KR20070032349A - Click chemistry route to triazole dendrimers - Google Patents

Abstract

High efficiency and high performance click chemistries allow for the production of many different dendrimers, including various functional groups, repeat units and / or cores at the chain end. Nearly quantitative yield is obtained during the synthesis. In some cases, filtration or solvent extraction is the only method needed for purification. This feature represents a significant advance in dendrimer chemistry and demonstrates the evolution of synergy between organic chemistry and functional materials.

Dendrimer, dendron, click chemistry

Description

Click chemistry route to triazole dendrimers

The present invention relates to a dendrimer and a method for producing the same. More particularly, the present invention relates to the use of click chemistry for synthesizing triazole dendrimers.

background:

The unique properties of dendrimers due to their regular structure have recently attracted considerable attention. DA Tomalia, et al., Angew. Chem. 1990, 102, 119-57; Angew. Chem., Int. Ed. 1990, 29, 138; DA Tomalia, HD Durst in Topics in Current Chemistry, Vol. 165 (Eds .: E. Weber), Springer-Verlag, Berlin, 1993; pp. 193-313; F. Zeng, SC Zimmerman Chem. Rev. 1997, 97, 1681-1712; CJ Hawker in Advances in Polymer Science, Vol. 147, Springer-Verlag, Berlin, Heidelberg, Germany, 1999, pp. 113-160; M. Fischer, F. Vogtle Angew. Chem. 1999, 111, 934-955; Angew. Chem., Int. Ed. 1999, 38, 884-905; AW Bosman, et al., Chem. Rev. 1999, 99, 1665-1688; J. -P. Majoral, A.-M. Caminade Chem. Rev. 1999, 99, 845-880; LJ Twyman, et al., Chem. Soc. Rev. 2002, 31, 69-82; JMJ Frechet Proc. Natl. Acad. Sci. USA, 2002, 99, 4782-4787. Many dendritic structures of varying sizes, solubility and functionality have been produced. However, most dendrimer synthesis requires high monomer loads and tedious and long chromatographic separations, especially in the late generation and generates considerable waste. See SM Grayson, JMJ Frechet Chem. Rev. 2001, 101, 3919-3967; JMJ Frechet J. Polym. Sci, Polym. Chem. 2003, 41, 3713-3725]. For example, the synthesis of polyether dendrimers based on sequential Williamson etherification and halogenation has the disadvantages of incompatibility and complex purification with various functional groups. See SC Zimmerman, et al., J. Am. Chem. Soc. 2003, 125, 13504-13518; S. Kimata, et al., J. Polym. Sci., Polym. Chem. 2003, 41, 3524-3530; A. Dahan, M. Portnoy Macromolecules 2003, 36, 1034-1038; EM Harth, et al., J. Am. Chem. Soc. 2002, 124, 3926-3938; FS Precup-Blaga, et al., J. Am. Chem. Soc. 2003, 125, 12953-12960. Surrounding protic functional groups such as -OH, -COOH and -NH ₂ are not suitable for Williamson etherification and halogenation.

Dendrimers have a variety of uses. For example, the recently discovered polydentate 1,4-disubstituted 1,2,3-triazole ligands have the ability to stabilize Cu (I) species even under aqueous aerobic conditions. See TR Chan, et al. , Org. Lett. Submitted] has already proved important in biological use. See, eg, Q. Wang, et al., J. Am. Chem. Soc. 2003, 125, 3192-3193; A. E. Speers, et al., J. Am. Chem. Soc. 2003, 125, 4686-4687; A. J. Link, D. A. Tirrell J. Am. Chem. Soc. 2003, 125, 11164-11165; A. Deiters, et al., J. Am. Chem. Soc. 2003, 125, 11782-11783. Triazole dendrimers can be used for this purpose. Dendrimers can also be used to make porous materials. That is, the dendrimer is mixed with the matrix material, the matrix material is solidified, and the dendrimer is vaporized. To achieve accurate porosity, uniform sized dendrimers should be used. Unfortunately, prior to the present invention, dendrimers of exactly uniform size, i.e., dendrimers of substantially the same size of all dendrimers, have not been produced.

There is a need for a simple process for producing dendrimers with precisely uniform size.

summary:

A very effective route for preparing triazole-based dendrimers is to use click chemistry. This route has the advantage of unprecedented reliability of Cu (I) catalyzed linkages of terminal acetylene and azide. The chemistry is very regioselective, resulting in 1,4-disubstituted triazoles. Various functional groups are suitable for this process and the only major byproduct formed in the reaction is NaCl. All second generation dendrons and some third generation dendrons are separated directly as pure solids (ie no separation by chromatography) while meeting the requirements for large scale applications.

,

,

,

,

및

의 그룹으로부터 선택된다.One aspect of the present invention relates to a method for preparing a product dendron having a single azide group. The method includes a first step of reacting _n organic azide molecules with an AB _n molecule. The AB _n molecule has n terminal acetylene functional groups where n is at least 2 and one halomethyl group. The reaction is carried out in the presence of sufficient copper catalyst to ensure complete reaction to produce a product molecule having n triazoles and one halomethyl group. In the second step of the process, the product molecule of the first step and sufficient sodium azide are dissolved in the organic / aqueous solvent mixture of the chloride of the halomethyl group of the product molecule to produce the product dendron having a single azide group. The reaction is carried out at a high temperature sufficient to cause a complete or nearly complete substitution reaction. In a preferred embodiment, the product dendron is first generation dendron. Preferred organic azides are of the formula

,

,

,

,

And

Is selected from the group of.

,

및

의 그룹으로부터 선택된다.In another preferred embodiment, n is 2. Preferred AB _n molecules are of the formula

,

And

Is selected from the group of.

