Nitrogen-Containing Heterocyclic Compounds Obtained from Monoterpenes or Their Derivatives: Synthesis and Properties

Abstract

Directed transformation of available natural compounds with native biological activity is a promising area of research in organic and medicinal chemistry aimed at finding effective drug substances. The number of scientific publications devoted to the transformation of natural compounds and investigations of their pharmacological properties, in particular, monoterpenes and their nearest derivatives, increases every year. At the same time, the chemistry of nitrogen-containing heterocyclic compounds has been actively developed since the 1950s after the news that the benzimidazole core is an integral part of the structure of vitamin B₁₂. At the time of writing this review, the data on chemical modifications of monoterpenes and their nearest derivatives leading to formation of compounds with a nitrogen-containing heterocycle core have not been summarized and systematized in terms of chemical transformations. In this review, we tried to summarize the literature data on the preparation and properties of nitrogen-containing heterocyclic compounds synthesized from monoterpenes/monoterpenoids and their nearest derivatives for the period from 2000 to 2021.

1 Introduction

Monoterpenes represent the largest class of secondary plant metabolites, ingredients of essential oils with a wide range of biological activities such as anticancer, antimicrobial, antioxidant, antiviral, analgesic, and anti-inflammatory [1,2,3,4,5,6,7]. Monoterpenes, in particular bicyclic monoterpenes with two condensed cycles, and their derivatives are key ingredients in the development and production of novel pharmacologically active compounds [8,9,10,11]. However, in addition to a wide range of native biological activity, monoterpenes and their derivatives possess high enantiomeric purity, which makes them a promising starting material for the synthesis of complexes used further in heterogeneous catalysis [12, 13]. Numerous reviews have now been published in the scientific literature detailing advances in research into the pharmacological properties of monoterpenes and their derivatives [14,15,16,17].

At the same time, the chemistry of nitrogen-containing (N-containing) heterocyclic compounds, both aliphatic and aromatic, is an important and unique area among the applied fields of organic chemistry. Much of the research is directed towards the development of new molecules and investigation of their physicochemical and biological properties. Molecules with N-containing cycle nuclei in their structure have attracted increasing attention of chemists in the last few decades. They have gained prominence in the rapidly developing fields of organic and medicinal chemistry, as well as in the pharmaceutical industry, due to their biological activity and ability both to protonate or deprotonate easily and to form various weak interactions, such as H-bonds, dipole–dipole interactions, and π-stacking [16, 18]. The ability of N-containing heterocycles to form these interactions allows them to easily form bonds with a variety of enzymes and receptors in biological targets, which increases their importance in the field of medicinal chemistry [19].

One promising direction in the search for organic compounds with targeted pharmacological activity could be combination of two fragments with proven biological activity in one molecule. Such a strategy could lead to compounds with novel pharmacological properties in comparison with the original molecules, as was clearly demonstrated in [15, 20,21,22,23,24,25,26]. Thus, substances combining fragments of an N-containing heterocycle and a monoterpene in their structure could prove to be valuable materials for both organic chemistry and medicinal chemistry.

Herein, we will summarize recent developments in the synthesis of N-containing heterocyclic compounds through modifications of different monoterpenes, monoterpenoids, and their derivatives. Chemical modifications of monoterpenes and monoterpenoids, structured according to the type of N-containing heterocyclic compounds obtained (spirocyclic, annulated, etc.), are discussed first, and then the properties of the target compounds (in particular catalytic or biological activity) are discussed. It is worth noting that the starting compounds are commercially available and their synthesis does not require discussion.

This review consists of two parts (Fig. 1). The first part (Sect. 2) includes the consideration of works devoted to the synthesis of compounds combining a heterocyclic nucleus with a monoterpene frame via a linker (Sects. 2.1, 2.2) or directly (Sect. 2.3), which do not include the stages of formation of the heterocyclic nucleus in the synthesis. In the second part (Sect. 3), studies on the preparation of heterocyclic compounds from monoterpenes and their nearest derivatives, which include the stages of heterocyclic core formation, are reviewed. The second part also includes the works devoted to the synthesis of nitrogen-containing heterocyclic compounds, which contains the stages of breaking the frame of the original natural compound (Sect. 3.5). In both parts, data on the biological/catalytic activity or properties of the compounds obtained are presented.

Fig. 1

Structure of review

To clarify the concept of the review, below are the necessary terms. Monoterpenes are hydrocarbons (C10) of biological origin having carbon skeletons formally derived from isoprene. Monoterpenoids are natural products and related compounds formally derived from isoprene units (C10) featuring oxygen in various functional groups. Nearest derivatives are chemical compounds structurally derived in one or more steps from others by a process of modification or partial substitution of at least one component wherein at least one structural feature is retained at each process step. Linkers are a group of atoms which connect two mentioned fragments. A monoterpene frame/residue is a fragment of a molecule in which the structure of the original monoterpene, from which this substance was synthesized, can be seen. The number of carbon atoms in this fragment can be 10 or different.

2 Synthesis and Properties of N-Containing Heterocyclic Compounds Synthesized from Monoterpenes or Their Derivatives, Not Involving the Formation of a Heterocyclic Nucleus

This section deals with the synthesis of compounds from monoterpenes, monoterpenoids or their derivatives including an N-containing heterocycle by combining two molecules via a linker or directly, but not including the step of forming the heterocyclic core. Synthesis of derivatives via a linker implies the addition of a bifunctional linker to the native functional groups of the monoterpenoid, followed by interaction of the resulting compound with the functionalized N-containing heterocycle. Another approach is the introduction of new functional groups into the monoterpene molecule and subsequent reaction with the N-containing heterocycle (in some cases with additional functional groups). Combining the fragments directly requires an initial modification of a monoterpene and/or heterocycle to create a functional group suitable for further transformation.

2.1 Combination of an N-Containing Heterocycle and Monoterpene Frame Via an Ester Linker

A convenient approach to the synthesis of hybrid compounds combining monoterpene and heterocyclic fragments in their structure is modification of native hydroxyl groups of monoterpenoids by esterification using chlorides of halogen-substituted carboxylic acids. The subsequent nucleophilic substitution reaction of the halogen atom with an N-containing heterocycle featuring N or S nucleophilic centers gives the target hybrid compounds in which the heterocycle nucleus is linked with the monoterpene backbone via an ester linker.

The synthesis of a variety of (–)-borneol esters 2a–2h, 3a–3h, and 4a–4e featuring pyrrolidine, morpholine, piperazine, and piperidine fragments is described by Sokolova et al. (Scheme 1) [21, 26]. Synthesis of target compounds was carried out via acylation of (–)-borneol (–)-1 with chloroacetic, 3-chloropropionic, and 4-chlorobutyric acids at the first stage followed by the reaction of nucleophilic chlorine atom substitution in obtained esters of (–)-borneol to pyrrolidine, morpholine, piperazine, piperidine, and their derivatives. The compounds obtained were investigated for their inhibitory activity against influenza A/Puerto Rico/8/34 (H1N1) virus replication. Compounds 2c and 3c featuring morpholine and monoterpene fragments were the most active (SI(2c) = 82; SI(3c) = 45; SI (Selectivity Index) is the ratio of 50% cytotoxic concentration of the compound to 50% virus-inhibiting concentration). Compounds 2d and 3d with the 1-methylpiperazine cycle in the structure showed moderate antiviral activity (SI(2d) = 23; SI(3d) = 25) [21]. In another work [26], compound 4c was shown to have moderate antiviral activity against vaccinia virus (SI(4c) = 23), while compounds 2c and 3c were more active (SI(2c) = 56; SI(3c) = 48). The commercially available agent Cidofovir was used as a positive control (SI = 11.8). The authors note that the cytotoxicity increases with increasing linker length connecting the monoterpene and heterocyclic fragments, which results in a decrease in the SI. Kononova et al. [27] showed that compounds 3a, 3b, 3e, 3h, and 2e possess antiviral activity (SI varied from 29 to 60) against Marburg virus (using the rVSIV-ΔG-MarV-GP pseudotype), exceeding that of the reference compound, an ion channel inhibitor verapamil (SI = 21). The authors showed that the starting (–)-borneol has no activity against the studied rVSIV-ΔG-MarV-GP pseudotype and, at the same time, has a low toxicity (CC₅₀ > 3000 µM, CC₅₀ = 50% cytotoxic concentration). It was shown that increasing the length of the linker connecting the (–)-borneol and heterocycle increases the antiviral activity against the rVSIV-ΔG-MarV-GP pseudotype.

Scheme 1

Synthesis of (–)-borneol esters with an N-containing heterocycle in structure

It should be noted that the same group of authors [28] also obtained structural analogues of compounds 2a–2h and 3a–3h: (±)-borneol ethers with the same heterocyclic moieties. The compounds desired were synthesized in two steps: alkylation of 2-bromoethanol and 3-bromoethanol with (±)-camphene in the presence of montmorillonite clay K-10 and, as a consequence of the Wagner–Meerwein rearrangement, the formation of bromine-containing ethers as a racemate; the next stage involved the nucleophilic substitution reaction of the halogen atom with secondary amines of cyclic structure under the conditions mentioned earlier. It should be noted that all the target products with a monoterpene frame connected through an ether linker with an N-containing heterocycle were racemates, and further evaluation of pharmacological activity was performed for racemates [28]. Thus, their antiviral activity against influenza A/Puerto Rico/8/34 (H1N1) virus was weaker than that of the (–)-borneol ester derivatives shown in Scheme 1. Also, as shown by biological studies, simple esters synthesized have no antiviral activity against vaccinia virus. But compounds 2c′ and 2h′ (Fig. 2) are efficient inhibitors of Ebola pseudotype virus (rVSV-ΔG-EBOV-GP) according to biological studies (IC₅₀(2c′) = 0.6 ± 0.2 μM; SI(2c′) = 1433; IC₅₀(2h′) = 0.12 ± 0.04 μM; SI(2h′) = 4166; IC₅₀ = 50% inhibitory concentrations); the reference drug used was sertraline (IC₅₀ = 0.7 ± 0.07 μM; SI = 582). It should be also noted that compounds 2c′ and 2h′ were much less active in biological studies of their antiviral properties against Ebola virus (strain Zaire); their selectivity indexes (SI) did not exceed 12.

Fig. 2

Borneol ethers: efficient inhibitors of Ebola pseudotype virus

Then, in the next work [29], the library of (–)-borneol derivatives was extended (Scheme 2), and their antiviral activity against influenza A/Puerto Rico/8/34 (H1N1) virus was investigated. Thus, esters 5a–5g featuring aliphatic and aromatic heterocyclic nuclei were synthesized by acylation of (–)-borneol with 3-chloropropanoyl chloride and further interaction with heterocyclic N and S nucleophiles. The results of biological studies showed that the esters 5d and 5g with triazole and imidazole rings, respectively, possess moderate antiviral activity against influenza A/Puerto Rico/8/34 (H1N1) virus (SI(5d) = 24; SI(5g) = 15). Compounds 5a, 5c, 5e, and 5f in turn exhibited lower 50% inhibitory concentrations (IC₅₀) as compared to 5d and 5g (IC₅₀ ranged from 7.1 to 17.5 μM), but were more cytotoxic (CC₅₀ ranged from 10.1 to 116.9 μM).

Scheme 2

Synthesis of (–)-borneol esters by acylation of (–)-borneol with 3-propanoyl chloride and further interaction with N and S nucleophiles

The synthesis of (–)-borneol esters 6a–6c, 7a, 7b, 9a, 9b, and 10 featuring a benzoazole moiety (Scheme 3) and investigation of their antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) are also described by Sokolova et al. [29]. Synthesis was performed by linker addition to (–)-borneol by acylation with chloroacetic and 3-chloropropionic acids in the presence of Et₃N. Subsequent nucleophilic interaction of obtained (–)-borneol esters with 2-mercaptobenzoazoles in the presence of bases (Et₃N, K₂CO₃ or KOH) led to compounds 6a–6c, 7a, and 7b. Upon acylation of (–)-borneol with 3-chloropropionyl chloride and subsequent elimination reaction in acetone with Et₃N α,β-unsaturated carbonyl, compound 8 was obtained. The Michael addition of 2-mercaptobenzothiazole and 2-mercaptobenzoxazole to compound 8 in the presence of Et₃N resulted in the formation of compounds 9a and 9b, respectively. Substitution of the base with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) resulted in the formation of compound 10 with two (–)-borneol fragments, whereas the reactions with 2-mercaptobenzothiazole and 2-mercaptobenzoxazole led to the formation of a complicated product mixture. A study of the antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) revealed compound 10 as the lead compound (SI(10) = 67).

