University of Groningen
Catalytic asymmetric carbon-carbon bond forming methodologies for synthesis of chiral N-containing heterocycles and chiral carboxamides
Guo, Yafei
DOI:
10.33612/diss.147535855
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Publication date: 2020
Link to publication in University of Groningen/UMCG research database
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Guo, Y. (2020). Catalytic asymmetric carbon-carbon bond forming methodologies for synthesis of chiral N-containing heterocycles and chiral carboxamides. University of Groningen.
https://doi.org/10.33612/diss.147535855
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17
Chapter 2: Highly enantioselective catalytic addition of
Grignard reagents to N-heterocyclic acceptors
In this chapter, general methods to prepare chiral N-heterocyclic molecular scaffolds are greatly sought after due to their significance in medicinal chemistry. Here we describe the first general catalytic methodology to access a wide variety of chiral 2- and 4-substituted tetrahydro-quinolones, dihydro-4-pyridones and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.
Part of this chapter has been published: Y. Guo, S. R. Harutyunyan. Angew. Chem. Int. Ed.
18
2.1 Introduction
Optically active piperidine and tetrahydroquinoline derivatives are ubiquitous structural motifs in alkaloid-based natural products, and bioactive and pharmaceutical compounds. Some examples to be highlighted include Torcetrapib, a drug used to treat elevated cholesterol levels, the antibiotic Helquinoline, as well as various alkaloids such as the Angustureine, Coniine, Myrtine, Solenopsin series and Indolizidine (Scheme 1).1-3
Scheme 1: Bioactive and alkaloid-based natural products and pharmaceuticals.
Accordingly, chiral piperidine and tetrahydroquinoline derivatives represent important synthetic targets. General asymmetric synthetic routes for their synthesis rely on several strategic approaches. Some of the most developed routes to chiral substituted tetrahydroquinolines make use of catalytic asymmetric hydrogenation of quinoline derivatives using chiral transition metal complexes andtransfer hydrogenations by chiral Brønsted acids with Hantzsch esters (Scheme 2).4-10 For example, Rueping and co-workers
reported the Brønsted acid catalyzed cascade transfer hydrogenation provides direct access to 2-aryl and 2-alkyl-substituted tetrahydroquinolines with excellent enantioselectivities (87-97% ee) under mild conditions and using very low amounts of catalyst (1-2 mol%).10
Moreover, this methodology was applied to the enantioselective total synthesis of alkaloids: Galipinine, Cuspareine, and Angustureine with high enantioselectivities and yields (Scheme 2). For the example of transition metal catalysed asymmetric hydrogenation, the group of Yu and Fan developed the classical asymmetric hydrogenation of quinolines catalyzed by chiral cationic η6-arene-N-tosylethylenediamine-Ru(II) complexes.5
19 In their work, wide range of quinoline derivatives, including alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions (Scheme 2).
Efficient catalytic asymmetric synthesis to access chiral hydroquinoline, quinolone and piperidone derivatives using intramolecular aza-Michael has been also explored (Scheme 3).11-17 For instances, Akiyama and co-workers disclosed a method to synthesize the chiral
2-substituted 2,3-dihydro-4-quinolones based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields and high enantioselectivities (up to 94% ee).12 In
addition, the aza-Diels-Alder reactions catalyzed by Lewis or Brønsted acids is a powerful way to afford chiral piperidines and tetrahydroquinolines (Scheme 4). The group of Kobayashi reported the first enantioselective aza-Diels-Alder reactions of imino dienophiles by using a chiral zirconium catalyst (Scheme 4).14 Optically active
2,3-dihydro-4-pyridone derivatives were prepared in high yields with good to high enantiomeric excesses (up to 93%).
Scheme 3: Intramolecular aza-Michael reactions to synthesize chiral hydroquinoline, quinolone and
piperidone derivatives.
Scheme 4: Intramolecular aza-Diels-Alder cyclization reactions to synthesize chiral piperidone derivatives.
Other potential alternative N-heterocyclic precursors for the synthesis of chiral piperidine and tetrahydroquinoline derivatives include piperidones, dihydropyridones and quinolones, which in addition are often found as part of more complex biologically active compounds.18-21
20
Scheme 5: Catalytic asymmetric conjugate addition reactions to synthesize chiral quinolone and piperidone
derivatives.
A common strategy that can access these precursors is the asymmetric conjugate addition of organometallics to N-heterocyclic acceptors using chiral auxiliaries.22-26 However,
catalytic enantioselective methodologies for conjugate additions to quinolone, pyridone, dihydropyridone and to acylpyridinium salts would constitute more attractive routes. Several such methods for additions of organometallics to 4-quinolones and dihydropyridone have been developed to date, with the most successful examples focusing on arylations (Scheme 5).27-33 For example, Shi and co-workers using low palladium(II)
complexes are effective catalysts for the asymmetric conjugate addition of arylboronic acids to 2,3-dihydro-4-pyridones, producing the synthetically and biologically important 2-aryl-4-piperidones in moderate-tohigh yields (up to 96%) along with excellent enantioselectivities (up to >99.5% ee) in most cases under mild conditions (Scheme 5).31 In
addition, Hayashi group developed the first catalytic asymmetric synthesis of 2-aryl-2,3-dihydro-quinolones by way of a rhodium-catalyzed 1,addition of arylzinc reagents to 4-quinolones (Scheme 5).28 These 1,4-adducts can be obtained with high enantioselectivity
by using the cheap (R)-BINAP as ligand, and high yields are realized by conducting the reactions in the presence of chlorotrimethylsilane.
In contrast, for asymmetric alkylations there are only few reports, which make use of dihydropyridone32-33 and acylpyridinium salt.1, 34-37 These alkylation methods suffer from
limited product scope with either low yields or moderate enantioselectivities. Furthermore, catalytic asymmetric alkylation of 4-quinolones and catalytic asymmetric conjugate additions in general to 2-quinolones as well as 4-pyridone37 are unknown. In pursuit of a
catalytic asymmetric approach to a wide variety of chiral N-heterocyclic compounds we were interested in developing a single catalytic system capable of harnessing the reactivity of various N-heterocyclic acceptors.
21
Scheme 6: The work in this chapter.
In this chapter, we describe the first general protocol for catalytic asymmetric addition of various Grignard reagents to a wide variety of N-heterocyclic acceptors with excellent yields and enantioselectivities (Scheme 6), requiring a single catalytic system based on copper salt and chiral diphosphine ligand.
2.2 Result and discussion
Our initial studies focused on the development of an efficient catalytic methodology for the alkylation of 4-quinolones (Table 1). To compensate for the relatively low reactivity of the 4-quinolone acceptor, we decided to take advantage of the high reactivity of Grignard reagents. For the screening of catalytic systems and reaction conditions, we chose the addition of EtMgBr to carboxybenzyl-protected (Cbz) 4-quinolone 1a as model reaction. Addition of EtMgBr in the absence of any catalyst did not provide substrate conversion, even at room temperature (entry 1).
Firstly, we set out to identify promising chiral catalysts, using 5 mol% of CuBr·SMe2 and 6
mol% of various chiral diphoshine (L1-L5), (only selected relevant results are presented) and phosphoarmidite (L6) ligands (Table 1). To our delight, using chiral diphosphine ligand
L1, developed by Pilkington et al.,38 the reaction proceeded to completion in 12 h at -78 oC
providing the isolated final product 2a in 99% yield and with 99% of enantiomeric excess. Optimization of the reaction temperature (entries 2-5) allowed us to establish highly practical conditions in which the addition product can be obtained at room temperature in only 20-30 min with a yield and enantiomeric purity of 98% (entry 5). This result is remarkable in its own right, as it represents the first example of highly enantioselective catalytic conjugate addition of Grignard reagents at room temperature.39
Further ligand screening revealed that none of the other diphosphine-type ligands L2, L3,
L4, L5, nor phosphoramidite-type ligand L6, work for this chemistry both in terms of yield
and enantioselectivity (entries 6-10). This is rather surprising, as all of these ligands are normally very efficient in Grignard additions to more conventional Michael acceptors.40-42
22
Table 1: Optimization of reaction conditions for the addition of EtMgBr to N-Cbz-4-quinolone 1a.a
Entry T (oC) Time (h) Ligand Yield (%)b ee (%)c
1d Rt 2 - 0 0 2 -78 12 L1 99 99 3 -20 2 L1 99 99 4 0 2 L1 99 98 5 Rt 0.5 L1 98 98 6 Rt 0.5 L2 21 28 7 Rt 0.5 L3 78 27 8 Rt 0.5 L4 82 57 9 Rt 0.5 L5 32 0 10 Rt 0.5 L6 71 0
aReaction conditions: N-Cbz-4-quinolone 1a (0.2 mmol), EtMgBr (2.0 equiv.), ligand L (6 mol%), CuBr·SMe2 (5
mol%) in CH2Cl2 (2 mL). bYields are those for the isolated products. cThe enantiomeric excess was determined
by HPLC on a chiral stationary phase. dReaction without CuBr·SMe2 and ligand.
