Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems
<h4>Background</h4> <p>1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron poor aromatic systems, is scarcely re...
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| Format: | Journal article |
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Beilstein-Institut
2017
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| _version_ | 1797105996124913664 |
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| author | Mottinelli, M Leese, MP Potter, BVL |
| author_facet | Mottinelli, M Leese, MP Potter, BVL |
| author_sort | Mottinelli, M |
| collection | OXFORD |
| description | <h4>Background</h4> <p>1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron poor aromatic systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evaluated. </p> <h4>Results</h4> <p>A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-activated systems use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives formed with significant amounts of 5-substituted by-product. The formation of the 4-hydroxy THIQs vs. the 4-methoxy THIQ products could be controlled through modification of the reaction concentration. In addition, while a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6- and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclusively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a double ring closure could be obtained utilizing HClO4.</p> <h4>Conclusions</h4> <p>Reactivity differences in aminoacetal precursors can be employed to control cyclization using PFB methodology. It is now possible to select confidently the right conditions for synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.</p> |
| first_indexed | 2024-03-07T06:55:23Z |
| format | Journal article |
| id | oxford-uuid:fdfa4eb3-b487-4729-b9f7-a38996a783cf |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:55:23Z |
| publishDate | 2017 |
| publisher | Beilstein-Institut |
| record_format | dspace |
| spelling | oxford-uuid:fdfa4eb3-b487-4729-b9f7-a38996a783cf2022-03-27T13:32:43ZAccessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systemsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fdfa4eb3-b487-4729-b9f7-a38996a783cfSymplectic Elements at OxfordBeilstein-Institut2017Mottinelli, MLeese, MPPotter, BVL <h4>Background</h4> <p>1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron poor aromatic systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evaluated. </p> <h4>Results</h4> <p>A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-activated systems use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives formed with significant amounts of 5-substituted by-product. The formation of the 4-hydroxy THIQs vs. the 4-methoxy THIQ products could be controlled through modification of the reaction concentration. In addition, while a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6- and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclusively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a double ring closure could be obtained utilizing HClO4.</p> <h4>Conclusions</h4> <p>Reactivity differences in aminoacetal precursors can be employed to control cyclization using PFB methodology. It is now possible to select confidently the right conditions for synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.</p> |
| spellingShingle | Mottinelli, M Leese, MP Potter, BVL Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title | Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title_full | Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title_fullStr | Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title_full_unstemmed | Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title_short | Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems |
| title_sort | accessing simply substituted 4 hydroxytetrahydroisoquinolines via pomeranz fritsch bobbitt reaction with non activated and moderately activated systems |
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