Cerium(III)-Catalyzed Facile Synthesis of Dihydrobenzofuran-Tethered Pyridines and Dihydroquinolin-5(6H)-ones from β-Enaminones

Abstract

A series of novel dihydrobenzofuran-tethered pyridines, dihydroquinolin-5(6H)-ones, and indeno[1,2-b]pyridin-5-ones were synthesized in very good yields by CeCl₃˙7H₂O-NaI catalyzed one-pot condensation of variants of the Bohlmann-Rahtz reaction, viz. β-enaminones derived from 7-acetyldihydrobenzofurans, acyclic and cyclic 1,3-dicarbonyls, and ammonium acetate. The protocol offers the advantages of easily accessible substrates, shorter reaction times, and easy work-up with a readily available catalyst. Further more, dihydrobenzofuran-substituted 2-(chloromethyl)pyridine was derivatized to its synthetic hybrid by reacting with piperazine.

The prevalence and diversity of polysubstituted aromatic nitrogen heterocycles, viz. pyridine and quinolinones, found in natural products and used in medicinal chemistry continues to fuel the development of newer methods and strategies for their synthesis. [¹] Notable natural products and other successful synthetic drug candidates having a 2,3,6-substituted pyridine central core unit are depicted in Figure  [¹] . [²] [³] In an effort to develop a new heterocyclic library with drug-like properties, we thought to synthesize a series of analogues containing both pyridine and dihydrobenzofuran moieties in one molecular frame. A promising approach for the preparation of these structurally related pyridine-dihydrobenzofuran conjugates [4] [5] would be through multicomponent reactions (MCR). [6] [7]

Incisive work from Bagley [²] [8] has unveiled a remarkable variant of the classical Bohlmann-Rahtz synthesis, [8c] wherein an alkynone was combined with aminoalkenoate to give substituted pyridine derivatives. From our research [9] as well as work from others [¹0] it is clear that β-enaminones could serve as Bohlmann-Rahtz variants of polarized alkynones in the synthesis of 2,3,6-trisubstituted pyridines. In recent years, among the lanthanide catalysts, cerium(III) chloride has emerged as an inexpensive, efficient, and green reagent (in fact, it shows the same toxicity­ level as sodium chloride) that is able to catalyze various selective chemical transformations and cyclizations. [¹¹] In most cases, the activity of cerium(III) chloride can be increased in combination with sodium iodide. [¹²] The successful utility of cerium(III) in reactions originated from 1,3-dicarbonyls [¹²] prompted us to investigate its applicability in the one-pot condensation of β-enaminones with 1,3-dicarbonyls and ammonium acetate.

We herein report an efficient CeCl₃˙7H₂O-NaI catalyzed regioselective conversion of newly synthesized dihydrobenzofuranyl-substituted enaminones 1a,b into novel substituted pyridines and dihydroquinolin-5(6H)-ones tethered with a dihydrobenzofuran group through a Michael addition, cyclodehydration, and elimination sequence. One-pot reaction of (E)-1-(2,3-dihydrobenzofuran-7-yl)-3-(dimethylamino)prop-2-enones 1a,b, derived from the respective commercially available 2′-hydroxy­acetophenones, with readily available acyclic and cyclic 1,3-dicarbonyls 2a-m and ammonium acetate in propan-2-ol in the presence of CeCl₃˙7H₂O-NaI catalyst resulted in the title compounds with high regioselectivity at the 2,3,6-positions. Furthermore the current method is easy to perform and broad in scope and generates a novel library of substituted dihydroquinolin-5-one motifs bearing dihydrobenzofurans in the tether. Dihydrobenzofuran-substituted 2-(chloromethyl)pyridine was also derivatized further to a synthetic hybrid by reacting with piperazine to give a complex drug-like structure.

Table 1 Optimization of the Catalyst and Reaction Conditions^a

Entry	Catalyst	mol%	Time (h)	Temp (˚C)	Solvent	Yieldb (%)
1	K5CoW12O40˙3H2O	20	8.0	reflux	i-PrOH	58
2	K5CoW12O40˙3H2O	30	8.0	reflux	i-PrOH	60
3	SnCl2˙2H2O	30	24.0	reflux	MeOH	15
4	CeCl3˙7H2O	30	24.0	reflux	i-PrOH	52
5	CeCl3 (anhyd)	30	24.0	reflux	i-PrOH	12
6	CeCl3˙7H2O-NaI	20	5.0	80	DMF	35
7	CeCl3˙7H2O-NaI	20	5.0	reflux	MeOH	66
8	CeCl3˙7H2O-NaI	20	8.0	reflux	MeCN	62
9	CeCl3˙7H2O-NaI	20	24.0	reflux	DCE	38
10	CeCl3˙7H2O-NaI	20	24.0	85	H2O	23
11	CeCl3˙7H2O-NaI	20	4.0	reflux	i-PrOH	82
12	CeCl3˙7H2O-NaI	20	4.0	85	neat	58
13	CeCl3˙7H2O-NaI	30	4.0	reflux	i-PrOH	80
14	CeCl3˙7H2O-NaI	10	4.0	reflux	i-PrOH	58
15	NaI	20	4.0	reflux	i-PrOH	<1
a All reactions were performed with 1a (1.0 mmol), 2a (1.2 mmol), NH4OAc (2.0 mmol). b Isolated yield.

Due to the presence of the ambident nucleophilic character of the enamine moiety and ambident electrophilic character of the enone moiety, β-enaminones are useful synthetic intermediates in organic synthesis. [¹0] A variety of intra- and intermolecular reactions have been performed taking advantage of their electronic properties. β-Enaminones are generally prepared by the condensation of the respective aryl methyl ketones with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in refluxing xylene. [¹0h] [i] Although the method is readily adopted, there is no synthetic protocol for the preparation of 2,3-dihydrobenzofuran-7-ylenaminones 1a,b. The required starting compound, (2,3-dihydrobenzofuran-7-yl)ethanone, [¹³] was prepared by following the reaction sequence depicted in Scheme  [¹] . It was then converted into β-enaminones 1a,b by refluxing with N,N-dimethylformamide dimethyl acetal in xylene [overall yields 1a (39%) and 1b (44%)]. The products 1a and 1b were fully characterized by ^¹H and ^¹³C NMR and mass spectral analysis.

