Regioselective Substitution of BINOL

1,1′-Bi-2-naphthol (BINOL) has been extensively used as the chirality source in the fields of molecular recognition, asymmetric synthesis, and materials science. The direct electrophilic substitution at the aromatic rings of the optically active BINOL has been developed as one of the most convenient strategies to structurally modify BINOL for diverse applications. High regioselectivity has been achieved for the reaction of BINOL with electrophiles. Depending upon the reaction conditions and substitution patterns, various functional groups can be introduced to the specific positions, such as the 6-, 5-, 4-, and 3-positions, of BINOL. Ortho-lithiation at the 3-position directed by the functional groups at the 2-position of BINOL have been extensively used to prepare the 3- and 3,3′-substituted BINOLs. The use of transition metal-catalyzed C–H activation has also been explored to functionalize BINOL at the 3-, 4-, 5-, 6-, and 7-positions. These regioselective substitutions of BINOL have allowed the construction of tremendous amount of BINOL derivatives with fascinating structures and properties as reviewed in this article. Examples for the applications of the optically active BINOLs with varying substitutions in asymmetric catalysis, molecular recognition, chiral sensing and materials are also provided.


INTRODUCTION
1,1′-Bi-2-naphthol (BINOL) is a fascinating and versatile chiral molecule that has garnered enormous attention in the fields of chemistry and materials science.It represents a unique class of atropisomeric compounds characterized by two naphthol rings connected by a 1,1′-bond with restricted rotation which imparts stable chiral configuration.Many methods have been developed to either resolve the racemic mixture of BINOL into its two enantiomers, 1−16 (R)-and (S)-BINOL, or directly prepare one of the enantiomers via asymmetric synthesis, 17−35 leading to the optically active BINOL.
The optically active BINOL has also become commercially available in large scale.When the optically active BINOL in dioxane solution was heated at 100 °C for 24 h, no racemization was observed. 2The energy barrier for the racemization of BINOL was determined to be 37.8 kcal/mol by heating its diphenyl ether solution at 220 °C. 36Under strongly acidic or basic conditions, BINOL undergoes a faster racemization, but the alkyl ethers of BINOL possess further enhanced stability.−50 It has become indispensable for many chemists and other researchers striving to create intriguing molecular, supramolecular, and macromolecular structures with precise control over their stereochemistry.Optically active BINOL not only can be directly used to conduct many asymmetric catalytic processes in the presence of various metal complexes but has also served as the starting material for the preparation of a great number of chiral catalysts, molecular probes, polymers, dendrimers, metal−organic frameworks (MOFs), and covalent organic frameworks (COFs), etc.
The direct electrophilic substitutions of the optically active BINOL are among the most convenient ways to modify the structure of BINOL.Remarkable regioselectivity has been observed in these reactions which has allowed the selective introduction of functional groups at the 6-, 5-, 4-, and 3-positions for the construction of many appealing chiral structures for diverse applications.The ortho-lithiation of BINOL at the 3position has allowed the introduction of a variety of functional groups at this position and has been extensively used in modifying the steric and electronic environment of asymmetric catalysts and molecular hosts. 51,52In recent years, transition metal-catalyzed C−H bond activation has also been utilized to functionalize BINOL at the 3-, 4-, 5-, 6-, and 7-positions with high regioselectivity.This paper will focus on reviewing these three types of regioselective substitution of the optically active BINOL.The closely related reactions of the racemic BINOL are also included.Examples of the optically active substituted BINOLs used in asymmetric synthesis, molecular recognition, chiral sensing, and materials are provided.Although substitutions of the hydroxy groups at the 2,2′-positions of BINOL with other functional units are also very useful to synthesize structurally modified BINOLs, 37−46 they will not be discussed in this review.
In one of the naphthol rings of BINOL, although the electrondonating hydroxy group can provide resonance stabilization for the carbon cation intermediates formed by electrophilic attack at the positions 3, 6, and 8 as shown in Figure 1, only the 6brominated product was obtained and no bromination at the 3or 8-positions.Figure 2 gives the HOMO orbital of (S)-BINOL obtained by a density functional theory (DFT) calculation using the Gaussian program (B3LYP) with 6-31G basis set.It shows that a node plane goes through the 3-carbon of the naphthol ring, which should make electrophilic addition at this position unfavorable.The steric environment around the 8-position should hinder substitution at this position.Thus, a highly regioselective electrophilic substitution at the para 6-position is generally observed as the most favorable reaction, giving the 6,6′-dibrominated compound (R)-1 as the predominated product.
Tetrabutylammonium tribromide (TBATB) was used for bromination of a 3,3′-ditriflate substituted BINOL (Scheme 2). 107When racemic 18 was heated with TBATB in a mixed solvent of chloroform and methanol at reflux for 20 h, the 6,6′dibrominated product 19 was obtained in 43% yield.This compound was used to prepare bowl-shaped cyclophanes in the construction of proton-responsive supramolecular polymers.

Nitration
When racemic BINOL in acetic acid/CH 2 Cl 2 solution was treated with nitric acid at room temperature for 16 h, 6,6′-dinitroBINOL (35) was obtained in 74% yield (Scheme 8). 123he nitro groups were converted to amine groups by hydrogenation of the dimethyl ether of 35.Compound 35 was also obtained in 61% yield by reacting BINOL with t BuONO in THF at room temperature (Scheme 8). 1246-NitroBINOL (36)  was obtained in 62% yield from the reaction of BINOL with concentrated nitric acid in dioxane at room temperature. 125e 6,6′-diamine compound (S)-37 was obtained from the hydrogenation of the dimethyl ether of (S)-35, which was then polymerized with a dialdehyde linker to give a polymer 38. 126his polymer showed fluorescence enhancement in the presence of F − .When the optically active (S)-44 was treated with fuming nitric acid in CH 2 Cl 2 /acetic acid, a mixture of 6-nitro and 8-nitro products (S)-45 and (S)-46 were obtained (Scheme 10). 131hese compounds were characterized by X-ray analyses.

Sulfonation or Thiolation
Treatment of a BINOL dialkyl ether with concentrated sulfuric acid at 50 °C for 16 h gave the 6,6′-disulfonic acid BINOL 47 in 75% yield (Scheme 11). 132In this reaction, two additional sulfonic acid groups were also introduced to the R groups.This compound showed significant affinity for uranyl ion.Chlorosulfonic acid (2.4 equiv) was also used as the sulfonation agent to react with (S)-BINOL-Me in CH 2 Cl 2 at 0 °C for 7 h (Scheme 12).After treatment with NaOH, (S)-48 was obtained in 85% yield. 133(S)-48 was used to form an ionic polymer with a chiral quaternary ammonium salt to catalyze the asymmetric alkylation of a glycine ester.Reaction of (R)-BINOL dihexyl ether with chlorosulfonic acid (12 equiv) in CHCl 3 at 0 °C to room temperature gave the 6,6′-dichlorosulfonyl product (R)-49 in 40% yield. 134(R)-49 was then converted to (R)-50 to catalyze asymmetric reactions such as an alkyne addition to aldehydes, a Zr-based Mannich-type reaction and an organocatalyzed Morita−Baylis−Hillman transformation.The macrocycle (S)-51 was synthesized from (S)-49 (R = n C 4 H 9 ) and used for enantioselective extraction of phenylglycine from aqueous solution to chloroform. 135hen (S)-or (R)-3,3′-diformylBINOL was treated with concentrated sulfuric acid at 40 °C for 18 h followed by addition of Na 2 CO 3 , compound (S)-or (R)-52 was obtained in 24% yield (Scheme 13). 136(S)-or (R)-52 was used as a water-soluble fluorescent probe for the enantioselective recognition of amino acids in aqueous solution.Compound (R)-53 with emission >730 nm, obtained from the condensation of (S)-52 with a rhodamine derivative, was used as a near-IR fluorescent probe for enantioselective recognition of amino acids. 137Combination of the green light emitting probe (S)-52 with the red light emitting probe (R)-54 allowed visual quantification of amino acid enantiomeric composition. 138rifluoromethyl sulfoxide 55 was used as a trifluoromethyl thiolation agent to react with BINOL-Me at −25 °C to room temperature in the presence of Tf 2 O and Et 2 NH to give the 6,6′dithiolated product 56 in 28% yield (Scheme 14). 139ianthrene-S-oxide 57 was used to react with BINOL-Me in the presence of Tf 2 O in CH 2 Cl 2 at −78 °C to room temperature which gave the 6,6′-disubstituted product 58 in 45% yield (Scheme 15). 140Treatment of 58 with KCN in acetonitrile at 80 °C for 12 h, a nucleophilic cine-substitution occurred to give the 5,5′-dicyano product 59 in 51% yield.Thus, this reaction allows the 6,6′-substituion of BINOL to be used to selectively functionalize the 5,5′-positions.the pure 6,6′-t Bu 2 BINOL (R)-or (S)-60 was obtained in ∼80% yield after hexane extraction (Scheme 16). 141NMR and X-ray analyses established the structure of this compound.This compound was used to prepare various phosphite and phosphoramidite derivatives to catalyze the asymmetric reduction of ketones.When the reaction of BINOL with t BuCl in the presence of AlCl 3 was conducted at 0 °C or room temperature, black materials were generated.
Reaction of (R)-BINOL with 2 equiv of 1-adamantanol in CH 2 Cl 2 in the presence of concentrated sulfuric acid gave a product in 60% yield, which was initially reported as a 3,3′disubstituted compound 142 and was later corrected as the 6,6′di(adamantan-1-yl)BINOL (R)-61 on the basis of a single crystal X-ray analysis (Scheme 17). 143This compound was converted to the corresponding chiral phosphoric acid to catalyze the asymmetric conjugated hydrocyanation of aromatic enones.A similar synthesis of (R)-61 was later reported in 95% yield. 144Compound (R)-62 was obtained in the same way by using diphenylmethanol in place of 1-adamantanol, and it was used to prepare catalysts for tandem Michael addition/ enantioselective Conia-ene cyclization. 145he 6,6′-dibromomethylBINOL dialkyl ether (S)-63 was synthesized from the reaction of a BINOL alkyl ether with a large excess amount of paraformaldehyde and HBr in glacial acetic acid at room temperature for 36 h (Scheme 18). 146This compound was applied for chiral molecular switch study.

