Titanium Tetraisopropoxide1


[546-68-9]  · C12H28O4Ti  · Titanium Tetraisopropoxide  · (MW 284.28)

(mild Lewis acid used as a catalyst in transesterification reactions, nucleophilic cleavages of 2,3-epoxy alcohols and isomerization reactions; additive in the Sharpless epoxidation reaction and in various reactions involving nucleophilic additions to carbonyl and a,b-unsaturated carbonyl compounds)

Physical Data: mp 18-20 °C; bp 218 °C/10 mmHg; d 0.955 g cm-3.

Solubility: sol a wide range of solvents including ethers, organohalides, alcohols, benzene.

Form Supplied in: low-melting solid; widely available.

Handling, Storage, and Precautions: flammable and moisture sensitive; acts as an irritant.

Transesterification and Lactamization Reactions.2-5

Ti(O-i-Pr)4, as well as other titanium(IV) alkoxides, has been recommended as an exceptionally mild and efficient transesterification catalyst which can be used with many acid-sensitive substrates (eq 1).2,3 Thus the acetonide as well as C=O, OH, OTBDMS, and lactam functional groups (eq 2) are unaffected by these conditions, although acetates are hydrolyzed to the parent alcohol. The alcohol solvent employed in such processes need not be anhydrous, nor need it be identical with the OR group in the titanate, because exchange of these moieties is generally slow compared to the transesterification reaction.

N-Protected esters of dipeptides can be transesterified using Ti(O-i-Pr)4 in the presence of 4 Å molecular sieves and this procedure provides a good way of converting methyl esters into their benzyl counterparts. Such reactions (eq 3) proceed without racemization in 70-85% yield.4 In a related process,5 b-, g-, and d-amino acids undergo lactamization on treatment with Ti(O-i-Pr)4 in refluxing 1,2-dichloroethane (eq 4).

Nucleophilic Cleavage of 2,3-Epoxy Alcohols and Related Compounds.6-10

Titanium alkoxides are weak Lewis acids which generally have no effect on simple epoxides. However, reaction of 2,3-epoxy alcohols (available, for example, from the Sharpless-type epoxidation of allylic alcohols) with nucleophiles in the presence of Ti(O-i-Pr)4 results in highly regioselective ring-cleavage reactions involving preferential nucleophilic attack at C-3 (eq 5).6 In the absence of the titanium alkoxide, no reaction is observed under otherwise identical conditions, except in the case of PhSNa.

These types of conversion can be extended7 to 2,3-epoxy carboxylic acids (glycidic acids) and the related amides. The former compounds are readily available through Ruthenium(VIII) Oxide-mediated oxidation of the appropriate 2,3-epoxy alcohols (eq 6).

The C-3:C-2 selectivity is, in the cases shown above, greater than 100:1, although lower selectivities (e.g. 20:1) are observed with other nucleophiles such as Et2NH and PhSH. It should be noted that glycidic acids and amides react preferentially with dialkylamines at C-2, but one equivalent or greater of Ti(O-i-Pr)4 ensures reaction occurs with high selectivity at C-3. Combining this type of protocol with the Sharpless asymmetric epoxidation reaction has permitted the development of stereoselective syntheses (eqs 7 and 8)6,7 of all four stereoisomers of the unusual N-terminal amino acid of amastatin, a tripeptide competitive inhibitor of aminopeptidases.8

The reaction of both open-chain and cyclic 2,3-epoxy alcohols with molecular Bromine or Iodine in the presence of Ti(O-i-Pr)4 at 0 °C leads to the regioselective formation of halo diols (eq 9).9a Interestingly, if these reactions are conducted at 25 °C a 1:1 mixture of the C-2 and C-3 cleavage products is obtained, and the same outcome is observed, even at 0 °C, when the acetate derivative of the 2,3-epoxy alcohol is involved as substrate. Dialkylamine hydrochlorides can be used as sources of halide nucleophiles in these types of epoxide ring-cleavage reactions.9b

2,3-Epithio alcohols have been obtained by reacting 2,3-epoxy alcohols with Thiourea at room temperature or 0 °C in the presence of Ti(O-i-Pr)4 and using THF as solvent (eq 10).10 The reactions proceed with high regio- and stereoselectivity, trans-substituted 2,3-epoxy alcohols giving only trans-2,3-epithio alcohols with complete inversion of configuration at both stereogenic centers. However, when cis-2,3-epoxy alcohols are used as starting materials the yields of epithio alcohols were low and thiodiols were also formed. Epithiocinnamyl alcohols could also be prepared from the corresponding epoxycinnamyl alcohols at 0 °C. However, these products were found to decompose to cinnamyl alcohol and sulfur on standing. Without Ti(O-i-Pr)4, thiourea was insoluble in THF and the reaction did not proceed. One equivalent of Ti(O-i-Pr)4 was required to achieve complete reaction, and THF was the best solvent (no reaction was observed in ether, CH2Cl2, or benzene under similar conditions).

