KBS30-4 - N-alkylation with KBS29

[KlementineJBS]

Link to HIRAC and master page.

Previous attempt is #149

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

Notes

Re-attempting alkylation on mono-alkylated product. Done in dry conditions this time.

Reaction scheme

[KlementineJBS]

7.12.23

1. added K2CO3 (62.5 mg, 0.452 mmol, 1.5 equiv.) to a flask on ice and backfilled with N2 x 3
2. Added mono-alkylated amine (202.4 mg, 0.292 mmol) dissolved in dry DMF (3 mL)
3. Added KBS29 (107 mg, 0.373 mmol, 1.3 equiv.) dissolved dry DMF (2 mL)
4. Left stirring on ice from 2.35 pm

[KlementineJBS]

First TLC'd after ~ 1 hour. Did a TLC with all starting materials to determine nature of spots (SM = mono alkylated product, 43 = nosylated amine, 29 = brominated pendant).

Pendant group is clearly still present, with no sign of hydrolysis this time. Not sure why SM has two spots.

[KlementineJBS]

Another TLC at 11.30 am the next day suggested that the pendant group was consumed (although this was added in excess), but amine SM remained. LRMS was employed to investigate.

[KlementineJBS]

LRMS

At least some of the mono-alkylated SM is present (692.24, [M-H]-). Unsure what the large peak at 939.26+ represents.

KBS30-4 RM.pdf
KBS30-4 RM.d.zip

[KlementineJBS]

08.12.23

Quenched with 20 mL ammonium chloride and put in fridge over the weekend.

[KlementineJBS]

12.12.23

Crystals/salt had formed in fridge over weekend. Worked up with ethyl acetate (3 x 25 mL) and brine wash. Possibly some material was left in the sep funnel.

Too much DMF to read NMR, so washed with water x 5 and brine x 1. Doesn't actually dissolve well in ethyl acetate - toluene is better but not great, DCM works quite well.

vial: 15.7538
mass: 252.9 mg (0.281 mmol assuming complete conversion, 96%)

[KlementineJBS]

Column details

Fractions	Vial mass (g)	Mass obtained (mg)	Identity/notes
8-9	15.9410	-	too little to characterise
10	15.7455	3	contains SM/mono
11-16	15.6697	161.4	contains SM, mono, bis
17-18	15.5883	9.8	contains mono
19-20	15.7448	3	contains bis
21-36	15.7191	39.6	doesn't seem to contain SM, mono or bis

[KlementineJBS]

LRMS

Signs of bis product (as well as mono and SM) in F11-16.

Positive: 923.25 is bis product [M+Na]+, 716.14 is mono product [M+Na]+. Negative: 485.04 is SM [M-H]-, 692.17 is mono [M-H]-, unsure about 975.23.

No sign of product or SM in F21-36 - peaks at 413.29+, 623.38+, 1023.79+, 1123+.

KBS30-4 F11-16.pdf
KBS30-4 F21-36.pdf
KBS30-4 F11-16.d.zip

This is interesting as it suggests that the 939+ peak previously seen in the crude sample was indeed indicative of bis-product having formed.

[KlementineJBS]

H NMR

KBS30-4 column fractions.pdf

KBS30-4 F10_1.zip
KBS30-4 F17-18_1.zip
KBS30-4 F19-20_1.zip
KBS30-4 F11-16_1.zip
KBS30-4 F21-36_1.zip

[KlementineJBS]

Need to recolumn F10-18 and try to achieve better separation. Consider alumina.

[KlementineJBS]

01.02.24

Tried another column using ethyl acetate/hexane with 0.1% triethlyamine.

H NMR

Only fractions 86+ contained product and this was still a mixture of mono and bis.

KBS30-4b fractions.pdf

KBS30-4b F44-68_1.zip
KBS30-4b F4-42_1.zip
KBS30-4b F71-85_1.zip
KBS30-4b F86+_1.zip

[KlementineJBS]

19.02.24

fractions 8+

vial tare: 15.6570
vial full: 15.8538
mass: 196.8 mg (0.218 mmol, 75%)