2
Synthesis of Chiral Ligands Containing Quinoline Motifs
2.1
Synthesis of Schiff Base Type Chiral Ligands
In 2008, Hayashi and co-workers reported the preparation of the N,N,P-ligands. The
N,N,P-tridentate Schiff base ligands 6a ,b were prepared from chiral amino alcohols 1 in five steps with high yields (Scheme [1 ]). The synthetic pathway started from chiral amino alcohols 1 , NH and OH-tosylation of which, followed by treatment with potassium hydroxide (KOH)
gave the anticipated substituted aziridines 3a ,b . The obtained amine-protected aziridines 3 were treated with KPPh2 to afford the corresponding N-tosylated amino phosphines 4 . Simple condensation of 2-quinolinecarboxaldehyde with these N-H free amino phosphines
5 gave the expected N,N,P-tridentate chiral Schiff bases 6a ,b in good yields. These N,N,P-tridentate Schiff base ligands were used quinoline-based
asymmetric catalysts in organic synthesis, such as 1,4-addition of R2 Zn to α,β-unsaturated ketones.
Scheme 1 Synthesis of chiral N,N,P-tridentate Schiff base ligands[68 ]
In the same year, Hayashi and co-workers reported the preparation of a library of
chiral Schiff base ligands 11a –f (Scheme [2 ]). Chiral imines were readily prepared by condensation of aldehydes 7 or ketones 9 with chiral amines. The keto-imine chiral Schiff bases, 11a –f were prepared by two different methods. In method 1, the addition of a Grignard reagent[69a ] to 2-quinolylaldehyde 7 produced the desired alcohol 8 in good yields; the obtained secondary alcohol was then effectively converted into
the corresponding ketones 9 via a radical oxidation process. In method 2, treatment of 2-quinoline cyanide 10 with a Grignard reagent furnished the required ketones 9 . Finally, condensation of ketones 9 with chiral amino alcohols in the presence of TiCl4 and Et3 N gave the corresponding chiral ligands 11a –f (Scheme [2 ]). These N,N-bidentate Schiff base ligands were applied to the allylic oxidation
of olefins.
Scheme 2 Synthesis of chiral keto-imine N,N-bidentate Schiff base ligands[69b ]
[c ]
In 2004, Suga and co-workers investigated the synthesis of diamine type chiral Schiff
base ligands 14a –f . Aldimine type chiral Schiff bases were synthesized by simple condensation of substituted
2/8-quinolylaldehyde 13a ,b with chiral 1,1′-binaphthyldiamine 12 in benzene under reflux (Scheme [3 ]). These binaphthyldiimine Schiff base ligands were found to be widely applicable
to various 1,3-dipolar cycloaddition reactions and Diels–Alder reactions.
Scheme 3 Synthesis of binaphthyldiimine chiral Schiff base ligands[70 ]
Eddine and co-workers demonstrated the preparation of iminium salt 17 via halogen–metal exchange reaction of (R )-2-(sec -butoxy)bromonaphthalene (15 ) with n -BuLi at low temperature to furnish the aryl lithium species 16 , which, upon subsequent nucleophilic addition to 8-cyanoquinoline followed by quenching
with methyl iodide (Scheme [4 ]), furnished the corresponding chiral N -methyl-1-(8-quinolinyl)-1-(2-(R )-sec -butoxynaphthyl)-methylenimime ligand 17 (Scheme [4 ]). These keto-imine type chiral Schiff base ligands were examined in effective phase-transfer
catalyzed asymmetric alkylation reactions.
Scheme 4 Synthesis of a keto-imine chiral Schiff base ligand[71 ]
2.2
Synthesis of Oxazolinyl-Type Chiral Ligands
In 1999, Chelucci and co-workers designed a simple synthesis of chiral oxazolinylquinoline
type ligands 21 and 22 . Oxidation of quinoline 18 with 3-chloroperbenzoic acid (m -CPBA) in DCM for 2 h and then treatment of the obtained N -oxide with 2.0 equivalents of KCN and PhCOCl in CH3 CN/MeOH at room temperature for 24 h, produced the corresponding compound 19 . Subsequent treatment with 2-cyanoquinoline 19 and chlorobenzene under reflux with the addition of a suitable chiral amino alcohol
20a in the presence of ZnCl2 produced the corresponding oxazolinylquinoline type chiral ligands 21 and 22 in yields of 10–99% (Scheme [5 ]). In a similar manner, chiral quinoline ligands 24a –c were synthesized from 2-cyanomethylquinoline 23 and the corresponding amino alcohol 20a , mediated by ZnCl2 under reflux conditions (Scheme [5 ]).
Scheme 5 Synthesis of N,N-chiral 2-quinolyloxazoline ligands[72 ]
Chelucci (2000) and co-workers expanded the library of quinoline ligands, by synthesizing
chiral oxazolines 28a –e , employing an amide–mesylate–oxazoline reaction sequence (Scheme [6 ]). Thus, 8-quinolyl carboxylic ester 25 was heated in toluene under reflux with chiral amino alcohol 26a in the presence of potassium cyanide to afford the corresponding amide derivates
27 in quantitative yields. Finally, the quinolyloxazolines 28a –e were obtained by the reaction of amino alcohol 27 with methane sulfonyl chloride (MeSO2 Cl) and Et3 N in DCM solvent. The obtained chiral ligands 28a –e were air-sensitive and, upon standing at 25 °C, underwent a ring opening reaction
to furnish the amide by-products. The chiral ligand 28d was treated with metal salts such as Cu(OTf)2 or PdCl2 to give the corresponding oxazoline transition-metal complexes 29 . These chiral quinolyloxazoline ligands were studied in Friedel–Crafts alkylation,
cyclopropanation of olefins, cascade intramolecular cyclization reactions, dialkoxylation
of 2-alkenes, intramolecular aerobic oxidative amination, and allylic alkylation.
Scheme 6 Synthesis of N,N-chiral 8-quinolyloxazoline ligands[72b ]
[73 ]
Muller and co-workers (2000) reported an innovative synthesis of oxazolinyl ligands
31 containing a hydroxyl group and silyl group 32 (Scheme [7 ]). The central chiral ligand was prepared by one-pot cyclization of 8-cyanoquinoline
and chiral amino benzyl alcohol 26b at 110 °C in the presence of ethylene glycol. The obtained oxazolinyl-OH ligand 31 was protected using TBDPSCl in the presence of imidazole at room temperature for
24 h. Likewise, the benzyl protected oxazolinyl ligand 33 was prepared.
