Afstudeerverslag Sten Cramer

Home , Trifluoroiodomethane, Trifluorotoluene

Eindhoven University of Technology

MASTER

Exploring the scope of the photocatalytic trifluormethylation of styrenes in batch and flow

Cramer, S.E.

Award date: 2018

Link to publication

Disclaimer This document contains a student thesis (bachelor's or master's), as authored by a student at Eindhoven University of Technology. Student theses are made available in the TU/e repository upon obtaining the required degree. The grade received is not published on the document as presented in the repository. The required complexity or quality of research of student theses may vary by program, and the required minimum study period may vary in duration.

General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.

• Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain Exploring the scope of the photocatalytic trifluoromethylation of styrenes in batch and flow

Sten E. Cramer

Graduation supervisors: prof. Volker Hessel and dr. Timothy Noël Daily supervisor: MSc Natan J.W. Straathof

Date: 25-08-2016

Abstract In this thesis, a method for the trifluoromethylation of styrene derivatives via a photoredox pathway with trifluoroiodomethane (CF3I) was successfully developed. This method uses CF3I gas as a more economical alternative for the commonly used Togni and Umemoto trifluoromethylating agents.

Reactions were performed with visible light at room temperature with fac-Ir(ppy)3, catalyst, cesium acetate and DMF.

Under these conditions, reactions were performed in batch and in microflow. While addition of CF3I gas in batch was done by means of a stock solution (of CF3I gas in DMF), in microflow it was directly introduced to the reaction mixture. For microflow the gas and liquid flowrates have been optimized (1.44 mL/min and 0.085 mL/min for gas and liquid, respectively).

A number of styrene derivatives (halogen substituted, hetero- and extended aromatics and beta- substituted) have been tested. The yield (32-75% and 29-95% for batch and flow, respectively) and reaction time (24-72 hours and 30-90 minutes for batch and flow, respectively) were substrate dependent. However, the selectivity towards the E-product was improved for all compounds in microflow (52-85% and 81-96% E-product for batch and flow, respectively).

Additionally, the robusticity tests that have been performed, showed that the reaction is not sensitive to moisture and air.

Contents Abstract ...... 2 Introduction ...... 4 Properties of fluorine ...... 5 Trifluoromethylation with photoredox catalysis ...... 8

Trifluoroiodomethane as CF3-source ...... 11 Microflow technology ...... 12 Proposed mechanism and project outline ...... 14 Results & discussion ...... 15 Preliminary research ...... 15 Trifluoromethylation in batch ...... 16 Trifluoromethylation in microflow ...... 17 Unanticipated results ...... 23 Conclusion and recommendations ...... 24 Acknowledgements ...... 24 References ...... 25 Appendix...... 28 Trifluoromethylation in batch (method A) ...... 28 Continuous-flow microfluidic setup ...... 29 Trifluoromethylation in continuous-flow (method B) ...... 29 Specific compound data – trifluoromethylation in batch ...... 30 Specific compound data – trifluoromethylation in flow ...... 35

Introduction In the last few decades, the incorporation of fluorine into chemical compounds has gained increasingly more attention in numerous branches of the industry, such as pharmaceutical, packaging, lubricant and agricultural industry. In the pharmaceutical industry, one or more fluorine atoms are incorporated into drug structures to tune the properties of the compounds, and to increase its lifetime. Furthermore, fluorinated compounds are used as isotope markers in Positron Emission Topography scans (fluorine-18 isotope, PET).[1] For the same reason, fluorination is used in material science to make materials with better properties. The introduction of fluorine in the proximity of functional groups can tune their properties.[2] This way it is possible to tune the hydrophobicity, hydrophilicity or lipophilicity of a material. Additionally, the incorporation of fluorine into materials makes them more durable and less likely to be excreted by metabolic breakdown. This effect is attributed to the relative high bond dissociation energy of the C-F bond. Because of the high durability and tunable properties imparted by the introduction of fluorine groups, fluorine chemistry is especially used heavily in the packaging material industry.[3] Furthermore, fluorinated compounds are sometimes used in lubricants, as the fluorine groups make the intermolecular Van der Waals interaction weaker.[4]Lastly agriculture uses a lot of fluorinated compounds as pest- and fungicides.[5] “Already today, around 25% of all pharmaceuticals and 30% of the applied agrochemicals contain at least one or more trifluoromethyl substituents, or a fluorine atom”.[6] This quote further highlights the increasing importance of fluorine chemistry in industry. But more importantly, the field of fluorine chemistry is still growing. In 2010 around 20% of all the approved drugs contained at least one or more fluorine or fluoroalkyl group and in recent years this number is steadily approaching the 30%.[7]

Properties of fluorine The reasons for this growing interest, as briefly stated, are the unique properties of fluorine groups. The atom is the most electronegative of all the elements, and has a relatively small Van der Waals radii (1.47 Å), which is in between that of a hydrogen and oxygen atom (1.2 Å and 1.52 Å, respectively).[8] The bond length of C–F is also much shorter than other C–X bonds (X = halogen) (see Table 1). On top of that, the bond dissociation energy of C–F bonds is incredibly high (110 Kcal/mol, Table 1). This causes an increase in the metabolic stability for fluorinated compounds. Additionally, fluorine has the lowest polarizability of all atoms (0.56 x 10-24 cm3). This causes very weak dispersion forces between fluorinated molecules. These weak dispersion force lead to a reduction in boiling point (higher volatility) as well as an increased hydrophobicity and lipophobicity.[4] Furthermore, fluorine groups can be used to tune the strength of adjacent functional groups via an inductive effect. Because of this ability to tune the properties of molecules, fluorination is often employed in biomolecules and drugs to change properties like; acidity, basicity, lipophilicity (which tunes the bioavailability), and protein binding affinity by affecting the adjacent functional groups.[2,8]

Table 1. Bond dissociation energies.(values taken from Ref. [8,10,11])

Bond C–H C–F C–Cl C–Br C–O C–CH3 C–CF3

Dissociation energy 117.9 109.9 83.7 70.3 92.0 90.2 102.6 (Kcal/mol)*

Bond length 1.09 1.35 1.79 1.97 1.43 1.53 1.34 (Å)[11]

*Calculated from values from Ref. [10]

There are several methods for the introduction of fluorine groups. One method is a chemical reaction where a single fluorine group is introduced. An alternative reaction is fluoroalkylation, where an alkyl chain with a number of fluorine groups is introduced. Trifluoromethylation in particular has received a lot of attention. This is due to the frequent appearance of trifluoromethyl group in medicinal chemistry.[9]

Previous studies in our group have been focused on the development of various trifluoromethylation protocols in batch and microflow. Which led to the development of the trifluoromethylation methodologies for heterocycles and thiols.[12,13] Building forth on this research, we sought to develop a mild and practical trifluoromethylation protocol for styrene derivatives. Styrenes are important and versatile building blocks that can easily be used in the construction of more complex molecules.[14] Furthermore styrenes are very popular in other fields such as polymer chemistry and medicinal chemistry. It is, therefore, relevant to investigate the direct functionalization of styrene with a trifluoromethyl group.

Several examples have demonstrated the construction of trilfluoromethylated styrenes in the last decade. Xiao and co-workers showed the oxidative trifluoromethylation of different styrene derivatives with S-(trifluoromethyl) diphenylsulfonium triflate. This yielded a trifluoromethylation at the beta position, simultaneously forming a keton on the alpha position (see Figure 1A).[15] While it proved to be an interesting reaction, the obtained yields were somewhat low (29-40%) and a large amount of both trifluoromethylating agent and reductor were essential. Szabó and co-workers investigated the cyanotrifluoromethylation using the Togni reagent I and tricyclohexylphosphine (see Figure 1B).[16] In comparison, yields were high (50-73%), however the styrenyl compounds required para or meta electron withdrawing substituents. Furthermore, the Togni reagent I used, is “explosive” and deuterated chloroform was used as a solvent. Yong-Min Liang and co-workers showed another cyanotrifluoromethylation, this time catalyzed with copper triflate.[17] They showed a large substrate scope with varying yields from 0 to 90%, and short reaction times 0.5 h. However the necessity to heat the reaction mixture to 60˚C is a slight drawback.

