Ring-opening reactions of nitrogen-containing heterocyclic compounds at the nitrogen–heteroatom bond

Over the past decade, the number of studies devoted to the synthesis of polyfunctional acyclic compounds from heterocycles based on the cleavage of carbon – heteroatom (O, N, etc.) bonds has increased. In 2019, our research team published a review article[1] in the Russian Chemical Reviews on reactions of nitrogen-containing heterocyclic compounds involving ring opening at the carbon – nitrogen bond. This review noted that the bond-cleavage approach allows for the simple and minimal number of steps required to obtain acyclic bifunctional compounds otherwise difficult to access. Most bond-cleavage reactions are stereoselective, which is crucial for the synthesis of biologically active compounds.

Since 2019, a number of reviews have appeared describing synthetic approaches to new derivatives by cleaving the carbon–heteroatom bond in heterocyclic compounds. Most of these studies reported ring opening at the carbon – heteroatom bond in small (three- and four-membered) heterocycles,[2-7] which is likely due to the ease of opening such strained systems (Fig. 1a). However, there are significantly fewer review articles describing similar processes in medium-sized (five- and six-membered) heterocycles (see Fig. 1b).[8-10]

Fig. 1

Synthesis of acyclic polyfunctional compounds based on ring opening of small (a) and medium-sized (b) rings at the carbon – heteroatom and nitrogen – heteroatom (c) bond

There are virtually no reviews devoted to the ring-opening of nitrogen-containing heterocycles at the nitrogen – heteroatom bond, which can provide an access to various functionalized acyclic nitrogen-containing compounds. Such compounds play an important role in the pharmaceutical and chemical industries[11-15] and are often used as synthons for the production of a variety of biologically active substances. This review provides the first summary of methods for synthesizing acyclic nitrogen-containing polyfunctional compounds by ring opening of nitrogen-containing heterocycles at the nitrogen – heteroatom bond (see Fig. 1c). The material is classified by the nature of the bond being cleaved and the type of reagent enabling the process. We hope this information will help synthetic chemists to gain a deeper insight into the state-of-the-art effective methods based on the ring opening of five-, six-, seven-, and eight-membered N-heterocycles at the nitrogen – heteroatom bond.

One of the most studied processes involving ring opening at the N – N bond is the reaction of heterocyclic compounds involving reducing agents. The widespread use of this method is due to its convenience and high selectivity. Hydrogen and samarium(II) iodide are most commonly used reducing agents.

This Section describes the types of the N – N bond cleavage that enable the synthesis of acyclic diamines, diamides, or aminoamides in which the functional groups are separated by spacers of different structures. Hydrogenolysis of the N – N bond in cyclic hydrazines 1a – c with two ester functionalities was carried out over platinum oxide under a stream of hydrogen in dilute hydrochloric acid (Scheme 1). This gave diamines 2a – c in good yields.[16]

Scheme 1

Several reactions involving pyrazolidine derivatives have been described. For example, hydrogenation of pyrazolidine 3a on palladium gives diamine 4a with high stereoselectivity (conditions a).[17] Similar reaction of compound 3b in the presence of platinum oxide also delivers diamine 4b but in significantly lower yield (conditions b).[18] The use of boron hydride as a reducing agent delivered diamine 4c as a racemate (conditions c).[19][20] And in the study,[21] 1,3-diphenylpropane-1,3-diamine (4d) with optical purity > 99% was synthesized by reduction of 1-acetyl-3,5-diphenylpyrazolidine (3d) with Raney nickel (Ni-Ra) followed by treatment with (–)-dibenzoyl-L-tartaric acid (conditions d ) (Scheme 2).

Scheme 2

The reaction sequence involving removal of tert-butoxycarbonyl (Boc) protective group from the nitrogen atom of 3,4-dihydrophthalazine 5, hydrogenolysis of the N–N bond, and subsequent protection of both nitrogen atoms to give the substituted 1,4-diamine 6 (Scheme 3).[22]

Scheme 3

Based on the reduction of triazabicyclo[3.2.1]octanes 7a – d in the presence of palladium on carbon, an effective method for the synthesis of (3S,5R)-piperidine-3,5-diamine derivatives 8a – d was developed (Scheme 4).[23-25] The target products are formed in moderate to high yields.

