Transition-metal-free approach to 4-ethynylpyrimidines via alkenynones

Article abstract of DOI:10.1002/ejoc.201402045

A practical approach to the synthesis of 4-ethynylpyrimidines by the condensation of arylamidines with 2-aryl-1-ethoxy-5-(trimethylsilyl)pent-1-en-4- yn-3-ones has been developed. As these latter ketones are easily accessible from bis(trimethylsilyl)acetylene and arylacetyl chlorides, the regioselective condensation reported herein provides a facile access to both TMS-protected and unprotected 4-ethynylpyrimidines in yields of up to 85%. Copyright

Full text of DOI:10.1002/ejoc.201402045

Job/Unit: O42045
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Date: 24-04-14 17:34:39
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FULL PAPER
DOI: 10.1002/ejoc.201402045
Transition-Metal-Free Approach to 4-Ethynylpyrimidines via Alkenynones
Pavel R. Golubev,[a] Alena S. Pankova,[a] and Mikhail A. Kuznetsov*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Alkynes / Amidines
A practical approach to the synthesis of 4-ethynylpyrimidines
by the condensation of arylamidines with 2-aryl-1-ethoxy-5-
(trimethylsilyl)pent-1-en-4-yn-3-ones has been developed.
As these latter ketones are easily accessible from bis(tri-
methylsilyl)acetylene and arylacetyl chlorides, the regiose-
lective condensation reported herein provides a facile access
to both TMS-protected and unprotected 4-ethynylpyrimid-
ines in yields of up to 85%.
Introduction
Results and Discussion
We have previously reported that the acetylenic ketones
4a,c,e are readily available from bis(trimethylsilyl)acetylene
(1) and arylacetyl chlorides (Scheme 1).[6] Because ketones
4a,c,e displayed high regioselectivity in their reactions with
monosubstituted hydrazines,[6] we decided to utilize the
enynones 4 as starting materials for the synthesis of other
acetylenic heterocycles. To extend the substrate scope of the
reported method,[6] we synthesized ketones 4b,d by the same
procedure in total yields of 45 and 33%, respectively
(Scheme 1).
The chemistry of pyrimidine derivatives has been inten-
sively studied due to the great pharmacological importance
of these compounds. Nucleobases with a pyrimidine core,
such as uracil, thymine, cytosine, adenine, and guanine, are
the fundamental building blocks of DNA and RNA, which
makes pyrimidine derivatives ubiquitous for rational drug
design.[1] Pyrimidines display a broad range of biological
activities, including analgesic, antibacterial, antifungal, an-
tihypertensive, and anti-inflammatory properties. In ad-
dition, the pyrimidine motif is found in pesticides and her-
bicides as well as in plant growth regulators.[2] In particular,
alkynyl-substituted pyrimidines are interesting because of
their inhibitory activity towards adenosine kinase and
thymidine synthase.[3]
Sonogashira coupling is a powerful method for the syn-
thesis of diverse acetylenic heterocycles and numerous
modifications of the original procedure have been suggested
to further expand its scope.[4] Nonetheless, this methodol-
ogy is limited as the most common and easily available pal-
ladium catalysts are suitable only for use with activated sub-
strates such as aryl iodides whereas with other electrophiles
non-conventional catalysts with complex ligands are re-
quired[5] and appropriate heterocyclic cross-coupling part-
ners may be tedious to obtain.
Scheme 1. Synthesis of ketones 4a–e.
Continuing our interest in the synthesis of acetylenic het-
erocycles,[6] we report herein a straightforward and transi-
tion-metal-free method for the synthesis of hitherto un-
known 4-ethynyl-substituted pyrimidines. Our strategy in-
cludes only three synthetic steps and utilizes cheap starting
materials.
The severe conditions required for the second step (pro-
longed heating at 130 °C in Ac2O) lead to notable tarring of
the reaction mixtures and diminished yields of the desired
enynones 4 in comparison with the ethoxymethylation of
activated substrates such as 1,3-dicarbonyl compounds.[7]
Nevertheless, we isolated compounds 4a–e in moderate
yields, and in all cases the ketones 4 were formed as single
stereoisomers with the (E)-configuration unambiguously es-
tablished by X-ray analysis for compound 4a.[6]
[a] Department of Chemistry, Saint Petersburg State University,
Universitetsky pr. 26, 198504 Saint Petersburg, Russia
E-mail: m.kuznetsov@spbu.ru
para-Substituted arylamidines 7a–e were chosen as nu-
cleophiles for the synthesis of pyrimidines by analogy with
our previous results and were synthesized by a modified
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P. R. Golubev, A. S. Pankova, M. A. Kuznetsov
FULL PAPER
Pinner amidine synthesis protocol (Scheme 2). In addition Table 1. Reactions of ketones 4a–e with arylamidines 7a–e.
to the few literature procedures based on the treatment of
nitriles with LiHMDS or dry HCl in ethanol,[8,9] we have
proven that basic conditions are more suitable for nitriles
with electron-withdrawing groups, whereas acidic condi-
tions are preferable for nitriles with electron-donating sub-
stituents (see the Exp. Sect. for details).
Entry Ketone R1
Aryl-
amidine
R2
Pyrimidine Method Isolated
yield [%]
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4e
4e
4e
4e
4e
NO2
NO2
NO2
NO2
NO2
Cl
Cl
Cl
Cl
Cl
7a
7b
7c
7d
7e
7a
7b
7c
7d
7e
7a
7b
7c
7d
7e
7a
7b
7c
7d
7e
7a
7b
7c
7d
7e
NO2
Cl
H
CH3
OCH3
NO2
Cl
8a
8b
8c
8d
8e
8f
8g
8h
8i
E
D
D
D
D
E
D
D
D
D
E
D
D
D
D
E
D
D
D
D
E
81
66
73
50
73
60
85
67
79
60
48
56
48
57
57
65
54
62
48
63
43
61
55
52
45
Scheme 2. Synthesis of arylamidines 7a–e.
