Recent Advances of 1,3,5-Triazinanes in Aminomethylation and Cycloaddition Reactions

Abstract

1,3,5-Trisubstituted 1,3,5-triazinanes (hexahydro-1,3,5-triazines), as stable and readily available surrogates for formaldimines, have found extensive applications for the construction of various nitrogen-containing compounds. The formaldimines, formed in situ from this reagent class, can participate in various aminomethylation and cycloaddition­ reactions. This short review presents recent advances in this field with emphasis on the conceptual ideas behind the developed methodologies and the reaction mechanisms.

1 Introduction

2 Aminomethylations with 1,3,5-Triazinanes

3 Cycloadditions with 1,3,5-Triazinanes

3.1 Use of 1,3,5-Triazinanes as Two-Atom Synthons

3.2 Use of 1,3,5-Triazinanes as Three-Atom Synthons

3.3 Use of 1,3,5-Triazinanes as Four-Atom Synthons

3.4 Use of 1,3,5-Triazinanes as Six-Atom Synthons

4 Conclusions

Introduction

Nitrogen-containing scaffolds are attractive structural units widely found in numerous biologically active natural alkaloids, agrochemicals, and pharmaceuticals.[1] Not surprisingly, a diverse range of synthetic approaches have been exploited for their synthesis. Despite this, the development of conceptually novel and versatile methods for the synthesis of structurally diverse nitrogen-containing compounds from readily available and practical building blocks is still highly desirable.[2]

1,3,5-Triazinanes (hexahydro-1,3,5-triazines), first reported by Bischoff and Reinfield in 1902,[3] can be easily prepared from the condensation of paraformaldehyde and various aryl- or alkyl-substituted amines in ethanol/water or toluene solution under basic or heating conditions (Figure [1]).[4] During the past few years, 1,3,5-triazinanes, as stable and readily available surrogates of formaldimines, have attracted increasing attention for the construction of various valuable nitrogen-containing compounds.[5] In this review, we will present recent advances in aminomethylation and cycloaddition reactions with 1,3,5-triazinanes. Special emphasis­ is also placed on the conceptual ideas behind the developed methodologies and the reaction mechanisms.

Aminomethylations with 1,3,5-Triazinanes

As bench-stable and readily available surrogates for formaldimines, 1,3,5-triazinanes have been extensively used as efficient electrophilic reagents in various aminomethylation reactions. In 2015, the Krische group reported a novel ruthenium(II)-catalyzed hydroaminomethylation of allenes 1 with N-arylformaldimines derived in situ from 1,3,5-triazinanes 2 (Scheme [1a]).[6] This process provided branched products of hydroaminomethylation 3 with full carbon quaternary centers. Under the optimal conditions, a series of 1,1-dialkyl- and 1-methyl-1-aryl-substituted allenes were well tolerated and gave the corresponding products 3 in moderate to good yields, but the reaction of monosubstituted allenes did not proceed well. In addition, N-alkyl-, N-acyl-, and N-sulfonyl-1,3,5-triazinanes and alkyl-substituted N-PMP imines are not suitable for this reductive coupling. Mechanistically, in this process, the ruthenium hydride complex hydrometalates the allene to form a nucleophilic allylruthenium complex 1-A. Then, the pentacoordinate allylruthenium species 1-A coordinates with formaldimine, and the addition reaction proceeds through a closed transition state structure 1-B to form homoallylruthenium amide 1-C. Finally, the amidoruthenium intermediate 1-C undergoes protonic cleavage by i-PrOH to release the product 3 and provide ruthenium isopropoxide, which forms acetone and regenerates the ruthenium hydride after β-hydride elimination.

In 2016, the Krische group further explored an interesting ruthenium-catalyzed hydroaminomethylation of 1,3-dienes 4 with 1,3,5-triazinanes 2 to form homoallylic amines 5, in which i-PrOH was also used as terminal reductant (Scheme [1b]).[7] Under similar reaction conditions, a range of 2-substituted 1,3-dienes 4 reacted with 1,3,5-triazinanes 2 smoothly to furnish products 5 as single regioisomers in good yields. Notably, in the presence of (R)-MeO-furyl-BIPHEP as chiral ligand, the reaction of isoprene (4a) with N-(2-methoxyphenyl)triazinane 2a provided homoallylic­ amine 5a in 54% yield with an enantiomeric ratio of 93:7.

