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Synthesis 2024; 56(09): 1381-1392
DOI: 10.1055/s-0043-1763679
paper

Stereoselective Synthesis of 3,4-Dihydrobenzofuro[3,2-b]pyridin-2(1H)-ones Enabled by Pd/Chiral Isothiourea Relay Catalysis

Mostafa Sayed∗
a   Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
b   Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt
,
Zhipeng Shi
a   Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
,
Tao Fan
a   Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
,
Hong-Cheng Shen
a   Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
,
Zhi-Yong Han∗
a   Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
› Author Affiliations

We are grateful for the financial support from NSFC (Grants 21831007, 21971231).
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Abstract

A highly enantioselective [4+2] cyclization of azadienes with ketene in situ generated from Pd-catalyzed carbonylation of benzyl bromides, is established through Pd/chiral isothiourea relay catalysis. The key in this transformation is the formation of a C1-ammonium enolate from the in situ generated ketene and a chiral isothiourea catalyst, which subsequently undergoes a formal [4+2] reaction, leading to 3,4-dihydrobenzofuro[3,2-b]pyridine derivatives in high yields and excellent levels of stereoselectivity.


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Key words

relay catalysis - C1-ammonium enolate - chiral isothiourea - azadiene - asymmetric catalysis

Table 1 Optimization of Catalysts and Reaction Conditionsa

Entry

Deviation from standard conditions

Yield (%)b

drc

ee d

 1

none

95

67:33

 68 (6)

 2

4j instead of 4a

96

67:33

–96 (–65)

 3

4b instead of 4a

90

80:20

 90 (30)

 4

[Pd(allyl)Cl]2 instead of Pd(dba)2

90

80:20

 96 (30)

 5

DCM instead of THF

50

75:25

 98 (3)

 6

2-MeTHF instead of THF

30

75:25

 90 (75)

 7

toluene instead of THF

traces

N.D.

 N.D.

 8

2 bar CO instead of 1 bar

50

75:25

 65 (42)

 9

K2CO3 instead of DIPEA

55

60:40

 60 (65)

10

Et3N instead of DIPEA

30

75:25

 66 (66)

11e

4b instead of 4a

95

80:20

 96 (30)

a Reaction conditions: 1a (0.225 mmol), 2a (0.1 mmol), Pd(dba)2 (0.01 mmol), Xantphos (0.011mmol), 4a (0.02 mmol), i-Pr2NEt (0.4 mmol), THF (1.0 mL), under CO (1 bar) at 30 °C.

b Determined by 1H NMR analysis of the crude reaction mixture.

c Determined by 1H NMR analysis of the crude reaction mixture. N.D.: Not determined.

d Determined by HPLC.

e Amount of 1a: 0.3 mmol.

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Scheme 1 Different approaches for asymmetric construction of benzofuro[3,2-b]pyridines
Zoom Image
Scheme 2 Substrate scope of aryl bromides. Reagents and conditions: 1 (0.3 mmol), 2a (0.1 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.011 mmol), 4b (0.02 mmol), i-Pr2NEt (0.4 mmol), THF (1.0 mL), under CO (1 bar) at 30 °C. Isolated yields of both diastereoisomers are given. The dr value was determined by1H NMR analysis of the crude reaction mixture and the ee was determined by HPLC analysis.

The integration of transition metal- and organocatalysis has been successively studied over the past two decades,[1] leading to a substantial array of asymmetric reactions. These endeavors have proven particularly fruitful in the construction of pharmacologically relevant frameworks.[2] Isothiourea catalysts (ITUs)[3] have been convinced to act as privileged Lewis base organocatalysts[4] that have enabled a variety of asymmetric transformations through the generation of nucleophilic C1-ammonium enolates[5] with carboxylic esters, anhydrides, and acyl imidazoles.[6] Since the seminal work by Snaddon and co-workers revealed that the ammonium enolate could participate in the coupling reaction with π-allylpalladium species,[7] the isothiourea/transition metal cooperative catalysis has been widely applied to the development of new asymmetric transformations. [8] On the other hand, there has been a growing interest in applying aurone-derived 1-azadienes as exceptionally reactive azadiene-type substrates in the establishment of annulation reactions due to the compelling force of aromatization. As a consequence, several approaches to access benzofuro[3,2-b]pyridine have been described[9] [10] since the highly efficient and diastereodivergent aza-Diels–Alder reaction was reported by Zhao and co-workers[11] (Scheme [1a]). In particular, Song reported a highly enantioselective [4+2] cyclization of aurone-derived 1-azadienes with ketenes in situ generated from visible-light photo-promoted Wolff rearrangement of α-diazoketones proceeded via the C1-ammonium enolate intermediate enabled by ITU catalysis (Scheme [1b]).[10] Our group has maintained a sustained focus on the catalytic generation of C1-ammonium enolates from halides and CO for asymmetric cascade reactions.[12] In our previous work, the trapping of the C1-ammonium enolate with N-tosylimines,[12a] vinyl benzoxazinanones,[12b] and α-ketophosphonates[12c] offers direct routes to chiral lactams and lactone motifs through asymmetric formal [1+1+4] and [1+1+2] annulation. Herein, we propose an enantioselective synthesis of 1,2-dihydrobenzofuro[3,2‑b]pyridines from three-component reaction of benzyl bromides, carbon monoxide, and aurone-derived 1-azadienes rendered by Pd/isothiourea relay catalysis. This protocol principally commences with the Pd-catalyzed carbonylation of benzyl bromide and subsequent ketene formation.[12] Afterwards, the ketene reacts with the chiral Lewis base to produce the C1-ammonuim enolate II, which undergoes asymmetric formal [4+2] cycloaddition to generate the chiral heterocyclic products (Scheme [1c]).

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Scheme 3 Substrate scope of azadienes. Reagents and conditions: 1 (0.3 mmol), 2a (0.1 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.011 mmol), 4b (0.02 mmol), iPr2NEt (0.4 mmol), THF (1.0 mL), under CO (1 bar) at 30 °C. Isolated yields of both diastereoisomers are shown. The dr value was determined by 1H NMR analysis of the crude reaction mixture and the ee was determined by HPLC analysis.

A three-component cascade reaction of benzyl bromide (1a), aurone-derived α,β-unsaturated imine 2a and CO catalyzed by palladium complex of Xantphos and chiral isothiourea 4a was initially investigated in THF by using i-Pr2NEt as base as shown in Table [1]. To our delight, the desired product 3a was isolated in 95% yield with 67:33 dr and 68%/6% ee (Table [1], entry 1). As the chiral isothiourea catalyst basically controls the stereoselectivity, a series of isothiourea derivatives 4 were evaluated and the isothiourea 4b turned out to be the optimal organocatalyst (entry 3), allowing the product 3a to be generated in 90% yield, 80:20 dr and 90%/30% ee. Subsequently, a variety of palladium complexes were investigated and [Pd(allyl)Cl]2 was identified to be the best pre-catalyst, which, in coordination with Xantphos, enabled the reaction to give 3a in 90% yield, 80:20 dr and 96%/30% ee (entry 4). Moreover, the screening of different solvents revealed that THF remains the best solvent for the reaction (entries 5–7). Higher pressure of CO (2 bar) resulted in a dropped yield of 50% (entry 8). The examination of acid scavengers suggested that i-Pr2NEt was still the optimal base (entries 9, 10). Finally, increasing the amount of benzyl bromide led to an even higher yield of 95% and maintained stereoselectivity (96%/30% ee and 80:20 dr) (entry 11). For all the optimization results, see the Supporting Information (Tables S1–S4).