Scheme 3

Synthesis of (–)-borneol esters featuring a benzoxazole moiety

2.2 Combination of an N-Containing Heterocycle and Monoterpene Frame Via an Amide Linker

In order to combine an N-heterocycle nucleus and a monoterpene fragment in one molecule, the latter must first be modified to introduce a carboxyl or amino group into the molecule. Subsequent interaction with N-heterocyclic compounds featuring an amino or carboxyl group leads to the formation of target products containing an amide bond.

Thus, the synthesis of several enantiopure proline amides 18a–18d from N-Boc-protected β-amino acid 14 was described in [30] (Scheme 4). Compound 14 was prepared from (+)-α-pinene (+)-11 according to the previously developed methodology [31]. First of all, (+)-α-pinene interacted with chlorosulfonyl isocyanate (CSI), which led to the stereoselective formation of compound 12. Subsequent reaction of lactam 12 with di-tert-butyl dicarbonate gave compound 13 in good yield, alkaline hydrolysis of which resulted in formation of N-Boc-protected β-amino acid 14 in excellent yield. Amino amides 15a–15e were prepared by coupling N-Boc-protected β-amino acid 14 with various amines using the mixed anhydride activation method. Removal of the Boc-protecting group using trifluoroacetic acid (TFA) resulted in the formation of chiral amino amides 16a–16d in excellent yields. Subsequent acylation of compounds 16a–16d by N-Cbz-protected (S)-proline and deprotection of 17a–17d with H₂ and Pd/C afforded the desired proline amides 18a–18d in moderate to good yields. Compound 19e was obtained by deprotection of compound 15e with H₂ and Pd/C. The catalytic activity of compounds 18a–18c in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde was examined. The reaction was carried out under neat conditions using 10 mol% of catalyst. Compound 18a incorporating a chiral and bulky amide in its structure catalyzed the asymmetric aldol reaction with significant stereoselectivity in favor of (2S,1′R)-enantiomer (yield of 87%; ee (enantiomeric excess) 78%).

Scheme 4

Synthesis of (S)-proline amides from (+)-α-pinene

A convenient synthesis of amides 22a–22c, 23a–23c, and 24a, their bioevaluation and identification as efflux pump inhibitors (EPIs) against S. aureus are reported in (Scheme 5). The synthesis of the target compounds was carried out from citral 20. The first step involved building up the carbon chain of citral 20 by the Wittig reaction using PPh₃ and BrCH₂CO₂Et followed by alkaline hydrolysis, leading to the formation of acid 21. Subsequent interaction of acid 21 with SOCl₂ and then with piperidine, pyrrolidine, and morpholine afforded amides 22a–22c, respectively, in excellent yields. It is worth noting that 14 amines of different structures were used in this work, but only the amines with the N-heterocyclic nucleus in their structure are shown in Scheme 5. Further oxidation of amides 22a–22c with SeO₂ resulted in the formation of compounds 23a–23c featuring an aldehyde group at the end of the chain in the moderate yields. Reduction of C₂–C₃ and C₄–C₅ bonds with H₂ and Pd/C in compound 23a resulted in the formation of compound 24a. Compounds 22a–22c, 23a–23c, and 24a in combination with antibacterial drug ciprofloxacin were subjected to bioevaluation for their possible role as EPI against S. aureus 1199 and NorA overexpressing S. aureus 1199B. As a result, compound 23a proved to be one of the most effective inhibitors (along with the other six compounds that do not contain a heterocyclic nucleus in their structure), which at concentration of 25 mg/ml, reduced the minimum inhibitory concentration of ciprofloxacin by a factor of 4.

Scheme 5

Synthesis of potential efflux pump inhibitors from citral

The transformation of the carbonyl group of the monoterpenoid into an amino group allows further nucleophilic substitution reactions with chloro-substituted esters, after which the addition of a heterocyclic nucleus to the resulting molecule by a nucleophilic substitution reaction with an N-heterocycle as the N-nucleophile becomes possible.

The synthesis of (+)-camphor derivatives 28a–28g with a piperidine, morpholine, and piperazine cycle attached to the molecule by amide bond through a linker of acetic, propionic, and butyric acid was described in [26] (Scheme 6). For the synthesis of target compounds, (+)-camphor (+)-25 was transformed into exo-bornylamine 27 by interaction with hydroxylamine and subsequent reduction with NaBH₄ in the presence of NiCl₂∙6H₂O according to previously developed methodology [32]. By further interaction of amine 27 with ethyl esters of chloroacetic, 3-chloropropionic, and 4-chlorobutyric acids and subsequent nucleophilic chlorine atom substitution with N-methylpiperidine, morpholine, and N-ethylpiperidine compounds 28a–28g were obtained in moderate yields. The antiviral activity and cytotoxicity of the synthesized derivatives against vaccinia virus were evaluated. The commercially available agent cidofovir (SI = 11.8) was used as a positive control. It is worth noting that the lead compounds in this series were compounds 28a, 28b, and 28d, whose selectivity indices were 54, 40, and 63, respectively. Compound 28a exhibited the lowest 50% inhibitory concentration (IC₅₀(28a) = 2.50 ± 0.17 µM), and at the same time it was the most cytotoxic of the three lead compounds (CC₅₀(28a) = 134.99 ± 33.37 µM). Compound 28d was the least cytotoxic among the lead compounds (CC₅₀(28d) = 501.80 ± 16.90 µM), but at the same time, its 50% inhibitory concentration (IC₅₀(28d) = 12.55 ± 4.24 µM) was five times higher than that of 28a.

Scheme 6

Synthesis of bornyl amide derivatives with N-containing heterocycles as vaccinia virus inhibitors

An alternative approach is to use sulfonic acids as starting compounds. Thus, the synthesis and antiviral activity against Ebola and Marburg viruses of (1S)-(+)-camphor-10-sulfonamides 31a–31h was described in [33] (Scheme 7). Synthesis was performed in two stages: from (1S)-(+)-camphor-10-sulfonic acid (+)-29 (which can be obtained by the action of concentrated H₂SO₄ on (+)-camphor in Ac₂O solution), camphorsulfochloride 30 was obtained according to the known procedure [34]; further amidation of compound 30 resulted in obtaining the desired sulfonamides 31a–31h with moderate yields. The antiviral activity against Ebola and Marburg viruses was estimated using a pseudovirus system based on the vesicular stomatitis virus for all compounds synthesized. According to the acquired experimental data, the compounds inhibit the glycoprotein of the Ebola virus (GP EBOV) more efficiently than the glycoprotein of the Marburg virus (GP MARV). Compounds 31a and 31h (SI(31a) = 921; SI(31h) = 1764) proved to be the most effective inhibitors of the Ebola virus glycoprotein with activity exceeding that of the reference drug sertraline (SI = 543).

Scheme 7

Synthesis of sulfonamides of (1S)-(+)-camphor-10-sulfonic acid

The authors of [35] obtained a series of sulfonamides (1S)- and (1R)-(+)-camphor-10-sulfonic acid, among which amides 34 and 35 featuring an N-heterocycle are present (Scheme 8). The desired sulfonamides were prepared in a similar way as described above by amidation of enantiomeric camphorsulfochlorides 30 and 32. It was shown that sulfonamides synthesized selectively inhibited the mitochondrial isozymes hCA VA and VB (h = human isoform; CA = carbonic anhydrases) over the cytosolic, off-target ones hCA I and II, with inhibition constants in the low nanomolar range. The best hCA VA and hCA VB inhibitors were the heterocyclic sulfonamides 34 and 35. The authors submitted that compound 35 was the most effective hCA VA inhibitor (inhibition constant K₁ = 5.9 nM) reported in the literature at the time of publication. Its enantiomer, compound 34, was 3.5 times less effective an hCA VA inhibitor, but was not inferior to the comparison drug zonisamide (K₁ = 20.0 nM). Also compounds 34 and 35 were the most effective hCA VB inhibitors with inhibition constants 7.3 and 7.8 nM, respectively, while the inhibition constants of all reference drugs were over 19.0 nM.

Scheme 8

Synthesis of sulfonamides of (1S)- and (1R)-(+)-camphor-10-sulfonic acid as hCA VA and hCA VB inhibitors

2.3 Combination of an N-Containing Heterocycle and Monoterpene Frame by Forming C–N or C=N, C–S, C–O, and C–C Bonds

Condensation of monoterpenoids featuring a carbonyl group with amines or other classes of compounds with an amino group in the structure allows the N-containing heterocyclic compounds and the monoterpene backbone to be joined directly by forming a single or double C–N bond.

Thus, the synthesis of hydrazide derivatives of citral 38a and 38b, (–)-camphor 39a and 39b, and carvone 40a and 40b, which contain an additional amide group besides the C=N bond, was described in [36] (Scheme 9). Monoterpenoids were introduced in a nucleophilic carbonyl group addition reaction with isoniazid 37a, nalidixic acid hydrazide 37b, and other drug hydrazides. As a result, hydrazides combining a monoterpene fragment and a heteroaromatic fragment were obtained. The anti-mycobacterial activity of the compounds synthesized was investigated against four Mycobacterium strains: Mycobacterium intercellulari (ATCC 35743), Mycobacterium xenopi (ATCC 14470), Mycobacterium cheleneo (ATCC 35751), and Mycobacterium smegmatis (ATCC 35797). Compound 40a exhibited significant growth inhibition of all tested mycobacterial strains with a MIC = 12.0 ± 0.03 mg/ml (MIC is minimum inhibitory concentration), comparable to that of the reference drug isoniazid (MIC = 12.5 mg/ml). Compounds 39a and 39b showed weak growth inhibition of all strains (MIC = 50 mg/ml).

Scheme 9

Synthesis of citral, (–)-camphor and carvone hydrazides using isoniazid and nalidixic acid hydrazide

Pyrrolidine derivative of 3-O-benzylcarvotacetone ((4S,5R)-4-(benzyloxy)-5-isopropyl-2-methylcyclohex-2-en-1-one) 41 was prepared in [37], and its antibacterial activity against methicillin-resistant Staphylococcus aureus bacteria and antifungal activity against Cryptococcus neoformans fungi were studied (Scheme 10). Enamine 42 was synthesized by direct interaction of compound 41 with pyrrolidine in the presence of a catalytic amount of p-TsOH. Piperitone derivative 42 showed no antifungal and antibacterial activity.

Scheme 10

Synthesis of pyrrolidine derivative with a piperitone fragment

Reaction of epoxides with N-nucleophiles is also one of the approaches to forming a C–N bond. The authors of [38] synthesized more than 30 benzothiazole derivatives, including compounds 47a and 47b possessing a monoterpene fragment attached through a hydroxyethyl linker at position 7 of the benzothiazole moiety (Scheme 11). The synthesis was carried out by the interaction of protected chiral epoxide 45 with a number of amines (including (R)-(+)-bornylamine (+)-43 and (+)-isopinocampheylamine (+)-44). Subsequent removal of the isopropyl and tert-butyl protecting groups with HCO₂H resulted in the target compounds 47a and 47b. The yields of compounds 46a, 46b, 47a, and 47b are not reported in the work. The library of all compounds synthesized was screened to determine their affinities for the human β₂-adrenoceptor in a radioligand binding assay versus the β-adrenoceptor antagonist CGP12177. Interestingly, for the compounds bearing monoterpene-derived N-substituents, 47a and 47b, relatively high binding selectivity for the β₂- over the β₁-adrenoceptor of 37- and 90-fold, respectively, were determined. This work identified monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by the structure of 47b.

Scheme 11

Synthesis of the 4-hydroxybenzothiazolone β₂-adrenoceptor agonists with a monoterpene fragment

A three-step synthesis of (+)-camphor imines 49a–49c with a pyridine and a thiazole substituent is described in [39] (Scheme 12). Initially, (+)-camphor oxime 26 was obtained from (+)-camphor (+)-25 in 90% yield. Reaction of the oxime 26 with NaNO₂ in AcOH allowed obtaining compound 48. Interaction of compound 48 with 2-aminopyridine, 4-aminopyridine, and 2-aminothiazole resulted in the formation of imines 49a–49c, respectively. The anti-mycobacterial activity of the compounds synthesized was assessed against M. tuberculosis ATCC 27294. The most active compounds were those that did not contain an N-heterocyclic nucleus; compounds 49a–49c showed no anti-mycobacterial activity.

