Iodomethylzinc Iodide1

ICH2ZnI
(1; ICH2ZnI)

[4109-94-8]  · CH2I2Zn  · Iodomethylzinc Iodide  · (MW 333.22) (2; BrCH2ZnBr)

[4109-95-9]  · CH2Br2Zn  · Bromomethylzinc Bromide  · (MW 239.22) (3; (ICH2)2Zn)

[14399-53-2]  · C2H4I2Zn  · Bis(iodomethyl)zinc  · (MW 347.25) (4; (ICH2)2Zn.DME)

[131457-21-1]  · C6H14I2O2Zn  · Bis(iodomethyl)zinc-Dimethoxyethane  · (MW 437.39) (5; (BrCH2)2Zn)

[92601-82-6]  · C2H4Br2Zn  · Bis(bromomethyl)zinc  · (MW 253.25) (6; (ClCH2)2Zn.DME)

[131457-22-2]  · C6H14Cl2O2Zn  · Bis(chloromethyl)zinc-Dimethoxyethane  · (MW 254.49)

(methylene transfer reagent: cyclopropanates alkenes,1 a1/d1 multicoupling reagent,2 transmetalation with various metal halides affords other iodomethylmetal compounds3)

Alternate Name: Simmons-Smith reagent.

Physical Data: an X-ray crystal structure of (ICH2)2Zn complexed to a glycol bis-ether is known;4 DME complexes of (ICH2)2Zn and (ClCH2)2Zn and an acetone complex of (ICH2)2Zn/ZnI2 have been characterized by NMR spectroscopy;4 1H NMR spectra attributed to THF complexes of BrCH2ZnBr and (BrCH2)2Zn have been reported.5

Solubility: ICH2ZnI generated from either CH2I2/Zn-Cu couple or EtZnI/CH2I2 is generally prepared in ethereal solvents (Et2O, DME). The Et2Zn/CH2I2 method of reagent generation can utilize noncoordinating solvents (CH2Cl2, ClCH2CH2Cl, toluene, etc.).

Preparative Methods: the two most widely used methods of preparing halomethylzinc reagents are the Simmons-Smith and Furukawa procedures, utilizing Diiodomethane/Zinc/Copper Couple and CH2I2/Diethylzinc (or Chloroiodomethane/Et2Zn),6 respectively. The reagent is often prepared in the presence of the substrate (usually an alkene). Various methods of reagent preparation are discussed below. The precursors are widely available.

Reagent Preparation.

There are a number of protocols for generating iodomethylzinc reagents, which can be categorized into three general classes: type 1, the oxidative addition of a dihalomethane to zinc metal, as typified by the original Simmons-Smith procedure;7,8 type 2, the reaction of a zinc(II) salt with a diazoalkane, first reported by Wittig and co-workers;9 and type 3, an alkyl exchange reaction between an alkyl zinc and a 1,1-dihaloalkane, often referred to as the Furukawa procedure.10

Type 1 reagent generation has been used most often in synthetic contexts due to the ease with which the reagent precursors can be handled. Although the initial method of preparation of the Zn-Cu couple was difficult and not easily reproducible,7 several simpler and highly reproducible methods soon followed.11 Treatment of the Zn-Cu couple with CH2I2 and a crystal of Iodine in Et2O followed by heating to reflux generates the active reagent. Other modifications include the use of CH2I2/Zn/CuCl,12a CH2I2/Zn-Ag couple,12b CH2Br2/Zn/TiCl4,12c and CH2Br2/Zn/AcCl/CuCl.12d

Type 2 reagent generation has been utilized much less frequently. The method consists of the treatment of an ethereal suspension of a zinc(II) salt (ZnCl2, ZnBr2, ZnI2, or Zn(OBz)2) with CH2N2 or an aryldiazomethane.9a

Type 3 halomethylzinc generation (originally reported in 1966)10a involves treatment of a solution (Et2O, hexane, toluene, etc.) of Et2Zn with CH2I2 to generate the reagent. The use of a 2:1 ratio of CH2I2 to Et2Zn generates (ICH2)2Zn,4 while a 1:1 ratio presumably generates EtZnCH2I.10 The reaction is accelerated by the presence of trace amounts of oxygen.6b Treatment of Et2Zn with substituted diiodides, such as benzylidene and ethylidene iodide, also gives rise to active cyclopropanating reagents.13 Recently, the substitution of ClCH2I for CH2I2 and the use of ClCH2CH2Cl (DCE) as the reaction solvent has been demonstrated to provide a more reactive reagent for certain applications.6a In addition, the combination of EtZnI and CH2I2 has also been shown to provide ICH2ZnI, thus avoiding the need for the highly pyrophoric Et2Zn.14

Cyclopropanations.

