Br?nsted acid mediated cyclizations of ortho-aryl(ethynyl)pyrimidines

Article abstract of DOI:10.1016/j.tet.2017.05.070

A high-yielding procedure for the synthesis of 5-aryl-4-(arylethynyl)pyrimidines from easily available 2-aryl-3-hydroxyacrylates is reported. These pyrimidines readily undergo cyclization in strong Br?nsted acids and, depending on the substitution in alky

Full text of DOI:10.1016/j.tet.2017.05.070

Accepted Manuscript
Brønsted acid mediated cyclizations of ortho-aryl(ethynyl)pyrimidines
Aleksandr N. Shestakov, Alena S. Pankova, Pavel Golubev, Alexander F. Khlebnikov,
Mikhail A. Kuznetsov
PII:
S0040-4020(17)30571-9
10.1016/j.tet.2017.05.070
TET 28736
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2017
Revised Date: 6 May 2017
Accepted Date: 19 May 2017
Please cite this article as: Shestakov AN, Pankova AS, Golubev P, Khlebnikov AF, Kuznetsov MA,
Brønsted acid mediated cyclizations of ortho-aryl(ethynyl)pyrimidines, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.05.070.
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Graphical Abstract
Brønsted acid mediated cyclizations of ortho-aryl(ethynyl)pyrimidines

