Electronic and Steric Tuning of an Atropisomeric Disulfoxide Ligand Motif and Its Use in the Rh(I)-Catalyzed Addition Reactions of Boronic Acids to a Wide Range of Acceptors

Article abstract of DOI:10.1021/acs.joc.8b01269

A novel chiral disulfoxide ligand pair bearing fluorine atoms at the 6 and 6′ position of its atropisomeric backbone, (M,S,S)- and (P,S,S)-p-Tol-6F-BIPHESO, was synthesized. Complexation to a rhodium(I) precursor gave rise to μ-Cl- and μ-OH-bridged rhodiu

Full text of DOI:10.1021/acs.joc.8b01269

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Article
Electronic and Steric Tuning of an Atropisomeric Disulfoxide
Ligand Motif and its Use in the Rh(I)-Catalyzed Addition
Reactions of Boronic Acids to a Wide Range of Acceptors
Guang-Zhen Zhao, Daven Foster, Gellert Sipos, Pengchao
Gao, Brian W. Skelton, Alexandre N. Sobolev, and Reto Dorta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01269 • Publication Date (Web): 06 Aug 2018
Downloaded from http://pubs.acs.org on August 10, 2018
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Electronic and Steric Tuning of an Atropisomeric Disulfoxide Ligand Motif
and its Use in the Rh(I)-Catalyzed Addition Reactions of Boronic Acids to a
Wide Range of Acceptors
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Guang-Zhen Zhao,a# Daven Foster,a# Gellért Sipos,a,b Pengchao Gao,a Brian W.
Skelton,a,c Alexandre N. Sobolev,a,c and Reto Dorta*a
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a
Department of Chemistry, School of Molecular Sciences, University of Western
Australia, 35 Stirling Highway, Perth WA 6009, Australia.
b Present address: ComInnex Inc., Zahony u. 7, Budapest, H-1031, Hungary.
c Centre for Microscopy, Characterisation and Analysis, University of Western
Australia, Perth WA 6009, Australia.
Abstract. A novel chiral disulfoxide ligand pair bearing fluorine atoms at the 6
and 6' position of its atropisomeric backbone, (M,S,S)- and (P,S,S)-p-Tol-6F-
BIPHESO, was synthesized. Complexation to a rhodium(I) precursor gave rise to
μ-Cl- and μ-OH-bridged rhodium dimer complexes incorporating the new
(M,S,S)-p-Tol-6F-BIPHESO ligand, while its sibling (P,S,S)-p-Tol-6F-BIPHESO was
not complexed efficiently to the rhodium precursor. The performance of this
disulfoxide ligand [(M,S,S)-p-Tol-6F-BIPHESO] in catalysis was tested in both 1,4-
and 1,2-addition reactions of arylboronic acids. We show that addition to both
cyclic and acyclic enones as well as N-tosylarylimines proceeds with high yields
and high enantioselectivities to give the corresponding products. The synthesis
of enantiomerically pure p-Tol-6F-BIPHESO is straightforward and inexpensive,
which together with the high catalytic performance and wide substrate scope for
these addition reactions makes it a very attractive alternative to more classical
chiral ligand entities.
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Keywords: chiral sulfoxide; atropisomers; rhodium; asymmetric catalysis;
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addition reactions
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1. Introduction
Enantioselective transition metal catalysis, which offers a very elegant and atom-
economical way to the production of all-important enantiomerically pure
compounds, has attracted extensive attention from the chemistry community
over the decades. What has clearly been established is the fact that reliable and
versatile catalysts with good reactivities and selectivities are highly dependent
on the chiral ligands coordinated to the central metals. Therefore, the correct
design as well as the facile synthesis of novel ligands has always been and
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continues to represent
a
major task in asymmetric catalysis.
Phosphorous, nitrogen and oxygen are frequently embedded as donor atoms in
such ligand architectures. Sulfoxides, due to their inherent chirality at sulfur,
have a well-known coordination chemistry and have played a very important
role in asymmetric catalysis as chiral auxiliaries initially.2 However, for a long
time, the utilizations of sulfoxides as ligands for transition metal catalysis,3
whether bound through oxygen or sulfur, did not enjoy much success. Seemingly,
their questionable binding ability and possibly unfortunate ligand design choices
did not offer efficient chiral environments for asymmetric metal catalysis.
In 2008, our group introduced the disulfoxide p-Tol-BINASO [1,1’-
binaphthalene-2,2’-diyl-bis(p-tolylsulfoxide)] (Figure 1, bottom left),4a as a
highly efficient ligand for the rhodium catalyzed 1,4-addition of arylboronic acid
to cyclic α,β-unsaturated ketones and esters.5,6,7 This first report on utilizing this
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ligand class in the Hayashi-Miyaura reaction has led to a renewed interest in the
development of chiral sulfoxide ligands.8 Later on, with the adoption of other C2-
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symmetric atropisomeric backbone units, new ligand analogues were
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synthesized and tested in our group. For example, p-Tol-Me-BIPHESO, a
sulfoxide analogue of BIPHEMP,4b was obtained similarly easily to p-Tol-BINASO
and showed even better catalytic results at lower catalyst loading for this
addition reaction (Figure 1, bottom center). By comparing the X-ray crystal
structures of Rh complexes of disulfoxide ligands p-Tol-BINASO and p-Tol-Me-
BIPHESO,4c it can be seen that this subtle modification of the backbone was
beneficial for the rhodium-catalyzed conjugate addition reactions, as the
particular geometry of the backbone and its associated characteristics (dihedral
angle and bite angle) were slightly modified.10 In these first studies, a few
problems though arose: First of all, even the most active ligand/metal
combination incorporating p-Tol-Me-BIPHESO as the ligand was not able to
asymmetrically add arylboronic acids to open-chain type chalcone substrates.
Indeed, what we saw was that the addition of an arylboronic acid to the parent
trans-1,3-diphenyl-2-propenone would give the addition product in low yield
and negligible enantioselectivity (20% ee).4b Secondly, all of the ligands with
these atropisomeric backbones have so far been particular in the sense that only
one of the diastereoisomers of the atropisomeric ligand pair was able to bind to
the rhodium precursor to give the precatalyst. And as a third point, modifications
done on the axially chiral backbones in these disulfoxide ligands until now
pertained to the synthesis of more electron-rich variations of p-Tol-BINASO,
whereas recently, electron-poor versions of the more widely studied chiral
diphosphine and diene ligands achieved significant success in various addition
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reactions.6j,11 For example, Sakai et al.,6j described the synthesis of MeO-F12-
BIPHEP, an atropisomeric diphosphine ligand with electron-poor, fluorinated
phenyl groups on phosphorous, which was very efficient in the Rh-catalyzed 1,4-
additions of arylboronic acids, clearly outperforming its non-fluorinated
congeners (Figure 1, top left). Ratovelomanana-Vidal et al.,11f employed (R)-3,5-
diCF3-SYNPHOS, again an electron-deficient diphosphine ligand with
atropisomeric backbone, in the same Rh-catalyzed asymmetric 1,4-addition of
arylboronic acids to α,β-unsaturated ketones and nonsubstituted maleimide with
equally high success (Figure 1, top middle). A group of chiral diene ligands with
an electron-poor tetrafluorobenzobarrelene backbone was developed by
Hayashi et al.,11c,d and shown to behave exceedingly well in similar rhodium-
catalyzed addition reactions (Figure 1, top right).11h,i
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F
O
F
F
F
P(Ar2)2
P(Ar2)2
P(Ar1)2
P(Ar1)2
O
O
MeO
MeO
Fc
Fc
O
F
F
F
CF3
Ar1 =
Ar2 =
Fc = ferrocenyl
CF3
(R)-MeO-F12-BIPHEP
(S,S)-Fc-tfb
(R)-3,5-diCF3-SYNPHOS
O
S
O
S
O
S
F
F
S
S
S
O
O
O
(M,S,S)-p-Tol-BINASO
(M,S,S)-p-Tol-Me-BIPHESO
Target Ligand
Figure 1. Sakai’s and Ratovelomanana-Vidal’s fluorous BINAP-type phosphorus
ligands, Hayashi’s fluorous diene ligand, atropisomeric disulfoxide ligands and
the target ligand (from top left to bottom right).
