Iron-catalyzed C-C bond formation via cross dehydrative coupling reaction of N-heterocyclic aminols with electron rich arenes: Facile access to C4-aryl-dihydroquinazolines

Article abstract of DOI:10.1016/j.tet.2015.12.040

The direct coupling of sp³ C-OH bond of N-heterocyclic aminols with sp² C-H bond of electron rich arenes have been achieved via iron catalyzed dehydrative cross coupling strategy. This novel protocol provides an efficient and straight forward route to access biologically important C4-aryl-3,4-dihydroquinazoline derivatives through the reaction of C4-hydroxy-3,4-dihydroquinazoline/aminol with phenol and aniline derivatives under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2015.12.040

Accepted Manuscript
Iron-catalyzed C-C bond formation via cross dehydrative coupling reaction of
heterocyclic aminols with electron rich arenes: Facile access to C4-aryl-3,4-
dihydroquinazolines
R. Arun Kumar, A. Srinivasulu, G. Saidulu, P. Santhosh Kumar, B. Sridhar, K.
Rajender Reddy
PII:
S0040-4020(15)30288-X
10.1016/j.tet.2015.12.040
TET 27366
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 August 2015
Revised Date: 18 December 2015
Accepted Date: 19 December 2015
Please cite this article as: Kumar RA, Srinivasulu A, Saidulu G, Santhosh Kumar P, Sridhar B, Reddy
KR, Iron-catalyzed C-C bond formation via cross dehydrative coupling reaction of heterocyclic aminols
with electron rich arenes: Facile access to C4-aryl-3,4-dihydroquinazolines, Tetrahedron (2016), doi:
10.1016/j.tet.2015.12.040.
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Iron-catalyzed C-C bond formation via cross dehydrative
coupling reaction of heterocyclic aminols with electron rich
arenes: facile access to C4-aryl-3,4-dihydroquinazolines
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R. Arun Kumar,a A. Srinivasulu,a G. Saidulu,a P. Santhosh Kumar,a B. Sridharb and K. Rajender Reddya*

1
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Tetrahedron
journal homepage: www.elsevier.com
Iron-catalyzed C-C bond formation via cross dehydrative coupling reaction of N-
heterocyclic aminols with electron rich arenes: facile access to C4-aryl-
dihydroquinazolines
R. Arun Kumar,a A. Srinivasulu,a G. Saidulu,a P. Santhosh Kumar,a B. Sridhar,b and K. Rajender Reddya*
aInorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana State – 500 007, India.
bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Telangana State, Hyderabad – 500 007, India.
ARTICLE INFO
ABSTRACT
The direct coupling of sp3 C-OH bond of N-heterocyclic aminols with sp2 C-H bond
Article history:
Received
Received in revised form
Accepted
of electron rich arenes have been achieved via iron catalyzed dehydrative cross coupling
strategy. This novel protocol provides an efficient and straight forward route to access
biologically important C4-aryl-3,4-dihydroquinazoline derivatives through the reaction of C4-
hydroxy-3,4-dihydroquinazoline/aminol with phenol and aniline derivatives under mild reaction
conditions.
Available online
Keywords:
Dihydroquinazoline
Iron
Phenols
Anilines
2009 Elsevier Ltd. All rights reserved
.
Dehydrative cross coupling
1. Introduction
Chemical reactions that generate new carbon-carbon
(C-C) bonds are more fundamental and vital tool for the
production of man-made chemicals such as fine chemicals,
agrochemicals, pharmaceuticals, polymers and etc. Over the past
few decades, numerous catalytic methods have been developed
for the construction of C-C bonds employing variety of pre-
formed coupling partners. Among them, particularly palladium
catalyzed cross coupling reaction between pre-functionalized
coupling partners are promising chemical tool for the formation
of C-C bonds and have been extensively applied for the synthesis
of natural products and biologically relevant organic molecules.1
On the other hand, the main drawbacks of these cross coupling
reactions are utilization of pre-functionalized starting materials
(organic halides and pseudo halides) and environmentally toxic
organometallic reagents and thus release stoichiometric amount
of undesirable by-products. As a consequence, these methods are
not attractable in the large-scale industrial applications.
Scheme 1. Cross coupling reactions between N-heterocyclic
aminols/peroxides and various pro-nucleophiles (Nu-H) to access C4-
substituted 3,4-dihydroquinazoline derivatives.
formation using simple and abundantly available starting
materials such as direct C-H bond activation/functionalization
through oxidative dehydrogenative cross coupling reaction
(CDC),2 decarboxylative coupling,3 C-O bond cleavage of
ethers,4 use of arylhydrazones5 and aryl-hydrazines.6 In particular,
direct coupling of readily available alcoholic C-OH bond and
unactivated C-H bond of pro-nucleophile to form new C-C bond
by dehydrative cross coupling reaction has emerged as an elegant
and attractive strategy in recent years.7 Mainly because, this
method offers more atom-economical and environmental friendly
route to access various C-C coupled products with the release of
water (H2O) as only by-product. In this regard, numbers of
transition-metal catalyzed and non-transition metal/metal-free
protocols have been disclosed to couple relatively activated
alcoholic pro-electrophiles bearing sp3 C-OH bond (benzylic,
Therefore,
the
development
of
atom-economical,
environmentally benign and waste-free cross coupling strategies
for the C-C bond formation using inexpensive, unfunctionalized
and harmless, precursors and catalysts are of great interest in
modern organic chemistry.
Over
the
past
decade,
several
alternative
approaches/strategies have been reported for the C-C bond
Corresponding author. E-mail address: rajender@iict.res.in;
rajenderkallu@gmail.com

2
Tetrahedron
Table 1 Preparation of 2,3-diaryl-3,4-dihydroquinazolin-4-ols using
propargyl and allylic alcohols) with variety of pro-nucleophiles
ACCEPTED MANUSCRIPT
KI/TBHP.a
such as alkynes,8 alkenes,9 phenol,10 N,N-dimethyl aniline,11
indoles,12 active methylene compounds,13 β-keto phosphonates,14
ketones,13a aldehydes,15 arenes and heteroarenes.16 Apart from
that, this strategy further extended to couple sp2 C-OH bond of
tautomerizable nitrogen heterocycles,17 4-hydroxycoumarin18 and
phenol19 with different pro-nucleophiles in the presence of
external OH group activating agents (i.e. phosphonium salt and
para-toluenesulphonyl chloride).
Recently, we have shown that N-heterocyclic α-
aminols and α-amino peroxides can be used as versatile iminium
ion precursors and coupling partners to generate C-C20a,20b and C-
X (X = N or P)20c for these sort of cross coupling reactions i.e.
dehydrogenative and dehydrative cross coupling reactions.
Furthermore, these protocols have applied for the simple,
efficient and direct route to synthesis of biologically important
N-hetetocycle namely, 3,4-dihydroquinazoline using metal
(Copper and Iron) and metal free catalytic system (Scheme 1).
a Reaction conditions: (i) 1,3-diamine 1 (3 mmol), aldehyde 2 (3 mmol),
EtOH (6 mL), r.t., 3 h. (ii) KI (20 mol%), 70 wt% TBHP in H2O (4
equiv.), r.t., overnight. (iii) dimethoxyethane (6 mL), 100 °C, 6 h.
b
Numbers in parentheses are isolated yield of the products after SiO2
column chromatography.
For initial studies, 2,3-diphenyl-3,4-dihydroquinazolin-
4-ol (3a) was chosen as a model substrate and treated with 2
equivalents of phenol in 2 mL of dichloroethane (DCE) at 75 oC
in the presence of 10 mol% of copper(II)triflate (Cu(OTf)2) and 4
Ao molecular sieves. To our delight, aminol 3a was completely
consumed within 3 hours and gave the desired coupling product
5a in excellent isolated yield (Table 2, entry 1).
