Recent Advances in the Synthesis of Hydrogenated Azocine-Containing Molecules

This review covers recent advances in synthesis of azocine-containing systems. The most approaches towards azocines are discussed. 1 Introduction 2 Ring-Expansion Reaction 2.1 Ring-Expansion Reaction of Cyclopentane Containing the 1,4-Diketone Moiety with Primary Amines (from 5 to 8) 2.2 Ring-Expansion Reaction of Annulated Tetrahydropyridines under the Action of Activated Alkynes (from 6 to 8) 2.3 Reductive Ring-Expansion Reaction of Cyclic Oximes 2.4 Other Ring-Expansion Reactions 3 Heck Reaction 4 Cycloaddition 5 Ring-Closing Metathesis (RCM) 6 Cyclization 6.1 Metal-Catalyzed Cyclization 6.2 Radical Cyclization 6.3 Friedel–Crafts Cyclization 6.4 Other Examples of Cyclizations 7 Microwave- and Photo-Assisted Reactions 8 Other Methods 8.1 Cascade and Tandem Reactions 8.2 Aldol Condensation 8.3 Thermolysis 8.4 Ring Opening 8.5 Other Methods 9 Conclusion


Introduction
The chemistry of annulated azocines has not been explored in detail owing to the lack of efficient methods for their synthesis. The only exception is azocinoindoles, which have been investigated extensively due to the great number of alkaloids with an azocinoindole fragment in their structure. This review highlights most recent approaches towards annulated azocine derivatives published after the year 2009; the previous review was published in 2008. 1

Ring-Expansion Reaction of Cyclopentane Containing the 1,4-Diketone Moiety with Primary Amines (from 5 to 8)
In 2006 the Cristoffers group 2 discovered a novel bismuth-catalyzed ring-expansion reaction of 1,4-diketones with primary amines that furnished an eight-membered ring. In 2011, they extended their relatively simple method to the synthesis of annulated azocines. Thus, starting from ethyl 1-oxo-indane-2-carboxylate 1, containing a 1,4-diketone motif, and primary amines under the bismuth-catalyzed ring-expansion reaction conditions gave benzo[c]azocine derivatives 2 in moderate yields (Scheme 1). 3 It was also shown that, in some cases, the presence of bismuth nitrate was not essential. 3 A bismuth-free strategy of ring enlargement was also successful in the case of regioisomeric pyrido[c]azocines. 4 Synthesized from commercially available materials, three cyclopentapyridine derivatives 3, 6, and 9, containing β-oxo Scheme 2 Synthesis of a pyrido [2,3-c]

Ring-Expansion Reaction of Annulated Tetrahydropyridines under the Action of Activated Alkynes (from 6 to 8)
In 2002, an alkyne-induced ring-expansion reaction of annulated tetrahydropyridines leading to the formation of azocine rings was found. 6 It is presumed that ring-expansion reaction involves the Michael addition of the tertiary N-atom in the (hetero)annulated pyridine system to the tri-ple bond of the activated alkyne, followed by a nucleophilic substitution (S N ) reaction in zwitterionic intermediate A (Scheme 8).

Review Syn thesis
cine 35 and dibenzo[b,f]azocine 36 in high yields as a single regioisomer with the nitrogen atom located in the position neighboring the aromatic ring (Scheme 11). [22][23][24] Based on this ring-expansion reaction of oximes, a concise synthesis of 17β-HSD3 inhibitor with a dibenzoazocine skeleton was carried out. 25 All attempts to convert oximes 37a,b into a single regioisomer failed, hence a mixture of dibenzoazocines 38a and 39a in the ratio 2:1 or dibenzoazocines 38b and 39b in the ratio 6:1 was used. After acylation of dibenzoazocines 38 and 39 the obtained regioisomers 40 and 41 were separated. Compound 40a was coupled under the Suzuki-Miyaura coupling conditions to provide 17β-HSD3 inhibitor 42 in 70% yield. Desulfurization of 42 with Raney Ni gave also 17β-HSD3 inhibitor 43 (Scheme 12). Since 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) is an enzyme involved in testosterone biosynthesis, inhibitors of 17β-HSD3 could provide new medicines for the treatment of prostate cancer.

