Sonogashira cross-coupling of arenediazonium salts

Article abstract of DOI:10.1002/anie.201000472

(Figure Presented) Star-crossed lovers: The domino iododediazoniation/ Sonogashira cross-coupling of terminal alkynes with arenediazonium salts has been developed. The arenediazonium salt synthesis/iododediazoniation/Sonogashira cross-coupling sequence can also be performed as a one-pot process, omitting the isolation of the arenediazonium salt.

Full text of DOI:10.1002/anie.201000472

Angewandte
Chemie
DOI: 10.1002/anie.201000472
Cross-Coupling
Sonogashira Cross-Coupling of Arenediazonium Salts**
Giancarlo Fabrizi, Antonella Goggiamani, Alessio Sferrazza, and Sandro Cacchi*
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Arenediazonium salts represent an attractive alternative to
aryl halides or triflates because of their higher reactivity, their
tolerance of milder conditions, their availability from inex-
pensive anilines, and because additional base is not required
in several applications. Arenediazonium salts have been used
in a variety of palladium-catalyzed reactions, including
Mizoroki–Heck reactions, Suzuki–Miyaura and Stille cross-
coupling reactions, and carbonylation reactions, in the syn-
thesis of sulfinic acids and boronic esters;[1] their use in
hydroarylation reactions has also been described.[2] Never-
theless, the alkynylation of arenediazonium salts continues to
represent a challenge. After the seminal works of Sonogashira
et al., Heck and Dieck, and Cassar on the alkynylation of aryl
iodides and bromides,[3] a great deal of work has been done to
extend the scope of the reaction to include an even wider
range of reactants;[4] however, the extension of the reaction to
arenediazonium salts remains unresolved.
To overcome this limit of the palladium-based chemistry
of arenediazonium salts, we reasoned that a strategy in which
arylacetylenes are formed by an iododediazoniation reaction,
followed by a Sonogashira cross-coupling might be successful.
Iododediazoniation is
a well-established reaction, and
recently remarkable advances have been reported in this
area.[7] Nevertheless, no examples of its utilization in a
sequential process with a palladium-catalyzed reaction have
yet been described. Herein, we show that such a sequential
process is indeed possible and report the first utilization of
arenediazonium salts in Sonogashira cross-coupling reactions.
An initial screen using [PdCl2(PPh3)2], CuI, and Et2NH in
MeCN at room temperature showed that 3a could be isolated
in 48% yield in the presence of nBu4NI (1.5 equiv) or NaI
(2 equiv; Table 1, entries 1 and 2). Optimization studies were
then performed by changing the nature and number of
equivalents of the base.
To the best of our knowledge, the sole attempt to involve
arenediazonium salts in the formation of arylacetylenes was
made by GenÞt and co-workers,[5] who obtained only small
amounts of the desired cross-coupling derivative by palla-
dium-catalyzed reaction of potassium 1-hexenyltrifluorobo-
rate with para-toluenediazonium tetrafluoroborate. We inves-
tigated the reaction using phenylacetylene (1a) and 4-meth-
oxybenzenediazonium tetrafluoroborate (2a) as the model
system. No evidence of the formation of cross-coupling
product 3a was found using [Pd2(dba)3] (dba = dibenzyl-
ideneacetone) or Pd(OAc)2 with a variety of phosphine (PPh3,
Xphos, HP(tBu)3BF4) or carbene ligands, generated from 1,3-
bis(2,6-diisopropylphenyl)imidazolium chloride in the pres-
ence of base;[6] a screen of different solvents (MeOH, THF,
DME, DMF), in the presence or absence of base (iPr2NEt,
K2CO3, Bu4NOAc) and CuI at temperatures ranging from
room temperature to 608C also afforded no cross-coupled
product. In all cases, complex reaction mixtures were
obtained, and anisole and 1,4-diphenyl-1,3-diyne were fre-
quently the main by-products.
Table 1: Optimization of the reaction conditions.[a]
Entry
Base
Added salt (equiv)
t [h]
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
9
Et2NH
Et2NH
Et2NH
Et2NH
iPr2NH
Et2NH
Et2NH
–
nBu4NI (1.5)
NaI (2.0)
1.5
9
1
1.5
1
5
9
6
1.5
48
48
78
67
79
81
nBu4NI (2.0)
nBu4NI (2.6)
nBu4NI (2.0)
NaI (2.0)/nBu4NI (0.2)
nBu4NI (2.0)
nBu4NI (2.0)
nBu4NI (0.2)
[c]
–
[d]
–
Et2NH
trace
[a] Unless otherwise stated, reactions were carried out at room temper-
ature on a 0.5 mmol scale in 3 mL of MeCN using 2 equiv of 1a, 1 equiv
of 2a, 10 equiv of base, 0.02 equiv of [PdCl2(PPh3)2], 0.04 equiv of CuI,
and nBu4NI or NaI. [b] Yields are given for isolated products. [c] Omit-
ting CuI. [d] Omitting Et2NH.