In another preferred embodiment, the product dendron is a second generation dendron and each of the n organic azide molecules is a first generation dendron. In this case, the first generation dendron may or may not be produced by the method of the present invention. In another preferred embodiment, the product dendron is a third generation dendron and each of the n organic azide molecules is a second generation dendron. In this case, the second generation dendron may or may not be produced by the method of the present invention. In another preferred embodiment, the product dendron is a fourth generation dendron and the n organic azide molecules are each third generation dendron. In this case, third generation dendron may or may not be produced by the method of the present invention.

,

,

및

의 그룹으로부터 선택된다.Another aspect of the invention relates to a process for the preparation of triazole containing dendrimers. The process involves the catalytic amount of copper (I) catalyzing a triazole-forming reaction for dendrimer formation in a suitable solvent with at least two dendrons each having a single azide functional group and a polyacetylene core compound containing at least two terminal acetylene groups. ) Reacting in the presence of the species. Optionally, the method may further comprise washing the product of the first step with an aqueous ammonium hydroxide / citrate solution sufficient to remove copper species that may be bound to the triazole moiety of the dendrimer. In a preferred embodiment of this aspect of the invention, the polyacetylene core is of the formula

,

,

And

Is selected from the group of.

The method can be used to prepare first generation, second generation, third generation, or fourth generation dendrimers, wherein the dendrons are first generation, second generation, third generation, or fourth generation dendrons, respectively.

Another aspect of the invention relates to first generation, second generation, third generation and fourth generation dendrimers prepared according to the above methods.

Another aspect of the invention relates to trifunctional reagents of the formula:

In the above formula,

X is a diradical selected from the group consisting of -O- and -S-,

R is a radical selected from the group consisting of -Cl and -Br,

n is 1 to 10,

m is 1 to 10.

일 수 있다.Preferred embodiments of this aspect of the invention are

Can be.

Another aspect of the invention relates to trifunctional reagents of the formula:

In the above formula,

R is a radical selected from the group consisting of -Cl and -Br,

n is 1 to 10,

m is 1 to 10.

일 수 있다.Preferred embodiments of this aspect of the invention are

Can be.

Another aspect of the invention relates to trifunctional reagents of the formula:

In the above formula,

R is a radical selected from the group consisting of -Cl and -Br,

n is 1 to 10,

m is 1 to 10.

일 수 있다.Preferred embodiments of this aspect of the invention are

Can be.

Another aspect of the invention relates to a core molecule of the formula

In the above formula,

n is 1 to 10.

1 shows an example of a large dendrimer that can be prepared by the method outlined,

FIG. 2 shows copper (I) catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles,

3 shows the reaction sequence in which individual branches or dendrons are constructed starting from the "outside" of the molecule,

4 shows three monomer structures selected for AB ₂ monomers,

5 shows the different monoazides used for the chain ends,

6 shows the NMR spectrum of the product bis-triazole,

FIG. 7 shows crude reaction product MEE-B- [G-4] -N ₃ (9d), MEE-B obtained by dendritic growth from benzyl ether monomer (11) and azido di (ethylene glycol) derivative (19). Shows GPC results for [G-3] -N ₃ (6d) and MEE-B- [G-2] -N ₃ (4d),

8 shows the structure of a polyacetylene core in which a dendron is anchored,

9 shows a representative example of a deadremer obtained by coupling a third generation dendron to a triacetylene core,

10 shows the MALD1-TOF mass spectrum of the dendrimer 7a.

details:

A very effective route for preparing triazole-based dendrimers is the use of click chemistry. This new valid and productively simple route results in a variety of dendritic structures with high purity and good yields (FIG. 1). A unique aspect of this pathway stems from the near perfect reliability of Cu ^I catalyzed synthesis of 1,2,3-triazole from azide and alkyne (FIG. 2) (VV Rostovtsev, et al., Angew. Chem. Int. Ed. 2002, 41, 2596-2599; CW Tornøe, et al., J. Org. Chem. 2002, 67, 3057]. The reaction is experimentally simple, proceeds well in aqueous solution without oxygen protection, requires only stoichiometric amounts of starting material and produces little by-products. Such extensive modifications, high selectivity and near quantitative yields are equally important. The best click response to date [HC Kolb, et al., Angew. Chem. Int. Ed. Although not surprising compared to 2001, 40, 2004-2021, the process involves simple mixing and stirring, where the pure product is separated by filtration or simple extraction.

Frechet's convergent approach is used in the dendrimer synthesis described herein. See C. J. Hawker, J. M. J. Frechet J. Am. Chem. Soc. 1990, 112, 7638-7647. Thus, individual branches or dendrons are created sequentially starting from the "outside" of the molecule. They are then coupled to the multivalent core (“core”) in the final step as shown in FIGS. 3A and 3B to produce various dendrimers with different chain end groups (R) and internal repeat units (X).

When using Cu (I) catalyzed reactions for dendrimer construction, various AB ₂ monomers can be considered based on terminal acetylene and alkyl halide functional groups. Easily available starting materials and simple synthesis strategies for introducing acetylenic groups result in significant structural diversity (FIG. 4). However, one structural feature is retained between the monomers 11, 12 and 13. That is, a single chloromethyl group is present. This is particularly incorporated in the synthetic strategies disclosed herein to facilitate activation of the focus group during dendrimer construction by the convergent growth method. Sodium azide is reacted with a dendritic fragment containing a single chloromethyl group to quantitatively form the desired azidomethyl group and then coupled with 11, 12 or 13 to give the next generation dendron (FIGS. 3A and FIG. 3B). When using AB ₂ monomer units, various chain ends with reactive functional groups of carboxylic acids to alcohols can be used to construct various triazole dendrimers (FIG. 5).