Figure 1. Bioactive C4-aryl-3,4-dihydroquinazoline analogues.
C4-substituted-3,4-dihydroquinazoline derivatives are
well known natural alkaloids21 and displayed different type of
biological
applications22.
Among
C4-substituted-3,4-
dihydroquinazoline derivatives, C4-aryl-3,4-dihydroquinazoline
are one of the important analogues and used as trypanothione
reductase (TryR) inhibitory agent (Figure 1).23 Due to broad
application possibilities, considerable efforts have made towards
Table 2. Optimization of reaction conditions of iron catalyzed dehydrative
cross coupling reaction.a
the
synthesis
of
this
C4-aryl-3,4-dihydroquinazoline
derivatives.23,24 However, the problems associated with these
reported methods are multi-step synthetic schemes, poor atom-
economy, limited substrate scope, employing relatively harmful
and unstable intermediates such as isocyanate, azide, and ortho-
iminophenyl lithium anion derivatives. In these view points,
development of operationally new protocols using readily
available, inexpensive and innocuous starting materials and
reagents to access this scaffold is highly desirable.
With these consideration, in this manuscript we wish to
describe the simple, efficient and straight forward method to
generate structurally diverse C4-aryl-dihydroquinazoline
derivatives through the direct dehydrative cross coupling reaction
between N-heterocyclic aminols and electron rich arenes
(phenols and anilines) under mild reaction conditions using iron
salt (FeCl2) as a catalyst.
2. Results and Discussion
In continuation of our previous works,20 we started the
investigation to synthesis C4-arylated-3,4-dihydroquinazoline
through
the
direct
coupling
of
C4-hydroxy-3,4-
dihydroquinazoline derivatives (aminols) with electron rich
arenes via cross dehydrative coupling reaction. C4-hydroxy-3,4-
dihydroquinazoline derivatives (3) are prepared by our previous
method using simple starting materials and reagents as shown in
table 1.20c They are easy to handle, purify (column
chromatography) quite stable solids and can be stored for long
time at low temperature.
a
Reaction conditions: (i) 2,3-diphenyl-3,4-dihydroquinazolin-4-ol 3a (0.25
mmol), catalyst (10 mol %), phenol 4a (0.5 mmol, 2 equiv.), Solvent (2 mL).
b Yields based on NMR analysis of crude reaction mixture.
c
Isolated yield of 5a after SiO2 column chromatography.
Under the same reaction conditions, iron salts (FeCl2 and FeCl3)
were tested as a catalyst in place of copper salt and showed that
iron also appropriate catalyst for this transformation (Table 2,

3
entries 2 and 8). Later, the reaction was performed in the absence
of catalyst at different temperature (Table 2, entries 3 and 4) and
even in the absence metal-catalyst the desired product 5a was
formed, but little longer time was required for the completion of
the reaction. Though the reaction proceeded in catalyst-free
condition, we decided to use most abundant, very low-priced and
less-toxic iron salts as a catalyst, to avoid prolonging reaction
time and energy consumption. Solvent screening (entries 6 and 7)
reveals that toluene was also suitable reaction media for this
dehydrative cross reaction. Finally, we chose the 1 equivalent of
3a and 2 equivalents of phenol in the presence of 10 mol% of
FeCl2 in 2 mL of DCE at 75 oC as a best condition (Table 2, entry
5). To find the scope of the reaction, variety of pre-synthesized
aminols and phenol derivatives were investigated as shown in
table 3.
catechol also coupled with aminol derivatives and the
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corresponding products 5h-j were obtained in good to excellent
yields (74-95%).The ortho substituted phenols namely, o-phenyl
and o-propyl phenols were also compatible, and the
corresponding products 5k and 5l were produced in good isolated
yields. The para-fluorophenol was then examined to couple with
3a under this condition and the desired product 5m was isolated
in 71% yield.
After the success in the direct coupling of aminol and phenol
derivatives to produce novel 4-(2,3-diaryl-3,4-dihydroquinazolin-
4-yl)phenol derivatives (5), we focused our attention to explore
this method with other electron rich arene and N,N-
dimethylaniline as a pro-nucleophile in place of phenols. The
2,3-diphenyl-3,4-dihydroquinazolin-4-ol (3a) was treated with 2
equivalents of N,N-dimethylaniline under the similar reaction
conditions (Table 4). The desired N,N-dimethylaniline coupled
product 7a was obtained in excellent isolated yield, which was
confirmed by spectroscopic analysis.11
Table 3. Iron catalyzed dehydrative cross coupling reaction between
heterocyclic aminol and phenol derivatives.a
In order to understand the influence of this iron catalyst in
reaction rate, N,N-dimethylaniline was treated with 3a performed
without catalyst and the reaction was not completed even after 24
hours. This result indicates that iron catalyst plays significant role
in this transformation. Under these conditions, different 2,3-
diaryl-3,4-dihydroquinazolin-4-ol
derivatives
(3)
were
successfully coupled with aniline derivatives such as substituted
anilines, N,N-dialkyl anilines and N-alkyl anilines (6) and the
desired coupled products (7) were obtained in good to excellent
isolated yields and the representative results are listed in Table 4.
Under these conditions, N,N-diethyl, N,N-dibutyl, N-methyl and
N-ethyl anilines coupled smoothly with aminols and afforded the
representative products (7b-f) in moderate to excellent isolated
yields (65-95%). Surprisingly, the simple aniline and its
derivatives also reacted with aminols and the corresponding
products 7g-l in moderate to excellent yields. Attempts with para-
substituted anilines were not successful under the present
conditions. One of the structure aniline couple products 7k was
confirmed by single crystal X-ray analysis (Figure 3).
aAll products were characterized by NMR, IR and mass spectroscopy.
bNumbers in parentheses are isolated yield of products after SiO2 column
chromatography.
Figure 2. A view of compound 5c (CCDC 1005829), showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 30% probability
level and H atoms are represented by circles of arbitrary radii. The compound
cToluene (2 mL) was used as solvent.
ꢀ
crystallized in triclinic P1 space group with two molecules (labelled A and B)
in the asymmetric unit. For sake of clarity only one molecule (labelled A) is
shown. The minor disordered component C131/C141/C281/C291/C301 have
been omitted.
The aminols (3) bearing electron donating and withdrawing
substituents on the benzene rings A, B and C did not affect the
reaction rates and yields significantly, and the desired phenol
couple products (5a-e) were isolated in good to excellent yields
(77-96%). As reported earlier,10 this cross coupling selectively
occur at para position of the phenol, which was further
confirmed by single crystal X-ray analysis of compound 5c
(Figure 2). In addition, aminol derivatives reacted smoothly with
2,6-dimethoxyphenol and afforded the desired products 5f and 5g
in satisfactory yields. Pleasingly, under this standard condition
Finally, based on our20,26 and others25 investigation, a
plausible mechanism for the product formation was illustrated in
scheme 2. Here one can expect two possible pathways for the
product formation: (a) without influence of catalyst (Path I) and
(b) with the influence of catalyst (Path II). In path I, initially the
weakly Brønsted acidic phenol protonates the hydroxyl group of

4
Tetrahedron
aminol 3a and the water is subsequently released to generate
product 5a. In a similar fashion, anilines (6) can react with
ACCEPTED MANUSCRIPT
iminium ion (In2) through the intermediate In1 and
Table 4. Iron catalyzed dehydrative cross coupling reaction between
heterocyclic aminol and aniline derivatives.a
aminols (3) in the presence of iron catalyst (Path II) to form the
aniline couple product 7 (Scheme 2).
N
N
N
N
N
N
N
N
N
7c (87%)
7a (94%)
7b (88%)
HN
HN
N
Scheme 2. Plausible mechanism for the formation of C4-aryl-3,4-
dihydroquinazoline derivatives via cross dehydrative coupling reaction.
