Catalyzed CâH Functionalization for the Synthesis of

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On Water Cp*Ir(III)-Catalyzed C–H Functionalization for the Synthesis of Chromones through Annulation of Salicylaldehydes with Diazo-Ketones Suvankar Debbarma, Md Raja Sk, Biswabrata Modak, and Modhu Sudan Maji J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00418 • Publication Date (Web): 19 Apr 2019 Downloaded from http://pubs.acs.org on April 20, 2019

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The Journal of Organic Chemistry

On Water Cp*Ir(III)-Catalyzed C–H Functionalization for the Synthesis of Chromones through Annulation of Salicylaldehydes with Diazo-Ketones Suvankar Debbarma, Md Raja Sk, Biswabrata Modak and Modhu Sudan Maji* Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India ABSTRACT: A high-valent Ir(III)-catalyzed C–H bond functionalization is carried out for the first time on water for the synthesis of biologically relevant chromone moiety. The C–H activation and annulation of salicylaldehydes with diazo-compounds provided the desired chromones. The synthesis of C3-substitution free chromones has also been demonstrated by a one-pot decarboxylation by employing tert.-butyl diazoester. C3 and C5 C–H activations of the product chromone are also carried out under different conditions for the further diversification.

INTRODUCTION In the last few decades, transition-metal catalyzed C–H bond activation method has become a powerful tool for step- and atom-economic1 synthesis of various target molecules.2 To reach a ground in the sustainable synthesis through transition-metal catalyzed C–H bond activation, the avoidance of toxic organic solvents and the use of more green-solvents are the key interest for practical purpose.3 Water, the universal solvent owing to its non-toxic, environment friendly 1 ACS Paragon Plus Environment

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and easy availability became a central attraction to the chemists for its use as a solvent in the various catalytic transformations related to the C–H bond activation.3 However, the C–H functionalization are difficult to occur in water medium as the reactants are insoluble in water and the water coordination to metal-catalyst can prevent the catalysis. In this line, although Pd,4 Rh5 and Ru6 catalyzed C–H bond activation have been investigated using water as a solvent, to the best of our knowledge Ir(III)-catalyzed C–H bond functionalizations on water is still not encountered. Because of their wide range of biological activities and medicinal importance, chromones have been an attractive target molecule.7 To minimize the number of reaction steps, bring versatility, and overcome obstacles for the synthesis of this heterocycle moiety,8 aldehyde C– H functionalization and annulation of salicylaldehydes with alkynes or diazo-compounds have been employed mainly under Rh,9 Ru10 and Co-catalysis.11 In these cases, ortho-hydroxy group of salicylaldehyde not only acts as a directing group for the aldehyde C–H bond activation,12 but also serves the heteroatom required for the construction of the heterocycle ring of chromone. We found the synthesis of the chromone is possible in a more efficient route as previous reports have drawbacks such as (1) organic solvents used which are toxic,9-11 (2) when an α-diazo carbonyl is incorporated as an electrophile, the functionalization of C3 of chromones are limited only to ester- or acyl-groups,9b and (3) catalyst-loading can only be minimized to 2.5 mol % for the electrophile α-diazo carbonyl to reach a practically useful yield of the products.9b To find a fruitful and benign catalyst system for the synthesis of chromone, herein we developed an Ir(III)-catalyzed C–H bond functionalization in water medium. To include versatility in this annulation process we have incorporated differently substituted salicylaldehydes and α-diazo carbonyls.13 Relatively low catalyst loading, short reaction time, and the use of ubiquitous and inexpensive water as solvent for Ir(III)-catalyzed C–H bond functionalization are main advantages of our present catalytic system. Additionally, a one-pot

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decarboxylation provided C3 free chromones, when a tert.-butyl diazoester was used as an electrophile (Scheme 1). Scheme 1: Catalytic Approach for the Synthesis of Chromone Heterocycles

RESULTS AND DISCUSSION To recognize a benign, optimize catalyst system, we have commenced our proof-of-concept study with the screening of the reaction parameters for the chromone synthesis (Table 1). Under the iridium catalyst system, the coupling of salicylaldehyde 1a with ethyl diazoacetate 2a in the presence of acetic acid (1.0 equiv) as additive was carried out at 80 oC, which results in 70% of coupling product 3a (Table 1, entry 1). Keeping these parameters constant while screening various organic solvents (entries 2–4) the reaction profile did not improve much. Table 1. Optimization of the Reaction Conditionsa

Entry

Solvent

Additive

Temp [oC]

Yield [%]b



a

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1

DCE

AcOH

80

70

2

TCE

AcOH

80

55

3

CHCl3

AcOH

80

40

4

MeOH

AcOH

80

68

5

H2 O

AcOH

80

75

6

H2O

PivOH

80

90

7

H2 O

NaOAc

80

44

8

H2 O

KOAc

80

30

9

H2 O

CsOAc

80

40

10

H2 O

none

80

trace

11c

H2 O

PivOH

80

n.d

12d

H2 O

PivOH

80

65

13

H2 O

PivOH

50

66

14e

H2 O

PivOH

80

n.d

15f

H2 O

PivOH

80

n.d

16g

H2 O

PivOH

80

30

Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol

%), additive (1.0 equiv), solvent (1.5 mL), 80 oC, 2 h. bIsolated yield of 3a. cNo catalyst. d0.5 mol % of [Cp*IrCl2]2. e[Ru(p-Cymene)Cl2]2 as catalyst. f[Cp*Co(CO)I2] as catalyst. g

