An efficient low-temperature stille-migita cross-coupling reaction for heteroaromatic compounds by Pd-PEPPSI-IPent

Article abstract of DOI:10.1002/chem.200903337

The reactivity of Pd-PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization, and Initiation) precatalysts in the Stille-Migita crosscoupling reaction between heteroaryl stannanes and aryl or heteroaryl halides was evaluated. In general, PdPEPPSI-IPent (IPent = diisopentylphenylimidazolium derivative) demonstrated high efficiency over a variety of challenging aryl or heteroaryl halides with thiophene-, furan-, pyrrole-, and thiazole-based organostannanes when compared with Pd-PEPPSI-IPr (IPr = diisopropylphenylimidazolium derivative). The transformations proceeded at appreciably lower temperatures (3080°C) than triarylphosphine-based Pd catalysts, improving the scope of this useful carbon-carbon bond-forming process.

Full text of DOI:10.1002/chem.200903337

FULL PAPER
DOI: 10.1002/chem.200903337
An Efficient Low-Temperature Stille–Migita Cross-Coupling Reaction for
Heteroaromatic Compounds by Pd–PEPPSI–IPent**
Meenakshi Dowlut, Debasis Mallik, and Michael G. Organ*[a]
Abstract: The reactivity of Pd–PEPPSI
(Pyridine, Enhanced, Precatalyst, Prep-
aration, Stabilization, and Initiation)
precatalysts in the Stille–Migita cross-
coupling reaction between heteroaryl
stannanes and aryl or heteroaryl hal-
ides was evaluated. In general, Pd–
PEPPSI–IPent (IPent=diisopentylphe-
nylimidazolium derivative) demonstrat-
ed high efficiency over a variety of
challenging aryl or heteroaryl halides
with thiophene-, furan-, pyrrole-, and
thiazole-based organostannanes when
compared with Pd–PEPPSI–IPr (IPr=
diisopropylphenylimidazolium deriva-
tive). The transformations proceeded
at appreciably lower temperatures (30–
808C) than triarylphosphine-based Pd
catalysts, improving the scope of this
useful carbon–carbon bond-forming
process.
Keywords: biaryls · cross-coupling ·
heterocycles
· Stille–Migita reac-
tion · palladium
Introduction
Fu[6] and Verkade[7] have reported excellent yields with aryl
bromides by using P(tBu)3 and proazaphosphatranes as the
AHCTUNGTRENNUNG
The application of organostannanes in natural product syn-
thesis is well known because of the relative ease of their for-
mation and their high stability to air and moisture. In partic-
ular, the Stille–Migita cross-coupling reaction[1a,b] is an effec-
tive method for the formation of carbon–carbon bonds be-
tween two sp2 centers.[1] Moreover, this protocol is a power-
ful route to the formation of heteroaromatic-containing
compounds that are prevalent in the structure of drugs[2,3]
and ligands[4] in metal catalysis.
By far, the majority of cross-coupling reactions to form
heterobiaryls utilize phosphane-ligand-based Pd catalysts,
such as tetrakis(triphenylphosphane)palladium(0).[5] These
protocols are plagued by the requirement for very high tem-
peratures, especially when aryl or heteroaryl chlorides are
used as coupling partners. Recently, a few Stille–Migita cou-
plings of active aryl bromides at room temperature were re-
ported employing bulky phosphane ligands. The groups of
supporting ligand for Pd, respectively. Verkade and co-work-
ers further extended the scope of the reaction to nonactivat-
ed chlorides, albeit at 1108C. In addition, lower temperature
(458C) couplings involving aryl iodides were reported by
Baldwin and co-workers.[8] Most recently, Buchwald and
Naber[9] have coupled activated aryl chlorides successfully at
808C by using the biaryl monophosphane ligand XPhos. Al-
though some progress has been made towards lowering the
temperature in Stille–Migita reactions of aryl bromides and
iodides, reactions with aryl chlorides, especially nonactivated
ones, remains a challenge.
