Phosphine-free Sonogashira coupling: reactions of aryl halides catalysed by palladium(II) complexes of azetidine-derived polyamines under mild conditions

Article abstract of DOI:10.1016/j.tet.2008.12.032

Readily synthesised, water-stable pyridylazetidine-based Pd(II) complexes have been studied as catalysts for the Sonogashira coupling reaction. Under low catalyst loadings, various aryl bromides and chlorides were efficiently coupled with phenylacetylene

Full text of DOI:10.1016/j.tet.2008.12.032

Tetrahedron 65 (2009) 1630–1634
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Phosphine-free Sonogashira coupling: reactions of aryl halides catalysed by
palladium(II) complexes of azetidine-derived polyamines under mild conditions
a
b
c
a
b
d
Dong-Hwan Lee , Young Hoon Lee , Jack M. Harrowfield , Ik-Mo Lee , Hong In Lee , Woo Taik Lim ,
e,
a,
*
*
Yang Kim , Myung-Jong Jin
a
Department of Chemical Engineering and Chemistry, Inha University, Incheon 402-751, South Korea
Department of Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Institut de Science et d’Ing e´ nierie Supramol e´ culaires, Universit e´ Louis Pasteur, 8, all e´ e Gaspard Monge, 67083 Strasbourg, France
Department of Applied Chemistry, Andong National University, Andong, Kyoungpook 760-749, South Korea
Department of Chemistry & Advanced Materials, Kosin University, 149-1 Dongsam-dong, Yeongdo-gu, Busan, South Korea
b
c
d
e
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily synthesised, water-stable pyridylazetidine-based Pd(II) complexes have been studied as catalysts
for the Sonogashira coupling reaction. Under low catalyst loadings, various aryl bromides and chlorides
were efficiently coupled with phenylacetylene at only moderately elevated temperatures (50–70 C) and,
in some cases, even at room temperature. Not only was the catalysis efficient under mild conditions but it
was also operative in aerated, partly aqueous and phosphine-free media.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 29 September 2008
Received in revised form 10 December 2008
Accepted 11 December 2008
Available online 16 December 2008
ꢀ
Keywords:
Sonogashira coupling
Pd complexes
Pyridylazetidines
Non-phosphine catalysis
5
e,8
1
. Introduction
to ligands such as N-heterocyclic carbenes,
some of which form
9
palladacycle species, with the activity retained even in mixed-
6
c,10
Many metal-catalyzed coupling reactions have been recognized
as convenient one-step methods for the construction of carbon–
aqueous solvents.
However, these catalysts worked well only
for activated and not for deactivated aryl chlorides. Thus, the
search for practical coupling catalysts that exhibit high activity
and broad applicability continues. In this context, we considered
that stable Pd(II) complexes of a new series of pyridylazetidine
ligands, some of which have been recently shown to give useful
catalysts for the Suzuki–Miyaura reaction in aqueous media,
might well be effective in Sonogashira coupling. The present work
is a report of our successful investigation of this possibility using
the species shown in Figure 1.
carbon bonds.1 Among them, the palladium-catalyzed sp –sp
,2
2
Sonogashira coupling reaction of terminal alkynes with aryl ha-
lides is one of the most valuable methods for the synthesis of
arylated alkynes. Conventionally, the reaction is performed by
using catalytic amounts of a palladium–phosphine complex and
CuI in the presence of a large excess of a secondary or tertiary
2
11
12
2
–8
amine or various simple bases such as alkali-metal carbonates.
However, many of the Pd–phosphine complexes are sensitive to
both air and moisture, and their cost and toxicity limit any large-
scale industrial applications. In addition, commonly used amines
such as piperidine, diethylamine and triethylamine add to the
environmental burden. The best results have been obtained with
reactive aryl iodides or aryl bromides, and the conditions are not
suitable for less reactive aryl chlorides unless relatively high cat-
alyst loadings of 1–5 mol % are used. Recently, non-phosphine
2. Experimental
2.1. Materials and equipment
All chemicals were purchased from Aldrich and used
without further purification. All organic solvents were dis-
tilled prior to use. Microanalysis was carried out with
7
Sonogashira coupling was reported to be effective with Pd bound
a
Chemtronics TEA-3000 instrument. GC/GC–MS analyses
were performed on an Agilent 6890N GC (He carrier gas, HP-
m) coupled to an Agi-
5
MS column, 0.25 m coil, 30 mꢁ0.25
m
*
Corresponding authors. Fax: þ82 51 403 3760 (Y.K.); fax: þ82 032 876 7469
M.-J.J.).
