Method for incorporation of pentafluorosulfanyl (SF5) substituents into aliphatic and aromatic compounds

This application claims the benefit of U.S. Provisional Application Ser. No. 60/448,831, filed Feb. 21, 2003, and also claims the benefit of U.S. Provisional Application Ser. No. 60/399,044, filed Jul. 25, 2002.

The subject invention was made with government support under a research project supported by the Air Force Office of Scientific Research, STTR Phase I Contract #F49620-01-C-0046. The United States government may have certain rights in this invention.

There is currently great interest in methods for the preparation of selectively fluorinated organic compounds. This interest results from the profound influence that fluorine incorporation can have on the physical properties, chemical properties, and biological activity of molecules. For example, methods for putting the bulky, highly electronegative and generally inert trifluoromethyl group into organic compounds have received much research attention during recent years.

Another fluorinated substituent that could attract interest among synthetic organic chemists is the pentafluorosulfanyl (SF 5 ) group (Winter et al., Inorganic Fluorine Chemistry—Toward the 21 st Century (1994) 555:128-47, Pub: American Chemical Society: Washington (Thrasher, J. S., Strauss, S. H., Eds.); Lentz et al., Chemistry of Hypervalent Compounds (1999) 295-326; Pub: Wiley-VCH: New York (Akiba, K., Ed.); Verma et al., Advances in Inorganic Chemistry (1994) 41:125-69, Pub: Academic Press: San Diego (Sykes, A. G., Ed.); pentafluorosulfanyl groups bear some similarity to trifluoromethyl groups, however, SF 5 is more electronegative (σ p =+0.68 versus +0.54 for CF 3 ; Sheppard, W. A., J. Am. Chem. Soc . (1962) 84:3072-6) and more sterically demanding.

However, until the development of the subject invention, methods for the addition of an SF 5 substituent to a benzene ring or other aliphatic compounds were inconvenient, dangerous, and many methods required the use of elemental F 2 or oxidative fluorination by AgF 2 (Sheppard, W. A., J. Am. Chem. Soc . (1962) 84:3064-3072; Chambers et al., Chem. Commun . (1999) 883-884; Bowden et al., Tetrahedron (2000) 56:3399-3408; Sipyagin et al., J. Fluorine Chem . (2001) 112:287-295) to incorporate an SF 5 group into aliphatic compounds (i.e., the methodologies relied on high pressure autoclave or specialized photochemical procedures) (Case et al., J. Chem. Soc . (1961) 2066-2070; Wessel et al., Chem. Ber . (1983) 116:2399-2407; Winter et al., J. Fluorine Chem . (1994) 66:109-116; Fokin et al., Russ. Chem. Bull . (1996) 45:2804-6). Thus, the introduction SF 5 into aliphatic compounds has not been widely practiced by synthetic organic chemists.

SF 5 Cl is presently the only commercially available “reagent” that can be used to introduce the SF 5 substituent into aliphatic compounds. As a gaseous pseudo halogen, this reagent cannot be used as an electrophilic source of SF 5 . It has, however, been used in free radical chain alkene/alkyne addition processes (Sidebottom et al., Trans. Faraday Soc . (1969) 65:2103-2109). These processes are generally done thermally, in an autoclave, with or without an initiator, or using room temperature gas phase or low temperature solution phase photochemical processes. For example (Case et al., J. Chem. Soc . (1961) 2066-2070):

In order for SF 5 -derivatives to become incorporated into the day-to-day strategic planning of working synthetic organic chemists, a convenient bench-top procedure for the introduction of SF 5 substituents into organic substrates is needed. The subject invention provides such a method—one that will allow convenient addition of SF 5 Cl to a large variety of aliphatic compounds (such as alkenes and alkynes) in excellent yield.