The copper (I) catalyzed reaction of the AB ₂ monomer with the chain end units was carried out at room temperature in the presence of 2-5 mol% CuSO ₄ and 5-10 mol% sodium ascorbate in a 1: 1 mixture of water and tert-butyl alcohol. To yield the desired bis-triazole in near quantitative yield. Trace amounts of copper salts in the product are easily removed by washing with ammonium hydroxide-citrate aqueous buffer. Due to the high efficiency it is possible to use stoichiometric amounts (2.0 equivalents) of azide. When combined with the absence of by-products, purification is greatly simplified. This is in stark contrast to the classic polyether dendrimer synthesis by astringent growth methods which typically use excess dendron (2.05-2.20 equivalents) to increase the yield of next generation dendritic fragments. In addition, purification by flash chromatography is commonly required at each step. See, eg, CJ Hawker, JMJ Frechet J. Am. Chem. Soc. 1990, 112, 7638-7647.

In the next step, the primary chloride is converted to the corresponding azide by reaction with 1.5 equivalents of sodium azide in the acetone / water mixture, which is also easy and usually yields greater than 95%, the only byproduct being NaCl. (The monochloride dendron produced from benzenesulfonamide (13) is converted to the corresponding azide in wet DMF.) The reaction of the dendron with the resulting azide and the initial monomers (11, 12 or 13) "Grow" through. All second generation dendrons are separated as pure white solids by simple filtration or aqueous workup, and second generation azide dendrons are produced in separation yields greater than 90%. As can be seen from the crude ¹ H NMR spectrum of dendron Bn-F- [G-2] -Cl (3b) (FIG. 6), the integral ratio for protons f and c is 2: 1, which is purely heat Compared with the mixture obtained by the process, the regioselectivity is 100%.

According to the same procedure, the amide monomer 12 having tert-butyl azide 17 and the benzyl ether monomer 11 having azide 19 are propagated to the fourth generation according to the same procedure. The monomers 12 having the azide 16 and the azide 19 around them are propagated in three generations, respectively. If the dendrimer is insoluble in the aqueous mixture, the reaction conditions can be slightly modified to achieve the same efficiency and near quantitative yield. For example, benzyl terminal dendrimers made from azide 14 and monomer 11 have been found to be insoluble in 1: 1 H ₂ O / THF solutions in the second generation so that no reaction occurs. Similarly, the conversion of chloromethyl groups to azide groups is not successful with aqueous sodium azide. To overcome this problem, a copper catalyzed reaction is carried out under microwave irradiation with organosoluble Cu (I) species (PPh ₃ ) ₃ CuBr in THF to produce the next generation dendritic fragments in quantitative yield. When substituted with sodium azide in DMF or DMSO, similar results are obtained for azide. Analysis of the dendron by MALDI-TOF mass spectroscopy and GPC does not give signs that the product has defects resulting from incomplete branching (FIG. 7).

Work by Tomalia, Frechet and other researchers demonstrate that the solubility properties of dendritic molecules are governed by their surroundings. See S. M. Grayson, J. M. J. Frechet Chem. Rev. 2001, 101, 3919-3967; J. M. J. Frechet J. Polym. Sci, Polym. Chem. 2003, 41, 3713-3725]. Similarly, observing the dendrimers described herein significantly follows this trend. The unique properties of these triazole-based dendrons become less soluble in ethyl acetate as the molecules reach higher generations and slightly more soluble in dichloromethane, chloroform, alcohol, and surprisingly aqueous mixtures. (In general, the dendrons produced from benzenesulfonamide 13 are less soluble than the dendrons prepared from acetamide 12 in all solvents tested, while incorporation of the azide 19 as a chain substantially reduces the solubility. To increase.)

Finally, some third and fourth generation triazole dendrimers are produced by anchoring these dendrons to various polyacetylene cores (FIG. 8).

A representative example is shown in FIG. 9, in which the 3rd generation dendron tBu-F- [G-3] -N ₃ (6a) is 2,4,6-tris in the presence of a Cu (I) catalyst produced in situ. Direct coupling with prop-2-ynyloxy- [l, 3,5] triazine (23). It is noteworthy that even at these low concentrations (0.06 M in alkyne and azide) the contact reaction proceeds sufficiently fast at room temperature and completes within 30 hours as indicated by LC-MS analysis. Dendrimer 7a (molecular weight 6322 Da) having 24 peripheral units was separated in 92% yield as a white solid. All dendrimers are characterized by ¹ H and ¹³ C NMR and the structure and purity are further confirmed by GPC and MALDI-TOF mass spectroscopy (FIG. 10). High polarity, good alcohol / water mixture solubility and strong UV absorbance at 210 and 229 nm are unique features of this new class of triazole dendrimers.

Detailed description of the drawings

1 shows an example of a large dendrimer that can be prepared by the method outlined. The different R groups shown make the solubility of the resulting dendrimer different.

2 shows a copper (I) catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles. Copper (I) is obtained by in situ reduction of copper (II) species, here from copper sulfate. The reaction proceeds in a water / alcohol solvent mixture at ambient temperature to give nearly quantitative yield of 1,2,3-triazole product.

3A and 3B show the reaction sequence in which individual branches or dendrons are produced starting from the “outside” of the molecule. They are then multivalently coupled to the core or "core" in the final stage. The internal repeat unit is "X" and the chain end group is "R".

4 shows three monomer structures selected for AB ₂ monomers. These are based on terminal acetylene and alkyl halide functional groups. In addition to the diacetylene, the structural feature retained between the three monomers 11, 12 and 13 is a chloromethyl group. Reaction of one chloromethyl group-containing dendritic fragment with sodium azide quantitatively forms azidomethyl groups and then couples with monomers (11, 12 or 13) to give the next generation dendron.

