Direct introduction of acetylene moieties into azines by SNH methodology

Article abstract of DOI:10.1016/j.tetlet.2009.01.070

The N-oxides of azines 1a-g react with lithium and/or potassium acetylides to give the corresponding ethynylazines 2a-g. Reaction with lithium acetylide requires subsequent acylation of the intermediate anionic adduct for rearomatization whereas in the case of potassium acetylide, auto-aromatization takes place.

Full text of DOI:10.1016/j.tetlet.2009.01.070

Tetrahedron Letters 50 (2009) 1444–1446
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Tetrahedron Letters
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H
Direct introduction of acetylene moieties into azines by SN methodology
Anton M. Prokhorov a, Mieczysław Ma˛kosza b, Oleg N. Chupakhin a,c,
*
a Ural State Technical University, Mira 19, Ekaterinburg 620002, Russia
b Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warszawa, Poland
c Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Kovalevskoy 22, Ekaterinburg 620219, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The N-oxides of azines 1a–g react with lithium and/or potassium acetylides to give the corresponding
ethynylazines 2a–g. Reaction with lithium acetylide requires subsequent acylation of the intermediate
anionic adduct for rearomatization whereas in the case of potassium acetylide, auto-aromatization takes
place.
Received 8 December 2008
Revised 22 December 2008
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Published by Elsevier Ltd.
Acetylenic derivatives of heterocycles, in particular of azines,
have attracted significant attention because of their possible appli-
cations in chemistry and material science.1 The acetylene moiety is
a very desirable function from many points of view. Due to its lin-
Recently, we demonstrated examples of the introduction of
phenyl and trimethylsilyl acetylenes into 3-(2-pyridyl)-1,2,4-tri-
azine by reaction of the corresponding 1,2,4-triazine N-oxide with
lithium acetylides.14 This approach was adopted for the synthesis
of bipyridine ligands bearing terminal acetylene and phenylacety-
lene moieties.15 The success of this work led us to study the reac-
tions with triazine oxides more comprehensively, and to see if this
methodology could be applied for the synthesis of ethynyl deriva-
tives of other azines that are less reactive than 1,2,4-triazines in
earity, rigidity, and extensive p-orbital network, it serves as a con-
jugating link between functional parts of molecular devices, and is
widely used in crystal engineering.2 Moreover, it opens routes to
polymers with special properties.3 Introduction of an ethynyl
group improves photophysical4 and magnetic properties signifi-
cantly.5 In addition, the presence of an ethynyl group offers the
possibility for further functionalization of azines and construction
of new heterocyclic systems.6,7 Thus, effective and easy methods
for the introduction of an acetylene moiety into azines are of great
synthetic interest.
At present, the standard method for introduction of acetylenes
into aromatic systems is cross-coupling reactions between suitable
halogen-containing heterocycles and acetylenes in the presence of
a palladium catalyst.8 In spite of its efficacy, this method has cer-
tain limitations. There is often poor availability of the halogen-con-
taining heterocycles, and the cost of the appropriate catalyst can be
high. In addition, the application of cross-coupling reactions can be
limited in pharmaceutical synthesis because of the presence of cat-
alyst traces in the product.
H
the SN reaction. As a result, we present herein a versatile method
for the introduction of an acetylene moiety into azaheterocycles by
deoxygenative nucleophilic aromatic substitution of hydrogen in
azine N-oxides.
We found that the N-oxides of pyridine 1a, quinoline 1b, quin-
oxaline 1c, and 1,2,4-triazines 1d–f react easily with lithium phen-
ylacetylide in THF at À50 °C to form intermediate
r
H-adducts A,
which are aromatized by addition of an acylating agent (procedure
A).16 As a result, the appropriate phenylethynylazines 2a–f17 were
obtained in yields of 20% for pyridine N-oxide and up to 70% for tri-
azine oxides (Scheme 1). The relatively poor yields are due to the
decomposition processes that apparently competes with the slow
addition reaction.
It is noteworthy that in the case of pyridine N-oxide 1a, increas-
ing the reaction time or temperature resulted in ring-opening lead-
ing to the open-chain products 3 or 4, depending on the reagent
used to quench the reaction. With acetyl chloride product 3 was
obtained, and in the case of acetic acid, 4 was formed. Such ring-
opening was described earlier in the reaction of pyridine N-oxide
with an acetylenic Grignard reagent.18
Earlier, we reported on the effectiveness of aromatic nucleo-
philic substitution of hydrogen (SNH) for fuctionalization of
p-defi-
cient aromatic heterocycles.9,10 For example, we demonstrated
that 1,2,4-triazine 4-oxides react with organometallic nucleophiles
such as Grignard reagents11 and lithium carboranes12 to give the
corresponding substituted 1,2,4-triazines. Also, the similar results
in the reactions of pyridine N-oxide and Grignard reagents were re-
ported previously.13 This method has none of the disadvantages of
cross-coupling reactions because halogen-containing derivatives
are not required.