In 2016, the Feng group reported that N,N′-dioxide-Ni(II) or N,N′-dioxide-Mg(II) complexes catalyzed the asymmetric Mannich reaction of α-tetralone-derived β-keto esters/amides 6 and 8 with 1,3,5-triazinanes 2 as Mannich reagents (Scheme [2]).[8] It was found that, under the optimal reaction conditions, a wide variety of β-keto esters or amides and substituted 1,3,5-triazinanes were well accommodated to deliver the corresponding β-amino compounds 7 or 9, respectively, with an all-carbon quaternary stereocenter in good to excellent yields with excellent enantioselectivity. In the transition state 6-A, the oxygen atoms of the N,N′-dioxide and the amide oxygen are coordinated to Ni(II) in a tetradentate manner, and β-keto ester 6 is activated after coordination with the nickel atom. Then, β-keto ester 6 attacks the N-formaldimine from the less sterically hindered Re-face to form the desired product with R configuration.

Besides, by using chiral-at-metal rhodium complexes Δ-Rh as the chiral Lewis acid, Kang and co-workers achieved a highly enantioselective Mannich reaction of 2-acylimidazoles 10 with 1,3,5-triazinanes 2 as N-arylformaldimine precursors (Scheme [3]).[9] In this protocol, a wide variety of 2-acylimidazoles 10 and 1,3,5-triaryl-1,3,5-triazinanes 2 bearing electron-donating or electron-withdrawing groups on the aryl ring were well tolerated to afford the corresponding β-amino derivatives 11 in high yields with good to excellent enantioselectivities. Notably, 0.1 mol% loading of Δ-Rh complex also allowed the gram-scale reaction to proceed smoothly without any loss of enantioselectivity. As shown in the transition state, the Si-face of the intermediate 10-A is effectively shielded by tert-butyl groups. Therefore, the Re-face of the intermediate 10-A attacks the in situ formed N-arylformaldimine to form the desired product with S configuration.

In 2019, by combining rhodium-catalyzed C–H activation and photoredox catalysis, Shi and co-workers achieved a site selective C–H aminomethylation at C3 of indoles (Scheme [4]).[10] The protocol exhibited broad substrate scope and excellent functional group tolerance. An array of substituted indoles with nitrogen-containing heterocycles as directing groups all proved amenable to the reaction, producing the corresponding products 13 in moderate to good yields. In addition, pyrroles with pyridine or pyrimidine as the directing group could also react smoothly under the standard conditions. Based on the widely recognized mechanism of C–H bond activation and the control experiments, it is postulated that formaldimine 2A is oxidized by excited state Eosin Y to give a cationic radical species 2A′. On the other hand, substrate 12 is activated by rhodium(III) complex to obtain intermediate 12-A, and reacts with 2A′ to generate the rhodium species 12-B. Then, a SET process between 12-B and Eosin Y^•– occurs to furnish the rhodium (III) species 12-C and ground state photocatalyst. Finally, intermediate 12-C undergoes a proton demetalation to regenerate the Rh(III) catalyst and release the desired product 13.

Cycloadditions with 1,3,5-Triazinanes

Different from these aminomethylation protocols, 1,3,5-triazinanes can also been used as versatile two-, three-, four-, and six-atom synthons in various cycloaddition reactions for the synthesis of nitrogen heterocycles (Figure [2]). In this section, selected examples of cycloadditions of 1,3,5-triazinanes are described according to their different reaction types.

Use of 1,3,5-Triazinanes as Two-Atom Synthons

In 2017, Werz and co-workers reported a formal [3+2]-cycloaddition reaction of donor-acceptor cyclopropanes 14 using the 1,3,5-triazinanes 2 as surrogates for formald­imines (Scheme [5a]).[11] In the presence of 10 mol% of MgI₂ as Lewis acid, this protocol tolerated a wide variety of functional groups in both components, and provided an efficient entry to diverse 2-unsubstituted pyrrolidines 15 in good yields of up to 93%. Furthermore, the donor-acceptor cyclobutanes 16 also proved to be suitable for this reaction under the standard conditions, leading to the formation of six-membered ring systems, piperidines 17 in good yields. The stereospecificity of the formal [3+2]-cycloaddition reaction of (S)-14a and 2b under the standard conditions was explored, and it was found that the reaction occurred with complete stereospecificity (Scheme [5b]).