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While these developments already gave us an incentive to see how such
incorporations of fluorine atoms would affect the reactivity of our disulfoxide
ligands, we also wanted to simultaneously come up with a ligand design that
might hopefully be able to address the shortcomings mentioned above in terms
of reactivity (no reactivity with open chain substrates) and diastereomer binding
[no binding of P,S,S (or M,R,R) diastereomers]. To this end, we chose the target
ligand shown in Figure 1 (bottom right). It incorporates a very small 6,6’-
difluorobiphenyl backbone that should hopefully enhance flexibility of its
dihedral angle, all the while reaching a new electronic situation in these ligands
(electron-poor vs electron-rich BINASO and derivatives).
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We herein report the facile and straightforward synthesis of this electron-
deficient disulfoxide ligand, report on its binding ability to rhodium and its use in
arylboronic acid additions to various acceptors. In particular, we show how
open-chain chalcone type substrates can be used successfully with this new
catalyst system. The fact that the same ligand/catalyst combination can be used
for the addition reaction of arylboronic acids to both cyclic/acyclic enones (1,4-
addition) and N-tosylarylimines (1,2-addition) makes this new catalyst system
rather unique, as high selectivity of a catalyst often precludes broadness of the
scope of substrates. Indeed, in the context of these addition reactions, very few
single ligand systems exist that successfully promote both the 1,4-addition to
α,β-unsaturated compounds and the 1,2-addition to imines,12 meaning that steric
or electronic tuning of the ligand is usually necessary to reach good results in
one or the other reaction scheme.
2. Results and Discussion
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Compared with other chiral ligand designs, the synthesis of enantiopure
sulfoxides is often significantly more straightforward, making them appealingly
practical and green. The new ligand that we describe here is no exception and its
synthesis involves a mere two steps to access in optically pure form (Scheme 1).
As a comparison, its diphosphine analogue 6,6’-difluorobiphenyl-2,2’-diyl-
bis(diphenylphosphine),13 needed four synthetic steps to access in racemic form
and a subsequent, tedious and expensive enantiomer resolution with a chiral
palladium complex to reach its optically pure version.
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The first synthetic step involved a copper-catalyzed Ullman coupling of
commercially available and reasonably priced 1-bromo-3-fluorobenzene 1 (ca.
40$ for 100 g). Here, various procedures were tested before establishing a
modified reaction process that gave the coupled, racemic dibromo derivative
2,2'-dibromo-6,6'-difluorobiphenyl (rac-2) in excellent yield (88%) after column
chromatography and crystallization.14 Subsequently, careful treatment with n-
butyllithium and reaction with commercially available (-)-menthyl-(S)-p-tolyl-
sulfinate led to the isolation of the desired disulfoxide 6,6’-difluorobiphenyl-2,2’-
diyl-bis(p-tolylsulfoxide (p-Tol-6F-BIPHESO, 3) as a pair of diastereoisomers.
The respective diastereomers were separated by simple column
chromatography to give the pure (M,S,S)-3 and (P,S,S)-3 ligands in equal
amounts (31% yield each) and in 62 % overall yield. The two diastereomeric
ligands were fully characterized by NMR spectroscopy (1H, 13C and 19F NMR) as
well as elemental analyses and their absolute configuration was determined and
attributed via X-ray diffraction studies (see discussion below).
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1) LDA, -78°C, 30 min
2) CuBr, LiCl, -78°C, 2h
F
Br
Br
F
5
6
F
Br
3) Benzoquinone, -78°C, 2h
88% yield
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rac-2
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O
O
O
1) n-BuLi, -78°C
S
S
S
S
Br
F
F
F
F
F
+
F
Br
2) (-)-menthyl-(S)-p-Tol-sulfinate
-40°C to RT
O
62% yield
rac-2
(P,S,S)-3
(M,S,S)-3
Scheme 1. Synthetic procedure for obtaining disulfoxide p-Tol-6F-BIPHESO (1).
Because the Van der Waals radius of fluorine is the smallest next to hydrogen, we
had to make sure that these diastereomers [(M,S,S)-3 and (P,S,S)-3 respectively]
would not interconvert via backbone rotation. While it is known in the literature
that the corresponding diphosphine ligand is resistant to thermally induced
racemization of its atropisomeric backbone,13 we nevertheless needed to
ascertain that it would not happen in our case. This because of the fact that the p-
tolyl sulfoxide unit is clearly less sterically demanding than the
diphenylphosphine moiety in its phosphine congener, translating into a possibly
rather facile rotation of the atropisomeric unit. Figure 2 [(M,S,S)-3] and Figure 3
1
[(P,S,S)-3] show the VT H NMR spectra (DMSO-d6) of our diastereomers and
these experiments clearly prove that racemization of the atropisomeric
backbone does not occur within the temperature range studied (up to 150° C).
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Figure 2. VT H NMR analysis of possible backbone racemization in (M,S,S)-p-
Tol-6F-BIPHESO [(M,S,S)-3]. Top spectrum in purple shows the 1H NMR
spectrum at 298 K after heating (signal at ca. 3.3 ppm is residual water in DMSO).
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Figure 3. VT H NMR (DMSO-d6) analysis of possible backbone racemization in
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(P,S,S)-p-Tol-6F-BIPHESO [(P,S,S)-3]. Top spectrum in purple shows the H NMR
spectrum at 298 K after heating (signal at ca. 3.3 ppm is residual water in DMSO).
As mentioned above, unambiguous assignment of the absolute stereochemistry
of the new ligands was possible by means of X-ray diffraction studies from
appropriately grown crystals of both diastereomers [(M,S,S)-3 and (P,S,S)-3].
