TBHP as Methyl Source under Metal-Free Aerobic Conditions To Synthesize Quinazolin-4(3H)-ones and Quinazolines by Oxidative Amination of C(sp3)–H Bond

Article abstract of DOI:10.1002/ejoc.201800495

tert-Butyl hydroperoxide (TBHP) served as the methyl source under metal-free aerobic conditions in the oxidative amination of the C(sp³)–H bond to synthesize quinazolin-4(3H)-ones and quinazolines from 2-aminobenzamides and 2-carbonyl-substituted anilines, respectively.

Full text of DOI:10.1002/ejoc.201800495

A Journal of
Accepted Article
Title: TBHP as the methyl source under Metal-free Aerobic conditions
for the synthesis of Quinazolin-4(3H)-ones and Quinazolines via
Oxidative Amination of C(sp3)-H Bond
Authors: Sushobhan Mukhopadhyay, Dinesh Singh Barak, and Sanjay
Batra
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800495
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800495
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10.1002/ejoc.201800495
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TBHP as the methyl source under Metal-free Aerobic conditions
for the synthesis of Quinazolin-4(3H)-ones and Quinazolines via
Oxidative Amination of C(sp3)-H Bond
Sushobhan Mukhopadhyay,[a], ¥ Dinesh S. Barak,[a],¥ and Sanjay Batra*[a],[b]
Abstract: The use of tert-butyl hydrogen peroxide (TBHP) as the
methyl source under metal-free aerobic conditions for carrying out
the oxidative amination of the C(sp3)-H bond toward synthesis of
quinazolin-4(3H)-ones from 2-aminobenzamides and quinazolines
from 2-carbonyl substituted anilines is described.
Introduction
The quinazolin-4(3H)-one core is a privileged heterocycle
ubiquitously found in natural products[1] and compounds with
diverse pharmacological activities.[2] A few representative natural
compounds L-Vasicinone, Rutaecarpine, Luotonin E, (–)-
Curcumadatin H and (–)-Benzomalvin C and bioactives are
shown in Fig. 1. Out of several strategies for the synthesis of this
scaffold,[3] the one from 2-aminobenzamides via oxidative
Figure 1. Natural and bioactive compounds containing quinazolin-4(3H)-one
core.
amination of C(sp3)-H bond has received considerable attention
in the recent past (Scheme 1). Such oxidative amination in 2-
aminobenzamides has been realized via a variety of one carbon
source including toluene,[4a] dicumyl peroxide,[4b] alcohol,[4c,d]
enaminone,[4e] heterocyclic analogs,[5a-c] tertiary amine,[5d]
acetophenone,[5e] alkyl acetoacetate[5f] and isonitrile[5g] both
under metal-mediated and metal-free conditions.
On the other hand, tert-butyl hydrogen peroxide (TBHP),
which is widely used as oxidant has been also reported to be a
source of radical methyl group in the presence of copper catalyst.
Mao et al. first disclosed an effective synthesis of methyl esters
from benzylic alcohols, aldehydes or acids via copper-catalyzed
C-C bond cleavage of TBHP (Fig. 2).[6] Subsequently, Li et al.
developed copper-catalyzed synthesis of methyl esters from
aromatic aldehydes and benzylic alcohols in the presence of
TBHP.[7] Recently, Wang and co-workers reported copper-
catalyzed S-methylation of sulfonyl hydrazides with TBHP in
water for preparing methyl sulphones.[8] Use of TBHP as the
methyl source is also listed during the screening of peroxide-
variants in several reports.[9] For example, Zou et al.[9a] recently
disclosed copper (I) chloride-catalyzed methylation of 1,3-
diketone by TBHP in 30% yield only in 24 h whereas Wang and
co-workers disclosed the formation of quinazolin-4(3H)-one in
20% yield via copper (II) acetate-mediated radical methylation of
2-aminobenzamides.[4b] But TBHP was discarded in favour of
peroxybenzoate and dicumyl peroxide, respectively in these
studies. Song and Li et al. examined the potential of TBHP as
the methyl source during their study related to metal-free
oxidative
1,2-arylmethylation
cascade
of
N-
(arylsulfonyl)acrylamide for the assembly of 2,2-disubstituted-N-
arylbutanamide but ditertiary butyl peroxide was found to be
relatively efficient for their methodology.[9b] We noticed that
though TBHP was used as efficient oxidant in a few of these
protocols, there is lack of report related to efficient use of TBHP
as the methyl source under metal-free conditions. Since metal-
free protocols are considered to be sustainable, we sought to
explore the possibility of oxidative amination of C(sp3)−H bond
in 2-aminobenzamide for preparing quinazolin-4(3H)-ones with
TBHP as the methyl source and herein we present successful
results related to this study. The scope of the developed protocol
was extended for preparing quinazolines from 2-carbonyl
substituted anilines in the presence of NH4OAc as the nitrogen
source under metal-free conditions.
[a]
S. Mukhopadhyay, D. S. Barak, S. Batra*
Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute,
Sector 10, Jankipuram extension, Sitapur Road, Lucknow-226031
E-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in
http://www.cdri.res.in/1426.aspx?id=1426
[b]
Academy of Innovative Scientific Research, New Delhi, 110025
¥Both authors have contributed equially to this work.
Supporting information for this article is given via a link at the end of
the document
Results and Discussion
Initially, in a pilot reaction 2-amino-N-(4-(tert-
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Scheme 1. Reported strategies for the synthesis of quinazolin-4(3H)-one via oxidative amination of C(sp3)−H bond.
literature,[6-9] the presence of metal catalyst was not essential for
TBHP to act as methyl source. To exclude DMF as the carbon
source, we next assessed acetonitrile as the medium under
identical condition which led to isolation of 3e in 38% yield (entry
3). But as the reaction still did not go to completion, the loading
of TBHP was increased to 10 equiv in the next experiment and
pleasingly now the reaction was completed in 10 h to afford 3e
in 81% yield (entry 4). Screening of solvents revealed that 3e
was isolated in inferior yield when DMF, DMSO or toluene was
used as the medium whereas no product was detected in THF
as the medium (entries 5-8). Among different inorganic bases
screened, we observed that Cs2CO3 was the most efficient one
(compare entry 4 with entries 9-10) but lowering its loading to
0.5 equiv resulted into drop in yield (72%) of 3e (entry 11).
Further, the reaction was successful even in the absence of
base to afford 48% of 3e (entry 12). To ascertain whether air
acts as co-oxidant in the reaction, we evaluated the reaction in
the presence of nitrogen and oxygen atmosphere. Whereas the
yield of 3e was <5% for the reaction performed under nitrogen,
the reaction conducted under oxygen was completed in 8 h to
afford 3e in 82% yield (entries 14-15). Since there was no
remarkable difference between the yield of 3e obtained from
reaction performed under oxygen and the one carried out in
open air, we persisted with reaction in the open flask. Thus the
condition identified to obtain quinazolin-4(3H)-one in optimal
yield was heating 1e with 10 equiv of TBHP (70% aq), 1.0 equiv
of Cs2CO3 in acetonitrile as the medium at 80 oC for 10 h.