As show in Scheme [6], donor-acceptor cyclopropane (S)-14a is activated by catalyst MgI₂ to obtain the more polarized cyclopropane (S)-14A. The iodide anion opens the cyclopropane through a S_N2 process to form (R)-14B. Then, enolate (R)-14B reacts with formaldimine 2B, originating in situ from 1,3,5-triazinane 2b, to give (R)-14C. Finally, the intermediate (R)-14C undergoes intramolecular cyclization through an additional S_N2 process to obtain (S)-15a with net retention at the stereogenic center.

In 2018, the Liu and Zheng group reported a similar AlCl₃­-catalyzed [3+2]-cycloaddition of donor-acceptor cyclopropanes with 1,3,5-triazinanes.[12] This protocol also allowed highly functionalized pyrrolidines to be synthesized in moderate to excellent yields under mild reaction conditions. However, the reaction was limited to 1,3,5-triaryl-1,3,5-triazinanes, while no desired product was observed in the case of 1,3,5-tribenzyl-1,3,5-triazinane. Mechanistically, the reaction is facilitated by the competitive S_N1 and S_N2 pathways to provide pyrrolidines. Based on this study, Liu and co-workers also developed a 1,3-dipolar cycloaddition of 1,3,5-triazinanes 2 and aziridines 18 (Scheme [7]).[13] Under the optimal reaction conditions, a wide variety of readily available 1,3,5-triazinanes 2 and phenyl- or allyl-substituted aziridines 18, bearing electron-donating or electron-withdrawing groups on the phenyl ring, were well tolerated to deliver the corresponding functionalized imidazolidine derivatives 19 in moderate to good yields. Notably, N-Ms- and N-Bn-aziridines also worked well, and furnished the corresponding products 19a and 19b in good yields, respectively. Moreover, N-Boc-protected aziridine could also be tolerated and gave imidazolidine 19c in 36% yield after deprotection of the Boc group under the acidic conditions; while substrate N-acetylaziridine was completely inactive and did not give 19d.

In addition, Sun and co-workers reported a novel base-promoted [3+2]-cycloaddition reaction of α-bromo hydroxamates 20 (X = Br) with 1,3,5-triazinanes 2 (Scheme [8]).[14] This mild and operationally simple protocol afforded the corresponding 3-alkoxyimidazolidin-4-ones 21 in moderate to good yields. In this reaction, the reactive intermediate azaoxyallyl cations 20-A, formed in situ from readily available starting materials α-halo hydroxamates 20 in the presence of t-BuOK as inorganic base, serve as a formal 1,3-dipole. Under the optimal reaction conditions, an array of mono- and dialkyl-substituted hydroxamates with various N-protecting groups such as methoxy, allyloxy, and propynyloxy all proved to be amenable to the reaction. Moreover, α-chloro hydroxamate 20 (X = Cl) was also compatible with the reaction albeit with relatively lower reactivity.

In 2019, the Yuan group disclosed the first organocatalytic asymmetric [3+2]-cycloaddition reaction of 3-isothiocyanato-oxindoles 22 with 1,3,5-triazinanes (Scheme [9]).[15] By using cinchona alkaloid derived thiourea A as the organocatalyst, a diverse variety of biologically important chiral spiro-imidazolidinethione-oxindoles 23 were obtained in generally good yields with excellent enantioselectivities. As shown in the transition state model 22-A, the thiourea part of catalyst A activates the formaldimine via double hydrogen bonds; on the other hand, the tertiary amine part of catalyst A works as a base to deprotonate the hydrogen atom at C3 of the 3-isothiocyanato-oxindole 22, thereby improving the nucleophilicity of the C3 position. Then, the activated C3 position attacks the formaldimine from the Re-face, followed by intramolecular cyclization to obtain the corresponding product with R configuration.

