Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
1999-11-04
2001-03-27
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S171000, C546S248000, C548S573000, C548S341500, C560S170000, C564S197000, C562S567000
Reexamination Certificate
active
06207828
ABSTRACT:
This invention relates to a new and convenient one step process for the preparation of 2-(trihaloacetyl)-3-(substituted amino)-2-propenoates and related derivatives thereof. These compounds are useful intermediates in the synthesis of trihalomethyl substituted heterocycles for pharmaceutical and agricultural applications.
It is known that N,N-dimethylamino derivatives are useful intermediates in organic synthesis, for example Burnett et al.,
Heterocycles,
45 (1997) and Kralj et al.,
J. Heterocyclic Chem.,
34, 247 (1997). In particular, N,N-dimethylamino-methylene derivatives (1) of &bgr;-ketoesters have been utilized in the synthesis of substituted heterocyclic compounds, many of which have important pharmaceutical and agricultural applications, for example Gelin et al.,
Synthesis,
566 (1983) and Mosti et al.,
Farmaco,
47, 427 (1992).
It also has been recognized that trifluoromethyl (CF
3
) groups can significantly modify the physico-chemical properties and the biological activities of compounds on which they are substituted, for example Banks et al., editors, “Organofluorine Chemistry, Principles and Applications”, Plenum Press, New York, N.Y. (1994) and Welch et al., editors, “Fluorine in Bioorganic Chemistry”, John Wiley and Sons, New York, N.Y. (1991). Therefore, the availability of the N,N-dimethylaminomethylene derivative (2) of ethyl trifluoroacetoacetate (3) would serve as a simple, but key intermediate for the construction of trifluoromethyl substituted heterocycles for pharmaceutical and agricultural applications.
Dimethylformamide (DMF) acetals have many functions in synthetic organic chemistry with one of the functions being the formation of N,N-dimethylaminomethylene derivatives with activated alkyl positions, for example Abdulla et al.,
Tetrahedron,
35, 1675 (1975). Thus, ethyl acetoacetate, Scheme 1, readily reacts at the active methylene site with DMF dimethylacetal to produce the N,N-dimethylaminomethylene derivative in good yields, for example Beck et al.,
J. Heterocyclic Chem.,
24, 693 (1987).
Although N,N-dimethylaminomethylene derivative of various &bgr;-ketoesters have been reported in the literature, the preparation of such a derivative from ethyl trifluoroacetoacetate (3) has not been successful. In fact, the reaction of (3) and DMF acetal has been reported to yield an undesirable product without the isolation of 2, for example Beck et al.,
J. Heterocyclic Chem.,
24, 739 (1987). Accordingly, compound (2) has not been available for the synthesis of biologically useful, trifluoromethyl substituted heterocycles and it is not commercially available.
I have found surprisingly conditions which allow the preparation of ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (2) from ethyl trifluoroacetoacetate and DMF acetals according to a general one-step reaction. Specifically, I found that compound 2 can be prepared in good yields (61-85%) by reacting ethyl trifluoroacetoacetate with DMF acetals in the presence of an organic acid such as acetic acid. While not wishing to be bound by theory, the success of this reaction condition appears to lie in the suppression of the loss of the trifluoroacetyl group from (2) through the attack of the alcohol by-products. In the absence of the organic acid, ethyl 3-(N,N-dimethylamino)-2-propenoate (4) is formed as the major product in all cases. My overall result is shown in Scheme 2.
My result is especially surprising in view of the results reported by Beck et al., vide supra, who attempted to prepare (2) by reacting ethyl trifluoroacetoacetate with DMF dimethyl acetal in the presence of a catalytic quantity of p-toluenesulfonic acid. The reaction resulted in the formation of ethyl 3-(N,N-dimethylamino)-2-propenoate (4) in 75% yield. Presumably, the methanol by-product further reacted with the target compound (2) to give the unexpected product and methyl trifluoroacetate.
The only other route leading to a N,N-dialkylaminomethylene derivative of ethyl trifluoroacetoacetate reported in the literature is by Bartnik, et al.,
Tet. Letters
33, 8751 (1996). These workers prepared ethyl 2-trifluoroacetyl-3-(N,N-diisopropylamino)-2-propenoate (6) as shown in Scheme 3. This was accomplished not by the one-step &bgr;-ketoester/DMF acetal reaction, but in two steps by converting the ketoester to the chloroacrolein (5) under Vilsmeier conditions and then treating this intermediate with diisopropylamine to give 6.
