Palladium-catalyzed Stille cross-coupling reaction of aryl chlorides using a pre-milled palladium acetate and XPhos catalyst system

Article abstract of DOI:10.1002/adsc.200800032

A highly active catalyst system based upon a biaryl monophosphine ligand, XPhos, for the palladium-catalyzed Stille reaction has been developed. This method allows for the coupling of aryl chlorides with a range of tributylarylstannanes to produce the corresponding biaryl compounds in good to excellent yields (61-98%) in short reaction times (4 h). Palladium(II) acetate [Pd(OAc)₂] and XPhos in a 1:1.1 ratio were milled into a fine powder that was used as pre-catalyst for these reactions.

Full text of DOI:10.1002/adsc.200800032

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DOI: 10.1002/adsc.200800032
Palladium-Catalyzed Stille Cross-CouplingReaction of Aryl
Chlorides usinga Pre-Milled Palladium Acetate and XPhos
Catalyst System
John R. Nabera and Stephen L. Buchwalda,*
a
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA
Fax : (+1)-617-253-3297; e-mail: sbuchwal@mit.edu
Received: January 16, 2008; Revised: February 14, 2008; Published online: March 12, 2008
This paper is dedicated to our good friend Andreas Pfaltz on the occasion of his 60th birthday and in recogni-
tion of his numerous seminal contributions to the field of organic chemistry.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A highly active catalyst system based
upon a biaryl monophosphine ligand, XPhos, for
the palladium-catalyzed Stille reaction has been de-
veloped. This method allows for the coupling of
aryl chlorides with a range of tributylarylstannanes
to produce the corresponding biaryl compounds in
good to excellent yields (61–98%) in short reaction
sures its continued relevance, particularly as a tool for
discovery chemists[5] and in natural product synthe-
sis.[6] Herein, we describe a highly active catalyst
system for the coupling of aryl chlorides with aryl-
stannanes.
A family of air-stable biaryl monophosphine ligands
has been developed in our laboratories and have
proven useful as components of highly active catalyst
times (4 h). Palladium(II) acetate [Pd(OAc)2] and
A
À
À
XPhos in a 1:1.1 ratio were milled into a fine
powder that was used as pre-catalyst for these reac-
tions.
systems for C C and C N bond-forming reac-
tions.[3b,c,7] Based on previous work in our group and
initial screening results, XPhos (Figure 1) was chosen
as a supporting ligand and was combined with Pd-
À
Keywords: aryl chlorides; biaryls; C C coupling;
(OAc)2 to generate a highly active catalyst system
that was used for further optimization.
palladium; phosphine ligands; Stille reaction
Recent work has shown that the addition of a
fluoride source increases the reactivity of arylstan-
nanes and results in a significant rate enhancemen-
t.[4a–c,f–h] While the use of TBAF and KF provided
The Stille cross-coupling reaction has proven to be a moderate results, CsF provided the greatest enhance-
powerful method for combining aryl halides and ment in the reaction rate (Table 1, entries 1–4). A fur-
arylstannanes to give a ready access to biaryl motifs,[1] ther optimization showed that reactions in ethereal
which are found in numerous biologically active com- solvents or tert-butanol provided the desired biaryl in
pounds including both natural products and pharma- a greater yield. Dimethoxyethane (DME) was chosen
ceutically interesting molecules.[2] Recent advances in over tert-butanol as the solvent for further studies due
the general area of cross-coupling have led to the de- to the high melting point of tert-butanol. We found
velopment of highly active catalyst systems that were that very similar results were obtained with ligand:Pd
capable of transforming aryl chlorides, which are less ratios of 1:1, 2:1 and 3:1, thus reactions were conduct-
expensive and more readily available than aryl io-
dides and bromides.[1f] While considerable research
has been devoted to the Suzuki–Miyaura reaction,[1f,3]
there have been fewer reports of catalytic methods
for the reaction of aryl chlorides with organostan-
nanes.[4] Although the tin by-products generated in
the Stille reaction tend to have relatively high molec-
ular weights and are toxic, the air- and moisture-sta-
bility of organostannanes combined with the broad
functional group tolerance of the Stille reaction en- Figure 1.
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John R. Naber et al.
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Table 1. Screen of solvents for the palladium-catalyzed
Table 2. Stille cross-coupling reactions of unactivated aryl
cross-coupling of 4-chloroanisole and mesitylstannane.[a]
chlorides and deactivated chlorides.[a]
[a]
Reaction conditions: 1.0 equiv of Ar-Cl, 1.1 equiv of (n-
Bu)3Sn-Ar, 1.0 mol% of Pd(OAc)2, 3.0 mol% of XPhos,
G
1.0 mL of solvent/mmol of Ar-Cl, DCE=1,2-dichloro-
ethane, NMP=N-methylpyrrolidine, DME=dimethoxy-
ethane, DEM=diethoxymethane.
[b]
GC Yield.
ed with only a slight excess of ligand (1.1:1, L:Pd). A
mixture of palladium acetate and XPhos, in the afore-
mentioned ratio, was milled with a mortar and pestle
to give a fine, beige powder that was used in subse-
quent reactions. The milling process allowed for ex-
cellent control of the palladium to ligand ratio and fa-
cilitated precision when weighing samples for reac-
tions. The results of reaction run with the powder
were identical to those performed with separate Pd-
[a]
Reactions conditions: 1.0 equiv of Ar-Cl, 1.1 equiv of (n-
Bu)3Sn-Ar, 2.2 equiv of CsF, 1.0 mol% of pre-milled Pd-