ACCEPTED MANUSCRIPT
Brønsted acid mediated cyclizations of ortho-aryl(ethynyl)pyrimidines
Aleksandr N. Shestakov, Alena S. Pankova, Pavel Golubev, Alexander F. Khlebnikov, and
Mikhail A. Kuznetsov*
Institute of Chemistry, Saint Petersburg State University, Universitetsky pr. 26, Saint Petersburg
198504 Russia. E-mail: m.kuznetsov@spbu.ru
Abstract: A high-yielding procedure for the synthesis of 5-aryl-4-(arylethynyl)pyrimidines from
easily available 2-aryl-3-hydroxyacrylates is reported. These pyrimidines readily undergo
cyclization in strong Brønsted acids and, depending on the substitution in alkynylpyrimidines
and the water content of the reaction mixture, yield either benzo[f]quinazolines or derivatives of
spiro[cyclohexa-2,5-diene-1,5’-cyclopenta[d]pyrimidin]-4-one. In most cases the cyclization
proceeds nearly quantitatively. DFT calculations support the proposed mechanisms induced by
the protonation of the triple bond in 5-aryl-4-(arylethynyl)pyrimidines. Fluorescent properties of
the obtained heterocycles are also described.
Keywords: cyclization; homogeneous catalysis; pyrimidines; benzo[f]quinazolines; alkynes
Introduction
Cyclization is a widely utilized, powerful and atom economical strategy to fused carbo- and
heterocycles.1-5 Namely, one such approach relies on transition-metal-catalyzed cyclization of
ortho-alkynylated biaryl derivatives.1 Other approaches use base2 or acid3 catalysis, oxidative
radical,4 or pyrolytic5 methods. Most of the published work described cyclizations of
alkynylcarbocycles and only rare examples of cycloisomerization of ortho-
alkynyl(aryl)heteroarenes are known.1a,c,5,6 Our interest in ethynylpyrimidines7 led us to utilize
these substrates in cycloisomerization towards benzoquinazolines; the latter heterocycles are
interesting as they exhibit a wide range of biological activities.8 In addition, a number of patents
on the preparation of benzoquinazolines target their application in organic electroluminescent
devices.9 Benzo[f]quinazolines are usually prepared from naphthylamine,8b,10 naphthalene8h,11 or
tetralone12 derivatives and nitrogen containing compounds; a multi-step approach using a
preformed pyrimidine was also described.13 A recent one-pot synthesis of benzo[f]quinazolines
from aliphatic nitriles and diynes requires severe reaction conditions (120 °C for 12 h) and gives
only modest yields.14 Here, we present a new synthetic strategy to 5-aryl-4-
(arylethynyl)pyrimidines and demonstrate that Brønsted acids efficiently induce
cycloisomerization of these compounds to benzo[f]quinazolines.
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Results and Discussion
Condensation of amidines with various 1,3-dielectrophiles is the most general and commonly
used approach to the pyrimidine core. Since readily available alkyl 2-aryl-3-hydroxyacrylate
electrophiles were once briefly mentioned in this context,15 we started by optimizing conditions
for the condensation of ester 1a with benzamidine 2 and identified acetonitrile as the solvent of
choice (see ESI for comparison of different solvents). We then utilized this reaction for the
preparation of several 5-aryl-2-phenylpyrimidin-4-ones 3a-e (Table 1). The nature of the aryl
substituent in esters 1 did not affect the reaction time or the yield of pyrimidinones 3. Treatment
of pyrimidin-4-ones 3a-e with POCl3 in DMF at 70 °C for 15 min provided 4-chloropyrimidines
4a-e in nearly quantitative yields. In order to simplify the synthesis of chloropyrimidines 4, we
performed both steps in a one-pot fashion, as exemplified for 4d that was isolated in a 94% yield
after a mixture of ester 1d and benzamidine 2 was heated in CH3CN followed by addition of
POCl3 and DMF.
Table 1. Synthesis of chloropyrimidines 4a-e.
R1
R2
OH
CH3CN
CO2Et
HN
NH2
+
40 oC, 2 h
O
R1
Ph
R2
N
NH
Ph
3a-e
1a-e
2
R1
R2
Cl
POCl3, DMF
70 oC, 15 min
4a-e
N
N
Ph
Ester R1
R2
Pyrimidinone,
Chloropyrimidine,
isolated yield (%) isolated yield (%)
H
Me
Cl
H
H
H
3a (94)
3b (89)
3c (86)
3d (94)
4a (96)
4b (95)
1a
1b
1c
4c (96)
1da
1ea
OMe H
OMe OMe 3e (90)
4d (97, 94b)
4e (95)
a Methyl ester.
b Over two steps without isolation of pyrimidinone 3d.
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Although chloroarenes are poor electrophiles, chloropyrimidines do engage in cross-coupling
reactions.16 Standard conditions for the Sonogashira coupling convert chloropyrimidines 4a-e
and arylacetylenes 5a,b to 5-aryl-4-(arylethynyl)pyrimidines 6a,b,d-g in good yields (72–81%)
(Table 2). The yield was lower when electron-deficient (4-nitrophenyl)acetylene 5c was used.
We found that DMF is the solvent of choice with phenylacetylene (5a), while reactions with
arylacetylenes 5b,c provide higher yields in acetonitrile. The electron-rich 6g was obtained in
31% yield in DMF and in 73% yield in CH3CN.
Table 2. Synthesis of pyrimidines 6a-h.
R1
R1
NO2
R2
R2
R3
R3
cond.a
cond.a
+
+
PhI
Cl
20 h
3 h
N
N
N
N
N
N
Ph
7
Ph
4a-e
Ph
5a-c
6a-h
8
Entry Halide R1
R2
Arylacetylene R3
Solvent Isolated yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
Me
Cl
OMe H
OMe OMe
OMe OMe
H
H
H
H
H
H
DMF
6a (79)
4a
4a
4a
4b
4c
4d
4e
4e
8
5a
5b
5c
5a
5a
5a
5a
5a
7
OMe CH3CN 6b (72)b
NO2 CH3CN 6c (43)
H
H
H
H
H
H
DMF
DMF
DMF
DMF
CH3CN 6g (73)b
CH3CN 6h (39)
6d (81)
6e (75)
6f (74)
6g (31)
NO2
H
a Reaction conditions: Pd(PPh3)2Cl2 (5 mol%), CuI, Et3N, 80 °C.
b Reaction time 6 h.
Unfortunately, synthetic protocols described above failed for ethyl 3-hydroxy-2-(4-
nitrophenyl)acrylate and therefore an alternative strategy was used for pyrimidine 6h. Pyrimidine
7 was prepared according to the literature method7 and coupled with iodobenzene to furnish 6h
in 39% yield (Table 2, entry 9).
To our delight, pyrimidines 6a,b,d,e smoothly cyclize into benzo[f]quinazolines 9a,b,d,e in
trifluoromethanesulfonic acid (TfOH) at room temperature within 2 h (Table 3).
The impact of both strong electron-withdrawing and donating substituents on the reaction
efficiency is worth noting. Electron-deficient substrates 6c,h were far less active and 4-
nitrophenyl group at the triple bond completely deactivated pyrimidine 6c towards cyclization as
the reaction did not occur even upon prolonged heating (Table 3, entry 3). When R1 is a nitro
group (6h) the cyclization is not completely suppressed and benzo[f]quinazoline 9h was obtained
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after 24 h at 50 °C in 20% yield along with a complex mixture of byproducts (traces of 9h were
observed when the reaction was run at room temperature overnight) (Table 3, entry 9). Note that
adverse influence of electron-withdrawing groups is known for the transition-metal catalyzed
cycloisomerization and only a few examples of successful alkenylation of electron-deficient
ortho-ethynylbiaryls were described.1c
Table 3. Cyclization of pyrimidines 6 in TfOH.
Entry Pyrimidine R1
R2
R3
H
Benzoquinazoline, Cyclohexadienone,
isolated yield (%) isolated yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
Me
Cl
H
H
H
H
H
9a (97)
0
6a
6b
6c
6d
6e
6f
6g
6g
6h
OMe 9b (95)
NO2
H
H
H
0
0
0
9d (98)
9e (97)
0
0
0
OMe H
OMe OMe H
OMe OMe H
10f (98)
9g (32)
9g (87)a
9h (20)b
10g (65)
0
0
NO2
H
H
a Reaction was carried out at 0 °C.
b Reaction was carried out at 50 °C for 24 h.
On the other hand, 4-methoxy group in the phenyl ring at C-5 in 6f changed the reaction pathway
dramatically (Table 3, entry 6). No benzo[f]quinazoline was formed, and the single isolated
product was spirocyclic 10f. The most characteristic spectral features of 10f are two multiplets (δ
6.62-6.65 and 6.68-6.71 ppm) of four cyclohexadiene protons and the signal of the spiro carbon
atom (δ 57.0 ppm). Compared to benzo[f]quinazoline 9a (H1 (δ 10.16 ppm), H5 (δ 7.92 ppm)),
the corresponding proton signals of 10f (H4’ (δ 8.42 ppm), H7’ (δ 7.59 ppm)) are shifted upfield.
Finally, the structure of 10f was confirmed by X-ray analysis (Figure 1).17 Both phenyl rings are
slightly turned off the plane of the bicyclic core (torsion angles ca. 12°).
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Figure 1. Olex2 representation of compound 10f crystal structure. Thermal ellipsoids are drawn
at 50% probability level.
To further compare these two cyclization pathways, we tested pyrimidine 6g with two methoxy
groups (Table 3, entries 7,8). The presence of a meta-methoxy group activates both ortho-
positions of the aryl substituent that could lead to the competitive formation of three products,
and two of them were indeed observed under the standard reaction conditions: the mixture of 9g
and 10g was obtained in a 1:2 ratio (97% total yield). The same reaction carried out at 0 °C
furnished 9g as a sole product in 87% yield. Complete regioselective cycloisomerization into 9g
should be noted because only one of two possible regioisomers was formed by attack on the
para- rather than ortho-position to the second methoxy group (R = OMe).
Next, we explored if less expensive acids could substitute TfOH and subjected 6a to several
Brønsted and Lewis acids (see ESI for details). Trifluoroacetic acid is ineffective even at
elevated temperature, however, we obtained high yields of 9a using sulfuric and polyphosphoric
acids. High viscosity of the latter impedes its utilization and thus sulfuric acid is preferable.
Lewis acids (PtCl2, AlCl3, InCl3) were completely inactive in this reaction.
Scheme 1. Formation of enol 11 from pyrimidine 6c.
Cyclizations of other pyrimidines in sulfuric acid were then attempted and the results of these
reactions were not always the same as in TfOH. Specifically, while unreactive in TfOH,
pyrimidine 6c furnished enol 11 in 81% yield after 2 h at 80 °C in concentrated sulfuric acid
(Scheme 1). Addition of water, which is present in conc. H2SO4 (98% grade), to the electron-
deficient triple bond of pyrimidine 6c proceeded regioselectively and the position of the hydroxy
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group was confirmed by 13C-1H HSQC and HMBC spectra. It means that the initial protonation
occurred on the same atom of the triple bond as for other substrates (see below) despite the
electron-withdrawing 4-nitrophenyl group that facilitated hydration rather than cyclization.
Conjugated enol 11 is apparently more favorable than the keto form because no signs of keto
tautomer were found in its 1H NMR spectrum.
Treating chloro-substituted pyrimidine 6e with concentrated sulfuric acid at 20 °C surprisingly
provided spiro-fused 10f as a single product (82% yield) with no trace of 8-
chlorobenzo[f]quinazoline 9e (Scheme 2). Thus the nature of acid completely changes the
reaction course in this case. Assuming the crucial role of water in this unusual transformation,
we cyclized pyrimidine 6e in TfOH having added a drop of water (ca. 10%) and obtained a
mixture of benzo[f]quinazoline 9e and spirocompound 10f in a 1:0.9 ratio (84% total yield).
Scheme 2. Cyclization of pyrimidine 6e in H2SO4.
Based on these results, mechanistic scenarios could be proposed for both transformations
(Scheme 3). The first step is a protonation of the triple bond leading to a vinyl cation 12
stabilized by conjugation with an aryl group. Pathway A includes electrophilic substitution at the
ortho-position of the aromatic ring at pyrimidine C-5 atom, resulting in the formation of the
conjugated fused tricyclic system of benzo[f]quinazoline 9. This process is still feasible even in
the presence of electron-withdrawing substituent R. But if R = OMe or Cl, these +M groups
activate by conjugative stabilization the ipso-position of the aromatic ring towards an
electrophilic attack of the intermediate cation (pathway B). The nucleophilic substitution of the
R group by the water molecule occurs during aqueous quenching to furnish nonaromatic
cyclohexadienone 10.
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Scheme 3. Plausible reaction mechanisms.
1
Supporting these hypotheses, the H NMR spectrum of pyrimidine 6e in TfOH matches the
structure of benzoquinazoline 9e with two protonated pyrimidine nitrogen atoms (downfield
signals of NH protons at δ > 13 ppm) (Figure 2).18 A dication also forms from pyrimidine 6f in
TfOH and its full signal assignment is presented in Figure 2 (see ESI for details). In this spiro
cation, still bearing the methoxy group, the partial double bond character of the C–O bond
provides two inequivalent faces of the cyclohexadiene moiety.
9.8 Hz
5.11
8.17
8.24
67.8
125.7 165.8
8.00
142.1
Cl
O
7.76
132.35
8.39
9.09
8.62
195.3
7.84
132.30
Ph
7.82
131.6
131.4
181.7
7.85
60.9
128.6
8.00
160.0
8.43
10.54
8.44
124.1
6.7 Hz
170.5
8.62
141.7
N
N
N
N
161.8
13.69
13.66
H
H
13.38
H
122.1
8.39
8.04
8.25
131.2
8.00
8.23
132.8
8.23
141.9
Figure 2. Signal assignment of dications formed from pyrimidines 6e (left) and 6f (right) in
TfOH according to the NMR spectra (proton chemical shifts are in regular font, these of carbons
– in italic).
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Similar ipso-cyclizations of phenol derivatives leading to spirocyclohexadienones were
previously reported under oxidative conditions19 or upon catalysis with transition metals.20 Only
a few examples of radical21 and electrophilic22 ipso-cyclization of chloro-substituted substrates
were described. In contrast to iodine reagents commonly used for cyclizations of arylalkynes,
TfOH (or H2SO4) activates the triple bond without introduction of any additional functional
group into the product, which could be useful in some synthetic strategies.
Iodonium-ion-induced ipso-cyclizations supposedly follow a similar mechanism for the
methoxy-substituted substrates although with a different last step, i.e., the transfer of a methyl
cation to the external nucleophile.6c,19e Weak nucleophilic properties of TfO¯ and HSO4¯ anions
and, more importantly, involvement of chloro-substituted pyrimidine in this transformation and
the key role of water led us to propose the hypothesis above that substitution of the whole
methoxy group takes place instead of the elimination of a methyl cation from the oxygen atom.23
Retention of the methyl group at the oxygen atom in the spiro cation from pyrimidine 6f in TfOH
confirms our speculations.
Thus, the presence of a +M group in the para-position of the aromatic ring governs the reaction
regioselectivity and accounts for the formation of the spirosystem despite dearomatization.
Electron-rich pyrimidine 6f follows manifold B in both TfOH and H2SO4. Substrate 6g is
activated by the two methoxy groups for both reaction pathways. Indeed, both products form at
room temperature, with spirocompound 10g being major, while at lower temperature the ratio
changes in favor of the aromatic 9g (Table 3, entry 8). A less M-donating R = Cl in pyrimidine
6e allows both transformations to occur such that in concentrated sulfuric acid the ipso-
cyclization into spirocyclic 10f via chlorine substitution is facilitated by water, whereas
formation of benzoquinazoline 9e is preferred in anhydrous TfOH.
In order to evaluate our mechanistic hypothesis, we assessed the reaction barriers and energies of
the proposed cationic intermediates by DFT quantum chemical calculations at the B3LYP/6-
31+g(d,p) level of theory with full geometry optimization. Firstly, the transformation pathways
of arylvinyl cation 12e from pyrimidine 6e were estimated in both sulfuric acid and water
(Figure 3; data for the corresponding dication is in ESI). Relatively small alterations of solvent
properties nearly do not influence the energies. Thus, all the calculations may be extended to
TfOH as its dielectric constant has to be closer to that of H2SO4.
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Figure 3. Energy profiles for the transformations of arylvinyl cation 12e. Relative Gibbs free
energies (in kcal mol–1, 298 K, PCM model for H2SO4 or H2O (data in parenthesis)) computed at
the B3LYP/6-31+g(d,p) level.
The barrier for ipso-cyclization of 12e into 14e is less than that of ortho-cyclization into 13e,
implying that spirocyclic 14e is a kinetic product. Assuming a subsequent irreversible
hydrolysis, this is the major reaction pathway. However, isomeric product 13e is significantly
more stable than 14e (by ca. 15 kcal mol–1) and, given the shallow transition states, the ortho-
attack to 13e is thermodynamically favored. Indeed, only diprotonated 8-
chlorobenzo[f]quinazoline 9e was observed in the 1H NMR spectrum of pyrimidine 6e in TfOH,
whereas in H2SO4, the kinetical spiro-cation readily affords spirocyclic 10f upon water
treatment. The experimental outcome of the reaction in wet TfOH also supports these
speculations.
No energy barrier was found for the ipso-cyclization of vinyl cation 12f from methoxy-
substituted pyrimidime 6f to spiro-cation 14f which is more stable by 14.4 kcal mol–1 (Figure 4).
This is in agreement with the formation of the spiro-cation from pyrimidine 6f in TfOH observed
by NMR and exclusive isolation of spirocyclic 10f.
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Figure 4. Energy profile for the transformation of cation 12f. Relative Gibbs free energies (in
kcal mol–1, 298 K, PCM model for H2O) computed at the B3LYP/6-31+g(d,p) level.
Formation of enol 11 from 4-(4-nitrophenylethynyl)pyrimidine 6c in sulfuric acid is also
supported by DFT calculations (Figure 5). Addition of the water molecule to vinyl cation is
favored for 6c because hydrate 16c is more stable than complex of 12c with water (by 6.7 kcal
mol–1) and the activation barrier is low. Once 16c is formed, it could easily eliminate proton to
give 11. In contrast, unfavorable hydration of protonated phenylethynylpyrimidine 12e allows
for its cyclization.
Figure 5. Energy profiles for the transformations of complexes of cations 12c and 12e with H2O
into the corresponding hydrates 16c,e. Relative Gibbs free energies (in kcal mol–1, 298 K, PCM
model for H2O) computed at the B3LYP/6-31+g(d,p) level.
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Finally, we recorded UV−vis spectra of synthesized heterocycles. The absorption maxima were
observed at 288-304 nm for benzoquinazolines 9, and at 276-278 nm for compounds 10 (see
ESI). Nitro-substituted benzo[f]quinazoline 9h had the lowest emission intensity while the
highest one was observed for dimethoxysubstituted compound 9g. For the latter we estimated the
fluorescence quantum yield following a reported procedure24 as 8±1%; a direct measurement on
a quantum sphere gave Φ value of 5.3%.
Conclusions
We have developed an efficient four-step protocol to 3,6-diarylbenzo[f]quinazolines (overall
yields are typically 54–69%). The key step is a cyclization of 5-aryl-4-(arylethynyl)pyrimidines
mediated by strong Brønsted acids, which proceeds smoothly and regioselectively leading to
targeted benzo[f]quinazolines in most cases. Selectivity of this reaction is governed by a
substituent in the phenyl ring at the C-5 atom of the alkynylpyrimidine. While substituents with
weak electronic effects and even strong electron-withdrawing groups allow for the formation of
the benzoquinazoline core, +M substituents (OMe and even Cl) change the reaction pathway to
spiro[cyclohexa-2,5-diene-1,5’-cyclopenta[d]pyrimidin]-4-one derivatives. ipso-Cyclization in
the latter case occurs via a nucleophilic substitution of these substituents by the water. para-
Nitrophenyl ring at the triple bond completely inhibits the cyclization yielding a selective
hydration of the triple bond. The resulting benzo[f]quinazolines exhibit fluorescence under UV
irradiation.
Experimental
General Information: NMR spectroscopic data were recorded in CDCl3 and DMSO-d6 and
were referenced to the solvent residual proton (δH = 7.26 and 2.50 ppm, respectively) and carbon
signals (δC = 77.16 and 39.52 ppm, respectively). UV−vis spectra were recorded for 10−5
M
solutions in CH2Cl2. Methyl 3-hydroxy-2-(3,4-dimethoxyphenyl)acrylate (1e) was prepared
according to the literature procedure.15b DFT B3LYP/6-31+g(d,p) quantum chemical
calculations25-27 were performed using Gaussian 09.28 Geometric parameters were optimized
according to the polarizable continuum model (PCM) for sulfuric acid and water. Stationary
points were identified as energy minima by calculating Hessian matrices.
General procedure for the preparation of 2-aryl-3-hydroxyacrylates 1a-d. Sodium hydride
(60% in oil, 6.0 g, 0.15 mol) was added portionwise over a period of 15 min to an ice-cold
mixture of arylacetate (0.03 mol) and ethyl formate (22.2 g, 0.30 mol) in dry Et2O (150 mL).
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Once addition was complete, cooling bath was removed and the reaction mixture was left at
room temperature for 12 h and then carefully poured into cold water (200 mL). The biphasic
mixture was acidified with small portions of conc. aq. HCl until steady pH 2-3 was achieved.
Layers were separated, organic phase was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure to dryness. Hydroxyacrylates 1a29 (yield 81%) and 1b29
(90%) were purified by distillation. Compounds 1c29 (70%) and 1d30 (75%) were washed by
decantation with several small portions of cold petroleum ether. Characterization data are given
in ESI.
General procedure for the preparation of 5-aryl-2-phenylpyrimidin-4-ones 3a-e. A stirred
mixture of ethyl 2-aryl-3-hydroxyacrylate 1a-e (2.0 mmol) and benzamidine (2) (240 mg, 2.0
mmol) in CH3CN (4 mL) was heated at 40 °C for 2 h. Upon completion, the solvent was
evaporated under reduced pressure and the residue was washed with cold CH2Cl2 (2×3 mL) to
provide pyrimidinones 3a-e. We were unable to record 13C NMR spectra of these compounds
because of their poor solubility.
2,5-Diphenylpyrimidin-4(3H)-one (3a).16 Colorless solid; yield 466 mg (94%); mp 290–291 °C
1
(dec.). H NMR (400 MHz, DMSO-d6): δ = 7.34–7.38 (m, 1 H), 7.42–7.45 (m, 2 H), 7.52–7.61
(m, 3 H), 7.78 (d, J = 7.5 Hz, 2 H), 8.17 (d, J = 7.0 Hz, 2 H), 8.30 (s, 1 H) ppm. HRMS (ESI):
calcd. for C16H13N2O 249.1022 [M + H]+; found 249.1027.
5-(4-Methylphenyl)-2-phenylpyrimidin-4(3H)-one (3b). Colorless solid; yield 466 mg (89%);
mp 295–296 °C (dec.). 1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 7.24 (d, J = 8.0 Hz, 2
H), 7.52–7.59 (m, 3 H), 7.68 (d, J = 8.0 Hz, 2 H), 8.16 (d, J = 7.0 Hz, 2 H), 8.28 (s, 1 H) ppm.
HRMS (ESI): calcd. for C17H15N2O 263.1179 [M + H]+; found 263.1185.
5-(4-Chlorophenyl)-2-phenylpyrimidin-4(3H)-one (3c). Colorless solid; yield 485 mg (86%);
mp >300 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.49 (d, J = 8.5 Hz, 2 H), 7.52–7.59 (m, 3 H),
7.85 (d, J = 8.5 Hz, 2 H), 8.18 (d, J = 7.0 Hz, 2 H), 8.34 (s, 1 H) ppm. HRMS (ESI): calcd. for
C16H12ClN2O 283.0633 [M + H]+; found 283.0630.
5-(4-Methoxyphenyl)-2-phenylpyrimidin-4(3H)-one (3d). Colorless solid; yield 522 mg
1
(94%); mp 285–286 °C. H NMR (400 MHz, DMSO-d6): δ = 3.80 (s, 3 H), 6.99–7.01 (m, 2 H),
7.49–7.57 (m, 3 H), 7.74–7.77 (m, 2 H), 8.14–8.17 (m, 2 H), 8.27 (s, 1 H) ppm. HRMS (ESI):
calcd. for C17H15N2O2 279.1128 [M + H]+; found 279.1134.
5-(3,4-Dimethoxyphenyl)-2-phenylpyrimidin-4(3H)-one (3e).31 Colorless solid; yield 554 mg
(90%); mp 230–231 °C (dec.). 1H NMR (400 MHz, DMSO-d6): δ = 3.79 (s, 3 H), 3.80 (s, 3 H),
12

