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

Jihyun Choi; Ge Hyeong Lee; Ikyon Kim

doi:10.1055/s-2008-1072721

LETTER

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;

Abstract

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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.

Key words

indolizinones - iodine - cyclizations - rearrangements - 1,2-migration

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References

References and Notes

<A NAME="RU00908ST-1A">1a</A> Kim I. Lee GH. No ZS. Bull. Korean Chem. Soc. 2007, 28: 685

<A NAME="RU00908ST-1B">1b</A> Kim I. Choi J. Won HK. Lee GH. Tetrahedron Lett. 2007, 48: 6863

<A NAME="RU00908ST-1C">1c</A> Kim I. Won HK. Choi J. Lee GH. Tetrahedron 2007, 63: 12954

<A NAME="RU00908ST-1D">1d</A> Kim I. Kim SG. Kim JY. Lee GH. Tetrahedron Lett. 2007, 48: 8976

<A NAME="RU00908ST-1E">1e</A> Kim I. Kim SG. Choi J. Lee GH. Tetrahedron 2008, 64: 664

<A NAME="RU00908ST-2A">2a</A> Smith CR. Bunnelle EM. Rhodes AJ. Sarpong R. Org. Lett. 2007, 9: 1169

<A NAME="RU00908ST-2B">2b</A> Yan B. Zhou Y. Zhang H. Chen J. Liu Y. J. Org. Chem. 2007, 72: 7783

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

Scheme 8

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

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.

For other unsuccessful iodocyclization results with terminal alkynes, see:

<A NAME="RU00908ST-6A">6a</A> Worlikar SA. Kesharwani T. Yao T. Larock RC. J. Org. Chem. 2007, 72: 1347

<A NAME="RU00908ST-6B">6b</A> Bew SP. El-Taeb GMM. Jones S. Knight DW. Tan W.-F. Eur. J. Org. Chem. 2007, 5759

<A NAME="RU00908ST-7">7</A> Reaction of I₂ with a small amount of H₂O contained in CH₂Cl₂ is known to produce HI, which would be responsible for generation of carbocation A

<A NAME="RU00908ST-8">8</A> Sromek AW. Rubina M. Gevorgyan V. J. Am. Chem. Soc. 2005, 127: 10500

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

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

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.

<A NAME="RU00908ST-12">12</A> Baldwin JE. J. Chem. Soc., Chem. Commun. 1976, 734

For the synthesis of 5,6,7,8-tetrahydro-8-quinolinone, see:

<A NAME="RU00908ST-13A">13a</A> Thummel RP. Lefoulon F. Cantu D. Mahadevan R. J. Org. Chem. 1984, 49: 2208

<A NAME="RU00908ST-13B">13b</A> Kelly TR. Lebedev RL. J. Org. Chem. 2002, 67: 2197

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.

For diastereoselective catalytic hydrogenation approaches to indolizidines, see:

<A NAME="RU00908ST-15A">15a</A> Shono T. Matsumura Y. Tsubata K. Inoue K. Nishida R. Chem. Lett. 1983, 21

<A NAME="RU00908ST-15B">15b</A> Jiang C. Frontier AJ. Org. Lett. 2007, 9: 4939 ; and references therein

<A NAME="RU00908ST-15C">15c</A> Azzouz R. Fruit C. Bischoff L. Marsais F. J. Org. Chem. 2008, 73: 1154 ; and references therein