Figure 2. TBHP as methyl source in the presence of copper-catalyst.
butyl)phenyl)benzamide 1e was treated with TBHP (5.0 equiv),
Cs2CO3 (1.0 equiv) in DMF as the medium at room temperature
but the reaction failed. Repeating the reaction at 100 oC and
working it up after 24 h, however resulted in isolation of a
product (36% yield) together with unreacted starting material.
This product was delineated to be the quinazolin-4(3H)-one (3e)
(Table 1, entry 2). This result suggested that contrary to the
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Table 1. Results of the optimization study for transforming 2-aminobenzamide (1e) into quinazolin-4(3H)-one (3e)[a]
entry
TBHP
solvent
base (equiv)
temp (oC)
time (h)
3e yield (%)[b]
(equiv)
1[c]
2[c]
3[c]
4
5.0
DMF
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Na2CO3 (1.0)
K2CO3 (1.0)
Cs2CO3 (0.5)
–
rt
24
24
24
10
10
10
10
10
10
10
10
10
10
10
8
ND[d]
36
38
81
73
ND
11
77
70
77
72
48
ND
4
5.0
DMF
100
80
5.0
MeCN
MeCN
DMSO
THF
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
–
80
5
100
70
6
7
Toluene
DMF
100
100
80
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14[e]
15[f]
80
80
80
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
80
10.0
10.0
80
80
82
[a]All reactions were carried out using 1e (0.1 g, 0.37 mmol), TBHP (70 wt. % in H2O), solvent (4 mL) under heating for indicated time. [b]Isolated yields after
purification. [c]Unreacted starting material recovered too. [d]ND = no product detected. [e]The reaction was conducted under nitrogen atmosphere. [f]The reaction
was performed in the presence of oxygen
With the optimized conditions in hand, the scope of the protocol
was tested with a variety of 2-aminobenzamides 1 and the
results are summarized in Scheme 2. In the first set of reactions
different 2-amino-N- substituted phenylbenzamides (1a-u) were
treated with TBHP under the optimized conditions. The 2-amino-
N-phenylbenzamide (1a) afforded 3a in 64% yield but the
formation of products for substrates bearing substituted phenyl
ring was influenced by the electronic nature and position of the
substituent. The substrates (1b-1k) with monosubstituted phenyl
ring carrying the substitution at the para or meta-positions
smoothly afforded the corresponding quinazolin-4-ones (3b-k).
The yields of products were observed to be superior for the
substrates bearing electron donating substituents as compared
to the electron withdrawing substituents. However, except for 1l
bearing ortho-trifluoromethyl group that gave 3l in 38% yield,
other substrates 1m-n bearing ortho substiuents failed to
furnished the product. Likewise for substrates bearing
disubstituted phenyl ring, while 1o-r afforded the respective
quinazolin-4(3H)-one 3o-r in 69-86% yields, 1s-t failed to afford
the corresponding products 3s-t. Next the scope was
investigated with substrates 1u-y wherein the phenyl group of
the amide was replaced with naphthyl, hydrogen, benzyl and
aliphatic group. We discovered that 1u-w gave the respective
products 3u-w but the amides bearing aliphatic groups failed to
react following the protocol. Subsequently the scope was tested
with substituted benzamides derivatives 1z-1af and it was
gratifying to note that all substrates afforded respective products
3z-3af in 67-75% yields. Finally, we investigated the scope with
heterocyclic substrates and found that whereas 1ag gave the
product 3ag, 1ah failed to afford the product 3ah.
In order to gain insight into the plausible mechanism a few more
control experiments were performed (Scheme 3). First the
reaction of 1a with TBHP was assessed in the presence of
radical quenchers including TEMPO and BHT and it was found
that the formation of product was impaired suggesting a radical
pathway similar to the report of Wang et al.[8] The LCMS profiling
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Scheme 2. Scope of the TBHP-mediated synthesis of quinazolin-4(3H)-one from 2-aminobenzamides. All reactions were performed at 0.2 g scale.
of the crude reaction mixture indicated the presence of
molecular ion peaks corresponding to methyl-TEMPO and tert-
butoxyl-TEMPO adducts together with that of product 3a.
Simultaneoulsy, 1b was also subjected to similar reaction in the
presence of TEMPO but now the reaction was arrested after 6 h.
Herein, the LCMS profiling of the reaction mixture showed up
the molecular ion peak corresponding to 5b together with the
peaks for 1b, methyl-TEMPO and tert-butoxyl-TEMPO adducts.
To ascertain whether the reaction is proceeding via the
formation of N-methylated product, we prepared 5a and
subjected it to reaction under the optimized condition which
resulted in the formation of 3a in 52% yield. Conversely
methylating the amide nitrogen to generate 6a and subjecting it
to reaction with TBHP under the optimized condition produced
3a in 10% yield.
Based on these experiments a plausible mechanism via a
radical pathway is outlined in Scheme 4. Initially, in the presence
of Cs2CO3 the tert-butoxyl radical is formed from TBHP.[10] Under
heating the tert-butoxyl radical affords the methyl radical with the
elimination of acetone.[11] On the other hand the tert-butoxyl
radical traps hydrogen either from the amino or the amide group
of the benzamide to form intermediate A or A'. The aminyl
radical reacts with the methyl radical to produce 2-(N-
methylamino)-
benzamide
B
or
2-amino-N-methyl-N-
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phenylbenzamide B' which in the presence of tert-butoxyl radical
loses an electron to offer iminyl cation (C or C') that undergoes
intramolecular nucleophilic addition[12] to produce the tetrahydro
quinazolin-4-one D. The intermediate D is oxidized in air to
afford the quinazolin-4(3H)-one 3.
This mechanism however does not account for the failure of
reaction with 2-aminobenzamide bearing N-aliphatic substitution.
Therefore, we investigated the reaction of N-cyclohexyl-2-
(methylamino)benzamide (5y) and 2-amino-N-cyclohexyl-N-
methylbenzamide (6y) under the optimized conditions for the
formation of the product if any (Scheme 5). We discovered that
whereas 6y failed to undergo the reaction, 5y gave a mixture of
several products from which we isolated the desired product 3y
in 10% yield only. This result provided clue that the reaction
proceeds via N-methylation followed by C-H amination and
oxidation pathway.
Scheme 3. Control experiments.
Scheme 4. Plausible mechanism for the synthesis of substituted quinazolin-4(3H)-one from 2-amino-N-substitutedphenyl benzamide.
Scheme 5. Reactions of N-cyclohexyl-2-(methylamino)benzamide (5y) and 2-
amino-N-cyclohexyl-N-methylbenzamide (6y)..
Like quinazolin-4(3H)-ones, synthesis of quinazolines from 2-
aminobenzophenones have been accomplished using oxidative
amination of C(sp3)−H bond in the presence of a nitrogen
source.[13] Given the significance of quinazolines in realms of
medicinal chemistry (Fig. 3)[14] and in order to enhance the
usefulness of TBHP as methyl source under metal-free condition,
we considered probing the synthesis of quinazolines from 2-
carbonyl substituted anilines. It is worth mentioning that initially
Figure 3. A few quinazoline-based anticancer drugs.
