Azocine derivatives

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

A special method, with only two examples, starts from 1,2,4-triazines.20 21 Diels-Alder reaction with the strained dienophile dimethyl tricyclo[4.2.2.02,5]deca-3,7,9-triene-7,8-dicarboxylate (14) is followed by an elimination of nitrogen via a retro-Diels-Alder process. The formed product, however, cannot be isolated, but reacts via another retro-Diels-Alder reaction and an electro-cyclic reaction to provide the azocine derivative 15. The sequence order of the reactions is not clear, but both pathways lead to the same product. 

Some azocine derivatives, synthesized via this protocol, exhibited acetylcholinesterase (AChE) inhibitory activity (06MI7205). 

The 1,2-dihydropyridines are also known to undergo [2 + 2] cycloadditions of the enamine double bond with alkynes (74JCS(P1)2496). The products of these reactions are azocine derivatives such as (259), which, after removal of the A-protecting group, have been used as intermediates in pyrrolizine synthesis (Scheme 47) (77JOC2903). 

Not only carbon-carbon triple bonds but also carbon-nitrogen triple bonds can undergo ortho photocycloaddition to derivatives of benzene. The reaction was discovered by Al-Jalal et al. [86] who found that irradiation (254 nm) of 4-cyanoanisole in acrylonitrile produced three 1 1 adducts in the ratio of 7 1 2. Two of these (ratio 7 1) were formed by the addition of the carbon-carbon double bond of acrylonitrile to positions 1,2 and 3,4, respectively, of 4-cyanoanisole. The third product was an azocine derivative, apparently formed by the addition of the carbon-nitrogen triple bond to positions 2,1 of the arene, followed by ring opening to an azacyclooctatetraene [87] (Scheme 48). 

Al-Jalal and co-workers showed that nitrile groups undergo photocycloaddition to benzene rings to give azocine derivatives (10) [75-77] in a manner analogous to that of acetylene [78-84] (Scheme 7). 

Ultraviolet (UV) spectra in cyclohexane of some azocine derivatives displayed absorption bands slightly above 300 nm <2003JOC1447>. 

Tetrahydroazocines. Tetrahydropyridines 34, obtained in four steps from readily available 3-a 1 ky 1 -N-benzyl-pyridinium salts, were used in the preparation of functionalized azocine derivatives 36 via their corresponding iminium salts (Scheme 9 <2005EJ01052, 2000TL6067>). Tetrahydropyridines were heated with ethyl propiolate in refluxing MeCN for 2 h to yield compounds such as 36 in good to excellent yields. 

Dihydroazocines. Azocines can be converted into the corresponding iminium salts by treatment with 1 equiv of acid, such as methanesulfonic acid, in CHCI3. Nucleophilic additions to iminium salt 226 afforded substituted azocine derivatives reaction with thiophenol in DCM/H20 at room temperature provided 227, while reaction with sodium azide in CHCI3/DMF provided 228 (Scheme 92 <2005EJ01052>). 

Some azocine derivatives showed insecticidal activity as assayed by oral administration to silkworms larvae <2000BBB1519>. The azocine ring was shown to be indispensable to form the active conformation. Benzazocine with the lactam structure was evaluated in the syntheses of homochiral polyamide polymers <1998TA3497>. 

Treatment of 92 with sodium in liquid ammonia brought about the reductive desulfurization and cleavage of the benzylic G-N bond to give an intermediate 6-hydroxylactam, which was cyclized with TiCU to give the diazocine 93 as minor product (6%) and the azocine derived from the cyclization on the 3-position of the indole, as major product (35%) (Equation 9) <2004JOC8681>. 

Azocine (4), even before its detection by Hedaya,48 was of theoretical interest because it is a heterocyclic analog of the 871 nonaromatic annulene cyclooctatetraene (COT). Although azocine itself was found to be quite unstable, earlier work by Paquette and co-workers52,53 on the synthesis of azocine derivatives indicated that appropriately substituted compounds could be more stable. Paquette68 has recently reviewed the chemistry of these compounds. The picture of azocine vis a vis cyclooctatetraene682 is outlined below. 

Azocine derivatives are reported to exhibit hypnotic and anticonvulsive action128 129 as well as central nervous system stimulation.130 136 N-Propionyl-[l-(octahydroazocin-l-yl)isopropyl-2-aminopyridine was one of... 

Azocine derivatives have been employed as antiparasitics,201 herbicides,202-209 insecticides,210 211 pesticides,212 marine antifoulants,213 214 corrosion inhibitors,215 217 vulcanization accelerators,218-220 dyes,221,222 polymer stabilizers and inhibitors,223-225 bacteriocides,226 and as com-plexing agents in the determination of metals.227-229... 

One Heteroatom. - Azocine derivatives have been synthesized by a variety of ring-opening reactions. The 3-lactam carboxylic acid (1) rearranges in H2SO4 to form the azocine (2). ... 

Intramolecular cyclization of (76) in the presence of NaH gave exo (77) and endo (78) products (Equation (9)) <90SL584). Allene-based electrophile-mediated cyclization afforded iV-tosyl iodohexa-hydroazocines <94JCS(Pl)3549>. Photochemical intramolecular cycloaddition of phthalimide in acetone afforded the ring-opened product <82TL498l>. An unstable enaminone azocine derivative (81) was formed after the desulfurization of the bicyclic aminal (80), which in turn was synthesized from... 

There is continuing interest in the synthesis and pharmacological properties of dibenzo[c,e]azocine derivatives related to apogalanthamine. ... 

---