Scheme 4

Reductive cleavage of the N – N bond in bicyclic hydrazides 9a,b provided an access to cyclopentane diamines 10a,b in good yields (Scheme 5).[26-29]

Scheme 5

It is worth noting the study,[30] which demonstrated the possibility of cleaving the N=N bond in compound 11. The process was carried out in a stream of hydrogen over Pd/C, followed by acylation of the amino groups. In this case, the final product 12 retains the silyl functionality (Scheme 6).

Scheme 6

In addition, publication[31] should be mentioned, describing the hydrogenation of the bicycle (–)-13 over Pd/C in methanol to afford dideoxystreptamine monoester (+)-14, which exhibits antibacterial activity (Scheme 7).

Scheme 7

Reduction of benzotriazole 15 gave diamine 16 in quantitative yield (Scheme 8).[32]

Scheme 8

Reactions involving benzotriazole derivatives are described in considerable detail in a review article by Katritzky et al.,[33] which also addresses issues related to the mechanism of triazole ring opening.

One-step transformation of compound 17 under catalytic hydrogenation conditions affords anti-1,2-aminoglycan 18. This structural motif is found in phytospingosines and HIV protease inhibitors,[34] which is an important area of application for the presented methodology (Scheme 9).[35]

Scheme 9

Hydrogenolysis of (S)-5-phenylpyrazolidin-3-one (19) over Raney nickel was proposed to obtain β-amino acid amide 20 in high yield (Scheme 10).[36-38]

Scheme 10

Ultrasonication-assisted catalytic hydrogenation of dihydro­cinnolin-3-one 21 also afforded chiral amide 22 (Scheme 11).[39]

Scheme 11

Shea and co-workers[40] developed a method for cleaving the N – N bond in bicycles 23a,b based on Raney nickel-catalyzed hydrogenation of the substrates in boiling ethanol. This method provides a convenient approach to seven- and eight-membered nitrogen-containing heterocyclic compounds 24a,b (Scheme 12).

Scheme 12

To carry out hydrogenolysis of the N – N bond in hexahydropyrazoloisoquinolines 25a,b, the nitrogen atom was first deprotected with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and LiBr, which ultimately allowed the reduction of hydrazines to amines 26a,b (Scheme 13).[41] Such amino derivatives can be useful for the preparation of peptides.

Scheme 13

Azomethine imines 27a – e were converted to β-aminoamides 28a – e by reductive cleavage of the nitrogen – nitrogen bond (Scheme 14).[42-44] This reaction was carried out in the presence of Raney nickel and sodium borohydride upon heating in methanol. Remarkably, the process does not run under standard conditions using hydrogen and Raney nickel.

Scheme 14

Reductive cleavage of the N – N bond in cyclic hydrazine 29 can also be accomplished in a mixture of powdered zinc, acetic acid, and trifluoroacetic acid (Scheme 15).[45] Further protection of the free amino groups with ethyl chloroformate in the presence of Hünig’s base gave dicarbamate 30. The authors proposed that reductive cleavage is initiated by a single-electron transfer to the doubly protonated hydrazine dication.

Scheme 15

Clavier and co-workers[46] described an unusual method for reductive ring opening in polycyclic hydrazide 31 with a substituent containing an acetoxy group at the allyl position. Thus, upon treatment of the substrate with sodium metal in liquid ammonia (2.5 equiv.), terminal alkene 32 was isolated. The authors suggested that this is due to isomerization followed by removal of the acetoxy group. It should be noted that the vinyl group of product 32 is in the trans configuration of the three-membered ring. Increasing the amount of sodium to 5 equiv. delivered vinylcyclopropane 33 as a single diastereomer (Scheme 16).

Scheme 16

The reductive cleavage of the N – N bond in cyclic hydrazide 34 was snown[47] to be best accomplished using lithium metal in ammonia, leading to substituted cyclobutane 35 (Scheme 17).

Scheme 17

The method for synthesizing acyclic diamines, diamides, or aminoamides described in this Section involves cleavage of the N – N bond in cyclic hydrazines or hydrazides by reducing agents. This method affords products with high stereoselectivity and in good yields. Platinum oxide is used primarily for the selective synthesis of acyclic diamines or aminoamides from monocyclic five- or six-membered nitrogen-containing heterocyclic compounds. Palladium on carbon and Raney nickel are less selective, forming diamines from monocyclic and polycyclic hydrazides. It should be noted that only palladium on carbon is used for the hydrogenolysis of the N=N double bond.