Isomerization Reactions.11-14

The reaction of certain 2,3-epoxy alcohols with Ti(O-i-Pr)4 can result in isomerization. For example (eq 11), reaction of the illustrated substrate in CH2Cl2 results in rearrangement to the isomeric enediol, and this conversion represents a key step in a synthesis of the marine natural product pleraplysillin.11

Under similar conditions, the pendant double bond attached to a 2,3-epoxy alcohol acts as an internal nucleophile attacking at C-3, resulting, after proton loss, in a mixture of cyclized products (eq 12).12 The cyclopropane-containing products are believed to arise via a retro-homo Prins reaction. Pendant triple bonds can also participate in related cyclization reactions and cyclic allenes result (eq 13).12 The observation that the threo isomer of the substrate shown in eq 12 is stable to Ti(O-i-Pr)4 has led to the suggestion that an intramolecular metal alkoxide is the active catalyst in successful cyclization reactions.

Ti(O-i-Pr)4 has also played a key role in the synthesis of taxanes (eq 14).12b,c

Allylic hydroperoxides, which are readily obtained by reaction of the corresponding alkene with Singlet Oxygen, have been shown to isomerize to the corresponding 2,3-epoxy alcohol when treated with catalytic amounts of Ti(O-i-Pr)4 (eq 15).13 The title reagent is the one of choice when converting di-, tri-, and tetrasubstituted alkenes (both cyclic and acyclic) into the corresponding 2,3-epoxy alcohols by this protocol. The reactions are generally highly stereoselective and deoxygenation of the allylic hydroperoxide (to give the corresponding allylic alcohol) is not normally a process which competes significantly with the isomerization reaction.

This type of chemistry has been extended to the preparation of epoxy diols from chiral allylic alcohols (eq 16).13,14 The methodology is impressive in that three successive chiral centers are constructed with predictable configuration. Furthermore, the rapid rate of the isomerization process is remarkable, given that a,b-unsaturated diols are generally poor substrates for titanium metal-mediated epoxidations. This rate enhancement is attributed to the tridentate nature of the intermediate hydroperoxides.

Asymmetric Epoxidation Reactions.15

While Ti(O-i-Pr)4 clearly has the capacity to bring about the nucleophilic ring-cleavage of 2,3-epoxy alcohols (see above), it remains the preferred species for the preparation of the titanium tartrate complex central to the Sharpless asymmetric epoxidation process (see, for example, eq 7). Since t-butoxide-mediated ring-opening of 2-substituted 2,3-epoxy alcohols (a subclass of epoxy alcohols particularly sensitive to nucleophilic ring-cleavage) is much slower than by isopropoxide, the use of Ti(O-t-Bu)4 is sometimes recommended in place of Ti(O-i-Pr)4. However, with the reduced amount of catalyst that is now needed for all asymmetric epoxidations, this precaution appears unnecessary in most instances.

Nucleophilic Additions to Carbonyl Compounds.16-28

A wide range of organometallic compounds react with Ti(O-i-Pr)4 to produce organotitanium/titanium-ate species which may exhibit reactivities that differ significantly from those of their precursor.1 Thus Ti(O-i-Pr)4 forms -ate complexes with, amongst others, Grignard reagents and the resulting species show useful selectivities in their reaction with carbonyl compounds. For example, the complex with allylmagnesium chloride is highly selective in its reaction with aldehydes in the presence of ketones, or ketones in the presence of esters (eq 17).16 Interestingly, the corresponding amino titanium-ate complexes react selectively with ketones in the presence of aldehydes.

