KBS17-3 - Propargylation of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC, original method and master page.

Next attempt is #22.

KBS17 Generic propargylation of 1,n-diamine.docx

Reaction scheme

Molecular weights
SM = 316.44
Product = 392.54
Predicted side product (mono-propargylated) = 354.49

Outcome

Only side product recovered (175 mg, 38%).

[KlementineJBS]

##28.06.22

1. KBS3 (410 mg, 1.30 mmol) was dissolved in dry DMF (15 mL) and added to a dry flask containing NaH (445 mg, 11.1 mmol, 60% mineral oil dispersion, 8.6 equiv.) under nitrogen
2. Propargyl bromide (0.51 mL, 4.55 mmol, 80% in toluene, 3.5 equiv.) was added
3. The mixture was stirred at room temperature from 11 am. It went a black colour (from a straw-yellow colour) shortly after the propargyl bromide was added

4. TLC at 3.30 pm indicated reaction was proceeding but not yet complete

[KlementineJBS]

29.06.22

5. TLC at 10 am indicated the reaction was complete

6. Quenched with NH4Cl (sat., 25 mL)
7. Extracted with diethyl ether (4 x 40 mL). Lots of black emulsion made separation more difficult. Both aqueous layer and combined organic extracts were a red-orange colour.

8. Brine wash (115 mL)
9. Dried over MgSO4 and rotovapped down

Vial (empty) = 15.7175
Vial (full) = 16.3033
Mass = 585.8 mg

NMR

1H NMR (300 MHz, Chloroform-d) δ 4.02 (s, 4H), 3.30 (s, 4H), 2.17 (s, 2H), 1.58 (s, 4H), 1.45 (d, J = 7.2 Hz, 18H), 1.26 (s, 4H).

KBS17-3 cr_1.zip
KBS17-3 cr processed.pdf

All expected peaks are present but integrals are too large for results < 2 ppm. Potentially due to having 2 products (mono and bis) which have minimally different peaks in this zone - need to figure out what the mono product is expected to look like.

[KlementineJBS]

30.06.22

Decided to try and figure out what might be in the aqueous layer, as it was strongly coloured (reddish brown). pH was neutral (see image), so added NaOH (2.5 M) until it reached pH 11/12 (as tested by universal indicator strips) - wouldn't go higher even with addition of copious amounts of NaOH.

Extracted with ethyl acetate (2 x 80 mL) and got a straw-coloured organic extract. Dried over MgSO4 and rotovapped down.

First extraction with ethyl acetate

[KlementineJBS]

LRMS

KBS17-3.pdf
20220701_KBS17-3c.d.zip

[KlementineJBS]

15.07.22

Tried and failed to rotovap down second extraction so dissolved in toluene (~ 5 mL) and washed with water (5 x 10 mL).

Vial (empty): 15.7032 g
Vial (full): 15.7215 g
Mass: 18.3 mg

NMR

Initial NMR analysis (1H NMR, 300 MHz) indicates that coloured substance is product rather than starting material.

KBS17-3 SP_1.zip
KBS17-3 SP processed.pdf

[KlementineJBS]

20.07.22

Columned crude product with upsetting results. First column produced 4 separate spots on TLC, each of which were collected separately.

A - F 1-5 - 88 mg
B - F 6-9 - 34 mg
C - F 10-12 - 3 mg
D - F >13 - 12 mg

However, as the mass total was significantly less than the ~ 500 mg crude product, the column was washed again with another gradient. All fractions showing signs of product of any kind were collected as one "runoff" sample.

Runoff = 176 mg

NMR analysis of the samples indicated that A contained only solvent and nothing of interest. B contained something, but had no tell-tale Boc peak at 1.45 so didn't appear to be either SM or product. C was not analysed as there was too little. D contained a very small amount of material which appeared to be the same as the product seen in the Runoff sample - this material had a Boc peak and was not SM.

The Runoff sample was then analysed via mass spec. This indicated the presence of the mono-propargylated product (377.24, [M+Na]) with only a tiny peak indicating that the bis-propargylated product might be present (393.23, [M+H]).

NMR

1H NMR (300 MHz, CDCl3) δ 4.53, 4.01, 3.29, 3.13, 3.09, 2.18, 1.46, 1.43, 1.21.

KBS17-3 column fractions.pdf

KBS17-3 column fractions.zip

LRMS

20220720_KBS17-3.d.zip

KBS17-3 runoff.pdf

F3-8

Empty vial: 15.7611
Full vial: 15.7960
Mass: 34.9 mg

F9-24

Empty vial: 15.8789
Full vial: 15.8911
Mass: 12.2 mg

[KlementineJBS]

20.07.22

Ran off remainder of column (30 -100% ethyl acetate in hexane over 12 CV).

F3-8

Empty vial: 15.7611
Full vial: 15.7960
Mass: 34.9 mg

F9-24

Empty vial: 15.8789
Full vial: 15.8911
Mass: 12.2 mg

[KlementineJBS]

25.07.22

Ultimately only one product was isolated. This was identified as the mono-propargylated side product rather than the bis-propargylated product. It was recovered in a yield of 38% (175 mg, 0.494 mmol).

This side product was carried on into #23.