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KlementineJBS / USYD_PhD_ELN

This repository forms the electronic laboratory notebook (ELN)for Klementine Burrell-Sander's PhD's
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KBS30 - master page #166

Open KlementineJBS opened 6 months ago

KlementineJBS commented 6 months ago

Link to HIRAC.

KBS30 - Generic alkylation of 1,x-diaminoalkane with naphthalene-triazole pendant (updated).docx

Reaction scheme

KBS30 alternative nosyl protected

KlementineJBS commented 6 months ago

Attempts

Identifier Link Yield (%) Further info Base Solvent
1 #58 mixed products unprotected amine K2CO3 DMF
2 #116 mixed products unprotected amine K2CO3 DMF
3 #149 80% of mono-alkylated product nosylated amine, solvent wasn't dry and pendant group was hydrolysed K2CO3 DMF
4 #165 - nosylated and mono-alkylated amine, dry solvent K2CO3, 1.5 equiv. DMF
5 #169 - nosylated amine, dry solvent NaH, 2.2 equiv. DMF
6 #175 - nosylated amine, dry solvent Cs2CO3, 6 equiv. DMF
7 #176 - nosylated amine, dry solvent Cs2CO3, 6 equiv. THF
8 #178 - nosylated amine, dry solvent NaH, 2.8 equiv. THF
KlementineJBS commented 6 months ago

Notes

Will be attempting alkylation with nosyl-protected amine. Literature suggests that this progress well with K2CO3 and DMF - see refs 1, 2. Some use additional catalysts e.g. 1,10-phrenanthroline and copper sulfate 3.

Ref Substrate Alkylating agent Equiv. Base Equiv.
1 methylamine propargyl bromide 1.2 K2CO3 1.5
1 methylamine 3-bromo-2-methylprop-1-ene 1.1 K2CO3 3
KlementineJBS commented 6 months ago

Plans

if returning to unprotected amine

Try different solvent/base combos.

Trying to control/limit alkylation by:

Reference for unprotected amine: https://doi.org/10.1021/acs.orglett.1c03950

KlementineJBS commented 6 months ago

try simply increasing equiv. of K2CO3 to at least double?

KlementineJBS commented 6 months ago

Suggestions for the new year

  1. Solvent/base screen (small scale)
Base/Solvent K2CO3 Cs2CO3 NaH
DMF #165 #175 #169
THF - #176 #178

  1. Try extracting with diethyl ether ? DCM works best to dissolve so far but complicates washing step. Not necessarily an issue if DMF is not used as the solvent.

  2. Try using mesylated group instead of brominated group (KBS29). E.g. see Weilin et al (using MeCN as solvent and no base, see compound 1a in SI) or Chrzanowski et al (scheme 1, using DCM and triethylamine).

  3. (Can also try making brominated KBS29 from mesylate - see #164).

  4. Try in methanol or ethanol (Lorenzo?)

KlementineJBS commented 5 months ago

Mass spec peaks summary

Identifier Link Positive peaks Negative peaks Other info
30-4 #165 716, 923, 939 485, 692, 975 different peaks visible after columning
30-5 #169 923 485, 692 peaks from different fractions
30-6 #175 - 485, 692 not yet columned
30-7 #176 - 485, 692 columned, unsuccessful
30-8 #178 509 565 from reaction mixture, not crude product
48-1 #180 313, 743, 777, 1133 692, 975 from reaction mixture, not crude product