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In Phil Baran's lectures on heterocyclic chemistry at Scripps, one of the lecture problems is concerned with this synthesis of Vioxx:

Vioxx synthesis

The first step supposedly involves an anti addition of the aryl Grignard reagent to the propargyl alcohol:

Grignard addition to propargyl alcohol

and this intermediate is trapped with $\ce{CO2}$ to form a lactone (a butenolide in this case), and mCPBA oxidises the sulfide to a sulfone.

Why does the aryl Grignard add to the alkyne in this case? I would expect it to deprotonate the alcohol, and it does seem to do so, but as far as I know, Grignards don't usually add to alkynes which aren't conjugated to electron-withdrawing groups. Why is this propargyl alcohol special?

On top of that, what is the rationale for the selectivity observed (both regio- and stereoselectivity)?

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  • $\begingroup$ It looks wrong. It doesn't seem to be made this way books.google.pl/… $\endgroup$
    – Mithoron
    Commented Jan 5, 2017 at 18:29
  • $\begingroup$ @Mithoron I think that this wasn't the one that Merck opted to go for. However, this alternative synthesis was reported in Tetrahedron Lett. 2000, 41 (1), 17–20 (apparently, there is a non-paywall version here as well). $\endgroup$
    – orthocresol
    Commented Jan 5, 2017 at 18:35
  • $\begingroup$ Then the reaction is rather with salt after neutralisation of alcohol. $\endgroup$
    – Mithoron
    Commented Jan 5, 2017 at 18:52
  • $\begingroup$ @orthocresol looks like reference 1 in that paper is the original report of that reaction. Check if they postulated a mechanism? $\endgroup$
    – Zhe
    Commented Jan 5, 2017 at 22:19

1 Answer 1

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The addition of Grignards to propargyl alcohols occurs via the alkoxide salt, after deprotonation:[1]

Reaction scheme

Here:

  • the reactivity may be explained by the stabilising influence of complexation;
  • the regioselectivity may be explained by the preference of a five-membered chelate ring over a four-membered one; and
  • the stereoselectivity arises because syn addition requires a five-membered ring with a trans double bond and is therefore precluded.

In fact, propargylic alcohols also get reduced by $\ce{LiAlH4}$ (Hans Reich's website has a page on it), with the same trans stereochemistry observed.

Reference

(1) Forgione, P.; Fallis, A. G. Magnesium mediated carbometallation of propargyl alcohols: direct routes to dihydroxydienes and enediyne alcohols. Tetrahedron Lett. 2000, 41 (1), 11–15. DOI: 10.1016/S0040-4039(99)01994-2.

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  • $\begingroup$ Note that the oxygen can withdraw electron drnsity from the methylebe grouo, giving it some catbovation character; this polarized carbon is then conjugated with the end of the triple bond where the nucleophilic part of the Grignard reagent attacks. $\endgroup$
    – Oscar Lanzi
    Commented Nov 6, 2023 at 16:29

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