Acylation
Aryl carboxylic acids were used for the 6,6′-diacylation of BINOL-Me in the presence of P 2 O 5 and methanesulfonic acid.The reactions were conducted at room temperature or 60 °C over 24 h to give the aryl ketones 64 in 71−100% yields (Scheme 19). 147Chiral polyaromatic ketones 65 were synthesized from the polymerization of (S)-64 (Ar = 4−F-C 6 H 4 ) with diols in the presence of K 2 CO 3 . 148Fluorescence properties of similar BINOL-based polyketones were studied. 149lkyl and aryl acyl chlorides were used to react with (R)-BINOL-Me in the presence of anhydrous AlCl 3 in CH 2 Cl 2 at −45 °C to room temperature over 3−8 h to give the 6,6′-diacyl compound (R)-66 in 68−87% yields (Scheme 20). 150These BINOL-based ketones were used to synthesize compounds such as 67 and 68 with extended fused arenes for optical and electrochemical study. 151,152The 6,6′-diacyl compound 69 showed enhanced two-photon absorption in the near-infrared region, and it can be used for photocleavable drug delivery. 153eaction of ethyl succinyl chloride (1.1 equiv) with (R)-BINOL-Me was conducted in the presence of AlCl 3 (1.1 equiv) at 0 °C to room temperature to give the monoacyl product (R)-70 in 60% yield. 154(R)-70 was converted to a polystyrene supported binaphthyl-2,2′-bis(diphenylphosphine) (BINAP) ligand for asymmetric hydrogenation.It was also converted to a polyethylene glycol-supported BINOL (R)-71, which in combination with Ca 2+ was used to catalyze the asymmetric Michael addition and epoxidation. 155-Acylation of a 6-substituted BINOL derivative 72 was conducted in the presence of ArCOCl and AlCl 3 at 0 °C for 4 h.After hydrolysis, a BINOL-based hydroxy ketone derivative 73 with two different functional groups at the 6,6′-positions was obtained in 74% yield.156

ELECTROPHILIC SUBSTITUTION AT 5-POSITION
In 2011, Yang et al. reported that when the acetate of (R)-BINOL was treated with bromine (6 equiv) in CH 2 Cl 2 in the presence of pyridine at room temperature for 81 h, a 5,5′dibromination took place to give (R)-74 in 42% yield (Scheme 21). 157The structure of this compound was confirmed by a single crystal X-ray analysis of its derivative (R)-75 prepared from the reaction of (R)-74 with imidazole in the presence of CuI followed by hydrolysis.The reduced electron-donating effect of the acetate groups versus the hydroxyl groups of BINOL have changed the regioselectivity of the electrophilic substitution from the 6-position to the 5-position.The monobromide (R)-76 was later prepared under the condition similar to the synthesis of (R)-74 and was used to make the dimeric compound (R)-77. 158Formation of (R)-74 and (R)-76 from the bromination of BINOL diacetate demonstrates that the regioselectivity in the electrophilic substitution of BINOL is highly sensitive toward the electronic property of the 2,2′hydroxyl groups.
In 2014, Agnes et al. conducted X-ray analyses on the products obtained in the bromination of BINOL.Formation of a small amount of a 5-brominated side product was identified. 159hat is, besides the formation of the predominated product 6,6′-Br 2 BINOL, (R)-or (S)-1, the 5,6′-dibromoBINOL 78 was also generated, albeit in very low yield.This indicates that the 5position could be the next reactive site after the 6-position in the electrophilic substitution.The 5,5′-dibromination shown in Scheme 21 demonstrates that when the electron-donating effect of the two hydroxyl groups is reduced, the 5,5′-positions becomes more reactive than the 6,6′-positions.
An intramolecular electrophilic substitution at the 5-position of BINOL was used to prepare helical ladder polymers as shown in Scheme 25. 165,166 Treatment of the 6,6′-polymerized BINOLs (R)-85a and (S)-85b with CF 3 CO 2 H in CH 2 Cl 2 led to an intramolecular cycloaromatization to form the helical ladder polymers (R)-86a and (S)-86b with fused polyaromatic rings in the repeating units.In the conversions of the polymers from (R)-85a and (S)-85b to (R)-86a and (S)-86b, the intramolecular electrophilic substitution is expected to occur selectively at the 5-position but not at the 7-position, which is supported by the reactions shown in Scheme 22−24.No electrophilic reaction at 7-positon is observed for BINOL and its derivatives.The fluorescence response of polymer (S)-86b toward amines was studied. 166

ELECTROPHILIC SUBSTITUTION AT 4-POSITION
In 1978, Cram et al. reported that when racemic BINOL-Me was treated with bromine (7.8 equiv) in CHCl 3 at 25 °C for 18 h, the 4,4′,6,6′-tetrabrominated compound 87 was obtained in 91% yield (Scheme 26). 160This result is in sharp contrast to the reaction of BINOL with excess bromine in refluxing CH 2 Cl 2 , which gave the 5,5′,6,6′-tetrabromo product 79 (see Scheme  22).This indicates that there is a subtle difference between the reactivity at 4-and 5-positions.After the 6-position is substituted with a bromine atom, further bromination of the unalkylated BINOL containing the more electron-donating hydroxyl groups occurs at 5-position, but that of the alkylated BINOL containing the less electron-donating alkoxy groups occurs at the less sterically hindered 4-position.
An intramolecular electrophilic substitution at the 4-position of BINOL was used to prepare chiral ladder polymers similar to the reaction at the 5-position shown in Scheme 25.Treatment of the 3,3′-polymerized BINOL (R)-104 with CF 3 CO 2 H in CH 2 Cl 2 led to an intramolecular cycloaromatization at the 4positions of the BINOL units to form the helical ladder polymer (R)-105 with fused polyaromatic rings in the repeating units. 165
In the reactions to form compounds 106−108, the electrophile is an iminimium ion generated from the alkoxymethyl amine, which can react with BINOL via a transition state like 110 (Scheme 30).Formation of the intermediate 111 from 110 gives the regioselective aminomethylation at the 3-position.The intermediate 111 undergoes tautomerization and proton loss to give the final product.
In 2005, Qin et al. reported the use of the optically pure (S)-BINOL to react with morpholinomethanol, generated from the reaction of morpholine with paraformaldehyde without purification, to synthesize the optically active (S)-106 (Scheme 31). 183,184When the reaction was conducted at 160 °C, the resulting product 106 was completely racemizaed.When the reaction was conducted at 95−100 °C under 30 psi N 2 for 3 d, (S)-107 was obtained in 60% yield with >99% ee.When the react was conducted at 110 °C under 30 psi N 2 for 3 d, (S)-106 was obtained in 55% yield with 75% ee which after recrystallization gave (S)-106 in 37% yield and >99% ee.The crystal structure of (S)-106 was obtained by X-ray analysis.(S)-106 was used to catalyze the asymmetric reactions of aldehydes with diphenylzinc and TMSCN.
In 2013, Truong and Daugulis reported the 3-and 3,3′arylation of BINOL by reaction with aryl chloride in the presence of t BuONa and AgOAc at elevated temperature (Scheme 32). 185When BINOL was reacted with 6 equiv of PhCl, 9 equiv of t BuONa, and 2 equiv of AgOAc in dioxane at 155 °C sealed under N 2 for 95 h, the 3,3′-diphenylBINOL 112 was obtained in 51% yield.The monophenyl product 113 was also obtained by the reaction of BINOL with 3.4 equiv of PhCl, 6 equiv of t BuONa, and 1.7 equiv of AgOAc at 155 °C for 48 h.Reaction of 113 with an more electron-deficient m-fluorochlorobenzene at a lower temperature gave the unsymmetrically 3,3′-diarylated product 114 in 60% yield.When the enantiomerically pure (R)-BINOL was used to react with mchloroanisole, the resulting monoarylated product (R)-115 was obtained with high enantiomeric purity (Scheme 33).Thus, the extent of racemization was very low even though the reaction was conducted at 130 °C.
A benzyne addition mechanism might be involved in these reactions as shown in Scheme 34.Benzyne generated from the reaction of phenyl chloride with t BuONa and AgOAc can react with the deprotonated BINOL to form the 4-membered ring intermediate 116.Ring-opening of 116 can give 117, which upon protonation and tautomerization should give the arylated product.
Reaction of the alkaline solution of BINOL with the diazonium chlorides prepared from β-naphthylamine at 0−5 °C gave the 3,3′-bis(diazene) compound 118 (Scheme 35). 186his compound was used to prepare the dinuclear complexes of metal ions including Co(II), Cu(II), Ni(II), Zn(II), Cd(II), and Hg(II).Compounds 119 and 120 as well as their metal complexes were also prepared in a similar way. 187t was found that when the 6,6′-positions of BINOL are substituted with bulky groups such as t Bu or 1-adamantanyl, the subsequent electrophilic substitutions take place at the least sterically hindered 3-position even though this position is not electronically favorable as shown by the HOMO orbital of BINOL in Figure 2. When (S)-6,6′-t Bu 2 BINOL, (S)-60, was reacted with t BuCl and AlCl 3 further at 0 °C for 1 h and at room temperature for 12 h, (S)-3,3′,6,6′-t Bu 4 BINOL, (S)-121, was obtained in 8−12% yield (Scheme 36). 141Reaction of (S)-60 with excess bromine in CH 2 Cl 2 at −78 °C for 3 h gave the 3,3′dibromo product (S)-122 in 80% yield.The structures of these 3,3′-substituted compounds were established by NMR and Xray analyses.

ELECTROPHILIC SUBSTITUTION AT 8-POSITION
As discussed in section 2.1, the 2-hydroxyl group of BINOL can provide resonance stabilization for the carbon cation intermediates formed from the electrophilic attack at the 3-, 6-, and 8positions of the 2-naphthol ring (see Figure 1).The node plane in the HOMO orbital of BINOL (see Figure 2) makes the electrophilic reaction less favorable at the 3-position, and the steric hindrance makes the reaction less favorable at the 8position.Thus, very few examples for the electrophilic substitution of BINOL at 8-position were reported.In section 2.4, nitration of (S)-44 gave 8-nitro product (S)-46 as a minor product in 18% yield (see Scheme 10). 131In this example, the high reactivity of the nitration agent might have partially overcome the steric hindrance at the 8-position to give the observed low yield production of the 8-substituted compound.The major product was the 6-substituted compound (S)-45.In Scheme 28, it is shown that when BINOL-Me was treated with excess iodonation agent 31 and TfOH, triflation at the 8,8′positions can take place to give compounds 102 and 103a−c after the 4,4′,6,6′-positions were substituted. 182The triflation reaction may be an oxidative nucleophilic substitution by TfOī nvolving a single electron transfer between a hypervalent intermediate like I(OTf) 3 and the BINOL compound.