A considerable number of studies have described the cleavage of the N – N bond by samarium(II) iodide, also known as Kagan’s reagent. It is a highly reactive, mild, and selective single-electron reducing agent that has found increasing use in organic synthesis in recent years.[48-50]

The mechanism of the SmI₂-mediated N – N bond reduction involves a single-electron transfer from the Sm²⁺ ion to the nitrogen atom of a cyclic hydrazine or hydrazide, resulting in an anion-radical, which splits into a radical and an anion (Scheme 18). In the next step, the proton plays a key role, the source of which is a protic solvent, most often an alcohol. Ultimately, an acyclic amine is formed from hydrazine, and an amide is formed from hydrazide.[51]

Scheme 18

Reduction of pyrazolidine derivatives 36a – d with samarium(II) iodide yields a mixture of optically active diamines 37a – d (Scheme 19), with an enantiomeric excess of > 90%. Despite the high cost of the catalyst, this method provides an access to enantiomerically pure 1,3-diamines in high yields under mild conditions.[52-57]

Scheme 19

Under the same conditions, the hexahydropyridazine ring in compound 38 is opened to give substituted 1,4-diamine 39 (Scheme 20).[58][59]

Scheme 20

Reductive cleavage of the N – N bond in heterocycles 40a – h occurs selectively in the presence of SmI₂ (Scheme 21).[60] Most diamides 41a – h were isolated in yields exceeding 90%. The lowest yields were observed for compounds containing electron-donating groups in the benzene rings.

Scheme 21

An example of the ring-opening in hexahydrocyclo­pentapyrazole 42 under similar conditions has been reported,[61] affording 1,3-diamine 43 (Scheme 22). Similar structural motif is found in the anti-influenza drug peramivir.[62][63]

Scheme 22

The iodide samarium(II)-mediated ring opening of one of the rings of hexahydro-1H-cyclopenta[c]pyridazine 44 gave carbocycle 45, containing two amide substituents (Scheme 23).[64]

Scheme 23

Acylation of the amine nitrogen atom of cyclic hydrazide 46 and reductive cleavage of the nitrogen – nitrogen bond gave trifluoroacetamide 47 (Scheme 24).[65]

Scheme 24

In 2016, Sarlah and co-workers[66][67] proposed an unusual method for the synthesis of 1,4-diaminocyclohex-2-ene derivatives (Scheme 25). The first step involves hydrolysis of the urazoline moiety of compounds 48a – h, followed by benzoylation of the intermediate hydrazine. The second step involves SmI₂-mediated reduction of the nitrogen – nitrogen bond methanol to afford the target products 49a – h.

Scheme 25

A number of studies[68-71] describe the cleavage of the N – N bond in hexahydropyrazoloisoquinoline 50, resulting in the polyfunctional tetrahydroisoquinoline 51 (Scheme 26). The high selectivity of the process should be noted, allowing the preservation of chiral centres, acetal, and benzoyl groups in the product.

Scheme 26

The single-electron reduction of hydrazide 52 followed by removal of the trifluoroacetyl protective group furnishes hydrogenated inloline 53 with two amino substituents (Scheme 27).[72]

Scheme 27

Consequently, cleavage of the N – N bond by samarium(II) iodide in mono- and polycyclic nitrogen-containing heterocyclic compounds leads to the target acyclic diamines, diamides, and aminoamides. Such reactions feature high product yields, selectivity, and tolerance to the presence of various functional groups in the substrate.

