Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-27
2003-09-16
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06620940
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to 3-chloro-4-halo-1,2,5-thiadiazole compounds and a method of producing novel mono- and di-substituted-1,2,5-thiadiazoles therefrom.
Since the discovery of 2,1,3-benzothiadiazole by Hinsberg in 1889 [1], chemists have shown an increasing interest in the chemistry of 1,2,5-thiadiazoles and 1,2,5-selenadiazoles.
Various compounds comprising a heteroaromatic ring of the 1,2,5-thiadiazole type present interesting properties in the pharmaceutical or agrochemical industry, and in the field of polymers. Thus, several molecules have been shown to have antibiotic [2], antihistamine [3], &bgr;-adrenergic [4] and anticholingergic activities [5], as well as inhibitory activities on HIV-1 transcriptase [6]. Other thiadiazoles are active as a fungicide [7], bactericide [8], herbicide [9], growth regulator [10], insecticide [11], coccidiostatic agent [12] or antihelmetic agent [13]. Finally, the 1,2,5-thiadiazole ring has also been incorporated in several polymers presenting, among other properties, high thermal and chemical stabilities [14].
The various syntheses of 1,2,5-thiadiazoles, largely developed during the '60s, can be grouped as a function of the precursor fragments used to construct the thiadiazole ring. The following approaches have been developed:
cyclization of an N—C—C—N fragment by a derivative S: [4+1] approach
cyclization of a C—C fragment with a derivative N—S—N: [3+2] approach (type A), and
cyclization of a C—C—N fragment by a derivative S—N: [3+2] approach (type B).
The [4+1] approaches use the cyclization with sodium mono- or dichloride of compounds of the following types: &agr;-aminoacetonitrile, &agr;-dioxime, &agr;-diamine, &agr;aminoamide, &agr;-cyanoimidate and &agr;-cyanoamide. This approach was largely developed by Weinstock [15] during the 1950s.
&agr;-aminoacetonitriles are prepared from aldehydes via a Strecker reaction:
&agr;-dioximes, prepared from 1,2-diketone precursors and &agr;-diamines lead to dialkyl- and diarylthiadiazoles:
&agr;-aminoamides, derived from amino acids, lead to hydroxylated thiadiazoles, which can be converted to halogenated thiadiazoles by treatment with phosphorus oxychloride or oxybromide [16]
Cyanogen, the precursor of &agr;-cyanoamides and &agr;-cyanoimidates, allows the production of 3-chloro-4-hydroxylated, 3-chloro-4-alkoxylated and 3,4-dichlorinated derivatives.
The syntheses of type [3+2] can be divided into two subclasses depending on whether the carbon fragment is of the C—C—N or C—C type. The first subclass ([3+2] type B) involves primarily the reaction of benzyl ketones, the corresponding oximes or the &agr;,&agr;-diahalogenoketoximes with derivatives of the sulfur diimide or tetranitride type in the cyclization step. Such an approach was applied to the preparation of numerous 3-chloro- and 3-bromo-4-aryl-1,2,5-thiadiazoles with excellent yields [17].
The second subclass ([3+2] type A) primarily uses disubstituted acetylene derivatives, as shown below (eq. 6):
where R and R′ are aryl, alkyl, CO
2
R or CN.
Unfortunately, all of the standard methods for construction of the 1,2,5-thiadiazole ring have various drawbacks when applied to large-scale syntheses, including:
unavailability of cyanogen and certain other precursors,
lengthy syntheses often leading to modest overall yields,
use of very toxic, corrosive and sometimes explosive reagents (for example: S
4
N
4
[18]), and
production of sulfur or its derivatives in the cyclization step, making purification difficult.
Alternate synthetic pathways, which are more general and allow the production of 3-chloro-4-alkyl- and 3-chloro-4-arylthiadiazoles, are therefore desirable. One of the fundamental methods of creating a carbon-carbon bond between a halogenated heterocycle and an aliphatic or aromatic group is the coupling reaction catalyzed by transition metals, as illustrated below:
where R and R′ are aryl, alkenyl, alkynyl, or alkyl; M is Li, Mg, Zn, Cu, Al, Si, Sn, or B and M′ is Pd or Ni. The application of transition metal chemistry for the production of various heterocyclic ring systems is known.
