Preparation of cycloalkylacetylene compounds

Details Preparation of cycloalkylacetylene compounds Preparation of cycloalkylacetylene compounds

1999-06-18

2001-10-16

Nazario-Gonzalez, Porfirio (Department: 1621)

Chemistry of carbon compounds

Miscellaneous organic carbon compounds

C-metal

C556S001000

Reexamination Certificate

active

06303057

ABSTRACT:

The invention relates generally to a novel method of preparing cycloalkylacetylenes. More specifically, the invention concerns the synthesis of cycloalkyacetylenes by reacting an alkynyl halide with a dialkylaminomagnesium halide compound such as diisopropylaminomagnesium chloride or a bis(dialkylamino)magnesium compound, such as bis(diisopropylamino)magnesium.
Cycloalkylacetylenes (CAA's) such as ethynylcyclopropane (cyclopropylacetylene) have previously been synthesized by reacting 2.4 equivalents of n-butyllithium (n-BuLi) in tetrahydrofuran (THF) with one equivalent of 5-chloropentyne. The yield of ethynylcyclopropane obtained by this method is temperature dependent, with lower temperatures resulting in higher yields due to less intermolecular head-to-tail coupling of the reaction intermediates. Yields range from 60% to 80% when the reaction is conducted at temperatures from 5° C. to −40° C., respectively.
Although n-BuLi is frequently used to carry out the aforementioned reaction, it is both expensive and pyrophoric. Thus, n-BuLi is not an ideal reagent because its use increases costs of production and presents significant safety hazards for users unfamiliar with the handling of pyrophoric materials.
In an effort to overcome the shortcomings associated with the use of n-BuLi, reactions have also been carried out using lithium diisopropylamide (LDA). LDA possesses a number of advantages over n-BuLi as a reagent in the aforementioned reactions. LDA is commercially available as a non-pyrophoric solution. It has also been found that when the aforementioned reaction is conducted with LDA in place of n-BuLi, a yield of 80% ethynylcyclopropane could be obtained at a temperature of 0° C., while the method utilizing n-BuLi as a reagent required a temperature of −40° C. to achieve such a yield.
Although LDA does obviate some of the problems associated with the use of n-BuLi, it still possesses a number of shortcomings. For example, stable and non-pyrophoric formations of LDA are relatively expensive. Furthermore, the reaction temperature must be maintained below 5° C. because tetrahydrofuran, the preferred solvent medium, is not stable in the presence of LDA at higher temperatures.
Accordingly, a need exists for a method of preparing cycloalkylacetylene compositions that gives good yields (e.g., in excess of 80%) at ambient temperatures or above, uses readily-available and inexpensive materials, requires standard laboratory or processing equipment, can be completed in a substantially short period of time (e.g. cycle times <24 hours), and which utilizes materials that do not present potentially grave safety hazards for the user (e.g., are not pyrophoric).
SUMMARY OF THE INVENTION
The process of the invention provides cycloalkylacetylene compounds having 5 to 20 carbons. Broadly, the process reacts an alkynyl halide with a dialkylaminomagnesium halide compound of the form R
2
NMgX or a bis(dialkylamino)magnesium compound of the form (R
2
N)
2
Mg to produce the desired cycloalkyacetylene compound.
The compounds produced by this process are cycloalkylacetylene compounds having the formula ZCHC
2
H where Z is a divalent alkylene bridge of the formula —(CH
2
)
n
— and n is equal to 2 to 17 units. These compounds are produced by the cyclization of alkynyl halides having the general formula X(CH
2
)
n
C
2
H where n is equal to 3 to 18 units and X is Cl, Br, or I. The process is especially useful to produce cyclopropylacetylene.
