Functionalized C3-Symmetric Building Blocks—The Chemistry of Triaminotrimesic Acid

A series of C3-symmetric fully substituted benzenes were prepared based on alkyl triamino-benzene-tricarboxylates. Starting with a one step-synthesis, the alkyl triamino-benzene-tricarboxylates were synthesized using the corresponding cyanoacetates. The reactivity of these electronically sophisticated compounds was investigated by the formation of azides, the click reaction of the azides and a Sandmeyer-like reaction. Caused by the low stability of triaminobenzenes, direct N-alkylation was rarely reported. The use of the stable alkyl triamino-benzene-tricarboxylates allowed us total N-alkylation under standard alkylation conditions. The molecular structures of the C3-symmetric structures have been corroborated by an X-ray analysis.

Fully substituted derivatives of type A (X, Y are non-hydrogen atoms, Figure 1) also exhibit additional properties due to steric crowding. The non-planarity of some derivatives leads to different functionalization of the side groups, e.g., carboxylic acids ( Figure 1, Structure B) [34].
The synthesis of such molecules can either start from condensation reactions (mostly carbonyl compounds in aldol-like reactions), the cyclotrimerization reactions of alkynes (Reppe-type chemistry) [35], or by the functionalization of appropriately equipped building blocks of type A, such as triesters, triamines and trihalides [36] (Figure 1). The synthesis of such molecules can either start from condensation reactions (mostl carbonyl compounds in aldol-like reactions), the cyclotrimerization reactions of alkyne (Reppe-type chemistry) [35], or by the functionalization of appropriately equipped build ing blocks of type A, such as triesters, triamines and trihalides [36] (Figure 1).
In particular, cores featuring nitrogen and/or carbon-based functionalized group have been successfully used in many materials. An overview is given in Table S1.
In particular, cores featuring nitrogen and/or carbon-based functionalized groups have been successfully used in many materials. An overview is given in Table S1.
Herein, it is our intention to report the syntheses, structures and reactivities of novel C 3 -symmetric fully substituted benzenes with the tandem amino/alkylcarboxylate groups, based on the easily manageable cyclotrimerization of alkyl cyanoacetates. These electronically sophisticated structures of alkyl triamino-benzene-tricarboxylates led to extremely challenging subsequent reactions of the amine group. However, azide formation and a SANDMEYER-like reaction were studied within this report. Due to the low stability of triaminobenzenes, direct N-alkylation was rarely reported. Using the stable alkyl triaminobenzene-tricarboxylates allowed us total N-alkylation. An overview of the synthesized building blocks is given in Scheme 1.

Syntheses of C 3 -Symmetric Alkyl Triamino-Benzene-Tricarboxylates
According to the literature-known synthesis for 2a, starting with the methylcyanoacetate, methyl triamino-benzene-tricarboxylate was synthesized in a moderate yield [38]. Despite extensive experimentation, the yield of the methyl triamino-benzene-tricarboxylate 2a could not be improved in our hands. However, this atom-economic reaction is scalable and provides the required building block in multi-gram amounts. Besides the methyl triamino-benzene-tricarboxylate 2a, cyclotrimerization of the alkylcyanoacetates 1b-g led to the derivatives 2b-g in moderate yields (Table 1).

