Oxygen as single oxidant for two steps: base-free one-pot Pd(II)-catalyzed alcohol oxidation & arylation to halogen-intact β-aryl α,β-enones

Abstract

Using oxygen as the sole oxidant for two steps, we developed a new method to synthesize β-aryl α,β-enones by fine-tuning the Pd(II)-catalyzed oxidation of allyl alcohol to subsequent arylation with arylboronic acids, arylboronic ester and aryltrifluoroborate salt. This one-pot green method does not require copper salt, base, and intermediate isolation. Halogen-bearing chalcones, dibenzylideneacetones and arylalkyl enones were synthesized in good yields.

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Chalcones represent one of the most-prevalent classes of natural products, which are widely abundant in plants and food items [e.g., fruits, vegetables, spices, tea, soy, hop and beer]. Chalcones are of considerable interest to both the academic and industrial community because of their wide range of pharmacological properties (Fig. 1).¹ They are known for their anti-oxidant, cytotoxicity, anti-cancer, anti-microbial, anti-protozoal, anti-ulcer, anti-histaminic, anti-inflammatory and immune-suppressive properties.² Nevertheless, the “α,β-unsaturated enone” motif is known for synthetic versatility (a) of delivering a diverse range of compounds through the use of Michael addition, cycloaddition, Heck coupling, etc., and (b) as building blocks to assemble a range of heterocyclic compounds, functional materials and chemotypes for lead optimization.³ The development of new methodologies for chalcones and the synthetically-important arylalkyl enones will expand the accessibility of these compounds for drug discovery.

Fig. 1 Pharmaceutically important β-aryl α,β-enones.

The conversion of allyl alcohols to the corresponding β-aryl enones through alcohol oxidation and Heck coupling with aryl halides is scarcely reported in the literature (only two hits found on SciFinder and Reaxys are displayed in Fig. 2).⁴ This versatile method suffers from limitations such as (i) the requirement of stoichiometric amount of toxic copper salt as the oxidant, (ii) a requirement for an organic/inorganic base, (iii) a lack of chemoselectivity between chalcones and dihydrochalcones and (iv) limited substrate scope. Importantly, the scope of such a reaction is limited in the ability to produce the α,β-unsaturated enones with intact halogens. Halogens are strategically deployed on aryl rings by medicinal chemists as handles⁵ to be exploited for diversification during lead optimization. Herein, we report a promising approach to β-arylated enones with –I and –Br functionalities through Pd(II)-mediated sequential oxidation of allyl alcohol followed by chelation-controlled oxidative arylation in one pot using arylboronic acids as the transmetalation substrates. Especially, this approach deploys molecular oxygen as the sole oxidant for both the steps and does not require a copper salt or a base (Fig. 2).

Fig. 2 Palladium-catalyzed synthesis of β-aryl enones from allylic alcohols.

We investigated oxidation-cum-arylation using I and PhB(OH)₂ as the model substrates, using the conditions conducive to alcohol oxidation⁶ and/or arylation⁷ (Table 1). Disappointingly, neither the keto intermediate nor the final product (β-aryl enone) was observed (entries 1–4). However, we were delighted to observe alcohol oxidation in excellent yield when PhB(OH)₂ and the ligand were excluded from the reaction (entries 5–7). This prompted us to first oxidize the alcohol and subsequently introduce PhB(OH)₂ and ligand in the same pot. Gratifyingly, we observed the formation of the desired β-aryl α,β-enone using THF as solvent, albeit in low yield (entry 8). Encouraged by this result, we undertook a comprehensive screening of metal, ligand, solvent and base. Improvement in the yield was observed on the exclusion of the base (entry 13). Dmphen, the oft-used bidentate ligand for Pd(II)-catalyzed oxidative Heck couplings, was identified as the superior ligand.⁸ Other nitrogen ligands, such as pyridine, Phen and Bphen, provided inferior yields (entries 16–18). The oxo-palladium source, Pd(OAc)₂, was turned to be the best Pd(II) pre-catalyst. Disappointing results were obtained with other Pd(II) precursors like Pd₂(dba)₃ and PdCl₂ (entries 14 and 15). Considering the requirement of the catalyst for two steps, the amount of the catalyst was increased further, which resulted in the best yield (entries 19 and 20). Interestingly, the reaction could be promoted in moderate yield even in the absence of both base and ligand (entries 21 and 22). However, our attempts to further optimize the yield proved futile, indicating the importance of the ligand in the stabilization of catalyst for high catalytic turnover (entries 23 and 24).

