Theoretical Elucidation of Potential Enantioselectivity in a Pd-Catalyzed Aromatic C-H Coupling Reaction

Article abstract of DOI:10.1021/acs.joc.6b02675

The mechanism of an aromatic C-H coupling reaction between heteroarenes and arylboronic acids using a Pd catalyst was theoretically and experimentally investigated. We identified the C-B transmetalation as the rate-determining step. The (S)-catalyst-reactant complex was found to be stabilized by hyperconjugation between π-orbitals on the tolyl group and the S-O σ* antibonding orbital in the catalyst ligand. Our findings suggest routes for the design of new, improved Pd catalysts with higher stereoselectivity.

Full text of DOI:10.1021/acs.joc.6b02675

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Note
Theoretical Elucidation of Potential Enantioselectivity
in a Pd-Catalyzed Aromatic C-H Coupling Reaction
Yoshio Nishimoto, Hiroki Kondo, Kazuya Yamaguchi, Daisuke
Yokogawa, Junichiro Yamaguchi, Kenichiro Itami, and Stephan Irle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02675 • Publication Date (Web): 11 Apr 2017
Downloaded from http://pubs.acs.org on April 12, 2017
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Theoretical Elucidation of Potential
Enantioselectivity in a Pd-Catalyzed Aromatic C–H
Coupling Reaction
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Yoshio Nishimoto,1,† Hiroki Kondo,1 Kazuya Yamaguchi,1 Daisuke Yokogawa,1,2 Junichiro
Yamaguchi,1,‡ Kenichiro Itami,1,2,3 and Stephan Irle*,1,2
1Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
2Institue of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya 464-8602, Japan.
3JST ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Nagoya 464-8602, Japan.
E-mail: sirle@chem.nagoya-u.ac.jp
Table of Contents/Abstract Graphic
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ABSTRACT. The mechanism of an aromatic C–H coupling reaction between heteroarenes and
arylboronic acids using a Pd catalyst has been theoretically and experimentally investigated. We
identified the C–B transmetalation as the rate-determining step. The (S) catalyst-reactant
complex was found to be stabilized by hyperconjugation between p-orbitals on the tolyl group
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and the S–O s* anti-bonding orbital in the catalyst ligand. Our findings suggest routes for the
design of new, improved Pd catalysts with higher stereoselectivity.
C–H functionalization is a rapidly growing field in organic chemistry because of its
potential applications in the synthesis of pharmaceuticals, natural products, agrochemicals, and
organic materials.1 The utility of C–H functionalization is particularly pronounced when
structural isomers and/or stereoisomers can be distinguished. As one of the most fundamental
reactions, the C–H coupling of heteroarenes with arylboron compounds has been extensively
studied both experimentally2 and computationally.2a,3 However, this type of reaction usually
requires a stoichiometric amount of co-oxidants such as 1,4-benzoquinone, Cu(II) halides and
Ag(I) salts, which results in chemical waste except in some rare cases.4 Moreover, these catalysts
generally exhibit low reactivity when sterically demanding substrates are employed.
Recently, Itami, Yamaguchi, and coworkers discovered an aromatic C–H coupling
reaction of heteroarenes and sterically hindered arylboronic acids utilizing a Pd/Fe dual catalyst
that could overcome the above-mentioned drawbacks.5 The dual catalyst consists of Pd(II)-
sulfoxide-oxazoline (sox) and iron-phthalocyanine (FePc), where FePc is considered to oxidize
Pd(0) to Pd(II) with oxygen in the air as the terminal oxidant. The reaction can be applied to an
enantioselective aromatic C–H coupling reaction between 2,3-dimethylthiophene (1A) and a
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hindered arylboronic acid 2a to afford the coupling product 3Aa (Figure 1). Despite the
aforementioned attractive features, the highest enantiomeric excess (ee) value was 61%,5 and
understanding of the reaction mechanism, which would aid in developing a catalyst which
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delivers
a
higher ee, has been limited. Although enantioselective C–H activation of
diarylmethanes and C(sp3)–H groups has been reported, atropselective C–H coupling for the
synthesis of biaryl compounds is rare.6 Herein, we report an experimental substituent effect study
of a model reaction as well as a theoretical investigation to clarify the reaction mechanism of the
representative reaction shown in Figure 1.
