Abstract
Background: 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. Results: 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 the use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives were formed with significant amounts of 5-substituted byproduct. 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. Conclusion: Reactivity differences in aminoacetal precursors can be employed to control cyclization using the PFB methodology. It is now possible to select confidently the right conditions for the synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.
| Original language | English |
|---|---|
| Pages (from-to) | 1871-1879 |
| Number of pages | 9 |
| Journal | Beilstein Journal of Organic Chemistry |
| Volume | 13 |
| DOIs | |
| Publication status | Published - 6 Sep 2017 |
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Keywords
- Cyclization
- Pomeranz-Fritsch
- Steroidomimetic
- Synthesis
- Tetrahydroisoquinoline
ASJC Scopus subject areas
- Organic Chemistry
Cite this
Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems. / Mottinelli, Marco; Leese, Mathew P.; Potter, Barry V.L.
In: Beilstein Journal of Organic Chemistry, Vol. 13, 06.09.2017, p. 1871-1879.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems
AU - Mottinelli, Marco
AU - Leese, Mathew P.
AU - Potter, Barry V.L.
PY - 2017/9/6
Y1 - 2017/9/6
N2 - Background: 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. Results: 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 the use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives were formed with significant amounts of 5-substituted byproduct. 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. Conclusion: Reactivity differences in aminoacetal precursors can be employed to control cyclization using the PFB methodology. It is now possible to select confidently the right conditions for the synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.
AB - Background: 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. Results: 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 the use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives were formed with significant amounts of 5-substituted byproduct. 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. Conclusion: Reactivity differences in aminoacetal precursors can be employed to control cyclization using the PFB methodology. It is now possible to select confidently the right conditions for the synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.
KW - Cyclization
KW - Pomeranz-Fritsch
KW - Steroidomimetic
KW - Synthesis
KW - Tetrahydroisoquinoline
UR - http://www.scopus.com/inward/record.url?scp=85029770319&partnerID=8YFLogxK
UR - http://dx.doi.org/10.3762/bjoc.13.182
U2 - 10.3762/bjoc.13.182
DO - 10.3762/bjoc.13.182
M3 - Article
VL - 13
SP - 1871
EP - 1879
JO - Beilstein Journal of Organic Chemistry
JF - Beilstein Journal of Organic Chemistry
SN - 1860-5397
ER -