A
[b]
[c]
[d]
Isolated yields (average of two runs).
2.0 mol% of pre-milled Pd(OAc)2:XPhos (1:1.1)
(OAc)2 and 1.1 mol% XPhos added as sepa-
AHCTREUNG
1.0 mol% Pd
rate solids.
ACHTREUNG
A
powder could be stored in a benchtop dessicator with
no loss of activity over a six-month period.
Encouraged by these results, we sought to examine chlorobenzo[d][1,3]dioxole (Table 2, entries 3 and 4),
G
the scope of this process. The results are shown in could be coupled in excellent yields with both aryl-
Table 2. These conditions constitute the lowest and heteroarylstannanes. Previously, this substrate has
temperature reactions and shortest reaction times re- been used in the Stille reaction to form a biaryl in
ported for the coupling of unactivated aryl chlorides only one other instance in which longer reaction
with arylstannanes reported to date. Chloroanilines, times and higher temperatures (45 h and 1108C) were
as a class of compounds, have not previously been required.[4h]
used to generate biaryl compounds via the Stille reac-
While the results in Table 3 do not represent the
tion.[8] One example of this class of compounds, N,N- lowest temperature reaction conditions reported for
dimethyl-3-chloroaniline, using our conditions, was Stille reactions with activated aryl chlorides,[9] they do
successfully coupled with a both aryl- and heteroaryl- represent a significant decrease over most of the reac-
stannanes (Table 2, entries 5 and 6). Similarly, while tion times reported and one of lowest operating tem-
4-chloroanisole has been combined with arylstan- peratures of available Stille methods with these sub-
nanes, the best reported conditions required that the strates. For instance, the coupling 2-chlorobenzonitrile
reactions be conducted at 1008C for 48 h.[4a,c] Employ- has been previously reported at temperatures greater
ing our catalyst system this substrate, in combination than 1008C with reaction times longer than 24 h.[4h,10]
with both a hindered arylstannane and a heteroaryl- By using our standard protocol, 2-chlorobenzonitrile
stannane, provided excellent yields of product in 4 h was efficiently coupled with aryl, heteroaryl and elec-
at 808C (Table 2, entries 1 and 2). Additionally, 5- tron-rich arylstannanes (Table 3, entries 1–3). En-
958
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Palladium-Catalyzed Stille Cross-Coupling Reaction of Aryl Chlorides
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Table 3. Stille cross-coupling reactions of aryl chlorides and
tries 4–7 of Table 3 show coupling reactions with
methyl 4-chlorobenzoate and a variety of stannanes
including allyl, heteroaryl and sterically-demanding
arylstannanes. While the importance of fluorinated ar-
omatic rings in pharmaceutically active compounds as
a means to alter a molecule’s pharmacokinetics is well
known,[11] examples of Stille reactions of fluoride-con-
taining aryl chlorides are relatively scarce. In the lone
example of coupling an aryl chloride with an ortho-
trifluoromethyl group, the process was carried out at
for 48 h at 1508C;[12] only one example was found for
a Stille coupling of fluorinated aryl chlorides.[13] By
using our conditions, both o-chlorobenzotrifluoride
and p-fluorochlorobenzene could be efficiently cou-
pled with arylstannanes (Table 3, entries 8 and 9). Ad-
ditionally, we found that by increasing the reaction
temperature to 1008C and choosing 1,4-dioxane as a
solvent to accommodate the increased temperature, it
was possible to couple heteroaryl chlorides (Table 3,
heteroaryl chlorides.[a]
entries 10 and 11) with tributyl
(phenyl)stannane.[14]
A
With regard to the arylstannane component: heter-
oaryl (Table 2, entries 1 and 3, Table 3, entries 2, 4
and 6), electron-rich aryl (Table 3, entries 3 and 9),
electron-deficient aryl (Table 2, entry 6) and allylstan-
nanes (Table 3, entry 5) were all coupled in high
yields. It is noteworthy to mention that 2,6-
dimethoxyphenyltributylstannane, which has not pre-
G
viously been used in Stille cross-coupling reactions,[15]
was found to perform well under our conditions
(Table 3, entries 3 and 9).
In conclusion, we have developed a highly active
catalyst system for the reaction of a diverse range of
aryl chlorides with a variety of arylstannanes. The use
of CsF as an activator allows for a reduction of the
temperatures commonly used in Stille reactions, and
the use of ethereal solvents such as DME along with
XPhos as a ligand allow for the reduction of the reac-
tion times regularly used in these reactions.
Experimental Section
Catalyst System
Palladium acetate (225 mg, 1.00 mmol) and XPhos (524 mg,
1.10 mmol) were ground together using a mortar and pestle
until a fine beige powder was formed. This powder (effec-
tive molecular weight: 749 gmolÀ1) was stored in a bench-
top dessicator for up to six months with no loss of activity
and was used as the pre-catalyst for all reactions described
in this paper.
[a]
Reactions conditions: 1.0 equiv of Ar-Cl, 1.1 equiv of (n-
Bu)3Sn-Ar, 2.2 equiv of CsF, 1.0 mol% of pre-milled Pd-
A
[b]
[c]
[d]
Isolated yields (average of two runs).
2.0 mol% of pre-milled Pd(OAc)2:XPhos (1:1.1).
Reactions run in dioxane at 1008C, with 2.0 mol% pre-
milled Pd(OAc)2:XPhos (1:3).
N,N-Dimethyl-2’-(trifluoromethyl)biphenyl-3-amine
(Table 2, entry 5)
Pre-milled palladium acetate and XPhos (15.0 mg, 2.0
mol%) and cesium fluoride (334 mg, 2.20 mmol) were added
to an oven-dried test tube. The tube was fitted with a rubber
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asc.wiley-vch.de
959

