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NATURE CHEMISTRY | www.nature.com/naturechemistry 1
SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.1836
K. S. L. Chan et al.
1
Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via
Pd(II)/Pd(0) catalysis
Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura
& Jin-Quan Yu
Table of Contents
General Information SI 2
Experimental Section
A. Substrates SI 3
B. Synthesis of Pd(OTf)2(MeCN)4 SI 9
C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl SI 10
C(sp3)–H Bonds with Organoboron Reagents: Optimization
D. Products SI 16
E. Deprotection SI 35
References SI 36
NMR Spectra SI 37
K. S. L. Chan et al.
1
Ligand-Enabled Cross-Coupling of C(sp3)–H Bonds with Arylboron Reagents via
Pd(II)/Pd(0) Catalysis
Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura & Jin-Quan
Yu
Table of Contents
General Information SI 2
Experimental Section
A. Substrates SI 3
B. Synthesis of Pd(OTf)2(MeCN)4 SI 9
C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl SI 10
C(sp3)–H Bonds with Organoboron Reagents: Optimization
D. Products SI 16
E. Deprotection SI 35
References SI 36
NMR Spectra SI 37
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General Information
Solvents were obtained from Sigma-Aldrich, Alfa-Aesar, Acros and EMD Chemicals and used
directly without further purification. Palladium catalysts were obtained from Sigma-Aldrich,
Pressure Chemical Company, and Strem Chemicals. Amines and amino acids were obtained
from Sigma-Aldrich, Alfa-Aesar, Acros, Bachem, and Oakwood, and used to prepare
corresponding triflamides. Trifluoromethanesulfonic anhydride was purchased from Oakwood,
and arylboron reagents were purchased from Boron Molecular, Frontier Scientific, and Combi-
Blocks. Trifluoromethanesulfonamide is abbreviated to triflamide. Tert-amyl alcohol is
abbreviated to tAmylOH.
Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Preparative
thin layer chromatography was performed on 0.5 mm silica gel purchased from Analtech.
Visualization was carried out with UV light and Vogel’s permanganate. NMR spectra were
recorded on a Bruker AMX-400 instrument (400 MHz for 1H; 100 MHz for 13C), Bruker DRX-
500 instrument (500 MHz for 1H; 125 MHz for 13C), or Bruker DRX-600 instrument (600 MHz
for 1H; 150 MHz for 13C) equipped with a 5 mm DCH cryoprobe. Calibration was done using
residual undeuterated solvent or SiMe4 as an internal reference for 1H and 13C. The following
abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution mass spectra (HRMS)
were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of
flight). IR spectra were recorded on a Perkin Elmer Spectrum BX FTIR spectrometer.
Enantiomeric excess values were determined on a Hitachi LaChrom Elite HPLC system using
commercially available chiral columns.
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Experimental Section
A. Substrate Preparation
Figure F1
General procedure A for the preparation of triflyl-protected methyl ester amino acid:
A methyl ester amino acid hydrochloride (20 mmol), either purchased or prepared from the
corresponding amino acid and thionyl chloride, was dissolved in CH2Cl2 (0.5 M), and the
reaction mixture was cooled to –78 °C. Triethylamine (2.0 equiv) was added and the reaction
mixture was stirred –78 °C for 5 minutes. Trifluoromethanesulfonic anhydride (1.05 equiv) was
then added dropwise and the reaction mixture was stirred at –78 °C for 1 to 2 hours, before
quenching with ice. The organic layer was separated, and the aqueous layer was extracted twice
with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered, and
then concentrated in vacuo. The products were purified by column chromatography with hexanes
and ethyl acetate as an eluent.
General procedure B for the preparation of triflyl-protected amines:
An amine (20 mmol) was dissolved in CH2Cl2 (0.5 M), and the reaction mixture was cooled to –
78 °C. Triethylamine (1.0 equiv) was added and the reaction mixture was stirred –78 °C for 5
minutes. Trifluoromethanesulfonic anhydride (1.05 equiv) was then added dropwise and the
reaction mixture was stirred at –78 °C for 1 to 2 hours, before quenching with ice. The organic
layer was separated, and the aqueous layer was extracted twice with CH2Cl2. The combined
organics were washed with brine, dried over Na2SO4, filtered, and then concentrated in vacuo.
The products were purified by column chromatography with hexanes and ethyl acetate as an
eluent.
NH2
CO2H
H
NH2•HCl
CO2Me
HSOCl2
MeOHNHTf
CO2Me
HTf2O, Et3N
CH2Cl2-78 °C
R R R
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Supplementary Table S1 | Substrate structures
Data:
(S)-methyl 2-(trifluoromethylsulfonamido)butanoate (1)
Substrate 1 was prepared from L-homoalanine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 5.90 (br s, 1H), 4.21 (t, J = 6.1 Hz, 1H), 3.82 (s, 3H), 1.98 to 1.92
(m, 1H), 1.85 to 1.77 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 171.49,
119.60 (q, J = 320.8 Hz), 58.27, 53.23, 26.94, 9.23.
(R)-2-acetamido-3,3-dimethylbutanoic acid (3)
To a solution of D-tert-leucine (1.0 g, 7.6 mmol) in acetic acid (8 mL) was added acetic
anhydride (0.85 mL, 9.1 mmol) and the reaction mixture stirred overnight at room temperature.
The solvent was removed in vacuo to afford compound 3 as a white solid (1.29 g, 98%). No
purification was necessary. Characterization data matched reported data.
NHTf
CO2Me
H
H
NHTf
CO2Me
H
H
MeNHTf
H
MeO2CNHTf
CO2Me
H
Et
NHTf
H
TBSONHTf
H
OBn
NHTf
H
EtNHTf
H
NHTf
CO2Me
H
1 5 6 7 8
9 10 11 12
NHTf
CO2Me
H
NHAc
CO2H
tBu
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(R)-methyl 2-(trifluoromethylsulfonamido)butanoate (4)
Substrate 4 was prepared from D-homoalanine using General Procedure A. 1H NMR and 13C NMR identical to 1.
(S)-methyl 3-methyl-2-(trifluoromethylsulfonamido)butanoate (5) Substrate 5 was prepared from L-valine methyl ester hydrochloride using General Procedure A. 1H NMR (500 MHz, CDCl3) ! 6.68 (br s, 1H), 4.07 (d, J = 5.1 Hz, 1H), 3.81 (s, 3H), 2.28 to 2.19
(m, 1H), 1.04 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) !
171.36, 119.64 (q, J = 321.1 Hz), 62.57, 52.95, 31.62, 18.78, 17.05.
(S)-methyl 3,3-dimethyl-2-(trifluoromethylsulfonamido)butanoate (6) Substrate 6 was prepared from L-tert-Leucine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 5.76 (br s, 1H), 3.90 (s, 1H), 3.80 (s, 3H), 1.03 (s, 9H); 13C NMR
(150 MHz, CDCl3) ! 170.74, 119.66 (q, J = 321.4 Hz), 65.61, 52.68, 34.97, 26.40.
NHTf
CO2Me
H
NHTf
CO2Me
H
H
NHTf
CO2Me
H
H
Me
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(2S,3S)-methyl 3-methyl-2-(trifluoromethylsulfonamido)pentanoate (7)
Substrate 7 was prepared from L-isoleucine using General Procedure A. 1H NMR (600 MHz, CDCl3) ! 4.13 (d, J = 4.8 Hz, 1H), 3.81 (s, 3H), 1.97 to 1.90 (m, 1H), 1.47
to 1.40 (m, 1H), 1.23 to 1.16 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13C
NMR (150 MHz, CDCl3) ! 171.11, 119.64 (q, J = 321.2 Hz), 61.77, 52.99, 38.68, 24.60, 15.37,
11.50.
