Electrocyclizations of Conjugated Azapolyenes Produced in Reactions of Azaheterocycles with Metal Carbenes

: Conjugated azapolyenes (azabuta-1,3-dienes, aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes) are highly reactive in electrocyclization reactions, which makes them convenient precursors for the synthesis of a wide range of four-, ﬁve-, and six-membered nitrogen heterocycles that are of relevance for medicinal chemistry. Ring opening reactions of 2 H -azirines and azoles containing an N–N or N–O bond, initiated by a transition metal carbene, have become increasingly important in recent years, since they easily allow the generation of azapolyenes with different numbers of double bonds and heteroatoms in various positions. This review summarizes the literature, published mainly in the last decade, on the synthetic and mechanistic aspects of electrocyclizations of azapolyenes generated by the carbene method.


Introduction
Conjugated azapolyenes such as azabuta-1,3-dienes and aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes ( Figure 1) are valuable building blocks in the synthesis of a variety of acyclic and heterocyclic nitrogen-containing compounds [1][2][3][4][5]. These highly unsaturated compounds are generally classified into three types: electron-rich, neutral, and electrondeficient azapolyenes. The compounds of the latter type, bearing one or more strong electron-withdrawing group in the polyene chain, exhibit especially diverse and sometimes unexpected reactivity. The most common reactions of electron-deficient azapolyenes are nucleophilic additions and pericyclic reactions including cycloadditions [6][7][8] and electrocyclizations [9][10][11]. Electrocyclizations of conjugated azapolyenes can occur via pericyclic or pseudopericyclic pathways [12] depending on the nature of the reaction centers in the reacting molecule. Electrocyclizations are of particular importance for the construction of thermally labile heterocycles since they do not require any additional reagents and usually proceed with high regio-and stereoselectivity under mild conditions. However, the use of electrocyclic reactions for the synthesis of heterocyclic compounds involves serious challenges due to the limited synthetic availability of azapolyenes of the required structure. Whereas 1-azabuta-1,3-dienes are readily available from a condensation of unsaturated carbonyl compounds with primary amines [13][14][15], the methods for the synthesis of their isomers, 2-azabuta-1,3-dienes, which include the Mannich olefination of alkylidene glycinates [16], the Wittig reaction of N-(diphenylmethylidene)oxamate [17], the coupling of imines with activated acetylenes [18], and the aza-Wittig reaction of Nvinylphosphazenes [19][20][21][22][23] are more complicated and allow the introduction of only a limited set of substituents. In recent years, another convergent approach to azapolyenes 6 and 9 based on the ring opening of three-and five-membered heterocycles 1 and 2 under the action of transition metal carbenes 3 has been intensively developed (Scheme 1). The reactions are believed to proceed via the formation of metal-bound ylides 4 and 7 and metal-free ylides 5 and 8. In this approach, metal carbenes 3 are generated from diazo compounds or their masked analogs, 1H-1,2,3-triazoles, in the presence of rhodium or copper catalysts, which are generally used for the initiation of the denitrogenative decomposition of diazo compounds [24]. This approach to azapolyenes is quite versatile since it allows one to synthesize conjugated N-, N,N-, and N,O-containing butadienes, hexatrienes, and even octatetraenes in one synthetic operation. The unique feature of the approach is the interchangeability of some three-and five-membered heterocycles in the reactions with transition metal carbenes. This allows flexibility of the starting material choice to obtain the azapolyene with the desired substitution pattern and configurations of double bonds.
In this short review, we summarize recent progress on electrocyclic reactions of azapolyenes generated by the transition metal catalyzed reaction of diazo compounds/1,2,3triazoles with 2H-azirines [25] or azoles containing the weak N-N or N-O bond. Scheme 1. Transition metal carbene reactions for the synthesis of azapolyenes and heterocycles.
