1,3-Dipolar cycloaddition of azinium ylides to alkynyl hetarenes: A synthetic route to indolizine and pyrrolo[2,1-a]isoquinoline based heterobiaryls

Article abstract of DOI:10.1016/j.tet.2016.03.050

For the first time, π-deficient alkynyl hetarenes were used as dipolarophiles in a 1,3-dipolar cycloaddition reaction with in situ generated azinium ylides. A three-component reaction of pyridine or isoquinoline, ethyl chloroacetate and alkynyl hetarene (

Full text of DOI:10.1016/j.tet.2016.03.050

Accepted Manuscript
1,3-Dipolar cycloaddition of azinium ylides to alkynyl hetarenes: a synthetic route to
indolizine and pyrrolo[2,1-a]isoquinoline based heterobiaryls
Julia I. Nelina-Nemtseva, Anna V. Gulevskaya, Alexander F. Pozharskii, Huong T.L.
Nguyen, Ekaterina A. Filatova
PII:
S0040-4020(16)30179-X
10.1016/j.tet.2016.03.050
TET 27590
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 January 2016
Revised Date: 7 March 2016
Accepted Date: 14 March 2016
Please cite this article as: Nelina-Nemtseva JI, Gulevskaya AV, Pozharskii AF, Nguyen HTL, Filatova
EA, 1,3-Dipolar cycloaddition of azinium ylides to alkynyl hetarenes: a synthetic route to indolizine and
pyrrolo[2,1-a]isoquinoline based heterobiaryls, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.050.
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ACCEPTED MANUSCRIPT
Graphical Abstract
1
,3-Dipolar cycloaddition of azinium ylides to alkynyl
Leave this area blank for abstract info.
hetarenes: a synthetic route to indolizine and
pyrrolo[2,1-a]isoquinoline based heterobiaryls
Julia I. Nelina-Nemtseva, Anna V. Gulevskaya, Alexander F. Pozharskii, Huong T. L. Nguyen, Ekaterina A.
Filatova
Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation

2
ACCEPTED MANUSCRIPT
1
,3-Dipolar cycloaddition of azinium ylides to alkynyl hetarenes: a synthetic route to
indolizine and pyrrolo[2,1-a]isoquinoline based heterobiaryls
a
a,
a
Julia I. Nelina-Nemtseva, Anna V. Gulevskaya, * Alexander F. Pozharskii, Huong T. L.
b
a
Nguyen, Ekaterina A. Filatova
a
Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don
44090, Russian Federation
Sai Gon University, 273 An Duong Vuong Street, District 5, Ho Chi Minh City, Vietnam
3
b
Abstract
For the first time, π-deficient alkynyl hetarenes were used as dipolarophiles in a 1,3-dipolar
cycloaddition reaction with in situ generated azinium ylides. A three-component reaction of
pyridine or isoquinoline, ethyl chloroacetate and alkynyl hetarene (pyrazine, quinoxaline, uracil,
or lumazine derivative) in the presence of a base gave the corresponding indolizine or
pyrrolo[2,1-a]isoquinoline based heterobiaryl in good yields. The reactions proceeded with high
regioselectivity; in all cases the most electron-deficient carbon atom of the C≡C bond of the
starting alkynyl hetarene adds to the side-chain carbon of the azinium ylide. 1,3-Dipolar
cycloaddition reactions of alkynyl hetarenes with azinium ylides or other 1,3-dipole reagents can
be considered as an alternative synthetic approach to heterobiaryls.
Keywords: 1,3-Dipolar cycloaddition; Azinium ylides; Alkynyl hetarenes; Indolizines;
Pyrrolo[2,1-a]isoquinolines; Heterobiaryls.
1
. Introduction
Many naturally occurring compounds, pharmaceuticals, ligands and functional materials
1
contains a biaryl fragment. The synthesis of biaryls has a long history: from the Ullmann
2
3
reaction to the Suzuki-Miyaura cross-coupling and related transition metal catalyzed
4
a
transformations of arylhalides (pseudohalides) with the arylmetals. Although cross-coupling
reactions have historically been developed for haloarene substrates, they are now widely applied
4
to haloheteroarenes as well. However, the application of catalyst systems, originally developed
5
for carbocyclic coupling partners, to their heterocyclic analogues is not always straightforward.
Even the widely practiced Suzuki coupling of heterocycles as one or both partners has several
limitations; such as sourcing of an appropriate functionalized heteroarylboronic acid or esters,
*
Corresponding author. Tel.: +7 863 297 5151 ; fax: +7 863 297 5151 ; e-mail addresses: аgulevskaya@sfedu.ru, anvasgul@gmail.com (A.V.
Gulevskaya).

3
ACCEPTED MANUSCRIPT
low reactivity due to binding of heteroatoms in the substrates or products to the catalyst, and
6
rather expensive ligands and catalysts. Meanwhile, heteroaryl-heteroaryl or heteroaryl-aryl
1
f
motifs are frequently present in the biologically active compounds. The development of new
strategies to enable the preparation of heterobiaryls therefore remains of major interest.
Recently, we have found that interaction of alkynyl derivatives of π-deficient azines with
sodium azide proceeds very easy, formally as a 1,3-dipolar cycloaddition of an azide ion to the
7
C≡C bond. For example, reaction of 3-alkynylquinoxaline-2-carbonitriles with NaN in DMF at
3
room temperature gives rise to 3-(2H-1,2,3-triazol-4-yl)quinoxaline-2-carbonitriles in good
7
b
yields (Scheme 1). From this we reasoned that interaction of 3-alkynylquinoxaline-2-
carbonitriles 1 and other alkynyl hetarenes with 1,3-dipole reagents could result in the formation
of heterobiaryls. In particular, the use of pyridinium ylides as 1,3-dipoles dipoles looked
promising for the synthesis of heteroaryl-indolizines (Scheme 2).
Scheme 1.
Scheme 2.
8
Indolizine is the structural basis of many natural alkaloids and other bioactive molecules. The
1
,3-dipolar cycloaddition of pyridinium ylides to alkynes is one of the most effective synthetic
8
a
methods for indolizines. Surprisingly in the known reactions of this type, esters of acetylene
8
-10
dicarboxylic and propiolic acids were mainly used as dipolarophiles.
To the best of our
1
1a,b
knowledge, only a few examples of using arylacetylenes (phenylacetylene,
p-
ethyl phenylpropiolate ) as dipolarophiles
were reported. The reaction of ethyl phenylpropiolate and phenylacetylene with pyridinium N-
1
1a
11a
11b
tolylacetylene,
1,4-diphenylbuta-1,3-diyne,
1
1b
dicyanomethylide was carried out under microwave irradiation in solvent-free conditions.
Intramolecular 1,3-dipolar cycloaddition reaction of 2-alkynyl-1-phenacylpyridinium bromides
1
1c,d
in the presence of DBU was also described.