All previously discussed groups studied a trifluoromethylation method with simultaneous introduction of an additional functional group. However, rather than a difunctionalization, it is more interesting to investigate a methodology that is not restricted to the parallel introduction of a second functional group. These reactions have been demonstrated before by other groups. For example Ji-Chang Xiao and co-workers continued their research and developed a copper catalyzed electrophilic trifluoromethylation reaction on styrene with Togni reagent II.[18] While they were able to get high yields even on non-functionalized styrenes, they required high catalyst loadings (20 mol%), high amounts of trifluoromethylating agent and elevated temperature. While others did not investigate it extensively, in 2014 Feng-Ling Qing and co-workers conducted research on trifluoromethylation reactions where they were able to direct the selectivity to either the Z or E product by changing the catalyst and trifluoromethylating agent.[19] They were able to obtain high yields with both reactions (50- 78% for the Z product and 55-86% for the E product). It should be stated, however that all substrates used were styrenyl derivatives with an electron donating group (-NMe2).

Figure 1. Reactions from literature, A) Ji-Chang Xiao et al. (Ref. [15]), B) Kálmán J. Szabó et al. (Ref. [16]), C) Yong-Min Liang et al. (Ref. [17]), D) Ji-Chang Xiao et al. (Ref. [18]), E1) and E2) Feng-Ling Qing et al. (Ref. [19])

As is discussed above, trifluoromethylation of styrene derivatives has been the research topic of many groups in the past years. However, many if not all, suffered from one or more drawbacks. Firstly, example A (see figure 1), had low yields and needed to be cooled down to 0˚C. In example B, an expensive reagent (Togni reagent I) and deuterated chloroform as a solvent was required. The same reagent was used in example C, which additionally needed to be heated to 60˚C. And whereas example B and C required 1.5 equivalents of expensive Togni reagent I, example D required 2.5 equivalents of Togni reagent II and 20 mol% of catalyst. Examples E1 and E2 required the expensive Togni II and Umemoto reagent, respectively, high catalyst loadings and an electron donating group were additionally required. In short, previously discussed examples suffer from numerous problems, including low yields, expensive trifluoromethylating agents (Togni and Umemoto reagents) combined with high catalyst loadings (at least 2%) and the requirement of directing groups.

Trifluoromethylation with photoredox catalysis As discussed in the previous section, trifluoromethylation reactions were typically done with expensive reagents like Togni or Umemoto reagent (Table 2). In this thesis, the trifluoromethylation of styrene has been investigated with an inexpensive CF3-source, specifically trifluoroiodomethane (CF3I). As illustrated in the table below, CF3I is an inexpensive source for CF3 radicals. Moreover, it is an experimental alternative for halon 1301 which is used as a fire extinguishing agent, so it is available as a bulk chemical.1

Table 2. Trifluoromethylating agents, all prices are taken from Sigma Aldrich (04-04-2016).

Bond Dissociation Price Compound Structure E (eV) 1/2 Energy (Kcal/mol)a (€/mol)

[20] Langois reagent 1.05 24.1 1428

[21] Trifluoroiodomethane -1.22 28.0 1648

Baran reagent ~1.05b 24.1 1883

Ruppert’s reagent 1.9 44c 2450

Triflyl chloride -0.18[21] 4.1 1711

Togni reagent I -1.10 – -0.94[22] 25.3 – 21.6 15709

Togni reagent II -1.82 – -1.09[22] 41.8 – 25.0 47313

Umemoto reagent -0.25[23] 5.7 17542

a calculated from the redox voltage (BDE = eV x 0.239/1.04x10-2), b estimation based on the similarity to Langois reagent, c estimated from the BDE of Si-CF3 (values taken from Ref. [10])

8 1 https://en.wikipedia.org/wiki/Trifluoroiodomethane As shown in Table 2 the oxidation potential for CF3I is relatively high (E1/2 = -1.22 eV vs SCE in DMF). In order for a CF3 radical fragment to be created, a strong reductant is required. This can be done with traditional metal catalysis. However for these kinds of activations typically more harsh conditions like high temperature and elevated pressures are required. Alternatively, the formation of CF3 radicals can be done by single electron reduction of CF3I by a photoredox catalyst, e.g. fac-Ir(ppy)3 (ppy = 2- phenylpyridine). A photo-active catalyst absorbs light, which can excite an electron from the metal center. Subsequently a single electron transfer (SET) can occur where iridium acts as an reductant through donation of this electron or as an oxidant by accepting an electron in its half empty orbital (See Figure 2 below).

Figure 2. Photoredox pathways of fac-Ir(ppy)3 (adjusted from Ref. [24]).

Common photoredox catalysts are described in the Table 3. The reason for using visible light instead of UV, is that UV can be absorbed by organic molecules directly giving the opportunity for side reactions, while visible light is generally only absorbed by the photoredox catalyst.[26]

Table 3. Common photoredox catalysts and their redox potentials.

Photoredox Excited state: Eox Excited state: Ered Reduced state: Ered Oxidized state: Eox Catalyst (*Mn/Mn+1) (eV) (*Mn/Mn-1) (eV) (Mn/Mn-1) (eV) (Mn/Mn+1) (eV)

[21] fac-Ir(ppy)3 -1.73 +0.31 -2.17 0.77

[21] Ir(ppy)2(dtbbpy) -0.96 +0.66 -1.51 1.21

2+[21] Ru(bpy)3 -0.81 +0.77 -1.33 1.29

Methylene blue - +0.02 -1.35 -

Trifluoroiodomethane as CF3-source

In order to reduce CF3I, the oxidation potential needs to be low enough so that the Gibbs free energy change of the reaction is negative. This Gibbs free energy change can be calculated with the following formula:

∆� = −� ∗ � ∗ ∆� (1)[25]

Where n is the number of electrons transferred, F is the Faraday constant and ΔE is the change in redox potential. In order for the reaction to proceed, the Gibbs free energy change should be negative. As both n and F are positive, to get a negative ΔG the ΔE needs to be positive. ΔE is calculated by subtracting the energy of the oxidation half reaction from the energy of the reduction half reaction as can be seen in equation 2:

[25] ∆� = �� − �� (2)

As discussed before, the ΔE should be positive for the reaction to progress. In order for CF3I to be reduced, the reductor should have a reduction potential (Eox) lower than the reduction potential (Ered) of

CF3I (-1.22V). Table 3 shows that fac-Ir(ppy)3 is the only suitable catalyst, as fac-Ir(ppy)3 exhibits a high reduction potential in its excited state (-1.73 eV). As stated in the previous section, the usage of a photoredox catalyst rather than the traditional metallic catalysts has the large advantage that light can be used as a cheap energy source. Since visible light is the driving force behind the reaction now, mild reaction conditions (room temperature and atmospheric pressure) can be applied. However, the usage of light as a reagent has the disadvantage that the reaction becomes dependent on the penetration depth of light. The absorption of light in a medium can be described with the Bouguer–Lambert–Beer equation:

�0 � = �� = �� = � ∗ � ∗ � (3)[26] 10 10 �

This equation shows that the absorbance is dependent on the molar extinction coefficient (ε), the concentration of the absorbing species (c) and the path length (l). Equation 3 shows that the longer the path length is, the higher the absorbance and the lower the light intensity (I) is. Thus the further the light has to travel in a medium, the less light is left to excite the photocatalyst.

