Parallel and combinatorial liquid-phase synthesis of alkylbiphenyls using pentaerythritol support

Article abstract of DOI:10.1021/co400136k

Unfunctionalized alkylbiphenyls were fabricated by a parallel and combinatorial synthesis using pentaerythritol as a tetrapodal soluble support for a sulfonate-based traceless multifunctional linker system. Nickel N-heterocyclic carbene-catalyzed reactions of pentaerythritol tetrakis(biphenylsulfonate)s with primary alkylmagnesium bromides generated the alkylbiphenyl derivatives by desulfitative cleavage/cross-coupling of the C-S bond without any memory of the attachment on the support. Though the reactions were completed with sufficient yields in 12 h at room temperature, even with only 1.5 equiv of nucleophiles, they still retained the benefits of facile isolation observed in polymer-supported reactions.

Full text of DOI:10.1021/co400136k

Research Article
pubs.acs.org/acscombsci
Parallel and Combinatorial Liquid-Phase Synthesis of Alkylbiphenyls
Using Pentaerythritol Support
Wang-Kyu Kim, Jong-Hoon Jang, Hyunjong Jo, and Kwangyong Park*
School of Chemical Engineering and Materials Science, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756,
Republic of Korea
S
* Supporting Information
ABSTRACT: Unfunctionalized alkylbiphenyls were fabricated
by a parallel and combinatorial synthesis using pentaerythritol
as a tetrapodal soluble support for a sulfonate-based traceless
multifunctional linker system. Nickel N-heterocyclic carbene-
catalyzed reactions of pentaerythritol tetrakis(biphenylsulfonate)s
with primary alkylmagnesium bromides generated the alkylbi-
phenyl derivatives by desulfitative cleavage/cross-coupling of the
C−S bond without any “memory” of the attachment on the
support. Though the reactions were completed with sufficient
yields in 12 h at room temperature, even with only 1.5 equiv of
nucleophiles, they still retained the benefits of facile isolation
observed in polymer-supported reactions.
KEYWORDS: pentaerythritol, traceless linker, multifunctional cleavage, combinatorial synthesis
alcohol derivatives8 have continued to be studied as atom-
INTRODUCTION
■
economical supports.9 We previously reported that a sulfonate-
Combinatorial chemistry affords efficient production of large
based linker system using a pentaerythritol soluble support had
libraries of structurally analogous compounds, especially for
great potential in combining the benefits of both SPOS and
generating lead molecules in drug discovery.1 The combinato-
rial approach has also been employed in the field of materials
science to discover new functional materials such as electronic,
conventional solution reaction chemistry.10 The pentaerythritol
system offered an efficient synthetic route to biphenyl and
magnetic, sensing, and luminescent materials and catalysts.2
terphenyl derivatives, which are frequently found to be bio-
logically11 and optically12 active, via the traceless multifunctional
Solid-phase organic synthesis (SPOS) using polymer
supports has become a powerful tool for combinatorial
chemistry and high-throughput screening. The simple isolation
and purification of reaction intermediates and products has
cleavage of carbon−sulfur bonds by arylmagnesium bromides.
Oligomeric π-conjugated compounds, including p-oligophen-
yls, have recently attracted much attention for potential
applications in a wide range of optoelectronic devices such as
made polymer-supported SPOS an extremely attractive
organic light-emitting diodes, organic field-effect transistors,
approach for the rapid production of libraries of structurally
organic photovoltaic cells, and organic solid-state lasers.13 Not
similar compounds.3 However, their heterogeneous character-
only have different scaffolds been explored to meet the desired
physical and optoelectronic properties, but also variously
substituted analogues have been thoroughly investigated to
fine-tune the specifications of the compounds. In particular, the
introduction of alkyl groups has often been desirable as a means
to increase solubility in organic solvents. Therefore, an efficient
parallel and combinatorial approach for producing unfunction-
alized π-conjugated compounds with various alkyl moieties is
quite necessary.
