KBS17-7 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Last attempt is #28

Next attempt is #33

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction Scheme

Using 1:5 mixture of DMF:THF as solvent.

Outcome

[KlementineJBS]

14.09.22

1. Added NaH (163.9 mg, 4.01 mmol, 3.23 equiv.) to a dry 50 mL flask under nitrogen
2. Added KBS3-3 (401 mg, 1.27 mmol) by solution transfer (3 mL dry DMF + 15 mL dry THF)
3. Allowed to stir for 15 minutes at rt. Reaction was grey.

4. Added propargyl bromide (0.5 mL, 80% in toluene, 4.67 mmol, 3.6 equiv.) and left stirring from 5 pm. Reaction was pale yellow.

[KlementineJBS]

15.09.22

TLC'd reaction at 10 am. Looked much the same as yesterday.

Added more propargyl bromide (0.2 mL) at 11.30 am and TLC'd again at 3 pm against reference of double-substituted product.

LRMS indicated nothing was present in reaction mixture but SM (peak at 339 is [M+Na]+).

KBS17-7 RM 15-09-22.pdf

Decided to abandon reaction. Will quench and attempt to recover starting material.

Next attempt will follow original method more closely - add NaH portionwise (and use only 3 equiv.), allow 1-2 hrs reaction time and cool reaction to 0 C before adding propargyl bromide.

[KlementineJBS]

19.09.22

Once again didn't actually quench and recover starting material - left over the weekend instead in the vague hope something would happen, and was pleasantly surprised.

TLC indicated that some of the desired bis-product has been produced.

R = reference spot of the bis-product. Eluent = 20:80 ethyl acetate:hexanes.\

5. Slowly added 25 mL NH4Cl (sat.) and left stirring

6. Diluted with 50 mL water extra

7. Extracted with toluene (3 X 50 mL)

8. Washed with water (5 X 100 mL)

9. Washed with brine (125 mL)

10. Dried over magnesium sulfate and concentrated

Empty vial:

LRMS

KBS17-7 cr.d.zip
KBS17-7 cr.pdf

Peaks indicate SM (339.23, [M+Na]+), mono product (377.25, [M+Na]+ and desired bis product (415.26, [M+Na]+).

H NMR

Also indicates presence of both products.

KBS17-7 cr_1.zip
KBS17-7 cr processed.pdf

[KlementineJBS]

17.10.22

Columned crude product manually with ~ 11 cm silica, ~2cm diameter column.

Loaded slurry with pet. benz. and ran in ethyl acetate:pet. benz (given as % ethyl acetate).

5% - 100 mL
10% - 100 mL
20% - 200 mL
30% - 100 mL
100% - 100 mL

All run in same solvent system, 20% ethyl acetate in pet. benz.

Code	Fractions	Tare weight	Final weight	Mass	Percentage yield (see notes)
A	10-14	15.9227	15.9379	15.2	3%
B	15-18	15.7223	15.7398	17.5	4%
C	19-20	15.6540	15.6670	12.7	3%
D	21-25	15.9306	16.0197	89.1	23%
E	26-31	15.7982	15.9069	108.7	24%
F	>32	15.7357	15.8434	107.7	27%

Total recovered yield: 84% by moles

For pure samples (B, D, F) - calculated moles according to m.w.
For mixed samples (C, E) - calculated moles according to m.w. of high m.w. component

[KlementineJBS]

H NMR

A

KBS17-7 A processed.pdf
Uploading KBS17-7 A_1.zip…

No clear product, just "junk".

B

KBS17-7 B processed.pdf
KBS17-7 B_1.zip

Appears to be desired product albeit in low concentration.

C - E

As expected - C = mixed mono/bis product, D = mono product, E = mixed mono product/SM

KBS17-7 C_1.zip
KBS17-7 D_1.zip
KBS17-7 E_1.zip

KBS17-7 C-E processed.pdf

F

Perfect NMR spectrum of SM.

KBS17-7 F_1.zip
KBS17-7 F processed.pdf

[KlementineJBS]

LRMS

A

KBS17-7 A.pdf
KBS17-7 A.d.zip

B

KBS17-7 B.d.zip
KBS17-7 B.pdf

C

KBS17-7 C.pdf
KBS17-7 C.d.zip