Axial chirality control during suzuki-miyaura cross-coupling reactions: The tert-Butylsulfinyl group as an efficient chiral auxiliary

Article abstract of DOI:10.1021/ol9020755

An efficient route to a new family of axially chiral biaryl ligands by a Suzuki-Miyaura cross-coupling reaction between ortho,ortho'-disubstituted aryl iodides bearing in ortho position a tert-butyl or p-tolylsulfinyl group and ortho-substituted phenyl boronic acids or esters is described. The comparison between the t-BuSO and p-TolSO groups as chiral controllers is reported. The modularity of the approach is demonstrated by the preparation of a variety of enantiopure axially chiral mixed S/N and S/P ligands.

Full text of DOI:10.1021/ol9020755

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5130-5133
Axial Chirality Control During
Suzuki-Miyaura Cross-Coupling
Reactions: The tert-Butylsulfinyl Group
as an Efficient Chiral Auxiliary
Franc¸oise Colobert,*,† Victoria Valdivia,†,‡ Sabine Choppin,† Fre´de´ric R. Leroux,†
,§
Inmaculada Ferna´ndez,* Eleuterio Alvarez, and Noureddine Khiar*
‡
,‡
´
Laboratoire de Ste´re´ochimie (UMR CNRS 7509), UniVersite´ de Strasbourg (ECPM),
25 rue Becquerel, 67087 Strasbourg Cedex 2, France, Instituto de InVestigaciones
Qu´ımicas, C.S.I.C-UniVersidad de SeVilla, c/Ame´rico Vespucio, 49, Isla de la Cartuja,
41092 SeVilla, Spain, and Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad
de Farmacia, UniVersidad de SeVilla, c/Professor Grac´ıa Gonza´lez, 2, 41012 SeVilla, Spain
francoise.colobert@unistra.fr; khiar@iiq.csic.es; inmaff@us.es
Received September 8, 2009
ABSTRACT
An efficient route to a new family of axially chiral biaryl ligands by a Suzuki-Miyaura cross-coupling reaction between ortho,ortho′-disubstituted
aryl iodides bearing in ortho position a tert-butyl or p-tolylsulfinyl group and ortho-substituted phenyl boronic acids or esters is described.
The comparison between the t-BuSO and p-TolSO groups as chiral controllers is reported. The modularity of the approach is demonstrated
by the preparation of a variety of enantiopure axially chiral mixed S/N and S/P ligands.
Chiral atropo-isomeric biaryl compounds have attracted great
interest in the past decade for two fundamental reasons. First,
it has been shown that there is an intimate relationship
between the absolute configuration of the axial axis and the
activity of a number of pharmacologically relevant biaryl
molecules.1 Second, the large amount of data gathered on
the structure activity relationship in the field of asymmetric
catalysis reveal that axial chirality is one of the most
important structural motifs within successful organic and
organometallic catalysts.2 Although several methods have
been used for the preparation of axially chiral biaryl
compounds, the most general and effective ones are those
based on asymmetric aryl-aryl coupling reactions.
One of the well-known examples of such approaches is
the palladium-catalyzed Suzuki-Miyaura cross-coupling
reaction.3 Both enantioselective and diastereoselective pro-
cedures have been followed for the development of efficient
asymmetric versions of this significant reaction. After the
pioneering work of Uemura at the beginning of the nineties,4
advances in this field have been very scarce, and it was not
† Laboratoire de Ste´re´ochimie, Universite´ de Strasbourg.
‡ Instituto de Investigaciones Qu´ımicas, C.S.I.C-Universidad de Sevilla.
§ Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de
Farmacia, Universidad de Sevilla.
(1) (a) Bringmann, G.; Gu¨nther, 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., Eds.; Springer: Vienna 2001; Vol. 82, pp
1-249. (b) Baudoin, O. Eur. J. Org. Chem. 2005, 4223, and references
cited therein.
(2) (a) Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Brunel, J. M. Chem. ReV. 2005, 105, 857.
