1. Ynamides By Marie-Eve Mayer – November 16 th, 2010

2.  Alkyne directly substituted by an amide or a N atom connected to a EWG group  An electron-deficient ynamine ynamidesYnecarbamates (yne-urethanes) ynureasynesulfonamidesynimides What is an ynamide? Utilities of EWG group : Stabilization Directing group Chiral auxilary

3. Ynamines vs ynamides  Ynamines : imposing an electronic bias  1 st isolated ynamine : Zaugg, in 1958  Ynamines are sensitive to hydrolysis Difficult storage, handling and synthesis  Ynamides : tempering the polarization by resonance  Enhanced stability towards heat, silica and aqueous workups Electrophiles add on the  position Nucleophiles add on the  position

4. Richard P. Hsung  Ph. D. in 1994 at the University of Chicago under supervision of William D. Wulff  Post. Doc. in 1996 at the University of Chicago under supervision of Lawrence R. Sita  Professor of Pharmaceutical Sciences and Chemistry at the University of Wisconsin- Madison  Associate professor at the University of Minnesota  150th publication will be out lately  Pioneer in ynamides chemistry  Visited UdeM in Spring 2005

5. This evening’s program...  Synthesis of ynamides  Elimination of halo-enamides  Starting from alkynyl iodonium salts  Isomerization of propargyl amides  Amidative Cross-Coupling with Cu  Reactivity of ynamides  Addition reactions At the  -position At the  -position (Umpolung) Cycloadditions  Oxidation reaction  Ring-closing metathesis

6. First pathway of synthesis: Elimination  Using a strong base to eliminate HX  First ynamide : Viehe et. al. in 1972 using phosgeneimmonium chloride  Procedure used by Hsung et. al. in 2001 H. G. Viehe et. al., Angew. Chem. Int. Ed. 1972, 11, 917. R.P. Hsung et. al. Tetrahedron 2001, 57, 459-466. Only the Z-isomer undergoes elimination

7. Starting from ,  -dichloro-enamides D. Brückner, Synlett 2000, 1402 – 1404. D. Rodriguez, M. F. Martnez-Espern, L. Castedo, C. Sa, Synlett 2007, 1963 – 1965. D. Rodriguez, L. Castedo, C. Sa, Synlett 2004, 783 – 786. S. Couty,M. Barbazanges, C. Meyer, J. Cossy, Synlett 2005, 905 –910.

8. Starting from alkynyl iodonium salts  Increase of publications about ynamides in late 90’s  1 st breakthrough: Feldman’s chiral ynamide synthesis (1996)  Based on Stang’s pionner work : Stang worked with push-pull ynamines Limited method due to the limited library of alkynyl iodonium salts Only substituted by silyl, aromatic or EWG groups Feldman, K.S. et. al.J. Org. Chem. 1996, 61, 5440-5452 Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255

9. Starting from alkynyl iodonium salts B. Witulski, T. Stengel, Angew. Chem. Int. Ed. 1998, 37, 489 – 492 EntryPGR Yield SM→ A (%) Yield A→ B (%) 1TolSO 2 nBu 8695 2TolSO 2 PhCH 2 7595 3CF 3 SO 2 PhCH 2 6555 4CF 3 COPhCH 2 77- 5PhCOPhCH 2 8198 6TolSO 2 CH 2 CH(CH 2 ) 2 8993 7TolSO 2 CH 2 CH(CHPh)CH 2 7078 8TolSO 2 CH 2 CHCH 2 CH(Ph) 2889 9TolSO 2 CH 2 CHCH 2 CH(Bu) 5091 10TolSO 2 (CH 2 CHCH 2 ) 2 CH 4383 Steric hindrance complicates nucleophilic attack

10. Starting from alkynyl iodonium salts  Ring-opening of aziridines Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037

11. Isomerization of propargyl amides  Method restricted to simple amides  Base-induced isomerization of acridone  Method not efficient on oxazolidinones or imidazolidinone  This paper shows the synthesis of allenamides and the failure to isomerise them into ynamides. Hsung et. Al. Tetrahedron, 2001, 57 459-466, Org. Lett. 2002, 4, 2417.