In a lab scale reactor this is not such a severe limitation, as path length are generally small. However for industrial scale reactors this becomes an enormous problem. As such for photo-catalysed reactions it is incredibly important to have a reactor with a high surface to volume ratio as to minimize the path length. While this rules out traditional batch (>1 m) and macro and meso-scale continuous flow reactors (>0.1 m), the newer microflow reactors (< 1 mm) are an ideal solution.

Microflow technology Microflow reactors thank their name to the micrometer dimensions of the reactor tubes. Because of these small dimensions a number of advantages are created. Firstly as discussed in the previous section, because of the small diameter the length that light travels in the reactor is minimized. This causes the absorption (A) to be very small and thus causes the light intensity (I) to be approximately the same at the ingoing wall of the reactor as at the outgoing wall. This causes the irradiation to be homogenous over the whole reactor. This is different from a batch reactor, where the light intensity at the center of the reactor already dropped significantly. Due to this enhancement, reaction times are shortened significantly and lower amounts of photocatalysts are required.[26] Secondly because of the small diameter of the reactor, the axial diffusion lengths are very small. This enhances the mass transport and thus makes it easier for relevant molecules to encounter each other.[26] The improved mass transport often leads to intensification of the reaction, which enables the use of shorter reaction times. Thirdly, the small diffusion length makes the heat transport inside the reactor easier. Additionally, the high surface to volume ratio of microreactors makes it easier to transfer the heat energy to the cooling medium.[26] This enhanced heat transfer makes that – with exclusion of highly exothermic reactions – most reactions can simply be carried out inside a microchannel without active cooling. The advantage of better cooling leads to the fourth advantage, the increased safety of micro reactors. As microreactors can handle the reaction energy better, there is less chance of appearance of hot spots. Additionally, because of the small volume, the quantity of (hazardous) chemicals constantly present in the system is low.[26] This increases the safety in the event of an accident as the amount of chemicals released would be far lower than in the case of a batch reactor.

While the usage of microreactor technology has a number of advantages, there is however a drawback in using a microflow reactor in comparison to a batch reactor. A common drawback with microflow reactors, as compared to batch reactors, is related to solid particles that can clog the microchannels. While in batch heterogeneous catalysis is not unusual, in microflow this is not frequently used especially with photoredox catalysis, as the particles can also cause light scattering. This means that it is of great importance that the reaction mixture is homogenous for microflow reactors. This does not mean however, that microflow is unsuited for multiphase systems. Rather, a gas-liquid reaction is much easier to control in microflow than in batch. Additionally, using a gas-liquid system in microflow brings the advantage of an even better mixing. At certain flow rates, a gas-liquid system can give rise to Taylor flow (see Figure 3)

Figure 3. The sketch of the mass transfer process in a Taylor flow regime in microchannels (taken from Ref. [27]).

In this flow pattern, because of the pressure in the capillary alternating liquid/gas segments are formed. This gives a rather large surface area between the gas and the liquid, as the gas bubbles are surrounded by a layer of liquid. This forms a very thin film where there is a huge interfacial area and a high photon flux. In theory this thin film is the place where the reaction is the most intensified.[26] Additionally, the gas slugs move slightly faster than the liquid slugs, giving rise to a circularly stream inside the liquid slugs, which enhances the mixing.

Proposed mechanism and project outline A detailed proposed mechanism is shown in Figure 4. It was mentioned above that commercially III available photoredox catalyst fac-Ir(ppy)3 (Ir ) will readily absorb visible light photons to yield a strongly III 3+ 4+ III reducing Iridium-complex (*Ir , Eox (*Ir /Ir ) = -1.73 eV). This excited state complex (*Ir ) will undergo IV single electron oxidation with CF3I to form a CF3-radical (•CF3) and Ir . The CF3-radical will undergo electrophilic-radical addition on the beta-position on styrene, which forms radical intermediate A. Once generated, oxidation of benzylic radical A to carbo-cationic intermediate B, by the oxidizing IrIV complex, highlights a crucial step in this transformation. Intermediate B can resolve in unwanted side-products as depicted in Figure 4, e.g. homo-dimerization or oxidation (D and E, respectively). Carbo-cation B is further deprotonated to yield the desired trifluoromethylated product 1-A.

Figure 4. Proposed trifluoromethylation mechanism and possible side reactions

The main goal of this thesis was to investigate the trifluoromethylation of styrene derivatives with trifluoroiodomethane and photoredox catalysis. However, prior to the investigation we anticipated a number of complications. Firstly, as discussed in the section “Properties of Fluorine”, the introduction of fluorine groups makes molecules more volatile. This could complicate the isolation of the products. Secondly, styrene is a very popular monomer in the polymer industry because it readily forms polymers when initiated by a radical. As a radical mechanism is theorized for the trifluoromethylation reaction, it is anticipated that an unwanted polymerization can occur. Lastly, the trifluoromethylating agent trifluoroiodomethane (CF3I) is a gas. Though it readily dissolved in some organic solvents, knowing the exact amount of CF3I added to the reaction mixture poses a limitation, which is especially the case in batch. This problem is elucidated by applying microflow technology, as the gas cannot diffuse out of the solvent in the enclosed reactor environment.

Results & discussion

Preliminary research As discussed in the introduction section “Trifluoromethylation with photoredox catalysis”, for the trifluoromethylation of styrene fac-Ir(ppy)3 was used as a catalyst. Preliminary optimization was performed prior to this works investigation. An overview of this data is presented in Table 4

Table 4. Optimization Studies for the photocatalytic trifluoromethylation of styrenea.

Entry Base/Solvent Yieldb (E/Z)b 1 DBU / DMF Trace -

2 K2CO3 / DMF 3%, (35% after 72 h) -

3 Cs2CO3 / DMF 5%, (57% after 72 h) - 4 CsOAc / DMF 89%, (75%)c 74:26 Change from best Entry Yieldb (E/Z)b conditions (entry 4) 5 No light 0% - 6 No photocatalyst 0% - 7 No base Trace - a Reaction conditions: Ir(ppy)3 (1 mol%), styrene (0.5 mmol), base (1.5 mmol), solvent (5 mL, 0.1 M), visible light (2 x 24 W CFL), room temperature, stirred for 18 hours. b Yield and E/Z values determined with 19F-NMR with α,α,α-trifluorotoluene as internal standard. c Volatile compounds results in lower isolated yield. Abbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMF = N,N-dimethylformamide.

As is shown in Table 4 cesium acetate (CsOAc) in N,N-dimethyl formamide (DMF) had the best selectivity and yield (entry 4). The reason for this was probably that the acetate group can stabilize the positive charge that is formed on the alpha styrene position (after the second SET, see Figure 4). This stabilization extends the intermediate lifetime, making the proton removal and subsequent reformation of the double bond easier. The same reasoning applies to the solvent, as DMF can also stabilize the positive charge. With this solvent and base combination and the previously mentioned conditions, the benchmark reaction was formulated as stated in Table 4 (entry 4) as the optimal conditions.

Trifluoromethylation in batch The scope of this reaction was investigated, using the optimal conditions, the following result were obtained for different stryrenyl substrates, bearing various functional groups (entries 2 and 3), extended aromatic and heteroaromatic systems (entries 4-7) and beta-substitutions (entries 8-10) (Figure 5)

Figure 5. Batch results: (i) Reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CF3I (1.2 mmol), CsOAc (3 mmol), DMF (10 mL, 0.1 M), visible light (2 x 24 W CFL), room temperature. (ii) Conversion verified with GC-MS every 24 h. (iii) Reported yields are isolated unless stated otherwise. (iv) The E/Z ratio was determined with 19F-NMR. *reaction performed by supervisor, added for completion, **GC Yield.