Herein, we present our efforts to develop a traceless and
multifunctional sulfonate-based linker system that allows the
rapid production of a variety of alkyl-substituted biphenyl
istics often require large excesses of reagents to overcome their
low reactivity. Difficulties in monitoring reaction progress and
identifying the reaction intermediates are unavoidable weak-
nesses in using heterogeneous supports. Accordingly, trials to
transform conventional solution reactions to SPOS suffer from
limitations, and only a few reactions have been well established
using this methodology.
Liquid-phase combinatorial synthesis using soluble supports,
which is expected to avoid the drawbacks related to the
heterogeneity of SPOS while maintaining its advantages, has
recently been considered as an alternative to SPOS.4 Soluble
polymerstypically, polyethylene glycol and non-cross-linked
compounds. Development of traceless linker strategies that
polystyreneare the most common soluble supports. How-
ever, relatively large amounts of supports and reagents are still
required owing to their low loading capacities. Therefore,
soluble dendrimers5 and small molecules such as functionalized
ionic liquids,6 polyfunctionalized core molecules,7 and benzyl
Received: October 24, 2013
Revised: February 18, 2014
Published: February 25, 2014
© 2014 American Chemical Society
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Research Article
enable the release of unfunctionalized compounds from the
support has been an important challenge in supported
syntheses.14 The results of the parallel and combinatorial
preparations of an unfunctionalized alkybiphenyl library via the
desulfitative carbon−carbon cross-coupling of biphenyl moi-
eties attached to a soluble tetrapodal support, pentaerythritol,
with primary alkyl Grignard reagents (Scheme 1) are presented
and discussed.
acids, 2{1−6}, 0.17 equiv each, in the presence of Pd(PPh3)4
for 8 h. After the standard workup, the reaction mixture was
passed through a small pad of silica gel to generate the
biphenylsulfonate mixture 3 as a yellow powder that was pure
enough to be used in the next step.
The relative composition of the biphenyl moieties in mixture
3 was investigated after their cleavage by the reductive coupling
reaction with each of 4{1−3}. GC and HPLC analyses of the
reaction mixture indicated that all 2{1−6} successfully
underwent the desired coupling reactions, as summarized in
Table 2. The averaged relative composition of the biphenyl
moieties after the one-pot synthesis of 3 is displayed in Figure 1.
2-Naphthylboronic acids showed relatively higher reactivity,
whereas 4-methoxyphenylboronic acid was discovered to be the
lowest.
Scheme 1. Preparation of Biphenyl Compounds 5
The final cross-coupling reaction of mixture 3 with a mixture
of 4{1−3} was performed under the standard reaction
conditions. To compensate for the higher reactivity of 4{1},
1.66 equiv each of 4{2} and 4{3} were added with 0.33 equiv of
4{1}. The pentaerythritol-supported combinatorial reaction
allowed an efficient preparation of an alkylbiphenyl library in
terms of reaction rate and atom economy. After 12 h of
reaction and standard workup, all of the expected alkylbiphenyl
derivatives 5 could be identified by GC analysis (Figure 2) and
HPLC analysis (Figure 3). All 5 were consistently produced
and identified from four independent combinatorial reactions
started from 1. The results are summarized in Table 3.
RESULTS AND DISCUSSION
■
The pentaerythritol-supported biphenylsulfonates 3 were prepared
by Suzuki−Miyaura reactions of tetrakis(bromobenzenesulfonate)
1 with arylboronic acids 2 and isolated by facile precipitations from
EtOAc or acetone in good purity according to our previous
report.10a To effect the desulfitative carbon−carbon cross-coupling
of the biphenyl moieties of 3 with the primary alkyl Grignard
reagents, various conventional phosphinonickel(0) catalysts were
initially investigated. However, the slow reaction rate of the
unactivated alkyl Grignard reagents required a large excess of the
nucleophiles, even at elevated temperatures. The inefficiency of
the reagents and the difficulty in isolating the final products from
the abundant dimerized byproducts of the alkyl nucleophiles
diminished the value of this approach. Therefore, the Ni/NHC
catalyst, which was readily generated in situ by the reaction of
Ni(acac)2 with 1,3-bis(2,6-diisoprorylphenyl)imidazolium trifluor-
oborate (IPr·HBF4),15 was explored.
