Diastereoselective room-temperature Pd-catalyzed α-arylation and vinylation of arylmandelic acid derivatives

Article abstract of DOI:10.1021/ol900131q

Palladium-catalyzed α-arylation and vinylation of dioxolane (S,S)-I, easily obtained from (S)-mandelic acid, proceeds with high yields and excellent diastereoselectivity at room temperature employing commercially available P(t-Bu)₃·HBF₄

Full text of DOI:10.1021/ol900131q

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1543-1546
Diastereoselective Room-Temperature
Pd-Catalyzed r-Arylation and Vinylation
of Arylmandelic Acid Derivatives
Lei Jiang, Stefan Weist, and Susanna Jansat*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16,
43007 Tarragona, Spain
sjansat@iciq.es
Received January 21, 2009
ABSTRACT
Palladium-catalyzed r-arylation and vinylation of dioxolane (S,S)-I, easily obtained from (S)-mandelic acid, proceeds with high yields and
excellent diastereoselectivity at room temperature employing commercially available P(t-Bu)3·HBF4 and Pd(OAc)2 as a catalytic precursor system.
This method displays general utility for a large variety of aryl, heteroaryl, and vinyl bromides.
Fully substituted carbon centers are found in a variety of
natural products and other molecules with pharmacological
and medicinal applications. Accordingly, methods able to
construct these sterically hindered positions selectively are
highly valuable.1 Among the existent protocols, metal-
catalyzed R-arylations and R-vinylations2,3 are powerful,
established methods for accessing stereogenic centers.3a,4 In
line with our desire to obtain target compounds with high
potential for pharmacological application, we decided to
develop the R-arylation of mandelic acid derivatives. Man-
delic acid is a ubiquitous biological intermediate with
antibacterial properties.5 Certain derivatives show muscarinic
antagonist properties.6 Recently, enantiomerically enriched
(3) Selected references on R-arylation of ketones: (a) Ahman, J.; Wolfe,
J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 1918. (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2000, 122, 1360. (c) Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 1473. (d) Ehrentraut, A.; Zapf, A.; Beller, M. AdV.
Synth. Catal. 2002, 344, 209. (e) Marion, N.; Navarro, O.; Kelly, R. A.,
III.; Nolan, S. P. Synthesis 2003, 2590. Selected references on R-arylation
of esters: (f) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7996. (g) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549. (h) Hama,
T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545. Selected references on
R-arylation of amino acid derivatives: (i) Gaertzen, O.; Buchwald, S. L. J.
Org. Chem. 2002, 67, 465. (j) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 8410. Selected references on R-arylation of amides:
(k) Cossy, J.; de Filippis, A.; Pardo, D. G. Org. Lett. 2003, 5, 3037. (l)
Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976.
Selected references on R- vinylation of ketones: (m) Hamada, T.; Buchwald,
S. L. Org. Lett. 2002, 4, 999. R-Arylation of aldehydes: (n) Terao, Y.;
Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002,
43, 101. (o) Lavallo, V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand,
G. Angew. Chem., Int. Ed. 2005, 44, 5705. (p) Martin, R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2007, 46, 7236. (q) Vo, G. D.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2008, 47, 2127. (r) Martin, R.; Buchwald, S. L. Org. Lett.
2008, 10, 4561.
(1) Selected examples in enantioselective construction of quaternary
centers: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. A. Eur. J. Org.
Chem. 2007, 5969. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473. (c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (d) Dessinova, I.; Barriault, L. Tetrahedron 2003, 59,
10105. (e) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688.
(f) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley & Sons: New York, 2000; Chapter 8E. (g) Donde, Y.; Overman,
L. E. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley & Sons:
New York, 2000; Chapter 8G.
(2) Selected reviews in R-arylation of carbonyl compounds: (a) Culkin,
D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (b) Miura, M.; Nomura,
M. Top. Curr. Chem. 2002, 219, 211
.
10.1021/ol900131q CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

