Samarium(II) Iodide1

SmI2

[32248-43-4]  · I2Sm  · Samarium(II) Iodide  · (MW 404.16)

(one-electron reducing agent possessing excellent chemoselectivity in reduction of carbonyl, alkyl halide, and a-heterosubstituted carbonyl substrates;1 promotes Barbier-type coupling reactions, ketyl-alkene coupling reactions, and radical cyclizations1)

Physical Data: mp 527 °C; bp 1580 °C; d 0.922 g cm-3.

Solubility: soluble 0.1M in THF.

Form Supplied in: commercially available as a 0.10 M solution in THF.

Preparative Methods: typically prepared in situ for synthetic purposes. SmI2 is conveniently prepared by oxidation of Samarium(0) metal with organic dihalides.2

Handling, Storage, and Precautions: is air sensitive and should be handled under an inert atmosphere. SmI2 may be stored over THF for long periods when it is kept over a small amount of samarium metal.

Reduction of Organic Halides and Related Substrates.

Alkyl halides are readily reduced to the corresponding hydrocarbon by SmI2 in the presence of a proton source. The ease with which halides are reduced by SmI2 follows the order I > Br > Cl. The reduction is highly solvent dependent. In THF solvent, only primary alkyl iodides and bromides are effectively reduced;2 however, addition of HMPA effects the reduction of aryl, alkenyl, primary, secondary, and tertiary halides (eq 1).3,4 Tosylates are also reduced to hydrocarbons by SmI2. Presumably, under these reaction conditions the tosylate is converted to the corresponding iodide which is subsequently reduced.4,5

Samarium(II) iodide provides a means to reduce substrates in which the halide is resistant to reduction by hydride reducing agents (eq 2).

Samarium(II) iodide has been utilized as the reductant in the Boord alkene-type synthesis involving ring scission of 3-halotetrahydrofurans (eq 3).6 SmI2 provides an alternative to the sodium-induced reduction which typically affords mixtures of stereoisomeric alkenes and overreduction in these transformations. When SmI2 is employed as the reductant, isomeric purities are generally >97% and overreduction products comprise <3% of the reaction mixture.

Reduction of a-Heterosubstituted Carbonyl Compounds.

Samarium(II) iodide provides a route for the reduction of a-heterosubstituted carbonyl substrates. A wide range of a-heterosubstituted ketones is rapidly reduced to the corresponding unsubstituted ketone under mild conditions (eq 4).7 The reaction is highly selective and may be performed in the presence of isolated iodides as well as isolated ketones.7

Samarium(II) iodide-induced reductive cleavage of a-hydroxy ketones provides a useful entry to unsubstituted ketones (eq 5).8

Samarium(II) iodide promotes the reductive cleavage of a-alkoxy ketones. Pratt and Hopkins have utilized this protocol in synthetic studies en route to betaenone B (eq 6).9

Likewise, this procedure provides a route for the reduction of a,b-epoxy ketones and a,b-epoxy esters to generate the corresponding b-hydroxy carbonyl compounds (eqs 7 and 8).3,10 The epoxy ketone substrates may be derived from Sharpless asymmetric epoxidation. Consequently, this procedure provides a means to prepare a variety of chiral, nonracemic b-hydroxy carbonyl compounds that are difficult to acquire by more traditional procedures.

Vinyloxiranes undergo reductive epoxide ring opening with samarium(II) iodide to provide (E)-allylic alcohols (eq 9).3,10b,11 These reaction conditions are tolerant of ketone, ester, and nitrile functional groups. Again, Sharpless asymmetric epoxidation chemistry may be utilized to gain entry to the desired nonracemic substrates, thereby providing a useful entry to highly functionalized, enantiomerically enriched allylic alcohols.

A useful method for preparation of b-hydroxy esters is accomplished by SmI2-promoted deoxygenation of an a-hydroxy ester followed by condensation with a ketone (eq 10).12 In some instances, excellent diastereoselectivities are achieved, although this appears to be somewhat substrate dependent.