[Cp*RhCl2]2 as catalyst. n.d = not detected. When methanol was employed, the output of the catalysis gave a positive hint towards the

effectiveness of polar protic solvent (entry 4). Based on this indication and to avoid organic solvents we have introduced water as solvent for this reaction, and noticed a positive outcome with respect to methanol (entry 5). Upon switching the additive from AcOH to pivalic acid, we were delighted to isolate 3a in excellent yield (90%, entry 6). In the presence of acetate additives, the reaction outcome did not improve (entries 7–9). In the absence of either catalyst or additives the reaction did not proceed (entries 10–11), which indicates the necessity of catalyst-additives combination. Moreover, the lowering of catalyst loading decreased the 4 ACS Paragon Plus Environment

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chemical yields dramatically (entry 12). On decreasing the reaction temperature to 50 oC outcome of 3a reduced to 66% (entry 13). Interestingly, the catalysis was not operative in presence of other catalysts like Ru(II) or Co(III) (entries 14–15). A moderate result was obtained in the presence of Cp*Rh(III)-catalyst instead of iridium catalyst (entry 16). To mention, the optimization of the reaction conditions did not require any co-solvent, surfactant, phase-transfer catalyst or silver salt. With the optimized reaction conditions in hand (Table 1, entry 6), we surveyed the scope of various salicylaldehydes (Scheme 2). Introduction of electron donating substituents such as methyl, methoxy, tert.-butyl at the different positions of salicylaldehyde were well tolerated, and the products 3a–3d were isolated in 77–90% yields. Moreover, highly electron-deficient salicylaldehyde bearing ester substituent was well tolerated under the reaction conditions and offered chromone 3e in 73% yield. Similarly, electron-deficient halide substituents namely chlorine, and iodine at the different positions of 1 were also well tolerated, and the products 3f–3h were isolated in 68–84% yields. Irrespective of the electronic nature, when the substituents are present at the ortho- position with respect to hydroxyl group, the chemical yields were reduced significantly (3i–3k, 52–62%). On the other hand, 1-hydroxy-2naphthaldehyde 1l showed an excellent reactivity under this optimized conditions and formed 3l in 84% yield. To show the broad efficiency of our catalyst systems a late-stage modification of a tyrosine derivative 1m was carried out through the optimized protocols. The substituted tyrosine aldehyde 1m was smoothly coupled with 2a under our optimized conditions and furnished chromone 3m in 50% yield. Salicylaldehyde bearing C4-methoxy groups provided 3n in 78% yield. When this annulation reaction was conducted in gram scale, 0.95 g of 3a was isolated (82% yield). Scheme 2. Scope of Salicylaldehydesa



a

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Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol

%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields. After a successful investigation on salicylaldehydes, next the reactivity of diazoacetates was studied which revealed that upon modification in the diazo-sources significantly switch their reactivity (Scheme 3). Changing the ester moiety in diazoketone 2 from ethyl to methyl, the chemical yield did not change much and we were pleased to isolate 4a in 88% yield. The benzyl substituted α-ketodiazo ester 2c underwent a smooth coupling with salicylaldehyde 1a to form a chromone 4b in 75% yield. In addition, the diacetyldiazomethane 2d also followed a similar reaction pathway, which provided chromones 4c and 4d in excellent yields. Moreover, we have investigated the reactivity of amide substituted diazo-acetates 2e–2g under the optimized conditions. The amide containing –NEt2, –NiPr2, –morpholine were well tolerated 6 ACS Paragon Plus Environment

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and formed chromones 4e–4h in moderate to good yields. When a phenyl containing α-diazo compound is used as an electrophile, only the trace amount of product formed as an inseparable mixture with unknown side products. Scheme 3. Scope of Substituted Diazo-Ketonesa

a

Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol

%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields. While negotiating on the reactivity of various diazo ketones, it was observed that on treatment of tert-butyldiazo acetate 2h under the catalysis followed a decarboxylative pathway to form chromone 5a in excellent yield of 86% (Scheme 4). After having a preliminary successful result in hand, we further explored this approach with several salicylaldehydes. Salicylaldehyde having electron-deficient substituents such as esters and halogens (F, Cl, Br) at different positions are completely viable to provide chromones 5b–5g in moderate to excellent yields (54–92%). Moreover, salicylaldehyde 1i bearing electron-donating methoxy group underwent a smooth coupling with 2h to form chromone 5h in good yield. Most importantly, the synthesized chromone 5h has an immense importance in medicinal chemistry and functions as HBV inhibitor.14a Further we have explored this strategy for the late-stage



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modifications of tyrosine and received a promising outcome through the coupling of 2h with tyrosine derived aldehyde (5i, 42% yield). 4-Methoxy salicylaldehyde furnished 5j in 81% yield. Scheme 4. Decarboxylation Approach of Chromones Synthesisa,b

a

Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2h (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol

%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields. Our studies with the tert.-butyl diazo compound 2h in DCE solvent provided no decarboxylation signifying a vital role of water as solvent to switch the product selectivity (Scheme 5). The possible reason could be a ready hydrolysis of the formed tert-butyl ester containing chromone in the presence of water and then a facile decarboxylation. When the product is heated at 100 oC in water, the hydrolysis followed by decarboxylation provided chromone 5. Scheme 5. Control Experiments for Decarboxylation Approach


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The literature represents several important features of chromones heterocycle in the various field, as mentioned in the introduction. To show a broader impact in applications of our synthesized chromones we have carried out several chemical transformations using chromone 5a as a key starting material (Table 2).14 The ketone directed C–H bond functionalizations at C5 position are possible for the diversification of the synthesized chromones. Thus C(5)–H allylation,14b amidation,14c oxidative alkenylation,14d and 1,4-addition14e are achieved for 5a. Furthermore, a Pd-catalyzed electrophilic metallation and oxidative alkenylation provided C3 alkenylated chromone.14f Table 2. Diversification of Chromone 5a



