Palladium-catalyzed β arylation of carboxylic esters

Article abstract of DOI:10.1002/anie.201003544

Alter ego: In the presence of an appropriate palladium(0) catalyst, carboxylic esters underwent β arylation instead of the more common α-arylation reaction with aryl halides containing an ortho electronegative substituent (see scheme; Cy = cyclohexyl). An asymmetric version of the reaction gave the product with an enantiomeric ratio of up to 77:23.

Full text of DOI:10.1002/anie.201003544

Angewandte
Chemie
DOI: 10.1002/anie.201003544
ꢀ
C H Functionalization
Palladium-Catalyzed b Arylation of Carboxylic Esters**
Alice Renaudat, Ludivine Jean-Gꢀrard, Rodolphe Jazzar, Christos E. Kefalidis, Eric Clot,* and
Olivier Baudoin*
ꢀ
The direct functionalization of C H bonds is an atom- and
step-economical alternative to more traditional synthetic
methods based on functional-group transformations, which
often require multistep sequences.[1] In particular, transition-
metal catalysis has emerged as a powerful tool for the
2
ꢀ
functionalization of otherwise unreactive C(sp ) H and
3
ꢀ
C(sp ) H bonds. These advances have enabled the construc-
tion of a variety of carbon–carbon and carbon–heteroatom
bonds with great efficiency and selectivity, even in structurally
complex organic molecules.[2] In this context, we previously
investigated the intramolecular arylation of unactivated
C(sp ) H bonds under palladium(0) catalysis. Intermolec-
ular C(sp ) H arylation reactions have also been developed
3
[3]
ꢀ
3
ꢀ
through the use of palladium(II)[4] or palladium(0)[5] catalysis
and the assistance of a coordinating group, such as a carbonyl
group (Scheme 1a).[6] This group directs arylation in the
b position through the formation of a chelated palladium
homoenolate.
ꢀ
The palladium(0)-catalyzed C H arylation a to an
Scheme 1. a) Directing-group strategy for the palladium-catalyzed b ar-
ylation of carbonyl compounds. b) Palladium-catalyzed a and b aryla-
tion of enolates generated in situ.
electron-withdrawing functional group (Scheme 1b, path 1)
has also been established as a powerful method for the
3
2
ꢀ
construction of C(sp ) C(sp ) bonds. An enantioselective
reaction is also possible with a chiral catalyst.[7] This reaction
ꢀ
takes advantage of the acidity of the C H bond a to the
electron-withdrawing group—in general a carbonyl group—
to generate a palladium enolate, which is converted into the
a-arylated product by reductive elimination. Herein, we
describe a diversion from this mechanism and the develop-
complementary to directing-group-controlled b arylation
reactions. In this regard, it presents a few interesting features;
for example, simple carboxylic esters can be used as substrates
at mild temperatures, and no polyarylation products are
formed. We also describe the proof of concept of an
enantioselective variant with a chiral catalyst and propose a
reaction mechanism on the basis of DFT calculations.