Reaction of certain sulfur-substituted allylic anions with Ti(O-i-Pr)4 produces a 3-(alkylthio)allyltitanium reagent that condenses, through its a-terminus, with aldehydes to give anti-b-hydroxy sulfides in a highly stereo- and regioselective manner (eq 18). These latter compounds can be transformed, stereoselectively, into trans-vinyloxiranes or 1,3-dienes.17

The titanium species derived from sequential treatment of a-alkoxy-substituted allylsilanes with s-Butyllithium then Ti(O-i-Pr)4 engages in a Peterson alkenation reaction with aldehydes to give, via electrophilic attack at the a-terminus of the allyl anion, 2-oxygenated 1,3-butadienes which can be hydrolyzed to the corresponding vinyl ketone (eq 19).18a

The titanium-ate complexes of a-methoxy allylic phosphine oxides, generated in situ by reaction of the corresponding lithium anion and Ti(O-i-Pr)4, condense with aldehydes exclusively at the a-position to produce homoallylic alcohols in a diastereoselective fashion.18b The overall result is the three-carbon homologation of the original aldehyde, and this protocol has been used in a synthesis of (-)-aplysin-20 from nerolidol.19 The titanium-ate complex produced by reaction of the chiral lithium anion of an (E)-crotyl carbamate with Ti(O-i-Pr)4 affords g-condensation products (homoaldols) on reaction with aldehydes.18c,d Allyl anions produced by the reductive metalation of allyl phenyl sulfides condense with a,b-unsaturated aldehydes in a 1,2-manner at the more substituted (a) allyl terminus in the presence of Ti(O-i-Pr)4.20 1,2-Addition of dialkylzincs to a,b-unsaturated aldehydes can be achieved with useful levels of enantiocontrol when the reaction is conducted using a chiral titanium(IV) catalyst in the presence of Ti(O-i-Pr)4 (eq 20).21 Higher ee values are observed when an a-substituent (e.g. bromine) is attached to the substrate aldehyde, but a b-substituent cis-related to the carbonyl group has the opposite effect.

Highly enantioselective trimethylsilylcyanation of various aldehydes can be achieved by using Cyanotrimethylsilane in the presence of a modified Sharpless catalyst consisting of Ti(O-i-Pr)4 and chiral diisopropyl tartrate.22 Best results are obtained using dichloromethane as solvent and isopropanol as additive and running the reaction at 0 °C. The same type of catalyst system also effects the asymmetric ring-opening of symmetrical cycloalkene oxides with Azidotrimethylsilane. trans-2-Azidocycloalkanols are obtained in up to 63% optical yield.22 The titanium amide complexes derived from the reaction of lithium dialkylamides with Ti(O-i-Pr)4 condense with alkyl and aryl aldehydes and the resulting aminal derivatives undergo C-O bond displacement by benzylmagnesium chloride, thereby generating a-substituted b-phenethylamines (eq 21).23

The aldol-type condensation of aldehydes and ketones with ketenimines24 and ketones25 can be catalyzed by titanium alkoxides and, in appropriate cases, useful levels of stereocontrol can be achieved (eq 22).

A variety of useful reducing agents have been generated by combining hydrides with Ti(O-i-Pr)4.26-28 For example, the combination of 5 mol % Ti(O-i-Pr)4 with 2.5-3.0 equiv of Triethoxysilane cleanly hydrosilylates esters to silyl ethers at 40-55 °C, and these latter compounds can be converted into the corresponding primary alcohols via aqueous alkaline hydrolysis (eq 23).26 The actual reducing agent is presumed to be a titanium hydride species which is produced by a s-bond metathesis process involving Ti(O-i-Pr)4 and the silane. The procedure has considerable merit in that no added solvent is required and the active reagent can be generated and used in air. Halides, epoxides, alcohols, and an alkyne all survive the reduction process. Lithium Borohydride reduction of 2,3-epoxy alcohols yields 1,2-diols highly regioselectively when used in the presence of Ti(O-i-Pr)4,27 while the combination of the reagent with Sodium Cyanoborohydride is reported28 to offer superior results in reductive amination processes with difficult carbonyls and those sensitive to acidic conditions.

Miscellaneous Applications.29-31

The chemoselective oxidation of alcohols and diols using Ti(O-i-Pr)4/t-Butyl Hydroperoxide has been reported.29 The title reagent has also been employed as a catalyst in Diels-Alder reactions30 and as an additive in the palladium-catalyzed reaction of aryl-substituted allylic alcohols with zinc enolates of b-dicarbonyl compounds (eq 24).31 The latter reaction is presumed to generate C-allylated b-dicarbonyl compounds as the primary products of reaction, but these compounds suffer deacylation in the presence of Ti(O-i-Pr)4.