mandelic acid has been obtained via R-arylation using Ley’s
auxiliary.7 The dioxolane (S,S)-I8 derivative of mandelic acid
has been used as a substrate in alkylations9 and Pd-catalyzed
allylic substitutions10 and as a chiral auxiliary for the
synthesis of R-hydroxy acids,11 diols,12 C-glycosyl norsta-
tines,13 and nitrobenzophenones.14 The principle behind the
selectivity in the majority of these processes is the self-
regeneration of the stereocenter at the R-carbon (Scheme 1).15
Several bases, solvents, and palladium sources were tested
in the arylation of dioxolane (S,S)-I17 with 4-tert-butylbro-
mobenzene (Figure 1). The most favorable conditions were
Scheme 1. Synthesis of Dioxolane Derivatives
To the best of our knowledge, no Pd-catalyzed asymmetric
arylation or vinylation has been previously reported using
(S,S)-I.
Figure 1. Pd-catalyzed R-arylation of (S,S)-I using L1-L6. (a)
Herein, we describe a highly efficient and general approach
for the R-arylation and -vinylation of mandelic acid derivative
using a chiral rigid five-membered ring to control the
stereochemical pathway of the process. After cleavage of
the auxiliary, the resulting compounds contain fully substi-
tuted centers and are easily converted to the corresponding
R-hydroxy acids and 1,2-diols in high optical purity.16
Reaction conditions: 2.3 mmol of dioxolane I, 1 mmol of ArBr, 2
mol % of Pd(OAc)2, 8 mol % of L1-L6, 2.5 mmol of LHMDS in
toluene (1 mL/0.25 mmol of ArBr). Diastereomeric ratio determined
by HPLC. No coupling products were formed in the absence of
catalyst. (b) Determined by GC. (c) Percent isolated yield.
found using Pd(OAc)2 as the metal source and LHMDS as
the base at 50 °C in toluene for 12 h. An excess of dioxolane
(2.3 equiv) was necessary to achieve full conversion of the
aryl halide due to the formation of Claisen byproducts from
I and its enolate.
(4) (a) Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1261. (b) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 3500. (c) Chietti, A. K.; Ahman, J.; Fox, J. M.; Buchwald,
S. L. Org. Lett. 2001, 3, 1897. (d) Lee, S.; Hartwig, J. F. J. Org. Chem.
2001, 66, 3402.
(5) Hamilton-Miller, J. B.; Brumfitt, J. W. InVest. Urol. 1977, 14, 287.
(6) (a) Kiesewetter, D. O.; Silverton, J. V.; Eckelman, W. C. J. Med.
Chem. 1995, 38, 1711. (b) Kiesewetter, D. O.; Carson, R. E.; Jagoda, E. M.;
Endres, C. J.; Der, M. G.; Herscovich, P.; Eckelman, W. C. Bioorg. Med.
Chem. 1997, 5, 1555.
Among the ligands examined, air-stable P(t-Bu)3·HBF4
(a ligand that has been used in the R-arylation of esters3g,h
)
gave the best results, yielding the desired product in 93%
yield and 96:4 diastereomeric ratio (dr).
Remarkably, this catalytic system was also effective at
room temperature, maintaining the activity and increasing
the diastereomeric excess (de) from 92% to 99%.3f
Encouraged by these preliminary results, we decided to
explore the generality of this transformation. As shown in
Table 1, we were pleased to find that both electron-donating
and electron-withdrawing substituents are well accom-
modated independently of their position (para or meta) in
(7) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
(8) Grover, P. T.; Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. J.
Org. Chem. 2000, 65, 6283.
(9) Frater, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron Lett. 1981, 42, 4221.
(10) Moorlag, H.; De Vries, J. G.; Kaptein, B.; Schoemaker, H. E.;
Kamphuis, J.; Kellogg, R. M. Recl. TraV. Chim. Pays-Bas 1992, 111, 129.
(11) (a) Seebach, D.; Naef, R. HelV. Chim. Acta 1981, 64, 2704. (b)
Barroso, S.; Blay, G.; Cardona, L.; Ferndandez, I.; Garcia, B.; Pedro, J. R.
J. Org. Chem. 2004, 69, 6821.
(12) (a) Hof, P. R.; Kellogg, R. M. J. Chem. Soc., Perkin Trans. 1 1996,
2051–2060. (b) Scholtis, S.; Ide, A.; Mahrwald, R. Org. Lett. 2006, 8, 5353.
(13) Guerrini, A.; Varchi, G.; Battaglia, A. J. Org. Chem. 2006, 71,
6785.
(14) Blay, G.; Cordona, L.; Fernandez, I.; Michelena, R.; Pedro, J. R.;
Ramirez, T.; Ruiz-Garcia, R. Synlett 2003, 2325.
(17) The synthesis of (S,S)-I is reproductible. See ref 7.
(15) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
1996, 35, 2708.
(18) Using chiral auxiliaries: see ref 6. Examples of asymmetric
intramolecular R-arylation: (a) Fortanet, J.-G.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 8108. (b) Jia, X.-Y.; Hillgren, J. M:; Watson,
L. E.; Marsden, S. P.; Ku¨ndig, E. P. Chem. Commun. 2008, 4040. For
examples of nonasymmetric R-arylations: see ref 3j and: (d) Liu, X.;
Hartwig, J. F. Org. Lett. 2003, 5, 1915.
(16) R-hydroxy acids: (a) Coppola, G. M.; Schuster, H. F. R-Hydroxy
Acids in EnantioselectiVe Synthesis; VCH: Weinheim, 1997. Diols: (b)
Zaitsev, A. B.; Adolfssom, H. Synthesis 2006, 1725. (c) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
1544
Org. Lett., Vol. 11, No. 7, 2009

