Synthesis and characterization of phenyl(1,3,6,8-tetraazatricyclo[4.3.1. 13,8]undecan-4-YL)-methanone and its derivatives

Article abstract of DOI:10.3987/COM-13-12897

A quick and highly efficient method for the synthesis of phenyl(1,3,6,8-tetraazatricyclo[4.3.1.1^3,8]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.

Full text of DOI:10.3987/COM-13-12897

HETEROCYCLES, Vol. 89, No. 3, 2014
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HETEROCYCLES, Vol. 89, No. 3, 2014, pp. 627 - 630. © 2014 The Japan Institute of Heterocyclic Chemistry
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, Beijing 100081, China
e-mail: dairongji@bit.edu.cn
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
N
N
N
N
N
N
N
N
N
N
N
N
1
2
4
3
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.
Scheme 1. Reaction of pentafluorophenacyl bromide with hexamine

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HETEROCYCLES, Vol. 89, No. 3, 2014
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.
Scheme 2. Plausible mechanism for the Stevens rearrangement
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).
Table 1. Optimization of reaction conditionsa

HETEROCYCLES, Vol. 89, No. 3, 2014
629
entry
1
2
3
4
5
6
7
8
solvent
anisole
toluene
ethylene glycol
pyridine
DMF
T (ºC) time (h) yield (%)b
90
90
90
90
90
90
110
70
50
30
70
70
70
2
2
2
2
2
2
2
2
2
19
29
67
34
87
23
81
89
82
32
84
90
88
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
2
0.5
1
3
a hexamine (3 eq) was used.
b isolated yield.
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).
Table 2. Reaction scope of 2-bromo-1-arylethanonesa
entry
Ar
product yield (%)b
1
2
3
4
5
6
7
8
9
Ph (5a)
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
91
89
90
90
92
93
93
92
81
4-MeC6H4 (5b)
3-MeOC6H4 (5c)
4-MeOC6H4 (5d)
4-PhC6H4 (5e)
3-FC6H4 (5f)
4-ClC6H4 (5g)
4-CF3C6H4 (5h)
2-thienyl (5i)
2-naphthyl (5j)
10
6j
a hexamine (3 eq) was used.
b isolated yield.

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HETEROCYCLES, Vol. 89, No. 3, 2014
Figure 1. The X-ray molecular structure of 6d
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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