1. (a) Shiihara, I.; Schwartz, W. T., Jr.; Post, H. W. CRV 1961, 61, 1. (b) Reetz, M. T. Top. Curr. Chem. 1982, 106, 3. (c) Seebach, D.; Weidmann, B; Widler, L. Mod. Synth. Methods 1983, 3, 217. (d) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986. (e) Hoppe, D.; Krämer, T.; Schwark, J.-R.; Zschage, O. PAC 1990, 62, 1999.
2. (a) Imwinkelried, R.; Schiess, M.; Seebach, D. OS 1987, 65, 230. (b) Seebach, D.; Hungerbühler, E.; Schnurrenberger, P.; Weidmann, B.; Züger, M. S 1982, 138.
3. (a) Schnurrenberger, P.; Züger, M. F.; Seebach, D. HCA 1982, 65, 1197. (b) Férézou, J. P.; Julia, M.; Liu, L. W.; Pancrazi, A. SL 1991, 618.
4. Rehwinkel, H.; Steglich, W. S 1982, 826.
5. Mader, M.; Helquist, P. TL 1988, 29, 3049.
6. (a) Caron, M.; Sharpless, K. B. JOC 1985, 50, 1557. (b) Aldrichim. Acta 1985, 18, 53.
7. Chong, J. M.; Sharpless, K. B. JOC 1985, 50, 1560.
8. Tobe, H.; Morishima, H.; Aoyagi, T.; Umezawa, H.; Ishiki, K.; Nakamura, K.; Yoshioka, T.; Shimauchi, Y.; Inui, T. ABC 1982, 46, 1865.
9. (a) Alvarez, E.; Nuñez, T.; Martin, V. S. JOC 1990, 55, 3429. (b) Gao, L.; Murai, A. CL 1989, 357.
10. Gao, Y.; Sharpless, K. B. JOC 1988, 53, 4114.
11. Masaki, Y.; Hashimoto, K.; Serizawa, Y.; Kaji, K. BCJ 1984, 57, 3476.
12. (a) Morgans, D. J., Jr.; Sharpless, K. B.; Traynor, S. G. JACS 1981, 103, 462. (b) Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. JACS 1988, 110, 6558. (c) Wender, P. A.; Mucciaro, T. P. JACS 1992, 114, 5878.
13. (a) Mihelich, E. D. US Patent 4 345 984 (CA 1983, 98, 125 739c). (b) Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.; Staab, E.; Will, B. JACS 1989, 111, 203. (c) Adam, W.; Nestler, B. JACS 1993, 115, 7226.
14. Adam, W.; Nestler, B. AG(E) 1993, 32, 733.
15. Johnson, R. A.; Sharpless, K. B. COS 1991, 7, 389.
16. Reetz, M. T.; Wenderoth, B. TL 1982, 23, 5259.
17. Furuta, K.; Ikeda, Y.; Meguriya, N.; Ikeda, N.; Yamamoto, H. BCJ 1984, 57, 2781.
18. (a) Murai, A.; Abiko, A.; Shimada, N.; Masamune, T. TL 1984, 25, 4951. (b) Birse, E. F.; McKenzie, A.; Murray, A. W. JCS(P1) 1988, 1039. (c) Férézou, J. P.; Julia, M.; Khourzom, R.; Pancrazi, A.; Robert, P. SL 1991, 611. (d) Hoppe, D.; Zschage, O. AG(E) 1989, 28, 69.
19. Murai, A.; Abiko, A.; Masamune, T. TL 1984, 25, 4955.
20. Cohen, T.; Guo, B.-S. T 1986, 42, 2803.
21. Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. TL 1993, 34, 3115.
22. (a) Hayashi, M.; Matsuda, T.; Oguni, N. JCS(P1) 1992, 3135. (b) Hayashi, M.; Kohmura, K.; Oguni, N. SL 1991, 774.
23. Takahashi, H.; Tsubuki, T.; Higashiyama, K. S 1988, 238.
24. Okada, H.; Matsuda, I.; Izumi, Y. CL 1983, 97.
25. Vuitel, L.; Jacot-Guillarmod, A. HCA 1974, 57, 1703.
26. Berk, S. C.; Buchwald, S. L. JOC 1992, 57, 3751.
27. Dai, L.; Lou, B.; Zhang, Y.; Guo, G. TL 1986, 27, 4343.
28. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. JOC 1990, 55, 2552.
29. Yamawaki, K.; Ishii, Y.; Ogawa, M. Chem. Express 1986, 1, 95.
30. McFarlane, A. K.; Thomas, G.; Whiting, A. TL 1993, 34, 2379.
31. Itoh, K.; Hamaguchi, N.; Miura, M.; Nomura, M. JCS(P1) 1992, 2833.

Martin G. Banwell

University of Melbourne, Parkville, Victoria, Australia

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