Me
Me
Me
Me
Me
Me
H
(HO)2B
10 mol% Pd-sox (L1)
5 mol% FePc
+
Me
Me
S
S
DMAc, 70 ˚C, 24 h
air
2a
1A
3Aa
61% yield, 61% ee
O
N
O
S
N
N
N
N
FeII
N
N
N
Me
Me
N
Me
sox
FePc
Figure 1. Aromatic C–H coupling reaction of a thiophene derivative and a hindered arylboronic
acid, assisted by a Pd/Fe dual catalyst.
All of structures were optimized using the density functional theory (DFT)7 as
implemented in Gaussian 09.8 We selected B3PW91 exchange–correlation functional9 using the
ultrafine grid with 6-31G(d) and LANL2DZ basis set for typical and Pd atoms respectively
(abbreviated as BSI).10 The character of stationary points has been confirmed with normal mode
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analysis. Thermodynamical correction was calculated at 343.15 K. The connections of stationary
points were verified by intrinsic reaction coordinate (IRC) calculations.11 Energy refinement for
optimized structures was performed at the MP2/(aug-)cc-pVTZ12 level of theory with the default
spin component scaling (SCS) values13 as implemented in MOLPRO 2012.14 We added
augmented functions12b,12c for N, O, and S atoms and pseudo-potential (ECP28MDF)12d for Pd
(BSII), and the density fitting (DF)15 with proper auxiliary functions, except for Pd for which we
used TZVPP auxiliary functions, were used.16 Solvent effect was implicitly added by performing
reference Hartree–Fock calculation with COSMO17 solvation model (e = 37.219; N,N-
dimethylformamide). We added non-electrostatic energies calculated with the SMD18 solvation
model.
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We first investigated the substituent effect of the sox ligand experimentally (Table 1).
The coupling reaction of 2,3-dimethylthiophene (1A) and hindered arylboronic acid 2b as model
substrates were conducted in the presence of 10 mol% Pd(OAc)2, 10 mol% ligand (L1–L6), and
5 mol% FePc in DMF at 80˚C under air for 12 h. All catalyst ligands gave the corresponding
product (3Ab), and the (S) stereoisomer was the dominant product in all the cases
(regioselectivity (C4:C5 ratio) > 89%; see Table 1). Compared to the standard sox ligand L1,
none of the other ligands resulted in better ee values (L2–L6). Racemization of the product does
not take place under the experimental conditions.19 In order to further improve ee, we decided to
conduct a computational study to better understand the mechanism and the origin of the
enantioselectivity.
Table 1. Experimental Substituent Effects of the Sox Ligand.
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Ligand
L1
Yield
92
C4:C5a
96:4
ee (%)
29
L2
41
89:11
98:2
14
L3
90
30
L4
78
96:4
22
L5
76
97:3
27
L6
28
95:5
23
aThe C4:C5 ratio was determined by 1H NMR.
As shown experimentally20 and theoretically,21 the role of FePc is to oxidize Pd(0) to
Pd(II), and therefore the reaction that involves FePc is not described here. (2-
Isopropylnaphthalen-1-yl)boronic acid (2a) which previously5 showed the highest
enantioselectivity of 61% ee (Figure 1) was selected as a reactant in this study to make the
difference in reaction profiles more apparent. The reaction mechanism (Figure 2) indicates that
the C–B bond of the arylboronic acid is first transmetalated by the Pd-sox (L1) catalyst. The
reaction profile (Figure 3) showed that the (S)-product should be dominant since the highest
activation energy of the transition state (TS) leading to the (S)-product (TS4-5S) is 3.0 kcal/mol
lower than the TS leading to the (R)-product (TS4-5R). This finding is consistent with the
S
experimental conditions at 70°C. Other important TSs are the C–C bond formation step (TS8-9
and TS8-9R) and the abstraction of proton to form a double bond on the thiophene ring (TS11-12
S
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and TS11-12R). Activation energies of these steps are lower than that of the C–B bond
transmetalation. The HOAc species generated in the catalytic cycle may be converted to OAc–
and water in the oxidation step. The water may then hydrolyze AcO–B(OH)2, resulting in
regeneration of 2oac.
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Figure 2. Proposed catalytic cycle. The oxidation mechanism20,21 marked by the gray box is not
considered in this study.
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Figure 3. Proposed reaction profile at the COSMO-DF-SCS-MP2/BSII//B3PW91/BSI level of
theory. Blue and red lines represent free energies of reaction coordinates leading to (S)- and (R)-
stereoisomers, respectively.
