Dibromomethane-Zinc-Titanium(IV) Chloride1


[74-95-3]  · CH2Br2  · Dibromomethane-Zinc-Titanium(IV) Chloride  · (MW 173.83) (Zn)

[7440-66-6]  · Zn  · Dibromomethane-Zinc-Titanium(IV) Chloride  · (MW 65.39) (TiCl4)

[7550-45-0]  · Cl4Ti  · Dibromomethane-Zinc-Titanium(IV) Chloride  · (MW 189.69)

(reagent for the methylenation of ketones1-5 and aldehydes;1 it methylenates highly enolizable1,4,6 and sterically hindered ketones;1 it selectively methylenates ketones and aldehydes in the presence of esters, while some variations allow the chemoselective methylenation of aldehydes and ketones;7 in combination with TMEDA it methylenates esters and lactones;1 similar reagents made from other 1,1-dibromoalkanes allow the alkylidenation of esters,8 lactones,8 silyl enol esters,9 thioesters,10 and amides10)

Alternate Name: Lombardo's reagent.

Solubility: partially sol solvents usually used for the reaction (THF and CH2Cl2).

Form Supplied in: not available commercially.

Preparative Methods: Oshima method:2,3 a suspension of Zinc dust (4.5 equiv) and Dibromomethane (1.5 equiv) in dry THF, stirred under N2 at rt, is treated with a 1.0 M solution of Titanium(IV) Chloride (1.1 equiv) in CH2Cl2. After 15 min the resulting dark brown mixture is treated dropwise with a solution of the ketone (1 equiv) in dry THF, and the mixture is stirred at rt for 4-40 h. Lombardo's reagent:4,5 to a suspension of Zn dust (4.3 equiv) and CH2Br2 (1.4 equiv) in dry THF, stirred under N2 at -40 °C, is added dropwise neat TiCl4. The mixture is then allowed to warm to 5 °C and is stirred for 1-3 days to produce a thick gray slurry of the active reagent. The cold slurry is added to a solution of the ketone in CH2Cl2 or THF. Usually, the reaction is complete within a few minutes.

Handling, Storage, and Precautions: moisture sensitive; decomposes at rt. Lombardo's reagent may be stored at -20 °C up to a year with only 5-10% loss of reactivity.

Methods for Carbonyl Methylenation.

The methylenation of aldehydes and ketones is often performed with the Wittig reagent, CH2=PPh3 (see Bis(cyclopentadienyl)dimethyltitanium), or by the addition of other P-, Si-, or S-stabilized methylene anions.11 As a result of the inherent basicity of these reagents, however, several limitations exist for their synthetic utility. Among the major drawbacks of the Wittig-type alkenation methods is their inability to alkenate readily enolizable carbonyls or substrates that undergo facile nucleophilic addition or elimination reactions. Furthermore, sterically hindered substrates are often methylenated only in low yields, while the alkenation of esters and lactones is usually not possible with these methods. Several alternative methylenation procedures have been developed that avoid most of the problems encountered with Wittig-type processes. Among these, the Tebbe reagent (see m-Chlorobis(cyclopentadienyl)(dimethylaluminum)-m-methylenetitanium)1,12 has been used for the methylenation of a variety of carbonyls, including aldehydes, enolizable ketones, esters, and lactones. This reagent, however, is not suitable for highly acid-labile substrates and requires strenuous inert-atmosphere techniques due to its high sensitivity to air and water. An experimentally convenient alternative to the Tebbe reagent is dimethyltitanocene (see Bis(cyclopentadienyl)dimethyltitanium)13 which is easier to prepare and handle and is suitable for the methylenation of both ketone and ester carbonyls, including highly enolizable and acid-labile substrates. Another widely used carbonyl methylenation procedure is the combination of CH2Br2-Zn-TiCl4, which was first reported by Oshima,2,3 and later modified by Lombardo4,5 and Takai.6,7

According to the initial procedure,2,3 a suspension of Zinc dust and Dibromomethane in THF are reacted with a solution of Titanium(IV) Chloride in CH2Cl2; after stirring for 15 min the dark brown mixture is combined with the carbonyl substrate in CH2Cl2 or THF. In this manner the completion of the methylenation reaction often requires prolonged stirring at rt. This in situ procedure is most effective for the methylenation of ketones and is less effective with aryl ketones and aldehydes, which undergo a competing pinacol-type reductive coupling.