4
ACCEPTED MANUSCRIPT
Herein, we wish to describe 1,3-dipolar cycloaddition reactions of some alkynyl hetarenes
with in situ generated pyridinium and isoquinolinium ylides allowing the synthesis of indolizine
and pyrrolo[2,1-a]isoquinoline based heterobiaryls in a simple and convenient way.
2
. Results and discussion
Alkynyl derivatives of pyrazine 1, quinoxaline 2, 1,3-dimethyluracil 3, 1,3-dimethyllumazine
4
and 1,3-dimethyl-1H-perimidin-2(3H)-one 5 have been chosen to be dipolarophiles (Fig. 1).
1
2
All these heterocycles constitute the core structures of many biologically active compounds.
Moreover, alkynyl hetarenes 1-5 are ready available via the Sonogashira coupling of the
1
3
14
7a
15
16
corresponding halides and 1-alkynes. Compounds 2a, 2b, 2c,d, 4, and 5a were prepared
in accordance with known procedures. Synthesis of alkynylpyrazines 1, 1,3-dimethyl-6-(p-
tolylethynyl)uracil 3 and 1,3-dimethyl-6-((4-nitrophenyl)ethynyl)-1H-perimidin-2(3H)-one 5b
were performed as described in Experimental Section.
N
X
N
X
N
N
Ph
a (X = Cl)
b (X = C C-Ph) 2b (X = CN, R = Ph)
R
1
1
2a (X = H, R = Ph)
2
c (X = C C-Ph, R = Ph)
2
d (X = C C-p-Tol, R = p-Tol)
O
Ph
O
Me
O
N
N
Me
N
N
N
Me
O
N
Me
p-Tol
3
4
Me
N
R
O
N
Me
5
a (R = Ph)
b (R = 4-NO -C H )
5
2
6 4
Fig. 1. Dipolarophiles used in this study.
To explore the feasibility of the above strategy, we began our investigations with 3-
phenylethynyl)quinoxaline-2-carbonitrile 2b and pyridinium salt 6 synthesized by the N-
(
quaternization of pyridine with ethyl chloroacetate (Scheme 3). Potassium tert-butoxide was
used to generate the ylide from salt 6. To our delight, ethyl 1-(3-cyanoquinoxalin-2-yl)-2-
phenylindolizine-3-carboxylate 7 was isolated in 47% yield from the reaction of 2b with 6 (1.5
equiv) in dry THF in the presence of t-BuOK (1.5 equiv) after 24 h under reflux (36% of the
starting compound was also isolated). The structure of quinoxalinyl-indolizine 7 was proved by
X-ray single crystal study (Fig. 2).

5
ACCEPTED MANUSCRIPT
Scheme 3.
Fig. 2. ORTEP plots for X-ray crystal structure of 7 (120K, P = 30%).
Thus, the observed 1,3-dipolar cycloaddition reaction did not touch the C≡N bond and
proceeded regioselectively. This high regioselectivity might be attributed to the electron-
withdrawing influence of the aza group of the starting molecule 2b, increasing the
electrophilicity of the C(β) atom of the C≡C bond (Scheme 4). 1,3-Dipole species 8, generated in
situ from N-alkylpyridinium salt 6 in the presence of a base, undergoes cycloaddition to the C≡C
bond of 2b as shown in Scheme 4 to form unstable intermediate 9. The latter rapidly undergoes
10c
10e
aromatization (presumably, via air oxidation or via elimination of hydrogen molecule ) to
afford 7 comprising a 10π electron system.

6
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t-BuOK
t-BuOH
KCl
N
Cl
N
H
N
-
H
H
-
CO Et
6
2
CO Et
CO Et
2
2
8
N
N
N
N
Ph
N
N
Ph
2b
+
7
H
H
H
N
CO Et
CO Et
2
2
N
H
8
9
Scheme 4.
This reaction, however, suffers from the inconvenience of handling hygroscopic pyridinium
salt 6. Therefore, we next checked the viability of a three-component one-pot reaction involving
1
,3-dipolar cycloaddition between the in situ generated dipole (from pyridine and ethyl
chloroacetate) and 3-(phenylethynyl)quinoxaline-2-carbonitrile 2b. Thus, pyridine and ethyl
o
chloroacetate were stirred for 1 h at 80 C. To the resulting mixture t-BuOK in dry THF were
added. After 20 min of refluxing and stirring, 3-(phenylethynyl)quinoxaline-2-carbonitrile 2b
was added and the reaction mixture was stirred for 24 h under reflux. The desired quinoxalinyl-
indolizine 7 was obtained in 46% yield (29% of 2b was recovered). The reaction carried out at
room temperature led to a poorer yield of 7. We attempted a similar reaction with other
base/solvent system, in particular, K CO /DMF and t-BuOK/DMSO, but the results were less
2
3
satisfactory (26 and 11% yields, respectively). In contrast, a combination of triethylamine and
o
DMSO (70 C, 24 h) afforded quinoxalinyl-indolizine 7 in 76% yield.
The reactions of other alkynyl hetarenes 1-5 were carried out under similar conditions
o
(
Et N/DMSO, 70 C, 24 h) using in situ generated pyridinium 8 and isoquinolinium 11 ylides
3
(Table 1). Excellent yields of the desired products were obtained with monoalkynyl quinoxalines
2
a,b and isoquinolinium ylide 11 (Table 1, entries 2,3). On the other hand, the π-deficiency of
the heterocyclic ring attached to the C≡C bond seems to play a key role in determining the
isolated yields. The reactions of less π-deficient 6-alkynyluracil 3 and 6-alkynyllumazine 4 with
ylide 11 gave the corresponding pyrrolo[2,1-a]isoquinolines 14 and 15 in moderate yields (Table
1
, entries 4,5). In our hand, the reaction of π-excessive 1,3-dimethylperimidone 5a with ylide 11
failed (Table 1, entry 6). However, introducing electron-withdrawing nitro group into the
o
phenylethynyl moiety and more harsh reaction conditions (100 C, 144 h) led to the formation
pyrrolo[2,1-a]isoquinoline product 16 in 55% yield (Table 1, entry 7).
Table 1

7
ACCEPTED MANUSCRIPT
Reactions of alkynyl hetarenes 1-5 with pyridinium and isoquinolinium ylides using
Et N/DMSO system
3
Entry Substrate Ylide
Product
Yield, %
76
1
2b
8
7
2
2b
11
72
12
3
4
2a
3
11
11
94
61
1
3
O
Me
O
N
p-Tol
N
Me
CO Et
2
N
1
4
a
5
4
11
32
1
5
b
6
7
5a
5b
11
11
No reaction
2
c
O N
55
Me
N
N
O
N
CO2Et
Me
16
d
8
1a
11
69
1
7

8
ACCEPTED MANUSCRIPT
9
2c
2d
1b
2c
2d
1b
8
76
83
1
1
0
2
2
8
p-Tol
p-Tol
1
0
1
2
3
4
8
N
N
CO Et
N
2
9
1
1
1
1
11
11
11
11
67
+
+
+
12 (23)
2
77
15 (24)
1
2
56
13 (25)
40
N
N
e
CO Et
2
+ 44 (20)
N
Ph
Ph
N
CO Et
2
2
3
2
2
1
1
5
6
2c
11
11
45
46 (21)
e
+
4
5
2d
57
+ 26 (22)
N
e
CO Et
2
N
p-Tol
p-Tol
N
CO Et
N
2
a
b
c
d
e
3
9
6% of 4 was recovered.
2% of 5 was recovered.
o
The reaction was carried out at 100 C for 144 h.
The reaction was carried out at room temperature for 118 h.
The reaction was carried out for 48 h with 2.5 equiv of ylide 11.