Given the apparent requirement for higher temperatures
in the Stille–Migita reaction, N-heterocyclic carbene (NHC)
ligands have attracted some attention for this application in
[10]
À
light of the high thermal stability of the Pd NHC bond.
The first example of a high-temperature coupling of aryl
chlorides by using NHC-based catalysts was reported by
Nolan and Grasa.[11] We have prepared a family of air-
stable, user-friendly Pd–NHC precatalysts and systematically
varied the electronic and steric properties about the metal
center.[12, 13] Consistently, the N-(2,6-diisopropylphenyl) var-
iants (i.e., 1 and 2) were the most effective in a variety of
cross-coupling reactions. Based on empirical data, Espinet
and co-workers suggested that bulky ligands tend to pro-
mote a tri-coordinated palladium intermediate, thereby low-
ering the overall activation energy in cross-coupling reac-
tions.[14] In a recent computational study of alkyl–alkyl Ne-
gishi couplings, we demonstrated that an increase in steric
[a] Dr. M. Dowlut, Dr. D. Mallik, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
[**] PEPPSI=pyridine, enhanced, precatalyst, preparation, stabilization,
and initiation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903337.
Chem. Eur. J. 2010, 16, 4279 – 4283
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4279

Table 1. Optimization of Stille–Migita cross-coupling conditions for 1.
bulk close to the metal center in the case of Pd–NHC cata-
lysts can play a role in promoting more than one step of the
catalytic cycle, but that the largest effect is seen in transme-
tallation, which we believe is rate limiting for at least that
particular coupling.[13c,d]
Additive
Solvent
Conversion [%][a]
1
2
3
4
5
6
7
8
none
none
KOAc
Na2CO3
LiCl
nBu4NBr
TBAF
CsF
1,4-dioxane
THF
THF
THF
THF
THF
THF
THF
DME
0
0
0
0
0
0
0
0
9
CsF
8[b]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CsF
CsF
CsF
LiF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
53[b]
53[c]
67[d,e]
35[b]
43[b]
66
We[13] and others,[15] have recognized not only the need for
bulk around the coordination sphere of the metal, but that
the bulk must be “fluid” or possess “conformational flexibil-
ity” to exert a positive influence on the cross-coupling pro-
cess. The high reactivity of Pd–PEPPSI–IPent, complex 3
(PEPPSI=pyridine, enhanced, precatalyst, preparation, sta-
bilization, and initiation), relative to the less-bulky Pd–
PEPPSI–IPr, complex 1, in Suzuki–Miyaura cross-coupling
reactions[13a] prompted us to explore the application of 3 in
Stille–Migita reactions between heteroaryl stannanes and
challenging aryl halides.
KF
CsCl
CsCl
CsF
CsF
CsF
CsF
CsF
CsF
CsF
52
70[f]
63[g]
91[c,g]
79[f,g] (76)[b]
45[d,g]
68[c,d,g]
56[b,h]
53[b,i]
CsF
[a] Determined by GC–MS with undecane as the calibrated internal stan-
dard (based upon an average of two runs). [b] Yield of the isolated prod-
uct. [c] Reaction was run for 48 h. [d] Reaction was performed at 508C.
[e] Reaction performed with catalyst 2. [f] Reaction was performed at
808C. [g] Reaction performed with catalyst 3. [h] Reaction was per-
formed by using 2 mol% catalyst. [i] Reaction was performed using
1 mol% catalyst.
Results and Discussion
Beginning with commercially available 1, we sought to de-
velop general, optimized coupling conditions by using the
model reaction outlined in Table 1. Attempts to couple 2-
(tributylstannyl)thiophene (4a) and deactivated 4-chloroto-
luene (5a) in the absence of an additive met with no reac-
tion at all (Table 1, entries 1 and 2). Interestingly, when a
number of well-established additives[16] were used to weaken
ies were conducted at that temperature. Initially, we investi-
gated the versatility of 3 in the coupling reactions of 4a to a
wide variety of oxidative addition partners.
