Aminophosphine Palladium Pincer-Catalyzed Carbonylative Sonogashira and Suzuki-Miyaura Cross-Coupling with High Catalytic Turnovers.

This work documents the first palladium pincer complex-catalyzed carbonylative Sonogashira (CS) and carbonylative Suzuki-Miyaura (CSM) cross-coupling. Compared to previous protocols, which employ hazardous and toxic solvents, the aminophosphine pincer complex {[C6H3-2,6-(NHP{piperidinyl}2)2]Pd(Cl)} (III) catalyzes both the cross-coupling reactions in propylene carbonate, an eco-friendly and sustainable polar aprotic solvent. Advantageously, employing III allows the CS cross-coupling to be carried out at a palladium loading of 10-4 mol % and the CSM cross-coupling to be carried out at 10-6 mol %, thus resulting in catalytic turnovers of 105 and 107, respectively. Relative comparison of the pincer complex with conventional palladium precursors Pd(OAc)2 and PdCl2(PPh3)2 shows the efficiency and robustness of the pincer complex in effecting higher catalytic activity at low palladium loadings.

Introduction

The development of protocols for the synthesis of biaryl ketones and ynones (α,β-acetylenic ketones) is extremely significant in synthetic organic chemistry.[1]

Biaryl ketones represent key structural motifs present in pharmaceutical drugs, sunscreen agents, and natural products. Ynones, on the other hand, are central building blocks present in biologically active molecules and are key intermediates in the synthesis of different heterocyclic functionalities and natural products (Figure ).

Figure 1

Representative examples of important molecules containing the biaryl ketone and ynone functionality.

Traditionally, biaryl ketones are synthesized through the Friedel–Crafts acylation, which is driven by utilizing stoichiometric amount of Lewis acid.[2] The presence of Lewis acid causes compatibility issues with functional groups and generation of large amounts of waste, thus resulting in poor atom economy. The lack of regioselectivity in accessing ortho and para isomers, their separation, synthesis of biaryl ketones with meta substitution, and electron-withdrawing functionalities are additional drawbacks associated with the Friedel–Crafts acylation. Ynones are conventionally synthesized by reacting acid chlorides with alkynyl organometallic reagents[3−7] or by the transition-metal-catalyzed cross-coupling between terminal alkynes and acid chlorides.[8−11] Given the reactive nature of acid chlorides, these protocols suffer from poor functional group tolerance and poor atom economy. The palladium-catalyzed three-component carbonylative cross-coupling between aryl halide and aryl boronic acid[12,13] [carbonylative Suzuki–Miyaura (CSM)] or terminal alkyne[14,15] [carbonylative Sonogashira (CS)] using carbon monoxide as a C1 source is a straightforward and convenient strategy for synthesizing biaryl ketones and ynones, respectively. Both these reaction protocols are atom-economic and have wide functional group tolerance. The fact that alkynes and aryl boronic acids are nontoxic and air-, moisture-, and thermally stable is an added advantage (Scheme ).

Scheme 1

Comparison of Different Reaction Protocols for the Synthesis of Biaryl Ketones (a) and Ynones (b)

The synthesis of biaryl ketones and ynones from aryl halides and pseudohalides through the CSM and CS cross-coupling using a range of homogenous and heterogeneous palladium catalysts is well documented.[13,16−33,15,34−49] However, to drive a carbonylative cross-coupling, typically higher palladium loadings are necessary. Noncarbonylative cross-coupling reactions, on the other hand, can be driven more efficiently and smoothly at lower palladium loadings. In fact, even a 50 ppb palladium contamination in commercially available sodium carbonate catalyzes the Suzuki–Miyaura cross-coupling of aryl bromides.[50] Thus, higher catalytic turnover numbers (TONs) and turnover frequencies (TOFs) are generally observed in the case of noncarbonylative cross-coupling reactions compared to carbonylative cross-coupling reactions. This is due to the fact that, in carbonylative cross-coupling reactions, excess of π-acidic CO is present compared to palladium. The reactivity of palladium toward oxidative addition of the aryl halide is greatly reduced due to binding of CO with palladium. Moreover, facile aggregation of palladium atoms in the presence of CO leads to the formation of nonactive palladium species, thereby reducing the catalytic activity. Thus, achieving high catalytic TONs and TOFs through low palladium loadings in carbonylative cross-coupling reactions is challenging.

It is however essential to use palladium in minimum quantities given its high cost and to reduce the existing metal contamination in the environment. Additionally, since biaryl ketone and ynone synthesis forms part of the pharmaceutical and fine chemical industry, it is essential to reduce the contamination of palladium in the end product down to the ppm level.

Palladacyclic complexes have been exhaustively reported as high-turnover catalysts for noncarbonylative cross-coupling reactions.[51−65] They are known to catalyze reactions at extremely low palladium loadings, thus resulting in high catalytic turnovers and, in some cases, enzymatic turnovers.[66] However, they have been seldom reported as high-turnover palladium precursors for carbonylative cross-coupling reactions.[67−71] In 2015, we reported Bedford’s mixed tricyclohexylphosphine–triarylphosphite palladacyclic complex (Figure , I) as a high-turnover catalyst for the CSM cross-coupling of aryl iodides.[72] Notably, the reaction could be carried out using 10–6 mol % of palladium and catalytic turnovers of the order of 107 were observed. Recently, we have also documented oxime palladacycle (Figure , II) as a robust and high-turnover catalyst for the CS cross-coupling of aryl iodides.[73] The reaction could be driven using a palladium loading of 10–3 mol %, resulting in catalytic turnovers of the order of 104.

Figure 2

High catalytic turnover palladacyclic (I), (II) and pincer complex (III), (IV).

Palladacycles are cyclic palladium complexes incorporating at least a single carbon–palladium bond. Pincers belong to the family of palladacycles and incorporate two fused palladacycles. In the 1970s, Shaw,[74] Noltes,[75] and van Koten[75] first reported the synthesis of pincer complexes. Over the years, many pincer complexes have been synthesized and their multifaceted catalytic applications systematically documented.[76−84] However, the NCN, PCP, and SCS pincer complexes are the most common as they can be easily synthesized from palladium sources, which are commonly used. In 2000, Bedford and co-workers reported the first bis(phosphinite)-based PCP palladium pincer complex as a high-turnover catalyst for the Suzuki–Miyaura cross-coupling of aryl bromides and chlorides.[85] A maximum TON of 190 000 could be achieved in the case of aryl bromides. In 2007 and 2010, Frech and co-workers reported the aminophosphine palladium pincer complexes (Figure , III and IV) for the Suzuki–Miyaura cross-coupling of aryl bromides and chlorides.[86,87] Advantageously, while using complex III, the aryl bromides could be coupled between 5 and 30 min at a catalyst loading of 10–3 mol %, thus resulting in maximum catalytic turnovers of 105 and activated aryl chlorides could be coupled within 180 min at a catalyst loading of 0.1 mol %, resulting in maximum turnovers of 103. The same group reported the palladium pincer-catalyzed Sonogashira cross-coupling under additive- and amine-free conditions.[88] A range of electronically deactivated, sterically hindered, and functionalized aryl iodides and aryl bromides were coupled with several alkynes at low catalyst loadings and short reaction times, wherein maximum catalytic turnovers of 106 were observed, while using complex III. Both the complexes can be readily synthesized from dichloro(bis(1,1′,1″-(phosphinetriyl)tripiperidine))palladium as a template and 1,3-diaminobenzene or resorcinol to generate the aromatic pincer core at the palladium center. The protocol does not require the need for synthesis and purification of air- and moisture-sensitive ligand systems and hence represents a facile, short, and high-yielding methodology for the synthesis of the pincer complex from inexpensive starting materials. Both the complexes are thermally stable up to 150 °C and do not undergo any decomposition in an oxygen atmosphere for more than a week.

