An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF3CCl3 afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF3-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H2O system initiated intramolecular cyclization to afford 2-CF3-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF3-indole.


Results
First, we investigated olefination of 2-nitrobenzaldehydes 1 to prepare the corresponding trifluoromethylated styrenes 2. The catalytic olefination reaction (COR) [15,[86][87][88][89][90] and Wittig reaction were used for the synthesis of these alkenes. We performed screening of the reaction conditions for COR (see Supplementary Materials, Scheme S1). It was found, that ethylene glycol [89] is the solvent of choice for these substrates, in contrast to EtOH traditionally used for COR with CF 3 CCl 3 [90]. It was also found, that the yield is very sensitive to the nature of the substituents (additional to ortho-nitro group) in aryl ring. The best yield in the whole series was obtained for unsubstituted 2-nitrobenzaldehyde, which was transformed by COR to styrene 2a in 88% yield. In the case of additional alkyl-, alkoxyand halogen substituents in the aryl ring corresponding styrenes were isolated in good to high yields. However, in the case of aldehydes 1j,l,m having strong EWG substituents (nitro-, cyano-and carboxymethyl-groups) in 4-position the corresponding alkenes 2j,l,m were synthesized in lower yields using COR. Therefore, we tried also alternative synthesis based on Wittig olefination. As a result, some improvement was observed for these problematic aldehydes. It should be noted that olefination of 2-nitrobenzaldehydes using both methods proceeds stereoselectively to form mostly Z-isomer in up to 96:4 ratio with minor E-isomer. Assignment of the configuration of the isomers was maintained by comparison with the literature NMR data of similar styrenes without ortho-nitro-group [90] (Scheme 1).

Results
First, we investigated olefination of 2-nitrobenzaldehydes 1 to prepare the corresponding trifluoromethylated styrenes 2. The catalytic olefination reaction (COR) [15,[86][87][88][89][90] and Wittig reaction were used for the synthesis of these alkenes. We performed screening of the reaction conditions for COR (see Supplementary Materials, Scheme S1). It was found, that ethylene glycol [89] is the solvent of choice for these substrates, in contrast to EtOH traditionally used for COR with CF3CCl3 [90]. It was also found, that the yield is very sensitive to the nature of the substituents (additional to ortho-nitro group) in aryl ring. The best yield in the whole series was obtained for unsubstituted 2-nitrobenzaldehyde, which was transformed by COR to styrene 2a in 88% yield. In the case of additional alkyl-, alkoxy-and halogen substituents in the aryl ring corresponding styrenes were isolated in good to high yields. However, in the case of aldehydes 1j,l,m having strong EWG substituents (nitro-, cyano-and carboxymethyl-groups) in 4-position the corresponding alkenes 2j,l,m were synthesized in lower yields using COR. Therefore, we tried also alternative synthesis based on Wittig olefination. As a result, some improvement was observed for these problematic aldehydes. It should be noted that olefination of 2-nitrobenzaldehydes using both methods proceeds stereoselectively to form mostly Z-isomer in up to 96:4 ratio with minor E-isomer. Assignment of the configuration of the isomers was maintained by comparison with the literature NMR data of similar styrenes without ortho-nitro-group [90] (Scheme 1). Scheme 1. Synthesis of ortho-nitrostyrenes 2.
Having in hand a series of trifluoromethylated ortho-nitrostyrenes, we investigated their transformation to 2-CF3-indoles. The treatment of styrenes 2 with an access of pyr-Scheme 1. Synthesis of ortho-nitrostyrenes 2.
