Method for preparing B (4) site alkylated carborane compound by using olefin as raw material

Abstract

The invention belongs to the field of boron chemistry, and discloses a method for preparing a B (4) site alkylated carborane compound by taking olefin as a raw material. 1-(alpha-carbonyl sulfoxide ylide)-carborane, olefin, silver salt, acetic acid and a rhodium catalyst are placed in a solvent for reaction, and after the reaction is finished, post-treatment is performed to obtain a target compound. According to the invention, commercially available olefin is innovatively used as an alkylation reagent for the first time, and regioselective alkylation of the B (4) site is realized on the premise of retaining a carbon site alpha-carbonyl sulfoxide ylide group. The method is easy and convenient to operate, mild in condition and capable of achieving large-scale production, and a practical and efficient way is provided for preparation of boron-containing compounds such as boron neutron capture therapy drugs.

Description

Technical Field

[0001] This invention belongs to the field of boron chemistry, and specifically relates to a method for preparing B(4) site alkylated carborane compounds from olefins. Background Technology

[0002] Replacing planar benzene rings with rigid three-dimensional bioisosteres (such as adamantane, bicycloalkanes, and cubane) can significantly improve drug properties, representing a promising research direction in medicinal chemistry. Closed carboranes (C2B...) 10 H 12 Boron boranes are the most readily available polyhedral higher boranes, constituting another important class of benzene-ring bioisosteres. Existing literature reports the applications of carboranes in medicinal chemistry, highlighting their enormous potential in the biopharmaceutical field. Benefiting from their high boron content, unique spherical geometry, three-dimensional σ-aromaticity, excellent thermal / chemical stability, and low biotoxicity, carboranes have become a favored framework in medicinal chemistry, functional materials, catalysis, and coordination and organometallic chemistry. In recent years, boron neutron capture therapy (BNCT), as a binary strategy for treating cancer, has received special attention from the scientific and industrial communities. However, the scarcity of existing boron drugs severely restricts the development of BNCT, necessitating the development of new methods for the efficient site-selective functionalization of carboranes.

[0003] Although the functionalization of carbon vertices (CH) in carboranes is relatively well-established, the direct site-selective functionalization of their inert BH bonds (with bond dissociation energies approaching 100 kcal / mol) remains a fundamental challenge. The highly similar reactivity of the ten BH vertices in carboranes makes regioselectivity control extremely difficult. Currently, strategies such as transition metal catalysis, electrophilic / nucleophilic substitution, oxidative coupling, electrocatalysis, and photoredox catalysis have been used to achieve BH bond activation. Among these, transition metal-catalyzed BH bond activation has attracted considerable attention due to its ability to directly construct BC or BX (heteroatom) bonds, thereby rapidly synthesizing novel carborane derivatives. Nevertheless, site-selective monofunctionalization, especially BC(sp...)... 3 The construction of the BH bond remains difficult to achieve due to the ease with which the BH bond undergoes iterative activation (continuous reaction).

[0004] It is noteworthy that in the field of metal catalysis, the development of BH alkylation of carboranes lags far behind its arylation, alkenylation, and alkynylation. Early methods relied on electrophilic all-boron site methylation or the use of ethyl diazonium as a carbene precursor, but typically yielded mixed products ranging from single to triple alkylation. Recent breakthroughs include: B(4,5) dialkylation with allyl alcohol via Rh(III)-catalyzed oxidation of Heck reaction; B(4) acyl methylation using α-carbonyl sulfoxide ylides as alkylating agents; and B(4) acyl methylation or B(3,5) diacyl methylation catalyzed by Ir(III) or Ru(II). Furthermore, B(4) alkylation has also been achieved using Rh(III)-catalyzed unstable α-diazodicarboxylic esters as alkylating agents. Recent literature reports a Rh(II)-catalyzed carbene insertion reaction, using α-aryldiazocarboxylic esters as raw materials to generate B(9)-alkylated carboranes. However, the reaction is accompanied by difficult-to-separate B(8) regioisomer byproducts. Although alkenes are classic Heck coupling agents, in existing metal-catalyzed systems, their reaction with carboranes mainly yields alkenylated (BC(sp...)... 2 Products. To date, the unit-site selective catalysis of BC(sp) with closed carboranes and alkenes has been studied. 3 The coupling reaction has not yet been achieved. Summary of the Invention

[0005] In order to overcome the problems existing in the prior art, this invention, for the first time, uses 1-substituted-α-carbonyl sulfoxide ylide-carborane and olefins as raw materials, and under the action of Rh(III) catalyst, successfully achieves efficient and highly selective synthesis of B(4) site monoalkylated carborane compounds with excellent yield.

