Iron-catalyzed sonogashira reactions

Article abstract of DOI:10.1002/anie.200801539

(Chemical Equation Presented) With an iron will: Terminal alkynes undergo reaction with aryl and heteroaryl iodides in the presence of an iron catalyst formed from FeCl₃ and N,N′-dimethylethylenediamine (dmeda, see scheme). The method displays

Full text of DOI:10.1002/anie.200801539

Communications
DOI: 10.1002/anie.200801539
À
C C Coupling
Iron-Catalyzed Sonogashira Reactions**
Mónica Carril, Arkaitz Correa, and Carsten Bolm*
The coupling between an aryl halide and a terminal alkyne,
widely known as the Sonogashira reaction, is nowadays the
submitted to the standard conditions used for the iron-
catalyzed arylation of nitrogen[6a] and sulfur atoms,[8] revealed
that the target transformation was indeed possible, and
afforded diphenylacetylene (3a), although in only moderate
yields (Table 1, entries 1 and 3, respectively). Conversely,
under the optimized conditions for the arylation of oxygen
2
À
most utilized reaction for the construction of C(sp ) C(sp)
bonds.[1] It allows the straightforward and facile synthesis of
aryl alkynes and conjugated enynes, which are prevalent
intermediates in the synthesis of a broad array of naturally
occurring products.[2] The vast majority of the existing
protocols for performing such transformations involve the
use of palladium catalysts, often assisted by a copper co-
catalyst.[3] The development of improved procedures in which
less expensive and more sustainable catalysts are used has
remained an elusive goal. In this respect, iron catalysts stand
out as valuable alternatives to those transition metals used in
Sonogashira coupling reactions.[4]
Table 1: Reagent screening for the iron-catalyzed coupling of phenyl-
acetylene (1) with phenyl iodide (2).[a]
Entry Fe source
Ligand Base
Solvent t [h] 3a [%][b]
The use of iron salts to perform established transition-
metal-catalyzed arylation reactions has recently gained sig-
nificant attention because of their numerous advantages,
namely, their low cost, nontoxicity, or interesting chemical
properties. In this context, iron-catalyzed cross-coupling
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
[Fe(acac)3]
L1
L2
L1
L1
L1
L1
L3
L4
L5
L6
L1
K3PO4
Cs2CO3
NaOtBuPhMe
K2CO3
PhMe
DMF
72
24
37
0
72
20
PhMe
72
18
120
120
24
24
24
24
24
48
24
72
43
31
95
33
traces
6
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
À
reactions that lead to the formation of C C linkages through
the use of Grignard reagents are well known in the field, and
have been intensively investigated in the last decade.[4c,5]
Likewise, we have recently demonstrated the ability of iron
catalysts to effect the formation of carbon–heteroatom bonds
by means of arylations with aryl halides.[6–8] However, an iron-
9
10
11
12
13
14
15[c]
0
FeCl3·6H2O L1
traces
6
traces
68
À
catalyzed C C coupling reaction involving a terminal alkyne
[Fe(bzac)3]
Fe(ClO4)2
FeCl3
L1
L1
L1
and an arylating counterpart has not so far been reported.
In our previous research on iron-catalyzed arylations we
observed that the combination of FeCl3 and appropriately
chosen ligands delivered remarkably versatile catalysts for the
coupling of nitrogen[6] oxygen,[7] and sulfur nucleophiles[8]
with aryl halides. Inspired by these findings, we decided to
test the efficacy of this key FeCl3/ligand association in
Sonogashira reactions, and the most relevant results are
reported herein.
[a] Reaction conditions:
(0.1 equiv), ligand
1
(1.0 equiv),
2
(1.5 equiv), Fe source
(2.0 equiv), solvent
(0.2 equiv),
base
(1 mLmmolÀ1), 1358C, under argon. [b] Yield of isolated product after
flash chromatography. [c] Use of 15 mol% FeCl3 and 30 mol% L1. acac=
acetylacetonate, bzac=benzoylacetonate.
