CN113087714B - Axial chiral aryl indole carbazole derivative and preparation method and application thereof - Google Patents
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Abstract
The invention provides an axial chiral aryl indole carbazole derivative and a preparation method thereof, wherein the axial chiral aryl indole carbazole derivative has a structure shown in a formula I, the axial chiral aryl indole carbazole derivative has high yield and excellent enantioselectivity, and the axial chiral aryl indole carbazole derivative is selectively synthesized through an N-H insertion reaction shaft between Rh (II) catalytic molecules, so that a research basis is provided for the late functional speech derivatization, novel materials, novel drug development and novel phosphoric acid catalyst development based on the framework.
Description
Technical Field
The invention belongs to the technical field of biological medicine synthesis, and relates to an axial chiral aryl indole carbazole derivative, a preparation method and application thereof.
Background
Atropisomerism is a prominent chiral structural element that is generated by limited rotation of single bonds and is prevalent in many natural products, drugs, chiral ligands and catalysts. Thus, the attractive properties and synthetic pathways of atropisomers have attracted considerable attention from chemical, pharmaceutical and material scientists worldwide. Over the past several decades, great progress has been made in the construction of various axial chiral scaffolds, particularly in the synthesis of biaryl and styrene containing the C-C axis. In addition to classical cross-coupling of two aryl structures, a number of novel and compact strategies have been demonstrated to be available for these atropisomers, including resynthesis of aryl groups, point-to-axis chiral transfer, (dynamic) kinetic resolution, ring opening strategies, and the like. In sharp contrast, although ubiquitous in natural products, and axial-to-point chiral transfer has been demonstrated as a ligand for heteroaryl groups with a C-N axis, its selective structure is still rare. The major obstacle may result from the presence of significant antagonism between (1) the low-fold stability of the C-N bond and the harsh reaction conditions typically required in various couplings; (2) The site selectivity of the more reactive C-H bond in competitive insertion makes regional and enantiomer control more challenging.
With such an attractive and challenging goal, researchers have completed an initial discovery of N-aryl indoles about the axial chiral C-N axis that are newly synthesized by Pd-catalyzed indole ring. Dynamic kinetic resolution and de novo aryl synthesis then gradually become ideal schemes for directly constructing the N-C axial chirality. In sharp contrast, however, transition metal-catalyzed C-N coupling reactions, such as the Ullmann and Buchwald-Huffman reactions, remain the benchmark schemes for constructing C-N bonds due to the broad range of substrates and the lack of preactivation. In 2012, studies have demonstrated the construction of racemic arylcarbazole by photoinduced ullmann C-N radical coupling of aryl halides and carbazole. To achieve atrophic isophthaloyl groups with the C-N axis, colobert laboratories disclosed a first axially selective Ullman synthesis of N-aryl indoles with C-N axis chirality by C-N coupling of highly active o-sulfoxide iodides with indoles. More recently, tan laboratories have disclosed a first organic catalytic strategy for the construction of new axial chiral n-aryl carbon azole scaffolds by chiral phosphoric acid catalyzed atropine-selective aromatic hydrocarbon C-H amination. Indole [2,3-a ] carbazol is a high affinity ligand and has become a key component in the development of new anticancer, antifungal, antibacterial and antihypertensive agents. The known components of the indolocarbazole alkaloid include staurosporine, lei Beika mycin, ji Pana azole, K252a and the like. The novel indole carbazole Libemycamycin can generate DNA single-strand break, thereby inhibiting the growth of human lung adenocarcinoma cells. Wherein, after the indole N-H proton is replaced by alkyl, the DNA interaction is obviously reduced, which indicates that the H bond between the indole N-H proton and the pyranose oxygen plays a crucial role. In addition, its derivative phthalate is a potent DNA intercalator, and has entered clinical trials for the treatment of various cancers. Inspired by the high affinity inherent to indolocarbazoles as ligands, we contemplate that the introduction of an additional N-H bond indolocarbazole on the azabiaryl scaffold can effectively bind hydrogen bond receptors and ultimately improve the enantiostimulation of chiral ligands.
