Palladium-catalyzed chemoselective cross-coupling of acyl chlorides and organostannanes

Article abstract of DOI:10.1021/jo051257o

Chemoselective cross-coupling of aliphatic and aromatic acyl chlorides with aryl-, heteroaryl-, and alkynylstannanes proceeds in up to 98% yield using 2.5 mol % of bis(di-tert-butylchlorophosphine)palladium(II) dichloride as the precatalyst. Various functional groups including aryl chlorides and bromides that usually undergo oxidative addition to palladium complexes bearing phosphinous acid or dialkylchlorophosphine ligands are tolerated. This procedure allows convenient ketone formation and eliminates inherent limitations of Friedel-Crafts acylations such as substituent-directing effects and typical reactivity requirements of Lewis acid-catalyzed electrophilic aromatic substitutions.

Full text of DOI:10.1021/jo051257o

Palladium-Catalyzed Chemoselective
Cross-Coupling of Acyl Chlorides and
Organostannanes
species that readily undergo oxidative addition even with
sterically hindered aryl chlorides. Noteworthy, Herr-
mann, Beller, Nolan, and others showed that palladium
complexes exhibiting sterically demanding N-heterocyclic
carbene ligands afford another class of catalysts provid-
Rachel Lerebours, Alejandra Camacho-Soto, and
Christian Wolf*
7
ing excellent results in cross-coupling reactions.
Numerous applications of Pd-catalyzed cross-coupling
reactions with alkyl, alkenyl, and aryl halides or triflates
have been developed in recent years. Interestingly, few
examples of cross-coupling reactions with acyl chlorides
can be found in the literature, although they are known
to readily undergo oxidative addition to Pd(0) species.
Stille et al. were first to employ acyl chlorides and
organotin compounds in the Pd-catalyzed formation of
Department of Chemistry, Georgetown University,
Washington, D.C. 20057
cw27@georgetown.edu
Received June 18, 2005
8
unsymmetrical ketones. They obtained good to excellent
results using aryl-, alkenyl-, and alkynylstannanes al-
though yields dropped when reactive aryl halide func-
tionalities such as in 4-bromobenzoyl chloride were
present. Apparently, competitive oxidative addition of
Pd(0) complexes with aryl halides limits the versatility
of this method. Neumann reported tin-mediated Friedel-
Crafts acylations using aluminum trichloride to avoid the
use of transition metals, but yields generally suffered
from concomitant Fries rearrangements.9 Since pal-
ladium/copper cocatalyzed cross-coupling reactions of acyl
chlorides with R-amino- and R-alkoxystannanes were
reported by Falck and co-workers,10 acyl chlorides have
Chemoselective cross-coupling of aliphatic and aromatic acyl
chlorides with aryl-, heteroaryl-, and alkynylstannanes
proceeds in up to 98% yield using 2.5 mol % of bis(di-tert-
butylchlorophosphine)palladium(II) dichloride as the pre-
catalyst. Various functional groups including aryl chlorides
and bromides that usually undergo oxidative addition to
palladium complexes bearing phosphinous acid or dialkyl-
chlorophosphine ligands are tolerated. This procedure allows
convenient ketone formation and eliminates inherent limita-
tions of Friedel-Crafts acylations such as substituent-
directing effects and typical reactivity requirements of Lewis
acid-catalyzed electrophilic aromatic substitutions.
11
12
been successfully employed in Sonogashira, Suzuki,
Negishi,13 and Stille-type couplings with R-sulfonami-
(
5) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-
3
388. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38,
411-2413. (c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
Palladium-catalyzed cross-coupling reactions utilizing
aryl halides and boronic acids (Suzuki), organostannanes
2
122, 4020-4028.
(
(
(
Stille), organosiloxanes (Hiyama), organozinc compounds
Negishi), Grignard reagents (Kumada coupling), alkynes
Sonogashira), or alkenes (Heck reaction) have found
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E.; Martinelli, J. R. Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
widespread popularity in synthetic chemistry during
recent years. The remarkable advance of organometallic
1
C-C, C-N, C-O, and C-S bond-forming reactions has
been possible through the development of effective and
versatile palladium complexes bearing electron-rich and
1
871-1876.
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(
2
bulky ligands. In particular, the introduction of 2-bi-
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K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M. Herrmann, W. A.
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R. A., III; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett.
phenyldicyclohexylphosphine ligands or tri-tert-butylphos-
2
phine and derivatives thereof in combination with Pd -
3
4
5
(dba)
3 2
and Pd(OAc) by Nishiyama, Hartwig, Fu, and
6
Buchwald proved to generate highly active catalyst
2003, 5, 1479-1482. (f) Altenhoff, G.; Goddard, R.; Lehmann, C. W.;
Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690-3693. (g) De Lewis,
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1
0.1021/jo051257o CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/17/2005
J. Org. Chem. 2005, 70, 8601-8604
8601

