Process for producing alcohols

Details Process for producing alcohols Process for producing alcohols

1999-09-07

2001-08-07

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C548S542000, C549S354000, C549S355000, C549S420000, C549S497000, C568S813000, C568S815000, C568S818000, C568S838000, C568S852000

Reexamination Certificate

active

06271425

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel process for producing alcohols and is useful in chemical and pharmaceutical fields.
BACKGROUND ART
The reaction utilizing the carbon radical formed from an organohalogen compound is important in organic synthesis as a means for constructing a cyclic skeleton by way of carbon—carbon linkage but, in many instances, the radical on the carbon skeleton is reduced by a hydrogen donor, which eliminates the functional group.
On the other hand, the inventors reported previously that an alcohol can be provided by capturing the alkyl radical intermediate formed from an alkyl halide in the presence of Bu
3
SnH and AIBN (2,2′-azobisisobutyronitrile) with molecular oxygen. This technology is instrumental in organic synthesis as a means for directly substituting a hydroxyl group for a halogen atom on a carbon skeleton. Meanwhile, Prandi and coworkers obtained a similar result by reacting a substrate halide with 0.05~0.1 equivalent of Bu
3
SnCl, 1 equivalent of the radical reaction promoter AIBN and 6 equivalents of NaBH
4
in hot ethanol under bubbling with air (Tetrahedron Letters, vol. 37, pages 3117-3120, 1996).
However, those methods also have aspects to be improved for application to large-scale reactions in that the halide which can be a substrate is limited to highly reactive compounds such as alkyl iodides, allyl bromide and benzyl bromide and that the reaction requires either 2 equivalents of an organotin compound or 0.05~0.1 equivalent of an organotin compound plus 1 equivalent of the unstable AIBN and, in addition, requires a large excess of oxygen as well.
DISCLOSURE OF THE INVENTION
Having been dedicated to solving the above problems, the inventors of this invention discovered that when the reaction is conducted in the presence of a reducing agent, as well as sodium iodide where necessary, which regenerates the organotin compound in the course of reaction, the objective alcohol can be provided in high yield using only a catalyst amount of the organotin compound and no more than a substantially stoichiometric amount of molecular oxygen in the absence of a radical initiator, which is unstable, or in the presence of only a very minor amount of the initiator. They have accordingly perfected the instant invention.
The novel process for producing alcohols according to this invention comprises reacting an organohalogen compound (I) of the following formula
R—X  (I)
(wherein R represents an organic residue and X represents halogen) with molecular oxygen in the presence of an organotin compound and a reducing agent, either in the absence of a radical initiator or in the presence of not more than 0.3 equivalent of a radical initiator based on said organohalogen compound to give an alcohol (II) of the following formula:
R—OH  (II)
(wherein R has the same meaning as defined above).
The novel process for producing alcohols in accordance with this invention is industrially more advantageous than the conventional production technology in that the use of a radical initiator, which is unstable and involves risks for hazards in mass handling, can be completely dispensed with or limited to a very low level, that the requirements of an organotin compound, which is also toxic, are no more than the catalyst amount, and that since the reaction condition is more or less neutral, the reaction can be carried out even in the presence of various functional groups. Furthermore, since the objective alcohol can be provided in high yield by using oxygen only in a substantially stoichiometric ratio to the substrate organohalogen compound, the process is also useful for reducing the cost of synthesis of labeled compounds which requires an expensive oxygen isotope.
This invention is now described in detail.
The organohalogen compound as the substrate to which this invention can be applied is not particularly restricted. In this invention, the halogen can be replaced with a hydroxyl group only provided that the carbon atom to which the halogen is attached has an sp
3
hybrid orbital. Furthermore, as will be apparent from the working examples presented hereinafter, the carbon atom bound to the halogen may be any of primary, secondary and tertiary carbons.
Therefore, the structure of the organic residue R of the organohalogen compound (I) is not particularly restricted but includes lower alkyl groups containing 1~6 carbon atoms (e.g. methyl, ethyl, etc.), higher alkyl groups containing 7~20 carbon atoms (e.g. heptyl, octyl, nonyl, bicyclo[5.2.0]nonyl, decyl, undecyl, dodecyl, tridecyl, adamantyl, etc.), lower alkenyl groups containing 3~6 carbon atoms (e.g. allyl, 2-butenyl, etc.), higher alkenyl groups containing 7~20 carbon atoms (e.g. 2-heptenyl, 3-octenyl, etc.), ether compound residues, ar(lower) alkyl groups (e.g. benzyl, benzhydryl, trityl, etc.), saccharide residues (e.g. glucose, galactose and other monosaccharide residues; sucrose, lactose and other oligosaccharide residues, etc.), amino acid residues, sulfide compound residues and amide compound residues, among others.
Those organic residues may contain functional groups which do not interfere with the reaction. For example, even compounds containing hydroxyl groups as functional groups can be used as the substrate of this invention without prior protection. Moreover, this reaction can be applied even to compounds containing an ester, lactone or amide function without any trouble provided that NaBH
3
CN is used as the reducing agent.
It should, of course, be understood that any organohalogen compound having a structure which will completely inhibit this reaction cannot be used as the substrate.
The foregoing is a matter which can be readily understood by those skilled in the art and, therefore, defining the substrate as “organohalogen compound” herein will not introduce ambiguity into this invention.
In this connection, when the substrate has a carbon-carbon double bond in an appropriate position within the molecule, there are cases in which the alkyl radical intermediate formed on removal of the halogen does not react directly with molecular oxygen but adds itself to the carbon-carbon double bond first to form a ring and the carbon radical formed de novo thereupon reacts with molecular oxygen to give the alcohol. Such cases also fall within the scope of this invention. Specific examples are given hereinafter in Table 2.
The halogen X in organohalogen compound (I) includes chloro, iodo, bromo, etc. but iodo is the most preferred halogen for purposes of this invention.
When the halogen is chloro or bromo and the progress of reaction is retarded, the oxygenation can be allowed to proceed with improved efficiency by conducting the reaction in the presence of 1~3 equivalents of sodium iodide. Moreover, when a primary halide is used as the substrate, the yield can be enhanced dramatically by conducting the reaction in the presence of perfluorodecalin.
The “organohalogen compound (1)” mentioned above can be prepared by any one skilled in the art, starting with a known compound and following a synthetic process per se known.
The “organotin compound” to be used in this invention includes but is not limited to organotin hydrides and organotin halides, preferably trialkyltin halides (e.g. tributyltin chloride, dibutyl(t-butyl) tin chloride, etc.), and triaryltin halides (e.g. triphenyltin chloride etc.).
The amount of the “organotin compound” to be used in this invention may be no more than a catalyst amount but is preferably 0.005~0.5 equivalent, more preferably 0.05~0.2 equivalent, based on the organohalogen compound (I).
The “reducing agent” for use in this invention includes but is not limited to borohydrides (e.g. sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium acetoxyborohydride, etc.).
In the practice of this invention, the “reducing agent” is preferably used in an amount of not less than 2 equivalents, more preferably 2~5 equivalents, still more preferably 2~3 equivalents, based on the substrate organohalogen compound (I).
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