Pyrazine- and pyridine-substituted prop-2-yn-1-ols, but-3-yn-2-ols, and but-3-yn-2-ones –purification, stability, and handling revised

Article abstract of DOI:10.1007/s10593-016-1811-0

A short series of alkynyl-substituted pyrazine and pyridine derivatives was synthesized by the palladium-catalyzed Sonogashira cross-coupling reactions between aryl halides and alkynes. All the products are either white solids or colorless liquids, which is partly in contrast to previous reports. After purification, a color change or intense darkening was observed, in some cases starting almost immediately. Both, the nature of the heteroaromatic ring and the substituents of the alkyne moiety affect their stability. Herein details of synthesis, characterization, and, most importantly, purification and handling are reported.

Full text of DOI:10.1007/s10593-016-1811-0

DOI 10.1007/s10593-016-1811-0
Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
Pyrazine- and pyridine-substituted prop-2-yn-1-ols,
but-3-yn-2-ols, and but-3-yn-2-ones –
purification, stability, and handling revised
1
1
Claudia Schindler , Carola Schulzke *
1
Institut für Biochemie, Ernst-Moritz-Arndt-Universität Greifswald,
4
Felix-Hausdorff-Straße, 17487 Greifswald, Germany
е-mail: carola.schulzke@uni-greifswald.de
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted October 23, 2015
Accepted November 15, 2015
2
015, 51(11/12), 1008–1013
R
Me
(
R = Me)
CH
X
N
Hal
HO
CuI, Pd(OAc) , PPh3
Et N, MeCN, 85°C
3
CrO , H SO
Me CO, H O
2 2
0
2
OH
3
2
4
O
+
X
N
X
R
°C, 1 h
N
Hal = Br, Cl; R = H, Me
A short series of alkynyl-substituted pyrazine and pyridine derivatives was synthesized by the palladium-catalyzed Sonogashira cross-
coupling reactions between aryl halides and alkynes. All the products are either white solids or colorless liquids, which is partly in con-
trast to previous reports. After purification, a color change or intense darkening was observed, in some cases starting almost immediately.
Both, the nature of the heteroaromatic ring and the substituents of the alkyne moiety affect their stability. Herein details of synthesis,
characterization, and, most importantly, purification and handling are reported.
Keywords: alkynylpyrazines, alkynylpyridines, alcohol oxidation, purification, Sonogashira cross-coupling reactions, stability.
Pyrazine- and pyridine-substituted prop-2-yn-1-ols, but-
-yn-2-ols, and but-3-yn-2-ones are mostly known as key
(molybdopterin) in the respective active sites (an example9b
see in Scheme 1c).
3
intermediates in synthetic reaction series, i.e., they are
predominantly used as building blocks for the construction
of target molecules. Reports about these very reactive
compounds are actually rather scarce in the literature, and
those that are available fall into quite different areas of
research, mostly in the organic and pharmaceutical
chemistry field, where they are used as attractive pre-
cursors to a number of heterocyclic compounds. These
alkynyl-substituted nitrogen heterocycles have been used in
the preparation of pentathiepins with potential anticancer
Nevertheless, when searching the literature for
analogous compounds with further substituents on both
ends of the alkyne moiety, i.e., on the heterocycle and/or on
the oxygen-bearing carbon, only a moderate number of
results could be found. The available literature is domi-
nated by patents with a focus on pharmaceutical applica-
tions including inhibiting a checkpoint kinase 1 (CHK1)
function relevant to cancer growth,10 treating and/or
preventing allergic and immune diseases, inflammatory
11
dermatosis and neurodegenerative disorders, the use as
1
12
and antibacterial activities (Scheme 1a), the preparation
antiulcer agents, cyclooxygenase-2 (COX-2) inhibitors
2
13
of neuronal acetylcholine-gated ion channel agonists, and
for treating inflammatory diseases and glucokinase
3
14
the synthesis of naphthofurans (Scheme 1b) and
activators for the treatment of type II diabetes.