Based on these results we adopted the following optimized conditions for further substrate scope studies: CuBr·SMe2 (5 mol%), (R,R)-L1 (6 mol%), Grignard reagent (2.0 equiv,), in
CH2Cl2 for 30 min at room temperature.
Next, we evaluated EtMgBr with quinolones featuring various substituents at the N-atom (Scheme 7). We found that quinolones with electron withdrawing groups such as Cbz and Boc are well tolerated and give the corresponding products (2a and 2b) with excellent yields and enantiomeric excess. However, for less reactive Bn- and Me-protected quinolones the addition products 2c and 2d can only be isolated in the presence of Lewis acid (TMSBr) with good yields and moderate 42-43% ee. Importantly, the addition of EtMgBr to unprotected quinolone substrate in the presence of TMSBr provided the corresponding product 2e with 52% yield and 96% ee).
Having established the effect of the substituents at the nitrogen atom of the quinolone we explored the scope of Grignard reagents with N-Cbz-4-quinolone 1a. We were pleased to find that our catalytic system enables the addition of a wide variety of alkyl Grignard reagents, including linear, α-, β- and γ-substituted, functionalized PhMgBr and pTolMgBr, providing products 2f-2n all with excellent results. This even extended to the markedly less
23 reactive MeMgBr, for which product 2o was obtained with 93% yield and 97% enantiomeric excess.
Scheme 7: Scope of the reaction between N-Cbz-4-quinolone substrates 1 and organomagnesium reagents.
Reaction conditions: N-Cbz-4-quinolones 1 (0.2 mmol), EtMgBr (2.0 equiv.), ligand L1 (6 mol%), CuBr·SMe2 (5
mol%) and CH2Cl2 (2 mL) at room temperature for 0.5 h. a Reactions with quinolones 1c-1e were carried out
in the presence of TMSBr (2.0 equiv.) at -78 oC for 12 h. Absolute configuration of 2k was established by X-ray
crystallography. bPhMgBr and pTolMgBr were added slowly via a syringe pump in 2 h at 0 oC.
Subsequently we examined the scope of the N-Cbz-4-quinolone substrates and found that substrates bearing functional groups such as Me, Br, CF3, ether, amide or ester at the 5, 6, and 7- position, were all converted to the corresponding final products (2p-2v) successfully. In all cases, our optimized system afforded the products in excellent yields
24
(66% to 99%) and enantioselectivities (ees 94% to 99%). However, when 2-Me-N-Cbz-4-quinolone was used as a substrate, a lack of reactivity prevented the formation of addition product 2w with quaternary stereocenter.
To expand this strategy towards the synthesis of chiral dihydro-pyridones and piperidones, we hypothesised that this protocol could also enable addition reactions to N-Cbz-4-pyridone 3. This substrate is more challenging for applications in catalysis as its aromatic character reduces the reactivity towards nucleophilic additions. As a result, pyridones have been hardly explored in asymmetric catalysis,37 even though there is major potential in the
application of these substrates in chemical synthesis: after the initial conjugate addition reaction the resulting chiral N-heterocyclic product with remaining Michael acceptor functionality can subsequently undergo further stereoselective functionalisations to provide 2,6-substituted chiral pyridines that can be very useful for natural product synthesis. We chose substrate 3 to evaluate its reactivity towards nucleophilic addition of organomagnesium reagents (Table 2). Using the reaction conditions optimized for N-Cbz-4-quinolones at -78 oC (Table 1, entry 2), the corresponding addition product 4a was not
obtained, but instead the side products derived from the addition of Grignard reagent to the carboxybenzyl moiety were found (Table 2, entry 1). In order to steer the chemoselectivity of the reaction towards conjugate addition product 4a, we decided to introduce Lewis acids.37 The initial test with the rather weak silylating agent TMSCl resulted in only 8% of
addition product 4a (entry 2). Promisingly, the stronger TMSBr provided increased conversion (64%) towards the desired product 4a with a moderate 80% ee (entry 3).
Table 2. Addition of EtMgBr to N-Cbz-4-pyridone 3.a
Entry Lewis acid Ratio (4a:SP) Conv. (%)b ee (%)
1 - 1:99 82 Nd
2 TMSCl 8:92 93 Nd
3 TMSBr 64:36 96 80
4 TMSOTf 77:23 99 34
5 BF3·OEt2 100:0 99 99
aReaction conditions: N-Cbz-4-pyridone 3 (0.2 mmol), EtMgBr (2.0 equiv.), ligand L1 (6 mol%), Lewis acid
(2.0 equiv.), CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL), at -78 oC for 12 h. bConversions were determined by 1H
NMR spectroscopy.
Using the highly reactive TMSOTf provided slightly better chemoselectivity but decreased the ee to 34% for the addition product (entry 4). Finally, with BF3·OEt2 as Lewis acid the
best possible results, with 99% NMR yield and more than 99% enantiomeric purity (entry 5), were obtained.
25
Scheme 8: Scope of the reaction of N-Cbz-4-pyridone 3 with organomagnesium reagents. Reaction
conditions: N-Cbz-4-pyridone 3 (0.2 mmol), Grignard reagents (2.0 equiv.), ligand L1 (6 mol%), BF3·OEt2 (2.0
equiv.), CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL) at -78 oC for 12 h.
With these reaction conditions we assessed the scope of organomagnesium reagents (Scheme 8). A number of chiral 2-substituted 2,3-dihydro-4-pyridone products derived from the addition of linear (4a-4d), β-, and γ-branched (4e-4f) and functionalized (4g-4i) Grignard reagents were synthesized with high yields. In all cases excellent enantioselectivities were observed as well (94% to >99%).
Although asymmetric conjugate addition of arylboronic acid, aryl and dialkylzinc nucleophiles to N-substituted-2,3-dihydro-4-pyridones has been well explored in recent years,22-32 we were interested to investigate the behavior of our catalytic system when
applied to these substrates. Given their substantially higher reactivity than N-Cbz-4-pyridone we anticipated that Lewis acids are not needed and that low temperatures will most likely be required to avoid non catalyzed addition of Grignard reagents. Indeed, quick screening of several Grignard reagents, namely MeMgBr, EtMgBr and nPrMgBr supported this notion and the corresponding chiral 2-substituted 4-piperidones (6a-6c) were obtained with excellent yields and enantiomeric excesses above 90% (Scheme 9).
Scheme 9: Scope of the reaction of N-Cbz-2,3-dihydro-4-pyridone 5 with organomagnesium reagents.
Reaction conditions: N-Cbz-2,3-dihydro-4-pyridone 5 (0.2 mmol), EtMgBr (2.0 equiv.), ligand L9 (6 mol%), CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL), -78 oC for 12 h.
26
Scheme 10: Scope of conjugate addition reactions of organomagnesium reagents to N-protected 2-quinolones 7. Reaction conditions: 2-quinolone 7 (0.2 mmol), EtMgBr (2.0 equiv.), Ligand L1 (6 mol%), TMSBr (2.0
equiv.), CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL), -78 oC for 12 h. Absolute configuration of 8j was established
by X-ray crystallography.
