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S1
t
N-Heterocyclic Carbene (NHC) Catalyzed Atom Economical
Construction of 2,3-Disubstituted Indoles
Battu Harish,a,b
Manyam Subbireddy,a and Surisetti Suresh*
a,b
aOrganic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007, India
bAcademy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007, India
Table of Contents:
1. General information S2
2. General experimental procedure for the optimization study S4
3. Optimisation survey S5
4. General procedure for NHC catalysed synthesis of 2-subsituted indole-3-acetic acid derivatives S10
5. Experimental procedure for the NHC catalysed gram-scale synthesis of 1q S11
6. Experimental procedure for Cu catalysed tandem N-arylation followed by amide bond formation (Paullone synthesis) S12
7. Experimental procedure for base mediated ester hydrolysis S13
Unless otherwise noted, all the reactions were performed in oven dried glassware with magnetic stirring and under an atmosphere of argon using Schlenk line technique. Reported temperatures are the oil bath surrounding temperature of the Schlenk tube or reaction vessel.
All the solvents which are used in the reactions were dried and freshly distilled solvents according to their standard procedures and transferred under argon. Dry DMF, DMSO, CH3CN, t-BuOH, DME and 1,4-dioxane were purchased from Finar scientifics, India. Which were stored over activated 4 Å molecular sieves.
All the reagents, aldehydes, anilines, acrylates and catalysts (NHCs) were purchased from Sigma-Aldrich, Alfa Aesar, and TCI, used without further purification. DBU was used under argon atmosphere.
Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates. Eluted plates were visualised by ultraviolet light (254 nm) lamp, iodine; 2,4-DNP, p-anisaldehyde were used as a developing agents followed by heating. Purification of products was carried out by column chromatography using 60-120 mesh silica and hexane, ethyl acetate were used as eluents, concentration under reduced pressure was performed by rotary evaporator at 40-45 oC, under reduced pressure. The yields were mentioned to the purified products.
1HNMR spectra were recorded at room temperature on a Bruker A V 300, A V 400 and 500 MHz instruments. Chemical
shifts (δ) are reported in ppm relative to TMS. The residual solvent signals were used as references like (CDCl3 δ H 7.26 ppm, DMSO-d6 δ H 2.54 ppm). Multiplicity of the compounds in the data reported as (s = singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiplet). Coupling constants (J) are represented in Hz.13
CNMR spectra were recorded on 75, 100, and 125 MHz spectrometers. Mass spectra was analysed by Electro spray Ionization (ESI) method was obtained on a Shimadzu LCMS-2020 mass spectrometer. High Resolution Mass Spectra data were obtained on a Thermo scientific ExactiveTM Orbitrap mass spectrometer or Q STAR XL Hybrid MS/MS. Infrared spectroscopy was performed neat on a
BRUKER FT-IR spectrophotometer in chloroform, and IR [KBr] spectra were recorded on a THERMO NICOLER NEXUS 670 FT-IR instrument
Melting points (MP) were determined using a Cintex – programmable melting point apparatus. MPs are uncorrected.
S3
Synthesis of substituted ortho-amino cinnamates / cinnamides / cinnamonitiles (3a-h)
ortho-Amino cinnamates 3a-f were synthesized by following literature reports.1
ortho-Amino cinnamide 3g was synthesized by following literature reports.2
ortho-Aminocinnamonitrile 3g was synthesized by following literature reports.1
S4
2. General experimental procedure for the optimization study
Experimental procedure for the synthesis of 1a via sequential aldimine formation—NHC catalysed
reaction
A clean and dry round bottom flask was charged with methyl (E)-3-(2-aminophenyl)acrylate 3a (0.5 mmol, 88 mg), benzaldehyde 4a (0.5 mmol, 53 mg) and added dry toluene (4 mL), 4 Å molecular sieves (1.5 g) (CAUTION: activated molecular sieves should be used, otherwise conversion to aldimine is not effective). The reaction mixture was stirred at reflux for 18 h. After completion of the reaction molecular sieves were filtered and solvent was removed and evacuated to obtain the crude aldimine 2a, which was used in the NHC catalysed transformation.
The crude aldimine 2a and NHC were taken in a clean and dry Schlenk tube, it was evacuated and back filled with argon gas (3-5 cycles).Then added dry solvent (4 mL) followed by base (1.2 equiv) under positive pressure of argon. Then reaction mixture was stirred at the temperature and time as mentioned in optimisation tables S1-S4. Then the mixture was diluted with EtOAc (10 mL) and filtered of through a short pad of silica gel, by eluting with EtOAc (20 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford methyl 2-(2-phenyl-1H-indol-3-yl) acetate 1a as a pure product.
Note: please see tables S1-S4, for various NHCs, bases, solvents and their ratios/quantities
Table S3: Screening of molar equivalents of NHC F, DBU and reaction conditions
CO2Me
NH2NH
CO2Me
1,4-dimethyl-1,2,4-triazolium iodide C
(xx mol%)
H
O
THF, temp, time
DBU (yy mol%)1a3a
4a
toulene, MS 4 Å,
110 oC, 18 h
Entry NHC precatalyst C
(1,4-dimethyl-1,2,4-triazolium iodide)
(xx mol %)
DBU
(yy mol %)
Temp.