A useful reaction sequence for transforming carbonyl compounds to one-carbon homologated nitriles has evolved from the ability of SmI2 to deoxygenate cyanohydrin O,O-diethyl phosphates (eq 11).13 The procedure is tolerant of a number of functional groups including alcohols, esters, amides, sulfonamides, acetals, alkenes, alkynes, and amines. Furthermore, it provides a distinct advantage over other previously developed procedures for similar one-carbon homologations.

Deoxygenation Reactions.

Sulfoxides are reduced to sulfides by SmI2 (eq 12).2,3,14 This process is rapid enough that reduction of isolated ketones is not a competitive process. Likewise, aryl sulfones are reduced to the corresponding sulfides by SmI2 (eq 13).3,12

Barbier-Type Reactions.

Samarium(II) iodide is quite useful in promoting Barbier-type reactions between aldehydes or ketones and a variety of organic halides. The efficiency of SmI2 promoted Barbier-type coupling processes is governed by the substrate under consideration in addition to the reaction conditions employed. In general, alkyl iodides are most reactive while alkyl chlorides are virtually inert. Typically, catalytic Iron(III) Chloride or Hexamethylphosphoric Triamide can be added to SmI2 to reduce reaction times or temperatures and enhance yields. Kagan and co-workers have recently applied an intermolecular SmI2-promoted Barbier reaction towards the synthesis of hindered steroidal alcohols. An intermolecular Barbier-type reaction between the hindered ketone and Iodomethane produced a 97:3 mixture of diastereomers in excellent yield (eq 14).15

Samarium(II) iodide-promoted intramolecular Barbier-type reactions have also been employed to produce a multitude of cyclic and bicyclic systems.1 Molander and McKie have employed an intramolecular Barbier-type reductive coupling reaction to promote the formation of bicyclo[m.n.1]alkan-1-ols from the corresponding iodo ketone substrates in good yield (eq 15).16

Annulation of five- and six-membered rings proceeds with excellent diastereoselectivity via an intramolecular Barbier-type process (eq 16).17 The Barbier-type coupling scheme provides a reliable and convenient alternative to other such methods for preparing fused bicyclic systems.

The SmI2-promoted Barbier-type reaction has also been utilized in the synthesis of polyquinanes. Cook and Lannoye have employed this method to effect a bis-annulation of an appropriately substituted diketone (eq 17).18

Substituted b-keto esters also provide excellent substrates for the intramolecular Barbier cyclization (eq 18).19 Diastereoselectivities are typically quite good but are highly dependent on substituent and solvent effects.

Nucleophilic Acyl Substitutions.

Samarium(II) iodide facilitates the highly selective intramolecular nucleophilic acyl substitution of halo esters (eqs 19 and 20).20

Unlike organolithium or organomagnesium reagents, SmI2-promoted nucleophilic substitution does not proceed with double addition to the carbonyl, nor are any products resulting from reduction of the final product observed. With suitably functionalized substrates, this procedure provides a strategy for the formation of eight-membered rings (eq 21).

Ketone-Alkene Coupling Reactions.

Ketyl radicals derived from reduction of ketones or aldehydes with SmI2 may be coupled both inter- and intramolecularly to a variety of alkenic species. Excellent diastereoselectivities are achieved with intramolecular coupling of the ketyl radical with a,b-unsaturated esters.21 In the following example, ketone-alkene cyclization took place in a stereocontrolled manner established by chelation of the resulting Sm(III) species with the hydroxyl group incorporated in the substrate (eq 22).21b

A similar strategy utilizing b-keto esters provided very high diastereoselectivities in the ketyl-alkene coupling process. In these examples, chelation control about the developing hydroxyl and carboxylate stereocenters was the source of the high diastereoselectivity achieved (eq 23).22

Alkynic aldehydes likewise undergo intramolecular coupling to generate five- and six-membered ring carbocycles. This protocol has been utilized as a key step in the synthesis of isocarbacyclin (eq 24).23 SmI2 was found to be superior to several other reagents in this conversion.

Samarium(II) iodide in the presence of HMPA effectively promotes the intramolecular coupling of unactivated alkenic ketones by a reductive ketyl-alkene radical cyclization process (eq 25). This protocol provides a means to generate rather elaborate carbocycles through a sequencing process in which the resulting organosamarium species is trapped with various electrophiles to afford the cyclized product in high yield.24

Pinacolic Coupling Reactions.

