Indole-functionalized bisphosphoramidites, methods for their preparation, and rhodium-ligand complexes

Abstract

Disclosed is an indole-functionalized bisphosphoramidite having a specific formula: A method for preparing a rhodium-ligand complex includes combining starting materials including (I) a rhodium catalyst precursor, (II) an indole-functionalized bisphosphoramidite, and, optionally, (III) a solvent.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the entire benefit of U.S. Provisional Patent Application No. 63 / 330,571, filed April 13, 2022, the contents of which are incorporated by reference.

[0002] FIELD OF THEINVENTION Disclosed is an indole-functionalized bisphosphoramidite having a specific formula. The indole-functionalized bisphosphoramidite is suitable for use as a ligand, in particular for preparing a rhodium-ligand complex. Also disclosed is a method for preparing a rhodium-ligand complex using the indole-functionalized bisphosphoramidite. [Background technology]

[0003] Aldehydes are important intermediates in the synthesis of other functionalized materials such as alcohols, carboxylic acids, and amines. The introduction of aldehyde functionality into olefins, especially via continuous processes, is important in many industries. The hydroformylation of olefins to prepare aldehydes is highly dependent on catalyst selection, both in terms of aldehyde selectivity (since linear aldehydes are generally preferred over branched aldehydes), production rate, and catalyst stability. Many conventional catalysts utilized in the hydroformylation of olefins, even if they have the desired selectivity, have low stability that deactivates over time, which is undesirable. Summary of the Invention

[0004] Indole-functionalized bisphosphoramidites are disclosed. The indole-functionalized bisphosphoramidites have a formula selected from the group consisting of C1), C2), or C3):

[0005] [ka]

[0006] In formulas C1) to C3), R1 ~R 42 are each independently selected from H, a hydrocarbyl group, a heteroaryl group, a halogen atom, or a heterocarbyl group, with the proviso that R 35 ~R 42 At least one of the following is not H. 1 ~Y 12 Each of the formula (I):

[0007] [ka] where R is an independently selected indole group of the formula 43 ~R 47 each of which is H, alkyl, aryl, heteroaryl, alkoxy, acyl, carboxyl, carboxylate, cyano, -SO 3 are independently selected atoms or groups selected from H, sulfonate, amino, trifluoromethyl, halogen, a group of formula (II) below, and combinations thereof.

[0008] For indole-functionalized bisphosphoramidites the following conditions apply: i)R 44 ~R 47 two or more of may optionally be joined together to provide one or more cyclic moieties; ii) Y 1 ~Y 4 , Y 5 ~Y 8 , and Y 9 ~Y 12 In at least one of each of a)R 43 ~R 47 At least one of the formula (II)

[0009] [ka] wherein R 48 ~R 52each is an independently selected atom or group selected from H, alkyl, aryl, and alkoxy; or b)R 44 ~R 47 two or more of are joined together to provide one or more cyclic moieties; iii) when the indole-functionalized bisphosphoramidite has the formula C1), Y 1 ~Y 4 At least one of R 44 ~R 46 At least one of the has the formula (II).

[0010] Also disclosed is a method for preparing a rhodium-ligand complex, the method comprising: 1) combining starting materials including (I) a rhodium catalyst precursor, (II) an indole-functionalized bisphosphoramidite, and, optionally, (III) a solvent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Indole-functionalized bisphosphoramidites are disclosed. The indole-functionalized bisphosphoramidites have a formula selected from the group consisting of C1), C2), or C3):

[0012] [ka]

[0013] In formulas C1) to C3), R 1 ~R 42 are each independently selected from H, a hydrocarbyl group, a heteroaryl group, a halogen atom, or a heterocarbyl group, with the proviso that R 35 ~R 42 At least one of the R is not H. 35 ~R 42 At least one of is not H, so R 35 ~R 42 At least one of is a hydrocarbyl group, a heteroaryl group, a halogen atom, or a heterocarbyl group.

[0014] R 1 ~R 42Suitable hydrocarbyl groups of may be independently linear, branched, cyclic, or combinations thereof. Cyclic hydrocarbyl groups include aryl groups, and saturated or non-conjugated cyclic groups. Cyclic hydrocarbyl groups may be monocyclic or polycyclic. Linear and branched hydrocarbyl groups may be independently saturated or unsaturated. An example of a combination of linear and cyclic hydrocarbyl groups is an aralkyl group. "Substituted" means that one or more hydrogen atoms may be replaced by an atom other than hydrogen (e.g., a halogen atom such as chlorine, fluorine, bromine, etc.). Suitable alkyl groups are exemplified by, but are not limited to, methyl, ethyl, propyl (e.g., iso-propyl and / or n-propyl), butyl (e.g., isobutyl, n-butyl, tert-butyl, and / or sec-butyl), pentyl (e.g., isopentyl, neopentyl, and / or tert-pentyl), hexyl, and branched saturated hydrocarbon groups of 6 carbon atoms. Suitable aryl groups are exemplified by, but are not limited to, phenyl, tolyl, xylyl, naphthyl, benzyl, and dimethylphenyl. Suitable alkenyl groups include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, heptenyl, hexenyl, and cyclohexenyl. Suitable monovalent halogenated hydrocarbon groups include, but are not limited to, halogenated alkyl groups having 1-6 carbon atoms or halogenated aryl groups having 6-10 carbon atoms. Suitable halogenated alkyl groups are exemplified by, but are not limited to, the above-mentioned alkyl groups in which one or more hydrogen atoms are replaced with a halogen atom such as F or Cl.For example, fluoromethyl, 2-fluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 5,5,5,4,4,3,3-heptafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, and 8,8,8,7,7-pentafluorooctyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclobutyl, 3,4-difluorocyclohexyl, and 3,4-difluoro-5-methylcycloheptyl, chloromethyl, chloropropyl, 2-dichlorocyclopropyl, and 2,3-dichlorocyclopentyl are examples of suitable halogenated alkyl groups.Suitable halogenated aryl groups are exemplified by, but not limited to, the above-mentioned aryl groups in which one or more hydrogen atoms are replaced with halogen atoms such as F or Cl.For example, chlorobenzyl and fluorobenzyl are suitable halogenated aryl groups. Suitable heterocarbyl groups include any of the hydrocarbyl groups described above, but containing one or more heteroatoms, such as oxygen, sulfur, nitrogen, etc. Suitable halogen atoms include F, Cl, Br, I, At, and Ts, alternatively F, Cl, and Br, alternatively Cl.

[0015] Y 1 ~Y 12 Each of the formula (I):

[0016] [ka] is an independently selected indole group of In the formula, R 43 ~R 47 each of which is H, alkyl, aryl, heteroaryl, alkoxy, acyl, carboxyl, carboxylate, cyano, -SO 3is an independently selected atom or group selected from H, sulfonate, amino, trifluoromethyl, halogen, a group of formula (II) below, and combinations thereof. Examples of alkyl, aryl, and heteroaryl are described above. In the above formula, the singlet bonded to N represents a bond since the above formula is monovalent.

[0017] For indole-functionalized bisphosphoramidites the following conditions apply: i)R 44 ~R 47 two or more of may optionally be joined together to provide one or more cyclic moieties; ii) Y 1 ~Y 4 , Y 5 ~Y 8 , and Y 9 ~Y 12 In at least one of each of a)R 43 ~R 47 At least one of the formula (II)

[0018] [ka] wherein R 48 ~R 52 each is an independently selected atom or group selected from H, alkyl, aryl, and alkoxy; or b)R 44 ~R 47 two or more of are joined together to provide one or more cyclic moieties; iii) when the indole-functionalized bisphosphoramidite has the formula C1), Y 1 ~Y 4 At least one of R 44 ~R 46 At least one of the has the formula (II).

[0019] All three of conditions (i)-(iii) apply to indole-functionalized bisphosphoramidites. However, only one of conditions (ii)(a) and (ii)(b) need apply, i.e., not both (ii)(a) and (ii)(b) are required since they are alternative requirements, and thus only one of (ii)(a) or (ii)(b) is required.

[0020] All three of conditions (i)-(iii) apply to indole-functionalized bisphosphoramidites, but condition (iii) is invoked only when the indole-functionalized bisphosphoramidite is of formula C1). Conditions (ii)(a) and (iii) are related to each other, but apply to different embodiments of indole-functionalized bisphosphoramidites. As will be understood by those skilled in the art in view of conditions (i)-(iii), when the indole-functionalized bisphosphoramidite is of formula C1), Y 1 ~Y 4 At least one of R 44 ~R 46 At least one of R has formula (II) under condition (iii). However, when the indole-functionalized bisphosphoramidite is of formula C2) or C3), R 43 ~R 47 at least one of R has formula (II) (i.e., condition (ii)(a)), or R 44 ~R 47 are linked together to provide one or more cyclic moieties (i.e., condition (ii)(b)). Under condition (iii), when the indole-functionalized bisphosphoramidite is of formula C1), Y 1 ~Y 4 At least one of R 44 ~R 46 As long as at least one of Y also has the formula (II), 1 ~Y 4 At least one of R 43 may still be of formula (II).

[0021] In certain embodiments, formula (II) independently has the following formula:

[0022] [ka] is selected from one of the following: In the above formula, the singlet attached to each aryl moiety represents the bond in the indole group of formula (I) rather than a methyl group because the above formula is monovalent. The methyl group is explicitly labeled as such.

[0023] R 43 ~R 47 has formula (II) based on proviso (ii)(a), then based on the selection of formula (II), Y 1 ~Y 12 may each independently be selected from the group consisting of (subject to the proviso that Me means methyl, OMe means methoxy, Ph means phenyl and tBu means t-butyl):

[0024] [ka]

[0025] [ka]

[0026] Alternatively, R 44 ~R 47 when two or more of Y are joined together to provide one or more cyclic moieties under proviso (ii)(b), 1 ~Y 12 An example of this is:

[0027] [ka] It is.

[0028] If condition (ii)(a) is true, then in certain embodiments, R 44 ~R 46 At least one of R has the formula (II). In specific embodiments where condition (ii)(a) is true, R 44 has the formula (II). In other embodiments where condition (ii)(a) is true, R 45 has the formula (II). In still other embodiments where condition (ii)(a) is true, R 46 has the formula (II):

[0029] In these or other embodiments, the indole-functionalized bisphosphoramidite has the formula C1): 1 ~R 20 Each of is H. In other embodiments, the indole-functionalized bisphosphoramidite has the formula C2), 21 ~R 34 Each of is H. In yet another embodiment, the indole-functionalized bisphosphoramidite has the formula C3), 35 and R 42 is H, and each of R 36 ~R 41 Each of is methyl.

[0030] In one embodiment, the indole-functionalized bisphosphoramidite has formula C1). In another embodiment, the indole-functionalized bisphosphoramidite has formula C2). In yet another embodiment, the indole-functionalized bisphosphoramidite has formula C3).

[0031] As an example, when the indole-functionalized bisphosphoramidite has the formula C1), and R 1 ~R 20 When each is H, the indole-functionalized bisphosphoramidite of formula C1) is

[0032] [ka] In the formula, Y 1 ~Y 4 are independently selected and are defined above.

[0033] As another example, when the indole-functionalized bisphosphoramidite has the formula C2), and R 21 ~R 34 When each is H, the indole-functionalized bisphosphoramidite of formula C2) is

[0034] [ka] In the formula, Y 5 ~Y 8 are independently selected and are defined above.

[0035] As yet another example, an indole-functionalized bisphosphoramidite has the formula C3), 35 and R 42 is H and R 36 ~R 41 When each of is methyl, the indole-functionalized bisphosphoramidite of formula C3) is

[0036] [ka] In the formula, Y 9 ~Y 12 are independently selected and are defined above.

[0037] In certain embodiments, the indole-functionalized bisphosphoramidite has formula C1), and conditions (i), (ii)(a), and (iii) apply, and R 1 ~R 20 and Y 1 ~Y 4 is selected such that the indole-functionalized bisphosphoramidite is selected from the group consisting of those in Table 1 (L1 to L9 or L13).

[0038] [Table 1-1]

[0039]

Table 1-2

[0040]

Table 1-3

[0041]

Table 1-4

[0042]

Table 1-5

[0043]

Table 1-6

[0044]

Table 1-7

[0045]

Table 1-8

[0046]

Table 1-9

[0047] Those skilled in the art will understand how to prepare the above indole-functionalized bisphosphoramidites in view of the examples herein, and will understand how to replace specific starting materials to modify desired structures under similar reaction schemes.In addition, the general method of preparing ligand structures is disclosed in U.S. Patent No. 9,795,952 to Diebolt et al, which is incorporated herein by reference in its entirety, and can be modified by those skilled in the art in view of the teachings herein to prepare the above indole-functionalized bisphosphoramidites.