Carbene insertion strategies are one of the general and promising ways to construct complex scaffolds. Unlike traditional, generic C-H functionalization, it uses a few simple substrates and catalysts that can generate enough reaction intermediates in situ to distinguish between many different C-H bonds, resulting in functional group independent regioselectivity and stereoselectivity. Notably, the Davise laboratory designed a series of highly efficient disodium tetracarboxylic acids to promote site-selective and stereoselective hydrocarbon insertion chemistry of various diazonium compounds. In recent years, numerous researchers have made tremendous progress in the insertion of highly enantioselective carbenes to the copper or rhodium complex catalyzed N-H, si-H, O-H bond. However, the axially selective synthesis involving carbene insertion processes is still neglected.
Accordingly, it is desirable in the art to develop an axially selective aryl indolocarbazole derivative and a method for preparing the same.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an axial chiral aryl indole carbazole derivative, and a preparation method and application thereof. The axial chiral aryl indole carbazole derivative has high yield and excellent enantiomer selectivity, and the axial chiral aryl indole carbazole derivative is selectively synthesized through an Rh (II) catalysis intermolecular N-H insertion reaction shaft, so that a research basis is provided for late functional speech derivatization, novel materials, novel drug development and development of novel phosphoric acid catalysts based on the framework.
To achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides an axial chiral arylindolocarbazole derivative, which has a structure shown in the following formula I:
wherein M is
R、R 3 、R 4 、R 5 And R is 6 Independently an electron withdrawing group or an electron donating group; r is R 1 And R is 2 Is hydrogen or R 1 And R is 2 A connection is formed into an aromatic ring or an aromatic heterocyclic ring; x is nitrogen or oxygen, L1 is hydrogen or benzyl, L 2 Is hydrogen, benzyl or
The electron withdrawing group is halogen or ester group;
preferably, the electron donating group is an alkyl or alkoxy group.
In the invention, as a preferable technical scheme, the axial chiral aryl indole carbazole derivative has a structure shown in the following formulas I-1 to I-1:
in the invention, the axial chiral aryl indole carbazole derivative is any one of the following compounds:
in another aspect, the present invention provides a method for preparing the axial chiral aryl indolocarbazole derivative as described above, wherein the method comprises the following steps:
when L2 is hydrogen, the compound of formula II-1 or the compound of formula II-2 or the compound of formula II-3 or the compound of formula II-4 and the compound of formula III are used for cross coupling reaction to prepare the axial chiral aryl indole carbazole derivative shown in formula I;
when L2 is not hydrogen, the compound of formula II-1 or the compound of formula II-2 or the compound of formula II-3 or the compound of formula II-4 is used for cross-coupling reaction with the compound of formula III, or the product is obtained by directly reacting the compound of formula III with halogenated compound under the condition of strong alkali.
Preferably, the molar ratio of the compound of formula II-1 or formula II-2 or formula II-3 or formula II-4 (diazonaphthoquinone derivative) to the compound of formula III (indolone [2,3-a ] carbazole derivative) is from 1:1 to 1:1.5, e.g. 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, etc.
Preferably, the cross-coupling reaction is carried out in the presence of a catalyst, preferably tetrakis [ (S) - (+) -1-adamantyl) - (N-phthalimido) acetate]Rhodium (II) (Rh) 2 (S-PTAD) 4 )。
Preferably, the catalyst is used in an amount of 1 to 3% by mass of the compound of formula II-1 or of the compound of formula II-2 or of the compound of formula II-3 or of the compound of formula II-4.
Preferably, the solvent of the cross-coupling reaction is chloroform or toluene.
Preferably, the halide is bromobenzyl.
Preferably, the temperature of the cross-coupling reaction is room temperature.
Preferably, the time of the cross-coupling reaction is from 6 to 18 hours, for example 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours or 18 hours.
The preparation method is simple and efficient, and can be used for industrially producing the chiral aryl indole carbazole derivative with high efficiency and high quality.
In another aspect, the invention provides the use of an axial chiral arylindolocarbazole derivative as described above for post-functionalization in biomolecules or as an organic optoelectronic material.