As depicted in Figure 5, A-2 had almost the same yield and a slightly lower selectivity than A-1. A-3 also achieved a reasonable yield, however there was almost no selectivity as E and Z product were produced in almost equal amounts (48:52 E/Z). So while the halogen substituents are not detrimental to the yield, they do lower the selectivity. A-4 showed high selectivity better than A-1, yet its yield was slightly lower (50% yield, after 48 hours reaction time). The low yield was due to the naphthalene group, which probably was electron rich enough to promote dimerization. The pyridines A-5 till A-7 had low yield and long reaction times (72-96 hours reaction time). These two drawbacks are related as the reaction mixture darkens significantly within 24 hours. This darkening caused light penetration to be less efficient and probably caused side reactions to become more dominant. For the beta-substituted styrene derivatives, both A-9 and A-10 showed reasonable yield and high selectivity (72:28 and 82:18 E/Z, respectively). On the contrary beta methyl styrene (A-8) showed a low yield (30%) and selectivity (69:31 E/Z). The high selectivity for A-9 and A-10 was most likely due to the bulky substituents (ester and acetate group). This also explains why A-8 with the relatively small methyl substituent had a lower selectivity.

Trifluoromethylation in microflow To compare the batch results with the microflow results, all conditions would ideally be the same. However cesium acetate does not dissolve well in DMF. While this did not pose a problem for batch reactions, in flow this can cause various problems such as clogging and/or light scattering. Since the addition of methanol gave lower yields in batch, it was decided to add 10% methanol in the microflow experiments as the necessity of a homogenous reaction mixture system is a limitation of microflow.

Another difference is the direct use of CF3I gas. For batch experiments a stock solution of CF3I gas in DMF was used. However for microflow multiple advantages can be obtained by utilizing a gas-liquid system (see section “Microflow Technology”). Thus during the continuous-flow experiments the reaction mixture was mixed with the CF3I gas in a static mixer, before being illuminated (see Figure 6).

Figure 6. Schematic representation of the microflow setup (taken from ref. [28]).

In Figure 6 a schematic representation of the microflow setup is shown. In the top part the reaction mixture in injected into the setup by means of a syringe pump. The CF3I gas flow is controlled by a mass flow controller and is later mixed with the reaction mixture with the static mixer (Tee-mixing Union piece). The mixed reaction mixture is pumped through the coiled microreactor which is irradiated by 2 blue LED strips. With this setup, two different flowrate can be changed to influence the residence time. As the desired residence time was 10 min, the total flowrate should be 0.125 mL/min. However, because the gas can be easily compressed, the total flowrate is mostly dominated by the liquid flowrate. Since, the gas flowrate has a large impact on the reaction, optimization studies for the gas flowrate were performed.

Styrene Conversion 100 90 80 70 Gas flow rate 60 0.36 mL/min 50 0.72 mL/min 40 1.44 mL/min

Conversion (%) Conversion 30 20 2.88 mL/min 10 0 0 10 20 30 40 50 60 Time (min)

Figure 7. Conversion of the trifluoromethylation of styrene in microflow with different CF3I gas flow rates. (i) Reaction conditions: fac-Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), DMF/MeOH (9 mL/1 mL, 0.1 M), visible light (3.12 W blue LED strip), room temperature, liquid flowrate adjusted to obtain a tR = 10 min(ii) conversions determined by GC-MS analysis.

Styrene Yield 100 90 80 70 Gas flow rate

60 0.36 mL/min 50 0.72 mL/min

Yield (%) Yield 40 1.44 mL/min 30 20 2.88 mL/min 10 0 0 10 20 30 40 50 60 residence time (min)

Figure 8. Yield of trifluoromethylation of styrene in microflow with different CF3I gas flow rates. (i) Reaction conditions: fac- Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), DMF/MeOH (9 mL/1 mL, 0.1 M), visible light (3.12 W blue LED strip), 19 room temperature, liquid flowrate adjusted to obtain a tR = 10 min (ii) conversions determined by F-NMR analysis with phenyl trifluoromethyl sulfide as internal standard added to reaction mixture.

As illustrated in the graphs above, while the conversion increased with increased gas flow (see Figure 7), the yield dropped significantly when the flowrate was changed from 1.44 to 2.88 mL/min (see Figure 8).

The reason for this was that more CF3I gas promoted the conversion of the styrene (shown in Figure 7). However when the amount of gas was too high (2.88 mL/min), the yield curve started to level off (Figure 8, red square line). This happened because a large excess of gas could promote unwanted side reactions. Thus resulting in a higher conversion yet a lower yield (shown in Figure 8). In this case, the point where the yield starts to drop was 2.88 mL/min flow rate. However, at which value precisely the yield started to decrease has not been investigated. It is possible that the obtained yields could be a little higher if the flow rate was increased more than 1.44 mL/min. However, as the increase was not expected to be large and to not make the CF3I gas consumption higher than necessary, 1.44 mL/min was chosen as the optimal flowrate and used for all following microflow experiments.

Trifluoromethylation in flow reaction scope

Figure 9. Continuous-flow results: (i) Reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 mL/min), DMF/MeOH (9 mL/1 mL, 0.1 M), visible light (3.12 W blue LED strip), room temperature. (ii) Conversion verified with GC-MS every 24 h. (iii) Reported yields are isolated unless stated otherwise. (iv) The E/Z ratio was determined with 19F- NMR. *reaction performed by supervisor, added for completion, **GC Yield because large amount of side product purification proved too challenging.

As can be seen in Figure 9 above, all reaction times were greatly reduced compared to the batch experiments (from days to minutes). Yields were also increased in most cases. This was most notable for the pyridine derivatives (B-5, B-6 and B-7, 46%, 50% and 60%, respectively). The reason for this was most likely that the darkening of the reaction mixture does not have a significant effect in microflow. The yield for B-9 and B-10 was low (29% and 30%, respectively). For B-9 this was due to unselective addition of the trifluoromethyl radical, as the methyl group can promote radical addition on the aromatic ring. For B-10 the reason was the addition of methanol to the reaction mixture. The methanol can cause a transesterification reaction with the acetate group, decreasing the yield of the desired product.

Comparison of batch vs. flow

Table 5. Comparison of batch and flow results.

Batch Flow E/Z E/Z Entry Compound Yield Yield selectivity Selectivity

1 75%a 72:281 95%1 96:4a

2 73% 68:32 69% 83:17

3 62% 48:52 81%a 95:5a

4 50% 87:13 50% 95:5

5 44%b - 46% 92:8

6 32% 71:29 50% 87:13

7 38% 85:15 60% 93:7

8 30% 69:31 47% 85:15

9 57% 82:18 29% 83:17

10 49% 72:28 30% 81:19 a reaction performed by supervisor, b GC yield

As can be clearly seen in Table 5, there is an outstanding increase in the E/Z-selectivity for all the reactions carried out in a microflow reactor. While some compounds are more affected than others, the preference to form either Z or E product is in every case increased. The yield however is very substrate dependent. For some substrates the yields are increased (such as the pyridine compounds, entry 5-7). Other substrates reach about the same yield (2,6-dichlorostyrene and 2-vinylnaphtalene, entry 2 and 4, respectively). While for other substrates yield decreases when going to microflow (cinnamyl ester and acetate, entry 9 and 10, respectively). As was discussed before in the “Microflow” results section the increase for the pyridine substrates is explained by a better light penetration. The unexpected decrease of the cinnamyl ester (entry 9) might be due to trifluoromethylation on the phenyl ring. While the decrease of the cinnamyl acetate (entry 10) is explained by their incompatibility with methanol in the reaction.

