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Reformatsky reaction

From Wikipedia, the free encyclopedia
Organic reaction
Reformatsky reaction
Named afterSergey Reformatsky
Reaction typeCoupling reaction
Identifiers
Organic Chemistry Portalreformatsky-reaction
RSC ontology IDRXNO:0000036

TheReformatsky reaction (sometimestransliterated asReformatskii reaction) is anorganic reaction whichcondensesaldehydes orketones with α-haloesters using metalliczinc to form β-hydroxy-esters:[1][2]

Substrates are a ketone (with undefined substituents R1 and R2) and an alpha bromo ester (with undefined substituent R3). Reagent is Zinc. Resulting structure is a beta-hydroxy ester with oxygen coordinating to zinc bromide. Acidic aqueous workup yields protonated beta-hydroxy ester.
The Reformatsky reaction

Theorganozinc reagent, also called a 'Reformatsky enolate', is prepared by treating an alpha-halo ester with zinc dust. Reformatsky enolates are less reactive than lithium enolates or Grignard reagents and hence nucleophilic addition to the ester group does not occur. The reaction was discovered bySergey Nikolaevich Reformatsky.

Some reviews have been published.[3][4]

In addition[5] to aldehydes and ketones, it has also been shown that the Reformatsky enolate is able to react withacid chlorides,[6]imines,[7]nitriles (seeBlaise reaction), andnitrones.[8] Moreover,[5] metals other than zinc have also been used, includingmagnesium,[9]iron,[10]cobalt,[11]nickel,[12]germanium,[13]cadmium,[14]indium,[15][16]barium,[17] andcerium.[18] Additionally,[5] metal salts are also applicable in place of metals, notablysamarium(II) iodide,[19][20]chromium(II) chloride,[21]titanium(II) chloride,[22] cerium(III) halides such ascerium(III) iodide,[23] andtitanocene(III) chloride.[24]

Structure of the reagent

[edit]

The crystal structures of theTHF complexes of the Reformatsky reagentstert-butyl bromozincacetate[25] and ethyl bromozincacetate[26] have been determined. Both form cyclic eight-membered dimers in the solid state, but differ in stereochemistry: the eight-membered ring in the ethyl derivative adopts a tub-shaped conformation and hascis bromo groups andcis THF ligands, whereas in thetert-butyl derivative, the ring is in a chair form and the bromo groups and THF ligands aretrans. Note that, in contrast to lithium and boron enolates, which have the metal(loid)s exclusively bond to oxygen, the zinc enolate moiety in the Reformatsky reagents have zinc atoms that are simultaneously O- and C-bound and can therefore be described as "organometallic".



ethyl bromozincacetate dimertert-butyl bromozincacetate dimer

Reaction mechanism

[edit]

Zinc metal is inserted into the carbon-halogen bond of the α-haloester byoxidative addition1. This compound dimerizes and rearranges to form two zinc enolates2. The oxygen on an aldehyde or ketone coordinates to the zinc to form the six-member chair like transition state3. A rearrangement occurs in which zinc switches to the aldehyde or ketone oxygen and a carbon-carbon bond is formed4. Acid workup5,6 removes zinc to yield zinc(II) salts and a β-hydroxy-ester7.[5]

Variations

[edit]

In one variation of the Reformatsky reaction[27] aniodolactam is coupled with analdehyde withtriethylborane intoluene at −78 °C.

