An N-Heterocyclic Carbene-Nickel Half-Sandwich Complex as a Precatalyst for Suzuki-Miyaura Coupling of Aryl/Heteroaryl Halides with Aryl/Heteroarylboronic Acids

Article abstract of DOI:10.1021/acs.joc.6b02666

A nickel half-sandwich complex supported by our original NHC ligand was developed as a robust precatalyst for Suzuki-Miyaura cross-coupling. The addition of PPh₃ was a crucial element in the suppression of side reactions and in accelerating the cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl, and heteroaryl-heteroaryl couplings were achieved.

Full text of DOI:10.1021/acs.joc.6b02666

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Note
A N-Heterocyclic Carbene-Nickel Half-sandwich Complex
as a Precatalyst for Suzuki-Miyaura Coupling of Aryl/
Heteroaryl Halides with Aryl/Heteroarylboronic Acids
Shin Ando, Hirofumi Matsunaga, and Tadao Ishizuka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02666 • Publication Date (Web): 28 Dec 2016
Downloaded from http://pubs.acs.org on December 28, 2016
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A N-Heterocyclic Carbene-Nickel Half-sandwich Complex as a Precatalyst for
Suzuki-Miyaura Coupling of Aryl/Heteroaryl Halides with Aryl/Heteroarylboronic Acids
Shin Ando,* Hirofumi Matsunaga, and Tadao Ishizuka*
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Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto
862-0973, Japan
ando@gpo.kumamoto-u.ac.jp (S.A), tstone@gpo.kumamoto-u.ac.jp (T.I.)
Abstract
A nickel half-sandwich complex supported by our original NHC ligand was
developed as a robust precatalyst for Suzuki-Miyaura cross coupling. The addition of PPh3
was a crucial element in the suppression of side reactions and in accelerating the
cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl,
and heteroaryl-heteroaryl couplings were achieved.
The development of stable precatalysts under air and moisture, which can be
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readily activated in a reaction vessel, is an attractive area for chemists due to their ease of
handling. A number of such precatalysts that contain palladium as an active transition metal
have already been developed and are often commercially available, but the first low
counterpart, nickel, is much less frequently mentioned in the literature. The addition to
powerful Ni catalysts supported by phosphine ligands,1 and more recently N-heterocyclic
carbene (NHC) ligands, has been actively applied in Ni-based catalysis, which has revealed
unique reactivities of NHC-Ni catalysts.2 Current NHC-Ni-based catalysts, however, are
traditionally formed using air- and moisture-sensitive Ni(COD)2 as a Ni(0) source, along
with isolated or in situ-formed NHC ligands,1b,3 which means that the development of a
stable source of NHC-based Ni precatalysts remains a highly sought accomplishment.
Among some types of the air- and moisture-stable NHC-Ni complexes,
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[Ni(NHC)CpCl] half-sandwich versions are good examples of easily accessible NHC-Ni
complexes, which can be prepared via a simple heating of the NHC precursor in the
presence of nickelocene.3–11 After the seminal report by Cowley and co-workers,4 most of
the ubiquitous NHC ligands were investigated to demonstrate their usefulness in this type
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of complex. During these investigations, some groups discovered that organometallic
reagents such as Grignard reagents,5 bases such as sodium tert-butoxide,6 and arylboronic
acids7 could activate a Ni(II) complex and produce catalytically active species. At this point,
several reactions were reported with the use of [Ni(NHC)CpCl] complexes as a precatalyst:
Buchwald-Hartwig type amination,6 Kumada-Tamao-Corriu (KTC) coupling,5 ketone
α-arylation,8 hydrosilylation,9 hydrothiolation,10 and polymerization of a styrene.11
Although some examples of Suzuki-Miyaura cross-coupling12 with these types of
complexes have also been reported,7,11a their substrate scope was limited to only
electron-deficient para-substituted aryl halides. Here, we present a [Ni(NHC)CpCl]
complex with our original bicyclic NHC ligand, which can catalyze the Suzuki-Miyaura
cross-coupling of sterically and/or electronically challenging aryl chlorides with
arylboronic acids. This precatalyst was even applicable to the coupling of heteroaryl halides
with aryl and heteroarylboronic acids.
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Our group designed and synthesized original bicyclic NHCs equipped with a
bicyclic architecture on the non-carbenic carbons,13 and this type of NHC ligand, which we
refer to as DHASI, is characterized by a stabilizing effect on the metal complexes that is
caused by the bulkiness of the DHASI ligands. Recently, we found that a
DHASIiPr-supported copper catalyst was more amenable to the borylation of sterically
hindered substrates than ubiquitous NHCs, which suggested that DHASI ligands are bulky
but accessible.14 We envisioned that the bulkiness would facilitate the activation of
[Ni(NHC)CpCl] precatalysts15 and that their accessibility would result in a much wider
scope of substrates for Suzuki-Miyaura coupling. Motivated by this hypothesis, we began
the synthesis of a [Ni(NHC)CpCl] complex using a DHASIiPr ligand. With a small
modification to the method reported by Albrecht and co-workers,7c we heated a mixture of
DHASIiPr•HBF4 1,14 freshly sublimed nickelocene, and n-Bu4NCl in degassed 1,4-dioxane
at reflux for 1h in an oil bath and obtained [Ni(DHASIiPr)CpCl] 2 in a 97% yield as an air-
and moisture-stable solid (eq 1). As far as we could ascertain, this is the first example of a
[Ni(NHC)CpCl] complex supported by a N,N’-dialkylated imidazolinylidene ligand. The
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structure of [Ni(DHASIiPr)CpCl] was confirmed by X-ray crystallography, and a thermal
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ellipsoid representation at the 50% probability level is shown in Figure 1.
