1st generation 1,2,3-triazole based dendrimers with arylmethyl Meldrum's acid surface groups – synthesis and radical scavenging activity

Abstract

Substituted Meldrum's acids are known as carbon centred antioxidants. Herein a series of 11 dendrimeric antioxidants with either a phenol-type, carboxylic acid or aliphatic alcohol core are synthesised. The dendrons are attached through a 1,4-disubstituted 1,2,3-triazole linker. The compounds are synthesised in a divergent approach through the Huisgen reaction, followed by the Knoevenagel condensation with Meldrum's acid and double bond reduction. Additionally, a telescoped Huisgen reaction without isolation of the azide intermediate is presented. The obtained dendrimers display considerable DPPH radical scavenging activity (Inh₁₀₀ = 68–88%). The antiradical activity for these compounds is remarkably higher than for such widely used antioxidants as ascorbic acid (DPPH test: Inh₁₀₀ = 14%) and BHT (DPPH test: Inh₁₀₀ = 16%). The antiradical activity slightly varies depending on the solvent. Some of the compounds have even demonstrated higher antiradical activity in less polar solvents, thus indicating the HAT mechanism as favourable for these compounds.

New dendritic architectures bearing C-centred antioxidative surface groups are synthesized. The results indicate the strong impact of the number of surface groups on the antiradical activity of the synthesized compounds.

Introduction

Dendrimers are a class of highly branched, symmetrical, spherical polymers (Fig. 1).¹ Dendrimers are characterized by a polyfunctional core, which is bound to multiple branching units called dendrons. The amount of branching determines the generation of the dendrimer. The terminal moieties of dendrimers are known as surface groups, which create a densely functionalised outer shell. The structure of the dendrons creates internal cavities in the dendrimer structure, which have garnered interest due to their ability to trap small molecules.^2–5 The poly-functionalized surface of the dendritic structures can be used to anchor directing groups for the targeted delivery of medicine.⁶

Fig. 1. Schematic representation of a dendrimer molecule.

Antioxidants are active molecules, which prevent oxidation processes. Oxidation is a radical-type process, which occurs when free radicals (typically reactive oxygen or nitrogen species, ROS and RNS, respectively) react with molecules.⁷ Undesired oxidation leads to food spoilage,⁸ rancidification of oils and fats,⁹ and degradation of the physical properties of various materials.¹⁰ In biological systems, an excess of free radicals can cause a state known as “oxidative stress”, which has been linked to such conditions as Alzheimer's¹¹ and Parkinson's¹² disease, asthma,¹³ cancer,¹⁴ and multiple cardiometabolic disorders.¹⁵

Antioxidants can act through various mechanisms, for example, scavenging of ROS and RNS, disruption of autooxidation chain reactions, and modulation of biological processes responsible for ROS and RNS generation. During these processes antioxidants first form stabilised radicals, which later degrade to benign species.¹⁶

When antioxidants are bound (either covalently or non-covalently) to dendrimers, properties such as solubility, stability, and activity can be improved.^17–21 Even dendrimers without distinctive antioxidant moieties display certain antioxidative activity.^22–24 Depending on the structure design dendrimeric antioxidants can both regulate biological processes responsible for the generation of ROS or RNS, or scavenge already formed radicals.²⁵ Furthermore, dendritic structures with antioxidant surface groups can be used to both deliver and stabilise small molecules which are prone to oxidation by incorporating them in the dendrimer internal cavities.

Our group has reported arylmethyl Meldrum's acids 1 as promising, novel 1,3-dicarbonyl type antioxidants²⁶ with a high tolerance to structural modifications – the aryl group substituents can be modified freely without a significant decrease in activity (Fig. 2a).²⁷ We have also established polyfunctionalized Meldrum's acid antioxidants 2, which are attached to the core through an ethereal linker (Fig. 2b).²⁸

Fig. 2. Arylmethyl Meldrum's acids as radical scavengers: (a) small molecule arylmethyl Meldrum's acids 1, and (b) polyfunctionalised Meldrum's acid derivatives 2.

In this work we expanded this research to dendritic antioxidants 3 containing a 1,2,3-triazole linker. Based on some literature evidence,^29–31 it is expected that such a structural unit could enhance the antioxidant capabilities of the compounds. Additionally, the 1,2,3-triazole unit is recognised as a hydrolytically stable amide bond bioisostere,³² thus these compounds can be considered as structural alternatives to widely used amide bond-containing PAMAM dendrimers. The newly constructed dendritic structures 3 have several advantages over the previously developed structures: (1) the linkers are longer thus leading to reduced steric crowding of the surface functional groups for the higher generation dendrimers;³³ (2) the volume of the internal cavities is increased thus the encapsulation of small molecules in the cavities of the dendritic structures is more feasible;³⁴ (3) the planar aromatic 1,2,3-triazole unit provides better structural integrity compared to flexible acyclic structures which may cause tangling of the structure³⁵ and (4) the 1,2,3-triazole could serve as a unit for noncovalent attraction of guest molecules.³⁶

Furthermore, this is a significant part for a comprehensive study of dendritic structures bearing insufficiently elaborated 1,3-dioxane-4,6-dione moieties as antioxidative units. Within this work we are (1) establishing the impact of both the 1,2,3-triazole unit and the core fragment on the antiradical properties of the newly synthesised structures and (2) demonstrating an effective route leading to such architectures.

Results and discussion

Synthesis

The retrosynthetic analysis of our target compounds 3 lead us to both a divergent and a convergent route (Scheme 1). The divergent route (path A) foresees incorporation of the surface groups 4 into the main dendrimeric structure 5 through sequential Knoevenagel condensation and reduction. The convergent route (path B) includes the Huisgen reaction between the dendrons 6 and the core moiety 7.

Scheme 1. Retrosynthetic analysis of the target compounds 2.

Our previous experience has demonstrated that path B fails mainly due to the incompatibility of the arylidene and arylmethyl Meldrum's acid derivatives with the “click” reaction conditions: in the case of simpler structures – arylmethyl Meldrum's acid derivatives modified with a long alkyl chain – a complex mixture of products was formed when the corresponding arylidene compound was utilized (including degradation of arylidene Meldrum's acid unit). When the arylmethyl Meldrum's acid derivative was used, although the “click” reaction was successful, the cleavage of the 1,3-dioxane-4,6-dione unit also occurred. Similarly, when the “click” reaction was attempted between alkyne 7c and azide 6a (Scheme 2) under the optimal conditions for the compound 5c (Table 2), a complex mixture was obtained consisting of both starting materials 7c and 6a, as well as some aldehydes, likely due to the retro-Knoevenagel reaction of the arylidene Meldrum's acid moiety in compound 6a. The 1,2,3-triazole containing compounds were observed in a negligible amount. Therefore, we turned all our efforts towards path A (Scheme 3).

Scheme 2. Attempted synthesis of compound 10c through path A.

Table 2. Reaction conditions and yields for “click” reaction (7 + 9b → 5).

Compound	Cu(i) source	Solvent	t, h	T, °C	Yield, %
5ab	Optimised conditionsa				82
5b	Optimised conditions				75
5c	Cu(PPh3)3Brc	MeCN : H2O = 1 : 1	24	r.t.	74
5db	Optimised conditions				57
5eb	Optimised conditions				59
5fb	Optimised conditions				57
5g	CuSO4·5H2O + sodium ascorbate	t-BuOH : H2O = 1 : 1	24	60	52
5h	Cu(PPh3)3Br	MeCN : H2O = 1 : 1	1.5	70	45
5i	Optimised conditions				29

^aCuSO₄·5H₂O, sodium ascorbate, Et₃N, AcOH, DMF : H₂O = 1 : 5, 40 °C, 24 h.

^bAzide 9b was not isolated (telescoped method).

^cAuramine was added.

Scheme 3. Synthesis of the target compounds 3a–i.

The key steps are as follows: (1) the propargylation of the core moiety 8; (2) the “click” reaction between the alkyne 7 and azide 9b; (3) the Knoevenagel condensation between the dendrimeric aldehyde 5 and Meldrum's acid (4); and (4) the reduction of the arylidene compound 10, leading to the desired product 3.

The synthesis of target compounds began with the propargylation of the core moieties 8, leading to compounds 7 (Table 1). We converted dihydroxy benzenes 8a,8b to the corresponding dipropargyl ethers 7a,7bvia alkylation with propargyl bromide in the presence of K₂CO₃. When we applied the same reaction conditions to phloroglucinol (8c), we observed considerable amounts of C-alkylation products in addition to the desired ether 7c (SI, S1). Selectivity was improved when propargyl mesylate was used. The esterification of the carboxylic acids – trimesic acid (8d) and citric acid (8e) – was limited by the low solubility of the respective potassium carboxylates in organic solvents: e.g., alkylation of citric acid in DMSO, where the potassium citrate is more soluble, increased the yield of the ester 7e twofold compared to DMF. As we were not trying to obtain a specific anomer of the glucose derivative 7f, we decided to forgo the conventional multistep synthesis,^37,38 alkylating d-glucose (8f) directly instead. Nonetheless, we were able to isolate the pure β anomer and decided to proceed with it for simpler compound characterisation despite the low yield. The purity of the propargylation reaction products for the aliphatic alcohols 8h and 8i was noticeably improved when hexanes were added to the reaction mixture.

Table 1. Synthesis of propargyl ethers and esters (8 → 7).

Compound	Base	X	Solvent	t, h	T, °C	Yield, %
7a	K2CO3	Br	Me2CO	25.5	56 → r.t.	95
7b	K2CO3	Br	Me2CO	17.5	r.t.	94
7c	K2CO3	OMs	DMF	24	80	33
7d	K2CO3	Br	DMF	24	60	24
7e	K2CO3	Br	DMSO	24	65	43
7fa	NaOH	Br	DMF	20	r.t	14
7g	NaH	Br	DMF	17.5	0 → 40	57
7h	NaOH	Br	DMF : Hex = 4 : 3	12	r.t	57
7i	NaOH	Br	DMF : Hex = 1 : 1	24	r.t	23

^aKI (0.1 eq.) was added.

The azide was synthesised from the corresponding halogenide with quantitative yield according to the procedure we have described previously (Scheme 4).³⁹

Scheme 4. Halogen-azide exchange of compound 9a.

With both the alkyne-decorated core and the azide in hand we turned to the Huisgen reaction (Table 2). The compound 5g was obtained in a 52% yield under typical conditions³⁹ – in the presence of in situ generated Cu(i) from CuSO₄·5H₂O and sodium ascorbate in t-BuOH : H₂O = 1 : 1. Unfortunately, for other compounds the yields were inconsistent: sometimes only a trace amount of product was observed. Thus, we began testing alternative reaction conditions (SI, S2). Initially, the Cu(PPh₃)₃Br catalyst⁴⁰ emerged as a suitable choice for the synthesis of the polyfunctionalized intermediates 5 (e.g. compounds 5c,5h), but the purification of the product was quite difficult. We suspected that the improvement in consistency was due to the stabilisation of the copper catalyst by either phosphine or amine ligands.

Therefore, we turned back to the in situ generation of Cu(i) with an additional ligand for stabilisation of the Cu(i) species. Upon optimisation of the reaction in the presence of various amines (SI, S2.1), we did not observe significant impact of the amine structure to the yield, thus we proceeded with triethylamine. During our investigations on the “click” reaction conditions we noticed the formation of the bis-triazole by-product 11b (up to 13% isolated yield) under basic, oxidative conditions, similarly as first reported by Sharpless et al.⁴¹ and later elucidated by Angell and Burgess.⁴² An acetic acid additive and an increased amount of sodium ascorbate effectively eliminated this side reaction.

To avoid the isolation of the azide intermediate 9b, we developed a telescoped procedure for the synthesis of the 1,2,3-triazole products 5. Yields remained consistent between the telescoped procedure and the synthesis from isolated substrates (SI, S2.3): when optimising the model reaction between phenylacetylene and the azide 9b, we obtained yields up to 65% (qNMR), while the telescoped procedure between phenylacetylene and the halogenide 9a procured the product with a 75% yield (isolated). However, the telescoping dictated the solvent system ultimately used for the optimised “click” reaction (we found DMF to be the most suitable solvent for the halogen-azide exchange of the substrate 9a).

The Knoevenagel condensation occurred even without any catalyst:²⁷ when the reaction was run for two days, we were able to acquire compounds 10c and 10h in satisfactory yield (77% and 60%, respectively) (Table 3). To reduce the reaction time, we turned to various catalysts, however most of the systems we tried (SI, S3) were not effective enough and/or resulted in a complex mixture of inseparable products. These issues are especially exacerbated on more complex substrates with multiple aldehyde moieties such as the dendrimers 5 synthesised in this work. Thus far we have identified (PhNH₃)₂CuCl₄ as⁴³ the most effective catalyst: the arylidene compounds 10 were isolated in up to quantitative yield.

Table 3. Reaction conditions and yields for the Knoevenagel condensation (5 → 10)^a.

Compound	Catalyst	Solvent (DCM : MeOH)	t, h	Yield, %
10a	(PhNH3)2CuCl4	1 : 1	38	Quant.
10b	(PhNH3)2CuCl4	1 : 9	19	Quant.
10c	—	1 : 3	48	77
10d	(PhNH3)2CuCl4	1 : 4	19	Quant.
10e	(PhNH3)2CuCl4	1 : 5	46	86
10f	(PhNH3)2CuCl4	1 : 4	21	55
10g	(PhNH3)2CuCl4	1 : 4	18	86
10h	—	1 : 2	48	60
10i	(PhNH3)2CuCl4	1 : 4	24	Quant.

^aMeldrum's acid, DCM : MeOH, 40 °C.

Previously in our group we have used NaBH₄ in the presence of acetic acid to reduce various arylidene Meldrum's acids. Unexpectedly, under these conditions the reaction with the complex arylidene compounds 10 was sluggish, and a huge excess of reductant (>10 equivalents per arylidene group) was necessary to keep the reaction in a reasonable timeframe. For example, the reduction of arylidene compound 10d was run overnight, thus warming it up to room temperature and an inseparable mixture of products was obtained, likely due to the degradation of the product 3d and/or the starting compound 10d. We were able to significantly reduce the NaBH₄ loading and the reaction time (typically the reaction was completed by the time the reductant solution was fully added) by switching to basic conditions (NaOH additive) leading to the products 3 in high yields (Table 4).

