Asymmetric rhodium-catalyzed 1,4- and 1,2-additions of arylboronic acids to activated ketones in water at room temperature using a mixed sulfur-olefin ligand

Article abstract of DOI:10.1002/adsc.201201065

Performing catalytic enantioselective reactions, especially enantioselective carbon-carbon bond forming reactions, in water without using any organic solvents is one of the important goals in modern asymmetric synthesis. Herein, we report an efficient enantioselective micellar catalytic approach for the 1,4-addition of arylboronic acids to cyclic ketones. Noteworthy, applying the same catalytic system we have also developed the first addition of boronic acids to the more challenging α-keto carbonyl compounds in water, affording tertiary carbinols with high yields and high enantioselectivities. Beside the mild conditions used, the reported processes use as catalyst precursor the robust sulfinamido-olefin mixed ligand 1 obtained on a multigram scale and in one step from a sugar-derived sulfinate ester. Copyright

Full text of DOI:10.1002/adsc.201201065

COMMUNICATIONS
DOI: 10.1002/adsc.201201065
Asymmetric Rhodium-Catalyzed 1,4- and 1,2-Additions of
Arylboronic Acids to Activated Ketones in Water at Room
Temperature Using a Mixed Sulfur-Olefin Ligand
Noureddine Khiar,a,* Victoria Valdivia,+a,b ꢀlvaro Salvador,+a,c Ahmed Chelouan,b
Ana Alcudia,b and Inmaculada Fernꢁndezb,*
a
Asymmetric Synthesis and Functional Nanosystem Group, Instituto de Investigaciones Quꢂmicas (IIQ), C.S.I.C –
Universidad de Sevilla, C/Amꢃrico Vespucio 49, 41092 Seville, Spain
Fax : (+34)-95-560-0426; phone: (+34)-95-448-9559; e-mail: khiar@iiq.csic.es
Departamento de Quꢂmica Orgꢁnica y Farmacꢃutica, Universidad de Sevilla, C/Profesor Garcꢂa Gonzꢁlez 2, 41012
b
Seville, Spain
Fax : (+34)-95-455-6737; phone: (+34)-95-455-5993; e-mail: inmaff@us.es
Present address: Institute of Organic Chemistry, University of Zꢄrich, Winterthurerstrasse 190, CH-8059 Zꢄrich,
c
Switzerland
+
These authors contributed equally to this work.
Received: December 4, 2012; Revised: February 25, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201065.
Abstract: Performing catalytic enantioselective re-
actions, especially enantioselective carbon-carbon
bond forming reactions, in water without using any
organic solvents is one of the important goals in
modern asymmetric synthesis. Herein, we report an
efficient enantioselective micellar catalytic ap-
proach for the 1,4-addition of arylboronic acids to
cyclic ketones. Noteworthy, applying the same cata-
lytic system we have also developed the first addi-
tion of boronic acids to the more challenging a-
keto carbonyl compounds in water, affording terti-
ary carbinols with high yields and high enantiose-
lectivities. Beside the mild conditions used, the re-
ported processes use as catalyst precursor the
robust sulfinamido-olefin mixed ligand 1 obtained
on a multigram scale and in one step from a sugar-
derived sulfinate ester.
Therefore, performing catalytic enantioselective reac-
tions, especially enantioselective carbon-carbon bond
forming reactions, in water without using any organic
solvents is a central goal in modern asymmetric syn-
thesis.[3] Nevertheless, despite the great efforts to con-
duct aqueous asymmetric processes, achieving high
enantiosectivities has proved to be extremely chal-
lenging. In addition to solubility constraint reasons,
many transition metal-based catalysts and intermedi-
ates are highly instable in water. A practical solution
to these drawbacks is the creation of a hydrophobic
nanoenvironment within the water phase able to solu-
bilize and stabilize both the catalyst and the substrate.
