KBS36-2 - Synthesis of 1-(5-phenylpyridin-2-yl)ethan-1-one (1 g)

[KlementineJBS]

Link to HIRAC and original method.

KBS36 - Synthesis of 1-(5-phenylpyridin-2-yl)ethan-1-one.docx

Previous attempt is #114

Reaction scheme

Need to do under nitrogen!

Outcome

[KlementineJBS]

17.08.23

1. Added the following to a 100 mL 2 neck flask: 2-acetyl-5-bromopyridine (1.0517 g, 5.26 mmol), phenylboronic acid (1.5466 g, 12.7 mmol, 2.4 equiv.), potassium carbonate (2.8897 g, 20.9 mmol, 3.98 equiv.), Pd(Ph3)4 (29.7 mg, 0.026 mmol)
2. Evacuated and backfilled flask with N2 x 5
3. Added toluene (25 mL) and water (5 mL)
4. Left stirring at 105 C from 5 pm

NOTE. equivalents are incorrect by mistake - for some reason have doubled the quantities of boronic acid and carbonate.

[KlementineJBS]

TLC indicated consumption of starting material.

NMR of reaction mixture indicated that a lot of starting material was probably present. (Peak at 2.69.)

KBS36-2 RM.pdf KBS36-2 RM_1.zip

[KlementineJBS]

TLC'd and decided to work up today. TLC was much the same as yesterday.

4. Added some extra water (~ 40 mL)
5. Extracted with ethyl acetate (3 x 60 mL)
6. Washed with brine (60 mL)
7. Dried over mag sulphate and evaporated

NOTE. First extraction was a yellow-green colour but second and third extractions were pale grey/contained some kind of inky material. Collected this in extractions and it seemed to be gone by the brine wash.

Product was a runny orange liquid that cooled into a white-orange, knobbly solid.

Vial: 15.7139 Full vial: 17.4821 Mass: 1.7862 g (9.06 mmol, 172%!) NOTE. Reaction was turned off on 18/08/23 and only turned back on around 12 pm on 19/08/23.

[KlementineJBS]

H NMR

Seems to indicate that contents of vial is almost entirely product - no real peak of SM is present. Probably need to leave on hi vac to remove excess solvent - unsure what else would account for excess mass.

KBS36-2 cr_1.zip KBS36-2 cr.pdf

[KlementineJBS]

LRMS

Peak at 219.97 [M+Na]+ confirms presence of product.

KBS36-2 cr.d.zip KBS36-2 cr.pdf

[KlementineJBS]

After hivaccing overnight, peaks have changed on NMR and mass has slightly reduced. (Vial is 17.2111, mass is 1.4972 - theoretical yield is 1.037 g)

Appears to be product mixed with leftover phenylboronic acid. Need to decide whether to column or simply pull through to next reaction. Probably due to mistake with proportions of phenylboronic acid.

KBS36-2 cr.pdf KBS36-2 dry_1.zip

[KlementineJBS]

Note: ended up passing through a silica plug which was incredibly effective at removing excess boronic acid