Double-Oxidative Dehydrogenative (DOD) [4+2]-Cyclization

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Double-Oxidative Dehydrogenative (DOD) [4+2]-Cyclization/Dehydrogenation/ Oxygenation Tandem Reaction of N-Arylglycine Derivatives with Cumenes Wei Jiang, Shuocheng Wan, Yingpeng Su, and Congde Huo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00506 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 28, 2019

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The Journal of Organic Chemistry

Double-Oxidative Dehydrogenative (DOD) [4+2]Cyclization/Dehydrogenation/Oxygenation Tandem Reaction of N-Arylglycine Derivatives with Cumenes Wei Jiang, Shuocheng Wan, Yingpeng Su, Congde Huo* Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education; College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China.

Ar' +

KEYWORDS:

O

- 8H, and +1O

Ar N H

Ar'

Ar

R

R

N O

O

N-arylglycine derivatives;

cumenes; one electron oxidation; oxidative

dehydrogenation; cyclization ABSTRACT: Double-oxidative dehydrogenative (DOD) cyclization is one of the most straightforward strategies for cyclic compounds synthesis. A novel approach to substituted 3,4dihydroquinoline-3-one derivatives via a Cu(II)/DDQ/O2 system-catalyzed DOD [4+2]cyclization/dehydrogenation/oxygenation

cascade

reaction

of

N-arylglycine

derivatives,

cumenes, and O2 has been developed.

ACS Paragon Plus Environment

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C–H bonds are ubiquitous in organic molecules and C–H functionalization has become useful tool in organic synthesis and sustainable alternatives to well established methodologies. Oxidative dehydrogenative coupling has attracted much attention and seen explosive growth in recent years. In simple terms, it means coupling of an X–H bond (X: carbon or hetero-atom) with a Y–H bond (Y: carbon or hetero-atom) directly to construct X–Y bond. Actually, C–C bond formation using this protocol has a long history dating back to the middle of the 20th century, Eglinton reaction reported in 1956 and Fujiwara-Moritani reaction reported in 1967, for examples.1 However, this kind of reaction has not been paid enough attention until 21st century. Recently, following the prevalence of the concepts of green chemistry, such as atom economy and step economy, Oxidative dehydrogenative coupling reactions have become a rapidly growing field in organic chemistry.2 The transfer of an electron (single electron transfer, SET) is the simplest elemental reaction in chemistry. One electron oxidation (OEO), ionized an electron from neutral organic compounds to form radical cation intermediates, changes the structure and reactivity of organic molecules apparently.3 When an organic molecule is oxidized to its radical cation, the -C–H bond will be significantly weakened and its acidity will be remarkably increased.4 According to this principle, OEO involved oxidative dehydrogenative C–H functionalization has become a valuable synthetic approach in the last decade.5 Povarov reaction is a powerful method for the synthesis of quinoline skeletons using aromatic imines and alkenes as substrates.6 Glycine is the simplest natural amino acid and can be manufactured industrially by treating chloroacetic acid with ammonia. In 2011, Mancheño et al developed an oxidative dehydrogenative Povarov/aromatization tandem reaction of Narylglycine derivatives with alkenes.7 Very recently, we proposed the concept of the double-


2

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oxidative dehydrogenative (DOD) cyclization which constructs two C−C bonds from four C−H bonds to construct a cycle directly (Scheme 1a).8 It represents one of the most straightforward and atom-economical methods for cyclic structure formation. In 2018, we reported a Cu(II)/DDQ/O2 system-catalyzed DOD [4+2]-annulation/oxidative aromatization tandem reaction of glycine derivatives with ethylbenzene (EB) derivatives (Scheme 1b).8a The oxidative Povarov reaction was advanced to a new level. In this transformation, a cascade oxidative aromatization reaction occurred after DOD cyclization and quinoline-2-carboxylate derivatives were obtained. Cumene (or isopropylbenzene, IPB) is one of the cheapest and most readily available organic solvents.9 We envisioned that replacement of the EB with IPB could inhibit the subsequently aromatization because the benzylic carbon of IPB is a 3o carbon atom which made the following aromatization impossible. Scheme 1. Design of Double-Oxidative Dehydrogenative (DOD) Annulations General Idea of Dual-Oxidative Dehydrogenative (DOD) Cyclization:

H H H H a)

-4H

b) previous work: benzylic C of akylbenzene is a 2o C. Ar'

Ar

DOD Povarov reaction

+ N H

Ar'

Ar'

2o

R

Aromatization Ar N H

O

R

O2

Ar

R

N O

O

c) this work: Ar' Ar'

Ar

CuBr2, DDQ, O2

+ N H

R O

o

80 C

O Ar

R

N O

Herein, we report the discovery of an OEO involved method for the synthesis of 3,4dihydroquinoline-3-one via a tandem DOD [4+2] cyclization/dehydrogenation/oxygenation reaction of N-Arylglycines with IPBs using an copper(II) salt as the catalyst and DDQ and O2 as the oxidants (Scheme 1c).


3


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Table 1. Screening of Reaction Conditions 2a +

O

1a entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 c 17 18 19

N H

Conditionsa

O

O

O

O

N 3aa

O

catalyst

loading

oxidant

CuCl2 CuCl CuBr2 CuBr Cu(OAc)2 FeCl3 FeCl2 Fe(OAc)2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2

10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 5 mol % 15 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol % 10 mol %

DDQ DDQ DDQ DDQ DDQ DDQ DDQ DDQ DDQ DDQ PBQ TBHP DTBP mCPBA oxone DDQ DDQ DDQ DDQ

O

atmosphere temperature (oC) 3aa yield (%) O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 air Ar O2 O2

80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 90 70

b

60 53 66 56 36 38 34 47 58 61 trace 0 0 0 0 53 0 62 51

[a] Reaction Conditions: 1a (0.5 mmol), 2a (1.2 mL), oxidant (1.5 mmol), atmosphere (O2 balloon), 8 h, 80 oC (oil bath). [b] Isolated Yields. [c] 20 h.

We

began

our

investigation

with

the

oxidative

cyclization

of

methyl

(4-

methoxyphenyl)glycinate (1a) and IPB (2a) with catalytic amount of redox-active metal salts in the presence of 3 equivalents of DDQ and 1 atm of O2 as the oxidant at 80 oC. After an extensive catalyst screening, CuBr2 was proven to be optimal to give product 3aa in 66% isolated yield (Table 1, entries 1-8). When the copper loading was reduced (5 mol %) or increased (15 mol %), desired product 3aa was obtained in lower yields (Table 1, entries 9-10). The oxidant species was screened then. DDQ was found to be the most suitable oxidant (Table 1, entries 11-15). A lower yield was observed when air (open flask) was used instead of pure oxygen gas (balloon) (Table 1, entry 16). Control experiments indicated that none of the desired reaction was observed under an argon atmosphere (Table 1, entry 17). Further survey of the reaction temperature indicated that both increasing and decreasing the temperature resulted in lower yields (Table 1, entries 18-19).


