Chemistry of hydrocarbon compounds – Unsaturated compound synthesis – From nonhydrocarbon feed
Reexamination Certificate
1999-10-28
2001-07-03
Griffin, Walter D. (Department: 1764)
Chemistry of hydrocarbon compounds
Unsaturated compound synthesis
From nonhydrocarbon feed
C585S639000, C544S106000, C544S154000, C544S170000, C544S178000
Reexamination Certificate
active
06255550
ABSTRACT:
Dimethyl titanocene is an effective methylenating reagent for a variety of carbonyl compounds, including esters and lactones (N. A. Petasis and E. I. Bzowej,
J. Am. Chem. Soc.,
112, 6392-6394 (1990); U.S. Pat. No. 5,087,790). It is well recognized in the art that dimethyl titanocene has become a valuable synthetic tool. The use of dimethyl titanocene has been extensive, see e.g. N. A. Petasis and M. A. Patane,
Tetrahedron Lett.,
31, 6799 (1990); P. DeShong and P. J. Rybczynski,
J. Org. Chem.,
56, 3207 (1991); J. S. Swenton, D. Bradin, B. D. Gates,
J. Org. Chem.,
56, 6156 (1991); N. A. Petasis and E. I. Bzowej,
Tetrahedron Lett.,
34, 1721 (1993); H. K. Chenault and L. F. Chafin,
J. Org. Chem.,
59, 6167 (1994); D. Kuzmich, S. C. Wu, D. -C. Ha, C. -S. Lee, S. Ramesh, S. Atarashi, J. -K. Choi and D. J. Hart,
J. Am. Chem. Soc.,
116, 6943 (1994). The preparation of dimethyl titanocene is disclosed in PCT Patent Publication WO 97/09336 and U.S. Pat. No. 5,892,082.
Synthetic methodology may require the availablity of dimethyl titanocene on a multi-kilogram scale, however, it has been noted that dimethyl titanocene is unstable in the solid phase and evaporation of solutions containing the reagent have decomposed unpredictably (for a discussion of the solid state stability of dimethyl titanocene see: G. J. Erskine, J. Hartgerink, E. L. Weinberg and J. D. McCowan
J. Organomet. Chem.,
170, 51 (1979) and references cited therein). Accordingly, it is hazardous to handle on a large scale. In addition, when methylenating esters or lactones dimethyl titanocene may react with the product vinyl ether, thereby reducing the yield.
Accordingly, there is a need in the art for methodology to enhance the safety and improve the efficiency of dimethyl titanocene. The present invention provides a safer and more efficient method for storing solutions of dimethyl titanocene and conducting reactions with the reagent dimethyl titanocene.
SUMMARY OF THE INVENTION
The present invention is directed to the use of a sterically hindered ester to stabilize the reagent dimethyl titanocene (CP
2
Ti(CH
3
)
2
). In an alternate embodiment, the present invention is directed to a solution of dimethyl titanocene (CP
2
Ti(CH
3
)
2
) which comprises an organic solvent and which further comprises a sterically hindered ester and optionally titanocene dichloride. Stability of the reagent dimethyl titanocene is enhanced by the presence of the sterically hindered ester.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the use of a sterically hindered ester to stabilize the reagent dimethyl titanocene (CP
2
Ti(CH
3
)
2
). In an alternate embodiment, the present invention is directed to a solution of dimethyl titanocene (CP
2
Ti(CH
3
)
2
) in an organic solvent which further comprises a sterically hindered ester and optionally titanocene dichloride.
In one embodiment, the present invention is directed to a process for the conversion of a starting material containing a carbon-oxygen double bond to a corresponding product containing a carbon-carbon double bond which comprises:
reacting the compound with dimethyl titanocene in a reaction mixture which comprises an organic solvent and a sterically hindered ester, whereby the carbon-oxygen double is replaced by a carbon-carbon double bond to provide an olefin.
In the present invention it is preferred that the starting compound containing a carbon-oxygen double bond is selected from the group consisting of aldehydes, ketones, esters, lactones, amides and lactams.
In the present invention it is preferred that at least one equivalent of dimethyl titanocene is employed. In the present invention it is more preferred that at least two equivalents of dimethyl titanocene are employed.
In the present invention it is preferred that titanocene dichloride and/or chloromethyl titanocene is present in the solution.
In an alternate embodiment, the process further comprises recovery of the product olefin from the reaction mixture.
