Coupling condensation synthesis of heterocycles

Details Coupling condensation synthesis of heterocycles Coupling condensation synthesis of heterocycles

2002-05-20

2004-08-10

Shah, Mukund (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C546S113000, C546S270700, C548S365100, C548S379100, C540S492000, C544S242000, C544S333000

Reexamination Certificate

active

06774229

ABSTRACT:

The invention relates to a process for the preparation of aromatic or non-aromatic heterocycles having from 4 to 10, preferably from 5 to 7, ring members. Those heterocycles are used as fungicides, antimicrobials and bactericides.
In the prior art such ring systems are prepared as follows.
Alkaline condensation (aldol condensation) of an aromatic or heteroaromatic aldehyde with acetyl aromatic entities or acetyl heteroaromatic entities results in the formation of 1,3-diaryl- or -diheteroaryl-substituted enones (chalcones). The substances are isolated and purified. In a second reaction, the chalcones are then reacted with difunctional nucleophiles, for example hydrazines, whereupon the above-mentioned ring systems are obtained.
The process described above has the disadvantage of not being a one-pot process. A one-pot process is understood to mean an especially multi-stage synthesis process wherein any interim products or intermediates are not worked up, for example isolated, concentrated or purified.
Further definitions of terms used hereinbelow are:
An electron-deficient aromatic entity, heteroaromatic entity or olefin/alkyne or, in general, an electron-deficient system is understood to mean a system the &pgr;-electron density of which is reduced by negative inductive effects or negative mesomeric effects (-I effects and -M effects, respectively). A list of substituents or groups giving rise to such effects will be found in any standard textbook of organic chemistry. Without limitation, there may be mentioned, as examples of -I substituents: OH, halogens, NO
2
and unsaturated groups; and of -M substituents: NO
2
, CN and aromatic entities. Those electron-withdrawing groups (EWG) must of course be in conjugation with the leaving group X, that is to say in the ortho- or para-position in the case of carbocycles, in order to be capable of exerting the desired effect.
An acceptor group is understood to mean a group that has the following general properties: stabilisation of negative charges and partial charges by means of delocalisation via p-atomic orbitals or &pgr;-molecular orbitals (mesomeric stabilisation by means of -M resonance effects, &pgr;-acceptor) and/or inductive or field effects of electronegative atoms or molecule moieties (inductive stabilisation by means of -I field effects, &sgr;-acceptor) and combinations of those two effects (for def. see also textbooks of organic chemistry, e.g. Jerry March, Advanced Organic Chemistry, 4
th
edition, Wiley-Interscience, New York, Chichester, Brisbane, Toronto, Singapore, p. 17ff, 36).
Examples of acceptor groups that may be mentioned, without limitation, are: carboxylic, sulphonic, phosphonic and boronic acids, and esters, amides, imides and hydrazides thereof; the cyano group, keto group, formyl group, imine group, trifluoromethyl group, trialkyl-ammonium group, trialkylsilyl group, &eegr;
6
-phenylCr(CO)
3
and &eegr;
6
-6-phenylFe
+
cyclopentadienyl complexes.
The problem of the present invention is to make available a one-pot process.
The problem is solved by the process of the invention according to claim
1
, wherein the process for the preparation of heterocycles is characterised in that the components:
The invention relates to a process for the preparation of heterocycles, characterised in that the following components:
i) a propargyl derivative of the general structural formula I
 wherein Het is an optionally substituted hetero atom and A is a substituted or unsubstituted aromatic entity, a substituted or unsubstituted aromatic heterocycle, a substituted or unsubstituted vinyl arene and/or a derivative thereof, an olefin, an alkyne, an acceptor group or a nitrile;
(ii) a compound of the general structural formula II
B—X  (II),
 wherein B is an electron-deficient substituted or unsubstituted aromatic entity with or without an acceptor group, an electron-deficient substituted or unsubstituted hetero-aromatic entity with or without an acceptor group, an electron-deficient olefin and/or alkyne, a metal complex, and X is a leaving group;
(iii) a nucleophile of the general structural formula III
Y—C
n
—Z  III,
 wherein Y and/or Z, each independently of the other, is an amino group, thio group (mercapto group), seleno group, telluro group, hydroxy group (alcohol group), imido group, carbonyl group, thiocarbonyl group, selenocarbonyl group, tellurocarbonyl group; C is a substituted or unsubstituted C atom, a substituted or unsubstituted or annelated CC double bond or single bond and n=0-10, preferably 1-5, preferably are reacted in a one-pot reaction by cyclocondensation to form 4- to 10-membered, preferably 5- to 7-membered, heterocyclic, aromatic or non-aromatic ring systems.
Further advantageous embodiments form the subject-matter of the subordinate claims.
The substituents are not subject to any particular limitations. Examples of suitable substituents (preference is given in general to one substituent, but two, three or more substituents are also possible according to the invention) are throughout the description, for example on the aromatic entities, heteroaromatic entities and/or aromatic heterocycles or vinyl arenes, halogen atoms such as chlorine, iodine, fluorine and bromine, aromatic entities such as phenyl groups, alkyl, alkoxy, amino, ester, nitrile, nitro, aldehyde, acetal or sulphone groups. The alkyl and alkoxy groups may be straight-chained or branched. The chain length may be, for example, from 1 to 25, from 1 to 20, from 1 to 15, from 1 to 10 or from 1 to 5 carb as in the case of methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl; methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy. The amino groups may be primary, secondary or tertiary. For example, the substituents at the nitrogen atom may be the alkyl groups defined above. In general, all substituents may themselves be substituted, for example by identical substituents.
In the process according to the invention preference is also given to the use of iv) at least one suitable metal catalyst and v) at least one amine compound and/or a metal salt, preferably basic metal salts and mixtures thereof.
In accordance with the invention it is advantageous for the components to be reacted at a temperature of ≧0° C., preferably ≧20° C., especially ≧70° C., in a suitable solvent, suitable solvents including aromatic and heteroaromatic solvents, aliphatic ethers, alcohols, acetonitrile, dimethylformamide, DMSO and water.
In component i), Het may represent, for example, optionally substituted O, S, Se, Te, N, P, As and Sb. Preferably, the electronegativity is equal to or greater than that of carbon (EN≧2.5). As substituents there may be mentioned, for example: for N: tosyl, aminooxy and acyl groups; for P, As and Sb: alkoxy, aryloxy and phosphorimide groups.
The substituent or group A includes those substituents and groups, respectively, that are capable of stabilising negative charges, for example by delocalisation into a &pgr; electron system. There are no particular limitations.
The expression “substituted and conjugated and carbocyclically and heterocyclically annelated” compounds means that the compounds may have those features and/or substituents at the same time or individually, with preference being given to unsubstituted compounds.
There follow specific, non-limiting examples of substituents A of component i), wherein alkyl groups may be defined as mentioned hereinbefore:
Aromatic entities selected from the group of substituted and unsubstituted and conjugated and carbocyclically and heterocyclically annelated alkyl- and aryl-benzenes, phenols, aryl ketones, aryl thioketones, benzaldehydes, anilines, alkyl- and aryl-aryl ethers, benzodioxoles, arylalkyl and arylaryl thioethers, arylalkyl selenoethers, arylaryl selenoethers, arylalkyl telluroethers, arylaryl telluroethers, sulphoxybenzenes, sulphonyl benzenes, dialkylaryl- and triaryl-phosphanes, dialkylaryl- and triaryl-phosphane oxides, dialkylaryl- and triaryl-arsanes, dialkylaryl- and triaryl-arsane oxides, dialkylaryl- and triaryl-stib

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