With the optimal conditions in hand, the substrate scope with respect to benzyl bromides 1 was initially examined by the reaction with N-{(Z)-2-[(Z)-benzylidene]benzofuran-3(2H)-ylidene}-4-methylbenzenesulfonamide (2a) (Scheme [2]). A broad range of benzyl bromides were tolerated to afford the target benzofuran fused dihydropyridinone derivatives 3 in high yields (up to 99%) and with excellent stereoselectivity (up to 92:8 dr, up to >99% ee). The benzyl bromides with either an electron-donating or electron-withdrawing substituent at the ortho-position were competent substrates and successfully underwent the three-component reaction, leading to the corresponding products 3b–e in high yields (75–95%) and with good to excellent stereoselectivities (86:14–92:8 dr, 94–99% ee). In addition, disubstituted benzyl bromides are also able to participate in the reaction, as exemplified by 2,3-dichlorobenzyl and 3,5-dimethylbenzyl bromides, which, respectively, gave products 3f and 3h in high yields and excellent levels of enantioselectivity. Additionally, meta-substituted benzyl bromides seemingly gave lower stereoselectivity than ortho-substituted counterpart (3g and 3h vs 3d). Although the reaction with para-substituted benzyl bromides could give high yields and enantioselectivity, the diastereoselectivity was moderate (3i–k). Finally, (1-bromomethyl)naphthalene successfully participated in this transformation to generate 3l in good yield and high stereoselectivity.

Zoom Image
Scheme 4Gram-scale reaction and synthetic applications

Next, the generality for azadienes was examined by the reaction with 2-methylbenzyl bromide (1d) (Scheme [3]). N-Ns-substituted azadiene substrate successfully delivered the desired product 3m in 70% yield with 89:11 dr and 90% ee. A variety of aurone-derived α,β-unsaturated imines containing either an electron-donating or withdrawing substituent at the benzene ring were well-tolerated, leading to the corresponding products 3n–v in excellent yields of up to 99% and with excellent stereoselectivities (up to 94:6 dr, >99% ee). Similarly, the azadienes substituted with either 2-naphthalene, 2-furan, or 2-thiophene successfully generated the target products 3w–y in excellent results (up to 95% yield, 84:16 dr, 99% ee). Furthermore, the presence of 6-OMe substituent at the benzofuran moiety was also allowed and gave excellent stereoselectivity (93:7 dr, >99% ee), but the yield was considerably lower (65%). The absolute configuration of the product 3p was assigned by single-crystal X-ray diffraction analysis[13] and those of other products were assigned by analogy.

To demonstrate the synthetic utility of this methodology, the standard reaction conditions were conducted on a gram-scale to afford the desired product 3p with maintained yield and stereoselectivity (Scheme [4]). Further transformations could be performed on product 3p. For instance, the treatment of 3p with Mg/methanol[14] led to the formation of δ-amino acid derivative 5 in 85% yield and with 92:8 dr, and >99% ee. Moreover, the 4-toluenesulfonyl group in 3p could be eliminated using SmI2, leading to the formation of lactam product 6 in a 90% yield and with notable stereoselectivity (90:10 dr, and >99% ee). Furthermore, the reduction of 3p employing DIBAL-H and Et3SiH/BF3·OEt2 afforded benzofurotetrahydropyridine 7 in 90% yield without loss stereoselectivity.

Based on the previous reports,[12] a mechanism of this three-component cascade reaction is proposed. As shown in Scheme [5], the reaction commences with the oxidative addition of Pd(0) to the C–Br bond of benzyl bromide 1a, leading to intermediate I. Upon CO insertion, the intermediate I is converted to acyl palladium complex II. Ketene intermediate III is generated from the β-H elimination of Pd complex II, which is then attacked by the isothiourea catalyst, leading to the formation of C1-ammonium enolate IV. The C1-ammonium enolate undergoes Michael addition to azadiene 2a, followed by lactonization, leads to the lactone product 3a and the regeneration of the catalyst.

Zoom Image
Scheme 5Proposed reaction mechanism

In summary, we have successfully developed an efficient method for the synthesis of chiral 3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-ones from benzyl bromides, CO, and azadiene substrates enabled by Pd/isothiourea relay catalysis. Under mild reaction conditions, various benzyl bromides and a variety of azadienes substrates were tolerated to give enantioenriched 3,4-dihydrobenzofuro [3,2-b] pyridin-2(1H)-one derivatives in excellent yields and with good diastereoselectivity and excellent enantioselectivity.

NMR spectra were recorded on a Bruker400 MHz spectrometer. Chemical shifts (δ) are given in ppm relative to TMS. The residual solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl3: δH = 7.26, δC = 77.16). The high-resolution mass spectra were recorded on a Thermo LTQ Orbitrap XL (ESI+) or a P-SIMS-Gly of Bruker Daltonics Inc (EI+).


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Synthesis of 3,4-Dihydrobenzofuro[3,2-b]pyridin-2(1H)-ones 3; General Procedure

Under N2 atmosphere, a flame dried Schlenk tube (25 mL) was charged with [Pd(allyl)Cl]2 (0.01 mmol, 3.8 mg), Xantphos (0.011 mmol, 6.4 mg), 4b (0.02 mmol, 6.2 mg), and azadiene 2 (0.1 mmol). The Schlenk tube was then evacuated and filled back with N2 three times and followed by addition of benzyl bromide derivative 1 (0.3 mmol), THF (1 mL), and i-Pr2NEt (0.4 mmol, 51.7 mg). The solution was frozen under liquid N2, the N2 atmosphere was evacuated from the tube in a Schlenk line and then was filled with 1 bar CO, and stirred under CO atmosphere at 30 °C for 12 h. The reaction was directly purified by flash column chromatography (FCC) on silica gel to give the pure product 3.


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(3R,4S)-3,4-Diphenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3a)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3a as a pale yellow solid; yield: 46.8 mg (95%); dr 80:20, 96% ee; mp 95–97 °C; [α]D 20 +145.9 (c = 0.59, CH2Cl2).

Enantiomeric excess: 96%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 8.5 min (major), t R = 12.5 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.27–8.16 (m, 1 H), 8.17–8.03 (m, 2 H), 7.46 (dd, J = 7.8, 1.6 Hz, 1 H), 7.41–7.31 (m, 4 H), 7.22–7.16 (m, 2 H), 7.12–7.01 (m, 4 H), 6.78–6.69 (m, 2 H), 6.63–6.53 (m, 2 H), 4.34 (s, 2 H), 2.48 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.58, 154.19, 147.23, 145.43, 135.42, 134.36, 133.54, 130.36, 129.73, 129.45, 129.28, 129.08, 129.00, 128.85, 128.45, 127.96, 127.86, 127.78, 127.13, 127.09, 125.09, 123.50, 122.76, 122.71, 118.94, 111.65, 56.09, 44.81, 21.78.

