Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives

Michael J. O’Sullivan; Richard J. D. Hatley; Christopher R. Wellaway; Sean P. Bew; Christopher J. Richards

doi:10.1016/j.tet.2021.132455

Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives

Michael J. O’Sullivan, Richard J. D. Hatley, Christopher R. Wellaway, Sean P. Bew, Christopher J. Richards

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Abstract

Reaction of methyl-2-(2-formylphenyl)acetate with primary amines in a reductive amination/cyclisation process resulted in N-substituted 1,4-dihydro-3(2H)-isoquinolinones. With H ₂NCH ₂R sodium borohyride is a suitable reductant (11 examples), but H ₂NCHR ¹R ² required a transfer hydrogenation using ammonium formate catalysed by palladium on carbon (9 examples). 4-Substituted-1,4-dihydro-3(2H)-isoquinolinones were synthesised by deprotonation (n-butyllithium) and addition of R ³CH ₂Br (12 examples with R ³ = alkyl, Ar, CH[dbnd]CH ₂, C[tbnd]CH). Modest diastereoselectivity was achieved with 1,4-dihydro-3(2H)-isoquinolinones derived from H ₂NCHMeR ² [R ² = (η ⁵-C ₅H ₄)Co(η ⁴-C ₄Ph ₄) - max. dr = 1.9: 1], but use of H ₂NCHMeFc (Fc = ferrocenyl) provided a new method of 1,4-dihydro-3(2H)-isoquinolinone N-deprotection with formic acid.

Original language	English
Article number	132455
Journal	Tetrahedron
Volume	100
Early online date	22 Sep 2021
DOIs	https://doi.org/10.1016/j.tet.2021.132455
Publication status	Published - 5 Nov 2021

Keywords

Deprotection
Ferrocenyl
Isoquinolinone
Reductive amination
α-Alkylation

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10.1016/j.tet.2021.132455

Accepted_ManuscriptAccepted author manuscript, 1.51 MBLicence: CC BY-NC-ND

https://linkinghub.elsevier.com/retrieve/pii/S0040402021007274

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title = "Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives",

abstract = "Reaction of methyl-2-(2-formylphenyl)acetate with primary amines in a reductive amination/cyclisation process resulted in N-substituted 1,4-dihydro-3(2H)-isoquinolinones. With H 2NCH 2R sodium borohyride is a suitable reductant (11 examples), but H 2NCHR 1R 2 required a transfer hydrogenation using ammonium formate catalysed by palladium on carbon (9 examples). 4-Substituted-1,4-dihydro-3(2H)-isoquinolinones were synthesised by deprotonation (n-butyllithium) and addition of R 3CH 2Br (12 examples with R 3 = alkyl, Ar, CH[dbnd]CH 2, C[tbnd]CH). Modest diastereoselectivity was achieved with 1,4-dihydro-3(2H)-isoquinolinones derived from H 2NCHMeR 2 [R 2 = (η 5-C 5H 4)Co(η 4-C 4Ph 4) - max. dr = 1.9: 1], but use of H 2NCHMeFc (Fc = ferrocenyl) provided a new method of 1,4-dihydro-3(2H)-isoquinolinone N-deprotection with formic acid. ",

keywords = "Deprotection, Ferrocenyl, Isoquinolinone, Reductive amination, α-Alkylation",

author = "O{\textquoteright}Sullivan, {Michael J.} and Hatley, {Richard J. D.} and Wellaway, {Christopher R.} and Bew, {Sean P.} and Richards, {Christopher J.}",

year = "2021",

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language = "English",

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T1 - Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives

AU - O’Sullivan, Michael J.

AU - Hatley, Richard J. D.

AU - Wellaway, Christopher R.

AU - Bew, Sean P.

AU - Richards, Christopher J.

PY - 2021/11/5

Y1 - 2021/11/5

N2 - Reaction of methyl-2-(2-formylphenyl)acetate with primary amines in a reductive amination/cyclisation process resulted in N-substituted 1,4-dihydro-3(2H)-isoquinolinones. With H 2NCH 2R sodium borohyride is a suitable reductant (11 examples), but H 2NCHR 1R 2 required a transfer hydrogenation using ammonium formate catalysed by palladium on carbon (9 examples). 4-Substituted-1,4-dihydro-3(2H)-isoquinolinones were synthesised by deprotonation (n-butyllithium) and addition of R 3CH 2Br (12 examples with R 3 = alkyl, Ar, CH[dbnd]CH 2, C[tbnd]CH). Modest diastereoselectivity was achieved with 1,4-dihydro-3(2H)-isoquinolinones derived from H 2NCHMeR 2 [R 2 = (η 5-C 5H 4)Co(η 4-C 4Ph 4) - max. dr = 1.9: 1], but use of H 2NCHMeFc (Fc = ferrocenyl) provided a new method of 1,4-dihydro-3(2H)-isoquinolinone N-deprotection with formic acid.

AB - Reaction of methyl-2-(2-formylphenyl)acetate with primary amines in a reductive amination/cyclisation process resulted in N-substituted 1,4-dihydro-3(2H)-isoquinolinones. With H 2NCH 2R sodium borohyride is a suitable reductant (11 examples), but H 2NCHR 1R 2 required a transfer hydrogenation using ammonium formate catalysed by palladium on carbon (9 examples). 4-Substituted-1,4-dihydro-3(2H)-isoquinolinones were synthesised by deprotonation (n-butyllithium) and addition of R 3CH 2Br (12 examples with R 3 = alkyl, Ar, CH[dbnd]CH 2, C[tbnd]CH). Modest diastereoselectivity was achieved with 1,4-dihydro-3(2H)-isoquinolinones derived from H 2NCHMeR 2 [R 2 = (η 5-C 5H 4)Co(η 4-C 4Ph 4) - max. dr = 1.9: 1], but use of H 2NCHMeFc (Fc = ferrocenyl) provided a new method of 1,4-dihydro-3(2H)-isoquinolinone N-deprotection with formic acid.

KW - Deprotection

KW - Ferrocenyl

KW - Isoquinolinone

KW - Reductive amination

KW - α-Alkylation

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U2 - 10.1016/j.tet.2021.132455

DO - 10.1016/j.tet.2021.132455

M3 - Article

VL - 100

JO - Tetrahedron

JF - Tetrahedron

SN - 0040-4020

M1 - 132455

ER -

Synthetic approaches to N- and 4-substituted 1,4-dihydro-3(2H)-isoquinolinone derivatives

Abstract

Keywords

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