The cyclopropanation of alkenes utilizing halomethylzinc reagents (ICH2ZnI being the prototypical reagent), known as the Simmons-Smith reaction,7 has proven to be an extremely versatile and general reaction. Typical examples of alkenes that have been successfully cyclopropanated are provided in eqs 1-5. A variety of isolated alkenes have been cyclopropanated with the Simmons-Smith reagent (e.g. eq 1),1a,12b and ICH2ZnI provides for a unique preparation of numerous spiro derivatives (eq 2).15 Electron-rich alkenes such as enol ethers (eq 3)16a-c and enamines (eq 4)16d,e also have been found to be good substrates under the proper conditions, as have certain steroidal enones (eq 5).16f,g Simmons-Smith reagents thus have been demonstrated to cyclopropanate alkenes ranging from electron rich to electron deficient. This contrasts with the analogous reagents generated from CH2I2/R3Al17 and ClCH2I/Sm(Hg):18 the former reacts preferentially with isolated alkenes, while the latter cyclopropanates allylic alcohols almost exclusively. Certain vinyl metal species (Al, Si, Ge, Sn, B) can also be cyclopropanated with some success with the Simmons-Smith reagent.19 For example, vinylalanes produced in situ from alkynes and Diisobutylaluminum Hydride react readily with CH2Br2/Zn-Cu couple; the intermediate cyclopropylalanes react with bromine to produce cyclopropyl bromides (eq 6).19b Generally, the reaction is most successful with electron-rich alkenes, indicative of the electrophilic nature of halomethylzinc reagents.1a

The reaction is not limited to unsubstituted methylene transfers.13 The combination of MeCHI213a-c or PhCHI213a,d with Et2Zn also provides active cyclopropanation reagents. The diastereoselectivity is highly substrate dependent, but good diastereoselectivity can be achieved in certain cases (eq 7), particularly with cyclic alkenes. The stereoselectivity is solvent dependent, with ethereal solvents affording the higher levels of selectivity.13d Halogen-substituted carbenoids can also be prepared from various XCHI2 (X = I, Br, F) or X2CHI (X = Br, Cl) and Et2Zn (eq 8).13e-g

Perhaps the most intriguing aspect of the Simmons-Smith reaction is the strong accelerating and stereodirecting effect of oxygen functions proximal to the alkene. First discovered in 1959,20 this reaction has been often utilized in synthetic efforts21 and the reaction itself has been the subject of several investigations.22 For example, cyclopropanation of 2-cyclohexen-1-ol provides the syn-cyclopropane almost exclusively.22a A study of various cyclic allylic alcohols demonstrates the generality of the effect (eq 9):22c the larger rings afford trans adducts due to conformational effects. The diastereoselectivity of the cyclopropanation of acyclic secondary allylic alcohols depends upon the configuration of the alkene. cis-Alkenes react with diastereoselectivities of >99:1 (eq 10), while trans-alkenes react with much less selectivity (<2:1).22f Homoallylic alcohols also show a similar directing effect in certain cases (eq 11).20,21e

Chiral auxiliary mediated cyclopropanations which exploit this oxygen-directing effect have recently been developed. The first Simmons-Smith reactions exhibiting effective diastereofacial control by chiral auxiliaries were reported simultaneously by two groups in 1985.23,24 Chiral acetals derived from cyclic enones undergo highly diastereoselective cyclopropanations upon treatment with CH2I2/Zn-Cu couple (eq 12). Acyclic enones are cyclopropanated with greatly attenuated diastereoselectivity.

Similarly, chiral acetals24 derived from a,b-unsaturated aldehydes and diisopropyl tartrate are cyclopropanated in a highly diastereoselective manner by CH2I2/Et2Zn (eq 13). Diastereoselectivities are uniformly high for dioxolane acetals derived from trans-disubstituted a,b-unsaturated aldehydes, but acetals derived from a,b-unsaturated ketones react less selectively, as do 2-alkenyl-1,3-dioxane acetals.

