Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus containing
Reexamination Certificate
2003-02-05
2004-05-04
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus containing
C568S008000
Reexamination Certificate
active
06730812
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to the solvent-free mechanochemical preparations of phosphonium salts and phosphorus ylides, and to utilizing such phosphorus ylides in carrying out the solvent-free synthesis of desired unsaturated organic compounds employing the Wittig-Horner reaction (also known as the Wittig reaction).
BACKGROUND OF THE INVENTION
Phosphonium salts are used as agricultural chemicals, phase transfer catalysts, physiologically active compounds, corrosion inhibitors, flame retardants, anti-static and softening agents (see, e.g., WO 99/28287; JP 2000-265085; EP 139260; U.S. Pat. Nos. 4,246,031; and 4,943,380). However, the current major application of phosphonium salts is considered to be their transformation into phosphorus ylides, which phosphorus ylides further participate in the Wittig-Horner reaction leading to diverse unsaturated organic compounds (W. A. Johnson,
Ylides and imines of phosphorus
. John Wiley & Sons, Inc. New York, 1993).
Typically, phosphonium salts are synthesized in solution by a broad variety of methods, which include reactions of phosphines with alcohols or oxiranes, with aromatic organic halides in the presence of metal salts, or with diazo compounds (P. Beck in
Organic Phosphorus Compounds vol
. 2, Eds.: G. M. Kosolapoff, L. Maier, John Wiley & Sons, Inc. New York, p. 189, 1972; DE 19914193; K. Sasse in
Methoden der Organischen Chemie
(
Houben
-
Weil
), Bd XII/1, Ed.: E. Müller, Georg Thieme Verlag, Stuttgart, p. 79, 1963; K. Jödden in
Methoden der Organischen Chemie
(
Houben
-
Weil
), Bd E1, Ed.: M. Regitz, Georg Thieme Verlag, Stuttgart, New York, p. 491, 1982). A conventional method of preparing alkyl-substituted phosphonium salts is the reaction of ternary phosphines with alkyl halides in appropriate organic solvents. Alternatively, liquid organic halides can be used as the reaction media. Although successful in many instances, the preparation of phosphonium salts from phosphines and alkyl halides using these methods can be complicated by side reactions, thus lowering the overall yield of the desired compounds. In particular, reactions of ternary phosphines with &agr;-bromoketones are unreliable because alkylation of phosphines is accompanied by the formation of O-phosphorylated products and by the dehydrobromination of the starting bromoketones (W. A. Johnson,
Ylides and imines of phosphorus
. John Wiley & Sons, Inc. New York, 1993; Borowitz et al.,
J. Org. Chem
. 34, 1595 (1969)).
In the presence of a base, phosphonium salts can form phosphorus ylides. Phosphorus ylides find use in the synthesis of vitamins, terpenoids, steroids, hormones, prostaglandins, amino acids, nucleotides, physiologically active compounds, and transition metal complexes, and in polymerization processes. However, as previously noted, it is believed that the major use of phosphorus ylides is their reaction with diverse organic carbonyl derivatives in the Wittig-Homer reaction, which allows for the preparation of various unsaturated organic substances. Conventionally and exclusively, the generation of phosphorus ylides is performed in a solution using a wide variety of solvents (see, e.g., W. A. Johnson,
Ylides and imines of phosphorus
. John Wiley & Sons, Inc. New York, 1993; WO 99/28287; Hudson in
The Chemistry of Organophosphorus Compounds vol
. 1, Ed.: F. R. Hartley, John Wiley & Sons, Ltd. New York, p. 386, 1990
; The Chemistry of Organophosphorus Compounds, vol
. 3
: Phosphonium Salts, Ylides and Phosphoranes
. Ed.: F. R. Hartley, John Wiley & Sons, Ltd. New York, 1994).
Additionally, the bases used in the preparation of such phosphorus ylides should possess an appropriate strength, as is known. Examples of suitable bases include alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, methyl, butyl or phenyllithium. As with the preparation of phosphonium salts, the generation of phosphorus ylides in solution can be complicated by undesirable side reactions. Consequently, phosphorus ylides must usually be prepared by means of meticulous, multiple-stage processes to avoid the preparation of the corresponding phosphonium salts (Aitken et al.,
Phosphorus, Sulfur and Silicon
101, 281 (1995)). Phosphorus ylides can sometimes react with the reaction solvent, thereby further complicating the synthesis. As a result, the choice of the reaction media is critical for both the generation of phosphorus ylides and in carrying out the Wittig-Horner reaction.
Environmental and health issues are other concerns with the use of organic solvents in the conventional preparation of phosphonium salts and phosphorus ylides. The reaction solvents can end up in waste streams, thereby straining the environment and causing health problems in the individuals exposed to them. Despite tremendous efforts directed towards the minimization of both environmental and health impacts of solvents, handling and elimination of solvents-related waste still remains one of the most difficult environmental and health problems. An effective approach to minimize the solvent-related chemical pollution is the replacement of solvents in both the industry and research laboratory by alternative materials acceptable from both environmental and health standpoints. However, a much more desirable method of resolving ecological problems caused by solvent wastes would be one that eliminates the use of solvents required for carrying out the particular chemical reactions altogether.
The present invention provides such a method. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The invention provides a method of preparing a phosphonium salt of the formula [R
1
R
2
R
3
P—CR
4
R
5
R
6
]X, comprising ball-milling a phosphine of the formula R
1
R
2
R
3
P with a compound of the formula XCR
4
R
5
R
6
; wherein R
1-3
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; wherein R
4-6
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; and wherein X is a mono- or polyvalent anion. The invention further provides a method of preparing a phosphorus ylide of the formula R
1
R
2
R
3
P═CR
4
R
5
, comprising ball-milling a phosphonium salt of the formula [R
1
R
2
R
3
P—HCR
4
R
5
]X (i.e., wherein R
6
is H) in the presence of a base; wherein R
1-3
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; wherein R
4
and R
5
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; and wherein X is a mono- or polyvalent anion. A third aspect of the invention provides a method of preparing an olefin of the formula R
4
R
5
C═CR
7
H or R
4
R
5
C═CR
7
R
8
, comprising ball-milling a phosphorus ylide of the formula R
1
R
2
R
3
P═CR
4
R
5
with a compound of the formula R
7
C(O)H or R
7
C(O)R
8
; wherein R
1-3
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; wherein R
4
and R
5
are independently selected from the group consisting of hydrogen, C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, and aryl; and wherein R
7
and R
8
are independently selected from the group consisting of C
1-25
alkyl, C
3-8
cycloalkyl, aralkyl, or aryl.
The inventive method thus produces phosphonium salts, phosphorus ylides and olefins by means of mechanical processing of solid reagents under solvent-free conditions. The advantages of the present invention over the previously known, i.e. conventional solution methods, include: (1) extremely high selectivity of quaternization reactions and therefore, the relative absence of side products; (2) high yields; (3) low processing temperatures; (4) simple and scalable reactions using commercially available equipment; and (5) the complete elimination of solvents from the re
Balema Viktor P.
Pecharsky Vitalij K.
Pruski Marek
Wiench Jerzy W.
Iowa State University & Research Foundation, Inc.
Leydig , Voit & Mayer, Ltd.
Vollano Jean F.
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