Having in hand a series of trifluoromethylated ortho-nitrostyrenes, we investigated their transformation to 2-CF 3 -indoles. The treatment of styrenes 2 with an access of pyrrolidine at room temperature led to α-CF 3 -enamines 3 in high yield. We assumed, that reduction of ortho-nitro aryl derived α-CF 3 -enamines 3 could led to 2-CF 3 -indoles 4 through formation of intermediate anilines 3 [91,92]. The reduction of model enamine 3a was studied in various conditions. It was found, that HCO 2 H-Pd/C, Fe-AcOH-H 2 O and Zn-AcOH-H 2 O systems worked well to give 2-CF 3 -indole 3a in 85, 86 and 85% yield correspondingly according to 19 F NMR. Although all these systems showed almost equal results, we used Fe-AcOH-H 2 O for our further transformations due to the lower price and toxicity of iron [93]. It should be noted, that crude enamine 3a can be used directly after evaporation of excessive pyrrolidine. So, the transformation of styrene 2 into indole 4 can be maintained as a one pot reaction without isolation of intermediate enamine 3. Moreover, this one pot conditions work for multigram scale reaction to afford 3.257 g (72%) of indole 4a in one run (Scheme 2). rolidine at room temperature led to α-CF3-enamines 3 in high yield. We assumed, that reduction of ortho-nitro aryl derived α-CF3-enamines 3 could led to 2-CF3-indoles 4 through formation of intermediate anilines 3′ [91,92]. The reduction of model enamine 3a was studied in various conditions. It was found, that HCO2H-Pd/C, Fe-AcOH-H2O and Zn-AcOH-H2O systems worked well to give 2-CF3-indole 3a in 85, 86 and 85% yield correspondingly according to 19 F NMR. Although all these systems showed almost equal results, we used Fe-AcOH-H2O for our further transformations due to the lower price and toxicity of iron [93]. It should be noted, that crude enamine 3a can be used directly after evaporation of excessive pyrrolidine. So, the transformation of styrene 2 into indole 4 can be maintained as a one pot reaction without isolation of intermediate enamine 3. Moreover, this one pot conditions work for multigram scale reaction to afford 3.257 g (72%) of indole 4a in one run (Scheme 2).
Using these optimal conditions, we performed the synthesis of various 2-CF3-indoles 4. It was found that the reaction has a general character allowing to prepare 2-CF3-indoles having both electron-donating and electron-withdrawing groups in various positions of indole ring in good to high yield. 6-Amino-2-CF3-indole 4j was synthesized in the case of styrene 2j having additional nitro-group. This indole is a perspective object for further modifications at amino group, which can provide compounds interesting for the medicinal chemistry.
One can notice that indoles 4 were mostly prepared in the yields higher than 50%, which is high enough taking into account the three step transformation. In contrast, indoles 4e and 4i were obtained in moderate yield (43% and 25%). The explanation of that fact is a side process taking place at the step of formation of enamine 3. Thus, monitoring of the reaction mixture in the reaction of 2c with pyrrolidine revealed the presence of compound 5c, which was isolated in 15% yield together with enamine 3c (80%). The structure of 5c was assigned by means of NMR and HRMS data. Thus, the key signals of 5c are the signals of carbonyl group (192.4 ppm), quaternary aminal carbon adjacent to CF3-group (quadruplet at 86.4 ppm, JCF = 28.1 Hz) in 13 C NMR and N-OH group (7.74 ppm) in 1 H NMR. We have also observed formation of similar N-hydroxy indolin-3-ones 5 in several other reactions. Thus, in case of enamines 3e and 3i the admixture of compounds 5e and 5i were 28% and 39%, correspondingly (by 19 F NMR; see Supplementary Materials for details). Even in the case of enamine 3a we observed formation of 5a in 4% Scheme 2. Synthesis of indoles 4 from ortho-nitrostyrenes 2.
Using these optimal conditions, we performed the synthesis of various 2-CF 3 -indoles 4. It was found that the reaction has a general character allowing to prepare 2-CF 3 -indoles having both electron-donating and electron-withdrawing groups in various positions of indole ring in good to high yield. 6-Amino-2-CF 3 -indole 4j was synthesized in the case of styrene 2j having additional nitro-group. This indole is a perspective object for further modifications at amino group, which can provide compounds interesting for the medicinal chemistry.