ꢀ
ment of a straightforward and conceptually new b-C H
arylation method (Scheme 1b, path 2). Because this new type
of b arylation is related mechanistically to a arylation, it is
Our initial studies focused on the palladium-catalyzed
arylation of the lithium enolate of tert-butyl isobutyrate (2a)
with ortho-, meta-, and para-fluorobromobenzene (1a–c;
Table 1; the lithium enolate was formed in situ from 2a and
lithium dicyclohexylamide (Cy2NLi)).[8] The palladium cata-
lyst was composed of tris(dibenzylideneacetone)dipalla-
dium(0) ([Pd2(dba)3]) and 2-dicyclohexylphosphanyl-2’-
(N,N-dimethylamino)biphenyl (davephos).[9] The reaction of
the lithium enolate of 2a with para- and meta-fluorobromo-
benzene in toluene at 288C gave an approximately 1:1
mixture of a-arylation (compounds 3a,b) and b-arylation
products (compounds 4a,b; Table 1, entries 1 and 2). In
contrast, the reaction with ortho-fluorobromobenzene (1c)
gave only the b-arylation product 4c, which was isolated in
63% yield (Table 1, entry 3). Similarly, the reaction of methyl
isobutyrate 2b with 1c gave only the b-arylation product 4d
(Table 1, entry 4). A slightly higher temperature (508C) was
required for complete conversion in the reaction of bromide
1c with ester 2a than for other reactions, and the product 4c
[*] A. Renaudat, Dr. L. Jean-Gꢀrard, Dr. R. Jazzar, Prof. Dr. O. Baudoin
Universitꢀ Claude Bernard Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie Molꢀculaires et Supramolꢀculaires
CPE Lyon, 43 Boulevard du 11 Novembre 1918
69622 Villeurbanne (France)
E-mail: olivier.baudoin@univ-lyon1.fr
Homepage: http://www.icbms.fr/user/main.asp?pag=494
Dr. C. E. Kefalidis, Dr. E. Clot
Institut Charles Gerhardt, UMR 5253, Universitꢀ Montpellier
2, case courrier 1501, Place Eugꢁne Bataillon
34000 Montpellier (France)
E-mail: clot@univ-montp2.fr
[**] This research was supported financially by the ANR (programme
blanc “AlCaCHA”), the Institut de Chimie des Substances Nature-
lles, and the CNRS (ATIP grant). We thank Dr. Paul Lhoste and Dr.
Caroline Toppan for assistance with HPLC and NMR experiments,
respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003544.
Angew. Chem. Int. Ed. 2010, 49, 7261 –7265
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7261

Communications
Table 1: Effect of the substitution of the aryl bromide on the arylation
pathway (a versus b).[a]
such as a methyl group (desired product 4i), only gave rise to
the more usual a-arylation product. Thus, electronegative
groups in ortho positions clearly favor b arylation. Remark-
ably, aryl chlorides also proved competent coupling partners,
as demonstrated by the b arylation of methyl ester 2b with
ortho-dichlorobenzene to furnish 4e in 63% yield. Only a
slightly higher temperature (508C) was required in this case.
Interestingly, a few heteroaryl chlorides, such as 2-chloro-
thiophenes (products 4l,m), a functionalized 2-chlorofuran
(product 4n), and 2-chloro-3-fluoropyridine (product 4o),
were also employed successfully in this reaction; the corre-
sponding b-arylated products were obtained in good yields.
Furan 4n was isolated as the corresponding aldehyde as a
result of acetal cleavage during workup. In the reaction to
form pyridine 4o, the a-arylation product was also observed
as a minor product (b/a 4:1); however, 4o could be separated
and isolated in pure form (56% yield). In contrast,
2-chloropyridine furnished only the a-arylation product
rather than the b-arylation product 4p. This result highlights
the effect of the ortho electronegative fluorine atom on the a/
b selectivity.
Entry
1
2
T [8C]
Product(s)
a/b[b]
Yield [%][c]
1
2
3
1a
1b
1c
1c
1c
2a
2a
2a
2b
2a
28
28
50
28
50
3a + 4a
3b + 4b
4c
4d
3c + 4c
47:53
47:53
<2:98
<2:98
85:15
91
95
63 (77)[d]
4
69
55
5[e]
[a] Reaction conditions: ester (2.0 equiv), Cy2NLi (2.2 equiv), toluene;
then aryl bromide (1.0 equiv), [Pd2(dba)3] (5 mol%), davephos
(10 mol%), 2 h. [b] The ratio of the products of a and b arylation was
determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [c] Yield of the isolated product (entries 3 and 4) or of the
mixture of products (entries 1, 2, and 5). [d] The product was obtained in
77% yield when the reaction was carried out at 1108C. [e] PtBu3 was used
instead of davephos as the ligand.
We also examined the scope of the reaction with respect to
the ester component (Scheme 2b). Different alkoxy groups
were tolerated well in the b arylation with 2-chlorobromo-
benzene (products 4q–u). We next attempted the reaction of
carboxylic esters containing other main carbon chains. The
presence of an a tertiary carbon atom (R2 ¼ H) was found to
be compulsory: propionic esters (R2 = H) furnished neither
the a- or the b-arylation product under these conditions.
Remarkably, the protected phenylalanine analogue 4v was
obtained in 63% yield from the reaction of the corresponding
protected alanine derivative with 2-fluorobromobenzene.