5 shows the different monoazides used for the chain ends. There are reactive end groups and non-reactive end groups for dendrimers. Non-reactive groups have aryl, alkyl and methoxyethoxy ends and reactive end groups have carboxylic acid, benzyl alcohol and protected primary amine functional groups.

6 is an NMR spectrum of the product bis-triazole. The spectrum shows the complete absence of all regioisomers in the product as expected from the thermal cycloaddition reaction. The integral ratio for protons f and c is 2: 1, indicating that only one regioisomer is formed in the cycloaddition reaction. The presence of two signals for both protons f and c is due to the different magnetic environment in the amide binding rotomer.

FIG. 7 shows crude reaction product MEE-B- [G-4] -N ₃ (9d), MEE-B obtained by dendritic growth from benzyl ether monomer (11) and azido di (ethylene glycol) derivative (19). GPC results for [G-3] -N ₃ (6d) and MEE-B- [G-2] -N ₃ (4d). These results do not show any indication that the product has a defect resulting from incomplete branching.

8 shows the structure of a polyacetylene core in which the dendron is anchored.

9 is a representative example of a dendrimer obtained by coupling a third generation dendron to a triacetylene core.

10 is a MALDI-TOF mass spectrum of the dendrimer 7a. This time-of-flight mass spectrum partially substantiates the purity of the product.

Experiment part:

Common way

Commercial reagents from Aldrich were obtained and used without further purification. Deuterated solvents are purchased from Cambridge Isotope Laboratories, Inc. Analytical TLC is performed on a commercially available Merck Plate coated with silica gel GF254 (0.24 mm thick). Silica gel for flash chromatography is Merck Kieselgel 60 (230-400 mesh, ASTM). Record the NMR ( ¹ H, ¹³ C) spectra measured with a Bruker AMX-400, AMX-500 or AMX-600 MHz spectrometer. Coupling constants reported (J) in hertz (Hz) and chemical shift (chemical shift) as an internal reference for the 2.50ppm or DMSO ⁽¹ H (77.2ppm about 7.26ppm and ¹³ C for ¹ H) CHCl ₃ And 39.5 ppm for ¹³ C) or CD ₃ OD (3.31 ppm for ¹ H and 49.0 ppm for ¹³ C) or acetone (2.05 ppm for ¹ H and 29.9 ppm for ¹³ C) Report as (δ). HPLC was prepared on a Dynamax HPLC system using a ZORBAX SB-C18 column (21.2 mm id × 25 cm) using H ₂ O / CH ₃ CN as the eluent and the flow rate was 6.5 ml / min. Tetrahydrofuran (THF) in Waters chromatography equipped with four 5 μm Waters columns (300 mm × 7.7 mm) connected in series to increase pore size (two mixed B, 10 ³ μs, 10 ⁵ μs) Gel permeation chromatography). Waters 410 parallax refractometer and 996 photodiode array detector were used. The molecular weight of the polymer was calculated against linear polystyrene standards. Modulated differential scanning calories (MDSC) are measured using TA Instruments DSC 2920 and a ramp rate of 4 ° C./min. Thermogravimetric measurements are performed at a gradient of 10 ° C./min using a TA Instruments Hi-Res TGA 2950 under a nitrogen purge. 2-chloro-N, N-di (prop-2-ynyl) acetamide (12) (AJ Speziale, PC Hamm, J. Am. Chem. Soc. 1956, 78, 2556-2229); Azide (15) (D. Charon, M. Mondange, JF Pons, K. Le Blay, R. Chaby, Bioorg. Med. Chem., 1998, 6, 755-765), Azide (16) (PG Mattingly) , Synthesis 1990, 366-368), azide 17 (JC Bottaro, PE Penwell, RJ Schmitt, Syn. Comm. 1997, 27, 1465-1467); 1,3,5-tris (prop-2-ynyloxy) benzene (20) (P. Place, R. Pepin ,. in FRXXBL FR 2598408 A1 19871113 FR. 1987), 1,1,1-tris (4 -(Prop-2-ynyloxy) phenyl) ethane (21) (D. O'Krongly, SR Denmeade, MY Chiang, R. Breslow, J. Am. Chem. Soc. 1985, 107, 5544-5545) Prepared according to the reported method.

The names used for the dendritic structures are as follows.

R-X- [G-n] -Y

In the above formula,

R is a peripheral functional group, Bn is benzyl, Boc is tert-butyl ethyl carbamate, tBu is tert-butyl, MEE is (2-methoxyethoxy) ethane,

X is an internal repeating unit, B is 1,3-deoxybenzene, F is formamide, S is benzenesulfonamide,

n is the number of generations,

Y is a functional group at the center and is chloride (Cl) or azide (N ₃ ).

Synthesis of Repeating Units

Methyl 3,5-bis (propargyloxy) benzoate: A stirred solution of methyl 3,5-dihydroxybenzoate (16.8 g, 100 mmol) and propargyl bromide (29.7 g, 220 mmol) in acetone (300 ml) To this was added potassium carbonate (15.1 g, 109 mmol) and 18-crown-6 (0.1 g, 0.4 mmol). The reaction mixture is heated to reflux under nitrogen for 24 hours, filtered and then evaporated to dryness. The crude material is then crystallized in methanol to yield the ester as light yellow crystals (20.6 g, 84.4%). ¹ H NMR (500 MHz, CDCl ₃ ): δ = 2.55 (t, J = 2.4 Hz, C≡CH, 2H), 3.92 (s, CH ₃ O, 3H), 4.73 (d, J = 2.4 Hz, CH ₂ C≡CH, 4H), 6.83 (s, p-Ar, 1H), 7.31 (s, o-Ar, 2H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ = 52.76 (s, CH ₃ O, 1C), 56.51 (s, CH ₂ C≡CH, 1C), 76.38 (s, C≡CH, 1C), 78.34 (s , C≡CH, 1C), 107.91 (s, p-Ar, 1C), 109.27 (s, o-Ar, 2C), 132.54 (s, CCOOCH ₃ , 1C), 158.90 (s, m-Ar, 2C) , 166.86 (s, COOCH ₃ , 1C).