Scheme 7 Synthesis of silyl protected chiral oxazolinyl ligands[74 ]
Ahn and co-workers (1999) designed and synthesized 8-diarylphosphino-2-oxazolinylquinoline
type chiral ligands 38a –c starting from 35 . 2-Cyano-8-hydroxyquinoline precursor 35 , synthesized from 8-hydroxyquinoline 34 according to the literature,[75 ] was used for the preparation of the target chiral ligands. The authors reported
that ZnCl2 -catalyzed oxazolinyl ring formation furnished better yields when the quinoline-alcohol
group was converted into the corresponding aryl triflate 36 ; otherwise, in the presence of the quinoline free OH group, oxazolinyl ligand derivatives
37 were obtained in lower yields. The condensation of l -valinol 20b and aryl cyanide 36 in the presence of ZnCl2 (10 mol%) with PhCl as a solvent, afforded the resulting oxazolines 37a –c in good yields. Introduction of the diphenylphosphino group (PPh2 ) was accomplished by Ni-catalyzed C–P coupling. Thus, reaction of the oxazoline derivatives
37 with diphenylphosphine in the presence of NiCl2 (dppe) (10 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 2 equiv) in DMF at 80 °C
afforded the subsequent N,N,P-ligands 38a –c in moderate isolated yields. When the coupling reaction was carried out at 100 °C
or above, as previously reported, the reaction yield was diminished (Scheme [8 ]).
Scheme 8 Synthesis of N,N,P-chiral 2-oxazolinylquinoline ligands[75 ]
2.3
Synthesis of Chiral N,N-Type Ligands
Bolm and co-workers prepared a wide range of quinoline-based C
1 -symmetric chiral monosulfoximine derivatives 41a –l , in which the second donor nitrogen atom is in a quinolinyl aromatic ring, by Pd(OAc)2 -catalyzed N-arylation of optically pure sulfoximines 39 with the corresponding 8-bromoquinoline derivatives 40 . The chiral sulfoximine substrate scope is summarized in Scheme [9 ].
Scheme 9 Synthesis of monosulfoximine chiral ligands[76 ]
Several N,N-bidentate type chiral quinoline derivatives have been prepared from the
corresponding ketones, as reported by Chelucci and co-workers in 2000. Chiral ligands
45a –c were prepared by the reaction of quinoline ketone 42 with vinyl ketone 43 (Scheme [10 ]) to produce the desired chiral quinoline intermediate 44 , which was subsequently deprotonated with LDA at –78 °C and then treated with alkyl
or benzyl iodide to give the corresponding alkylated ligands 45a –c .
Scheme 10 Synthesis of chiral N,N-bidentate quinoline ligands[77 ]
Quinoline analogues 48a –c were successfully synthesized from methyl ketones 46 under similar reaction conditions (Scheme [10 ]) using LDA and alkyl halides.
A new class of chiral ligands containing the quinoline moiety 51a –d was developed by Yamamoto and co-workers in 2004. The coupling reaction of bis-aryl
iodo compound 49 with quinoline derivatives 50 in the presence of LDA and BBr3 furnished the required bis quinoline compounds 51a –d (Scheme [11 ]). Chiral ligands 51a –d were then treated with Et2 AlCl or CrCl2 to give the corresponding tethered bis(8-quinolinato) (TBOx) aluminum complexes 52a –d in good yields. These N ,N -quinoline ligands were applied in pinacol couplings, the Pudovik reaction, hydrogenation
of ketones and allylic alkylations.
Scheme 11 Synthesis of N,N,O-chiral bis-quinoline ligands[78 ]
2.4
Synthesis of Amine-Based Chiral Ligands
In 2007, Romanelli and co-workers reported a series of quinoline ligands 57 prepared by the alkylation of alcohol 53 in the presence of TsCl (1.2 equiv) and pyridine at room temperature. Subsequent
alkylation of 6-hydroxyquinoline 55 with Ts-ester 54 in the presence NaH (2 equiv) in DMF at 80 ° for 4 h was followed by reduction with
LAH and then MeI was added to furnish the required chiral amine salt (R )-57 in high yield (Scheme [12 ]).
Scheme 12 Synthesis of chiral quinoline with amine salt 57
[79 ]
Kwong et al. introduced a novel synthesis of bisamide ligand-containing quinolines,
whose asymmetric synthesis started from condensation of cyclohexyl diamine 59 with heterocyclic aldehydes 58 and 61 to give amide-based unsymmetrical ligands 62 and symmetrical ligands 60 in good yields (Scheme [13 ]).
Scheme 13 Synthesis of amide-type chiral ligands[80 ]
Judeh and co-workers described a series of quinoline ligand derivatives 68a –m , whose synthesis starts from simple condensation of phenylethylamine 63 with diethyl oxalate in ethanol to give compound 64 in high yield (Scheme [14 ]). Then, rac -65 was synthesized under double Bischler–Napieralski conditions. Bis-amide 64 was then reacted with polyphosphoric acid (PPA) at 190 °C for 12 h to furnished the
target compound rac -65 in 86% yield. Reaction of compound 65 with a stoichiometric amount of enantiopure (S )-(–)-α-methylbenzyl isocyanate furnished the diastereomeric urea analogues 66a and 66a′ in excellent yield. When a solution of 66a or 66a′ was treated with n -BuONa in warm n -BuOH (Scheme [14 ]), the cleaved products (+)-67a and (–)-67a′ , were obtained in up to 61% yield and 99% ee. Fortunately, one of the products could
be recrystallized from ethanol and gave a very high enantiomeric excess >99%.
Scheme 14 Synthesis of chiral isoquinoline amine ligands[81 ]
Various alkyl groups were introduced by reaction of (+)-67 with alkyl halides in the presence of K2 CO3 with CH3 CN as a solvent at 50 °C. Likewise, compound (+)-67 reacted with 1 equivalent of isocyanates and thioisocyanates in DCM at room temperature
to give the target products 68a –m in excellent yields (Scheme [14 ]).
Yus and co-workers studied a practical method for the preparation of camphor sulfonamide-based
quinoline ligands 71a ,b . Their synthesis started from cyclohexyldiamine 59 by reaction with arylsulfonyl chloride in two steps, followed by treatment with camphor
sulfonyl methyl chloride 70 . Friedlander annulation in the presence of ruthenium chloride as a catalyst then
furnished the expected camphor sulfonamide-based quinoline ligands 71a ,b in moderate yields (Scheme [15 ]).
Scheme 15 Synthesis of camphor sulfonamide-based quinoline ligands[82 ]
Felluga et al. efficiently synthesized the enantiopure amine-based ligands 75 . Baker’s yeast mediated reduction of methyl ketone 72 afforded alcohol (S )-73 . However, the required chiral alcohol (S )-73 could also be obtained by a kinetic resolution approach. Thus, azide precursors (R )-74 were obtained in good yield from the benzyl alcohol in the presence of DPPA/DBU and
reduction with triphenylphosphine (Ph3 P) led to the desired amine ligands 75 with high enantioselectivity (Scheme [16 ]).