fication and is confirmed by the characteristic chlorine
isotopic pattern in the mass spectra of these arylation
products.
Table 1. Pd-Catalyzed R-Arylation of (S,S)-I Using Ligand L6a
As shown in Table 1, the arylation shows high diastereo-
selectivity (93-99% de) using substituted halobenzenes
(Table 1, entries 1-11). Yields remain high, but diastereo-
selectivities decrease for the heteroaryl bromides tested
(entries 12 and 13). This fact could be explained by the role
of secondary donor interactions in the Pd(II) intermediate
due to the complexation ability of N and S atoms. Although
these small interactions on the Pd catalytic species are
deleterious in the sense of asymmetric induction, they are
not strong enough to inactivate the catalyst. Despite the fact
that metal-catalyzed asymmetric R-arylations are established
and useful synthetic methods, the use of heteroaryl groups
as coupling partners remains to date challenging.18
Diastereomeric excesses were determined by HPLC analy-
sis. In all cases, only one isomer was observed by NMR
spectroscopy (Table 1). Conversion of the trimethylsilyl
moiety of (2S,5R)-7 (Table 1, entry 7) to an iodine (2S,5R)-
14 provides a derivative whose configuration was crystal-
lographically determined (Scheme 2). X-ray analysis found
Scheme 2. Synthesis of (2S,5R)-14 and Its ORTEP Diagram
the relative and absolute configuration of compound 14 to
be (2S,5R). This result is consistent with the approach of
the aryl group moving toward the less hindered face of the
chiral enolate and is in accordance with previously reported
alkylations and allylations of dioxolane (S,S)-I.9
It is important to note that the conditions originally
developed for arylation are also applicable to vinyl bromides
of varying substitution pattern and geometry. In all cases,
good yields and diastereoselectivities were achieved for the
Pd-catalyzed vinylation of mandelic acid derivative I. The
range of vinyl substrates includes R-branched, trisubstituted
vinyl bromides and proceeds with retention of the double-
bond configuration (as determined by coupling constants of
the vinyl moiety by 1H and 13C NMR spectroscopy). In some
cases, diastereomeric excesses were determined from the
enantiomeric excesses of the corresponding diols (entries
4-6, Table 2).
The synthetic utility of these fully substituted mandelic
acid derivatives is illustrated in Scheme 3. Reduction using
LiAlH4 proceeds in excellent yield at room temperature and
leads to the synthesis of 1,2-diols with complete retention
of configuration. Furthermore, the corresponding R-hydroxy
acids could be obtained quantitatively via basic hydrolysis
under mild conditions.
a Reaction conditions: 2.3 mmol of dioxolane I, 1 mmol of ArX, 2 mol
% of Pd(OAc)2, 8 mol % of P(t-Bu)3·HBF4, 2.5 mmol of LHMDS in toluene
(1 mL/0.25 mmol ArX), rt. Isolated yield are averages of two runs.
b Diastereomeric ratio determined by HPLC. (R,R)-I and (S,S)-I gave similar
results. c Reaction carried at 50 °C for 12 h.
the aromatic ring. It is noteworthy that ester, nitrile, ketal,
thioether, ether, trifluoromethyl, halide, silyl, and heterocyclic
moieties remain intact as evidenced by the high yields
obtained.
Hydrolysis of base-sensitive groups on the aryl bromide
was not observed (Table 1, entries 4 and 9, 96% and 93%
yield, respectively).
Coupling with bifunctional bromides such as 1-bromo-3-
chlorobenzene and 2-bromo-5-chlorothiophene (Table 1,
entries 8 and 13) occurred exclusively at the bromine. The
conservation of the chloride group allows subsequent modi-
Org. Lett., Vol. 11, No. 7, 2009
1545

