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Synlett 2010(16): 2397-2402  
DOI: 10.1055/s-0030-1258544
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Synthesis of de novo Imidates via Aza-Claisen Rearrangements of N-Allyl Ynamides

Kyle A. DeKorver, Troy D. North, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, Rennebohm Hall, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA
Fax: +1(608)2625345; e-Mail: rhsung@wisc.edu;
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Publication History

Received 22 June 2010
Publication Date:
26 August 2010 (online)

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Abstract

A novel thermal 3-aza-Claisen rearrangement of N-allyl ynamides for the synthesis of α-allyl imidates is described. Also, a sequential aza-Claisen, palladium-catalyzed Overman rearrangement is described for the synthesis of azapin-2-ones.

Key words

ynamide - aza-Claisen - imidate - ketenimine - Overman rearrangement

    References and Notes

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14

Selected Experimental Procedures and Characterizations Synthesis of Nitrile 8
To a stirring solution of ynamide 5a (75.0 mg, 0.19 mmol) in toluene (2 mL) at r.t. was slowly added freshly prepared NaOMe (31.0 mg, 0.58 mmol). After addition, the reaction mixture was sealed under dry nitrogen and heated to 100 ˚C for 1 h. Over the course of the reaction, TsOMe was observed to precipitate out of solution and was subsequently removed by filtration of the crude reaction mixture through a plug of CeliteTM to afford the pure nitrile 8 (45.6 mg, 0.19 mmol, >95% yield) as a colorless oil.
R f  = 0.45 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.00-1.41 (m, 21 H), 2.05 (dd, 1 H, J = 7.5, 4.0 Hz), 2.28-2.34 (m, 1 H), 2.35-2.44 (m, 1 H), 5.14 (d, 1 H, J = 10.5 Hz), 5.17 (d, 1 H, J = 18.0 Hz), 5.88-5.98 (m, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 11.3, 14.4, 18.9, 31.8, 117.2, 122.7, 136.2. IR (film): 2946 (m), 2869 (m), 2222 (w), 1595 (m), 1377 (m) cm-¹. MS (APCI): m/e (%) = 238 (100) [M + H]+.
Synthesis of Alcohol 10 To a stirring solution of ynamide 9 (315.0 mg, 0.77 mmol) in THF (2 mL) at r.t. was slowly added TBAF (0.85 mL, 1.0 M in THF). After 2 h, the solvent was removed via rotary evaporation, and the crude oil was purified by flash silica gel column chromatography [isocratic eluent: hexanes-EtOAc, 1:1] to afford the alcohol 10 (191.0 mg, 0.65 mmol, 85% yield) as a pale yellow oil.
R f  = 0.09 (hexanes-EtOAc = 2:1). ¹H NMR (500 MHz, CDCl3): δ = 1.52 (br s, 1 H), 1.73 (pent, 2 H, J = 6.5 Hz), 2.38 (t, 2 H, J = 7.0 Hz), 3.71 (d, 2 H, J = 7.0 Hz), 3.91 (d, 2 H, J = 7.0 Hz), 5.19 (d, 1 H, J = 10.5 Hz), 5.24 (d, 1 H, J = 17.5 Hz), 5.72 (ddt, 1 H, J = 17.5, 10.5, 7.0 Hz), 7.34 (d, 2 H, J = 8.0 Hz), 7.78 (d, 2 H, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 15.4, 21.9, 31.8, 54.4, 61.9, 69.9, 73.8, 120.0, 128.0, 130.0, 131.4, 135.0, 144.8. IR (film): 3200 (br s), 2981 (m), 2878 (m), 1644 (m) cm-¹. MS (APCI): m/e (%) = 294 (100) [M + H]+. Nitrile 12 R f  = 0.41 (hexanes-EtOAc, 8:1). ¹H NMR (400 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.86 (s, 9 H), 1.66-1.85 (m, 2 H), 2.05 (dd, 2 H, J = 8.4, 6.8 Hz), 2.48 (s, 3 H), 2.67-2.79 (m, 2 H), 3.59 (t, 2 H, J = 6.0 Hz), 5.24 (d, 1 H, J = 16.8 Hz), 5.26 (d, 1 H, J = 10.0 Hz), 5.82 (ddt, 1 H, J = 17.6, 10.0, 7.2 Hz), 7.40 (d, 2 H, J = 8.0 Hz), 7.88 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 5.2, 18.4, 22.0, 26.1, 28.3, 28.7, 36.8, 62.1, 65.8, 116.9, 121.9, 129.8, 130.2, 131.0, 131.7. IR (film): 2929 (m), 2857 (m), 2238 (w), 1596 (m), 1331 (s), 1150 (s) cm-¹. MS (APCI): m/e (%) = 408 (100)
[M + H]+, ESI-HRMS: m/e calcd for C21H33NO3SSiNa: 430.1843; found: 430.1860.