4
γ-butyrolactol ether derivatives. They are part of investiga-
This diversity emphasizes the significant and general
potential of heterocycle-substituted prop-2-yn-1-ols, but-
3-yn-2-ols, and but-3-yn-2-ones with respect to a broad
range of available chemical transformations and medicinal
applications of the respective products. Bearing a reactive
alkynyl function in conjugation to a heteroaromatic ring,
these compounds can undergo various cycloaddition and
intramolecular cyclization reactions to produce derivatives
of fused heterocycles of pharmaceutical interest. There are
several reports on the biological activity of fused aromatic
tions regarding the synthesis of α,β-acetylenic aldehydes
5
from terminal alkynes, new solid state procedures/
6
7
immobilization methods, novel Sonogashira catalysts, and
8
the regiochemistry of Mitsunobu alkylations. Pyrazine-
substituted but-3-yn-2-ones also play an important role in
the context of bioinorganic model chemistry of molybdenum-
9
dependent oxidoreductases, which is in fact our main
interest in respect to this class of compounds, where they
are used for mimicking a complex organic ligand
0
009-3122/15/51(11/12)-1008©2015 Springer Science+Business Media New York 1008

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
Scheme 1
S
OEt
OEt
S
EtO
S
S
2
–
O
Mo
S
S
S
S
S8
rt, 3–5 h
S
S
2[Et N]+
4
N
N
+
S
S
(a)
(b)
N
N
S
Me
O
Ar
OH
OH
DEAD, PPh3
THF
+
Ar
Ar = 2-Py, 3-Py, pyrazin-2-yl, 2-thienyl
S
O
S
S
S
Me
S
(c)
N
N
+
N
N
S
1
50°C
Ph
Me
O
compounds with pyrazine functionalities.10–15 However,
despite their promising chemical structures, the synthetic
potential of alkynylpyridines/pyrazines has not been fully
exploited in the past, possibly due to difficulties of
purification and handling. Few of these N-heterocyclic
alkynes have ever been properly characterized. One reason
might be that in the course of most research projects such
compounds were not necessarily isolated as intermediates,
but used immediately for the following reaction steps. As
we needed to obtain alkynylpyrazines as precursors for
quite ambitious synthetic undertakings we, in the present
work, have reinvestigated the synthesis of some known or
at least "literature-mentioned'' alkyne-substituted pyridines
and pyrazines, optimized the respective purification and
handling protocols, and even amended some characteri-
zations of these compounds from previous reports. This
knowledge might lead to a more frequent use of this class
of compounds in the future and hence broaden the
spectrum of easily accessible yet complex N-heterocyclic
reagents.
In the present study, N-heterocycle-substituted alkynes
served as intermediates in a reaction series adapted from
procedures developed by Joule, Garner, and Taylor for the
generation of bioinorganic model compounds.9
a,b,d,16
Our
aim was the synthesis of pyrazine- or pyridine-substituted
prop-2-yn-1-ols and but-3-yn-2-ols and, in a subsequent
synthetic step, the corresponding aldehydes or ketones. For
comparison, the corresponding pyridine derivatives were
also investigated. The pyridine alkynes are much more
stable and it is, hence, considerably easier to work with
them. Heteroaryl halides 1, 2 and propargylic alcohol 3a or
3-butyn-2-ol 3b were subjected to the common palladium-
catalyzed Sonogashira coupling reaction conditions1
yielding the corresponding alkynyl-substituted N-
heterocycles 4a,b and 5a,b (Scheme 2, Table 1).
7
For the synthesis of pyrazine derivatives, 2-chloro-
pyrazine (1) could be used as the heterocyclic starting
material. 3-Chloropyridine was not active under the same
reaction conditions. Instead, 3-bromopyridine (2) had to be
used, and the reaction times needed to be extended from
Scheme 2
R
Me
(
R = Me)
CH
X
N
Hal
HO
CuI, Pd(OAc) , PPh3
Et3N, MeCN, 85°C
CrO , H SO
Me2CO, H2O
0°C, 1 h
2
OH
3
2
4
O
+
X
X
N
R
N
1, 2
3a,b
4a,b, 5a,b
6, 7
1
Hal = Cl, 2 Hal = Br
Table 1. Yields and properties of alkynyl-substituted pyrazines 4a,b, 6 and pyridines 5a,b, 7
Halide
Alcohol
Product
X
R
Yield, %
Look
Timespan of stability (at rt in air)
1
1
–
2
2
–
3a
3b
–
4a (primary alcohol)
4b (secondary alcohol)
6 (ketone)
N
N
H
32
43
42
71
78
48
White solid
Colorless liquid
White solid
Days
Hours
Me
Me
H
N
Minutes to hours
Days
3a
3b
5a (primary alcohol)
5b (secondary alcohol)
7 (ketone)
CH
CH
CH
White solid
Me
Me
Colorless liquid
Colorless liquid
Days
Minutes to hours
1
009

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
6
to 20 h. The lower reactivity of the 3-chloropyridine
compared to 2-chloropyrazine (1) is due to the lack of –M
and –I effects based on the absence of the second nitrogen,
as observed and described previously.
