KBS24-1 - Click coupling of bis-propargyl diaminohexane and azidomethylferrocene

[KlementineJBS]

Link to HIRAC, original method and [master page].

KBS24 Linear amine click coupling with azidomethylferrocene.docx

Reaction scheme

Outcome

62.1 mg (0.071 mmol), 70%

[KlementineJBS]

Amounts:

• 40 mg (0.102 mmol) linear amine
• need 2.3 equiv. azidomethylferrocene = 0.234 mmol = 56.5 mg
• reduce solvent to 2 mL each water/THF
• need 0.2 equiv. copper sulphate = 0.0204 mmol = 5.1 mg
• need 0.5 equiv. NaAsc = 0.051 mmol = 10.1 mg

Checked azide was OK before using - see NMRs.

KBS16-4 25-10-22_1.zip
KBS16-4 25-10-22 processed.pdf

[KlementineJBS]

25.10.22

Sparged water and THF.

Added copper sulfate pentahydrate (10.0 mg) and sodium ascorbate (23.2 mg) to flask, evacuated and backfilled with N2 three times. Added sparged water (2 mL).

Added azidomethylferrocene (58.2 mg, 0.241 mmol, 2.3 equiv.) and bis-propargyl diaminohexane (42 mg, 0.107 mmol), each dissolved in 1 mL sparged THF.

Initially the reaction mixture settled into two layers - mostly green with a ring of orange on top. Adding 1 mL water increased the amount of green, adding 3 mL THF reduced the ring of orange. Left stirring from 6pm.

[KlementineJBS]

26.10.22

TLC'd at 12 pm. Appears to show that while starting material is consumed, there is a mixture of mono and bis click products.

SM = azidomethylferrocene
solvent = 95:4.5:0.5 DCM:methanol:NH4OH

LRMS

KBS24-1 RM 26-10-22.pdf
KBS24-1 RM 26-10-22.d.zip

Peaks indicate formation of mono click product (656.30, [M+Na]) and bis click product (897.34, [M+Na]). Small amounts of boc-protected amine and bis propargyl amine present (339, 415). Unsure about 495, 510, 41, 822, 1021 peaks.

Worked up at 4.30 pm - removed THF by rotary evaporation, extracted with DCM (4 x 5 mL) and washed with brine (20 mL). Left in conical over long weekend.

[KlementineJBS]

26.10.22

At 2.30 pm, added more sodium ascorbate (28.7 mg) as the green colour of reaction indicated oxidation of copper. Green colour gradually lessened.

[KlementineJBS]

31.10.22

Dried over MgSO4 and rotovapped down.

Empty vial: 15.7889
Full vial: 15.9281
Mass: 139.2 mg

LRMS

KBS24-1 cr.pdf
KBS24-1 cr.d.zip

Peak at 897.32 [M+H]. Unsure what peaks at 959.45, 981.42 and 1021.33 represent - 1021 was also seen in reaction mixture earlier, but other two were not.

H NMR

KBS24-1 cr_1.zip
KBS24-1 cr.pdf

Initial analysis indicates product has formed - boc peaks at 1.44, ferrocene peaks around 4.14 - 4.40.

[KlementineJBS]

08.11.22

Trying to find solvent system for columning.

TLCs in 2%, 3% and 5% MeOH in DCM

TLCs in 2%, 3% and 5% MeOH in DCM - MeOH contains 10% ammonium hydroxide

Determined on 0-5% then 5% using MeOH with 10% NH4OH.

[KlementineJBS]

09.11.22

Column conditions

Pooled fractions 5-7 to give a bright yellow coloured liquid. Rotovapped down.

Empty vial: 15.7074
Full vial: 15.7695
Mass: 62.1 mg

H NMR

KBS24-1 F5-7_1.zip
KBS24-1 09-11-22.pdf

1H NMR (300 MHz, CDCl3) δ 7.49 (2H), 5.25 (4H), 4.39 (4H), 4.15-4.24 (18H), 3.18 (4H), 1.53 (2H), 1.43 (4H), 1.40 (18H), 1.19 (4H).

Partial assignment (using numbers from MestreNova prediction): δ 7.49 (triazole, 11 & 17), 5.25 (methylene, 34 & 48), 4.39 (methylene, 9 & 15), 4.15-4.24 (ferrocene, varied), 3.18 (hexane), 1.53 (hexane), 1.43 (hexane), 1.40 (boc groups), 1.19 (hexane).

LRMS

KBS24-1 09-11-22.pdf
KBS24-1 09-11-22.d.zip

Peak at 897.34 [M+Na]. Can see minor peak at 655 (indicates mono click coupling product).

[KlementineJBS]

10.11.222

Isolated other fractions that had spots on TLC and NMR'd.

KBS24-1 F2-4, F8.pdf
KBS24-1 F2-4_1.zip
KBS24-1 F8_1.zip

Cannot identify compound in F2-4. F8 appears to be just solvent + impurities.

[KlementineJBS]

FTIR

KBS24-1.pdf
KBS24-1.0.zip

[KlementineJBS]

HRMS

20221130_Service_HiRes_ESI_000017-full.pdf

20221130_Service_HiRes_ESI_000017.pdf

HiRes ESI MeOH pos [M+Na]+ 0.2 ppm

[KlementineJBS]

IR

KBS24-1 04-02-2024.pdf
KBS24-1 04-02-2024 all peaks.pdf