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DOI: 10.1055/s-0037-1610774
Simple Synthesis of Fluorinated Ene-Ynes via In Situ Generation of Allenes
Funding was provided by UCLA, the National Science Foundation Major Research Instrumentation Program (NSF MRI; CHE-1048804), the Alfred P. Sloan Foundation (FG-2018-10855 to E.M.S.) and the NSF (GRFP 2018270309 to J.A.J.).
Abstract
Fluorination of small molecules is a key route toward modulating reactivity and bioactivity. The 1,3 ene-yne functionality is an important synthon towards complex products, as well as a common functionality in biologically active molecules. Here, we present a new synthetic route towards fluorinated ene-ynes from simple starting materials. We employ gas chromatography-mass spectrometry analysis to probe the sequential eliminations necessary for this transformation and observe an allene intermediate. The ene-yne products are sufficiently fluorous to enable purification via fluorous extraction. This methodology will allow facile access to functional, fluorous ene-ynes.
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Since the incorporation of a single fluorine atom in uracil to make Fluorouracil 1 (Scheme [1]A) in 1957, fluorination has been a valuable strategy for the medicinal chemistry community.[1] [2] The unique combination of electronic and steric properties imparted by fluorine provide opportunities to tune stability, pharmacokinetics, and binding affinities of small molecule therapeutics. Methods to introduce a single fluorine,[3,4] trifluoromethyl groups (as seen in Fluoxetine 2),[5] [6] [7] [8] and even longer perfluoroalkyl chains have been extensively pursued.[9] [10]
As methodology has progressed, access to more advanced fluorous motifs has been granted. In particular, nonaromatic sp2 hybridized fluoride containing compounds are of growing interest based on their prevalence in bioactive compounds and function as non-hydrolyzable mimics of amide bonds.[11] [12] For example, monofluoro dipeptide mimic 3 (Scheme [1]A) was incorporated into an analogue of neuropeptide Substance P (SP), and found to have similar binding affinities to natural SP for its receptor. Pheromones have also been synthesized that contain vinyl fluoride functionality.[13]
Conjugation of a vinyl fluoride to an alkyne gives a new class of compounds, namely, 1,3 ene-ynes. Vitamins, prostaglandins, pheromones and unsaturated fatty acids containing fluorinated ene-ynes have been prepared.[14] [15] [16] Notably, monofluoro ene-yne 4 (Scheme [1]A) was found to have improved antipheromone properties when compared to its hydrogen analogue.[17] Not only are ene-ynes present in biologically active compounds,[18] but they are also useful synthetic intermediates.[19] Conjugated fluorous ene-ynes have been utilized as Michael acceptors and as intermediates towards fluorous diynes.[20] [21] Additionally, the conjugated vinyl fluoride can be displaced via acetylides to give ene-diyne inhibitors.[22] Finally, fluorinated ene-ynes can serve as a starting material for fluorous allenes (Scheme [1]B), another fluorinated functional group with rising popularity.[23] [24] [25] [26] [27]
a Conversion determined based on peak integration of gas chromatography (GC) trace. Isolated yield given in parentheses.
b Phenol coupled product accounts for the remaining yield.
c Products were observed by NMR analysis that were not visible by GC-MS.
d Determined by integration of the 1H NMR spectra.
Previous work to access vinyl-fluoride containing ene-ynes has largely involved palladium-catalyzed Sonogashira-type couplings of functionalized olefins (Scheme [1]C, middle).[14] [21] [22] , [28] [29] [30] [31] Metal-free approaches to fluorinated ene-ynes include couplings with fluorinated sulfonates or phosponates via Julia or Horner–Wadsworth–Emmons olefination, respectively.[18] [32] These methods are often limited by the multistep syntheses required to reach the requisite vinyl fluoride coupling partners. Currently, there is only a single reported method to incorporate a fluorous chain onto 1-fluoro ene-ynes without use of a metal catalyst (Scheme [1]C, left).[20] This approach involves allene starting materials, which limit the scope of ene-ynes that can be prepared. Here, we report a new, simple, metal-free approach to fluorinated ene-yne preparation from readily available terminal alkynes and perfluoroalkyl iodide starting materials (Scheme [1]C, right). We envision that the simplicity of these starting materials would enable a larger scope of ene-yne products to be accessed when compared to existing methods.
It is well-established that perfluoroalkyl iodide addition into terminal alkynes generates 1,2-disubstituted vinyl iodides as a mixture of E- and Z-isomers.[33] [34] [35] [36] Previously, we had found that the reaction of fluorous vinyl iodides with phenols and catalytic copper under basic conditions gave a mixture of an Ullmann coupled vinyl ether and a fluorinated ene-yne.[37] Looking to better understand the mechanism of ene-yne formation and to establish the optimized conditions for this unique transformation, we built from the Ullmann conditions (Table [1], entry 1), employing vinyl iodide 5 as a model substrate and monitoring conversion by gas chromatography-mass spectrometry (GC-MS). The Ullmann conditions produced the desired ene-yne 6 in 55% yield, measured by integration of GC peaks. Removing both the copper and phenol required for the Ullmann coupling decreased the desired ene-yne product conversion by 50%, providing a mixture of equivalent amounts of starting material 5 and alkyne 7 (entry 2). Although only trace amounts of 6 were observed, this result suggested that copper catalysis was not necessary for ene-yne formation. The yield of 6 was significantly improved when 2,5-dimethylphenol was introduced as an additive (entry 3). Pre-forming the phenol salt improved the conversion into 6, but introduced phenoxide addition impurity 8 (entry 4). 2,4,6-trimethylphenol proved to be superior to 2,5-dimethylphenol, yielding 45% 6 but the increased electron density of the aromatic system increased the nucleophilicity of the phenol and byproduct 8 was also observed (entry 5). Increasing the base loading and temperature improved conversion to 6 (entry 6–8) but significant amounts of 8 were detected via GC-MS and other addition products not visible by GC-MS were apparent in the nuclear magnetic resonance (NMR) spectra.
We further probed the role of the phenol, considering two hypotheses: 1) phenol aided in solubilizing the carbonate base, and 2) phenol facilitated fluoride elimination. To probe the first hypothesis, 18-crown-6 ether (18-C-6) was added in place of the phenol (Table [1], entries 9 and 10). Significant differences in the production of 6 with 2,5-dimethylphenol and 18-C-6 as additives were observed, with 18-C-6 producing poorer conversion to 6 (entries 9 vs. 8). To test the second hypothesis, a silane additive was employed to further sequester the fluoride. A silicon oil/dioxane mixture was utilized as the solvent with the 18-C-6 coadditive. Here, we found a significant increase in the formatuon of 6, with an 82% yield by GC-MS analysis (entry 11). These data suggested that stabilization of fluoride was important and prompted a change to the more polar dimethylformamide (DMF), yielding almost full conversion to 6 (entry 12). Unfortunately, our isolated yield was rather modest (47%), which we believe to be due to polymeric byproducts that were not observed in the GC-MS analysis. Although the solubility of Cs2CO3 is increased in DMF, we found that 18-C-6 was still necessary to achieve high conversions (entry 13). From these data, we believe that the major role of phenol was aiding fluoride elimination, with the solubilization of Cs2CO3 being a secondary factor. Further reactions with phenol additives were then attempted with the use of DMF as solvent (entries 14 and 15). 2,4,6-Trimethylphenol gave addition product 8 as the main product, while 2,5-dimethylphenol provided excellent conversion to 6 based on GC analysis. In both cases, significant amounts of phenol addition products that were not observable by GC were found with NMR analysis.