F
N
N
N
N
N
N
3. Conclusions
We have demonstrated the simple and efficient method
for the formation of new C-C bond through direct coupling of C-
OH bond of aminol and C-H bond of electron rich arenes via iron
catalyzed dehydrative cross coupling reaction. Furthermore, this
protocol was applied for the construction of structurally diverse
and biologically important C4-arylated-3,4-dihydroquinazoline
derivatives in good to excellent isolated yields through
dehydrative coupling reaction between heterocyclic aminols and
electron rich arenes (phenol and anilines) using inexpensive and
environmentally benign iron catalyst under mild reaction
conditions. Further studies on detail mechanism and application
of this protocol to synthesize target oriented C-4-aryl 3,4-
dihydroquinqzoline are ongoing in our laboratory.
7e (82%)
7d (65%)
7f (90%)
NH2
NH2
NH2
O
N
N
N
N
N
N
7g (86%)c
7i (86%)c
7h (69%)c
NH2
NH2
NH2
N
N
N
N
N
N
7j (92%)c
7l (84%)c
7k (61%)c
aAll products were characterized by NMR, IR and mass spectroscopy.
bNumbers in parentheses are isolated yield of products after SiO2 column
chromatography.
4. Experimental
4.1. General information
c 4 equivalents of aniline was used.
All the other chemicals and solvents were obtained
from commercial sources, and used as recieved. Silica gel (100–
200 mesh) was used for column chromatography and thin-layer
chromatography was performed on pre-coated silica gel 60-F254
plates and visualized by UV-light and developed by iodine. The
1
IR values are reported in reciprocal centimeters (cm-1). All H
and 13C {1H} NMR spectras were recorded on a 300, 400, and
500 MHz spectrometer. Chemical shifts (δ) are reported in ppm,
using TMS (δ =0) as an internal standard in CDCl3. The peak
patterns are indicated as follows: bs, broad singlet; s, singlet; d,
doublet; t, triplet; dd, doublet of doublet; sep, septet; m,
multiplet. The coupling constants (J), are reported in Hertz (Hz).
Mass spectral data was compiled using MS (ESI), HRMS
mass spectrometers at national centre for mass spectroscopy
(CSIR-Indian institute of chemical technology, Hyderabad,
India) and the orbitrap mass analyser was used for the HRMS
measurement. N-(2-aminobenzyl)anilines (2) were prepared by
the literature procedure.20c, 28
Figure 3. A view of compound 7k (CCDC 1005828), showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 30% probability
level and H atoms are represented by circles of arbitrary radii
.
substitution reaction of hydroxyl group in α-aminols by relatively
Brønsted acidic pro-nucleophiles is well known phenomenon.20,25
Then, in situ formed iminium ion (In2)26 reacted with para
directing electron rich phenoxide to furnish the final product via
aromatic electrophilic substitution reaction (SEAr).In path II, the
aminol (3a) is converted into iminium ion (In4) via a reversible
heterolytic cleavage catalyzed by Lewis acid (Cun+ or Fen+).20b-
4.2. General procedure for the preparation of 3,4-diaryl-
dihydroquinazolin-4-ol using KI/TBHP catalytic system:
To a solution of N-(2-aminobenzyl) substituted anilines
1 (1,3-diamine) (3 mmol) in 8 mL of ethanol, aldehyde 2 (3
mmol) was added and stirred at room temperature for 3 hours. To
the same solution, KI (20 mol%) and 1.5 mL of 70 wt% TBHP in
H2O (4 equivalent) added dropwise for 5 minutes and stirred at
room temperature for overnight. The solvent (EtOH) was
c,25,26
Subsequently, intermediate In4 is trapped by 4a through
aromatic electrophilic substitution reaction at para-position
(SEAr) to form intermediate In3, which further afford the final

5
removed under reduced pressure. The residue was diluted with 8
mL of dimethoxy ethane (DME) and the mixture was stirred at
100 oC for 5-6 hours. The progress of the reaction was monitored
by TLC. After cooling to RT, the solvent (DME) was removed
under vacumm. The crude product was purified by column
chromatography using petroleum ether/ethyl acetate mixture as
4.2.4. 3-phenyl-2-(4-(trifluoromethyl)phenyl)-3,4-
ACCEPTED MANUSCRIPT
dihydroquinazolin-4-ol: (3d) White solid. m.p. 188-190 oC.
Isolated yield: 740 mg (67%). (Petroleum ether/Ethyl acetate =
2:1, Rf = 0.5). IR vmax (cm-1): 3143, 2961, 2880, 1586, 1546,
1
1480, 1358, 1252, 1055, 970, 842, 698, 550, 520. H NMR (300
MHz, CDCl3, ppm) δ 7.38-7.29 (m, 6H), 7.24-7.14 (m, 3H),
7.11-7.06 (m, 2H), 6.95-6.90 (m, 2H), 5.96 (s, 1H). 13C NMR
(125 MHz, CDCl3, ppm) δ 151.7, 144.3, 139.9, 137.5, 130.5,
129.3, 128.9, 126.2, 125.7, 124.7, 124.4, 124.0, 82.4. MS (ESI)
m/z = 369 (M + H)+; (ESI-HRMS) calculated for C21H16ON2F3
(M+H)+ = 369.12092, found 369.12226.
1
an eluent and the obtained product was analyzed H NMR, 13C
NMR, IR, ESI-MS and ESI-HRMS. In ESI-HRMS analysis of
3,4-diphenyl-dihydroquinazolin-4-ol (3a) showed m/z value
corresponding to methanol (solvent) substituted product, where
we dissolved 3a in methonal and the solution was used for ESI-
HRMS analysis (Scheme 3). Additionally, we did ESI analysis of
compound 3a in ethanol solution, where we observed m/z value
corresponding to ethanol substituted product, whereas in
acetonitrile solution we could observe the exact molecular ion of
the aminols 3.
4.2.5. 2-(4-tert-butylphenyl)-3-phenyl-3,4-dihydroquinazolin-4-ol
(3e): White solid. m.p.194-196 oC. Isolated yield: 865 mg (81%).
(Petroleum ether/Ethyl acetate = 2:1, Rf = 0.5). IR vmax (cm-1):
3464, 2964, 2872, 1579, 1544, 1482, 1361, 1251, 1054, 1014,
1
841, 697,565, 468. H NMR (300 MHz, CDCl3) δ 7.23-7.05 (m,
11H), 6.99 (d, J = 7.3 Hz, 1H), 6.90 (t, J = 6.9 Hz, 1H), 5.93 (s,
1H), 1.26 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm) δ 153.1,
152.3, 145.2, 140.3, 130.8, 130.4, 128.9, 128.4, 125.8, 125.2,
125.0, 124.9, 124.2, 123.5, 82.7, 34.5, 31.1. MS (ESI) m/z = 357
(M + H)+; (ESI-HRMS) calculated for C24H25ON2 (M+H)+
357.19614, found 357.19713.
=
4.2.6. 6-fluoro-2,3-diphenyl-3,4-dihydroquinazolin-4-ol: (3f)
o
White solid. m.p 202-204 C. Isolated yield: 764 mg (80%).
(Petroleum ether/Ethyl acetate = 2:1, Rf = 0.5). IR vmax (cm-1):
2946, 2828, 1590, 1550, 1489, 1398, 1243, 1038, 943, 831,
698,555, 504.1H NMR (500 MHz, CDCl3, ppm) δ 7.23-7.17 (m,
4H), 7.13-7.02 (m, 7H), 6.83 (t, J = 8.6 Hz, 6.57 (d, J = 8.2 Hz,
1H), 5.85 (s, 1H). 13C NMR (125 MHz, CDCl3, ppm) δ 161.1,
159.2, 152.8, 144.8, 136.5, 133.2, 130.5, 129.5, 128.6, 127.3,
125.5, 125.2, 125.0, 124.7, 116.5, 116.3, 112.1, 112.0, 82.2. MS
(ESI) m/z = 319 (M + H)+, (ESI-HRMS) calculated for
C20H16ON2F (M+H)+ = 319.12412, found 319.12489.
