KBS43-1 - Nosyl protection of 1,6-diaminohexane

[KlementineJBS]

Link to HIRAC and master page.

KBS43 - Nosyl protection of linear diamine .docx

Rationale

Nosyl is an electron deficient PG and will help to stabilise the N- required during the alkylation reaction. Alternatiavely, a nosyl-protected amine could participate in the Fukuyama-Mitsunobu reaction.

Reaction scheme

Outcome

92.6 mg, 11%

Incorrectly calculated amount of NEt3 required. Human error likely led to loss of product (solubility issues).

[KlementineJBS]

1. Added 1,6-diaminohexane (215.3 mg, 1.85 mmol, 0.6 equiv.) and triethylamine (1.25 mL, 8.97 mmol, 3 equiv.) to a vial
2. Added DCM (4 mL)
3. Added nosyl chloride (661.1 mg, 2.99 mmol). Some bubbling and colour change.
4. Stirred for ~ 2.5 hours. Reaction was a pale green with lots of precipitate.

First TLC is 20% EtOAc in hexanes, second and third are in 1:9:90 NH4:MeOH:DCM

First TLC was at 15 minutes reaction time. Second at ~45 minutes. Third right before workup.

5. Added sat. ammonium chloride solution to remove triethylamine.
6. Extracted with DCM (3 x 25 mL) and washed with water (2 x 50 mL) and brine (25 mL). Resulting organic extracts were very cloudy.
7. Rotovapped off solvent, diluted with water and worked up with ethyl acetate instead (3 x 30 mL)
8. Brine washed (25 mL)
9. Added mag sulphate and filtered

[KlementineJBS]

LRMS

Crude reaction mixture. Peaks at 487.11 [M+H]+, 509.05 [M+Na]+, 485.11 [M-H]- indicate presence of doubly substituted product.

KBS43-1 RM.pdf KBS43-1 RM.d.zip

[KlementineJBS]

Empty vial: 15.6565 full vial: 15.7491 Mass: 92.6 mg (0.19 mmol, 11%)

[KlementineJBS]

LRMS

Crude product after workup. Peaks at 509.05 [M+Na]+, 485.11 [M-H]- indicate presence of doubly substituted product. Unsure why the 486+ peak is no longer present and unsure whether the peaks at 525+ and 521- are meaningful.

KBS43-1 cr.pdf KBS43-1 cr.d.zip

[KlementineJBS]

H NMR

Appears to be product but a little difficult to determine exact peaks.

1H NMR (300 MHz, Chloroform-d) δ 8.12 – 7.98 (m, 2H), 7.85 – 7.75 (m, 2H), 7.74 – 7.64 (m, 4H), 5.16 (s, 2H), 3.00 (q, J = 6.7 Hz, 4H), 1.20 (q, J = 6.9 Hz, 6H).

Peaks at 1.17 - 1.24 (8H) and 3.00 (4H) are probably amine chain. Theoretically the aromatic peaks should show up as 4 x 2H peaks but seem to be 2 x 2H and 1 x 4H instead.

KBS43-1 cr_1.zip KBS43-1 cr.pdf

[KlementineJBS]

Column details

Decided to column to get purer samples.

Fractions	Mass	Compound	NMR
1-2	12 mg	Uncertain	KBS43-1 F1-2_1.zip
3-5	22 mg	Product, messy	KBS43-1 F3-5_1.zip

KBS43-1 column.pdf

F1-2 is very clean but not product. Could be nosyl chloride but NMR doesn't quite match literature, which generally reports 3H as a multiplet from 7.8 - 8.0. (Here, there are two distinct peaks below 7.80 with a total integral of 3.)

F1-2

[KlementineJBS]

LRMS

LRMS of F1-2 has not shed much light.

KBS43-1 F1-2.d.zip KBS43-1 F1-2.pdf