Other Ring-Expansion Reactions
Treatment of 1-vinyl-substituted indolinium salt 44 in refluxing THF with the Hoveyda-Grubbs second-generation catalyst (H-G II) resulted in allylic rearrangement to give azocino [5,4-b]indole 45, the product of ring expansion, in 44% yield (Scheme 13). 26 A conceptually new and elegant strategy for the construction of 1H-azocino [5,4-b]indoles 47 and 48 via a goldcatalyzed ring expansion of 2-propargyl-β-tetrahydrocarbolines 46 was developed by Zhang and co-workers. 27 The azocinoindoles 47 and 48 were obtained in moderate to excellent yields. The method features mild conditions and wide functional group tolerance (Scheme 14).

Review Syn thesis
Binaphthyl-azocines 50 were synthesized by the direct copper-catalyzed ring-expansion reaction of binaphthylazepines 49 and α-diazocarbonyl reagents. 28 This transformation is considered to be an example of a [1,2-]Stevens rearrangement and presents a facile access to binaphthyl-azocines in moderate to high yields (Scheme 15).
Naphtho [1,8-ef]pyrimido [4,5-b]azocines 53 were prepared from acenaphthoquinone (51) and 6-aminouracil derivatives 52 in high yields. 29 The ring expansion was carried out as a one-pot process and included two steps: the addition reaction of starting compounds and the subsequent oxidation cleavage of the intermediate in the presence of Pd(OAc) 4 (Scheme 16).

b]azocines
Azocine 55 and annulated azocine 57 were produced by a ring-expansion transformation of the piperidine ring of compounds 54 and 56 under the action of methyl propynoate and dimethyl butynedioate, respectively (Scheme 17). 30

Heck Reaction
The intramolecular Heck reaction is considered to be one of the most useful methods for the construction of medium-sized heterocycles due to its functional group tolerance and high stereoselectivity. In 2009, the Majumdar group developed an interesting and simple procedure for the synthesis of various annulated azocines from unactivated allylic substrates using a combination of two reactions, the aza-Claisen rearrangement and a palladium-catalyzed intramolecular Heck reaction. Thus, an appropriate substrate 59, prepared from N-allylanilines 58 by aza-Claisen This strategy was successfully used for the synthesis of dibenzo[b,f]azocinones. 32 The precursors 61 for the Heck reaction were obtained from N-allyl-substituted anilines by aza-Claisen rearrangement, tosylation, and amidation with 2-iodobenzoyl chloride. The products of the Heck reaction depended on the conditions used. It was shown that Jeffrey's two-phase protocol 32 led to endocyclic product 63 whereas phosphine-assisted standard conditions yielded exocyclic products 62 (Scheme 19).

Scheme 19 Synthesis of dibenzo[b,f]azocines via the intramolecular Heck reaction
The same combined aza-Claisen rearrangement and intramolecular Heck reaction was successfully applied to the synthesis of coumarin-or quinolone-annulated azocines 65 33 and pyrimidoazocines 67. 34 The precursors 64 for the Heck reaction were synthesized using aza-Claisen rearrangement of N-allylcoumarins or N-allylquinolones followed by alkylation with benzyl bromides. The intramolecular Heck reaction afforded azocine 65 in 75-79% yields (Scheme 20).
The Majumdar group achieved another efficient and straightforward method for the construction of dibenzoazocinones 72 and coumarin-and quinolone-annulated azoci-
Kim and co-workers obtained tetracyclic azocine systems 77 from indole derivatives 76 by applying the intramolecular palladium-catalyzed Heck reaction. 36 The required starting materials were synthesized by the reaction of Baylis-Hillman acetates 74 and indoles 75 (Scheme 23).

Review Syn thesis 4 Cycloaddition
In 2009, Rovis and co-workers developed the first enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes 102 and dienyl isocyanates 103 leading to the formation of bicyclic azocines 104 and 105. 43 Pyrrolo[1,2-a]azocines 104 and 105 were obtained in good to high yields and excellent enantioselectivity (Scheme 32). The geometry of the diene moiety had a significant effect on the selectivity of the products and used pure (E)-diene was used as the starting substrate.
Louie and co-workers demonstrated in 2012 that azetidin-3-ones 110 under the action of diynes 109 underwent a Ni/IPr-catalyzed cycloaddition reaction leading to dihy- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Review Syn thesis
droazocinones 111 (Scheme 34). 45 The method involves a Csp 2 -Csp 3 bond-cleavage step that proceeds at low temperatures.

