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The Alkyl -- proposed synthesis Haverford College #403

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rbroadrup-HC opened this Issue Jun 7, 2016 · 12 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.

Revised proposed synthetic plan based on comments below:
the alkyl rev 1

the alkyl

FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CCC4=CC=CC=C4)N32
InChI=1S/C20H16F2N4O/c21-20(22)27-17-10-7-15(8-11-17)19-25-24-18-13-23-12-16(26(18)19)9-6-14-4-2-1-3-5-14/h1-5,7-8,10-13,20H,6,9H2
QKTHSIJWBSHMDZ-UHFFFAOYSA-N

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drc007 Jun 8, 2016

Rather than phenethyl Grignard, you could use a Sonogashira coupling with phenyl acetylene. Lindlar hydrogenation to alkene, or functionalise the triple bond to make some other interesting linking groups as well as hydrogenation to alkane.

drc007 commented Jun 8, 2016

Rather than phenethyl Grignard, you could use a Sonogashira coupling with phenyl acetylene. Lindlar hydrogenation to alkene, or functionalise the triple bond to make some other interesting linking groups as well as hydrogenation to alkane.

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MFernflower Jun 8, 2016

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MFernflower commented Jun 8, 2016

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alintheopen Jun 9, 2016

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Yes, I like @drc007's idea. We can really think about using the triple bond as a handle for the introduction of some interesting functionality.

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alintheopen commented Jun 9, 2016

Yes, I like @drc007's idea. We can really think about using the triple bond as a handle for the introduction of some interesting functionality.

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@rbroadrup-HC @alintheopen If one is made with a double bond how to separate cis/trans isomers? cis isomer might be inactive because it distorts the geometry between the two pendant rings

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MFernflower commented Jun 9, 2016

@rbroadrup-HC @alintheopen If one is made with a double bond how to separate cis/trans isomers? cis isomer might be inactive because it distorts the geometry between the two pendant rings

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Sonogashira reaction would give a triple bond. If we choose to generate an alkene we can pick a stereoselective reaction. @drc007 suggested Lindlar reduction, which leads to the syn-addition of H to give the cis isomer. Dissolving metal reductions would favour trans. Although of course sometimes we get a mixture of isomers, chromatographic separation is possible, silver nitrate columns can also be employed in trickier cases. It would be nice to test both geometries of course.

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alintheopen commented Jun 9, 2016

Sonogashira reaction would give a triple bond. If we choose to generate an alkene we can pick a stereoselective reaction. @drc007 suggested Lindlar reduction, which leads to the syn-addition of H to give the cis isomer. Dissolving metal reductions would favour trans. Although of course sometimes we get a mixture of isomers, chromatographic separation is possible, silver nitrate columns can also be employed in trickier cases. It would be nice to test both geometries of course.

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Could not agree with you more

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MFernflower commented Jun 9, 2016

Could not agree with you more

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rbroadrup-HC Jun 16, 2016

I revised the synthetic plan to incorporate the Sonogashira suggested by @drc007. If the group agrees, I can fully reduce some of acetylene and also attempt to produce the cis-alkene with Lindlar.

rbroadrup-HC commented Jun 16, 2016

I revised the synthetic plan to incorporate the Sonogashira suggested by @drc007. If the group agrees, I can fully reduce some of acetylene and also attempt to produce the cis-alkene with Lindlar.

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drc007 Jun 17, 2016

The unsaturation in the chain would also allow for further functionalisation, for example oxygenation.

drc007 commented Jun 17, 2016

The unsaturation in the chain would also allow for further functionalisation, for example oxygenation.

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alintheopen Jun 24, 2016

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I agree with @drc007's suggestion for this one @rbroadrup-HC :)

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alintheopen commented Jun 24, 2016

I agree with @drc007's suggestion for this one @rbroadrup-HC :)

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mattodd Jun 24, 2016

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+1 Sonogashira

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mattodd commented Jun 24, 2016

+1 Sonogashira

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@rbroadrup-HC @mattodd @alintheopen

Did some ClogP calculations - Some of the compounds are quite greasy but I feel they should all be sent for testing - What do you all think?

alkyl: 3.27
olefin cis/trans: 3.28
parent alkyne: 3.26

I also searched the wiki and found this interesting tidbit:
untitled

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MFernflower commented Jun 24, 2016

@rbroadrup-HC @mattodd @alintheopen

Did some ClogP calculations - Some of the compounds are quite greasy but I feel they should all be sent for testing - What do you all think?

alkyl: 3.27
olefin cis/trans: 3.28
parent alkyne: 3.26

I also searched the wiki and found this interesting tidbit:
untitled

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mattodd Sep 14, 2016

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Closing since taken on to #424

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mattodd commented Sep 14, 2016

Closing since taken on to #424

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