The concerted metalation-deprotonation (CMD) mechanism22 is well known in palladium-
catalyzed C–H arylation. However, the corresponding TSCMD (Figure 4 (A)) requires a higher
energy than any TS in Figure 3. We found that CH3COO– prefers to abstract the proton at the C5
position. This observation disagrees with the experimental product mainly consisting of a C4
product, which requires at least 35.9 kcal/mol in CMD mechanism. These results are consistent
with the relative acidity at the C4 and C5 positions of thiophene.23 Therefore, we conclude
CH3COO– does not abstract protons on the thiophene ring at the early stage of the reaction. A
structural isomer of C–B transmetalation TS4-5iso (Figure 4 (B)) is also higher in energy, because
of the steric repulsion between the sox ligand and the arylboronic acid. The oxidative addition of
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Ar–B(OH)2 is prohibited, because we could not find an Ar–(Pd-sox)–B(OH)2-type intermediate.
Ar–B(OH)3– may be formed, but a reaction with the Pd catalyst is spontaneous, so the species
cannot influence on the enantioselectivity. We could locate a TS which involves 2OAc– (TS2oac),
but it required an activation barrier of 56.4 kcal/mol. These three observations are discussed in
the Supporting Information (Figures S1–S3).
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Figure 4. Structures and free energies of TSs of (A) CMD pathway and (B) a structural isomer.
As we have shown in Figures 3 and 4, (2-isopropylnaphthalen-1-yl)boronic acid
approaches from one side. There is still a possibility of isomerization between two intermediates
that would lead to (S)- and (R)-products: the rotation and flip of the aryl group. However, TSs of
such motion given in the Supporting Information (Figure S4) respectively require free energies
of 32.7 (TSrotation) and 34.0 (TSflip) kcal/mol, which suggests that such isomerization does not
take place under the experimental condition. From Figures 3, 4, and S4, we conclude that the
stereoselectivity of the catalytic reaction is kinetically controlled at the C–B transmetalation step
R
TS4-5S and TS4-5
.
The main question is why the energy difference of 3.0 kcal/mol emerges at this
enantioselective step. To address this, we calculated the interaction energy between the aryl
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group on the Pd center and the tolyl group of the sox ligand. To extract the interaction energy
specifically, we created a truncated model containing mainly these groups and saturated the
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S
dangling bond by a hydrogen atom, using the optimized geometries of TS4-5 and TS4-5R. The
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basis set superposition error was removed using standard Boys–Bernardi counterpoise
correction. The interaction energies at the DF-SCS-MP2/BSII level of theory are 1.9 and 1.8
S
kcal/mol for TS4-5 and TS4-5R, respectively, so the difference of 0.2 kcal/mol only represents
~5% of the total energy difference of 3.0 kcal/mol, implying that steric repulsion alone cannot
reasonably explain the enantioselectivity of the catalytic reaction. In fact, the different
orientation of the iPr group induces the rotation of the tolyl group by 44.2° in the dihedral angle
i
between the O–S–C–C atoms (y, see Figure 5A) to minimize the steric repulsion between Pr
and tolyl groups, resulting in the small difference of the interaction energies.
Figure 5. (A) Definition of dihedral angle y, (B) dihedral angles of TS4-5S and hypothetical TS4-
S, and (C) schematic hyperconjugation between C–C p-orbital and S–O s*-orbital.