Our next quest was to access chiral products derived from additions to N-substituted-2-quinolones that are formally cyclic α, β-conjugated amides and expected to be less reactive than 4-quinolones (Scheme 10). We were pleased to find that when using 2-quinolones with an OMe protecting group at the N-atom the corresponding deprotected products
8a-8h were obtained with excellent enantiomeric excess and chemical yields. However, to
reach full conversion and high yields it is necessary to use a Lewis acid, with TMSBr performing best. Importantly, the methoxy substituent at the N-atom is removed upon reaction work up. Using this protocol, we obtained a variety of products using various Grignard reagents as well as substrates with different substituents in the aromatic ring. It is noteworthy that this catalytic system tolerates 2-quinolone substrates with various protecting groups at the N-atom such as Me, Bn and Allyl. The products 8i-8k, derived from conjugate addition of EtMgBr to these substrates, were obtained with enantiomeric purities above 93% and yields above 72%.
Finally, to demonstrate the potential applications of our reaction protocol, we carried out a scale reaction as well some additional transformations (Scheme 11). For the gram-scale reaction, we chose N-Cbz-4-quinolone (1a, 1.17g) as the starting reactant. Upon decrease of standard catalyst loading from 5 mol% to 1 mol%, we could still obtain the product 2a in 93% yield and 96% ee. Further transformation of this product into secondary amine 2e was successfully achieved in 86% yield and 96% ee was achieved by deprotection using KOH (Scheme 11a). Presence of additional conjugated double bond in in the addition
27 product of pyridine allows construction of second chiral center. For instance, the single two chiral centers product 2,6-substituted piperidine 9 was acquired in 87% yield. Hence, with this method, kinds of 2,6-substituted piperidines can be designed which are very important intermediates for the synthesis of alkaloids. As mentioned above, chiral 2-piperidones are very common to see in the natural products. For example, using our methodology, we could synthesize the natural product Corniine in a high yield (Scheme 11c).27 Furthermore, this
methodology also is a convenient way to afford the natural product (+)-Angustureine with a 92% yield and 97% ee in three steps.
Scheme 11: Gram-scale reaction and useful derivatisations.
2.3 Conclusions
In summary, we have developed the first general protocol for the alkylation of various classes of N-heterocyclic electrophiles with organomagnesium, utilizing one catalytic system based on Cu(I) complex with (R,R)-Ph-BPE. Alkylation of 2-quinolones, quinolones and pyridones provides easy access to various derivatives of chiral 2- and 4-substituted tetrahydroquinolones and dihydro-4-pyridones in excellent yields and enantioselectivities. Significantly, addition reactions to N-substituted-4-quinolones can be carried out at room temperature, while consecutive alkylation of pyridone and the resulting 2,3-dihydro-4-pyridones allows for a convenient catalytic access to 2,6-substituted diastereomerically and enantiomerically pure piperidones. We anticipate that this methodology will be a valuable synthetic tool and find practical application in the synthesis of complex building blocks and natural and pharmaceutical compounds.
28
2.4 Experimental section
2.4.1 General experimental information
All reactions were carried out with anhydrous solvents (vide infra) under a nitrogen atmosphere using oven-dried glassware and standard Schlenk techniques. Reactions were monitored by 1H NMR. Purification of the products was performed by column
chromatography using Merck 60 A 230-400 mesh silica gel. Components were visualized by UV and KMnO4 staining (TLC). NMR data was collected on Varian VXR400 (1H at 400.0 MHz; 13C at 100.58 MHz) equipped with a 5 mm z-gradient broadband probe. Chemical shifts are
reported in parts per million (ppm) relative to residual solvent peak (CDCl3, 1H: 7.26 ppm; 13C: 77.16 ppm). Coupling constants are reported in Hertz. Multiplicity is reported with the
usual abbreviations. Enantiomeric excesses (ee) were determined by chiral HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. Exact mass spectra were recorded on a LTQ Orbitrap XL apparatus with ESI ionization.
Unless otherwise indicated, reagents and substrates were purchased from commercial sources and used as received. Solvents not required to be dry were purchased as technical grade and used as received. Dry solvents were freshly collected from a dry solvent purification system prior to use. Inert atmosphere experiments were performed with standard Schlenk techniques with dried (P2O5) nitrogen gas. Grignard reagents were
purchased from Sigma-Aldrich (EthylMgBr, MethylMgBr, PhenylMgBr (3.0 M in Et2O), pTolMgBr (0.5 M in Et2O); iButylMgBr, CylopentylMgBr, nPentylMgBr, iPentylMgBr,
HexylMgBr, (2.0 M in Et2O). All other Grignard reagents were prepared from the
corresponding alkyl bromides and Mg activated with I2 in Et2O. All Grignard reagents were
titrated by 1H NMR before using. Chiral ligands were purchased from Sigma Aldrich and
Strem Chemicals. All reported compounds were characterized by 1H and 13C NMR, HRMS
and compared with literature data. All new compounds were fully characterized by 1H and 13C NMR and HRMS techniques.
2.4.2 Determination of absolute configuration
A single crystal of compound 2k was mounted on top of a cryoloop and transferred into the cold nitrogen stream (100 K) of a Bruker-AXS D8 Venture diffractometer. Data collection and reduction was done using the Bruker software suite APEX3.43 The final unit cell was
obtained from the xyz centroids of 9958 reflections after integration. A multiscan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS).The structures were solved by direct methods using SHELXT44 and refinement of the structure was performed using SHELXL.45
The hydrogen atoms were generated by geometrical considerations, constrained to idealised geometries and allowed to ride on their carrier atoms with an isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms. The absolute structure was chosen based on a refinement of Flack’s parameter (x = -0.01(4)). Crystal data and details on data collection and refinement are presented in Table 3.
29
Scheme 12: Molecular structure of compound 2k, showing 50% probability ellipsoids. Table 3: Crystallographic data for 2k.
chem formula C22 H23 N O3
Mr 349.41
cryst syst orthorhombic color, habit colorless, needle size (mm) 0.75 x 0.32 x 0.31 space group P212121 a (Å) 5.7607(2) b (Å) 17.1973(5) c (Å) 17.8857(5) V (Å3) 1771.91(9) Z 4 calc, g.cm-3 1.310 µ(Cu K), cm-1 0.695 F(000) 744 temp (K) 100(2) range (deg) 3.565 - 74.402 data collected (h,k,l) -7:7, -21:21, -22:22 no. of rflns collected 21135
30 observed reflns 3567(Fo 2 (Fo)) R(F) (%) 2.74 wR(F2) (%) 6.72 GooF 1.051 Weighting a,b 0.0303, 0.4534 params refined 236 restraints 0
min, max resid dens -0.175, 0.308 Flack x -0.01(4)
As a result, the absolute configuration of 2k is R structure. The absolute configuration of
4a32 and 6d34 were determined by comparing with the data in the reported work.
Scheme 13: Molecular structure of compound 8j, showing 50% probability ellipsoids.
A single crystal of compound 8j was mounted on top of a cryoloop and transferred into the cold nitrogen stream (100 K) of a Bruker-AXS D8 Venture diffractometer. Data collection and reduction was done using the Bruker software suite APEX3.43 The final unit cell was
obtained from the xyz centroids of 9958 reflections after integration. A multiscan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS).The structures were solved by direct methods using SHELXT44 and refinement of the structure was performed using SHELXL.45
The hydrogen atoms were generated by geometrical considerations, constrained to idealised geometries and allowed to ride on their carrier atoms with an isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms. The absolute structure was chosen based on a refinement of Flack’s parameter (x = -0.03(6)). Crystal data and details on data collection and refinement are presented in Table 4.
