Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by a Sterically Highly Demanding Chiral-at-Rhodium Lewis Acid

Article abstract of DOI:10.1021/acs.joc.7b01394

The enantioselective catalytic alkynylation of aromatic aldehydes is reported using a sterically highly hindered bis-cyclometalated rhodium-based Lewis acid catalyst featuring the octahedral metal as the only stereogenic center. Yields of 58-98% with 79-9

Full text of DOI:10.1021/acs.joc.7b01394

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Article
Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed
by a Sterically Highly Demanding Chiral-at-Rhodium Lewis Acid
Shipeng Luo, Xiao Zhang, Yu Zheng, Klaus Harms, Lilu Zhang, and Eric Meggers
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01394 • Publication Date (Web): 31 Jul 2017
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The Journal of Organic Chemistry
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Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by a Sterically
Highly Demanding Chiral-at-Rhodium Lewis Acid
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Shipeng Luo,1,2 Xiao Zhang,1 Yu Zheng,1 Klaus Harms,1 Lilu Zhang,1 and Eric Meggers1*
1Fachbereich Chemie, PhilippsꢀUniversität Marburg, HansꢀMeerweinꢀStrasse 4, 35043 Marburg,
Germany
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2School of Chemistry and Environmental Engineering, Jiangsu University of Technology,
Changzhou 213001, P. R. China
Abstract: The enantioselective catalytic alkynylation of aromatic aldehydes is reported using a
sterically highly hindered bisꢀcyclometalated rhodiumꢀbased Lewis acid catalyst featuring the
octahedral metal as the only stereogenic center. Yields of 58ꢀ98% with 79ꢀ98% enantiomeric excess
were achieved using 1ꢀ2 mol% of catalyst. This work complements previous work from our
laboratory on the enantioselective alkynylation of 2ꢀtrifluoroacetyl imidazoles (Chem. Eur. J. 2016,
22, 11977ꢀ11981) and trifluoromethyl ketones (J. Am. Chem. Soc. 2017, 139, 4322ꢀ4325) using
catalysts with octahedral metalꢀcentered chirality.
TOC graphic:
PF6
PF6
S
S
N
N
Me
Me
Me
Me
C
C
C
N
N
N
Rh
N
Rh
N
N
C
S
S
-enantiomer
-enantiomer
OH
1-2 mol% cat
(3.0 eq)
R
H
O
Ar
Et3N (0.2 eq), room temperature
up to 98% yield, up to 98% ee
Ar
H
R
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Introduction
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Enantioenriched propargylic alcohols are versatile chiral building blocks in organic synthesis since
both hydroxyl group and triple bond can be subjected to further reactions, including etherifications,
nucleophilic propargylic substitutions, a variety of 1,2ꢀadditions, coupling reactions, cyclizations,
isomerizations, and reduction of the alkyne to the corresponding alkene or alkane, among others.1
The enantioselective addition of alkyne nucleophiles to aldehydes or ketones constitutes one of the
most direct methods for the preparation of enantioenriched propargylic alcohols.2 We recently
contributed to this area of research by applying chiralꢀatꢀmetal3 Lewis acids to the catalytic
enantioselective alkynylation of carbonyl compounds.4 The chiral diastereomeric rhodium
complexes ΛꢀRhPP and ꢀꢀRhPP containing two metallocyclic 2ꢀphenylꢀ5,6ꢀ(S,S)ꢀpinenopyridine
ligands showed excellent results for the enantioselective alkynylation of 2ꢀtrifluoroacetyl
imidazoles,5 whereas the chiralꢀatꢀruthenium complexes Λ/ꢀꢀRu1,2 containing two
Nꢀ(2ꢀpyridyl)ꢀsubstituted Nꢀheterocyclic carbene chelate ligands catalyzed the alkynylation of
trifluoromethyl ketones with very high enantioselectivity at catalysts loadings down to 0.2 mol%
(Scheme 1a).6 However, both catalysts featured limitations as they appear to be restricted to
trifluoromethyl ketone substrates. Here, we report that a sterically highly hindered
chiralꢀatꢀrhodium Lewis acid Λ/ꢀꢀRhS(Ad) catalyzes the alkynylation of aromatic aldehydes with
high enantioselectivity at room temperature only requiring catalytic amounts of a base such as
triethylamine (Scheme 1b).
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a) Previous work
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PF6
PF6
6
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N
Rh
N
N
Rh
N
Me
Me
Me
C
C
N
N
N
N
C
C
Me
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R
-RhPP
-RhPP
O
HO
N
N
R
H
N
CF3
CF3
N
Et3N, THF, r.t.
Requirement for imidazole and CF3
up to 99% yield
up to >99% ee
(PF6)2
Me
R
(PF6)2
R
N
N
N
Ru
N
N
Ru
N
N
Me
Me
C
C
C
C
N
N
N
N
N
N
Mes
Mes
Mes
Mes
N
N
N
Me
R
R
-Ru1 (R = 3,5-Me2Ph)
-Ru2 (R = H)
-Ru1 (R = 3,5-Me2Ph)
-Ru2 (R = H)
R
O
R
H
HO
Ar
CF3
Ar
CF3
Et3N, THF, 60 C
up to 99% yield
up to >99% ee
Requirement for CF3
b) This work
PF6
PF6
S
N
S
N
Me
Me
C
N
C
C
N
N
Rh
Rh
N
C
N
N
S
Me
Me
S
-RhS(Ad)
-RhS(Ad)
OH
R
H
O
Ar
Ar
H
Et3N, DMAc, r.t.
R
up to 98% yield
up to 98% ee
Scheme 1. Enantioselective alkynylations of ketones and aldehydes with chiralꢀatꢀmetal Lewis acid
catalysts.
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Results and Discussion
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Catalyst synthesis. The synthesis of enantiopure Λꢀ and ꢀꢀRhS(Ad) is shown in Scheme 2 and
follows the synthesis of related bisꢀcyclometalated chiralꢀatꢀrhodium catalysts developed in our
laboratory.7,8 Accordingly, rhodium trichloride hydrate was first converted into the corresponding
racemic bisꢀcyclometalated catalyst in a yield of 72% by reacting with 2.05 equivalents
5ꢀ(1ꢀadamantyl)ꢀ2ꢀphenylbenzothiazole (1) at reflux for 4.5 hours, followed by treatment with 2.5
equivalents of AgPF6 in MeCN at 60 °C for 16 hours. Afterwards, the racemic catalyst was reacted
with the chiral salicyloxazoline auxiliary (R)ꢀ2 to afford a diastereomeric mixture of the complexes
Λꢀ(R)ꢀ3 and ꢁꢀ(R)ꢀ3, which could be resolved by silica gel chromatography. Finally, starting from
the individual pure diastereoisomers Λꢀ(R)ꢀ3 (41% yield) or ꢁꢀ(R)ꢀ3 (45% yield), the coordinated
auxiliary ligands were removed by treatment with trifluoroacetic acid in MeCN to generate the
individual enantiomers ΛꢀRhS(Ad) (90% yield) and ꢀꢀRhS(Ad) (90% yield). The structure of
ΛꢀRhS(Ad) including the absolute configuration was confirmed by Xꢀray crystallography (Figure
1).
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RhCl3•3H2O
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S
1) EtO(CH2)2OH/ H2O
(3:1, reflux, 4.5 h)
72%
N
Ad
2) AgPF6, CH3CN, 60 C
1
(2.05 equiv)
PF6
Ad
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S
N
Me
C
N
Rh
N
N
C
Me
S
Ad
rac-RhS(Ad)
F
O
N
K2CO3/ EtOH, 70 °C
Ph
OH
(R)-2
41%
45%
Ph
chromatography
Ph
N
N
O
O
C
C
C
C
N
N
F
F
Rh
Rh
N
O
O
N
-(R)-3
-(R)-3
CF3CO2H, CH3CN, r.t.
then NH4PF6
90%
90%
-RhS(Ad)
-RhS(Ad)
Scheme 2. Auxiliary mediated synthesis of Λꢀ and ꢀꢀRhS(Ad).
