Access to 2,3-bis(buta-1,3-diynyl)pyridines

Article abstract of DOI:10.1016/j.mencom.2011.01.008

Sonogashira cross-coupling of 2-chloro-3-iodopyridines with buta-1,3-diynes gave products of only iodine substitution; in the case of 2-bromo-3- iodopyridine either 2-bromo-3-(buta-1,3-diynyl)- or 2,3-bis(buta-1,3-diynyl) pyridines were obtained depending

Full text of DOI:10.1016/j.mencom.2011.01.008

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 19–20
Access to 2,3-bis(buta-1,3-diynyl)pyridines
Viktor N. Sorokoumov,a Vladimir V. Popikb and Irina A. Balova*a
a Department of Chemistry, St. Petersburg State University, 198504 St. Petersburg, Russian Federation.
Fax: +7 812 428 6939; e-mail: irinabalova@yandex.ru
b Department of Chemistry, The University of Georgia, Athens, GA 30602, USA
DOI: 10.1016/j.mencom.2011.01.008
Sonogashira cross-coupling of 2-chloro-3-iodopyridines with buta-1,3-diynes gave products of only iodine substitution; in the case of
2-bromo-3-iodopyridine either 2-bromo-3-(buta-1,3-diynyl)- or 2,3-bis(buta-1,3-diynyl)pyridines were obtained depending on the
reaction conditions.
Reversible cyclization of compounds containing a (Z)-hex-3-ene-
1,5-diyne moiety to form the reactive p-benzyne biradical was
i, LAETA
ii, H2O
C6H13
C
C
C
C
C6H13
C12H25 C C C CH
first reported in 1972 and has become known as the Bergman
cyclization.1 This rather esoteric reaction has attracted a lot of
attention in the past two decades when it was found to be the
cause of extreme cytotoxicity of natural enediyne antibiotics.2 The
development of safer and more selective analogues of Neo-
carzinostatin, Esperamicin, and other natural enediynes is an
important goal of the modern medicinal chemistry.3,4 Thermal
Bergman cycloaromatization of bis-ortho-ethynylarenes is also
used in preparation of novel materials with unique optical pro-
perties.5 There is only a single example of such cyclization of
enetetraynes,6 apparently due to the complexity of their prepara-
tion. In addition, ‘double’ Bergman cyclization can be considered
as a facile access to acenes and heteroacenes, which are of interest
as organic electronics, for example, semiconductors including
organic thin film transistors7 and organic light-emitting diodes.8
It is also known that enediynes fused to electron-deficientnitrogen-
containing heterocycles, for example, 2,3-diethylpyridine, have a
lower activation energy in cycloaromatization compared with
carbocyclic enediynes.9
We present here the first example of the synthesis of a pyri-
dine-based enetetrayne system, 2,3-bis(buta-1,3-diynyl)pyridines
(Scheme 1). 2-Chloro-3-iodopyridines 3 and 2-bromo-3-iodo-
pyridine 4, which were prepared from commercially available
2-aminopyridines,10 were introduced into Pd/Cu-catalyzed Sona-
gashira cross-coupling11 with two terminal diacetylenes: hexa-
deca-1,3-diyne 2a and phenylbuta-1,3-diyne 2b. Because of low
stability of terminal diynes, the synthesis was carried out as one-
pot procedure. Hexadeca-1,3-diyne 2a was obtained by multi-
positional prototropic isomerization (‘diacetylene zipper reaction’)
of internal isomer hexadeca-7,9-diyne 1a upon treatment with
lithium 2-aminoethylamide (LAETA). This approach was pre-
viously successfully used to produce functionalized 1-(het)aryl-
alka-1,3-diynes.12 2-Methyl-6-phenylhexa-3,5-diyn-2-ol 1b served
as a synthetic precursor of the diyne 2b in the retro-Favorskii
reaction.13
1a
2a
R
I
R
R'
2a
Pd0/Cu+
N
Cl
N
Cl
3a R = Me
3b R = I
5a R = Me, R' = CºC–CºC–C12H25 (68%)
5b R = R' = CºC–CºC–C12H25 (57%)
Ph
C
C
C
Me
C
Ph
C
C
C
CH
N
N
Br
2b
Pd0/Cu+
5c (51%)
Me
I
R
C
C
C
2a,b
Pd0/Cu+
N
Br
C
Me
C
C
4
C
C
6a R = C12H25 (26%)
6b R = Ph (43%)
R
Scheme 1
Pd(PPh3)4 catalyst at 65°C gave only products of iodine sub-
stitution, namely, the corresponding 2-chloro-5-methyl-3-(hexa-
1,3-diynyl)pyridine 5a† and 2-chloro-3,5-bis(hexa-1,3-diynyl)
pyridine 5b (Scheme 1). Conducting the reactions at a higher
temperature led to the decomposition of unstable terminal diynes.
†
2-Chloro-3-(hexa-1,3-diynyl)-5-methylpyridine 5a was obtained from
hexadeca-7,9-diyne 1a and 2-chloro-3-iodo-5-methylpyridine 3a in 68%
yield (for details of the sequence ‘diacetylene zipper’–Sonogashira cross-
coupling, see ref. 12). Mp 33–34°C. IR (CCl4, n/cm–1): 3028, 2934,
2912, 2848, 2243, 1854, 1556, 1471, 1407, 1383, 1135, 1065, 902. 1H NMR
(400 MHz, CDCl3) d: 0.87 (t, 3H, Me, J 7 Hz), 1.26–1.63 [m, 20H,