Table 1 Optimization protocol for sequential allylic alcohol oxidation and oxidative Heck arylation^a

Entry	Pd	Additive	Solvent	Ligand	Yield^b of 1 (%)
a Unless specified, the reaction was carried out with allyl alcohol (I; 1.0 mmol),Pd source (0.05 equiv.), and additive (0.1 equiv.) under an oxygen balloon (1 atm.) at 90 °C in a solvent (3.0 mL) for 4.0 h. After adding ligand (0.1 equiv.) and PhB(OH)2 (II; 1.2 mmol), the reaction was continued for 18.0 h.b Isolated yield (average of two runs).c Isolated yield of Intermediate A (entries 5–8, 19 and 20: 99%).d The reaction was carried out with I (1.0 mmol), II (1.2 mmol), Pd (0.05 equiv.), ligand (0.1 equiv.) and additive (0.1 equiv.) under oxygen balloon (1 atm.) at 90 °C in a solvent (3.0 mL) for 18.0 h.e Intermediate A was not consumed fully.f Pd(OAc)2 (0.1 equiv.), Dmphen (0.2 equiv.).g Dmphen = 2,9-dimethyl-1,10-phenanthroline, Bphen = 4,7-diphenyl-1,10-phenanthroline & Phen = 1,10-phenanthroline.
1^d	Pd(OAc)2	Et3N	Toluene	—	0
2^d	Pd(OAc)2	Et3N	Toluene	Dmphen^g	0
3^d	Pd(OAc)2	—	DMF	—	0
4^d	Pd(OAc)2	—	DMF	Dmphen	0
5^c^,^e	Pd(OAc)2	Et3N	Toluene	—	0
6^c^,^e	Pd(OAc)2	Et3N	Toluene	Dmphen	0
7^c^,^e	Pd(OAc)2	—	Toluene	Dmphen	0
8^c^,^e	Pd(OAc)2	Et3N	THF	Dmphen	15
9^e	Pd(OAc)2	Et3N	DMSO	Dmphen	10
10^e	Pd(OAc)2	Et3N	DMA	Dmphen	20
11^e	Pd(OAc)2	Et3N	DMF	Dmphen	25
12^e	Pd(OAc)2	Na2CO3	DMF	Dmphen	31
13	Pd(OAc)2	—	DMF	Dmphen	60
14^e	Pd2(dba)3	—	DMF	Dmphen	36
15	PdCl2	—	DMF	Dmphen	0
16^e	Pd(OAc)2	—	DMF	Pyridine	28
17^e	Pd(OAc)2	—	DMF	Phen^g	44
18^e	Pd(OAc)2	—	DMF	Bphen^g	33
19^c^,^f	Pd(OAc)2	—	DMF	Dmphen	97
20^c^,^f	Pd(OAc)2	—	DMAc	Dmphen	94
21^e	Pd(OAc)2	—	DMF	—	40
22^e	Pd(OAc)2	—	DMAc	—	35
23^e	Pd(OAc)2	—	DCE	—	0
24^e	Pd(OAc)2	—	1,4-Dioxane	—	0

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With an efficient condition (entry 19, Table 1), we then investigated the influence of electronic and steric factors on the preparative scope by coupling diverse arylboronic acids and allyl alcohols (Schemes 1–4). The electron-rich arylboronic acids gave very good yields (Scheme 1, 2 & 3) of the corresponding propenones. Interestingly, the electron-deficient arylboronic acids, which are known to be sluggish substrates in the Pd(II)-Dmphen catalysis, also gave excellent yields (4 & 5). The ortho-substituted arylboronic acids underwent efficient coupling (6 & 7), undeterred by steric overloading. Importantly, the halogen-bearing arylboronic acids (–Cl, –Br, –I and –F) gave the desired products (8–12) chemoselectively without the concurrent formation of by-products, resulting from Pd(0)-catalysed oxidative addition of the Ar–X (X: I, Br & Cl) bond (Heck, Suzuki and dehalogenation reactions). This chemoselectivity provides an opportunity for organic and medicinal chemists to preserve the halogen handles, to be utilized for transition-metal catalyzed C–C, C–N, C–O bond-forming diversification like Heck, Suzuki, Sonogashira, Buckwald and Ullmann-type coupling to derive pharmaceutically important compounds. Reasonably-deactivated aryl ring systems, naphthyl and biphenyl, also underwent efficient coupling (13 & 14). The heteroaryl-bearing boronic acids (2-furyl & 2-thienyl) underwent smooth coupling to give the corresponding products in good yields (15 & 16), indicating the compatibility of the catalytic method with furan and thiophene ring systems.

Scheme 1 Synthetic scope of chalcones from organoboronic acids.

Scheme 2 Synthetic scope of chalcones from allylic alcohols.