HRMS (ESI): m/z (M + H)+ calcd for C30H24NO4S: 494.1426; found: 494.1426.


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(3R,4S)-3-(2-Chlorophenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3b)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3b as a pale yellow solid; yield: 50.1 mg (95%); dr 91:9, >99% ee; mp 75–77 °C; [α]D 20 +48.6 (c = 0.63, CH2Cl2).

Enantiomeric excess: >99% ee, determined by HPLC (Daicel Chirapak OD, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 5.1 min (major), t R = 23.8 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.23–8.19 (m, 1 H), 8.16 (d, J = 8.4 Hz, 2 H), 7.52–7.46 (m, 1 H), 7.43–7.37 (m, 4 H), 7.34 (dd, J = 8.1, 1.3 Hz, 1 H), 7.17 (m, 2 H), 7.08 (m, 2 H), 6.83 (td, J = 7.6, 1.3 Hz, 1 H), 6.78–6.70 (m, 2 H), 6.22 (dd, J = 7.9, 1.6 Hz, 1 H), 5.02 (d, J = 7.0 Hz, 1 H), 4.40 (d, J = 7.0 Hz, 1 H), 2.48 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.25, 154.36, 146.87, 145.64, 135.75, 134.41, 134.20, 133.08, 131.35, 129.71, 129.67, 129.63, 129.46, 129.02, 128.79, 128.65, 128.19, 127.67, 125.90, 125.30, 123.64, 122.71, 118.94, 111.89, 51.93, 42.76, 21.92.

HRMS (ESI): m/z (M + H)+ calcd for C30H23ClNO4S: 528.1036; found: 528.1038.


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(3R,4S)-3-(2-Bromophenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3c)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3c as a pale yellow solid; yield: 55.3 mg (97%); dr 91:9, 94% ee; mp 79–82 °C; [α]D 20 +80.4 (c = 0.69, CH2Cl2).

Enantiomeric excess: 94%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 5.9 min (major), t R = 9.0 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.25–8.19 (m, 1 H), 8.17 (d, J = 8.4 Hz, 2 H), 7.56–7.45 (m, 2 H), 7.44–7.34 (m, 4 H), 7.22–7.15 (m, 1 H), 7.11–6.98 (m, 3 H), 6.87 (td, J = 7.6, 1.3 Hz, 1 H), 6.78–6.68 (m, 2 H), 6.20 (dd, J = 7.9, 1.7 Hz, 1 H), 5.00 (d, J = 7.1 Hz, 1 H), 4.43 (d, J = 7.1 Hz, 1 H), 2.48 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.27, 154.37, 146.78, 145.64, 135.77, 134.34, 133.30, 132.99, 132.38, 129.70, 129.63, 129.32, 128.81, 128.65, 128.19, 126.48, 125.30, 125.20, 123.63, 122.70, 118.92, 111.91, 54.92, 42.72, 21.92.

HRMS (ESI): m/z (M + Na)+ calculated for C30H22BrNO4SNa: 594.0351; found: 594.0355.


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(3R,4S)-4-Phenyl-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3d)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3d as a pale yellow solid; yield: 48.2 mg (95%); dr 92:8, >99% ee; mp 96–98 °C; [α]D 20 +50.3 (c = 0.6, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.3 min (major), t R = 10.6 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.26–8.18 (m, 1 H), 8.18–8.07 (m, 2 H), 7.48 (dd, J = 8.0, 1.5 Hz, 1 H), 7.44–7.32 (m, 4 H), 7.24–7.15 (m, 1 H), 7.12–7.00 (m, 4 H), 6.78 (td, J = 7.4, 1.9 Hz, 1 H), 6.76–6.71 (m, 2 H), 6.11 (d, J = 7.9 Hz, 1 H), 4.59 (d, J = 6.7 Hz, 1 H), 4.32 (d, J = 6.8 Hz, 1 H), 2.48 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 170.17, 154.62, 147.42, 145.86, 136.56, 136.03, 134.81, 132.11, 131.54, 130.56, 130.11, 129.93, 129.88, 129.39, 128.81, 128.39, 128.06, 127.75, 125.64, 125.51, 123.95, 123.19, 123.07, 112.15, 52.14, 43.67, 22.22, 20.07.

HRMS (ESI): m/z (M + H)+ calcd for C31H26NO4S: 508.1583; found: 508.1591.


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(3R,4S)-3-([1,1′-Biphenyl]-2-yl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3e)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3e as a pale yellow solid; yield: 54.1 mg (95%); dr 86:14, 98% ee; mp 84–86 °C; [α]D 20 +43.3 (c = 0.68, CH2Cl2).

Enantiomeric excess: 98%, determined by HPLC (Daicel Chirapak IE, hexane/i-PrOH 85:15, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 19.5 min (major), t R = 21.6 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.18–8.06 (m, 3 H), 7.44–7.29 (m, 7 H), 7.22–7.01 (m, 8 H), 6.86 (ddd, J = 8.0, 7.1, 1.8 Hz, 1 H), 6.79–6.71 (m, 2 H), 6.02 (dd, J = 8.1, 1.2 Hz, 1 H), 4.51 (d, J = 7.2 Hz, 1 H), 4.12 (d, J = 7.2 Hz, 1 H), 2.49 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 170.37, 154.15, 146.52, 145.57, 143.03, 140.87, 135.68, 134.74, 131.52, 131.31, 129.83, 129.56, 129.52, 129.43, 129.14, 129.01, 128.72, 128.64, 128.57, 128.12, 127.70, 127.37, 126.51, 125.05, 123.45, 122.72, 118.69, 111.76, 52.35, 44.24, 21.93.

HRMS (ESI): m/z (M + H)+ calcd for C36H28NO4S: 570.1739; found: 570.1742.


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(3R,4S)-3-(2,3-Dichlorophenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3f)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3f as a white solid; yield: 50.5 mg (90%); dr 84:16, 90% ee; mp 92–94 °C; [α]D 20 +136.2 (c = 0.63, CH2Cl2).

Enantiomeric excess: 90%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.2 min (minor), t R = 7.8 min (major).

1H NMR (500 MHz, CDCl3): δ = 8.24–8.19 (m, 1 H), 8.18–8.14 (m, 2 H), 7.45–7.34 (m, 5 H), 7.24–7.04 (m, 5 H), 6.86–6.63 (m, 2 H), 6.15 (dd, J = 7.9, 1.5 Hz, 1 H), 5.07 (d, J = 7.0 Hz, 1 H), 4.41 (d, J = 6.9 Hz, 1 H), 2.49 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 168.82, 154.24, 146.51, 145.65, 135.51, 134.72, 134.07, 133.56, 132.51, 132.38, 131.22, 129.99, 129.70, 129.66, 129.56, 129.40, 128.99, 128.66, 128.24, 127.52, 127.39, 126.09, 125.30, 123.59, 122.58, 122.50, 118.79, 111.82, 52.62, 48.05, 42.51, 21.83.

HRMS (ESI): m/z (M + H)+ calcd for C30H22Cl2NO4S: 562.0647; found: 562.0641.