31
Table 4: Crystallographic data for 8j.
chem formula C18 H19 N O
Mr 265.34
cryst syst tetragonal color, habit colorless, block size (mm) 0.43 x 0.24 x 0.17 space group P41 a (Å) 8.8385(3) b (Å) 8.8385(3) c (Å) 18.1483(7) V (Å3) 1417.73(11) Z 4 calc, g.cm-3 1.243 µ(Cu K), cm-1 0.595 F(000) 568 temp (K) 100(2) range (deg) 5.567 – 69.948 data collected (h,k,l) -10:10, -10:10, -22:22 no. of rflns collected 15603
no. of indpndt reflns 2654
observed reflns 2624(Fo 2 (Fo)) R(F) (%) 2.56 wR(F2) (%) 6.53 GooF 1.082 Weighting a,b 0.0354, 0.2214 params refined 182 restraints 1
min, max resid dens -0.168, 0.124
32
2.4.3 General procedure for synthesis of substrates
A solution of 4-hydroxyquinoline (452 mg, 3.11 mmol) in THF (10 mL) was added to a suspension of NaH (346 mg, 8.65 mmol; 60 wt% in mineral oil) in THF (15 mL) at room temperature, and the resulting mixture was stirred for 15 min at 55 °C. Benzyl chloroformate (790 mg, 4.63 mmol) was then added to the solution dropwise, and the mixture was stirred for 12 h at room temperature. The reaction was quenched with water and extracted with Et2O. The organic layer was dried over MgSO4, filtered, and concentrated
under vacuum. The residue was chromatographed on silica gel to afford compound 1a as a white solid (671 mg, 2.40 mmol; 77% yield).28 This method was also employed for the
synthesis of 1b (Boc2O), 1c (BnBr) and 1d (MeI).
To a solution of 4-hydroxypyridine (475 mg, 5.0 mmol) in tBuOH (5.0 mL), sodium hydride (260 mg, 6.5 mmol; 60 wt% in mineral oil) was added under argon, and the reaction mixture was heated in hot water bath (60 °C) until the mixture turned to a slurry (20-30 minutes). Then benzyl chloroformate (0.928 mL, 6.5 mmol) in tBuOH (2.0 mL) was added dropwise. The reaction mixture was cooled to 30 °C and stirred for 12 h at this temperature. The reaction mixture was quenched with water (5.0 mL) with caution and the aqueous portion was extracted with ether (3 × 5.0 mL). The ether layers were combined, dried over anhydrous MgSO4, filtered and concentrated to give the crude product 3. The
residue was chromatographed on silica gel with eluent (1-3% MeOH in CH2Cl2) to afford
compound 3 as a white solid (890 mg, 3.9 mmol; 78% yield).37
A solution of 4-methoxypyridine (0.545 mL, 5 mmol) in methanol (10 mL) was stirred with NaBH4 (208 mg, 5.5 mmol) at -78 °C for 15 min. A solution of benzyl chloroformate (0.856
mL, 6 mmol) in ether (1 mL) was added dropwise over a 30 min period. The reaction mixture was stirred for 1 h at -78 °C and then quenched with 10 mL of water. The solution was warmed to room temperature and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and then with brine (10 mL).
33 The organic layer was concentrated, and then the crude product was purified by silica gel chromatography (1:2 Et2O/pentane) to afford 5 (690 mg, 60% yield) as a white solid.47
A solution of Meldrum’s acid (1.08g, 7.5 mmol) and trimethyl orthoformate (13.7 mL) was heated to reflux at 110 oC for 2 h under argon. The solution was cooled to room
temperature, the aniline (5 mmol) was added and the mixture was heated to reflux at 110
oC for 2 h. The precipitated product was washed with hexane (10 mL) and dried. Without
further purification, the products (1.0 equiv) and diphenyl ether (10 mL) were heated at 250 oC for 1 h. The solution was allowed to cool to room temperature and hexane (50 mL)
was added. The precipitate formed was collected by filtration, washed with hexane (50 mL), and dried in vacuo.
After getting the crude 4(H)-quinolones, next step is to protect the nitrogen with benzyl chloroformate. A solution of 4(1H)quinolone (3.11 mmol) in THF (10 mL) was added to a suspension of NaH (346 mg, 8.65 mmol; 60 wt% in mineral oil) in THF (15 mL) at room temperature, and the resulting mixture was stirred for 15 min at 55 °C. Benzyl chloroformate (790 mg, 4.63 mmol) was then added dropwise, and the mixture was stirred for 21 h at room temperature. The reaction was quenched with water and extracted with Et2O. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum.
The residue was chromatographed on silica gel to afford the final compounds 1p-u.47
mCPBA (558 mg, 2.5 mmol; 77% purification) and quinoline (2 mmol) were added to CH2Cl2 (4 ml) solution in a dry schlenk tube at 0 °C. The reaction was allowed to stir at
room temperature for 12h. Then, remove the CH2Cl2 by evaporation and purify the crude
product by flash chromatography on silica gel eluting with EtOAc/hexane (3:1) to afford the quinoline N-oxide.
A mixture of trimethyloxonium tetrafluoroborate (325.6 mg, 2.2 mmol, 1.1 equiv.) and quinoline N-oxide (2.0 mmol, 1 equiv.) were stirred in CH2Cl2 (4 mL) for 4 h. Then the
reaction mixture was concentrated in vacuo, and the crude product was recrystallized in EtOAc to obtained the N-methoxyquinoline-1-ium tetrafluoroborate salts. A glass reaction tube equipped with a magnetic stir bar was charged with N-methoxyquinoline-1-ium tetrafluoroborate salts (0.5 mmol), sodium hydroxide (30 mg, 0.75 mmol, 1.5 equiv.) and dioxane/H2O (1:1, 4 mL). The reaction mixture was then stirred at room temperature under
air atmosphere for 48 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated in vacuo, and then extracted with CH2Cl2 three times. The combined
organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired product 7a, 7f-h.48-49
34
To a solution of 2-hydroxyquinoline (725 mg, 5 mmol) in dry DMF (5mL) under an argon atmosphere was added NaH (240 mg, 6 mmol, 60 % wt) in one portion. Upon the completion of gas evolution, MeI (BnBr or AllylBr, 6 mmol) was added in 1 portion and the resulting solution was stirred overnight at 60 °C. Excess sodium hydride was quenched by the addition of water (15 mL). The solution was extracted with ethyl acetate (3×30 mL), washed with water and then brine. The organic phase was dried over anhydrous MgSO4,
filtered and then concentrated in vacuo. The crude solid was purified by column chromatography with EtOAc/hexane (1:1) to afford the to afford the desired products
7i-k.27
Characterization of N-heterocyclic acceptor substrates 1-Benzyloxycarbonyl-4-quinolone (1a)
1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.9 Hz, 1H), 8.36 (d, J = 8.5 Hz, 2H),
7.71-7.61 (m, 1H), 7.53-7.39 (m, 6H), 6.25 (d, J = 8.6 Hz, 1H), 5.46 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 178.90, 151.28, 138.44, 138.18, 133.93, 132.90,
129.27, 128.95, 128.85, 126.54, 125.50, 119.96, 112.52, 109.99, 70.49. HRMS (ESI+, m/Z): calcd for C17H13NO3 [M+H]+: 280.0973, found: 280.0976.
Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:3).
White solid, isolated yield: 77%. The NMR data are in accordance with data described in reference.28
Benzyl 4-oxopyridine-1(4H)-carboxylate (3)
1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.3, 2.6 Hz, 2H), 7.45-7.34 (m, 5H),
6.30 (dd, J = 8.2, 3.8 Hz, 2H), 5.41 (d, J = 2.6 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 180.43, 149.74, 134.81, 133.42, 129.48, 128.96, 128.93, 118.69,
71.18. HRMS (ESI+, m/Z): calcd for C13H11NO3 [M+Na]+: 252.0636, found:
252.0631. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 78%. The NMR data are in
accordance with data described in reference.37
Benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (5)
1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 5.2 Hz, 1H), 7.36-7.17 (m, 5H), 5.25
(d, J = 7.5 Hz, 1H), 5.18 (s, 2H), 3.94 (t, J = 7.3 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 193.18, 152.41, 143.28, 134.98, 128.71, 128.69,
128.40, 107.55, 68.94, 42.53, 35.54. HRMS (ESI+, m/Z): calcd for C13H13NO3
[M+Na]+: 232.0968, found: 232.0965. Purification by flash column
chromatography on silica gel (eluent, pentane:Et2O = 1:1). White solid, isolated yield: 68%.
The NMR data are in accordance with data described in reference.46
1-Methyl-4-quinolone (1d)
1H NMR (400 MHz, CDCl3) δ 8.43 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.48
(d, J = 2.4 Hz, 1H), 7.36 (d, J = 5.0 Hz, 2H), 6.28-6.14 (m, 1H), 3.77 (s, 3H). 13C
35 123.68, 115.27, 110.01, 40.58. HRMS (ESI+, m/Z): calcd for C10H9NO [M+H]+:160.0756 ,
found:160.0754. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 2:1). White solid, isolated yield: 88%.