Wang et al. reported a metal-free synthesis of quinazoline from
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Table 2. Results of the screening of nitrogen source for the metal-free
synthesis of quinazoline 8a.[a]
entry
Nitrogen source
(equiv)
time (h)
8a yield (%)[b]
1
2
3
4
5
NH3 (aq) (5.0)
NH4Cl (1.0)
12
12
12
12
12
52
32
61
78
70
NH4OAc (1.0)
NH4OAc (2.0)
NH4OAc (1.5)
[a] All reactions were carried out using 7a (0.1 g, 0.51 mmol), Cs2CO3 (0.166 g,
0.51 mmol), TBHP (70 wt. % in H2O), MeCN (4 mL) at 80 oC at indicated time.
[b] Isolated yields after purification.
Scheme 6. Scope of the synthesis of quinazoline in the presence of TBHP
under metal-free conditions. All reactions were performed at 0.2 g scale. [a] The
time required for this reaction is 5 h. [b] The time required for these reactions is
24 h.
this substrate in the presence of iodine, ammonia, TBHP and
dimethylacetamide (DMA).[13a] Whereas ammonia served as the
nitrogen source, the carbon was derived from DMA.
Subsequently, in a minor variation to this protocol, Yan et al.
prepared similar quinazolines using NH4Cl as the nitrogen
source and TMEDA as the carbon source in the presence of
oxygen.[13b] Strikingly however, they did not detect any product if
the reaction was conducted in the presence of NIS (20 mol%),
TBHP (4.0 equiv) and ammonia (2.0 equiv) as nitrogen source
and DMSO as the medium. Contrary to this observation, we
discovered that if the reaction of 2-aminobenzophenone (7a) is
performed in the presence of TBHP (10.0 equiv), Cs2CO3 (1.0
equiv) and ammonia aqueous (25%, 5.0 equiv) in MeCN as the
medium, quinazoline 8a was isolated in 52% yield after 10 h of
reaction time (Table 2, entry 1). Buoyed by this success we
considered optimizing the nitrogen source in this reaction. It was
found that the reaction was incomplete in the presence of NH4Cl
even after 12 h and 8a could be isolated in 32% yield only (entry
2). However, performing the reaction by using NH4OAc (1.0
equiv) as the nitrogen source gave 8a in 61% yield together with
recovery of the starting material. Increasing the amount of
NH4OAc to 2.0 equiv and keeping all other condition constant,
the reaction was completed in 12 h to furnish 8a in 78% yield
(entry 4).
In the light of reported work,[13b] the present results generated
interest to study the fate of reaction of 7a with TBHP (4.0 equiv)
in the presence of iodine (0.2 equiv) and NH4OAc (2.0 equiv) in
o
DMSO under heating at 120 C without the addition of TMEDA
(Scheme 7). We observed that the reaction was successful to
afford the quinazoline 8a in 69% yield. This result inferred that
TMEDA was not required as the methyl source if TBHP was
used in the reaction. Since TBHP and I2 both have the
propensity to act as oxidant, we next investigated the same
reaction in the absence of iodine but 10.0 equiv of TBHP to
successfully isolate 8a in 89% yield. However, this reaction
when performed in the absence of TBHP failed to produce 8a.
Thus it is apparent that if TBHP is used in the reaction it acts
both as the methyl source and oxidant and TMEDA or I2 is not
required.
Next we tested the scope of the protocol by including a variety of
2-carbonyl substituted anilines (7a-g) (Scheme 6). It was
gratifying to note that all substrates afforded the respective
quinazolines 8a-8g in 78-90% yields. Replacing phenyl group
with isopropyl as in 7h, afforded the corresponding quinazoline
8h in 83% yield. The scope was finally evaluated with 1-
aminoanthraquinone (7i) and 1,4-diaminoanthraquinone (7j) to
give the corresponding perimidin-7-one derivatives (8i-j) in 48%
and 79% yields, respectively.
Scheme 7. Experiments to demonstrate that amine and iodine are not
required for the synthesis of quinazoline in the presence of TBHP..
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Scheme 8. Plausible mechanism for the TBHP-mediated synthesis of quinazolines from 2-carbonyl substituted anilines.
silica gel plates. After elution, plate was visualized under UV illumination
at 254 nm for UV active materials. Further visualization was achieved by
placing the plate in Iodine chamber or via spraying with KMnO4 solution.
The melting points were recorded on a hot stage apparatus and are
uncorrected. IR spectra were recorded using a FTIR spectrophotometer.
1H NMR and 13C NMR spectra were recorded on 400 or 500 MHz NMR
spectrometers with CDCl3 or DMSO-d6 as solvent, using TMS as an
internal standard (chemical shifts in ). Peak multiplicities of 1H-NMR
signals were designated as s (singlet), brs (broad singlet), d (doublet), dd
(doublet of doublet), t (triplet), q (quartet), m (multiplet) and coupling
constants (J) are in Hz. The LC-ESI-MS were recorded on triple
quadrupole Mass spectrometer. Column chromatography was performed
using silica gel (100-200 mesh). Analytical grade solvents for the column
chromatography were used as received.
Based on these control experiments, it is proposed that the
formation of quinazoline from 2-carbonyl substituted anilines
may follow either path A or path B as outlined in Scheme 8. As
reported by Wang et al.,[13a] there is a possibility of initial
alkylation followed by addition of amino group which then
undergo intramolecular cyclization as shown for path A.
Alternatively, the likelihood of simultaneous imine formation
along with the formation of iminyl cation as for quinazolin-3(4H)-
one followed by intramolecular cyclization as shown for path B is
not ruled out.
Conclusions
General procedure for the synthesis of Quinazolin-4(3H)-ones (3a-
3ah) as exemplified for the synthesis of 3e.
In conclusion, we have demonstrated the use of TBHP as
source of the methyl group under metal-free aerobic conditions.
We have shown that the oxidative amination of the C(sp3)-H
bond in 2-aminobenzamides in the presence of TBHP and a
base efficiently affords quinazolin-4(3H)-ones. A probe into the
mechanistic detail suggests that the reaction follows a radical
pathway that involves one C-C bond cleavage and two C-N
bond formation. The usefulness of the protocol was enhanced
by demonstrating its application for the synthesis of quinazolines
from 2-carbonyl substituted anilines in the presence of NH4OAc.
Whereas the scope for the synthesis of quinazolin-4(3H)-ones
from 2-aminobenzamide excludes substrates bearing N-aliphatic
substitution, the synthesis of quinazolines is accomplished from
aliphatic as well as aromatic 2-carbonyl substituted anilines. We
have also updated the literature by demonstrating that the
carbon insertion could be achieved exclusively via TBHP and
TMEDA is not required as reported.