Compared with the prior art, the invention has the following beneficial effects:
the axial chiral aryl indole carbazole derivative has high yield and excellent enantiomer selectivity, is synthesized through the N-H insertion reaction shaft selectivity among Rh (II) catalytic molecules, has the characteristics of excellent enantiomer selectivity and high yield compared with the existing preparation method of the axial chiral aryl indole carbazole derivative, and is suitable for rapid mass production. The preparation method of the compound provides a research foundation for drug development and asymmetric synthesis of key chiral organic catalysts.
To verify the synthetic use of this Rh (II) -catalyzed N-H insertion process, we successfully achieved gram-grade 3da synthesis, resulting in high conversion, moderate yield and excellent swing selectivity. In addition, post-functionalization of natural products and bioactive molecules has been explored. The novel antifungal potential antitumor drug tjinanazole I is derived through N-H insertion reaction 20 A mixture of axially chiral N-naphthalocyanine carbazole 6 was obtained (yields 50%,97% and 98% ee). In addition, N-protected Arcyriafilavin A7 is also suitable for this conversion, giving a structure of enantiomer 8 with a yield of 51% and 98% ee. In addition, the late functionalization of the biologically active benzofurancarbazoles proceeds smoothly with a pronounced enantioselectivity, despite a slightly pronounced decrease in yield.
The axial chiral aryl indole carbazole derivative provided by the invention can be used as a main material of OLEDs due to a large conjugated system. Under the standard reaction condition, only a trace amount of corresponding polyaromatic N-aryl indolocarbazole can be obtained by taking diazodione 1t as a substrate. With Rh 2 (OAc) 4 Substituted chiral Rh 2 (S-PTAD) 2 The desired high yield of the racemic product can be obtained. In addition, the double protection strategy opens up a new way for the direct and efficient construction of attractive polyaromatic molecules (14,89%).
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1: synthesis of 3aa
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was cross-coupled at room temperature for 6h, after which the solvent was distilled off by spinning to give 3aa as a pale yellow solid with a yield of 68% and an enantioselectivity of 99%.
1 H NMR(600MHz,CDCl 3 ):δ＝8.24(d,J＝7.8Hz,1H),8.16(d,J＝7.7Hz,1H),8.07–8.03(m,2H),7.75–7.70(m,4H),7.75–7.70(m,1H),7.52(s,broad,1H),7.43–7.42(m,2H),7.40–7.33(m,3H),7.27–7.24(m,2H). 13 C NMR(151MHz,CDCl 3 ):δ＝141.24,139.09,138.91,130.59,128.95,128.29,126.79,125.66,125.54,125.43,125.06,124.29,122.76,121.98,120.76,120.54,120.42,120.21,113.17,112.82,111.27,110.11.HRMS(ESI):calcd for C 28 H 19 ON 2 [M+H] + :399.1492,found 399.1487。
Note that: 1 H-NMR 13 C-NMR testing was performed by nuclear magnetic resonance spectroscopy (Avance II 400MHz,600 MHz); HRMS is performed by electrospray mass spectrometer (ESI) detection; HPLC was performed by Shimadzu (Shimadzu) LC-20AD detection.
Example 2: synthesis of 3ba
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was cross-coupled at room temperature for 6h, and after completion of the reaction the solvent was distilled off in a spin to give 3ba as a pale yellow solid with 62% yield and 98% enantioselectivity.
1 H NMR(600MHz,CDCl 3 ):δ＝8.31–8.28(m,1H),8.11(dd,J＝7.9,2.3Hz,2H),8.03(d,J＝8.3Hz,1H),7.89(d,J＝8.2Hz,1H),7.48(s,1H),7.42–7.40(m,1H),7.37–7.34(m,2H),7.28–7.26(m,1H),7.23–7.16(m,4H),7.12(d,J＝8.1Hz,1H),7.04–7.03(m,4H),6.14(s,1H),4.35–4.27(m,2H),2.03–1.98(m,2H),1.14(t,J＝7.4Hz,3H). 13 C NMR(151MHz,CDCl 3 ):δ＝147.14,144.81,141.33,139.26,128.90,128.10,127.86,127.52,126.37,125.97,125.78,125.59,125.22,125.12,124.39,122.68,122.54,122.02,120.68,120.60,120.38,120.00,117.33,113.05,112.99,111.20,110.63,108.40,71.38,22.87,11.02.HRMS(ESI):calcd for C 31 H 25 O 2 N 2 [M+H] + :457.1911,found 457.1908。
HPLC: chiralpak IE; mobile phase (n-hexane/EtOH), 1.0mL/min; t is t R (major)＝42.36min,t R (minor)＝49.33min。
[α] D 21 ＝151.2(c＝0.067,CHCl 3 )。
Example 3: synthesis of 3ea
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was cross-coupled at room temperature for 12h, after which the solvent was distilled off by spinning to give 3ea as a pale yellow solid with a yield of 60% and an enantioselectivity of 98%.
