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Hazard and Risk Assessment:
Procedure:MNR11-8 (3.96 g, 10.63 mmol) was dissolved in EtOH (21 mL) and HCl (1M) (110 mL) and heated to reflux for 2.5 hours. The solution was allowed to cool to room temperature then cooled in an ice bath, basified with NaOH pellets (approx 8 g, pellets used to minimise volume of aqueous material) to pH 12-13 and extracted with DCM (4 x 100 mL). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give an orange crispy solid (1.008 g).
TLCReaction mixture after 2.5 hours ran in 100% EtOAc
Strings Starting material InChI=1S/C21H28N2O4/c1-26-18-10-15-8-9-23-17(16(15)11-19(18)27-2)12-22(13-20(23)24)21(25)14-6-4-3-5-7-14/h10-11,14,17H,3-9,12-13H2,1-2H3 Product InChI=1S/C14H18N2O3/c1-18-12-5-9-3-4-16-11(7-15-8-14(16)17)10(9)6-13(12)19-2/h5-6,11,15H,3-4,7-8H2,1-2H3
Synthesis of MNR11-17
Synthesis of MNR11-16
Starting material from
Preparation of the dimethoxy Ugi-intermediate (MNR8-5)
Hazard and Risk Assessment:
To a solution of MNR8-5 (4.88 g, 10.5 mmol) in toluene (35 mL) at room temperature was added methanesulfonic acid (1.47 mL, 22.58 mmol) and the mixture was refluxed for 1 hour. The reaction was allowed to cool to room temperature and was quenched with saturated sodium carbonate and extracted with EtOAc (50 mL x 3). The organic fractions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a thick orange oil.
Crude - 3.965 g, 101 %
100% EtOAc. Starting material, co=spot, reaction mixture after work up
Crude product taken on to the next step without further purification.
Hydrolysis of MNR11-18 to give MNR26-7
Synthesis of SC3-3 and SC3-4 from SC2-1.
Refer to risk/hazard assessment prepared for SC3-1 and SC3-2.
3rd October 2012
Aim: to repeat SC3-1 and SC3-2.
This experiment is a repeat of SC3-1 and SC3-2. These original products were obtained on 3/9/12 as crude yellow oils. Chromatographic separation yielded the cyclised products expected, plus additional products, as was evident in significant co-spotting observed on TLCs of the fractions. Suspected contamination of the laboratory hexane supply used for the column purification warrants repetition of the reactions. The procedure is described below.
SC2-1 (0.0996 g, 0.34 mmol) was reacted with acetyl chloride (0.05 mL, 0.61 mmol) in the presence of 2,6-lutidine (0.05 mL, 0.48 mmol) in acetonitrile (0.03 M, 13 mL), under argon gas and with stirring for 25 hr, to give SC3-3.
SC2-1 (0.0975 g, 0.33 mmol) was again reacted under the same conditions, with the addition of freshly prepared Yb(OTf)3 (0.0115 g/mL, 1.0 mL, 0.018 mmol) to give SC3-4.
Both reactions changed in hue from colourless to a transparent yellow over the first two hours. Unlike the previous experiment, there were small particles visible in the SC3-4 reaction mixture after 25 hr. This is thought to be Yb(OTf)3. Since the same concentration of Yb(OTf)3 was used in SC3-2 and SC3-4, it is possible that the freshness of the Yb(OTf)3 had an effect on how readily it dissolved in the reaction mixture.
TLC analysis confirmed that both reactions had gone to completion, however, residual lutidine was present, as was the case for SC3-1 and SC3-2.
4th October 2012
Products were extracted in ethyl acetate (10mL) and sodium hydrogen carbonate (10mL). The aqueous layer was twice more extracted in ethyl acetate (i.e. 2 x 10mL). Organic fractions were combined and the solvent was removed using rotary evaporation. Crude products were dark yellow/orange oils.
Attempted Synthesis of MNR46-5
To a solution of KAB18-2 (0.29 g, 1.39 mmol) in HPLC grade acetonitrile (14 mL) under argon at 0 °C , was added was added acetyl chloride (0.177 mL, 2.49 mmol), lutidine (0.23 mL, 1.94 mmol) and Yb(OTf)3 (0.086 g, 0.14 mmol). The reaction was then stirred at room temperature for 16 hours and then the mixture was washed saturated sodium bicarbonate solution (20 mL) and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil (0.334 g, 96%)
TLC did not look promising as it looked like mainly starting material and lutidine.
Crude NMR confirmed this.
Reaction not taken any further.
re-synthesis of MNR46 to try and get a clean sample for characterisation and HPLC analysis
To a solution of KAB22-1 (0.60 g, 2.36 mmol) in HPLC grade acetonitrile (25 mL) under argon at 0 °C , was added was added acetyl chloride (0.30 mL, 4.25 mmol), lutidine (0.38 mL, 3.30 mmol) and Yb(OTf)3 (0.146 g, 0.24 mmol). The reaction was then stirred at room temperature for 16 hours and then the mixture was washed saturated sodium bicarbonate solution (20 mL) and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The organic fractions were combined and washed with citric acid (10%) (30 mL). The organic fraction was then dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil (0.857 g, 122%)
Column using 30-40% EtOAC/Hex.
Product eluted (by TLC) between fractions 15 and 35 but to test purity of the samples early and late fractions were kept separate.
Fracs 15-20 - 0.140 g
Fracs 21-30 - 0.202 g
Fracs 31-35 - 0.018 g
Fractions 15-20 and 31-35 were immediately vac'd down and dried under high vacuum. 1H NMR of 15-20 showed clean product. 1H NMR of 31-35 was messy.
Frac 15-20 - Clean product
Frac 31-35 - messy
The remaining fractions containing product (fracs 21-30) we combined but not concentrated to complete dryness on the day of running the column due to time. Upon drying, 1H NMR showed only hydrolysis products.
This is unusual as the hydrolysis products run higher on TLC and came off before fraction 15. Also, it's exclusively mono-Ac amine where as the higher running spot contains di-Ac amine.
Monday, 2nd October 2012
TLC of the three batches of fractions spotted against MNR46-4 (still product by NMR) showed none of the 3 batches contained product any more.
running a new sample of MNR46-13 fracs 15-20 confirmed this
Using Yb(OTf)3 under catalytic conditions the reaction goes to completion in 16 hours. However, it has become clear that the product can decompose back to the relevant aldehyde and mono-Ac amine. This appears to take place in solvent but at this stage it's unclear the rate of this reverse reaction.