1-Benzyl-4-quinolone (1c)
1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.50 (t, J = 7.7 Hz, 1H), 7.40-7.19 (m, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.31 (d, J = 7.7 Hz, 1H), 5.30 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 146.35, 142.74,
137.78, 134.83, 131.86, 130.92, 129.96, 129.62, 128.70, 126.37, 118.77, 112.97, 104.99, 59.12. HRMS (ESI+, m/Z): calcd for C16H13NO [M+Na]+:
258.08894, found: 258.08937. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:1). White solid, isolated yield: 62%.
1-Boc-4-quinolone (1b)
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.9 Hz, 1H), 8.37 (d, J = 8.0 Hz,
1H), 8.30 (d, J = 8.5 Hz, 1H), 7.65 (t, J = 8.8 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 6.25 (d, J = 8.5 Hz, 1H), 1.67 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.04,
149.88, 138.71, 138.56, 132.57, 126.58, 126.47, 125.15, 119.94, 111.86, 86.54, 27.95. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 3:1). White solid, isolated yield: 90%.
1-Benzyloxycarbonyl-6-Methoxy-4-quinolone (1p) 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 9.6 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 3.1 Hz, 1H), 7.45-7.26 (m, 5H), 7.16 (dd, J = 9.6, 3.2 Hz, 1H), 6.15 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 178.48, 156.92, 151.13, 137.64, 134.00, 132.57, 129.17, 128.88, 128.78, 127.81, 122.35, 121.72, 111.52, 106.10, 70.37, 55.58. HRMS (ESI+, m/Z): calcd for C18H15NO4 [M+H]+: 310.1079, found: 310.1074. Purification by flash column
chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 58%.
1-Benzyloxycarbonyl-6-Bromo-4-quinolone (1q)
1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 9.3 Hz, 1H), 8.47 (s, 1H), 8.36 (d, J =
8.5 Hz, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.56-7.36 (m, 5H), 6.30-6.20 (m, 1H), 5.46 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 177.48, 150.98, 138.35, 137.23,
135.74, 133.70, 129.39, 129.13, 128.99, 128.92, 127.97, 122.05, 119.52, 112.62, 70.78. HRMS (ESI+, m/Z): calcd for C17H12BrNO3 [M+H]+: 358.0078,
found: 358.0070. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 62%.
1-Benzyloxycarbonyl-6-Trifloromethyl-4-quinolone (1r)
1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 9.2 Hz, 1H), 8.65 (s, 1H), 8.40 (d, J =
8.6 Hz, 1H), 7.86 (dd, J = 9.3, 1.8 Hz, 1H), 7.54-7.40 (m, 5H), 6.31 (d, J = 8.6 Hz, 1H), 5.49 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 180.45, 153.61, 143.05,
141.38, 136.22, 135.57, 132.12, 131.68, 131.63, 129.04, 127.00, 126.96, 124.83, 123.71, 115.63, 73.66. HRMS (ESI+, m/Z): calcd for C18H12F3NO3
[M+H]+: 348.0847, found: 348.0844. Purification by flash column chromatography on silica
36 1-Benzyloxycarbonyl-6-Ethoxycarbonyl-4-quinolone (1t) 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 9.2 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.29 (dd, J = 9.2, 2.2 Hz, 1H), 7.56-7.35 (m, 5H), 6.29 (d, J = 8.6 Hz, 1H), 5.48 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 178.35, 165.41, 151.07, 141.16, 138.48, 133.65, 133.29, 129.41, 129.00, 128.95, 128.52, 127.53, 126.23, 120.25, 113.06, 70.87, 61.39, 14.34. HRMS (ESI+, m/Z): calcd for C20H17NO5 [M+H]+:
352.1185, found: 352.1178. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:3). White solid, isolated yield: 52%.
1-Benzyloxycarbonyl-6,7-methylenedioxy-4-quinolone (1u)
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.64 (s,
1H), 7.49-7.36 (m, 5H), 6.13 (d, J = 8.5 Hz, 1H), 6.02 (s, 2H), 5.40 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 177.58, 152.19, 151.22, 146.04, 137.11, 135.10,
133.92, 129.23, 128.91, 128.83, 122.60, 111.85, 103.61, 102.26, 100.06, 70.52. HRMS (ESI+, m/Z): calcd for C18H13NO5 [M+H]+: 324.0872, found:
324.0865. The NMR data are in accordance with data described in reference.28 Purification
by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:3). White solid,
isolated yield: 38%. 1-Benzyloxycarbonyl-5,7-Dimethyl-4-quinolone (1s) 1H NMR (400 MHz, CDCl3) δ 8.24-8.11 (m, 2H), 7.53-7.34 (m, 5H), 6.99 (s, 1H), 6.10 (d, J = 8.5 Hz, 1H), 5.43 (s, 2H), 2.82 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 181.09, 151.72, 142.12, 140.88, 140.08, 136.25, 134.11, 130.14, 129.17, 128.91, 128.76, 123.17, 118.18, 114.18, 70.21, 23.86, 21.98. HRMS (ESI+, m/Z): calcd for C19H17NO3 [M+H]+: 308.1286, found: 308.1282.
Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:1).
White solid, isolated yield: 70%.
Benzyl 6-(dimethylcarbamoyl)-4-oxoquinoline-1(4H)-carboxylate (1v) 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 9.0 Hz, 1H), 8.35 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 11.1 Hz, 1H), 6.23 (d, J = 8.6 Hz, 1H), 5.45 (s, 2H), 3.10 (s, 3H), 2.99 (s, 3H). 13C NMR (101 MHz, cdcl3) δ 180.95, 172.55, 153.73, 141.57, 141.15, 136.40, 135.86, 134.65, 131.97, 131.60, 131.55, 128.51, 127.74, 123.27, 115.32, 73.40, 42.26, 38.08. HRMS (ESI+, m/Z): calcd for C20H18N2O4 [M+H]+:
351.13468, found: 351.13452. Purification by flash column chromatography on silica gel (eluent, pentane:EtOAc = 1:5). White solid, isolated yield: 42%.
1-Benzyloxycarbonyl-2-Methyl-4-quinolone (1w)
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz,
1H), 7.64 (t, J = 7.7 Hz, 1H), 7.50-7.28 (m, 6H), 7.27 (s, 1H), 5.29 (s, 2H), 2.70 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.84, 154.15, 152.31,
149.43, 134.36, 130.15, 128.98, 128.76, 128.62, 126.88, 126.10, 120.90, 120.11, 112.41, 70.90, 25.61. HRMS (ESI+, m/Z): calcd for C18H15NO3 [M+H]+: 294.11247, found: 294.11241. Purification by flash
column chromatography on silica gel (eluent, pentane:Et2O = 1:5). White solid, isolated
37
1-Methoxy-2-quinolone (7a)
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 9.6 Hz, 1H), 7.64-7.54 (m, 3H),
7.33-7.21 (m, 1H), 6.73 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 157.76, 138.33, 137.99, 131.14, 128.38, 122.85, 122.52, 120.00, 111.76, 62.82. HRMS (ESI+, m/Z): calcd for C10H9NO2 [M+H]+: 176.0706, found:
176.0705. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O
= 1:2). White solid, isolated yield: 60%. The NMR data are in accordance with data described in reference.49 1,6-Dimethoxy-2-quinolone (7f) 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.16 (dd, J = 9.1, 2.7 Hz, 1H), 6.96 (d, J = 2.7 Hz, 1H), 6.67 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H), 3.80 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.22, 155.34, 137.76, 132.50, 123.01, 120.74, 120.07, 113.19, 109.85, 62.79, 55.68. HRMS (ESI+, m/Z): calcd for C11H11NO3 [M+H]+: 206.0811, found:
206.0810. Purification by flash column chromatography on silica gel (eluent, pentane:Et2O
= 1:3). Brown solid, isolated yield: 40%. The NMR data are in accordance with data described in reference.49
1-Dimethoxy-6-methyl-2-quinolone (7g)
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 9.6 Hz, 1H), 7.50 (d, J = 8.5 Hz,
1H), 7.44-7.34 (m, 2H), 6.70 (d, J = 9.5 Hz, 1H), 4.07 (s, 3H), 2.41 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 157.65, 138.08, 136.00, 132.51, 132.42,
128.07, 122.45, 120.04, 111.70, 62.77, 20.67. HRMS (ESI+, m/Z): calcd for C11H11NO2 [M+H]+: 190.0862, found: 190.0860. Purification by flash column
chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 52%.