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Figure 1. Crystal structure of the catalyst ΛꢀRhS(Ad) (CCDC number 1552828). ORTEP drawing
with 50% thermal ellipsoids.
Initial Catalysis Experiments. We chose the alkynylation of the electronꢀdeficient
pentafluorobenzaldehyde (4a) with phenylacetylene (5a) to provide the propargylic alcohol 6a as
our model reaction. Our previously reported catalyst ꢀꢀRhPP at a catalyst loading of 4.0 mol%
using an excess of 3 equivalents of phenylacetylene and Et3N (0.2 equivalents) as the base afforded
the propargylic alcohol (S)ꢀ6a at room temperature after 16 hours with a yield of 51% but
disappointing 25% ee (Table 1, entry 1). The previously reported chiralꢀatꢀruthenium catalyst
ꢀꢀRu1 provided under the same conditions (S)ꢀ6a with 88% yield and 48% ee (entry 2). Further
improvements were observed when the chiralꢀatꢀrhodium catalysts ꢀꢀRhO and ꢀꢀRhS were
examined, providing (S)ꢀ6a with yields of 92% and 71% ee respectively 89% ee (entries 3 and 4).
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We next envisioned to improve the effectivity of the asymmetric induction by increasing the steric
hindrance of the chiral Lewis acid. Gratifyingly, when we replaced the tertꢀbutyl groups of the
catalyst ꢀꢀRhS with adamantyl substituents, providing the catalyst ꢀꢀRhS(Ad), the
enantioselectivity could be raised significantly to 92% ee (entry 5). Next, after having identified a
suitable catalyst, we focused on optimizing the reaction conditions. We found that the catalyst
loading could be reduced to 2.0 mol% (entry 6) and even 1.0 mol% (entry 7) without affecting
enantioselectivity. Screening different solvents (entries 8ꢀ11 and Supporting Information) resulted
in the identification of N,Nꢀdimethylacetamide (DMAc) as the solvent of choice, reaching 95%
yield and 96% ee after 24 hours at room temperature by just using 1.0 mol% of the catalyst
ꢀꢀRhS(Ad) (entry 11). Interesting for practical reasons, the catalytic reaction can be performed
under air without affecting the enantioselectivity although the yield decreased somewhat (entry 12),
and the reaction is not sensitive to the addition of water (10 equivalents based on
pentafluorobenzaldehyde) (entry 13). Control experiments confirm that both the base9 and the
catalyst are essential for this reaction (entries 14 and 15).
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Table 1. Initial experiments and optimizations.
4
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PF6
PF6
tBu
S
X
6
7
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9
N
N
Me
Me
Me
C
C
C
N
N
N
N
Rh
N
Rh
N
C
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Me
S
X
tBu
RhS(Ad)
RhO
RhS
-
-
(X = O),
-
(X = S)
Ph
5a
H
F
F
OH
F
(3.0 eq)
F
F
CHO
F
F
F
conditions
F
4a
F
(S)-6a
Entry Catalyst
Conditionsa
standard
standard
standard
standard
standard
standard
standard
standard
standard
standard
standard
under air
added waterd
1.2 eq of 5a
2.0 eq of 5a
no base
Time (h) Solvent
Yield (%)b Ee (%)c
1
16
16
16
16
16
16
24
48
24
24
24
24
24
24
24
24
24
THF
51
88
92
92
92
92
91
25
92
81
95
83
95
82
90
0
25
48
71
89
92
92
92
95
93
94
96
96
96
94
96
n.a.e
n.a.
ꢀꢀRhPP (4.0 mol%)
ꢀꢀRu1 (4.0 mol%)
ꢀꢀRhO (4.0 mol%)
ꢀꢀRhS (4.0 mol%)
2
THF
3
THF
4
THF
5
THF
ꢀꢀRhS(Ad) (4.0 mol%)
ꢀꢀRhS(Ad) (2.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
ꢀꢀRhS(Ad) (1.0 mol%)
none
6
THF
7
THF
8
CH3CN
DCM
DMF
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
9
10
11
12
13
14
15
16
17
standard
0
a
Standard conditions: Pentafluorobenzaldehyde (0.2 mmol), phenylacetylene (0.6 mmol), Et3N
(0.04 mmol), in 0.4 mL solvent was stirred at room temperature under an atmosphere of molecular
nitrogen. Isolated yield. Determined by HPLC on a chiral stationary phase. d Presence of 2.0
b
c
mmol of H2O. e n.a. = not applicable.
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Substrates scope. First, we investigated the substrate scope with respect to aldehydes (Scheme 3).
The reaction of phenylacetylene (5a) with a range of benzaldehydes bearing one or more
electronꢀwithdrawing or electronꢀdonating substituents (F, Br, I, CF3, CO2Me, SMe, OMe, Me) in
the phenyl moiety were examined under optimized reaction conditions (1ꢀ2 mol% ꢀꢀRhS(Ad), 0.2
equiv. Et3N, DMAc, r.t., 24ꢀ48 hours) and provided the corresponding propargylic alcohols 6aꢀ6n in
58ꢀ98% yield and with 86ꢀ98% ee. For example, 4ꢀbromoꢀ2ꢀfluorobenzaldehyde afforded the
propargylic alcohol 6d in 98% yield and with 94% ee, whereas 3,4,5ꢀtrimethoxylbenzaldehyde
provided the propargylic alcohol 6l in 91% yield and with excellent 98% ee. It is noticeable that for
all these examples, enantioselectivities are higher compared to benzaldehyde itself, which leads to
propargylic alcohol 6o in 82% yield with only 85% ee. The heteroaromatic aldehyde
4ꢀbromothiopheneꢀ2ꢀcarboxaldehyde provided the propargylic alcohol 6p also with 82% yield and
85% ee. However, the aliphatic aldehydes phenylacetaldehyde and hexanal yielded the
corresponding propargylic alcohols 6q and 6r only with very low enantioselectivity. We propose
that the requirement for aromatic aldehydes stems for a πꢀπ stacking between the substrate and one
cyclometalated ligands of the catalyst. Finally, we compared RhS(Ad) and RhS for three additional
randomly selected aldehydes (products 6d, 6h, and 6l) which confirmed that RhS(Ad) is the
catalyst of choice over RhS for this reaction (Scheme 3). While the two catalysts provide 6l with
identical enantiomeric excess, RhS(Ad) provides ee values that are 2% higher for the propargylic
alcohols 6d and 6h.
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Next, we evaluated the substrate scope with respect to different terminal alkynes using the
reaction with pentafluorobenzaldehyde under our standard conditions. Gratifyingly, the substrate
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scope appears to be broad as shown in Scheme 4. Phenylacetylenes with alkyl, electronꢀdonating,
and electronꢀaccepting substituents provide the corresponding propargylic alcohols 6sꢀ6x in 80ꢀ98%
yields and 92ꢀ96% ee. 2ꢀEthynylthiophene gave the propargyl alcohol 6y in 90% yield and 95% ee.
A propargyl alcohol with a conjugated alkene 6z was synthesized with 95% yield and 94% ee.
Furthermore, aliphatic substituents (nBu and tBu) and a trimethylsilyl group are also well
accommodated and afford the propargylic alcohols 6aa1 (94% ee), 6ab (90% ee), and 6ac (91% ee)
with satisfactory enantioselectivities. Alone the highly bulky (iPr)3Si group reduces the
enantiomeric excess to 79% ee (product 6ad). Typically, 1 mol% of ꢀꢀRhS(Ad) was sufficient for
most substrates, with the only exception of oꢀmethylphenylacetylene which reacted more sluggishly
and needed an increased catalysts loading of 2 mol% in order to achieve satisfactory results. We
also reacted 3,4,5ꢀtrimethoxybenzaldehyde with pꢀmethoxyphenylacetylene and 1ꢀhexyne under
standard conditions and obtained the corresponding propargyl alcohols in 98% yield with 97% ee
(6x2) and 77% yield with 95% ee (6aa2), respectively. Furthermore, the reaction of benzaldehyde
with 4ꢀtertꢀbutylbenzaldehyde under standard conditions afforded the expected propargyl alcohol in
85% yield with 84% ee (6v2). These results are consistent with the trends obtained with
pentafluorobenzaldehyde.