This has been usually achieved by the use of amphi-
philes which, above their critical micellar concentra-
tion (CMC), self-organize into micelles with a hydro-
phobic inner core and hydrophilic outer phase that
are able to host hydrophobic molecules.[4] On the
À
Keywords: enantiopure tertiary carbinols; enantio-
selective catalysis in water; green chemistry; micel-
lar catalysis; mixed sulfur-olefin ligand
other hand, within C C bond formation reactions, the
Rh(I)-catalyzed addition of boronic acids to activated
ketones is one of the most salient approaches.[5] Al-
though many attempts have been made to carry out
these transformations in water, only two successful
cases have been reported for the special case of the
asymmetric 1,4-addition of boronic acids to cyclic ke-
The utilization of water as a cheap, safe and green tones,[6] using an amphiphilic resin-supported BINAP
solvent in organic transformations is receiving an in- ligand at 1008C,[7a] and
a hydrophilic bicycle-
creasing attention in academia and in chemical indus-
[3.3.0]diene ligand.[7b] In the case of the more chal-
ACHTUNGTRENNUNG
tries.[1] Among these transformations, those allowing lenging 1,2-addition, and as far as we know, no aque-
the preparation of optically pure compounds, ubiqui- ous approach has been reported yet. Herein, we dis-
tous in pharmaceuticals, are of particular interest.[2] close a highly efficient and enantioselective protocol
Adv. Synth. Catal. 2013, 355, 1303 – 1307
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1303

Noureddine Khiar et al.
COMMUNICATIONS
Table 1. Effect of surfactants on the Rh-catalyzed 1,4-addi-
tion of phenylboronic acid 3 on cyclohexenone 2 in water.[a]
Figure 1. Enantioselective 1,4- and 1,2-addition of arylbor-
onic acids to activated ketones using sulfolefin ligand 1.
for the 1,4- and 1,2-addition of boronic acid to alke-
nones, a-keto esters and a-diketones in water at room
temperature (Figure 1).
Within our interest in the synthesis and applications
of chiral sulfur derivatives in organic and metal-pro-
moted catalysis,[8] we have recently reported that
mixed sulfinamido-olefin ligands, “sulfolefins”, are
highly efficient in the 1,4-addition of boronic acids to
cyclic ketones.[9] Inspired by the high efficiency of the
simple cinnamylsulfinamide 1, as catalyst precursor,
we decided to assay the system in pure water. Using
the addition of phenylboronic acid 3 to cyclohexen-
ACHTUNGTRENNUNG
one 2 as model reaction,[10] we were pleased to find
that the reaction takes place and affords the desired
compound 4 with 68% yield and an interesting 88%
ee (Scheme 1).
Encouraged by this positive result, we decided to
enhance the yield and the enantioselectivity of the
process through the application of micellar catalysis.
A number of commercially available amphiphiles in-
cluding a cationic (CTAB), anionic (SDS), and two
neutral ones (Brijꢆ 58, and PTS), known to self-or-
ganize in nanometer-size micelles, were screened in
the model reaction (Table 1).
[a]
All reactions were conducted by mixing the ligand to-
gether with [RhACTHNUGTRNEUNG(C2H4)2Cl]2 in surfactant/water solution
at room temperature.
Isolated product.
Catalytic activity proved to be highly dependent on
the nature of the surfactant used, affording in most
cases the desired product 4 with better yield and
[b]
[c]
Determined by chiral stationary phase HPLC
enantioselectivity than in water alone. The cationic
micellar medium formed by CTAB afforded the prod-
uct 4S with 90% yield and 84% ee (entry 2), similar
to the result obtained in water alone. In contrast, the
use of anionic surfactant SDS leads to the formation
of the desired compound 4S in excellent yield and
enantioselectivity (entries 3 and 4). The same result
was obtained with the neutral amphiphile Brijꢆ 58
Scheme 1. Enantioselective 1,4-addition of phenylboronic
acid 3 to cyclohexenone 2 in pure water.