Scheme 16 Synthesis of chiral benzo[h ]quinoline ligands and their osmium complexes[83 ]
Osmium metal complexes 77 and 78 were prepared by treatment of [OsCl2 (PPh3 )3 ] with (S ,R )-Josiphos (1.2 equiv) in mesitylene at 110 °C for 2 h to give an uncharacterized
mixture of products, which was then reacted with 2-aminomethylbenzo[h ]quinoline 75 (1.4 equiv) in the presence of triethylamine (Et3 N) at 140 °C for 24 h to furnish the corresponding coordination metal complexes 77 and 78 in good yields (Scheme [16 ]). These amine-based ligands were studied in catalytic applications such as 1,2-addition
of organozinc reagents to substituted aldehydes, 1,4-addition of Grignard reagents
(R1 MgX) to cyclic enones, allylic alkylations, and C−H bond arylation reactions
2.5
Synthesis of P,N-Type Chiral Ligands
The efficient synthesis of QUIPHOS type chiral ligands 81a –h by the reaction of phosphane 79 and pyrrolidine 80 followed by addition of hydroxyquinoline 34 (method 1, Scheme [17 ]) afforded the desired ligands 81a –h in moderate to good yields, as reported by Buono and co-workers. Applying a similar
reaction protocol led to a wide range of P,N-quinoline–phosphine ligand derivatives
83a –h ; selected examples are shown in method 2, Scheme [17 ].
Scheme 17 Synthesis of chiral N,P,O-quinoline–phosphine ligands[84 ]
Quinoline-based chiral Pd complex 87 was effectively prepared via halogen–metal (Li–Br) exchange of heterocyclic bromo
compound 84 and s -BuLi, followed by quenching with PCl(NMe2 )2 to give quinoline–phosphine ligand 85 . Reaction of P,N-ligand 85 with chiral amine 80 produced the corresponding chiral ligand 86 and this was treated with [PdCl2 (CH3 CN)2 ] in DCM to produce the desired N ,N ,P -Pd complex 87 in excellent yield (Scheme [18 ]).
Scheme 18 Synthesis of N,N,P-chiral quinoline–phosphine ligand 86 and its Pd complex[85 ]
The phosphonito, nitrogen ligand (R )-90 has been synthesized in a one-pot, two-step process (Scheme [19 ]). trans -Metalation of 8-bromoquinoline 84 with n -butyllithium (n -BuLi) and subsequent treatment with PCl(NEt2 )2 to form phosphine compound 88 , followed by the reaction with (R )-binaphthol 89 in toluene at reflux, furnished P,N-ligand (R )-90 in good yield. This ligand was reacted with Pd, Pt and Rh complexes to furnish the
desired metal complexes 91 –93 in good yields.
Scheme 19 Synthesis of N,P,O-chiral quinoline–phosphine ligand (R )-90 and its Pd, Pt, Rh complexes[86 ]
In 2000, Faraone and Leitner introduced the enantioselective synthesis of phosphane/phosphoramidite
ligands 96a and 96a′ in a one-pot procedure from readily available 8-biarylphosphinoquinoline 94 by nucleophilic addition of organometallic lithium reagents and direct quenching
with PCl3 to obtain P,N-ligand 95 , followed by addition to chiral 1,1′-bi-2-naphthol 89 in the presence of Et3 N. Under the same reaction conditions, a 1:1 mixture of diastereomers containing 2-substituted
quinoline ligands 99a –d and 99a′ –d′ was obtained from phosphinoquinoline 94 . Selected examples are illustrated in Scheme [20 ].
Scheme 20 Synthesis of chiral phosphane/phosphoramidite ligands[87 ]
Knochel and co-workers examined the synthesis of P,N-ligands 104 from commercially available starting materials. Treatment of (+)-camphor 100 with Tf2 NPh in THF at 0 °C produced the desired compound 101 in 90% yield (Scheme [21 ]). The chiral camphor triflate 101 efficiently underwent a Pd-catalyzed Negishi cross-coupling reaction with the quinoline
organozinc reagent,[88` ]
[b ]
[c ]
[d ] affording the desired 2-alkenylquinoline 102 in acceptable yield. Subsequent hydrophosphination with Ph2 P(O)H, in the presence of a catalytic amount of t -BuOK (20 mol%) in DMSO provided phosphine oxide 103 (Scheme [21 ]). Reduction of compound 103 was accomplished in the presence of HSiCl3 and Et3 N in toluene at reflux, to generate the chiral aminophosphine 104 in good yield.
Scheme 21 Synthesis of a chiral P ,N -quinolinyl ligand and its Ir complexes[88e ]
[f ]
Chiral Ir complex 105 was synthesized by reaction of [Ir(cod)Cl]2 and P,N-ligand 104 in DCM at reflux. After treatment with NaBArF in a biphasic DCM–H2 O system, the subsequent orange colored salt 105 was obtained after chromatographic purification. The iridium chiral metal complexes
were stable towards moisture and oxygen.
Jiang et al. have designed and synthesized a series of phosphine–quinoline ligands.
Their synthetic protocol began from optically pure paracyclophane 106 . Hence, treatment of (Rp
)-106 with n -butyllithium (n -BuLi) followed by successive addition to 2-quinolinylcarboxaldehyde, produced two
diastereoisomers, (Sp
,S )-107a′ and (Sp
,R )-107a that could be readily separated by flash column chromatography (Scheme [22 ]). Modifying (Sp ,S )-107a′ and (Sp ,R )-107a by silylation in the presence of TBSOTf and lutidine as a base produced (Sp ,S )-108a′ in 98% yield and (Sp ,R )-108a in 97% yield, respectively.
Scheme 22 Synthesis of chiral phosphino-quinoline paracyclophane P,N-ligands[89 ]
Ruzzicon et al. investigated the valuable synthesis of P,N-bidentate planar chiral
ligands 111 and 114 . Deprotonation of methyl compound 109 with n -BuLi at 0 °C, involved the 2-methyl quinoline, giving the 2-methyllithium intermediate,
exclusively. The borane complex (R )-110 was achieved in high yield, by the reaction of Ph2 PCl with BH3 ·OMe2 (Scheme [23 ]). The subsequent air-stable borane complex (R )-110 was treated with DABCO, to obtain the expected phosphine (R )-111 . On the other hand, bromo-compound 113 was prepared from alcohol 112 by treating with CBr4 and PPh3 in Et2 O at 25 °C and successfully underwent nucleophilic substitution with lithium (diphenylphosphine)methylborane
complex, followed by treatment with DABCO, providing the corresponding P,N-chiral
ligand (R )-114 in 70% overall yield (Scheme [23 ]).
Scheme 23 Synthesis of P,N-planar chiral ligands[90 ]
Scheme 24 Synthesis of P ,N -isoquinoline chiral ligand[91 ]
[75 ]
Brown et al. focused on the synthesis of chiral ligands 121a –g (QUINAP). Boronic acid 116 underwent smooth cross-coupling with aryl chloride 115 in the presence of 3 mol% Pd(PPh3 )4 and Na2 CO3 in DME to give carbon–carbon coupled product 117 in 96% yield. Cleavage of the methyl group from aryl methyl ether 117 with boron tribromide (BBr3 ) gave the required phenol analogue 118 , which was further converted into the triflate 119 (Scheme [24 ]). Finally, palladium-catalyzed cross-coupling of triflate 119 with diphenylphosphine oxide gave the phosphine oxide 120 . Subsequently, compound 120 was reduced to the phosphine ligand 121 with HSiCl3 and Et3 N in 84% yield.
Finally, the racemic ligand 121 was reacted with the chiral palladacycle 122 to form diastereomers, from which the desired enantiopure R or S ligands 121a –g were obtained in good yields after fractional recrystallization and ligand decomplexation
(Scheme [24 ]).