Scheme 12

Synthesis of imines (+)-camphor using nitroimine (+)-camphor

A method for reductive amination of (+)-camphor (+)-25 was developed, and a library of tertiary amines featuring a bicyclic (+)-camphor fragment as one of substituents was synthesized, including tertiary amines 50a–50f, which were synthesized using secondary amines of the cyclic structure as initial amines [40] (Scheme 13). It was shown that the most effective reducing agent is Fe(CO)₅. The authors showed that all tested primary amines react with the selective formation of only exo-products, whereas the use of cyclic secondary amines results in a mixture of exo/endo products in ratios from 4:1 to 1.8:1. The biological activity or other possible applications of the target tertiary amines 50a–50f have not been investigated in this work.

Scheme 13

Direct reductive amination of (+)-camphor using Fe(CO)₅ as reducing agent

The authors of [41] synthesized a number of secondary amine hydrochlorides 52a–52f with an imidazole core and (–)-isopinocampheylamine (–)-44 in their structure from aldehydes, and investigated their antiviral activity as inhibitors of the A/M2-WT protein of wild-type influenza A virus ((A/Hong Kong/68 (H3N2)) and the A/M2-S31N protein of adamantan-resistant influenza A virus (A/WSN/33 (H1N1)) to explore the impact of the imidazole core on the inhibition of the A/M2 channel (Scheme 14). The imidazole-containing imine 51 [42] was the first of compounds synthesized. Subsequently, a reductive amination of different imidazole-containing aldehydes with (–)-44 using NaBH(OAc)₃ as reducing agent in CH₃OH [43], followed by treatment with HCl/CH₃OH, provided the salts of 52c–52f with good yields. Another two salts, 52a and 52b, were obtained via the reduction of corresponding amides 53a and 53b, respectively. All of the compounds obtained were examined for cytotoxicity and the inhibitory activity on M2 ion channels (A/M2 WT and A/M2 S31N). This study indicated that linking a secondary amine to an imidazole or guanazole may further increase the inhibition of A/M2 channel activity. Compound 52e, which was able to inhibit A/M2-WT by more than 95% and had IC₅₀ = 1.86 µM, was identified as the lead compound in the work. Amantadine was used as a reference drug, which was found to inhibit A/M2-WT by 94% and had IC₅₀ = 0.53 µM. The inhibitory activity of compound 52e against mutant M2 ion channels (A/WSN/33 (H1N1)) exceeded that of the reference drug (26.7% inhibition with 52e; IC₅₀ = 80 µM; 10% < inhibition with amantadine; IC₅₀ = 102 µM).

Scheme 14

Synthesis of (–)-isopinocampheylamine derivatives as anti-influenza A M2 ion channel inhibitors

Synthesis of stable pyrazolinium salts based on terpenes and study of their antiviral activity against influenza A/Puerto Rico/8/34 (H1N1) virus were described in [44]. The target compounds 57a–57e, 58a, 59b–59d, 60a, 60e, and 61b–61e were synthesized by interaction of 3-substituted-4,5-dihydro-1H-pyrazoles 54a–54e with (+)-camphor (+)-25, (–)-camphor (–)-25, (+)-carvone (+)-36, (+)-camphorquinone (+)-55, and (–)-myrtenal (–)-56, respectively, in the presence of HBF₄ as catalyst (Scheme 15). According to the results of biological studies, only compound 57a showed good activity against influenza virus A/Puerto Rico/8/34 (H1N1) (IC₅₀ = 6.2 µM; SI = 107). It is worth noting that its stereoisomer 58a showed no activity at all.

Scheme 15

Synthesis of pyrazolinium salts based on terpenoids and their derivatives

A convenient approach to the synthesis of compounds combining an N-containing heterocycle and a monoterpene framework is the use of the native OH group of monoterpenoids in nucleophilic substitution reactions with the SH group of N-heterocyclic compounds.

Thioethers 64a–64c and 65a–65c were synthesized from (–)-menthol (–)-62 and 4-isocaranol 63, respectively, and studied for antioxidant activity in [45] (Scheme 16). The target compounds 64a–64c and 65a–65c were prepared by activation of the native hydroxyl group of the starting monoterpenoids (–)-62 and 63 by interaction with TsCl followed by nucleophilic substitution with various 2-mercaptotriazoles in the presence of a base. The antioxidant activity of compounds 64a–64c and 65a–65c was assessed in vitro in cellular (laboratory mouse blood erythrocytes) and acellular (laboratory mouse brain lipids) models. It was shown that isocaranol thioethers 65a–65c are more active than (–)-menthol thioethers 64a–64c. The most active compounds were the free amino group compounds 64c and 65c at a concentration of 1 µM. However, when the concentration was increased to 10 µM and 100 µM, compounds 64c and 65c already showed strong pro-oxidant activity in the H₂O₂-induced hemolysis model.

Scheme 16

Synthesis of neomenthyl and caranyl thiotriazoles

Synthesis of 1,3,4-triazoles featuring a monoterpene fragment from cys- and trans-myrtanols was reported in [46]. The synthesis of target compounds was carried out in the same way as described above and resulted in compounds 67a–67c and 68a–68c (Scheme 17). It should be noted that during the interaction of alcohols (+)-cis-66 and (+)-trans-66 with 1,2,4-triazol-2-thiol, the nitrogen atom acted as nucleophile in the reaction, which resulted in formation of compounds 67c and 68c. Antioxidant activity of synthesized myrtanylthiotriazoles 67a–67c and 68a–68c was studied in vitro in extracellular and cellular model systems. Biological studies in an extracellular model showed that compounds 67a, 67c, 68a, and 68c without a phenyl substituent have antioxidant activity at a concentration of 1 mM. Compound 68c exhibited the greatest inhibitory activity if the concentration was reduced to 0.1 mM. All compounds obtained, except 68b and 68c, which were highly cytotoxic at a concentration of 0.1 mM, were studied for antioxidant and membrane-protective activities in the cellular model system. The antioxidant activity of compounds 67a–67c and 68a in a cellular model was evaluated by their ability to prevent hemoglobin and lipid oxidation. Compounds 67a, 68a, and 67c slowed the oxidation of oxyhemoglobin to methemoglobin by 1.5–1.6 times, whereas 68a and 67c reduced the rate of accumulation of secondary products of lipid peroxidation by 1.3–1.4 times.

Scheme 17

Synthesis of substituted 1,3,4-triazoles from cys- and trans-myrtanols

The coupling of an N-containing heterocycle with a monoterpene backbone via C–C bond formation without the use of linkers or heterocycle assembly steps is an unconventional task. It is worth noting that very few works have been devoted to such transformations.

The authors of [47] developed the procedure of photocatalytic reductive coupling of heteroaryl bromides with non-activated alkenes (Scheme 18). The reaction takes place via photoinduced electron transfer from a tertiary amine to an aryl bromide that fragments to provide an aryl radical and subsequently reacts with an alkene to form a C–C bond. An amine also serves as the final reductant. The method is unique in that it is easy to operate; it does not affect labile functional groups and is highly selective. Thus, a number of 2-substituted benzimidazoles, benzothiazoles, and thiazoles were synthesized by interaction of various 2-bromoazoles 69a–69e with various non-activated alkenes, including monoterpenes and their derivatives, such as (–)-carvone (–)-36, (–)-perillyl alcohol (–)-71 and its benzyl ester (–)-70, and (+)-camphene (+)-72, respectively. The monoterpene residue is directly linked to the azole ring at position 2 by a single C–C bond in the compounds 73a, 74e, 75d, and 76a–76c obtained.

Scheme 18

Photocatalytic reductive coupling of 2-bromoazoles with non-activated alkenes-monoterpenes and their derivatives

Also, the authors of this work found that this reaction with terpenes featuring a vinyl cyclobutane motif results in reductive ring opening with good yields, high regioselectivity and diastereoselectivity. For example, the interaction of (+)-α-pinene (+)-11 with 2-bromo-4,6-difluorobenzo[d]thiazole 69f afforded compound 77 (Scheme 19). No studies on the biological or catalytic activity of all compounds obtained were carried out.

Scheme 19

Reductive ring opening of (+)-α-pinene in reaction with 2-bromo-4,6-difluorobenzo[d]thiazole

The synthesis and use of tmp₃La∙3MgCl₂∙5LiCl (tmp-2,2,6,6-tetramethylpiperidyl) base in ortho-metalation reactions with subsequent interaction with electrophiles are described in [48]. The authors reported that new base tmp₃La∙3MgCl₂∙5LiCl is highly chemoselective and displays good atom economy, since all three tmp groups can be used for directed metalation. For example, compound 79 was obtained in a good yield by interaction of (–)-camphor (–)-25 and benzothiazole 78 using tmp₃La∙3MgCl₂∙5LiCl as a base (Scheme 20). The authors have shown that this base can be used for the synthesis of organolanthanum compounds, which can further give sterically hindered alcohols in reactions with ketones.

Scheme 20

Ortho-metalation of benzothiazole and subsequent interaction with (–)-camphor

Thus, in this section, we considered the ways to synthesize compounds combining in their structure monoterpene fragments and N-containing heterocycles linked via an amide or ester linker or directly through C–N, C–S, C–O, and C–C bonds. The reactions of esterification or nucleophilic substitution of native hydroxyl groups of monoterpenoids, as well as nucleophilic addition reactions at native carbonyl groups of functionalized N-containing heterocycles or linkers to which the heterocyclic nucleus was subsequently attached, were used to form such molecules. The introduction of an amino or carboxylic group into the structure of monoterpenes or their derivatives as well as the use of sulfonic acids as starting compounds allowed the formation of amide bonds to a linker or an N-containing heterocycle. The most unfrequently used approach to the synthesis of compounds desired was the reductive coupling of halogen-substituted N-containing heterocycles with alkenes and the reactions of organometallic compounds with the ketones. Some of the synthesized compounds presented in this section have exhibited antiviral, anti-mycobacterial, antioxidant, antifungal, herbicidal, and other activities, as well as catalytic properties.

3 Synthesis and Properties of N-Containing Heterocyclic Compounds Synthesized from Monoterpenes or Their Derivatives, Including the Formation of a Heterocyclic Nucleus

The synthesis of N-containing heterocyclic compounds is an extensive area of synthetic organic chemistry. In this section, approaches to the synthesis of molecules combining in their structure a heterocyclic core and a monoterpene/monoterpenoid or their derivatives will be considered, including the stages of formation of the heterocyclic core. Synthesis of derivatives in which the heterocycle and monoterpene fragment are linked by exocyclic C–C or C–N bonds is performed from monoterpenoids and their derivatives by preparation of carboxylic acid derivatives, reductive amination reactions, or synthesis of semicarbazones followed by cyclization of the intermediate compounds. When a monoterpene fragment and a heterocycle are coupled via a linker, reactions to produce polyfunctional imines based on monoterpenoids and their subsequent cyclization are usually used. To synthesize a heterocyclic nucleus annulated with a monoterpene, the 1,3-dipolar cycloaddition reactions on the monoterpene multiple bond, domino reactions, or functionalization of the original monoterpenoid followed by closure of the N-heterocycle are used in most cases. The synthesis of a heterocyclic spirocyclic nucleus coupled with a monoterpene backbone is most often performed from the carbonyl group of the monoterpenoid.

3.1 Formation of an N-Containing Heterocycle Nucleus Coupled to the Monoterpene Residue by an Exocyclic C–C or C–N Bond

The heterocycle nucleus is often formed from the carboxylic group by esterification or amidation reactions with subsequent cyclization. In this case, the heterocycle is bound by an exocyclic C–C bond to a carboxylic acid residue.