12. Isomerization of propargyl amides  Base-induced isomerization on propargyl urethanes is still ineffective  Propargyl amides substituted with alkyl linear chains readily isomerize to the ynamide Hsung et. Al., Org. Lett. 2002, 4, 2417.

13.  First synthesis of ynamides by a metal-mediated reaction ¨ Undesired side product by Balsamo and Domiano in 1985  Alkynylation of N nucleophiles using  Bromoalkynes  Terminal alkynes  Vinyl dibromides Amidative Cross-Coupling with Cu Balsamo, A. Domiano, P. Tet. Lett. 1985, 26, 4141

14. Amidative Cross-Coupling with Cu using bromoalkynes ConditionsHsung (2003)Danheiser (2003)Hsung (2004) Cu sourceCuCN (5%)CuI (1 eq) CuSO 4  5H 2 O (5-20%) Ligand(10%)-(10-40%) BaseK 3 PO 4 KHMDSK 3 PO 4 Solvent, T (°C)Toluene, 110°CPyridine, rtToluene, 60-95°C Examples231944 Yield (%)10-85%40-82%37-98% ProsFirst time using methodRoom tempEfficient with amides ConsHigh temp, sulfonamides not suitableStrong baseQuality of K 3 PO 4 is crucial R. P. Hsung, J. Am. Chem. Soc. 2003, 125, 2368 – 2369. Org. Lett. 2004, 6, 1151 – 1154, J. Org. Chem. 2006, 71, 4170 – 4177 Org. Synth. 2007, 84, 359. R. L. Danheiser, Org. Lett. 2003, 5, 4011 – 4014; Org. Synth. 2007, 84, 88 – 101. [

15. Amidative Cross-Coupling with Cu using bromoalkynes  Since we love macrocyclizations in our group...  Hsung applied his method to make macrolactones including enamides Securine B Securamine B Hsung, R. P.; J. Org. Chem. 2006, 71,4170 isolated from the marine bryozoan Securiflustra securifrons

16. Amidative Cross-Coupling with Cu using bromoalkynes  Other catalysts with a different metal ?  Y. Zhang reports use of FeCl 3 as efficient catalyst  But Buchwald publishes a paper about contaminants in FeCl 3 that might do all the work... Y. Zhang, J. Org. Chem. 2009, 74, 4630 – 4633. S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586 – 5587 FeCl 3 98 % (Merck) 98 % (Aldrich) 99.99 (Aldrich) 99.99 % + 5 ppm Cu 2 O 99.99 % +10 ppm Cu 2 O no Fe + ligand +5 ppm Cu 2 O no Fe + no ligand +5 ppm Cu 2 O Yield (%)8726978797723

17. Amidative Cross-Coupling with Cu using terminal alkynes  Stahl (2008) comes up with a catalytic process :  Limitations of the method : ¨ Use of 5 eq of the nucleophile ¨ Inhibits Glayser-Hay competitive reaction ¨ Low reactivity of some susbstrates (pyrrolidinones, acyclic amides etc) = = Stahl, S. S.; J. Am. Chem. Soc. 2008, 130, 833

18. Amidative Cross-Coupling with Cu using terminal alkynes  Proposed mechanism by Stahl Stahl, S. S.; J. Am. Chem. Soc. 2008, 130, 833 L substitution Red. Elim. L substitution Red. Elim. A B C D Excess of the amide favors formation of Cu II (alkynyl)(amidate) species C over bis-alkynyl-Cu II species D

19. Amidative Cross-Coupling with Cu using vinyl dibromides  Using vinyl dibromides : synthetic equivalent of bromoalkynes  Proposed mechanism : Isolated at low T°C Coste, A; Angew. Chem. Int. Ed. 2009, 48, 4381-4385 Ox. Ad. Red. Elim. Mild base and low T°C discards the hypothesis

