The Unions Of The Ucr And Further Reactions

Already in the early days of the U-4CR, several types of 5CRs were found.3,72 It was also observed long ago that an autoxydizing 6-component reaction of two iso-cyanides took place besides the main U-4CR,73 and the structure of one of these by-products was determined by an X-ray measurement.74 The reaction mechanism of such autoxydation was determined75 by the assistance of the computer program RAIN.76 At that time it was not yet known that the MCRs of isocyanides with more than four educts proceed by different reaction mechanisms.

The new era of isocyanide chemistry was determined by two aspects. First, it was the formation of products by MCRs with high numbers of educts and second, the recently initiated search for new desirable products in libraries of MCR

— ¡-Pr-CHO + NH3 + NaSH + BrCMf^-CHO + C02 + MeOH 64 35 34 36 65 66

t-Bu-NC 27

t-Bu

HN-Tif C02Me i-Bu o

f-Bu-NC 27

+ Me0C02H 67

+ Me0C02 70

Scheme 1.17 The first 7-CR.

products.1 In 1995, the chemical industry began to search for new compounds in the libraries of products formed by the U-4CR and related reactions.

Using this new technology, a single chemist can now form more than 20,000 new compounds a day, whereas before a good chemist could accomplish up to 10,000 syntheses in the 40 years of his or her professional life. MCRs are especially suitable for the formation of libraries, since they have the big advantage that their products can be prepared with a minimum of work, chemical compounds and energy, and in essentially higher yields than by conventional methods.

In 1993 the first MCR composed of seven educts was introduced,77 and it was soon recognized that such higher MCRs are usually unions39 of the U-4CR and additional reactions.38 In the first 7-CR, the intermediate 63 was formed by an A-4CR and underwent with the equilibrating product 67 the a-addition of the cations and ions onto the isocyanide 27. Finally, this a-adduct, 69, rearranges into the final product, 71 (Scheme 1.17).

The variety of educts and products of the higher MCRs is illustrated here. Product 72 (Scheme 1.18) is formed from the five functional groups of lysine, benzaldehyde, and tert-butylisocyanide.78 The synthesis of 73 is achieved with hydrazine, furanaldehyde, malonic acid, and the isocyano methylester of acetic acid,57,79 compound 74 results from the reaction of benzylamine, 5-methyl-2-furanaldehyde, maleic acid mono-ethylester, and benzylisocyanide.80 Zhu et al.81 prepared a variety of related products, such as, 75, from O-amino-methyl cinnamate, heptanal, and a-isocyano a-benzyl acetamides.

HN"

N^C02Me s

N^C02Me

.C02Et

Scheme 1.18 Products of higher MCRs.

NH,C1

COOH

OH N1l ccCH0+

COOMe

1.U-4CR

2. Pictet-Spengler

Bu-NC CHO 3.02

82 27 83

Scheme 1.19 Polycyclic products of higher MCRs.

COOMe

1.U-4CR

2. Pictet-Spengler

84 85 86

MeOH n.

MeOH n.

88 COOMe

88 COOMe

Scheme 1.20 Heterocycle formation by MCRs.

,NMe2

MeOOC NC

89 64

Scheme 1.21 MCR employing a thioacid.

COOMe h2n

.NMe2

MeOOC NC

89 64

86 COOMe

Scheme 1.22 Examples of MCRs with up to nine reacting functional groups.

In the last decade, Bossio et al.82 have formed cyclic products of many different types by using a variety of new MCRs. Thus, 80 was made from 76-79 (Scheme 1.19). Recently, Domling and Chi83 prepared 83 from 81, 82, and 27, and synthesized similar polycyclic products from other a-aminoacids with 82 and 27.

In 1979, Schollkopf et al.84 formed a-isocyano-b-dimethylamino-acryl methyl esters 86, and Bienayme prepared many similar isocyanides,85 which can undergo a variety of heterocycles, forming reactions like the synthesis of 88 86 from 84 - 87 (Scheme 1.20).

Domling et al.87 made react b-amino butyric thioacid, 89, the isobutyraldehyde 64, and 86 into the product 90, which simultaneously contains a B-lactam group and a thiazole system.

A variety of MCRs with seven to nine functional groups of several pairs of educts can be carried out, as is illustrated by the four subsequent reactions.88-90 (Scheme 1.22).

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