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To know the nature of the C–H-metallation we performed H/D-exchange experiments in the presence of deuterium sources (Scheme 6).15 Around 17% deuterium exchange was observed for the aldehyde C–H bond indicating a reversible C–H bond activation. Scheme 6 H/D-Exchange Experiment

Based on our primary investigation and previous reports12,13 a plausible catalytic cycle can be proposed (Scheme 7). In the presence of pivalic acid, the active catalyst A is formed. The catalyst A forms the cyclometallated species B, after hydroxyl coordination and irreversible aldehyde C–H activation. The formation of the intermediate B was supported by LC-MS analysis.15 The intermediate B reacts with the diazo-compound 2a to give an iridium-carbenoid species C. The migratory insertion to the carbenoid species produces the intermediate D, which delivers the compound E and regenerates the catalyst A in the presence of pivalic acid. A nucleophilic addition followed by dehydration in E, finally gives the desired product 3a. 10 ACS Paragon Plus Environment

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Scheme 7. Proposed Mechanism of Chromone Synthesis CONCLUSION Thus, we successfully developed Ir(III)-catalyzed C–H activation in water medium and employed the concept for the chromone synthesis. The annulation between salicylaldehydes and α-diazo carbonyl compounds were efficiently executed to achieve the target under the reaction conditions. A one-pot annulation followed by decarboxylation of a tert-butyl diazoester with salicylaldehydes provided C3-substitution free chromones in useful way. We hope the method could be helpful in finding more reactions for Ir-catalyzed C–H activation in water medium. Experimental Section General: All reactions were carried out in an oven dried reaction tube. Unless otherwise stated, all solvents were dried by standard procedure: 1,2-dichloroethane was distilled over calcium hydride. Analytical thin layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm), exposure to iodine vapour or treatment with KMnO4 solution followed by heating. 11 ACS Paragon Plus Environment


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Column chromatography was performed through silica gel (100-200 mesh) using a proper solvent system. Infrared (IR) spectra were recorded by FTIR spectrometer and reported in terms of wave number (cm-1). The 1H NMR spectroscopic data were recorded with a Bruker 400, 500 or 600 MHz NMR instruments. 13C NMR spectra were similarly recorded by using 101, 126 or 151 MHz NMR instruments applying a broadband decoupled mode. Proton and carbon NMR chemical shifts (δ) are reported in parts per million (ppm) relative to residual proton signals in CDCl3 (δ = 7.26, 77.16) and DMSO-d6 (d = 2.50, 39.52). Coupling constants (J) are reported in Hertz (Hz) and refer to apparent multiplicities. The following abbreviations are used for the multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, dd: doublet of doublets, dt: doublet of triplets, ddd: doublet of doublet of doublets, tt: triplet of triplets, td: triplet of doublets, m: multiplet, br: broad. High resolution mass spectra (HRMS) were recorded in ESI (+ Ve) method using TOF mass analyzer. Other chemicals were obtained from commercial sources and used without further purification. All salicylaldehydes were bought from the commercial sources and used without further purifications. The tyrosine aldehyde 1m was synthesized according to the known literature procedure.9b All the known compounds are characterized through NMR analysis and comparing the spectral data with the reported value. General Procedure for the synthesis of diazo-compounds 2: The substituted diazo-ketones were synthesized according to a known literature procedure with slight modifications.13e In an oven dried 100 mL two-neck round bottom flask 1,3dicarbonyl compound (5.0 mmol, 1.0 equiv) and tosyl azide (6.0 mmol, 1.2 equiv) were dissolved in 15 mL acetonitrile under nitrogen atmosphere. The reaction mixture was then cooled down to 0 oC, and DBU (6.0 mmol, 1.2 equiv) in 10 mL of acetonitrile was added. The reaction was then allowed to stir at room temperature for 3h. After completion of the reaction, as indicated by TLC, the reaction mixture was extracted with ethyl acetate, the combined 12 ACS Paragon Plus Environment

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organic layers were washed with brine, dried over anhydrous sodium sulphate and solvent was removed under vaccuo. The crude reaction mixture was purified by silica gel flash column chromatography. The reported diazo-compounds [2a, 2c-d],13k 2b,16 [2e-g],13l 2h.13m are analysed by comparing the known literature data. To show the purity of our synthesized diazo compounds we have provided the proton NMR spectra of all the compound.15 General Procedure for the annulation of salicylaldehydes with diazo-compounds: (GP I) In a 10.0 mL screw capped sealed tube salicylaldehydes 1 (0.2 mmol, 1.0 equiv), diazocopmpounds 2 (0.3 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (1.6 mg, 0.002 mmol, 1.0 mol %) and pivalic acid (20.4 mg, 0.2 mmol, 1.0 equiv) were taken and 1.5 mL of water was successively added. Then the reaction mixture was heated at 80 oC temperature for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was extracted with ethyl acetate and the collected organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated in rotary-evaporator and the crude residue was purified by silica gel column chromatography by using petroleum ether/ ethylacetate eluent to obtain 3a–3m and 4a–4h. General Procedure for the annulation of salicylaldehydes with tert.-butyl diazocompound 2h: (GP II) In a 10.0 mL screw capped sealed tube salicylaldehydes 1 (0.2 mmol, 1.0 equiv), tert.-butyl diazo-compound 2h (0.3 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (1.6 mg, 0.002 mmol, 1.0 mol %) and pivalic acid (20.4 mg, 0.2 mmol, 1.0 equiv) were taken and 1.5 mL of water was successively added. Then the reaction mixture was heated at 100 oC temperature for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was extracted with ethyl acetate and the collected organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated in rotary-evaporator and purified by silica gel column chromatography using petroleum ether/ ethylacetate eluent to obtain 5a–5i.