Lombardo4,5 found that prior low temperature aging of the CH2Br2-Zn-TiCl4 system, which presumably alters the composition of the reagent, significantly speeds up the methylenation process and limits the exposure of the carbonyl substrate to Zn and TiCl4. This methodology leads to increased methylenation yields and suppressed side reactions. The use of CD2Br2 or 13CH2Br2 in these reactions allows the incorporation of D or 13C into the substrate.

Takai6 has reported that a more reactive system consisting of Diiodomethane-Zinc-Titanium(IV) Chloride is very effective for the methylenation of highly enolizable ketones. Two other variations, CH2I2-Zn-Ti(O-i-Pr)4 and CH2I2-Zn-Me3Al, allow the chemoselective methylenation of aldehydes in the presence of ketones.7

Methylenation of Ketones.

The Oshima procedure effectively methylenates a variety of ketones which, under the usual Wittig conditions, are unreactive or give much lower yields. The presence of carboxylic ester groups, which often interfere with the Wittig methylenation of ketones, do not present such problems with this methylenation process. A similar advantage can exist over the use of the Tebbe reagent which also alkenates the ester functionality.14 Due to the nonbasic conditions, this method is suitable for substrates that undergo facile enolization, such as b,g-unsaturated ketones (eq 1)15 and cyclopentanones (eq 2).14

Lombardo's reagent is often the best choice for the methylenation of base-sensitive ketones. This system has been employed extensively in the synthesis of gibberellins4,16,17 and related compounds. Although this type of bridged ketone is susceptible to enolization and epimerization, the desired alkenes are obtained in high yield without any loss of stereochemistry (eqs 3 and 4).4,17 Free hydroxy and carboxylic acid groups are also tolerated by this reagent.

This methylenation method proceeds without enolization of the carbonyl group, even in cases where this is a very facile process. For example, while Wittig-type methodologies often fail completely with b,g-unsaturated ketones, the use of Lombardo's reagent gives excellent yields of the corresponding alkenes (eqs 5 and 6).18,19

This reagent has been used widely in prostaglandin synthesis. A variety of cyclopentanones bearing the usual protective groups were successfully methylenated without epimerization or elimination of the b-silyloxy (eq 7)20 or even b-acyloxy functionalities (eq 8).21

b-Acyloxy ketones are methylenated more efficiently with CH2I2-Zn-TiCl4 (eq 9).6

These reagents are also suitable for the methylenation of sterically hindered ketones (eq 10)22 and enones (eq 11),23 reactions that often fail with Wittig-type methods.

In some cases the methylenation products undergo subsequent cyclopropanation (eq 12),24 a reaction that can be more efficient in the presence of copper.25

The CH2I2-Zn-TiCl4 system is effective for the methylenation of nonracemic a-amino ketone derivatives (eq 13).26

Substituents containing other heteroatoms, such as tin (eq 14),27 sulfur (eq 15),28,29 or selenium (eq 16),29 are well tolerated in this process.

Methylenation of Aldehydes.

Aldehydes are not as good substrates as ketones for the methylenation with the CH2Br2-Zn-TiCl4 system due to complications arising from reductive coupling of the carbonyl. In some cases, however, an aldehyde moiety can be methylenated even in the presence of the phosphonoacetate group (eq 17).30

The chemoselective methylenation of aldehydes in the presence of ketones (eq 18) can be done with CH2I2-Zn-Ti(O-i-Pr)4 or CH2I2-Zn-Me3Al.7 The reverse selectivity, i.e. the methylenation of a ketone in the presence of an aldehyde, can be accomplished by the in situ protection of the aldehyde with Titanium Tetrakis(diethylamide), followed by reaction with CH2I2-Zn-TiCl4 and deprotection (eq 19).7

Methylenation of Esters.

The CH2Br2-Zn-TiCl4 reagent is selective for ketones and aldehydes, and it alkenates these carbonyls in the presence of esters. Although the reagent of choice for the methylenation of esters and lactones is often the Tebbe reagent1,12 or dimethyltitanocene,13 it is possible to alkenate esters with the CH2Br2-Zn-TiCl4 system if TMEDA is mixed with TiCl4 prior to its exposure to Zn and CH2Br2.8 These conditions were used to convert allyl esters to allyl enol ethers (eq 20)31 and to alkenate carbohydrate ester intermediates (eq 21).32

A lactone methylenation was similarly accomplished by using an excess of all of the ingredients (eq 22).33

Alkylidenation of Carbonyl Compounds.

