Synthesis of 4,8,9,10-Tetrafunctionalized 2-Azaadamantanes and Their 2-Azaprotoadamantane Skeleton Isomers

doi:10.6023/cjoc202210027

Abstract

The multi-step synthesis of rigid and multifunctionalized azaadamantane skeletons from small molecules has always been a challenge in the field of adamantane chemistry. In this work, the bisepoxidized intermediate was obtained via ketalization, bromination, elimination, and Prilezhaev oxidation using bicyclo[3.3.1]nonane-2,6-dione as the raw material, which was then ammonolyzed and cyclized to generate 9,10-dihydroxy-2-azaadamantane-4,8-dione bis(ethylene ketal) with ammonia at 120 ℃. After that, 9,10-dinitroyloxy-2-nitro-2-azaadamantane-4,8-dione bis(ethylene ketal) was synthesized by N,O-nitration with the overall yield of 10% over six steps. Furthermore, when the bisepoxidized intermediate was ammonolyzed at 135 ℃, a skeleton isomer 4,10-dihydroxy-2-azaprotoadamantane-5,9-dione bis(ethylene ketal) was formed, which was then transformed to the corresponding O-nitrated and N,O-dinitrated derivatives through N-acetylation, deketalization and nitration, respectively. These provide a reliable method for the subsequent derivation of multifunctional 2-azaadamantane and its skeleton isomer 2-azaprotoadamantane, which might be used as basic scaffolds for high energy density cage-like compounds.

Key words: azaadamantane, azaprotoadamantane, functionalization, ammonolysis, cyclization, nitramine, synthesis design

Cite this article

Rongbin Cai, Bing Li, Qi Zhou, Longyi Zhu, Jun Luo. Synthesis of 4,8,9,10-Tetrafunctionalized 2-Azaadamantanes and Their 2-Azaprotoadamantane Skeleton Isomers[J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2217-2225.

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Fig. & Tab. 7

Figure 1. Representative compounds bearing azaadamantane skeleton

Figure 2. Synthetic strategy of 4,8,9,10-tetrafunctional-2-azaadamantane

Scheme 1. Attempts at the epoxidation of bicyclo[3.3.1]nona-3,7-diene-2,6-diol/dione

Scheme 2. Construction of 9,10-dihydroxy-2-azaadamantane-4,8-dione bis(ethylene ketal) and its skeleton isomer

Entry	Temp./℃	Time/h	Recovery^b/% of 9	Yield^b/% of 12/14
1	100	24	86	<5/0
2	105	24	81	8/0
3	110	24	73	12/0
4	115	24	64	21/0
5	120	24	53	30/0
6	125	24	50	26/7
7	130	24	46	19/18
8	135	24	40	14/26
9	140	24	39	12/24
10	120	36	36	37/0
11	120	48	30	42/0
12	120	60	25	40/0
13	135	36	36	18/33
14	135	48	27	17/39
15	135	60	18	11/36
16^c	120	48	34	38/0
17^c	135	48	28	13/36
18^d	135	48	—	96/0

Table 1. Optimization of ring closing reaction conditions for ammonolysis

Scheme 3. Nitration of 9,10-dihydroxy-2-azaadamantane-4,8- dione bis(ethylene ketal) and its isomer

Figure 3. Crystal structures of compounds 17 and 19?H2O

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4,8,9,10-四官能化的2-氮杂金刚烷及其2-氮杂原金刚烷骨架异构体的合成