Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-20
2003-01-21
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S452000, C549S029000, C549S429000, C260S66500B
Reexamination Certificate
active
06509474
ABSTRACT:
This invention relates to a method of lithiating CH-acidic five-membered heterocycles, wherein the five-membered heterocycle is reacted with metallic lithium in an ether-containing solvent in the presence of an H acceptor. The invention also relates to a use of the products of the method.
Hydrocarbons are more readily metalated the higher their CH-acidity, the more electropositive the metal, the larger the active surface area of the metal and the more polar the solvent. In this way alkynes, cyclopentadiene (and derivatives) and, for example, triphenylmethane can be deprotonated by means of alkali metals. The problem, however, is that secondary reactions such as, for example, hydrogenations and/or CC-splitting, lead to poor yields. These secondary reactions become prominent particularly in highly polar solvents (for example, hexamethylphosphorous triamide (HMPT), 1,2-dimethoxyethane (1,2-DME)) or protic solvents (for example, NH
3
) . On the other hand, in solvents which are not highly polar (for example, benzine, ether), the reaction rate is too-low to enable the direct metalation principle to be widely utilised. Thus, for example, the metalation of triphenylmethane with potassium in boiling 1,2-DME requires 10 hours. Caesium is a special case since, for example, it reacts quantitatively with toluene at relatively elevated temperatures to form insoluble benzylcaesium.
Five-membered heterocycles have a considerably lower CH-acidity than do alkynes and cyclopentadienyls and are therefore harder to metalate. Thus furan yields only small quantities of furan-2-carboxylic acid following reaction with potassium or K/Na alloy and subsequent derivatisation with CO
2
. Thionaphthene which has been activated by benzoanellation reacts with Na and, after reaction with CO
2
and H
2
O, produces the derivatisation product in moderate yield:
It may be assumed that the poor yields are the result of double-bond hydrogenation.
Thiophene itself reacts with a lithium metal dispersion in THF only very slowly and with moderate yields. After a reaction time of one week, a conversion of only 12% was observed by von Screttas (C. G. Screttas, J. C. S. Perkin Transactions II, 1974, 745-748, XP002102778).
The same article reports reactions of lithium with thiophene to form thienyllithium in the presence of various arenes such as, for example, naphthalene and/or &agr;-methylstyrene. Thus at least 2 mol lithium was required for the preparation of 1 mol thienyllithium in the presence of an approximately stoichiometric quantity of naphthalene. The remaining lithium, or lithium dihydronaphthalenide, was used up by secondary reactions. In Example 3 of the cited literature reference (p. 748), the metalation was carried out in the presence of a large excess of thiophene. The yield of thienyllithium was 41% based on lithium used and less than 20% based on thiophene used.
The reaction of preformed lithium dihydronaphthalenide with excess thiophene (Example 4, p. 748) likewise resulted in poor product yields: 52% based on the lithium reagent and 8% based on thiophene. The product yield in the reaction of lithium dihydronaphthalenide with thiophene could be improved by admixing certain hydrocarbons such as 1,1-diphenylethylene or &agr;-methylstyrene. In Example 5 (p. 748) the yield based on the lithium reagent was 95%, a distinct increase. However, a large excess (300% to 500%) of thiophene was used and consequently the metalation yields based on thiophene were below 50%. The molar quantity of the auxiliary reagent diphenylethylene or &agr;-methylstyrene also exceeded the quantity of lithium or of lithium naphthalenide by a factor of at least 1.5.
The disadvantages of the syntheses described by von Screttas are in general the extremely poor to moderate yields based on the lithium reagent and/or, in particular, based on thiophene. Moreover, the reactions with lithium dihydronaphthalenide are two-step syntheses in which, in the first step, it is necessary to prepare the unstable and not easily handled lithium dihydronaphthalenide which, in a second step, is reacted with thiophene. In all the cases described, large quantities of useless secondary products, namely naphthalene and, optionally, decomposition products are formed in the reactions.
The secondary reactions and unwanted secondary products observed when metals are used can be avoided if organometallic compounds such as butyllithium are used as metalating reagents. However, butyllithium and other lithium organyls prepared from alkyl halides or aryl halides have the disadvantage that ultimately only 50% at most of the metal employed for their synthesis can be used for the 5-ring metalation, because in their synthesis according to the equation
R—Hal+2Li→R—Li+LiHal↓
R=alkyl, aryl; Hal=Cl, Br, I
50% of the costly metal is converted into a salt of inferior value (LiHal). They are consequently expensive.
Of particular interest are organolithium syntheses which utilise the lithium as quantitatively as possible and, in a one-step reaction, also allow the best possible yields based on the organic substrate, in this case five-membered heterocycles. Metalated five-membered heterocycles are used very frequently in organic synthesis, as they are indispensable for the synthesis of valuable pharmaceuticals and plant protection products.
The object of the invention is to eliminate the disadvantages of the prior art and to provide a method which, starting from metallic lithium, permits the. direct, i.e. one-step, lithiation of CH-acidic five-membered heterocycles with high yields (for example, 70% and more) and makes it possible for the introduced metal to be utilised as quantitatively as possible for the deprotonation, without the formation of useless secondary products such as, for example, alkali halides. Moreover, the process is to proceed selectively, i.e. only certain CH functions of the heterocycle are to be metalated and there is to be no hydrogenation of the C═C double bonds present in the heterocycle.
This object is achieved by the method given in claims 1 and 2. Claims 3 to 13 give further particulars of the given method. Claims 14 and 15 give a particularly advantageous use of the compounds produced by the method according to the invention.
In order to lithiate CH-acidic five-membered heterocycles having a pK
a
value of 30 to 40, the five-membered heterocycle is reacted with metallic lithium in an ether-containing solvent in the presence of a hydrogen acceptor (H acceptor).
The method according to the invention proceeds from the method given in DE 19725192, in which the direct metalation of CH-acidic compounds containing one or more CH structural elements having pK
a
values of between 10 and 30 is described. Surprisingly, it has now been found that considerably less acidic electron-rich five-membered heterocycles having a pK
a
value of >30 can also be metalated with a good yield through a suitable choice of the reactants and of the reaction conditions. It has further been found that where the hydrogen acceptors according to the invention are used, the product yields of >50% up to nearly 100% are distinctly higher than the 41% obtained with the use of naphthalene or lithium naphthalenide.
The CH-acidic five-membered heterocycles used are compounds which contain as ring members, in addition to at least one acidic CH group, a maximum of 4 hetero elements selected from O, S, N and Se. These are five-membered heterocycles containing one hetero atom such as e.g.
five-membered heterocycles containing two hetero atoms such as e.g.
five-membered heterocycles containing three hetero atoms such as e.g.
or five-membered heterocycles containing four hetero atoms such as e.g.
wherein R=H, alkyl, aryl,
All the above compounds can also be partially substituted, except those species which, apart from the CH-acidic hydrogen atom, do not contain any other hydrogen atom in the five-membered ring.
Particularly suitable CH-acidic five-membered heterocycles are those 5-membered ring systems which have at least one olefinic CH grou
Hauk Dieter
Lischka Uwe
Rittmeyer Peter
Wietelmann Ulrich
Antonelli Terry Stout & Kraus LLP
Chemetall GmbH
McKane Joseph K.
Small Andrea D.
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