Syntheses of C3-Symmetric Alkyl Triamino-Benzene-Tricarboxylates
According to the literature-known synthesis for 2a, starting with the methylcyanoacetate, methyl triamino-benzene-tricarboxylate was synthesized in a moderate yield [38]. Despite extensive experimentation, the yield of the methyl triamino-benzene-tricarboxylate 2a could not be improved in our hands. However, this atom-economic reaction is scalable and provides the required building block in multi-gram amounts. Besides the methyl triamino-benzene-tricarboxylate 2a, cyclotrimerization of the alkylcyanoacetates 1b-g led to the derivatives 2b-g in moderate yields (Table 1). In comparison to 1,3,5-triaminobenzene and several other derivatives, which darken slowly after being left in air, the synthesized alkyl triamino-benzene-tricarboxylates do not show a color change after several months stored in air [39]. In comparison to 1,3,5-triaminobenzene and several other derivatives, which darken slowly after being left in air, the synthesized alkyl triamino-benzene-tricarboxylates do not show a color change after several months stored in air [39].
Herein, we report the syntheses of 1,3,5-triazidobenzenes, substituted with ester groups in a 2,4,6-position. The syntheses of triazides 3a-g proceeded from the triamines 2a-g under established conditions through a diazotization reaction. The triazides 3a-g were obtained in yields of 36% to 60% ( Table 2). The yields that were achieved for the triazides 3a-g were in the range of other reported triazides that were synthesized from the corresponding amines [40,44]. A procedure in which the diazotization was carried out with tert-butyl nitrite and tosylic acid at 21 • C, followed by the addition of sodium azide, did not result in the formation of the triazide 3a. Triazides 3a-c and 3g were stable at normal conditions (daylight included) for several weeks. In the case of the alkyl triamino-benzenetricarboxylates 2d, 2e and 2f, the mono-and diazides that were also formed during the conversion to the triazide could not be separated from the corresponding triazides via column chromatography. Therefore, these structures are not listed in Table 2.
Cautionary note: azides with a C/N ratio of around 1:1 are potentially explosive [56,57]. In the following, the deprotection of the ester was successfully performed to give the triazidobenzene-tricarboxylic acid 4 in a moderate yield of 60% (Scheme 2). These structures might serve as interesting building blocks, e.g., for the generation of trinitrenes [58][59][60] or the synthesis of HKUST1-comparable MOFs. corresponding amines [40,44]. A procedure in which the diazotization was carried out with tert-butyl nitrite and tosylic acid at 21 °C, followed by the addition of sodium azide, did not result in the formation of the triazide 3a. Triazides 3a-c and 3g were stable at normal conditions (daylight included) for several weeks. In the case of the alkyl triaminobenzene-tricarboxylates 2d, 2e and 2f, the mono-and diazides that were also formed during the conversion to the triazide could not be separated from the corresponding triazides via column chromatography. Therefore, these structures are not listed in Table 2. Cautionary note: azides with a C/N ratio of around 1:1 are potentially explosive [56,57].
In the following, the deprotection of the ester was successfully performed to give the triazidobenzene-tricarboxylic acid 4 in a moderate yield of 60% (Scheme 2). These structures might serve as interesting building blocks, e.g., for the generation of trinitrenes [58][59][60] or the synthesis of HKUST1-comparable MOFs. Due to the ability to form the azide, we thought that reactions based on the diazonium salt, such as SANDMEYER reactions, should be possible. Nevertheless, SANDMEYERlike reactions using tert-butyl nitrite or sodium nitrite/hydrochloric acid and potassium iodide failed several times. Many attempts were necessary until conditions were found, which lead to a triple-halogenated compound 5. This method uses tert-butyl nitrite for  Cautionary note: azides with a C/N ratio of around 1:1 are potentially explosive [56,57].
In the following, the deprotection of the ester was successfully performed to give the triazidobenzene-tricarboxylic acid 4 in a moderate yield of 60% (Scheme 2). These structures might serve as interesting building blocks, e.g., for the generation of trinitrenes [58][59][60] or the synthesis of HKUST1-comparable MOFs.

Scheme 2. Synthesis of triazidobenzene-tricarboxylic acid 4.
Due to the ability to form the azide, we thought that reactions based on the diazonium salt, such as SANDMEYER reactions, should be possible. Nevertheless, SANDMEYERlike reactions using tert-butyl nitrite or sodium nitrite/hydrochloric acid and potassium iodide failed several times. Many attempts were necessary until conditions were found, which lead to a triple-halogenated compound 5. This method uses tert-butyl nitrite for Due to the ability to form the azide, we thought that reactions based on the diazonium salt, such as SANDMEYER reactions, should be possible. Nevertheless, SANDMEYER-like reactions using tert-butyl nitrite or sodium nitrite/hydrochloric acid and potassium iodide failed several times. Many attempts were necessary until conditions were found, which lead to a triple-halogenated compound 5. This method uses tert-butyl nitrite for diazotization and TMS-bromide for halogen transfer. Upon optimization, we find that the addition of the diazotization compound and TMS-bromide must take place alternately, leading to the tribromide 5 in a moderate yield of 34% (Scheme 3). This indicates that diazotization can only be performed at one amine group at a time. Compared to another synthesis route, which has five reaction steps from mesitylene to methyl tribromobenzene tricarboxylate 5, this route only needs two steps, starting with methylcyanoacetate [8,14]. diazotization and TMS-bromide for halogen transfer. Upon optimization, we find that the addition of the diazotization compound and TMS-bromide must take place alternately, leading to the tribromide 5 in a moderate yield of 34% (Scheme 3). This indicates that diazotization can only be performed at one amine group at a time. Compared to another synthesis route, which has five reaction steps from mesitylene to methyl tribromobenzene tricarboxylate 5, this route only needs two steps, starting with methylcyanoacetate [8,14].

