Organic Syntheses Procedure

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Org. Synth. 2002, 79, 19

DOI: 10.15227/orgsyn.079.0019

DIMETHYLTITANOCENE

[ Titanium, bis(η⁵-2,4-cyclopentadien-1-yl)dimethyl- ]

Submitted by Joseph F. Payack¹ , David L. Hughes¹ , Dongwei Cai¹ , Ian F. Cottrell² , and Thomas R. Verhoeven.¹ .

Checked by Mark Kerr and Louis Hegedus.

1. Procedure³

A 1-L, three-necked, round-bottomed flask, equipped for mechanical stirring, and outfitted with a 250-mL, pressure equalizing addition funnel, and a Claisen adapter bearing a thermometer and a nitrogen inlet/outlet vented through a mineral oil bubbler, is placed under a nitrogen atmosphere and charged with 41.5 g (0.167 mol) of titanocene dichloride (Note 1), and 450 mL of dry toluene (Note 2). The slurry is efficiently stirred and chilled to an internal temperature of −5°C in a ice/methanol bath; then 126 mL of a 3 M solution (0.38 mol) of methylmagnesium chloride in tetrahydrofuran (THF) (Note 1) is added dropwise via the addition funnel over 1 hr, at a rate of addition adjusted to maintain an internal temperature below +8°C. The resulting orange slurry (Note 3) is mechanically stirred at an internal temperature of 0 to +5°C for 1 hr, or until the insoluble purple titanocene dichloride is no longer seen in the suspension (Note 4). The addition funnel is removed and replaced by a rubber septum, and the reaction is assayed by ¹H NMR (Notes 5, 6).

While the reaction is aging at 0° to +5°C, a 2-L, three-necked, round-bottomed flask, equipped for mechanical stirring, and outfitted with a rubber septum, and a Claisen adapter bearing a thermometer and a nitrogen inlet/outlet vented through a mineral oil bubbler, is placed under a nitrogen atmosphere and charged with 117 mL of 6% aqueous ammonium chloride (7.0 g diluted to 117 mL) (Note 1). The solution is chilled to 1 to 2°C, with efficient mechanical stirring. When the formation of dimethyltitanocene is judged to be complete, the toluene /THF reaction mixture is quenched into (Note 7) the well-stirred aqueous ammonium chloride solution via a cannula (Note 8) over a period of 1 hr, maintaining an internal temperature of 0° to +5°C in both flasks. Toluene (30 mL) is used to rinse the reaction flask. The biphasic mixture is then poured into a 2-L separatory funnel, with another 30 mL of toluene rinse, and the aqueous phase is separated (Note 9). The organic layer is washed sequentially with three portions of cold water (100 mL each) and brine (100 mL), then dried over anhydrous sodium sulfate (Na₂SO₄, 35 g). The organic layer is filtered and carefully (Note 10) concentrated under reduced pressure on a rotary evaporator at a bath temperature of no more than 35°C to a weight of 150 g. The resulting orange solution is assayed by ¹H NMR (Note 11) to be 20 weight percent dimethyltitanocene (29.55 g, 85.0%). If the solution is to be stored for more than a week, the reagent should be diluted with 160 mL of dry THF (Note 2), which has a stabilizing effect on the labile reagent (Note 12). The solution is stored at 0° to 10°C under nitrogen in a rubber septum-sealed, round-bottomed flask. It proved effective in the conversion of a complex ester to an enol ether (Note 13).

2. Notes

1. This reagent was purchased from Aldrich Chemical Company, Inc., and used without further purification.

2. This solvent was purchased from Fisher Scientific Company and dried over 3Å sieves to a water content of less than 150 µg/mL by Karl Fisher titration.

3. The sparingly soluble titanocene dichloride reacts in stepwise fashion with methylmagnesium chloride to give the soluble red Cp₂Ti(Me)Cl, then the soluble orange dimethyltitanocene , precipitating magnesium chloride (MgCl₂). The mixture becomes thick with MgCl₂ as the reaction proceeds and vigorous stirring is required.