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Figure 1. ORTEP diagram of [Ni(DHASIiPr)CpCl] 2; thermal ellipsoids are shown at the
50% probability level (CCDC 1512438). H atoms and solvents are omitted for clarity.
For a preliminary trial of this stable NHC-Ni complex 2, we tried the
Suzuki-Miyaura coupling of 4-bromoanisole 3a, which is electronically deactivated
arylbromide, with phenylboronic acid 4a. Under a representative condition for a similar
transformation, we obtained 59% of the cross-coupled product 5aa with 8% of the
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homo-coupled product 6 and 33% of recovered S.M. 3a (based on H NMR of the crude
product) after 5 h at 90 °C (eq 2). Although these were the same level as the highest activity
of the related complexes reported to date,7a we noticed that a significant amount of biphenyl
7 was formed via the homo-coupling of phenylboronic acid 4a, which resulted in the
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complete consumption of 4a.16 This indicated that a loss in the activity of the nickel catalyst
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was not the reason that the cross-coupling of challenging substrates resulted in a poor yield.
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Encouraged by the above-mentioned promising results, we extensively studied
the reaction conditions to accomplish the coupling of 4-chloroanisole 8a, which is a
somewhat more challenging substrate, with 1.5 eq. of phenylboronic acid 4a using 1.0
mol% of [Ni(DHASIiPr)CpCl] 2 (Table 1). We then found that the phosphine co-ligand,
particularly PPh3,17 was effective in suppressing the undesired homo coupling of
phenylboronic acid 4a and that a toluene/tert-BuOH (10/1) solvent system was superior to
1,4-dioxane for this coupling (see Supporting Information for other optimizations). Among
the phosphine ligands we tested, PPh3 was the only effective co-ligand that could reduce
the formation of biphenyl 7 with a high conversion to cross coupling (Table 1, Entries 1 to
5). Intriguingly, an increased PPh3 accelerated the reaction, and the reaction using 20 mol%
of PPh3 with 1.0 mol% of Ni precatalyst 2 at 90 °C was completed within 8 h to give the
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coupled product 5aa in a 95 % yield (Entry 6). To obtain more information about the effects
of PPh3, we heated a mixture of PhB(OH)2, K3PO4, and the Ni catalyst 2 in the absence of
arylhalide. Interestingly, under these conditions biphenyl was formed in a ca. 3% yield
regardless of the addition of PPh3.18 These results suggested that another active pathway
would be generated in the presence of an arylhalide19 and would result in the
homo-coupling of PhB(OH)2. The addition of PPh3 seems to prioritize the cross-coupling
over the homo-coupling, and the acceleration of the reaction by an excess amount of PPh3
would be caused by increasing the rate of the reductive elimination step.
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Table 1. Effects of a phosphine co-ligand in Suzuki-Miyaura coupling
Entr
y
Products ratio in a crude mixturea
consumed
PhB(OH)2
0.74 eq.
0.47 eq.
0.28 eq.
0 eq.
P co-ligand
PPh3
5aa
55
6a
8a
40
1
5
trace
0
2
P(o-tol)3
P(OPh)3
dppe
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80
3
0
100
100
85
4
0
0
5
PCy3•HBF4
PPh3
14
1
0.59 eq.
1.13 eq.
6b
95 (95)
5
0
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a
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Calculated using H NMR. 20 mol% of PPh3 was used. Yield after isolation by
b
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chromatography is shown in parenthesis.
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With the optimal reaction conditions (condition A) in hand, we tested a scope of
substrates for a [Ni(DHASIiPr)CpCl] precatalyst, and focused on ortho-substituted versions
to establish steric capacity (Figure 2). A variety of EWG- and EDG-substituted
arylchlorides was coupled with phenylboronic acid in an efficient manner (5ba–5ia). The
catalyst worked in non-distilled standard solvents on a 70 mmol scale with 0.25 mol%
loading to give the coupled product in a 90% yield (10.6 g of 5ea; see Table S6 in
Supporting Information). For the coupling of more bulky substrates, a somewhat higher
temperature in toluene/tert-amylalcohol (condition B) was required in order to accomplish
the reaction in 24 h (5ja to 5na). Although free aniline showed better reactivity (5ha), BOC
protected and acetylated aniline derivatives were also reacted in moderate yields with 2
mol% of catalyst 2 (5la and 5ma). Unfortunately, di-ortho-methylated arylchloride was not
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tolerated, and only 37% of the product was observed in the H NMR of a crude mixture
even with 2-bromo-m-xylene as a substrate. When we tested the coupling with
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ortho-methyl- and methoxy-phenylboronic acids (4b and 4c), the coupling reactions of
arylchlorides possessing EWG and EDG with 4b smoothly proceeded, while reactions with
4c required a higher level of catalyst loading (5ab-5ec). In particular, a comparison
between 5cb and 5ec clearly showed that a methoxy group at the 2-position of arylboronic
acid caused a severe bottleneck, which was effectively alleviated by switching the coupling
partner.