ORTHO-LITHIATION AT 3-POSITION
Because the 3-and 3,3′-positions of BINOL are close to the active sites when BINOLs are applied in asymmetric synthesis, catalysis, and molecular recognitions, a great number of the 3and 3.3′-substituted BINOL derivatives have been synthesized in order to modify the steric and electronic environment of BINOL for those applications.Most of those compounds are prepared by ortho-lithiation of BINOL, directed by the ether, methoxymethyl ether, and other functional groups at the 2,2′positions, followed by reactions with a great variety of electrophiles.
In this section, the ortho-lithiation reactions are classified according to the O-protecting groups (P) of the BINOL substrates as shown by 132a.Among these, the conversions of 132a containing P = Me, MeOCH 2 , and P(O)R 2 to the products 132b are further categorized according to the electrophilic additions used to introduce the X groups after the ortholithiation.

Reactions of BINOL Methyl Ether
Ortho-lithiation of BINOL-Me was used to prepare many 3-and 3,3′-substituted BINOLs.BINOL-Me was generally prepared from the reactions of BINOL with MeI in the presence of K 2 CO 3 191 or with Me 2 SO 4 in the presence of NaOH 214 or with NaH followed by reaction with Me 2 SO 4 . 217.1.1.Halogenation.In 1981, Cram and co-workers reported the ortho-lithiation of racemic, (R)-and (S)-BINOL-Me with n BuLi in the presence of tetramethylethylenediamine (TMEDA) to make racemic, (R)-and (S)-3,3′-dibromoBINOL 133 via an intermediate like 134 (Scheme 39). 191In this reaction, the methoxy groups of the substrate directed the lithiation at the ortho-position and TMEDA increased the basicity of n BuLi for deprotonation.The reaction was conducted by treatment of BINOL-Me with 2.3 equiv of n BuLi and 2.1 equiv of TMEDA at 25 °C for 3 h, followed by addition of excess bromine (9.4 equiv) at 75 °C for 10 min and then at 25 °C for 4 h to give 133 in 72% yield.This compound was used to prepare 3,3′-substituted BINOLs, which were then used to make crown ethers for chiral recognition.For example, the Ni(II)-catalyzed cross coupling of 133 with PhMgBr gave the 3,3′-diphenyl compound and the methyl ether was hydrolyzed after treatment with BBr 3 to give 3,3′-Ph 2 BINOL, 112.In the same way, the optically active (S)-BINOL-Me was used to prepare various (S)-3,3′-diarylBINOLs such as (S)-112, (S)-135a, and (S)-135b. 192hese compounds were used in combination with BH 3 •THF to promote the asymmetric Diels−Alder reactions.−202 The reaction was conducted by treatment of BINOL-Me in Et 2 O with 3.7 equiv of n BuLi and 3.7 equiv of TMEDA at 20 °C for 6 h, followed by addition of excess I 2 (4.0 equiv) at −78 °C, which gave (R)-136 in 90% yield. 201This compound was used to prepare 3,3′-diarylBINOLs for the Y(III)-catalyzed asymmetric olefin hydroamination/cyclization. 202−208 7.1.2.Borylation.In 1998, Jørgensen and co-workers prepared (R)-3,3′-diboronic acid BINOL, (R)-137, from the reaction of (R)-BINOL-Me with n BuLi-TMEDA, followed by addition of B(OEt) 3 at −78 °C and then acidic hydrolysis (Scheme 41). 209(R)-137 was purified by recrystallization from toluene and was used to prepare a series of optically active 3,3′diaryl BINOLs by the Suzuki couplings with aryl bromides, followed by removal of the methyl groups with BBr 3 .−212 Racemic 137 was prepared in 48% yield by ortho-lithiation of racemic BINOL-Me followed by addition of B(OMe) 3 , which was used to react with a variety of aryl halides (Ar-X) to prepare a number of racemic 3,3′-diaryl BINOLs. 213The use of B(OMe) 3 gave lower yield than the use of B(OEt) 3 (87%) for the synthesis of the BINOL 3,3′-diboronic acid 137.
7.1.5.Addition to Aldehydes and Ketones.When BINOL-Me was treated with 2.9 equiv of n BuLi in THF solution at room temperature for 3 h followed by the addition of isovaleraldehyde and acetone at −78 °C, the mono-and disubstituted compounds 143−146 were obtained (Scheme 44). 214en the ortho-lithiated (R)-BINOL-Me was reacted with benzophenone, (R)-147 was obtained in 60% yield (Scheme 45). 215The fluorescence of this compound was studied.
7.1.6.Addition to Acyl Chloride.After (S)-BINOL-Me was treated with 5 equiv of n BuLi in Et 2 O at room temperature for 3 h, addition of 5 equiv of benzoyl chloride gave (S)-3,3′-dibenzoylBINOL, (S)-148, in 72% yield upon acidic workup (Scheme 46). 2161.7.Addition to DMF.When the ortho-lithiated BINOL-Me was reacted with DMF at 0 °C, a 3,3′-diformyl product 149 was obtained in 70% yield after acidic hydrolysis (Scheme 47).217 The monoformyl product 150 was also obtained in 20% yield.Because BCl 3 was found to only promote the cleavage of the ether at the ortho-position of the carbonyl, a mixture of 149 and 150 were deprotected with BCl 3 rather than BBr 3 .This gave a mixture of 151 and 152, which were easily separated because, unlike 151, compound 152 was not soluble in NaOH solution.
When the ortho-lithiation of the optically active (S)-BINOL-Me was conducted in THF at 0 °C, compound (S)-149 was obtained only in 24% yield.However, when the ortho-lithiation was conducted in refluxing Et 2 O solution followed by reaction with DMF, (S)-149 was obtained as the only product in 76% yield. 218This compound was enantiomerically pure as determined by HPLC analysis.
(S)-or (R)-149 was used to prepare compound (S)-or (R)-153 as a fluorescent probe for chiral discrimination of monosaccharides, 219 and sugar acids. 220,221Compound (S)-154 was synthesized from (S)-3,3′-diformylBINOL, (S)-151, for optical study. 2221.8.Addition to CO 2 .Ortho-lithiation of (S)-BINOL-Me with n BuLi and TMEDA in refluxing Et 2 O was used to prepare a 3,3′-dicarboxylic acid BINOL (Scheme 48).223 After the lithiation, dry CO 2 gas was introduced to the reaction mixture at 0 °C to give (S)-155, which was isolated in 66% yield after acidic workup and recrystallization from benzene.This compound was used as a precursor to modify the structure of iron porphyrins to catalyze the asymmetric epoxidation of styrene derivatives.
7.1.9.Addition to Cr(CO) 6 .Ortho-lithiation of racemic (R)-and (S)-BINOL-Me were used to prepare the Fischer-type carbene complexes. 224After the racemic BINOL-Me was treated with 4 equiv of t BuLi in THF at −40 °C for 6 h, Cr(CO) 6 was added to react at −40 °C for 5 h and then at 0 °C for 15 h (Scheme 49).Removal of the solvent followed by the addition of Me (R)-/(S)-158 were obtained and their CD and UV−vis absorption spectra were studied.(R)-156 was reacted with 3hexyne in refluxing THF, with further substitutions at the 4,4′positions of the BINOL unit to give the benzannulation product (R)-159 (Scheme 50).When the benzannulation was followed with oxidative demetalation in the presence of (NH 4 ) 2 Ce-(NO 3 ) 6 , the chiral bisphenanthrenequinones (R)-160 and (R)-161 were obtained in 36−56% yields. 225everal methods were tested for the demethylation of (R)-160 and different products were obtained depending upon the reagents used (Scheme 51). 225Using excess amount of BBr 3 not only removed the methyl groups but also brominated at the 6,6′positions to give (R)-162.The use of TMS-I produced a central furan ring in the product (R)-163 whose X-ray structure was obtained.When AlCl 3 (10 equiv) were used, clean demethylation took place to give (R)-164.The two quinone units of compounds (R)-160, (R)-161, and (R)-164 were shown to be electrochemically independent by their CV plots.

Reactions of Other BINOL Alkyl Ethers
BINOL dihexyl ether was used to prepare the diboronic acid 165, which was purified by column chromatograph on silica gel eluted with ethyl acetate/petroleum ether followed by recrystallization from ethyl acetate (Scheme 52). 226Compound 165 was then converted to the corresponding boronic ester to Scheme 50.Cycloaddition of the BINOL Carbene (R)-156 with 3-Hexyane make polymers for LED application.The monoboronic acid (R)-166 was synthesized from (R)-BINOL diethyl ether in a similar way in 51% yield after purification by column chromatography on silica gel. 111 BINOLbis(dichlorodifluoroethyl) ether (R)-167 was prepared from (R)-BINOL in 96% yield (Scheme 53). 227en this compound was treated with 12 equiv of n BuLi in THF at −78 °C to room temperature, a remarkably clean rearrangement took place, which upon quenching with 1 N HCl gave (R)-3,3′-diethynylBINOL, (R)-168, in 90% yield.The basepromoted dehalogenation of (R)-168 could generate an anionic intermediate like 169, which could undergo cyclization to form 170 (Scheme 54). 228Ring-opening of 170 would give 171, which upon acidic workup would give the product (R)-168.This compound was used to prepare bisBINOL macrocycles by Sonogashira coupling reactions.

Reactions of Alkyl Bridged BINOLs
BINOL with a methylene bridge was synthesized from the reaction of BINOL with CH 2 I 2 in the presence of t BuOK (Scheme 55). 218The resulting product 172 was subjected to ortho-lithiation followed by reaction with DMF to give the monoaldehyde 173 and the dialdehyde 174 in low yields.
Reaction of (S)-BINOL with Br(CH 2 ) n Br (175, n = 1 or 3) in the presence of NaI and K 2 CO 3 in acetone at 60 °C gave compounds (S)-172 and (S)-176 (Scheme 56). 229In the reaction of (S)-172 with n BuLi, DME (dimethoxyethane) was added instead of TMEDA.After the ortho-lithiation, CO 2 gas was introduced, which upon acidic workup gave (S)-177 in 63% yield.For the reaction of (S)-176 to synthesize (S)-178, a mixed solvent of Et 2 O and THF was used and DME was also added.These compounds were used to prepare polymeric membranes.

