Cascade reaction for the construction of CF₃ containing tetrasubstituted furan ring

Abstract

Activated olefins are well known nucleophiles, but proton abstraction from the substituted α-methyl group in nitroolefin is rare. We report the first DBU-catalysed one-pot reaction of TFMK and activated nitroolefin followed by intramolecular cyclization reaction, to construct stereogenic center containing a furan core with CF₃ in excellent yields (up to >95%).

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Introduction

Heterocyclic compounds with diverse structural motifs play a significant role in the pharmaceutical, agrochemical and fine chemicals sectors.¹ Much attention has been devoted to developing catalytic methods for the synthesis of desired heterocyclic systems with specific functionalities for biological evaluation in order to develop potential therapeutic agents. Therefore, a large number of heterocyclic molecules with different heteroatoms (X= N, O, S etc.) and ring sizes have been reported in the literature.² In particular the furan moiety is an important building block in many natural products and pharmaceuticals.³ Further, CF₃ containing tetra substituted stereogenic centers were also found in biologically and pharmaceutically active heterocyclic compounds (Fig. 1). Furthermore, substituted furans with oxime group are also found to be important intermediates in organic synthesis.^4–6

Fig. 1 Tetra-substituted stereogenic center containing biologically and pharmaceutically active heterocyclic compounds.

In addition, organo-fluorine compounds have gain importance due to the fact that the physiological and chemical properties of parent molecules, particularly in the field of pharmaceutical and agrochemical (for example chemical/metabolic stability, lipophilicity, polarity, electrostatic potential, dipole moment, binding selectivity, and bioavailability) are greatly altered by the incorporation of fluorine atoms and increase the target activity of drugs.^7,8

Among these, trifluoromethylated compounds have attracted a lot of attention,^9–22 however, the synthesis of compounds with furan core having CF₃ group is scarcely reported.^23a–c Further, to the best of our knowledge there is no report on the synthesis of furan compound with CF₃ containing tetra substituted stereogenic center via nucleophilic addition reaction of trifluoromethyl ketone (TFMK) and activated nitroolefin (Scheme 1). In this context, we have developed a catalytic protocol where a C–CF₃ stereogenic center was incorporated in the furan framework under metal-free conditions. In this protocol trifluoromethyl ketone was allowed to react with an activated nitroolefin in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst and CF₃-furan framework forms via intramolecular cyclization in a “single step’’ to afford (Z)-3,5-diphenyl-5-(trifluoromethyl)furan-2(5H)-1-oxime derivatives in excellent yields under mild reaction conditions.

Scheme 1 General scheme for nucleophilic addition reaction.

Results and discussion

We have been engaged in developing privileged catalytic frameworks for efficient C–C bond formation reactions and implementation of diverse functionalities.²⁴ In this aspect, recently we are interested in emerging new organic reaction for the construction of tetrasubstituted stereogenic centers. Considering the great potential of CF₃ derived scaffolds, we have synthesized nitroolefin 2a, and allowed it to react with CF₃ based ketone 1a to form cyclized product furan derivative 3a in a cascade C–C bond formation reaction.