[0048] In another embodiment, the indole-functionalized bisphosphoramidite has formula C1), and conditions (i), (ii)(b), and (iii) apply, and R 1 ~R 20 and Y 1 ~Y 4 is selected such that the indole-functionalized bisphosphoramidite has the following formula in Table 2 (L12).

[0049] [Table 2]

[0050] Those skilled in the art will understand how to prepare the above indole-functionalized bisphosphoramidites in view of the examples herein, and will understand how to replace specific starting materials to modify desired structures under similar reaction schemes.In addition, the general method of preparing ligand structures is disclosed in U.S. Patent No. 9,795,952 to Diebolt et al, which is incorporated herein by reference in its entirety, and can be modified by those skilled in the art in view of the teachings herein to prepare the above indole-functionalized bisphosphoramidites.

[0051] In another embodiment, the indole-functionalized bisphosphoramidite has the formula C2): 21 ~R 34 and Y 5 ~Y 8is selected such that the indole-functionalized bisphosphoramidite has the following formula in Table 3 below (L11).

[0052] [Table 3]

[0053] Those skilled in the art will understand how to prepare the above indole-functionalized bisphosphoramidites in view of the examples herein, and will understand how to replace specific starting materials to modify desired structures under similar reaction schemes.In addition, the general method of preparing ligand structures is disclosed in U.S. Patent No. 9,795,952 to Diebolt et al, which is incorporated herein by reference in its entirety, and can be modified by those skilled in the art in view of the teachings herein to prepare the above indole-functionalized bisphosphoramidites.

[0054] In yet another embodiment, the indole-functionalized bisphosphoramidite has the formula C3): 35 ~R 42 and Y 9 ~Y 12 is selected such that the indole-functionalized bisphosphoramidite has the following formula in Table 4 below (L10).

[0055] [Table 4]

[0056] Those skilled in the art will understand how to prepare the above indole-functionalized bisphosphoramidites in view of the examples herein, and will understand how to replace specific starting materials to modify desired structures under similar reaction schemes.In addition, the general method of preparing ligand structures is disclosed in U.S. Patent No. 9,795,952 to Diebolt et al, which is incorporated herein by reference in its entirety, and can be modified by those skilled in the art in view of the teachings herein to prepare the above indole-functionalized bisphosphoramidites.

[0057] Also disclosed is a method for preparing a rhodium-ligand complex. The method includes combining starting materials including (I) a rhodium catalyst precursor, (II) an indole-functionalized bisphosphoramidite, and, optionally, (III) a solvent. A rhodium-ligand complex is formed from starting materials (I) and (II), and, optionally, with starting material (III).

[0058] For example, the rhodium-ligand complex may be prepared by a process comprising combining a rhodium catalyst precursor and an indole-functionalized bisphosphoramidite as described above under conditions to form the complex. Alternatively, the rhodium / ligand complex may be formed in situ by introducing the rhodium catalyst precursor to the reaction medium and the indole-functionalized bisphosphoramidite to the reaction medium (e.g., before, during, and / or after introduction of the rhodium catalyst precursor) during the hydroformylation reaction, for example, as described below. The rhodium catalyst precursor may be rhodium dicarbonyl acetylacetonate, Rh 2 O 3、 Rh 4 (CO) 12 , Rh 6 (CO) 16 , and Rh(NO 3 ) 3 Additional methods for preparing certain indole-functionalized bisphosphoramidites are described herein in the accompanying Examples.

[0059] For example, a rhodium catalyst precursor, such as rhodium dicarbonyl acetylacetonate, optionally starting material (D), a solvent, and an indole-functionalized bisphosphoramidite may be combined by any convenient means, such as, for example, by mixing.

[0060] The rhodium-ligand complexes are particularly suitable for hydroformylation processes involving olefins. The hydroformylation processes described herein use starting materials including (A) a gas containing hydrogen and carbon monoxide, (B) an olefin, and (C) a rhodium-ligand complex catalyst. The starting materials may optionally further include (D) a solvent.

[0061] The gaseous starting material (A) used in the hydroformylation process is carbon monoxide (CO) and hydrogen gas (H 2 For example, the gas may be synthesis gas. As used herein, "syngas" (from synthesis gas) refers to gas that contains varying amounts of CO and H. 2 It refers to a gas mixture containing CO and H. Methods of production are well known and include, for example, (1) steam reforming and partial oxidation of natural gas or liquid hydrocarbons, and (2) gasification of coal and / or biomass. 2 is typically the major component of synthesis gas, which also contains carbon dioxide as well as CH 4 , N 2 , and inert gases such as Ar. 2 Molar ratio of H 2 The CO and H molar ratio (CO / H) varies widely but can range from 1:100 to 100:1, alternatively 1:10 to 10:1. Syngas is commercially available and is often used as a fuel source or as an intermediate to produce other chemicals. Alternatively, CO and H from other sources (i.e., other than syngas) can be used. 2 may be used as starting material (A) herein. Alternatively, H in starting material (A) for use herein 2 The H:CO molar ratio can be from 3:1 to 1:3, alternatively from 2:1 to 1:2, alternatively 1:1.

[0062] The starting material (B) is an olefin that is not limited. The starting material (B) may be substituted or unsubstituted and may be selected from optically active (prochiral and chiral) and non-optically active (achiral) olefinically unsaturated compounds containing 2 to 40, alternatively 2 to 30, alternatively 2 to 20 carbon atoms and one or more carbon-carbon double bonds (C=C).

[0063] The starting material (B) may be terminally or internally unsaturated and may be of linear, branched or cyclic structure. Olefin mixtures (such as so-called dimer, trimer or tetramer propylene) as obtained from the oligomerization of propene, butene and isobutene, as well as mixed butenes, such as raffinate I and raffinate II, known to those skilled in the art, may also be used.

[0064] Illustrative examples of alpha and internal olefins suitable for starting material (B) include ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-undecene, 1-dodecene, 1-tridecene, 1-tetradecene, 1-pentadecene, 1-hexadecene, 1-heptadecene, 1-octadecene, 1-nonadecene, 1-eicosene, 2-butene, 2-methylpropene (isobutylene), 2-methylbutene, 2-pentene, 2-hexene, 3-methylpropene, 3-methylbut ... Hexane, 2-heptene, 2-octene, cyclohexene, propylene dimer, propylene trimer, propylene tetramer, butadiene, piperylene, isoprene, 2-ethyl-1-hexene, styrene, 4-methylstyrene, 4-isopropylstyrene, 4-tert-butylstyrene, alpha-methylstyrene, 4-tert-butyl-alpha-methylstyrene, 1,3-diisopropenylbenzene, 3-phenyl-1-propene, 1,4-hexadiene, 1,7-octadiene, 3-cyclohexene, 1,3-dienes, butadienes, alkyl alkenoates, e.g., methyl pentenoate; alkenyl alkanoates, alkenyl alkyl ethers, alkenols, e.g., pentenol; alkenals, e.g., pentenal; allyl alcohol, allyl butyrate, hex-1-en-4-ol, oct-1-en-4-ol, vinyl acetate, allyl acetate, 3-butenyl acetate, vinyl propionate, allyl propionate, methyl methacrylate, vinyl ethyl ether. ether, vinyl methyl ether, allyl ethyl ether, n-propyl-7-octenoate, 3-butenenitrile, 5-hexenamide, eugenol, isoeugenol, safrole, isosafrole, anethole, 4-allylanisole, indene, limonene, beta-pinene, dicyclopentadiene, cyclooctadiene, camphene, linalool, oleic acid and its esters, e.g., methyl oleate, and such species include homologous unsaturated fatty acids and unsaturated fatty acid esters.Examples of suitable substituted and unsubstituted olefin starting materials include the olefin compounds described in Kirk-Othmer, Encyclopedia of Chemical Technology, Fourth Edition, 1996, the relevant portions of which are incorporated herein by reference.

[0065] (C) The rhodium-ligand complex is described above and may be introduced into the reactor, optionally with an excess of indole-functionalized bisphosphoramidite. Alternatively, the rhodium catalyst precursor, (D) solvent, and ligand may be combined with the starting materials (A) and / or (B) olefin in the reactor, and the rhodium-ligand complex may be formed in situ. The relative amounts of ligand and rhodium catalyst precursor are sufficient to provide a molar ratio of indole-functionalized bisphosphoramidite / Rh of 10 / 1 to 1 / 1, alternatively 5 / 1 to 1 / 1, alternatively 3 / 1 to 1 / 1, alternatively 2.5 / 1 to 1.5 / 1. In addition to the rhodium-ligand complex, an excess (e.g., uncomplexed) indole-functionalized bisphosphoramidite may be present in the reaction mixture. The excess indole-functionalized bisphosphoramidite can be the same as the indole-functionalized bisphosphoramidite in the rhodium-ligand complex, or it can be different.

[0066] The amount of (C) rhodium-ligand complex catalyst (catalyst) is sufficient to catalyze the hydroformylation of (B) olefin. The exact amount of catalyst depends on various factors, including the type of olefin selected for starting material (B), its exact vinyl content, and reaction conditions such as temperature and pressure of starting material (A). However, the amount of (C) catalyst may be sufficient to provide a rhodium metal concentration of at least 0.1 ppm, alternatively 0.15 ppm, alternatively 0.2 ppm, alternatively 0.25 ppm, alternatively 0.5 ppm, based on the weight of (B) olefin. At the same time, the amount of (C) catalyst may be sufficient to provide a rhodium metal concentration of up to 300 ppm, alternatively up to 100 ppm, alternatively up to 20 ppm, alternatively up to 5 ppm, on the same basis. Alternatively, the amount of (C) catalyst may be sufficient to provide from 0.1 ppm to 300 ppm, alternatively from 0.2 ppm to 100 ppm, alternatively from 0.25 ppm to 20 ppm, alternatively from 0.5 ppm to 5 ppm, based on the weight of the (B) olefin.

[0067] The hydroformylation process reaction may be carried out without additional solvent. Alternatively, the hydroformylation process reaction may be carried out using a solvent to facilitate mixing and / or delivery of one or more of the above starting materials, such as (C) catalyst and / or starting material (B). Solvents are exemplified by aliphatic or aromatic hydrocarbons capable of dissolving the starting materials, such as toluene, xylene, benzene, hexane, heptane, decane, cyclohexane, or combinations of two or more of these. Additional solvents include THF, dibutyl ether, diglyme, and texanol. Without wishing to be bound by theory, it is believed that the solvent may be used to reduce the viscosity of the starting materials. The amount of solvent is not critical, but if present, the amount of solvent may be 5% to 70% based on the weight of the olefin, which is the starting material (B).

[0068] In the process described herein, step 1) is carried out at a relatively low temperature. For example, step 1) can be carried out at a temperature of at least 30°C, alternatively at least 50°C, alternatively at least 70°C. At the same time, the temperature in step 1) can be up to 150°C, alternatively up to 100°C, alternatively up to 90°C, alternatively up to 80°C. Without wishing to be bound by theory, it is believed that lower temperatures, for example, 30°C-90°C, alternatively 40°C-90°C, alternatively 50°C-90°C, alternatively 60°C-90°C, alternatively 70°C-90°C, alternatively 80°C-90°C, alternatively 30°C-60°C, alternatively 50°C-60°C, may be desirable to obtain high selectivity and ligand stability.

[0069] In the process described herein, step 1) may be carried out at a pressure of at least 101 kPa (ambient pressure), alternatively at least 206 kPa (30 psi), alternatively at least 344 kPa (50 psi). At the same time, the pressure in step 1) may be up to 6,895 kPa (1,000 psi), alternatively up to 1,379 kPa (200 psi), alternatively up to 1000 kPa (145 psi), alternatively up to 689 kPa (100 psi). Alternatively, step 1) may be carried out at 101 kPa to 6,895 kPa, alternatively 344 kPa to 1,379 kPa, alternatively 101 kPa to 1,000 kPa, alternatively 344 kPa to 689 kPa. Without wishing to be bound by theory, it is believed that it may be beneficial to use relatively low pressures in the processes herein, e.g., <-6,895 kPa, and the ligands described herein enable low pressure hydroformylation processes, which have the benefits of lower cost and better safety than high pressure hydroformylation processes.

[0070] The hydroformylation process may be carried out in batch, semi-batch, or continuous mode using one or more suitable reactors, such as a fixed bed reactor, a fluidized bed reactor, a continuous stirred tank reactor (CSTR), or a slurry reactor. The choice of (B) olefin, and (C) catalyst, and (D) whether a solvent is used, may affect the size and type of reactor used. One reactor, or two or more different reactors may be used. The hydroformylation process may be carried out in one or more steps, which may be influenced by balancing capital costs, achieving high catalyst selectivity, activity, life, and ease of operation, as well as the reactivity of the particular starting materials and the reaction conditions selected, and the products desired.