H
CH3
OCH3
NO2
Cl
Most substituted arylamidines are only sparingly soluble 10
8j
8k
8l
11
12
13
14
15
16
17
18
19
20
H
H
H
H
in organic solvents and so are hard to obtain in the form
of the free base due to difficulties in their purification. For
this reason, a one-pot deprotonation/cyclization procedure
using arylamidine hydrochloride salts was designed for the
synthesis of the target pyrimidines (Table 1). We first at-
tempted to use sodium methoxide in methanol to depro-
tonate the hydrochloride salts followed by the addition of a
methanolic solution of enynone 4. Although this approach
H
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
8w
8x
8y
CH3
OCH3
NO2
Cl
H
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
CH3
OCH3
NO2
Cl
H
CH3
OCH3
was effective with arylamidines 7b–e, leading to the corre- 21
22
23
24
25
D
D
D
D
sponding pyrimidines in good yields, only traces of desired
products were isolated when the nitro-substituted amidine
7a was used. On the other hand, the heterogeneous
NaHCO3/EtOH system afforded the corresponding pyrim-
idines in good yields albeit with longer reaction times: the
reaction of 4-nitrobenzamidine (7a) required about 12 h at
room temperature to reach full conversion with NaHCO3, groups, with all the products obtained containing an unsub-
1
whereas the cyclization of arylamidines 7b–e in the presence stituted ethynyl fragment. This is clear from the H NMR
of sodium methoxide was complete within 10–60 min at the spectra in which no upfield signal of the TMS group was
same temperature.
observed, but instead a singlet arising from the ϵCH pro-
As compounds 4a–e possess three electrophilic centers, ton [δ ≈ 3.5 (CDCl3) or 4.8 ppm ([D6]DMSO)]. Comparison
the formation of different heterocycles in reactions with bi- of the NMR spectroscopic data of all the investigated pyr-
nucleophiles may a priori be anticipated. Our previous imidines revealed that they show a very consistent set of
studies showed that the triple bond in compounds 4 was signals from the core molecule. The most characteristic sig-
not involved in reactions with hydrazines,[6] and therefore nal in the 1H NMR spectra is found at δ = 8.74–8.90
we expected that the reactions between enynones 4a–e and (CDCl3) or 9.03–9.18 ppm ([D6]DMSO) and belongs to 6-
arylamidines 7a–e (symmetrical binucleophiles) would lead H of the pyrimidine core. The four signals at δ ≈ 133 (C-5),
to pyrimidines 8 as single products, as was indeed observed 147 (C-4), 157 (C-6), and 162 ppm (C-2) are constant in the
in all reactions. The triple bond remained intact, as can be 13C NMR spectra independent of the solvent used and arise
seen from the pairs of signals at δ = 80–81 and 83–89 ppm, from the pyrimidine core carbon atoms.
which correspond to the CϵC fragment, in the 13C NMR
Finally, the structures of the pyrimidines obtained were
spectra of all the pyrimidines. However, the amidines ap- confirmed by X-ray analysis of compounds 8l[10] (Figure 1)
pear to be sufficiently basic to allow removal of the TMS and 8v.[11] In pyrimidine 8l, the value of the dihedral angle
2
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Approach to 4-Ethynylpyrimidines via Alkenynones
between the pyrimidine ring and the aryl substituent at the (Z)-configuration. Once formed, the dihydropyrimidinol C
2-position is 1.7(2)°, whereas the dihedral angle C4–C5– eliminates a molecule of water to furnish the final product.
C9–C10 is 44.3(2)°. The deviation from planarity in this It is unclear during which step the TMS group is removed,
fragment is caused by the spatial proximity of the ethynyl but it does not seem to interfere with the main reaction
group and the phenyl ring at the 5-position. It was also pathway.
established that pyrimidine 8v with a methoxy group forms
dimers in the solid state through hydrogen bonds between
the oxygen atom and the ϵCH proton, which results in par-
allel layers of the molecules (Figure 2).
Scheme 3. Proposed reaction mechanism.
Figure 1. OLEX2 representation of pyrimidine 8l. Thermal ellip-
soids are drawn at the 50% probability level.
The deprotection of the triple bond during the course of
reaction was not a surprise because it is well known that
the TMS group readily undergoes elimination upon treat-
ment with bases in protic solvents.[12] We therefore per-
formed a series of experiments by using dichloromethane
as an aprotic solvent and dry magnesium sulfate as water
scavenger to obtain the TMS-protected pyrimidines 9
(Scheme 4).
Figure 2. Molecular packing in the crystal structure of 8v.
Scheme 4. Synthesis of trimethylsilyl-substituted pyrimidines 9a–c.
Variation of the substituents in the phenyl rings of the
enynones 4 and amidines 7 has no significant influence on
the yields of pyrimidines 8 or the reaction time (with the
exception of amidine 7a). Nevertheless, our previous obser-
vation that enynones containing electron-withdrawing
groups were more active in reactions with hydrazines was
confirmed in this work. We generally obtained better results
with the more electron-poor substrates 4a,b than with the
ketones 4c–e. It is also worth mentioning that due to the
low solubility of pyrimidines 8 in alcohols, the products
could be isolated in high purity by simple filtration followed
by washing with cold ethanol and water.
The reactions of compounds 4c,e with free benzamidine
proceeded smoothly to give the desired pyrimidines 9b,c in
good yields, although it was necessary to purify 9b by col-
umn chromatography to remove 3% of the desilylated prod-
uct 8m. Surprising results were obtained when enynone 4a
was used in this reaction; in this case the diminished yield
of the target pyrimidine is offset by the formation of ethyl
p-nitrophenylacetate as the major product. The mechanism
of this unusual transformation is as yet unclear and is the
subject of our current investigations.
The proposed reaction mechanism (Scheme 3) starts with
nucleophilic substitution of the ethoxy group by an amidine
nitrogen atom to form enamine A, which exists in equilib-
Conclusions
We have developed a general and efficient practical pro-
rium with its tautomeric form B. The latter can undergo cedure for the synthesis of previously unknown 2,5-diaryl-
cyclization provided the C(Ar1)=CH(N) double bond has a 4-ethynylpyrimidines from readily available precursors.
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P. R. Golubev, A. S. Pankova, M. A. Kuznetsov
FULL PAPER
4-Nitrobenzamidine Hydrochloride (7a): Yellow solid; yield 1.64 g
(60%); m.p. 277–279 °C (ref.:[14] 285–287 °C). 1H NMR (300 MHz,
[D6]DMSO): δ = 8.10 (d, J = 8.5 Hz, 2 H, o-H), 8.40 (d, J = 8.5 Hz,
2 H, m-H), 9.40 [br. s, 4 H, C(NH)NH2·HCl] ppm.
Good yields and the selective formation of the title com-
pounds along with easy work-up make this facile method a
convenient tool for the synthesis of acetylenic pyrimidines.
Method B Ϫ Preparation of Benzamidine Hydrochloride (7c): A
solution of benzonitrile (25.75 g, 0.25 mol) in a mixture of meth-
anol (16.2 mL, 0.4 mol), water (3.4 mL, 0.19 mol), and diethyl ether
(18 mL) was cooled to 0 °C on an ice bath. Thionyl chloride
(14.6 mL, 0.2 mol) was added dropwise to this solution and the
resulting mixture was stirred at 0 °C for 1 h and then left overnight
at room temperature. The precipitate was filtered off, washed with
Et2O (2ϫ 15 mL), and dried at 40 °C in vacuo. The dry methyl
benzimidate hydrochloride was suspended in methanol (50 mL)
and methanolic ammonia solution (0.325 mol, 140 mL) was added
in one portion. After stirring at room temperature for about 4 h,
the precipitate completely dissolved and the reaction mixture was
kept at room temperature for 2 d. The solvent was removed by
distillation and the crude product was obtained by trituration with
diethyl ether. Washing with Et2O (2ϫ 15 mL) and acetonitrile (2ϫ
15 mL) provided the pure amidine hydrochloride 7c.