Synthesis of Compound 13 To a solution of ynamide 10 (75.0 mg, 0.26 mmol) in THF (5 mL) at 0 ˚C was added NaH (19.0 mg, 0.46 mmol, 60% wt/wt in mineral oil). The reaction mixture was warmed to r.t. and stirred for 20 min to allow for complete deproto-nation and then sealed under dry nitrogen and heated to 85 ˚C for 3 h. The reaction mixture was quenched with H2O, and the organic phase was extracted with EtOAc and then dried over Na2SO4. Removal of the solvent by rotary evaporation and purification by flash silica gel column chromatography (hexanes-EtOAc, 4:1) afforded 13 (50.0 mg, 0.17 mmol, 65% yield) as a colorless oil.
Compound 13
R f  = 0.35 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.90 (pent, 2 H, J = 9.5 Hz), 2.40 (s, 3 H), 2.49 (td, 2 H, J = 9.5, 2.0 Hz), 3.96 (t, 2 H, J = 8.0 Hz), 3.97 (d, 2 H, J = 8.5 Hz), 4.86 (s, 1 H), 5.06 (dd, 1 H, J = 13.0, 2.0 Hz), 5.14 (dd, 1 H, J = 20.0, 2.0 Hz), 5.76 (ddt, 1 H, J = 20.0, 13.0, 8.5 Hz), 7.26 (d, 2 H, J = 9.5 Hz), 7.70 (d, 2 H, J = 9.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 21.8, 24.6, 28.4, 52.3, 72.0, 94.9, 117.6, 127.7, 129.4, 134.1, 136.9, 143.1, 157.4. IR (film): 3055 (m), 2980 (m), 1597 (s), 1337 (s) cm-¹.
MS (APCI): m/e (%) = 294 (100) [M + H]+. ESI-HRMS: m/e calcd for C15H19NO3SNa: 316.0978; found: 316.0986. Compound 14
R f  = 0.38 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.99 (pent, 2 H, J = 7.0 Hz), 2.43 (s, 3 H), 2.80 (td, 2 H, J = 8.0, 2.0 Hz), 3.66 (d, 2 H, J = 6.5 Hz), 4.16 (t, 2 H, J = 6.5 Hz), 4.76 (t, 1 H, J = 2.0 Hz), 5.08-5.13 (m, 2 H), 5.70 (ddt, 1 H, J = 17.0, 10.0, 6.5 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.67 (d, 2 H, J = 8.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 21.8, 24.4, 28.1, 54.8, 72.1, 97.8, 119.1, 127.9, 129.8, 133.1, 135.0, 143.5, 166.8. MS (APCI): m/e (%) = 294 (20) [M + H]+.
General Procedure for the Synthesis of Imidates 4a-l To a flame-dried vial containing 4 Å MS was added the appropriate ynamide and anhydrous alcohol solvent (0.04 M in ynamide). The reaction mixture was sealed under dry nitrogen and heated to 75-95 ˚C for 2-5 d. Upon cooling to r.t., the mixture was filtered through a plug of CeliteTM. Removal of the alcohol solvent in vacuo followed by flash

silica gel column chromatography afforded the respective imidate.