[0071] Alternatively, the hydroformylation process can be carried out in a continuous manner. For example, the process used can be as described in U.S. Pat. No. 10,023,516, except that the catalyst described therein is replaced with the (C) rhodium-ligand complex described herein.

[0072] Step 1) of the hydroformylation process forms a reaction fluid containing aldehyde-functional compounds. The reaction fluid may further include additional materials, such as those intentionally used during step 1) of the process or those formed in situ. Examples of such materials that may also be present include unreacted (B) olefins, unreacted (A) carbon monoxide and hydrogen gas, and / or by-products formed in situ, such as indole-functionalized bisphosphoramidite decomposition products and their adducts, and high-boiling liquid aldehyde condensation by-products, and (D) solvents, if used. The term "indole-functionalized bisphosphoramidite decomposition products" includes, but is not limited to, any and all compounds resulting from one or more chemical transformations of at least one of the ligand molecules used in the process.

[0073] The hydroformylation process may further include one or more additional steps, such as 2) recovering (C) the rhodium-ligand complex from the reaction fluid containing the aldehyde-functional compound. Recovering (C) the rhodium-ligand complex may be carried out by methods known in the art, including, but not limited to, adsorption and / or membrane separation (e.g., nanofiltration). Suitable recovery methods are described, for example, in U.S. Patent No. 5,681,473 to Miller et al., U.S. Patent No. 8,748,643 to Priske et al., and U.S. Patent No. 10,155,200 to Geilen et al.

[0074] However, one benefit of the process described herein is that it is not necessary to remove and reuse the (C) catalyst. Due to the low level of Rh required, it may be more cost-effective not to recover and reuse the (C) catalyst, and the aldehyde-functional compounds produced by the process may be stable even if the catalyst is not removed. Therefore, alternatively, the above process may be carried out without step 2).

[0075] Alternatively, the hydroformylation process may further include 3) purification of the reaction product. For example, the aldehyde-functional compound may be isolated from the additional materials described above by any convenient means, such as stripping and / or distillation, optionally using reduced pressure.

[0076] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the invention in any way.

[0077] The specific components utilized in the examples are set forth in Table 5 below.

[0078] [Table 5-1]

[0079] [Table 5-2]

[0080] [Table 5-3]

[0081] The structure and composition of the product are 1 H, 13 C, and 29 This was confirmed by Si Nuclear Magnetic Resonance (NMR).

[0082] 1 H, 13 C, and 29 Si NMR spectra were recorded on a Varian 400-NMR spectrometer (400 MHz, 1 H). 1 H and 13 Chemical shifts (δ) for C spectra are referenced to internal solvent resonances and reported relative to tetramethylsilane. Perkin-Elmer ChemDraw version 18.2.0.48 software was used to perform the analysis. 1 H and 13 The predicted chemical shifts of the C spectrum were obtained.

[0083] Preparation example: Ligand synthesis Unless otherwise stated, all solvents and reagents were obtained from commercial suppliers and used as received. Anhydrous toluene, hexane, tetrahydrofuran, and diethyl ether were purified by passage through activated alumina. Solvents used in experiments performed in a nitrogen-filled glove box were further dried by storage over activated 3 Å molecular sieves. Moisture-sensitive reaction glassware was dried overnight in an oven (120 °C) before use. NMR spectra were recorded on a Bruker 400-MHz spectrometer. LC-MS analyses were performed using a Waters e2695 separations module coupled with a Waters 2424 ELS detector, a Waters 2998 PDA detector, and a Waters 3100 ESI mass detector. LC-MS separations were performed on an XBridge C18 3.5 μm 2.1 × 50 mm column using a gradient of 5:95 to 100:0 acetonitrile to water with 0.1% formic acid as the ionization agent. HRMS analysis was performed using an Agilent 1290Infinity LC equipped with a Zorbax Eclipse Plus C18 1.8 μm 2.1×50 mm column coupled to an Agilent 6230TOF mass spectrometer with electrospray ionization. 1 H NMR data are reported as follows: chemical shifts (multiplicities (br=broadline, s=singlet, d=doublet, t=triplet, q=quartet, p=quintet, sex=sextet, sept=septet, and m=multiplet), integrals, and assignments). 1 Chemical shifts for 1 H NMR data are reported in ppm with deuterated solvents as standards. 13 C NMR data is 1 H decoupling was used and chemical shifts are reported in ppm relative to tetramethylsilane (TMS, δ scale) using residual carbon in the deuterated solvent as the standard. 31 Chemical shifts for P NMR data are reported in ppm (H 3 PO 4 (see also).

[0084] Preparation example 1: Ligand 1

[0085] [ka] N 2 In a purged glovebox, a 220 mL jar was charged with 2.0 g (12.45 mmol) of 1H-indole-6-boronic acid (1a), 0.2 g (0.24 mmol) of precatalyst, and 85 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 2.34 g (11.75 mmol) of 2-bromo-1,3,5-trimethylbenzene 2a was added to the solution, followed by approximately 70 mL of potassium phosphate tribasic (70 mL of H2SO4). 2 An aqueous solution of 7.48 g (35.26 mmol) of 1H2O was added. The reaction mixture was then stirred at room temperature overnight. The next day, the reaction was removed from the glove box. Diethyl ether (80 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 80 mL of diethyl ether (2x). The organic layers were combined and washed with MgSO 4 and dried over activated charcoal. The ether solution was then filtered through a silica plug and the solvent removed under reduced pressure to give a white solid. The solid was washed with cold hexane and dried under vacuum. Yield: 2.70 g (97%). 1 H NMR (400MHz, C 6 D 6 )δ 7.68(dq,J=8.0,0.7Hz,1H),6.99(ddd,J=8.1,1.4,0.6Hz,1H),6.97-6.91(m,3H),6.72(s,1H),6.59 (ddd,J=3.1,2.4,0.6Hz,1H),6.50(ddd,J=3.1,2.1,0.9Hz,1H),2.25(s,3H),2.16(d,J=0.7Hz,6H). 13 C{ 1 H}NMR (101MHz, C 2 D 6 )δ 140.62,136.58,136.46,136.25,135.47,128.54,127.16,124.18,121.86,121.13,111.73,102.68,21.21.

[0086] [ka] N 2 In a purged glovebox, phosphorus trichloride (0.36 g, 2.65 mmol) and triethylamine (1.08 g, 10.62 mmol) were added to 75 mL of toluene in a 110 mL glass jar. The solution was placed in a glovebox freezer (-35 °C) for 1 h to cool. Indole 3a (1.25 g, 5.31 mmol) was weighed into a 20 mL vial and dissolved in 10 mL of toluene. The indole solution was also cooled in the glovebox freezer for 1 h. The two solutions were removed from the freezer and the cold indole solution was stirred while adding cold PCl. 3 / Net 3 The solution was added dropwise. A large amount of white precipitate formed during the addition. The reaction mixture was stirred at room temperature overnight and the reaction was monitored throughout. Upon completion, the reaction was filtered through Celite to remove triethylammonium chloride and the pale yellow filtrate was pumped to dryness. The material 4b was deemed pure enough to carry on to the next step of the reaction. 31 P{ 1 H}NMR (162MHz, CDCl 3 )δ 103.9(s)ppm.

[0087] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.15 g, 0.51 mmol) and bis[6-(2.4,6-trimethyl-phenyl)-1H-indolyl]chlorophosphine (4a, 0.545 g, 1.01 mmol) were weighed into a 110 mL glass jar and dissolved in 25 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35°C) for 1 hour. Triethylamine (0.2 g) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50°C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 It was analyzed by P NMR spectroscopy. 31 P NMR shows complete conversion to the desired bisphosphoramidite product with some cyclic phosphoramidite and triphosphoramidite products. The solid was purified by neutral alumina chromatography to give 200 mg (30% yield) of the product (ligand L1). 1 H NMR (400 MHz, CDCl 3 )δ 7.66-7.54(m,4H),7.26-7.24(m,2H),7.12(s,2H),7.01-6.92(m,12H),6.91-6.88(m,4H),6.88-6.82(m,4H),6.51-6.37(m,4H),2.8 0-2.55(m,4H),2.46-2.41(m,12H),2.38(m,2H),2.21(m,2H),2.00(s,6H),1.90(s,6H),1.79(s,6H),1.69(s,6H),1.62-1.32(m,8H). 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 107.18(s)ppm.

[0088] Preparation example 2: Ligand 2

[0089] [ka] N 2In a purged glovebox, a 220 mL jar was charged with 2.06 g (12.8 mmol) of 1H-indole-6-boronic acid (1a), 0.22 g (0.25 mmol) of precatalyst, and 80 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 3.54 mL (14.1 mmol) of 1-bromo-3,5-dimethylbenzene 2b was added to the solution, followed by approximately 60 mL of potassium phosphate tribasic (60 mL of H 2 An aqueous solution of 7.92 g (37.3 mmol) of 1H2O in 1H2O was added. The reaction mixture was then stirred at room temperature overnight. The next day, the reaction was removed from the glove box. Diethyl ether (80 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 80 mL of diethyl ether (2x). The organic layers were combined and washed with MgSO 4 and dried over activated charcoal. The ether solution was then filtered through a plug of basic alumina and the solvent was removed under reduced pressure to give a white solid. The solid was washed with cold hexane and dried under vacuum. Yield: 2.03 g (6.23 mmol, 49.4%). 1 H NMR (400 MHz, CDCl 3 )δ 8.15(br s,1H,NH),7.65(dt,J=8.2,0.7Hz,1H,Ar-H),7.57(dt,J=1.6,0.8Hz,1H,Ar-H),7.35(dd,J=8.2,1.6Hz,1H,Ar-H),7.27-7.24(m ,2H,Ar-H),7.21(dd,J=3.2,2.4Hz,1H,Ar-H),6.96-6.94(m,1H,Ar-H),6.55(ddd,J=3.1,2.0,1.0,Hz,Ar-H),2.37(overlapping singlet,6H,CH 3 ). 13 C{ 1 H}NMR (101 MHz, CDCl 3 )δ 142.5(s),138.4(s),136.5(s),136.0(s),128.5(s),127.3(s),125.6 (s),124.9(s),121.0(s),120.1(s),109.7(s),102.8(s),21.7(s)ppm.

[0090] [ka] N 2 In a purged glove box, phosphorus trichloride (0.34 mL, 3.9 mmol) and triethylamine (2.5 mL, 18 mmol) were added to 70 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35 °C) for 1 h to cool. 6-(3,5-Dimethylphenyl)-1H-indole 3b (1.75 g) was weighed into a 20 mL vial and dissolved in 15 mL of toluene. The indole solution was also cooled in the glove box freezer for 1 h. The two solutions were removed from the freezer and the cold indole solution was stirred while adding cold PCl. 3 / Net 3 The solution was added dropwise. A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The mixture was analyzed by P NMR spectroscopy. The spectrum showed the formation of the desired product at δ 103 ppm. The reaction mixture was filtered through Celite to remove triethylammonium chloride and the yellow filtrate was pumped to dryness. Yield: 1.56 g (3.08 mmol, 78.0%). Note: 31 87% pure by P NMR. The material 4b was deemed pure enough to carry on to the next step of the reaction. 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 104.7(s)ppm.

[0091] [ka] N 2In a purged glovebox, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.45 g, 1.5 mmol) and bis[6-(3,5-dimethylphenyl)-1H-indolyl]chlorophosphine (4b, 1.55 g, 3.06 mmol) were weighed into a 110 mL glass jar and dissolved in 80 mL of toluene to produce a yellow solution. Triethylamine (1 mL, 7 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred overnight at room temperature. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction mixture was analyzed by P NMR spectroscopy. The spectrum showed conversion to the desired product (L2, 105 ppm) at approximately 60% purity. The reaction mixture was filtered through Celite to remove triethylammonium chloride and the yellow filtrate was pumped to dryness. The material was loaded onto a 24 g Gold silica column and eluted with 10 column volumes of pure hexane. Chloroform was then introduced into the eluent and gradually increased to 20% chloroform (80% hexane) over 5 column volumes. This solvent mixture (20 / 80) was used for another 10 column volumes. A total of 520 mg of pure material ligand L2 (white powder) was obtained. Overall yield: 0.520 g (0.421 mmol, 27.5%). 1 H NMR (400MHz, C 6 D 2 )δ 7.88(s,4H,Ar-CH),7.47(t,J=7.8Hz,4H,Ar-CH),7.39(dt,J=8.2,1.6Hz,4H,Ar- CH),7.22(dt,J=3.0,1.3Hz,2H,Ar-CH),7.18-7.14(m,8H,Ar-CH),7.08(dt,J=3. 2,1.5Hz,2H,Ar-H),6.86(d,J=8.3Hz,2H,Ar-H),6.81-6.76(m,4H,Ar-H),6.60(d ,J=8.4Hz,2H,Ar-H),6.42(ddd,J=5.6,3.4,0.8Hz,4H,Ar-H),2.50-2.28(m,6H,CH 2 ), 2.17(s,12H,CH 3 ), 2.16(s,12H,CH 3), 2.14-2.04(m,2H,CH 2 ), 1.42-1.19(m,8H,CH 2 ). 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 107.8(s)ppm.