Experimental Section
General: NMR spectroscopic data were recorded with Bruker
DPX-300 and Avance 400 spectrometers (300.13 and 400.13 MHz
1
for H, 75.47 and 100.61 MHz for 13C, respectively) in CDCl3 and
[D6]DMSO and are referenced to the residual solvent proton (δH
= 7.26 and 2.50 ppm, respectively) and carbon signals (δC = 77.00
and 39.52 ppm, respectively). The atoms of the phenyl rings at the
5-position of the pyrimidines are referred to as “A” atoms and those
of the phenyl rings at the 2-position as “B” atoms. The AAЈXXЈ
and AAЈXXЈY proton systems of para- and mono-substituted
phenyl rings, respectively, cannot be clearly seen in the 1H NMR
spectra and therefore “apparent” coupling constants are given for
the observed “doublets” and “triplets” of the corresponding aro-
matic protons. DEPT spectra were used for the assignment of car-
bon signals. Melting points were determined with a Stuart SMP30
instrument. High-resolution mass spectra were recorded with a
Bruker Maxis HRMS-ESI-qTOF spectrometer (electrospray ion-
ization mode). X-ray diffraction analysis was performed with an
Agilent Technologies Xcalibur diffractometer. Ketones 3a–e were
prepared according to reported procedures.[13] The ketones 4a,c,e
were synthesized as described by us earlier,[6] and this procedure
was used to prepare 4b,d.
Benzamidine Hydrochloride (7c):[8] Colorless solid; yield 33.3 g
(85%); m.p. 169–171 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
7.59–7.64 (m, 2 H, m-H), 7.71–7.76 (m, 1 H, p-H), 7.85–7.88 (m, 2
H, o-H), 9.40 [br. s, 4 H, C(NH)NH2·HCl] ppm.
Method C Ϫ Preparation of Arylamidines 7b,d,e: Dry HCl was
bubbled through a suspension of the corresponding nitrile
(0.25 mol) in methanol (20 mL, 0.5 mol) and diethyl ether (40 mL)
at 0 °C until saturation was achieved (normally 4 h) and the reac-
tion mixture was then left overnight at 5 °C. The precipitate was
filtered off, washed with diethyl ether (2ϫ 10 mL), and dried in
vacuo at 40 °C. The dry imino ester hydrochloride was suspended
in methanol (50 mL) and methanolic ammonia solution
(0.325 mol, 140 mL) was added in one portion. After stirring at
room temperature for 4 h, the resulting suspension was kept at
room temperature for 2 d. The solvent was removed by distillation
and the crude product was obtained by trituration with diethyl
ether. Washing with Et2O (2ϫ 15 mL) and acetonitrile (2ϫ 15 mL)
provided the pure amidine hydrochloride.
(1E)-2-(4-Chlorophenyl)-1-ethoxy-5-(trimethylsilyl)pent-1-en-4-yn-
3-one (4b): Orange-brown solid; yield 1.32 g (53%); m.p. 67–69 °C.
1H NMR (300 MHz, CDCl3): δ = 0.27 [s, 9 H, Si(CH3)3], 1.39 (t,
J = 7.0 Hz, 3 H, CH3), 4.23 (q, J = 7.0 Hz, 2 H, CH2), 7.25 (d, J
= 8.5 Hz, 2 H, m-H), 7.32 (d, J = 8.5 Hz, 2 H, o-H), 7.97 (s, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.7 [Si(CH3)3], 15.3
(CH3), 72.0 (CH2), 97.0, 100.5 (CϵC), 122.2 (C=CH), 128.0, 131.5
(C-o,m), 129.4 (C-i), 133.2 (C-p), 165.5 (CHOEt), 175.8
(C=O) ppm. HRMS (ESI): calcd. for C16H19O2ClSi 307.0916 [M
+ H]+; found 307.0917.
(1E)-1-Ethoxy-2-(4-methylphenyl)-5-(trimethylsilyl)pent-1-en-4-yn-
3-one (4d): Red solid; yield 0.95 g (41%); m.p. 41–43 °C. H NMR
4-Chlorobenzamidine Hydrochloride (7b):[15] Colorless solid; yield
1
1
20.0 g (42%); m.p. 239–241 °C. H NMR (300 MHz, [D6]DMSO):
(300 MHz, CDCl3): δ = 0.26 [s, 9 H, Si(CH3)3], 1.39 (t, J = 7.0 Hz,
3 H, CH3), 2.34 (s, 3 H, ArCH3), 4.21 (q, J = 7.0 Hz, 2 H, CH2),
7.15–7.21 (m, 4 H, o,m-H), 7.95 (s, 1 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = –0.7 [Si(CH3)3], 15.3 (CH3), 21.3 (ArCH3),
71.7 (CH2), 96.4, 100.8 (CϵC), 123.4 (C=CH), 128.0 (C-i), 128.6,
129.9 (C-o,m), 137.2 (C-p), 165.2 (CHOEt), 176.4 (C=O) ppm.
HRMS (ESI): calcd. for C17H22O2Si 287.1462 [M + H]+; found
287.1453.
δ = 7.72 (d, J = 8.6 Hz, 2 H, m-H), 7.87 (d, J = 8.6 Hz, 2 H, o-H),
9.32, 9.51 [2 br. s, 4 H, C(NH)NH2·HCl] ppm.
4-Methylbenzamidine Hydrochloride (7d):[16] Colorless solid; yield
1
27.7 g (65%); m.p. 213–214 °C. H NMR (300 MHz, [D6]DMSO):
δ = 2.40 (s, 3 H, CH3), 7.41 (d, J = 8.2 Hz, 2 H, m-H), 7.77 (d, J
= 8.2 Hz, 2 H, o-H), 9.24, 9.40 [2 br. s, 4 H, C(NH)NH2·HCl] ppm.
4-Methoxybenzamidine Hydrochloride (7e):[17] Grey solid; yield
General Procedures for the Preparation of Arylamidines 7a–e
1
31.2 g (67%); m.p. 217–219 °C. H NMR (300 MHz, [D6]DMSO):
Method A Ϫ Preparation of 4-Nitrobenzamidine Hydrochloride (7a):
A solution of NaOCH3 (73 mg, 1.35 mmol) in methanol (2 mL)
was added to a suspension of 4-nitrobenzonitrile (2 g, 13.5 mmol)
in methanol (13 mL) and the resulting mixture was stirred first at
50 °C for 15 min and then left overnight at room temperature.
Next, dry NH4Cl (0.8 g, 14.85 mmol) was added and the reaction
mixture was set aside for 2 d. After this period, the precipitate was
separated by filtration and washed three times with 8 mL of meth-
anol to separate the organic fractions from inorganic salts. Meth-
anol was removed from the filtrates by distillation in vacuo, and
finally the resulting solid was washed four times with acetonitrile
(5 mL) to remove the unreacted starting material to provide the
pure amidine hydrochloride 7a.
