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Synlett 2011(7): 982-988  
DOI: 10.1055/s-0030-1259722
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Halopalladation Cyclization of Alkynes with Azides: Selective Synthesis of 4-Haloisoquinolines and 3-Haloindoles

Hong-Ping Zhanga,b, Shang-Ci Yua, Yun Lianga, Peng Penga, Bo-Xiao Tanga, Jin-Heng Li*a
a Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University, Changsha 410081, P. R. of China
Fax: +86(731)88872101; e-Mail: jhli@hunnu.edu.cn;
b Department of Biology and Chemical Engineering, Shaoyang University, Shaoyang 422000, P. R. of China
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Publication History

Received 8 August 2010
Publication Date:
10 March 2011 (online)

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Abstract

A new, selective method for the synthesis of 4-haloisoquinolines and 3-haloindoles is presented by the halopalladation cyclizations of alkynes with azides. In the presence of PdX2 (X = Br, Cl) and halide sources, a variety of 2-alkynyl benzyl azides or 2-alkynyl aryl azides smoothly underwent the halopalladation ­cyclization reaction to afford the corresponding 3-substituted 4-­haloisoquinolines and 2-substituted 3-haloindoles in moderate to good yields.

Key words

palladium - halopalladation - cyclization - 2-alkynyl azide - 4-haloisoquinoline - 3-haloindole

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General Procedure for the Chloropalladation Reaction: To a flame-dried Schlenk tube equipped with a magnetic stirring bar were added azide 1 (0.3 mmol), PdCl2 (5 mol%), CuCl2 (3 equiv), Cy2NH2Cl (0.2 equiv) and CH2ClCH2Cl (5 mL). The reaction mixture was stirred at 80 ˚C for 24 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the mixture was poured into EtOAc, washed with brine (3 × 10 mL), and extracted with EtOAc. The combined organic layers were dried over anhyd Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (hexane-EtOAc) to afford the desired product.
4-Chloro-3-phenylisoquinoline (2a):6g,¹5 colorless oil. ¹H NMR (500 MHz, CDCl3): δ = 9.24 (s, 1 H), 8.35 (d, J = 8.5 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.85 (t, J = 8.5 Hz, 1 H), 7.81 (d, J = 11.5 Hz, 2 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.45 (t, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 150.5, 150.1, 139.1, 134.7, 131.6, 130.0, 128.5, 128.4, 128.0, 127.9, 127.7, 124.1, 109.4. LRMS (EI, 70 eV): m/z (%) = 241 (21) [M+ + 2], 239 (67) [M+], 204 (100) [M+ - Cl].
General Procedure for the Bromopalladation Reaction: To a flame-dried Schlenk tube equipped with a magnetic stirring bar were added azide 1 (0.3 mmol), PdBr2 (5 mol%), CuBr2 (3 equiv), LiBr (2 equiv) and MeCN (5 mL). The reaction mixture was stirred at 80 ˚C for 24 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the mixture was poured into EtOAc, washed with brine (3 × 10 mL), and extracted with EtOAc. The combined organic layers were dried over anhyd Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (hexane-EtOAc) to afford the desired product.
4−Βροµο−3−πηενψλισοθυινολινε (3α):15 Χολορλεσσ οιλ. 1Η ΝΜΡ (500 ΜΗζ, ΧΔΧλ3): δ = 9.23 (σ, 1 Η), 8.33 (δ, ϑ = 8.5 Ηζ, 1 Η), 8.01 (δ, ϑ = 8.0 Ηζ, 1 Η), 7.84 (τ, ϑ = 8.0 Ηζ, 1 Η), 7.73 (δ, ϑ = 8.5 Ηζ, 2 Η), 7.68 (τ, ϑ = 8.0 Ηζ, 1 Η), 7.50 (τ, ϑ = 7.8 Ηζ, 2 Η), 7.45 (τ, ϑ = 8.0 Ηζ, 1 Η). 13Χ ΝΜΡ (125 ΜΗζ, ΧΔΧλ3): δ = 152.3, 151.1, 140.7, 136.0, 131.9, 129.9, 128.6, 128.3, 128.0, 127.9, 127.7, 127.0, 118.3. ΛΡΜΣ (ΕΙ, 70 ες): µ/ζ (%) = 285 (23) [Μ+ + 2], 283 (25) [Μ+], 204 (100) [Μ+ ∠ Βρ].