Scheme 3. ESI mass analysis of compound 3a in different solvents.
4.2.1. 2,3-diphenyldihydroquinazolin-4-ol: (3a)
White solid. m.p 185-187 oC. Isolated yield: 708 mg (78%)
(Petroleum ether/Ethyl acetate = 1;1, Rf = 0.5). IR v
cm-1:
max
1
3061, 2930, 1588, 1547, 1487, 1405, 1250, 1029, 763. H NMR
(CDCl3, 300 MHz, ppm): δ 7.29-6.95 (m, 14 H), 5.98 (s, 1H). 13C
NMR (75 MHz, CDCl3, ppm): δ 153.3, 144.9, 140.2, 134.1,
130.5, 129.3, 129.1, 128.5, 127.4, 126.0, 125.5, 125.1, 124.9,
124.2, 123.7, 82.5. MS (ESI) m/z = 301 (M + H)+; (ESI-HRMS)
calculated for C20H17ON2 (M+H)+: 301.13354, found: 301.13411.
4.2.7. 3-(4-methoxyphenyl)-2-phenyl-3,4-dihydroquinazolin-4ol:
(3g) White solid. m.p. 208-210 oC. Isolated yield: 623 mg (63%).
(Petroleum ether/Ethyl acetate = 2:1, Rf = 0.4). IR vmax (cm-1):
3061, 2891, 1587, 1551, 1508, 1357, 1290, 1054, 998, 834,
1
661,576, 497. H NMR (500 MHz, CDCl3, ppm) δ 7.29-7.25 (m,
4H), 7.20 (t, J = 8.0 Hz, 2H), 7.12-7.07 (m, 3H), 7.00 (t, J = 8.2
4.2.2. 3-phenyl-2-p-tolyl-3,4-dihydroquinazolin-4-ol: (3b)
Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 5. 93 (s, 1H), 3.71 (s, 3H). 13
C
o
White solid. m.p. 188-190 C. Isolated yield: 794 mg (84%)
(Petroleum ether/Ethyl acetate = 2:1, Rf = 0.5). IR vmax (cm-1):
NMR (125 MHz, CDCl3, ppm) δ 157.1, 153.2, 140.5, 138.2,
134.5, 130.4, 129.1, 127.4, 126.3, 126.1, 125.3, 124.0, 123.9,
113.7, 82.7, 55.3. MS (ESI) m/z = 331 (M + H)+; (ESI-HRMS)
3302, 2884, 1586, 1548, 1483, 1321, 1250, 1054, 994, 823,
1
629,560, 466. H NMR (500 MHz, CDCl3, ppm) δ 7.22 (d, J =
calculated for C21H19O2N2 (M+H)+
331.14475.
= 331.14410, found
7.7 Hz, 1H), 7.16-7.09 (m, 7H), 7.03 (t, J = 7.1 Hz, 2H), 6.96 (d,
J = 7.0 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 5.95 (s, 1H), 2.26 (s,
3H). 13C NMR (75 MHz, CDCl3, ppm) δ 153.2, 145.1, 140.4,
139.3, 131.4, 130.4, 129.1, 128.4, 128.1, 126.0, 125.1, 125.0,
124.9, 124.1, 123.8, 82.5, 21.3. MS (ESI) m/z = 315 (M + H)+;
(ESI-HRMS) calculated for C21H19ON2 (M+H)+ = 315.14919,
found 315.14973.
4.3. General procedure for synthesis of 4-(2,3-diaryl-3,4-
dihydroquinazolin-4-yl)phenol derivatives via iron catalyzed
dehydrative cross coupling reaction.
To a solution of 3,4-diaryl-dihydroquinazolin-4-ol (3)
(0.25 mmol) and phenol (4) (0.5 mmol, 2 equiv.) in 2 mL of
DCE, FeCl2 (10 mol%) was added and the mixture was stirred
4.2.3. 3-phenyl-2-m-tolyl-3,4-dihydroquinazolin-4-ol: (3c)
o
o
magnetically at 75 C for 3 hours. The progress of the reaction
White solid. m.p. 170-172 C, Isolated yield: 753 mg (80%).
(Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
cm-1:
was monitored by TLC. After completion of reaction, the
reaction mixture was allowed to cool to RT and filtered through
celite using chloroform/ethylacetate. The solution was
concentrated under vacumm to afford the crude product. The
crude product was purified by column chromatography using
petroleum ether/ethyl acetate mixture as eluent and the obtained
product was analyzed by 1H NMR, 13C NMR, ESI-HRMS.
max
3057, 2924, 2379, 2311, 1588, 1550, 1483, 1252, 1039. 1H NMR
(CDCl3 + DMSO-d6, 500 MHz, ppm): δ 7.32-6.90 (m, 13H),
5.97 (s, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, CDCl3 + DMSO-
d6, ppm): δ 150.4, 142.9, 138.9, 135.0, 134.5, 128.0, 127.9,
126.7, 124.7, 123.1, 122.7, 122.4, 122.3, 78.8, 19.08. MS (ESI):
m/z (M+H)+ = 329 amu. HRMS (ESI) calculated for C22H21ON2
(M)+ methanol adduct: 329.16484, found: 329.16240.
4.3.1. 4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)phenol: (5a)

6
Tetrahedron
ACCEPTED MANUSCRIPT
White solid. m.p. 232-234. Isolated yield: 90 mg (96%).
0.4). IR v ax cm-1: 2936, 2928, 2845, 2379, 2320, 2312, 1545,
m
(Petroleum ether/Ethyl acetate = 1:1, Rf = 0.5). IR v
2965, 2377, 2312, 1585, 1536, 1511, 1493, 1454, 1396, 1250,
1171. H NMR (DMSO-d6, 300 MHz, ppm): δ 9.41 (bs, 1H),
7.59 (d, J = 6.6 Hz, 2H), 7.27-6.88 (m, 14H), 6.71 (d, J = 7.9 Hz,
2H), 5.91 (s, 1H). 13C NMR (CDCl3 + DMSO-d6, 75 MHz,
ppm): δ 155.2, 152.3, 143.9, 138.9, 134.3, 133.0, 127.7, 127.5,
126.8, 126.1, 125.9, 125.4, 124.7, 124.1, 123.7, 122.3, 121.7,
113.8, 62.2. MS (ESI): m/z (M+H)+ = 377 amu. HRMS (ESI)
calculated for C26H21ON2 (M+H)+: 377.16484, found: 377.16589.
cm-1:
1484, 1116, 1025. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.63 (d, J
= 7.6 Hz, 2H), 7.35-7.27 (m, 4H), 7.21-7.04 (m, 6H), 6.96 (d, J =
7.6 Hz, 2H), 6.66 (s, 2H), 5.80 (s, 1H), 3.79 (s, 6H). 13C NMR
(CDCl3, 100 MHz, ppm): δ 158.1, 154.7, 147.6, 145.7, 137.4,
135.8, 134.7, 129.8, 129.4, 128.8, 128.2, 126.6, 125.0, 124.5,
115.3, 115.1, 1134, 112.5, 112.2, 112.0, 102.1, 65.99, 56.38. MS
(ESI): m/z (M+H)+ = 437 amu. HRMS (ESI) calculated for
C28H25O3N2 (M+H)+: 437.18597, found: 437.18577.
max
1
4.3.7. 4-(6-fluoro-2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-2,6-
dimethoxyphenol: (5g) Pale yellow solid. m.p. 184-186. Isolated
yield: 80 mg (71%). (Petroleum ether/Ethyl acetate = 3:2, Rf =
0.4). IR v max cm-1: 2942, 2924, 2849, 2838, 2379, 2319, 1417,
1116, 1023. 1H NMR (CDCl3, 300 MHz, ppm): δ 7.62 (d, J = 7.0
Hz, 2H), 7.33-7.27 (m, 4H), 7.24-7.22 (m, 1H), 7.15-7.09 (m,
3H), 7.03 (d, J = 7.1 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 6.67 (d, J
= 8.8 Hz, 2H), 5.77 (s, 1H), 2.93 (s, 6H). 13C NMR (CDCl3, 100
MHz, ppm): δ 155.5, 147.6, 135.9, 134.7, 130.1, 129.6, 128.8,
128.4, 128.3, 126.1, 126.0, 125.6, 125.3, 124.8, 124.1, 102.3,
66.2, 56.3. MS (ESI): m/z (M+H)+ = 455 amu. HRMS (ESI)
calculated for C28H24O3N2F (M+H)+: 455.17655, found:
455.17636.
