Room temperature Stille cross-coupling reaction of unreactive aryl chlorides and heteroaryl chlorides

Article abstract of DOI:10.1039/b917711f

Phosphanyl-β-ketoiminate Pd complexes serve as highly effective catalysts in the Stille coupling reaction of aryl chlorides and heteroaryl chlorides with organostannanes at room temperature.

Full text of DOI:10.1039/b917711f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Room temperature Stille cross-coupling reaction of unreactive
aryl chlorides and heteroaryl chloridesw
Dong-Hwan Lee, Abu Taher, Wha-Seung Ahn and Myung-Jong Jin*
Received (in Cambridge, UK) 1st September 2009, Accepted 20th October 2009
First published as an Advance Article on the web 12th November 2009
DOI: 10.1039/b917711f
Phosphanyl-b-ketoiminate Pd complexes serve as highly
effective catalysts in the Stille coupling reaction of aryl chlorides
and heteroaryl chlorides with organostannanes at room
temperature.
The palladium-catalyzed Stille reaction of organohalides with
organostannanes represents one of the most important cross-
couplings for the formation of carbon–carbon bonds.1 This
coupling reaction has been used in the synthesis of biaryl
compounds that are important intermediates in natural
products, polymers, and pharmaceuticals.2 Much attention
has been made to develop efficient catalysts for the Stille
reaction. Aryl iodides and bromides have been widely
employed as substrates in the coupling reactions.3 From a
practical point of view, the use of aryl chlorides is highly
desirable because aryl chlorides are readily available and
Scheme 1 Synthesis of phosphanyl-b-ketoiminate Pd complexes 2.
inexpensive. However, they are much more difficult to activate
than aryl iodides and bromides.4 Recently, attention has been
directed towards coupling reactions employing aryl chlorides
as one of the coupling partners.5 Although significant progress
has been achieved with highly active Pd catalysts in this
area, the successful examples with aryl chlorides are rare.6
Moreover, most of the reactions require a high loading of the
catalyst and elevated reaction temperature. To the best of our
knowledge, the coupling of aryl chlorides at room temperature
has not been reported. The efficient coupling of unreactive aryl
chlorides is still challenging.
b-ketoimines 1 in 5 min in quantitative yield. Deprotonation
of 1 with EtOTl in THF, followed by treatment with
11
Pd2(m-Cl)2Me2(PEt3)2 which led to the formation of the
corresponding Pd complexes, respectively.
With the Pd catalysts 2 in hand, we tested Stille coupling of
4-chlorotoluene with tributylphenylstanne as a model reaction
(Table 1). The reaction was initially performed in the presence
of 1.0 mol% of catalyst 2a and 2.0 equiv. of CsF in THF.
Both excellent conversion and good yield were obtained in 5 h
(entry 1). High catalytic activity was still maintained in the
presence of 0.5–0.1 mol% of 2a (entries 2 and 3). Such
activities obtained with this catalyst are remarkably superior
Herein, we present phosphanyl-b-ketoiminate palladium
complexes 2 as useful catalysts for room temperature Stille
coupling of aryl and heteroaryl chlorides. b-Ketoimines are
interesting compounds in coordination chemistry due to their
resonance stability and easy modification to tailor the electronic
and steric factors by changing the substituent on the N atom.7
b-Ketoiminate complexes have been used as precursors for
metalloorganic chemical vapor deposition8 and as catalysts for
olefin polymerization.9 In contrast, they have received little
attention in other catalytic processes. Recently, Pd catalyst 2b
was found to be highly active for the Suzuki–Miyaura
coupling reaction in our laboratories.10 Similar to the previous
method, Pd complexes 2 were easily prepared from 2,4-pentane-
dione as shown in Scheme 1. Condensation of 2,4-pentane-
dione and primary amines under microwave heating gave
Table 1 Stille coupling of 4-chlorotoluene with tributylphenyltina
Entry
2 (mol%)
Solvent
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
2a (1.0)
2a (0.5)
2a (0.1)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2a (0.5)
2b (0.5)
2c (0.5)
2d (0.5)
THF
THF
THF
Acetonitrile
Toluene
NMP
5
5
8
5
5
5
5
5
5
5
5
97 (94)
95 (93)
90
87
79
92
DME
93 (85)
88 (82)
86
87
72
1,4-Dioxane
THF
THF
9
10
11
THF
Department of Chemical Engineering and Chemistry, Inha University,
Incheon 402-751, Korea. E-mail: mjjin@inha.ac.kr;
Fax: 82-32-860-0959; Tel: 82-32-860-7469
w Electronic supplementary information (ESI) available: General
experimental procedures, synthesis and characterization details. See
DOI: 10.1039/b917711f
a
Reaction conditions: 1.0 mmol of 4-chlorotoluene, 1.1 mmol of
tributylphenylstanne, 2.0 mmol of CsF, and a catalytic amount of 2.