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a
Figure 2. Coupling of arylhalides with arylboronic acids using [Ni(DHASIiPr)CpCl] 2.
The reaction was attempted on a 70 mmol scale. 0.25 mol% of Ni cat. 2 and 20 mol% of
PPh3 were used. b 2.0 mol% of Ni cat. 2 and 40 mol% of PPh3 were used. c Calculated using
1H NMR of a crude mixture.
We subsequently addressed the coupling of heteroarylhalide with phenylboronic
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acid and found that our catalytic system successfully catalyzed the coupling (Figure 3). In
these coupling reactions, the rate was generally faster than that shown in Figure 2, and the
phenylated heteroarenes (10aa–10ha) were isolated in good to excellent yields; however,
the reaction at the reactive 2-position of heteroarene resulted in an incompletion, which was
not helped by increasing the catalyst with protracted heating (10ia and 10ja).20 The catalyst
loading for the coupling between 4-chloropyridine and phenylboronic acid (10aa) was
reduced to 0.25 mol%. Even for the heteroaryl-aryl coupling, steric hindrance caused no
problem (10kb).
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Figure 3. Coupling of heteroarylhalides with arylboronic acids using [Ni(DHASIiPr)CpCl]
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2. a0.25 mol% of Ni cat. 2 was used. bThe coupling was run at 110 °C in
toluene/tert-AmylOH (10/1). c3.0 eq. of PhB(OH)2 and 6.0 eq. of K3PO4 were used.
We finally attempted the most challenging coupling between heteroarylhalides
(9a–c) and heteroarylboronic acids (11a and 11b),1h,21 and a 10:1 mixture of 1,4-dioxane
and tert-BuOH proved to be an optimal solvent system (Figure 4). The couplings of
3-chloropyridine, 4-chloropyridine, and 5-bromopyrimidine with 3-thiphene and 3-furan
boronic acids were sufficiently catalyzed by [Ni(DHASIiPr)CpCl] (12aa–12cb). Also,
3-bromothiophene was coupled with 3-furanboronic acid under this catalysis (12db), even
though couplings at the 2-positions of heteroarylboronic acids were fruitless.
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Figure 4. Coupling of heteroarylhalides with heteroarylboronic acids using
[Ni(DHASIiPr)CpCl] 2
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In addition to the typical Suzuki-Miyaura cross-coupling, we applied
[Ni(DHASIiPr)CpCl] 2 to the Ni-NHC catalyzed Suzuki-Miyaura coupling of amide,
which was recently reported by Garg and co-workers.2a This reaction is a powerful method
for ketone syntheses, but the active catalyst was formed using Ni(COD)2 along with an
isolated NHC ligand. As a result, [Ni(DHASIiPr)CpCl] 2 worked for the coupling between
amide 13 and phenylboronic acid 4a to give benzophenone 14 in a 85 % yield (eq 3).22 This
result suggested that [Ni(DHASIiPr)CpCl] 2 would be a useful precatalyst to seek reactions,
wherein NHC-Ni complexes could demonstrate their characteristic effects.
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In conclusion, the [Ni(NHC)CpCl] complex supported by our original DHASIiPr
ligand covered a much wider scope of substrates during Suzuki-Miyaura coupling
compared with that of related nickel complexes. This robust complex is the first example of
a [Ni(NHC)CpCl] complex supported by N,N’-dialkylated imidazolinylidene ligands, and
its structure was confirmed by X-ray crystallography. In the Suzuki-Miyaura coupling using
[Ni(DHASIiPr)CpCl] as a precatalyst, PPh3 was found to be a crucial co-ligand to suppress
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the problematic homo-coupling of phenylboronic acid and also to accelerate the reaction.
The established catalytic system successfully catalyzed the coupling reaction of aryl and
heteroaryl halides with aryl and heteroaryl boronic acids with 0.25 to 2 mol% of catalyst
loading. Further investigations into the application of this robust precatalyst to other useful
reactions are being conducted in our laboratory.
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Experimental Section
General Procedure and Chemicals. All reactions were carried out under an argon
atmosphere with freshly distilled solvents under anhydrous conditions, unless otherwise
noted. 1,4-Dioxane was distilled from sodium benzophenone ketyl. Toluene was distilled
from CaH2. tert-BuOH was distilled from CaH2. tert-Amylalcohol was distilled from
K2CO3. Nickelocene was sublimed at 100 °C prior to use. Reagents were used without
further purification. Yields refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise stated. 1H and 13C NMR spectra were recorded at
600 and 151 MHz, respectively. Chemical shifts are reported in δ ppm referenced to an
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internal tetramethylsilane or solvent peaks. High-resolution mass spectra were recorded on
a double-focusing magnetic-sector mass analyzer operating in a FAB mode.