4.3.2. 4-(3-phenyl-2-p-tolyl-3,4-dihydroquinazolin-4-yl)phenol:
o
(5b) White solid. m.p. 242-244 C. Isolated yield: 75 mg (77%).
(Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
cm-1:
max
2927, 2853, 2378, 2312, 1546, 1453, 1021. 1H NMR (DMSO-d6,
300 MHz, ppm): δ 9.34 (bs, 1H), 8.09 (s, 1H), 7.52 (d, J = 8.1
Hz, 2H), 7.32-7.25 (m, 2H), 7.23-7.05 (m, 7H), 7.01-6.90 (m,
3H), 6.72 (d, J = 8.4 Hz, 2H), 5.87 (s, 1H), 2.29 (s, 3H) . 13C
NMR (CDCl3 + DMSO-d6, 75 MHz, ppm): δ 155.2, 152.4, 144.2,
139.1, 137.6, 133.0, 131.5, 127.6, 126.8, 126.0, 125.5, 124.7,
124.1, 123.5, 122.5, 121.7, 113.8, 62.44, 19.28 . MS (ESI): m/z
(M+H)+ = 391 amu. HRMS (ESI) calculated for C27H23ON2
(M+H)+: 391.18049, found: 391.18127.
4.3.3. 4-(2-(4-tert-butylphenyl)-3-phenyl-3,4-dihydroquinazolin-
4-yl)phenol: (5c) White solid. m.p. 236-238 oC. Isolated yield: 85
mg (78%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
max cm-1: 2958, 2932, 2379, 2315, 1612, 1585, 1544, 1483, 1289,
4.3.8. 4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)benzene-1,2-
diol: (5h) White solid. m.p. 248-250 C. Isolated yield: 80 mg
o
(82%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
max
cm-1: 2934, 2839, 2378, 2312, 1586, 1544, 1484, 1454, 1397,
1
1
1025. H NMR (CDCl3, 500 MHz, ppm): δ 7.52 (d, J = 8.5 Hz,
1283, 1245, 1024. H NMR (DMSO-d6, 300 MHz, ppm): δ 8.67
3H), 7.30-7.26 (m, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.14-7.09 (m,
3H), 7.03-6.99 (m, 4H), 6.93 (d, J = 7.4 Hz, 2H), 6.27 (d, J = 8.3
Hz, 2H), 5.70 (s, 1H), 1.23 (s, 9H) . 13C NMR (CDCl3, 125 MHz,
ppm): δ 157.1, 156.3, 133.6, 129.9, 129.3, 128.7, 128.3, 126.8,
126.5, 126.1, 125.2, 124.4, 121.5, 116.6, 65.4, 34.7, 31.0. MS
(ESI): m/z (M+H)+ = 433 amu. HRMS (ESI) calculated for
C30H29ON2 (M+H)+: 433.22744, found: 433.22720.
(bs, 1H), 8.57 (bs, 1H), 7.86-7.62 (m, 2H), 7.35-7.21 (m, 5H),
7.13-7.08 (m, 5H), 7.00-6.92 (m, 4H), 6.82-6.73 (m, 2H), 5.74 (s,
1H). 13C NMR (DMSO-d6, 75 MHz, ppm): δ 154.0, 145.7, 145.5,
144.9, 140.6, 136.1, 135.6, 129.6, 129.3, 128.7, 127.9, 127.7,
127.2, 126.1, 125.4, 124.2, 123.4, 116.2, 115.6, 112.9, 79.0, 63.8.
MS (ESI): m/z (M+H)+ = 393 amu. HRMS (ESI) calculated for
C26H21O2N2 (M+H)+: 393.15975, found: 393.15955.
4.3.4. 4-(3-phenyl-2-m-tolyl-3,4-dihydroquinazolin-4-yl)phenol:
4.3.9. 4-(3-(4-methoxyphenyl)-2-phenyl-3,4-dihydroquinazolin-4-
(5d) White solid. m.p. 206-208. Isolated yield: 90 mg (92%).
yl)benzene-1,2-diol: (5i)
White solid. m.p. 260-262 C. Isolated yield: 100 mg (95%).
(Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
o
(Petroleum ether/Ethyl acetate = 3:2, Rf = 0.3). IR v
cm-1:
max
2927, 2860, 2379, 2311, 1589, 1537, 1513, 1493, 1389, 1226,
cm-1:
max
1
1028. H NMR (CDCl3, 500 MHz, ppm): δ 7.49-7.47 (m, 2H),
2943, 2923, 2837, 2379, 2312, 1510, 1452, 1146, 1023. 1H NMR
(CDCl3 + DMSO-d6, 500 MHz, ppm): δ 7.54-7.45 (m, 3H), 7.23-
7.15 (m, 4H), 7.08-7.05 (m, 1H), 6.95-6.93 (m, 2H), 6.76-6.71
(m, 3H), 6.65-6.63 (m, 1H), 6.54-6.50 (m, 2H), 5.60 (s, 1H), 3.60
(s, 3H). 13C NMR (CDCl3 + DMSO-d6, 75 MHz, ppm): δ 154.6,
152.7, 143.9, 143.3, 139.1, 137.2, 134.7, 134.3, 127.6, 127.4,
126.0, 125.8, 125.1, 124.2, 123.8, 123.4, 122.4, 114.5, 113.8,
112.0, 111.2, 63.2, 53.3. MS (ESI): m/z (M+H)+ = 423 amu.
HRMS (ESI) calculated for C27H23O3N2 (M+H)+: 423.17032,
found:423.17014.
7.30-7.26 (m, 2H), 7.12-6.97 (m, 9H), 6.93 (d, J = 7.4 Hz, 2H),
6.36 (d, J = 7.4 Hz, 2H), 5.70 (s, 1H), 2.20 (s, 3H). 13C NMR (75
MHz, CDCl3 + DMSO-d6, ppm): δ 156.3, 154.3, 145.2, 139.9,
136.9, 135.4, 134.7, 129.6, 129.3, 127.8, 127.1, 126.9, 126.3,
125.9, 124.9, 124.7, 123.8, 123.7, 123.3, 115.2, 64.5, 28.7, 20.5.
MS (ESI): m/z (M+H)+ = 391 amu. HRMS (ESI) calculated for
C27H23ON2 (M+H)+: 391.18049, found: 391.17788.
4.3.5.
4-(6-fluoro-2,3-diphenyl-3,4-dihydroquinazolin-4-
o
yl)phenol: (5e) White solid. m.p. 228-230 C. Isolated yield: 75
mg (77%). (Petroleum ether/Ethyl acetate = 1:1, Rf = 0.5). IR v
max cm-1: 2927, 2860, 2378, 2311, 1514, 1508, 1482, 1287, 1149,
4.3.10.
yl)benzene-1,2-diol:(5j)
Pale brown solid. m.p. 218-220 C. Isolated yield: 76 mg (74%).