(R)-methyl 2-methyl-3-(trifluoromethylsulfonamido)propanoate (8) Substrate 8 was prepared from (R)-3-amino-2-methylpropionic acid using General Procedure A.1 1H NMR (400 MHz, CDCl3) ! 5.89 (br s, 1H), 3.74 (s, 3H), 3.41 (dq, J = 6.1, 13.8 Hz, 2H), 2.83
to 2.74 (m, 1H), 1.26 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) ! 175.47, 119.78 (q, J =
321.0 Hz), 52.50, 46.28, 39.98, 14.62.
N-(2-((tert-butyldimethylsilyl)oxy)propyl)-1,1,1-trifluoromethanesulfonamide (9) To a solution of 1-amino-2-propanol (1.50 g, 20 mmol) and triethylamine (5.56 mL, 40 mmol) in
CH2Cl2 (20 mL) at 0 °C was added dropwise a solution of tert-butyldimethylsilyl chloride (3.01
g, 20 mmol) in CH2Cl2 (20 mL). The reaction mixture was allowed to warm to room temperature
and stirred overnight. The reaction mixture was quenched with NH4Cl (sat. aq.), extracted with
CH2Cl2, and the combined organics washed with brine, dried over Na2SO4, filtered, and
NHTf
CO2Me
H
Et
NHTf
H
MeO2C
NHTf
H
TBSO
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concentrated in vacuo to afford the product as a colorless oil (99.9%). No purification was
necessary.1
Substrate 9 was thereafter prepared from the crude amine using General Procedure B. 1H NMR (400 MHz, CDCl3) ! 5.11 (br s, 1H), 4.04 to 3.97 (m, 1H), 3.33 (dd, J = 3.6, 13.0 Hz,
1H), 3.13 (dd, J = 6.4, 12.9 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 6H); 13C
NMR (100 MHz, CDCl3) ! 119.81 (q, J = 321.0 Hz), 67.30, 51.13, 25.85, 20.87, 18.09, -4.30, -
4.84.
N-(3-(benzyloxy)-2-methylpropyl)-1,1,1-trifluoromethanesulfonamide (10) A solution of 2-methylpropane-1,3-diol (1.80 g, 20 mmol) in THF (10 mL) was added dropwise
to a suspension of NaH in THF (50 mL). After the addition was complete, the mixture was
stirred at 50 °C for 1 h. Benzyl bromide (2.44 mL, 20.4 mmol) was then added dropwise and the
resulting mixture was stirred at 65 °C overnight. The reaction was quenched by addition of
NH4Cl (sat. aq.). The reaction mixture was diluted with ethyl acetate, washed with NH4Cl (sat.
aq.), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by
column chromatography and 3-(benzyloxy)-2-methylpropan-1-ol was afforded as a colorless oil
(2.50 g, 70%).2
To a solution of 3-(benzyloxy)-2-methylpropan-1-ol (1.00 g, 5.55 mmol),
trifluoromethanesulfonamide (1.65 g, 11.1 mmol), and triphenylphosphine (2.91 g, 11.1 mmol)
in THF (50 mL) at 0 °C was added neat diethyl diazodicarboxylate (1.93 g, 11.1 mmol). The
reaction mixture was stirred at room temperature overnight, and was quenched with water, then
diluted with ethyl acetate. The organics were separated, then washed with NaHCO3 (sat.) and
brine. The combined organics were then dried over Na2SO4, filtered, and concentrated in vacuo.
The crude residue was purified by column chromatography to afford substrate 10 as a colorless
oil (780 mg, 45 %).3
NHTf
H
OBn
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1H NMR (500 MHz, CDCl3) ! 7.35 to 7.32 (m, 2H), 7.29 to 7.26 (m, 3H), 6.13 (br s, 1H), 4.50 to
4.45 (m, 2H), 3.51 (dd, J = 9.4, 4.0 Hz, 1H), 3.26 to 3.27 (m, 2H), 3.17 (ddd, J = 12.4, 7.8, 3.9
Hz), 2.10 to 2.01 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) ! 137.54,
128.64, 128.04, 127.75, 119.90 (q, J = 321.4 Hz), 74.81, 73.47, 49.32, 33.57, 14.28.
1,1,1-trifluoro-N-(2-methylbutyl)methanesulfonamide (11)
Substrate 11 was prepared from 2-methylbutylamine using General Procedure B. 1H NMR (400 MHz, CDCl3) ! 5.42 (br s, 1H), 3.21 (dt, J = 11.7, 5.6 Hz, 1H), 3.08 (dt, J = 12.8,
6.2 Hz, 1H), 1.67 to 1.56 (m, 1H), 1.49 to 1.39 (m, 1H), 1.25 to 1.14 (m, 1H), 0.95 (d, J = 6.7
Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 119.84 (q, J = 321.1 Hz),
50.00, 35.24, 26.38, 16.54, 10.98.
1,1,1-trifluoro-N-(o-tolyl)methanesulfonamide (12) Substrate 12 was prepared from o-toluidine using General Procedure B. 1H NMR (500 MHz, CDCl3) ! 7.36 (d, J = 6.9 Hz, 1H), 7.26 to 7.19 (m, 3H), 2.35 (s, 3H); 13C
NMR (125 MHz, CDCl3) ! 134.20, 132.19, 131.32, 128.51, 127.24, 126.65, 119.94 (q, J = 322.3
Hz), 17.83.
NHTf
H
Et
NHTf
H
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B. Synthesis of Pd(OTf)2(MeCN)44
To a dark orange solution of palladium(II) acetate (2.04 g, 9.09 mmol) in acetonitrile (172 mL),
neat trifluoromethanesulfonic acid (2.35 mL, 26.52 mmol) was added dropwise while stirring.
The reaction mixture subsequently changed to a pale yellow color. Diethyl ether (240 mL) was
then added, and a fine pale yellow powder precipitated. The suspension was set aside for 2 h and
the supernatant liquid was decanted. The residual powder was washed with diethyl ether and
dried under a stream of nitrogen to afford Pd(OTf)2(MeCN)4 as a pale yellow powder (3.75 g,
73%).
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C. Ligand-Accelerated Pd(II)-Catalyzed Cross-Coupling of Alkyl C(sp3)–H Bonds with
Organoboron Reagents
Supplementary Table S2 | Further illustration of match/mismatch effect using D-substrate
NB: L-ligand performs better with D-substrate 4, compared to the D-ligand.
NHTf
CO2Me
H
CO2Me
BPin
cat. Pd(OAc)2 cat. Ac-tLeu-OH
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
NHTf
CO2Me
CO2Me
Entry Yield* (%)
Experiments were performed with D-subtrate 4 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol), ligand (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (BQ) (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.0 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
4 2 4a
1 542 65
Ligand
Ac-D-tLeu-OHAc-L-tLeu-OH
(R)(R)
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Optimization:
Supplementary Table S3 | Optimization of bases
Entry Base Yield* (%)
1 33NaH2PO42 72Na2HPO43 70Na3PO44 23KH2PO456
41K2HPO4
738K3PO4
81KOtBu
910
0NaOtBu
11
0LiOtBu
12
55LiOTf
13
0CsF
14
21KF
1516
53NaOAc
17
6KOAc0CsOAc65Na2CO369Li2CO3
Equiv.
4.02.01.54.02.01.54.04.04.04.04.04.04.04.04.02.02.0
18 K2CO3 2.0 4119 Cs2CO3 2.0 220 KHCO3 4.0 6321 NaHCO3 4.0 7022 Na3PO4 2.0 5823 Na2HPO4 3.0 6924 NaHCO3 6.0 74
Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.02 mmol), 3 (0.04 mmol), base, Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
NHTf
CO2Me
H
CO2Me
BPin
cat. Pd(OAc)2cat. Ac-D-tLeu-OH, 3
Ag2CO3, baseBQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
NHTf
CO2Me
CO2Me1 2 1a
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Supplementary Table S4 | Optimization of catalyst
Supplementary Table S5 | Optimization of Ag oxidant
Entry Catalyst Yield* (%)
1 74Pd(OAc)22 82Pd(OTf)2(MeCN)43 73Pd(TFA)24 57[Pd(allyl)Cl]2
Equiv.
