HETEROCYCLES

Communication | Regular issue | Vol. 89, No. 3, 2014, pp. 627-630
Received, 24th November, 2013, Accepted, 24th January, 2014, Published online, 28th January, 2014.
DOI: 10.3987/COM-13-12897

■ Synthesis and Characterization of Phenyl(1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecan-4-yl)methanone and Its Derivatives

Cong Liu, Rongji Dai,* Guowei Yao, and Yulin Deng*

School of Life Science, Beijing Institute of Technology, 5 South Zhongguancun Street Beijing 100081, China

Abstract

A quick and highly efficient method for the synthesis of phenyl(1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecan-4-yl)methanone and its derivatives from hexamine and 2-bromo-1-arylethanones has been established via a Stevens rearrangement. Structures of the products were characterized by NMR and X-ray crystallography.

1,3,5,7-Tetraazatricyclo[3.3.1.13,7]decane (hexamine or urotropine, 2) is a cage aminal with structure like adamantine (1). It has been widely used in medicinal and materials chemistry, such as the production of phenolic resins and solid fuel tablets.1,2 Besides, hexamine is easily trapped by metal-organic compounds to form various molecular adducts.3,4 The ring-enlargement derivative of hexamine, 1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane5-7 (TATU, 3), which is also applied in organic synthesis, has been the subject of structural and chemical research in recent years.8,9

In 1999, Henry10 combined hexamine and pentafluorophenacyl bromide to generate a complex ring-enlargement product (Scheme 1). The reaction was performed in chloroform for over 24 h and the yield was low. In 2004, Rivera11,12 treated 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD, 4) with ammonium fluoride in water to obtain TATU by cleavage of only one ethylene bridge. A variety of quaternary ammonium salts of TATU could be prepared by Menschutkin reaction.8 However, there have been few reports about modification of TATU at methylene. In this paper, a highly efficient method of synthesizing benzoyl-TATU was created.

When heated at high temperature, hexamine slowly decompose into formaldehyde and ammonia. Based on this characteristics, we designed a new route to synthesize 4-phenyl-1H-imidazole from 2-bromo-1-phenylethanone (5) by employing hexamine to initiate the Debus condensation.13 However, hexamine was transformed into a ring-enlargement product, phenyl(1,3,6,8-tetraazatricyclo- [4.3.1.13,8]undecan-4-yl)methanone (6) in high yield before its decomposition. According to the literature, the mixture of hexamine and 2-bromo-1-phenylethanone yields bromine substitute ammonium salt (7) at room temperature.14,15 The result of our experiment indicated that 7 could transform to amine 6 when the temperature was more than 50 ºC (Scheme 2). This transformation in higher temperature was never reported before. In Henry’s literature,10 a ring-enlargement product of hexamine was obtained through an ortho fluorine elimination and two Stevens rearrangements (Scheme 1). If there was no fluorine on the benzene ring, a one step Stevens rearrangement would lead to benzoyl-TATU 6. The Stevens rearrangement is a transformation from quaternary ammonium salts to amines in the presence of a strong base.16-20 In this reaction, as hexamine itself is a strong base, no additional base was needed.

Based on the initial result, several reaction parameters, such as solvent, temperature, and reaction time were successively investigated for the optimal reaction conditions. The results are shown in Table 1. The solvent optimization disclosed that DMF was the best reaction medium and gave 87% yield (Table 1, entry 5). Other solvents were found to go against this transformation, and much lower yields were observed (Table 1, entries 1-4, 6). Moreover, temperature was crucial for this process. High yields were obtained when the reactions were carried out at more than 50 oC (Table 1, entries 8, 9). Too long time or too high temperature could easily result in by-products (Table 1, entries 7, 13). The best result was achieved when the mixture was stirred at 70 ºC for 1 h (Table 1, entry 12).

Having established the optimal reaction conditions, we explored the scope of this rearrangement process. A series of 2-bromo-1-arylethanones were examined. The results were shown in Table 2. Aromatic 2-bromo-1-phenylethanones 5a-h with electron-neutral, electron-withdrawing or electron-donating substitutions at the benzene ring proceeded well to give good yields (Table 2, entries 1-8). Different substitution at benzene ring had little effect on the yield. This procedure was also performed well with heterocycle and fused ring substrates (Table 2, entries 9, 10). Furthermore, the structure of 6d was confirmed by X-ray crystallography21 (Figure 2).

In conclusion, we have developed a highly efficient approach for the synthesis of phenyl(1,3,6,8- tetraazatricyclo[4.3.1.13,8]undecan-4-yl)methanone and its derivatives from hexamine and 2-bromo- 1-arylethanones through a Stevens rearrangement. The aminal can be converted to TATU in a short time with good yield. Further studies on the applications of the products will be reported in due course.

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