Palladium-catalyzed carbonylative coupling of aryl iodides with an organocopper reagent: a straightforward procedure for the synthesis of aryl trifluoromethyl ketones

Abstract

A palladium-catalyzed carbonylative coupling of aryl iodides with a (trifluoromethyl)copper reagent has been developed. A wide range of substrates have been transformed into their corresponding trifluoromethyl ketones in good to excellent yields under mild conditions with high efficiency and excellent functional-group compatibility. Preliminary mechanistic investigations suggest that the transmetallation of an acylpalladium intermediate with the (trifluoromethyl)copper reagent seems to be involved in the catalytic cycle. Notably, this report represents one of the few studies on carbonylative coupling with organocopper reagents.

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Owing to its high electronegativity and small size, the introduction of fluorine atoms into organic molecules greatly alters the molecules' physical, chemical and biological properties, such as lipophilicity, bioavailability, chemical/metabolic stability and binding selectivity.¹ For these reasons, a great deal of efforts have been paid to develop synthetic methods for preparing fluorinated organic molecules.² Among these fluorinated organic molecules, trifluoromethylketones (TFMKs) are a unique substructure in medicinal chemistry, which have proven particularly useful as probes in the study of hydrolytic enzymes³ and as potent enzyme inhibitors.⁴ Moreover, trifluoromethylketones are of important intermediates for the synthesis of CF₃-substituted heterocycles,⁵ medicinal compounds,⁶ and fluorinated analogues of natural products.⁷

Despite a variety of procedures available for preparing aliphatic trifluoromethyl ketones,^8,9 the related methods for the synthesis of aryl trifluoromethyl ketones are still scarce. Friedel–Crafts reaction is a commonly used method for the synthesis of aromatic and heterocyclic trifluoromethyl ketones; however, the highly nucleophilic aromatic compounds are generally required and the regioselectivity is often limited to the para position.¹⁰ Reactions between organometallic reagents (Grignard and oranolithium reagents) and trifluoroacetic acids derivatives have been extensively used for the synthesis of aryl trifluoromethyl ketones; however the low functional group tolerance and formation of double-addition by-products represent major limitations.¹¹ While other methods such as oxidation of secondary trifluoromethyl carbinols,¹² nucleophilic trifluoromethylation of carboxylic acids derivatives¹³ and Suzuki cross-coupling reactions¹⁴ have been developed to make aryl trifluoromethyl ketones, highly efficient and general protocol are still needed.

The palladium-catalyzed multi-component cross-coupling reaction of aryl halides, carbon monoxide and organometallic reagents is a valuable method for the synthesis of unsymmetrical ketones.¹⁵ This strategy enables the formation of two carbon–carbon bonds in a single operation and provides products that might be difficult to access otherwise. Over the past decades, a variety of organometallic reagents including organoaluminium,¹⁶ organosilane,¹⁷ and organotin compounds¹⁸ as well as arylboronic acids¹⁹ have been used for these carbonylative cross-coupling reactions. However, the carbonylative coupling with organocopper reagents are still rarely reported. From mechanism point of view, these reactions proceed through a sequence of oxidative addition of the aryl halide to Pd(0) providing Ar–Pd–X (I), migratory insertion of CO giving acylpalladium intermediate (II), transmetallation of organometallic reagents and finally reductive elimination to generate the desired ketones and reproduce Pd(0) species. We hypothesized that with a suitable organocopper reagent would potentially trap the reactive acylpalladium species II and subsequently reductive elimination to afford the desired aryl ketones as well. In order to confirm this hypnosis, we performed experiments and we wish to describe here a successful example on palladium-catalyzed carbonylative coupling of aryl iodides with organocopper reagent. This procedure also represents a convenient and straightforward methodology for the synthesis of aryl trifluoromethyl ketones.

Initially, the reaction of 2-iodonaphthalene with different commercially available (trifluoromethyl)copper reagents, such as Hartwig's trifluoromethylator²⁰ and Grushin's (trifluoromethyl)copper reagents,²¹ in the presence of 5 mol% of PdCl₂(PPh₃)₂ and 20 bar carbon monoxide was investigated (Table 1, entries 1–3). To our delight, the desired product 1a was obtained in moderate yields (46% and 41%) with Grushin's (trifluoromethyl)copper reagents (Table 1, entries 2 and 3). Encouraged by these initial results, different palladium catalysts were tested (Table 1, entries 4–8). As expected, the reaction didn't show any conversion in the absence of palladium catalyst (Table 1, entry 4), while albeit slightly higher yield was observed when using PdI₂(PPh₃)₂ as the catalyst (Table 1, entry 8). To further improve the reaction, we evaluated the influence of critical reaction parameters such as carbon monoxide pressure, temperature and solvent. Lower yields were observed at 10 bar or 40 bar carbon monoxide pressure (Table 1, entries 9–10). The reaction temperature is crucial for the process. When the reaction performed at 50 °C, the yield decreased to 10% (Table 1, entry 11). Gratifyingly, during the survey of reaction solvents excellent yield can be achieved when using xylene as the solvent (Table 1, entry 16). Remarkably, nearly quantitative yield was obtained with a slightly excess amount of (PPh₃)₃CuCF₃ (Table 1, entry 17). In general, due to the coordination behavior of CO, increased pressure might kill the palladium catalyst and lead to lower yield. Temperature can affect CO insertion and decarbonylation step and oxidative addition step, hence yields changing can be observed in temperature variation.