(Petroleum ether/Ethyl acetate = 1:1, Rf = 0.4). IR v
cm-1:
4-(3-phenyl-2-m-tolyl-3,4-dihydroquinazolin-4-
1
o
1030. H NMR (DMSO-d6, 300 MHz, ppm): δ 9.28 (bs, 1H),
7.62-7.59 (m, 2H), 7.36-7.22 (m, 6H), 7.14-7.09 (m, 2H), 7.01-
6.90 (m, 5H), 6.75 (d, J = 8.4 Hz, 2H), 5.80 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz, ppm): δ 161.0, 158.6, 156.9, 153.5, 145.4,
137.3, 135.8, 134.2, 129.6, 129.1, 128.8, 128.0, 126.56, 125.8,
124.3, 123.4, 115.6, 63.0. MS (ESI): m/z (M+H)+ = 395 amu.
HRMS (ESI) calculated for C26H20ON2F (M+H)+: 395.15542,
found: 395.15610.
max
2927, 2853, 2379, 2310, 1545, 1493, 1454, 1250, 1117, 1023. 1H
NMR (CDCl3, 500 MHz, ppm): δ 7.39 (d, J = 7.3 Hz, 1H), 7.20-
7.17 (m, 2H), 7.09-6.99 (m, 5H), 6.91 (d, J = 7.4 Hz, 1H), 6.87-
6.80 (m, 4H), 6.74 (t, J = 7.6 Hz, 1H), 6.55-6.47 (m, 2H), 5.6 (s,
1H), 2.03 (s, 3H). 13C NMR (75 MHz, DMSO-d6, ppm): δ 154.0,
145.7, 145.4, 144.9, 140.6, 137.1, 136.0, 135.6, 130.2, 129.8,
128.7, 127.7, 127.1, 126.4, 126.0, 125.3, 124.1, 124.0, 123.4,
116.2, 115.5, 113.0, 63.8, 20.8. MS (ESI): m/z (M+H)+ = 407
amu. HRMS (ESI) calculated for C27H23O2N2 (M+H)+:
407.17540, found: 407.17277.
4.3.6.4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-2,6
dimethoxyphenol: (5f) Pale yellow solid. m.p. 190-192. Isolated
yield: 75 mg (69%). (Petroleum ether/Ethyl acetate = 3:2, Rf =

7
125.8, 124.9, 124.59, 124.53, 112.8, 65.6, 40.5. MS (ESI): m/z
ACCEPTED MANUSCRIPT
4.3.11. 5-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)biphenyl-2-
(M+H)+ = 404 amu. HRMS (ESI) calculated for C28H26N3
(M+H)+: 404.21212, found: 404.21215.
o
ol: (5k) White solid. m.p. 238-240 C. Isolated yield: 80 mg
(70%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR v
max
1
cm-1: 2946, 2838, 2378, 2319, 1545, 1518, 1453, 1023. H NMR
4.4.2.
4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-N,N-
(CDCl3, 500 MHz, ppm): δ 9.62 (bs, 1H), 7.65 (d, J = 7.6 Hz,
2H), 7.45-7.13 (m, 16H), 7.01-6.91 (m, 4H), 6.05 (s,1H). 13C
NMR (75 MHz, CDCl3 + DMSO-d6, ppm): δ 155.1, 147.7,
146.3, 140.8, 137.7, 136.4, 131.4, 130.1, 128.3, 127.6, 127.3,
126.7, 126.6, 125.5, 125.4, 124.7, 124.1, 111.6, 65.4, 50.6, 29.6,
29.2, 21.2, 20.2, 13.9. MS (ESI): m/z (M+H)+ = 453 amu. HRMS
(ESI) calculated for C32H25ON2 (M+H)+: 453.19614, found:
453.19207.
diethylaniline:(7b) Sticky yellow oil. Isolated yield: 95 mg
(88%). (Petroleum ether/Ethyl acetate = 4:1, Rf = 0.5). H NMR
1
(CDCl3, 500 MHz, ppm): δ 7.65-7.63 (m, 2H), 7.30-7.23 (m,
7H), 7.14-7.10 (m, 3H), 7.05-6.97 (m, 4H), 6.61-6.59 (m, 2H),
5.75 (s, 1H), 5.75 (s, 1H), 3.32 (q, J = 7.0 Hz, 4H), 1.13 (t, J =
7.0 Hz, 6H). 13C NMR (CDCl3, 100 MHz, ppm): δ 155.1, 147.4,
146.0, 131.4, 129.6, 129.5, 128.4, 128.0. 127.8, 126.7, 125.7,
125.6, 124.5, 124.49, 124.41, 111.7, 65.5, 44.1, 12.5. MS (ESI):
m/z (M+H)+ = 432 amu. HRMS (ESI) calculated for C30H30N3
(M+H)+: 432.24342, found: 432.24275.
4.3.12.
4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-2-
o
propylphenol: (5l) White solid. m.p. 198-200 C. Isolated yield:
85 mg (81%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR
v
4.4.3. 4-(2-(4-tert-butylphenyl)-3-phenyl-3,4-dihydroquinazolin-
4-yl)-N,N-diethylaniline: (7c) White solid. m.p. 104-106 oC.
Isolated yield: 110 mg (87%). (Petroleum ether/Ethyl acetate =
:1, Rf = 0.6). IR v max cm-1: 2966, 2926, 2379, 2308, 1611, 1544,
1519, 1493, 1479, 1269, 1250, 1185, 1153. 1H NMR (CDCl3, 300
MHz, ppm): δ 7.58 (d, J = 8.4 Hz, 2H), 7.32-7.23 (m, 6H), 7.13-
6.98 (m, 7H), 6.59 (d, J = 8.8 Hz, 2H), 5.73 (s, 1H), 3.30 (q, J =
6.9 Hz, 4H), 1.25 (s, 9H), 1.12 (t, J = 6.9 Hz, 6H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 155.1, 152.9, 147.4, 146.2, 131.3,
129.4, 128.5, 127.8, 126.7, 125.6, 125.0, 124.3, 111.8, 65.7, 44.2,
34.6, 31.1, 12.7. MS (ESI): m/z (M+H)+ = 488 amu. HRMS
(ESI) calculated for C34H38N3 (M+H)+: 488.30602, found:
488.30530.
1
max cm-1: 2936, 2835, 2379, 2312, 1545, 1417, 1397, 1023. H
NMR (CDCl3, 500 MHz, ppm): δ 7.59 (d, J = 7.4 Hz, 2H), 7.50
(d, J = 7.4 Hz, 1H), 7.28-7.24 (m, 2H), 7.19 (t, J = 7.9 Hz, 2H),
7.13-6.9 (m, 8H), 6.74-6.71 (m,1H), 6.07 (d, J = 8.2 Hz, 1H),
5.69 (s, 1H), 2.46 (t, J = 7.4 Hz, 2H), 1.45 (sextet, J = 7.3 Hz,
2H), 0.85 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3, ppm):
δ 156.1, 154.8, 145.3, 134.1, 130.2, 129.9, 129.8, 128.6, 128.0,
126.7, 126.1, 125.7, 125.0, 124.5, 124.0, 123.7, 116.7, 65.5, 32.2,
22.6, 13.9. MS (ESI): m/z (M+H)+ = 419 amu. HRMS (ESI)
calculated for C29H27ON2 (M+H)+: 419.21179, found: 419.20817.
4.3.13.
2-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-4-
o
fluorophenol: (5m) White solid. m.p. 156-158 C. Isolated yield:
70 mg (71%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.4). IR
4.4.4. N,N-dibutyl-4-(3-phenyl-2-m-tolyl-3,4-dihydroquinazolin-
4-yl)aniline: (7d) Pale yellow sticky oil. Isolated yield: 80 mg
v
cm-1: 2923, 2838, 2377, 2324m 1588, 1485, 1445, 1397,
max
1
1249, 1026. H NMR (DMSO-d6, 300 MHz, ppm): δ 9.74 (bs,
1H), 7.83-7.75 (m, 1H), 7.64-7.57 (m, 2H), 7.38-6.76 (m, 14H),
6.44 (s, 1H). 13C NMR (CDCl3+DMSO-d6, 100 MHz, ppm): δ
153.6, 146.7, 144.3, 128.2, 128.0, 127.2, 126.7, 126.3, 124.4,
124.1, 123.2, 123.0, 122.2, 115.4, 113.7, 113.6, 111.7, 111.4,
56.7. MS (ESI): m/z (M+H)+ = 395 amu. HRMS (ESI) calculated
for C26H20ON2F (M+H)+: 395.15542, found: 395.15627.