E-mail addresses: ykim@kosin.ac.kr (Y. Kim), mjjin@inha.ac.kr (M.-J. Jin).
(
lent 5975 Network Mass Selective Detector (electron impact
ionization at 70 eV).
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.032

D.-H. Lee et al. / Tetrahedron 65 (2009) 1630–1634
1631
Figure 1. The ligands giving rise to the Pd(II) complexes (composition of the isolated solids indicated) used as catalysts in the present study.
ꢀ
2
.2. Syntheses
were obtained by collecting 72 sets of frames with 5 scans and an
exposure time of 1 s per frame. This highly redundant dataset was
corrected for Lorentz and polarization effects; negligible correc-
tions for crystal decay were also applied. The space group P-1 was
[Pd(L1)Cl]CF
3 3 4
SO (1), [Pd(L2)Cl]ClO (2) and L3 were prepared
12
as described previously.
14
determined by the program XPREP. The structure was solved by
direct methods and refined on F by full-matrix least-squares
15
2
2
.3. {2-(3-Methyl-3-(pyridin-2-yl)azetidin-1-yl)-N-(pyridin-2-
16
procedures. The hydrogen atoms were placed geometrically, with
N–H distances in 0.91 Å and C–H distances in 0.97 Å, and these
atoms were refined using a riding model. Table 1 contains summary
data relating to the crystal structures and their refinements. Full
details have been deposited with the Cambridge Crystallographic
Data Base under deposition number CCDC 703477. These data can
be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ylmethyl)ethanamine}palladium(II) perchlorate,
4 2
[Pd(L3)](ClO ) , 3
2
PdCl (0.80 g; 4.5 mmol) was added to a solution of L3 (1.3 g;
4
.6 mmol) in ethanol (80 mL) plus acetone (20 mL). The mixture
was heated at reflux under nitrogen for 48 h, during which time
most of PdCl dissolved. The remaining insoluble material was fil-
tered off and the yellow filtrate was evaporated to dryness under
reduced pressure. Yield: 1.3 g (60%). The yellow powder was
redissolved in a mixture of ethanol (20 mL) and acetone (5 mL)
containing excess LiClO
produced yellow crystals suitable for crystallography. Anal. Calcd
for C17 Pd: C, 34.74; H, 3.77; N, 9.53. Found: C, 34.2; H,
2
3. Results and discussion
4
. Gradual reduction of the solvent volume
Complexes 1¼[Pd(L1)Cl]CF
SO
3 3
,2¼[Pd(L2)Cl]ClO and3¼[Pd(L3)]-
4
2 4 8
H22Cl N O
(
4 2
ClO ) used as catalysts here were derived from ligands L1–L3 (Fig. 1)
3
.7; N, 9.6%.
