KBS35-1 - Formation of propanoate intermediate

[KlementineJBS]

Link to HIRAC.

Reaction scheme

Outcome

148.9, 27%

[KlementineJBS]

Changing plan for reduction - instead of lith-al, will try this two-step reduction via the ethyl acetate product. (Lith-al risks overreduction to secondary alcohol).

See lit references 1, 2 and 3.

Ref 3 uses absolute benzene so probably not ideal. Ref 1 and 2 both use potassium tert-butoxide and do a two-step synthesis, isolating the intermediate. Ref 1 has higher yield for first step (98%), ref 2 has higher yield for second step (70%).

[KlementineJBS]

1. Dissolved KBS34 (#112 ) (431.2 mg, 2.30 mmol) in ethyl acetate (10 mL)
2. Added KOtBu (337 mg, 3 mmol, 1.3 equiv.)
3. Stirred at rt for 20 minutes - reaction was fluoro yellow with lots of solid.

TLC indicated SM was consumed but two products had formed.

30% ethyl acetate in hexane

4. Quenched with water (~ 10 mL)
5. Extracted with ethyl acetate (50 mL) - had to add lots of water, ~90 mL, to get fluoro yellow solid to dissolve.
6. Extracted with ethyl acetate (2 x 25 mL)
7. Washed with brine (20 mL)
8. Dried on mag sulphate and rotovapped down

Vial: 15.8618 Full vial: 16.2334 Mass: 371.6 mg (1.53 mmol, 66%)

[KlementineJBS]

LRMS

Evidence of desired product: 266.15 [M+Na]+, 242.05 [M-H]-, 507.20 [2M - 2H + Na]-.

Other peaks: 224.13 (+), 425.11 (+), 427.12 (+), 354.13 (-).

KBS35-1.pdf KBS35-1.d.zip

[KlementineJBS]

NMR

H NMR indicates that product has formed in reasonable quantity, but some impurity is present - integrals don't quite make sense and some extra peaks are present.

Peaks at 4.34, 4.22, 1.22 indicate ethyl acetate/propanoate portion of molecule.

Problem peaks include: 6.54 (minimal), 4.56, 3.43, 1.49

KBS35-1 crude.pdf KBS35-1_1.zip

[KlementineJBS]

Column

Fractions

Code	Fractions	Vial tare	Mass (mg)	Identity	Yield
A	9 - 16	15.6596	148.9	product	27%
B	16 - 23	15.8320	71.6	product/messy	13%
C	24 - 32	16.1312	155.9	unknown	-

[KlementineJBS]

LRMS

F9: evidence of product - 244.14 [M+H]+, 266.12 [M+Na]+, 509.05 [2M + Na]+.

F25: unknown compound believed to have mass of 201 - 202.14 [M+H]+, 224.13 [M+Na]+, 425.10 [2M + Na]+.

KBS25-1 F9.d.zip KBS35-1 F25.pdf KBS35-1 F9.pdf

[KlementineJBS]

H NMR

NMR results are interesting.

A and B have peaks at 8.31, 8.28 and 8.19, 8.16, 8.13 while C has 3 peaks at 8.37, 8.33, 8.30 and 8.21, 8.18.

A and B have the same singlet at 4.36 and quartet at 4.20. C lacks these and instead has a quartet at 4.57.

A and B have two singlets at 3.44 and 3.75 but they are much larger in B - solvent impurity? C lacks these.

All have singlet at 2.27. C has a triplet at 1.50.

KBS35-1 A_1.zip KBS35-1 B_1.zip KBS35-1 C_1.zip KBS35-1 column.pdf

[KlementineJBS]

20230728_BS5-3.pdf 20230728_BS5-3.d.zip