Table 4. Reaction conditions and yields for arylidene reduction (10 → 3).

Compound	Additive	Solvent	t, min	Yield, %
3a	AcOH	CHCl3	60	75
3b	NaOH	DCM : EtOH = 1 : 5	5	88
3c	NaOH	DCM : EtOH = 10 : 3	5	90
3d	AcOH	DCM	30	95
3e	NaOH	DCM : EtOH = 1 : 1	5	45
3f	NaOH	DCM : EtOH = 1 : 3	5	89
3g	AcOH	DCM	90	81
3h	NaOH	DCM : EtOH = 1 : 2	5	83
3i	NaOH	DCM : EtOH = 1 : 4	5	65

To investigate the impact of the connectivity pattern in the 1,2,3-triazole cycle on the activity of the final compound, we synthesised the “reversed” methyl 3,5-dihydroxybenzoate-centred dendrimer 12 (Scheme 5). The key steps were the same as for the other dendrimers, except the “click” reaction partners (azide and alkyne) were reversed: a diazide 13b was synthesised in two steps from methyl 3,5-dihydroxybenzoate 8b through the 3-halopropylated intermediate 13a, and propargylated vanillin (14) was used as the alkyne. Afterwards, aldehyde 15a was subjected to the Knoevenagel condensation, and the resulting arylidene Meldrum's acid 16 was reduced to obtain the desired product 12.

Scheme 5. Synthesis of reversed methyl 3,5-dihydroxybenzoate-centred dendrimer 12.

Recognising the previously mentioned bis-triazole side product 11b as an analogue of our dendrimers (where the 1,2,3-triazole linkers are directly connected to each other, instead of a core moiety), this compound was subjected to the Knoevenagel reaction with Meldrum's acid and sequential reduction (Scheme 6). Both the arylidene derivative 17 and arylmethyl Meldrum's acid 18 were obtained in good yield (83% and 90%, respectively).

Scheme 6. Synthesis of bis-triazole-centred dendrimer 18.

Antiradical activity

To investigate their antioxidant potential, all synthesised arylmethyl Meldrum's acid derivatives were tested for radical scavenging ability using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The antiradical activity was characterized by the inhibition of DPPH (Inh₁₀₀) when the ratio of the antioxidant and the free radical is 1 : 1 (100 µM) and IC₅₀ – the antioxidant concentration, which inhibits 50% of the free radical.

Typically, our group runs these tests in ethanol: under these conditions the sequential proton loss electron transfer (SPLET) mechanism is postulated. When a less polar solvent is used, it is expected that the reaction mechanism changes from the SPLET to the hydrogen atom transfer (HAT) process (Scheme 7).

Scheme 7. Most prevalent radical scavenging mechanisms.

Several studies have indicated that the SPLET mechanism is more effective and faster at quenching free radicals.⁴⁴ Considering this, we initially planned to perform the DPPH assay in EtOH this time as well. However, we observed that the newly synthesised compounds are more lipophilic compared to the parent compound 1a and are poorly soluble in EtOH. To ensure the required concentration, the samples were dissolved in a ethanol-DCM mixture.

Under these conditions the synthesised compounds displayed high radical scavenging activity in the DPPH assay (IC₅₀ = 11–36 µM) (Table 5). However, the activity of dendrimers possessing multiple Meldrum's acid moieties is similar to the simple arylmethyl Meldrum's acid 1a (IC₅₀ = 18.7 µM). We hypothesise that this is due to steric hindrance: access of the relatively large DPPH radical to the active site (antioxidant moiety) may be partially blocked by the bulky nature of the dendrimers.

Table 5. DPPH assay^a results for synthesised and reference compounds.

^ac(DPPH) = 100 µM, DCM : EtOH = 1 : 9 (v/v), 30 min, λ = 515 nm.

^bc(DPPH) = 100 µM, EtOH, 30 min, λ = 515 nm.

Our synthesised compounds demonstrated significantly higher antiradical activity than such widely used antioxidants as ascorbic acid and BHT: neither of them was able to reach 50% inhibition even at a 100 µM concentration under the test conditions.

There is little difference between an ester and an ether linkage at the aromatic dendrimer core: the trimesic acid-centred 3d (IC₅₀ = 17.2 µM) and the phloroglucinol-centred 3b (IC₅₀ = 15.4 µM) dendrimers demonstrate comparable activity. One of the most active dendrimers is the citric acid-centred dendrimer 3e (the IC₅₀ value is half of that of the structurally similar glycerol-centred dendrimer 3h). This difference may be attributed to either structure conformational effects or some electron acceptor effects of the core.

We observed the lowest activity for the tetraethylene glycol-centred 3i (IC₅₀ = 36.1 µM) and the hydroquinone-centred 3a (IC₅₀ = 29.9 µM) dendrimers. These are the dendrimers where the Meldrum's acid moieties are likely furthest apart due to the long, linear ethylene glycol chain and the p-substitution pattern of the hydroquinone, respectively. This implies that some amount of forced surface group proximity, such as in compounds 3b (IC₅₀ = 25.6 µM) and 18 (IC₅₀ = 18.1 µM) may be beneficial for the activity of these dendrimers.

A perspective application of the dendrimeric arylmethyl Meldrum's acid unit-bearing architectures presented in this work could be the stabilisation of oxidatively unstable compounds. Although many of the dedrimeric structures demonstrated a lower effect towards DPPH compared to the model compound 1a, a systematic and careful optimization of the structure has demonstrated a steady effect of the number of active surface groups. Comparing the aliphatic alcohol-centred dendrimers with 2–5 surface groups 3f–i we can observe a gradual decrease in the IC₅₀ value: 36.1 µM (3i, 2 groups) >29.5 µM (3h, 3 groups) >21.0 µM (3g, 4 groups) >14.1 µM (3f, 5 groups).

The “reversed” 1,2,3-triazole substitution pattern of the compound 12 (IC₅₀ = 19.1 µM) also seems to yield slightly higher activity compared to the analogous compound 3b. However, as the benefit is quite small, we did not explore this type of attachment further, mainly due to potential safety concerns regarding the polyazide intermediates.

It is well established that depending on the solvent where the reaction between the DPPH and the compound is run, the reactivity may be changed dramatically. Historically it was considered that the reaction between the DPPH and antioxidants occurs via the HAT mechanism. Later a strong kinetic solvent effect on the reaction rate with a fast beginning was observed and the opinion on the mechanistic pathway was revised^45,46 – the SPLET process generally dominates in solvents supporting the ionization of the molecules. The DPPH assay for the Meldrum's acid derivative 1a was run in both ethanol and the ethanol-DCM mixture. When the test was transferred to the less polar system, the antiradical activity increased twofold. To elaborate the impact of the solvent on the reactivity of the synthesised compounds with the DPPH, the reaction between DPPH and compound 3d was run in various solvents (Fig. 3). The reactivity was characterized by the inhibition of DPPH: higher inhibition of DPPH indicates a faster reaction. We found that, while more polar solvents (like acetone and MeCN) promote faster radical scavenging, some activity can also be observed in less polar solvents (e.g. DCM and EtOAc). In non-polar solvent, the reaction between the dendrimer and the DPPH was nearly stopped. These findings support competitive simultaneous processes. The enhanced reaction in acetone could be attributed to stronger hydrogen bond formation between the solvent and the hydrogen at the 5th position of the arylmethyl Meldrum's acids, thus promoting ionization of the molecule, which could later result in a shift in the dominant reaction mechanism. These findings demonstrate that the reaction between dendrimer and DPPH strongly depends on the solvent. Thus, the choice of solvent effects the mechanism by which the antioxidant and free radical reacts.

Fig. 3. Solvent effects on DPPH inhibition ability of compound 3d: (a) DPPH inhibition kinetics in different solvents, and (b) DPPH inhibition at 170 s (plateau) dependance on solvent polarity.

A few of the synthesised compounds were also subjected to the Rancimat analysis. Unexpectedly we observed a strong pro-oxidant effect for the compound 1a in comparison to the blank sample: the induction periods were 8.4 h and 29.3 h, respectively. On the contrary, when the dendritic compounds 3a, 3d, 12 were added, the measured induction period varied from 26.9 h to 28.1 h. Although a strong antioxidant effect was not observed, these results demonstrate increased oxidative resistance of the newly synthesised compounds in comparison to the small molecular Meldrum's acid derivative 1a. The results seem to coincide with the DPPH assay, dendrimers with higher activity in the DPPH test also brought about longer induction time – 28.6 h for compound 3d and 27 h for 3a. Additionally, the negative impact of the arylmethyl Meldrum's acids on the oxidation induction period is concentration dependant – higher dendrimer 3a loading yielded shorter induction times. These findings are of particular significance in the context of the next steps in the comprehensive study, i.e. when these architectures are utilized as hosts for saving and delivering small, oxidatively unstable compounds.

Experimental

Materials and methods

Commercially available reagents were used without additional purification; solvents were distilled before use. Propargyl mesylate,⁴⁷ Cu(PPh₃)₃Br,⁴⁸ and (PhNH₃)₂CuCl₄ were⁴⁹ prepared according to the literature procedures. The halogenide 9a and azide 9b were prepared as described previously.³⁹ Reaction progress was monitored using Merck Silicagel 60 F₂₅₄ TLC plates and visualised under UV (λ = 254 nm) or with a basic aqueous KMnO₄ solution. NMR spectra were recorded on a Bruker Avance 500 spectrometer (¹H: 500 MHz; ¹³C: 126 MHz) and calibrated to the residual solvent peak (CHCl₃, ¹H: δ = 7.26 ppm; ¹³C: δ = 77.16 ppm, or DMSO, ¹H: δ = 2.50 ppm; ¹³C: δ = 39.52 ppm). HRMS analyses were run on a Vanquish Core high performance liquid chromatography system coupled with an Orbitrap Exploris 120 mass spectrometer. The separation was performed using an UHPLC HSS T3 column (2.1 × 100 mm, 1.7 µm), which was maintained at 30 °C. Mobile phases consisted of A – (H₂O with a 0.1% formic acid additive) and B (MeCN with a 0.1% formic acid additive), and were operated under isocratic conditions with 50% B for 1.5 minutes. The flow rate was set to 0.3 mL min⁻¹ and injection volume was 2 µL. Samples were ionized using a heated electrospray ionization source (H-ESI). The spray voltage was set to 3500 V, with vaporizer and ion transfer tube temperatures maintained at 350 °C and 325 °C, respectively. Ionisation gases – sheath gas, aux gas and sweep gas were set at 50, 10 and 1 arbitrary units. For analyte detection, a targeted selected ion monitoring (t-SIM) method (resolution: 30 000) was used. UV-vis measurements were done on a Camspec M501 single beam spectrometer. Rancimat analysis was run on a Metrohm Rancimat 743 apparatus.

Synthetic procedures

Methyl 3,5-bis(3-halopropoxy)benzoate 13a

Methyl 3,5-dihydroxybenzoate (8b) (0.34 g, 2.02 mmol, 1 eq.) was dissolved in DMF (2 mL), K₂CO₃ (0.83 g, 6.05 mmol, 3 eq.) and 1-bromo-3-chloropropane (1.2 mL, 12.10 mmol, 6 eq.) were added and the mixture was stirred at 90 °C for 1 h, then allowed to cool to room temperature and stirred overnight. The mixture was diluted with brine (10 mL), acidified with HCl (10% in H₂O, 10 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (20 : 1) → (10 : 1) → (7 : 1)) to afford the mixture of products (total Cl : Br = 2.6 : 1, NMR data) as a viscous, colourless oil (0.54 g, 78%). ¹H NMR (500 MHz, CDCl₃) δ 7.19 (d, J = 1.9 Hz, 2H, C(2,6)H), 6.65 (t, J = 1.9 Hz, 1H, C(4)H), 4.18–4.09 (m, 4H, Cl/BrCH₂CH₂CH₂O), 3.90 (s, 3H, OMe), 3.74 (t, J = 6.3 Hz, 0.72* × 4H, ClCH₂CH₂CH₂O), 3.60 (t, J = 6.4 Hz, 0.28* × 4H, BrCH₂CH₂CH₂O), 2.35–2.29 (m, 0.28* × 4H, BrCH₂CH₂CH₂O), 2.27–2.20 (m, 0.72* × 4H, ClCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 166.9, 159.9, 159.8, 132.2, 108.1, 108.1, 106.7, 65.7, 64.7, 52.4, 41.5, 32.3, 32.3, 30.0. HRMS(ESI+): calc. for C₁₄H₁₉Cl₂O₄⁺ 321.0655 [M + H]⁺; found: 321.0638.

*Integrals correspond to the halogenide molar ratio: Cl : Br = 2.6 : 1 or 72 mol% [Cl], 28 mol% [Br].

Methyl 3,5-bis(3-azidopropoxy)benzoate (13b)

The mixture of halogenides 13a (1.64 g, 4.69 mmol, 1 eq.) was dissolved in DMF (18 mL), NaN₃ (1.07 g, 16.42 mmol, 3.5 eq.) was added and the mixture was stirred at 60 °C overnight. The mixture was diluted with brine (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na₂SO₄, filtered, and evaporated. The product was obtained as a yellow oil (1.12 g, 72%). The product was spectroscopically pure and was used in the next step without additional purification. ¹H NMR (500 MHz, CDCl₃) δ 7.19 (d, J = 2.3 Hz, 2H, C(2,6)H), 6.64 (t, J = 2.3 Hz, 1H, C(4)H), 4.07 (t, J = 5.9 Hz, 4H, NCH₂CH₂CH₂O), 3.90 (s, 3H, OMe), 3.52 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 2.10–2.01 (m, 4H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 166.9, 159.8, 132.2, 108.0, 106.8, 65.0, 52.4, 48.3, 28.8. HRMS(ESI+): calc. for C₁₄H₁₉N₆O₄⁺ 335.1463 [M + H]⁺; found: 335.1466.