In an alternate embodiment, the process further comprises reacting of the product olefin in situ prior to recovery from the reaction mixture. Such reacting may comprise catalytic hydrogenation or hydroboration.
In the present invention it is preferred that the sterically hindered ester be of the formula:
wherein:
R
1
and R
4
are hydrogen;
R
2
and R
3
are independently selected from the group consisting of:
(1) C
1-8
alkyl, wherein the alkyl is unsubstituted or substituted with C
1-6
alkyl, C
5-8
cycloalkyl or phenyl, and wherein R
2
and R
3
may be joined together to form a C
5-8
cycloalkyl ring,
(2) C
5-8
cycloalkyl, and
(3) phenyl;
R
5
and R
6
are independently selected from the group consisting of:
(1) C
1-8
alkyl, wherein the alkyl is unsubstituted or substituted with C
1-6
alkyl, C
5-8
cycloalkyl or phenyl, and wherein R
5
and R
6
may be joined together to form a C
5-8
cycloalkyl ring,
(2) C
5-8
cycloalkyl, and
(3) phenyl;
or
R
1
, R
2
and R
3
are hydrogen and R
4
, R
5
and R
6
are independently selected from the group consisting of:
(1) C
1-8
alkyl, wherein the alkyl is unsubstituted or substituted with C
1-6
alkyl, C
5-8
cycloalkyl, phenyl, and wherein two of R
4
, R
5
and R
6
may be joined together to form a C
5-8
cycloalkyl ring,
(2) C
5-8
cycloalkyl, and
(3) phenyl.
In the sterically hindered ester it is preferred that:
R
1
, R
2
and R
3
are hydrogen;
R
4
and R
5
are methyl; and
R
6
is selected from: methyl, ethyl, propyl, benzyl and cyclohexylmethyl.
In the sterically hindered ester it is also preferred that:
R
1
and R
4
are hydrogen;
R
2
and R
3
are methyl; and
R
5
and R
6
are independently selected from: methyl, ethyl, propyl, or R
5
and R
6
are joined together to form cyclohexyl.
In a preferred embodiment, the sterically hindered ester is selected from the group consisting of: t-butyl acetate; 1,1-dimethyl-2-phenylethyl acetate; 1,1-dimethyl-3-phenylpropyl acetate; dihydroterpinyl acetate; isopropyl cyclohexane carboxylate; isopropyl isobutyrate; methyl pivalate; ethyl acetate; and isobutyl acetate.
In a more preferred embodiment, the sterically hindered ester is selected from the group consisting of: 1,1-dimethyl-2-phenylethyl acetate; and t-butyl acetate.
In an even more preferred embodiment, the sterically hindered ester is 1,1-dimethyl-2-phenylethyl acetate.
It will be appreciated by one skilled in the art that the sterically hindered ester which is employed to stabilize the dimethyl titanocene is present in addition to any substrate carbonyl compound which may be present. It will be further appreciated by one skilled in the art that the appropriate sterically hindered ester will meet two requirements: (1) its rate of reaction with the reagent dimethyl titanocene will be slower than the rate of reaction of the substrate carbonyl compound with the reagent dimethyl titanocene; and (2) its rate of reaction with the reagent dimethyl titanocene will be faster than the rate of reaction of the product vinyl compound with the reagent dimethyl titanocene, thereby expending any excess dimethyl titanocene which may be present. The relative rate of reaction of the sterically hindered ester may be readily determined by one skilled in the art through routine experimentation.
In a preferred embodiment, dimethyl titanocene is prepared from the reaction of titanocene dichloride with slightly more than two equivalents of methylmagnesium chloride. The reaction is exothermic and should be maintained below 5° C. to avoid decomposition. The reaction mixture is quenched into an aqueous mixture below 5° C., and the quenched mixture is filtered to avoid emulsions in the phase separation and water wash. The wet dilute dimethyltitanocene solution is vacuum distilled to azeotropically dry and to reach the desired reaction volume. The potential instability of dimethyltitanocene requires some special consideration. Unstabilized solutions of dimethyl titanocene can undergo rapid exothermic decomposition, generating methane gas, initiating at temperatures as low as 40° C. In the presence of an ester, th
Griffin Walter D.
Merck & Co. , Inc.
Rose David L.
Thies J. Eric
LandOfFree
Stabilization of the reagent dimethyl titanocene does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Stabilization of the reagent dimethyl titanocene, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stabilization of the reagent dimethyl titanocene will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2463971