[0092] Preparation example 3: Ligand 3

[0093] [ka] A 2 L three-necked round bottom flask was charged with 25 g (155.3 mmol) of 1H-indole-6-boronic acid (1a), 2.7 g (3.1 mmol) of precatalyst, and 500 mL of THF. The mixture was stirred at room temperature. After 5 min, 41.2 g (170.8 mmol) of 1-bromo-3,5-di-tert-butylbenzene (2c) was added to the solution, followed by approximately 600 mL of aqueous potassium phosphate tribasic (99 g, 600 mL of H2SO4). 2 3H 2 O (466 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The next morning an aliquot was removed and analyzed by UP-LC, which indicated complete consumption of the starting material. Diethyl ether (400 mL) was added and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 200 mL of diethyl ether (2×). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at rt. The solvent was removed under reduced pressure to give a brownish solid. The material was then dissolved in diethyl ether and treated with activated charcoal for decolorization. The product was filtered through a Celite™ pad and concentrated to give a brownish solid. The solid was purified by trituration as follows:

[0094] Trituration procedure: Hexane (300 mL, approximately 10 mL / g crude material) was added to the crude material. The mixture was heated in a water bath (55° C.) for 15 min to dissolve non-polar impurities, and the mixture was quickly filtered through a fritted filter to recover the pure product. After the first trituration, 23.0 g of pure product 3c was isolated as a white powder. The filtrate from the first trituration was concentrated on a rotary evaporator to give a solid residue, which was purified by silica gel column chromatography using hexane:ethyl acetate as the eluent to give the second batch of product (3c, 7.5 g) as a white solid. 1 H NMR(400MHz,chloroform-d)δ 8.18(s,1H),7.72(d,J=8.2Hz,1H),7.62(dt,J=1.7,0.8Hz,1H),7.51(d,J=1.8Hz,2H),7.45(t,J=1.8H z,1H),7.42(dd,J=8.2,1.5Hz,1H),7.25-7.21(m,1H),6.60(ddd,J=3.1,2.0,1.0Hz,1H),1.43(s,18H). 13 C NMR (101 MHz, chloroform-d) δ 150.95, 141.70, 136.91, 136.35, 127.02, 124.59, 122.00, 120.79, 120.72, 120.19, 109.73, 102.54, 34.97, 31.57.

[0095] [ka] Triethylamine (34 mL, 245.5 mmol) in toluene (50 mL) was placed in a 110 mL glass jar and cooled in a glove box refrigerator. PCl was placed in a 1 L round bottom flask with 50 mL of toluene. 3 (3.6 mL, 41.1 mmol) were simultaneously placed in the glove box refrigerator. After 1 h, both solutions were removed from the refrigerator and the triethylamine solution was dissolved in PCl 3 An additional 175 mL of chilled toluene was added to the flask to bring the concentration to approximately 0.2 M (PCl 36-(3,5-Di-tert-butyl)-1H-indole (3c, 25.0 g, 81.8 mmol) was weighed into a 110 mL glass jar and slowly added to the cooled PCl in small portions over a period of 0.5-1 h with vigorous stirring. 3 / NEt 3 A white precipitate began to form during the addition. The reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. 31 The reaction mixture was monitored by P NMR. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The crude reaction mixture was analyzed by P NMR spectroscopy. The NMR indicates the formation of the desired mono-chlorophosphoramidite (4c, δ 108.17 ppm) as the major product along with a small amount of tri(indolyl)phosphine (δ 70.95 ppm). The crude reaction mixture was passed through a Celite™ pad. The filtrate was transferred to a 1 L flask and concentrated to a volume of 200 mL using a glove box vacuum pump (vacuum trap cooled with liquid nitrogen). The crude reaction mixture was 31 It was sampled for P NMR and then used directly in the next step.

[0096] [ka] N 2 In a purged glove box, bis[6-(3,5-di-tert-butylphenyl)-1H-indolyl]chlorophosphine (4c, 27.75 g, 41.1 mmol) and toluene (200 mL) were charged in a 1 L round bottom flask and stored in the glove box freezer (-35 °C) for 1 h. A solution of 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 5.5 g, 18.7 mmol) in 50 mL of toluene was slowly added. Triethylamine (15.5 mL, 112 mmol) was then added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture later turned cloudy and yellow. The mixture was stirred at room temperature. After 1 h, an aliquot of the reaction mixture was removed, filtered, and 31Analysis by P NMR showed complete conversion to the bis-phosphoramidite product (ligand L3, δ 112.73 ppm) along with some cyclic phosphoramidite (<2%, δ 130.53 ppm) and tri(indolyl)phosphine (<6%, δ 70.96 ppm) by-products. The reaction mixture was removed from the glovebox and passed through a Celite™ pad to remove all inorganic salts, and the filtrate volatiles were removed on a rotary evaporator leaving an orange foamy solid. This crude material was split into two batches (each batch was approximately 10-12 g crude material) for silica gel chromatography. Two 330 g columns were used to purify the material using hexane-DCM as the eluent. After purification of the two batches, the total product isolated was approximately 20 g of white powdery material in 71% yield and 98% purity. 1 H NMR(400MHz,chloroform-d)δ 7.54(dd,J=15.6,8.3Hz,2H),7.38-7.27(m,6H),7.20(d,J=1.8Hz,2H),7.15(d,J=1.8Hz,2 H),7.13-7.08(m,1H),6.98-6.91(m,1H),6.74(d,J=1.5Hz,2H),6.56(d,J=3.4Hz,1H),6.4 2(d,J=3.4Hz,1H),2.49(dt,J=16.3,6.3Hz,1H),2.28(dt,J=16.2,6.3Hz,1H),2.15(dt,J= 17.2,6.4Hz,1H),2.03(dt,J=17.4,6.2Hz,1H),1.33(d,J=8.0Hz,39H),1.28-1.14(m,1H). 31 P{ 1 H}NMR (162MHz, chloroform-d) δ 110.59ppm.

[0097] Preparation example 4: Ligand 4

[0098] [ka] A 250 mL three-necked round bottom flask was charged with 2.0 g (12.4 mmol) of 1H-indole-6-boronic acid (1a), 210 mg (0.25 mmol) of precatalyst, and 80 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 4.2 g (13.7 mmol) of 1-bromo-3,5-diphenylbenzene (2d) was added to the solution, followed by approximately 50 mL of potassium phosphate tribasic [25 mL of H 2 An aqueous solution of 7.9 g (38 mmol) in 20 was added. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was monitored by LC-MS. Once all starting material was consumed, diethyl ether (80 mL) was added and the reaction mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 80 mL of diethyl ether (2×). The organic layers were combined and washed with MgSO 4 and dried over activated charcoal. The solvent was removed under reduced pressure to give a brownish solid, which was purified by silica gel chromatography (5% to 15% ethyl acetate in hexanes) to give 1.98 g (46% yield) of product. 1 H NMR (400 MHz, chloroform-d δ 8.22 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.78 (m, 2H), 7.77-7.69 (m, 6H), 7.56-7.45 (m, 5H), 7.45-7.36 (m, 2H), 7.26 (m, 1H), 6.62 (t, J = 2.6 Hz, 1H). 13 C NMR (101 MHz, chloroform-d) δ 143.38, 142.24, 141.34, 136.37, 135.42, 128.81, 127.45, 127.37, 125.41, 124.94, 124.57, 121.01, 119.91, 109.73, 102.63.

[0099] [ka] N 2In a purged glove box, phosphorus trichloride (0.4 mL, 4.6 mmol) and triethylamine (6.9 mL) were added to 50 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35 °C) for 1 hour to cool. 6-(3,5-di-tert-butyl)-1H-indole (3d, 3.0 g, 9.8 mmol) was weighed into a 50 mL glass jar and dissolved in 25 mL of toluene. PCl 3 / NEt 3 Remove the solution from the freezer and add cold PCl while stirring the indole solution. 3 / NEt 3 The solution was added dropwise (via an addition funnel). A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction was analyzed by P NMR spectroscopy. The NMR spectrum showed the formation of the desired mono-chloro phosphoramidite (δ 105.61 ppm) as the major product along with the bis-chloro compound (δ 145.42 ppm) as a by-product. After 12 h, 0.2 equivalents of the indole compound was slowly added and after 1 h the reaction was cooled to room temperature. 31 Further analysis by P NMR spectroscopy showed complete conversion, primarily to the desired mono-chloro phosphoramidite (δ 105.61 ppm), with approximately 4-5% of the bis-chloro compound (δ 145.42 ppm) as a by-product. The crude mixture was filtered through a plug of Celite to remove inorganic salts, and the filtrate was further evaporated using the glovebox vacuum pump (while maintaining liquid nitrogen in the trap) to leave 3.11 g of the desired mono-chloro phosphoramidite as a yellowish powder (yield >90%), which was then used directly in the next step.

[0100] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 11, 1.2 g, 4.1 mmol) and bis[6-(3,5-diphenyl-phenyl)-1H-indolyl]chlorophosphine (4d, 7.25 g, 8.6 mmol) were weighed into a 220 mL glass jar and dissolved in 80 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35 °C) for 1 hour. Triethylamine (3.4 mL, 24.5 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50 °C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 Analysis by P NMR spectroscopy showed complete conversion to the product (δ 111.01 ppm) along with some cyclic phosphoramidite product (δ 128.22 ppm). A two-step purification was required to remove all the associated by-products. In the first step, a 330 g gold silica gel column (5-30% dichloromethane in hexane) was utilized to purify the bis product along with the remaining by-products. In the second step, a 160 g neutral alumina column was utilized to further purify the bisphosphoramidite product from the indole by-product (5-20% dichloromethane in hexane). After column purification, 1.9 g of pure bisphosphoramidite product (ligand L4) was obtained in 24% yield. 1 H NMR(400MHz,chloroform-d)δ 7.70(m,2H),7.65-7.55(m,9H),7.51-7.41(m,14H),7.37(m,6H),7.34-7.26(m,1H),7.06(m,1H),6.99-6.93(m,1H),6.77(d,J=8.3Hz,1 H),6.66(d,J=8.4Hz,1H),6.52(d,J=3.4Hz,1H),6.37(d,J=3.4Hz,1H),2.47(m,1H),2.22(m,2H),2.03(m,1H),1.40(m,3H),1.26(m,3H). 31 P{ 1 H}NMR (162MHz, chloroform-d) δ 110.53 ppm.

[0101] Preparation example 5: Ligand 5

[0102] [ka] A 2 L three-necked round bottom flask was charged with 2 g (12.4 mmol) of 1H-indole-6-boronic acid (1a), 0.2 g (0.25 mmol) of precatalyst, and 80 mL of THF. The mixture was stirred at room temperature. After 5 min, 3.0 g (13.7 mmol) of 1-bromo-3,5-di-methoxy-benzene (2e) was added to the solution, followed by approximately 50 mL of potassium phosphate tribasic (25 mL of H 2 An aqueous solution of 7.9 g (38 mmol) in 20 was added. The reaction mixture was then stirred at room temperature overnight. The next morning an aliquot was removed and analyzed by LC-MS, which indicated complete consumption of the starting material. Diethyl ether (80 mL) was added and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 50 mL of diethyl ether (2×). The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at rt. The solvent was removed under reduced pressure to give a brownish solid. The solid was purified by silica gel column chromatography using hexane:ethyl acetate as eluent to give 2.1 g of product (3e, 66% yield). 1 H NMR (400 MHz, CDCl 3 )δ 8.21(s,1H),7.70(d,J=8.2Hz,1H),7.63-7.56(m,1H),7.39(dd,J=8.2,1.6Hz,1H),7.24- 7.18(m,1H),6.82(d,J=2.2Hz,2H),6.73-6.53(m,1H),6.48(t,J=2.3Hz,1H),3.87(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ 160.97,144.61,136.23,135.49,127.46,124.92,120.80,119.73,109.59,105.71,102.55,98.73,55.39.