Synthesis of alkynes

1,4-Bis(prop-2-yn-1-yloxy)benzene (7a)

Hydroquinone (8a) (110 mg, 1.00 mmol, 1 eq.) was dissolved in acetone (1.5 mL) and K₂CO₃ (414 mg, 3.00 mmol, 3 eq.) was added. Propargyl bromide (80% sol. in toluene, 0.28 mL, 2.50 mmol, 2.5 eq.) was diluted with acetone (0.5 mL) and added dropwise. The reaction mixture was refluxed for 6.5 h and then stirred at room temperature overnight. The solvent was evaporated, and DCM (10 mL) and brine (10 mL) were added. The mixture was acidified with HCl (10% sol. in H₂O, 10 mL), layers were separated, and the aqueous phase was extracted with DCM (2 × 10 mL). The combined organic layers were sequentially washed with brine (10 mL), sat. aqueous NaHCO₃ solution (2 × 10 mL) and brine (10 mL). The DCM solution was dried over Na₂SO₄, filtered, and evaporated. The product was obtained as a beige solid (177 mg, 95%), which was spectroscopically pure and used in the next step without additional purification. ¹H NMR (500 MHz, CDCl₃) δ 6.93 (s, 4H, H^Ar), 4.65 (d, J = 2.4 Hz, 4H, CH₂), 2.51 (t, J = 2.4 Hz, 2H, C CH). The NMR data corresponds to the literature.⁵⁰

Methyl 3,5-bis(prop-2-yn-1-yloxy)benzoate (7b)

The compound was obtained from methyl 3,5-dihydroxybenzoate (8b) (100 mg, 0.60 mmol), K₂CO₃ (246 mg, 1.79 mmol, 3 eq.), and propargyl bromide (80% sol. in toluene, 0.17 mL, 1.49 mmol, 2.5 eq.), in acetone (1.2 mL) analogous to the procedure described for compound 7a. The product was obtained as a beige solid (110 mg, 94%). ¹H NMR (500 MHz, CDCl₃) δ 7.29 (d, J = 2.3 Hz, 2H, C(2,6)H), 6.81 (t, J = 2.3 Hz, 1H, C(4)H), 4.72 (d, J = 2.3 Hz, 4H, CH₂), 3.91 (s, 3H, COOMe), 2.55 (t, J = 2.3 Hz, 2H, C CH). The NMR data corresponds to the literature.⁵¹

1,3,5-Tris(prop-2-yn-1-yloxy)benzene (7c)

Phloroglucinol (8c) (0.55 g, 4.33 mmol, 1 eq.) was dissolved in DMF (15 mL), K₂CO₃ (1.85 g, 13.43 mmol, 3.1 eq.) and propargyl mesylate (1.80 g, 13.43 mmol, 3.1 eq.) were added. The mixture was stirred at 80 °C for 24 h. The mixture was cooled to room temperature, diluted with brine (15 mL), acidified with HCl (10% in H₂O), and extracted with DCM (3 × 10 mL). The combined organic layers were sequentially washed with brine (10 mL), 10% hydrochloric acid solution (3 × 10 mL), brine (10 mL), NaHCO₃ solution (sat., H₂O, 2 × 10 mL), and brine (2 × 10 mL). The DCM solution was dried over Na₂SO₄, filtered, and evaporated. The crude product was crystalized from isopropanol to afford the product as light brown crystals (341 mg, 33%). ¹H NMR (500 MHz, CDCl₃) δ 6.27 (s, 3H, H^Ar), 4.65 (s, 6H, CH₂), 2.53 (s, 3H, C CH). The NMR data corresponds to the literature.⁴⁰

Trimesic acid tripropargyl ester 7d

Trimesic acid (8d) (5.00 g, 23.81 mmol, 1 eq.) was dissolved in DMF (10 mL). K₂CO₃ (13.14 g, 95.24 mmol, 4 eq.) and propargyl bromide (80% sol. in toluene, 10.57 mL, 95.24 mmol, 4 eq.) were added. The mixture was stirred at 60 °C for 24 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL) and water (100 mL) until all the solids were dissolved, and the layers were separated. The water layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (4 × 30 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (7 : 3)) to afford the product as a white solid (1.37 g, 24%). ¹H NMR (500 MHz, CDCl₃) δ 8.93 (s, 3H, H^Ar), 5.00 (d, J = 2.4 Hz, 6H, CH₂), 2.56 (t, J = 2.4 Hz, 3H, C CH). The NMR data corresponds to the literature.^52,53

Citric acid tripropargyl ester 7e

Citric acid (8e) (0.50 g, 2.60 mmol, 1 eq.) was dissolved in DMSO (25 mL), K₂CO₃ (1.19 g, 8.59 mmol, 3.3 eq.) and propargyl bromide (80% sol. in toluene, 0.95 mL, 8.59 mmol, 3.3 eq.) were added. The mixture was stirred at 65 °C for 24 h. The mixture was cooled to room temperature, diluted with brine (125 mL), acidified with HCl (10% in H₂O), and extracted with EtOAc (7 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (5 : 1)) to afford the product as a viscous, yellow oil (0.34 g, 43%). ¹H NMR (500 MHz, CDCl₃) δ 4.82 (d, J = 2.3 Hz, 2H, C(2)COOCH₂), 4.70 (d, J = 2.3 Hz, 4H, C(1,3)COOCH₂), 4.04 (brs, 1H, OH), 2.98 (d, J = 15.8 Hz, 2H, C(1,3)H^a), 2.89 (d, J = 15.8 Hz, 2H, C(1,3)H^b), 2.53 (t, J = 2.3 Hz, 1H, C(2)COOCH₂C CH), 2.49 (t, J = 2.3 Hz, 2H, C(1,3)COOCH₂C CH), 1.62 (brs, 1H, 0.5 × H₂O; from NOESY). ¹³C NMR (126 MHz, CDCl₃) δ 172.4, 168.8, 77.1, 76.8, 76.0, 75.5, 73.3, 54.0, 52.7, 43.0. HRMS(ESI+): calc. for C₁₅H₁₅O₇⁺ 307.0813 [M + H]⁺; found: 307.0810.

Penta-O-propargyl β-d-glucopyranoside 7f

d-Glucose (8f) (2.00 g, 11.11 mmol, 1 eq.) was dissolved in DMF (20 mL), cooled to 0 °C, and NaOH (2.67 g, 66.67 mmol, 6 eq.) and KI (0.18 g, 1.11 mmol, 0.1 eq.) were added. Propargyl bromide (80% sol. in toluene, 7.40 mL, 66.67 mmol, 6 eq.) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was diluted with brine (40 mL), and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (5 : 1)) to afford the product as a viscous, yellow oil (0.56 g, 14%). [α]_D = −19.0 (c = 1, CHCl₃). ¹H NMR (500 MHz, CDCl₃) δ 4.57–4.36 (m, 9H, C(1′–4′)H₂, C(1)H), 4.25 (dd, J = 15.9, 1.9 Hz, 1H, C(6′)H^a), 4.19 (dd, J = 15.9, 1.9 Hz, 1H, C(6′)H^b), 3.84 (dd, J = 10.7, 1.1 Hz, 1H, C(6)H^a), 3.78 (dd, J = 10.7, 4.5 Hz, 1H, C(6)H^b), 3.58 (dd, J = 8.8, 8.2 Hz, 1H, C(3)H), 3.47 (dd, J = 9.7, 8.8 Hz, 1H, C(4)H), 3.45–3.37 (m, 2H, C(2)H, C(5)H), 2.60–2.28 (m, 5H, C CH). The NMR data corresponds to the literature.³⁷

Tetra-O-propargyl pentaerythritol 7g

The compound 7g was prepared according to the literature procedure⁵⁴ from pentaerythritol (8h) (50 mg, 0.37 mmol, 1 eq.), NaH (106 mg, 4.41 mmol, 12 eq.), and propargyl bromide (80% sol. in toluene, 0.24 mL, 2.22 mmol, 6 eq.) in DMF (2 mL). The crude product was purified on silica (Hex : EtOAc (5 : 1)) to afford the product as colourless crystals (61 mg, 57%). ¹H NMR (500 MHz, CDCl₃) δ 4.12 (d, J = 2.0 Hz, 8H, CH₂C CH), 3.53 (s, 8H, C(1–4)H₂), 2.40 (t, J = 2.0 Hz, 4H, C CH). The NMR data corresponds to the literature.⁵⁴

Tri-O-propargyl glycerol 7h

Glycerol (8h) (100 mg, 1.09 mmol, 1 eq.) was dissolved in DMF (3 mL), cooled to 0 °C, and NaOH (174 mg, 4.35 mmol, 4 eq.) was added. Propargyl bromide (80% sol. in toluene, 0.48 mL, 4.35 mmol, 4 eq.) was added dropwise. Hexanes (3 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with brine (10 mL), the layers were separated, the aqueous layer was extracted with hexanes (5 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and evaporated. The product was obtained as a spectroscopically pure yellow oil (128 mg, 57%), which was used in the next step without additional purification. ¹H NMR (500 MHz, CDCl₃) δ 4.34 (d, J = 2.3 Hz, 2H, C(2)OCH₂), 4.19 (d, J = 2.3 Hz, 4H, C(1,3)OCH₂), 3.93 (tt, J = 5.5, 4.4 Hz, 1H, C(2)H), 3.70 (dd, J = 10.2, 4.4 Hz, 2H, C(1,3)H^a), 3.66 (dd, J = 10.2, 5.5 Hz, 2H, C(1,3)H^b), 2.46–2.41 (m, 3H, C CH). The NMR data corresponds to the literature.⁵⁵

Di-O-propargyl tetraethylene glycol 7i

The compound was obtained from tetraethylene glycol (8i) (0.89 mL, 5.15 mmol, 1 eq.), NaOH (0.81 g, 20.2 mmol, 4 eq.) and propargyl bromide (80% sol. in toluene, 2.24 mL, 20.2 mmol, 4 eq.) in DMF : Hex (20 mL, 1 : 1 v/v) according to the procedure described for the compound 7h. The product was obtained as a yellow oil (52 mg, 4%). After extraction with hexanes, the aqueous layer was extracted again with DCM (3 × 10 mL). The DCM solution was washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and evaporated. Spectroscopically pure product was obtained from both extracts, and they were combined (320 mg, 23%). ¹H NMR (500 MHz, CDCl₃) δ 4.20 (d, J = 1.8 Hz, 4H, 2 × CH₂C CH), 3.72–3.67 (m, 8H, C(1,2,1′,2′)H₂), 3.66–3.64 (m, 8H, C(3,4,3′,4′)H₂), 2.42 (t, J = 1.8 Hz, 2H, C CH). The NMR data corresponds to the literature.⁵⁶

3-Methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (14)

Vanillin (2.00 g, 13.16 mmol, 1.0 eq.) was dissolved in acetonitrile (25 mL), K₂CO₃ (2.72 g, 19.74 mmol, 1.5 eq.) and propargyl bromide (80% sol. in toluene, 1.75 mL, 15.79 mmol, 1.2 eq.) were added. The mixture was stirred at 60 °C overnight. The solvent was evaporated, the solid residue was dissolved in EtOAc (25 mL) and brine (20 mL), acidified with HCl (10% in H₂O, 10 mL), layers were separated, and the organic phase was washed with brine (2 × 20 mL). The EtOAc solution was dried over Na₂SO₄, filtered, and evaporated. The product was obtained as beige crystals (2.33 g, 93%), which were spectroscopically pure and used in the next step without further purification. ¹H NMR (500 MHz, CDCl₃) δ 9.88 (s, 1H, CHO), 7.47 (dd, J = 8.2, 1.4 Hz, 1H, C(6)H), 7.44 (d, J = 1.4 Hz, 1H, C(2)H), 7.15 (d, J = 8.2 Hz, 1H, C(5)H), 4.86 (d, J = 1.9 Hz, 2H, CH₂), 3.95 (s, 3H, OMe), 2.56 (t, J = 1.9 Hz, 1H, C CH). The NMR data corresponds to the literature.⁵⁷

Synthesis of 1,4-disubstituted 1,2,3-triazoles

Phloroglucinol-centred dendrimeric aldehyde 5c

The alkyne 7c (150 mg, 0.63 mmol, 1 eq.) and azide 9b (588 mg, 2.50 mmol, 4 eq.) were dissolved in H₂O : MeCN (8 mL, 1 : 1 v/v). Cu(PPh₃)₃Br (87 mg, 0.09 mmol, 0.15 eq.) and auramine (25 mg, 0.09 mmol, 0.15 eq.) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with brine (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were sequentially washed with brine (10 mL), a sat. NH₄Cl aqueous solution (2 × 10 mL), and brine (10 mL). The DCM solution was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (1 : 2) → EtOAc (100%) → EtOAc : MeOH (30 : 1) → EtOAc : MeOH (20 : 1)) to afford the product as a light pink solid (591 mg, 74%). ¹H NMR (500 MHz, CDCl₃) δ 9.81 (s, 3H, CHO), 7.70 (s, 3H, H^triaz.), 7.43–7.34 (m, 6H, C(9)H, C(11)H), 6.90 (d, J = 8.6 Hz, 3H, C(12)H), 6.19 (s, 3H, C(2,4,6)H), 5.08 (s, 6H, C(1)OCH₂), 4.62 (t, J = 6.7 Hz, 6H, NCH₂CH₂CH₂O), 4.07 (t, J = 5.8 Hz, 6H, NCH₂CH₂CH₂O), 3.90 (s, 9H, OMe), 2.52–2.44 (m, 6H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 160.1, 153.4, 150.0, 143.9, 130.6, 126.7, 123.6, 112.0, 109.5, 95.1, 65.3, 62.1, 56.0, 47.1, 29.7. HRMS(ESI+): calc. for C₄₈H₅₂N₉O₁₂⁺ 946.3730 [M + H]⁺; found: 946.3689.