The authors of [49] synthesized 1,2,4-oxadiazoles 85–87 and 1,3,4-oxadiazoles 90 and 91 from carboxylic acids (–)-80 and (+)-81 featuring bicyclic α-(–)-pinene and (+)-carene backbone, respectively, according to the known method [50] (Scheme 21). The synthesis of the 1,2,4-oxadiazole heterocyclic nucleus was performed in three stages: in the first step, activation of the carboxyl group of compounds (–)-80 and (+)-81 with N,N-carbonyldiimidazole (CDI) in CH₂Cl₂ was performed, then the reaction with aromatic amidoximes was performed to form O-acylamidoximes 82–84, and in the final step, an intramolecular cyclization of O-acylamidoximes was carried out in the presence of tetrabutylammonium fluoride (TBAF) as a base, resulting in the formation of 1,2,4-oxadiazoles 85–87 in 73–89% yields. Synthesis of 1,3,4-oxadiazoles 90 and 91 was performed according to a similar method: N,N-diacylhydrazines 88 and 89 were obtained by sequential activation of the carboxyl group with CDI and interaction with benzhydrazide, and formation of 1,3,4-oxadiazole cycle was performed under the action of POCl₃ and subsequent treatment with aqueous NaHCO₃ solution. It should be noted that treatment of compound 89 with POCl₃ resulted in compound 91 with ring rearrangement of the 2-carene framework accompanied by a loss of chirality.

Scheme 21

Synthesis of monoterpene-based 1,2,4- and 1,3,4-oxadiazoles

Subsequent stereoselective sin-dihydroxylation of all heterocyclic compounds 85–91 obtained by the Criegee reaction led to the formation of diols 92–96; compound 96 was obtained as a racemic mixture (Scheme 22). The catalytic activity in enantioselective reaction of Et₂Zn and PhCHO affording the formation of chiral 1-phenyl-1-propanol as a reference product was studied for compounds 92–96. The best enantioselectivity was observed for compound 92 with S selectivity (74% ee; 87% yield).

Scheme 22

Dihydroxylation of monoterpene-based 1,2,4- and 1,3,4-oxadiazoles

The antiproliferative activities of compounds 82–88, 90, 92, 93, and 95 against a panel of human malignant cell lines isolated from cervical (HeLa), ovarian (A2780), and breast (MCF7 and MDA-MB-231) cancers was also investigated. O-Acylated amidoximes 82–84 exhibited remarkable growth inhibitory activities against HeLa (IC₅₀ values ranged from 11.46 to 13.62 µM) comparable to those of reference agent cisplatin (IC₅₀ = 12.43 µM). Compounds 82–84 showed inhibitory activity (IC₅₀ values ranged from 1.44 to 2.05 μM), lower than that of the comparison drug cisplatin (IC₅₀ = 1.30 μM) against A2780 cell lines. Compounds 82–84 showed no inhibitory activity against breast tumor cell lines (MCF7 and MDA-MB-231). All oxadiazoles 85–87, 90, 93, 93, and 95 showed no activity against all the tumor cell lines studied.

A set of O-acylamidoximes 98a–98t and 1,2,4-oxadiazoles 99a–99t from (+)-ketopinic acid (+)-97 (a derivative of (+)-camphor) were synthesized in a similar way [50] in a recent publication [51] (Scheme 23). (+)-Ketopinic acid was synthesized from (1S)-(+)-camphor-10-sulfonic acid (+)-29, as was published previously [52]. All compounds synthesized were tested in vitro for cytotoxicity against the MDCK cell line and for antiviral activity against influenza viruses A\Puerto Rico/8/34 (H1N1) and A/Anhui/1/2013 (H7N9). It was shown that of 40 tested compounds, 17 had SI values of 10 and higher, making them good candidates for further studies. Compounds 99g, 99h, 99m, 99p, and 99s had SI values higher than 56 against A\Puerto Rico/8/34 (H1N1). It should be noted that some of the compounds synthesized show good antiviral properties against a genetically distinct influenza virus of the H7N9 subtype (IC₅₀(98k) = 3 ± 0.4 µM; SI(98k) = 118; IC₅₀(99o) = 8 ± 1 µM; SI(99o) = 120).

Scheme 23

Synthesis of O-acylamidoximes and 1,2,4-oxadiazoles from (+)-ketopinic acid

Triazole derivatives with a monoterpene fragment in their structure were synthesized by the authors of [53] from myrtenal 56 (Scheme 24). It is worth noting that in [53, 54], myrtenal 56 was synthesized by oxidation of α-pinene with SeO₂, but configuration of the stereocenters in the aliphatic cycle was not indicated. At the first stage, myrtenal 56 was oxidized with NaClO₂-H₂O₂ as oxidant in aqueous solution to give myrtenic acid 80 in 80% yield. Subsequent interaction of acid 80 with SOCl₂ and further acylation of methylthiosemicarbazide resulted in product 101. Further, compounds 102a–102n featuring a heterocyclic 1,2,4-triazole nucleus were synthesized by one-pot sequential processes involving the cyclization reaction of compound 101 under microwave irradiation and the nucleophilic substitution with different alkyl halides. Antifungal activity of the compounds 102a–102n was evaluated by the in vitro method against Fusarium oxysporum cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, and Gibberella zeae at 50 µg/ml. Compounds 102a, 102c, and 102l showed 91–98% inhibition of Physalospora piricola growth, comparable to the 96% inhibition of the commercial reference drug azoxystrobinoma.

Scheme 24

Synthesis of myrtenal-based triazole derivatives

Within the scope of continuing the search for new biologically active myrtenal derivatives, the same authors [54] synthesized and evaluated antifungal and herbicidal activity of a number of N-acylated derivatives 104a–104p synthesized from 4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione 103 (Scheme 24). Compound 103, in turn, was obtained by cyclization of compound 101 in the presence of KOH under microwave irradiation. The authors assumed that acylation of the triazole fragment would produce more active agents than 102a–102n. However, the antifungal activity of synthesized compounds 104a–104p was lower than that of 102a–102n. Most of the compounds synthesized showed excellent herbicidal activity (more than 80% growth inhibition of Brassica campestris at a concentration of 100 mg/l). It was shown that myrtenal exhibited weak herbicidal activity (20% inhibition of B. campestris), and the comparison drug flumioxazin showed 63% growth inhibition of B. campestris at concentrations of 100 mg/l. Thus, the authors were able to synthesize a library of compounds with myrtenal and triazole fragments in their structure that are promising for further biological research.

Another approach to creating a monoterpenoid-based heterocyclic core is to modify the carbonyl group. For example, the authors of [55] synthesized more than 50 tetrazole derivatives using the Ugi reaction. The authors reported for the first time the use of ammonia in the Ugi tetrazoles variation, leading to unprotected amino tetrazoles, which then can be used to carry out many transformations for the synthesis of biologically active substances. It was found that aliphatic ketones enter the investigated transformations perfectly, and target tetrazoles are obtained in good yields. In addition, sterically hindered (+)-camphor (+)-25 enters into this transformation with the formation of compound 105 in 57% yield (Scheme 25). Other monoterpenoids were not used by the authors of this work.

Scheme 25

(+)-Camphor as an oxo-component in the Ugi reaction

Synthesis of molecules featuring an imidazoline cycle and a monoterpene fragment is performed by dimerization of initial monoterpenoid by the reaction of a carbonyl group with a diamine or amino group of the monoterpenoid derivative with dialdehyde followed by cyclization. In this case, the heterocyclic nucleus is linked directly to the monoterpene residue by an exocyclic C–N bond.

The synthesis of imidazolidene ligands 106 and 107 from bicyclic amines –(–)-isopinocampheylamine (–)-44 and (+)-bornylamine (+)-43, respectively, was described in [56] (Scheme 26). The synthesis of salts 106 and 107 was carried out by interaction of amines (–)-44 and (+)-43 with glyoxal, followed by reduction of the C=N bond with NaBH(OAc)₃ and condensation with triethyl orthoformate (HC(OEt)₃) in the presence of ammonium tetrafluoroborate (NH₄BF₄) at the final stage. The yields of salts 106 and 107 at the final stage were 64 and 92%, respectively. These salts were further used as ligands in the asymmetric synthesis of oxindoles with 67 and 71% enantioselectivity, respectively.

Scheme 26

Synthesis of imidazolidene ligands from (–)-isopinocampheylamine and (+)-bornylamine

The authors of [57] suggested that an increase in the volume of the substituents in the imidazolinium salts could lead to an increase in enantioselectivity of the corresponding imidazoline carbene ligands in asymmetric reactions. Thus, they synthesized imidazolinium salt 113 from (–)-fenchone (–)-108 (Scheme 27). Interaction of (–)-fenchone with hydroxylamine hydrochloride in the presence of pyridine as a base led to the formation of oxime 109, whose heating with aqueous NaNO₂ solution allowed generation of nitroimine 110. Reaction of 110 with a half of a molar equivalent of ethylenediamine was accompanied by the formation of diimine 111 in a quantitative yield. Reduction of diimine 111 with NaBH₄ in EtOH resulted in the formation of compound 112 in a high yield. Condensation of diamine 112 with HC(OEt)₃ in the presence of NH₄BF₄ led to the formation of imidazolium salt 113 in 36% yield. The authors of the work planned to synthesize N-heterocyclic carbene by interaction of the salt 113 with potassium tert-amylate (tert-AmylOK) and copper(II) triflate (Cu(OTf)₂) at the next stage, but this reaction led to an unexpected transformation of the imidazoline core of compound 113 in a mixture of substituted piperazine-2-one 114 and urea derivative 115. The possible mechanism of this reaction is discussed in detail in the work. The biological or catalytic activity of compounds obtained has not been investigated.

Scheme 27

Synthesis of the difenchylimidazolinium tetrafluoroborate carbene ligand precursor from (–)-fenchone

Acylation and subsequent intramolecular cyclization of monoterpene derivatives containing an amino group can also lead to the formation of heterocyclic compounds of interesting structure. For example, in [58], the synthesis of chiral benzisoselenazol-3(2H)-ones substituted on the nitrogen atom with monoterpene fragments was described. Compounds synthesized were studied for antioxidant and anticancer activity. Thus, a series of compounds 118a–118h were synthesized from acid 116, containing monoterpene moieties p-menthane 118a–118c, pinane 118d–118f, and carane 118g, and 118h in their structure (Scheme 28). Acid 116 was obtained by a multistep procedure from anthranilic acid according to the previously described procedure [59], the subsequent reaction of acid 116 with SOCl₂ led to the formation of compound 117. Interaction of compound 117 with monoterpene amines allowed obtaining compounds 118a–118h with yields from 20 to 90%. The ability to reduce H₂O₂ was tested by a frequently used procedure, where the Se-catalyst reduces the peroxide and, in the oxidized form, is able to transform the dithiol to a disulfide. The most efficient H₂O₂ reduction was observed for compounds possessing pinane fragment 118d and 118f, with the total substrate conversion observed in 30 and 60 min, respectively. The antiproliferative capacity was measured by the MTT ((3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl tetrazolium bromide)) assay on breast cancer MCF-7 and human promyelocytic leukemia HL-60 cell lines. According to biological investigations, compound 118d exhibited the highest antiproliferative potential (IC₅₀(118d) = 7.1 ± 0.4 µM). It is worth noting that the presence of methylene groups between the fragments of the heterocycle and the monoterpene (compound 118f) significantly decreases the activity (IC₅₀(118f) = 250.0 ± 24.7 µM). The best anticancer activity against MCF-7 cells was observed for compound 118c (IC₅₀(118c) = 11.9 ± 0.2 µM). In [59], compound 118i with a bicyclic exo-borneol moiety showed high antioxidant activity (total substrate conversion was observed in 15 min) (Scheme 28).

Scheme 28

Synthesis of chiral benzisoselenazol-3(2H)-ones containing a monoterpene moiety

3.2 Formation of an N-Containing Heterocycle Nucleus Coupled to the Monoterpene Frame Via a Linker

A common approach to the synthesis of N-containing heterocycles that are coupled via a linker to a monoterpene fragment is the modification of the monoterpene/monoterpenoid with a linker, such as thiosemicarbazide, polyfunctional amines, or an aromatic fragment, which are then used to form the heterocyclic core. In this case, there is an acyclic or alicyclic linker between the heterocyclic nucleus and the monoterpene moiety.