In
a
round-bottom
flask
containing
2-amino-N-(4-(tert-
butyl)phenyl)benzamide 1e (0.2 g, 0.74 mmol) in MeCN (6 mL) were
added Cs2CO3 (0.241 g, 0.74 mmol) and TBHP (70% aq) (0.95 mL, 7.4
mmol) at room temperature and the mixture was heated at 80 °C for 10 h
in air. After completion of the reaction (as monitored by TLC) the solvent
was removed under vacuum and the residue was diluted with H2O (20
mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer
was dried over anhydrous Na2SO4 and evaporated under reduced
pressure to offer a residue that was purified by column chromatography
over silica gel using hexanes/ EtOAc (8:2, v/v) as eluent to afford the
desired product 3e (0.168 g from 0.2 g, 81%) as a white solid. 3-(4-(tert-
Butyl)phenyl)quinazolin-4(3H)-one (3e).[4b] Mp 120-122 oC, (Lit. mp
120-121 oC); Rf = 0.62 (hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1685
(CO) cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.38 (s, 9H), 7.34-7.36
(m, 2H), 7.54-7.57 (m, 3H), 7.75-7.82 (m, 2H), 8.13 (s, 1H), 8.37 (dd, J1 =
8.0 Hz, J2 = 0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 31.3,
34.8, 122.4, 126.4, 126.6, 127.2, 127.6, 134.5, 134.8, 146.3, 147.9,
152.2, 160.9. MS (ESI+): m/z = 279.1. ESI-HR-MS calculated for
C18H18N2O (M++H): 279.1497, found: 279.1499.
Experimental Section
3-Phenylquinazolin-4(3H)-one (3a).[4a] Yield: 64% (0.134 g from 0.2 g);
o
o
a white solid, mp 154-155 C, (Lit. mp 153-155 C); Rf = 0.65 (hexanes:
EtOAc, 7:3, v/v); IR (KBr) νmax: 1683 (CO) cm-1. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.35-7.37 (m, 2H), 7.40-7.44 (m, 1H), 7.46-7.50 (m, 3H),
General. Unless otherwise stated all reactions were performed in non-
dry glassware under an air atmosphere and were monitored by analytical
thin layer chromatography (TLC). TLC was performed on pre-coated
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7.69-7.76 (m, 2H), 8.06 (s, 1H), 8.30 (dd, J1 = 8.1 Hz, J2 = 1.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ (ppm) = 122.4, 127.0, 127.2, 127.6, 127.7,
129.1, 129.6, 134.6, 137.5, 146.1, 147.9, 160.8. MS (ESI+): m/z = 223.0.
ESI-HR-MS calculated for C14H10N2O (M++H): 223.0871, found:
223.0874.
134.8, 138.7 (d, J = 10 Hz), 145.5, 147.7, 160.5, 162.8 (d, J = 248 Hz).
MS (ESI+): m/z = 241.1. ESI-HR-MS calculated for C14H9FN2O (M++H):
241.0777, found: 241.0778.
3-(3-Bromophenyl)quinazolin-4(3H)-one (3i). Yield: 74% (0.153 g from
0.2 g); a white solid, mp 175-177 oC; Rf = 0.62 (hexanes: EtOAc, 7:3,
3-(4-Fluorophenyl)quinazolin-4(3H)-one (3b).[4b] Yield: 68% (0.142 g
v/v); IR (KBr) νmax: 1679 (CO) cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
1
from 0.2 g); a white solid, mp 161-163 oC, (Lit. mp 164-166 oC); Rf = 0.61
7.29-7.36 (m, 2H), 7.48 (t, J = 6.5 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.68-
7.74 (m, 2H), 8.01 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 122.2, 123.0, 125.8, 127.2, 127.7, 127.9, 130.3, 130.9,
132.4, 134.8, 138.6, 145.4, 147.8, 160.5. MS (ESI+): m/z = 301.2. ESI-
HR-MS calculated for C14H9BrN2O (M++H): 300.9977, found: 300.9980.
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1687 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.22-7.27 (m, 2H), 7.40-7.44 (m, 2H), 7.53-7.56 (m,
1H), 7.75-7.78 (m, 2H), 8.02 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 115.9 (d, J = 23 Hz), 121.7, 126.1, 126.7 (d,
J = 25 Hz), 127.3 (d, J = 13 Hz), 132.2 (d, J = 18 Hz), 133.8, 144.7, 146.7,
159.6, 161.6 (d, J = 225 Hz). MS (ESI+): m/z = 241.1. ESI-HR-MS
calculated for C14H9FN2O (M++H): 241.0777, found: 241.0773.
3-(3-Chlorophenyl)quinazolin-4(3H)-one (3j).[15c] Yield: 77% (0.160 g
from 0.2 g); a white solid, mp 167-169 oC, (Lit. mp 164-166 oC); Rf = 0.60
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1680 (CO) cm-1. H NMR (400
3-(4-Bromophenyl)quinazolin-4(3H)-one (3c).[15a] Yield: 74% (0.153 g
MHz, CDCl3): δ (ppm) 7.32-7.35 (m, 1H), 7.47-7.50 (m, 3H), 7.54-7.58 (m,
1H), 7.76-7.84 (m, 2H), 8.09 (s, 1H), 8.36 (dd, J1 = 8.0 Hz, J2 = 0.9Hz,
1H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 122.2, 125.3, 127.2, 127.5,
127.7, 127.9, 129.4, 130.6, 134.8, 135.3, 138.5, 145.4, 147.7, 160.5. MS
(ESI+): m/z = 257.0. ESI-HR-MS calculated for C14H9ClN2O (M++H):
257.0482, found: 257.0487.
from 0.2 g); a white solid, mp 184-186 oC, (Lit. mp 185-187 oC); Rf = 0.66
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1680 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.32 (d, J = 8.7 Hz, 2H), 7.54-7.58 (m, 1H), 7.69 (d,
J = 7.5 Hz, 2H), 7.76-7.79 (m, 2H), 8.08 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ (ppm) = 122.3, 123.5, 126.9, 127.1, 128.2,
128.9, 133.3, 134.8, 136.8, 145.7, 147.4, 160.9. MS (ESI+): m/z = 301.2.
ESI-HR-MS calculated for C14H9BrN2O (M++H): 300.9977, found:
300.9979.
3-(3-Nitrophenyl)quinazolin-4(3H)-one (3k).[15d] Yield: 61% (0.127 g
from 0.2 g); a white solid, mp 153-155 oC, (Lit. mp 154-156 oC); Rf = 0.64
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1681 (CO) cm-1. H NMR (400
3-(p-Tolyl)quinazolin-4(3H)-one (3d).[4b] Yield: 79% (0.165 g from 0.2
MHz, DMSO-d6): δ (ppm) 7.63 (t, J = 7.3 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H),
7.86-7.93 (m, 2H), 8.07 (d, J = 7.7 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H), 8.38
(d, J = 8.1 Hz, 1H), 8.44 (s, 1H), 8.55 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 122.3, 123.4, 124.1, 126.9, 127.9, 128.0, 131.1,
134.9, 135.4, 138.9, 147.1, 148.1, 148.5, 160.5. MS (ESI+): m/z = 268.1.
ESI-HR-MS calculated for C14H9N3O3 (M++H): 268.0722, found:
268.0724.
g); a white solid, mp 152-154 oC, (Lit. mp 150-151 oC); Rf = 0.59
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1684 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 7.22 (d, J = 8.4 Hz, 2H), 7.27 (d, J =
8.3 Hz, 2H), 7.45-7.49 (m, 1H), 7.68-7.75 (m, 2H), 8.04 (s, 1H), 8.29 (dd,
J1 = 8.2 Hz, J2 = 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 21.2,
122.4, 126.7, 127.2, 127.6, 130.2, 134.5, 134.9, 139.2, 146.3, 147.9,
160.9. MS (ESI+): m/z = 237.2. ESI-HR-MS calculated for C15H12N2O
(M++H): 237.1028, found: 237.1023.