Thus, this method provides a route to novel nonproteinogenic
amino acids, which are difficult to access by other methods.
Compound 4e, synthesized as described above by the
b arylation of methyl isobutyrate (2b) with 2-chlorobromo-
was formed in higher yield (77%) when the reaction mixture
was heated at reflux (Table 1, entry 3). Other bases, solvents,
Pd sources, and ligands were screened in the reaction of aryl
bromide 1c with methyl ester 2b,[10] but the conditions
described in Table 1 were found to give the highest yield of
4d. To the best of our knowledge, b arylation has been
reported only once as a side reaction during a-arylation
studies.[8b] In the present study, the structure of both the aryl
halide and the palladium ligand was found to be key to the
high selectivity observed in favor of b arylation. For example,
with P(tBu)3 as the palladium ligand instead of davephos, the
ratio of a- to b-arylation products was reversed (Table 1,
entry 5).
We carried out a few control experiments to gain a better
understanding of this new process. Control reactions between
1c and 2b in the absence of a base or catalyst failed to give
any of the coupling product. Furthermore, the reaction of 1c
with the nonenolizable ester methyl pivalate (tBuCO2Me)
failed to give any of the b-arylation product. This result shows
that the present b arylation does not occur through a
directing-group controlled mechanism (Scheme 1a). Finally,
a similar reactivity was observed between the isolated lithium
enolate formed from 2b and the lithium enolate formed in
situ from 2b in reactions with Cy2NLi. These results show
again that this enolate is most probably the reactive species
and that dicyclohexylamine, which is liberated in the in situ
procedure, has no influence on the course of the reaction.
We next examined the scope of the b arylation of
carboxylic esters with aryl and heteroaryl halides
(Scheme 2). In agreement with the above observations, the
reaction was more efficient and more selective with aryl
bromides bearing an electronegative group in the ortho
position, such as a chlorine (product 4e) or fluorine atom
(product 4j,k), or a trifluoromethyl (product 4 f), trifluor-
omethoxy (product 4g), or methoxy group (product 4h;
Scheme 2a). Other functional groups in the ortho position,
benzene, was subjected to a second b arylation with
2-fluorobromobenzene. The reaction was slower, presumably
for steric reasons, and required a higher temperature (708C)
to reach completion. Nevertheless, the desired bisarylated
product 4w was isolated in 67% yield. Esters bearing a
trifluoromethyl or phenyl group in the a position proved
unreactive under these conditions, presumably as a result of
excessive steric hindrance at this position, and the corre-
sponding products 4x,y were not isolated. Finally, the reaction
of the deuterated ester (CD3)2CHCO2Bn gave rise to product
4z with complete deuterium transfer from the b to the
a position. This result indicates that the b-arylation product
does not undergo deprotonation under the reaction condi-
tions. In other words, the lithium enolate of the starting ester,
which was added in slight excess with respect to the aryl
halide, is not sufficiently basic to deprotonate the product.
This experiment is key to the development of an asymmetric
version of this reaction. Indeed, the asymmetric b arylation of
symmetrical esters, such as isobutyrates, would yield a chiral
product containing a stereogenic center a to the ester. This
center should not epimerize under the reaction conditions.
Encouraged by these preliminary results, we next inves-
tigated the enantioselective b arylation of tert-butyl isobuty-
7262 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7261 –7265

Angewandte
Chemie
and co-workers.[13] Gratify-
ingly, products 4c, 4g, 4l,
and 4q were obtained in
good yields with enantio-
meric ratios (e.r.) between
67:33 and 77:23 in the pres-
ence of the chiral catalyst
formed in situ from [Pd2-
(dba)3] and the aR-config-
ured ligand L*. The abso-
lute configuration of all
major enantiomers was
determined to be
R by
reduction of the tert-butyl
ester group to the primary
alcohol and formation of an
a-methoxy-a-trifluorome-
thylphenylacetyl (MTPA)
ester.[14] Although the enan-
tioselectivities were only
moderate, the asymmetric
transformation constitutes
a proof of concept and pro-
vides a blueprint for the
development of more effi-
cient chiral catalysts.