1 H NMR(600MHz,CDCl 3 ):δ＝9.22(d,J＝9.6Hz,1H),8.27(d,J＝7.5Hz,1H),8.10–8.02(m,1H),7.67(d,J＝9.6Hz,1H),7.40–7.35(m,1H),7.30–7.28(m,1H),7.22–7.16(m,1H),7.01(d,J＝8.5Hz,1H),6.97(dd,J＝7.0,1.1Hz,1H),5.98(s,broad,1H),4.52(q,J＝7.1Hz,2H),1.49(t,J＝7.2Hz,3H). 13 C NMR(151MHz,CDCl 3 ):δ＝168.04,152.76,141.17,139.35,133.53,130.18,128.96,128.76,127.65,127.60,127.38,126.93,126.24,125.74,125.51,124.06,123.03,122.28,121.60,120.82,120.36,120.31,119.97,116.94,113.97,112.92,111.58,110.51,61.97,14.87.HRMS(ESI):calcd for C 31 H 23 O 3 N 2 [M+H] + 471.1703, found471.1700.HPLC: chiralpak IE; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (major)＝26.43min,t R (minor)＝29.11min。
[α] D 21 ＝126.6(c＝0.067,CHCl 3 )。
Example 4: synthesis of 3ga
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was cross-coupled at room temperature for 10h, and after completion of the reaction the solvent was distilled off in a spin to give 3ga as a pale yellow solid with 71% yield and 98% enantioselectivity.
1 H NMR(600MHz,CDCl 3 ):δ＝8.28–8.27(m,1H),8.10–8.03(m,4H),7.74(s,1H),7.51(d,J＝9.0Hz,1H),7.38–7.36(m,2H),7.28–7.27(m,1H),7.22–7.12(m,3H),7.02(dd,J＝6.7,1.9Hz,2H),6.77(d,J＝8.6Hz,1H),5.71(s,1H),2.43(s,3H). 13 C NMR(151MHz,CDCl 3 ):δ＝151.77,141.14,139.33,134.88,131.43,130.98,130.82,130.04,127.97,127.46,126.12,125.86,125.56,125.46,124.13,122.87,122.22,122.04,121.40,120.75,120.39,120.19,118.27,116.66,113.78,112.87,111.44,110.60,21.81.HRMS(ESI):calcd for C 29 H 21 ON 2 [M+H] + :413.1648,found 413.1643。
HPLC: chiralpak IE; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (major)＝41.73min,t R (minor)＝44.79min。
[α] D 21 ＝171.4(c＝0.067,CHCl 3 )。
Example 5: synthesis of 3qa
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was cross-coupled at room temperature for 10h, and after completion of the reaction the solvent was distilled off by spin to give 3qa as a pale yellow solid with 55% yield and 75% enantioselectivity.
1 H NMR(600MHz,CDCl 3 ):δ＝8.28–8.27(m,1H),8.12–8.04(m,4H),7.84(d,J＝8.7Hz,1H),7.54(d,J＝9.0Hz,1H),7.48(dd,J＝8.7,1.8Hz,1H),7.40–7.38(m,2H),7.31–7.29(m,1H),7.24–7.21(m,1H),7.16–7.10(m,3H),6.99–6.98(m,1H),5.81(s,1H). 13 C NMR(151MHz,CDCl 3 ):δ＝153.49,140.86,139.33,134.08,132.13,130.61,128.90,128.21,126.92,126.30,125.71,125.68,125.51,124.27,124.17,123.67,123.09,122.37,121.64,120.90,120.47,120.35,118.81,116.00,114.03,113.02,111.42,110.40.HRMS(ESI):calcd for C 28 H 18 ON 2 Br[M+H] + :477.0597,found 477.0594。
HPLC: chiralpak IE; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝25.80min,t R (major)＝28.30min.