0.10.10.10.05
Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd catalyst, 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
5 0none 0
NHTf
CO2Me
H
CO2Me
BPin
cat. Pdcat. Ac-D-tLeu-OH, 3
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
NHTf
CO2Me
CO2Me1 2 1a
cat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3
Ag salt, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
Entry Yield* (%)
1 82Ag2CO32 51Ag2O3 32AgOAc4 15Ag3PO4
Equiv.
2.02.04.01.5
Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag salt, 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
Ag
NHTf
CO2Me
H
CO2Me
BPin
NHTf
CO2Me
CO2Me1 2 1a
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Supplementary Table S6 | Optimization of solvents
cat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3
Ag2CO3, NaHCO3BQ, DMSO, H2O
solvent100 °C, N2, 18 h
Entry Solvent Yield* (%)
1 0N,N-dimethylformamide (DMF)2 0N,N-dimethylacetamide3 281,2-dichloroethane4 481,2-dimethoxyethane56
1acetonitrile
727toluene
843ethyl acetate
910
54tetrahydrofuran
11
651,4-dioxane
12
64tBuOH
13
82tAmylOH76tAmylOH/dioxane (9:1)69tAmylOH/THF (9:1)
Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in solvent (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. †No dimethylsulfoxide was added. ‡N,N-dimethylformamide (0.08 mmol) was added instead of dimethylsulfoxide.
14 tAmylOH 7615 tAmylOH 6816 tAmylOH 017† tAmylOH 7818‡ tAmylOH 76
H2O (equiv.)
5.55.55.55.55.55.55.55.55.55.55.55.55.51.010505.55.5
NHTf
CO2Me
H
CO2Me
BPin
NHTf
CO2Me
CO2Me1 2 1a
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Supplementary Table S7 | Optimization of other variables
cat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOHtemperature, atmosphere, 18 h
Entry Temperature (°C) Yield* (%)
1 75802 821003 661204 76100
Experiments were performed with 1 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (6.0 equiv.), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at specified temperature under specified atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
Atmosphere
N2N2N2O2
NHTf
CO2Me
H
CO2Me
BPin
NHTf
CO2Me
CO2Me1 2 1a
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Supplementary Table S8 | Ligand optimization
Me
Me
Experiments were performed with 4 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), ligand (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
Entry Ligand Yield* (%) Entry Ligand Yield* (%)R PG R PG
1 0 14 0iPr iPrMe Ts
2 18 15 31iPriPrFormyl
3 68iPr Ac
4 12iPr Boc
5 15iPr Fmoc
6 9iPr Cbz
7 0iPr Troc
NHTf
CO2Me
H
CO2Me
BPin
NHTf
CO2Me
CO2Me4 2 4a
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
HN
PGR
CO2H(S)
(R)(R)
8 31H Ac
9 50Me Ac
10 68nPr Ac
11 57iBu Ac
12 75tBu Ac
13 82Ac
OMe
O
O
16 43iPr F
O17 9iPr
18 8iPr
19 0iPr
20 6iPr
21 19iPr
22 58iPr
CF3
O
tBu
O
OMe
O
Bn
O
O
O
Me
Me
Ph
O
23 47iPr
24 0iPr
cat. Pd(OTf)2(MeCN)4
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D. Products
Supplementary Table S9 | Complete coupling partner scope
cat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
NHTf
CO2Me1r, (23%)†‡
NHTf
CO2Me1s, (23%)†
Ac BocN
NHTf
CO2Me
H
BPin
X
NHTf
CO2Me
CO2Me1a, 82%
NHTf
CO2Me1b, 73%
NHTf
CO2Me1c, 64%
NHTf
CO2Me1d, 66%
NHTf
F
CO2Me1e, 62%
NHTf
CO2Me1f, 60%
NHTf
CF3
CO2Me1g, 71%
NHTf
CO2Me1h, 73%
NHTf
CF3
CO2Me1i, 60%
NHTf
F
CO2Me1j, 50%
NHTf
Cl
CO2Me1k, 63%
NHTf
CO2Me1l, 16%
NHTf
OMe
CO2Me1m, 54%
NHTf
CO2Me1n, 43%
NHTf
CO2Me1p, 61%
NHTf
CO2Me1q, 63%
F
CF3
CO2Me CO2Me
CO2Me
F CN
Br
OMe
OMe
Experiments were performed with 1 (0.2 mmol), arylboronic acid pinacol ester (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), dimethylsulfoxide (0.08 mmol), water (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Isolated yields. †Product was not isolated and yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. ‡Reaction was performed with Ac-D-Val-OH (0.04 mmol) instead of 3.
NHTf
CO2Me1o, 38%
NHAc
1
NHTf
CO2Me
X
1a–s
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Supplementary Table S10 | Unreactive coupling partners
Figure F2 | Arylation with ArI
NHTf
CO2Me
Hcat. Pd(OTf)2(MeCN)4cat. Ac-D-tLeu-OH, 3
Ag2CO3, NaHCO3BQ, DMSO, H2O
tAmylOH100 °C, N2, 18 h
het
NHTf
CO2Me
1
het–BPin
Experiments were performed with 1 (0.2 mmol), arylboronic acid pinacol ester (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol), 3 (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), DMSO (0.08 mmol), H2O (1.1 mmol) in tAmylOH (1 mL) for 18 h at 100 °C under N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
NHTf
CO2Me
0%
O
O
O NHTf
CO2Me
O
(S)(S)
0%
NHTf
CO2Me
NN
0%
Me
NHTf
CO2Me
0%
N
Experiment was performed with 11 (0.2 mmol), iodobenzene (0.6 mmol), Pd(OAc)2 (0.02 mmol), 3 (0.04 mmol), Ag2CO3 (0.4 mmol) in tBuOH (1 mL) for 18 h at 120 °C under air. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. Comparable to yields from cross-coupling reaction with PhBPin.
NHTf
H
I
cat. Pd(OAc)2cat. Ac-D-tLeu-OH, 3
PhI, Ag2CO3tBuOH
120 °C, air, 18 h
NHTf
11 11a, 53%*
Et Et
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General Procedure
In a 50 mL Schlenk tube, the starting material (0.2 mmol), arylboronic acid pinacol ester (0.4
mmol), Pd(OTf)2(MeCN)4 (11.4 mg, 0.02 mmol), Ac-D-tLeu-OH 3 (6.9 mg, 0.04 mmol),
NaHCO3 (100.8 mg, 1.2 mmol), Ag2CO3 (110.3 mg, 0.4 mmol), and 1,4-benzoquinone (10.8 mg,
0.1 mmol) were combined. The flask was evacuated and backfilled with N2 three times, before a
solution of dimethylsulfoxide (6.0 mg, 0.076 mmol), water (20 mg, 1.1 mmol), and tAmylOH (1
mL, 0.2M) was added. The reaction mixture was then stirred at 100 °C for 18 h. After being
allowed to cool to room temperature, the mixture was diluted with a 1:1 mixture of hexanes:ethyl
acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the
resulting mixture purified by column chromatography using an eluent of hexanes: ethyl acetate.