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Scheme 2. Tandem DOD [4+2]-Cyclization/Dehydrogenation/Oxygenation Reaction of Glycine Derivatives (1) with IPB Derivatives (2)a,b Ar'

2

Ar'

+ N H

1

O

R

O

O

O

O

O

O O

O 3ca (67%)

O

O

O

O

N

O

3ea (61%)

O

O O

3fa (59%)

O

O

O

O

N

O

O H

3ha (48%)

H

O

O H N

O

O

O H N

O

O O

O

O O

O 3ra (54%)

O

O O

N

O

O 3ua (51%)

3ta (53%)

F

O O

O

Cl

O

O

N

O

N

O

O

O

3wa (48%)

3va (52%)

I

O O

N

O

N

O

3sa (53%)

N

O

N

O

O

O

3oa (56%)

3qa (66%)

O

O

O

O N

3pa (68%)

N

H N

N

3na (60%)

O

3xa (52%)

O O

N O

O 3za (45%)

Br

O

O H N

O

3ma(58%)

3ya (50%)

3la (55%)

O N

O

N

H N O

3ka (60%)

N

Br

O N

O

3ja (61%)

O

O H N

N

O

O

3ia (56%)

O

H

N

H N

N

O

3ga (56%)

O

O

N

O

O 3da (65%)

N

O

N

O 3ba (64%)

N

O

O

N

3aa (66%)

O

R

N 3

O

O

Ar

O

O

O N

O

CuBr2, DDQ, O2

Ar

O

I

O

O O

N

O

O O

N

O

O

O

3ab (51%)

O

N O

O 3ad (42%)

3ac (54%)

Br

O

O

O O

N

O O

N O

O 3ae (53%)

3af (48%)

[a] Reaction Conditions for cumene 2a: 1 (0.5 mmol), 2a (1.2 mL), CuBr2 (10 mol %), DDQ (1.5 mmol), O2 (balloon), 8-24 h, 80 oC (oil bath). Reaction Conditions for substituted IPBs 2b-f: 1 (0.5 mmol), 2 (0.75 mmol), toluene (1.2 mL), CuBr2 (10 mol %), DDQ (1.5 mmol), O2 (balloon), 8-24 h, 80 oC (oil bath). [b] Isolated Yields.


5


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With the best reaction conditions in hand, we examined the scope of the reaction with respect to the N-arylglycine derivatives partner. Firstly, as shown in Scheme 3, a range of N-arylglycine esters and also amides could be smoothly transformed into the corresponding products 3aa-3na in good yields. It is worth mentioning that dipeptide 1o was also successfully converted into the desired product 3oa in good yield. And notably, a glycine ester with a more elaborate molecular architecture, for example, the (+)-dehydroisoandrosterone (DHEA) derivative, was also a suitable substrate and afforded the corresponding product 3ha in high yield. Above two examples help demonstrate the value of this method in providing rapid access to complex molecules. These products may also have potential utility in pharmaceutical chemistry. We next turned our attention to glycine esters bearing different N-aryl groups. When the aromatic ring on the N-arylglycine ester was substituted with electron-donating groups, the reactions provided desirable 3,4-Dihydroquinoline-3-ones 3pa-3va in high yields. We then evaluated substrates substituted with electron-withdrawing groups such as halogen atoms. The reactions of 1w-1z provided desired products 3wa-3za in moderate to good yields. Glycine derivatives without para substituent groups gave complex reaction mixture. The scope of the reaction with respect to the IPB substrates was then evaluated. A range of IPB derivatives smoothly delivered the corresponding cyclization products in moderate to good yields. Furthermore, we were pleased to find that substrate 2d derived from (+)-menthol was suitable substrates for the reaction, affording the desired product 3ad in 42% yield. This example also helps demonstrate the value of this method in providing rapid access to complex compounds. Scheme 3. Scalability of the Reaction to the Multi-Gram Scale. 2a (160 mL) O

CuBr2, DDQ, O2

+ N H 1a (13.1 g)

O O

O

O

80 oC, overnight 50 %

N

O

3aa (10.8 g) O


6

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To demonstrate the applicability of this DOD method in organic synthesis, we carried out the reaction on a 10-gram scale under the standard reaction conditions. The desired annulation product 3aa was obtained in 50% yield without further optimization (Scheme 3). Scheme 4. Control Experiments

Cu, DDQ, O2, TEMPO

O

1a

N H

1a

N H

O

+

O

X

2a

N 3aa (0%) O

O

Cu, DDQ, Ar

O O

+

1a

O

+

N 3aa (0%) O

Cu, O2

C

O

+

2a

Cu, DDQ, O2

O

3aa (63%)

Cu, O2

B

O

+

C

O

N

O

N

O

O

80oC

O

O

N 3aa (62%)

O

N

O

O

80oC

O

O

O

80 oC

O

O

B

O

X

2a

O N H

O

80 oC

O

O

O

80oC

O

N

O

3aa (77%)

O

intermediates detected by HRMS (after 4 h under standard reaction conditions) O OMe

N B

O

C10H11NNaO3 [M+Na] m/z 216.0631 found 216.0630

C9H11 [M+H] m/z 119.0855 found 119.0854 C

O

D

N H

O

OMe

O

OMe O


O

O

H

C19H20NO3 [M+H] m/z 310.1438 found 310.1439

O

E

OOH

OMe

N

O

N F

C19H22NO3 [M+H] m/z 312.1594 found 312.1594

N H

OMe


O

To further probe the mechanism of this cascade reaction, several control experiments were conducted. When TEMPO (3 equiv) was included in the reaction mixture containing 1a and 2a, no desired product 3aa was obtained under standard reaction conditions, which suggests that a SET pathway was involved in the reaction. The reaction of 1a and 2a under an argon atmosphere


7


Page 8 of 29

was investigated, and none of the desired product 3aa was obtained. This result indicates that oxygen is crucial for the reaction. O2 act as both the oxidant and the oxygen source in this transformation. To detect the active intermediates of this transformation, an in situ HRMS experiment of the template reaction of 1a with 2a was conducted. Fortunately, through data analysis, the signals of imine B, alkene C, tetrahydroquinoline D, dihydroquinoline E, peroxide F and dihydroquinolinone H were found. This result indicates B, C, D, E, F, H may be intermediates of the reaction. To assess this possibility, we studied the reaction of 1a with alkene C, the reaction of imine B with 2a, and the reaction of imine B with alkene C. As expected, under the optimal reaction conditions, 3aa was obtained in a yield similar to that for the reaction of 1a with 2a. These experiments confirmed the intermediacy of B and C. Scheme 5. Proposed Mechanism

O2

O O

N

E

2a O

C CuBr2, O2

N H 1a

O

O O

O

3aa

O

OOH N H

- H 2O

O

O

O O

O

N

O2

path B

O

O

O

O2

G

- H 2O

O N H

O

N B

path A

O D

O O

O2 [4+2]

OOH N

F

O DDQ

O

H

O N H

O O

On the basis of the above mentioned control experiments, as well as previously reported results, a plausible mechanism was outlined in Scheme 5 using glycine ester 1a and IPB 2a as model substrates. Firstly, glycine ester 1a is oxidized to imine B under copper-catalyzed aerobic conditions through an OEO process. And on the other hand, IPB 2a was oxidized to alkene C in the presence of DDQ as the oxidant through an OEO process too. Subsequently, the reactive intermediates B and C undergo an imino-Diels-Alder reaction to afford the corresponding tetrahydroquinazoline intermediate D. There are two possible pathways from D to the product


8

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3aa. Path A: secondary amine D was oxidized to generate dihydroquinoline E. Subsequently, the 3-postion C–H bond adjacent to nitrogen atom of intermediate E was further oxidized by O2 to deliver peroxide F. Finally, the desired 3,4-dihydroquinoline-3-one 3aa was afforded by the dehydration of intermediate F. Path B: the 3-postion C–H bond adjacent to nitrogen atom of intermediate D was further oxidized by O2 to deliver peroxide G. Subsequently, elimination of water occurred to afford desired dihydroquinolinone H. Finally, the desired 3,4dihydroquinoline-3-one 3aa was afforded by the dehydrogenation of intermediate H. In conclusion, we have developed a novel Cu(II)/DDQ/O2-catalyzed [4+2] annulation between N-arylglycine derivatives and IPB derivatives. The reaction involves a sequential double oxidative

dehydrogenation/[4+2]

cycloaddition/oxidative

dehydrogenation/oxygenation

procedure and provides a new and efficient method for the construction of complex 3,4Dihydroquinoline-3-ones in an atom-economic manner. This transformation is highly efficient with the removal of eight H atoms and introduction of one O atom, including the functionalization of four C–H bonds. The reaction involves easily available starting materials, mild reaction conditions, broad substrate scope and simple operation. Significantly, this reaction can be carried out in 10-gram scale by simply increasing the size of the bottle. One more successful proof of DOD concept was presented in this article, which may inspire people to investigate with DOD cyclization strategy to the larger range of substrate classes.


