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

Kyle A. DeKorver; Troy D. North; Richard P. Hsung

doi:10.1055/s-0030-1258544

LETTER

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;

Abstract

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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

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References

References and Notes

For reviews, see:

1a DeKorver KA. Li H. Lohse AG. Hayashi R. Lu Z. Zhang Y. Hsung RP. Chem. Rev. 2010, 110: in press

1b Evano G. Coste A. Jouvin K. Angew. Chem. Int. Ed. 2010, 49: 2840

For examples in 2010, see:

2a Li H. Antoline JE. Yang J.-H. Al-Rashid ZF. Hsung RP. New J. Chem. 2010, 34: in press

2b Kramer S. Madsen JLH. Rottländer M. Skrydstrup T. Org. Lett. 2010, 12: 2758

2c Banerjee B. Litvinov DN. Kang J. Bettale JD. Castle SL. Org. Lett. 2010, 12: 2650

2d Gourdet B. Rudkin ME. Lam HW. Org. Lett. 2010, 12: 2554

2e Jia W. Jiao N. Org. Lett. 2010, 12: 2000

2f Burley GA. Davies DL. Griffith GA. Lee M. Singh K. J. Org. Chem. 2010, 75: 980

2g Yamasaki R. Terashima N. Sotome I. Komagawa S. Saito S. J. Org. Chem. 2010, 75: 480

3 Zhang Y. DeKorver KA. Lohse AG. Zhang Y.-S. Huang J. Hsung RP. Org. Lett. 2009, 11: 899

4 DeKorver KA. Hsung RP. Lohse AG. Zhang Y. Org. Lett. 2010, 12: 1840

For leading reviews on aza-Claisen rearrangements, see:

5a Majumdar KC. Bhayyacharyya T. Chattopadhyay B. Nandi RK. Synthesis 2009, 2117

5b Nubbemeyer U. Top Curr. Chem. 2005, 244: 149

For some examples of aza-Claisen rearrangements, see:

5c Majumdar KC. Samanta S. Chattopadhyay B. Nandi RK. Synthesis 2010, 863

5d Cheung LLW. Yudin AK. Org. Lett. 2009, 11: 1281

5e Cant AA. Bertrand GHV. Henderson JL. Roberts L. Greaney MF. Angew. Chem. Int. Ed. 2009, 48: 5199

For reviews on the chemistry of ketenimines, see:

6a Krow GR. Angew. Chem., Int. Ed. Engl. 1971, 10: 435

6b Gambaryan NP. Usp. Khim. 1976, 45: 1251

6c Dondoni A. Heterocycles 1980, 14: 1547

6d Barker MW. McHenry WE. In The Chemistry of Ketenes, Allenes and Related Compounds Part 2: Patai S. Wiley-Interscience; Chichester: 1980. p.701-720

6e Alajarin M. Vidal A. Tovar F. Targets Heterocycl. Syst. 2000, 4: 293

For examples of imidates serving as prodrugs, see:

7a Maryanoff BE. McComsey DF. Costanzo MJ. Yabut SC. Lu T. Player MR. Giardino EC. Damiano BP. Chem. Biol. Drug. Des. 2006, 68: 29

7b Poon SF. Stock N. Payne JE. McGuire AR. Stearns B. Yang X. Chen W. Munoz B. Smith ND. Bioorg. Med. Chem. Lett. 2005, 15: 2259

7c Bundgaard H. Drustrup Larsen J. J. Med. Chem. 1988, 31: 2066

For recent examples of amidine formation, see:

8a Shang Y. He X. Hu J. Wu J. Zhang M. Yu S. Zhang Q. Adv. Synth. Catal. 2009, 351: 2709

8b She J. Jiang Z. Wang Y. Synlett 2009, 2023

8c Yu RT. Rovis T. J. Am. Chem. Soc. 2008, 130: 3262

8d Yoo EJ. Ahlquist M. Bae I. Sharpless B. Fokin V. Chang S. J. Org. Chem. 2008, 73: 5520

For recent examples of imidate formation, see:

9a Song W. Lu W. Wang J. Lu P. Wang Y. J. Org. Chem. 2010, 75: 3481

9b Yoo EJ. Park SH. Lee SH. Chang S. Org. Lett. 2009, 11: 1155

9c Yoo EJ. Bae I. Cho SH. Han H. Chang S. Org. Lett. 2006, 8: 1347

10 For a recent example of α-functionalization of imidates, see: Matsubara R. Berthiol F. Kobayashi S. J. Am. Chem. Soc. 2008, 130: 1804

11 For a related 1,3-shift, see: Bendikov M. Duong HM. Bolanos E. Wudl F. Org. Lett. 2005, 7: 783

12a For leading references, see: Anderson CE. Overman LE. J. Am. Chem. Soc. 2003, 125: 12412

12b For a review, see: Overman LE. Acc. Chem. Res. 1980, 13: 218

Also see:

12c Overman LE. J. Am. Chem. Soc. 1974, 96: 597

12d Overman LE. J. Am. Chem. Soc. 1976, 98: 2901

13 Tomooka K. Suzuki M. Uehara K. Shimada M. Akiyama T. Synlett 2008, 2518

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 Celite^TM 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 Celite^TM. 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.