Figure 1. Average composition of biphenyl moieties in 3.
Cross-coupling reactions of 3 with alkylmagnesium bromides
4 were performed in the presence of the catalytic system.
Biphenylsulfonate moieties attached to a flexible neopentyl core
efficiently underwent the desired traceless multifunctional
cleavage reaction at room temperature. From the results of a
brief study to optimize the reactant ratios, only 1.5 equiv of the
nucleophiles was found to be sufficient. The results are
summarized in Table 1. Three alkyl nucleophiles were coupled
with the biphenyl moieties via the cleavage of carbon−sulfur bonds
to produce the corresponding alkylbiphenyls 5 in competitive
yields within 12 h. The neopentyl- and benzylmagnesium
bromides 4{2−3} showed a slightly lower yield than the methyl
nucleophile 4{1}. The relatively higher reactivity of the methyl
nucleophile was consistently observed when a 1.0 M solution of
methylmagnesium chloride in THF was used.
Application of this strategy to the combinatorial synthesis of
an alkylbiphenyl library was demonstrated. Bromobenzenesul-
fonate 1 was treated with an equimolar mixture of six boronic
Figure 2. GC Analysis of 5 produced by combinatorial reaction of 3
with 4.
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a
Table 1. Ni/NHC Catalyzed Coupling of 3 with 4 to Produce 5
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Table 1. continued
a
Reactions between 3 (0.100 mmol) and 4 (0.600 mmol) in THF (3.0 mL) were carried out at 25 °C in the presence of Ni(acac)2 (0.0200 mmol)
b
and IPr·HBF4 (0.0200 mmol). Isolated yield based on 3.
cleavage of biphenyl moieties without any “memory,” typically a
polar functional group such as a hydroxyl, carboxyl, or amino group,
of their attachment on the support. The reaction rate obtained using
only 1.5 equiv of the nucleophiles, even at room temperature, made
this approach more attractive. To the best of our knowledge, this is
the first general application of sulfonate-based linkers on supports
for the traceless preparation of an alkyl-substituted biphenyl library.
The synthetic strategy using pentaerythritol as a soluble support
was observed to combine the benefits of both conventional
reactions and SPOS. The homogeneous reaction conditions
allowed a fast reaction rate and a convenient analysis of reaction
progress expected in conventional solution-phase reactions. On
the other hand, the facile isolation of intermediates by simple
filtration through a small pad of silica gel made this approach as
attractive as that with SPOS. In addition, inexpensive pentaery-
thritol is an atom-economical support that wastes only one
equivalent of the small neopentyl core unit while producing four
equivalents of alkylbiphenyls.
Figure 3. HPLC analysis of 5 produced by combinatorial reaction of 3
with 4.
This small tetrapodal support would be an efficient and
economical substitute for common polymer supports in the
appropriate combinatorial chemistry. Especially, the traceless
multifunctional release is believed to show potential for
combinatorial synthesis of larger libraries of π-conjugated
hydrocarbons.