5
We next focused on the electronic structure effect of the rotation of the tolyl group. To
S
minimize non-relevant effects, we compared those of TS4-5 (y = 84.2°) and a hypothetical TS
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R
S
structure whose dihedral angle is equivalent to that of TS4-5 (y = 128.4°) based on the TS4-5
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8
9
structure as shown in Figure 5B, viewed through the S–C (atom 2–3 in Figure 5 (A)) bond
perpendicularly. We adopted the natural bond orbital (NBO) analysis24 at the B3PW91/BSI level
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S
of theory. Our analysis revealed that TS4-5 and hypothetical TS4-5 are stabilized by 5.9 and 3.3
S
kcal/mol, respectively, by the interaction between the donor (occupied C–C p-orbital on the tolyl
group) and the acceptor (unoccupied S–O s*-orbital on the sox ligand) NBOs. The interaction is
schematically depicted in Figure 5C, corresponding to the hyperconjugation25 between these
orbitals. In TS4-5S, the molecular plane of the tolyl group is almost perpendicular to the S–O
bond; therefore the overlap between the C–C p- and the S–O s*-orbitals is at its maximum. On
R
the other hand, the tilted tolyl group in the hypothetical TS structure representing TS4-5
decreases the overlap between two orbitals, resulting in a smaller stabilization by the
hyperconjugation. The difference of the interaction energies is 2.6 kcal/mol, which is close to the
S
difference of the activation energies at TS4-5 and TS4-5R, namely 3.0 kcal/mol. The analysis
i
above has been conducted for 2a with the Pr group, while 2b used in our experiment has the
methyl group. 2b induces a smaller degree of rotation of the tolyl group (y) in the structure of
TS4-5S and TS4-5R. As a consequence, the destabilization in TS4-5R is smaller than the case with 2a;
hence the difference of TS energies is also smaller, leading to lower ee value. There are a few
studies which theoretically revealed that hyperconjugation may affect regioselectivity,25c
conformation,25d and enantioselecvitity.25e
As discussed above, the key for stereoselectivity is the enhancement of the
hyperconjugation between the C–C p-orbitals and the S–O s*-orbital. In order to correlate
experimental and theoretical results, we computationally investigated the substituent effect of
ligands (as introduced in Table 1) at the B3PW91/BSI level of theory. To save computational
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effort, we simply took the 2oac structure, and the dihedral angle y is fixed at 84.2° and 128.4°.
The computed differences of the energy are 1.7, 0.6, 1.7, 1.6, 1.7, and 1.3 kcal/mol for L1–L6,
respectively, and the results are qualitatively consistent with the experimental tendency; smaller
differences do not give higher ee. We note that the substitution with hydroxyl groups at the 4 and
6 positions or with methoxy groups at the 3 and 5 positions on tolyl group gives a difference of
2.6 or 2.3 kcal/mol, respectively, which is expected to result in higher ee than the original sox
ligand, L1 (1.7 kcal/mol). Unfortunately, these substitutions are difficult to realize in
experimental chemistry.
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We theoretically and experimentally investigated the mechanism of a Pd-catalyzed C–H
coupling reaction of a thiophene derivative and an arylboronic acid (Figure 1). Our study
indicates that the rate-determining and stereoselective step of the reaction is the C–B
transmetalation of the arylboronic acid. NBO analysis reveals that the difference between the
S
activation energy of two TSs leading to (S)- and (R)-products (TS4-5 and TS4-5R) is attributed to
the hyperconjugation between p-orbitals on the tolyl and the S–O s*-bonding orbitals on the sox
ligand. Our investigations of the substituent effect of the sox ligand imply that the design of a
highly selective catalyst is challenging.
Experimental Section
General Methods. Unless otherwise noted, all materials including dry solvents were obtained
from commercial suppliers and used as received. 2-Methylnaphthalen-1-ylboronic acid (2a),26
(S)-4-isopropyl-2-(2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole (L1),27 and (S)-2-(2-
bromophenyl)-4-isopropyl-4,5-dihydrooxazole (S1)28 were synthesized according to procedures
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reported in the literature. Unless otherwise noted, all reactions were performed with dry solvents
under an atmosphere of argon in flame-dried glassware using standard vacuum-line techniques.
All C–H coupling reactions were performed in screw-cap 20 mL glass vessel tubes and heated in
an 8-well reaction block (heater + magnetic stirrer). All work-up and purification procedures
were carried out with reagent-grade solvents in air.
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Analytical thin-layer chromatography (TLC) was performed using silica gel (60 F254) precoated
plates (0.25 mm). The developed chromatogram was analyzed by UV lamp (254 nm). Flash
column chromatography was performed with silica gel 60 (230–400 mesh). Preparative thin-
layer chromatography (PTLC) was performed using B5-F silica coated plates (0.75 mm)
prepared in our laboratory. Gas chromatography (GC) analysis was conducted with a 30 m ´
0.25 mm column. GCMS analysis was conducted with a 30 m ´ 0.25 mm column. Chiral HPLC
analysis was conducted with a 4.6 mm x 250 mm column. Nuclear magnetic resonance (NMR)
1
spectra were recorded using H 400 MHz, C 100 MHz, H 500 MHz, C 125 MHz, H 600
13
1
13
1
13
1
MHz, and C 150 MHz spectrometers. Chemical shifts for H NMR are expressed in parts per
million (ppm) relative to tetramethylsilane (δ 0.00 ppm). Chemical shifts for 13C NMR are
expressed in ppm relative to CDCl3 (δ 77.0 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, sep =
septet, m = multiplet, br = broad signal), coupling constant (Hz), and integration.
