Ketenes 25/01/2014 Part 1

Home , Allenes, Diphenylketene, Ketene, Ketenimine, Nucleophilic addition, Reaction mechanism

Baran Group Meeting Hai Dao Ketenes 25/01/2014 Part 1. Introduction Ph Ph n H Pr3N C A brief history Cl C Ph + nPr NHCl Ph O 3 1828: Synthesis of urea = the starting point of modern organic chemistry. O 1901: Wedekind's proposal for the formation of ketene equivalent (confirmed by Staudinger 1911) Wedekind's proposal (1901) 1902: Wolff rearrangement, Wolff, L. Liebigs Ann. Chem. 1902, 325, 129. 2 Wolff adopt a ketene structure in 1912. R 2 hν R R2 1905: First synthesis and characterization of a ketene: in an efford to synthesize radical 2, 1 ROH R C Staudinger has synthesized diphenylketene 3, Staudinger, H. et al., Chem. Ber. 1905, 1735. N2 1 RO CH or Δ C R C R1 1907-8: synthesis and dicussion about structure of the parent ketene, Wilsmore, O O J. Am. Chem. Soc. 1907, 1938; Wilsmore and Stewart Chem. Ber. 1908, 1025; Staudinger and Wolff rearrangement (1902) O Klever Chem. Ber. 1908, 1516. Ph Ph Cl Zn Ph O hot Pt wire Zn Br Cl Cl CH CH2 Ph C C vs. C Br C Ph Ph HO O O O O O O O 1 3 (isolated) 2 Wilsmore's synthesis and proposal (1907-8) Staudinger's synthesis and proposal (1908) wanted to make Staudinger's discovery (1905) Latest books: ketene (Tidwell, 1995), ketene II (Tidwell, 2006), Science of Synthesis, Vol. 23 (2006); Latest review: new direactions in ketene chemistry: the land of opportunity (Tidwell et al., Eur. J. Org. Chem. 2012, 1081). Search for ketenes, Google gave 406,000 (vs. allenes: 950,000 ) Jan 23,2014.

Structure and Physical properties Frontier orbitals Resonance structure Dipole moment Spectroscopy data

Nu C C O Cβ Cα β α H C C O C O H LUMO C C O (2.27 D) IR: distinctive absorptions near 2200-2100 cm-1 (vs. alkene: 1680 cm-1, alkynes: 2200 cm-1; allenes: 1950- 1960 cm-1, carbonyl 1760-1665 cm-1). (IR is frequently used to detect the formation of reactive H ketene species) C C O C C O H HOMO 13 (1.45 D) C NMR: δCα =203-178 ppm; δCβ = 48-33 ppm.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014 Part 2. Synthesis of Ketenes Due to its highly reactivity, many ketenes are synthesized in situ as intermediates which then react with other reagents to generate products

2.1 Ketenes from Carboxylic Acids and Their Derivatives From Esters From Acyl halides and Activated Acids (Wedekind's Method) E1cB mechanism (crowed esters...) or similar pathway o OLi 25 C Me3Si Me3Si O LDA Me3Si NCbz O H C O Cl(H2C)3 O Et3N t o t 60% Me3Si Cl(H2C)3 Me3Si O Bu −78 C Me3Si O Bu C O 75% Cl cyclohexane N Rethke, M. W. et al. J. Org. Chem. 1977, 2038. Cbz reflux Cl(H2C)3 H Cevasco, G.; Thea, S. et al. J. Org. Chem. 1999, 5422. 2.2 Ketenes from Diazo Ketones (Wolff's Rearrangement) From α-Halo Carboxylic Derivatives (Staudinger's Method) O Me HMe Me Et O xylene H 70% H O Zn, DME Cl PhC CEt C O Cl C C O N2 3 Et O Cl reflux Cl 2 Cl 88% Ph O O O ultrasound Cl H H O H Rizzo, C. J. et al. Synth. Commun. 1995, 2781. From Acid Anhydrides Miller, R.D., et al. J. Org. Chem. 1991, 1453 Et Me O O o O quinidine 500 C C O H O O Ph2C O Ph2C Ph2C Me MeOH O Me DCM, −78 oC hν C O CO2Me 2 O 99% ee Me Me Ph2C N2 Ph C Calter, M. A. et al. Org. Lett. 2001, 1499. Ph2C 2 From Acids Ueda, K.; Toda, F. et al. Chem. Lett. 1975, 1421.