b
GC yield was determined using n-dodecane as an internal
standard. Isolated yield is given in parenthesis.
ꢀc
This journal is The Royal Society of Chemistry 2010
478 | Chem. Commun., 2010, 46, 478–480

View Article Online
Table 2 Stille coupling of aryl chlorides with organostannanesa
to any previously reported results on Stille coupling. It is
noteworthy that the catalyst shows outstanding performance
at room temperature. The solvent effect on the activity was
examined with different solvents. When the reaction was
conducted in acetonitrile, toluene, NMP, DME and 1,4-dioxane
instead of THF, the catalytic activity was somewhat reduced
under the same conditions (entries 4–8). Similar catalysts 2b–d
were also tested in the coupling of 4-chlorotoluene with
tributylphenylstanne (entries 9–11). In this process, the use
of 2b–d led to a decrease in the rate. Consequently, Pd complex
2a stood out as the most effective catalyst. It is interesting that
2a exhibits a catalytic activity that is superior to 2b. This could
be explained by the fact that the triethylphosphanyl group has
stronger s-donating ability compared to that of the triphenyl-
phosphanyl one.12 In addition, the results reveal that the
alkoxybenzyl moiety as a hemilabile arm has a beneficial effect
in enhancing the reactivity of this Stille coupling. Less change
of the activity was observed on exposure of the system to air
and water in the reaction.
Entry Aryl chloride
Organostannane
Time/h Yield (%)b
1
2
3
4
3
3
4
5
96 (92)
94 (92)
93 (91)
92 (90)
5
6
6
5
95 (91)
93 (90)
To further expand the scope of our catalytic system, we next
investigated the coupling of substituted aryl chlorides with
various organostannanes in the presence of 0.5 mol% of 2a at
room temperature (Table 2). Excellent catalytic activity was
observed in the coupling of chlorobenzene, activated 1-chloro-
4-nitrobenzene, and 4-chlorobenzonitrile (entries 1–3).
Deactivated aryl chlorides possessing electron-donating
substituents were found to furnish the corresponding biaryl
products in high yields (entries 4 and 5). 1-Chloro-naphthalene
and 9-chloroanthrancene coupled well with tributylphenyltin
in high yields (entries 6 and 7). Importantly, the catalyst was
found to be active for the coupling of unprotected 4-chloro-
phenol and 2-chloroaniline (entries 8 and 9). Furthermore, the
catalyst system was also efficient for the couplings of aryl
chlorides with electron-rich arylstannanes (entries 10–13). It is
noteworthy that deactivated and sterically hindered 2-chloro-
1,3-dimethylbenzene could be coupled in good yield,
although elevated temperature and longer time were required
(entries 14 and 15). One of the most useful applications of the
Stille reaction is the coupling with vinyl- and allylstannanes.