Glycerol-centred dendrimeric aldehyde 5h

The alkyne 7h (234 mg, 1.14 mmol, 1 eq.), azide 9b (800 mg, 3.40 mmol, 3 eq.), and Cu(PPh₃)₃Br (74 mg, 0.08 mmol, 0.07 eq.) were dissolved in H₂O : MeCN (6 mL, 1 : 1 v/v). The mixture was stirred at 70 °C for 1.5 h, then diluted with brine (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were sequentially washed with brine (10 mL), a 5% aqueous trilon B solution (2 × 10 mL), and brine (10 mL). The DCM solution was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (EtOAc → EtOAc : MeOH (10 : 1)) to afford the product as an orange oil (468 mg, 45%). ¹H NMR (500 MHz, CDCl₃) δ 9.79 (s, 3H, CHO), 7.68 (s, 1H, C(2)OCH₂CCH̲^triaz.), 7.63 (s, 2H, C(1,3)OCH₂CCH̲^triaz.), 7.41–7.35 (m, 6H, C(9)H, C(11)H), 6.89 (d, J = 7.9 Hz, 3H, C(12)H), 4.70 (s, 2H, C(2)OCH₂), 4.61–4.54 (m, 10H, C(1,3)OCH₂, NCH₂CH₂CH₂O), 4.09–4.02 (m, 6H, NCH₂CH₂CH₂O), 3.88 (s, 9H, OMe), 3.72 (tt, J = 5.7, 4.4 Hz, 1H, C(2)H), 3.56 (dd, J = 10.3, 4.4 Hz, 2H, C(1,3)H^a), 3.52 (dd, J = 10.3, 5.7 Hz, 2H, C(1,3)H^b), 2.46–2.40 (m, 6H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 153.42, 153.40, 149.9, 145.4, 144.9, 130.50, 130.48, 126.7, 123.5, 123.3, 111.99, 111.97, 109.4, 77.2, 70.2, 65.41, 65.38, 64.8, 63.8, 56.0, 47.0, 46.9, 29.7. HRMS(ESI+): calc. for C₄₅H₅₄N₉O₁₂⁺ 912.3886 [M + H]⁺; found: 912.3841.

Pentaerythritol-centred dendrimeric aldehyde 5g

The alkyne 7g (100 mg, 0.35 mmol, 1 eq.) and azide 9b (412 mg, 1.73 mmol, 5 eq.) were dissolved in H₂O:t-BuOH (2 mL, 1 : 1 v/v). Sodium ascorbate (21 mg, 0.10 mmol, 0.3 eq.) and CuSO₄·5H₂O (26 mg, 0.10 mmol, 0.3 eq.) were added and the mixture was stirred at 60 °C overnight. After cooling to room temperature, water (20 mL) and DCM (20 mL) were added until all solids dissolved. The layers were separated and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (4 × 20 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (3 : 1) → EtOAc (100%) → EtOAc : MeOH (6 : 1)) to afford the product as a white solid (221 mg, 52%). ¹H NMR (500 MHz, CDCl₃) δ 9.83 (s, 4H, CHO), 7.62 (s, 4H, H^triaz.), 7.42–7.39 (m, 8H, C(9)H, C(11)H), 6.92 (d, J = 7.9 Hz, 4H, C(12)H), 4.60 (t, J = 6.6 Hz, 8H, NCH₂CH₂CH₂O), 4.49 (s, 8H, C(1–4)OCH₂), 4.08 (t, J = 5.8 Hz, 8H, NCH₂CH₂CH₂O), 3.91 (s, 12H, OMe), 3.38 (s, 8H, C(1–4)CH₂), 2.49–2.44 (m, 8H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 153.5, 150.0, 145.4, 130.6, 126.8, 123.2, 112.0, 109.5, 69.1, 65.5, 65.0, 56.1, 47.0, 45.4, 29.8. HRMS(ESI+): calc. for C₆₁H₇₄N₁₂O₁₆²⁺ 615.2668 [M + 2H]²⁺; found: 615.2670.

Trimesic acid-centred dendrimeric aldehyde 5d

In the reaction vessel A, halogenide 9a (1151 mg, 4.93 mmol, 3.2 eq.) was dissolved in DMF (10 mL), NaN₃ (331 mg, 5.09 mmol, 3.3 eq.) was added and the mixture was stirred at 60 °C overnight, then cooled to room temperature. In a separate reaction vessel B, the alkyne 7d (500 mg, 1.54 mmol, 1 eq.) was dissolved in DMF (10 mL) and, under vigorous stirring, aqueous solutions of additives were sequentially added: Et₃N (0.12 mL, 0.77 mmol, 0.5 eq., in 9.6 mL H₂O), sodium ascorbate (31 mg, 0.15 mmol, 0.1 eq., in 10.6 mL H₂O), CuSO₄·5H₂O (19 mg, 0.08 mmol, 0.05 eq., in 10.6 mL H₂O), and AcOH (0.04 mL, 0.77 mmol, 0.5 eq., in 8 mL H₂O). Additional water (71 mL) was slowly added to reach a total ratio of DMF : H₂O 1 : 5 (v/v). The azide solution from the vessel A was filtered into the alkyne-containing mixture in the vessel B and washed with a small amount of DMF (2 mL). When all components were added, a light-yellow suspension was formed. The obtained reaction mixture was stirred at 40 °C overnight, then diluted with brine (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were sequentially washed with brine (20 mL), a 5% aqueous trilon B solution (2 × 20 mL), and brine (20 mL). The DCM solution was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc (100%) → MeCN (100%)) to afford the product as a white solid (908 mg, 57%). ¹H NMR (500 MHz, CDCl₃) δ 9.80 (s, 3H, CHO), 8.75 (s, 3H, C(2,4,6)H), 7.79 (s, 3H, H^triaz.), 7.41–7.34 (m, 6H, c(9)H, C(11)H), 6.90 (d, J = 8.0 Hz, 3H, C(12)H), 5.47 (s, 6H, C(1,3,5)COOCH₂), 4.64 (t, J = 6.7 Hz, 6H, NCH₂CH₂CH₂O), 4.08 (t, J = 5.8 Hz, 6H, NCH₂CH₂CH₂O), 3.92 (s, 9H, OMe), 2.53–2.47 (m, 6H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 164.7, 153.4, 150.0, 142.4, 135.1, 131.0, 130.6, 126.7, 125.1, 112.0, 109.5, 65.3, 58.7, 56.1, 47.1, 29.6. HRMS(ESI+): calc. for C₅₁H₅₂N₉O₁₅⁺ 1030.3578 [M + H]⁺; found: 1030.3549.

Hydroquinone-centred dendrimeric aldehyde 5a

The compound was obtained according to a modified procedure described for the compound 5d: from alkyne 7a (250 mg, 1.34 mmol, 1 eq.), halogenide 9a (658 mg, 2.58 mmol, 2.1 eq.), and NaN₃ (188 mg, 2.89 mmol, 2.15 eq.) in the presence of CuSO₄·5H₂O (17 mg, 0.07 mmol, 0.05 eq.), sodium ascorbate (27 mg, 0.13 mmol, 0.1 eq.), Et₃N (0.11 mL, 0.67 mmol, 0.5 eq.), and AcOH (0.04 mL, 0.67 mmol, 0.5 eq.) in DMF : H₂O (132 mL, 1 : 5 v/v). After the dilution of the reaction mixture with brine, the precipitate was filtered, repeatedly washed with water and DCM and air-dried. The product was obtained as a beige solid (727 mg, 82%). ¹H NMR (500 MHz, CDCl₃) δ 9.85 (s, 2H, CHO), 7.66 (s, 2H, H^triaz.), 7.45–7.39 (m, 4H, C(9)H, C(11)), 6.91 (d, J = 8.6 Hz, 2H, C(12)H), 6.86 (s, 4H, C(2,3,5,6)H), 5.13 (s, 4H, C(1,4)OCH₂), 4.64 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 4.08 (t, J = 5.8 Hz, 4H, NCH₂CH₂CH₂O), 3.93 (s, 6H, OMe), 2.54–2.46 (m, 4H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.1, 153.4, 152.8, 150.0, 144.5, 130.7, 126.8, 123.4, 115.9, 112.0, 109.4, 65.3, 62.7, 56.1, 47.1, 29.7. HRMS: calc. for C₃₄H₃₇N₆O₈⁺ 657.2668 [M + H]⁺; found: 657.2668.

Methyl 3,5-dihydroxybenzoate-centred dendrimeric aldehyde 5b

The compound was obtained from alkyne 7b (50 mg, 0.20 mmol, 1 eq.) and azide 9b (101 mg, 0.43 mmol, 2.1 eq.) in the presence of CuSO₄·5H₂O (3 mg, 0.01 mmol, 0.05 eq.), sodium ascorbate (4 mg, 0.02 mmol, 0.1 eq.), Et₃N (0.02 mL, 0.10 mmol, 0.5 eq.), and AcOH (0.01 mL, 0.12 mmol, 0.6 eq.) in DMF : H₂O : DCM (19.5 mL, 1 : 2.2 : 0.4 v/v/v) according to a modified procedure described for the compound 5d. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc (100%) → EtOAc : MeOH (5 : 1)) to afford the product as a white solid (109 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.85 (s, 2H, CHO), 7.69 (s, 2H, H^triaz.), 7.45–7.38 (m, 4H, C(9)H, C(11)H), 7.25 (d, J = 2.0 Hz, 2H, C(2,6)H), 6.91 (d, J = 8.6 Hz, 2H, C(12)H), 6.76 (t, J = 2.0 Hz, 1H, C(4)H), 5.19 (s, 4H, C(3,5)OCH₂), 4.65 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 4.09 (t, J = 5.8 Hz, 4H, NCH₂CH₂CH₂O), 3.93 (s, 6H, C(8)OMe), 3.90 (s, 3H, COOMe), 2.55–2.46 (m, 4H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 166.6, 159.3, 153.4, 150.0, 143.7, 132.3, 130.6, 126.7, 123.6, 112.0, 109.5, 108.6, 107.0, 65.3, 62.3, 56.0, 52.4, 47.1, 29.7. HRMS(ESI+): calc. for C₃₆H₃₉N₆O₁₀⁺ 715.2723 [M + H]⁺; found: 715.2719.

Citric acid-centred dendrimeric aldehyde 5e

The compound was obtained from alkyne 7e (100 mg, 0.33 mmol, 1 eq.), halogenide 9a (244 mg, 1.05 mmol, 3.2 eq.), and NaN₃ (70 mg, 1.08 mmol, 3.3 eq.) in the presence of CuSO₄·5H₂O (4 mg, 0.02 mmol, 0.05 eq.), sodium ascorbate (7 mg, 0.03 mmol, 0.1 eq.), Et₃N (0.03 mL, 0.16 mmol, 0.5 eq.), and AcOH (0.01 mL, 0.16 mmol, 0.5 eq.) in DMF : H₂O (24 mL, 1 : 5 v/v) according to the procedure described for the compound 5d. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc → MeOH). The solid residue was dissolved in DCM and filtered through Celite to afford the product as a white solid (196 mg, 59%). ¹H NMR (500 MHz, CDCl₃) δ 9.83 (s, 2H, C(10)CH̲O), 9.82 (s, 1H, C(10′)CH̲O), 7.77 (s, 1H, C(2)COOCH₂CCH̲^triaz.), 7.65 (s, 2H, C(1,3)COOCH₂CCH̲^triaz.), 7.43–7.38 (m, 6H, C(9,9′)H, C(11,11′)H), 6.92 (d, J = 7.9 Hz, 3H, C(12,12′)H), 5.22 (s, 2H, C(2)COOCH₂), 5.14 (d, J = 12.7 Hz, 2H, C(1,3)COOCH^a), 5.10 (d, J = 12.7 Hz, 2H, C(1,3)COOCH^b), 4.65–4.60 (m, 6H, NCH₂CH₂CH₂O), 4.12–4.05 (m, 7H, NCH₂CH₂CH₂O, OH), 3.92 (s, 6H, C(8)OMe), 3.91 (s, 3H, C(8′)OMe), 2.80 (d, J = 15.7 Hz, 2H, C(1,3)H^a), 2.71 (d, J = 15.7 Hz, 2H, C(1,3)H^b), 2.50–2.44 (m, 6H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.03, 191.01, 173.0, 169.3, 153.44, 153.42, 150.0, 142.4, 141.8, 130.64, 130.62, 126.73, 126.71, 125.2, 124.5, 112.07, 112.06, 109.53, 109.51, 73.2, 65.4, 65.3, 59.3, 58.1, 56.1, 47.1, 43.2, 29.73, 29.69. HRMS(ESI+): calc. for C₄₈H₅₄N₉O₁₆⁺ 1012.3684 [M + H]⁺; found: 1012.3680.

Glucose-centred dendrimeric aldehyde 5f

The compound was obtained from alkyne 7f (50 mg, 0.13 mmol, 1 eq.), halogenide 9a (189 mg, 0.81 mmol, 6 eq.), and NaN₃ (53 mg, 0.81 mmol, 6 eq.) in the presence of CuSO₄·5H₂O (5 mg, 0.02 mmol, 0.15 eq.), sodium ascorbate (8 mg, 0.04 mmol, 0.3 eq.), Et₃N (0.03 mL, 0.20 mmol, 1.5 eq.), and AcOH (0.01 mL, 0.20 mmol, 1.5 eq.) in DMF : H₂O : DCM (18.5 mL, 1 : 5 : 0.2 v/v/v) according to the procedure described for the compound 5d. The crude product was purified on silica (Hex : EtOAc (2 : 1) → EtOAc (100%) → EtOAc : MeOH (10 : 1)) to afford the product as a white solid (119 mg, 57%). ¹H NMR (500 MHz, CDCl₃) δ 9.81–9.78 (m, 5H, CHO), 8.02 (s, 1H, C(2′/3′)CCH̲^triaz.), 7.99 (s, 1H, C(2′/3′)CCH̲^triaz.), 7.91 (s, 1H, C(1′)CCH̲^triaz.), 7.85 (s, 1H, C(4′)CCH̲^triaz.), 7.72 (s, 1H, C(6′)CCH̲^triaz.), 7.39–7.34 (m, 10H, C(9)H, C(11)H), 6.91–6.87 (m, 5H, C(12)H), 4.94 (d, J = 12.6 Hz, 1H, C(1′)H^a), 4.90 (d, J = 11.6 Hz, 1H, C(2′)H^a), 4.87 (d, J = 11.1 Hz, 1H, C(3′)H^a), 4.83 (d, J = 11.4 Hz, 1H, C(4′)H^a), 4.80 (d, J = 11.1 Hz, 1H, C(3′)H^b), 4.77 (d, J = 12.6 Hz, 1H, C(1′)H^b), 4.73 (d, J = 11.6 Hz, 1H, C(2′)H^b), 4.69 (d, J = 12.5 Hz, 1H, C(6′)H^a), 4.63–4.57 (m, 12H, NCH₂CH₂CH₂O, C(4′)H^b, C(6′)H^b), 4.35 (d, J = 7.7 Hz, 1H, C(1)H), 4.10–4.05 (m, 10H, NCH₂CH₂CH₂O), 3.91–3.87 (m, 15H, OMe), 3.75–3.68 (m, 2H, C(6)CH₂), 3.46–3.37 (m, 2H, C(3)H, C(4)H), 3.30–3.23 (m, 2H, C(2)H, C(5)H), 2.49–2.43 (m, 10H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 190.99, 190.97, 153.51, 153.50, 153.49, 153.47, 153.4, 149.9, 145.0, 144.73, 144.67, 144.4, 130.55, 130.53, 130.49, 126.71, 126.70, 126.67, 124.4, 124.3, 124.1, 124.0, 123.6, 112.0, 111.9, 109.48, 109.46, 109.4, 102.3, 83.9, 81.6, 77.2, 74.5, 68.9, 66.5, 65.8, 65.7, 65.53, 65.51, 65.50, 65.48, 65.4, 64.8, 62.9, 56.05, 56.03, 47.1, 47.02, 47.01, 29.7. HRMS(ESI+): calc. for C₇₆H₈₉N₁₅O₂₁²⁺ 773.8173 [M + 2H]²⁺; found: 773.8180.