1
7f
Besides the
N-heterocyclic reagent, the alkyne precursor, too, has an
effect on the reaction course. The yields summarized in
Table 1 show that under the same conditions better yields
were observed for but-3-yn-2-ol (3b) compared to unsub-
stituted propargylic alcohol (3a); i.e., the reaction yield
using a secondary alcohol as the reactant was better than
using a primary alcohol, which is typical for palladium-
17f
catalyzed coupling reactions.
Ketones 6 and 7 were synthesized from secondary
alcohols 4b and 5b using Jones' reagent in acetone at 0°C
The attempted oxidation of compounds 4a and 5a to the
corresponding aldehydes could not be achieved neither
under the same conditions (Jones' reagent in acetone at 0°C)
nor with any of the various oxidation agents tested (MnO
CrO /H SO N-chlorosuccinimide/N-(tert-butyl)benzene-
sulfenamide, DMSO/cyanuric chloride).
2
,
3
2
4
,
1
5a,18
The reason for
this may be an increased instability of the oxidation
products of the primary alcohols compared to the
secondary alcohols, in accordance with the already
comparably lower yields of the respective primary products
4
a and 5a.
The crude products 4a,b, 5a,b obtained by extraction are
brown oils. Even after purification by column chromato-
graphy, it was only possible to obtain brownish-stained or
brown-colored products. This was the case even with com-
pound 4a, which is described in literature as a "red
Figure 1. Top: IR spectra of 4-(pyrazin-2-yl)-but-3-yn-2-ol (4b);
19
amorphous solid".
(a) freshly prepared, (b) after 4 days, and (c) after 6 months; bot-
–
1
tom: the same IR spectra in the range of 1750–1550 cm . Here
transmissions were corrected to ensure comparability.
After trying several different methods, the purification
of products 4a,b, 5a,b, 6, 7 eventually succeeded by rather
convenient sublimation or microdistillation at a tempe-
rature around 40°C under reduced pressure (0.02 mbar).
Notably, a simple isolation process, such as sublimation or
distillation is for these pyridine- and pyrazine-containing
alkyne alcohols and ketones much more efficient and
reliable than using the rather tedious (and costly) separation
by a column; a fact which to date went unnoticed. All
products, purified in such way, are colorless or white and,
depending on the nature of the substituents, are either
viscous liquids or solids. Upon standing, however, they
change their color to brown or even black (compound 6).
Depending on the structure the color change is more or less
rapid. In general, pyridyl alkynes are more stable than
pyrazinyl alkynes. A possible reason for this could be the
π-electron deficiency of the pyridines compared to
pyrazines. The oxidized forms 6, 7 are generally the least
stable ones. The rapidity of the color change also depends
on whether the compound is in its pure form or in solution.
Compound 6 decomposes after a few minutes in air
accompanied by a color change to brown and, after some
hours, to even black. In solution, this process takes
somehow longer; the color change from colorless to intense
brown takes place within a couple of days. Compound 4a
changes its color to brown within a few days. Notably, this
process is faster in solution as opposed to compound 6.