9


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EXPERIMENTAL SECTION General Information The starting materials, reagents and solvents, purchased from commercial suppliers, were used without further purification. Literature procedures were used for the preparation of glycine derivatives 1a-1z10 and isopropylbenzene derivative 2d.11 Analytical TLC was performed with silica gel GF254 plates, and the products were visualized by UV detection. Flash chromatography was carried out using silica gel 200−300. 1H NMR (600 MHz) and

13C{1H}

NMR (150 MHz) spectra were measured with CDCl3 as solvent. All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. High resolution mass spectra (HR-MS) were recorded under electrospray ionization (ESI-TOF) conditions.

General Procedure for Tandem DOD [4+2]-Cyclization/Dehydrogenation/Oxygenation Reaction of Glycine Derivatives (1) with IPB Derivatives (2) to Construct 3,4Dihydroquinoline-3-ones. To a 10 mL reaction tube with a magnetic stirring bar, CuBr2 (0.05 mmol), DDQ (1.5 mmol) and isopropylbenzene derivatives (2, 1.2 mL) were added successively. The resulting reaction mixture was performed at 80 oC in oil bath for 3 hours. Glycine derivatives (1, 0.5 mmol) was added. The solution was then stirred under an oxygen atmosphere (balloon) at 80 oC in oil bath and completed within 5-21 hours as monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to afford the desired compounds 3 (ethyl acetate/petroleum ether = 1:20 to 1:10).


10

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Characterization of the substrates and productsMethyl (4-methoxyphenyl)glycinate (1a). The desired pure product was obtained in 89% yield (867.8 mg) as a white solid; mp 82–84 °C; 1H

NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9 Hz, 2H), 4.02 (brs, 1H),

3.87 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.9, 152.7, 141.2, 114.9, 114.4, 55.7, 52.1, 46.6; HRMS (ESI-TOF) exact mass calcd for C10H13NNaO3 [M+Na] m/z 218.0788, found 218.0793. Ethyl (4-methoxyphenyl)glycinate (1b). The desired pure product was obtained in 85% yield (888.7 mg) as a white solid; mp 46–48 °C; 1H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.93 (brs, 1H), 3.84 (s, 2H), 3.73 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.4, 152.6, 141.3, 114.9, 114.4, 61.2, 55.7, 46.8, 14.2; HRMS (ESI-TOF) exact mass calcd for C11H15NNaO3 [M+Na] m/z 232.0944, found 232.0945. Isopropyl (4-methoxyphenyl)glycinate (1c). The desired pure product was obtained in 86% yield (959.4 mg) as a light yellow liquid; 1H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 5.13 – 5.04 (m, 1H), 3.99 (brs, 1H), 3.81 (s, 2H), 3.73 (s, 3H), 1.25 (d, J = 6.3 Hz, 6H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.9, 152.6, 141.4, 114.9, 114.3, 68.8, 55.7, 47.0, 21.8; HRMS (ESI-TOF) exact mass calcd for C12H17NNaO3 [M+Na] m/z 246.1101, found 246.1098. Tert-butyl (4-methoxyphenyl)glycinate (1d). The desired pure product was obtained in 79% yield (936.7 mg) as a light yellow solid; mp 31–33 °C; 1H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 4.00 (brs, 1H), 3.75 (s, 2H), 3.74 (s, 3H), 1.47 (s, 9H); 13C{1H}

NMR (151 MHz, CDCl3) δ 170.5, 152.5, 141.5, 114.9, 114.3, 81.8, 55.7, 47.5, 28.1;

HRMS (ESI-TOF) exact mass calcd for C13H19NNaO3 [M+Na] m/z 260.1257, found 260.1266. Butyl (4-methoxyphenyl)glycinate (1e). The desired pure product was obtained in 83% yield (984.1 mg) as a light yellow solid; mp 32–34 °C; 1H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9 Hz, 2H), 4.17 (t, J = 6.7 Hz, 3H), 4.02 (brs, 1H), 3.85 (s, 2H), 3.74 (s, 3H), 1.66 – 1.59 (m, 2H), 1.40 – 1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H);

13C{1H}

NMR (151

MHz, CDCl3) δ 171.5, 152.6, 141.3, 114.9, 114.4, 65.1, 55.7, 46.8, 30.6, 19.0, 13.6; HRMS (ESI-TOF) exact mass calcd for C13H19NNaO3 [M+Na] m/z 260.1257, found 260.1263. Allyl (4-methoxyphenyl)glycinate (1f). The desired pure product was obtained in 82% yield (906.5 mg) as a light yellow liquid; 1H NMR (600 MHz, CDCl3) δ 6.79 (d, J = 8.9 Hz, 2H), 6.59


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(d, J = 8.8 Hz, 2H), 5.94 – 5.88 (m, 1H), 5.32 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 5.8 Hz, 2H), 3.90 (s, 2H), 3.74 (s, 3H), 3.55 (brs, 1H);

13C{1H}

NMR (151 MHz,

CDCl3) δ 171.1, 152.7, 141.2, 131.6, 118.8, 114.9, 114.4, 65.8, 55.7, 46.8; HRMS (ESI-TOF) exact mass calcd for C12H15NNaO3 [M+Na] m/z 244.0944, found 244.0947. Benzyl (4-methoxyphenyl)glycinate (1g). The desired pure product was obtained in 75% yield (1016.7 mg) as a whie solid; mp 70–72 °C; 1H NMR (600 MHz, CDCl3) δ 7.40 – 7.32 (m, 5H), 6.79 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.21 (s, 2H), 4.05 (brs, 1H), 3.92 (s, 2H), 3.75 (s, 3H);

13C{1H}

NMR (151 MHz, CDCl3) δ 171.3, 152.7, 141.2, 135.4, 128.6, 128.5, 128.4,

114.9, 114. 4, 66.9, 55.7, 46. 9; HRMS (ESI-TOF) exact mass calcd for C16H17NNaO3 [M+Na] m/z 294.1101, found 294.1103. (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl

(4-methoxyphenyl)glycinate

(1h).

The

desired pure product was obtained in 35% yield (789.7 mg) as a whie solid; mp 188–190 °C; 1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 5.42 – 5.38 (m, 1H), 4.73 – 4.65 (m, 1H), 4.00 (brs, 1H), 3.83 (s, 2H), 3.72 (s, 3H), 2.51 – 2.40 (m, 1H), 2.39 – 2.29 (m, 2H), 2.15 – 2.03 (m, 2H), 1.97 – 1.82 (m, 4H), 1.70 – 1.45 (m, 7H), 1.33 – 1.24 (m, 2H), 1.19 – 1.10 (m, 1H), 1.04 (s, 3H), 0.87 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 220.8, 170.7, 152.6, 141.3, 139.6, 122.1, 114.9, 114.4, 74.7, 55.7, 51.7, 50.1, 47.5, 47.1, 38.0, 36.8, 36.7, 35.8, 31.4, 31.4, 30.7, 27.6, 21.8, 20.3, 19.3, 13.5; HRMS (ESI-TOF) exact mass calcd for C28H37NNaO4 [M+Na] m/z 474.2615, found 474.2606. 2-((4-methoxyphenyl)amino)-N-methylacetamide (1i) The desired pure product was obtained in 72% yield (698.8 mg) as a brown solid, mp 123–125 °C. 1H NMR (600 MHz, CDCl3) δ 6.81 (brs, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.9 Hz, 2H), 3.99 (brs, 1H), 3.74 (s, 3H), 3.73 (s, 2H), 2.82 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.4, 153.2, 141.2, 115.0, 114.3, 55.7, 49.6, 25.9. HRMS (ESI-TOF) exact mass calcd for C10H14N2NaO2 [M+Na] m/z 217.0947, found 217.0952. N-ethyl-2-((4-methoxyphenyl)amino)acetamide(1j). The desired pure product was obtained in 71% yield (738.8 mg) as a brown solid; mp 73–75 °C; 1H NMR (600 MHz, CDCl3) δ 6.81 (brs, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.01 (brs, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 3.34 – 3.28 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H);