One can notice that indoles 4 were mostly prepared in the yields higher than 50%, which is high enough taking into account the three step transformation. In contrast, indoles 4e and 4i were obtained in moderate yield (43% and 25%). The explanation of that fact is a side process taking place at the step of formation of enamine 3. Thus, monitoring of the reaction mixture in the reaction of 2c with pyrrolidine revealed the presence of compound 5c, which was isolated in 15% yield together with enamine 3c (80%). The structure of 5c was assigned by means of NMR and HRMS data. Thus, the key signals of 5c are the signals of carbonyl group (192.4 ppm), quaternary aminal carbon adjacent to CF 3 -group (quadruplet at 86.4 ppm, J CF = 28.1 Hz) in 13 C NMR and N-OH group (7.74 ppm) in 1 H NMR. We have also observed formation of similar N-hydroxy indolin-3-ones 5 in several other reactions. Thus, in case of enamines 3e and 3i the admixture of compounds 5e and 5i were 28% and 39%, correspondingly (by 19 F NMR; see Supplementary Materials for details). Even in the case of enamine 3a we observed formation of 5a in 4% yield (by 19 F NMR). We did not investigate this side reaction thoroughly, but possible mechanism of this transformation was proposed using the literature data (Scheme 3) [94,95]. At first step dehydrochlorination of 2c leads to alkyne 6 [78]. Next, it is attacked by pyrrolidine to give zwitterion 7. Proton transfer in 7 affords enamine 3c. Alternatively, transformation of 7 leads to transfer of oxygen to form nitroso compound 8. This intermediate has in the structure a strong electron-donating fragment of "enoloenamine". Intramolecular attack of this fragment to nitroso group led to indolin-1-olate derivative 9. Its protonation leads to N-hydroxy indolin-3-one 5c. 6, x FOR PEER REVIEW 5 of 22 yield (by 19 F NMR). We did not investigate this side reaction thoroughly, but possible mechanism of this transformation was proposed using the literature data (Scheme 3) [94,95]. At first step dehydrochlorination of 2c leads to alkyne 6 [78]. Next, it is attacked by pyrrolidine to give zwitterion 7. Proton transfer in 7 affords enamine 3c. Alternatively, transformation of 7 leads to transfer of oxygen to form nitroso compound 8. This intermediate has in the structure a strong electron-donating fragment of "enoloenamine". Intramolecular attack of this fragment to nitroso group led to indolin-1-olate derivative 9. Its protonation leads to N-hydroxy indolin-3-one 5c. Scheme 3. Possible mechanism of formation of side product 5c in the reaction of 2c with pyrrolidine.
Interesting results were obtained in the case of styrenes 2n,o. These alkenes have halogens in para-position to nitro-group, which activates nucleophilic substitution of them. It was found that treatment of 4-fluorostyrene 2o with pyrrolidine led to substitution of both fluorine and chlorine during 1-2 h to give enamine 3n in 90% yield (Scheme 4). Similarly, substitution of both chlorine atoms in 4-chlorostyrene 2n afforded enamine 3n in 72% yield. However, in this case about 2-3 days were needed for full substitution of chlorine adjacent to aryl ring. It is not surprising, because fluorine is a better leaving group than chlorine. Next, we performed one pot synthesis of indole 10a from 4-fluorostyrene 2o. As a result, indole 10a was isolated in 45% yield (Scheme 4). We proposed that using less nucleophilic amines would allow to perform selective synthesis of enamine without substitution of halogen in aryl ring. However, the reaction of 4-fluorostyrene 2o with piperidine afforded a mixture of enamine 11a and styrene 2p at room temperature. The heating of this reaction mixture at 90 °C for 3 h led to selective transformation of 2p into 11a (by 19 F NMR), which was converted into indole 10b in 44% yield (one-pot). To our delight, the reaction of 4-chlorostyrene 2n with piperidine proceeded only at the double bond to form enamine 11b (observed in 19 F NMR) after 1h at room temperature. One pot transformation of 11b under standard conditions afforded 5-chloro-2-CF3-indole 4n in total 71% yield (Scheme 5). Interesting results were obtained in the case of styrenes 2n,o. These alkenes have halogens in para-position to nitro-group, which activates nucleophilic substitution of them. It was found that treatment of 4-fluorostyrene 2o with pyrrolidine led to substitution of both fluorine and chlorine during 1-2 h to give enamine 3n in 90% yield (Scheme 4). Similarly, substitution of both chlorine atoms in 4-chlorostyrene 2n afforded enamine 3n in 72% yield. However, in this case about 2-3 days were needed for full substitution of chlorine adjacent to aryl ring. It is not surprising, because fluorine is a better leaving group than chlorine. Next, we performed one pot synthesis of indole 10a from 4-fluorostyrene 2o. As a result, indole 10a was isolated in 45% yield (Scheme 4).