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Ethyl 2-diazo-3-oxobutanoate (2a).13k The compound 2a was synthesized according to the given procedure in 78% yield. 1H NMR (200 MHz, CDCl3) δ (ppm) 4.30 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). Methyl 2-diazo-3-oxobutanoate (2b).16 The compound 2b was synthesized according to the given procedure in 75% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.83 (s, 3H), 2.47 (s, 3H). Ethyl 2-diazo-3-oxo-5-phenylpentanoate (2c).13k The compound 2c was synthesized according to the given procedure in 72% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.31– 7.24 (m, 4H), 7.22–7.18(m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.20 (t, J = 7.7 Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 3-Diazopentane-2,4-dione (2d).13k The compound 2d was synthesized according to the given procedure in 80% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.42 (s, 6H). 2-Diazo-N,N-diisopropyl-3-oxobutanamide (2e).13l The compound 2e was synthesized according to the given procedure in 55% yield. 1H NMR (200 MHz, CDCl3) δ (ppm) 3.77– 3.57 (m, 2H), 2.30 (s, 3H), 1.33 (d, J = 6.7 Hz, 12H). 2-Diazo-N,N-diethyl-3-oxobutanamide (2f).13l The compound 2f was synthesized according to the same procedure as literature report in 66% yield. 1H NMR (200 MHz, CDCl3) δ (ppm) 3.38 (q, J = 7.1 Hz, 4H), 2.34 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H). 2-Diazo-1-morpholinobutane-1,3-dione (2g).13l The compound 2g was synthesized according to the given procedure in 50% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.72– 3.70 (m, 4H), 3.57–3.44 (m, 4H), 2.31 (s, 3H). tert-Butyl 2-diazo-3-oxobutanoate (2h).13m The compound 2h was synthesized according to the given procedure in 74% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.41 (s, 3H), 1.49 (s, 9H). Ethyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (3a).9b The titled compound 3a was prepared according to the GP I and isolated as white solid (41.8 mg, 90%). 1H NMR (400


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MHz, CDCl3): δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 7.66–7.62 (m, 1H), 7.41–7.36 (m, 2H), 4.39 (q, 7.1 Hz, 2H), 2.49 (s, 3H), 1.38 (t, J = 7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 174.5, 166.8, 165.2, 155.7, 134.1, 126.2, 125.6, 123.4, 118.3, 117.8, 61.8, 19.6, 14.3. Gram scale synthesis of 3a: Salicylaldehyde 1a (0.61 g, 5.0 mmol, 1.0 equiv), diazocopmpounds 2a (1.17 g, 7.5 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (39.8 mg, 0.05 mmol, 1.0 mol %) and pivalic acid (0.51 g, 5.0 mmol, 1.0 equiv) were taken in a 60 mL pressure tube and 37.0 mL of water was added. Then the reaction mixture was heated at 80 oC temperature for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was extracted with ethyl acetate and the collected organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated in rotary-evaporator and the crude residue was purified by silica gel column chromatography by using petroleum ether/ ethylacetate eluent to obtain 0.95 g of pure 3a (82% yield). Ethyl 2,6,8-trimethyl-4-oxo-4H-chromene-3-carboxylate (3b). The titled compound 3b was prepared according to the GP I and isolated as yellow solid (40 mg, 77 %). IR (KBr): 2924, 1641, 1719, 1475, 1268 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.81 (s, 1H), 7.31 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 175.0, 166.3, 165.5, 152.5, 136.4, 135.1, 126.9, 123.2, 117.9, 61.8, 29.8, 21.0, 19.6, 15.5, 14.3. HRMS (ESI) m/z: [M+H]+ calcd for C15H17O4 261.1121; found 261.1101. Ethyl 6-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3c).9b The titled compound 3c was prepared according to the GP I and isolated as yellow solid (41.9 mg, 81%). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.53 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.21 (dd, J = 9.1, 3.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13

C NMR (126 MHz, CDCl3): δ (ppm) 174.4, 166.5, 165.4, 157.2, 150.5, 124.1, 123.9, 119.2,

117.5, 105.4, 61.8, 56.0, 19.5, 14.3.



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Ethyl 6-(tert-butyl)-2-methyl-4-oxo-4H-chromene-3-carboxylate (3d). The titled compound 3d was prepared according to the GP I and isolated as white solid (50.6 mg, 88%). IR (KBr): 2958, 1729, 1646, 1435, 1352 cm-1. 1H NMR (500 MHz, CDCl3): δ (ppm) 8.17 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.5 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 1H), 2.49 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3): δ (ppm) 174.8, 166.6, 165.5, 153.9, 149.0, 131.9, 122.8, 122.1, 118.1, 117.4, 61.8, 35.0, 31.4, 19.6, 14.3. HRMS (ESI) m/z: [M+H]+ calcd for C17H21O4 289.1434; found 289.1409. Ethyl 6-acetoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3e). The titled compound 3e was prepared according to the GP I and isolated as yellow solid (42.34 mg, 73%). IR (KBr): 2922, 1715, 1615, 1437, 1273 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.84 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.51 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.8, 167.0, 165.7, 164.8, 158.0, 134.8, 128.6, 127.7, 123.2, 118.7, 118.3, 62.1, 52.6, 19.6, 14.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H15O6 291.0863; found 291.0837. Ethyl 6-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3f).17 The titled compound 3f was prepared according to the GP I and isolated as yellow sticky solid (41.5 mg, 78%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.14 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.3, 167.1, 164.9, 154.0, 134.3, 131.7, 125.6, 124.5, 119.6, 118.2, 62.0, 19.7, 14.3. Ethyl 6-iodo-2-methyl-4-oxo-4H-chromene-3-carboxylate (3g).17 The titled compound 3g was prepared according to the GP I and isolated as white solid (48.7 mg, 68%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.49 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,