In 2018, the Krasavin group demonstrated a formal [4+2]-cycloaddition of homophthalic anhydride (HPA, 24) with 1,3,5-triazinanes 2 (Scheme [10]).[16] This Castagnoli–Cushman-type reaction enabled the direct preparation of hitherto unknown 3-unsubstituted tetrahydroisoquinolonic acid methyl esters 25. This protocol showed a broad substrate scope of aryl- and alkyl-substituted 1,3,5-triazinanes. However, byproducts 26 and 27, which were generated by direct aminolysis of HPA and addition of two equivalents of HPA with formaldehyde, respectively, were observed in large quantities, suggesting that the reaction conditions require further optimization.

The Sun group reported a copper-catalyzed asymmetric formal [4+2]-cycloaddition of 1,3,5-triazinanes 2 with copper allenylidenes generated in situ from 4-ethynyl-3,1-benz­oxazinan-2-ones 28 (Scheme [11]).[17] This protocol exhibited a broad substrate scope. A large number of alkyl-, aryl-, and benzyl-substituted 1,3,5-triazinanes 2, and various functionalized 4-ethynyl-3,1-benzoxazinanones 28 reacted effectively to produce the desired chiral tetrahydroquinazolines 29 in moderate to good yields with good enantio­selectivities. A plausible transition state 28-A for this [4+2]-cycloaddition is proposed, wherein formaldimines tend to attack the copper allenylidenes from the Re-face, followed by a cyclization reaction to produce the final product with high enantioselectivity.

In 2019, Liu and co-workers revealed an inverse-electron­-demand [4+2]-cycloaddition reaction of in situ generated aza-o-quinone methides with 1,3,5-triazinanes (Scheme [12]).[18] In this reaction, aza-o-quinone methides 30-A were generated in situ via base-mediated 1,4-elimination from 2-(chloromethyl)anilines 30, which subsequently reacted with 1,3,5-triazinanes to afford the corresponding diversely functionalized tetrahydroquinazolines 31 in moderate to good yields. It was worth noting that the N-protective group in the 2-(chloromethyl)aniline was not limited to arylsulfonyl­ groups, and the N-CO₂Me group was also suitable for this reaction under the optimal conditions.

In 2020, the Xuan group documented a [4+2]-cycloaddition of o-hydroxyphenyl-substituted p-QMs 32 with 1,3,5-triazinanes (Scheme [13]) without any catalyst or additive under mild conditions.[19] The protocol also demonstrates broad substrate scope with respect to both reaction components, giving the corresponding 1,3-benzoxazine derivatives 33 in moderate to good yields. Remarkably, in this work, the reaction was expanded to pharmaceutical-derived­ 1,3,5-triazinanes and the expected products 33a and 33b were isolated in satisfactory yields. These results showed the potential application of this protocol in the late-stage structural functionalization of drugs.

Also in 2020, the Xiao and Chen group developed a novel visible-light-induced [4+2]-cycloaddition of in situ formed aza-o-quinone methides with formaldimines derived from 1,3,5-triazinanes (Scheme [14]).[20] In this three-component process, highly functionalized aza-o-QMs were generated in situ from 2-vinyl-substituted anilines 34 and perfluoroalkyl radical precursors, such as Umemoto reagent­ 35a, via a visible-light-driven radical-mediated strategy. This redox-neutral protocol featured simple operation, readily available substrates, good functional-group tolerance, and scaling-up potential, providing a generally applicable access to diverse tetrahydroquinazolines 36 in moderate to good yields. Notably, α-halocarbonyl compound 35b and 35c, haloalkanes 35d, and cholesterol-derived bromide 35e were also compatible with the reaction.

As shown in Scheme [15, a] possible mechanism is proposed for this reaction. The reaction begins with SET reduction of Umemoto reagent 35a by the excited state photocatalyst, giving the CF₃ radical. Then, the CF₃ radical undergoes addition to the olefin moiety of 34 to provide benzylic radical 34-A. Subsequently, radical 34-A is further oxidized by the oxidizing state photocatalyst to form benzylic cation 34-B, which undergoes facile deprotonation in the presence of base to give the key intermediate aza-o-QM 34-C. Finally, an inverse-electron-demand [4+2]-cycloaddition of the aza-o-QM 34-C with formaldimine 2A, derived in situ from 2, occurs to furnish the product 36.