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Ph
H
OH
4
5
6
7
8
9
(5a, 3.0 eq)
R
R CHO
-RhS(Ad) (1 or 2 mol%)
Et3N (0.2 eq)
6a-r
4a-r
DMAC, r.t.
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F
F
F
F
F
F
F
F
6ab
6ba
6ca
84% yield
88% ee
95% yield
96% ee
92% yield
86% ee
F
Br
F3C
F
6db
6ea
6fb
94% yield
91% ee
82% yield
98% yield, 94% ee
(96% yield, 92% ee)c 90% ee
Br
I
MeO2C
6ga
6ha
6ib
95% yield
92% ee
82% yield
90% ee
94% yield, 93% ee
(94% yield, 91% ee)c
MeO
Br
MeO
MeO
MeO
MeO
6ja
6ka
6la
71% yield
90% ee
84% yield
94% ee
91% yield, 98% ee
(90% yield, 98% ee)c
Me
MeS
6ma
6na
58% yield
90% ee
6oa
80% yield
93% ee
82% yield
85% ee
S
nPent
Bn
Br
6pa
6qb
92% yield
26% ee
6rb
93% yield
4% ee
82% yield
85% ee
Scheme 3. Substrate scope with respect to aldehydes. 2.0 mol% catalyst loading was used. b 1.0
a
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mol% catalyst loading was used. c Reaction performed with ΛꢀRhS instead for comparison.
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Ar CHO
OH
4a
Ar
R
H
-RhS(Ad) (1.0 mol%)
Et3N (0.2 eq)
R
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(5, 3.0 eq)
6s-6ad
DMAC, r.t.
Me
Me
Me
6u (Ar = C6F5)a
6s (Ar = C6F5)
6t (Ar = C6F5)
95% yield
95% ee
96% yield
96% ee
80% yield
92% ee
tBu
F
MeO
6v1 (Ar = C6F5):
6x1 (Ar = C6F5):
6w (Ar = C6F5)
98% yield, 96% ee
6v2 (Ar = C6H5):a
85% yield, 84% ee
98% yield, 94% ee
6x2 (Ar = 3,4,5-(MeO)3Ph):a
98% yield, 97% ee
95% yield
96% ee
S
nBu
6aa1 (Ar = C6F5)
92% yield, 94% ee
6aa2 (Ar = 3,4,5-(MeO)3Ph):a
77% yield, 95% ee
6y (Ar = C6F5)
6z (Ar = C6F5)
90% yield
95% ee
95% yield
94% ee
tBu
Me3Si
(iPr)3Si
6ab (Ar = C6F5)
6ac (Ar = C6F5)
6ad (Ar = C6F5)
82% yield
90% ee
83% yield
91% ee
81% yield
79% ee
Scheme 4. Substrate scope with respect to terminal alkynes. a 2.0 mol% catalyst loading instead.
Comparison with other catalysts. Many laboratories have contributed to the catalytic
enantioselective alkynylation of aldehydes and excellent methods exist.2,10ꢀ14 Much efforts have
been dedicated to alkylzincꢀmediated enantioselective alkynylations in the presence of chiral
ligands such as ephedrine derivatives, or chiral catalysts.10 The most attractive methods rely on a
“soft metalation strategy”2 in which terminal alkynes are metalated in situ using catalytic amounts
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of zinc(II),11 indium(III),12 or copper(I)13 salts in the presence of a base and a chiral ligand.
Furthermore, a rutheniumꢀPheboxꢀcatalyzed enantioselective alkynylation has been developed.14
Our rhodiumꢀcatalyzed method contributes to the softꢀmetalation strategy. We are convinced that
this method will find applications as it is characterized by a combination of low catalyst loadings
(1ꢀ2 mol%), modest amounts of base (e.g. 20 mol% Et3N), room temperature conditions, little
influence by air, and no effect by small amounts of water.
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It is striking that the here introduced rhodium complex RhS(Ad) and the previously reported
sterically less demanding congener RhS are capable of catalyzing the enantioselective alkynylation
of aromatic aldehydes, whereas the complexes RhPP and Ru1 −which follow a quite similar
structural blueprint− only provide inferior results with respect to both catalytic activity and
enantioselectivity (Table 1, entries 1 and 2). Interestingly, likewise RhS(Ad) is not suitable for the
catalytic enantioselective alkynylation of trifluoroacetyl imidazoles (preferred substrates for RhPP)
and trifluoroacetophenones (preferred substrates for Ru1) (see Supporting Information for details).
The reasons for this distinct reactivity pattern is unclear but it demonstrates that even allegedly
small structural changes in these propellerꢀtype chiralꢀatꢀmetal complexes results in significantly
modified catalytic properties.
Conclusions
In summary, we here reported the enantioselective alkynylation of aromatic aldehydes employing a
sterically highly demanding rhodium(III)ꢀbased chiralꢀatꢀmetal Lewis acid catalyst. The new
catalyst expands our family of bisꢀcyclometalated iridium(III) and rhodium(III) catalysts relying
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exclusively on metalꢀcentered chirality for the asymmetric induction. ꢀꢀRhS(Ad) at catalyst
loadings of 1ꢀ2 mol% converts aromatic aldehydes and terminal alkynes into their corresponding
chiral propargylic alcohols in 58ꢀ98% yields and with 79ꢀ98% ee at room temperature. Whereas the
enantioselectivity with aromatic aldehydes significantly varies with the nature of the substituents
and the substitution pattern, a broad scope exist with respect to terminal alkynes. This method
nicely complements previously developed catalytic enantioselective alkynylations of
2ꢀtrifluoroacetylimidazoles and aromatic trifluoromethylketones with chiralꢀatꢀmetal catalysts. The
application of catalytic enantioselective alkynylations to the efficient synthesis of drugs and drug
candidates is ongoing in our laboratory.
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Experimental Section
General Methods and Materials. All reactions were carried out under an atmosphere of
nitrogen with magnetic stirring. Catalytic reactions were performed in Schlenk tubes (10 mL).
Solvents were freshly distilled under nitrogen from calcium hydride (CH3CN and CH2Cl2) or
sodium/benzophenone (THF). All aldehydes were purchased with highest purity or were freshly
distilled. Oother reagents from commercial suppliers were used without further purification. Flash
column chromatography was performed with silica gel 60 M from MachereyꢀNagel (irreg. shaped,
230ꢀ400 mesh, pH 6.8, pore volume: 0.81 mL × g–1, mean pore size: 66 Å, specific surface: 492 m2
1
× g–1, particle size distribution: 0.5% < 25 ꢁm and 1.7% > 71 ꢁm, water content: 1.6%). H NMR,
protonꢀdecoupled 13C NMR spectra, and protonꢀcoupled 19F NMR spectra were recorded on Bruker
Avance 300 (300 MHz) or 500 (500 MHz) spectrometers at ambient temperature. NMR standards
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were used as follows: H NMR spectroscopy: δ = 7.26 ppm (CDCl3), δ = 5.32 ppm (CD2Cl2). C
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NMR spectroscopy:
δ
= 77.0 ppm (CDCl3), δ = 54.0 ppm (CD2Cl2). All 13C NMR signals are
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singlets unless noted otherwise. IR spectra were recorded on a Bruker Alpha FTꢀIR
spectrophotometer. CD spectra were recorded on a JASCO Jꢀ810 CD spectropolarimeter (200ꢀ600
nm, 1 nm bandwidth, 50 nm/min scanning speed, accumulation of 3 scans). Highꢀresolution mass
spectra were recorded either on an HRꢀESIꢀMS from Bruker En Apex Ultra 7.0 TFTꢀMS instrument
(FTꢀICR analyzer) or HRꢀFDꢀMS from AccuTOF GCv 4G (JEOL) Time of Flight (TOF analyzer).
