Atom-economical synthesis of 3,3,3-trifluoropropanal dialkyl acetals through Pd/C catalyzed acetalization of 3,3,3-trifluoropropene

Abstract

A facile and efficient procedure for one-step synthesis of 3,3,3-trifluoropropanal dialkyl acetals from readily available 3,3,3-trifluoropropene (TFP) has been developed. The catalyst can be recycled for 4 times without obvious deactivation. This process provides a novel and atom-economical synthetic strategy for the preparation of functional CF₃-containing compounds.

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Trifluoromethylated compounds have shown important applications in pharmaceutical chemistry,¹ agrochemistry,² and materials science³ due to their unique chemical and biological properties.⁴ Great efforts have been made to develop useful methods for introducing the CF₃ group into organic compounds.⁵ The building block approach is considered to be a practical and powerful tool.⁶ Therefore, the development of diverse CF₃-containing building blocks is highly desirable. Meanwhile, the 3,3,3-trifluoropropanal dialkyl acetals are important CF₃-containing building blocks for 3,3,3-trifluoropropanoic acid, alkyl-3,3,3-trifluoropropionate,⁷ and β-CF₃ alcohols.⁸

Several research groups had reported the synthesis of 3,3,3-trifluoropropanal dialkyl acetals.^7–9 However, their two-step methods using expensive 1-chloro-3,3,3-trifluoropropene⁷ or 2-bromo-3,3,3-trifluoropropene⁹ as a starting material have restricted the synthetic application. A more convenient synthetic method involving fewer steps and the readily available starting materials is highly desired.

Acetalization reaction of alkene is a powerful method for the synthesis of acetals in a short sequence. Hosokawa¹⁰ and Jiang¹¹ reported the acetalization of acrylates by the use of Pd^II species. Ishii et al.¹² reported the acetalization of acrylates catalyzed by Pd(OAc)₂/NPMoV supported on active carbon. Recently, Li et al.¹³ reported the synthesis of alkyl-3,3-dialkoxy-propionates by the acetalization of acrylates using a nanosized CS–Fe₃O₄–Pd catalyst. The facile formation of 3,3,3-trifluoropropanal dialkyl acetals via the acetalization of alkene is expected. Trifluoropropene (TFP), as an important fundamental building block, is commercially available and its functionalizations e.g., addition reaction,¹⁴ polymerization,¹⁵ hydroformylation¹⁶ and hydroboration¹⁷ have been studied. However, the acetalization of TFP has not been reported so far, presumably due to the fact that TFP is gas at room temperature.

Here we firstly report a convenient and efficient method for one-step preparing 3,3,3-trifluoropropanal dialkyl acetals by the acetalization of TFP with various alcohols using heterogeneous Pd/C–CuCl₂ system (Scheme 1).

Scheme 1 Methods for synthesis of 3,3,3-trifluoropropanal dialkyl acetals.