1-Dimethoxy-6-bromo-2-quinolone (7g)
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.9, 2.1
Hz, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.23, 137.13,
136.90, 133.89, 130.50, 123.78, 121.29, 115.59, 113.55, 62.97. HRMS (ESI+, m/Z): calcd for C10H8NO2Br [M+H]+: 253.9811, found: 253.9810. Purification by flash
column chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated
yield: 59%. The NMR data are in accordance with data described in reference.49
1-Methyl-2-quinolone (7i)
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 11.6 Hz, 1H), 7.55 (d, J = 7.7 Hz,
2H), 7.36 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 9.5 Hz, 1H), 3.71 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.32, 140.00, 138.94, 130.61,
128.73, 122.08, 121.75, 120.65, 114.13, 29.40. HRMS (ESI+, m/Z): calcd for C10H9NO [M+H]+: 160.0756, found: 160.0756. Purification by flash
column chromatography on silica gel (eluent, pentane:Et2O = 1:1). White
solid, isolated yield: 70%. The NMR data are in accordance with data described in reference.51
1-Benzyl-2-quinolone (7j)
38
1H), 7.37 (t, J = 7.9 Hz, 1H), 7.30-7.16 (m, 6H), 7.14 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 9.5 Hz, 1H), 5.54 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 162.44, 139.60, 139.44, 136.37, 130.63,
128.85, 128.78, 127.26, 126.59, 122.20, 121.59, 120.90, 115.01, 45.86. HRMS (ESI+, m/Z): calcd for C16H13NO [M+H]+: 236.1069, found: 236.1068. Purification by flash column
chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 88%.
The NMR data are in accordance with data described in reference.51
1-Allyl-2-quinolone (7k)
1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 9.5 Hz, 1H), 7.49-7.36 (m, 2H), 7.20
(d, J = 8.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 9.5 Hz, 1H), 5.92-5.77 (m, 1H), 5.10 (d, J = 9.8 Hz, 1H), 4.99 (d, J = 17.3 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 161.77, 139.28, 139.23, 131.72, 130.46,
128.73, 122.02, 121.47, 120.67, 116.89, 114.70, 44.38. HRMS (ESI+, m/Z): calcd for C12H11NO [M+H]+: 186.0913, found: 186.0912. Purification by flash column
chromatography on silica gel (eluent, pentane:Et2O = 1:2). White solid, isolated yield: 69%.
The NMR data are in accordance with data described in reference.52
2.4.4 General procedure for asymmetric addition
Cu-catalyzed asymmetric addition of Grignard reagents to N-Cbz-4-quinolones (1): In
a flame-dried Schlenk tube equipped with septum and magnetic stirring bar, N-Cbz-4-quinolone (0.2 mmol, 1.0 equiv.), CuBr·SMe2 (2.06 mg, 5 mol%), and ligand L1 (6.07 mg, 6
mol%) were dissolved in DCM (2 mL) and stirred under nitrogen atmosphere for 20 min at room temperature (18-25 oC). Then, RMgBr (2.0 equiv.) was added dropwise in 5 min
(PhMgBr and pTolPhMgBr were diluted to 1 mL and added slowly in 2 h with a syringe pump at 0 oC and stirred at this temperature for 2 h; for 2k and 2v, the Grignard reagents
were added at -78 oC in 5 min and stirred at this temperature for 2 h). After stirring for 0.5
h at room temperature, the reaction was quenched by saturated aqueous NH4Cl. Reaction
mixture was extracted with DCM (3×3 mL). Combined organic phases were dried over MgSO4, filtered and solvents were evaporated on rotary evaporator. The crude was purified
by flash chromatography on silica gel.
Cu-catalyzed asymmetric addition of Grignard reagents to N-Cbz-4-pyridones (3): In a
flame-dried Schlenk tube equipped with septum and magnetic stirring bar, CuBr·SMe2 (2.06
mg, 5 mol%), and ligand L1 (6.07 mg, 6 mol%) were dissolved in DCM (2 mL) and stirred under nitrogen atmosphere for 20 min. The N-Cbz-4-pyridone (0.2 mmol, 1.0 equiv.) was added at once. After stirring for 5 min at room temperature (18-25 oC), the solution was
transferred to -78 oC. Then, BF3·OEt2 (0.4 mmol, 2.0 equiv.; ≥46.5% BF3 basis) was added
dropwise and stirred at this temperature for 20 min. Next, RMgBr (2.0 equiv.) was added slowly in 5-10 min. After stirring for 12 h, the reaction was quenched by saturated aqueous NH4Cl. Reaction mixture was extracted with DCM (3×3 mL). The combined organic phases
were dried over MgSO4, filtered and solvents were evaporated on rotary evaporator. The
crude was purified by flash chromatography on silica gel.
Cu-catalyzed asymmetric addition of Grignard reagents to N-Cbz-2,3-dihydro-4-pyridone (5): In a flame-dried Schlenk tube equipped with septum and magnetic stirring
bar, CuBr·SMe2 (2.06 mg, 5 mol%), and ligand L1 (6.07 mg, 6 mol%) were dissolved in DCM
(2 mL) and stirred under nitrogen atmosphere for 20 min. The NCbz2,3dihydro4pyridone (5) (0.2 mmol, 1.0 equiv.) was added at once and the solution was transferred to -78 oC. RMgBr (2.0 equiv.) was added dropwise in 5 min. After stirring for 12 h, the reaction
was quenched by saturated aqueous NH4Cl. The reaction mixture was extracted with DCM
39 evaporated on rotary evaporator. The crude was purified by flash chromatography on silica gel.
Cu-catalyzed asymmetric addition of Grignard reagents to N-OMe-2-quinolone (7): In
a flame-dried Schlenk tube equipped with septum and magnetic stirring bar, CuBr·SMe2
(2.06 mg, 5 mol%), ligand L1 (6.07 mg, 6 mol%) and N-OMe-2-quinolone (0.2 mmol, 1.0 equiv) were dissolved in DCM (2 mL) and stirred under nitrogen atmosphere for 20 min. After that, the solution was transferred to -78 oC and TMSBr (2.0 equiv.) was added
dropwise and stirred at this temperature for 20 min. Then, RMgBr (2.0 equiv.) was added dropwise in 5 min. After stirring for 12 h at -78 oC, the reaction was quenched by saturated
aqueous NH4Cl. The reaction mixture was extracted with DCM (3×10 mL). The combined
organic phases were dried over MgSO4, filtered and solvents were evaporated on rotary
evaporator. The crude was purified by flash chromatography on silica gel.
Reduction reaction procedure of 2f to (+)-Angustureine: In a flame-dried Schlenk tube
equipped with septum and magnetic stirring bar, Pd/C (15 mg) was added to a flask under a hydrogen atmosphere (hydrogen balloon). Then, a solution of 2f (70.2 mg, 0.2 mmol) in MeOH (5 mL) was injected to the flask and TFA (1 mL) was added to the solution. The reaction was stirred at room temperature for 12 h. After that, the Pd/C was filtered and evaporated to remove the TFA and solvent. The residue was used for the next step without further purification.
To a solution of above crude product and K2CO3 (82.8 mg, 0.6 mmol) in THF (4 mL), MeI
(0.062 mL, 1 mmol) was added under nitrogen atmosphere. After refluxing for 12 h, the reaction mixture was quenched with water and extracted with CH2Cl2 (3×10 mL). The
combined organic layers were washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent, the residue was purified by flash column chromatography on silica gel (pentane: Et2O = 9: 1) to give (+)-Angustureine (92% yield, 97% ee).