The subject invention provides methods for the convenient addition of pentafluorosulfanyl substituents into aliphatic organic compounds. In various embodiments, pentafluorosulfanyl substituents are incorporated into pharmaceutical compounds or agrochemical compounds containing aliphatic groups. An exemplary reaction is:

The subject invention provides methods for the convenient addition of pentafluorosulfanyl substituents into aliphatic organic compounds. In various embodiments, pentafluorosulfanyl substituents are incorporated into pharmaceutical compounds or agrochemical compounds containing aliphatic groups. The invention also provides aromatic SF 5 substituted compounds and methods of preparing such compounds comprising the addition of SF 5 Cl to cyclohexene and cyclohexadiene derivatives followed by elimination/oxidation steps.

The simplicity of new method provided by the subject invention, combined with the generally excellent yields that are obtained, constitutes a breakthrough in SF 5 synthetic methodology that opens the door to the convenient, bench top preparation of a multitude of SF 5 -containing aliphatics by synthetic organic chemists. Thus, the subject invention has application to broad applicability to any compound containing aliphatic groups, including functionalized or substituted compounds.

Exemplary compounds into which pentafluorosulfanyl substituents can be incorporated include those compounds containing one or more functional groups selected from the group consisting of substituted or unsubstituted aliphatic groups, substituted or unsubstituted aromatic groups, substituted or unsubstituted alicyclic groups, substituted or unsubstituted alkene groups, substituted or unsubstituted alkyne groups, substituted or unsubstituted styrene groups, disubstituted alkene groups (e.g., 2,2-disubstituted alkenes), substituted or unsubstituted non-terminal alkene groups, substituted or unsubstituted non-terminal alkyne groups, cyclohexene groups, substituted cyclohexene groups, cyclohexadiene groups, substituted cyclohexadiene groups, and combinations of such functional groups, or derivatives of the aforementioned functional groups. These compounds may also be referred to as compounds of interest within this specification.

In various embodiments, pharmaceutical compounds or agrochemical compounds (e.g., herbicides, insecticides, pesticides, vermin poisons) comprising one or more aliphatic, aromatic, alicyclic, alkene, alkyne, styrene, disubstituted alkene, non-terminal alkene, or non-terminal alkyne functional groups can be treated according to the subject process to incorporate pentafluorosulfanyl substituents into their respective structures. The mildness of the alkylborane, dialkylborane, trialkylborane, and/or 9-borabicyclo[3.3.1]nonane-catalyzed reaction conditions contributes to the broad applicability of the methods provided by the subject invention.

With a boiling point of −21° C., SF 5 Cl is readily condensed into hexane which, in some embodiments, contains the aliphatic, aromatic, alicyclic, alkene, or alkyne substrate of interest. When an initiator or catalyst is added (e.g., by syringe), an immediate reaction is evident, and, for many substrates, the reaction is effectively complete after 30 minutes. Initiators/catalysts suitable for use in the subject invention include alkylboranes, dialkylboranes, trialkylboranes, and/or 9-borabicyclo[3.3.1]nonane; alternatively, one or more initiators/catalysts (e.g., various combinations of the aforementioned initiators/catalysts) can be used in the methods taught herein. The terms initiator and catalyst may be used interchangeably in the context of the subject invention. Solutions containing SF 5 Cl and/or compounds of interest can be maintained at temperatures of about −20° C. to −40° C., −30° C. to −40° C., or −20° C. to −30°C.

