Tetrahydroisoquinoline: Oxidative imine formation, nucleophilic addition reactions and asymmetric...
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Tetrahydroisoquinoline: Oxidative imine formation, nucleophilic addition reactions and asymmetric selectivity James Fuster, Dr. Rina Soni, Professor Martin Wills University of Warwick Introduction 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) 3 Cl 2 , BrCCl 3 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. References: 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 R 2 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 1 H-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 R 2 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. Conclusion Simply 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. N N Br R 2 R 2 R 1 R 1 Ru(bipy) 3 Cl 2 ,Blue LED, BrCCl 3 NH B c d N Ph N Ph Br N Ph Br N Ph An Example of a Wills catalyst Ru N Cl N Ph Ph Ts H Stereoselective reduction One of the main target objectives was to try and isolate a selective enantiomer from a racemic 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 I After 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 II Unlike 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 III In 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 N Ph c d A N Ph N Ph * N Ph NO 2 N Ph 1.Ru(bipy) 3 Cl 2 ,Blue LED ,BrC C l 3 2.N Et 3 , M eN O 2 II NH Y NH X CuI, K 3 PO 4 Iodobenzene N Ph Ph N Ph N Ph N Ph NO 2 N Ph M eO O C COOMe N Ph Br o r N Ph Br N Ph Br o r N Ph Br NH 2 O N NH X 1.Ru(bipy) 3 Cl 2 , Blue LED , BrCCl 3 2. M eM gBr, TH F, ZnCl 2 I 1.Ru(bipy) 3 Cl 2 , Blue LED , BrCCl 3 2. M eM gBr, TH F, ZnCl 2 A ceticanhydride NEt 3 POCl 3 , P 2 O 5 Toluene, reflux DCM , N a(CH 3 COO) 3 BH Benzylbrom ide DCM , N Et 3 1.Ru(bipy) 3 Cl 2 ,Blue LED ,BrC C l 3 III Benzylbrom ide DCM , N Et 3 1.Ru(bipy) 3 Cl 2 ,Blue LED ,BrC C l 3 IIIcont. 1.Ru(bipy) 3 Cl 2 , Blue LED , BrCCl 3 2. M eM gBr, TH F, ZnCl 2 CuI, K 3 PO 4 Iodobenzene Doublet/ doublet NMR of B Triplet NMR of A 1. “Functionally Diverse Nucleophilic trapping of Iminium Intermediates Generated Utilizing Visible Light ” David B. Freeman et al. Organic Letters 2012 Vol. 14, No.1 94-97 2. “Highly Efficient Alkylation to Ketones and Aldimines with Grignard Reagents Catalyzed by Zinc((I) Chloride” Manabu Hatano et al, Journal of American Chemical Society, 2006, 128, 9998-9999 3. “First enantioselective synthesis of the antitumour alkaloid (+)-Crispine A and determination of its enantiomeric purity by HNMR” Joanna Szakalo et al. Tetrahedron: Asymmetry 16 (2005) 3619-3621 4. “General Procedure for the synthesis of 2-aryl-1,2,3,4-tetrahydroisoquinoline” Organic Letters, 2013 , 15, 574-577 Supporting Information W illsCatalyst FA :TEA in D M F 0°C, 10h
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Transcript of Tetrahydroisoquinoline: Oxidative imine formation, nucleophilic addition reactions and asymmetric...
Tetrahydroisoquinoline: Oxidative imine formation, nucleophilic addition reactions and asymmetric selectivity
James Fuster, Dr. Rina Soni, Professor Martin WillsUniversity of Warwick
IntroductionTetrahydroisoquinoline 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.
References:
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.
Conclusion
Simply 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.
N N
Br
R2 R2
R1 R1
Ru(bipy)3Cl2, Blue LED, BrCCl3
NH
B
c
d
N
PhN
PhBr
N
PhBrN
Ph
An Example of a Wills catalyst
RuN Cl
N
Ph
Ph
Ts
H
Stereoselective reduction
One of the main target objectives was to try and isolate a selective enantiomer from a racemic 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
N
Ph
cd
A
NPh N
Ph
*
NPh
NO2
NPh
1.Ru(bipy)3Cl2, Blue LED, BrCCl3
2.NEt3, MeNO2
II
NH
Y
NH
X
CuI
, K3 P
O4
Iodo
benz
ene
N
Ph
Ph
N Ph N Ph
N Ph
NO2
N Ph
MeOOC COOMe
N PhBr
or
N PhBr
N PhBr
or
N PhBr
NH2
ON
NH
X
1.Ru(bipy)3Cl2, Blue LED, BrCCl3
2. MeMgBr, THF, ZnCl2
I
1.Ru(bipy)3Cl2, Blue LED, BrCCl3
2. MeMgBr, THF, ZnCl2
Acetic anhydride
NEt3
POCl3, P2O5
Toluene, ref lux DCM,
Na(CH3COO)3BH
Ben
zyl b
rom
ide
DC
M, N
Et
3
1.Ru(bipy)3Cl2, Blue LED, BrCCl3
III
Ben
zyl b
rom
ide
DC
M, N
Et
3
1.Ru(bipy)3Cl2, Blue LED, BrCCl3
III cont.1.Ru(bipy)3Cl2, Blue LED, BrCCl3
2. MeMgBr, THF, ZnCl2
CuI
, K3 P
O4
Iodo
benz
ene
Doublet/doublet NMR of B
Triplet NMR of A
1. “Functionally Diverse Nucleophilic trapping of Iminium Intermediates Generated Utilizing Visible Light” David B. Freeman et al. Organic Letters 2012 Vol. 14, No.1 94-97
2. “Highly Efficient Alkylation to Ketones and Aldimines with Grignard Reagents Catalyzed by Zinc((I) Chloride” Manabu Hatano et al, Journal of American Chemical Society, 2006, 128, 9998-9999
3. “First enantioselective synthesis of the antitumour alkaloid (+)-Crispine A and determination of its enantiomeric purity by HNMR” Joanna Szakalo et al. Tetrahedron: Asymmetry 16 (2005) 3619-3621
4. “General Procedure for the synthesis of 2-aryl-1,2,3,4-tetrahydroisoquinoline” Organic Letters, 2013 , 15, 574-577 Supporting Information
Wills Catalyst
FA:TEA in DMF0°C, 10h