Reformatsky reaction Danishefsky variation[27]
Reformatsky reaction Danishefsky variation[27]

See also

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References

[edit]
  1. ^Reformatsky, S. (1887)."Neue Synthese zweiatomiger einbasischer Säuren aus den Ketonen".Berichte der Deutschen Chemischen Gesellschaft.20 (1):1210–1211.doi:10.1002/cber.188702001268.
  2. ^Reformatsky, S. (1890). "Action of zinc and ethyl chloroacetate on ketones and aldehydes".J. Russ. Phys. Chem. Soc.22: 44.
  3. ^Shriner, R. L. (1942). "The Reformatsky Reaction".Organic Reactions.1:1–37.doi:10.1002/0471264180.or001.01.ISBN 9780471264187.{{cite journal}}:ISBN / Date incompatibility (help)
  4. ^Rathke, M. W. (1975). "The Reformatsky Reaction".Organic Reactions.22:423–460.doi:10.1002/0471264180.or022.04.ISBN 0471264180.
  5. ^abcdKurti, L.; Czako, B.Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington, 2005.
  6. ^Sato, Toshio; Itoh, Toshiyuki; Fujisawa, Tamotsu (1982). "Facile synthesis of β-ketoesters by a coupling reaction of the Reformatsky reagent with acyl chlorides catalyzed by a palladium complex".Chemistry Letters.11 (10):1559–1560.doi:10.1246/cl.1982.1559.
  7. ^Gilman, Henry; Speeter, Merrill (1943). "The Reformatsky Reaction with Benzalaniline".Journal of the American Chemical Society.65 (11):2255–2256.Bibcode:1943JAChS..65.2255G.doi:10.1021/ja01251a503.
  8. ^Stamm, H.; Steudle, H. (1979). "Nitrone—XI Isoxazolidin-verbindungen—VIII : N-substituierte 5-isoxazolidinone durch reformatzky-reaktion mit nitronen".Tetrahedron.35 (5):647–650.doi:10.1016/0040-4020(79)87010-6.
  9. ^Moriwake, Tosio (1966). "The Reformatsky Reaction. I. Condensation of Ketones and t-Butyl Bromoacetate by Magnesium".The Journal of Organic Chemistry.31 (3):983–985.doi:10.1021/jo01341a524.
  10. ^Liu, Xuan-Yu; Li, Xiang-Rui; Zhang, Chen; Chu, Xue-Qiang; Rao, Weidong; Loh, Teck-Peng; Shen, Zhi-Liang (2019). "Iron(0)-Mediated Reformatsky Reaction for the Synthesis of β-Hydroxyl Carbonyl Compounds".Organic Letters.21 (15):5873–5878.doi:10.1021/acs.orglett.9b01999.PMID 31318222.S2CID 197541600.
  11. ^Orsini, Fulvia; Pelizzoni, Francesca; Pulici, Maurizio; Vallarino, Lidia M. (1994). "A cobalt-phosphine complex as mediator in the formation of carbon-carbon bonds".The Journal of Organic Chemistry.59 (1):1–3.doi:10.1021/jo00080a001.
  12. ^Inaba, Shin-ichi; Rieke, Reuben D. (1985). "Reformatsky type additions of haloacetonitriles to aldehydes mediated by metallic nickel".Tetrahedron Letters.26 (2):155–156.doi:10.1016/S0040-4039(00)61867-1.
  13. ^Kagoshima, Hirotaka; Hashimoto, Yukihiko; Oguro, Dai; Saigo, Kazuhiko (1998). "An Activated Germanium Metal-Promoted, Highly Diastereoselective Reformatsky Reaction".The Journal of Organic Chemistry.63 (3):691–697.doi:10.1021/jo971672j.PMID 11672062.
  14. ^Burkhardt, Elizabeth R.; Rieke, Reuben D. (1985). "The direct preparation of organocadmium compounds from highly reactive cadmium metal powders".The Journal of Organic Chemistry.50 (3):416–417.doi:10.1021/jo00203a036.
  15. ^Chao, Li-Chung; Rieke, Reuben D. (1975). "Activated metals. IX. New reformatsky reagent involving activated indium for the preparation of β-hydroxy esters".The Journal of Organic Chemistry.40 (15):2253–2255.doi:10.1021/jo00903a031.