HPLC chromatography on chiral stationary phase was performed with Agilent 1200 or 1260 HPLC
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systems. Optical rotations were measured on a PerkinꢀElmer 241 polarimeter with [α]D values
reported in degrees with concentrations reported in g/100 mL.
Synthesis of the benzothiazole ligand 1
Oꢀ(4ꢀ(Adamantanꢀ1ꢀyl)ꢀ2ꢀnitrophenyl) dimethylcarbamothioate (7). To a suspension of NaH
(60% in mineral oil, 600 mg, 15.0 mmol) in DMF (40.0 mL) at 0 º C were added
4ꢀ(adamantanꢀ1ꢀyl)ꢀ2ꢀnitrophenol15 (1.37 g, 5.0 mmol) in DMF (5 mL) dropwise under an
atmosphere of nitrogen. After being stirred for 30 minutes at 0 ºC, dimethylcarbamothioic chloride
(1.23 g, 10 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was warmed to 90 º
C and stirred at that temperature for 2 hours. The reaction mixture was cooled to 0 ºC and
quenched with a solution of aqueous saturated NH4Cl (50 mL) dropwise, and then diluted with H2O
(200 mL). The mixture was extracted with EtOAc (3 × 50 mL), the combined organic layers were
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washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica gel (Rf = 0.2, EtOAc/
nꢀhexane = 1:20) to give compound 7 (1.26 g, 3.5 mmol, yield: 70%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 2.4 Hz, 1H), 7.65 (dd, J =8.6, 2.4 Hz, 1H), 7.18 (d, J =
8.6 Hz, 1H), 3.46 (s, 3H), 3.38 (s, 3H), 2.18ꢀ2.08 (m, 3H), 1.97ꢀ1.89 (m, 6H), 1.87ꢀ1.65 (m, 6H).
13C NMR (75 MHz, CDCl3) δ 186.2, 150.4, 144.8, 141.6, 131.2, 125.9, 122.3, 43.5, 42.9, 39.0,
36.44, 36.38, 28.7. IR (film): ν (cm−1) 2900, 2845, 2533, 1490, 1450, 1395, 1343, 1288, 1229, 1178,
1133, 1083, 1053, 837, 717, 760, 516, 453. HRMS (ESI, m/z) calcd for C19H25N2O3S [M+H]+:
361.1580, found: 361.1581.
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4ꢀ(Adamantanꢀ1ꢀyl)ꢀ2ꢀnitrobenzenethiol (8). Compound 7 (1.38 g, 4.0 mmol) was heated
without solvent and stirred at 200 ºC for 3 hours at an atmosphere of nitrogen. Thereafter, the
reaction mixture was cooled to room temperature, KOH (448 mg, 8.0 mmol) in MeOH/THF (1/1,
40 mL) was added and stirred for 3 hours at room temperature. Then, the reaction mixture was
cooled to 0 ºC and HCl aqueous (1 mol/L) was added dropwise until pH = 2.0. The mixture was
diluted with water (100 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was recrystallized from EtOAc/ nꢀhexane to give compound 8 (948
1
mg, 82%) as a yellow solid. H NMR (300 MHz, CDCl3) δ 8.20 (d, J = 2.1 Hz, 1H), 7.45 (dd, J
=8.4, 2.1 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.96 (s, 1H), 2.18ꢀ2.08 (m, 3H), 1.94ꢀ1.86 (m, 6H),
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1.86ꢀ1.68 (m, 6H). C NMR (75 MHz, CDCl3) δ 150.1, 145.3, 131.7, 131.0, 129.9, 122.6, 42.8,
36.4, 36.1, 28.7. IR (film): ν (cm−1) 2907, 2874, 2849, 2549, 1514, 1475, 1449, 1335, 1303, 1278,
1124, 1052, 978, 885, 834, 809, 751, 679, 572, 455. HRMS (ESI, m/z) calcd for C16H18NO2S
[MꢀH]ꢀ: 288.1064, found: 288.1062.
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5ꢀ(Adamantanꢀ1ꢀyl)ꢀ2ꢀphenylbenzo[d]thiazole (1). Under an atmosphere of nitrogen, to a
mixture of compound 8 (578 mg, 2.0 mmol) and metal indium powder (460 mg, 4.0 mmol) in
anhydrous toluene (20.0 mL) were added acetic acid (1.14 mL, 20 mmol) and
(trimethoxymethyl)benzene (0.687 mL, 4.0 mmol) in one portion. The mixture was warmed to 100
°C and stirred for 24 hours at the same temperature. The reaction mixture was cooled to room
temperature and the solid was filtered, then a solution of saturated NH4Cl (25 mL) was added and
the reaction mixture was diluted with water (50 mL). The mixture was extracted with EtOAc (3 ×
20 mL) and the combined organic layers were washed with brine (5 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel (Rf = 0.2, EtOAc/ nꢀhexane = 1:50) to provide benzothiazole ligand 1
1
(304 mg, 0.88 mmol, 44%) as a yellow solid. H NMR (300 MHz, CDCl3) δ 8.16ꢀ8.04 (m, 3H),
7.84 (d, J = 8.4 Hz, 1H), 7.57ꢀ7.43 (m, 4H), 2.20ꢀ2.10 (m, 3H), 2.08ꢀ1.96 (m, 6H), 1.88ꢀ1.74 (m,
13
6H). C NMR (75 MHz, CDCl3) δ 168.0, 154.6, 150.4, 133.8, 132.0, 130.8, 129.0, 127.5, 122.9,
121.0, 119.5, 43.4, 36.8, 36.4, 29.0. IR (film): ν (cm−1) 2900, 1845, 1600, 1541, 1477, 1448, 1313,
1241, 962, 921, 878, 828, 801, 761, 689, 652, 481. HRMS (ESI, m/z) calcd for C23H24NS [M+H]+:
346.1624, found: 346.1625.
Synthesis of rac-RhS(Ad). The racemic rhodium catalyst was synthesized according to a route
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reported in our laboratory with some modifications.8 Benzothiazole ligand 1 (362 mg, 1.05 mmol)
was added to RhCl3•3H2O (131 mg, 0.50 mmol) in a solvent mixture of 2ꢀethoxyethanol and water
(v/v = 3/1, 10 mL). The reaction mixture was heated at 120 °C for 4.5 hours under an atmosphere of
nitrogen, then it was concentrated by reduced pressure to give a brown black solid. The solid was
used in the next step without further purification. To the brown black solid in CH3CN (10 mL) was
added AgPF6 (316 mg, 1.25 mmol) in one portion and stirred at 60 °C overnight under an atmosphere
of nitrogen. After being cooled to room temperature, the mixture was filtered and the filtrate was
collected, evaporated to dryness, and purified by column chromatography on silica gel (Rf = 0.2,
100% CH2Cl2 to CH2Cl2/CH3CN = 20:1) to provide racꢀRhS(Ad) (366 mg, 0.36 mmol, 72% yield
over two steps) as a pale yellow solid. 1H NMR (300 MHz, CD2Cl2) δ 8.43 (d, J = 1.0 Hz, 2H), 8.03
(d, J = 8.6 Hz, 2H), 7.76ꢀ7.64 (m, 4H), 7.03 (t, J = 7.4 Hz, 2H), 6.88ꢀ6.78 (m, 2H), 6.20 (d, J = 7.8 Hz,
2H), 2.18 (s, 6H), 2.17ꢀ2.09 (m, 6H), 2.08ꢀ1.98 (m, 12H), 1.90ꢀ1.74 (m, 12H). 13C NMR (75 MHz,
CD2Cl2) δ 176.94, 176.89, 161.1, 160.7, 153.1, 150.4, 140.6, 133.6, 131.4, 129.31, 129.30, 126.4,
125.2, 124.7, 123.1, 122.3, 117.0, 44.0, 37.4, 37.1, 29.6, 3.8. IR (film): ν (cm−1) 2903, 2847, 1578,
1444, 1416, 1302, 1236, 1184, 1127, 984, 879, 753, 724, 659, 522, 477, 446. HRMS (ESI, m/z) calcd
for C46H44N2RhS2 [Mꢀ2CH3CNꢀPF6]+: 791.1995, found: 791.2001.