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[Ni(DHASIiPr)CpCl] 2. 1,4-Dioxane was degassed via the freeze-thaw technique prior to
use. A flask was charged with DHASIiPr•HBF4 1 (74 mg, 177 mmol),14 freshly sublimed
nickelocene (50 mg, 265 mmol), n-Bu4NCl (54 mg, 194 mmol) and a magnetic stir bar at
25 °C. The flask was evacuated and back-filled with argon (repeated this sequence three
times). 1,4-Dioxane (5.6 mL) was then added to the resulting flask at 25 °C, and the
reaction mixture was stirred at reflux for 1 h. The reaction solution was cooled to 25 °C,
and the solvent was removed under reduced pressure. The residue was treated with boiling
toluene (10 mL), and the resulting red solution was filtered. This process was repeated three
times, and the combined filtrates were transferred to a separatory funnel and washed with
H2O (20 mL × 3). The organic layer was dried over Na2SO4, filtered, and the volume of the
resulting solution was reduced to ca. 2 mL under reduced pressure. n-Hexane was slowly
added to this solution to precipitate the title complex [Ni(DHASIiPr)CpCl] 2 (84 mg, 97%)
as a reddish orange solid. A single crystalline for X-ray diffraction analysis was grown by
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the slow vapor diffusion of n-hexane into a toluene solution. mp 199–201 °C (decomp.); 1H
NMR (600 MHz, CDCl3, 297 K): δ = 7.29 (dd, J = 5.4, 3.0 Hz, 2H), 7.28–7.25 (m, 2H),
7.16 (dd, J = 5.4, 3.0 Hz, 2H), 7.14 (dd, J = 5.4, 3.0 Hz, 2H), 6.48 (sep, J = 7.2 Hz, 2H),
4.75 (s, 5H), 4.58 (s, 2H), 4.39 (dd, J = 1.2, 1.2 Hz, 2H), 1.60 (d, J = 7.2 Hz, 6H), 1.40 (d, J
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= 7.2 Hz, 6H) ppm; C{1H} NMR (151 MHz, CD2Cl2, 303 K): δ = 199.0, 139.9, 138.7,
13
126.5, 126.1, 125.6, 124.5, 91.0, 63.7, 53.5, 48.2, 23.0, 19.6 ppm; IR (KBr pellet): νmax
=
3040, 2972, 2938, 2873, 1470, 1459, 1368, 1297, 1269, 1184, 1126, 1085, 1035, 833, 779,
759 cm-1; HRMS (FAB+) calcd. for C28H31ClN2Ni (M+) 488.1529, found 488.1533.
Typical procedure for the Ni(NHC)CpCl catalyzed Suzuki-Miyaura cross coupling. A
test tube with screw cap was charged with [Ni(DHASIiPr)CpCl] 2 (2.0 mg, 4.0 ꢀmol),
K3PO4 (255 mg, 1.2 mmol), PPh3 (21 mg, 80 ꢀmol), phenylboronic acid (73 mg, 0.60
mmol) and magnetic stir bar at 25 °C (if an aryl chloride was solid, the aryl chloride was
added to this test tube at this point), and the resulting test tube was capped with rubber
septa. The test tube was evacuated and back-filled with argon (repeated this sequence three
times). Degassed solvent (1.0 mL, (2.0 mL in the case of solid aryl chloride)) was then
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added to the resulting vessel at 25 °C, and the reaction mixture was stirred at 25 °C until the
color of the solution changed from red to yellow. Aryl chloride (0.40 mmol) in degassed
solvent (0.5 mL) was added by a syringe through the septa, and an additional 0.5 mL of
degassed solvent was used to rinse the flask which had been charged with the aryl chloride
(skipped this process in the case of solid aryl chloride). The rubber septa was replaced with
a screw cap promptly, and the reaction solution was then heated at 90 °C for 24 hr. The
reaction was quenched with H2O (20 mL) at 0 °C, and the resulting mixture was extracted
with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue
was purified by flash column chromatography on silica gel (30 mL) to afford the
cross-coupled product. The coupling reaction using 1-chloro-2-(1-methylethoxy)benzene or
ethyl 2-chlorobenzoate was heated at 110 °C in toluene/tert-amylalcohol.
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4-Methoxybiphenyl (5aa).23 Eluent for column chromatography: 1 to 5 %
1
EtOAc/n-hexane; Yield: 71 mg (96%); State of the product: colorless solid; H NMR (600
MHz, CDCl3, 298 K):  = 7.55 (dd, J = 8.4, 1.2 Hz, 2H), 7.53 (d, J = 8.4, 2H), 7.41 (dd, J
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= 7.2, 7.2 Hz, 2H), 7.30 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 3.85
(s, 3H) ppm.
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2-Fluorobiphenyl (5ba; obtained as an inseparable mixture with biphenyl).23 Eluent for
1
column chromatography: n-hexane; Yield: 66 mg (90% yield based on H NMR); State of
1
the product: colorless solid; H NMR (600 MHz, CDCl3, 298 K):  = 7.56–7.53 (m, 2H),
7.46–7.41 (m, 3H), 7.36 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.33–7.28 (m, 1H), 7.20 (ddd,
J = 7.2, 7.2, 1.2 Hz, 1H), 7.15 (ddd, J = 10.8, 7.2, 1.2 Hz, 1H) ppm.
2-Methoxybiphenyl (5ca).23 Eluent for column chromatography: 1 to 5 %
1
EtOAc/n-hexane; Yield: 64 mg (86%); State of the product: colorless oil; H NMR (600
MHz, CDCl3, 298 K):  = 7.53–7.51 (m, 2H), 7.40 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 2H),
7.33–7.29 (m, 3H), 7.02 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 3.79 (s,
3H) ppm.