In 1972, Kumada [19] and Corriu [20] independently reported that the reaction between Grignard reagents and alkyl or aryl halides can be effectively catalyzed by nickel complexes. Murahashi [21] later published the first example of catalysis with palladium using the same reaction. Extraordinary advances in the field of coupling reactions catalyzed by transition metals followed with the use of derivatives of zinc, aluminum and zirconium [22], lithium [23], copper [24], silicon [25], tin [26] and boron [27].
Palladium catalysis has been applied to form numerous &pgr;-deficient heterocycles such as pyridine, pyrimidine and pyrazines [28]. However, palladium catalysis infrequently has been applied to other heterocyclic systems, including 1,2,5-thiadiazoles. A few recent publications reported the synthesis of 3,4-diaryl-1,2,5-thiadiazoles by reacting 3-bromo- or 3-trifluoromethanesulfonyl-4-aryl-1,2,5-thiadiazoles and arylstannanes ([29], JP 10025284 A2 980127, and JP 05163258 A2 930629).
When applied to the more readily available 3-chloro analogs, the above approach was unproductive. That is, the reaction with 3-chloro-4-phenyl-1,2,5-thiadiazole and tributyl(4-chlorophenyl)stannane led to the diarylated derivative with a yield of only 37%.
Thus, despite these recent advances, novel methods of producing 1,2,5-thiadiazoles with broader applicability for various substituents are desirable.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method of synthesizing 3-chloro-4-substituted derivatives by reacting 3-chloro-4-halo-1,2,5-thiadiazoles with an organostannane or organ oborane in the presence of a catalytic amount of palladium (eq 9):
where X is chloro, bromo, or iodo; and
RM is an organometallic group such as an organostannane or an organoborane (where R is an alkyl, alkenyl, alkynyl, aryl, or heteroaromatic group)
The present invention also provides a method of synthesizing novel 3,4-disubstituted-1,2,5-thiadiazoles from previously unknown 3-chloro-4-substituted-1,2,5-thiadiazoles by a further palladium-catalyzed cross-coupling reaction (eq 10):
where R is as defined above; and
R′M is an organometallic group such as an organostannane or an organoborane (where R′ is an alkyl, alkynyl, vinyl, allyl, aryl, or heteroaromatic group or is —OR
5
, —SR
5
or —NR
5
R
6
)
In the above formulae, R and R′ may be unsubstituted or substituted one to three times with a substituent selected from the group consisting of alkyl, alkenyls, alkynyls, halogen, hydroxy, oxo, phosphoryl, thiol, sulfinyl, sulfonyl, aryl, heterocyclic, amine, imine, nitro, cyano, amidino, carbonyl; wherein the moieties substituted on the hydrocarbon chain can themselves be substituted with one to three further substituents.
The present invention provides novel 3-chloro-4-substituted-1,2,5-thiadiazoles of the formula (1):
where R is —CR
1
═CR
2
R
3
or —C≡CR
4
;
R
1
is hydrogen, alkyl, —OR
5
, —SR
5
or —NR
5
R
6
;
R
2
and R
3
are each, independently, hydrogen, fluorine, alkyl, nitriles, O-protected alcohols, S-protected thiol, N-protected amine, CO-protected aldehydes, esters, alkylaryl and phosphine,
R
4
is alkyl, aryl, or a C-protecting group (such as trimethylsilyl (TMS) or t-butyl-dimethylsilyl (TBS)); and
R
5
and R
6
are each, independently, a protecting group, alkyl, alkenyl, alkynyl, aryl, heterocyclic or heteroaromatic group or where R
5
and R
6
together with the N which they substitute, form a heteroaromatic or heteroaromatic group.
The present invention also provides novel thiadiazole
Eli Lilly and Company
Palmberg Arleen
Stemerick David M.
Stockton Laura L.
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