Process for the selective N-formylation of N-hydroxylamines

Details Process for the selective N-formylation of N-hydroxylamines Process for the selective N-formylation of N-hydroxylamines

2001-03-30

2002-02-26

Richter, Johann (Department: 1621)

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

Organic compounds

Hydroxamate esters or chalcogen analogues thereof

C560S129000, C562S621000, C564S218000, C564S219000, C564S221000, C564S224000

Reexamination Certificate

active

06350902

ABSTRACT:

TECHNICAL FIELD
This invention relates to a process for the selective N-formylation of N-hydroxylamines.
BACKGROUND OF THE INVENTION
While there are several published methods for the N-formylation of N-hydroxylamines, many of these routes have proven to be problematic. Disproportionation of the hydroxylamine to oximes and formylated primary amines is common, as is the formation of O-formylated and N,O-bis-formylated by-products. Methods which have proven to minimize by-product formation often require extended reaction times and elevated temperatures, which are impractical for large-scale preparations. Thus, there is a continuing need for an efficient method of selectively formylating the nitrogen of an N-hydroxylamine.
The instant invention discloses a large-scale synthesis of N-hydroxyformamides from N-hydroxylamines and 2,2,2-trifluoroethylformate. While the formylation of enolates with 2,2,2-trifluoroethylformate has been disclosed (Zayia, G. H.
Organic Lett
. 1999, 1, 989-991), the formylation of N-hydroxylamines with this reagent has not previously been described.
SUMMARY OF THE INVENTION
The process of the instant invention provides a selective N-formylation of N-hydroxylamines to provide N-hydroxyformamides which minimizes by-product formation.
In one embodiment of the instant invention is provided a process for the conversion of an N-hydroxylamine to an N-hydroxyformamide comprising reacting the N-hydroxylamine with 2,2,2-trifluoroethylformate in an optionally buffered solvent.
DETAILED DESCRIPTION OF THE INVENTION
The following terms have the meanings specified:
The term “alkyl,” as used herein, represents a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
The term “C
1
-C
4
alkyl group,” as used herein, represents a straight or branched chain saturated hydrocarbon radical having from one to four carbon atoms. Alkyl groups of this invention include methyl, ethyl, propyl, tert-butyl, and the like.
The term “aryl,” as used herein, represents phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, and indenyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through either the saturated or unsaturated part of the group.
The term “arylalkyl,” as used herein, represents an aryl group attached to the parent group through an alkyl group.
The term “buffered solvent,” as used herein, represents a solvent containing an agent capable in solution of neutralizing acids and bases and thereby maintaining a pH at or near the original pH of a solution during the course of a reaction. Representative buffering agents carbonate salts such as sodium carbonate, potassium carbonate, calcium carbonate, and the like; bicarbonate salts such as sodium bicarbonate, potassium bicarbonate, and the like; phosphate salts such as potassium phosphate, potassium hydrogenphosphate, sodium dihydrogenphosphate, and the like; tertiary amines such as triethylamine, diisopropylethylamine, and the like; optionally substituted pyridines such as 2,6-lutidine, pyridine, collidine, and the like; imidazole; and carboxylate salts such as sodium formate, potassium carbonate, and the like.
The term “cycloalkyl,” as used herein, represents a monovalent saturated cyclic hydrocarbon group.
The term “(cycloalkyl)alkyl,” as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkylene group.
The term “—C
2
-C
8
dialkyl ether,” as used herein, represents —R
1
—O—R
2
, wherein R
1
and R
2
are independently a C
1
-C
4
alkyl group, or, R
1
and R
2
, together with the oxygen atom to which they are attached, form a tetrahydrofuranyl or tetrahydropyranyl ring.
The term “electron-withdrawing group,” as used herein, represents a group which draws electrons to itself more than a hydrogen atom occupying the same position in the molecule would. Examples of electron-withdrawing groups include alkanoyl, arylsulfonyl, alkylsulfonyl, and the like.
The term “heteroaryl,” as used herein, represents a cyclic aromatic group having five or six ring atoms wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. Heteroaryl groups of this invention include those derived from furan, imidazole, isoquinoline, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, quinoline, thiazole, 1,3,4-thiadiazole, thiene, triazole, and tetrazole.
The term “heteroarylalkyl,” as used herein, represents a heteroaryl group attached to the parent molecular moiety through an alkyl group.
The term “N-hydroxylamine,” as used herein, represents NHR
3
(OR
4
), wherein R
3
is any group considered by those skilled in the art to be stable under the reaction conditions; and R
4
is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl, and heteroarylalkyl.
The term “N-hydroxyformamide,” as used herein, represents NR
3
(CHO)(OR
4
), wherein R
3
and R
4
have been previously defined.
The term “substituted pyridine,” as used herein, represents a pyridine optionally substituted with one, two, or three methyl groups. Examples of substituted pyridines include 2-picoline; 3-picoline; 4-picoline; 2,6-lutidine; 2,5-lutidine; 2,4-lutidine; 2,4,6-collidine; 2,3,5-collidine; and the like.
Synthetic Processes
The compounds and process of the instant invention will be better understood in connection with the following synthetic scheme which illustrates the method by which the compounds of the instant invention are prepared.
As shown in Scheme 1, compounds of formula (1) can be converted to compounds of formula (3) by treatment with 2,2,2-trifluoroethyl formate (2), which can be prepared according to the procedure described in
J. Chem. Soc
. B 1971, 826-831. Examples of solvents used in these reactions include tetrahydrofuran, methyl tert-butyl ether, diethyl ether, ethyl acetate, isopropyl acetate, 2,2,2-trifluorethanol, formic acid, toluene, and mixtures thereof. The reaction temperature is about 35° C. to about 75° C. and depends on the solvent chosen. Reaction times are typically about 4 to about 18 hours. When the compounds of formula (1) or the compounds of formula (3) are acid-sensitive, the reaction is preferably buffered. Representative buffering agents include carbonate salts, bicarbonate salts, phosphate salts, tertiary amines, optionally substituted pyridines, imidazole, and carboxylate salts. Preferably, the buffer is either imidazole or a carboxylate salt. More preferably, the buffer is either imidazole or sodium formate.


REFERENCES:
patent: 9906361 (1999-02-01), None
Blackburn, G.M.; “Kinetics of Hydrolysis and Aminolysis of N-Acetyl-O-formylserinamide”, Journal of Chemical Society, B, pp. 826-831, 1971.
Zayia, Gregory H.; “First General Method for Direct Formylation of Kineetically-Generated Ketone Enolates”, Organic Letters; vol. 1 No. 7, pp. 989-991, 1999.

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