Data:
(S)-methyl 4-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate (1a)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1a was obtained as a pale yellow liquid (62.9 mg, 82 %). 1H NMR (600 MHz, CDCl3) ! 7.97 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.19 (br s, 1H),
4.28 to 4.26 (m, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.80 (t, J = 8.0 Hz, 2H), 2.27 to 2.21 (m, 1H),
2.11 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.14, 167.21, 145.19, 130.11, 128.58,
119.59 (q, J = 321.0 Hz), 56.79, 53.35, 52.29, 34.73, 31.27; IR (neat) ! 3205, 2955, 1751, 1722,
1702, 1438, 1382, 1286, 1231, 1193, 1148, 1112, 990 cm–1; HRMS (ESI-TOF) Calcd for
C14H17F3NO6S (MH+): 384.0723; found: 384.0718.
NHTf
CO2Me
CO2Me
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(S)-methyl 3-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate (1b)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1b was obtained as a pale yellow liquid (56.0 mg, 73 %). 1H NMR (600 MHz, CDCl3) ! 7.90 (dd, J = 6.6, 2.2 Hz, 1H), 7.88 (s, 1H), 7.40 to 7.36 (m, 2H),
6.12 (d, J = 9.0 Hz, 1H), 4.28 (dt, J = 4.8, 8.5 Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 2.84 to 2.76
(m, 2H), 2.28 to 2.22 (m, 1H), 2.12 to 2.06 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.20,
167.29, 140.13, 133.26, 130.56, 129.57, 128.87, 127.96, 119.59 (q, J = 321.0 Hz), 56.86, 53.37,
52.37, 34.97, 31.08; IR (neat) ! 3175, 2962, 1751, 1723, 1438, 1382, 1292, 1231, 1198, 1148,
1111, 989 cm–1; HRMS (ESI-TOF) Calcd for C14H17F3NO6S (MH+): 384.0723; found: 384.0722.
(S)-dimethyl 5-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)isophthalate (1c) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3,5-bismethoxycarbonylphenylboronic
acid pinacol ester (128.1 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1c was obtained as an off-white solid (56.5 mg, 64 %). 1H NMR (600 MHz, CDCl3) ! 8.54 (s, 1H), 8.08 (s, 2H), 6.28 (d, J = 9.0 Hz, 1H), 4.29 (dt, J =
4.7, 8.6 Hz, 1H), 3.95 (s, 6H), 3.81 (s, 3H), 2.91 to 2.83 (m, 2H), 2.31 to 2.25 (m, 1H), 2.16 to
2.06 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.10, 166.39, 140.81, 133.93, 131.04, 129.11,
119.59 (q, J = 321.0 Hz), 56.85, 53.43, 52.62, 34.78, 31.03; IR (neat) ! 1727, 1436, 1383, 1337,
1253, 1198, 1148, 1001, 758 cm–1; HRMS (ESI-TOF) Calcd for C16H19F3NO8S (MH+): 442.0778;
found: 442.0769.
NHTf
CO2Me
CO2Me
NHTf
CO2Me
CO2Me
CO2Me
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(S)-methyl 4-phenyl-2-(trifluoromethylsulfonamido)butanoate (1d)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6
mg, 0.4 mmol) following the general procedure. After purification by column chromatography,
1d was obtained as a pale yellow liquid (43.1 mg, 66 %). 1H NMR (600 MHz, CDCl3) ! 7.31 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 (dd, J = 7.8,
1.2 Hz, 2H), 5.79 (br s, 1H), 4.29 (dd, J = 7.5, 4.9 Hz, 1H), 3.77 (s, 3H), 2.73 (t, J = 8.0 Hz, 2H),
2.26 to 2.20 (m, 1H), 2.10 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.26, 139.66,
128.80, 128.52, 126.70, 119.59 (q, J = 320.9 Hz), 56.88, 53.32, 35.20, 31.16; IR (neat) ! 3252,
1735, 1436, 1381, 1231, 1195, 1146, 1103, 988 cm–1; HRMS (ESI-TOF) Calcd for
C12H15F3NO4S (MH+): 326.0668; found: 326.0674. The enantiomeric purity of the product was
determined by HPLC analysis (CHIRALCEL IC column, 2% isopropanol in hexanes, flow rate
0.3 mL/min, retention time 25.993 min (major) and 27.773 min (minor)), 96% ee.
DAD-CH1 results
Retention Time Area% 25.993 97.908 27.773 2.092 Total 100%
(S)-methyl 4-(4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1e)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-fluorophenylboronic acid pinacol
ester (88.8 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1e was obtained as a pale yellow liquid (42.6 mg, 62 %).
NHTf
CO2Me
NHTf
F
CO2Me
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1H NMR (600 MHz, CDCl3) ! 7.14 (dd, J = 5.4, 8.5 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 5.92 (br s,
1H), 4.26 (dd, J = 4.9, 7.7 Hz, 1H), 3.78 (s, 3H), 2.71 (t, J = 7.9 Hz, 2H), 2.22 to 2.16 (m, 1H),
2.06 to 2.00 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.29, 161.72 (d, J = 244.5 Hz), 135.28
(d, J = 3.3 Hz), 129.97 (d, J = 7.9 Hz), 119.58 (q, J = 320.9 Hz), 115.58 (d, J = 21.3 Hz), 56.73,
53.37, 35.32, 30.38; IR (neat) ! 3272, 2959, 1733, 1604, 1510, 1436, 1378, 1187, 1143, 1107,
1090, 987, 890, 827, 773 cm–1; HRMS (ESI-TOF) Calcd for C12H14F4NO4S (MH+): 344.0574;
found: 344.0590.
(S)-methyl 4-(3-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1f) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-fluorophenylboronic acid pinacol
ester (88.8 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1f was obtained as a pale yellow liquid (41.2 mg, 60 %). 1H NMR (600 MHz, CDCl3) ! 7.27 (dt, J = 6.1, 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.94 to
6.88 (m, 2H), 5.84 (d, J = 8.9 Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.80 (s, 3H), 2.77 to 2.70
(m, 2H), 2.25 to 2.19 (m, 1H), 2.09 to 2.02 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.17,
163.09 (d, J = 246.1 Hz), 142.17 (d, J = 7.3 Hz), 130.28 (d, J = 8.3 Hz), 124.21 (d, J = 2.7 Hz),
119.58 (q, J = 321.0 Hz), 115.41 (d, J = 21.2 Hz), 113.65 (d, J = 20.7 Hz), 56.75, 53.41, 34.94,
30.91; IR (neat) ! 3266, 2960, 1733, 1618, 1590, 1489, 1438, 1380, 1230, 1192, 1143, 1104,
988, 942, 869, 784 cm–1; HRMS (ESI-TOF) Calcd for C12H14F4NO4S (MH+): 344.0574; found:
344.0568.
NHTf
CO2Me
F
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(S)-methyl 4-(4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate (1g)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-trifluoromethylphenylboronic acid
pinacol ester (108.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1g was obtained as a pale yellow liquid (55.8 mg, 71 %). 1H NMR (500 MHz, CDCl3) ! 7.57 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.75 (d, J = 8.9
Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.79 (s, 3H), 2.85 to 2.75 (m, 2H), 2.28 to 2.21 (m, 1H),
2.11 to 2.03 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.02, 143.75, 128.91, 125.75 (q, J = 3.6
Hz), 124.28 (q, J = 272.0 Hz), 119.59 (q, J = 321.0 Hz), 56.72, 53.47, 34.97, 31.02; ; IR (neat) !
3274, 2930, 1735, 1619, 1438, 1380, 1324, 1231, 1192, 1145, 1120, 1067, 1019, 988, 848, 825
cm–1; HRMS (ESI-TOF) Calcd for C13H13F6NO4SNa (MNa+): 416.0362; found: 416.0357.