Cu-catalyzed asymmetric addition of EtMgBr to N-Cbz-4-quinolone (Gram scale): In a
flame-dried Schlenk tube equipped with septum and magnetic stirring bar, CuBr·SMe2 (8.24
mg, 1 mol%), and ligand L1 (24.28 mg, 1 mol%) were dissolved in DCM (10 mL) and stirred under nitrogen atmosphere for 20 min. The N-Cbz-4-quinolones (1.12 g, 4.0 mmol, 1.0 equiv.) was added at once. After stirring for 5 min at room temperature (20 oC), RMgBr (2.0
equiv.) was added dropwise in 1h with a syringe pump. After stirring for 0.5 h at room temperature, the reaction was quenched by saturated aqueous NH4Cl. Reaction mixture was
extracted with DCM (10 mL × 3). Combined organic phases were dried over MgSO4, filtered
and solvents were evaporated on rotary evaporator. The crude was purified by flash chromatography on silica gel (eluent, Et2O:pentane=1:2) to give 2a (93% yield, 96% ee).
Deprotection of 2a: KOH (1 mL; 40% aqueous) was added to a solution of 2a (62 mg, 0.2
mmol; 96% ee) in MeOH (1 mL) and the mixture was refluxed for 1 h. After cooling to room temperature, the reaction mixture was extracted with Et2O and the organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The
residue was chromatographed on silica gel (Et2O:hexane = 1:4) to afford compound 2e
(86% yield, 96% ee).28
General procedure for the preparation of racemic products: For the preparation of
racemic products, we used the same method but the racemic ligand BINAP was used to replace L1(Yields: 23-86%).
40
(2S)-benzyl-2-ethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2a)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 2:1). white solid, 97% yield, 98% ee] 1H NMR (400 MHz,
CDCl3) δ 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.56-7.46
(m, 1H), 7.46-7.29 (m, 5H), 7.22-7.11 (m, 1H), 5.40-5.19 (m, 2H), 4.99-4.84 (m, 1H), 3.04 (dd, J = 17.6, 5.8 Hz, 1H), 2.64 (dd, J = 17.6, 1.7 Hz, 1H), 1.69-1.39 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.35, 154.19,
140.85, 135.80, 134.35, 128.64, 128.36, 128.06, 126.77, 124.99, 124.70, 124.16, 68.16, 55.42, 43.12, 24.62, 10.71. HRMS (ESI+, m/Z): calcd for C19H29NO3 [M+H]+: 310.1443,
found: 310.1446. HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC,
detection at 254 nm. Retention time (min): 24.05 (major) and 26.50 (minor).
(2S)-tert-butyl-2-ethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2b)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 5:1). Colorless oil, 96% yield, 92% ee] 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.8 Hz,
1H), 7.12 (t, J = 7.2 Hz, 1H), 4.90-4.73 (m, 1H), 3.03 (dd, J = 17.6, 5.8 Hz, 1H), 2.62 (dd, J = 17.5, 1.5 Hz, 1H), 1.64-1.41 (m, 11H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 196.41, 155.87, 144.15, 136.75, 129.34, 127.43, 127.42,
126.25, 84.58, 57.65, 45.82, 30.94, 27.32, 13.37. HRMS (ESI+, m/Z): calcd for C16H21NO3
[M+H]+: 276.1594, found: 276.1592. HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 95:5,
0.5 mL/min, 40 oC, detection at 254 nm. Retention time (min): 9.48 (major) and 10.75
(minor)
(2S)-ethyl-1-benzyl-2,3-dihydroquinolin-4(1H)-one (2c)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:2). Colorless oil, 90% yield, 43% ee] 1H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 7.8 Hz, 1H), 7.38-7.19 (m, 6H), 6.65 (t, J = 7.4 Hz, 1H),
6.54 (d, J = 8.6 Hz, 1H), 4.75 (d, J = 16.6 Hz, 1H), 4.39 (d, J = 16.6 Hz, 1H), 3.66-3.42 (m, 1H), 3.02 (dd, J = 16.1, 6.0 Hz, 1H), 2.71 (dd, J = 16.1, 2.1 Hz, 1H), 1.78-1.58 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 195.92, 152.03, 140.42, 138.28, 131.50, 130.23, 130.03, 129.10, 122.04, 118.78, 115.99, 63.62, 56.77, 43.67, 25.07, 13.18. HRMS (ESI+, m/Z): calcd for C18H19NO [M+Na]+:
288.13589, found: 288.13599. HPLC analysis: Chiracel-OBH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254 nm. Retention time (min): 27.64 (minor) and 40.78
(major).
(2S)-ethyl-1-methyl-2,3-dihydroquinolin-4(1H)-one (2d)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 3:1). Colorless oil, 99% yield, 42% ee] 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 9.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.66 (t, J = 7.4 Hz,
1H), 6.59 (d, J = 8.5 Hz, 1H), 3.48-3.37 (m, 1H), 3.03 (s, 3H), 2.95 (dd, J = 16.2, 6.1 Hz, 1H), 2.65 (dd, J = 16.2, 2.5 Hz, 1H), 1.72-1.52 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.45, 150.11, 135.69, 127.46, 119.12, 115.88,
112.75, 62.83, 41.08, 38.19, 21.66, 10.50. HRMS (ESI+, m/Z): calcd for C12H15NO
41 0.5 mL/min, 40 oC, detection at 254 nm. Retention time (min): 24.25 (major) and 18.76
(minor).
(2S)-2-ethyl-2,3-dihydroquinolin-4(1H)-one (2e)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 3:1). Colorless oil, 52% yield, 96% ee] 1H NMR (400 MHz,
CDCl3) δ 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.38-7.23 (m, 1H), 6.81-6.60 (m, 2H),
4.33 (s, 1H), 3.68-3.46 (m, 1H), 2.68 (dd, J = 16.1, 3.7 Hz, 1H), 2.47 (dd, J = 16.1, 12.7 Hz, 1H), 1.76-1.60 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
194.10, 151.42, 135.15, 127.46, 119.09, 117.91, 115.72, 54.65, 43.48, 28.05, 9.66. HRMS (ESI+, m/Z): calcd for C11H13NO [M+H]+: 176.1075, found: 176.1068. HPLC analysis:
Chiracel-OBH, n-heptane/i-PrOH 90:10, 0.5 mL/min, 40 oC, detection at 254 nm. Retention
time (min): 26.99 (minor) and 29.36 (major).
(2S)-benzyl-2-pentyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2f)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 5:1). Colorless oil, 95% yield, 98% ee] 1H
NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.58-7.47 (m, 1H), 7.74-7.23(m, 5H), 7.17 (t, J = 7.5 Hz, 1H), 5.35-5.24 (m, 2H), 5.06-4.91 (m, 1H), 3.03 (dd, J = 17.5, 5.8 Hz, 1H), 2.62 (dd, J = 17.5, 1.5 Hz, 1H), 1.65-1.53 (m, 1H), 1.50-0.96 (m, 7H), 0.80 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.42, 154.08, 140.90, 135.79, 134.34, 128.62, 128.37, 128.09, 126.76, 124.98, 124.73, 124.17, 68.16, 54.04, 43.29, 31.40, 31.17, 25.82, 22.39, 13.86. HRMS (ESI+, m/Z): calcd for C22H25NO3 [M+H]+: 352.1912, found: 352.1914.
HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254
nm. Retention time (min): 19.50 (major) and 20.45 (minor).
(2S)-benzyl-2-hexyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2g)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 5:1). Colorless oil, 99% yield, 99% ee] 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.54-7.48 (m, 1H), 7.43-7.29 (m, 5H), 7.17 (t, J = 7.5 Hz, 1H), 5.34-5.24 (m, 2H), 5.04-4.94 (m, 1H), 3.03 (dd, J = 17.5, 5.8 Hz, 1H), 2.62 (dd, J = 17.5, 1.5 Hz, 1H), 1.65-1.53 (m, 1H), 1.48-1.37 (m, 1H), 1.33-1.13 (m, 8H), 0.83 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.41, 154.08, 140.91, 135.80, 134.34, 128.62, 128.36, 128.09, 126.76, 124.99, 124.74, 124.17, 68.15, 54.04, 43.30, 31.56, 31.44, 28.68, 26.11, 22.44, 13.99. HRMS (ESI+, m/Z): calcd for C23H27NO3 [M+H]+: 366.2069, found: 366.2072. HPLC analysis: Chiracel-ADH,
n-heptane/i-PrOH 98:2, 0.5 mL/min, 40 oC, detection at 254 nm. Retention time (min): 32.88 (major)
and 36.72 (minor).