9
ACCEPTED MANUSCRIPT
2
-Chloro-3-(phenylethynyl)pyrazine 1a was also a suitable dipolarophile for this
cycloaddition process (Table 1, entry 8). The reaction of 1a with ylide 11 carried out at room
temperature left the chlorine atom of 1a intact. Applying standard conditions for this reaction (70
o
C, 24 h) led to partial tarring of the reaction mixture and gave 17 in 51% yield only.
Exposure of 2,3-dialkynyl quinoxalines 2c,d to the reaction with pyridinium ylide 8 (1.5
equiv) delivered the corresponding indolizines 18,19 in good yields (Table 1, entries 9,10).
However, the same reactions of diacetylenes 1b and 2c,d with isoquinolinium ylide 11 (1.5
equiv) gave the corresponding pyrrolo[2,1-a]isoquinolines 20-22 (56-77%) together with
products of double cycloaddition 23-25 (12-15%) (Table 1, entries 11-13). The use of 2.5 equiv
of ylide 11 and more prolonged heating changed the products ratio in favor of bis-pyrrolo[2,1-
a]isoquinolines 23-25 (Table 1, entries 14-16). Fortunately, both mono- and bis-pyrrolo[2,1-
a]isoquinoline products were easily separated by flash column chromatography.
The structures of synthesized heterobiaryls 7, 12−25 were supported by a combination of
1
13
elemental analysis, mass-spectrometry, IR, H and C NMR spectroscopic measurements. All of
the compounds are yellow-colored with λmax 358−433 nm. Their mass spectra included the
molecular peak ion, which for 12, 13, 15−18, 20, 23 was the most intensive. Their IR spectra
-1
indicated the presence of C=O group (ν 1672−1694 cm ). In cases of alkynyl derivatives 18−22
-1
the characteristic νC≡C band at 2206−2216 cm was also registered. The spectra of nitriles 7, 12
-1
1
included a νC≡N band at 2232−2234 cm . Notably, in the H NMR spectra the H(8) proton of the
indolizines 7, 18, 19 and the H(10) proton of pyrrolo[2,1-a]isoquinolines 12−17, 20−25 appeared
as a low-field doublet at 9.3−9.7 ppm. The structures of 21 (Fig. 3) and 24 (Fig. 4) were proved
by X-ray single crystal studies.

1
0
ACCEPTED MANUSCRIPT
Fig. 3. ORTEP plots for X-ray crystal structure of 21 (120K, P = 30%).
Fig. 4. ORTEP plots for X-ray crystal structure of 24 (120K, P = 30%, the only heteroatoms’
numbering is indicated).
It should be stressed again that in all cases the 1,3-dipolar cycloaddition reaction proceeded
regioselectively. Similarly to substrate 2b (Scheme 4), the most electron-deficient carbon atom
of the C≡C bond of the starting alkynyl hetarene (due to its conjugation with electron-

1
1
ACCEPTED MANUSCRIPT
withdrawing aza or nitro group) adds to the side-chain carbon of the azinium ylide as shown in
Scheme 5. No other regioisomers were detected in the reaction mixtures.
Scheme 5.
3
. Conclusions
The methodology reported herein denotes a highly regioselective, three-component, one-pot
,3-dipolar cycloaddition reaction of π-deficient alkynyl hetarenes and in situ generated azinium
1
ylides, which is expected to be a general route for the facile synthesis of a wide range of
indolizine and pyrrolo[2,1-a]isoquinoline based heterobiaryls. The 1,3-dipolar cycloaddition
process operates efficiently with alkynyl and ortho-dialkynyl derivatives of pyrazine,
quinoxaline, uracil and lumazine. The alkynyl hetarenes with ortho-chloro and ortho-cyano
substituents are well-tolerated. Considering the importance of indolizines as core structures in
8
b
pharmacologically active substances, this method may become attractive for both synthetic and
medicinal chemistry. Further investigation in this direction is ongoing in our laboratory.
4
. Experimental
4
.1. General
1
13
Proton ( H) and carbon ( C) nuclear magnetic resonance (NMR) spectra were recorded on a
1
13
Bruker DPX−250 spectrometer (250 and 62.9 MHz, respectively). H and C NMR chemical
shifts are in parts per million relative to Me Si. Coupling constants are in Hertz. The IR spectra
4
were recorded on a FT FSM-1202 spectrometer (http://infraspek.ru) using KBr. The UV-vis
spectra were recorded on Varian Cary 50 Probe spectrophotometer in CHCl . Mass spectra were
3
measured on a Finnigan MAT INCOS 50 spectrometer. CHN analysis was accomplished by
combustion analysis (Dumas and Pregl method). Melting points were determined in glass
capillaries using a Stuart SMP30 device and are uncorrected. Flash column chromatography was
performed on silica gel. All commercial reagents were purchased from Acros and Aldrich.
4
.2. X-ray structure determination

1
2
ACCEPTED MANUSCRIPT
Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited
at the Cambridge Crystallographic Data Centre (CCDC) and allocated the deposition numbers
CCDC 1441346 (7), CCDC 1441186 (21) and CCDC 1441194 (24).
4
.3. General procedure for the synthesis of hetaryl-indolizines and hetaryl-pyrrolo[2,1-
a]isoquinolines
Ethyl chloroacetate (55 mg, 0.45 mmol) and pyridine (36 mg, 0.45 mmol) or isoquinoline (53
mg, 0.45 mmol) were heated at 80 ºC for 1 h. Et N (0.5 mL) and DMSO (3 mL) were then added
3
and the reaction mixture was stirred for 20 min. Then the corresponding alkynyl hetarene 1-4
(0.30 mmol) was added. The reaction mixture was stirred at 70 ºC for 24 h (for synthesis of 17:
room temperature, 118 h) and treated with H O (100 mL). The resulting mixture was extracted
2
with CHCl (5 × 20 mL). The extract was dried over Na SO and evaporated to dryness. The
3
2
4
residue was purified by flash column chromatography on silica gel (3 × 30 cm) with CH Cl as
2
2
the eluent. Usually the fraction with R 0.5−0.7 was the recovered starting compound. The
f
yellow fraction with R 0.3−0.5 gave the corresponding hetaryl-indolizine or hetaryl-pyrrolo[2,1-
f
a]isoquinoline 7, 12-14, 17-22 (see Table 1 for yields). Bis-pyrrolo[2,1-a]isoquinoline products
2
3-25 were isolated from yellow fraction with R 0.2−0.3. For isolation of compound 15 a short
f
chromatography column (3 × 15 cm) was used. The fraction with R 0.2 was recovered 4. The
f
yellow fraction with R 0.1 gave 15.
f
4
.3.1. Ethyl 1-(3-cyanoquinoxalin-2-yl)-2-phenylindolizine-3-carboxylate (7). Dark yellow solid
o
1
with mp 203−205 C (heptane); H NMR (CDCl ) δ ppm: 1.03 (t, J=7.1 Hz, 3Н, СН CH ), 4.18
3
2
3
(
q, J=7.1 Hz, 2Н, СН CH ), 6.98 (td, J=7.0, 1.3 Hz, 1H), 7.15−7.35 (m, 6Н), 7.61 (dt, J=8.9, 1.2
2 3
Hz, 1H), 7.82 (ddd, J=8.4, 6.9, 1.7 Hz, 1H), 7.90 (ddd, J=8.4, 6.9, 1.7 Hz, 1H), 8.07−8.15 (m,
1
3
2
1
1
3
H), 9.68 (dt, J=7.2, 1.0 Hz, 1H); C NMR (CDCl ) δ ppm: 14.2, 60.5, 110.7, 113.1, 114.6,
3
16.4, 117.5, 125.1, 127.7, 128.0, 128.6, 129.6, 130.0, 131.5, 131.7, 132.2, 133.6, 133.9, 136.7,
-1
37.9, 140.5, 142.8, 151.0, 162.2; IR, cm : 1672 (C=O), 2232 (С≡N); UV−vis, λ
(lg ε), nm:
max
+
23 (3.73), 333 (3.72), 433 (3.14); MS m/z: 418 ([M ], 8), 346 (10), 293 (10), 216 (15), 190
(
11), 76 (21). Anal. calcd for C H N O : C, 74.63; H, 4.34; N, 13.39. Found: C, 74.54; H, 4.17;
26 18 4 2
N, 13.17.
4
.3.2. Ethyl 1-(3-cyanoquinoxalin-2-yl)-2-phenylpyrrolo[2,1-a]isoquinoline-3-carboxylate (12).
o
1
Yellow solid with mp 217−218 C (heptane); H NMR (CDCl ) δ ppm: 1.01 (t, J=7.1 Hz, 3Н,
3
СН CH ), 4.07−4.33 (m, 2Н, СН CH ), 7.10 (d, J=8.1 Hz, 1H), 7.17−7.24 (m, 4Н), 7.28−7.39
2
3
2
3