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7.01 (d, J = 9.0 Hz, 1 H), 7.39–7.41 (m, 2 H), 7.52–7.59 (m, 3 H), 8.16 (d, J = 7.0 Hz, 2 H), 8.32
(s, 1 H) ppm. HRMS (ESI): calcd. for C18H17N2O3 309.1234 [M + H]+; found 309.1239.
General procedure for the preparation of 5-aryl-4-chloro-2-phenylpyrimidines 4a-e. POCl3
(0.5 mL, 0.8 g, 5 mmol) was added to a suspension of pyrimidinone 3a-e (2.0 mmol) in DMF (4
mL) and the reaction mixture was stirred at 70 °C for 15 min. Then the reaction mixture was
cooled to room temperature, poured into cold water (30 mL), and extracted with Et2O (3×10
mL). The combined extracts were washed with water (2×10 mL) and dried over Na2SO4. Solvent
was evaporated under reduced pressure to provide pure pyrimidines 4a-e.
4-Chloro-2,5-diphenylpyrimidine (4a).32 Colorless solid; yield 512 mg (96%); mp 123–124 °C.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.55 (m, 8 H), 8.48–8.52 (m, 2 H), 8.71 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 128.6, 128.82, 128.84, 129.1, 129.5, 131.6, 132.1, 134.1, 136.2,
158.5, 159.5, 164.1 ppm. HRMS (ESI): calcd. for C16H12ClN2 267.0684 [M + H]+; found
267.0689.
4-Chloro-5-(4-methylphenyl)-2-phenylpyrimidine (4b). Colorless solid; yield 534 mg (95%);
mp 118–119 °C. 1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.43
(d, J = 8.0 Hz, 2 H), 7.50–7.54 (m, 3 H), 8.48–8.51 (m, 2 H), 8.70 (s, 1 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 21.5, 128.6, 128.8, 129.3, 129.5, 131.1, 131.5, 132.0, 136.2, 139.1, 158.5,
159.5, 163.8 ppm. HRMS (ESI): calcd. for C17H14ClN2 281.0840 [M + H]+; found 281.0847.
4-Chloro-5-(4-chlorophenyl)-2-phenylpyrimidine (4c). Colorless solid; yield 577 mg (96%);
mp 148–149 °C. 1H NMR (400 MHz, CDCl3): δ = 7.44–7.54 (m, 7 H), 8.47–8.50 (m, 2 H), 8.67
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 128.7, 128.9, 129.1, 130.8, 131.0, 131.7, 132.5,
135.4, 136.0, 158.3, 159.4, 164.4 ppm. HRMS (ESI): calcd. for C16H11Cl2N2 301.0294 [M + H]+;
found 301.0303.
4-Chloro-5-(4-methoxyphenyl)-2-phenylpyrimidine (4d). Colorless solid; yield 576 mg
(97%); mp 142–143 °C. 1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3 H), 7.02–7.06 (m, 2 H),
13
7.45–7.49 (m, 2 H), 7.49–7.53 (m, 3 H), 8.46–8.50 (m, 2 H), 8.69 (s, 1 H) ppm. C NMR (100
MHz, CDCl3): δ = 55.5, 114.3, 126.2, 128.5, 128.8, 130.8, 131.4, 131.8, 136.2, 158.4, 159.5,
160.3, 163.6 ppm. HRMS (ESI): calcd. for C17H14ClN2O 297.0789 [M + H]+; found 297.0799.
4-Chloro-5-(3,4-dimethoxyphenyl)-2-phenylpyrimidine (4e). Colorless solid; yield 621 mg
(95%); mp 146–147 °C. 1H NMR (400 MHz, CDCl3): δ = 3.94 (s, 3 H), 3.95 (s, 3 H), 6.99 (d, J =
8.0 Hz, 1 H), 7.05-7.09 (m, 2 H), 7.49–7.52 (m, 3 H), 8.46–8.49 (m, 2 H), 8.71 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 56.1, 56.2, 111.4, 112.7, 122.2, 126.5, 128.5, 128.8, 131.5, 131.9,
13