Ring-Closing Metathesis (RCM)
Another powerful method for the construction of medium-sized nitrogen-containing systems that has received considerable attention in recent years is ring-closing metathesis.
Starting from styryldiazoacetate 120, azocine 122 was obtained by a sequence of two reactions: N-H insertion and RCM. 49 It was also possible to combine the carbenoid N-H insertion and RCM reactions in a one-pot procedure for the synthesis of methyl 1,2,5,6,7,8-hexahydroazocine-2-carboxylate 122 (Scheme 38).

Review Syn thesis
bromide provided the required precursor 134 for RCM using the Grubbs first-generation catalyst (Grubbs I) to give 135.

Review Syn thesis
Dash and co-workers constructed imidazo[1,5-a]azocine 163 from commercially available hydantoin 162 via a four-step procedure involving selective N-allylation and C5alkylation and with the key step being RCM (Scheme 48). 58 Moss reported the efficient synthesis of a range of heterocycle-fused azocine derivatives 165-167 employing a directed metalation/ruthenium-catalyzed RCM approach. 59 The RCM precursors 164 were synthesized from carboxylic acids or 2-chloro-4-iodopyridine in three to four steps (Scheme 49).
Rao and co-workers developed a common strategy for the construction of polyhydroxy azocine derivatives, including a novel example, from D-1,5-gluconolactone 168, using an RCM protocol as the key step. 60 D-1,5-Gluconolactone 168 was converted into compound 169 by a five-step procedure. Compound 169 was subjected to allylation with allyl chloride producing N-allyl derivative 170; subsequent deprotection, oxidative cleavage, and reaction with vinylmagnesium bromide gave 171. RCM of compound 171 afforded the cyclized products 172 and 173. The final deprotection and hydrogenation of azocines 172 and 173 provided polyhydroxy azocine derivatives 174 and 175 in 72% and 66% yields, respectively (Scheme 50).
Bertozzi and Sletten synthesized a novel strained azacyclooctyne 181, which represents a new class of heterocyclic substrates for Cu-free click chemistry. 61 The synthesis in- A. V. Listratova, L. G. Voskressensky

Review Syn thesis
volved nine steps beginning from 6-bromoglucopyranoside 176. First, compound 176 was transformed into acyclic diene 177 via zinc reduction/reductive amination reaction followed by amide formation with methyl succinyl chloride. The eight-membered ring was constructed by RCM giving azocine 178, which was converted into ketone 179 by oxidation and subsequent hydrogenation. The condensation of 179 with semicarbazide and then oxidation with selenium dioxide led to selenadiazole 180. Subsequent thermal decomposition followed by saponification of the ester produced azocine 181 (Scheme 51).
In 2011, Danheiser and co-workers showed that the combination of ynamide-based benzannulation with RCM provides an expeditious strategy for the assembly of benzofused nitrogen heterocycles including azocines 187-189. 62 The precursors 184-186 for RCM were obtained via benzannulation from cyclobutenones with ynamide 183, prepared by reaction of carbamate 182 with 5-bromopent-1-en-4-yne. RCM occurred in the presence of the Grubbs II catalyst in dichloromethane (Scheme 52).
The synthetic use of this strategy is illustrated in its application in a concise enantioselective route to the benzoazocine core 190 of the antitumor agents (+)-FR900482 and A. V. Listratova, L. G. Voskressensky

Review Syn thesis
(+)-FR66979. The synthesis of the benzoazocine core 191 and the completion of the formal total synthesis of FR900482 and Fr66979 are shown in Scheme 53.
In their investigations to develop concise total syntheses of some indole alkaloids possessing the azocine ring, Bennasar and co-workers successfully applied the combination of RCM and vinyl halide Heck cyclization for the construction of the azocinoindole moiety. The first unsuccessful attempt to work out the total synthesis of (±)-apparicine led to unexpected tetracycle 198. 64 The required RCM substrates 195a,b, prepared from 2-vinylindole-3-carbaldehyde 194 by reductive amination followed by N-acylation or sulfonylation, were subjected to RCM giving azocinoindoles 196,b in acceptable yields. The removal of the Boc group in azocinoindole 196a, subsequent alkylation with (Z)-2-iodobut-2-enyl tosylate and Heck cyclization yielded compound 198 possessing a bridged azocine ring (Scheme 55).
Changing the cyclization site from 5,6-position to 4,5position by using as a RCM precursor 2-allyl-3-[(allylamino)methyl]indole 199 and introducing an additional isomerization step before the Heck cyclization, they succeeded in accomplishing the first total synthesis of (±)-apparicine (Scheme 56). 64 The combination RCM/Heck cyclization successfully was utilized for the synthesis of the upper-half of vinorelbine. 65 Reductive amination of aldehyde 200 followed by Boc-protection of the aliphatic nitrogen gave carbamate 201, which smoothly underwent RCM in the presence of the Grubbs second-generation catalyst to give azocinoindole 202. The sequence of N-Boc deprotection, alkylation with allylic bromide, N-indole-deprotection, and Heck cyclization gave the upper-half of vinorelbine 205 (Scheme 57).
RCM for the building of eight-membered nitrogen-containing cycle has also found application in the completion of the total synthesis of (-)-nakadomarin A, which shows interesting cytotoxic and antibacterial activity. A concise diastereoselective total synthesis was completed in 21 steps from D-pyroglutamic acid, wherein one of the key steps was the construction of the azocine ring via RCM (Scheme 58). 66