12
as described previously, except that in the case of L3 a more extended
reaction period and use of a different solvent (see Experimental) led to
the isolation of 3 as the diperchlorate, rather than the chloride-per-
chlorate. This complex was subsequently characterised by a crystal
structure determination (Table 1), which showed it to differ from 1 and
2
.4. General procedure for the conduct of Sonogashira
coupling
Reactions were carried out in a glass ampoule equipped with
a Teflon screw cap. Aryl halide (1.0 mmol), the alkyne (1.1 mmol),
Na CO (2.0 mmol), CuI (1.0 mmol) and n-dodecane (15–20 mg) as
an internal GC standard were dispersed in H O/DMA (2 mL, 1:1 v/v)
2
3
Table 1
Crystal and refinement data
2
and then a solution of the catalyst, e.g., 2, [Pd(L2)Cl]ClO
4
, in H
2
O/
Chemical formula
M/g mol
Crystal system
Space group
a/Å
b/Å
c/Å
17 2 4 8
C H22Cl N O Pd (3)
ꢂ1
DMA (1.0
mmol mL ) was added to the mixture. The resulting
ꢂ1
587.69
Triclinic
P-1
mixture was stirred at the appropriate temperature (see Tables 3
and 4). Samples were withdrawn periodically and analyzed by GC/
GC–MS. GC yield was determined using n-dodecane as an internal
standard and based on the amount of aryl halide employed. The
8.4480(17)
9.7110(19)
13.702(3)
96.62(3)
103.61(3)
102.17(3)
1051.7(4)
1.856
reaction mixture was filtered and the filtrate washed with H
Et O several times. The organic phase in the combined filtrates was
separated and dried over MgSO , and the solvent was evaporated
2
O and
ꢀ
a
/
ꢀ
ꢀ
2
b/
g
/
4
3
V/Å
D
Z
under reduced pressure. The product was isolated by column
chromatography on silica gel.
ꢂ3
c
/g cm
2
Crystal size (mm)
T (K)
0.30ꢁ0.15ꢁ0.05
100(2)
2
.5. Crystallography
l
(Mo K
a
)/Å
0.76999
1.191
30.33
ꢂ1
m
(MoK
a
ꢀ
)/mm
X-ray diffraction data for the single crystal were collected at
93(2) K using an ADSC Quantum210 detector at Beamline 4A
2
q
max
/
2
hkl range
N
N
N
N
R1(F)
2
wR (F )
GoF(all)
Drmin/e Å
0ꢃhꢃ11, ꢂ12ꢃkꢃ12, ꢂ7ꢃlꢃ17
4450
MXW of the Pohang Light Source. Crystal evaluation and data
collection were done using
to-crystal distance of 6.0 cm. Preliminary cell constants and an
orientation matrix were determined from 36 sets of frames col-
ind (Rmerge
obs (I>2s(I))
)
4450 (0.0000)
3996
291
0.0886
0.2797
1.325
l
¼0.76999 Å radiation with a detector-
var
ꢀ
2
lected at scan intervals of 5 with an exposure time of 1 s per frame.
The basic scale file was prepared using the program HKL2000.13 The
reflections were successfully indexed by the automated indexing
ꢂ3
ꢂ3
ꢂ2.090
Drmax/e Å
2.412
13
routine of the DENZO program. The 8750 reflections (see Table 1)

1632
D.-H. Lee et al. / Tetrahedron 65 (2009) 1630–1634
Table 3
a
Sonogashira coupling of bromobenzene with phenylacetylene
Experiment Catalyst
Solvent
DMA/H
Base
Temperature Time (h) Yieldc (%)
( C)
a
ꢀ
no.
(mol %)
1
2
3
4
5
6
7
8
9
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.01)
2 (0.001)
2
O
O
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
50
50
50
50
50
50
50
50
2
2
2
2.5
3
3
2
2
99 (95)
97
98
97 (93)
94
95
DMF/H
DMSO/H
NMP/H
EtOH/H
MeOH/H
2
2
O
2
O
2
O
2
O
DMA/H
DMA/H
DMA/H
DMA/H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
K
K
3
PO
CO
4
94 (91)
84
2
3
NaOAc 50
2
65
10
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
Na
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
50
50
40
25
50
50
50
25
50
25
5
12
5
24
3
3
2
24
2
91
80 (77)
88
73
11
34
83 (81)
51
73 (70)
37
11
2 (0.0002) DMA/H
1
13
2
2 (0.01)
2 (0.1)
DMA/H
DMA/H
DMA
1
4
2 (0.01)
2 (0.01)
1 (0.01)
1 (0.1)
b
1
5
DMA/H
DMA/H
DMA/H
DMA/H
DMA/H
2
2
2
2
2
O
O
O
O
O
1
6
17
Figure 2. A view of the stoichiometric unit present in the lattice of complex 3. Hy-
drogen atoms omitted for clarity, probability displacement ellipsoids shown at the 50%
level.
