Cleavage cyclative

Fig. 19 Synthesis and cyclative cleavage of 2,4,6-trisubstituted pyrimidines using microwave-assisted solid-phase protocol. Reagents and conditions a DMF, camphorsul-phonic acid, MW 80 °C, 30 min, open vessel b EtONa, EtOH/THF (4/1), MW 130 °C, to min, closed vessel. Y = O, NEt2 R = Me, i-Pr R = Et R" = H, alkyl, cycloalkyl, aryl, benzyl R" = H, Me, Et...

Fluorous Synthesis of Dihydropteridinones by Microwave-Assisted Cyclative Cleavage... 

Dichloro-2( lff)-pyrazinones 273 Dihydropteridinones, fluorous synthesis, cyclative cleavage 113... 

Libraries of the pyrazino[2,l-A [l,3]oxazines 373 with variable R1 and R2 substituents were synthesized on solid phase, the last step being the cyclative cleavage of 372 with formic acid (Equation 42) <2002W02002/092010>. 

Scheme 7.49 Preparation of bicyclic dihydropyrimidinones employing cyclative cleavage.

Alternatively, pyrrolo[3,4-d]pyrimidine-2,5-diones were synthesized using the same pyrimidine resin precursor, which was first treated with a representative set of primary amines to substitute the chlorine. Subsequent cyclative cleavage was carried out as described previously, leading to the corresponding pyrrolopyrimidine-2,5-dione products in high purity but moderate yield. 

Pyrimido[4,5-d]pyridazine-2,5-diones were synthesized in a similar manner, employing several hydrazines (R3 = H, Me, Ph) for the nucleophilic substitution prior to cyclative cleavage. Due to the high nucleophilicity of the hydrazines, reaction times for the substitution step could be reduced to 30 min. In the case of phe-nylhydrazine, concomitant cyclization could not be avoided, which led to very low overall yields of the isolated products. 

In analogy to the thiohydantoin synthesis, the PEG-bound diamines have also been treated with various alkyl and aryl isothiocyanates and, after applying traceless cyclative cleavage, the desired thioxotetrahydropyrimidinones were obtained in excellent yields. In contrast to the thiohydantoin synthesis, purification of the products was more complicated if the excess of isothiocyanate amounted to more than 2.2 equivalents [85],... 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

Scheme 7.79 Generation of dihydropteridinones by cyclative cleavage from a fluorous tag.

Cyclative cleavage strategies release the final compound into solution following intramolecular attack of a nucleophile or electrophile upon the linkage site. Synthesis byproducts and intermediates do not incorporate the necessary nucleophile or electrophile therefore only the desired products are released into solution to yield high purity materials. Seminal examples of this approach are the library syntheses of benzodiazepines and hydantoins (Scheme 3). 

Scheme 3. Cyclative cleavage strategies for the synthesis of (a) benzodiazepines and (b) hydantoins.

Stannane based Hnkers (Tab. 3.8) are used for the StiUe reaction (see below, section 3.3.2.1) onsoHd supports [119]. Nicolaouetal. developed polymer-bound aUcenylstan-nanes to obtain the natural product (S)-zearalenone by an intramolecular StiUe reaction and a cyclative cleavage [120]. 

Cyclative-cleavage strategy is a process in which activation promotes the cleavage, while an intramolecularly located nucleophile, electrophile, radical or another group attacks, so that the product is released from the sohd support (Scheme 3.4). 

Therefore it has to be distinguished from traceless-cleavage. As the intramolecular step is in general faster than any intermolecular step, this strategy provides an additional purification step, because only cychzed structures are detached from the resin. The method of cyclative cleavage by nucleophihc displacement has been... 

Scheme 3.5 Synthesis of 1,4-benzodiazepin-2-ones (83) by cyclative cleavage [172].

Besides nucleophilic attack, cyclative cleavage can be eaffected for example by Stille reactions [120], Wittig olefmation reactions [177], Wittig-Horner [178, 179] or metathesis reactions [180-183]. For more details of C-C-bond formation, see Section 3.3.2. 

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

Campbell J, Blackwell HE (2009) Efficient constmction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri. J Comb Chem 11(6) 1094-1099... 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

Scheme 2.1.3.9 Immobilization of carboxybenzaldehydes 32 on Merrifield resin (31) and synthesis of benzobutyrolactones 34 with dialkylzinc addition using a cyclative-cleavage approach [36].

Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products... 

This category represents the most popular subclass of cyclative cleavage reactions. There are many solid-phase sequences with resin attachment via carboxylic acids, followed by elaboration to a free amine five centers away... 

Fig. 3. Further examples of hydantoin synthesis by cyclative cleavage.

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