(oC)
Time
(h)
% Yield of 1a
1. 30 120 60 6 85
2. 20 120 60 6 76
3. 10 120 60 6 64
4. 30 30 60 6 42
5. 30 60 60 6 62
6. 30 100 60 6 80
7. 30 120 rt 6 40 8. 30 120 rt 24 65
9. 30 120 40 6 68
10. 30 120 80 4 90
S9
Table S4: Screening of various solvents
Entry Solvent % Yield of 1a
1. CH3CN 72
2. 1,4-Dioxane 78
3. Dimethyl sulfoxide (DMSO) 82
4. N,N-Dimethylformamide (DMF) 70
5. 1,2-Dimethoxyethane (DME) 64
6. t-BuOH 68
Table S5: Reaction without using NHC precatalyst (or) base
(Optimized conditions mentioned entry 10, Table S3 were used)
Entry NHC precatalyst Base Solvent % Yield of 1a
1. 1,4-dimethyl-1,2,4-triazolium iodide No base THF —
2. No catalyst DBU THF —
S10
4. General procedure for NHC catalysed synthesis of 2-subsituted indole-3-acetic acid
derivatives
A clean and dry round bottom flask was charged with ortho-amino cinnamate / ortho-amino cinnamide /ortho-amino cinnamonitrile (1 equiv, 0.5 mmol) and aromatic/heteroaromatic/vinyl aldehyde (1 equiv, 0.5 mmol) (solid aldehydes were weighed in atmospheric conditions and liquid aldehydes were transferred via syringe under the positive pressure of argon) and added dry toluene (4 mL) and activated 4 Å molecular sieves (1.5 g). The reaction mixture was stirred at reflux temperature for 18-24 h to obtain for complete conversion of amine (reaction was monitored by TLC). After completion of the reaction molecular sieves were filtered off and solvent was removed and evacuated to obtain the crude aldimine, which was used in the NHC catalysed transformations.
The crude aldimine and NHC precatalyst C (30 mol%) were taken into a clean and dry Schlenk tube, and it was evacuated and back filled with argon gas (3-5 cycles). Then added dry freshly distilled THF (4 mL) via syringe followed by the addition of DBU (1.2 equiv) via syringe under positive pressure of argon. Then reaction mixture was stirred in a pre-heated oil bath at 80
oC for 4 h. The reaction mixture was brought to room temperature and diluted with EtOAc (10 mL) and filtered of through a short pad of silica gel by eluting with EtOAc (20 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 2-subsituted indole-3-acetic acid derivatives.
S11
5. Experimental procedure for the NHC catalysed gram-scale synthesis of 1q
NH2
O
H
OBr
N Br
O
NH
O
O
Br
O
O 16.6 mmol, 5.71 g
N+
NN
I-
DBU, THF.
80 oC, 4 h
Triazolium NHC C
Gram-scale synthesis (20 mmol scale)
2q
toluene,110 oC,
4 Ao MS 18 h
3a83% yield
1q
A clean and oven dried two necked round bottom flask was charged with methyl (E)-3-(2-aminophenyl) acrylate 3a, (20 mmol, 3.54 g), 2-bromobenzaldehyde (20 mmol, 2.32 mL) and dry toluene (160 mL). To this added activated 4 Å molecular sieves (10 g). The reaction mixture was stirred at reflux temperature for 18 h. Then molecular sieves were filtered off, solvent was removed and evacuated to obtain the crude aldimine 2q. Which was used in the NHC catalysed transformation.
The crude aldiimine 2q and 1,4-dimethyl-1,2,4-triazolium iodide C (30 mol%, 4.48 g) were taken into a clean and dry round bottom flask and it was evacuated and back filled with argon gas (3-5 cycles). Then dry freshly distilled THF (160 mL) was added via cannula under the positive pressure of argon gas followed by the addition of DBU (1.2 equiv, 3 mL, from a freshly opened bottle) under positive pressure of argon. Then reaction mixture was stirred in a pre-heated oil bath at 80
oC for 4 h. After completion of the reaction, it was brought to room temperature and diluted with EtOAc (100 mL) and filtered of through a short pad of silica gel, by eluting with EtOAc (200 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford methyl 2-(2-(2-bromophenyl)-1H-indol-3-yl) acetate 1q (5.71 g) as a yellow solid, with 83% yield.
S12
6. Experimental procedure for copper catalysed tandem-N-arylation followed by amide bond
formation (Paullone synthesis)
Copper iodide (10 mol%, 0.2 mmol, 38 mg), L-proline ( 20 mol%, 0.4 mmol 46 mg), potassium carbonate (2 equiv, 4 mmol, 552 mg) and methyl 2-(2-(2-bromophenyl)-1H-indol-3-yl) acetate 1q, (1 equiv, 2 mmol, 688 mg) were taken in a pressure tube under argon atmosphere. Then dry DMSO (8 mL), ammonium (2 mL, NH3 in 25% aq.solution) were added under argon atmosphere. The tube was sealed and the reaction mixture was stirred at 120 oC for 6 h.