Representations are shown in Figure 4 with figure captions that include selected
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bond lengths and angles. Not surprisingly, (M,S,S)-3 and (P,S,S)-3 show very
similar structures, with differing axial chirality of the backbone. The average S=O
bond lengths reveal a near identical value {1.494 Å (av.) [(M,S,S)-3] and 1.492Å
(av.) [(P,S,S)-3]}, which incidentally is very close to the average S=O bond
distances recorded for the parent p-Tol-BINASO [1.4922(16)Å] and p-Tol-Me-
BIPHESO [1.4988(16)Å] ligands.4a,b This indicates that the electronic situation in
3 is not sufficiently different to translate into significant changes in S=O bond
length values in the solid state.
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Figure 4. Top: Molecular structure of (P,S,S)-p-Tol-6F-BIPHESO (3) (50%
probability ellipsoids). Selected bond lengths (Å) and angles (deg): S1-O1,
1.4830(18); S2-O2, 1.5011(16); F16-C16, 1.354(2); F26-C26, 1.354(3); S1-C12,
1.811(2); S2-C22, 1.804(2); C111-S1-C12, 98.42(10); C211-S2-C22, 99.87(10).
Bottom: Molecular structure of (M,S,S)-p-Tol-6F-BIPHESO (3) (50% probability
ellipsoids). Selected bond lengths (Å) and angles (deg): S1-O1, 1.4933(18); S2-O2,
1.4953(19); F16-C16, 1.356(3); F26-C26, 1.352(3); S1-C12, 1.823(2); S2-C22,
1.809(2); C111-S1-C12, 96.30(10); C211-S2-C22, 98.12(10).
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The next step in our investigation was to see how this new ligand, with its
smaller and more flexible backbone, would behave when binding it to the
rhodium precursor [RhCl(C2H4)2]2. Synthesis of the chloro-bridged rhodium
precatalyst [RhCl{(M,S,S)-p-Tol-6F-BIPHESO}]2 (C1) by reacting (M,S,S)-p-Tol-
6F-BIPHESO (3) at room temperature with the ethylene-bridged dimer
[RhCl(C2H4)2]2 in CH2Cl2 was straightforward and gave, after appropriate
workup, complex C1 as an orange powder in 94% yield (Scheme 2, top). Our
hope that the second diastereomer (P,S,S)-p-Tol-6F-BIPHESO (3) would also
undergo straightforward ligation to the metal was unfortunately not met with
success. Repeated attempts invariably led to complicated mixtures of products
that were difficult to interpret by NMR spectroscopy. Following the ligation
event by running the complexation in various deuterated solvents (CD2Cl2, THF-
d8, C6D6) indicated that a clean complex was not generated during the time
course of the reaction, in contrast to an identical run recorded for (M,S,S)-p-Tol-
6F-BIPHESO (3) with dimer [Rh(C2H4)2Cl]2 (see Supporting Information for
spectra).
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The corresponding OH-bridged dimer [Rh(OH){(M,S,S)-p-Tol-6F-BIPHESO}]2 (C2)
was successfully synthesized by treating complex C1 with KOH in acetone and
was obtained in a 70% yield after workup. The synthetic pathway to these new
disulfoxide complexes is shown in Scheme 2.
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H
O
O
O
O
0.5 equiv [RhCl(C2H4)2]2
Cl
O
2.5 M KOH
S
S
S
S
S
S
F
F
F
F
F
F
Rh
Rh
CH2Cl2
(94% yield)
Acetone
(70% yield)
O
O
2
2
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(M,S,S)-3
C1
C2
O
O
0.5 equiv [RhCl(C2H4)2]2
CH2Cl2, THF, Toluene
Cl
S
S
S
S
F
F
F
F
Rh
O
O
2
(P,S,S)-3
Scheme 2. Synthesis of rhodium precatalysts C1 and C2.
Crystals suitable for an X-ray diffraction study of the chloro-bridged rhodium
complex C1,15 were grown by slow diffusion of diethyl ether into a concentrated
CH2Cl2 solution containing the compound and representations of [RhCl{(M,S,S)-
p-Tol-6F-BIPHESO}]2 (C1), together with selected bond lengths and angles, are
shown in Figure 5. When comparing the S-Rh-S bond angles, the bond lengths
for Rh-Cl, Rh-S and Cbackbone-S in complex C1 with corresponding values
measured for the previously reported Rh complex analogues formed with
ligands p-Tol-Me-BIPHESO and p-Tol-BINASO (Table 1), we note that the value
for the S-Rh-S bond angle is slightly bigger in complex C1. There is an apparent
and rather significant difference between the new complex and the former two
with respect to the dihedral angles of the two planes of backbone units. The
value for C1 is 68.3°, while the one for the p-Tol-BINASO analogue measures 74.1°
and the one for the p-Tol-Me-BIPHESO is highest at 75.6°. This trend is to be
expected based on the fact that lower values for the dihedral angle can only be
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accommodated in ligand structures where the two halves of the atropisomeric
backbone can appropriately approach each other given their lower steric
pressure (see introduction part). Not surprisingly, the different backbone
orientation that we see in C1 is translated onto the overall structure of the dimer.
In fact, the dihedral angle between the two coordination planes defined by two
groups of Cl—Rh—Cl of the four-membered ‘RhClRhCl’ ring is 173.9(4)°, which
is the maximum value among the three μ-chloro-bridged rhodium(I) dimers that
we compare. As a consequence, [RhCl{(M,S,S)-p-Tol-6F-BIPHESO}]2 (C1)
possesses the largest intermetallic separation [3.5577(7) Å]. Finally, another
expected outcome of the sulfoxide moiety binding to the metal through its lone
electron pair at sulfur is the fact that the S=O / S-O bond length is shortened
[going from 1.494(2) (av) Å in ligand 3 to 1.476(4) (av) Å in C1].
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Figure 5. Two views of the molecular structure of [RhCl{(M,S,S)-p-Tol-6F-
BIPHESO}]2 (C1) (50% probability ellipsoids; hydrogen atoms omitted for
clarity). Selected bond lengths (Å) and angles (deg): Rh1-Cl1, 2.3757(13), Rh1-
Cl2, 2.3625(14); Rh1-S1, 2.1833(13), Rh1-S2, 2.1926(14); S1-O1, 1.481(4), S2-O2,
1.471(4); S1-Rh1-S2, 99.15(5); Cl1-Rh1-S2, 90.58(5); Cl2-Rh1-S2, 172.83(5); Cl1-
Rh1-S1, 169.87(5); Cl2-Rh1-S1, 88.00(5); Cl1-Rh1- Cl2, 82.25(5). Rh(2)-S(4)
2.1822(14); Rh(2)-S(3) 2.1928(13); Rh(2)-Cl(2) 2.3505(13); Rh(2)-Cl(1)
2.3782(14); S(4)-Rh(2)-S(3) 98.43(5); S(4)-Rh(2)-Cl(2) 89.22(5); S(3)-
Rh(2)Cl(2)171.81(5);S(4)-Rh(2)-Cl(1)171.23(5); S(3)-Rh(2)-Cl(1); 89.77(5);
Cl(2)Rh(2)Cl(1) 82.45(5)
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Bond
4a
4b
4b
lengths/angles
C1
[RhCl(p-Tol-BINASO)]2 [RhCl(p-Tol-Me-BIPHESO)]2
[RhCl(BIPHEMP)]2
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7
8
9
Rh-S/P
Rh-Cl
2.188(1) Å(av)
2.366(1) Å(av)
1.807(6) Å(av)
3.5577(7) Å
98.79(5)°
2.192(1) Å(av)
2.370(1) Å(av)
1.804(7) Å(av)
3.0193(5) Å
98.14(4)°
2.196(1) Å(av)
2.384(1) Å(av)
1.801(4) Å(av)
3.1993(3) Å
98.00(3)°
2.198(1) Å(av)
2.406(1) Å(av)
1.854(6) Å(av)
3.3526(7) Å
91.61(6)°
C
backbone-S/P #
Rh.....Rh
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S/P-Rh-S/P
Dihedral angle
(backbone)
68.3(7)°
74.1(2)°
75.6(1)°
73.9(1)°
#
and C32/C42
Cbackbone = C12 / C22
Table 1. Structural comparison of C1 with μ2-Cl bridged dimeric disulfoxide- and
diphosphine-rhodium complexes.