General Procedure for the Synthesis of Ligand precursors S2–S6. To a round-bottom flask,
a solution of carboxylic acid (3.0 mmol), (S)-2-amino-3-methylbutan-1-ol (340 mg, 3.3 mmol,
1.1 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC: 378 mg, 3.6 mmol, 1.2
equiv) and 1-hydroxybenzotriazole (HOBt: 203 mg, 1.5 mmol, 0.5 equiv) in DMF (10 mL) were
added. After stirring for 2 h at room temperature, saturated aqueous NaHCO3 was added to the
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mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with
brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the
corresponding amide. This crude product was used in next step without purification.
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Amide (1.0 equiv), p-TsCl (743 mg, 3.9 mmol, 1.3 equiv), NEt3 (2.1 mL, 15 mmol, 5 equiv)
were dissolved in CH2Cl2 (30 mL) in a round-bottom flask equipped with a reflux condenser.
The reaction mixture was stirred at 70 °C for overnight. After cooling to room temperature,
saturated aqueous NH4Cl was added and extracted with CH2Cl2. The organic layer was washed
with brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo. The residue
was purified by silica-gel column chromatography to give the corresponding phenyloxazoline.
(S)-2-(2-Bromo-3-methylphenyl)-4-isopropyl-4,5-dihydrooxazole (S2): The crude product
was purified by silica-gel column chromatography (hexane/ethyl acetate = 10:1 to 4:1) to give S2
(459 mg, 54%) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz, 1H), 7.30 (d,
J = 7.2 Hz, 1H), 7.23 (dd, J = 7.8, 7.2 Hz, 1H), 4.48–4.40 (m, 1H), 4.20–4.12 (m, 2H), 2.45 (s,
3H), 1.96–1.87 (m, 1H), 1.06 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 163.7, 139.3, 132.3, 131.3, 128.5, 126.8, 124.0, 72.9, 70.4, 32.7, 23.7, 18.8, 18.3;
HRMS (DART Orbitrap) m/z calcd for C13H17BrNO [M+H]+: 282.0494, found: 282.0489.
(S)-2-(2-Bromo-4-fluorophenyl)-4-isopropyl-4,5-dihydrooxazole (S3): The crude product
was purified by silica-gel column chromatography (hexane/ethyl acetate = 10:1 to 5:1) to give S3
(535 mg, 62%) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 7.70 (dd, J = 8.9, 6.2 Hz, 1H),
7.38 (dd, J = 8.2, 2.7 Hz, 1H), 7.08–7.03 (m, 1H), 4.45–4.40 (m, 1H), 4.19–4.12 (m, 2H), 1.94–
1.85 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
163.1 (d, JFC = 254 Hz), 162.0, 132.7 (d, JFC = 7.5 Hz), 126.3 (d, JFC = 3.0 Hz), 122.5 (d, JFC
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10.5 Hz), 121.1 (d, JFC = 25.5 Hz), 114.4 (d, JFC = 22.5 Hz), 72.9, 70.3, 32.7, 18.7, 18.2; HRMS
(DART) m/z calcd for C12H14BrFNO [M+H]+: 286.0243, found: 286.0238.
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(S)-2-(2-Bromo-5-methoxyphenyl)-4-isopropyl-4,5-dihydrooxazole (S4):29 The crude
product was purified by silica-gel column chromatography (hexane/ethyl acetate = 4:1) to give
S4 (541 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 1H), 7.20
(d, J = 3.2 Hz, 1H), 6.83 (dd, J = 8.8, 3.2 Hz, 1H), 4.47–4.38 (m, 1H), 4.21–4.11 (m, 2H), 3.79
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(s, 3H), 1.98–1.83 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3) δ 162.6, 158.4, 134.3, 130.6, 117.9, 116.0, 112.0, 72.8, 70.2, 55.5, 32.5, 18.7,
18.1; HRMS (DART) m/z calcd for C13H17BrNO2 [M+H]+: 298.0443, found: 298.0445.
