Palladium-catalyzed α-arylation of aldehydes with bromo- and chloroarenes catalyzed by [{Pd(allyl)Cl}2] and dppf or Q-phos

Article abstract of DOI:10.1002/anie.200705357

(Chemical Equation Presented) Pd source matters: A general method for palladium-catalyzed a-arylation of aldehydes (see scheme) was developed to couple linear and branched aldehydes with electron-poor and electron-rich bromo- and chloroarenes.

Full text of DOI:10.1002/anie.200705357

Angewandte
Chemie
DOI: 10.1002/anie.200705357
a-Arylation of Aldehydes
Palladium-Catalyzed a-Arylation of Aldehydes with Bromo- and
Chloroarenes Catalyzed by [{Pd(allyl)Cl}2] and dppf or Q-phos**
Giang D. Vo and John F. Hartwig*
a-Aryl carbonyl compounds are precursors to many impor-
tant synthetic intermediates bearing alcohol, imine, amine,
olefin, and nitrile functional groups.[1–5] The palladium-
catalyzed a-arylation of carbonyl compounds has evolved
into one of the more important methods for the preparation
of compounds.[6,7] The a-arylation process now encompasses
the couplings of ketones,[8–10] amides,[11–13] esters,[12,14] malo-
nates,[9,15] and cyanoacetates[15,16] with a broad range of aryl
halides and sulfonates. The a-arylation of aldehydes [Eq. (1)],
however, has been challenging to develop because of
competing aldol condensations under the cross-coupling
reaction conditions. Accordingly, only three reports on the
a-arylation of aldehydes have been published. The first
examples were reported by Miura and co-workers in 2002.[17]
Miuraꢀs protocols employed high temperatures and high
catalyst loadings to give modest yields of the coupled
products, and the substrate scope was limited. In 2005
Bertrand and co-workers described the a-arylation of iso-
butanal with 2-chlorotoluene in the presence of a pallad-
ium(II) catalyst ligated by a cyclic(amino)alkyl carbene.[18]
Recently, Martín and Buchwald described improved proto-
cols for the a-arylation of aldehydes, but most examples in
this work involved the coupling of electron-poor aryl halides;
few reactions of haloarenes that could be considered to be
electron-neutral or electron-rich were reported, and the one
example of the reaction of an electron-rich haloarene was
sterically biased.[19]
electron-rich aryl bromides. The coupling of linear aldehydes
with electron-poor or electron-neutral bromoarenes occurred
in good yield when catalyzed by complexes having a
bisphosphine ligand. The coupling of branched aldehydes
with bromo- and chloroarenes occurred in high yield when
catalyzed by complexes bearing monophosphine 1,2,3,4,5-
pentaphenyl-1’-(di-tert-butylphosphino)ferrocene (Q-phos)
that was developed in our laboratory.[20] One factor that
leads to the efficiency of this process is the use of these ligands
in combination with a palladium precursor that is known[21] to
undergo facile generation of active [LnPd0] species.
Our initial study focused on the identification of a catalyst
for a-arylation that reacted with rates that were faster than
those of the competing aldol condensations. We examined
various combinations of palladium precursors and ligands for
the coupling of octanal with 1-bromo-4-tert-butylbenzene in
the presence of various bases, and the results of this study are
summarized in Table 1. Reactions conducted with either
[Pd(dba)2] (dba = trans,trans-dibenzylideneacetone) or Pd-
(OAc)2 as a catalyst precursor and cesium carbonate as a base
formed the coupled product in modest yields. Catalysts
generated from [Pd(dba)2] or Pd(OAc)2 and bisphosphine
ligands bis[2-(diphenylphosphino)phenyl]ether (dpephos),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xant-
Table 1: Effects of catalyst components on the coupling of octanal with
1-bromo-4-tert-butylbenzene.[a]
Entry Pd precursor ([mol%]) Ligand ([mol%]) Base
Yield [%][b]
1
2
3
4
5
6
7
8
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[Pd(dba)2] (5)
[{PdBr[P(tBu)3]}2] (2.5)
APC (2.5)
APC (2.5)
APC (2.5)
APC (2.5)
APC (2.5)
dpephos (5)
xantphos (5)
dppf (5)
rac-binap (5)
dpephos (5)
P(tBu)3 (5)
Q-phos (5)
–
dppf (5)
dppf (10)
dppf (10)
dppf (10)
Cs2CO3 40
Cs2CO3 60
Cs2CO3 68
Cs2CO3 66
Cs2CO3 49
Cs2CO3 65
Cs2CO3 60
Cs2CO3 30
Cs2CO3 24
Cs2CO3 94
Herein we report a more general system for palladium-
catalyzed coupling of aldehydes with electron-poor and
[*] G. D. Vo, Prof. Dr. J. F. Hartwig
Department of Chemistry
9
10
11
12
13
14
15
16
University of Illinois Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
K2CO3
K3PO4
61
72
xantphos (5)
rac-binap (10)
P(tBu)3 (10)
Q-phos (10)
Cs2CO3 88
Cs2CO3 32
Cs2CO3 66
Cs2CO3 82
E-mail: jhartwig@uiuc.edu
APC (2.5)
APC (2.5)
APC (2.5)
[**] We are grateful to the NIH (GM-58108) for support of this work and
Johnson-Matthey for gifts of palladium. dppf=1,1’-bis(diphenyl-
phosphino)ferrocene; Q-phos=1,2,3,4,5-pentaphenyl-1’-(di-tert-
butylphosphino)ferrocene.