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(3R,4S)-4-Phenyl-3-(m-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3g)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3g as a pale yellow solid yield: 40.6 mg (80%); dr 83:17, 97% ee; mp 75–77 °C; [α]D 20 +67.1 (c = 0.51, CH2Cl2).

Enantiomeric excess: 97%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.9 min (minor), t R = 13.6 min (major).

1H NMR (400 MHz, CDCl3): δ = 8.23–8.17 (m, 1 H), 8.12 (d, J = 8.4 Hz, 2 H), 7.50–7.44 (m, 1 H), 7.41–7.32 (m, 4 H), 7.23–7.15 (m, 2 H), 7.08 (dd, J = 8.4, 6.9 Hz, 2 H), 7.01–6.93 (m, 2 H), 6.82–6.68 (m, 2 H), 6.36 (d, J = 6.9 Hz, 1 H), 4.33 (d, J = 6.7 Hz, 1 H), 4.29 (d, J = 6.7 Hz, 1 H), 2.47 (s, 3 H), 2.12 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.74, 154.16, 147.34, 145.40, 137.35, 135.42, 134.48, 133.34, 131.26, 129.67, 129.45, 129.27, 128.98, 128.92, 128.37, 127.94,132 127.69, 127.31, 127.10, 125.06, 123.49, 122.74, 122.61, 118.87, 111.07, 56.15, 44.70, 21.79, 21.30.

HRMS (ESI): m/z (M + H)+ calcd for C31H26NO4S: 508.1583; found: 508.1584.


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(3R,4S)-3-(3,5-Dimethylphenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3h)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3h as a pale yellow solid; yield: 39.1 mg (75%); dr 80:20, 97% ee; mp 88–90 °C; [α]D 20 +133.0 (c = 0.49, CH2Cl2).

Enantiomeric excess: 97%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.7 min (major), t R = 15.4 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.25–8.19 (m, 1 H), 8.16–8.09 (m, 2 H), 7.47 (dd, J = 8.2, 1.4 Hz, 1 H), 7.42–7.33 (m, 4 H), 7.24–7.19 (m, 1 H), 7.11 (t, J = 7.7 Hz, 2 H), 6.80 (dd, J = 8.1, 1.5 Hz, 3 H), 6.14 (d, J = 1.5 Hz, 2 H), 4.32 (d, J = 6.7 Hz, 1 H), 4.24 (d, J = 6.7 Hz, 1 H), 2.48 (s, 3 H), 2.08 (s, 6 H).

13C NMR (126 MHz, CDCl3): δ = 169.88, 154.16, 147.44, 145.33, 138.52, 137.15, 135.54, 134.63, 133.21, 129.60, 129.45, 129.38, 129.26, 129.02, 128.96, 128.29, 128.26, 127.91, 127.10, 125.02, 124.81, 123.48, 122.75, 122.54, 118.85, 111.68, 56.25, 44.65, 21.18.

HRMS (ESI): m/z (M + H)+ calcd for C32H28NO4S: 522.1739; found: 522.1749.


#

(3R,4S)-3-(4-(tert-Butyl)phenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3i)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3i as a pale yellow solid; yield: 46.7 mg (85%); dr 67:33, 96% ee; mp 101–103 °C; [α]D 20 +126.1 (c = 0.58, CH2Cl2).

Enantiomeric excess: 96%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 0.5 mL/min, T = 30 °C, 254 nm); t R = 14.3 min (major), t R = 18.1 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.26–8.19 (m, 1 H), 8.12 (d, J = 8.4 Hz, 2 H), 7.38 (m, 5 H), 7.13–7.09 (m, 2 H), 7.06 (m, 3 H), 6.79–6.71 (m, 2 H), 6.58–6.47 (m, 2 H), 4.35 (d, J = 6.7 Hz, 1 H), 4.31 (d, J = 6.7 Hz, 1 H), 2.48 (s, 3 H), 1.23 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 169.87, 154.15, 150.61, 147.49, 145.40, 138.23, 135.36, 134.55, 129.92, 129.75, 129.44, 128.88, 128.40, 127.01, 126.13, 124.83, 122.70, 118.83, 111.66, 55.60, 44.59, 34.45, 31.26, 21.81.

HRMS (ESI): m/z (M + H)+ calcd for C34H32NO4S: 550.2052; found: 550.2057.


#

(3R,4S)-3-(4-Fluorophenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3j)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3j as a pale yellow solid; yield: 39.8 mg (80%); dr 67:33, 95% ee; mp 90–93 °C; [α]D 20 +81.6 (c = 0.50, CH2Cl2).

Enantiomeric excess: 95%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 0.5 mL/min, T = 30 °C, 254 nm); t R = 7.2 min (major), t R = 10.4 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.26–8.19 (m, 1 H), 8.12 (dd, J = 8.7, 2.2 Hz, 2 H), 7.42–7.31 (m, 5 H), 7.28–7.12 (m, 5 H), 6.98–6.65 (m, 4 H), 4.34 (d, J = 6.8 Hz, 1 H), 4.30 (d, J = 6.8 Hz, 1 H), 2.48 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.50, 163.51, 161.05, 154.19, 147.04, 145.58, 145.43, 137.40, 135.24, 134.12, 129.74, 129.50, 129.41, 129.34, 129.03, 128.80, 128.58, 127.21, 125.20, 123.56, 122.71, 116.14, 115.92, 114.94, 114.73, 111.72, 111.69, 55.28, 43.60, 21.77.

HRMS (ESI): m/z (M + H)+ calcd for C30H23FNO4S: 512.1332; found: 512.1324.


#

(3R,4S)-3-(4-(Methylsulfonyl)phenyl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3k)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3k as a pale yellow solid; yield: 48.5 mg (85%); dr 80:20, 93% ee; mp 83–85 °C; [α]D 20 +71.3 (c = 0.61, CH2Cl2).

Enantiomeric excess: 93%, determined by HPLC (Daicel Chirapak OD, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 11.3 min (major), t R = 14.2 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.24–8.19 (m, 1 H), 8.14–8.04 (m, 2 H), 7.62–7.49 (m, 2 H), 7.49–7.30 (m, 5 H), 7.18–7.11 (m, 1 H), 7.01 (t, J = 7.7 Hz, 2 H), 6.95–6.87 (m, 2 H), 6.69–6.52 (m, 2 H), 4.99–4.89 (m, 2 H), 2.94 (s, 3 H), 2.50 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 170.83, 154.33, 145.73, 144.88, 143.43, 139.03, 135.45, 133.91, 131.07, 129.94, 129.63, 129.46, 129.14, 128.39, 128.09, 126.49, 125.27, 123.73, 122.54, 122.32, 120.57, 117.64, 111.83, 59.42, 49.08, 44.48, 21.81.

HRMS (ESI): m/z (M + H)+ calcd for C31H26NO6S2: 572.1202; found: 572.1201.


#

(3R,4S)-3-(Naphthalen-1-yl)-4-phenyl-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3l)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3l as a pale yellow solid; yield: 47.7 mg (90%); dr 84:16, 90% ee; mp 105–107 °C; [α]D 20 +83.0 (c = 0.60, CH2Cl2).

