Introduction

Catalysis1,2,3,4,5,6,7,8,9,10,11,12 is a frontier research field in the chemical sciences and their allied branches as catalysis plays a pivotal role in the synthesis of almost every chemical, pharmaceutical, agrochemical and material required for the rapid development of mankind, especially our highly-demanding modern society. A catalyst promoter or initiator9,10,11,12 is a cocatalyst which is crucial for significant improvement of reaction rate and/or selectivity13 in some catalysis reactions. Herein, we introduce a new concept of catalyst originator using readily available and inexpensive small molecule ArCH(OMe)2 as the first example. Unlike promoter or initiator, catalyst originator reacts with a completely inactive procatalyst of a reaction and eventually alters oxidation state of the procatalyst which is crucial to empower outstanding catalytic activity for the initiation, execution and completion of the desired transformation with high synthetic efficiency13. Development of highly efficient catalytic processes for annulation reactions14 to natural and unnatural functional molecules is the central focus in modern organic synthesis. Catalytic selective activation4,5,15,16,17 and transformation of C-H, N-H, C-O and π-bonds can be utilized for highly selective annulation reaction. Development of new benign and robust strategies is desirable such as discovery of new atom-economical domino reactions18,19,20 towards direct synthesis of several target molecules using an efficient catalytic system. Acetoacetanilide (1, Figure 1) is a commercially available inexpensive laboratory reagent that has found very limited application in synthetic organic chemistry, including synthesis of the lepidone, martinellic acid derivative21, unsymmetrical urea22 and our recently reported FeCl3.6H2O-catalysed diastereoselective construction of trans-1,2,3,4-tetrahydro-2-pyridones7. Furthermore, the three important reactive centres (C2-H, C4-H and N-H) of acetoacetanilide can be exploited in a selective and cascade fashion for annulation with designed propargyl compounds (2, 3 etc.). However, the use of halide precursors (2 and 3; X and Y, eq. ii and iii) will generate a considerable amount of byproduct waste in the reaction. Thus, the use of keto (X = O) and alcohol (Y = OH) precursors are highly desirable because the waste can be removed as an environmentally benign water molecule. We envisioned that breaking of a C-O bond in an aromatic aldehyde dimethyl acetal (4, eq. I, Figure 1) is possible through formation of a stabilized species I. So, ArCH(OMe)2 may be incorporated into an inactive procatalyst (PtII) by oxidative insertion to the C-O bond, leading to the in situ generation of a stabilised organometallic (II) of higher oxidation state (e.g., PtIV) which may be efficiently used in catalysis for development of a robust cyclization process.

Figure 1
figure 1

Proposed intermolecular annulation strategy by suggested PtIV-active catalyst with ArCH(OMe)2.

Full size image

Gratifyingly, we found in situ generated PtIV-species as an efficient catalyst for new organic transformations such as intermolecular annulation reactions (eq. ii, iii). This approach involving a catalysis originator is especially attractive from a synthetic perspective because it performs selective activation, functionalisation and annulation involving C-C and C-N bond formation to valuable 2-pyridone23,24,25 (6, eq. ii), C-C and C-C coupling to cyclohexenone26,27,28 (7, eq. iii) or C-O and C-O joining to afford the 3(2H)-furanone29,30 framework, which are available in a number of bioactive natural products, such as the antibiotic tenellin23, the antimalarial longirostrerone C26 and the antibiotic gregatin analogues29,30, respectively. We have recently initiated a national research program, OSDD31, towards the easy access of these functionalised molecules through a simple, step-economical and cost-effective process and these molecules will be developed as inexpensive drugs for millions of patients suffering from deadly malaria32 and tuberculosis33. After completion of a desired reaction, the PtII-procatalyst will be regenerated for the next cycle (eq. i) along with ArCH(OMe)2 equivalent aromatic aldehyde (5). The aldehyde may be converted to 4 through a simple acetal formation.