Tetraethylene glycol-centred dendrimeric aldehyde 5i

The compound was obtained from alkyne 7i (50 mg, 0.19 mmol, 1 eq.), and azide 9b (91 mg, 0.39 mmol, 2 eq.) in the presence of CuSO₄·5H₂O (2 mg, 0.01 mmol, 0.05 eq.), sodium ascorbate (4 mg, 0.02 mmol, 0.1 eq.), Et₃N (0.01 mL, 0.09 mmol, 0.5 eq.), and AcOH (0.01 mL, 0.09 mmol, 0.5 eq.) in DMF : H₂O (15 mL, 1 : 5 v/v) according to a modified procedure described for the compound 5d. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc (100%) → EtOAc : MeOH (10 : 1)) to afford the product as a white solid (39 mg, 29%). ¹H NMR (500 MHz, CDCl₃) δ 9.85 (s, 2H, CHO), 7.63 (s, 2H, H^triaz.), 7.46–7.39 (m, 4H, C(9)H, C(11)H), 6.93 (d, J = 8.5 Hz, 2H, C(12)H), 4.65 (s, 4H, C(1,1′)OCH₂), 4.61 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 4.09 (t, J = 5.9 Hz, 4H, NCH₂CH₂CH₂O), 3.93 (s, 6H, OMe), 3.67–3.61 (m, 16H, C(1–4,1′–4′)H₂), 2.52–2.45 (m, 4H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.0, 153.5, 150.0, 145.3, 130.7, 126.8, 123.3, 112.0, 109.5, 70.7, 70.6, 69.9, 65.5, 64.8, 56.1, 47.0, 29.8. HRMS(ESI+): calc. for C₃₆H₅₀N₆O₁₁²⁺ 371.1764 [M + 2H]²⁺; found: 371.1760.

Reversed methyl 3,5-dihydroxybenzoate-centred dendrimeric aldehyde 15a

The compound was obtained from the alkyne 14 (125 mg, 0.66 mmol, 2.2 eq.) and azide 13b (100 mg, 0.30 mmol, 1 eq.) in the presence of CuSO₄·5H₂O (4 mg, 0.02 mmol, 0.05 eq.), sodium ascorbate (6 mg, 0.03 mmol, 0.1 eq.), Et₃N (0.02 mL, 0.15 mmol, 0.5 eq.), and AcOH (0.01 mL, 0.15 mmol, 0.5 eq.) in DMF : H₂O (15 mL, 1 : 5 v/v) according to a modified procedure described for the compound 5d. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc) to afford the product as a white solid (160 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 9.83 (s, 2H, CHO), 7.68 (s, 2H, H^triaz.), 7.44–7.37 (m, 4H, C(9)H, C(11)H), 7.20 (d, J = 8.0 Hz, 2H, C(12)H), 7.14 (d, J = 2.1 Hz, 2H, C(2,6)H), 6.57 (t, J = 2.4 Hz, 1H, C(4)H), 5.38 (s, 4H, C(7)OCH₂), 4.58 (t, J = 6.9 Hz, 4H, NCH₂CH₂CH₂O), 3.98 (t, J = 5.7 Hz, 4H, NCH₂CH₂CH₂O), 3.90 (s, 9H, COOMe, C(8)OMe), 2.45–2.38 (m, 4H, NCH₂CH₂CH₂O). ¹³C NMR (126 MHz, CDCl₃) δ 191.1, 166.6, 159.5, 153.1, 150.0, 143.5, 132.4, 130.7, 126.9, 123.7, 112.6, 109.3, 108.1, 106.6, 64.4, 63.0, 56.1, 52.5, 47.3, 29.9. HRMS(ESI+): calc. for C₃₆H₃₉N₆O₁₀⁺ 715.2723 [M + H]⁺; found: 715.2721.

Bis-1,2,3-triazole-centred dendrimeric aldehyde 11b

The bis-1,2,3-triazole 11b was prepared according to the literature procedure⁴² from phenylacetylene (100 mg, 0.98 mmol, 1 eq.) and azide 9b (230 mg, 0.98 mmol, 1 eq.) in the presence of Cu (63 mg, 0.98 mmol, 1 eq.), CuSO₄·5H₂O (25 mg, 0.10 mmol, 0.1 eq.), and Na₂CO₃ (312 mg, 2.94 mmol, 3 eq.) in MeCN : H₂O (3 mL, 1 : 1.1 v/v). The crude product was purified on silica (Hex : EtOAc (2 : 1) → (3 : 2)) to afford the product as a white solid (86 mg, 13%). ¹H NMR (500 MHz, CDCl₃) δ 9.78 (s, 2H, CHO), 7.55–7.50 (m, 4H, C(2,6)H), 7.31 (d, J = 1.7 Hz, 2H, C(9)H), 7.29–7.26 (m, 8H, C(3–5)H, C(11)H), 6.69 (d, J = 8.2 Hz, 2H, C(12)H), 4.13 (dt, J = 14.0, 7.0 Hz, 2H, NCH^aCH₂CH₂O), 4.05 (dt, J = 14.0, 6.7 Hz, 2H, NCH^bCH₂CH₂O), 3.92–3.86 (m, 4H, NCH₂CH₂CH₂O), 3.81 (s, 6H, OMe), 2.31–2.20 (m, 2H, NCH₂CH^aCH₂O), 2.22–2.10 (m, 2H, NCH₂CH^bCH₂O) δ 190.9, 153.1, 149.8, 147.4, 130.5, 129.5, 129.3, 129.2, 126.5, 126.1, 120.5, 111.6, 109.3, 65.0, 55.9, 45.5, 28.5. HRMS(ESI+): calc. for C₃₈H₃₇N₆O₆⁺ 673.2770 [M + H]⁺; found: 673.2754.

Synthesis of arylidene Meldrum's acids

Phloroglucinol-centred dendrimeric arylidene Meldrum's acid 10c

The dendrimeric aldehyde 5c (50 mg, 0.05 mmol, 1 eq.) was dissolved in DCM (0.5 mL) and methanol (1.3 mL) was added. Meldrum's acid (4) (76 mg, 0.53 mmol, 10 eq.) was added, the mixture was stirred at 40 °C for 2 days, and the solvent was evaporated. The crude product was purified on silica (Hex : EtOAc (2 : 1) → EtOAc (100%) → EtOAc : MeOH (10 : 1)) to afford the product as an orange solid (54 mg, 77%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 3H, C(10)CH), 8.27 (d, J = 1.6 Hz, 3H, C(9)H), 7.69 (s, 3H, H^triaz.), 7.58 (dd, J = 8.5, 1.6 Hz, 3H, C(11)H), 6.87 (d, J = 8.5 Hz, 3H, C(12)H), 6.23 (s, 3H, C(2,4,6)H), 5.11 (s, 6H, C(1,3,5)OCH₂), 4.63 (t, J = 6.7 Hz, 6H, NCH₂CH₂CH₂O), 4.12 (t, J = 6.0 Hz, 6H, NCH₂CH₂CH₂O), 3.93 (s, 9H, OMe), 2.54–2.47 (m, 6H, NCH₂CH₂CH₂O), 1.79 (s, 18H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.1, 160.7, 160.1, 158.1, 153.6, 149.0, 143.9, 132.4, 125.5, 123.6, 116.1, 112.0, 111.1, 104.3, 95.2, 65.4, 62.0, 56.1, 47.1, 29.6, 27.2. HRMS(ESI+): calc. for C₆₆H₇₀N₉O₂₁⁺ 1324.4681 [M + H]⁺; found: 1324.4642.

Glycerol-centred dendrimeric arylidene Meldrum's acid 10h

The compound was obtained from dendrimer 5h (147 mg, 0.16 mmol, 1 eq.) and Meldrum's acid (4) (247 mg, 1.61 mmol, 10 eq.) in DCM : MeOH (18 mL, 1 : 2 v/v) according to the procedure described for compound 10c. The crude product was ground in a mortar with ethanol (6 mL), water was added (6 mL), the suspension was filtered and washed with EtOH : H₂O (1 : 3 v/v, 50 mL). The solid residue was air-dried to afford the product as a yellow solid (143 mg, 60%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 3H, C(10)CH), 8.27 (d, J = 1.9 Hz, C(9)H), 7.71 (s, 1H, C(2)OCH₂CCH̲^triaz.), 7.65 (s, 2H, C(1,3)OCH₂CCH̲^triaz.), 7.58 (dd, J = 8.4, 1.9 Hz, 3H, C(11)H), 6.88 (d, J = 8.4 Hz, 3H, C(12)H), 4.74 (s, 2H, C(2)OCH₂), 4.64–4.54 (m, 10H, C(1,3)OCH₂, NCH₂CH₂CH₂O), 4.15–4.08 (m, 6H, NCH₂CH₂CH₂O), 3.93 (s, 9H, OMe), 3.76 (tt, J = 5.8, 4.3 Hz, 1H, C(2)H), 3.61 (dd, J = 10.1, 4.3 Hz, 2H, C(1,3)H^a), 3.57 (dd, J = 10.1, 5.8 Hz, 2H, C(1,3)H^b), 2.53–2.42 (m, 6H, NCH₂CH₂CH₂O), 1.79 (s, 18H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.2, 160.8, 158.2, 153.7, 149.1, 145.6, 145.1, 132.4, 125.6, 123.5, 123.4, 116.1, 112.0, 111.1, 104.4, 77.3, 70.3, 65.51, 65.46, 64.9, 63.9, 56.1, 47.00, 46.98, 29.70, 29.68, 27.7. HRMS(ESI+): calc. for C₆₃H₇₂N₉O₂₁⁺ 1290.4838 [M + H]⁺; found: 1290.4828.

Hydroquinone-centred dendrimeric arylidene Meldrum's acid 10a

The dendrimeric aldehyde 5a (100 mg, 0.15 mmol, 1 eq.) was dissolved in DCM (8 mL) and MeOH (8 mL) was added. Meldrum's acid (4) (95 mg, 0.66 mmol, 4.3 eq.) and (PhNH₃)₂CuCl₄ (0.9 mg, 2.2 µmol, 0.01 eq.) were added, and the mixture was stirred at 40 °C for a day. The solvents were evaporated, and the solid residue was ground in a mortar with EtOH (3 mL) and water (3 mL). The resulting suspension was transferred to vials with water (12 mL), held in an ultrasound bath for 10 s, and centrifuged at 3700 rpm for 1 min. The water/EtOH was decanted, the solid residue was dissolved in DCM, dried over anhydrous Na₂SO₄, filtered, and evaporated. The product was obtained as a yellow solid (138 mg, quant.). ¹H NMR (500 MHz, CDCl₃) δ 8.34 (s, 2H, C(10)CH), 8.29 (d, J = 1.6 Hz, 2H, C(9)H), 7.66 (s, 2H, H^triaz.), 7.58 (dd, J = 8.5, 1.6 Hz, 2H, C(11)H), 6.91–6.82 (m, 6H, C(12)H, C(2,3,5,6)H), 5.13 (s, 4H, C(1,4)CH₂), 4.63 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 4.10 (t, J = 5.9 Hz, 4H, NCH₂CH₂CH₂O), 3.93 (s, 6H, OMe), 2.54–2.47 (m, 4H, NCH₂CH₂CH₂O), 1.79 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.2, 160.7, 158.2, 153.6, 152.8, 149.1, 144.5, 132.4, 125.6, 123.4, 116.1, 115.9, 111.2, 104.4, 65.3, 62.8, 56.1, 47.0, 29.6, 27.7. HRMS: calc. for C₄₆H₄₉N₆O₁₄⁺ 909.3302 [M + H]⁺; found: 909.3294.

Methyl 3,5-dihydroxybenzoate-centred dendrimeric arylidene Meldrum's acid 10b

The compound was obtained from dendrimer 5b (80 mg, 0.11 mmol, 1 eq.) and Meldrum's acid (4) (64 mg, 0.45 mmol, 4 eq.) in the presence of (PhNH₃)₂CuCl₄ (1.8 mg, 4.5 µmol, 0.04 eq.) in DCM : MeOH (10 mL, 1 : 9 v/v) according to the procedure described for compound 10a. The product was obtained after a day as a yellow solid (108 mg, quant.). ¹H NMR (500 MHz, CDCl₃) δ 8.34 (s, 2H, C(10)CH), 8.28 (d, J = 1.1 Hz, 2H, C(9)H), 7.69 (s, 2H, H^triaz.), 7.59 (dd, J = 8.4, 1.1 Hz, 2H, C(11)H), 7.26 (from HSQC (overlapping with CHCl₃), 2H, C(2,6)H), 6.87 (d, J = 8.4 Hz, 2H, C(12)H), 6.78 (t, J = 2.3 Hz, 1H, C(4)H), 5.19 (s, 4H, C(3,5)OCH₂), 4.64 (t, J = 6.6 Hz, 4H, NCH₂CH₂CH₂O), 4.12 (t, J = 5.7 Hz, 4H, NCH₂CH₂CH₂O), 3.94 (s, 6H, C(8)OMe), 3.90 (s, 3H, COOMe), 2.56–2.48 (m, 4H, NCH₂CH₂CH₂O), 1.79 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 166.6, 164.2, 160.7, 159.4, 158.2, 153.6, 149.1, 143.8, 132.4, 132.4, 125.7, 123.6, 116.2, 112.0, 111.2, 108.8, 107.1, 104.4, 65.3, 62.4, 56.1, 52.5, 47.1, 29.7, 27.7. HRMS(ESI+): calc. for C₄₈H₅₁N₆O₁₆⁺ 967.3357 [M + H]⁺; found: 967.3358.