[a] Reaction conditions: octanal (0.24 mmol), 1-bromo-4-tert-butylben-
zene (0.20 mmol), base (0.40 mmol), 1,4-dioxane (1.0 mL). [b] Yields
were determined by GC with dodecane as an internal standard.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 2127 –2130
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2127

Communications
Table 2: Palladium-catalyzed a-arylation of linear aldehydes with aryl
phos), 1,1’-bis(diphenylphosphino)ferrocene (dppf), and 2,2’-
bromides.[a]
bis(diphenylphosphino)-1,1’-binapthyl (rac-binap) did not
allow complete conversion of the bromoarene after
24 hours. This slow rate led to aldol condensation products
in more than 20% yield (Table 1, entries 1–5). Although
catalysts generated from monophosphine ligands Q-phos and
P(tBu)3 exhibited higher rates of conversion of the aryl
bromide, about 15–20% of tert-butylbenzene was formed
from hydrodebromination of the 1-bromo-4-tert-butylben-
zene (Table 1, entries 6and 7).
Entry
1
Aldehyde
Product
Yield [%][b]
83
Since the efficiency of generating active catalysts from
precursors could affect rates of the coupling reactions, several
palladium precursors that are known to undergo facile
reduction to the active [LnPd0] species were examined.[22]
The reaction conducted with 1.0 mol% of allylpalladium-
chloride ([{Pd(h3-allyl)Cl}2]; APC) proceeded with complete
conversion of the bromoarene after 14 hours. Of the catalysts
generated from APC, a combination of 2.5 mol% of the APC
dimer and 10 mol% of dppf in the presence of Cs2CO3
formed the coupled product in the highest yield (Table 1,
entry 10). The same coupling reactions conducted with either
K3PO4 or K2CO3 as a base occurred in lower yields (Table 1,
entries 11 and 12), and reactions catalyzed by complexes
bearing other bisphosphine and monophosphine ligands
formed the coupled product in lower yields (Table 1,
entries 13–16). Additional experimentation with the combi-
nation of APC and dppf showed that reactions conducted
with 1 mol% of APC, 4 mol% of dppf, 2 equivalents of
Cs2CO3, 0.25m bromoarene, and 0.30m aldehyde in dioxane
formed the coupled product in the highest yields.
We evaluated the scope of the coupling of linear
aldehydes with various aryl bromides by using the optimized
reaction conditions, and the results are summarized in
Table 2. The scope of this process encompassed electron-
neutral, electron-poor, and in one case electron-rich bro-
moarenes. Octanal coupled with electron-neutral 1-bromo-4-
tert-butylbenzene and 2-bromotoluene in excellent yields
(Table 2, entries 1 and 2), and reactions with the electron-
poor methyl 4-bromobenzoate formed the coupled product in
good yield (Table 2, entry 3). The steric properties of the
bromoarene favorably affected the yield of the coupled
product; for example, the electron-rich 2-bromoanisole
formed the coupled product in high yield (Table 2, entry 4),
whereas the less hindered electron-rich 4-bromoanisole
formed the coupled product in about 30% yield.
2
3
4
5
93
67
77
67
6
7
8
9
75
70
70
67
10
11
76
61
[a] Reaction conditions: aldehyde (1.0–1.2 mmol), aryl halide
(1.0 mmol), Cs2CO3 (2.00 mmol), 1,4-dioxane (4 mL). [b] Yield of
isolated product (average of two runs).