i Pr2NEt, MeCN OHC CO2H + OHC C nanocluster (Ag) 4 3 O n N Cl rt CO2H Ph 4 N2 Ph I Me proposed 4 Ph 4 O dioxane 80-91% H o C O 60 C, H2O 2-98 Mukaiyama's reagent 9-O-acetylquinine O 51%, 86% ee O Sudrik, S. G. et al. Org. Lett. 2003, 2355. H other metal catalysts: Ag, Cu, Rh

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014

2.3 Ketenes from Metal Carbene Complexes From Cycloalkanones and Enones through Photolysis

Cr(CO)5 OMe O O Cr(CO)3 OMe O H C CO2Me h hν MeOH OMe ν C [2+2] O tBu tBu tBu tBu THF 78% O 96% Norrish Type I O Agosta, W. C.; Wolff, S. et al. J. Am. Chem. Soc. 1976, 4182. MeO Cr(CO) C 5 [2+2] OMe Cr(CO)3 45 oC O CO2H 63% H H mechanism OH OMe OH hυ, MeOH HO HO Hegedus, L. S. et al. J. Am. Chem. Soc. 1996, 7873. 20% N2 Me MeO2C Ph (30% decarboxylation) Me O O O Pd2(dba)3 Me C Me C Ph Buscemi, S. et al. Photochem. Photobiol., A, 2003, 145. + N Ph PdLn CO, PhMe 93% N Ph O Ph O Ph From Cyclohexadienones and Other Cycloalkenones 60 oC Ph Bn Wang, J. et al. J. Am. Chem. Soc. 2011, 4330. O Ph N O Ph C PhCH=NBn O 2.4 Other Methods Me From Cyclobutanones and Cyclobutenones Ph Ph O Me Me EtO C CO Et 2 O EtO2C H O EtO2C Barton-Quinkert reaction 2 2 Quinkert, G. et al. Helv. Chim. Acta 1997, 1683. C O CO2H N2 Rh cat 75% From Dioxinones Cai, W. -L. et al. J. Chem. Soc. Perkin 1 1996, 2337. O O O C O OH O OH O O Δ EtO O EtO O O ArLi 1, Δ EtO C EtO O O O 68% O 2, FeCl3 84% O EtO O O EtO O EtO OH O EtO comercial available Boeckmann, R. K. et al. J. Am. Chem. Soc. 1989, 8286. OH squaric acid O derivative Moore, H. W. et al. Org. Synth 1990, 220.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014

3.1 [2+2] Cycloaddition Part 3. Reaction of Ketenes

Reaction Mechanism: Concerted [π2s+π2a] vs. Two-step Reaction Involving a Dipolar Intermediate

R' O R' O H R H R H H R H R H R H H H H C O C O C O + C O C O R' R' R' R' R' H R H R + H R H R H R R R R R less hindered bond rotation Features and Supported Evidences Features and Supported Evidences - stereospecific to thermodynamically less stable cyclobutanones - initial orthogonal approach of the ketene to alkene from the least - Z olefins are more reactive than E olefine hindereddirection following by rotation at C2 lead to the same H O stereochemisty outcome as in concerted mechanism tBu - high level calculation by Houk showed that the forming bond + C O CN length of the carbonyl carbone is 1.78 Å; the other is 2.43 Å NC - solvent effects observed (it could be a ground state effect only) H tBu - evidence from studies of intramolecular [2+2] H O tBu C O H + C O CN H NC O H tBu

Montaigne, R. et al. Angew. Chem., Int. Ed. 1968, 221. relative reactivity: stereochemisty = a net [π2s+π2s] Cl2C C O > Ph2C C O > Me2C C O > H2C C O Retigeranic acid synthesis: Corey, E. J. et al. J. Am. Chem. Soc. 1985, 4339.

[2+2] Cycloaddition with Alkynes [2+2] Cycloaddition with Electrorich Olefins: Stepwise Mechanism R' O H SO R' O Cl R R' 2 4 O O O Ph Ph C O O Ph Ph Cl Cl C O Cl + R Cl R O Cl Cl Cl O Zn, AcOH O O

O R' O O Reynolds, P. W. et al. J. Am. Chem. Soc. 1984, 4566. R' C R' C Cl O Cl O Bn Cl R C C O + NH R R O bisketene Cl OR 69% vinylketene dr = 94:6 RO Bn Danheiser, R. L. et al. Tetraherdon Lett. 1987, 3299; RO Bn Ammann, A. A. et al. Helv. Chim. Acta 1987, 321. Kanazawa, A. t al. J. Org. Chem. 1998, 4660.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014

chiral organic base or NHC catalysis [2+2] Cycloaddition with Imines: Staudinger Ketene-Imine Cycloaddition Et O Ph uncatalyzed mechanism: stepwise formation of zwitterion followed by Boc contotatory ring closure to give cis-product Ph NHC, Cs2CO3 N C O + N o C6H4Cl Boc Et C H Clo 6 4 THF, rt cis:trans = 91:9 R O R O 71% 99%ee R1 R conrot. C imine N + C O N R2 N N Cs CO N 2 1 2 2 3 N R 1 R R R NPh NPh ketene NPh cis-adduct N N N planar BF4 Ph O Ph Ph OTBS Ph Ph Arrieta, A. et al. J. Org. Chem. 1998, 5869. Ph Ph OTBS TBSO Et NHC Me Bn BnO O Zhang, Y. -R. et al. Org. Lett. 2008, 277. N BnO OTBS O + N β-amino CO2Bn NTs C O Me O 80% Bn acids N O Me OTBSO BQ, In(OTf) O 3 N O N Cl Et3N BnO2C Ts o CO Ph Palomo, C. et al. Chem. Commun. 1996, 1269. PhMe, -78 C cis:trans = 99:1 2 59% 99%ee BQ Townsend, C. A. et al. Org. Lett. 2009, 3609. Me CO Bn N 2 CO2Bn general reaction mode (apart from concerted [π2s+π2a] ): BnN O N Me BnN O C solvents + CO2Bn R C R R X E N NR' substrates BnN 2 N NR'2 C O C intra- or intermolecular C O R R or catalysts R O reactions - R electrophilic X nucleophilic

CO2Bn more stable 3.2 Other Cycloadditions BnN O Formal [4+2] Cycloaddition: with electro-deficient dienes con. R N R O 58-74% N N R N C O N N Ar Ar S N R = Ar, Cl Ar Ar N trans-adduct 75-95% S Diez, E. et al. Org. Lett. 2004, 2749. Dutta, B. C. et al., Chem. Res. (S) 1999, 36.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014 N [3+2] Cycloaddition NPh N O BF4 Et OH O Ph Ph O Ph O Ph Ph O O Ph C O + N Ph C + Ph OTBS N H H Ph HN EtO2C Ph EtO2C Ph N N O Ph Et Cs2CO3, THF N O O oC to rt 79%, 91% ee dr = 24:1 3.3 Other Reactions Zhang, Y. -R. et al. Chem. Eur. J. 2008, 8473. Nucleophilic Addition and/or Rearrangement acylketenes often work as good dienes in [4+2] reaction: O OH O OH O CR1R2 O C 95 % C 1 2 + + CHR R N OH 52-83% N NH2 1 2 BuO O Me BnO O Me R R H electron rich from dioxinone Coleman, R. S. et al. J. Org. Chem. 1993, 385. olefin Olagbemiro, R. O. et al. Recl. Trav. Chim. Pays-Bas 1995, 337. Cycloaddition with Carbonyl Groups

ketenes undergo [2+2] cycloaddition with electrophilic carbonyl group: O + C N CCl Bn Cl Amine base catalyzed reactions N 2 N Bn Bn 96% Cl O O Cl Cl O O C O quinidine H + N PhMe, −50 oC CCl3 O Edstrom, E. D. et al. J. Am. Chem. Soc. 1991, 6690. CCl3CH=O O Cl3C R 89%, 98% ee O O O O O N N Me NBoc Wynberg, H. et al. J. Org. Chem. 1985, 1977. Ph Boc Ar O O Ar CO2 C Lewis acid catalyzed reactions Me THF, − 78 oC N N O N Ar Me Boc C O C TMS MgBr , DCM H O TMS 2 o Bn O KF O Me + −43 C Me CO Ar O MeCN BnO Ar 2 Me Br Mg O OBn O NH4Cl Br syn:anti = 2:98 N O N 94% Me Boc 91%, 90% ee N H Vemribo, R. et al. Tetrahedron Lett. 1995, 4159. Smith, A. D. et al. Org. Lett. 2009, 3858.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014

Wittig Reaction Ketenes in Polymer Chemistry O O New approach for polimer modification: polymer crosslinking through ketene dimerization C O O O C CH2 O NaBARF O PPh3 O Pd(II) O Δ Buono, G. et al. Tetrahedron Lett. 1990, 4859. − acetone O DCM O − CO2 Ph Ph Ph O Ph Ph O n C O C O Ph Ph PPh3 Ph N NH Meldrum's acid derivatives N N N N 71% O C O ketenimine CHPh Ph Ph C O Molina, P. et al. Tetrahedron Lett. 1991, 4041.

n −1 O Moore's Cyclization IR: 2103 cm n n Ph Ph used for printing submicrometer-scale patterns for microcontact printing O PhMe Ph O O Aida, T. et al. J. Am. Chem. Soc. 2011, 2840. 110 oC Ph C Ph Organometallic Compounds MeO MeO MeO OMe OMe OMe H Py, rt Ag Br2, CCl4, rt Br Ph C O + AgOAc C O C O H HCl Ag Br

O O O Silver ketenide X-ray structure Ph 71% Ph Ph Blues, E. T. J. Chem. Soc. Perkin Trans. 2, 1993, 1631

MeO MeO O O MeO R1 Ph Ph Ph OCH2 OMe decarbonylation M(CO) L L M R LnM x y Moore, H. W. et al. J. Org. Chem. 1992, 3765. n 2 O R2 unreactive R1 dimerization R O 2 2 + by products O cat. R O η (C−O) η (C−C) C + O modes of ketene coordination with transition metals R O R R To develop the transition metal catalyzed-reaction with ketenes, it is crucial to ratio of the mixture depends on:R, cat. find the right ligands to stablize the ketene-metal complexes Clemens, R. J. et al. Chem. Rev. 1986, 241.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014 Epicoccins O O (CO2Me)2 H H C Me O H O O Ni(COD)2 (5 mol%) Sx OH OH DPPB (5 mol%) O H H + C N N N N (MeO2C)2C o H proposal H C H , 60 C, 24 h OH Sy OH Ph Et 6 6 Ph Me Me 86% Et O O H Me H H O O single isomer epicoccin O O H O H Louie, J. et al. J. Am. Chem. Soc. 2011, 7719. H t t O CO2 Bu CO2 Bu CO2 N N N H Boc H Boc Part 4. Ketenes in Synthesis H H2 OH cis-adduct

Et3N O O CO tBu cyclohexane Ginkgolide Synthesis C + 2 N reflux Cl Boc O 75% HO Brase, S et al. Chem. Eur. J. 2010, 11624. HO H O O (+)-20R-dihydrocleavamine O O H H HO HO Me O H tBu hυ HO HO tBu HO HO O O H MeOH HO O O H C CO Me ginkgolide B O O 2 enantiomer Me MeO Boc OMe N OMe O N3 N O H O Me O 1. (COCl)2 O Me N H OBn H H H H H OBn H H t n H Bu 2. Bu3N t tBu Bu N H HO2C 20 O C O H (+)-20R-dihydrocleavamine Corey et al. J. Am. Chem. Soc. 1998, 649. N H Ogasawara, K. et al. Tetrahedron Lett. 2001, 7311.

Saturday, January 25, 14 Baran Group Meeting Hai Dao Ketenes 25/01/2014

Hirsutine Synthesis (+)-FR900482 Synthesis OBn OCONH OTBS 2 OTBS OH OBn OH OBn N H N H OH Et Et OMe N H N H O NH H H H H OHC N N N t OMOM t MeO2C MeO2C OMOM CO2 Bu CO2 Bu hirsutine OTBS PhMe OPMB O O BnO o C 80-110 C NCbzH NCbz 88-94% Et OPMB + hetero-DA Et O H N H N N O OMOM t H H then -Me2CO, H OMOM CO2 Bu O -CO2, O Danheiser, R. L. et al. J. Org. Chem. 2011, 1852. O O (+)-Artemisinin Synthesis Me Me Tietze, L. F. et al. Angew. Chem. Int. Ed. 1999, 38, 2045. H Me O Me Macrocidin Synthesis O O O H H O O O H O O Me Me RN OH RN O RHN O O MeO OTIPS CO Me Me CO2Me 2 Me Me >95% O Et2AlCl PhMe + reflux TIPSO OMe DCM 86% 78 oC to rt O O O O − O O O silyl ketene acetal = ketene equivalence macrocidin A O Cook. S. P. et al. J. Am. Chem. Soc. 2012, 13577. R = p-azidobenzyl C HRN O Part 5. Important References

CO Me 1. Ketenes; Thomas T. Tidwell , John Wiley and Sons, 1995. 2 2. Ketenes II; Thomas T. Tidwell , John Wiley and Sons, 2006. 3. Science of Synthesis, Vol. 23 (2006) 4. New Directions in Ketene Chemistry: The Land of Opportunity, Tidwell, T. T. Hoye, T. R. et al. J. Org. Chem. 2010, 7052. et al. Eur. J. Org. Chem. 2012, 1081.

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