With the two Rh complexes C1 and C2 at hand, we proceeded to evaluating their
enantioinduction abilities as catalyst precursors in the rhodium-catalyzed
carbon-carbon bond-forming addition reactions. We first turned our attention to
the 1,4-addition of arylboronic acids to the
α,β-unsaturated cyclic enone 2-
cyclohexen-1-one. As is shown in Table 2, experiments were carried out in a
mixture of toluene/water/KOH using our chloro-bridged precatalyst C1,
following the procedure established by our group in 2008,4a but with using a
slightly lower reaction temperature of 35 °C. To our delight, all catalytic runs
showed excellent reactivity and gave high isolated yields of product with typical
reaction runs lasting 1.5 h. Moreover, the enantioselectivities were excellent
throughout, underlining the usefulness of the new chiral disulfoxide ligand
(M,S,S)-3 in this reaction. The brief survey employing electron-donating and
electron-withdrawing boronic acids highlighted the fact that the catalytic system
is relatively insensitive to the electronic nature of the nucleophile. Furthermore,
para-, meta- as well as ortho-substituted arylboronic acids are tolerated and give
similarly high yields and enantioselectivities. Overall, the catalytic results
recorded in this first assessment of (M,S,S)-(3) were very encouraging and are
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comparable to those obtained with the 'classical' disulfoxide ligand p-Tol-
BINASO.4a
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9
O
O
C1 (1 mol%)
Ar-B(OH)2
KOH (50 mol%), Tol/H2O (10/1)
35 oC, 1-3h
Ar
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6
4a
5a-i
O
O
O
O
Cl
6aa
6ab
6ac
91% yield
96% ee (R)
92% yieldb
95% ee (R)c
85% yield
>99% ee (R)
O
O
O
O
Cl
F
6ae
6ad
6af
92% yield
96% ee (R)
90% yield
96% ee (R)
90% yield
99% ee (R)
O
O
O
F
CF3
6ag
6ah
6ai
92% yield
99% ee (R)
70% yield
93% ee (R)
80% yield
88% ee (R)
a Reaction conditions: Amixture of enone (0.80 mmol), boronic acid
(0.88 mmol), KOH (0.4 mmol) and C1 (1 mol%) was stirred in toluene
(1.6 mL) and H2O (0.2 mL) at 35 oC for 1-3 h. b Isolated yields after
column chromatography. c Determined by HPLC analysis; absolute
stereochemistry assigned by comparing with reported results.
Table 2. Precatalyst C1 for the 1,4-additon reactions to 2-cyclohexen-1-one.a
With these first positive results on the catalytic assessment of (M,S,S)-(3) in hand,
we moved on to study the rhodium-catalyzed arylation of N-tosylarylimines with
aryl boronic acids.16 Here, the development of chiral disulfoxide ligands is still in
its infancy with the only report containing such a ligand system having been
recently published by our group.16d The OH-bridged rhodium complex C2 was
therefore tested in this reaction with results shown in Table 3. Here again and
using extremely simple reaction conditions with low catalyst loadings of C2, high
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reactivity at room temperature gave excellent yields (up to 98%) and high
optical purities (> 90% ee) of the products. While the list of tested substrates is
not exhaustive, the substitution pattern of the imine electrophile was rather
systematically varied, pointing towards a catalyst system that can accommodate
a wide range of both different electrophiles and nucleophiles.
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Ts
HN
C2 (0.25-0.75 mol%)
Ts
Ar
Ar-B(OH)2
N
R
R
Tol/H2O (6/1),
25 oC, 12-14h
7a-h
5a,b,j
8
SO2pTol
SO2pTol
SO2pTol
HN
HN
HN
Cl
O
8ca
8aa
8ba
90% yielde
98% yieldb
94% yielde
96% ee (S)
93% ee (S)c,d
94% ee (S)
SO2pTol
SO2pTol
SO2pTol
HN
HN
HN
CF3
8da
8ea
81% yielde
8ej
82% yieldf
96% yielde
94% ee (S)
91% ee (S)
91% ee (S)
SO2pTol
SO2pTol
SO2pTol
HN
HN
HN
O
O
O
O
8fb
87% yieldf
91% ee (S)
8gb
72% yieldf
90% ee (S)
8hb
70% yielde
92% ee (S)
a Reaction conditions: A mixture of imine (0.45 mmol), boronic acid (0.90 mmol), and
C2 was stirred in toluene (6.0 mL) and H2O (1.0 mL) at 25 oC for 12-14 h. b Isolated
yields after column chromatography. c Determined by HPLC analysis; absolute
stereochemistry assigned by comparison with reported results. d 0.75 mol% C2 was
used. e 0.5 mol% C2 was used. f 0.25 mol% C2 was used.
Table 3. 1,2-addition reactions of arylboronic acids to imines catalyzed by
precatalyst C2.[a]
As a last application of this new catalyst/chiral ligand system, we finally tackled
the problem that we had encountered earlier with our atropisomeric backbone-
type chiral disulfoxides. This pertains to their apparent inability to be used
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efficiently in the rhodium-catalyzed 1,4-addition of arylboronic acids to
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chalcone-type, open chain
α,β
-unsaturated carbonyl substrates.4b It should be
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pointed out that such asymmetric additions of arylboronic acids to chalcones are
overall far less developed than normal 1,4-addition reactions and reported
methods generally provide lower enantioselectivities, 17 although creating
stereocenters that incorporate the diarylmethine motif through this reaction
would potentially provide an easy entry into this class of compounds, which
occurs in many pharmaceuticals and natural products.18 The results that we have
now obtained using our new catalyst C1 are shown in Table 4. While the
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reactivity was indeed lower than for the cyclic
α,β-unsaturated carbonyl
compound shown in Table 2, increasing the catalyst loading of C1 to 2-4 mol%
gave high yields and excellent enantioselectivities for the addition of arylboronic
acids to these chalcone-type substrates at room temperature. It should be noted
that for these substrates, we also needed to confirm the absolute
stereochemistry, as there is some uncertainty over it in the literature.19 We did
so by crystallizing product 10ab from a cold pentane solution and subjecting it
to an X-ray crystallographic analysis that confirmed the proposed absolute
stereochemistry (S). While the selectivities recorded with our catalyst are of the
highest reported, there still seem to be limitations as to what catalyst C1 can do.