Compound 4b behaves like compound 6, but it is
significantly more stable. Common to all synthesized
compounds is that once dissolved in chloroform the color
change is accompanied by the formation of an insoluble
residue which could not be identified despite all efforts. In
DMSO, however, no residue is formed, i.e., in this solvent
only the color change serves as an indicator of decompo-
sition. For the corresponding pyridine compounds, the
decomposition time relations are similar (in the same order
depending on the substituents), but they are generally more
stable. In the NMR spectra of all the products, a distinct
signal broadening can be observed with time, which
indicates radical formation20 and/or the formation of
polymers, possibly with extensive double bond conjuga-
tion. This assumption is also supported by an increasingly
intense coloration, as the presence of unpaired electrons
and extensive conjugation result in a dark or intensely
colored material based on allowed electron transitions
between orbitals.21 The IR spectrum of compound 4b, for
instance, displays broad absorption bands in the region
1718–1653 cm–1
The number and intensity of these bands
.
increase with time when compound 4b is kept as isolated
pure substance in air (see Fig. 1), suggesting that carbonyl
species are prevalent in the decomposed material. Simulta-
–1
neously, some changes were observed at around 3300 cm ,
the region of OH groups and hydrogen bonding in
general.
1
010

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
None of the investigated compounds 4a,b, 5a,b, 6, 7 had
MICRO elemental analyzer. Melting points were
determined with a Sanyo Gallenkamp melting point
apparatus. Acetonitrile was dried over 0.3 nm molecular
sieves. Other chemicals were used as purchased.
a considerably long shelf life even when purified and
stored at low temperature. Apparently they inevitably
undergo decomposition. This is most likely due to poly-
merization into a material bearing conjugated double
bonds, as discussed above. The decomposition products,
unfortunately, could not be characterized unequivocally, as
they likely form complex mixtures together with non-
decomposed material. Compounds 4a,b, 5a,b, 6, 7, and
likely other compounds of this class, should be used either
in situ, where possible, or they should be used for a
following consecutive reaction as soon as possible after
isolation. Any kind of coloration is evident of a beginning
decomposition, and this should be kept in mind when
adjusting the respective stoichiometries for the following
reactions. When an interruption of the reaction series
cannot be avoided, keeping in a deep freezer at –78°C
under inert gas is highly recommended, though even these
quite drastic measures do not keep the compounds stable
for more than a few days.
Synthesis of alkynyl-substituted pyrazines and
pyridines 4a,b and 5a,b (General method). Palladium
acetate (92.1 mg, 0.41 mmol), triphenylphosphine (640.0 mg,
2.44 mmol), and copper(I) iodide (465.0 mg, 2.44 mmol)
were added to a degassed solution of aryl halide 1, 2
(45 mmol), alkyne 3a,b (49 mmol), triethylamine (20 ml),
and acetonitrile (50 ml). The reaction mixture was stirred at
85°C for 6 h (synthesis of products 4a,b) or 20 h (synthesis
of products 5a,b) under a nitrogen atmosphere. The
mixture was allowed to cool to room temperature and the
solvent was evaporated. Then the residue was extracted
with water (80 ml) and ethyl acetate (100 ml). The
resulting mixture was filtered through silica, the layers
were separated and the aqueous layer extracted with ethyl
acetate (3×50 ml). The combined organic extracts were
washed with brine (50 ml), dried over sodium sulfate, and
evaporated to yield brown oil. After microdistillation or
sublimation at 40°C with the use of a cooling finger under
vacuum (0.02 mbar), the pure product was obtained.
In conclusion, pyrazine- and pyridine-substituted
alkynes which have been mentioned in the literature before
as intermediate products in multistep reactions were
reinvestigated with respect to their synthesis. More
importantly, optimized methods for their isolation and
purification were developed and the stability of compounds
was studied, as this has not been done before. Notably, we
could show that sublimation or microdistillation yield
much purer products than column chromatography and is
certainly less laborious and time-consuming. Because of
the presence of N-heterocyclic moieties and their substantial
reactivity alkynylpyrazines do have a great potential for
synthetic developments in different fields of research.
Predominantly, their use in a pharmaceutical context can be
envisioned, as they can be relatively easy obtained using
the Sonogashira reaction. The most important finding was
that even under inert gas in a deep freezer it is only
possible to store these compounds for a limited time due to
their high intrinsic reactivity. Instead, it is requisite to
continue with any following reaction steps immediately or
at least as soon as possible, until the alkyne function has
been transformed. These findings will hopefully encourage
an increased use of this group of reactive compounds, since
now they can be isolated more conveniently and have been
characterized in pure form.
1
3-(Pyrazin-2-yl)prop-2-yn-1-ol (4a). Yield 1.93 g (32%).