This Section discusses not only intramolecular processes but also intermolecular ones. The N – N bond cleavage was accomplished under the action of either reducing agents (in examples not included in the previous sections), metal catalysts, or nucleophilic reagents. Thus, the 1,2-diazetidine ring opening in compound 54 by lithium di-tert-butylbiphenyl (DBB) as a reducing agent gave diamide 55 in high yield (Scheme 28).[73]

Scheme 28

The reaction of ester 56 with azomethine imine 57 in the presence of a catalytic amount of rhodium acetate at room temperature in dichloromethane afforded acyclic diimine 58 rather than the expected cycloaddition product. The authors suggest that the reaction proceeds via an intermediate compound, which is formed from rhodium acetate, ester 56, and azomethine imine 57 (Scheme 29).[74][75]

Scheme 29

A method for the synthesis of various 3-(alkoxyalkyl)-1H-indoles based on the reaction of pyrazolidinone 59 with cyclic ketone 60 in the presence of dimeric (p-cymene)ruthenium dichloride has been reported (Scheme 30).[76-79] The advantages of the proposed method are a good product yield and high regioselectivity achieved by optimizing the reaction conditions. Various bases (NaOAc, KOAc, CsOAc, LiOAc, K₂CO₃, Na₂CO₃) were used and it was the use of NaOAc that allowed the product to be obtained in the highest yield. Based on mechanistic experiments, the authors proposed a plausible reaction pathway. The lower part of Scheme 30 shows only the main steps of the process. In the first step, ligand exchange delivers an active catalyst, which in turn reacts with pyrazolidin-3-one 59. Subsequently, through a series of steps, the N – N and C – C bonds are cleaved, ultimately leading to indoles 61a – d.

Scheme 30

Mention should be made of the study,[80] which reports the oxidative ring opening of 3-aminoindazole 62 at the N – N bond to afford various 2-aminobenzoates 63a – j (Scheme 31). When optimizing the reaction conditions, the authors focused on the choice of oxidizing agent. When using O₂, di-tert-butyl peroxide, benzoyl peroxide, meta-chloroperoxybenzoic acid, and (diacetoxyiodo)benzene, the reaction did not proceed. Trace amounts of the product were formed only under the action of K₂S₃O₈, Na₂S₃O₈, or tert-butyl peroxybenzoate.

Scheme 31

The reaction of substituted 4-anilino-1,2,3-benzotriazine 64 with cyclic secondary amines (pyrrolidine, piperidine, and morpholine) affords 2-amino-N-(2-aryl)-N'N'-disubstituted benzamidines 65a – c in high yields (Scheme 32).[81][82] It should be noted that heating 1,2,3-benzotriazine derivatives typically promotes the cleavage of bonds in the triazine ring, releasing a nitrogen molecule. The remaining part of the molecule reacts with amines to give more stable compounds.[83]

Scheme 32

This Section presents examples of the N – N bond cleavage leading to ring expansion. Unlike other Sections, in which the reaction products are acyclic nitrogen-containing compounds, this Section presents synthetic approaches to macrocyclic compounds. This is because cleavage of the N – N bridging bond in two-ring heterocycles does not result in the formation of new bonds, as demonstrated in previous Sections. It should be emphasized that the products of such reactions are polyfunctional macrocyclic compounds, which are extremely difficult to obtain using ‘classical’ methods. Such ring enlargement occurs primarily through hydrogenolysis of the N – N bond in tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole derivatives. For example, hydrogenation of tetrahydro-1H,5H-pyrazolo[1,2-a]­pyrazol-1-one 66 in the presence of Raney nickel at room temperature for 1 day afforded 1,5-diazacyclooctan-2-one 67 in a nearly quantitative yield (Scheme 33).[84]

Scheme 33

Treatment of tetrahydropyrazolopyrazolone derivative 68 with sodium metal in liquid ammonia furnished macrocyclic amide 69 (Scheme 34).[85] However, the yield of the product in this case was only 30%.

Scheme 34

It was observed that during high-pressure hydrogenation of heterocycle 70, not only the valuable eight-membered macrocycle 71 was formed, but also the multiple bond and the keto group of the cyclopentane moiety were reduced.[86] Product 71 was isolated in good yield and with fairly high enantioselectivity (Scheme 35).

Scheme 35

Using this approach, Lee et al.[87] obtained annulated macrocycle 73 from tetracycle 72 (Scheme 36). The product yield was 98% with a great predominance of one of the diastereomers (dr > 50 : 1).

Scheme 36

It is important to mention studies,[88][89] in which a stereoselective method for the synthesis of macrocycle 76 was developed based on the reaction of 6-phenyl-1,5-diazabicyclo[3.1.0]hexane (74) with cyclopropene 75. The cycloaddition product was isolated in good yield. Scheme 37 shows the plausible reaction pathway. In the first step, the cyclopropene unit undergoes ring-opening to form the Z-isomer of the alkene. Diaziridine 74 attacks the alkene to afford an intermediate ester. Then, nucleophilic substitution occurs involving the second nitrogen atom, accompanied by cleavage of the N – N bond and the formation of product 76.