To illustrate the robusticity of the trifluoromethylation protocol a series of control experiments, with additives such as water and oxygen, have been performed (Table 6).

Entry Changes from benchmark Yield1 1 No addition (normal reaction) 75%

2 Water addition2 76%

3 Oxygen addition3 56%

4 No purge4 73%

Table 6. Robusticity experiments performed with batch reaction conditions: Ir(ppy)3 (1 mol%), styrene (0.5 mmol), CF3I (0.6 mmol), CsOAc (1.5 mmol), DMF (5 mL, 0.1 M), visible light (2 x 24 W CFL), room temperature. 1) Entry 1 is an isolated yield, yields of entry 2-4 are determined by GC MS, 2) 14 mg (0.78 mmol) demi-water added, 3) oxygen was bubble through solution with a balloon of oxygen connected to a needle, 4) the purging of the tube before addition of solvent was skipped.

The reactions that were done with the addition of 14 miligrams of water and without purging still showed comparable yield with that of the normal reaction conditions (75% isolated yield). Based on these results it was assumed that both the presence of moisture or air is of no consequence for the reaction. The reaction where oxygen was added however, showed a significant decrease in yield. Yet when no purge was preformed (so oxygen was still present in the system), the yield was roughly the same as the normal reaction (entry 4 and 1 respectively). So the drop in yield was most likely not caused by the oxygen itself, but by the addition method used. The oxygen was added by bubbling it slowly through the reaction mixture, which was done after the addition of CF3I. Most likely the bubbling of the oxygen removed a part of the dissolved CF3I from the solution, thus resulting in the lower yield.

Unanticipated results The scope showed previously did not encompass all substrates tested. Several examples did not give the desired product and were left out of the main scope. These compounds will be discussed in this section.

Figure 10. List of reactions that did not yield the desired product.

Firstly, the reaction of 1-vinylnaphtalene (Figure 10A) was investigated. The reaction gave a complex mixture and the conversion was low (~10%) after a long reaction time (48 hours). It was intriguing though that 2-vinylnaphtalene gave the desired product, whereas 1-vinylnaphtalene gave a complex mixture. This means that the inductive effect of the naphthalene ring had a large influence on the reaction. Furthermore, in substrate scopes in literature 1-vinylnaphtalene is also omitted. This in addition to the slow reaction caused the decision to stop further investigation of this substrate.[19]

The second reaction had a high conversion in a short reaction time (<24h). However when analyzed, the product that was formed proved to be the decarboxylated product (see Figure 10B). This was not unexpected as such a reaction has been reported before in literature.[29] While this reaction gave high conversion, as the mechanism is different from the one described in this thesis, further investigation was not performed.

Reaction C similarly reached a high conversion in short reaction time (~24 h). However, while some desired product was formed, the trifluoromethylated cinnamyl acetate (see Figure 10C) formation predominated. As chloride could function as a leaving group, the CsOAc was able to react with the cinnamyl chloride to form cinnamyl acetate. This reaction was faster than the trifluoromethylation of the cinnamyl chloride, so little desired product was formed. In an attempt to obtain the desired product, reactions were performed with cesium hydrocarbonate (CsHCO3) and cesium carbonate (Cs2CO3). However, these tests showed very little conversion.

Lastly, the reaction of 1,2-hydronaphtalene was performed (Figure 10D). While conversion was high in a short time reaction time (<24 h), analysis showed that the regioselectivity was low.

Conclusion and recommendations

The trifluoromethylation of styrenes with CF3I and photoredox catalysis was succesfull. This investigation demonstrates that the reaction is tolerant to a variety of different styrenyl substrates with different functional groups (including halogens, esters, and hetero atom containing structures). The reaction was also carried out in microflow; while the reaction in microflow and batch exhibited roughly the same yield (30% to 73% yield), the E/Z selectivity of the reaction was significantly improved in microflow. Moreover, the reaction in microflow is intensified leading to much shorter reaction times than in batch (from days to minutes). These results show that the developed protocol is a practical alternative to previous reports. Furthermore, experiments demonstrated the robusticity of the reaction, which showed that an inert atmosphere was not essential.

In this thesis, a method for the trifluoromethylation of exclusively styrenes has been found and investigated. Therefore, we wish to expand the trifluoromethylation methodology to other substrate classes, such as alkene chains and other unsaturated aliphatic chains, as it was demonstrated that the trifluoromethylation of unsaturated bonds is a promising strategy. Furthermore it is interesting to know, if the trifluoromethylation methodology can be further expanded to a more general alkylation methodology.

Acknowledgements I would sincerely like to thank daily supervisor Natan J.W. Straathof, my project supervisor dr. Timothy Noël and my graduation prof. dr. Volker Hessel for giving me the opportunity to work on this research in the SCR-SFP group. Furthermore, I would like to thank everybody of the SFP group for the great time I had both in and outside the lab.

References [1] O. Jacobson, D.O. Kiesewetter, and X. Chen, “Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes”, Bioconjugate Chem. 2015, 26, 1-18

[2] H. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Müller, U. Obst-Sander and M. Stahl, “Fluorine in Medicinal Chemistry”, ChemBioChem 2004, 5, 637-643

[3] B.E. Smart, J.C. Tatlow, “Organofluorine Chemistry: Principles and Commercial Applications”, Springer Science & Business Media 1994

[4] D.M. Lemal, “Perspective on Fluorocarbon Chemistry”, J. Org. Chem. 2004, 69, 1-11

[5] P. Jeschke, “The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop Protection”, ChemBioChem 2004, 5, 570-589

[6] K. Natte, R.V. Jagadeesh, L. He, J. Rabeah, J. Chen, C. Taeschler, S. Ellinger, F. Zaragoza, H. Neumann, A. Brückner, and M. Beller, “Palladium-Catalyzed Trifluoromethylation of (Hetero)Arenes with CF3Br”, Angew. Chem. Int. Ed. 2016, 55, 1-6

[7] Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Acena, V.A. Soloshonok, K. Izawa and H. Liu, “Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas”, Chem. Rev. 2016, 116 (2), 422–518

[8] D. O’Hagan, “Understanding organofluorine chemistry. An introduction to the C–F bond”, Chem. Soc. Rev. 2008, 37, 308–319

[9] G.K. Surya Prakash and F. Wang, ”Fluorine: the new kingpin of drug discovery”, Chimica Oggi, 2012, 30-35

[10] Yu-Ran Luo, “Handbook of Bond Dissociation Energies in Organic Compounds”, CRC Press 2002

[11] F.H. Allen, O. Kennard, and D.G. Watson, L. Brammer and A.G. Orpen, R. Taylor, ” Tables of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond lengths in organic compounds”, J. Chem. Soc. Perkin Trans. 1987, 11

[12] N.J.W. Straathof, B.J.P. Tegelbeckers, V. Hessel, X. Wang and T. Noël, ”A mild and fast photocatalytic trifluoromethylation of thiols in batch and continuous-flow”, Chem. Sci. 2014, 5, 4768–4773

[13] N.J.W. Straathof, H.P.L. Gemoets, X. Wang, J.C. Schouten, V. Hessel and T. Noël, “Rapid Trifluoromethylation and perfluoroalkylation of Five-Membered Heterocycles by Photoredox Catalysis in Continuous flow”, ChemSusChem, 2014, 7 (6), 1612-1617

[14] A.S. Kalgutkar, D. Dalvie, R.S. Obach, D.A. Smith, “Reactive Drug Metabolites”, John Wiley & Sons 2012

[15] C. Zhang, Z. Wang, Q. Chen, C. Zhang, Y. Gu and J. Xiao, ”Generation of the CF3 radical from trifluoromethylsulfonium triflate and its trifluoromethylation of styrenes”, Chem. Commun. 2011,47, 6632-6634

[16] N.O. Ilchenko, P.G. Janson and K.J. Szabó, “Copper-Mediated Cyanotrifluoromethylation of Styrenes Using the Togni Reagent”, J. Org. Chem. 2013, 78, 11087-11091

[17] Y. He, L. Li, Y. Yang, Z. Zhou, H. Hua, X. Liu and Y. Liang, “Copper-Catalyzed Intermolecular Cyanotrifluoromethylation of Alkenes”, Org. Lett. 2014, 16, 270-273

[18] X. Wang, J. Lin, C. Zhang, J. Xiao and X. Zheng, “Copper-catalyzed trifluoromethylation of alkenes with an electrophilic trifluoromethylating reagent”, Beilstein J. Org. Chem. 2013, 9, 2635-2640.