À
the C Sn bond by in situ stannate complex formation, no
Couplings involving 2-(tributylstannyl)thiophene (4a): Thio-
phene-based biaryl motifs are found not only in natural
products, but also in the structure of drug candidates and
functional materials.[17] Although Suzuki–Miyaura aryl–aryl
coupling is a popular choice to prepare heterobiaryls, proto-
deboration of 2-thiopheneboronic acids (or related deriva-
tives) in polar, protic solvents necessitates the use of activat-
ed oxidative addition partners.[18] In general, the cross-cou-
pling of aryl halides becomes more sluggish as the electro-
philic partner becomes more sterically demanding or elec-
tron rich, which provides more opportunity for side
reactions to occur, such as reduction. Drawing on our expe-
rience with hindered boronic acids treated with catalyst
3,[13a] we envisioned that the flexible bulk of the flanking iso-
pentyl groups in 3 would impart similar steric assistance to
facilitate reductive elimination, and possibly even transme-
tallation,[13c,d] thereby enhancing coupling and minimizing
byproduct formation with organostannanes. Sterically hin-
dered halides (Table 2, entries 2 and 4) were coupled
cross-coupled product was obtained (Table 1, entries 3–8).
Switching the countercation from tetrabutylammonium to
cesium showed some promise when the reaction was carried
out in 1,2-dimethoxyethane (DME; Table 1, entry 9). Fur-
ther improvement was seen with 1,4-dioxane as the solvent
(Table 1, entry 10). Lithium or potassium fluoride (Table 1,
entries 13 and 14) in 1,4-dioxane gave lower conversion,
which could be an issue of solubility. We lowered the cata-
lyst loading of 1 to 2 (Table 1, entry 23) and 1 mol%
(Table 1, entry 24), which did not diminish conversion to the
product. With these results in hand, we further explored the
effect of temperature and found that 808C led to better con-
version (Table 1, entry 17).
When compound 3 was used under the initial conditions
optimized for 1 at 608C, conversion improved from 53 to
63% (Table 1, entry 18). Similar to 1, catalyst 3 had an ap-
preciable change in conversion when the temperature was
increased to 808C (Table 1, entry 20), thus application stud-
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Chem. Eur. J. 2010, 16, 4279 – 4283

Low-Temperature Stille–Migita Cross-Coupling Reaction
FULL PAPER
smoothly in good yields and changing the chloride to a bro-
mide allowed the anthracene-biaryl to form equally well at
608C; similar results were found for p-tolyl halides (Table 2,
Couplings involving 2-(tributylstannyl)furan (7): Furan com-
pounds are important constituents of natural products, fra-
grances, flavors, and pharmacological agents.[17,20] A serious
limitation in synthesizing substituted furans is the facile de-
composition[21] of furan metalloids (e.g., 2-furanboronic acid
and the corresponding trifluoroborate salt) under polar,
Table 2. Stille–Migita cross-coupling of aryl and heteroaryl halides with
2-(tributylstannyl)thiophene.
protic conditions. Iodo- and bromoACHTUNTRGNEUNG(hetero)aryl systems are
common substrates in palladium-catalyzed cross-coupling re-
actions with a few activated chloride examples.[22] On the
other hand, Verkade and co-workers reported the Stille–
Migita reaction between 2-(tributylstannyl)furan and hetero-
aryl bromides at 508C.[7b] The application of our optimized
conditions to couplings with 7 led to good conversions with
both moderately activated and nonactivated aryl bromides
and chlorides (Table 3). In addition, the reaction was com-
patible with reactive functional groups, such as sulfonamide
and ketone moieties, illustrating the catalytic efficiency and
versatility of catalyst 3.
Aryl halide
Product
Conv.[a] (Yield)[b]
[%]
1
2
6a 79 (X=Cl) (76)
75 (X=Br)[c,d]
6b 77 (X=Cl)
78 (X=Br) (74)[c]
6c 70 (62)
Table 3. Stille–Migita cross-coupling of aryl- and heteroaryl halides with
2-(tributylstannyl)furan.