13C{1H}

NMR (151 MHz, CDCl3) δ 170.5, 153.1,


12

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141.3, 114.9, 114.4, 55.7, 49.8, 34.0, 14.8; HRMS (ESI-TOF) exact mass calcd for C11H16N2NaO2 [M+Na] m/z 231.1104, found 231.1108. 2-((4-methoxyphenyl)amino)-N-propylacetamide (1k). The desired pure product was obtained in 71% yield (788.6 mg) as a brown solid; mp 54–56 °C; 1H NMR (600 MHz, CDCl3) δ 6.84 (brs, 1H), 6.78 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.02 (brs, 1H), 3.74 (s, 3H), 3.72 (s, 2H), 3.25 – 3.20 (m, 2H), 1.52 – 1.45 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H);

13C{1H}

NMR (151 MHz,

CDCl3) δ 170.6, 153.1, 141.3, 114.9, 114.4, 55.7, 49.8, 40.8, 22.8, 11.3; HRMS (ESI-TOF) exact mass calcd for C12H18N2NaO2 [M+Na] m/z 245.1260, found 245.1255. N-butyl-2-((4-methoxyphenyl)amino)acetamide (1l). The desired pure product was obtained in 73% yield (861.9 mg) as a brown solid; mp 63–65 °C; 1H NMR (600 MHz, CDCl3) δ 6.86 (brs, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 4.15 (brs, 1H), 3.71 (s, 3H), 3.68 (s, 2H), 3.24 (q, J = 13.5, 6.8 Hz, 2H), 1.45 – 1.38 (m, 2H), 1.29 – 1.21 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); 13C{1H}

NMR (151 MHz, CDCl3) δ 170.7, 153.0, 141.4, 141.4, 114.9, 114.3, 55.7, 49.7, 38.8,

31.6, 20.0, 13.7; HRMS (ESI-TOF) exact mass calcd for C13H20N2NaO2 [M+Na] m/z 259.1417, found 259.1421. N-(tert-butyl)-2-((4-methoxyphenyl)amino)acetamide (1m). The desired pure product was obtained in 72% yield (850.1 mg) as a brown solid; mp 88–90 °C; 1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.9 Hz, 2H), 6.66 (brs, 1H), 6.55 (d, J = 8.9 Hz, 2H), 4.13 (brs, 1H), 3.73 (s, 3H), 3.59 (s, 2H), 1.32 (s, 9H); 13C NMR (151 MHz, CDCl3) δ 169.9, 153.0, 141.5, 141.4, 114.9, 114.4, 55.7, 50.8, 50.5, 28.6; HRMS (ESI-TOF) exact mass calcd for C13H20N2NaO2 [M+Na] m/z 259.1417, found 259.1420. N-benzyl-2-((4-methoxyphenyl)amino)acetamide (1n). The desired pure product was obtained in 68% yield (918.5 mg) as a brown solid; mp 78–80 °C; 1H NMR (600 MHz, CDCl3) δ 7.30 – 7.23 (m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 7.16 (brs, 1H), 6.78 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.02 (brs, 1H), 3.78 (s, 2H), 3.74 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 170.7, 153.2, 141.1, 138.1, 128.6, 127.6, 127.4, 115.0, 114.5, 55.7, 49.7, 43.1; HRMS (ESI-TOF) exact mass calcd for C16H18N2NaO2 [M+Na] m/z 293.1260, found 293.1258. 2-((4-methoxyphenyl)amino)-N-(2-oxopentyl)acetamide (1o). The desired pure product was obtained in 78% yield (1037.9 mg) as a brown solid; mp 102–104 °C;

1H

NMR (600 MHz,

CDCl3) δ 7.28 (brs, 1H), 6.78 (d, J = 7.8 Hz, 2H), 6.58 (d, J = 7.9 Hz, 2H), 4.17 (q, J = 6.0 Hz, 2H), 4.03 (d, J = 4.8 Hz, 2H), 3.79 (brs, 1H), 3.78 (s, 2H), 3.73 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H);


13


13C{1H}

Page 14 of 29

NMR (151 MHz, CDCl3) δ 171.3, 169.6, 153.2, 141.2, 114.9, 114.5, 61.4, 55.7, 49.6,

41.0, 14.1; HRMS (ESI-TOF) exact mass calcd for C13H18N2NaO4 [M+Na] m/z 289.1159, found 289.1155. Methyl (4-ethoxyphenyl)glycinate (1p). The desired pure product was obtained in 83% yield (867.8 mg) as a white solid; mp 73–75 °C; 1H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 3.97 (brs, 1H), 3.94 (q, J = 7.0 Hz, 2H), 3.86 (s, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.9, 151.9, 141.2, 115.7, 114.3, 64.0, 52.1, 46.6, 15.0; HRMS (ESI-TOF) exact mass calcd for C11H15NNaO3 [M+Na] m/z 232.0944, found 232.0943. Methyl (4-phenoxyphenyl)glycinate (1q). The desired pure product was obtained in 82% yield (1054.2 mg) as a white solid; mp 87–89 °C; 1H NMR (600 MHz, CDCl3) δ 7.28 (t, J = 8.0 Hz, 2H), 7.04 – 7.00 (m, 1H), 6.96 – 6.90 (m, 4H), 6.61 (d, J = 8.8 Hz, 2H), 4.24 (brs, 1H), 3.91 (s, 2H), 3.79 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.6, 158.9, 148.4, 143.6, 129.5, 122.1, 121.2, 117.3, 114.0, 52.2, 46.2; HRMS (ESI-TOF) exact mass calcd for C15H15NNaO3 [M+Na] m/z 280.0944, found 280.0949. Methyl p-tolylglycinate (1r). The desired pure product was obtained in 85% yield (761.2 mg) as a white solid; mp 81–83 °C; 1H NMR (600 MHz, CDCl3) δ 7.00 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 8.3 Hz, 2H), 4.13 (brs, 1H), 3.89 (s, 2H), 3.77 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 144.7, 129.8, 127.5, 113.2, 52.2, 46.1, 20.4; HRMS (ESI-TOF) exact mass calcd for C10H13NNaO2 [M+Na] m/z 202.0838, found 202.0835. Methyl (4-ethylphenyl)glycinate (1s). The desired pure product was obtained in 83% yield (801.4 mg) as a yellow solid; mp 35–37 °C; 1H NMR (600 MHz, CDCl3) δ 7.04 (d, J = 6.7 Hz, 2H), 6.57 (d, J = 8.2 Hz, 2H), 4.17 (brs, 1H), 3.91 (s, 2H), 3.78 (s, 3H), 2.56 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171. 8, 144.9, 134.1, 128.6, 113.2, 52.2, 46.0, 27.9, 15.9; HRMS (ESI-TOF) exact mass calcd for C11H15NNaO2 [M+Na] m/z 216.0995, found 216.0995. Methyl (4-isopropylphenyl)glycinate (1t). The desired pure product was obtained in 83% yield (859.6 mg) as a colorless solid; mp 36–38 °C; 1H NMR (600 MHz, CDCl3) δ 7.08 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 4.15 (brs, 1H), 3.91 (s, 2H), 3.78 (s, 3H), 2.86 – 2.78 (m, 1H), 1.22 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 145.0, 138.8, 127.2, 113.1, 52.2,


