A new pathway for the preparation of biologically active 2-substituted 1,5-dihydrobenzo[ e ][1,2,4]oxadiazepines and related compounds by palladium-catalyzed cyclization of amidoximes with o -iodobenzyl bromide or 2-bromo-3-chloromethylpyridine

A simple palladium-catalyzed one-pot synthesis of 2-substituted 1,5-dihydrobenzo[ e ][1,2,4]- oxadiazepines from corresponding ( E )-amidoximes and o -iodobenzyl bromide or 2-bromo-3-chloromethylpyridine is described. Of the derivatives prepared 2-[6-(quinolin-2-ylsulfanyl)- hexyl]-1,5-dihydrobenzo[ e ][1,2,4]oxadiazepine exhibits high activity on HT-1080 (hyman fibro-sarcoma) and MG-22A (mouse hepatoma) cancer cell lines.

The structure of compound 17 was supported by single crystal X-ray structural data (Figure 1).The atoms N(4), C(5), C (6) and C (7) in the seven-membered cycle lie in one plane, which correspond to the benzene ring plane of C( 6  The experimental data suggests that the double cyclization forming two large membered rings can be achieved in the case of 2-bromophenyl amidoxime (for example, compound 10).
Our first experiments showed that cyclization of oxime 10 in the system 2-iodobenzyl bromide (11a)/solid Cs 2 CO 3 /Pd 2 (dba) 3 /Xantphos/dry dioxane afforded oxadiazepine 24 as a main product in 32% yield.Bicyclic product 25 was identified by LC-MS and 1 H NMR only in trace amounts because of the side reactions in the synthesis of nine-membered ring (for example oligomerization of intermediate 24 in the presence of palladium catalyst) (Table 1, entry 13).

Scheme 3
The proposed mechanism of formation of desired 1,2,4-oxadiazepines 12-24 included selective oxime O-alkylation leading to an intermediate A, which undergo oxidative addition of (Xantphos)Pd( 0 The above data suggests that similar cyclization reaction was carried out using (E)acetophenone O-(2-iodobenzyl)oxime (28), prepared from acetophenone oxime and 2iodobenzyl bromide (11a), in the presence of base/Pd2(dba)3/Xantphos/dioxane system (Scheme 4).The influence of base on the cyclization of ether 28 to oxazepine 29 was studied.Thus, cyclization of the oxime ether 28 in the system Cs2CO3 (3 equiv)/Pd2(dba)3 (4 mol %)/Xantphos (4 mol %) gave the desired product 29 in 55% yield (GC-MS data).While the replacement of solid dry Cs2CO3 by t-BuOK diminished the yield of product 29 to 45%.The use of solid KOH as base in the palladium-catalyzed cyclization of 29 was essentially ineffective.Unfortunately, product 29 was unstable and therefore was characterized by 1 H NMR and GC-MS only.2).These compounds were selected from a wide range of 3substituted 1,2,4-oxadiazepines because of high activity of corresponding quinoline and thiazole containing N-hydroxy--(hetarylmethoxy or hetarylthio)alkanamidines, the synthesis and cytotoxicity of which were presented in our earlier work.11c Beside this, compounds 19 and 23 formally are masked amidoxime O-benzyl ethers.Thus, compound 23 exhibit high activity on both cancer cell lines.N-Hydroxy-7-(quinolin-2-ylsulfanyl)heptanamidine 11c exhibits similar cytotoxicity to compound 23.However, compound 19 was inactive on the MG-22A and HT-1080 cancer cell lines.
Toxicity of compounds 19 and 23 (LD50 313 and 639 mg/kg) was detected on mouse normal fibroblasts.

Figure 1 .
Figure 1.A perspective view of compound 17 showing the thermal ellipsoids and the atomic labels followed in the text.

Table 2 .
CytotoxicityCytotoxic activity of compounds 19 and 23 was tested in vitro on two monolayer tumor cell lines: MG-22A and HT-1080 (Table