CONCLUSION
■
This study shows that pentaerythritol is an efficient tetrapodal
soluble support for the parallel/combinatorial synthesis of various
alkylbiphenyl compounds. A neopentyl core possessing four
sulfonate linkers allowed the highly efficient traceless multifunctional
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Table 2. Composition of 5 Produced by Reaction of 3 with
Each of 4
Table 3. A Library of Alkylbiphenyls 5 Produced by
a
a
Combinatorial Reaction
composition
composition
b
bc
,
b
bc
,
entry
R
Ar
5
(%)
range (%)
entry
R
Ar
5
(%)
range (%)
1
methyl
methyl
methyl
methyl
methyl
methyl
Ph
5{1,1}
5{2,1}
5{3,1}
13.83
15.25
16.24
8.21
10−29
11−16
10−20
7−10
23−36
11−21
1
methyl
methyl
methyl
methyl
methyl
methyl
Ph
4-Me-Ph
4-t-Bu-Ph
5{1,1}
5{2,1}
5{3,1}
5.56
11.62
1.71
0.83
11.35
4.35
4.55
3.23
5.68
3.12
8.50
4.22
5.08
4.27
10.94
5.13
5.94
3.91
5−7
2−15
2−7
2
4-Me-Ph
2
3
4-t-Bu-Ph
3
4
4-MeO-Ph 5{4,1}
2-naphthyl 5{5,1}
4
4-MeO-Ph 5{4,1}
2-naphthyl 5{5,1}
1−3
5
35.68
10.79
5
4−22
3−14
2−10
1−4
2−6
1−3
3−9
2−9
5−14
2−11
5−11
2−5
6
4-CF3-Ph
5{6,1}
6
4-CF3-Ph
5{6,1}
5{1,2}
5{2,2}
5{3,2}
total
7
100
7
neopentyl Ph
neopentyl Ph
5{1,2}
5{2,2}
5{3,2}
15.68
10.50
19.00
9.98
16−27
11−15
15−19
6−10
20−36
8−16
8
neopentyl 4-Me-Ph
neopentyl 4-t-Bu-Ph
8
neopentyl 4-Me-Ph
neopentyl 4-t-Bu-Ph
9
9
10
11
12
13
14
15
16
17
18
neopentyl 4-MeO-Ph 5{4,2}
neopentyl 2-naphthyl 5{5,2}
10
11
12
total
13
14
15
16
17
18
total
neopentyl 4-MeO-Ph 5{4,2}
neopentyl 2-naphthyl 5{5,2}
36.41
8.43
neopentyl 4-CF3-Ph
5{6,2}
5{1,3}
5{2,3}
5{3,3}
neopentyl 4-CF3-Ph
5{6,2}
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
Ph
100
4-Me-Ph
4-t-Bu-Ph
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
Ph
5{1,3}
5{2,3}
5{3,3}
22.53
14.58
18.77
11.20
12.36
20.57
20−30
14−19
18−24
7−11
12−22
13−21
4-Me-Ph
4-t-Bu-Ph
4-MeO-Ph 5{4,3}
2-naphthyl 5{5,3}
3−6
2−6
4-MeO-Ph 5{4,3}
2-naphthyl 5{5,3}
4-CF3-Ph
5{6,3}
a
Reaction of 3 (240 mg, approximately 0.209 mmol) with 4 (totally
3.07 mmol) was carried out in the presence of Ni(acac)2 (10.8 mg,
0.0418 mmol) and IPr·HBF4 (19.9 mg, 0.0418 mmol) in THF (6.0 mL)
at 25 °C. Relative composition based on GC area. Composition
range observed from four independent experiments from 1.
4-CF3-Ph
5{6,3}
100
b
c
a
Reaction of 3 (40.0 mg, approximately 0.0349 mmol) with each of 4
(0.209 mmol, 4{1}: 3.0 M in diethyl ether, 0.069 mL; 4{2} and 4{3}:
1.0 M in THF, 0.209 mL) was carried out in the presence of Ni(acac)2
(1.80 mg, 7.0 μmol) and IPr·HBF4 (3.33 mg, 7.0 μmol) in THF (3.0 mL)
at 25 °C. Relative composition based on GC area. Composition
range observed from four independent experiments from 1.
7.45 (d, J = 8.32 Hz, 2H), 7.49 (d, J = 7.98 Hz, 2H), 7.53 (d, J =
8.32 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 29.4 (× 3), 31.4
(× 3), 31.8, 34.5, 49.9, 125.6 (× 2), 126.2 (× 2), 126.6 (× 2), 130.8
(× 2), 138.2, 138.4, 138.6, 149.9. HRMS (EI, 70 eV) calcd for
C21H28 (M+): 280.2191. Found: 280.2195.
b
c
EXPERIMENTAL PROCEDURES
■
Solvents were distilled from appropriate drying agents prior to
use: THF and DME from sodium-benzophenone ketyl as well
as Et2O and toluene from CaH2. 1H NMR (300, 500, or 600 MHz)
and 13C NMR (75 or 150 MHz) were acquired using CDCl3 as a
solvent and tetramethylsilane (TMS) as an internal standard.
