MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem. 2005; 43: 351–358 Published online 21 February 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1553 Low-temperature 1 H and 13 C NMR spectra of N - substituted 1,2,3,4-tetrahydropyrazino[1,2-a]indoles Alan R. Katritzky, 1* Novruz G. Akhmedov, 1 Evgeniy M. Myshakin, 2 Akhilesh K. Verma 3 and C. Dennis Hall 1 1 Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611-7200, USA 2 Department of Chemistry and Center for Molecular and Materials Simulations, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA 3 Dr B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi-110007, India Received 3 December 2004; Revised 22 November 2004; Accepted 13 December 2004 The temperature-dependent 1 H and 13 C NMR spectra of 2-(2-butynyl)-10-methyl-1,2,3,4-tetrahydropyra- zino[1,2-a]indole (4) (as a representative example of 1–9) in CFCl 3 + CD 2 Cl 2 solution are described and discussed. Below 183 K, the hexahydropyrazine ring inversions become slow on the NMR time-scale and 4 exists in principle as two conformational diastereomers. In fact, only one was observed with the N-2 substituent in an equatorial position as shown by a low-temperature NOESY experiment. The energy barrier for conformational interchange was calculated from NMR data to be 8.3 kcal mol -1 (1 kcal = 4.184 kJ), in agreement with quantum chemical calculations. Unambiguous assignments for all proton and carbon resonances of 1–9 were made using 1D (APT, DEPT, NOE difference) and 2D (COSY, NOESY, gHMQC, gHMBC) NMR techniques. Copyright  2005 John Wiley & Sons, Ltd. KEYWORDS: NMR; 1 H NMR; 13 C NMR; DNMR; hexahydropyrazine; conformation; ring inversion; nitrogen inversion INTRODUCTION Compounds containing a hexahydropyrazine ring are of biochemical interest as enzymatic cofactors essential in purine biosynthesis and they also have useful applications as dual antagonists of platelet activating factor (PAF) and histamine and as inhibitors of the HIV protease enzyme. 1 Note on nomenclature: compounds 1 – 9 are correctly referred to as tetrahydro derivatives because the fully unsaturated tricyclic ring system pyrazin[1,2-a]indole is I. However, NMR data of 1 – 9 within this paper are appropriately compared with those from a piperazine (or hexahydropyrazine) ring. Tetrahydropyrazine ring conformations (where two ortho-coupled carbon atoms are fused with a six-membered ring) in solution at room temperature have been stud- ied for 5-formyl 5,6,7,8-tetrahydrofolate. 2 On the basis of spin–spin coupling constants ( 3 J), it was proposed that the tetrahydropyrazine ring is in the half-chair conforma- tion. For 5,6,7,8-tetrahydrofolic acid, it was found that the tetrahydropyrazine ring exists in a roughly equal mix- ture of two half-chair conformations. 3 Similar half-chair L Correspondence to: Alan R. Katritzky, Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611-7200, USA. E-mail: katritzky@chem.ufl.edu conformations were documented for other derivatives of 5,6,7,8-tetrahydrofolic acid. 4 Conformations of hexahydropyrazine rings (where the carbon and nitrogen atoms are not connected to any fused rings) have also been studied by Cross et al. 5 At room temperature and low pH (2.90), a single chair conformation was found for both piperazine rings in the DNA minor groove-binder, Hoechst 32 985. X-ray analytical data showed that some piperazine derivatives adopt a chair conformation with N-substituents at equatorial positions 6a whereas other substituents can adopt a variety of conformations with small energy differences. 6b The piperazine rings of two 2,4,6- tris(amino)-5-triazines were shown, by 1 H and 13 C NMR, to undergo both ring and aliphatic nitrogen inversion, resulting in a dynamic process involving exchange of geminal protons between axial and equatorial environments of chair conformations. 7a Dynamic exchange processes have also been detected through variable-temperature 1 H and 13 C NMR spectra of buspirone and analogues. 7b The conformational equilibria in N,N 0 -dimethylpiperazine have been studied by Anet and Yavari 8a and by Harris and Sprass, 8b and NMR studies of ring and nitrogen inversion have thrown much light on these processes. 9 However, low-temperature NMR studies of tetrahydro- pyrazino[1,2-a]indoles have not been reported. For com- pounds 1 – 9, one nitrogen atom of the hexahydropyrazine ring is attached to a variety of alkyl groups (Scheme 1), and the other nitrogen is fused within the indole ring. In a continuation of our synthetic work 10 and our interest in 1 – 9, which contain the hexahydropyrazine ring system, we present low-temperature spectra of 4 and 7 as representative Copyright  2005 John Wiley & Sons, Ltd.