KBS51-1 - Mitsunobu reaction with KBS28 and KBS50

[KlementineJBS]

Link to HIRAC and master page #174.

HIRAC KBS48 Mitsunobu reaction on linear amines.docx

Reaction scheme

Outcome

Mass purified: 183.2 mg (0.166 mmol = 42% yield)

[KlementineJBS]

1. Added KBS50 (269.9 mg, 0.393 mmol), KBS28 (211.4 mg, 0.939 mmol, 2.4 equiv.) and PPh3 (310.4 mg, 1.18 mmol, 3 equiv.)
2. Backfilled and evacuated x 5
3. Added dry THF (5 mL)
4. Cooled to 0 C
5. Added DIAD (0.23 mL) at 3.10 pm

[KlementineJBS]

LRMS of RM

Evidence of mono-alkylated product at 892.17- from [M-H]- but no clear evidence of bis product. Confounded by large amounts of triphenylphosphine oxide adducts. Little sign of SM, which is good.

Unsure about 1133.70 (3+) peak - this is ~33 off the desired product mass (could be some sort of alcohol adduct?) - and 1145.26- peak which is 44 off.

KBS51-1 RM.d.zip KBS51-1 RM.pdf

[KlementineJBS]

11.04.24

Worked up as usual - removed solvent, triturated with cold ether (5 x 2-3 mL) and rotovapped down again. NMR suggests that material is mainly desired product, with the usual DIAD/hydrazine byproducts.

vial: 15.7942 mass: 977.6 mg (0.888 mmol, far more than possible)

[KlementineJBS]

Column conditions

**

Fractions	Tare vial (g)	Mass (mg)	Substances
1-4
5-15	15.5329	432.8	bis product, hydrazine
16-31	15.9906	211.4	bis product, hydrazine
32-40	15.7869	44.2	unsure - something aromatic
41-50	15.6560	72.7	aromatic
51-68	15.6459	92.5	aromatic, KBS28

[KlementineJBS]

H NMR

Fractions 5-15 were the cleanest, containing mostly bis compound and DIAD hydrazine. Fractions 51-68 contained recognisable starting material KBS28. 32-50 appears to be PPh3O (confirmed by TLC).

nmr300_20240416_KBS51-1 F41-50_1.zip nmr300_20240416_KBS51-1 F5-15_1.zip nmr300_20240415_KBS51-1 F16-31_1.zip nmr300_20240415_KBS51-1 F32-40_1.zip nmr300_20240416_KBS51-1 F51-68_1.zip

[KlementineJBS]

Column b

Only fractions 5-15 used as TLC indicated fewer spots in this. Solvent chosen was 5% acetone in DCM.

Column

Results

Fractions	Tare vial (g)	Mass (mg)	Substances
2-14	15.8674	12.9	bis/maybe mono, DIAD
15-36	15.6159	215.3	bis, DIAD
37-89	15.7202	183.2	bis, minimal DIAD

Note: 183.2 mg = 0.166 mmol = 42% yield

[KlementineJBS]

H NMR

KBS51-1b fractions.pdf

nmr300_20240417_KBS51-1b F2-14_1.zip nmr300_20240417_KBS51-1b F15-36_1.zip nmr300_20240416_KBS51-1b F37-89_1.zip

[KlementineJBS]

LRMS

Evidence of product at 1123.28+ [M+Na]+, with a seemingly related peak at 1233.21+ (unknown).

In negative mode, evidence at 1135.27- [M+Cl]-, again with a seemingly related peak at 1175.22- .

KBS51-1b F37-89.d.zip KBS51-1b F37-89.pdf

[KlementineJBS]

Column d

Needed more material so pooled column a, F16-31 and column b, F15-36 to get ~400 mg crude material. Used Lau group isolera so report is slightly different but used a gradient of 2.5% - 10% acetone in DCM.

Total mass recovered was ~ 376 mg.

Fractions	Vial	Mass	Substance
B1-21	15.7939	130.3	bis, lots of DIAD hydrazine
B22-34	15.6957	83.6	bis, some hydrazine (more than below)
A1-20	15.9347	139.8	bis, some hydrazine
A21-30	15.9075	22.5	bis and mono, some hydrazine

[KlementineJBS]

H NMR

KBS51-1d fractions.pdf

nmr300_20240508_KBS51-1d B22-34_1.zip NEO500-20240508-17_KBS51-1d A21-30_1.zip NEO500-20240508-16_KBS51-1d B1-21_1.zip nmr300_20240507_KBS51-1d A1-20_1.zip