Chemical shifts are reported in δ units (ppm) by assigning the TMS
resonance in the 1H NMR spectrum as 0.00 ppm and the CDCl3
resonance in the 13C NMR spectrum as 77.2 ppm. All coupling
constants (J) are reported in hertz (Hz). GC analyses were
performed on a bonded 5% phenylpolysiloxane BPX 5 capillary
column (SGE, 30 m, 0.32 mm i.d.). Electron impact (EI, 70 eV)
was used as the ionization method for mass spectrometry.
2-(4-Neopentylphenyl)naphthalene, 5{5,2}. 2-(4-Neo-
pentylphenyl)naphthalene 5{5,2} was prepared by the reaction
of 3{5} (120.1 mg, 0.100 mmol) with 4{2} (1.0 M in THF,
0.600 mL, 0.600 mmol) in the presence of Ni(acac)2 (5.10 mg,
0.0200 mmol) and IPr·HBF4 (9.50 mg, 0.0200 mmol). The crude
product was purified by column chromatography on silica gel to
afford 5{5,2} (80.1 mg, 73%) as a white solid: TLC Rf 0.66 (Et2O/
n-hexane = 1:4). mp 87−88 °C. 1H NMR (500 MHz, CDCl3): δ
0.96 (s, 9H), 2.56 (s, 2H), 7.24 (d, J = 8.19 Hz, 2H), 7.45−7.51 (m,
2H), 7.63 (d, J = 8.19 Hz, 2H), 7.76 (dd, J = 8.48, 1.72 Hz, 1H),
7.86 (d, J = 7.79 Hz, 1H), 7.89 (d, J = 7.17 Hz, 1H), 7.90 (d, J =
8.48 Hz, 1H), 8.04 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 29.5
(× 3), 32.0, 50.0, 125.7, 125.8, 126.0, 126.5, 126.9 (× 2), 127.9,
128.4, 128.6, 131.3 (× 2), 132.8, 134.0, 138.7, 138.8, 139.3. HRMS
(EI, 70 eV) calcd for C21H22 (M+): 274.1722. Found: 274.1727.
4-Neopentyl-4′-trifluoromethylbiphenyl, 5{6,2}. 4-Neo-
pentyl-4′-trifluoromethylbiphenyl 5{6,2} was prepared by the
reaction of 3{6} (127.3 mg, 0.100 mmol) with 4{2} (1.0 M in
THF, 0.600 mL, 0.600 mmol) in the presence of Ni(acac)2
(5.10 mg, 0.0200 mmol) and IPr·HBF4 (9.50 mg, 0.0200 mmol).
The crude product was purified by column chromatography on
silica gel to afford 5{6,2} (87.7 mg, 75%) as a white solid: TLC Rf
General Procedure for Cross-Coupling Reactions of 3
with 4. To a stirred solution of 3 (0.100 mmol), Ni(acac)2
(0.0200 mmol), and IPr·HBF4 (0.0200 mmol) in THF (3.0 mL)
under an argon atmosphere was slowly added the alkyl Grignard
reagent 4 (0.600 mmol). The reaction mixture was stirred at room
temperature for 12 h and diluted with Et2O. The organic layer was
washed with 1% aqueous HCl, water, and brine; dried over
MgSO4; and concentrated in vacuo. The resulting crude product
was purified by column chromatography on silica gel.