FOR PEER REVIEW 5 of 22
yield (by 19 F NMR). We did not investigate this side reaction thoroughly, but possible mechanism of this transformation was proposed using the literature data (Scheme 3) [94,95]. At first step dehydrochlorination of 2c leads to alkyne 6 [78]. Next, it is attacked by pyrrolidine to give zwitterion 7. Proton transfer in 7 affords enamine 3c. Alternatively, transformation of 7 leads to transfer of oxygen to form nitroso compound 8. This intermediate has in the structure a strong electron-donating fragment of "enoloenamine". Intramolecular attack of this fragment to nitroso group led to indolin-1-olate derivative 9. Its protonation leads to N-hydroxy indolin-3-one 5c. Scheme 3. Possible mechanism of formation of side product 5c in the reaction of 2c with pyrrolidine.
Interesting results were obtained in the case of styrenes 2n,o. These alkenes have halogens in para-position to nitro-group, which activates nucleophilic substitution of them. It was found that treatment of 4-fluorostyrene 2o with pyrrolidine led to substitution of both fluorine and chlorine during 1-2 h to give enamine 3n in 90% yield (Scheme 4). Similarly, substitution of both chlorine atoms in 4-chlorostyrene 2n afforded enamine 3n in 72% yield. However, in this case about 2-3 days were needed for full substitution of chlorine adjacent to aryl ring. It is not surprising, because fluorine is a better leaving group than chlorine. Next, we performed one pot synthesis of indole 10a from 4-fluorostyrene 2o. As a result, indole 10a was isolated in 45% yield (Scheme 4). We proposed that using less nucleophilic amines would allow to perform selective synthesis of enamine without substitution of halogen in aryl ring. However, the reaction of 4-fluorostyrene 2o with piperidine afforded a mixture of enamine 11a and styrene 2p at room temperature. The heating of this reaction mixture at 90 °C for 3 h led to selective transformation of 2p into 11a (by 19 F NMR), which was converted into indole 10b in 44% yield (one-pot). To our delight, the reaction of 4-chlorostyrene 2n with piperidine proceeded only at the double bond to form enamine 11b (observed in 19 F NMR) after 1h at room temperature. One pot transformation of 11b under standard conditions afforded 5-chloro-2-CF3-indole 4n in total 71% yield (Scheme 5). We proposed that using less nucleophilic amines would allow to perform selective synthesis of enamine without substitution of halogen in aryl ring. However, the reaction of 4-fluorostyrene 2o with piperidine afforded a mixture of enamine 11a and styrene 2p at room temperature. The heating of this reaction mixture at 90 • C for 3 h led to selective transformation of 2p into 11a (by 19 F NMR), which was converted into indole 10b in 44% yield (one-pot). To our delight, the reaction of 4-chlorostyrene 2n with piperidine proceeded only at the double bond to form enamine 11b (observed in 19 F NMR) after 1h To investigate the scope of the synthesis of 5-amino substituted indoles, we performed several reactions of styrene 2o with other primary and secondary amines. As a result, new family of 2-CF3-indoles 10c-g having amine fragments of morpholine, azepane, diethylamine, methylamine and n-hexylamine was synthesized in good yields (Scheme 6). Scheme 6. Synthesis of amino substituted indoles 10c-g.