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Synthesis of Enantiomerically Pure Rhodium Catalysts. Λꢀ(R)ꢀ3 and ꢀꢀ(R)ꢀ3. To a mixture of
racꢀRhS(Ad) (305 mg, 0.30 mmol) and K2CO3 (124 mg, 0.60 mmol) in absolute ethanol (6.0 mL)
was added (R)ꢀ3ꢀfluoroꢀ2ꢀ(4ꢀphenylꢀ4,5ꢀdihydrooxazolꢀ2ꢀyl)phenol ((R)-2, 91 mg, 0.33 mmol) in
one portion. After being stirred at 70 °C for 16 hours under an atmosphere of nitrogen, the reaction
mixture was cooled to room temperature and concentrated to dryness. The residue was subjected to
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flash chromatography on silica gel (Rf = 0.1, CH2Cl2/ nꢀhexane = 1/20 to 5:1) providing ꢁꢀ(R)-3 (142
mg, 45% yield) as a yellow solid and Λꢀ(R)-3 (132 mg, 41% yield) as a yellow solid (for Λꢀ(R)-3, a
second flash chromatography is necessary to get the pure product), respectively. ꢀꢀ(R)ꢀ3: CD
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(MeOH): λ, nm (ꢁε, Mꢀ1cmꢀ1) 418 (+22), 347 (−30), 300 (+36), 272 (−6), 249 (−7), 235 (+6). H
NMR (500 MHz, CD2Cl2) δ 8.87 (d, J = 1.7 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.6 Hz,
1H), 7.64ꢀ7.56 (m, 2H), 7.53 (dd, J = 8.6, 1.9 Hz, 1H), 7.45 (dd, J = 8.6, 1.9 Hz, 1H), 7.37ꢀ7.33 (m,
1H), 6.99ꢀ6.77 (m, 6H), 6.74ꢀ6.68 (m, 2H), 6.43 (dd, J = 8.8, 1.0 Hz, 1H), 6.27 (d, J = 7.2 Hz, 2H),
5.88ꢀ5.82 (m, 2H), 4.90ꢀ4.84 (m, 2H), 4.01ꢀ3.95 (m, 1H), 2.20ꢀ2.12 (m, 3H), 2.04ꢀ1.94 (m, 9H),
1.92ꢀ1.75 (m, 12H), 1.75ꢀ1.64 (m, 6H). 13C NMR (125 MHz, CD2Cl2) δ 177.6, 177.5, 175.92, 175.90,
175.08, 175.05, 170.3, 170.0, 168.6, 168.3, 166.22, 166.19, 164.0 (d, J = 257.3 Hz), 152.1, 152.0,
151.9, 151.6, 142.0, 141.60, 141.57, 135.4, 133.4, 133.0, 132.9, 130.2, 129.8, 129.7, 129.1, 128.2,
127.7, 126.1, 126.0, 123.8, 123.4, 123.2, 122.60, 122.57, 121.5, 121.02, 121.00, 119.8, 116.4, 101.1
(d, J = 6.2 Hz), 98.7 (d, J = 24.0 Hz), 75.8, 69.7, 43.8, 43.7, 37.15 (2C), 37.07, 37.02, 29.64, 29.61. IR
(film): ν (cm−1) 3055, 2913, 1849, 1735, 1615, 1583, 1527, 1443, 1373, 1316, 1290, 1218, 1158,
1095, 1032, 988, 941, 793, 753, 727, 694, 664, 609, 579, 530, 454. HRMS (ESI, m/z) calcd for
C61H56FN3O2RhS2 [M+H]+: 1048.2848, found: 1048.2844. Λꢀ(R)ꢀ3: CD (MeOH): λ, nm (ꢁε,
Mꢀ1cmꢀ1) 420 (−23), 376 (+16), 298 (−24), 274 (+14), 249 (+17), 226 (+6). H NMR (500 MHz,
1
CD2Cl2) δ 8.97 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.6
Hz, 1H), 7.61ꢀ7.57 (m, 1H), 7.56ꢀ7.48 (m, 2H), 7.29 (dd, J = 7.6, 1.0 Hz, 1H), 8.96ꢀ6.74 (m, 8H), 6.60
(td, J = 7.3, 1.0 Hz, 1H), 6.36ꢀ6.28 (m, 3H), 6.03 (d, J = 7.8 Hz, 1H), 5.91 (qd, J = 7.8, 1.0 Hz, 1H),
4.23 (dd, J = 9.3, 8.4 Hz, 1H), 4.03 (dd, J = 11.1, 9.3 Hz, 1H), 3.93 (dd, J = 11.1, 8.4 Hz, 1H),
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2.12ꢀ2.06 (m, 3H), 2.00ꢀ1.86 (m, 9H), 1.84ꢀ1.72 (m, 12H), 1.70ꢀ1.56 (m, 6H). 13C NMR (125 MHz,
CD2Cl2) δ 176.8, 176.7, 176.53, 176.50, 174.69, 174.67, 169.9, 169.6, 168.8, 168.6, 167.3, 163.6 (d, J
= 254.4 Hz), 153.0, 151.7, 151.6, 151.3, 141.3, 140.6, 139.7, 135.5, 133.6, 133.1, 133.0, 130.4, 129.8,
129.0, 128.9, 128.4, 127.7, 127.6, 126.0, 125.8, 124.0, 123.8, 123.1, 122.5, 122.2, 122.1, 120.26,
120.25, 119.1, 117.8, 117.0, 103.2 (d, J = 6.6 Hz), 98.7 (d, J = 23.0 Hz), 75.0, 70.2, 43.7, 43.6, 37.19,
37.15, 37.10, 37.07, 29.6. IR (film): ν (cm−1) 3054, 2900, 2846, 1617, 1579, 1530, 1442, 1372, 1317,
1291, 1264, 1221, 1095, 1031, 986, 792, 753, 726, 696, 665, 582, 529, 453. HRMS (ESI, m/z) calcd
for C61H56FN3O2RhS2 [M+H]+: 1048.2848, found: 1048.2844.
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ΛꢀRhS(Ad) and ꢀꢀRhS(Ad). To a suspension of Λꢀ(R)ꢀ3 (210 mg, 0.20 mmol) or ꢁꢀ(R)ꢀ3 (210 mg,
0.20 mmol) in CH3CN (5 mL) was added TFA (88 ꢁL, 1.2 mmol) in one portion and then stirred at
room temperature for 0.5 hours in the dark. The color of the mixture changed to colorless. The
reaction mixture was evaporated to dryness, then subjected to the flash chromatography on silica
gel (100% CH2Cl2 to CH2Cl2/ CH3CN = 20:1) to remove the auxiliary carefully, followed by the
addition of excess NH4PF6 (30 equiv) on the top of the silica gel in the column, and an eluent
(CH2Cl2/CH3CN = 10:1 to 5:1) was used to exchange the counter ion. The obtained pale yellow
filtrate was concentrated, providing the enantiopure catalysts ΛꢀRhS(Ad) (183 mg, 0.18 mmol,
90% yield) or ꢁꢀRhS(Ad) (183 mg, 0.18 mmol, 90% yield) as yellow solids. CD (CH3OH) for
ΛꢀRhS(Ad): λ, nm (ꢁε, Mꢀ1cmꢀ1) 407 (–42), 366 (+76), 358 (+66), 299 (–60), 259 (+29), 245 (+38).