(65%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.6). IR v
max
cm-1: 2956, 2927, 2872, 2391, 2311, 1621, 1545, 1493, 1455,
1
1378, 1181. H NMR (CDCl3, 500 MHz, ppm): δ 7.64-7.63 (m,
1H), 7.47-7.44 (m, 1H), 7.31-7.22 (m, 4H), 7.08-6.94 (m, 9H),
6.57-6.55 (m, 2H), 5.71 (s, 1H), 3.22-3.21 (m, 4H), 2.28 (s, 3H),
1.54-1.53 (m, 4H), 1.34-1.26 (m, 4H), 0.95-0.91 (m, 6H). 13C
NMR (75 MHz, CDCl3, ppm): δ 155.1, 147.7, 146.3, 140.8,
137.7, 136.4, 131.4, 130.1, 128.3, 127.6, 127.3, 126.7, 126.6,
125.5, 125.4, 124.7, 124.1, 111.6, 65.4, 50.6, 29.6, 29.2, 21.2,
20.2, 13.9. MS (ESI): m/z (M+H)+ = 502 amu. HRMS (ESI)
calculated for C35H40N3 (M+H)+: 502.32167, found: 502.31774.
4.4. General procedure for synthesis of 4-(2,3-diaryl-3,4-
dihydroquinazolin-4-yl)aniline derivatives via iron catalyzed
dehydrative cross coupling reaction.
To a solution of 3,4-diaryl-dihydroquinazolin-4-ol (3)
(0.25 mmol) and N,N-dialkyl/N-alkylaniline (6) (0.5 mmol, 2
equiv.) in 2 mL of DCE, FeCl2 (10 mol%) was added and the
mixture was stirred magnetically at 75 oC for 4 hours. The
progress of the reaction was monitored by TLC. After completion
of reaction, the reaction mixture was allowed to cool to RT and
filter through celite using chloroform/ethylacetate. The solution
was concentrated under vacumm to afford the crude product. The
crude product was purified by column chromatography using
petroleum ether/ethyl acetate mixture as eluent and the obtained
product was analyzed by 1H NMR, 13C NMR, ESI-MS.
In case of anilines and 2,6-disubstituted anilines 4 equivalents (1
mmol) were taken to couple with 3,4-diaryl-dihydroquinazolin-4-
ols (3).
4.4.5.
4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-N-
o
methylaniline: (7e) White solid. m.p. 156-158 C. Isolated yield:
80 mg (82%). (Petroleum ether/Ethyl acetate = 4:1, Rf = 0.4). IR
v
cm-1: 2927, 2808, 2378, 2310, 1586, 1545, 1455, 1386,
max
1284, 1248, 1153. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.63-7.61
(m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 7.32-7.30 (m, 2H), 7.27-7.19
(m, 4H), 7.11-7.07 (m, 3H), 7.04-7.02 (m, 1H) 6.98-6.95 (m,
3H), 6.55 (d, J = 8.5 Hz, 2H), 5.73 (s, 1H), 2.79 (s, 3H) . 13C
NMR (CDCl3, 75 MHz, ppm): δ 155.3, 149.1, 146.0, 133.7,
129.7, 128.6, 128.1, 128.0, 127.0, 126.8, 125.8, 125.7, 124.7,
124.6, 112.8, 65.8, 30.6. MS (ESI): m/z (M+H)+ = 390 amu.
HRMS (ESI) calculated for C27H24N3 (M+H)+: 390.19647, found:
390.19622.
4.4.1.
4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-N,N-
4.4.6. N-ethyl-4-(6-fluoro-2,3-diphenyl-3,4-dihydroquinazolin-4-
yl)aniline: (7f) While solid. m.p. 164-166 C. Isolated yield: 95
o
dimethylaniline: (7a) Sticky yellow oil. Isolated yield: 95 mg
(94%). (Petroleum ether/Ethyl acetate = 4:1, Rf = 0.4). IR v
mg (90%). (Petroleum ether/Ethyl acetate = 4:1, Rf = 0.5). IR v
max
1
cm-1: H NMR (CDCl3, 300 MHz, ppm): δ 7.62 (d, J = 7.0 Hz,
max cm-1: 2966, 2927, 2378, 2311, 1613, 1548, 1519, 1485, 1179,
1
2H), 7.33-7.22 (m, 7H), 7.14-7.09 (m, 3H), 7.01 (d, J = 7.1 Hz,
2H), 6.96 (d, J = 7.6 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.77 (s,
1H), 2.93(s, 6H) . 13C NMR (CDCl3, 100 MHz, ppm): δ 155.2,
150.0, 146.3, 133.0, 129.7, 129.6, 128.1, 127.9, 127.3, 126.7,
1148. H NMR (CDCl3, 300 MHz, ppm): δ 7.61-7.58 (m, 2H),
7.27-7.19 (m, 6H), 7.12-7.07 (m, 2H), 7.01-6.92 (m, 4H), 6.74-
6.70 (m, 1H), 6.54 (d, J = 9.0 Hz, 2H), 5.68 (s, 1H), 3.12 (q, J =
7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H) . 13C NMR (CDCl3, 125

8
Tetrahedron
MHz, ppm): δ 161.7, 159.7, 154.7, 148.45, 146.01, 133.1,
132.9, 130.1, 129.6, 129.5, 128.9, 128.1, 127.9, 127.7, 126.0,
ACCEPTED MANUSCRIPT
129.7, 129.6, 128.7, 128.1, 126.9, 126.3, 124.8, 124.6, 115.0,
114.8, 113.1, 112.3, 112.1, 65.5, 38.3, 14.8. MS (ESI): m/z
(M+H)+ = 422 amu. HRMS (ESI) calculated for C28H25N3F
(M+H)+: 422.20270, found: 422.20213.
125.7, 124.7, 120.3, 66.4, 27.9, 22.37, 22.31. MS (ESI): m/z
(M+H)+ = 460 amu. HRMS (ESI) calculated for C32H34N3
(M+H)+: 460.27472, found: 460.27402.
4.4.12.
2,6-diisopropyl-4-(3-phenyl-2-m-tolyl-3,4-
4.4.7. 4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)aniline:(7g)
Sticky yellow oil. Isolated yield: 80 mg (86%). (Petroleum
ether/Ethyl acetate = 1:1, Rf = 0.5). IR v max cm-1: 2934, 2861,
2378, 2311, 1621, 1545, 1493, 1481, 1455, 1387, 1216, 1178. 1H
NMR (CDCl3, 300 MHz, ppm): δ 7.62-7.59 (m, 2H), 7.50 (d, J =
7.5 Hz, 1H) 7.29-7.17 (m, 6H), 7.13-7.06 (m, 3H), 7.03-6.93 (m,
4H), 6.60 (d, J = 8.3 Hz, 2H), 5.73 (s, 1H), 3.45 (bs, 2H). 13C
NMR (CDCl3, 100 MHz, ppm): δ 155.3, 146.3, 145.7, 129.7,
129.6, 128.6, 128.0, 126.9, 125.9, 125.71, 124.8, 124.6, 124.4,
115.4, 65.71. MS (ESI): m/z (M+H)+ = 376 amu. HRMS (ESI)
calculated for C26H22N3 (M+H)+: 376.18082, found: 376. 18130.