(S)-methyl 4-(3-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate (1h)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-trifluoromethylphenylboronic acid
pinacol ester (108.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1h was obtained as a pale yellow liquid (57.4 mg, 73 %). 1H NMR (500 MHz, CDCl3) ! 7.49 (d, J = 7.6 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.38 (d, J = 7.4 Hz,
1H), 5.86 (d, J = 8.8 Hz, 1H), 4.28 (dt, J = 4.8, 8.3 Hz, 1H), 3.79 (s, 3H), 2.81 (t, J = 7.9 Hz,
2H), 2.29 to 2.22 (m, 1H), 2.12 to 2.04 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.09, 140.59,
132.01, 131.14 (q, J = 33.2 Hz), 129.28, 125.22 (q, J = 3.8 Hz), 124.19 (q, J = 272.2 Hz), 123.64
(q, J = 3.8 Hz), 119.59 (q, J = 321.0 Hz), 56.74, 53.46, 34.99, 31.04; IR (neat) ! 3264, 2921,
NHTf
CF3
CO2Me
NHTf
CO2Me
CF3
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2852, 1735, 1439, 1380, 1330, 1231, 1196, 1145, 1122, 1073, 987, 902, 802 cm–1; HRMS (ESI-
TOF) Calcd for C13H13F6NO4SNa (MNa+): 416.0362; found: 416.0350.
(S)-methyl 4-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido) butanoate (1i)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-fluoro,4-trifluoromethyl
phenylboronic acid pinacol ester (116.0 mg, 0.4 mmol) following the general procedure. After
purification by column chromatography, 1i was obtained as a pale yellow liquid (49.4 mg, 60
%). 1H NMR (400 MHz, CDCl3) ! 7.54 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 9.8, 13.5 Hz, 2H), 5.75 (br
s, 1H), 4.27 (dd, J = 4.8, 7.8 Hz, 1H), 3.82 (s, 3H), 2.84 to 2.74 (m, 2H), 2.29 to 2.20 (m, 1H),
2.10 to 2.01 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 170.87, 159.98 (d, J = 254.5 Hz), 146.80
(d, J = 8.0 Hz), 127.61 to 127.53 (m), 124.24 (d, J = 3.4 Hz), 122.72 (q, J = 272.2 Hz), 119.58
(q, J = 321.1 Hz), 116.96, 116.82, 56.60, 53.56, 34.65, 30.90; IR (neat) ! 3271, 2921, 1738,
1631, 1585, 1512, 1434, 1380, 1324, 1230, 1178, 1128, 1046, 988, 877, 832 cm–1; HRMS (ESI-
TOF) Calcd for C13H12F7NO4SNa (MNa+): 434.0267; found: 434.0261.
(S)-methyl 4-(3-cyano-4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1j) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3-cyano,4-fluorophenylboronic acid
pinacol ester (98.8 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1j was obtained as a pale yellow liquid (36.8 mg, 50 %).
NHTf
CF3
CO2Me
F
NHTf
F
CO2Me
CN
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1H NMR (600 MHz, CDCl3) ! 7.47 to 7.43 (m, 2H), 7.17 (tt, J = 1.1, 8.4 Hz, 1H), 5.93 (br s,
1H), 4.24 (dd, J = 4.7, 8.1 Hz, 1H), 3.83 (s, 3H), 2.78 (t, J = 8.0 Hz, 2H), 2.26 to 2.18 (m, 1H),
2.08 to 1.99 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 170.87, 162.07 (d, J = 258.4 Hz), 136.77
(d, J = 3.8 Hz), 135.38 (d, J = 8.1 Hz), 133.15, 119.56 (d, J = 321.0 Hz), 116.87 (d, J = 19.5 Hz),
113.97, 101.69 (d, J = 15.6 Hz), 56.51, 53.57, 34.88, 30.12; IR (neat) ! 3233, 1746, 1502, 1439,
1380, 1255, 1229, 1192, 1146, 1114, 990, 899, 835, 774 cm–1; HRMS (ESI-TOF) Calcd for
C13H13F4N2O4S (MH+): 369.0527; found: 369.0509.
(S)-methyl 4-(4-chlorophenyl)-2-(trifluoromethylsulfonamido)butanoate (1k)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-chlorophenylboronic acid pinacol
ester (95.4 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1k was obtained as a pale yellow liquid (45.3 mg, 63 %). 1H NMR (600 MHz, CDCl3) ! 7.27 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 5.69 (br s, 1H),
4.26 (dd, J = 7.7, 4.8 Hz, 1H), 3.79 (s, 3H), 2.74 to 2.67 (m, 2H), 2.23 to 2.17 (m, 1H), 2.06 to
2.00 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.07, 138.05, 132.52, 129.90, 128.92, 119.58 (q,
J = 320.7 Hz), 56.70, 53.42, 35.18, 30.52; IR (neat) ! 3244, 2960, 1735, 1493, 1437, 1381, 1231,
1196, 1146, 1093, 1015, 989, 896, 811, 759 cm–1; HRMS (ESI-TOF) Calcd for C12H14ClF3NO4S
(MH+): 360.0279; found: 360.0296.
(S)-methyl 4-(4-bromophenyl)-2-(trifluoromethylsulfonamido)butanoate (1l)
NHTf
Cl
CO2Me
NHTf
CO2Me
Br
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Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-bromophenylboronic acid pinacol
ester (113.2 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1l was obtained as a pale yellow liquid (12.9 mg, 16 %). 1H NMR (600 MHz, CDCl3) ! 7.43 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 5.66 (br s, 1H),
4.26 (br s, 1H), 3.79 (s, 3H), 2.73 to 2.65 (m, 2H), 2.23 to 2.17 (m, 1H), 2.06 to 2.00 (m, 1H); 13C
NMR (150 MHz, CDCl3) ! 171.04, 138.58, 131.88, 130.29, 120.53, 119.58 (q, J = 321.0 Hz)
56.69, 53.43, 35.11, 30.59; IR (neat) ! 3248, 2958, 1737, 1489, 1437, 1381, 1231, 1197, 1146,
1094, 1073, 1011 cm–1; HRMS (ESI-TOF) Calcd for C12H13BrF3NO4SNa (MNa+): 425.9593;
found: 425.9572.
(S)-methyl 4-(4-methoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate (1m) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-methoxyphenylboronic acid pinacol
ester (93.6 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1m was obtained as a pale yellow liquid (38.4 mg, 54 %). 1H NMR (600 MHz, CDCl3) ! 7.10 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 5.70 (d, J = 8.8
Hz, 1H), 4.27 (dt, J = 5.0, 8.4 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.67 (t, J = 7.8 Hz, 3H), 2.23 to
2.16 (m, 1H), 2.11 to 1.99 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 171.27, 158.39, 131.62,
129.50, 119.59 (q, J = 321.0 Hz), 114.20, 56.82, 55.43, 53.31, 35.45, 30.26; IR (neat) ! 3244,
2929, 2853, 1748, 1613, 1513, 1439, 1381, 1232, 1195, 1147, 1100, 1035, 991, 823, 767 cm–1;
HRMS (ESI-TOF) Calcd for C13H17F3NO5S (MH+): 356.0774; found: 356.0764.
NHTf
OMe
CO2Me
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(S)-methyl 4-(3,5-dimethoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate (1n)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 3,5-bismethoxyphenylboronic acid
pinacol ester (105.7 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 1n was obtained as a pale yellow liquid (33.1 mg, 43 %). 1H NMR (600 MHz, CDCl3) ! 6.34 (s, 3H), 5.73 (d, J = 9.0 Hz, 1H), 4.28 (dt, J = 4.6, 8.4 Hz,
1H), 3.79 (s, 3H), 3.78 (s, 6H), 2.67 (t, J = 7.9 Hz, 2H), 2.24 to 2.18 (m, 1H), 2.08 to 1.99 (m,
1H); 13C NMR (150 MHz, CDCl3) ! 171.24, 161.10, 142.02, 119.58 (q, J = 321.1 Hz), 106.62,
98.59, 56.83, 55.45, 53.33, 35.05, 31.48; IR (neat) ! 3244, 2927, 2843, 1748, 1598, 1461, 1433,
1381, 1295, 1231, 1198, 1148, 1103, 1059, 992, 837 cm–1; HRMS (ESI-TOF) Calcd for
C14H19F3NO6S (MH+): 386.0880; found: 386.0872.
