Palladium-Mediated Intramolecular
Buchwald-Hartwig α-Arylation of β-Amino
Esters: Synthesis of Functionalized Tetrahydroisoquinolines

A. Gopi Krishna Reddy; J. Krishna; G. Satyanarayana

doi:10.1055/s-0030-1260934

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Synlett 2011(12): 1756-1760
DOI: 10.1055/s-0030-1260934

LETTER

Palladium-Mediated Intramolecular Buchwald-Hartwig α-Arylation of β-Amino Esters: Synthesis of Functionalized Tetrahydroisoquinolines

A. Gopi Krishna Reddy, J. Krishna, G. Satyanarayana*
Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus, Yeddumailaram 502 205, Medak District, Andhra Pradesh, India
Fax: +91(40)23016032; e-Mail: gvsatya@iith.ac.in;

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Publication History

Received 7 April 2011
Publication Date:
05 July 2011 (online)

Abstract
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Abstract

A concise and efficient three-step strategy for the synthesis of functionalized 1,2,3,4-tetrahydroisoquinolines based on an intramolecular Buchwald-Hartwig α-arylation of β-amino esters is described. The synthesis presented is operationally simple and is amenable for the synthesis of a number of analogues.

Key words

palladium catalysis - α-arylation - tetrahydroisoquinolines - natural products

Supporting Information

References and Notes

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25

General Procedure for Buchwald-Hartwig Cyclization: The following Procedure for 4a is Representative In an oven-dried Schlenk tube under nitrogen atmosphere were taken Pd(OAc)₂ (10 mol%), Ph₃P (20 mol%), and Cs₂CO₃ (2 mmol) in toluene (ca. 1.5 mL), and the mixture was stirred for 5 min. To this mixture was added ester 3a (1 mmol) in toluene (ca. 3.0 mL), and the reaction mixture was stirred for 24 h at 80 ˚C. Progress of the reaction was monitored by TLC, and, after the reaction is complete, it was quenched by addition of aq NH₄Cl and extracted with CH₂Cl₂ (3 × 20 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel using PE-EtOAc as eluent furnished the product 4a in 82% yield.
Representative Analytical Data Compound 4a: IR: 3027, 2982, 1732, 1684, 1452, 1242, 1166, 1034, 741 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.10 (m, 8 H, ArH), 7.06-6.98 (m, 1 H, ArH), 4.20-4.10 (m, 2 H, OCH ₂CH₃), 3.85 (dd, 1 H, J = 5.2, 5.2 Hz,