Moving forward, we retained the polar solvents for fluoride stabilization and looked to remove any necessary additive by increasing the strength of a non-nucleophilic base. Tetramethylguanidine (TMG) provided 6 in modest conversion (Table [1], entry 16), while 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave rapid conversion to 6, although the isolated yields remained modest (entry 17). 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) was the most successful of the bases, with 94% conversion to 6 in only 2 hours (entry 18). Even with strong base, we confirmed that polar solvent was necessary for rapid reaction times (entries 18–20). Increasing the loading of MTBD to 4 equivalents increased conversion to 99% with an acceptable 64% isolated yield (entry 21).
With the knowledge gained from the reaction optimization, we looked to better understand the mechanism of ene-yne formation (Scheme [2]). As multiple eliminations are necessary to convert 5 into 6, we envisioned that sequential additions of MTBD and careful GC-MS analysis would enable intermediate identification (Scheme [2]A). Addition of 1 equivalent of MTBD gave primarily alkyne 7 after 2 hours, with about 10% of starting material and ene-yne product also present in the reaction mixture (Scheme [2]B, ii trace). Addition of 2 more equivalents of MTBD and further reaction for an hour showed nearly full conversion into 6 (Scheme [2]B, iii trace). These data suggest that alkyne 7 is an intermediate in the transformation of vinyl iodide 5 into ene-yne 6. Looking closer at these data, in the 2 h trace, in addition to 6 there were two small peaks at 5.80 and 5.85 minutes (designated with asterisk (*) and hash (#), respectively, in Scheme [2]B, ii trace) both with an isomeric mass to alkyne 7. Our first proposal for the identity of one of these intermediates was an allene intermediate (10, Scheme [3]A).
We independently synthesized the hypothesized allene intermediate 10 from activated triflate 9 (Scheme [3]A). With 10 in hand as a standard, we were able to confirm that the previously observed GC-MS peak at 5.80 minutes (Scheme [2]B, asterisk) was an allene intermediate (Figure S2). Next, we employed isolated allene 10 as a starting material to probe for ene-yne conversion and attempted to identify the isomeric peak at 5.85 minutes (Scheme [3]A). We found that 1 equivalent of MTBD in DMF at 50 °C gave clean and rapid isomerization from allene 10 to ene-yne 6 in 1 hour (Scheme [3]B, Condition A). Switching the solvent from polar DMF to nonpolar toluene, greatly slowed conversion to ene-yne 6 and enabled the peak at 5.85 minutes to be observed (Scheme [3]B, Condition B, green peak). The species eluting at 5.85 minutes was also present when using a weaker base, Cs2CO3, with 18-C-6 as an additive, in DMF (Scheme [3]A, Condition C). Notably, in none of the given conditions did we observe alkyne 7 generated from allene 10, suggesting that under basic conditions alkyne 7 irreversibly isomerizes to allene 10. Similar isomerization patterns have been observed from aryl substituted trifluoromethyl allenes.[38]
Upon further GC-MS and NMR spectra analysis (Scheme [3]C, Figure S3), we proposed the compound with a 5.85 min retention (Scheme [2]B, hash) arose from the activated alkyne 11. Unfortunately, we were unable to obtain an analytical standard of 11 as there are no facile methods that selectively produce internal alkynes beta to a perfluorinated chain, likely due to synergistic activation of the methylene protons being both propargylic and adjacent to a fluorous chain. Separation challenges prevented the isolation of 11 from 10. We moved forward to confirm the identity of 11 in the mixture obtained after purification of the condition C reaction on a silica gel column eluting with hexanes. The isolated mixture of compounds was compared to standards of allene (10) and ene-yne (6). Analysis of the 1H NMR spectra showed a new triplet centered at 3.03 ppm that was not consistent with either 10 or 6 (Scheme [3]C, green peaks, top trace) with a J coupling of 16.2 Hz and integration of 2 (assigned Hc), suggesting a methylene group coupled to a CF2. This peak matches a similar fluorous acetylenic compound found in the literature.[39] Additionally, a secondary peak was observed, centered at 2.18 ppm, split into a triplet of triplets with J couplings of 7.2 and 2.5 Hz, respectively. These couplings are consistent with long-range interactions across a C–C triple bond. Further analysis of the 13C NMR spectra indicated two new signals in the 65–90 ppm range that were not consistent with either allene 10 or ene-yne 6 (Scheme [3]C, green peaks, middle trace). Additionally, the carbon labeled Cc of alkyne 11 is split into a triplet with a J coupling of 6.0 Hz, consistent with a carbon that is beta to a CF2 group. Finally, the 19F NMR spectra of the purified reaction C mixture was analyzed and compared to those of allene 10 and ene-yne 6. As with the previous spectra, two new notable peaks were observed that were not consistent with either standards (Scheme [3]C, green peaks, bottom trace): a multiplet centered at –112.1 ppm and a broad singlet centered at –121.8 ppm match closely to the previously mentioned acetylenic literature compound.[39]
To better observe these key intermediates starting from vinyl iodides, the reaction of vinyl iodide 5 with Cs2CO3 and 18-C-6 as an additive (Table [1], entry 13) was monitored over an extended reaction period of 18 hours (Figure S4). In contrast to trials with use of MTBD as a base, allene intermediate 10 was prominent within an hour of reaction, with ene-yne 6 and alkyne 11 found in lesser amounts throughout the reaction.
Collectively, our studies and observations have led us to propose the mechanism in Scheme [4]. The strong electron-withdrawing nature of the perfluoroalkyl group provides fast elimination of the vinyl iodide in starting material 5 to yield internal alkyne 7. From the internal alkyne, irreversible isomerization to allene 10 occurs, giving the active intermediate. This key isomerization step is likely aided by the electron-withdrawing perfluoroalkyl group stabilizing the anionic intermediate alpha to the fluorous chain. From 10, the mechanism is dependent on reaction conditions. In a nonpolar solvent, where fluoride release is disfavored, or in a polar solvent with a weak base, the dominant pathway proceeds through further isomerization from allene 10 to internal alkyne 11. From 11, HF is eliminated to give ene-yne 6. Alternatively, if MTBD is used with a polar solvent, direct elimination of HF from allene 10 is observed as the dominant pathway to give 6. A similar one-step elimination has previously been reported via cyclic allenyl halides;[40] however, we cannot rule out that MTBD acts as an efficient proton shuttle and rapidly passes through internal alkyne 11. The small amount of 11 observed in Scheme [2]B suggests that the two pathways compete.
Finally, we looked to explore the substrate scope of this newly developed sequential elimination reaction. In some cases, the starting vinyl iodides were easily prepared in one step through perfluoroalkyl addition to terminal alkynes to give the desired products (6, 12a, 13a, 18a, Table [2]). In other cases, perfluoroalkylation of terminal alkynes gave an intermediate carboxylic acid or tosylate for further derivatization (Scheme S1). Higher complexity was added to the vinyl iodide substrates through an acid chloride coupling or tosylate substitution to give substrates 14a–17a (Table [2]).
a Purified via fluorous extraction.
b Purified via column chromatography.
c Range in yield due to volatility of product.
d Determined by integration of 1H NMR signal.
e Determined by integration of 19F NMR signal.