A related oxygen-directed cyclopropanation has also been reported.25 Vinyl boronates derived from tartaric esters or amides were shown to undergo highly diastereoselective cyclopropanations upon treatment with CH2I2/Zn-Cu couple. These adducts were conveniently converted to enantiomerically enriched cyclopropanols. The carbohydrate 2-hydroxy-3,4,6-tri-O-benzyl-b-D-glucopyranose appended to an allylic alcohol also functions as an effective chiral auxiliary, affording cyclopropanes with extremely high levels of diastereoselectivity (eq 14).26 Other chiral auxiliaries have also been shown to direct halomethylzinc cyclopropanations with good to excellent stereocontrol.13g,27

Although the potential for preparing enantioselective halomethylzinc reagents was recognized early on,28 only since 1992 have encouraging levels of enantioselectivity been observed.29 The best results reported to date utilize chiral C2-symmetric sulfonamides in substoichiometric amounts as the source of chirality (eq 15).29a A zinc complex of this ligand is proposed to act as a chiral Lewis acid catalyst in this reaction. All of the enantioselective halomethylzinc cyclopropanations reported to date utilize allylic alcohols as substrates, and the free hydroxy group appears to play an essential role.29

Methylene Homologation Reactions.

The carbon bound iodine atom of ICH2ZnI can be easily displaced by nucleophiles to generate new organozinc reagents.9b For example, various copper nucleophiles displace the carbon bound iodine from ICH2ZnI or (ICH2)2Zn, generating new organometallic reagents that react with allyl halides.2,30 Copper nucleophiles such as CuCN/LiCl, NCCH2Cu, copper amides, vinylcoppers, and heteroarylcopper compounds all participate in this reaction (eq 16). This reaction has proven to be especially useful for the conversion of alkenylcoppers into allylic copper-zinc reagents which react with aldehydes affording homoallylic alcohols (eq 17). An expedient route to a-methylene-g-butyrolactones that exploits this behavior has also been developed (eq 18).30e

Transmetalation Reactions.

Like other alkylzinc reagents,31 halomethylzinc reagents have also been shown to participate in transmetalation reactions.3,14a This methodology provides an expedient route to iodomethylmercury and iodomethyltin compounds. For example, treatment of Me3SnCl with ICH2ZnI derived from EtZnI and CH2I2 provides Me3SnCH2I in 78% yield.14a Bu3SnCH2I may be prepared similarly in 96% yield.32 Substituted diiodides also provide zinc reagents that participate well in this reaction.14a

[2,3]-Rearrangements.

A method for the generation of sulfur ylides from allylic phenyl sulfides and CH2I2/Et2Zn has been described.33 The intermediate sulfur ylides undergo a sigmatropic [2,3]-rearrangement affording homoallylic sulfides (eq 19). The reaction gives (E)-alkenes selectively.

Related Reagents.

1,1-Diiodoethane; Diiodomethane.