The process can be carried out in an ether, (e.g., tetrahydrofuran (THF), dibutyl ether, etc.) an ether/hydrocarbon mixture, or a hydrocarbon medium where the hydrocarbons can be either aromatic (e.g., benzene, toluene, xylene, etc.) or linear or branched alkanes (e.g., Isopar C, Isopar G, Isopar H, etc.). The preferred solvent is tetrahydrofuran (THF). It has been determined experimentally that THF is stable to dialkylaminomagnesium halides and bis(dialkylamino)magnesium compounds for hours at reflux (64° C.). Depending on the specific CAA being formed, a higher boiling medium may be preferred in order to speed up the cyclization process or to aid in the isolation of the product. Thus, the choice of other solvents or solvent mixtures may prove more desirable. The process can be carried out at temperatures as low as −5 ° C. and is typically limited by the stability of the dialkylaminomagnesium halides/bis(dialkylamino)magnesium compounds and the amount of dehydrohalogenated by-products which can form at elevated temperatures. For example, the preparation of cyclopropylacetylene requires a reaction temperature of less than 40° C. in order to minimize the amount of dehydrohalogenated by-products.
The R
2
NMgX compounds are readily obtained by reacting a dialkylamine (R
2
NH where R is a branched, linear, or cyclic alkyl substituent having 1 to 6 carbon atoms or where the R substituents combine to form a heterocyclic alkyl amine having 3 to 6 carbon atoms) with a Grignard (R′MgX where R′ is a 1°, 2° or 3° alkyl substituent and X is Cl, Br, or I) at ambient or slightly elevated temperatures (<64° C.). For the present, the structures of the dialkylaminomagnesium halides are given on the assumption of metathesis reactions. No consideration of complexation, aggregation, or other complication is included.
The bis(dialkylamino)magnesium compounds (R
2
N)
2
Mg are readily obtained by reacting the dialkylaminomagnesium halide with the desired lithium amide (R
2
NLi where R is a branched, linear, or cyclic alkyl substituent having 1 to 6 carbon atoms or where the R substituents combine to form a heterocyclic alkyl amine having 3 to 6 carbon atoms). Alternatively, the bis(dialkylamino)magnesium compounds can also be prepared by refluxing the appropriate dialkylamine (R
2
NH where R is defined as above) with a dialkylmagnesium compound (e.g., with dibutylmagnesium) in an ether, or ether/hydrocarbon mixture, or a hydrocarbon medium where the hydrocarbons can be either aromatic (e.g., benzene, toluene, xylene, etc.) or linear or branched alkanes (e.g., Isopar C, Isopar G, Isopar H, etc.). The bis(dialkylamino)magnesium compounds differ from the dialkylaminomagnesium halides in that they are more soluble in hydrocarbon solvents and are stronger bases. For the present, the structures of the bis(dialkylamino)magnesium compounds are given on the assumption of metathesis reactions. No consideration of complexation, aggregation, or other complication is included.
The preferred dialkylaminomagnesium halides for use in the present invention include diisopropylaminomagnesium bromide (DAMB), diisopropylaminomagnesium chloride (DAMC), 2,2,6,6-tetramethylpiperidinomagnesium bromide (TMPMB), and 2,2,6,6-tetramethylpiperidinomagnesium chloride (TMPMC). Preferred bis(dialkylamino)magnesium compounds for use in the present invention include bis(2,2,6,6-tetramethylpiperidino)magnesium (BTMPM) and bis(diisopropylamino)magnesium (BDAM).
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be understood more fully from the description which follows, and from the accompanying examples, in which particular embodiments of the process of the invention are shown. It is understood at the outset, however, that persons of skill in the appropriate arts may modify the invention herein described while still achieving the favorable results thereof. Accordingly, the description and examples which follow are to be understood as being a broad teaching disclosure directed to persons of skill in the appropriate arts, and are not to be understood as limiting upon the present invention. The scope of the invention is to be determined by the appending claims.
The process is initiated by reacting a secondary amine (R
2
NH as previously defined) with an alkylmagnesium halide (i.e. a Grignard reagent of the form R′MgX where R′ is typically a primary, secondary to tertiary alkyl group) to produce a reaction mixture containing the dialkylaminomagnesium halide compound of the form R
2
NMgX. The alkynyl halide is then added to the reaction mixture. Generally, the

Affiliated with

Also associated with

Rating

Preparation of cycloalkylacetylene compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of cycloalkylacetylene compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of cycloalkylacetylene compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2565304