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7th September 2012 @ 02:52
Mnr: 41-50
Attempts To Cyclise KAB22-1 using AcCl and AlCl3 as the lewis acid

Ref - NEW METHOD FOR SYNTHESIS OF 2-ACYL-1-ARYL-1,2,3,4-TETRAHYDROISOQUINOLINES
Author: MOLLOV, NM (MOLLOV, NM); VENKOV, AP (VENKOV, AP)
Source: SYNTHESIS-STUTTGART Issue: 1 Pages: 62-63 Published: 1978

MNR46-5%20scheme.png
mnr46-5%20table.PNG

Hazard Assessment
MNR46-5.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 eq), lutidine (1 eq) and AlCl3(0.1-2 eqs). The reaction was then stirred at room temperature (20 °C)

TLC after 2 hours

SANY0272.JPG


50% EtOAc/Hex. spots from left to right: Starting material, lutidine, 46-5, 46-6, 46-7, MNR46-4 (Product)

All three reactions look to be progressing to product but still SM in all three reactions. Also, there's an intense spot running lower on the TLC plate, unsure what this is, will need to keep an eye on this.

Reaction left to stir.

TLC on Monday morning

SANY0281.JPG


Look very similar to after 2 hours. There's doesn't appear to be any product in 46-7. All three to be worked up.
Attached Files
31st August 2012 @ 07:26
Mnr: 41-50
Attempts To Cyclise KAB22-1 using AcCl

MNR46-1%20scheme.png
mnr46-2%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 ambient temperature, was added was added acetyl chloride (1.8 eqs), base (1.4 eqs) and catalyst (0.4 eqs). The reaction was then stirred at room temperature (19 °C) over the weekend.

Monday morning

46-2 was a clear yellow solution
46-3 was a cloudy yellow mixture
46-4 was a cloudy yellow mixture

46 2 hours
46 Monday



Work Up


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.

Post work up TLC showed faint new spot in both Yb reactions, 46-4 selected for column as the spot looked more intense. This spot did appear to be in all 3 reactions pre-work up.

MNR46-4

Column using 40% EtOAC/Hex. new spot collected in fractions 11-20. Lutidine spot ran lower and slightly co-spotted but this can be vac'd away.

NMR shows what looks like product as a mixture of rotamers. NMR also contains traces of EtOAc and an extra Ac peak.

Frac 11-20 0.040 g as a yellow oil.

46-4_column

mnr46-4_frac11-20_1H.pdf

mnr46-4_frac11-20_13C.pdf


Frac 1-9 - 0.020 g as a pale yellow solid (thought to be starting material, turned out to be a mixture of hydrolysis products, no starting material found)

mnr46-4_frac1-9_1H.pdf

mnr46-4_frac1-9_13C.pdf


Conclusion

This cyclisation appears to have worked and was not expected. Has increased catalyst loading aided the reaction or is it increased reaction time? Now need to go back and column the control and the other Yb reaction to test for more cyclisation product.

Crude NMRs of MNR46-2 and MNR46-3

Crude 1H NMR of MNR46-2 showed only hydrolysis products (Ac, mono or di-protected)

mnr46-2_1H_crude.pdf


Crude 1H NMR of MNR46-3 was messy but looked like like mainly hydrolysis products (Ac, mono or di-protected) with the possibility of traces of product but it was decided not to waste time running it through a column,

mnr46-3_1H_crude.pdf


Overlay

mnr46-2to4_overlay.pdf


LCMS

Expected products

mnr46_LCMS.png

Hydrolysis products are too small to be detected by LCMS as the cut off is 250.

LCMS - Starting Material

kab22-1.pdf


Peak with RT of 15 mins with very little m/s activity but SM+H (=255) detected.

LCMS - MNR46-4 frac 11-20


mnr46-4_frac11-20.pdf


Peak with a RT of 22 minsshows m/s peak of Prod+H (=297)

Overall Conclusions

The cyclisation looks to have worked using Yb(OTf)3. Is it catalytic? Based on scale it's hard to tell therefore this needs repeated. Reaction also needs repeated at lower Yb(OTf)3 loadings to understand the reaction more also following the reaction over time will be useful.