[0103] [ka] N 2 In a purged glove box, phosphorus trichloride (0.3 mL, 3.2 mmol) and triethylamine (2.7 mL) were added to 20 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35°C) for 1 hour to cool. 6-(3,5-di-methoxy-phenyl)-1H-indole (3e, 1.65 g, 6.5 mmol) was weighed into a 50 mL glass jar and dissolved in 10 mL of toluene. PCl 3 / NEt 3 Remove the solution from the freezer and add cold PCl while stirring the indole solution. 3 / NEt 3 The solution was added dropwise (via an addition funnel). A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The crude mixture was analyzed by P NMR spectroscopy. The NMR spectrum indicated the formation of the desired mono-chlorophosphoramidite (d 102.64 ppm) as the major product. The crude mixture was filtered through a plug of Celite to remove inorganic salts, and the filtrate was further evaporated using a glove box vacuum pump (while maintaining liquid nitrogen in the trap) to give the desired mono-chlorophosphoramidite as a yellowish powder (yield >90%). The compound was used directly in the next step without further purification.

[0104] [ka] N 2In a purged glovebox, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.44 g, 1.48 mmol) was dissolved in 5 mL of toluene and added slowly to a cooled solution of bis[6-(3,5-di-methoxyphenyl)-1H-indolyl]chlorophosphine (4e, 3 mmol in 5 mL of toluene) in a 110 mL glass jar. Triethylamine (2.5 mL, 17 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a yellow precipitate. The reaction mixture was stirred at room temperature and allowed to warm slowly to room temperature overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction mixture was analyzed by P NMR spectroscopy; it showed complete conversion to the product, bisphosphoramidite (δ 109.00 ppm), along with some cyclic phosphoramidite (δ 129.16 ppm). The reaction mixture was passed through a Celite pad, washed with toluene, and the filtrate was concentrated to a reddish oil. Silica gel purification was required to remove all the accompanying by-products. A 330 g gold silica gel column (50-100% dichloromethane in hexane) was utilized to purify the desired product along with the remainder of the by-products, and after column purification, 0.5 g of pure bisphosphoramidite product (ligand L5) was obtained in 25% yield. 1 H NMR(400MHz,chloroform-d)δ 7.52(d,J=8.3Hz,1H),7.47(d,J=8.2Hz,1H),7.42(d,J=6.9Hz,2H),7.29(ddd,J=8.2,4.6,1.5 Hz,2H),7.08-7.06(m,1H),7.03-6.94(m,1H),6.81-6.74(m,2H),6.54(dd,J=10.4,2.2Hz,4H) ,6.50(d,J=3.5Hz,1H),6.41-6.40(m,2H),6.38(d,J=3.5Hz,1H),3.76(s,6H),3.75(s,6H),2. 57(dt,J=16.4,6.3Hz,1H),2.39(dt,J=16.4,6.1Hz,1H),2.26-1.99(m,2H),1.65-1.19(m,4H). 31 P{ 1H}NMR (162MHz, chloroform-d) δ 107.72ppm.

[0105] Preparation example 6: Ligand 6

[0106] [ka] A 250 mL three-neck round bottom flask was charged with 4 g (24.849 mmol) of 1H-indole-6-boronic acid (1a), 420 mg (0.497 mmol) of precatalyst, and 160 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 5.825 (27.334 mmol) of 1-bromo-4-tert-butylbenzene (2f) was added to the solution, followed by approximately 50 mL of tribasic potassium phosphate (16 g, 25 mL of H2SO4). 2 An aqueous solution of 38 mmol) in 20 was added. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was monitored by LC-MS. Diethyl ether (80 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 80 mL of diethyl ether (2x). The organic layers were combined and washed with MgSO 4 The mixture was dried over ice. The solvent was removed under reduced pressure to give a brownish solid. The solid was purified by silica gel chromatography to give 4.2 g (65% yield) of product (3f). 1 H NMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.66-7.57 (m, 3H), 7.50 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 6.59 (s, 1H), 1.41 (s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ 149.53,139.36,136.38,135.42,127.02,126.97,125.63,124.63,120.80,119.75,109.32,102.49,34.47,31.40.

[0107] [ka] N 2 In a purged glove box, phosphorus trichloride (0.52 mL, 5.9 mmol) and triethylamine (4.9 mL) were added to 70 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35 °C) for 1 hour to cool. 6-(4-tert-butyl-phenyl)-1H-indole (3f, 4.1 g, 11.87 mmol) was weighed into a 50 mL glass jar and dissolved in 10 mL of toluene. PCl 3 / NEt 3 Remove the solution from the freezer and add cold PCl while stirring the indole solution. 3 / NEt 3 The solution was added dropwise (via an addition funnel). A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The crude mixture was analyzed by P NMR spectroscopy. The NMR spectrum indicated the formation of the desired mono-chlorophosphoramidite (δ 100.99 ppm) as the major product. The crude mixture was filtered through a plug of Celite to remove inorganic salts, and the filtrate was further evaporated using a glove box vacuum pump (while maintaining liquid nitrogen in the trap) to give the desired mono-chlorophosphoramidite as a brownish powder. The compound was used directly in the next step without further purification.

[0108] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.5 g, 1.7 mmol) and bis[6-(4-tert-butylphenyl)-1H-indolyl]chlorophosphine (1.3 g, 2.335 mmol) were weighed into a 110 mL glass jar and dissolved in 34 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35°C) for 1 hour. Triethylamine (1.4 mL) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50°C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 It was analyzed by P NMR spectroscopy. 31 P NMR shows complete conversion to the desired bisphosphoramidite product with some cyclic phosphoramidite and triphosphoramidite products. The solid was purified by silica gel chromatography to give 240 mg (11% yield) of the product (ligand L6). 1 H NMR (400 MHz, CDCl 3 )δ 7.70-7.45(m,6H),7.44-7.32(m,8H),7.10-6.99(m,2H),6.77-6.68(m,2H),6.48(d,J=3.5Hz,1H),6.41(d,J=3.4Hz, 1H),2.55(dt,J=16.7,6.2Hz,1H),2.42-2.31(m,1H),2.29-2.16(m,1H),2.07(dt,J=17.5,6.3Hz,1H),1.34(m,22H). 31 P{ 1 H}NMR (162MHz, chloroform-d) δ 104.97ppm.

[0109] Preparation Example 7: Ligand 7

[0110] [ka] A 250 mL three-neck round bottom flask was charged with 2 g (12.4 mmol) of 1H-indole-6-boronic acid (1a), 0.2 g (0.25 mmol) of precatalyst, and 80 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 2.5 g (13.7 mmol) of 4-bromoanisole (2 g) was added to the solution, followed by approximately 50 mL of potassium phosphate tribasic (7.9 g, 25 mL of H2SO4). 2 An aqueous solution of 38 mmol in 20 was added. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was monitored by LC-MS. Diethyl ether (80 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 80 mL of diethyl ether (2x). The organic layers were combined and washed with MgSO 4 and dried over activated charcoal. The solvent was removed under reduced pressure to give a brownish solid. The solid was purified by silica gel chromatography to give 2.0 g (70%) of product (3g). 1 H NMR (400 MHz, chloroform-d) δ 8.15 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.63-7.55 (m, 2H), 7.55-7.51 (m, 1H), 7.36 (dd, J = 8.2, 1.6 Hz, 1H), 7.24-7.18 (m, 1H), 7.04-6.96 (m, 2H), 6.58 (ddd, J = 3.2, 2.1, 1.0 Hz, 1H), 3.87 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 158.69, 136.43, 135.26, 134.93, 128.32, 126.79, 124.54, 120.82, 119.57, 114.16, 109.04, 102.51, 55.35.

[0111] [ka] N 2In a purged glove box, phosphorus trichloride (0.3 mL, 3.2 mmol) and triethylamine (2.7 mL) were added to 20 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35°C) for 1 hour to cool. 6-(4-Methoxyphenyl)-1H-indole (3 g, 1.45 g, 6.5 mmol) was weighed into a 50 mL glass jar and dissolved in 10 mL of toluene. PCl 3 / NEt 3 Remove the solution from the freezer and add cold PCl while stirring the indole solution. 3 / NEt 3 The solution was added dropwise (via an addition funnel). A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The crude mixture was analyzed by P NMR spectroscopy. The NMR spectrum indicated the formation of the desired mono-chlorophosphoramidite (d 103.29 ppm) as the major product. The crude mixture was filtered through a plug of Celite to remove inorganic salts, and the filtrate was further evaporated using a glove box vacuum pump (while maintaining liquid nitrogen in the trap) to leave 3.1 g of the desired mono-chlorophosphoramidite as a yellowish powder (yield >90%). The compound was used directly in the next step without further purification.

[0112] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.4 g, 1.4 mmol) and bis[6-(4-methoxyphenyl)-1H-indolyl]chlorophosphine (4 g, 1.5 g, 2.9 mmol) were weighed into a 110 mL glass jar and dissolved in 10 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35 °C) for 1 hour. Triethylamine (1.2 mL) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50 °C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 Analyzed by P NMR spectroscopy; complete conversion to the bisphosphoramidite product (δ 104.37 ppm). A two-step purification was required to remove all accompanying by-products. In the first step, a 330 g gold silica gel column (5-20% dichloromethane in hexane) was utilized to purify the bis product along with the remaining by-products. In the second step, a 160 g neutral alumina column was utilized to further purify the bisphosphoramidite product from the indole by-product (5-20% dichloromethane in hexane). After column purification, 0.6 g of pure bisphosphoramidite product (ligand L7) was obtained in 35% yield. 1 H NMR(400MHz,chloroform-d)δ 7.62(d,J=6.4Hz,4H),7.52(d,J=8.2Hz,2H),7.47(d,J=8.2Hz,2H),7.39-7.26(m,12H),7.19-7.13(m,2H) ),7.06(dt,J=3.2,1.5Hz,2H),6.85-6.74(m,10H),6.71(d,J=8.4Hz,2H),6.48(dd,J=3.4,0.8Hz,2H),6. 42-6.36(m,2H),3.78(s,6H),3.77(s,6H),2.55(dt,J=16.7,6.3Hz,2H),2.35(dt,J=16.6,6.1Hz,2H),2. 22(dt,J=17.8,6.4Hz,2H),2.08(dt,J=17.5,6.2Hz,2H),1.60-1.40(m,4H),1.34(tq,J=8.7,2.8Hz,4H). 31P{ 1 H}NMR (162MHz, chloroform-d) δ 104.37ppm.

[0113] Preparation example 8: Ligand 8

[0114] [ka] A 2 L three-necked round bottom flask was charged with 1 equivalent of 3,5-di-tert-butyl-phenylboronic acid (1b), 0.02 equivalents of pre-catalyst, followed by the addition of THF to a final concentration of approximately 0.3 M. The mixture was stirred at room temperature for 5 min. Then, 1.1 equivalents of bromo-indole 2h were added to the solution, followed by a 1 M aqueous solution of potassium phosphate tribasic (3 equivalents of K 3 PO 4 ) was added. The reaction mixture was then stirred at room temperature overnight. The next morning an aliquot was removed and analyzed by LC-MS. Once the reaction showed complete consumption of the starting material, diethyl ether was added and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with diethyl ether. The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at rt. The solvent was removed under reduced pressure to give the crude product. The material was then dissolved in diethyl ether and treated with activated charcoal for decolorization. The product was filtered through a Celite™ pad, concentrated, and then purified by silica gel column chromatography (20% ethyl acetate in hexanes) to isolate the pure material (3h, 69% yield). 1 H NMR (400 MHz, CDCl 3 )δ 8.17(s,1H),7.91-7.85(m,1H),7.51(d,J=1.8Hz,2H),7.49-7.45(m,2H),7. 43(t,J=1.8Hz,1H),7.24(t,J=2.8Hz,1H),6.67-6.60(m,1H),1.42(s,18H). 13 C NMR (101 MHz, CDCl 3)δ 150.87,141.89,135.18,134.70,128.33,124.72,122.29,122.02,120.49,119.38,111.04,102.95,34.96,31.57.

[0115] [ka] In a nitrogen purged glove box, triethylamine (6 equiv.) was added in toluene to a 110 mL glass jar and placed in the glove box refrigerator. 3 (1 equiv.) in toluene was added to a 110 mL glass jar and placed simultaneously in the glove box refrigerator. After 1 h, both solutions were removed from the refrigerator and the triethylamine solution was diluted with PCl 3 An additional amount of toluene was added to the flask to bring the final concentration to approximately 0.2 M (PCl 3 The substituted indole 3h (2 equiv.) was weighed into a 110 mL glass jar, dissolved in a minimum amount of toluene, and cooled to 50° C. 3 / NEt 3 The solution was slowly added over a period of 15-30 minutes with vigorous stirring. A white precipitate began to form during the addition. The reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. The progress of the reaction was monitored by 31 The reaction mixture was monitored by P NMR. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 Analysis by P NMR confirmed that the desired bis(indolyl)chlorophosphine 4h had formed as the major product. The crude reaction mixture was passed through a Celite™ pad to remove inorganic salts, and the filtrate was transferred to a 220 mL glass jar and concentrated to approximately ¼ of its original volume using a glove box vacuum pump (vacuum trap cooled with liquid nitrogen). 31 It was sampled for P NMR and used directly in the next step.