Trimesic acid-centred dendrimeric arylidene Meldrum's acid 10d

The compound was obtained from dendrimer 5d (200 mg, 0.19 mmol, 1 eq.) and Meldrum's acid (4) (140 mg, 0.97 mmol, 5 eq.) in the presence of (PhNH₃)₂CuCl₄ (3.8 mg, 9.7 µmol, 0.05 eq.) in DCM : MeOH (15 mL, 1 : 4 v/v) according to the procedure described for compound 10a. The product was obtained after a day as a yellow solid (138 mg, quant.). ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 3H, C(2,4,6)H), 8.31 (s, 3H, C(10)CH), 8.26 (d, J = 1.5, 3H, C(9)H), 7.79 (s, 3H, H^triaz.), 7.56 (dd, J = 8.1, 1.5 Hz, 3H, C(11)H), 6.87 (d, J = 8.1 Hz, 3H, C(12)H), 5.47 (s, 6H, C(1,3,5)COOCH₂), 4.65 (t, J = 6.8 Hz, 6H, NCH₂CH₂CH₂O), 4.11 (t, J = 5.9 Hz, 6H, NCH₂CH₂CH₂O), 3.93 (s, 9H, OMe), 2.55–2.47 (m, 6H, NCH₂CH₂CH₂O), 1.79 (s, 18H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.7, 164.2, 160.7, 158.2, 153.6, 149.1, 142.4, 135.1, 132.4, 131.0, 125.6, 125.1, 116.1, 111.9, 111.1, 104.4, 65.3, 58.8, 56.1, 47.1, 29.6, 27.7. HRMS(ESI+): calc. for C₆₉H₇₀N₉O₂₄⁺ 1408.4529 [M + H]⁺; found: 1408.4506.

Citric acid-centred dendrimeric arylidene Meldrum's acid 10e

The compound was obtained from dendrimer 5e (100 mg, 0.10 mmol, 1 eq.) and Meldrum's acid (4) (53 mg, 0.37 mmol, 3.8 eq.) in the presence of (PhNH₃)₂CuCl₄ (1.2 mg, 3.0 µmol, 0.03 eq.) in DCM : MeOH (12 mL, 1 : 5 v/v) according to the procedure described for compound 10a. The product was obtained after 2 days as a yellow solid (119 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 2H, C(10)CH), 8.32 (s, 1H, C(10′)CH), 8.26 (d, J = 1.7 Hz, 2H, C(9)H), 8.25 (d, J = 1.7 Hz, 1H, C(9′)H), 7.77 (s, 1H, C(2)COOCH₂CCH̲^triaz.), 7.65 (s, 2H, C(1,3)COOCH₂CCH̲^triaz.), 7.62–7.55 (m, 3H, C(11,11′)H), 6.89 (d, J = 8.5 Hz, 3H, C(12,12′)H), 5.23 (s, 2H, C(2)COOCH₂), 5.16 (d, J = 12.8 Hz, 2H, C(1,3)COOCH^a), 5.11 (d, J = 12.8 Hz, 2H, C(1,3)COOCH^b), 4.66–4.59 (m, 6H, NCH₂CH₂CH₂O), 4.12 (t, J = 5.8 Hz, 6H, NCH₂CH₂CH₂O), 4.05 (brs, 1H, OH), 3.93 (s, 6H, C(8)OMe), 3.92 (s, 3H, C(8′)OMe), 2.81 (d, J = 15.7 Hz, 2H, C(1,3)H^a), 2.72 (d, J = 15.7 Hz, 2H, C(1,3)H^b), 2.53–2.45 (m, 6H, NCH₂CH₂CH₂O), 1.79 (s, 18H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 169.3, 164.2, 160.7, 158.21, 158.18, 153.6, 149.1, 142.4, 141.9, 132.4, 132.3, 125.61, 125.59, 125.3, 124.5, 116.2, 112.03, 112.00, 111.2, 104.4, 73.2, 65.38, 65.36, 59.3, 58.2, 56.1, 47.11, 47.09, 43.2, 29.68, 29.66, 27.7. HRMS(ESI+): calc. for C₆₆H₇₂N₉O₂₅⁺ 1390.4634 [M + H]⁺; found: 1390.4636.

Glucose-centred dendrimeric arylidene Meldrum's acid 10f

The compound was obtained from dendrimer 5f (70 mg, 0.05 mmol, 1 eq.) and Meldrum's acid (4) (65 mg, 0.45 mmol, 10 eq.) in the presence of (PhNH₃)₂CuCl₄ (1.8 mg, 4.5 µmol, 0.1 eq.) in DCM : MeOH (10 mL, 1 : 4 v/v) in a day according to a modified procedure described for compound 10a. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc (100%) → EtOAc : MeCN (5 : 1) → EtOAc : MeOH (5 : 1)) to afford the product as a yellow solid (54 mg, 55%). ¹H NMR (500 MHz, CDCl₃) δ 8.35–8.28 (m, 5H, C(10)CH), 8.27–8.20 (m, 5H, C(9)H), 8.07 (s, 1H, C(2′/3′)CCH̲^triaz.), 8.03 (s, 1H, C(2′/3′)CCH̲^triaz.), 7.94 (s, 1H, C(1′)CCH̲^triaz.), 7.89 (s, 1H, C(4′)CCH̲^triaz.), 7.74 (s, 1H, C(6′)CCH̲^triaz.), 7.59–7.54 (m, 5H, C(11)H), 6.91–6.83 (m, 5H, C(12)H), 4.97 (d, J = 12.6 Hz, 1H, C(1′)H^a), 4.93 (d, J = 11.7 Hz, 1H, C(2′)H^a), 4.91 (d, J = 11.5 Hz, 1H, C(3′)H^a), 4.86 (d, J = 11.7 Hz, 1H, C(4′)H^a), 4.83 (d, J = 11.5 Hz, 1H, C(3′)H^b), 4.80 (d, J = 12.6 Hz, 1H, C(1′)H^b), 4.77 (d, J = 11.7 Hz, 1H, C(2′)H^b), 4.72 (d, J = 12.5 Hz, 1H, C(6′)H^a), 4.66–4.57 (m, 12H, NCH₂CH₂CH₂O, C(4′)H^b, C(6′)H^b), 4.39 (d, J = 7.6 Hz, 1H, C(1)H), 4.17–4.08 (m, 10H, NCH₂CH₂CH₂O), 3.94–3.88 (m, 15H, OMe), 3.77–3.73 (m, 2H, C(6)CH₂), 3.50–3.41 (m, 2H, C(3)H, C(4)H), 3.35–3.26 (m, 2H, C(2)H, C(5)H), 2.52–2.44 (m, 10H, NCH₂CH₂CH₂O), 1.78 (s, 30H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.2, 160.7, 158.23, 158.20, 153.78, 153.77, 153.76, 153.72, 153.67, 149.1, 145.0, 144.82, 144.75, 144.6, 132.47, 132.46, 132.42, 132.40, 125.54, 125.51, 125.48, 125.47, 124.5, 124.3, 124.1, 124.0, 123.7, 116.14, 116.12, 112.0, 111.9, 111.09, 111.06, 111.01, 111.00, 104.38, 104.36, 102.5, 83.9, 81.7, 77.3, 74.6, 69.0, 66.5, 65.85, 65.78, 65.63, 65.57, 65.5, 64.8, 63.1, 56.1, 47.10, 47.05, 29.7, 27.6. HRMS(ESI+): calc. for C₁₀₆H₁₁₉N₁₅O₃₆²⁺ 1089.3983 [M + 2H]²⁺; found: 1089.3971.

Pentaerythritol-centred dendrimeric arylidene Meldrum's acid 10g

The compound was obtained from dendrimer 5g (76 mg, 0.06 mmol, 1 eq.) and Meldrum's acid (4) (72 mg, 0.50 mmol, 8 eq.) in the presence of (PhNH₃)₂CuCl₄ (2.0 mg, 5.0 µmol, 0.08 eq.) in DCM : MeOH (15 mL, 1 : 4 v/v) according to a modified procedure described for compound 10a. After a day, the reaction mixture was allowed to cool to room temperature, DCM (20 mL) and water (20 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (4 × 20 mL), dried over Na₂SO₄, filtered, and evaporated. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc : MeOH (12 : 1)) to afford the product as a yellow solid (93 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 4H, C(10)CH), 8.26 (d, J = 1.2 Hz, 4H, C(9)H), 7.65 (s, 4H, H^triaz.), 7.58 (dd, J = 8.4, 1.2 Hz, 4H, C(11)H), 6.89 (d, J = 8.4 Hz, 4H, C(12)H), 4.60 (t, J = 6.5 Hz, 8H, NCH₂CH₂CH₂O), 4.51 (s, 8H, C(1–4)OCH₂), 4.12 (t, J = 6.0 Hz, 8H, NCH₂CH₂CH₂O), 3.92 (s, 12H, OMe), 3.42 (s, 8H, C(1–4)H₂), 2.51–2.44 (m, 8H, NCH₂CH₂CH₂O), 1.79 (s, 24H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.2, 160.8, 158.2, 153.7, 149.1, 145.5, 132.4, 125.5, 123.2, 116.1, 111.9, 111.1, 104.4, 69.2, 65.6, 65.0, 56.1, 47.0, 45.4, 29.8, 27.7. HRMS(ESI+): calc. for C₈₅H₉₈N₁₂O₂₈²⁺ 867.3302 [M + 2H]²⁺; found: 867.3301.

Tetraethylene glycol-centred dendrimeric arylidene Meldrum's acid 10i

The compound was obtained from dendrimer 5i (33 mg, 0.04 mmol, 1 eq.) and Meldrum's acid (4) (26 mg, 0.18 mmol, 4.5 eq.) in the presence of (PhNH₃)₂CuCl₄ (0.7 mg, 1.8 µmol, 0.04 eq.) in DCM : MeOH (5 mL, 1 : 4 v/v) according to the procedure described for compound 10a. The product was obtained after a day as a yellow solid (44 mg, quant.). ¹H NMR (500 MHz, CDCl₃) δ 8.34 (s, 2H, C(10)CH), 8.28 (d, J = 1.4 Hz, 2H, C(9)H), 7.63 (s, 2H, H^triaz.), 7.59 (dd, J = 8.3, 1.4 Hz, 2H, C(11)H), 6.88 (d, J = 8.3 Hz, 2H, C(12)H), 4.65 (s, 4H, C(1,1′)OCH₂), 4.60 (t, J = 6.7 Hz, 4H, NCH₂CH₂CH₂O), 4.11 (t, J = 6.0 Hz, 4H, NCH₂CH₂CH₂O), 3.93 (s, 6H, OMe), 3.68–3.60 (m, 16H, C(1–4,1′–4′)H₂), 2.52–2.45 (m, 4H, NCH₂CH₂CH₂O), 1.79 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.2, 160.7, 158.2, 153.6, 149.1, 145.4 (from HMBC), 132.4, 125.6, 123.4 (from HSQC), 116.1, 111.9, 111.1, 104.4, 70.7, 70.6, 69.8, 65.4, 64.7, 56.1, 47.0, 29.7, 27.6. HRMS(ESI+): calc. for C₄₈H₆₂N₆O₁₇²⁺ 497.2080 [M+2H]²⁺; found: 497.2081.

Reversed methyl 3,5-dihydroxybenzoate-centred dendrimeric arylidene Meldrum's acid 16

The compound was obtained from dendrimer 15a (100 mg, 0.14 mmol, 1 eq.) and Meldrum's acid (4) (50 mg, 0.35 mmol, 2.5 eq.) in the presence of (PhNH₃)₂CuCl₄ (1.1 mg, 2.8 µmol, 0.02 eq.) in DCM : MeOH (12 mL, 1 : 5 v/v) according to the procedure described for compound 10a. The product was obtained after 2 days as a yellow solid (127 mg, 94%). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 2H, C(10)CH), 8.28 (d, J = 1.9 Hz, 2H, C(9)H), 7.69 (s, 2H, H^triaz.), 7.56 (dd, J = 8.2, 1.9 Hz, 2H, C(11)H), 7.18–7.13 (m, 4H, C(2,6)H, C(12)H), 6.59 (t, J = 2.3 Hz, 1H, C(4)H), 5.39 (s, 4H, C(7)OCH₂), 4.58 (t, J = 6.8 Hz, 4H, NCH₂CH₂CH₂O), 4.00 (t, J = 5.6 Hz, 4H, NCH₂CH₂CH₂O), 3.90 (s, 6H, C(8)OMe), 3.89 (s, 3H, COOMe), 2.44–2.38 (m, 4H, NCH₂CH₂CH₂O), 1.78 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 166.6, 164.2, 160.7, 159.5, 158.2, 153.3, 149.1, 143.2, 132.4, 132.4, 125.7, 123.8, 116.0, 112.6, 111.2, 108.2, 106.7, 104.4, 64.5, 62.9, 56.1, 52.5, 47.4, 29.9, 27.6. HRMS(ESI+): calc. for C₄₈H₅₁N₆O₁₆⁺ 967.3357 [M + H]⁺; found: 967.3354.

