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The Tianyi -- proposed synthesis Haverford College #410

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rbroadrup-HC opened this Issue Jun 7, 2016 · 9 comments

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rbroadrup-HC commented Jun 7, 2016

Proposed synthetic routes have been developed in collaboration with students as part of an organic chemistry class I teach at Haverford College. The molecules are seen as being desirable targets as per #390. This Issue has been created for community feedback on the routes, which can then be attempted in the lab by us or others.

the tianyi

CC1=C(C2=CC=C(OC(F)F)C=C2)N3C(C=NC=C3OCC@@(C4=CC=CC=C4)O)=N1
InChI=1S/C22H19F2N3O3/c1-14-21(16-7-9-17(10-8-16)30-22(23)24)27-19(26-14)11-25-12-20(27)29-13-18(28)15-5-3-2-4-6-15/h2-12,18,22,28H,13H2,1H3/t18-/m0/s1
VGNPLLBRBOUQAA-SFHVURJKSA-N

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MFernflower Jun 7, 2016

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@rbroadrup-HC Would you consider producing my bicyclic terpene idea?
img_20160601_234113

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MFernflower commented Jun 7, 2016

@rbroadrup-HC Would you consider producing my bicyclic terpene idea?
img_20160601_234113

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rbroadrup-HC Jun 7, 2016

Love to. Meeting with a beekeeper now. Will be in touch. R
On Jun 7, 2016 4:01 PM, "MFernflower" notifications@github.com wrote:

@rbroadrup-HC https://github.com/rbroadrup-HC Would you consider
producing my bicyclic terpene idea?
[image: img_20160601_234113]
https://cloud.githubusercontent.com/assets/3164942/15872767/11841554-2cc9-11e6-8701-634a83071cdc.jpg


You are receiving this because you were mentioned.
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#410 (comment),
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.

rbroadrup-HC commented Jun 7, 2016

Love to. Meeting with a beekeeper now. Will be in touch. R
On Jun 7, 2016 4:01 PM, "MFernflower" notifications@github.com wrote:

@rbroadrup-HC https://github.com/rbroadrup-HC Would you consider
producing my bicyclic terpene idea?
[image: img_20160601_234113]
https://cloud.githubusercontent.com/assets/3164942/15872767/11841554-2cc9-11e6-8701-634a83071cdc.jpg


You are receiving this because you were mentioned.
Reply to this email directly, view it on GitHub
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.

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alintheopen Jun 9, 2016

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I'm v. interested in the difluoromethylation step. I do think it is better for the students to start with 4-(Difluoromethoxy)benzaldehyde for synthetic ease and precedent in the project, but really like that this reagent has been considered. I looked up the paper and SDS and it does indeed seem, as stated, to be a 'benign difluorocarbene precursor'. The paper details it's use in functionalisation of phenols and thiophenols but doesn't mention (unless I missed it in a quick scan) the use of aliphatic alcohols. We could really use a method to introduce this group. The 'difluorocarbene' reagent I have tried gave no joy, although I do have a friskier relative waiting in the cupboard, which we could revisit once the health and safety forms have been resumed. A benign alternative would be great since we have already established that it isn't possible to use Freon gas in Australia.

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alintheopen commented Jun 9, 2016

I'm v. interested in the difluoromethylation step. I do think it is better for the students to start with 4-(Difluoromethoxy)benzaldehyde for synthetic ease and precedent in the project, but really like that this reagent has been considered. I looked up the paper and SDS and it does indeed seem, as stated, to be a 'benign difluorocarbene precursor'. The paper details it's use in functionalisation of phenols and thiophenols but doesn't mention (unless I missed it in a quick scan) the use of aliphatic alcohols. We could really use a method to introduce this group. The 'difluorocarbene' reagent I have tried gave no joy, although I do have a friskier relative waiting in the cupboard, which we could revisit once the health and safety forms have been resumed. A benign alternative would be great since we have already established that it isn't possible to use Freon gas in Australia.

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@rbroadrup-HC Why don't you produce the 5-chloro-3-[4-(difluoromethoxy)phenyl]-2-methylimidazo[1,2-a]pyrazine fragment first and then couple it to the same protected alcohol used to make MMV688895? - a simple deprotection of the pyran ether in acid followed by purification/recrystallization should give the product in (hopefully) good yields

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MFernflower commented Jun 27, 2016

@rbroadrup-HC Why don't you produce the 5-chloro-3-[4-(difluoromethoxy)phenyl]-2-methylimidazo[1,2-a]pyrazine fragment first and then couple it to the same protected alcohol used to make MMV688895? - a simple deprotection of the pyran ether in acid followed by purification/recrystallization should give the product in (hopefully) good yields

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mattodd Sep 14, 2016

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@rbroadrup-HC am I right in thinking this is not being pursued experimentally in the Superlab? If so we should close this Issue for now but retain this compound (and this Issue) on a list of potential targets on the Series wiki.

