Organic compounds -- part of the class 532-570 series – Organic compounds – Diazo or diazonium
Reexamination Certificate
2001-08-20
2004-10-19
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Diazo or diazonium
C560S115000, C560S114000, C560S008000
Reexamination Certificate
active
06806357
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to nucleophilic substitution of alcohols, and, especially, to fluorous nucleophilic substitution of alcohols and fluorous reagents therefor.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The Mitsunobu reaction is one of the most popular and powerful reactions in organic, synthesis and its uses range from natural products synthesis to parallel synthesis and combinatorial chemistry. See, for example, Hughes, D. L. “Progress in the Mitsunobu reaction. A review.” Org. Prep. Proced. Int. 1996, 28,-127-164; Hughes, D. L. “The Mitsunobu reaction.” Org. React. (N.Y.) 1992; 42, 335-656; and Mitsunobu, O. “Synthesis of Alcohols and Ethers.” in Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 6; pp 1 32. The Mitsunobu reaction is so commonly used because it allows the one-step substitution of a primary or secondary alcohol by a nucleophile. Nucleophilic substitutions of alcohols are common synthetic transformations but other general methods require two or more steps.
A traditional solution phase Mitsunobu reaction as illustrated in
FIG. 1
combines an alcohol a, an acidic pro-nucleophile b, diethylazodicarboxylate c (typically referred to as “DEAD”) and triphenylphosphine d in an organic solvent such as dichloromethane or tetrahydrofuran (THF). The reagents and reactants can be combined in different orders according to several standard procedures. The products of the reaction are the desired substitution product e, the hydrazine f derived from the reduction of c and triphenylphosphine oxide g derived from the oxidation of d. If either reagent c or d is used in excess, then this unreacted reagent may also be present. The desired product of the reaction e is typically separated from the reagent byproducts and any excess reagents by chromatography.
The need for a careful chromatographic separation is a substantial limitation of the Mitsunobu reaction. The required separation is expensive on large scale. On small scale, the time and effort needed for multiple chromatographic separations limit combinatorial and parallel applications of the reaction.
Two general approaches have been. taken to facilitate separation in Mitsunobu reactions. First, both the phosphine and the azodicarboxylate have been attached to polymeric solid phases. See, for example, Tunoori, A. R.; Dutta, D.; Georg, G. I. “Polymer-Bound Triphenylphosphine as Traceless Reagent for Mitsunobu Reactions in Combinatorial Chemistry: Synthesis of Aryl Ethers from Phenols and Alcohols” Tetrahedron Lett. 1998, 39, 8751-8754; and Arnold, L. D.; Assil, H. I.; Vederas, J. “Polymer-Supported Alkyl Azodicarboxylates for Mitsunobu Reactions” J. Am. Chem. Soc. 1989, 111, 3973-3976. Polymer-bound reagents and reactants can be removed from final products by simple filtration. However, in the Mitsunobu reaction, the polymer approach only solves half the problem since the two polymer-bound reagents (azodicarboxylate and phosphine) cannot be used simultaneously. These reagents must react with each other and this reaction is blocked if both are bound to polymers. So only one polymer-bound reagent can be used and the other must be a soluble reagent.
In the second approach, soluble reagents are used and then these reagents are transformed by a chemical reaction after the Mitsunobu reaction is over. See, for example, Starkey, G. W.; Parlow, J. J.; Flynn, D. L. “Chemically-Tagged Misunobu Reagents for Use in Solution Phase Chemical Library Synthesis”
Bioorg. Med. Chem. Lett.,
8, 2384-89 (1998). For example, soluble phosphine and azodicarboxylate reagents with suitable functionalities can be polymerized after a Mitsunobu reaction is over and then removed by filtration. This second approach is inefficient since it requires an extra chemical reaction (with associated reagents, time and effort, etc.) which contributes only to separation and not to formation of a desired product. In addition, the desired product cannot contain any functionality that would participate in the polymerization reaction. The second approach of facilitating separation thus imposes limitations that are not imposed by a normal Mitsunobu reaction.
It is very desirable to develop improved methods for nucleophilic substitution of alcohols and reagents thereofor to, for example, reduce or eliminate the above problems with current Mitsunobu reactions.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method of effecting a nucleophilic substitution of an alcohol to produce a target product including the steps of: reacting the alcohol and a nucleophile with an azodicarboxylate and a phosphine. At least one of the azodicarboxylate and the phosphine including at least one fluorous tag. In several embodiments, the azodicarboxylate includes at least one fluorous tag, and the phosphine includes at least one fluorous tag.
The method preferably further includes the step of separating the target product from the fluorous tagged azodicarboxylate and/or the fluorous tagged phosphine via a fluorous separation technique. The fluorous separation technique can, for example be a liquid-liquid extraction. The fluorous separation technique can also be a solid-liquid extraction. The fluorous separation technique can also be a fluorous solid phase extraction or a fluorous chromatography.
The term “nucleophile”as used herein refers generally to an ion or a molecule that donates a pair of electrons to an atomic nucleus to form a covalent bond. Suitable nucleophiles for use in the present invention are conjugate bases of organic or inorganic acids. These acids should have a pKa preferably less than or equal to about 20, and more preferably less than or equal to about 15. Even more preferably, the pKa is less than or equal to about 12. The conjugate bases of many types of organic acids are known by those skilled in the art to be suitable for Mitsunobu reactions. Suitable nucleophiles include, but are not limited to, the conjugate bases derived from carboxylic acids, phenols, hydroxamic acids, imides, sulfonimides, sulfonamides, thiols, thioacids, thioamides, beta-dicarbonyls and assorted heterocycles. Nucleophilic conjugate bases derived from inorganic acids such as hydrogen halides or hydrogen azide, are also suitable.
Organic alcohols include a saturated carbon bonded to a hydroxyl group. Alcohols that participate in the Mitsunobu reaction are well known to those skilled in the art and include methanol and primary (for example, ethanol, propanol, allyl alcohol) and secondary (for example isopropanol and 1-phenylethanol) alcohols. Tertiary alcohols are less preferred but can still be used in some (especially intramolecular) applications.
The alcohol and the nucleophile can be in different molecules, or in the same molecule. In the later case (an intramolecular Mitsunobu reaction), a new ring is formed.
The fluorous tagged azodicarboxylate can, for example, have the formula:
Z
1
O
2
C—N═N—CO
2
Z
2
wherein Z, is
In the above formula n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently 1 or 0. X
1
, X
2
, X
3
, X
4
, X
5
, X
6
, X
7
, X
8
, X
9
, X
10
, X
11
, X
12
, X
13
, X
14
, X
15
, X
16
, X
17
, X
18
, X
19
and X
20
are independently H, F, Cl, an alkyl group, an aryl group or an alkoxy group. R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
and R
16
are indenpendently H, F, Cl, an alkyl group, an alkoxy group, a thioalkyl group, a dialkylamino group, a nitro group, a cyano group, a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group, a fluorinated amine group, O—Rf
1
, S—Rf
2
, or —N(Rf
3
)(R
22
), wherein R
22
is an alkyl group or Rf
4
, and wherein Rf
4
, Rf
2
, Rf
3
and Rf
4
are independently a fluorous group selected from t
Curran Dennis P.
Dandapani Sivaraman
Bartony & Hare, LLP
Desai Rita
Reyes Hector M
University of Pittsburgh
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