The synthesis of 1,3,4-thiadiazoles derivatives 121a–121k with an aromatic substituent and R-(+)-limonene fragment in their structure and possessing trypanocidal activity against epimastigote and trypomastigote forms of Trypanosoma cruzi was described in [60] (Scheme 29). The target 1,3,4-thiadiazoles 121a–121k were synthesized by cyclization of benzaldehyde thiosemicarbazones 120a–120k under reflux in an aqueous alcoholic solution in the presence of FeCl₃ in 35–85% yields. Compounds 120a–120k were prepared by a multistep procedure from R-(+)-limonene-(+)-119 according to the previously described procedure [61]. The results of biological studies of trypanocidal activity showed that the limonene fragment significantly increases the biological activity of 1,3,4-thiadiazoles, since the 121a–121k compounds were much more active than similar derivatives but with a free amino group. Also, all compounds with a R-(+)-limonene fragment were less cytotoxic as compared to compounds with a free amino group. The 50% inhibitory concentration against T. cruzi compound 121k with a fluorine atom in the fourth position of the benzene ring was 6.9 ± 1.6 μM. A comparison of the activity of compounds 121e–121g showed that the compound with a nitro group in the ortho-position of the benzene ring has the lowest 50% inhibitory concentration, but the compound 121g featuring a nitro group in the para-position was the least cytotoxic. Among the chloride-containing compounds 121h–121j, the lowest 50% inhibitory concentration of 1.6 μM was observed for compound 121i (IC₅₀(121i) = 1.6 μM), but it proved to be the most cytotoxic (CC₅₀(121h) = 950.0 ± 25.4 μM; CC₅₀(121i) = 166.7 ± 17.9 μM; CC₅₀(121j) = 793.3 ± 60.4 μM).

Scheme 29

Synthesis of 1,3,4-thiadiazoles with an R-(+)-limonene fragment as substituent

The authors of [62] synthesized 2-substituted 1H-benzimidazoles containing a phenol fragment with isobornyl and tert-butyl groups. Thus, the condensation of substituted benzaldehydes 122a–122d with o-phenylenediamine allowed obtaining a series of 2-substituted benzimidazoles 123a–123d (Scheme 30). Their antioxidant and membrane-protective properties were evaluated in in vitro models and compared with those of known analogues. The greatest antioxidant activity was observed for compounds 123c and 123d, which contain bicyclic and aliphatic substituents in the phenol ortho-positions. The less antioxidant activity was observed for compounds with two isobornyl fragments 123a and 123b. The highest membrane-protective activity was observed for compounds 123c and 123d (the percent of hemolysis after 5 h of the experiment was 5.8 ± 0.3 and 16.1 ± 0.7 for compounds 123c and 123d, respectively, while in the control experiment, the percent of hemolysis was 49.8 ± 0.7).

Scheme 30

Synthesis of 2-substituted benzimidazoles containing an isobornyl moiety

The synthesis of β-pinene-based thiazole derivatives 128a–128x was described in a recent publication [58] (Scheme 31). It is worth noting that the configuration of the optical centers in the original β-pinene 124 is not specified in the work. At the first stage, β-pinene was oxidized with KMnO₄ to form compound 125. Subsequent aldol condensation of ketone 125 with a series of 4-substituted benzaldehydes allowed compounds 126a–126f to be obtained, and further nucleophilic addition of thiosemicarbazide to compounds 126a–126f led to the formation of thiosemicarbazones 127a–127f. Compounds 127a–127f were cyclized with para-substituted phenacyl bromides to form the target compounds 128a–128x with a substituted thiazole heterocycle in their structure. The designed 24 compounds were evaluated for cytotoxicity against three cancer cell lines (colon tumor CT-26 cells, human cervical carcinoma Hela cells, and human hepatocarcinoma SMMC-7721 cells) using the MTT assay with etoposide (IC₅₀(Hela) = 7.89 ± 1.37 µM; IC₅₀(CT-26) = 2.22 ± 1.26 µM; IC₅₀(SMMC-7721) = 40.44 ± 0.29 µM) as a positive control. Compound 128g showed the lowest IC₅₀ values (IC₅₀(Hela) = 3.48 ± 0.14 µM; IC₅₀(CT-26) = 8.84 ± 0.16 µM; IC₅₀(SMMC-7721) = 6.69 ± 0.15 µM). The results of a study of the mechanism of compound 128g action were also described in [58].

Scheme 31

Synthesis of β-pinene-based thiazole derivatives

The synthesis of a set of N-containing heterocyclic compounds 130a–130g, 132a–132d, 133, 134a, and 134b with thiazole and thiazolidin-4-one nuclei from (+)-camphor (+)-25 was described in [63] (Scheme 32). In the first step, (+)-camphor thiosemicarbazone 129 was synthesized. Further, thiazole derivatives 130a–130g were obtained by interaction of thiosemicarbazone 129 with different para-substituted phenacyl bromides. Interaction of thiosemicarbazone 129 with BrCH₂CO₂Et resulted in the formation of thiazolidin-4-one 131 in 59% yield. Compounds 132a–132d featuring different substituents at the nitrogen atom of the heterocyclic nucleus, thiazolidinedione 133, and compounds 134a and 134b with an aromatic substituent at the fifth position of the heterocyclic nucleus were obtained by modification of compound 131. The antiviral activity and cytotoxicity of the synthesized derivatives 130a–130g, 132a–132d, 133, 134a, and 134b against vaccinia virus were evaluated; cidofovir (IC₅₀ = 40.01 ± 2.8 µM; TC₅₀ = 475.3 ± 74.9 µM) was used as a positive control. The IC₅₀ values for compounds 130b, 130c, and 130e containing the thiazole and aromatic fragments ranged from 2.4 to 3.7 μM. However, the cytotoxicity (TC₅₀) of these compounds was rather high and ranged from 64.1 to 93.6 μM. This work shows that modifications of compound 131 (TC₅₀ = 305.2 ± 74.3 µM) lead to increased toxicity in its derivatives 132–134 (TC₅₀ = 17.5–287.8 µM). Of all thiazolidin-4-one derivatives, compound 134b exhibits moderate antiviral activity and is the least cytotoxic (IC₅₀ = 9.5 ± 2.5 µM; TC₅₀ = 120.5 ± 4.7 µM). It is worth noting that all compounds synthesized in this work were more cytotoxic as compared to the reference drug Cidofovir.

Scheme 32

Synthesis of (+)-camphor-based thiazole and thiazolidin-4-one derivatives

A series of 1,2,3-triazole derivatives 137a–137d and 140a–140j featuring the (+)-camphor (+)-25 frame in their structure was synthesized in [64] by the [2+3] cycloaddition reaction of azides to acetylenes catalyzed by Cu (II) salts (Scheme 33). At the first stage, the interaction of (+)-camphor with 2-aminoethanol resulted in compound 135. Further transformations were carried out with the OH group, whereby the carbon residue of ethanol acted as a linker between the (+)-camphor residue and the heterocyclic nucleus. Interaction of 135 with NaH and the subsequent nucleophilic substitution reaction with propargyl bromide resulted in the formation of propargyl ether 136, which was then used in reactions with different azides to obtain 1,2,3-triazoles 137a–137d in good yields. Compound 139 was obtained by sequential interaction of alcohol 135 with MsCl followed by nucleophilic substitution with NaN₃. Further reaction of azide 139 with a number of substituted acetylenes resulted in the formation of the target 4-substituted 1,2,3-triazoles 140a–140j in good yields. Cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) were evaluated in vitro for all compounds synthesized. Compounds 140d, 140e, 140g, and 140j as well as compound 137a had low cytotoxicity (CC₅₀ > 800 μM), while the 50% inhibitory concentration was below 60 μM, so that all these compounds had a selectivity index greater than 10. It is also worth noting that the mentioned compounds were more active than three reference drugs (amantadine (SI = 4), rimantadine (SI = 5), and deitiforin (SI = 6)) and much less cytotoxic.

Scheme 33

Synthesis of (+)-camphor-based 1,2,3-triazole derivatives

The same research group [65] synthesized a series of (+)-camphor and (–)-cytisine conjugates and studied their antiviral activity (Scheme 34). Coupling of two pharmacophore blocks was also performed by the [2 + 3] cycloaddition of azides to acetylenes catalyzed by Cu (II) salts. It should be noted that in this case, the 1,2,3-triazole nucleus served as a linker between the cytisine and camphor moieties. Cytisine 141 underwent a nucleophilic substitution reaction with bromoalkyl azides to form compounds 142a–142d. Next, the azides 142a–142d obtained reacted with compound 136, the synthesis of which from (+)-camphor has been described earlier, to form 1,2,3-triazoles 143a–143d. Compound 145 was obtained by the interaction of azide 139 and propargyl 144 in 70% yield. Cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) were evaluated in vitro for all compounds synthesized. The lead compound 143d (IC₅₀ = 8.0 ± 1.0 μM; CC₅₀ = 168 ± 11.0 μM) was more effective than the reference drug rimantadine (IC₅₀ = 67.0 ± 5.0 μM; CC₅₀ = 335 ± 16.0 μM), and the 50% inhibitory concentration of the remaining compounds ranged from 65 to 519 μM, according to biological studies.

Scheme 34

Synthesis 1,2,3-triazoles-conjugates (+)-camphor and (–)-cytisine

3.3 Synthesis of Annulated N-Containing Heterocyclic Compounds from Monoterpene and Their Derivatives

The main approaches to the synthesis of an N-containing heterocyclic derivatives featuring a heterocycle condensed with a monoterpene framework are reactions of 1,3-dipolar addition to multiple C–C bonds, as well as modification of native or introduction of new functional groups into the original monoterpene/monoterpenoid and further cyclization reactions.

A novel copper-catalyzed annulation of oxime acetates and xanthates for the synthesis of thiazole derivatives was developed in [66]. The authors show that this transformation is applicable to a wide range of compounds, both aromatic and aliphatic as well as natural. Thus, the [3+2] annulation reaction produced thiazol-2-yl ethers 147 and 149 with cyclocitral and camphor fragments in their structure, respectively (Scheme 35). The work also presents the proposed mechanism of transformations under study, while the biological or catalytic activity of the compounds obtained has not been investigated.

Scheme 35

Synthesis of thiazole derivatives from cyclocitral and camphor oxime acetates

Reactions of 1,3-dipolar addition are often used for the convenient one-step synthesis of five-membered heterocyclic compounds. For example, the cycloaddition of nitrile oxides to multiple bonds is of a great synthetic value, since the reaction produces the isoxazoline core, which occurs in many compounds that have a wide spectrum of biological activity [67, 68].

In [69], compounds 155a–155c and 156b–160b (Scheme 36) featuring an isoxazoline cycle condensed with a bicyclic monoterpene fragment were synthesized by cycloaddition of nitrile oxides 151a–151c to different alkenes. The parent compounds containing the double C–C bond were used: (1R)-(+)-α-pinene (+)-11, (1S)-(–)-α-pinene (–)-11, (1R)-(–)-myrtenol (–)-152, (1R)-(–)-myrtenol acetate (–)-153, (1S)-(–)-verbenone (–)-154, and (1R)-(–)-myrtenal (–)-56. The biological or catalytic activity of the synthesized compounds 155a–155c and 156b–160b has not been investigated, but the authors of [69] suggest that these compounds could find application as ligands in asymmetric catalysis.

Scheme 36

Synthesis of isoxazoline derivatives from monoterpenes/monoterpenoids containing a double C–C bond

The authors of [70] synthesized a series of 2-aminopyrimidines 163a–163e and isoxazolines 164a–164c and 164f condensed with a bicyclic alcohol derived from α-(–)-pinene (–)-11 (Scheme 37). In the first step, α-(–)-pinene (–)-11 was oxidized with KMnO₄ to give (+)-2-hydroxy-3-pinanone 161. Subsequent aldol condensation of 161 with aromatic aldehydes led to the formation of conjugated enones 162a–162f in yields of 42–83%. Interaction of enones 162a–162f with guanidine hydrochloride and hydroxylamine hydrochloride led to the formation of the target 2-aminopyrimidines 163a–163e and isoxazolines 164a–164c and 164f, respectively. A study of the antibacterial activity against C. albicans, A. niger, G. tropicalis, E. coli, S. aureus, B. subtilis, and P. fluorescens of all compounds obtained showed that compounds 163b and 164b exhibited strong antibacterial activity against E. coli bacteria (MIC = 3.9 µg/ml), and compounds 163a, 163d, and 163e exhibited moderate activity against E. coli bacteria (MIC = 7.8 µg/ml). Compounds 163b and 163e have moderate antibacterial activity against B. subtilis bacteria (MIC = 7.8 µg/ml).

Scheme 37

Synthesis of 2-aminopyrimidines and isoxazolines from α-(–)-pinene

A series of novel 3-cyanopyridine derivatives 167a–167m and 168a–168l of β-(–)-pinene.

(–)-124 was synthesized by one-pot four-component domino reactions in [71] (Scheme 38). In the first step, (+)-nopinone (+)-165 was synthesized by oxidation of commercially available.