Click Reactions
Tris-1,2,3-triazoles originating from triazides of type 3 are unknown, except for a single benzotriazole [61] and theoretical investigations [62]. In our hands, the click chemistry that was applied in the case of triazide 3a in a reaction with phenyl ethyne and p-bromophenyl ethyne gave the triazoles 6a-Ph and 6a-C6H4Br, respectively (Table 3). A click reaction with the triazide 3b, containing an ethyl ester instead of the methyl ester of 3a, resulted in triazole 6b-Ph. The yield of 6b-Ph is noticeably better than that of 6a-Ph, which can be explained by the better solubility of the ethyl ester 3b and intermediates on the way to compound 6b-Ph. Substituted alkynes enable different reactions of these molecules, e.g., network building via dialkynes or coupling reactions of the bromo-substituted tristriazole 6a-C6H4Br. Table 3. Syntheses of tris-1,2,3-triazoles 6.

Click Reactions
Tris-1,2,3-triazoles originating from triazides of type 3 are unknown, except for a single benzotriazole [61] and theoretical investigations [62]. In our hands, the click chemistry that was applied in the case of triazide 3a in a reaction with phenyl ethyne and p-bromophenyl ethyne gave the triazoles 6a-Ph and 6a-C 6 H 4 Br, respectively (Table 3). A click reaction with the triazide 3b, containing an ethyl ester instead of the methyl ester of 3a, resulted in triazole 6b-Ph. The yield of 6b-Ph is noticeably better than that of 6a-Ph, which can be explained by the better solubility of the ethyl ester 3b and intermediates on the way to compound 6b-Ph. Substituted alkynes enable different reactions of these molecules, e.g., network building via dialkynes or coupling reactions of the bromo-substituted tristriazole 6a-C 6 H 4 Br. Table 3. Syntheses of tris-1,2,3-triazoles 6.
Tris-1,2,3-triazoles originating from triazides of type 3 are unknown, except for a single benzotriazole [61] and theoretical investigations [62]. In our hands, the click chemistry that was applied in the case of triazide 3a in a reaction with phenyl ethyne and p-bromophenyl ethyne gave the triazoles 6a-Ph and 6a-C6H4Br, respectively (Table 3). A click reaction with the triazide 3b, containing an ethyl ester instead of the methyl ester of 3a, resulted in triazole 6b-Ph. The yield of 6b-Ph is noticeably better than that of 6a-Ph, which can be explained by the better solubility of the ethyl ester 3b and intermediates on the way to compound 6b-Ph. Substituted alkynes enable different reactions of these molecules, e.g., network building via dialkynes or coupling reactions of the bromo-substituted tristriazole 6a-C6H4Br.
Using the stable methyl triamino-benzene-tricarboxylate 2a enabled the study of the total N-alkylation of 1,3,5-triamino benzenes. To investigate the reactivity of the methyl triamino-benzene-tricarboxylate 2a, we used different alkyl iodides. The previously unknown hexa-alkyl-triamines 7a-c were successfully synthesized. Purification via column chromatography gave the alkylated structures 7a-c in yields between 38% and 51% (
Using the stable methyl triamino-benzene-tricarboxylate 2a enabled the study of the total N-alkylation of 1,3,5-triamino benzenes. To investigate the reactivity of the methyl triamino-benzene-tricarboxylate 2a, we used different alkyl iodides. The previously unknown hexa-alkyl-triamines 7a-c were successfully synthesized. Purification via column chromatography gave the alkylated structures 7a-c in yields between 38% and 51% ( Table 4). The reaction was performed at 100 • C and stirred for 16 h in case of 7a and 2d, in case of 7b and 7c. TLC of the crude reaction mixtures showed less alkylated fractions. Nevertheless, longer reaction times could not improve the yields. Table 4. Chemo-selective hexa-N-alkylation of methyl triamino-benzene-tricarboxylate 2a.
Molecules 2022, 27, x FOR PEER REVIEW 6 of 11 4). The reaction was performed at 100 °C and stirred for 16 h in case of 7a and 2d, in case of 7b and 7c. TLC of the crude reaction mixtures showed less alkylated fractions. Nevertheless, longer reaction times could not improve the yields. Table 4. Chemo-selective hexa-N-alkylation of methyl triamino-benzene-tricarboxylate 2a.