Imidate 4a R f  = 0.45 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.15 (d, 9 H, J = 7.5 Hz), 1.20 (d, 9 H, J = 7.5 Hz), 1.35 (sept, 3 H, J = 7.5 Hz), 2.46 (s, 3 H), 2.50 (m, 1 H), 2.62 (ddd, 1 H, J = 20.5, 12.5, 8.5 Hz), 3.71 (dd, 1 H, J = 3.0, 12.0 Hz), 3.73 (s, 3 H), 4.92 (dd, 1 H, J = 10.0, 1.0 Hz), 5.00 (ddt, 1 H, J = 17.0, 3.0, 1.5 Hz), 5.73 (dddd, 1 H, J = 22.5, 14.0, 8.5, 5.5 Hz), 7.31 (d, 2 H, J = 8.0 Hz), 7.86 (d, 2 H, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 19.1, 19.1, 21.8, 32.6, 34.2, 54.0, 115.8, 126.9, 129.4, 137.5, 140.2, 143.0, 178.4. IR (film): 2948 (m), 2868 (m), 1582 (s), 1288 (s) cm-¹. MS (APCI): m/e (%) = 424 (100) [M + H]+. ESI-HRMS: m/e calcd for C22H37NO3SSiNa: 446.2156; found: 446.2161.
Imidate 4b R f  = 0.38 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.11 (d, 9 H, J = 7.5 Hz), 1.16 (d, 9 H, J = 7.5 Hz), 1.24 (t, 3 H, J = 7.0 Hz), 1.31 (sept, 3 H, J = 7.5 Hz), 2.41 (s, 3 H), 2.59 (dt, 1 H, J = 13.5, 9.0 Hz), 3.64 (dd, 1 H, J = 12.5, 3.0 Hz), 4.04-4.17 (m, 2 H), 4.87 (d, 1 H, J = 10.0 Hz), 4.95 (d, 1 H, J = 16.5 Hz), 5.63-5.73 (m, 1 H), 7.26 (d, 2 H, J = 7.5 Hz), 7.80 (d, 2 H, J = 8.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.7, 13.9, 19.1, 19.1, 21.7, 32.4, 34.2, 64.2, 115.7, 126.8, 129.3, 137.5, 140.2, 142.8, 177.8. IR (film): 2948 (m), 2871 (m), 1965 (w), 1575 (s), 1289 (s), 1155 (s) cm-¹. MS (APCI): m/e (%) = 438 (100) [M + H]+. ESI-HRMS: m/e calcd for C23H39NO3SSiNa: 460.2313; found: 460.2295.
Imidate 4c R f  = 0.19 (hexanes-EtOAc, 15:1). ¹H NMR (500 MHz, CDCl3): δ = 1.13 (d, 9 H, J = 7.5 Hz), 1.14 (d, 3 H, J = 6.0 Hz), 1.15 (d, 9 H, J = 7.5 Hz), 1.25 (d, 3 H, J = 6.0 Hz), 1.31 (sept, 3 H, J = 7.5 Hz), 2.41 (s, 3 H), 2.40-2.48 (m, 1 H), 2.57 (dt, 1 H, J = 14.0, 8.5 Hz), 2.84 (dd, 1 H, J = 12.0, 3.0 Hz), 4.86 (d, 1 H, J = 10.0 Hz), 4.96 (dd, 1 H, J = 17.0, 1.0 Hz), 5.03 (sept, 1 H, J = 6.0 Hz), 5.68 (dddd, 1 H, J = 17.0, 10.0, 8.5, 5.5 Hz), 7.26 (d, 2 H, J = 8.0 Hz), 7.80 (d, 2 H, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 19.2, 21.6, 21.7, 21.8, 32.4, 34.4, 71.9, 115.8, 126.8, 129.3, 137.4, 140.4, 142.7, 177.2. IR (film): 2946 (m), 2868 (m), 1570 (s), 1464 (m), 1287 (m), 1153 (s) cm-¹. MS (APCI): m/e (%) = 410 (100) [M - propene + H]+. ESI-HRMS: m/e calcd for C24H41NO3SSiNa: 474.2469; found: 474.2446.