After a comprehensive literature survey, we found that, to the best of our knowledge, palladium-based pincer complexes have not been reported as precatalysts for the CSM and CS cross-coupling. We also found that both the aforementioned reactions have been typically carried out in hydrocarbon solvents (anisole or toluene), dioxane, dimethylacetamide (DMA), methyl tert-butyl ether (MTBE), N,N-dimethylformamide (N,N-DMF), and tetrahydrofuran (THF). Although the reactions proceed efficiently in these solvents, amide, ethereal, and hydrocarbon solvents are hazardous, toxic, and unsustainable. In present-day chemistry, the effect of reaction solvents on health, safety, and environment needs a meticulous examination. In the course of time, there will be constraint and restriction on production of solvents and their usage under Registration, Evaluation, Authorisation and restriction of CHemicals (REACH[89])—a regulation passed by the European Union. Hence, we envisaged in identifying an alternate sustainable solvent for both the reactions.

Organic cyclic carbonates are environmentally friendly solvents in synthetic chemistry as they are nontoxic, biodegradable, odorless, and possess low vapor pressure.[90−96] Inexpensive, industrial-scale, and sustainable methodologies for their synthesis from renewable feedstocks have been established.[97−99] Ethylene carbonate and propylene carbonate (Figure ) have been rated good to excellent, showing points of no concern, when benchmarked across various parameters, by the GlaxoSmithKline solvent selection guide.[100] Moreover, ethylene and propylene carbonate have higher boiling points compared to amide (N,N-DMF and DMA), ethereal (dioxane, MTBE, and THF), and hydrocarbon (anisole and toluene) solvents. This not only results in lower atmospheric emissions, but also makes them safe to handle and store. Further, since organic cyclic carbonates are made up of only carbon, hydrogen, and oxygen, oxides of nitrogen and sulfur are not produced and emitted on their combustion or incineration.

Figure 3

Structures of ethylene carbonate (A) and propylene carbonate (B).

Carbonylation reactions are known to proceed efficiently in cyclic carbonates. This is mainly attributed to the high solubility of CO in cyclic carbonates. Okamoto’s group has done extensive research on the application of propylene carbonate as an advantageous solvent for the synthesis of polycarbonates by oxidative carbonylation of bisphenol A.[101−103] Propylene carbonate is also known to stabilize palladium clusters/colloidal palladium accessible from bulk palladium[104] and has been applied for Sonogashira cross-coupling of aryl chlorides[105] and cyclocarbonylation reactions.[106] Recently, we have reported the Pd/C-catalyzed phenoxycarbonylation of aryl iodides under CO surrogacy in propylene carbonate as a sustainable solvent.[107] Taking into consideration our continued interest in developing high-turnover catalysts and identifying environmentally benign and sustainable solvents for carbonylation reactions, we herein report the first aminophosphine pincer complex-catalyzed carbonylative Suzuki–Miyaura and carbonylative Sonogashira cross-coupling in propylene carbonate (Scheme ).

Scheme 2

Comparison of Previous Reaction Protocols with the Current Protocol

Results and Discussion

Carbonylative Sonogashira Cross-Coupling

We initiated the reaction optimization by monitoring the carbonylative cross-coupling between iodobenzene 1a and phenylacetylene 2a, resulting in the synthesis of 1,3-diphenylprop-2-yn-1-one 3a in toluene using 0.1 mol % pincer complex III (Table ).

Table 1

Optimization of Reaction Parameters for Carbonylative Sonogashira Cross-Couplinga

entry	CO pressure (bar)	base	time (h)	temperature (°C)	solvent	conversionc (%)	selectivityc (%)	TONd	TOF (h–1)
Effect of CO Pressure
1	1	K2CO3	5	100	toluene	99	89	881	176
2	2	K2CO3	5	100	toluene	99	96	940	188
3	4	K2CO3	5	100	toluene	98	95	931	186
Effect of Base
4	2	K2CO3	5	100	toluene	99	96	950	190
5	2	Na2CO3	5	100	toluene	83	94	780	156
6	2	K3PO4	5	100	toluene	85	89	756	151
7	2	Et3N	5	100	toluene	69	78	538	107
8	2	TMEDAb	5	100	toluene	70	84	588	117
Effect of Solvent
9	2	K2CO3	5	100	toluene	99	96	950	190
10	2	K2CO3	5	100	N,N-DMF	98	91	891	178
11	2	K2CO3	5	100	dioxane	92	90	828	165
12	2	K2CO3	5	100	ethylene carbonate	88	92	809	161
13	2	K2CO3	5	100	propylene carbonate	97	96	931	186
Effect of Time
14	2	K2CO3	2	100	propylene carbonate	63	95	598	299
15	2	K2CO3	4	100	propylene carbonate	90	96	864	216
16	2	K2CO3	5	100	propylene carbonate	96	97	931	186
17	2	K2CO3	6	100	propylene carbonate	97	96	931	155
Effect of Temperature
18	2	K2CO3	5	80	propylene carbonate	79	95	750	150
19	2	K2CO3	5	100	propylene carbonate	97	96	931	186
20	2	K2CO3	5	110	propylene carbonate	98	95	931	186

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [Pd, III] (0.1 mol %), base (1.0 mmol), solvent (10 mL).

TMEDA = N,N,N′,N′-tetramethylethylenediamine.

Conversion and selectivity were based on iodobenzene and determined by gas chromatography–mass spectrometry (GC–MS).

TON = mol product per mol Pd.

The effect of CO pressure and base revealed that the reaction proceeded with 99% conversion and 96% selectivity when a CO pressure of 2 bar was applied and K2CO3 was taken as the base. Other inorganic (Na2CO3 and K3PO4) and organic bases (Et3N, TMEDA) gave inferior results (Table , entries 1–3 and 4–8). The solvent study showed that the reaction proceeded well in toluene, with slightly decreased selectivity observed in the case of N,N-DMF and dioxane (Table , entries 9–11). Delightfully, the former hazardous solvents could be avoided, as the reaction proceeded well in ethylene and propylene carbonate (Table , entries 12 and 13). Propylene carbonate being a liquid at room temperature was chosen as the solvent of choice. The time and temperature study showed that a reaction time of 5 h and a temperature of 100 °C are required for achieving maximum conversion and selectivity (Table , entries 14–20).

Having optimized the reaction conditions, we focussed our attention on the effect of catalyst loading (Table ).

Table 2

Effect of Catalyst Loading for Carbonylative Sonogashira Cross-Couplinga

entry	III (Pd mol %)	conversionc (%)	selectivityc (%)	TONd	TOF (h–1)
1	10–1	99	96	9.5 × 102	1.9 × 102
2	10–2	96	95	9.1 × 103	1. 8 × 103
3	10–3	79	93	7.3 × 104	1. 4 × 104
4	10–4	52	94	4.8 × 105	9.7 × 104
5b	10–4	86	94	8.0 × 105	1. 0 × 105
6b	10–5	34	74	2. 5 × 106	3. 1 × 105
7	blank	00	00

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), CO (2 bar), K2CO3 (1.0 mmol), propylene carbonate (10 mL) at 100 °C for 5 h.

120 °C for 8 h.

Based on iodobenzene, determined by GC–MS, and calculated as an average of triplicate measurements.

mol product per mol Pd.

