An Efficient and Practical Method for the Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols

Article abstract of DOI:10.1002/adsc.201701212

An efficient sulfinamide/olefin based chiral ligand, MetSulfolefin, has been developed for the enantioselective rhodium-catalysed addition of aryl-boronic acids to trifluoromethyl ketones. This shelf-stable ligand is insensitive to air, oxygen and moisture, and it is obtained in only two high yielding steps from cheap commercially available (R)-tert-butanesulfinamide. The new ligand tolerates the use of hindered boronic acids and leads to the formation of a series of chiral trifluoromethyl-substituted tertiary carbinols in high yields and excellent enantioselectivities (up to >99% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.201701212

Title: An efficient and practical method for the enantioselective
synthesis of tertiary trifluoromethyl carbinols.
Authors: Lorenzo G. Borrego, Rocío Recio, Manuel Alcarranza,
Inmaculada Fernández, and Noureddine Khiar
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701212
Link to VoR: http://dx.doi.org/10.1002/adsc.201701212

10.1002/adsc.201701212
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An efficient and practical method for the enantioselective
synthesis of tertiary trifluoromethyl carbinols
Lorenzo G. Borrego,a, ∫ Rocío Recio,a, ∫ Manuel Alcarranza,a Noureddine Khiar,b* and
Inmaculada Fernández.b*
a
Departamento de Química Orgánica y Farmacéutica, Universidad de Sevilla. C/ Profesor García González 2, 41012
Seville, Spain.
Phone: +34954556735; e-mail: inmaff@us.es
Departamento de Química Bioorgánica, Instituto de Investigaciones Químicas (IIQ), C.S.I.C-Universidad de Sevilla.
b
C/ Américo Vespucio 49, 41092, Seville, Spain
Fax: +34955600426; Phone: +34954489559; e-mail: khiar@iiq.csic.es
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
compounds and aldehydes,[6] the addition of carbon
Abstract. An efficient sulfinamide/olefin based chiral
ligand, MetSulfolefin, has been developed for the nucleophiles to trifluoromethyl ketones is still a
enantioselective rhodium-catalysed addition of aryl-boronic
acids to trifluoromethyl ketones. This shelf-stable ligand is
insensitive to air, oxygen and moisture, and it is obtained in
only two high yielding steps from cheap commercially
available (R)-tert-butanesulfinamide. The new ligand
tolerates the use of hindered boronic acids and leads to the
formation of a series of chiral trifluoromethyl-substituted
tertiary carbinols in high yields and excellent
enantioselectivities (up to >99% ee).
challenging synthetic problem, as the methods
developed so far, generally afford the fluorinated
compounds with a tetrasubstitued chiral carbon with
moderate yields and ee’s.[7] In the few approaches
developed for this transformation, the use of P-
coordinating chiral ligands containing a phosphine,[4b]
phosphite[4f] or phosphoradimite group[4a] prevails. Of
these ligands, the best results have been obtained with
the C2-symmetric P-chiral ligands BIPOPs,[4b]
developed initially in the laboratories of Boeringer
Keywords: Tertiary trifluoromethylcarbinols; Chiral
sulfinamide-olefin; Enantioselective rhodium-catalysed
arylation; Shelf-stable ligand; Cost effective synthetic
approximation
[8]
Ingelheim,
whose synthesis require an arduous
process of more than 10 steps of which one is a
kinetic resolution. [9]
In the field of asymmetric catalysis, ligand design has
played a central role for the development of efficient
[10]
metal and organo-catalysed processes.
