KBS4-6 - Screening of allylation of 1,6-diaminohexane

[KlementineJBS]

Allylation of boc-protected 1,6-hexadiamine

Link to HIRAC and original method

Outcome

Reaction Scheme

Method

Characterisation

NMR

Mass spec

[KlementineJBS]

To consider

[KlementineJBS]

17.06.21

Entry	NaH (mg)	Solvent (8 mL)	KBS3 (mg)
A	170	manually dried DMF	104
B	168	PureSolv DMF	90
C	170	PureSolv MeCN	99

• added NaH under positive nitrogen pressure to evacuated flask
• solution transfer of KBS3
• added allyl bromide (0.4 mL each) after just 20 minutes activation time
• left at 4.45 pm

[KlementineJBS]

18.06.21

TLC'd at 11.45 am (EtOAC:hexane = 20:80)

added extra allyl bromide (0.2 mL each) at 3pm

[KlementineJBS]

21.06.21

• added extra NaH (A = 89.5 mg, B = 92.3 mg, C = 114.4 mg) and allyl bromide (0.2 mL each) at 12 pm
• TLC'd at 4 pm

[KlementineJBS]

22.06.21

• TLC'd and decided to work up

• added 10 mL ammonium chloride to each
• extraction: 3 x 20 mL ethyl acetate, 40 mL brine wash, MgSO4 drying and rotvapped
• crude NMRs:

KBS4-6 A-C cr.pdf

[KlementineJBS]

09.07.21

• Columned A (dissolved in hexane w tiny bit of DCM)

[KlementineJBS]

15.07.21

• divided fractions into 5 parts and rotvapped those with a single spot

• F9-10 = top spot (15.9 mg)

• F13 = middle spot ( weight unknown)

• F16 = bottom spot (10.2 mg)

• NMR suggests F9-10 is desired product

• mass spec suggests desired product in F9-10, mixed/mono-allylated product in F13

KBS4-6 A F9-10.pdf (419 = [M+Na], 815 =[2M+Na])

KBS4-6 A F13.pdf (356 = [M+H], 735 = [2M+Na])

Taking F9-10 as product, yield = 16 mg = 12.3%

[KlementineJBS]

19.07.21

• Columned B (dry-loaded) and divided fractions into 4 parts

NMR: KBS4-6 B all fractions.pdf

• F13 = top spot + middle spot (8 mg) -- NMR suggests no product
• F14-16 = middle spot (19 mg) -- NMR suggests product
• F17-18 = middle + bottom spots (15 mg) -- NMR suggests mono-product
• F19-20 = bottom spot (31 mg) -- NMR suggests mono product

Mass spec

KBS4-6 B F13.pdf no desired peaks apparent

KBS4-6 B F14-16.pdf 419, 815 - suggests product

KBS4-6 B F17-18 (product simulation).pdf 396, 735 - suggests mixture

KBS4-6 B F19-20.pdf 356, 735 - suggests mono product only

Taking F14-16 as product, yield = 17%

[KlementineJBS]

KBS4-6 B F13.pdf KBS4-6 B F14-16.pdf KBS4-6 B F17-18 (product simulation).pdf KBS4-6 B F19-20.pdf KBS4-6 A F9-10.pdf KBS4-6 A F13.pdf

[abrennan5]

Hi! I've been a semi-regular contributor to the OSM project recently and spotted this tweet https://twitter.com/Inorganick_/status/1450652400168046594

A couple of hopefully helpful tips, firstly I really wouldn't recommend heating NaH in DMF, it still gets done fairly regularly but fundamentally isn't safe. https://cen.acs.org/safety/lab-safety/Chemists-continue-forget-safety-concerns-about-sodium-hydride/97/web/2019/08

I've had success in the past with Fukuyama amine synthesis. The protecting group goes on nicely and is super cheap, the resulting sulphonamide is way easier to deprotonate (pot carb) and is even amenable to Mistonobu reactions. Slight downside is the use of a thiol (usually thioglycolic acid) to remove the protecting group. https://en.chem-station.com/reactions-2/2014/03/fukuyama-amine-synthesis.html

Edit: You also get a cracking chromophore from the nitroarene!

Good luck! Alfie