14

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46.0, 33.2, 24.2; HRMS (ESI-TOF) exact mass calcd for C12H17NNaO2 [M+Na] m/z 230.1151, found 230.1150. Methyl (4-butylphenyl)glycinate (1u). The desired pure product was obtained in 76% yield (840.3 mg) as a colorless solid; mp 35–37 °C; 1H NMR (600 MHz, CDCl3) δ 7.01 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.2 Hz, 2H), 4.23 (brs, 1H), 3.90 (s, 2H), 3.77 (s, 3H), 2.50 (t, J = 7.7 Hz, 2H), 1.58 – 1.51 (m, 2H), 1.37 – 1.30 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);

13C{1H}

NMR (151 MHz,

CDCl3) δ 171.8, 144.8, 132.8, 129.2, 113.1, 52.2, 46.1, 34.7, 33.9, 22.3, 14.0; HRMS (ESI-TOF) exact mass calcd for C13H19NNaO2 [M+Na] m/z 244.1308, found 244.1303. Methyl (4-(tert-butyl)phenyl)glycinate (1v). The desired pure product was obtained in 78% yield (862.4 mg) as a colorless solid; mp 74–76 °C; 1H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 4.20 (brs, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 1.31 (s, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 144.6, 141.0, 126.1, 112. 8, 52.2, 46.0, 33. 9, 31.5; HRMS (ESI-TOF) exact mass calcd for C13H19NNaO2 [M+Na] m/z 244.1308, found 244.1309. Methyl (4-fluorophenyl)glycinate (1w). The desired pure product was obtained in 72% yield (659.1 mg) as a gray solid; mp 88–90 °C; 1H NMR (600 MHz, CDCl3) δ 6.92 – 6.87 (m, 2H), 6.56 – 6.52 (m, 2H), 4.16 (brs, 1H), 3.87 (s, 2H), 3.77 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 171.5, 156.3 (d, J = 235.8 Hz), 143.3, 115.8 (d, J = 22.5 Hz), 113.9 (d, J = 7.5 Hz), 52.2, 46.2; HRMS (ESI-TOF) exact mass calcd for C9H10FNNaO2 [M+Na] m/z 206.0588, found 206.0592. Methyl (4-chlorophenyl)glycinate (1x). The desired pure product was obtained in 73% yield (726.5 mg) as a gray solid; mp 117–119 °C; 1H NMR (600 MHz, CDCl3) δ 7.13 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 4.25 (brs, 1H), 3.88 (s, 2H), 3.78 (s, 3H);

13C{1H}

NMR (151

MHz, CDCl3) δ 171.3, 145.5, 129.2, 122.9, 114.0, 52.3, 45.7; HRMS (ESI-TOF) exact mass calcd for C9H10ClNNaO2 [M+Na] m/z 222.0292, found 222.0296. Methyl (4-bromophenyl)glycinate (1y). The desired pure product was obtained in 71% yield (862.6 mg) as a white solid; mp 112–114 °C; 1H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 8.8 Hz, 2H), 6.48 (d, J = 8.8 Hz, 2H), 4.29 (brs, 1H), 3.87 (s, 2H), 3.78 (s, 3H);

13C{1H}

NMR (151

MHz, CDCl3) δ 171.2, 145.9, 132.0, 114.5, 110.0, 52.3, 45.6; HRMS (ESI-TOF) exact mass calcd for C9H10BrNNaO2 [M+Na] m/z 265.9787, found 265.9780. Methyl (4-iodophenyl)glycinate (1z). The desired pure product was obtained in 65% yield (945.7 mg) as a light red solid; mp 107–108 °C; 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 8.7 Hz, 2H), 4.30 (brs, 1H), 3.87 (s, 2H), 3.78 (s, 3H);

13C{1H}

NMR (151 MHz,


15


Page 16 of 29

CDCl3) δ 171.2, 146.5, 137.9, 115.1, 79.1, 52.3, 45.4; HRMS (ESI-TOF) exact mass calcd for C9H10INNaO2 [M+Na] m/z 313.9648, found 313.9644. (1S,2S,5S)-2-isopropyl-5-methylcyclohexyl 4-isopropylbenzoate (2d). The desired pure product was obtained in 95% yield (1435.6 mg) as a colorless liquid; 1H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.96 – 4.86 (m, 1H), 3.00 – 2.90 (m, 1H), 2.11 (d, J = 11.9 Hz, 1H), 1.99 – 1.93 (m, 1H), 1.72 (d, J = 11.6 Hz, 2H), 1.59 – 1.51 (m, 2H), 1.26 (d, J = 6.9 Hz, 6H), 1.15 – 1.05 (m, 3H), 0.91 (t, J = 7.3 Hz, 6H), 0.78 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.1, 154.1, 129.7, 128.5, 126.4, 74.5, 47.3, 41.0, 34.3, 34.2, 31.4, 26.5, 23.7, 23.7, 23.7, 22.0, 20.8, 16.5; HRMS (ESI-TOF) exact mass calcd for C20H30NaO2 [M+Na] m/z 325.2138, found 325.2136. Methyl 6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3aa). The desired pure product was obtained in 66% yield (106.6 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 1H), 7.27 – 7.22 (m, 3H), 7.00 – 6.97 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.84 (d, J = 2.7 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 1.84 (s, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.4, 163.2, 162.2, 148.0, 140.6, 139.0, 133.9, 133.8, 128.9, 128.0, 127.3, 114.8, 112.8, 55.7, 55.6, 52.9, 22.4; HRMS (ESI-TOF) exact mass calcd for C19H17NNaO4 [M+Na] m/z 346.1050, found 346.1055. Ethyl 6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3ba).12 The desired pure product was obtained in 64% yield (107.8 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 1H), 7.27 – 7.21 (m, 3H), 6.99 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 6.83 (s, 1H), 4.38 – 4.29 (m, 2H), 3.85 (s, 3H), 1.84 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H);

13C{1H}

NMR (151 MHz, CDCl3) δ 193.6, 162.9, 162.0, 148.6, 140.5, 139.1, 133.9,

133.7, 128.9, 128.0, 127.3, 114.8, 112.7, 62.0, 55.7, 55.6, 22.5, 14.1; HRMS (ESI-TOF) exact mass calcd for C20H19NNaO4 [M+Na] m/z 360.1206, found 360.1199. Isopropyl 6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3ca). The desired pure product was obtained in 67% yield (117.7 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.7 Hz, 1H), 7.27 – 7.21 (m, 3H), 7.01 – 6.98 (m, 2H), 6.93 (dd, J = 8.7, 2.8 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 5.25 – 5.13 (m, 1H), 3.84 (s, 3H), 1.82 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.8, 162.7, 161.8, 149.3, 140.4, 139.2, 134.0, 133.6, 128.8, 128.0, 127.4, 114.8, 112.6, 69.9, 55.7,


16

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55.5, 22.6, 21.6, 21.6; HRMS (ESI-TOF) exact mass calcd for C21H21NNaO4 [M+Na] m/z 374.1363, found 374.1367. Tert-butyl 6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3da).12 The desired pure product was obtained in 65% yield (118.6 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.7 Hz, 1H), 7.27 – 7.22 (m, 3H), 7.02 – 6.98 (m, 2H), 6.93 (dd, J = 8.7, 2.7 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 1.82 (s, 3H), 1.50 (s, 9H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 194.1, 162.4, 161.6, 150.3, 140.2, 139.2, 134.0, 133.4, 128.7, 127.9, 127.4, 114.7, 112.6, 83.3, 55.6, 55.5, 27.9, 22.5; HRMS (ESI-TOF) exact mass calcd for C22H23NNaO4 [M+Na] m/z 388.1519, found 388.1517. Butyl

6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3ea).