However,
The preparation of organofluorine compounds is an
important goal in modern synthetic chemistry,
consequence of their significance in important fields
including pharmaceuticals, agrochemicals, material
science and catalysis.[1] Particularly enantiomerically
enriched trifluoromethyl-substituted alcohols having
modern asymmetric catalysis requires ligands that are
not only highly enantioselective but also structurally
simple, chemically stable, and that both enantiomers
are easily accessible by practical, cost effective
synthetic approximations. In this sense, sulfinyl-
based ligands present indubitable advantages for their
application in asymmetric catalysis. [11] They are air,
oxygen, and moisture stable, and currently a number
of highly efficient approaches allow the rapid
synthesis of both enantiomers of sulfinyl-based
ligands and to easily modulate their structure.[12]
Moreover, and much like the synthetically
challenging P-chiral phosphines, they are ideally
suited for the construction of diverse metal-ligand
complexes with a well-defined chiral environment
due to the close proximity of the chiral sulfur atom to
the coordination sphere of the metal. Within the
chiral sulfinyl ligands developed recently, mixed
sulfur/olefin ligands have shown excellent behaviour
in Rh-catalysed asymmetric catalysis. [13]
a
tetrasubstitued chiral center are important
compounds with remarkable biological activities.[2]
Thus, the preparation of enantiomerically pure
tertiary trifluoromethyl carbinols has been a standing
area of interest in the last two decades. In this sense,
numerous methods for the trifluoromethylation of
carbonyl compounds have been attempted affording
in general low enantioselectivities.[3] A significant
alternative that has been lately carried out is the
asymmetric
rhodium-catalysed
addition
of
arylboronic acids to trifluoromethyl ketones.[4]
Boronic acids are attractive nucleophiles because of
their wide availability, good stability and non-toxic
nature apart from being compatible with a large range
of functional groups.[5] In contrast to the Rh-catalysed
addition of boronic acids to -unsaturated carbonyl
1
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
Scheme 1: Synthesis of Sulfinamide-olefin derivatives 1-5 (C.C stands for column chromatography).
In
particular,
simple
tert-butylsulfinamide
corresponding -unsaturated carbonyl compound
7-11, [17] followed by the reduction of the obtained
derivative 1 (Sulfolefin, figure 1), enclosing a
chiral sulfur atom as the sole stereogenic center,
proved to be efficient catalyst precursor for Rh-
catalysed addition of arylboronic acids to activated
tert-butylsulfinyl
imines,
12-16.[18]
The
chemoselective reduction of the C=N double bond
with sodium borohydride yielded the desired
sulfinamide-olefins in high chemical yields. The
methyl and phenyl allylic substituted derivatives
4[15c] and 5[15d] were obtained as a pair of
diastereomers, epimers at the allylic position, and
were separated by column chromatography
(Scheme 1). The obtained sulfinamide/olefin
derivatives were then assayed as chiral ligands in
the enantioselective rhodium-catalysed addition of
p-tolylboronic acid 17 to trifluoromethyl p-
chlorophenyl ketone 18, as model reaction. The
reaction was carried out using 5 mol% of the chiral
ligand, in diethyl ether, under reflux during 3 hours,
using KF or K2CO3 as the base, and the results are
collected in table 1.
ketones including trifluoromethyl ketones, albeit
with moderate enantioselectivities.
[14]
Taking into
account these results, and in order to enhance the
enantioselectivity, so that the process is of synthetic
interest, in the present work differently substituted
tert-butylsulfinamide-olefin ligands (2-5) were
synthesized. The ligands were designed in order to
assess the importance of the substituents at both
olefinic carbons (compounds 2 and 3, Figure 1),
and at the allylic position (compounds 4 and 5,
Figure 1). We have also evaluated the influence of
the stereochemistry of the chiral allylic carbon of
this type of ligands on the stereochemical outcome
of the rhodium-catalysed reaction (Figure1).
As can be seen from Table 1, the assayed ligands 1-
4 were active catalyst precursors for the addition
reaction, as the final trifluoromethylcarbinol 19 was
obtained in good chemical yield (entries 1-10, table
1). A significant decrease in the chemical yields of
the additions was observed in the case of both
diastereomers of the phenyl derivatives 5S and 5R
(entries 11 and 12, table 1), indicating the lower
catalytic activity of these ligands. Neither
potassium fluoride nor potassium carbonate, used
as bases significantly influences the chemical yield
nor the stereoselectivity of the process (entries 1-10,
table 1). Comparison of the results obtained with
the different ligands clearly illustrates the lack of
influence of the nature of the substituent at the
allylic position or its stereochemistry, R or S, on the
enantioselectivity of the process. In the case of both
diastereomeric methyl derivatives, 4R and 4S, the
ee’s were similar to that previously obtained with
the non-substituted sulfolefin 1 (compare entries 7
Figure 1. Sulfolefin type ligands used in this work
Ligands 1-5[15] were obtained in excellent yields
and in only 2 simple synthetic steps from
commercially available (R)-tert-butanesulfinamide
6,[16] Scheme 1, by condensation with the
2
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
and 9 vs 1, Table 1), but a small decrease in the
enantioselectivity was observed in the case of the
phenyl substituted ligands 5S and 5R (entries 11
and 12, table 1), indicating the lower inductive
capacity of both of them.
the trifluoromethyl ketone 18 (compare entries 5
and 6 vs 1 and 2, table 1). Encouraged by the good
result obtained with this sulfinamide-olefin 3,
which we have denominated MetSulfolefin, we
decided to determine the scope of the reaction with
this ligand using boronic acids with varied steric
and electronic nature and different trifluoromethyl
ketones. Taking into account that, as previously
indicated in table 1, similar enantioselectivities
were obtained using potassium carbonate or
potassium fluoride as base, all the new additions
were conducted with KF, and the results are
collected in table 2.