[α] D 21 ＝168.8(c＝0.067,CHCl 3 )。
Example 6: synthesis of 3ra
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone derivatives (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole (0.15 mmol,1.5 equivalent) was subjected to cross-coupling reaction at room temperature for 6h, and after completion of the reaction, the solvent was distilled off by spin to give 3ra as a pale yellow solid with 67% yield, and enantioselectivity94％。
1 H NMR(600MHz,CDCl 3 ):δ＝8.94(d,J＝8.4Hz,1H),8.83(d,J＝8.3Hz,1H),8.64(d,J＝8.0Hz,1H),8.37(d,J＝7.7Hz,1H),8.19–8.13(m,3H),7.99–7.97(m,1H),7.88(t,J＝7.5Hz,1H),7.57(t,J＝7.5Hz,1H),7.46–7.42(m,3H),7.32–7.26(m,3H),7.15–7.13(m,2H),6.89(d,J＝8.2Hz,1H),6.50(s,1H).
13 C NMR(151MHz,CDCl 3 ):δ＝149.32,141.15,139.37,132.24,130.78,129.26,128.74,127.72,127.62,127.17,126.17,125.96,125.84,125.56,125.28,124.62,124.09,123.49,123.42,122.94,122.76,122.35,121.53,120.76,120.32,120.17,113.89,113.22,112.88,111.52,110.73.HRMS(ESI):calcd for C 32 H 21 ON 2 [M+H] + :449.1648,found 449.16456。
HPLC: chiralpak IC; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝11.47min,t R (major)＝20.82min。
[α]D21＝150.2(c＝0.05,CHCl 3 )。
Example 7: synthesis of 3ab
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole derivative (0.15 mmol,1.5 equivalent) was subjected to cross-coupling reaction at room temperature for 5h, and after the reaction was completed, the solvent was distilled off by spin to give 3ab as a pale yellow solid with a yield of 72% and an enantioselectivity of 96%.
1 H NMR(600MHz,CDCl 3 ):δ＝8.12(d,J＝9.0Hz,1H),8.07(s,1H),8.03(d,J＝8.5Hz,1H),7.99–7.95(m,2H),7.88(s,1H),7.55(d,J＝9.0Hz,1H),7.38–7.35(m,1H),7.19–7.17(m,2H),7.10–7.08(m,1H),7.02–7.00(m,1H),6.91(d,J＝8.2Hz,1H),6.86(d,J＝8.5Hz,1H),5.63(s,1H),2.59(s,3H),2.49(s,3H). 13 CNMR(151MHz,CDCl 3 ):δ＝152.45,139.39,137.59,132.73,132.03,130.97,129.78,129.54,128.89,128.73,127.67,127.40,126.97,126.17,125.76,125.15,124.32,122.67,122.23,122.04,120.74,120.24,118.18,116.93,113.65,112.66,111.05,110.28,22.03,21.93.HRMS(ESI):calcd for C 30 H 23 ON 2 [M+H] + :427.1804,found 427.1803。
HPLC: chiralpak IA; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (major)＝32.54min,t R (minor)＝53.43min。
[α] D 21 ＝159.6(c＝0.067,CHCl 3 )。
Example 8: synthesis of 3ah
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]The carbazole derivative (0.15 mmol,1.5 equivalent) was subjected to a cross-coupling reaction at room temperature for 6h, after which the solvent was distilled off by spinning to give 3ah as a pale yellow solid with a yield of 74%, an enantioselectivity of 94% and a site-selective ratio of 3:2.