(S)-2-(2-Bromo-5-fluorophenyl)-4-isopropyl-4,5-dihydrooxazole (S5):30 The crude product
was purified by silica-gel column chromatography (hexane/ethyl acetate = 10:1 to 5:1) to give S5
(492 mg, 57%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.8, 5.2 Hz, 1H),
7.42 (dd, J = 8.8, 2.8 Hz, 1H), 7.05–6.97 (m, 1H), 4.49–4.40 (m, 1H), 4.21–4.13 (m, 2H), 1.97–
1.83 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
161.3 (d, JFC = 246 Hz), 161.7, 135.2 (d, JFC = 6.0 Hz), 131.5 (d, JFC = 9.0 Hz), 118.8 (d, JFC = 23
Hz), 118.5 (d, JFC = 24 Hz), 116.1 (d, JFC = 2.9 Hz), 73.0, 70.5, 32.7, 18.7, 18.2; HRMS (DART)
m/z calcd for C12H14BrFNO [M+H]+: 286.0243, found: 286.0243.
(S)-2-Ferrocenyl-4-(1-methylethyl)oxazoline (S6):5 Following the general procedure with
ferrocenecarboxylic acid (690 mg, 3.0 mmol), the crude amide was obtained (659 mg) as a
brown solid. In the cyclization, the crude amide (580 mg), p-TsCl (456 mg, 2.4 mmol), and NEt3
(1.3 mL, 9.2 mmol) were used. The crude product was purified by silica-gel column
chromatography (hexane/ethyl acetate = 4:1 to 3:1) to give S6 (377 mg, 69%) as a brown solid.
1H NMR (400 MHz, CDCl3) δ 4.74 (dd, J = 13.8, 1.4 Hz, 2H), 4.34–4.25 (m, 3H), 4.19 (s, 5H),
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4.07 (t, J = 7.8 Hz, 1H), 4.02–3.95 (m, 1H), 1.93–1.80 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.94 (d,
J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 72.3, 70.13, 70.09, 69.5, 69.3, 69.0, 68.9, 32.3,
18.9, 17.8; HRMS (DART) m/z calcd for C16H20FeNO [M+H]+: 298.0894, found: 298.0890.
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General Procedure for the Synthesis of L1–L6. To a solution of (S)-2-(2-bromophenyl)-4-
isopropyl-4,5-dihydrooxazole29 (S1: 678 mg, 3.0 mmol) in THF (15 mL) was slowly added n-
BuLi (1.6 M in hexane, 2.1 mL, 3.3 mmol) at –78 ˚C under nitrogen atmosphere. After stirring at
–78 ˚C for 1 h, a solution of (1R,2S,5R)-(-)-menthyl (S)-p-toluenesulfinate (971 mg, 3.3 mmol)
in THF (15 mL) was added dropwise, stirred at –78 ˚C for 30 min, then room temperature for 30
min. To the mixture was added saturated aqueous NH4Cl and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous
Na2SO4. The solvent was removed in vacuo. The residue was purified by silica-gel column
chromatography (hexane/ethyl acetate = 3:1) to give L1 (697 mg, 71%) as a white solid.
(S)-4-Isopropyl-2-(2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole (L1):19 1H NMR (400
MHz, CDCl3) δ 8.34 (dd, J = 8.2, 1.4 Hz, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.75–7.68 (m, 1H),
7.58–7.48 (m, 3H), 7.16 (d, J = 8.2 Hz, 2H), 4.34 (dd, J = 9.2, 7.3 Hz, 1H), 4.15–4.01 (m, 2H),
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2.32 (s, 3H), 1.82–1.70 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 160.65, 146.19, 143.62, 140.85, 131.79, 130.19, 129.68, 129.47, 126.45,
125.56, 125.28, 73.29, 69.84, 32.44, 21.28, 18.93, 17.85; HRMS (DART) m/z calcd for
C19H22NO2S [M+H]+: 328.1371, found: 328.1373.
(S)-4-Isopropyl-2-(3-methyl-2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole
(L2):
Following the general procedure with (S)-2-(2-bromo-3-methylphenyl)-4-isopropyl-4,5-
dihydrooxazole (S2: 330 mg, 1.2 mmol), n-BuLi (1.6 M in hexane, 0.8 mL, 1.3 mmol), and
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(1R,2S,5R)-(-)-menthyl (S)-p-toluenesulfinate (448 mg, 1.5 mmol), the crude product was
purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1) to give L2 (148 mg,
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37%) as a yellow oil. H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 7.2 Hz,
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1H), 7.39 (dd, J = 7.8, 7.2 Hz, 1H), 7.26–7.20 (m, 3H), 4.46 (t, J = 7.8 Hz, 1H), 4.16–4.08 (m,
2H), 2.38 (s, 3H), 2.33 (s, 3H), 1.91–1.81 (m, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz,
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3H); C NMR (150 MHz, CDCl3) δ 162.2, 141.7, 140.9, 140.5, 139.8, 135.4, 131.0, 130.6,
129.2, 127.1, 125.4, 73.4, 71.1, 32.9, 21.2, 19.0, 18.6, 18.3; HRMS (DART) m/z calcd for
C20H24NO2S [M+H]+: 342.1528, found: 342.1530.