Bis-1,2,3-triazole-centred dendrimeric arylidene Meldrum's acid 17

The compound was obtained from dendrimer 11b (54 mg, 0.08 mmol, 1 eq.) and Meldrum's acid (38 mg, 0.26 mmol, 3.3 eq.) in the presence of (PhNH₃)₂CuCl₄ (1.3 mg, 3.2 µmol, 0.04 eq.) in DCM : MeOH (9 mL, 1 : 8 v/v) according to the procedure described for the compound 10a. The product was obtained after 2 days as a yellow solid (61 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 8.27 (s, 2H, C(10)CH), 8.14 (d, J = 1.0 Hz, 2H, C(9)H), 7.57–7.50 (m, 4H, C(2,6)H), 7.46 (dd, J = 8.4, 1.0 Hz, 2H, C(11)H), 7.32–7.27 (m, 6H, C(3–5)H), 6.66 (d, J = 8.4 Hz, 2H, C(12)H), 4.15 (ddd, J = 13.9, 7.0, 6.8 Hz, 2H, NCH₂^aCH₂CH₂O) 4.06 (ddd, J = 13.9, 7.0, 6.6 Hz, 2H, NCH₂^bCH₂CH₂O), 3.97–3.90 (m, 4H, NCH₂CH₂CH₂O), 3.82 (s, 6H, OMe), 2.30–2.22 (m, 2H, NCH₂CH₂^aCH₂O), 2.22–2.12 (m, 2H, NCH₂CH₂^bCH₂O), 1.79 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 164.1, 160.7, 158.2, 153.3, 148.9, 147.5, 132.1, 129.5, 129.3, 129.2, 126.1, 125.5, 120.6, 116.0, 111.6, 111.1, 104.4, 65.1, 55.9, 45.5, 28.5, 27.7. HRMS(ESI+): calc. for C₅₀H₄₉N₆O₁₂⁺ 925.3403 [M + H]⁺; found: 925.3398.

Synthesis of arylmethyl Meldrum's acids

Hydroquinone-centred dendrimeric arylmethyl Meldrum's acid 3a

The arylidene Meldrum's acid 10a (100 mg, 0.11 mmol, 1 eq.) was dissolved in CHCl₃ (5 mL), cooled in an ice bath and AcOH (0.19 mL, 3.30 mmol, 30 eq.) was added. After 5 min NaBH₄ (125 mg, 3.30 mmol, 30 eq.) was added portion-wise. Once the solution turned colourless (1 h), the excess of NaBH₄ was quenched with water (6 mL), and the pH was adjusted to 5 with AcOH (0.5 mL). The layers were separated and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na₂SO₄, filtered, and evaporated. The product was obtained as a white, spectroscopically pure solid (76 mg, 75%). ¹H NMR (500 MHz, CDCl₃) δ 7.67 (s, 2H, H^triaz.), 6.89 (d, J = 1.8 Hz, 2H, C(9)H), 6.88 (s, 4H, C(2,3,5,6)H), 6.83 (dd, J = 8.2, 1.8 Hz, 2H, C(11)H), 6.74 (d, J = 8.2 Hz, 2H, C(12)H), 5.14 (s, 4H, C(1,4)OCH₂), 4.61 (t, J = 6.7 Hz, 4H, NCH₂CH₂CH₂O), 3.96 (t, J = 5.6 Hz, 4H, NCH₂CH₂CH₂O), 3.84 (s, 6H, OMe), 3.73 (t, J = 4.8 Hz, 2H, CH^MA), 3.44 (d, J = 4.8 Hz, 4H, C(10)CH₂), 2.43–2.37 (m, 4H, NCH₂CH₂CH₂O), 1.73 (s, 6H, Me^MA), 1.51 (s, 6H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 152.9, 149.6, 147.1, 144.4, 130.9, 123.5, 122.2, 116.0, 114.2, 113.9, 105.4, 65.6, 62.8, 56.0, 48.4, 47.3, 32.0, 30.0, 28.6, 27.5. HRMS(ESI+): calc. for C₄₆H₅₃N₆O₁₄⁺ 913.3615 [M + H]⁺; found: 913.3615. HRMS(ESI−): calc. for C₄₆H₅₁N₆O₁₄⁻ 911.3468 [M − H]⁻; found: 911.3445.

Trimesic acid-centred dendrimeric arylmethyl Meldrum's acid 3d

The compound was obtained from arylidene Meldrum's acid 10d (100 mg, 0.07 mmol, 1 eq.), NaBH₄ (135 mg, 3.55 mmol, 50 eq.), AcOH (0.41 mL, 7.10 mmol, 100 eq.) in DCM (8 mL)for 30 min according to the procedure described for compound 3a. The product was obtained as a white solid (106 mg, 95%). ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 3H, C(2,4,6)H), 7.77 (s, 3H, H^triaz.), 6.87 (d, J = 1.5 Hz, 3H, C(9)H), 6.79 (dd, J = 8.1, 1.5 Hz, 3H, C(11)H), 6.73 (d, J = 8.1 Hz, 3H, C(12)H), 5.47 (s, 6H, C(1,3,5)COOCH₂), 4.61 (t, J = 6.2 Hz, 6H, NCH₂CH₂CH₂O), 3.96 (t, J = 5.8 Hz, 6H, NCH₂CH₂CH₂O), 3.84 (s, 9H, OMe), 3.75 (t, J = 4.3 Hz, 3H, CH^MA), 3.40 (d, J = 4.3 Hz, 6H, C(10)CH₂), 2.43–2.37 (m, 6H, NCH₂CH₂CH₂O), 1.73 (s, 9H, Me^MA), 1.51 (s, 9H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.5, 164.7, 149.6, 147.0, 142.3, 135.1, 131.0, 130.9, 125.0, 122.1, 114.1, 113.9, 105.3, 65.6, 58.8, 56.0, 48.4, 47.3, 31.9, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₆₉H₇₆N₉O₂₄⁺ 1414.4998 [M + H]⁺; found: 1414.4991. HRMS(ESI−): calc. for C₆₉H₇₄N₉O₂₄⁻ 1412.4852 [M − H]⁻; found: 1412.4814.

Pentaerythritol-centred dendrimeric arylmethyl Meldrum's acid 3g

The compound was obtained from arylidene Meldrum's acid 10g (54 mg, 0.03 mmol, 1 eq.), NaBH₄ (60 mg, 1.56 mmol, 50 eq.), AcOH (0.10 mL, 1.56 mmol, 50 eq.) in DCM (20 mL) for 1.5 h according to the procedure described for compound 3a. The product was obtained as a white solid (44 mg, 81%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 4H, H^triaz.), 6.88 (d, J = 1.8 Hz, 4H, C(9)H), 6.81 (dd, J = 8.1, 1.8 Hz, 4H, C(11)H), 6.73 (d, J = 8.1 Hz, 4H, C(12)H), 4.56 (t, J = 6.9 Hz, 8H, NCH₂CH₂CH₂O), 4.51 (s, 8H, C(1–4)OCH₂), 3.96 (t, J = 6.0 Hz, 8H, NCH₂CH₂CH₂O), 3.83 (s, 12H, OMe), 3.76 (t, J = 5.2 Hz, 4H, CH^MA), 3.46–3.38 (m, 16H, C(1–4)H₂, C(10)CH₂), 2.41–2.34 (m, 8H, NCH₂CH₂CH₂O), 1.73 (s, 12H, Me^MA), 1.52 (s, 12H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 149.5, 147.1, 145.4, 130.8, 123.2, 122.1, 113.9, 113.8, 105.4, 69.2, 65.7, 65.1, 56.0, 48.4, 47.2, 45.4, 31.9, 30.1, 28.6, 27.4. HRMS(ESI+): calc. for C₈₅H₁₀₆N₁₂O₂₈²⁺ 871.3615 [M + 2H]²⁺; found: 871.3569. HRMS(ESI−): calc. for C₈₅H₁₀₂N₁₂O₂₈²⁻ 869.3469 [M − H]²⁻; found: 869.3456.

Bis-1,2,3-triazole-centred dendrimeric arylmethyl Meldrum's acid 18

The compound was obtained from arylidene Meldrum's acid 17 (42 mg, 0.05 mmol, 1 eq.), NaBH₄ (52 mg, 1.36 mmol, 30 eq.), AcOH (0.10 mL, 1.82 mmol, 40 eq.) in DCM (10 mL) for 1 h according to the procedure described for compound 3a. The product was obtained as a white solid (38 mg, 90%). ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.39 (m, 4H, C(2,6)H), 7.32–7.26 (m, 6H, C(3–5)H), 6.81 (d, J = 1.4 Hz, 2H, C(9)H), 6.73 (dd, J = 8.2, 1.4 Hz, 2H, C(11)H), 6.53 (d, J = 8.2 Hz, 2H, C(12)H), 4.12–3.97 (m, 4H, NCH₂CH₂CH₂O), 3.83–3.74 (m, 6H, CH^MA, NCH₂CH₂CH₂O), 3.72 (s, 6H, OMe), 3.38 (d, J = 4.7 Hz, 4H, C(10)CH₂), 2.11–2.00 (m, 2H, NCH₂CH₂^aCH₂O), 2.00–1.90 (m, 2H, NCH₂CH₂^bCH₂O), 1.74 (s, 6H, Me^MA(a)), 1.53 (s, 6H, Me^MA(b)). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 149.4, 147.3, 146.7, 130.7, 129.6, 129.3, 129.1, 126.2, 122.0, 120.5, 113.7, 113.5, 105.4, 65.2, 55.9, 48.5, 45.8, 31.9, 28.8, 28.6, 27.4. HRMS(ESI+): calc. for C₅₀H₅₃N₆O₁₂⁺ 929.3716 [M + H]⁺; found: 929.3714. HRMS(ESI−): calc. for C₅₀H₅₁N₆O₁₂⁻ 927.3570 [M − H]⁻; found: 927.3541.

Methyl 3,5-dihydroxybenzoate-centred dendrimeric arylmethyl Meldrum's acid 3b

The arylidene Meldrum's acid 10b (50 mg, 0.05 mmol, 1 eq.) was dissolved in DCM (1 mL) and cooled in an ice bath. In another container, NaBH₄ (8 mg, 0.21 mmol, 4 eq.) was dissolved in a 0.01–0.02 M NaOH solution in ethanol (5 mL). The NaBH₄ solution was added dropwise to the arylidene solution. Once the solution turned colourless (approx. 5 min), the unreacted NaBH₄ was quenched with water (2 mL), and the pH was adjusted to 5 with AcOH (1 mL). The volatile solvents were evaporated, brine (8 mL) was added, and the mixture was extracted with DCM (3 × 8 mL). The combined organic layers were washed with brine (2 × 8 mL) and water (8 mL), dried over Na₂SO₄, filtered, and evaporated. The product was obtained as a white, spectroscopically pure solid (44 mg, 88%). ¹H NMR (500 MHz, CDCl₃) δ 7.70 (s, 2H, H^triaz.), 7.27 (d, J = 2.5 Hz, 2H, C(2,6)H), 6.89 (d, J = 1.6 Hz 2H, C(9)H), 6.82 (dd, J = 8.2, 1.6 Hz, 2H, C(11)H), 6.80 (t, J = 2.5 Hz, 1H, C(4)H), 6.74 (d, J = 8.2 Hz, 2H, C(12)H), 5.19 (s, 4H, C(3)OCH₂), 4.61 (t, J = 6.7 Hz, 4H, NCH₂CH₂CH₂O), 3.96 (t, J = 5.8 Hz, 4H, NCH₂CH₂CH₂O), 3.89 (s, 3H, COOMe), 3.84 (s, 6H, C(8)OMe), 3.74 (t, J = 4.8 Hz, 2H, CH^MA), 3.43 (d, J = 4.8 Hz, 4H, C(10)CH₂), 2.43–2.38 (m, 4H, NCH₂CH₂CH₂O), 1.73 (s, 6H, Me^MA), 1.51 (s, 6H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 166.7, 165.6, 159.4, 149.6, 147.1, 143.6, 132.3, 130.9, 123.7, 122.2, 114.2, 113.9, 108.7, 107.2, 105.4, 65.6, 62.4, 56.0, 52.5, 48.4, 47.3, 32.0, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₄₈H₅₅N₆O₁₆⁺ 971.3670 [M + H]⁺; found: 971.3669. HRMS(ESI−): calc. for C₄₈H₅₃N₆O₁₆⁻ 969.3523 [M − H]⁻; found: 969.3496.

Phloroglucinol-centred dendrimeric arylmethyl Meldrum's acid 3c

The compound was obtained from arylidene Meldrum's acid 10c (40 mg, 0.03 mmol, 1 eq.), NaBH₄ (6.9 mg, 0.18 mmol, 6 eq.) in DCM : EtOH (13 mL, 10 : 3 v/v). The product was obtained as a white solid (36 mg, 90%) according to the procedure described for compound 3b. ¹H NMR (500 MHz, CDCl₃) δ 7.70 (s, 3H, H^triaz.), 6.89 (d, J = 1.8 Hz, 3H, C(9)H), 6.82 (dd, J = 8.2, 1.8 Hz, 3H, C(11)H), 6.74 (d, J = 8.2 Hz, 3H, C(12)H), 6.25 (s, 3H, C(2,4,6)H), 5.12 (s, 6H, C(1,3,5)OCH₂), 4.61 (t, J = 6.9 Hz, 6H, NCH₂CH₂CH₂O), 3.97 (t, J = 5.8 Hz, 6H, NCH₂CH₂CH₂O), 3.84 (s, 9H, OMe), 3.74 (t, J = 4.7 Hz, 3H, CH^MA), 3.43 (d, J = 4.7 Hz, 6H, C(10)CH₂), 2.45–2.36 (m, 6H, NCH₂CH₂CH₂O), 1.73 (s, 9H, Me^MA), 1.51 (s, 9H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 160.2, 149.6, 147.1, 143.9, 130.9, 123.6, 122.2, 114.2, 113.9, 105.4, 95.1, 65.7, 62.2, 56.0, 48.4, 47.3, 32.0, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₆₆H₇₆N₉O₂₁⁺ 1330.5150 [M + H]⁺; found: 1330.5114.