Metal-Catalyzed Cyclization
Chowdhury and co-workers described an elegant method for the synthesis of benzo[c][1,2,3]triazolo[1,5-a]azocines 208 via palladium/copper-catalyzed heterocyclization. 67 The starting ortho-iodo azides 206 were prepared from the corresponding alcohols by mesylation and subsequent azidation. ortho-Iodo azides 206 underwent palladium/copper-catalyzed azide-alkyne cycloaddition with various terminal acetylenes 207 followed by arylation of the triazole to give azocine derivatives 208. Employing 1,3-diethynylbenzene (209) as a reactant, led to bis-heteroannulation giving azocine 210 in moderate yield (Scheme 59). It is worth noting that the protocol included the formation of one C-C and two C-N bonds in a one-pot reaction.
Pyrroloazocine 219 and azocinoindoles 217 were obtained via a palladium-catalyzed norbornene-mediated tandem process involving the intramolecular ortho-alkylation of an aromatic C-H bond followed by intramolecular direct arylation reaction from compounds 216 and 218, respectively (Scheme 61). 69

Review Syn thesis
The Van der Eycken group, in 2009, developed a short and selective approach towards azocino [5,4-b]indoles 221 using a microwave-assisted Hg(OTf) 2 -catalyzed intramolecular carbocyclization of amides 220 prepared from corresponding tryptamines and 3-substituted prop-2-ynoic acids (Scheme 62). 70 In 2011, the Van der Eycken group elaborated a novel procedure for the construction of the interesting azocino[cd]indoles 224 via a Pd-catalyzed intramolecular acetylene hydroarylation. 71 The required for the cyclization, sub- The Van der Eycken group have also reported the synthesis of azocinoindoles via an efficient gold-catalyzed post-Ugi intramolecular hydroarylation. 72,73 Ugi-adducts 225 and 227 underwent 8-endo-dig cyclization leading to azocino [5,4,3-cd]indoles 226 and azocino [5,4-b]indoles 228, respectively. The merits of this method are good to excellent yields, a wide range of functional groups introduced during the Ugi reaction, and selectivity for 8-endo-dig cyclization (Scheme 64).

Review Syn thesis
Echavarren and co-workers reported the synthesis of the azocino [5,4-b]indole core skeleton of the lundurines by gold-catalyzed 8-endo-dig cyclization of an alkynylindole. 76 The AuCl 3

Radical Cyclization
The Majumdar group developed a new efficient method for the synthesis of pyrimidoazocine derivatives 238 via the first example of an 8-endo-trig thiophenol-mediated radical cyclization. 77 The radical precursors 237 were prepared from pyrimidines 235, products of the aza-Claisen rearrangement of N-allyl-substituted pyrimidines, by tosylation and the subsequent reaction of intermediates 236 with propargyl bromide. The alkenyl radicals were generated from thiophenol initiated by benzoyl peroxide. The pyrimido [5,4-b]azocines 237 were obtained in excellent yields (Scheme 68). Scheme 60 Synthesis of benzo [5,6]azocino [3,4-b] A. V. Listratova, L. G. Voskressensky