1304
asc.wiley-vch.de
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1303 – 1307

Asymmetric Rhodium-Catalyzed 1,4- and 1,2-Additions of Arylboronic Acids to Activated Ketones
Table 2. Substrate scope of the Rh-catalyzed 1,4-addition of
(entry 5), and the vitamin E-derived amphiphile
PTS[11] (entries 7 and 8), where the product was ob-
tained in quantitative yield and mostly as a single
enantiomer. Efforts to reduce the catalyst loading
show that use of 2.5 mol% of the sulfolefin
boronic acids to cycloalkenones in water/surfactant media.[a]
1 {1.25 mol% of [RhACHTNUTRGNE(UGN C2H4)2Cl]2}, in the presence of
SDS afforded the product with moderate yield (68%)
and moderate enantioselectivity (Table 1, entry 4).
Interestingly enough, in PTS/water solution, lower-
ing the ligand concentration to 1.25 mol%
{0.65 mol% of [RhACHTNUTRGNE(UNG C2H4)2Cl]2} still affords the prod-
uct with acceptable yield (72%) and an interesting
94% ee (Table 1, entry 9). It is worthy of mention that
under the best conditions, the Rh(I) catalyst derived
from (S)-BINAP (5 mol%) gave product 4 with very
low yield (11%) and a disappointing 22% ee (Table 1,
entry 10), highlighting the efficiency of sulfolefin
ligand 1.
Based on these results, we can conclude that both
neutral and anionic amphiphiles are able to form an
adequate milieu for the reaction to take place with
complete enantioselectivity and quantitative yield. In
this sense, a TEM analyses of the reaction media
showed the formation of spherical nanomicelles both
in the case of SDS/water and in the case of PTS/water
(see the Supporting Information for TEM images),
which support the hypothesis that the reactions are
taking place within the micelles.
Next, and in order to determine the reaction scope,
we conducted a study using different cyclic ketones
and different boronic acids in the presence of either
SDS or PTS as surfactants (Table 2).
Excluding the case of cyclic lactone 7 (entries 5 and
6), where the product 10S was obtained as a single
enantiomer in SDS and PTS micellar media, the later
was better both in terms of reactivity and enantiose-
lectivity (compare entry 1 with entry 2, entry 3 with
entry 4, and entry 5 with entry 6). Indeed the product
8S, resulting from the addition of phenyl boronic acid
on cyclopentenone 5 (entry 2), and the product 9S,
deriving from the addition of phenylboronic acid on
cycloheptenone 6 (entry 4), were obtained as single
enantiomers in quantitative yields when PTS was
used as amphiphile. The same trend was observed in
the case of addition of other arylboronic acids to cy-
[a]
All reactions were conducted using 5 mol% of the ligand
together with 2.5 mol% of [RhACHTNUGTRNE(UNG C2H4)2Cl]2 in water at
room temperature, in the presence of SDS or PTS.
Chromatographically isolated product.
Determined by chiral stationary phase HPLC.
The reaction was conducted in 3M NaCl, PTS/water.
[b]
[c]
[d]
Inspired by the success obtained in the 1,4-addition
clohexenone, where SDS was less efficient than PTS of boronic acids to cyclic alkenones, we decided to
(compare entry 7 with entry 8, entry 9 with entry 10, see whether this approach could be extended to the
and entry 11 with entry 12). Additionally, at this point more challenging 1,2-addition to a-keto-carbonyl
of our research we have found that the addition of compounds. Tetrasubstituted carbon stereocenters in
NaCl to the PTS solution ameliorates substantially general, and chiral b-hydroxy carbonyl compounds in
the results.[12] Using the optimal conditions (PTS with particular, are commonly found in numerous classes
3M NaCl), various phenylboronic acids with different of natural products and pharmaceutical intermedi-
steric and electronic characters were added to cyclo- ates.[13] Although a number of methods have been de-
hexenone affording the corresponding adducts 11–13 veloped to selectively access this versatile structural
with excellent yields and enantioselectivities (en- motif, the preparation of compounds containing these
tries 8, 10, and 12).
centers with high enantioselectivity is fairly limited.[14]
Additionally, and as far as we know, there is no aque-
Adv. Synth. Catal. 2013, 355, 1303 – 1307
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1305

Noureddine Khiar et al.