The

desired pure product was obtained in 61% yield (111.3 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 1H), 7.26 – 7.21 (m, 3H), 7.00 – 6.97 (m, 2H), 6.94 (dd, J = 8.7, 2.7 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 4.34 – 4.21 (m, 2H), 3.85 (s, 3H), 1.83 (s, 3H), 1.69 – 1.63 (m, 2H), 1.39 – 1.33 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.7, 163.1, 161.9, 148.9, 140.4, 139.0, 134.0, 133.7, 128.8, 128.0, 127.3, 114.8, 112.7, 65.8, 55.7, 55.6, 30.4, 22.3, 19.0, 13.6; HRMS (ESI-TOF) exact mass calcd for C22H23NNaO4 [M+Na] m/z 388.1519, found 388.1520. Allyl

6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3fa).

The

desired pure product was obtained in 59% yield (102.1 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 1H), 7.28 – 7.19 (m, 3H), 7.02 – 6.97 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 5.97 –5.90 (m, 1H), 5.34 (dd, J = 17.2, 1.5 Hz, 1H), 5.24 (dd, J = 10.5, 1.3 Hz, 1H), 4.81 – 4.72 (m, 2H), 3.85 (s, 3H), 1.84 (s, 3H);

13C{1H}

NMR (151 MHz, CDCl3 δ 193.5, 162.6, 162.1, 148.3, 140.6, 139.0, 133.9, 133.8, 131.3, 128.9, 128.0, 127.3, 118.8, 114.8, 112.7, 66.3, 55.7, 55.6, 22.5; HRMS (ESI-TOF) exact mass calcd for C21H19NNaO4 [M+Na] m/z 372.1206, found 372.1202. Benzyl 6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3ga).12 The desired pure product was obtained in 56% yield (111.7 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.7 Hz, 1H), 7.37 – 7.30 (m, 5H), 7.23 – 7.21 (m, 3H), 7.00 – 6.97 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 5.36 (d, J = 12.5 Hz, 1H), 5.28 (d, J = 12.5 Hz, 1H), 3.85 (s, 3H), 1.84 (s, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.6, 162.8, 162.1, 148.5, 140.6, 139.0, 135.2, 134.0, 133.9, 128.9, 128.5, 128.2, 128.1, 128.0, 127.4,


17


Page 18 of 29

114.8, 112.7, 67.4, 55.7, 55.7, 22.4; HRMS (ESI-TOF) exact mass calcd for C25H21NNaO4 [M+Na] m/z 422.1363, found 422.1369. (8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl

6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-

dihydronaphthalene-2-carboxylate (3ha). The desired pure product was obtained in 48% yield (139.0 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 8.7 Hz, 1H), 7.28 – 7.19 (m, 3H), 7.01 – 6.98 (m, 2H), 6.94 (dd, J = 8.7, 2.7 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 5.42 – 5.37 (m, 1H), 4.83 – 4.77 (m, 1H), 3.84 (s, 3H), 2.48 – 2.40 (m, 3H), 2.12 – 2.04 (m, 3H), 1.95 – 1.87 (m, 2H), 1.82 (s, 3H), 1.69 – 1.61 (m, 5H), 1.54 – 1.45 (m, 2H), 1.31 – 1.25 (m, 3H), 1.17 – 1.13 (m, 1H), 1.04 (s, 3H), 0.87 (s, 3H) ;

13C{1H}

NMR (151 MHz, CDCl3) δ 221.0, 193.8,

162.6, 162.5, 161.9, 149.1, 141.0, 140.5, 139.7, 139.2, 134.2, 133.7, 128.8, 128.0, 127.4, 122.1, 120.9, 114.8, 112.6, 75.7, 75.7, 71.5, 55.7, 55.5, 51.8, 51.7, 50.2, 50.1, 47.5, 47.5, 42.2, 37.7, 37.2, 36.9, 36.9, 36.7, 35.8, 31.6, 31.5, 31.4, 31.4, 30.7, 27.4, 22.6, 21.9, 20.4, 20.3, 19.4, 19.3, 13.5; HRMS (ESI-TOF) exact mass calcd for C37H41NNaO5 [M+Na] m/z 602.2877, found 602.2881. 6-methoxy-N,4-dimethyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxamide

(3ia).12

The

desired pure product was obtained in 56% yield (90.2 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.74 (brs, 1H), 7.72 (s, 1H), 7.27 – 7.20 (m, 3H), 6.99 – 6.94 (m, 3H), 6.81 (d, J = 2.7 Hz, 1H), 3.85 (s, 3H), 2.90 (d, J = 5.0 Hz, 3H), 1.83 (s, 3H);

13C{1H}

NMR (151 MHz,

CDCl3) δ 196.7, 162.3, 162.1, 147.1, 140.8, 139.1, 133.9, 133.9, 129.0, 128.1, 127.2, 114.6, 112.9, 56.0, 55.7, 26.3, 22.7; HRMS (ESI-TOF) exact mass calcd for C19H18N2NaO3 [M+Na] m/z 345.1210, found 345.1217. N-ethyl-6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxamide (3ja). The desired pure product was obtained in 61% yield (102.5 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3)δ 7.73 (brs, 1H), 7.72 (s, 1H), 7.27 – 7.21 (m, 3H), 6.99 – 6.96 (m, 2H), 6.94 (dd, J = 8.7, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 3.43 – 3.34 (m, 2H), 1.82 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 196.8, 162.0, 161.5, 147.2, 140.9, 139.2, 133.9, 133.9, 198.0, 128.1, 127.3, 114.6, 112.8, 56.0, 55.7, 34.5, 22.8, 14.5; HRMS (ESITOF) exact mass calcd for C20H20N2NaO3 [M+Na] m/z 359.1366, found 359.1365. 6-methoxy-4-methyl-3-oxo-4-phenyl-N-propyl-3,4-dihydroquinoline-2-carboxamide (3ka). The desired pure product was obtained in 60% yield (105.0 mg) as a yellow oily liquid; 1H NMR


18

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(600 MHz, CDCl3) δ 7.77 (brs, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.28 – 7.19 (m, 3H), 6.99 – 6.97 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 3.37 – 3.26 (m, 2H), 1.83 (s, 3H), 1.60 – 1.52 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ;

13C{1H}

NMR (151 MHz,

CDCl3) δ 197.0, 162.0, 161.6, 147.2, 140.9, 139.2, 134.0, 133.9, 129.0, 128.1, 127.3, 114.6, 112.8, 56.1, 55.7, 41.4, 22.8, 22.5, 11.4; HRMS (ESI-TOF) exact mass calcd for C21H22N2NaO3 [M+Na] m/z 373.1523, found 373.1531. butyl-6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxamide

(3la).

The

desired pure product was obtained in 55% yield (100.1 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.75 (brs, 1H), 7.73 (s, 1H), 7.27 – 7.20 (m, 3H), 6.99 – 6.96 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 3.38 – 3.32 (m, 2H), 1.82 (s, 3H), 1.56 – 1.48 (m, 2H), 1.37 – 1.31 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 197.0, 162.0, 161.6, 147.2, 140.9, 139.2, 134.0, 133.9, 128.9, 128.1, 127.3, 114.6, 112.8, 56.1, 55.7, 39.4, 31.3, 22.8, 20.1, 13.7; HRMS (ESI-TOF) exact mass calcd for C22H24N2NaO3 [M+Na] m/z 387.1679, found 387.1685. N-(tert-butyl)-6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxamide (3ma). The desired pure product was obtained in 58% yield (105.6 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.7 Hz, 1H), 7.65 (brs, 1H), 7.28 – 7.23 (m, 3H), 7.01 – 6.99 (m, 2H), 6.94 (dd, J = 8.7, 2.7 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 1.82 (s, 3H), 1.39 (s, 9H) ;