SciFinder searching -
Ph ring open - 1466 Reactions

With only a Ph ring - 89 Reactions

With H's on the Et chain - 21 reactions from 6 refs

With Ac group - 6 reactions from 2 refs (only one looks useful - A new method for synthesizing 2-acyl-1-aryl-1,2,3,4-tetrahydroisoquinolines, Mollov, N. and Venkov, A. Synthesis, 62-3; 1978

mnr46_lit.PNG
Attached Files
31st August 2012 @ 07:23
Mnr: 41-50
Attempts To Cyclise KAB18-1 using AcCl

MNR45-1%20scheme.png
mnr45-2%20table.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of KAB18-1 (1eq) in HPLC grade acetonitrile (0.03 M) under argon at ambient temperature, was added was added acetyl chloride (1.8 eqs), base (1.4 eqs) and catalyst (0.4 eqs). The reaction was then stirred at room temperature (19 °C) over the weekend.

Monday morning

45-2 was a clear yellow solution
45-3 was a cloudy yellow mixture
45-4 was a cloudy yellow mixture

45-2 was spilt while trying to take a TLC, over 75% of it lost.

2 hours
SANY0244.JPG



Work Up


MNR45-3 looked the most promising by TLC although the spots were very faint. Column 40% EtOAc/Hex

Frac 15-30 - 15.366g

Frac 32-42
Attached Files
29th August 2012 @ 02:32
Mnr: 41-50
Attempts To Cyclise KAB22-1 without AcCl
MNR48-1 - Yb(OTf)3 and lutidine
MNR48-2 - Yb(Cl)3 and lutidine

MNR48-1%20scheme.png
MNR48-1-2.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 ambient temperature, was added was added base (1.4 eqs) and catalyst (0.4 eqs). The reaction was then stirred at room temperature (19 °C) for 22 hours.

Work Up


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.

TLC of the crude mixtures showed mainly starting material and lutidine
SANY0239.JPG
SANY0240.JPG


TLCs in 50% EtoAc/Hex.

Column

MNR48-1 was ran through a column using 40% EtOAc/Hex.

The lower runnig spot was isolated in fractions 8-18. on concentration it was clear that there was something wrong as the RBF contained over 1 g of oil/solvent. I turned out that the hexane used was contaminated with kerosene/octane or some other high boiling point organic fraction. Unsure where this came from but other people in the group experienced the same with the previous 24 hours. Bottle identified, returned to stores and taken out of use.

The issolated fraction were taken up in clean hexane and filtered through a plug of silica washing with hexane then EtOAc.

by TLC Fraction 4-7 showed product.

upon drying both flasks contained next to nothing, NMR confirmed this with no distinguishable peaks found. This confirms that the spot was due to lutidine from the reaction which has been lost on the hi-vac.

Conclusions


KAB22-1 can not be cyclised using Yb(OTf)3 or Yb(Cl)3
Attached Files
29th August 2012 @ 02:29
Mnr: 41-50
Attempts To Cyclise MNR42 without AcCl.
MNR47-1 - Yb(OTf)3 and TEA
MNR47-2 - Yb(Cl)3 and TEA
MNR47-3 - Yb(OTf)3 and lutidine
MNR47-4 - Yb(Cl)3 and lutidine

MNR47-1%20scheme.png
MNR47-1-4.PNG

Hazard Assessment
HIRAC MNR41_47_48.pdf


Procedure
To a solution of MNR42-1 (1eq) in HPLC grade acetonitrile (0.03 M) under argon at ambient temperature, was added was added base (1.4 eqs) and catalyst (0.4 eqs). The reaction was then stirred at room temperature (19 °C) for 22 hours.

Work Up

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.

TLC of the crude mixtures showed MNR47-1 and MNR47-2 did not react. MNR47-3 and MNR47-4 showed signs of something but co-spotting with KAB24-2 showed it was something else. It looks like KAB24-2 has decomposed but there is still a major spot in the TLC sample.

SANY0238.JPG


TLCs in 50% EtoAc/Hex.

sample 4 = MNR47-1
sample 5 = MNR47-2
sample 6 = MNR47-3
sample 7 = MNR47-4

Column

MNR47-3 was ran through a column using 40% EtOAc/Hex.

upon drying the fractions that contained the lower running spot, next to nothing was recovered. NMR confirmed this with no distinguishable peaks found. This confirms that the spot was due to lutidine from the reaction which has been lost on the hi-vac.

Conclusions

MNR42-1 can not be cyclised using Yb(OTf)3 or Yb(Cl)3 in the absence of AcCl.
Attached Files