[0006] This invention provides a method for preparing B(4) site alkylated carborane compounds from olefins. 1-(α-carbonyl sulfoxide ylide)-carborane a and olefin b are reacted in a solvent with an Rh(III) catalyst and additives via a B(4)-H bond alkylation reaction to generate the B(4) site alkylated carborane compound c. The general reaction formula is as follows:

[0007] Among them, R 1 Selected from alkyl or aryl; R 2 Selected from ester, aryl, or sulfone groups.

[0008] Furthermore, the molar ratio of 1-α-carbonyl sulfoxide ylide-carborane a to olefin b is 1:1.

[0009] Furthermore, the molar ratio of the 1-α-carbonyl sulfoxide ylide-carborane to the catalyst is 1:0.05.

[0010] Furthermore, the Rh(III) catalyst is selected from... .

[0011] Furthermore, the additive comprises at least one of silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, zinc acetate, or sodium acetate, and acetic acid.

[0012] Furthermore, the solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, hexafluoroisopropanol, trifluoroethanol, or ethyl acetate.

[0013] Furthermore, the reaction temperature was 100 °C and the reaction time was 3 h.

[0014] Furthermore, after the reaction was completed, the mixture was cooled to room temperature, the solvent was removed to obtain the crude product, and then the crude product was separated by column chromatography using a mixed solvent of dichloromethane and ethyl acetate as the eluent.

[0015] The present invention also provides a B(4) site alkylated carborane compound prepared by the above method using olefins as raw materials.

[0016] Beneficial Effects: This invention is the first to propose a method for achieving highly regioselective monoalkylation in one step using 1-(α-carbonyl sulfoxide ylide)-carborane and olefins as raw materials, under the action of Rh(III) catalyst, through α-carbonyl sulfoxide ylide-guided B(4)-H activation. Its advantage lies in the direct construction of BC(sp) from inexpensive olefins. 3 The α-carbonyl sulfoxide ylide bond breaks through the traditional B-alkenylation limitation; it has both directing and convertible group functions, and can precisely control the selectivity of B(4) site; the reaction conditions are mild (100℃, 3 h), the operation is simple, and it can be produced on a large scale. Detailed Implementation

[0017] The present invention will now be described in detail with reference to the embodiments.

[0018] A method for preparing B(4) site alkylated carborane compounds containing α-carbonyl sulfoxide ylide substituents at carbon sites of the carborane skeleton. The method includes: reacting 1-(α-carbonyl sulfoxide ylide)-carborane, an alkene, a silver salt, acetic acid, and other additives and a rhodium catalyst in a solvent; and obtaining the target compound after post-treatment after the reaction. This invention innovatively uses commercially available alkenes as alkylating agents for the first time, achieving regioselective alkylation of the B(4) site while retaining the α-carbonyl sulfoxide ylide group at the carbon site.

[0019] Example 1: Optimization of Reaction Conditions Using compound a1 and ethyl acrylate b1 as templates, the reaction conditions were optimized, as shown in the table below:

[0020]

[0021] 1a (0.1 mmol), 2a (0.10 mmol), catalyst (5 mol%), additives, solvent (1.0 mL).