ACCEPTED MANUSCRIPT
136.2, 149.1, 149.9, 158.4, 159.4, 163.7 ppm. HRMS (ESI): calcd. for C18H16ClN2O2 327.0895
[M + H]+; found 327.0901.
One-pot preparation of 4-chloro-5-(4-methoxylphenyl)-2-phenylpyrimidine 4d. A stirred
mixture of methyl 3-hydroxy-2-(4-methoxylphenyl)acrylate (1d) (832 mg, 4.0 mmol) and
benzamidine (2) (480 mg, 4.0 mmol) in CH3CN (8 mL) was heated at 40 °C for 2 h. Upon
completion, DMF (1 mL) and POCl3 (1 mL, 1.6 g, 10 mmol) were added and the reaction
mixture was stirred at 70 °C for 15 min. Then the reaction mixture was cooled to room
temperature, poured into cold water (60 mL), and extracted with Et2O (3×15 mL). The combined
extracts were washed with water (2×10 mL), dried over Na2SO4. Solvent was evaporated under
reduced pressure to provide pure 4-chloro-5-(4-methoxylphenyl)-2-phenylpyrimidine (4d). Yield
1.12 g (94%).
General procedures for the preparation of 5-aryl-4-(arylethynyl)-2-phenylpyrimidines 6a-
g.
Method A: Degassed DMF (5 mL) was added to a mixture of 5-aryl-4-chloro-2-
phenylpyrimidine 4a-e (0.5 mmol), Pd(PPh3)2Cl2 (17.6 mg, 5 mol %) and CuI (4.8 mg, 5 mol %)
under atmosphere of argon. The flask was sealed with rubber septum and flushed with argon,
then phenylacetylene (5a) (56 mg, 0.061 mL, 0.55 mmol) and Et3N (0.174 mL, 1.25 mmol) were
added via syringe. The reaction mixture was stirred at 80 °C for 20 h, cooled to room
temperature, poured into water (50 mL) and extracted with EtOAc (3×10 mL). The combined
extracts were washed with water (2×5 mL) and dried over Na2SO4. Solvent was evaporated and
the residue was purified by column chromatography on silica (hexane/EtOAc, 10:1) to provide
pure pyrimidines 6a,d-g.
Method B: Degassed CH3CN (5 mL) was added to a mixture of 5-aryl-4-chloro-2-
phenylpyrimidine 4a,e (0.5 mmol), Pd(PPh3)2Cl2 (17.6 mg, 5 mol %) and CuI (4.8 mg, 5 mol %)
under atmosphere of argon. Arylacetylene 5a-c (0.55 mmol) and Et3N (0.174 mL, 1.25 mmol)
were added and the flask was sealed with rubber septum and flushed with argon. The reaction
mixture was stirred at 80 °C for 6 h (for 6c 20 h), cooled to room temperature and evaporated
under reduced pressure. The residue was purified by column chromatography on silica (hexane/
EtOAc, 10:1) to provide pure pyrimidines 6b,c,g.
2,5-Diphenyl-4-(phenylethynyl)pyrimidine (6a). Method A. Colorless solid; yield 131 mg
(79%); mp 146–147 °C. 1H NMR (400 MHz, CDCl3): δ = 7.32–7.41 (m, 3 H), 7.45–7.48 (m, 2
13
H), 7.50–7.57 (m, 6 H), 7.71–7.74 (m, 2 H), 8.52–8.55 (m, 2 H), 8.87 (s, 1 H) ppm. C NMR
(100 MHz, CDCl3): δ = 87.5, 95.9, 121.7, 128.5, 128.6, 128.7, 128.8, 128.9, 129.3, 129.9, 131.0,
14