In contrast, reaction of 1,2,4-triazine 4-oxide 1g with lithium
trimethylsilylacetylide allowed isolation of the cyclic
r
H-adduct
5 by treating carefully the reaction mixture with acetic acid. The
product proved to be relatively stable, and was aromatized by acyl-
ation with acetyl chloride (Scheme 2).19
In order to avoid side reactions and to optimize the yields, we
attempted to modify the reaction conditions. Thus, we found that
* Corresponding author. Tel.: +7 343 3754501; fax: +7 343 3740458.
E-mail address: chupakhin@ios.uran.ru (O.N. Chupakhin).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.070

A. M. Prokhorov et al. / Tetrahedron Letters 50 (2009) 1444–1446
Procedure A:
1445
LiC CPh
for 1a
H
THF,
- 50 º C
10 min
30 min
N
N
OLi
Ph
OLi
Ph
A
B
AcOH
0 º C
AcCl
0 º C
AcCl,
- 50 oC
N +
O
Procedure B:
HC CPh
1a-f
t-BuOK,
DMF
N
N
N
- 20 º C
20 min
OH
Ph
Ph
OAc
Ph
2a-f
3
4
N
1a:
=
1b:
1c:
N +
O
N +
N +
O
N +
O
O
N
Ph
N
Ph
N
Tol
N
N
N
1d:
1e:
1f:
Ph
N +
O
N +
O
Tol
N +
O
Scheme 1.
Me Si
1.
N
t-B3uLi, THF
N
N
N
N
N
N
AcCl
N
N+
O
2. AcOH
H
N
Me3Si
OH
N
Me3Si
N
1g
5
2g (43%)
Scheme 2.
the azine N-oxides 1a–f readily reacted with potassium phenyl-
acetylide generated from phenylacetylene in the presence of a
three-fold excess of potassium tert-butoxide in dry DMF (proce-
dure B).16 These conditions induced the auto-aromatization of
the latter promotes elimination of hydroxide and auto-aromatiza-
tion. The yields of the acetylenic derivatives were 35%, 50%, and
40% for products 2a,b,c, respectively.
The reaction of quinoxaline N-oxide 1c with phenylacetylene
gave an unexpected result. When a twofold excess of potassium
phenylacetylide was used, 2,3-bis(phenylethynyl)quinoxaline 6
was obtained (Scheme 3). Further studies revealed that treatment
of monosubstituted quinoxaline 2c with 1 equiv of potassium
phenylacetylide under the same conditions also gave 6 in moder-
ate yield. It was found that quinoxaline 7 also reacts with 1 equiv
of phenylacetylene yielding the monosubstituted product 2c, while
the intermediate
r
H-adducts with loss of oxygen. Hence, there
was no need for further acylation or protonation to obtain aromatic
products 2a–f. This difference in behavior between lithium and
potassium phenylacetylide can be explained by the much higher
polarity of the solvent as well as the difference between the O-me-
tal bond characters in the
r
H-adducts: the O–Li bond is rather
covalent, whereas the O–K bond is ionic. The ionic character of
HC CPh
1 eq.
C CPh
1 eq.
N
t-BuOK
DMF
t-BuOK
air,
N
- 20 oC
2c (40 %)
Ph
DMF
N
N
N
- 20 oC
KC CPh
1 eq.
N+
O
Ph
7
HC CPh
excess
C
CPh
1c
N
excess
t-BuOK
t-BuOK
air,
N
DMF
- 20 oC
Ph
6 (55%)
DMF
- 20 oC
Scheme 3.

1446
A. M. Prokhorov et al. / Tetrahedron Letters 50 (2009) 1444–1446
Kozhevnikov, D. N.; Rusinov, V. L.; Kalinin, V. N.; Olshevskaya, V. A.; Glukhov, I.
V.; Antipin, M. Yu. Mendeleev Commun. 2003, 165.
13. (a) Van Bergen, T. J.; Kellog, R. M. J. Org. Chem. 1971, 36, 1705; (b) Andersson,
with 2 equiv of phenylacetylene gives the disubstituted product 6.
In the case of quinoxaline 7, the presence of an N-oxide function
was not necessary. When the reactions were carried out under con-
ditions that exclude air, the yields of products 2c and 6 were much
H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335.