Reactions of BINOL Methoxymethyl Ether
Ortho-lithiation of BINOL dimethoxymethyl ether (BINOL-MOM) followed by reaction with a broad range of electrophiles has been used to prepare many 3,3′-disubstituted or 3monosubstituted BINOLs for diverse applications.This section is classified according to the reactions of the ortho-lithiated BINOL-MOM with various electrophiles.BINOL-MOM was prepared from the reaction of BINOL with MOMCl in the presence of dry K 2 CO 3 214 or with NaH followed by addition of MOMCl. 297,313The MOM groups can be easily removed by treatment with HCl(aq) or CF 3 CO 2 H. prepare various 3-or 3,3′-functionalized BINOLs. 230When BINOL-MOM was treated with 2.2 equiv of t BuLi in THF at −78 °C for 1 h, followed by the addition of 1,2dibromotetrafluoroethane, the monobrominated compound 179 was obtained in 72% yield (Scheme 57).
A 3-monothiolated BINOL-MOM 183 (see Scheme 68 for synthesis) was treated with 2 equiv of n BuLi in Et 2 O at room temperature for 3 h, which was then reacted with a chlorination or a bromination agent to give the unsymmetrically 3,3′disubstituted products 184 and 185 in 72−84% yields (Scheme 59). 230 the reactions of BINOL-MOM with an alkyl lithium, intermediates like 186 and 187 may be involved to direct the ortho lithiation at the 3-position of BINOL before the subsequent reaction with electrophiles.
3,3′-Dihydroxy BINOL was prepared from ortho-lithiation followed by borylation and oxidation.As shown in Scheme 65, after ortho-lithiation of (S)-BINOL-MOM with n BuLi in THF, B(OMe) 3 was added to give a 3,3′-diborylated compound.Without isolation of this diborylated compound, it was oxidized by H 2 O 2 (30% aq) to give (S)-197 in 88% yield. 2334.3.Zincation.When the ortho-lithiated (S)-BINOL-MOM was reacted with ZnCl 2 , the arylzinc product (S)-198 was obtained in 93% yield (by 1 H NMR analysis) (Scheme 66).268 The stock solution of (S)-198 in THF was stored at −20 °C under argon for subsequent cross coupling reactions with aryl bromides, followed by further conversions to make the 3,3′- When BINOL-MOM was treated with 3 equiv of n BuLi in Et 2 O at room temperature for 3 h, followed by the addition of R 3 SiCl, the 3,3′-disilyl products 200 and 201 were obtained in 79% and 51% yields, respectively (Scheme 67).In the reaction of Ph 3 SiCl to form 201, HMPA was added as a cosolvent.230 The 3,3′-disilyl BINOLs such as (R)-202a−d were prepared in a similar way after removal of the MOM groups and used for asymmetric catalysis.102,269−277 For example, these compounds in combination with AlMe 3 were used to catalyze the asymmetric hetero-Diels−Alder reaction of enamide aldehydes with Danishefsky's diene.102 7.4.5.Thiolation and Selenation.When BINOL-MOM was treated with 2.2 equiv of t BuLi in THF at −78 °C for 1 h followed by the addition of PhSSPh, the monothiolated product 183 was obtained in 71% yield (Scheme 68).230 When BINOL-MOM was treated with 3 equiv of n BuLi in Et 2 O at room temperature for 3 h followed by the addition of PhSSPh, the dithiolated product 203a was obtained in 89% yield.8,279 When the electrophile was MeSeSeMe, the 3,3′-diselenate (S)-204 was obtained.278 These compounds were deprotected by reaction with HCl (37%) in methanol at room temperature to give the deprotected products (S)-205a−c and (S)-206. Thewere used in combination with [Cu(MeCN) 4 BF 4 to catalyze the Michael addition of dialkylzincs to enones.278 The undeprotected compound (S)-203b was used for the asymmetric Simmons−Smith-mediated epoxidation.279 The 3,3′-dimercap-to compound (R)-207 was obtained in 85% yield from the reaction of the ortho-lithiated (R)-BINOL-MOM with S 8 followed by deprotection.280 This compound was used to catalyze the asymmetric intramolecular Morita−Baylis−Hillman and Rauhut−Currier reactions.7.4.6.Azidation.Azide groups were incorporated into BINOL by ortho-lithiation. Treent of (S)-BINOL-MOM with t BuLi at −78 °C in THF followed by the addition of TosN 3 gave the monoazide product (S)-208 in 59% yield (Scheme 69).281 Reaction of (S)-BINOL-MOM with n BuLi in Et 2 O at 0 °C to room temperature followed by the addition of TosN 3 gave the diazide (S)-209 in 63% yield.The "click" cyclization of these compounds with a variety of terminal alkynes were conducted to give compounds (S)-210 and (S)-211.These compounds were used in combination with Ti(O i Pr) 4 to catalyze the reaction of ZnEt 2 with aldehydes.
7.4.7.Phosphorylation.Ortho-lithiation of BINOL-MOM with n BuLi in THF solution at room temperature followed by the addition of diphenylphosphinic chloride gave the mono and disubstituted products 212 and 213 (Scheme 70). 214(R)-214 was obtained in 70% yield from the reaction of (R)-BINOL-MOM with n BuLi in Et 2 O/THF followed by treatment with Ph 2 PCl. 282After removal of the MOM groups of (R)-214 with HCl/MeOH, it was then converted to (R)-215, which in combination with [Rh(cod) 2 ]BF 4 was used to catalyze the asymmetric hydrogenation of aryl enamides.7.4.8.Alkylation.When BINOL-MOM was treated with 2.2 equiv of t BuLi in THF at −78 °C for 1 h, followed by the addition of MeI, the monomethylated product 216 was obtained in 71% yield (Scheme 71). 230When (S)-BINOL-MOM was treated with 3 equiv of n BuLi in Et 2 O at room temperature for 3 h, followed by the addition of MeI, the 3,3′-dimethylated product (S)-217 was obtained in 82% yield (Scheme 72).
Retention of the chiral configuration of BINOL in this reaction was established. 230(R)-217 was obtained in 96% yield by a slightly modified procedure. 231,262,272After deprotection with Amberlyst 15, the resulting compound (R)-218 was used for the asymmetric allyboronate addition to aldehydes.The ortholithiated racemic BINOL-MOM was reacted with 1-bromooctane to give 219 in 81.9% yield. 232Treatment of 219 in THF with HCl (concentrated) removed the MOM groups to give 220 in >99% yield without the need for further purification.
7.4.9.Addition to Ethylene Oxide and Propylene Oxide.Ortho-lithiation of BINOL-MOM with n BuLi in THF solution at room temperature followed by the addition of ethylene oxide gave the mono-and disubstituted products 225 and 226 (Scheme 74). 214he reaction of the ortho-lithiated (S)-BINOL-MOM with ethylene oxide was further investigated to synthesize (S)-226 (Scheme 75).After the starting material was treated with 3 equiv of n BuLi in THF at room temperature for 8 h, 50 equiv of ethylene oxide was added at −78 °C and the reaction mixture was allowed to slowly warm up to 0 °C before workup to give (S)-226 in 56% yield. 284Addition of ethylene oxide and BF 3 • OEt 2 at −96 °C after ortho-lithiation of (R)-BINOL-MOM in Et 2 O solution gave (R)-226 in 50% yield. 285(S)-and (R)-226 were used to prepare compounds such as (S)-227 284 and (R,R)-228, 285 which in combination with La(III) were used to catalyze the asymmetric reaction of dialkyl phosphites with aldehydes (Pudovik reaction) 284 and the aldol reactions. 285rtho-lithiation of (R)-BINOL-MOM followed by reaction with propylene oxide gave the 3,3′-bis(3-hydroxylpropyl)-BINOL, (R)-229, in 51% yields (Scheme 76). 286This compound was converted to the thioacetal (R)-230.The thiolated compounds (R)-231 were prepared from (R)-226.These chiral sulfur-containing compounds were used in combination with CuX 2 (X = OAc, OTf, etc.) to catalyze the asymmetric Michael addition of ZnEt 2 to enones and nitroalkenes.
7.4.10.Addition to Aldehydes.When BINOL-MOM was treated with 2.2 equiv of t BuLi in THF at −78 °C for 1 h followed by the addition of benzaldehyde, the monoaddition product 232 was obtained as a 1.7:1 mixture of diastereomers in 58% yield (Scheme 77). 230rtho-lithiation of BINOL-MOM with n BuLi in THF solution at room temperature followed by the addition of isovaleraldehyde and paraformaldehyde gave the mono-and  214 The MOM groups of the products were removed by reaction with 10% HCl (aq) in methanol solution for 3 h.The optically active compound (S)-234b was prepared from the reaction of (S)-BINOL-MOM with t BuLi in THF at −78 °C followed by the addition of paraformaldehyde (Scheme 79). 281S)-234b was used to make the azide compound (S)-235, which was subjected to the "click" cyclization with phenyl acetylene to make compound (S)-236.This compound was used in combination with Ti(O i Pr) 4 to catalyze the asymmetric reaction of ZnEt 2 with benzaldehyde.
Addition of the ortho-lithiated (R)-BINOL-MOM to an aromatic aldehyde gave (R)-237 as a mixture of diastereomers because of the newly formed chiral alcohol centers (Scheme 80). 287(R)-237 was converted to (R)-238 by deprotection and Et 3 SiH reduction.This tetraalcohol product in combination with Nb(OMe) 5 was used to catalyze the enantioselective desymmetrization of meso-epoxides with aromatic amines.Additional compounds (R)-239 with R = H, Me, t Bu, and Ph were also prepared and investigated for asymmetric catalysis. 288he monosubstituted BINOLs (R)-240 were synthesized in a similar way by using 1.2 equiv of n BuLi for the ortho-lithiation of (R)-BINOL-MOM.These compounds in combination with Nb(OR) 5 (R = alkyl) were used to catalyze the asymmetric Mannich-type reaction of imines with silyl enolates. 289hen the ortho-lithiated (R)-BINOL-MOM was added to (R)-3-formylBINOL-MOM, (R)-241, the bisBINOL-MOM compound (R,R)-242 was obtained in 62% yield (Scheme 81). 290 7.4.11.Addition to Ketones.Reaction of BINOL-MOM with n BuLi in THF solution at room temperature followed by the addition of acetone gave the mono-and disubstituted products 244a and 244b in 27% and 10% yields, respectively (Scheme 82). 214en the ortho-lithiated (R)-or (S)-BINOL-MOM was reacted with benzophenone, compounds (R)-245 or (S)-245 were obtained in 91−95% yields (Scheme 83). 215,242,291protection of the MOM groups of (R)-245 with 3 N HCl in THF gave the tetrahydroxyl product (R)-246 in 90% yield. 162his compound was used for enantioselective fluorescent recognition of chiral amino alcohols.When (S)-245 was treated with CF 3 CO 2 H in CH 2 Cl 2 , besides the removal of the MOM protecting groups, the two diphenylmethanol units were also reduced to diphenylmethane to give (S)-247 in 88% yield. 215his compound was used to catalyze the asymmetric reaction of ZnEt 2 with aldehydes.
7.4.12.Addition to Esters.Reaction of the ortho-lithiated (S)-BINOL-MOM with ethyl trifluoroacetate gave the BINOLderived trifluoromethyl ketone (S)-250 in 62% yield (Scheme 85). 293Deprotection of (S)-250 was conducted by using CF 3 CO 2 H in CH 2 Cl 2 at 0 °C to room temperature to give (S)-251 in 84% yield.The use of CF 3 CO 2 H avoided the reflux conditions in the use of HCl/EtOH.(S)-251 showed different fluorescence responses toward a chiral diamine at two different emission wavelengths and was used to simultaneously determine the concentration and enantiomeric composition of the chiral substrates.Compound (S)-252 was obtained in a similar way by using (S)-BINOL-MOM and ethyl difluoroacetate. 294.4.13.Addition to Acyl Chlorides.After (S)-BINOL-MOM was treated with 5 equiv of n BuLi in Et 2 O at 0 °C for 3 h, addition of 5 equiv of benzoyl chloride gave (S)-253 in 84% yield upon acidic workup (Scheme 86). 216The MOM groups of (S)-253 were removed by heating in HCl (3N, aq) and ethanol at reflux to give (S)-254 in 86% yield.Enantioselective fluorescence quenching by N-Boc amino carboxylates, amino alcohols, and mandelate was investigated.
A perfluoroalkyl ketone (S)-255 was obtained in 72% yield by treatment of (S)-BINOL-MOM with n BuLi at room temperature followed by reaction with perfluorooctanoyl chloride at −78 to 0 °C (Scheme 87). 295Deprotection of (S)-255 was conducted by using CF 3 CO 2 H in CH 2 Cl 2 at 0 °C to room temperature to give (S)-256 in 85% yield.(S)-256 showed enantioselective fluorescence enhancement in the presence of amino alcohols in the fluorous phase.
Compound (S)-256 with a shorter perfluoroalkyl group was prepared in a way.It reacted with amino acid TBA salts (TBA = n Bu 4 N + ) in DMSO at room temperature to give the amides (S)-257 with enantioselective fluorescence enhancement (Scheme 88). 2964.14.Addition to DMF.Ortho-lithiation of (S)-BINOL-MOM with n BuLi and TMEDA in refluxing Et 2 O followed by reaction with DMF gave (S)-258 in 78% yield (Scheme 89).218 It was later found that the addition of TMEDA and the refluxing conditions were not necessary.Ortho-lithiation of (S)-BINOL-MOM with n BuLi in Et 2 O at room temperature in the absence of TMEDA followed by the reaction with DMF gave (S)-258 in 68% yield.297 The MOM protecting groups of (S)-258 were removed by treatment with HCl (6 N) in refluxing ethanol solution to give (S)-3,3′-diformylBINOL, (S)-151, in 90% yield.Polymerization of (S)-151 with diamines in the presence of Ni(II) was studied.297 In an earlier study, (S)-151 was obtained from the resolution of BINOL 3,3′-dicarboxylic acid followed by reduction 298 and was found to react with (R,R)-1,2diphenyletnylenediamine to form the [2 + 2] macrocycle 259 but with (S,S)-1,2-diphenylethylenediamine to give polymers.299 Macrocycle 260 was prepared from the reaction of (S)-151 with (R,R)-1,2-diaminocyclohexane followed by reduction with NaBH 4 .300 This compound was used to carry out the enantioselective fluorescent recognition of mandelic acid, an α-hydroxyl carboxylic acid. It s also used for the fluorescent recognition of Hg 2+ .301 (S)-or (R)-151 in combination with Zn(OAc) 2 was used to conduct the enantioselective fluorescent recognition of chiral functional amines, including diamines, amino alcohols, and amino acids.302−304 Compound (R)-261a was prepared from the condensation of (R)-151 with 2-naphthylamine and used as a dual responsive fluorescent probe to simultaneously determine the concentration and enantiomeric composition of chiral functional amines.303 Compounds (S)-261b and (S)-261c were prepared from the condensation of (S)-151 with the corresponding chiral amino alcohols, followed by reduction for the enantioselective fluorescent recognition of chiral αhydroxycarboxylic acids.305−307 The 3,3′-diformylBINOLs also served as the precursors to prepare other BINOL derivatives for application in asymmetric catalysis.For example, the sulfur-containing compounds (R)-262a,b were prepared from (R)-151 for the asymmetric reaction of ZnEt 2 with enones in the presence of Cu(OTf) 2 .286 Compound (S)-262c was prepared from (S)-258 and was used in combination with Ti(O i Pr) 4 to catalyze the asymmetric reaction of ZnEt 2 with benzaldehyde.281 A BINOL monoMOM ether was synthesized from the reaction of (S)-BINOL with 1.5 equiv of bromomethyl methyl ether in the presence of diisopropylethylamine (Scheme 90).308 Treatment of the THF solution of the BINOL monoMOM ether with 3.2 equiv of n BuLi at 0 °C to room temperature followed by the addition of DMF gave the monoaldehyde compound (S)-263 in 62% yield over the three steps (Scheme 90).This compound and its enantiomer served as the precursor to a variety of BINOL-aldehyde-based fluorescent probes such as compounds (S,S)-264, 309 (S)-265a, 310 (S)-265b, 311 and (R,R,R)-266 312 for the recognition of amino acids and metal ions.
7.4.15.Addition to CO 2 .BINOL 3,3′-dicarboxylic acid and its derivatives were prepared from the ortho-lithiation of BINOL-MOM.As shown in Scheme 91, after ortho-lithiation with n BuLi in THF, CO 2 was added as the electrophile, which after treatment with HCl in an alcoholic solution gave (R)-267 in 70% yield. 313,314−316 For example, (R)-267 was converted to several amide derivatives (R)-268 with >99% ee.These chiral amides were used to catalyze the Simmons−Smith cyclopropanation of allylic alcohols with ZnEt 2 and CH 2 I 2 to give chiral cyclopropanes, and the asymmetric reaction of ZnEt 2 with propargyl aldehyde. 313,314.4.16.Nucleophilic Reactions with Arenes and Heteroarenes.Reaction of the ortho-lithiated (R)-BINOL-MOM with hexafluorobenzene gave the nucleophilic substitution product (R)-269 in 71% yield (Scheme 92). 244,262After removal of the MOM groups, it was used to catalyze the asymmetric vinyl boronic acid addition to enones.Compound (R)-270 was prepared from (R)-269 to catalyze the asymmetric ring expansion of cyclic silanes with alkynes in the presence of [Rh(CH 2 �CH 2 ) 2 Cl] 2 . 317Similar to the synthesis of (R)-269, compounds (S)-271a−d were synthesized from the reaction of the ortho-lithiated (S)-BINOL-MOM with the fluorinated arenes followed by removal of the MOM groups with HCl/ MeOH under refluxing. 318These compounds were converted to the phosphoric acids (S)-272 to catalyze the asymmetric αhydroxylation of α-branched cyclic ketones with PhNO.
Nucleophilic addition of the ortho-lithiated (S)-BINOL-MOM to quinoline was conducted.After (S)-BINOL-MOM was treated with 3 equiv of n BuLi in THF at −78 °C to room temperature, it was reacted with quinoline at 0 °C to room temperature to give 273 (Scheme 93). 283Addition of nitrobenzene and water followed by heating at reflux converted 273 to (S)-274 in 86% yield in this one-pot reaction.When 1.2 equiv of n BuLi was used for the ortho-lithiation, the monosubstituted product (S)-275 was obtained in 55% yield.After removal of the MOM groups with 6 N HCl in MeOH/CH 2 Cl 2 , the resulting compounds (S)-276 and (S)-277 in combination with Ti-(O i Pr) 4 were used to catalyze the asymmetric reaction of ZnEt 2 with aryl aldehydes.Oxidation of 273 with MnO 2 in CH 2 Cl 2 also gave 274 in 78% yield over the two steps. 114This compound was used to make BINOL-phosphoramidities that are useful for asymmetric catalysis.The aggregation-induced red phosphorescence and circularly polarized luminescence of the Pt(II) complexes of (S)-276 were studied. 319ucleophilic substitution of cyanuric chloride by the monoortho-lithiated (R)-BINOL-MOM formed from the reaction with 1.1 equiv of n BuLi gave (R)-278, which upon reaction with HNMe 2 and NaOH gave (R)-279 in 52% yield over the two steps (Scheme 94). 254Removal of the MOM protecting groups of (R)-279 gave (R)-280.In a similar way, the disubstituted compound (R)-281 was obtained.These compounds were used to catalyze the reaction of ZnEt 2 with aryl aldehydes.