Scheme 25 Synthesis of P ,N -benzo ring-fused isoquinoline chiral ligand[91 ]
Furthermore, the same group developed a method for the preparation of benzo ring fused
isoquinoline and indole-based chiral P,N-ligands 128 and 134 (Scheme [25 ] and Scheme [26 ]).
Scheme 26 Synthesis of chiral P,N-ligands with an indole unit[91 ]
Scheme 27 Synthesis of chiral P,N-ligands with a spiro -skeleton[92 ]
Ding and co-workers have synthesized spiro -based P,N-ligand 146 through a sequence of reactions as shown in Scheme [27 ]. Nucleophilic addition of compound 136 , to a ketal derivative 137 generated a protected spiro-diketone 138 . Then Friedländer condensation of 139 with 2-amino benzaldehyde 140 in the presence of KOH and EtOH furnished the polycyclic quinoline 141 in 70% yield. Selective deprotection of compound 141 in aq. TFA at room temperature for 1 h furnished the corresponding spiro -ketone 142 in excellent yield. Subsequent treatment of spiro -compound 142 with LiHMDS, followed by addition of PhNTf2 , gave enol triflate 143 in 96% yield. Next, the coupling reaction of compound 143 with Ph2 P(O)H in the presence of Pd catalyst afforded racemic phosphine oxide 144 in 85% yield, which was readily resolved by chiral HPLC to give both enantiomers
in enantiomerically pure form.
The resulting chiral phosphine oxide 145 was simply reduced with HSiCl3 in the presence of pyridine, affording the required chiral nitrogen ligand (S)-146 in moderate yield (Scheme [27 ]). The reaction of nitrogen based P,N-ligand 146 with [Ir(cod)-Cl]2 in DCM followed by addition of NaBArF after counter-anion exchange gave the corresponding
desired Ir metal complex (+)-147 in 87% yield.
Scheme 28 Synthesis of silyl substituted chiral quinolinyl phosphane ligands and their Ir complexes[80 ]
[93 ]
Multi-step synthesis of silyl substituted chiral quinolinyl phosphane ligands 153a –c has been achieved by Pfaltz and co-workers. In the initial step, hydroxylation of
compound 148 using a metal catalyst gave the corresponding 1,2-diol 149 in moderate yield and high enantiomeric excess on a gram scale (46% yield, 94% ee).
Selective tosylation of the primary alcohol 149 in the presence of TsCl with pyridine, followed by silylation of benzyl alcohol 150 using TBDMSCl and imidazole generated enantiomerically pure compound 151 after recrystallization.
Next, sulfonate 151 was treated with LiPPh2 ·BH3 at –78 °C to furnish the phosphine-protected ligand 152 in good yield (Scheme [28 ]). Finally, the P–B bond was successfully cleaved using diethylamine to afford the
desired P,N-ligands 153a –c in good yield.
Additionally, Ir-based transition-metal complexes 154a –c were produced from N -heteroaryl phosphane derivatives 153a –c . Warming a DCM solution of the requisite organocatalysts 153 in the presence of [Ir(cod)Cl]2 (0.5 equiv) for 2 h at 30–40 °C followed by counter-ion exchange with NaBArF (1.6
equiv), provided the metal complexes as orange solids. These types of metal complexes
are generally stable to air and moisture, and are simply purified by flash column
chromatography on silica gel (Scheme [28 ]).
Scheme 29 Synthesis of quinoline based P,N-chelating ligands[94 ]
Chelucci et al. reported a new class of bidentate ligands 160 , 164 and 168 that were synthesized from the corresponding starting materials (+)-nopinone, (+)-camphor
and 5-androst-2-en-17-one. The direct lithiation of compound 155 with t -BuLi at low temperature and then quenching with electrophile DMF affording coupled
aldehyde 156 . The N -Boc aldehyde 156 thus obtained reacts with acyclic ketone 157 in the presence of t -BuOK at 25 °C, leading to 159 in good yield (Scheme [29 ]). Finally, treatment of compound 159 with LiPPh2 gave the desired acridine 160 in 82% yield. The same group used similar reaction conditions to prepare additional
quinoline-based P,N-chelating chiral ligands 164 and 168 in good yields (Scheme [29 ]).
Wild and co-workers introduced an efficient method for the preparation of (R or S )-carbene ligands 173 (Scheme [30 ]). The reaction of halogenated quinoline 169 with Na(PMePh) in THF furnished the desired compound 170 in very good yield. This racemic product was resolved by crystallization of a pair
of internally diastereoisomeric Pd(II) complexes (R ,R )- and (R ,S )-171a ,a′ derived from the chelating ligand (R )-122 . The resulting tertiary phosphine (R )- and (S )-172 was accessed by treatment with H2 SO4 and LiCl (Scheme [30 ]). Finally square-planar palladium complexes (R )- and (S )-172 were successfully converted into the optically pure enantiomers (S )- and (R )-173 with aq. KCN and DCM/H2 O in a biphasic reaction medium.
Scheme 30 Synthesis of chiral P,N-carbene ligands[75 ]
[95 ]
These quinoline-based P,N-ligands were broadly applied as asymmetric catalysts in
cyclopropanation of olefins, Heck reactions, hydrogenation of olefins, ketones and
imines, hydroformylation, allylic alkylation, and oxidative hydroboration.
2.6
Synthesis of Chiral N -Oxide and Nitrogen Ligands
Martinez et al. developed an efficient method for the preparation of camphor sulfonamide-based
quinoline chiral ligands and their N -oxide derivatives. These chiral amine ligands 174a –c (C
2 -symmetry) were prepared by the addition of camphorsulfonyl chloride 70 to 1,2-cyclohexanodiamine 59 and, without additional purification, the resulting intermediates were treated with
an aminobenzyl alcohol (Scheme [31 ]) to afford the desired camphor sulfonamide-based quinoline ligands 174a –c in high yields. The quinoline N -dioxide ligands 175a –c were simply synthesized from the corresponding ligands 174a –c (C
2 -symmetry) by oxidation with m CPBA in DCM at 0 °C. The resulting amine type N -dioxide ligands 175a –c were formed in reasonable yields and were typically stable enough to be purified
by flash column chromatography.
Scheme 31 Synthesis of camphorsulfonamide-based quinoline N ,N ′-dioxide ligands[82 ]
Scheme 32 Synthesis of bis-quinoline-based chiral N ,N ′-dioxide ligands[96 ]
Nakajima et al. successfully developed a protocol for the synthesis of C
2 -symmetric 2,2′-biquinoline N ,N ′-dioxide (R or S )-178 and 1,1′-biisoquinoline N ,N ′-dioxide (R or S )-182 (Scheme [32 ]). The racemic compound 177 was prepared by m CPBA oxidation of 3,3′- dimethyl-2,2′-biquinoline 176 , and the product was resolved through a hydrogen-bonding complex with (S )- or (R )-binaphthol to afford desired chiral compounds (R )-178a and (S )-178a ′ (Scheme [32 ]). The enantiomerically pure ligand 1,1′-biisoquinoline N ,N ′-dioxide (S )-182 was prepared by preparative chiral HPLC from racemic compound 181 , which was in turn synthesized by N-oxidation of 1,10-bisisoquinoline 180 using H2 O2 .