Scheme 37

The information presented in this Section on ring expansion by the N – N bond cleavage indicates the high potential of this approach. Its advantages primarily stem from the elimination of the need for preliminary multi-step modification of the starting compounds to introduce the desired functional groups, as well as the high yields of macrocyclic compounds.

The cleavage of the bond between the nitrogen and sulfur atoms in heterocyclic compounds leads to derivatives of amino(amido)sulfide and aminosulfonic acid, which are widely used in organic, bioorganic, and medicinal chemistry.[90][91] Such structural motifs are part of drugs such as diltiazem,[92] ectinaskidine-743,[93] taurine,[94] etc., and therefore simple approaches to compounds of this class are needed. For example, Song and co-workers[95] used the treatment of substituted benzo[d]isothiazol-3(2H)-one 77 with sodium borohydride followed by methylation at the sulfur atom to obtain arylmethylthioether 78 in quantitative yield (Scheme 38).

Scheme 38

Reboul et al.[96] proposed a method for the preparation of benzo[d]isothiazole dimer 79 with the S – S bond in the presence of cesium fluoride and water. The reaction yields unstable sulfenyl fluoride, which, when treated with water, is converted to disulfide 80 (Scheme 39).

Scheme 39

Treatment of 2,3-dihydrobenzo[d]isothiazole-1,1-dioxide 81 with naphthalene sodium (NaphNa) in 1,2-dimethoxyethane with cooling for 2 min gave 2-(aminomethyl)benzenesulfinic acid derivative 82 in moderate yield (Scheme 40).[97-99] According to the authors, such optically pure amino acid derivatives can serve as building blocks for the synthesis of biologically active compounds.

Scheme 40

The reaction of 1,2-thiazetidin-1,1-dioxide 83 with 2-phenylethan-1-ol in the presence of triethylamine in dichloromethane at room temperature afforded 2-aminoethane-1-sulfonic acid ester 84 in high yield (Scheme 41).[100][101]

Scheme 41

The reaction between 1,2-thiazetidin-3-one 1-oxide 85 and pyrrolidine is of interest as it produces polyfunctional amide 86, which was isolated in high yield and with high enantiomeric excess (Scheme 42).[102]

Scheme 42

A synthetic approach to polyfunctional thioesters is described in a number of papers.[103-106] It involves reactions of carboxylic acid ester 87 with various carbonyl compounds 88a – h (Scheme 43). The resulting products 89a – h are potential agents for the treatment of type 2 diabetes mellitus.

Scheme 43

In 2017, Morimoto et al.[107] studied the reactions of N-alkyl- and N-arylbenzoisothiazolones 90a – g with p-toluic acid in the presence of triethyl phosphite in DMF. The products were S-toluoyl-substituted thioanalogs of salicylamides 91a – g (Scheme 44).

Scheme 44

2-Phenylbenzo[d]isothiazol-3(2H)-one (92) can react with methyl propiolate in the presence of silver acetate. This method allows the 2-(ethynylthio)benzamide derivative 93 to be obtained in a good yield in a single step under mild conditions (Scheme 45).[108][109] The reaction is likely commenced with the formation of silver acetylide, which reacts with heterocycle 92. The resulting cleavage of the N–S bond ultimately gives amide 93.

Scheme 45

Scheme 46 shows the reaction of amide 94 with amines, which occurs in THF upon cooling to –60°C for 15 min to give diamides 95a–e in high yields (see Scheme 46).[110][111]

Scheme 46

A method for synthesizing ortho-sulfonamide-substituted 2-arylpyrroles, which are extremely difficult to obtain otherwise, deserves attention.[112][113] It is based on the reaction of sultam 96 with aliphatic amines (Scheme 47). Benzylamine proved to be the least reactive — the yield of product 97d was only 15%. The resulting 2-arylpyrroles 97a – d may find application in organic light-emitting devices (OLEDs).