1
3
ACCEPTED MANUSCRIPT
(
m, 3Н), 7.50 (ddd, J=8.1, 7.0, 1.2 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.94−8.05 (m, 2Н), 8.22 (dd,
1
3
J=7.9, 1.9 Hz, 2H), 9.54 (d, J=7.6 Hz, 1H); C NMR (CDCl ) δ ppm: 13.6, 60.2, 113.1, 113.8,
3
1
1
14.6, 115.7, 123.1, 124.4, 125.0, 127.2 (2C), 127.5, 127.7, 128.0, 129.3, 129.7, 129.8, 131.0,
-1
31.4, 131.8, 132.1, 133.5, 133.7, 137.0, 140.5, 142.3, 152.6, 161.8; IR, cm : 1681 (C=O), 2234
(С≡N); UV−vis, λmax (lg ε), nm: 265 (4.66), 274 (4.62), 326 shoulder (4.17), 344 (4.15), 362
+
(
4.11), 423 (3.29); MS m/z: 468 ([M ], 100), 396 (50), 370 (32), 368 (12), 343 (19), 220 (16).
Anal. calcd for C H N O : C, 76.91; H, 4.30; N, 11.96. Found: C, 77.13; H, 4.08; N, 11.79.
3
0
20
4
2
4
.3.3. Ethyl 2-phenyl-1-(quinoxalin-2-yl)pyrrolo[2,1-a]isoquinoline-3-carboxylate (13). Yellow
o
1
solid with mp 222−224 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.98 (t, J=7.1 Hz, 3Н, СН CH ),
3
2
3
4
.18 (q, J=7.1 Hz, 2Н, СН CH ), 7.15−7.30 (m, 7Н), 7.44−7.47 (m, 1Н), 7.70 (d, J=8.2 Hz, 2H),
2 3
1
3
7
.79−7.82 (m, 2H), 8.10−8.16 (m, 2H), 8.62 (s, 1H), 9.52 (d, J=7.6 Hz, 1H); C NMR (CDCl ) δ
3
ppm: 13.6, 60.0, 113.7, 114.2, 116.2, 124.0, 124.8, 127.1, 127.2, 127.3, 127.4 (2C), 127.9, 129.3,
-
1
1
1
29.4, 129.8, 130.1, 130.7 (2C), 131.5, 134.5, 136.8, 140.8, 142.2, 147.8, 151.2, 161.8; IR, cm :
684 (C=O); UV−vis, λmax (lg ε), nm: 278 (4.67), 346 (4.14), 358 (4.13), 387 shoulder (3.80);
+
MS m/z: 443([M ], 100), 415 (14), 370 (20), 368 (10), 184 (11), 76 (19). Anal. calcd for
C H N O : C, 78.54; H, 4.77; N, 9.47. Found: C, 78.21; H, 4.56; N, 9.57.
29
21
3
2
4
.3.4. Ethyl 3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-2-p-tolylpyrrolo[1,2-
o
1
a]quinoline-1-carboxylate (14). Yellow solid with mp 226−228 C (i-PrOH); H NMR (CDCl )
3
δ ppm: 0.93 (t, J=7.1 Hz, 3Н, СН CH ), 2.35 (s, 3H, CH ), 3.09 (s, 3H, N-CH ), 3.38 (s, 3H, N-
2
3
3
3
CH ), 4.10 (q, J=7.1 Hz, 2Н, СН CH ), 5.80 (s, 1H), 7.05−7.14 (m, 5Н), 7.43−7.56 (m, 2Н),
3
2
3
1
3
7
6
1
.69−7.79 (m, 2H), 9.35 (d, J=7.6 Hz, 1H); C NMR (CDCl ) δ ppm: 13.6, 21.3, 28.2, 33.0,
3
0.2, 105.7, 109.8, 113.7, 114.7, 122.8, 123.9, 124.8, 127.4, 128.3, 128.5, 128.6, 129.0, 129.6,
-1
29.8, 130.4, 135.3, 137.4, 149.4, 152.7, 161.5, 162.3; IR, cm : 1653, 1668, 1706 (C=O);
UV−vis, λmax (lg ε), nm: 272 (4.90), 322 shoulder (4.27), 336 (4.19), 361 (4.18); MS m/z: 467
+
(
[M ], 71), 411 (30), 410 (100), 382 (15), 366 (16), 352 (17), 338 (29), 334 (11), 325 (11), 322
14), 308 (51), 293 (37), 280 (57), 266 (39), 253 (25), 241 (17), 191 (11), 182 (78), 175 (17), 161
22), 154 (33), 147 (50), 139 (33), 127 (18), 82 (24), 58 (18). Anal. calcd for C H N O : C,
(
(
28
25
3
4
7
1.93; H, 5.39; N, 8.99. Found: C, 72.12; H, 5.43; N, 8.74.
4
.3.5. Ethyl 3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropteridin-6-yl)-2-phenylpyrrolo[1,2-
o
1
a]quinoline-1-carboxylate (15). Yellow solid with mp 295−296 C (i-PrOH); H NMR (CDCl )
3
δ ppm: 0.89 (t, J=6.8 Hz, 3Н, СН CH ), 3.53 (s, 3H, N-CH ), 3.65 (s, 3H, N-CH ), 4.08 (q, J=6.8
2
3
3
3