Table 1. Enantioselective Rh-catalysed addition of p-
tolylboronic acid to the trifluoromethyl p-cholorophenyl
ketone using sulfinamide/olefins 1 - 5 as chiral ligands.a
The reaction is not dependent on the electronic
factors of both boronic acids and ketones. In this
sense, boronic acids with electron donor (17, 20, 25
and 26) or acceptor substituents (24) on the aryl
group gave the products of addition with very high
yields (compare entries 1-12, table 2). One of the
first conclusions to be drawn from the data
collected in the table is the superiority of the
methyl-substituted ligand 3 compared to Sulfolefin
1 in terms of stereoselectivity (entries 1 and 2, table
1). The enantioselectivities obtained in the
additions of aryl boronic acids 17 (entry 1, table 2)
and 20 (entry 2, table 2) to the ketone 18 are
significantly higher in the case of MetSulfolefin 3
as ligand, with 96% and 94% ee respectively,
compared to the ee's obtained with the Sulfolefin 1
that are under 65%. It should be noted that with
ligand 3 not only the para-substituted aryls could
be introduced, with very high enantioselectivities
and good yields on the less hindered ketones
(entries 1, 2, 15 and 17, table 2), but also the meta-
and ortho-substituted aryls (entries 4, 5, 7-12, table
2). Thus, the addition of meta-tolylboronic acid 25
to the trifluoromethyl ketone 19 gives the
corresponding trifluoromethylcarbinol 36, as a
single enantiomer (entry 7, table 2) in very high
chemical yields (91%). Interestingly the addition of
the more challenging hindered boronic acids, which
are less reactive and less enantioselective with the
catalysts developed to date, affords the desired
aAll reaction were conducted using 0.67 mmol of ketone
18, 1.34 mmol of boronic acid 17, 2.01 mmol of base
(KF or K2CO3), 5 mol % of ligand 1-5, and 2.5 mol % of
[Rh(C2H4)2Cl]2 under reflux in diethyl ether for 3 hours.
The absolute configuration was determined by
comparison with literature value.[4b, 4c] bIsolated product.
cDetermined by chiral stationary phase HPLC using
d
Chiralcel OJ-H® column. The starting ketone 18 was
not consumed despite prolonging the reaction time
overnight.
products
with
good
yields
and
high
enantioselectivities. In this sense, addition of 1-
naphthylboronic acid 22 and ortho-tolylboronic
acid 26 to the trifluoromethyl ketone 18 gives the
corresponding trifluoromethyl carbinols 33 and 37
in high chemical yields and in 96 and 90% ee
respectively (entries 4 and 8). As far as we know
these are the best enantioselectivities obtained in
these types of transformations to date. In the case
of the nonsubstituted ketophenone 27 the
corresponding adduct 38 was obtained with 86% ee
and 92% chemical yield (entry 9, table 2). The
enantioselectivity was higher in the case of the
meta-fluoro substituted ketone 28 allowing the
formation of the corresponding carbinol 39 in 96%
ee and 75% chemical yield (entry 10, table 2).
However, in the case of the addition on the most
challenging hindered ketones, the products can still
be obtained with good enantiomeric excesses
Fortunately, the modification of the nature of the
substituents at the vinylic position gave better
results. Thus, a slight but not very significant
increase in the enantiomeric excess was obtained
when the phenyl group in ligand 1 was substituted
by the naphthyl group in 2 (entry 3 vs 1, table 1).
