Internal Lewis acid assisted benzoic acid catalysis

Article abstract of DOI:10.1055/s-0031-1291048

Internal Lewis acid assisted benzoic acid derivatives are introduced as new low-molecular-weight single-hydrogen-bond donor catalysts for the activation of nitroalkenes. Selected 2-borylbenzoic acid derivatives gave good yields of products in the addition of indoles to nitroalkenes. Control experiments suggest that both the internal Lewis acid coordination and the carboxylic acid functionalities are critical to the optimal performance of these catalysts. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1291048

Journal of Synthetic Organic Chemistry
SUPPORTING INFORMATION
SYNTHESIS
Supporting Information
for DOI: 10.1055/s-0031-1291048
© Georg Thieme Verlag KG Stuttgart · New York 2012
Thieme

Internal Lewis Acid Assisted Benzoic Acid Catalysis
*
Tyler J. Auvil and Anita E. Mattson
Department of Chemistry, The Ohio State University, 88 W. 18th Ave., Columbus, OH 43210
Supplemental Section Table of Contents
1. General methods
S1-S2
2. Synthesis boronate benzoic acids
S2-S6
3. General procedure for the preparation of silicate benzoic acids
S7-S8
4. General procedure for the conjugate addition of indoles to nitroalkenes.
S9-S10
8. References
S11
8. Selected NMR spectra
S12-S35
General Methods: Methylene chloride, toluene, and DMF were purified by passage
through a bed of activated alumina.1i Purification of reaction products was carried out by
flash chromatography using Aldrich 60 Å (40 - 63 µm). Analytical thin layer
chromatography was performed on EMD Chemicals 0.25 µm silica gel 60-F254 plates.
Visualization was accomplished with UV light and potassium permanganate or ceric
ammonium molybdate stains followed by heating. Melting points (mp) were obtained on
a Thermo Scientific Mel-temp apparatus and are uncorrected. Infrared spectra (IR) were
obtained on a Perkin Elmer Spectrum 100R spectrophotometer. Infrared spectra were
obtained by preparing a KBr pellet containing the title compound. Proton nuclear
magnetic resonances (1H NMR) were recorded in deuterated solvents on a Bruker
Avance DPX 400 (400 MHz) spectrometer. Chemical shifts are reported in parts per
million (ppm, δ) using the solvent as internal standard (CHCl3, δ 7.26 and DMSO, δ
1
2.50) H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), or
quartet (q). Splitting patterns that could not be interpreted or easily visualized are
designated as multiplet (m) or broad (br). Coupling constants are reported in Hertz (Hz).
Proton-decoupled carbon (13C-NMR) spectra were recorded on a Bruker Avance DPX
400 (100 MHz) spectrometer and are reported in ppm using the solvent as an internal
standard (CHCl3, δ 77.0; DMSO, δ 39.5). Proton decoupled fluorine (19F-NMR) spectra
were recorded on a Bruker Avance DPX 400 spectrometer and are reported in ppm using
1

CF3C6H4CH3 as an external standard (-63.72). Boron spectra (11B-NMR) were recorded
on a Bruker Avance DPX 500 spectrometer and are reported in ppm using BF3•OEt2 as
an external standard (0.00). Electrospray mass spectra (ESI-MS) were obtained using a
Bruker MicrOTOF Mass Spectrometer. Gas Chromatography (GC) analysis data were
obtained on Agilent 6850 Series GC System with a 7673 Series Injector. An HP-1
capillary 30 m column was employed (19091Z-413E). 2-carboxybenzene boronic acid
and (2-(methoxycarbonyl)phenyl)boronic acid was purchased from Boron Molecular and
used without further purification. 2-Amino-4-(trifluoromethyl)benzoic acid was
purchased from TCI America and used without further puridication. Unless otherwise
noted, all other commercially available reagents and solvents were purchased from
Aldrich and used without further purification.
Procedures for the preparation of boronate catalysts 8a-8d, 10b, 11:
8a: 2-carboxybenzene boronic acid (2.00g , 12.0 mmol) and pinacol (1.43 g,
Bpin
12.1 mmol) were added to a 100 mL flame-dried flask equipped with a
CO2H
Dean Stark trap and a reflux condensor. Toluene (25 mL) was then added to
the reaction pot and the heterogeneous mixture was heated reflux with
vigorous stirring for 24 h. The reaction mixture was then allowed to cool to room
temperature and the solvent was removed in vacuo. Excess pinacol was removed by
trituration of the resulting white solid in ether. This afforded 8a as a white powder, 2.89 g
1
(97%), decomposed 331.2 – 333.6 ºC; IR (KBr) 2975, 1679, 1451, 1152, 1088 cm-1; H
NMR (400 MHz, DMSO d6) δ 7.38 (d, 1H, J = 7.2 Hz); 7.33-7.24 (m, 2H); 7.13 (m, 1H);
1.09 (s, 12H); 13C NMR (100 MHz, DMSO d6) δ 173.1, 138.1, 130.1, 128.7, 125.7,
11
122.2, 77.66 25.5 (the carbon bonded to boron was not seen due to broadening)2; B
NMR (160 MHz, DMSO d6) δ 10.4 (br s); HRMS (ESI): Mass calculated for C13H16BO4
[M–H]–, 247.1147. Found [M–H]–, 247.1147.
8b: The esterification was carried out as previously reported.3 2-Bromo-
F
Bpin
4-fluorobenzoic acid (1.00 g, 4.6 mmol) was dissolved in MeOH (6 mL),
concentrated HCl (50 µL) was added, and the reaction mixture was
CO2H
heated to 65 ºC for 24 h. After allowing to cool to room temperature, the reaction mixture
as extracted with methylene chloride (3 x 50 mL), washed with NaHCO3, washed with
brine, dried with Na2SO4, and concentrated to afford methyl 2-bromo-4-fluorobenzoate as
a clear oil (850 mg, 80 %); 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, 1H, J = 8.8, 6.0 Hz);
7.40 (dd, 1H, J = 8.0, 2.4 Hz); 7.07 (ddd, 1H, J = 10.4, 7.6, 2.4 Hz); 3.92 (s, 3H).
This borylation procedure was performed on a similar compound.4 An oven-dried 50 mL
schlenk flask was brought into the glove box and methyl 2-bromo-4-fluorobenzoate (500
mg, 2.15 mmol), bis(pinacolato)diboron (589 mg, 2.36 mmol, 1.1 eq.), PdCl2(dppf)•DCM
(89 mg, 0.108 mmol, 5 mol %), and KOAc (645 mg 6.45 mmol, 3.0 eq.) were added. The
reaction flask was sealed with a septum and removed from the glove box. The reaction
flask was purged with nitrogen (3x) and dioxane (11.2 mL) was added. The reaction
mixture was then heated to 80 ºC for 24 h under a nitrogen atmosphere. After cooling to
room temperature the reaction mixture was filtered through celite, and the solid was
2