1
19
8
3 (0.01)
3 (0.1)
24
a
All reactions were performed with bromobenzene (1.0 mmol), phenylacetylene
1.1 mmol), base (2.0 mmol), CuI (1.0 mmol), DMA/H O or the other solvent mixtures
(
(
2
2 mL, 1:1 v/v) and the indicated amounts of catalyst 1, 2 or 3.
2
in that the Pd is present in an approximately square-planar N
4
, rather
b
Without CuI.
than N Cl environment (Fig. 2). Coordination of the additional pyridyl
3
c
GC yield was determined using n-dodecane as an internal standard. Isolated
unit causes the ligand to adopt a non-planar, helical conformation
about the metal ion, as found in various quadridentate, pyridine-donor
yield is given in parenthesis.
17
ligands. However, this distortion has no obvious marked conse-
quences in terms of the Pd–N bond lengths when compared with those
in 1 and 2 (Table 2). In the lattice of 3, perchlorate–O atoms are found in
what might be considered axial binding sites on Pd but the Pd/O
distances are very long (3.380(8), 3.066(8) Å). In fact, the use of
CrystalExplorer18 to provide dnorm Hirshfeld surfaces indicates that
there is no significant interaction and that the proximity of the per-
chlorate anions to the cation is determined rather by aliphatic CH/O
interactions. Such anion–O/HC interactions are also apparent in the
lattices of 1 and 2, where again there are no indications of significant
axial interactions with the metal. While the helicity of the complex and
of the saturated five-membered chelate ring, as well as the asymmetry
of N(2), might be expected to result in diastereoisomerism, in the lattice
modified ones with a large non-coordinating substituent and a co-
ordinating substituent, respectively. The fact that the pyridyl arm in
3
is found to be coordinated to Pd atom raises the important issue
of whether a readily replaced ligand (such as Cl in 1 and 2) is
necessary to ensure catalytic activity.
Given that complex 2 had proved to be the most effective cat-
12
alyst of 1–3 in Suzuki–Miyaura coupling, we began investigation
of Sonogashira catalysis with this species, using the coupling of
bromobenzene with phenylacetylene in the presence of Na
2
CO
3
and CuI as a model reaction (Table 3). The reaction in DMA/H
2
O
(
0
2
1:1) was initially performed with catalyst loading as low as
.01 mol %. The reaction proceeded to completion at 50 C within
h (entry 1). Solvent effects on the activity of 2 were examined
ꢀ
N N
of 3 only the enantiomeric M(l)R and P(d)S species are present.
Presumably as a consequence of the coordination of its attached
N-donor centre, the 2-pyridylmethyl substituent in 3 occupies an
with different polar solvents. When the reaction was conducted in
aqueous DMF, DMSO, NMP, EtOH and MeOH instead of aqueous
DMA, similar results were obtained under the same conditions
equatorial position of the saturated five-membered ring, in contrast to
(entries 2–6). It is interesting that the reactions in aqueous ethanol
2
2
, where the unbound benzyl group is axially situated.1 In the solid
and methanol gave excellent results. Parameters such as the nature
of the base, the catalyst loading and the reaction temperature were
lattice, there are contacts indicative of CH/p interactions between the
substituent pyridine rings, contacts which presumablycould also occur
as part of the approach of an aromatic substrate to the catalyst.
also surveyed. Na
PO , K CO and NaOAc (entries 7–9). When the catalyst loading
was decreased to 0.001 mol %, high conversion was still achieved
entry 10). Indeed, the reaction remained efficient even when using
2 3
CO as a base gave slightly better results than
K
3
4
2
3
12
In our earlier investigation of the Suzuki–Miyaura reaction,
amino moieties of complexes 1–3 were found to have a significant
effect on their catalytic activities. Complex 1 may be regarded as the
parent species, whereas complexes 2 and 3 may be regarded as
(
a much lower catalytic loading of 0.0002 mol %, for which a high
ꢂ1
TOF of 33,300 h was obtained (entry 11). Further optimization of
the reaction conditions was not attempted. Catalyst 2 still showed
ꢀ
outstanding performance at lower temperatures of 25–40 C (en-
Table 2
ꢀ
ꢀ
tries 12 and 13), its activity at 25 C being particularly noteworthy.