It was found that azadienes bearing one substituent at C4 undergo cyclization more readily if the C=C double bond has the E configuration. For example, dihydroazete 21 was obtained only from azadiene E-20, while its Z isomer was found to be inactive in the cyclization (Scheme 3) [29]. 4,4-Disubstituted 2-azabuta-1,3-dienes can be generated by the reactions of azirines or isoxazoles with diazocarbonyl compounds under rhodium catalysis [30,31] (Scheme 4). It was found that a prerequisite for the 1,4-electrocyclization of the resulting 2-azabuta-1,3-dienes 26 is the presence of two electron-withdrawing groups at C1. In most cases, the cyclization reactions occur only at elevated temperatures in reversible fashion. 4-Halo-substituted azadienes 26 with the E configuration of the C=C bond were used to explore the influence of the substituents on the azadiene-dihydroazete equilibrium in C 6 D 6 at 100 • C [31]. It was found that replacing iodine with chlorine led to a change in the azadiene/dihydroazete ratio from 2.6:1 to 1:1.3. The introduction of an electron-donating 4-MeO group to the phenyl ring located at the C3 of the 2-azadiene shifts the equilibrium from a 1:1 to 1:2.5 ratio in favor of dihydroazete 27. A decrease in the electron-withdrawing ability of the substituent at the C1 of the azadiene (replacement of CO 2 Me with CF 3 ) shifts the equilibrium toward the azadiene. Since 3-halo-2,3-dihydroazetes 27 are rather stable at room temperature, their preparation in satisfactory yields turned out to be possible by using repeated heating of the azadiene to obtain an equilibrium azadiene-dihydroazete mixture and separation of the dihydroazete at each stage [31]. The 2-azadiene, prepared from the diazo Meldrum's acid, also underwent reversible 1,4-electrocyclization upon heating, leading to the spirocyclic derivative of 2,3-dihydroazete 28 [32]. Dihydroazete 28 turned out to be stable at room temperature, which made it possible to isolate it in pure form.
For the synthesis of 2,3-dihydroazetes 37 bearing a 2-pyridyl substituent at C3, it was necessary to protect the pyridine nitrogen in the starting 2-(pyridin-2-yl)-2H-azirines 34 in order to avoid deactivation of the rhodium catalyst due to complexation (Scheme 6) [33]. For this purpose, one-pot protection/deprotection with a trimethylsilyl group was successfully used. The reaction of rhodium carbenes with azirines and isoxazoles is still the only way to synthesize 2,3-dihydroazetes having a carbon substituent at C4. Despite the low thermal stability of many representatives of these compounds, they can be easily detected in reaction mixtures due to the characteristic chemical shift of C4 in the 13 C NMR spectra, which is about 190 ppm.
An attractive feature of these compounds is the feasibility of a reverse reaction, ring opening, which determines their use as thermo-and photochromic materials as well as starting compounds for the synthesis of other heterocycles. In addition, under certain conditions, aromatization of the dihydro derivatives can take place to give azines. If a heteroatom is located at the end of the triene system, 1,6-cyclization occurs as a pseudopericyclic process [12]. Such reactions are characterized by a flattened structure of the cyclization transition state; therefore, they proceed through a lower activation barrier than classical 1,6-electrocyclizations, in which carbon atoms are at the ends of the triene system.
3.1. 1,6-Electrocyclization of 1-Oxa-5-azahexa-1,3,5-trienes to 2H-1,3-Oxazines Manning and Davies reported the rhodium catalyzed synthesis of 2H-1,3-oxazines 42 from diazocarbonyl compounds 35 and isoxazoles 39 (Scheme 7) [37]. The authors proposed the mechanism for the formation of oxazine 42 involving the generation of isoxazolium ylide 40, the ring opening to 1-oxa-5-azatriene 41, followed by 1,6-electrocyclization. The scope of the reaction was further expanded by the work in [38]. The authors of [38] confirmed the intermediate formation of 1-oxa-5-azatrienes in the reactions of rhodium metal carbenes with isoxazoles by experimental and computational methods. The density functional theory (DFT) calculations revealed that the metal-free isoxazolium ylides 40 are extremely unstable species, which undergo ring opening practically without an energy barrier, and their formation in these reactions therefore seems rather unlikely. The isoxazolium ring undergoes opening, most likely, at the stage of metal-bound ylides 44 (Scheme 8). The latter undergo simultaneous cleavage of the N-C and Rh-C bonds to give oxazatrienes 45 with the Z configuration of the C=C double bond. It is notable that the analogous reaction of 5-alkoxyisoxazoles 43 stops at the stage of oxazatrienes 45, which is one more piece of evidence for the reaction to proceed through the oxazatriene intermediate [38]. The quantum chemical calculations confirmed that oxazatrienes 45 are thermodynamically more stable than their 1,3-oxazine isomers 46 by 16 kcal/mol, and 1,6-electrocyclization in this case is thermodynamically unfavorable. Scheme 8. Synthesis of 2-alkoxy-1-oxa-5-azahexa-1,3,5-trienes stable to 1,6-electrocyclization.