δ = 3.86 (s, 3 H, OCH3), 7.15 (d, J = 8.7 Hz, 2 H, m-H), 7.88 (d, J
= 8.7 Hz, 2 H, o-H), 9.14, 9.31 [2 br. s, 4 H, C(NH)NH2·HCl] ppm.
General Procedures for the Preparation of Pyrimidines 8 and 9: All
pyrimidines except 8a,f,k,p,u were prepared by method D and pyr-
imidines 8a,f,k,p,u by method E. The trimethylsilyl-substituted pyr-
imidines 9a–c were synthesized by method F.
Method D: Amidine hydrochloride 7b–e (1.25 mmol) was added to
a solution of sodium methoxide (67.5 mg, 1.25 mmol) in methanol
(5 mL) and the resulting suspension was stirred at room tempera-
ture for 30 min. Next, a solution of the corresponding ketone 4a–
e (1 mmol) in methanol (5 mL) was added in one portion and the
reaction mixture stirred at room temperature until TLC showed
4
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Approach to 4-Ethynylpyrimidines via Alkenynones
that no starting ketone remained (10–60 min). Upon completion,
the reaction vessel was placed in a refrigerator (–15 °C) for 2 h and
the resulting heavy precipitate was filtered off, washed with cold
ethanol (2ϫ 5 mL) and water (3ϫ 5 mL), and dried at 80 °C at
normal pressure.
(C-6), 162.9 (C-2) ppm. HRMS (ESI): calcd. for C19H13N3O2
316.1080 [M + H]+; found 316.1079.
4-Ethynyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)pyrimidine (8e):
Yellow solid; yield 240 mg (73%); m.p. 225–227 °C (dec.). 1H NMR
(300 MHz, CDCl3): δ = 3.37 (s, 1 H, CϵCH), 3.90 (s, 3 H, OCH3),
7.02 (d, J = 8.7 Hz, 2 H, m-HB), 7.81 (d, J = 8.7 Hz, 2 H, o-HA),
8.36 (d, J = 8.7 Hz, 2 H) and 8.47 (d, J = 8.7 Hz, 2 H, m-HA, o-
HB), 8.80 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.4
(OCH3), 80.4 (CϵCH), 87.7 (CϵCH), 114.3 (C-mB), 123.5 (C-mA),
128.4 (C-iB), 129.7, 130.5 (C-oA,B), 131.2 (C-5), 140.9 (C-iA), 146.9
(C-4), 147.5 (C-pA), 157.9 (C-6), 162.1 (C-pB), 162.8 (C-2) ppm.
HRMS (ESI): calcd. for C19H13N3O3 332.1029 [M + H]+; found
332.1031.
Method E: A solution of the corresponding ketone 4a–e (1 mmol)
in absolute ethanol (5 mL) was added in one portion to a stirred
suspension of amidine hydrochloride 7a (252 mg, 1.25 mmol) and
anhydrous NaHCO3 (840 mg, 10 mmol) in absolute ethanol (5 mL)
and the reaction mixture was stirred at room temperature for 24 h.
Upon completion, the reaction vessel was placed in a refrigerator
(–15 °C) for 2 h. The resulting heavy precipitate was filtered off,
washed with cold ethanol (2ϫ 5 mL) and water (3ϫ 5 mL), and
dried at 80 °C.
5-(4-Chlorophenyl)-4-ethynyl-2-(4-nitrophenyl)pyrimidine (8f): Col-
orless solid; yield 200 mg (60%); m.p. 227–228 °C (dec.). 1H NMR
(400 MHz, [D6]DMSO): δ = 4.83 (s, 1 H, CϵCH), 7.63 (d, J =
8.5 Hz, 2 H, m-HB), 7.76 (d, J = 8.5 Hz, 2 H, o-HB), 8.39 (d, J =
8.8 Hz, 2 H, o-HA), 8.62 (d, J = 8.8 Hz, 2 H, m-HA), 9.10 (s, 1 H,
6-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 80.0 (CϵCH),
87.5 (CϵCH), 123.4 (C-mB), 128.2, 128.6, 130.5 (3 CHAr), 132.1
(C-iA), 133.3 (C-5), 133.9 (C-pA), 141.6 (C-iB), 146.8 (C-4), 148.9
(C-pB), 157.7 (C-6), 160.3 (C-2) ppm. HRMS (ESI): calcd. for
C18H10N3O2Cl 336.0534 [M + H]+; found 336.0529.
Method F: Free benzamidine (150 mg, 1.25 mmol) was added to a
mixture of enynone 4a,c,e (1 mmol) and dry MgSO4 (200 mg) in
anhydrous dichloromethane (5 mL), which was then stirred at room
temperature for about 2 h (TLC monitoring). After completion, the
inorganic precipitate was filtered off and the solvent removed by
distillation. The residue was purified by column chromatography
on silica gel (hexanes/CH2Cl2, 3:2) to provide pure pyrimidines 9a–
c.
4-Ethynyl-2,5-bis(4-nitrophenyl)pyrimidine (8a): Dark-orange solid;
2,5-Bis(4-chlorophenyl)-4-ethynylpyrimidine (8g):[18] Colorless solid;
1
yield 280 mg (81%); m.p. 218–220 °C (dec.). H NMR (300 MHz,
1
yield 276 mg (85%); m.p. 205–207 °C (dec.). H NMR (300 MHz,
[D6]DMSO): δ = 4.90 (s, 1 H, CϵCH), 8.03 (d, J = 8.7 Hz, 2 H,
o-HA), 8.39–8.43 (m, 4 H, m-HA, o-HB), 8.67 (d, J = 8.7 Hz, 2 H,
m-HB), 9.18 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 80.0 (CϵCH), 88.8 (CϵCH), 123.6 (C-mA), 124.0 (C-mB), 129.1
(C-oA), 130.7 (C-oB), 133.0 (C-5), 140.3 (C-iA), 141.6 (C-iB), 147.2
(C-4), 147.7 (C-pA), 149.2 (C-pB), 158.4 (C-6), 161.0 (C-2) ppm.
HRMS (ESI): calcd. for C18H10N4O4 369.0594 [M + Na]+; found
369.0593.
[D6]DMSO): δ = 4.80 (s, 1 H, CϵCH), 7.63–7.73 (m, 4 H, o,m-HA,
m-HB), 8.41 (d, J = 7.4 Hz, 2 H, o-HB), 9.03 (s, 1 H, 6-H) ppm.
HRMS (ESI): calcd. for C18H10N2Cl2 325.0294 [M + H]+; found
325.0304.