3
4
6d 93 (85)
Aryl halide
Product
Conv.[a] (Yield)[b] [%]
75 (70)
5
6
6e 85 (84)
6 f 99 (92)
1
8a
2
3
8b
8c
90 (81)
99 (75)
7
8
9
6g 99 (86)
6g 99[e]
6g 99[d,f]
4
5
6
8d
8e
8 f
99 (88)
99 (96)
99 (91)
10
6h 74 (67)
[a] Determined by 1H NMR spectroscopy. [b] Yield of the isolated prod-
uct following silica-gel chromatography (based upon an average of two
runs). [c] Reaction performed at 608C. [d] Reaction performed with 1.
[e] Reaction performed with 2 at 308C for 30 h. [f] Reaction performed
at 408C.
7
8g
99 (99)
[a] Determined by 1H NMR spectroscopy. [b] Yield of the isolated prod-
uct following silica-gel chromatography (based upon an average of two
runs).
entry 1). There does not seem to be an obvious reliance on
activated oxidative addition partners since aryl chlorides
and bromides all coupled very well. Reactions involving
chloropyridines and chloropiperazines (Table 2, entries 6–9)
are known to be problematic under Suzuki–Miyaura reac-
tion conditions;[17] with 3, we observed near quantitative
conversions in most cases involving 4a.[19]
Couplings involving 2-(tributylstannyl)-N-methyl pyrrole
(9): The synthesis of biaryls containing a pyrrole motif by
using organoboron derivatives is limited by the difficulty of
reacting pyrrole-based metalloids with hindered or heteroar-
yl halides under standard Suzuki–Miyaura conditions.[23]
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M. G. Organ et al.
Table 5. Stille–Migita cross-couplings of electron-deficient heterostannyl
compounds.
Recognizing the importance of pyrrole-containing com-
pounds with pharmacological properties,[24] we sought to
apply our Stille–Migita protocol to pyrrole-based stannanes.
The reactions proceeded well and a variety of pyrrole-based
biaryls were prepared in excellent yields from a diverse
array of oxidative addition partners, including hindered aryl-
and heteroaryl bromides (Table 4). It is noteworthy that poi-
soning of the palladium catalyst, which is a common cause
for the failure of pyrrole-based cross-coupling reactions, was
not observed with 3; there was no clear formation of palla-
dium black in any of the reactions performed in this study.
Aryl halide
Product
Conv.[a] (Yield)[b] [%]
99 (75)
1
2
3
13a
13b
13c
99 (98)
99 (90)
Table 4. Stille–Migita cross-coupling of aryl- and heteroaryl halides with
2-(tributylstannyl)-N-methyl pyrrole.
[a] Determined by 1H NMR spectroscopy. [b] Yield of the isolated prod-
uct following silica-gel chromatography (based upon an average of two
runs).
tractiveness and applicability of this reaction. Catalyst 3 was
able to perform the control coupling reaction in 45% con-
version at 508C (Table 1, entry 21), although only moderate
conversion was attained when the temperature was lowered
to 408C. When left for an additional 24 h, the conversion
improved to a respectable 68% (Table 1, entry 22). We have
demonstrated previously in couplings involving Grignard re-
agents that the saturated NHC version of the catalyst was
more reactive than the unsaturated one.[25] To this end, we
repeated the control experiment with 2 and found that it
was active at 508C (Table 1, entry 12), whereas catalyst 1
was ineffective at this temperature. It is possible that the in-
creased conformational flexibility of 2, relative to 1, is, at
least in part, responsible for the higher level of reactivity
seen.