It turned out that the obtained 1,3-oxazines are capable of reversible ring opening to 1-oxa-5-azahexatrienes at elevated temperatures (Scheme 10) [40]. 1,3-Oxazine 51 bearing a hydrogen atom at C6 produces oxazatriene 52 upon heating, which undergoes a cascade of transformations, leading to the formation of pyrrolinones 55. This isomerization occurs most easily for the 1,3-oxazines containing a cyano group at C2. The synthesis of pyrrolones 55 can also be carried out starting from azirines and diazo compounds, without isolation of the intermediate 1,3-oxazines. Scheme 10. Synthesis of pyrrolinones via electrocyclic ring opening of 2H-1,3-oxazines.
An interesting feature of the obtained monocyclic 2H-1,4-oxazines 60 is their photoand thermochromic activity, which is attractive for their practical applications. When irradiated with UV light of a mercury lamp, colorless oxazines (λ max 315-360 nm) convert to oxazatrienes 59, colored from yellow to red (λ max 380-455 nm) [42] (Scheme 12). After the termination of irradiation, the cyclization occurs again. For a series of oxazines, the half-life times of the open-chain form were determined; these were in a range of 0.5-29 h, and these times were highly dependent on the substitution pattern. Thermochromism was most pronounced for spirooxazines containing a fluorene fragment at C2 [42]. . The use of azirine-2-carbaldimines as the starting material makes it possible to obtain 1,2,2,4,5-pentasubstituted dihydropyrimidines [44]. Due to the peculiarities of the reactivity of pyrazoles (completely substituted pyrazoles do not react with rhodium carbenes), the reactions of pyrazoles are more suitable for obtaining 1,2,2,5,6-pentasubstituted dihydropyrimidines [45].
It is interesting that the synthesized 1,2-dihydropyrimidines exist in an equilibrium with 1,5-diazatrienes in solution at room temperature [44]. An indirect evidence of this fact, which was also confirmed by the results of quantum chemical calculations, is the rapid epimerization of a dihydropyrimidine, which contains two chiral centers. Thus, dihydropyrimidine (RS,RS)-77, which is stable in a solid state, rapidly transforms into a 1:1 mixture of two diastereomers in CDCl 3 solution via the ring opening-cyclization sequence (Scheme 15). Several approaches to the preparation of 1,4-diazahexa-1,3,5-trienes have been studied to date, the 1,6-electrocyclization of which provides access to 1,2-dihydropyrazine derivatives.
The reaction of isoxazoles 79 with rhodium azavinyl carbenes, generated from 1sulfonyl-1,2,3-triazoles 80 under rhodium(II) catalysis, allows for the generation of 1,4diazahexa-1,3,5-trienes 81 with a sulfonyl substituent at N1 [46]. In these reactions, two products were formed: 3-aminopyrrole 82 and 1,2-dihydropyrazine 83 (Scheme 16). The result of the reaction turned out to be extremely sensitive to reaction conditions (catalyst, solvent, temperature, etc.). The reaction, carried out in chloroform at 100 • C in the presence of Rh 2 (OAc) 4 as a catalyst, is most suitable for the synthesis of 4-aminopyrrole-3-carboxylates 82. The use of dirhodium tetrapivaloate (Rh 2 (Piv) 4 ) in boiling toluene led to the formation of 1,2-dihydropyrazine-2-carboxylates 83 as the major products. The dihydropyrazines 83 were not very stable and gradually underwent dehydrosulfonylation; for this reason, they were converted without isolation to aromatic pyrazines 84 in the presence of TsOH. The NMR spectroscopy data and quantum chemical calculations showed that both products, pyrrole 92 and dihydropyrazine 93, formed from (5Z)-1,4-diazahexa-1,3,5-triene intermediate Z-90 (Scheme 17) [46]. The formation of pyrrole 92 proceeds via 5-exo-trigcyclization of diazahexatriene Z-90 to betaine 91. The effect of the catalyst on the reaction direction can be explained by the stabilization of the betaine through coordination of the catalyst with the betaine anionic nitrogen.
Analogous 1,4-diazatrienes with a sulfonyl substituent at the nitrogen can also be generated from 2H-azirines 86 (Scheme 17) [46,47]. In this case, 3-aminopyrroles 92 are predominantly formed. The reason for this is associated with the selective ring opening of azirinium ylides 88 to (5E)-1,4-diazahexa-1,3,5-trienes E-90, which, as follows from quantum chemical calculations, undergo 5-exo-trig-cyclization through a lower energy barrier than the corresponding Z-isomers Z-90 [46]. Isoxazolium ylide complexes 89, due to geometrical reasons, can provide only diazahexatrienes Z-90 with the C=C bond in the Z configuration, which is of crucial importance for the formation of pyrazines 93. On the other hand, it turned out that the introduction of a strong electron-withdrawing substituent at the C5 of 1,4-diazatriene makes the 5-exo-trig cyclization to betaine 91 unfavorable, probably due to a decrease in the nucleophilicity of the C6 of the diazatriene [46]. As a result, in this case, 1,6-electrocyclization to dihydropyrazine 93 predominantly occurs. Furthermore, it is most likely that this fact helped the authors of [48] to synthesize the aromatic pyrazines 97 in good yields (Scheme 18). 1,4-Diazahexatrienes 100 containing an aryl or alkyl substituent at the C6 and an aryl substituent at the C5 can be converted to dihydropyrazines 102 or 3-aminopyrroles 103 depending on the reaction conditions (Scheme 19) [49]. Tang and coworkers reported the conditions that provided good yields of both cyclic products. In contrast, 1,4-diazahexatrienes 100 containing an aryl substituent at C6 and an alkyl substituent at the C5 position exclusively underwent 1,6-electrocyclization to give dihydropyrazines 101.
