Formamidines alkylation

Propyl-1-azacycloheptane has been prepared by reduction of 2-aza-l-oxo-3-propylcycloheptane with lithium aluminum hydride, and from azacycloheptane by conversion to its formamidine, alkylation with 1-iodopropane, and subsequent hydrazinolysis... 

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>. 

Because silylation with HMDS 2/TCS 14 in acetonitrile at ambient temperature converts the unreactive a-chloroketone moiety of 743 into an /Z-mixture of reactive alkyl 4-chloro-3-trimethylsilyloxycrotonates 746a, b [230, 231] which can be isolated and distilled, if humidity is excluded, silylation of 743a, b in the presence of ami dine salts such as 745 gives the desired ethyl or methyl imidazole(4,5)-acetates 748a, b via IMz and 747b. The reaction of formamidine acetate with 746a,b affords 745 (with R=H) in up to 70% yield [232, 233] (Scheme 5.79). As side reactions one must, e.g., take into account the reaction of 746 with ammonia to give 755 which subsequently dimerizes to the pyrazine 756, as discussed in Section 5.5.3. 

Deprotonation of chiral formamidines of 6,7-dimethoxy- and 6,7-methylenedioxytetra-hydroisoquinolines, followed by alkylation affords 1-substituted tetrahydroisoquinolyl... 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

The mechanism of this sequence is enlightening when contrasted with the mechanism of the formamidine auxiliary (Scheme 56). Scheme 59a illustrates the results of some deprotonation-alkylation experiments on deuteriated diastereomers. ° ° Two features of the product of these experiments were examined the diastereomer ratio and the percent deuterium incorporation. The deuterium incorporation in the product reveals that there is a preference for removal of the -proton. When deuterium is in the -position, this selectivity is opposed by the isotope effect, and the product has about half the original deuterium remaining. When deuterium is in the a-position, the selectivity for the -proton (imposed by the chiral auxiliary) and the isotope effect act in concert, and virtually all the... 

Isoindole is an interesting precursor for successive alkylations at the a- and a -positions because both are benzylic. Oxazoline ° and formamidine auxiliaries have been used to accomplish the a,a -dialkylation to give a C2-symmetric amine. The C2-symmetric amine products are envisioned as possible tools for a variety of asymmetric processes. The diastereoselectivity of the second alkylation is enhanced by the presence of the stereocenter formed in the first alkylation (Scheme 61). ° Several other electrophiles were evaluated with the formamidine auxiliary. ... 

A similar result has been achieved using heterocyclic formamidine derivatives (Scheme 31) (81TL5119). In addition to alkyl halides, aldehydes were also suitable electrophiles in this reaction. 

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

Die Umwandlung von (2-Oxo-alkyl)-l, 2,4-triazolium-Salzen mit Natriumhydrid in Dimethyl-formamid fiihrt zu 4-Acyl-5-amino-imidazolen. Diese Reaktion verlauft iiber offenkettige N-Cyan-formamidine, was in einem Beispiel durch Isolierung des N-Cyan-formamidins und dessen thermische Cyclisierung zum 4-Acyl-5-amino-imidazol nachgewiesen wurde. Die Ausbeuten liegen im allgemeinen um 30%. In einem Fall wurden 60% Ausbeute erzielt [5-Amino-l-(4-chlor-benzyl)-4-(2,4-dichlor-benzoyl)-imidazol Schmp. 220°]373 ... 

A typical example of the reaction of isocyanates with formamidines is shown in equation (92). Alkyl isocyanates can react in a similar way, but there can be mixed products formed under certain circumstances, as in the reaction of methyl isocyanate with N,N- dialkyl-N 1-arylformamidines (166). The predicted product (167 equation 93) is formed except when AT,AT-dimethyl-N-arylformamidines are used. In the latter case a mixture of (168) and (169) is formed (equation 94). The mechanism of the formation of (169) is shown in Scheme 104 (73HCA776). 

N==Ca+—Aua which makes the isocyanide ligands susceptible to nucleophilic attack and has led to formation of carbene complexes, iminoalkyl complexes and catalytic conversion of isocyanides to formamidines using alkyl or aryl isocyanide complexes of gold(I).301,402 4(y7-409-415 A review of this significant work has been published.16... 

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. 

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

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