Aryl halide
Product
Conv.[a] (Yield)[b] [%]
79 (78)
1
2
3
10a
10b
10c
95 (90)
95 (85)
We next evaluated substrates at lower temperatures that
would provide more biologically interesting, heterobiaryl
products. Compound 4a was coupled with 2-chloropyrazine
quantitatively at 408C by using 1 (Table 2, entry 9). A fur-
ther reduction in temperature for this coupling was possible
by using 2 at 308C (Table 2, entry 8); reproducibly there was
no reaction at room temperature (ꢀ238C). Control experi-
ments conducted under similar conditions with PdCl2 (for
the results shown in Tables 1–5) produced no cross-coupled
biaryl products. We were also pleased to see quantitative
conversion when 2-chloropyrazine was coupled to 2-(tribu-
tylstannyl)thiazole (Table 5, entry 2). To the best of our
knowledge, this is the first example of a palladium-catalyzed
Stille–Migita cross-coupling reaction that has taken place at
a temperature as low as 608C involving 2-(tributylstan-
nyl)thiazole with N-heteroaryl chlorides.
4
5
10d
10e
99 (98)
99 (89)
[a] Determined by 1H NMR spectroscopy. [b] Yield of the isolated prod-
uct following silica-gel chromatography (based upon an average of two
runs).
Couplings involving highly electron-deficient heteroarylstan-
nanes (11): Although the cross-coupling of heteroarylstan-
nanes containing a single nitrogen or oxygen can be difficult,
more electron-poor substrates with multiple heteroatoms
are even more challenging. Moreover, competing side reac-
tions (e.g., ring opening of thiazoles and oxazoles) further
complicate the reaction. We were pleased to see quantitative
conversions of electron-deficient organostannanes with both
2-chloropyridine and -pyrazine (Table 5). To the best of our
knowledge, this is the first example of a palladium-catalyzed
Stille–Migita cross-coupling reaction that has taken place at
a temperature as low as 608C involving 2-(tributylstan-
Conclusion
Stille–Migita cross-coupling reactions with 3 have shown
that the flexible steric bulk of the IPent ligand plays a deter-
mining role in effective cross-coupling reactions of hetero-
biaryls. Pd–PEPPSI precatalysts helped solve a few major
problems associated with Stille–Migita reactions: 1) The
nyl)thiazole with N-heteroACHTUNTRGNEUNG(aryl)chlorides.
This result encouraged us to look in more detail at the
coupling temperature. Certainly, the very high temperatures
generally required for Stille–Migita coupling limits the at-
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Low-Temperature Stille–Migita Cross-Coupling Reaction
FULL PAPER
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Experimental Section
General Stille–Migita cross-coupling procedure: The Pd–PEPPSI preca-
talyst (0.02 mmol, 0.04 equiv) and the aryl halide (if the halide was a
solid) (0.50 mmol, 1.00 equiv) were added to a glass vial containing a
magnetic stirrer bar, dry CsF (156 mg, 1.02 mmol, 2.0 equiv), and activat-
ed, crushed 4 ꢁ molecular sieves (50 mg). The vial was then purged twice
with argon and anhydrous 1,4-dioxane (1 mL) was added. If the aryl
halide (0.50 mmol, 1.00 equiv) was a liquid, it was added after the addi-
tion of 1,4-dioxane. The mixture was stirred vigorously for 1 min at RT,
after which time the organostannane (0.55 mmol, 1.10 equiv) was added.
The reaction was stirred at the desired temperature for 16 h. At this
time, the mixture was filtered through a prepacked pad of Celite/CsF
(3:1 w/w) and the Celite/CsF pad was washed with CH2Cl2 (2ꢂ4 mL).
The solvent was removed in vacuo and the crude product was diluted
with hexanes or CH2Cl2 (2 mL). The solution was filtered through a pre-
packed pad of silica/CsF (1:1 w/w) to remove any remaining tin byprod-
ucts. The crude material was then loaded onto a Biotage KP-SiL samplet
and purified by using a Biotage KP-SiL column containing an additional
layer of CsF (200 mg) on top with hexanes/diethyl ether or hexane/
CH2Cl2 as the eluent.
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Received: December 4, 2009
Published online: March 5, 2010
Chem. Eur. J. 2010, 16, 4279 – 4283
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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