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CDCl3): δ (ppm) 173.0, 167.1, 164.8, 155.1, 142.7, 135.1, 125.1, 119.9, 118.5, 89.5, 62.0, 19.7, 14.3. Ethyl 7-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3h). The titled compound 3h was prepared according to the GP I and isolated as white solid (44.7 mg, 84%). IR (KBr): 2980, 1731, 1640, 1605, 1427 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 4.41 (q, J = 6.9 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.7, 167.0, 164.9, 155.8, 140.2, 127.7, 126.6, 122.1, 118.6, 118.0, 62.0, 19.6, 14.3. HRMS (ESI) m/z: [M +H]+ calcd for C13H12ClO4 267.0419; found 267.0395. Ethyl 8-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3i).9b The titled compound 3i was prepared according to the GP I and isolated as white solid (32.5 mg, 62%). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.73–7.72 (m, 1H), 7.30–7.26 (m, 1H), 7.15–7.13 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 2.54 (s, 3H), 1.38 (t, J = 7.7 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ (ppm) 174.4, 166.5, 165.2, 148.5, 146.1, 125.3, 124.6, 118.3, 117.0, 114.8, 61.9, 56.4, 19.6, 14.3. Ethyl 8-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3j). The titled compound 3j was prepared according to the GP I and isolated as yellow solid (29.3 mg, 55%). IR (KBr): 2977, 1727, 1645, 1601, 1627, 1408 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.10 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.35–7.31 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.9, 167.0, 164.8, 151.4, 136.3, 134.4, 125.7, 124.9, 122.9, 118.5, 62.1, 19.6, 14.3. HRMS (ESI) m/z: [M+H]+ calcd for C13H12ClO4 267.0419; found 267.0412. Ethyl 8-fluoro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3k). The titled compound 3k was prepared according to the GP I and isolated as white solid (26 mg, 52%). IR (KBr): 2971, 1726, 1645, 1488, 1404 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96–7.96 (m, 1H), 7.47–



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7.42 (m, 1H), 7.36 – 7.31 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ (ppm) 173.6 (d, J = 2.9 Hz), 166.4, 164.8, 150.9 (d, J = 253.7 Hz), 144.5 (d, J = 11.5 Hz), 125.4, 125.3 (d, J = 6.5 Hz), 121.3 (d, J = 4.1 Hz), 119.9 (d, J = 16.6 Hz), 118.7, 62.1, 19.6, 14.3. 19F NMR (376 MHz, CDCl3) δ (ppm) -133.48 (s, 1F). HRMS (ESI) m/z: [M+H]+ calcd. for C13H13FO4 251.0714; found 251.0700. Ethyl 2-methyl-4-oxo-4H-benzo[h]chromene-3-carboxylate (3l).9b The titled compound 3l was prepared according to the GP I and isolated as white solid (47.3 mg, 84%). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.45 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.73–7.66 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ (ppm) 174.5, 165.9, 165.2, 153.2, 136.1, 129.6, 128.3, 127.4, 125.8, 123.6, 122.2, 121.0, 119.9, 119.4, 62.0, 19.5, 14.4. Ethyl6-(2-(1,3-dioxoisoindolin-2-yl)-3-methoxy-3-oxopropyl)-2-methyl-4-oxo-4Hchromene-3-carboxylate (3m).9b The titled compound 3m was prepared according to the GP I and isolated as white solid (31.7 mg, 50%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.50 (dd, J = 8.6, 2.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 5.14 (dd, J = 11.1, 5.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.72–3.58 (m, 2H), 2.44 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.1, 169.1, 167.5, 166.6, 165.2, 154.7, 134.7, 134.4, 131.6, 126.3, 123.8, 123.4, 118.3, 61.9, 53.2, 34.4, 19.6, 14.3. Ethyl 7-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3n). The titled compound 3n was prepared according to the GP I and isolated as gummy solid (40.8 mg, 78%). IR (KBr): 2982, 1728, 1630, 1438, 1398 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 8.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.46 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.9, 166.2,


Page 19 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


165.4, 164.4, 157.4, 127.6, 118.1, 117.2, 114.7, 100.2, 61.8, 55.9, 19.4, 14.3. HRMS (ESI) m/z: [M+H]+ calcd for C14H15O5 263.0914; found 263.0917. Methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (4a).9b The titled compound 4a was prepared according to the GP I and isolated as white solid (38.4 mg, 88%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.17 (dd, J = 7.9, 1.6 Hz, 1H), 7.67–7.63 (m, 1H), 7.41–7.36 (m, 1H), 3.92 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.4, 167.4, 165.7, 155.6, 134.1, 126.2, 125.7, 123.4, 117.8, 52.7, 19.7. Ethyl 4-oxo-2-phenethyl-4H-chromene-3-carboxylate (4b). The titled compound 4b was prepared according to the GP I and isolated as white solid (48.3 mg, 75%). IR (KBr): 2981, 1724, 1646, 1616, 1465, 1383 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.20 (d, J = 6.9 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 6.3 Hz, 2H), 7.30–7.26 (d, J = 6.6 Hz, 2H), 7.23– 7.21 (m, 3H), 4.38 (q, J = 7.1 Hz, 2H), 3.12–3.04 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.7, 168.6, 165.1, 155.7, 139.9, 134.1, 128.8, 128.6, 128.4, 126.7, 126.3, 125.7, 123.5, 118.4, 117.9, 61.9, 35.2, 33.7, 14.34. HRMS (ESI) m/z: [M+H]+ calcd for C20H19O4 323.1278; found 323.1276. 3-Acetyl-2-methyl-4H-chromen-4-one (4c).9b The titled compound 4c was prepared according to the GP I and isolated as yellow solid (36.4 mg, 90%). 1H NMR (500 MHz, CDCl3): δ (ppm) 8.17 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.41–7.38(m, 2H), 2.62 (s, 3H), 2.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 200.6, 176.0, 168.7, 155.5, 134.2, 126.0, 125.7, 123.9, 123.8, 117.8, 32.3, 19.9. 3-Acetyl-6-bromo-2-methyl-4H-chromen-4-one (4d). The titled compound 4d was prepared according to the GP I and isolated as white solid (42.6 mg, 76%). IR (KBr): 2924, 1696, 1644, 1607, 1426 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) δ 8.29 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 2.61 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm)