The catalyst loading study showed that, as the palladium loading is decreased from 10–1 to 10–4 mol %, the conversion of 1a drastically drops from 99 to 52%. This resulted in catalytic TONs and TOFs of 105 and 104, respectively (Table , entries 1–4). The conversion and selectivity toward 3a at palladium loading of 10–4 mol % could be increased by carrying out the reaction at 120 °C for 8 h (Table , entry 5). Further decrease in palladium loading drastically brings down the conversion and selectivity, although a catalytic TON of 106 could be observed (Table , entry 6). Subsequently, we studied the scope of substrates that could be synthesized at low palladium loadings under the optimized conditions (Table ).

Table 3

Scope of Pincer Complex-Catalyzed Carbonylative Sonogashira Cross-Couplinga

Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), [Pd, III] (10–4 mol %), CO (2 bar), K2CO3 (1.0 mmol), propylene carbonate (10 mL) at 120 °C for 8 h.

Isolated yields.

TON = mol product per mol Pd.

TOF in h–1.

[Pd, III] (10–1 mol %), GC–MS yield.

Aromatic ring with electron-releasing substitutent (ortho- and para-OCH3) could be smoothly coupled with phenylacetylene and N,N-dimethyl-substituted phenylacetylene to furnish the products 3b and 3c in 76 and 84% yields, respectively (Table , entries 1 and 2). Polyaromatic naphthyl ynones 3d–f could be synthesized in 81, 85, and 79%, yields respectively (Table , entries 3–5). Incidentally, aliphatic cyclic alkyne-cyclopropylacetylene could also be coupled with 1-iodonaphthalene to afford the ynone 3g in 74% yield (Table , entry 6). Aromatic ring with electron-withdrawing substituents (para-Cl and ortho-Cl) could be coupled resulting in ynones 3h and 3i in 82 and 78% yields, respectively. Ynone 3j could be synthesized in 75% yield by coupling 1-bromo-4-iodobenzene and 4-fluorophenylacetylene (Table , entry 9). However, aromatic ring bearing strong electron-withdrawing substituents (para-nitro and cyano) could not be carbonylatively coupled to afford the corresponding ynones and only the corresponding noncarbonylative cross-coupling products were obtained. Increasing the palladium loading to 10–1 mol % and CO pressure to 8 bar did not result in the synthesis of the ynone. However, delightfully, on applying low palladium loading and under a CO pressure of 2 bar, heteroaromatic thiophene-containing ynones 3k–n could be synthesized in 68–86% yields (Table , entries 10–13). Attempts to carbonylatively couple the challenging ortho-disubstituted aryl iodide failed under the optimized condition. However, increasing the palladium loading to 10–1 mol % resulted in a 19% yield of the ynone 3o (Table , entry 14). The tetramethoxy ynone 3p could be synthesized in 87% yield from 5-iodo-1,2,3-trimethoxybenzene and 4-methoxyphenylacetylene (Table , entry 15).

Carbonylative Suzuki–Miyaura Cross-Coupling

Next, we turned our attention to optimize the reaction conditions for the carbonylative cross-coupling between iodobenzene 1a and phenylboronic acid 4a, leading to the synthesis of benzophenone 5a in anisole using 0.1 mol % of pincer complex III (Table ).

Table 4

Optimization of Reaction Parameters for Carbonylative Suzuki Cross-Couplinga

entry	CO pressure (bar)	base	time (h)	temperature (°C)	solvent	conversionc (%)	selectivityc (%)	TONd	TOF (h–1)
Effect of CO Pressure
1	1	K2CO3	3	100	anisole	94	93	874	291
2	2	K2CO3	3	100	anisole	92	95	874	291
Effect of Base
3	1	K2CO3	3	100	anisole	94	93	874	291
4	1	Na2CO3	3	100	anisole	88	85	748	249
5	1	K3PO4	3	100	anisole	73	89	649	216
6	1	Et3N	3	100	anisole	37	49	181	60
7	1	TMEDAb	3	100	anisole	41	39	159	53
Effect of Solvent
8	1	K2CO3	3	100	anisole	94	93	874	291
9	1	K2CO3	3	100	N,N-DMF	98	19	186	62
10	1	K2CO3	3	100	dioxane	89	86	765	255
11	1	K2CO3	3	100	ethylene carbonate	91	79	718	239
12	1	K2CO3	3	100	propylene carbonate	95	94	893	297
Effect of Time
13	1	K2CO3	0.5	100	propylene carbonate	6	80	48	96
14	1	K2CO3	1	100	propylene carbonate	60	89	534	534
15	1	K2CO3	2	100	propylene carbonate	89	90	801	400
16	1	K2CO3	3	100	propylene carbonate	95	94	893	297
Effect of Temperature
17	1	K2CO3	3	80	propylene carbonate	81	91	737	245
18	1	K2CO3	3	100	propylene carbonate	95	94	893	297
19	1	K2CO3	3	110	propylene carbonate	95	96	912	304

Reaction conditions: 1a (0.5 mmol), 4a (0.75 mmol), [Pd, III] (0.1 mol %), base (1.5 mmol), solvent (10 mL).

TMEDA = N,N,N′,N′-tetramethylethylenediamine.

Conversion and selectivity were based on iodobenzene and determined by GC–MS.

TON = mol product per mol Pd.

The CO pressure and base screening showed that the reaction could be advantageously carried out at atmospheric pressure of CO and that K2CO3 gives superior conversion and selectivity compared to other inorganic and organic bases (Table , entries 1–7). It is well a well-known fact that the carbonylative Suzuki–Miyaura cross-coupling proceeds well in nonpolar solvents. In polar aprotic solvents like N,N-DMF, formation of the corresponding carboxylic acid is observed.[13] The solvent screening showed that the reaction proceeds well in anisole and dioxane with lower values of selectivity observed in N,N-DMF (Table , entries 8–10). However, to our delight, the reaction proceeded efficiently in ethylene and propylene carbonate as alternate polar aprotic solvents (Table , entries 11 and 12). The time and temperature screening revealed that the reaction could be carried out at 100 °C in 3 h with a 95% conversion and 94% selectivity (Table , entries 13–19).

We subsequently proceeded to study the effect of catalyst loading (Table ). The palladium loading could be decreased up to 10–5 mol %, resulting in a conversion and selectivity of 81 and 89%, respectively, and catalytic turnovers of the order of 106 at 100 °C for 3 h (Table , entries 1–5).

Table 5

Effect of Catalyst Loading for Carbonylative Suzuki–Miyaura Cross-Couplinga

entry	III (Pd mol %)	conversionc (%)	selectivityc (%)	TONd	TOF (h–1)
1	10–1	99	96	9.5 × 102	3.1 × 102
2	10–2	97	95	9.2 × 103	3.0 × 103
3	10–3	95	94	8.9 × 104	2.9 × 104
4	10–4	91	95	8.6 × 105	2.8 × 105
5	10–5	81	89	7.2 × 106	2.4 × 106
6	10–6	51	74	3.7 × 107	1.2 × 107
7b	10–6	85	89	7.5 × 107	1.5 × 107
8b	10–7	44	46	2.0 × 108	4.0 × 107
9	blank	00	00

Reaction conditions: 1a (0.5 mmol), 4a (0.75 mmol), CO (1 bar), K2CO3 (1.5 mmol), propylene carbonate (10 mL) at 100 °C for 3 h.

120 °C for 5 h.

Based on iodobenzene, determined by GC–MS and calculated as an average of triplicate measurements.

mol product per mol Pd.