However, the excellent result obtained with the
ligand 3, with a methyl substituent at the double
bond, highlights the importance of the substituent
at the non-terminal position of the olefin in this
type of ligands. Thus, we were pleased to find that
with this ligand the reaction affords the desired
carbinol 19 with an interesting 90-96% ee (entries 5
and 6, table 1). This represents a significant
improvement of the result obtained with the
Sulfolefin ligand 1, in terms of enantioselectivity of
the rhodium catalysed arylboronic addition of 17 to
3
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
although with low chemical yields (entries 13-17,
table 2).
aAll reactions were conducted using 0.67 mmol of the
ketone, 1.34 mmol of the arylboronic acid, 2.01 mmol
of KF, 5 mol % of ligand 1 or 3, and 2.5 mol % of
[Rh(C2H4)2Cl]2 under reflux in diethyl ether for 3h. The
absolute configuration was determined by comparison
with literature values.[4b, 4c] and on the basis of similar
stereochemical models. Isolated product. Determined
by chiral stationary. dIn brackets are given the yields and
ees obtained with MetSulfolefin 1.
Table 2: Reaction scope of the enantioselective rhodium
catalysed addition of arylboronic acids to trifluoromethyl
ketones with MetSulfolefin 3 as chiral ligand.a
b
c
In the case of ortho-methoxy substituted ketone 29,
the addition of phenyl boronic acid 21, meta-
tolylboronic acid 25, and para-tolylboronic acid 17
gave the trifluoromethyl carbinols 42 (entry 13,
table 2), 43 (entry 14, table 2) and 44 (entry 15,
table 2) in 90, 72 and 82% ee although with only 22,
13 and 30% chemical yield respectively. Similarly,
in the case of ortho-methyl substituted ketone 30,
the addition of meta-tolylboronic acid 25, and
para-tolylboronic acid 17 yield the addition
products 45 (entry 16, table 2) and 46 (entry 17,
table 2) with a good 82 and 90% ee and with 38%
and 25% yield respectively.
It is worth of mentioning that the possibility of
permuting between the aromatic groups of the
ketone and the boronic acid together with the easy
access to ent-MetSulfolefin, considerably increases
the number of structures accessible in both
enantiomeric forms by this method, and mitigates
the lower reactivity of the hindered ketones.
Clearly, the presence of the "flag methyl" group[19]
in the olefinic position of ligand 3 has improved
significantly the enantioselectivity in the rhodium-
catalysed additions of arylboronic acids to
trifluoromethyl ketones, highlighting subtle effects
in the steric and electronic reorganizations of the
coordinated transition states, figure 2. In this sense,
although the sulfolefin-type ligands can coordinate
the rhodium in different ways, NMR and RX
studies have shown that they generally act as
bidentate ligands capable of coordinating the metal
through the sulfur and the double bond. [13d, 14]
(a)
(b)
4
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
this ligand in other rhodium-catalysed processes are
currently under investigation and the results will be
reported in due course
Experimental Section
(R,E)-N-2-Methyl-3-phenylprop-2-en-2-yl tert-
butylsulfinamide, 14.
To a solution of -methylcinnamaldehyde (1.05 mL,
7.50 mmol, 100 mol%) and (R)-tert-butanesulfinamide 6
(1.0 g, 8.25 mmol, 110 mol%) in dry THF (25 mL), at
room temperature under argon atmosphere, Ti(OEt)4
(1.73 mL, 8.25 mmol, 110 mol%) was added. Once the
starting material was consumed (24 h), the reaction
mixture was hydrolysed with a saturated NaCl aqueous
solution (25 mL). The resulting suspension was filtered
through a pad of Celite. The aqueous phase was
extracted with CH2Cl2 (3 x 40 mL) and the combined
organic phases were dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and the
resulting residue was purified by flash chromatography
(EtOAc:hexane, 1:10) to give 1.53 g of
Figure 2.(a) Conformations, A(minor) and B(major),
proposed for the square planar complex intermediate [3-
RhL2]. (b) Structure of the transition states, B1 and B2,
proposed for the attack of the aryl group to the si and re
face of the trifluoromethyl ketone.
In the square planar complex intermediate, figure 2,
and due to an unfavourable steric interaction with
the cis vinylic methyl group of ligand 3, the phenyl
group cannot be coplanar with the double bond,
figure 2(a), and rotates slightly out of this plane to
give a new conformation, figure 2(b), in order to
minimize this interaction. In the new conformation,
the phenyl ring points to the same side than the
tert-butyl group, key element in the observed
enantioselectivity, thus enhancing the whole
stereochemical outcome of the process. In this
sense, of the two possible intermediates B1 and B2,
formed through substrate coordination to the aryl
rhodium intermediate in the proposed catalytic
cycle of the Rh-catalysed addition of boronic acid
to activated ketone, intermediate B1 is much more
favorable than intermediate B2 with ligand 3. Thus,
insertion of the aromatic ring to the carbonyl group
in intermediate B1 (siface attack), followed by
transmetallation explains the formation of the
observed major isomer, figure 2.