(S)-2-(4-Fluoro-2-((S)-p-tolylsulfinyl)phenyl)-4-isopropyl-4,5-dihydrooxazole
(L3):
Following the general procedure with (S)-2-(2-bromo-4-fluorophenyl)-4-isopropyl-4,5-
dihydrooxazole (S3: 400 mg, 1.4 mmol), n-BuLi (1.6 M in hexane, 1.0 mL, 1.5 mmol), and
(1R,2S,5R)-(-)-menthyl (S)-p-toluenesulfinate (532 mg, 1.8 mmol), the crude product was
purified by silica-gel column chromatography (hexane/ethyl acetate = 2:1) to give L3 (276 mg,
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58%) as a white solid. H NMR (600 MHz, CDCl3) δ 8.08 (dd, J = 8.9, 2.8 Hz, 1H), 7.93 (dd, J =
8.9, 5.5 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.20–7.15 (m, 3H), 4.33 (dd, J = 9.6, 8.3 Hz, 1H),
4.13–4.07 (m, 1H), 4.04 (t, J = 8.2 Hz, 1H), 2.33 (s, 3H), 1.81–1.72 (m, 1H), 0.89 (d, J = 6.9 Hz,
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3H), 0.71 (d, J = 6.9 Hz, 3H); C NMR (150 MHz, CDCl3) δ 164.9 (d, JFC = 256 Hz), 159.9,
149.9 (d, JFC = 5.9 Hz), 143.1, 141.2, 132.1 (d, JFC = 8.6 Hz), 129.6, 126.5, 121.5 (d, JFC = 4.4
Hz), 117.4 (d, JFC = 22 Hz), 112.9 (d, JFC = 26 Hz), 73.3, 69.8, 32.4, 21.3, 19.0, 17.8; HRMS
(DART) m/z calcd for C19H21FNO2S [M+H]+: 346.1277, found: 346.1279.
(S)-4-Isopropyl-2-(5-methoxy-2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole
(L4):
Following the general procedure with (S)-2-(2-bromo-5-methoxyphenyl)-4-isopropyl-4,5-
dihydrooxazole (S4: 400 mg, 1.3 mmol), n-BuLi (1.6 M in hexane, 0.9 mL, 1.5 mmol), and
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(1R,2S,5R)-(-)-menthyl (S)-p-toluenesulfinate (513 mg, 1.7 mmol), the crude product was
purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1 to 1:1) to give L4 (210
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mg, 44%) as a white solid. H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 1H), 7.54 (d, J =
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8.3 Hz, 2H), 7.41 (d, J = 2.8 Hz, 1H), 7.20 (dd, J = 9.0, 2.8 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H),
4.34 (dd, J = 9.7, 7.6 Hz, 1H), 4.13–4.08 (m, 1H), 4.05 (t, J = 8.3 Hz, 1H), 3.88 (s, 3H), 2.33 (s,
3H), 1.79–1.71 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 161.0, 160.5, 144.0, 140.7, 137.1, 129.4, 127.3, 127.0, 126.2, 117.5, 114.7, 73.3, 69.9,
55.7, 32.5, 21.3, 18.9, 17.9; HRMS (DART) m/z calcd for C20H24NO3S [M+H]+: 358.1477,
found: 358.1481.
(S)-2-(5-Fluoro-2-((S)-p-tolylsulfinyl)phenyl)-4-isopropyl-4,5-dihydrooxazole
(L5):
Following the general procedure with (S)-2-(2-bromo-5-fluorophenyl)-4-isopropyl-4,5-
dihydrooxazole (S5: 400 mg, 1.4 mmol), n-BuLi (1.6 M in hexane, 1.0 mL, 1.5 mmol), and
(1R,2S,5R)-(-)-menthyl (S)-p-toluenesulfinate (532 mg, 1.8 mmol), the crude product was
purified by silica-gel column chromatography (hexane/ethyl acetate = 10:1 to 3:1) to give L5 (93
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mg, 19%) as a white solid. H NMR (600 MHz, CDCl3) δ 8.32 (dd, J = 9.0, 6.0 Hz, 1H), 7.61
(dd, J = 9.0, 3.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.41–7.37 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H),
4.35 (dd, J = 9.6, 8.3 Hz, 1H), 4.15–4.10 (m, 1H), 4.06 (t, J = 8.3 Hz, 1H), 2.33 (s, 3H), 1.81–
1.72 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.5 (d, JFC = 253 Hz), 159.7, 143.5, 141.7 (d, JFC = 2.8 Hz), 141.1, 129.5, 128.0 (d, JFC = 8.6
Hz), 127.6 (d, JFC = 8.6 Hz), 126.3, 118.8 (d, JFC = 22 Hz), 116.8 (d, JFC = 25 Hz), 73.5, 70.0,
32.4, 21.3, 18.9, 17.8; HRMS (DART) m/z calcd for C19H21FNO2S [M+H]+: 346.1277, found:
346.1275.