Citric acid-centred dendrimeric arylmethyl Meldrum's acid 3e

The compound was obtained from arylidene Meldrum's acid 10e (35 mg, 0.03 mmol, 1 eq.), NaBH₄ (3.2 mg, 0.08 mmol, 3.3 eq.) in DCM : EtOH (2 mL, 1 : 1 v/v) according to the procedure described for the compound 3b. The crude product was purified on silica (Hex : EtOAc (1 : 1) → EtOAc (100%) → EtOAc : MeOH (5 : 2)) to afford the product as a white solid (16 mg, 45%). ¹H NMR (500 MHz, CDCl₃) δ 7.77 (s, 1H, C(2)COOCH₂CCH̲^triaz.), 7.65 (s, 2H, C(1,3)COOCH₂CCH̲^triaz.), 6.92–6.85 (m, 3H, C(9,9′)H), 6.83–6.77 (m, 3H, C(11,11′)H), 6.76–6.70 (m, 3H, C(12,12′)H), 5.23 (s, 2H, C(2)COOCH₂), 5.14 (d, J = 12.7 Hz, 2H, C(1,3)COOCH^a), 5.10 (d, J = 12.7 Hz, 2H, C(1,3)COOCH^b), 4.62–4.56 (m, 6H, NCH₂CH₂CH₂O), 3.97–3.93 (m, 6H, NCH₂CH₂CH₂O), 3.86–3.81 (m, 9H, OMe), 3.79–3.73 (m, 3H, CH^MA), 3.48–3.34 (m, 6H, C(10,10′)CH₂), 2.80 (d, J = 15.8 Hz, 2H, C(1,3)H^a), 2.72 (d, J = 15.8 Hz, 2H, C(1,3)H^b), 2.43–2.34 (m, 6H, NCH₂CH₂CH₂O), 1.73 (s, 9H, Me^MA), 1.57–1.47 (m, 9H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 173.1, 169.4, 165.62, 165.58, 149.6, 149.5, 147.05, 147.03, 142.3, 141.8, 130.93, 130.86, 125.2, 124.5, 122.15, 122.09, 114.05, 113.97, 113.9, 113.8, 105.4, 73.2, 65.6, 65.5, 59.4, 58.2, 56.0, 48.4, 47.29, 47.26, 43.2, 31.91, 31.85, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₆₆H₇₈N₉O₂₅⁺ 1396.5104 [M + H]⁺; found: 1396.5015. HRMS(ESI−): calc. for C₆₆H₇₅N₉O₂₅²⁻ 696.7442 [M − H]²⁻; found: 696.7429.

Glucose-centred dendrimeric arylmethyl Meldrum's acid 3f

The compound was obtained from arylidene Meldrum's acid 10f (25 mg, 0.01 mmol, 1 eq.), NaBH₄ (2.4 mg, 0.06 mmol, 5.5 eq.) in DCM : EtOH (1.35 mL, 1 : 2.86 v/v) according to the procedure described for the compound 3b. The product was obtained as a white solid (22 mg, 89%). ¹H NMR (500 MHz, CDCl₃) δ 8.00 (s, 1H, C(2′/3′)CCH̲^triaz.), 7.97 (s, 1H, C(2′/3′)CCH̲^triaz.), 7.93 (s, 1H, C(1′)CCH̲^triaz.), 7.85 (s, 1H, C(4′)CCH̲^triaz.), 7.73 (s, 1H, C(6′)CCH̲^triaz.), 6.89–6.84 (m, 5H, C(9)H), 6.82–6.76 (m, 5H, C(11)H), 6.75–6.70 (m, 5H, C(12)H), 4.96 (d, J = 13.2 Hz, 1H, C(1′)H^a), 4.94 (d, J = 11.6 Hz, 1H, C(2′)H^a), 4.93 (d, J = 11.6 Hz, 1H, C(3′)H^a), 4.87 (d, J = 11.5 Hz, 1H, C(4′)H^a), 4.84 (d, J = 11.6 Hz, 1H, C(3′)H^b), 4.81 (d, J = 13.2 Hz, 1H, C(1′)H^b), 4.77 (d, J = 11.8 Hz, 1H, C(2′)H^b), 4.71 (d, J = 12.4 Hz, 1H, C(6′)H^a), 4.63 (d, J = 12.4 Hz, 1H, C(6′)H^b), 4.62 (d, J = 11.6 Hz, 1H, C(6′)H^b), 4.59–4.53 (m, 10H, NCH₂CH₂CH₂O), 4.39 (d, J = 7.6 Hz, 1H, C(1)H), 3.99–3.93 (m, 10H, NCH₂CH₂CH₂O), 3.84–3.79 (m, 15H, OMe), 3.78–3.72 (m, 7H, C(6)CH₂, CH^MA), 3.50–3.43 (m, 2H, C(3)H, C(4)H), 3.39 (d, J = 4.1 Hz, 10H, C(10)CH₂), 3.35–3.27 (m, 2H, C(2)H, C(5)H), 2.41–2.34 (m, 10H, NCH₂CH₂CH₂O), 1.72 (s, 15H, Me^MA(a)), 1.51 (s, 15H, Me^MA(b)). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 149.5, 147.2, 147.14, 147.10, 145.0, 144.9, 144.8, 144.7, 144.5, 130.79, 130.76, 130.7, 124.3, 124.2, 124.04, 123.98, 123.6, 122.13, 122.10, 114.01, 113.98, 113.95, 113.9, 113.8, 105.4, 102.4, 83.9, 81.7, 77.4, 74.6, 69.0, 66.6, 65.9, 65.82, 65.79, 65.7, 64.9, 63.0, 56.0, 48.4, 47.29, 47.25, 47.2, 31.9, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₁₀₆H₁₂₉N₁₅O₃₆²⁺ 1094.4374 [M + 2H]²⁺; found: 1094.4285. HRMS(ESI−): calc. for C₁₀₆H₁₂₅N₁₅O₃₆²⁻ 1092.4228 [M − H]²⁻; found: 1092.4216.

Glycerol-centred dendrimeric arylmethyl Meldrum's acid 3h

The compound was obtained from arylidene Meldrum's acid 10h (21 mg, 0.02 mmol, 1 eq.), NaBH₄ (4 mg, 0.10 mmol, 6 eq.) in DCM : EtOH (1.5 mL, 1 : 2 v/v) according to the procedure described for compound 3b. The product was obtained as a white solid (18 mg, 83%). ¹H NMR (500 MHz, CDCl₃) δ 7.70 (s, 1H, C(2)OCH₂CCH̲^triaz.), 7.65 (s, 2H, C(1,3)OCH₂CCH̲^triaz.), 6.88 (s, 3H, C(9)H), 6.80 (d, J = 7.7 Hz, 3H, C(11)H), 6.74 (d, J = 7.7 Hz, 3H, C(12)H), 4.74 (s, 2H, C(2)OCH₂), 4.61–4.53 (m, 10H, C(1,3)OCH₂, NCH₂CH₂CH₂O), 3.95 (t, J = 6.0 Hz, 6H, NCH₂CH₂CH₂O), 3.83 (s, 9H, OMe), 3.79–3.72 (m, 4H, CH^MA, C(2)H), 3.63–3.52 (m, 4H, C(1,3)H₂), 3.41 (d, J = 3.8 Hz, 6H, C(10)CH₂), 2.42–2.33 (m, 6H, NCH₂CH₂CH₂O), 1.73 (s, 9H, Me^MA), 1.51 (s, 9H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 149.6, 149.5, 147.11, 147.09, 145.4, 144.9, 130.8, 123.5, 123.4, 122.2, 114.1, 114.0, 113.9, 105.4, 77.3, 70.3, 65.72, 65.67, 64.9, 63.9, 56.0, 48.4, 47.22, 47.19, 31.9, 30.0, 28.6, 27.4. HRMS(ESI+): calc. for C₆₃H₇₈N₉O₂₁⁺ 1296.5307 [M + H]⁺; found: 1296.5230. HRMS(ESI−): calc. for C₆₃H₇₅N₉O₂₁²⁻ 646.7544 [M − H]²⁻; found: 646.7533.

Tetraethylene glycol-centred dendrimeric arylmethyl Meldrum's acid 3i

The compound was obtained from arylidene Meldrum's acid 10i (36 mg, 0.04 mmol, 1 eq.), NaBH₄ (9 mg, 0.23 mmol, 6.5 eq.) in DCM : EtOH (5 mL, 1 : 4 v/v) according to the procedure described for the compound 3b. The product was obtained as a white solid (23 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (s, 2H, H^triaz.), 6.89 (d, J = 1.4 Hz, 2H, C(9)H), 6.83 (dd, J = 8.3, 1.4 Hz, 2H, C(11)H), 6.75 (d, J = 8.3 Hz, 2H, C(12)H), 4.66 (s, 4H, C(1,1′)OCH₂), 4.58 (t, J = 6.9 Hz, 4H, NCH₂CH₂CH₂O), 3.97 (t, J = 5.8 Hz, 4H, NCH₂CH₂CH₂O), 3.85 (s, 6H, OMe), 3.74 (t, J = 4.5 Hz, 2H, CH^MA), 3.69–3.60 (m, 16H, C(1–4,1′–4′)H₂), 3.44 (d, J = 4.5 Hz, 4H, C(10)CH₂), 2.43–2.36 (m, 4H, NCH₂CH₂CH₂O), 1.74 (s, 6H, Me^MA), 1.52 (s, 6H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 165.6, 149.6, 147.1, 145.2, 130.8, 123.3, 122.2, 114.1, 113.9, 105.4, 70.7, 70.6, 69.8, 65.7, 64.8, 56.0, 48.4, 47.2, 32.0, 30.1, 28.6, 27.5. HRMS(ESI+): calc. for C₄₈H₆₅N₆O₁₇⁺ 997.4401 [M + H]⁺; found: 997.4341. HRMS(ESI−): calc. for C₄₈H₆₂N₆O₁₇²⁻ 497.2091 [M − H]²⁻; found: 497.2079.

Reversed methyl 3,5-dihydroxybenzoate-centred dendrimeric arylmethyl Meldrum's acid 12

The compound was obtained from arylidene Meldrum's acid 16 (70 mg, 0.07 mmol, 1 eq.), NaBH₄ (11 mg, 0.29 mmol, 4 eq.) in DCM : EtOH (4 mL, 1 : 1 v/v) according to the procedure described for compound 3b. The product was obtained as a white solid (56 mg, 79%). ¹H NMR (500 MHz, CDCl₃) δ 7.64 (s, 2H, H^triaz.), 7.15 (d, J = 2.2 Hz, 2H, C(2,6)H), 6.92 (d, J = 8.2 Hz, 2H, C(12)H), 6.87 (d, J = 1.6 Hz, 2H, C(9)H), 6.80 (dd, J = 8.2, 1.6 Hz, 2H, C(11)H), 6.60 (t, J = 2.2 Hz, 1H, C(4)H), 5.23 (s, 4H, C(7)OCH₂), 4.56 (t, J = 6.9 Hz, 4H, NCH₂CH₂CH₂O), 3.99 (t, J = 5.7 Hz, 4H, NCH₂CH₂CH₂O), 3.89 (s, 3H, COOMe), 3.81 (s, 6H, C(8)OMe), 3.74 (t, J = 4.9 Hz, 2H, CH^MA), 3.42 (d, J = 4.9 Hz, 4H, C(10)CH₂), 2.43–2.35 (m, 4H, NCH₂CH₂CH₂O), 1.73 (s, 6H, Me^MA), 1.50 (s, 6H, Me^MA). ¹³C NMR (126 MHz, CDCl₃) δ 166.7, 165.6, 159.6, 149.5, 146.8, 144.4, 132.3, 130.9, 123.4, 122.1, 114.3, 113.8, 108.2, 106.7, 105.4, 64.5, 63.3, 56.0, 52.5, 48.4, 47.2, 31.9, 29.9, 28.6, 27.4. HRMS(ESI+): calc. for C₄₈H₅₅N₆O₁₆⁺ 971.3670 [M + H]⁺; found: 971.3608. HRMS(ESI−): calc. for C₄₈H₅₂N₆O₁₆²⁻ 484.1725 [M − H]²⁻; found: 484.1711.

DPPH assay

The DPPH assay was performed according to a modified literature procedure.⁵⁸ Stock solutions of dendrimers were prepared by dissolving the compound in DCM (1/5 of the final volume), then brought to the desired volume with EtOH. Samples for tests (10 µM − 250 µM) were prepared from the stock solution and a mixture of DCM : EtOH (1 : 4). DPPH solution in EtOH (2 mL, 200 µM) was added to the antioxidant solution (2 mL) and mixed. After 30 min the absorption at λ = 515 nm was measured. Radical inhibition (Inh_i) was calculated using the eqn (1).

1

where A₀ is the absorbance of a solution containing only DPPH (100 µM) and A_i is the absorbance of a solution containing the antioxidant (i µM) and DPPH (100 µM). IC₅₀ and Inh₁₀₀ values were calculated assuming a linear function between the two closest measured values. Inhibition errors for individual points on the radical inhibition graph (SI) were calculated by the partial derivation method (eqn (2)).

2

For all samples two independent experiment series were run. The measurement at each concentration was repeated three times.

Solvent effects

A solution of compound 3d (200 µM) in various solvents (toluene, DCM, EtOAc, acetone, DCM : EtOH = 1 : 4 v/v, MeCN) was mixed in a 1 : 1 volume ratio with a DPPH solution (200 µM) in the same solvent. Absorption at 515 nm was measured every 10 s for a total of 180 s. The DPPH inhibition at every point was calculated using eqn (1). The experiment was repeated 3 times for each solvent and measurement deviation at each point was calculated using eqn (2).

Rancimat analysis

The compound 3a,3b,3d (0.068 mmol calculated per amount of Meldrum's acid units) as well as small molecular compound 1a (0.068 mmol) was added to flaxseed oil methyl esters (3 g), the samples were heated at 70 °C and dry air was bubbled through the sample (10 L min⁻¹). Later the formed volatile products were trapped in water and the conductivity for the water was measured.

Conclusions

We have demonstrated a divergent synthetic route for the synthesis of dendritic compounds bearing a 1,2,3-triazole linker with arylmethyl Meldrum's acid as the surface groups. The compounds were obtained via sequential Huisgen reaction, Knoevenagel condensation and reduction. Additionally, a telescoped Huisgen reaction is elaborated, thus overcoming the need to isolate the azide intermediate, which is especially important for the synthesis of higher generation dendrimers. The elaborated reaction sequence was applied for the synthesis of a small library of arylmethyl Meldrum's acid-bearing 1,2,3-triazole based 1st generation dendrimers. All compounds display good DPPH scavenging activity which was higher than that for the widely used antioxidants BHT and ascorbic acid. The dendrimers demonstrate solvent-dependent inhibition of DPPH. Because of this, the dendrimers can tolerate a broad range of system polarity, which would make them a highly versatile antioxidant for use in various industries.

Author contributions

Laima B. – investigation, formal analysis, writing (original draft); Krista B., Melānija G., Līva B., Līva P. – investigation; Inese M. – conceptualization, writing (review & editing).

Conflicts of interest

There are no conflicts to declare.

Data availability

NMR raw data available on request.

Supplementary information (SI): NMR spectra of new compounds, optimisation tables, and DPPH assay graphs. See DOI: https://doi.org/10.1039/d6ra02273a.