13C{1H}

NMR (151 MHz, CDCl3) δ 197.0, 161.9, 160.6, 147.6, 141.1, 139.5, 133.9,

133.8, 128.9, 128.0, 127.3, 114.6, 112.8, 56.1, 55.7, 51.5, 28.6, 23.3; HRMS (ESI-TOF) exact mass calcd for C22H24N2NaO3 [M+Na] m/z 387.1679, found 387.1682. N-benzyl-6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxamide (3na). The desired pure product was obtained in 60% yield (119.4 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 8.04 (brs, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.33 – 7.22 (m, 8H), 7.01 – 6.97 (m, 2H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 4.56 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 1.83 (s, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 196.6, 162.1, 161.6, 147.0, 140.9, 139.1, 137.8, 134.0, 133.9, 129.0, 128.7, 128.1, 127.9, 127.5, 127.8, 114.7, 112.9, 56.1, 55.7, 43.7, 22.8; HRMS (ESI-TOF) exact mass calcd for C25H22N2NaO3 [M+Na] m/z 421.1523, found 421.1527. Ethyl (6-methoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carbonyl)glycinate (3oa). The desired pure product was obtained in 56% yield (110.4 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 8.22 (brs, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.26 – 7.20 (m, 3H), 6.99 – 6.94


19


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(m, 3H), 6.82 (d, J = 2.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.14 (t, 2H), 3.86 (s, 3H), 1.84 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 196.0, 169.4, 162.2, 161.6, 146.5, 141.0, 139.0, 134.1, 133.9, 129.0, 128.1, 127.2, 114.7, 112.9, 61.5, 56.0, 55.7, 41.6, 22.6, 14.1; HRMS (ESI-TOF) exact mass calcd for C22H22N2NaO5 [M+Na] m/z 417.1421, found 417.1414. Methyl

6-ethoxy-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3pa).

The

desired pure product was obtained in 68% yield (114.6 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.7 Hz, 1H), 7.26 – 7.21 (m, 3H), 7.00 – 6.97 (m, 2H), 6.93 (dd, J = 8.7, 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.13 – 4.03 (m, 3H), 3.85 (s, 3H), 1.83 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.5, 163.2, 161.6, 147.9, 140.7, 139.1, 133.8, 133.7, 128.9, 128.0, 127.3, 115.3, 113.2, 64.1, 55.6, 52.8, 22.4, 14.6; HRMS (ESITOF) exact mass calcd for C20H19NNaO4 [M+Na] m/z 360.1206, found 360.1211. Methyl 4-methyl-3-oxo-6-phenoxy-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3qa). The desired pure product was obtained in 66% yield (127.1 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 8.7 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.29 – 7.24 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 7.02 – 6.99 (m, 3H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 3.87 (s, 3H), 1.82 (s, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.3, 163.0, 160.5, 155.2, 149.1, 140.7, 138.7, 135.1, 133.7, 130.1, 129.0, 128.2, 127.2, 124.8, 120.0, 117.7, 116.8, 55.5, 52.9, 22.2; HRMS (ESI-TOF) exact mass calcd for C24H19NNaO4 [M+Na] m/z 408.1206, found 408.1205. Methyl 4,6-dimethyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3ra). The desired pure product was obtained in 54% yield (82.9 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 1H), 7.29 – 7.22 (m, 4H), 7.14 (s, 1H), 6.98 (dd, J = 7.9, 1.7 Hz, 2H), 3.87 (s, 3H), 2.42 (s, 3H), 1.86 (s, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.6, 163.1, 150.2, 142.4, 139.0, 137.9, 137.7, 131.7, 129.5, 128.9, 128.7, 128.0, 127.3, 55.3, 52.9, 22.3, 21.8; HRMS (ESI-TOF) exact mass calcd for C19H17NNaO3 [M+Na] m/z 330.1101, found 330.1110. Methyl 6-ethyl-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3sa). The desired pure product was obtained in 53% yield (85.1 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0, 1.8 Hz, 1H), 7.27 – 7.23 (m, 3H), 7.17 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.0, 1.7 Hz, 2H), 3.87 (s, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.87 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.7, 163.1, 150.3, 148.5, 139.0,


20

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137.9, 137.9, 131.9, 128.9, 128.2, 128.0, 127.6, 127.3, 55.4, 52.9, 29.1, 22.2, 15.2; HRMS (ESITOF) exact mass calcd for C20H19NNaO3 [M+Na] m/z 344.1257, found 344.1263. Methyl 6-isopropyl-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3ta). The desired pure product was obtained in 53% yield (88.8 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.1, 1.9 Hz, 1H), 7.27 – 7.23 (m, 3H), 7.20 (d, J = 1.9 Hz, 1H), 6.96 (dd, J = 8.0, 1.7 Hz, 2H), 3.86 (s, 3H), 3.02 – 2.93 (m, 1H), 1.87 (s, 3H), 1.28 (d, J = 5.0 Hz, 3H), 1.26 (d, J = 5.0 Hz, 3H) ;

13C{1H}

NMR (151 MHz, CDCl3) δ

193.8, 163.1, 153.1, 150.3, 139.0, 138.1, 137.8, 131.9, 128.9, 128.0, 127.3, 127.3, 127.3, 126.7, 126.3, 55.5, 52.9, 34.4, 23.7, 22.2; HRMS (ESI-TOF) exact mass calcd for C21H21NNaO3 [M+Na] m/z 358.1414, found 358.1406. Methyl

6-butyl-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3ua).

The

desired pure product was obtained in 51% yield (89.0 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 1H), 7.30 – 7.22 (m, 4H), 7.15 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 7.9, 1.6 Hz, 2H), 3.87 (s, 3H), 2.72 – 2.62 (t, J = 7.8 Hz, 2H), 1.87 (s, 3H), 1.65 – 1.54 (m, 2H), 1.41 – 1.31 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ; 13C{1H} NMR (151 MHz, CDCl3) δ 193.7, 163.1, 150.2, 147.3, 139.1, 137.9, 137.8, 131.8, 128.9, 128.8, 128.1, 128.0, 127.3, 55.3, 52.9, 35.8, 33.3, 22.3, 22.2, 13.9; HRMS (ESI-TOF) exact mass calcd for C22H23NNaO3 [M+Na] m/z 372.1570, found 372.1572. Methyl 6-(tert-butyl)-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3va). The desired pure product was obtained in 52% yield (90.7 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.27 – 7.22 (m, 3H), 6.95 (dd, J = 8.0, 1.7 Hz, 2H), 3.87 (s, 3H), 1.88 (s, 3H), 1.34 (s, 9H) ; 13C{1H}

NMR (151 MHz, CDCl3) δ 193.8, 163.0, 155.3, 150.5, 139.0, 137.7, 137.3, 131.5, 128.9,

128.0, 127.3, 125.8, 125.1, 55.6, 52.9, 35.3, 31.1, 22.1; HRMS (ESI-TOF) exact mass calcd for C22H23NNaO3 [M+Na] m/z 372.1570, found 372.1573. Methyl 6-fluoro-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate (3wa).

The

desired pure product was obtained in 48% yield (74.7 mg) as a yellow oily liquid; 1H NMR (600 MHz, CDCl3) δ 7.76 (dd, J = 8.7, 5.6 Hz, 1H), 7.30 – 7.25 (m, 3H), 7.19 – 7.14 (m, 1H), 7.05 (dd, J = 9.1, 2.8 Hz, 1H), 6.99 – 6.96 (m, 2H), 3.88 (s, 3H), 1.86 (s, 3H) ; 13C{1H}13C{1H} NMR (151 MHz, CDCl3) δ 192.7, 164.9, 163.2, 162.9, 150.4 (d, J = 3.6 Hz), 141.0 (d, J = 8.4 Hz), 138.3, 136.4 (d, J = 3.2 Hz), 133. 9 (d, J = 9.6 Hz), 129.1, 128.3, 127.2, 115.7 (q, J = 48.9, 23.5


21


Page 22 of 29

Hz), 55.4, 53.0, 22.4; HRMS (ESI-TOF) exact mass calcd for C18H14FNNaO3 [M+Na] m/z 334.0850, found 334.0853. Methyl

6-chloro-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3xa).