Environment of the cation in 3: selected distances (Å) and angles ( ). Atom num-
bering is given in Figure 2. Values in square brackets are the corresponding measures
in complexes 1 and 2, respectively
To apply mild conditions while using Na
require aqueous solvents in order to ensure dissolution of Na
CO
as base appears to
CO
2
3
2
3
Bond distances
Bond angles
(entry 14). As expected, the CuI cocatalyst has an important in-
fluence on the reaction rate (entry 15). Only very minor changes in
the catalyst activity were observed on exposure of the system to air
Pd–N(1) 2.065(6)
N(1)–Pd–N(2) 80.6(2)
Pd–N(2) 2.017(5) [2.020(3); 2.032(2)] N(1)–Pd–N(3) 165.2(2)
Pd–N(3) 2.018(6) [2.020(3); 2.031(2)] N(1)–Pd–N(4) 104.9(2)
Pd–N(4) 2.077(5) [2.079(3); 2.061(2)] N(2)–Pd–N(3) 85.2(2) [84.06(11); 84.52(9)]
N(3)–Pd–N(4) 89.7(2) [90.15(10); 90.07(9)]
and water during reaction. Under the same conditions as used with
ꢀ
2
at 50 C, catalysts 1 and 3 gave significantly inferior performance
(entries 16 and 18, cf. entry 1). That the ‘parent’ complex 1, lacking

D.-H. Lee et al. / Tetrahedron 65 (2009) 1630–1634
1633
Table 4
Encouraged by these results, we investigated the coupling of
several aryl chlorides (entries 13–24) expected to be less reactive.
The coupling of chlorobenzene at 70 C in the presence of 0.5 mol %
a
Sonogashira coupling of aryl halides with terminal alkynes
ꢀ
of 2 proceeded rapidly, giving 91% yield in 8 h (entry 16), although
at lower temperatures and loadings (entries 13–15) the yields were
considerably reduced, even after longer reaction periods. Activated
Experiment R1
no.
X
R2
Catalyst (2)
loading (mol %) ( C)
Temperature Time Yieldb
1
-chloro-4-nitrobenzene was coupled almost quantitatively in 5 h
ꢀ
(h)
(%)
ꢀ
at 70 C with 0.5 mol % catalyst (entry 17). Attempts to couple
deactivated aryl chlorides were of limited success and required
more extended reaction times for high yields (entries 18–20). Aryl
chlorides were found to react with other alkynes such as propargyl
1
2
3
4
5
6
7
8
9
4-O
2-O
2
N
N
Br Ph
Br Ph
0.01
0.01
0.01
0.01
0.01
50
50
50
50
50
50
50
50
50
50
50
50
50
50
70
70
70
70
70
70
70
70
70
70
90
2
2
99 (95)
97
2
4-MeO Br Ph
2-MeO Br Ph
4-Me
2-Me
H
2.5 90
3
2.5 91
3
3
4
4
5
5
93 (89)
Br Ph
Br Ph
Br CH
Br n-C
Br Si(i-Pr)
OH 0.01
13 0.01
ꢀ
alcohol, (triisopropylsilyl)acetylene and 1-octyne at 70 C (entries
0.01
95
93
91
94 (90)
92
78
81
29
45 (41)
73
91
94
88
82 (77)
71
84 (80)
69
74
51
83
21–23). However, low yields were observed in the case of deacti-
2
OH 0.01
13 0.01
vated aryl chlorides and higher temperatures were required to
reach satisfactory conversion (entries 24 and 25).