Scheme 47

Thus, ring opening at the nitrogen – sulfur bond primarily occurs in 2,3-dihydrobenzo[d]isothiazole derivatives, which is likely due to the availability of this heterocyclic compound. Sodium borohydride or naphthalene are used as reducing agents. The N – S bond cleavage is primarily carried out by the action of nucleophilic reagents, such as alcohols, amines, and ketones. Most of the reactions described in this Section are intermolecular.

Selenium-containing amino acids are a class of organic compounds that have been actively studied in recent decades. This is primarily due to the fact that such derivatives exhibit varying biological activity.[114-118] For example, selenocysteine, a selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. The chemistry of selenocysteine has attracted the attention of many specialists working in the fields of chemical biology, organic chemistry, and pharmacology.

One method for synthesizing diselenides involves the reduction of compounds 98 with sodium borohydride in an inert atmosphere. The N–Se bond can be reversibly reduced in the presence of potassium iodate (Scheme 48). Diselenides 99a – j possess antioxidant and antitumour properties.[119-123]

Scheme 48

Diselenides 99k,l can be obtained from benzo[d][1,2]- selenazole-3(2H)-ones 98 by treatment with triphenylphosphine in dichloromethane at room temperature for 2 h (Scheme 49), in practically quantitative yield.[124][125]

Scheme 49

Opening of the selenazolidine ring in compound 100 with sodium in liquid ammonia followed by treatment with hydrochloric acid leads to selenol 101 (Scheme 50).[126]

Scheme 50

When attempting to obtain selenoxide by treating benzo- [d][1,2]selenazol-3(2H)-ones 98 with hydrogen peroxide, hydroperoxy(aryl)selenium derivatives 102a – d were unexpectedly isolated (Scheme 51).[127][128]

Scheme 51

Alkylaryl and arylaryl selenides 104a – g were obtained in good yields by reacting 2H-benzo[d][1,3,2]thiaselenazole-1,1-dioxides 103 with Grignard reagents. The lowest yield was observed for selenide 104b, which contained two butyl groups (Scheme 52).[129]

Scheme 52

Ring opening reactions at the nitrogen–selenium bond primarily involve derivatives of benzo[d][1,2]selenazol-3(2H)-one, due to the availability of such heterocyclic compounds. When using reducing agents, the products are amide-substituted selenols. Treatment with hydrogen peroxide allows the isolation of individual hydroperoxy(aryl)selenium derivatives.

The N – P bond cleavage in heterocycles delivers acyclic aminophosphoryl derivatives. Such compounds are phosphorus analogs of natural proteinogenic amino acids and, as a consequence, exhibit a wide spectrum of biological activities.[130][131] Aminophosphoryl compounds are also of interest as ligands for coordination chemistry.[132-134]

Ring opening in 2-ethoxy-1,2-azaphospholidin-2-oxides 105a,b as a result of their sequential treatment with hydrochloric acid and methyloxirane leads to amino acids 106a,b (Scheme 53).[135]

Scheme 53

Acidic hydrolysis of the N – P bond in heterocycles 107a,b affords aminophosphonic acids 108a,b. It should be noted that the target compounds can be obtained under mild conditions in virtually quantitative yields (Scheme 54).[136-138]

Scheme 54

A method for the synthesis of aminophosphoryl compounds based on the cleavage of their N – P bond by various nucleophiles has been reported.[139][140] Dibenzo[c,e][1,2]azaphosphinine-6-oxide 109 reacts with organolithium compounds to give phosphine oxides 110a – c (Scheme 55). The authors note that Grignard reagents do not react with this substrate, which is possibly due to their low nucleophilicity.

Scheme 55

The preparation of aminophosphines by reduction of the similar phosphamide 111 to phosphine followed by cleavage of the N – P bond with lithium reagents is described. It should be noted that when using phenyllithium, the enantiomeric excess of products 112a,b was 96% (Scheme 56).[141]

Scheme 56

Examples of the N – P bond cleavage in heterocycles are represented primarily by reactions of 1,2-azaphospholidine-2-oxide and 5H-dibenzo[c,e][1,2]azaphosphinine-6-oxide derivatives under the action of acids and electrophilic agents, respectively. Processes involving organolithium compounds, accompanied by ring opening, allow the functionalization of aminophosphine and aminophosphine oxide in a single step.