Enantiomeric excess: 90%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.9 min (major), t R = 14 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.24 (dt, J = 7.9, 1.1 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.86–7.81 (m, 1 H), 7.81–7.75 (m, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.52–7.45 (m, 2 H), 7.42–7.31 (m, 4 H), 7.27 (d, J = 4.2 Hz, 2 H), 7.24–7.18 (m, 2 H), 7.17–7.10 (m, 3 H), 6.98 (d, J = 7.1 Hz, 1 H), 5.01 (d, J = 2.9 Hz, 1 H), 4.55 (d, J = 2.9 Hz, 1 H), 2.48 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 170.31, 154.25, 145.48, 138.14, 134.60, 133.65, 131.34, 129.71, 129.64, 129.49, 129.38, 129.16, 128.72, 128.34, 127.10, 125.18, 125.00, 124.63, 122.66, 118.63, 111.78, 54.09, 44.32, 21.81.

HRMS (ESI): m/z (M + H)+ calcd for C34H26NO4S: 544.1583; found: 544.1592.


#

(3R,4S)-1-((4-Nitrophenyl)sulfonyl)-4-phenyl-3-(o-tolyl)-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3m)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3m as a pale yellow solid; yield: 37.6 mg (70%); dr 89:11, 90% ee; mp 89–92 °C; [α]D 20 +16.7 (c = 0.47, CH2Cl2).

Enantiomeric excess: 90%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.7 min (major), t R = 9.5 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.23–8.17 (m, 2 H), 8.16–8.06 (m, 3 H), 7.49–7.33 (m, 3 H), 7.21 (ddd, J = 8.6, 7.2, 1.1 Hz, 2 H), 7.16–7.06 (m, 5 H), 6.92 (td, J = 7.5, 1.9 Hz, 1 H), 6.67–6.61 (m, 1 H), 4.53 (d, J = 3.5 Hz, 1 H), 4.36 (d, J = 3.5 Hz, 1 H), 2.28 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 170.72, 154.66, 150.80, 146.15, 143.25, 137.78, 136.05, 134.09, 131.43, 131.10, 130.69, 129.24, 128.92, 128.59, 128.33, 128.10, 127.10, 126.98, 126.23, 125.47, 124.06, 123.94, 123.87, 122.58, 122.40, 118.60, 112.02, 53.70, 43.69.

HRMS (ESI): m/z (M + H)+ calcd for C30H23N2O6S: 539.1277; found: 539.1284.


#

(3R,4S)-4-(2-Bromophenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3n)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3n as a pale yellow solid; yield: 54.4 mg (93%); dr = 84:16, >99% ee; mp 101–102 °C; [α]D 20 +90.6 (c = 0.68, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.5 min (major), t R = 9.9 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.24–8.20 (m, 1 H), 8.16 (d, J = 8.5 Hz, 2 H), 7.52–7.47 (m, 1 H), 7.45–7.38 (m, 4 H), 7.37–7.33 (m, 1 H), 7.11–7.01 (m, 5 H), 6.77 (td, J = 7.5, 1.7 Hz, 1 H), 6.23–5.83 (m, 1 H), 5.16 (d, J = 7.1 Hz, 1 H), 4.62 (d, J = 7.1 Hz, 1 H), 2.48 (s, 3 H), 2.23 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.72, 154.20, 146.27, 145.55, 136.94, 135.68, 134.07, 132.86, 131.01, 130.34, 130.11, 129.64, 129.56, 129.54, 129.50, 129.47, 127.75, 126.49, 125.32, 125.30, 123.58, 122.61, 122.53, 119.43, 111.80, 50.98, 40.72, 21.82, 19.72.

HRMS (ESI): m/z (M + H)+ calcd for C31H25BrNO4S: 586.0688; found: 586.0690.


#

(3R,4S)-4-(3-Fluorophenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3o)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3o as a pale yellow solid; yield: 36.8 mg (70%); dr 89:11, >99% ee; mp 89–91 °C; [α]D 20 +5.8 (c = 0.46, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 90:10, flow rate 0.5 mL/min, T = 30 °C, 254 nm); t R = 31.9 min (major), t R = 44.7 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.28–8.17 (m, 1 H), 8.16–8.09 (m, 2 H), 7.51–7.47 (m, 1 H), 7.44–7.33 (m, 4 H), 7.13–7.05 (m, 2 H), 6.82–6.64 (m, 5 H), 6.13 (d, J = 7.9 Hz, 1 H), 4.57 (d, J = 6.7 Hz, 1 H), 4.32 (d, J = 6.7 Hz, 1 H), 2.48 (s, 3 H), 2.17 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.65, 163.63, 161.17, 154.21, 146.69, 145.56, 136.12, 135.58, 131.52, 131.06, 130.66, 130.58, 130.25, 130.15, 130.12, 129.60, 129.49, 127.77, 125.33, 125.22, 123.60, 122.67, 122.62, 118.91, 115.42, 115.21, 111.75, 51.72, 42.40, 21.78, 19.63.

HRMS (ESI): m/z (M + H)+ calcd for C31H25FNO4S: 526.1488; found: 526.1485.


#

(3R,4S)-4-(m-Tolyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3p)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3p as a white solid; yield: 46.9 mg (90%); dr 94:6, >99% ee; mp 143–145 °C; [α]D 20 +216.8 (c = 0.59, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.7 min (major), t R = 9.5 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.21 (dd, J = 7.2, 2.0 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 2 H), 7.48 (dd, J = 7.4, 1.8 Hz, 1 H), 7.44–7.32 (m, 4 H), 7.16–6.89 (m, 4 H), 6.83–6.76 (m, 1 H), 6.66 (s, 1 H), 6.53 (d, J = 7.6 Hz, 1 H), 6.16 (d, J = 7.9 Hz, 1 H), 4.57 (d, J = 6.8 Hz, 1 H), 4.30 (d, J = 6.8 Hz, 1 H), 2.46 (s, 3 H), 2.18 (s, 3 H), 2.16 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.89, 154.19, 147.13, 145.31, 138.25, 136.10, 135.94, 134.16, 131.76, 131.28, 130.07, 129.87, 129.48, 129.47, 128.71, 128.22, 127.61, 125.89, 125.13, 125.01, 123.49, 122.73, 122.45, 118.71, 111.76, 51.85, 43.16, 21.76, 21.23, 19.62.

HRMS (ESI): m/z (M + H)+ calcd for C32H28NO4S: 522.1739; found: 522.1754.


#

(3R,4S)-4-(3-Methoxyphenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3q)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3q as a pale yellow solid; yield: 47.8 mg (89%); dr 93:7, >99% ee; mp 89–92 °C; [α]D 20 +89.6 (c = 0.60, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 85:15, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 13 min (major), t R = 19.2 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.22–8.17 (m, 1 H), 8.16–8.10 (m, 2 H), 7.48 (dd, J = 7.8, 1.6 Hz, 1 H), 7.44–7.32 (m, 4 H), 7.14–7.03 (m, 2 H), 6.98 (t, J = 8.1 Hz, 1 H), 6.85–6.72 (m, 2 H), 6.40–6.30 (m, 2 H), 6.22 (d, J = 7.9 Hz, 1 H), 4.57 (d, J = 6.8 Hz, 1 H), 4.31 (d, J = 6.9 Hz, 1 H), 3.62 (s, 3 H), 2.45 (s, 3 H), 2.16 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.96, 159.73, 154.31, 146.95, 145.45, 135.97, 135.88, 131.86, 131.31, 130.24, 129.60, 129.56, 129.46, 127.78, 125.42, 125.19, 123.64, 122.80, 122.52, 121.26, 118.88, 114.58, 114.07, 111.90, 55.37, 51.97, 43.34, 21.89, 19.74.