Reactions of Other BINOL Alkoxymethyl Ethers
Ortho-lithiation of BINOL trimethylsilylethoxymethyl ether (BINOL-SEM) was studied. 230As shown in Scheme 95, after BINOL-SEM was treated with 2.7 equiv of t BuLi in THF at −78 When BINOL-SEM was treated with 2.5 equiv of n BuLi in Et 2 O at room temperature for 3 h, its reaction with a number of electrophiles gave 3,3′-disubstitited products in 51−90% yields (Scheme 96).When the optically active (S)-BINOL-SEM was used for the methylation, (S)-3,3′-dimethylBINOL-SEM was obtained with the retention of the chiral configuration.
(R)-BINOL 2-methoxyethoxymethyl ether (BINOL-MEM) was used to prepare (R)-3,3′-dimethyl BINOL. 320As shown in Scheme 97, after (R)-BINOL-MEM in THF was treated with 3 equiv of n BuLi at 0 °C for 45 min, it was then reacted with 3 equiv of dimethyl sulfate at room temperature for 16 h to give the 3,3′-dimethyl product (R)-282 in 85% yield.(R)-282 was converted to the monobromo compound (R)-283 by reaction with Br 2 followed by HBr promoted deprotection of the MEM groups.This compound was used to prepare a poly-(organosiloxane)-supported bisBINOL crown ether (R,R)-284 for chiral resolution of amino esters.

