KBS28-1 - Click coupling of 1-azido-naphthyl and propargyl alcohol

[KlementineJBS]

Link to HIRAC and [master page](KBS28-1 - Click coupling of 1-azido-naphthyl and propargyl alcohol). Original method can be found in J. Batten's PhD thesis (2022).

Reaction scheme

Outcome

115.1 mg (0.511 mmol, 46%)

Significant amount of unreacted azide was recovered - possibly need to react for longer/heat. Need to keep azide SM aside for TLC.

Jamie notes on p 87 that higher temps + longer reaction times are needed for the naphthyl pendant than the naphthalimide. Need to use GSP 7.3.1 ii - this involves heating the reaction to 50 C overnight (instead of rt for 1 hr).

[KlementineJBS]

12.01.23

1. Added sodium ascorbate (113 mg, 0.570 mmol, 0.5 equiv.) and copper sulfate pentahydrate (56 mg, 0.224 mmol, 0.2 equiv.) to a 2 neck flask
2. Evacuated and backfilled with N2 x 5
3. Added 1-azido-naphthyl (186.6 mg, 1.10 mmol) dissolved in sparged THF (4 mL)
4. Added sparged distilled water (1.3 mL)

5. Added propargyl alcohol (0.65 mL, 11.3 mmol, 10.2 equiv.)
6. Left stirring from 1.50 pm
7. Added extra sodium ascorbate (78 mg) at 3.40 pm

[KlementineJBS]

13.01.23

8. Quenched with sodium hydrogen carbonate (~ 7 mL)
9. Extracted with DCM (4 x 10 mL)
10. Washed with water (40 mL) and brine (40 mL)
11. Dried over mag sulphate and filtered
12. Rotovapped down

Vial: 15.9535 Full vial: 16.1794 Mass: 222.9 mg

H NMR

NMR of crude product is inconclusive, will column and try again.

KBS28-1 cr_1.zip KBS28-1 cr.pdf

Will likely require APCI for mass spec.

[KlementineJBS]

17.01.23

Columned crude product twice.

Letter	Fractions	Empty vial weight	Mass	Assignment
A	7-14	15.6905	42.2	Azide SM
B	16-20	-	-	nil
C	21-22	-	-	nil
D	23-24	-	-	nil

Only real product was unreacted azide which was recovered as a yellow liquid.

H NMR

KBS28-1 column 1 fractions A - D.pdf

KBS28-1 B_1.zip KBS28-1 C_1.zip KBS28-1 D_1.zip KBS28-1 A_1.zip

Letter	Fractions	Empty vial weight	Mass (mg)	Assignment
2A	3	15.7407	-	-
2B	4-5	-	-	nil
2C	6-11	15.9327	10.5	nil
2D	14-19	15.6696	14.7	nil
2E	21-26	-	-	nil

Nothing meaningful recovered.

H NMR

KBS28-1 column 2 fractions 2C, 2D.pdf

KBD28-1 2D_1.zip KBD28-1 2C_1.zip

TLC information

10% ethyl acetate in hexane, PMA stain

Top spot (fractions 7 - 10) were unreacted azide but all other spots were nothing.

[KlementineJBS]

19.01.23

Did one final column as no product had been recovered.

Went off UV response rather than TLCing exhaustively. Fractions 18+ showed nothing but solvent by NMR, but 3A (fractions 6-10) appeared to contain product. Fractions 2-5 and 11-13 were also collected and pooled (titled "2-13" although they do not include 6-10).

H NMR

KBS28-1 3 2-13_1.zip KBS28-1 3A_1.zip

KBS28-1 column 2 fractions 2-13.pdf

Empty vial: 15.7860 Full vial: 15.9011 Mass: 115.1 mg (0.511 mmol, 46%)

Conclusions

Need to confirm characterisation by IR, mass spec before continuing.

[KlementineJBS]

FTIR

KBS28-1.pdf KBS28-1.zip

LRMS (ESI)

KBS28-1.d.zip KBS28-1.pdf

Somewhat messy but molecule is evident - 226.13 [M+H]+ and 248.11 [M+Na]+. May not ionise well.

[KlementineJBS]

HRMS

20230124_Service_HiRes_ESI__000007.pdf 20230124_Service_HiRes_ESI__000007_full.pdf

high res pos ESI, found [M+Na]+, error = 0.93 ppm