CD (CH3OH) for ꢀꢀ RhS(Ad): λ, nm (ꢁε, Mꢀ1cmꢀ1) 406 (+44), 365 (–66), 358 (–58), 298 (+69), 260
(–20), 244 (–25).
General Procedure for the Alkynylation of Aromatic Aldehydes. A dried 10 mL Schlenk
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tube was charged with the rhodium catalyst ꢁꢀRhS(Ad) (1ꢀ2 mol%) and the corresponding
aldehydes (0.20 mmol, 1.0 eq). The tube was purged with nitrogen, DMAc (0.4 mL) and Et3N (5.6
µL, 0.2 eq, Merck) were added via syringe, followed by adding the corresponding alkynes (0.60
mmol, 3.0 eq). The vial was sealed and the reaction was stirred at room temperature for 24ꢀ48 hours
under an atmosphere of nitrogen. Then, the reaction mixture was diluted with CH2Cl2 (2 mL) and
silica (200 mg) was added. The solvent was removed under reduce pressure and the residue was
purified by flash chromatography on silica gel to afford the corresponding propargylic alcohols.
Racemic reference products were obtained using racꢀRhS(Ad).
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(S)ꢀ1ꢀ(Perfluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6a).10f Starting from pentafluorobenzaldehyde
(39.2 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢁꢀRhS(Ad) (2.0 mg, 0.002
mmol), according to the general procedure, reacting at room temperature for 24 hours to give 6a as
a white solid (56.6 mg, 0.190 mmol, yield: 95%). Rf = 0.3 (10% ethyl acetate in nꢀhexane).
Enantiomeric excess was established by HPLC analysis using a Daicel Chiralcel ASꢀH column, ee =
96% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 95:5, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 8.3 min, tr (minor) = 12.4 min). [α]D = −10.2° (c 1.0, CH2Cl2). H NMR (300 MHz, CDCl3) δ
7.49ꢀ7.41 (m, 2H), 7.37ꢀ7.29 (m, 3H), 5.98 (d, J = 7.8 Hz, 1H), 2.71 (d, J = 7.8 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 131.9, 129.2, 128.4, 121.5, 86.7, 85.5, 55.5. IR: 3209, 2921, 2188, 1499, 1332,
1294, 1120, 1032, 987, 799, 855, 692, 632, 570, 478. 19F NMR (282 MHz, CDCl3) –144.18 ꢀ
–144.36 (m, 2F), –154.44 ꢀ –154.66 (m, 1F), –161.98 ꢀ –161.26 (m, 2F). HRMS (FD, m/z) calcd for
C15H7F5O [M]+: 298.0412, found: 298.0410.
(R)ꢀ1ꢀ(3,5ꢀDifluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6b).11b Starting from 3,5ꢀdifluorobenzaldeꢀ
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hyde (28.4 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004
mmol), according to the general procedure, reacting at room temperature for 24 hours to give 6b as
a white solid (44.9 mg, 0.184 mmol, yield: 92%). Rf = 0.3 (10% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ASꢀH column, ee =
86% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 96:4, flow rate 1.0 mL/min, 25 °C, tr (major)
= 12.2 min, tr (minor) = 14.0 min). [α]D22 = +9.4° (c 1.0, EtOH). Lit.11b: [α]D25 = +11° (c 1.0, EtOH,
99.8% ee for Rꢀconfiguration). 1H NMR (300 MHz, CDCl3) δ 7.55ꢀ7.43 (m, 2H), 7.41ꢀ7.29 (m, 3H),
7.22ꢀ7.10 (m, 2H), 6.85ꢀ6.73 (m, 1H), 5.67 (d, J = 5.6 Hz, 1H), 2.46 (d, J = 5.6 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 163.0 (dd, J = 249.1, 12.5 Hz), 161.4 (t, J = 8.8 Hz), 131.8, 129.0, 128.4, 121.8,
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109.6 (dd, J = 17.6, 8.4 Hz), 103.6 (t, J = 5.4 Hz), 87.4, 87.2, 63.0 (t, J = 2.2 Hz). F NMR (282
MHz, CDCl3) δ –63.36. IR (film): ν (cm−1) 3326, 2924, 2854, 2227, 1621, 1595, 1443, 1317, 1116,
1035, 978, 917, 857, 753, 685, 635, 572, 515, 428. HRMS (ESI, m/z) calcd for C15H9F2O [MꢀH]ꢀ:
243.0627, found: 243.0626.
(S)ꢀ1ꢀ(2ꢀFluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6c).16 Starting from 2ꢀfluorobenzaldehyde
(24.8 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004
mmol), according to the general procedure, reacting at room temperature for 48 hours to give 6c as
a pale yellow oil (38.0 mg, 0.168 mmol, yield: 84%). Rf = 0.3 (20% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee =
88% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 9.5 min, tr (minor) = 12.5 min). [α]D = –4.8° (c 1.0, CHCl3). Lit.16: [α]D = +6.5° (c 0.71,
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CHCl3, 94% ee for Rꢀconfiguration). H NMR (300 MHz, CDCl3) δ 7.80ꢀ7.70 (m, 1H), 7.53ꢀ7.45
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(m, 2H), 7.41ꢀ7.29 (m, 4H), 7.24ꢀ7.05 (m, 2H), 5.98 (s, 1H), 2.58 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 160.2 (d, J = 248.4 Hz), 131.8, 130.2 (d, J = 8.3 Hz), 128.6, 128.4 (d, J = 3.5 Hz), 128.3,
127.9 (d, J = 13.2 Hz), 124.4 (d, J = 3.5 Hz), 122.2, 115.6 (d, J = 21.2 Hz), 87.6, 86.6, 59.6 (d, J =
5.0 Hz). 19F NMR (282 MHz, CDCl3) δ –119.88. IR (film): ν (cm−1) 3347, 2907, 2851, 2238, 2851,
1602, 1504, 1440, 1416, 1291, 1224, 1156, 1096, 1020, 961, 835, 754, 664, 555, 515. HRMS (ESI,
m/z) calcd for C15H10F [M+H–H2O]+: 209.0761, found: 209.0762.
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(S)ꢀ1ꢀ(4ꢀBromoꢀ2ꢀfluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6d). Starting from 4ꢀbromoꢀ2ꢀ
fluorobenzaldehyde (46.4 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad)
(2.0 mg, 0.002 mmol), according to the general procedure, reacting at room temperature for 24
hours to give 6d as a white solid (59.8 mg, 0.196 mmol, yield: 98%). Rf = 0.3 (20% ethyl acetate in
nꢀhexane). Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ASꢀH
column, ee = 94% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 96:4, flow rate 1.0 mL/min,
25 °C, tr (major) = 18.7 min, tr (minor) = 21.0 min). [α]D22 = –12.8° (c 1.0, CH2Cl2). 1H NMR (300
MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.49ꢀ7.43 (m, 2H), 7.38ꢀ7.26 (m, 5H), 5.92 (d, J = 5.8 Hz,
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1H), 2.41 (d, J = 5.8 Hz, 1H). C NMR (75 MHz, CDCl3) δ 159.9 (d, J = 253.2 Hz), 131.8, 129.6
(d, J = 4.2 Hz), 128.8, 128.3, 127.7 (d, J = 3.6 Hz), 127.1 (d, J = 13.2 Hz), 122.7 (d, J = 9.6 Hz),
122.0, 119.3 (d, J = 14.6 Hz), 87.0, 86.9, 59.1 (d, J = 4.6 Hz). 19F NMR (282 MHz, CDCl3) δ
–117.08. IR (film): ν (cm−1) 3322, 3087, 2220, 1602, 1576, 1479, 1396, 1245, 1217, 1042, 963, 872,
827, 752, 683, 662, 586, 539, 509, 473. HRMS (ESI, m/z) calcd for C15H11BrFO [M+H]+: 304.9972,
found: 304.9975.