5-(4-Chlorophenyl)-4-ethynyl-2-phenylpyrimidine (8h): Colorless so-
lid; yield 195 mg (67 %); m.p. 164–165 °C (dec.). 1H NMR
(300 MHz, CDCl3): δ = 3.37 (s, 1 H, CϵCH), 7.47–7.59 (m, 7 H,
o,m-HA, m.p-HB), 8.48–8.51 (m, 2 H, o-HB), 8.82 (s, 1 H, 6-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 80.6 (CϵCH), 83.7 (CϵCH),
128.4, 128.6, 128.9, 130.3 (4 CHAr), 131.1 (C-pB), 132.7 (C-iA),
133.0 (C-5), 135.2 (C-pA), 136.5 (C-iB), 147.2 (C-4), 157.4 (C-6),
163.6 (C-2) ppm. HRMS (ESI): calcd. for C18H11N2Cl 291.0684
[M + H]+; found 291.0681.
2-(4-Chlorophenyl)-4-ethynyl-5-(4-nitrophenyl)pyrimidine (8b): Grey
1
solid; yield 222 mg (66%); m.p. 210–213 °C. H NMR (300 MHz,
CDCl3): δ = 3.41 (s, 1 H, CϵCH), 7.49 (d, J = 8.5 Hz, 2 H, m-
HB), 7.82 (d, J = 8.5 Hz, 2 H, o-HA), 8.38 (d, J = 8.5 Hz, 2 H, m-
HA), 8.47 (d, J = 8.5 Hz, 2 H, o-HB), 8.85 (s, 1 H, 6-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 80.0 (CϵCH), 84.6 (CϵCH), 123.9
(C-mA), 129.0, 129.9, 130.0 (3 CHAr), 132.2 (C-iB), 134.7 (C-5),
137.9 (C-pB), 140.8 (C-iA), 147.5 (C-4), 148.1 (C-pA), 157.3 (C-6),
163.5 (C-2) ppm. HRMS (ESI): calcd. for C18H10N3O2Cl 336.0534
[M + H]+; found 336.0526.
5-(4-Chlorophenyl)-4-ethynyl-2-(4-methylphenyl)pyrimidine (8i):
Colorless solid; yield 240 mg (79%); m.p. 160–161 °C (dec.). 1H
NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 3.35 (s, 1 H,
CϵCH), 7.31 (d, J = 8.1 Hz, 2 H, m-HB), 7.48 (d, J = 8.4 Hz, 2
H, m-HA), 7.57 (d, J = 8.5 Hz, 2 H, o-HA), 8.39 (d, J = 8.2 Hz, 2
H, o-HB), 8.79 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 21.5 (CH3), 80.7 (CϵCH), 83.5 (CϵCH), 128.4, 128.9, 129.4,
130.3 (4 CHAr), 132.7 (C-iA), 132.9 (C-5), 133.8 (C-iB), 135.1 (C-
pA), 141.5 (C-pB), 147.2 (C-4), 157.3 (C-6), 163.7 (C-2) ppm.
HRMS (ESI): calcd. for C19H13N2Cl 305.0839 [M + H]+; found
305.0831.
4-Ethynyl-5-(4-nitrophenyl)-2-phenylpyrimidine (8c): Colorless solid;
1
yield 220 mg (73%); m.p. 180–182 °C (dec.). H NMR (300 MHz,
CDCl3): δ = 3.40 (s, 1 H, CϵCH), 7.52 (m, 3 H, m,p-HB), 7.82 (d,
J = 8.7 Hz, 2 H, o-HA), 8.37 (d, J = 8.7 Hz, 2 H, m-HA), 8.49–8.52
(m, 2 H, o-HB), 8.86 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 80.1 (CϵCH), 84.4 (CϵCH), 123.9 (C-mA), 128.5,
128.7, 130.0 (3 CHAr), 131.5 (C-pB), 132.0 (C-5), 136.2 (C-iB), 140.9
(C-iA), 147.4 (C-4), 148.0 (C-pA), 157.2 (C-6), 164.4 (C-2) ppm.
HRMS (ESI): calcd. for C18H11N3O2 302.0924 [M + H]+; found
302.0933.
5-(4-Chlorophenyl)-4-ethynyl-2-(4-methoxyphenyl)pyrimidine (8j):
Colorless solid; yield 193 mg (60%); m.p. 172–173 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 3.34 (s, 1 H, CϵCH), 3.89 (s, 3 H,
OCH3), 7.01 (d, J = 8.9 Hz, 2 H, m-HB), 7.48 (d, J = 8.5 Hz, 2 H,
m-HA), 7.57 (d, J = 8.5 Hz, 2 H, o-HA), 8.45 (d, J = 8.9 Hz, 2 H,
o-HB), 8.76 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
55.4 (OCH3), 80.7 (CϵCH), 83.4 (CϵCH), 113.9 (C-mB), 128.9,
130.1, 130.3 (3 CHAr), 129.2 (C-iB), 132.2 (C-iA), 132.9 (C-5), 135.0
(C-pA), 147.1 (C-4), 157.3 (C-6), 162.2, 163.4 (C-pB, C-2) ppm.
HRMS (ESI): calcd. for C19H13N2Cl 321.0789 [M + H]+; found
321.0784.
4-Ethynyl-5-(4-nitrophenyl)-2-(4-methylphenyl)pyrimidine (8d): Grey
solid; yield 156 mg (50 %); m.p. 213-215 °C (dec.). 1H NMR
(400 MHz, [D6]DMSO): δ = 2.40 (s, 3 H, CH3), 4.79 (s, 1 H,
CϵCH), 7.38 (d, J = 8.1 Hz, 2 H, m-HB), 7.99 (d, J = 8.8 Hz, 2
H, o-HA), 8.32 (d, J = 8.1 Hz, 2 H, o-HB), 8.38 (d, J = 8.8 Hz, 2
H, m-HA), 9.05 (s, 1 H, 6-H) ppm. 13C NMR (100 MHz, [D6]
DMSO): δ = 21.0 (CH3), 80.3 (CϵCH), 87.9 (CϵCH), 123.5 (C-
mA), 127.9 (C-mB), 129.5 (C-oB), 130.6 (C-oA), 131.7 (C-5), 133.5 4-Ethynyl-2-(4-nitrophenyl)-5-phenylpyrimidine (8k): Colorless so-
(C-iB), 140.8 (C-iA), 141.5 (C-pB), 146.9 (C-4), 147.5 (C-4), 158.0 lid; yield 144 mg (48 %); m.p. 173–175 °C (dec.). 1H NMR
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42045
/KAP1
Date: 24-04-14 17:34:39
Pages: 9
P. R. Golubev, A. S. Pankova, M. A. Kuznetsov
FULL PAPER
(300 MHz, CDCl3): δ = 3.41 (s, 1 H, CϵCH), 7.52–7.54 (m, 3 H, H, m-HB), 7.54 (d, J = 8.0 Hz, 2 H, o-HA), 8.44 (d, J = 8.5 Hz, 2
m.p-HA), 7.62–7.65 (m, 2 H, o-HA), 8.34 (d, J = 8.7 Hz, 2 H, o- H, o-HB), 8.82 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ
HB), 8.69 (d, J = 8.7 Hz, 2 H, m-HB), 8.90 (s, 1 H, 6-H) ppm. 13C = 21.3 (CH3), 80.9 (CϵCH), 83.4 (CϵCH), 128.80, 128.84, 129.4,
NMR (75 MHz, CDCl3): δ = 80.4 (CϵCH), 84.2 (CϵCH), 123.8
129.6 (4 CHAr), 131.2 (C-iA), 134.3 (C-5), 135.2 (C-iB), 137.2 (C-
(C-mB), 128.8, 129.0, 129.2 (3 CHAr), 129.3 (C-pA), 133.7 (C-5), pB), 139.0 (C-pA), 147.2 (C-4), 157.6 (C-6), 162.1 (C-2) ppm.