Coupling reactions of n-butyraldehyde occurred in good
yields, albeit slightly lower than those reported with octanal.
Reactions of butyraldehyde with 1-bromo-4-tert-butylben-
zene and 2-bromotoluene occurred in 67 and 75% yield,
respectively (Table 2, entries 5 and 6). Although subtle, we
attribute this difference in yields to the difference in steric
bulk of the aldehydes (e.g. Table 2, entry 1 versus entry 5).
Presumably the increased bulk leads to faster reductive
elimination of the coupled products from the arylpalladium
complexes of the octanal enolate than from complexes of the
butyraldehyde enolate. Again, the steric properties of the
bromoarene affected the yield; electron-rich 2-bromoanisole
and 3-bromoanisole coupled with butyraldehyde in good
yields (Table 2, entry 7 and 8). Reactions of ortho- and meta-
substituted bromoarenes with the aromatic linear hydro-
cinnamyl aldehyde formed the coupled products in good
yields (Table 2, entries 9–11). In contrast, reactions of the
linear aldehydes with chloroarenes and bromopyridines
resulted in low conversions and yields after 24 hours at 808C.
Reactions of branched aldehydes in the presence of APC
and dppf occurred in substantially lower yields than did those
of linear aldehydes. However, additional studies showed that
high yields could be obtained when the reactions were
catalyzed by combinations of APC and monophosphines. In
particular, reactions conducted with APC (0.5 mol%), Q-
phos (1 mol%), Cs2CO3 (2 equivalents), bromoarene (0.50m),
and aldehyde (0.60m) in THF formed the coupled product in
2128
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2127 –2130

Angewandte
Chemie
Table 3: Palladium-catalyzed a-arylation of branched aldehydes with aryl
the highest yields. Chloroarenes also reacted with branched
aldehydes under these conditions to give high yields of
coupled products, albeit with higher catalyst loadings
(1 mol% of APC and 2 mol% of Q-phos).
halide.[a]
The scope of the reactions of the branched aldehydes is
illustrated in Table 3. Electron-rich, electron-poor, and elec-
tron-neutral aryl bromides reacted with a-branched 2-meth-
ylbutyraldehyde to give a-aryl aldehydes bearing a quater-
nary center at the a position in high yields (Table 3, entries 1–
4, 6and 8). Both ortho- and meta-subtituted aryl bromides
coupled with this aldehyde in high yields (Table 3, entries 9
and 10), whereas aryl chlorides such as methyl 4-choroben-
zoate, 4-chlorobenzonitrile, and 3-chloroanisole reacted with
2-methylbutyraldehyde to give the corresponding a-aryl
aldehydes in good yields (Table 3, entries 5, 7, and 11).
Under the conditions used for reactions of a-branched
aldehydes, b-branched isovaleraldehyde reacted with bro-
moarenes to form coupled products in good yields. The scope
of the reaction with respect to the aryl bromide is broad;
electron-neutral (Table 3, entry 12), electron-rich (Table 3,
entries 13 and 14), and electron-poor (Table 3, entry 15)
bromoarenes formed the b-branched, a-aryl aldehydes in
good yields. In some cases, reactions of b-branched aldehydes
occurred under the conditions used for reactions of linear
aldehydes. For example, the reaction between 1-bromo-4-
(trimethylsilyl)benzene and b-branched isovaleraldehyde
formed the coupled product in good yield when catalyzed
by APC with dppf (Table 3, entry 16).
Entry
1
Product
Yield [%][b]
91
X=Br
X=Br
X=Br
2
3
81
86
4
5
X=Br
X=Cl
81
77
6
7
X=Br
X=Cl
80
67
8
9
X=Br
X=Br
79
71
During our investigation of the direct a-arylation of
aldehydes, Martín and Buchwald described the use of 2 mol%
Pd(OAc)2 and 3 mol% rac-binap for the a-arylations of linear
aldehydes and 3 mol% of 2-dicyclohexylphosphino-2’,6’-
dimethoxy-1,1’-biphenyl (S-phos) for the a-arylations of
branched aldehydes (see above).[19] Table 4 provides a com-
parison of the reactions of electron-neutral bromoarenes with
linear aldehydes and electron-rich bromoarenes with a-
branched aldehydes catalyzed under the conditions of the
previous work (conditions A) and under the conditions
reported herein (conditions B).[23]
The coupling of both n-butanal and n-octanal with the
electron-neutral 1-bromo-4-tert-butylbenzene occurred in
substantially lower yields with Pd(OAc)2 and rac-binap as
the catalyst than with APC and dppf. Likewise, the reactions
of 2-methylbutyraldehyde with electron-rich 4-bromo-N,N-
dimethylaniline and 4-bromoanisole formed the coupled
products in much higher yields with the catalyst generated
from APC and Q-phos than with the catalyst generated from
Pd(OAc)2 and S-phos.