Page 20 of 32

200.2, 174.7, 169.0, 154.3, 137.2, 128.7, 125.3, 123.8, 119.8, 119.2, 32.3, 20.0. HRMS (ESI) m/z: [M+H]+ calcd. for C12H10BrO3 280.9808; found 280.9793. N,N-Diisopropyl-2-methyl-4-oxo-4H-chromene-3-carboxamide (4e). The titled compound 4e was prepared according to the GP I and isolated as yellow solid (35.2 mg, 68%). IR (KBr): 2928, 1616, 1571, 1447, 1398 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.42 – 7.36 (m, 2H), 3.85–3.79 (m, 1H), 3.55 – 3.48 (m, 1H), 2.41 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.9, 164.3, 163.1, 156.1, 133.8, 126.1, 125.2, 123.4, 122.6, 117.9, 51.7, 46.2, 21.5, 21.0, 20.6, 20.3, 18.8. HRMS (ESI) m/z: [M+H]+ calcd. for C17H22NO3 288.1594; found 288.1578. N,N-Diethyl-2-methyl-4-oxo-4H-chromene-3-carboxamide (4f).18 The titled compound 4f was prepared according to the GP I and isolated as yellow solid (37.3 mg, 72%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.43–7.37 (m, 2H), 3.58 (q, J = 7.1 Hz, 2H), 3.32–3.22 (m, 2H), 2.41 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.8, 164.7, 163.9, 156.1, 133.9, 126.1, 125.4, 123.3, 121.3, 117.9, 43.3, 39.5, 19.1, 14.6, 13.0. N,N-Diethyl-6-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxamide (4g).18 The titled compound 4g was prepared according to the GP I and isolated as yellow solid (29.2 mg, 51%). 1

H NMR (400 MHz, CDCl3): δ (ppm) 7.53 (d, J = 3.0 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H), 7.24

(dd, J = 9.1, 3.1 Hz, 1H), 3.86 (s, 3H), 3.58 (q, J = 7.1 Hz, 2H), 3.29–3.23 (m, 2H), 2.40 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.6, 164.9, 163.6, 157.1, 150.9, 123.9, 120.6, 119.3, 105.2, 56.0, 43.2, 39.5, 19.0, 14.6, 12.9. 2-Methyl-3-(morpholine-4-carbonyl)-4H-chromen-4-one (4h). The titled compound 4h was prepared according to the GP I and isolated as yellow solid (30.6 mg, 56%). IR (KBr): 2922, 1715, 1621, 1462, 1270, 1250 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.17 (d, J =


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7.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.45–7.39 (m, 2H), 3.98–3.73 (m, 4H), 3.60–3.35 (m, 4H), 2.45 (s, 3H). 13C NMR (151 MHz, CDCl3): δ (ppm) 174.5, 164.9, 163.9, 155.9, 134.1, 126.0, 125.5, 123.0, 119.8, 117.8, 67.2, 66.8, 47.3, 42.3, 19.1. HRMS (ESI) m/z: [M+H]+ calcd for C15H16NO4 274.1074; found 274.1080. 2-Methyl-4H-chromen-4-one (5a).19 The titled compound 5a was prepared according to the GP II and isolated as yellow solid (27.52 mg, 86%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.65–7.61 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 6.17 (s, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 178.4, 166.3, 156.6, 133.6, 125.8, 125.1, 123.7, 117.9, 110.7, 20.7. Methyl 2-methyl-4-oxo-4H-chromen-6-carboxylate (5b). The titled compound 5b was prepared according to the GP II and isolated as white solid (40.1 mg, 92%). IR (KBr): 3058, 1721, 1670, 1609, 1421, 1261 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.82 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.18 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.6, 166.6, 165.9, 159.0, 134.2, 128.3, 127.1, 123.3, 118.4, 111.1, 52.5, 20.7. HRMS (ESI) m/z: [M +H]+ calcd for C12H11O4 219.0652; found 219.0654. 6-Chloro-2-methyl-4H-chromen-4-one (5c).20 The titled compound 5c was prepared according to the GP II and isolated as white solid (21.0 mg, 54%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 6.17 (s, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.1, 166.6, 154.9, 133.8, 131.0, 125.3, 124.7, 119.7, 110.7, 20.7. 7-Chloro-2-methyl-4H-chromen-4-one (5d).21 The titled compound 5d was prepared according to the GP II and isolated as yellow solid (26.8 mg, 69%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.09 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.5, 166.5, 156.7, 139.6, 127.2, 125.9,