[0116] [ka] N 2 In a purged glove box, a 110 mL glass jar was charged with a solution of bis(indolyl)chlorophosphine 4h (2.5 equiv.) in toluene and stored in the glove box freezer (-35 °C) for 1 h. 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 1 equiv.) was dissolved in toluene in a vial and slowly added to the solution of bis(indolyl)chlorophosphine at -35 °C. An additional amount of toluene was added to the glass jar to maintain an overall concentration of approximately 0.15-0.2 M. Triethylamine (4 equiv.) was then added dropwise to the stirring solution at -35 °C and slowly warmed to room temperature, resulting in the immediate formation of a white precipitate. The reaction mixture later turned cloudy and yellow. The mixture was stirred at room temperature for 1 h, after which an aliquot of the reaction mixture was removed, filtered, and 31 The reaction was analyzed by P NMR. When the reaction showed complete conversion to the bisphosphoramidite product, the reaction mixture was removed from the glove box and passed through a Celite™ pad to remove all inorganic salts. The volatiles of the filtrate were removed on a rotary evaporator to leave a yellowish oil. The crude material was further purified by silica gel column chromatography (20% dichloromethane in hexane) to isolate the pure bisphosphoramidite ligand L8 (22% yield and 80% purity). 1 H NMR (400 MHz, CDCl 3 )δ 7.78-7.73(m,3H),7.56(dd,J=5.7,3.3Hz,1H),7.51-7.40(m,6H),7.39- 7.28(m,2H),7.13-7.04(m,2H),6.91(d,J=8.5Hz,1H),6.80(d,J=8.4Hz,1 H),6.61(td,J=4.2,3.4,1.9Hz,1H),6.57(dd,J=3.4,0.9Hz,1H),2.78-2 .51(m,2H),2.40-2.08(m,2H),1.72-1.52(m,3H),1.40(d,J=1.7Hz,37H). 31 P{ 1 H}NMR (162MHz, CDCl 3 )δ 106.70ppm.

[0117] Preparation example 9: Ligand 9

[0118] [ka] A 2 L three-necked round bottom flask was charged with 1 equivalent of 3,5-di-tert-butyl-phenylboronic acid (1b), 0.02 equivalents of pre-catalyst, followed by the addition of THF to a final concentration of approximately 0.3 M. The mixture was stirred at room temperature for 5 min. Then, 1.1 equivalents of bromo-indole 2i were added to the solution, followed by a 1 M aqueous solution of potassium phosphate tribasic (3 equivalents of K 3 PO 4 ) was added. The reaction mixture was then stirred at room temperature overnight. The next morning an aliquot was removed and analyzed by LC-MS. Once the reaction showed complete consumption of the starting material, diethyl ether was added and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with diethyl ether. The organic layers were combined and washed with anhydrous MgSO 4 The mixture was dried at rt. The solvent was removed under reduced pressure to give the crude product. The material was then dissolved in diethyl ether and treated with activated charcoal for decolorization. The product was filtered through a Celite™ pad, concentrated, and then purified by silica gel column chromatography (20% ethyl acetate in hexanes) to isolate the pure material (3i, 73% yield). 1 H NMR (400 MHz, CDCl 3 )δ 8.23(s,1H),7.58(d,J=1.8Hz,2H),7.46(t,J=1.9Hz,1H),7.40(dt,J=7.9,1.1Hz,1H),7 .30(t,J=7.6Hz,1H),7.27-7.25(m,2H),6.75(ddd,J=3.2,2.1,1.0Hz,1H),1.42(s,18H). 13 C NMR (101 MHz, CDCl 3 )δ 150.66,140.27,136.26,135.64,126.27,124.25,123.24,122.32,120.87,119.70,109.90,102.46,34.97,31.58.

[0119] [ka] N 2 In a purged glove box, triethylamine (6 equiv.) was added to a 110 mL glass jar in toluene and placed in the glove box refrigerator. 3 (1 equiv.) in toluene was added to a 110 mL glass jar and placed simultaneously in the glove box refrigerator. After 1 h, both solutions were removed from the refrigerator and the triethylamine solution was diluted with PCl 3 An additional amount of toluene was added to the flask to bring the final concentration to approximately 0.2 M (PCl 3 The substituted indole 3i (2 equiv.) was weighed into a 110 mL glass jar, dissolved in a minimum amount of toluene, and cooled to 50° C. 3 / NEt 3 The solution was slowly added over a period of 15-30 minutes with vigorous stirring. A white precipitate began to form during the addition. The reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours. The progress of the reaction was monitored by 31 The reaction mixture was monitored by P NMR. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 Analysis by P NMR confirmed that the desired bis(indolyl)chlorophosphine 4h had formed as the major product. The crude reaction mixture was passed through a Celite™ pad to remove inorganic salts, and the filtrate was transferred to a 220 mL glass jar and concentrated to approximately ¼ of its original volume using a glove box vacuum pump (vacuum trap cooled with liquid nitrogen). 31 It was sampled for P NMR and used directly in the next step.

[0120] [ka] N 2In a purged glove box, a 110 mL glass jar was charged with a solution of bis(indolyl)chlorophosphine 4i (2.5 equiv.) in toluene and stored in the glove box freezer (-35 °C) for 1 h. 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 1 equiv.) was dissolved in toluene in a vial and slowly added to the solution of bis(indolyl)chlorophosphine at -35 °C. An additional amount of toluene was added to the glass jar to maintain an overall concentration of approximately 0.15-0.2 M. Triethylamine (4 equiv.) was then added dropwise to the stirring solution at -35 °C and slowly warmed to room temperature, resulting in the immediate formation of a white precipitate. The reaction mixture later turned cloudy and yellow. The mixture was stirred at room temperature for 1 h, after which an aliquot of the reaction mixture was removed, filtered, and 31 The reaction was analyzed by P NMR. Once the reaction showed complete conversion to the bisphosphoramidite product, the reaction mixture was removed from the glove box and passed through a Celite™ pad to remove all inorganic salts. The volatiles of the filtrate were removed on a rotary evaporator to leave a yellowish oil. The crude material was further purified by silica gel column chromatography (20% dichloromethane in hexanes) to isolate the pure bisphosphoramidite ligand L9 (50% yield). 1 H NMR (400 MHz, CDCl 3 )δ 7.54-7.43(m,8H),7.29-7.23(m,2H),7.20-7.16(m,3H),7.16-7.08(m,1H),6.90-6.79(m,2H),6.72(t,J=3.2Hz, 2H),2.70-2.63(m,1H),2.58-2.51(m,1H),2.40-2.31(m,1H),2.21-2.14(m,1H),1.71-1.49(m,3H),1.42(m,37H). 31 P{ 1 H}NMR (162MHz, CDCl 3 )δ 104.70 ppm.

[0121] Preparation example 10: Ligand 10

[0122] [ka] N 2 In a purged glove box, 4,4',5,5',6,6'-hexamethyl-[1,1'-biphenyl]-2,2'-diol (5b, 1.0 g, 3.7 mmol) and bis[6-(3,5-di-tert-butylphenyl)-1H-indolyl]chlorophosphine (4c, 6.2 g, 8.13 mmol) were weighed into a 220 mL glass jar and dissolved in 75 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35 °C) for 1 hour. Triethylamine (1.6 mL, 11.1 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50 °C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The product was analyzed by P NMR. A two-step purification was required to remove all the associated by-products. In the first step, a 330 g gold silica gel column (5-20% dichloromethane in hexane) was used to purify the bis product along with the remaining by-products. In the second step, a 160 g neutral alumina column was used to further purify the bisphosphoramidite product (5-20% dichloromethane in hexane). After column purification, 1.2 g of pure bisphosphoramidite ligand L10 was obtained in 28% yield. 1 H NMR(400MHz,chloroform-d)δ 7.56(dd,J=8.0,2.8Hz,4H),7.40-7.29(m,12H),7.21(dt,J=6.0,1.3Hz,8H),7.07(dt,J=11.6,2.9Hz,4 H),6.58(s,2H),6.53-6.45(m,4H),2.01(s,6H),1.80(s,6H),1.76(s,6H),1.33(dd,J=3.4,1.1Hz,72H). 31 P{ 1 H}NMR (162MHz, chloroform-d) δ 109.41 ppm.

[0123] Preparation Example 11: Ligand 11

[0124] [ka] N 2 In a purged glovebox, 2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diol (5c, 0.275 g, 1.2 mmol) was added to a cooled solution of bis[6-(3,5-di-tert-butylphenyl)-1H-indolyl]chlorophosphine (4c, 2.8 mmol) in toluene (10 mL) in a 110 mL glass jar. Triethylamine (0.7 mL, 4.8 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and allowed to warm slowly to room temperature overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction was analyzed by P NMR spectroscopy; the reaction was very clean with only one major peak (δδ 105.28 ppm) along with some minor products observed. The glass jar was removed from the glove box and the reaction mixture was passed through a Celite pad. The filtrate was concentrated and loaded directly onto a 330 g silica column using liquid injection. The silica gel column was necessary to remove all the accompanying by-products. A 330 g gold silica gel column (5-25% dichloromethane in hexane) was utilized to purify the bis product along with the rest of the by-products, and after column purification, 0.95 g of pure bisphosphoramidite ligand L11 was obtained in 51% yield. 1H NMR(400MHz,chloroform-d)δ 7.56(dd,J=10.6,8.1Hz,4H),7.47-7.40(m,4H),7.40-7.31(m,8H),7.24(dd,J=8.8,1.8Hz,8H),6 .99(t,J=3.3Hz,2H),6.84(t,J=3.2Hz,2H),6.76(dd,J=8.1,7.3Hz,2H),6.68(d,J=8.0Hz,2H),6.6 2(d,J=7.3Hz,2H),6.53(dd,J=3.4,0.9Hz,2H),6.47(dd,J=3.4,0.8Hz,2H),2.78(m,2H),2.43(dd ,J=16.0,8.6Hz,2H),2.08(dd,J=12.6,7.6Hz,2H),2.03-1.89(m,2H),1.36(s,36H),1.33(s,36H). 31 P{ 1 H}NMR (162MHz, chloroform-d) δ 105.28 ppm.

[0125] Preparation Example 12: Ligand 12

[0126] [ka] N 2 In a purged glove box, phosphorus trichloride (0.6 mL, 7.0 mmol) and triethylamine (3.0 mL) were added to 20 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35°C) for 1 hour to cool. 6,7-fused-1H-indole (3 l, 1.1 g, 7.0 mmol) was weighed into a 50 mL glass jar and dissolved in 15 mL of toluene. PCl 3 / NEt 3 Remove the solution from the freezer and add cold PCl while stirring the indole solution. 3 / NEt 3 The reaction mixture was allowed to warm to room temperature and stirred for an additional 3 hours. After 3 hours, an aliquot of the reaction mixture was removed, filtered, and 31The crude mixture was analyzed by P NMR spectroscopy. The NMR spectrum indicated the formation of the desired di-chloroindolylphosphine 4l' (δ 147.30 ppm) as the major product. The crude NMR was clean enough to proceed to the next step. The crude mixture was filtered through a plug of Celite to remove inorganic salts and the filtrate was further concentrated to a 10 mL solution using the glove box vacuum pump (while maintaining liquid nitrogen in the trap).

[0127] The di-chloroindolylphosphine solution (4 l') was then kept in a glove box freezer (-35°C) for 1 hour to cool. 1H-Indole (0.82 g, 7.0 mmol) was weighed into a 50 mL glass jar and dissolved in 15 mL of toluene. The di-chloroindolylphosphine solution was removed from the freezer and 3.0 mL of triethylamine was added to the solution. The indole solution was then added dropwise to the reaction solution with stirring. The reaction mixture was allowed to warm to room temperature and stirred for an additional 3 hours. After 3 hours, an aliquot of the reaction mixture was removed, filtered, and 31 The crude mixture was filtered through a plug of Celite to remove inorganic salts and the filtrate was further concentrated to a 10 mL solution using the glove box vacuum pump (while maintaining liquid nitrogen in the trap).