[*] Prof. G. Fabrizi, Dr. A. Goggiamani, Dr. A. Sferrazza, Prof. S. Cacchi
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza
Universitꢀ di Roma, P.le A. Moro 5, 00185 Rome (Italy)
Fax: (+39)06-4991-2780
These investigations revealed that when 2 equivalents of
nBu4NI were used, 3a was isolated in a satisfactory 78% yield
after 1 hour (Table 1, entry 3). Increasing the number of
equivalents of nBu4NI led to a lower yield (Table 1, entry 4),
whereas comparable results were obtained by substituting
iPr2NH for Et2NH (Table 1, entry 5) or using 2 equivalents of
NaI in the presence of 0.2 equivalents of nBu4NI (Table 1,
entry 6). No cross-coupled product was formed when CuI
(Table 1, entry 7) or Et2NH were omitted from the reaction
(Table 1, entry 8).
E-mail: sandro.cacchi@uniroma1.it
[**] We gratefully acknowledge GlaxoSmithKline for their generous
financial support and a fellowship position as well as Dr. Alcide
Perboni and Dr. Paolo Stabile of GlaxoSmithKline for valuable
discussions. We are also indebted to MURST and to La Sapienza,
University of Rome.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000472.
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Table 2: Reaction of phenylacetylene with arenediazonium tetrafluoro-
The scope and generality of the process was explored next
borates.[a]
using the conditions from Table 1, entry 3, although the
conditions described in Table 1, entries 5 and 6 provided
similar results. As shown in Table 2, electron-rich and
electron-poor arenediazonium tetrafluoroborates react with
phenylacetylene to give the corresponding cross-coupling
products in good to excellent yields. The reaction tolerates a
variety of substituents including chloro, bromo, keto, ester,
cyano, and nitro groups. Substituents in the ortho position are
also tolerated (Table 2, entries 2, 4, 6, and 12).
Entry
Ar
2
t [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-MeOC6H4
2-MeOC6H4
Ph
2,4-Me2C6H3
4-ClC6H4
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
1
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
78
66
91
75[c]
77
85
90
85
79
78
83
74
86
90
91
1.5
1.5
2
2
2
1.5
0.5
2
1
2
The extension of the reaction to a variety of terminal
alkynes was also examined. Our initial results are summarized
in Table 3.
2-ClC6H4
3,4,5-MeOC6H2
4-MeCOC6H4
3-MeOC6H4
4-MeO2CC6H4
4-BrC6H4
Formation of 3 f, 3l, and 3v–x is particularly noteworthy
given that alkynylarenes that contain 2-halo- and 2-aminoaryl
moieties have been widely used for the preparation of
indoles,[6,8] and that those containing 2-hydroxyaryl moieties
are useful intermediates for the synthesis of benzo[b]furans
using transition-metal-catalyzed cyclization reactions.[9] This
chemistry might provide an exceedingly useful tool for
appending heterocyclic rings to aniline fragments.
As an example, we explored the formation of 2-phenyl-
indole from 2-ethynylaniline (1g) and benzenediazonium
tetrafluoroborate (2c) through a process that would omit the
isolation of the cross-coupling intermediate. After some
experimentation, we were pleased to find that adding
5 mol% of NaAuCl4 and MeCN to the crude product mixture
after work-up of the Sonogashira reaction gave the
desired indole product in 64% overall yield after
2-BrC6H4
2
1
2
1.5
4-NCC6H4
3-CF3C6H4
4-O2NC6H4
[a] Unless otherwise stated, reactions were carried at room temperature
out on a 0.5 mmol scale in 3 mL of MeCN using 2 equiv of 1a, 1 equiv of
2, 10 equiv of Et2NH, 0.02 equiv of [PdCl2(PPh3)2], 0.04 equiv of CuI, and
2 equiv of nBu4NI. [b] Yields are given for isolated products. [c] At 608C
using (iPr)2NH.
Table 3: Reaction of terminal alkynes with arenediazonium tetrafluoroborates.[a]
12 hours at 608C.
The entire diazonium salt synthesis/iododediazo-
niation/cross-coupling sequence can also be performed
in a one-pot domino process, omitting the isolation of
the intermediate arenediazonium salt (Scheme 1).[10]
The best results were obtained when the reagents
required for the alkynylation step were added to a
crude mixture following the preparation of the diazo-
nium salts that had been concentrated under reduced
pressure.