14 (6.13 mmol, 82% yield) as yellow liquid. [α]D20: -
1
401.4 (c1, CHCl3). H-NMR (500 MHz, CDCl3): δ 8.30
(s, 1H), 7.46-7.45 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.31
(m, 1H), 7.10 (bs, 1H), 2.20 (d, J = 1.2 Hz, 3H), 1.24 (s,
9H) ppm. 13C-NMR (125 MHz, CDCl3): δ 167.2, 144.2,
136.0, 135.3, 128.8, 128.6, 57.5, 27.6, 13.2 ppm.
HRMS: Calc. for C14H19NOS [M+H]+: 250.1260; found
250.1255 (-2.2111 ppm).
(R,E,E)-N-2-Methyl-3-phenyl-prop-2-en-1-ylidene
tert-butylsulfinamide, MetSulfolefin, 3.
To a solution of the N-tert-butylsulfinylimine 14 (750
mg, 3 mmol, 100 mol%) in dry MeOH (20 mL), under
argon atmosphere, at 0°C, NaBH4 (113.8 mg, 6 mmol,
200 mol%) was added. Once the starting material was
consumed, a saturated NH4Cl aqueous solution was
added. The aqueous phase was extracted with EtOAc (3
x 40 mL) and the combined organic phases were dried
over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure and the resulting residue was
purified by flash chromatography (EtOAc/hexane 1:3) to
give 651.5 mg of 3 (2.59 mmol, 86% yield) as a white
In conclusion, we have developed an efficient
sulfinamide/olefin
based
chiral
ligand,
MetSulfolefin, for the enantioselective rhodium-
catalysed addition of aryl-boronic acids to
trifluoromethyl ketones. This shelf stable ligand is
insensitive to air, oxygen and moisture, and it is
obtained in only two high yielding steps from
1
solid. M.p.: 72-73°. [α]D20: -47.9 (c 1, CHCl3). H-NMR
cheap
commercially
available
(R)-tert-
(500 MHz, CDCl3): δ 7.35-7.32 (m, 2H), 7.27-7.26 (m,
2H), 7.24-7.21 (m, 1H), 6.50 (bs, 1H), 3.82 (AB
fragment of an ABX system, Δν = 58.7 ppm, J = 7.5, 5.1
and 14.0 Hz, 2H), 3.32 (t, J = 6.0 Hz, 1H), 1.91 (d, J =
0.8 Hz, 3H), 1.26 (s, 9H) ppm.13C-NMR (125 MHz,
CDCl3): δ 137.5, 135.5, 129.0, 128.3, 127.7, 126.8, 56.0,
54.2, 22.8, 16.4 ppm. HRMS: Calc. for C14H21NOS
[M+H]+: 274.1236; found 274.1231 (-1.9480 ppm).
butanesulfinamide. The new ligand leads to the
formation of a series of chiral trifluoromethyl-
substituted tertiary carbinols in high yields and
excellent enantioselectivities (up to 100% ee). To
the best of our knowledge "MetSulfolefin" can be
considered as one of the best chiral ligands
developed for this rhodium-catalysed process, up to
now. The presence of a methyl group at the non-
terminal vinylic position of this new chiral ligand
seems to be the key to its success. Applications of
Rhodium-catalysed 1,2-addition of boronic acids to
trifluoromethyl ketones. Typical Procedure.
5
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
To a mixture of the arylboronic acid (1.34 mmol), KF
(2.01 mmol), the chiral ligand 3 (8.42 mg, 0.03 mmol, 5
mol %) and [Rh(C2H4)2Cl]2 (0.015 mmol, 2.5 mol %)
was added the trifluoromethyl ketone (0.67 mmol) and
Et2O (10 mL). After stirring the mixture at reflux for 3
hours, the reaction mixture was directly purified by flash
chromatography on silica gel (Hexane/CH2Cl24:1) to
afford the desired trifluoromethyl carbinol. The
enantioselectivity was determined by chiral HPLC.
G. Pattison, Chem. Commun. 2016, 52, 11116-
11119; d) V. Valdivia, I. Fernández, N. Khiar, Org.