[0022] Based on this, the optimal conditions for synthesis 1 were determined by optimizing the feed ratio: a1 (1.0 equiv), b1 (1.0 equiv). (5 mol%), AgSbF6 (20 mol%), and HOAc (100 mol%) were reacted in hexafluoroisopropanol (0.1 M) at 100 °C for 3 hours, with an NMR yield of 88% and a separation yield of 86%. 1 H NMR (600 MHz, Chloroform- d ) δ 7.66 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.7 Hz,2H), 4.69 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.50– 2.34 (m, 2H), 1.35 – 1.18 (m, 5H). 13 C{ 1 H} NMR (151 MHz, Chloroform- d ) δ174.9, 168.7, 131.5, 130.9, 130.2, 128.3, 83.9, 83.2, 74.4, 60.3, 41.3, 41.2,33.4, 14.4, 10.5. HRMS (ESI) Calcd for C 17 B 10 H 31 O4S [M+H + ]: 439.2949, Found:439.2949. Example 2

[0023]

[0024] The method for preparing B(4) site monoalkylated carborane compounds using the reaction conditions of Example 1, No. 10: 1-α-carbonyl sulfoxide ylidene 2-phenyl-carborane a1 (0.1 mmol) and ethyl acrylate b2 (0.10 mmol) were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100 o After reacting at C for 3 h and undergoing post-processing, the target product 2 was obtained with a yield of 72%. 1 H NMR (600MHz, Chloroform- d ) δ 7.65 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.29(t, J = 7.7 Hz, 2H), 4.68 (s, 1H), 3.63 (s, 3H), 3.13 (s, 3H), 2.97 (s, 3H), 2.51 – 2.34 (m, 2H), 1.35 – 1.17 (m, 2H). 13 C{ 1 H} NMR (151 MHz, Chloroform- d )δ 175.4, 168.8, 131.5, 131.0, 130.2, 128.3, 83.9, 83.2, 77.4, 76.9, 74.3,51.6, 41.4, 41.3, 33.2, 10.6. HRMS (ESI) Calcd for C 16 B 10 H 29 O4S [M+H + ]:425.2792, Found: 425.2792. Example 3

[0025]

[0026] The method for preparing B(4) site monoalkylated carborane compounds according to Example 2 was as follows: a1 (0.1 mmol) and benzyl acrylate b3 (0.1 mmol) were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100o After reacting at C for 3 h and undergoing post-processing, the target product 3 was obtained with a yield of 65%. 1 H NMR (600 MHz, Chloroform- d ) δ 7.65 (d, J = 7.9 Hz,2H), 7.39 – 7.27 (m, 8H), 5.08 (s, 2H), 4.67 (s, 1H), 3.05 (s, 3H), 2.93 (s,3H), 2.56 – 2.41 (m, 2H), 1.30 (m, 2H). 13 C{ 1 H} NMR (151 MHz, Chloroform- d ) δ174.6, 168.7, 136.3, 131.5, 130.9, 130.2, 128.7, 128.4, 128.28, 128.26, 83.9,83.2, 74.3, 66.3, 41.22, 41.19, 33.5, 10.6. HRMS (ESI) Calcd for C 22 B 10 H 33 O4S[M+H + ]: 502.3079, Found: 502.3079. Example 4

[0027]

[0028] The method for preparing B(4) site monoalkylated carborane compounds according to Example 2 was as follows: a1 (0.1 mmol) and acrylate b4 (0.15 mmol) were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100 o After reacting at C for 3 h and undergoing post-processing, the target product 4 was obtained with a yield of 82%. 1 H NMR (600 MHz, Chloroform- d ) δ 7.68 – 7.62 (m, 2H), 7.38 – 7.34 (m, 1H), 7.33 – 7.27 (m, 4H), 7.25 – 7.19 (m, 3H), 4.67 (s, 1H), 4.26 (td, J= 7.1, 1.0 Hz, 2H), 3.08 (s, 3H), 2.95 (s, 3H), 2.93 (t, J = 7.1Hz, 2H), 2.50 – 2.34 (m, 2H), 1.32 – 1.18 (m, 2H). 13 C{ 1 H} NMR (151 MHz, Chloroform- d ) δ 174.8, 168.8, 138.0, 131.5, 130.9, 130.2, 129.0,128.6,128.3,126.6, 83.9, 83.2, 74.3, 64.9, 41.3, 41.2, 35.2, 33.4, 10.5. HRMS (ESI) Calcdfor C 22 B 10 H 35 O4S [M+H + ]: 522.3236, Found: 522.3240. Example 5

[0029] The method for preparing B(4) site monoalkylated carborane compounds according to Examples 2-4 was as follows: 0.1 mmol of a1 and 0.1 mmol of other olefins were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100 o After reacting at C for 3 h and undergoing post-processing, the target product 5-27 was obtained, as shown below.

