Org Prep Daily

February 15, 2010

4-(2′-bromoethyl)-2-indolinone by chemoselective transfer hydrogenation

Filed under: procedures — milkshake @ 2:15 pm

4-(2′-bromoethyl)-3-chloro-2-indolinone 3.00g (10.93 mmol) and Pd-C 300mg [10% Pd on charcoal, Aldrich] was suspended in ethyl acetate 50 mL in a round flask and the mixture was brought to reflux on a 100C bath with vigorous stitting. A solution of NaH2PO2.H2O 3.0g in water 12ml was gradually added through the condenser over a 30 min period. After the complete hypophosphite addition the mix was stirred at reflux for additional 2 hours, then cooled to about 40C and filtered while warm to remove the catalyst. (The spent catalyst was washed with additional water 100mL and EtOAc 100mL). The combined filtrates were separated, the aqueous phase was re-extracted with another portion of EtOAc (100mL). The combined organic extracts were dried (MgSO4) and evaporated. The solid residue was suspended in EtOAc 20mL, the solids were collected by filtration, washed with freezer-chilled EtOAc and dried by suction and on highvac, to provide the 1.428g of a pure product. A second crop 0.850g (95% pure by HPLC) was obtained by evaporating the supernatants and re-crystallizing the residue from EtOAc 10mL (reflux, then RT, then 0C fridge overnight). The combined Y=2.278g of a white crystalline solid (87% th)

1H-NMR (d6-DMSO, 400MHz): 10.360(s, 1H), 7.123(t, 7.8Hz, 1H), 6.848(d, 7.6Hz, 1H), 6.702(d, 7.7Hz, 1H), 3.720(t, 7.4Hz, 2H), 3.505(s, 2H), 3.054(t, 7.3Hz, 2H)

Note: Sodium hypophosphite is on the DEA-watched precursors list in US because it could be supposedly used as a red P replacement in home manufacture of meth. Since hypophosphite has only limited chemistry uses and the chemistry supplier may not be familiar with its application in the transfer hydrogenation, the shipment can be held up. So put it on a separate order, prepare an explanation with a literature reference, and expect that the order shipment can be delayed for 1-2 weeks until the baloney gets sorted out. (To speed things along be ready to complain to the supplier that they are concerned with pleasing the government instead of their customers).


  1. If you have the NMR Spectrum send it to me here: antonyDOTwilliamsATchemspiderDOTcom and I will upload it here:

    Comment by ChemSpiderman — February 15, 2010 @ 3:02 pm

    • I will do that, when I get my scanner up and running. Unfortunately I only have a printout with pencil-written coupling constants, not the electronic file

      Comment by milkshake — February 15, 2010 @ 7:41 pm

  2. Nice procedure, was this based off a reference? What other groups does this tolerate, if you know?

    Comment by hb — February 26, 2010 @ 4:27 pm

    • it is actually from a ropinirole process paper, from 80s but I don’t have a reference at hand. That bromoethyl is not very reactive. My guess is that hypophosphite – apart from providing hydrogen – also attenuates Pd-C so that it leaves the bromoethyl unmolested.

      What really surprised me is that they run it in EtOAc-water mix – but I did not feel like modifying anything (in this critical step). They had few other examples of 3-chlorooxindole dehalogenation by transfer hydrogenation in that paper but for analogs without the bromoethyl they would use something more common like hydrazine

      Comment by milkshake — February 26, 2010 @ 4:43 pm

      • For the details, You can refer oprd 1998, 2, 3-9 – “development of large scale synthesis of Ropinirole in the pursuit of a manufacturing process”

        Comment by pash — March 22, 2011 @ 5:01 am

  3. nice reaction,i have did this reaction in bigger scale,i feel this is good chemistry,hypophosphate is a hydrogen source for pd/c and this reaction canotbe done in
    autoclave due to HCL generation.

    Comment by seshu — November 24, 2010 @ 4:05 am

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