Bringing down the palladium loading from 10–5 to 10–6 mol % results in a drastic decrease in conversion (Table , entry 6). However, increasing the reaction temperature and time to 120 °C and 5 h, respectively, resulted in a conversion of 85%. To our delight, a catalytic turnover of 107 was observed (Table , entry 7). Decreasing the palladium loading further leads to a decrease in conversion, although resulting in a catalytic TON of 108 (Table , entry 8).

Next, we screened the scope of substrates that could be synthesized through the CSM cross-coupling catalyzed by the pincer complex (Table ).

Table 6

Scope of Pincer Complex-Catalyzed Carbonylative Suzuki–Miyaura Cross-Couplinga

Reaction conditions: 1 (0.5 mmol), 4 (0.75 mmol), [Pd, III] (10–6 mol %), CO (1 bar), K2CO3 (1.5 mmol), propylene carbonate (10 mL) at 120 °C for 5 h.

Isolated yields.

TON = mol product per mol Pd.

TOF in h–1.

[Pd, III] (10–2 mol %).

The CSM cross-coupling of aryl iodides bearing electron-withdrawing substituents is known to undergo biaryl formation without the insertion of CO.[108] However, we observed that aryl iodide bearing a para- and meta-nitro substituent could be smoothly coupled with 4-cyanophenylboronic acid and 4-flurophenylboronic acid leading to the synthesis of biaryl ketones 5b and 5c in 81 and 82% yields, respectively (Table , entries 1 and 2). 1-Bromo-4-iodobenzene and 4-iodobenzonitrile could be coupled with 4-fluorophenylboronic acid to afford ketones 5d and 5e in 77 and 79% yields, respectively (Table , entries 3 and 4). Ketone 5f, bearing a meta-fluoro and para-cyano substituent, 5g, bearing a meta-fluoro and methylenedioxy unit, and 5h, bearing difluoro and biphenyl functionality could be synthesized in 73, 84, and 80% yields, respectively (Table , entries 5–7). Polyaromatic, naphthyl biaryl ketones 5i and 5j could be synthesized from 1-iodonaphthalene in 83 and 78% yields, respectively (Table , entries 8 and 9). Polyhalogenated ketones 5k and 5l could be synthesized in 75 and 76% yields, respectively (Table , entries 10 and 11). The more challenging ortho-disubstituted ketone 5m could be synthesized from 2-iodo-meta-xylene in 68% yield, incorporating a palladium loading of 10–2 mol % (Table , entry 12). Notably, under a CO pressure of 1 bar and palladium loading of 10–6 mol %, heteroaromatic thiophene-containing ketones 5n and 5o could be synthesized in 82 and 81%, yields (Table , entries 13 and 14).

To demonstrate the practical applicability of the developed protocol, (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (5p)—an antineoplastic, and benzophenone-3 (oxybenzone) (5q)—a sunscreen agent, were synthesized. (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone is a cytotoxic compound belonging to the phenstatin family, which causes cell apoptosis by inhibiting tubulin polymerization.[109−113] Oxybenzone is a photostabilizer and photoprotective agent capable of absorbing UVB and short-wave UVA rays, thus providing a broad-spectrum protection against UV ray damage.[1] The CSM cross-coupling of 5-iodo-1,2,3-trimethoxybenzene with 4-methoxyphenylboronic acid resulted in the synthesis of 5p in 78% yield. On the other hand, oxybenzone could be synthesized in 65% yield by carbonylatively cross-coupling 2-iodo-5-methoxyphenol with phenylboronic acid (Scheme ). Synthesis of 5p and 5q could be carried out resulting in catalytic turnovers of 105 and 104, respectively.

Scheme 3

Carbonylative Synthesis of (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (5p) and Oxybenzone (5q)

Comparison of Catalytic Activity

Next, we carried out a comparative study of the palladium pincer complex (III) with conventional palladium sources Pd(OAc)2 and PdCl2(PPh3)2 as well as with oxime palladacycle (II) for CS cross-coupling and with Bedford’s palladacycle (I) for the CSM cross-coupling (Table ). In the case of CS cross-coupling, at 10–4 mol % palladium loading, the pincer exhibits a conversion and selectivity of 85 and 95%, respectively, compared to Pd(OAc)2 (5 and 32%) and PdCl2(PPh3)2 (11 and 41%) (Table , entries 1, 2, and 5). In the case of CSM cross-coupling, at 10–6 mol % palladium loading, the pincer effects a conversion and selectivity of 84 and 91%, respectively, compared to Pd(OAc)2 (6 and 21%) and PdCl2(PPh3)2 (18 and 32%) (Table , entries 7, 8, and 11). The catalytic TONs thus observed in the case of pincer catalysis in CS cross-coupling are 50 and 17 times greater than those observed in the case of Pd(OAc)2 and PdCl2(PPh3)2, respectively. In the case of CSM cross-coupling, they are 63 and 13 times greater than those observed for Pd(OAc)2 and PdCl2(PPh3)2, respectively. The combination of Pd(OAc)2 with amine ligands 4-dimethylaminopyridine (DMAP) and ethylenediamine for the CS and CSM cross-coupling results in better values of conversion and selectivity compared to only using Pd(OAc)2. However, the catalytic activity still falls short of what the pincer complex achieves (Table , entries 3, 4, 9, and 10). Notably, both the cross-coupling reactions could be carried out in gram scale (5 mmol) without any change in catalytic activity (Table , entries 6 and 12).

Table 7

Comparison of Palladacyclic Complexes with Conventional Palladium Precursors

entry	catalyst	conv.i (%)	select.i (%)	TONj	TOF (h–1)
Carbonylative Sonogashiraa
1	III	85	95	8.0 × 105	1.0 × 105
2	Pd(OAc)2	05	32	1.6 × 104	2.0 × 103
3b	Pd(OAc)2	19	40	7.6 × 104	9.5 × 103
4c	Pd(OAc)2	26	44	1.1 × 105	1.0 × 104
5	PdCl2(PPh3)2	11	41	4.5 × 104	5.6 × 103
6d	III	82	91	7.4 × 105	9.3 × 104
Carbonylative Suzuki–Miyaurae
7	III	84	91	7.6 × 107	1.5 × 107
8	Pd(OAc)2	06	21	1.2 × 106	2.5 × 105
9f	Pd(OAc)2	22	36	7.9 × 106	1.5 × 106
10g	Pd(OAc)2	30	39	1.1 × 107	2.3 × 106
11	PdCl2(PPh3)2	18	32	5.7 × 106	1.1 × 106
12h	III	83	92	7.6 × 107	1.5 × 107

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [Pd] (10–4 mol %), CO (2 bar), K2CO3 (1.0 mmol), propylene carbonate (10 mL) at 120 °C for 8 h.

10–3 mol % DMAP.

10–3 mol % ethylenediamine.

Scale up: 1a (5 mmol), 2a (6 mmol), [Pd] (10–4 mol %), CO (2 bar), K2CO3 (10 mmol), propylene carbonate (20 mL) at 120 °C for 8 h.

Reaction conditions: 1a (0.5 mmol), 4a (0.75 mmol), [Pd] (10–6 mol %), CO (1 bar), K2CO3 (1.5 mmol), propylene carbonate (10 mL) at 120 °C for 5 h.

10–5 mol % DMAP.

10–5 mol % ethylenediamine.

Scale up: 1a (5 mmol), 4a (7.5 mmol), [Pd] (10–6 mol %), CO (1 bar), K2CO3 (15 mmol), propylene carbonate (20 mL) at 120 °C for 5 h.

Based on iodobenzene, determined by GC–MS and calculated as an average of triplicate measurements.

mol product per mol Pd.