3,5-bis (propargyloxy) benzyl alcohol: A small amount of lithium aluminum hydride (3.99 g, 105 mmol) is added to a stirred solution of ester (20.6 g, 84.4 mmol) in anhydrous THF (170 ml). Beckstrom reagent (25 g) is added to quench the remaining lithium aluminum hydride. The reaction mixture is filtered under vacuum and the solid is washed with dichloromethane and then the filtrate is dried over MgSO ₄ . After evaporation of the solvent, the alcohol is recovered as white crystals (16.4 g, 90.1%). ¹ H NMR (500 MHz, CDCl ₃ ): δ = 2.46 (t, J = 2.4 Hz, C≡CH, 2H), 4.45 (s, CH ₂ OH, 2H), 4.61 (d, J = 2.4 Hz, CH ₂ C≡CH, 4H), 6.46 (s, p-Ar, 1H), 6.56 (s, o-Ar, 2H). ¹³ C NMR (500 MHz, CDCl ₃ ): δ = 56.30 (s, CH ₂ C≡CH, 1C), 65.50 (s, CH ₂ OH, 1C), 76.09 (s, C≡CH, 2C), 78.76 (s , C≡CH, 2C), 101.88 (s, p-Ar, 1C), 106.60 (s, o-Ar, 2C), 143.97 (s, CCH ₂ OH, 1C), 159.23 (s, m-Ar, 2C ).

3,5-bis (propargyloxy) benzyl chloride (11): Pyridine (10.7 g, 136.0 mmol) was added to a stirred solution of alcohol (14.7 g, 68.0 mmol) in dichloromethane (200 ml), and the mixture was poured into an ice bath. Position it. Thionyl chloride (12.1 g, 102 mmol) dissolved in dichloromethane (20 ml) is added dropwise to the reaction mixture and the ice bath is allowed to warm to room temperature. The reaction mixture is stirred for 14 h under Ar and then quenched with water. The organic layer is separated, washed with water (3 x 100 ml), dried over MgSO ₄ , filtered and evaporated to dryness. The crude product is purified by flash chromatography, charged with 1: 1 dichloromethane: hexane and eluting with 2: 1 dichloromethane: hexane, to give the chloromethyl monomer (1) as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ = 2.57 (t, 2H, ≡CH), 4.55 (s, 2H, CH ₂ Cl), 4.73 (d, 4H, CH ₂ O), 6.59 (t, 2H, ArH ), And 6.80 (d, 1H, ArH).

4- (Chloromethyl) -N, N-di (prop-2-ynyl) benzenesulfonamide (13): This compound is prepared using a method analogous to that for monomer (11). ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.15 (t, J = 2.4 Hz, C≡CH, 2H), 4.17 (d, J = 2.4 Hz, CH ₂ C≡CH, 4H), 4.61 (s , CH ₂ Cl, 2H), 7.52 (d, J = 6.4 Hz, Ar-H, 2H), 7.82 (d, J = 6.4 Hz, Ar-H, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 36.4 (s, CH ₂ C≡CH, 2C), 45.1 (s, CH ₂ Cl, 1C), 74.4 (s, C≡CH, 2C), 76.1 ( s, C≡CH, 2C), 129.2 (s, Ar-C, 2C), 129.3 (s, Ar-C, 2C), 138.2 (s, CCH ₂ Cl, 1C), 142.9 (s, CSO ₂ , C ).

Synthesis of monofunctional azide

1-azido-2- (2-methoxyethoxy) ethane (19): 1-bromo-2- (2-methoxyethoxy) ethane (12.4 g, 67.8 mmol) and sodium in water (150 ml) A solution of azide (13.2 g, 203 mmol) is stirred under reflux for 16 h. The aqueous phase is extracted with dichloromethane (2 x 200 ml), dried over MgSO ₄ and evaporated to dryness to afford azide 19 as a colorless oil in 87.3% yield. ¹ H NMR (500 MHz, CDCl ₃ ): δ = 3.29 (s, CH ₃ O, 3H), 3.30 (t, J = 5.2 Hz, CH ₂ N ₃ , 2H), 3.44-3.48 (m, CH ₃ OCH ₂ , 2H), 3.53-3.60 (m, CH ₂ OCH ₂ , 4H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ = 50.89 (s, CH ₂ N ₃ , 1C), 59.27 (s, CH ₃ O, 1C), 70.29 (s, CH ₃ OCH ₂ CH ₂ , 1C), 70.84 (s, CH ₃ OCH ₂ CH ₂ , 1C), 72.21 (s, CH ₂ CH ₂ N ₃ , 1C).

Synthesis of core

Diprop-2-ynyl piperazine-1,4-dicarboxylate (22): 86 mg of piperazine was added to 4 ml of a CH ₂ Cl ₂ solution of propargyl chloroformate (237 mg, ₂ mmol) at 0 ° C., followed by Et ₃ N is added dropwise. The reaction is then stirred at rt for 3 h until LC-MS indicates complete reaction. 5 ml of 10% HCl is added and the separated organic phase is washed with NaHCO ₃ (sat) and brine and then dried over Na ₂ SO ₄ . After evaporation of the solvent, the crude product was purified by flash chromatography (hexane: ethyl acetate 3: 1) to give 220 mg (88) of diprop-2-ynyl piperazine-1,4-dicarboxylate (22) as a white solid. %). ¹ H NMR (600 MHz, [D ₆ ] acetone): δ = 3.03 (t, J = 2.6 Hz, C≡CH, 2H), 3.48 (br, NC ₂ H ₄ N, 8H), 4.72 (d, J = 2.6 Hz, CH ₂ C≡CH, 4H). ¹³ C NMR (150 MHz, [D ₆ ] acetone): δ = 44.3 (s, NC ₂ H ₄ N, 4C), 53.4 (s, CH ₂ C≡CH, 2C), 76.2 (s, CH ₂ C≡ CH, 2C), 79.6 (s, C≡CH, 2C), 154.9 (s, CO, 2C). Melting point 101 to 102 ° C.