We began our substrate exploration through shortening and lengthening the fluorous chain. Perfluorobutyl derivative 12b was readily synthesized from 12a, with full conversion observed by GC-MS. Variable isolated yields (41–84%) were obtained due to the volatile nature of 12b. Unexpectedly, the perfluorooctyl substrate 13a required longer reaction times than necessary for 5 or 12a to convert to ene-yne product. After 18 h, conversion was nearly complete and 13b was isolated in 62% yield via fluorous extraction. While generally purification via partitioning into the fluorous phase requires an eight-carbon perfluoroalkyl chain, as found in 13b,[41] we were also able to purify shorter-chain containing ene-ynes 6 and 12b by fluorous extraction.
Next, we looked to expand the ene-ynes able to be accessed to include alcohols, acids, esters, amides, and amines as these are important functional groups in bioactive molecules. To increase the compatibility with these polar functional groups, base loading was lowered from 4 to 3 equivalents. In the case of alcohols and carboxylic acid derivatives, complex mixtures of oligomers, cyclized products, and ene-ynes were observed, owing to the basic reaction conditions and available acidic protons. Although conversion to ene-yne derivatives containing esters was well tolerated, we noted additional isomerization occurred to give a complex mixture of isomeric products after loss of fluoride (Figure S5). We believe this pathway could be blocked in the future through lengthening of the alkyl chain spacer between the vinyl iodide and ester group. In comparison, amides proceeded readily at room temperature with elongated reaction times. Disubstituted amide 14b was isolated via extraction from methoxy perfluorobutyl ether with no remaining alkyne, in 73% yield and monosubstituted benzyl amide 15b was isolated in 60% yield with small amounts of alkyne 15c. While direct implementation of amino groups was unsuccessful, phthalimide-protected amine 16b could be isolated in 56% yield, again with low amounts of alkyne 16c. Notably, we returned to 4 equivalents of MTBD in this trial due to the unreactive nature of the phthalimide and decreased concerns for degradation. It has been observed that when aromatic groups are present, extraction into the fluorous phase is reduced due to the polarizable π-system[42] and column chromatography was required for purification of both 15b and 16b.
We also designed substrates with terminal alkene and alkyne functionality that would allow for further modification by click chemistries.[43] The installation of click functional handles was first demonstrated through monosubstituted amide 17b containing an allyl group, which could be synthesized in a modest yield of 64%, with low amounts of alkynes 17c in the mixture. Similar to disubstituted amide 15b, allyl containing substrate 17b could be purified via extraction with methoxy perfluorobutyl ether.
The terminal alkene of 17b provides a handle for thiol-ene chemistries or olefin metathesis.[44] [45] Continuing in our pursuit towards functionalizable ene-ynes, terminal alkyne 18b was readily synthesized in 73% yield and purified via extraction with perfluorohexanes. The terminal alkyne of 18b provides opportunities for further click chemistry derivatization or bioconjugation.[46] [47]
To conclude, we have explored the preparation of fluorous ene-ynes from fluorinated vinyl iodide starting materials. Notably, this reaction proceeded through a distinguishable allene intermediate, in contrast to previously established methods. The fluorinated ene-ynes were produced in modest to good yields. In addition, a variety of functional groups could be appended to the starting materials including terminal alkynes and alkenes, aromatic groups, amides, and phthalimides. In general, this route provides a simple approach to fluorous ene-ynes as the requisite vinyl iodides are readily synthesized from widely available starting materials, the reaction proceeds under mild conditions with no exclusion of air or water, and in most cases the products can be purified through facile fluorous extraction. Furthermore, formation of an electrophilic allene as a key intermediate could lead to nucleophilic trapping to form complex fluorinated small molecules. We envision that this method could allow access to a range of ene-ynes previously unavailable in as little as two steps.
Chemical reagents were purchased from Sigma–Aldrich, Alfa Aesar, Fisher Scientific, or Acros Organics and used without purification unless noted otherwise. No unexpected or unusually high safety hazards were encountered. Anhydrous and deoxygenated solvents toluene (PhMe), tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (MeCN), and dimethylformamide (DMF) were dispensed from a Grubbs-type Phoenix Solvent Drying System.[48] Thin-layer chromatography was performed using Silica Gel 60 F254 (EMD Millipore) plates. Flash chromatography was executed with technical grade silica gel with 60 Å pores and 40–63 μm mesh particle size (Sorbtech Technologies). Solvent was removed under reduced pressure with a Büchi Rotovapor with a Welch self-cleaning dry vacuum pump and further dried with a Welch DuoSeal pump. Nuclear magnetic resonance (1H NMR, 13C NMR, and 19F NMR) spectra were taken with Bruker Avance 500 (1H NMR and 13C NMR) or AV-400 (19F NMR) instruments and processed with MestReNova software. All 1H and 13C spectra are reported in ppm relative to residual solvent signals. 19F NMR spectra are reported with trifluoroacetic acid as the reference peak at –76.0 ppm as external standard. High-resolution mass spectra were collected with an Agilent 7890B-7520 Quadrupole Time-of-Flight GC-MS (Electron Impact (EI)) or via DART-MS spectra collected with a Thermo Exactive Plus MSD (Thermo Scientific) equipped with an ID-CUBE ion source and a Vapur Interface (IonSense Inc.) (Atmospheric pressure chemical ionization (APCI)). Low-resolution mass spectra (Electron impact) were collected with an Agilent 6890N-5975 Quadrupole GC-MS. Photochemical reactions were performed in a photochemical reactor with a Hanovia 450 W medium-pressure mercury vapor UV lamp.
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General Procedures
Procedure 1
Starting materials 5, 12a, and 13a were prepared by a modified procedure from Mallouk et al.[49]
Procedure 2
Starting materials 14a, 15a, 17a and S2 were prepared by using the following procedure using synthesized 7,7,8,8,9,9,10,10,11,11,12, 12,12-tridecafluoro-5-iodododec-5-enoic acid (S1) as starting acid.
7,7,8,8,9,9,10,10,11,11,12,12,12-Tridecafluoro-5-iodododec-5-enoic acid (S1) (0.880 g, 1.58 mmol, 1.0 equiv) and thionyl chloride (0.426 g, 3.60 mmol, 2.28 equiv) were stirred at reflux for 2 hours then cooled to r.t. Excess thionyl chloride was then removed under vacuum and the resulting acid chloride was dissolved in CH2Cl2 (5 mL, anhydrous) and used without further purification. Pyridine (0.214 g, 2.70 mmol, 1.5 equiv, anhydrous) and desired amine (2.7 mmol, 1.5 equiv) were added and the mixture was stirred for 18 hours at r.t. The reaction was quenched with a saturated solution of NH4Cl (5 mL) and the mixture was extracted with DCM (3 × 5 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil, which was purified via flash chromatography.
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Synthesis of Ene-Yne-Containing Products 6, 12b–18b
Procedure 3
Starting vinyl iodide (0.100 mmol, 1.0 equiv) was dissolved in DMF (0.25 mL) after which MTBD (0.046–0.061 g, 0.30–0.40 mmol, 3.0–4.0 equiv) was added and the solution was stirred at the desired temperature and time (see Table [2]). The resulting reaction was quenched with a saturated solution of NH4Cl (5 mL) and the mixture was extracted against either fluorous solvent or DCM (3 × 1 mL). Removal of solvent either gave pure product or was further purified via flash chromatography to give a mixture of stereoisomers (ratio calculated through integration of 1H NMR signals) and small amounts of remaining alkyne (remainder calculated through integration of 19F NMR signals, see Table [2] for ratios and purification).
