KBS30 - master page

[KlementineJBS]

Link to HIRAC.

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

Reaction scheme

[KlementineJBS]

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]

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]

Plans

• try with 1,8-diaminooctane (KBS45 - master page  #167)
• use catalysts as mentioned in notes above
• nBuLi, cesium carbonate as bases

if returning to unprotected amine

Try different solvent/base combos.

Trying to control/limit alkylation by:

• diluting alkylating agent and adding dropwise over a long period
• keeping reaction times short
• keeping reaction temperature low

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

[KlementineJBS]

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

[KlementineJBS]

Suggestions for the new year

1. Solvent/base screen (small scale)

Base/Solvent	K2CO3	Cs2CO3	NaH
DMF	#165	#175	#169
THF	-	#176	#178

2. 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.

3. 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).

4. (Can also try making brominated KBS29 from mesylate - see KBS29 - master page  #164).

5. Try in methanol or ethanol (Lorenzo?)

[KlementineJBS]

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