Org Prep Daily

November 10, 2009

Intramolecular Carboacylation with rhodium C-C insertion

Filed under: Chris Douglas, procedures — milkshake @ 2:57 pm

C-C insertion

To a cooled solution (–78 °C) of 8-bromoquinoline (2.25 g, 10.8 mmol) in THF (70 mL) in a flame-dried flask under N2 was added n-BuLi (2.5 M in hex, 6 mL, 15 mmol) drop-wise. The dark orange mixture was allowed to stir for 10 min. Aldehyde (2.84 g, 16.2 mmol, readily available from salicylaldehyde and 1-chloro-2-methyl-2-propene) was slowly delivered as a solution in THF (3 mL) over a span of 10 min to give a dark cloudy red solution. The reaction was stirred at –78 °C for 20 min, and allowed to warm to room temperature over 2 h. The clear orange solution was quenched with saturated NH4Cl (60 mL), and the layers were separated. The organic layer was washed with water (10 mL), and the combined aqueous washes were extracted with Et2O (2 x 50 mL). The combined organic portions were washed with brine (30 mL), dried over Na2SO4, and concentrated. The resulting orange-yellow residue was taken up in Et2O and a colorless precipitate formed. Collection of this precipitate by vacuum filtration gave the alcohol (1.80 g, 5.9 mmol, 55%), which was carried on directly. The intermediate alcohol (1.53 g, 5 mmol) was dissolved in DMSO (33 mL) and allowed to react with IBX (2.92 g, 10 mmol). The solution was maintained at room temperature for 2 h. Ethyl acetate (20 mL) and water (20 mL) were added, and the resulting colorless precipitate was removed by filtration through Celite. The layers were separated, and the aqueous portion was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated. The yellow-orange oil was purified by column chromatography over silica gel (1:9 EtOAc:Hex) gave 1 as viscous yellow oil (1.20 g, 3.97 mmol, 79%, 43% over the two steps). Rf .23 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J = 1.8, 4.2 Hz, 1H), 8.13 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.8, 7.5 Hz, 1H), 7.81 (dd, J = 1.5,8.4 Hz, 1H), 7.78 (dd, J = 0.9, 6.6 Hz, 1H), 7.54 (app t, J = 7.8 Hz, 1H) 7.47-7.41 (m, 1H), 7.34 (dd, J = 4.2, 8.1 Hz, 1H), 7.05 (app t, J = 7.5, Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.49-4.36 (m, 2H), 3.97 (s, 2H). 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.8, 158.1, 150.3, 145.9, 141.6, 139.7, 135.7, 133.6, 131.2, 129.8, 129.5, 128.2, 128.0, 125.8, 121.2, 120.5, 112.6, 112.2, 72.0, 18.7; IR (thin film) 3078, 2915, 1645, 1595, 1573, 1485, 1451, 1322, 1294, 1246, 1158, 1109, 1040, 1006, 926, 907, 798, 754, 626; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1329.

A 0.2 M solution of 1 in PhMe was prepared in a N2 atmosphere glove box. RhCl(PPh3)3 (10 mg, 0.01 mmol) catalyst was carefully weighed into a 1 dram vial, and the solution of 1 (0.5 mL, 0.1 mmol) was added followed by toluene (0.5 mL). The vial was capped with a PTFE lined screw-cap and resulting yellow-orange solution was maintained at 130 °C for 48 h. The cloudy brown mixture was removed from the glove box and concentrated onto Celite. Column chromatography (EtOAc:Hex) gave 2 as colorless viscous oil (28.7 mg, 0.095 mmol, 96%).  Rf 0.31 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.94 (dd, J = 2.1, 4.5 Hz, 1H), 8.18 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.5, 8.4 Hz, 1H). 7.81 (dd, J = 1.8, 7.2 Hz, 1H), 7.56 (dd, J = 7.2, 8.1 Hz, 1H), 7.44 (dd, J = 4.2, 8.4 Hz, 1H), 7.13-7.07 (m, 2H), 6.83-6.78 (m, 2H), 4.72-4.55 (m, 2H), 3.97-3.75 (m, 2H), 1.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.7, 159.1, 150.5, 145.5, 140.1, 136.3, 135.5, 131.2, 129.0, 128.23, 128.2, 126.1, 122.9, 121.5, 120.4, 109.7, 83.0, 54.2, 44.4, 25.9; IR (thin film), 3045, 2961 1681, 1595, 1568, 1479, 1346, 1247, 1216, 970, 831, 792, 750; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1337. The structure was confirmed by HMQC, COSY, and HMBC.


  1. Inplace of IBX, I have had a good luck with oxidizing benzhydryl alcohols (where one of the aryls was 2-arylamino-5-pyrydinyl) with “catalytic Jones” system from Merck process group: The substrate is dissolved in acetonitrile-water 400:3 mix (v/v) and a solution of 0.25M H5IO6 and 1.25mM CrO3 in the same 400:3 mix is added at room temp. The workup is just filtration, and portioning the mix between EtOAc and bicarb. The amount of water in acetonitrile is crucial as the water attenuates CrO3 and keeps it from over-oxidizing things like benzylic methylenes, but adding too much water would kill the activity. With basic N-substrates like my pyridine-benzhydryl alcohol, sometimes one has to use >2 equivs of H5IO6 as one equiv probably gets deactivated by formation of a salt.