3-(2-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (3l).[4b] Yield: 38%
(0.079 g from 0.2 g); a white solid, mp 156-158 oC, (Lit. mp 157-159 oC);
Rf = 0.62 (hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1685 (CO) cm-1. 1H
NMR (500 MHz, CDCl3): δ (ppm) 7.47 (d, J = 7.8 Hz, 1H), 7.55-7.58 (m,
1H), 7.68 (t, J = 7.7 Hz, 1H), 7.75-7.85 (m, 3H), 7.89 (d, J = 7.7 Hz, 1H),
7.97 (s, 1H), 8.35 (dd, J1 = 8.0, J2 =1.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 122.1, 122.8 (d, J = 272 Hz), 127.2, 127.7, 127.7 (d, J
= 6 Hz), 127.8, 128.6 (d, J = 31 Hz), 130.3, 131.0, 133.5, 134.9, 135.3,
145.6, 147.9, 160.9. MS (ESI+): m/z = 291.0. ESI-HR-MS calculated for
C15H9F3N2O (M++H): 291.0745, found: 291.0744.
3-(4-Methoxyphenyl)quinazolin-4(3H)-one (3f).[4b] Yield: 78% (0.162 g
from 0.2 g); a white solid, mp 208-210 oC, (Lit. mp 210-212 oC); Rf = 0.65
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1682 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 3.79 (s, 3H), 6.96 (d, J = 8.9 Hz, 2H), 7.25 (d, J =
8.9 Hz, 2H), 7.45-7.49 (m, 1H), 7.67-7.74 (m, 2H), 8.04 (s, 1H), 8.29 (d, J
= 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 55.6, 114.9, 122.4,
127.2, 127.6, 128.2, 130.2, 134.5, 146.5, 147.9, 159.9, 161.1. MS (ESI+):
m/z = 253.1. ESI-HR-MS calculated for C15H12N2O2 (M++H): 253.0977,
found: 253.0975.
3-(3,4-Dichlorophenyl)quinazolin-4(3H)-one (3o).[15e] Yield: 77% (0.159
g from 0.2 g); a white solid, mp 167-169 oC, (Lit. mp 164-166 oC); Rf =
0.51 (hexane: EtOAc, 7:3, v/v); IR (KBr) νmax: 1687 (CO) cm-1. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.31 (dd, J1 = 8.5 Hz, J2 = 2.5Hz, 1H), 7.55-
7.59 (m, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.81-7.85
(m, 1H), 8.07 (s, 1H), 8.35 (dd, J1 = 8.0 Hz, J2 = 1.2Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 122.1, 126.4, 127.2, 128.0, 129.2, 131.3,
133.7, 134.9, 136.5, 145.0, 147.7, 160.4. MS (ESI+): m/z = 291.0. ESI-
HR-MS calculated for C14H8Cl2N2O (M++H): 291.0092, found: 291.0089.
3-(4-Nitrophenyl)quinazolin-4(3H)-one (3g).[15b] Yield: 63% (0.131 g
from 0.2 g); a white solid, mp 197-199 oC, (Lit. mp 199-200 oC); Rf = 0.54
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1681 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.60 (t, J = 7.1 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H),
7.80-7.86 (m, 2H), 8.16 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.43 (d, J = 8.8
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 122.5, 125.0, 127.3,
127.8, 128.0, 128.3, 135.2, 142.7, 144.6, 147.3, 148.3, 160.3. MS (ESI+):
m/z = 268.1. ESI-HR-MS calculated for C14H9N3O3 (M++H): 268.0722,
found: 268.0720.
3-(3-Chloro-4-fluorophenyl)quinazolin-4(3H)-one (3p).[15f] Yield: 69%
(0.143 g from 0.2 g); a white solid, mp 210-212 oC, (Lit. mp 212-214 oC);
Rf = 0.59 (hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1681 (CO) cm-1. 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.42-7.44 (m, 2H), 7.54-7.58 (m, 2H),
7.76-7.83 (m, 2H), 8.13 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ (ppm) = 122.4, 127.0, 127.2, 127.6, 127.7, 129.1, 129.7,
134.6, 137.5, 146.1, 147.9, 156.6 (d, J = 220 Hz), 160.8. MS (ESI+): m/z
3-(3-Fluorophenyl)quinazolin-4(3H)-one (3h).[4b] Yield: 69% (0.144 g
from 0.2 g); a white solid, mp 157-159 oC, (Lit. mp 158-160 oC); Rf = 0.59
(hexane: EtOAc, 7:3, v/v); IR (KBr) νmax: 1684 (CO) cm-1. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.20-7.23 (m, 3H), 7.50-7.58 (m, 2H), 7.76-7.82 (m,
2H), 8.10 (s, 1H), 8.36 (dd, J1 = 8.1, J2 =0.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 114.9 (d, J = 23 Hz), 116.3 (d, J = 21 Hz), 122.2,
122.7 (d, J = 3 Hz), 127.2, 127.8 (d, J = 18 Hz), 130.9 (d, J = 9 Hz),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800495
European Journal of Organic Chemistry
FULL PAPER
= 275.0. ESI-HR-MS calculated for C14H8ClFN2O (M++H): 275.0387,
found: 275.0385.
5-Chloro-3-phenylquinazolin-4(3H)-one (3z). Yield: 72% (0.150 g from
0.2 g); a white solid, mp 167-169 oC; Rf = 0.61 (hexanes: EtOAc, 7:3,
v/v); IR (KBr) νmax: 1680 (CO) cm-1. 1H NMR (400 MHz, DMSO-d6): δ
(ppm) 7.33-7.42 (m, 2H), 7.60-7.64 (m, 2H), 7.74-7.78 (m, 3H), 7.86-7.89
(m, 1H), 8.00 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 124.9,
127.0, 127.7, 128.4, 129.2, 129.3, 132.7, 134.5, 136.9, 145.9, 147.2,
160.4. MS (ESI+): m/z = 257.1. ESI-HR-MS calculated for C14H9ClN2O
(M++H): 257.0482, found: 257.0480.
3-(3,4-Dimethoxyphenyl)quinazolin-4(3H)-one (3q).[15g] Yield: 86%
(0.178 g from 0.2 g); a white solid, mp 191-193 oC; Rf = 0.53 (hexanes:
EtOAc, 7:3, v/v); IR (KBr) νmax: 1683 (CO) cm-1. 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 3.78 (s, 3H), 3.83 (s, 3H), 7.09 (d, J = 10.3 Hz, 2H),
7.19 (s, 1H) 7.60 (t, J = 7.1 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.88 (t, J =
6.9 Hz, 1H), 8.20 (d, J = 7.3 Hz, 1H), 8.32 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 56.2, 112.0, 112.1, 120.0, 122.4, 126.9, 127.7,
127.8, 130.9, 135.0, 148.0, 148.2, 149.3, 149.5, 160.6. MS (ESI+): m/z =
283.1. ESI-HR-MS calculated for C16H14N2O3 (M++H): 283.1083, found:
283.1084.