[0128] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.82 g, 2.8 mmol) was dissolved in 5 mL toluene in a 110 mL glass jar. A toluene solution of bis[indolyl]chlorophosphine 4l (7.0 mmol in 10 mL) was slowly added to the toluene solution and the reaction was kept in a freezer (-35 °C) for 1 h. Triethylamine (2.3 mL) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred overnight at room temperature. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The product was analyzed by P NMR spectroscopy; complete conversion to the bisphosphoramidite (δ 101.68 ppm) along with some minor products was observed. A silica gel column was required to remove all the accompanying by-products. A 330 g gold silica gel column (20-50% dichloromethane in hexane) was utilized to purify the bis product along with the rest of the by-products. After column purification, 0.9 g of pure bisphosphoramidite product (ligand L12) was obtained in 36% yield. 1 H NMR (400 MHz, CDCl 3 )δ 7.51(d,J=7.6Hz,1H),7.42(d,J=8.1Hz,1H),7.36(d,J=7.9Hz,1H),7.10(td,J=7.5,1.1 Hz,1H),7.07-6.99(m,3H),6.89-6.78(m,2H),6.68(d,J=8.4Hz,1H),6.50(d,J=3.5Hz,1 H),6.43(dd,J=3.5,0.8Hz,1H),3.20(dt,J=14.5,6.9Hz,1H),3.01-2.83(m,3H),2.72-2 .51(m,2H),2.33-2.21(m,1H),2.20-2.09(m,1H),2.07-1.99(m,2H),1.75-1.41(m,4H). 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 100.79(s)ppm.

[0129] Preparation Example 13: Ligand 13

[0130] [ka] A 250 mL three-neck round bottom flask was charged with 2.0 g of 3,5-di-tert-butyl-boronic acid (1c), 145 mg of precatalyst, and 25 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 1.97 g of 3-methyl-6-bromo-indole (2m) in 5 mL of THF solution was added to the reaction flask, followed by approximately 40 mL of potassium phosphate tribasic (40 mL of H2SO4). 2 An aqueous solution of 5.3 g (25 mmol) in 20 was added. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was monitored by LC-MS. Diethyl ether (40 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 40 mL of diethyl ether (2×). The organic layers were combined and washed with MgSO 4 The mixture was dried over ice. The solvent was removed under reduced pressure to give a brownish solid. The solid was purified by ISCO silica gel chromatography to give 1.54 g (55% yield) of product. 1 H NMR (400 MHz, CDCl 3 )δ 7.92(s,1H),7.65(d,J=8.2Hz,1H),7.56(s,1H),7.50(t,J=1.5Hz,2H),7.47-7.36(m,2H),7.00(s,1H),2.38(s,3H),1.42(s,18H). 13 C NMR (101 MHz, CDCl 3 )δ 150.92,141.82,136.82,136.78,127.49,122.05,122.01,120.73,119.45,118.87,111.71,109.72,34.97,31.57,9.70.

[0131] [ka] N 2In a purged glove box, phosphorus trichloride (0.6 mL) and triethylamine (5.2 mL) were added to 40 mL of toluene in a 110 mL glass jar. The solution was placed in a glove box freezer (-35 °C) for 1 hour to cool. 6-(3,5-di-tert-butyl)-3-methyl-1H-indole (3 m, 4.0 g) was weighed into a 40 mL vial and dissolved in 20 mL of toluene. The indole solution was also cooled in the glove box freezer for 1 hour. The two solutions were removed from the freezer and the cold indole solution was stirred while adding cold PCl. 3 / NEt 3 The solution was added dropwise (via an addition funnel). A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred at 60° C. overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction mixture was analyzed by P NMR spectroscopy. NMR showed the formation of the desired mono-chloro phosphoramidite (δ 102.43 ppm) as the major product, but also the bis-chloro compound (δ 143.52 ppm) as a by-product. After 12 hours, 0.2 equivalents of the indole compound was slowly added to the reaction mixture, and after 1 hour, the reaction was cooled to 30° C. 31 The reaction was further analyzed by P NMR spectroscopy. The reaction showed complete conversion to the desired mono-chloro phosphoramidite (δ 102.43 ppm) as the major product, with approximately 4-5% of the bis-chloro product (δ 143.52 ppm) as a by-product. The crude mixture was filtered through a plug of Celite to remove inorganic salts, and the filtrate was further evaporated using a glovebox vacuum pump (while maintaining a liquid nitrogen trap), isolating 4.4 g of the desired mono-chloro phosphoramidite (4m) as a yellowish powder (yield >90%).

[0132] [ka] N 2In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.7 g) and bis[6-(3,5-di-tert-butylphenyl)-3-methyl-1H-indolyl]iodophosphine (4m, 3.8 g) were weighed into a 110 mL glass jar and dissolved in 46 mL of toluene to produce a reddish yellow solution that was kept in a freezer (-35°C) for 1 hour. Triethylamine (2.0 mL) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred at room temperature and slowly warmed to 50°C overnight. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 It was analyzed by P NMR spectroscopy. 31 P NMR shows complete conversion to the product (δ 107.89 ppm) along with some monoalcohol and cyclic phosphoramidite products. A two-step purification was used to remove all the indole by-products. Specifically, the first column purified the bis product along with the rest of the by-products (silica gel column) and the second column purified the bis product from the indole by-products (alumina column). NMR shows pure product (ligand L13, 1.2 g) in 31% yield (purity >95%). 1 H NMR (400 MHz, CDCl 3 )δ 7.56-7.45(m,4H),7.41-7.34(m,4H),7.33-7.21(m,4H),6.88(d,J=8.4Hz,1H),6.84-6.75(m,2H),6.60(s,1 H),2.68-2.51(m,1H),2.43-2.38(m,1H),2.28-2.17(m,4H),2.13-2.04(m,4H),1.50-1.29(d,J=6.7Hz,40H). 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 107.89(s)ppm.

[0133] Preparation Example 14: Comparative Ligand 2

[0134] [ka] In a water-containing glovebox, a 110 mL jar was charged with (tert-butyloxycarbonyl)boronic ester 1c (1.35 g, 3.94 mmol), precatalyst (0.06 g, 0.07 mmol), and THF (25 mL). The reaction mixture was then stirred for 5 min. After 5 min, 1-bromo-3,5-di-tert-butylmethylbenzene (2c, 1.00 g, 3.71 mmol) was added to the reaction mixture, and an aqueous solution of potassium phosphate tribasic (2.36 g, 11.14 mmol in 20 mL water) was added to the reaction mixture. The reaction mixture was then stirred overnight at room temperature. The next day, an aliquot was removed, worked up with diethyl ether, and checked by mass spectroscopy. The reaction was complete, quenched, and removed from the glovebox. Diethyl ether (50 mL) was added to the reaction mixture, which was then transferred to a separatory funnel. The aqueous layer was then washed with an equal volume of diethyl ether (2×). The organic layers were then combined and diluted with MgSO 4 The mixture was dried at 40° C. and filtered through a plug of neutral alumina and activated charcoal. The filtrate was then concentrated to give 1.5 g, 99.5%, as a brown solid. Compound (3j') was analyzed by NMR and carried on to the deprotection step.

[0135] In a water-containing glovebox, a 50 mL jar was charged with tert-butyl 3-(3,5-di-tert-butylphenyl)-1H-indole-1-carboxylate (3j', 1.50 g, 3.70 mmol), THF (30 mL), and a stir bar. 25 wt % sodium methoxide (2.4 g, 11.10 mmol) was added slowly to avoid a large exotherm. The reaction was stirred at room temperature overnight. In the morning, water was added, the reaction was removed from the glovebox, and water (30 mL) was added. The mixture was stirred for 15 min and then transferred to a separatory funnel. The product was extracted three times with diethyl ether, and the combined organic layers were washed with MgSO 4 The crude material was then dissolved in dichloromethane and passed through a silica gel plug. The filtrate was concentrated to give 0.88 g of pure product 3j. Yield: 77.5%. 1 H NMR (400 MHz, CDCl3 )δ 8.16(s,1H),7.92(ddq,J=7.8,1.5,0.8Hz,1H),7.52(dd,J=1.9,0.8Hz,2H),7. 44-7.40(m,1H),7.40-7.34(m,2H),7.29-7.16(m,2H),1.40(d,J=0.8Hz,18H). 13 C NMR (101 MHz, CDCl 3 )δ 151.18,136.80,134.63,126.17,122.45,122.20,121.74,120.41,120.35,120.08,119.57,111.50,35.09,31.72.

[0136] [ka] N 2 In a purged glovebox, phosphorus trichloride (0.19 g, 1.40 mmol) and triethylamine (0.57 g, 5.62 mmol) were added to 50 mL of toluene in a 110 mL glass jar. The solution was placed in a glovebox freezer (-35 °C) for 1 h to cool. Indole 3j (0.86 g, 2.81 mmol g) was weighed into a 20 mL vial and dissolved in 10 mL of THF. The indole solution was also cooled in the glovebox freezer for 1 h. The two solutions were removed from the freezer and the cold indole solution was stirred while adding cold PCl. 3 / NEt 3 The solution was added dropwise. A large amount of white precipitate formed during the addition. The reaction mixture was stirred at 50° C. for 24 hours. 31 P NMR was performed to monitor the reaction. Once the reaction was complete, it was filtered through Celite to remove triethylammonium chloride, and the pale yellow filtrate was pumped to dryness. The resulting residue was taken up in hexane, filtered, and concentrated to give 0.72 g of crude 4j. The material was carried directly to the next step without any further purification. 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 100.0(s)ppm.

[0137] [ka] N 2 In a purged glove box, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.09 g, 0.29 mmol) and 1,1'-(chlorophosphanediyl)bis(3-(3,5-di-tert-butylphenyl)-1H-indole) (4j, 0.39 g, 0.58 mmol) were weighed into a 50 mL glass jar containing a Teflon coated stir bar. Toluene (10 mL) was added to dissolve the mixture. Triethylamine (0.12 g, 1.16 mmol) in toluene (5 mL) was added dropwise to the solution with stirring. The reaction mixture was stirred at room temperature overnight. An aliquot of the reaction mixture was removed and filtered, 31 The reaction mixture was analyzed by P NMR spectroscopy. The spectrum showed partial conversion to the desired product (δ 104 ppm). An additional 0.04 g of diol was added and the reaction was stirred at room temperature for another 24 h. Once all the starting chloride was gone, the reaction mixture was filtered through Celite to remove triethylammonium chloride and the colorless filtrate was pumped to dryness to give a light brown solid. An alumina column was required to remove all the accompanying by-products. A 24 g gold silica gel column was utilized to purify the bis product along with the remaining by-products. After column purification, 0.1 g of pure bisphosphoramidite product (ligand CL2) was obtained in 22% yield. 1 H NMR (400 MHz, CDCl 3 )δ 7.78(dd,J=14.6,7.9Hz,5H),7.58(d,J=8.2Hz,2H),7.55-7.46(m,2H),7.41-7.38(m,14H),7.24-7.11(m,5H),7.08 -7.0(m,4H),6.67(d,J=8.3Hz,2H),6.54(d,J=8.4Hz,2H),2.48-2.22(m,6H),2.19-1.98(m,5H),1.51-1.19(m,77H). 31 P{ 1 H}NMR (162MHz, C 6 D6 )δ 104.4(s)ppm.

[0138] Preparation Example 15: Comparative Ligand 3

[0139] [ka] N 2 In a purged glovebox, a 110 mL jar was charged with 4.43 g (12.87 mmol) of 1-(tert-butoxycarbonyl)indole-3-boronic acid pinacol ester (1c), 0.21 g (0.24 mmol) of precatalyst, and 40 mL of THF. The mixture was stirred at room temperature for 5 min. After 5 min, 1.65 mL (12.14 mmol) of 1-bromo-3,5-dimethylbenzene (2b) was added to the solution, followed by approximately 30 mL of potassium phosphate tribasic (30 mL of H 2 An aqueous solution of 7.75 g (36.51 mmol) of 1H2O in 1H2O was added. The reaction mixture was then stirred at room temperature overnight. The next day, the reaction was removed from the glove box. Diethyl ether (40 mL) was added to the reaction mixture, and the mixture was then transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further washed with 40 mL of diethyl ether (2x). The organic layers were combined and washed with MgSO 4 and dried over activated charcoal. The ether solution was then filtered through a plug of basic alumina and the solvent was removed under reduced pressure to give a white solid. Yield: 3.9 g of impure material, believed to be a mixture of the desired compound (3k') and pinacol bromoborane. The crude material was used in the next step of the reaction without any further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (br d, J = 8.0 Hz, 1H, indole-CH), 7.81 (d, J = 0.5 Hz, 1H, indole-CH), 7.68 (s, 1H, para-aryl-CH), 7.37-7.31 (m, 1H, indole-CH), 7.30-7.26 (m, 1H, indole-CH), 7.26-7.24 (stacked singlet, 2H, ortho-aryl-CH), 6.99 (s, indole-CH), 2.40-2.37 (stacked singlet, 6H, aryl-CH3 ), 1.68(s,9H,C(CH 3 ) 3 ), 1.23(s, 7H, pinacol-CH 3 ) ppm.