On the basis of our previous work, [9] initially, β-enaminone 1a (a polarized variant of a Bohlmann-Rahtz alkynone) was selected to react with ethyl acetoacetate (2a) and ammonium acetate in the presence of 20 mol% of potassium dodecatungstocobaltate (K₅CoW₁₂O₄₀˙3H₂O) catalyst. The target product ethyl 6-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methylnicotinate (3aa) was obtained in 58% yield. In order to improve the reaction efficiency, the reaction conditions were optimized (Table  [¹] ). A study designed to optimize yields showed CeCl₃˙7H₂O-NaI (20 mol%) to be superior to K₅CoW₁₂O₄₀˙3H₂O. The reaction was facile only when CeCl₃˙7H₂O in combination with sodium iodide was used and no reaction took place with sodium iodide alone. In the absence of sodium iodide, the reaction with CeCl₃˙7H₂O requires 24 hours to give product 3aa in 52% yield (entry 4). The results described here established that the water associated with the cerium(III) salt plays a role in the ability of the CeCl₃˙7H₂O-NaI to promote the condensation of enaminone 1a with ethyl acetoacetate­ (2a). Screening various solvents (DMF, MeOH, i-PrOH, MeCN, H₂O, and neat) and reaction conditions resulted optimum yield (82%; entry 11) of 3aa in propan-2-ol at reflux temperature.

Table 2 Cerium(III)-Catalyzed One-Pot Synthesis of Dihydrobenzofuranyl Nicotinates 3aa-3bb ^a

Entry	Enaminone	1,3-Dicarbonyl			Time (h)	Product	Yieldb (%)
		R²	R³
1	1a	Me	OEt	2a	4.0	3aa	82
2	1a	Me	Me	2b	4.0	3ab	78
3	1a	Me	Ot-Bu	2c	4.0	3ac	60
4	1a	Me	OMe	2d	4.0	3ad	85
5	1a	CH2Cl	OEt	2e	6.0	3ae	83
6	1a	Pr	OEt	2f	6.0	3af	64
7	1a	CF3	OEt	2g	12.0	3ag	<1
8	1a	Me	OCF3	2h	12.0	3ah	<1
9	1b	Me	OEt	2a	4.0	3ba	80
10	1b	Me	OMe	2b	4.0	3bb	82
a Reaction conditions: 1a,b (1.0 mmol), 2a-h (1.2 mmol), NH4OAc (2.0 mmol), i-PrOH, reflux. b Yields refer to pure isolated products after column chromatography.

After screening the reaction parameters, we next examined the broader scope of the reaction with various acyclic 1,3-dicarbonyls 2a-h and ammonium acetate under optimal conditions [CeCl₃˙7H₂O-NaI (20 mol%), i-PrOH, reflux]. All the acyclic 1,3-dicarbonyls except 2g and 2h reacted well with both the enaminones 1a and 1b and the corresponding dihydrobenzofuran-tethered 2,3,6-trisubstituted pyridines 3 were obtained in very good yields (Table  [²] ). However, the cerium(III)-catalyzed condensation of enaminone 1a with the trifluoromethyl analogues of 1,3-dicarbonyls 2g,h and ammonium acetate (entries 7 and 8) was sluggish resulting in the formation of several unidentified byproducts. The structures of dihydrobenzofuran-conjugated 2,3,6-trisubstituted pyridines 3 were clearly assigned from their IR, ^¹H and ^¹³C NMR, ESI-MS, and HRMS analysis. Further the structures of 3aa and 3ae were unambiguously confirmed by single crystal X-ray diffraction analysis (Figures  [²] and  [³] ).

Encouraged by the good results acquired from acyclic 1,3-dicarbonyls in the generation of pyridine scaffolds, we then proceeded to investigate scope of this reaction with cyclic 1,3-dicarbonyls 2i-m. An array of dihydrobenzo­furan-appended quinolinones (Scheme  [²] ) with structural diversity was synthesized in an effort to generate novel analogues of lavendamycin-like compounds (lavendamycin is an anticancer drug). For example, the reaction of β-enaminone 1a with cyclohexane-1,3-dione (2i) and ammonium acetate in the presence of CeCl₃˙7H₂O-NaI under optimized conditions afforded 2-(2,4-dimethyl-2,3-dihydrobenzofuran­-7-yl)-7,8-dihydroquinolin-5(6H)-one (4ai) in 85% yield (Scheme  [²] ). In a similar fashion, β-enaminones 1a,b reacts with 4,4-dimethylcyclohexane-1,3-dione (2k) regioselectively to give 6,6-dimethyl-7,8-dihydroquinolin-5(6H)-ones 4ak and 4bk, respectively, as the sole product in 76% and 72% yields. Other cyclic 1,3-diketones such as dimedone (2j) and cycloheptane-1,3-dione (2l) also proceeded efficiently to afford 7,8-dihydroquinolin-5(6H)-ones 4aj, 4bj, and 4al. On the other hand, to achieve further diversity, β-enaminones 1a,b were condensed with indane-1,3-dione 2m under the standard one-pot protocol resulting in novel analogues of indeno[1,2-b]pyridin-5-ones 4am and 4bm in very good yields. The structures of all the products were fully characterized by IR, ^¹H and ^¹³C NMR, ESI-MS, and HRMS analysis.

Further to generate more complex pharmacophoric derivatives, ethyl 2-(chloromethyl)-6-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)nicotinate (3ae) was treated with pyridine, 4-(dimethylamino)pyridine, and N-phenylpiperazine in acetonitrile at room temperature (Scheme  [³] ). Ethyl 6-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)-2-[(4-phenylpiperazin-1-yl)methyl]nicotinate (5) was obtained in 77% yield and it was fully characterized by IR, ^¹H and ^¹³C NMR, ESI-MS, and HRMS analysis. A plausible mechanism for the tandem Michael addition-cyclodehydration-elimination sequence using the reaction of enaminone 1a and ethyl acetoacetate (2a) as an example is shown in Scheme  [4] . At first cerium-activated reaction of 1,3-dicarbonyl 2a with ammonium acetate would occur provide an amine. This amine, further undergoes cerium-assisted regioselective Michael addition on the polarized β-enaminone 1a followed by cyclodehydration. Aromatization leading to the pyridine ring with elimination of dimethylamine completes the catalytic cycle.

In summary, we have developed an efficient cerium(III)-catalyzed protocol for one-pot regioselective synthesis of novel dihydrobenzofuran-tethered pyridines and dihydroquinolin-5(6H)-ones employing β-enaminones 1a,b and acyclic and cyclic 1,3-dicarbonyls as novel variants of the Bohlmann-Rahtz substrate, and ammonium acetate in refluxing propan-2-ol. Mechanistically, the reaction proceeds through sequential Michael addition, cyclodehydration, and elimination reactions. The method appears to be very general and reactive with respect to starting materials. It is likely that the efficiency and novelty of this method combined with its operational simpli­city will make it attractive for the construction of a library of compounds.

All reactions were monitored by TLC (recoated silica plates and visualizing under UV light). Air-sensitive reagents were transferred by syringe or a double-ended needle. Evaporation of solvents was performed at reduced pressure on a Buchi rotary evaporator. ^¹H and ^¹³C NMR spectra of samples in CDCl₃ were recorded on Bruker UXNMR FT-300 MHz (Avance) spectrometer and Varian FT-500 MHz (Inova) relative to an internal standard TMS. Mass spectra were recorded under EI conditions at 70 eV on a LC-MSD (Agilent technologies) spectrometer. All HRMS were recorded on a QSTAR XL hybrid MS/MS system (Applied Biosystems/MDS sciex), equipped with an ESI source (IICT, Hyderabad). Column chromatography was performed on silica gel (60-120 mesh) supplied by Acme Chemical Co., India. TLC was performed on Merck 60 F-254 silica gel plates. Optical rotations were measured with a Jasco DIP-370 polarimeter at 25 ˚C. Commercially available anhyd solvents CH₂Cl₂, THF, and EtOAc were used as such without further purification. Methyl isobutyl ketone = MIBK.