COMMUNICATIONS
Table 3. Substrate scope of the Rh-catalyzed 1,2-addition of
boronic acids to a-keto carbonyl compounds in water/surfac-
tant media.[a]
enantioselectivities depending on the surfactant used
(entries 1–4). In this case, the use of PTS in the pres-
ence of 3M NaCl also afforded the products of addi-
tion with better enantioselectivity than obtained with
SDS. Using the optimized conditions, products 16
(entry 2) and 17 (entry 4), derived from the addition
of p-tolyl- and p-methoxyphenylboronic acids, were
obtained with 86% and with 92% ee respectively.
Next, we turned our attention to the addition of bor-
onic acids to the more challenging a-diketone sub-
strates in order to obtain tertiary a-hydroxy ketones
(entries 5–9). Pleasingly, the addition of p-tolylboron-
ic acid to benzil 15 afforded the tertiary hydroxy
ketone 18 with the S absolute configuration in 87%
yield and 99% ee (entry 5). Addition of other boronic
acids such as p-methoxy- and p-chlorophenylboronic
acids led to the formation of the corresponding terti-
ary alcohols 19 (entry 7) and 20 (entry 9) with moder-
ate to good yields and with excellent enantioselectivi-
ties (96 and 98% ee, respectively).
In summary, we have developed a green,[15] and ef-
ficient micellar catalytic approach for the 1,4-addition
of arylboronic acids to cyclic ketones which permits
the synthesis of chiral ketones in high yields and high
enantioselectivities. Noteworthy, applying the same
catalytic system we have also developed the first addi-
tion of boronic acids to the more challenging a-keto
carbonyl compounds in water, affording tertiary carbi-
nols with high yields and high enantioselectivities.
The reactions take place under very mild conditions
using water as solvent and at room temperature, in
contrast to the conditions generally required for such
transformations in organic solvents. Additionally, the
processes use the robust sulfolefin ligand 1 with a sul-
finyl sulfur as sole chiral center as catalyst precursor,
which can be obtained on a multigram scale and in
one step from a sugar-derived sulfinate ester.[9,16] The
applications of the present system in other organic
and metal-promoted enantioselective processes, are
being actively investigated in our laboratories, and
will be reported in due course.
[a]
All reactions were conducted using 5 mol% of the ligand
together with 2.5 mol% of [RhACHTNUGTRNE(UNG C2H4)2Cl]2 in water at
room temperature, in the presence of SDS or 3M NaCl/
PTS.
Chromatographically isolated product.
Determined by chiral stationary phase HPLC.
Experimental Section
[b]
[c]
Typical Procedure for the Rhodium-Catalyzed 1,4-
and 1,2-Addition of Boronic Acids to Activated
Ketones
ous catalytic approach for the enantioselective prepa-
ration of these important intermediates, making this
an excellent goal to test the effectiveness of our
method. We firstly assayed our system, in the addition
of arylboronic acids to a-keto esters for the asymmet-
ric synthesis of a-hydroxy esters and the results are
summarized in Table 3. Using ethyl phenylglyoxylate
14 as electrophilic partner, we were pleased to find
that the additions take place at room temperature af-
A Schlenk tube, equipped with a magnetic stirring bar, was
charged with [{RhACTHNUTRGNE(UNG CH2CH2)2Cl}2] (6.0 mg, 5 mol%), sulfole-
fin 1 (7.1 mg, 2.5 mol%) and water (1.4 mL) containing the
surfactant at or over its critical micellar concentration was
added and the mixture was stirred for 15 min at room tem-
perature. Then, the arylboronic acid (1.2 mmol, 2 equiv.),
the a,b-unsaturated substrate or dicarbonyl substrate
(0.6 mmol, 1 equiv.) and 2.5M KOH aqueous solution were
fording the desired products in moderate to good added. The reaction mixture was stirred for 24 h, and then
1306
asc.wiley-vch.de
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1303 – 1307

Asymmetric Rhodium-Catalyzed 1,4- and 1,2-Additions of Arylboronic Acids to Activated Ketones
extracted with AcOEt (2 mL). The solvent was removed
under vacuum to afford the crude product which was subse-
quently purified by flash chromatography on silica gel.