1 H NMR(600MHz,CDCl 3 )(mixture):δ＝8.26(d,J＝7.4Hz,1H),8.13–7.96(m,9H),7.89(s,1H),7.55(d,J＝9.0Hz,1H),7.39–7.34(m,1H),7.30–7.26(m,1H),7.22–7.01(m,9H),6.93–6.86(m,3H),5.83(s,2H),2.60(s,3H),2.50(s,2H). 13 C NMR(151MHz,CDCl 3 )(mixture):δ＝152.53,141.12,139.48,139.35,137.65,132.78,132.75,132.07,132.02,130.95,129.78,129.55,128.88,128.73,127.70,127.47,127.01,126.17,126.05,125.92,125.68,125.56,125.52,125.13,124.32,124.18,122.81,122.20,122.16,121.41,120.73,120.35,120.25,120.18,118.32,118.28,116.92,116.79,113.79,113.63,112.87,112.65,111.40,111.08,110.59,110.31,22.00,21.90.HRMS(ESI):calcd for C 29 H 21 ON 2 [M+H] + :413.1648,found 413.1646。
HPLC: chiralpak IA; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝30.39min,t R (major)＝48.13min。
[α] D 21 ＝159.2(mixture,c＝0.067,CHCl 3 )。
Example 9: synthesis of 3ak
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]The carbazole derivative (0.15 mmol,1.5 equivalent) was subjected to cross-coupling reaction at room temperature for 8h, after which the solvent was distilled off by spinning to give 3ak as a pale yellow solid in 51% yield, 96% enantioselectivity and 15% position selectivity: 1.
1 H NMR(400MHz,CDCl 3 )(major):δ＝8.29–8.27(m,1H),8.15–8.09(m,2H),8.02–7.97(m,2H),7.85(d,J＝7.8Hz,1H),7.56(d,J＝9.0Hz,1H),7.40–7.38(m,3H),7.20–7.18(m,2H),7.14–6.98(m,3H),6.86(d,J＝8.4Hz,1H),5.85(s,1H). 13 C NMR(151MHz,CDCl 3 )(major):δ＝152.45,150.22,148.61,141.18,132.56,132.38,129.78,129.07,128.79,127.68,127.65,127.51,127.44,127.35,126.40,126.05,125.29,125.20,122.85,122.84,122.77,121.97,121.56,120.86,120.53,120.49,118.27,116.42,116.08,116.06,113.94,113.49,110.80,110.73,110.69.HRMS(ESI):calcd for C 28 H 18 ON 2 F[M+H] + :417.1397,found417.1396。
HPLC: chiralpak IA; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝33.11min,t R (major)＝41.40min。
[α] D 21 ＝177.6(c＝0.067,CHCl 3 )。
Example 10: synthesis of 3ao
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]The carbazole derivative (0.15 mmol,1.5 equivalent) was subjected to a cross-coupling reaction at room temperature for 6h, after which the solvent was distilled off by spinning to give 3ao as a pale yellow solid with a yield of 55%, an enantioselectivity of 98% and a site-selective ratio of 16:1.
1 H NMR(600MHz,CDCl 3 ):δ＝8.42(dd,J＝8.7,1.2Hz,1H),8.22(d,J＝9.0Hz,2H),8.13(d,J＝8.7Hz,1H),8.04(d,J＝8.2Hz,1H),7.76(d,J＝7.5Hz,1H),7.60(d,J＝9.0Hz,1H),7.50–7.43(m,4H),7.34(s,1H),7.29–7.24(m,2H),6.86(d,J＝8.4Hz,1H),5.83(s,1H). 13 C NMR(151MHz,CDCl 3 ):δ＝152.59,141.87,138.49,132.91,132.44,129.80,129.26,129.18,128.06,127.70(q,J C-F ＝31.7Hz),126.67,126.37,126.16(d,J C-F ＝27.2Hz),125.59,125.51,124.36(d,J C-F ＝27.2Hz),123.73(q,J C-F ＝31.7Hz),122.41,121.71,121.31,120.99,120.24,119.41(q,J C-F ＝6.0Hz),118.46,117.14(q,J C-F ＝3.0Hz),116.56(q,J C-F ＝4.5Hz),115.72,114.72,114.62,109.03(q,J C-F ＝4.5Hz).HRMS(ESI):calcd for C 30 H 15 ON 2 F 6 [M-H] - :533.1094,found 533.1096。
HPLC: chiralpak IA; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (major)＝43.08min,t R (minor)＝45.93min。
[α] D 21 ＝201.7(c＝0.034,CH 2 Cl 2 )。
Example 11: synthesis of 3ap
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 Diazonaphthoquinone (0.1 mmol,1.0 equivalent) and indolone [2,3-a ] as catalysts]Carbazole derivatives (0.15 mmol,1.5 equivalent) cross at room temperatureCoupling reaction for 12h, after the reaction, the solvent is distilled off in a rotating way to obtain a pale yellow solid 3ap, the yield is 51%, the enantioselectivity is 98%, and the position selection ratio is 19:1.