The reaction mixture was brought to room temperature and diluted with ethyl acetate (20 mL) and washed with ice cold water (3 x 20 mL). The organic phase was further diluted with ethyl acetate (50 mL) and washed with water (100 mL). Then it was dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by column chromatography on silica gel to obtain paullone 5.
S13
7. Experimental procedure for base mediated ester hydrolysis
To a solution of methyl 2-(2-(2-bromophenyl)-1H-indol-3-yl) acetate 1q (1 equiv, 1 mmol, 343 mg) in THF/H2O (6 mL/2 mL) was added LiOH (4 equiv, 1 mmol, 96 mg) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude was diluted in ethyl acetate (30 mL) and neutralised using 1N HCl. The contents were extracted with ethyl acetate (2 x 50 mL). The organic phase was separated, dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by column chromatography on silica gel to obtain the product 2-(2-(2-bromophenyl)-1H-indol-3-yl) acetic acid 6 in 96% yield.
C-NMR (101 MHz, CDCl3) δ = 14.3, 31.3, 61.0, 105.6, 111.1, 119.3, 120.0, 122.5, 128.0, 128.3, 129.0, 129.1, 132.5, 136.0, 136.3, 172.6; MS (ESI) m/z 280 [M+H]+ HRMS (ESI, m/z): calcd for C18H18NO2 [M+H]+ 280.13321, found 280.13403. The spectroscopic data were in good agreement with the reported data.2
C-NMR (126 MHz, CDCl3) δ =24.4, 25.6, 26.0, 31.3, 43.1, 46.9, 106.9, 110.7, 119.8, 120.0, 122.4, 128.0, 128.3, 128.9, 132.7, 135.2, 135.9, 169.4 ; MS (ESI) m/z 319 [M+H]+. The spectroscopic data were in good agreement with the reported data.2
C-NMR (101 MHz, CDCl3) δ = 13.8, 101.1, 111.2, 118.2, 118.4, 120.7, 123.1, 127.8, 128.2, 128.7, 129.3, 131.5, 135.6, 136.3; MS (ESI) m/z 231 [M-H]+ HRMS (ESI, m/z): calcd for C16H13N2 [M+H]+ 233.10732, found 233.10684. The spectroscopic data were in good agreement with the literature report.1
C-NMR (126 MHz, CDCl3) δ = 16.6, 21.5, 31.0, 52.1, 105.5, 116.5, 119.8, 125.0, 128.0, 128.3, 128.8, 128.9, 129.7, 132.7, 133.6, 136.1, 172.8; MS (ESI) m/z 294 [M+H]+. The spectroscopic data were in good agreement with the reported data.1
C-NMR (126 MHz, CDCl3) δ = 30.9, 52.3, 107.7, 111.2, 111.3, 118.7, 119.6, 120.6, 123.7, 128.5, 128.8, 132.7, 133.9, 136.2, 136.8, 172.3; MS (ESI) m/z 291 [M+H]+ HRMS (ESI, m/z): calcd for C18H14N2O2Na [M+Na]+ 313.09475, found 313.09457. The spectroscopic data were in good agreement with the reported data.1
C-NMR (126 MHz, CDCl3) δ = 30.7, 52.0, 106.1, 111.0, 119.3, 120.1, 122.3, 122.9, 128.9, 129.7, 131.2, 132.1, 135.0, 135.7, 172.6; MS (ESI) m/z 344 [M+H] + HRMS (ESI, m/z): calcd for C17H14NO2BrNa [M+Na]+ 366.01001, found 366.00944. The spectroscopic data were in good agreement with the reported data.1
C-NMR (101 MHz, CDCl3) δ =31.0, 52.0, 55.3, 104.7, 110.8, 114.4, 119.0, 120.0, 122.2, 124.8, 129.0, 129.5, 135.6, 136.2, 159.5, 172.9; MS (ESI) m/z 296 [M+H] + HRMS (ESI, m/z): calcd for C18H18NO3 [M+H]+ 296.12812, found 296.12805. The spectroscopic data were in good agreement with the reported data.1
C-NMR (75 MHz, CDCl3) δ = 30.1, 52.2, 108.7, 110.6, 116.6, 119.0, 120.0, 123.4, 126.4 (2C), 127.5, 127.9, 128.8 (2C), 133.7, 136.4, 136.9, 171.7; MS (ESI) m/z 292 [M+H]+ HRMS (ESI, m/z): calcd for C19H18NO2 [M+H]+ 292.13080, found 292.13319. The spectroscopic data were in good agreement with the reported data.3
C-NMR (75 MHz, DMSO-d6) δ = 31.6, 107.5, 111.4, 117.9, 119.1, 122.1, 122.2, 122.8, 123.6, 126.8, 127.9, 128.7, 132.4, 135.4, 137.4, 171.5; MS (ESI) m/z 247 [M-H]+ HRMS (ESI, m/z): calcd for C16H11NO2 [M-H]+ 247.08659, found 247.08905. The spectroscopic data were in good agreement with literature report.1