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5th October 2012 @ 12:39
Sc: 1-10
Synthesis of SC3-3 and SC3-4 from SC2-1.

HIRAC

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.
26th September 2012 @ 05:42
Mnr: 41-50
re-synthesis of MNR46 to try and get a clean sample for characterisation and HPLC analysis

MNR46-1%20scheme.png
mnr46-13%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
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.

1H NMR

Frac 15-20 - Clean product
mnr46-13_frac15-20_1H.pdf
mnr46-13_frac15-20.zip


Frac 31-35 - messy
mnr46-13_frac31-35_1H.pdf
mnr46-13_frac31-35.zip


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.

Frac 21-30
mnr46-13_frac21-30_1H.pdf
mnr46-13_frac21-30.zip


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.

Frac 1-11
mnr46-13_frac1-11_friday.pdf
mnr46-13_frac1-11.zip


------------------------------------------------------------------

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.

SANY0334.JPG


running a new sample of MNR46-13 fracs 15-20 confirmed this

mnr46-13_frac15-20_monday.pdf
mnr46-13_f15-20_monday.zip


Conclusions

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.

MNR46-13%20decomp%20scheme.png
Linked Posts
Attached Files
20th September 2012 @ 03:14
Sc: 1-10
Synthesis of SC4-1 and SC4-2 from SC2-1.

HIRAC


SC4 HIRAC.jpeg


Procedure followed:

The procedure was identical to that used for SC3-1 and SC3-1. Reactions were also performed on a 0.1 g scale.

SC1-1 (0.1023 g, 0.41 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, to give SC4-1.
SC1-1 (0.0997 g, 0.40 mmol) was again reacted under the same conditions, with the addition of Yb(OTf)3 (0.0085 g/mL, 1.3 mL, 0.017 mmol) to give SC4-2.

SC4%20reaction%20image.png

reaction%20values.PNG

SC4 reaction.JPG


13th September 2012

TLC analysis showed that SC4-1 and SC4-2 reactions had progressed considerably after 40 minutes of reaction time. (See TLC below.)

14th September 2012

Stirring was ceased after 21 hr.
SC4 reaction progress.JPG


SC4-2 had partially crystallised overnight as there were visible particulates in the reaction mixture. SC4-1 remained in solution. Samples refrigerated over the weekend.

18th September 2012

Products were extracted in ethyl acetate (3 x 10mL) using sodium hydrogen carbonate, as done for SC3-1 and SC3-2. The products were obtained as white/light-brown solids. Crude yields are listed below. Residual lutidine is suspected; both solids exuded an aroma characteristic of lutidine.

Crude yield for SC4-1: 0.1199 g, 0.41 mmol, 100.2%
Crude yield for SC4-2: 0.1393 g, 0.48 mmol, 119.5%

19th September 2012

SC4-1 was purified using silica column chromatography using ethyl acetate/hexane eluent. TLC analysis showed a clean reaction mixture. No co-spotting was observed, unlike during the purification of both SC3-1 and SC3-2 reaction mixtures. Fractions 15-33 were collected.

TLC analysis of SC4-1 crude sample:
column purification fractions 1-20.JPG
column purification fractions 21-40.JPG


20th September 2012

SC4-2 was column purified. A single spot was observed, indicative of one product. Fractions 15-40 were collected.

TLC analysis of SC4-2 crude sample:
SC4-2 fractions 1-20.JPG
SC4-2 fractions 21-40.JPG


21st September 2012

Final yields for purified products were obtained.
SC4-1: 0.0581g, 0.20 mmol, 48.6%, m.p.
SC4-2: 0.0539g, 0.19 mmol, 46.2%, m.p.