Reactions of BINOL Carbamates
The carbamate groups of BINOL were used to direct the ortholithiation at the 3,3′-positions.As shown in Scheme 98, after the BINOL dicarbamate was treated with 2.5 equiv of t BuLi in the presence of TMEDA in THF at −78 °C in 1 h, several electrophiles were added to give the 3,3′-disubstituted products in 60−96% yields. 230he optically active (S)-285 and (S)-286 were prepared according to Scheme 98 from the corresponding (S)-BINOL carbamates and were then subjected to deprotection with LiAlH 4 or MeLi (Scheme 99). 278It was found that (S)-285 was converted to (S)-287 cleanly, but the reaction of (S)-286 was sluggish and failed to give clean deprotection.Thus, it is easier to remove the MOM protecting groups of BINOLs than the carbamate groups.
BINOL carbamates were found to undergo the Fries rearrangements.When (R)-BINOL was reacted with even excess amount of dialkylcarbamoyl chlorides in the presence of . 321This is attributed to the intramolecular hydrogen bond of (R)-288, which makes the second hydroxyl group less reactive.When compounds (R)-288 were treated with 2.2 equiv of s BuLi-TMEDA at −80 or −100 °C, a Fries rearrangement took place to give the 3-amido products (R)-289 in 33−62% yields.When 1 equiv of MeI was added to the above reaction mixture before warming up, the 3methylated product (R)-290 was obtained in 35−77% yields.
The carbamate groups of compounds (R)-290 (R = Et) and (R)-293 (R = Et) were removed by reaction with an excess amount of LiAlH 4 to give compounds (R)-295 and (R)-218 in 46% and 73% yields, respectively.Reduction of the 3,3′-diamido compound (R)-292 with LiAlH 4 in THF at 0 °C − reflux followed by quenching the reaction with aqueous KF gave the 3,3′-diaminomethyl compound (R)-296 in 63% yield (Scheme 102). 323The aluminum complex of this compound was used to catalyze the asymmetric reactions of a variety of cyanides with aldehydes.
The BINOL carbamate (R)-297 (≥99% ee) was prepared from the reaction of (R)-BINOL with i PrNCO in THF in the presence of DMAP at 60 °C for 2 d (Scheme 103). 324Treatment of (R)-297 with TMS-OTf gave a N-silylated intermediate which underwent ortho-lithiation in the presence of 5 equiv of s BuLi-TMEDA at −78 °C.Addition of 6 equiv of TMSCl followed by workup gave (R)-298 in 96% yield.Ortho-lithiation of 301 with LDA led to a phosphor− Fries rearrangement to form the 3,3′-bisphosphine oxide 302 with the retention of the configuration at the phosphorus center. 326he two-step reaction from (R)-BINOL to the 3,3′bisphosphine oxide (R)-303 was conducted in almost quantitative yield by a phosphor−Fries rearrangement (Scheme . 327The single crystal X-ray structure of (R)-303 was obtained.Compounds (R)-304 and (R)-305 were obtained by using the method similar to the preparation of (R)-303. 328,329en the phosphoramide (R)-306 was treated with 10 equiv of LDA, only the monophospho−Fries rearrangement took place to give (R)-307 (Scheme 106). 328,329Protection of (R)-307 with a PMB group gave (R)-308, which underwent the phosphor−Fries rearrangement in the presence of LDA, followed by acidic deprotection to give the 3,3′-diphosphoamidate BINOL (R)-309 in 92% and 68% yields respectively for the two steps.These 3,3′-disubstituted BINOLs were used to catalyze the asymmetric reaction of dialkylzincs and diphenylzinc with aldehydes.7.7.2.Iodonation.The phosphorodiamidate groups of BINOL can direct the ortho-lithiation-iodonation at 3,3′positions (Scheme 107). 330After the BINOL-phosphorodiamidate was treated with 2.5 equiv of s BuLi in THF at −78 °C for 90 min, it was quenched with the addition of I 2 to give the diiodide 310 in 39% yield.
Ortho-lithiation of (S)-BINOL-N-triflylphosphoramide (S)-316 with 6 equiv of s BuLi in THF at −78 °C for 1−3 h followed by addition of I 2 gave the diiodo product (S)-317 in 42% yield (Scheme 110). 331(S)-316 was treated with 2.5−3.0 equiv of n BuLi in THF at −78 to 30 °C for 1−3 h followed by addition of I 2 , the monoiodide 318 was obtained in 40% yield with a diastereomeric ratio >9:1.In 318, the phosphorus center is chiral due to the unsymmetric 3,3′-positions of the BINOL unit.7.7.3.Zincation.Ortho-lithiation of (S)-316 with 6 equiv of s BuLi followed by addition of ZnBr 2 gave the dizinc complex 319 (Scheme 111). 331Without isolation, 319 was reacted with p-t BuC 6 H 4 I to give the Negishi coupling product (S)-320 in 27% yield.When racemic 316 was treated with 2.8 equiv of n BuLi at −78 °C to −50 °C followed by reaction with ZnBr 2 at 80 °C, the resulting monozinc complex was coupled with p-t BuC 6 H 4 I to give (S,S/R,R)-321 in 56% yield.A single crystal X-ray analysis established its structure.In a way similar to the synthesis of (S,S/ R,R)-321, when (S)-316 and PhI were used, (S,S)-322 was obtained in 50% yield as one diastereomer.On the basis of the Xray analysis, an intermediate like 323 was proposed to account for the diastereoselectivity of the first ortho-lithiation step.When (S,S)-322 was treated with s BuLi and ZnBr 2 followed by the Negishi coupling with 2-bromopyridine, the unsymmetrically disubstituted compound (S,S)-324 was obtained in 47% yield.

Reactions of BINOL Sulfonates
Ortho-lithiation of BINOL triflate 328 led to a thia-Fries rearrangement to 3,3′-substututed BINOL 329 (Scheme 115). 333Sequential treatment of BINOL triflate with 2 × 1 equiv of LDA at −78 °C to room temperature in THF led to the formation of 329 in 51% yield.The single crystal X-structure of 329 was obtained.Much lower yields (7%) were observed when the CF 3 group of the BINOL triflate were replaced with other fluorinated alkyl groups such as C 4 F 9 and C 8 F 17 . 334The optically active (R)-329 was used to catalyze the asymmetric reactions of allylic halides with imines in the presence of In(0).

