Efficient stereochemical controllers in biaryl Suzuki coupling reactions: Benzylic carbinols bearing in β-position thioether, dimethylamino, or sulfoxide groups

Article abstract of DOI:10.1021/ol051382m

(Chemical Equation Presented) Highly atropo-diastereoselective Suzuki coupling between aryl halides bearing stereogenic benzylic carbinols with sulfoxide, thioether, or dimethylamino groups as efficient internal chelating ligands and 2-methoxy-1-naphthylboronic acid were performed with high yields; a palladacycle is proposed as a potential transition state.

Full text of DOI:10.1021/ol051382m

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3737-3740
Efficient Stereochemical Controllers in
Biaryl Suzuki Coupling Reactions:
Benzylic Carbinols Bearing in
Thioether, Dimethylamino, or Sulfoxide
Groups
â-Position
Pierre-Emmanuel Broutin and Franc¸oise Colobert*
Laboratoire de ste´re´ochimie associe´ au CNRS, UMR 7509 UniVersite´ Louis Pasteur,
ECPM 25 rue Becquerel, 67087 Strasbourg Cedex 2, France
fcolober@chimie.u-strasbg.fr
Received June 13, 2005
ABSTRACT
Highly atropo-diastereoselective Suzuki coupling between aryl halides bearing stereogenic benzylic carbinols with sulfoxide, thioether, or
dimethylamino groups as efficient internal chelating ligands and 2-methoxy-1-naphthylboronic acid were performed with high yields; a palladacycle
is proposed as a potential transition state.
Axially chiral biaryls are common structural motifs in natural
products and chiral ligands, and they constitute attractive
synthetic targets because of their interesting properties.1 The
key step in such syntheses is always the coupling reaction
between the two aromatic units. A high number of synthetic
approaches have been reported.2 However, efficient examples
of asymmetric Suzuki reactions are quite rare and have been
reported only in the past few years. The use of chiral ligands
was first explored by Nicolaou3 in the total synthesis of
vancomycin. Cammidge,4 Buchwald,5 Baudoin,6 Johannsen,7
and very recently Mikami8 reported atropo-enantioselective
Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944. ( i) Lin, G.-G.;
Zhong, M. Tetrahedron: Asymmetry 1997, 8, 1369-1372. (j) Brusse, J.;
Groenendijk, J. L. G.; te Copele, J. M.; Jansen, A. C. A. Tetrahedron 1985,
41, 3313-3319. (k) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am.
Chem. Soc. 1988, 10, 8153-8156. (l) Hayashi, T.; Hayashizaki, K.; Ito, Y.
Tetrahedron Lett. 1989, 30, 215-218. (m) Hayashi, T.; Niizuma, S.;
Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101-
9102. (n) Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455-3466.
(3) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T.-Y.; Natarajan, S.; Chu, X.-J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999,
5, 2584-2601.
(1) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Moore, R. E., Tamm, C., Eds; Springer: New York,
2001; Vol. 82.
(2) (a) Knight, D. W. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds; Pergamon Press: New York, 1991; Vol. 3, p 481. (b)
Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359-1469. (c) Meyers, A. I.; Lutomski, K. A. J. Am. Chem.
Soc. 1982, 104, 879-881. (d) Meyers, A. I.; Himmelsbach, R. J. J. Am.
Chem. Soc. 1985, 107, 682-685. (e) Wilson, J. M.; Cram, D. J. J. Org.
Chem. 1984, 49, 4930-4943. (f) Wilson, J. M.; Cram, D. J. J. Am. Chem.
Soc. 1982, 104, 881-884. (g) Feldmann, K. S.; Smith, R. S. J. Org. Chem.
1996, 61, 2606-2612. (h) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.;
(4) (a) Cammidge, A. N.; Crepy, K. V. L.Chem. Commun. 2000, 1723-
1724. (b) Cammidge, A. N.; Crepy, K. V. L. Tetrahedron 2004, 60, 4377-
4386.
(5) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051-12052.
10.1021/ol051382m CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/29/2005