4-t-Butyl-4′-neopentylbiphenyl, 5{3,2}. 4-t-Butyl-4′-neo-
pentylbiphenyl 5{3,2} was prepared by the reaction of 3{3}
(122.6 mg, 0.100 mmol) with 4{2} (1.0 M in THF, 0.600 mL,
0.600 mmol) in the presence of Ni(acac)2 (5.10 mg, 0.0200 mmol)
and IPr·HBF4 (9.50 mg, 0.0200 mmol). The crude product was
purified by column chromatography on silica gel to afford 5{3,2}
(87.5 mg, 78%) as a yellow solid: TLC Rf 0.88 (Et2O/n-hexane =
1:4). mp 92−93 °C (uncorrected). 1H NMR (300 MHz, CDCl3):
δ 0.93 (s, 9H), 1.36 (s, 9H), 2.52 (s, 2H), 7.18 (d, J = 7.98 Hz, 2H),
1
0.78 (Et2O/n-hexane = 1:4). mp 71−72 °C (uncorrected). H
NMR (300 MHz, CDCl3): δ 0.94 (s, 9H), 2.55 (s, 2H), 7.23 (d, J =
7.89 Hz, 2H), 7.50 (d, J = 7.89 Hz, 2H), 7.68 (s, 4H). 13C NMR
(150 MHz, CDCl3): δ 29.4 (× 3), 31.9, 49.9, 124.3 (q, J = 271.85
Hz, 1C), 125.6 (q, J = 3.78 Hz, 2C), 126.4 (× 2), 127.2
(× 2), 129.0 (q, J = 32.49 Hz, 1C), 131.1 (× 2), 137.1, 140.0, 144.6.
HRMS (EI, 70 eV) calcd for C18H19F3 (M+): 292.1439. Found:
292.1444.
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2-(4-Benzylphenyl)naphthalene, 5{5,3}. 2-(4-Benzyl-
phenyl)naphthalene 5{5,3} was prepared by the reaction of
3{5} (120.1 mg, 0.100 mmol) with 4{3} (1.0 M in THF,
0.600 mL, 0.600 mmol) in the presence of Ni(acac)2 (5.10 mg,
0.0200 mmol) and IPr·HBF4 (9.50 mg, 0.0200 mmol). The
crude product was purified by column chromatography on silica
gel to afford 5{5,3} (84.8 mg, 72%) as a white solid: TLC Rf
0.76 (Et2O/n-hexane = 1:4). mp 101−102 °C (uncorrected).
1H NMR (600 MHz, CDCl3): δ 4.05 (s, 2H), 7.20−7.26 (m,
3H), 7.31 (d, J = 8.01 Hz, 2H), 7.32 (t, J = 5.97, 7.41 Hz, 2H),
7.45−7.51 (m, 2H), 7.65 (d, J = 8.01, 2H), 7.73 (dd, J = 8.58,
1.85 Hz, 1H), 7.86 (d, J = 7.82 Hz, 1H), 7.88 (d, J = 9.43 Hz,
1H), 7.90 (d, J = 8.58 Hz, 1H), 8.02 (d, J = 0.40 Hz, 1H). 13C
NMR (150 MHz, CDCl3): δ 41.6, 125.50, 125.52, 125.8, 126.1,
126.2, 127.5 (× 2), 127.6, 128.1, 128.3, 128.5 (× 2), 128.9 (× 2),
129.4 (× 2), 132.5, 133.7, 138.3, 138.9, 140.4, 141. HRMS (EI,
70 eV) calcd for C23H18 (M+): 294.1409. Found, 294.1414.
4-Benzyl-4′-trifluoromethylbiphenyl, 5{6,3}. 4-Benzyl-
4′-trifluoromethylbiphenyl 5{6,3} was prepared by the reaction
of 3{6} (127.3 mg, 0.100 mmol) with 4{3} (1.0 M in THF,
0.600 mL, 0.600 mmol) in the presence of Ni(acac)2 (5.10 mg,
0.0200 mmol) and IPr·HBF4 (9.50 mg, 0.0200 mmol). The
crude product was purified by column chromatography on silica
gel to afford 5{6,3} (87.5 mg, 70%) as a white solid: TLC Rf
AUTHOR INFORMATION
■
Corresponding Author
*Phone: 82-2-820-5330. E-mail: kypark@cau.ac.kr.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Chung-Ang University
Excellent Student Scholarship in 2014 and the National
Research Foundation of Korea Grant funded by the Korean
Goverment (MEST). (NRF-2012R1A1A2043846).
