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A tunable synthesis of indigoids: targeting indirubin through temperature
Shriver, James A. ; Kaller, Kaylie S. ; Kinsey, Ally L. ; Wang, Katelyn R. ; Sterrenberg, Summer R. ; Van Vors, Madison K. , et al.
Abstract: The spontaneous conversion of 3-indoxyl to indigo was a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids.
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Purchased from AmBeed: 1006-94-6 ; 3420-02-8 ; 1670-82-2 ; 10075-50-0 ; 3189-13-7 ; 933-67-5 ; 17422-33-2 ; 17422-32-1 ; 4769-96-4 ; 271-63-6 ; 6146-52-7 ; 614-96-0 ; 15861-24-2 ; 479-41-4 ; 25235-85-2 ; 1670-81-1 ; 120-72-9 ; 1074-88-0 ; 84-40-2 ; 19201-53-7 ; 482-89-3
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CAS No. : | 1006-94-6 |
Formula : | C9H9NO |
M.W : | 147.17 |
SMILES Code : | COC1=CC2=C(NC=C2)C=C1 |
MDL No. : | MFCD00005674 |
InChI Key : | DWAQDRSOVMLGRQ-UHFFFAOYSA-N |
Pubchem ID : | 13872 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | General procedure: (a) A solution of 3 (16.1 mmol) in 40 ml of glacial acetic acid was refluxed during 20 h. The reaction mixture was cooled down, a yellowish mixture of 2 and 5 was filtered off and washed thoroughly with hot ethanol. The yields of 2a, b, e, and f containing 15e20percent of the respective 5 (evidenced by the presence of the 1H NMR signal about 5.7 ppm) varied between 5percent (2e/5e), 40percent (2a/5a), 74percent (2f/5f), and 80percent (2b/5b). (b) A solution of 5-methoxyindole (3 mmol), 2-chloro-4(5)-methoxybenzaldehyde (3 mmol) and hydroiodic acid (1.4 mmol)(57percentwater solution) in 20 ml of acetonitrilewas refluxed under Ar for 15 h. After evaporation of the solvent, the residue was washed by methanol, filtered and washed with acetonitrile. The resulting mixtures of 2c/5c (10percent yield) and 2d/5d (4percent yield) were used in the next step without further purification. Derivative 5e was isolated by crystallization of the mixture of 2e and 5e from DMSO as colorless crystals involving one molecule of DMSO. C32H26Cl2N2O5S1. Unit cell parameters: a¼13.4133(4), b¼8.6773(2), c¼15.3735(4), b¼101.709(1), space group P 21/c. Deposition number CCDC 905653. The mixtures were used in the next step without further purification.The mixture of 2 and 5 (2.3 mmol), CuI (2.3 mmol), and tetrabutylammonium hydroxide (5.13 mmol) (40percent methanol solution) were suspended in 30 ml of freshly distilled DMF under Ar and heated at 120 C during 24 h. The mixturewas cooled down to room temperature, and the yellow precipitatewas filtered off andwashed with MeCN. Pure products can be obtained by crystallization from benzonitrile.4.2.3.3 2,7,11,16-Tetramethoxydibenzo[2,3; 5,6]pyrrolizino[1,7-bc]indolo[1,2,3-lm]carbazole (1c) Yellow microcrystals from benzonitrile, 10percent yield, sublime above 300 °C. Calcd C34H24N2O4: C (77.85percent), H (4.61percent), N (5.34percent). Found: C (77.89percent), H (4.50percent), N (5.37percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen iodide; In water; acetonitrile; for 15h;Reflux; Inert atmosphere; | (a) A solution of 3 (16.1 mmol) in 40 ml of glacial acetic acid was refluxed during 20 h. The reaction mixture was cooled down, a yellowish mixture of 2 and 5 was filtered off and washed thoroughly with hot ethanol. The yields of 2a, b, e, and f containing 15e20percent of the respective 5 (evidenced by the presence of the 1H NMR signal about 5.7 ppm) varied between 5percent (2e/5e), 40percent (2a/5a), 74percent (2f/5f), and 80percent (2b/5b). The mixtures were used