Suzuki couplings induced by chiral ligands for the synthesis
of binaphthyl or phenylnaphthyl compounds. We recently
communicated the asymmetric Suzuki coupling with chiral
phosphine ligands: BINAP and Tol-BINAP with Pd(OAc)2
or (η3-allylPdCl)2 in the synthesis of 2,2′-dimethoxy-1,1′-
dinaphthalene.9 Only two atropo-diastereoselective Suzuki
couplings were reported by Uemura10 using chiral arene-
(chromium) halide complexes and by Lipshutz using as a
chiral auxiliary a stereocenter attached to a phosphine
ligand.11
Recently, we reported the use of a stereogenic benzylic
carbinol substituent as an efficient stereochemical controller
in the biaryl Suzuki coupling reaction.12 This stereogenic
benzylic group was introduced by the reduction of a
â-ketosulfoxide13 ortho to the aryl halide unit (Scheme 1).
bearing a benzylic stereocenter. We postulated that the
diastereoselectivity of the coupling reaction is mainly
controlled by the stereogenic carbon atom closer to the biaryl
C-C-bond formed.
To generalize the use of benzylic carbinols as efficient
precursors to asymmetric biaryl moieties, we proposed to
understand the exact role of the stereogenic sulfur atom: the
sulfoxide group. We report herein the biaryl Suzuki coupling
between 2-methoxy-1-naphthylboronic acid and aryl iodide
with a stereogenic benzylic hydroxy group in the ortho
position, bearing in the â position, instead of a p-tolylsul-
foxide group as in 1, a p-tolyl thioether (compound 2), a
p-tolyl sulfone (compound 3), no substituent (compound 4),
a methoxy as in 6, benzyloxy as in 7, p-tolyloxy group in 8,
or a N,N-dimethylamino group in 9.
Syntheses of these aryl iodides were performed using
known methods. Starting from the sulfoxide derivative 1,
reduction by treatment with trifluoroacetic anhydride and
sodium hydride in acetone afforded the corresponding
p-tolylthioether 2 in quantitative yield.18 On the other hand,
oxidation of 1 with m-CPBA in CH2Cl2 led to the corre-
sponding sulfone 3 in 99% yield (Scheme 2).
Scheme 1. Asymmetric Biaryl Suzuki Coupling Using
Stereogenic Benzyloxy Groups
Scheme 2. Reduction and Oxidation of the Sulfoxide Group
The synthetic sequence leading to the aryl iodide bearing
in the ortho position the stereogenic methylcarbinol 4 without
a subtituent in â position is outlined in Scheme 3.19
This new atropo-diastereoselective Suzuki coupling reaction
allows the synthesis of biphenyl, binaphthyl, and phenyl-
naphthyl derivatives with excellent control of the axial
chirality up to 98% de and excellent yield up to 99%.
Simultaneously to our first communication,12 diastereo-
selective Suzuki coupling between a chiral benzylic alcohol
and sterically hindered arylboronic esters was reported in
the approach to cyclooctadiene lignans.14
Scheme 3. Synthesis of Benzylic Carbinol without a
Substituent in the â Position
The presence of a chiral center such as a chiral benzylic
alcohol in the ortho position of the aryl halide could be very
useful in the total synthesis of biologically active compounds
such as (-)-steganacin,15 korupensamine A,16 and the biaryl
Treatment of the sulfoxide 1 under typical Pummerer
conditions20 [(i) trifluoroacetic anhydride (TFAA), 2,6-
lutidine; (ii) K2CO3; (iii) NaBH4] gave in excellent yield the
corresponding alcohol 5 which was converted to the methyl
ether and benzyl ether by treatment with sodium hydride and
17
unit of vancomycin which could arise from precursors
(6) Herrbach, A.; Marinetti, A.; Baudoin, O.; Guenard, D.; Gueritte, F.
J. Org. Chem. 2003, 12, 4897-4905.
(7) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025-3028.
(8) Mikami, K.; Miyamoto, T.; Hatano, M. Chem. Commun. 2004, 2082-
2083.
(9) Castanet, A.-S.; Colobert, F.; Broutin, P.-E.; Obringer, M. Tetrahe-
dron: Asymmetry 2002, 13, 659-665.
(10) Kamikawa, K.; Uemura, M. Synlett 2000, 938-949.
(11) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999, 38,
3530-3533.
(12) (a) Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5, 3281-3284. (b)
Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.
(13) Solladie´, G.; Carren˜o, M. C. In Organosulfur Chemistry: Synthetic
Aspects; Page, P. C. B., Ed.; Academic Press: New York, 1995; pp 1-47.
(14) Baudoin, O.; De´cor, A.; Cesario, M.; Gue´ritte, F. Synlett 2003, 13,
2009-2012.
(15) Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, C. J.;
Restivo, R. J.; Brian, R. F. J. Am. Chem. Soc. 1973, 95, 1335-1336.
(16) Hallock, Y. F.; Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H. II;
Schaˆffer, M.; Gulden, K. P.; Bringmann, G.; Lee, A. Y.; Clardy, J.; Franc¸ois,
G.; Boyd, M. R. J. Org. Chem. 1994, 59, 6349-6355.
(17) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1172-1193.
(18) Arnone, A.; Bravo, P.; Farina, A.; Frigerio, M.; Valdo Meille, S.;
Viani, F. Tetrahedron: Asymmetry 1995, 6, 2695-2707.
(19) Hirth, U. H.; Springler, B.; Wirth, T. J. Org. Chem. 1998, 63, 7674-
7679.
(20) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
3738
Org. Lett., Vol. 7, No. 17, 2005