1 H NMR(600MHz,CDCl 3 ):δ＝8.92(d,J＝8.0Hz,1H),8.82(d,J＝8.3Hz,1H),8.36(d,J＝7.0Hz,1H),8.18(d,J＝9.1Hz,1H),8.00(d,J＝2.8Hz,1H),7.90(d,J＝8.2Hz,1H),7.82(d,J＝9.1Hz,1H),7.48–7.45(m,2H),7.24–7.13(m,3H),7.01(t,J＝7.6Hz,1H),6.92–6.84(m,2H),6.65(s,1H),6.43–6.38(m,2H). 13 C NMR(151MHz,CDCl 3 )δ＝154.77,148.40,142.60,140.41,134.08,133.23,130.65,130.17,129.63,128.85,126.70,126.65,124.85,124.82,124.72,124.27,123.35,123.33,123.02,122.95,122.92,122.31,121.66,121.63,121.40,121.39,119.69,119.29,115.73,114.40,112.62.HRMS(ESI):calcd for C 31 H 20 ON 3 [M+H] + :450.1600,found 450.1598。
HPLC: chiralpak IE; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝38.09min,t R (major)＝41.82min。
[α] D 21 ＝255.7(c＝0.067,CHCl 3 )。
Example 12:6 synthesis
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 As a catalyst, diazonaphthoquinone (0.1 mmol,1.0 equivalent) and Ji Ben (0.15 mmol,1.5 equivalent) were cross-coupled at room temperature for 6h, and after completion of the reaction, the solvent was distilled off by spinning to give 6 as a pale yellow solid in 50% yield, 98% and 97% enantioselectivity.
1 H NMR(400MHz,CDCl 3 )(mixture,r.r.6:5):δ＝8.26–8.25(M,1H),8.22(d,J＝1.9Hz,1H),8.13(dd,J＝9.0,1.9Hz,2H),8.09–7.94(m,8H),7.55(dd,J＝9.0,1.6Hz,2H),7.40–7.36(m,4H),7.31–7.28(m,2H),7.23–7.19(m,4H),7.15–7.12(m,3H),7.05–7.01(m,2H),6.92(d,J＝8.6Hz,1H),6.86(d,J＝8.5Hz,1H),6.83(d,J＝8.5Hz,1H). 13 C NMR(101MHz,CDCl 3 ):δ＝152.51,141.18,139.51,139.41,137.64,132.67,132.58,132.39,132.24,129.81,129.00,128.96,128.87,128.17,127.31,127.08,126.69,126.56,126.41,126.18,125.86,125.76,125.71,125.65,125.40,125.35,125.32,125.27,124.02,123.44,122.77,122.10,122.07,121.95,121.61,121.30,120.88,120.53,120.48,120.39,120.08,118.34,116.59,116.36,114.22,113.83,113.33,112.91,112.44,111.67,111.50,110.67.
HRMS(ESI):calcd for C 28 H 18 ON 2 Cl[M+H] + :433.1102,found 433.1101。
HPLC: chiralpak IA; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (minor)＝34.40min,t R (minor)＝36.90min,t R (major)＝43.35min,t R (major)＝47.81min。
[α] D 21 ＝348.3(mixture,c＝0.034,CH 2 Cl 2 )。
Example 13:11 synthesis
Will dissolve in CHCl 3 2mol% Rh in (1 mL) 2 (S-PTAD) 4 As a catalyst, phenanthrenequinone (0.1 mmol,1.0 equivalent) and benzoindolocarbazole (0.15 mmol,1.5 equivalent) were subjected to cross-coupling reaction at room temperature for 6h, and after the reaction was completed, the solvent was distilled off to give a pale yellow solid 11 in 46% yield and 96% enantioselectivity.
