Fluorine-containing functionalized cyclopentene scaffolds through ring contraction and deoxofluorination of various substituted cyclohexenes

: Fluorination of some highly-functionalized cyclopentene derivatives, obtained from various substituted cyclohexenes through a ring-opening/ring-contraction procedure has been investigated. Transformations have been found to be highly substrate dependent resulting in various functionalized alicycles or heterocycles possessing allyl difluoride or vinyl fluoride moieties in their structure


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Late-stage fluorination with various commercial nucleophilic reagents is a common method for the introduction of fluorine into an organic molecule and to access a number of different fluorine-containing molecular entities. [1]Late-stage fluorination based on hydroxyfluorine or carbonyl-difluorine exchange is considered to be a relatively simple synthetic approach.In certain circumstances, these type of transformations were found to be highly substrate-dependent and the presence of various functional groups strongly determined and directed the outcome of the deoxofluorination reaction.Some deoxofluorinations proceed with high chemoselectivity; nucleophilic fluorinating agents, such as Deoxofluor, DAST or XtalFluor, are able to transform the hydroxy or oxo moieties of various highly-functionalized substrates with chemodiscrimination between these groups. In view of the high pharmaceutical relevance of fluorinated organic molecules, [3] fluorination techniques including the late-stage fluorination protocol, such as oxo-difluorine interconversion, especially of highly functionalized scaffolds, are still considered to be an interesting challenge for synthetic chemists.Therefore, in order to investigate the chemical behavior under deoxofluorination conditions of some polyfunctionalized substrates, we selected some functionalized alicycles possessing carboxylate and amide or carbamate groups.
The use of β-amino acid derivatives (as promising bioactive derivatives) [4] as well as some alicyclic esters and N-protected compounds allowed us to study both the independent and synergic habit of these moieties.

Results and Discussion
Taking into consideration some unexpected findings during our earlier experimental investigations on the late-stage fluorination of various functionalized alicycles, [2] our intention in the framework of this project was to continue and explore the chemical behavior of some variously polysubstituted six-membered carbocycles through oxidative ring-opening/ringcontraction/fluorination.Because of the high biological relevance of β-amino acids, [4] we have first selected some cyclohexene β-amino acid stereo-and regioisomers, as model compounds for our experiments.Thus, cis-or trans-2-aminocyclohexenecarboxylic acids (±)-1 and (±)-5 were first converted by known procedures to the corresponding dihydroxylated amino esters (±)-2 and (±)-6 (Scheme 1). [5].1002/ejoc.201800057

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European Journal of Organic Chemistry Scheme 1.
The aldol reaction and its intramolecular asymmetric version [6] of various substituted scaffolds (e.g.amino, nitro, halogen, hydroxy and other substituted compounds as well as carbonyl derivatives, or some oxo esters) are well-known basic approaches for the formation of varied molecules with an α,β-unsaturated carbonyl moiety.

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Scheme 2.
The cyclization process to (±)-11 can be interpreted as shown in Scheme 3.
Intramolecular hydrogen bonding effects in the transition state are probably responsible for the selectivity of the reaction.A stable structure may arise through a hydrogen bonding interaction between the amide NH and enamine nitrogen lone electron pair (formed in the reaction of morpholine with the formyl group located furthest from the amide).On the other hand, an enamine intermediate resulting from the reaction of morpholine with the formyl moiety close to the amide would afford an unfavorable structure (Figure 1).Scheme 3.

Figure 1.
In continuation, cyclopentene acylamino ester (±)-11 possessing an α,β-unsatursated aldehyde moiety with two electrophilic centers for 1,2-or 1,4-addition was subjected to fluorination under various experimental conditions, affording practically the same result.The experiments were systematically performed under various conditions in view of the used solvents (CH2Cl2, PhMe, THF), nucleophilic fluorinating agents (Deoxofluor, DAST), and temperature (0 °C, room temperature).Unfortunately, no significant effect either on the yield or selectivity of the products could be found.Namely, two products were formed nearly in 1:1 ratio, which could be separated by chromatography, isolated and characterized by NMR or Xray analysis.One of the products was identified as the expected difluorinated compound (±)-12 (Figure 2 and Scheme 2).The other product, (±)-13, somewhat surprisingly, was identified as a heterocyclic compound with a vinyl fluoride moiety.While the formation of product (±)-12 with an allyl difluoride element is unambiguous, formation of (±)-13 might be the result of an intramolecular attack of the amide oxygen atom to the electrophilic sp 2 carbon atom of intermediate T7.It contains a good leaving group system formed from the formyl group and Deoxofluor leading Z-selectively to an oxazoline derivative with a vinyl fluoride moiety (Scheme 4).The structure of (±)-13 was determined on the basis of 2D NMR analysis.8a] In addition, allyl difluorides are motifs found in a series of pharmaceuticals and agrochemicals. [8]In view of the importance of these fluorinated derivatives, we found it interesting to continue our investigation of the intramolecular cyclization and subsequent fluorination protocol using other scaffolds.Diol derivative (±)-14, a stereoisomer of (±)-10 accessed from (±)-9, underwent ring opening in reaction with NaIO4 giving formyl-substituted cyclic amino ester (±)-15 through unstable dialdehyde derivative 10.1002/ejoc.201800057

