Palladium Iodide Catalyzed Multicomponent Carbonylative Synthesis of 2-(4-Acylfuran-2-yl)acetamides

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54–81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization.


Introduction
Functionalized furans are a very important class of heterocyclic derivatives [1], known to possess important biological activities (see, for example, references [2,3]) and being useful precursors for further transformations (for a review, see reference [4]).
Among the synthetic methods available to prepare multisubstituted furans (for recent reviews, see references [5][6][7]), transition metal-catalyzed cyclization (TMCC) of suitable acyclic precursors is particularly attractive (for recent reviews, see references [8,9]; for a book, see reference [10]; for a recent example, see reference [11]). By this approach, the final compound with the desired substitution pattern can be obtained in one synthetic step starting from readily available substrates.
On the other hand, carbon monoxide is a very important C-1 building block in organic synthesis (for a recent book on carbonylation chemistry in organic synthesis, see reference [12]). In fact, CO can be installed in a large variety of organic substrates under different conditions, including transition-metal catalysis, to give high value-added carbonyl compounds (carbonylation reactions), including carbonylated heterocycles (for selected book chapters and reviews on metal-catalyzed carbonylation reactions, also leading to carbonylated heterocycles, see references [12][13][14][15][16][17][18][19][20][21][22][23]). Accordingly, the combination between TMCC and catalytic carbonylation with the appropriate acyclic precursor may represent an excellent entry to the direct synthesis of carbonyl-functionalized furan derivatives [12].
In particular, the catalytic system based on PdI 2 in conjunction with an excess of KI, developed by our research group [24,25] (for a recent review, see reference [26], has proved very valuable for the realization of several important carbonylative cyclization processes, particularly under oxidative conditions, with the one-step formation of carbonylated This approach, therefore, allows the direct synthesis of a new subclass of furan derivatives (2-(4-acylfuran-2-yl)acetamides 3) by the catalytic assembly of very simple building blocks (2-propargyl-1,3-dicarbonyl compounds 1, amines 2, CO, and O 2 ), with formation of water as benign coproduct.

Results and Discussion
We started our investigation using 3-(prop-2-yn-1-yl)pentane-2,4-dione 1a as model substrate. The initial reaction was carried out in MeCN (0.10 mmol of 1a per mL of MeCN) at 100 °C in the presence of PdI2 (1 mol%), KI (KI:PdI2 molar ratio = 100) and Et2NH 2a (3 equiv) under 20 atm (at 25 °C) of a 4:1 mixture CO-air. After 15 h, 1a conversion was complete, and, after column chromatography purification, 2-(4-acetyl-5-methylfuran-2yl)-N,N-diethylacetamide 3aa was recovered in 61% yield (based on starting 1a), in perfect agreement with our work hypothesis (Table 1, entry 1). After a brief optimization study, in which we varied some reaction parameters (such as solvent, amount of KI and amine, substrate concentration, and total pressure; Table 1), a 72% isolated yield of 3aa was achieved under conditions similar to those of the first experiment, but with a higher substrate concentration (0.22 mmol of 1a per mL of MeCN) and using 4 equiv of Et 2 NH 2a ( Table 2, entry 1). The reaction could also be performed with a lower catalyst loading (0.33 mol% PdI 2 , maintaining the KI:PdI 2 molar ratio = 100), with an acceptable 55% isolated yield of 3aa (Table 2, entry 2).

General Experimental Methods
Melting points were measured with a Leitz Laborlux 12 POL polarizing optical microscope (Leitz Italia GmbH/Srl, Lana, BZ, Italy) and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded at 25 °C in CDCl3 at 500 MHz and 125 MHz, respectively, with Me4Si as internal standard using Bruker DPX Avance 300 and Bruker DPX Avance 500 NMR Spectrometers (Bruker Italia s.r.l., Milano, Italy); chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy).

Preparation of Substrates
Substrates 1 were prepared and characterized as described in the Supporting Information. All other materials were commercially available and were used without further purification.