John R. Naber et al.
COMMUNICATIONS
septum, sealed with electrical tape, and evacuated and back-
filled with argon (this process was repeated a total of 3
times). Dimethoxyethane (DME, 1.0 mL), 3-chloro-N,N-di-
methylaniline (137 mL, 1.00 mmol) and tributyl[2-(trifluoro-
methyl)phenyl]stannane (389 mL, 1.10 mmol) were added
via syringe to the tube. The reaction was heated to 808C
with stirring for 4 h. At this time the reaction vessel was re-
moved from the oil bath, allowed to cool to room tempera-
ture, diluted with ethyl acetate (5 mL) and filtered through
a pad of silica gel eluting with ethyl acetate (150 mL). The
solvent was removed with the aid of a rotary evaporator,
and the residue was taken up in dichloromethane (20 mL)
and added to silica gel (~1 g). The solvent was concentrated
under reduced pressure and the residue (adsorbed on silica)
was loaded onto the top of a Biotage 25M column and puri-
fied by flash chromatography using a Biotage SP4 to pro-
vide the titled compound as pale yellow oil; yield: 229 mg
(87%).
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Acknowledgements
We thank the National Institutes of Health (GM 46059) for
G
support of this work. BASF is thanked for a gift of palladium
acetate and Merck, Amgen, and Boehringer Ingelheim are
thanked for additional support.
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