methyl iodide or benzyl chloride in DMF affording 6 and 7,
respectively21 (Scheme 4).
Table 1. Suzuki Couplings between Aryl Iodides 1-4 and
6-9 and 2-Methoxy-1-naphthylboronic Acida
Scheme 4. Synthesis of Benzylic Carbinol with an Ether in
the â Position
aryl
entry iodide
time yield
axial
chiralityc
R
(h)
(%)
drb
1
2
3
4
5
6
7
8
1
2
3
4
6
7
8
9
SO-p-Tol
S-p-Tol
SO2-p-Tol
H
OMe
OBn
1
1
2
20
2
1
99
99
94
77
91
91
79
73d
>99/1
>99/1
85/15
60/40
70/30
70/30
65/35
>95/5
aR
aR
aR
aR
aR
aR
aR
aR
O-p-Tol
NMe2
4
2
A Mitsunobu-type reaction22 performed on 5 with p-
methylphenol, PPh3, and DEAD in THF led to the p-tolyl
ether 8 in good yield (Scheme 4).
To obtain the aryl iodide with the N,N-dimethylamino
group 9, alcohol 5 was submitted to a Mitsunobu-type
reaction with HN3, PPh3, and DEAD in THF23 followed by
reduction of the formed azo group with 1,3-propanedithiol
and Et3N in MeOH.24 Methylation of the primary amine with
formaldehyde and formic acid25 gave 9 in 54% overall yield
(Scheme 5).
a Reaction conditions: 1-4, 6-9 (1 equiv), 2-methoxy-1-naphthylboronic
acid (2 equiv), Pd(OAc)2 (10 mol %), PPh3 (30 mol %), CsF (4 equiv),
dioxane, reflux. b Determined by H NMR on the crude mixture. c Deter-
1
mined by X-ray crystallography and 1H NMR NOESY experiments.12
d Yield nonoptimized.
high yield and diastereoselectivity (Table 1, entry 2).
Similarly, with the dimethylamino group excellent selectivity
was obtained (Table 1, entry 8). These results indicate that
the presence of coordinating atoms, with a high affinity to
palladium, is essential for a total control of the selectivity.
With a methoxy, benzyloxy, or p-tolyloxy group, diastereo-
selectivity is much lower (30-40%), probably due to the
steric hindrance without coordination of the oxygen atom to
the palladium (Table 1, entries 5-7). In the coupling reaction
with the sulfone,12 70% diastereomeric excess was obtained
(Table 1, entry 3).
Scheme 5. Synthesis of Benzylic Carbinol with a
Dimethylamino Group in the â Position
Finally, weak selectivity was observed in the coupling with
iodide 3 bearing the stereogenic methoxy with no substituent
in the â position (Table 1, entry 4).
In conclusion, a plausible mechanism responsible for the
high selectivity might reasonably invoke the formation of a
palladacycle during oxidative addition in which palladium
is coordinated to the internal chelating ligand such as a p-tolyl
sulfoxide,26 a p-tolyl thioether (coordination by the sulfur
atom), or a dimethylamino group (coordination by the
nitrogen atom) (Scheme 6).
With the desired aryl iodides in hand, we began the study
of their Suzuki coupling reactions with 2-methoxy-1-naph-
thylboronic acid (Table 1). The reactions were conducted
using as catalyst Pd(OAc)2 with PPh3 and cesium fluoride
as a base in dioxane at reflux.
Scheme 6. Palladacycle Transition State with Sulfoxide
With the p-tolyl thioether instead of the p-tolyl sulfoxide,
the coupling reaction was still very efficient, proceeding with
(21) Bravo, P.; Frigerio, M.; Resnati, G. J. Org. Chem. 1990, 55, 4216-
4218.
(22) Petitou, M.; Duchaussoy, P.; Choay, J. Tetrahedron Lett. 1988, 29,
1389-1390.
(23) Hugues, D. L.; Org. React. 1992, 42, 335-656.
(24) Bayley, H.; Standring, D. N.; Knowles, J. R. Tetrahedron Lett. 1978,
19, 3633-3634.
(25) (a) Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829-832.
(b) Brunet, E.; Gallego, M. T.; Garcia Ruano, J. L.; Alcudia, F. Tetrahedron
1986, 42, 1423-1438.
Considering the case of the sulfoxide, coordination of the
sulfur atom to the palladium should give a rigid six-
membered palladacycle I. At this point, the transmetalation
Org. Lett., Vol. 7, No. 17, 2005
3739