(R)ꢀ1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6e).16 Starting from 4ꢀfluorobenzaldehyde
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(24.8 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004
mmol), according to the general procedure, reacting at room temperature for 48 hours to give 6e as
a pale yellow oil (37.1 mg, 0.164 mmol, yield: 82%). Rf = 0.3 (20% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee =
90% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 9.5 min, tr (minor) = 25.8 min). [α]D = +6.0° (c 1.0, CHCl3). Lit.16: [α]D = –6.3° (c 0.78,
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CHCl3, 94% ee for Sꢀconfiguration). H NMR (300 MHz, CDCl3) δ 7.64ꢀ7.56 (m, 2H), 7.51ꢀ7.45
(m, 2H), 7.37ꢀ7.29 (m, 3H), 7.14ꢀ7.04 (m, 2H), 5.68 (s, 1H), 2.47 (s, 1H), 13C NMR (75 MHz,
CDCl3) δ 162.6 (d, J = 247.9 Hz), 136.5 (d, J = 3.1 Hz), 131.7, 128.7, 128. 6 (d, J = 8.3 Hz), 128.3,
122.2, 115.5 (d, J = 21.8 Hz), 88.5, 86.9, 64.4. 19F NMR (282 MHz, CDCl3) δ –114.12. IR (film): ν
(cm−1) 3309, 2928, 2209, 1589, 1488, 1452, 1225, 1177, 1022, 961, 834, 751, 689, 630, 582, 530,
498. HRMS (ESI, m/z) calcd for C15H11FONa [M+Na]+: 249.0686, found: 249.0687.
(R)ꢀ3ꢀPhenylꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propꢀ2ꢀynꢀ1ꢀol
(6f).14
Starting
from
4ꢀ(trifluoromethyl)benzaldehyde (34.2 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and
ꢀꢀRhS(Ad) (2.0 mg, 0.002 mmol), according to the general procedure, reacting at room
temperature for 24 hours to give 6f as a white solid (51.9 mg, 0.188 mmol, yield: 94%). Rf = 0.3
(20% ethyl acetate in nꢀhexane). Enantiomeric excess established by HPLC analysis using a Daicel
Chiralcel ODꢀH column, ee = 91% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90: 10, flow
rate 1.0 mL/min, 25 °C, tr (major) = 8.0 min, tr (minor) = 25.0 min). [α]D22 = +11.8° (c 1.0, EtOH).
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Lit.14: [α]D = +10.9° (c 1.0, EtOH, 90% ee for Rꢀconfiguration). H NMR (300 MHz, CDCl3) δ
7.74 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.51ꢀ7.43 (m, 2H), 7.39ꢀ7.29 (m, 3H), 5.76 (s,
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1H), 2.41 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 144.4, 131.8, 130.5 (q, J = 32.5 Hz), 128.9, 128.4,
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127.0, 125.6 (q, J = 3.8 Hz), 124.0 (q, J = 272.5 Hz), 122.0, 87.9, 87.3, 64.4. F NMR (282 MHz,
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CDCl3) δ –63.36 (3H). IR (film): ν (cm−1) 3367, 2225, 1619, 1489, 1418, 1323, 1163, 1117, 1064,
1017, 962, 922, 842, 754, 689, 660, 604, 533, 475, 442. HRMS (ESI, m/z) calcd for C16H10F3O
[MꢀH]ꢀ: 275.0689, found: 275.0691.
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(R)ꢀMethylꢀ4ꢀ(1ꢀhydroxyꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)benzoate (6g).17 Starting from methyl
4ꢀformyl benzoate (32.8 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad)
(4.1 mg, 0.004 mmol), according to the general procedure, reacting at room temperature for 48
hours to give 6g as a pale yellow oil (43.7 mg, 0.164 mmol, yield: 82%). Rf = 0.3 (20% ethyl
acetate in nꢀhexane). Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel
ODꢀH column, ee = 90% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol =90:10, flow rate 1.0
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mL/min, 25 °C, tr (major) = 15.7 min, tr (minor) = 47.2 min). [α]D = +6.4° (c 1.0, CHCl3). Lit.17:
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[α]D = +7.56° (c 1.5, CHCl3, 97% ee for Rꢀconfiguration). H NMR (300 MHz, CDCl3) δ
8.10ꢀ8.04 (m, 2H), 7.72ꢀ7.04 (m, 2H), 7.50ꢀ7.44 (m, 2H), 7.37ꢀ7.29 (m, 3H), 5.74 (d, J = 5.6 Hz,
1H), 3.93 (s, 3H), 2.58 (d, J = 5.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 166.8, 145.4, 131.7, 130.1,
129.9, 128.8, 128.3, 126.6, 122.1, 88.1, 87.1, 64.6, 52.2. IR (film): ν (cm−1) 3340, 2949, 2922, 2230,
1714, 1607, 1487, 1429, 1282, 1186, 1107, 1039, 1019, 960, 862, 838, 803, 756, 732, 689, 611, 552,
522, 480. HRMS (ESI, m/z) calcd for C17H14O3Na [M+Na]+: 289.0835, found: 289.0836.
(R)ꢀ1ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6h).14 Starting from 4ꢀbromobenzaldehyde
(37.0 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004
mmol), according to the general procedure, reacting at room temperature for 24 hours to give 6h as
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a white solid (54.0 mg, 0.188 mmol, yield: 94%). Rf = 0.3 (20% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee =
93% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 9.7 min, tr (minor) = 22.6 min). [α]D = +7.6° (c 1.0, CHCl3). Lit.14: [α]D = +7.9° (c 0.76,
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CHCl3, 93% ee for Rꢀconfiguration), and Daicel Chiralcel ODꢀH column, 254 nm, nꢀhexane/
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isopropanol = 80:20, flow rate 1.0 mL/min, 25 °C. tr (major) = 6.7 min, tr (minor) = 21.2 min. H
NMR (300 MHz, CDCl3) δ 7.51ꢀ7.43 (m, 6H), 7.37ꢀ7.29 (m, 3H), 5.66 (d, J = 6.0 Hz, 1H), 2.35 (d,
13
J = 6.0 Hz, 1H). C NMR (75 MHz, CDCl3) δ 139.6, 131.7 (2C), 128.8, 128.41, 128.35, 122.4,
122.1, 88.1, 87.0, 64.4. IR (film): ν (cm−1) 3332, 2929, 2229, 1483, 1399, 1285, 1237, 1175, 1070,
1006, 951, 841, 794, 749, 686, 580, 531, 499, 471, 409. HRMS (ESI, m/z) calcd for C15H10BrO
[MꢀH]ꢀ: 284.9921, found: 284.9921.
(R)ꢀ1ꢀ(4ꢀIodophenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6i).18 Starting from 4ꢀIodobenzaldehyde (46.4
mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004 mmol),
according to the general procedure, reacting at room temperature for 24 hours to give 6i as a brown
solid (63.5 mg, 0.19 mmol, yield: 95%). Rf = 0.3 (20% ethyl acetate in nꢀhexane). Enantiomeric
excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee = 92% (HPLC:
ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major) = 11.2 min,
tr (minor) = 35.9 min). [α]D22 = +11.6° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.77ꢀ7.69 (m,
13
2H), 7.49ꢀ7.43 (m, 2H), 7.41ꢀ7.29 (m, 5H), 5.64 (d, J = 6.0 Hz, 1H), 2.36 (d, J = 6.0 Hz, 1H). C
NMR (75 MHz, CDCl3) δ 140.3, 137.7, 131.7, 128.8, 128.6, 128.3, 122.1, 94.1, 88.1, 87.0, 64.5. IR
(film): ν (cm−1) 3318, 3055, 2230, 1483, 1399, 1285, 1237, 1175, 1069, 1006, 951, 841, 794, 749,
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686, 580, 531, 499, 471, 409. HRMS (ESI, m/z) calcd for C15H10IO [MꢀH]ꢀ: 332.9782, found:
332.9783.