135.2 (C-iA), 142.4 (C-iB), 147.5 (C-4), 149.4 (C-pB), 157.9 (C-6), HRMS (ESI): calcd. for C19H13N2Cl 305.0839 [M + H]+; found
161.1 (C-2) ppm. HRMS (ESI): calcd. for C18H11N3O2 324.0744
[M + Na]+; found 324.0733.
305.0846.
4-Ethynyl-5-(4-methylphenyl)-2-phenylpyrimidine (8r): Colorless so-
lid; yield 168 mg (62%); m.p. 101–103 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.45 (s, 3 H, CH3), 3.34 (s, 1 H, CϵCH), 7.32 (d, J =
8.0 Hz, 2 H, m-HA), 7.50–7.52 (m, 3 H, m,p-HB), 7.55 (d, J =
8.0 Hz, 2 H, o-HA), 8.48–8.53 (m, 2 H, o-HB), 8.85 (s, 1 H, 6-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 81.0
(CϵCH), 83.2 (CϵCH), 128.3, 128.6, 128.9, 129.4 (4 CHAr), 130.9
(C-pB), 131.3 (C-iA), 134.1 (C-5), 136.7 (C-iB), 138.9 (C-pA), 147.1
(C-4), 157.6 (C-6), 163.1 (C-2) ppm. HRMS (ESI): calcd. for
C19H14N2 271.1230 [M + H]+; found 271.1234.
2-(4-Chlorophenyl)-4-ethynyl-5-phenylpyrimidine (8l): Colorless so-
lid; yield 162 mg (56 %); m.p. 166–167 °C (dec.). 1H NMR
(300 MHz, CDCl3): δ = 3.35 (s, 1 H, CϵCH), 7.46–7.54 (m, 5 H,
m,p-HA, m-HB), 7.62–7.65 (m, 2 H, o-HA), 8.45 (d, J = 8.5 Hz, 2
H, o-HB), 8.84 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 80.7 (CϵCH), 83.5 (CϵCH), 128.7, 128.8, 129.0, 129.7 (4 CHAr),
128.9 (C-pA), 134.2, 134.3 (C-iA, C-5), 135.2 (C-iB), 137.3 (C-pB),
147.3 (C-4), 157.6 (C-6), 162.4 (C-2) ppm. HRMS (ESI): calcd. for
C18H11N2Cl 291.0683 [M + H]+; found 291.0681.
4-Ethynyl-2,5-bis(4-methylphenyl)pyrimidine (8s): Colorless solid;
yield 137 mg (48%); m.p. 98–99 °C. H NMR (300 MHz, CDCl3):
4-Ethynyl-2,5-diphenylpyrimidine (8m): Colorless solid; yield
123 mg (48 %); m.p. 126–128 °C (dec.). 1H NMR (300 MHz,
CDCl3): δ = 3.34 (s, 1 H, CϵCH), 7.45–7.55 (m, 6 H, m.p-HA, m,p-
HB), 7.63–7.66 (m, 2 H, o-HA), 8.48–8.52 (m, 2 H, o-HB), 8.86 (s,
1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 80.8 (CϵCH),
83.3 (CϵCH), 128.3, 128.61, 128.64, 129.0 (4 CHAr), 128.9 (C-pA),
131.0 (C-pB), 134.1, 134.3 (C-iA, C-5), 136.7 (C-iB), 147.3 (C-4),
157.6 (C-6), 163.4 (C-2) ppm. HRMS (ESI): calcd. for C18H12N2
257.1073 [M + H]+; found 257.1079.
1
δ = 2.44 (s, 6 H, 2 CH3), 3.33 (s, 1 H, CϵCH), 7.29–7.32 (m, 4 H,
m-HA,B), 7.54 (d, J = 7.4 Hz, 2 H, o-HA), 8.38 (d, J = 7.8 Hz, 2 H,
o-HB), 8.81 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.3, 21.5 (2 CH3), 81.1 (CϵCH), 83.0 (CϵCH), 128.3, 128.9, 2ϫ
129.4 (4 CHAr), 131.5 (C-iA), 133.8 (C-iB), 134.1 (C-5), 138.8 (C-
pA), 141.3 (C-pB), 147.1 (C-4), 157.5 (C-6), 163.2 (C-2) ppm.
HRMS (ESI): calcd. for C20H16N2 285.1386 [M + H]+; found
285.1388.
4-Ethynyl-5-phenyl-2-(4-methylphenyl)pyrimidine (8n): Colorless so-
lid; yield 154 mg (57%); m.p. 111–112 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.44 (s, 3 H, CH3), 3.33 (s, 1 H, CϵCH), 7.31 (d, J =
8.0 Hz, 2 H, m-HB), 7.47–7.53 (m, 3 H, m,p-HA), 7.63–7.65 (m, 2
H, o-HA), 8.40 (d, J = 8.0 Hz, 2 H, o-HB), 8.83 (s, 1 H, 6-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 80.9 (CϵCH), 83.2
(CϵCH), 128.3, 128.6, 129.0, 129.4 (4 CHAr), 128.8 (C-pA), 133.8,
134.0 (C-iB, C-5), 134.4 (C-iA), 141.3 (C-pB), 147.2 (C-4), 157.6 (C-
6), 163.4 (C-2) ppm. HRMS (ESI): calcd. for C19H14N2 271.1230
[M + H]+; found 271.1225.
4-Ethynyl-2-(4-methoxyphenyl)-5-(4-methylphenyl)pyrimidine (8t):
Colorless solid; yield 190 mg (63%); m.p. 171–173 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 2.44 (s, 3 H, ArCH3), 3.33 (s, 1 H,
CϵCH), 3.89 (s, 3 H, OCH3), 7.01 (d, J = 8.8 Hz, 2 H, m-HB),
7.31 (d, J = 8.0 Hz, 2 H, m-HA), 7.53 (d, J = 8.0 Hz, 2 H, o-HA),
8.45 (d, J = 8.8 Hz, 2 H, o-HB), 8.79 (s, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.3 (ArCH3), 55.4 (OCH3), 81.1 (CϵCH),
82.9 (CϵCH), 113.9 (C-mB), 128.8, 129.3, 129.9 (3 CHAr), 129.4
(C-iB), 131.5 (C-iA), 133.3 (C-5), 138.8 (C-pA), 147.0 (C-4), 157.5
(C-6), 162.1 (C-pB), 162.9 (C-2) ppm. HRMS (ESI): calcd. for
C20H16N2O 323.1156 [M + Na]+; found 323.1165.