Initially, we tried to seek an effective system for the Pd/C catalyzed acetalization of TFP to produce 3,3,3-trifluoropropanal dimethyl acetals (3a) with O₂ as the oxidant. The effects of different solvents on yield of reaction were investigated including DMF, PEG400, toluene, THF, MeCN and MeOH (Table 1, entries 1–6). The results revealed that the solvent was critical for the success of this reaction because the gas material TFP should be dissolved in the solvent firstly before reaction. Methanol was found to be the optimal solvent providing an excellent yield of 3a. In addition, the effects of co-catalysts such as CuCl₂, CuBr₂, and CuSO₄ on yield of reaction were studied (Table 1, entries 6–8). Based on the results, CuCl₂ showed the highest activity among the tested co-catalysts. No target product was observed in the absence of CuCl₂ (Table 1, entry 9). The co-catalyst CuCl₂ could play dual roles, which oxidized Pd⁰ to Pd^II as co-oxidant and also acted as a ligand to prevent the deactivation of the catalyst.¹⁸ The influences of additives on catalytic activity were also tested such as LiCl, CH₃SO₃H, Na₂HPO₄ and K₂CO₃ (Table 1, entries 10–13). Although the addition of CH₃SO₃H increased the conversion of TFP, the yield of 3,3,3-trifluoropropenyl methyl ether (Michael adduct) also increased. However, the use of dibasic Na₂HPO₄ as an additive could prevent the formation of the Michael adduct, leading to a little decrease of TFP conversion. This result is consistent with Hosokawa's studies.^10a Finally, the effects of O₂ pressure and temperature were studied. A lower yield of 3a was obtained when the reaction was run at the O₂ pressure of 0.6 MPa (Table 1, entry 14). However, increasing the reaction pressure to 1.4 MPa had no significant effect on the yield of product 3a (Table 1, entry 15). The reaction without O₂ or Pd/C did not give the desired product at all (Table 1, entries 16 and 17). A decrease in the temperature led to a decrease in the yield (Table 1, entries 18 and 19). Furthermore, we compared the catalytic activity of heterogeneous catalyst Pd/C with homogeneous catalyst PdCl₂. To our pleasure, the heterogeneous catalyst Pd/C displayed similar activity to the homogeneous catalyst PdCl₂ (Table 1, entry 20). The benefit using heterogeneous catalytic system is that the catalyst is easily separated by filtration. The catalyst recycle was also checked and it was reusable for at least 4 times with the addition of a small amount of CuCl₂ (Fig. 1).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Co-catalyst	Additive	T (°C)	Yield^b (%)
a Reaction conditions: 1a (30 mmol), 2a (60 mmol), catalyst (1 mol%), co-catalyst (2 mol%), additive (1 mol%), solvent (20 mL), O2 1 MPa, 120 °C, 8 h.b Yields determined by GC.c O2 0.6 MPa.d O2 1.4 MPa.e O2 0 MPa.f Catalyst free.g PdCl2 (1 mol%).
1	DMF	CuCl2	—	120	Trace
2	PEG400	CuCl2	—	120	60
3	Toluene	CuCl2	—	120	68
4	THF	CuCl2	—	120	53
5	MeCN	CuCl2	—	120	40
6	MeOH	CuCl2	—	120	92
7	MeOH	CuBr2		120	10
8	MeOH	CuSO4		120	0
9	MeOH	—	—	120	0
10	MeOH	CuCl2	LiCl	120	68
11	MeOH	CuCl2	CH3SO3H	120	80
12	MeOH	CuCl2	Na2HPO4	120	91
13	MeOH	CuCl2	K2CO3	120	27
14	MeOH^c	CuCl2	—	120	48
15	MeOH^d	CuCl2	—	120	91
16	MeOH^e	CuCl2	—	120	Trace
17	MeOH^f	CuCl2	—	120	0
18	MeOH	CuCl2	—	100	67
19	MeOH	CuCl2	—	80	46
20	MeOH^g	CuCl2	—	120	93

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Fig. 1 Recyclability study of Pd/C catalyst. Reaction conditions: 1a (30 mmol), catalyst (1 mol%), co-catalyst (2 mol%), solvent (20 mL), O₂ 1 MPa, 120 °C, 8 h. Yields determined by GC.

We next explored the scope and the utility of this method with other olefins and various alcohols. Table 2 shows the acetalization of TFP with various alcohols. In almost all the cases tested primary alcohols, the acetalization went smoothly, giving a high yield of the desired products. The substituted groups on the beta position of primary alcohol seemed to have little influence on the product yields (Table 2, entries 3i and 3k). Isopropanol 2l, as secondary alcohol, could also be converted into the corresponding acetal with moderate yield (Table 2, entry 12). However, when cyclohexanol and tert-butyl alcohol were explored, only a little desired product could be detected. In general, the desired products could be obtained with higher yields from primary alcohols than that from secondary alcohols. Additionally, the alcohol containing aromatic ring such as benzyl alcohol leads to the corresponding product of 23% yield, which was also lower than that of primary alcohols because a part of benzyl alcohol was transferred to benzaldehyde and benzyl ether (Table 2, entry 13). Furthermore, the reaction of ethylene glycol with TFP gave the desired product of 32% yield (Table 2, entry 14). Unfortunately, when glycerol was used, the reaction failed to afford the desired product. The reaction of 2-aminoethanol also failed to afford the desired product but gave 3o in 73% yield. Those alcohols containing ester, ketone such as methyl glycolate, hydroxyacetone were found to afford a little desired product.