Fernꢁndez, V. Valdivia, M. Pernia Leal, N. Khiar, Org.
Lett. 2007, 9, 2215; c) I. Fernꢁndez, A. Alcudia, B.
Gori, V. Valdivia, M. V. Garcꢂa, N. Khiar, Org. Biomol.
Chem. 2010, 8, 4388.
[9] N. Khiar, A. Salvador, A. Chelouan, A. Alcudia, I.
Fernꢁndez, Org. Biomol. Chem. 2012, 10, 2366.
[10] For other recent reports using chiral sulfur-olefin li-
gands in Rh-catalyzed asymmetric catalysis see: a) T.
Thaler, L.-N. Guo, A. K. Steib, M. Raducan, K. Kara-
ghiosoff, P. Mayer, P. Knochel, Org. Lett. 2011, 13,
3182; b) X. Feng, Y. Wang, B. Wei, J. Yang, H. Du,
Org. Lett. 2011, 13, 3300; c) G. Chen, J. Gui, L. Li, J.
Liao, Angew. Chem. 2011, 123, 7823; Angew. Chem.
Int. Ed. 2011, 50, 7681; d) X. Feng, B. Wei, J. Yang, H.
Du, Org. Biomol. Chem. 2011, 9, 5927; e) F. Xue, X.-C.
Li, B.-S. Wan, J. Org. Chem. 2011, 76, 7256; f) Y. Wang,
X. Feng, H. Du, Org. Lett. 2011, 13, 4954.
Acknowledgements
This work was supported by the Ministerio de Economꢀa y
Competitividad (grant No. CTQ2010-21755-CO2-00), and the
Junta de Andalucꢀa (P07-FQM-2774). A. Chelouan thanks
the Ministerio de Asuntos Exteriores y de Cooperacion for
a predoctoral MAEC-AECID. We gratefully thank CITIUS
for NMR facilities
References
[11] B. H. Lipshutz, S. Ghorai, Aldrichimica Acta 2008, 41,
59.
[12] B. H. Lipshutz, S. Ghorai, W. W. Y. Leong, B. R. Taft, J.
Org. Chem. 2011, 76, 5061.
[13] a) J. L. Stymiest, V. Bagutski, R. M. French, V. K. Ag-
garwal, Nature 2008, 456, 778; b) H. K. Scott, V. K. Ag-
garwal, Chem. Eur. J. 2011, 17, 13124; c) M. Shibasaki,
M. Kanai, Chem. Rev. 2008, 108, 2853.
[1] a) B. Cornils, W. A. Herrmann, Aqueous Phase Organ-
ometallic Catalysis. Concepts and Applications; Wiley,
Weinheim, 2004; b) S. Kobayashi, K. Manabe, Acc.
Chem. Res. 2002, 35, 209.
[2] a) D. Sinou, Adv. Synth. Catal. 2002, 344, 221; b) T.
Dwars, G. Oehme, Adv. Synth. Catal. 2002, 344, 239;
c) J.-P. GenÞt, S. Darses, V. Michelet, Pure Appl. Chem.
2008, 80, 831.
[14] a) R. Shintani, M. Inoue, T. Hayashi, Angew. Chem.