Scheme 3 Synthetic scope of dibenzylideneacetone derivatives.

Scheme 4 Synthesis of β-aryl α,β-enones from allylic alcohols.

Next, we investigated the scope and limitation of different types of allyl alcohols (Schemes 2–4). 1-Arylpropenols with differently activated aryl ring systems of electron-donating, electron-withdrawing and halogen substitutions reacted efficiently (Scheme 2; 17–20). A fused 1-(1-naphthyl)propenol also furnished the coupling product in good yield (21), indicating the generality of the procedure. This methodology is also amenable to multi-gram scale (5.0 g), as demonstrated in the synthesis of 2′-hydroxy chalcone derivative (22) [required by us for the construction of flavanone and flavone derivatives]⁹ from the corresponding propenol in excellent yield.¹⁰ The successful reaction outcome in the presence of unprotected phenolic group indicated the generality of the method.

Dibenzylideneacetone (DBA) derivatives serve as important building blocks in organic synthesis¹¹ (e.g., construction of piperidones, spiro compounds, etc.). Dibenzylideneacetone is widely used as a ligand in organometallic chemistry¹² [e.g., tris(dibenzylideneacetone)dipalladium(0)] and also as a sunscreen component to prevent skin cancer. The 1-styrenylpropen-1-ol reacted efficiently with electronically-different arylboronic acids to give the desired dibenzylideneacetone derivatives (Scheme 3, 23–28). DBA analogues with –I, –Br and –Cl substitutions were also realized with excellent yields.

The replacement of 1-aryl substitution with 1-alkyl substitution (e.g., 1-methyl, 1-ethyl, 1-isopropyl and 1-pentyl) did not affect the reaction outcome (Scheme 4, 29–33).¹³ Even the β-substituted cyclohex-2-en-1-ol underwent productive oxidation-cum-arylation to afford β-phenylcyclohex-2-en-1-one (34).

To further expand the scope of this green catalysis, two different alternatives of phenylboronic acid were considered for oxidative coupling with propenol (Scheme 5).¹⁴ The pinacolboronic ester (IIb) and potassium phenyltrifluoroborate (IIc) underwent efficient oxidative coupling to afford the desired α,β-unsaturated β-aryl carbonyl compound (1) with a good yield.

Scheme 5 Synthetic scope of boronic ester and borate salt.

A plausible mechanism is illustrated in Fig. 3. The first step, which involves the oxidation of allylic alcohol to enone, begins with the coordination of alcohol to L_nPd^IIX₂ (X = OAc) to form the complex B, which subsequently undergoes deprotonation to afford the Pd–alkoxide complex C. Subsequent β-hydride elimination leads to enone II and Pd^II–H D. Then, D decomposes to Pd(0) species E, which is oxidized by O₂ and HX, regenerating the active Pd^II catalyst. The second step, which involves the chelation-controlled oxidative arylation of the enone, begins with the generation of a (neocuproine)Pd^IIX₂ complex G [through the chelation of neocuproine to E followed by oxidation or the chelation of neocuproine to A directly] by the addition of neocuproine into the reaction mixture. G undergoes transmetalation with the arylboronic acid to afford the cationic aryl(neocuproine)Pd(II) species H. This is followed by the migratory insertion of enone II to form Pd^II–alkyl complex I. Consequent β-hydride elimination liberates the β-aryl α,β-enone III and (neocuproine)Pd^II–H J. Then, J undergoes reductive elimination to give Pd(0) species F, which is oxidized by O₂ and HX, regenerating the (neocuproine)Pd(II) catalyst.

Fig. 3 Plausible mechanism of Pd-catalyzed alcohol oxidation and subsequent oxidative arylation.

Conclusions

In conclusion, a sustainable methodology was developed for synthetically- and pharmaceutically-important β-aryl α,β-enones by employing oxygen as the non-toxic oxidant for two steps of the Pd(II)-modulated oxidation of allyl alcohol and oxidative arylation. The method eliminated the requirement of copper salt and base by using organoboronic acids as the surrogates of aryl halides. The reaction was highly chemoselective, thereby allowing access to halogen-installed β-aryl enones that were not accessible previously.

Acknowledgements

We thank the Director, IICT for the generous support and CSIR, New Delhi for funding through the programme TREAT XII FYP (BSC-0116). V. M. thanks Council of Scientific and Industrial Research for CSIR-SRF fellowship.

Notes and references

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10. Multi-gram scale synthesis of 2′-hydroxy chalcone from 2-hydroxybenzaldehyde is given below
    .
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12. Heck, Suzuki and Sonagasira coupling reactions.
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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra07478e

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