Biomol. Chem. 2014, 12, 1211-1214; e) J. R. White,
G. J. Price, P. K. Plucinsky, C. G. Frost, Tetrahedron
Lett. 2009, 50, 7365-7368; f) V. R. Jumde, S.
Faccheti, A. Iuliano, Tetrahedron: Asymmetry 2010,
21, 2775-2781.
[5] a) D. G. Hall, In Boronic Acids: Preparation and
Applications in Organic Synthesis and Medicine.
Wiley-VCH: Weinheim, 2005; b) R. Shintai, M.
Inoue, T. Hayashi, Angew. Chem. Int. Ed. 2006, 45,
3353-3356; c) H. F. Duan, J.-H. Xie, X.-C. Qiao, L.
X. Wang, Q.-L. Zhou, Angew. Chem., Int. Ed. 2008,
47, 4351-4353.
Acknowledgements
This work was supported by the "Ministerio de Economía y
Competitividad" CTQ2016-78580-C2-2-R and CTQ2016-
78580-C2-1-R), and the Junta de Andalucía (P11-FQM-
08046). We gratefully thank CITIUS for NMR facilities
[6] a) G. Berthon, T. Hayashi, In Catalytic Asymmetric
Conjugate Reactions. Córdova, A., Eds.; Wiley-
VCH: Weinheim, 2010, chap. 1; b) K. Yoshida, T.
Hayashi, In Modern Rhodium-Catalysed Organic
Reactions. P. A. Evans, Eds,; Wiley-VCH:
Weinheim, 2005, chap. 3; c) H. J. Edwards, J. D.
Hargrave, S. D. Penrose, C. G. Frost, Chem. Soc. Rev.
2010, 39, 2093-2105; d) C. Defieber, H.
Grútzmacher, E. M. Carreira, Angew. Chem. Int. Ed.
2008, 47, 4482-4502; e) J. B. Johnson, T. Rovis,
Angew. Chem. Int. Ed. 2008, 47, 840-871.
References
[1] a) J. Wang, M. Sánchez Roselló, J. L. Aceña, C. del
Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432-
2506; b) I. Ojima, J. R. McCarthy, J. T. Welch, In
Biomedical Frontiers of Fluorine Chemistry; ACS
Editions: Washington DC, 1996; c) T. Hiyama, In
Organofluorine
compounds.
Chemistry
and
Applications; Yamamoto, H., Eds.; Springer: New
York, 2000.
[7] a) V. L. Steven, In Quaternary Stereocenters.
Challenges and Solutions for Organic Synthesis. J.
Christoffers, A. Baro, Eds.; Wiley-VCH: Weinheim,
2005; b) E. J. Corey, A. Guzman-Perez, Angew.
Chem. Int. Ed. 1998, 37, 389-401; c) J. Christoffers,
A. Baro, Adv. Synth.Catal. 2005, 247, 1473-1482; d)
B. M. Trost, C. Jiang, Synthesis 2006, 3, 369-396.
[2] a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103,
2763-2793; b) O. Riant, J. Hannedouche, Org.
Biomol. Chem. 2007, 5, 873-888; c) P. Tian, H.-Q.
Dong, G.-Q. Lin, ACS Catal. 2012, 2, 95-119; d) B.
Jiang, Y.-G. Si, Angew. Chem, Int. Ed. 2004, 43,
216-218; e) M. L. P. Price, W. J. Jorgensen, J. Am.
Chem. Soc. 2000, 122, 9455-9466; f) L. Tan, C.-Y.
Chen. R. D. Tillyer, E. J. J. Grabowski, P. J. Reider,
Angew. Chem. Int. Ed. 1999, 38, 711-713; g) F. Xu,
R. A. Reamer, R. Tyllier, J. M. Cummins, E. J. J.
Grabowski, P. J. Reider, D. B. Collum, J. C.
Huffman, J. Am. Chem. Soc. 2000, 122, 11212-
11218.
[8] W. Tang, B. Qu, A. G. Capacci, S. Rodriguez, X.
Wei, N. Haddad, B. Narayanan, S. Ma, N. Grinberg,
N. K. Yee, D. Krishnamurthy, C. Senanayake, Org.
Lett. 2010, 12, 176-179.
[9] G. Li, X.-J. Wang, Y. Zhang, Z. Tan, P. DeCroos, J.
C. Lorenz, X. Wei, N. Grinberg, N. K. Yee, C. H.
Senanayake, J. Org. Chem. 2017, 82, 5456-5460.