2-Phenylbenzonitrile (5da).23 Eluent for column chromatography: 5 to 9 %
1
EtOAc/n-hexane; Yield: 63 mg (88%); State of the product: colorless oil; H NMR (600
MHz, CDCl3, 299 K):  = 7.76 (dd, J = 7.2, 1.2 Hz, 1H), 7.64 (ddd, J = 7.2, 7.2, 1.2 Hz,
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1H), 7.57–7.54 (m, 2H), 7.52 (dd, J = 7.2, 1.2 Hz, 1H), 7.51–7.47 (m, 2H), 7.46–7.42 (m,
2H) ppm.
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2-Methylbiphenyl (5ea; obtained as an inseparable mixture with biphenyl).23 Eluent for
1
column chromatography: n-hexane; Yield: 59 mg of mixture (80% yield based on H
1
NMR); State of the product: colorless liquid; H NMR (600 MHz, CDCl3, 298 K): δ =
7.41–7.38 (m, 2H), 7.34–7.30 (m, 3H), 7.27–7.21 (m, 4H), 2.27 (s, 3H) ppm.
Biphenyl-2-carboxaldehyde (5fa).23 Eluent for column chromatography: 1 to 3 %
1
EtOAc/n-hexane; Yield: 64 mg (88%); State of the product: colorless oil; H NMR (600
MHz, CDCl3, 298 K):  = 9.99 (d, J = 0.6 Hz, 1H), 8.03 (dd, J = 7.8, 1.2 Hz, 1H), 7.64
(ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.52–7.44 (m, 5H), 7.40–7.36 (m, 2H) ppm.
2-(Trifluoromethyl)biphenyl (5ga; obtained as an inseparable mixture with biphenyl).23
1
Eluent for column chromatography: n-hexane; Yield: 88 mg (99% yield based on H
NMR); State of the product: colorless liquid; 1H NMR (600 MHz, CDCl3, 298 K):  = 7.74
(d, J = 7.8 Hz, 1H), 7.55 (dd, J = 7.8, 7.8 Hz, 1H), 7.46 (dd, J = 7.8, 7.8 Hz, 1H), 7.41–7.37
(m, 3H), 7.34–7.31 (m, 3H) ppm.
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2-Aminobiphenyl (5ha).23 Eluent for column chromatography: 10% EtOAc/n-hexane;
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Yield: 60 mg (89%); State of the product: pale yellow solid; H NMR (600 MHz, CDCl3,
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298 K):  = 7.47–7.42 (m, 4H), 7.34 (dddd, J = 6.6, 6.6, 1.2, 1.2 Hz, 1H), 7.15 (ddd, J =
7.8, 7.8, 1.2 Hz, 1H), 7.13 (dd, J = 7.2, 1.2 Hz, 1H), 6.82 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H),
6.76 (dd, J = 7.8, 1.2 Hz, 1H), 3.74 (br s, 2H) ppm.
1-Phenylnaphthalene (5ia; obtained as an inseparable mixture with a trace amount of
biphenyl).23 Eluent for column chromatography: n-hexane; Yield: 79 mg (97%); State of the
product: colorless liquid; 1H NMR (600 MHz, CDCl3, 298 K):  = 7.90 (d, J = 9.6 Hz, 2H),
7.85 (d, J = 7.8 Hz, 1H), 7.53–7.46 (m, 6H), 7.44–7.40 (m, 3H) ppm.
Ethyl 2-phenylbenzoate (5ja).23 Eluent for column chromatography: 5% EtOAc/n-hexane;
1
Yield: 89 mg (98%); State of the product: colorless oil; H NMR (600 MHz, CDCl3, 298
K):  = 7.82 (dd, J = 7.8, 1.2 Hz, 1H), 7.51 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.42–7.33 (m,
5H), 7.32–7.30 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H) ppm.
2-(1-Methylethoxy)biphenyl (5ka).23 Eluent for column chromatography: 0 to 1 %
Et2O/n-hexane; Yield: 74 mg (87%); State of the product: colorless oil; 1H NMR (600 MHz,
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CDCl3, 298 K):  = 7.57–7.54 (m, 2H), 7.39 (dd, J = 7.2, 7.2 Hz, 2H), 7.33 (dd, J = 7.8,
1.8 Hz, 1H), 7.32–7.25 (m, 2H), 7.01 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 6.99 (d, J = 7.8 Hz,
1H), 4.42 (sep, J = 6.0 Hz, 1H), 1.24 (d, J = 6.0 Hz, 6H) ppm.
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1,1-Dimethylethyl
N-Biphenyl-2-ylcarbamate
(5la).23
Eluent
for
column
chromatography: 1 to 5% EtOAc/n-hexane; Yield: 68 mg (63%; 13% of Boc cleaved
1
product 5ha was also isolated); State of the product: colorless solid; H NMR (600 MHz,
CDCl3, 297 K):  = 8.11 (d, J = 6.6 Hz, 1H), 7.49 (dd, J = 7.2, 7.2 Hz, 2H), 7.41 (dddd, J =
7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.39–7.36 (m, 2H), 7.34 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.20 (dd,
J = 7.2, 1.2 Hz, 1H), 7.08 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 6.50 (br s, 1H), 1.46 (s, 9H) ppm.
