S. Mhaske and N. P. Argade, Tetrahedron,
2006, 62, 9787; (b) U. A. Kshirsagar, Org. Biomol. Chem.,
2015, 13, 9336; (c) R. Bouley, D. Ding, Z. Peng, M. Bastian,
(a) C. Larksarp and H. Alper, J. Org. Chem., 2000, 65, 2773;
(b) F. Zeng and H. Alper, Org. Lett., 2008, 10, 829;
(c) F. Zeng and H. Alper, Org. Lett., 2010, 12, 1188;
(d) F. Zeng and H. Alper, Org. Lett., 2010, 12, 3642.
E. Lastochkin, W. Song, M. A. Suckow, V. A. Schroeder, 10 (a) L. Ackermann, R. Vicente and A. R. Kapdi, Angew.
W. R. Wolter, S. Mobashery and M. Chang, J. Med. Chem.,
2016, 59, 5011.
Chem., Int. Ed., 2009, 48, 9792; (b) M. Zhang, Y. Zhang,
X. Jie, H. Zhao, G. Li and W. Su, Org. Chem. Front., 2014, 1,
843; (c) T. Gensch, M. N. Hopkinson, F. Glorius and
J. Wencel-Delord, Chem. Soc. Rev., 2016, 45, 2900;
(d) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu and Y. Zhang,
Org. Chem. Front., 2015, 2, 1107; (e) A. R. Kapdi, Dalton
Trans., 2014, 43, 3021; (f) V. Gayakhe, Y. S. Sanghvi,
I. J. S. Fairlamb and A. R. Kapdi, Chem. Commun., 2015, 51,
11944.
3 (a) S. von Niementowski, J. Prakt. Chem., 1895, 51, 564;
(b) M. M. Endicott, E. Wick, M. L. Mercury and
M. L. Sherrill, J. Am. Chem. Soc., 1946, 68, 1299;
(c) H. Takeuchi, S. Hagiwara and S. Eguchi, Tetrahedron,
1989, 45, 6375; (d) B. B. Snider and M. V. Busuyek,
Tetrahedron, 2001, 57, 3301; (e) D. J. Connolly and
P. J. Guiry, Synlett, 2001, 1707; (f) M. K. Vogtle and
A. L. Marzinik, QSAR Comb. Sci., 2004, 23, 440; 11 (a) Z. Li, S. Bohle and C.-J. Li, Proc. Natl. Acad. Sci. U. S. A.,
(g) H. Nakano, N. Kutsumura and T. Saito, Synthesis, 2012,
3179; (h) Y.-F. Wang, F.-L. Zhang and S. Chiba, Org. Lett.,
2006, 103, 8928; (b) A. Gini, T. Brandhofer and
O. G. Mancheno, Org. Biomol. Chem., 2017, 15, 1294.
2013, 15, 2842; (i) L. He, H. Li, J. Chen and X.-F. Wu, RSC 12 A. Modak, U. Dutta, R. Kancherla, S. Maity, M. Bhadra,
Adv., 2014, 4, 12065. S. M. Mobin and D. Maiti, Org. Lett., 2014, 16, 2602.
4 Copper-catalysed substituted quinazolinone synthesis: 13 J. S. Haynes, S. J. Rettig, J. S. Sams, J. Trotter and
(a) L. Xu, Y. Jiang and D. Ma, Org. Lett., 2012, 14, 1150; R. C. Thompson, Inorg. Chem., 1998, 27, 1237.
(b) H. Chen and S. Chiba, Org. Biomol. Chem., 2014, 12, 42; 14 CCDC number for 2a is 1548639.†
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017

View Article Online
Organic & Biomolecular Chemistry
Paper
15 J. K. Kochi, A. Bemis and C. L. Jenkins, J. Am. Chem. Soc.,
1968, 90, 4616.
16 M. Nishino, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2011, 76, 6447.
17 (a) D. Maiti, H. C. Fry, J. S. Woertink, M. A. Vance,
E. I. Solomon and K. D. Karlin, J. Am. Chem. Soc., 2007, 129,
264; (b) D. Maiti, D. H. Lee, K. Gaoutchenova, C. Wurtele,
M. C. Holthausen, A. A. N. Sarjeant, J. Sundermeyer,
S. Schindler and K. D. Karlin, Angew. Chem., Int. Ed., 2008,
47, 82; (c) E. A. Lewis and W. B. Tolman, Chem. Rev., 2004,
104, 1047; (d) L. M. Mirica, X. Ottenwaelder and
T. D. P. Stack, Chem. Rev., 2004, 104, 1013.
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery, J. E. Peralta Jr.,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,
M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
D. J. Fox, Gaussian 09, Revision C.01, Gaussian, Inc.,
Wallingford CT, 2010.
18 A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi,
M. C. Burla, G. Polidori and M. Camalli, SIRPOW.92 – a
program for automatic solution of crystal structures by
direct methods optimized for powder data, J. Appl. 22 J. S. Haynes, S. J. Rettig, J. R. Sams, J. Trotter and
Crystallogr., 1994, 27, 435. R. C. Thompson, Inorg. Chem., 1988, 27, 1237.
19 G. M. Sheldrick, A short history of SHELX, Acta Crystallogr., 23 S. Guo, Y. Li, L. Tao, W. Zhanga and X. Fan, RSC Adv., 2014,
Sect. A: Fundam. Crystallogr., 2008, 64, 112. 4, 59289.
20 L. Farrugia, WinGX and ORTEP for Windows: an update, 24 T. Kotipalli, V. Kavala, D. Janreddy, V. Bandi, C. W. Kuo
J. Appl. Crystallogr., 2012, 45, 849. and C. F. Yao, Eur. J. Org. Chem., 2016, 1182.
21 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, 25 A. Modi, W. Ali, P. R. Mohanta, N. Khatun and B. K. Patel,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, ACS Sustainable Chem. Eng., 2015, 3, 2582.
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, 26 D. Maiti, A. Modak and U. Dutta, Indian Pat. Appl,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
IN2014MU01468A20151120, 2015.
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