3-substituted pyridine compounds and related synthesis

Details 3-substituted pyridine compounds and related synthesis 3-substituted pyridine compounds and related synthesis

2001-01-22

2003-01-21

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S296000

Reexamination Certificate

active

06509471

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 3-substituted and 2,3-disubstituted pyridine compounds which are useful as intermediates in the synthesis of pyridylsulfonylurea herbicides. The invention also relates to arylation of alcohols using a pyridinediazonium salt. More particularly the arylation process of the instant invention relates to the synthesis of 2,3-disubstituted pyridine compounds via anhydrous diazotization of 3-aminopyridines to form a diazonium salt intermediate that is then reacted with the appropriate alcohol to produce the desired product. The invention additionally relates to pyridine-3-diazonium salt intermediates.
BACKGROUND OF THE INVENTION
Arylation reactions involving dediazotization of a diazonium salt have been used to introduce various groups on to an aryl ring. March et al.,
Advanced Organic Chemistry,
4
th
Ed., John Wiley & Sons, (1992), pages 721-725. Aromatic and heteroaromatic sulfides have been successfully prepared from primary aromatic and heteroaromatic amines by adding the appropriate amine to a solution of isopentyl nitrite and excess of dimethylsulfide which is heated to 80-90° C. Giam et al., J. Chem. Soc., Chem. Commun., 1980, 756-757. Arylation of olefins by the combination of arylamines (such as 3-aminopyridine) and tert-butyl nitrite under palladium catalysis in the presence of acid has also been described in the chemical journal literature. Kikukawa et al., J. Org. Chem., 1981, Vol.46, 4885-4888. It is believed that the reaction of an arylamine and an alkyl nitrite gives an aryl radical under neutral conditions, whereas it affords a diazonium salt under acidic conditions. Replacement of the primary aromatic amino group by hydrogen has been accomplished by decomposing diazonium fluoborates in the presence of ethanol and zinc, however, when 3-aminopyridine is used, an additional by-product is obtained as the 3-ethoxypyridine in low yield (12.2%). Roe et al., J. Amer. Chem. Soc. 1952, Vol. 74, 6297-6298. 2-chloro-3-hydroxypyridine has been prepared by reacting 3-amino-2-chloropyridine with a nitrite in the presence of acid. Schickh et al., Berichte d. D. Chem. Gesellschaft, 1936, Vol. 69, 2593-2605.
The relative reactivity of aniline derivatives and primary aminopyridine compounds is not analogous in the context of diazotization and de-diazotization reactions. It would be overly simplistic to view the pyridine ring as analogous to a benzene (i.e. pyridine is not a benzene ring merely having a nitrogen ring atom therein). There is a dramatic difference in the reactivity of benzene and pyridine moieties that is caused by the presence and electronic effects of the nitrogen in the ring of the latter. Similarly, there may be significant differences in the stability of the corresponding benzenediazonium salts and pyridinediazonium salts containing these moieties. Additionally, 3-aminopyridine moieties are not functionally equivalent to 2-aminopyridine moieties when considered in the context of diazotization-dediazotization reactions. The electronic effects and chemistry are completely different for the diazonium salts prepared from 2-aminopyridines as compared to the diazonium salts prepared from 3-aminopyridines. The most relevant difference is that pyridine-2-diazonium salts are very unstable and can not be isolated. See
Heterocyclic Compounds,
Volume 14, supplement part 3, page 74 (1974) and R. N. Butler,
Chemical Reviews,
1975, Volume 75, No. 2, page 250.
What is commonly observed when a diazonium salt is treated with an alcohol is reduction of the diazonium salt (ArN
2
+
) to the ArH species. For a general discussion of diazonium chemistry see Nathan Komblum,
Organic Reactions,
Volume 2, page 262 (1944). Surprisingly, it has now been discovered that the use of halogenated alcohols yields the corresponding alkoxide as the major product.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the invention is the compounds of formula I:
wherein R
1
is a C
1
-C
4
haloalkyl and R
4
is H, halogen or C
1
-C
4
alkylthio; and acid addition salts thereof. The haloalkyl groups may be branched or unbranched. The halogen(s) of the haloalkyl group and R
4
, when halogen, are independently selected from fluoro, chloro, bromo and iodo. The degree of halogen substitution of R
1
may range from monohalogen substitution to polyhalogen substitution wherein all the hydrogens of the alkyl group have been replaced by halogens (e.g. perfluoroalkyl groups). Compounds of formula Ia constitute preferred embodiment of the invention:
wherein R
1
is defined as above. Another preferred embodiment of the invention is wherein R
1
is selected from the group consisting of —CH
2
CF
3
, —CH
2
CCl
3
, and —CH
2
CH
2
Cl. An ultimately preferred embodiment of the invention is the compound having the formula:
2-chloro-3-(2,2,2-trifluoroethoxy)pyridine.
Another aspect of the invention is the pyridinediazonium salt of formula II:
wherein A
−
is a counter-anion derived from an organic acid or inorganic mineral acid, HA; and R
4
is defined as above. A
−
is preferably an anion of the formula
−
OSO
2
R
2
(i.e. the conjugate base of a sulfonic acid), wherein R
2
is C
1
-C
4
alkyl, phenyl, C
7
-C
10
alkylaryl, or C
5
-C
10
cycloalkyl (preferably methyl); or an anion of the formula
−
OOC—R
2a
(i.e. the conjugate base of a carboxylic acid) wherein R
2a
is C
1
-C
4
haloalkyl, preferably trifluoromethyl; and R
4
is defined as above. The pyridinediazonium salt of formula II is useful as an intermediate for the preparation of the compounds of formula I.
A preferred pyridinediazonium salt is the pyridinediazonium sulfonate salt of formula II′:
wherein R
2
and R
4
are defined as above. A preferred feature of the invention is where R
2
is methyl or a 10-camphoryl group (i.e. a pyridinediazonium 10-camphorsulfonate salt).
Another aspect of the invention is the product produced from the process of diazotizing a 3-aminopyridine with an alkyl nitrite and acid under substantially anhydrous conditions. The pyridinediazonium salt of formula II or the product from the process of diazotization (to the extent there is a difference) are both features of the instantly disclosed invention. The scope of the invention as to the diazonium salts and the process of preparing the compound of formula I disclosed herein should not be construed to be limited by any particular chemical theory relating to the complexation, equilibration, reaction or acid-base chemistry of the components used to make the diazonium salt or the final product. Another aspect of the invention is pyridinediazonium salts of formula II wherein said salt has interacted chemically so as to result in a changed form of the salt or has interacted with other chemical components so as to form another more stable compound or acid addition salt thereof. Accordingly, the present invention encompasses the substantially unaltered static composition of the appropriate components as well as the chemically integrated composition. “Static composition” denotes 1) the composition composed of components wherein the components have not substantially changed by virtue of their combination or interaction with other composition components, or 2) the composition that has reacted to a point of relative stasis. “Chemically integrated composition” means a composition that results from any equilibration, complexation, dissociation or other chemical transformation (if any) that may occur after combination of the reagents used to prepare the product composition containing the salts of formula II and prior to ultimate use for the preparation of the compounds of formula I. Therefore, the “chemically integrated composition” of the instant invention by definition encompasses the situation where there is an unchanged “static composition” as well as the equilibrated or semi-equilibrated composition existing at any point between initial creation and ultimate use. In other words, the disclosed invention relating to diazonium salts is not limited to a static composition of chemically unaltere

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