Efficient synthesis of 2-pyridylenynes and application in cobalt-catalysed benzannulation reactions

Article abstract of DOI:10.1055/s-0033-1338384

The cobalt-catalysed benzannulation of 2-pyridine-substituted enynes gave 2,3-bis(2-pyridyl)styrenes in moderate yields. The reaction with dibromomethane as well as diiodomethane generated the corresponding planar-chiral bispyridinium salts in good yields

Full text of DOI:10.1055/s-0033-1338384

LETTER
▌1101
letter
Efficient Synthesis of 2-Pyridylenynes and Application in Cobalt-Catalysed
Benzannulation Reactions
Synthesis of 2-Pyridylenynes
Philipp Röse, Florian Pünner, Gerhard Hilt,* Klaus Harms
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
Received: 19.02.2013; Accepted after revision: 20.03.2013
For the synthesis of the enynes commercially available 2-
Abstract: The cobalt-catalysed benzannulation of 2-pyridine-sub-
iodopyridine and 2-bromopyridine derivatives were se-
stituted enynes gave 2,3-bis(2-pyridyl)styrenes in moderate yields.
lected. Following a more traditional stepwise reaction se-
quence for the synthesis of the enynes, a Sonogashira
The reaction with dibromomethane as well as diiodomethane gen-
erated the corresponding planar-chiral bispyridinium salts in good
yields. On the other hand, the transformations with reagents of the coupling with TMS acetylene, followed by a deprotection
type RCHBr2 to afford diastereomeric products led to the desired
conversion. However, these products could not be obtained in pure
form.
and isolation of the product, and a second Sonogashira
coupling with vinyl bromide were conducted (Scheme 2).4
Key words: benzannulation, cobalt, enynes, pyridines, styrenes
1. PdCl2(PPh3)2, CuI
i-Pr2NH, toluene
r.t., 2 d
PdCl2(PPh3)2, CuI
i-Pr2NH, THF
r.t., 2 d
Br/I
The benzannulation of enynes is a very facile reaction for
the fast assembly of multiple functionalised styrene deriv-
atives. Two transition-metal-catalysed methods have been
described to realise this transformation efficiently. First,
the well-documented palladium-catalysed benzallulation
reported by Yamamoto and Gevorgyan which can be ap-
plied for the homo-benzannulation1 as well as for the
SiMe3
N
N
N
R
R
R
2. K2CO3, MeOH
r.t., 3.5 h
Br
4
5
6
Scheme 2
cross-benzannulation2 utilising an enyne and an alkyne as The results of this two-step procedure are summarised in
starting materials. The second method is the cobalt-cata- Table 1.
lysed benzannulation described by us which has only been
Inspired by the sequential one-pot procedure reported by
applied for the homo-benzannulation thus far.3 The
Doye,5 we also applied this sequence for the efficient syn-
benzannulation of enynes 1 (Scheme 1) can lead to two re-
thesis of the desired 2-pyridyl enynes 6 (Scheme 3).
gioisomers 2 and 3. While in the palladium-catalysed re-
action the products of type 2 are obtained exclusively, the
cobalt-catalysed process is strongly solvent-dependent
1. PdCl2(PPh3)2, CuI, i-Pr2NH, THF, r.t., 2 d
and in these reactions both regioisomers can be generated
as major regioisomers.
Br/I
SiMe3
N
2. KOH, MeOH–H2O (4:1), r.t., 3 h
3. vinyl bromide, r.t., 16 h
R
N
R
Pd(0) or Co(I)
R
R
R
R
4
6
2
+
Scheme 3
R
1
2
3
The results of the one-pot reaction sequence are also in-
corporated in Table 1 (right column).6 The comparison of
the two reaction sequences reveals that the yields are con-
siderably higher when the labile intermediates of type 5
are not isolated. The one-pot protocol has the high advan-
tage of sustainability avoiding additional workup proce-
dures, reducing the amount of palladium catalyst and
reagents, and consuming less time. Only in a single case
(Table 1, entry 4), for whatever unrevealed reason, the
one-pot reaction sequence was not successful. Moreover,
the electron-deficient pyridine derivatives applied in en-
tries 7 and 8 (Table 1) could not be converted into the de-
sired products. Also, when 2-bromo-4-aminopyridine was
used (Table 1, entry 6) no desired product could be isolat-
Scheme 1
We were particularly interested in enynes bearing a 2-pyr-
idyl substituent. The thereof generated bispyridyl prod-
ucts of type 3 could act as bidentate planar-chiral ligands,
but also unprecedented diastereomers were envisaged
when the bispyridyl derivatives were reacted with gemi-
nal dibromomethane derivatives (see below).
SYNLETT 2013, 24, 1101–1104
Advanced online publication: 23.04.2013
DOI: 10.1055/s-0033-1338384; Art ID: ST-2013-B0156-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1102
P. Röse et al.
LETTER
Table 1 Results of the Reaction Sequence for the Synthesis of
Enynes of Type 6
R
R
CoBr2(dppp)
2
Entry Alkyne 5
Enyne 6
One-pot
N
N
(single-step yield, %) (single-step yield, %)
yield (%)
Zn, ZnI2
DMSO, r.t.
N
R
6
7
1
2
74
89
N
N
5a 85%
6a 72%
H3C
H3C
N
N
N
N
N
N
N
N
5b 74%
6b 83%
7a (52%)
(2a/7a = 1:10)
7b (46%)
(2b/7b = 1:10)
7c (41%)
(2c/7c = 1:9)
N
N
3
4
87
–
Scheme 4
6c 69%
5c 72%
F
F
yields. Nevertheless, with these three bispyridyl deriva-
tives in hand, we tested the reaction with dibromo- and di-
iodomethane under various conditions to generate
bispyridinium salts of type 8 (Scheme 5).8
N
N
6d 46%
5d 65%
O
O
NH
NH
R
5
6
83
R
N+
N
N
CH2X2
N
2 X–
5e 72%
H2N
6e 69%
N
N+
R
R
7
8
–
–
N
Scheme 5
5f 0%
F3C
Interestingly, the conversion into the products 8 generates
planar chiral compounds (as racemates) which could be
verified in the X-ray crystal structure analysis of com-
pound 8a (Figure 1).9 Unfortunately, we were not success-
ful in separation of the racemates by recrystallization with
chiral carboxylates, such as D-tartrate.
7
8
–
–
–
–
N
5g 0%
O2N
N
5h 0%
ed. Nevertheless, five enynes of type 6 could be obtained
and used in the cobalt-catalysed benzannulation reaction