–1
White solid. Mp 71–73°C. IR spectrum (KBr), ν, cm :
642 (w), 711 (s br), 1014 (vs), 1030 (vs), 1063 (s), 1141
(s), 1159 (w), 1183 (w), 1226 (w), 1276 (s), 1360 (m),
1399 (s), 1460 (vs), 1515 (m), 1573 (vw), 1641 (vw br),
2214 (m), 2246 (w), 2408 (vw), 2660 (vw), 2857 (vw),
1
2915 (vw), 3257 (vs). H NMR spectrum (CDCl
3
), δ, ppm
); 8.51 (1H,
d, J = 2.6, H-5); 8.56 (1H, dd, J = 2.6, J = 1.6, H-6); 8.69
(J, Hz): 3.64 (1H, br. s, OH); 4.58 (2H, s, CH
2
3
3
4
4
13
(1H, d, J = 1.5, H-3). C NMR spectrum (CDCl ), δ, ppm:
3
50.9 (CH ); 81.6 (C≡C); 92.4 (C≡C); 139.6 (C-2); 143.1
2
(CHN); 144.3 (CHN); 147.6 (C-3). Mass spectrum (EI,
+
70 eV, 350°C), m/z (Irel, %): 134 [M] (55), 105 (100).
Found, %: C 62.85; H 4.47; N 20.53. C
7
H
6
N O. Calculated,
2
%: C 62.68; H 4.51; N 20.88.
8
4-(Pyrazin-2-yl)but-3-yn-2-ol (4b). Yield 2.87 g (43%).
–1
Colorless liquid. IR spectrum (thin film), ν, cm : 754 (w),
852 (m), 940 (m), 1013 (s), 1038 (s), 1064 (s), 1115 (s),
1142 (s), 1180 (m), 1273 (m), 1328 (m), 1371, 1397 (s),
1465 (s), 1518 (m), 1568 (w), 1641 (vw br), 2238 (m),
1
2872, 2934, 2983, 3069, 3340 (s br). H NMR spectrum
3
(CDCl
3
), δ, ppm (J, Hz): 1.60 (3H, d, J = 6.6, CH
3
); 3.36
3
(
1H, br. s, OH); 4.82 (1H, q, J = 6.7, CH); 8.50 (1H, d,
Experimental
3
3 4
J = 2.5, H-5); 8.55 (1H, dd, J = 2.5, J = 1.6, H-6); 8.67
4
13
IR spectra were recorded on a Perkin-Elmer System
(1H, d, J = 1.5, H-3). C NMR spectrum (CDCl
3
), δ, ppm:
2
000 Fourier-transform infrared spectrophotometer or a
23.8 (CH ); 58.1 (CH); 80.1 (C≡C); 95.9 (C≡C); 139.6
3
1
13
Shimadzu IR Affinity-1 spectrophotometer. H and
C
(C-2); 143.0 (CHN); 144.2 (CHN); 147.5 (C-3).
2,7
NMR spectra were recorded on a Bruker Avance II 300
spectrometer (300 and 75 MHz, respectively). All chemical
3-(Pyridin-3-yl)prop-2-yn-1-ol (5a). Yield 4.25 g
2
(71%). White solid. Mp 100–101°C (mp 99–100°C ; mp
1
7
–1
shifts are quoted in respect to TMS for the H signals and
101–102°C ). IR spectrum (KBr), ν, cm : 636 (s), 704
(vs), 742 (s), 806 (s), 951 (m), 1027 (vs), 1188 (m), 1232
(m), 1264 (m), 1354 (m), 1407 (s), 1478 (vs), 1562 (m),
1
3
deuterated solvent for the C signals (CDCl δ 77.0 ppm,
3
1
3
DMSO-d δ 39.5 ppm). C NMR signals were assigned
6
using the DEPT experiment. Electron ionization mass
spectra were recorded on a single focussing sector-field
Waters AMD40 spectrometer. Elemental analyses (C, H,
N, and S) were carried out with an Elementar Vario
1588 (m), 2848 (w), 2937 (vw), 3045 (m), 3195 (s), 3381
1
(m). H NMR spectrum (DMSO-d
6
), δ, ppm (J, Hz): 4.34
3
3
(2H, d, J = 5.9, CH
2
); 5.42 (1H, t, J = 5.9, OH); 7.42 (1H,
3
3
4
3
ddd, J = 7.9, J = 4.9, J = 0.7, H-5); 7.85 (1H, dt, J = 7.9,
1
011

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
4
3
J = 1.9, H-4); 8.56 (1H, br. d, J ≈ 4, H-6); 8.63 (1H, br. s,
δ, ppm: 32.7 (CH ); 85.7 (C≡C); 90.4 (C≡C); 116.4 (C-3);
3
13
H-2). C NMR spectrum (DMSO-d
0.4 (C≡C); 93.2 (C≡C); 119.5 (C-3); 123.6 (C-5); 138.7
C-4); 148.7 (C-6); 151.4 (C-2). Mass spectrum (EI, 70 eV,
6
), δ, ppm: 49.4 (CH
2
);
123.8 (C-5); 140.1 (C-4); 151.1 (C-6); 152.8 (C-2); 184.0
(C=O).