4. Since the titanocene dichloride is insoluble and the intermediate Cp₂Ti(Me)Cl is soluble, the second methyl group adds much faster than the first. Reaction progress can be monitored by visually observing the disappearance of the purple crystalline titanocene dichloride .

5. A ca. 200 µL-sample is removed via wide bore syringe or pipet (so that a representative sample is pulled from the heterogeneous reaction mixture) and is quenched into 1 mL of water. The mixture is extracted with 1 mLCDCl₃ , the organic phase is dried with sodium sulfate , and the solution is filtered into an NMR tube. The progress is evaluated by observing the Cp singlets: the reaction is considered complete when less than 3% combined of titanocene dichloride and Cp₂Ti(Me)Cl remains by ¹H-NMR.

6. The spectra are as follows: ¹H NMR (CDCl₃) Cp₂TiMe₂: δ 6.05 (s, 10 H), −0.05 (s, 6 H) . Cp₂TiClMe: δ 6.22 (s, 10 H), 0.80 (s, 3 H) . Cp₂TiCl₂: δ 6.56 (s, 10 H) . ¹³C NMR Cp₂TiMe₂: δ 113.20 (Cp₂), 45.77 (Me₂). Cp₂TiClMe: δ 115.86 (Cp₂), 50.37 (Me). Cp₂TiCl₂: δ 120.18 .

7. The reaction must be quenched into 6% aq ammonium chloride , or substantial decomposition will occur. The amount of ammonium chloride is optimized.

8. The reaction mixture is very thick and is too viscous to flow through a standard 12-gauge cannula. The transfer is best accomplished by using 1/4" to 3/8" i.d. inert tubing (PTFE, polytetrafluoroethylene, or polypropylene) inserted through both septa. The mixture can then be transferred by applying only slight positive pressure on the reaction flask.

9. The workup may be done in a normal separatory funnel under air.

10. The solution must not be allowed to evaporate to dryness: dimethyltitanocene is unstable in the solid phase and could decompose with heat and gas evolution. The compound is also known to be unstable in neat solution at temperatures above 60°C. The concentration must be done at high (20 mm or less) vacuum.

11. The ¹H NMR weight percent assay is done by diluting several drops of the solution into 1 mL of CDCl₃ and running the spectrum with a 10-sec relaxation delay between pulses to ensure an accurate integration. The product Cp singlet is integrated against the toluene methyl singlet and any residual THF.

12. The submitters have some evidence that thermally stressed solutions of dimethyltitanocene are more stable when diluted with an equal volume of THF. No complete study of the long term 5°C stability of the solution has been done, but a 10 wt% solution in THF/ toluene can be stored for several months in the refrigerator.

13. A 50-mL, nitrogen-purged round-bottomed flask was charged with cis-ester 1 ( (2R-cis)-3-(4-fluorophenyl)-4-benzyl-2-morpholinyl 3,5-bis(trifluoromethyl)benzoate) (2.41 g, 4.57 mmol), dimethyltitanocene in toluene (12 mL of a 20% w/w solution in toluene), and titanocene dichloride (71 mg, 0.28 mmol). The red/orange mixture was heated to 80°C and was aged in the dark for 5.5 hr, then cooled to ambient temperature. Sodium bicarbonate (0.60 g), methanol (9.6 mL) and water (0.36 mL) were added, and the mixture was heated to 40°C for 14hr. (The hot aqueous methanol treatment was done to decompose the titanium residues into an insoluble solid. The decomposition was judged to be complete when gas evolution ceased.) The green mixture was cooled to ambient temperature and the titanium residues were removed by filtration. The solution was evaporated under reduced pressure and flushed with methanol . The crude material was recrystallized by dissolving in hot (60°C) methanol (24 mL), cooling to ambient temperature, then adding water (7.2 mL) over 2 hr. The material was stirred for 18 hr then isolated via filtration at ambient temperature. The filtercake was washed with 25% aq methanol (6 mL) and the solid was dried at ambient temperature under nitrogen. Vinyl ether 2 ((2R-cis)-2-[[1-[3,5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-benzylmorpholine) (2.31 g, 96%) was isolated as a pale yellow solid.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Petasis, et al. have discovered that dimethyltitanocene is an excellent substitute for the Tebbe reagent⁴ for the methylenation of heteroatom-substituted carbonyl compounds.⁵^,⁶