10
11
X=Br
X=Cl
83
76
12
X=Br
X=Br
X=Br
X=Br
X=Br
80
73
67
67
85
13
14
15
16[c]
We attribute this difference in yields to both the palladium
precursor and the ligand. The beneficial effect of the
precursor is shown by reactions of octanal conducted with
both dppf and rac-binap (Table 5). The catalyst generated
from 4.5 mol% [Pd(dba)2] and 9.0 mol% dppf formed the
coupled product in lower yield than the catalyst generated
from 1 mol% APC and 4 mol% dppf. The catalyst generated
from 10 mol% rac-binap and 2.5 mol% APC formed the
coupled product in higher yield than that generated from
2 mol% Pd(OAc)2 and 3 mol% rac-binap. However, the yield
from the reaction catalyzed by APC and rac-binap remained
[a] Reaction conditions: aldehyde (1.2 mmol), aryl halide (1.0 mmol),
Cs2CO3 (2.00 mmol). For X=Br: APC (0.005 mmol), Q-phos
(0.01 mmol), THF (2 mL), 808C; for X=Cl: APC (0.01 mmol), Q-phos
(0.02 mmol), THF (4 mL), 908C. [b] Yield of isolated product (average of
two runs). [c] Reaction conducted with 1.0 mol% APC, 4.0 mol% dppf in
1,4-dioxane.
low, and a comparison of the reactions (Table 5) in which
APC and dppf or binap are used shows that dppf contributes
significantly to the high yield of coupled product.
Angew. Chem. Int. Ed. 2008, 47, 2127 –2130
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2129

Communications
back-filled with nitrogen three times. A solution of a linear aldehyde
(1.00–1.10 mmol) and an aryl halide (if it is a liquid) (1.00 mmol) in
1,4-dioxane (4 mL) was then added by a gas-tight syringe. The flask
was placed in an oil bath at 808C for 10–13 h. The reaction mixture
was diluted with ethyl acetate (10 mL) and filtered through a pad of
celite. The filtrate was concentrated in vacuo, and the crude product
was purified using flash column chromatography on silica gel
(hexanes/diethyl ether) to give the a-aryl aldehyde.
Procedure for reactions assembled inside the drybox: all reagents
as described in the procedure above were added to a 5-dram
scintillation vial containing a magnetic stir bar and sealed by a cap
lined with teflon. The vial was removed from the drybox and placed in
an oil bath at 808C.
Table 4: Comparison of protocols.
Yield [%]
Conditions A[a]
Entry
Conditions B[b]
67
1
2
3
4
R1 =Et, R2 =H
R3 =p-tBu
10
10
65
44
R1 =nC6H13, R2 =H
R3 =p-tBu
83
86
81
R1 =Et, R2 =Me
R3 =p-NMe2
R1 =Et, R2 =Me
R3 =p-OMe
Received: November 21, 2007
Published online: February 7, 2008
[a] Reaction conditions A for entries 1 and 2: aldehyde (1.2 mmol),
bromoarene (1.0 mmol), Cs2CO3 (1.2 mmol), Pd(OAc)2 (0.020 mmol),
rac-binap (0.030 mmol), 1,4-dioxane (4 mL), 14 h. For entries 3 and 4; S-
phos (0.030 mmol) was used for reaction time of 16.5 h. Yields were
determined by GC methods. [b] Reaction conditions B for entries 1 and
2: aldehyde (1.0–1.2 mmol), bromoarene (1.0 mmol), Cs2CO3
(2.0 mmol), APC (0.010 mmol), dppf (0.04 mmol), 1,4-dioxane (4 mL).
For entries 3 and 4: APC (0.005 mmol), Q-phos (0.010 mmol), and THF
(2 mL) was used instead. Yields of isolated products.
Keywords: aldehydes · arylation · cross-coupling · palladium
.
[1] S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem. Soc. 2006, 128,
13074 – 13075.
[2] X. Li, B. List, Chem. Commun. 2007, 1739 – 1741.
[3] J. H. Xie, Z. T. Zhou, W. L. Kong, Q. L. Zhou, J. Am. Chem. Soc.