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1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluoro-8-iodotetradec-7-ene (5)
Pocedure 1
To a quartz tube, 1-octyne (1.65 g, 15.0 mmol, 1.0 equiv) was added, followed by iodoperfluorohexane (7.36 g, 16.5 mmol, 1.1 equiv). The reaction mixture was illuminated under 254 nm light for 1 hour. The reaction mixture was placed on high vacuum to remove starting materials to give 5 as a pink oil and a mixture of E- and Z-isomers (87:13 E/Z, 8.14 g, 14.6 mmol, 97%). Spectra matched literature compound.[36]
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1,1,1,2,2,3,3,4,4,5,5,6-Dodecafluorotetradec-6-en-8-yne (6)
Pocedure 3
Extracted from perfluorohexanes as a yellow oil (15:85 E/Z).
Yield: 0.026 g (0.064 mmol, 64%).
1H NMR (500 MHz, CDCl3): δ = 6.04 (E, ddt, J = 15.5, 4.3, 2.3 Hz, 0.15 H), 5.71 (Z, dt, J = 29.3, 2.3 Hz, 0.85 H), 2.39 (Z, t, J = 7.1 Hz, 1.7 H), 2.34 (E, t, J = 8.2 Hz, 0.3 H), 1.65–1.49 (m, 2 H), 1.45–1.26 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 152.4 (Z, dt, J = 272.0, 28.5 Hz), 118.9–107.4 (5 C, m), 103.5 (Z, d, J = 6.7 Hz), 98.3 (Z, q, J = 6.2 Hz), 69.4, 31.1, 28.0, 22.3, 19.9, 14.1.
19F NMR (376 MHz, CDCl3): δ = –80.65 (t, J = 9.7 Hz, 3 F), –116.04 (E, q, J = 12.7 Hz, 0.2 F), –117.86 (Z, q, J = 13.6 Hz, 1.8 F), –118.59 (Z, q, 0.9 F), –120.23 (E, m, 0.1 F), –122.36 to –123.45 (m, 4 F), –126.07 (m, 2 F).
HRMS (EI): m/z [M]+ calcd for C14H12F12: 408.0747; found: 408.0739.
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1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluorotetradec-7-yne (7)
Vinyl iodide 5 (0.50 g, 0.90 mmol, 1.0 equiv) was dissolved in toluene (2.5 mL). MTBD (0.41 g, 2.7 mmol, 3.0 equiv) was added dropwise and the solution was stirred for 5 hours at r.t. The reaction mixture was diluted with water (5 mL) and extracted with hexanes (3 × 5 mL), then the organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil, which was further purified via a short silica plug with hexanes as the eluent to give compound 7 (0.31 g, 0.71 mmol, 79%) as a clear oil in 90% purity with 5% remaining 5 and 5% ene-yne 6 as determined by 19F NMR spectroscopy. Spectra matched literature compound.[50]
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1,3,5-Trimethyl-2-((1,1,1,2,2,3,3,4,4-nonafluorotetradeca-5-en-7,9-diyn-5-yl)oxy)benzene (8)
Vinyl iodide 5 (0.200 g, 0.360 mmol, 1.0 equiv) and 2,4,6-trimethylphenol (0.220 g, 1.62 mmol, 4.50 equiv) were dissolved in DMF (2 mL). Cesium carbonate (0.527 g, 1.62 mmol, 4.50 equiv) was then added and the mixture was stirred at 85 °C for 18 hours. The resulting slurry was cooled to r.t. and diluted with diethyl ether (5 mL), which was then extracted against water (4 × 5 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil. The crude oil was purified further by flash chromatography with pentane as the eluent (Rf = 0.5) to give the enriched product 8 (0.029 g, 0.060 mmol, 17%) as a yellow oil. The enriched product was further purified by preparative thin-layer chromatography for analysis and structural determination. E and Z assignments match the 13C NMR J coupling values of a similar compound reported in the literature[51] and was further confirmed by NOESY NMR analysis.
1H NMR (500 MHz, CDCl3): δ = 6.88 (E, s, 0.6 H), 6.80 (Z, s, 1.4 H), 5.34 (Z, s, 0.7 H), 5.00 (E, s, 0.3 H), 2.44–1.98 (m, 11 H), 1.53–1.34 (m, 4 H), 0.94–0.86 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 150.3 (Z, t, J = 24.1 Hz), 148.4, 136.4, 130.4, 128.7, 120.3–106.2 (m, 4 C), 88.3 (Z, t, J = 8.0 Hz), 87.3, 82.1, 64.7, 63.9, 30.4, 21.9, 20.8, 19.3, 15.8, 13.5.
19F NMR (376 MHz, CDCl3): δ = –80.95 (m, 3 F), –113.93 (E, t, J = 12.9 Hz, 0.7 F), –115.74 (Z, t, J = 13.5 Hz, 1.4 F), –121.93 to –122.39 (m, 2 F), –125.40 to –126.12 (m, 2 F).
MS (EI): m/z [M]+ calcd for C23H11F9O: 484.1; found: 484.1.
HRMS (APCI): m/z [M + H]+ calcd for C23H11F9O: 485.1521; found: 485.1522.
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9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluorotetradeca-6,7-diene (10)
The compound was synthesized by a modified procedure described by Ichihara and co-workers.[52]
1-Octyn-3-ol (6.31 g, 5.00 mmol, 1 equiv) and iodoperfluorohexane (2.45 g, 5.50 mmol, 1.1 equiv) were dissolved in a MeCN/water mixture (10 mL/7.5 mL). Sodium bicarbonate (0.532 g, 6.33 mmol, 1.15 equiv) was added followed by sodium dithionite (1.10 g, 6.33 mmol, 1.15 equiv) and the solution was stirred for 2 hours at r.t. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (3 × 15 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil, which was used without purification in the next step. The resulting crude fluorous alcohol (2.26 g, ca. 4.00 mmol, 1.00 equiv) was dissolved in DCM (10 mL, anhydrous). Triethylamine (0.481 g, 11.8 mmol, 1.2 equiv) was added and then cooled to 0 °C. Trifluoroacetic acid (1.34 g, 4.76 mmol, 1.2 equiv) was then added dropwise and allowed to warm to r.t. overnight. The reaction was quenched with a saturated solution of NH4Cl (10 mL) and the organic layer was extracted with DCM (3 × 15 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give crude oil (9, 2.00 g, 2.84 mmol, 1.0 equiv) which was used without purification in the next step.
Previously synthesized 9,9,10,10,11,11,12,12,13,13,14,14,14-tridecafluoro-7-iodotetradec-7-en-6-yl trifluoromethanesulfonate 9 (2.00 g, 2.84 mmol, 1.0 equiv) was dissolved in THF (3 mL, anhydrous). Activated zinc (0.371 g, 5.68 mmol, 2.0 equiv) was then added and the mixture was stirred at reflux for 18 hours. The resulting slurry was filtered and washed with dichloromethane (10 mL). This solution was concentrated and purified via flash chromatography with hexanes as the eluent (Rf = 0.9) to give the product as a clear oil (0.386 g, 0.90 mmol, 32%).