  16. ^Araki, Shuki; Ito, Hirokazu; Butsugan, Yasuo (1988). "Synthesis of β-Hydroxyesters by Reformatsky Reaction Using Indium Metal".Synthetic Communications.18 (4):453–458.doi:10.1080/00397918808064009.
  17. ^Yanagisawa, Akira; Takahashi, Hiroshi; Arai, Takayoshi (2004). "Reactive barium-promoted Reformatsky-type reaction of α-chloroketones with aldehydes".Chemical Communications (5):580–581.doi:10.1039/B314752P.PMID 14973617.
  18. ^Imamoto, Tsuneo; Kusumoto, Tetsuo; Tawarayama, Yoshinori; Sugiura, Yasushi; Mita, Takeshi; Hatanaka, Yasuo; Yokoyama, Masataka (1984). "Carbon-carbon bond-forming reactions using cerium metal or organocerium(III) reagents".The Journal of Organic Chemistry.49 (21):3904–3912.doi:10.1021/jo00195a006.
  19. ^Tabuchi, Takanori; Kawamura, Kisa; Inanaga, Junji; Yamaguchi, Masaru (1986). "Preparation of medium- and large-ring lactones. SmI2-induced cyclization of ω-(α-bromoacyloxy) aldehydes".Tetrahedron Letters.27 (33):3889–3890.doi:10.1016/S0040-4039(00)83907-6.
  20. ^Molander, Gary A.; Etter, Jeffrey B. (1987). "Lanthanides in organic synthesis. 8. 1.3-Asymmetric induction in intramolecular Reformatskii-type reactions promoted by samarium diiodide".Journal of the American Chemical Society.109 (21):6556–6558.Bibcode:1987JAChS.109.6556M.doi:10.1021/ja00255a076.
  21. ^Dubois, Jacques-Emile; Axiotis, Georges; Bertounesque, Emmanuel (1985). "Chromium (II) chloride : a new reagent for cross-aldol reactions".Tetrahedron Letters.26 (36):4371–4372.doi:10.1016/S0040-4039(00)98737-9.
  22. ^Ishihara, Takashi; Yamanaka, Tohru; Ando, Teiichi (1984). "New low-valent titanium catalyzed reaction of chlorodifluoromethyl ketones leading to α,α-difluorinated β-hydroxy ketones".Chemistry Letters.13 (7):1165–1168.doi:10.1246/cl.1984.1165.
  23. ^Fukuzawa, Shin-Ichi; Fujinami, Tatsuo; Sakai, Shizuyoshi (1985). "Carbon–carbon bond formation between α-halogenoketones and aldehydes promoted by cerium(III) iodide or cerium(III) chloride–sodium iodide".Journal of the Chemical Society, Chemical Communications (12):777–778.doi:10.1039/C39850000777.
  24. ^Parrish, J. D.; Shelton, Daniel R.; Little, R. Daniel (2003). "Titanocene(III)-Promoted Reformatsky Additions".Organic Letters.5 (20):3615–3617.doi:10.1021/ol035269c.PMID 14507186.
  25. ^Dekker, J.; Budzelaar, P. H. M.; Boersma, J.; van der Kerk, G. J. M. & Spek, A. J. (1984). "The Nature of the Reformatsky Reagent. Crystal Structure of (BrZnCH2COO-t-Bu · THF)2".Organometallics.9 (3):1403–1407.doi:10.1021/om00087a015.
  26. ^Miki, S.; Nakamoto, K.; Kawakami, J.; Handa, S.; Nuwa, S. (2008). "The First Isolation of Crystalline Ethyl Bromozincacetate, Typical Reformatsky Reagent: Crystal Structure and Convenient Preparation".Synthesis.2008 (3):409–412.doi:10.1055/s-2008-1032023.
  27. ^abLambert, T. H.; Danishefsky, S. J. (2006). "Total Synthesis of UCS1025A".Journal of the American Chemical Society.128 (2):426–427.Bibcode:2006JAChS.128..426L.doi:10.1021/ja0574567.PMID 16402826.
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