Literature Seminar

1
Reformatsky Reloaded

• Literature Seminar
• 29.03.05
• W. Felzmann

2

• Overview
• General aspects
• Metals involved
• Electrophiles
• Nucleophiles
• Stereochemistry/Asymmetric Variations

3
Historical aspects First time reported in 1887 1
Definition today Reactions defined as those
resulting from metal insertions into
carbon-halogen bonds activated by carbonyl-,
carbonyl-derived or carbonyl-related groups in
vicinal or vinylogous positions with practically
all kinds of electrophiles
1 Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887,
20, 1210
4
Structure of the Reformatsky Species Zinc
enolates Esters C-metallated species more stable
Dimeric form (Crystal structure) Monomers
possible in polar solvents
Ketones O-metallated species more stable
Z-Enolate
5
Used as metal (maybe activated)
Used as salt (catalytic)
6

• needs activation before use
• add crumbs of iodine
• Acid wash
• Couples (Cu/Zn, Ag/Zn etc.) prepared best fresh
  from MOAc/Zn (110) in AcOH
• Rieke Zn (Prepared from ZnCl2 by reduction with
  K)
• Zn or Ag/Zn on graphite (reported to be safer )
• Et2Zn/RhCl(PPh3)3 also generates reactive
  Zn-Organyls

Reactivity
has no oxide layer ultrasound is enough for
activation Asymmetric induction possible (chiral
aminoalcohols) Indium enolates not quenched by
free hydroxy groups can be reduced
electrochemically (anode gets oxidized)
7
Alkali and alkaline earth metals metals
themselves are used, not very widespread

• Very stable oxide layer activation necessary
• Remove oxides with TMSCl
• Reduce Li2MnCl4 (MnCl2 2 LiCl) with Mg

Employed as Fe(CO)5
Employed as Co(PPh3)4
Employed as Ni(COD)2
8
CrCl2used (can be bought or reduced from CrCl3
with LiAlH4) Catalytic pathway possible Solvents
THF, DMF, CH3CN Excellent chemoselectivity
SmI2 used (single electron reducing agent!)
bought or selfmade Sm metal and other
lanthanides also useable Catalytic pathway
possible Excellent chemoselectivity and
diastereoselectivity, especially for medium and
large rings
Cp2TiIIICl used (prepared from Cp2TiCl2 with Zn
or Mn) Catalytic pathway possible anti-selectivity
9
GeI2 (less reactive) or Ge used (reduced from
GeI2 with K) Good stereoselectivity
Sn used (prepared by reduction of SnCl2 with
LiAlH4) Good stereoselectivity Comparable to
chromium Ate-complex Bu2SnI3-Li reactive with
?-iodo-ketones High syn-selectivity
10
Electrophiles Classical electrophiles
aldehydes, ketones
On ?,?-unsaturated compounds normally
1,2-addition If organozinc or carbonyl-position
is bulky, then conjugate addition is favored
?-bromobutanoates add 1,2
11
Nitrils
Imines
?-lactams can be formed in contrast to aldehydes
O,O-, N,O-, N,S-acetals also react
Up to 84 d.e.
Aryl halides, vinyl halides, acid chlorides can
be coupled with Pd0 catalysis (HMPA!)
12
Nucleophiles
Halides Normally bromides or iodides are used,
chlorides only work with Rieke-Zn or Zn-graphite
?-bromo-amides
?-silyl-esters
?-acetoxy-carbonyls
Availability of ?-silyl-esters limited use of
?-hydroxy-esters limited to SmI2
Polyhalogenated carbonyls
Halohydrins are available using Zn/Ag-graphite
base gives glycidates Addition of Et2AlCl yields
a,b-unsaturated compounds Reformatsky reaction
is an excellent way to introduce fluorine!
13
Reformatsky-Claisen Rearrangement
Dreiding-Schmidt-reaction
Reaction is SE2
14
?-bromo-crotonates
Electrophile
Nucleophile

Hudlicky et al., J. Org. Chem. 1985, 50, 4300-4306
15
Stereochemistry Intermolecular

• Thermodynamic stereoselection

• Some Zn-enolates tend to equilibrate Usually
  3070 synanti
• The bigger R2 gets, the bigger the
  syn-preference (some is true for amides)
• Equilibrium in aldol-reaction step (stopped by
  Zn2 complexation)
• Ketones tend to give better selectivity

Addition of (-)-sparteine inverts
diastereoselectivity synanti 17 83
16
Syn-selectivity
Useful syn selectivity is obtained with
oxazolidinones (anti with Li-enolates)
17
SnII-Enolates
Mukaiyama et al., Chem. Lett., 1982, 161-164
SnIV-Enolates
Shibata et al., Org. Lett., 2002, 301-303
Only works with iodo-ketones- Esters much less
diastereoselective
TiIV-Enolates Anti-selectivity
Little et al., Org. Lett., 2003, 3615-3617
18
Chromium-Reformatsky
Regarding Enolate formation similar to Zn But
?-hydroxy-carbonyl stabilized (O-CrIII-Bond
strong)
4-bromo-crotonates react like allylbromides not
like chromium dienolates
19
(No Transcript)
20
Intramolecular Reformatsky
SmI2 shows excellent d.e.s!
With ?-bromopropionates bad d.e.!
Molander et al., J. Am. Chem. Soc. 1991, 113,
8036-8045
21
No data on propionate Evans acetate gives high
ees!
CrCl2 also gives high d.e.s with acetates!
22
NerzStormesThornton T.S.
Zimmermann-Traxler T.S.
23

• Outlook
• Catalysis
• Expensive (or toxic) metals can be reoxidized
• Ti (Mn, Zn), SmI2 (Mg), Cr (Mn)
• Sacrificial electrode (In, Zn)
• Asymmetric Induction
• In, Zn
• Aminoalcohols mostly used
• Problem is the reactivity of all metallated
  species

24
Do I have a choice?
NO
YES
Li-Enolates (not Reformatsky)
Intramolecular?
Intermolecular?
Failure!
SmI2 or CrCl2
Evans-Aldol?
Sensitive aldehyde/ Functional groups
Stable material
Zn or CrCl2
Anti-Evans
Syn-Evans
CrCl2, Sn or In
Acetate-Transfer
CrCl2
Zn, Ge, In
CrCl2, SmI2, Sn
25

• References
• A. Fürstner, Recent Advancements in the
  Reformatsky Reaction, Synthesis, 1989, 571-589
• R. Ocampo, W. R. Dolbier, The Reformatsky
  Reaction in organic synthesis. Recent Advances,
  Tetrahedron, 2004, 60, 9325-9374
• M. W. Rathke, P. Weipert, Zinc Enolates the
  Reformatsky and Blaise Reactions, Comprehensive
  Organic Synthesis, Vol. 2, pp.277
• L.A. Wessjohann, G. Scheid, Recent Advances in
  Chromium(II)- and Chromium(III)-Mediated Organic
  Synthesis, Synthesis, 1999, 1-36