A plausible mechanism for this alkynylation reac-
tion involves the initial iododediazoniation of the
arenediazonium salt, followed by formation of a s-
aryl palladium iodide by oxidative addition, subsequent
reaction of s-aryl palladium iodides with copper
acetylides that are formed in situ, and reductive
elimination of the resultant s-alkyne–s-aryl palladium
complexes to give the cross-coupling product 3 and
regenerate the active catalyst species.
The intervention of an alternative mechanism that
involves the formation of s-aryl palladium iodides from
the reaction pathway outlined in Scheme 2 has been
ruled out on the basis of the following experiments: The
reaction of 1a with 2c was carried out under standard
conditions using nBu4NBr instead of nBu4NI. If s-aryl
palladium bromides were generated by trapping s-aryl
palladium cations (C)[11] with bromide anions, the
traditional reluctance of aryl bromides to undergo
oxidative addition with palladium catalysts that are
coordinated to triphenylphosphine[12] should be circum-
Entry
R
1
2
Product (t [h])
Yield
[%][b]
3p
(2 h)
1
2
3
4
5
nC5H11
HOCH2
HOCH2
Me3Si
1b 2h
1c 2h
1c 2a
1d 2h
1e 2h
75
78
72
72
87
3q
(3 h)
3r
(2 h)
3s
(2 h)
3t
(1.5 h)
2-pyridyl
3u
(2 h)
6
7
2-pyridyl
1e 2c
1 f 2 f
92
63
3v
(2 h)
3w
(6 h)
8
9
1g 2c
1h 2c
82
92
3x
(4 h)
[a] Unless otherwise stated, reactions were carried at room temperature out on a
0.5 mmol scale in 3 mL of MeCN using 2 equiv of 1, 1 equiv of 2, 10 equiv of
Et2NH, 0.02 equiv of [PdCl2(PPh3)2], 0.04 equiv of CuI, and 2 equiv of nBu4NI.
[b] Yields are given for isolated products.
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sponding cross-coupling product should then form. Taken
together, these results strongly support the view that the
Sonogashira cross-coupling of arenediazonium salts with
terminal alkynes in the presence of nBu4NI proceeds through
a domino process that starts with the iododediazoniation step.
In conclusion, the efficient cross-coupling of terminal
alkynes with arenediazonium salts has been developed. To the
best of our knowledge, this transformation is the first example
of the alkynylation of arenediazonium salts. The reaction
occurs under mild conditions in the presence of nBu4NI and
proceeds through a domino iododediazoniation/Sonogashira
cross-coupling sequence. Good to excellent yields are usually
obtained. A variety of alkyl, aryl, and heteroaryl substituents
on the alkyne substrate can be used and many useful
functionalities including bromo, chloro, keto, ester, ether,
cyano, and nitro substituents on the arenediazonium salt are
also tolerated. ortho Substituents, both in the arenediazonium
salt and the alkynylarene, are also tolerated. The formation of
alkynylarenes bearing 2-chloro-, 2-bromo-, 2-amino-, and 2-
hydroxyaryl moieties may be exceedingly useful for append-
ing heterocyclic rings to aniline fragments. The entire
arenediazonium salt synthesis/iododediazoniation/cross-cou-
pling sequence can also be performed as a one-pot domino
process, omitting the isolation of the arenediazonium salt.
Scheme 1. One-pot domino cross-coupling of anilines with phenyl
acetylene.
Scheme 2. Formation of ArPdX through the reaction of halide anions
with ArPd+ intermediates.
vented, and formation of cross-coupling products should be
observed. No evidence for the formation of compound 3a was
found after 5 hours at room temperature, whereas bromo-
benzene was obtained in 90% yield,[13] suggesting that the
bromodediazoniation process is faster than the reaction
shown in Scheme 2. To consider whether the lack of cross-
coupling product in the presence of nBu4NBr might be due, at
least in part, to a different reactivity of s-arylpalladium iodide
and bromide intermediates towards copper acetylides, we
explored the reactions of preformed [PhPdI(PPh3)2][14] and
[PhPdBr(PPh3)2][15] with phenylacetylene at room temper-
ature.[16] As shown in Figure 1, the bromide complex shows a
higher reactivity in the initial phases of the reaction, which in
both cases led to approximately 42% yield of 3a after 2 hours.
If s-aryl palladium bromides were generated by trapping s-
aryl palladium cations C with bromide anions, the corre-
Received: January 26, 2010
Revised: March 5, 2010
Published online: April 26, 2010
Keywords: arenediazonium salts · cross-coupling ·
.
domino reactions · homogeneous catalysis · palladium
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*
^
Figure 1. Reaction of [PhPdI(PPh3)2] ( ) and [PhPdBr(PPh3)2] ( ) with
phenylacetylene in the presence of CuI and Et2NH in MeCN at room
temperature.
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