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(R)ꢀ1ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6j).16 Starting from 4ꢀmethoxybenzaldehyde
(30.4 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004
mmol), according to the general procedure, reacting at room temperature for 48 hours to give 6j as a
pale yellow oil (33.8 mg, 0.142 mmol, yield: 71%). Rf = 0.3 (20% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee =
90% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 16.3 min, tr (minor) = 30.0 min). [α]D = +4.4° (c 1.0, CHCl3). Lit.16: [α]D = ꢀ5.4° (c 0.78,
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CHCl3, 93% ee for Sꢀconfiguration). H NMR (300 MHz, CDCl3) δ 7.59ꢀ7.57 (m, 2H), 7.50ꢀ7.44
(m, 2H), 7.37ꢀ7.29 (m, 3H), 6.97ꢀ6.29 (m, 2H), 5.65 (d, J = 5.6 Hz, 1H), 3.82 (s, 3H), 2.23 (d, J =
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5.6 Hz, 1H). C NMR (75 MHz, CDCl3) δ 159.8, 133.0, 131.7, 128.5, 128.3, 128.2, 122.5, 114.0,
88.9, 86.5, 64.8, 55.3. IR (film): ν (cm−1) 3352, 2922, 2854, 2221, 1596, 1490, 1283, 1261, 1179,
1084, 1029, 955, 751, 685, 549, 463. HRMS (FD, m/z) calcd for C16H14O2 [M]+: 238.0994, found:
238.0977.
(R)ꢀ1ꢀ(3ꢀBromoꢀ4ꢀmethoxyphenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6k). Starting from 3ꢀbromoꢀ4ꢀ
methoxybenzaldehyde (43.0 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and
ꢀꢀRhS(Ad) (4.1 mg, 0.004 mmol), according to the general procedure, reacting at room
temperature for 48 hours to give 6k as a pale yellow oil (53.3 mg, 0.168 mmol, yield: 84%). Rf =
0.3 (20% ethyl acetate in nꢀhexane). Enantiomeric excess established by HPLC analysis using a
Daicel Chiralpak ASꢀH column, ee = 94% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10,
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flow rate 1.0 mL/min, 25 °C, tr (major) = 16.4 min, tr (minor) = 17.6 min). [α]D = +7.0° (c 1.0,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 2.1 Hz, 1H), 7.55ꢀ7.43 (m, 3H), 7.37ꢀ7.29 (m,
3H), 6.91 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 3.90 (s, 3H), 2.39 (s, 1H). 13C NMR (75 MHz, CDCl3) δ
155.9, 134.3, 131.8, 131.7, 128.7, 128.3, 127.0, 122.2, 111.8, 111.7, 88.3, 86.9, 64.0, 56.3. IR (film):
ν (cm−1) 3360, 2839, 2200, 1596, 1491, 1442, 1402, 1257, 1183, 1150, 1050, 1018, 965, 890, 858,
814, 753, 683, 618, 569, 524, 471, 434. HRMS (ESI, m/z) calcd for C16H12BrO [M+HꢀH2O]+:
299.0066, found: 299.0067.
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(R)ꢀ3ꢀPhenylꢀ1ꢀ(3,4,5ꢀtrimethoxyphenyl)propꢀ2ꢀynꢀ1ꢀol (6l).10n Starting from 3,4,5ꢀtrimethoxyꢀ
benzaldehyde (39.2 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1
mg, 0.004 mmol), according to the general procedure, reacting at room temperature for 24 hours to
give 6l as a white solid (54.3 mg, 0.182 mmol, yield: 91%). Rf = 0.3 (30% ethyl acetate in
nꢀhexane). Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ASꢀH
column, ee = 98% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 80:20, flow rate 1.0 mL/min,
25 °C, tr (major) = 14.3 min, tr (minor) = 15.6 min). [α]D22 = +8.8° (c 1.0, CHCl3). Lit.10n: [α]D
=
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–6.1° (c 1.3, CHCl3, 82% ee for Sꢀconfiguration). 1H NMR (300 MHz, CDCl3) δ 7.51ꢀ7.43 (m, 2H),
7.37ꢀ7.31 (m, 3H), 6.86 (s, 2H), 5.64 (d, J = 5.9 Hz, 1H), 3.89 (s, 6H), 3.86 (s, 3H), 2.39 (d, J = 5.9
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 153.4, 138.1, 136.3, 131.7, 128.7, 128.4, 122.3, 103.8, 88.6,
86.7, 65.2, 60.8, 56.2. IR (film): ν (cm−1) 3311, 2931, 2839, 2219, 1592, 1502, 1458, 1416, 1325,
1239, 1187, 1070, 1035, 998, 917, 841, 754, 687, 529, 487. HRMS (ESI, m/z) calcd for C18H18O4Na
[M+Na]+: 321.1097, found: 321.1097.
(R)ꢀ1ꢀ(4ꢀ(Methylthio)phenyl)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀol (6m). Starting from 4ꢀ(methylthio)
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benzaldehyde (30.4 mg, 0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1
mg, 0.004 mmol), according to the general procedure, reacting at room temperature for 48 hours to
give 6m as a pale yellow oil (40.7 mg, 0.16 mmol, yield: 80%); Rf = 0.3 (20% ethyl acetate in
nꢀhexane). Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ASꢀH
column, ee = 93% (HPLC: ASꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min,
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25 °C, tr (major) = 20.3 min, tr (minor) = 22.4 min). [α]D = +5.0° (c 1.0, CH2Cl2). 1H NMR (300
MHz, CDCl3) δ 7.53ꢀ7.47 (m, 2H), 7.46ꢀ7.39 (m, 2H), 7.33ꢀ7.21 (m, 5H), 5.61 (d, J = 5.2 Hz, 1H),
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2.46 (s, 3H), 2.36 (d, J = 5.2 Hz, 1H). C NMR (75 MHz, CDCl3) δ 138.9, 137.5, 131.7, 128.6,
128.3, 127.3, 126.7, 122.4, 88.6, 86.7, 64.7, 15.8. IR (film): ν (cm−1) 3355, 2917, 2850, 2224, 1594,
1486, 1414, 1288, 1263, 1183, 1090, 1019, 957, 815 750, 685, 599, 549, 518, 467. HRMS (ESI, m/z)
calcd for C16H13S [M+HꢀH2O]+: 237.0372, found: 237.0373.
(S)ꢀ3ꢀPhenylꢀ1ꢀ(oꢀtolyl)propꢀ2ꢀynꢀ1ꢀol (6n).16 Starting from 2ꢀmethylbenzaldehyde (24.0 mg,
0.20 mmol), phenylacetylene (61.3 mg, 0.60 mmol) and ꢀꢀRhS(Ad) (4.1 mg, 0.004 mmol),
according to the general procedure, reacting at room temperature for 48 hours to give 6n as a pale
yellow oil (25.7 mg, 0.116 mmol, yield: 58%). Rf = 0.3 (20% ethyl acetate in nꢀhexane).
Enantiomeric excess established by HPLC analysis using a Daicel Chiralcel ODꢀH column, ee =
90% (HPLC: ODꢀH, 254 nm, nꢀhexane/ isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr (major)
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= 10.0 min, tr (minor) = 20.2 min). [α]D = −9.8° (c 1.0, CHCl3). Lit.16: [α]D = +11.9° (c 1.0,
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CHCl3, 95% ee for Rꢀconfiguration). H NMR (300 MHz, CDCl3) δ 7.67ꢀ7.59 (m, 2H), 7.51ꢀ7.43
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(m, 2H), 7.39ꢀ7.25 (m, 6H), 5.85 (d, J = 5.2 Hz, 1H), 2.51 (s, 3H), 2.18 (d, J = 5.2 Hz, 1H). C
NMR (75 MHz, CDCl3) δ 138.4, 136.0, 131.7, 130.8, 128.53, 128.46, 128.3, 126.6, 126.3, 122.5,
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