Carbonylative annulation of unsaturated compounds using molybdenum hexacarbonyl: an efficient synthesis of 2(1 H )- quinolones

A ligand-and CO gas-free condition is developed in palladium-catalyzed three-component reaction of iodoanilines, unsaturated compounds and Mo(CO) 6 as a solid carbon monoxide source. The approach allows for smooth construction of biologically interesting 3,4-disubstituted (dihydro)quinolin-2(1 H )-ones in presence of catalytic amounts of palladium and avoids the problematic use of gaseous carbon monoxide


Introduction
][11][12][13][14][15][16] Although carbonylations of a wide spectrum of organometallic reagents have been performed using gaseous carbon monoxide but the use of highly toxic flammable gaseous carbon monoxide is often impractical as it associates with risky and troublesome handling and needs highly specialized equipments.According to limited synthetic applications of gaseous carbon monoxide, employing alternative CO sources including metal carbonyls generating carbon monoxide in situ during the reaction would be more appealing.Among them, Mo(CO)6 represents an ideal easily handled solid reagent for in situ release of carbon monoxide.8][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Recently we also reported a facile route to diaryl ketones through palladium-catalyzed three-component cross-coupling of aryl and heteroaryl halides, Mo(CO)6 and boronic acids and offered a mild base/solvent combination for efficient microwave-free extrusion of carbon monoxide in the course of the reaction. 33Continuing our interest in carbonylation reactions, we further attempted to synthesize (dihydro)quinolones via carbonylative annulation reactions of readily available 2iodoanilines and unsaturated compounds.Quinolones are interesting structural motifs found in numerous biologically active natural products.5] For instance compounds of type 1 and 2 are known to be selective Androgen receptor modulators and to have positive inotropic effects, respectively (Figure 1). 36Linomide 3, a synthetic immunomodulator, has been also investigated in treatment of various types of cancers and autoimmune disorders (Figure 1). 37hus, general and versatile synthetic methods for construction of these interesting frameworks are of great interest in synthetic organic chemistry.Although various classic methodologies exist for construction of 2-quinolinones, [38][39][40][41][42][43][44][45][46][47] their utility in construction of 3,4-disubstituted quinolones are limited and they usually lead to monosubstituted scaffolds.9][50][51][52][53][54][55][56][57][58][59][60] Some recent developments in metal-catalyzed construction of these privileged scaffolds include cycloaddition of o-cyanophenylbenzamides [61][62] and Narylcarbamoyl chlorides 63 with internal alkynes, ring closing metathesis (RCM) reaction of Nphenylacrylamides, 64 domino Heck/Buchwald-Hartwig reaction of o-bromocinnamamide and iodoarenes 65 and cyclization of 3,3-diarylacrylamides through intramolecular C-H amination 66 which often require employing complicated starting materials.Larock et al. developed a palladium-catalyzed carbonylative annulation of alkynes with readily available anilines employing gaseous CO. [67][68] Recently Xiao et al. further developed this strategy through a microwave-assisted Pd(OAc)2/dppe catalyzed carbonylative annulation of terminal alkynes with iodoanilines using solid carbon monoxide source. 69The protocol however encountered some limitations where no reactivity was observed with internal alkynes or N-protected 2-iodoanilines and the approach typically led to only monosubstituted quinolones.
Prompted by the recent advances in CO gas-free carbonylative reactions and continuing our interest in the field, we attempted to construct 3,4-disubstituted quinolone scaffold through a palladium-catalyzed three-component reaction of iodoaniline, internal alkynes/alkenes and Mo(CO)6 as a solid carbon monoxide source.The protocol is experimentally simple, uses readily available starting materials and is a ligand and microwave-free choice for construction of 3,4disubstituted (dihydro)quinolin-2(1H)-ones.Furthermore, the annulation reactions proceed with insertion of unsaturated compounds into the arylpalladium bond in preference to insertion of carbon monoxide where no isomeric quinolones were observed.