1H NMR (500 MHz, CDCl3): δ = 5.75–5.65 (m, 1 H), 5.36 (tdd, J = 11.2, 6.4, 3.2 Hz, 1 H), 2.12 (dtd, J = 8.1, 6.9, 3.1 Hz, 2 H), 1.45 (tt, J = 7.2, 5.4 Hz, 2 H), 1.36–1.28 (m, 4 H), 0.89 (t, J = 6.9 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 206.9, 126.1–104.4 (m, 6 C), 98.6, 84.3 (t, J = 28.3 Hz), 31.3, 28.3, 27.7, 22.5, 14.0.
19F NMR (376 MHz, CDCl3): δ = –80.66 (t, J = 9.9 Hz, 3 F), –106.20 to –109.43 (m, 2 F), –121.44 (m, 2 F), –122.78 (m, 2 F), –123.19 (m, 2 F), –126.00 (m, 2 F).
MS (EI): m/z [M–H]+ calcd for C14H13F13: 427.1; found: 427.1.
HRMS (EI): m/z [M – C2H5]+ calcd for C14H13F13: 399.0418; found: 399.0413.
#
9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluorotetradec-6-yne (11)
Allene 10 (0.038 g, 0.09 mmol, 1.0 equiv) and 18-crown-6 (0.024 g, 0.09 mmol, 1.0 equiv) were dissolved in DMF. Cesium carbonate (0.029 g, 0.09 mmol, 1.0 equiv) was then added and the temperature was raised to 50 °C for 1 hour. The resulting slurry was run through a silica plug with hexanes as the eluent to give a mixture of ene-yne 6, allene 10, and proposed alkyne 11 (0.025 g, 33:49:17 molar ratio as determined by 19F NMR analysis).
#
1,1,1,2,2,3,3,4,4-Nonafluoro-6-iodododec-5-ene (12a)
Pocedure 1
To a quartz tube, 1-octyne (0.186 g, 1.69 mmol, 1.0 equiv) was added, followed by iodoperfluorobutane (0.700 g, 2.02 mmol, 1.2 equiv) and the reaction mixture was illuminated under 254 nm light for 1 hour. The reaction mixture was placed on high vacuum to remove starting materials to give 12a as a clear oil and a mixture of E and Z isomers (89:11 E/Z, 0.62 g, 1.37 mmol, 81%). Spectra matched data from a reported compound.[53]
#
1,1,1,2,2,3,3,4-Octafluorododec-4-en-6-yne (12b)
Pocedure 3
Extracted from perfluorohexanes as a yellow oil (13:87 E/Z).
Yield: 0.013–0.026 g (0.041–0.084 mmol, 41–84%).
1H NMR (400 MHz, CDCl3): δ = 6.04 (E, ddt, J = 15.9, 4.4, 2.1 Hz, 0.13 H), 5.71 (Z, dt, J = 28.5, 2.1 Hz, 0.87 H), 2.39 (Z, t, J = 6.7 Hz, 1.8 H), 2.34 (E, t, J = 6.8 Hz, 0.2 H), 1.59 (dd, J = 14.6, 7.3 Hz, 2 H), 1.43–1.29 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 152.2 (Z, dt, J = 273.6, 29.6 Hz), 120.3–107.8 (m, 3 C), 103.5 (Z, d, J = 6.1 Hz), 98.2 (Z, q, J = 6.9 Hz), 69.4, 31.1, 28.0, 22.3, 19.8, 14.1.
19F NMR (376 MHz, CDCl3): δ = –80.59 (m, 3 F), –117.02 (E, m, 0.2 F), –118.83 (m, 2.8 F), –127.10 (m, 2 F).
MS (EI): m/z [M]+ calcd for C12H12F8: 308.1; found: 308.1.
#
9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,16-Heptadecafluoro-7-iodohexadec-7-ene (13a)
Pocedure 1
To a quartz tube, 1-octyne (0.186 g, 1.69 mmol, 1.0 equiv) was added, followed by iodoperfluorooctane (1.10 g, 2.02 mmol, 1.2 equiv), and the reaction mixture was illuminated under 254 nm light for 1 hour. The reaction mixture was placed under high vacuum to remove starting materials to give 13a as a pink oil and a mixture of E- and Z-isomers (86:14 E/Z, 0.830 g, 1.26 mmol, 75%). Spectra matched data from a reported compound.[53]
#
9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,16-Hexadecafluorohexadec-8-en-6-yne (13b)
Pocedure 3
Extracted from perfluorohexanes as a yellow oil (17:83 E/Z).
Yield: 0.031 g (0.061 mmol, 61%).
1H NMR (500 MHz, CDCl3): δ = 6.04 (E, ddt, J = 15.5, 4.3, 2.3 Hz, 0.17 H), 5.71 (Z, dt, J = 29.3, 2.3 Hz, 0.83 H), 2.39 (Z, t, J = 7.1 Hz, 1.6 H), 2.34 (E, t, J = 7.6 Hz, 0.4 H), 1.70–1.51 (m, 2 H), 1.47–1.25 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 152.4 (dt, J = 272.2, 28.5 Hz), 121.3–107.4 (m, 7 C), 103.5 (Z, d, J = 6.7 Hz), 98.3 (Z, q, J = 6.2 Hz), 69.5, 31.1, 28.0, 22.3, 19.9, 14.1.
19F NMR (376 MHz, CDCl3): δ = –80.59 (t, J = 9.8 Hz, 3 F), –115.96 (E, q, J = 11.7 Hz, 0.2 F), –117.78 (Z, q, J = 13.4 Hz, 1.8 F), –118.55 (Z, 0.9 F), –120.16 (E, m, 0.1 F), –121.83 (m, 4 F), –122.67 (m, 4 F), –125.94 (m, 2 F).
MS (EI): m/z [M]+ calcd for C16H12F16: 508.1; found: 508.1.
#
N,N-Diethyl-7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-5-iodododec-5-enamide (14a)
Pocedure 2
Yield: 0.476 g (0.78 mmol, 49%); yellow oil; Rf = 0.30 (20% EtOAc/Hexanes), E isomer only.
1H NMR (500 MHz, CDCl3): δ = 6.37 (t, J = 14.4 Hz, 1 H), 3.37 (q, J = 7.0 Hz, 2 H), 3.28 (q, J = 7.0 Hz, 2 H), 2.73 (t, J = 7.1 Hz, 2 H), 2.31 (t, J = 7.5 Hz, 2 H), 1.97 (p, J = 7.4 Hz, 2 H), 1.16 (t, J = 7.1 Hz, 3 H), 1.11 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 170.8, 127.3 (t, J = 23.7 Hz), 122.4 (t, J = 6.1 Hz), 119.9–107.2 (m, 6 C), 42.0, 40.5 (E, t, J = 2.4 Hz), 40.3, 31.3, 25.5, 14.3, 13.2.
19F NMR (376 MHz, CDCl3): δ = –80.74 (m, 3 F), –105.16 (m, 2 F), –121.62 (m, 2 F), –122.82 (m, 2 F), –123.20 (m, 2 F), –126.13 (m, 2 F).
HRMS (EI): m/z [M – I]+ calcd for C16H17F13INO: 486.1103; found: 486.1122.
#
N,N-Diethyl-7,8,8,9,9,10,10,11,11,12,12,12-dodecafluorododec-6-en-4-ynamide (14b)
Pocedure 3
Extracted from methoxy perfluorobutyl ether as a yellow oil (21:79 E/Z).
