Selective Monoderivatization of Propane‐1,3‐diamine with Acid Chlorides: ‘Hexahydropyrimidine method’ vs. statistic methods

Abstract

The selective N-monoderivatization of propane-I ,3-diamine (5) with carbonyl and sulfonyl chlorides via 2-phenylhexahydropyrimidine (6) was compared with the direct statistic monoderivatization. It was found that, under optimized conditions, both methods are competitive to one another, depending, however, strongly on the reactivity of the electrophile used. The 'hexahydropyrimidine method' is more reliable with respect to yields, which are moderate but invariably between 54 and 69%, whereas the 'statistic method' leads in certain cases to exceptionally high yields (up to 96%), in others, however, almost none.Introduction. -Naturally occurring polyamines have been shown to be important in living cells. For instance, they show high affinity towards nucleic acids and provide numerous effects on nucleic-acid biosynthesis and metabolism [ 11. Not only the polyamines but also natural and artificial polyamine derivatives display [2-51 various physiological activities. Polyamines are also used as spacer elements for the interconnection of receptor pharmacophores to form unsymmetrical bivalent ligands [6] or for the linkage of pharmacophores with alkylating or photolabile groups to generate affinity labels [7]. For the chemical synthesis of such physiologically interesting derivatives, polyamines in their terminally N-monoprotected form represent the starting material of choice [S-141. Preparation of these compounds, however, is not facile [3] [15], not even in the simplest cases of the synthesis of N-monoderivatized alkane-a,w-diamines.In [16], we have reported that N-substituted propane-l,3-diamines can efficiently be monoderivatized at the secondary N-atom using a hexahydropyrimidine intermediate of type 1. We have proposed that heterocycles of type 1 rapidly undergo ring opening to imino-amino species of the type 2, which, in turn, react with eletrophiles to compounds of type 3. These gave, after hydrolysis, rise to the corresponding diamine derivatives of type 4 (Scheme 1). The hexahydropyrimidine moieties acted in this reaction sequence as the precursors of the protecting imino groups for the aliphatic primary amines. Since this procedure should invariantly lead to analogous products starting from hexahydropyrimidines that are not substituted at the N-atoms, we expected the hexahydropyrimidine protocol for monoderivatization of propane-l,3-diamine (5) to be a competitive alternative to the statistic methods used so far [17-221.We describe in this paper our results obtained with 2-phenylhexahydropyrimidine as the precursor of N-monofunctionalized propane-l,3-diamines 12 a-d (Scheme 2) and compare our findings to results of an optimized statistic derivatization method.

Asymmetric Cyclopropanation of Allylic Alcohols Employing Sulfonamide/Schiff Base Ligands

“…Methods to monoderivatize trans -1,2-diaminocyclohexane have generally resulted in formation of substantial amounts of mono and bis(derivatized) products. − …”

“…Methods to monoderivatize trans-1,2-diaminocyclohexane have generally resulted in formation of substantial amounts of mono and bis(derivatized) products. [24][25][26][27] We have found that formation of the aminosulfonamides (1-6) can be cleanly accomplished employing a slight excess of the diamine (1.5 equiv) relative to the sulfonyl chloride (Scheme 1). 18 The reaction was performed in the presence of triethylamine or diisopropylethylamine.…”

Recent Developments in the Ring‐Chain Tautomerism of 1,3‐Heterocycles

“…The reactions of the methyl or ethyl-substituted hexahydropyrimidines occurred mainly on the cyclic tautomer to yield compounds 108 or 110, while for isopropyl-or phenyl-substituted compounds, derivatives of the open forms 107 and 109 were the main products (Scheme 34). [47] For chiral 1,3-O,N-heterocyclic derivative 111, obtained from (2S,3S)-2,3-diamino-1,4-butanediol and salicylaldehyde or 3,5-di-tert-butylsalicylaldehyde, the ring-chain tautomeric equilibria were strongly shifted towards the open tautomer 111A. The Mn 3ϩ complexes 112 of the open form were tested as chiral catalysts for the epoxidation of indene 113.…”

Monofunctionalization of Symmetric Difunctional Substrates

“…The selectivity of acylations or alkylations of polyamines can also be modulated by protonation [78] or by conversion to cyclic aminals [71,79,80]. The latter strategy has, for instance, been used successfully for the preparation of monofunctionalized 1,4,7-triazacyclononanes (Scheme 10.18).…”