of the naphthyl moiety with the methoxy group in front
would lead to a nonbinding interaction between the stereo-
genic methoxy and the naphthylmethoxy groups (Scheme
7).
Scheme 7. Mechanistic Study
To explain the diastereoselectivity obtained in the coupling
reaction with the sulfone, we propose a coordination of one
of the oxygen atoms to the palladium giving a seven-
membered transition state which is less rigid than the six-
membered transition state and would lead to a less selective
approach (Figure 1).
Figure 1. Palladacycle transition state with sulfone.
In summary, we have shown that the high atropo-
diastereoselectivity obtained in the Suzuki cross-coupling
reaction between aryl halides bearing stereogenic benzylic
carbinols and boronic acids is essentially due to the presence
of an internal chelating ligand â to the stereogenic carbinol
giving a rigid palladacycle as an intermediate. Further
applications of this method to the asymmetric synthesis of
biologically active compounds containing biaryl units are
now in progress.
would take place on the opposite side of the stereogenic
carbinol (pathway B). Isomerization of the trans-palladium
complex II to the cis-complex would occur giving prefer-
entially after reductive elimination one atropo-diastereomer
aR with the naphthylic methoxy group in the back. Approach
Acknowledgment. This work was supported by the
CNRS and Ministe`re de la Recherche. P.-E.B. thanks la
re´gion Alsace for a fellowship.
Supporting Information Available: Experimental pro-
cedures and data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(26) (a)Grennberg, H.; Gogoll, A.; Ba¨ckvall, J.-E. J. Org. Chem. 1991,
56, 5808-5811. (b) Hiroi, K.; Suzuki, Y. Tetrahedron Lett. 1998, 39, 6499-
6502. (c) Garcia-Ruano, J. L.; Gonzalez, A. M.; Lopez-Solera, I.; Masaguer,
J. R.; Navarro-Ranninger, C.; Raithby, P. R.; Rodriguez, J. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1351.
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