(3) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
10.1021/ol9020755 CCC: $40.75
Published on Web 10/19/2009
 2009 American Chemical Society

until the past few years that efficient enantioselective methods
were reported.5 However, the new methods on record, which
include the use of palladium nanoparticles5g and solid
supported catalysts,5h deal mainly with the coupling of rather
simple substrates. Surprisingly, diastereoselective approaches
with chiral auxiliaries, presumably less substrate dependent,
have been rarely investigated, and up to now only three kinds
of atropo-diastereoselective Suzuki-Miyaura coupling reac-
tions were reported.6 On the other hand, although sulfoxides
have proved to be efficient chiral controllers in asymmetric
synthesis especially in C-C bond formations,7 only a few
examples are known in asymmetric transition metal-catalyzed
reactions,8 and their use in a diastereoselective Suzuki-
Miyaura cross-coupling is still unprecedented.
On the basis of these premises, we supposed that the use
of aryl iodide having in the ortho position either the widely
used p-tolyl sulfinyl group 1a or the more hindered tert-
butyl sulfinyl counterpart 1b may be suitable for the
development of a diastereoselective Suzuki-Miyaura cross-
coupling reaction. Indeed, this was the case, as the condensa-
tion of iodide 1b with various aryl boronic acids or esters
2a-g afforded a new family of atropo-enantiopure biaryl
ligands 3 bearing different ortho and ortho′ substituents on
each aromatic unit (Figure 1). For the preparation of
Scheme 1. Synthesis of Enantiopure Aryl Iodides 1a,b
or with enantiopure (RS)-diacetone-D-glucose tert-butylsul-
finate10 5 to give the corresponding enantiopure sulfoxides
in good to excellent yields. Ortholithiation with LDA (-78
°C, THF) followed by addition of iodine at -78 °C afforded
the aryl iodides 1a,b.
Next, we studied the Suzuki-Miyaura cross-coupling
reaction between the aryl iodide tethered sulfoxides 1a,
1b and the boronic acids 2a-g, and the results are
summarized in Table 1. In the case of aryl iodide 1a with
a p-tolylsulfinyl group (Table 1, entries 1-5), we found
that the use of conditions established for hindered
Suzuki-Miyaura coupling reactions afforded the biaryl
compounds in good to excellent yields and modest to
variable diastereoselectivities.11 Disappointingly low at-
ropo-diastereoinduction was obtained especially in the
reaction between the iodide 1a and the o-methoxyphenyl
boronic acid 2b (Table 1, entry 2).
To explain the low diastereoselectivity for compound 3ab
(45:55, Table 1, entry 2), we studied its racemization rate at
different temperatures. At 100 °C, complete racemization
was obtained after 45 min. Thus, the torsional barrier of this
compound is too low, resulting in a rapid racemization under
the coupling conditions. On the other hand, the highest
atropo-diastereoselectivity was observed in the coupling
reaction between the iodide 1a and naphthyl boronic acid
2f affording the corresponding biaryl compound in 50% yield
and 80:20 diastereomeric ratio (Table 1, entry 5).
The use of the iodide 1b bearing the more sterically
hindered tert-butylsulfinyl group in the Suzuki-Miyaura
cross coupling turned out to be a more challenging synthetic
Figure 1. Atropo-diastereoselective Suzuki-Miyaura cross-
coupling reaction.
(6) (a) Kamikawa, K.; Uemura, M. Synlett 2000, 938. (b) Lipshutz, B. H.;
Keith, J. M. Angew. Chem., Int. Ed 1999, 38, 3530. (c) Baudoin, O.; De´cor,
A.; Cesario, M.; Gue´ritte, F. Synlett 2003, 13, 2009. (d) Broutin, P.-E.;
Colobert, F. Org. Lett. 2003, 5, 3281. (e) Broutin, P.-E.; Colobert, F. Org.
Lett. 2005, 7, 3737.
enantiopure iodides 1a,b, we developed a practical two-step
procedure starting from commercially available 3-bromoani-
sole. The synthesis depicted in Scheme 1 started with
condensation of the Grignard reagent of the anisyl bromide
either with enantiopure (SS)-menthyl p-toluenesulfinate9 4
(7) (a) Solladie´, G.; Carren˜o, M. C. In Organosulfur Chemistry: Synthetic
Aspects; Page, P. C. B., Ed.; Academic Press: New York, 1995; p 1. (b)
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Tetrahedron:
Asymmetry 1997, 8, 1339. (c) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717.