1-[2-(Allyloxy)-4-methylphenyl]ethanone; Typical Procedure

To a soln of 2′-hydroxy-4′-methylacetophenone (31.53 g, 0.21 mol) in MIBK (470 mL) was added anhyd K₂CO₃ (29.0 g, 0.21 mol) followed by allyl bromide (32 mL, 0.25 mol). The mixture was refluxed for 8 h and then it was filtered, the residue was washed with MIBK (3 × 25 mL), and the combined solvent was evaporated to dryness. The crude residue was redissolved in CHCl₃ (175 mL), washed with H₂O (3 × 50 mL) and brine (50 mL), dried (Na₂SO₄), and concentrated under vacuum. Purification by column chromatography (silica gel, hexane-EtOAc, 9:1) yielded the product (37.1 g, 93%) as a white solid; mp 48 ˚C (Lit. [¹] 48-49 ˚C).

^¹H NMR (300 MHz, CDCl₃): δ = 7.64 (d, J = 7.7 Hz, 1 H), 6.77 (d, J = 7.7 Hz, 1 H), 6.69 (s, 1 H), 6.01-6.14 (m, 1 H), 5.29-5.46 (m, 2 H), 4.62 (dt, J = 5.2, 1.5 Hz, 2 H), 2.58 (s, 3 H), 2.38 (s, 3 H).

1-(3-Allyl-2-hydroxy-4-methylphenyl)ethanone; Typical Procedure

1-[2-(Allyloxy)-4-methylphenyl]ethanone (15.92 g, 83.78 mmol) was heated neat at 180 ˚C for 5 h (TLC monitoring). The mixture was then cooled to r.t. and purified by column chromatography (silica gel, hexane-EtOAc, 9:1) to give the product (14.64 g, 92%) as a light yellow syrup.

^¹H NMR (300 MHz, CDCl₃): δ = 12.6 (s, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 5.80-5.93 (m, 1 H), 4.88-4.97 (m, 2 H), 3.42 (d, J = 6.0 Hz, 2 H), 2.58 (s, 3 H), 2.31 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 204.0, 160.4, 146.2, 135.0, 128.2, 126.6, 122.3, 120.6, 114.6, 29.5, 26.3, 19.9.

1-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone; Typical Procedure

To a soln of 1-(3-allyl-2-hydroxy-4-methylphenyl)ethanone (10 g, 52.63 mmol) in 1,4-dioxane (225 mL) was added concd H₂SO₄ (29 mL) at 0 ˚C with stirring over 10 min. The mixture was heated to 100 ˚C for 4 h and then it was cooled to r.t. and neutralized (sat. aq Na₂CO₃). The soln was taken in a separating funnel and EtOAc (80 mL) was added; the combined organic layer was separated, washed with H₂O (3 × 30 mL) and brine (25 mL), dried (Na₂SO₄), and concentrated. Column chromatography (silica gel, hexane-EtOAc, 9:1) gave the product (6.50 g, 65%) as a white solid; mp 75 ˚C (Lit. [¹³] 73-74 ˚C).

^¹H NMR (300 MHz, CDCl₃): δ = 7.57 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 8.0 Hz, 1 H), 4.99-5.08 (m, 1 H), 3.24 (dd, J = 9.1, 6.2 Hz, 1 H), 2.71 (dd, J = 7.3, 8.0 Hz, 1 H), 2.55 (s, 3 H), 2.24 (s, 3 H), 1.52 (d, J = 6.2 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 196.9, 159.6, 140.3, 128.0, 127.6, 121.4, 118.4, 80.4, 35.3, 30.8, 22.0, 19.2.

3-(Dimethylamino)-1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)propenone (1a); Typical Procedure

To a soln of 1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone (2.0 g, 10.52 mmol) in xylene (20 mL) was added DMF-DMA (2.94 mL, 21.05 mmol) under N₂ and the mixture was refluxed for 7 h (TLC monitoring). Xylene was then removed by distillation and the crude residue was triturated with hexane. The solid residue thus formed was filtered to give 1a (1.8 g, 70%) as a pure light brown solid; mp 139 ˚C.

IR (KBr): 2908, 1635, 1545, 1360, 1259, 1232, 1081, 905, 877 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, J = 12.2 Hz, 1 H), 7.63 (d, J = 7.1 Hz, 1 H), 6.65 (d, J = 7.1 Hz, 1 H), 6.02 (d, J = 12.2 Hz, 1 H), 4.96-5.03 (m, 1 H), 3.23 (dd, J = 9.1, 6.1 Hz, 1 H), 3.01 (br s, 6 H), 2.71 (dd, J = 7.1, 7.1 Hz, 1 H), 2.23 (s, 3 H), 1.52 (d, J = 6.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 186.2, 157.7, 153.4, 137.6, 128.3, 126.8, 121.2, 79.7, 44.7, 35.4, 22.0, 19.0.

MS (ESI): m/z = 246 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀NO₂: 246.1494; found: 246.1497.

1-[2-(Allyloxy)-5-fluorophenyl]ethanone

Following the typical procedure for 1-[2-(allyloxy)-4-methylphenyl]ethanone using 5′-fluoro-2′-hydroxyacetophenone (27.8 g, 0.18 mol), MIBK (400 mL), anhyd K₂CO₃ (24.9 g, 0.18 mol), and allyl bromide (18.8 mL, 0.21 mol); washing with MIBK (3 × 30 mL), redissolved in CHCl₃ (150 mL), washed with H₂O (3 × 50 mL) and brine soln (50 mL), column chromatography (silica gel, hexane-EtOAc, 9:1) yielded the product (33.6 g, 96%) as a low melting white solid; mp 38 ˚C.

^¹H NMR (300 MHz, CDCl₃): δ = 7.43 (dd, J = 3.1, 5.7 Hz, 1 H), 7.07-7.11 (m, 1 H), 6.87 (dd, J = 3.9, 5.2 Hz, 1 H), 6.01-6.09 (m, 1 H), 5.41 (dd, J = 1.3, 1.3 Hz, 1 H), 5.32 (dd J = 1.3, 1.0 Hz, 1 H), 4.60 (d, J = 5.2 Hz, 2 H), 2.60 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 198.2, 158.2, 155.0, 132.3, 120.0, 119.7, 118.3, 116.5, 114.2, 69.9, 31.7.