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(L6): Following the general procedure with (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline (S6:
297 mg, 1.0 mmol), n-BuLi (1.6 M in hexane, 0.7 mL, 1.1 mmol), and (1R,2S,5R)-(-)-menthyl
(S)-p-toluenesulfinate (353 mg, 1.2 mmol), the crude product was purified by silica-gel column
chromatography (hexane/ethyl acetate = 4:1 to 1:1) to give L6 (158 mg, 36%) as a brown solid.
1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.95 (s, 1H),
4.42–4.33 (m, 2H), 4.20–4.08 (m, 7H), 3.94 (s, 1H), 2.47 (s, 3H), 1.95–1.87 (m, 1H), 1.04 (d, J =
6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 163.2, 141.5, 140.6, 129.3,
126.0, 94.7, 72.55, 72.52, 72.1, 71.2, 70.7, 70.5, 69.8, 32.4, 21.5, 19.0, 18.0; HRMS (DART) m/z
calcd for C23H26FeNO2S [M+H]+: 436.1034, found: 436.1037.
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General Procedure for C–H Coupling of 2,3-dimethyl thiophene (1A) with Hindered
Arylboronic Acid (2b). To a screw-cap 20 mL glass vessel containing a magnetic stirring bar
were added 2,3-dimethylthiophene (1A: 28 mg, 0.25 mmol), (2-methylnaphthalene-1-yl)boronic
acid (2b: 186 mg, 1.0 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), L1 (8.2 mg, 0.025 mmol), FePc
(7.1 mg, 0.0125 mmol) and DMF (0.2 mL). The mixture was stirred at 80 ˚C for 12 h under air,
cooled to room temperature, passed through a short pad of silica gel (ethyl acetate) and the
filtrate was evaporated under reduced pressure. The residue was purified by preparative thin-
layer chromatography (hexane) to give (S)-3Ab (58 mg, 92%, C4/C5 = 96:4, 29% ee) as a
colorless oil. C4/C5 ratio was determined by 1H NMR. The enantiomeric excess was determined
by HPLC with a Chiracel OD-H column, UV detected at 254 nm, flow rate 1.0 mL/min (hexane).
Retention times (tr): major enantiomer tr = 11.7 min, minor enantiomer tr = 10.0 min. According
to the literature,19 the absolute configuration was determined to be of S-configuration.
2,3-Dimethyl-4-(2-methylnaphthalen-1-yl)thiophene (3Ab):19 1H NMR (400 MHz, CDCl3)
δ7.86–7.73 (m, 2H), 7.44–7.31 (m, 4H), 6.84 (s, 1H), 2.47 (s, 3H), 2.22 (s, 3H), 1.71 (s, 3H).
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ASSOCIATED CONTENT
Supporting Information.
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Free energies of reaction profiles at the COSMO-DF-SCS-MP2/(aug-)cc-pVTZ(-PP) level of
theory, Cartesian coordinates of optimized structures,1H, 13C NMR and HPLC spectra of all
compounds described in the experimental section.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sirle@chem.nagoya-u.ac.jp. Phone: +81 (0)52 747-6397.
Present Addresses
†Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho,
Sakyo-ku, 606-8103, Japan
‡Faculty of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo, 169-
8555, Japan
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Prof. Odile Eisenstein for helpful discussions and the Research Center for
Computational Science, Okazaki, Japan, for providing computational resources. Y.N. was
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supported by a Research Fellowship of the Japan Society for Promotion of Science for Young
Scientists (DC1). Y.N. and H.K. thank IGER Program in Green Natural Sciences, Nagoya
University for fellowship. S.I. acknowledges partial support by a CREST grant from JST.
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