Park and coworkers showed that azirines 104 can react with diazo oxime ethers 105 under catalysis with copper(II) hexafluoroacetylacetonate (Scheme 20) [50]. In this case, 1,4-diazahexatrienes 106 are formed as intermediates, which are capable of undergoing 1,6electrocyclization to dihydropyrazines 107. Upon further heating of the dihydropyrazines at high temperature, the elimination of methanol takes place, leading to the formation of completely substituted pyrazine-2-carboxylates 108 in good yields.
The reactions of diazoindolinimines 110 with various 2H-azirines 109 give ortho-fused pyrazines 113 resulting from the 1,6-electrocyclization of intermediate 1,4-diazatrienes 111. These reactions have been studied in detail in the works of three research groups (Scheme 21) [51][52][53]. In all these studies, the formation of the intermediate 1,2-dihydropyrazines 112 was observed. It was found that the aromatization of the 1,2-dihydropyrazines 112 can occur without any additives (when R 2 = CO 2 Me), but at rather high temperature. To carry out this process under milder conditions, it was necessary to add a base (Et 3 N, t-BuOK) or TsOH. Under these conditions, 5H-pyrazino[2,3-b]indoles 113 were obtained in good yields. To obtain 5H-pyrazino[2,3-b]indoles 117 containing an ester substituent, according to the results of previous studies, it would be more convenient to use 5-alkoxyisoxazoles 114 rather than azirines 115 (Scheme 22). Unfortunately, however, isoxazoles 114 proved to be inactive toward diazoindolinimines in the presence of rhodium carboxylates. The authors of the work [53] took advantage of the isomerization of 5-alkoxyisoxazoles 114 to azirine-2-carboxylates 115 found in a previous study. It was found that the isomerization is catalyzed by the same rhodium carboxylate as the subsequent reaction with the diazo compound. Using this procedure, a number of pyrazinoindoles 117 bearing an ester substituent were obtained in good yields.

Conclusions
Reactions of transition metal carbenes with 2H-azirines and azoles containing an N-N or N-O bond is becoming an active field of research, as justified by the growing number of papers covered in this review. This approach is a novel versatile tool for the design of new reactive azapolyene intermediates suitable for the synthesis of various heterocycles via an electrocyclization (i.e., under atom-economical conditions). In contrast to other known methods, the present one features a wide diversity of accessible azapolyenes and, therefore, is able to provide a powerful impetus for the further development of the electrocyclization strategy in heterocyclic synthesis. The method has been exploited for the synthesis of unique 2,3-dihydroazetes, 2H-1,3-oxazines, 2H-1,4-oxazines, 1,2-dihydropyrimidines, various pyrazine and pyridine derivatives, etc. Moreover, the method provided azapolyenes, which are capable of undergoing an unprecedented 1,5-electocyclization to pyrrole and indole derivatives.
Although a great number of studies has been conducted, the described approach is just at the beginning stage. We believe that the use in the reactions of azirines and azoles containing polyene and heteropolyene substituents seems to be promising for further unlocking the potential of the method. Furthermore, the reactions of transition metal carbenes with azoles ortho-fused with aromatic and heteroatomatic rings remain practically unexplored. At the same time, these reactions should result in the formation of azapolyenes, which are most promising for the development of new photochromic materials. Another fruitful area of upcoming research, in our opinion, is switchable electrocyclizations of azapolyenes upon treatment by a specific catalyst, providing selective access to several heterocyclic systems from the same starting materials. In this context, it seems prospective to intensify the search for cheaper catalytic systems for azapolyene generation and pay attention to the reactions of azoles and their derivatives with copper carbenes. It also seems promising to study the transformation of non-aromatic diaza-and oxaza-derivatives of a cyclohexa-1,3-diene to stable aromatic heterocycles.