Mechanistic Insight

To gain insight into the reaction mechanism, a time-dependent conversion study was carried out for both the cross-coupling reactions using 0.1 mol % III at 100 °C. When conversion was plotted as a function of time, we observed sigmoidal-shaped curves[114] and a 60 min induction period in the case of CS cross-coupling and a 30 min induction period in the case of CSM cross-coupling (Figure ). Moreover, the addition of 15 mol % tetra-n-butylammonium bromide, a salt which stabilizes palladium nanoparticles in catalytic reactions,[114] leads to a drastic drop in conversion and catalytic activity. These results strongly point to the formation of heterogeneous palladium species (palladium nanoparticles/nanoclusters or colloidal palladium), resulting from the decomposition of the pincer architecture due to the reducing nature of gaseous CO.[115]

Figure 4

Plot of conversion vs time. (a) Carbonylative Sonogashira cross-coupling: 1a (0.5 mmol), 2a (0.6 mmol), [Pd, III] (10–1 mol %), CO (2 bar), K2CO3 (1.0 mmol), propylene carbonate (10 mL) at 100 °C. (b) Carbonylative Suzuki–Miyaura cross-coupling: 1a (0.5 mmol), 4a (0.75 mmol), [Pd, III] (10–1 mol %), CO (1 bar), K2CO3 (1.5 mmol), propylene carbonate (10 mL) at 100 °C.

To isolate and characterize the heterogeneous palladium species formed in situ, the CSM cross-coupling reaction of 1a and 4a was carried out using 4.6 mol % (∼15 mg) of III for 5 h. The reaction mixture was then centrifuged at 10 000 rpm for 30 min. The supernatant propylene carbonate was decanted carefully and the black residue was washed with water and ethanol and characterized by field-emission gun (FEG)-scanning electron microscopy (SEM) (Figure , Supporting Information), energy-dispersive spectrometry (Figure , Supporting Information), high-resolution transmission electron microscopy (HR-TEM), and X-ray photoelectron spectroscopy (XPS).

HR-TEM analysis (Figure ) reveals narrow particle size distribution with no appreciable agglomeration.

Figure 5

HR-TEM images (a–c) and particle size distribution (d) of the in situ synthesized palladium nanoparticles.

Formation of palladium nanoparticles with an average particle size of about 6.5 nm was observed. The XPS study (Figure ) reveals binding energies of 336.3 and 341.4 eV corresponding to the Pd(0) 3d5/2 and 3d3/2 energy levels. The pincer thus acts as a reservoir and dispenses highly energetic palladium nanoparticles under the reaction conditions. Hence, the reaction mechanism proceeds through the classical Pd(0)/Pd(II) redox pathway (Figure ).

Figure 6

(a) XPS survey scan of in situ synthesized palladium nanoparticles and (b) XPS image showing Pd 3d5/2 and 3d3/2 binding energy.

Figure 7

Proposed mechanism for the palladium pincer-catalyzed carbonylative Sonogashira and carbonylative Suzuki-–Miyaura cross-coupling.

Conclusions

In conclusion, through this work, we have established the first pincer complex-catalyzed carbonylative Sonogashira (CS) and carbonylative Suzuki–Miyaura (CSM) cross-coupling in propylene carbonate as an eco-friendly aprotic solvent. Advantageously, applying the aminophosphine palladium pincer complex (III) as the precatalyst allowed the CS cross-coupling to be carried out at a palladium loading of 10–4 mol % and the CSM cross-coupling to be carried out at 10–6 mol %, thus resulting in catalytic turnovers of the order of 105 and 107, respectively. A range of biaryl ketones and ynones could be synthesized, including the synthesis of an antineoplastic and a photostabilizer cum photoprotective agent. The comparison of the palladium pincer complex (III) with conventional palladium precursors Pd(OAc)2 and PdCl2(PPh3)2 shows the superiority and robustness of the pincer complex in effecting higher catalytic activity at lower palladium loadings.

The plot of the time-dependent conversion study showed a brief induction period with a sigmoidal-shaped curve. Addition of tetra-n-butylammonium bromide resulted in a decrease in the catalytic activity, thus indicating the formation of heterogeneous palladium species from the pincer architecture. The isolation and characterization of the in situ formed heterogeneous palladium species revealed the formation of Pd(0) nanoparticles with narrow particle size distribution and an average particle size of 6.5 nm. Hence, both the carbonylative cross-coupling reactions proceed through the classical Pd(0)/Pd(II) pathway. Thus, the combination of low palladium loadings and high catalytic turnovers through the application of the palladium pincer complex as a precatalyst in propylene carbonate represents a sustainable process for the synthesis of biaryl ketones and ynones.

Experimental Section

General

The aminophosphine palladium pincer complex (III) was sourced from Sigma-Aldrich and was used as received. All chemicals and solvents were sourced from different commercial vendors and used as received without any additional purification. Catalyst stock solutions dissolved in propylene carbonate of varying concentrations (10–1–10–10 mol %) were made by taking known catalyst concentration (1 mol %), which was followed by successive dilutions of the initial catalyst solution. Special precautions for the preparation of the catalyst stock solutions were not taken, and the catalysts were handled in air. The progress of the reaction was monitored by GC–MS and thin-layer chromatography using Merck silica gel 60 F254 plates. The reaction products were visualized with a 254 nm UV lamp. The GC–MS-QP 2010 instrument (Rtx-17, 30 m × 25 mm ID, film thickness (df) = 0.25 μm) (column flow, 2 mL min–1; 100–240 °C at 10 °C min–1 rise) was used for the mass analysis of the products. Purification of the products was carried out by column chromatography on 100–200 mesh silica gel. The 1H NMR spectra were recorded on 500 MHz spectrometers in CDCl3 using tetramethylsilane (TMS) as an internal standard. The 13C NMR spectra were recorded on 125 MHz spectrometers in CDCl3. Chemical shifts were reported in parts per million (δ) relative to tetramethylsilane as an internal standard, and J (coupling constant) values were reported in hertz. The splitting patterns of protons are described as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), and m (multiplet). Field emission gun high-resolution transmission electron microscopy (300 kV) was carried out on Tecnai (FEI) G2, F30 instrument. X-ray photoelectron spectroscopy was carried out on AXIS Supra (Kratos Analytical, U.K.).

Typical Procedure for Carbonylative Sonogashira Cross-Coupling

Aryl iodide (0.5 mmol), phenylacetylene (0.6 mmol), [Pd, III] (10–4 mol %), and K2CO3 (1.0 mmol) in 10 mL of propylene carbonate were added to a 100 mL stainless steel autoclave. Subsequently, the autoclave was closed and flushed three times with CO. The autoclave was then pressurized with CO to 2 bar (∼30 psi) at ambient temperature. The reaction mixture was stirred with a mechanical stirrer (450 rpm) at 120 °C for 8 h. The pressure was carefully released after cooling to room temperature. To remove traces of product, the reactor vessel was washed with ethyl acetate (3 × 5 mL). The ethyl acetate layer was washed with water (2 × 5 mL), dried over Na2SO4, and evaporated by rotary evaporation to obtain the crude product. The crude product was subjected to purification by column chromatography (silica gel, 100–200 mesh size), with petroleum ether–ethyl acetate as the eluent, to yield the pure product.