To the best of our knowledge, this kind of nucleophilic activation and the resultant cyclized product is not known in the literature. To optimize the reaction parameters for this unusual reaction, substrates 1a and nitroolefin 2a were used to find a suitable organic/inorganic bases (catalyst), catalysts loading, solvent and temperature (Table 1). Accordingly, the nucleophilic addition reactions of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone 1a (0.5 mmol) as a model substrate was carried out by using activated nitroolefin 2a (0.6 mmol) as a nucleophile in the presence of several inorganic and organic bases as catalysts (20 mol%) in CH₃CN at 40 °C and the results are summarized in Table 1. Among the organic bases screened (viz. DBU, 2,6-dimethyl amino pyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO) and Et₃N; entries 1–4) DBU gave the product 3a in highest yield (entry 1). On the other hand inorganic bases (entries 5–7) were found to be relatively less active. Therefore, DBU was taken as a preferred catalyst for this reaction and was used further for process optimization viz., catalyst loading (entries 8–12), solvents (entries 13–18) and temperature (entries 19–22) variations. First we have screened catalyst loading from 60 to 10 mol% using CH₃CN (ACN) as a solvent at 40 °C for 20 min in presence of DBU as a catalyst. Highest product yield was obtained at 20 mol% catalyst loading (entry 1) among other catalyst loadings (Table 1, entries 8–12). Although none of the solvents varied could match the results obtained with CH₃CN (entry 1), CH₂Cl₂ and THF (entries 13 & 14) gave the product in respectable yields (90 & 88% respectively). Toluene (yield 45%, entry 15) as solvent was found to be poor choice, whereas highly polar and alcoholic solvents (entries 16–18) failed to give the product (no reaction). Further, temperature variation studies (entries 19–22) revealed that 40 °C is optimum as either below (entries 19 & 20) or above (entries 21–22) this temperature the yield of the product affected adversely. It should be further noted that in the absence of a base catalyst (entry 23) the reaction failed to proceed under the above optimized reaction condition as per the entry 1. The above optimized reaction conditions for the condensation of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone 1a with nitroolefin 2a (as per entry 1, Table 1) was used to explore the utility of this protocol for a series of substituted trifluoromethyl ketones (TFMK) 1a–j with activated nitroolefin 2a and the data are given in (Table 2).

Table 1 Optimization of reaction parameters for the reaction of trifluoromethyl ketone 1a and activated nitroolefin 2a in the presence of various Lewis bases, catalysts loading, solvents and temperature^a

Entry	Lewis base	Solvent	Catalyst loading	Temperature °C	Yield^c [%]
a The reaction was carried out with 1a (0.5 mmol, 1.0 eq.) and 2a (0.6 mmol, 1.2 eq.).b Product not detected.c Isolated yields.d Without base.
1	DBU	CH3CN	20	40	95
2	DABCO	CH3CN	20	40	60
3	DMAP	CH3CN	20	40	35
4	Et3N	CH3CN	20	40	20
5	K2CO3	CH3CN	20	40	35
6	KO^tBu	CH3CN	20	40	65
7	Cs2CO3	CH3CN	20	40	70
8	DBU	CH3CN	10	40	83
9	DBU	CH3CN	30	40	89
10	DBU	CH3CN	40	40	81
11	DBU	CH3CN	50	40	72
12	DBU	CH3CN	60	40	65
13	DBU	DCM	20	40	90
14	DBU	THF	20	40	88
15	DBU	Toluene	20	40	45
16	DBU	DMSO	20	40	—^b
17	DBU	MeOH	20	40	—^b
18	DBU	DMF	20	40	—^b
19	DBU	CH3CN	20	20	60
20	DBU	CH3CN	20	30	85
21	DBU	CH3CN	20	50	92
22	DBU	CH3CN	20	60	90
23	—^d	CH3CN	20	40	—

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Table 2 Scope of the reaction with substituted trifluoromethyl ketones 1a–j using activated nitroolefin 2a in current reaction parameters^a

a Reaction conditions: substrates 1a–j (0.5 mmol, 1 equiv.) and 2a (0.6 mmol, 1.2 equiv.) in CH₃CN (0.8 mL) at 40 °C with DBU (20 mol%) in 20 min. Reaction time was determined by TLC on the basis of consumption of the starting materials 1a–j.b Isolated yields after column chromatography.

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The data clearly show that substrates having electron withdrawing group in the aromatic ring of trifluoromethyl ketone (entries 1–5) and trifluoromethyl thiophene ketone (entry 6) gave the corresponding products in excellent yields, whereas unsubstituted (entry 7) and electron donating groups containing trifluoromethyl ketone (entries, 8–10) gave the products in moderate to good yields.

Furthermore, we have also demonstrated the scope of the cascade reaction using trifluoromethyl ketones 1a′–g′ with 4-chloro substituted nitroolefin 2b using above optimized reaction parameters and data are summarized in Table 3.

Table 3 Scope of the reaction with substituted trifluoromethyl ketones 1a′–i′ using activated nitroolefin 2b and 2c in current reaction parameters^a

a Reaction conditions: substrates 1a′–i′ (0.5 mmol, 1 equiv.) and (2b and 2c) (0.6 mmol, 1.2 equiv.) in CH₃CN (0.8 mL) at 40 °C with DBU (20 mol%) in 20 min. Reaction time was determined by TLC on the basis of consumption of the starting materials.b Isolated yields after column chromatography.