4-Ethynyl-2-(4-methoxyphenyl)-5-phenylpyrimidine (8o): Colorless
solid; yield 163 mg (57 %); m.p. 120–122 °C (dec.). 1H NMR
(300 MHz, CDCl3): δ = 3.32 (s, 1 H, CϵCH), 3.89 (s, 3 H, OCH3),
7.01 (d, J = 8.7 Hz, 2 H, m-HB), 7.48–7.51 (m, 3 H, m,p-HA), 7.62–
7.64 (m, 2 H, o-HA), 8.46 (d, J = 8.7 Hz, 2 H, o-HB), 8.80 (s, 1 H,
6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.4 (OCH3), 80.9
(CϵCH), 83.0 (CϵCH), 113.9 (C-mB), 128.6, 129.0, 130.0 (C-o,mA,
C-oB), 128.7 (C-pA), 129.3 (C-iB), 133.4 (C-5), 134.5 (C-iA), 147.1
(C-4), 157.5 (C-6), 162.1 (C-pB), 163.1 (C-2) ppm. HRMS (ESI):
calcd. for C19H14N2O 287.1179 [M + H]+; found 287.1191.
4-Ethynyl-5-(4-methoxyphenyl)-2-(4-nitrophenyl)pyrimidine (8u):
Yellowish solid; yield 143 mg (43%); m.p. 212–215 °C (dec.). 1H
NMR (300 MHz, [D6]DMSO): δ = 3.84 (s, 3 H, OCH3), 4.80 (s, 1
H, CϵCH), 7.12 (d, J = 8.0 Hz, 2 H, m-HA), 7.70 (d, J = 8.0 Hz,
2 H, o-HA), 8.40 (d, J = 8.5 Hz, 2 H, o-HB), 8.63 (d, J = 8.5 Hz, 2
H, m-HB), 9.08 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 55.3 (OCH3), 80.8 (CϵCH), 87.7 (CϵCH), 114.2 (C-
mA), 124.1, 128.9, 130.5 (3 CHAr), 125.5 (C-iA), 134.4 (C-5), 142.1
(C-iB), 146.7 (C-4), 149.0 (C-pB), 158.3 (C-6), 159.7, 160.1 (C-2, C-
pA) ppm. HRMS (ESI): calcd. for C19H13N3O3 354.0850 [M +
Na]+; found 354.0848.
4-Ethynyl-5-(4-methylphenyl)-2-(4-nitrophenyl)pyrimidine (8p): Col-
orless solid; yield 205 mg (65%); m.p. 163–165 °C (dec.). 1H NMR
(400 MHz, [D6]DMSO): δ = 2.39 (s, 3 H, CH3), 4.81 (s, 1 H,
CϵCH), 7.37 (d, J = 8.0 Hz, 2 H, m-HA), 7.63 (d, J = 8.0 Hz, 2
H, o-HA), 8.40 (d, J = 9.0 Hz, 2 H, o-HB), 8.63 (d, J = 9.0 Hz, 2
H, m-HB), 9.09 (s, 1 H, 6-H) ppm. 13C NMR (100 MHz, [D6]
DMSO): δ = 20.8 (CH3), 80.6 (CϵCH), 87.8 (CϵCH), 124.0 (C-
mB), 128.9, 129.0, 129.2 (3 CHAr), 130.5 (C-iA), 134.6 (C-5), 138.8
(C-pA), 141.9 (C-iB), 146.9 (C-4), 149.0 (C-pB), 158.3 (C-6), 159.9
(C-2) ppm. HRMS (ESI): calcd. for C19H13N3O2 316.1081 [M +
H]+; found 316.1083.
2-(4-Chlorophenyl)-4-ethynyl-5-(4-methoxyphenyl)pyrimidine (8v):
Colorless solid; yield 195 mg (61%); m.p. 194–196 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 3.36 (s, 1 H, CϵCH), 3.88 (s, 3 H,
OCH3), 7.04 (d, J = 8.5 Hz, 2 H, m-HA), 7.46 (d, J = 8.5 Hz, 2 H,
m-HB), 7.59 (d, J = 8.5 Hz, 2 H, o-HA), 8.44 (d, J = 8.5 Hz, 2 H,
o-HB), 8.82 (s, 1 H, 6-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 55.0 (OCH3), 80.6 (CϵCH), 86.4 (CϵCH), 113.8 (C-mA), 125.6
(C-iA), 128.3, 129.0, 129.9 (3 CHAr), 133.3 (C-5), 135.0 (C-iB), 135.6
(C-pB), 146.2 (C-4), 157.4 (C-6), 159.7 (C-pA), 160.4 (C-2) ppm.
HRMS (ESI): calcd. for C19H13N2OCl 321.0789 [M + H]+; found
321.0791.
2-(4-Chlorophenyl)-4-ethynyl-5-(4-methylphenyl)pyrimidine (8q):
Colorless solid; yield 164 mg (54%); m.p. 155–156 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 2.45 (s, 3 H, CH3), 3.35 (s, 1 H,
CϵCH), 7.32 (d, J = 8.0 Hz, 2 H, m-HA), 7.47 (d, J = 8.5 Hz, 2
4-Ethynyl-5-(4-methoxyphenyl)-2-phenylpyrimidine (8w): Colorless
solid; yield 158 mg (55 %); m.p. 158–160 °C (dec.). 1H NMR
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42045
/KAP1
Date: 24-04-14 17:34:39
Pages: 9
Approach to 4-Ethynylpyrimidines via Alkenynones
(300 MHz, CDCl3): δ = 3.36 (s, 1 H, CϵCH), 3.88 (s, 3 H, OCH3),
7.04 (d, J = 8.6 Hz, 2 H, m-HA), 7.49–7.51 (m, 3 H, m,p-HB), 7.60
(d, J = 8.6 Hz, 2 H, o-HA), 8.47–8.50 (m, 2 H, o-HB), 8.84 (s, 1 H,
CϵCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.3 (OCH3), 81.1
(CϵCH), 83.1 (CϵCH), 114.1 (C-mA), 126.4 (C-iA), 128.2, 128.6,
130.2 (3 CHAr), 130.9 (C-pB), 133.8 (C-5), 136.7 (C-iB), 146.9 (C-
4), 157.5 (C-6), 160.2 (C-pA), 162.9 (C-2) ppm. HRMS (ESI): calcd.
for C19H14N2O 287.1179 [M + H]+; found 287.1183.