Review Syn thesis
On developing the total synthesis of (±)-apparacine, Bennasar and co-workers prepared azocino [4,3-b]indole 242 via radical cyclization. 64 The synthesis of compounds 242 began with the preparation of selenoester 241 as the radical precursor. Selenoester 241 was prepared by reductive amination of aldehyde 239, followed by Boc protection of the resulting secondary amine, and phenylselenenation of the corresponding carboxylic acid. The treatment of selenoester 241 with Bu 3 SnH as the radical mediate and Et 3 B as the initiator led to the formation of azocinoindole 242. The reaction of 242 with methyllithium followed by Scheme 64 Synthesis of azocino [5,4,3-cd]indoles and azocino [5,4b]  In their investigations, Li and co-workers generated azocine derivatives 245 and 247 starting from diesters 244 and 246 by a sequence of reactions in which the azocine-formation step was radical cyclization. 78 In the case of azocine 245 it was a Mn(III)-mediated oxidative radical process, whereas the azocine system 247 was obtained by a reductive radical process (Scheme 70).
Diaba, Bonjoch, and co-worker obtained morphan compounds 249 via the first intramolecular atom transfer radical process between trichloroacetamide and enol acetate used as a radical acceptor. 79 The reaction was promoted by Grubbs II catalyst, thus expending the scope of these catalysts beyond the metathesis reaction (Scheme 71).
This reaction enabled the construction of the tricyclic skeleton of the immunosuppressant FR901483. The required proradical trichloroacetamide 251 was synthesized in five steps starting from azaspirodecane 250. The treatment of ketone 251 with isopropenyl acetate gave a regioisomeric mixture of enol acetate 252 in a 1.8:1 ratio, the unseparated mixture was treated with Grubbs II catalyst affording the diazatricyclic derivative 253, its epimer 254, and unexpected mixture of enones 255. The reaction of compound 253 with zinc led to dechlorinated derivative 256, possessing the tricyclic skeleton of immunosuppressant FR901483, in 58% yield (Scheme 72). 79 Li and co-workers used a route based on the iodineatom-transfer radical 8-endo cyclization to synthesize a number of azocine derivatives. 80 Thus, N-acyloxazolidin-ones 257 underwent 8-endo cyclization promoted by BF 3 ·OEt 2 /H 2 O leading to the formation of oxazoloazocine 258 in high yields with excellent regio-and stereoselectivity (Scheme 73). It is interesting to note that the product configuration was changed from 3,8-trans to 3,8-cis.
Li and co-workers also showed that in the presence of Mg(ClO 4 ) 2 and a bis(oxazoline) ligand, N-ethoxycarbonyl-  A. V. Listratova, L. G. Voskressensky
Kim and Seo used the Friedel-Crafts reaction as the key step for the construction of azocine ring in the tetracyclic compound 274. 83 Aminoacrylate 271, prepared from 3,4-dimethoxyphenethylamine via amidation reaction with 2-iodobenzoic acid and subsequent Michael addition of ethyl propynoate, was subjected to the Heck reaction giving isoindole 272. The hydrogenation of isoindole 272 followed by hydrolysis provide derivative 273 which by the action of polyphosphoric acid was converted into tetracyclic compound 274 (Scheme 78).

Review Syn thesis
The same sequence of reactions was used in the case of the synthesis of an azocine alkaloid, magallanesine (Scheme 79). 83

Other Examples of Cyclization
In a new synthetic route for the synthesis of the dasycarpidone skeleton and for the total synthesis of (±)uleine, Patir and Uludag used acid-catalyzed intramolecular cyclization to construct the azocino[4,3-b]indole core. 84 Reduction of ketoamide 275 with borane-dimethyl sulfide complex and the subsequent acidification of the resulted alcohol 276 with TFA led to 277, which was treated in situ with DDQ furnishing the desired tetracyclic compounds 278 in good yield. Four further steps were required to complete the total synthesis of (±)-uleine from azocinoindole 278 (Scheme 80).
Azocinoindoles 280 and 283 were obtained by Hamada and co-workers via a novel acid-promoted skeletal rearrangement of 2-or 3-alkylideneindolenium cations generated from compounds 279 and 282. 85,86 A reaction cascade leading to the azocine system involved intramolecular ipso-Friedel-Crafts alkylation of phenols, rearomatization of the Scheme 77 Synthesis of azocino [5,4-b] A. V. Listratova, L. G. Voskressensky

Review Syn thesis
spirocyclohexadienone unit, and iso-Pictet-Spengler reaction. In addition to the targeted azocinoindoles, pyrrolidine derivatives 281 and 284 were isolated as the major byproducts (Scheme 81).
Reitz and co-workers have prepared benzo[d]azocines 294 and 295 which are formally analogues of Phe-Ala or Ala-Phe dipeptides joined together on their side chains. 88 The synthesis began with the conversion of the N-Boc-pro-