Having prepared a set of 2-CF3-indoles we found surprisingly that many typical reactions known for indoles are unknown for 2-CF3-indoles. To fill this gap, we maintained reactions of indole 4a with several C-centered electrophiles. In our hands, formylation reaction by POCl3-DMF afforded 3-formyl-2-CF3-indole 17 in 53% yield. Friedel-Crafts acylation with AcCl-AlCl3 led to corresponding ketone 18 in 64% yield. Reaction with ethoxy CF3-enone 19 under catalysis with BF3·Et2O gave α,β-unsaturated CF3 ketone 20, which is a valuable building block for the synthesis of complex fluorinated molecules. Very interesting results were observed in the reactions of 2-CF3-indole with arylaldehydes in the media of alcohols under catalysis with MeSO3H. The reaction with benzaldehyde, 4-chloro-and 4-methoxybenzaldehydes in methanol afforded methoxy-derivatives 21 in good yields. The reaction with 1.2 equivalents of benzaldehyde in ethanol led to ethoxy-derivative 22 in 74% yield, while the reaction with 0.5 equivalents of benzaldehyde in ethanol resulted in bisindolylmethane derivative 23 in moderate yield (Scheme 7). NMR monitoring of the reaction revealed, that after first few hours both indoles 22 and 23 can be found in the reaction mixture. Further heating led to decreasing of the amount of 22, while the amount of 23 showed increase. Based on that fact, we rationalized possible mechanism of formation of 23 as follows. At first step, 4a reacts with aldehyde to form 22, which is protonated by strong methanesulfonic acid to give oxonium salt 24. Friedel-Crafts alkylation of indole 4a by this oxonium salt afforded bisindolylmethane derivative 23. To investigate the scope of the synthesis of 5-amino substituted indoles, we performed several reactions of styrene 2o with other primary and secondary amines. As a result, new family of 2-CF 3 -indoles 10c-g having amine fragments of morpholine, azepane, diethylamine, methylamine and n-hexylamine was synthesized in good yields (Scheme 6). To investigate the scope of the synthesis of 5-amino substituted indoles, we performed several reactions of styrene 2o with other primary and secondary amines. As a result, new family of 2-CF3-indoles 10c-g having amine fragments of morpholine, azepane, diethylamine, methylamine and n-hexylamine was synthesized in good yields (Scheme 6). Scheme 6. Synthesis of amino substituted indoles 10c-g.
Having prepared a set of 2-CF3-indoles we found surprisingly that many typical reactions known for indoles are unknown for 2-CF3-indoles. To fill this gap, we maintained reactions of indole 4a with several C-centered electrophiles. In our hands, formylation reaction by POCl3-DMF afforded 3-formyl-2-CF3-indole 17 in 53% yield. Friedel-Crafts acylation with AcCl-AlCl3 led to corresponding ketone 18 in 64% yield. Reaction with ethoxy CF3-enone 19 under catalysis with BF3·Et2O gave α,β-unsaturated CF3 ketone 20, which is a valuable building block for the synthesis of complex fluorinated molecules. Very interesting results were observed in the reactions of 2-CF3-indole with arylaldehydes in the media of alcohols under catalysis with MeSO3H. The reaction with benzaldehyde, 4-chloro-and 4-methoxybenzaldehydes in methanol afforded methoxy-derivatives 21 in good yields. The reaction with 1.2 equivalents of benzaldehyde in ethanol led to ethoxy-derivative 22 in 74% yield, while the reaction with 0.5 equivalents of benzaldehyde in ethanol resulted in bisindolylmethane derivative 23 in moderate yield (Scheme 7). NMR monitoring of the reaction revealed, that after first few hours both indoles 22 and 23 can be found in the reaction mixture. Further heating led to decreasing of the amount of 22, while the amount of 23 showed increase. Based on that fact, we rationalized possible mechanism of formation of 23 as follows. At first step, 4a reacts with aldehyde to form 22, which is protonated by strong methanesulfonic acid to give oxo-Scheme 6. Synthesis of amino substituted indoles 10c-g.