For example, there is a clear dependence on the conjugation pattern of the
chalcone motif. When the R1 group was changed to a methyl group instead of a
phenyl, reactivity and enantioselectivity remained excellent, whereas when
omitting the aryl group that is conjugated to the olefinic bond (R2), both the yield
as well as the optical purity of the product dropped rather significantly (10fb, 67%
yield, 76% ee). Another limitation that remains in these conjugate addition
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reactions to chalcone-type substrates is the inability of C1 (or of any of the
previously reported catalyst systems) to add sterically demanding aryl boronic
acids to them (10ai, last entry in Table 4).20 Overall though, the new disulfoxide
ligand (M,S,S)-3, which combines both a less sterically hindered as well as a
modified, electron-poor backbone, generates a catalyst system that expands the
reactivity profile of this disulfoxide ligand family and as such further underlines
the validity of the overall design of this type of chiral disulfoxide ligands.
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O
Ar
O
C1 or ent-C1 (2-4 mol%)
Ar-B(OH)2
R1
R2
R1
R2
O
KF, Tol/H2O (2/1)
25 oC, 14h
9a-g
5a,b,k,i
10
O
O
O
O
O
Cl
10bb
81% yielde
93% ee (S)
10ab
10cb
88% yielde
93% ee (S)
86% yieldb
96% ee (S)c,d
F
F
O
O
O
O
10ak
90% yieldb
91% ee (S)
10bk
93% yieldb
94% ee (R)
10da
84% yieldb,f
93% ee (R)
O
O
O
O
O
10eb
96% yieldb,g
96% ee (S)
10fb
67% yieldb,f
76% ee (R)
10ai
<10% conversionf
a Reaction conditions: A mixture of enone (0.10 mmol), boronic acid (0.15 mmol), KF
(0.40 mmol) and precatalyst (C1 or ent-C1, 2 mol %) was stirred in toluene (1.0 mL)
and H2O (0.5 mL) at 25 oC for 14 h. b ent-C1; isolated yields after column
chromatography. c Determined by HPLC analysis. d Absolute stereochemistry
assigned by comparison with reported results. e C1; isolated yields after column
chromatography. f 4 mol % ent-C1 was used. g 3 mol % ent-C1 was used.
Table 4. Representative examples of 1,4-addition reactions to chalcones using
precatalyst C1/ent-C1.
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3. Conclusion
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In summary, we have reported the straightforward and inexpensive synthesis of
a new type of C2-symmetric chiral disulfoxide ligand bearing an electron-
deficient atropisomeric backbone. One of the diastereomers of the ligand
[(M,S,S)-3] was used to synthesize both chloro- and hydroxo-bridged dimeric
rhodium catalyst precursors C1 and C2 and both the diastereomers of the ligand
[(M,S,S)-3 and (P,S,S)-3] and the dimeric, μ-chloro-bridged rhodium complex C1
were analyzed by X-ray diffraction studies. Unfortunately, even the very flexible
atropisomeric backbone of this new ligand did not permit efficient coordination
of the (P,S,S)-3 stereoisomer to the rhodium metal center.
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The two well-defined rhodium complexes with the (M,S,S)-3 ligand were then
tested as catalysts in various addition reactions of arylboronic acids to different
kinds of electrophilic acceptors. The μ-chloro-bridged rhodium complex C1 was
shown to be highly efficient for the 1,4-addition of a variety of representative
arylboronic acids to the prototypical cyclic enone 2-cyclohexen-1-one, while the
μ-hydroxo-bridged rhodium complex C2 was successfully utilized in 1,2-addition
to N-tosylarylimines under equally simple and mild reaction conditions. Results
are overall very similar to using our previously reported atropisomeric
disulfoxide ligands, meaning that they compare very favorably to other ligand
classes that have been developed for these reactions.
Most importantly, the reactivity seen for precatalyst C1 in the addition reaction
of arylboronic acids to chalcone-type substrates expands the utility of these
atropisomeric chiral disulfoxide ligands to a new class of reactions, that
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incidentally represents one of the substrate types where this asymmetric
addition reactions does not seem to perform well with other ligand families.17a
Taken together with the fact that all of the reactions reported here can be run
under very mild conditions, the new (M,S,S)-3 ligand represents one of the most
powerful single ligands for rhodium-catalyzed addition reactions. As outlined
elsewhere,4d,21 the versatility of this particular type of chiral disulfoxide ligands
seems to originate from the appropriate synergy between classical steric and
unique electrostatic effects, enforcing high differentiation between prochiral
faces of a wide array of substrates. Overall, further studies on more electron-
deficient and / or less sterically demanding variations of our disulfoxide ligand
family seem warranted.
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4. Experimental Section
4.1. General experimental methods
All reactions were carried out using standard Schlenk lines or gloveboxes
(Innovative Technology) under a nitrogen (Schlenk lines) or argon (gloveboxes)
22
23
atmosphere. [RhCl(C2H4)2]2,
chalcones,17 and imines,
were prepared
according to literature procedures. All other chemicals were purchased from
commercial suppliers and used as received. Solvents were purged with argon
and passed through alumina columns in a solvent purification system
(Innovative Technology) or distilled under nitrogen from appropriate drying
agents and kept in gloveboxes over activated molecular sieves of appropriate
size. Solvents for NMR spectroscopy of metal complexes were degassed with
nitrogen, dried over molecular sieves and stored in gloveboxes. TLC analysis was
performed using Merck silica gel 60 F254 aluminum-backed silica plates. Column
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chromatography was conducted using Silicycle or Davisil silica gel (40-63 µm).
Optical rotations were determined using AUTOPOL I, KRÜSS P8000 or KRÜSS
P1000 polarimeters. Enantiomeric excess values were obtained by HPLC analysis
with a JASCO Chrompass system using the appropriate Daicel columns. NMR
spectra were recorded on Bruker Avance IIIHD 500 MHz or 600 MHz NMR,
Varian INOVA 300 MHz or Varian 400 MHz NMR spectrometers. Chemical shifts
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1
are given in ppm and the spectra were calibrated to the residual H and 13C
signals of the solvent or 100% CF3COOH (for 19F NMR spectra). Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), and broad (br). High-resolution mass spectra (HRMS) were performed on a
Waters LCT Premier XE mass spectrometer or a Waters GCT Premier mass
spectrometer (TOF) or a Waters LCT Premier XE instrument (TOF). X-ray
crystallography was performed on an Oxford Diffraction Gemini diffractometer
fitted with Mo or Cu Κα radiation. Elemental analyses were performed by the
Elemental Analysis Service at London Metropolitan University, UK. All catalytic
reactions were carried out in duplicates.
