The Modern Chemistry Of The Isocyanides

A new era of the isocyanide chemistry began in 1958 when the isocyanides became generally available by dehydrating the corresponding formylamines in the presence of suitable bases (Scheme 1.3).4 A systematic search for the most suitable dehydrating reagent revealed early on that phosgene31 is excellent for this purpose. Later, when phosgene transportation was not allowed anymore, it was locally produced from triphosgene.32 Also diphosgene33 and phosphorus oxychlor-ide,4 can be used, particularly in the presence of di-isopropylamine.34 Baldwin et al.35 prepared naturally occurring epoxy-isocyanides from the corresponding formylamines by dehydrating the latter with trifluoromethyl sulfonic acid anhydride in the presence of di-isopropylamine.

In the 1971 book Isonitrile Chemistry3 325 isocyanides were mentioned, and almost all of them had been prepared by dehydration of formylamines.

After some model reactions, Ugi et al.3a-d accomplished a new way of preparing Xylocaine® by one of the first U-4CRs. In 1944 Xylocaine 1236 (Scheme 1.4) was introduced by the A. B. Astra company in Sweden, and since then Xylocaine has been one of the most often used local anasthetics, particularly by dentists. In its early period, A. B. Astra patented 26 chemical methods of preparing 12.

In January 1959, Ugi and co-workers decided to prepare 12 from diethylamine 9, formaldehyde 10, and 2,6-xylylisoxcyanide 11. Initially they considered this as a variation of the Mannich reaction.10 In their first experiment they noticed that this reaction is so exothermic that an immediate mixing of the educts can initiate an explosion,3,37 and it was realized that this reaction was in reality a 4-component reaction in which water 7 also participates.


Scheme 1.3 General formation of isocyanides.

Me O Me

11 12

Scheme 1.4 Four-component reaction of Xylocaine®.

Scheme 1.5 The Ugi reaction.

During the first month of this experiment, it was realized that this reaction is extremely variable. Thus, diverse amines (ammonia, primary and secondary amines, hydrazine derivatives, hydroxylamines) 13, carbonyl compounds (aldehydes, ketones) 14, acid components 15 or their anions (H2O, Na2S2O3, H2Se, R2NH, RHN-CN, HN3, HNCO, HNCS, RCO2H, RCOSH, ROCO2H, etc.), and the isocyanides 83,4,38 could form the a-adducts 16 that rearrange into their products 17 (Scheme 1.5).

Since 1962, this reaction has been called the Ugi reaction,4a or it is abbreviated as the U-CC,38a or as the U-4CR.38b The U-4CR can formally be considered to be a union,39 4CR = HO-3CR U P-3CR 18 (Scheme 1.6), of the HO-3CR and the P-3CR that have in common the carbonyl compounds and acids, while the HO-3CR also needs an amine and the P-3CR an isocyanide.

In each type of chemical reaction, the skeleton of the product is characteristic, and only its substituents can be different, whereas in the U-4CR and related reactions of the isocyanides the skeleton of the products can also include different types of amines and acid components. This is illustrated by the eight skeletally different products in Scheme 1.7. Besides these compounds, many other types of compounds also can be prepared by the U-4CR.

Ordinary chemical reactions have their "scopes and limitations" for various reasons. Many sterically crowded products cannot be formed by conventional syntheses, but they can still be prepared by the U-4CR. Thus, the product 2240 can be formed only by the U-4CR, (Scheme 1.8).

The U-4CR forms its products by less work and in higher yields than other syntheses. The U-4CR is nowadays one of the most often used chemical reaction



Scheme 1.6 The U-4CR as a union of the HO-3CR and the P-3CR.















R6 X


R2' R3

Scheme 1.7 The wide variability of the U-4CR.

for the formation of chemical libraries. These libraries had already been proposed in 1961 (Ref. 3, p.149; Ref. 41), but only in the 1980s the chemical industry has recognized the advantages of the libraries.5,42,43

In ordinary reactions where two educts participate, 10 different components of each educt type can form 100 constitutionally different products. The U-4CR can form 10,000 different products when 10 different starting materials of each type of educt44 are involved. In this way, libraries of an extremely high number


Scheme 1.8 Synthesis of a sterically extremely hindered product by the U-4CR.


Scheme 1.8 Synthesis of a sterically extremely hindered product by the U-4CR.

of products can be formed via the U-4CR. Combined with other combinatorial methods, the search for new desirable products can thus be accomplished particularly well.