The process of the present invent avoids the problems associated with the use of POCl
3
and attendant disposal of associated phosphorous and chloride by-products. Moreover, since the present process is but one step, it may be run under very productive and economical conditions in a single reaction vessel.
Thus, the present invention provides a process to prepare a compound of formula (I) by the reaction of a trihaloacetyl compound of formula (II) with an acetal of formula (III) in the presence of an organic acid and an optional solvent
wherein
A is an oxygen atom or a sulfur atom,
B is R, OR, N(R)
2
or SR,
R is a hydrogen atom, alkyl, haloalkyl, alkenyl, alkynyl, phenyl or phenyl substituted with up to three substituents independently selected from halo, alkyl and haloalkyl, or phenalkyl or phenalkyl substituted on the phenyl ring with up to three substituents independently selected from halo, alkyl and haloalkyl,
R
1
and R
2
are both alkyl or alkenyl, or together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, thiomorpholin-4-yl, 1-pyrrolyl or 1-imidazolyl,
R
3
and R
4
are both alkyl, cycloalkyl, benzyl or phenethyl, or together with the carbon atom to which they are attached form 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl or catech-2-yl,
X is fluoro or chloro, and the organic acid is formic, acetic, trifluoroacetic, propionic, benzoic, toluic or phenylacetic.
In this invention, the term alkyl refers to either a straight chain (C
1
-C
6
)alkyl such as, but not limited to, methyl, ethyl, n-propyl, n-butyl and n-hexyl or a branched chain (C
3
-C
6
)alkyl such as, but not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl and &agr;-methylneopentyl. Cycloalkyl is a cyclo(C
5
-C
6
)alkyl, such as cyclopentyl and cyclohexyl. Alkenyl means a linear (C
3
-C
6
)alkenyl group and includes, for example, allyl and 2-butenyl. Alkynyl means a linear (C
3
-C
6
)alkynyl group and includes, for example, propargyl and 2-butynyl. Halo is fluoro, chloro, bromo or iodo. Haloalkyl means a linear or branched (C
1
-C
6
)alkyl group substituted with one or more halo and includes, for example, trifluoromethyl, perfluoroethyl and 2,2,2-trifluoroethyl. Phenalkyl is phen(C
1
-C
4
)alkyl and includes, for example, benzyl and phenethyl.
In a preferred embodiment of this invention,
A is an oxygen atom,
B is R or OR,
R is a hydrogen atom, (C
1
-C
4
)alkyl, (C
3
-C
4
)alkenyl, (C
3
-C
4
)alkynyl, phenyl or phenyl substituted with up to three substituents independently selected from fluoro, chloro, (C
1
-C
2
)alkyl and halo(C
1
-C
2
)alkyl, or phen(C
1
-C
2
)alkyl or phen(C
1
-C
2
)alkyl substituted on the phenyl ring with up to three substituents independently selected from fluoro, chloro, halo(C
1
-C
2
)alkyl and (C
1
-C
2
)alkyl,
R
1
and R
2
are both (C
1
-C
4
)alkyl or (C
3
-C
4
)alkenyl, or together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, thiomorpholin-4-yl, 1-pyrrolyl or 1-imidazolyl,
R
3
and R
4
are both (C
1
-C
4
)alkyl, cyclo(C
5
-C
6
)alkyl, benzyl or phenethyl, or together with the carbon atom to which they are attached form 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl or catech-2-yl,
X is fluoro or chloro, and the organic acid is formic, acetic, propionic or phenylacetic.
In a more preferred embodiment of this invention,
A is an oxygen atom,
B is OR,
R is (C
1
-C
2
)alkyl, (C
3
-C
4
)alkenyl, (C
3
-C
4
)alkynyl, phenyl, or phen(C
1
-C
2
)alkyl,
R
1
and R
2
are both (C
1
-C
4
)alkyl or (C
3
-C
4
)alkenyl, or together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-pi
Carpenter Clark R.
Patel Sudhaker B.
Rolm and Haas Company
Shah Mukund J.
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