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mattodd commented Sep 14, 2016

@rbroadrup-HC am I right in thinking this is not being pursued experimentally in the Superlab? If so we should close this Issue for now but retain this compound (and this Issue) on a list of potential targets on the Series wiki.

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alintheopen Sep 21, 2016

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I received this email from Lincoln Satterthwaite (thanks Lincoln!) on Sept 21st, posting here so that we can all offer some advice:
"Alice,
My lab partner and I have been working on the synthesis of the triazolopyriazine core via the route outline by Tom McDonald, but we're not having much luck with the first step of the synthesis. We get what appears to be the crude product (based on the images from Haochuan Mao here, but we can't see it in an NMR after running a column using 30% EtOAC in hexanes.
My question for you is this: were there any special conditions that you used for the column/reaction when you did it? Light sensitivity, higher heat, etc. Any help would be greatly appreciated.
Best,
Lincoln"

Hi Lincoln, I wonder if the product has stuck to the column? Did you flush the silica with 100% EtOAc at the end? Haochuan used a Biotage Isolera to purify his compound (an automated columning machine) and also managed to recrystalise from the crude - from memory using EtOAc. Haochuan also modified the synthesis to add the reagents at different stages which prevented the formation of a heterogeneous mixture: See the Log part of HM 1-5
Hope this helps! Will email Haochuan too to ask for any advice! Cheers Alice

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alintheopen commented Sep 21, 2016

I received this email from Lincoln Satterthwaite (thanks Lincoln!) on Sept 21st, posting here so that we can all offer some advice:
"Alice,
My lab partner and I have been working on the synthesis of the triazolopyriazine core via the route outline by Tom McDonald, but we're not having much luck with the first step of the synthesis. We get what appears to be the crude product (based on the images from Haochuan Mao here, but we can't see it in an NMR after running a column using 30% EtOAC in hexanes.
My question for you is this: were there any special conditions that you used for the column/reaction when you did it? Light sensitivity, higher heat, etc. Any help would be greatly appreciated.
Best,
Lincoln"

Hi Lincoln, I wonder if the product has stuck to the column? Did you flush the silica with 100% EtOAc at the end? Haochuan used a Biotage Isolera to purify his compound (an automated columning machine) and also managed to recrystalise from the crude - from memory using EtOAc. Haochuan also modified the synthesis to add the reagents at different stages which prevented the formation of a heterogeneous mixture: See the Log part of HM 1-5
Hope this helps! Will email Haochuan too to ask for any advice! Cheers Alice

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alintheopen Sep 22, 2016

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Email from Haochuan who can't access GH now he's back home in Nanjing:

"Hi Lincoln,
I'm so excited that you read my lab notebook.
I didn't use any special condition for that reaction or column, and the refluxing temperature was about 110 degree Celsius. But the I used 75% of EtOAc in hexane as the fluent phase when conducting the manual column,because the desired product was quite polar and I even tried 100% of EtOAc directly using Isolara and the result was good. I hope this can be of help.

Plus, as was mentioned by Alice, adding catalyst later will help rid the reaction off some annoying sticky solid.

Good luck!
Haochuan"

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alintheopen commented Sep 22, 2016

Email from Haochuan who can't access GH now he's back home in Nanjing:

"Hi Lincoln,
I'm so excited that you read my lab notebook.
I didn't use any special condition for that reaction or column, and the refluxing temperature was about 110 degree Celsius. But the I used 75% of EtOAc in hexane as the fluent phase when conducting the manual column,because the desired product was quite polar and I even tried 100% of EtOAc directly using Isolara and the result was good. I hope this can be of help.

Plus, as was mentioned by Alice, adding catalyst later will help rid the reaction off some annoying sticky solid.

Good luck!
Haochuan"

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mattodd Sep 26, 2016

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Hey @alintheopen not sure the above two comments are in the right place - this issue is on the Tianyi compound. If so, can you delete and add to the right Issue, and then delete this (my) comment?

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mattodd commented Sep 26, 2016

Hey @alintheopen not sure the above two comments are in the right place - this issue is on the Tianyi compound. If so, can you delete and add to the right Issue, and then delete this (my) comment?

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mattodd Sep 26, 2016

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Closing this Issue for now. The need for the compound has been added to the "desirable compounds" section on the wiki, and a synthetic branch has been installed on the relevant page. This compound is still needed, and can be found here again through a search on "Tianyi"

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mattodd commented Sep 26, 2016

Closing this Issue for now. The need for the compound has been added to the "desirable compounds" section on the wiki, and a synthetic branch has been installed on the relevant page. This compound is still needed, and can be found here again through a search on "Tianyi"

@mattodd mattodd closed this Sep 26, 2016

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