HRMS (ESI): m/z (M + H)+ calcd for C32H28NO5S: 538.1688; found: 538.1680.


#

(3R,4S)-3-(o-Tolyl)-4-(p-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3r)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3r as a white solid; yield: 51.7 mg (>99%); dr 93:7, >99% ee; mp 170–172 °C; [α]D 20 +283.0 (c = 0.65, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 7.0 min (major), t R = 10.1 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.24 (dd, J = 7.4, 1.8 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 2 H), 7.48 (dd, J = 7.7, 1.6 Hz, 1 H), 7.41 (ddd, J = 15.5, 7.8, 5.9 Hz, 4 H), 7.09 (qd, J = 7.9, 1.9 Hz, 2 H), 6.89 (d, J = 7.8 Hz, 2 H), 6.82 (td, J = 8.1, 7.3, 2.2 Hz, 1 H), 6.64 (d, J = 7.9 Hz, 2 H), 6.19 (d, J = 7.9 Hz, 1 H), 4.58 (d, J = 6.7 Hz, 1 H), 4.31 (d, J = 6.7 Hz, 1 H), 2.49 (s, 3 H), 2.28 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.97, 154.23, 147.45, 145.45, 137.76, 136.23, 135.72, 131.83, 131.28, 131.23, 130.19, 129.70, 129.54, 129.17, 128.91, 127.67, 125.31, 125.09, 123.57, 122.87, 122.64, 118.75, 111.81, 51.78, 42.95, 21.87, 21.23, 19.76.

HRMS (ESI): m/z (M + H)+ calcd for C32H28NO4S: 522.1739; found: 522.1754.


#

(3R,4S)-4-(4-Fluorophenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3s)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3s as a pale yellow solid; yield: 39.4 mg (75%); dr 87:13, >99% ee; mp 131–133 °C; [α]D 20 +108.0 (c = 0.49, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.5 min (major), t R = 9.1 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.24–8.18 (m, 1 H), 8.11 (d, J = 8.5 Hz, 2 H), 7.48 (dd, J = 7.7, 1.8 Hz, 1 H), 7.42–7.34 (m, 4 H), 7.11–7.08 (m, 2 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.84 (td, J = 8.2, 7.3, 2.5 Hz, 1 H), 6.65 (d, J = 8.5 Hz, 2 H), 6.16 (d, J = 7.9 Hz, 1 H), 4.57 (d, J = 6.7 Hz, 1 H), 4.31 (d, J = 6.8 Hz, 1 H), 2.48 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.76, 163.47, 161.50, 154.30, 146.79, 145.67, 136.22, 135.65, 131.61, 131.16, 130.76, 130.69, 130.35, 130.25, 130.23, 129.70, 129.59, 129.53, 127.87, 125.43, 125.32, 123.71, 122.77, 122.71, 119.01, 115.50, 115.33, 111.86, 51.82, 42.49, 21.89, 19.74.

19F NMR (376 MHz, CDCl3): δ = –113.86.

HRMS (ESI): m/z (M + H)+ calcd for C31H25FNO4S: 526.1488; found: 526.1491.


#

(3R,4S)-4-(4-Chlorophenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3t)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3t as a pale yellow solid; yield: 43.3 mg (80%); dr = 89:11, 96% ee; mp 184–185 °C; [α]D 20 +173.2 (c = 0.54, CH2Cl2).

Enantiomeric excess: 96%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.5 min (major), t R = 9.1 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.32–8.16 (m, 1 H), 8.12 (d, J = 8.3 Hz, 2 H), 7.48 (dd, J = 6.8, 2.4 Hz, 1 H), 7.45–7.34 (m, 4 H), 7.13–7.08 (m, 2 H), 7.07–6.99 (m, 2 H), 6.89–6.75 (m, 1 H), 6.78–6.48 (m, 2 H), 6.17 (d, J = 7.9 Hz, 1 H), 4.57 (d, J = 6.7 Hz, 1 H), 4.32 (d, J = 6.7 Hz, 1 H), 2.49 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.65, 154.31, 146.55, 145.71, 136.24, 135.60, 134.03, 133.00, 131.51, 131.12, 130.39, 129.69, 129.61, 129.19, 128.63, 127.93, 125.50, 125.37, 123.73, 122.75, 122.73, 119.12, 111.86, 51.66, 42.56, 21.89, 19.76.

HRMS (ESI): m/z (M + H)+ calcd for C31H25ClNO4S: 542.1193; found: 542.1190.


#

(3R,4S)-4-(4-Bromophenyl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3u)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3u as a pale yellow solid; yield: 54.4.mg (93%); dr 84:16, 99% ee; mp 162–164 °C; [α]D 20 +206.7 (c = 0.68, CH2Cl2).

Enantiomeric excess: 99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 6.7 min (major), t R = 9.5 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.26–8.18 (m, 1 H), 8.14–8.06 (m, 2 H), 7.49 (dd, J = 7.7, 1.7 Hz, 1 H), 7.45–7.34 (m, 4 H), 7.22–7.16 (m, 2 H), 7.12–7.07 (m, 2 H), 6.85 (ddd, J = 8.4, 6.1, 2.7 Hz, 1 H), 6.60 (d, J = 8.5 Hz, 2 H), 6.18 (d, J = 7.9 Hz, 1 H), 4.58 (d, J = 6.7 Hz, 1 H), 4.31 (d, J = 6.7 Hz, 1 H), 2.49 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.62, 154.31, 146.48, 145.72, 136.24, 135.59, 133.51, 132.15, 131.59, 131.48, 131.11, 130.71, 130.41, 129.68, 129.61, 129.49, 129.45, 129.09, 127.94, 126.86, 125.52, 125.38, 123.74, 122.78, 122.74, 122.20, 119.15, 111.86, 51.58, 42.61, 21.89, 19.76.

HRMS (ESI): m/z (M + H)+ calcd for C31H25BrNO4S: 586.0688; found: 586.0677.


#

(3R,4S)-3-(o-Tolyl)-1-tosyl-4-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzofuro[3,2-b]pyridine 2(1H)-one (3v)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3v as a pale yellow solid; yield: 50.1 mg (87%); dr 84:16, >99% ee; mp 85–87 °C; [α]D 20 +124.4 (c = 0.63, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 5.3 min (major), t R = 7.2 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.28–8.20 (m, 1 H), 8.17–8.08 (m, 2 H), 7.49 (dd, J = 7.7, 1.8 Hz, 1 H), 7.45–7.41 (m, 2 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.11 (tdd, J = 7.6, 6.0, 1.7 Hz, 3 H), 6.86 (d, J = 8.0 Hz, 2 H), 6.12 (d, J = 7.9 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 1 H), 4.41 (d, J = 6.8 Hz, 1 H), 2.48 (s, 3 H), 2.19 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.52, 154.38, 146.09, 145.81, 138.61, 136.26, 135.55, 131.34, 131.01, 130.49, 129.71, 129.65, 129.58, 129.48, 129.46, 128.05, 127.82, 125.50, 125.49, 125.39, 125.36, 125.33, 123.81, 122.79, 122.71, 119.41, 111.89, 51.60, 42.89, 21.80, 19.73.