Molecular Structures
The structures of the alkyl triamino-benzene-tricarboxylates 2a-c were additionally confirmed by X-ray crystallography. The molecular structures show the possible formation of hydrogen bonds between the amino and ester groups, leading to the expected planar structure of 2. While 2a showed a planar propeller-like arrangement, the sterically more demanding ester groups of 2b and 2c twisted the functional groups marginally out of the plane (Figure 2).

Molecular Structures
The structures of the alkyl triamino-benzene-tricarboxylates 2a-c were additionally confirmed by X-ray crystallography. The molecular structures show the possible formation of hydrogen bonds between the amino and ester groups, leading to the expected planar structure of 2. While 2a showed a planar propeller-like arrangement, the sterically more demanding ester groups of 2b and 2c twisted the functional groups marginally out of the plane (Figure 2).

Molecular Structures
The structures of the alkyl triamino-benzene-tricarboxylates 2a-c were additionally confirmed by X-ray crystallography. The molecular structures show the possible formation of hydrogen bonds between the amino and ester groups, leading to the expected planar structure of 2. While 2a showed a planar propeller-like arrangement, the sterically more demanding ester groups of 2b and 2c twisted the functional groups marginally out of the plane (Figure 2). Beside the triamines 2a-c, the structure of 3a was also confirmed by the molecular structure, but due to the poor crystal quality we will not discuss this further (Figure 3). Beside the triamines 2a-c, the structure of 3a was also confirmed by the molecular structure, but due to the poor crystal quality we will not discuss this further ( Figure 3).

General Procedure for Cyclotrimerizations
A pressure tube was charged with Cu(OAc)2*H2O (0.10 equiv.) and 1,4-dioxane. Alkyl cyanoacetate (1.00 equiv.) was added, and the mixture was bubbled with argon for 5 min. The mixture was heated to 130 °C for 72 h. After cooling to room temperature, the solid was filtered off, and the solvent was removed under reduced pressure. The product was purified by column chromatography (cyclohexane/ethyl acetate).

General Procedure for Cyclotrimerizations
A pressure tube was charged with Cu(OAc) 2 *H 2 O (0.10 equiv.) and 1,4-dioxane. Alkyl cyanoacetate (1.00 equiv.) was added, and the mixture was bubbled with argon for 5 min. The mixture was heated to 130 • C for 72 h. After cooling to room temperature, the solid was filtered off, and the solvent was removed under reduced pressure. The product was purified by column chromatography (cyclohexane/ethyl acetate).

Crystal Structure Determination
The single-crystal X-ray diffraction studies were carried out on a Bruker D8 Venture diffractometer with a PhotonII detector at 123(2) K; 173(2) K; or 298(2) K using Cu-Kα radiation (λ = 1.54178 Å). Dual space methods (SHELXT) [66] were used for the structure solution, and refinement was carried out using SHELXL (full-matrix least-squares on F 2 ) [67]. Hydrogen atoms were localized by difference electron density determination and refined using a riding model (H(N, O) free). Semi-empirical absorption corrections were applied. CCDC 2,102,766 (2a); 2,102,767 (2b); and 2,102,768 (2c) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif (accessed on 12 August 2021). Due to the bad quality of the data of 3a (completeness approx. 82%), the data were not deposited with The Cambridge Crystallographic Data Centre).

NMR Measurements
The NMR spectra were recorded at 25 • C on an BRUKER Avance 400 NMR instrument. More details on the NMR measurements can be found in the Supplementary Information.

Conclusions
Different C 3 -symmetric building blocks based on alkyl triamino-benzene-tricarboxylates have been reported in this manuscript. Despite only moderate yields, the simplicity of the syntheses allowed gram amounts of the alkyl triamino-benzene-tricarboxylates. Starting from the remarkably stable alkyl-triamino-benzene-tricarboxylates, we investigated azide formation and SANDMEYER-like reactions, as well as chemo-selective N-hexa-alkylation. More interestingly, click reactions were possible with the synthesized triazides, allowing further studies on the formation of porous organic polymers (POP). With the triazidobenzenetricarboxylic acid, we have presented a building block that can be used, for example, in a similar way to trimesic acid in the synthesis of MOFs.