Org Prep Daily

June 17, 2007

New reactions from Carreira

Filed under: lit highlights — milkshake @ 5:52 pm


A fundamentally useful addition reaction that gives good yields with variety of substrates in ethanol at room temperature on a gram scale.
Markovnikov product, no stereoselectivity with chiral substrates, no ee’s reported with Jacobsen Co-salene as a catalyst (so probably there aren’t any). 
The catalysts are either commercial or 1 step to make. The azides can be transformed to triazoles or amines in situ. Works great with safrole.   


  1. Hey…this is nice and simple!

    Comment by wisemanleo — June 17, 2007 @ 9:34 pm

  2. Is there a reference to the mechanism for that reaction, if it is known?

    Comment by Spiro — June 18, 2007 @ 12:09 am

  3. There is a mechanistic discussion in the literature on analogous C=C hydroperoxidation reaction, Org. Lett. 4(21) (2002), 3595 – looking at it I am not enlightened. I think a free-radical step is involved in the new bond formation therefore the poor stereoselectivity. I guess the peroxide keeps the Co as Co(III) – and that reacts with the silane to form Co(III)-H species and this then adds to the C=C. The formed alkyl-Co(III) then fragments homolytically and the produced secondary(or tertiary) radical is trapped with TsN3 or TsCN.
    I cannot really explain the preference for Markovnikov product in the Co(III)H addition. Secondary, tertiary and benzylic radicals are more stabilized than primary radicals – so maybe there never is a real alkyl-Co species along the path and Co(III)H serves as a functional equivalent of the hydrogen radical.

    Comment by milkshake — June 18, 2007 @ 12:27 am

  4. haha @ the safrole.. trying to boost the hits to the site?

    Comment by tom — June 18, 2007 @ 11:28 am

  5. Tom- had the same thought. There’s nothing special about *that* substrate, right? 😉

    Comment by Jose — June 18, 2007 @ 11:30 am

  6. I am not trying to boost any hits (the mainline hits, the contract hits or the Barry Manilow greatest hits). Please note that it was Carreira who published the solution of a long-standing unmet chemistry need, a functional one-pot equivalent of safrole hydroamination. I am just highlighting.

    Comment by milkshake — June 18, 2007 @ 7:41 pm

  7. #3

    Thanks for your suggestions and the reference. Things are a bit clearer in my mind.

    I imagined a carbocationic mechanism 🙂 A radicalar one makes more sense.

    Comment by Spiro — June 18, 2007 @ 10:07 pm

  8. Off-topic, but I’m in a bind. I’m attempting to do a mukaiyama-aldol reaction of a silyl enol-ether derived from a cyclohexenone with an acetal, and eventuallly a ketal hopefully. I’m have bad luck with most of the stuff I’ve tried (TiCl4, TMSOTf, BF3OEt2). Does anyone have any suggestions on things to try or procedural tweaks that have worked for you? Thanks!

    Comment by carbazole — June 19, 2007 @ 1:02 am

  9. Try Cu(II)-triflate in DCM

    Comment by milkshake — June 19, 2007 @ 1:27 am

  10. Haha. I guess some people will be ecstatic about this chemistry…

    Comment by Russ — June 19, 2007 @ 7:30 am

  11. TsN3 is extremely, rapidly toxic by all routes of absorption – and much more so for anybody on hypertension meds or taking Viagra, Cialis, Levitra. That is why we have grad students and technicians.

    Comment by Uncle Al — June 19, 2007 @ 2:15 pm

  12. Are you sure you are talking about TsN3 and not TMS-N3 ?
    TMS-N3 is a volatile liquid that hydrolyzes instantly. Ts-N3 is somewhat explosive crystalline material, stable to moisture – people in our lab were making Ts-N3 on a fifty gram scale (for making MeCOC(N2)PO(OMe)2, the reagent for making terminal acetylenes from aldehydes) and there were no mishaps. Whereas there was a number of lab personel sickenings from accidental TMS-azide spills.

    Comment by milkshake — June 19, 2007 @ 2:22 pm

  13. 11: that is why… = because of Viagra, Cialis, Levitra?

    Comment by liquidcarbon — June 19, 2007 @ 11:01 pm

  14. Apologies for the offtopic post – I’ve noticed that you’ve done some work with pyrazole derivatives in the past, so I thought I’d ask. I am currently trying to benzylate the N-H proton on a 3,5-disubstituted pyrazole ring, but I’ve run into some trouble. The only precedent I’ve been able to find so far (BnBr, K2CO3, acetone) doesn’t seem to work. In addition, the starting material is insoluble in anything less polar than DCM (THF, diethyl ether, toluene, among others), so I don’t think I can lithiate the amine and then alkylate (I’ve tried KHMDS in THF – no go). Do you have any suggestions? Thank you!

    Comment by Ron — June 20, 2007 @ 5:26 am

  15. I would use DMF or DMAc as a solvent with caesium carbonate as a base, with benzyl bromide, RT to 60C.

    Comment by milkshake — June 20, 2007 @ 9:59 am

  16. YES! Phenylsilane! Work with that stuff all the time…it smells awesome!

    Comment by mevans — June 20, 2007 @ 2:54 pm

  17. Note that the cyanation doesn’t require TBHP with the achiral salen catalyst. There are some mechanistic investigations in this full paper: JACS, 2006, 128, 11693. Btw, I never noticed any unpleasant smell of phenylsilane, though it’s not odourless….

    Comment by sumathra — June 22, 2007 @ 10:11 am

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