1.4- Diazocin-5 -ones

A number of the purported syntheses of dibenzo[f>,/][l,4]diazocines in the literature have to be revised and the structure of the products corrected.1 Instead of the expected 1,4-diazocine derivatives 1, isoindolobenzimidazoles 2 are actually isolated, the formation of which requires a hydride shift after transannular attack of one imine group onto the other. 

The reaction of 4-phenylbut-3-yn-2-one and TV-alkylated benzimidazoles 9 leads to benzo[b [l,4]diazocine derivatives 10 in very low yields.32... 

The unsubstituted parent 1,5-diazocine (1) is hitherto unknown. Benzannulated systems, however, have been prepared, particularly dibenzo f>,/][l, 5]diazocine and its derivatives which have been intensively investigated due to their pharmacological properties. So far, all compounds synthesized show no evidence for delocalization of the 7t-electrons. One special review on the chemistry of 1,5-diazocines is available.1... 

Photolytic nitrogen elimination from 8f/-quinazolino[3,2-c][l,2,3]benzotriazin-8-one (1) leads to two intermediates, only one of which can be isolated. When the reaction is performed in the presence of nucleophiles, both intermediates react, via ring enlargement, to provide di-benzo[l,5]diazocines.43 In addition to morpholine and methanol, other alcohols or water can be used as the nucleophile. 

From the general structure of 1,2-diheterocines 1 with identical heteroatoms other than the scries with two nitrogen atoms (X — NR, which have already been discussed in Section 1.2. as they can be regarded as 1,2-dihydro-l, 2-diazocines), only one other example of such a 1,2-di-hcterocine system exists i.e. dibenzo derivative 4 containing the 1,2-dithiocin system 2.1... 

A one-pot synthesis of 3-methyl-5-aryl-4//-pyrrolo[2,3-<7]isoxazoles was performed in high yields by Sharpless epoxidation of 4-amino-3-methyl-5-styrylisoxazoles <06TL4957>. 1,2,4,5-Tetrazines were condensed with isoxazolylcyclobutanones in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7-dihydro-5//-[l,2]diazocin-4-ones <06JOC2480>. 

Conformationally restricted 6-isoxazol-5-yl-6,7-dihydo-5i/-[l,2]diazocin-4-ones were synthesized from 1,2,4,5-tetrazines and isoxazolylcyclobutanone <06JOC2480>. 

Most of the highly unsaturated monocyclic eight-membered heterocycles contain one or two nitrogen atoms and have been obtained by bond reorganization processes from strained bicyclic or polycyclic precursors. Although several of the less substituted compounds without stabilizing substituents are highly labile substances, 1,4-dihydro-1,4-diazocines qualify as dihetera[8]annulenes and display distinct aromatic properties. 

One of the earliest authentic eight-membered heterocyclic compounds to be described was 6,7-diphenyldibenzo[e,g][l,4]diazocine (212) prepared by Tauber in 1892 by condensation of 2,2 -diaminobiphenyl and benzil. The diazocine ring is opened hydrolytically under vigorous conditions and is reduced to the 5,6,7,8-tetrahydro compound with sodium amal-... 

The parent l,4-dihydro-l,4-diazocine (232) and a number of AT,AT-derivatives have been prepared and thoroughly characterized by Prinzbach and Vogel and their colleagues (79AG(E)962, 964, 80CB3161). The benzene diimine precursors have been obtained by two routes. In one case cis benzene dioxide was converted in several steps to the mesyl derivative (225) and thence to the diimine dimesylate. The second proceeds from cis,cis- benzene trioxide to the triimine (227). Two equivalents of acid chloride give the diamides (228) in good yield, and nitrosation with cheletropic elimination of N2O leads to the N,AT -disub-stituted diimines (229). 

In another cyclization procedure for the 1,5-benzodiazodne system, the nitriles (296) are converted to the aminodihydrodiazocines (297) (79CPB2589). Attack of nucleophiles on (297) occurs at the N-5—C-6 bond to give the 3,4,5,6-tetrahydrodiazodnes (298) with NaBH4 and the jS-aminoethylquinazolines (301) on hydrolysis. The diazocines (297) behave as typical amidines. Oxidation leads to the amidoximes (300) which on hydrolysis are converted to 2,1-benzisoxazoles (302), and reaction with diketene leads to the fused pyrimidinones (299 and l-methyl-3-one isomer) (79CPB2927). 

Many 1,2-diazocines, including the parent (12) (79JOC1264) and its 3,8-diaryl-4,7-dichloro derivatives, are yellow (85CJC1829). However, the color is quite sensitive to substituents, as replacing one or both chlorines in the 4 and 7 positions by nitrogen or sulfur substituents, leads to colorless compounds (87BCJ731). 

Since the most common group of 1,3-diazocines is related to cyclic urea 104 (called, for example, perhydro-l,3-diazocine-2-one or N,N -pentamethyleneurea), a separate section is devoted to the synthesis, chemistry, and applications of 104, substituted 104, and related molecules such as thiourea 105, guanidines 106, and carbodiimide 107. 

In a study of the diastereoselective hydrogenation of one of the chiral precursors of lysine, i.e., 170, this compound was hydrogenated in acetic anhydride and potassium hydroxide using Raney nickel to produce diace-tyllysineamide 171, A,AT-diacetyl-1,5-diaminopentane, and, if the amount of alkali is increased, imidazolono-1,3-diazocine 172. It was concluded that 172 arose from ring closure of 171 (87JOU306). 

As an example of general trends of fragmentation of large heterocycles, one can mention 1,2-diazocine 48 (R = H). 

The enantiomerization of 6,7-dihydro-dibenzo[///][l,2]diazocine-5,8-dione 2 was investigated using quantum-mechanical methods. At the density functional theory (DFT) B3LYP/6-31G(d,p) level, two enantiomeric -symmetric transition states (TSs) and two enantiomeric pathways were found with a calculated barrier of 155.6 kj mol-1. The pathways can be divided into two steps one involving primarily inversion of the amidic bridge and the other movement of the aromatic rings <2004TA537>. 

X-Ray crystallography studies on 1,2-diazocines are limited to six derivatives. A single crystal X-ray analysis was performed on 3,8-diphenyl-6-(3-phenylisoxazol-5-yl)-6,7-dihydro-577-[l,2]diazocin-4-one 1 and confirmed the results obtained with theoretical calculations conducted on a model of 1 in which Ar= R= H (vide infra). In fact, the major contribution to the thermodynamic isomer is given by the twist-boat-chair conformer having the substituent in position 6 in a pseudoequatorial orientation relative to the eight-membered ring <2006JOC2480>. 

Lactam 86, when treated with diisobutylaluminium hydride (DIBAL-H), led to a 6 2 1 mixture of 89b, 90b, and 91b (95% combined yields) (Scheme 20) <1996T3563>. In the case of reaction of 83 with l-(2-hydroxy-l-phenylethyl)-5,6-dihydropyridin-2(l//)-one, an equimolecular mixture of cis- and trans-lactams of type 85 (R = CH(Ph)CH2OH, R = R2 = H) was obtained in 88% yield. Reduction of the trans-lactam with Red-Al gave the diazocine 89 (R = CH(Ph)CH2OH) and an analogue of 91 with an oxazolidine ring annelated to the piperidine moiety <1995TL1693>. 

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