(Scheme 4).7 For three of the enynes 6a–c the cobalt-cat-
alysed benzannulation reaction led to the desired products
in moderate yields. Although a number of reaction condi-
tions and workup procedures were tested, the yield for the
previously reported derivative 7a could only be increased
by about 12%.
For the enyne 6d only traces of the desired product 7d
could be detected by GC–MS analysis while the con-
version of 6e to the corresponding product 7e gave no
conversion at all. The regioselectivities of the cobalt-cat-
alysed benzannulation reactions are good and proved to be
best when the reactions were performed in dimethylsulf-
oxide (DMSO) as solvent. After column chromatography
the pure regioisomers 7a–c were obtained in acceptable
Figure 1
Synlett 2013, 24, 1101–1104
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Pyridylenynes
1103
The results of the conversion of starting materials 7a and
7b with dibromomethane and diiodomethane are given in
Table 2.10
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft.
Table 2 Results of the Reactions of 7a and 7b with CH2Br2 and
CH2I2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Entry
Product 8
Yield (%)
References and Notes
(1) (a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.;
Tando, K.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118,
3970. (b) Weibel, D.; Gevorgyan, V.; Yamamoto, Y. J. Org.
Chem. 1998, 63, 1217. (c) Gevorgyan, V.; Tando, K.;
Uchiyama, N.; Yamamoto, Y. J. Org. Chem. 1998, 63, 7022.
(d) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem.
1999, 576, 232.
1
2
8a X = Br 85
8b X = I 85
N+
N+
2 X–
(2) (a) Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem.
Soc. 1997, 119, 11313. (b) Gevorgyan, V.; Sadayori, N.;
Yamamoto, Y. Tetrahedron Lett. 1997, 38, 8603.
N+
N+
3
4
8c X = Br 67
8d X = I 75
(c) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. J. Org.
Chem. 1998, 63, 1244. (d) Gevorgyan, V.; Takeda, A.;
Homma, M.; Sadayori, N.; Radhakrishnan, U.; Yamamoto,
Y. J. Am. Chem. Soc. 1999, 121, 6391. (e) Gevorgyan, V.;
Quan, L. G.; Yamamoto, Y. J. Org. Chem. 1999, 65, 568.
(f) Saito, S.; Uchiyama, N.; Gevorgyan, V.; Yamamoto, Y.
J. Org. Chem. 2000, 65, 4338. (g) Gevorgyan, V.; Tsuboya,
N.; Yamamoto, Y. J. Org. Chem. 2001, 66, 2743. (h) Rubin,
M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265.
(i) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2006, 128, 5818.
2 X–
The reactions of 7c with dibromo- and diiodomethane re-
sulted not in the formation of the bispyridinium salts most
likely caused by steric hindrance of the adjacent methyl
substituents. Based on these partially encouraging results
we envisaged the use of substituted dibromomethane de-
rivatives 9 as these would result in the formation of diaste-
reomers with a chiral centre and an axial chirality (10,
Scheme 6).
(3) Pünner, F.; Hilt, G. Chem. Commun. 2012, 48, 3617.
(4) General Procedure for the Stepwise Sonogashira
Reaction of 2-Iodo- and 2-Bromopyridines of Type 4
PdCl2(PPh3)2 (42 mg, 2.0 mol%), CuI (11 mg, 2.0 mol%),
and Ph3P (32 mg, 4.0 mol%) were suspended in toluene (10
mL). To the suspension, degassed i-Pr2NH (1.0 mL, 7.00
mmol, 2.3 equiv), 2-iodo- or 2-bromopyridine 4 (3.00 mmol,
1.0 equiv) and ethynyltrimethylsilane (0.5 mL, 3.60 mmol,
1.2 equiv) were added successively, and the reaction mixture
was stirred at r.t. for 2 d. K2CO3 (2.90 g, 21.0 mmol, 7.0
equiv) and MeOH (20 mL) were added to the mixture and
stirred at r.t. until complete conversion was observed by
TLC or GC–MS analysis. The reaction mixture was
concentrated under reduced pressure, H2O was added
followed by extraction with CH2Cl2, and dried over Na2SO4.
The crude product was purified by column chromatography
to give the desired product 5 [the same procedure was used
for the second Sonogashira reaction with vinyl bromide (1 M
in THF, 1.2 equiv) instead of ethynyltrimethylsilane].
(5) Severin, R.; Reimer, J.; Doye, S. J. Org. Chem. 2010, 75,
3518.
R
R
R
RCHBr2
N+
N+
9
H
R
N
N
2 Br–
C
R
10
7a,b
Scheme 6
Unfortunately, the conversions of 7a and 7b with aryl-
substituted dibromomethane derivatives (R = Ph, 4-
Me2NC6H4, 4-F3CC6H4, and 2-BrC6H4) under various re-
action conditions did not result in the formation of the de-
sired products in pure form.
(6) One-Pot Procedure for the Synthesis of 2-Pyridyl enynes
of Type 6
PdCl2(PPh3)2 (42 mg, 2.0 mol%), CuI (11 mg, 2.0 mol%),
and Ph3P (32 mg, 4.0 mol%) were suspended in THF (10
mL). To the suspension, degassed i-Pr2NH (1.0 mL, 7.00
mmol, 2.3 equiv), 2-iodo- or 2-bromopyridine 4 (3.00 mmol,
1.0 equiv), and ethynyltrimethylsilane (0.5 mL, 3.60 mmol,
1.2 equiv) were added successively, and the reaction mixture
was stirred at r.t. for 2 d. KOH (1.18 g, 21.0 mmol, 7.0 equiv)
in MeOH–H2O (15 mL, 4:1 v/v) were added to the mixture
and stirred at r.t. for 3.5 h. Then vinyl bromide [3.6 mL (1 M
in THF), 3.60 mmol, 1.2 equiv] were added and stirred at r.t.
for another 16 h. The reaction mixture was concentrated
under reduced pressure, H2O was added followed by
extraction with CH2Cl2, and dried over Na2SO4. The crude
In summary, we have shown that an efficient one-pot pro-
cess for the synthesis of 2-pyridyl-substituted enynes 6
can be realised and in most cases good yields were ob-
tained. The enynes were then converted in a regioselective
benzannulation utilising a cobalt catalyst to generate the
products of type 7 in moderate yields. The conversion of
the bispyridine derivatives 7 with dibromo- and diiodo-
methane could be realised to form the bispyridinium salts
of type 8. In the reactions with the dibromo derivatives
RCHBr2 the desired products of type 10 could not be iso-
lated in pure form.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1101–1104