In the absence of a proton source, both aldehydes and ketones are cleanly coupled in the presence of SmI2 to the corresponding pinacol.25 Considerable diastereoselectivity has been achieved in the coupling of aliphatic 1,5- and 1,6-dialdehydes, providing near exclusive formation of the cis-diols (eq 26).26

Intramolecular cross coupling of aldehydes and ketones proceeds with excellent diastereoselectivity and high yield in suitably functionalized systems wherein chelation control by the resulting SmIII species directs formation of the newly formed stereocenters (eq 27).22a,27 A similar strategy has been utilized with a b-keto amide substrate to provide a chiral, nonracemic oxazolidinone species. This strategy permits entry to highly functionalized, enantiomerically pure dihydroxycyclopentanecarboxylate derivatives (eq 28).

Radical Addition to Alkenes and Alkynes.

Samarium(II) iodide has proven effective for initiation of various radical addition reactions to alkenes and alkynes. Typically, tin reagents are used in the initiation of these radical cyclization reactions; however, the SmI2 protocol often provides significant advantages over these more traditional routes.

Samarium(II) iodide-mediated cyclization of aryl radicals onto alkene and alkyne acceptors provides an excellent route to nitrogen- and oxygen-based heterocycles (eq 29).28

The SmI2 reagent is unique in that it provides the ability to construct more highly functionalized frameworks through a sequential radical cyclization/intermolecular carbonyl addition reaction.29 Thus the intermediate radical formed after initial cyclization may be further reduced by SmI2, forming an organosamarium intermediate which may be trapped by various electrophiles, affording highly functionalized products (eq 30).

Samarium(II) iodide further mediates the cyclization reactions of alkynyl halides (eq 31).30 When treated with SmI2, the alkynyl halides are converted to the cyclized product in good yield. Addition of DMPU as cosolvent provides slightly higher yields in some instances.

Highly functionalized bicyclic and spirocyclic products are obtained in good yield and high diastereoselectivity by a tandem reductive cleavage-cyclization strategy (eq 32).31 Radical ring opening of cyclopropyl ketones mediated by samarium(II) iodide-induced electron transfer permits the elaboration of a tandem ring opening-cyclization strategy wherein the resultant samarium enolate may be trapped by either oxygen or carbon electrophiles.

Related Reagents.

Samarium(II) Iodide-1,3-Dioxolane.