27th September 2012
NMR analyses of SC4-1 and SC4-2 show that cyclisation has occurred.
Starting material (SC1-1):
SC1-1 1H-NMR.pdf.pdf

SC4-1:
SC4-1 column frac 15-33 1H-NMR.pdf.pdf

SC4-2:
SC4-2 column frac 15-40 1H-NMR.pdf.pdf


Attached Files
14th September 2012 @ 07:21
Mnr: 41-50
Aim repeat of the previous reaction but switching the temperatures.

MNR46-11, 10 mol% Yb at reflux
MNR46-11, stoichiometric Yb at room temperature

MNR46-1%20scheme.png
mnr46-11%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB22-1 (1eq) in HPLC grade acetonitrile (0.03 M) under argon at 0 °C , was added was added acetyl chloride (1.8 eqs), lutidine (1.4 eqs) and Yb(OTf)3 (0.1-1 eqs). The reaction was then stirred at room temperature or at reflux and aliquots taken at noted time intervals for LC analysis.

Sample were taken up to 5 hours then the reaction were left overnight.

As shown in MNR46-10, both reactions showed decrease in product over time.

mnr46-11_plot.PNG

SANY0300.JPG


All reactions quenched on Friday afternoon and TLC only showed traces in 9 and 11. No product visible in reactions containing 100mol%
Attached Files
12th September 2012 @ 02:06
Mnr: 41-50
The aim over the next few reactions is to compare reaction rate, conversion and yield varying reaction temperature and Yb loading

MNR46-8, 10 mol% Yb at room temperature
MNR46-9, flasks were mixed up therefore ended up being a duplicate of
MNR46-10, stoichiometric Yb at reflux

MNR46-1%20scheme.png
mnr46-8%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB22-1 (1eq) in HPLC grade acetonitrile (0.03 M) under argon at 0 °C , was added was added acetyl chloride (1.8 eqs), lutidine (1.4 eqs) and Yb(OTf)3 (01-1 eqs). The reaction was then stirred at room temperature or at reflux and aliquots taken at noted time intervals for LC analysis.

Sample were taken up to 5 hours then the reaction were left overnight.

Only MNR46-8 showed significant signs of product. Surprisingly, MNR46-10 showed signs of the product degrading over time (assuming the last data point is an outlier)

mnr46-8_plot.PNG

MNR46-8 was worked up after 48 hours.

The mixture was washed saturated sodium bicarbonate solution (10 mL) and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil, 0.329 g.

TLC in 50% EtOAC/Hex. Spot left to right, lutidine, KAB22-1, co-spot, worked up MNR46-8, co-spot, product (MNR46-4). Two spots were seen in the SM spot, this can be put down to some hydrolysis in the TLC spotter sample as it was a few weeks old. TLC also show complete consumption of SM to two new spots, them being desired product and hydrolysis products.

mnr46-8.JPG


Column in 40% EtOAc/Hexane

Frac 1-7 - mainly CHO, not as much amine, volatile?? 0.049 g

mnr46-8_frac1-7_1H.pdf
mnr46-8_frac1-7.zip


Frac 9-18 - product with unknown peak at 2.25. Product appears to come up as two conformers in a ration of 2:1. This is clearer in the 13C. 0.080 g, 0.27 mmol, 34 %

mnr46-8_frac9-18_1H.pdf

mnr46-8_frac9-18_13C.pdf
mnr46-8_frac9-18.zip


Conclusion

At 10 mol% the reaction IS catalytic, at room temperature the reaction takes about 2 days to go to completion.

The reaction using 1 eq of catalyst appears to have a negative effect of the progress of the reaction or it degrades the product. This needs looked into further.

-----------------------------

MNR46-9

quenched and worked up as normal but then volume reduced and washed with 10% citric acid.

SANY0301.JPG


one wash appeared to get rid of most of the lutidine, crude mass 0.190 g

running the crude down a column yielded product but upon standing the product hydrolysed back to aldehyde and amine. Yields and masses not calculated.

mnr46-9_overlay.pdf


see Re-synthesis of MNR46-13 for a fuller account and explanation.
Linked Posts
Attached Files