Review Syn thesis
Hexahydrochromeno [3,4-c]azocine 297 was obtained from chromene 296 by cyclization which occurred during Duff formylation, but the yield of the cyclic product was poor at only 9% (Scheme 84). 89

Microwave-and Photo-Assisted Reactions
Alcaide, Almendos, and co-workers developed a method for the synthesis of structurally novel bicyclic azocinefused β-lactams 299 and 300 in the absence of any metal catalyst. 90 This was the first example of metal-free preparation of eight-membered rings by the thermolysis of nonconjugated azetidin-2-one-tethered bis(allenes) 298 on application of microwave irradiation. Azocines 299 and 300 were isolated as single regio-and diastereoisomers (Scheme 85).
The Van der Eycken group elaborated a new approach towards the construction of 5,6,7,8-tetrahydrodibenzo[c,e]azocines 303 via a microwave-assisted copper-catalyzed intramolecular A 3 -coupling reaction. 91 Formed in situ by Boc deprotection of biaryl compounds 301, biaryl derivatives 302 with both amino and aldehyde groups reacted with the suitable alkynes in the presence of CuBr under focused microwave irradiation thus forming dibenzo[c,e]azocines 303 in good to excellent yields (Scheme 86).

Review Syn thesis
ran-containing pendant tethered either via the aniline nitrogen or through the carbonyl-group-containing fragment (Scheme 89). 95 8 Other Methods

Cascade and Tandem Reactions
Nakamura and co-workers elaborated an efficient synthesis of azocine derivatives 313 from O-propargylic oximes 312 in good to excellent yields by the means of a Rh-cata-lyzed 2,3-rearrangement/heterocyclization cascade sequence. 96 It is noteworthy that the chirality of the substrate was maintained throughout the cascade process to afford optically active azocines 313d (Scheme 90).  Kumar and co-workers synthesized benzo[b]azocines 318 through an unprecedented one-pot, triflic acid mediated, tandem Michael addition-Fries rearrangement of sorbylanilides 319. 99 The reaction is proposed to proceed via a δlactam intermediate, earlier considered unreactive for the Fries rearrangement (Scheme 93).

Scheme 90 Synthesis of azocine derivatives
In their research concerning the total synthesis of (±)actinophyllic acid, Martin and co-workers constructed the tetracyclic core of the natural compound in a single chemical operation via a novel Lewis acid catalyzed cascade of reactions involving stabilized carbocations and π-nucleophiles. 100 The treatment of a mixture of electrophile precursor indole 320 and π-nucleophiles 321 with TMSOTf in the presence of 2,6-di-tert-butylpyridine, followed by addition of NaOMe in MeOH at -78 °C gave tetracyclic systems 322 in 53-80% yields (Scheme 94).

Review Syn thesis
Thermolysis of the 12-membered ring aza-enediyne 331 in benzene in the presence of catalytic amounts of ptoluenesulfonic acid produced the addition-dehydration product, naphtho [2,3-b]azocine 332 in 18% yield, however, the major product of this reaction was N-tosyl lactam 333 in 28% yield (Scheme 98). 105

Scheme 102
Synthesis of a series of optically active morphan derivatives Xu, Li, and co-workers have designed and synthesized novel neonicotinoid analogues 346-348 with an azabridged azocine fragment. 110 Azocine derivatives 346-348 were prepared by reaction of imidazole 345 with glutaraldehyde and a primary amine hydrochloride (aliphatic amines, phenylhydrazines, and anilines) (Scheme 103).
These methods were extended to the preparation of dibenzo[c,e]azocines 369/370 and 371 via insertion of CO and isocyanide, respectively (Scheme 110). 119

Conclusion
In recent years, many new pathways towards eightmembered azaheterocycles have been elaborated including domino approaches, MCRs, metal-catalyzed cyclizations, RCM, and ring-expansion strategies. These approaches provide environmentally friendly and step-economical access towards several annulated azocines with substantial biolog- A. V. Listratova, L. G. Voskressensky

Review Syn thesis
ical activity and natural compounds. However, much work remains to be done to elaborate general synthetic strategy towards medium-sized nitrogen heterocycles including azocines.   This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.