We addressed the com-
petition between a and b ar-
ylation
computationally
with DFT(B3PW91) calcu-
lations[10] of the correspond-
ing reaction mechanisms
from the C-enolate complex
[Pd(Ar)(PCy3)(C(Me)2-
(CO2Me))] (Ar= 2-F-C6H4,
Figure 1).
phosphane,
Tricyclohexyl-
which was
shown experimentally to
give similar results,[10] was
used as a model for struc-
turally more complex dave-
phos. The initial palladium–
C-enolate complex results
ꢀ
from the C Br oxidative
addition of the bromoarene
to [Pd(PCy3)], followed by
bromide substitution with
the ester enolate. The pre-
ferred pathway (blue in
Figure 1) involves the fol-
lowing sequence of steps:
Scheme 2. Scope of the Pd0-catalyzed b arylation with respect to a) the (hetero)aryl halide and b) the ester.
Bn=benzyl; yields refer to the isolated b-arylation product.
1) b-H elimination from an
°
rate (2a) with various (hetero)aryl halides (Scheme 3).[11,12] In
this study, tert-butyl ester 2a was the preferred ester substrate
because it tended to give less of the Claisen condensation by-
products and thus cleaner reaction mixtures. As the first type
of chiral palladium ligands considered for this reaction, we
logically turned our attention to the chiral version of
davephos, L*, which was prepared as described by Buchwald
agostic C H bond of one b-methyl group (DG = 10.6 kcal
ꢀ
molꢀ1), 2) 1808 rotation of the coordinated olefin (DG° =
ꢀ1
ꢀ
8.4 kcalmol ), 3) insertion of the olefin into the Pd H
°
ꢀ
bond with the formation of a Pd Cb bond (DG = 1.2 kcal
molꢀ1), and 4) reductive elimination of the b-arylation
product (DG° = 10.3 kcalmolꢀ1).[15] From the product of b-H
elimination, dissociation of the olefin was computed to be
Angew. Chem. Int. Ed. 2010, 49, 7261 –7265
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7263

Communications
formation of the b-arylation product; thus, any kinetic
formation of the a-arylation product is ruled out. Moreover
the b-arylation product is 6 kcalmolꢀ1 more stable than the
a-arylation product; therefore, the former is both the kinetic
and the thermodynamic product of the reaction. Although
these calculations explain many of the experimental obser-
vations in this study, further investigations into the influence
of the ortho electronegative group of the bromoarene on the
selectivity for b/a arylation are under way.
In conclusion, we have developed a mild and efficient
3
ꢀ
intermolecular arylation of unactivated C(sp ) H bonds b to
carboxylic esters on the basis of a novel concept. The reaction
gives a range of synthetically useful functionalized carboxylic
esters, such as phenylalanine analogues and new fluorinated
building blocks.[16] In an asymmetric version with a chiral
palladium ligand related to davephos, b-arylated products
were obtained with enantiomeric ratios up to 77:23. Compu-
tational studies indicated that the mechanism involves a
2
ꢀ
=
b-hydride elimination/Pd h (C C) bond rotation/hydride
insertion/reductive elimination manifold, and that b arylation
is kinetically favored over a arylation with the substrates and
catalyst studied. Our current research includes the general-
ization of this b functionalization to other enolates and
electrophiles, as well as the improvement of enantioselectiv-
ities.
Scheme 3. Enantioselective b arylation. For the determination of enan-
tiomeric ratios and the absolute configuration of the major enantio-
mers, see the Supporting Information.
Received: June 10, 2010
Revised: July 15, 2010
Published online: August
19, 2010
Keywords: arylation ·
.
ꢀ
C C coupling ·
ꢀ
C H functionalization ·
esters · palladium
[1] Topics in Current
Chemistry, Vol. 292
(Eds.: J.-Q. Yu, Z.
Shi), Springer, Hei-
delberg, 2010.
[2] For selected general
reviews, see: a) F.
Kakiuchi, N. Cha-
tani, Adv. Synth.
Figure 1. Gibbs free energy (kcalmolꢀ1) diagram for the a- and b-arylation pathways (L=PCy3, Ar=2-fluorophenyl).
more difficult than rotation of the olefin (DG° = 14.4 versus
Catal. 2003, 345,
1077 – 1101; b) A. R.