Initially, the coupling of phenylacetylene (1) with phenyl
iodide (2) was selected as a model system. To our delight,
preliminary experiments, in which those substrates were
[*] Dr. M. Carril, Dr. A. Correa, Prof. Dr. C. Bolm
Institut für Organische Chemie, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
atoms[7] (Table 1, entry 2) the Sonogashira coupling product
was not detected. The use of K2CO3 and Cs2CO3 (instead of
K3PO4 or NaOtBu) in combination with FeCl3 and N,N’-
dimethlethylenediamine (dmeda) led to improved results
(Table 1, entries 4 and 5). In particular, the use of Cs2CO3 was
considered superior, since it delivered the target compound in
a similar yield as obtained under the previously tested
conditions, but in a significantly shorter reaction time
[**] We are grateful to the Fonds der Chemischen Industrie for financial
support. M.C. thanks the Spanish Ministry of Education and Science
(MEC) as well as the Spanish Foundation of Science and Technology
(FECYT), and A.C. thanks the Basque Government for support
through “Programa de Perfeccionamiento de Doctores en el
extranjero del Departamento de Educación, Universidades e
Investigación”.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801539.
4862
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Chemie
Table 2: Iron-catalyzed Sonogashira coupling of terminal alkynes with aryl iodides.[a]
(Table 1, entry 5 versus entries 1, 3,
and 4). Therefore, Cs2CO3 was
selected as the base of choice for
further screening reactions.
It is noteworthy that the reac-
tion time was a key parameter of
the process, and when the coupling
Entry
1
1
2
3
Yield [%][b]
X=I, 68 (95)[c]
X=Br, traces
X=OTs, 0
3a
3b
3c
reaction between
1 and 2 was
allowed to proceed for prolonged
times, the target acetylene 3a was
obtained in 95% yield (Table 1,
entry 6). Unfortunately, initial
attempts to decrease the reaction
time without a significant loss in the
yield failed. The use of different
nitrogen- and/or oxygen-based che-
lating ligands in combination with
FeCl3 resulted in either low yields of
3a or recovered starting material
(Table 1, entries 7–10). Likewise,
iron sources other than FeCl3
failed to accomplish the target ary-
lation of 1 (Table 1, entries 11–14).
Moreover, the use of different sol-
vents such as acetonitrile, o-xylene,
or dioxane had a detrimental effect
on the outcome of the reaction.
Eventually, by raising the catalyst
loading from 10 to 15 mol%, 3a was
obtained in lower, but still good,
yield after a more reasonable reac-
tion time (Table 1, entry 15). Test
experiments carried out in the
absence of the FeCl3/ligand system
led to recovered starting materials,
which illustrated the key role of the
iron catalyst in this transformation.
Likewise, the use of an isolated
preformed catalyst, obtained by
combining FeCl3 and dmeda,[9] led
to very low conversion of the start-
ing materials. Hence, it was con-
cluded on the basis of the reaction
times and yields that the best con-
ditions involved 15 mol% FeCl3,
30 mol% dmeda, and 2 equivalents
of Cs2CO3 in toluene at 1358C for
72 h.
2
3
74
60
4
5
6
3d
3e
3 f
89
69
89
7
8
9
3g
3h
3i
86
80
90
10
11
12
3j
3k
3l
73
40
58
13
14
3m 85
3n
99.9
15
16
3o
3p
54
51
17
3q
55
Next, the scope of this iron-
catalyzed Sonogashira reaction was
explored by treating different acet-
ylene derivatives with an array of
aryl halides under the aforemen-
tioned optimized conditions. As
shown in Table 2, all reactions
18
19
3r
77
15
3s
afforded the desired arylated [a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), FeCl3 (0.15 equiv), dmeda (0.30 equiv), Cs2CO3
(2.0 equiv), toluene (1 mLmmolÀ1), 1358C, 72 h, under argon. [b] Yield of isolated product after flash
chromatography. [c] The value in brackets refers to the yield after 5 days using 10 mol% FeCl3 and
alkynes 3 in good to excellent
yields, as long as aryl iodides were
used as the arylating agents. Indeed,
20 mol% dmeda. Bn=benzyl, Cy=cyclohexyl.
