Org Prep Daily

November 8, 2006

Isatins from indoles – A chlorination orgy

Filed under: procedures — milkshake @ 2:24 pm

isatins.gif

Caution – there is an exothermic  gas evolution with a delayed induction in this first chlorination step. Don’t exceed the 20g scale on first run. (I have done only 20 and 30g run with identical yield – but the induction period was different) A large wide-mouth flask with internal thermometer should be used for the reaction.

A slurry of 5-methoxyindole-2-carboxylic acid 20.462g (107 mmol) in 80% acetic acid 270mL in a 1L wide-mouth Erlenmeyer flask was cooled on ice/salt bath to -10C. Ethyldichlorourethane 34.5g (Arcos, 218 mmol) was added dropwise over 20 minutes while keeping the internal temperature below +5C (exothermic). After complete addition, the mixture was stirred at 0C on ice bath. After about 10 minutes, a vigorous gas evolution occurred while the internal reaction temperature spontaneously rose up to +15C. After this exothermic decarboxylation event, the mixture was stirred on ice for extra 1 hour and then at ambient temperature for 1 hour. The precipitated crude product 17.091g (light beige solid, 60%Y, containing about 5% of 3,3,4,7-tetrachloro-5-methoxy-2-indolinone as an impurity) was collected by filtration, washed with a 1:1 mix of AcOH + water, then with water and dried carefully on highvac. The crude product was divided into two portions. Recrystallizing 8.680g of the crude material from benzene (450mL, to RT) provided 6.780g of pure 3,3, 4-trichloro-5-methoxy-2-indolinone as an off-white crystalline solid. (47% overall Y). 1H(CDCl3, 400MHz): 11.342(br s, 1H), 7.207(d, 9.0Hz, 1H), 6.903(d, 8.6Hz, 1H), 3.846(s, 3H)

A slurry of pure 3,3,4-trichloro-5-methoxy-2-indolinone  6.692g (25.11 mmol) in 1:1 mixture of water+methanol (70mL total) was refluxed vigorously on an oil bath (120C) for 18 hours. The reaction mixture was cooled to RT and placed into a refrigerator (+5C) for 1hour. The precipitated product was collected by filtration, washed with a mix 5:1 water/MeOH and dried on highvac. Y=5.103g (96%) of a deep-brown shiny crystalline solid. 1H(d6-DMSO, 400MHz): 10.996(br s, 1H), 7.338(d, 8.6Hz, 1H), 6.791(d, 8.6Hz, 1H), 3.825(s, 3H)

isatins3.gif 

3,3,4-trichloro-5-methoxy-2-indolinone 8.220g (30.84mmol, a crude material can be used) was suspended in neat acetic acid 110mL and ethyl dichlorourethane 13.391g (9.7mL) was added. The mixture was refluxed on oil bath (135-145C) for 30 min (chlorine evolution!), then cooled to R.T. and poured into cold water 0.5L. The slurry was stirred and sonicated for 20 minutes (untill the gummy precipitate solidified) and stirred at RT for additional 3 hours and placed into a fridge overnight. The precipitate was collected by filtration, washed with water and dried on highvac. The crude product was dissolved in benzene, filtered and evaporated to dryness. The solid residue was refluxed with cyclohexane 200mL for 10 min and then allowed to crystallize at RT for 3 hours. The precipitated product was collected by filtration, washed with hexane+cyclohexane (1:1) and dried on highvac. Y=5.633g (51%) of a pale-yellow crystalline solid. 1H(CDCl3, 400MHz): 8.063(br s, 1H) [very acidic NH, the signal shifts to 8.804 ppm with a concentrated sample 50mg/mL], 3.873(s, 3H), 2.426(s, 3H); 13C(CDCl3, 100MHz): 168.90, 167.36, 146.65, 144.67, 133.61, 126.82, 123.51, 110.03, 74.16, 62.10, 27.24, 20.63; LC/MS(-cAPCI):  358, (360, 356)

The acetoxytetrachloro intermediate 5.48g (15.265mmol, powdered before use) was refluxed vigorously in a 1:1 mixture of methanol/water 200mL for 76 hours (oil bath 110-120C). The mixture was diluted with water (100mL) while hot and allowed to crystallize at RT overnight (16 hours). The precipitated product was collected by filtration, washed with ice-cold 2:1 water/methanol mixture and dried on highvac. Y=3.831g (84.5%) of a dark red-brown needles. 1H(d6-DMSO, 400MHz): 11.349(s, 1H), 3.708(s, 3H), 3.164(s, 1.5H); 13C(CDCl3, 100MHz): 178.37, 159.85, 156.28, 146.95, 139.87, 124.81, 106.77, 103.43, 61.09, 48.59(0.5C); LC/MS(-cAPCI): 280, (282, 278) 

Note: This is a reproduction of a published procedure from Tetrahedron 27 (1971), 3263-70. The second chlorination (with excess of Cl2NCO2Et in refluxing AcOH) was supposed to produce 3,3,4,7-tetrachloro-5-methoxy-2-indolinone. I believe these conditions are in error, the 3-acetoxy-3,4,6,7-tetrachloro-5-methoxy-2-indolinone was obtained instead. The actual conditions that I used for preparation of 3,3,4,7-tetrachloro-5-methoxy-2-indolinone were: 0.6 eq. of Cl2NCO2Et, 60C, 2 days, 65.5%Y (after recrystallization from benzene). 1H(d6-DMSO): 11.842(br s, 1H), 7.370(s, 1H), 3.879(s, 3H)

6 Comments »

  1. How loud was the vigorous gas evolution?

    Comment by Klug — November 8, 2006 @ 6:47 pm

  2. Not loud if you ask Chuck Norris to hold the stopper down. It is actualy not that terrible effect but it happens quite suddenly (about 2.5L of CO2 bubling out all at once and there is a spike in the react temperature at the same time) – so a person who does not expect it might be in for a surprise (especially if using a small flask filled up to its neck.)

    Comment by milkshake — November 8, 2006 @ 7:04 pm

  3. Milkshake, what is the mechanism for the first step? A radical process?

    Comment by diketene — November 8, 2006 @ 10:42 pm

  4. Frankly I have no clear idea. I would put my money on some electrophilic mechanism. Also, pyrroles-2-carboxylic acid and indoles-2-carboxylic acid decarboxylate very easily. I have seen halogenation inplace of 2-carboxylic group in pyrroles. But who knows how relevant that is to our case. Maybe you get the first two chlorines in 3 position with a double bond shift to N and then the intermediate decarboxylates. But you are alright that some part of the process could be radical chain, maybe this would explain the induction period for the decarboxylation.

    Comment by milkshake — November 9, 2006 @ 11:31 am

  5. Does the mixing rate change the induction period or is the induction period just a result of reactive processes?

    Comment by Hap — November 9, 2006 @ 2:33 pm

  6. The smaller scale reaction was done with slower addition and more careful cooling and the decarboxylation initiated later + the temperature spike was smaller – with the bigger run it initiated right before complete addition of Cl2NCO2Et. But I run the first chlorination only twice. The induction period was mentioned in the original article but I don’t know what does it. Maybe gradual buildup of HCl brings about the decarboxylation at some point which in turn causes fast chlorination and steep exotherm at the end, I don’t know. But it would be easy enough to try and add some catalytic amount of sulfuric acid, to see if the induction problem goes away.

    Comment by milkshake — November 9, 2006 @ 3:08 pm


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