N-Biphenyl-2-ylacetamide (5ma).23 Eluent for column chromatography: 20 to 50%
EtOAc/n-hexane; Yield: 51 mg (60%; 22% of acetanilide was also isolated); State of the
product: colorless crystalline; 1H NMR (600 MHz, CDCl3, 298 K):  = 8.27 (d, J = 8.4 Hz,
1H), 7.49 (dd, J = 7.2, 7.2 Hz, 2H), 7.42 (dd, J = 7.2, 7.2 Hz, 1H), 7.40–7.36 (m, 3H), 7.24
(d, J = 7.2 Hz, 1H), 7.18 (dd, J = 7.2, 7. 2 Hz, 1H), 7.12 (br s, 1H), 2.02 (s, 3H) ppm.
9-Phenylanthracene (5na).23 Eluent for column chromatography: n-hexane; Yield: 99 mg
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(97%); State of the product: colorless crystalline; H NMR (600 MHz, CDCl3, 299 K):  =
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8.49 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.57 (dddd, J = 7.2, 7.2, 1.2,
1.2 Hz, 2H), 7.52 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.47–7.41 (m, 4H), 7.35 (dd, 7.8, 1.2
Hz, 1H), 7.33 (dd, 6.6, 1.2 Hz, 1H) ppm.
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4-Methoxy-2’-methylbiphenyl (5ab).23 Eluent for column chromatography: 0 to 2%
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Et2O/n-hexane; Yield: 53 mg (67%); State of the product: pale yellow oil; H NMR (600
MHz, CDCl3, 298 K):  = 7.26–7.20 (m, 6H), 6.95 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H), 2.27
(s, 3H) ppm.
2, 4’-Dimethoxy-biphenyl (5ac).23 Eluent for column chromatography: 2 to 4%
1
EtOAc/n-hexane; Yield: 69 mg (81%); State of the product: colorless solid; H NMR (600
MHz, CDCl3, 298 K):  = 7.47 (d, J = 9.0 Hz, 2H), 7.31–7.27 (m, 2H), 7.01 (ddd, J = 7.2,
7.2, 1.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H), 3.81 (s,
3H) ppm.
2-Fluoro-2’-methylbiphenyl (5bb; obtained as an inseparable mixture with 2,
2’-dimethylbiphenyl).23 Eluent for column chromatography: n-hexane; Yield: 76 mg (99%
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yield based on H NMR); State of the product: colorless oil; H NMR (600 MHz, CDCl3,
298 K):  = 7.33 (dddd, J = 7.8, 7.2, 4.8, 1.8 Hz, 1H), 7.31–7.27 (m, 2H), 7.24 (ddd, J =
7.2, 7.2, 1.8 Hz, 1H), 7.22 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.19 (ddd, J = 7.2, 7.2, 1.2 Hz,
1H), 7.13 (ddd, J = 9.6, 8.4, 1.2 Hz, 1H), 2.20 (s, 3H) ppm.
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2-Methoxy-2’-methylbiphenyl (5cb, 5ec).23 Eluent for column chromatography: 0 to 1%
Et2O/n-hexane; Yield: 78 mg (98%); State of the product: colorless oil; 1H NMR (600 MHz,
CDCl3, 298 K):  = 7.34 (ddd, J = 8.4, 7.8, 1.2 Hz, 1H), 7.26–7.21 (m, 3H), 7.18 (d, J =
7.2 Hz, 1H), 7.14 (dd, J = 7.2, 1.8 Hz, 1H), 7.01 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 6.96 (d, J =
7.8 Hz, 1H), 3.76 (s, 3H), 2.14 (s, 3H) ppm.
2-(2-Methylphenyl)benzonitrile (5db).23 Eluent for column chromatography: 5 to 7%
1
EtOAc/n-hexane; Yield: 76 mg (98%); State of the product: colorless oil; H NMR (600
MHz, CDCl3, 298 K):  = 7.75 (dd, J = 7.8, 1.2 Hz, 1H), 7.63 (ddd, J = 7.8, 7.8, 1.2 Hz,
1H), 7.45 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.34 (ddd, J = 7.2, 7.2,
1.2 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.27 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.20 (dd, J = 7.8,
1.2 Hz, 1H), 2.19 (s, 3H) ppm.
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2-(2-Methoxyphenyl)benzonitrile (5dc).23 Eluent for column chromatography: 5 to 7%
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EtOAc/n-hexane; Yield: 74 mg (89%); State of the product: colorless oil; H NMR (600
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MHz, CDCl3, 298 K):  = 7.72 (dd, J = 7.8, 1.2 Hz, 1H), 7.62 (ddd, J = 7.8, 7.8, 1.2 Hz,
1H), 7.45 (d, J = 7.2 Hz, 1H), 7.43–7.39 (m, 2H), 7.25 (dd, J = 7.2, 1.2 Hz, 1H), 7.06 (ddd,
J = 7.2, 7.2, 1.2 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H) ppm.
4-Phenylpyridine (10aa).23 Reaction time: 4 h; Eluent for column chromatography: 40%
1
EtOAc/n-hexane; Yield: 61 mg (98%); State of the product: colorless solid; H NMR (600
MHz, CDCl3, 299 K):  = 8.65 (dd, J = 4.2, 1.2 Hz, 2H), 7.64–7.62 (m, 2H), 7.51–7.46 (m,
4H), 7.43 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H) ppm.