1-(3-Allyl-5-fluoro-2-hydroxyphenyl)ethanone

Following the typical procedure for 1-(3-allyl-2-hydroxy-4-methylphenyl)ethanone using 1-[2-(allyloxy)-5-fluorophenyl]ethanone (30.1 g, 0.155 mol) gave the product (27.1 g, 90%) as a light yellow syrup.

^¹H NMR (300 MHz, CDCl₃): δ = 12.27 (s, 1 H), 7.22 (dd, J = 3.0, 5.4 Hz, 1 H), 7.08 (dd, J = 3.0, 5.4 Hz, 1 H), 5.86-5.99 (m, 1 H), 5.07-5.12 (m, 2 H), 3.39 (d, J = 6.8 Hz, 2 H), 2.59 (s, 3 H).

1-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)ethanone

Following the typical procedure for 1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone using 1-(3-allyl-5-fluoro-2-hydroxy­phenyl)ethanone (9.34 g, 48.14 mmol), 1,4-dioxane (225 mL), and concd H₂SO₄ (25.6 mL); workup used EtOAc (100 mL) and H₂O (3 × 50 mL) and brine (25 mL). Column chromatography (silica gel, hexane-EtOAc, 9:1) gave the product (6.53 g, 70%) as a thick syrup.

^¹H NMR (300 MHz, CDCl₃): δ = 7.27 (d, J = 9.8 Hz, 1 H), 6.96 (d, J = 7.1 Hz, 1 H), 4.98-5.08 (m, 1 H), 3.32 (dd, J = 7.7, 7.9 Hz, 1 H), 2.81 (dd, J = 7.5, 7.3 Hz, 1 H), 2.54 (d, J = 3.9 Hz, 3 H), 1.52 (dd, J = 3.2, 3.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 195.7, 158.2, 155.1, 131.2, 129.3, 117.4, 112.8, 81.1, 36.3, 30.8, 21.6.

3-(Dimethylamino)-1-(5-fluoro-2,3-dihydrobenzofuran-7-yl)propenone (1b)

Following the typical procedure for 1a using 1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone (2.50 g, 12.8 mmol), xylene (30 mL), and DMF-DMA (3.60 mL, 25.7 mmol) gave 1b (2.34 g, 73%) as a pure light brown solid; mp 78 ˚C.

IR (KBr): 2926, 1634, 1552, 1438, 1364, 1255, 1171, 1103, 1037, 972, 800, 741 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 12.7 Hz, 1 H), 7.39 (dd, J = 2.9, 6.8 Hz, 1 H), 6.87 (dd, J = 2.9, 3.9 Hz, 1 H), 6.00 (d, J = 12.7 Hz, 1 H), 4.95-5.02 (m, 1 H), 3.29 (dd, J = 6.8, 8.8 Hz, 1 H), 3.02 (br s, 6 H), 2.80 (dd, J = 7.8, 7.8 Hz, 1 H), 1.50 (d, J = 6.8 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 184.4, 158.6, 155.5, 153.8, 129.7, 129.6, 123.6, 114.8, 113.7, 80.2, 44.7, 36.7, 21.8.

MS (ESI): m/z = 250 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₇NO₂F: 250.1243; found: 250.1249.

2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-7,8-dihydroquinolin-5(6 H )-one (4ai); Typical Procedure

To a mixture of 1a (0.245 g, 1.0 mmol), dione 2i (0.13 g, 1.2 mmol), and NH₄OAc (0.15 g, 2.0 mmol) in i-PrOH (5 mL) was added CeCl₃˙7H₂O (75 mg, 0.2 mmol) and NaI (30 mg, 0.2 mmol) and the mixture was refluxed for 4 h (TLC monitoring). The mixture was cooled to r.t. and the solid precipitate was filtered and washed (cold i-PrOH). The combined solvent was evaporated and the crude residue was subjected to column chromatography (silica gel, hexane-EtOAc, 9:1) to give 4ai (0.25 g, 85%) as a pale yellow solid; mp 112 ˚C.

IR (KBr): 2924, 2853, 1682, 1577, 1454, 1420, 1382, 1240, 1189, 1020, 898, 815, 775 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.22 (d, J = 8.3 Hz, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.01 (d, J = 7.5 Hz, 1 H), 6.74 (d, J = 7.5 Hz, 1 H), 5.01-5.08 (m, 1 H), 3.28 (dd, J = 9.0, 6.0 Hz, 1 H), 3.16 (t, J = 6.0 Hz, 2 H), 2.76 (dd, J = 7.5, 7.5 Hz, 1 H), 2.66 (t, J = 6.0 Hz, 2 H), 2.26 (s, 3 H), 2.17-2.23 (m, 2 H), 1.54 (d, J = 6.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 198.0, 163.2, 158.4, 157.8, 136.8, 135.1, 128.1, 127.0, 125.7, 122.0, 121.8, 80.0, 38.6, 35.6, 32.8, 29.6, 22.1, 14.0.

MS (ESI): m/z = 294 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀NO₂: 294.1494; found: 294.1496.

Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methyl­nicotinate (3aa)

Yield: 82%; mp 96 ˚C.

IR (KBr): 2981, 1714, 1578, 1449, 1372, 1257, 1195, 1035, 863, 823, 724 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.18 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 5.00-5.09 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.27 (dd, J = 8.8, 6.0 Hz, 1 H), 2.86 (s, 3 H), 2.75 (dd, J = 7.5, 7.7 Hz, 1 H), 2.26 (s, 3 H), 1.53 (d, J = 6.3 Hz, 3 H), 1.40 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.4, 159.2, 157.7, 156.3, 138.7, 136.1, 128.3, 126.6, 122.4, 121.9, 120.3, 118.5, 79.7, 60.6, 35.8, 25.3, 22.2, 19.1, 14.4.

MS (ESI): m/z = 312 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₂NO₃: 312.1599; found: 312.1597.

1-[6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methylpyridin-3-yl]ethanone (3ab)

Yield: 78%; mp 110 ˚C.

IR (KBr): 2926, 2853, 1740, 1580, 1419, 1359, 1244, 1189, 1152, 1032, 903, 821, 702 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.05 (q, 2 H), 7.97 (d, J = 8.3 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 5.00-5.08 (m, 1 H), 3.28 (dd, J = 9.0, 6.0 Hz, 1 H), 2.80 (s, 3 H), 2.76 (dd, J = 7.5, 7.54 Hz, 1 H), 2.57 (s, 3 H), 2.27 (s, 3 H), 1.54 (d, J = 6.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 199.9, 164.1, 157.6, 137.6, 136.5, 135.3, 129.6, 128.0, 121.9, 120.1, 114.2, 79.9, 35.7, 25.3, 22.1, 19.0, 14.3.

MS (ESI): m/z = 282 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₂: 282.1494; found: 282.1501.

tert -Butyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methyl­nicotinate (3ac)

Yield: 60%.