Having prepared a set of 2-CF 3 -indoles we found surprisingly that many typical reactions known for indoles are unknown for 2-CF 3 -indoles. To fill this gap, we maintained reactions of indole 4a with several C-centered electrophiles. In our hands, formylation reaction by POCl 3 -DMF afforded 3-formyl-2-CF 3 -indole 17 in 53% yield. Friedel-Crafts acylation with AcCl-AlCl 3 led to corresponding ketone 18 in 64% yield. Reaction with ethoxy CF 3 -enone 19 under catalysis with BF 3 ·Et 2 O gave α,β-unsaturated CF 3 ketone 20, which is a valuable building block for the synthesis of complex fluorinated molecules. Very interesting results were observed in the reactions of 2-CF 3 -indole with arylaldehydes in the media of alcohols under catalysis with MeSO 3 H. The reaction with benzaldehyde, 4-chloroand 4-methoxybenzaldehydes in methanol afforded methoxy-derivatives 21 in good yields. The reaction with 1.2 equivalents of benzaldehyde in ethanol led to ethoxy-derivative 22 in 74% yield, while the reaction with 0.5 equivalents of benzaldehyde in ethanol resulted in bisindolylmethane derivative 23 in moderate yield (Scheme 7). NMR monitoring of the reaction revealed, that after first few hours both indoles 22 and 23 can be found in the reaction mixture. Further heating led to decreasing of the amount of 22, while the amount of 23 showed increase. Based on that fact, we rationalized possible mechanism of formation of 23 as follows. At first step, 4a reacts with aldehyde to form 22, which is protonated by strong methanesulfonic acid to give oxonium salt 24. Friedel-Crafts alkylation of indole 4a by this oxonium salt afforded bisindolylmethane derivative 23. It should be noted that a lot of attention has been paid to the elaboration of novel strategies for the synthesis of bisindolylmethane derivatives, because many of them exhibit a various kinds of physiological activity [96][97][98][99]. Thus, bisindolylmethanes revealed properties of antibacterial, antifungal, antimicrobial, anti-inflammatory and anti-cancer agents [100][101][102][103][104][105]. In addition, this structural unit can be found in the natural sources, for example in marine alkoloids [106][107][108]. To the best of our knowledge fluorinated bisindolylmethanes have not been reported to date. We believe that our approach to these compounds can be useful in design of potentially active physiologically active compounds.

Materials and Methods
General remarks. 1 H, 13 C) as internal reference. The 19 F chemical shifts were referenced to C6F6, (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). ESI-MS spectra were measured at Micro-Tof Bruker Daltonics instrument. TLC analysis was performed on "Merck 60 F254" plates. Column chromatography was performed on silica gel. All reagents were of reagent grade and were used as such or were distilled prior to use. β-Chloro-β-trifluoromethylstyrenes 1 were prepared as reported previously by catalytic olefination reaction [89,90] or by Wittig reaction [109]. Melting points were determined on an Electrothermal 9100 apparatus.
Synthesis of styrenes 2 by catalytic olefination reaction in EtOH or DMSO (general procedure I, 5 mmol scale) [90]. One neck 100 mL round bottomed flask was charged with N2H4·H2O (0.265 g, 5.25 mmol), and solution of corresponding benzaldehyde (5 mmol in 25 mL of EtOH or DMSO) was added and stirred for 3 h until aldehyde disappeared (TLC control). Next, 1,2-ethylenediamine (0.65 mL, 7.5 mmol), CuCl (0.050 g, 0.5 mmol) were added and stirred for 1-2 min. After that CF3CCl3 (1.78 mL, 15 mmol) was It should be noted that a lot of attention has been paid to the elaboration of novel strategies for the synthesis of bisindolylmethane derivatives, because many of them exhibit a various kinds of physiological activity [96][97][98][99]. Thus, bisindolylmethanes revealed properties of antibacterial, antifungal, antimicrobial, anti-inflammatory and anti-cancer agents [100][101][102][103][104][105]. In addition, this structural unit can be found in the natural sources, for example in marine alkoloids [106][107][108]. To the best of our knowledge fluorinated bisindolylmethanes have not been reported to date. We believe that our approach to these compounds can be useful in design of potentially active physiologically active compounds.