3-Phenylpyridine (10ba).21e Reaction time: 7 h; Eluent for column chromatography: 40%
EtOAc/n-hexane; Yield: 61 mg (98%); State of the product: pale yellow oil; 1H NMR (600
MHz, CDCl3, 299 K):  = 8.85 (d, J = 1.8 Hz, 1H), 8.58 (dd, J = 4.8, 1.8 Hz, 1H), 7.86
(ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.59–7.56 (m, 2H), 7.47 (dddd, J = 8.4, 8.4, 1.8, 1.8 Hz, 2H),
7.40 (dddd, J = 8.4, 8.4, 1.8, 1.8 Hz, 1H), 7.35 (ddd, J = 7.8, 4.8, 0.6 Hz, 1H) ppm.
5-Phenylpyrimidine (10ca).23 Reaction time: 0.5 h; Eluent for column chromatography:
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30% EtOAc/n-hexane; Yield: 60 mg (96%); State of the product: colorless oil; H NMR
(600 MHz, CDCl3, 297 K):  = 9.21 (s, 1H), 8.96 (s, 2H), 7.60–7.57 (m, 2H), 7.53 (dddd, J
= 7.8, 7.8, 1.2, 1.2 Hz, 2H), 7.48 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H) ppm.
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3-Phenylthiophene (10da; obtained as an inseparable mixture with biphenyl).23 Reaction
time: 2 h; Eluent for column chromatography: n-hexane; Yield: 49 mg (72% yield based on
1H NMR); State of the product: colorless solid; H NMR (600 MHz, CDCl3, 299 K):  =
1
7.59 (dd, J = 7.2, 1.2 Hz, 2H), 7.45–7.43 (m, 1H), 7.39–7.36 (m, 4H), 7.28 (dddd, J = 7.2,
7.2, 1.2, 1.2 Hz, 1H) ppm.
1-Methyl-3-phenylindole (10ea).23 Reaction time:
5
h; Eluent for column
chromatography: 0 to 10% CH2Cl2/n-hexane; Yield: 45 mg (54%); State of the product:
colorless oil; 1H NMR (600 MHz, CDCl3, 298 K):  = 7.94 (ddd, J = 7.8, 0.6, 0.6 Hz, 1H),
7.65 (dd, J = 7.8, 1.2 Hz, 2H), 7.43 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 2H), 7.36 (d, J = 8.4 Hz,
1H), 7.28 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.26 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.22 (s,
1H), 7.19 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 3.83 (s, 3H) ppm.
5-Phenylindole (10fa).23 Reaction time: 2 h; Eluent for column chromatography: 15 to
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20% EtOAc/n-hexane; Yield: 72 mg (93%); State of the product: pale yellow solid; H
NMR (600 MHz, CDCl3, 297 K):  = 8.20 (brs, 1H), 7.86 (d, J = 0.6 Hz, 1H), 7.65 (dd, J =
7.8, 1.2 Hz, 2H), 7.46–7.45 (m, 2H), 7.44 (dddd, J = 8.4, 8.4, 1.8, 1.8 Hz, 2H), 7.31 (dddd,
J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.24 (dd, J = 3.0, 2.4 Hz, 1H), 6.61 (dd, J = 3.0, 2.4 Hz, 1H)
ppm.
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3-Phenylquinoline (10ga).21e Reaction time: 6 h; Eluent for column chromatography: 30%
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EtOAc/n-hexane; Yield: 81 mg (99%); State of the product: colorless oil; H NMR (600
MHz, CDCl3, 297 K):  = 9.18 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.15 (d, J =
8.4 Hz, 1H), 7.87 (dd, J = 7.8, 0.6 Hz, 1H), 7.73–7.69 (m, 3H), 7.57 (ddd, J = 7.8, 7.2, 1.2
Hz, 1H), 7.52 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 2H), 7.43 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz,
1H) ppm.
4,7-Diphenylquinoline (10ha).23 Reaction time: 18 h; Eluent for column chromatography:
20 to 30% EtOAc/n-hexane; Yield: 104 mg (92%); State of the product: colorless solid; 1H
NMR (600 MHz, CDCl3, 299 K):  = 8.97 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H),
7.99 (d, J = 9.0 Hz, 1H), 7.79–7.76 (m, 3H), 7.56–7.49 (m, 7H), 7.41 (dddd, J = 7.2, 7.2,
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1.2, 1.2 Hz, 1H), 7.33 (d, J = 4.2 Hz, 1H) ppm.
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10% EtOAc/n-hexane, pure product for the analysis were obtained after the removal of
residual S.M via distillation under reduced pressure; Yield: 21 mg (34%); State of the
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product: pale yellow oil; H NMR (600 MHz, CDCl3, 298 K):  = 8.69 (ddd, J = 5.4, 1.2,
1.2 Hz, 1H), 8.00–7.97 (m, 2H), 7.76–7.71 (m, 2H), 7.47 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz,
2H), 7.41 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 1H), 7.22 (ddd, J = 6.6, 4.8, 1.8 Hz, 1H) ppm.