[0140] In a fume hood, the crude material from the previous reaction (3.9 g) was charged to a three-neck round-bottom flask equipped with a nitrogen inlet, septum, and stir bar. The flask was placed under nitrogen and further charged with 1.50 g (35.7 mmol) of sodium methoxide, 40 mL of THF, and 10 mL of methanol. The reaction mixture was stirred overnight at room temperature. The next day, 50 mL of water was slowly added to the reaction mixture. The mixture was then transferred to a separatory funnel. The aqueous layer was extracted three times with equal amounts of diethyl ether (approximately 50 mL). The organic layers were combined and diluted with MgSO 4 The mixture was dried at rt and the solvent removed under reduced pressure. The material isolated was a yellow / brown solid. Hexane was added to the product and the mixture was heated using a water bath until the solid dissolved. The hexane solution was cooled to room temperature during which time a solid precipitated. The white solid was isolated by filtration and washed with cold hexane. The product 3k was dried under vacuum to give 1.52 g of material (6.87 mmol, 56.6% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (br s, 1H, NH), 7.93 (ddd, J = 7.9, 1.3, 0.7 Hz, 1H, indole-CH), 7.43-7.39 (m, 1H, aryl / indole-CH), 7.33 (d, J = 2.5 Hz, aryl / indole-CH), 7.30-7.27 (m, 2H, ortho-aryl CH), 7.26-7.15 (m, 2H, aryl / indole-CH), 6.96-6.91 (m, 1H, indole-CH), 2.38 (overlapping singlet, 6H, aryl-CH 3 ) ppm.

[0141] [ka] N 2In a purged glovebox, phosphorus trichloride (0.26 mL, 3.0 mmol) and triethylamine (2 mL, 14 mmol) were added to 60 mL of toluene in a 110 mL glass jar. The solution was placed in a glovebox freezer (-35 °C) for 1 hour to cool. 3-(3,5-Dimethylphenyl)-1H-indole 3k (1.34 g, 6.04 mmol) was weighed into a 20 mL vial and dissolved in 10 mL of toluene. The indole solution was also cooled in the glovebox freezer for 1 hour. The two solutions were removed from the freezer and the cold indole solution was stirred while adding cold PCl. 3 / NEt 3 The solution was added dropwise. A large amount of white precipitate formed during the addition. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction mixture was filtered through Celite to remove triethylammonium chloride and the pale yellow filtrate was pumped to dryness. The resulting white residue was triturated with 40 mL of hexane to leave a white solid. The solid was dried under vacuum for 1 h. Yield: 1.19 g (2.35 mmol, 77.7%) Note: 31 87% pure by P NMR. The material 4k was deemed pure enough to carry on to the next step of the reaction. 31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 103.2(s)ppm.

[0142] [ka] N 2In a purged glovebox, 5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol (5a, 0.32 g, 1.1 mmol) and bis(3-(3,5-dimethylphenyl)indolyl)chlorophosphine (4k, 1.10 g, 2.17 mmol) were weighed into a 110 mL glass jar and dissolved in 60 mL of toluene to produce a yellow solution. Triethylamine (1 mL, 7 mmol) was added dropwise to the solution with stirring, resulting in the immediate formation of a white precipitate. The reaction mixture was stirred overnight at room temperature. The next morning, an aliquot of the reaction mixture was removed, filtered, and 31 The reaction mixture was analyzed by P NMR spectroscopy. The spectrum showed good conversion to the desired product CL3 (105 ppm) at about 82% purity. The reaction mixture was filtered through Celite to remove triethylammonium chloride and the yellow filtrate was pumped to dryness. The filtrate was directly loaded onto a 330 g silica column using liquid injection. The silica gel column was necessary to remove all the accompanying by-products. A 330 g gold silica gel column (5-25% dichloromethane in hexanes) was utilized to purify the product (CL3) along with the rest of the by-products. Overall yield: 47.3%. 1 H NMR (400MHz, C 6 D 6 )δ 7.93(dd,J=12.7,7.9Hz,4H,Ar-H),7.77(d,J=8.1Hz,2H,Ar-H),7.64(d,J=8.2H z,2H,Ar-H),7.51(s,2H,Ar-H),7.44(s,2H,Ar-H),7.26-7.19(m,8H,Ar-H),7.14 -7.02(m,6H,Ar-H),7.02-6.94(m,2H,Ar-H),6.84(d,J=8.3Hz,2H,Ar-H),6.80(d ,J=8.6Hz,4H,Ar-H),6.59(d,J=8.4Hz,2H,Ar-H),2.53(dt,J=17.4,5.7Hz,2H,CH 2 ), 2.40-2.19(m,6H,CH 2 ), 2.18(s,12H,CH 3 ), 2.14(s,12H,CH 3 ), 1.44-1.28(m,8H,CH 2 ).31 P{ 1 H}NMR (162MHz, C 6 D 6 )δ 106.1(s)ppm.

[0143] Examples 1 to 13 and Comparative Examples 1 to 3: In the following Examples 1 to 13 and Comparative Examples 1 to 3, the reaction conversion rate, selectivity, and position selectivity (N / I ratio) were measured using the 6 D 6 In 1 The structure and composition of the product were determined by H NMR. 6 D 6 In 13 This was confirmed by C NMR.

[0144] The reaction mixture 1 H and 13 The hydroformylation of pure substrates involved either catalyst activation during an initial reaction period or catalyst preactivation in toluene prior to hydroformylation, followed by transfer of the activated catalyst to the specific substrate utilized. In addition to linear aldehydes (i.e., n-butanal) as the main product, hydroformylation produced branched aldehydes (i.e., isobutanal) as by-products, which were detected and analyzed by NMR.

[0145] Unless otherwise indicated, the examples and comparative experiments are carried out in a 90 mL flow-through Fisher Porter reactor immersed in an oil bath to establish a reactor temperature of 90° C. The reactor is further equipped with a mass flow meter to precisely control the gas flow, and the reactor pressure is established and maintained by a back pressure regulator. The reactor off-gas is analyzed by an online GC to determine the molar composition. Mixing in the flow reactor is affected by a continuous gas flow through a sparger at the bottom of the reactor. This reactor design is described in detail in U.S. Pat. No. 5,731,472, the teachings of which are incorporated by reference. The reaction rate is expressed as moles of aldehyde produced per volume of catalyst solution per unit time (moles / L-hour), which is further divided by the propylene partial pressure to help attenuate the effect of small, unavoidable fluctuations in the propylene feed rate (rate / olefin). Product selectivity is expressed as the ratio of normal to iso aldehydes (N:I).

[0146] General Hydroformylation Procedure Examples 1-13 and Comparative Examples 1-3 follow the general hydroformylation procedure. In the general hydroformylation procedure, a reactor is charged with Solvent 2 (20 mL) and N 2 Sparge overnight with 500 mL of rhodium (Rh(acac)(CO) 2 A final concentration of 50 ppm Rh and specific ligand (type and equivalent defined in Table 6 below) introduced as a 25 mL solution is added, and the resulting solution is sparged with 1:1 syngas for 3-4 hours to generate the active Rh(ligand)-dicarbonyl hydride catalyst species and remove the toluene overhead. The hydroformylation reaction is then run under 50 psi CO, 50 psi H 2 , and 3-5 psi of olefin (total pressure was 165 psia, with the balance made up of N2). A summary of the initial rates and regioselectivities (N:I) determined over the first 3-4 days of operation is shown in Table 6.

[0147] Catalyst Stability: To determine catalyst stability, the general hydroformylation procedure is run continuously for about one week for each of Examples 1-13 and Comparative Examples 1-3. Rate / olefin is plotted versus time, and the slope of the resulting line provides a quantitative measure of deactivation. A slope of zero indicates no catalyst deactivation, while a more negative slope indicates a faster rate of deactivation, which is undesirable.

[0148] [Table 6]

[0149] [Table 7]

[0150] Problem to be solved: The lack of a good catalytic system constitutes a significant challenge to the commercialization of hydroformylation processes for alkenes. Previously proposed processes suffer from one or more of the following drawbacks: slow reaction rate, low linear selectivity, and high catalyst loading, and poor stability in continuous processes. Poor stability leads to deactivation in continuous processes, which in turn leads to low productivity, and replacing the catalyst increases costs due to the high price of rhodium.

[0151] The present hydroformylation process offers one or more advantages over previously proposed processes, namely, faster reaction rates, improved selectivity, improved stability, and lower catalyst loadings to achieve these.

Claims

【Request 1】 【Chemistry 1】 An indole-functionalized bisphosphoramidite having a formula selected from the group consisting of: R １ ~R ４２ are each independently selected from H, a hydrocarbyl group, a heteroaryl group, a halogen atom, or a heterocarbyl group, with the proviso that R ３５ ~R ４２ At least one of is not H, Y １ ~Y １２ Each of the formula (I): 【Chemistry 2】 where R ４３ ~R ４７ each of which is H, alkyl, aryl, heteroaryl, alkoxy, acyl, carboxyl, carboxylate, cyano, -SO ３ are independently selected atoms or groups selected from H, sulfonate, amino, trifluoromethyl, halogen, a group of formula (II) below, and combinations thereof, with the proviso that: i) R ４４ ~R ４７ two or more of may optionally be joined together to provide one or more cyclic moieties; ii) Y １ ~Y ４ , Y ５ ~Y ８ , and Y ９ ~Y １２ In at least one of each of a) R ４３ ~R ４７ At least one of the formula (II) 【Chemistry 3】 having In the formula, R ４８ ~R ５２ each is an independently selected atom or group selected from H, alkyl, aryl, and alkoxy; or b) R ４４ ~R ４７ two or more of are joined together to provide one or more cyclic moieties; iii) when the indole-functionalized bisphosphoramidite has the formula C1), Y １ ~Y ４ At least one R ４４ ~R ４６ at least one of which has the formula (II):

2. Formula (II) 【Chemistry 4】 2. The indole-functionalized bisphosphoramidite of claim 1, selected from the group consisting of:

3. In formula C1), R １ ~R ２０ is H; In formula C2), R ２１ ~R ３４ is H; In formula C3), R ３５ and R ４２ is H, and R ３６ ~R ４１ 3. The indole-functionalized bisphosphoramidite of claim 1 or 2, wherein each of is methyl.

4. Condition (ii)(a) is true, and R ４４ ~R ４６ 4. The indole-functionalized bisphosphoramidite of claim 1, wherein at least one of the following has the formula (II):

5. Condition (ii)(a) is true, and R ４５ and / or R ４６ 5. The indole-functionalized bisphosphoramidite of claim 1, wherein one of the following has the formula (II):

6. The indole-functionalized bisphosphoramidite is L1) 2,2'-bis((bis(6-mesityl-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L2) 2,2'-bis((bis(6-(3,5-dimethylphenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L3) 2,2'-bis((bis(6-(3,5-di-tert-butylphenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L4) 2,2'-bis((bis(6-([1,1':3',1''-terphenyl]-5'-yl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L5) 2,2'-bis((bis(6-([1,1':3',1''-terphenyl]-5'-yl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L6) 2,2'-bis((bis(6-(4-(tert-butyl)phenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L7) 2,2'-bis((bis(6-(4-methoxyphenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L8) 2,2'-bis((bis(5-(3,5-di-tert-butylphenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L9) 2,2'-bis((bis(4-(3,5-di-tert-butylphenyl)-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, L10) 1,1',1'',1'''-(((4,4',5,5',6,6'-hexamethyl-[1,1'-biphenyl]-2,2'-diyl)bis(oxy))bis(phosphanetriyl))tetrakis(6-(3,5-di-tert-butylphenyl)-1H-indole), L11) 4,4'-bis((bis(6-(3,5-di-tert-butylphenyl)-1H-indol-1-yl)phosphanyl)oxy)-1,1',3,3'-tetrahydro-2,2'-spirobi[indene], L12) 2,2'-bis(((7,8-dihydrocyclopenta[g]indol-1(6H)-yl)(1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene, and L13) 2,2'-bis((bis(6-(3,5-di-tert-butylphenyl)-3-methyl-1H-indol-1-yl)phosphanyl)oxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene.

7. 1. A process for preparing a rhodium-ligand complex, the process comprising: １） (I) a rhodium catalyst precursor; 8. A method comprising combining starting materials comprising: (II) an indole-functionalized bisphosphoramidite according to any one of claims 1 to 7; and, optionally, (III) a solvent.

8. The rhodium catalyst precursor is Rh ２ O ３ , Rh ４ (CO) １２ , Rh ６ (CO) １６ , and Rh(NO ３ ) ３ The method of claim 6, wherein the compound is selected from the group consisting of:

9. The process according to claim 7 or 8, wherein the rhodium-ligand complex has a molar ratio of ligand / Rh of from 1 / 1 to 10 / 1.

10. A rhodium-ligand complex prepared by the method according to any one of claims 7 to 9.

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