Materials and Methods
General remarks. 1 H, 13 C) as internal reference. The 19 F chemical shifts were referenced to C 6 F 6 , (−162.9 ppm). The coupling constants (J) are given in Hertz (Hz). ESI-MS spectra were measured at MicroTof Bruker Daltonics instrument. TLC analysis was performed on "Merck 60 F 254 " plates. Column chromatography was performed on silica gel. All reagents were of reagent grade and were used as such or were distilled prior to use. β-Chloro-β-trifluoromethylstyrenes 1 were prepared as reported previously by catalytic olefination reaction [89,90] or by Wittig reaction [109]. Melting points were determined on an Electrothermal 9100 apparatus.
Synthesis of styrenes 2 by catalytic olefination reaction in EtOH or DMSO (general procedure I, 5 mmol scale) [90]. One neck 100 mL round bottomed flask was charged with N 2 H 4 ·H 2 O (0.265 g, 5.25 mmol), and solution of corresponding benzaldehyde (5 mmol in 25 mL of EtOH or DMSO) was added and stirred for 3 h until aldehyde disappeared (TLC control). Next, 1,2-ethylenediamine (0.65 mL, 7.5 mmol), CuCl (0.050 g, 0.5 mmol) were added and stirred for 1-2 min. After that CF 3 CCl 3 (1.78 mL, 15 mmol) was added in one portion at cooling by cold water bath. Reaction mixture stirred overnight at room temperature, poured into water (100 mL) and extracted with CH 2 Cl 2 (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na 2 SO 4 . Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH 2 Cl 2 as an eluent.
Synthesis of styrenes 2 by catalytic olefination reaction in ethylene glycol (general procedure II) [89]. One neck 50 mL round bottomed flask was charged with 1 mmol of corresponding benzaldehyde, 10 mL of ethylene glycol, 0.25 mL (5 mmol) of N 2 H 4 ·H 2 O and stirred 0.5-1h until aldehyde disappeared (TLC control). Next, 0.38 mL (4.4 mmol) of 1,2-ethylenediamine, 0.0086 g (0.05 mmol) of CuCl 2 ·2H 2 O was added and stirred for 1-2 min. After that CF 3 CCl 3 (0.71 mL, 6 mmol) was added in one portion at cooling by cold water bath. Reaction mixture stirred overnight at room temperature, poured into water (50 mL) and extracted with CH 2 Cl 2 (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na 2 SO 4 . Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH 2 Cl 2 as an eluent.

Synthesis of styrene 2a by catalytic olefination reaction in EtOH (150 mmol scale).
One neck 1000 mL round bottomed flask was charged with N 2 H 4 ·H 2 O (5.25 g, 105 mmol), and solution of 2-nitrobenzaldehyde (15.11 g, 100 mmol in 175 mL of EtOH) was added at vigorous stirring. The reaction mixture was stirred for 3 h until aldehyde disappeared (TLC control). Next, 1,2-ethylenediamine (10 mL, 150 mmol), CuCl (1 g, 10 mmol) were added and stirred for 1-2 min. After that CF 3 CCl 3 (18 mL, 150 mmol) was added in one portion at cooling by cold water bath. The reaction mixture stirred overnight at room temperature, poured into HCl water solution (1000 mL,~0.4-0.5 M) and extracted with CH 2 Cl 2 (3 × 150 mL). Combined extract was washed with water (200 mL) and dried over Na 2 SO 4 . Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad (~120-150 cm 3 of silica gel) using 3:1 mixture of hexane as an eluent. Evaporation of the solvents afforded pure 2a as slightly yellow oil. Yield 17.1 g (68%).