2,4,6-tris (prop-2-ynyloxy) -1,3,5-triazine (23): propargyl alcohol (10 ml) was mixed with cyanuric chloride (2.2 g, 12.1 mmol) in 15 ml of THF. ) Is added slowly at room temperature, followed by K ₂ CO ₃ (5.2 g, 36.3 mmol). The reaction is heated at 60 ° C. overnight. The reaction mixture is filtered. After evaporation of the solvent, the residue is dissolved in 80 ml of CH ₂ Cl ₂ and washed with dilute citric acid (10%) and saturated brine. Dry with MgSO ₄ and evaporate to give 2,4,6-tris (prop-2-ynyloxy) -1,3,5-triazine 23 as a white solid in 90% yield. ¹ H NMR (600 MHz, [D ₆ ] acetone): δ = 3.13 (t, J = 2.2 Hz, C≡CH, 3H), 5.10 (d, J = 2.2 Hz, CH ₂ C≡CH, 6H). ¹³ C NMR (150 MHz, [D ₆ ] acetone): δ = 53.4 (s, CH ₂ C≡CH, 3C), 77.3 (s, CH ₂ C≡CH, 3C), 78.4 (s, C≡CH, 3C), 173.5 (s, Ar-C, 3C). Melting point 69-70 ° C.

Representative method (A) for Cu (I) catalyzed triazole linkage reaction: benzyl azide 2-chloro-N, N-di (prop-2-ynyl) acetamide (12) (300 mg, 1.765 mmol) (14) Mix with 470 mg (3.529 mmol, 2.00 equiv). The mixture is mixed with 2 ml of a 1: 1 tBuOH / H ₂ O solution. Sodium ascorbate (35 mg, 0.177 mmol, 0.10 equiv) is added as a solid, followed by CuSO ₄ (22 mg, 0.089 mmol, 0.05 equiv). The reaction is stirred overnight at room temperature. The cloudy white suspension is diluted with 10 ml of H ₂ O and 1 ml of concentrated NH ₄ OH, then stirred for 10 minutes and filtered. The resulting filtrate white powder was washed three times with 10 ml of H ₂ O and dried to give pure Bn-F- [G-1] -Cl (1b) (737 mg, yield 96%),

Representative Method (B) for Cu (I) Catalyzed Triazole Linking Reaction: 300 mg (1.765 mmol) of monomer (12) are mixed with 656 mg (3.529 mmol, 2.00 equiv) of Boc-protected azidoethylamine (16) . The mixture is mixed with 2 ml of a 1: 1 tBuOH / H ₂ O solution. Sodium ascorbate (35 mg, 0.177 mmol, 0.10 equiv) is added as a solid, followed by CuSO ₄ (22 mg, 0.089 mmol, 0.05 equiv). The reaction is stirred overnight at room temperature. The pale yellow mixture is diluted with 10 ml of H ₂ O and 1 ml of concentrated NH ₄ OH, stirred for 10 minutes, and washed three times with 30 ml of EtOAc. The organic layer is washed twice with saturated NaCl, dried over MgSO ₄ and evaporated to give the pure product Boc-F- [G-1] -Cl (1c) (898 mg, 94% yield).

Representative method of converting dendritic chloride to azide: 500 mg (1.36 mmol) of compound (1a) are dissolved in 4 ml of acetone / water (4: 1). NaN ₃ (132 mg, 2.04 mmol, 1.5 equiv) is added and the mixture is heated to 60 ° C. for 1 h. The mixture is cooled to room temperature, the acetone is evaporated, then diluted with 10 ml of H ₂ O and extracted three times with EtOAc. The organic layer is washed with saturated NaCl, dried over MgSO ₄ and evaporated. tBu-F- [G-1] -N ₃ (2a) is obtained as a white solid (490 mg, 96%).

General method for non-aqueous click chemistry catalyzed by Cu (PPh ₃ ) ₃ Br: 3,5-bis (propargyloxy) benzyl chloride (11) (234 mg, 1.00 mmol) in tetrahydrofuran (5 ml), A solution of benzyl azide (4) (266 mg, 2.00 mmol), N, N-diisopropylethylamine (48 mg, 0.37 mmol) and Cu (PPh ₃ ) ₃ Br (55 mg, 0.12 mmol) was treated at 140 ° C. (nominal temperature). In the microwave for 5 minutes. The crude product was purified by filtration through a silica plug eluting with a 9: 1 mixture of dichloromethane and methanol to give Bn-B- [G-1] -Cl (1d) as a colorless oil (477 mg, 95.5%). To obtain. ¹ H NMR (500 MHz, CDCl ₃ ): (= 4.62 (s, CH ₂ Cl, 2H), 5.06 (s, CH ₂ O, 4H), 5.41 (s, CH ₂ N, 4H), 6.67 (s, ArH , 3H), 7.21-7.37 (m, ArH, 10H) and 8.23 (s, ArH, 2H).