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3. Seyferth, D.; Andrews, S. B. JOM 1971, 30, 151.
4. (a) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. JACS 1991, 113, 723. (b) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. JACS 1992, 114, 2592.
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8. This reagent was first prepared by Emschwiller: Emschwiller, G. CR(C) 1929, 188, 1555.
9. (a) Wittig, G.; Schwarzenbach, K. AG 1959, 71, 652. (b) Wittig, G.; Schwarzenbach, K. LA 1962, 650, 1. (c) Wittig, G.; Wingler, F. LA 1962, 656, 18. (d) Wittig, G.; Wingler, F. CB 1964, 97, 2146. (e) Wittig, G.; Jautelat, M. LA 1967, 702, 24.
10. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. TL 1966, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. T 1968, 24, 53. (c) Nishimura, J.; Furukawa, J.; Kawabata, N.; Kitayama, M. T 1971, 27, 1799.
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13. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. TL 1968, 3495. (b) Nishimura, J.; Kawabata, N.; Furukawa, J. T 1969, 25, 2647. (c) Nishimura, J.; Furukawa, J.; Kawabata, N. BCJ 1970, 43, 2195. (d) Nishimura, J.; Furukawa, J.; Kawabata, N.; Koyama, H. BCJ 1971, 44, 1127. (e) Nishimura, J.; Furukawa, J. CC 1971, 1375. (f) Miyano, S.; Hashimoto, H. BCJ 1974, 47, 1500. (g) Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S. TL 1992, 33, 3483; 3487.
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21. For some recent examples, see: (a) Corey, E. J.; Virgil, S. C. JACS 1990, 112, 6429. (b) Oppolzer, W.; Radinov, R. N. JACS 1993, 115, 1593. (c) Johnson, C. R.; Barbachyn, M. R. JACS 1982, 104, 4290. (d) Neef, G.; Cleve, G.; Otow, E.; Seeger, A.; Wiechert, R. JOC 1987, 52, 4143. (e) Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. JACS 1993, 115, 6078.
22. (a) Dauben, W. G.; Berezin, G. H. JACS 1963, 85, 468. (b) Chan, J. H.-H.; Rickborn, B. JACS 1968, 90, 6406. (c) Poulter, C. D.; Friedrich, E. C.; Winstein, S. JACS 1969, 91, 6892. (d) Staroscik, J. A.; Rickborn, B. JOC 1972, 37, 738. (e) Kawabata, N.; Nakagawa, T.; Nakao, T.; Yamashita, S. JOC 1977, 42, 3031. (f) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyere, M. JCR(S) 1978, 179.
23. (a) Mash, E. A.; Nelson, K. A. JACS 1985, 107, 8256. (b) Mash, E. A.; Hemperly, S. B. JOC 1990, 55, 2055, and references cited therein.
24. (a) Arai, I.; Mori, A.; Yamamoto, H. JACS 1985, 107, 8254. (b) Mori, A.; Arai, I.; Yamamoto, H. T 1986, 42, 6447.
25. Imai, T.; Mineta, H.; Nishida, S. JOC 1990, 55, 4986.
26. (a) Charette, A. B.; Côté, B.; Marcoux, J.-F. JACS 1991, 113, 8166. (b) Charette, A. B.; Côté, B. JOC 1993, 58, 933.
27. (a) Sugimura, T.; Katagiri, K.; Tai, A. TL 1992, 33, 367, and references cited therein. (b) Seebach, D.; Stucky, G. AG(E) 1988, 27, 1351. (c) Fukuyama, Y.; Hirono, M.; Kodama, M. CL 1992, 167. (d) Morikawa, T.; Sasaka, H.; Mori, K.; Shiro, M.; Taguchi, T. CPB 1992, 40, 3189. (e) de Frutos, M. P.; Fernandez, M. D.; Fernandez-Alvarez, E.; Bernabe, M. TL 1991, 32, 541.
28. (a) Sawada, S.; Oda, J.; Inouye, Y. JOC 1968, 33, 2141. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. TL 1968, 3495.
29. (a) Takahashi, H.; Yoshioka, M.; Ohno, M. Kobayshi, S. TL 1992, 33, 2757. (b) Ukakji, Y.; Nishimura, M.; Fujisawa, T. CL 1992, 61. (c) Denmark, S. E.; Edwards, J. P. SL 1992, 229. (d) Denmark, S. E.; Christenson, B. L.; Coe, D. M.; O'Connor, S. P. TL 1995, 36, 2215. (e) Denmark, S. E.; Christenson, B. L.; O'Connor, S. P. TL 1995, 36, 2219.
30. (a) Knochel, P.; Chou, T.-S.; Chen, H. G.; Yeh, M. C. P.; Rozema, M. J. JOC 1989, 54, 5202. (b) Knochel, P.; Jeong, N.; Rozema, M. J.; Yeh, M. C. P. JACS 1989, 111, 6474. (c) Knochel, P.; Rao, S. A. JACS 1990, 112, 6146. (d) Rozema, M. J.; Knochel, P. TL 1991, 32, 1855. (e) Knochel, P.; Rozema, M. J.; Tucker, C. E.; Retherford, C.; Furlong, M.; Sidduri, A. R. PAC 1992, 64, 361. (f) Sidduri, A. R.; Knochel, P. JACS 1992, 114, 7579.
31. Boersma, J. In Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, 1984; Vol. 2, Chapter 16.
32. Still, W. C. JACS 1978, 100, 1481.
33. Kosarych, Z.; Cohen, T. TL 1982, 23, 3019.

James P. Edwards

Ligand Pharmaceuticals, San Diego, CA, USA

Paul Knochel

Philipps-Universität, Marburg, Germany



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