(d) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
(8) (a) Colobert, F.; Hanquet, G.; Lanners, S.; Solladie´, G. ArkiVoc 2003,
7, 328. (b) Ferna´ndez, I.; Khiar, N. In Organosulfur Chemistry in
Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2008; p 275.
(4) Uemura, M.; Nishimura, H.; Hayashi, T. Tetrahedron Lett. 1993,
34, 107.
(5) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
(b) Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723. (c)
Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025. (d) Mikami, K.;
Miyamoto, T.; Hatano, M. Chem. Commun. 2004, 2082. (e) Genov, M.;
Almorin, P.; Espinet, P. Chem. Eur. J. 2006, 12, 9346. (f) Bermejo, A.;
Ros, A.; Fernández, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2008, 130,
15798. (g) Sawai, K.; Tatumi, R.; Nakahodo, T.; Fujihara, H. Angew. Chem.,
Int. Ed. 2008, 47, 6917. (h) Uozumi, Y.; Matsuura, Y.; Arakawa, T.;
Yamada, Y. M. A. Angew. Chem., Int. Ed. 2009, 48, 2708.
(9) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1986, 173.
(10) (a) Ferna´ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789. (b) Khiar, N.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett.
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Org. Lett., Vol. 11, No. 22, 2009
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the iodide 1b and the boronic ester 2d afforded product 3bd
in high yield (86%) and an excellent 95:5 diastereomeric
ratio (Table 1, entry 7). It is worth mentioning that under
the same conditions, the Suzuki-Miyaura coupling reaction
between the p-tolylsulfinyl derivative 1a and the same
boronic ester 2d gave the biaryl compound 3ad in 83% yield
and with low diastereoselectivity (65:35 ratio of both atropo-
diastereomers) (Table 1, entry 4). Better diastereoselectivity
was obtained in the case of the coupling of 1b and the
naphthyl boronic acid 2f, where the biaryl compound 3bf
was obtained in an excellent 97:3 diastereomeric ratio.
Interestingly, even the electron poor boronic acid 2e and the
boronic acid 2g with a coordinating sulfur atom could be
coupled under these conditions, affording the functionalized
biaryl compounds with interesting 75:25 and 85:15 diaster-
eomeric ratios, respectively (Table 1, entries 8 and 10). Taken
all together, these results show the superiority of the tert-
butylsulfinyl group compared to the widely used p-tolyl-
sulfinyl group as chiral auxiliary in the diastereoselective
Suzuki-Miyaura coupling reaction.
Table 1. Atropo-Diastereoselective Suzuki-Miyaura
Cross-Coupling Reaction with a p-Tolyl and a tert-Butylsulfinyl
Group As Chiral Auxiliarya
One of the main characteristics of the present method is
its ability to afford functionalized and modular biaryl
systems. Hence, in order to prepare enantiopure biarylamines,
important intermediates in the synthesis of biologically
relevant compounds, and in the synthesis of nitrogen based
chiral ligands, we performed the deprotection of enantiopure
Boc-protected biaryls. Treatment of the biarylamines 3ad
and 3bd with TFA in CH2Cl2 gave, after flash chromatog-
raphy, the free biaryl amines 4ad and 4bd as a single
atropoisomer in 75% and 76% yield, respectively (Scheme
2). The versatility of enantiopure biarylamine 4bd was further
Scheme 2. Synthesis of Biarylamines 4ad and 4bd
demonstrated by its transformation to a number of mixed
ligands. Condensation of 4bd with benzaldehyde in the
presence of activated molecular sieve afforded the axially
chiral imino sulfoxide 5. The reduction of the sulfinyl group
by treatment with trichlorosilane and triethylamine in toluene
at reflux affords the corresponding electron-rich enantiopure
thioether 6 in excellent yields. Recently, we and others have
shown that mixed S/P ligands are excellent precursors for
the synthesis of efficient catalysts with wide applicability.13
Condensation of diphenylchlorophosphine with 6 afforded
axially chiral mixed S/P ligand 7 in good yield, while the
condensation of o-diphenylphosphine benzaldehyde with 6
in the presence of anhydrous copper sulfate gave the S/N/P
ligand 8 in excellent yield (Scheme 3).