Table 2 The acetalization of TFP with various alcohols^a

Entry	Alcohols	Products	Yield^b (%)
a Reaction conditions: 1a (30 mmol), 2 (20 mL), Pd/C catalyst (1 mol%), CuCl2 (2 mol%), O2 1 MPa, 120 °C, 8 h.b Yields determined by GC. Number in parentheses is isolated yield.
1			92(72)
2			89(74)
3			87(75)
4			89(82)
5			90(83)
6			83(80)
7			81(78)
8			80(78)
9			80(75)
10			78(73)
11			77(74)
12			70(62)
13			48(23)
14			56(32)
15			85(73)

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In order to further demonstrate the utility of this protocol, various alkenes were examined. Table 3 shows the acetalization of various olefins with methanol by the Pd/C–CuCl₂ system. Methyl acrylate, ethyl acrylate and n-butyl acrylate in methanol provided the corresponding acetals in good yields (Table 3, entries 1–3) which were the useful precursors for the preparation of various heterocyclic compounds.¹⁹ Acrylonitrile afforded the corresponding product in 30% yield (Table 3, entry 4). The decrease in the π-electron density of olefins due to competitive coordination ability of the CN group to Pd^II retards the reaction.^10a When styrene was explored, only 10% yield of 4f was obtained because most of styrene were transferred to hypnone and benzaldehyde (Table 3, entry 5). Unfortunately, when the terminal alkenes bearing substituent on the alpha or beta position such as 2-bromo-3,3,3-trifluoropropene, 2-chloro-3,3,3-trifluoropropene, methyl methacrylate and methyl cinnamate were explored, the reaction failed to afford the desired products.

Table 3 The acetalization of various olefins with methanol^a

Entry	Alkenes	Products	Yield^b (%)
a Reaction conditions: 1 (30 mmol), 2a (20 mL), Pd/C catalyst (1 mol%), CuCl2 (2 mol%), O2 1 MPa, 50 °C, 8 h.b Isolated yield.c 120 °C yields determined by GC.
1			91
2			92
3			91
4			30
5			10^c
6			0

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To explore the possible reaction pathway, the Michael adduct 3,3,3-trifluoropropenyl methyl ether C was synthesised according to reference.⁹ Then the Michael adduct C was used to react with methanol under the same conditions of model reaction (Scheme 2). The desired product D was obtained in 97% yield.

Scheme 2 Synthesis of D from C.

Based on the previous mechanism reported^10a,11b and our results, a plausible pathway is provided in Scheme 3. In this pathway, the key step is the production of the Michael adduct C, which has been detected by GC-MS in our experiments. First of all, Pd⁰ was oxidized to Pd^II in the presence of CuCl₂ and O₂ as the conventional redox couples.^11b,18a Our experimental results (Table 1, entries 9, 16 and 20) also concludes that the Pd^II is the true catalytic active species. Second, a Pd^II catalyst undergoes oxypalladation with A to afford a organopalladium intermediate B, followed by β-H elimination reaction to intermediate C. Finally, the intermediate C undergoes oxypalladation again and then affords the desired product D. For 2-bromo-3,3,3-trifluoropropene, 2-chloro-3,3,3-trifluoropropene and methyl methacrylate, their organopalladium intermediates B can not occur β-H elimination reaction because β-H is replaced by Cl, Br and CH₃. So the results that there is no corresponding product for them can be explained.

Scheme 3 Possible reaction mechanism.

Conclusions

In summary, we developed a new strategy for one-step synthesis of 3,3,3-trifluoropropanal dialkyl acetals via a simple Pd/C–CuCl₂ system catalyzed acetalization reaction of commercial TFP with alcohols. The catalyst system can be recycled for 4 times without obvious deactivation. The wide scope to a large number of primary alcohols and alkenes with electron-withdrawing substituent, makes this strategy remarkably practical for the synthesis of functional acetal compounds. Atom-economical characteristics and the recyclable catalyst system of this method are beneficial to industrial applications.

Acknowledgements

The authors wish to thank the National Natural Science Foundation of China (Grant No. 21403163, 21503610) and Natural Science Basic Research Plan in Shaanxi Province of China (Program No. 2014JQ2062) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, ¹H, ¹³C, ¹⁹F NMR, IR and MS spectra. See DOI: 10.1039/c6ra03208g

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