2007, 129, 1868 – 1869.
[4] H. Venkatesan, M. C. Davis, Y. Altas, J. P. Snyder, D. C. Liotta, J.
Org. Chem. 2001, 66, 3653 – 3661.
[5] S. Edmondson, S. J. Danishefsky, L. Sepp-Lorenzino, N. Rosen,
J. Am. Chem. Soc. 1999, 121, 2147 – 2155.
Table 5: Effects of the Pd precursor and the ligand.[a]
[6] D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234 – 245.
[7] M. Miura, M. Nomura, Top. Curr. Chem. 2002, 219, 211 – 241.
[8] A. Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Catal. 2002, 344,
209 – 217.
[9] J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald, J. Am. Chem.
Soc. 2000, 122, 1360 – 1370.
[10] M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 1473 –
1478.
[11] T. Hama, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2006,
128, 4976– 4985.
[12] T. Hama, X. Liu, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc.
2003, 125, 11176– 11177.
[13] S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402 – 3415.
[14] W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123,
7996– 8002.
Ligand=dppf[b]
Conv. Yield Precursor
Ligand=rac-binap
Precursor
Conv. Yield
4.5 mol% [Pd-
(dba)2]
1 mol% APC
81% 60% 2 mol% Pd-
52% 10%
[d]
(OAc)2
100% 83%[c] 2.5 mol% APC[e]
85% 32%
[a] Conversions and yields were determined by GC with dodecane as an
internal standard. [b] A ratio of 2:1 of dppf to palladium was used.
[c] Isolated yield of coupled product. [d] Used 3 mol% of rac-binap.
[e] Used 10 mol% of rac-binap.
[15] N. A. Beare, J. F. Hartwig, J. Org. Chem. 2002, 67, 541 – 555.
[16] S. R. Stauffer, N. A. Beare, J. P. Stambuli, J. F. Hartwig, J. Am.
Chem. Soc. 2001, 123, 4641 – 4642.
[17] Y. Terao, Y. Fukuoka, T. Satoh, M. Miura, M. Nomura,
Tetrahedron Lett. 2002, 43, 101.
[18] V. Lavallo, Y. Canac, C. Prasang, B. Donnadieu, G. Bertrand,
Angew. Chem. 2005, 117, 5851 – 5855; Angew. Chem. Int. Ed.
2005, 44, 5705 – 5709.
[19] R. Martín, S. L. Buchwald, Angew. Chem. 2007, 119, 7374 – 7377;
Angew. Chem. Int. Ed. 2007, 46, 7236– 7239.
[20] a) Q. Shelby, N. Kataoka, G. Mann, J. Hartwig, J. Am. Chem.
Soc. 2000, 122, 10718 – 10719; b) N. Kataoka, Q. Shelby, J. P.
Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553 – 5566.
[21] N. Marion, O. Navarro, J. Mei, E. P. Stevens, N. M. Scott, S. P.
Nolan, J. Am. Chem. Soc. 2006, 128, 4101 – 4111.
[22] J. P. Stambuli, R. Kuwano, J. F. Hartwig, Angew. Chem. 2002,
114, 4940 – 4942; Angew. Chem. Int. Ed. 2002, 41, 4746– 4748.
[23] Using conditions reported by Martín and Buchwald, we were
able to obtain 72% yield of the isolated coupled product from
the coupling of butyraldehyde with 2-bromoanisole. This result is
consistent with that reported by Buchwald.
In conclusion, we have developed an improved method
for the palladium-catalyzed a-arylation of aldehydes. The
scope of the arylation of linear aldehydes encompasses
electron-poor and electron-neutral aryl bromides, whereas
the scope of the arylation of branched aldehydes encompasses
electron-rich, electron-neutral, and electron-poor aryl hal-
ides. One key to this broad substrate scope includes the use of
a palladium precursor that can be easily reduced to an active
[LnPd0] species. Studies on improving the scope and the
understanding of the mechanism for this process are ongoing
in our laboratories.
Experimental Section
General procedure for the a-arylation of linear aldehydes (Table 2):
Outside the drybox, [{Pd(h3-allyl)Cl}2] (3.7 mg, 0.010 mmol), dppf
(22.2 mg, 0.0400 mmol), Cs2CO3 (0.652 g, 2.00 mmol), and an aryl
halide (if it is a solid) (1.00 mmol) were added to a 25-mL Schlenk
flask that contained a magnetic stir bar. The flask was evacuated and
2130
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2127 –2130