Dan_Ny Posted March 22, 2011 Posted March 22, 2011 (edited) I have no idea about the mechanism of this reaction. Anybody could help? Since according to wikipedia, TiCl4 is a Lewis, acid, we could propose this mechanism: One drawback is, that i would not see how we get rid of the Titanium lewis-acid in the last step to furnish a reduced product. (Reductive workup perhaps?) The second thing is that wikipedia states, that TiCl4 is an oxophiliic lewis acid. So, coordination to the oxygen in the first step in order to activate the carbon... The problem is, that lewsi activation of vinly ethers activate the carbon beta to the ether oxygen and the thiol would attack at the wrong carbon. Plus, we need double activation to get both sulfurs at the carbon. Does anybody have an idea? Edited March 22, 2011 by Dan_Ny
Horza2002 Posted March 22, 2011 Posted March 22, 2011 If you can wait until the morning, I have a paper on my desk at work outlining exactly why you use titanium in methathesis reactions
Dan_Ny Posted March 23, 2011 Author Posted March 23, 2011 Wow, thanks But this is not a metathesis reaction (my mistake, i shouldn't have called it ring-opening)
Horza2002 Posted March 23, 2011 Posted March 23, 2011 Oopps sorry...given you overt love of methathesis reactions, I only read the title and assumed you wanted to know why 1st generation Grubbs catalysts required a titanium cocatalyst while 2nd/3rd generationones didn't. Sorry it was late when I posted! From looking at your proposed mechanism, I don't think the titatnium would become covalently attatched to the substrate. The doesn't look right to me. Also, I very much doubt the last step goes stepwise. The secondary cation generated won't be that stable. I would actually guess that the thiol attakcs the thio-acetal carbon and then breaks the C-O(H)+ in a concerted process. I've got a set of 5 flash columns I need to do today, so I'll have plenty of time to have a think and come up with a reason as to why you use the titanium.
Dan_Ny Posted March 23, 2011 Author Posted March 23, 2011 5 columns, hm? i hope you have access to a biotage (auto-column), then... You're right, Horza, what I proposed does not make too much sense. But how does the Titanium activate the vinylether? I'll look through the web later, perhaps wikipedia has something to say about it...
Horza2002 Posted March 23, 2011 Posted March 23, 2011 Nope, we don't have a biotage, I did them all by hand...turned out to be 6 as I forgot I had one extra to do. Just to point out, you have one to many carbon atoms in your product thatn you have in your starting material. There should only be four carbons between the alcohol and the thioacetal. I still can't work out why they use titatium. I found this paper in which they do this reaction but they do it a different way. They use borontriflouride as the Lewis acid but pretreat the 2,3-dihydrofuran with tosic acid and methanol to get an intermediate which then undergoes the reaction with the dithiol. Maybe this will help you. Asymmetric synthesis of the macrolide (−)-aspicilin , Guy Solladie, Inmaculada Fernandez and Carmen Maestro, Tetrahedron: Asymmetry, Volume 2, Issue 8, 1991, Pages 801-819
Dan_Ny Posted March 23, 2011 Author Posted March 23, 2011 6 columns. Well, i hope you are doing small-scale reactions. You were right, I had one carbon too much, apologies... I have a new idea: So, in my opinion, substitution at an olefin does not exist. to bypass that, what do you think about activation of the double bond by the lewis acid, attack of the first thiol group and subsequent coordination of the oxygen and attack of the second thiol group? does that sound reasonable? Nope, we don't have a biotage, I did them all by hand...turned out to be 6 as I forgot I had one extra to do. They use borontriflouride as the Lewis acid but pretreat the 2,3-dihydrofuran with tosic acid and methanol to get an intermediate which then undergoes the reaction with the dithiol. Maybe this will help you. Asymmetric synthesis of the macrolide (−)-aspicilin , Guy Solladie, Inmaculada Fernandez and Carmen Maestro, Tetrahedron: Asymmetry, Volume 2, Issue 8, 1991, Pages 801-819 Yeah, that would be explained by a olefin then oxygen activation; first a protic acid for the double bond and then an oxophile. what do you think?
mississippichem Posted March 23, 2011 Posted March 23, 2011 From looking at your proposed mechanism, I don't think the titatnium would become covalently attatched to the substrate. The doesn't look right to me. True, that coordination geometry is not allowed for a titanium(IV) species. Assuming the entire catalytic cycle is an [ce] 18e^{-} [/ce] cycle [don't worry about counting them, nothing but an inorganic convention referring to the number of electrons that are available to participate] you would be correct in ruling this out. A temporary reduction to titanium (III) might allow this though, which opens up a new can of worms about the mechanism. I honestly don't know the catalytic cycle for this reaction though. I'll have a look when I get a spare second.
Dan_Ny Posted March 23, 2011 Author Posted March 23, 2011 Titanium is a reagent in this reaction and used as in excess... Not a catalyst.
mississippichem Posted March 23, 2011 Posted March 23, 2011 Titanium is a reagent in this reaction and used as in excess... Not a catalyst. Oops, read Horza's post and got confused, though this was a metathesis! Sorry. The rest of my post should still stand though about the allowed geometries. If it coordinates to the substrate, it is a transition state.
Horza2002 Posted March 23, 2011 Posted March 23, 2011 Yer sorry, I got mixed up at the start. Your new mechanism seems more plausible to me...the second step is definately feaseable and probable. However, I don't like the first step. It just doesnt look right to me really....I'm not sure sure if titanium can activate an alkene in this manor.
Dan_Ny Posted March 24, 2011 Author Posted March 24, 2011 (edited) I totally and completely agree, titanium activatin an alkene does not sound right at all for me. But as long as you invent a good explanation... By the way, what exactly is the role of TiCl4 in metathesis reactions (sorry!!! I just "love 'em", like you know very well). What does it do to the first gen. grubbs? I might ask a few questions about the diels alder as a ring-closing element in synthesis later. What we have so far is: Macrolactonization, RCM, DA. What else is there? I just want to know the best ways to close a ring... Edited March 24, 2011 by Dan_Ny
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