19F NMR (376 MHz, CDCl3): δ = –62.64.

HRMS (ESI): m/z (M + H)+ calcd for C32H25F3NO4S: 576.1456; found: 576.1459.


#

(3R,4S)-4-(Naphthalen-2-yl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3w)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3w as pale yellow solid; yield: 53.1 mg (95%); dr 80:20, 99% ee; mp 102–104 °C; [α]D 20 +121.1 (c = 0.66, CH2Cl2).

Enantiomeric excess: 99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 14.3 min (major), t R = 25.2 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.26–8.19 (m, 1 H), 8.18–8.07 (m, 2 H), 7.79–7.71 (m, 1 H), 7.57–7.35 (m, 8 H), 7.34–7.29 (m, 2 H), 7.16–7.00 (m, 2 H), 6.78 (dd, J = 8.5, 1.9 Hz, 1 H), 6.73–6.61 (m, 1 H), 6.19–5.98 (m, 1 H), 4.66 (d, J = 6.7 Hz, 1 H), 4.52 (d, J = 6.7 Hz, 1 H), 2.43 (s, 3 H), 2.18 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.96, 154.37, 147.19, 145.49, 136.25, 135.94, 133.21, 132.88, 132.03, 131.80, 131.27, 130.31, 129.63, 129.60, 129.30, 129.21, 128.34, 128.16, 128.11, 127.80, 127.64, 126.74, 126.47, 126.38, 126.33, 125.45, 125.24, 123.68, 122.88, 122.64, 119.00, 111.92, 53.86, 51.97, 43.33, 21.89, 19.82.

HRMS (ESI): m/z (M + H)+ calcd for C35H28NO4S: 558.1739; found: 558.1734.


#

(3R,4S)-4-(Furan-2-yl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3x)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3x as a pale yellow solid; yield: 47.7 mg (96%); dr = 84:16, >99% ee; mp 75–77 °C; [α]D 20 +232.6 (c = 0.60, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm): t R = 8.6 min (major), t R = 15.2 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.23–8.20 (m, 1 H), 8.15–8.11 (m, 2 H), 7.53–7.45 (m, 1 H), 7.43–7.36 (m, 4 H), 7.15–7.06 (m, 2 H), 6.96–6.85 (m, 2 H), 6.17 (dd, J = 3.3, 1.9 Hz, 1 H), 6.12–6.05 (m, 1 H), 5.93 (dd, J = 3.3, 0.8 Hz, 1 H), 4.52 (d, J = 6.3 Hz, 1 H), 4.34 (d, J = 6.4 Hz, 1 H), 2.51 (s, 3 H), 2.23 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.34, 154.11, 147.80, 145.21, 144.80, 142.33, 136.02, 135.57, 132.06, 130.31, 130.22, 129.87, 129.23, 127.87, 125.70, 125.26, 123.66, 123.15, 123.00, 119.11, 111.75, 110.78, 109.91, 50.50, 37.18, 21.88, 19.86.

HRMS (ESI): m/z (M + H)+ calcd for C29H24NO5S: 498.1375; found: 498.1384.


#

(3R,4S)-4-(Thiophen-2-yl)-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3y)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3y as a pale yellow solid; yield: 50.3 mg (98%); dr 80:20, 99% ee; mp 79–82 °C; [α]D 20 +156.2 (c = 0.63, CH2Cl2).

Enantiomeric excess: 99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 8.8 min (major), t R = 11.6 min (minor).

1H NMR (400 MHz, CDCl3): δ = 8.22–8.16 (m, 1 H), 8.12 (d, J = 8.4 Hz, 2 H), 7.53–7.45 (m, 1 H), 7.44–7.34 (m, 4 H), 7.16–7.05 (m, 2 H), 6.99–6.81 (m, 2 H), 6.16 (dd, J = 3.3, 1.9 Hz, 1 H), 6.08 (d, J = 7.9 Hz, 1 H), 5.93 (d, J = 3.1 Hz, 1 H), 4.50 (d, J = 6.3 Hz, 1 H), 4.33 (d, J = 6.4 Hz, 1 H), 2.50 (s, 3 H), 2.22 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 169.36, 154.13, 147.83, 145.22, 144.82, 142.35, 136.04, 135.60, 132.08, 130.33, 130.24, 129.89, 129.71, 129.38, 129.25, 127.90, 125.73, 125.28, 123.68, 123.17, 123.03, 119.13, 111.77, 110.79, 109.93, 50.52, 37.21, 21.91, 19.88.

HRMS (ESI): m/z (M + H)+ calcd for C29H24NO4S2: 514.1147; found: 514.1149.


#

(3R,4S)-7-Methoxy-4-phenyl-3-(o-tolyl)-1-tosyl-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (3z)

The product was directly purified by flash column chromatography (PE/EtOAc 10:1) on silica gel to give 3z as a pale yellow solid; yield: 35.1 mg (65%); dr = 93:7, >99% ee; mp 94–96 °C; [α]D 20 +190.6 (c = 0.44, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 9.4 min (major), t R = 14.3 min (minor).

1H NMR (500 MHz, CDCl3): δ = 8.11 (dd, J = 10.4, 8.5 Hz, 3 H), 7.37 (d, J = 8.1 Hz, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.11–6.95 (m, 6 H), 6.77 (td, J = 7.5, 1.8 Hz, 1 H), 6.73–6.59 (m, 2 H), 6.09 (d, J = 7.9 Hz, 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.29 (d, J = 6.8 Hz, 1 H), 3.88 (s, 3 H), 2.48 (s, 3 H), 2.17 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 169.86, 158.44, 155.32, 145.72, 145.50, 136.21, 135.58, 134.74, 131.83, 131.21, 130.20, 129.76, 129.54, 129.01, 128.42, 127.97, 127.68, 125.27, 123.06, 118.90, 116.25, 112.48, 96.20, 77.41, 77.16, 76.91, 55.94, 43.30, 21.90, 19.76.

HRMS (ESI): m/z (M + H)+ calcd for C32H28NO5S: 538.1688; found: 538.1686.


#

Methyl (2R,3S)-3-(3-((4-Methylphenyl)sulfonamido)benzofuran-2-yl)-3-(m-tolyl)-2-(o-tolyl)propanoate (5)

Substrate 3p (52.1 mg, 0.1 mmol, >95:5 dr, >99% ee) and Mg (48 mg, 2.0 mmol) were charged to a Schlenk tube under N2 atmosphere, then anhyd MeOH (2.0 mL) was added. The reaction mixture was allowed to stir at 60 °C for 6 h. The reaction was quenched with sat. aq NH4Cl (3.0 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (4 × 3.0 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel FCC (PE/EtOAc 8:1) to afford the title compound 5 as a pale yellow solid; yield: 47.1 mg (85%); dr 92:8, >99% ee; mp 77–97 °C; [α]D 20 –66.2 (c = 0.59, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 9.3 min (minor), t R = 10.4 min (major).