[10] a) Nelson, J. H. In Chiral Auxiliaries and Ligands
in Asymmetric Synthesis; J. Seyden-Penne, Ed.;
Wiley-Interscience: New York, 1995; b) D. A. Evans,
J. S. Johnson, In Comprehensive Asymmetric
Catalysis, Vol. I-III,; E. N. Jacobsen, A. Pfaltz, H.
Yamamoto, Eds.; Springer: Berlin, 1999; c) C. S.
[3] a) Chang, Y.; Cai, C. Tetrahedron Lett. 2005, 46,
3161-3164; b) S. Roussel, T. Billard, B. R. Langlois,
Chem. Eur. J. 2005, 11, 939-944; c) G. K. S. Prakash,
J. Hu, J. A. Olah, J. Org. Chem. 2003, 68, 4457-
4463; d) B. R. Langlois, T. Billard, Synthesis 2003, 2,
185-194 e) J. Joubert, S. Roussel, C. Christophe, T.
Billard, B. T. Langlois, T. Vidal, Angew. Chem. Int.
Ed. 2003, 42, 3133-3136; f) G. K. S. Prakash, J. Hu,
G. A. Olah, Org. Lett. 2003, 5, 3253-3256; g) S.
Roussel, T. Billard, B. R. Langlois, Synlett, 2004,
2119-2122; h) S. Mizuta, N. Shibata, S. Akiti, H.
Fujimoto, S. Nakamura, T. Toru, Org. Lett. 2007, 9,
3707-3710; i) H. Kawai, K. Tachi, E. Tokunaga, M.
Shiro, N. Shibata, Org. Lett. 2010, 12, 5104-5107; j)
J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1-
PR43.
Kramer,
Enantioselective
S.
Bräse,
Organocatalysis:
In
Comprehensive
Catalysts,
Reactions, and Applications. P. Dalko, Ed. Wiley-
VCH: Weinheim, 2013; d) W. Zhang, Y. Shi, X.
Zhang, Acc. Chem. Res. 2007, 40, 1278-1290; (e) A.
Pfaltz, W.J. Drury, PNAS 2004, 101, 5723-5726.
[11] a) I. Fernández, N. Khiar, In Organosulfur
Chemistry in Asymmetric Synthesis; T. Toru, C.
Bolm, Eds.; Wiley-VCH-Verlag:Weinheim, 2008, pp.
265; b) B. M. Trost, M. Rao, Angew. Chem. Int. Ed.
2015, 54, 5026-5043; c) G. Sipos, E. M. Drinkel, R.
Dorta, Chem. Soc. Rev. 2015, 44, 3834-3860. d) S.
Otocka, M. Kwiatkowska, L. Madalinska, P.
Kiełbasinski, Chem. Rev. 2017, 117, 4147-4181.
[4] a) S. L. X. Martina, B. C. J. Richard, J. G. de Vries,
F. L. Feringa, A. J. Minnard, Chem. Commun. 2006,
4093-4095; b) R. Luo, K. Li, Y. Hu, W. Tang, Adv.
Synth. Catal. 2013, 355, 1297-1302; c) L. S. Dobson,
6
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
[12] a) E. Wojaczynska, J. Wojaczynkski, Chem. Rev.
2010, 110, 4303-4356; b) M. C. Carreño, G.
Hernández-Torres, M. Ribagorda, A. Urbano, Chem.
Commun. 2009, 6129-6144; c) C. H. Senanayake, D.
Krishnamurthy, Z.-H. Lu, Z. Han, I. Gallou, Aldrich.
Chim. Acta 2005, 38, 93-104; d) I. Fernández, N.
Khiar, Chem. Rev. 2003, 103, 3651-3705.
Zhu, M.-H. Xu, Org. Biomol. Chem. 2012, 10, 1764-
1768; c) A. Adamkiewicz, J. Mlynarski, Eur. J. Org.
Chem. 2016, 5, 1060-1065; d) Z.-J. Liu, J.-T. Liu,
Chem. Comm. 2008, 41, 5233-5235.
[16] M. T. Robak, M. A. Herbage, J. A. Ellman, Chem.
Rev. 2010, 110, 3600–3740.
[17] a) A. Nordqvist, C. Björkelid, M. Andaloussi, A.M.
Jansson, S. L. Mowbray, A. Karlén, M. Larhed, J.