    The reagent is prepared by dissolving H5IO6 and CrO3 in MeCN-water mix on a warm water bath and filtration, and is perfectly bottle stable (sometimes H5IO6 crystallyzes out if the mix is kept in fridge – one can just re-heat it to complete dissolution before use. The refrigeration is unnecessary.)

    Comment by milkshake — November 11, 2009 @ 10:43 am

  2. Not to mention, one could use “NaH as an oxidant” for the same oxidation… Did you notice the paper is finally back as a supposedly modified ASAP on the JACS website? Still, no mention that I could find about the role of O2 in the whole process.

    Comment by HPCC — November 11, 2009 @ 11:58 am

  3. Do you have a reference on hand for the catalytic Jones oxidation?

    Comment by Reaction Runner — November 11, 2009 @ 7:46 pm

  4. Take it from here I think

    Comment by Ed — November 12, 2009 @ 3:45 am

  5. I wanted to use MnO2, but we had really mixed results with that. A homemade batch we borrowed from the Hoye lab worked great, but others (like the stuff from Aldrich and Acros in particular) did absolutely nothing. The literature preps for “active” MnO2 didn’t look to fun. Anyone have a favorite way to prep that reagent?

    Comment by Chris Douglas — November 12, 2009 @ 7:02 pm

    • I once re-activated a lazy bottle of MnO2 by just spreading the stuff in a wide dish and placing it into a glassware-drying oven at 110-120C overnight, then letting it cool in a closed bottle. MnO2 is like Al2O3 – it gets deactivated by moisture. Also it works better in non-polar solvents like benzene.

      The dried stuff in my hands was a lot faster with farnesol as a substrate but the reaction mix was less clean and I saw more cis/trans C=C isomerization of the product also. I wonder if anyone tried to add powdered sieves to MnO2 oxidations – people use sieves with TPAP/NMO (and PDC as well) but I have not seen it with MnO2.

      (Then there is BaMnO4, an alternative to MnO2 thats made from permanganate quite easily.)

      Comment by milkshake — November 12, 2009 @ 7:14 pm

      • We did bake our Aldrich swag in the oven (125 C), but no luck.

        Forgot about BaMnO4 – might be easier in the work-up than IBX. think we need to worry about quinoline N-oxide formation with that?

        Comment by Chris Douglas — November 12, 2009 @ 7:25 pm

      • I think not because permanganate is even a stronger oxidant and it is fully compatible with pyridine (in fact some permanganate oxidations of poorly soluble substrates use pyridine as a co-solvent). BaMnO4 is commercial but I remember a long time ago we made it by combining 1 equiv of NaOH and 1 equiv of BaCl2 with aqueous KMnO4 solution and then adding slowly 0.125 eq of KI solution (as a reducing agent, it goes all the way up to periodate) and BaMnO4 falls out as a dark-green solid.

        Comment by milkshake — November 12, 2009 @ 7:48 pm

  6. I’ve always used Fluka MnO2 – never had any trouble. Then again, its always been used on pretty robust substrates where 15-20 eq. could be used no problem at all!

    Comment by Ed — November 13, 2009 @ 3:21 am

  7. Can you provide a a ref. for 1 to 2?

    Comment by MattW — November 15, 2009 @ 12:07 pm

  8. I have used Aldrich-bought MnO2 for simple alcohol oxidations, and it worked quite well without any prior activation. I did, however, use powdered 4A molecular sieves that were stored in a 110 °C oven. It greatly improved the reaction for me, but I don’t know how general it is. Also, still used 10 equiv of the oxidant, so for scale this will probably be a problem.

    Comment by Cru Jones — November 15, 2009 @ 10:32 pm

  9. Hi Milkshake,

    I don’t know if this has been asked yet but would Dess-Martin Periodinane (DMP) suffice for the oxidation here? DMP is usually a preferred oxidant as it is so much easier to handle. A lot of the guys use it in our lab. Also why did you use DMSO it is usually such a beast to remove is the intermediat alcohol a pain to dissolve?

    Comment by OrganicOverdose — November 17, 2009 @ 2:36 am

    • we used IBX since we had it and it worked well and the DMSO did not prove too difficult to remove in this case. I would not expect any trouble with DMP.

      Comment by Chris Douglas — November 22, 2009 @ 12:06 pm

  10. Recently I scaled up a MnO2 oxidation (fluka MnO2, a 3,4dihydroquinoline to quinoline, 1-1,5 Kg of substrate, 4 batches) and it has been a painful experience. No way to use less than 3 equivalents of oxidant, excellent selectivity but low recovery also with 2-3 reextractions of the cake. Main problem Mn2+ contamination, but next step was an Ullmann amination so I got rid of all metal traces in the final purification. No time to screen other oxidations, because these days all the preclinical scaled up chemistry must be executed in hurry, hurry, hurry.
    Reading this thread, maybe an azeotropic drying of the catalist was a possible way to improve the reaction.

    Comment by processchemist — November 21, 2009 @ 7:29 am

RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

The Shocking Blue Green Theme Blog at


Get every new post delivered to your Inbox.

Join 136 other followers

%d bloggers like this: