Fritsch-Buttenberg-Wiechell Rearrangement VinylcarbenoidVinylcarbene

A Mechanistic Odyssey in the Realm of Vinylcarbenes & Vinylcarbenoïds (Journey through the life of reactive intermediates) Leading references Knorr, R, Chem. Rev. 2004, 104, Braun, M. Angew. Chem. Int. Ed. 1998, 37,

1)General consideration about FBW rearrangement 2)Free vinylcarbene formation General From vinyl triflates From diazoalkenes From iodonium ylides From vinyl halides 3) Vinylcarbenoids formation General considerations Strained cycles Outline

FBW : General Discovered in 1894 by Fritsch, Buttenberg and Wiechell Retro FBW Possible in gaz phase at >650C but generaly very disfavored. Exeption : very strained alkynes

Vinylcarbenes (alkylidenecarbene) caracteristics Spin multiplicity Electrophilicity/nucleophilicity Determined by examination of the [1+2] reaction of vinylcarbene with a serie of substituted styrenes. S0S0 S1S1 T1T1 S 0 state confirmed by stereochemistry of addition to double bond and theorical calculations  = Vinylcarbene are mildly electrophilic species Stang, P. Chem. Rev. 1978, 78, 383

Association with Metals Do not seem to have much influence. Steric effects The [1+2] addition of vinylcarbenes is sensible to hinderance on the double bond (tetrasubstitued alkenes reacts slowly) Vinylcarbenes (alkylidenecarbene) caracteristics

Generation of vinylcarbenes Nitrosocarbonamides N-(aziridyl)aldimines Vinyl triflates Diazoalkenes Iodonium Ylides 1-Halogenoalkenes

Synthesis of vinyl triflates Stang, P. J. Acc. Chem. Res. 1978, 11, 108

Deprotonation is effected in polar solvent at or below 0C Most used base : KOt-Bu To know if a deprotonation is at equlibrum, perform the reaction in adequate deuterated solvent and perform NMR of residual starting material Driving force to high energy carbene is probably the large pKa difference between KOt-Bu and KOTf pKa (DMSO) t-BuOH29.4 TfOH-13 Deprotonation of vinyl triflates

Carbenes from vinyl triflates : Common side-products Addition of nucleophilic solvents THF can act as Lewis base and add on the carbene to gives an oxonium ion that can be opened by alcohols 1 via 2

Carbenes from vinyl triflates : Comparative studies Comparaison between [1+2] and insertion

Carbenes from vinyl triflates : Comparative studies General reactivity order: H & Ph migration > [1+2] > OH insert = SiH insert > 1,5- CH insert

How to prove the intermediacy of carbene Like carbenes, carbenoïds can perform OH insertion and [1+2]. Witch one is the reactive species? Product From E18.8%7.3%31.8%42.1% From Z18.8%7.7%32.0%41.6% If two precursor can lead to product directly or via a common intermediate, an identical products distribution for each is a necessary albeit not sufficient condition for the existence of the common intermediate Stang, P.J.; Mangum, D.P.F.; Haak, P. J. Am. Chem. Soc. 1974, 96, 4562 Conclusion: Vinyl triflates probably generates free carbenes

How to prove the intermediacy of carbene, part 2! Starting Material Conclusion Vinyl triflates generates free carbenes A way to prove a reaction intermediate is to generate it from at least 2 independent sources. If the reactivity of that intermediate remain the same, it is probably real.

Carbenes from diazoalkenes Deprotonated diazoalkenes can be considered as nitrogen complex of carbenes Synthesis Seyfert-Gilbert reagent (DAMP) Peterson olefination 1 2

Carbenes from diazoalkenes Similar to carbenes from vinyl trilfates H and Ar migrate easily and the alkyne is obtained in good yield. (40 – 90%) Exception: (destabilize  + charge in the transition state) Side-reactions have enough time to occur. Since alkyl groups do not migrate well, OH & NH insertion reaction can occur in good yield. FBW Insertion

1,5-CH insertion of vinylcarbenes Intramolecular 1,5-CH insertion are possible with vinylcarbenes with an appropriate chain. Competition experiments gave the following (not surprising) selectivity: Works well :o) The strange case of amides migration and CH insertion The problem: Like H and Ar, amides migrate very well. However, carbenes with tertiary amide do prefer 1,5-CH insertion of primary H Insertion into chiral CH occur with >99% retention

The strange case of amides migration & CH insertion Amide group is essential! Answer comes from conformational analysis 1. Dipole minimization 2. Amide conformation 3. Rate of amide rotation is not competitive with the rate of decomposition and CH insertion Stabilisation of radical transition state

Other sources of diazoalkenes & vinylcarbenes Nitrosocarbonamides N-(aziridyl)aldimines Carbene are produced in medium yield SM is difficult to prepare Not very appealing… Kim, S.; Cho., C. M. Tetrahedron Lett. 1994, 35, 8405

Carbenes from iodonium ylides StructureStability Relatively stable if R = EWG C-I do not have a double bond character If R is not EWG, compound isn't isolable but can be generated in situ

Iodonium ylides synthesis From stannylacetylenes: Good nucleophiles: Activated carbonyl, NR 2, N 3, PPh 3, Phenoxydes, sulfonates, phosphonates, carboxylates Bad nucleophiles: Enolates, alkoxydes, RLi

Iodonium ylides conformational stability Result: Z ylide form the alkyne 3.7 times faster than E ylide Conclusion: No fast equilibrium of ylides Carbene formation?

Vinylic carbocation formation? Result: Complete retention of configuration Conclusion: No vinylic carbocation One way to choose between two mechanism is to perform a reaction on a chiral substrate that form an achiral intermediate according to one mechanism and not according to the other. Chiral product = No achiral intermediate Racemic product = Achiral intermediate IPh is one of the best known leaving group times better than Triflate times better than Tosylate

Iodonium ylides in nucleophilic medium Low [Cl - ] = B is favored Medium [Cl - ] = A is favored High [Cl - ] = B is favored Note: For large R, ligand coupling mechanism leads to Cl insertion with retention

Carbenes from 1-Halogenoalkenes The Base : Base cannot be BuLi because Br-Li exchange is faster than deprotonation Bad bases = NaH, i-Pr 2 NEt Good bases = NaHMDS, KHMDS, KOt-Bu Deprotonation :

Competion between Carbene & Carbenoid Similar ratio show that CH insertion is only performed by the carbene FBW vs 1,5-CH insertion 1,5-CH insertion : primary vs secondary vs tertiary

Summary of reactivity

Half-Meeting traditional question (+ beer time) Propose a mechanism for the following transformation

Half-Meeting traditional question answer (beer time is over…) Brown, R. F. C. et al. Aust. J. Chem. 1974, 27, 2373

Vinylcarbenoids: General Structure Li- 13 C coupling constant show that Li,Br carbenoïds are monomers in THF Residual SM can catalyse the isomerisation via fast M-Br exchange. Stability Boche, G.; Marsch, M.; Muller, A.; Harms, K. Angew. Chem. Int. Ed. Engl. 1993, 32, 1032 Hafner, K. Pure Appl. Chem, 1990, 62, 531

Vinylcarbenoids: Common side-products

Mechanistic black hole Should come from the migration of CH 2 without net breaking the C-Br bound. “ Thus, the detailled mechanisms of both syn and anti migrations are open problems. ” - R. Knorr - Erikson, K. L. J. Org. Chem. 1971, 36, 1031 Samuel, S. P.; Niu, T.; Erikson, K. L. J. Am. Chem. Soc. 1989, 111, 1429

Strained cycle formation

Expansion from 7 to 8 membered ring Usually do not occur. (Remember: alkyl groups do not migrate well…) Expansion from 6 to 7 membered ring Cyclobutyne is the smallest stable cyclic alkyne Do not occur. Curtin, D. Y.; Richardson, W. H. J. Am. Chem. Soc. 1959, 81, 4719

Expansion from 5 to 6 membered ring norborynebenzyne Seem to occur, the cycloalkyne can be trapped with various agents Strange behavior due to high ring strain cyclohexyne Benzyne 1

2 Norboryne Expansion from 5 to 6 membered ring

2 Cyclohexyne

Gilbert, J. C.; Baze, M. E. J. Am. Chem. Soc. 1983, 105, 664 Bachrach, S. M.; Gilbert, J. C.; Laird, D. W. J. Am. Chem. Soc. 2001, 123, 6706 Expansion from 4 to 5 membered ring Cyclopropyne is so strained that it can be considered as a 1,2-dicarbene (and react like so) Seem to occur, the cycloalkyne can be trapped with various agents Still more strange behavior due to high ring strain

Expansion from 4 to 5 membered ring, part 2 Cyclopentyne reactivity depend of the way it is generated Source[2+2][4+2] Organometalic precursor Standard precursor 11.5 Explanation: There must be an other intermediate. Variation of M and X on the organometallic precursor should be done as well as 13 C labeling. Gilbert, J. C.; McKinley, E. G.; Hou, D-R. Tetrahedron 1997, 53, 9891

Expansion from 3 to 4 membered ring Expansion from 2 to 3 membered ring Do not occur. “Cyclopropyne ring was calculated not to be a local minimum” – Rudolf Knorr Do not occur. Theorical existence of cyclobutyne is controversial Johnson, R. P.; Daoust, K. J. J. Am. Chem. Soc. 1995, 117, 362 Jonas, V.; Böhme, M.; Frenking, G. J. Phys. Chem. 1992, 96, 1640

CH insertion of carbenoïds 1,5-CH insertion are rare for vinylcarbenoïds. The corresponding carbene can never be excluded Fisher, R. H.; Baumann, M., Köbrich, G Tetrahedron Lett. 1974, 1207

Migration of unsaturated substituents Fienemann, H.; Köbrich, G Chem. Ber. 1974, 107, 2797

Carbenes vs. Carbenoids : kinetic 2 cases: At low temperature, carbenoïds are kinetically stable and can react in a plain bimolecular reaction. The carbene reacts much more faster than the carbenoid 1 2

Case 1: Stable carbenoid react in a bimolecular reaction without rate-controlling intermediate Case 2:Carbenoid is in fast equilibrium with the carbene and only the carbene react in a bimolecular reaction Decreased rate for increased MX concentration Independence of the rate and MX concentration Carbenes vs. Carbenoïds : kinetic

Summary of migration capability of vinylcarbenoids Heteroatom migration Small ring migration Newman, M. S.; Gromelski, S. J. J. Am. Chem. Soc. 1972, 37, 3220

Summary of migration capability of vinylcarbenoids Alkoxyde do not migrates, but helps the migration of other groups Alkoxyde migration Enol ether migration Kowalski, C. J.; Reddy, R. E. J. Org. Chem. 1992, 57, 7194 Explanation OiPr destabilize the SP center in the transition state via its inductive effect (s = -0.12) even if it is a strong p- donor. Calculations show then O-iPr do not solvate the Li atom

Summary Good migrating groups in the FBW rearrangement are H and Ar 1,5-CH insertion of vinylcarbenes & vinylcarbenoids can be a clean reaction Vinyl triflates, vinyl diazonium salts and vinyl iodonium ylides produce free vinylcarbenes 1,1-bromolithioolefins produce a mix of free carbenes and carbenoids Vinylcarbenoids are stable at low temperature Cycloalkynes can be produced in situ from vinylcarbenes & vinylcarbenoids Vinylcarbenoids behavior is mechanistically underdeveloped

The End