Similar results were also obtained in the reaction of chloro-
benzene with tributylvinylstanne and allyltributylstanne at
room temperature (entries 16 and 17). Regardless of the
substituents, most of the coupling reactions were very clean
and highly efficient under mild conditions. To our knowledge,
our catalyst 2a showed the highest catalytic activity reported
for the Stille coupling of aryl chlorides.
7
8
9
5
5
6
90 (83)
87 (81)
94 (91)
10
11
5
6
92 (88)
92 (90)
12
13
8
8
90 (85)
83 (80)
14c
15
15
84 (81)
75 (70)
15c
16
6
6
84 (81)
91 (90)
17
Stille coupling of heteroaryl halides is of particular interest
to the pharmaceutical industry since many biologically active
compounds are accessed through this methodology.13 Despite
their importance, the coupling of heteroaryl chlorides remains
a challenge, especially at low temperature. Development of
effective catalysts are thus highly desired in this area. We
therefore attempted the coupling of heteroaryl chlorides at
room temperature (Table 3). Chloropyridines bearing a chloride
in the 2-, 3-, or 4-position underwent the coupling with
tributylphenylstanne in high yields (entries 1–3). A somewhat
decreased yield was obtained for the reaction of 2-chloropyridine
with tributyl(p-toly)stannane (entry 4). Satisfyingly, sterically
hindered 2-chloro-3-methylpyridine could be coupled with a
a
Reaction conditions: 1.0 mmol of aryl chloride, 1.1 mmol of
b
organostannane, 2.0 mmol of CsF, and 0.5 mol% of 2a. GC yield
was determined using n-dodecane as an internal standard. Isolated
c
yield is given in parenthesis. Reaction performed at 50 1C.
prolonged reaction time (entry 5). Other heteroaryl chlorides
such as 4-chloropyrimidine and 2-chloroquinoline also gave
promising results under the mild conditions (entries 6 and 7).
Chlorothiophenes in the coupling reaction are challenging
substrates due to the strong affinity of the sulfur for the Pd.14
2-Chlorothiophene or 3-chlorothiophene were converted to the
corresponding products in satisfactory yields (entries 8 and 9).
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 478–480 | 479

View Article Online
Table 3 Stille coupling of heteroaryl chlorides with organostannanesa
heteroaryl chlorides. We envisage the application of these
catalysts could be extended to a wide range of catalytic
processes.
This work was supported by National Research Foundation
of Korea Grant funded by the Korean Government
(2009–0072013).
Entry Heteroaryl chloride Organostannane Time/h Yield (%)b
1
4
90 (86)
Notes and references
1 For reviews of the Stille reaction see: (a) J. K. Stille, Pure Appl.
Chem., 1985, 57, 1771; (b) M. Pereyre, J. P. Quintard and
A. Rahm, Tin in Organic Synthesis, Butterworth, London, 1987;
(c) V. Farina, V. Krishnamurthy and W. J. Scott, The Stille
2
3
4
5
4
6
92 (89)
97 (91)
84 (80)
Reaction, John Wiley
(d) T. N. Mitchell, Metal-catalyzed Cross-coupling Reactions,
Wiley-VCH, Weinheim, 2004; (e) P. Espinet and
A. M. Echavarren, Angew. Chem. Int. Ed., 2004, 43, 4704.
&
Sons, New York, NY, 1998;
2 (a) G. Bringmann and D. Menche, Acc. Chem. Res., 2001, 34, 615;
(b) G. Bringmann, Y. Reichert and V. V. Kane, Tetrahedron, 2004,
60, 3539; (c) T. W. Wallace, Org. Biomol. Chem., 2006, 4, 3197;
(d) T. C. Roberts, P. A. Smith, R. T. Cirz and R. E. Romesberg,
J. Am. Chem. Soc., 2007, 129, 15830.
5
8
87 (81)
6
7
8
8
93 (90)
90 (85)
3 (a) J.-H. Li, Y. Liang, D.-P. Wang, W.-J. Liu, Y.-X. Xie and
D.-L. Yin, J. Org. Chem., 2005, 70, 2832; (b) S. P. H. Mee, V. Lee
and J. E. Baldwin, Chem.–Eur. J., 2005, 11, 3294; (c) J. Hammerle,
¨
¨
M. Schnurch and P. Stanetty, Synlett., 2007, 2975; (d) W.-J. Zhou,
8
6
6
5
91 (88)
84 (80)
93 (91)
K.-H. Wang and J.-X. Wang, Adv. Synth. Catal., 2009, 351, 1378.