1 H NMR(600MHz,(CD 3 ) 2 CO-d 6 ):δ＝10.24(s,1H),9.85(s,1H),9.18–9.17(m,1H),9.09(dd,J＝7.2,2.1Hz,1H),9.02(d,J＝8.4Hz,1H),8.89(d,J＝8.3Hz,1H),8.85(d,J＝8.1Hz,1H),8.67–8.63(m,2H),7.96–7.93(m,1H),7.87–7.85(m,1H),7.80–7.76(m,2H),7.50–7.46(m,2H),7.36–7.33(m,1H),7.29–7.27(m,1H),7.19–7.17(m,2H),7.09(d,J＝8.2Hz,1H),7.02(d,J＝8.1Hz,1H),6.60(dd,J＝8.3,0.6Hz,1H). 13 C NMR(151MHz,(CD 3 ) 2 CO-d 6 ):δ＝151.21,141.67,139.97,133.02,132.27,129.90,129.20,128.54,127.78,127.70,127.67,127.42,127.29,127.06,125.86,125.49,125.00,124.88,124.82,124.73,124.71,124.64,124.56,124.40,123.88,123.83,122.45,122.12,122.00,120.86,115.94,115.87,112.74,112.65,112.61,111.48.HRMS(ESI):calcd for C 36 H 23 ON 2 [M+H] + :499.1804,found 499.1800。
HPLC: chiralpak IB; mobile phase (n-hexane/EtOH), 1.0mL/min, t R (major)＝32.07min,t R (minor)＝37.38min。
[α] D 21 ＝267.6(c＝0.067,CHCl 3 )。
The applicant states that the axial chiral arylindole carbazole derivatives of the present invention and the preparation method thereof are illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be carried out depending on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (11)
1. The preparation method of the axial chiral aryl indole carbazole derivative is characterized in that the axial chiral aryl indole carbazole derivative has a structure shown in the following formula I:
wherein M is
R、R 3 、R 4 、R 5 And R is 6 Independently an electron withdrawing group or an electron donating group; r is R 1 And R is 2 Is hydrogen or R 1 And R is 2 A connection is formed into an aromatic ring or an aromatic heterocyclic ring; x is a nitrogen or oxygen atom, L 1 Is hydrogen, benzyl, aliphatic chain, aromatic ring, L 2 Is hydrogen, benzyl or->
The preparation method comprises the following steps:
when L2 is hydrogen, the compound of formula II-1 or the compound of formula II-2 or the compound of formula II-3 or the compound of formula II-4 and the compound of formula III are used for cross coupling reaction to prepare the axial chiral aryl indole carbazole derivative shown in formula I;
when L 2 When the compound is not hydrogen, the compound of the formula II-1 or the compound of the formula II-2 or the compound of the formula II-3 or the compound of the formula II-4 and the compound of the formula III are used for cross coupling reaction, or the compound of the formula III directly reacts with a halogenated compound to obtain a product under the condition of strong alkali;
the cross-coupling reaction is carried out in the presence of a catalyst which is tetrakis [ (S) - (+) -1-adamantyl) - (N-phthalimido) acetate ] rhodium (II).
2. The method according to claim 1, wherein the electron withdrawing group is a halogen or an ester group.
3. The method of claim 1, wherein the electron donating group is an alkyl or alkoxy group.
4. The preparation method according to claim 1, wherein the axial chiral arylindolocarbazole derivative has a structure represented by the following formulas I-1 to I-1:
5. the preparation method according to claim 1, wherein the axial chiral arylindolocarbazole derivative is any one of the following compounds:
6. the process according to claim 1, wherein the molar ratio of the compound of formula II-1 or the compound of formula II-2 or the compound of formula II-3 or the compound of formula II-4 to the compound of formula III is from 1:1 to 1:1.5.
7. The process according to claim 1, wherein the catalyst is used in an amount of 1 to 3% by mass of the compound of formula II-1 or the compound of formula II-2 or the compound of formula II-3 or the compound of formula II-4.
8. The method of claim 1, wherein the solvent for the cross-coupling reaction is chloroform or toluene.
9. The method of claim 1, wherein the halide is bromobenzyl.
10. The method of claim 1, wherein the cross-coupling reaction is at room temperature.
11. The method of claim 1, wherein the time of the cross-coupling reaction is between 6 and 18 hours.
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