1. (a) Molander, G. A. CRV 1992, 92, 29. (b) Molander, G. A. In The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Ed.; Wiley: Chichester, 1989; Vol. 5, Chapter, 8. (c) Kagan, H. B. NJC 1990, 14, 453. (d) Soderquist, J. A. Aldrichim. Acta 1991, 24, 15. (e) Molander, G. A. COS 1991, 1, Chapter 1.9.
2. (a) Girard, P.; Namy, J. L.; Kagan, H. B. JACS 1980, 102, 2693. (b) Namy, J. L.; Girard, P.; Kagan, H. B. NJC 1977, 1, 5. (c) Namy, J. L.; Girard, P.; Kagan, H. B. NJC 1981, 5, 479.
3. Inanaga, J. HC 1990, 3, 75.
4. Inanaga, J.; Ishikawa, M.; Yamaguchi, M. CL 1987, 1485.
5. Kagan, H. B.; Namy, J. L.; Girard, P. T 1981, 37, 175, Suppl. 1.
6. Crombie, L.; Rainbow, L. J. TL 1988, 29, 6517.
7. (a) Molander, G. A.; Hahn, G. JOC 1986, 51, 1135. (b) Smith, A. B., III; Dunlap, N. K.; Sulikowski, G. A. TL 1988, 29, 439. (c) Castro, J.; Sörensen, H.; Riera, A.; Morin, C.; Moyano, A.; Pericàs, M. A.; Greene, A. E. JACS 1990, 112, 9388.
8. (a) White, J. D.; Somers, T. C. JACS 1987, 109, 4424. (b) Holton, R. A.; Williams, A. D. JOC 1988, 53, 5981.
9. Pratt, D. V.; Hopkins, P. B. TL 1987, 28, 3065.
10. (a) Molander, G. A.; Hahn, G. JOC 1986, 51, 2596. (b) Otsubo, K.; Inanaga, J.; Yamaguchi, M. TL 1987, 28, 4437.
11. Molander, G. A.; La Belle, B. E.; Hahn, G. JOC 1986, 51, 5259.
12. Enholm, E. J.; Jiang, S. TL 1992, 33, 313.
13. (a) Yoneda, R.; Harusawa, S.; Kurihara, T. TL 1989, 30, 3681. (b) Yoneda, R.; Harusawa, S.; Kurihara, T. JOC 1991, 56, 1827.
14. Handa, Y.; Inanaga, J.; Yamaguchi, M. CC 1989, 298.
15. Sasaki, M.; Collin, J.; Kagan, H. B. NJC 1992, 16, 89.
16. Molander, G. A.; McKie, J. A. JOC 1991, 56, 4112.
17. (a) Molander, G. A.; Etter, J. B. JOC 1986, 51, 1778. (b) Zoretic, P. A.; Yu, B. C.; Caspar, M. L. SC 1989, 19, 1859. (c) Daniewski, A. R.; Uskokovic, M. R. TL 1990, 31, 5599.
18. (a) Lannoye, G.; Cook, J. M. TL 1988, 29, 171. (b) Lannoye, G.; Sambasivarao, K.; Wehrli, S.; Cook, J. M.; Weiss, U. JOC 1988, 53, 2327.
19. Molander, G. A.; Etter, J. B.; Zinke, P. W. JACS 1987, 109, 453.
20. Molander, G. A.; McKie, J. A. JOC 1993, 58, 7216.
21. (a) Hon, Y.-S.; Lu, L.; Chu, K.-P. SC 1991, 21, 1981. (b) Kito, M.; Sakai, T.; Yamada, K.; Matsuda, F.; Shirahama, H. SL 1993, 158. (c) Fukuzawa, S.; Iida, M.; Nakanishi, A.; Fujinami, T.; Sakai, S. CC 1987, 920. (d) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. JCS(P1) 1988, 1669. (e) Enholm, E. J.; Trivellas, A. TL 1989, 30, 1063. (f) Enholm, E. J.; Satici, H.; Trivellas, A. JOC 1989, 54, 5841. (g) Enholm, E. J.; Trivellas, A. JACS 1989, 111, 6463.
22. (a) Molander, G. A.; Kenny, C. JACS 1989, 111, 8236. (b) Molander, G. A.; Kenny, C. TL 1987, 28, 4367.
23. (a) Shim, S. C.; Hwang, J.-T.; Kang, H.-Y.; Chang, M. H. TL 1990, 31, 4765. (b) Bannai, K.; Tanaka, T.; Okamura, N.; Hazato, A.; Sugiura, S.; Manabe, K.; Tomimori, K.; Kato, Y.; Kurozumi, S.; Noyori, R. T 1990, 46, 6689.
24. Molander, G. A.; McKie, J. A. JOC 1992, 57, 3132.
25. (a) Namy, J. L.; Souppe, J.; Kagan, H. B. TL 1983, 24, 765. (b) Fürstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H. JCS(P1) 1988, 1729.
26. Chiara, J. L.; Cabri, W.; Hanessian, S. TL 1991, 32, 1125.
27. Molander, G. A.; Kenny, C. JACS 1989, 111, 8236.
28. Inanaga, J.; Ujikawa, O.; Yamaguchi, M. TL 1991, 32, 1737.
29. (a) Molander, G. A.; Harring, L. S. JOC 1990, 55, 6171. (b) Curran, D. P.; Totleben, M. J. JACS 1992, 114, 6050.
30. Bennett, S. M.; Larouche, D. SL 1991, 805.
31. Batey, R. A.; Motherwell, W. B. TL 1991, 32, 6649.

Gary A. Molander & Christina R. Harris

University of Colorado, Boulder, CO, USA



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