"sulfolefin": A mixed sulfinamido-olefin ligand in enantioselective rhodium-catalyzed addition of arylboronic acids to trifluoromethyl ketones

Article abstract of DOI:10.1039/c3ob41888j

Performing catalytic enantioselective carbon-carbon bond forming reactions, especially for the synthesis of tertiary carbinols, is one of the most challenging goals in modern asymmetric synthesis. Herein, we report an efficient enantioselective catalytic

Full text of DOI:10.1039/c3ob41888j

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“Sulfolefin”: a mixed sulfinamido-olefin ligand in
enantioselective rhodium-catalyzed addition of
arylboronic acids to trifluoromethyl ketones†
Cite this: Org. Biomol. Chem., 2014,
12, 1211
Received 16th September 2013,
Accepted 17th December 2013
Victoria Valdivia,a,b Inmaculada Fernández*b and Noureddine Khiar*a
DOI: 10.1039/c3ob41888j
www.rsc.org/obc
Performing catalytic enantioselective carbon–carbon bond trifluoromethylated carbinols with modest yields and ee’s in
forming reactions, especially for the synthesis of tertiary carbinols, most cases.8 The three methods employ P-coordinating
is one of the most challenging goals in modern asymmetric syn- ligands, either as a phosphine, phosphite, or phosphoramidite
thesis. Herein, we report an efficient enantioselective catalytic group. Despite their excellent coordinating behavior, P-based
approach for the 1,2-addition of arylboronic acids to trifluoro- ligands which are generally obtained through multistep syn-
methyl ketones affording tertiary trifluoromethyl-substituted alco- theses suffer moreover from their poor stability toward oxygen,
hols with high yields and good enantioselectivities. The reported which imposes stringent experimental conditions. In sharp
process uses as a catalyst precursor the shelf stable sulfinamido- contrast, sulfinyl-based ligands, which have been scarcely used
olefin ligand 1, “sulfolefin”, obtained on a multigram scale and in as catalyst precursors, present undeniable advantages for their
one step from a sugar derived sulfinate ester.
applications in asymmetric catalysis.9 In this sense, sulfinyl
derivatives are air, oxygen and moisture stable, and are ideally
suited for the construction of diverse metal–ligand complexes
with a well-defined chiral environment as a result of the close
proximity of the chiral sulfur atom to the coordination sphere
of the metal.10 Within our interest in the synthesis and appli-
cations of chiral sulfur derivatives in organic11 and metal-
promoted catalysis,12 we have recently reported that C2-sym-
metric bis-sulfoxides13 and C1 mixed sulfinamido-olefin
ligands are good catalyst precursors in Rh-promoted addition
of boronic acids to activated alkene and ketones in organic
solvents and in water.14
Fluorinated compounds have found extensive application in
the fields of materials, pharmaceuticals and agrochemistry.1
Particularly, the syntheses of chiral tertiary trifluoromethyl-
substituted alcohols have gained increasing interest due to
their unique properties and unusual reactivities.2 In this
context, numerous methods for the trifluoromethylation of
carbonyl compounds have been reported.3 However, enantio-
selective trifluoromethylation is difficult to achieve and good
enantiomeric excesses are rarely reached.4
An alternative strategy for the syntheses of trifluoromethyl
substituted tertiary alcohols would be the addition of boronic
acids to trifluoromethyl ketones, due to the ready availability,
good stability, and non-toxic nature of various boronic acids as
the starting materials.5 However, the formation of tetrasubsti-
tuted carbons via the addition of carbon nucleophiles to
ketones still constitutes a major challenge in synthetic chem-
istry.6 Indeed, only three catalytic enantioselective arylations of
fluorinated ketones have been reported,7,8 affording
Based on these premises, in the present work we report on
the utilization of the simple cinnamylsulfinamide 1 ligand in
the rhodium-catalyzed addition of arylboronic acids to
trifluoromethylketones for the asymmetric synthesis of chiral
trifluoromethylated tertiary alcohols, Fig. 1.
