Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

3-Aryl-1-(trifluoromethyl)prop-2-yn-1-iminium triflate salts represent a novel, highly reactive class of acetylenic iminium salts. Herein we present several reactions which are based on the electron-poor acetylenic bond and on the high electrophilicity of the CF3-substituted iminium group. These salts were found to be highly reactive dienophiles in Diels–Alder reactions with cyclopentadiene, 2,3-dimethylbutadiene and even anthracene. At higher temperature, the cycloadducts undergo an intramolecular SE(Ar) reaction leading to condensed carbocycles incorporating a 1-(trifluoromethyl)-1-(dimethylamine)indene ring system. With styrenes and some substituted styrenes, cascade reactions take place, which likely include cyclobutene and several cationic intermediates and mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene as the substrate.


Introduction
In recent years, a trifluoromethyl substituent has been included quite often in the design of compounds which were developed for applications in various fields, such as biological and medicinal chemistry, agrochemicals, transition metal ligands, and materials science [1][2][3][4][5]. The particular characteristics of the C-F bond [6,7] are the basis for the electronic and steric properties of the CF 3 group, such as a strong electron-withdrawing (−I) effect, the accumulation of negative charge density in a relatively small volume and the low polarizability of the fluoro atoms. These and other substituent effects can modulate the conformational, physicochemical and electronic properties of a molecule.
Two major strategies exist to introduce a CF 3 group into a target molecule: formation of a carbon-or heteroatom-CF 3 bond [8,9] and the use of preformed CF 3 -substituted building blocks. During our studies on acetylenic iminium salts, among the numerous CF 3 -substituted building blocks α-(trifluoromethyl)iminium salts RCH(CF 3 )=N + R' 2 X − attracted our attention, because a) the CF 3 group should significantly increase the electrophilicity of the iminium functional group and b) these salts are known to react with a variety of nucleophiles to afford products containing a C(CF 3 )NR 2 moiety. In particular C(CF 3 )NHR and C(CF 3 )NH 2 groups are of interest as pharmacophores in the design of bioactive compounds [10][11][12][13].

