KBS22-1 - Linear click coupling of bis-propargyl diaminohexane and azidoadamantane

[KlementineJBS]

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

KBS22 Linear amine click coupling with azidoadamantane.docx

Reaction scheme

Outcome

256 mg (0.343 mmol), 109%

[KlementineJBS]

KBS17 (122.9 mg, 0.313 mmol) needs 0.72 mmol azidoadamantane (127.6 mg)

Copper: 0.0626 mmol = 15.6 mg Sodium ascorbate: 0.1565 mmol = 31.0 mg

1. Added azidoadamantane, copper sulfate and sodium ascorbate to RBF.
2. Evacuated and filled with nitrogen (x 3)
3. Added KBS17 (#22) - 122.9 mg, 0.313 mmol - via solution transfer with sparged THF (6 mL)
4. Added sparged water (5 mL)
5. Left stirring from Monday afternoon until Thursday afternoon - probably unnecessarily long but delayed by strike action

Tuesday morning

[KlementineJBS]

18.08.22

TLC indicated completion - azide didn't show up well but has an Rf just slightly lower than the RM spot.

BP = bis-propargyl amine, RM = reaction mixture, AA = azidoadamantane. Unmarked spots are cospots of the two adjacent compounds. Run in 4.5% MeOH : 0.5% NH4 : 95% DCM.

6. Added ammonium chloride solution (Sat., 5 mL)
7. Extracted with DCM (3 x 10 mL)
8. Washed with brine (~15 mL)
9. Dried over MgSO4 and rotovapped

Empty vial: 16.1107 Full vial: 16.3665 Mass: 255.8

[KlementineJBS]

22.08.22

LRMS

Peaks at 747.54 [M+H], 769.51 [M+Na].

KBS22-1 cr.d.zip KBS22-1 cr.pdf

H NMR

KBS22-1 cr_1.zip KBS22-1 cr processed.pdf

[KlementineJBS]

07.09.22

Needed to column crude product - ran TLC's to determine solvent system.

Fractions	Empty vial	Full vial	Mass (mg)	Moles	%	Product
2	-	-	-	-	-	Unseparated crude product
3-4	15.8771	15.8912	14.1	0.0189	6	Product
5-10	15.9034	15.9518	48.4	0.0648	21	Product

H NMR

KBS22-2 F5+_1.zip KBS22-2 F3-4_1.zip KBS22-1 F3-10 processed.pdf

[KlementineJBS]

08.09.22

Recolumned but had same issue - compound shot straight through column.

Kept fractions and 5 and 6 and decided to column a third time with ethyl acetate and hexane. Solvent system of 20 - 40% ethyl acetate was determined upon by TLC.

[KlementineJBS]

09.09.22

[KlementineJBS]

12.09.22

TLC'd fractions again after the weekend.

Believed bottom spot to be product, so only isolated select fractions.

Fractions	Empty vial	Full vial	Mass (mg)	Moles	%	Species
3	15.8309	15.8374	6.5	-	-	Azidoadamantane
1,2,4-6, 11-17	15.8090	15.8732	64.2	-	-	Mixture
18-19	15.7425	15.7447	2.2	-	-	Unknown
20-25	15.5487	15.5607	12	0.016	5	Presumed product, unclean
Column flush	15.7096	15.8169	107.3	0.144	46	Presumed product

H NMR

KBS22-1 C3 F20-25_1.zip KBS22-1 C3 flush_1.zip KBS22-1 C3 F3_1.zip

KBS22-1 C3 F3, F20-25, flush processed.pdf

TLC showing pooled fractions on left and flush on right, eluent = 30/70 ethyl acetate/hexanes, flush Rf = 0.24

[KlementineJBS]

14.09.22

LRMS

KBS22-1 C3 pooled fractions.d.zip KBS22-1 C3 pooled fractions.pdf

Peaks at 429.36, 445.36, 543.42

KBS22-1 C3 flush.d.zip KBS22-1 C3 flush.pdf

Peaks at 747.56 [M+H]+, 769.53 [M+Na]+

[KlementineJBS]

15.09.22

Did a hexane wash (3 x 2 mL spectroscopic grade hexane) of 22-1 and hi-vacced overnight. Some solvent (ethyl acetate, hexane?) or potentially grease remaining - will repeat hexane wash and hi-vac again.

KBS22-1 C3 flush 15-09-22_1.zip KBS22-1 C3 flush 15-09-22 processed.pdf

Spectrum looks very promising otherwise - almost perfect match to MestreNova predictions.

[KlementineJBS]

26.09.22

Attempted ether wash but ether dissolved product - removed by rotary evaporation and put on hi vac overnight. This time, upon being put on hi vac, the product foamed up pleasingly.

Empty vial: 15.7096 Full vial: _need to measure_

[KlementineJBS]

IR

KBS22-1 04-11-22.pdf KBS22-1.zip

[KlementineJBS]

H and C NMR, 500 MHz

20221108_KBS22-1 real_2 (1).zip 20221108_KBS22-1 real_1 (1).zip

KBS22-1 09-11-22.pdf

13C NMR (126 MHz, CDCl3) δ 79.59, 59.43, 43.00, 35.93, 29.46, 28.53, 26.59. 1H NMR (500 MHz, CDCl3) δ 7.43 - 7.57 (2H), 4.44 (4H), 3.21 (4H), 2.24 (6H), 2.20 (12H), 1.77 (unknown- 12H?), 1.48 (4H), 1.44 (18H), 1.22 (4H).

[KlementineJBS]

HRMS

Hi Res ESI OK [M+Na] found error = 1.19 ppm

20221111_Service_HiRes_ESI_000011_2.pdf 20221111_Service_HiRes_ESI_000011.pdf