Results

1. Development of the catalyst originator for the intermolecular annulation reaction

We initiated the domino18,19,20 annulation reaction between N-(4-bromophenyl)-3-oxo-butyramide (1a: R1 = 4-BrC6H4) with 1,3-diphenylpropynone (2a: X = O; R2 = R3 = C6H5) in the presence of benzaldehyde dimethyl acetal (4a) and several transition metals (NiBr2, PdCl2, AuCl3, RuCl3 etc.) and rare-earth metals (La(OTf)3, CeCl3, Yb(OTf)3 etc.) as prospective procatalysts (entry 1, Table 1). Unfortunately, all attempts were unsuccessful, even under heating conditions. Compared to the widespread application of platinum compounds in catalysis34, PtBr2-catalysed reactions are limited to only a few. For instance, this catalyst was utilised in the hydroamination of olefin35, in intramolecular enyne metathesis36 and in Markownikoff's hydroarylation of terminal alkynes37. Gratifyingly, treatment of PtBr2 (3 mol%) at ambient temperature afforded the desired heterocycle 3-acetyl-1-(4-bromophenyl)-4,6-diphenyl-1H-pyridin-2-one (6a) with moderate yield (60%, entry 2). PtBr2 is insoluble in acetonitrile solvent. Surprisingly, it dissolved in the reaction mixture on addition of PhCH(OMe)2 and transformed the colourless reaction mixture into the reddish brown solution. On the other hand, formation of even traces of desired product (6a) was not observed in the absence of the catalyst originator, which was confirmed by monitoring the reaction using TLC, HPLC and NMR spectroscopy. The reaction was optimised (entries 3–6) to improve the yield (86%), reaction rate (9 h) and procatalyst loading (2 mol%, entry 5). However, the role of PhCH(OMe)2 is not a desiccant for the reaction which was verified using activated magnesium sulfate and molecular sieve (entry 7). The aromatic dimethyl acetal (4) possessing an activated aromatic nucleus (4b, entry 8) provided a comparable yield (82%) where as the deactivated one (4c, entry 9) drastically reduced the yield (50%). As expected, the reaction did not occur with aliphatic acetal and ketal without assistance from the aromatic ring (entries 10,11) which is essential for breaking the C-O bond and stabilising the active PtIV-catalyst.

Table 1 Optimisation of the intermolecular annulation reaction
Full size table

2. N-C and C-C coupling to functionalized 2-pyridones

The reported synthesis of 2-pyridones includes multistep strategies, microwave and metathesis protocols, the one-pot Blaise reaction, direct synthesis involving the oxidative annulation of α,β-unsaturated amide and ketone and our recently reported ring opening of chromone aldehydes with tandem cascade cyclisation7,38. Substituted 2-pyridones are potential candidates for antihepatitis B, antitumor, human rhinovirus (HRV) 3C protease (3CP) inhibitor and noncompetitive antagonist related to epilepsy39,40. We developed the direct construction of substituted 2-pyridone compounds (6a–k, Figure 2) from readily available chemicals acetoacetanilide (1) and 1,3-disubstituted propynone (2) at ambient temperature under neutral and benign reaction conditions. The substrate scope of this reaction revealed that the electron-donating substituent on the aryl group of acetoacetanilide derivatives significantly improved the reaction rate and yield relative to the precursor with an electron-withdrawing substituent (6g) or no-substituent (6c and 6e). Aromatic and aliphatic substituents (6e) were tolerated in this highly regioselective bimolecular reaction. The annulation reaction was very selective to non-terminal precursor 2 as it was unsuccessful with terminal propynone precursors (2, R2 = H). Exact mechanism of the reaction is unknown to us. Herein, PtIV-active catalyst (II) is expected to bind with the triple bond (III) and carbonyl oxygen (IV) of 2 and subsequently N-C and C-C coupled cyclization (V–VII) with acetoacetanilide (1) in a cascade fashion led to removal of PhCHO (5a) and MeOH. The putative fused-intermediate VII immediately underwent reductive elimination to produce the desired heterocycle (6) along with the regenerated PtBr2 procatalyst.

Figure 2
figure 2

Bimolecular annulation process to 2-pyridones.