(S)-methyl 4-(4-acetamidophenyl)-2-(trifluoromethylsulfonamido)butanoate (1o)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 4-acetamidophenylboronic acid pinacol
ester (104.5 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography with a eluent of dichloromethane:acetone (4:1), 1o was obtained as a pale
yellow solid (29.1 mg, 38 %). 1H NMR (600 MHz, CDCl3) ! 7.62 (br s, 1H), 7.38 (br s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.02 (d,
J = 8.3 Hz, 2H), 4.15 (dt, J = 4.5, 9.0 Hz, 1H), 3.68 (s, 3H), 2,74 to 2.66 (m, 1H), 2.60 to 2.53
(m, 1H), 2.14 (s, 3H), 2.10 to 2.02 (m, 1H), 2.00 to 1.90 (m, 1H); 13C NMR (150 MHz, CDCl3) !
171.48, 169.64, 136.46, 136.04, 129.02, 120.49, 119.70 (q, J = 321.0 Hz), 57.18, 53.05, 34.78,
31.22, 24.44; IR (neat) ! 3378, 3293, 3045, 2932, 1748, 1665, 1602, 1535, 1438, 1413, 1376,
NHTf
CO2Me
OMe
OMe
NHTf
NHAc
CO2Me
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27
1320, 1229, 1194, 1149, 1099, 1001, 837 cm–1; HRMS (ESI-TOF) Calcd for C14H18F3N2O5S
(MH+): 383.0883; found: 383.0884.
(S)-methyl 4-(naphthalen-2-yl)-2-(trifluoromethylsulfonamido)butanoate (1p) Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 2-napthaleneboronic acid pinacol ester
(101.7 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1p was obtained as a pale yellow liquid (45.8 mg, 61 %). 1H NMR (600 MHz, CDCl3) ! 7.79 (q, J = 8.3, 7.3 Hz, 3H), 7.63 (s, 1H), 7.48 to 7.43 (m, 2H),
7.30 (dd, J = 8.4, 1.8 Hz, 1H), 5.77 (d, J = 5.8 Hz, 1H), 4.33 (q, J = 6.6 Hz, 1H), 3.76 (s, 3H),
2.93 to 2.86 (m, 2H), 2.35 to 2.29 (m, 1H), 2.18 to 2.12 (m, 1H); 13C NMR (150 MHz, CDCl3) !
171.25, 137.07, 133.66, 132.35, 128.49, 127.78, 127.62, 126.93, 126.90, 126.35, 125.74, 119.61
(q, J = 320.7 Hz), 56.89, 53.36, 35.15, 31.32; IR (neat) ! 3257, 2954, 1730, 1436, 1379, 1316,
1230, 1193, 1147, 1099, 991, 858, 821, 751 cm–1; HRMS (ESI-TOF) Calcd for C16H17F3NO4S
(MH+): 376.0825; found: 376.0809.
(S)-methyl 4-(naphthalen-1-yl)-2-(trifluoromethylsulfonamido)butanoate (1q)
Substrate 1 (49.8 mg, 0.2 mmol) was cross-coupled with 1-napthaleneboronic acid pinacol ester
(101.7 mg, 0.4 mmol) following the general procedure. After purification by column
chromatography, 1q was obtained as a pale yellow liquid (47.3 mg, 63 %). 1H NMR (600 MHz, CDCl3) ! 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.2
Hz, 1H), 7.54 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.50 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 7.40 (dd, J =
NHTf
CO2Me
NHTf
CO2Me
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8.2, 7.0 Hz, 1H), 7.33 (d, J = 6.9 Hz, 1H), 5.76 (d, J = 8.8 Hz, 1H), 4.42 to 4.38 (m, 1H), 3.77 (s,
3H), 3.23 to 3.15 (m, 2H), 2.38 to 2.32 (m, 1H), 2.23 to 2.17 (m, 1H); 13C NMR (150 MHz,
CDCl3) ! 171.16, 135.77, 134.07, 131.60, 129.15, 127.60, 126.39, 125.87, 125.71, 123.21,
119.64 (q, J = 321.0 Hz), 57.19, 53.37, 34.46, 28.43; IR (neat) ! 3288, 2956, 1733, 1436, 1381,
1231, 1196, 1146, 1103, 986, 894, 798, 780 cm–1; HRMS (ESI-TOF) Calcd for C16H17F3NO4S
(MH+): 376.0825; found: 376.0811.
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Products from Table 4 of paper:
Methyl 4-((3S)-4-methoxy-2-methyl-4-oxo-3-(trifluoromethylsulfonamido)butyl) benzoate (5a)
Substrate 5 (52.6 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, mono-arylated 5a was obtained as a mixture of diastereomers in a form
of a pale yellow liquid (45.1 mg, 57 %), and in a d.r. of 4.7:1. In addition, di-arylated 5b was
also isolated as an off-white solid (41.7 mg, 39 %).
1H NMR (600 MHz, CDCl3) Major diastereomer: ! 7.98 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz,
2H), 5.85 (br s, 1H), 4.18 (d, J = 3.9 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.82 (dd, J = 5.1, 13.2
Hz, 1H), 2.48 (dd, J = 9.5, 13.1 Hz, 1H), 2.46 to 2.35 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHz, CDCl3) Major diastereomer: ! 170.49, 167.07, 144.16, 130.02, 129.21, 128.76,
119.61 (q, J = 321.3 Hz), 61.37, 53.23, 52.27, 38.95, 38.41, 15.79; IR (neat) ! 3207, 2957, 1749,
1722, 1612, 1439, 1382, 1286, 1233, 1194, 1147, 1114, 1021, 966, 760 cm–1; HRMS (ESI-TOF)
Calcd for C15H19F3NO6S (MH+): 398.0880; found: 398.0877.
(S)-dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)propane-1,3-
diyl)dibenzoate (5b)
NHTf
CO2Me
CO2Me
Me
NHTf
CO2Me
CO2Me
MeO2C
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1H NMR (600 MHz, CDCl3) ! 7.99 to 7.96 (m, 4H), 7.25 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz,
2H), 5.75 (br s, 1H), 4.21(s, 1H), 3.91 (s, 6H), 3.67 (s, 3H), 2.86 (dd, J = 6.7, 13.6 Hz, 1H), 2.74
to 2.62 (m, 4H); 13C NMR (150 MHz, CDCl3) ! 170.26, 167.01, 166.89, 143.87, 143.51, 130.16,
130.13, 129.31, 129.20, 129.03, 128.96, 58.66, 53.41, 52.31, 52.27, 45.78, 36.68, 35.74; IR
(neat) ! 3174, 2922, 1748, 1722, 1611, 1438, 1384, 1282, 1233, 1194, 1147, 1112, 1020, 765
cm–1; HRMS (ESI-TOF) Calcd for C23H25F3NO8S (MH+): 532.1247; found: 532.1231.
(S)-methyl 4-(4-methoxy-2,2-dimethyl-4-oxo-3-(trifluoromethylsulfonamido) butyl)benzoate
(6a) Substrate 6 (55.5 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, both mono-arylated 6a (36.4 mg, 44 %) and di-arylated 6b were
isolated (41.9 mg, 38 %) as off-white solids.
1H NMR (600 MHz, CDCl3) ! 7.97 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 6.03 (br s, 1H),
4.05 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.79 (d, J = 13.0 Hz, 1H), 2.63 (d, J = 13.0 Hz, 1H), 0.94
(d, J = 4.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) ! 170.52, 167.16, 142.23, 130.99, 129.46,
128.77, 119.64 (q, J = 321.5 Hz), 65.42, 52.90, 52.26, 44.32, 38.69, 23.37, 22.82; IR (neat) !