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122.2, 118.0, 110.9, 20.7. HRMS (ESI) m/z: [M+Na]+ calcd for C10H7ClO2Na 217.0027; found 217.0019. 6-Bromo-2-methyl-4H-chromen-4-one (5e).17 The titled compound 5e was prepared according to the GP II and isolated as yellow solid (30.6 mg, 64%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.29 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 6.18 (s, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.0, 166.7, 155.4, 136.6, 128.5, 125.1, 119.9, 118.5, 110.8, 20.7. HRMS (ESI) m/z: [M+Na]+ calcd for C10H7BrO2Na 260.9522; found 260.9514. 8-Fluoro-2-methyl-4H-chromen-4-one (5f). The titled compound 5f was prepared according to the GP II and isolated as white solid (23.5 mg, 66%). IR (KBr): 2924, 1716, 1644, 1362, 1264 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.92 (d, J = 8.0 Hz, 1H), 7.43–7.38 (m, 1H), 7.32 – 7.28 (m, 1H), 6.20 (s, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.3 (d, J = 2.8 Hz), 166.2, 151.1 (d, J = 253.0 Hz), 145.3 (d, J = 11.1 Hz), 125.6, 124.6 (d, J = 6.6 Hz), 120.8 (d, J = 4.2 Hz), 119.4 (d, J = 16.7 Hz), 111.0, 20.6. 19F NMR (376 MHz, CDCl3) δ (ppm) -133.67 (s, 1F). HRMS (ESI) m/z: [M+H]+ calcd. for C10H8FO2 179.0503; found 179.0507. 8-Chloro-2-methyl-4H-chromen-4-one (5g). The titled compound 5g was prepared according to the GP II and isolated as white solid (27.7 mg, 71%). IR (KBr): 2921, 1646, 1600, 1473, 1359 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 6.20 (s, 1H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.6, 166.5, 152.3, 133.9, 125.1, 125.07, 124.4, 122.9, 110.9, 20.7. HRMS (ESI) m/z: [M+H]+ calcd for C10H8ClO2 195.0207; found 195.0220. 8-Methoxy-2-methyl-4H-chromen-4-one (5h).17 The titled compound 5h was prepared according to the GP II and isolated as white solid (26.6 mg, 70%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.72 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H),


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6.18 (s, 1H), 3.98 (s, 3H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 178.3, 166.1, 148.7, 147.0, 124.7, 116.7, 114.3, 110.8, 56.4, 20.8. Methyl 2-(1,3-dioxoisoindolin-2-yl)-3-(2-methyl-4-oxo-4H-chromen-6-yl) propanoate (5i). The titled compound 5i was prepared according to the GP II and isolated as white solid (33 mg, 42%). IR (KBr): 2922, 1716, 1651, 1360, 1033 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.95 (d, J = 2.0 Hz, 1H), 7.79–7.76 (m, 2H), 7.70–7.67 (m, 2H), 7.47 (dd, J = 8.6, 2.2 Hz, 1H), 7.28 (s, 1H), 6.08 (s, 1H), 5.14 (dd, J = 11.1, 5.0 Hz, 1H), 3.78 (s, 3H), 3.68–3.57 (m, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 178.0, 169.1, 167.5, 166.2, 155.6, 134.4, 134.2, 134.0, 131.6, 125.9, 123.8, 123.6, 118.3, 110.7, 53.3, 53.2, 34.4, 20.7. HRMS (ESI) m/z: [M+H]+ calcd. for C22H18NO6 392.1134; found 392.1129. 7-methoxy-2-methyl-4H-chromen-4-one (5j).22 The titled compound 5j was prepared according to the GP II and isolated as gummy solid (30.7 mg, 81%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.3 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 3.87 (s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.8, 165.7, 164.0, 158.3, 127.1, 117.5, 114.1, 110.5, 100.3, 55.9, 20.5. 5-Allyl-2-methyl-4H-chromen-4-one (6). The titled compound 6 was prepared according to the literature known procedure14b using 0.2 mmol of 5a and isolated as white solid (18.8 mg, 47%). IR (KBr): 2923, 1649, 1603, 1471, 1388 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.50 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.13–6.05 (m, 2H), 5.04–4.99 (m, 2H), 4.10 (d, J = 6.3 Hz, 2H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 180.0, 164.3, 158.2, 142.8, 137.9, 132.7, 126.9, 121.4, 116.5, 115.5, 112.1, 38.8, 20.2. HRMS (ESI) m/z: [M+Na]+ calcd for C13H12O2Na 223.0730; found 223.0721. N-(2-Methyl-4-oxo-4H-chromen-5-yl)benzamide (7). The titled compound 7 was prepared according to the literature known procedure14c using 0.2 mmol of 5a and isolated as yellow solid (29.7 mg, 53%). IR (KBr): 2926, 1647, 1619, 1595, 1493, 1386 cm-1. 1H NMR (400



Page 24 of 32

MHz, CDCl3): δ (ppm) 13.58 (s, 1H), 8.85 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 8.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H), 2.41 (s, 3H). 13

C NMR (101 MHz, CDCl3): δ (ppm) 182.5, 166.4, 166.3, 157.5, 141.2, 135.0, 134.8, 132.1,

128.9, 127.7, 115.0, 111.7, 111.4, 110.9, 20.5. HRMS (ESI) m/z: [M+Na]+ calcd for C17H13NO3Na 302.0788; found 302.0782. (E)-Methyl 3-(2-methyl-4-oxo-4H-chromen-5-yl) acrylate (8). The titled compound 8 was prepared according to the literature known procedure14d using 0.2 mmol of 5a and isolated as white solid (22.1 mg, 45%). IR (KBr): 2922, 1712, 1648, 1616, 1365 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.98 (d, J = 16.0 Hz, 1H), 7.61–7.57 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 6.14 (s, 1H), 3.81 (s, 3H), 2.35 (s, 3H) 13C NMR (101 MHz, CDCl3): δ (ppm) 179.5, 167.1, 165.1, 157.6, 145.2, 137.0, 132.9, 124.6, 121.2, 121.1, 119.5, 112.0, 51.9, 20.3. HRMS (ESI) m/z: [M+Na]+ calcd for C14H12O4Na 267.0628; found 267.0604. 1-Methyl-3-(2-methyl-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione

(9).