Full size image

3. Dual C-C coupling to functionalized cyclohexenones

In recent studies, cyclohexenone compounds were utilised as versatile synthons for the total synthesis of the antimalarial (+)-artemisinin41, the antibiotic platencin42, the important skeleton of the antimicrobial alkaloid (+)-2-oxo-agelasidine C43 and for biosynthetic intermediates44. However, reports on synthesis of functionalised cyclohexenone are very limited45,46. The selective activation of C2-H and C4-H of acetoacetanilide derivatives and double C-C coupling with an appropriate propargyl moiety (eq. iii, Figure 1) led to the formation of functionalised cyclohexenone (7). However, this is a challenging task because C-C/C-N coupling is a more facile process (Figure 2) in the presence of a -NH- group. To overcome this challenge, we changed the precursor alkyne ketone (2) to its reduced form (3: Y = OH). We hypothesized that first C-C coupling (Figure 3) between 3 and 1 (C2-H) occurred with II by replacing the hydroxyl group of 3 (VIII) which expelled PhCHO (5a) and methanol. Second C-C bond formation (X) with CH3CO- group proceeded through formation of intermediate IX. The cyclic intermediate X subsequently underwent reductive elimination of the PtBr2 procatalyst with formation of the desired product 2-oxo-4-phenylcyclohex-3-enecarboxylic acid aryl amides (7). Interestingly, the annulation reaction to compound 7 occurred under similar reaction conditions (entry 5, Table 1) and was very selective and the corresponding N-C coupling 2-pyridones (6) were not observed in the post-reaction mixture. Herein, no product was observed using 1,3-disubstituted propargyl alcohol precursor (R3 = Ph, VIII), which might be due to the considerable steric hindrance and/or electronic repulsion that appeared during reaction of propargyl alcohol (3) and acetoacetanilide with PtIV-active catalyst (II, Figure 1). The reaction was also very selective to non-terminal propargyl alcohol because the reaction was completely blocked when investigated using terminal alkynyl alcohols, such as propargyl alcohol.

Figure 3
figure 3

Regioselective cascade annulation to cyclohexenones.

Full size image

4. Dual C-O coupling to substituted 3(2H)-furanones

The 3(2H)-furanone (8) compound is a human tyrosinase inhibitor47, the aroma component of soy sauce48 and is used as a valuable synthon for the total synthesis of the renal cancer cell lines inhibitor (−)-Englerin A49. The widespread application of the heterocyclic scaffold and the availability of only a few synthetic methods in the literature prompted us to establish an easy synthetic method. Gratifyingly, double O-C coupling intramolecular cyclization of non-terminal butyne-1,2-dione (5) with the PhCH(OMe)2 was observed under the similar reaction conditions to afford 3(2H)-furanone (8, Figure 4). In fact, this developed method is the second approach for the direct synthesis of 2-alkoxy-3(2H)-furanones following the AuCl3-catalysed annulation of 3-oxo-butyne analogues reported by Liu50 and coworkers. From a synthetic perspective, this reaction is straightforward, high yielding (85–95%), tolerant to double bonds (8d) and aromatic rings and can also directly synthesise a complex compound bearing three heterocycles (8e). It is proposed that the intramolecular cyclisation occurred involving formation of C = O and triple bond-coordinated PtIV-activated intermediate XI which subsequently transformed to 8 by the migration of -OMe, as well as the formation of O-C bond involving the conversion of C≡C to C = C. Interestingly, the PtIV-species was so selective for binding to precursor 5 that even in presence of acetoacetanilide (1), it did not form the corresponding 2-pyridone (6) by annulation with the R2-C≡C-CO- moiety (Figure 2).

Figure 4
figure 4

Synthesis of 3(2H)-furanone with trapping of the OMe group.

