Palladium-Catalyzed Cyanation Reactions of Thiophene Halides

Article abstract of DOI:10.1055/s-2003-42490

The described method provides an efficient cyanation reaction of thiophene halides using tris(dibenzylidene-acetone)dipalladium(0), 1,1′-bis- (diphenylphosphino)ferrocene) and zinc powder as the catalyst system and Zn(CN)₂ as the cyanide source

Full text of DOI:10.1055/s-2003-42490

SHORT PAPER
23
Palladium-Catalyzed Cyanation Reactions of Thiophene Halides
P
alladium-Cata
h
lyze
d
Cyana
o
tion
R
eaction
m
s
of
T
hiophene Ha
l
a
ide
s
s Erker,* Stephanie Nemec
Institute of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
Fax +43(1)42779551; E-mail: thomas.erker@univie.ac.at
Received 20 October 2003
version in N,N-dimethylacetamide (DMA). Zn(CN)2 was
used as cyanide source.
Abstract: The described method provides an efficient cyanation re-
action of thiophene halides using tris(dibenzylidene-acetone)di-
palladium(0), 1,1 -bis-(diphenylphosphino)ferrocene) and zinc
powder as the catalyst system and Zn(CN)2 as the cyanide source.
Several thiophenes with various substituents are effectively cyanat-
ed under these conditions.
As Table 1 shows, much higher conversion rates up to
91% could be observed for some of the thiophene halides
at 80 °C reaction temperature, when the conversion was
very low at 120 °C.
Key words: nitriles, thiophene, palladium , catalysis, cyanation
We did temperature studies with 3,4-dibromothiophene
17 (entry 10) because it gave the highest conversion to the
corresponding nitriles 18a,b. It can be seen from Figure 1,
that the conversion into the thiophenedinitrile 18a rises up
to 90% at 80 °C reaction temperature, but decreases with
heating to higher temperatures. As a consequence 18b
reaches the lowest point of conversion (3.9%) at 80 °C
and rises up to 40% with increasing temperature.
In continuation of the synthesis of thiophene derivatives,1
we wanted to develop a general procedure yielding
thiophene nitriles. Aryl and heteroaryl nitriles are very
important intermediates in organic synthesis because they
can be transformed to various other functional groups
such as acyl, carboxy, formyl, and carbamoyl. Several
methods have been reported for the synthesis of aryl and
heteroaryl nitriles.2 Among them, the following methods
for the direct introduction of a cyano group to arenes and
heteroarenes are known as classical methods: the cyan-
ation of aryl and heteroaryl halides with copper(I) cyanide
(CuCN), the Reissert–Henze cyanation of -deficient het-
eroaromatic N-oxides, and the electrophilic cyanation of
-sufficient heteroaromatics. Unfortunately the classic
copper-mediated cyanations often involve the use of stoi-
chiometric quantities of copper cyanide at high tempera-
tures (>150 °C) followed by an often difficult workup to
remove the copper salts from the product. Therefore the
palladium-catalyzed displacement of aryl and heteroaryl
halides with cyanide ions to afford the corresponding aryl
and heteroaryl nitriles has been reported as a more favor-
able alternative.3
Figure 1
To sum up our results, we have optimized the reaction
procedure for a palladium-catalyzed cyanation of
thiophene halides. Most of the substances tested showed
modest to very good conversion rates into the correspond-
ing thiophene nitriles, which can be used in further syn-
thesis.
Three years ago F. Jin and P. N. Confalone4 reported the
cyanation of some electron-deficient and electron-rich
aryl chlorides with a palladium catalyst and Zn(CN)2 as
the cyanide source.5
Cynanation; General Procedure
We tried to optimize the method for thiophene halides
bearing various substituents. Pd2(dba)3 [tris(diben-
zylidene-acetone)dipalladium(0)] and dppf [1,1 -bis-
(diphenylphosphino)ferrocene)] used as ligand to enhance
the reactivity of the palladium complex were reported to
show the best results in conversion. Most of the tested
thiophene halides gave conversion rates above 54% under
these conditions. More than half of the experiments at
120 °C showed modest (26.8%) to very good (86%) con-
The thiophene halide (3.0 mmol), Pd2(dba)3 (3 mol%), dppf (5.7
mol%), Zn powder (17 mol%) and Zn(CN)2 (0.86 mmol) were
placed in a dry 3-neck flask flushed with argon and dissolved in
dimethylacetamide (5 mL) which was added via syringe. The reac-
tion was stirred and heated to 120 °C under an argon atmosphere,
until the highest conversion was detected with GC-MS. The mixture
was cooled to r.t., diluted with EtOAc (25 mL) and then washed aq
NH4OH (2 M) and sat. aq NaCl. After drying (Na2SO4), the organic
layer was concentrated by rotary evaporation. The residue was pu-
rified via column chromatography on silica gel (toluene–EtOAc,
8:2).
SYNTHESIS 2004, No. 1, pp 0023–0025
Advanced online publication: 17.11.2003
DOI: 10.1055/s-2003-42490; Art ID: Z15603S.pdf
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
3
5-Acetyl-2-thienylcyanide (2)
1H NMR: = 7.68–7.66 (d, J = 4.1 Hz, 1 H), 7.65–7.63 (d, J = 4.1
Hz, 1 H), 2.64 (s, 3 H).

24
T. Erker, S. Nemec
SHORT PAPER
Table 1 Palladium(0)-Catalyzed Cyanation of Thiophene Halides
Entry
1
Substrate
Temp (°C)/
Time (h)
Product
Conversion (%)b
78.7 (32.1)c
1
3
5
120/48
120/72
120/1.5a
26
47
67
2
3
48.7 (27.5)c
32.7 (13.5)c
4
5
7
9
120/27
130/3a
8 8
86.0 (n.r.)c
26.8 (n.r.)c
8.4 (n.r.)c
66.5 (n.r.)c
11.3 (n.r.)c
83.0
9
10a
10b10
10a9
10b10
1311
6
7
11
12
120/23
80/48
8
9
14
15
80/18
80/50
88
90.5
68.4
1612
10
17
80/50
18a9
18b13
2014
91.0
3.9
11
12
19
21
80/46
80/30
54.2
22a9
41.2
3.9
22b15
a The product does not remain stable with heating.
b Conversion rate detected via GS-MS.
c Conversion rate at 80 °C reaction temperature (n.r. = no reaction product detected).
13C NMR: = 188.7, 148.7, 136.7, 130.2, 115.3, 112.3, 26.1.
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