washed with ethyl acetate (100 mL). The filtrate was then washed with water (2 x 100
mL), washed with brine, and dried with MgSO4. After concentrating, the crude mixture
was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to
afford methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a clear
1
oil (546 mg, 91 %); H NMR (400 MHz, CDCl3) δ 7.96 (dd, 1H, J = 8.4 Hz, 5.2 Hz);
7.14 (dd, 1H, J = 8.8 Hz, 2.8 Hz); 7.07 (dt, 1H, J = 8.4 Hz, 2.4 Hz); 3.90 (s, 3H); 1.42 (s,
12 H).
The methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (100 mg,
0.376 mmol) was added to an 8 mL vial and dissolved in THF (2.0 mL) under an argon
atmosphere. Aqueous LiOH (2 M, 0.50 mL, 1 mmol) was then added at 23 ºC and the
reaction mixture was allowed to stir at 23 ºC for ~1 h (monitored by TLC). After the
reaction reached completion the reaction mixture was diluted with water, acidified, and
extracted with ethyl acetate (3 x 50 mL). The organic layer was then washed with brine
and dried with MgSO4. The solvent was removed to afford 8b (74 mg, 77%) as a white
1
solid, mp 136.2 – 137.9 ºC; IR (KBr) 2980, 1675 cm-1; H NMR (400 MHz, CDCl3)
δ 8.13-8.00 (m, 1H); 7.17 (d, 1H, J = 7.2 Hz); 7.15-7.05 (m, 1H); 1.39 (s, 12H);
13C NMR (100 MHz, CDCl3) δ 168.9, 164.5 (d, J = 250 Hz), 131.2, 129.8, 117.2 (d, J =
20 Hz), 115.3 (d, J = 22 Hz), 82.43, 24.6 (the carbon bonded to boron was not seen due
19
to broadening)2; F NMR (376 MHz, CDCl3) δ −105.7; 11B NMR (160 MHz, CDCl3)
δ 30.1 (br s); HRMS (ESI): Mass calculated for C13H15BFO4 [M–H]–, 265.1047. Found
[M–H]–, 265.1045.
8c: A modified version of the previously published procedure was
F3C
Bpin
used.5 2-Amino-4-(trifluoromethyl)benzoic acid (2.05 g, 10.0 mmol, 1
eq.) was dissolved in a mixture of acetic acid (6 mL), 48 % HBr (4 mL),
and water (4 mL) and cooled to -10º C. A solution of sodium nitrite
CO2H
(690 mg, 10.0 mmol, 1 eq.) in water (2 mL) was added dropwise over 5 min. The
temperature was raised to 0 ºC and allowed to stir at this temperature for 3 h. The
resulting slurry was added dropwise via syringe to a solution of CuBr (1.435 g, 10.0
mmol, 1 eq.) in 48% HBr (5 mL) at 60 ºC over 20 min. After the addition the reaction
mixture was heated for 1 h at 60 ºC. The reaction mixture was then allowed to cool to 23
ºC and poured into ice cold water (200 mL). The resulting precipitate was collected in
vacuo and washed with water (100 mL). The solid was then stirred in boiling DCM for 5
min and the solid was removed by vacuum filtration. The filtrate was concentrated to
1
afford 2-bromo-4-(trifluoromethyl)benzoic acid as a tan solid (1.884 g, 70 %); H NMR
(400 MHz, CDCl3) δ 8.08 (d, 1H, J = 8.0 Hz); 7.98 (s, 1H); 7.68 (d, 1H, J = 8.0 Hz).
This methylation procedure has been previously reported was followed.6 2-bromo-4-
(trifluoromethyl)benzoic acid (422 mg, 1.57 mmol) was dissolved in DMF (4.2 mL)
under an argon atmosphere. Potassium carbonate (240 mg, 1.73 mmol, 1.1 eq.) and
iodomethane (120 µL, 1.88 mmol, 1.2 eq.) were then added. The reaction mixture was
stirred at 23 ºC for 24 h then poured into water (100 mL). The water was extracted with
ethyl acetate (3 x 40 mL) and the organic layers were washed with NaHCO3, washed with
water, washed with brine, dried with Na2SO4, and concentrated to afford methyl 2-
3