[0030]

[0031] Example 6 The method for preparing B(4) site monoalkylated carborane compounds according to Examples 2-5: 0.1 mmol of the 1-α-carbonyl sulfoxide ylide-carborane a and b1 were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100 o After reacting at C for 3 h and undergoing post-processing, the target product (26-32) was obtained, as shown below.

[0032]

[0033] Example 7 The method for preparing B(4) site monoalkylated carborane compounds according to Examples 2-6: 0.1 mmol of a1 and α-carbonyl sulfoxide ylide b derived from drug molecules or bioactive molecules were added to hexafluoroisopropanol (1.0 mL), followed by the addition of AgSbF6 (0.02 mmol). (0.005 mmol) and acetic acid (0.1 mmol), under a nitrogen atmosphere, 100 o After reacting at C for 3 h and undergoing post-processing, the target product (33-36) was obtained, as shown below.

[0034]

[0035] Example 8: Derivatization and Application Subsequent derivatization of B(4)-site monoalkylated carboranes was performed to synthesize BNCT potential compounds. The method for preparing B(4)-site monoalkylated carborane compounds in Examples 2-6 was scaled up tenfold, yielding product 1 with a separation yield of 78%. Given the importance of amides in pharmaceuticals, biochemistry, and materials science, amide 37 was successfully synthesized from 1 and NaNH2BH3 with a separation yield of 60%. Based on this, a metal-free intermolecular dehydrogenation NN coupling reaction was used to target bioactive hydrazine compounds. Late modification of the bioactive amino acid was achieved using Lewis basic L-alanine ethyl ester, yielding carborane hydrazine product 38 with a separation yield of 71%.

[0036]

[0037] The above embodiments are merely specific implementations listed to facilitate understanding of the technical solutions of the present invention by those skilled in the art, and are not intended to limit the present invention. Those skilled in the art can make reasonable modifications or adjustments to the embodiments without departing from the essence of the present invention, and can also apply the principles of the present invention to other technical scenarios. All equivalent substitutions, process parameter optimizations, or application extensions made based on the technical concept of the present invention are within the protection scope of the present invention.

Claims

1. A method for preparing B(4) site alkylated carborane compounds from olefins, characterized in that, 1-(α-carbonyl sulfoxide ylide)-carborane a and alkene b, in the presence of Rh(III) catalyst and additives, undergo a B(4)-H bond alkylation reaction in a solvent to generate the B(4) site alkylated carborane compound c; the general reaction formula is as follows: ； Among them, R 1 Selected from alkyl or aryl; R 2 Selected from ester, aryl, or sulfone groups.

2. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 1, characterized in that, The molar ratio of 1-α-carbonyl sulfoxide ylide-carborane a to olefin b is 1:

1.

3. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 2, characterized in that, The molar ratio of 1-α-carbonyl sulfoxide ylide-carborane to catalyst is 1:0.

05.

4. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 3, characterized in that, The Rh(III) catalyst is selected from .

5. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 4, characterized in that, The additive comprises at least one of silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, zinc acetate, or sodium acetate, and acetic acid.

6. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 5, characterized in that, The solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, hexafluoroisopropanol, trifluoroethanol, or ethyl acetate.

7. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 6, characterized in that, The reaction temperature was 100 ℃ and the reaction time was 3 h.

8. The method for preparing B(4) site alkylated carborane compounds from olefins as described in claim 7, characterized in that, After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed to obtain the crude product, and then the crude product was separated by column chromatography using a mixed solvent of dichloromethane and ethyl acetate as the eluent.

9. A method for preparing B(4) site alkylated carborane compounds from olefins, characterized in that, It is prepared by the method described in any one of claims 1-7.

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