The

titled

compound 9 was prepared according to the literature knpwn procedure14f using 0.2 mmol of 5a and isolated as white solid (37.9 mg, 57%). IR (KBr): 2925, 1697, 1647, 1361, 1278 cm-1. 1H NMR (400 MHz, DMSO-D6): δ (ppm) 7.75–7.71 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 6.0 Hz, 1H), 6.18 (s, 1H), 4.47–4.28 (m, 1H), 3.07–2.94 (m, 1H), 2.89 (s, 3H), 2.56–2.52 (m, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, DMSO-D6): δ (ppm) 178.2, 177.5, 176.6, 166.0, 157.7, 133.6, 120.4, 118.9, 110.7, 37.1, 24.5, 19.6. HRMS (ESI) m/z: [M+Na]+ calcd for C15H13NO4Na 294.0737; found 294.0731. (E)-Butyl 3-(2-methyl-4-oxo-4H-chromen-3-yl)acrylate (10). The titled compound 10 was prepared according to the literature known procedure14e using 0.2 mmol of 5a and isolated as white solid (24.6 mg, 43%). IR (KBr): 2957, 1710, 1647, 1613, 1288 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.22 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 15.8 Hz,


Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1H), 7.42–7.36 (m, 3H), 4.20 (t, J = 6.6 Hz, 2H), 2.62 (s, 3H), 1.69–1.66 (m, 2H), 1.46–1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 176.4, 168.2, 167.8, 155.2, 134.9, 133.8, 126.4, 125.6, 123.6, 123.3, 117.8, 116.3, 64.5, 30.9, 19.3, 13.9. HRMS (ESI) m/z: [M+Na]+ calcd for C17H18O4Na 309.1097; found 309.1074. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Mechanistic studies and NMR spectra (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Modhu Sudan Maji: 0000-0001-9647-2683 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT M.S.M. gratefully acknowledge SERB, Department of Science and Technology, New Delhi, India (Sanction No. CRG/2018/000317) for funding. S.D. and M.R.S. sincerely thanks IIT Kharagpur for fellowships. REFERENCES (1) (a) Trost, B. M. The Atom Economy-a Search for Synthetic Efficiency. Science 1991, 254, 1471. (b) Wender, P. A.; Miller, B. L. Synthesis at the Molecular Frontier. Nature 2009, 460, 197.



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Commun. 2015, 51, 13791. (g) Grenet, E.; Waser, J. ridium- and Rhodium-Catalyzed Directed C–H Heteroarylation of Benzaldehydes with Benziodoxolone Hypervalent Iodine Reagents. Org. Lett. 2018, 20, 1473. (h) Debbarma, S.; Maji, M. S. Cp*RhIII-Catalyzed Directed Amidation of Aldehydes with Anthranils. Eur. J. Org. Chem. 2017, 3699. (i) Debbarma, S.; Bera, S. S. Maji, M. S. Harnessing Stereospecific Z‑Enamides through Silver-Free Cp*Rh(III) Catalysis by Using Isoxazoles as Masked Electrophiles. Org. Lett. 2019, 21, 835. (13) For selected examples on α-diazo carbonyl, see: (a) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Modern Organic Synthesis with α‑Diazocarbonyl Compounds. Chem. Rev. 2015, 115, 9981. (b) Hyster, T. K.; Ruhl, K. E.; Rovis, T. A Coupling of Benzamides and Donor/Acceptor Diazo Compounds to Form γ‑Lactams via Rh(III)Catalyzed C−H Activation. J. Am. Chem. Soc. 2013, 135, 5364. (c) Shi, Z.; Koester, D. C.; Boultadakis-Arapinis M.; Glorius, F. Rh(III)-Catalyzed Synthesis of Multisubstituted Isoquinoline and Pyridine N‑Oxides from Oximes and Diazo Compounds. J. Am. Chem. Soc. 2013, 135, 12204. (d) Das, D.; Biswas, A.; Karmakar, U.; Chand, S. Samanta, R. C6-Selective Direct Alkylation of Pyridones with Diazo Compounds under Rh(III)-Catalyzed Mild Conditions. J. Org. Chem. 2016, 81, 842. (e) Li, J.; Tang, M.; Zang, L.; Zhang, X.; Zhang, Z.; Ackermann, L. Amidines for Versatile Cobalt(III)-Catalyzed Synthesis of Isoquinolines through C−H Functionalization with Diazo Compounds. Org. Lett. 2016, 18, 2742. (f) Li, B.; Zhang, B.; Zhang, X.; Fan, X. Regio-Selective Synthesis of Diversely Substituted Benzo[a]carbazoles through Rh(III)-Catalyzed Annulation of 2-Arylindoles with α-Diazo Carbonyl Compounds. Chem. Commun. 2017, 53, 1297. (g) Shen, B.; Wan, B.; Li, X. Enantiodivergent

Desymmetrization

in

the

Rhodium(III)-Catalyzed

Annulation

of

Sulfoximines with Diazo Compounds. Angew. Chem. Int. Ed. 2018, 57, 15534. (h) Aher, Y. N.; Lade, D. M.; Pawar, A. B. Cp*Ir(III)-Catalyzed C–H/N–H Functionalization of Sulfoximines for the Synthesis of 1,2-Benzothiazines at Room Temperature. Chem. Commun.


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(18) Macklin, T. K.; Panteleev, J.; Snieckus, V. Carbamoyl Translocations by an Anionic ortho‐Fries

and

Cumulenolate

α‐Acylation

Pathway:

Regioselective

Synthesis

of

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