General method for nonaqueous synthesis of dendritic azide

A mixture of dendritic chloride (1d) (500 mg, 1.00 mmol) and sodium azide (325 mg, 5.0 mmol) is dissolved in DMSO (5 ml). The reaction is heated at 60 ° C. for 24 h and poured into water (200 ml). The aqueous layer is extracted with CH ₂ Cl ₂ (3 × 50 ml), combined, washed with water (2 × 50 ml), dried over MgSO ₄ and evaporated to dryness. Purification by filtration through a silica plug eluting with 10% MeOH: EtOAc affords pure azidomethyl derivative (2d). Yield: 492 mg, 97.1%. ¹ H NMR (500 MHz, CDCl ₃ ): δ = 4.36 (s, CH ₂ Cl, 2H), 5.03 (s, CH ₂ O, 4H), 5.44 (s, CH ₂ N, 4H), 6.63 (d, ArH , 2H), 6.68 (t, ArH, 1H), 7.22-7.35 (m, ArH, 10H) and 8.21 (s, ArH, 2H).

Bn-F- [G-1] -Cl (1b): ¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.53 (s, 2H), 7.36 (m, 6H), 7.23 (m, 4H), 5.47 ( s, 2H), 5.43 (s, 2H), 4.65 (s, 2H), 4.56 (s, 2H), 4.42 (s, 2H). ¹³ C NMR (125 MHz, CDCl ₃ ): δ = 167.1, 134.4, 129.4, 129.1, 54.5, 43.1, 41.9. Melting point 111-112 ° C.

tBu-F- [G-1] -N ₃ (2a): ¹ H NMR (500 MHz, CDCl ₃ ): δ = 7.72 (s, 1H), 7.70 (s, 1H), 4.66 (s, 2H), 4.59 (s, 2H), 4.35 (s, 2H), 1.66 (s, 9H), 1.65 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ = 163.8, 142.5, 121.9, 120.9, 60.4, 51.6, 43.1, 41.5, 30.6 ppm. % Elemental analysis calculated for C ₁₆ H ₂₆ N ₁₀ O: C, 51.32, H, 7.00, N, 37.41. Found (%): C, 51.21, H, 6.95, N, 36.50. Melting point 113 to 115 ° C.

nF- [G-2] -Cl (3b): ¹ H NMR (500 MHz, [D6] DMSO): δ = 8.24 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.91 ( s, 1H), 7.35 (m, 20H), 5.70 (d, 4H), 5.60 (s, 4H), 5.54 (s, 4H), 4.67 (m, 8H), 4.55 (s, 2H), 4.51 (s , 4H). ¹³ C NMR (125 MHz, [D6] DMSO): δ = 167.1, 144.1, 137.3, 137.2, 130.1, 129.5, 125.3, 125.2, 54.2, 54.1, 52.3, 44.0, 43.1, 42.6, 32.6. MALDI-TOF: 1076 (MNa ⁺ ), PDI: 1.01.

Boc-F- [G-2] -Cl (3c): ¹ H NMR (500 MHz, [D6] acetone): δ = 8.04 (s, 1H), 8.02 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.77 (s, 2H), 6.25 (br, 4H), 5.75 (s, 4H), 4.75 (m, 8H), 4.62 (m, 6H), 4.48 (m, 8H), 3.55 (m, 8 H), 1.37 (s, 36 H). ¹³ C NMR (125 MHz, [D6] acetone): δ = 167.1, 166.9, 166.7, 156.8, 144.2, 143.9, 143.7, 126,2, 124.8, 124.7, 124.5, 79.3, 52.1, 50.7, 50.5, 43.5, 43.3, 42.5, 41.5, 28.7 ppm. MALDI-TOF: 1267 (MH ⁺ ), 1289 (MNa ⁺ ).

tBu-F- [G-2] -N ₃ (4a): ¹ H NMR (500 MHz, [D6] acetone): δ = 8.16 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H) , 7.86 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 5.77 (d, 4H), 4.80 (s, 2H), 4.77 (s, 2H), 4.74 (s, 2H), 4.67 (s, 2H), 4.60 (d, 4H), 4.41 (s, 2H), 1.68 (s, 9H), 1.67 (s, 9H), 1.63 (s, 18H). ¹³ C NMR (125 MHz, [D6] acetone): δ = 168.7, 166.8, 166.6, 144.2, 143.8, 143.7, 143.3, 126.2, 126.1, 121.4, 60.6, 60.1, 59.9, 52.1, 51.2, 42.6, 41.8, 41.5, 30.2 ppm. MALDl-FTMS: MH ⁺ predicted 925.5353, found 925.5368.

tBu-F- [G-3] -N ₃ (6a): ¹ H NMR (600 MHz, [D6] DMSO): δ = 8.29 (d, 4H), 8.17 (d, 2H), 8.14 (s, 1H) , 8.03 (d, 4H), 8.00 (s, 1H), 7.96 (d, 2H), 5.76 (m, 12H), 4.77 (s, 4H), 4.72 (d, 8H), 4.56 (t, 16H), 4.40 (s, 2 H), 1.61 (s, 36 H), 1.57 (s, 36 H). ¹³ C NMR (150 MHz, [D6] acetone): δ = 168.2, 166.6, 166.4, 166.3, 166.2, 143.5, 143.4, 143.3, 143.1, 142.7, 125.8, 120.9, 59.5, 59.3, 51.6, 51.5, 50.6, 42.2, 41.9, 41.4, 40.8, 29.5 ppm, 29.1. MALDI-TOF: 2026 (MH ⁺ ), 2048 (MNa ⁺ ), PDI: 1.005.