20. Chemistry of ynamides  Addition reactions  At the  -position Brönsted acid-catalyzed Transition metal catalyzed Radical processes  At the  -position (Umpolung)  Cycloadditions [2+2] [4+2] [2+2+2] Cyclotrimerization  Oxidation reaction  Ring-closing metathesis 

21. Additions : to the  -position Brönsted Acid catalyzed addition  Hsung synthesis of (E)-  -haloenamides MgX 2 and DCM forms HX in situ Hsung et. Al., Org. Lett. 2003, 5, 1547. No yield with CuI, ZnCl 2, NaBr

22.  Arene-Ynamide cyclization via a Keteniminium Pictet-Spengler Cyclization Hsung et. Al., Org. Lett. 2005, 7, 1047. Additions : to the  -position Brönsted Acid catalyzed addition Z Z

23.  Arene-Ynamide cyclization via a Keteniminium Pictet-Spengler Cyclization  E:Z selectivity is inversed with PtCl 4 (π-acid) is used instead Hsung et. Al., Org. Lett. 2005, 7, 1047. Additions : to the  -position Brönsted Acid catalyzed addition With Bronsted acid :With π-acid :

24. Additions : to the  -position Brönsted Acid catalyzed addition  Asymmetric Ficini-Claisen rearrangement Approach of the allylic alcohol from the same side of the hetero-cumulene H gives a E-ketene aminal Hsung et. Al., Org. Lett. 2002, 4, 1383. EntryRR1R1 Yield (%)Syn : Isomers 1n-C 5 H 11 Me70%93 : 7 2n-C 4 H 9 Ph77%96 : 4 3n-C 4 H 9 CH 2 OBn63%95 : 5

25. Additions : to the  -position Brönsted Acid catalyzed addition  Asymmetric Saucy-Marbet rearrangement Stereochemistry of the allene is transmitted from the chiral propargyl alcohol Hsung et. Al., Org. Lett. 2003, 5, 2663. Forced mismatched reaction give dr : 1:1

26. Additions : to the  -position Transition metal catalyzed addition  Starting point: desired [2+2+2] product not obtained with change of silver salt Pro-M Pro-P Yield : 94% M : P = 4 : 1 Hsung et. Al., Org. Lett. 2007, 9, 2361. Bidentate coordination of ynamide to the rhodio(I) intermediate : Accepted pathway for [2+2+2] cycloaddition

27.  Demethylation-cyclization sequence using Wilkinson catalyst  Ag salts increases coordinating ability of Rh catalyst by stripping of Cl -  Nu : H 2 O  Sodium tetrafluoroborate works synergistically with Wilkinson Cat to promote demethylation Additions : to the  -position Transition metal catalyzed addition Hsung et. Al., Org. Lett. 2007, 9, 2361.

28. Additions : to the  -position Transition metal catalyzed addition  Demethylation vs cycloaddition

29. Additions : to the  -position Transition metal catalyzed addition  Aminoindoles synthesis  o-aminoaryl-ynamide intermediates obtained by amination of the o-halo corresponding derivative or by Sonogashira coupling Hsung et. Al., Org. Lett. 2008, 10, 4275. Skrydstrup, T. et. Al. Org Lett. 2009, 11, 221. Metal-mediated hydroamination

30. Additions : to the  -position Radical addition  Radical cascade : 5-exo-dig cyclization followed by a 6- endo-trig radical trapping Malacria, M. Org. Lett. 2003, 5, 5095. Terminal alkynes seems compatible only with o-iodo substituted aryls Activated alkynes make possible the addition of tin on C  C : Yield ↓

31. Additions : to the  -position Radical addition  Radical cascade : 5-exo-dig cyclization followed by a 6- endo-trig radical trapping Malacria, M. Org. Lett. 2003, 5, 5095.