2006, 118, 3431; Angew. Chem. Int. Ed. 2006, 45, 3353;
b) P. Y. Toullec, R. B. C. Jagt, J. G. de Vries, B. L. Ferin-
ga, A. J. Minnaard, Org. Lett. 2006, 8, 2715; c) S. L. X.
Martina, R. B. C. Jagt, J. G. de Vries, B. L. Feringa,
A. J. Minnaard, Chem. Commun. 2006, 4093; d) H.-F.
Duan; J.-H. Xie; X.-C. Qiao; L.-X. Wang; Q.-L. Zhou,
Angew. Chem. 2008, 120, 4423; Angew. Chem. Int. Ed.
2008, 47, 4351; e) Y. Yamamoto, T. Shirai, M. Wata-
nabe, K. Kurihara, N. Miyaura, Molecules 2011, 16,
5020; f) T.-S. Zhu, S.-S.; Jin, M.-H. Xu, Angew. Chem.
2012, 124, 804; Angew. Chem. Int. Ed. 2012, 51, 780.
[15] a) Green Chemistry: Theory and Practice, (Eds.: P. T.
Anastas, J. C. Warner), Oxford University Press, New
York, 2000; b) Green Chemistry and Catalysis, (Eds.:
R. A. Sheldon, I. Arends, U. Hanefeld), Wiley-VCH,
Weinhem, 2007.
[16] Both enantiomers of 1 can be obtained in an enantiodi-
vergent manner using the DAG methodology: see: a) I.
Fernꢁndez, N. Khiar, J. M. Llera, F. Alcudia, J. Org.
Chem. 1992, 57, 6789; b) N. Khiar, I. Ferꢁndez, F. Alcu-
dia, Tetrahedron Lett. 1994, 35, 5719; c) D. Balcells, G.
Ujaque, I. Fernꢁndez, N. Khiar, F. Maseras, J. Org.
Chem. 2006, 71, 6388.
[3] S. Kobayashi, Adv. Synth. Catal. 2002, 344, 219.
[4] a) T. Dwars, E. Paetzold, G. Oehme, Angew. Chem.
2005, 117, 7338; Angew. Chem. Int. Ed. 2005, 44, 7174;
b) B. H. Lipshutz, S. Ghorai, Aldrichimica Acta 2012,
45, 3.
[5] a) G. Berthon, T. Hayashi, in: Catalytic Asymmetric
Conjugate Reactions, (Ed.: A. Cꢇrdova), Wiley-VCH,
Weinheim, 2010, chap. 1; b) K. Yoshida, T. Hayashi, in:
Modern Rhodium-Catalyzed Organic Reactions, (Ed.:
P. A. Evans), Wiley-VCH, Weinheim, 2005, chap. 3.
[6] For recent reviews on rhodium-catalyzed asymmetric
1,4-additions, see: a) P. Tian, H.-Q. Dong, G.-Q. Lin,
ACS Catal. 2012, 2, 95; b) H. J. Edwards, J. D. Har-
grave, S. D. Penrose, C. G. Frost, Chem. Soc. Rev. 2010,
39, 2093; c) C. Defieber, H. Grffltzmacher, E. M. Car-
reira, Angew. Chem. 2008, 120, 4558; Angew. Chem.
Int. Ed. 2008, 47, 4482; d) J. B. Johnson, T. Rovis,
Angew. Chem. 2008, 120, 852; Angew. Chem. Int. Ed.
2008, 47, 840.
[7] a) Y. Otomaru, T. Senda, T. Hayashi, Org. Lett. 2004, 6,
3357; b) C.-G. Feng, Z.-Q. Wang, C. Shao, M.-H. Xu,
G.-Q. Lin, Org. Lett. 2008, 10, 4101.
[8] a) N. Khiar, F. Alcudia, J.-L. Espartero, L. Rodrꢂguez,
I. Fernꢁndez, J. Am. Chem. Soc. 2000, 122, 7598; b) I.
Adv. Synth. Catal. 2013, 355, 1303 – 1307
ꢅ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1307