Formation of novel thiazolomorphinans and thiazoloaporphines Levente Gira ´n, Sa ´ ndor Bere ´ nyi, Attila Sipos * Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary article info Article history: Received 2 June 2008 Received in revised form 3 August 2008 Accepted 21 August 2008 Available online 28 August 2008 Keywords: Morphinandiene Aporphine Acid-catalyzed rearrangement Kaufmann-type thiazole formation Microwave promotion DFT calculations abstract A novel strategy has been developed for the synthesis of ring A fused thiazolomorphinans and ring D fused thiazoloaporphines offering the possibility of formation of regioisomeric products. The conven- tional thermal thiazole-forming reaction was replaced with microwave initiation and a detailed dis- cussion has been presented on the proposed mechanism of the ring closure. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Thiazole ring systems are widely used structural elements in medicinal chemistry. This structure, especially in the case of 2-amino substitution, has been applied in the development of the treatment of allergies, hypertension, inflammation, schizophrenia, bacterial and HIV infections. 1 Go ¨ rlitzer and Schumann 2a and our research group 2b prepared thiazole-fused morphinans at their ring C in order to test the effect of this novel moiety on the affinity at opioid receptors (Fig. 1). Recently, Neumeyer’s group 3 synthesized ring A fused 2 0 -aminothiazole derivatives of benzomorphans and morphinans to study their opioid agonist properties (Fig. 1). The affinity of these novel series was somewhat reduced from that of their phenol prototypes, one compound has been identified as possessing high affinity and selectivity at the k receptor. The 2-aminothiazole functionality has been successfully applied as a heterocyclic bioisostere of the phenol moiety also in dopamine agonists such as B-HT 920, 4a PD 118440 1d and pramipexole 4b resulting in improved pharmacological properties (Fig. 1). In the last two decades considerable amount of research activity was devoted to the synthesis and pharmacological evaluation of molecules possessing significant D-1 receptor activity with antag- onistic character. 5 Regarding new aporphinoids developed for this neuropharmacological field two different approaches were applied for the formation of these compounds. One of them utilized and substituted natural origin aporphines, such as boldine and pre- dicentrine. 6 The other procedure started with the acid-catalyzed rearrangement of the derivatives of natural morphine yielding R-aporphinoids and then applied a racemization/resolution se- quence. 7 They found the presence of H-bond donor/acceptor 9-OH or H-bond acceptor 9-OCH 3 groups (substituted boldines/pre- dicentrines) besides 8-halo/amino and 10/11-OCH 3 functions favourable. Generally, aporphine backbones with highly function- alized D-rings and substituents having the ability to form H-bonds are considered a promising starting point of the development of D1-active ligands. Ring D fused thiazoloaporphines were also synthesized by our group targeting primarily the D2-receptor subtypes. 2b In the light of these studies on both thiazolomorphinans and dopaminergic thiazolo compounds we decided to form A- and D-ring fused (morphinan and aporphine backbone, respectively) de- rivatives retaining the free phenolic hydroxyl function of the alkaloid skeletons. 2. Results and discussion Our attention turned to the formation of ring A fused thiazolo- morphinans after the successful application of the Hantzsch-type thiazole synthesis for the introduction of this moiety to the ring C of morphinans. 2b We aimed the development of a novel heteroring- forming methodology retaining the highly important pharmaco- phore 3-OH group 8 in order to obtain new, potentially opioid-active compounds with interesting substitution pattern on ring A. The structure of these compounds also offers the opportunity for the * Corresponding author. Tel.: þ36 52512900; fax: þ36 52512836. E-mail address: asipos@puma.unideb.hu (A. Sipos). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.08.069 Tetrahedron 64 (2008) 10388–10394