1
4
ACCEPTED MANUSCRIPT
Hz, 2Н, СН CH ), 7.09 (d, J=7.5 Hz, 1H), 7.21 (app. s, 6H), 7.38−7.52 (m, 2Н), 7.65 (d, J=7.5
2
3
1
3
Hz, 1H), 8.31 (s, 1H), 9.41 (d, J=7.4 Hz, 1H); C NMR (CDCl ) δ ppm: 13.5, 29.1, 29.4, 60.0,
3
1
1
13.7, 114.0, 114.5, 123.7, 124.7 (2C), 126.8, 127.1, 127.2, 127.3, 127.4, 127.8, 129.2, 130.7,
-1
31.7, 134.5, 136.7, 146.3, 146.9, 149.9, 150.7, 159.8, 161.7; IR, cm : 1663, 1719 (C=O);
UV−vis, λmax (lg ε), nm: 267 (4.90), 281 (4.93), 326 shoulder (4.48), 339 (4.40), 364 (4.33), 401
+
(
3.65); MS m/z: 505 ([M ], 100), 476 (15), 458 (21), 432 (22). Anal. calcd for C H N O : C,
2
9
23
5
4
6
8.90; H, 4.59; N, 13.85. Found: C, 68.81; H, 4.45; N, 14.09.
4
.3.6. Ethyl 1-(3-chloropyrazin-2-yl)-2-phenylpyrrolo[2,1-a]isoquinoline-3-carboxylate (17).
o
1
Yellow solid with mp 144−146 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.99 (t, J=7.0 Hz, 3Н,
3
СН CH ), 4.18 (m, 2Н, СН CH ), 7.08−7.17 (m, 2Н), 7.21−7.32 (m, 6Н), 7.48 (t, J=7.4 Hz, 1Н),
2
3
2
3
1
3
7
.72 (d, J=7.8 Hz, 1H), 8.37 (s, 1H), 8.60 (d, J = 1.5 Hz, 1H), 9.48 (d, J=7.6 Hz, 1H); C NMR
(
CDCl ) δ ppm: 13.6, 60.0, 113.4, 114.0, 114.3, 123.1, 125.0, 127.0, 127.1, 127.2, 127.6, 127.7,
3
-1
1
29.0, 130.2, 130.3, 130.6, 134.4, 136.4, 142.5, 142.7, 151.2, 151.3, 161.8; IR, cm : 1694
(C=O); UV−vis, λmax (lg ε), nm: 276 (4.88), 326 (4.23), 346 (4.19), 364 (4.14); MS m/z: 427
+
(
[M ], 100), 355 (40), 346 (16), 318 (54), 292 (12), 266 (16), 159 (25). Anal. calcd for
C H ClN O : C, 70.18; H, 4.24; Cl, 8.29; N, 9.82. Found: C, 70.34; H, 4.05; Cl, 8.03; N, 10.11.
25
18
3
2
4
.3.7. Ethyl 2-phenyl-1-(3-(phenylethynyl)quinoxalin-2-yl)indolizine-3-carboxylate (18). Yellow
o
1
solid with mp 182−184 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.97 (t, J=7.1 Hz, 3Н, СН CH ),
3
2
3
4
1
1
1
.14 (m, 2Н, СН CH ), 6.93 (td, J=7.0, 1.3 Hz, 1H), 7.04−7.32 (m, 11Н), 7.58 (dm, J=8.9 Hz,
2 3
13
H), 7.68−7.75 (m, 2H), 7.96−8.08 (m, 2H), 9.68 (d, J=7.2 Hz, 1H); C NMR (CDCl ) δ ppm:
3
3.7, 59.9, 88.0, 94.3, 112.0, 113.1, 113.6, 117.9, 121.8, 123.7, 126.9, 127.0 (2C), 127.9, 128.3,
28.8, 129.1, 129.3, 130.1, 130.4, 130.9, 132.2, 134.6, 136.2, 137.7, 140.4, 140.7, 151.1, 162.1;
-1
IR, cm : 1677 (C=O), 2216 (С≡С); UV−vis, λ
(lg ε), nm: 286 (4.64), 338 (4.59), 412 (3.92);
max
+
MS m/z: 493 ([M ], 100), 420 (13), 293 (33), 210 (11). Anal. calcd for C H N O : C, 80.31; H,
3
3
23
3
2
4
.70; N, 8.51. Found: C, 80.54; H, 4.55; N, 8.37.
4
.3.8. Ethyl 2-p-tolyl-1-(3-(p-tolylethynyl)quinoxalin-2-yl)indolizine-3-carboxylate (19). Yellow
o
1
solid with mp 176−177 C (i-PrOH); H NMR (CDCl ) δ ppm: 1.02 (t, J=7.1 Hz, 3Н, СН CH ),
3
2
3
2
7
.22 (s, 3H, CH ), 2.32 (s, 3H, CH ), 4.17 (m, 2Н, СН CH ), 6.87−6.94 (m, 3Н), 7.04−7.15 (m,
3 3 2 3
Н), 7.55 (dm, J=8.9 Hz, 1H), 7.68−7.74 (m, 2H), 7.98−8.08 (m, 2H), 9.65 (d, J=7.2 Hz, 1H);
1
3
C NMR (CDCl ) δ ppm: 13.8, 21.2, 21.6, 59.8, 87.6, 94.8, 112.0, 113.1, 113.5, 117.8, 118.8,
3
1
23.5, 127.7, 127.9, 128.8, 129.0, 129.1, 130.0, 130.2, 130.8, 131.5, 132.1, 136.2, 136.5, 137.9,