8
(
+
1
3
00°C), m/z (Irel, %): 133 [M] (17), 79 (100). Found, %:
Supplementary information to this article containing H,
13
C 71.72; H 5.15; N 10.52. C
C 72.16; H 5.30; N 10.52.
8
H
7
NO. Calculated, %:
C NMR, and IR spectra of the synthesized compounds is
available online at http://link.springer.com/journal/10593.
4
4
-(Pyridin-3-yl)but-3-yn-2-ol (5b). Yield 5.17 –
g
1
(
78%). Colorless liquid. IR spectrum (thin film), ν, cm :
Generous financial support from the European Research
Council (project MocoModels) and support by COST
Action CM1003 are gratefully acknowledged.
7
1
1
2
05 (m), 807 (m), 856 (m), 935 (m), 1028, 1049, 1077,
112 (s), 1188 (m), 1262, 1330 (m), 1370 (m), 1409 (s),
478 (m), 1566 (m), 1588 (w), 1668 (vw), 2869, 2932,
1
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80 ml) and diethyl ether (80 ml) were added, the layers
. (a) Bradshaw, B.; Dinsmore, A.; Ajana, W.; Collison, D.;
Garner, C. D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1
were separated, and the aqueous layer extracted with
diethyl ether (3×50 ml). The combined organic layers were
2
001, 3239. (b) Bradshaw, B.; Dinsmore, A.; Garner, C. D.;
washed with saturated aq. NaHCO
3
, brine (50 ml), dried
Joule, J. A. Chem. Commun. 1998, 417. (c) Pilato, R. S.;
Eriksen, K. A.; Greaney, M. A.; Stiefel, E. I.; Goswami, S.;
Kilpatrick, L.; Spiro, T. G.; Taylor, E. C.; Rheingold, A. L.
J. Am. Chem. Soc. 1991, 113, 9372. (d) Taylor, E. C.;
Goswami, S. Tetrahedron Lett. 1991, 32, 7357.
over sodium sulfate, and the solvent was evaporated to
yield brown oil. After sublimation at 40°C with the use of a
cooling finger under vacuum (0.02 mbar), the pure product
was obtained.
-(Pyrazin-2-yl)but-3-yn-2-one (6).1
42%). White solid. Mp 36–37°C (mp 36°C ). IR spect-
6a
10. Collins, I.; Reader, J. C.; Matthews, T. P.; Cheung, K. M.;
Proisy, N.; Williams, D. H.; Klair, S. S.; Scanlon, J. E.; Piton, N.;
Addison, G. J.; Cherry, M., WO Patent 2009044162A1.
4
Yield 1.14 g
16a
(
–1
rum (KBr), ν, cm : 726 (m), 753 (m), 865 (s), 991 (m),
1
1. Page, P.; Schwarz, M.; Sebille, E.; Cleva, C.; Merlot, C.;
Maio, M. WO Patent 2006111560A2.
1
1
2
014 (s), 1054 (m), 1146 (m), 1159 (m), 1184 (s), 1282 (s),
296 (s), 1369 (s), 1404 (s), 1466 (s), 1519 (w), 1675 (vs),
12. Niho, T.; Yamamoto, I.; Mochizuki, H.; Kimura, I.; Imai, A.;
Nakase, T. EU Patent 685468A1.