14. Kozhevnikov, D. N.; Kozhevnikov, V. N.; Prokhorov, A. M.; Ustinova, M. M.;
Rusinov, V. L.; Chupakhin, O. N.; Aleksandrov, G. G.; Koenig, B. Tetrahedron Lett.
2006, 47, 869.
15. Prokhorov, A. M.; Slepukhin, P. A.; Kozhevnikov, D. N. J. Organomet. Chem. 2008,
693, 1886.
lower. We can therefore assume that the
r
H-adducts are oxidized
by atmospheric oxygen. At present, we cannot explain why such
easy oxidative auto-aromatization takes place only in the case of
quinoxaline.
16. Procedure A for the synthesis of the ethynyl azines 2a–g: A solution of lithium
phenylacetylide in THF, prepared by addition of butyllithium (1.05 mmol) to a
solution of phenylacetylene (1 mmol) in 10 ml of THF, was added with stirring
to a solution of N-oxide 1 (1 mmol) in 10 ml of THF at À50 °C under an argon
atmosphere. After 10 min, acetyl chloride (1.05 mmol) was added to the
reaction mixture at the same temperature. The solvent was removed, the
residue was dissolved in chloroform, and the corresponding ethynylazine was
isolated by column chromatography. Procedure B. A solution of N-oxide 1
(1 mmol) in 10 ml of dry DMF was added with stirring to a suspension of
potassium phenylacetylide at À20 °C under an argon atmosphere, which was
In conclusion, the reported method for the direct introduction
H
of acetylenes into heterocyclic systems using SN methodology is
a versatile tool for the synthesis of a series of ethynyl azines. The
method requires no expensive reagents, and can be used as a com-
plementary method to Sonogashira cross-coupling reactions.
Acknowledgments
prepared by addition of phenylacetylene (1 mmol) to
a suspension of
potassium tert-butoxide (2 mmol) in 10 ml of dry DMF. After 30 min, acetic
acid (2 mmol) was added to the reaction mixture at the same temperature.
Then, water (100 ml) was added, and the resulting suspension was treated
with chloroform. The organic phase was dried over sodium sulfate, and the
corresponding phenylethynylazine was isolated by column chromatography.
17. Compound 2a: Yield 35% (obtained by procedure B). Mp: 32 °C (from hexane).
1H NMR (300 MHz, CDCl3, ppm): 7.23 (m, 1H, H-5), 7.25–7.40 (m, 3H, Ph), 7.52
(m, 1H, H-3), 7.59–7.63 (m, 2H, Ph), 7.67 (m, 1H, H-4), 8.61 (m, 1H, H-6). 13C
NMR (75 MHz, CDCl3, ppm): 88.55, 89.16, 122.20, 122.69, 127.09, 128.33,
128.92, 131.99, 136.10, 143.41, 150.01. HRMS (EI): C13H9N requires M+,
179.0735, found 179.0737. Compound 2b: Yield 50% (obtained by procedure
B). Mp: 58 °C (from hexane). 1H NMR (300 MHz, CDCl3, ppm): 7.40 (m, 3H, Ph),
7.55 (m, 1H, H-6), 7.61 (m, 2H, Ph), 7.61 (d, J = 8.0 Hz, 1H, H-3), 7.73 (m, 1H, H-
7), 7.81 (dd, J = 8.0, 1.0 Hz, 1H, H-8), 8.14 (dd, J = 8.0, 1.0 Hz, 1H, H-5), 8.15 (d,
This work was started during the summer training of A. Prokho-
rov in ICHO PAS, and was subsequently supported by the Russian
Foundation for Basic Research and President Program for Leading
Scientific Schools of the Russian Federation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.070.