Typical Procedure for Carbonylative Suzuki–Miyaura Cross-Coupling

Aryl iodide (0.5 mmol), aryl boronic acid (0.75 mmol), [Pd, III] (10–6 mol %), and K2CO3 (1.5 mmol) in 10 mL of propylene carbonate were added to a 100 mL stainless steel autoclave. Subsequently, the autoclave was closed and flushed three times with CO. The autoclave was then pressurized with CO to 1 bar (∼15 psi) at ambient temperature. The reaction mixture was stirred with a mechanical stirrer (450 rpm) at 120 °C for 5 h. The pressure was carefully released after cooling to room temperature. To remove traces of product, the reactor vessel was washed with ethyl acetate (3 × 5 mL). The ethyl acetate layer was washed with water (2 × 5 mL), dried over Na2SO4, and evaporated by rotary evaporation to obtain the crude product. The crude product was subjected to purification by column chromatography (silica gel, 100–200 mesh size), with petroleum ether–ethyl acetate as the eluent, to yield the pure product.

Typical Procedure for Synthesis of 5p and 5q

In the case of 5p, 5-iodo-1,2,3-trimethoxybenzene (0.5 mmol), 4-methoxyphenylboronic acid (0.75 mmol), [Pd, III] (10–4 mol %), and K2CO3 (1.5 mmol) in 10 mL of propylene carbonate were added to a 100 mL stainless steel autoclave. In the case of 5q, 2-iodo-5-methoxyphenol (0.5 mmol), phenylboronic acid (0.75 mmol), [Pd, III] (10–3 mol %), and K2CO3 (1.5 mmol) in 10 mL of propylene carbonate were added to a 100 mL stainless steel autoclave.

In both the cases, the autoclave was closed and flushed with CO three times. The autoclave was then pressurized with CO to 1 bar (∼15 psi) at ambient temperature. The reaction mixture was stirred with a mechanical stirrer (450 rpm) at 120 °C for 5 h. The pressure was carefully released after cooling to room temperature. To remove traces of product, the reactor vessel was washed with ethyl acetate (3 × 5 mL). The ethyl acetate layer was washed with water (2 × 5 mL), dried over Na2SO4, and evaporated by rotary evaporation to obtain the crude product. The crude product was subjected to purification by column chromatography (silica gel, 100–200 mesh size), with petroleum ether–ethyl acetate as the eluent, to yield 5p and 5q as the pure products.

Scale-Up Study

Carbonylative Sonogashira Cross-Coupling

Iodobenzene (5 mmol, 1.020 g), phenylacetylene (6.0 mmol, 0.612 g), [Pd, III] (10–4 mol %), and K2CO3 (10 mmol, 1.382 g) in 20 mL of propylene carbonate were added to a 100 mL stainless steel autoclave. The autoclave was closed and flushed three times with CO. It was then pressurized with CO to 2 bar (∼30 psi) at ambient temperature. The reaction mixture was stirred with a mechanical stirrer (450 rpm) at 120 °C for 8 h. The pressure was carefully released after cooling to room temperature. To remove traces of product, the reactor vessel was washed with ethyl acetate (4 × 5 mL). The layer of ethyl acetate was washed with water (3 × 5 mL), dried over Na2SO4, and evaporated by rotary evaporation to obtain the crude product. The crude product was subjected to GC–MS analysis.

Carbonylative Suzuki–Miyaura Cross-Coupling

Iodobenzene (5 mmol, 1.020 g), phenylboronic acid (7.5 mmol, 0.910 g) [Pd, III] (10–6 mol %), and K2CO3 (15 mmol, 2.070 g) in 20 mL of propylene carbonate were added to a 100 mL stainless steel autoclave. The autoclave was closed and flushed three times with CO. It was then pressurized with CO to 1 bar (∼15 psi) at ambient temperature. The reaction mixture was stirred with a mechanical stirrer (450 rpm) at 120 °C for 5 h. The pressure was carefully released after cooling to room temperature. To remove traces of product, the reactor vessel was washed with ethyl acetate (4 × 5 mL). The layer of ethyl acetate was washed with water (3 × 5 mL), dried over Na2SO4, and evaporated by rotary evaporation to obtain the crude product. The crude product was subjected to GC–MS analysis.

1-(2-Methoxyphenyl)-3-phenylprop-2-yn-1-one (3b)

89.7 mg, yield 76%.

1H NMR (400 MHz, CDCl): δ 8.08 (d, J = 6.3 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.41 (dt, J = 14.0, 6.6 Hz, 3H), 7.09–6.98 (m, 2H), 3.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.7, 159.8, 135.0, 132.9, 132.6, 130.4, 128.5, 126.7, 120.6, 120.2, 112.1, 91.6, 89.1, 55.9. GC–MS (electron ionization (EI), 70 eV): m/z (%): 236 (40), 235 (100), 207 (46), 178 (20), 129 (76).

3-(4-(Dimethylamino)phenyl)-1-(4-methoxyphenyl)prop-2-yn-1-one (3c)

117.3 mg, yield 84%.

1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.03 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.7, 163.9, 151.6, 134.9, 131.6, 130.7, 113.6, 111.5, 105.8, 96.5, 87.5, 55.5, 40.0. GC–MS (EI, 70 eV): m/z (%): 279 (100), 251 (19), 236 (45), 172 (22), 144 (18).

1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-one (3d)

103.8 mg, yield 81%.

1H NMR (400 MHz, CDCl3): δ 9.25 (d, J = 8.7 Hz, 1H), 8.65 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.9 Hz, 3H), 7.58 (q, J = 8.0, 7.2 Hz, 2H), 7.44 (dd, J = 16.8, 6.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): 13C NMR (101 MHz, chloroform-d) δ 179.7, 135.1, 134.5, 133.8, 132.9, 132.9, 130.7, 130.6, 128.9, 128.6, 128.6, 126.7, 125.9, 124.4, 120.3, 91.7, 88.5. GC–MS (EI, 70 eV): m/z (%): 256 (72), 255 (100), 202 (11), 129 (38).

3-(4-Methoxyphenyl)-1-(naphthalen-1-yl)prop-2-yn-1-one (3e)

121.6 mg, yield 85%.

1H NMR (400 MHz, CDCl3): δ 9.21 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.70–7.53 (m, 5H), 6.93 (d, J = 7.8 Hz, 2H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.8, 161.5, 135.0, 134.7, 134.1, 133.8, 133.2, 130.7, 128.7, 128.5, 126.6, 126.0, 124.4, 114.3, 112.1, 92.8, 88.4, 55.4. GC–MS (EI, 70 eV): m/z (%): 286 (76), 285 (100), 258 (28), 243 (60), 215 (53), 159 (41), 129 (28).

3-(4-Fluorophenyl)-1-(naphthalen-1-yl)prop-2-yn-1-one (3f)

108.3 mg, yield 79%.

1H NMR (400 MHz, CDCl3): δ 9.22 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 6.0 Hz, 2H), 7.58 (q, J = 8.0, 7.4 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.5, 163.9 (d, J = 253.6 Hz), 135.2, 135.1, 134.4, 133.8, 132.8, 130.7, 128.9, 128.5, 126.7, 125.9, 124.4, 116.4 (d, J = 3.3 Hz), 116.1 (d, J = 22.3 Hz), 90.6, 88.3.

3-Cyclopropyl-1-(naphthalen-1-yl)prop-2-yn-1-one (3g)

81.5 mg, yield 74%.

1H NMR (400 MHz, CDCl3): δ 9.14 (d, J = 8.7 Hz, 1H), 8.45 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.67–7.59 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 1.53 (p, J = 6.6 Hz, 1H), 1.06–0.99 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.7, 134.6, 134.1, 133.7, 133.1, 130.6, 128.6, 128.4, 126.5, 125.9, 124.3, 99.5, 77.1, 9.7, 0.0. GC–MS (EI, 70 eV): m/z (%): 220 (50), 219 (100), 205 (24), 164 (64), 127 (33).