1
5
ACCEPTED MANUSCRIPT
-1
1
39.7, 140.6, 140.7, 140.8, 151.3, 162.2; IR, cm : 1678 (C=O), 2206 (С≡С); UV−vis, λ (lg ε),
max
+
nm: 292 (3.32), 345 (4.32), 407 (3.70); MS m/z: 521 ([M ], 60), 307 (11), 292 (11), 231 (11),
2
29 (11), 216 (36), 209 (11), 140 (26), 115 (13), 78 (13), 29 (100). Anal. calcd for C H N O :
35 27 3 2
C, 80.59; H, 5.22; N, 8.06. Found: C, 80.67; H, 5.43; N, 7.89.
4
.3.9. Ethyl 2-phenyl-1-(3-(phenylethynyl)pyrazin-2-yl)pyrrolo[2,1-a]isoquinoline-3-carboxylate
o
1
(
20). Yellow solid with mp 139−140 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.98 (t, J=7.0 Hz,
3
3
7
Н, СН CH ), 4.18 (q, J=7.0 Hz, 2Н, СН CH ), 7.02 (d, J=7.0 Hz, 2Н), 7.15−7.31 (m, 10Н),
2 3 2 3
1
3
.45−7.51 (m, 2Н), 7.72 (d, J=7.8 Hz, 1H), 8.58 (d, J=4.1 Hz, 2H), 9.53 (d, J=7.6 Hz, 1H); C
NMR (CDCl ) δ ppm: 13.6, 60.0, 86.5, 95.3, 113.2, 113.9, 115.6, 121.6, 123.7, 124.8, 124.9,
3
1
1
26.8, 127.0, 127.1, 127.5, 127.7, 128.3, 129.0, 129.2, 130.5, 131.1, 131.8, 134.6, 137.0, 141.6,
-1
42.4, 142.8, 153.8, 162.0; IR, cm : 1680 (C=O), 2215 (C≡C); UV−vis, λ
(lg ε), nm: 270
max
+
(
4.84), 276 shoulder (4.40), 326 shoulder (4.84), 343 (4.14), 365 (4.11); MS m/z: 493 ([M ],
1
00), 420 (16), 127 (8). Anal. calcd for C H N O : C, 80.31; H, 4.70; N, 8.51. Found: C, 80.58;
33 23 3 2
H, 4.58; N, 8.23.
4
.3.10.
Ethyl
2-phenyl-1-(3-(phenylethynyl)quinoxalin-2-yl)pyrrolo[2,1-a]isoquinoline-3-
o
1
carboxylate (21). Yellow solid with mp 212−215 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.91 (t,
3
J=7.1 Hz, 3Н, СН CH ), 4.12 (q, J=7.1 Hz, 2Н, СН CH ), 6.97−7.03 (m, 2Н), 7.05−7.29 (m,
2
3
2
3
1
1Н), 7.38 (ddd, J=8.1, 6.7, 1.7 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.69−7.81 (m, 2H), 8.00−8.12
1
3
(
m, 2H), 9.49 (d, J=7.6 Hz, 1H); C NMR (CDCl ) δ ppm: 13.6, 60.0, 87.4, 95.2, 113.3, 113.9,
3
1
15.9, 123.8, 124.9, 126.8, 127.0 (2C), 127.6, 127.7, 128.3 (2C), 129.0, 129.1, 129.4 (2C), 130.5
-1
(
2C), 130.6, 131.4, 132.0 (2C), 134.5, 137.2, 140.6, 141.0, 141.3, 153.1, 162.0; IR, cm : 1686
(C=O), 2214 (С≡С); UV−vis, λmax (lg ε), nm: 266 (4.88), 347 (4.52), 363 (4.52), 411 (3.66); MS
+
m/z: 543 ([M ], 29), 343 (17), 235 (13), 127 (22), 76 (22), 29 (100). Anal. calcd for C H N O :
3
7
25
3
2
C, 81.75; H, 4.64; N, 7.73. Found: C, 81.61; H, 4.82; N, 7.95.
4
.3.11.
Ethyl
2-p-tolyl-1-(3-(p-tolylethynyl)quinoxalin-2-yl)pyrrolo[2,1-a]isoquinoline-3-
o
1
carboxylate (22). Yellow solid with mp 169−171 C (i-PrOH); H NMR (CDCl ) δ ppm: 1.01 (t,
3
J=7.1 Hz, 3Н, СН CH ), 2.24 (s, 3H, CH ), 2.33 (s, 3H, CH ), 4.15−4.24 (m, 2Н, СН CH ),
2
3
3
3
2
3
6
.91−6.97 (m, 4Н), 7.06 (d, J=8.0 Hz, 2Н), 7.15−7.24 (m, 5Н), 7.43 (ddd, J=8.1, 6.2, 1.9 Hz,
1
3
1
H), 7.71 (d, J=7.9 Hz, 1H), 7.77−7.88 (m, 2H), 8.09−8.18 (m, 2H), 9.53 (d, J=7.6 Hz, 1H); C
NMR (CDCl ) δ ppm: 13.7, 21.1, 21.6, 60.0, 87.0, 95.7, 113.2, 113.9, 116.0, 118.5, 123.8, 124.9,
3
1
25.0, 127.0, 127.5, 127.6, 127.7, 128.9, 129.0, 129.1, 129.4, 130.3, 130.4, 130.5, 131.3, 131.4,

1
6
ACCEPTED MANUSCRIPT
-1
1
32.0, 136.3, 137.3, 139.8, 140.6, 141.0, 141.5, 153.3, 162.1; IR, cm : 1686 (C=O), 2208 (С≡С);
UV−vis, λmax (lg ε), nm: 267 (4.84), 347 (4.48), 363 (4.50), end absorbtion up to 463 nm; MS
+
m/z: 571 ([M ], 24), 140 (13), 119 (20), 45 (85), 29 (100). Anal. calcd for C H N O : C, 81.94;
39
29
3
2
H, 5.11; N, 7.35. Found: C, 82.11; H, 5.29; N, 7.09.
4
.3.12. Diethyl 1,1'-(pyrazine-2,3-diyl)bis(2-phenylpyrrolo[2,1-a]isoquinoline-3-carboxylate)
o
1
(
23). Yellow solid with mp 272−274 C (i-PrOH); H NMR (CDCl ) δ ppm:
0
.77 (t, J=6.9 Hz,
3
6
6
9
1
Н, 2 СН CH ), 3.88−4.10 (m, 4Н, 2 СН CH ), 6.02−6.09 (m, 2Н), 6.17 (d, J=8.2 Hz, 2Н),
2
3
2
3
.20−6.85 (m, 8Н), 6.93−7.05 (m, 4Н), 7.31−7.40 (m, 2Н), 7.55 (d, J=7.6 Hz, 2Н), 8.87 (s, 2Н),
1
3
.37 (d, J=7.5 Hz, 2H). C NMR (CDCl ) δ ppm: 13.4, 59.7, 113.1, 113.4, 115.4, 124.1, 124.3,
3
24.5, 125.3, 126.1, 126.2, 127.0, 128.7 (2C), 129.3, 132.8, 134.3, 135.1, 142.8, 151.6, 162.2. IR,
-1
cm : 1683 (С=О); UV−vis, λ
(lg ε), nm: 268 (4.97), 284 (4.95), 330 (4.30), 350 (4.39), 367
max
+
(
4.35); MS m/z: 706 ([M ], 100), 633 (16), 560 (11). Anal. calcd for C H N O : C, 78.17; H,
4
6
34
4
4
4
.85; N, 7.93. Found: C, 77.98; H, 4.81; N, 8.14.
4
.3.13. Diethyl 1,1'-(quinoxaline-2,3-diyl)bis(2-phenylpyrrolo[2,1-a]isoquinoline-3-carboxylate)
o
1
(
24). Yellow solid with mp 253−254 C (i-PrOH); H NMR (CDCl ) δ ppm: 0.72 (t, J=7.1 Hz,
3
6
Н, 2 СН CH ), 3.82−4.06 (m, 4Н, 2 СН CH ), 5.94 (ddd, J=7.5, 6.4, 1.2 Hz, 2H), 6.21−6.30
2 3 2 3
(m, 6Н), 6.40−6.60 (m, 4Н), 6.72 (ddd, J=8.4, 7.2, 1.3 Hz, 2H), 6.98 (d, J=7.6 Hz, 2H),
7
.22−7.29 (m, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.83−7.90 (m, 2H), 8.13−8.20 (m, 2H), 9.32 (d, J=7.6
13
Hz, 2H); C NMR (CDCl ) δ ppm: 13.3, 59.8, 113.2, 113.6, 115.9, 124.2, 124.3, 124.5, 125.3,
3
1
25.9, 126.2, 127.0, 128.7 (2C), 129.1, 129.5, 130.4, 133.3, 134.2, 135.2, 141.3, 152.1, 162.2; IR,
-1
cm : 1685 (C=O); UV−vis, λ
(lg ε), nm: 270 (4.82), 286 (4.80), 330 (4.28), 349 (4.34), 366
max
+
(
4.36), 410 (3.76); MS m/z: 756 ([M ], 11), 387 (28), 343 (100), 305 (11), 267 (26), 240 (11), 44
(
21), 29 (27). Anal. calcd for C H N O : C, 79.35; H, 4.79; N, 7.40. Found: C, 79.18; H, 4.92;
50 36 4 4
N, 7.69.
4
.3.14. Diethyl 1,1'-(quinoxaline-2,3-diyl)bis(2-p-tolylpyrrolo[2,1-a]isoquinoline-3-carboxylate)
o
1
(
25). Yellow solid with mp 264−265 C (i-PrOH); H NMR (CDCl ) δ ppm:
0
.76 (t, J=7.1 Hz,
3
6
6
7
7
1
Н, 2 СН CH ), 1.42 (s, 6Н, 2 CH ), 3.84−4.08 (m, 4Н, 2 СН CH ), 6.09−6.13 (m, 4Н),
2
3
3
2
3
.31−6.55 (m, 6Н), 6.76 (t, J=7.6 Hz, 2Н), 6.98 (d, J=7.6 Hz, 2Н), 7.25 (dd, J=8.6, 6.1 Hz, 2Н),
.49 (d, J=7.7 Hz, 2Н), 7.85 (dd, J=6.3, 3.4 Hz, 2Н), 8.15 (dd, J=6.3, 3.4 Hz, 2Н), 9.29 (d, J =
1
3
.6 Hz, 2H). C NMR (CDCl ) δ ppm: 13.4, 20.8, 59.8, 113.4, 116.0, 124.2, 124.3, 124.8, 125.7,
3
26.4, 127.0, 127.3, 128.6 (2C), 129.1, 129.3, 130.3, 131.5, 133.2, 135.3, 135.9, 141.2, 152.1,