6-Bromo-3-phenylquinazolin-4(3H)-one (3aa).[4b] Yield: 73% (0.151 g
from 0.2 g); a white solid, mp 182-184 oC, (Lit. mp 185-186 oC); Rf = 0.60
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1689 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.40-7.43 (m, 2H), 7.51-7.58 (m, 3H),7.64 (d, J =
8.7 Hz, 1H), 7.88 (dd, J1 = 8.7 Hz, J2 = 2.3 Hz, 1H), 8.13 (s, 1H), 8.49 (d,
J = 2.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 121.3, 123.8,
126.9, 129.3, 129.4, 129.8, 137.2, 137.8, 146.4, 146.7, 159.6. MS (ESI+):
m/z = 301.2. ESI-HR-MS calculated for C14H9BrN2O (M++H): 300.9977,
found: 300.9979.
3-(3,5-Dimethoxyphenyl)quinazolin-4(3H)-one (3r).[15h] Yield: 80%
(0.166 g from 0.2 g); a white solid, mp 227-228 oC, (Lit. mp 225-228 oC);
Rf = 0.60 (hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1681 (CO) cm-1. 1H
NMR (500 MHz, CDCl3): δ (ppm) 3.75 (s, 6H), 6.48-6.50 (m, 3H), 7.48 (t,
J = 7.8 Hz, 1H), 7.68-7.75 (m, 2H), 8.04 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ (ppm) = 55.6, 101.3, 105.5, 122.4, 127.2,
127.5, 127.6, 134.6, 139.1, 146.0, 147.8, 160.6, 161.4. MS (ESI+): m/z =
283.1. ESI-HR-MS calculated for C16H14N2O3 (M++H): 283.1083, found:
283.1081.
6-Iodo-3-phenylquinazolin-4(3H)-one (3ab).[15j] Yield: 73% (0.150 g
from 0.2 g); a white solid, mp 132-134 oC; Rf = 0.62 (hexanes: EtOAc, 7:3,
1
v/v); IR (KBr) νmax: 1682 (CO) cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
7.19 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H),
7.66 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 101.3, 120.5, 125.4, 125.9, 129.2, 134.0,
137.0, 137.6, 139.9, 145.7, 162.7. MS (ESI+): m/z = 349.0. ESI-HR-MS
calculated for C14H9IN2O (M++H): 348.9838, found: 348.9833.
3-(Naphthalen-1-yl)quinazolin-4(3H)-one (3u).[4b] Yield: 75% (0.156 g
from 0.2 g); a white solid, mp 140-142 oC, (Lit. mp 142-144 oC); Rf = 0.59
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1686 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.45-7.56 (m, 6H), 7.77-7.79 (m, 2H), 7.90 (d, J =
7.9 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 8.33 (d, J = 7.7 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 122.0, 122.4, 125.5, 126.0,
126.9, 127.3, 127.7, 127.7, 127.8, 128.6, 129.8, 130.3, 134.1, 134.4,
134.7, 146.9, 148.2, 161.1. MS (ESI+): m/z = 273.1. ESI-HR-MS
calculated for C18H12N2O (M++H): 273.1028, found: 273.1025.
6-Nitro-3-phenylquinazolin-4(3H)-one (3ac).[4b] Yield: 67% (0.139 g
from 0.2 g); a white solid, mp 222-224 oC, (Lit. mp 223-225 oC); Rf = 0.56
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1679 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.44 (d, J = 7.0 Hz, 2H), 7.54-7.61 (m, 3H), 7.90 (d,
J = 8.9 Hz, 1H), 8.26 (s, 1H), 8.59 (dd, J1= 6.4 Hz, J2 = 2.6 Hz , 1H), 9.21
(d, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 122.7, 123.8,
126.8, 128.6, 129.3, 129.7, 129.9, 136.7, 146.4, 148.9, 151.9, 159.6. MS
(ESI+): m/z = 268.1. ESI-HR-MS calculated for C14H9N3O3 (M++H):
268.0722, found: 268.0721.
Quinazolin-4(3H)-one (3v).[15i] Yield: 62% (0.133 g from 0.2 g); a white
o
o
solid, mp 200-201 C, (Lit. mp 200-202 C); Rf = 0.36 (hexanes: EtOAc,
7:3, v/v); IR (KBr) νmax: 1698 (CO) cm-1. 1H NMR (400 MHz, DMSO-d6): δ
(ppm) 7.52 (t, J = 7.4 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 7.4 Hz,
1H), 8.09 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 12.23 (brs, 1H); 13C NMR (100
MHz, DMSO-d6): δ (ppm) = 123.1, 126.3, 127.2, 127.7, 134.7, 145.8,
149.2, 161.2. MS (ESI+): m/z = 147.0. ESI-HR-MS calculated for
C8H6N2O (M++H): 147.0558, found: 147.0559.
7-Fluoro-3-phenylquinazolin-4(3H)-one (3ad).[4a] Yield: 71% (0.148 g
from 0.2 g); a white solid, mp 196-198 oC, (Lit. mp 197-199 oC); Rf = 0.61
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1688 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.24-7.29 (m, 1H), 7.40-7.43 (m, 3H), 7.49-7.58 (m,
3H), 8.14 (s, 1H), 8.38 (dd, J1 = 8.9 Hz, J2 = 0.1Hz, 1H); 13C NMR (100
MHz, CDCl3): δ (ppm) = 113.1 (d, J = 22 Hz), 116.4 (d, J = 24 Hz), 119.1,
127.0, 129.3, 129.7, 130.0 (d, J = 10 Hz), 137.2, 147.4, 150.1 (d, J = 13
Hz), 160.0, 166.6 (d, J = 253 Hz). MS (ESI+): m/z = 241.1. ESI-HR-MS
calculated for C14H9FN2O (M++H): 241.0777, found: 241.0780.
3-Benzylquinazolin-4(3H)-one (3w).[4b] Yield: 52% (0.108 g from 0.2 g);
o
o
a white solid, mp 116-118 C, (Lit. mp 117-118 C); Rf = 0.55 (hexanes:
EtOAc, 7:3, v/v); IR (KBr) νmax: 1678 (CO) cm-1. 1H NMR (400 MHz,
CDCl3): δ (ppm) 5.20 (s, 2H), 7.31-7.36 (m, 5H), 7.50 (t, J = 7.5 Hz, 1H),
7.69-7.75 (m, 2H), 8.11 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ (ppm) = 49.6, 122.2, 126.9, 127.4, 127.5, 128.0, 128.3,
129.0, 134.3, 135.8, 146.3, 148.1, 161.1. MS (ESI+): m/z = 237.2. ESI-
HR-MS calculated for C15H12N2O (M++H): 237.1028, found: 237.1030.
7-Chloro-3-phenylquinazolin-4(3H)-one (3ae).[15k] Yield: 75% (0.156 g
from 0.2 g); a white solid, mp 196-198 oC, (Lit. mp 197-199 oC); Rf = 0.58
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1681 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 7.41-7.44 (m, 2H), 7.51-7.58 (m, 4H), 7.78 (s, 1H),
8.13 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
(ppm) = 120.9, 126.9, 127.2, 128.3, 128.7, 129.3, 129.7, 137.2, 140.9,
147.3, 148.9, 160.2. MS (ESI+): m/z = 257.0. ESI-HR-MS calculated for
C14H9ClN2O (M++H): 257.0482, found: 257.0485.