The racemic compound 117 was prepared from 1-chloro isoquinoline 115 via Suzuki cross-coupling reaction in the presence of boronic acid 116 . Racemic 117 was further reacted with m CPBA, and was resolved via a complex with (S )-binaphthol to give the required chiral compounds (R )-183 .
The ligands (–)-185 and (+)-186 were obtained by resolution of rac -184 with d and l -dibenzoyltartaric acid, respectively. The absolute configuration of chiral ligand
(S )-186 was determined by single-crystal X-ray analysis (Scheme [32 ]). Quinoline-based N -oxide ligands were studied in various asymmetric catalytic reactions such as 1,4-addition
and Michael addition reactions, allylation of aromatic and heteroaromatic aldehydes,
and Strecker reactions.
Finally, in this section, Meyers et al. established the synthesis of chiral naphthylquinoline
ligands 188 and 189 . Addition of naphthyllithium (1.1 equiv) to quinoline oxazoline 187 in THF at –78 °C for 2–3 h followed by oxidation with dichlorodicyanoquinone (DDQ)
in THF at –78 °C gave 1-naphthyl-4-quinoline (S )-188a ,b in good yield. A similar process using 187 and arylmagnesium reagents[97a ] followed by oxidation with DDQ (THF, –78 °C) gave the biaryl compounds (R )-189a ,b in high yields (Scheme [33 ]).
Scheme 33 Synthesis of chiral naphthylquinoline ligands[97b ]
[c ]
3
Homogeneous Catalytic Asymmetric Reactions
3.1
Asymmetric Carbon–Carbon Bond-Formation Reactions
Catalytic asymmetric C–C bond-forming reactions provide one of the most efficient
methods to synthesize chiral molecules, and a range of pyridine and quinoline-based
chiral catalysts have been developed in the past two decades, finding a wide range
of applications.[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
[26 ]
[27 ]
[28 ]
[29 ]
[30 ]
[31 ]
3.1.1
Asymmetric Addition of Dialkylzinc to Aldehydes
In 2008 Cozzi, Yus, Ramón and co-workers described the preparation of camphor sulfonamide-based
quinoline ligands. This type of chiral quinoline ligands has been used for the synthesis
of trisubstituted chiral alcohols. The enantioselective 1,2-addition of organozinc
reagents to substituted aldehydes 190 , provides alcohols 191 with high enantioselectivities (up to 96% ee) with either aromatic or aliphatic substrates
(Scheme [34 ]). These reactions were carried out using 10 mol% chiral amine ligand 71a organozinc reagent (2.4 equiv) and 1.1 equivalents of Ti(O-i -Pr)4 .
Scheme 34 Enantioselective addition of dialkylzinc reagents to aldehydes[82 ]
In 2010, Judeh and co-workers synthesized constrained chiral C
1 -symmetric 1,10-bisisoquinoline ligands. The consequences of their geometrical conformations
were found to have a significant effect on the catalytic asymmetric addition of diethylzinc
to aromatic aldehydes 190 . To study the reaction scope and limitations of ligand (+)-67a′ , several aromatic aldehydes having electron-donating and electron-withdrawing substituents
were examined under the optimized reaction conditions. In general, this protocol produced
excellent yields and high enantioselectivities of the secondary alcohols 192 (Scheme [35 ]).
Scheme 35 Enantioselective addition of diethylzinc to aldehydes[81 ]
3.1.2
Asymmetric 1,4-Additions of Dialkylzincs to Enones
Buono and co-workers investigated the use of a copper catalyst involving QUIPHOS 81a –h as a chiral ligand. This system was applied to the 1,4-addition of Et2 Zn to α,β-unsaturated cyclic ketones. Notably, additives such as water or zinc hydroxide
had a significant effect, leading to an improved enantiomeric excess from 7 to 61%
ee in this enantioselective 1,4-addition system (Scheme [36 ]).
Faraone and co-workers examined the Cu(II)-catalyzed asymmetric 1,4-addition of diethylzinc
to 2-cyclohexen-1-one, in the presence of a catalytic amount of chiral ligands 96a and 83h with appropriate metal salts. The 1,4-adducts were formed with enantioselectivities
up to 70% ee with BINAPHOSHQUIN 96a (Scheme [36 ]).
Scheme 36 Enantioselective 1,4-addition of dialkylzinc to cyclic enones[68 ]
[84 ]
[98 ]
Later, Hayashi and co-workers developed mild and effective methods for the synthesis
of chiral alcohols with excellent enantioselectivity. The copper-catalyzed enantioselective
conjugate 1,4-addition of dialkylzinc reagents to α,β-unsaturated cyclic ketones 193 with catalytic amounts (0.2 mol%) of Cu(OTf)2 and 0.25 mol% of one of the N,N,P-tridentate Schiff base ligands 6a ,b gave cyclic ketone adducts 194 in up to 99% ee in good yield (Scheme [36 ]). The impact on the enantioselectivity and reactivity of many other variables, such
as the nature of the metal catalyst, ligands, and ligand/catalyst loading involved
were also examined in detail and the results obtained are summarized in Scheme [36 ].
Moreover, Hayashi and co-workers further expanded the scope of the 1,4-addition reaction
to access disubstituted ketones via copper-catalyzed 1,4-addition of dialkylzincs
to α,β-unsaturated ketones. The reactive zinc enolate intermediates were trapped efficiently
with reactive allyl iodides to afford the corresponding disubstituted ketones 195 with excellent diastereo- and enantioselectivity. The desired 1,4-addition reactions
were performed using 1 mol% Cu(OTf)2 and 1.5 mol% Schiff base ligand 6a ,b . The results obtained are summarized in Scheme [37 ].
Scheme 37 Enantioselective 1,4-addition followed by trapping of zinc enolate by allyl iodides[68b ]
3.1.3
Asymmetric Conjugate Addition of Grignard Reagents to Enones
Highly constrained C
1 -1,10-bisisoquinoline chiral ligands (+)/(–)-67 were examined in the enantioselective 1,4-addition of Grignard reagents (R1 MgX) to cyclic enones 193 . The desired 1,4-adducts 194 were obtained in very good yields but with low enantioselectivity (up to 35% ee)
(Scheme [38 ]).
Scheme 38 Grignard reagent conjugate addition to cyclic enones in the presence of copper salts
and chiral ligands[99 ]
3.1.4
Asymmetric Conjugate 1,4-Addition of Thiols to Cyclic Enones
Nakajima and co-workers examined the enantioselective conjugate nucleophilic 1,4-addition
of thiols to enones under mild reaction condition, leading to the corresponding sulfides
196 with moderate enantioselectivities (up to 78% ee). This protocol provided the first
example of using a cadmium complex in an asymmetric thiol 1,4-addition reaction (Scheme
[39 ]).