Acknowledgments
The authors thank Saint Petersburg State University for financial
support (grant numbers 12.38.16.2011 and 12.38.195.2014). NMR,
HRMS and XRD analyses were performed at the Saint Petersburg
State University Center for Magnetic Resonance, Center for Chem-
ical Analysis and Materials Research and X-ray Diffraction Center,
respectively. The authors thank Dr. Alexey Fedorov (ETH Zürich)
for his help in the preparation of this manuscript.
4-Ethynyl-5-(4-methoxyphenyl)-2-(4-methylphenyl)pyrimidine (8x):
Colorless solid; yield 156 mg (52%); m.p. 178–179 °C (dec.). 1H
NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H, ArCH3), 3.34 (s, 1 H,
CϵCH), 3.88 (s, 3 H, OCH3), 7.03 (d, J = 8.7 Hz, 2 H, m-HA),
7.30 (d, J = 8.0 Hz, 2 H, m-HB), 7.59 (d, J = 8.7 Hz, 2 H, o-HA),
8.38 (d, J = 8.0 Hz, 2 H, o-HB), 8.81 (s, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.2 (ArCH3), 55.1 (OCH3), 80.9 (CϵCH),
83.0 (CϵCH), 113.9 (C-mA), 126.3 (C-iA), 127.9, 129.1, 130.0 (3
CHAr), 133.3 (C-iB), 133.8 (C-5), 140.9 (C-pB), 146.7 (C-4), 157.2
(C-6), 159.9 (C-pA), 162.7 (C-2) ppm. HRMS (ESI): calcd. for
C20H16N2O 301.1335 [M + H]+; found 301.1320.
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4-Ethynyl-2,5-bis(4-methoxyphenyl)pyrimidine (8y): Colorless solid;
1
yield 143 mg (45%); m.p. 179–181 °C (dec.). H NMR (300 MHz,
CDCl3): δ = 3.33 (s, 1 H, CϵCH), 3.87 (s, 3 H, OCH3), 3.89 (s, 3
H, OCH3), 6.99–7.04 (m, 4 H, m-HA,B), 7.58 (d, J = 8.7 Hz, 2 H,
o-HA), 8.44 (d, J = 8.7 Hz, 2 H, o-HB), 8.78 (s, 1 H, 6-H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 55.3, 55.4 (2 OCH3), 81.2 (CϵCH),
82.9 (CϵCH), 113.9, 114.1 (C-mA,B), 126.6 (C-iA), 129.4 (C-iB),
129.9, 130.2 (C-oA,B), 133.0 (C-5), 146.8 (C-4), 157.4 (C-6), 160.1
(C-pA), 162.0 (C-pB), 162.7 (C-2) ppm. HRMS (ESI): calcd. for
C20H16N2O2 317.1284 [M + H]+; found 317.1289.
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5-(4-Nitrophenyl)-2-phenyl-4-[(trimethylsilyl)ethynyl]pyrimidine
(9a): Colorless solid; yield 55 mg, (15 %); m.p. 156–158 °C. 1H
NMR (400 MHz, CDCl3): δ = 0.21 [s, 9 H, Si(CH3)3], 7.49–7.52
(m, 3 H, m,p-HB), 7.84 (d, J = 8.7 Hz, 2 H, o-HA), 8.35 (d, J =
8.7 Hz, 2 H, m-HA), 8.50–8.52 (m, 2 H, o-HB), 8.84 (s, 1 H, 6-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = –0.8 [Si(CH3)3], 100.8
(CϵCSi), 104.4 (CϵCSi), 123.6 (C-mA), 128.5, 128.7, 130.1 (3
CHAr), 131.4 (C-pB), 131.7 (C-5), 136.4 (C-iB), 141.3 (C-iA), 147.9,
148.0 (C-pA, C-4), 157.0 (C-6), 164.4 (C-2) ppm. HRMS (ESI):
calcd. for C21H19N3O2Si 374.1319 [M + H]+; found 374.1312.
2,5-Diphenyl-4-[(trimethylsilyl)ethynyl]pyrimidine (9b): Yellowish
solid; yield 200 mg (61%); m.p. 93–95 °C. 1H NMR (300 MHz,
CDCl3): δ = 0.20 [s, 9 H, Si(CH3)3], 7.46–7.51 (m, 6 H, m,p-HA,B),
7.65–7.68 (m, 2 H, o-HA), 8.49–8.52 (m, 2 H, o-HB), 8.84 (s, 1 H,
6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.7 [Si(CH3)3], 101.7
(CϵCSi), 102.9 (CϵCSi), 128.4 (C-mA,B), 128.5 (C-oA), 128.7 (C-
pA), 129.1 (C-oB), 130.8 (C-pB), 134.0 (C-5), 134.6 (C-iA), 136.9 (C-
iB), 147.9 (C-4), 157.3 (C-6), 163.3 (C-2) ppm. HRMS (ESI): calcd.
for C21H20N2Si [M + H]+ 329.1468; found 329.1473.
5-(4-Methoxyphenyl)-2-phenyl-4-[(trimethylsilyl)ethynyl]pyrimidine
(9c): Yellowish solid; yield 268 mg (75%); m.p. 106–107 °C. 1H
NMR (300 MHz, CDCl3): δ = 0.22 [s, 9 H, Si(CH3)3], 3.88 (s, 3 H,
OCH3), 7.01 (d, J = 8.5 Hz, 2 H, m-HA), 7.48–7.50 (m, 3 H, m,p-
HB), 7.62 (d, J = 8.5 Hz, 2 H, o-HA), 8.46–8.50 (m, 2 H, o-HB),
8.82 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.7
[Si(CH3)3], 55.4 (OCH3), 101.9 (CϵCSi), 102.6 (CϵCSi), 113.9 (C-
mA), 126.8 (C-iA), 128.3, 128.5, 130.4 (3 CHAr), 130.7 (C-pB), 133.6
(C-5), 136.9 (C-iB), 147.5 (C-4), 157.1 (C-6), 160.1 (C-pA), 162.8
(C-2) ppm. HRMS (ESI): calcd. for C22H22N2OSi 359.1574 [M +
H]+; found 359.1579.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O42045
/KAP1
Date: 24-04-14 17:34:39
Pages: 9
P. R. Golubev, A. S. Pankova, M. A. Kuznetsov
FULL PAPER
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Received: March 13, 2014
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42045
/KAP1
Date: 24-04-14 17:34:39
Pages: 9
Approach to 4-Ethynylpyrimidines via Alkenynones
Acetylenic Pyrimidines
P. R. Golubev, A. S. Pankova,
M. A. Kuznetsov* .............................. 1–9
Transition-Metal-Free Approach to 4-
Ethynylpyrimidines via Alkenynones
A three-step method for the synthesis of 4-
alkynylpyrimidines by the transformation
of bis(trimethylsilyl)acetylene into en-
ynones followed by their condensation with
arylamidines is described. Alkynylpyrimid-
ines with either a deprotected triple bond
or a TMS group can be obtained selectively
by adjustment of the conditions of the last
step.
Keywords: Synthetic methods / Nitrogen
heterocycles / Alkynes / Amidines
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9