1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one (3h)

98.7 mg, yield 82%.

1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 7.1 Hz, 3H), 7.42 (t, J = 6.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.6, 140.7, 135.2, 133.0, 130.9, 130.8, 128.9, 128.7, 119.8, 93.6, 86.5. GC–MS (EI, 70 eV): m/z (%): 240 (86), 212 (98), 201 (30), 176 (28), 139 (100).

1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-one (3i)

93.9 mg, yield 78%.

1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.50–7.44 (m, 3H), 7.40 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.7, 135.8, 133.5, 133.3, 133.0, 132.5, 131.5, 130.9, 128.6, 126.8, 119.9, 93.9, 88.2. GC–MS (EI, 70 eV): m/z (%): 240 (45), 212 (80), 176 (23), 139 (100).

1-(4-Bromophenyl)-3-(4-fluorophenyl)prop-2-yn-1-one (3j)

113.7 mg, yield 75%.

1H NMR (400 MHz, CDCl3): δ 8.09–8.01 (m, 2H), 7.71–7.61 (m, 4H), 7.12 (t, J = 7.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.7, 164.1 (d, J = 254.4 Hz), 135.5, 135.4 (d, J = 8.9 Hz), 132.0, 130.8, 129.6, 116.3 (d, J = 22.4 Hz), 115.9 (d, J = 3.4 Hz), 92.5, 86.4. GC–MS (EI, 70 eV): m/z (%): 302 (43), 276 (54), 274 (61), 194 (22), 147 (100).

3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-one (3k)

88.1 mg, yield 83%.

1H NMR (400 MHz, CDCl3): δ 8.03–7.95 (m, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.1 Hz, 1H), 7.40 (t, J = 7.3 Hz, 2H), 7.20–7.15 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): 13C NMR (101 MHz, chloroform-d) δ 169.7, 144.8, 135.2, 135.1, 133.0, 130.8, 128.6, 128.3, 119.8, 91.7, 86.4. GC–MS (EI, 70 eV): m/z (%): 212 (90), 183 (100), 152 (20), 129 (65).

3-(4-Methoxyphenyl)-1-(thiophen-2-yl)prop-2-yn-1-one (3l)

104.2 mg, yield 86%.

1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 2.7 Hz, 1H), 7.70 (d, J = 4.9 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.17 (t, J = 4.3 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 161.7, 145.0, 135.0, 134.8, 134.7, 128.2, 114.4, 111.6, 92.9, 86.3, 55.4. GC–MS (EI, 70 eV): m/z (%): 242 (100), 214 (39), 199 (60), 159 (38).

1-(Thiophen-2-yl)-3-(p-tolyl)prop-2-yn-1-one (3m)

90.5 mg, yield 80%.

1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 3.0 Hz, 1H), 7.70 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.18 (dd, J = 12.5, 5.8 Hz, 3H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 145.0, 141.6, 135.0, 134.9, 133.0, 129.4, 128.3, 116.7, 92.4, 86.3, 21.7. GC–MS (EI, 70 eV): m/z (%): 226 (100), 198 (85), 197 (49), 143 (59).

3-(4-Fluorophenyl)-1-(thiophen-2-yl)prop-2-yn-1-one (3n)

78.3 mg yield 68%.

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 3.5 Hz, 1H), 7.69–7.63 (m, 2H), 7.18 (t, J = 3.5 Hz, 1H), 6.95 (t, J = 8.3 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 164.0 (d, J = 254.0 Hz), 144.8, 135.3 (d, J = 4.6 Hz), 135.2, 135.0, 128.3, 116.2 (d, J = 22.3 Hz), 115.2 (d, J = 21.5 Hz), 90.6, 86.3. GC–MS (EI, 70 eV): m/z (%): 230 (93), 202 (100), 170 (15), 147 (54), 119 (16).

1-(2,6-Dimethylphenyl)-3-phenylprop-2-yn-1-one (3o)

GC–MS yield: 19%.

GC–MS (EI, 70 eV): m/z (%): 233(100), 202 (16), 191 (36), 132 (20), 104 (10).

3-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one (3p)

141.9 mg, yield 87%.

1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.1 Hz, 2H), 7.49 (d, J = 1.6 Hz, 2H), 6.96–6.90 (m, 2H), 3.95 (d, J = 1.6 Hz, 6H), 3.94 (d, J = 1.6 Hz, 3H), 3.85 (d, J = 1.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 176.8, 161.7, 153.0, 143.3, 135.0, 132.3, 129.1, 114.4, 106.7, 94.1, 86.7, 61.0, 56.2, 55.4. GC–MS (EI, 70 eV): m/z (%): 326 (100), 283 (50), 255 (10), 159 (30).

4-(4-Nitrobenzoyl)benzonitrile (5b)

102.1 mg, yield 81%.

1H NMR (400 MHz, CDCl3): δ 8.35 (t, J = 10.5 Hz, 2H), 7.91 (dd, J = 18.6, 8.1 Hz, 2H), 7.85–7.77 (m, 2H), 7.73 (t, J = 8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 193.2, 150.2, 141.3, 139.6, 132.5, 130.7, 130.2, 123.8, 117.6, 116.6. GC–MS (EI, 70 eV): m/z (%): 252 (57), 151 (10), 150 (67), 130 (100), 102 (41).

(4-Fluorophenyl)(3-nitrophenyl)methanone (5c)

100.5 mg, yield 82%.

1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.41 (d, J = 9.4 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.82 (dd, J = 8.8, 5.4 Hz, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 8.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 192.6, 165.8 (d, J = 256.1 Hz), 148.0, 138.8, 135.2, 132.6 (d, J = 9.4 Hz), 132.4 (d, J = 3.0 Hz), 129.7, 126.7, 124.4, 115.9 (d, J = 22.1 Hz). GC–MS (EI, 70 eV): m/z (%): 245 (25), 123 (100), 95 (40), 75 (13).

(4-Bromophenyl)(4-fluorophenyl)methanone (5d)

107.4 mg, yield 77%.

1H NMR (400 MHz, CDCl3): δ 7.84–7.77 (m, 2H), 7.65–7.60 (m, 4H), 7.16 (t, J = 7.9 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 194.1, 165.4 (d, J = 254.8 Hz), 136.1, 133.3 (d, J = 3.1 Hz), 132.5 (d, J = 9.2 Hz), 131.6, 131.3, 127.5, 115.6 (d, J = 21.9 Hz). GC–MS (EI, 70 eV): m/z (%): 280 (28), 278 (31), 199 (18), 183 (28), 123 (100).

4-(4-Fluorobenzoyl)benzonitrile (5e)

88.9 mg, yield 79%.

1H NMR (400 MHz, CDCl3): δ 7.84 (d, 2H), 7.82 (d, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 193.5, 165.8 (d, J = 256.1 Hz), 141.0, 132.7 (d, J = 9.4 Hz), 132.5 (d, J = 3.0 Hz), 132.2, 130.0, 117.9, 116.0, 115.7. GC–MS (EI, 70 eV): m/z (%): 225 (46), 130 (22), 123 (100), 102 (20), 95 (33).

4-(3-Fluorobenzoyl)benzonitrile (5f)

82.2 mg, yield 73%.

