Formamidines activity

One aspect of the reactivity of unsymmetrical formamidines such as those shown in Scheme 6 is the selective deprotonation at a benzylic position. This selectivity was used in the illustrated synthesis of nicotine, which also demonstrates the mild conditions for removal of the formamidine activating group by hydrazinolysis. ... 

Typically, an acetanilide (1 mol. equiv.) was treated with the Vilsmeier reagent generated from POCI3 (7 mol. equiv.) and V,V-dimethylformamide (DMF, 2.5 mol. equiv.) at 75 °C for 4 - 20 h. The reaction products were readily obtained by filtration after pouring the reaction mixture onto ice-water minor reaction products were isolated after basification of the filtrate. A variety of acetanilides were studied under these optimised reaction conditions and some significant observations were noted. Activated acetanilides 3 [e.g. R = 4-Me (70%), 4-OMe (56%)] reacted faster and in better yield to give quinolines 4 than other strongly deactivated systems 3 [e.g. R = 4-Br (23%), 4-Cl (2%), 4-NO2 (0%)] — in these cases, formamidines 5 and acrylamides 6 were the major reaction products. 

Continuing his studies on the metallation of tetrahydro-2-benzazepine formamidines, Meyers has now shown that the previously unsuccessful deprotonation of 1-alkyl derivatives can be achieved with sec-butyllithium at -40 °C <96H(42)475>. In this way 1,1-dialkylated derivatives are now accessible. The preparation of 3//-benzazepines by chemical oxidation of 2,5- and 2,3-dihydro-l/f-l-benzazepines has been reported <96T4423>. 3Af-Diazepines are also formed by rearrangement of the 5//-tautomers which had been previously reported to be the products of electrochemical oxidation of 2,5-dihydro-lAf-l-benzazepine <95T9611>. The synthesis and radical trapping activities of a number of benzazepine derived nitrones have been reported <96T6519, 96JBC3097>. 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

Fig. 11.10. Mechanism postulated for activation of formamidines (11.67) as potential prodrugs of anti-HIV nucleoside analogues [103]...

Amidines. After the initial observation that formamidines are agonists for OA receptors in the firefly (14,15 58), these compounds have been shown to mimic OA in virtually every insect system known to contain OA receptors, including the DUMETi system (59)f the glandular lobe of the corpus cardiacum (60) and the fat body ( ) of the locust, and various CNS adenylate cyclase preparations (26-28). The structure-activity relations of amidines as octopaminergic agonists have been examined in several systems including adenylate cyclase stimulation in the firefly lantern and... 

Formamidines at 1.0 yM. Formamidines at 0.02 yM. jInduction of locomotor activity. Behavioral syndrome. 

Stereoselective alkylation of racemic lithiated 4- < r -butylpiperidines using formamidine or urethane activating groups is possible62. 

Nucleophilic attack at the fully conjugated 1,3,5-triazine usually results in ring cleavage. Thus, active methylene compounds react with 1,3,5-triazine in aminomethylenation reactions. A three-component reaction of cyclopentadiene with 1,3,5-triazine and a secondary amine leads to /V,7V-di substituted pentafulven-6-amines (304) and N2-(6-pentafulvenyl)formamidines (305)... 

Some results of this inhibitor screening are summarized in Table 1. It is immediately clear that formamidine acetate and its N-alkylated derivatives are good dehalogenation inhibitors. The selectivity achieved is comparable to that of dicyandiamide while the hydrogenation time observed is considerably lower. Compared to the unmodified system, the other inhibitors do not show a significantly improved selectivity but have a positive effect on the activity. 

Meyers, A. I. Milot, G. a-Alkylation and stereochemistry of cis- and trans-decahydroqui-nolines mediated by the formamidine and Boc activating groups. Synthesis of pumiliotoxin C.J. Am. Chem. Soc. 1993, 335, 6652-6660. Elworthy, T. R. Meyers, A. I. The configurational stability of chiral lithio a-amino carbanions. The effect of Li-O vs Li-N complexa-tion. Tetrahedron 1994, 50, 6089-6096. 

Formamidines have been recognized as good activators for the a-deprotonation of amines at the a-position.141 Trapping the anions with trimethylchlorosilane led to the corresponding SMA.142... 

Formamidines also activate secondary centres towards lithiation, and have been used extensively in the synthesis of the benzylisoquinolines, where the lithiation takes place at a benzylic position. Formamidines bearing chiral substituents (for example the serine-derived 85) allow the introduction of asymmetry at such centres.58... 

Metallation-alkylation of chiral formamidine derivatives of 1,2,3,4-tetrahydroisoquin-oline provides optically active 1-alkyl-1.2,3,4-tetrahydroisoquinolines. The formam-idines of 10 optically active amino alcohols have been examined as the chiral auxiliaries and of these, the bistrimethylsilyl ether 2 (S.S-BISPAD) of 1 proved to be the mc>st efficient as well as consistent (equation II). The configuration (S) was established by synthesis of the benzoquinolizine (S)-5, a degradation product of an alkaloid. 

Reaction of dimethylformamide dimethyl acetal or formamidine with chiral 1,2-diamines provides optically active imidazolines <1997JOC3586, 1997JMC2931, 20040L43> (Scheme 311). In these examples, the 2-position in the imidazolines is unsubstituted. 

Even though the diethylbutanamides are cleavable, the conditions required are quite harsh aqueous hydrochloric acid at reflux for 3 d. A much better activating group was introduced in 1980 by Meyers the formamidines shown in Scheme 5. The decreased reactivity of the C-=NR bond relative to the bond toward nucleophilic attack obviates the need for a bulky group to shield the carbonyl carbon. In the initial report, both N-cyclohexyl-, N- -butyl- and N-f-butyl-formamidines were employed, but subsequent reports have focussed on the latter. 

Compounds that alter insect behavior in other ways may also be useful e.g. chemicals that increase insect locomotor activity should enhance the uptake of pesticides from treated surfaces. Such compounds are already known among the formamidines insecticides and their relatives that stimulate octopamine receptors (12), and further research in this area of pest biochemistry could reveal other locomotor stimulators such as phosphodiesterase inhibitors. A... 

Interest in octopamine receptors has grown with the discovery that a novel group of pesticides, the formamidines, are octopamine agonists (95). Thus chlordimeform (CDM) or demethylchlordimeform (DCDM) are able to activate octopamine receptors in firefly lantern (95,96), tobacco hornworm central nervous system (88), locust skeletal muscle (97), locust oviduct muscle (91,), locust corpora cardiaca (98), locust fat body (99). and cockroach haemocytes (39). 

One problem with the formamidines as pesticides is that their range of activity is limited to a relatively few insect species (25) This species selectivity appears to be directly related to the ability of the compounds to activate adenylate cyclase activity in different insects. For example, as shown in Table I, we have... 

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