Yield: 0.034 g (0.073 mmol, 73%).
1H NMR (500 MHz, CDCl3): δ = 6.03 (E, ddt, J = 15.4, 4.2, 1.9 Hz, 0.2 H), 5.70 (dt, J = 28.2, 2.2 Hz, 1.8 H), 3.39 (q, J = 7.0 Hz, 2 H), 3.32 (q, J = 7.1 Hz, 2 H), 2.77 (Z, t, J = 7.3 Hz, 1.6 H), 2.71 (E, t, J = 7.1 Hz, 0.4 H), 2.59 (Z, t, J = 7.5 Hz, 1.6 H), 2.53 (E, t, J = 7.9 Hz, 0.4 H), 1.19 (t, J = 7.2 Hz, 3 H), 1.11 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 169.5, 152.4 (Z, dt, J = 274.1, 29.5 Hz), 128.1–107.4 (m, 5 C), 102.1 (Z, d, J = 6.2 Hz), 98.0 (Z, q, J = 6.9 Hz), 69.6, 41.9, 40.3, 31.6, 15.9, 14.3, 13.0.
19F NMR (376 MHz, CDCl3): δ = –80.63 (t, J = 9.8 Hz, 3 F), –115.97 (E, q, J = 12.5 Hz, 0.2 F), –117.90 (Z, m, 2.7 F), –119.45 (E, 0.10 F), –122.36 to –123.70 (m, 4 F), –126.07 (m, 2 F).
HRMS (EI): m/z [M]+ calcd for C16H15F12NO: 465.0962; found: 465.0964.
#
N-Benzyl-7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-5-iodododec-5-enamide (15a)
Pocedure 2
Yellow solid; Rf = 0.20 (20% EtOAc/Hexanes), 71:29 E/Z.
Yield: 0.518 g (0.80 mmol, 51%).
1H NMR (500 MHz, CDCl3): δ = 7.39–7.26 (m, 5 H), 6.38 (E, t, J = 14.4 Hz, 0.7 H), 6.27 (Z, t, J = 13.0 Hz, 0.3 H), 4.44 (d, J = 5.6 Hz, 2 H), 2.75 (Z, t, J = 6.9 Hz, 0.6 H), 2.71 (E, t, J = 7.3 Hz, 1.4 H), 2.22 (dt, J = 11.8, 7.3 Hz, 2 H), 1.98 (p, J = 7.6, 7.1 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 171.4, 138.1, 128.8, 127.9, 127.6, 127.4 (E, t, J = 23.8 Hz), 121.5 (E, t, J = 6.1 Hz), 119.5–107.0 (6 C, m), 43.7, 40.2 (E, t, J = 2.5 Hz), 34.7, 25.7.
19F NMR (376 MHz, CDCl3): δ = –82.11 (m, 3 F), –106.53 (E, m, 1.4 F), –109.94 (Z, m, 0.6 F), –122.99 (m, 2 F), –124.15 (m, 2 F), –124.57 (m, 2 F), –127.47 (m, 2 F).
MS (EI): m/z [M]+ calcd for C19H15F13INO: 647.0; found: 647.0.
#
N-Benzyl-7,8,8,9,9,10,10,11,11,12,12,12-dodecafluorododec-6-en-4-ynamide (15b)
Pocedure 3
Purified via flash chromatography with a gradient from 15–50% EtOAc in hexanes.
Yield: 0.030 g (0.06 mmol, 60%); yellow solid; 15:85 E/Z; Rf = 0.5 (50% EtOAc/Hexanes).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H), 5.98 (E, dt, J = 15.4, 2.6 Hz, 0.15 H), 5.88 (bs, 1 H), 5.64 (Z, dt, J = 29.0, 2.2 Hz, 0.85 H), 4.53–4.41 (m, 2 H), 2.78 (Z, t, J = 6.9 Hz, 1.7 H), 2.72 (E, t, J = 7.2 Hz, 0.3 H), 2.47 (Z, t, J = 7.1 Hz, 1.7 H), 2.43 (E, t, J = 7.5 Hz, 0.3 H).
13C NMR (126 MHz, CDCl3): δ = 170.4, 152.7 (Z, dt, J = 272.4, 28.1 Hz), 138.0, 128.7, 127.8, 127.6, 119.4–105.7 (m, 5 C), 101.1 (Z, d, J = 6.8 Hz), 97.7 (Z, q, J = 6.3 Hz), 70.2, 43.8, 34.9, 16.2.
19F NMR (376 MHz, CDCl3): δ = –80.61 (t, J = 9.6 Hz, 3 F), –115.98 (E, q, J = 12.7 Hz, 0.2 F), –117.21 (Z, m, 0.9 F), –117.89 (Z, q, J = 13.6 Hz, 1.8 F), –118.72 (E, m, 0.1 F), –122.16 to –123.46 (m, 4 F), –126.05 (m, 2 F).
MS (EI): m/z [M]+ calcd for C19H13F12NO: 499.1; found: 499.1.
#
2-(6,6,7,7,8,8,9,9,10,10,11,11,11-Tridecafluoro-4-iodoundec-4-en-1-yl)isoindoline-1,3-dione (16a)
Previously synthesized 6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-4-iodoundec-4-en-1-yl 4-methylbenzenesulfonate (S4) (0.680 g, 1.00 mmol, 1.0 equiv) was dissolved in DMF (5 mL, anhydrous) and potassium phthalimide (0.661 g, 5.00 mmol, 5 equiv) was added. The resulting solution was stirred at r.t. for 18 hours at which point the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracted with EtOAc (4 × 5 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil. Purification via flash chromatography (10% EtOAc/Hexanes) gave the product as a white solid with 10% tosylate remaining (Rf = 0.25, E isomer only, 0.249 g, 0.37 mmol, 37%).
1H NMR (500 MHz, CDCl3): δ = 7.85 (dd, J = 5.5, 3.0 Hz, 2 H), 7.72 (dd, J = 5.4, 3.0 Hz, 2 H), 6.34 (t, J = 14.3 Hz, 1 H), 3.73 (t, J = 7.1 Hz, 2 H), 2.73 (t, J = 7.7 Hz, 2 H), 1.98 (p, J = 7.5 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 168.4, 134.2, 132.1, 127.5 (t, J = 24.1 Hz), 123.4, 120.4 (t, J = 6.1 Hz), 38.8 (t, J = 2.8 Hz), 36.7, 29.1.
19F NMR (376 MHz, CDCl3): δ = –80.75 (m, 3 F), –105.53 (m, 2 F), –121.75 (m, 2 F), –122.87 (m, 2 F), –123.21 (m, 2 F), –126.14 (m, 2 F).
HRMS (EI): m/z [M – I]+ calcd for C15H13F13INO: 532.0582; found: 532.0600.
#
2-(6,7,7,8,8,9,9,10,10,11,11,11-Dodecafluoroundec-5-en-3-yn-1-yl)isoindoline-1,3-dione (16b)
Pocedure 3
Purified via flash chromatography (25% EtOAc/Hexanes).
Yield: 0.029 g (0.056 mmol, 56%); yellow solid; 15:85 E/Z; Rf = 0.67 (25% EtOAc/Hexanes).
