KBS49-1 - Mitsunobu reaction with KBS28 and KBS45

[KlementineJBS]

Link to HIRAC and master page #174.

HIRAC KBS48 Mitsunobu reaction on linear amines.docx

Reaction scheme

Outcome

272.6 mg (0.294 mmol, well over 100%)

[KlementineJBS]

12.02.24

1. Added amine KBS45 (95.3 mg, 0.185 mmol) and PPh3 (169.5 mg, 3.5 equiv.) to a dry flask.
2. Backfilled + evacuated with N2 x 5
3. Added KBS28 (106.8 mg, 0.474 mmol, 2.6 equiv.) dissolved in dry THF (4 mL)
4. Cooled to 0 C
5. Added DIAD (0.125 mL, 3.5 equiv.) and stirred from 3 pm

TLC'd at end of day (left) + at midday the next day (right).

Eluent is 95:4.5:0.5 DCM:MeOH:NH4OH

Left solvent to evaporate overnight.

14.02.24

Triturated with ether (5 x 3 mL) to remove excess PPh3O, then rotovapped down to give crude product as a sticky brown solid that foamed up while rotovapping.

Vial tare: 15.6752 Vial full: 15.9478 Mass: 272.6 mg (0.294 mmol, well over 100%)

[KlementineJBS]

LRMS

Evidence of bis product, 951.31 [M+Na]+, and no sign of mono product (might expect 720 - or 722 +). Also evidence of SM amine, 513.11- [M-H]-.

Lots of PPh3O dimers etc - 279.15 [M+H]+, 579.14 [2M+Na]+, 856.83 (3+) and 1133.67 (4+) also likely to be some kind of adduct of PPh3O.

KBS49-1 cr.pdf KBS49-1 cr.d.zip

[KlementineJBS]

H NMR

Looks reasonably clean and approximately matches predicted spectrum for bis comopund. (One extra peak as compared with KBS48-1.) Likely needs some purification before further reaction but a good start!

KBS49-1 cr_1.zip KBS49-1 cr.pdf

[KlementineJBS]

Column

Used 2.5% of the MeOH/NH4OH mixture in DCM.

Fractions	Tare (g)	Mass (mg)	Substance
1-6	15.8674	3.4	unclear, maybe mono
7	15.9515	27 mg	clean bis product
8-10	15.9918	200.1	bis product, some DIAD but otherwise clean
11-17	16.0759	12.8	bis product, DIAD - messy
18-28	16.1153	7.1	as above

see also MS table on #174

[KlementineJBS]

H NMR

F8-10 actually looks a lot cleaner than F11-17. Will have to inspect F7 as well.

nmr300_20240220_KBS49-1 F11-17_1.zip nmr300_20240220_KBS49-1 F8-10_1.zip nmr300_20240220_KBS49-1 F7_1.zip nmr300_20240221_KBS49-1 F1-6_1.zip nmr300_20240221_KBS49-1 F18-28_1.zip

KBS49-1 column.pdf

[KlementineJBS]

LRMS of fractions

As predicted: F7 contains evidence of product (951+) but no PPh3O, while F8-10 contains both. F7 also contains 313+, unsure what this is as yet but doesn't seem to be a common contaminant.

KBS49-1 F8-10.d.zip KBS49-1 F7.pdf KBS49-1 F8-10.pdf

[KlementineJBS]

22.02.24

Did another column on fractions 8-18 to try and remove excess DIAD, starting with straight DCM this time.

Fractions	Tare (g)	Mass (mg)	Substance
6	15.8329	46.5	bis, some DIAD still
7	15.9315	138.4
8-14	15.6315	30.0

[KlementineJBS]

H NMR

DIAD seems to come off nicely in the 100% DCM - but still have 3 spots in the fractions that seem "clean" by NMR. Assume at least one is PPh3O but then what is the other?

KBS49-1 column c.pdf

nmr300_20240222_KBS49-1c F8-18_1.zip nmr300_20240222_KBS49-1c F7_1.zip nmr300_20240221_KBS49-1 F1-6_1.zip

[KlementineJBS]

23.02.24

Tried an HCl wash (1 M, 3 x 3 mL) with product dissolved in DCM to remove excess DIAD - tried with 49-1c F7 but didn't really make any difference by NMR.

nmr300_20240223_KBS49-1c F7 wash_1.zip