IR (neat): 2924, 1714, 1584, 1457, 1370, 1281, 1145, 1079, 909, 786 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.10 (d, J = 8.3 Hz, 1 H), 8.02 (d, J = 7.5 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 6.73 (d, J = 7.5 Hz, 1 H), 5.01-5.08 (m, 1 H), 3.27 (dd, J = 6.7, 7.5 Hz, 1 H), 2.83 (s, 3 H), 2.74 (dd, J = 6.7, 8.3 Hz, 1 H), 2.26 (s, 3 H), 1.59 (s, 9 H), 1.52 (d, J = 6.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.1, 158.5, 157.5, 155.9, 138.5, 136.0, 128.1, 126.6, 124.1, 121.8, 120.2, 118.4, 79.6, 51.2, 35.7, 27.8, 22.6, 18.9, 14.0.

MS (ESI): m/z = 340 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₆NO₃: 340.1912; found: 340.1902.

Methyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methylnicotinate (3ad)

Yield: 85%; mp 82 ˚C.

IR (KBr): 2936, 2846, 1715, 1584, 1426, 1371, 1268, 1241, 1190, 1158, 1082, 1034, 903, 824 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.16 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.2 Hz, 1 H), 6.74 (d, J = 8.2 Hz, 1 H), 5.02-5.07 (m, 1 H), 3.90 (s, 3 H), 3.28 (dd, J = 9.0, 6.0 Hz, 1 H), 2.86 (s, 3 H), 2.76 (dd, J = 7.3, 7.8 Hz, 1 H), 2.26 (s, 3 H), 1.54 (d, J = 6.3 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.7, 159.4, 156.5, 138.7, 136.0, 128.6, 126.5, 122.0, 120.3, 118.5, 79.7, 51.8, 35.9, 22.4, 19.2, 14.8.

MS (ESI): m/z = 298 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₃: 298.1443; found: 298.1433.

Ethyl 2-(Chloromethyl)-6-(2,4-dimethyl-2,3-dihydrobenzo­furan-7-yl)nicotinate (3ae)

Yield: 83%; mp 77 ˚C.

IR (KBr): 2976, 2854, 1720, 1585, 1492, 1461, 1418, 1366, 1192, 1108, 1028, 801, 738 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 8.1 Hz, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 5.12 (s, 2 H), 5.02-5.09 (m, 1 H), 4.41 (q, J = 7.1, 6.9 Hz, 2 H), 3.28 (dd, J = 8.6, 6.4 Hz, 1 H), 2.76 (dd, J = 6.9, 8.6 Hz, 1 H), 2.27 (s, 3 H), 1.54 (d, J = 5.8 Hz, 3 H), 1.44 (t, J = 6.9 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 165.5, 157.8, 156.9, 156.6, 139.5, 128.4, 126.8, 122.5, 122.1, 117.8, 80.0, 61.3, 46.3, 35.7, 22.2, 19.1, 14.3.

MS (ESI): m/z = 346 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₁NO₃Cl: 346.1209; found: 346.1199.

Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-propyl­nicotinate (3af)

Yield: 64%.

IR (neat): 2965, 2930, 1718, 1583, 1455, 1374, 1259, 1194, 1153, 1027, 792 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 6.74 (d, J = 7.9 Hz, 1 H), 4.98-5.07 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.27 (dd, J = 8.8, 6.6 Hz, 1 H), 3.17 (t, J = 7.9 Hz, 2 H), 2.76 (dd, J = 6.4, 7.7 Hz, 1 H), 2.26 (s, 3 H), 1.76-1.88 (m, 2 H), 1.53 (d, J = 6.2 Hz, 3 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.03 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 162.4, 157.6, 156.1, 138.6, 136.0, 128.2, 126.6, 122.4, 121.8, 120.0, 118.5, 79.6, 60.6, 35.7, 31.8, 29.6, 22.8, 14.23, 14.21.

MS (ESI): m/z = 340 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₆NO₃: 340.1912; found: 340.1919.

Ethyl 6-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-2-methyl­nicotinate (3ba)

Yield: 80%; mp 60 ˚C.

IR (KBr): 2924, 2853, 1728, 1584, 1467, 1430, 1264, 1210, 1177, 1083, 1032, 908, 816 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.19 (d, J = 8.7 Hz, 1 H), 8.06 (d, J = 8.7 Hz, 1 H), 7.88 (dd, J = 2.9, 7.7 Hz, 1 H), 6.86 (dd, J = 1.9, 4.8 Hz, 1 H), 5.01-5.06 (m, 1 H), 4.36 (q, J = 7.7 Hz, 2 H), 3.32 (dd, J = 8.7, 6.7 Hz, 1 H), 2.86 (s, 3 H), 2.83 (dd, J = 7.7, 7.7 Hz, 1 H), 1.52 (d, J = 5.8 Hz, 3 H), 1.40 (t, J = 7.7 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.0, 159.3, 159.1, 155.9, 154.8, 138.8, 129.4, 129.2, 123.2, 120.5, 114.0, 113.5, 80.3, 60.7, 36.9, 25.3, 21.9, 14.4.

MS (ESI): m/z = 316 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₉NO₃F: 316.1348; found: 316.1344.

Methyl 6-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-2-methylnicotinate (3bb)

Yield: 82%; mp 80 ˚C.

IR (KBr): 2924, 2853, 1728, 1584, 1467, 1430, 1264, 1210, 1177, 1083, 1032, 908, 816 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.18 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H), 7.88 (dd, J = 3.0, 7.5 Hz, 1 H), 6.86 (dd, J = 2.2, 4.5 Hz, 1 H), 5.00-5.09 (m, 1 H), 3.90 (s, 3 H), 3.32 (dd, J = 9.0, 6.7 Hz, 1 H), 2.86 (s, 3 H), 2.83 (dd, J = 7.5, 7.5 Hz, 1 H), 1.52 (d, J = 6.7 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 159.4, 159.0, 155.1, 154.0, 138.9, 129.8, 123.0, 120.5, 113.7, 113.6, 113.2, 80.5, 52.0, 36.8, 21.7, 14.0.

MS (ESI): m/z = 302 [M + H]⁺.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₆NO₃FNa: 324.1011; found: 324.1020.

2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-7,8-di­hydroquinolin-5(6 H )-one (4bi)

Yield: 79%; mp 124 ˚C.

IR (KBr): 2926, 1680, 1580, 1474, 1440, 1389, 1327, 1273, 1244, 1173, 1123, 1030, 839, 783 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 8.3 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.84 (dd, J = 2.6, 7.9 Hz, 1 H), 6.90 (dd, J = 2.8, 4.3 Hz, 1 H), 5.00-5.09 (m, 1 H), 3.35 (dd, J = 8.8, 6.7 Hz, 1 H), 3.17 (t, J = 6.2 Hz, 2 H), 2.85 (dd, J = 7.7, 7.9 Hz, 1 H), 2.67 (t, J = 6.9 Hz, 2 H), 2.22 (q, J = 6.4 Hz, 2 H), 1.54 (d, J = 6.2 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 197.0, 163.0, 159.1, 156.7, 154.1, 135.4, 129.6, 126.4, 122.1, 114.0, 113.7, 80.5, 38.6, 36.9, 32.9, 29.8, 22.1.