bromo-4-(trifluoromethyl)benzoate as a orange oil (427 mg, 96 %). 1H NMR (400 MHz,
CDCl3) δ 7.92 (s, 1H); 7.87 (d, 1H, J = 8.0 Hz); 7.62 (d, 1H, J = 8.0 Hz), 3.97 (s, 3 H).
This borylation procedure was performed on a similar compound.4 An oven-dried 25 mL
schlenk flask was brought into the glove box and methyl 2-bromo-4-
(trifluoromethyl)benzoate (300 mg, 1.06 mmol), bis(pinacolato)diboron (290 mg, 1.16
mmol, 1.1 eq.), PdCl2(dppf)•DCM (44 mg, 0.053 mmol, 5 mol %), and KOAc (318 mg,
3.18 mmol, 3.0 eq.) were added. The reaction flask was sealed with a septum and
removed from the glove box. The reaction flask was purged with nitrogen (3x) and
dioxane (5.6 mL) was added. The reaction mixture was then heated to 80 ºC for 24 h
under a nitrogen atmosphere. After cooling to room temperature the reaction mixture was
filtered through celite, and the solid was washed with ethyl acetate (100 mL). The filtrate
was then washed with water (2 x 100 mL), washed with brine, and dried with MgSO4.
After concentrating, the product was purified by silica gel column chromatography (10%
ethyl acetate in hexanes) to afford methyl 4-(trifluoromethyl)-2-(4,4,5,5-tetramethyl-
1
1,3,2-dioxaborolan-2-yl)benzoate as a light yellow oil (317 mg, 91 %). H NMR (400
MHz, CDCl3) δ 8.03 (d, 1H, J = 8.4 Hz); 7.74 (s, 1H); 7.70-7.65 (m, 1H), 3.95 (s, 3 H),
1.43 (s, 12H).
Methyl 4-(trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (100
mg, 0.303 mmol) was added to an 8 mL vial and dissolved in THF (2 mL) under an argon
atmosphere. Aqueous LiOH (2 M, 0.50 mL, 1 mmol) was then added at 23 ºC and the
reaction mixture was allowed to stir at 23 ºC for ~1 h (monitored by TLC). After the
reaction reached completion the reaction mixture was diluted with water, acidified, and
extracted with ethyl acetate (3 x 50 mL). The organic layer was then washed with brine
and dried with MgSO4. The solvent was removed to afford 8c as a white solid (85 mg,
85%), mp 133.3 – 136.4 ºC; IR (KBr) 2990, 1696, 1500, 1360, 1309, 1137, 1076 cm-1; 1H
NMR (400 MHz, CDCl3) δ 11.45 (br s, 1H); 8.15 (d, 1H, J = 8.0 Hz); 7.77 (s, 1H); 7.19
(d, 1H, J = 8.0 Hz); 1.42 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 172.3, 135.8, 134.4
(q, J = 33 Hz), 130.1, 129.4 (m), 126.3 (q, J = 3 Hz), 123.8 (q, J = 271 Hz), 84.8, 24.9
19
(the carbon bonded to boron was not seen due to broadening)2; F NMR (376 MHz,
CDCl3) δ −63.20; 11B NMR (160 MHz, CDCl3) δ 30.8 (br s); HRMS (ESI): C14H15BF3O4
[M–H]–, 315.1015. Found [M–H]–, 315.1013.
MeO
Bpin
8d: The o-borylation procedure reported on a similar compound by
Leigh and coworkers was followed.7 N,N,N’-trimethylethylenediamine
(0.82 mL, 6.4 mmol) was dissolved in dry THF (16 mL) under an argon
CO2H
atmosphere and cooled to -20 ºC. nBuLi (1.3 M, 4.8 mL, 6.2 mmol) was added dropwise
at -20 ºC and allowed to stir at -20 ºC for 15 min. Freshly distilled aldehyde (0.73 mL,
6.0 mmol) was then added at -20 ºC and allowed to stir at -20 ºC for an additional 15 min.
An additional volume of nBuLi (1.3 M, 13.9 mL, 18 mmol) was added at -20 ºC and the
reaction mixture was stirred at -20 ºC for 24 h. The solution was then cooled to -78 ºC
and a solution of triisopropyl borate (8.3 mL, 36 mmol, 6.0 eq) in toluene (10 mL) was
added. The reaction mixture was stirred at -78 ºC for 1 h, allowed to warm to 23 ºC, and
stirred for an additional 2 h. The resulting slurry was then poured into 1 M HCl solution
4