1104
P. Röse et al.
LETTER
(8) Almarzoqi, B.; George, A. V.; Isaacs, N. S. Tetrahedron
product was purified by column chromatography to give the
desired product 6.
1986, 42, 601.
(7) General Procedure for the Cobalt-Catalysed
Benzannulation Reaction of 2-Pyridyl Enynes of Type 6
CoBr2(dppp) (126 mg, 20 mol%), Zn powder (26 mg, 40
mol%), and ZnI2 (128 mg, 40 mol%) were dissolved in
DMSO (1.5 mL), and the enynes of type 6 were added (1.00
mmol). The reaction mixture was stirred at r.t. until complete
conversion was observed by TLC or GC–MS analysis. A
solution of EDTA (584 mg, 2.00 mmol) in aq NH3 buffer (20
mL, pH 10) was added followed by extraction with CH2Cl2.
The organic layers were combined, dried over Na2SO4, the
solvent was evaporated, and the crude product was purified
by column chromatography to give the desired styrene
derivatives 7.
(9) The supplementary crystallographic data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre; CCDC 924471.
(10) Representative Procedure for the Synthesis of the
Bispyridinium Salt 8a
CH2Br2 (20 μL, 0.29 mmol, 1.45 equiv) was added to a
solution of 2,3-bis(2-pyridyl)styrene 7a (52 mg, 0.20 mmol,
1.0 equiv) in MeCN (1.0 mL) and was stirred at 70 °C for 3
d. The solvent was removed, the residue washed
successively with 3.0 mL CH2Cl2, Et2O, and pentane and
dried under reduced pressure to give the desired product 8a.
Synlett 2013, 24, 1101–1104
© Georg Thieme Verlag Stuttgart · New York

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