152 (w), 2218 (vs), 2921 (w), 3007 (w), 3043 (w), 3075
1
(
(
w), 3438 (m br). H NMR spectrum (CDCl
3
), δ, ppm
13. (a) Matsuoka, H.; Kato, N.; Takahashi, T.; Maruyama, N.;
Ishizawa, T.; Suzuki, Y. WO Patent 9961436A1.
(b) Matsuoka, K.; Takahashi, T.; Maruyama, T.; Ishizawa, T.;
Kato, Y. JP Patent 2000136182A.
3
J, Hz): 2.51 (3H, s, CH ); 8.63 (1H, d, J = 2.5, H-5); 8.66
3
3
4
4
(
1H, dd, J = 2.5, J = 1.5, H-6); 8.81 (1H, d, J = 1.4, H-3).
1
3
C NMR spectrum (CDCl
3
), δ, ppm: 32.7 (CH ); 84.1
3
1
4. (a) Chen, S.; Corbett, W. L.; Guertin, K. R.; Haynes, N.-E.;
Kester, R. F.; Mennona, F. A.; Mischke, S. G.; Qian, Y.;
Sarabu, R.; Scott, N. R.; Thakkar, K. C. WO Patent
(
(
C≡C); 89.0 (C≡C); 137.8 (C-2); 144.7 (CHN); 144.9
CHN); 148.7 (C-3); 183.6 (C=O). Found, %: C 65.32;
H 4.04; N 18.84. C
H 4.14; N 19.17.
8
H
6
N
2
O. Calculated, %: C 65.75;
2004052869A1. (b) Qian, Y.; Corbett, W. L.; Berthel, S. J.;
Choi, D. S.; Dvorozniak, M. T.; Geng, W.; Gillespie, P.;
Guertin, K. R.; Haynes, N.-E.; Kester, R. F.; Mennona, F. A.;
Moore, D.; Racha, J.; Radinov, R.; Sarabu, R.; Scott, N. R.;
Grimsby, J.; Mallalieu, N. L. ACS Med. Chem. Lett. 2013,
5
4
-(Pyridin-3-yl)but-3-yn-2-one (7). Yield 1.29 g (48%).
–
1
Colorless liquid. IR spectrum (thin film), ν, cm : 704 (s),
8
1
1
08 (s), 979 (s), 1023 (s), 1122 (m), 1162 (vs), 1190 (s),
280 (s), 1360 (s), 1409 (s), 1478 (s), 1564 (s), 1584 (s),
4
, 414.
1
5. (a) Kher, S. S.; Penzo, M.; Fulle, S.; Ebejer, J. P.; Finn, P. W.;
674 (vs), 2132 (m), 2207 (vs), 2918 (w), 3007 (w), 3047
Blackman, M. J.; Jirgensons, A. Chem. Heterocycl. Compd.
1
(
(
w), 3332 (w), 3380 (w br). H NMR spectrum
2
015, 50, 1457. [Khim. Geterotsikl. Soedin. 2014, 1583.]
DMSO-d
6
), δ, ppm (J, Hz): 2.48 (3H, s, CH ); 7.54 (1H,
3
(
b) Ukrainets, I. V.; Bereznyakova, N. L. Chem. Heterocycl.
3
3
5
3
ddd, J = 7.9, J = 4.9, J = 0.8, H-5); 8.10 (1H, dt, J = 7.9,
Compd. 2012, 48, 155. [Khim. Geterotsikl. Soedin. 2012,
161.] (c) Amer, A. M.; El-Farargy, A. F.; Yousif, N. M.;
Fayed, A. A. Chem. Heterocycl. Compd. 2011, 47, 101.
4
3
4
J = 1.9, H-4); 8.72 (1H, dd, J = 4.8, J = 1.4, H-6); 8.84
4
13
(
1H, d, J = 1.3, H-2). C NMR spectrum (DMSO-d ),
6
1
012

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1008–1013
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1
1
6. (a) Taylor, E. C.; Dötzer, R. J. Org. Chem. 1991, 56, 1816.
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(
1
992, 33, 3371. (c) Alphonse, F.-A.; Karim, R.; Cano-
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1
013