(50 mL) and stirred at 23 ºC for 30 min. The layers were separated and the aqueous layer
was extracted with ether (3 x 75 mL). The organic layer was washed with brine, dried
with MgSO4, and concentrated to give a yellow oil. The product was purified by silica gel
chromatography (5 % MeOH in methylene chloride). Crystallization of the pure product
by dissolution in hot ethyl acetate and the addition of cold hexanes afforded 2-Formyl-4-
methoxyphenyl boronic acid (549 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO
d6) δ 9.97 (s, 1H); 8.23 (br s, 1H); 7.85 (d, 1H, J = 8.8 Hz); 7.10-7.04 (m, 2 H); 3.85 (s,
3H).
A modified oxidation procedure described by Lindsey et. al was followed.8 2-Formyl-4-
methoxyphenyl boronic acid (400 mg, 2.22 mmol) was dissolved in a 2.5 M NaOH
solution (3.6 mL) and a solution of KMnO4 (350 mg, 2.22 mmol) in H2O (13 mL) was
added at 23 ºC for 4 h. The reaction mixture was then filtered through celite. The filtrate
was acidified, extracted with ethyl acetate (3 x 80 mL), dried with Na2SO4, and
concentrated to give 2-carboxy-4-methoxyphenyl boronic acid as light yellow foam (195
mg, 45%). 1H NMR (400 MHz, MeOD d4) δ 7.90 (d, 1H, J = 8.8 Hz); 6.99-6.90 (m, 2H);
3.86 (s, 3H).
2-Carboxy-4-methoxyphenyl boronic acid (110 mg, 0.561 mmol) and pinacol (70 mg,
0.589 mmol) were added to a flame-dried round bottom flask equipped with Dean Stark
trap and a reflux condensor. Toluene (6 mL) was added and the reaction mixture was
stirred in refluxing toluene for 20 h. The reaction mixture was allowed to cool to 23 ºC
and the toluene was removed in vacuo to afford a yellow solid. Ether (5 mL) was added
to the reaction flask and stirred for 30 min. The filtrate was concentrated to afford 8d
(141mg, 90%) as a white solid, mp 170.2 – 172.5 ºC; IR (KBr) 2981, 1675, 1604, 1560,
1411, 1228, 1145 cm-1; 1H NMR (400 MHz, DMSO d6) δ 7.79 (d, 1H, 8.6 Hz); 6.98 (dd,
13
1H, J = 8.6, 2.4 Hz); 8.66 (d, 1H, J = 2.4 Hz); 3.82 (s, 3H); 1.29 (s, 12H); C NMR (100
MHz, DMSO d6) δ 168.7, 161.9, 130.2, 126.2, 116.4, 113.8, 83.0, 55.3, 24.6 (the carbon
11
bonded to boron was not seen due to broadening)2; B NMR (160 MHz, DMSO d6)
δ 29.6 (br s); HRMS (ESI): C14H18BO5 [M–H]–, 277.1247. Found [M–H]–, 277.1246.
10b: (2-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.78 mmol),
Bpin
pincaol (328 mg, 2.78 mmol), and toluene (5 mL) were added to a flame-
dried 25 mL round bottom flask equipped with a Dean Stark trap and a
CO2Me
reflux condensor. The contents were then heated to reflux for 24 h under a nitrogen
atmosphere. After cooling to 23 ºC, the contents were concentrated and the product was
purified by silica gel column chromatography (15% ethyl acetate in hexanes) to afford
methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a colorless oil (648
1
mg, 89 %). H NMR (400 MHz, CDCl3) δ 7.97-7.91 (m, 1H); 7.53-7.46 (m, 2H); 7.45-
7.37 (m, 1H); 3.91 (s, 3H); 1.419 (s, 12H).
11: This borylation procedure was performed on a similar compound.4
An oven-dried 10 mL schlenk flask was brought into the glove box and
pinB
CO2H
methyl
3-bromobenzoate
(100.0
mg,
0.465
mmol),
5