Results and Discussion
The Diels-Alder reaction of 1-CF 3 -substituted propyn-1iminium salt 1a with cyclopentadiene was carried out in order to assess the dienophilic reactivity of the cation. High conversion into cycloaddition product 2 was observed already within one hour at 0 °C. Because of its high hydrolytic lability, adduct 2 was not isolated but directly converted into the norbornadienyl trifluoromethyl ketone 3 (Scheme 1). The smooth [4 + 2] cycloaddition of 1a as compared to comparably harsh thermal conditions of other propyne ketiminium salts with an internal acetylenic bond reveals the activating influence of the CF 3 group, which has both an electronic (electron-withdrawing) and steric (e.g., CF 3 vs a phenyl substituent [28]) component. Moreover, a comparison with the thermal conditions of the Diels-Alder reaction of 4-phenyl-1,1,1-trifluorobut-3-yn-2-one and cyclopentadiene [29] confirms the expected accelerating effect of the iminium activation. The Diels-Alder reaction of alkyne 1a with 2,3-dimethylbutadiene also occurred under very mild conditions and yielded the iminium-substituted 1,4-cyclohexadiene 4-Ch (Scheme 2), which, due to its high sensitivity toward moisture, was not purified but was further converted in two steps into cyclohexadienyl ketone 5-Ch by intentional hydrolysis followed by dehydrogenating aromatization leading to biphenyl-2-yl trifluoromethyl ketone 6. The latter product was more effectively prepared in a one-pot cycloaddition/hydrolysis/aromatization sequence. 1 H NMR spectra of unpurified 1,4-cyclohexadien-1iminium salt 4-Ch and 1,4-cyclohexadien-1-yl ketone 5-Ch indicated the presence of a minor byproduct. In the case of 5-Ch, obtained as an oil, the two components could not be separated by column chromatography; however, the 1 H NMR spectrum suggested the cyclobutene structure 5-Cb for the byproduct. Thus, signals of the two methyl groups (δ 1.63, 1.78 ppm) and two terminal olefinic protons (δ 4.88 ppm, m) are observed, and the ring-CH 2 protons appear as an AB spin system (δ 2.75 and 2.92 ppm, 2 J = 15.2 Hz). Obviously, 4-Cb and 5-Cb result from a formal [2 + 2] cycloaddition of 1a and 2,3-dimethylbutadiene (DMBD), the regioselectivity of which is as expected for a highly asynchronous transition state with effective stabilization of the positive charge or a two-step ionic process (vide infra). The high electrophilic power of the 1-CF 3 -substituted propyn-1iminium ion presumably renders an ionic [2 + 2] cycloaddition pathway competitive with the Diels-Alder reaction. The few reported examples of cyclobutene formation from alkynes and unactivated 1,3-dienes include the sensitized photocycloaddition of phenylacetylene and DMBD [30] and the gold(I)-catalyzed reaction of phenylacetylene and DMBD or isoprene [31]. On the other hand, the 1,1-diphenylpropargyl cation was found to react with 2,4-dimethyl-1,3-pentadiene to afford a product derived from an initial [4 + 2] cycloaddition [32]. When the Diels-Alder reaction of 1a with DMBD was carried out at room temperature instead of 0 °C, 19 F NMR monitoring of the reaction's progress indicated the appearance of a second product beside the 1,4-cyclohexadien-1-iminium salt 4-Ch. Further investigations revealed that the new product was the dihydrofluorene 7, resulting from 4-Ch by an intramolecular electrophilic aromatic substitution with the reactive (trifluoromethyl)iminium group as the electrophile (Scheme 2). The thermal conversion of 4-Ch into 7 was optimized and finally allowed the preparation of the latter from 1a in a one-pot, twostep, temperature-dependent Diels-Alder reaction/intramolecular S E (Ar) reaction sequence in good yield. Dehydrogenation of 7 with chloranil then provided 9-(dimethylamino)-9-(trifluoromethyl)fluorene 8.
In an analogous reaction sequence, 11H-benzo[a]fluorene derivative 9 was obtained from 3-(2-naphthyl)propyn-1-iminium salt 1b and 2,3-dimethylbutadiene (Scheme 2) in a one-pot three-step sequence. On the other hand, the successful thermal iminium-ion induced S E (Ar) reactions shown in Scheme 2 were not applicable to the iminium-substituted norbornadiene 2, which suffered undefined polymerization on moderate heating in various solvents.
The remarkable dienophilic reactivity of 1-CF 3 -substituted propyn-1-iminium salts is also exemplified by the Diels-Alder reaction of 1a with anthracene (Scheme 3). After 12 h at room temperature, a 91% conversion was observed, and subsequent moderate heating gave the cycloaddition product 10 in 95% yield. The subsequent iminium-induced electrophilic cyclization required extended heating in refluxing toluene and finally furnished the neutral polycycle 11 in good yield. The paddle-wheel-shaped structure of 11 was established by an XRD structure determination and is shown in Figure 1.  The reactivity of 1a in the Diels-Alder reaction with anthracene may be compared with that of other dienophiles. Thus, other propyn-1-iminium salts with an internal C,C triple bond and not containing a CF 3 substituent (toluene, 120 °C, several hours [28]), DMAD (no solvent, 170-180 °C, 1 h [36]) and hexafluoro-2-butyne (200 °C, 2 h [37]) react only under harsher conditions, whereas terminal propyn-1-iminium salts (CH 2 Cl 2 , rt, 2-4 h [38]) and tetracyanoethylene (rt, 12 h [39]) were found to react equally well or even faster than 1a. Although these comparisons are only qualitative, they suggest that 1-CF 3substituted propyn-1-iminium salts have a high electrophilicity power and therefore, are candidates for polar Diels-Alder reactions [40,41].
Styrenes are also known to behave as dienes in [4 + 2] cycloaddition reactions [45]. Thus, while styrene and maleic anhydride react only at elevated temperatures, with the more electrophilic (methoxycarbonyl)maleic anhydride two 2:1 adducts are already formed at room temperature: one by two consecutive Diels-Alder reactions, the other one by a Diels-Alder/ene reaction sequence [46]. Taking into account the presumably high electrophilic character of the 1-(trifluoromethyl)propyn-1iminium ion, for its reaction with styrenes we could not exclude a priori an initial electrophilic addition at the olefinic bond (with formation of a benzyl cation intermediate).