1H NMR (500 MHz, CDCl3): δ = 7.58 (dd, J = 7.8, 1.4 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.20–7.13 (m, 3 H), 7.09 (dd, J = 13.5, 8.0 Hz, 3 H), 7.06–6.94 (m, 5 H), 6.92–6.83 (m, 3 H), 4.73–4.59 (m, 2 H), 3.37 (s, 3 H), 2.31 (s, 3 H), 2.26 (s, 3 H), 2.05 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 172.39, 153.71, 152.92, 143.81, 138.06, 137.89, 137.07, 136.77, 135.06, 130.72, 129.72, 129.32, 128.19, 128.16, 127.91, 127.55, 126.95, 126.28, 125.71, 125.65, 124.31, 122.94, 119.40, 113.66, 111.10, 52.08, 50.31, 46.23, 21.62, 21.60, 19.26.

HRMS (ESI): m/z (M + Na)+ calcd for C33H31NO5SNa: 576.1821; found: 576.1832.


#

(3R,4S)-4-(m-Tolyl)-3-(o-tolyl)-3,4-dihydrobenzofuro[3,2-b]pyridin-2(1H)-one (6)

Under N2 atmosphere, to a solution of 3p (52.1 mg, 0.1 mmol, 95:5 >dr, >99% ee) in anhyd THF (1 mL) at 0 °C was added a solution of SmI2 (0.1 M in THF, 2 mL, 0.2 mmol). The reaction mixture was stirred at 0 °C for 1 h. Then the mixture was quenched with sat. aq Na2S2O3 (1 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to afford the crude product. The crude product was purified by silica FCC (PE/EtOAc 8:1) to give 6 as a pale yellow solid; yield: 33.1 mg (90%); dr 90:10, >99% ee; mp 135–137 °C; [α]D 20 +233.2 (c = 0.41, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); t R = 5.5 min (major), t R = 7.2 min (minor).

1H NMR (400 MHz, CDCl3): δ = 9.11 (s, 1 H), 7.59–7.49 (m, 1 H), 7.44–7.37 (m, 1 H), 7.33–7.22 (m, 2 H), 7.16–7.06 (m, 2 H), 7.01–6.94 (m, 2 H), 6.93–6.83 (m, 1 H), 6.61–6.53 (m, 2 H), 6.50 (s, 1 H), 4.81 (d, J = 7.7 Hz, 1 H), 4.56 (d, J = 7.7 Hz, 1 H), 2.31 (s, 3 H), 2.12 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 170.52, 154.22, 140.93, 137.91, 136.19, 135.90, 133.10, 131.12, 130.04, 129.52, 128.93, 128.42, 128.14, 127.57, 127.21, 125.76, 125.13, 124.62, 123.00, 120.48, 119.19, 117.60, 111.96, 77.36, 77.04, 76.73, 44.23, 21.27, 19.63.

HRMS (ESI): m/z (M + H)+ calcd for C25H22NO4: 368.1651; found: 368.1642.


#

(3R,4S)-4-(m-Tolyl)-3-(o-tolyl)-1-tosyl-1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridine (7)

A solution of 3p (52.1 mg, 0.1 mmol, >95:5 dr, >99% ee) in anhyd DCM (2.0 mL) was introduced to a flame-dried Schlenk tube under N2 atmosphere, then DIBAL-H (1.0 M solution in hexane, 0.4 mL, 0.4 mmol) was added at 0 °C. The mixture was stirred for 1 h at 0 °C. The reaction mixture was quenched with MeOH and H2O and the aqueous layer was extracted with DCM (4 × 3.0 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE/EtOAc 8:1) to afford the alcohol intermediate. Under N2 atmosphere, the obtained alcohol intermediate and anhyd DCM (2.0 mL) were added to a flame-dried 10 mL Schlenk tube. Then, Et3SiH (48 μL, 0.3 mmol) was added to the reaction mixture at –78 °C, followed by BF3·OEt2 (37 μL, 0.3 mmol). The resulting solution was stirred at –78 °C for 30 min. The residue was purified by silica gel column chromatography (PE/EtOAc 8:1) to afford the title compound 7 as a pale yellow solid; yield: 45.6 mg (90%); dr >95:5, >99% ee; mp 82–84 °C; [α]D 20 –3.2 (c = 0.57, CH2Cl2).

Enantiomeric excess: >99%, determined by HPLC (Daicel Chirapak IC, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): t R = 21.48 min (major), t R = 24.5 min (minor).

1H NMR (500 MHz, CDCl3): δ = 7.54–7.49 (m, 2 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 7.25–7.03 (m, 9 H), 7.00–6.90 (m, 2 H), 6.80 (dd, J = 7.9, 1.4 Hz, 1 H), 4.40 (d, J = 11.4 Hz, 1 H). 3.99 (ddd, J = 11.8, 7.6, 4.8 Hz, 1 H), 3.64 (qd, J = 11.2, 6.2 Hz, 2 H), 2.37 (s, 3 H), 2.37 (s, 3 H), 2.15 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 155.51, 152.81, 143.73, 138.54, 138.31, 138.24, 137.85, 136.73, 130.70, 129.62, 129.50, 128.46, 128.17, 127.48, 127.00, 126.20, 126.08, 125.63, 124.02, 122.80, 118.85, 112.87, 111.12, 65.05, 46.28, 45.58, 21.63, 21.59, 19.44.

HRMS (ESI): m/z (M + H)+ calcd for C32H30NO3S: 368.1651; found: 368.1642.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

MS acknowledges to the CAS-TWAS fellowship for financial support.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0043-1763679.
  • Supporting Information

Corresponding Authors

Zhi-Yong Han
Department of Chemistry, University of Science and Technology of China
Hefei 230026
P. R. China   

Mostafa Sayed
Chemistry Department, Faculty of Science, New Valley University
El-Kharja 72511
Egypt   

Publication History

Received: 27 November 2023

Accepted after revision: 22 January 2024

Article published online:
13 February 2024

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Zoom Image
Scheme 1 Different approaches for asymmetric construction of benzofuro[3,2-b]pyridines
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Scheme 2 Substrate scope of aryl bromides. Reagents and conditions: 1 (0.3 mmol), 2a (0.1 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.011 mmol), 4b (0.02 mmol), i-Pr2NEt (0.4 mmol), THF (1.0 mL), under CO (1 bar) at 30 °C. Isolated yields of both diastereoisomers are given. The dr value was determined by1H NMR analysis of the crude reaction mixture and the ee was determined by HPLC analysis.
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Scheme 3 Substrate scope of azadienes. Reagents and conditions: 1 (0.3 mmol), 2a (0.1 mmol), [Pd(allyl)Cl]2 (0.01 mmol), Xantphos (0.011 mmol), 4b (0.02 mmol), iPr2NEt (0.4 mmol), THF (1.0 mL), under CO (1 bar) at 30 °C. Isolated yields of both diastereoisomers are shown. The dr value was determined by 1H NMR analysis of the crude reaction mixture and the ee was determined by HPLC analysis.
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Scheme 4Gram-scale reaction and synthetic applications
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Scheme 5Proposed reaction mechanism