bis(pinacolato)diboron (127 mg, 0.508 mmol, 1.1 eq.), PdCl2(dppf)•DCM (20 mg, 0.024
mmol, 5 mol %), and KOAc (140 mg, 1.40 mmol, 3.0 eq.) were added. The reaction flask
was sealed with a septum and removed from the glove box. The reaction flask was
purged with nitrogen (3x) and dioxane (2.4 mL) was added. The reaction mixture was
then heated to 80 ºC for 24 h under a nitrogen atmosphere. After cooling to room
temperature the reaction mixture was filtered through celite, and the solid was washed
with ethyl acetate (100 mL). The filtrate was then washed with water (2 x 100 mL),
washed with brine, and dried with MgSO4. After concentrating, the product was purified
by silica gel column chromatography (10% ethyl acetate in hexanes) to afford methyl 4-
(trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as a light
yellow oil (114 mg, 93 %). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H); 8.12 (d, 1H, J =
12.4 Hz); 7.98 (d, 1H, J = 12.0 Hz); 7.45 (t, 1H, 12.0 Hz); 3.92 (s, 3H); 1.36 (s, 12H).
Methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (114 mg, 0.435 mmol)
was added to an 8 mL vial and dissolved in THF (2 mL) under an argon atmosphere.
Aqueous LiOH (2 M, 0.50 mL, 1 mmol) was then added at 23 ºC and the reaction
mixture was allowed to stir at 23 ºC for 18 h (monitored by TLC). After the reaction
reached completion the reaction mixture was diluted with water, acidified, and extracted
with ethyl acetate (3 x 50 mL). The organic layer was then washed with brine and dried
1
with MgSO4. The solvent was removed to afford 11 as a white solid (79 mg, 73%); H
NMR (400 MHz, DMSO d6) δ 12.94 (br s, 1H); 8.26 (s, 1H); 8.05 (d, 1H, J = 7.6 Hz);
11
7.88 (d, 1H, J = 7.2 Hz); 7.52 (t, 1H, J = 7.6 Hz); 1.31 (s, 12H). B NMR (160 MHz,
DMSO d6) δ 29.8 (br s).
6

General Procedure for the preparation of silicate benzoic acids 7a-7d:
TMS
1. N,N,N'-trimethylethylenediamine
nBuLi,THF, -20 ºC, 24 h
CHO
CHO
2. TMSCl
R
R
The ortho-lithiation procedure developed by Comins and Brown was followed.9 N,N,N’-
trimethylethylenediamine (0.82 mL, 6.4 mmol) was dissolved in dry THF (16 mL) under
an argon atmosphere and cooled to -20 ºC. nBuLi (1.3 M, 4.8 mL, 6.2 mmol) was added
dropwise at -20 ºC and allowed to stir at -20 ºC for 15 min. Freshly distilled aldehyde
(0.73 mL, 6.0 mmol) was then added at -20 ºC and allowed to stir at -20 ºC for an
additional 15 min. An additional volume of nBuLi (1.3 M, 13.9 mL, 18 mmol) was added
at -20 ºC and the reaction mixture was stirred at -20 ºC for 24 h. The reaction mixture
was then cooled to -40 ºC and freshly distilled TMSCl (4.57 mL, 36 mmol) was added
dropwise. The reaction mixture was stirred at -40 ºC for 30 min and 23 ºC for 30 min
before being quenched by pouring into 50 mL of 1M HCl. The mixture was extracted
with ether, washed with brine and dried with MgSO4. The yellow residue was purified via
column chromatography (0% to 5% ethyl acetate in hexanes) to afford the pure product
as a colorless oil.
TMS
TMS
KMnO4
CHO
CO2H
Acetone, H2O, 23 ºC, 2 h
R
R
The oxidation procedure developed by Schultz et al. was followed.10 The 2-
trimethylsilylbenzaldehyde was (2.6 mmol) added to a 50 mL flask and dissolved in
mixture of acetone (7.2 mL) and water (1.2 mL). The solution was cooled to 0 ºC and
KMnO4 (0.50 g, 3.2 mmol) was added slowly with rapid stirring. After 5 min the reaction
mixture was allowed to warm to 23 ºC and stirred at 23 ºC. After completion of the
reaction (monitored by TLC, about 1.5 h), acetone was removed in vacuo and the
concentrate was dissolved in concentrated Na2SO3 and filtered through celite. The solid
was washed with DCM (100 mL) and water (50 mL). The filtrate was acidified (pH ~
2.5) and extracted with DCM (3 x 50 mL), dried with Na2SO4, and concentrated to afford
the pure 2-trimethylsilylbenzoic acid.
TMS
7a: 74 % - 2 steps. white solid, mp 93.0 – 94.5 ºC; IR (KBr) 2948, 1690,
1
1588, 1471, 1409, 1110 cm-1; H NMR (400 MHz, CDCl3) δ 12.53 (br s,
CO2H
1H); 8.19 (d, 1H, J = 7.6 Hz); 7.75 (d, 1H, J = 7.6 Hz); 7.58 (dt, 1H, J = 7.6
13
Hz, J = 1.6 Hz); 7.48 (dt, 1H, J = 7.6 Hz, J = 1.6 Hz); 0.37 (s, 9H); C NMR (100 MHz,
CDCl3) δ 173.9, 144.0, 135.8, 134.3, 132.6, 131.1, 129.1, 0.5; HRMS (ESI): Mass
calculated for C10H14SiO2Na [M+Na]+, 217.0655. Found [M+Na]+, 217.0644.
7