(2S)-benzyl-2-undecyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2h)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:1).
Colorless oil, 83% yield, 98% ee] 1H NMR (400
42 7.78 (d, J = 8.3 Hz, 1H), 7.55-7.47 (m, 1H), 7.45-7.26 (m, 5H), 7.17 (t, J = 8.0 Hz, 1H), 5.39-5.23 (m, 2H), 5.05-4.92 (m, 1H), 3.03 (dd, J = 17.5, 5.8 Hz, 1H), 2.62 (dd, J = 17.5, 1.6 Hz, 1H), 1.66-1.52 (m, 1H), 1.49-1.38 (m, 1H), 1.38-1.06 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.40, 154.08, 140.91, 135.80, 134.33, 128.62, 128.36, 128.08, 126.76, 124.99, 124.73, 124.16, 68.15, 54.05, 43.31, 31.89, 31.43, 29.58, 29.43, 29.37, 29.31, 29.02, 26.15, 22.67, 14.11. HRMS (ESI+, m/Z): calcd for C28H37NO3 [M+H]+: 436.2851,
found: 436.2855. HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC,
detection at 254 nm. Retention time (min): 12.51 (major) and 13.28 (minor).
(2S)-benzyl-2-ipentyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2i)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 4:1). Colorless oil, 92% yield, 98% ee] 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.55-7.47 (m, 1H), 7.43-7.30 (m, 5H), 7.20-7.13 (m, 1H), 5.30 (s, 2H), 5.00-4.90 (m, 1H), 3.04 (dd, J = 17.5, 5.8 Hz, 1H), 2.63 (dd, J = 17.5, 1.7 Hz, 1H), 1.64-1.50 (m, 1H), 1.50-1.36 (m, 2H), 1.29-1.17 (m, 1H), 1.16-1.04 (m, 1H), 0.77 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.43, 154.08, 140.86, 135.80, 134.35, 128.62, 128.36, 128.09, 126.76, 124.97, 124.72, 124.18, 68.14, 54.28, 43.33, 35.27, 29.26, 27.49, 22.48, 22.29. HRMS (ESI+, m/Z): calcd for C22H25NO3 [M+H]+: 352.1912, found: 352.1915. HPLC analysis:
Chiracel-ADH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254 nm. Retention time
(min): 19.16 (major) and 20.34 (minor).
(2S)-benzyl-2-ibutyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2j)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 2:1). Colorless oil, 96% yield, 98% ee] 1H NMR
(400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.57-7.47 (m, 1H), 7.44-7.27 (m, 5H), 7.17 (t, J = 7.5 Hz, 1H), 5.35-5.23 (m, 2H), 5.18-5.03 (m, 1H), 3.04 (dd, J = 17.5, 5.7 Hz, 1H), 2.58 (dd, J = 17.5, 1.6 Hz, 1H), 1.62-1.46 (m, 2H), 1.32-1.16 (m, 1H), 0.90 (d, J = 6.3 Hz, 3H), 0.78 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.44, 154.02, 140.93, 135.71, 134.30, 128.61, 128.38, 128.16, 126.72, 125.10, 125.02, 124.28, 68.22, 52.40, 43.53, 40.46, 25.12, 22.75, 22.15. HRMS (ESI+, m/Z): calcd for C21H23NO3 [M+H]+: 338.1756, found:
338.1760. HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 98:2, 0.5 mL/min, 40 oC,
detection at 254 nm. Retention time (min): 33.92 (major) and 37.26 (minor).
(2R)-benzyl-2-cyclopentyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2k)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:1). Colorless oil, 91% yield, 96% ee] 1H NMR
(400 MHz, CDCl3) δ 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (s, 1H), 7.55-7.46 (m, 1H), 7.42-7.28 (m, 5H), 7.21-7.11 (m, 1H), 5.36-5.21 (m, 2H), 4.69 (dd, J = 11.1, 4.3 Hz, 1H), 3.01 (dd, J = 17.6, 5.6 Hz, 1H), 2.75 (dd, J = 17.6, 1.7 Hz, 1H), 2.07-1.94 (m, 1H), 1.73-1.34 (m, 7H), 1.22-1.11 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 193.59, 154.13, 141.29, 135.84, 134.28, 128.62, 128.33, 128.02, 126.62, 125.58, 124.87, 124.22, 68.14, 59.16, 42.58, 40.79, 30.06, 29.87, 25.47, 24.97. HRMS (ESI+, m/Z): calcd for C22H23NO3 [M+H]+: 350.1756, found: 350.1760. HPLC analysis:
43 Chiracel-ODH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254 nm. Retention
time (min): 16.12 (major) and 18.85 (minor).
(2R)-benzyl-2-phenyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2l)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:1). Colorless oil, 95% yield, 91% ee] 1H NMR (400
MHz, CDCl3) δ 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H),
7.52-7.33 (m, 6H), 7.25-7.11 (m, 5H), 7.08 (t, J = 7.1 Hz, 1H), 6.25 (t, J = 3.9 Hz, 1H), 5.46-5.30 (m, 2H), 3.38-3.24 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 192.65, 154.30, 141.50, 138.08, 135.61, 134.54, 128.70, 128.63, 128.48,
128.16, 127.57, 126.87, 126.56, 125.07, 124.41, 124.19, 68.52, 56.17, 42.34. HRMS (ESI+, m/Z): calcd for C23H19NO3 [M+H]+: 358.1443, found: 358.1442. HPLC analysis:
Chiracel-ODH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254 nm. Retention time
(min): 29.20 (minor) and 39.66 (major).
(2R)-benzyl-2-Tol-phenyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2la)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 1:3). Colorless oil, 93% yield, 92% ee] 1H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H),
7.50-7.31 (m, 6H), 7.12-7.04 (m, 3H), 7.01 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 5.45-5.29 (m, 2H), 3.36-3.22 (m, 2H), 2.23 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 195.47, 156.96, 144.16, 139.92, 138.31, 137.68, 137.14,
131.97, 131.34, 131.12, 130.81, 129.49, 129.15, 127.75, 127.09, 126.79, 71.13, 58.62, 45.03, 23.57. HRMS (ESI+, m/Z): calcd for C24H21NO3 [M+Na]+: 394.14136, found: 394.14166.
HPLC analysis: Chiracel-ODH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC, detection at 254
nm. Retention time (min): 26.11 (minor) and 36.61 (major).
(2S)-benzyl-2-phenethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2m)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 2:1). Colorless oil, Quant. yield, 99% ee] 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 7.8, 1.5 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.57-7.46 (m, 1H), 7.39 (d, J = 3.5 Hz, 5H), 7.24-7.12 (m, 4H), 7.07-6.96 (m, 2H), 5.36-5.24 (m, 2H), 5.11-5.03 (m, 1H), 3.06 (dd, J = 17.6, 5.8 Hz, 1H), 2.77-2.53 (m, 3H), 2.02-1.87 (m, 1H), 1.72-1.87 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 193.15, 154.05, 140.77, 140.69, 135.71, 134.41, 128.68, 128.44, 128.40, 128.20, 128.18, 126.81, 126.06, 125.02, 124.90, 124.38, 68.26, 53.86, 43.36, 33.02, 32.52. HRMS (ESI+, m/Z): calcd for C25H23NO3 [M+H]+: 386.1756,
found: 386.1761. HPLC analysis: Chiracel-ADH, n-heptane/i-PrOH 95:5, 0.5 mL/min, 40 oC,
detection at 254 nm. Retention time (min): 38.35 (major) and 42.78 (minor).
(2S)-benzyl-2-(but-3-en-1-yl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2n)
[Purification by flash column chromatography on silica gel (eluent, pentane:Et2O = 2:1). Colorless oil, 95% yield, 99% ee] 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.5 Hz, 1H), 7.77