4.2. Synthesis of ligand and metal complexes
4.2.1. Synthesis of rac-2,2'-dibromo-6,6'-difluorobiphenyl (rac-
number: 1316276-94-4):14
2; CAS registry
Diisopropylamine (14 mL, 0.098 mol) was added to a Schlenk flask containing a
solution of n-butyllithium (38 mL, 0.098 mol, 2.54 M in hexane) in THF (150 mL)
that was cooled to -78 °C with an acetone / dry ice bath. The solution was stirred
for 1 hour reaching -20 °C. The solution was then cooled down again to -78 °C
and 1-bromo-3-fluorobenzene (10 mL, 0.089 mol) in THF (90 mL) was added
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slowly via a dropping funnel. The solution was left stirring at -78 °C for 2 hours.
Keeping the temperature at -78 °C, anhydrous CuBr (6.42 g, 0.045 mol) and LiCl
(2.28 g, 0.054 mol) were added to the solution which was stirred for another 2
hours at -78°C. Finally, benzoquinone (14.51 g, 0.134 mol) was added, the
solution was stirred for another hour at -78°C before removing the acetone/dry
ice bath and letting the solution warm slowly to room temperature.
Subsequently, the reaction was quenched and filtered through a silica pad. The
filtrate was dried with MgSO4 and the solvent removed by rotary evaporation.
The residue was chromatographed on silica gel with hexane / CH2Cl2 (8:1) to
afford the final product as a white crystalline material after drying under vacuum
(13.70 g, 0.039 mol, 88% yield). 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 7.1 Hz,
2H), 7.32 (m, 2H), 7.16 (t, J = 8.5 Hz, 2H).
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4.2.2. Synthesis of p-Tol-6F-BIPHESO (3)
In a 50 mL Schlenk flask was added rac-2,2'-dibromo-6,6'-difluorobiphenyl (2,
347.9 mg, 1.0 mmol) and THF (4.0 mL). The solution was cooled to -50 °C and n-
BuLi (0.88 mL, 2.2 mmol, 2.5M in hexane) was added dropwise via syringe. The
resulting green-yellow suspension was further stirred for 45 minutes at -50 °C
and then cooled to -78 °C. Under stirring, (1R,2S,5R)-(-)-menthyl-(S)-p-Tol-
sulfinate (647.8 mg, 2.2 mmol) in 10 mL THF was added dropwise (syringe). The
dark-grey suspension was stirred and allowed to slowly warm to room
temperature. The reaction was then quenched by addition of an aqueous NH4Cl
solution (10 mL, 1 M) and the water phase was extracted with Et2O (3 times 10
mL) and THF (3 times 5 mL). The combined organic phase was dried with MgSO4
and the solvent was then removed by rotary evaporation. The residue was
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chromatographed on silica gel with CH2Cl2 / EtOAc (2:1) to afford the two
diastereomers (P,S,S)- and (M,S,S)-p-Tol-6F-BIPHESO (3, 291.0 mg, 0.62 mmol,
62% combined yield) as white solids.24
9
(P,S,S)-p-Tol-6F-BIPHESO [(P,S,S)-3, 145.1 mg, 0.31 mmol, 31% yield, first
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diastereomer eluted from flash chromatography]: H NMR (500 MHz, CDCl3); δ
7.60–7.56 (td, J = 8.0, 5.0 Hz, 2H), 7.45 – 7.42 (m, 2H), 7.31 (t, J = 8.4 Hz, 2H), 7.14
(t, J = 2.0 Hz, 8H), 2.37 (s, 6H). 13C NMR (126 MHz, CDCl3); δ 160.0 (d, J = 253.1
Hz), 146.8, 141.8, 139.5, 132.0 (d, J = 8.4 Hz), 130.0, 125.9, 122.7, 119.2 (d, J =
17.3 Hz), 119.0 (d, J = 22.4 Hz), 21.6. 19F NMR (470 MHz, CDCl3); δ -108.71. [α]D
20
= +232.75 (c 0.80, CDCl3). M.p. 226-228 °C. Elemental analysis: Calcd for
C26H20F2O2S2: C, 66.93; H, 4.32; Found: 66.79; H, 4.26. A concentrated solution of
(P,S,S)-3 in CH2Cl2 layered with a mixture of hexane / EtOAc (3:1) afforded
colorless crystals of (P,S,S)-3 suitable for an X-ray structure analysis.
(M,S,S)-p-Tol-6F-BIPHESO [(M,S,S)-3, 146.0 mg, 0.31 mmol, 31% yield, second
diastereomer eluted from flash chromatography]:, 1H NMR (400 MHz, CDCl3); δ
8.16 (d, J = 7.1 Hz, 2H), 7.69 (m, 2H), 7.04 (d, J = 8.3 Hz, 4H), 7.02 – 6.84 (m, 6H),
2.30 (s, 6H). 13C NMR (100 MHz, CDCl3); δ 159.9 (d, J = 250.7 Hz), 146.8, 142.7,
140.7, 131.9 (d, J = 5.9 Hz), 129.9, 126.3, 119.9, 117.8 (d, J = 22.3 Hz), 115.9 (d, J =
20.1 Hz), 21.6. 19F NMR (470 MHz, CDCl3); δ -112.80. [α]D = -238.62 (c 0.59,
20
CDCl3). M.p. 240-242 °C. Elemental analysis: Calcd for C26H20F2O2S2: C, 66.93; H,
4.32; Found: 66.97; H, 4.40. A concentrated solution of (M,S,S)-3 in CH2Cl2
layered with a mixture of hexane / EtOAc (3:1) afforded colorless crystals
suitable for an X-ray structure analysis.
4.2.3. Preparation of [RhCl{(M,S,S)-p-Tol-6F-BIPHESO}]2 (C1
)
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Inside the glovebox, a solution of of (M,S,S)-p-Tol-6F-BIPHESO [(M,S,S)-3, 368.2
mg, 0.79 mmol] in CH2Cl2 (50 mL) was added to a solution of [Rh(C2H4)2Cl]2
(149.0 mg, 0.38 mmol) in CH2Cl2 (48 mL). The mixture was stirred for 15 hours
at room temperature, keeping the stopcock valve slightly open to release
ethylene. The reddish solution was then filtered through Celite® and washed
with additional CH2Cl2. The solution was concentrated to 1 mL. Pentane (15 mL)
was added drop by drop to the stirred CH2Cl2 solution of C1 in order to
precipitate the product, which was then dried under vacuum to afford the
corresponding complex as an orange-red, finely divided powder (437.7 mg, 0.36
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mmol, 94% yield). 13C DEPT-135, 1H-1H COSY, H-13C HSQC, H-13C HMBC
measurements were performed to assign all protons and carbons. X-ray quality
crystals were obtained by using the following method: Inside the glovebox,
complex C1 (11 mg) was dissolved in CH2Cl2 (0.5 mL) and the solution was
placed in an NMR tube. Diethyl ether was carefully layered on top of it (ca. 2 mL),
the NMR tube was fitted with a cap and placed inside a freezer (-30 °C) for 2
days, affording platelike orange crystals of C1.24
1H NMR (500 MHz, CD2Cl2); δ 8.07 (d, J = 7.9
13
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11
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Hz, 4H, 3-H), 7.98 (d, J = 7.9 Hz, 8H, 12,8-H),
7.51 (td, J = 8.1, 4.4 Hz, 4H, 4-H), 7.07 (d, J =
8.1 Hz, 8H, 11,9-H), 6.78 (t, J = 7.9 Hz, 4H, 5-
H), 2.35 (s, 12H, 13-H). 13C NMR (126 MHz,
CD2Cl2); δ 158.8 (d, J = 128.5 Hz, C-6), 147.5
12
9
3
5
7
O8
Cl
6
2
S
S
F
F
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Rh
O
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(C-2), 143.7 (C-7), 141.0 (C-10), 131.7 (C-4), 129.8 (C-9,11), 128.3 (C-8,12),
121.9 (C-3), 118.3 (d, J = 22.4 Hz, C-5), 114.6 (d, J = 19.4 Hz, C-1), 21.6 (C-13). 19F
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NMR (282 MHz, CD2Cl2); δ -110.90. [α]D = -554.5 (c 0.33, CD2Cl2). Elemental
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analysis: Calcd for C52H40Cl2F4O4Rh2S4: C, 51.62; H, 3.33; Found: C, 51.53; H, 3.28.