1H NMR (500 MHz, CDCl3): δ = 7.86 (td, J = 5.4, 2.9 Hz, 2 H), 7.73 (dd, J = 5.5, 3.1 Hz, 2 H), 5.99 (E, ddt, J = 15.5, 4.6, 2.5 Hz, 0.15 H), 5.65 (Z, dt, J = 29.1, 2.3 Hz, 0.85 H), 3.93 (Z, t, J = 7.0 Hz, 1.7 H), 3.88 (E, t, J = 7.0 Hz, 0.3 H), 2.83 (Z, t, J = 7.4 Hz, 01.7 H), 2.79 (E, t, J = 7.5 Hz, 0.4 H).
13C NMR (126 MHz, CDCl3): δ = 168.1, 153.0 (Z, dt, J = 274.3, 28.8 Hz), 134.3, 132.1, 123.5, 121.5–107.7 (m, 5 C), 98.5 (Z, d, J = 7.0 Hz), 97.6 (Z, q, J = 6.8 Hz), 71.2, 36.2, 19.8.
19F NMR (376 MHz, CDCl3): δ = –80.62 (t, J = 9.7 Hz, 3 F), –116.09 (E, q, J = 11.9 Hz, 0.2 F), –116.62 (Z, 0.9 F), –117.99 (Z, q, J = 13.9 Hz, 1.8 F), –118.27 (E, m, 0.1 F), –122.15 to –123.67 (m, 4 F), –126.07 (m, 2 F).
MS (EI): m/z [M]+ calcd for C19H13F12NO: 511.0; found: 511.0.
#
N-Allyl-7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-5-iodododec-5-enamide (17a)
Pocedure 2
Yield: 0.461 g (0.77 mmol, 49%); yellow oil; Rf = 0.16 (20% EtOAc/Hexanes); 81:19 E/Z.
1H NMR (500 MHz, CDCl3): δ = 6.37 (E, J = 14.4 Hz, 0.8 H), 6.30 (Z, t, J = 13.0 Hz, 0.2 H), 5.92–5.77 (m, 1 H), 5.52 (bs, 1 H), 5.26–5.10 (m, 2 H), 3.89 (t, J = 5.7 Hz, 2 H), 2.75 (Z, t, J = 7.2 Hz, 0.4 H), 2.70 (E, t, J = 7.3 Hz, 1.6 H), 2.27–2.17 (m, 2 H), 1.96 (p, J = 7.5 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 171.5, 134.2, 127.5 (E, t, J = 23.7 Hz), 121.7 (E, t, J = 6.1 Hz), 116.8, 116.5–107.9 (6 C, m), 42.2, 40.3 (E, t, J = 2.2 Hz), 34.8, 25.9.
19F NMR (376 MHz, CDCl3): δ = –81.32 (m, 3 F), –105.71 (E, m, 1.6 F), –109.14 (Z, S, 0.4 F), –122.19 (m, 2 F), –123.37 (m, 2 F), –123.76 (m, 2 F), –126.67 (m, 2 F).
MS (EI): m/z [M]+ calcd for C15H13F13INO: 597.0; found: 597.0.
#
N-Allyl-7,8,8,9,9,10,10,11,11,12,12,12-dodecafluorododec-6-en-4-ynamide (17b)
Pocedure 3
Extracted from methoxy perfluorobutyl ether.
Yield: 0.028 g (0.064 mmol, 64%); yellow oil; 20:80 E/Z.
1H NMR (500 MHz, CDCL3): δ = 6.02 (E, ddt, J = 15.5, 4.3, 2.3 Hz, 0.2 H), 5.90–5.77 (m, 1 H), 5.70 (Z, dt, J = 29.2, 2.3 Hz, 0.8 H), 5.65 (bs, 1 H), 5.24–5.10 (m, 2 H), 3.91 (tt, J = 5.8, 1.5 Hz, 2 H), 2.77 (Z, t, J = 7.1 Hz, 1.6 H), 2.71 (E, t, J = 7.2 Hz, 0.4 H), 2.46 (Z, t, J = 7.2 Hz, 1.6 H), 2.41 (E, t, J = 7.3 Hz, 0.4 H).
13C NMR (126 MHz, CDCl3): δ = 170.3, 152.7 (Z, dt, J = 272.9, 28.4 Hz), 133.9, 116.6, 122.8–106.8 (m, 5 C), 101.1 (Z, d, J = 6.9 Hz), 97.74 (Z, q, J = 6.4 Hz), 70.2, 42.1, 35.0, 16.1.
19F NMR (376 MHz, CDCl3): δ = –80.62 (t, J = 9.7 Hz, 3 F), –115.97 (E, q, J = 11.4 Hz, 0.2 F), –117.25 (m, 0.9 F), –117.93 (Z, q, J = 13.5 Hz, 1.8 F), –118.75 (m, 0.1 F), –122.82 (m, 4 F), –126.06 (m, 2 F).
MS (EI): m/z [M]+ calcd for C15H11F12NO: 449.1; found: 449.0.
#
11,11,12,12,13,13,14,14,15,15,16,16,16-Tridecafluoro-9-iodohexadec-9-en-1-yne (18a)
Iodoperfluorohexane (0.446 g, 1.00 mmol, 1.0 equiv) and 1,9-decadiyne (0.402 g, 3.00 mmol, 3.0 equiv) were dissolved in a MeCN/water mixture (2.0 mL:1.5 mL). Sodium bicarbonate (0.0960 g, 1.15 mmol, 1.15 equiv) was added, followed by sodium dithionite (0.200 g, 1.15 mmol, 1.15 equiv) and the solution was stirred at r.t. for 2 hours. The reaction mixture was then diluted with water (5 mL) and extracted with hexanes (3 × 2 mL). The organic layer was dried with Na2SO4, decanted, and concentrated to give a crude oil. Purification through flash chromatography with hexanes as the eluent yielded the product as a clear oil and mixture of E- and Z-isomers (Rf = 0.50 (hexanes), 88:12 E/Z).
Yield: 0.172 g (0.300 mmol, 30%).
1H NMR (500 MHz, CDCl3): δ = 6.32 (E, t, J = 14.5 Hz, 0.94 H), 6.24 (Z, t, J = 13.0 Hz, 0.06 H), 2.67 (Z, t, J = 7.4 Hz, 0.12 H), 2.63 (E, t, J = 7.5 Hz, 1.88 H), 2.19 (td, J = 7.0, 2.6 Hz, 2 H), 1.94 (t, J = 2.7 Hz, 1 H), 1.63–1.30 (m, 8 H).
13C NMR (126 MHz, CDCl3): δ = 126.5 (E, t, J = 23.8 Hz), 122.8 (E, t, J = 6.0 Hz), 118.8–107.6 (6 C), 84.4, 68.2, 41.0 (E, t, J = 2.4 Hz), 29.9, 28.3, 28.2, 27.9, 18.3.
19F NMR (376 MHz, CDCl3): δ = –80.80 (m, 3 F), –105.36 (E, m, 1.88 F), –108.55 (Z, m, 0.12 F), –121.69 (m, 2 F), –122.85 (m, 2 F), –123.28 (m, 2 F), –126.15 (m, 2 F).
HRMS (EI): m/z [M – I]+ calcd for C16H14F13I: 453.0888; found: 453.0881.
#
11,12,12,13,13,14,14,15,15,16,16,16-Dodecafluorohexadeca-10-en-1,8-diyne (18b)
Pocedure 3
Extracted from perfluorohexanes as a yellow oil (17:83 E/Z).
Yield: 0.031 g (0.073 mmol, 73%).