Imidate 4d R f  = 0.41 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.12 (d, 9 H, J = 9.5 Hz), 1.15 (d, 9 H, J = 9.5 Hz), 1.31 (sept, 3 H, J = 9.5 Hz), 1.50-1.82 (m, 8 H), 2.41 (s, 3 H), 2.40-2.47 (m, 1 H), 2.55 (dt, 1 H, J = 18.0, 10.5 Hz), 3.64 (dd, 1 H, J = 15.5, 4.0 Hz), 4.86 (d, 1 H, J = 12.5 Hz), 4.94 (d, 1 H, J = 21.0 Hz), 5.12-5.16 (m, 1 H), 5.62-5.74 (m, 1 H), 7.25 (d, 2 H, J = 10.0 Hz), 7.80 (d, 2 H, J = 10.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 19.2, 21.7, 23.8, 24.2, 32.2, 32.9, 34.4, 81.4, 115.6, 126.8, 129.3, 137.6, 140.5, 142.7, 117.5. IR (film): 2946 (m), 2869 (m), 1571 (s), 1463 (w), 1287 (m), 1153 (s) cm-¹. MS (APCI): m/e (%) = 410 (100) [M - cyclopentene + H]+. ESI-HRMS: m/e calcd for C26H43NO3SSiNa: 500.2626; found: 500.2618.
Imidate 4e R f  = 0.42 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.12 (d, 9 H, J = 9.0 Hz), 1.16 (d, 9 H, J = 9.5 Hz), 1.26 (t, 3 H, J = 9.0 Hz), 1.32 (sept, 3 H, J = 9.5 Hz), 2.44-2.52 (m, 1 H), 2.61 (dt, 1 H, J = 17.5, 11.0 Hz), 3.59 (dd, 1 H, J = 15.5, 4.0 Hz), 4.05-4.15 (m, 2 H), 4.93 (d, 1 H, J = 12.5 Hz), 4.99 (d, 1 H, J = 21.0 Hz), 5.71-5.82 (m, 1 H), 8.09 (d, 2 H, J = 11.5 Hz), 8.32 (d, 2 H, J = 11.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 13.9, 19.0, 19.1, 33.5, 34.3, 64.8, 116.1, 124.2, 128.0, 137.3, 148.6, 179.5. IR (film): 2943 (w), 2868 (w), 1566 (s), 1531 (s), 1295 (s), 1159 (s) cm-¹. MS (APCI): m/e (%) = 469 (100) [M + H]+. ESI-HRMS: m/e calcd for C22H36N2O5SSiNa: 491.2007; found: 491.2007.
Imidate 4f R f  = 0.27 (hexanes-EtOAc, 15:1). ¹H NMR (400 MHz, CDCl3): δ = 1.14 (d, 9 H, J = 7.2 Hz), 1.15 (d, 3 H, J = 6.4 Hz), 1.17 (d, 9 H, J = 7.6 Hz), 1.28 (d, 3 H, J = 6.4 Hz), 1.32 (sept, 3 H, J = 7.6 Hz), 2.46-2.52 (m, 1 H), 2.60 (dt, 1 H, J = 14.4, 8.8 Hz), 3.61 (dd, 1 H, J = 12.0, 3.6 Hz), 4.93 (d, 1 H, J = 10.0 Hz), 4.96-5.04 (m, 2 H), 5.76 (dddd, 1 H, J = 17.0, 10.0, 8.8, 5.2 Hz), 8.10 (d, 2 H, J = 9.2 Hz), 8.33 (d, 2 H, J = 8.8 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 19.1, 19.1, 21.5, 21.8, 33.4, 34.4, 72.9, 116.1, 124.2, 128.0, 137.3, 148.7, 149.9, 178.9. IR (film): 2946 (m), 2869 (m), 1562 (s), 1531 (s), 1349 (s), 1296 (s), 1156 (s) cm-¹. MS (APCI): m/e (%) = 441 (30) [M - propene + H]+. ESI-HRMS: m/e calcd for C23H38N2O5SSiNa: 505.2163; found: 505.2164.