[19] Q. Lin, X. Xu and F. Qing, “Chemo‑, Regio‑, and Stereoselective Trifluoromethylation of Styrenes via Visible Light-Driven Single-Electron Transfer (SET) and Triplet−Triplet Energy Transfer (TTET) Processes”, J. Org. Chem. 2014, 79, 10434-10446

[20] D.J. Wilger, N.J. Gesmundo and D.A. Nicewicz, “Catalytic hydrotrifluoromethylation of styrenes and unactivated aliphatic alkenes via an organic photoredox system”, Chem. Sci., 2013, 4, 3160- 3165

[21] C.K. Prier, D.A. Rankic and D.W.C. MacMillan, “Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis”, Chem. Rev. 2013, 113, 5322-5363

[22] J. Charpentier, N. Fruh and A. Togni, “Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents”, Chem. Rev. 2015, 115, 650-682

[23] C. Zhang, “Recent advances in trifluoromethylation of organic compounds using Umemoto’s reagents”, Org. Biomol. Chem. 2014, 12, 6580-6589

[24] C.K. Prier, D.A. Rankic and D.W.C. MacMillan, “Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis”, Chem. Rev. 2013, 113, 5322-5363

[25] J. Ho, M.L. Coote, C.J. Cramer, D.G. Truhlar, “Organic Electrochemistry, Fifth Edition “, CRC Press 2015, Ch.6

[26] Y. Su, N.J.W. Straathof, V. Hessel and Timothy Noël, “Photochemical Transformations Accelerated in Continuous-Flow Reactors: Basic Concepts and Applications”, Chem. Eur. J. 2014, 20, 10562- 10589

[27] H.P.L. Gemoets, Y. Su, M. Shang, V. Hessel, R. Luque, T. Noël, “Liquid Phase Oxidation Chemistry in Continuous-Flow Microreactors”, Chem. Soc. Rev. 2016, 45, 83-117.

[28] N.J.W. Straathof, S.E. Cramer, V. Hessel and T. Noël, “Practical Photocatalytic Trifluoromethylation and Hydrotrifluoromethylation of Styrenes in Batch and Flow”, 2016, submitted

[29] P. Xu, A. Abdukader, K. Hu, Y. Chenga and C. Zhu, “Room temperature decarboxylative trifluoromethylation of α,β-unsaturated carboxylic acids by photoredox catalysis”, Chem. Commun. 2014, 50, 2308-2310

Appendix

Trifluoromethylation in batch (method A)

In an oven-dried reaction tube (7.5 mL) was prepared with fac-Ir(ppy)3 (3.3 mg, 1 mol%), CsOAc (287 mg, 1.5 mmol, 3 equiv.) and a magnetic stirring bar, sealed with a rubber septum and subsequently degassed by purged with argon using standard

Schlenk-techniques. To the reaction tube, 5 mL of stock solution of CF3I in DMF (C =0.12 M)was added. Finally, 0.5 mmol of the vinylic compound (1 equiv., C =0.1 M) was added to the mixture. The addition of the vinylic substrate was done with a microsyringe on a balance. The reaction mixture was then stirred and irradiated with a fluorescent light source (2 x 24 W, approx. 5 cm away from the sources, temperature was kept around 23±1 °C by cooling with an air current) until completion upon judgement GC analysis (24 – 72 hours). Reaction workup was done by first diluting the reaction mixture with equal amounts of

Et2O, followed by extraction with 1 M HCl, aqueous saturated NaHCO3 and finally Brine. The combined aqueous layers were extracted once with Et2O. The organic layers were combined and dried over MgSO4 and concentrated in vacuo. The residue was then purified by column chromatography with silica gel and solvent system as indicated below, to afford the desired product.

The CF3I in DMF stock solution was made by filling a purged reaction tube sealed with a rubber septum with 20 mL of DMF, and bubbeling CF3I gas directly into the solution. The weight increase was used to calculate the concentration of CF3I in solution, and the stock solution was wrapped in aluminium foil and stored in the freezer (-26˚C).

Continuous-flow microfluidic setup The continuous microflow setup was constructed according to a previous reported Figure.. in the “Microflow” section of the Results & Discussion. A quick-connect Luer adapters (IDEX Health & Science, part no. P-658) was used to connect the syringes to the microfluidic tubing. The syringes were loaded onto a Syringe pump (Fusion 200). The Mass Flow Controller (MFC) was connected to the pressure regulator accordingly, which was then fitted with a Stainless-Steel adapter to which can be connected to the microfluidic PFA tubing (SS adapter, Valco Instruments Company, part no. CTA2S6). The micro-reactor assembly was constructed of high purity PFA tubing (IDEX health and science, part no. 1622L) (L = 2.5 meter, ID = 0.5 mm, V = 1.25 mL), in combination with an array of Blue LED (3.12 W), as portrayed below. All three components (syringe-pump, MFC and the microreactor) were interconnected with microfluidic PFA tubing to a Tee-piece (IDEX Health & Science, part no. P-714). The outlet of the micro-reactor was fitted with PFA tubing (IDEX health and science, part no. 1622L) which led to the collection vial where the reaction mixture was collected during operation.

Trifluoromethylation in continuous-flow (method B)

A oven-dried reaction tube was filled with 6.5 mg fac-Ir(ppy)3 (1 mol%) and 575 mg CsOAc (3 mmol, 3 equiv.). The reaction tube was subsequently degassed by purged with argon using standard Schlenk-techniques. To the reaction tube 1 mL of methanol, 9 mL of DMF and the vinylic compound (0.5 mmol, 1 equiv., C = 0.1 M) was added. The latter was added with a microsyringe on a balance. The reaction mixture was then transferred into a disposable syringe (10 mL) and loaded into the syringe pump. The CF3I supply was enabled; by setting the pressure gauge at 30 psi, and the MFC (1.44 mL min-1, normalized amount per minute). The reaction mixture was pumped through the microreactor assembly with the desired flowrate (85 L min-1) provided by the syringe pump. These flowrates gave a residence time of 10 min(timed). The microreactor assembly was irradiated with a Blue LED array (2 x 3.12 Watts), with an accommodation temperature of 23±1 °C.

The continuous reaction was allowed to reach steady state prior to collection of the product fractions. A standard residence time of 10 minutes was utilized each reaction iteration. When more residence time (reaction time) was required; the collected sample was run again through the microreactor. Optionally, the residence time could be increased by lowering the flow rates (see Table S7) or by increasing the length and volume of the microreactor PFA tubbing. The crude product was collected at the end of the reactor assembly and directly analysed with GC and 19F-NMR analysis. Workup and purification were done following the batch procedure (vide infra).

Specific compound data – trifluoromethylation in batch

(E)-1,3-dichloro-2-(3,3,3-trifluoroprop-1-enyl)benzene (E-A-2) & (Z)-1,3-dichloro-2- (3,3,3-trifluoroprop-1-enyl)benzene (Z-A-2). Compound A-2 was prepared according to the described general procedure A, with 2,6-dichloro-styrene as starting material (1.0 mmol scale). The reaction was run for 24-48 hours. Column chromatography (100% petroleum ether) afforded a mixture of E/Z products as a colourless liquid (172 mg, 73% yield, 68 : 32 E/Z)

+ TLC: Rf = 0.85 (100% petroleum ether). GC-MS: (m/z) 239.2 [M ]. IR: (neat) max 609, 688, 721, 735, 775, 797, 839, 885, 966, -1 1120, 1184, 1273, 1311, 1431, 1558 cm .

1 (E-product) [major] H-NMR (399 MHz, CDCl3): δ 7.22 (dd, J = 13.5, 8.0 Hz, 2H), 7.13 (dq, J = 16.3, 2.4 Hz, 1H), 7.10 – 7.05 (m, 13 1H), 6.29 (dq, J = 16.3, 6.3 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 134.90, 131.59 (q, J = 7.5 Hz), 131.01, 128.92, 127.79, 124.64 (q, 19 J = 33.9 Hz), 123.03 (q, J = 269.9 Hz). F-NMR (377 MHz, CDCl3): δ -53.14 (d, J = 5.6 Hz).

1 (Z-product) [minor] H-NMR (399 MHz, CDCl3): δ 7.22 (dd, J = 13.5, 7.9 Hz, 1H), 7.11 – 7.04 (m, 2H), 6.65 (d, J = 11.9 Hz, 1H), 13 5.92 (dq, J = 12.1, 7.9 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 135.43, 133.09 (q, J = 5.5 Hz), 132.69, 130.10, 129.77, 122.78 (q, J = 19 33.8 Hz), 122.31 (q, J = 271.6 Hz). F-NMR (377 MHz, CDCl3): δ -51.18 (d, J = 7.6 Hz).

(E)-1-bromo-3-(3,3,3-trifluoroprop-1-enyl)benzene (E-A-3) & (Z)-1-bromo-3- (3,3,3-trifluoroprop-1-enyl)benzene (Z-A-3). Compound A-3 was prepared according to the described Method A, with 3-bromo-styrene as starting material (1.0 mmol scale). The reaction was run for 48-72 hours. Column chromatography (100% petroleum ether) afforded a mixture of E/Z products as a colourless liquid (181 mg, 62% yield, 97 : 3 E/Z).

+ TLC: Rf = 0.7 (100% hexane). GC-MS: (m/z) 251.1 [M ]. IR: (neat): max 577, 663, 683, 777, 792, 893, 968, 1072, 1113, 1178, 1223, 1273, 1311, 1668 cm-1.

1 (Z-product) [major] H-NMR (399 MHz, CDCl3): δ. 7.56 – 7.15 (m, 4H), 6.81 (d, J = 12.6 Hz, 1H), 5.77 (dq, J = 12.6, 8.9 Hz, 1H). 13 C-NMR (100 MHz, CDCl3): δ 138.14 (q, J = 6.0 Hz), 135.79, 133.01, 131.83 (q, J = 2.4 Hz), 130.53, 130.44, 123.17, 122.67 (d, J = 19 271.4 Hz), 119.53 (q, J = 34.9 Hz). F-NMR (377 MHz, CDCl3): δ -57.61 (d, J = 8.8 Hz).

1 (E-product) [minor] H-NMR (399 MHz, CDCl3): δ 7.56 – 7.15 (m, 4H), 7.02 (dd, J = 16.1, 2.4 Hz, 1H), 6.15 (dq, J = 16.1, 6.4 Hz, 13 1H). C-NMR (100 MHz, CDCl3): δ 136.34 (q, J = 6.8 Hz), 135.57, 132.07, 129.97, 127.47 (q, J = 2.9 Hz), 126.28, 122.44, 123.43 (q, 19 J = 268.7 Hz), 117.40 (q, J = 34.0 Hz). F-NMR (377 MHz, CDCl3): δ -63.61 (d, J = 5.1 Hz).

(E)-2-(3,3,3-trifluoroprop-1-enyl)naphthalene (E-A-4) & (Z)-2-(3,3,3- trifluoroprop-1-enyl)naphthalene (Z-A-4). Compound A-4 was prepared according to the described Method A, with 2-vinyl-naphthalene as starting material (1.0 mmol scale). The reaction was run for 24-48 hours. Column chromatography (100% petroleum ether) afforded a mixture of E/Z products as an off-white solid (57 mg, 50% yield, 87 : 13 E/Z).

+ TLC: Rf = 0.7 (100% petroleum ether). GC-MS: (m/z) 222.0 [M ]. IR: (neat): max 669, 734, 750, 817, 871, 966, 1093, 1116, 1276, -1 1298, 1313, 1653, 1664 cm .

1 (E-product) [major] H-NMR (400 MHz, CDCl3): δ 7.77 – 7.70 (m, 4H), 7.51 – 7.38 (m, 3H), 7.20 (dq, J = 16.1, 2.3 Hz, 1H), 6.21 13 (dq, J = 16.1, 6.5 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 137.88 (q, J = 6.8 Hz), 134.17, 133.38, 130.98, 129.21, 128.92, 128.54, 19 127.93, 127.30, 126.93, 123.89 (d, J = 268.8 Hz), 123.25, 116.12 (q, J = 33.8 Hz). F-NMR (377 MHz, CDCl3): δ -63.12 (d, J = 6.3 Hz).

1 (Z-product) [minor] H-NMR (400 MHz, CDCl3): δ 7.84 – 7.67 (m, 4H), 7.61 – 7.37 (m, 3H), 6.97 (d, J = 12.6 Hz, 1H), 5.74 (dq, J = 13 12.6, 9.1 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 139.84 (q, J = 6.0 Hz), 134.56, 133.64, 131.27, 129.74, 129.42, 128.58, 128.12, 19 127.34, 127.05, 122.84 (q, J = 269.8 Hz), 119.88, 118.28 (q, J = 35.1 Hz). F-NMR (377 MHz, CDCl3): δ -57.30 (d, J = 9.1 Hz).

(E)-2-(3,3,3-trifluoroprop-1-enyl)pyridine (E-A-5) & (Z)-2-(3,3,3-trifluoroprop-1- enyl)pyridine (Z-A-5). Compound A-5 was prepared according to the described Method A, with 2-vinyl-pyridine as starting material (1.0 mmol scale). The reaction was run for 72-96 hours. Precipitation with organic HCl in methanol afforded no isolated compound, as such no isolated yield and E/Z ratio could be obtained.(GC yield = 44%).

(E)-3-(3,3,3-trifluoroprop-1-enyl)pyridine (E-A-6) & (Z)-3-(3,3,3-trifluoroprop-1- enyl)pyridine (Z-A-6). Compound A-6 was prepared according to the described Method A, with 3-vinyl-pyridine as starting material (1.0 mmol scale). The reaction was run for 72-96 hours. Precipitation with organic HCl in methanol afforded a mixture of E/Z products as a brown sticky liquid (54 mg, 32% yield, 71 : 29 E/Z).[17,19]

GC-MS: (m/z) 173.0 [M+]. IR: (neat) 520, 680, 877, 1116, 1132, 1282, 1321, 1456, 1504, 2555, 2565, 3358, 3381, 3392 cm-1.

(E-product) [major] 1H-NMR (399 MHz, D4-MeOH) δ 9.23 (s, 1H), 8.97 (dd, J = 14.8, 6.9 Hz, 2H), 8.22 (q, J = 6.9 Hz, 1H), 7.54 (dd, J = 16.1 Hz, 1H), 7.05 (dq, J = 16.1, 6.4 Hz, 1H). 13C-NMR (100 MHz, D4-MeOH): 145.90, 143.06, 142.29, 135.30, 132.63 (q, J = 7.2 Hz), 128.98, 124.20 (q, J = 269.1 Hz), 123.96 (q, J = 34.5 Hz). 19F-NMR (377 MHz, D4-MeOH): δ -65.93 (d, J = 6.0 Hz).