1
7
ACCEPTED MANUSCRIPT
-1
1
62.2; IR, cm : 1684 (С=О); UV−vis, λ
(lg ε), nm: 286 (4.88), 329 (4.33), 349 (4.39), 365
max
+
(
4.39), 401 (3.81); MS m/z: 784 ([M ], 24), 401 (41), 392 (19), 387 (20), 383 (16), 357 (100),
3
1
5
42 (72), 333 (11), 319 (63), 311 (16), 282 (24), 279 (22), 266 (21), 254 (15), 192 (10), 165 (12),
28 (22), 119 (46), 116 (11), 105 (12), 91 (22), 76 (26). Anal. calcd for C H N O : C, 79.57; H,
5
2
40
4
4
.14; N, 7.14. Found: C, 79.69; H, 5.04; N, 7.30.
4
.4. Synthesis of ethyl 2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-perimidin-6-yl)-1-(4-
nitrophenyl)pyrrolo[2,1-a]isoquinoline-3-carboxylate (16)
Ethyl chloroacetate (34 mg, 0.28 mmol) and isoquinoline (39 mg, 0.28 mmol) were heated at
8
0 ºC for 2 hours. Et N (2 mL) and DMSO (7 mL) were then added and the reaction mixture was
3
stirred for 20 min. Then compound 5b (48 mg, 0.13 mmol) was added. The reaction mixture was
stirred at 100 ºC for 44 h. To this mixture 2-(2-ethoxy-2-oxoethyl)isoquinolinium chloride
(specially prepared from ethyl chloroacetate (34 mg, 0.030 mL, 0.28 mmol) and isoquinoline (39
mg, 0.035 mL, 0.28 mmol) for 2 h at room temperature), Et N (1 mL) and DMSO (2 mL) were
3
added. The reaction mixture was stirred at 100 ºC for 100 h and treated with H O (100 mL). The
2
resulting mixture was extracted with CHCl (5 × 20 mL). The extract was dried over Na SO and
3
2
4
evaporated to dryness. The residue was purified by flash column chromatography on silica gel (3
20 cm) with CH Cl as the eluent. The yellow fraction with R 0.3 gave 16 (41 mg, 55%).
×
2
2
f
o
1
Yellow solid, decomp. > 205 C; H NMR (CDCl ) δ ppm: 0.56 (t, J=7.1 Hz, 3Н, СН CH ), 3.48
3
2
3
(s, 3H, N-CH ), 3.50 (s, 3H, N-CH ), 3.88−4.02 (m, 2Н, СН CH ), 6.51 (d, J=7.9 Hz, 1H), 6.61
3 3 2 3
(d, J=7.6 Hz, 1H), 7.09 (d, J=7.8 Hz, 2H), 7.18 (d, J=7.6 Hz, 1H), 7.18−7.26 (m, 3Н), 7.51 (t,
J=7.5 Hz, 1H), 7.18−7.26 (m, 2Н), 7.76 (d, J=7.8 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 8.20 (d, J=7.8
1
3
Hz, 1H), 9.51 (d, J=7.6 Hz, 1H); C NMR (CDCl ) δ ppm: 13.3, 30.6, 30.8, 59.7, 103.2, 104.0,
3
1
13.3, 114.3, 115.1, 117.8, 118.6, 123.4, 123.6, 123.7, 124.2, 124.8, 124.9, 127.3, 127.4, 127.6,
1
27.7, 129.0, 129.4, 130.2, 131.4, 132.0, 133.5, 134.0, 137.1, 137.7, 143.4, 146.9, 150.9, 161.6;
-1
IR, cm : 1344 (NO , s), 1519 (NO , as), 1674 and 1686 (C=O); UV−vis, λ (lg ε), nm: 270
max
2
2
+
(
4.79), 324 (4.38), 348 (4.41), 363 (4.28); MS m/z: 570 ([M ], 100), 498 (8), 225 (17), 203 (9).
Anal. calcd for C H N O : C, 71.57; H, 4.59; N, 9.82. Found: C, 71.44; H, 4.72; N, 9.58.
3
4
26
4
5
4
.5. Synthesis of 2-chloro-3-(phenylethynyl)pyrazine (1a)
A mixture of 2,3-dichloropyrazine (75 mg, 0.50 mmol), Pd(PPh ) Cl (35 mg, 0.05 mmol),
3
2
2
CuI (5 mg, 0.026 mmol), K CO (99 mg, 0.72 mmol) and DMF (2 mL) was stirred under argon
2
3
for 20 min at room temperature. Then a solution of phenylacetylene (65 mg, 0.07 mL, 0.64
mmol) in DMF (1 mL) was added drop wise. The resulting mixture was stirred for 2 h at room
temperature, filtered and washed with Et O. The filtrate was treated with H O (100 mL and then
2
2