A product of the U-4CR is only formed in a good yield and purity if the optimal reaction conditions are used. The U-4CR proceeds faster and in a higher yield, when the amine component and the carbonyl compound are precondensed, and the acid component and the isocyanide are added later.44 Very often methanol or trifluoroethanol are suitable solvents, but sometimes a variety of other solvents can be used as well. Furthermore, the sequence of the educts and their concentrations must be optimal and a suitable temperature of the reaction must be used. In many cases, the U-4CR can be improved by a catalyst.1'45

In a special case, the reaction mechanism of the U-4CR was investigated.3'44'46 The aldehyde and chiral amine were precondensed into the Schiff-base isobutyraldehyde-(S)-a-phenylethylamine that was reacted with benzoic acid and tert-butylisocyanide in methanol at O°C. In one series of experiments, the dependence of the electrical conductivity of this Schiff-base and the carboxylic acid was determined, and in a second series of experiment, the relation between the educt concentrations and the ratio of diastereoisomeric products caused by competing different stereoselective U-4CRs was investigated. The ratio of the diaster-eomeric products was determined by their optical rotations.44 The large collection of numerical values of these experimental data were evaluated by a mathematically based computer program. It was found that four pairs of stereoselective processes compete and, depending on the concentrations of the educts, one or the other diastereomeric product is preferentially formed. This knowledge made it generally possible to find the optimal conditions of the U-4CR by fewer experiments than usual.

Rather early it was recognized how much easier natural products and related compounds can be prepared by the U-4CR,1,4 but the advantages of searching for new desirable pharmaceutical and plant-protecting compounds became evident only during the last few years, when industry began to produce the U-4CR products.1,42

For a whole decade a research group at Hofmann-LaRoche AG tried, without success, to find suitable thrombine inhibitors by the coventional methods. But only in 1995 Weber et al.47 discovered two such desired products, 23a and 23b (Scheme 1.9), when they used libraries of 4-CR products for their systematically planned search, which also included mathematically oriented methods.

Recently, the Merck Research Laboratory demonstrated an important example.48 Initially the HIV protease inhibitor Crixivan (MK 639) 29 (Scheme 1.10) could not be prepared very well by a complicated conventional multistep synthesis, but 29 became available when it was prepared by an easier synthesis, whose essential step was accomplished by a U-4CR.

Park et al.49 used U-4CR libraries to prepare Ras-Raf protein-binding compounds like 30 that are active against HIV. The patented product 31 has been formed by Lockhoff50 at the Bayer AG using a U-4CR of four different protected glucose derivatives that were later deprotected. The product 32 of


(b: R = /»-hydroxy-benzoyl) Scheme 1.9 Thrombine inhibitors by Weber et al.

Domling et al.51 can be prepared very easily by the U-4CR. This compound is related to the PNA compounds of Nielsen.52

Many cyclic products have been formed by U-4CRs from multifunctional educts. This is illustrated here by a few examples (Scheme 1.12).

The synthesis of the penicillin-related compound 39, introduced in 1962, begins with an A-4CR of 37a, which is hydrolized into 37b. This undergoes a U-4CR with isopropyl-isocyanide 38 and forms 39.53 During the following decades, a large variety of antibiotically active b-lactam derivatives was produced.54 Recently 42, compound 43, and one of its stereoisomers were stereospe-cifically prepared by U-4CRs.55

"NH2 26


CHO O 28


Crixivan Ugi Reaction
Scheme 1.10 Synthesis of Crixivan (MK 639).





30 31 32

30 31 32

Scheme 1.11 Biologically active compounds synthesized via U-4CR.

A variety of cyclic products have been prepared from educts containing carbo-nyl as well as carboxylic groups. Thus, Hanusch-Kompa and Ugi56'57 prepared a large number of five-membered cyclic gamma-lactam compounds like 44 from levulinic acid. Other carbonylic acids can lead to compounds like 45, which is made from phthalaldehyde acid, valine methylester, and tert-butylisocyanide. The products like 46 and 47 can result from the U-4CR and further cyclization.

In addition, the six- to eight-membered lactams like 48, 49,58 and 5059 have been formed from amines, carbonyl-carboxylic acids, and isocyanides (Scheme 1.14).

Product 56 (Scheme 1.15) with a particularly complicated structure was prepared by the U-4CR of 51 -54, followed by a few further steps.60

33 36

Me Me

Me i-Pr-NC

Me Me

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