Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

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.

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β‐Hydroxysteroid Dehydrogenase 1 Inhibitors

“…N ‐(2,2‐Dimethoxyethyl)‐4‐methoxy‐ N ‐(3,4,5‐trimethoxybenzyl)aniline (3 r) : The crude compound was purified by column chromatography (eluent: from 0 to 50 % EtOAc in pet. ether) to give the product as an orange oil (7.71 g, 98 %) which showed as previously reported: [17] 1 H NMR (400 MHz, CDCl 3 ): δ =3.37 (6H, s), 3.47 (2H, d, J =5.1 Hz), 3.74 (3H, s), 3.78 (6H, s), 3.81 (3H, s), 4.47 (2H, s), 4.56 (1H, t, J =5.1 Hz), 6.46 (2H, s), 6.72 (2H, d, J =9.2 Hz) and 6.79 (2H, d, J =9.2 Hz) ppm. HRMS (ES + ) calcd.…”

“…N ‐(2,2‐Dimethoxyethyl)‐ N ‐(4‐methoxybenzyl)aniline (3 c) : The crude compound was purified by column chromatography (from 0 to 10 % EtOAc in pet. ether) to give the product as a yellowish oil (2.09 g, 69 %) which showed as previously reported: [17] 1 H NMR (400 MHz, CDCl 3 ): δ =3.41 (6H, s, CHOC H 3 ), 3.56 (2H, d, J =5.0 Hz, NC H 2 CH), 3.79 (3H, s, ArOCH 3 ), 4.60–4.65 (3H, m, C H (OR) 2 , ArCH 2 ), 6.61–6.73 (1H, m, ArH), 6.76 (2H, d, J =8.3 Hz, ArH), 6.85 (2H, d, J =8.3 Hz, ArH), 7.14 (2H, d, J =8.4 Hz, ArH) and 7.20 (2H, t, J =7.8 Hz, ArH) ppm. 13 C NMR (101 MHz, CDCl 3 ): δ =53.7 (N C H 2 CH), 54.3 (ArOCH 3 ), 54.6 (CH(O C H 3 ) 2 ), 55.4 (ArCH2), 103.4 (CH(OR) 2 ), 112.4 (ArCH), 114.1 (ArCH), 116.6 (ArCH), 127.8 (ArCH), 129.3 (ArCH), 130.7 (ArCCH 2 ), 148.7 (ArCN) and 158.6 (Ar C OCH 3 ) ppm.…”

“…4‐Chloro‐ N ‐(2,2‐dimethoxyethyl)‐ N ‐(3‐methoxybenzyl)aniline (3 g) : The crude compound was purified by column chromatography (eluent: from 0 to 20 % EtOAc in pet. ether) to give the product as a pale yellow oil (9.08 g, 90 %) which showed as previously reported: [17] 1 H NMR (500 MHz, CDCl 3 ): δ =3.40 (6H, s, CH(OC H 3 ) 2 ), 3.54 (2H, d, J =5.1 Hz, CHC H 2 ), 3.76 (3H, s, ArOCH 3 ), 4.58 (1H, t, J =5.1 Hz, C H CH 2 ), 4.60 (2H, s, ArCH 2 N), 6.63 (2H, d, J =9.2 Hz, ArH, aniline), 6.71–6.74 (1H, m, ArH, benzyl), 6.74–6.80 (2H, m, ArH, benzyl), 7.10 (2H, d, J =9.2 Hz, ArH, aniline) and 7.22 (1H, t, J =7.9 Hz, ArH, benzyl) ppm. 13 C NMR (126 MHz, CDCl 3 ): δ =54.2 (CH C H 2 ), 54.7 (CH(O C H 3 ) 2 ), 55.1 (ArCH 2 N), 55.3(ArOCH 3) , 103.3 ( C H(OCH 3 ) 2 ), 112.0 (ArCH, benzyl), 112.4 (ArCH, benzyl), 113.6 (ArCH, aniline), 118.8 (ArCH, benzyl), 121.6 (ArCCl), 129.1 (ArCH, aniline), 129.8 (ArCH, benzyl), 140.2 (ArCCH 2 ), 147.2 (ArCN) and 160.1 (ArCO) ppm.…”

“…The first step of the Pomeranz‐Fritsch‐Bobbitt approach involves a double reductive amination (Scheme 1), followed by cyclization with standard or modified conditions (6 M HCl or 70 % HClO 4 , respectively) as dictated by the substitution pattern (Scheme 2), as per literature precedent [17] . Cyclization of 3 e (Scheme 2) yielded a mixture of two regioisomers 8 a and 9 a , which could be directly separated.…”

A Short Approach to N-Aryl-1,2,3,4-tetrahydroisoquinolines from N-(2-Bromobenzyl)anilines via a Reductive Amination/Palladium-Catalyzed Ethoxyvinylation/Reductive N-Alkylation Sequence

“…A Pomeranz-Fritsch-type cyclization of N-aryl-N-benzylaminoacetaldehyde acetals to 4-hydroxy-N-aryl-1,2,3,4-tetrahydroisoquinolines is hampered by the strongly acidic conditions required and the formation of diverse side products. 8 Consequently, the development of convenient approaches to N-aryl-1,2,3,4-tetrahydroisoquinolines is still a promising task. In continuation of our research on bioactive isoquinolines 9 we were interested in the synthesis of Naryl-1,2,3,4-tetrahydroisoquinolines as rigid analogues of steroids 3a and azobenzenes.…”