In 2018, the Yang group disclosed a palladium-catalyzed [5+2] cyclization of vinylethylene carbonates 37 (X = O) and 1,3,5-triazinanes 2 (Scheme [16]).[21] Notably, the reactions of substrates with aromatic functional groups (R¹) attached to vinylethylene carbonates afforded higher yields than those with non-aromatic functional groups. Possibly, the aromatic functional groups stabilize the π-allylpalladium intermediate and prevented it from losing activity. One example of the palladium-catalyzed [5+2] cyclization of 3-vinyloxazolidin-2-ones 37 (X = NNs) and 1,3,5-triazinanes 2 was reported to give the corresponding tetrahydro-1,3-diazepine 38 in low yield. Moreover, a different type of 5-membered N-heterocyclic ring, imidazolidine 39, could be synthesized from vinylethylene carbonates 37 and N-aryl-substituted 1,3,5-triazinanes by judicious modification of the catalyst and solvent. A plausible mechanism is proposed in Scheme [16]. First, π-allylpalladium intermediate 37-A is formed by the oxidative addition of Pd(0) to 37a and release of carbon dioxide. This complex then reacts with formaldimine 2B to form the intermediate 37-B, followed by reductive elimination to obtain the formal [5+2]-cycloaddition product 38a, with regeneration of the Pd(0) catalyst. After that, the seven­-membered ring product 38a is further oxidized by the Pd(0) species to form an intermediate 37-B, which is then captured by another formaldimine 2B and a ten-membered ring intermediate 37-C is obtained. Subsequently, 37-C undergoes reductive elimination and intramolecular rearrangement to provide a formal migration [2+3]-cycloaddition product 39a, and a molecule of formaldehyde is released.

Use of 1,3,5-Triazinanes as Three-Atom Synthons

In 2017, the Sun group reported an unprecedented intermolecular formal [3+3] cycloaddition between imines 40 and 1,3,5-triazinanes 2 under catalyst-free conditions (Scheme [17]).[22] This protocol offers a straightforward and mild access to a diverse range of polysubstituted tetra­hydropyrimidines 41 in moderate to excellent yields. Different from previous transformations, the 1,3,5-triazinanes were used as a type of formal three-atom synthon in such cycloaddition reactions. As described in the proposed mechanism, the enamine 40-A, isomerized from imine 40, reacts with in situ formed formaldimine 2A to generate intermediates β-aminoimine 40-B or 1,3-diamine 40-C through a formal aza-ene-type reaction. Moreover, formaldimine 2A can also undergo hydrolysis to the amine and formaldehyde due to the existence of a small amount of water. Then, intermediate 40-C undergoes condensation with the in situ formed formaldehyde to generate the final product tetrahydropyrimidine 41, and one molecule of water is released. This protocol features operational simplicity and mild conditions, opening a new way to the reaction modes of 1,3,5-triazinanes.

In 2019, Yang and co-workers revealed a Pd-catalyzed [3+3]-cycloaddition reaction of vinylethylene carbonates 37 with 1,3,5-triazinanes 2 (Scheme [18]).[23] Distinct from their previous [5+2] cycloaddition (Scheme [16]),[21] the reaction mode in this process was completely changed, wherein a stepwise addition process was involved. The formal [3+3]-cycloaddition products, polysubstituted tetrahydropyrimidines 42, were obtained in moderate to good yields under similar reaction conditions. Mechanistically, vinylethylene carbonate 37a is decarboxylated under Pd catalysis to form zwitterionic π-allylpalladium intermediate 37a-A, which can be converted into unsaturated enol 37a-B via β-H elimination, and then isomerizes to α,β-unsaturated aldehyde 37a-C. Subsequently, it reacts with in situ formed formald­imine 2B to give the intermediate 37a-D, which loses a formaldehyde via route a or b to provide the intermediate 37a-G. Finally, 37a-H is formed through an intramolecular condensation reaction, followed by the loss of one molecule of water to form the final product 42a.

Use of 1,3,5-Triazinanes as Four-Atom Synthons

In 2015, the Ferreira group described a new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones 44 by a sequential reaction of 2-hydroxy-1,4-naphthoquinone 43 and 1,3,5-triazinanes under microwave irradiation (Scheme [19]).[24] Although this protocol only included six examples of 1,3,5-triazinanes 2, it demonstrated that 1,3,5-triazinanes 2 could participate in the reaction not only as a single-molecule of formaldimine, but also as a four-atom synthon through sequential reaction.

