Synlett 2008(8): 1243-1249  
DOI: 10.1055/s-2008-1072721
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of Highly Substituted Indolizinones via Iodocyclization and 1,2-Shift

Jihyun Choi, Ge Hyeong Lee, Ikyon Kim*
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
Fax: +82(42)8607160; e-Mail: ikyon@krict.re.kr;
Further Information

Publication History

Received 31 January 2008
Publication Date:
16 April 2008 (online)

Abstract

The 5-endo-dig iodocyclization of propargylic alcohols followed by a 1,2-shift provided rapid access to 2-iodoindolizinones, while the 5-endo-trig iodocyclization of allylic alcohols and subsequent dehydroiodination and 1,2-shift led to indolizinones. A number of highly substituted indolizinones were constructed under these mild reaction conditions.

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We also observed the direct synthesis of indolizinones from propargylic alcohols with Cs2CO3 (Scheme [8] ). These results will be communicated elsewhere.

Scheme 8

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When Et3N was employed instead to initiate the 1,2-shift, very long reaction times (more than 48 h) and elevated temperatures were required.

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General Procedure: To a stirred solution of propargylic alcohol 5a (0.84 mmol) in CH2Cl2 (3 mL) was added iodine (1.5 equiv) at r.t. After being stirred at r.t. for 5 h, the reaction mixture was quenched by the addition of excess aq NaHSO3 solution. The solid (indolizinium salt 6a) was filtered, washed with CH2Cl2, and dried.1-Hydroxy-2-iodo-1-methyl-3-phenyl-1 H -indolizinium Iodide (6a) 1H NMR (300 MHz, DMSO-d 6) δ = 8.64-8.59 (m, 2 H), 8.49 (d, J = 7.2 Hz, 1 H), 7.97 (t, J = 7.2 Hz, 1 H), 7.70-7.65 (m, 5 H), 6.71 (s, 1 H), 1.63 (s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 160.0, 145.6, 142.6, 136.6, 132.1, 131.3, 130.3, 128.3, 126.4, 124.0, 114.5, 82.6, 24.8. IR (KBr): 3496, 3214, 3080, 1622, 1481, 1360 cm-1. ESI-HRMS: m/z calcd for C15H14INO [M + 1]+: 351.0036; found: 351.0041.
A mixture of indolizinium salt 6a (0.31 mmol) and Cs2CO3 (1.5 equiv) in MeOH (10 mL) was heated to reflux for 1 h. After being cooled to r.t., the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and washed with H2O. The water layer was extracted with EtOAc one more time. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes-EtOAc-CH2Cl2, 7:1:2) to give 2-iodoindolizinone 7a.
2-Iodo-8a-methyl-3-phenylindolizin-1(8a H )-one (7a) 1H NMR (300 MHz, CDCl3): δ = 7.57-7.55 (m, 3 H), 7.50-7.46 (m, 2 H), 6.30 (d, J = 7.2 Hz, 1 H), 5.97-5.89 (m, 2 H), 5.33 (t, J = 6.3 Hz, 1 H), 1.48 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 199.0, 131.2, 129.2, 129.1, 129.0, 123.9, 123.1, 122.2, 109.3, 67.8, 63.5, 25.5. IR (KBr): 3092, 2978, 1674, 1522, 1420, 1295 cm-1. HRMS (EI): m/z calcd for [C15H12INO]+: 348.9964; found: 348.9968.

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The different nucleophilicity of the nitrogens in pyridine and quinoline should be also important. We thank one of the reviewers for this comment.

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The diastereomeric ratios of indolizinium salts 9 vary depending on the cyclization substrates 8 although they were inconsequential.

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1-Hydroxy-2-iodo-1-methyl-3-phenyl-2,3-dihydro-1 H -indolzinium iodide (9a) Mixture of diastereomers (1.1:1). 1H NMR (300 MHz, DMSO-d 6): δ = 8.70-8.65 (d, J = 7.8 Hz, 1 H), 8.43, 8.34 (d, J = 8.1 Hz, 1 H), 8.27, 8.25 (d, J = 6.0 Hz, 1 H), 7.99, 7.93 (d, J = 7.5 Hz, 1 H), 7.64-7.54 (m, 5 H), 6.89, 6.87 (s, 1 H), 6.20, 6.17 (d, J = 10.8 Hz, 1 H), 4.77, 4.74 (d, J = 10.8 Hz, 1 H), 1.79, 1.66 (s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 159.9, 157.5, 147.7, 140.7, 140.4, 132.4, 132.3, 131.3, 131.1, 130.4, 130.2, 130.0, 129.9, 128.3, 128.1, 123.7, 123.6, 78.9, 78.1, 76.8, 76.7, 37.7, 37.5, 28.3, 22.2. IR (KBr): 3100, 1678, 1536, 1486, 1392, 1251 cm-1. ESI-HRMS: m/z calcd for C15H16INO [M + 1]+: 353.0193; found: 353.0198.
8a-Methyl-3-phenylindolizin-1 (8a H )-one (10a) 1H NMR (300 MHz, CDCl3): δ = 7.56-7.47 (m, 5 H), 6.53 (d, J = 7.3 Hz, 1 H), 5.98-5.88 (m, 2 H), 5.38 (ddd, J = 6.8, 4.7, 1.9 Hz, 1 H), 5.18 (s, 1 H), 1.45 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 203.2, 172.7, 131.2, 129.8, 129.2, 128.3. 124.0. 123.0, 122.1, 109.0, 99.0, 68.8, 25.2. IR (KBr): 3275, 2939, 1622, 1573, 1485, 1380, 1261, 1136 cm-1. HRMS (EI): m/z calcd for [C15H13NO]+: 223.0997; found: 223.0993.

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Nonaqueous workup, i.e. filtration of the reaction mixture, was used in this case to isolate the indolizinium salt 6n. Addition of aq NaHSO3 solution to the reaction mixture resulted in uncharacterizable product instead, indicating that 6n is, unlike others, unstable to an aqueous environment.