Full size image

Discussion

We have demonstrated that aromatic aldehyde dimethyl acetal is a keen catalyst originator for transforming the catalytically inactive transition metal procatalyst PtBr2 to an active catalyst PtIV-species for both inter- and intramolecular annulation to several valuable heterocycles and carbocycles. Organic ligands greatly influence the catalytic activity of a metallic compounds5. The annulation reaction was examined using different bidentate ligands and conventional additives, such as ethylene glycol dimethyl ether, dimethyl tartarate, 1,2-diphenyl ethylene glycol, catechol, DPPE, COD, α-pinene, norbornadiene, etc. and all attempts were unsuccessful to provide compound 6. These observations strongly supported that the role of ArCH(OMe)2 was not simple as a conventional ligand in the remarkable catalysis approach. To the best of our knowledge, there is no such example in the literature of using a catalyst originator to a procatalyst that displays outstanding catalytic activity. To understand the involvement of PtIV-species in this process, reactions were performed separately with PtIV-compounds such as PtCl4, H2PtCl6, PtCl4-4a and H2PtCl6-4a. Unfortunately, the formation of the desired product (6a) was not observed in these reaction mixtures. UV-vis spectroscopic analyses of PtBr2 and PhCH(OMe)2 in acetonitrile and also the reaction mixture (entry 5, Table 1) revealed the presence of PtIV-species through the characteristic absorbance51 band that appeared at 259.84 and 260.02 nm respectively (supplementary information). These observations clearly indicated that only 4a-modified PtIV was the active catalyst for the robust annulation processes. The formation of PhCHO (5a) was observed due to reaction of catalyst originator PhCH(OMe)2 and in situ generated water during the course of the annulation process. Compound 5a was isolated from the post-reaction mixture and characterized. The formation of MeO-/MeOH was also verified by trapping it in an intramolecular cyclisation of disubstituted but-3-yne-1,2-diketone (5) to afford 2-methoxy-3(2H)-furanone derivative (8, Figure 4). Interestingly, the activated PtIV-species was so selective for binding to precursor 3 (Figure 3) and 5 (Figure 4) that even in presence of acetoacetanilide (1), it did not form the corresponding 2-pyridone (6). This inexpensive and readily available organic catalyst originator installed novel catalytic power to procatalyst PtBr2 for activation of C-H, N-H, C-O and π-bonds towards selective C-C/C-N, C-C/C-C and C-O/C-O coupled annulation to achieve the direct synthesis of ubiquitous carbocycles and heterocycles. The robust synthetic protocol was developed under benign and neutral reaction conditions to obtain highly functionalised 2-pyridones (6), cyclohexenones (7) and 3(2H)-furanones (8) in excellent yield and with very low catalytic loading using the common laboratory reagent acetoacetanilide, non-halogenated precursor α-ketoalkynes and propargyl alcohol and environmentally safe water was generated as a byproduct (Figure 5). The transformation of the catalyst originator to its corresponding aldehyde, trapping of the fragmented –OMe group and the in situ generation of the PtIV-active catalyst were experimentally confirmed. We anticipate that this new concept in catalysis will find immense application in synthetic organic chemistry towards innovative catalyst design, the development of new catalyst originator, procatalysts and novel reactions; and the newly designed catalysts will dominate as a work-horse in the facile synthesis of novel functional molecules with high synthetic efficiency.

Figure 5
figure 5

Catalyst originator mediated diverse annulation reactions.

Full size image

Methods

A solution of β-ketoanilide (1, 1.0 mmol), benzaldehyde dimethyl acetal (4a, 152 mg, 1.0 mmol) and 1,3-disubstituted 1-propynone (2, 1.0 mmol) in acetonitrile (10 mL) was stirred at 0°C. Platinum (II) bromide (7 mg, 2 mol%) was added and the mixture was stirred at ambient temperature. The progress of the reaction was monitored by TLC and the reaction was complete within 8–25 h depending on the use of the substrates. The post-reaction mixture was concentrated in a rotary evaporator under reduced pressure at room temperature and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with distilled water (3 × 10 mL), dried over activated sodium sulphate and concentrated in a rotary evaporator. Thus, the reaction with N-(4-bromophenyl)-3-oxo-butyramide (1a, 256 mg, 1.0 mmol) and 1,3-diphenylpropynone (2a, 206 mg, 1.0 mmol) afforded 3-acetyl-1-(4-bromophenyl)-4,6-diphenyl-1H-pyridin-2-one (6a) in an yield of 86% (380 mg, 0.86 mmol) after purification by column chromatography on basic alumina (100–200 mesh) with 8% ethyl acetate in hexane as an eluent. All of the new 2-pyridone compounds (6a–k) were characterised using NMR (1H, 13C and DEPT), FT-IR and mass (HR-MS) spectroscopy and single crystal XRD analyses. Functionalised cyclohexenones (7) and 2-methoxy-3(2H)-furanones (8) were also synthesised under similar reaction conditions and fully characterised (supplementary information). The structures of all the new compounds (6–8) were elucidated by performing NMR, FT-IR and ESI-MS spectroscopic measurements and single crystal XRD-analyses52 of 6k, 7g and 8f.