1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): 13C NMR (101 MHz, chloroform-d) δ 193.6, 162.5 (d, J = 249.1 Hz), 140.5, 138.2 (d, J = 6.4 Hz), 132.3, 130.3 (d, J = 7.7 Hz), 130.1, 125.8 (d, J = 3.1 Hz), 120.3 (d, J = 21.4 Hz), 117.8, 116.7 (d, J = 22.6 Hz), 115.9. GC–MS (EI, 70 eV): m/z (%): 225 (69), 130 (69), 123 (100), 102 (39), 95 (40).

Benzo[d][1,3]dioxol-5-yl(3-fluorophenyl)methanone (5g)

102.6 mg, yield 84%.

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 7.7 Hz, 1H), 7.46–7.40 (m, 2H), 7.34 (d, J = 9.1 Hz, 2H), 7.25 (t, J = 8.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.06 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 193.5, 162.3 (d, J = 248.0 Hz), 151.8, 148.0, 140.1 (d, J = 6.4 Hz), 131.2, 129.8 (d, J = 7.8 Hz), 126.9, 125.3 (d, J = 3.1 Hz), 118.9 (d, J = 21.3 Hz), 116.4 (d, J = 22.5 Hz), 109.7, 107.7, 101.9. GC–MS (EI, 70 eV): m/z (%): 244 (59), 149 (100), 123 (15), 121 (24), 95 (26).

(2-Fluoro-[1,1′-biphenyl]-4-yl)(3-fluorophenyl)methanone (5h)

117.7 mg, yield 80%.

1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 1.4 Hz, 1H), 7.64–7.60 (m, 1H), 7.60–7.56 (m, 3H), 7.56–7.50 (m, 2H), 7.50–7.38 (m, 4H), 7.34–7.26 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 193.4, 163.7, 160.9 (d, J = 65.4 Hz), 158.1, 139.1 (d, J = 6.3 Hz), 137.5 (d, J = 6.7 Hz), 134.5, 133.5 (d, J = 13.7 Hz), 130.7 (d, J = 3.5 Hz), 130.1 (d, J = 7.7 Hz), 129.0 (d, J = 3.1 Hz), 128.6, 128.5, 125.8 (d, J = 40.4 Hz), 119.6 (d, J = 21.4 Hz), 117.6 (d, J = 24.5 Hz), 116.6 (d, J = 22.5 Hz). GC–MS (EI, 70 eV): m/z (%): 294 (73), 199 (100), 170 (30), 123 (40), 95 (28).

(4-Fluorophenyl)(naphthalen-1-yl)methanone (5i)

103.9 mg, yield 83%.

1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.88 (ddd, J = 12.3, 6.1, 1.6 Hz, 3H), 7.57–7.45 (m, 4H), 7.10 (t, J = 8.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.3, 165.8 (d, J = 255.4 Hz), 136.0, 134.6 (d, J = 2.9 Hz), 133.6, 133.0 (d, J = 9.4 Hz), 131.3, 130.8, 128.4, 127.4, 127.2, 126.5, 125.5, 124.3, 115.6 (d, J = 21.9 Hz). GC–MS (EI, 70 eV): m/z (%): 250 (85), 155 (78), 127 (100), 95 (60), 75 (24).

4-(1-Naphthoyl)benzonitrile (5j)

100.3 mg, yield 78%.

1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 6.8 Hz, 3H), 7.75 (d, J = 7.3 Hz, 2H), 7.61–7.46 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.2, 141.7, 134.7, 133.7, 132.4, 132.2, 130.7, 130.5, 128.7, 128.5, 127.7, 126.7, 125.3, 124.2, 117.9, 116.2. GC–MS (EI, 70 eV): m/z (%): 257 (100), 256 (50), 155 (99), 127 (70), 102 (22).

(4-Chloro-2-fluorophenyl)(4-fluorophenyl)methanone (5k)

94.7 mg, yield 75%.

1H NMR (400 MHz, CDCl3): 7.89–7.77 (m, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.30–7.24 (m, 1H), 7.20 (d, J = 9.5 Hz, 1H), 7.17–7.11 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 190.71, 166.04 (d, J = 256.0 Hz), 159.85 (d, J = 256.2 Hz), 138.61 (d, J = 10.1 Hz), 133.50, 132.37 (d, J = 10.5 Hz), 131.62 (d, J = 3.8 Hz), 125.21 (d, J = 14.7 Hz), 125.03 (d, J = 3.6 Hz), 117.11 (d, J = 25.3 Hz), 115.78 (d, J = 22.1 Hz). GC–MS (EI, 70 eV): m/z (%): 252 (46), 157 (38), 123 (100).

(4-Bromo-2-fluorophenyl)(4-chlorophenyl)methanone (5l)

119.1 mg, yield 76%.

1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 7.6 Hz, 4H), 7.36 (d, J = 9.4 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 191.1, 158.4, 141.0, 140.1, 135.4, 131.8 (d, J = 3.3 Hz), 131.0, 128.9, 128.0 (d, J = 3.6 Hz), 120.1, 119.9. GC–MS (EI, 70 eV): m/z (%): 314 (35), 312 (28), 203 (32), 201 (35), 139 (100).

(2,6-Dimethylphenyl)(phenyl)methanone (5m)

71.5 mg, yield 68%.

1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 2H), 2.11 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 200.4, 139.6, 136.9, 134.1, 133.6, 129.3, 128.8, 128.7, 127.5, 19.3. GC–MS (EI, 70 eV): m/z (%): 210 (86), 209 (100), 195 (35), 194 (28), 133 (56), 105 (72), 77 (63).

Thiophen-2-yl(thiophen-3-yl)methanone (5n)

79.7 mg, yield 82%.

1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 2.7, 1.0 Hz, 1H), 7.76 (dd, J = 3.8, 1.1 Hz, 1H), 7.71–7.63 (m, 1H), 7.61–7.56 (m, 1H), 7.36 (dd, J = 5.0, 2.9 Hz, 1H), 7.18–7.08 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 181.1, 143.9, 141.0, 133.6, 133.5, 132.1, 128.1, 127.9, 126.3. GC–MS (EI, 70 eV): m/z (%): 194 (48), 166 (8), 111 (100), 83 (25), 45 (4).

(4-Chlorophenyl)(thiophen-2-yl)methanone (5o)

90.2 mg, yield 81%.

1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.6 Hz, 2H), 7.73–7.69 (m, 1H), 7.60 (dd, J = 3.7, 1.0 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.17–7.12 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 186.8, 143.1, 138.6, 136.3, 134.7, 134.4, 130.5, 128.7, 128.0. GC–MS (EI, 70 eV): m/z (%): 222 (35), 187 (15), 139 (23), 111 (100), 75 (15).

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (5p)

117.9 mg, yield 78%.

1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 1.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.90 (d, J = 1.6 Hz, 3H), 3.87 (d, J = 1.6 Hz, 3H), 3.85 (d, J = 1.4 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 194.6, 163.0, 152.7, 141.4, 133.3, 132.3, 130.2, 113.5, 107.3, 60.9, 56.2, 55.4.

(2-Hydroxy-4-methoxyphenyl)(phenyl)methanone (5q)

77.6 mg, yield 68%.

1H NMR (400 MHz, CDCl3): δ 12.67 (s, 1H), 7.65–7.59 (m, 2H), 7.58–7.43 (m, 4H), 6.51 (d, J = 2.4 Hz, 1H), 6.39 (dd, J = 9.0, 2.5 Hz, 1H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 13C NMR (101 MHz, chloroform-d) δ 200.0, 166.3, 166.1, 138.2, 135.2, 131.4, 128.8, 128.2, 113.1, 107.3, 101.0, 55.6. GC–MS (EI, 70 eV): m/z (%): 228 (64), 227 (100), 151 (68), 77 (16).