MS (ESI): m/z = 298 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₇NO₂F: 298.1243; found: 298.1244.

2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-7,7-dimethyl-7,8-dihydroquinolin-5(6 H )-one (4aj)

Yield: 82%; mp 105 ˚C.

IR (KBr): 2924, 1678, 1578, 1450, 1380, 1241, 1194, 1024, 905, 804, 765 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.20 (d, J = 8.3 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.01-5.09 (m, 1 H), 3.28 (dd, J = 8.8, 6.2 Hz, 1 H), 3.05 (s, 2 H), 2.76 (dd, J = 7.3, 7.3 Hz, 1 H), 2.50 (s, 2 H), 2.27 (s, 3 H), 1.54 (d, J = 6.2 Hz, 3 H), 1.14 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 198.1, 161.8, 158.8, 151.7, 136.8, 134.7, 128.2, 127.0, 124.7, 122.0, 121.7, 80.0, 52.1, 46.7, 35.7, 29.6, 28.3, 22.1, 19.0.

MS (ESI): m/z = 322 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₄NO₂: 322.1807; found: 322.1818.

2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-7,7-dimethyl-7,8-dihydroquinolin-5(6 H )-one (4bj)

Yield: 76%; mp 101 ˚C.

IR (KBr): 2930, 1682, 1578, 1460, 1384, 1286, 1176, 1113, 1028, 847, 756 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.23 (d, J = 7.8 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.85 (dd, J = 2.9, 6.8 Hz, 1 H), 6.90 (dd, J = 2.9, 3.9 Hz, 1 H), 5.02-5.09 (m, 1 H), 3.35 (dd, J = 6.8, 7.8 Hz, 1 H), 3.06 (s, 2 H), 2.86 (dd, J = 7.8, 7.8 Hz, 1 H), 2.52 (s, 2 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.14 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 196.8, 161.5, 159.2, 158.1, 157.0, 134.9, 125.5, 122.0, 114.3, 114.04, 114.01, 113.7, 80.5, 52.2, 46.8, 37.0, 33.0, 28.6, 28.5, 22.0.

MS (ESI): m/z = 326 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₁NO₂F: 326.1556; found: 326.1570.

2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6 H )-one (4ak)

Yield: 76%; mp 97 ˚C.

IR (KBr): 2922, 1675, 1582, 1381, 1238, 1191, 1025, 903, 781 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.24 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 5.01-5.06 (m, 1 H), 3.28 (dd, J = 9.7, 5.8 Hz, 1 H), 3.17 (t, J = 6.81 Hz, 2 H), 2.76 (dd, J = 7.8, 7.8 Hz, 1 H), 2.27 (s, 3 H), 2.04 (t, J = 6.8 Hz, 2 H), 1.54 (d, J = 6.2 Hz, 3 H), 1.23 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 202.4, 162.0, 158.2, 157.7, 136.7, 136.0, 128.1, 127.0, 124.4, 122.0, 121.8, 118.4, 80.0, 41.3, 35.7, 35.4, 29.6, 29.1, 24.2, 22.1, 19.0.

MS (ESI): m/z = 322 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₄NO₂: 322.1807; found: 322.1819.

2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6 H )-one (4bk)

Yield: 72%; mp 106 ˚C.

IR (KBr): 2928, 1679, 1471, 1442, 1386, 1353, 1324, 1238, 1182, 1103, 1031, 898, 791 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.28 (d, J = 8.7 Hz, 1 H), 8.14 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 10.7 Hz, 1 H), 6.90 (d, J = 5.8 Hz, 1 H), 5.02-5.09 (m, 1 H), 3.35 (dd, J = 6.8, 7.8 Hz, 1 H), 3.18 (t, J = 5.8 Hz, 2 H), 2.86 (dd, J = 7.8, 7.8 Hz, 1 H), 2.05 (t, J = 5.8 Hz, 2 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.24 (s, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 202.3, 162.1, 159.0, 156.7, 155.9, 136.2, 130.0, 125.1, 122.0, 114.0, 113.7, 113.4, 80.6, 41.4, 36.8, 35.3, 29.0, 24.1, 21.7.

MS (ESI): m/z = 326 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₁NO₂F: 326.1556; found: 326.1566.

2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-6,7,8,9-tetra­hydro-5 H -cyclohepta[ b ]pyridin-5-one (4al)

Yield: 58%; mp 79 ˚C.

IR (KBr): 2924, 2853, 1673, 1579, 1455, 1379, 1271, 1194, 906, 818 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.00-8.08 (m, 3 H), 6.73 (d, J = 8.3 Hz, 1 H), 4.97-5.10 (m, 1 H), 3.21-3.31 (m, 3 H), 2.71-2.81 (m, 3 H), 2.26 (s, 3 H), 1.88-2.02 (m, 4 H), 1.53 (d, J = 6.2 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 197.4, 166.7, 157.0, 156.1, 137.2, 131.1, 128.3, 122.0, 121.3, 79.8, 40.9, 36.1, 35.8, 31.9, 22.2, 21.4, 14.2.

MS (ESI): m/z = 308 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₂NO₂: 308.1650; found: 308.1660.

2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-5 H -indeno[1,2- b ]pyridin-5-one (4am)

Yield: 68%; mp 107 ˚C.

IR (KBr): 2921, 2851, 1706, 1574, 1406, 1346, 1251, 1194, 1098, 1024, 910, 806 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.18 (d, J = 8.1 Hz, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 7.93 (d, J = 7.3 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.69 (d, J = 7.3 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.3 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 5.02-5.11 (m, 1 H), 3.30 (dd, J = 9.0, 6.2 Hz, 1 H), 2.78 (dd, J = 7.3, 7.9 Hz, 1 H), 2.29 (s, 3 H), 1.57 (d, J = 6.2 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 186.9, 161.8, 159.0, 157.7, 134.6, 131.6, 130.5, 130.2, 128.7, 123.8, 122.6, 122.1, 121.0, 79.9, 35.9, 22.4, 16.7.

MS (ESI): m/z = 328 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₁₈NO₂: 328.1337; found: 328.1344.

2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-5 H -indeno[1,2- b ]pyridin-5-one (4bm)

Yield: 62%; mp146 ˚C.

IR (KBr): 2923, 2853, 1710, 1577, 1461, 1410, 1259, 1180, 1033, 911, 841, 763 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 8.16 (d, J = 8.3 Hz, 1 H), 8.01 (dd, J = 2.2, 8.30 Hz, 1 H), 7.94 (d, J = 7.5 Hz, 1 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 6.92 (dd, J = 2.2, 4.5 Hz, 1 H), 5.03-5.11 (m, 1 H), 3.37 (dd, J = 9.0, 6.7 Hz, 1 H), 2.88 (dd, J = 7.5, 7.5 Hz, 1 H), 1.57 (d, J = 6.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 188.7, 162.7, 159.2, 157.5, 142.0, 134.8, 131.7, 130.7, 123.9, 122.9, 121.1, 120.7, 114.3, 114.1, 113.9, 113.7, 80.6, 37.0, 22.1.