ACCEPTED MANUSCRIPT
132.5, 133.9, 135.1, 137.2, 148.7, 157.3, 163.6 ppm. HRMS (ESI): calcd. for C24H17N2 333.1386
[M + H]+; found 333.1385.
4-(4-Methoxyphenyl)ethynyl-2,5-diphenylpyrimidine (6b). Method B. Colorless solid; yield
130 mg (72%); mp 187–188 °C (dec.). 1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 6.86 (d, J
= 7.5 Hz, 2 H), 7.40 (d, J = 7.5 Hz, 2 H), 7.52 (br. s, 6 H), 7.71–7.74 (m, 2 H), 8.54 (br. s, 2 H),
8.84 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.5, 86.8, 96.6, 113.7, 114.3, 128.5, 128.6,
128.7, 128.8, 129.3, 130.9, 133.6, 134.2, 135.2, 137.3, 149.0, 157.1, 161.0, 163.5 ppm. HRMS
(ESI): calcd. for C25H18N2NaO 385.1311 [M + Na]+; found 385.1320.
4-(4-Nitrophenyl)ethynyl-2,5-diphenylpyrimidine (6c). Method B, reaction time 20 h. Yellow
solid; yield 81 mg (43%); mp 201-202 °C. 1H NMR (400 MHz, CDCl3): δ = 7.52–7.60 (m, 8 H),
7.68–7.70 (m, 2 H), 8.21 (d, J = 8.5 Hz, 2 H), 8.51–8.54 (m, 2 H), 8.91 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 91.6, 92.5, 123.8, 128.4, 128.5, 128.81, 128.82, 129.2, 129.3, 131.3,
133.1, 134.4, 134.7, 136.9, 147.7, 148.0, 157.7, 163.8 ppm. HRMS (ESI): calcd. for
C24H15N3NaO2 400.1056 [M + Na]+; found 400.1047.
5-(4-Methylphenyl)-2-phenyl-4-(phenylethynyl)pyrimidine (6d). Method A. Yellow solid;
yield 140 mg (81%); mp 126–127 °C. 1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H), 7.33–7.40
(m, 5 H), 7.48–7.54 (m, 5 H), 7.63 (d, J = 8.0 Hz, 2 H), 8.51–8.54 (m, 2 H), 8.86 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.5, 87.7, 95.6, 121.8, 128.5, 128.6, 128.7, 129.1, 129.4,
129.8, 130.9, 132.1, 132.4, 133.8, 137.2, 138.9, 148.5, 157.4, 163.3 ppm. HRMS (ESI): calcd.
for C25H19N2 347.1543 [M + H]+; found 347.1551.
5-(4-Chlorophenyl)-2-phenyl-4-(phenylethynyl)pyrimidine (6e). Method A. Colorless solid;
yield 137 mg (75%); mp 200–201 °C (dec.). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.42 (m, 3
H), 7.47–7.53 (m, 7 H), 7.67 (d, J = 8.0 Hz, 2 H), 8.53 (br. s, 2 H), 8.83 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 87.2, 96.2, 121.5, 128.6, 128.7, 128.8, 129.0, 130.1, 130.6, 131.2, 132.5,
132.7, 133.6, 135.2, 137.0, 148.6, 157.2, 163.9 ppm. HRMS (ESI): calcd. for C24H16ClN2
367.0997 [M + H]+; found 367.0997.
5-(4-Methoxyphenyl)-2-phenyl-4-(phenylethynyl)pyrimidine (6f). Method A. Colorless solid;
yield 134 mg (74%); mp 166–167 °C. 1H NMR (400 MHz, CDCl3): δ = 3.90 (s, 3 H), 7.05–7.09
(m, 2 H), 7.33–7.40 (m, 3 H), 7.49–7.54 (m, 5 H), 7.66–7.70 (m, 2 H), 8.51–8.54 (m, 2 H), 8.85
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6, 87.7, 95.6, 114.2, 121.8, 127.3, 128.4,
128.6, 128.7, 129.8, 130.6, 130.9, 132.5, 133.5, 137.3, 148.4, 157.2, 160.3, 163.1 ppm. HRMS
(ESI): calcd. for C25H19N2O 363.1492 [M + H]+; found 363.1497.
15

ACCEPTED MANUSCRIPT
5-(3,4-Dimethoxyphenyl)-2-phenyl-4-(phenylethynyl)pyrimidine (6g). Method B. Colorless
solid; yield 143 mg (73%); mp 146–147 °C. By method A, yield was 31%. 1H NMR (400 MHz,
CDCl3): δ = 3.89 (s, 3 H), 3.98 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.24 (dd, J = 8.5, 2.0 Hz, 1 H),
13
7.32–7.40 (m, 4 H), 7.47–7.54 (m, 5 H), 8.51–8.54 (m, 2 H), 8.86 (s, 1 H) ppm. C NMR (100
MHz, CDCl3): δ = 56.1, 56.2, 87.7, 95.8, 111.4, 112.5, 121.7, 121.9, 127.6, 128.4, 128.67,
128.74, 129.9, 130.9, 132.4, 133.7, 137.2, 148.3, 149.0, 149.8, 157.3, 163.2 ppm. HRMS (ESI):
calcd. for C26H20N2NaO2 415.1417 [M + Na]+; found 415.1424.
5-(4-Nitrophenyl)-2-phenyl-4-(phenylethynyl)pyrimidine (6h). Degassed CH3CN (5 mL) was
added to a mixture of iodobenzene (8) (102 mg, 0.5 mmol), Pd(PPh3)2Cl2 (17.6 mg, 5 mol %)
and CuI (4.8 mg, 5 mol %) under atmosphere of argon. 4-Ethynyl-5-(4-nitrophenyl)-2-
phenylpyrimidine (7) (165 mg, 0.55 mmol) and Et3N (0.174 mL, 1.25 mmol) were added and the
flask was sealed with rubber septum and flushed with argon. The reaction mixture was stirred at
80 °C for 3 h, cooled to room temperature and evaporated under reduced pressure. The residue
was purified by column chromatography on silica (CH2Cl2/hexane, 2:1) to provide pyrimidine 6h
1
as colorless solid; yield 74 mg (39%); mp 240–241 °C. H NMR (400 MHz, DMSO-d6): δ =
7.44–7.61 (m, 8 H), 8.12 (d, J = 8.5 Hz, 2 H), 8.43–8.48 (m, 4 H), 9.14 (s, 1 H) ppm. HRMS
(ESI): calcd. for C24H16N3O2 378.1237 [M + H]+; found 378.1238. We were unable to record 13C
NMR spectrum of this compound because of its poor solubility.
General procedure for the cyclization of 5-aryl-4-(arylethynyl)-2-phenylpyrimidines. A
solution of pyrimidine 6a-h (0.2 mmol) in TfOH (0.5 mL) was stirred at room temperature for 2
h (for 6h 24 h at 50 °C). The reaction mixture was poured into cold water (20 mL) and extracted
with CH2Cl2 (2×5 mL). The combined extracts were washed with water (2×5 mL) and dried over
Na2SO4. Solvent was evaporated under reduced pressure, and the residue was purified by column
chromatography on silica (hexane/EtOAc, 5:1) to provide pure products.
3,6-Diphenylbenzo[f]quinazoline (9a). Colorless solid; yield 64 mg (96%); mp 239–240 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.54–7.64 (m, 9 H), 7.75–7.80 (m, 1 H), 7.92 (s, 1 H), 7.98 (d, J =
8.0 Hz, 1 H), 8.67 (d, J = 7.0 Hz, 2 H), 8.79 (d, J = 8.0 Hz, 1 H), 10.16 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 119.9, 122.2, 127.5, 127.8, 127.9, 128.3, 128.6, 128.7, 128.8, 129.4,
129.8, 130.8, 131.2, 138.1, 139.5, 148.1, 151.8, 154.5, 162.4 ppm. One signal is overlapped.
HRMS (ESI): calcd. for C24H17N2 333.1386 [M + H]+; found 333.1389. UV-Vis λmax (ε×10-4):
288 (4.3) nm. Emission λmax 373 nm.
6-(4-Methoxyphenyl)-3-phenylbenzo[f]quinazoline (9b). Colorless solid; yield 69 mg (95%);
mp 206–208 °C. 1H NMR (400 MHz, CDCl3): δ = 3.93 (s, 3 H), 7.09 (d, J = 8.0 Hz, 2 H), 7.50–
16