1H NMR (500 MHz, CDCl3): δ = 6.04 (E, ddt, J = 15.5, 4.3, 2.2 Hz, 0.17 H), 5.71 (Z, dt, J = 29.2, 2.3 Hz, 0.83 H), 2.41 (Z, t, J = 6.4 Hz, 1.6 H), 2.36 (Z, t, J = 7.3 Hz, 0.4 H), 2.24–2.15 (m, 2 H), 1.94 (t, J = 2.6 Hz, 1 H), 1.64–1.50 (m, 6 H).
13C NMR (126 MHz, CDCl3): δ = 152.5 (Z, dt, J = 271.3, 28.0 Hz), 122.3–106.2 (m, 5 C), 103.0 (Z, d, J = 6.7 Hz), 98.2 (Z, q, J = 6.3 Hz), 84.4, 69.7, 68.5, 28.1, 28.0, 27.8, 19.8, 18.4.
19F NMR (376 MHz, CDCl3): δ = –80.68 (t, J = 8.8 Hz, 3 F), –116.04 (E, q, J = 12.1 Hz, 0.2 F), –117.91 (Z, q, J = 13.3 Hz, 1.8 F), –118.15 (Z, m, 0.9 F), –120.02 (E, m, 0.1 F), –122.77 to –123.72 (m, 4 F), –126.11 (m, 2 F).
MS (EI): m/z [M – H]+ calcd for C16H12F12: 431.1; found: 431.1.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank the lab of Prof. Miguel García-Garibay for use of their UV reaction vessel.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1610774.
- Supporting Information
-
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- 24 Yang C, Liu ZL, Dai DT, Li Q, Ma WW, Zhao M, Xu YH. Org. Lett. 2020; 22: 1360
- 25 Qi S, Gao S, Xie X, Yang J, Zhang J. Org. Lett. 2020; 22: 5229
- 26 Shen H, Xiao H, Zhu L, Li C. Synlett 2020; 31: 41
- 27 Huang J, Jia Y, Li X, Duan J, Jiang Z.-X, Yang Z. Org. Lett. 2021; 23: 2314
- 28 Fujino T, Hinoue T, Usuki Y, Satoh T. Org. Lett. 2016; 18: 5688
- 29 Jayaraman A, Lee S. Org. Lett. 2019; 21: 7923
- 30 Eddarir S, Mestdagh H, Rolando C. Tetrahedron Lett. 1991; 32: 69
- 31 Wang Y, Xu J, Burton DJ. J. Org. Chem. 2006; 71: 7780
- 32 Zapata AJ, Gu Y, Hammond GB. J. Org. Chem. 2000; 65: 227
- 33 Jennings MP, Cork EA, Ramachandran PV. J. Org. Chem. 2000; 65: 8763
- 34 Slodowicz M, Barata-Vallejo S, Vázquez A, Nudelman NS, Postigo A. J. Fluorine Chem. 2012; 135: 137
- 35 Rong G, Keese R. Tetrahedron Lett. 1990; 31: 5615
- 36 Xu T, Cheung CW, Hu X. Angew. Chem. Int. Ed. 2014; 53: 4910
- 37 Jaye JA, Sletten EM. ACS Macro Lett. 2020; 9: 410
- 38 Ji Y.-L, Luo J.-J, Lin J.-H, Xiao J.-C, Gu Y.-C. Org. Lett. 2016; 18: 1000
- 39 Hung MH. Tetrahedron Lett. 1990; 31: 3703
- 40 Perscheid M, Schollmeyer D, Nubbemeyer U. Eur. J. Org. Chem. 2011; 5250
- 41 Rocaboy C, Hampel F, Gladysz JA. Org. Lett. 2002; 67: 6863
- 42 Yang L, Adam C, Cockroft SL. J. Am. Chem. Soc. 2015; 137: 10084
- 43 Kolb H, Finn MG, Sharlpess BK. Angew. Chem. Int. Ed. 2001; 40: 2004
- 44 Sinha AK, Equbal D. Asian J. Org. Chem. 2019; 8: 32
- 45 Ogba OM, Warner NC, O’Leary DJ, Grubbs RH. Chem. Soc. Rev. 2018; 12: 4510
- 46 Pickens CJ, Johnson SN, Pressnall MM, Leon MA, Berkland CJ. Bioconjugate Chem. 2018; 29: 686
- 47 Meldal M, Tomøe CW. Chem. Rev. 2008; 108: 2952
- 48 Pangborn AB, Giardello MA, Grubbs RH, Rosen RK, Timmers FJ. Organometallics 1996; 15: 1518
- 49 Habib MH, Mallouk TE. J. Fluorine Chem. 1991; 53: 53
- 50 Umemoto T, Gotoh Y. Bull. Chem. Soc. Jpn. 1986; 59: 439
- 51 Kharrat S, Laurent P, Blancou H. J. Org. Chem. 2006; 71: 6742
- 52 Yamazaki T, Yamamoto T, Ichihara R. J. Org. Chem. 2006; 71: 6251
- 53 Konno T, Chae J, Kanda M, Nagai G, Tamura K, Ishihara T, Yamanaka H. Tetrahedron 2003; 59: 7571
Corresponding Author
Publication History
Received: 18 March 2021
Accepted after revision: 27 April 2021
Article published online:
16 June 2021
© 2021. Thieme. All rights reserved
Georg Thieme Verlag KG
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-
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- 36 Xu T, Cheung CW, Hu X. Angew. Chem. Int. Ed. 2014; 53: 4910
- 37 Jaye JA, Sletten EM. ACS Macro Lett. 2020; 9: 410
- 38 Ji Y.-L, Luo J.-J, Lin J.-H, Xiao J.-C, Gu Y.-C. Org. Lett. 2016; 18: 1000
- 39 Hung MH. Tetrahedron Lett. 1990; 31: 3703
- 40 Perscheid M, Schollmeyer D, Nubbemeyer U. Eur. J. Org. Chem. 2011; 5250
- 41 Rocaboy C, Hampel F, Gladysz JA. Org. Lett. 2002; 67: 6863
- 42 Yang L, Adam C, Cockroft SL. J. Am. Chem. Soc. 2015; 137: 10084
- 43 Kolb H, Finn MG, Sharlpess BK. Angew. Chem. Int. Ed. 2001; 40: 2004
- 44 Sinha AK, Equbal D. Asian J. Org. Chem. 2019; 8: 32
- 45 Ogba OM, Warner NC, O’Leary DJ, Grubbs RH. Chem. Soc. Rev. 2018; 12: 4510
- 46 Pickens CJ, Johnson SN, Pressnall MM, Leon MA, Berkland CJ. Bioconjugate Chem. 2018; 29: 686
- 47 Meldal M, Tomøe CW. Chem. Rev. 2008; 108: 2952
- 48 Pangborn AB, Giardello MA, Grubbs RH, Rosen RK, Timmers FJ. Organometallics 1996; 15: 1518
- 49 Habib MH, Mallouk TE. J. Fluorine Chem. 1991; 53: 53
- 50 Umemoto T, Gotoh Y. Bull. Chem. Soc. Jpn. 1986; 59: 439
- 51 Kharrat S, Laurent P, Blancou H. J. Org. Chem. 2006; 71: 6742
- 52 Yamazaki T, Yamamoto T, Ichihara R. J. Org. Chem. 2006; 71: 6251
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