4′-H), 3.80 [d, 1 H, J = 14.9 Hz, NCH₂(a,b)], 3.74 [d, 1 H, J = 13.2 Hz, NCH₂(a′,b′)], 3.65 [d, 1 H, J = 13.2 Hz, NCH₂(a′,b′)], 3.59 [d, 1 H, J = 14.9 Hz, NCH₂(a,b)], 3.18 (dd, J = 11.5, 5.6 Hz, 1 H, NCH _2aCHCOOEt), 2.85 (dd, J = 11.5, 4.8 Hz, 1 H, N-CH _2bCHCOOEt), 1.23 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃) ppm. ^¹³C NMR (50 MHz, CDCl₃): δ = 173.25 (s, OC=O), 138.13 (s, ArC), 135.19 (s, ArC), 131.58 (s, ArC), 129.31 (d, ArC), 129.05 (d, 2 C, ArC), 128.32 (d, 2 C, ArC), 127.25 (d, ArC),126.92 (d, ArC), 126.75 (d, ArC), 126.31 (d, ArC), 62.31 (t, NCH₂), 60.95 (t, OCH₂CH₃), 56.11 (t, NCH₂), 52.95 (t, C-3′), 45.46 (d, C-4′), 14.22 (q, OCH₂ CH₃) ppm.
Compound 4b: 79% yield. IR: 2931, 2828, 1729, 1610, 1514, 1455, 1252, 1134, 1031, 741 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.41-7.24 (m, 5 H, ArH), 6.74 (s, 1 H, ArH), 6.52 (s, 1 H, ArH), 4.26-4.06 (m, 2 H, OCH ₂CH₃), 3.85 (s, 3 H, ArOCH₃), 3.83 (s, 3 H, ArOCH₃), 3.78 (dd, 1 H, J = 5.0, 5.0 Hz, 4′-H), 3.74 [d, 1 H, J = 13.1 Hz, NCH₂(a′,b′)], 3.67 [d, 1 H, J = 14.5 Hz, NCH₂(a,b)], 3.65 [d, 1 H, J = 13.1 Hz, NCH₂(a′,b′)], 3.52 [d, 1 H, J = 14.5 Hz, NCH₂(a,b)], 3.17 (dd, 1 H, J = 11.4, 5.5 Hz, NCH _2aCHCOOEt), 2.85 (dd, 1 H, J = 11.4, 4.8 Hz, NCH _2bCHCOOEt), 1.22 (t, 3 H, J = 7.1 Hz, OCH₂CH ₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 173.3 (s, OC=O), 148.1 (s, ArC), 147.48 (s, ArC), 138.10 (s, ArC), 129.05 (d, 2 C, ArC), 128.29 (d, 2 C, ArC), 127.36 (s, ArC), 127.22 (d, ArC), 123.27 (s, ArC), 111.82 (d, ArC), 109.22 (d, ArC), 62.23 (t, NCH₂), 60.87 (t, OCH₂CH₃), 55.92 (q, ArOCH₃), 55.83 (q, ArOCH₃), 55.66 (t, NCH₂), 52.98 (t, C-3′), 44.91 (d, C-4′), 14.24 (q, OCH₂ CH₃) ppm. HRMS (ESI⁺): m/z calcd for [C₂₁H₂₅NNaO₄]⁺ = [M + Na]⁺: 378.1676; found: 378.1685.
Compound 4c: 85% based on the recovery of 19% of starting material. IR: 2938, 2834, 1732, 1598, 1458, 1238, 1118, 741 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.42-7.20 (m, 5 H, ArH), 6.35 (s, 1 H, ArH), 4.25-4.00 (m, 2 H, OCH ₂CH₃), 3.87 (s, 3 H, ArOCH₃), 3.83 (s, 3 H, ArOCH₃), 3.81 (s, 3 H, ArOCH₃), 3.80-3.67 (m, 1 H, 4′-H), 3.74 [d, 1 H, J = 14.8 Hz, NCH₂(a,b)], 3.72 [d, 1 H, J = 13.2 Hz, NCH₂(a′,b′)], 3.70 [d, 1 H, J = 14.8 Hz, NCH₂(a,b)], 3.60 [d, 1 H, J = 13.2 Hz, NCH₂(a′,b′)], 3.08 (dd, 1 H, J = 11.5, 5.1 Hz, NCH _2aCHCOOEt), 2.81 (dd, 1 H, J = 11.5, 5.1 Hz, NCH _2bCHCOOEt), 1.20 (t, 3 H, J = 7.2 Hz, OCH₂CH ₃) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 173.86 (s, OC=O), 152.79 (s, ArC), 151.54 (s, ArC), 140.05 (s, ArC), 138.05 (s, ArC), 130.75 (s, ArC), 128. 94 (d, ArC), 128.59 (s, ArC), 128.30 (d, ArC), 127.22 (d, ArC), 118.36 (s, ArC), 104.82 (d, ArC), 61.98 (t, NCH₂), 60.71 (q, ArOCH₃), 60.69 (t, NCH₂), 60.33 (q, ArOCH₃), 55.90 (t, 2 C, OCH₂CH₃ and OCH₃), 53.48 (t, NCH₂CHCOOEt), 41.27 (d, NCH₂ CHCOOEt), 14.23 (q, OCH₂ CH₃) ppm. HRMS (ESI⁺): m/z calcd for [C₂₂H₂₇NNaO₄]⁺ = [M + Na]⁺: 408.1781; found: 408.1787.

Supplementary Material

Supporting Information