SCHEME 1. PXPd-Catalyzed Formation of
Benzophenone, 3, from Benzoyl Chloride, 1, and
Phenyltrimethyltin, 2
During our search for palladium-phosphinous acids
and dialkylchlorophosphine analogues that would cata-
lyze cross-coupling of acyl chlorides with organostan-
nanes but not affect aryl halide bonds we found that
ketone formation from benzoyl chloride, 1, and 1.3 equiv
of phenyltrimethyltin, 2, proceeds in the presence of 5
mol % of PXPd after refluxing in acetonitrile for 20 h in
98% yield. Further studies revealed that benzophenone,
FIGURE 1. Structures of palladium-phosphinous acid com-
plexes POPd, POPd1, and POPd2 and bis(di-tert-butylchloro-
phosphine)palladium(II) dichloride, PXPd.
doorgannostannanes14 and vinylstannanes15 and in mul-
ticomponent reactions involving vinylstannanes and
1
6
imines.
The use of palladium-phosphinous acid complexes
such as [(t-Bu) P(OH)] PdCl (POPd), [[(t-Bu) P(OH)(t-
Bu) PO)]PdCl] (POPd1), and [(t-Bu) P(OH)PdCl (PO-
3
, can be obtained from 1 and 1.1 equiv of stannane 2
using 2.5 mol % of PXPd without compromising yields
Scheme 1). The reaction does not require any base or
2
2
2
2
(
2
2
2
2 2
]
fluoride additives. Interestingly, slow ipso-substitution
in the absence of the catalyst was also observed resulting
in the formation of 10% of 3 under the same conditions.
Based on our experience with Stille cross-couplings of
aryl halides and organostannanes using palladium-
phosphinous acid catalysts we anticipated that under
these conditions PXPd might promote coupling with acyl
chlorides but not with aryl halides thus extending
selectivity and functional group tolerance of this meth-
Pd2) for various cross-coupling reactions has recently
been reported by us and others (Figure 1).17 General fea-
tures of palladium-phosphinous acid catalysts include
simple preparation from readily available phosphine
oxides, RR′P(O)H, and Pd (dba) , Pd(cod)Cl or Pd(OAc) ,
2 3 2 2
stability to air, and high catalytic activity. The catalysts
can be stored under air without loss in activity and can
be directly employed in C-C, C-N, and C-S bond-form-
ing reactions. Moreover, palladium-phosphinous acid-
catalyzed coupling reactions do not have to be performed
in anhydrous solvents and under inert atmosphere. The
structure of bis(di-tert-butylchlorophosphine)palladium-
17d,g
od.
We were pleased to find that excellent coupling results
can be obtained with a variety of acyl chlorides and
organostannanes (Table 1). Coupling of 1 and tributyl-
(
II) dichloride, PXPd, is similar to palladium-phosphinous
(
5
phenylethynyl)tin, 4, gave the corresponding alkynone
in 93% yield (entry 2, Table 1). The reaction proceeds
equally well with heteroaryltin compounds. For example,
acids POPd, POPd1, and POPd2. The latter are known
to form negatively charged and thus strongly electron-
donating phosphine ligands (t-Bu) PO that greatly
2
-
2
9
4
6
-(tributylstannyl)furan, 7, affords ketones 8 and 10 in
2 and 96 yield, respectively, although coupling with
-methoxybenzoyl chloride, 12, provides ketone 13 in only
7% (entries 3, 4, and 6). Comparison of results obtained
facilitate oxidative addition of the corresponding Pd(0)
species to aryl halides including aryl chlorides under
basic conditions. Since the di-tert-butylphosphinous acid
groups are replaced by less activating di-tert-butylchlo-
rophosphine ligands, we rationalized that PXPd might
be a useful catalyst for selective Stille-type cross-coupling
reactions with acyl chlorides. Herein, we wish to report
PXPd-catalyzed Stille cross-coupling reactions of aryl-
and alkynylstannanes with acyl chlorides exhibiting
various functional groups including aryl chlorides and
bromides.
with substituted benzoyl chloride derivatives indicates
that incorporation of electron-withdrawing groups in-
creases yields (entries 2-6). PXPd-catalyzed cross-
coupling of piperonyloyl chloride, 14, with 2-(tributyl-
stannyl)thiophene, 16, or stannanes 4 and 7 gave ketones
1
5, 17, and 18 in 76-82% yield (entries 7-9). As
expected, the method can also be used to produce ketones
from aliphatic acyl chlorides. Employing 19 and 21 in
the coupling reaction with stannanes 7 and 16 yielded
ketones 20 and 22 in 78 and 85% (entries 10 and 11).
We then decided to screen ortho-, meta-, and para-
halosubstituted benzoyl chlorides to evaluate competition
between ketone formation via Stille-type coupling involv-
ing oxidative addition to an acyl chloride moiety and
biaryl formation via cross-coupling utilizing an aryl
halide functionality (Scheme 2). For example, 4-chlo-
robenzoyl chloride, 23, can be expected to undergo Pd-
(0)-catalyzed reaction with stannane 7 toward ketone 24
followed by biaryl formation to give ketone 26. Alterna-
tively, oxidative addition of the palladium catalyst to the
aryl halide bond could proceed first to yield acyl chloride
(
13) Østergaard, N.; Skjaerbaek, N.; Begtrup, M.; Vedso, P. J. Chem.
Soc., Perkin Trans. 1 2002, 428-433.
14) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666-
5667.
15) Thibonnet, J.; Abarbri, M.; Parrain, J.-L.; Duch eˆ ne, A. J. Org.
Chem. 2002, 67, 3941-3944.
16) Davis, J. L.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2004, 43, 590-594.
17) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (b)
Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677-
681. (c) Li, G. Y. J. Org. Chem. 2002, 67, 3643-3650. (d) Wolf, C.;
(
1
(
(
(
8
Lerebours, R. J. Org. Chem. 2003, 68, 7077-7084. (e) Wolf, C.;
Lerebours, R.; Tanzini, E. H. Synthesis 2003, 2069-2073. (f) Yang,
W.; Wang, Y.; Corte, J. R. Org. Lett. 2003, 5, 3131-3134. (g) Wolf, C.;
Lerebours, R. J. Org. Chem. 2003, 68, 7551-7554. (h) Wolf, C.;
Lerebours, R. Org. Lett. 2004, 6, 1147-1150. (i) Wolf, C.; Lerebours,
R. Org. Biomol. Chem. 2004, 2, 2161-2164.
8602 J. Org. Chem., Vol. 70, No. 21, 2005