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Scheme 5.
The experimental findings described above with respect to oxidative ringopening/intramolecular aldol reaction/fluorination performed with some cyclic β-amino acid derivatives motivated us to continue these investigations on other six-membered systems as well.The selected compounds bearing either ester or protected amino groups on their skeleton allowed to test the independent influence of the functional groups on the outcome of the reaction.2e] This symmetric molecule gave formyl-substituted derivative (±)-19 as the single product as a result of ringopening/intramolecular cyclization.Fluorination of this diester with DAST or Deoxofluor under various experimental conditions furnished allyl difluoride derivative (±)-20 as the sole product.The highest yield was attained with DAST in CH2Cl2 at room temperature (Scheme 6).The selective formation can be attributed to the absence of the internal nucleophile.

Scheme 6.
More interesting results have been expected by the evaluation of six-membered benzyl cyclohexenecarboxylate (±)-21. [9]Dihydroxylation of (±)-21 provided an inseparable mixture of cis and trans diols (±)-22.Since both isomers give the same dialdehyde, this mixture was further used in the oxidative ring-opening/cyclization step.According to our expectation, the intramolecular aldol reaction afforded two formylated derivatives which, in turn, were separated and identified as compounds (±)-23 (minor) and (±)-24 (major).Fluorination of (±)-only geminal difluorinated products (±)-29 and (±)-30 were detected and isolated.The highest yields, again, were attained with the use of DAST in CH2Cl2 at room temperature (Scheme 8).Noteworthy, that substituted five-membered ring systems, in general, are more expensive than their six-membered analogs.Consequently, functionalized cyclopentene derivatives synthesized according to Schemes 6-8 might be regarded as valuable scaffolds for a wide variety of further transformations.

Conclusions
The synthesis of various fluorine-containing molecular scaffolds has been achieved from readily available six-membered functionalized carbocycles involving oxidative ringopening/ring-contraction/fluorination sequences leading to molecules possessing allyl or vinyl fluoride moieties.Ring closing through intramolecular aldol reaction has been found to be substrate dependent and afforded various functionalized α,β-unsaturated aldehyde systems, whose fluorination gave either 1,2-or 1,4-addition products.The extension of these methods towards the access of the enantiomers, as well as studies on the regioselectivity of the intramolecular aldol reaction on various systems are currently being studied in our laboratory.

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Furthermore, additional experiments are currently investigated in our group on related transformations with other nucleophilic reagents and on various other highly-functionalized cycloalkane substrates.

General procedure for ring contraction reactions. Synthesis of formyl-substituted cyclopentene amino esters:
To a solution of diol derivative (200 mg, 0.65 mmol) in THF/H2O (11 mL, v/v 10:1) NaIO4 (279 mg, 1.3 mmol) was added and the reaction mixture was stirred for 1 h at room temperature under an Ar atmosphere, resulting in the corresponding diformyl derivative.
Water (20 mL) was then added to the reaction mixture and it was extracted with CH2Cl2 (2 × 15 mL).The combined organic phases were dried over Na2SO4, filtered and evaporated in vacuo.The resulting unstable dialdehyde was dissolved in 10 ml of dry THF followed by the addition of morpholinium TFA salt (131 mg, 0.65 mmol) .The mixture was stirred for 1 h at room temperature, then washed with water (2 × 15 ml), dried over Na2SO4, filtered and evaporated under reduced pressure.Purification of the crude mixture by means of column chromatography on silica gel (n-hexane-EtOAc) yielded the corresponding α,β-unsaturated aldehyde derivative.

General procedure for the fluorination of formyl-substituted cyclopentene amino esters:
To a solution of formyl derivative (144 mg, 0.5 mmole) in CH2Cl2 (10 mL) DAST or Deoxofluor (see text) was added at 20 °C and the mixture was stirred at this temperature for 4 h.Then it was diluted with CH2Cl2 (20 mL), washed with saturated NaHCO3 solution (2 × 15 mL), dried (Na2SO4) and concentrated and the crude residue was purified by column chromatography on silica gel.

Accepted Manuscript
European Journal of Organic Chemistry This article is protected by copyright.All rights reserved.

Accepted Manuscript
European Journal of Organic Chemistry This article is protected by copyright.All rights reserved.
This article is protected by copyright.All rights reserved.