32. Additions : to the  -position Radical addition  Radical cascade with ynamides bearing an aromatic terminator  Type I  Type 2 Malacria, M. Org. Lett. 2003, 5, 5095. Carbonyl plays an electronic and steric effect in the radical trapping

33. Additions : to the  -position  Can be considered as Umpolung addition  Controlled either by Steric hindrance Chelation with the EWG group 

34. Additions : to the  -position Electrophilic trapping of  -metalated derivatives  Regiochemically controlled carbometallation  Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098. ERYield (%) Method AMethod B Hn-Bu7281 HPh8490 allyln-Bu55N.D. In-Bu60N.D.

35. Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.  Single-pot preparation of an aldol surrogate Retrosynthesis : Additions : to the  -position Electrophilic trapping of  -metalated derivatives

36. Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.  One-pot carbocupration/Zn-homologation/allylation sequence  In situ generation of Simmons-Smith-Furukawa zinc carbenoid Transmetallation of Cu to Zn using ZnBr 2 prevents the direct addition to the aldehyde Additions : to the  -position Electrophilic trapping of  -metalated derivatives

37. Das, J. P.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128.  One-pot carbocupration/Zn-homologation/allylation sequence  In situ generation of Simmons-Smith-Furukawa zinc carbenoid Zimmerman-Traxler T.S. With R 3 in pseudo- equatorial position can rationalize the absolute stereochemistry Additions : to the  -position Electrophilic trapping of  -metalated derivatives

38.  Sulfonamides intramolecular addition via a 6-endo-dig mechanism  The sulfonylamino group next to the acetylene moiety promotes endo-type closure Additions : to the  -position Intramolecular addition Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820.  Addition 6-endo-dig  Addition 5-exo-dig

39.  Ti cyclopropene complex leading to  –hydroxy- enamines Additions : to the  -position ynamide-titanium complexes EntryR1R1 R 2 CHOYield (%) 1SiMe 3 PhCHOQuant 2C 6 H 13 93 3SiMe 3 C 8 H 17 CHO91 4C 6 H 13 Quant 5SiMe 3 i-PrCHO94 6C 6 H 13 71 7SiMe 3 87 8C 6 H 13 54 H. Urabe et al. Org Lett 2003, 5, 67-70.

40. Additions : to the  -position ynamide-titanium complexes  Acetylene-titanium complexes leading to dienamides S. Hirano et al. Tetrahedron 2006, 62 3896–3916

41. Additions : to the  -position  -hydroxy enamines by catalytic process  Oppolzer’s synthesis of asymmetric secondary E-allyl alcohol from acetylenes based on Srebnik’s work  Applied on ynamides : (not an Umpolung process) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. Srebnik, M. Tetrahedron Lett. 1991, 32, 2449 Walsh, P. J. Et. Al. J. Am. Chem. Soc. 2010, 132, 14179. Alkenyl boranes undergo reversible transmetalation with dialkylzinc reagents to generate vinylzinc intermediates ++ --

42.  Asymmetric synthesis of (E)-trisubstituted  –hydroxy enamines  Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170. Srebnik, M. Tetrahedron Lett. 1991, 32, 2449 Walsh, P. J. Et. Al. J. Am. Chem. Soc. 2010, 132, 14179. (-)-MIB Addition does not strongly depend on the nature of the Ar group Hindered amides: ↓ yield Aldehydes that lack  -branching : ↓ ee Additions : to the  -position  -hydroxy enamines by catalytic process

43. Danheiser,R. L. et al. Tetrahedron 2006, 62, 3815. [2+2] Cycloadditions  Synthesis of 3-aminocyclobutenones derivatives

44. Intramolecular [2+2] cycloaddition  LA catalyzed intramolecular hetero [2+2] cycloaddition/ring-opening sequence Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. N-acyl imidinium intermediate