dihydroquinazolin-4-yl)aniline: (7l) Pale yellow solid. m.p. 198-
o
200 C. Isolated yield: 100 mg (84%). (Petroleum ether/ethyl
acetate = 3:2, Rf = 0.4). IR v max cm-1: 2956, 2934, 2379, 2310,
1
1562, 1482, 1017. H NMR (CDCl3, 300 MHz, ppm): δ 7.60 (s,
1H), 7.43-7.17 (m, 6H),7.11-7.06 (m, 6H), 7.10-6.92 (m, 2H),
5.77 (s, 1H), 2.87 (spt, J= 6.7 Hz , 2h), 2.27 (s, 3H), 1.20-1.77
(m, 12H). 13C NMR (75 MHz, CDCl3, ppm): δ 155.1, 147.7,
146.3, 140.8, 137.7, 136.4, 131.4, 130.1, 128.3, 127.6, 127.3,
126.6, 125.5, 125.4, 12.7, 124.1, 111.6, 65.4, 50.6, 29.6, 29.2,
21.2, 20.2, 13.9. MS (ESI): m/z (M+H)+ = 474 amu. HRMS
(ESI) calculated for C33H36N3 (M+H)+ 474.29037, found:
474.28637.
4.4.8. 4-(3-(4-methoxyphenyl)-2-phenyl-3,4-dihydroquinazolin-4-
yl)-2,6-dimethylaniline: (7h) Sticky yellow oil. Isolated yield: 75
mg (69%). (Petroleum ether/Ethyl acetate = 3:2, Rf = 0.5). IR v
max cm-1: 2923, 2852, 2379, 2311, 1545, 1491, 1378, 1491, 1378,
Acknowledgements
R.A.K, A.S, G.S and P.S thank Council of Scientific and
Industrial Research (CSIR-India) and University Grants
Commission (UGC-India) for the award of Research Fellowships
and K.R.R thank CSIR for financial support under net-work
project CSC-0123.
1
1284, 1254. H NMR (CDCl3, 300 MHz, ppm): δ 7.60-7.57 (m,
2H), 7.28-7.20 (m, 4H), 7.11-6.96 (m, 4H), 6.85 (d, J = 9.0 Hz,
2H), 6.61 (d, J = 9.0 Hz, 1H), 5.61 (s, 1H), 3.68 (s, 3H), 2.12 (s,
6H). 13C NMR (CDCl3, 125 MHz, ppm): δ 156.8, 155.5, 142.6,
139.0, 134.8, 129.5, 129.4, 128.0, 127.8, 126.6, 126.3, 125.7,
125.6, 124.3, 122.2, 113.7, 66.3, 55.2, 17.7. MS (ESI): m/z
(M+H)+ = 434 amu. HRMS (ESI) calculated for C29H28ON3
(M+H)+: 434.22269, found: 434.22182.
References and notes
1
2
Selected reviews on Palladium catalyzed C-C coupling reaction in
organic synthesis, see: (a) Nicolaou, K. C.; Bulger P. G.; Sarlah, D.
Angew. Chem. Int. Ed. 2005, 44, 4442; (b) Suzuki, A. Angew. Chem.
Int. Ed. 2011, 50, 6723; (c) Kambe, N.; Iwasakia, T.; Teraob, J. Chem.
Soc. Rev. 2011, 40, 4937; (d) Seechurn, C. C. C. J.; Kitching, M. O.;
Colacot T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062.
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2012, 45, 788; (b) Neufeldt S. R.; Sanford, M. S. Acc. Chem. Res. 2012,
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Angew. Chem. Int. Ed. 2012, 51, 10236; (d) Arockiam, P. B.; Bruneau
C.; and Dixneuf, P. H. Chem. Rev. 2012, 112, 5879; (e) Song, G.;
Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651; (f) Rouquet G.;
Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726; (g) Murahashi S.-
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(j) Yeung C. S.; Dong V. M. Chem. Rev. 2011, 111, 1215; (k) Liu, C.;
Zhang, H.; Shi W.; Lei, A. Chem. Rev. 2011, 111, 1780; (l) Klussmann
M.; Suresh kumar, D. Synthesis, 2011, 353; (m) Zhang, S.-Y.; Zhang,
F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40, 1937; (n) Wendlandt, A. E.;
Suess, A. M.; Stahl, S. S. Angew. Chem. Int. Ed. 2011, 50, 11062; (o)
Shi L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687; (p) Zhang, C.; Tang C.
; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464; (q) Yamaguchi, J.;
Yamaguchi A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960; (s)
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4.4.9. 2,6-dimethyl-4-(3-phenyl-2-m-tolyl-3,4-dihydroquinazolin-
4-yl)aniline: (7i) Pale yellow solid. m.p. 112-114 C. Isolated
o
yield: 90 mg (86%). (Petroleum ether/ethyl acetate = 3:2, Rf =
0.5). IR v
cm-1: 2923, 2854, 2318, 2311, 1545,1491, 1378,
max
1
1251, 1218, 1149. H NMR (CDCl3, 300 MHz, ppm): δ 7.60 (s,
1H), 7.50-7.47 (m, 1H),7.28-7.23 (m, 3H), 7.11-6.94 (m, 10H),
5.68 (s, 1H), 2.29 (s, 3H), 2.12 (s, 6H). 13C NMR (125 MHz,
CDCl3, ppm): δ 155.37, 146.2, 142.5, 137.8, 134.8, 130.3, 130.2,
128.4, 127.7, 126.7, 125.5, 124.6, 124.1, 124.0, 119.9, 66.0, 29.6,
29.6, 27.9, 22.3, 21.2. MS (ESI): m/z (M+H)+ = 418 amu. HRMS
(ESI) calculated for C29H28N3 (M+H)+: 418.22777, found:
418.22466.
4.4.10.
4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-2,6-
o
diethylaniline: (7j) Pale Yellow solid. m.p. 82-84 C. Isolated
yield: 100 mg (92%). (Petroleum ether/Ethyl acetate = 3:2, Rf =
0.5). IR v max cm-1: 2966, 2935, 2928, 2378, 2310, 1545, 1455,
1
1386, 1284, 1248, 1153. H NMR (CDCl3, 300 MHz, ppm): δ
7.65-7.63 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.27-7.26 (m, 4H),
7.12-7.06 (m, 6H), 6.97-6.94 (m, 3H), 5.73 (s, 1H), 3.62 (bs, 2H),
2.47 (q, J = 7.4 Hz, 4H), 1.17 (t, J = 7.6 Hz, 6H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 155.3, 146.1, 141.5, 134.9, 130.3,
129.6, 128.6, 128.6, 128.2, 128.1, 127.9, 127.6, 127.2, 125.8,
125.7, 125.0, 124.7, 124.6, 124.4, 123.3, 69.0,24.39, 13.0. MS
(ESI): m/z (M+H)+ = 432 amu. HRMS (ESI) calculated for
C30H30N3 (M+H)+: 432.24342, found:432.24283.
3
4
5
6
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4-(2,3-diphenyl-3,4-dihydroquinazolin-4-yl)-2,6-
diisopropylaniline: (7k) Pale yellow solid. m.p. 204-206 oC.
Isolated yield: 70 mg (61%). (Petroleum ether/Ethyl acetate =
3:2, Rf = 0.5). IR v max cm-1: 2960, 2923, 2378, 2312, 1585, 1545,
7
1
1493 1386, 1283, 1249. H NMR (CDCl3, 300 MHz, ppm): δ
7.69-7.67 (m, 2H), 7.30-7.23 (m, 5H), 7.17-7.08 (m, 6H), 7.00-
6.93 (m, 3H), 5.79 (s, 1H), 2.88 (spt, J = 6.8 Hz, 2H), 1.21-1.18
(m, 12H). 13C NMR (CDCl3, 125 MHz, ppm): δ 155.5, 140.2,

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ACCEPTED MANUSCRIPT
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