a Reaction conditions: Method A: aryliodide (1 equiv), boronic acid
(2 equiv), Pd(OAc)2 (10 mol %), dppf (30 mol %), CsF (4 equiv), dioxane,
reflux. Method B: Pd(OAc)2 (10 mol %), S-Phos (15 mol %), Cs2CO3
(4 equiv), dioxane/H2O, 70 °C. b Determined by 1H NMR on the crude
mixture. c DMF/H2O was used as solvent. d Mixture of both diastereomers.
goal. After testing several Suzuki-Miyaura coupling reaction
conditions, we have found that those described by Buchwald,
slightly modified,12 afforded the coupling products in good
yields and in good to excellent diastereoselectivities (Table
1, 6-10). The Suzuki-Miyaura coupling reaction between
(12) Walker, S. D.; Barder, T. E.; Martinelli, J. L.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. These conditions were found to
work well also for the coupling of iodide 1a.
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Org. Lett., Vol. 11, No. 22, 2009

Scheme 3. ORTEP Diagram of Enantiopure Biarylamine 4bd
and the Synthesis of Some Useful Sulfur-Based Mixed Ligands
Starting from 4bd
Figure 2. Model explaining the stereochemical outcome of the
Suzuki-Miyaura coupling.
of this change of coordination type are geometrical, steric,
and mainly electronic due to the strong trans influence of
the C-donor.15 Under basic conditions, the approximation
of the boronate 2d to the complex 1b′ in the transmetalation
step should take place with minimization of steric hindrance
affording after reductive elimination compound 3bd.
Finally, to get better insight into the high diastereoselection
observed with the tert-butylsulfinyl group, suitable crystals
of the amine 4bd were obtained as well as the structure
(RS,aR),14 which was determined by X-ray analysis. Interest-
ingly, there is a strong intramolecular hydrogen bond between
the arylamine and the methyl ether, which may be important
in the conformational stability of the molecule, and on its
catalytic behavior. To explain the diastereoselectivity ob-
served in the Suzuki-Miyaura coupling, we invoke as a first
step an oxidative insertion of the palladium atom into the
C1-I bond of the aryl iodide sulfoxide 1b giving the five-
member-ring palladacycle 1b′ (Figure 2).
In conclusion, tert-butylsulfinyl groups in the ortho posi-
tion of aryliodides allowed the highly atropo-diastereose-
lective synthesis of biaryls by a Suzuki-Miyaura cross-
coupling reaction. This methodology showed the efficiency
of the tert-butylsulfinyl group compared to the p-tolylsulfinyl
group as a chiral controller. An access to various trisubsti-
tuted biaryl ligands in atropo-diastereomerically pure form
is reported. We are currently investigating the use of these
chiral biaryl ligands in asymmetric catalysis.
The proposed coordination of the ambidentate sulfoxide
group to the palladium atom is through the oxygen atom,
instead of the lone pair of sulfur in contrast to known
S-bonding of the sulfoxide to soft metals. The main reasons
Acknowledgment. We thank the Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (grant No. CTQ2006-
15515-CO2-01 and CTQ2007-61185), la Junta de Andaluc´ıa
(grant P07-FQM-2774).
(13) (a) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;
Gagne, M. R. J. Am Chem Soc. 2000, 122, 7905. (b) Manchen˜o, O. G.;
Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456. (c)
Supporting Information Available: Experimental pro-
cedures for the synthesis and characterization of all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
´
Khiar, N.; Navas, R.; Sua´rez, B.; Alvarez, E.; Ferna´ndez, I. Org. Lett. 2008,
10, 3697.
(14) Crystallographic data (excluding structure factors) for structure 4bd
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC-706230.
Copies of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: (internat.) + 44 1223/
336-033; e-mail: deposit@ccdc.cam.ac.uk].
OL9020755
(15) Nonoyayama, N.; Kiyohiko, N. Polyhedron 1999, 18, 533.
Org. Lett., Vol. 11, No. 22, 2009
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