Results and Discussion
Initially when iodoaniline 1a and norbornene 2a where reacted under the conditions applied for construction of diarylketones, only traces of the desired product 3a was obtained.Next optimization reactions with respect to catalyst, base and solvents were conducted (Table 1).When PdCl2 as the catalyst and DBU as an organic base in presence of an additive (TBAC) in THF were employed, a 30% of the desired annulated product 3a was obtained (entry 1).Upon optimization of the palladium catalyst and base, Pd(OAc)2 and py showed superior reactivity (entries 2-5).As screening reactions with respect to ligands including PPh3, Pcy3, Pcy3.HBF4, dppe and TFP, resulted in only comparable or lower yields of tricyclic product, ligand-free condition was established for later investigations (entries 6-10).Finally, between various solvents investigated, the carbonylation/cyclization reaction proceeded in higher yield in DMF (entries 11-15).The optimal conditions of o-iodoaniline, norbornene (5 equiv.),py (3 equiv.),Pd(OAc)2 (10 mol%) and Mo(CO)6 (1.5 equiv.) in DMF at 160 °C for 12 h, led to formation of hexahydrophenanthridinone 3a in 45% isolated yield (Table 2, entry 1).It is noteworthy that norbornene adds to the arylpalladium intermediate in a cis-exo manner followed by CO insertion and intramolecular amination.The slow CO liberation in the course of reaction also provides an efficient pressure of the gas to promote the carbonylative reaction.This protocol merges three Heck, carbonylation and amination reactions to construct two C-C and one C-N bonds in one pot.Next protection of the amino group of the aniline was explored.Gratifyingly, with an ethoxycarbonyl protecting group, tricyclic adduct 3a was obtained in almost quantitative yield (95%, entry 2).Ethyl ester deprotection proceeded in the course of the reaction and completed during the workup.Encouraged by the results, we explored some other protecting groups.The carbonylative annulation reaction of norbornene with N-tosyl-o-iodoaniline afforded the desired product in 80% yield (entry 3).Sulfonyl and acyl protecting groups also resulted in the annulated products in 85 and 87% yields, respectively (entries 4-5).Next internal alkynes were employed to investigate the scope and limitations of the approach in constructing 3,4-disubstituted quinolones.Although annulation reaction of dipropyl acetylene with unprotected iodoaniline afforded only 25% of the desired quinolone 3b, but protected anilines resulted in the same product in high to excellent yields exceeding 85% (entries 6-9).When aniline with tosyl protecting group was used in the reaction, a moderate yield of the desired product was obtained (entry 10).5-Decyne also was employed in annulation reaction and afforded product 3c in high yield (entry 11).Next the reactivity of substituted iodoaniline was examined in the carbonylative annulation reaction of alkynes.Accordingly, o-iodoaniline 1f was reacted with 4-octyene and the desired quinolone 3d was obtained in 78% isolated yield (entry 12).Unfortunately, diphenylacetylene did not participate in this annulation reaction and only traces of the desired product were obtained.Homo-coupling and polymerization of diarylacetylene, could not be overcome during the liberation of carbon monoxide in the course of reaction.

Conclusions
We have developed a versatile and efficient route to 3,4-disubstituted 2-quinolones via palladium catalyzed carbonylative annulation of internal alkynes as well as norbornene under mild reaction conditions.The presented methodology employs readily available starting materials including iodoanilines, unsaturated compounds and Mo(CO)6 and establishes CO gas free conditions which seems to overcome the trouble of using gaseous carbon monoxide and looks suitable for highthroughput carbonylative reactions.Furthermore, the reaction is compatible with various Nprotected anilines and results in deprotected amines in the course of the reaction.

Experimental Section
General.All reagents and metal catalysts were commercially available and used as received.All carbonylative annulation reactions were carried out in an oil bath using Microwave Vials (2-5 mL).IR spectra were recorded on a Shimadzu FT-IR 4300 spectrometer.IR is reported as characteristic bands (cm -1 ) in their maximal intensity. 1H and 13 C NMR spectra were recorded at room temperature on a Bruker AC 300 MHz or 500 MHz spectrometers using CDCl3 as the NMR solvent.Mass spectra of the products were obtained with a HP (Agilent Technologies) 5937 Mass Selective Detector.Elemental analyses were obtained using a Flash EA 1112 elemental analysis instrument.

Table 1 .
Optimization of carbonylative annulation reaction a b 160 °C.

Table 2 .
Scope of annulation reactions of N-substituted o-iodoanilines