In 2016, the Sun group demonstrated an unprecedented gold-catalyzed [4+1]- and [4+3]-cycloaddition reactions of 1,3,5-triazinanes 2 with different diazo esters 45 and enol diazoacetates 47 (Scheme [20]).[25] The catalytic system showed exceptional broad substrate scope, and enabled diverse annulations to provide five- or seven-membered heterocycles 46 and 48, respectively, in moderate to high yields under mild reaction conditions. It was noteworthy that when the vinyl-substituted diazoacetates were used, the catalytic system provided the desired five-membered imidazolidines 46 in modest yields; when enol diazoacetates 47 were used in the reaction, seven-membered heterocycles 48 were formed through a formal [4+3]-cyclization reaction.

Detailed mechanistic investigations disclosed that the 1,3,5-triazinanes participate in the reactions directly, rather than as formaldimine precursors. As for the formal [4+1] cycloaddition, it is postulated that the reaction of the 1,3,5-triazinanes 2 with in situ formed metal-carbene 45-A provides intermediate 45-B. Then, 45-B undergoes intramolecular cyclization and loses one molecule of formaldimine to afford the final product 46, with regeneration of the gold catalyst (Scheme [21a]). For the formal [4+3] cycloaddition, the enol diazoacetate 47 interacts with the gold catalyst to form the gold enolcarbene species 47-A or 47-B. Then, the nucleophilic addition of 2 at the vinylogous position of enolcarbene affords intermediate 47-C, which undergoes intramolecular cycloaddition to provide the final product 48, with release of a formaldimine molecule and regeneration of the gold catalyst (Scheme [21b]).

In addition, the Sun group further reported an interesting gold-catalyzed [3+2+2] cycloaddition of enynones 49 with 1,3,5-triazinanes 2 (Scheme [22]).[26] This methodology also exhibited broad substrate scope of enynones and 1,3,5-triazinanes. Notably, the reactions of both acyclic ketones and cyclic ketones proceeded smoothly to provide the corresponding 3,4-fused bicyclic furan compounds 50 in moderate to good yields. This protocol featured formation of multiple bonds in a single operation. The mechanistic studies indicated that formaldimine derived in situ from 1,3,5-triazinane, instead of 1,3,5-triazinane itself, was involved in the cycloaddition. It is postulated that the furanyl gold intermediate 49-A, generated from gold-catalyzed cyclization of enynone 49, is captured by formaldimine 2A to yield intermediate 49-B. Then, addition of another molecule of 2A to 49-B affords intermediate 49-C, which undergoes intramolecular cyclization to deliver 50, regenerating the gold catalyst. At almost the same time, the Xu and Qiu group also reported a similar gold-catalyzed tandem dual heterocyclization of enynones with 1,3,5-triazinanes using PPh₃AuNTf₂ as gold catalyst.[27]

As a continuation of their study on the chemistry of 1,3,5-triazinanes, Sun and co-workers also developed an interesting gold-catalyzed [2+2+2]-cycloaddition reaction between allenes 51 and 1,3,5-triazinanes 2 (Scheme [23]).[28] The reaction provides an access to diverse valuable six-membered N-heterocycles with moderate to excellent yields under mild conditions. Importantly, different types of functionalized allenes such as N-allenamides 51 and allenoates 53 showed distinct selectivity and reactivity under the same reaction conditions.

Detailed mechanistic studies involving control and deuterium-labeling experiments revealed that such cycloaddition proceeds through stepwise and iterative additions of formaldimines to the allene moieties. As shown in Scheme [24], the cationic gold complex firstly reacts with N-allen­amide 51 to produce gold species 51-A (route a). The intermediate 51-A undergoes a nucleophilic addition reaction with one molecule of formaldimine to produce intermediate 51-B. Then, 51-B reacts with another molecule of formaldimine in a cycloaddition manner to give intermediate 51-C. Finally, deauration furnishes the desired product 52. Alternatively, the gold complex can work as a Lewis acid catalyst to activate the carbonyl group of allenoate 53 (route b). The nucleophilic cycloaddition reaction of activated allenoate 53 with two molecules of formaldimine provides intermediate 53-C, which undergoes isomerization to afford the final product 54.