This methodology was extended to the alkylidenations of carbonyls by the use of 1,1-dihaloalkanes in the presence of TMEDA.8 In this manner, esters and lactones are converted to the corresponding enol ethers in good yields and with (Z) selectivities (eq 23).8 This type of reaction was utilized in a synthesis of spiroacetals (eq 24).34

Silyl esters afford silyl enol ethers when they are subjected to these conditions with the geometry of the products being predominantly (Z) (eq 25).9

Alkylidenation of thioesters (eq 26) and amides (eq 27), to produce alkenyl sulfides and enamines respectively, is also possible with this methodology.10

1. (a) Pine, S. H. OR 1993, 43, 1. (b) Stille, J. R. In Comprehensive Organometallic Chemistry, 2nd edn.; Wilkinson, G., Ed.; Pergamon: Oxford, 1995; in press. (c) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986.
2. Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. TL 1978, 27, 2417.
3. Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. BCJ 1980, 53, 1698.
4. Lombardo, L. TL 1982, 23, 4293.
5. Lombardo, L. OS 1987, 65, 81.
6. Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. TL 1985, 26, 5579.
7. Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H. TL 1985, 26, 5581.
8. Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. JOC 1987, 52, 4410.
9. Takai, K.; Kataoka, Y.; Okazoe, T.; Utimoto, K. TL 1988, 29, 1065.
10. Takai, K.; Fujimura, O.; Kataoka, Y.; Utimoto, K. TL 1989, 30, 211.
11. (a) Maercker, A. OR 1965, 14, 270. (b) Bestman, H. J.; Vostrowsky, O. Top. Curr. Chem. 1983, 109, 85. (c) Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic: London, 1979. (d) Larock, R. C. Comprehensive Organic Transformations; VCH: New York, 1989; Chapter 4.
12. (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. JACS 1978, 100, 3611. (b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. JACS 1980, 102, 3270. (c) Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. JOC 1985, 50, 1212.
13. Petasis, N. A.; Bzowej, E. I. JACS 1990, 112, 6392.
14. Jacobs, R. T.; Feutrill, G. I.; Meinwald, J. JOC 1990, 55, 4051.
15. Imagawa, T.; Sonobe, T.; Ishiwari, H.; Akiyama, T.; Kawanisi, M. JOC 1980, 45, 2005.
16. Furber, M.; Mander, L. N.; Patrick, G. L. JOC 1990, 55, 4860.
17. Lombardo, L.; Mander, L. N. JOC 1983, 48, 2298.
18. Rigby, J. H.; Wilson, J. A. Z. JOC 1987, 52, 34.
19. Leyendecker, F.; Comte, M. T. T 1987, 43, 85.
20. Suzuki, M.; Koyano, H.; Noyori, R. JOC 1987, 52, 5583.
21. Torisawa, Y.; Yamaguchi, T.; Sakata, S.; Ikegami, S. CPB 1985, 33, 4625.
22. Mash, E. A.; Math, S. K.; Flann, C. J. T 1989, 45, 4945.
23. Jasperse, C. P.; Curran, D. P. JACS 1990, 112, 5601.
24. Klindukhova, T. K.; Suvorova, G. N.; Koroleva, L. B.; Komendantov, M. I. ZOR 1984, 20, 529.
25. Friedrich, E. C.; Lunetta, S. E.; Lewis, E. J. JOC 1989, 54, 2388.
26. Burgess, K.; Ohlmeyer, M. J. JOC 1991, 56, 1027.
27. Krishnamurti, R.; Kuivila, H. G. JOC 1986, 51, 4947.
28. Iyer, R. S.; Kuo, G.; Helquist, P. JOC 1985, 50, 5898.
29. Yamazaki, S.; Katoh, S.; Yamabe, S. JOC 1992, 57, 4.
30. Nicoll-Griffith, D.; Weiler, L. CC 1984, 659.
31. Gajewski, J. J.; Gee, K. R.; Jurayj, J. JOC 1990, 55, 1813.
32. Barrett, A. G. M.; Melcher, L. M.; Bezuidenhoudt, B. C. B. Carbohydr. Res. 1992, 232, 259.
33. Johnson, B. M.; Vollhardt, K. P. C. SL 1990, 4, 209.
34. Mortimore, M.; Kocienski, P. TL 1988, 29, 3357.

Nicos A. Petasis & James P. Staszewski

University of Southern California, Los Angeles, CA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.