Table 1 Influences of different reaction parameters on the palladium-catalyzed carbonylative trifluoromethylation of 2-iodonaphthalene^a

Entry	Organocopper	[Pd]	Solvent	CO (bar)	Yield^b(%)
a General reaction conditions: 2-iodonaphthalene (0.1 mmol), MCF3 (0.125 mmol), solvent (2 mL), Pd catalyst (5 mol%), 70 °C, 24 h.b Determined by ^19F NMR using trifluorotoluene as an internal standard.c 50 °C.d 90 °C.e 1.5 equiv. of (PPh3)3CuCF3. Phen: 1, 10-phenanthroline.
1	[(phen)CuCF3]	PdCl2(PPh3)2	Toluene	20	0
2	[(Ph3P)3CuCF3]	PdCl2(PPh3)2	Toluene	20	46
3	[(p-Tol3P)3CuCF3]	PdCl2(PPh3)2	Toluene	20	41
4	[(Ph3P)3CuCF3]	—	Toluene	20	0
5	[(Ph3P)3CuCF3]	Pd(dba)2	Toluene	20	0
6	[(Ph3P)3CuCF3]	Pd(PPh3)4	Toluene	20	8
7	[(Ph3P)3CuCF3]	Pd(dppf)Cl2	Toluene	20	0
8	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Toluene	20	50
9	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Toluene	10	45
10	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Toluene	40	31
11^c	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Toluene	20	10
12^d	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Toluene	20	50
13	[(Ph3P)3CuCF3]	PdI2(PPh3)2	DMF	20	0
14	[(Ph3P)3CuCF3]	PdI2(PPh3)2	THF	20	10
15	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Benzene	20	62
16	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Xylene	20	89
17^e	[(Ph3P)3CuCF3]	PdI2(PPh3)2	Xylene	20	99

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To gain insight into the reaction mechanism, some stoichiometric reactions using isolated palladium complexes were performed (Scheme 1). When Ar–Pd–CF₃ complex 3 was treated with 20 bar CO at 70 °C in xylene, the desired product 2b could not be observed (Scheme 1a). However, treatment of an acylpalladium complex 4 with 1.5 equiv. (PPh₃)₃CuCF₃ at 70 °C in xylene allowed the formation of the desired product 2b in 60% yield (Scheme 1b). These results support the reaction go through acylpalladium complex 4 as the key intermediate.‡

Scheme 1 Mechanistic studies.

Based on our mechanistic studies and previous literature,^18c–e a most plausible catalytic cycle is proposed in Scheme 2. It is believed that this process started from oxidation addition of the aryl iodide to Pd(0) providing Ar–Pd–I (A), and subsequent migratory insertion of CO giving the acylpalladium intermediate B, then transmetallation of (PPh₃)₃CuCF₃ generating intermediate C and finally reductive elimination to yield the desired trifluoromethyl ketone and reproduce Pd(0) species for next cycle.

Scheme 2 Proposed reaction pathway.

Encouraged by these results, we studied the generality of this catalyst system in more detail (Table 2). Various aryl iodides were transformed smoothly into their corresponding trifluoromethyl ketones with good to excellent yields. In most cases, both electron-withdrawing and electron-donating groups showed little impact on the reaction activities. This process could also be easily scaled up; the same isolated yield can be achieved on 5 mmol scale without problem (Table 2, entry 5).

Table 2 Palladium-catalyzed carbonylative trifluoromethylation of aryl iodides to form aryl trifluoromethyl ketones^a

Entry	Product	Yield^b (%)
a General reaction conditions: aryl iodides (0.2 mmol), (PPh3)3CuCF3 (0.3 mmol), xylene (5 mL), CO (20 bar), Pd catalyst (5 mol%), 70 °C, 24 h.b Yield determined by ^19F NMR using trifluorotoluene as an internal standard. The number within the parentheses represents the isolated yield.c Isolated yield for 5 mmol scale.
1		99
2		99
3		99
4		99 (80)
5		85 (78)
		75^c
6		99 (96)
7		99
8		83
9		52
10		50
11		85 (77)
12		84
13		80
14		87 (75)
15		62
16		99
17		88 (78)
18		98
19		99 (86)
20		(45)

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Then the functional group tolerances of this catalyst system were investigated. Dialkylamine, ester, nitrile, amide, ketal, trifluoromethylsulfoxide as well as heteroaromatic compound were well tolerated; however, substrates containing aldehydes or ketones are not suitable, presumably because of the nucleophilic addition of CF₃ anion to form the corresponding trifluoromethyl carbinols. To highlight the utility of this protocol for the late-stage functionalize of bio-active molecular, the carbonylative trifluoromethylation of estrone-derived aryl iodide was attempted, which yielded the corresponding trifluoromethyl ketone in 45% yield (Table 2, entry 20).

Conclusions

In summary, we have developed the first palladium-catalyzed carbonylative coupling of aryl iodides with organocopper reagent. The reaction allows the straightforward and efficient preparation of a wide range of aryl trifluoromethyl ketones. The ready availability of starting materials, broad substrates scope as well as excellent functional group tolerance should make the new protocol useful for drug discovery.

Acknowledgements

We appreciate the generous supports from Professor Matthias Beller in LIKAT.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details and NMR spectrum. See DOI: 10.1039/c6ra12287f

‡ General reaction procedure: A 30 mL autoclave was charged with aryl iodides (0.2 mmol), (PPh₃)₃CuCF₃ (0.3 mmol), (PPh₃)₂PdI₂ (0.01 mmol), xylene (5 mL) and a magnetic stirring bar. Once sealed, the autoclave was purged 3 times with CO, then pressurized to 20 bar and heated at 70 °C for 24 h. After reaction, the autoclave was cooled to room temperature and depressurized. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to give the corresponding compound.

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