General Experimental Methods
Melting points were measured with a Leitz Laborlux 12 POL polarizing optical microscope (Leitz Italia GmbH/Srl, Lana, BZ, Italy) and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded at 25 °C in CDCl3 at 500 MHz and 125 MHz, respectively, with Me4Si as internal standard using Bruker DPX Avance 300 and Bruker DPX Avance 500 NMR Spectrometers (Bruker Italia s.r.l., Milano, Italy); chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy). All reactions were analyzed by TLC on silica gel 60 F254 and by GC-MS analysis using a Shimadzu QP-2010 GC-MS apparatus (Smimadzu Italia s.r.l., Milano, Italy) at 70 eV ionization voltage equipped with a 95% methyl polysiloxane-5% phenyl polysiloxane capillary column (30 m × 0.25 mm, 0.25 μm). Column chromatography was performed on silica gel 60 (Merck, 70-230 mesh; Merck Life Science s.r.l., Milano, Italy). Evaporation refers to the removal of solvent under reduced pressure. The HRMS spectra were taken on an Agilent 1260 Infinity UHD accurate-mass Q-TOF-MS mass spectrometer, equipped with an electrospray ion source (ESI) operated in dual ion mode. A total of 10 μL of the sample solutions (CH3OH) were introduced by continuous infusion at a flow rate of 200 L min −1 with the aid of a syringe pump. Experimental conditions were performed as follows: capillary voltage, 4000 V; nebulizer pressure, 20 psi; flow rate of drying gas, 10 L/min; temperature of sheath gas, 325 °C; flow rate of sheath gas, 10 L/min; skimmer voltage, 60 V; OCT1 RF Vpp, 750 V; fragmentor voltage, 170 V. The spectra data were recorded in the m/z range of 100-1000 Da in a centroid pattern of full-scan MS analysis mode. The MS/MS data of the selected compounds were obtained by regulating diverse collision energy (18-45 eV).

Preparation of Substrates
Substrates 1 were prepared and characterized as described in the Supporting Information. All other materials were commercially available and were used without further purification.

General Experimental Methods
Melting points were measured with a Leitz Laborlux 12 POL polarizing optical microscope (Leitz Italia GmbH/Srl, Lana, BZ, Italy) and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded at 25 • C in CDCl 3 at 500 MHz and 125 MHz, respectively, with Me 4 Si as internal standard using Bruker DPX Avance 300 and Bruker DPX Avance 500 NMR Spectrometers (Bruker Italia s.r.l., Milano, Italy); chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy). All reactions were analyzed by TLC on silica gel 60 F 254 and by GC-MS analysis using a Shimadzu QP-2010 GC-MS apparatus (Shimadzu Italia s.r.l., Milano, Italy) at 70 eV ionization voltage equipped with a 95% methyl polysiloxane-5% phenyl polysiloxane capillary column (30 m × 0.25 mm, 0.25 µm). Column chromatography was performed on silica gel 60 (Merck, 70-230 mesh; Merck Life Science s.r.l., Milano, Italy). Evaporation refers to the removal of solvent under reduced pressure. The HRMS spectra were taken on an Agilent 1260 Infinity UHD accurate-mass Q-TOF-MS mass spectrometer (Agilent Technologies, Santa Clara, CA, USA), equipped with an electrospray ion source (ESI) operated in dual ion mode. A total of 10 µL of the sample solutions (CH 3 OH) were introduced by continuous infusion at a flow rate of 200 L min −1 with the aid of a syringe pump. Experimental conditions were performed as follows: capillary voltage, 4000 V; nebulizer pressure, 20 psi; flow rate of drying gas, 10 L/min; temperature of sheath gas, 325 • C; flow rate of sheath gas, 10 L/min; skimmer voltage, 60 V; OCT1 RF Vpp, 750 V; fragmentor voltage, 170 V. The spectra data were recorded in the m/z range of 100-1000 Da in a centroid pattern of full-scan MS analysis mode. The MS/MS data of the selected compounds were obtained by regulating diverse collision energy (18-45 eV).

Preparation of Substrates
Substrates 1 were prepared and characterized as described in Supplementary Materials. All other materials were commercially available and were used without further purification.