The reaction of propyn-1-iminium salt 1a with styrene in acetonitrile was considered first and was monitored by 19 F NMR spectroscopy. Whereas no reaction appeared to occur at room temperature, a slow transformation into two fluorine-containing products was observed at 70 °C, which after neutralization and work-up were identified by their NMR and analytical data as 2-(1-phenylvinyl)indene 12a and a small amount of benzo[a]fluorene 13a (δ F = −69.74 and −69.20 ppm, respectively).
The results obtained with styrenes bearing a substituent at the olefinic bond provide useful information with respect to the reaction mechanism. Thus, the reaction of 1a with α-methylstyrene or 1,1-diphenylethene proceeded at a faster rate than with styrene and yielded 3-methyl-and 3-phenyl-2-vinylindenes 12b and 12c (structure confirmed by an XRD analysis, see Figure 2) in high yields. Benzo[a]fluorenes were found to a minor extent (13c) or not at all (13b) (Scheme 4). A remarkable stereochemical aspect accompanied the reaction of 1a with (E)-1-phenyl-1-propene leading to 2-((E)-1-phenylprop-1enyl)indene 12d, where trans(Ph,Me)→cis isomerization at the olefinic bond has occurred. The E-configuration was assigned based on NOESY NMR experiments and confirmed by an X-ray structure determination (see Figure 3).
A mechanistic scheme for the formation of indenes 12 and benzo[a]fluorenes 13 is proposed in Scheme 5. The electrophilic propyn-1-iminium ion 1a adds chemoselectively (by conjugate addition) and regioselectively (Markovnikov-type addition) at the olefinic bond of the styrene to form the resonance-stabi-    The intermediacy of a cyclobutene 15 in the mechanistic scenario of Scheme 5 is corroborated by the isolation of cyclobutene 18 from the reaction of 1a with 1,2-dihydronaphthalene, a cyclic styrene derivative (Scheme 6; compare also the cyclobutene byproduct in Scheme 2). The structure of 18 was derived from its 1 H and 13 C NMR chemical shifts; a NOE NMR experiment indicated the vicinity of the phenyl ring and the CH 2 CH part or the molecule in line with the expected orientation of the cycloaddition. Cis-annelated cyclobutene 18 ( 1 H NMR: 3 J H,H = 3.8 Hz for the angular protons) and the iminium-substituted primary cycloadduct are not expected to undergo a fast ring opening under moderate thermal conditions, because the orbital-symmetry-allowed concerted conrotatory process [47,48] would create a strained cis,trans-dihydrobenzo [8]annulene ring system. Cyclobutenes resulting from a [2 + 2] cycloaddition of electrophilic alkynes and alkenes under moderate thermal conditions have been isolated also from the reaction of CF 3 -free propyn-iminium salts with cyclic enol ethers [49] and of other very electrophilic alkynes (i.e., Lewis acid-activated acetylenic esters [50], 1-(trifluoroacetyl)-3-haloacetylenes [44] and 4-chloro-2oxobut-3-ynoic esters [51][52][53] with unactivated alkenes (including cyclohexene [51], which did not react with 1a). For the 3-arylpropyn-1-iminium ions 1, a charge delocalization can be assumed, which is described by the resonance structure of a 1-aryl-3-aminoallenyl cation, hence their electronic structure shows a certain analogy to the triphenylpropargyl/triphenylallenyl cation. It has been reported that this cation reacts with cyclopentadiene in two different ways: concerted [4 + 2] cycloaddition and a stepwise [2 + 2] cycloaddition via an allenylcyclopentenyl cation (which could be trapped with OH − ) [54,55].
Styrene structural moieties are also present in (E,E)-1,4diphenylbuta-1,3-diene. Therefore, it was of interest to know whether it would react with propyn-1-iminium salts 1 as a styrene or a 1,3-diene. With 3-(4-bromophenyl)propyn-1iminium salt 1c in acetonitrile, no reaction was observed at 20 °C, but within two hours at 45 °C, an unclean reaction took place, which became evident by a multitude of 19 F NMR signals. Assuming that some of the signals represented products that would easily undergo further thermal reactions, the solution was additionally heated at 70 °C for 40 hours. The resulting reaction mixture still contained several products, of which only the major fluorine-containing component (δ F = −46.76 ppm, a value quite different from those of products 12 and 13) could finally be isolated in modest yield and was identified by an X-ray structure analysis as the CF 3 -substituted fulvene 19 (Scheme 7).
A reaction pathway leading to fulvene 19 is proposed in Scheme 8. It begins with the formal [2 + 2] cycloaddition of 1c and the diene component, which is probably a two-step process as shown in Scheme 5. Cyclobutene 20 is prone to a thermally induced conrotatory electrocyclic ring-opening, which yields iminium-substituted triene 21. In a similar reaction, an α-phenyliminium salt structurally analogous to 21 could be isolated [56]. A cationic 1,5-cylization converts 21 into cyclopentene 22, from which fulvene 19 is formed by deprotonation and a formal 1,4-shift of the NMe 2 group. The details of this rearrangement are not known, an N,N-dimethyldihydropyrrolium intermediate may be involved.

Conclusion
This study has uncovered new applications of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium ions as CF 3 -substituted C 3 building blocks. They are not only very electrophilic dienophiles in Diels-Alder reactions with normal electron demand (HOMO diene -LUMO dienophile controlled, in the language of FMO theory), but also represent powerful 1,3-biselectrophiles. Thus, Diels-Alder reactions followed by an intramolecular S E (Ar) reaction of the α-(trifluoromethyl)iminium functional group were achieved as a two-step one-pot synthesis. On the other hand, an electrophilic (Markownikow type) addition of the propyn-1-iminium ion via its C3-position to the olefinic bond of styrenes initiated a reaction cascade which was again terminated by the already mentioned cyclization step through intramolecular electrophilic aromatic substitution, resulting in the formation of 2-(1-phenylvinyl)-1-(trifluoromethyl)-1-(dimethylamino)indenes as the major products. Various other synthetic applications of these reactive propyn-1-iminium salts will be reported in due course.

Supporting Information
Supporting Information File 1 Experimental procedures, NMR ( 1 H, 13 C, 19 F) and IR spectra of synthesized compounds.

Supporting Information File 2
Crystal and structure refinement data for compounds 11, 12c, 12d and 19.