MS (ESI): m/z = 332 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₅NO₂F: 332.1086; found: 332.1082.

Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-[(4-phenylpiperazin-1-yl)methyl]nicotinate (5)

To a soln of 3ae (0.1 g, 0.29 mmol) in MeCN (3 mL), was added pyridine (0.5 mL), DMAP (10 mg), and N-phenylpiperzine (50 µL, 0.3 mmol) at r.t. The mixture was stirred for 6 h, it was concentrated under vacuum, and the residue was dissolved in EtOAc (10 mL), washed with H₂O (5 mL) and brine (5 mL), dried (anhyd Na₂SO₄), and evaporated. Purification by column chromatography (silica gel) yielded 6 (0.105 g, 77%) as a light brown solid; mp 158 ˚C.

IR (KBr): 2928, 1723, 1585, 1504, 1451, 1379, 1270, 1219, 911, 771 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.09 (d, J = 8.1 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.16 (q, J = 7.3 Hz, 2 H), 6.82 (d, J = 9.6 Hz, 2 H), 6.75 (t, J = 8.4 Hz, 2 H), 4.98-5.07 (m, 1 H), 4.32 (q, J = 6.9 Hz, 2 H), 4.05 (s, 2 H), 3.24 (dd, J = 8.6, 6.4 Hz, 1 H), 3.11 (t, J = 4.9 Hz, 4 H), 2.73 (dd, J = 7.3, 7.9 Hz, 1 H), 2.67 (t, J = 5.2 Hz, 4 H), 2.24 (s, 3 H), 1.51 (d, J = 6.2 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 157.6, 156.2, 155.5, 151.0, 138.1, 136.1, 128.9, 128.3, 126.5, 124.5, 122.0, 121.5, 119.7, 118.2, 116.1, 79.7, 62.1, 60.9, 52.9, 48.6, 35.7, 22.2, 19.0, 14.3.

MS (ESI): m/z = 472 [M + H]⁺.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₄O₃N₃: 472.2600; found: 472.2611.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis. Included are copies of ^¹H, ^¹³C NMR and mass (HRMS) spectra of all the new compounds.

Acknowledgment

Authors are thankful to Dr. J. S. Yadav, Director and Dr. V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT, Hyderabad for continuous support, encouragement and financial assistance through­ MLP project. D.A. (JRF) is thankful to CSIR for financial assistance.

References

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• For cerivastatin:
• 3b Angerbauer R. Bischoff H. Steinke W. Ritter W. Drugs Future  1994,  19:  537 
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• 6e Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
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• 9a Kantevari S. Chary MV. Vuppalapati SVN. Tetrahedron  2007,  63:  13024 
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• 9b Kantevari S. Chary MV. Vuppalapati SVN. Lingaiah N. J. Heterocycl. Chem.  2008,  1009 
• 10a Wan J.-P. Pan Y.-J. Chem. Commun.  2009,  2768 
• 10b Alnajjar A. Abdelkhalik MM. Al-Enezi A. Elnagdi MH. Molecules  2009,  14:  68 
  Search in Google Scholar
• 10c Riyadh SM. Abdelhamid IA. Al-Matar HM. Hilmy NM. Elnagdi MH. Heterocycles  2008,  75:  1849 
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• 10e Senaiar RS. Young DD. Deiters A. Chem. Commun.  2006,  1313 
• 10f Davis JM. Truong A. Hamilton AD. Org. Lett.  2005,  7:  5405 
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  Search in Google Scholar
• 10h Al-Saleh B. Abdelkhalik MM. Eltoukhy AM. Elnagdi MH. J. Heterocycl. Chem.  2002,  39:  1035 
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• 11b Comelles J. Moreno-Mañas M. Vallribera A. ARKIVOC  2005,  ix:  207 ; http://www.arkat-usa.org/home
  Search in Google Scholar
• 12a Bartoli G. Marcantoni E. Sambri L. Synlett  2003,  2101 
• 12b Bartoli G. Fernández-Bolaños JG. Antonio GD. Foglia G. Giuli S. Gunnella R. Mancinelli M. Marcantoni E. Paoletti M. J. Org. Chem.  2007,  72:  6029 
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• 12c Khodaei MH. Khosropour AR. Kookhazadeh M. Synlett  2004,  1980 
• 12d Christofeers J. Kauf T. Werner T. Rossle M. Eur. J. Org. Chem.  2006,  2601 
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  Search in Google Scholar
• 12f Sabitha G. Babu RS. Rajkumar M. Srividya R. Yadav JS. Org. Lett.  2002,  4:  343 
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• 13 Huang Z. Zhao Q. Huang R. Wang Q. Lett. Org. Chem.  2009,  6:  29 
  CrossrefSearch in Google Scholar

CCDC-771475 (3aa) and CCDC-771476 (3ae) contain the crystallographic data and can be obtained free of charge from the Cambridge Crystallographic Data centre via www.ccdc.cam.ac.uk/data_request/cif.