The advantages of this reagent are its straightforward synthesis and relative air stability. The previous procedure⁷ for the synthesis of dimethyltitanocene used methyllithium in diethyl ether , which is unsuitable for large scale operations because of its extreme pyrophoricity.⁸ In addition, the method isolated the compound as a crystalline solid, which the submitters have found to be very unstable.⁹ The method described here addresses both of these concerns, and can be used to prepare multiple kilograms of the reagent.

References and Notes

Department of Process Research, Merck Research Laboratories, Division of Merck & Co., Inc. P. O. Box 2000, Rahway, NJ 07065.
Development Laboratories Merck Research Laboratories, Division of Merck & Co., Inc. Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, England.
A less detailed version of this procedure has been published: Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Prep. Proced., Int. 1995, 27, 707.
(a) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 1980, 102, 3270; (b) Pine, S. H.; Kim, G.; Lee, V. Org. Synth. 1990, 69, 72.
(a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392; (b) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1995, 36, 2393.
For some applications see: (a) Petasis, N. A.; Patane, M. A. Tetrahedron Lett. 1990, 31, 6799; (b) DeShong, P.; Rybczynski, P. J. J. Org. Chem. 1991, 56, 3207; (c) Swenton, J. S.; Bradin, D.; Gates, B. D. J. Org. Chem. 1991, 56, 6156; (d) Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 1721; (e) Chenault, H. K.; Chafin, L. F. J. Org. Chem. 1994, 59, 6167; (f) Kuzmich, D.; Wu, S. C.; Ha, D. -C.; Lee, C. -S.; Ramesh, S.; Atarashi, S.; Choi, J. -K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 6943.
Clauss, K.; Bestian, H. Justus Liebigs Ann. Chem. 1962, 654, 8.
The preparation of dimethyltitanocene from methylmagnesium iodide and dichlorotitanocene in diethyl ether has been reported in a German patent. Few details of the procedure are provided, and a yield of 58% is reported. German Patent #1,037,446 (March 12, 1959) to Farbwerke Hoechst (Chem. Abstr., 1960, 54:18546f;).
For a discussion of the solid state stability of dimethyltitanocene, see: Erskine, G. J.; Hartgerink, J.; Weinberg E. L.; McCowan, J. D. J. Organomet. Chem. 1979, 170, 51 and references therein.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Dimethyltitanocene:
Titanium, di-π-cyclopentadienyldimethyl- (8);
Titanium, bis(η⁵-2,4-cyclopentadien-1-yl)dimethyl- (9); (1271-66-5)

Titanocene dichloride: ALDRICH:
Bis(cyclopentadienyl)titanium dichloride:
Titanium, dichloro-π-cyclopentadienyl- (8);
Titanium, dichlorobis(η⁵-2,4-cyclopentadienyl-1-yl)- (9); (1271-19-8)

Methylmagnesium chloride:
Magnesium, chloromethyl- (8, 9); (676-58-4)

Chloromethyltitanocene:
Titanium, chlorodi-π-cyclopentadienylmethyl- (8);
Titanium, chlorobis(η⁵-2,4-cyclopentadien-1-yl)methyl- (9); (1278-83-7)

Benzoic acid, 3,5-bis(luoromethyl)-, (2R,3S)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ester (9); (170729-77-8)

Morpholine, 2-[[1-[3,5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)-, (2R,3S)- (9); (170729-78-9)

Notes

References/EndNotes

Article Compounds

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