In 2017, the Hashmi group disclosed a gold-catalyzed regioselective cyclocarboamination of ynamides 55 with 1,3,5-triazinanes under mild conditions (Scheme [25]).[29] This protocol provided a facile and modular approach for the synthesis of valuable 4-aminotetrahydropyrimidines 56. In this process, a series of aryl-substituted ynamides 55 bearing various protecting groups such as mesyl, tosyl, oxazolidinone, and benzosultam on the nitrogen atom all proved to be suitable for this reaction, giving good to excellent yields. Detailed mechanism studies suggested that the intermolecular cyclocarboamination results from a pseudo-three-component [2+2+2] cycloaddition. First, formaldimines 2A, generated in situ from 1,3,5-triazinanes, regiospecifically attacks the gold-activated ynamides to form the intermediates 55-A, which reacts with another molecule of 2A to afford intermediate 55-B. Then, intramolecular cyclization of 55-B occurs to give intermediate 55-C. Finally, 55-B undergoes protodeauration to provide the final six-membered products 56. In this process, 1,3,5-triazinanes also work as four-atom synthons.

Remarkably, the Sun group revealed that gold catalysis also enabled a novel [2+2+2+2]-annulation reaction between 1,3,5-triazinanes 2 and alkoxyallenes 57, providing eight-membered heterocycles 58 in good to excellent yields (Scheme [26a]).[30] In their previous study, the gold-catalyzed reaction of allenamides with 1,3,5-triazinanes in a 1:1 ratio resulted in the formation of only six-membered heterocycles.[28] However, as shown in Scheme [26b], one equivalent of 2c and 57a yielded 58a and 58a′ in 43% and 56% yields, respectively. A further control experiment using of 58a′ and 57a in a ratio of 1:1, performed under the standard conditions, provided 58a in high yield (Scheme [26c]). This observation indicated that the six-membered products such as 58′ should be the possible intermediate, and could react with another molecule of allyl diene to form the corresponding eight-membered adduct.

The plausible reaction mechanism for this reaction is shown in Scheme [27]. First, the in situ generated formald­imine 2C attacks the gold-activated allene intermediate 57-A to provide the intermediate 57-B. Then, the desired product 58a can be obtained by [4+4] cyclization between two molecules of intermediates 57-B, with regeneration of the gold catalyst. Alternatively, the reaction of gold species 57-B with 2C will also deliver intermediate 57-C, which gives the six-membered product 58a′ through intermolecular cyclization. Nevertheless, in the presence of a gold catalyst, 58a′ can also return to intermediate 57-C, which is captured by another intermediate 57-A to afford the final product 58a.

In addition to the gold-catalyzed cyclization of 1,3,5-triazinanes, the Sun group also developed a novel metal-free [2+1+2]-cycloaddition reaction of tosylhydrazones 59 and 1,3,5-triazinanes using the base LiOt-Bu (Scheme [28]).[31] The reaction provided the corresponding imidazolidines 60 in moderate to good yields under mild reaction conditions. Interestingly, some control experiments revealed that LiOt-Bu not only works as a base to enable slowly release of the diazo from tosylhydrazone, but also promotes the ensuing cycloaddition. First, diazo 59a′, which is slowly released from tosylhydrazone 59a in the presence of LiOt-Bu, and formaldimine 2C undergo a formal [2+1]-cycloaddition reaction to form aziridine intermediate 59-C through intermediates 59-A or 59-B. Then, aziridine 59-C undergoes a base-promoted­ ring-opening reaction by another molecule of 2C to provide the intermediate 59-D, which further undergoes an intramolecular cyclization to furnish the final product 60a.