References

• 1a Spandl RJ. Bender A. Spring DR. Org. Biomol. Chem.  2008,  6:  1149 
  Search in Google Scholar
• 1b Tan DS. Nat. Chem. Biol.  2005,  1:  74 
  Search in Google Scholar
• 1c Bagley MC. Dale JW. Merritt EA. Xiong X. Chem. Rev.  2005,  105:  685 
  Search in Google Scholar
• 1d Burke MD. Schreiber SL. Angew. Chem. Int. Ed.  2004,  43:  46 
  Search in Google Scholar
• 1e Henry GD. Tetrahedron  2004,  60:  6043 
  Search in Google Scholar
• 2a Aulakh VS. Ciufolini MA. J. Org. Chem.  2009,  74:  5750 
  Search in Google Scholar
• 2b Bagley MC. Chapaneri K. Dale JW. Xiong X. Bower J. J. Org. Chem.  2005,  70:  1389 
  Search in Google Scholar
• 2c Bagley MC. Xiong X. Org. Lett.  2004,  6:  3401 
  Search in Google Scholar
• 2d Bagley MC. Dale JW. Xiong X. Bower J. Org. Lett.  2003,  5:  4421 
  Search in Google Scholar
• 2e Bagley MC. Dale JW. Ohnesorge M. Xiong X. Bower J. J. Comb. Chem.  2003,  5:  41 
  Search in Google Scholar
• 2f Bagley MC. Bashford KE. Hesketh CL. Moody CJ. J. Am. Chem. Soc.  2000,  122:  3301 
  Search in Google Scholar
• For streptonigrin:
• 3a Harding MM. Long GV. Brown CL. J. Med. Chem.  1993,  36:  3056 
  Search in Google Scholar
• For cerivastatin:
• 3b Angerbauer R. Bischoff H. Steinke W. Ritter W. Drugs Future  1994,  19:  537 
  Search in Google Scholar
• 3c Chen B.-C. Bednarz MS. Zhang H. Guo P. Jemal M. Robl JA. Biller SA. Sundeen JE. Balasubramanian B. Barrish JC.
  J. Labelled Compd. Radiopharm.  2006,  49:  311 
  Search in Google Scholar
• For lavendamycin:
• 3d Hassani M. Cai W. Holley DC. Lineswala JP. Maharjan BR. Ebrahimian GR. Seradj H. Stocksdale MG. Mohammadi F. Marvin CC. Gerdes JM. Beall HD. Behforouz M. J. Med. Chem.  2005,  48:  7733 
  Search in Google Scholar
• 4 For a review of the chemistry and synthesis of benzofurans, see: Hou X.-L. Yang Z. Wong HNC. Furans and Benzofurans, In Progress in Heterocyclic Chemistry   Vol. 14:  Gribble GW. Gilchrist TL. Pergamon; Oxford: 2002.  p.139-179  
  CrossrefSearch in Google Scholar
• 5a Lu B. Wang B. Zhang Y. Ma D. J. Org. Chem.  2007,  72:  5337 
  Search in Google Scholar
• 5b Hagihara K. Kashima H. Iida K. Enokizono J. Uchida S.-i. Nonaka H. Kurokawa M. Shimada J. Bioorg. Med. Chem. Lett.  2007,  17:  1616 
  Search in Google Scholar
• 5c Dixit M. Sharon A. Maulik PR. Goel A. Synlett  2006,  1497 
• 5d Wyatt PG. Allen MJ. Chilcott J. Gardner CJ. Livermore DG. Mordaunt JE. Nerozzi F. Patel M. Perren MJ. Weingarten GG. Shabbir S. Woollard PM. Zhou P. Bioorg. Med. Chem. Lett.  2002,  12:  1405 
  Search in Google Scholar
• For recent reviews and books see:
• 6a Sunderhaus JD. Martin SF. Chem. Eur. J.  2009,  15:  1300 
  Search in Google Scholar
• 6b Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
  Search in Google Scholar
• 6c Domling A. Chem. Rev.  2006,  106:  17 
  Search in Google Scholar
• 6d Multicomponent Reactions   Zhu J. Bienaymé H. Wiley; Weinheim: 2005. 
• 6e Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
  Search in Google Scholar
• 6f Banfi L. Riva R. Org. React.  2005,  65:  1 
  Search in Google Scholar
• 6g Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
  Search in Google Scholar
• 7a Ganem B. Acc. Chem. Res.  2009,  42:  463 
  Search in Google Scholar
• 7b Zhu W. Mena M. Jnoff E. Pasau P. Ghosez L. Angew. Chem. Int. Ed.  2009,  48:  5880 
  Search in Google Scholar
• 7c Elders N. van der Born D. Hendrickx LJD. Timmer BJJ. Krause A. Janssen E. de Kanter FJJ. Ruijter E. Orru RVA. Angew. Chem. Int. Ed.  2009,  48:  5856 
  Search in Google Scholar
• 8a Bagley MC. Glover G. Merritt EA. Synlett  2007,  2459 
• 8b Merritt EA. Bagley MC. Synlett  2007,  954 
• 8c Bohlmann F. Rahtz D. Chem. Ber.  1957,  90:  2265 
  Search in Google Scholar
• 9a Kantevari S. Chary MV. Vuppalapati SVN. Tetrahedron  2007,  63:  13024 
  Search in Google Scholar
• 9b Kantevari S. Chary MV. Vuppalapati SVN. Lingaiah N. J. Heterocycl. Chem.  2008,  1009 
• 10a Wan J.-P. Pan Y.-J. Chem. Commun.  2009,  2768 
• 10b Alnajjar A. Abdelkhalik MM. Al-Enezi A. Elnagdi MH. Molecules  2009,  14:  68 
  Search in Google Scholar
• 10c Riyadh SM. Abdelhamid IA. Al-Matar HM. Hilmy NM. Elnagdi MH. Heterocycles  2008,  75:  1849 
  Search in Google Scholar
• 10d Lieby-Muller F. Allais C. Constantieux T. Rodriguez J. Chem. Commun.  2008,  4207 
• 10e Senaiar RS. Young DD. Deiters A. Chem. Commun.  2006,  1313 
• 10f Davis JM. Truong A. Hamilton AD. Org. Lett.  2005,  7:  5405 
  Search in Google Scholar
• 10g Bashford KE. Burton MB. Cameron S. Cooper AL. Hogg RD. Kane PD. MacManus DA. Matrunola CA. Moody CJ. Robertson AAB. Warne MR. Tetrahedron Lett.  2003,  44:  1627 
  Search in Google Scholar
• 10h Al-Saleh B. Abdelkhalik MM. Eltoukhy AM. Elnagdi MH. J. Heterocycl. Chem.  2002,  39:  1035 
  Search in Google Scholar
• 10i Omran FA. Awadi NA. Khair AAE. Elnagdi MH. Org. Prep. Proced. Int.  1997,  29:  285 
  Search in Google Scholar
• 11a Tambade PJ. Patil YP. Bhanage BM. Curr. Org. Chem.  2009,  13:  1805 
  Search in Google Scholar
• 11b Comelles J. Moreno-Mañas M. Vallribera A. ARKIVOC  2005,  ix:  207 ; http://www.arkat-usa.org/home
  Search in Google Scholar
• 12a Bartoli G. Marcantoni E. Sambri L. Synlett  2003,  2101 
• 12b Bartoli G. Fernández-Bolaños JG. Antonio GD. Foglia G. Giuli S. Gunnella R. Mancinelli M. Marcantoni E. Paoletti M. J. Org. Chem.  2007,  72:  6029 
  Search in Google Scholar
• 12c Khodaei MH. Khosropour AR. Kookhazadeh M. Synlett  2004,  1980 
• 12d Christofeers J. Kauf T. Werner T. Rossle M. Eur. J. Org. Chem.  2006,  2601 
• 12e Sabitha G. Reddy GSKK. Reddy KB. Reddy NM. Yadav JS. Adv. Synth. Catal.  2004,  346:  921 
  Search in Google Scholar
• 12f Sabitha G. Babu RS. Rajkumar M. Srividya R. Yadav JS. Org. Lett.  2002,  4:  343 
  Search in Google Scholar
• 13 Huang Z. Zhao Q. Huang R. Wang Q. Lett. Org. Chem.  2009,  6:  29 
  CrossrefSearch in Google Scholar

CCDC-771475 (3aa) and CCDC-771476 (3ae) contain the crystallographic data and can be obtained free of charge from the Cambridge Crystallographic Data centre via www.ccdc.cam.ac.uk/data_request/cif.

• Supplementary Material