3234, 2959, 1723, 1612, 1439, 1382, 1285, 1234, 1194, 1147, 1115, 1082, 1021, 767, 747, 715
cm–1; HRMS (ESI-TOF) Calcd for C16H21F3NO6S (MH+): 412.1036; found: 412.1034.
NHTf
CO2Me
CO2Me
Me
Me
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(S)-dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)-2-
methylpropane-1,3-diyl)dibenzoate (6b) 1H NMR (600 MHz, CDCl3) ! 7.98 to 7.95 (m, 4H), 7.27 to 7.23 (m, 4H), 4.18 (s, 1H), 3.92 (s,
3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.03 (d, J = 13.3 Hz, 1H), 2.90 (d, J = 13.2 Hz, 1H), 2.73 (d, J =
13.3 Hz, 1H), 2.59 (d, J = 13.2 Hz, 1H), 0.88 (s, 3H); 13C NMR (150 MHz, CDCl3) ! 170.26,
167.08, 167.03, 141.56, 141.55, 131.17, 131.07, 129.70, 129.65, 129.11, 129.00, 119.49 (q, J =
321.6 Hz), 62.62, 53.09, 52.31, 52.28, 42.41, 42.05, 41.88, 22.00; IR (neat) ! 3223, 2955, 1721,
1611, 1438, 1383, 1284, 1233, 1196, 1147, 1112, 1020, 965, 767, 712 cm–1; HRMS (ESI-TOF)
Calcd for C24H27F3NO8S (MH+): 546.1404; found: 546.1404.
Methyl 4-((2R,3S)-2-ethyl-4-methoxy-4-oxo-3-(trifluoromethylsulfonamido) butyl)benzoate
(7a)
Substrate 7 (55.5 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure. After purification by
column chromatography, 7a was obtained as a pale yellow liquid (41.1 mg, 50 %). 1H NMR (400 MHz, CDCl3) ! 8.00 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 5.68 (br s, 1H),
4.21 (d, J = 2.9 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.73 (d, J = 7.2 Hz, 2H), 2.25 to 2.18 (m,
1H), 1.41 to 1.33 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) ! 170.99,
167.13, 144.56, 130.06, 129.35, 128.72, 119.60 (q, J = 321.6 Hz), 58.95, 53.25, 52.24, 45.61,
36.46, 22.27, 11.77; IR (neat) ! 3211, 2959, 1748, 1723, 1611, 1439, 1382, 1284, 1231, 1194,
NHTf
CO2Me
CO2Me
MeO2C
Me
NHTf
CO2Me
CO2Me
Et
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1147, 1114, 1020, 755 cm–1; HRMS (ESI-TOF) Calcd for C16H21F3NO6S (MH+): 412.1036;
found: 412.1019.
(R)-methyl 2-benzyl-3-(trifluoromethylsulfonamido)propanoate (8a)
Substrate 8 (50.6 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6
mg, 0.4 mmol) following the general procedure using Ac-L-tLeu-OH (0.04 mmol) instead. After
purification by column chromatography, 8a was obtained as a pale yellow liquid (37.4 mg, 57
%). 1H NMR (600 MHz, CDCl3) ! 7.25 (dd, J = 6.6, 8.1 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J
= 7.2 Hz, 2H), 5.58 (br d, J = 4.6 Hz, 1H), 3.66 (s, 3H), 3.36 to 3.29 (m, 2H), 3.01 (dd, J = 6.0,
13.8 Hz, 1H), 2.94 to 2.89 (m, 1H), 2.78 (dd, J = 8.2, 13.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
! 174.37, 137.01, 128.97, 128.90, 127.29, 119.71 (q, J = 321.1 Hz), 52.55, 46.97, 44.25, 35.55;
IR (neat) ! 3254, 2957, 1721, 1495, 1440, 1378, 1231, 1193, 1147, 1082, 835, 746, 702 cm–1;
HRMS (ESI-TOF) Calcd for C12H15F3NO4S (MH+): 326.0668; found: 326.0661.
N-(2-((tert-butyldimethylsilyl)oxy)-3-phenylpropyl)-1,1,1-trifluoromethanesulfonamide (9a)
Substrate 9 (66.3 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6
mg, 0.4 mmol) following the general procedure using Na2CO3 (42.4 mg, 0.4 mmol) instead.
After purification by column chromatography, 9a was obtained as a pale yellow liquid (44.6 mg,
56 %). 1H NMR (400 MHz, CDCl3) ! 7.31 (d, J = 7.2 Hz, 2H), 7.27 to 7.22 (m, 1H), 7.17 (d, J = 6.8 Hz,
2H), 5.08 (br s, 1H), 4.06 to 4.01 (m, 1H), 3.30 to 3.22 (m, 2H), 2.86 (dd, J = 6.4, 13.6 Hz, 1H),
NHTfMeO2C
NHTfTBSO
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2.78 (dd, J = 7.1, 13.6 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 3H), -0.09 (s, 3H); 13C NMR (150 MHz,
CDCl3) ! 136.93, 129.63, 128.80, 127.03, 119.79 (q, J = 321.4 Hz), 72.11, 48.63, 41.33, 25.88,
18.12, -4.77, -4.85; IR (neat) ! 3320, 2954, 2932, 2858, 1418, 1374, 1256, 1233, 1193, 1148,
1106, 1046, 988, 837, 808, 788, 749, 700 cm–1; HRMS (ESI-TOF) Calcd for C16H27F3NO3SSi
(MH+): 398.1427; found: 398.1423.
N-(2-benzyl-3-(benzyloxy)propyl)-1,1,1-trifluoromethanesulfonamide (10a) Substrate 10 (62.3 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6
mg, 0.4 mmol) following the general procedure using Na2CO3 (42.4 mg, 0.4 mmol) instead.
After purification by column chromatography, 10a was obtained as a pale yellow liquid (47.3
mg, 61 %). 1H NMR (600 MHz, CDCl3) ! 7.38 (ddd, J = 7.5, 6.3, 1.5 Hz, 2H), 7.35 to 7.32 (m, 1H), 7.31 to
7.28 (m, 4H), 7.24 to 7.21 (m, 1H), 7.12 (dd, J = 8.1, 1.4 Hz, 2H), 5.99 (br s, 1H), 4.52 to 4.46
(m, 2H), 3.58 (dd, J = 9.6, 3.5 Hz, 1H), 3.44 to 3.40 (m, 2H), 3.31 to 3.27 (m, 1H), 2.64 (dq, J =
7.5, 13.9 Hz, 2H), 2.25 to 2.19 (m, 1H); 13C NMR (150 MHz, CDCl3) ! 138.58, 137.29, 129.00,
128.83, 128.80, 128.32, 127.94, 126.76, 119.89 (q, J = 321.4 Hz), 73.78, 72.75, 48.02, 40.30,
35.36; IR (neat) ! 3313, 2916, 1453, 1425, 1375, 1231, 1192, 1148, 1066, 743, 700 cm–1; HRMS
(ESI-TOF) Calcd for C18H21F3NO3S (MH+): 388.1189; found: 388.1173.
N-(2-benzylbutyl)-1,1,1-trifluoromethanesulfonamide (11a)
Substrate 11 (43.9 mg, 0.2 mmol) was cross-coupled with phenylboronic acid pinacol ester (81.6
mg, 0.4 mmol) following the general procedure using Na2CO3 (42.4 mg, 0.4 mmol) instead.