REFERENCES
■
(1) For recent reviews, see: (a) Scott, W. L.; O’Donnell, M. J.
Distributed drug discovery, Part 1: linking academia and combinatorial
chemistry to find drug leads for developing world diseases. J. Comb.
Chem. 2008, 11, 3−13. (b) Kennedy, J. P.; Williams, L.; Bridges, T. M.;
Daniels, R. N.; Weaver, D.; Lindsley, C. W. Application of
combinatorial chemistry science on modern drug discovery. J. Comb.
Chem. 2008, 10, 345−354.
1
0.86 (Et2O/n-hexane = 1:4). mp 64−65 °C (uncorrected). H
NMR (600 MHz, CDCl3): δ 4.03 (s, 2H), 7.21−7.24 (m, 3H), 7.30
(d, J = 8.28 Hz, 2H), 7.32 (t, J = 7.40, 7.46 Hz, 2H), 7.53 (d, J =
8.24 Hz, 2H), 7.67 (s, 4H). 13C NMR (150 MHz, CDCl3): δ 41.6,
124.3 (q, J = 271.84 Hz, 1C), 125.7 (q, J = 3.79 Hz, 2C), 126.2,
127.2 (× 2), 127.3 (× 2), 128.6 (× 2), 128.9 (× 2), 129.4 (q, J =
42.55 Hz, 1C), 129.7 (× 2), 137.5, 140.7, 141.4, 144.5. HRMS
(EI, 70 eV) calcd for C20H15F3 (M+): 312.1128. Found: 312.1133.
Procedure for Combinatorial Reaction of 1 with 2. To
a solution of 1 (400 mg, 0.396 mmol) and Pd(PPh3)4 (9.13 mg,
0.0792 mmol) in toluene (16 mL) was added 2.0 M aq.
Na2CO3 (1.58 mL, 3.16 mmol). To the resulting mixture was
added 2{1−6} (2{1}, 32.2 mg; 2{2}, 35.9 mg; 2{3}, 47.0 mg;
2{4}, 40.1 mg; 2{5}, 45.4 mg; and 2{6}, 50.1 mg; 0.264 mmol
each) dissolved in EtOH (4.0 mL). The reaction mixture was
refluxed for 8 h with vigorous stirring and then cooled to room
temperature. The residue was diluted with CH2Cl2. The organic
layer was washed with 1% aqueous HCl, water, and brine; dried
over MgSO4; and concentrated in vacuo. The resulting crude
product was dissolved in ether and passed through a small pad
of silica gel to generate 3 as a yellow powder, which did not
show a noticeable amount of impurity by TLC analysis.
Procedure for Combinatorial Cross-Coupling Reac-
tion of 3 with 4. To a stirred solution of 3 (240 mg,
approximately 0.209 mmol), Ni(acac)2 (10.8 mg, 0.0418 mmol),
and IPr·HBF4 (19.9 mg, 0.0418 mmol) in THF (6.0 mL) under
an argon atmosphere were slowly added the alkyl Grignard
reagents 4{1} (3.0 M in diethyl ether, 0.093 mL, 0.279 mmol),
4{2} (1.0 M in THF, 1.395 mL, 1.395 mmol), and 4{3} (1.0 M in
THF, 1.395 mL, 1.395 mmol). The reaction mixture was stirred at
room temperature for 12 h and diluted with CH2Cl2. The organic
layer was washed with 1% aqueous HCl, water, and brine; dried
over MgSO4; and concentrated in vacuo.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Further details on the experimental procedures and spectra are
given. This material is available free of charge via the Internet at
http://pubs.acs.org.
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ACS Combinatorial Science
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