F
TMS
7b: 49 % - 2 steps. white solid, mp 109.8 – 111.7 ºC; IR (KBr) 2954,
1
1698, 1576, 1423, 1312, 1252, 1212, 1130 cm-1; H NMR (400 MHz,
CO2H
CDCl3) δ 12.37 (br s, 1H); 8.22 (dd, 1H, J = 8.4 Hz, J = 5.2 Hz); 7.40 (dd,
1H, J = 9.2 Hz, J = 2.8 Hz); 7.12 (m, 1H); 0.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.6, 165.6 (d, J = 255 Hz), 148.68 (d, J = 5 Hz), 134.0 (d, J = 9 Hz) 130.1 (d, J = 3
19
Hz), 122.8 (d, J = 20 Hz), 115.8 (d, J = 22 Hz), 0.3; F NMR (376 MHz, CDCl3)
δ −105.9; HRMS (ESI): Mass calculated for C10H13SiFNaO2 [M+Na]+, 235.0561. Found
[M+Na]+, 235.0553.
F3C
TMS
7c: 86 % - 2 steps. white solid, mp 129.5 – 130.8 ºC; IR (KBr) 2955,
1
1705, 1482, 1411, 1321, 1264, 1136, 1077 cm-1; H NMR (400 MHz,
CO2H
CDCl3) δ 11.28 (br s, 1H); 8.27 (d, 1H, J = 8.2 Hz); 7.96 (s, 1H); 7.73
13
(d, 1H, J = 8.2); 0.40 (s, 9H); C NMR (100 MHz, CDCl3) δ 172.7, 145.5, 137.5, 133.9
19
(q, J = 32 Hz), 132.3, 131.29, 126.0, 124.0 (q, J = 270 Hz), 0.3; F NMR (376 MHz,
CDCl3) δ −63.2; HRMS (ESI): Mass calculated for C11H13SiNaF3O2 [M+Na]+, 285.0529.
Found [M+Na]+, 285.0527.
7d: 86 % - 2 steps. white solid, mp 136.8 – 138.0 ºC; IR (KBr) 2951,
MeO
TMS
1682, 1585, 1417, 1318, 1240, 1138 cm-1; 1H NMR (400 MHz, CDCl3)
δ 12.60 (br s, 1H); 8.20 (d, 1H, J = 8.8 Hz); 7.24 (d, 1H, J = 2.8 Hz);
6.93 (dd, 1H, J = 8.8 Hz, J = 2.8 Hz); 0.36 (s, 9H); 13C NMR (100
CO2H
MHz, CDCl3) δ 173.2, 162.9.0, 146.8, 133.8, 126.4, 122.4, 112.90, 55.5, 0.5; HRMS
(ESI): Mass calculated for C11H16SiO3Na [M+Na]+, 247.0761. Found [M+Na]+,
247.0754.
TMS
10a: The esterification procedure that was previously described was
followed.10 2-Trimethylsilylbenzoic acid (75 mg, 0.39 mmol), potassium
CO2Me
carbonate (133 mg, 0.958 mmol, 2.5 eq.), acetone (3.5 mL), and dimethyl
sulfate (90 µL, 0.96 mmol, 2.5 eq.) were added to a flame-dried 10 mL round bottom
flask equipped with a reflux condensor. The reaction mixture was then heated to 56 ºC
for 24 h. After allowing to cool to 23 ºC, the reaction was quenched by the addition of
water (1 mL) and stirred at 23 ºC for 1 h. The reaction mixture was extracted with ethyl
acetate (3 x 20 mL), washed with NaHCO3, washed with brine, and dried with Na2SO4.
The ethyl acetate was removed in vacuo to afford methyl 2-trimethylsilylbenzoate as a
colorless oil (72 mg, 90 %). 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, 1H, J = 7.6 Hz, 1.6
Hz); 7.69 (dd, 1H, J = 7.2 Hz, 1.6 Hz); 7.50 (dt, 1H, J = 7.2 Hz, 1.6 Hz); 7.42 (dt, 1H, J =
7.6 Hz, 1.6 Hz); 3.91 (s, 3H); 0.326 (s, 9H). All spectral data match those that were
previously reported.10
8