(CH2)10], 1.29 (s, 3H, MeCAr), 2.38 (t, 2H, ºCCH2, J 7 Hz), 7.60 (s, 1H),
8.14 (s, 1H, HCAr). 13C NMR (100 MHz, CDCl3) d: 14.1, 17.44, 19.67,
22.67, 28.06, 28.88, 29.06, 29.34, 29.44, 29.58, 29.62, 29.63, 31.90,
64.65, 69.13, 81.27, 87.86, 119.00, 131.70, 142.73, 142.76, 148.85, 150.18.
MS, m/z (Irel, %): 345 [M+2]+ (6), 343 [M]+ (18), 308 (24), 246 (18),
231 (59), 230 (88), 208 (76), 194 (100), 182 (65), 168 (76), 152 (76), 140
(71), 126 (75), 105 (21). Found (%): C, 76.87; H, 8.78; N, 4.12. Calc. for
C22H30ClN (%): C, 76.83; H, 8.79; N, 4.07.
The rate of halogen substitution in the cross-coupling reactions
is known to decrease in the rank I > Br > Cl. At the same time,
halogen atoms at the 2- or 4-positions of pyridine ring are more
active in the cross-coupling reactions, as compared to halogen at
the 3-position.9,14 However, to the best of our knowledge, com-
parative rates of different halogen atoms substitution in pyridine
have not been investigated earlier.
In fact, Sonogashira cross-coupling of 2-chloro-3-iodopyri-
dines 3a,b with the terminal diyne 2a using PdCl2(PPh3)2 or
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 19–20
In contrast to 3, the outcome of the cross-coupling of 2-bromo-
product being a pyridine enetetrayne derivative. Moreover, selec-
tivity of different halogen reactivity can be further exploited for
synthesis of unsymmetrical 2,3-butadiynylpyridines.
3-iodo-5-methylpyridine 4 with terminal diacetylenes depended
on the reaction conditions. At 20°C, the reaction with phenyl-
1,3-butadiyne 2b in the presence of either PdCl2(PPh3)2 or Pd(PPh3)4
results in a selective replacement of iodine at the 3-position, with
the formation of 2-bromo-5-methyl-3-(4-phenylbuta-1,3-diynyl)
pyridine 5c. Substitution products of both iodine and bromine –
2,3-bis(buta-1,3-diynyl)pyridines 6a,b‡ were obtained only in
the presence of Pd(PPh3)4 at 45°C. The yields of 6a,b are lower
in comparison with those of 5a–c, because the increase in tempe-
rature led to decomposition of unstable 1,3-diynes.
This work was supported by the National Science Foundation
(grant no. CHE-0449478) and Georgia Cancer Coalition. VS and
AB acknowledge also St. Petersburg State University for a research
grant.
References
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In conclusion, we showed that the rate of substitution of iodine
atoms at the 3- and 5-positions of pyridine ring is significantly
higher compared to that of bromine and chlorine atoms at the
2-position in the cross-coupling reactions. This phenomenon gives
a possibility for selective introduction of butadiynyl substituents
at the 3-position of pyridine ring. In the meanwhile, the use of
2-bromo-3-iodopyridines as the starting material provided access
to 2,3-bis(butadiynyl)-substituted pyridine for the first time, the
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‡
General procedure for 1,3-diyne 2 coupling with 4. Hexadeca-7,9-diyne
1a or 2-methyl-6-phenylhexa-3,5-diyn-2-ol 1b (6 mmol) were used for
in situ 1,3-diyne 2 preparation. When the ‘diacetylene zipper’12 (for obtain-
ing 2a) or the retro-Favorskii reaction13 (for obtaining 2b) was complete,
2-bromo-3-iodopyridine 4 (2 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), PPh3
(52.5 mg, 0.2 mmol), Et3N (5 ml) and CuI (57 mg, 0.3 mmol) were added
sequentially, in this order to a solution of the 1,3-diyne 2. The reaction
mixture was stirred for a further 8–12 h at 45°C (TLC control). Upon
completion, the reaction mixture was poured into water and the resulting
mixture was extracted with diethyl ether (4´25 ml). The combined organic
extracts were washed with water and dried over MgSO4. After solvent
evaporation, the product was isolated by flash chromatography on silica
gel, eluting with hexane, then hexane–diethyl ether (1:1, v/v) mixtures.
5-Methyl-2,3-bis(4-phenylbuta-1,3-diynyl)pyridine 6b was obtained in
1
43% yield (293 mg, 0.86 mmol). H NMR (400 MHz, CDCl3) d: 2.54
(s, 3H, Me), 7.32–7.40 (m, 6H), 7.55–7.57 (m, 4H, HCPh), 7.62 (d, 1H,
J 1 Hz), 8.39 (d, 1H, HCPy, J 1 Hz). 13C NMR (100 MHz, CDCl3) d: 18.3,
73.7, 73.8, 78.8, 80.3, 83.6, 83.7, 84.0, 84.1, 121.4, 122.2, 122.8, 128.9,
128.5, 128.6, 129.5, 132.6, 132.7, 132.8, 140.3, 141.9, 150.5. MS, m/z
(Irel, %): 342 [M + 1]+ (30), 341 [M]+ (100), 313 (16), 170 (16), 150 (14).
14 L. Anastasia and E.-i. Negishi, Chem. Rev., 2003, 103, 1979.
Received: 13th August 2010; Com. 10/3583
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