Org. Chem. 2011, 76, 8986–8998. b) N. Solin, L.
Han, S. Che, O. Terasaki, Catal. Commun. 2009, 10,
1386–1389.
[13] a) R. Mariz, X. J. Luan, M. Gatti, A. Linden, R.
Dorta, J. Am. Chem. Soc. 2008, 130, 2172-2173; b) J.
J. Burgi, R. Mariz, M. Gati, E. Drinkel, X. J. Luan, S.
Blummenrit, A. Linden, R. Dorta, Angew. Chem. Int.
Ed. 2009, 48, 2768-2771; c) T. Thaler, L.-N. Guo, A.
K. Steib, M. Raducan, K. Karaghiosoff, P. Maer, P.
Knochel, Org. Lett. 2011, 13, 3182-3185; d) X. Feng,
Y. Wang, B. Wei, J. Yang, H. Du, Org. Lett. 2011,
13, 3300-3303; e) G. Chen, J. Gui, L. Li, J. Liao,
Angew. Chem. 2011, 123, 7823-7827; Angew. Chem.
Int. Ed. 2011, 50, 7681-7685; f) X. Feng, B. Wei, J.
Yang, H. Du, Org. Biomol. Chem. 2011, 9, 5927-
5929; g) F. Xue, X.-C. Li, B.-S. Wan, J. Org. Chem.
2011, 76, 7256-7262; h) Y. Wang, X. Feng, H. Du,
Org. Lett. 2011, 13, 4954-4957.
[18] a) J.L. García-Ruano, I. Fernández, M. del Prado, A.
Alcudia, Tetrahedron: Asymmetry 1996, 7, 3407-
3414. b) G. K. Surya-Prakash, M. Mandal, G. A.
Olah, Org. Lett. 2001, 3, 2847-2850. c) J. P.
McMahon, J. A. Ellman, Org. Lett. 2005, 7, 5393-
5396.
[19] The term "flag methyl" was introduced by the Ciba
Geygi group in the development of Imatinib [R.
Capdeville, E. Buchdunger, J. Zimmermann, A.
Matter, Nat. Rev. Drug Discov. 2002, 1, 493-502].
Thus, the improved activity and selectivity of the
rhodium catalysed addition of arylboronic acids to
trifluoromethyl ketones with ligand 3, the methylated
analogue of sulfolefin 1, could be considered similar
to the well known effect of methylation of substrates
in medicinal chemistry, favouring a conformation
suitable for the ligand-enzyme interaction.
[14] a) V. Valdivia, N. Bilbao, J. F. Moya, C. Rosales-
Barrios, A. Salvador, R. Recio, I. Fernández,
N. Khiar, RSC Adv. 2016, 6, 3041-3047; b) N.
Khiar, A. Salvador, V. Valdivia, A. Chelouan, A.
Alcudia, E. Álvarez, I. Fernández, J. Org. Chem.
2013, 78, 6510-6521; c) N. Khiar, V. Valdivia, A.
Salvador, A. Chelouan, A. Alcudia, I. Fernández,
Adv. Synth. Catal. 2013, 355, 1303-1307; d) N. Khiar,
A. Salvador, A. Chelouan, A. Alcudia, I. Fernández,
Org. Biomol. Chem. 2012, 10, 2366-2368.
[15] a) T.-S. Zhu, S.-S. Jin, M.-H. Xu, Angew. Chem. Int.
Ed. 2012, 51, 780 –783; b) S.-S. Jin, H. Wang, T.-S.
7
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10.1002/adsc.201701212
Advanced Synthesis & Catalysis
COMMUNICATION
An efficient and practical method for the
enantioselective synthesis of tertiary
trifluoromethyl carbinols
O
MetSulfolefin (5 mol%)
HO CF3
[Rh(C2H4)2Cl2]2 (2.5 mol %)
F3C
R
B(OH)2
X
X
Et2O, reflux
KF
R
up to 99%
up to > 99% ee
O
S
Adv. Synth. Catal. Year, Volume, Page – Page
- Shelf stable
- Obtained in 2 high yielding steps
- Both enantiomers are easily accesible.
- Cheap commercially available starting materials
tBu
N
H
CH3
Lorenzo G. Borrego,a, ∫ Rocío Recio,a, ∫ Manuel
Alcarranza,aNoureddine Khiar,b* and Inmaculada
Fernández.b*
MetSulfolefin
8
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