Thus, the subject invention provides novel pentafluorosulfanyl substituted compounds and methods of making pentafluorosulfanyl substituted compounds. The subject invention also provides for the production of SF 5 Cl compounds that have been enantiomerically enriched according to methods known in the art. Substituted compounds according to the subject invention can be made by adding of SF 5 Cl to hexane to form a SF 5 Cl containing hexane solution, contacting a hexane solution comprising one or more compounds of interest containing one or more functional groups selected from the group consisting of substituted or unsubstituted aliphatic groups, substituted or unsubstituted aromatic groups, substituted or unsubstituted alicyclic groups, substituted or unsubstituted alkene groups, substituted or unsubstituted alkyne groups, substituted or unsubstituted styrene groups, disubstituted alkene groups (e.g., 2,2-disubstituted alkenes), substituted or unsubstituted non-terminal alkene groups, substituted or unsubstituted non-terminal alkyne groups, cyclohexene groups, substituted cyclohexene groups, cyclohexadiene groups, substituted cyclohexadiene groups, and combinations of such functional groups, or derivatives of the aforementioned functional groups, with the SF 5 Cl hexane solution, and adding one or more catalyst(s)/initiator(s) selected from the group consisting of dialkylboranes, trialkylboranes, and 9-borabicyclo[3.3.1] nonane. The reactants are mixed and maintained under conditions suitable for the addition of pentafluorosulfanyl substituents to the compounds of interest. The reaction can be terminated at any point, however, allowing the reaction to proceed to completion results in increased yields of SF 5 -substituted compounds. In embodiments where cyclohexenes (or derivatives thereof) and/or cyclohexadienes (or derivatives thereof) are substituted with SF 5 Cl, elimination/oxidation steps may be used to form SF 5 aromatics.

Pentfluorosulfanyl substituted compounds may, optionally, be hydrolyzed and, optionally, dried over a suitable desiccant. The pentfluorosulfanyl substituted compounds can then, optionally, be passed over a short column (containing, for example, a sizing gel or silica gel) to remove contaminants (such as, for example, catalyst/initiator or unsubstituted compounds). Purity and/or analysis of the pentafluorosulfanyl substituted compounds of the invention can be determine using methods well-known to those skilled in the art, including, and not limited to, NMR analysis. In various embodiments, the catalyst(s)/initiator(s) may be added to one or more of a hexane solution containing SF 5 Cl or a hexane solution containing one or more compounds of interest prior to the combination of these hexane solutions.

A specific embodiment of the subject invention is directed to methods of synthesis for compounds substituted with pentafluorosulfanyl. A method of the subject invention is directed to contacting a hexane solution of one or more compounds with SF 5 Cl solution. Preferably, the compounds are unsaturated. More preferably, the unsaturated compounds are substituted or unsubstituted aliphatic or alicyclic alkenes or alkynes, where the substituents may be one or more aryl or alkyl groups that themselves may bear functional groups such as alkenes, alcohols, halogens, ketones, aldehydes, carboxylic acids, carboxyhic acid derivatives or other common organic functional groups.

The method further comprises contacting the resulting solution with one or more initiators. The initiator is selected from the group consisting of dialkylboranes, trialkylboranes, 9-borabicyclo[3.3.1]nonane, and mixtures thereof. The initiated injection of said compounds and said SF 5 Cl solution can proceed under conditions suitable for addition of pentafluorosulfanyl substituents to the compounds. Preferably, the reaction is allowed to proceed to completion.

Opiionally, the pentafluorosulfanyl substituted compounds can undergo climination or oxidation, hydrolysis, drying, and/or purification. Preferably, any drying is performed over a desiccant.

In another embodiment, the initiator is added to a hexane solution containing SF 5 Cl before the resulting solution is contacted with the one or more compounds. In yet another embodiment, the initiator is added to a hexane solution containing one or more compounds prior to the combination of the solution containing SF 5 Cl and the solution containing a compound.

A preferred method is directed to the synthesis of a pentafluorosulfanyl aromatic, specifically a pentafluorosulfanyl benzene. A combination of 4,5-dichloro-1-cyclohexene, CH 2 Cl 2 , SF 5 Cl, and a catalyst selected from the group consisting of dialkylboranes, trialkylboranes, 9-borabicyclo[3.3.1]nonane, and mixtures thereof is prepared. The solvent is evaporated from the combination. The product produced thereby is contacted with a solution of sodium ethoxide(NaOEt in ethanol). Water is added to this solution, which is extracted. The extract is washed and dried over a desiccant. Solvent is evaporated from the extract, and pentafluorosulfanyl benzene is recovered.

Following are examples which illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.