Scheme 39 Enantioselective conjugate 1,4-addition of thiols to enones[96c ]
[d ]
3.1.5
Asymmetric Michael Addition Reaction
In 2003, Nakajima et al. studied the catalytic, enantioselective Michael addition
of β-keto esters to α,β-unsaturated carbonyl compounds using a chiral biquinoline
N ,N ′-dioxide–Sc(OTf)3 (R )-178a complex as catalyst. The Michael adducts 198 were produced in good yields with moderate enantioselectivities (up to 84% ee) (Scheme
[40 ]). Electron-donating indanone substrates 197 were tested using 5 mol% quinoline N ,N ′-dioxide ligand–Sc(OTf)3 .
Scheme 40 Enantioselective Michael addition of β-keto esters to methyl vinyl ketone (MVK)[96e ]
[100 ]
3.1.6
Asymmetric Friedel–Crafts Alkylation
Zhou and co-workers (2006) investigated an efficient asymmetric Friedel–Crafts alkylation
of free N–H indoles 199 with nitro compound 200 catalyzed by Zn(OTf)2 -oxazoline complexes 28e . The nitroindole 201 was prepared in good yield, but very low enantioselectivities (up to 9% ee) were
observed in the presence of 12 mol% chiral ligand 28e and 10 mol% Zn(OTf)2 at 0 °C for 20 h (Scheme [41 ]).
Scheme 41 Asymmetric catalytic Friedel–Crafts alkylation of indole with trans -β-nitrostyrene[101 ]
3.2
Asymmetric Allylic Reactions
3.2.1
Asymmetric Allylic Oxidation
In 2008 Hayashi and co-workers studied the copper (I)-catalyzed enantioselective allylic
oxidation of several cyclic olefins with tert -butyl perbenzoate (PhCO3 But ) enabled by N,N-bidentate Schiff base ligands 11a , which were effective in conferring high reactivity and moderate-to-good enantioselectivity
(up to 84% ee). The authors examined the allylic oxidation of numerous cyclic olefins
202 using a Cu(CH3 CN)4 PF6 and Schiff base ligand system. The results, summarized in Scheme [42 ], were obtained using a catalytic amount of chiral N,N-bidentate ligand 11a .
Scheme 42 Enantioselective allylic oxidation of cyclic olefins[69 ]
Later, in 2009, Hayashi and co-workers developed an enantioselective desymmetrization
by allylic oxidation of 4,5-epoxycyclohex-1-ene 205 in the presence of 3 mol% of chiral N,N-bidentate Schiff base ligand 11a and 2.5 mol% of Cu(CH3 CN)4 PF6 to afford phenyl epoxide 206 in 84% ee, which was improved to >99% ee after derivatization with 4-nitro benzoyl
chloride and recrystallization to give the corresponding nitroaryl epoxide derivatives
207 (Scheme [43 ]).
Scheme 43 Enantioselective allylic oxidation of 4,5-epoxycyclohex-1-ene[102 ]
3.2.2
Asymmetric Allylation of Aldehydes with Allylchlorosilanes
In 2002, Malkov, Koćovský and co-workers developed the Sakurai–Hosomi-type allylation
of aromatic aldehydes 190 catalyzed by C
2 -symmetric 2,2′-biquinoline N ,N ′-dioxide (S )-178 , leading to the corresponding chiral alcohol 209 in good enantioselectivities (up to 88% ee) and 85% reaction yield (Scheme [44 ])
Scheme 44 Sakurai–Hosomi-type allylation of aromatic and heteroaromatic aldehydes[103 ]
Later, the same group (2003) revealed that the addition of allyltrichlorosilane 208 to aromatic aldehyde 190 in the presence of quinoline N -oxide ligand (R )-183 (5 mol%) at –40 °C in DCM for 0.5–12 h, produced the corresponding alcohol derivatives
209 with 5–96% ee and good yields. The aldehyde substrate scope is summarized in Scheme
[45 ].
Scheme 45 Allylation of aldehydes catalyzed by quinoline N -oxide ligand[80 ]
[96f ]
3.2.3
Asymmetric Phase-Transfer Allylic Alkylation
Later, in 2008, Eddine and co-workers reported the phase-transfer-catalyzed asymmetric
alkylation of ester 210 with allyl bromide in the presence of 10 mol% of chiral N,N-bidentate Schiff base
salt 17 with the use of NaOH, affording the desired compound 211 in good yield and very low enantioselectivity (Scheme [46 ]).
Scheme 46 Allylation of keto-imine under phase-transfer conditions[71 ]
3.3
Asymmetric Cycloadditions
3.3.1
Asymmetric Diels–Alder Reactions
Buono and co-workers (1998) reported the asymmetric Diels–Alder reaction catalyzed
by copper-phosphene complexes. The nitrogen-based copper(II) catalyst was prepared
by mixing Cu(OTf)2 and chiral quinolinephosphine ligand 81a in DCM and further used in the Diels–Alder reaction of 3-acryloyloxazolidin-2-one
213 with cyclopentadiene 212 , leading to the corresponding amide product 214 in excellent yields and remarkable enantioselectivities (up to 99%) (Scheme [47 ]).
Scheme 47 Copper-catalyzed asymmetric Diels–Alder reactions of cyclopentadiene with N -acyl oxazolidinones[104 ]
Subsequently, in 2004, Suga et al. developed an efficient method for Ni(II)-catalyzed
asymmetric Diels–Alder reactions of cyclopentadiene 212 and 3-alkenoyl-2-oxazolidinones 215 in the presence of the ligand BINIM-2QN 14a (Scheme [48 ]). Even loadings down to 1 mol% Ni(II) catalyst promoted Diels–Alder reactions with
high conversions and enantioselectivities (endo -addition with up to 94% ee).
Scheme 48 BINIM-2QN catalyzed asymmetric Diels–Alder reactions of cyclopentadiene with 3-acryloyl-2-oxazolidinone[70a ]
3.3.2
Asymmetric Hetero-Diels–Alder Reactions
Scheme 49 Enantioselective hetero-Diels–Alder reactions catalyzed by monosulfoximine ligands[76 ]
Bolm et al. studied the first example of a copper-catalyzed hetero-Diels–Alder reaction
of cyclohexa-1,3-diene (217 ) and keto ester 218 in the presence of 10 mol% Cu(OTf)2 and C
1 -symmetric sulfoximine ligands 41a –l , leading to cycloadducts in good yields and high enantioselectivities (up to 96%
ee) as shown in Scheme [49 ].
Asymmetric cycloaddition of nitrones 220 and 3-(2-alkenoyl)-2-thiazolidinethiones 221 using chiral binaphthyldiimine–Ni(II) complexes 14a –e to afford products in high exo -diastereoselectivities and enantioselectivities was reported by Suga et al. in 2005
(Scheme [50 ]).
Scheme 50 Asymmetric cycloaddition reactions catalyzed by chiral BINIM–Ni(II) complexes[70b ]
3.3.3
Asymmetric 1,3-Dipolar Cycloaddition Reactions
Shi and co-workers reported chiral binaphthalenediimine-Ni(II) complex 14a as an active catalyst in the 1,3-dipolar cycloaddition reactions of azomethine ylides
223 and 1-phenyl-1H -pyrrole-2,5-dione 224 to give the corresponding adducts 225 in very low yields and poor enantiomeric excesses (up to 8%) in Scheme [51 ].