3-Cyclohexylquinazolin-4(3H)-one (3y).[4b] Yield: 10% (0.019 g from 0.2
g); a white solid, mp 116-118 oC, (Lit. mp 118-119 oC); Rf = 0.59
1
(hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 1670 (CO) cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 1.24-1.28 (m, 1H), 1.48-1.70 (m, 4H), 1.78-1.81 (m,
1H), 1.93-2.03 (m, 4H), 4.78-4.86 (m, 1H), 7.47-7.52 (m, 1H), 7.69-7.77
(m, 2H), 8.13 (s, 1H), 8.32 (dd, J1 = 7.0 Hz, J2 = 1.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 25.3, 25.9, 32.6, 53.4, 121.9, 126.9, 127.1,
127.2, 134.1, 143.9, 147.5, 160.7. MS (ESI+): m/z = 229.1. ESI-HR-MS
calculated for C14H16N2O (M++H): 229.1341, found: 229.1338.
7-Bromo-3-phenylquinazolin-4(3H)-one (3af). Yield: 70% (0.145 g from
0.2 g); a white solid, mp 143-145 oC; Rf = 0.66 (hexanes: EtOAc, 7:3,
1
v/v); IR (KBr) νmax: 1684 (CO) cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
7.42 (d, J = 7.2 Hz, 2H), 7.50-7.56 (m, 3H), 7.65 (d, J = 8.2 Hz, 1H), 7.95
(s, 1H), 8.12 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 121.3, 126.9, 128.7, 129.3, 129.7, 130.4, 131.1, 137.2,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800495
European Journal of Organic Chemistry
FULL PAPER
147.2, 148.9, 160.3. MS (ESI+): m/z = 301.1. ESI-HR-MS calculated for
C14H9BrN2O (M++H): 300.9977, found: 300.9978.
6-Nitro-4-phenylquinazoline (8e).[13a] Yield: 84% (0.174 g from 0.2 g); a
yellow solid, mp 129-131 oC, (Lit. mp 131-132 oC); Rf = 0.58 (hexanes:
1
EtOAc, 6:4, v/v); H NMR (500 MHz, CDCl3): δ (ppm) 7.59-7.67 (m, 3H),
7.82 (d, J = 5.1 Hz, 2H), 8.28 (d, J = 9.1 Hz, 1H), 8.68(d, J = 8.7 Hz, 1H),
9.08 (s, 1H), 9.52 (s, 1H); 13C NMR (125 MHz, CDCl3): δ (ppm) = 122.1,
124.2, 127.0, 129.1, 130.1, 131.1, 131.2, 135.8, 146.2, 153.5, 157.2,
170.7. MS (ESI+): m/z = 252.2. ESI-HR-MS calculated for C14H9N3O2
(M++H): 252.0773, found: 252.0771.
3-Phenylthieno[2,3-d]pyrimidin-4(3H)-one (3ag). Yield: 72% (0.150 g
from 0.2 g); a white solid, mp 121-123 oC; Rf = 0.62 (hexanes: EtOAc, 7:3,
1
v/v); IR (KBr) νmax: 1678 (CO) cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
7.39 (d, J = 5.3 Hz, 1H), 7.42-7.44 (m, 2H), 7.49-7.58 (m, 3H), 7.85 (d, J
= 5.3 Hz, 1H), 8.15 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 124.0,
125.3, 127.1, 129.3, 129.6, 134.8, 137.0, 147.5, 156.8, 156.9. MS (ESI+):
m/z = 229.0. ESI-HR-MS calculated for C12H8N2OS (M++H): 229.0436,
found: 229.0439.
6-Chloro-4-(2-fluorophenyl)quinazoline (8f).[15l] Yield: 81% (0.168 g
from 0.2 g); a white solid, mp 117-119 oC; Rf = 0.60 (hexanes: EtOAc, 6:4,
v/v); 1H NMR (500 MHz, CDCl3): δ (ppm) 7.30 (t, J = 7.2 Hz, 1H), 7.39 (d,
J = 5.9 Hz, 1H), 7.59-7.61 (m, 2H), 7.80 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H),
8.08 (d, J = 7.1 Hz, 1H), 9.42 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
(ppm) = 116.3 (d, J= 21 Hz), 124.5, 124.8, 124.9, 125.6 (d, J= 4 Hz),
130.6, 131.5 (d, J= 3 Hz), 132.2 (d, J= 8 Hz), 133.8, 135.1, 149.1, 154.9,
159.7 (d, J= 249 Hz), 163.7. MS (ESI+): m/z = 259.1. ESI-HR-MS
calculated for C14H8ClFN2 (M++H): 259.0438, found: 259.0432.
General procedure for the synthesis of Quinazolines (8a-8h) as
exemplified for the synthesis of 8a.
In a round-bottom flask containing (2-aminophenyl)(phenyl)methanone
7a (0.2 g, 1.0 mmol) in MeCN (8 mL) were added Cs2CO3 (0.325 g, 1.0
mmol), NH4OAc (0.154 g, 2.0 mmol) and TBHP (70% aq) (1.3 mL, 10.0
mmol) at room temperature and the mixture was heated at 80 °C for 12 h
in air. Upon completion as monitored by TLC, the solvent was removed
from the reaction under vacuum and the residue was diluted with H2O (20
mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer
was dried over anhydrous Na2SO4 and evaporated under reduced
pressure to offer a residue that was purified by column chromatography
over silica gel using hexanes/ EtOAc (8:2, v/v) as eluent to afford the
desired product 8a (0.163 g from 0.2 g, 78%) as a yellow solid. 4-
Phenylquinazoline (8a).[13a] Mp 96-98 oC, (Lit. mp 96-97 oC); Rf = 0.56
(hexanes: EtOAc, 6:4, v/v); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.58-
7.61 (m, 4H), 7.78-7.80 (m, 2H), 7.91-7.95 (m, 1H), 8.13-8.16 (m, 2H),
9.41 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 123.2, 127.2, 127.8,
128.7, 128.8, 129.9, 130.1, 133.8, 137.0, 150.9, 154.5, 168.6. MS (ESI+):
m/z = 207.2. ESI-HR-MS calculated for C14H10N2 (M++H): 207.0922,
found: 207.0914.
6-Chloro-4-(2-chlorophenyl)quinazoline (8g).[15m] Yield: 82% (0.169 g
from 0.2 g); a yellow solid, mp 76-78 oC, (Lit. mp 78-80 oC); Rf = 0.65
(hexanes: EtOAc, 6:4, v/v); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.46-
7.47 (m, 1H), 7.48-7.51 (m, 1H), 7.53-7.55 (m, 1H), 7.59-7.61 (m, 1H),
7.63 (d, J = 2.0 Hz, 1H), 7.86 (dd, J1 = 9.0 Hz, J2 = 2.3 Hz, 1H), 8.09 (d, J
= 9.0 Hz, 1H), 9.42 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 124.4,
125.6, 127.2, 130.2, 130.6, 130.8, 131.1, 132.7, 133.8, 135.1, 135.4,
149.1, 154.8, 166.4. MS (ESI+): m/z = 275.1. ESI-HR-MS calculated for
C14H8Cl2N2 (M++H): 275.0143, found: 275.0141.