TABLE 1. PXPd-Catalyzed Coupling of Acyl Chlorides
and Organostannanes
TABLE 2. PXPd-Catalyzed Ketone Formation Using
Halobenzoyl Chlorides and Organostannanes
reactions with chloro- and bromoaryl ketones such as 24
1
7
under the reaction conditions employed in this study.
Employing the same reaction conditions as discussed
above, we found that 23 undergoes PXPd-catalyzed
ketone formation with stannane 7 to give 4-chlorophenyl-
2
-furan ketone, 24, in 80% yield and chlorobenzoyl
chlorides 27 and 29 produced ketones 28 and 30 in 80
and 87% yield, respectively (Table 2, entries 1-3).
Similar results were obtained with stannanes 4 and 16
SCHEME 2. Possible Cross-Coupling Pathways of
Pd(0)-Catalyzed Cross-Couplings between
4-Chlorobenzoyl Chloride, 23, and Stannane 7
(
entries 4-6). The coupling procedure also tolerates the
presence of aryl bromides. In contrast to the results
obtained with chlorosubstituted benzoyl chlorides 23, 27,
and 29, the highest yields were observed with 4-bro-
mobenzoyl chloride providing 4-bromophenyl-2-furan
ketone 35 in 85% yield while 2- and 3-bromobenzoyl
chlorides 36 and 38 gave the corresponding ketones in
only 57-62% (entries 7-9).
We assume that PXPd undergoes reduction and dis-
sociation favored by the bulky di-tert-butylchlorophos-
phine ligands to generate a catalytically active Pd(0)
species that readily reacts with acyl halides under the
reaction conditions used in this study, Scheme 3. The
previously reported high catalytic activity of palladium-
phosphinous acids POPd, POPd1, and POPd2 under basic
conditions has been attributed to formation of Pd(0)
2
5 which may react further to ketone 26. Although one
might expect that oxidative addition of a Pd(0) species
proceeds faster with acyl chlorides than with aryl chlo-
rides or bromides, competition between these two pro-
cesses could compromise overall yields of halo-substituted
ketones such as 24 limiting the usefulness of this method.
This problem becomes evident since it has been shown
that palladium-phosphinous acids and dialkylchloro-
phosphine palladium catalysts promote cross-coupling
species bearing negatively charged and thus strongly
-
electron-donating phosphine ligands (t-Bu)
2
PO that
greatly facilitate oxidative addition.17 By contrast, the di-
tert-butylchlorophosphine ligands of PXPd are less elec-
tron-donating and can therefore be used for chemoselec-
tive activation of the acyl halide moiety of halobenzoyl
J. Org. Chem, Vol. 70, No. 21, 2005 8603