NHTf
OBn
NHTfEt
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After purification by column chromatography, 11a was obtained as a pale yellow liquid (31.9
mg, 54 %). 1H NMR (600 MHz, CDCl3) ! 7.32 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 6.7 Hz, 1H), 7.16 (d, J = 6.9
Hz, 2H), 4.59 (br s, 1H), 3.28 to 3.17 (m, 2H), 2.72 (dd, J = 6.6, 13.9 Hz, 1H), 2.54 (dd, J = 7.9,
13.9 Hz, 1H), 1.89 to 1.79 (m, 1H), 1.45 to 1.38 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H); 13C NMR (150
MHz, CDCl3) ! 139.41, 129.05, 128.88, 126.72, 119.78 (q, J = 320.1 Hz), 47.29, 42.20, 38.23,
24.09, 10.95; IR (neat) ! 3314, 2966, 2932, 1430, 1371, 1231, 1192, 1147, 1061, 740, 701 cm–1;
HRMS (ESI-TOF) Calcd for C12H16F3NO2SNa (MNa+): 318.0746; found: 318.0743.
Methyl 4-(2-(trifluoromethylsulfonamido)benzyl)benzoate (12a) Substrate 12 (47.8 mg, 0.2 mmol) was cross-coupled with 4-methoxycarbonylphenylboronic acid
pinacol ester (104.8 mg, 0.4 mmol) following the general procedure but using Pd(OTf)2(MeCN)4
(0.01 mmol, 5 mol%), 3 (0.02 mmol, 10 mol%) and at a lowered temperature of 80 °C for only 8
h. After purification by column chromatography, 12a was obtained as a yellow liquid (52.7 mg,
71 %). 1H NMR (600 MHz, CDCl3) ! 7.94 (d, J = 8.3 Hz, 2H), 7.42 to 7.39 (m, 1H), 7.36 to 7.32 (m,
2H), 7.28 to 7.26 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 4.16 (s, 2H), 3.88 (s, 3H); 13C NMR (150
MHz, CDCl3) ! 166.97, 144.13, 136.66, 132.33, 131.59, 130.44, 129.12, 128.91, 128.82, 128.46,
127.78, 119.83 (q, J = 322.2 Hz), 52.35, 38.15; IR (neat) ! 3159, 1700, 1612, 1493, 1434, 1370,
1290, 1221, 1194, 1143, 1114, 958, 752 cm–1; HRMS (ESI-TOF) Calcd for C16H15F3NO4S
(MH+): 374.0668; found: 374.0653.
NHTf
CO2Me
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E. Deprotection5, 6
Figure 3
To a mixture of substrate (0.50 mmol, 219.2 mg) and K2CO3 (0.60 mmol, 82.9 mg) in acetone (2
mL) was added bromoacetonitrile (0.60 mmol, 72.0 mg) or 4-nitrobenzyl bromide (0.60 mmol,
129.6 mg). The reaction mixture was stirred at room temperature overnight, and the solvent was
removed in vacuo thereafter. Water (5 mL) was added and the mixture was extracted with ethyl
acetate, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The
product was afforded as a colorless oil (129.1 mg for R= CN, and 177.2 mg for R = aryl, quant.
for both). No purification was required.
Figure 4
To a solution of substrate (0.5 mmol, 177.2 mg) in THF (3 mL) was added Cs2CO3 (0.66 mmol,
217.0 mg). The reaction mixture was warmed overnight at 30 °C and then cooled to room
temperature. The reaction mixture was then acidified with 1M HCl (aq) (2 mL), and the THF
was removed in vacuo. The aqueous layer was washed with ether (5 mL x 2) and the organics
discarded. The aqueous layer was then placed in an ice bath. 1N NaOH (5 mL) was added, and
benzoyl chloride (1.5 mmol, 210.8 mg) was added at 0 °C portionwise over 30 min, and the
reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction
mixture was extracted with ethyl acetate. The combined organics were washed with brine (5
mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by
column chromatography (0 ! 20% ethyl acetate in hexanes) and product was afforded as a
colorless oil (71.7 mg, 75%). Similar yields are obtained for R = CN.
Br RK2CO3
acetone
quant.
R = CN, or
NO2
Et
Me
NHTfEt
MeTfN R
Cs2CO3, THF 1. HCl (aq.)
2. PhCOCl, NaOH (aq)
75% over 3 steps
Et
MeTfN
Et
Me
NEt
MeHN Ph
O
NO2 NO2
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References:
1. WO2011121350A1, page 125.
2. WO2010111353A1, PCT/US2010/028444 page 79.
3. Sakakura, A., Kondo, R., Matsumura, Y., Akakura, M. & Ishihara, K. J. Am. Chem. Soc. 131,
17762–17764 (2009).
4. E. Drent, J. A. M. van Broekhoven, M. J. Doyle, J. Organomet. Chem. 417, 235 (1991).
5. Hendrickson, J. B., Bergeron, R., Giga, A. & Stembach, D. J. Am. Chem. Soc. 95, 3412–3413
(1973).
6. Amos, D. T., Renslo, A. R. & Danheiser, R. L. J. Am. Chem. Soc. 125, 4970–4971 (2003).
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NMR Spectra
NHTf
CO2Me
CO2Me
NHTf
CO2Me
CO2Me
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NHTf
CO2Me
CO2Me
NHTf
CO2Me
CO2Me
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NHTf
CO2Me
CO2Me
CO2Me
NHTf
CO2Me
CO2Me
CO2Me
© 2014 Macmillan Publishers Limited. All rights reserved.
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NHTf
CO2Me
NHTf
CO2Me
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NHTf
F
CO2Me
NHTf
F
CO2Me
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NHTf
CO2Me
F
NHTf
CO2Me
F
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NHTf
CF3
CO2Me
NHTf
CF3
CO2Me
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NHTf
CO2Me
CF3
NHTf
CO2Me
CF3
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NHTf
CF3
CO2Me
F
NHTf
CF3
CO2Me
F
© 2014 Macmillan Publishers Limited. All rights reserved.
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46
NHTf
F
CO2Me
CN
NHTf
F
CO2Me
CN
© 2014 Macmillan Publishers Limited. All rights reserved.
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47
NHTf
Cl
CO2Me
NHTf
Cl
CO2Me
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48
NHTf
CO2Me
Br
NHTf
CO2Me
Br
© 2014 Macmillan Publishers Limited. All rights reserved.
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49
NHTf
OMe
CO2Me
NHTf
OMe
CO2Me
© 2014 Macmillan Publishers Limited. All rights reserved.
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50
NHTf
CO2Me
OMe
OMe
NHTf
CO2Me
OMe
OMe
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51
NHTf
NHAc
CO2Me
NHTf
NHAc
CO2Me
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52
NHTf
CO2Me
NHTf
CO2Me
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53
NHTf
CO2Me
NHTf
CO2Me
© 2014 Macmillan Publishers Limited. All rights reserved.
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54
NHTf
CO2Me
CO2Me
Me
NHTf
CO2Me
CO2Me
Me
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55
NHTf
CO2Me
CO2Me
MeO2C
NHTf
CO2Me
CO2Me
MeO2C
© 2014 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY | www.nature.com/naturechemistry 56
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56
NHTf
CO2Me
CO2Me
Me
Me
NHTf
CO2Me
CO2Me
Me
Me
© 2014 Macmillan Publishers Limited. All rights reserved.
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57
NHTf
CO2Me
CO2Me
MeO2C
Me
NHTf
CO2Me
CO2Me
MeO2C
Me
© 2014 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY | www.nature.com/naturechemistry 58
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58
NHTf
CO2Me
CO2Me
Et
NHTf
CO2Me
CO2Me
Et
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NATURE CHEMISTRY | www.nature.com/naturechemistry 59
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59
NHTfMeO2C
NHTfMeO2C
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60
NHTfTBSO
NHTfTBSO
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61
NHTf
OBn
NHTf
OBn
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62
NHTfEt
NHTfEt
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63
NHTf
CO2Me
NHTf
CO2Me
© 2014 Macmillan Publishers Limited. All rights reserved.