4-Isopropylquinazoline (8h).[13a] Yield: 83% (0.175 g from 0.2 g); a
yellow oil; Rf = 0.61 (hexanes: EtOAc, 6:4, v/v); 1H NMR (400 MHz,
CDCl3): δ (ppm) 1.45 (d, J = 6.8 Hz, 6H), 3.91-3.98 (m, 1H), 7.62-7.66 (m,
1H), 7.86-7.89 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),
9.27 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 21.7, 30.9, 123.2,
124.1, 127.4, 129.3, 133.3, 150.0, 154.7, 175.8. MS (ESI+): m/z = 173.2.
ESI-HR-MS calculated for C11H12N2 (M++H): 173.1079, found: 173.1072.
4-(4-Bromophenyl)quinazoline (8b).[13a] Yield: 83% (0.171 g from 0.2
g); a yellow solid, mp 150-152 oC, (Lit. mp 152-154 oC); Rf = 0.52
(hexanes: EtOAc, 6:4, v/v); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.61-
7.65 (m, 1H), 7.66-7.69 (m, 2H), 7.71-7.74 (m, 2H), 7.91-7.96 (m, 1H),
8.08 (dd, J1 = 8.5 Hz, J2 = 0.6 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 9.38 (s,
1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 122.9, 124.8, 126.6, 127.9,
129.1, 131.5, 131.9, 133.9, 136.0, 151.2, 154.6, 167.2. MS (ESI+): m/z =
285.1. ESI-HR-MS calculated for C14H9BrN2 (M++H): 285.0027, found:
285.0022.
7H-Benzo[e]perimidin-7-one (8i).[15l,n] Yield: 48% (0.099 g from 0.2 g); a
brown solid, mp 178-180 oC; Rf = 0.45 (hexanes: EtOAc, 3:7, v/v); 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 7.88-7.92 (m, 1H), 7.98-8.02 (m,
1H), 8.25-8.29 (m, 1H), 8.35 (dd, J1 = 6.7 Hz, J2 = 1.0 Hz, 1H), 8.44 (dd,
J1 = 7.5 Hz, J2 = 0.96 Hz, 1H), 8.56 (dd, J1 = 6.3 Hz, J2 = 0.96 Hz, 1H),
8.86 (dd, J1 = 6.9 Hz, J2 = 0.92 Hz, 1H), 9.58 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 123.3, 124.6, 125.6, 129.8, 130.7, 132.9, 133.4,
134.7, 135.0, 135.2, 135.8, 147.2, 149.2, 152.9, 181.4. MS (ESI+): m/z =
233.2. ESI-HR-MS calculated for C15H8N2O (M++H): 233.0715, found:
233.0721.
7-Methyl-4-phenylquinazoline (8c). [15l] Yield: 90% (0.188 g from 0.2 g);
a white solid, mp 94-96 oC; Rf = 0.55 (hexanes: EtOAc, 6:4, v/v); 1H NMR
(400 MHz, CDCl3): δ (ppm) 2.61 (s, 3H), 7.43 (dd, J1 = 8.6 Hz, J2 = 1.4
Hz, 1H), 7.56-7.58 (m, 3H), 7.76-7.78 (m, 2H), 7.89 (s, 1H), 8.01 (d, J =
8.6 Hz, 1H), 9.33 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) = 22.1,
121.3, 126.8, 127.8, 128.6, 129.9, 129.9, 130.0, 137.3, 144.8, 151.4,
154.8, 167.8. MS (ESI+): m/z = 221.2. ESI-HR-MS calculated for
C15H12N2 (M++H): 221.1079, found: 221.1085.
6-Amino-7H-benzo[e]perimidin-7-one (8j).[15o] Yield: 79% (0.164 g from
0.2 g); a brown solid, mp 272-274 oC, (Lit. mp 277-278 oC); Rf = 0.38
1
(hexanes: EtOAc, 2:8, v/v); H NMR (400 MHz, DMSO-d6): δ (ppm) 7.65
(d, J = 9.4 Hz, 1H), 7.83-7.92 (m, 2H), 8.02 (d, J = 9.4 Hz, 1H), 8.42 (d, J
= 7.6 Hz, 1H), 8.77 (brs, 1H), 8.89 (d, J = 7.6 Hz, 1H), 9.27 (s, 1H), 10.13
(brs, 1H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 102.2, 120.3, 124.9,
126.6, 129.4, 131.8, 132.9, 133.9, 134.3, 136.9, 145.5, 149.5, 152.3,
154.9, 180.9. MS (ESI+): m/z = 248.2. ESI-HR-MS calculated for
C15H9N3O (M++H): 248.0824, found: 248.0818.
6-Chloro-4-phenylquinazoline (8d).[13a] Yield: 86% (0.179 g from 0.2 g);
a yellow solid, mp 136-137 oC, (Lit. mp 135-136 oC); Rf = 0.61 (hexanes:
1
EtOAc, 6:4, v/v); H NMR (400 MHz, CDCl3): δ (ppm) 7.59-7.61 (m, 3H),
7.76-7.78 (m, 2H), 7.85 (dd, J1 = 8.9 Hz, J2 = 2.2 Hz, 1H), 8.07 (d, J = 8.9
Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 9.38 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 123.7, 125.8, 128.9, 129.8, 130.4, 130.7, 133.5, 134.7,
136.6, 149.6, 154.8, 167.7. MS (ESI+): m/z = 241.1. ESI-HR-MS
calculated for C14H9ClN2 (M++H): 241.0533, found: 241.0534.
Acknowledgements
Two of the authors SM and DB acknowledge CSIR, New Delhi
for the financial assistance in the form of fellowships. Authors
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800495
European Journal of Organic Chemistry
FULL PAPER
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P. Li, J. Zhao, R. Lang, C. Xia, F. Li, Tetrahedron Lett. 2014, 55, 390–
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acknowledge the Sophisticated Analytical Instrumentation facility
at this institute for providing the spectroscopic data. CDRI
Communication No. 9671.
Y. Yang, Y. Bao, Q. Guan, Q. Sun, Z. Zha, Z. Wang, Green Chem.
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Keywords: Aerobic oxidation; C-N bond formation; Nitrogen
heterocycles; Radical reaction.
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10.1002/ejoc.201800495
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Entry for the Table of Contents (Please choose one layout)
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tert-Butyl hydrogen peroxide (TBHP)
serves as the methyl source under
metal-free aerobic conditions for
carrying out the oxidative amination of
the C(sp3)-H bond toward preparing
quinazolin-4(3H)-ones and
Nitrogen heterocycles*
S. Mukhopadhyay, D. S. Barak, and S.
Batra**
Page No. – Page No.
TBHP as the methyl source under
Metal-free Aerobic conditions for the
synthesis of Quinazolin-4(3H)-ones
and Quinazolines via Oxidative
Amination of C(sp3)-H Bond
quinazolines is reported.
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