TRANSITION METAL CATALYZED C−H ACTIVATION
Transition metal-catalyzed C−H activation has been used to functionalize BINOLs.As described in this section, with the assistance of a functional group at an adjacent position, highly regioselective C−H activations of BINOL in the presence of transition metal catalysts have been achieved at various positions.
A proposed mechanism of this reaction is shown in Scheme 119.Coordination of the pyridyl methyl group of 333 with Pd(OAc) 2 can direct the C−H activation at the 3-position to form the 7-membered metallacycle intermediate 335.An alkene substrate can then coordinate to the Pd(II) center to form the intermediate 336, which can undergo a regioselective migratory insertion to form 337. β-Elimination of 337 will give the vinylation product 334, and the resulting Pd intermediate can be oxidized by O 2 to the catalytically active Pd(II) complex.
When one of the hydroxyl group of BINOL is methylated, the reaction can be controlled at monoarylation as shown in Scheme 121.Reaction of 338 with an aryl halide (3.6 equiv)) catalyzed by [RhCl(cod)] 2 (2.5 mol %) complex in the presence of Cs 2 CO 3 (2.0 equiv) and three ligands, including t Bu 2 PCl (20 mol %), Ph 2 -cod (5 mol %), and Cy 3 PH + BF 4 − (2.5 mol %), was conducted in toluene at 150 °C to give 339 in up to 96% yields.The reaction of the monomethylated BINOL gave higher yields than BINOL for the reaction with the sterically bulky aryl bromides.−340 It was found that the above reaction conditions to prepare the 3-aryl and 3,3′-diaryl BINOLs led to racemization when the optically active BINOL was used.The racemization took place even at 70 °C in the presence of Cs 2 CO 3 .The racemic 3,3′-diphenylBINOL can be resolved into the optically active (R)- and (S)-compounds with 95% to >99% ee's by using Nbenzylcinchonidinium chloride.
Scheme 122 shows a proposed mechanism for the Rh(I)catalyzed arylation of BINOL.Under basic conditions, BINOL reacts with t BuPCl 2 and the Rh(I) complex in the presence of other ligands (L and L′) to give complex 340.The bulky ligands allow the Rh(I) to coordinate to only one phosphorus atom rather than the formation of the chelated diphosphine coordination.This is important for the catalytic activity of the intermediate 340.Oxidative addition of an aryl halide with 340 will form the intermediate 341.The subsequent C−H activation and elimination of HX converts 341 to 342.Reductive elimination of 342 gives 343.Reaction of 343 with BINOL releases the arylated product and regenerates the catalytically active intermediate 340.
In 2020, Dong and co-workers reported the use of the BINOL esters and other derivatives (R)-345 for the similar reactions (Scheme 124). 342It was found that in the presence of 7 mol % [Cp*RhCl 2 ] 2 , 0.3 equiv of AgSbF 6 , and 3.0 equiv of Cu(OAc) 2 • H 2 O, (R)-345 reacted with 6.0 equiv of methyl acrylate in DCE at 160 °C over 20−24 h to give a mixture of (R)-346 and (R)-347.It is remarkable that the BINOL compounds maintained their optical purity under this high reaction temperature.Among the BINOL starting materials, the reactions of the BINOL carbamates (R = NMe 2 and NEt 2 ) gave the corresponding divinyl products (R)-346 in 93% and 84% yields, respectively, similar to that shown in Scheme 123.
The reactions of other alkyl acrylates with (R)-345 (R = Me) gave results similar to those of methyl acrylate, and the reaction of vinyl phenyl sulfone gave predominately the monovinyl product (52%).Two fluorinated alkyl acrylates gave a mixture of divinyl and monovinyl products in higher yields.The substrates such as phenyl acrylate, acrylonitrile, acryl aldehyde, acrylic acid, methyl methacrylate, styrene, an enone, an acrylamide, and a vinyl ester gave little or no product for this reaction.When the 6,6′-positions of (R)-345 (R = Me) were substituted with groups such as Me, t Bu, and OMe, the resulting compounds were reacted with methyl acrylate to give product mixtures similar to the reactions of (R)-345 (R = Me).The reaction of 6,6′-diphenyl-substituted (R)-345 (R = Me) with methyl acrylate gave only the monovinyl product in 41% yield, and those of the 6,6′-dihalogenated (R)-345 (R = Me) gave almost no product at all.
Scheme 125 shows a proposed mechanism for the Rhcatalyzed vinylation.When (R)-345 is treated with the Rh(III) complex, the ester group of the BINOL can direct an ortho-C−H activation at the 3-position to generate the intermediate 348 conducted under much milder conditions in high yields. 343It was found that in the presence of 10 mol % (Rh content) [CpRhI 2 ] n , 20 mol % AgNTf 2 and 40 mol % Cu(OAc) 2 , 291 (R = Me) (0.2 mmol) reacted with 3.0 equiv of methyl acrylate or styrene in DCE at 40 °C over 72 h in air to give the corresponding 3,3′-divinyl product 351 in 95% or 99% yield (Scheme 126).When 1 mmol of 291 was used to react with styrene, the 3,3′-divinyl product was obtained in 79% yield.In this case, the conversion of 291 was incomplete, but no monovinylation product was obtained.It suggests that the monovinylation product might undergo a faster vinylation to give the divinyl product.This reaction used a catalytic amount of both the Rh complex and Cu(OAc) 2 in air.Thus, after oxidation of a Rh(I) intermediate to a catalytically active Rh(III) species by the Cu(II) complex similar to that shown in Scheme 125, the resulting Cu(I) can be oxidized back to Cu(II) by air.
In 2021, Dong and co-workers reported the reaction of (R)-3-formylBINOL-MOM, (R)-241, prepared by the ortho-lithiation of BINOL-MOM followed by reaction with DMF, with pyridine-2-amine (352, 1.5 equiv) and an alkyne (353, 2.5 equiv) catalyzed by [Cp*RhCl 2 ] 2 (Scheme 127). 344This reaction was carried out in THF at 120 °C by using [Cp*RhCl 2 ] 2 (5 mol %) in the presence of AgNTf (0.2 equiv) and Cu(OAc) 2 •H 2 O (2.0 equiv).It directed a C−H activation at the 4-position of (R)-241 to give the products (R)-354 in up to 94% yields with the retention of the optical purity.The highest yield was observed for the reaction of the alkyne with R = R′ = 4-MeOC 6 H 4 and much lower yields for the reaction of aliphatic alkynes.Other BINOL substrates with various 3-substituents (R 1 ) and 6-substituents (R 2 ) were also reacted with diphenylacetylene and 352 to give (R)-355 in 64−87% yield.However, when R 2 = Br (R 1 = H), only a trace of the product was observed.Thus, a bromine substituent interfered the reaction.When the BINOL substrate did not have the MOM protecting groups, the product (R)-356 was obtained in 43% yield.When the Ac protected substrate was used, the product (R)-357 was obtained in 37% yield.When the substrate had other protecting groups such as Me, Bn, TBDPS, and OMSM, little product formation was observed.They also tested the reaction of (R)-241 with diphenylacetylene and various derivatives of 352 such as 358−361.When 358 with various R substituents were used, the corresponding products were obtained in 44−80% yields, but little product was obtained when R = 4-CN or 6-Me.Compound 359 gave the corresponding product in 65% yield, but compounds 360 and 361 gave little product.This indicates that the ring nitrogen and its proximity with the amine group are important for the reaction.
It was found that when (R)-241 was treated with 352 under the reaction conditions, an oxidative amide formation and a partial hydrolysis took place to form 362 before C−H activation (Scheme 128).In the presence of a catalytically active Rh(III) complex, C−H activation of 362 at the 4-position can give the intermediate 363, which upon coordination with an alkyne substrate will give 364.This intermediate can undergo a migratory insertion to form 365. Reductive elimination of 365 will give the functionalized BINOL product 354 and generate a Rh(I) intermediate.Oxidation of the Rh(I) intermediate by the Cu(II) complex will regenerate the catalytically active Rh(III) complex.
As shown in Scheme 134 (vide infra), the 6-pyrazole group of BINOL can direct the Co-catalyzed C−H activation at the less sterically hindered 7-position to form the product 390. 345The pyrazole group of 390 was found to further direct a C−H activation at the 5-position upon Rh(III) catalysis (Scheme 129).In the presence of 5
Scheme 131 shows a proposed mechanism for the Cocatalyzed C−H activation and amidation.In the first step, the Co(III) complex 370 reacts with AgSbF 6 and KOAc to form a catalytically active intermediate 376.Reaction of 376 with the thiocarbamate substrate 368 to form the intermediate 377.This C−H activation step might be a base-assisted internal electrophilic substitution.Coordination of 377 with the dioxazolone 369 gives 378.Intermediate 378 undergoes migratory insertion with the extrusion of CO 2 to give 379.Proto-demetalation of 379 with acetic acid releases the amidation product 371 and regenerates the catalytically active 376.
Reaction of the BINOL dicarbamate (R)-291 (R = Me) with methyl acrylate in dichloroethane in the presence of the Co(III) catalyst 370 (30 mol %), AgSbF 6 (60 mol %), KOAc (40 mol %), and pivalic acid (80 mol %) at 100 °C for 18 h gave the 3,3′-dialkylBINOL product (R)-380 in 48% yield (Scheme 132). 346 small amount (12%) of the 3,3′-dinvinylBINOL compound (R)-381 was also obtained.The addition of pivalic acid was to reduce the amount of the vinyl product.It was found that an In 2023, Liu et al. reported the use of a 6-pyrazole group to direct a C−H activation at the 7-position of BINOL by using the Co(III) catalyst 370 (Scheme 134). 345Compound 388 was synthesized from the reaction of 6-bromoBINOL with pyrazole in the presence of Cu 2 O and K 2 CO 3 in DMSO at 130 °C over 2 d under argon.Significant racemization of BINOL was observed in this step.As shown in Scheme 134, in the presence of 5 mol % Cp*Co(CO)I 2 (370), 0.2 equiv of Zn(OTf) 2 , 0.5 equiv of PhCO 2 H, and 388 were heated with 2 equiv of 389 in DCE at 120 °C for 15 h to give 390 in 78% yield.The crystal structure of 390 was obtained by X-ray analysis.When the enantiomerically enriched substrate was used, significant racemization was also observed in this reaction.When the 6′-substituted BINOL starting materials were used, the resulting products 391a−d were also obtained in similar yields.When the 6,6′-di(pyrazole) substituted BINOL was used, the 7,7′-disubstituted product 392 was obtained in 50% yield.The reaction of the acyclic and cyclic alkyl ethers of the BINOL starting material gave products 393a− c in over 80% yields, but only a trace amount of 393d was obtained for the reaction of the BINOL acetal.Compound 393e cannot be obtained from the BINOL phosphoric acid.When the R groups of the substrate were methoxymethyls, a similar product was obtained with hydrolysis of the methoxymethyl groups.
When 4-methyl pyrazole was used as the directing group, the corresponding product 394 was obtained in 64% yield over 48 h.
Only trace amount of 395 was observed when 3-methyl pyrazole was used as the directing group, probably due to steric hindrance.When 4-chloropyrazole was used, besides the expected product 396, a styrenyl product 397 was also obtained due to the C−C bond cleavage of 389 at the tertiary carbon.
Other aza-cycles such as 398−400 were found to be ineffective for this reaction.
When various substitutents were introduced to the phenyl group of 389 for the reaction with 388, the corresponding products were obtained except when the strong electronwithdrawing groups like p-CO
0 Similar to that shown in Scheme 137 for the formation of the catalytically active Ir(III) complex 415, complex 420 can be generated from the reaction of [Ir(cod)-(OMe)] 2 with B 2 eg 2 and dtbpy.Compound 421 can be generated in situ from the reaction of (R)-BINOL with B 2 eg 2 .Interaction of 420 with 421 might achieve a transition state as shown by 422 in which the electrostatic attraction between the partially negative OBeg unit and the partially positive bipyridine unit directs the ortho-C−H activation and borylation to give 423.Hydrolysis of 423 gives the 3,3′-diborylated BINOL product (R)-419.The Ir intermediate 424 can react with B 2 eg 2 to regenerate the catalytically active 420.
It was found that in the Ir-catalyzed borylation shown in Scheme 138 when the diborolane substrate B 2 eg 2 (418) was replaced with the sterically more bulky B 2 pin 2 (410) in combination with HBpin, the regioselectivity of the C−H activation and borylation changed to the least sterically hindered 6,6′-positions (Scheme 140). 349The reaction of (R)-BINOL with B 2 pin 2 (2.5 equiv) and HBpin (3.0 equiv) catalyzed by [Ir(cod)(OMe)] 2 (1.5 mol %) in the presence of dtbpy (3.0 mol %) in THF at 80 °C for 12 h gave the 6,6′-diborylated BINOL product (R)-425 in 87% yield.This Ir-catalyzed borylation of BINOL can be combined with the Pd-catalyzed Suzuki coupling with a variety of aryl bromides to generate 6,6′-diarylBINOLs in one pot in good yields with high enantiomeric purity.
It was proposed that the bulky Bpin group inhibits the ortho-C−H activation as shown in 426 because of the large steric repulsion.This allows the C−H activation and borylation to take place at the least sterically hindered 6-position as shown in 427.