In addition to gold catalysts, other commonly used metals such as iron and copper have also recently been exploited to catalyze the cycloaddition reaction of 1,3,5-triazinanes as four-atom synthons. For example, the Sun group reported a general iron-catalyzed [2+2+1]-cycloaddition reaction of diazo surrogates 61 and 45 with 1,3,5-triazinanes (Scheme [29a]).[32] Importantly, different from their former gold catalyst system that was only suitable for donor­/acceptor diazo substrates 45,[25] the Sun group used MnO₂ as oxidant to generate the active diazo intermediates in situ from simple hydrazines 61. Thus, they achieved an efficient [2+2+1]-cycloaddition reaction of donor/donor diazo substrates, providing the corresponding imidazolidines 62 in moderate to high yields. In addition, donor/acceptor diazo compounds 45 were also well tolerated in this iron-catalyzed process without the use of MnO₂ giving imidazole-4-carboxylates 63. In 2017, the Werz group reported a formal [4+3]-cycloaddition reaction between donor-acceptor cyclopropanes 64 and 1,3,5-triazinanes using Sc(OTf)₃ as Lewis acid (Scheme [29b]).[33] This mild reaction enabled synthesis of diversely functionalized 1,3-diazepanes 65 with generally high yields. Competition experiment results suggest that 1,3,5-triazinanes directly participate in the reaction rather than being decomposed into three formaldimine molecules. It was worth noting that direct treatment of 1,3-diazepanes 65 with acid allowed its efficient conversion into 1,4-diamines 66. As a result, a one-pot ring-opening procedure was developed to directly transform donor-acceptor cyclopropanes into significant acyclic 1,4-diamines. In 2019, the Wang and Lu group documented a copper(I)-catalyzed formal [2+2+1]-cycloaddition reaction between 3-diazoindolin-2-imines 67 and 1,3,5-triazinanes 2 (Scheme [29c]).[34] The reaction proceeded under very mild conditions and tolerated a variety of functional groups, allowing synthesis of densely functionalized spirocyclic products 68 in moderate to good yields. The key step of this reaction­ also involves formation of a copper-carbene intermediate­ from diazo substrates and further cyclization with 1,3,5-triazinane-derived formaldimines or 1,3,5-triazinanes.

Use of 1,3,5-Triazinanes as Six-Atom Synthons

In 2019, Bao and co-workers reported that an elegant intermolecular cycloaddition reaction between a diverse range of (hetero)aryl- and alkyl-substituted N-sulfonyl-1,2,3-triazoles 69 and 1,3,5-triazinanes 2 could be successfully achieved using Rh(II) catalyst (Scheme [30]).[35] Different from the formal [4+n]-cycloaddition reactions of diazo carbene precursors with 1,3,5-triazinanes, the Rh(II)-azavinyl carbene intermediates generated in situ by Rh(II)-catalyzed denitrogenation of 1,2,3-triazoles 69 exhibited unique reactivity mode in cycloaddition with 1,3,5-triazinanes, and produced octahydro-1H-purine derivatives 70 in moderate to good yields. It is worth noting that N₂ was the only byproduct in this reaction. On the basis of detailed mechanism experiments and DFT calculation studies, a possible mechanism for this reaction has been proposed. First, Rh(II)-azavinyl carbene intermediate 69-A is generated from Rh(II)-catalyzed denitrogenation of 1,2,3-triazole 69. Then, 1,3,5-triazinane directly undergoes a nucleophilic addition reaction with Rh intermediate 69-A to form intermediate 69-B. Competitive experiments indicated that the dissociation/association of formaldimine fragment from 69-B might occur. An intramolecular cyclization of 69-B occurs to give the formal [6+3]-cycloaddition adduct, nine-membered ring intermediate 69-C, which undergoes another intramolecular nucleophilic cyclization to afford the intermediate 69-D. Finally, 69-D undergoes a sequential ring-opening and intramolecular cyclization to give the desired product 70 through the intermediate 69-E. Notably, in this process, the whole molecule of 1,3,5-triazinane is incorporated into the final product.

Conclusions

In conclusion, we have presented here an overview of the recent advances in the chemistry of 1,3,5-triazinanes. Such types of reagents have been established as readily available and versatile surrogates for formaldimine, and enabled the development of various synthetically important aminomethylation and cyclization reactions. Notably, 1,3,5-triazinanes can serve as two-, three-, four-, and six-atom synthons to take part in various cycloaddition reactions for the synthesis of nitrogen heterocycles of different sizes. Despite these significant advances, however, further development of new strategies to construct larger ring systems, such as nine- and ten-membered rings, is still a challenging but desirable task. Moreover, the catalytic asymmetric variants of the above-mentioned aminomethylations and cyclizations of 1,3,5-triazinanes are still in their infancies. Considering the growing field of catalysis[36] [37] and development of new synthetic methods for 1,3,5-triazinane synthesis,[38] it is believed that additional new and useful 1,3,5-triazinane chemistry will be discovered in the near future.

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