1
8
ACCEPTED MANUSCRIPT
extracted with CHCl (5 × 20 mL). The extract was dried over Na SO and evaporated to dryness.
3
2
4
The residue was mixed with Al O and purified by flash column chromatography on Al O (3 ×
2
3
2
3
3
0 cm) with CH Cl as the eluent. The colorless fraction with R 0.8 gave 1a (62 mg, 57 %). The
2 2 f
colorless fraction with R 0.3 gave 1b (7 mg, 5 %).
f
o
1
4
.5.1. 2-Chloro-3-(phenylethynyl)pyrazine (1a). White solid with mp 74−76 C (i-PrOH); H
NMR (CDCl ) δ ppm: 7.34−7.45 (m, 3H), 7.60−7.67 (m, 2H), 8.28 (d, J=2.3 Hz, 1H), 8.49 (d,
3
1
3
J=2.3 Hz, 1H); C NMR (CDCl ) δ ppm: 84.9, 98.0, 121.7, 129.0, 130.4, 132.7, 140.0, 142.1,
3
-1
+
1
42.7, 151.1; IR, cm : 2219 (С≡С); MS m/z: 214 ([M ], 100), 179 (79), 152 (13), 128 (27), 77
11). Anal. calcd for C H ClN : C, 67.15; H, 3.29; Cl, 16.52; N, 13.05. Found: C, 67.19; H,
(
1
2
7
2
3
.03; Cl, 16.38; N, 13.21.
o
1
4
.5.2. 2,3-Bis(phenylethynyl)pyrazine (1b). White solid with mp 79−80 C (i-PrOH); H NMR
1
3
(
CDCl ) δ ppm: 7.36−7.44 (m, 6H), 7.63 (d, J=7.6 Hz, 4H), 8.48 (s, 2H); C NMR (CDCl ) δ
3
3
-1
ppm: 86.4, 97.0, 122.1, 129.0, 130.1, 132.6, 142.3, 142.7; IR, cm : 2199 (С≡С); MS m/z: 280
+
(
[M ], 80), 253 (13), 140 (13), 127 (100), 100 (15). Anal. calcd for C H N : C, 85.69; H, 4.31;
2
0
12
2
N, 9.99. Found: C, 85.78; H, 4.13; N, 10.13.
4
.6. Synthesis of 2,3-bis(phenylethynyl)pyrazine (1b)
A mixture of 2,3-dichloropyrazine (373 mg, 2.50 mmol), Pd(PPh ) Cl (35 mg, 0.05 mmol),
3
2
2
CuI (5 mg, 0.026 mmol), K CO (345 mg, 2.50 mmol) and DMF (4 mL) was stirred under argon
2
3
for 20 min at room temperature. Then a solution of phenylacetylene (530 mg, 0.57 mL, 5.19
o
mmol) in DMF (1 mL) was added dropwise. The resulting mixture was stirred at 60 C for 22 h,
treated with H O (100 mL) and extracted with CHCl (5 × 20 mL). The extract was dried over
2
3
Na SO and evaporated to dryness. The residue was mixed with Al O and purified by flash
2
4
2
3
column chromatography on Al O (3 × 30 cm) with CH Cl as the eluent. The colorless fraction
2
3
2
2
with R 0.8 gave 1a (100 mg, 19 %). The colorless fraction with R 0.3 gave 1b (352 mg, 50 %).
f
f
4
.7. Synthesis of 1,3-dimethyl-6-(p-tolylethynyl)pyrimidine-2,4(1H,3H)-dione (3)
A mixture of 6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (349 mg, 2.0 mmol),
Pd(PPh ) Cl (28 mg, 0.04 mmol), CuI (8 mg, 0.04 mmol), Et N (3 mL) and DMSO (5 mL) was
3
2
2
3
stirred under argon for 20 min at room temperature. Then a solution of p-tolylacetylene (255 mg,
.28 mL, 2.2 mmol) was added dropwise over 40 min. The reaction mixture was stirred for 24 h
at room temperature. Et N was then evaporated. The resulting mixture was treated with H O (100
0
3
2

1
9
ACCEPTED MANUSCRIPT
mL) and extracted with CHCl (5 × 20 mL). The extract was dried over Na SO and evaporated
3
2
4
to dryness. The residue was mixed with Al O and purified by flash column chromatography on
2
3
Al O (3 × 20 cm) with CH Cl as the eluent. The yellowish fraction with R 0.2 gave 3 (453
2
3
2
2
f
o
1
mg, 89%). Yellowish solid with mp 166−168 C (i-PrOH); H NMR (CDCl ) δ ppm: 2.40 (s,
3
3
H, C-CH ), 3.34 (s, 3H, N-CH ), 3.58 (d, J=1.1 Hz, 3H, N-CH ), 6.03 (d, 1Н, J=1.1 Hz,), 7.21
3 3 3
13
(
d, J=7.8 Hz, 2Н), 7.44 (d, J=7.8 Hz, 2Н); C NMR (CDCl ) δ ppm: 21.7, 27.9, 33.9, 79.8,
3
-1
1
01.2, 105.5, 117.1, 129.5, 131.9, 136.8, 141.2, 151.8, 162.1; IR, cm : 1653, 1706 (C=O), 2217
+
(
С≡С); MS m/z: 254 ([M ], 100), 197 (12), 168 (22), 154 (25), 140 (19), 113 (10). Anal. calcd
for C H N O : C, 70.85; H, 5.55; N, 11.02. Found: C, 70.69; H, 5.32; N, 11.15.
1
5
14
2
2
4
.8. Synthesis of 1,3-dimethyl-6-((4-nitrophenyl)ethynyl)-1H-perimidin-2(3H)-one (5b)
1
7
A mixture of 6-bromo-1,3-dimethyl-1H-perimidin-2(3H)-one (145 mg, 0.5 mmol),
Pd(PPh ) Cl (70 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), Et N (3 mL) and DMSO (6 mL) was
3
2
2
3
stirred under argon for 20 min at room temperature. Then a solution of 1-ethynyl-4-nitrobenzene
(147 mg, 2.0 mmol) in DMSO (2 mL) was added dropwise. The resulting mixture was stirred for
o
3
6 h at 70 C. Et N was then evaporated. The residue was treated with water (100 mL) and
3
extracted with CH Cl (3 ×30 mL). The extract was dried over Na SO , concentrated in vacuo
2
2
2
4
and purified by flash column chromatography on silica gel (4.5 × 20 cm) with CH Cl as the
2
2
eluent. The orange fraction with R 0.3 gave 144 mg of a mixture of starting compound and 5b.
f
Recrystallization from i-PrOH (30 mL) gave pure 5b (38 mg, 21%) as red-orange needles,
o
1
decomp. > 230 C; H NMR (CDCl ) δ ppm: 3.48 (pseudosinglet, 6H, 2 N-CH ), 6.59 (d, J=8.1
3
3
Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 7.68−7.72 (m, 3H), 7.79 (d, J=8.4 Hz,
13
1
H), 8.22 (d, J=8.7 Hz, 2H); C NMR (CDCl ) δ ppm: 30.9, 31.0, 91.7, 93.6, 104.0, 104.6,
3
-
1
05.2, 110.6, 114.3, 117.7, 118.7, 123.7, 129.1, 130.7, 134.1, 138.0, 139.2, 146.7, 150.5; IR, cm
1
+
:
2199 (С≡С); MS m/z: 357 ([M ], 100), 311 (13), 292 (11), 290 (11), 267 (17). Anal. calcd for
C H N O : C, 70.58; H, 4.23; N, 11.76. Found: C, 70.32; H, 4.56; N, 11.91.
21
15
3
3
Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic Research (grant No 14-03-00032-
а) for financial support of this research. We also thank Drs. Anna V. Tkachuk and Oleg N. Burov
(Scientific and Educational Laboratory of Resonance Spectroscopy, Department of Natural and
High Molecular Compounds Chemistry, Southern Federal University) for NMR measurements.
X-Ray studies were performed by Drs. Julia V. Nelyubina and Kyrill Y. Suponitsky (A. N.
Nesmeyanov Institute of Organoelement Compounds, Moscow).

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