SCHEME 3. Catalytic Cycle of PXPd-Promoted Stille-Type Coupling of Acyl Chlorides and
Organostannanes
chlorides. Formation of an acyl Pd(II) complex by oxida-
tive addition is then followed by transmetalation with
an organostannane and reductive elimination to complete
the catalytic cycle (Scheme 3).
We found that increasing the amount of stannane 7
employed in the reaction with 4-chlorobenzoyl chloride,
yields. Various functional groups including aryl chlorides
and bromides that usually undergo oxidative addition to
palladium complexes bearing phosphinous acid or di-
alkylchlorophosphine ligands are tolerated. This proce-
dure allows convenient ketone formation and eliminates
inherent limitations of Friedel-Crafts acylations such as
substituent-directing effects and reactivity requirements
of Lewis acid-catalyzed electrophilic aromatic substitu-
tions.
23, from 1 to 2 equiv still affords ketone 24. No sign of
PXPd-catalyzed Stille coupling of the aryl chloride moiety
of 23 and the additional equivalent of 7 was observed
which proves the high chemoselectivity of the catalyst
favoring ketone formation under the reaction conditions
used. Accordingly, PXPd-catalyzed Stille coupling of
stannane 7 and 4-chloroacetophenone, 40, was found to
be very sluggish providing 4-(2-furan)acetophenone, 41,
in only 15%. Employing 4-bromoacetophenone, 42, and
Experimental Section
Representative Coupling Procedure. A mixture of 4-cy-
anobenzoyl chloride 9 (250 mg, 1.51 mmol), PXPd (20.3 mg, 2.5
mol %), 2-(tributylstannyl)furan 7 (571 mg, 1.60 mmol) in 5 mL
of anhydrous acetonitrile was stirred under nitrogen at 82 °C
for 20 h. The reaction mixture was allowed to cool to room
temperature, quenched with water, and extracted with meth-
ylene chloride. The combined organic layers were washed
7
in the same reaction gave the corresponding Stille
cross-coupling product 41 in 85%. However, a competition
experiment using equal amounts of stannane 7, 4-bro-
moacetophenone 42, and 4-bromobenzoyl chloride 34
gave acylation product 35 in 90% while unreacted 42 was
recovered quantitatively. The observed chemoselectivity
of the PXPd-catalyzed cross-coupling of stannanes and
halogenated benzoyl chloride derivatives can thus be
4
withbrine and dried over MgSO , and the solvents were removed
under vacuum. Purification by flash chromatography (1:1 diethyl
ether/hexanes) gave 4-cyanophenyl 2-furan ketone 10 (286 mg,
1
1
.45 mmol, 96%) as yellow crystals: mp 136-138 °C; H NMR
δ 6.67 (dd, J ) 1.0 Hz, 3.4 Hz, 1H), 7.33 (d, J ) 3.4 Hz, 1H),
7.76 (d, J ) 1.0 Hz, 1H). 7.83 (d, J ) 8.2 Hz, 2H), 8.10 (d, J )
attributed to a fast acylation process that is favored over
relatively slow or sluggish biaryl formation.18
8.2 Hz, 2H);
40.8, 148.1, 152.1, 180.9. Anal. Calcd for C12
H, 3.58; N, 7.10. Found: C, 73.19; H, 3.56; N, 6.91.
13C NMR δ 113.0, 116.1, 118.2, 121.5, 130.0, 132.5,
1
7 2
H NO : C, 73.09;
In summary, we have shown that the selectivity of bis-
di-tert-butylchlorophosphine)palladium(II) dichloride to-
(
ward cross-coupling of acyl chlorides with organostan-
nanes in refluxing acetonitrile provides a means to
prepare aliphatic and aromatic ketones in good to high
Acknowledgment. We thank Combiphos Catalysts,
Inc., New Jersey (www.combiphos.com), for PXPd.
Supporting Information Available: Synthetic proce-
dure, characterization data of all coupling products, and NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
18) Attempts to apply the acylation procedure to the coupling of
benzoyl chlorides and tetraalkylstannanes were not successful. Em-
ploying 4-cyanobenzoyl chloride 9 and tetrabutylstannane or tetra-
methylstannane in the PXPd-catalyzed coupling reaction did not result
in the formation of the corresponding arylalkyl ketones and all starting
materials were recovered.
JO051257O
8604 J. Org. Chem., Vol. 70, No. 21, 2005