4 V. V. Grushin and H. Alper, in Activation of Unreactive Bonds and
Organic Synthesis, ed. S. Murai, Springer, Berlin, 1999.
5 (a) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41,
4176; (b) R. B. Bedford, C. S. J. Cazin and D. Holder, Coord.
Chem. Rev., 2004, 248, 2283; (c) A. F. Littke, L. Schwarz and
G. C. Fu, J. Am. Chem. Soc., 2002, 124, 6343; (d) C. Wolf and
R. Lerebours, J. Org. Chem., 2003, 68, 7551.
9
10
11
10
81 (79)
6 (a) W. Su, S. Urgaonkar, A. Patrick, McLaughlin and G. Verkade,
J. Am. Chem. Soc., 2004, 126, 16433; (b) J. R. Naber and
S. L. Buchwald, Adv. Synth. Catal., 2008, 350, 957.
7 (a) S. Doherty, R. J. Errington, N. Housley, J. Ridland, W. Clegg
and M. R. J. Elsegood, Organometallics, 1999, 18, 1018;
(b) H. Hatem, D. B. Isabelle, M. Perrin and R. Lamartine,
J. Org. Chem., 2004, 69, 6521.
a
Reaction conditions: 1.0 mmol of heteroaryl chloride, 1.1 mmol of
b
organostannane, 2.0 mmol of CsF, and 0.5 mol% of 2a. GC yield
was determined using n-dodecane as an internal standard. Isolated
yield is given in parenthesis.
8 S. W. Lim, J. C. Lee, D. S. Shon, W. I. Lee and I. M. Lee, Chem.
Mater., 2002, 14, 1548.
9 D. Zhang, G. X. Jin and N. Hu, Chem. Commun., 2002, 574.
10 (a) D.-H. Lee, J.-Y. Jung, I. M. Lee and M.-J. Jin, Eur. J. Org.
Chem., 2008, 356; (b) D.-H. Lee, H. Qiu, M.-H. Cho, I. M. Lee and
M.-J. Jin, Synlett., 2008, 1657.
11 F. T. Ladipo and G. K. Anderson, Organometallics, 1994, 13, 303.
12 (a) S.-L. Ku, X.-P. Hui, C.-A. Chen, Y.-Y. Kuo and H.-M. Gau,
Chem. Commun., 2007, 3847; (b) G. C. Fu, Acc. Chem. Res., 2008,
41, 1555.
13 (a) A. F. Pozharskii, A. T. Spldartenko and A. Katritzky, Hetero-
cycles in Life and Society, Wiley, New York, 1997; (b) E. Tyrell and
P. Brookes, Synthesis, 2004, 4, 469.
As expected, 2-chlorothiophene showed higher reactivity than
deactivated 3-chlorothiophene. The important aldehyde functional
group was tolerated under the present conditions (entry 10).
2-Chlorothiophene was also coupled with tributyl(p-toly)-
stannane in good yield (entry 11). This is the first example of
the Stille coupling of aryl and heteroaryl chlorides at room
temperature as well as one of the most powerful catalysts.
In conclusion, we have achieved the general Stille reaction
of aryl chlorides at room temperature. The catalyst 2a is highly
active with structurally and electronically diverse aryl and
14 I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036.
ꢀc
This journal is The Royal Society of Chemistry 2010
480 | Chem. Commun., 2010, 46, 478–480