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Communications
neither phenylbromide nor phenyl tosylate furnished the
In summary, we have developed a novel iron-catalyzed
arylation of terminal alkynes by utilizing catalytic amounts of
FeCl3 in conjunction with dmeda. The use of an iron catalyst
instead of the commonly used palladium or copper ones
renders the reported methodology comparatively more
economical, experimentally simple, and, therefore, appealing
for industry. Furthermore, a novel iron-catalyzed domino
Sonogashira/hydroalkoxylation of alkynes has been reported,
which increases the significance of the iron catalyst system as
a versatile tool in organic synthesis. The extension of the
herein presented Sonogashira coupling to other arylating
agents as well as attempts to improve the catalyst perfor-
mance are currently being targeted.
coupling product 3a in more than trace amounts when treated
with phenylacetylene (Table 2, entry 1). The coupling reac-
tions of various terminal alkynes with both electron-rich and
electron-deficient aryl iodides provided products in good
yields. 2-Thiophenyl iodide and 3-pyridinyl iodide led to the
corresponding arylated alkynes in moderate yields (Table 2,
entries 11 and 12). In general, the presence of ortho sub-
stituents in the electrophilic reagent did not hamper the
reaction, which proceeded smoothly in those cases, and
afforded the corresponding products 3 in good yields (Table 2,
entries 3, 6, 7, 10, 13, and 15). In regard to the alkynes, both
aryl acetylenes (Table 2, entries 1–7 and 14–18) as well as
triethylsilylacetylene (Table 2, entries 8–13) underwent effi-
cient arylation with a number of aryl iodides (Table 2,
entries 8–13). Conversely, alkyl-substituted acetylenes Experimental Section
General procedure for the iron-catalyzed Sonogashira coupling: A
proved less reactive (Table 2, entry 19). It is noteworthy that
alkyne homocoupling products were not detected in any
reaction, despite the oxidative character of FeCl3.
sealable tube equipped with a magnetic stir bar was charged with
Cs2CO3 (2.0 equiv) and FeCl3 (0.15 equiv). The aperture of the tube
was then covered with a rubber septum, and an argon atmosphere was
established. Phenyl iodide (2, 1.5 equiv), N,N’-dimethylethylenedi-
amine (0.30 equiv), phenylacetylene (1, 1.0 equiv), and toluene
(1mLmmol À1 of 1) were added by syringe. The septum was then
replaced by a teflon-coated screw cap, and the reaction vessel was
placed in an oil bath at 1358C. After stirring the heterogeneous
mixture at this temperature for 72 h, it was cooled to room temper-
ature and diluted with dichloromethane. The resulting solution was
directly filtered through a pad of silica gel and concentrated to afford
the product, which was purified by chromatography on silica gel
(pentane) to yield diphenylacetylene 3a. The identity and purity of
known products was confirmed by 1H and 13C NMR spectroscopic
analysis, and new products were fully characterized. See the
Supporting Information for full details.
Interestingly, the coupling reactions with both N-benzyl-
substituted and non-substituted 2-iodoaniline as the arylating
agents were very clean, and selectively delivered the pro-
jected Sonogashira coupling products in high yields, without
competitive side reactions on the amine moiety (Table 2,
entries 6, 7, and 13). In contrast, when 2-iodophenol (4) was
employed, benzofurans 6 resulting from domino Sonogashira
coupling reactions followed by intramolecular hydroalkoxy-
lations were isolated in moderate yields along with recovered
aryl acetylenes 1 (Scheme 1). Although the use of iron
catalysts assisted by silver additives for the addition of a
Received: April 2, 2008
Published online: May 28, 2008
À
Keywords: arylation · C C coupling · homogeneous catalysis ·
iron · synthetic methods
.
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Chemie
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