Scheme 38

Synthesis of 3-cyanopyridine derivatives of β-(–)-pinene

β-(–)-pinene (–)-124 with KMnO₄. Further compounds 167a–167m and 168a–168l were synthesized by one-pot four-component domino reactions between (+)-nopinone (+)-165, different aromatic aldehydes 166a–166m, ethyl cyanoacetate (or malononitrile), and NH₄OAc using Yb(OTf)₃ as catalyst. The authors of [71] suggested that combining two biologically active molecules, cyanopyridine [72] and pinene, would produce compounds with new biological activity. The targeted compounds were evaluated for their antimicrobial activity against four bacteria (Klebsiella pneumoniae, Enterobacter aerogenes, Staphylococcus aureus, and Staphylococcus epidermidis) and a fungus (Candida albicans). Among all compounds synthesized, compound 167h featuring an aromatic ring with two fluorine atoms (MIC = 15.6 mg/l) was the most active against S. epidermidis and E. aerogenes bacteria, whereas the MIC of the reference drug kanamycin was 3.9 mg/l.

The pyrimidine derivatives 178a and 178b and 1,3-oxazine 176 were synthesized by the authors of [31] from (+)-3-carene (+)-169 (Scheme 39). In the first step, the cycloaddition reaction of (+)-3-carene with chlorosulfonyl isocyanate (CSI) led to the stereoselective formation of compound 170 in 76% yield. Subsequent reaction of lactam 170 with di-tert-butyl dicarbonate resulted in compound 171, alkaline hydrolysis of which led to the formation of N-Boc-protected ester 172 in 98% yield. Removal of the Boc-protective group with trifluoroacetic acid (TFA) resulted in ester 173 in 96% yield. Ester 173 was reduced by LiAlH₄ to amino alcohol 174. By reaction of the amino group of compound 174 with PhNCS thiosemicarbazide 175 was obtained, which was further converted to 2-phenylimino-1,3-oxazine 176 condensed with the residue of the initial (+)-3-carene. The reaction of methyl ester 173 with PhNCO and PhNCS allowed obtaining urea 177a and thiourea 177b in 76 and 91% yield, respectively. The compounds 177a and 177b, in turn, were easily converted to 2-thioxo-4-pyrimidinone 178b and 2,4-pyrimidinedione 178a by base-catalyzed cyclizations. The biological activity or other applications of the target compounds were not discussed in this work.

Scheme 39

Synthesis of pyrimidine derivatives and 1,3-oxazine from (+)-3-carene

A simple method for the synthesis of chiral nopinane-annulated pyridine 180 and obtaining its oxidation products 181 and 182 is presented in [73] (Scheme 40). Compound 180 was synthesized by treatment of (+)-pinocarvone oxime (+)-179 with 2-morpholino-cyclopent-2-enone in the presence of FeCl₃. Oxidation of compound 180 with SeO₂ led to the formation of a mixture of compounds 181 and 182, the latter of which was obtained as a product of oxidative dimerization. The structure of compounds 180–182 was confirmed by X-ray crystallography. The authors of [74] have obtained chiral luminescent ZnLCl₂ and [CdLCl₂]_n complexes where L is chiral compound 180 and investigated their fluorescent properties. It was shown that the chelation-enhanced fluorescence (CHEF) effect is manifested in the complexes.

Scheme 40

Synthesis of chiral nopinane-annulated pyridine and obtaining its oxidation products

The synthesis of chiral 1H-pyrazolo[3,4-b]pyridines 183a–183d and 184 condensed with a nopinene frame from (+)-pinocarvone oxime (+)-179 is described in [75] (Scheme 41). Interaction of oxime (+)-178 with 1-aryl-1H-pyrazol-5-amines without solvent in the presence of FeCl₃ upon heating gave corresponding 3-methyl-1-aryl-1H-pyrazolo[3,4-b]pyridines 183a–183d and 184 in 15–35% yield. Compounds 183a–183d and 184 were also obtained under microwave irradiation, the addition of FeCl₃∙6H₂O did not increase the yield of the target products. Biological activity or other applications are not described in the work, but the authors hope to use the synthesized compounds 183a–183d and 184 as ligands or fluorescent markers and investigate their biological activity in the future.

Scheme 41

Synthesis of chiral 1H-pyrazolo[3,4-b]pyridines from (+)-pinocarvone

The synthesis of triazolium salts 191a–191e from (+)-hydroxymethylenecamphor (+)-185 was described in [76] (Scheme 42). The synthesis started with (+)-3-(hydroxymethylene)camphor (+)-185, whose interaction with (carbamoylmethyl)triphenylphosphonium chloride resulted in compound 186. Heating compound 186 in acetate buffer for 40 h led to the closure of 2-pyridinone cycle and formation of compound 187 in 58% yield, in which the bicyclic frame of (+)-camphor condensed with N-heterocycle according to previously published work [77]. Treatment of 187 with Tf₂O in the presence of Et₃N gave 188 in 96% yield. The key step in the synthesis of the compounds desired was the Pd-catalyzed coupling of arylhydrazines with pyridyltriflate 188 which resulted in compounds 189a–189e. Further removal of the Boc-protecting group by AcCl or 2,6-dimethylpyridine with tert-butyldimethylsilyl triflate (TBSOTf) (method A and method B, respectively) led to the formation of hydrazines 190a–190e. In the final step of the synthesis, compounds 190a–190e underwent condensation with HC(OMe)₃ in the presence of NH₄PF₆ to form triazolium salts 191a–191e.

Scheme 42

Synthesis of triazolium salts from (+)-hydroxymethylenecamphor

The triazolium salts are used as precursors for the production of N-heterocyclic carbenes (NHC), which have found wide application as ligands in metal-based catalysis [78,79,80,81]. In the basic medium, the detachment of hexafluorophosphate ion from the triazolium salts (e.g. 191a–191e), the migration of the double C=N bond electrons to the nitrogen atom, and the subsequent detachment of the proton from the carbon atom to form a stable N-heterocyclic carbenes (e.g. 192a–192e) occur (Fig. 3). The annulation of NHC with aliphatic rings having optical centers can be considered as a promising approach for the synthesis of ligands for asymmetric catalysis with high reactivity and enantio-/diastereoselectivity [82,83,84].

Fig. 3

Structures of triazolium salts and NHC

A series of chiral triazolium salts 196a–196e has been synthesized from (+)-camphor (+)-25 in [85], and their catalytic activity in intramolecular crossed aldehyde–ketone benzoin reactions affording α-ketols has been evaluated (Scheme 43). At the first stage, camphorquinone-3-oxime 193 was synthesized in 89% yield from (+)-camphor and i-amylnitrite in the presence of tert-BuOK according to procedure [86]. The reduction of oxime 193 with LiAlH₄ in an inert atmosphere led to the formation of 3-exo-aminoisoborneol 194 in 92% yield. Subsequent interaction of exo-amino alcohol 194 with ClCH₂COCl resulted in lactam 195, in which the morpholine-3-one cycle is condensed with a bicyclic (+)-camphor frame. At the next stage, a series of triazolium salts 196a–196e was synthesized by interaction of compound 195 with arylhydrazides and further condensation with HC(OEt)₃ in accordance with previously developed methodology [87].

Scheme 43

Synthesis of triazolium salts from (+)-camphor

All the salts 196a–196e obtained were evaluated for their catalytic activity in intramolecular benzoin condensation of 2-(2-oxo-2-phenylethoxy)benzaldehyde into optically active tertiary alcohol in the presence of 10 mol % Et₃N as a base. The best results (95% yield; ee 71%) were observed using salt 196d (12 mol%) as a precatalyst. Only trace amounts of the desired α-ketole were observed when using salts 196a–196c as precatalysts in the similar conditions. As a result, the use of salt 196e as a precatalyst turned out to be worse than that of 196d. The authors have studied the obtained triazolium salt 196d as a precatalyst in the reactions of intramolecular benzoin condensation of other 2-substituted benzaldehydes: the ee of the target products exceeded 76%; the yields were 90% or more (using 6 mol% 196d). The use of triazolium salt 196d as a precursor of NHC and the catalytic activity of the latter in intramolecular benzoin condensations of other aldehydes have been described in [88].

It is worth noting that subsequent work by the same scientific group found that the 196a–196e salts could also be used as catalysts for the asymmetric intramolecular Michael reactions. As it was mentioned in [89], the NHC generated from salt 196c (5 mol%) and DIPEA proved to be highly efficient for a wide range of substrates in intramolecular Michael reaction (up to 99% yield; 99% ee).

It was shown that the NHCs generated from salts 196a–196e are highly efficient for the asymmetric intramolecular Stetter reaction. With 10 mol% of the catalyst, the target products were obtained in excellent yields with up to 97% ee [90, 91]. Although in these works the use of salt 196c as precatalyst did not show the desired result, when using 10 mol% 196d salt as NHC precursor in the presence of DIPEA (10 mol%), the target products of the intramolecular Stetter reaction were obtained in good yields with over 90% ee [88]. In [91], the best results were also observed when using 196d salt as a precatalyst (target products were obtained in yields over 50%; ee higher than 70%).

Another research group [92] synthesized chiral triazolium salts 197a–197c from (–)-β-pinene using the above-mentioned methodology (Fig. 4). It was shown that NHC generated from triazolium salt 197b exhibited excellent catalytic activity (yield of over 90%; er (enantiomer ratio) of up to 99:1) in the intramolecular Stetter reaction. It was also shown by the authors of this work that the use of triazolium salts 197a and 197c reduced significantly the yield of the target products in the intramolecular Stetter reaction.

Fig. 4

Chiral triazolium salts synthesized from (–)-β-pinene

The authors of [93] synthesized triazolium salts 198–201 in a similar way to the above-mentioned method (Fig. 5), but in this case, the salts were synthesized from (–)-3-endo-aminoborneol, obtained by the well-known method [94]. The potential of four new catalysts and several readily available chiral NHC precursors in the enantioselective intramolecular crossed-benzoin reaction of 2-(2-oxo-2-phenylethoxy)benzaldehyde and its derivatives was investigated. The target acyloins were obtained in yields above 80% (after column chromatography) and with an ee of over 90% when using 15 mol% salt 201 as a precatalyst. It is also worth mentioning that NHC generated from salt 201 proved to be such an effective catalyst that complete conversion of 2-substituted benzaldehydes was already observed after 1 h.

Fig. 5

Chiral triazolium salts synthesized from (–)-3-endo-aminoborneol

The authors of [95] synthesized a series of compounds containing annulated pyrazole cycle; in particular, compound 202 was synthesized in one step from (+)-3-(hydroxymethylene)camphor (+)-185 and 2-hydrazinopyridine (Scheme 44). No biological activity or other studies have been carried out, but the authors suggest that the compounds obtained will find application in the chemistry of luminescent metal chelates.

Scheme 44

Synthesis of annulated pyrazole derivative from (+)-3-(hydroxymethylene)camphor

The authors of [96] synthesized a series of compounds 203, 206, 209a, and 209b possessing an annulated pyrazole cycle from (+)-camphor (+)-25, (–)-menthone (–)-204, and (+)-pulegone (+)-207 (Scheme 45). The procedure involves formylation at the less hindered α position of starting ketone followed by cyclocondensation of resulting compounds (+)-185, 205, and 208 with N₂H₄ to obtain pyrazoles 203, 206, 209a, and 209b. It should be noted that condensation of ketone (–)-204 with HCO₂Et resulted in the formation of compound 205 as a mixture of cis/trans isomers in a 13:1 ratio. Subsequent cyclocondensation of the mixture of isomers 205 with N₂H₄ led to the formation of the target pyrazoles. The separation of isomers was carried out by HCl treatment and further recrystallization of cis-206 from a mixture of chloroform/methyl tert-butyl ether followed by treatment with NaHCO₃ in 37% yield. Compound 208 as a mixture of cis/trans isomers in the ratio of 1:2 was obtained by interaction of (+)-pulegone (+)-207 with the Grignard reagent and subsequent condensation with HCO₂Et. Further cyclocondensation of the mixture of isomers 208 with N₂H₄ resulted in a mixture of pyrazoles 209a and 209b, which were separated as hydrochlorides by recrystallization from hexane (trans-isomer) and toluene (cis-isomer). After treatment with NaHCO₃, the target compounds 209a and 209b were obtained in 37 and 13% yields, respectively. Biological activity or other applications are not described in the work.