ACCEPTED MANUSCRIPT
7.57 (m, 5 H), 7.61–7.66 (m, 1 H), 7.76–7.80 (m, 1 H), 7.91 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H),
13
8.66 (d, J = 7.0 Hz, 2 H), 8.80 (d, J = 8.0 Hz, 1 H), 10.17 (s, 1 H) ppm. C NMR (100 MHz,
CDCl3): δ = 55.6, 114.1, 119.8, 122.2, 127.4, 127.80, 127.84, 128.3, 128.6, 128.8, 129.5, 130.8,
131.0, 131.4, 131.8, 138.2, 147.8, 151.9, 154.4, 159.8, 162.3 ppm. HRMS (ESI): calcd. for
C25H18N2NaO 385.1311 [M + Na]+; found 385.1317. UV-Vis λmax (ε×10-4): 292 (4.6) nm.
Emission λmax 397 nm.
8-Methyl-3,6-diphenylbenzo[f]quinazoline (9d). Colorless solid; yield 68 mg (98%); mp 235–
1
236 °C. H NMR (400 MHz, CDCl3): δ = 2.50 (s, 3 H), 7.51–7.62 (m, 9 H), 7.74 (s, 1 H), 7.89
(s, 1 H), 8.64–8.70 (m, 3 H), 10.12 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.0, 119.9,
122.0, 127.1, 127.3, 127.5, 128.3, 128.5, 128.6, 128.8, 129.8, 130.1, 130.7, 131.2, 138.0, 138.2,
139.7, 147.7, 151.4, 154.2, 161.9 ppm. HRMS (ESI): calcd. for C25H19N2 347.1543 [M + H]+;
found 347.1551. UV-Vis λmax (ε×10-4): 291 (6.5) nm. Emission λmax 378 nm.
8-Chloro-3,6-diphenylbenzo[f]quinazoline (9e). Colorless solid; yield 71 mg (97%); mp 253–
254 °C. 1H NMR (400 MHz, CDCl3): δ = 7.53–7.56 (m, 8 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.94 (s,
13
2 H), 8.65 (d, J = 6.5 Hz, 2 H), 8.72 (d, J = 9.0 Hz, 1 H), 10.11 (s, 1 H) ppm. C NMR (100
MHz, CDCl3): δ = 119.6, 123.7, 127.0, 127.7, 128.6, 128.7, 128.8, 128.9, 129.7, 130.9, 132.3,
134.2, 137.9, 138.8, 147.0, 151.7, 154.4, 162.6 ppm. Two signals are overlapped. HRMS (ESI):
calcd. for C24H16ClN2 367.0997 [M + H]+; found 367.1000. UV-Vis λmax (ε×10-4): 290 (6.1) nm.
Emission λmax 375 nm.
2',6'-Diphenyl-4H-spiro[cyclohexa-2,5-diene-1,5'-cyclopenta[d]pyrimidin]-4-one
(10f).
Yellowish solid; yield 68 mg (98%); mp 186–187 °C. 2D NOESY, HSQC and HMBC spectra
1
were used for signals assignment. H NMR (400 MHz, CDCl3): δ = 6.61–6.65 (m, 2 H, H-2,6),
6.68–6.72 (m, 2 H, H-3,5), 7.37–7.42 (m, 3 H, Hm,p-Ph), 7.49–7.53 (m, 3 H, Hm,p-Ph), 7.59 (s, 1 H,
13
H-7’), 7.61–7.65 (m, 2 H, Ho-Ph), 8.42 (s, 1 H, H-4’), 8.46–8.50 (m, 2 H, Ho-Ph) ppm. C NMR
(100 MHz, CDCl3): δ = 57.0 (C-1), 126.9 (Co-Ph), 128.5 (Co-Ph), 128.8 (Cm-Ph), 129.2 (Cm-Ph),
129.8 (C-7’), 130.5 (Cp-Ph), 130.7 (C-4a’), 131.1 (Cp-Ph), 131.9 (C-3,5), 133.0 (Ci-Ph), 137.6 (Ci-
Ph), 147.2 (C-2,6), 150.5 (C-4’), 157.4 (C-6’), 165.6 (C-2’), 170.9 (C-7a’), 185.3 (C=O) ppm.
HRMS (ESI): calcd. for C24H17N2O 349.1335 [M + H]+; found 349.1333. UV-Vis λmax (ε×10-4):
276 (2.9) nm. Emission λmax 423 nm.
According to the general procedure, reaction of pyrimidine 6g resulted in a mixture of 9g and
10g in the ratio 1:2, total yield 74 mg, 97%. When initial mixing of reagents was performed in an
ice bath (TfOH was slowly added to pyrimidine 6g, then the bath was removed and the reaction
17