General procedure for the conjugate addition of indoles to nitroalkenes:
A dry 4 mL vial equipped with a magnetic stirbar was charged with catalyst (0.0752
mmol, 20 mol %) and nitroalkene (0.376 mmol). Methylene chloride (90 µL) was then
added, followed by indole, (0.564 mmol, 1.5 equiv) and a second portion of methylene
chloride (100 µL). The vial was then sealed and the reaction mixture was stirred under
ambient conditions for the indicated time. The reaction mixture was then immediately
purified by flash column chromatography on silica gel.
6a: Purified by column chromatography (5 to 20 % ethyl acetate in
NH
hexanes) to afford 83.2 mg (83%) of 6a as a light yellow solid. 1H NMR
(400 MHz, CDCl3) δ 8.07 (br s, 1H); 7.45 (app d, 1H, J = 7.6 Hz); 7.38-
7.29 (m, 5H); 7.29-7.24 (m, 1H); 7.20 (app t, 1H, J = 8.0 Hz); 7.09 (app t,
NO2
1H, J = 6.8 Hz); 7.03 (app d, 1H, J = 2.0 Hz); 5.20 (app t, 1H; J = 8.0Hz);
5.07 (dd, 1H, J =12.4, 7.6 Hz); 4.95 (dd, 1H, J = 12.4, 8.4 Hz); All spectral data match
those that were previously reported.11
6b: Purified by column chromatography (5 to 25 % ethyl acetate in
NH
hexanes) to afford 86.3 mg (79%) of 6b as a white crystalline solid.
1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H); 7.43 (app d, 1H, J =
NO2
8.0 Hz); 7.36 (app d, 1H, J = 8.0 Hz); 7.24-7.18 (m, 2H); 7.08 (app
td, 1H, J = 8.0, 0.8 Hz); 7.02 (app d, 1H, J = 2.0); 6.88-6.83 (m,
MeO
2H); 5.14 (app t, J = 8.8 Hz, 1H); 5.05 (dd, J = 12.4, 8.4 Hz, 1H); 4.90 (dd, J = 12.4, 8.4
Hz, 1H); 3.78 (s, 3H). All spectral data match those that were previously reported.11
6c: Purified by column chromatography (5 to 25 % ethyl acetate in
hexanes) to afford 92.1 mg (72%) of 6c as a light yellow solid. H
NH
1
NMR (400 MHz, CDCl3) δ 8.11 (br s, 1H); 7.45 (app d, 2H, J = 8.4,
NO2
2.4 Hz); 7.42-7.35 (m, 2H); 7.24-7.18 (m, 3H); 7.09 (app td, 1H, J =
7.0, 1.2 Hz); 7.04-7.01 (m, 1H); 5.16 (app t, 1H, J = 7.6 Hz); 5.05
Br
(dd, 1H, J = 12.4, 7.4 Hz); 4.91 (dd, 1H, J = 12.4, 8.8 Hz). All spectral data match those
that were previously reported.11
6d: Purified by column chromatography (5 to 20 % ethyl acetate in
NH
hexanes) to afford 81.5 mg (85%) of 6d as a light yellow solid. 1H NMR
(400 MHz, CDCl3) δ 8.12 (br s, 1H); 7.56 (app d, 1H, J = 8.0 Hz); 7.41 -
NO2
7.36 (m, 2H); 7.23 (app dt, 1H, J = 7.2 Hz, J = 1.2 Hz); 7.17-7.12 (m,
2H); 6.31 (dd, 1H, J = 3.2, 1.6); 6.17 (app d, 1H, J = 3.2 Hz); 5.26 (app t,
O
1H, J = 8.0 Hz); 5.06 (dd, 1H, J = 12.4, 8.0 Hz); 4.92 (dd, 1H, J = 12.4, 7.2 Hz); All
spectral data match those that were previously reported.12
6e: Purified by column chromatography (5 to 15 % ethyl acetate in
NH
hexanes) to afford 65.4 mg (64%) of 6e as a light yellow solid. 1H NMR
(400 MHz, CDCl3) δ 8.05 (br s, 1H); 7.60 (m, 1H); 7.36 (m, 1H); 7.21
NO2
(m, 1H); 7.13 (m, 1H); 7.00 (s, 1H); 4.86-4.78 (m, 1H); 4.78-4.68 (m,
1H); 3.72-3.65 (m, 1H); 1.89-1.65 (m, 6H); 1.30-0.95 (m, 5 H). All
spectral data match those that were previously reported.13
9