J = 8.0 Hz, 1H, H-4). HRMS (EI): C17H11
N
requires M+, 229.0891, found
References and notes
229.0882. Compound 2c: Yield 40% (obtained by procedure B). Mp 61 °C
(from hexane). 1H NMR (300 MHz, CDCl3, ppm): 7.43 (m, 3H, Ph), 7.69 (m, 2H),
7.79 (m, 2H, Ph), 8.11 (m, 2H), 8.99 (s, 1H, H-3). Found: C, 83.30; H, 4.49; N,
7.15. Calcd for C16H10N2: C, 83.46; H, 4.38; N, 12.17. Compound 2d: Yield 65%
(obtained by procedure A). Mp 113 °C (from acetonitrile). 1H NMR (300 MHz,
CDCl3, ppm): 7.37–7.61 (m, 8H), 8.12 (m, 2H), 9.61 (s, 1H, H-3). 13C NMR
(75 MHz, CDCl3, ppm): 85.54, 100.80, 120.46, 128.44, 128.69, 129.36, 130.69,
130.79, 132.57, 133.88, 142.16, 155.08, 159.37. HRMS (EI): C17H11N3 requires
M+, 257.0953, found 257.0963. Compound 2e: Yield 70% (obtained by
procedure A). Mp 175 °C (from acetonitrile). 1H NMR (300 MHz, CDCl3, ppm):
7.38–7.58 (m, 11H), 8.17 (m, 2H), 8.63 (m, 2H). 13C NMR (75 MHz, CDCl3, ppm):
86.38, 99.57, 120.74, 128.37, 128.64, 128.85, 129.29, 130.38, 130.56, 131.70,
132.53, 134.09, 134.38, 141.85, 156.62, 161.39. HRMS (EI): C23H15N3 requires
M+, 333.1266, found 333.1254. Compound 2f: Yield 63% (obtained by
procedure A). Mp 165 °C (from acetonitrile). 1H NMR (300 MHz, CDCl3, ppm):
2.47 (s, 6H, 2CH3), 7.41 (m, 5H, Ph), 7.46 (m, 2H, Ph), 7.60 (m, 2H, Ph), 8.08 (m,
2H, Ph), 8.40 (m, 2H, Ph). Found: C, 83.15; H, 5.21; N, 11.65. Calcd for C25H19N3:
C, 83.08; H, 5.30; N, 11.63.
1. Ziessel, R.; Hissler, M.; El-Ghayoury, A.; Harriman, A. Coord. Chem. Rev. 1998,
178–180, 1251.
2. (a) Ziessel, R.; Grosshenny, V.; Hissler, M.; Stroh, C. Inorg. Chem. 2004, 43, 4262;
(b) Altuna-Urquijo, M.; Stanforth, S. P.; Tarbit, B. Tetrahedron Lett. 2005, 46,
6111.
3. Goeb, S.; De Nicola, A.; Ziessel, R. J. Org. Chem. 2005, 70, 1518.
4. Birckner, E.; Grummt, U.-W.; Goller, A. H.; Pautzsch, T.; Egbe, D. A. M.; Al-
Higari, M.; Klemm, E. J. Phys. Chem. A 2001, 105, 10307.
5. Ziessel, R.; El-Ghayoury, A. Synthesis 2000, 14, 2137.
6. Faust, R.; Weber, Ch. Tetrahedron 1997, 53, 14655.
7. Ames, D. E.; Brohi, M. I. J. Chem. Soc., Perkin Trans. 1 1979, 1384.
8. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467; (b)
Sakamoto, T.; Shiraiwa, M.; Kondo, Y.; Yamanaka, H. Synthesis 1983, 312; (c)
Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Kawanisi, M. Bull. Chem. Soc. Jpn.
1987, 60, 215.
9. Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleophilic Aromatic
Substitution of Hydrogen; Academic Press: NY, San Diego, 1994. 367 p.
10. Ma˛kosza, M.; Wojczechowski, K. Chem. Rev. 2004, 104, 2631.
11. Prokhorov, A. M.; Kozhevnikov, D. N.; Rusinov, V. L.; Chupakhin, O. N. Polish J.
Chem. 2003, 1157.
18. Schiess, P.; Monnier, Ch.; Ringele, P.; Sendi, E. Helv. Chim. Acta 1974, 57, 1676.
19. Compound 5: Yield 56%. Mp 168 °C (from acetonitrile). 1H NMR (CDCl3, ppm):
0.25 (s, 9H, SiMe3), 2.41 (s, 3H, CH3), 5.82 (s, 1H), 7.25 (m, 2H, Ph), 7.42 (ddd,
J = 7.8, 4.7, 1.2 Hz, 1H, Py), 7.73 (d, 2H, Ph), 7.91 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H,
Py), 8.67 (dd, J = 7.8, 1.2, 1H, Py), 9.56 (dd, J = 4.7, 1.2 Hz, 1H, Py), 10.17 (s, 1H).
Found: C, 66.65; H, 5.91; N, 15.65. Calcd for C20H22N4OSi: C, 66.27; H, 6.12; N,
15.46.
12. (a) Prokhorov, A. M.; Kozhevnikov, D. N.; Rusinov, V. L.; Chupakhin, O. N.;
Glukhov, I. V.; Antipin, M. Yu.; Kazheva, O. N.; Chekhlov, A. N.; Dyachenko, O. A.
Organometallics 2006, 25, 2972; (b) Chupakhin, O. N.; Prokhorov, A. M.;