H
H
6
H
3
0.01
1
0
4-MeO Br CH
4-MeO Br n-C
4-MeO Br Si(i-Pr)
2
1
1
6
H
4. Conclusions
12
3
0.01
0.01
0.1
5
13
H
Cl Ph
Cl Ph
Cl Ph
Cl Ph
Cl Ph
24
24
12
8
Both tri- and quadri-dentate pyridylazetidine derivatives form
14
H
15
H
0.1
Pd(II) complexes, which are efficient catalysts for Sonogashira
coupling reactions in aqueous dispersions. Thus, the coupling can
be conducted in the absence of phosphine ligands and under con-
ditions requiring minimal precautions. Various aryl bromides un-
dergo coupling with alkynes in the presence of very low amounts of
catalyst and the catalyst system is also effective for the reactions of
aryl chlorides. The presence of at least one readily replaced
unidentate ligand in the Pd(II) complex presumed to be an actual
precursor of the true catalytic species appears, on the basis of the
present results, to be unnecessary. The addition of CuI to the re-
action mixture, although leading to faster rates, does not appear to
be essential.
16
H
0.5
0.5
0.5
0.5
0.5
17
4-O
2
N
5
18
4-MeO Cl Ph
12
12
18
12
18
18
24
24
1
9
4-Me
2-Me
H
Cl Ph
Cl Ph
Cl CH
Cl n-C
Cl Si(i-Pr)
20
21
2
OH 0.5
6
H13 0.5
22
23
24
25
H
H
3
3
3
0.5
0.5
0.5
4-MeO Cl Si(i-Pr)
4-MeO Cl Si(i-Pr)
a
All reactions were performed with aryl halides (1.0 mmol), alkynes (1.1 mmol),
2
base (2.0 mmol), CuI (1.0 mmol), DMA/H O (2 mL, 1:1 v/v) and the indicated
amounts of catalyst 2.
b
GC yield was determined using n-dodecane as an internal standard. Isolated
yield is given in parenthesis.
References and notes
1
. For reviews of metal-catalyzed cross-coupling reactions, see: (a) Diederich, F.;
Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: New York, NY,
998; (b) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions,
a substituent on the terminal amino group, is an inferior catalyst to
2
perhaps reflects the greater ability of a secondary N-donor to
1
enhance electron density on Pd and thus to facilitate intermediate
oxidative addition steps or the greater acidity of a secondary NH
donor, which could be important in an internal redox reaction of
2nd ed.; Wiley-VCH: Weinheim, 2004; (c) Beller, M.; Bolm, C. Transition Metals
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. For recent reviews: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176;
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Chem. Rev. 2007, 107, 874.
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McGaffin, G.; de Meijere, A. Synthesis 1994, 583; (c) Chow, H.-F.; Wan, C.-W.;
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R e´ p a´ si, J.; Kotschy, A. J. Org. Chem. 2003, 68, 3327; (e) Adjabeng, G.; Brenstrum,
T.; Frampton, C. S.; Robertson, A. J.; Hillhouse, J.; McNulty, J.; Capretta, A. J. Org.
Chem. 2004, 69, 5082; (f) Hierso, J.-C.; Fihri, A.; Amardeil, R.; Meunier, P. Org.
Lett. 2004, 6, 3473.
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2
2
the deprotonated complex to give a Pd(0) intermediate. It is sig-
nificant that 3 is only a slightly poorer catalyst than 2, since this
indicates that the presence of a readily displaced unidentate ligand
such as chloride is not essential to the catalyst activity. The mech-
anism of the Sonogashira reaction is complicated, though
3
2
understood in essence, and the present systems extend an area,
which has had rather limited study,2
,5–10
this being the use of
ligands of denticities higher than two to form the catalyst precursor
complex. If it is indeed critical that the bound NH centre is involved
in an internal redox reaction to give a Pd(0)–imine complex, then
dissociation of one or more donors may occur as a non-rate-de-
termining step in this species.
4
5
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substituents, all these aryl bromides were rapidly coupled in the
presence of 2, and a catalyst loading of 0.01 mol % was sufficient
1
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ꢀ
to achieve high TOFs, with the reactions being complete at 50 C
8
in less than 3 h. We extended the scope of the coupling of the
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sopropylsilyl)acetylene and 1-octyne (entries 7–12), the reaction
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