1-(5-phenylthiophen-2-yl)ethan-1-one (10ja).23 Reaction time: 3.5 h; Eluent for column
chromatography: 5 to 7% EtOAc/n-hexane; Yield: 38 mg (47%; 51% of S.M. was
recovered); State of the product: pale yellow solid; 1H NMR (600 MHz, CDCl3, 298 K): 
= 7.67–7.64 (m, 3H), 7.42 (dddd, J = 7.2, 7.2, 1.2, 1.2 Hz, 2H), 7.37 (dddd, J = 7.2, 7.2, 1.2,
1.2 Hz, 1H), 7.32 (d, J = 4.2 Hz, 1H), 2.57 (s, 3H) ppm.
4-Methyl-3-(2-methylphenyl)pyridine (10kb).21a Reaction time: 16 h; Eluent for column
chromatography: 30 to 40% EtOAc/n-hexane; Yield: 71 mg (97%); State of the product:
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colorless oil; H NMR (600 MHz, CDCl3, 300 K):  = 8.46 (d, J = 5.4 Hz, 1H), 8.33 (s,
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1H), 7.31–7.29 (m, 2H), 7.25 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 7.09
(d, J = 7.8 Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H) ppm.
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4-(Thiophen-3-yl)pyridine (12aa).23 Reaction time: 2.5 h; Eluent for column
chromatography: 20 to 40% EtOAc/n-hexane; Yield: 63 mg (98%); State of the product:
off-white solid; 1H NMR (600 MHz, CDCl3, 298 K):  = 8.65 (app d, J = 6.0 Hz, 2H), 7.68
(dd, J = 3.0, 1.2 Hz, 1H), 7.51 (dd, J = 4.2, 1.2 Hz, 2H), 7.46–7.43 (m, 2H) ppm.
4-(Furan-3-yl)pyridine (12ab).23 Reaction time: 12 h; Eluent for column chromatography:
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30 to 50% EtOAc/n-hexane; Yield: 57 mg (98%); State of the product: beige oil; H NMR
(600 MHz, CDCl3, 297 K):  = 8.58 (dd, J = 4.2, 1.2 Hz, 2H), 7.88 (dd, J = 1.2, 1.2 Hz,
1H), 7.53 (dd, J = 1.2, 1.2 Hz, 1H), 7.37 (dd, J = 4.2, 1.2 Hz, 2H), 6.74 (dd, J = 1.8, 0.6 Hz,
1H) ppm.
3-(Thiophen-3-yl)pyridine (12ba).1h,21e Reaction time: 5 h; Eluent for column
chromatography: 30 to 40% EtOAc/n-hexane; Yield: 60 mg (93%); State of the product:
pale yellow oil; 1H NMR (600 MHz, CDCl3, 300 K):  = 8.88 (s, 1H), 8.54 (d, J = 3.0 Hz,
1H), 7.88 (ddd, J = 7.8, 1.8, 1.8 Hz, 1H), 7.53 (dd, J = 3.0, 1.2 Hz, 1H), 7.45 (dd, J = 4.8,
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3.0 Hz, 1H), 7.40 (dd, J = 5.4, 1.2 Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 1H) ppm.
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3-(Furan-3-yl)pyridine (12bb).1h Reaction time: 12 h; Eluent for column chromatography:
30 to 40% EtOAc/n-hexane; Yield: 55 mg (95%); State of the product: yellow oil; 1H NMR
(600 MHz, CDCl3, 298 K):  = 8.77 (d, J = 1.8 Hz, 1H), 8.50 (dd, J = 4.8, 1.8 Hz, 1H),
7.78 (dd, J = 1.2, 1.2 Hz, 1H), 7.76 (ddd, J = 7.8, 1.8, 1.8 Hz, 1H), 7.53 (dd, J = 1.8, 1.8 Hz,
1H), 7.31 (ddd, J = 7.8, 4.8, 1.2 Hz, 1H), 6.72 (dd, J = 1.8, 1.2 Hz, 1H) ppm.
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5-(Thiophen-3-yl)pyrimidine (12ca).1h,21e Reaction time: 1 h; Eluent for column
chromatography: 30 to 40% EtOAc/n-hexane; Yield: 62 mg (96%); State of the product:
pale yellow solid; 1H NMR (600 MHz, CDCl3, 300 K):  = 9.14 (s, 1H), 8.96 (s, 2H), 7.61
(dd, J = 3.0, 1.2 Hz, 1H), 7.51 (dd, J = 4.8, 3.0 Hz, 1H), 7.41 (dd, J = 4.8, 1.2 Hz, 1H) ppm.
5-(Furan-3-yl)pyrimidine (12cb).1h,21e Reaction time: 1 h; Eluent for column
chromatography: 30% EtOAc/n-hexane; Yield: 55 mg (94%); State of the product: colorless
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needle; H NMR (600 MHz, CDCl3, 297 K):  = 9.12 (s, 1H), 8.86 (s, 2H), 7.85 (dd, J =
1.2, 1.2 Hz, 1H), 7.58 (dd, J = 1.8, 1.8 Hz, 1H), 6.74 (dd, J = 1.8, 0.6 Hz, 1H) ppm.
3-(Thiophen-3-yl)furan (12db).23 Reaction time: 4 h; Eluent for column chromatography:
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