Sequential nucleophilic substitutions

Reaction of 1-tetralone with aryl cyanides or methyl thiocyanate, followed by aromatisation with DDQ gave good yields of benzoquinazolines. The further transformation of the methylthio product 31, via oxidation and selective sequential nucleophilic substitution of the resulting sulfones, illustrates the utility of this substituent. 2-Tetralone reacted similarly but substantial amounts of by-products were formed <06T2799>. 

The use of alkyl esters in place of ketones resulted in the formation of alkoxypyrimidines 33 which could be converted in high yields, via selective sequential nucleophilic substitutions, into amino dialkoxy and trialkoxy pyrimidines 34 <06EJO3332>. 

Dimethyl A(-cyanoisothiourea (126) can undergo sequential nucleophilic substitution by an amine followed by methylhydrazine to give the corresponding -methyltriazole. A number of closely related reactions are known (Scheme 22) <82JHC1157,83CB1547,84H(2i)580,87JHCH89,88JOC3120>. 

It is possible to displace the amino groups. Thus melamine is hydrolyzed to cyanuric acid by sequential nucleophilic substitution of the amino groups. Similarly, the amino groups are transaminated with alkyl or aryl amines at high temperature (58CRV131). The amino-... 

Scharn, D., Germeroth, L., Schneider-Mergener J. and Wenschuh, H., Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines a novel approach to cyclic peptidomimetics, /. Org. Chem., 2001,66, 507-513. 

New Strategies for the Solid-Phase Synthesis of Highly Functionalized, Small Molecules Sequential Nucleophilic Substitutions on Polymer-Bound Polyelectrophiles... 

FG = NR2, OH, SH protective groups are not required Sequential nucleophilic substitutions ... 

Various examples of 2-fold sequential nucleophilic substitutions on insoluble supports have been reported in the literature. Suitable polyelectro-philes are polyhalo triazines, pyrimidines, and purines, and the most common nucleophiles are amines, thiols, and phenols. The use of 2,3-dichloropropionic acid18 and 4,5-difluoro-2-nitrobenzoic acid19 is discussed below to illustrate the scope and limitations of this strategy for the preparation of lead-like compound arrays. 

Fig. 2. Two-fold sequential nucleophilic substitution at support-bound 2,3-dichloropro-pionic acid for the synthesis of 3-amino-2-thiopropionic acid derivatives. X = O, NR.

Fig. 3. Examples of products prepared by sequential nucleophilic substitution at support-bound 2,3-dichloropropionic acid derivatives. Purities were determined by HPLC monitoring at 214 nm.

Fig. 5. Examples of substituted benzamides prepared by 3-fold sequential nucleophilic substitution on an insoluble support.

The technical assistance of Henrik Stephensen during the development of sequential nucleophilic substitutions at support-bound 2,3-dichloropropionic acid is gratefully acknowledged. Thanks are also extended to Marie Grimstrup, who optimized the synthesis of substituted benzamides. 

The sequential nucleophilic substitution Barbier additions are controlled by the diflerent rates of reduction of the alkyl halides or the tether length, if the... 

Not all substitution reactions under basic conditions occur with simple inversion. Sometimes, nucleophilic substitution at stereogenic C proceeds with retention of configuration. In such a reaction, two sequential nucleophilic substitutions have usually occurred. For example, the reaction of a-diazoniocarboxylic acids with nucleophiles such as Cl occurs with retention. In the first Sn2 substitution, the O of the carboxylate acts as a nucleophile, displacing N2 with inversion to give a three-membered ring (an a-lactone). In the second Sn2 substitution, Cl displaces O with inversion to give the product with overall retention. 

Sequential nucleophilic substitution reactions involving tetrafluoropyrimidine and a range of nucleophiles would, in principle, lead to the synthesis of many novel polyfunctional pyrimidine derivatives. Highly functionalized pyrimidine derivatives are of great importance to the life science industries and, indeed, many pyrimidine derivatives have been used for various medicinal applications.However, the use of tetrafluoropyrimidine as a starting material for the synthesis of a range of... 

Han [49] reported a diastereoselective method for the synthesis of P-chiral phosphine oxides. The sequential nucleophilic substitution of 1,3,2-... 

There is one example reported by Koizumi and co-workers where phosphinates were prepared from bicylic oxazaphospholidine oxides or sulfides by the sequential nucleophilic substitution and acidic methanolysis (Scheme 4.52). 

The high selectivity in sequential nucleophilic substitution in perfluorodiazines made them attractive scaffolds for the synthesis of a diverse array of polysubstituted diazines. These approaches were recently developed by Stanford group. Thus, tetra-fluoropyritnidine may be used as a scaffold for the synthesis of a range of 2,4,6-trisubstituted pyrimidine derivatives upon sequential displacement of the fluorine atoms attached to the strongly activated 4-, 6- and 2-positions (Table 9) [158]. The first two substitutions proceed in very mild conditioned (0 °C or room temperature). The last nucleophilic substitution of fluorine at 2-position proceeds in harsh conditions and needs MW heating. 

Pattison G, Sandford G, Yufit DS, Howard JAK, Christopher JA, Miller DD (2009) Polysubstituted pyridazinones from sequential nucleophilic substitution reactions of tetra-fluoropyridazine. J Org Chem 74 5533-5540... 

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