ACCEPTED MANUSCRIPT
mixture was stirred at room temperature for 2 h), benzo[f]quinazoline 9g was obtained as the
only product, yield 68 mg (87%).
8,9-Dimethoxy-3,6-diphenylbenzo[f]quinazoline (9g). Colorless solid; yield 25 mg (32%); mp
1
208–209 °C (dec.). H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 4.16 (s, 3 H), 7.34 (s, 1 H),
7.52–7.58 (m, 8 H), 7.82 (s, 1 H), 8.09 (s, 1 H), 8.64 (d, J = 6.5 Hz, 2 H), 10.04 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 56.0, 56.3, 102.3, 107.7, 119.4, 124.4, 125.7, 126.3, 128.3, 128.5,
128.75, 128.76, 129.6, 130.6, 138.2, 139.9, 147.1, 150.1, 150.7, 150.9, 154.1, 161.3 ppm. HRMS
(ESI): calcd. for C26H21N2O2 393.1598 [M + H]+; found 393.1591. UV-Vis λmax (ε×10-4): 304
(5.1) nm. Emission λmax 413 nm.
3-Methoxy-2',6'-diphenyl-4H-spiro[cyclohexa-2,5-diene-1,5'-cyclopenta[d]pyrimidin]-4-one
1
(10g). Yellowish solid; yield 49 mg (65%); mp 209–210 °C. H NMR (400 MHz, CDCl3): δ =
3.63 (s, 3 H), 5.53 (d, J = 2.5 Hz, 1 H), 6.60 (dd, J = 9.5, 2.5 Hz, 1 H), 6.71 (d, J = 9.5 Hz, 1 H),
7.36–7.41 (m, 3 H), 7.48–7.51 (m, 3 H), 7.55 (s, 1 H), 7.60–7.62 (m, 2 H), 8.40 (s, 1 H), 8.45–
13
8.49 (m, 2 H) ppm. C NMR (100 MHz, CDCl3): δ = 55.4, 57.4, 113.6, 126.9, 128.5, 128.7,
129.19, 129.22, 130.4, 131.0, 131.5, 132.0, 133.0, 137.7, 147.5, 150.2, 153.8, 157.7, 165.5,
170.5, 180.6 ppm. HRMS (ESI): calcd. for C25H19N2O2 379.1441 [M + H]+; found 379.1449.
UV-Vis λmax (ε×10-4): 278 (3.6) nm. Emission λmax 409 nm.
8-Nitro-3,6-diphenylbenzo[f]quinazoline (9h). Colorless solid; yield 15 mg (20%); mp 274–
275 °C. 1H NMR (400 MHz, CDCl3, 40 °C): δ = 7.55–7.66 (m, 8 H), 8.07 (s, 1 H), 8.55 (dd, J =
9.0, 2.5 Hz, 1 H), 8.67–8.70 (m, 2 H), 8.89 (d, J = 2.5 Hz, 1 H), 8.92 (d, J = 9.0 Hz, 1 H), 10.19
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 40 °C): δ = 119.1, 122.1, 123.60, 123.63, 128.9,
129.0, 129.20, 129.22, 129.77, 129.78, 131.0, 131.5, 133.6, 137.6, 138.1, 147.0, 148.2, 153.0,
155.3, 163.9 ppm. HRMS (ESI): calcd. for C24H16N3O2 378.1237 [M + H]+; found 378.1238.
UV-Vis λmax (ε×10-4): 297 (4.1) nm.
Cyclization of pyrimidine 6d in cyclohexadienone 10f. A solution of pyrimidine 6e (55 mg,
0.15 mmol) in concentrated (98%) H2SO4 (0.5 mL) was stirred at room temperature for 20 h. The
reaction mixture was poured into cold water (20 mL) and extracted with CH2Cl2 (2×5 mL). The
combined extracts were washed with water (2×5 mL) and dried over Na2SO4. Solvent was
evaporated under reduced pressure, and the residue was purified by column chromatography on
silica (hexane/EtOAc, 5:1) to provide pure compound 10f. Yield 43 mg (82%).
2-(2,5-Diphenylpyrimidin-4-yl)-1-(4-nitrophenyl)ethylenol (11). A solution of pyrimidine 6c
(14.1 mg, 0.037 mmol) in concentrated (98%) H2SO4 (0.3 mL) was stirred at 80 °C for 2 h. The
18

ACCEPTED MANUSCRIPT
reaction mixture was poured into cold water (15 mL) and extracted with CH2Cl2 (2×5 mL). The
combined extracts were washed with water (2×5 mL) and dried over Na2SO4. Solvent was
evaporated under reduced pressure, and the residue was purified by column chromatography on
silica (hexane/EtOAc, 10:1) to provide pure compound 11. Orange solid; yield 12.0 mg (81%);
mp 203–205 °C. 13C-1H HSQC and HMBC spectra were used for signals assignment. The
signals of the phenyl ring at C-5 of pyrimidine are referred to as “A”, the ones of the phenyl ring
at C2 as “B”, the ones of the 4-nitrophenyl ring as “C”. The signals of the pyrimidine ring are
1
marked with apostrophe. H NMR (400 MHz, CDCl3): δ = 6.33 (s, 1 H, H-2), 7.47–7.61 (m, 8
H), 7.90–7.94 (m, 2 H, o-HC), 8.22–8.26 (m, 2 H, m-HC), 8.35–8.38 (m, 2 H, o-HB), 8.58 (s, 1 H,
H-6’), 16.55 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 92.7 (C-2), 123.8 (m-CC),
127.1 (o-CC), 127.9 (o-CB), 128.6 (C-5’), 128.9 (p-CA), 129.2 (m-CB), 129.3 (m-CA), 129.4 (o-
CA), 131.7 (p-CB), 134.8 (i-CA), 135.3 (i-CB), 142.3 (i-CC), 148.8 (p-CC), 156.6 (C-6’), 159.4 (C-
2’), 160.3 (C-4’), 169.1 (C-1) ppm. HRMS (ESI): calcd. for C24H17N3O3 396.1343 [M + H]+;
found 396.1339.
Acknowledgements
The authors thank Dr. Alexey Fedorov (ETH Zurich) for his invaluable help in the preparation of
this manuscript and acknowledge the Russian Foundation for Basic Research for financial
support (grant no. 16-33-00171). NMR, HRMS, UV, and XRD analyses were performed at the
Saint Petersburg State University Center for Magnetic Resonance, Center for Chemical Analysis
and Materials Research, Educational Resource Center of Chemistry and Center for optical and
laser materials research, and X-ray Diffraction Center, respectively.
References
1. (a) J. Carreras, G. Gopakumar, L. Gu, A. Gimeno, P. Linowski, J. Petuškova, W. Thiel,
M. Alcarazo, J. Am. Chem. Soc. 2013, 135, 18815–18823. (b) V. Mamane, P. Hannen, A.
Fürstner, Chem. Eur. J. 2004, 10, 4556–4575. (c) Y. Yamamoto, K. Matsui, M. Shibuya,
Chem. Eur. J. 2015, 21, 7245–7255. (d) H.-C. Shen, J.-M. Tang, H.-K. Chang, C.-W.
Yang, R.-S. Liu, J. Org. Chem. 2005, 70, 10113–10116. (e) V. Mamane, A. Fürstner, J.
Org. Chem. 2002, 67, 6264–6267. (f) A. Jančařík, J. Rybáček, K. Cocq, J. Vacek
Chocholoušová, J. Vacek, R. Pohl, L. Bednárová, P. Fiedler, I. Císařová, I. G. Stará, I.
Starý, Angew. Chem. Int. Ed. 2013, 52, 9970–9975. (g) T.-A. Chen, R.-S. Liu, Chem.
Eur. J. 2011, 17, 8023–8027. (h) T.-A. Chen, T.-J. Lee, M.-Y. Lin, S. M. A. Sohel, E.
19

ACCEPTED MANUSCRIPT
W.-G. Diau, S.-F. Lush, R.-S. Liu, Chem. Eur. J. 2010, 16, 1826–1833. (i) B. S. Shaibu,
S.-H. Lin, C.-Y. Lin, K.-T. Wong, R.-S. Liu, J. Org. Chem. 2011, 76, 1054–1061.
2. (a) Y. Wang, D. J. Burton, Org. Lett. 2006, 8, 5295–5298. (b) A. Kondoh, T. Aoki, M.
Terada, Chem. Eur. J. 2015, 21, 12577–12580.
3. (a) A. Mukherjee, K. Pati, R.-S. Liu, J. Org. Chem. 2009, 74, 6311–6314. (b) M. B.
Goldfinger, K. B. Crawford, T. M. Swager, J. Am. Chem. Soc. 1997, 119, 4578–4593.
4. K. Pati, C. Michas, D. Allenger, I. Piskun, P. S. Coutros, F. Gomes, I. V. Alabugin, J.
Org. Chem. 2015, 80, 11706–11717.
5. I. Dix, C. Doll, H. Hopf, P. G. Jones, Eur. J. Org. Chem. 2002, 2547–2556.
6. (a) A. K. Mandadapu, M. D. Dathi, R. K. Arigela, B. Kundu, Tetrahedron 2012, 68,
8207-8215. (b) J. Storch, J. Čermák, J. Karban, I. Císařová, J. Sýkora, J. Org. Chem.
2010, 75, 3137–3140. (c) A. V. Gulevskaya, Eur. J. Org. Chem. 2016, 4207–4214.
7. P. R. Golubev, A. S. Pankova, M. A. Kuznetsov, Eur. J. Org. Chem. 2014, 3614–3621.
8. (a) C. Brullo, M. Rocca, P. Fossa, E. Cichero, E. Barocelli, V. Ballabeni, L. Flammini, C.
Giorgio, F. Saccani, G. Domenichini, O. Bruno, Bioorg. Med. Chem. Lett. 2012, 22,
1125–1129. (b) A. Rosowsky, P. C. Huang, N. Papathanasopoulos, E. J. Modest, J. Med.
Chem. 1974, 17, 1217–1222. (c) M. T. Conconi, G. Marzaro, L. Urbani, I. Zanusso, R. D.
Liddo, I. Castagliuolo, P. Brun, F. Tonus, A. Ferrarese, A. Guiotto, A. Chilin, Eur. J.
Med. Chem. 2013, 67, 373–383. (d) F. Godde, J.-J. Toulmé, S. Moreau, Biochem. 1998,
37, 13765–13775. (e) M. H. Hanlon, R. Ferone, Cancer Res. 1996, 56, 3301–3306. (f) G.
Marzaro, L. D. Via, A. Toninello, A. Guiotto, A. Chilin, Bioorg. Med. Chem. 2011, 19,
1197–1204. (g) A. Rosowsky, J. H. Freisheim, J. B. Hynes, S. F. Queener, M. Bartlett, J.
W. Smith, H. Lazarus, E. J. Modest, Biochem. Pharmacol. 1989, 38, 2677–2684. (h) W.
Pendergast, J. V. Johnson; S. H. Dickerson, I. K. Dev, D. S. Duch; R. Ferone, W. R. Hall,
J. Humphreys; J. M. Kelly; D. S. Wilson, J. Med. Chem. 1993, 36, 2279–2291.
9. Selected patents: (a) J. H. Park, S. H. Lee, S. Y. Moon, B. S. Lee, J. U. Lee, M. G. Kim,
G. H. Lee, KR 1604647, 2016. (b) J. W. Jang, H. Y. Jung, S.-G. Kim, W. S. Kim, J. H.
Byun, J. H. Park, S. P. Hwang, WO 2016032150, 2016. (c) H.-I. Lee, D.-W. Ryu, J.-H.
Lui, C.-J. Shin, E.-S. Yu, S.-H. Jung, WO 2016013732, 2016. (d) J. W. Jang, S. G. Kim,
W. S. Kim, Y. R. Kim, J. T. Kwon, KR 2016005944, 2016. (e) S. J. Han, C. J. Shin, H. I.
Lee, Y. G. Kim, S. H. Min, E. S. Yoo, H. G. Jung, KR 2015140127, 2015. (f) H.
Kawakami, M. Funahashi, T. Yoshinaga, H. Toyoshima, WO 2015020217, 2015. (g) R.
Kwong, S. T. Lam, C. H. Lee, US 20140332758, 2014.
20