The

desired pure product was obtained in 52% yield (85.0 mg) as a yellow oily liquid. 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.3 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.30 – 7.26 (m, 3H), 6.99 – 6.95 (m, 2H), 3.88 (s, 3H), 1.86 (s, 3H) ； 13C{1H} NMR (151 MHz, CDCl3) δ 192.4, 162.8, 151.3, 139.8, 138.4, 138.2, 137.6, 132.8, 129.2, 129.1, 128.4, 128.3, 127.2, 55.2, 53.1, 22.2. HRMS (ESI-TOF) exact mass calcd for C18H14ClNNaO3 [M+Na] m/z 350.0554, found 350.0548. Methyl

6-bromo-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3ya).

The

desired pure product was obtained in 50% yield (92.8 mg) as a yellow oily liquid. 1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 1.1 Hz, 2H), 7.49 – 7.47 (m, 1H), 7.30 – 7.26 (m, 3H), 6.97 (dd, J = 7.9, 1.7 Hz, 2H), 3.88 (s, 3H), 1.86 (s, 3H) . 13C{1H} NMR (151 MHz, CDCl3) δ 192.4, 162.8, 151.5, 139.9, 138.8, 138.1, 133.0, 132.2, 131.2, 129.1, 128.4, 127.2, 126.1, 55.1, 53.1, 22.2. HRMS (ESI-TOF) exact mass calcd for C18H14BrNNaO3 [M+Na] m/z 394.0049, found 394.0045. Methyl

6-iodo-4-methyl-3-oxo-4-phenyl-3,4-dihydroquinoline-2-carboxylate

(3za).

The

desired pure product was obtained in 45% yield (94.3 mg) as a yellow oily liquid； 1H NMR (600 MHz, CDCl3) δ 7.84 (dd, J = 8.2, 1.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.31 – 7.26 (m, 3H), 6.96 (dd, J = 7.8, 1.7 Hz, 2H), 3.87 (s, 3H), 1.86 (s, 3H)；

13C{1H}

NMR (151 MHz, CDCl3) δ 192.3, 162.7, 151.7, 139.7, 139.4, 138.4, 138.2, 137.1, 133.0, 129.1, 128.4, 127.2, 98.4, 55.0, 53.1, 22.1 ； HRMS (ESI-TOF) exact mass calcd for C18H14INNaO3 [M+Na] m/z 441.9911, found 441.9908. Methyl

4-(4-bromophenyl)-6-methoxy-4-methyl-3-oxo-3,4-dihydroquinoline-2-carboxylate

(3ab).12 The desired pure product was obtained in 51% yield (102.3 mg) as a yellow oily liquid； 1H

NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 6.96 (dd, J =

8.7, 2.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 2.6 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 1.82 (s, 3H) ；

13C{1H}

NMR (151 MHz, CDCl3) δ 192.9, 163.1, 162.3, 147.8, 140.1, 138.2,

134.0, 133.7, 132.0, 129.1, 122.4, 114.9, 112.9, 55.7, 55.2, 53.0, 22.6； HRMS (ESI-TOF) exact mass calcd for C19H16BrNNaO4 [M+Na] m/z 424.0155, found 424.0164.


22

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Methyl 4-(4-iodophenyl)-6-methoxy-4-methyl-3-oxo-3,4-dihydroquinoline-2-carboxylate (3ac). The desired pure product was obtained in 54% yield (121.2 mg) as a yellow oily liquid ； 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.7 Hz, 1H), 7.60 – 7.57 (m, 2H), 6.96 (dd, J = 8.7, 2.7 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.75 – 6.72 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 1.81 (s, 3H)； 13C{1H}

NMR (151 MHz, CDCl3) δ 192.9, 163.1, 162.3, 147.8, 140.1, 139.0, 138.0, 134.0, 133.7,

129.3, 114.9, 112.9, 94.1, 55.7, 55.3, 53.0, 22.5 ； HRMS (ESI-TOF) exact mass calcd for C19H16INNaO4 [M+Na] m/z 472.0016, found 472.0009. Methyl

4-(4-(((2-isopropyl-5-methylcyclohexyl)oxy)carbonyl)phenyl)-6-methoxy-4-methyl-3-

oxo-3,4- dihydroquinoline-2-carboxylate (3ad). The desired pure product was obtained in 42 % yield (106.1 mg) as a yellow oily liquid； 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.7 Hz, 1H), 7.10 – 7.06 (m, 2H), 6.97 (dd, J = 8.7, 2.5 Hz, 1H), 6.79 – 6.76 (m, 1H), 4.90 – 4.85 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.07 (d, J = 12.1 Hz, 1H), 1.93 – 1.88 (m, 1H), 1.86 (d, J = 3.2 Hz, 3H), 1.70 (d, J = 11.5 Hz, 2H), 1.56 – 1.46 (m, 2H), 1.28 – 1.23 (m, 1H), 1.12 – 1.03 (m, 2H), 0.90 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H) ；

13C{1H}

NMR (151 MHz, CDCl3) δ 193.0, 192.9, 165.4, 163.1, 163.1, 162.3, 162.3,

147.8, 144.0, 140.3, 140.2, 134.0, 133.7, 133.7, 130.6, 130.1, 127.4, 115.1, 112.9, 75.0, 55.7, 55.7, 55.6, 52.9, 47.2, 47.2, 40.9, 34.3, 31.4, 26.4, 26.4, 23.6, 23.5, 22.7, 22.7, 22.0, 20.7, 20.7, 16.5, 16.4 ； HRMS (ESI-TOF) exact mass calcd for C30H35NNaO6 [M+Na] m/z 528.2357, found 528.2353. Methyl 4-(3-isopropylphenyl)-6-methoxy-4-methyl-3-oxo-3,4-dihydroquinoline-2-carboxylate (3ae).The desired pure product was obtained in 53% yield (96.8 mg) as a yellow oily liquid； 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 8.7 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 8.7, 2.7 Hz, 1H), 6.90 – 6.87 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.84 – 2.77 (m, 1H), 1.83 (s, 3H), 1.16 (d, J = 3.0 Hz, 3H), 1.15 (d, J = 3.1 Hz, 3H)； 13C{1H}

NMR (151 MHz, CDCl3) δ 193.9, 163.1, 162.0, 149.5, 148.3, 140.7, 138.7, 134.0, 133.8,

128.9, 126.0, 125.8, 124.5, 114.8, 112.7, 55.7, 55.7, 52.8, 34.1, 23.9, 23.7, 22.2； HRMS (ESITOF) exact mass calcd for C22H23NNaO4 [M+Na] m/z 388.1519, found 388.1520. Methyl

4-(3-bromophenyl)-6-methoxy-4-methyl-3-oxo-3,4-dihydroquinoline-2-carboxylate

(3af). The desired pure product was obtained in 48% yield (96.2 mg) as a yellow oily liquid； 1H

NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.7 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.15 – 7.12 (m, 2H),


23


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6.96 (dd, J = 8.7, 2.7 Hz, 1H), 6.94 – 6.91 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 1.82 (s, 3H)； 13C{1H} NMR (151 MHz, CDCl3) δ 192.9, 163.1, 162.3, 147.8, 141.5, 140.0, 134.0, 133.6, 131.3, 130.3, 130.3, 126.2, 123.2, 115.0, 112.9, 55.8, 55.3, 53.0, 22.8 ； HRMS (ESI-TOF) exact mass calcd for C19H16BrNNaO4 [M+Na] m/z 424.0155, found 424.0161.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDEGEMENT We thank the National Natural Science Foundation of China (21562037) for financially supporting this work.

Supporting Information: Copies of NMR spectra of the substrates 1, 2d and the products 3; HRMS spectra of reaction intermediates.

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Double-Oxidative Dehydrogenative (DOD) [4+2]-Cyclization

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