45. Intramolecular [4+2] cycloaddition Ag salts gives Rh(I) species Thermolysis gives mixture of tetrahydroindole and rearomatised product EntryREWGAgSBF 6 T (°C)Y (%) 1SiMe 3 TsNone20 to 1000 2SiMe 3 Ts5mol%2089 3HCF 3 CO5mol%2083 4SiMe 3 Ts5mol%2086 5PhTs5mol%2070 6n-BuTs5mol%2079 Witulski, B.; Lumtscher, J.; Berstraber, U. Synlett 2003, 708 Hsung, R. P.; J. Org. Chem. 2006, 71,4170  1 st example : Witulski et. al. (2003)  Hsung applies protocol to intermolecular reactions (2006)

46.  Conjugated enynes with ynamides (C 4 = H)  Utility of BHT :  Suppress polymerization of enyne  Eases isomerization Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. Intramolecular [4+2] cycloaddition

47.  Conjugated enynamides with alkynes (C 1 = H) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. Intramolecular [4+2] cycloaddition

48. [2+2+2] Cycloaddition  Rh(I) catalyzed cyclotrimerization  With acetylene EntryR1R2 Yield (%) 1HPh85 2HTMS68 3PhTMs93 4CH 2 OTHPTMS95 5CO 2 MeTMS92 N-(3-butynyl)-1-alkynylamide EntryR1Yield (%) 1H91 2(CH 2 ) 2 OH70 3(CH 2 ) 2 OBzI55 4CH 2 OTHP57 5NHTs65 6Ph65 7CO 2 Me43 4 4 7

49. [2+2+2] Cycloaddition  Rh(I) catalyzed cyclotrimerization  With substituted alkynes N-(3-butynyl)-1-alkynylamide nR Yield (%) rr 1H601.3:1 2H851.0:1 3H631.0:1 2Ph6810:1 2TMS602.7:1 62% Witulski, B. & Stengel, T. Angew. Chem. Int. Ed. 1999, 38, 2426

50.  The elimination of the sulfonamide group is the driving force Cyclotrimerization of nitriles leading to pyridines R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780 dialkoxytitanacyclopentadienes

51.  Using  -methoxyacetonitrile with bulky amino- protecting group favors elimination of the sulfonyl group Cyclotrimerization of nitriles leading to aminopyridines B A R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780

52.  Elimination of the sulfonyl group Cyclotrimerization of nitriles leading to aminopyridines Ti-C and N-Si bond are perpendicular to place bulky amino group in less hindered position : favorable for elimination of SO 2 Ar ArSO 2 Yield (%) of BA : B TolSO 2 51%35:65 MesSO 2 62%16:84 R. Tanaka, A. Yuza, Y. Watai, D. Suzuki, Y. Takayama, F.Sato, M. Urabe, J. Am. Chem. Soc. 2005, 127, 7774 – 7780 A B

53. Oxidation: Chemoselective epoxydation of Ene-ynamides  Hetero-substituted triple bond enhances nucleophilicity towards the oxidizing reagent  -aza-  -oxocarbene Method not suitable with terminal-substituted alkynes No diastereoisomeric induction Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819.

54. RCM : Cyclic amido-dienes synthesis  1 st synthesis : Ene-ynamide RCM using Grubbs II (2002)  Pyrrolidine derivatives  Hsung uses same RCM conditions the same year  Piperidine derivatives N. Saito, Y. Sato,M. Mori, Org. Lett. 2002, 4, 803 – 805 J. Huang, H. Xiong, R. P. Hsung, C. Rameshkumar, J. A. Mulder, T. P. Grebe, Org. Lett. 2002, 4, 2417 – 2420. RCM products are good Diels-Alder dienes

55. Conclusion  Ynamides are storable, stable upon aqueous work-ups, silica gel, heating  Take home message :  Reviewing all ynamide chemistry within an 1-2h talk is a hard task!  Left behind reactions: Pt and Au cycloisomerizations Different types of formal ‘’stepwise’’ cycloadditions  Recent reviews :  Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840-2859  DeKorver, K.A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064-5106 Electrophiles add on the  position Nucleophiles add on the  position