Currently, organosilicon compounds find various applications. For example, silyl protection is often used in organic chemistry, which is associated with the easy cleavage of the silicon – heteroatom bond.[142-144] The importance of organo­silicon polymers for humans is difficult to overestimate, with polymers containing aminoxyloxane monomers being of particular interest due to their widespread use in industry and everyday life.[145][146] Aminosiloxanes impart new properties to materials or improve existing ones, for example, adhesion, flexibility, etc.[147-150] One method for synthesizing such polymers involves the reaction of oligomer 113 with 2,2,4-trimethyl-1,2-azasilolidine (114) in a stream of hydrogen, leading to product 115 (Scheme 57).[151]

Scheme 57

The reaction of 1-aza-2-silacyclobutane 116 with methyl, isopropyl, and tert-butyl alcohols in diethyl ether under mild conditions gave aminosilanes 117a – c (Scheme 58).[152]

Scheme 58

As a result of the initial cleavage of the N–Si bond in azasilacyclopentene 118, the prop-2-ene-1-amine derivative 119 is formed. Di-tert-butylsilane was isolated as a by-product in this reaction (Scheme 59).[153]

Scheme 59

Direct oxidation of azasilolanes 120 under various conditions afforded phenols 121 in low yields (< 20%) due to competitive oxidation of the amino group, which required the authors to protect it before the silane oxidation. Thus, exposure of azasilolanes 120a – e to air for 2 h promoted the formation of amides 122a – e. Subsequent oxidation of amides 122 afforded amidophenols 121a – e (Scheme 60).[154]

Scheme 60

Analyzing the literature data presented above, we can conclude that methods for synthesizing acyclic polyfunctional compounds from nitrogen-containing heterocycles by cleaving the nitrogen–heteroatom bond are finding increasing application in organic chemistry. Simple reactions give rise to complex compounds that are difficult to obtain using labor-intensive ‘classical’ methods based on the creation of new bonds. When the initial cyclic compound molecule contains several chiral centres, bond cleavage prevents racemization, which is crucial for the synthesis of both biologically active compounds and catalysts.

Among all the methods presented in this review, the synthesis of macrocyclic compounds by cleavage of the N – N bond in bicyclic nitrogen-containing heterocycles may also be noted. This approach allows for the single-step synthesis of high-yield macrocycles containing multiple functional groups, which are extremely difficult to obtain from linear molecules. In our opinion, this particular approach will see rapid development in the coming years, leading to the emergence of new compounds and materials with practically useful properties.

Samarium(II) iodide is considered the most promising reducing agent for cleaving the N – N bond. This is primarily due to its selectivity, which provides the synthesis of polyfunctional amines and amides in a single step. However, the high cost of samarium(II) iodide is a serious obstacle to its widespread use in the chemical industry.

One effective method for synthesizing a wide range of aminosulfonic acid derivatives involves cleavage of the N – S bond in heterocyclic compounds. The proposed approach allows for the production of products under mild conditions with high stereoselectivity, which is crucial for identifying potential biologically active compounds.

Despite the advances made in the synthesis of polyfunctional nitrogen-containing acyclic compounds based on the cleavage of the nitrogen – heteroatom bond in cyclic precursors, further work is needed in this area, particularly in the area of stereoselective heterocycle opening. Addressing this problem will open up new possibilities for obtaining structurally diverse polyfunctional amines, which will be of great importance for the development of new drugs and catalysts, and will also provide convenient starting materials for the creation of modern materials.

The following abbreviations are used in this review:

All — allyl,

Boc — tert-butoxycarbonyl,

CAN —cerium(IV)-ammonium nitrate,

Cbz — carboxybenzyl,

DBB — di-tert-butykbiphenyl,

DBU — 1,8-diazabicyclo[5.4.0]undec-7-ene,

DMAP — 4-dimethylaminopyridine,

dr — diastereomeric ratio,

EDTA — ethylene diamine tetraacetic acid,

ee — enantiomeric excess,

HEPES — 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid,

HMPA — hexamethylphosphoric triamide,

NaphNa — sodium naphthalene,

NBS — N-bromosuccinimide,

Ni-Ra — Raney nickel,

rt — room temperature,

TBS — tert-butyldimethylsilyl,

TIPS — triisopropylsilyl,

TMS — trimethylsilyl,

Ts — p-toluenesulfonyl (tosyl).