Scheme 51 Enantioselective 1,3-dipolar cycloadditions catalyzed by Ni(ClO4 )2 ·6H2 O and chiral ligands[70c ]
Furthermore, in 2011, Suga et al. demonstrated that BINIM–Ni(II) catalysts 14a –c were efficient for enantioselective 1,3-dipolar cycloaddition reactions between ethyl
diazoacetate 226 and 3-acryloyl-2-oxazolidinones 227 to produce the corresponding adducts 228 in high yields and enantiomeric excesses (up to 93%) as shown in Scheme [52 ].
Scheme 52 Reactions of ethyl diazoacetate with 2-(2-alkenoyl)-3-pyrazolidinones catalyzed by
(R )-BINIM–Ni(II) complexes[105 ]
The same group had previously reported in 2007 the first example of highly enantioselective
1,3-dipolar cycloaddition reactions between azomethine imines 229 and 3-acryloyl-2-oxazolidinone 230 using 10 mol% of chiral BINIM–Ni(II) complex 14b (Scheme [53 ]).
Scheme 53 Cycloaddition reactions of azomethine imines with 3-acryloyl-2-oxazolidinone[70d ]
3.4
Asymmetric Carbene Insertions
A simple and efficient method for Cu-catalyzed enantioselective C–H carbene insertion
between methyl phenyldiazoacetate and THF in the presence of 2.2 mol% of chiral N,N-bidentate
Schiff-base ligand 28e and 2.0 mol% of copper catalyst to afford the corresponding syn -product 234 in 45% ee, was reported by Fraile et al. in 2007. Copper salts such as Cu(OTf)2 , CuBr2 , Cu(OAc)2 , CuCl, and CuSbF6 were examined to optimize the reaction and copper triflate furnished better results
(Scheme [54 ]).
Scheme 54 Reaction between methyl phenyldiazoacetate and THF catalyzed by oxazole-copper complexes[106 ]
3.5
Asymmetric Pinacol Couplings
In 2004, Yamamoto and co-workers introduced a new class of chiral tetradentate ligand,
TBOx 52a , as a catalyst for pinacol coupling. Chromium complex TBOxCrCl 235 was shown to be an efficient catalyst for the asymmetric pinacol coupling reactions
of both functionalized aromatic and aliphatic aldehydes 190 . With aromatic substrates, the catalyst system was shown to be quite insensitive
to changes in steric effects on the substrates as well as to the presence of electron-donating
and electron-withdrawing substituents on the aromatic ring, providing high enantiomeric
excesses (up to 98%, Scheme [55 ]).
Scheme 55 Pinacol coupling reaction of aromatic aldehydes[78a ]
3.6
Asymmetric Pudovik Reactions
The same group in 2008 developed the catalytic enantioselective Pudovik reaction of
aldehydes 190 and aldimines 239 with tethered bis(8-quinolinato) (TBOx) aluminum complexes 52a –d . α-Hydroxy- and α-aminophosphonates 238 and 240 were prepared in high yields and enantioselectivities (96–98% ee) using a low catalyst
loading (1 mol%). This was a significant improvement over other catalysts in that
they generally required higher catalyst loadings, typically >5 mol% and extended reaction
times. The chiral ligand could be easily recovered in high purity after simple purification
without loss in either reactivity or selectivity (Scheme [56 ]).
Scheme 56 Catalytic enantioselective Pudovik reaction of aldehydes/aldimines with tethered
bis(8-quinolinato) (TBOx) aluminum complexes[78b ]
3.7
Asymmetric Strecker Reactions
Feng and co-workers (2003) investigated enantioselective Strecker reactions with trimethylsilyl
cyanide (TMSCN) 242 and aryl imines 241 catalyzed by chiral N ,N ′-dioxide ligand 178 . These chiral quinoline N ,N -dioxide Lewis base promoters were effectively applied to the chiral synthesis of
α-amino aryl nitrile analogues 243 with high enantioselectivities (up to 95% ee). Enantiomerically pure products (up
to 99% ee ) were subsequently obtained by recrystallization (Scheme [57 ]).
Scheme 57 Enantioselective Strecker reactions between aldimines and TMSCN[96g ]
[h ]
4
Heterogeneous Catalytic Asymmetric Reactions
Fraile, Mayoral and co-workers reported quinoline-based oxazoline ligands, a class
of C
1 -symmetric chiral ligands, in the enantioselective cyclopropanation of styrene (244 ) with ethyl diazoacetate 245 in DCM at 25 °C, which proceeded with excellent cis -selectivity (up to 65%). This result may be synthetically of interest, given that
cis -cyclopropanes are generally difficult to obtain. The substrate scope is summarized
in Scheme [58 ].
Scheme 58 Cyclopropanation reaction between styrene and diazoacetate esters[107 ]
4.1
Asymmetric Cyclopropanation of Olefins
In 1998, Ahn and co-workers studied the Ru(II)-catalyzed intramolecular cyclopropanation
of diazo-alkenes 247 . The catalytic chiral system demonstrated good reactivity and stability, and produced
high yields with moderate enantioselectivities (Scheme [59 ]).
Scheme 59 Ru(II)-catalyzed asymmetric intramolecular cyclopropanations using a chiral diphenylphosphino(oxazolinyl)quinoline
ligand[75a ]
4.2
Asymmetric Heck Reactions
In 2004 Pfaltz and co-workers described the generality and utility of ligands 153a ,b in palladium-catalyzed enantioselective Heck reactions. The results are summarized
in Scheme [60 ].
Scheme 60 Enantioselective Heck reaction using chiral quinolyl phosphane ligands[93 ]
4.3
Asymmetric Hydrogenations
4.3.1
Asymmetric Hydrogenation of Alkenes
P,N-Chiral iridium complexes 154a –c were efficiently applied to asymmetric hydrogenation of di-substituted alkenes 253 (Scheme [61 ], entries 1–3), resulting in up to 56% ee, as reported by Pfaltz and co-workers in
2004. The reactivities of the metal complexes are summarized in Scheme [61 ]. In general, phosphinites were excellent in terms of both enantioselectivity and
reactivity. Additionally, in 2003, Knochel and co-workers demonstrated that ligand
105 mediated Ir-catalyzed asymmetric hydrogenation reactions of tri-substituted alkenes
(Scheme [61 ], entries 4–6) leading to hydrogenated products with high enantioselectivity (up
to 95% ee).
Scheme 61 Iridium-catalyzed hydrogenation of alkenes[88 ]
[93 ]
4.3.2 Asymmetric Hydrogenation of Ketones
In 2005, Leitner and co-workers developed a highly enantioselective ruthenium-catalyzed
hydrogenation of aromatic ketones with (R
a ,S
c )-QUINAPHOS 99a in the presence of substituted and non-substituted diamines as co-catalysts. The
hydrogenation results obtained are summarized in Scheme [62 ].