SUMMARY AND OUTLOOK
Three major strategies to selectively substitute the protons of BINOL at the specific positions, including electrophilic substitution, ortho-lithiation, and transition metal-catalyzed C−H activation, have been to prepare various functionalized BINOLs for applications in asymmetric catalysis, molecular recognition, chiral sensing, and materials.
Electrophilic substitution of the optically active BINOL displays selectivity at the 3-, 4-, 5-, and 6-positions with the retention of the chiral configuration.The most prevalent pathway involves the substitution at the 6-or 6,6′-positions of BINOL as well as its dialkyl ethers.This pronounced 6substitution selectivity is attributed to the potent electrondonating effect exerted by the 2-hydroxyl or 2-alkoxy groups on the naphthol rings.When the two hydroxyl groups of BINOL are converted to acetate groups, the reaction with Br 2 occurs mainly at the 5,5′-positions (see Scheme 21).Thus, reducing the electron-donating ability of the 2,2′-hydroxy groups of BINOL significantly alters the regioselectivity.However, no systematic effort has been devoted to studying the effect of varying electronic properties of the hydroxy groups of BINOL on the regioselective electrophilic substitution.When the 6,6′-positions of BINOL are occupied by the first electrophilic substitution, the next electrophilic reaction occurs at the 5,5′-positions (see Schemes 22−24).Whereas, when the 6,6′-positions of BINOL dialkyl ethers are occupied by the first electrophilic substitution, the next reaction with electrophiles occurs at the 4,4′-positions (see Schemes 26−28).These observations further demonstrate the high sensitivity of the regioselectivity for the electrophilic substitution of BINOL when the electronic property of its two hydroxy groups alters.This calls for a systematic investigation in order to gain a better understating on these effects and to further develop their synthetic applications.
Electrophilic substitution of BINOL is also found to be significantly influenced by the steric environment.When the 6,6′-positions of BINOL are occupied by sterically bulky tertiary butyl groups, the subsequent electrophilic reaction occurs at the less sterically hindered 3,3′-positions rather than the sterically more crowded 5,5′-positions (see Scheme 36, 37) even though the 3,3′-positions are not electronically favorable for electrophilic reaction as discussed in section 2.1.The hydroxyl groups at the 2,2′-positions of BINOL are also found to direct certain electrophilic reactions at the 3,3′-positions when there are possible favorable interactions between the hydroxyl groups and the electrophiles (see Schemes 29−35).Although the 8,8′positions of BINOL should be electronically favorable for an electrophilic reaction, there are only two reports on low yield electrophilic reactions at the 8-position due to significant steric hindrance around this position (see section 2.1 and Scheme 10 and 28).No electrophilic substitution at the 7-position of BINOL has been reported yet.This position does not sense the resonance electron-donating effect of the 2-hydroxyl group, and it is also at the edge of the node plan of the HOMO orbital of BINOL as shown in Figure 2. It would be both fundamentally interesting and potentially useful to vary the electronic properties of BINOL in order to facilitate the substitution at the 7-position.Although the 3,3′-positions of BINOL are not electronically favorable for many electrophilic reactions, ortho-lithiation at the 3-position, directed by the functional groups, such as ethers, alkoxymethyl ethers, and carbamates at the 2,2′-positions, have been extensively used to prepare many 3-or 3,3′-substituted BINOLs for diverse applications.Among these reactions, the use of the ortho-lithiation of the methoxymethyl ether of BINOL is the most popular because of the easy introduction and removal of this directing group (see section 7.4).
The use of the transition metal-catalyzed C−H activations of BINOL has shown very promising application in preparing the selectively substituted BINOLs.These reactions generally require the introduction of a functional group to direct the C−H activation at the ortho position.This strategy has allowed selective substitutions at the 3-, 4-, 5-, 6-, and 7-positions.For example, Schemes 138 and 140 show that BINOL can be directly functionalized at the 3,3′-or 6,6′-positions in the presence of an Ir(I) catalyst by using two borylating agents that have very different steric demands.In principle, all the positions on BINOL can be selectively functionalized by using the transition metal-catalyzed C−H activation as long as an appropriate directing group is introduced at the adjacent position.However, there are still significant challenges in using this strategy to prepare structurally modified BINOLs for various applications.
Although functionalization at the 3,3′-positions has become more readily applicable because of the easy introduction and removal of the directing groups at the 2,2′-positions via transformation of the two hydroxy groups, and introduction and removal of the directing groups at other positions are not as straightforward and can become difficult.No work has been reported to remove the directing groups at the 3-and 6-positions that were used to direct the reactions at the 4-, 7-, and 5positions.There is also little research conducted on the transition metal-catalyzed C−H activation at the 5-and 8positions of BINOL.As shown in Schemes 129 and 134, the functional group at the 6-position directs the reaction at the less sterically hindered 7-position first.Only when the 7-position is occupied, can the reaction take place at the more sterically hindered 5-position.In order to introduce a substituent to the 8position, one needs to introduce a directing group to the 7position, which requires a directing group at 6-position.The directing group at the 6-position will also direct a substitution at the 5-position after the 7-position is occupied.Thus, this approach would fill the 6-, 7-, and 5-positions before the 8position could be filled.It remains a challenge to selectively introduce a substituent to the 8-position.A few of the C−H activation reactions also lead to racemization of BINOL because of the high temperature and strongly basic conditions.For example, Scheme 120 shows that the Rh(I)-catalyzed conversion of BINOL to the synthetically very useful 3,3′-diarylBINOLs can be conducted in one step, but the products were completely racemized.Therefore, continuous research in this area is necessary in order to develop efficient methods to selectively functionalize BINOL especially at positions other than the 3-and 6-positions.
In summary, the techniques outlined in this article, including the electrophilic substitution, the ortho lithiation, and the transition metal-catalyzed C−H functionalization at various positions, have enabled researchers to leverage the distinctive structure of BINOL to craft a wide range of chiral materials for exciting applications.It is anticipated that research into the development and understanding of BINOL's reactivity, as well as further exploration of its applications, will continue to expand.The versatility of BINOL will always present challenges to the imagination of researchers in diverse fields.

Scheme 139 .
Scheme 139.Proposed Mechanism for the Ir-Catalyzed C−H Activation

Chemical Reviews pubs.acs.org/CR Review
Examples for the application of 4,4′-dibromination of BINOLs.
https://doi.org/10.1021/acs.chemrev.4c00132Chem.Rev. 2024, 124, 6643−6689 3 O + BF 4 − in CH 2 Cl 2 gave a mixture of products 156, 157, and 158.After column chromatography, the biscarbene product 156 was obtained in 50% yield, and the monocarbene compound 157 was converted to the monocarbene 158, which was isolated in 36% yield.The structure of 156 was established by a single crystal X-ray analysis.The optically active (R)-/(S)-156 and BuCO), 20 mol % HOTf, 3 equiv of Ar 2 I + TfO − , and 1 equiv of Piv 2 O at 60 °C for 24 h.After the reaction, deprotection with DIBAL gave the 3,3′-diarylBINOLs in 35−43% yields.Scheme 117 shows a proposed mechanism for this reaction.In the first step, coordination of the ester group of the substrate 330 with the Pd(II) center directs an adjacent C−H activation to form a Pd(II) intermediate 331.Oxidative addition of an aryl group to 331 by Ar 2 IOTf can generate a Pd(IV) intermediate 332.Reductive elimination of 332 should give the desired arylation product and regenerate the Pd(II) catalyst. t

.
Coordination of 348 with methyl acrylate can generate the intermediate 349, which can undergo a regioselective migratory insertion to form 350. β-Elimination of 350 followed by reductive elimination will give the products (R)-346 and (R)-347 and form a Rh(I) intermediate.Oxidation of the Rh(I) intermediate with the Cu(II) complex can regenerate the catalytically active Rh(III) complex.In 2020, Tanaka et al. reported that by using [CpRhI 2 ] n as the catalyst, the reaction of a BINOL carbamate with alkenes can be mol % [Cp*RhCl 2 ] 2 , 0.2 equiv of AgSbF 6 , and 4.0 equiv of PivOH, 390 reacted with 3.0 equiv of methyl acrylate in TFE at 120 °C under air for 18 h to give the 5alkylated product 366 in 73% yield.The proposed mechanism in Scheme 125 shows that the intermediate 350 undergoes β-elimination to give the vinylation product.However, the intermediate 367 generated from the reaction of 390 with methyl acrylate might undergo a protonation demetalation faster than the β-elimination to give the alkylation product 366.
https://doi.org/10.1021/acs.chemrev.4c00132Chem.Rev. 2024, 124, 6643−6689 Scheme 129.Rh-Catalyzed Reaction at 5-Position of BINOL Similar to that shown in Scheme 131, the catalytically active intermediate 376 (R = Me) can be generated from the reaction of 370 with AgSbF 6 .The reaction of 376 with the BINOL carbamate 291 will give 385 via C−H activation of the substrate.Coordination of 385 with methyl acrylate gives 386.The intermediate 386 undergoes a regioselective migratory insertion to give 387.Proto-demetalation of 387 with pivailic acid will give the alkylated product 380 and regenerate the catalytically active 376 (R = t Bu).The vinyl side product 381 can be generated from the β-elimination of 387.Thus, addition of pivalic acid suppresses this side reaction.
https://doi.org/10.1021/acs.chemrev.4c00132Chem.Rev. 2024, 124, 6643−6689 The Cp*Co(III)-promoted C−H activation of 388 will give the intermediate 405 directed by the 6-pyrazole group to the 7-position, probably due to the less steric hindrance than the 5-position.Coordination of 389 to 405 will give 406.Migratory insertion of 406 will give 407.Protodemetalation of 407 will give 408 and regenerate the catalytically active Co(III) complex.Under acidic conditions, 408 undergoes an intramolecular Friedel−Crafts alkylation to give the final product 390.
2 Me or p-NO 2 was incorporated, which gave little or no reaction.When the cyclohexanol derivative 401 was used, product 402 was obtained in 65% yield.When phenyl acetylene and diphenyl acetylene were used in place of 389, products 403 and 404 were obtained in 87 and 88% yields, respectively.
349plex 414 can be generated from the reaction of the Ir complex 411 with the ligand 412 and the diborylate 410.Dissociation of the coordinated cyclooctene in 414 generates the active catalyst 415.Reaction of 415 with the silane substrate 409 generates the intermediate 416, which can undergo the silyl-directed ortho-C−H activation to give the intermediate 417.Reductive elimination of 417 gives the desired product 413, and oxidative addition with the diborylate 410 regenerates the active catalyst 415.In 2019, Chattopadhyay reported a Ir-catalyzed C−H activation and borylation of BINOL without the need to preincorporate a directing group.349Asshown in Scheme 138, the reaction of (R)-BINOL with the ethylene glycol-derived diborolane 418 (B 2 eg 2 , 4.0 equiv) catalyzed by [Ir(cod)-(OMe)] 2 (2.0 mol %) in the presence of 4,4′-t Bu 2 bipyridine (dtbpy, 4.0 mol %) in THF at 80 °C for 12 h gave the 3,3′diborylated BINOL product (R)-419 in 79% yield, which was converted to the more stable pinacol boroester for isolation.The Ir-catalyzed borylation of BINOL can be combined with the Pdcatalyzed Suzuki coupling with a variety of aryl bromides to Scheme 135.Proposed Mechanism for the Co(III)-Catalyzed C−H Activation Scheme 136.Ir(I)-Catalyzed Borylation of a BINOL Silane 137.Proposed Mechanism for the Ir-Catalyzed C−H Activation Scheme 138.Ir(I)-Catalyzed Borylation of BINOL with B 2 eg 2 3′-diarylBINOLs in one-pot in good yields with high enantiomeric purity.Scheme 139 shows a proposed mechanism for the Ir-catalyzed borylation of BINOL.