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4.2.4. Preparation of [Rh(OH){(M,S,S)-p-Tol-6F-BIPHESO}]2 (C2
)
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A solution of [RhCl{(M,S,S)-p-Tol-6F-BIPHESO}]2 (C1) (120.9 mg, 0.1 mmol) in
acetone (10 mL) was prepared in a Schlenk tube inside the glovebox. The
Schlenk tube was taken outside, connected to a Schlenk line and aqueous KOH
(0.5 mL, 2.5 M, degassed) was added under stirring. The solution was stirred at
room temperature for 1.5 hours and then the solvent was removed under
vacuum. Dichloromethane (10 mL) was added to the crude solid in the Schlenk
flask, and the organic layer was washed with degassed water (3 x 5 mL) that was
decanted off. Anhydrous Na2SO4 was added to the flask and the organic layer was
then concentrated to a small volume (~1.0 mL). At this point, the Schlenk flask
was reintroduced into the glove box and the content was filtered through
Celite® and the cake was washed with an additional amount of CH2Cl2 (ca. 4 mL).
All solvent was removed under vacuum. The residue was redissolved in a
minimum amount of CH2Cl2 (0.5 mL) and pentane (10 mL) was added drop by
drop to precipitate the product. The supernatant solution was subsequently
decanted and the residual solid was dried under vacuum for 5 hours to afford the
corresponding complex C2 as an orange-yellow, finely divided powder (82.3 mg,
0.07 mmol, 70% yield). 1H NMR (600 MHz, CD2Cl2); δ 8.09 (d, J = 5.6 Hz, 8H), 7.90
(d, J = 7.9 Hz, 4H), 7.50 – 7.47 (m, 4H), 7.07 (d, J = 8.0 Hz, 8H), 6.76 (t, J = 7.7 Hz,
4H), 2.39 (s, 12H), 0.36 (s, 2H). 13C NMR (151 MHz, CD2Cl2); δ 159.0 (d, J = 253.3
Hz), 148.0, 143.5, 142.1, 131.3, 129.6, 128.2, 121.0, 117.8 (d, J = 22.2 Hz), 114.4
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(d, J = 18.9 Hz), 21.6. 19F NMR (564 MHz, CD2Cl2); δ -110.61. Elemental analysis:
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Calcd for C52H42F4O6Rh2S4: C, 53.25; H, 3.61; Found: C, 53.18; H, 3.51.
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4.3. Typical procedure for the 1,4-addition to cyclic enones and
characterization of products
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In a 20 mL vial, inside a glove box, was added α,β-unsaturated substrate (0.80
mmol) and precatalyst C1 (9.7 mg, 1.0 mol%) followed by the addition of toluene
(1.6 mL) and arylboronic acid (0.88 mmol). The vial was fitted with a magnetic
stirbar, closed with a teflon cap, and taken out of the glovebox. Degassed KOH
(0.16 mL, 2.5 M in Milli-Q H2O, 0.40 mmol) was then added via syringe. The
reaction was stirred at 35°C for 1-3 hours. After this, the solvent was removed
under vacuum. The residue was dissolved in a minimum amount of CH2Cl2 and
charged on top of a silica gel column and purified by column chromatography
(hexane/ethyl acetate or diethyl ether as eluents). Products were then dried
under vacuum and analyzed.
All reactions were performed in duplicate. Racemic products were obtained in a
similar way but using [Rh(COD)Cl]2 (5 mol%) instead of precatalyst C1. All
reactions were performed in duplicate.
4.3.1. (R)-3-phenylcyclohexan-1-one (6aa CAS registry number: 34993-51-6)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5a (107.3 mg, 0.88
O
mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6aa
obtained as a transparent oil (128.8 mg, 0.74 mmol, 92%) yield.
1H NMR (500 MHz, CDCl3) δ 7.35 – 7.32 (m, 2H), 7.25 – 7.22 (m, 3H), 3.02 (t, J =
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11.8 Hz, 1H), 2.61– 2.38 (m, 4H), 2.18 – 2.07 (m, 2H), 1.88 – 1.79 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 211.2, 144.5, 128.8, 126.84, 126.72, 49.1, 44.9, 41.3,
32.9, 25.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C12H14ONa: 197.0942;
Found 197.0947. HPLC analysis: Daicel Chiralcel OD-H column; hexane/2-
propanol (98:2); flow = 0.5 mL/min; detected at 220 nm; 95% ee. Retention
times (first run): 23.7 min [(S) minor], 25.5 min [(R) major].4,25
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4.3.2. (R)-3-(4-methoxyphenyl)cyclohexan-1-one (6ab CAS registry number:
479586-33-9)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5b (133.7 mg,
O
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6ab
obtained as a white solid (138.1 mg, 0.68 mmol, 85% yield). 1H
O
NMR (600 MHz, CDCl3) δ 7.14 (d, J = 8.6 Hz, 2H), 6.87 (d, J =
8.6 Hz, 2H), δ 3.80 (s, 3H), 2.97 (tt, J = 11.8, 3.9 Hz, 1H), 2.69 – 2.26 (m, 4H), 2.22
– 1.95 (m, 2H), 1.91 – 1.67 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 211.3, 158.4,
136.7, 127.6, 114.1, 55.4, 49.4, 44.1, 41.3, 33.2, 25.6. HPLC analysis: Daicel
Chiralcel OJ-H column; hexane/2-propanol (99:1); flow = 1.0 mL/min; detected
at 220 nm; >99.5% ee. Retention times: 37.9 min [(S) minor], 43.2 min [(R)
major].4
4.3.3. (R)-3-(4-chlorophenyl)cyclohexan-1-one (6ac CAS registry number: 843674-
22-6)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5c (137.6 mg,
O
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6ac
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obtained as a white solid (152,2 mg, 0.73 mmol, 91% yield). H NMR (600 MHz,
CDCl3) δ 7.32 – 7.27 (m, 2H), 7.18 – 7.13 (m, 2H), 2.99 (dt, J = 11.7, 3.9 Hz, 1H),
2.57 (m, J = 1H), 2.53 – 2.42 (m, 2H), 2.37 (m, 1H), 2.22 – 1.99 (m, 2H), 1.91 –
1.70 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 210.6, 142.9, 132.5, 128.93, 128.06,
48.9, 44.2, 41.2, 32.8, 25.5. HPLC analysis: Daicel Chiralcel OJ-H column;
hexane/2-propanol (99:1); flow = 1.0 mL/min; detected at 220 nm; 96% ee.