Scheme 62 Asymmetric hydrogenation of ketones in the presence of chiral metal complexes[83a ]
[b ]
[108 ]
Later, in 2010, Baratta et al. employed ruthenium metal complexes (MC) 255a –d and osmium complexes 77 and 78 in the presence of t -BuOK, to catalyze chemoselective asymmetric hydrogenation (5 atm H2 ) of aromatic and aliphatic ketones to give the desired chiral alcohols in high conversions
and good selectivities (Scheme [62 ]).
4.3.3
Asymmetric Hydrogenation of Imines
In 2010, Ding and co-workers reported a chiral ligand bearing a spiro -scaffold-based Ir-complex 147 and successfully applied it in the enantioselective hydrogenation of aryl-imine 258 , furnishing the corresponding chiral amine with enantioselectivities up to 58% ee
(Scheme [63 ]).
Scheme 63 Asymmetric hydrogenation of imines catalyzed by chiral iridium complex[92b ]
4.4
Asymmetric Hydroformylation of Styrene
Rh-catalyzed asymmetric hydroformylation of styrene 260 in the presence of P,N-chiral quinoline ligand 99a was reported by Leitner and co-workers in 2007. The P,N-chiral Rh complexes were
applied to asymmetric hydroformylations of mono-substituted alkenes to give the corresponding
product 261 with up to 74% enantiomeric excess, with a linear aldehyde by-product 262 also being observed (Scheme [64 ]).
Scheme 64 Rhodium-catalyzed hydroformylation of styrene[87b ]
4.5
Asymmetric Dialkoxylation of 2-Propenylphenols
Sigman and co-workers (2007) successfully developed a direct O2 -coupled Pd(II)-catalyzed enantioselective dialkoxylation of 2-alkenylphenols by using
quinoline oxazoline ligands 21a –d (Scheme [65 ]). Pd(II)-catalyzed enantioselective dialkoxylation of 2-alkenylphenols 263 , at room temperature for 24–72 h furnished the desired phenol 264 with enantioselectivities up to 92% ee.
Scheme 65 Scope of Pd(II)-catalyzed enantioselective dialkoxylation[109 ]
4.6
Asymmetric Cascade Cyclizations
In 2009 Yang and co-workers reported the structurally tunable and an air-stable oxazoline
21c -Pd catalyst system for the highly enantioselective oxidative cascade intramolecular
cyclization reaction of a variety of substituted bis-olefins 265 , with excellent enantioselectivities (up to 98% ee), good yields and high diastereoselectivities
(dr >24:1) (Scheme [66 ]).
Scheme 66 Pd(II)-catalyzed enantioselective cascade cyclization[72c ]
4.7
Asymmetric Allylic Alkylations
Several chiral phosphine-quinoline ligand analogues were found to be good candidates
for Pd-catalyzed asymmetric allylic alkylation reactions, as reported by Jiang et
al. in 2008. Catalytic allylic alkylation has been demonstrated to be a powerful tool
for stereoselective carbon–carbon bond-formation reactions in the presence of palladium-nitrogen
ligand systems. Among many quinoline-based ligands designed for this chiral reaction,
chiral bi- and tri-dentate type P,N-ligands have played a significant role owing to
their electronic and steric parameters. The reactions were carried out using 1.0–6.4
mol% Pd catalyst and 2.5–12.8 mol% chiral quinoline ligand. The results from a range
of ligands are summarized in Scheme [67 ]. Other protocols have been successfully examined for allylic alkylation reactions
using various phosphine-quinoline based chiral ligands as outlined in Scheme [67 ].[72 ]
[74 ]
[77 ]
[84 ]
[89 ]
[90 ]
[94 ]
[110 ]
Scheme 67 Asymmetric allylic alkylation (AAA) of 1,3-diphenylprop-2-enyl acetate with dimethyl
malonate[72a ]
[b ]
[74 ]
[77a ]
[b ]
[84c ]
[89 ]
[90 ]
[94a ]
[b ]
[110 ]
Trost and co-workers (2002) investigated Mo-catalyzed enantioselective allylic alkylations
with sodium dimethyl malonate in the presence of diamide or amine type ligands 62 . Allylic alkylation of ester 270 with sodium dimethyl malonate 271 furnished the corresponding chiral product 272 in low yields but high enantioselectivities (up to 98%) (Scheme [68 ]).
4.8
Asymmetric Alkylation of β-Keto Esters
Buono and co-workers studied the use of the palladium catalyst QUIPHOS 81a as a chiral ligand in the enantioselective alkylation of β-keto esters 273 with allyl substrate 274 , leading to chiral products with high enantioselectivity (up to 95% ee) depending
on the nature of the substrates and specific reaction conditions. In particular, solvents
such as THF led to poor enantioselectivity (5–30% ee); whereas the alkylation reaction
performed with a five-membered-ring keto ester in DCM at –10 °C gave the desired product
275 in 75% yield and high enantiomeric excess (95% ee) (Scheme [69 ]).
Scheme 68 Mo-catalyzed asymmetric allylic alkylation with sodium dimethyl malonate[111 ]
Scheme 69 Palladium-catalyzed asymmetric allylic alkylation of β-keto esters[112 ]
4.9
Asymmetric C−H Bond Arylation Reactions
In 2019, Yu, Bertrand and co-workers studied the C–C bond coupling reaction reactivity
and selectivity of quinoline-based amine ligands 278 in palladium-catalyzed β‑C(sp3 )–H bond asymmetric arylation reactions. They disclosed the ligand synthesis, isolation,
and detailed characterization of APAPy (acetyl-protected aminoethylpyridine) and APAQ
(acetyl-protected aminoalkyl quinoline) ligands (Scheme [70 ]).[113 ]
Scheme 70 Palladium catalyzed C–H bond arylation reactions[113 ]
4.10
Intramolecular Aerobic Oxidative Amination of Alkenes
Stahl and co-workers (2011) described the enantioselective aerobic oxidative amination
of cyclic alkenes 281 in the presence of chiral quinoline-oxazoline ligand 21d . The intramolecular addition of alkenes with a protected amine in the presence of
Pd catalyst 5 mol% and chiral quinoline-oxazoline ligands 21d (7.5 mol%) gave the corresponding product in low yield but with up to 66% enantiomeric
excess (Scheme [71 ]).
Scheme 71 Enantioselective oxidative amination employing a quinoline oxazoline ligand[114 ]
4.11
Asymmetric Oxidative Hydroboration of Alkenes
Brown and co-workers systematically studied the asymmetric hydroboration/oxidation
of vinyl-arenes 284 at ambient temperature in the presence of rhodium complexes of 1,1′-(2-diarylphosphino-1-naphthyl)isoquinolines.
Vinyl-arene substrates 284 bearing electron-withdrawing or -donating groups on the aryl ring led to the desired
alcohol 286 with enantioselectivities up to 94% ee in the most favorable cases. The enantioselectivity
of this specific conversion is moderately sensitive to the structure of the phosphorus
type ligand, with the difurylphosphino ligand 121b furnishing excellent results using an electron-deficient styrene 284 . Diphenylphosphino-ligand 121a showed the best results using an electron-donating alkene substrate (Scheme [72 ]).[75 ]
[91 ]
Scheme 72 Enantioselective oxidative hydroboration of electron-rich and electron-deficient
vinylarenes[75b ]
[91b ]
[c ]