Imidate 4g R f  = 0.36 (hexanes-EtOAc, 10:1). ¹H NMR (400 MHz, CDCl3): δ = 1.13 (d, 9 H, J = 7.2 Hz), 1.16 (d, 9 H, J = 7.6 Hz), 1.33 (sept, 3 H, J = 7.6 Hz), 1.50-1.88 (m, 8 H), 2.46-2.51 (m, 1 H), 2.58 (dt, 1 H, J = 14.0, 8.4 Hz), 3.60 (dd, 1 H, J = 12.0, 3.2 Hz), 4.92 (d, 1 H, J = 10.0 Hz), 5.00 (d, 1 H, J = 16.8 Hz), 5.09-5.14 (m, 1 H), 5.70-5.82 (m, 1 H), 8.11 (d, 2 H, J = 8.4 Hz), 8.33 (d, 2 H, J = 8.8 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 11.8, 19.1, 23.8, 24.1, 32.2, 32.9, 33.2, 34.4, 82.2, 116.0, 124.1, 128.0, 137.4, 148.7, 149.9, 179.1. IR (film): 2947 (m), 2871 (m), 1565 (s), 1531 (s), 1349 (s), 1303 (m), 1157 (s) cm-¹. MS (APCI): m/e (%) = 441 (30)
[M - cyclopentene + H]+. ESI-HRMS: m/e calcd for C25H40N2O5SSiNa: 531.2320; found: 530.2333. Imidate 4h R f  = 0.30 (hexanes-EtOAc, 4:1). ¹H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 3.59 (tt, 2 H, J = 6.0, 1.2 Hz), 3.69 (s, 3 H), 4.49 (t, 1 H, 6.0 Hz), 5.10 (ddt, 1 H, J = 10.4, 2.8, 1.6 Hz), 5.16 (ddt, 1 H, J = 17.2, 2.8, 1.6 Hz), 5.72 (ddt, 1 H, J = 17.2, 10.4, 6.0), 7.24-7.34 (m, 7 H), 7.76 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 21.6, 41.3, 45.8, 52.2, 117.7, 127.2, 127.3, 128.7, 129.4, 129.8, 133.2, 134.1, 137.1, 143.6, 172.2. IR (film): 3034 (m), 2951 (m), 1735 (s), 1597 (m), 1325 (s) cm-¹. MS (APCI): m/e (%) = 344 (100) [M + H]+. ESI-HRMS: m/e calcd for C19H21NO3SNa: 366.1135; found: 366.1150.
Imidate 4i R f  = 0.48 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.26 (t, 3 H, J = 7.0 Hz), 2.41 (s, 3 H), 2.63 (dt, 1 H, J = 13.5, 6.5 Hz) 2.83 (dt, 1 H, J = 16.5, 8.0 Hz), 4.09 (dq, 1 H, J = 11.0, 7.0 Hz), 4.19 (dq, 1 H, J = 11.0, 7.0 Hz), 4.98-5.04 (m, 2 H), 5.10 (dd, 1 H, J = 17.0, 1.5 Hz), 5.70-5.80 (m, 1 H), 7.23-7.28 (m, 3 H), 7.32 (t, 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 7.5 Hz), 7.77 (d, 2 H, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 13.7, 21.7, 36.0, 37.9, 48.9, 64.6, 117.7, 126.9, 127.8, 128.8, 129.0, 129.5, 134.9, 137.8, 143.3, 174.6. IR (film): 2985 (w), 1592 (s), 1301 (s), 1152 (s) cm-¹. MS (APCI): m/e (%) = 358 (100) [M + H]+. ESI-HRMS: m/e calcd for C20H23NO3SNa: 380.1291; found: 380.1287. Imidate 4j R f  = 0.32 (hexanes-EtOAc, 6:1). ¹H NMR (500 MHz, CDCl3): δ = 1.14 (d, 3 H, J = 6.0 Hz), 1.25 (d, 3 H, J = 6.5 Hz), 2.40 (s, 3 H), 2.59 (dt, 1 H, J = 12.5, 5.5 Hz), 2.80 (dt, 1 H, J = 14.5, 8.5 Hz), 4.97 (m, 3 H), 5.10 (d, 1 H, J = 17.5 Hz), 5.70-5.79 (m, 1 H), 7.22-7.27 (m, 3 H), 7.31 (t, 2 H, J = 7.5 Hz), 7.44 (d, 2 H, J = 8.0 Hz), 7.75 (d, 2 H, J = 8.5 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 21.3, 21.4, 21.7, 38.1, 48.9, 72.5, 117.7, 126.8, 127.7, 128.7, 128.8, 129.5, 134.8, 137.9, 139.7, 143.1, 174.0. IR (film): 2984 (w), 1592 (s), 1302 (s), 1156 (s) cm-¹. MS (APCI): m/e (%) = 330 (100)