Scheme 45

Synthesis of pyrazole derivatives from (+)-camphor, (–)-menthone, and (+)-pulegone

A series of imidazoles 210a–210d and 213a–213d, pyrazines 211a–211e and 214a–214e annulated with a bicyclic (+)-camphor and a (+)-nopinane frames was synthesized in [97] (Scheme 46). The synthesis of the target compounds was carried out in one step by condensation of a number of primary amines with camphor-3-oxime 193 and nopinone-3-oxime 212. It is worth noting that when oximes 193 and 212 were condensed with 1.5 equiv. of primary amines, pyrazines 211a–211e and 214a–214e were observed as by-products, but when the amount of reacting amines was increased to 2.5 equiv., pyrazines 211a–211e and 214a–214e became the main products of condensation. The use of amines with an aliphatic substituent at the α-carbon atom resulted in the formation of imino-oximes only. The biological activity or other applications of the synthesized compounds were not investigated in this work.

Scheme 46

Solvent-free synthesis of imidazoles and pyrazines annulated with (+)-camphor and (+)-nopinone frames

The synthesis of camphor-1,2,4-triazines 216a, 216b, 217, and 220 fused with five-membered N-heterocycles was described in [98] (Scheme 47). Starting 3-amino-camphor-1,2,4-triazine 215 was obtained in one step by condensation of (+)-camphorquinone (+)-55 with guanidine bicarbonate. Compounds 216a and 216b were obtained by condensation of compound 215 with 2-bromoacetophenone and 2-oxo-2-phenylacetaldehyde, respectively. Construction of a thiadiazole ring was carried out by treatment of triazine 215 with chlorocarbonylsulfenyl chloride resulted in the formation of compound 217. Compound 220 containing the triazole cycle was synthesized from 2-aminotriazine 215 in three steps: first, compound 215 was converted to the corresponding formamidine 218, which was subsequently treated with NH₂OH∙HCl to obtain oxime 219, which was further cyclized to the target triazotriazine 220.

Scheme 47

Synthesis of camphor-1,2,4-triazines fused with five-membered N-heterocycles

The compounds 222–227 in which a six-membered ring is annulated to camphor-1,2,4-triazine were synthesized as shown in Scheme 48. Condensation of the triazine 215 with diethyl ethoxymethylenemalonate and subsequent cyclization upon heating in a eutectic mixture of biphenyl with diphenyl oxide (Dowtherm A) resulted in the formation of compound 222 in 80% yield. Its structural analogue, compound 223, was obtained by condensation of compound 215 with ethyl acetoacetate. Heating 2-aminotriazine 215 with methyl propiolate in EtOH resulted in the formation of compound 224. The bifunctional electrophilic reagent N-(chlorocarbonyl)-isocyanate reacted with compound 215 in the presence of Et₃N to form compound 225. Treatment of 2-aminotriazine 215 with 3-chloropropionyl chloride yielded salt 226, which further converted to the free base 227 in an alkaline medium. The CNS stimulant activity of all compounds shown in Schemes 47 and 48 was investigated using mice. The target compounds do not have CNS stimulant activity according to biological evaluation.

Scheme 48

Synthesis of camphor-1,2,4-triazines fused with six-membered N-heterocycles

As a continuation of their work on the search for CNS stimulants, the aforementioned research group [99] reported the cycloaddition reaction of camphor-1,2,3-triazine 228 with diphenylcyclopropenone and oxidation of 1,2,3-triazine 228 with meta-chloroperbenzoic acid (MCPBA) (Scheme 49). The synthesis of 1,2,3-triazine 228 was not described in [99]. The interaction of triazine 228 with diphenylcyclopropenone resulted in the formation of two regioisomers 229a and 229b in a 2:1 ratio. Oxidation of triazine 228 resulted in the formation of triazine-2-oxide 230 as the main product and triazine-2,3-dioxide 231 as a by-product. A study of the CNS stimulant activity of compounds 229a, 229b, and 230 showed that compound 230 had the strongest effect at a dose of 50 mg/kg. Its activity was comparable to that of the reference drug pentylenetetrazole. Compounds 229a and 229b had no CNS stimulant activity.

Scheme 49

Synthesis of benzotriazinones and triazine-oxides from camphor-1,2,3-triazine

The authors of [100] synthesized a racemic mixture of indole derivatives of ( ±)-camphor 233a, 233b and ( ±)-menthone 234a, 234b by the aldol reaction of isatin 232 with ketones 25 and 204, respectively, in the presence of tert-BuOK (Scheme 50). The authors failed to separate the isomers 233a, 233b and 234a, 234b neither by recrystallization nor by column chromatography. Further condensation of mixtures 233a, 233b and 234a, 234b with o-phenylenediamine, ethylenediamine, urea, and thiourea was accompanied by the formation of mixtures of spirocyclic compounds 237, 241, 245, and 246 (from (±)-camphor), 238, 242, 247, and 248 (from (±)-menthone) and polycyclic compounds 239, 243, 249, and 250 (from (±)-camphor), 240, 244, 251, and 252 (from (±)-menthone); each of them was isolated individually. The interaction of 2-aminopyridine with mixtures 233a, 233b and 234a, 233b resulted in the formation of spirocyclic compounds 235 and 236, respectively, as the sole reaction products. All compounds synthesized were screened for their antibacterial activity against E. coli, B. sublitis, and B. cereus bacteria and for antifungal activity against Aspergillus niger, Pencillium species, and Cladosporium species. However, none of the compounds synthesized showed either antibacterial or antifungal activity comparable to the reference drugs norfloxacin (antibacterial) and fluconazole (antifungal).

Scheme 50

Synthesis of some indole-based spiro and condensed heterocycles from camphor and menthone

3.4 Synthesis of N-Heterocyclic Compounds, Incorporating a Spirocyclic System, from Monoterpenoids and Their Derivatives

The main approach to the synthesis of spirocyclic compounds containing an N-heterocyclic core and monoterpene frame is represented by nucleophilic addition reactions on the native carbonyl group of monoterpenoids with simultaneous or subsequent cyclization of the heterocycle.

Spirocyclic triazin derivatives were synthesized in [101] by interaction of 2-guanidinobenzimidazole 253 with a number of ketones of various structures, including camphor 25. It is worth noting that the configuration of stereocenters in the original camphor 25 is not specified in the work. The synthesis of compound 254 was performed by nucleophilic addition of the guanidine imino group to the carbonyl group of camphor 25 followed by cyclization by nucleophilic addition of the nitrogen atom of the benzimidazole nucleus (Scheme 51). The antibacterial activity of all synthesized spirocyclic compounds featuring the 1,3,5-triazine core was also investigated against gram-positive and gram-negative bacteria. Unfortunately, compound 254 had the weakest antibacterial activity against all types of bacteria.

Scheme 51

Synthesis of substituted triazin-2-amine from camphor

The synthesis of chiral spirocyclic 1,3,4-thiadiazoline derivatives 257–259 with a monoterpene frame in structure was described in [102] (Scheme 52). The synthesis was carried out by interaction of (±)-camphor 25, (–)-fenchone (–)-108, and (–)-menthone 204 with thiosemicarbazide at the first stage to form thiosemicarbazones 129, 255, and 256, respectively, in yields of 40–99%. In the next step, treatment of the thiosemicarbazones in acetylation conditions with Ac₂O afforded spirocycles 257–259. The reaction proceeded with the formation of one stereoisomer in each case. The configuration of the spirocyclic stereocenter was established by X-ray analysis and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. Thus, for spirocyclic compounds 257 and 258 (obtained from (±)-camphor and (–)-fenchone, respectively), the spirocyclic stereocenter possessed configuration R, and for compound 259 (obtained from (–)-menthone), it had configuration S. The biological or catalytic activity of the compounds obtained was not investigated.

Scheme 52

Synthesis of spirocyclic 1,3,4-thiadiazoline derivatives from camphor, (–)-fenchone, and (–)-menthone

In continuation of the works devoted to the synthesis of triazolium salts and the study of their catalytic activity, the (+)-camphor-derived triazolium salts 263a–263c incorporating a spirocyclic system were synthesized in [103] (Scheme 53). At the first stage, (+)-camphor (+)-25 reacted diastereoselectively with trimethylsilyl cyanide (TMSCN) to form compound 260. Further reduction of ether 260 by LiAlH₄ resulted in almost quantitative formation of amino alcohol 261. Spirocyclic lactam 262 was obtained in two stages: at the first stage, amino alcohol 261 was acylated with ClCH₂COCl, and then the resulting amide was cyclized under the action of tert-BuOK. Further interaction of morpholine-3-one 262 with arylhydrazines and condensation with HC(OEt)₃ resulted in spirocyclic triazolium salts 263a–263c. The precatalysts obtained were investigated as NHC precursors for their catalytic activity in the asymmetric benzoin condensation of PhCHO in (R)-2-hydroxy-1,2-diphenylethan-1-one. The catalyst derived from salt 263a showed low selectivity (71:29 er; yield of 31%). The catalyst derived from salt 263b gave desired benzoin in an excellent yield with low selectivity (52:48 er; yield of 99%).

Scheme 53

Synthesis of (+)-camphor-derived triazolium salts, incorporating a spirocyclic system

The authors of [103] further synthesized the triazolium salt 266 from lactam 262 (Scheme 54). Interaction of lactam 262 with trimethyloxonium tetrafluoroborate resulted in compound 264 in 97% yield. In the next step, salt 265 was obtained by interaction of compound 264 and 2,4,6-trimethylphenylhydrazine hydrochloride. Condensation of salt 265 with HC(OEt)₃ resulted in the formation of spirocyclic triazolium salt 266. The catalyst derived from salt 266 gave the best results [103], affording the benzoin product in 98% yield and 71.5:28.5 enantiomeric ratio. The catalyst derived from salt 266 and DIPEA was successfully employed in the asymmetric benzoin condensation of substituted benzaldehydes. The resulting acyloins were obtained in moderate to excellent yields and acceptable enantioselectivities.

Scheme 54

Synthesis of (+)-camphor-derived triazolium salt, incorporating a spirocyclic system and mesitylene fragment

The preparation of triazolium salts 267, 268a, 268b, 269a, and 269b containing a spirocyclic system from (+)-fenchone and (+)-camphorquinone was described in [104] (Fig. 6). The NHC precursors synthesized were employed in the catalytic asymmetric benzoin condensation of different benzaldehydes. The synthesis was carried out similarly to the methods described above, except for the synthesis of (+)-camphorquinone-derived triazolium salts 269a and 269b, where the carbonyl group at the 3 position was protected in the first step. The yields in Fig. 6 are shown for the last stage of synthesis of the target compounds. The catalyst derived from salt 269b (10 mol%) and dicyclohexylethylamine (DCyEA) turned out to be the most active as a chiral NHC catalyst for the benzoin condensation of benzaldehyde and its derivatives (more than 70:30 er; yield of isolated benzoin over 26%).

Fig. 6

(+)-Fenchone- and (+)-camphorquinone-derived triazolium salts containing a spirocyclic system

The authors of [105] performed a one-step diastereoselective synthesis of spirocyclic compound 271 from (–)-fenchone(–)-108 and anthranilamide 270 (Scheme 55). Solvent-free condensation of (–)-fenchone and anthranilamide in the presence of ZnCl₂ resulted in the formation of a diastereomeric mixture of spirocyclic quinazolinones, whose subsequent column chromatography isolated the compound 271 in 65% yield. The authors were able to isolate a crystal of compound 271 and study its crystal structure and porosity. Biological studies of compound 271 were not carried out in [105].

Scheme 55

Synthesis of spirocyclic quinazolinone derivative from (–)-fenchone

3.5 Synthesis of N-Containing Compounds from Monoterpenes, Monoterpenoids, and Their Derivatives Including the Stages of Breaking the Frame of the Starting Compound

Bicyclic monoterpenes and monoterpenoids have a rigid and strained structure. Some monoterpenes contain a cyclopropane or cyclobutane ring in their structure. Therefore, during chemical reactions, the structural integrity of such monoterpenes and monoterpenoids can be disturbed, leading to the frame breaking. However, the synthesis of new heterocyclic compounds, from monoterpenes and monoterpenoids, during which the bicyclic frame of a native molecule is broken, is an urgent research area. Such transformations open the way to obtain optically active compounds, promising objects for the study of their biological or catalytic properties.