Dick, M. S. Sanford,
Tetrahedron
2006,
62, 2439 – 2463; c) K. Godula, D. Sames, Science 2006, 312, 67 –
72; d) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417 –
424.
8.4 kcalmolꢀ1). Such a dissociated olefin was observed in
small amounts in some b-arylation experiments, in agreement
with the computational data. After rotation of the olefin,
[3] a) O. Baudoin, A. Herrbach, F. Guꢀritte, Angew. Chem. 2003,
115, 5914 – 5918; Angew. Chem. Int. Ed. 2003, 42, 5736 – 5740;
b) J. Hitce, P. Retailleau, O. Baudoin, Chem. Eur. J. 2007, 13,
792 – 799; c) M. Chaumontet, R. Piccardi, N. Audic, J. Hitce, J.-L.
Peglion, E. Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130,
15157 – 15166; d) M. Chaumontet, R. Piccardi, O. Baudoin,
Angew. Chem. 2009, 121, 185 – 188; Angew. Chem. Int. Ed. 2009,
48, 179 – 182.
ꢀ
ꢀ
insertion into the Pd H bond and C Ar reductive elimination
to give the b-arylation product (blue pathway) were com-
ꢀ
puted to be preferred over olefin insertion into the Pd Ar
°
ꢀ1
ꢀ
bond (DG = 15.8 kcalmol ), followed by C H reductive
elimination (green pathway). From the initial C-enolate
ꢀ
complex, the transition state for Ar C reductive elimination
to form the a-arylation product (red pathway) is 6.1 kcal
[4] For selected recent examples, see: a) R. Giri, N. Maugel, J.-J. Li,
D.-H. Wang, S. P. Breazzano, L. B. Saunders, J.-Q. Yu, J. Am.
molꢀ1 higher than the highest point along the pathway for the
7264 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7261 –7265

Angewandte
Chemie
Chem. Soc. 2007, 129, 3510 – 3511; b) D.-H. Wang, M. Wasa, R.
Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 7190 – 7191.
[5] For the first example of a palladium(0)-catalyzed directed
b arylation, see: M. Wasa, K. M. Engle, J.-Q. Yu, J. Am. Chem.
Soc. 2009, 131, 9886 – 9887.
[6] For a recent review, see: R. Jazzar, J. Hitce, A. Renaudat, J.
Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16, 2654 –
2672.
[7] a) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234 –
245; b) C. C. C. Johansson, T. J. Colacot, Angew. Chem. 2010,
122, 686 – 718; Angew. Chem. Int. Ed. 2010, 49, 676 – 707; c) F.
Bellina, R. Rossi, Chem. Rev. 2010, 110, 1082 – 1146.
[8] For similar conditions used in the a arylation of esters, see:
a) W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123,
7996 – 8002; b) M. Jørgensen, S. Lee, X. Liu, J. P. Wolkowski, J. F.
Hartwig, J. Am. Chem. Soc. 2002, 124, 12557 – 12565.
[9] D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998,
120, 9722 – 9723.
[10] See the Supporting Information for details.
[11] For enantioselective a arylations, see Ref. [7b].
3
ꢀ
[12] For an enantioselective directed C(sp ) H alkylation, see: B.-F.
Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. 2008, 120,
4960 – 4964; Angew. Chem. Int. Ed. 2008, 47, 4882 – 4886.
[13] A. Chieffi, K. Kamikawa, J. ꢁhman, J. M. Fox, S. L. Buchwald,
Org. Lett. 2001, 3, 1897 – 1900.
[14] M. Tsuda, Y. Toriyabe, T. Endo, J. Kobayashi, Chem. Pharm.
Bull. 2003, 51, 448 – 451.
[15] For related mechanisms, see: a) T. Satoh, M. Miura, M. Nomura,
J. Organomet. Chem. 2002, 653, 161 – 166; b) J. P. Wolfe, Eur. J.
Org. Chem. 2007, 571 – 582.
[16] For the relevance of fluorine in pharmaceuticals, see: K. Mꢂller,
C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886.
Angew. Chem. Int. Ed. 2010, 49, 7261 –7265
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7265