6f: Purified by column chromatography (5 to 15 % ethyl acetate in
hexanes) to afford 75.6 mg (81%) of 6f as a light yellow solid. H
NH
1
NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H); 7.65 (m, 1H); 7.40 (m,
NO2
1H); 7.24 (m, 1H); 7.17 (m, 1H); 7.07 (m, 1H); 4.75-4.61 (m, 2H);
3.87-3.77 (m, 1H); 1.96-1.75 (m, 2H); 1.40-1.22 (4H); 0.86 (t, 3 H, J = 7.0 Hz); All
spectral data match those that were previously reported.14
6g: Purified by column chromatography (5 to 20 % ethyl acetate in
hexanes) to afford 86.2 mg (79%) of 6g as a light yellow solid. H
1
NH
MeO
NMR (400 MHz, CDCl3) δ 7.98 (br s, 1H); 7.37-7.24 (m, 6H); 7.01
(app d, J = 2.4 Hz, 1H); 6.88 (app d, J = 2.4 Hz, 1H); 6.86 (br s,
1H); 5.16 (app t, J = 8.0 Hz, 1H); 5.06 (dd, J = 12.4, 7.6 Hz, 1H);
4.95 (dd, J = 12.4, 8.4 Hz, 1H); 3.79 (s, 3H). All spectral data match
NO2
those that were previously reported11.
6h: Purified by column chromatography (5 to 30 % ethyl acetate in
hexanes) to afford 89.5 mg (69%) of 6h as a light yellow solid. H
NH
1
Br
NMR (400 MHz, CDCl3) δ 8.14 (br s, 1H); 7.55 (app d, 1H, J = 2.0
Hz); 7.37-7.24 (m, 7H); 7.08 (app d, 1H, J = 2.4 Hz); 5.13 (app t, J =
8.0 Hz, 1H); 5.03 (dd, J = 12.4, 8.0 Hz, 1H); 4.92 (dd, J = 12.4, 8.0
NO2
Hz, 1H); All spectral data match those that were previously reported.15
6i: Purified by column chromatography (5 to 35 % ethyl acetate in
hexanes) to afford 51.2 mg (42%) of 6i as a white foam. H NMR
NH
1
(400 MHz, CDCl3) δ 8.35 (br s, 1H); 7.60 (app dd, 1H, J = 7.2, 0.8
Hz); 7.52 (app dd, 1H, J = 8.0, 0.8 Hz); 7.31-7.19 (m, 6H); 7.08 (app
dd, J = 2.8 Hz, 0.8 Hz, 1H); 5.83 (app t, J = 8.0 Hz, 1H); 5.06 (dd, J
MeO2C
NO2
= 13.2, 7.4 Hz, 1H); 4.86 (dd, J = 13.2, 8.4 Hz, 1H); 3.85 (s, 3H); All spectral data match
those that were previously reported.16
Me
6j: Purified by column chromatography (5 to 15 % ethyl acetate in
N
hexanes) to afford 15.2 mg (14%) of 6j as a light yellow solid. 1H NMR
(400 MHz, CDCl3) δ 7.45 (app d, 1H, J = 8.0 Hz); 7.37-7.20 (m, 7H);
NO2
7.10-7.07 (m, 1H); 6.86 (s, 1H); 5.19 (app t, J = 8.0 Hz, 1H); 5.06 (dd, J
= 12.4, 7.6 Hz, 1H); 4.94 (dd, J = 12.4, 8.4 Hz, 1H); 3.75 (s, 3H); All
spectral data match those that were previously reported.15
10

References:
1 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometal. 1996, 15, 1518-1520.
2 Wrackmeyer, B. In Modern Magnetic Resonance; Webb, G. A., Ed.; Springer:
Netherlands: 2006; Part 1, pp 455-457
3 Berggren, K et al. New 5,6-Dihydropyrin-2-one Compounds as Useful Inhibitors of
Thrombin. W.O. Patent. 2005058826 A1, Jun 6, 2005.
4
Smallheer, J.M.; Corte, J.R.; Bicyclic Heterocycles Useful As Serine Protease
Inhibitors. U.S. Patent 2005228000 A1. Apr 11, 2005.
5
LaTorse M. et al. Fungicidal Phenylbenzamides. U.S. Patent. 5514719 A, May 7, 1996.
6 Kolczewski S. et al. Carbocyclc GLYT1 Receptor Antagonists. U.S. Patent.
2011053904 A1, Mar 3, 2011.
7 Blight, B.A.; Leigh, D.A.; McNab, H.; Thomson, P.I.T.; Hunter, C.A. Nat. Chem. 2011,
3, 244.
8
Ruzié, C.; Krayer, M.; Balasubramanian, T.; Lindsey, J.S.; J. Org. Chem. 2008, 73,
5806.
9
Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078.
10 Schultz, A.G..; Antoulinakis, E.G. J. Org. Chem. 1996, 61, 4555.
11 Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
12 Xiang, J.; Tong, H.; Yu, Y.; Synth. Comm. 2011, 41, 372.
13
Lu, S.F.; Du, D.M.; Xu, J. Org. Lett. 2006, 8, 2115.
Wu, J.; Li, X.; Wu, F.; Wan, B.; Org. Lett. 2011, 13, 4834.
An, L.T.; Zou, J.P.; Zhang, L.L.; Zhang, Y. Tetrahedron Lett. 2007, 48, 4297.
14
15
16 Gmeiner, P.; Sommer, J.; Hoefner, G. Arch. Pharm. 1995, 238, 329.
11

13
ppm
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10
ppm

13
12 ppm
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10
ppm

−20
−30
−40
−50
−60
−70
−80
−90
ppm

13 12 11 10 ppm
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10
ppm

−45
−50
−55
−60
−65
−70
−75
−80
ppm

13
ppm
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10 ppm

9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
ppm

30
25
20
15
10
5
0
−5
ppm

9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
0
ppm

43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 ppm

−80
−85
−90
−95
−100
−105
−110
−115
−120
−125
−130 ppm

12.0
11.5
11.0 ppm
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm