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

23 Dec.,2024

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

Several years ago, we have elaborated convenient approach to α-CF-β-aryl enamines on the base of the reaction of β-chloro-β-trifluromethylstyrenes with amines [ 78 80 ]. This potent CF-building blocks were successfully used as synthetic equivalents of trifluoromethyl benzyl ketones in the Fisher and Pictet&#;Spengler reaction to give 2-CF-3-arylindoles and CF-β-carbolines [ 81 ], synthesis of CF-enones [ 82 84 ] and α-CF-phenethylamines [ 85 ]. In continuation of the investigation of synthetic potential of α-CF-β-aryl enamines, we report in this article one pot two step synthesis of 2-CF-indoles ( Figure 2 ).

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Most synthetic approaches to such indoles can be divided to the methods of direct trifluoromethylation of indole core and cyclizations of various precursors having CFgroup in appropriate position [ 38 ]. Both radical and electrophilic trifluoromethylations was performed using bis(perfluoroalkanoyl) peroxides [ 48 ], difluorodiiodomethane [ 49 ], hypervalent iodine reagents [ 50 53 ], CFI [ 54 58 ], Umemoto&#;s reagents [ 59 60 ], [(phen)CuCF] [ 61 ], and CFSONa [ 62 65 ]. Cyclization approaches are based on formation of C2-C3 bond as a key step and deal with transformations of compounds having-toluidine fragment [ 66 76 ]. One work reported transformation of 4- and 6-nitro-1-hydroxy indoles to NH indoles under treatment with bromoacetophenone ( Figure 2 ) [ 77 ].

The brilliant example of such interest are 2-CF-indoles. According to the Reaxys database, this class of compounds enjoyed a boom of attention last decade. Thus, 107 out of 152 research articles dealing with 2-CF-indoles were published from to . Previous decade revealed 19 articles, and 26 articles were published in period from to [ 42 ]. These massive investigations gained several promising bioactive 2-CF-indoles ( Figure 1 ). The 2&#;-trifluoromethyl analogue of Indomethacinwas appeared to be a potent and selective COX-2 inhibitor [ 43 ]. Compoundhaving 2-CF-indole and cinnamic amide moieties possess anti-inflammatory and neuroprotective actions [ 44 ]. Indolyl-pyridinyl-propenonewas found to possess properties of antiproliferative [ 45 ] and antineoplastic agent [ 46 ]. 2-CF-indolerevealed antifungal properties ( Figure 1 ) [ 47 ].

Chemistry of fluorinated organic compounds is a booming area of modern organic chemistry, which is a result of unique physicochemical as well as biological properties of these compounds [ 12 23 ]. Thus, about 20% (more than 300 compounds) of currently used drugs [ 24 31 ] contain at least one fluorine atom [ 32 ]. In , approximately 25% (14 out of 53) of all drugs and about 35% (14 out of 40) of &#;small-molecule drugs&#; approved by the FDA are fluorinated compounds [ 33 ]. At the same time, about 59% of all small-molecule drugs have a nitrogen heterocyclic motif [ 10 ]. Last year revealed, that three out of every four small-molecule drugs approved by the FDA in (28 out of 37) are representatives of that class [ 33 ]. Hence, elaboration of novel pathways to fluorinated nitrogen heterocycles are of great demand [ 34 41 ].

Indole has been discovered in by Bayer [ 1 ]. This type of heterocycles became an object of intensive investigations [ 2 8 ] and recognized as a &#;privileged structure&#; in drug discovery [ 9 ]. Indole motif is an important structural unit of many pharmaceuticals and natural products [ 10 ]. Seven derivatives of indole can be found in the list of 200 best selling drugs in . Tagrisso (4.328 Bn), Trikafta (3.864 Bn), Ofev (2.448 Bn), Leuprorelin (1.834 Bn), Alecensa (1.292 Bn), Zoladex (0.888 Bn) and Sutent (0.819 Bn) were sold for more than15 billion totally in worldwide [ 11 ].

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 99 ]. Thus, bisindolylmethanes revealed properties of antibacterial, antifungal, antimicrobial, anti-inflammatory and anti-cancer agents [ 100 105 ]. In addition, this structural unit can be found in the natural sources, for example in marine alkoloids [ 106 108 ]. 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.

Having prepared a set of 2-CF-indoles we found surprisingly that many typical reactions known for indoles are unknown for 2-CF-indoles. To fill this gap, we maintained reactions of indolewith several C-centered electrophiles. In our hands, formylation reaction by POCl-DMF afforded 3-formyl-2-CF-indolein 53% yield. Friedel&#;Crafts acylation with AcCl-AlClled to corresponding ketonein 64% yield. Reaction with ethoxy CF-enoneunder catalysis with BF·EtO gave α,β-unsaturated CFketone, which is a valuable building block for the synthesis of complex fluorinated molecules. Very interesting results were observed in the reactions of 2-CF-indole with arylaldehydes in the media of alcohols under catalysis with MeSOH. The reaction with benzaldehyde, 4-chloro- and 4-methoxybenzaldehydes in methanol afforded methoxy-derivativesin good yields. The reaction with 1.2 equivalents of benzaldehyde in ethanol led to ethoxy-derivativein 74% yield, while the reaction with 0.5 equivalents of benzaldehyde in ethanol resulted in bisindolylmethane derivativein moderate yield ( Scheme 7 ). NMR monitoring of the reaction revealed, that after first few hours both indolesandcan be found in the reaction mixture. Further heating led to decreasing of the amount of 22, while the amount ofshowed increase. Based on that fact, we rationalized possible mechanism of formation ofas follows. At first step,reacts with aldehyde to form 22, which is protonated by strong methanesulfonic acid to give oxonium salt. Friedel&#;Crafts alkylation of indoleby this oxonium salt afforded bisindolylmethane derivative

To investigate the scope of the synthesis of 5-amino substituted indoles, we performed several reactions of styrenewith other primary and secondary amines. As a result, new family of 2-CF-indoleshaving amine fragments of morpholine, azepane, diethylamine, methylamine and-hexylamine was synthesized in good yields ( Scheme 6 ).

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-fluorostyrenewith piperidine afforded a mixture of enamineand styreneat room temperature. The heating of this reaction mixture at 90 °C for 3 h led to selective transformation ofinto(byF NMR), which was converted into indolein 44% yield (one-pot). To our delight, the reaction of 4-chlorostyrenewith piperidine proceeded only at the double bond to form enamine(observed inF NMR) after 1h at room temperature. One pot transformation ofunder standard conditions afforded 5-chloro-2-CF-indolein total 71% yield ( Scheme 5 ).

Interesting results were obtained in the case of styrenes. These alkenes have halogens in-position to nitro-group, which activates nucleophilic substitution of them. It was found that treatment of 4-fluorostyrenewith pyrrolidine led to substitution of both fluorine and chlorine during 1&#;2 h to give enaminein 90% yield ( Scheme 4 ). Similarly, substitution of both chlorine atoms in 4-chlorostyreneafforded enaminein 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 indolefrom 4-fluorostyrene. As a result, indolewas isolated in 45% yield ( Scheme 4 ).

One can notice that indoleswere mostly prepared in the yields higher than 50%, which is high enough taking into account the three step transformation. In contrast, indolesandwere 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. Thus, monitoring of the reaction mixture in the reaction ofwith pyrrolidine revealed the presence of compound, which was isolated in 15% yield together with enamine(80%). The structure ofwas assigned by means of NMR and HRMS data. Thus, the key signals ofare the signals of carbonyl group (192.4 ppm), quaternary aminal carbon adjacent to CF-group (quadruplet at 86.4 ppm,= 28.1 Hz) inC NMR and N-OH group (7.74 ppm) inH NMR. We have also observed formation of similar N-hydroxy indolin-3-onesin several other reactions. Thus, in case of enaminesandthe admixture of compoundsandwere 28% and 39%, correspondingly (byF NMR; see Supplementary Materials for details). Even in the case of enaminewe observed formation ofin 4% yield (byF 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 ofleads to alkyne 78 ]. Next, it is attacked by pyrrolidine to give zwitterion. Proton transfer inaffords enamine. Alternatively, transformation ofleads to transfer of oxygen to form nitroso compoundThis 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 derivativeIts protonation leads to N-hydroxy indolin-3-one

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.

Having in hand a series of trifluoromethylated-nitrostyrenes, we investigated their transformation to 2-CF-indoles. The treatment of styreneswith an access of pyrrolidine at room temperature led to α-CF-enaminesin high yield. We assumed, that reduction of ortho-nitro aryl derived α-CF-enaminescould led to 2-CF-indolesthrough formation of intermediate anilines. The reduction of model enaminewas studied in various conditions. It was found, that HCOH-Pd/C, Fe-AcOH-HO and Zn-AcOH-HO systems worked well to give 2-CF-indolein 85, 86 and 85% yield correspondingly according toF NMR. Although all these systems showed almost equal results, we used Fe-AcOH-HO for our further transformations due to the lower price and toxicity of iron [ 93 ]. It should be noted, that crude enaminecan be used directly after evaporation of excessive pyrrolidine. So, the transformation of styreneinto indolecan be maintained as a one pot reaction without isolation of intermediate enamine. Moreover, this one pot conditions work for multigram scale reaction to afford 3.257 g (72%) of indolein one run ( Scheme 2 ).

First, we investigated olefination of 2-nitrobenzaldehydesto prepare the corresponding trifluoromethylated styrenes. The catalytic olefination reaction (COR) [ 15 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 CFCCl 90 ]. It was also found, that the yield is very sensitive to the nature of the substituents (additional to-nitro group) in aryl ring. The best yield in the whole series was obtained for unsubstituted 2-nitrobenzaldehyde, which was transformed by COR to styrenein 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 aldehydeshaving strong EWG substituents (nitro-, cyano- and carboxymethyl- groups) in 4-position the corresponding alkeneswere 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-isomer in up to 96:4 ratio with minor-isomer. Assignment of the configuration of the isomers was maintained by comparison with the literature NMR data of similar styrenes without-nitro-group [ 90 ] ( Scheme 1 ).

3. Materials and Methods

General remarks.1H, 13C and 19F NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer in CD3CN, DMSO-

and CDCl3 at 400, 100 and 376 MHz, respectively. Chemical shifts (

) in ppm are reported with the use of the residual CHD2CN, DMSO-

5 and chloroform signals (1.94, 2.54 and 7.25 for 1H and 1.30, 39.5 77.0 for 13C) as internal reference. The 19F chemical shifts were referenced to C6F6, (&#;162.9 ppm). The coupling constants (

) are given in Hertz (Hz). ESI-MS spectra were measured at MicroTof 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 [

H,C andF NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer in CDCN, DMSO-and CDClat 400, 100 and 376 MHz, respectively. Chemical shifts () in ppm are reported with the use of the residual CHDCN, DMSO-and chloroform signals (1.94, 2.54 and 7.25 forH and 1.30, 39.5 77.0 forC) as internal reference. TheF chemical shifts were referenced to C, (&#;162.9 ppm). The coupling constants () are given in Hertz (Hz). ESI-MS spectra were measured at MicroTof Bruker Daltonics instrument. TLC analysis was performed on &#;Merck 60 F&#; 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-trifluoromethylstyreneswere prepared as reported previously by catalytic olefination reaction [ 89 90 ] or by Wittig reaction [ 109 ]. Melting points were determined on an Electrothermal 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 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 CH2Cl2 (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na2SO4. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH2Cl2 as an eluent.

One neck 100 mL round bottomed flask was charged with N·HO (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 CFCCl(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 CHCl(3 × 20 mL). Combined extract was washed with water (20 mL) and dried over NaSO. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CHClas 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 N2H4·H2O and stirred 0.5&#;1h until aldehyde disappeared (TLC control). Next, 0.38 mL (4.4 mmol) of 1,2-ethylenediamine, 0. g (0.05 mmol) of CuCl2·2H2O was added and stirred for 1&#;2 min. After that CF3CCl3 (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 CH2Cl2 (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na2SO4. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CH2Cl2 as an eluent.

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·HO and stirred 0.5&#;1h until aldehyde disappeared (TLC control). Next, 0.38 mL (4.4 mmol) of 1,2-ethylenediamine, 0. g (0.05 mmol) of CuCl·2HO was added and stirred for 1&#;2 min. After that CFCCl(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 CHCl(3 × 20 mL). Combined extract was washed with water (20 mL) and dried over NaSO. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad using 3:1 mixture of hexane and CHClas an eluent.

Synthesis of styrene 2a by catalytic olefination reaction in EtOH (150 mmol scale). One neck mL round bottomed flask was charged with N2H4·H2O (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 CF3CCl3 (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 ( mL, ~0.4&#;0.5 M) and extracted with CH2Cl2 (3 × 150 mL). Combined extract was washed with water (200 mL) and dried over Na2SO4. Solvents were evaporated in vacuo, the residue was purified by passing through a short silica gel pad (~120&#;150 cm3 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%).

Synthesis of styrenes 2 by Wittig reaction (general procedure III, 5 mmol scale) [109]. One neck 20 mL vial with a screw cap was charged with corresponding benzaldehyde (2 mmol), PPh3 (1.258 g, 4.8 mmol), K2CO3 (0.028 g, 0.2 mmol), MeCN (2 mL) and CF3CCl3 (0.561 g, 3 mmol). The reaction mixture was stirred for 3&#;5 h at 80 °C and then poured into water (100 mL) and extracted with CH2Cl2 (3 × 20 mL). Combined extract was washed with water (20 mL) and dried over Na2SO4. Solvents were evaporated in vacuo, the residue was purified by column chromatography on silica gel using 3:1 (2b,g,i,k,n) and 1:1 (2j,l,m) mixtures of hexane and CH2Cl2 as eluents.

One neck 20 mL vial with a screw cap was charged with corresponding benzaldehyde (2 mmol), PPh(1.258 g, 4.8 mmol), KCO(0.028 g, 0.2 mmol), MeCN (2 mL) and CFCCl(0.561 g, 3 mmol). The reaction mixture was stirred for 3&#;5 h at 80 °C and then poured into water (100 mL) and extracted with CHCl(3 × 20 mL). Combined extract was washed with water (20 mL) and dried over NaSO. Solvents were evaporated in vacuo, the residue was purified by column chromatography on silica gel using 3:1 () and 1:1 () mixtures of hexane and CHClas eluents.

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene (2a). Obtained from 2-nitrobenzaldehyde. Obtained from 2-nitrobenzaldehyde 1a (0.151 g, 1 mmol) by procedure II. &#;olorless oil, yield 0.223 g (88%). Mixture of

isomers (82:18; by 19F NMR). NMR data of styrene 2a (see

Obtained from 2-. Obtained from 2-nitrobenzaldehyde(0.151 g, 1 mmol) by procedure II. &#;olorless oil, yield 0.223 g (88%). Mixture ofisomers (82:18; byF NMR). NMR data of styrene(see Supplementary Materials ) are in agreement with those in the literature [ 110 ].

4-Chloro-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene (2b). Obtained from 4-chloro-2-nitrobenzaldehyde 1b (0.185g, 1 mmol) by procedure II. Light yellow oil, yield 0.223 g (78%). Mixture of

isomers (90:10; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.21 (d, 1H, 4

= 2.1 Hz), 7.75&#;7.67 (m, 2H), 7.61 (d, 1H, 3

= 8.3 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.6, 136.4, 133.9, 132.4, 128.2 (q, 3

CF = 4.8 Hz), 125.9, 125.4, 123.4 (q, 2

CF = 38.0 Hz), 120.2 (q, 1

CF = 272.8 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;70.4 (d, 3F, 4

= 1.0 Hz).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.65 (dd, 1H, 3

= 8.3 Hz, 4

= 2.2 Hz), 7.46 (s, 1H), 7.32 (d, 1H, 3

= 8.3 Hz). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 136.2, 133.8, 132.1, 126.8, 125.2. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.2 (s, 3F). HRMS (ESI-TOF):

[M + Ag]+ Calcd for C9H4Cl2F3NO2Ag+: 393.; found: 393..

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-methoxy-2-nitrobenzene(2c). Obtained from 3-methoxy-2-nitrobenzaldehyde 1c (0.188 g, 1.039 mmol) by procedure II. Yellow crystals, mp 42&#;44 °&#;, yield 0.211 g (75%). Mixture of

isomers (76:24; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.50 (t, 1&#;, 3

= 8.2 Hz), 7.34 (d, 1&#;, 3

= 7.8 Hz), 7.24 (s, 1H), 7.13 (d, 1&#;, 3

= 8.5 Hz), 3.91 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 151.26, 140.4, 131.43, 125.4, 125.0 (q, 3

CF = 4.5 Hz), 124.9 (q, 2

CF = 37.6 Hz), 121.0, 120.1 (q, 1

CF = 273.9 Hz), 114.0, 56.51. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.3 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.43 (t, 1&#;, 3

= 8.2 Hz), 7.17 (s, 1H), 7.08 (d, 1&#;, 3

= 8.5 Hz), 6.86 (d, 1&#;, 3

= 7.8 Hz), 3.90 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 151.24, 139.2, 131.48, 130.0 (q, 3

CF = 2.1 Hz), 126.8, 125.3 (q, 2

CF = 37.6 Hz), 120.8 (q, 4

CF = 2.5 Hz), 119.8 (q, 1

CF = 273.9 Hz), 113.4, 56.46. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.6 (s, 3F). HRMS (ESI-TOF):

[M + NH4]+ Calcd for C10H11ClF3N2O3+: 299.; found: 299..

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxy-1-nitrobenzene(2d). Obtained from 5-methoxy-2-nitrobenzaldehyde 1d (0.183 g, 1.011 mmol) by procedure II. Yellow oil, yield 0.234 g (82%). Mixture of

isomers (84:16; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.25&#;8.21 (m, 1H), 7.75 (s, 1H), 7.05&#;6.99 (m, 2H), 3.92 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 163.6, 140.0, 130.1 (q, 3

CF = 4.8 Hz), 130.0, 127.7, 120.4 (q, 1

CF = 272.6 Hz), 121.9 (q, 2

CF = 37.7 Hz), 116.2, 114.7, 56.1. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.2 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.20 (d, 1H, 3

= 6.6 Hz), 7.51 (s, 1H), 6.97 (d, 1H, 3

= 2.8 Hz), 6.77 (d, 1H, 3

= 2.7 Hz), 3.90 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 163.5, 139.2, 134.1 (q, 3

CF = 2.3 Hz), 130.9, 127.5, 120.1 (q, 1

CF = 274.2 Hz), 121.2 (q, 2

CF = 37.5 Hz), 115.9 (q, 3

CF = 2.6 Hz), 114.5, 56.04. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.0 (s, 3F). HRMS (ESI-TOF):

[M + Na]+ Calcd for C10H7ClF3NO3Na+: 303.; found: 303..

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3,5-dimethyl-2-nitrobenzene (2e). Obtained from 3,5-dimethyl-2-nitrobenzaldehyde 1e (0.174 g, 0.972 mmol) by procedure II. Yellow oil, yield 0.214 g (77%). Mixture of

isomers (78:22; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.36 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 2.40 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.8, 141.5, 133.4, 131.4, 128.1, 126.8 (q, 3

CF = 4.6 Hz), 124.9, 123.7 (q, 2

CF = 37.5 Hz), 120.2 (q, 1

CF = 272.7 Hz), 21.1, 18.2. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.3 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.23 (s, 1H), 7.13 (s, 1H), 6.94 (s, 1H). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 146.6, 141.6, 133.1, 131.8 (q, 3

CF = 2.3 Hz), 131.6, 127.9 (q, 4

CF = 2.4 Hz), 126.4, 123.8 (q, 2

CF = 37.4 Hz), 119.9 (q, 1

CF = 274.5 Hz), 20.9, 18.3. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.5 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H10ClF3NO2+: 280.; found: 280..

6-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxine (2f). Obtained from 7-nitro-2,3-dihydrobenzo[

][1f (0.212 g, 1.014 mmol) by procedure II. Pale yellow crystals, mp 104&#;106 °&#;, yield 0.241 g (78%). Mixture of

isomers (80:20; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.81 (s, 1H), 7.68 (

pseudo-

d, 1H, 4

= 0.8 Hz), 7.10 (s, 1H), 4.45&#;4.28 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 148.2, 143.9, 129.2 (q, 3

CF = 4.6 Hz), 121.5, 121.4 (q, 2

CF = 37.5 Hz), 120.5 (q, 1

CF = 272.3 Hz), 119.3, 115.0, 64.7, 64.3. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.2 (d, 3F, 4

= 1.0 Hz).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.80 (s,1H), 7.43 (

pseudo-

d, 1H, 4

= 0.8 Hz), 6.79 (s, 1H). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.8, 140.5, 133.8 (q, 3

CF = 2.3 Hz), 122.6, 121.5 (q, 2

CF = 37.3 Hz), 120.2 (q, 1

CF = 274.1 Hz), 119.0 (q, 3

CF = 2.5 Hz), 114.8, 64.2. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.1 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H8ClF3NO4+: 310.; found: 310..

Obtained from 7-nitro-2,3-dihydrobenzo[][ 1 4 ]dioxine-6-carbaldehyde(0.212 g, 1.014 mmol) by procedure II. Pale yellow crystals, mp 104&#;106 °&#;, yield 0.241 g (78%). Mixture ofisomers (80:20; byF NMR). For the mixture of isomers:-isomer:H NMR (CDCl, 400.1 MHz): δ 7.81 (s, 1H), 7.68 (d, 1H,= 0.8 Hz), 7.10 (s, 1H), 4.45&#;4.28 (m, 4H).C{H} NMR (CDCl, 100.6 MHz): δ 148.2, 143.9, 129.2 (q,= 4.6 Hz), 121.5, 121.4 (q,= 37.5 Hz), 120.5 (q,= 272.3 Hz), 119.3, 115.0, 64.7, 64.3.F NMR (CDCl, 376.5 MHz): δ &#;70.2 (d, 3F,= 1.0 Hz).- isomer:H NMR (CDCl, 400.1 MHz): δ 7.80 (s,1H), 7.43 (d, 1H,= 0.8 Hz), 6.79 (s, 1H). Other signals are overlapped with those of major isomer.C{H} NMR (CDCl, 100.6 MHz): δ 143.8, 140.5, 133.8 (q,= 2.3 Hz), 122.6, 121.5 (q,= 37.3 Hz), 120.2 (q,= 274.1 Hz), 119.0 (q,= 2.5 Hz), 114.8, 64.2. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer.F NMR (CDCl, 376.5 MHz): δ &#;63.1 (s, 3F). HRMS (ESI-TOF):[M + H]Calcd for CClFNO: 310.; found: 310..

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-1,4-dimethoxy-3-nitrobenzene(2g). Obtained from 1,4-dimethoxy-3-nitrobenzaldehyde 1g (0.222 g, 1.052 mmol) by procedure II. Pale yellow crystals, mp 72&#;73 °&#;, yield 0.254 g (78%). Mixture of

isomers (91:9; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.18 (s, 1H), 7.07 (d, 1H, 3

= 9.3 Hz), 7.03 (d, 1H, 3

= 9.2 Hz), 3.87 (s, 3H), 3.83 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 150.2, 145.1, 126.8 (q, 2

CF = 37.8 Hz), 124.0 (q, 3

CF = 4.6 Hz), 119.9 (q, 1

CF = 272.9 Hz), 115.4, 114.4, 113.9, 57.0, 56.5. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.3 (d, 3F, 4

= 1.0 Hz).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 6.99 (d, 1H, 3

= 3.2 Hz), 6.98 (d, 1H, 3

= 3.2 Hz), 6.88 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 144.7, 140.4, 113.3, 56.9, 56.3. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;67.8 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H10ClF3NO4+: 312.; found: 312..

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4,5-dimethoxy-2-nitrobenzene(2h). Obtained from 2,5-dimethoxy-3-nitrobenzaldehyde 1h by procedure I (0.539 g, 2.55 mmol, DMSO) and by procedure II (0.245 g, 1.161 mmol). Pale yellow solid, mp 95&#;97 °&#;, yield 0.374 g (47%, I) yield 0.128 g (43%, II). Mixture of

isomers (80:20; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.79&#;7.74 (m, 2H), 7.02 (s, 1H), 3.99 (s, 3H), 3.99 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 153.2, 149.4, 140.1, 129.9 (q, 3

CF = 4.7 Hz), 121.6, 121.4 (q, 2

CF = 37.3 Hz), 120.4 (q, 1

CF = 272.4 Hz), 112.1, 107.7, 56.6, 56.40. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.1 (d, 3F, 4

= 1.0 Hz).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.52 (

pseudo-

d, 1H, 4

= 0.6 Hz), 6.71 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 149.3, 138.9, 134.3 (q, 3

CF = 2.3 Hz), 122.7, 120.2 (q, 1

CF = 274.3 Hz), 121.1 (q, 2

CF = 37.2 Hz), 112.1, 107.5, 56.5, 56.38. 19F NMR (CDCl3, 376.5 MHz): δ &#;62.8 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H10ClF3NO4+: 312.; found: 312..

5-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-6-nitrobenzo[d][1,3]dioxole (2i). Obtained from 4,5-ethylendioxy-2-nitrobenzaldehyde 1i (0.207 g, 1.062 mmol) by procedure II. Pale yellow solid, mp 100&#;103 °&#;, yield 0.155 g (52%). Mixture of

isomers (79:21; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.68&#;7.66 (m, 2H), 6.99 (s, 1H). 6.19 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 152.22, 148.9, 141.8, 129.7 (q, 3

CF = 4.8 Hz), 123.9, 121.8 (q, 2

CF = 37.5 Hz), 120.4 (q, 1

CF = 272.5 Hz), 109.6, 105.7, 103.64. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.2 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.65 (s, 1H), 7.43 (d, 1&#;, 4

= 0.6 Hz), 6.70 (s, 1H), 6.17 (s, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 152.19, 148.8, 140.6, 134.0 (q, 3

CF = 2.8 Hz), 124.9, 121.3 (q, 2

CF = 37.4 Hz), 120.1 (q, 1

CF = 274.5 Hz), 109.5 (q, 4

CF = 2.8 Hz), 105.4, 103.62. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.2 (s, 3F). HRMS (ESI-TOF):

[M + Na]+ Calcd for C10H5ClF3NO4Na+: 317.; found: 317..

Obtained from 4,5-ethylendioxy-2-nitrobenzaldehyde(0.207 g, 1.062 mmol) by procedure II. Pale yellow solid, mp 100&#;103 °&#;, yield 0.155 g (52%). Mixture ofisomers (79:21; byF NMR). For the mixture of isomers:-isomer:H NMR (CDCl, 400.1 MHz): δ 7.68&#;7.66 (m, 2H), 6.99 (s, 1H). 6.19 (s, 2H).C{H} NMR (CDCl, 100.6 MHz): δ 152.22, 148.9, 141.8, 129.7 (q,= 4.8 Hz), 123.9, 121.8 (q,= 37.5 Hz), 120.4 (q,= 272.5 Hz), 109.6, 105.7, 103.64.F NMR (CDCl, 376.5 MHz): δ &#;70.2 (s, 3F).- isomer:H NMR (CDCl, 400.1 MHz): δ 7.65 (s, 1H), 7.43 (d, 1&#;,= 0.6 Hz), 6.70 (s, 1H), 6.17 (s, 2H).C{H} NMR (CDCl, 100.6 MHz): δ 152.19, 148.8, 140.6, 134.0 (q,= 2.8 Hz), 124.9, 121.3 (q,= 37.4 Hz), 120.1 (q,= 274.5 Hz), 109.5 (q,= 2.8 Hz), 105.4, 103.62.F NMR (CDCl, 376.5 MHz): δ &#;63.2 (s, 3F). HRMS (ESI-TOF):[M + Na]Calcd for CClFNONa: 317.; found: 317..

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,4-dinitrobenzene (2j). Obtained from 2,4-dinitrobenzaldehyde by procedure (II, 0.196 g) and (III, 0.65 g). Yellow viscous oil, yield 0.014 g (5%, II), 0.248 (25%, (III). Mixture of

isomers (96:4; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 9.03 (

pseudo-

d, 1H, 4

~ 1.5 Hz), 8.58 (dd, 1H, 3

= 8.5 Hz, 4

= 2.3 Hz), 7.91 (d, 1H, 3

= 8.5 Hz), 7.78 (s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 148.1, 147.4, 140.2, 133.0, 127.9, 127.6 (q, 3

CF = 4.5 Hz), 125.0 (q, 2

CF = 38.0 Hz), 120.6, 119.9 (q, 1

CF = 273.2 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;69.4 (d, 3F, 4

= 0.6 Hz).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.78 (br.s, 1H), 8.52 (dd, 1H, 3

= 8.5 Hz, 4

= 2.3 Hz), 7.64 (d, 1H, 3

= 8.5 Hz), 7.53 (s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): 127.0. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;62.2 (s, 3F). HRMS (ESI-TOF):

[M-H]- Calcd for C9H3ClF3N2O4&#;: 294.; found: 294..

1-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitro-4-(trifluoromethyl)benzene (2k). Obtained from 2-nitro-4-(trifluoromethyl)benzaldehyde 1k by procedure II (0.438 g, 2 mmol) and by procedure III (0.438 g, 2 mmol). Yellow oil, yield 0.395 g (62%, II), 0.365 g (57%, III). Mixture of

isomers (92:8; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 8.49 (

pseudo-

d, 1H, 4

~ 1.0 Hz), 7.99 (dd, 1H, 3

= 8.0 Hz, 4

= 0.7 Hz), 7.81 (d, 1H, 3

= 8.1 Hz), 7.77 (s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.2, 132.8 (q, 2

CF = 34.6 Hz), 132.4, 131.12, 130.3 (q, 3

CF = 3.4 Hz), 128.2 (q, 3

CF = 4.8 Hz), 124.3 (q, 2

CF = 38.1 Hz), 122.53 (q, 3

CF = 3.8 Hz), 122.46 (q, 1

CF = 273.1 Hz), 120.1 (q, 1

CF = 272.8 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;69.5 (s, 3F), &#;63.3 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.94 (dd, 1H, 3

= 8.0 Hz, 4

= 0.7 Hz), 7.56 (s, 1H), 7.53 (d, 1H, 3

= 8.2 Hz). Other signals are overlapped with those of major isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;62.3 (s, 3F). Other signals are overlapped with those of major isomer. HRMS (ESI-TOF):

[M + Ag]+ Calcd for C10H4ClF6NO2Ag+: 425.; found: 425..

4-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-nitrobenzonitrile (2l). Obtained from 4-cyano-2-nitrobenzaldehyde 1l by procedure II (0.176 g, 1 mmol) and by procedure III (0.88 g, 5 mmol). Yellow oil, yield 0.070 g (25%) (II), 0.278 g (20%, III). Mixture of

isomers (96:4; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ

δ 8.51 (d, 1H, 4

= 1.6 Hz), 8.01 (dd, 1H, 3

= 8.1 Hz, 4

= 1.6 Hz), 7.81 (d, 1H, 3

= 8.1 Hz), 7.75 (s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.1, 136.6, 132.5, 131.7, 128.7, 127.9 (q, 3

CF = 4.7 Hz), 124.3 (q, 2

CF = 38.5 Hz), 119.8 (q, 1

CF = 273.0 Hz, CF3), 115.9, 114.4. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.5 (s, 3F).

-isomer: 1H NMR (CDCl3, 400.1 MHz): δ 7.95 (dd, 1H, 3

= 8.0 Hz, 4

= 1.6 Hz), 7.50 (s, 1H). Other signals are overlapped with those of major isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.3 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C10H5ClF3N2O2+: 276.; found: 276..

Methyl 4-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-nitrobenzoate (2m). Obtained from methyl 4-formyl-3-nitrobenzoate 1m by procedure II (0.209 g, 1 mmol) and by procedure III (0.209 g, 1 mmol). Beige crystals, yield 0.040 g (13%, II), 0.079 g (22%, III). Mixture of

isomers (95:5; by 19F NMR). 1H NMR (CDCl3, 400.1 MHz):

δ 8.81 (d, 1H, 4

= 1.7 Hz), 8.35 (dd, 1H, 3

= 8.0 Hz, 4

= 1.7 Hz), 7.76 (s, 1H), 7.73 (d, 1H, 3

= 8.1 Hz), 3.99 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 164.3, 147.2, 134.2, 132.4, 131.7, 131.4, 128.6 (q, 3

CF = 4.7 Hz), 126.1, 123.7 (q, 2

CF = 38.0 Hz), 120.1 (q, 1

CF = 272.9 Hz), 53.0. 19F NMR (CDCl3, 376.5 MHz): δ &#;70.4 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H8ClF3NO4+: 310.; found: 310..

4-Chloro-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-1-nitrobenzene (2n). Obtained from 5-chloro-2-nitrobenzaldehyde 1n (0.191g, 1.03 mmol) by procedure II. Yellow crystals, mp 46&#;48 °&#;, yield 0.221 g (75%). Mixture of

isomers (91:9; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 8.19 (d, 1&#;, 3

= 8.8 Hz), 7.70 (s, 1H), 7.61 (d, 1&#;, 4

= 2.1 Hz), 7.58&#;7.55 (m, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 145.3, 140.4, 131.1, 130.3, 129.2, 128.3 (q, 3

CF = 4.8 Hz), 126.5, 123.4 (q, 2

CF = 38.0 Hz), 120.1 (q, 1

CF = 272.9 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;70.5 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 7.46 (s, 1H). Other signals are overlapped with those of major isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;63.3 (s, 3F). HRMS (ESI-TOF):

[M + Ag]+ Calcd for C9H4Cl2F3NO2Ag+: 395.; found: 395..

2-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-fluoro-1-nitrobenzene (2o). Obtained from 5-fluoro-2-nitrobenzaldehyde 1o (0.175g, 1.04 mmol) by procedure II. White crystals, mp 35&#;38 °&#;, yield 0.204 g (73%). Mixture of

isomers (83:17; by 19F NMR). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 8.28 (dd, 1&#;, 3

= 9.1 Hz, 3

= 5.1 Hz), 7.73 (s, 1H), 7.34 (dd, 1&#;, 3

= 8.5 Hz, 4

= 2.6 Hz), 7.31&#;7.25 (m, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 164.9 (d, 1

CF = 259.2 Hz), 143.3 (d, 4

CF = 2.5 Hz), 130.6 (d, 3

CF = 10.0 Hz), 128.5 (qd, 3

CF = 4.5 Hz, 4

CF = 0.9 Hz), 128.1 (d, 3

CF = 10.2 Hz), 123.4 (q, 2

CF = 37.9 Hz), 120.2 (q, 1

CF = 272.8 Hz), 118.4 (d, 2

CF = 25.1 Hz), 117.3 (d, 2

CF = 23.1 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;70.5 (s, 3F), &#;102.55&#;&#;102.71 (m, 1F).

- isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 7.48 (s, 1H), 7.25&#;7.22 (m, 1H) 7.07 (dd, 1&#;, 3

= 8.2 Hz, 4

= 2.7 Hz). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 164.7 (d, 1

CF = 259.8 Hz), 142.4, 132.3 (br.s), 131.4 (d, 3

CF = 9.9 Hz), 127.9 (d, 3

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CF = 10.2 Hz), 122.6 (q, 2

CF = 37.5 Hz), 120.0 (q, 1

CF = 274.4 Hz), 116.9, 118.0 (q, 4

CF = 2.4 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;63.3 (s, 3F), &#;102.73&#;&#;102.88 (m, 1F). HRMS (ESI-TOF):

[M-F]+ Calcd for C9H4ClF3NO2+: 249.; found: 249..

Synthesis of α-CF3-β-(2-nitroaryl)enamines by the reaction with pyrrolidine in neat (general procedure) [2 (10 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1&#;3 h until all starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in vacuum, the viscous residue was dissolved in CH2Cl2 (50 mL), washed with water (3 × 50 mL) and dried over Na2SO4. CH2Cl2 was removed in vacuo, and the residue was filtered through a short silica gel pad using appropriate mixture 1:1 of hexane and CH2Cl2.78 ]. A one neck 25 mL round bottomed flask was charged with dry pyrrolidine (8.5 mL, 100 mmol), cooled down to &#;18 °C and corresponding styrene(10 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1&#;3 h until all starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in vacuum, the viscous residue was dissolved in CHCl(50 mL), washed with water (3 × 50 mL) and dried over NaSO. CHClwas removed in vacuo, and the residue was filtered through a short silica gel pad using appropriate mixture 1:1 of hexane and CHCl1-[(1
Z
)-2-(2-Nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3a). Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene 2a (6.04 g, 24 mmol). Yellow oil, yield 6.733 g (98%). Mixture of

isomers (86:14; 19F NMR). NMR data of enamine 3a (see

Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2-nitrobenzene(6.04 g, 24 mmol). Yellow oil, yield 6.733 g (98%). Mixture ofisomers (86:14;F NMR). NMR data of enamine(see Supplementary Materials ) are in agreement with those in the literature [ 78 ].

1-[(1
Z
)-2-(3-Methoxy-2-nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3c). Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-methoxy-2-nitrobenzene 2c (0.211 g, 0.75 mmol). Orange oil, yield 0.190 g (80%). Mixture of

isomers (84:16; 19F NMR). NMR data of enamine 3&#;(see

Obtained from 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-methoxy-2-nitrobenzene(0.211 g, 0.75 mmol). Orange oil, yield 0.190 g (80%). Mixture ofisomers (84:16;F NMR). NMR data of enamine(see Supplementary Materials ) are in agreement with those in the literature [ 84 ].

1-Hydroxy-7-methoxy-2-(pyrrolidin-1-yl)-2-(trifluoromethyl)indolin-3-one (5c). Obtained from 1-[2-chloro-3,3,3-trifluoro-1-propenyl]-3-methoxy-2-nitrobenzene 2c as an admixture in the synthesis of enamine 3c. Orange oil, yield 0.036 g (15%). 1H NMR (CDCl3, 400.1 MHz):

δ 7.74 (s, 1H), 7.24&#;7.28 (m, 1H), 7.01&#;7.15 (m, 2H), 3.90 (s, 3H), 3.11 (dd, 2&#;, 3

= 7.2 Hz), 2.95 (q, 2&#;, 3

= 6.9 Hz), 1.78 (t, 4&#;, 3

= 6.2 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 192.4, 152.3, 149.3, 124.9, 122.6, 122.4 (q, 1

CF = 284.8 Hz), 118.9, 115.6, 86.4 (q, 2

CF = 28.1 Hz), 55.9, 47.8, 24.4. 19F NMR (CDCl3, 376.5 MHz): δ &#;73.6 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C14H16F3N2O3+: 317.; found: 317..

1-[(1
Z
)-2-(5-methoxy-2-nitrophenyl)-1-(trifluoromethyl)vinil]pyrrolidine (3d). Obtained from 2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxy-1-nitrobenzene 2d (0.976 g, 3.465 mmol). Orange oil, yield 1.074 g (98%). Mixture of

isomers (86:14; 19F NMR). NMR data of enamine 3d (see

Obtained from 2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-methoxy-1-nitrobenzene(0.976 g, 3.465 mmol). Orange oil, yield 1.074 g (98%). Mixture ofisomers (86:14;F NMR). NMR data of enamine(see Supplementary Materials ) are in agreement with those in the literature [ 84 ].

1-[(1

)-(4-nitro-3-(3,3,3-trifluoro-2-(pyrrolidin-1-yl)prop-1-en-1-yl)phenyl]pyrrolidine (3n). Obtained from styrenes 2n (0.286 g, 1 mmol) or from styrene 2o (0.396 g, 1.469 mmol). Yellow orange solid, mp 145&#;147 °&#;, yield 0.255 g (72% from 2n), 0.468 g (90% from 2o). Mixture of

isomers (84:16; 19F). For the mixture of isomers:

-isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 8.07 (d, 1&#;, 3

= 9.3 Hz), 6.39&#;6.33 (m, 2&#;), 6.20 (d, 1H, 4

= 2.4 Hz), 3.39&#;3.30 (m, 4&#;), 3.02 (t, 4&#;, 3

= 6.4 Hz), 2.11&#;2.02 (m, 4&#;), 1.69&#;1.80 (m, 4&#;). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 150.2, 135.8, 135.0, 133.9 (q, 2

CF = 28.7 Hz), 127.7, 121.9 (q, 1

CF = 277.8 Hz), 112.9, 109.21, 104.1 (q, 3

CF = 6.8 Hz), 50.4 (d, 4

CF = 1.1 Hz), 47.7, 25.4, 25.3. 19F NMR (CDCl3, 376.5 MHz): δ &#;65.8 (s, 3F).

- isomer: 1H NMR (CDCl3, 400.1 MHz):

δ 8.08 (d, 1&#;, 3

= 9.3 Hz), 5.97 (s, 1&#;), 6.27 (d, 1H, 4

= 2.4 Hz), 3.24 (t, 4&#;, 3

= 6.5 Hz), 1.97&#;1.90 (m, 4&#;). Other signals are overlapped with those of major isomer. 13C{1H} NMR (CDCl3, 100.6 MHz): δ 135.5 (q, 2

CF = 27.3 Hz), 127.6, 113.8 (q,

= 3.4, CH = CCF3), 109.24, 106.2 (q, 3

CF = 3.4 Hz), 49.30 (d, 4

CF = 1.1 Hz), 47.6, 24.6. Other signals are overlapped with those of major isomer or cannot be seen in the spectrum due to the low concentration of minor isomer. 19F NMR (CDCl3, 376.5 MHz): δ &#;59.2 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C17H21F3N3O2+: 356.; found: 356..

Synthesis of indoles 4 by the reduction of nitro-substituted enamines 3 (general procedure IV). A one neck 25 mL round bottomed flask was charged with enamine 3 (0.5 mmol), glacial acetic acid (2 mL), water (0.2 mL) and Fe powder (0.112 g, 2 mmol). Reaction mixture was kept at 80 °&#; under stirring for 1&#;2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH2Cl2 (2&#;5 mL) and transferred on the short silica gel pad. The product was isolated using appropriate mixture of hexane and CH2Cl2 (3:1 for 4a, 4d); and mixture of CH2Cl2 and MeOH (100:1 for 4o) as eluents.

Multi-gram scale synthesis of indole 4a. A one neck 250 mL round bottomed flask was charged with enamine 3a (7.01 g, 24.5 mmol), glacial acetic acid (100 mL), water (20 mL) and Fe powder (5.49 g, 98 mmol). Reaction mixture was kept at 80&#;90 °&#; under stirring for 2 h until dissolving of Fe powder. The reaction mixture was poured into water ( mL), the precipitate formed was filtered off and washed by water (100 mL). Next, precipitate was washed with CH2Cl2 (2 × 50 mL), organic phase was dried over Na2SO4 and evaporated in vacuo to give pure indole 4a as colorless plates.

One pot synthesis of indoles 4 from styrenes 2 (general procedure V). A one neck 25 mL round bottomed flask was charged with pyrrolidine (1 mL, 11.8 mmol) and corresponding styrene 2 (0.5 mmol) was added in one portion with vigorous stirring. The reaction mixture was stirred at room temperature for 1&#;3 h until all starting styrene was consumed (TLC or NMR monitoring). The excess of pyrrolidine was evaporated in vacuum and the viscous residue was dissolved in glacial acetic acid (2 mL) and water (0.2 mL). After that Fe powder (0.112 g, 2 mmol) was added and the reaction mixture was kept at 80 °&#; under stirring for 1&#;2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH2Cl2 (2&#;5 mL) and transferred on the short silica gel pad. The product was isolated using appropriate mixtures of hexane and CH2Cl2 (3:1 for 4b,4c,4e,4k,4n; 1:1 for 4f,4g,4h,4i); CH2Cl2 (for 4l,4m) and mixture of CH2Cl2 and MeOH (100:1 for 4j,4o) as eluents.

2-(Trifluoromethyl)-1
H
-indole (4a). Obtained from enamine 3a (0.107 g, 0.374 mmol) by procedure IV. White crystals, m.p. 111&#;112 °C, yield 0.059 g (85%). NMR data of indole 4a (see

. Obtained from enamine(0.107 g, 0.374 mmol) by procedure IV. White crystals, m.p. 111&#;112C, yield 0.059 g (85%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

6-Chloro-2-(trifluoromethyl)-1
H
-indole (4b). Obtained from styrene 2b (0.100 g, 0.35 mmol) by procedure V. Slightly yellow oil, yield 0.035 g (48%). NMR data of indole 4b (see

. Obtained from styrene(0.100 g, 0.35 mmol) by procedure V. Slightly yellow oil, yield 0.035 g (48%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

7-Methoxy-2-(trifluoromethyl)-1
H
-indole (4c). Obtained from styrene 2c (0.149 g, 0.53 mmol) by procedure V. Colorless oil, yield 0.058 g (51%). NMR data of indole 4c (see SI) are in agreement with those in the literature [

. Obtained from styrene(0.149 g, 0.53 mmol) by procedure V. Colorless oil, yield 0.058 g (51%). NMR data of indole(see SI) are in agreement with those in the literature [ 67 ].

5-Methoxy-2-(trifluoromethyl)-1
H
-indole (4d). Obtained from enamine 3d (0.088 g, 0.28 mmol) by procedure IV. Colorless crystals, m.p. 48&#;49 °C, yield 0. g (64%). NMR data of indole 4d (see

. Obtained from enamine(0.088 g, 0.28 mmol) by procedure IV. Colorless crystals, m.p. 48&#;49C, yield 0. g (64%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

5,7-Dimethyl-2-(trifluoromethyl)-1

-indole (4e). Obtained from styrene 2e (0.109 g, 0.391 mmol) by procedure V. Slightly yellow oil, yield 0.036 g (43%). 1H NMR (CDCl3, 400.1 MHz): δ 8.16 (br.s, 1H), 7.30 (s, 1&#;), 6.96 (s, 1&#;), 6.88&#;6.82 (m, 1&#;), 2.48 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 134.3, 130.7, 127.0, 126.5, 125.4 (q, 2

CF = 38.9 Hz), 121.4 (q, 1

CF = 267.4 Hz), 120.6, 119.0, 104.3 (q, 3

CF = 3.4 Hz), 21.3, 16.5. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.6 (d, 3F, 4

= 1.0 Hz). HRMS (ESI-TOF):

[M-H]- Calcd for C11H9F3N&#;: 212.; found: 212..

7-(Trifluoromethyl)-2,3-dihydro-6
H
-[1,4]dioxino[2,3-
f
]-indole (4f). Obtained from styrene 2f (0.154 g, 0.497 mmol) by procedure V. White powder, m.p. 136&#;138 °C, yield 0.098 g (81%). 1H NMR (CDCl3, 400.1 MHz): δ 8.24 (br.s, 1H), 7.13 (s, 1&#;), 6.87 (s, 1&#;), 6.77 (s, 1&#;), 4.28 (q, 4&#;, 3

= 5.2 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.1, 140.1, 131.7, 125.5 (q, 2

CF = 38.9 Hz), 121.2 (q, 1

CF = 267.3 Hz), 121.0, 107.9, 103.8 (q, 3

CF = 3.4 Hz), 98.6, 64.5, 64.1. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.5 (s, 3F). HRMS (ESI-TOF):

[M-H]- Calcd for C11H7F3NO2&#;: 242.; found: 242..

. Obtained from styrene(0.154 g, 0.497 mmol) by procedure V. White powder, m.p. 136&#;138C, yield 0.098 g (81%).H NMR (CDCl, 400.1 MHz): δ 8.24 (br.s, 1H), 7.13 (s, 1&#;), 6.87 (s, 1&#;), 6.77 (s, 1&#;), 4.28 (q, 4&#;,= 5.2 Hz).C{H} NMR (CDCl, 100.6 MHz): δ 143.1, 140.1, 131.7, 125.5 (q,= 38.9 Hz), 121.2 (q,= 267.3 Hz), 121.0, 107.9, 103.8 (q,= 3.4 Hz), 98.6, 64.5, 64.1.F NMR (CDCl, 376.5 MHz): δ &#;61.5 (s, 3F). HRMS (ESI-TOF):[M-H]Calcd for CNO: 242.; found: 242..

4,7-Dimethoxy-2-(trifluoromethyl)-1

-indole (4g). Obtained from styrene 2g (0.107 g, 0.309 mmol) by procedure V. Light beige crystals, m.p. 74&#;76 °C, yield 0.053 g (70%). 1H NMR (CDCl3, 400.1 MHz): δ 8.73 (br.s, 1H), 7.05&#;7.01 (m, 1&#;), 6.62 (d, 1&#;, 3

= 8.3 Hz), 6.42 (d, 1&#;, 3

= 8.3 Hz), 3.92 (s, 3H), 3.91 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 148.2, 140.9, 128.2, 124.3 (q, 2

CF = 39.5 Hz), 121.2 (q, 1

CF = 267.5 Hz), 119.0, 103.9, 102.2 (q, 3

CF = 3.3 Hz), 99.6, 55.7, 55.6. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.4 (d, 3F, 4

= 0.9 Hz). HRMS (ESI-TOF):

[M]+ Calcd for C11H10F3NO2+: 245.; found: 245..

5,6-Dimethoxy-2-(trifluoromethyl)-1
H
-indole (4h). Obtained from styrene 2h (0.129 g, 0.416 mmol) by procedure V. White crystals, m.p. 89&#;90 °C, yield 0.055 g (54%). NMR data of indole 4h (see

. Obtained from styrene(0.129 g, 0.416 mmol) by procedure V. White crystals, m.p. 89&#;90C, yield 0.055 g (54%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

6-(Trifluoromethyl)-5
H
-[1,3]dioxolo[4.5-
f
]-indole (4i). Obtained from styrene 2i (0.125 g, 0.38 mmol) by procedure V. White crystals, m.p. 113&#;115 °C, yield 0.022 g (25%). NMR data of indole 4i (see

. Obtained from styrene(0.125 g, 0.38 mmol) by procedure V. White crystals, m.p. 113&#;115C, yield 0.022 g (25%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 74 ].

2-(Trifluoromethyl)-1
H
-indole-6-amine (4j). Obtained from styrene 2j (0.293 g, 0.99 mmol) by procedure V. 8 Equivalents of Fe (0.448 g, 8 mmol) was used due to the presence of second nitro-group in the styrene 2j. Beige crystals, m.p. 124&#;126 °C, yield 0.119 g (60%). NMR data of indole 4j (see

. Obtained from styrene(0.293 g, 0.99 mmol) by procedure V. 8 Equivalents of Fe (0.448 g, 8 mmol) was used due to the presence of second nitro-group in the styrene. Beige crystals, m.p. 124&#;126C, yield 0.119 g (60%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

2,6-Bis(trifluoromethyl)-1
H
-indole (4k). Obtained from styrene 2k (0.240 g, 0.75 mmol) by procedure V. Yellow crystals, m.p. 46&#;47 °C, yield 0. g (47%). NMR data of indole 4k (see

. Obtained from styrene(0.240 g, 0.75 mmol) by procedure V. Yellow crystals, m.p. 46&#;47C, yield 0. g (47%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

2-(Trifluoromethyl)-1

-indole-6-carbonitril (4l). Obtained from styrene 2l (0.080 g, 0.291 mmol) by procedure V. Slightly brown solid, m.p. 112&#;114 °C, yield 0. g (50%). 1H NMR (CDCl3, 400.1 MHz): δ 9.18 (br.s, 1H), 7.85 (

pseudo-

d, 1&#;, 4

~ 1.1 Hz), 7.77 (d, 1&#;, 3

= 8.3 Hz), 7.43 (dd, 1&#;, 3

= 8.3 Hz, 4

= 1.3 Hz), 6.99 (

pseudo-

dt, 1&#;, 4

~ 2.1 Hz, 4

~ 1.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 134.9, 129.7, 129.5 (q, 2

CF = 39.2 Hz), 123.7, 123.1, 120.6 (q, 1

CF = 268.6 Hz), 119.8, 117.0, 107.2, 104.4 (q, 3

CF = 3.2 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;62.2 (d, 3F, 4

= 0.9 Hz). HRMS (ESI-TOF):

[M-H]- Calcd for C10H4F3N2&#;: 209.; found: 209..

Methyl 2-(trifluoromethyl)-1
H
-indole-6-carboxylate (4m). Obtained from styrene 2m (0.126 g, 0.408 mmol) by procedure V. Pale brown solid, yield 0. g (53%). NMR data of indole 4m (see

. Obtained from styrene(0.126 g, 0.408 mmol) by procedure V. Pale brown solid, yield 0. g (53%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 67 ].

5-Cloro-2-(trifluoromethyl)-1
H
-indole (4n). Obtained from styrene 2n (0.083 g, 0.29 mmol) by procedure V (piperidine was used instead of pyrrolidine). Pale yellow crystals, m.p. 59&#;61 °C, yield 0. g (71%). NMR data of indole 4n (see

. Obtained from styrene(0.083 g, 0.29 mmol) by procedure V (piperidine was used instead of pyrrolidine). Pale yellow crystals, m.p. 59&#;61C, yield 0. g (71%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 64 ].

5-(Pyrrolidin-1-yl)-2-(trifluoromethyl)-1

-indole (10a). Obtained from enamine 3n (0.160 g, 0.45 mmol) by procedure V. Orange crystals, m.p. 130&#;131 °C, yield 0.052 g (45%). 1H NMR (CDCl3, 400.1 MHz): δ 8.11 (br.s, 1H), 7.26 (d, 1&#;, 3

= 9.1 Hz), 6.86&#;6.70 (m, 3&#;), 3.32 (t, 4&#;, 3

= 6.6 Hz), 2.09&#;2.00 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.9, 129.4, 127.9, 125.6 (q, 2

CF = 38.5 Hz), 121.4 (q, 1

CF = 267.5 Hz), 113.2, 112.1, 103.2 (q, 3

CF = 3.3 Hz), 101.7, 48.6, 25.3. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.5 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C13H14F3N2+: 255.; found: 255..

One pot synthesis of indoles 10 from styrenes 2 (general procedure VI). A 4 mL vial with a screw cup was charged with corresponding amine (5 mmol) and styrene 2n (0.5 mmol). The reaction mixture was heated at appropriate temperature for several hours (see further) or at room temperature (for MeNH2) until starting styrene was consumed (TLC or NMR monitoring). The excess of amine was evaporated in vacuo, the viscous residue was dissolved in glacial acetic acid (2 mL) and transferred into a one neck 25 mL round bottomed flask. Next, water (0.2 mL), Fe powder (0.112 g, 2 mmol) was added, and the reaction mixture was kept at 80 °&#; at stirring for 1&#;2 h until dissolving of Fe powder. Volatiles were evaporated in vacuo, the residue was suspended in CH2Cl2 (2&#;5 mL) and filtered through a short celite pad. The filtrate was evaporated, and the residue was purified by column chromatography on silica gel using appropriate mixtures of CH2Cl2 and MeOH (100:1 for 10b-e and 30:1 for 10f,g) as eluents.

5-(Piperidin-1-yl)-2-(trifluoromethyl)-1

-indole (10b). Obtained styrene 2n (0.109 g, 0.404 mmol) and piperidine (0.572 g) by heating at 90 °C for 3 h. Pale green-brown solid, m.p. 104&#;106 °C, yield 0.048 g (44%). 1H NMR (CDCl3, 400.1 MHz): δ 8.46 (br.s, 1H), 7.25 (d, 1&#;, 3

= 8.9 Hz), 7.17 (

pseudo-

d, 1&#;, 4

~ 2.1 Hz), 7.12 (dd, 1&#;, 3

= 8.9 Hz, 4

= 2.3 Hz), 6.82 (br.s, 1H), 3.14&#;3.07 (m, 4&#;), 1.77 (dt, 4H, 3

= 11.3 Hz, 3

= 5.7 Hz), 1.62&#;1.54 (m, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.9, 131.5, 127.2, 125.8 (q, 2

CF = 38.8 Hz), 121.3 (q, 1

CF = 267.6 Hz), 119.5, 112.1, 108.4, 103.9 (q, 3

CF = 3.4 Hz), 53.1, 26.2, 24.2. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.4 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C14H16F3N2+: 269.; found: 269..

4-(2-(Trifluoromethyl)-1

-indol-5yl)morpholine (10c). Obtained from styrene 2n (0.104 g, 0.385 mmol) and morpholine (0.530 g) by heating at 100 °C for 4 h. Pale green-brown solid, m.p. 167&#;169 °C, yield 0.061 g (59%). 1H NMR (CDCl3, 400.1 MHz):

δ 9.91 (br.s, 1&#;), 7.42&#;7.36 (m, 1&#;), 7.12&#;7.07 (m, 2&#;), 6.84 (

pseudo

-dt, 1 H, 4

~ 2.1 Hz, 4

~ 1.0 Hz), 3.84&#;3.75 (m, 4H), 3.10&#;3.01 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 147.8, 133.0, 127.9, 126.3 (q, 2

CF = 38.6 Hz), 122.6 (q, 1

CF = 266.5 Hz), 118.9, 113.5, 107.8, 104.1 (q, 3

CF = 3.4 Hz), 67.6, 52.1. 19F NMR (CDCl3, 376.5 MHz): δ &#;59.5 (d, 3F, 4

= 1.0 Hz). HRMS (ESI-TOF):

[M + H]+ Calcd for C13H14F3N2O+: 271.; found: 271..

5-(Azepan-1-yl)-2-(trifluoromethyl)-1

-indole (10d). Obtained from styrene 2n (0.107 g, 0.396 mmol) and hexamethyleneimine (0.480 g) by heating at 100 °C for 4 h. Pale yellow-brown solid, m.p. 65&#;67 °C, yield 0.060 g (54%). 1H NMR (CDCl3, 400.1 MHz): δ 8.12 (br.s, 1&#;), 7.23 (d, 1&#;, 3

= 9.0 Hz), 6.92 (dd, 1&#;, 3

= 9.0 Hz, 4

= 2.4 Hz), 6.88 (

pseudo

-d, 1 H, 4

~ 2.2 Hz), 6.79 (br.s, 1H), 3.56&#;3.47 (m, 4H), 1.89&#;1.79 (m, 4H), 1.61&#;1.53 (m, 4H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 144.6, 129.1, 128.0, 125.6 (q, 2

CF = 38.7 Hz), 121.4 (q, 1

CF = 267.4 Hz), 112.9, 112.2, 103.3 (q, 3

CF = 3.1 Hz), 101.5, 50.0, 27.9, 27.1. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.5 (d, 3F, 4

= 0.9 Hz). HRMS (ESI-TOF):

[M + H]+ Calcd for C15H18F3N2+: 283.; found: 283..

N,N

-Diethyl-2-(trifluoromethyl)-1
H
-indole-5-amine (10e). Obtained from styrene 2n (0.101 g, 0.374 mmol) and diethylamine (0.480 g) by heating at 100 °C for 10 h. Pale brown oil, yield 0.041 g (43%). 1H NMR (CDCl3, 400.1 MHz): δ 8.29 (br.s, 1&#;), 7.26 (d, 1&#;, 3

= 8.7 Hz), 7.02&#;6.93 (m, 2&#;), 6.79 (s, 1H), 3.33 (q, 4H, 3

= 7.1 Hz), 1.13 (t, 6H, 3

= 7.1 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.7, 130.3, 127.6, 125.7 (q, 2

CF = 38.9 Hz), 121.4 (q, 1

CF = 267.4 Hz), 116.4, 112.2, 106.0, 103.5 (q, 3

CF = 3.2 Hz), 45.9, 12.3. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.6 (d, 3F, 4

= 1.1 Hz). HRMS (ESI-TOF):

[M + H]+ Calcd for C13H16F3N2+: 257.; found: 257..

-Methyl-2-(trifluoromethyl)-1
H
-indole-5-amine (10f). Obtained from styrene 2n (0.116 g, 0.430 mmol) and

-methylamine (2 mL of 3.65 M solution in MeOH) by keeping the reaction mixture for 11 days. Pale green-brown solid, m.p. 133&#;135 °C, yield 0.040 g (44%). 1H NMR (CD3CN, 400.1 MHz): δ 9.74 (br.s, 1&#;), 7.26 (d, 1&#;, 3

= 8.7 Hz), 6.80&#;6.68 (m, 3&#;), 2.77 (s, 3H). 13C{1H} NMR (CD3CN, 100.6 MHz): δ 145.9, 131.4, 128.5, 125.7 (q, 2

CF = 38.5 Hz), 122.8 (q, 1

CF = 266.3 Hz), 116.2, 113.5, 103.4 (q, 3

CF = 3.4 Hz), 101.0, 31.4. 19F NMR (CD3CN, 376.5 MHz): δ &#;59.3 (d, 3F, 4

= 0.9 Hz). HRMS (ESI-TOF):

[M + H]+ Calcd for C10H10F3N2+: 215.; found: 215..

-Hexyl-2-(trifluoromethyl)-1
H
-indole-5-amine (10g). Obtained from styrene 2n (0.100 g, 0.370 mmol) and

-hexylamine (0.482 g) by heating at 100 °C for 4 h. Pale yellow-brown solid, m.p. 88&#;90 °C, yield 0.047 g (45%). 1H NMR (CDCl3, 400.1 MHz): δ 8.31 (br.s, 1&#;), 7.17 (d, 1&#;, 3

= 8.8 Hz), 6.82 (d, 1&#;, 4

= 2.1 Hz), 6.77&#;6.69 (m, 2H), 3.16&#;3.10 (m, 2&#;), 2.96 (br.s, 1H), 1.65 (dt, 2&#;, 3

= 14.7 Hz, 3

= 7.2 Hz), 1.48&#;1.29 (m, 6H), 0.91 (t, 3H, 3

= 7.0 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 143.4, 130.3, 127.7, 125.6 (q, 2

CF = 38.6 Hz), 121.4 (q, 1

CF = 267.4 Hz), 115.4, 112.3, 103.3 (q, 3

CF = 3.3 Hz), 102.2, 45.1, 31.7, 29.5, 26.9, 22.6, 14.0. 19F NMR (CDCl3, 376.5 MHz): δ &#;61.5 (d, 3F, 4

= 1.0 Hz). HRMS (ESI-TOF):

[M + H]+ Calcd for C15H20F3N2+: 285.; found: 285..

Reactions of indole 4a with electrophiles.

Synthesis of 2-(trifluoromethyl)-1
H
-indol-3-carbaldehyde (17). A 4 mL vial with a screw cup was charged with DMF (0.5 mL), cooled to &#;18 °C (in the fridge) and then POCl3 (0.210 g, 1.37 mmol) was added. The reaction mixture was kept at 5&#;7 °C (in the fridge) for 30 min and then indole 4a (0.108 g, 0.58 mmol). The reaction mixture was stirred for 6h at 80 °C, cooled down to room temperature and transferred to separating funnel with water (50 mL) using CH2Cl2 (30&#;40 mL). After shaking, organic phase was separated, water phase was extracted with CH2Cl2 (20 mL). Combined organic phase was washed with water (20 mL), and dried over Na2SO4. Volatiles were evaporated in vacuo, the residue formed was suspended in hexane-CH2Cl2 mixture (3:1, 2 mL). The precipitate was filtered off and dried in vacuo to give pure 17. Beige powder, m.p. 167&#;169 °C, yield 0.066 g (53%). NMR data of indole 17 (see

. A 4 mL vial with a screw cup was charged with DMF (0.5 mL), cooled to &#;18 °C (in the fridge) and then POCl(0.210 g, 1.37 mmol) was added. The reaction mixture was kept at 5&#;7 °C (in the fridge) for 30 min and then indole(0.108 g, 0.58 mmol). The reaction mixture was stirred for 6h at 80 °C, cooled down to room temperature and transferred to separating funnel with water (50 mL) using CHCl(30&#;40 mL). After shaking, organic phase was separated, water phase was extracted with CHCl(20 mL). Combined organic phase was washed with water (20 mL), and dried over NaSO. Volatiles were evaporated in vacuo, the residue formed was suspended in hexane-CHClmixture (3:1, 2 mL). The precipitate was filtered off and dried in vacuo to give pure. Beige powder, m.p. 167&#;169C, yield 0.066 g (53%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 66 ].

1-(2-(Trifluoromethyl)-1

-indol-3-yl)ethanone (18). An 8 mL vial with a screw cup was charged with 1,2-dichloroethane (1.5 mL), AlCl3 (0.124 g, 0.93 mmol), cooled to &#;18 °C (in the fridge) and then AcCl (0.047 g, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then indole 4a (0.089 g, 0.48 mmol) was added. The reaction mixture was stirred overnight and poured into water (50 mL). Water phase was extracted with CH2Cl2 (3 × 20 mL). Combined organic phase was washed with water (20 mL), and dried over Na2SO4. Volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using CH2Cl2 followed by mixture of CH2Cl2 and MeOH (100:1) as eluents. Beige powder, m.p. 125&#;127 °C, yield 0.070 g (64%). 1H NMR (CD3CN, 400.1 MHz): δ 10.77 (br.s, 1&#;), 8.11 (d, 1&#;, 3

= 8.2 Hz), 7.60&#;7.56 (m, 1&#;), 7.41&#;7.36 (m, 1&#;), 7.35&#;7.30 (m, 1H), 2.66 (s, 3H). 13C{1H} NMR (DMSO-

, 100.6 MHz): δ 192.7, 134.8, 126.9 (q, 2

CF = 38.1 Hz), 125.4, 125.3, 124.8 (d, 4

CF = 3.0 Hz), 123.0, 121.9, 121.1 (q, 1

CF = 269.6 Hz), 116.9 (q, 3

CF = 1.5 Hz), 113.4 (d, 3

CF = 6.2 Hz), 31.0. 19F NMR (CD3CN, 376.5 MHz): δ &#;58.0 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C11H9F3NO+: 228.; found: 228..

(

)-1,1,1-Trifluoro-4-(2-(trifluoromethyl)-1H-indol-3-yl)but-3-en-2-one (20). An 8 mL vial with a screw cup was charged with indole 4a (0.091 g, 0.49 mmol), (

)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one 19 (0.090 g, 0.54 mmol), 1,2-dichloroethane (1 mL), and BF3·Et2O (0.083 g, 0.059 mmol). The reaction mixture was stirred for 2h at 80 °C and poured into water (30 mL). Water phase was extracted with CH2Cl2 (3 × 20 mL). Combined organic phase was washed with water (20 mL), and dried over Na2SO4. Volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using mixtures of hexane and CH2Cl2 (3:1 followed by 1:1) as eluents. Yellow powder, m.p. 125&#;127 °C, yield 0. g (37%). 1H NMR (CDCl3, 400.1 MHz): δ 9.07 (br.s, 1&#;), 8.30 (d, 1&#;, 3

= 15.9 Hz), 7.98 (d, 1&#;, 3

= 8.0 Hz), 7.53 (d, 1&#;, 3

= 8.0 Hz), 7.50&#;7.43 (m, 1&#;), 7.43&#;7.38 (m, 1H), 7.20 (d, 1&#;, 3

= 15.9 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 180.1 (q, 2

CF = 35.1 Hz), 139.7, 135.3, 128.9 (q, 2

CF = 37.4 Hz), 126.2, 125.0, 123.7, 121.7, 120.7 (q, 1

CF = 270.5 Hz), 116.5 (q, 1

CF = 290.6 Hz), 116.6, 112.8, 112.7 (q, 3

CF = 2.3 Hz). 19F NMR (CDCl3, 376.5 MHz): δ &#;59.0 (d, 3F, 4

= 0.8 Hz), &#;78.7 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C13H8F6NO+: 308.; found: 308..

Reactions of indole 4a with benzaldehydes in alcohols under catalysis with MeSO3H (general procedure VII). A 4 mL vial with a screw cup was charged with indole 4a (0. g, 0.5 mmol), alcohol (MeOH or EtOH, 1 mL), corresponding benzaldehyde (0.6 mmol or 0.25 mmol for 23) and MeSO3H (0.050g, 0.53 mmol). The reaction mixture was heated at 80 °C for appropriate time, volatiles were evaporated in vacuo, the residue was purified by column chromatography on silica gel using mixtures of hexane and CH2Cl2 (3:1 followed by 1:1) as eluents.

3-(Methoxy(phenyl)methyl)-2-(trifluoromethyl)-1
H
-indole (21a). Obtained by the reaction of 4a (0. g, 0.5 mmol) with benzaldehyde (0.065 g, 0.6 mmol) in MeOH by heating for 8h. White crystals, m.p. 86&#;88 °C, yield 0.100 g (68%). NMR data of indole 21a (see

. Obtained by the reaction of(0. g, 0.5 mmol) with benzaldehyde (0.065 g, 0.6 mmol) in MeOH by heating for 8h. White crystals, m.p. 86&#;88C, yield 0.100 g (68%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 84 ].

3-((4-Chlorophenyl)(methoxy)methyl)-2-(trifluoromethyl)-1H-indole (21b). Obtained by the reaction of 4a (0. g, 0.5 mmol) with 4-chlorobenzaldehyde (0.084 g, 0.6 mmol) in MeOH by heating for 10h. White crystals, m.p. 112&#;113 °C, yield 0.112 g (66%). 1H NMR (CDCl3, 400.1 MHz): δ 8.44 (br.s, 1&#;), 7.72 (d, 1&#;, 3

= 8.1 Hz), 7.46&#;7.35 (m, 3&#;), 7.35&#;7.25 (m, 3&#;), 7.11 (ddd, 1&#;, 3

= 8.1 Hz, 3

= 7.0 Hz, 4

= 1.0 Hz), 5.79 (s, 1H), 3.41 (s, 3&#;). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 139.8, 135.4, 133.0, 128.3, 127.7, 125.2, 125.1, 123.2 (q, 2

CF = 37.1 Hz), 122.7, 121.7 (q, 1

CF = 269.3 Hz), 121.2, 117.3 (q, 3

CF = 2.4 Hz), 111.7, 56.9. 19F NMR (CDCl3, 376.5 MHz): δ &#;58.2 (s, 3F). HRMS (ESI-TOF):

[M-MeO]- Calcd for C16H10ClF3N+: 308.; found: 308..

3-(Methoxy(4-methoxyphenyl)methyl)-2-(trifluoromethyl)-1
H
-indole (21c). Obtained by the reaction of 4a (0.098 g, 0.53 mmol) with 4-methoxybenzaldehyde (0.087 g, 0.636 mmol) in MeOH by heating for 12h. Pale brown powder, m.p. 138-140 °&#;, yield 0.092 g (52%). NMR data of indole 21c (see

. Obtained by the reaction of(0.098 g, 0.53 mmol) with 4-methoxybenzaldehyde (0.087 g, 0.636 mmol) in MeOH by heating for 12h. Pale brown powder, m.p. 138-140 °&#;, yield 0.092 g (52%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 84 ].

3-(Ethoxy(phenyl)methyl)-2-(trifluoromethyl)-1
H
-indole (22). Obtained by the reaction of 4a (0.048 g, 0.259 mmol) with benzaldehyde (0.033 g, 0.306 mmol) in EtOH by heating for 8h. White crystals, m.p. 129&#;132 °C, yield 0.061 g (74%). NMR data of indole 22 (see

. Obtained by the reaction of(0.048 g, 0.259 mmol) with benzaldehyde (0.033 g, 0.306 mmol) in EtOH by heating for 8h. White crystals, m.p. 129&#;132C, yield 0.061 g (74%). NMR data of indole(see Supplementary Materials ) are in agreement with those in the literature [ 84 ].

3,3&#;-(Phenylmethylene)bis(2-(trifluoromethyl)-1

-indole) (23). Obtained by the reaction of 4a (0.087 g, 0.47 mmol) with benzaldehyde (0.026 g, 0.241 mmol) in EtOH by heating for 12h. Brown oil, yield 0. g (45%). 1H NMR (CDCl3, 400.1 MHz): δ 8.41 (br.s, 2&#;), 7.39 (d, 2&#;, 3

= 8.3 Hz), 7.27 (d, 2&#;, 4

= 2.2 Hz), 7.25&#;7.16 (m, 5H), 6.84 (ddd, 2&#;, 3

= 8.1 Hz, 3

= 7.0 Hz, 4

= 1.0 Hz), 6.72 (d, 2&#;, 3

= 8.1 Hz), 6.54 (s, 1H). 13C{1H} NMR (CDCl3, 100.6 MHz): δ 142.0, 135.0, 128.8, 128.3, 127.2, 126.8, 124.3, 122.4 (q, 2

CF = 37.5 Hz), 122.3, 121.7 (q, 1

CF = 269.6 Hz), 120.8, 118.8 (q, 3

CF = 1.5 Hz), 111,7, 38,0. 19F NMR (CDCl3, 376.5 MHz): δ &#;60.0 (s, 3F). HRMS (ESI-TOF):

[M + H]+ Calcd for C25H17F6N2+: 459.; found: 459..

Benzaldehyde stable Isotopes

Benzaldehyde stable Isotopes and its Related Products

Displaying 57 results of Benzaldehyde stable Isotopes

Benzaldehyde is a highly versatile chemical that is used in a wide range of applications, including as a flavoring agent, fragrance, and intermediate in the production of pharmaceuticals and agrochemicals. Stable isotopes of benzaldehyde, such as deuterated and carbon-13 labeled variants, are commonly used in research and development applications, including drug metabolism studies, environmental monitoring, and chemical synthesis. These isotopes offer unique advantages in terms of specificity, sensitivity, and accuracy, making them an essential tool for many analytical and scientific applications.

Displayingresults ofBenzaldehyde is a highly versatile chemical that is used in a wide range of applications, including as a flavoring agent, fragrance, and intermediate in the production of pharmaceuticals and agrochemicals. Stable isotopes of benzaldehyde, such as deuterated and carbon-13 labeled variants, are commonly used in research and development applications, including drug metabolism studies, environmental monitoring, and chemical synthesis. These isotopes offer unique advantages in terms of specificity, sensitivity, and accuracy, making them an essential tool for many analytical and scientific applications.

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