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According to the Table 3, substrates having electron withdrawing group in the aromatic ring of trifluoromethyl ketone (entries 1–4) gave the corresponding products in excellent yields (89–94%). Among these substrates, 4-chloro substituted TFMK (4d) exhibited highest yield (94%) whereas remaining substrates (entries 5–7) gave the products in moderate to good yield. We have also demonstrated the scope of this reaction with 4-fluoro substituted nitroolefin 2c using 4-chloro (1h′) and 3-fluoro (1i′) substituted TFMK in optimized reaction parameters. The results are summarized in Table 3 (entries 8–9). These results are in line with the findings obtained in Table 2. Apart from the TFMK, acetophenone (5a), aldehyde (6a) and isatin (7a) were not tolerated under optimized reaction condition (Scheme 2), suggesting the importance of –CF₃ group to deliver the cyclized product. In this reaction –CF₃ group play an important role to facilitate the intramolecular cyclization reaction. The CF₃ group destabilizes the incipient carbanion by electron-withdrawing effect and delivered the corresponding product, whereas in acetophenone, aldehyde and isatin such type of effect is absent.^23b,c

Scheme 2 Reaction of activated nitroolefin 2a, 2b and 2c with acetophenone, aldehyde and isatin.

A most plausible mechanism for the formation of phenyl-trifluoromethyl furan oxime is proposed based on the formation of the product by the condensation of trifluoromethyl ketones and nitroolefin (Scheme 3).

Scheme 3 Plausible reaction mechanism.

Accordingly, proton abstraction from the α-methyl group of nitro-olefin is proposed here, which is contrary to the previous reports where proton abstraction from the C–H bond directly attached to the electron withdrawing nitro group takes place. The catalytic abstraction of proton from nitroolefin is promoted by Lewis base DBU used in this reaction to form an intermediate carbanion A-1 which attacked at –C=O group of TFMK to form an intermediate A-2, which is stabilized by tautomerism. An intramolecular nucleophilic addition and subsequent cyclization gives the intermediate A-3, which on dehydration produces the desired product in high yield.

The product 3a, 3j and 4g were characterized by single crystal X-ray and other physicochemical analysis. In the case of compound 3a, 3j and 4g, the structures were unambiguously confirmed by single-crystal X-ray analysis (Fig. 2).²⁵

Fig. 2 ORTEP diagram of 3a, 3j and 4g depicting one of the organic molecule present in the asymmetric unit with atom numbering scheme (40% probability factor for the thermal ellipsoids).

Conclusions

In conclusion, a simple yet powerful one-pot synthetic protocol for the synthesis of stereogenic center containing furan core with CF₃ (yield and selectivity up to >95%) is reported by using DBU as catalyst. Based on the product formation as established by single crystal X-ray analysis a probable mechanism of the reaction is proposed. This unexpected and novel approach precedents the catalytic method to notable utility for producing diverse organic molecules. Efforts are in progress to stabilize the asymmetric version of present reaction and will be reported in due course.

Acknowledgements

(CSMCRI Communication No. 041/2016). Manoj K. Choudhary and RIK are thankful to DST and CSIR-Indus Magic Project CSC0123 for financial assistance. Manoj K. Choudhary is thankful to CSIR for awarding SRF and AcSIR for Ph. D registration. Authors are also thankful to Analytical Science and Centralized Instrumentation facility Discipline for providing instrumental facilities.

Notes and references

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25. CCDC 1473287 (3a), CCDC 1471857 (3J) and CCDC 1490162 (4g) contain the supplementary crystallographic data for this paper.†.

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Footnotes

† Electronic supplementary information (ESI) available: All experimental details, HPLC chromatogram, crystallographic data in CIF, NMR (¹H and ¹³C), IR and HRMS were provided in this section. CCDC 1473287, 1471857 and 1490162. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra19782e

‡ All authors are agreed to publish this work in your journal.

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