The synthesis and study of the herbicidal activity of 1,3,4-thiadiazole derivatives 276a–276h synthesized from α-pinene 11 (the configuration of the stereocenters is not specified in the work) was described in [106] (Scheme 56). At the first stage of the synthesis, α-pinene was oxidized with KMnO₄ to form acid 272. Further oxidation of acid 272 by NaOBr resulted in the formation of dicarboxylic acid 273 possessing a cyclobutane ring. Successive esterification and nucleophilic substitution reactions with N₂H₄ led to the formation of dihydrazide 274. Interaction of the latter with isothiocyanates led to the formation of compounds 275a–275h, whose intramolecular cyclization in acidic medium gave N-substituted 2-aminothiadiazoles 276a–276h connected through a methylcyclobutane linker. It is worth noting that the study lacks a number of experimental data, including the yields of the target and intermediate products of the synthesis. It was found that most of the target compounds exhibited a certain growth inhibition activity against root of rape B. Campestris, in which compounds 276b and 276c had inhibition rates of 72.3% and 68.3%, respectively. Biological studies have shown that compounds 275a–275h do not exhibit herbicidal activity, contrary to compounds 276a–276h. Thus, the authors claim that cyclization of compounds 275a–275h enhances herbicidal activity.

Scheme 56

Synthesis of 1,3,4-thiadiazole derivatives from α-pinene

The authors of [107] synthesized pyrazole 281a–281c and 2-isoxazoline 282 and 283a–283c derivatives from (+)-3-carene (+)-168 (Scheme 57). Thus, cyclopropane derivative 277 possessing a cyano and carbonyl group was obtained from (+)-3-carene (+)-168 in several steps by the known method [108] in 58% yield. Subsequent intramolecular cyclization of compound 277 in an alkaline medium led to the formation of bicyclic enaminone 278 [109]. Its treatment with HCl in an aqueous-alcoholic solution resulted in hydrolysis of the enamine fragment and formation of enol 279 in 85% yield. Compound 279 can be also obtained by another route: oxidative cleavage of the (+)-3-carene double bond by the known method [110] to obtain a substituted cyclopropane 280, which is further cyclized by the action of MeONa into enol 279 in yield of 81%. Pyrazoles 281a and 281c were obtained by the interaction of compound 278 with N₂H₄ and compound 279 with PhNHNH₂, respectively. Compound 281b, in turn, was obtained by acylation of 281a in the presence of pyridine. The reaction of enol 279 with NH₂OH resulted in 2-isoxazoline 282. Compounds 283a–283c were synthesized by subsequent substitution of the hydroxyl group in compound 282 with a chlorine atom, methoxy group or acetoxy group. The biological activity of the compounds obtained was not investigated in this work, and their applications were not discussed.

Scheme 57

Synthesis of pyrazole and 2-isoxazoline derivatives from (+)-3-carene

The synthesis of substituted 1,3,4-thiadiazoles 288a–288l from α-pinene 11 (the configuration of the stereocenters is not specified in the work) and their antifungal activity against Fusarium graminearum and Physalospora piricola were described in [111] (Scheme 58). Compound 286 was synthesized by nucleophilic addition of thiosemicarbazide to campholenic aldehyde 285, which was obtained by epoxidation of α-pinene 11 and further rearrangement under the action of ZnCl₂ in toluene [112]. Its subsequent cyclization in an aqueous-alcoholic solution of FeCl₃ led to the formation of 5-substituted 2-amino-1,3,4-thiadiazole 287. The target amides 288a–288l were obtained by acylation of the free amino group with acyl chlorides of various structures. Compounds 288h and 288j inhibit the growth of the fungi Physalospora piricola and Fusarium graminearum by 98 and 94%, respectively, according to biological evaluation.

Scheme 58

Synthesis of substituted 1,3,4-thiadiazoles from α-pinene

Tetrazoles and their derivatives are considered important pharmacophores in medicinal chemistry because of their unique structure and a wide range of biological activities [113,114,115]. Therefore, the synthesis of tetrazole derivatives with a monoterpene fragment in the structure is of great interest for medicinal chemistry. A facile procedure of the synthesis of 1,5-disubstituted tetrazole from cyclic ketones was developed in [116]. Tetrazole 289 was synthesized by grinding a mixture of (+)-camphor (+)-25 and NaN₃ in the presence of AlCl₃ at 50 °C without solvent (Scheme 59). The advantages of this method for the synthesis of 1,5-disubstituted tetrazoles are short reaction time and good yields. The biological or catalytic activity of the compounds obtained was not investigated.

Scheme 59

Synthesis of 1,5-fused tetrazole from (+)-camphor

An interesting study of the interaction of bicyclic ketones with o-substituted anilines was performed in [117]. The investigation describes a solvent-free one-step interaction of (+)-camphor (+)-25 and (–)-fenchone (–)-108 with o-substituted anilines in the presence of ZnCl₂, which resulted in a series of 2-substituted benzoazoles 291a–296a and 291b–296b (benzoxazoles, benzothiazoles, and benzimidazoles) (Scheme 60). Condensation of monoterpenoids with o-substituted anilines was accompanied by breaking of a bicyclic frame of the starting ketones at the most substituted C–C bond (C₁–C₂ in the case of (+)-camphor; C₂–C₃ in the case of (–)-fenchone) and formation of mixture of two diastereomers in all cases. The configuration of stereocenters in the obtained benzoazoles was established by X-ray analysis of some complex compounds, which were also synthesized in this work. The assumed mechanism of the investigated transformations was established; biological studies were not carried out.

Scheme 60

Solvent-free interaction of (+)-camphor and (–)-fenchone with o-substituted anilines

A similar breaking of the bicyclic (+)-camphor frame in the condensation of camphorquinone 55 and a series of 4,5-disubstituted o-aminophenols 296a–296g were described in [118] (Scheme 61). A series of cis-(benzoxazole-2-yl)cyclopentanecarboxylic acids 297a–297g was synthesized by interaction of (±)-camphorquinone 55, (+)-camphorquinone (+)-55, and (–)-camphorquinone (–)-55 with o-aminophenols 296a–296g in EtOH. Using enantiomerically pure camphorquinones ((+)-55 and (–)-55), compounds (1R, 3S)-297f and (1S, 3R)-297f were obtained, respectively. The structure of compound 297f was confirmed by X-ray diffraction analysis.

Scheme 61

Condensation of camphorquinone with 4,5-disubstituted o-aminophenols

The authors of [119] synthesized a number of polycyclic compounds 299–303 from (+)-camphoric acid (+)-298 and a number of diamines of various structures, and studied their antiviral activity against influenza A virus (strains H1N1, H3N2, and H5N2) (Scheme 62). (+)-Camphoric acid is a dicarboxylic acid that is formed by oxidation of bicyclic monoterpenoid (+)-camphor (+)-25 by the known method [120], and it is a commercially available reagent. Solvent-free cyclocondensation of (+)-camphoric acid with o-phenylenediamine and 1,8-diaminonaphthalene resulted in formation of isomeric compounds 299a, 299b and 300a, 300b, respectively. Each isomer was isolated in pure form by column chromatography. At the same time, it is worth noting that the interaction of (+)-camphoric acid with o-phenylenediamine under other conditions was already studied by another group of researchers [121]. The structural analogue of quinazoline alkaloids 301 was obtained by interaction of acid (+)-298 with o-aminobenzylamine. The reaction of (+)-camphoric acid with aliphatic diamines was carried out in phenol as a solvent, resulting in individual compounds 302 and 303. According to biological studies, compounds 299a, 302, and 303 exhibited moderate antiviral activity against A/Puerto Rico/8/34 (H1N1), higher than that of the reference drugs: rimantadine, amantadine, and deitiforin (SI(299a) = 21; SI(302) = 28; SI(303) = 37; SI(rimantadine) = 6; SI(amantadine) = 5; SI(deitiforin) = 7), while compound 301 proved to be the lead compound (SI(301) = 62). It is worth noting that compound 301 exhibited antiviral activity against other strains of influenza A virus (SI(301(H3N2) = 41; SI(301(H5N2) = 53), comparable with that of the reference drugs mentioned above (SI(H3N2) reference drugs varied from 56 to 82, and SI(H5N2) reference drugs varied from 50 to 55).

Scheme 62

Synthesis of imidazole and pyrimidine derivatives from (+)-camphoric acid

Thus, in this section, the ways to synthesize N-containing heterocycles derivatives by modification of carboxyl, carbonyl, or amino groups of monoterpene derivatives, including the stages of heterocycle core formation, were considered. In such compounds, the heterocycle and the monoterpene frame are connected directly by an exocyclic C–C or C–N bond, or through a linker attached to the monoterpene frame by a C=N or C–C bond. The construction of a heterocycle core condensed with a monoterpene frame is performed by the reactions of 1,3-dipolar cycloaddition of nitriloxides at the double C=C bonds of monoterpenes or their derivatives; aldol reaction with monoterpenoids featuring a carbonyl group or synthesis of amino alcohols on their basis with subsequent interaction with nucleophilic agents accompanied by closure of the heterocycle; or multicomponent domino reactions with carbonyl-containing monoterpenoids. The synthesis of functionalized N-containing heterocycles condensed with the monoterpene frame allows the synthesis of condensed polycyclic systems by forming an additional five- or six-membered heterocycle by modifications of the heterocycle already present in the molecule. A good example is the triazolium salts, which are used as NHC precursors in asymmetric reactions. Monoterpenoids with a carbonyl group are used in the synthesis of heterocycles containing a spirocyclic system. The synthesis of N-containing derivatives of heterocycles containing cyclobutane or cyclopentane fragments obtained by modification of monoterpenes and monoterpenoids accompanied by a rupture of the bicyclic frame was also considered.

4 Conclusions and Outlook

The present review aims to provide essential support to chemists in the search for new N-heterocyclic compounds with a monoterpene frame in the structure, which may have wide potential in medicinal chemistry and catalysis. We have reviewed the approaches to the synthesis of N-containing heterocyclic compounds with spirocyclic or annulated structures as well as the coupling to the monoterpene frame via C–C, C–N, and other bonds directly or via linkers of different structures. The properties of the heterocyclic compounds obtained, the commercial availability of the initial monoterpenes and their derivatives, and the acceptable yields of the target compounds considered in this review, indicate that the combination of the N-heterocycle nucleus and monoterpene frame in one molecule is a promising direction of investigation in the field of natural product chemistry. Despite numerous exciting advances in the synthesis of N-heterocyclic compounds from monoterpenes and their derivatives, there is still an urgent need both to develop new approaches to synthesis and to expand the libraries of synthesized heterocycles. Work in this direction could lead to the discovery of pharmacologically active and, at the same time, nontoxic substances and to the obtaining of metal complex systems in which the active center and its near surroundings possess a sufficiently rigid framework for the further obtaining of highly stereoselective catalytic systems. On the basis of the review presented, the following can be assumed:

• 1. Much effort will further be invested in developing robust, flexible and scalable approaches to the synthesis of N-containing heterocyclic compounds based on monoterpenes and their derivatives and the subsequent structure–activity relationship for each biological target. An important strategy will be the use of some functional groups or structural fragments that are favorable for affinity to specific target sites. Such a strategy will produce compounds capable of forming intermediate target/substrate complexes with reduced transition-state energies.

• 2. The structural modification of natural compounds will be actively used by chemists in the near future. Such an approach may make it possible to obtain surface-active substances with an amphiphilic structure. Currently, researchers pay special attention to surface-active substances with a natural biocompatible fragment. Such amphiphiles can provide additional affinity of surface-active substances to biological systems. Additionally, the modification of monoterpenes and their derivatives leads to the formation of small molecules that can often penetrate through the lipid bilayer of the cell membrane and reach their intracellular targets quite quickly (provided they are sufficiently lipophilic).

• 3. The study of stereoselective reactions will continue to be one of the most important tasks of modern organic chemistry and will play a fundamental role in the pharmaceutical industry. Considerable efforts will be devoted to the synthesis of highly efficient metal complex systems used in asymmetric catalysis, which still remains one of the most powerful and cost-effective ways to produce enantiomerically enhanced compounds needed for pharmacology. In particular, the synthesis of N-heterocyclic carbenes using monoterpenes and their derivatives as starting platforms shows good prospects. The molecular design of new NHCs will focus primarily on steric factors, as it has been found to increase the steric hindrance of the carbene carbon atom which often leads to increased stereoselectivity of NHC–metal complexes.