Synthesis of Dendrimer (7a): 160.2 mg (0.08 mmol) of tBu-F- [G-3] -N ₃ (6a) was added to 2,4,6-tris-prop-2-ynyloxy- [1,3, 5] Mix with triazine (23) 6.4 mg (0.026 mmol). The mixture is diluted with 0.8 ml of a 1: 1 tBuOH: H ₂ O solution. Sodium ascorbate (3.1 mg, 0.016 mmol, 0.20 equiv) is added as a solid, followed by CuSO ₄ (2 mg, 0.008 mmol, 0.10 equiv). The reaction is stirred at room temperature and the reaction is complete overnight, which is confirmed by LC-MS. The reaction mixture is diluted with 5 ml of H ₂ O and ₁ ml of concentrated NH ₄ OH / citrate buffer, stirred for 2 minutes, and then extracted three times with 30 ml of CHCl ₃ . The organic layer was washed with brine, dried over NaSO ₄ and evaporated to afford a white solid which was pre-HPLC (pump flow gradient setting-solvent CH ₃ CN / H ₂ O; flow rate: 6.5 ml / min, 0 Min, 29% CH ₃ CN; 2 min, 58% CH ₃ CN, 30 min 80% CH ₃ CN) to give 150 mg (90% yield) of pure dendrimer 7a. ¹ H NMR (600 MHz, [D6] DMSO) δ = 8.26 (m, 16H), 8.20 (s, 3H), 8.15 (d, 6H), 8.00 (m, 15H), 7.95 (d, 5H), 5.76 ( m, 44H), 5.51 (s, 6H), 4.74 (m, 44H), 4.55 (m, 44H), 1.59 (dd, 108H), 1.54 (dd, 108H). ¹³ C NMR (150 MHz, [D6] acetone) δ 167.3, 143.9, 143.6, 143.4, 143.1, 126.8, 122.2, 121.9, 119.3, 113.6, 60.7, 60.4, 52.4. 42.7, 41.4, 30.1. MALDI-TOF: Calculated for (C ₂₇₆ H ₃₉₃ N ₁₅₉ O ₂₄ + Na) ⁺ : 6345, Found: 6345 ± 0.1%, PDI: 1.027.

Claims (33)

Sufficient to ensure a complete reaction for producing AB _n molecules having n terminal acetylene functional groups and one halomethyl group and n organic azide molecules to produce a product molecule having n triazoles and one halomethyl group Reacting in the presence of a copper catalyst (A), where n is at least 2 and Complete or near complete substitution of the halomethyl chloride of the product molecule to produce the product dendron having a single azide group in the organic / aqueous solvent mixture with the product molecule of step (A) and sufficient sodium azide A process for producing a product dendron having a single azide group, comprising the step (B) of reacting at a high temperature sufficient to cause a reaction. The method of claim 1 wherein the product dendron is a first generation dendron. The organic azide of claim 2 wherein

,

,

,

,

And

A process for producing a product dendron having a single azide group, selected from the group of: The process of claim 1 wherein n is 2, wherein the product dendron has a single azide group. The process of claim 4, wherein the AB _n molecules of step (A) are

,

And

A process for producing a product dendron having a single azide group, selected from the group of: The method of claim 1, wherein the product dendron is a second generation dendron and each of the n organic azide molecules is a first generation dendron. The method of claim 6, wherein each of the n organic azide molecules is the product dendron of claim 2. The method of claim 1, wherein the product dendron is a third generation dendron and each of the n organic azide molecules is a second generation dendron. The method of claim 8, wherein each of the n organic azide molecules is the product dendron of claim 6. The method of claim 1, wherein the product dendron is a fourth generation dendron and each of the n organic azide molecules is a third generation dendron. The method of claim 10, wherein each of the n organic azide molecules is the product dendron of claim 8. Two or more dendrons each having a single azide functional group to a polyacetylene core compound containing two or more terminal acetylene groups and a catalytic amount of copper (I) species catalyzing the triazole-forming reaction for dendrimer formation in a suitable solvent. A process for producing a triazole-containing dendrimer, comprising the step (A) of reacting in the presence. The tria of claim 12, further comprising the step (B) of washing the product of step (A) with an aqueous ammonium hydroxide / citrate solution sufficient to remove copper species that may be bound to the triazole moiety of the dendrimer. Method for producing a sol-containing dendrimer. 13. The polyacetylene core compound of claim 12, wherein

,

,

And

A process for producing a triazole-containing dendrimer, selected from the group of: The method for producing a first generation dendrimer according to claim 12, wherein the dendron used in step (A) is a first generation dendron. The method for producing a second generation dendrimer according to claim 12, wherein the dendron used in step (A) is a second generation dendron. The method for producing a third generation dendrimer according to claim 12, wherein the dendron used in step (A) is a third generation dendron. A method for producing a fourth generation dendrimer according to claim 12, wherein the dendron used in step (A) is a fourth generation dendron. First-generation dendron produced according to the method of claim 2. Second generation dendron produced according to the method of claim 6. Third generation dendron produced according to the method of claim 8. A fourth generation dendron prepared according to the method of claim 10. A first generation dendrimer prepared according to the method of claim 15. A second generation dendrimer prepared according to the method of claim 16. A third generation dendrimer prepared according to the method of claim 17. A fourth generation dendrimer prepared according to the method of claim 18. Trifunctional reagent of formula

In the above formula, X is a diradical selected from the group consisting of -O- and -S-, R is a radical selected from the group consisting of -Cl and -Br, n is 1 to 10, m is 1 to 10. The chemical formula of claim 27 wherein

Trifunctional reagent. Trifunctional reagent of formula

In the above formula, R is a radical selected from the group consisting of -Cl and -Br, n is 1 to 10, m is 1 to 10. The chemical formula of claim 29 wherein

Trifunctional reagent. Trifunctional reagent of formula

In the above formula, R is a radical selected from the group consisting of -Cl and -Br, n is 1 to 10, m is 1 to 10. 32. The chemical formula of claim 31, wherein

Trifunctional reagent. Core molecule of formula

In the above formula, n is 1 to 10.

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