The addition of p-tolylboronic acid 3a to 2,2,2-trifluoroaceto-
phenone 2a was used as a model reaction, and we were
aInstituto de Investigaciones Químicas, C.S.I.C-Universidad de Sevilla, c/. Américo
Vespucio, 49., Isla de la Cartuja, 41092 Sevilla, Spain. E-mail: khiar@iiq.csic.es;
Fax: +34954460565; Tel: +34954489559
bDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad de Sevilla, c/. Profesor García González, 2, 41012 Sevilla, Spain.
E-mail: inmaff@us.es; Fax: +34954556737; Tel: +34954555993
†Electronic supplementary information (ESI) available: Experimental procedures
for the sulfolefin-Rh-catalyzed 1,2 addition of boronic acids to trifluoromethyl
ketones, 1H and 13C spectra and HPLC chromatograms of the adducts 4a–4i are
given. See DOI: 10.1039/c3ob41888j
Fig. 1 Rh-catalyzed addition of boronic acids to trifluoromethyl
ketones using sulfolefin 1 as a ligand.
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Table 1 Solvent effect on the enantioselective rhodium-catalyzed
addition of the arylboronic acids 3a and 3b to the trifluoromethyl ketone
2aa
Table 2 Effect of the base on the enantioselective rhodium-catalyzed
addition of arylboronic acid 3b to trifluoromethyl ketone 2aa
Entry
Base
Yieldb (%)
erc (% ee)
Entry
R
Solvent
Time (h)
Yieldb (%)
erc (% ee)
5
1
2
4
5
K2CO3
K3PO4
Et3N
KOH
KF
63
54
12
—
99
85 : 15 (70%)
82 : 18 (64%)
85 : 15 (70%)
—
1
2
3
4
5
Me
Me
Me
Me
TBME
Dioxane
THF
Et2O
Et2O
20
20
20
3
27
15
0
73
63
83 : 17 (66%)
83 : 17 (66%)
—
84 : 16 (68%)
85 : 15 (70%)
85 : 15 (72%)
a All reactions were conducted using 5 mol% of the ligand together
with 2.5 mol% of [Rh(C2H4)Cl]2. b Isolated product. c Determined by
chiral stationary phase HPLC using Chiralcel OJ-H® column.
OMe
3
a All reactions were conducted using 5 mol% of the ligand together
with 2.5 mol% of [Rh(C2H4)Cl]2. b Isolated product. c Determined by
chiral stationary phase HPLC using a Chiralcel OJ-H® column.
With these results in hand, the scope of the reaction was
pleased to find that the reaction takes place and provides investigated using boronic acids with varied steric and elec-
promising results (Table 1, entries 1–4). Using [Rh(C2H4)Cl]2 tronic nature to different trifluoromethyl ketones. As similar
(2.5 mol%) as the catalyst precursor and “sulfolefin” 1 (5 mol%) enantioselectivities were obtained with potassium carbonate
as the ligand, the addition proceeded at 60 °C for 20 h to and with potassium fluoride, all condensations were con-
provide the desired product 4a in an acceptable ee (66%), ducted with both bases (Table 3, entries 1–14). Lowering the
albeit in low yield in TBME described as the best solvent in the temperature to 40 °C leads to the product in very low ee, so the
three catalytic enantioselective arylations of trifluoromethyl reactions were conducted in Et2O at 60 °C. The reaction is
ketones reported to date (entry 1).7,8 In an attempt to amelio- dependent on the electronic factors of both boronic acids and
rate the yield and enantioselectivity of the process, we con- ketones. In this sense, boronic acids with electron donating
ducted a study using different ethereal solvents (Table 1, substituents on the aryl group gave the products of addition
entries 1–4). The use of dioxane (Table 1, entry 2) afforded the with good yields (compare entries 1–14). While para-substi-
product with identical ee (66%), but in lower conversion (15% tuted aryls could be introduced with acceptable enantio-
isolated yield), while the use of THF (Table 1, entry 3) inhibits selectivities and good yields (Table 3, entries 3–6 and 11–14),
the reaction as no trace of the product 4a was detected in the meta-substituted aryls proceeded with lower ee’s and lower
