Dynamic NMR

The stereodynamic behavior of 1-arylpyrrolidin-2-imines, having a C aryl −N stereogenic axis, has been studied by means of dynamic nuclear magnetic resonance and density functional theory calculations, evaluating the steric effect of ortho-aryl substituents. The rotational barrier due to E/Z isomerism about the −CN−H bond was also determined. The dynamic stereochemistry of homologous six-and seven-membered iminoazacycloalkane rings and their oxo-analogues was also comparatively investigated, evidencing a ring size effect. It was found that the seven-membered heterocycle shows additional dynamic features because of ring inversion. ■ INTRODUCTION Many drugs containing small-ring nitrogen heterocycles exhibit a wide range of biological activities, 1 and it is widely reported that the potency and selectivity are strongly sensitive to the conformational constraints, as the ring size enlarges from five to seven members. The combination of ring size and the appropriate spatial and steric properties of the substituents bonded to the ring lead to the preparation of potent and selective drugs of great interest in medicinal chemistry. In particular, 2-iminoazaheterocycles are potent inhibitors of human nitric oxide synthase (iNOS), 2 and a recent synthesis of 1-aryl-2-iminoazacycloalkanes from ω-halonitriles using poly-phosphoric acid esters such as ethyl polyphosphate (PPE) or trimethylsilyl polyphosphate (PPSE) 3 gave the possibility to study the conformational behavior about the N-aryl stereo-genic axis in five to seven membered heterocyclic rings. These compounds can be easily converted into their oxo-analogues by exposure to air (Scheme 1). Examples of dynamic conformational analysis due to a C sp 2 −N stereogenic axis have been reported: 4 barbiturates are the most studied class of biologically active compounds, 5 and lactams, 6 pyrroles, 7 indoles, 8 imides, 9 azalidine-4-ones, 10 thiazolidine-2-thiones, 11 and xanthines 12 are found to exhibit stereodynamic properties. 1-Aryl-2-iminoazacycloalkanes are expected to have the plane of the ortho-substituted phenyl ring significantly twisted with respect to the time-averaged plane of the five-, six-, and seven-membered heterocyclic ring. The existence of such an Ar−N stereogenic axis would originate, in principle, a pair of stereolabile enantiomeric forms when the rotation rate is rendered sufficiently slow in the nuclear magnetic resonance (NMR) time scale. The aim of this paper is a thorough investigation of the stereodynamic behavior of a new class of compounds having a C aryl −N stereogenic axis in a five-membered saturated ring, 13 (1-arylpyrrolidin-2-imines 1−9 and their oxo-analogues 18−20 Scheme 1), and the evaluation of the steric effect of the ortho-aryl substituents. Moreover, the six-and seven-membered imino homologues (10−13 and 14− 17, respectively) and their oxo-analogues 21−22 have been prepared to evaluate the effect of the ring size and of the exocyclic heteroatom on the N-aryl rotational barrier. ■ RESULTS AND DISCUSSION When an ortho-substituted aryl ring is bonded to pyrrolidin-2-imines (Scheme 1), the steric hindrance caused by the ortho-substituent forces the aryl ring to adopt a skewed conformation with respect to the almost planar heterocyclic ring, thus generating a stereogenic axis and a pair of conformational enantiomers when the rotational barrier is frozen; depending

A series of 5-aza-9-deaza- analogues of purine was effectively prepared using highly selective annulation of 1,3,5-triazine ring onto 5-aminopyrazole-4-carboxylates via a one-pot, multicomponent, microwave-assisted approach. The products were obtained in good yields and high purity. This catalyst-free method was demonstrated to be scalable and highly reproducible in different microwave reactors. Some structural features of the prepared compounds were studied in details using dynamic NMR spectroscopy and X-ray crystallography.