GU Project 5: Synthesis of the Heterooxazole

[mcoster]

Outline
GU Project 5 will focus on synthesis of "the Heterooxazole":

Note: we will be getting familiar with the chemistry via the 4-chlorophenyl series (from 4-chlorobenzaldehyde) until our order of 4-(difluoromethoxy)benzaldehyde arrives.

Our plan is basically to follow the route proposed in GHI #462, involving C-H arylation of the oxazole. This paper suggests a Pd catalysed, silver-assisted process with the oxazole may be feasible. Other conditions were also suggested in #462, eg. Pd(OAc)₂, X-Phos or CataCXium A, K₂CO₃, pivalic acid - Org. Lett. 2010, 12, 3578-3581. We will also try a different approach to access the expensive 2-phenyloxazole.

The project is being undertaken by Daisy, who is completing the fourth year of her degree at Griffith University as part of a collaboration between GU and Nanjing University of Chinese Medicine.

Links:
AEW 85-x
EGT 24-2, EGT 25-6
C-H arylation of oxadiazoles and other heteroaromatics - Adv. Synth. Cat. 2017, 359, 772-778.
C-H arylation of oxazoles, eg. Pd cat. + X-Phos - Org. Lett. 2010, 12, 3578-3581
ArCl -> ArI using CiI, KI, DMI: Patent WO 2011111423
ArCl -> ArI using NaI, AcOH, H2SO4, MeCN: Tetrahedron 1998, 54, 9701-9710.
2-phenyloxazoline from benzonitrile and 2-aminoethanol - Open Catalysis Journal 2009, 2, 163-165
Oxidation of 2-phenyloxazoline to 2-phenyloxazole - Org. Lett. 2010, 12, 4686-4689
Haverford Superlab ELN - the Heterooxazole
Previous synthetic planning - #462, #407
Earlier discussion of Griffith Uni OSM contributions - #508
OSM Desirable Compounds Not Yet Synthesised (DC-NYS)

Files:
Daisy - synthetic plan.zip

Strings:
"Heterooxazole" (R = OCHF2)
InChIKey=FBTBZFMQUBZDSN-UHFFFAOYSA-N
InChI=1S/C21H13F2N5O2/c22-21(23)29-15-8-6-13(7-9-15)19-27-26-18-12-24-10-16(28(18)19)17-11-25-20(30-17)14-4-2-1-3-5-14/h1-12,21H
FC(F)OC1=CC=C(C=C1)C1=NN=C2C=NC=C(N12)C1=CN=C(O1)C1=CC=CC=C1

Edit (8 Aug 2017): Fixed typo in scheme "Heterooxadiazole" -> "Heterooxazole"

[mattodd]

Ditto vs #521. Lovely chemistry and very interested to see how it plays out. Ditto development of reliable routes to the coupling partners as an important thing to promote any future coupling campaigns, should Daisy not quite get there (but let's be optimistic - of course she'll get there!).

Just to clarify - when the lab notebooks are up and running you'll add the link to the above post, right?

[MFernflower]

The synthesis plan of the 2-phenyloxazole is simply beautiful

[drc007]

Label in scheme should read Heterooxazole not Heterooxadizole

[MFernflower]

If you got extra product will you try to couple 2-phenyloxazoline too? Two molecules for the price of one! @mcoster

…

On Jul 31, 2017 2:43 AM, "Chris Swain" ***@***.***> wrote: Label in scheme should read Heterooxazole not Heterooxadizole — You are receiving this because you commented. Reply to this email directly, view it on GitHub <#522 (comment)>, or mute the thread <https://github.com/notifications/unsubscribe-auth/ADBLDvMVKVzP2BRSvQv4O__jwLUJkg4Nks5sTXeXgaJpZM4OgbfE> .

[mcoster]

@drc007 - well spotted! Fixed.

@MFernflower - I'm always keen to get two molecules for the price of one, but I suspect these types of C-H activations require heteroaromatics, with C(sp²)-H bonds being activated.

[MFernflower]

@mcoster I figured it would work by adding across the C=C bond - I'd be curious as to see if you could couple to phenylfuran - just a thought!

[mcoster]

Daisy finished working on this project in October. She was able to synthesise the chloro 4-(difluoromethoxy)triazolopyrazine, however, the one attempt to convert this compound to the corresponding iodide was not successful. Issue closed.