crude reaction mixture and the starting material was recovered yields (Table 3, entries 1–2 and 7–8). Ketone 2b with a para-
unaltered. Gratifyingly, the use of diethyl ether (Et2O) as the fluoro substituent (Table 3, entries 3–10) gave the corres-
solvent did ameliorate not only the yield (73%) and the ponding tertiary trifluoromethylated alcohols in slightly better
enantioselectivity (68% ee) but also reduced the reaction time yields and enantioselectivities than phenyl ketone 2a and
from 20 hours to only 3 hours (Table 1, entry 4). The use of ketone 2c with a para-chloro substituent (Table 3, entries
p-methoxyphenylboronic acid as a nucleophile afforded the 11–14). In the addition of para-tolyl and para-methoxyphenyl
corresponding tertiary trifluoromethyl alcohol 4b in good yield groups to ketone 2b, the corresponding tertiary alcohols 4d
(65%) and good ee (70%), identifying Et2O as the most suitable and 4e were obtained with high yields and enantioselectivities
solvent in terms of activity and enantioselectivity for this reac- of 78% and 76%, respectively (Table 3, entries 3 and 5). Sur-
tion (Table 1, entry 5).
prisingly, while in general potassium fluoride gave the final
Next, and in order to unravel the effect of the base on the product in higher yield than potassium carbonate, a reversal
reaction, various inorganic and organic bases were screened effect was observed when using the 2-naphthyl boronic acid
on the addition reaction of 4-methoxyphenylboronic acid 3b (Table 3, entries 9 and 10). In this case, the corresponding ter-
with trifluoroacetophenone 2a (Table 2). The use of potassium tiary alcohol 4g was obtained with a significant decrease in
phosphate as a base (Table 2, entry 2) afforded the desired yield from 99%, obtained with potassium carbonate (Table 3,
product 4b with acceptable ee (64%) and modest yield (54%). entry 9), to 33% when potassium fluoride was used as a base
Triethylamine afforded the product with enhanced ee (70%) (Table 3, entry 10).
but in very low yield (Table 2, entry 3), while no product was
With regard to the stereochemical outcome of the reaction,
formed when using potassium hydroxide as a base (Table 2, one must take into account that ligand 1 can coordinate to
entry 4). Satisfyingly, the use of potassium fluoride gave the rhodium in different ways, due to the presence of an alkene
product in almost quantitative yield (99%) and with 72% ee function together with various heteroatoms, namely nitrogen,
(Table 2, entry 5).
sulfur, and oxygen. Nevertheless, previous NMR studies have
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Table 3 Reaction scope of “sulfolefin”-catalyzed enantioselective
rhodium-catalyzed addition of arylboronic acids to trifluoromethyl
ketonesa
Entry
Product
Base
Yieldb (%)
erc,d (% ee)
1
2
K2CO3
KF
35
99
78 : 22 (56%)
74 : 26 (48%)
Fig. 2 Proposed model for the stereochemical outcome of the
3
4
K2CO3
KF
86
64
89 : 11 (78%)
82 : 18 (64%)
reaction.
“sulfolefin” catalyst. We are currently directing our efforts at
enhancing the enantioselectivity of this methodology and its
applications for the syntheses of biologically active molecules.
5
6
K2CO3
KF
90
93
88 : 12 (76%)
86 : 14 (72%)
7
8
K2CO3
KF
29
40
83 : 17 (66%)
84 : 16 (68%)
Acknowledgements
9
10
K2CO3
KF
99
33
72 : 28 (44%)
75 : 25 (50%)
This work was supported by the Ministerio de Economía y Com-
petitividad (grant no. CTQ2010-21755-CO2-00). We acknowledge
CITIUS for NMR facilities.
11
12
K2CO3
KF
58
90
83 : 17 (66%)
81 : 19 (62%)
Notes and references
13
14
K2CO3
KF
61
99
87 : 13 (74%)
82 : 18 (64%)
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