[M - propene + H]+. ESI-HRMS: m/e calcd for C21H25NO3SNa: 394.1448; found: 394.1440. Imidate 4k R f  = 0.33 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.25 (t, 3 H, J = 7.0 Hz), 2.62 (dt, 1 H, J = 13.5, 7.0 Hz), 2.83 (dt, 1 H, J = 15.5, 8.5 Hz), 3.84 (s, 3 H), 4.09 (dq, 1 H, J = 11.0, 7.0 Hz), 4.18 (dq, 1 H, J = 11.0, 7.0 Hz), 4.99-5.04 (m, 2 H), 5.09 (d, 1 H, J = 17.0 Hz), 5.70-5.59 (m, 1 H), 6.91 (d, 2 H, J = 9.0 Hz), 7.26 (t, 1 H, J = 7.5 Hz), 7.32 (d, 2 H, J = 7.5 Hz), 7.45 (d, 2 H, J = 7.5 Hz), 7.81 (d, 2 H, J = 9.0 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 13.7, 37.9, 48.8, 55.7, 64.8, 114.0, 117.7, 127.7, 128.8, 128.9, 128.9, 133.1, 134.9, 137.8, 162.9, 174.4. IR (film): 2986 (w), 1593 (s), 1499 (m), 1298 (s), 1150 (s) cm-¹. MS (APCI): m/e (%) = 374 (100) [M + H]+. ESI-HRMS: m/e calcd for C20H23NO4SNa: 396.1231; found: 396.1240.
Imidate 4l R f  = 0.20 (hexanes-EtOAc, 4:1). ¹H NMR (500 MHz, CDCl3): δ = 1.55-1.83 (m, 8 H), 2.59 (dt, 1 H, J = 12.5, 6.5 Hz), 2.79 (dt, 1 H, J = 17.0, 8.0 Hz), 3.85 (s, 3 H), 4.99 (dd, 1 H, J = 9.0, 7.0 Hz), 5.02 (d, 1 H, J = 11.0 Hz), 5.09 (dd, 1 H, J = 17.0, 1.5 Hz), 5.12-5.17 (m, 1 H), 5.74 (dddd, 1 H, J = 17.0, 10.0, 7.5, 5.5 Hz), 6.92 (d, 2 H, J = 9.0 Hz), 7.24-7.28 (m, 1 H), 7.31 (t, 2 H, J = 7.0 Hz), 7.43 (d, 2 H, J = 7.5 Hz), 7.81 (d, 2 H, J = 9.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 24.0, 32.4, 32.6, 38.0, 48.8, 55.8, 81.8, 114.0, 117.6, 127.7, 128.7, 128.8 128.8, 134.6, 134.9, 137.9, 162.7, 173.9. IR (film): 2968 (w), 2850 (w), 1579 (s), 1294 (s), 1257 (s), 1150 (s) cm-¹. MS (APCI): m/e (%) = 346 (100) [M - cyclopentene + H]+. ESI-HRMS: m/e calcd for C23H27NO4SNa: 436.1553; found: 436.1552.
Imidate 15
R f  = 0.50 (hexanes-EtOAc, 4:1). ¹H NMR (400 MHz, CDCl3): δ = 1.11 (d, 9 H, J = 7.6 Hz), 1.17 (d, 9 H, J = 7.6 Hz), 1.31 (sept, 3 H, J = 7.6 Hz), 2.41 (s, 3 H), 2.43-2.48 (m, 1 H), 2.61 (td, 1 H, J = 13.6, 8.8 Hz), 3.67 (dd, 1 H, J = 12.0, 3.2 Hz), 4.47 (dd, 1 H, J = 12.8, 6.0 Hz), 4.59 (dd, J = 12.8, 6.0 Hz), 4.87 (d, 1 H, J = 10.0 Hz), 4.95 (d, 1 H, J = 17.2 Hz), 5.22 (d, 1 H, J = 10.4 Hz), 5.28 (dd, 1 H, J = 16.0, 1.2 Hz), 5.63-5.74 (m, 1 H), 5.87 (ddt, 1 H, J = 16.8, 10.0, 6.0 Hz), 7.26 (d, 2 H, J = 8.0 Hz), 7.80 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 11.8, 19.1, 21.7, 32.5, 34.2, 69.1, 115.9, 119.8, 126.8, 126.9, 129.4, 131.6, 137.4, 140.1, 142.9, 177.4 cm-¹. IR (film): 2943 (m), 2869 (m), 1584 (s), 1302 (m), 1155 (s) cm-¹. MS (APCI): m/e (%) = 450 (100) [M + H]+. ESI-HRMS: m/e calcd for C24H39NO3SSiNa: 472.2313; found: 472.2305.
