[AlphaScent]

Does any one have a reference for the addition of an organozinc (Reformatsky) to a Weinreb amide?

Does anyone think it will work?  I lean towards no because the Zn ion may be too large to properly stabilize the 5-membered transition state.

I also know that organozinc reactivity is lower in reactivity than say organolithiums and Grignrds.

Any advice, guidance, thoughts, or telling me I am crazy are greatly appreciated.

Cheers!

[AWK]

Rather no reaction.
see scheme 54
https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0028-1083226

[AlphaScent]

AWK,

Can you write the reference out for me?  The link does not direct me to even the title page.  I appreciate it.

So I have been reading about the vinylogous Mukaiyama aldol reaction (VMAR) and it seems this reaction works quite well.  See the review below.

Nat. Prod. Rep., 2014, 31, 563 (VMAR review)

What do you think about a vinylogous lithium enolate, that has bulk via a methyl group at the alpha position, adding to a Weinreb amide?  Are there any refs you know of where that is accomplished.  I have been finding some refs using the benzotriazole as a leaving group but I would really like to just use a Weinreb amide.  Just some thoughts.

Cheers!

[AWK]

Synthesis 2008(23): 3707-3738 
DOI: 10.1055/s-0028-1083226
The Growing Synthetic Utility of the Weinreb Amide
Sivaraman Balasubramaniam, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
Fax: +91(44)22574202; e-Mail: isingh@iitm.ac.in;

I found it in Google Scholar searching: Weinreb amide Reformatsky
https://scholar.google.com/scholar?q=Weinreb%20amide%20Reformatsky

[AlphaScent]

AWK,

Thank you so much.  I have devised a better route I believe doing vinylogous Mukaiyama aldol type reaction.  I was interested in organozinc and Weinreb amide so upon addition I can keep the ketone functionality.  I then thought about the addition of organozinc addition to a nitrile.  This is a named reaction: the Blaise reaction.  Upon inspection of the literature I found is quite fickle, so I abandoned that route.  The vinylogous Mukaiyama aldol is well studied reaction that gives good to excellent yields, see JACS 2004, 126, 13604 for its use as a vinylketene N,O-silyl acetal.  Also a good review in Nat. Prod. Rep. 2014, 31, 563.

JOC 1989, 54, 4229 illustrates that lithium ester enolates add to Weinreb amides in good yields.  So my idea first is to try an addition of the vinylogous lithium enolate to a Weinreb amide first.  If that does not work (due to the greater affinity for alkylation at the alpha position of the enolate as opposed to the remote, gamma position.  I hope to over come this because I already have a methyl group substituted at the alpha position; sterics may help here???) I will then try the addition of a vinylketene N,O-silyl acetal to a Weinreb amide under Mukaiyama aldol conditions (Lewis acid such as TiCl₄ ) . If that proves to not work then I can just do the vinylogous Mukaiyama aldol using an aldehyde instead of the Weinreb amide.  The subsequent alcohol can then be oxidized to the ketone.  In the end I am just trying to save an oxidation step.  The literature is filled with examples of my 3rd protocol working well.

We shall see!

I have attached schemes to illustrate what I am trying to do.