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Presentations text content in Tetrahydroisoquinoline



: Oxidative imine formation,


addition reactions and asymmetric selectivity

James Fuster, Dr.


Soni, Professor Martin WillsUniversity of Warwick


Tetrahydroisoquinoline analogues have been and continue to be investigated for medicinal use, making them interesting compounds for research. Particularly since their biological effects are dependent on the substituent groups, having a better understanding of their overall chemistry would be ideal. This project focuses on post-oxidation reactions of tetrahydroisoquinoline and some of its derivatives, paying close attention to the synthesis and chemistry of methylated tetrahydroisoquinoline, an unknown compound and investigates any potential enantiomeric selective synthesis through asymmetric reduction.

How might tetrahydroisoquinoline react?Tetrahydroisoquinoline can undergo many organic transformations mainly because it contains a C-N bond which is alpha to an aromatic ring. This allows it to be easily oxidized to an imine which is conjugated with the aromatic benzene ring. This polarized imine, is then ideally suited for nucleophilic attack at the δ+ carbon.There are different methods to achieve this, but the repeated oxidation used in this project was the oxidation of the amine to imine using a ruthenium catalyst, Ru(bipy)3Cl2, BrCCl3 and blue LED light. It is thought that the mechanism for the reaction is through radical formation, the Blue LED light effectively excites the molecule and catalyst, allowing radical formation to take place.


The structure of tetrahydroisoquinoline

Looking at the 3D structure of tetrahydrosioquinoline, we observe that the 6 membered ring next to the benzene ring is not flat. Because all the R groups are hydrogen atoms, it doesn’t really matter, however, by changing the R2 substituent, the molecule behaves slightly differently. The bulkier group influences the overall structure of the molecule. The two hydrogens bonded to the tetrahedral carbons are now no longer in the same chemical environment. This can be used to quickly observe if the reaction has taken place using 1H-NMR. For example, by comparing the spectra of two products isolated during the project. We can observe that the hydrogens at carbon ‘c’ in B are in different environments and couple as a doublet/doublet conformation while in A, with no R2 group, the hydrogens at ‘c’ are in the same environment and therefore only couple to ‘d’ forming a triplet. Hence in characterizing the products of some of the synthetic steps seen below, the splitting that was seen in the NMR could quickly indicate if the reaction took place and in some ways could provide a quantitative indication as well.

ConclusionSimply in focusing on the C-N relationship in the tetrahydroisoquinoline molecule, this project highlights only a fraction of the possible synthetic reactions that can take place. In particular, this project provides evidence in the simplicity of the imine oxidation in using a ruthenium catalyst, which is activated using visible light, and the possible subsequent nucleophilic additions that can occur. Moreover, it is shown how in a three step process the methyl derivative, not known in literature, can be formed. However, asymmetric experiments highlighted the difficulty in achieving reductions with enantiomeric selectivity.

Reaction syntheses: Below is a comparison of the key reactions between the synthesized methyl substituted tetrahydoisoquinoline (X) and the non-methylated, comercially available tetrahydroisoquinoline (Y), including the conditions for the reactions and comments on some of the observations.



xample of a Wills catalyst



One of the main target objectives was to try and isolate a selective


from a


starting material.

As shown, taking the racemic methylated

tetrahydroisoquinoline above and oxidizing it, the anticipated product is the iminium salt:By then using a an asymmetric catalyst, such as Wills catalyst, it is hoped that the salt will interact with the chiral catalyst in a way that will heavily favour reduction to only one of the methyl enantiomers.By monitoring the selectivity using gas chromatography, it was observed that although the salt reduced readily, it unfortunately would not reduce with any enantiomeric selectivity, it was effectively just giving the racemic starting material again.

Comment IAfter easy addition of Grignard reagent to N-Ph to form the singly methylated version*, and good oxidation thereafter, it would seem likely that further addition of methyl could occur, however it was found not to be the case, perhaps because of steric hindrance but also perhaps because the second methyl could act as a base.

Comment IIUnlike N-benzyl, N-Ph substituted tetrahydroisoquinoline oxidized readily and nucleophilic addition was successful albeit for small nucleophiles. Attempted addition of phenyl failed, suggesting that addition of another bulky phenyl group is not possible.

3 step synthesis of unknown methyl substituted tetrahydroisoquinoline (X)

Comment IIIIn comparing the two N-benzyl reactions, interestingly, the non methylated changed colour, a good indication that it seemed to oxidize while the methylated simply did not. However, all attempts at nucleophilic addition did not work, leading to suggest that perhaps it didn’t form the imine but maybe formed a different intermediate or that steric clashing leads to unfavourable addition.

Non-flat ringed structure



Doublet/doublet NMR of B

Triplet NMR of A

Functionally Diverse


trapping of


Intermediates Generated Utilizing Visible Light

” David B. Freeman et al.

Organic Letters 2012 Vol. 14, No.1 94-97

“Highly Efficient Alkylation to




with Grignard Reagents


by Zinc((I) Chloride”



et al,

Journal of American Chemical Society, 2006, 128, 9998-9999



synthesis of the


alkaloid (+)-


A and determination of its


purity by HNMR”



et al.

Tetrahedron: Asymmetry 16 (2005) 3619-3621

“General Procedure for the synthesis of 2-aryl-1,2,3,4-tetrahydroisoquinoline”


Letters, 2013 , 15, 574-577



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