Synthesis of Amide 16 To a stirring solution of imidate 15 (35.0 mg, 0.078 mmol) in DCE (0.4 mL) was added PdCl2(PhCN)2 (1.5 mg, 0.004 mol). The reaction was stirred under a nitrogen atmosphere for 3 h at r.t., and then the solvent was removed by rotary evaporation. The crude residue was purified by flash silica gel column chromatography [isocratic eluent: hexanes-EtOAc, 20:1] to afford the amide 16 (35.0 mg, 0.078 mmol, >95% yield) as a colorless oil.
R f  = 0.50 (hexanes-EtOAc, 4:1). ¹H NMR (400 MHz, CDCl3): δ = 1.05 (d, 9 H, J = 6.8 Hz), 1.11 (d, 9 H, J = 6.8 Hz), 1.13-1.25 (m, 3 H), 2.26 (dd, 1 H, J = 11.6, 6.4 Hz), 2.43 (s, 3 H), 2.66 (td, 1 H, J = 13.2, 7.2 Hz), 3.00 (br s, 1 H), 4.34 (dd, 1 H, J = 16.4, 6.8 Hz), 4.47-4.54 (m, 1 H), 4.69 (d, 1 H, J = 10.0 Hz), 4.82 (d, 1 H, J = 16.8 Hz), 5.21 (d, 1 H, J = 10.0 Hz), 5.27 (d, 1 H, J = 17.2 Hz), 5.21-5.37 (m, 1 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.83 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 11.8, 18.8, 19.2, 21.8, 34.8, 49.5, 116.0, 119.0, 128.0, 128.8, 129.5, 133.6, 137.4, 144.6, 176.0. IR (film): 2950 (m), 2870 (m), 1678 (s), 1352 (s)
cm-¹. MS (APCI): m/e (%) = 450 (100) [M + H]+. ESI-HRMS: m/e calcd for C24H39NO3SSiNa: 472.2313; found: 472.2317. Synthesis of Azapin-2-one 17
To a solution of amide 16 (35.0 mg, 0.078 mmol) in DCE was added Grubbs I catalyst (3.2 mg, 0.004 mmol). The reaction vial was flushed with dry nitrogen, sealed, and heated to 70 ˚C for 16 h. The solvent was removed by rotary evaporation, and the crude residue was purified by flash silica gel column chromatography [isocratic eluent: hexanes-EtOAc, 10:1] to afford azapin-2-one 17 (29.5 mg, 0.070 mmol, 90% yield) as a white solid.
R f  = 0.30 (hexanes-EtOAc, 8:1). Mp 129-130 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.95 (d, 9 H, J = 7.5 Hz), 0.99 (d, 9 H, J = 7.5 Hz), 1.18 (sept, 3 H, J = 7.5 Hz), 2.28-2.40 (m, 1 H), 2.41 (s, 3 H), 2.41-2.48 (m, 1 H), 2.90 (dd, 1 H, J = 13.0, 2.5 Hz), 4.49 (dt, 1 H, J = 18.0, 3.0 Hz), 4.81 (dd, 1 H, J = 18.0, 8.0 Hz), 5.75-5.79 (m, 1 H), 5.83-5.88 (m, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.83 (d, 2 H, J = 8.0 Hz). ¹³C NMR (120 MHz, CDCl3): δ = 11.2, 19.3, 21.8, 28.1, 31.0, 43.1, 123.9, 128.5, 129.3, 133.6, 136.8, 144.3, 175.4. IR (film): 2943 (m), 2866 (m), 1963 (s), 1597 (w), 1350 (s) cm-¹. MS (APCI): m/e (%) = 422 (100) [M + H]+. ESI-HRMS: m/e calcd for C22H35NO3SSiNa: 444.2000; found: 444.2000.