in the next step without further purification. (b) A solution of 5-methoxyindole (3 mmol), 2-chloro-4(5)-methoxybenzaldehyde (3 mmol) and hydroiodic acid (1.4 mmol)(57percentwater solution) in 20 ml of acetonitrilewas refluxed under Ar for 15 h. After evaporation of the solvent, the residue was washed by methanol, filtered and washed with acetonitrile. The resulting mixtures of 2c/5c (10percent yield) and 2d/5d (4percent yield) were used in the next step without further purification. Derivative 5e was isolated by crystallization of the mixture of 2e and 5e from DMSO as colorless crystals involving one molecule of DMSO. C32H26Cl2N2O5S1. Unit cell parameters: a¼13.4133(4), b¼8.6773(2), c¼15.3735(4), b¼101.709(1), space group P 21/c. Deposition number CCDC 905653. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: A heterogeneous mixture of <strong>[521-73-3]isoquinoline-1,3,4-trione</strong>(17.5 mg, 0.1 mmol), indole (14.0 mg, 0.12 mmol) and alginic acid (1.76 mg,0.01 mmol, purchased from Sigma Aldrich) in H2O (0.2 mL) was stirred for 24 h(monitored by TLC). Afterwards, the reaction mixture was concentrated under reduced pressure to leave the crude residue which was purified by column chromatography over silica-gel using ethyl acetate/hexane as a mixture of solvent to give the pure compound 3aa in75% yield (21.9 mg) as a white solid.4-Hydroxy-4-(1H-indol-3-yl)isoquinoline-1,3(2H,4H)-dione (3aa): yield 75%; mp:188-190 C; Rf = 0.25 (EtOAc/hexane = 1:3); 1H NMR (400 MHz, acetone-d6) d10.24 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.14 (d, J = 7.8 Hz, 1H), 7.89 (d,J = 7.8 Hz, 1H), 7.76-7.79 (m, 2H), 7.59-7.63 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H),7.06-7.10 (m, 1H), 6.96-7.00 (m, 1H), 6.65-6.66 (m, 1H), 5.66 (br s, 1H, OH); 13CNMR (100 MHz, acetone-d6) d 175.0 (CO), 164.7 (CO), 144.3, 138.0, 134.7,129.2, 128.2, 127.9, 125.8, 125.8, 124.8, 122.6, 122.4, 121.7, 120.1, 112.4, 74.7(C-4, quaternary); HRMS (ESI) m/z calcd For C17H12N2O3 [M+Na]+: 315.0897.Found 315.0953. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride; In tetrahydrofuran; methanol; at 20℃; for 2h; | 5-Methoxyindole (I) (1.42 g, 9.6 mmol) and concentrated hydrochloricacid (2 ml) were slowly added to tetrahydrofuran(1.1 ml) and methanol (11 ml) solution of <strong>[110677-45-7]4-(9H-carbazol-9-yl)benzaldehyde</strong> (1) (0.99 g, 3.6 mmol), and the mixture was stirredfor 2 h at room temperature. The resulting solutionwas poured intowater and filtered. The precipitate was dissolved in ethylacetateand washed with 10% NaOH solution. The separated organic layerwas dried over anhydrous Na2SO4. The crude product was purifiedby crystallization from diethyl ether to afford the product as brightyellow crystals. Yield 1.52 g, 76%. 1H NMR spectrum (300 MHz,DMSO, δ, ppm): 10.76 (s, 2H, NH), 8.23 (d, J 7.7 Hz, 2H, Ar), 7.67 (d,J 8.3 Hz, 4H), 7.53 (d, J 8.3 Hz, 2H, Ar) 7.44-7.22 (m, 8H, Ar), 6.99(d, J 2.3 Hz, 2H, Ar), 6.86 (d, J 2.3 Hz, 2H, Ar), 6.74 (dd, J1 8.3 HzJ2 2.3 Hz, 2H, Ar), 5.94 (s, 1H, CH), 3.64 (s, 6H, CH3). 13C NMRspectrum (75.4 MHz, DMSO, δ, ppm): 153.8,140.7,131.4,130.1,127.4,126.6, 125.7, 124.4, 123.3, 120.2, 119.5, 118.7, 112.2, 111.6, 109.7, 101.9,55.8, 40.1. IR (KBr, cm-1): 3416 (NH); 3052 (C-H, Ar); 2993, 2936,2829 (C-H); 1624, 1582 (C]C Ar); 1512, 1482 (C]C, Ar and CH);1452, 1439 (OCH3); 1360, 1335, 1315 (C-N, Ar); 1211 (C-N); 797,773, 751, 715, 625 (C-H Ar). MS (APCI+, 20 V), m/z: 549 ([MH]).Anal. Calcd. for C37H29N3O2: C, 81.15; H, 5.34, N, 7.67; O, 5.84%;found C 81.22, H 5.33, N 7.62%. |