Retention times: 23.9 min [(S) minor], 28.1 min [(R) major].4
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4.3.4. (R)-3-(3-methoxyphenyl)cyclohexan-1-one (6ad CAS registry number:
610273-85-3)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5d (133.7 mg,
O
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6ad
O
obtained as a light yellow oil (147.6 mg, 0.72 mmol, 90%
yield). 1H NMR (600 MHz, CDCl3) δ 7.28 – 7.22 (m, 2H), 6.87 – 6.70 (m, 3H), 3.81
(s, 3H), 2.98 (tt, J = 12.0, 3.9 Hz, 1H), 2.66 – 2.30 (m, 4H), 2.26 – 1.98 (m, 2H),
1.93 – 1.67 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 211.1, 160.0, 146.2, 129.8,
119.0, 112.8, 111.8, 55.3, 49.1, 44.9, 41.3, 32.8, 25.7. HPLC analysis: Daicel
Chiralcel AD-H column; hexane/2-propanol (95:5); flow = 0.5 mL/min; detected
at 220 nm; 96% ee. Retention times: 19.8 min [(S) minor], 21.2 min [(R) major].4
4.3.5. (R)-3-(3-chlorophenyl)cyclohexan-1-one (6ae CAS registry number: 479639-
20-8)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5e (137.6 mg,
O
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6ae
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was obtained as a light yellow oil (151.7 mg, 0.73 mmol, 92% yield). H NMR
(500 MHz, CDCl3) δ 7.30 – 7.18 (m, 3H), 7.09 (d, J = 7.5 Hz, 1H), 2.99 (tt, J = 11.8,
3.9 Hz, 1H), 2.58 (m, 1H), 2.54 – 2.43 (m, 2H), 2.37 (m, 1H), 2.24 – 1.99 (m, 2H),
1.93 – 1.66 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 210.4, 146.4, 134.6, 130.1,
127.04, 126.95, 125.0, 48.8, 44.5, 41.2, 32.7, 25.6. HPLC analysis: Daicel Chiralcel
OD-H column; hexane/2-propanol (99.5:0.5); flow = 0.5 mL/min; detected at 220
nm; 96% ee. Retention times: 44.9 min [(S) minor], 50.4 min [(R) major].4
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4.3.6. (R)-3-(3-fluorophenyl)cyclohexan-1-one (6af CAS registry number: 1092695-
24-3)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5f (123.1 mg,
O
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product 6af
F
was obtained as a colorless oil (138.6 mg, 0.72 mmol, 90%
1
yield). H NMR (600 MHz, CDCl3) δ 7.32 – 7.27 (m, 1H), 6.99 (d, J = 7.7 Hz, 1H),
6.96 – 6.89 (m, 2H), 3.01 (tt, J = 11.8, 3.9 Hz, 1H), 2.59 (m, 1H), 2.55 – 2.43 (m,
2H), 2.37 (m, 1H), 2.23 – 2.01 (m, 2H), 1.91 – 1.69 (m, 2H). 13C NMR (151 MHz,
CDCl3) δ 210.6, 163.7 (d, J = 246.1 Hz), 147.0 (d, J = 7.6 Hz), 130.3 (d, J = 9.1 Hz),
122.4 (d, J = 1.5 Hz), 113.73 (d, J = 12.1 Hz), 113.59 (d, J = 12.1 Hz), 48.8, 44.5 (d, J
= 1.5 Hz), 41.2, 32.7, 25.5. HPLC analysis: Daicel Chiralcel OJ-H column;
hexane/2-propanol (99:1); flow = 0.5 mL/min; detected at 220 nm; 99% ee.
Retention times: 31.4 min [(R) major], 35.1 min [(S) minor].4,6k
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4.3.7. (R)-3-(3-(trifluoromethyl)phenyl)cyclohexan-1-one
number: 1160606-10-9)
(6ag CAS registry
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Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5g (167.1 mg,
0.88 mmol); C1 (9.7 mg, 0.008 mmol, 1.0 mol%). Product
6ag was obtained as a white solid (177.7 mg, 0.73 mmol, 92%
O
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yield). H NMR (600 MHz, CDCl3) δ 7.53 – 7.38 (m, 4H), 3.07 (tt, J = 12.1, 3.9 Hz,
1H), 2.61 (m, 1H), 2.58 – 2.45 (m, 2H), 2.39 (m, 1H), 2.25 – 2.04 (m, 2H), 1.96 –
1.70 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 210.2, 145.3, 131.1 (q, J = 31.7 Hz),
130.20, 129.3, 125.1, 123.76 (q, J = 4.5 Hz), 123.45 (q, J = 4.5 Hz), 48.8, 44.6, 41.2,
32.7, 25.6. HRMS (ESI--TOF) m/z: [M - H]- Calcd. for C13H12OF3: 241.0840; Found
241.0845. HPLC analysis: Daicel Chiralcel OJ-H column; hexane/2-propanol
(99.5:0.5); flow = 1.0 mL/min; detected at 220 nm; 99% ee. Retention times: 20.1
min [(R) major], 23.4 min [(S)minor].4,26
4.3.8. (R)-3-(2-fluorophenyl)cyclohexan-1-one (6ah CAS registry number: 141632-
32-8)
Enone 4a (76.9 mg, 0.8 mmol); boronic acid 5h (167.9 mg, 1.2
O
F
mmol); C1 (9.7, 0.008 mmol, 1.0 mol%). Product 6ah was
1
obtained as a colorless oil (108.1 mg, 0.56 mmol, 70% yield). H
NMR (500 MHz, CDCl3) δ 7.21 (d, J = 7.8 Hz, 2H), 7.15 – 7.07 (m, 1H), 7.02 (d, J =
8.1 Hz, 1H), 3.31 (td, J = 8.4, 3.6 Hz, 1H), 2.57 (d, J = 8.6 Hz, 2H), 2.52 – 2.27 (m,
2H), 2.22 – 1.97 (m, 2H), 1.98 – 1.68 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 210.5,
160.6 (d, J = 245.7 Hz), 131.1 (d, J = 13.9 Hz), 128.2 (d, J = 8.8 Hz), 127.7 (d, J =
5.0 Hz), 124.4 (d, J = 3.8 Hz), 115.7 (d, J = 22.7 Hz), 47.3, 41.3, 38.2 (d, J = 1.3 Hz),
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