Table 2. Pd-Catalyzed R-Vinylation of (S,S)-I Using Ligand
Scheme 3
.
Synthesis of Derivatives Starting from Coupling
Products
L6a
result in high enantioselectivities when deprotected by
hydrolysis or reduced to the corresponding acid or 1,2-diol.
To conclude, we showed two examples of coupling using
heteroaryl bromides in high yields and selectivities demon-
strating that this new method could be extended to the
coupling of these challenging moieties. Experiments for
application in the synthesis of biologically active compounds
are currently underway.
a Reaction conditions: 2.3 mmol of dioxolane I, 1 mmol of vinyl halide,
2 mol % of Pd(OAc)2, 8 mol % of P(t-Bu)3·HBF4, 2.5 mmol of LHMDS in
toluene (1 mL/0.25 mmol ArX), rt. Isolated yield in % and diastereomeric
excess determined by HPLC are averages of two runs. b Cis/trans (90:10)
mixture was used as starting material; product was also obtained as cis/
trans (90:10) mixture. c I/vinyl bromide ) 2:1. d ee determined by HPLC
of the corresponding diol. e Reaction at 50 °C for 12 h. de determined by
GC.
Acknowledgment. S.J. sincerely thanks Prof. Steven
Buchwald (MIT) for his support. This research was
supported by NCI (L.J., T32CA09112) and DFG awards
(S.W., WE 3549/2-1). We are grateful to Dr. Timothy
Barder (MIT) for crystallographic analysis of (2S,5R)-14.
The Bruker Advance 400 MHz spectrometer used in this
work was purchased with funding from the National
Institutes of Health (GM 1S10RR13886-01).
Diol 21 and hydroxy acid 22 coming from 12 and 13,
respectively, showed an ee in agreement with the de of the
coupling products (see entries 12 and 13 in Table 1).
In summary, we have developed a new method for Pd-
catalyzed R-arylation and -vinylation of a mandelic acid
derivative under mild conditions. The high diastereoselec-
tivities of these fully substituted, protected R-hydroxy acids
Supporting Information Available: Experimental pro-
cedures and data for all synthesized new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900131Q
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Org. Lett., Vol. 11, No. 7, 2009