ACCEPTED MANUSCRIPT
10. (a) G. Marzaro, A. Chilin, G. Pastorini, A. Guiotto, Org. Lett. 2006, 8, 255–256. (b) H.
Parrot-Lopez, J.-M. Delacotte, J. Renault, J. Heterocyclic Chem. 1986, 23, 1039–1043.
(c) M. Nowak, Z. Malinowski, E. Fornal, A. Jozwiak, E. Parfieniuk, G. Gajek, R.
Kontek, Tetrahedron 2015, 71, 9463–9473.
11. (a) A. Rosowsky, E. J. Modest, J. Org. Chem. 1966, 31, 2607–2613. (b) T. Ohshima, Y.
Tomioka, M. Yamazaki, Chem. Pharm. Bull. 1981, 29, 1292–1298.
12. (a) A. Herrera, R. Martínez-Alvarez, M. Chioua, R. Chatt, R. Chioua, A. Sánchez, J.
Almy, Tetrahedron 2006, 62, 2799–2811. (b) R. P. Chaudhary, Der Pharma Chemica
2011, 3, 288–292.
13. T. J. Delia, W. D. Munslow, J. Heterocyclic Chem. 1979, 16, 239–240.
14. L. Yang, R. Hua, Chem. Lett. 2013, 42, 769–771.
15. F. Eiden, B. S. Nagar, Naturwissenschaften 1963, 50, 403–403.
16. (a) C. S. Ceide, A. G. Montalban, Tetrahedron Lett. 2006, 47, 4415–4418. (b) I. Malik,
Z. Ahmed, S. Reimann, I. Ali, A. Villinger, P. Langer, Eur. J. Org. Chem., 2011, 2088–
2093. (c) S. Sinha, D. Ahire, S. Wagh, D. Mullick, R. Sistla, K. Selvakumar, J. C. Cortes,
S. P. Putlur, S. Mandlekar, B. M. Johnson, Chem. Res. Toxicol. 2014, 27, 2052–2061. (d)
K. L. Billingsley, K. W. Anderson, S. L. Buchwald, Angew. Chem. Int. Ed. 2006, 45,
3484–3488.
17. CCDC 1490103 (for compound 10f) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
18. Protonation of nitrogen heterocycles in superacid medium was described: D. A. Klumpp,
R. Rendy, Y. Zhang, A. McElrea, A. Gomez, H. Dang, J. Org. Chem. 2004, 69, 8108–
8110.
19. (a) T. Dohia, Y. Kita, Chem. Commun. 2009, 16, 2073–2085. (b) B.-X. Tang, D.-J. Tang,
S. Tang, Q.-F. Yu, U.-H. Zhang, Y. Liang, P. Zhong, J.-H. Li, Org. Lett. 2008, 10, 1063–
1066. (c) T. Hromjakova, P. Retailleau, L. Grimaud, V. Gandon, L. Chabaud, C. Guillou,
Eur. J. Org. Chem. 2015, 7494–7503. (d) T. Dohi, D. Kato, R. Hyodo, D. Yamashita, M.
Shiro, Y. Kita, Angew. Chem. Int. Ed. 2011, 50, 3784–3787. (e) X. Zhang, R. C. Larock,
J. Am. Chem. Soc. 2005, 127, 12230–12231. (f) P.-C. Qian, Y. Liu, R.-J. Song, J.-N.
Xiang, J.-H. Li, Synlett 2015, 26, 1213–1216.
21

ACCEPTED MANUSCRIPT
20. (a) M. D. Aparece, P. A. Vadola, Org. Lett. 2014, 16, 6008–6011. (b) T. Nemoto, Z.
Zhao, T. Yokosaka, Y. Suzuki, R. Wu, Y. Hamada, Angew. Chem. Int. Ed. 2013, 52,
2217–2220. (c) S. Rousseaux, J. García-Fortanet, M. A. Del Aguila Sanchez, S. L.
Buchwald, J. Am. Chem. Soc. 2011, 133, 9282–9285.
21. (a) X.-H. Yang, X.-H. Ouyang, W.-T. Wei, R.-J. Song, J.-H. Li, Adv. Synth. Catal. 2015,
357, 1161–1166. (b) D. Li, T. Yang, H. Su, W. Yu, Adv. Synth. Catal. 2015, 357, 2529–
2539. (c) H.-L. Hua, Y.-T. He, Y.-F. Qiu, Y.-X. Li, B. Song, P. Gao, X.-R. Song, D.-H.
Guo, X.-Y. Liu, Y.-M. Liang, Chem. Eur. J. 2015, 21, 1468–1473. (d) D.-P. Jin, P. Gao,
D.-Q. Chen, S. Chen, J. Wang, X.-Y. Liu, Y.-M. Liang, Org. Lett. 2016, 18, 3486–3489.
22. E. Miyazawa, T. Sakamoto, Y. Kikugawa, J. Org. Chem. 2003, 68, 5429–5432.
23. The similar last step was proposed for the ipso-cyclization of bis(4-
methoxybenzylthio)acetylene by ICl. See: T. R. Appel, N. A. M. Yehia, U. Baumeister,
H. Hartung, R. Kluge, D. Ströhl, E. Fanghänel, Eur. J. Org. Chem. 2003, 47–53.
24. “A Guide to Recording Fluorescence Quantum Yields” manual by HORIBA Jobin Yvon
SAS.
25. A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
26. A. D. Becke, Phys. Rev. A 1988, 38, 3098.
27. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785.
28. Gaussian 09, Revision D.01. M J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H.
Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T.
Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford
CT, 2013.
22

ACCEPTED MANUSCRIPT
29. D. Benito-Garagorri, J. Wiedermann, M. Pollak, K. Mereiter, K. Kirchner,
Organometallics 2007, 26, 217–222.
30. H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett. 2009, 11, 4258–4261.
31. Hoffmann-La Roche Inc. Patent: US5438052 A1, 1995.
32. H. W. van Meeteren, H. C. van der Plas, Recl. Trav. Chim. Pay-B 1971, 90, 105–116.
23