(Z-product) [minor] 1H-NMR (399 MHz, D4-MeOH): 9.23 (s, 1H), 9.08 – 8.82 (m, 2H), 8.26 – 8.17 (m, 1H), 7.37 (d, J = 12.3 Hz, 1H), 6.43 (dq, J = 12.3, 8.7 Hz, 1H). 13C-NMR (100 MHz, D4-MeOH): δ 147.59, 142.62, 142.19, 135.62, 134.07 (q, J = 5.8 Hz), 128.65, 124.95 (q, J = 34.4 Hz), 123.63 (q, J = 271.2 Hz). 19F-NMR (377 MHz, D4-MeOH): δ -59.34 (d, J = 8.5 Hz).

(E)-4-(3,3,3-trifluoroprop-1-enyl)pyridine (E-A-7) & (Z)-4-(3,3,3-trifluoroprop-1- enyl)pyridine (Z-A-7). Compound A-7 was prepared according to the described Method A, with 4-vinyl-pyridine as starting material (1.0 mmol scale). The reaction was run for 72-96 hours. Precipitation with organic HCl in methanol afforded a mixture of E/Z products as a brown sticky liquid (69 mg, 38% yield, 85 : 15 E/Z).

GC-MS: (m/z) 173.1 [M+]. IR: (neat) 688, 831, 879, 991, 112, 1141, 1224, 1280, 1309, 1323, 1346, 1514, 1608, 1635 cm-1.

(E-product) [major] 1H-NMR (399 MHz, D4-MeOH): δ. δ 8.88 (d, J = 6.8 Hz, 2H), 8.26 (d, J = 6.8 Hz, 2H), 7.54 (dq, J = 16.2, 2.0 Hz, 1H), 7.18 (dq, J = 16.2, 6.4 Hz, 1H). 13C-NMR (100 MHz, D4-MeOH): δ 143.82, 140.56, 134.61 (d, J = 7.0 Hz), 127.59 (d, J = 35.1 Hz), 126.63. 19F-NMR (377 MHz, D4-MeOH): δ -66.48 (d, J = 4.3 Hz).

(Z-product) [minor] 1H-NMR (399 MHz, D4-MeOH): δ. 8.88 (d, J = 6.4 Hz, 2H), 8.02 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 12.7 Hz, 1H), 6.45 (dq, J = 12.7, 8.6 Hz, 1H). 13C-NMR (100 MHz, D4-MeOH): insufficient signal to noise ratio. 19F-NMR (377 MHz, D4-MeOH): δ -59.41 (d, J = 8.3 Hz).

(E)-(3,3,3-trifluoro-2-methylprop-1-enyl)benzene (E-A-8) & (Z)-(3,3,3-trifluoro-2- methylprop-1-enyl)benzene (Z-A-8). Compound A-8 was prepared according to the described Method A, with beta-methyl-styrene as starting material (1.0 mmol scale). The reaction was run for 24-48 hours. Column chromatography (100% petroleum ether) afforded a mixture of E/Z products as a colourless liquid (61 mg, 30% yield, 69 : 31 E/Z).

TLC: Rf = 0.88 (100% petroleum ether). GC-MS: (m/z) 186.01 [M+]. IR: (neat) 692, 742, 972, 1072, 1112, 1174, 1204, 1274, 1312, 1337, 1456, 1673 cm-1

1 13 (E-product) [major] H-NMR (399 MHz, CDCl3): δ 7.34 – 7.14 (m, 5H), 6.97 (s, 1H), 1.92 (d, J = 0.8 Hz, 3H). C-NMR (100 MHz,

CDCl3): δ 135.14 (q, J = 3.7 Hz), 134.73, 131.41 (q, J = 6.4 Hz), 129.30, 128.60, 128.37, 126.44 (q, J = 28.9 Hz), 124.73 (q, J = 272.7 19 Hz), 12.27 (d, J = 1.4 Hz). F-NMR (377 MHz, CDCl3): δ -69.47.

1 13 (Z-product) [minor] H-NMR (399 MHz, CDCl3): δ 7.34 – 7.14 (m, 5H), 6.70 (s, 1H), 1.95 (d, J = 1.7 Hz, 3H). C-NMR (100 MHz,

CDCl3): δ δ 135.35, 131.41 (q, J = 6.4 Hz), 129.30, 128.47, 128.12, 127.93, 126.52 (q, J = 29.7 Hz), 123.87 (q, J = 274.9 Hz), 19.17 19 (d, J = 2.9 Hz). F-NMR (377 MHz, CDCl3): δ -61.06.

(E)-ethyl 3-p-tolyl-2-(trifluoromethyl)acrylate (E-A-9) & (Z)-ethyl 3-p-tolyl-2-(trifluoromethyl)acrylate (Z-A-9). Compound A-9 was prepared according to the described Method A, with 4-methyl- ethyl-cinnamate as starting material (1.0 mmol scale). The reaction was run for 24 hours. Column chromatography (100% petroleum ether) afforded a mixture of E/Z products as an orange liquid (87 mg, 57% yield, 82 : 18 E/Z).

TLC: Rf = 0.67 (2% EtOAc in petroleum ether). GC-MS: (m/z) 258.1 [M+]. IR: (neat) 732, 810, 1028, 1126, 1159, 1203, 1224, 1278, 1296, 1321, 1381, 1728 cm-1.

1 (Z-product) [minor] H-NMR (399 MHz, CDCl3): δ 7.32 – 7.06 (m, 5H), 4.20 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 163.72, 148.33 (d, J = 3.0 Hz), 141.00, 140.11 (q, J = 5.9 Hz), 129.41, 129.17, 122.67 (q, J = 31.1 Hz), 19 122.43 (q, J = 273.0 Hz), 62.02, 21.58, 13.88. F-NMR (377 MHz, CDCl3): δ -58.00.

1 (E-product) [major] H-NMR (399 MHz, CDCl3): δ 7.31 – 7.06 (m, 5H), 4.27 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 163.72, 140.89, 140.11 (q, J = 5.9 Hz), 129.86 (q, J = 2.6 Hz), 129.74, 129.48, 122.16 (q, J = 274.0 Hz), 19 121.84 (q, J = 32.1 Hz), 62.02, 21.58, 14.25. F-NMR (377 MHz, CDCl3): δ -63.72.

(E)-3-phenyl-2-(trifluoromethyl)allyl acetate (E-A-10) & (Z)- 3-phenyl-2- (trifluoromethyl)allyl acetate (E-A-10). Compound A-10 was prepared according to the described Method A. Cinnamyl acetate, which was synthetically prepared according to literature procedure, was used as starting material (1.0 mmol scale). The reaction was run for 48 hours. Column chromatography (10% EtOAc in petroleum ether) afforded a mixture of E/Z products as an colourless liquid (60 mg, 49% yield, 72 :28 E/Z).

TLC: Rf = 0.65 (10% EtOAc in petroleum ether). GC-MS: (m/z) 244.2 [M+]. IR: (neat) 698, 750, 935, 1026, 1076, 1087, 1116, 1163, 1219, 1371, 1743 cm-1.

1 13 (E-product) [major] H-NMR (399 MHz, CDCl3): δ. 7.38 – 7.18 (m, 6H), 4.76 (s, 2H), 2.05 (s, 3H). C-NMR (100 MHz, CDCl3): δ 170.59, 139.03 (q, J = 5.9 Hz), 133.06, 129.63, 129.17, 128.92, 125.06 (q, J = 29.3 Hz), 123.95 (q, J = 273.7 Hz), 57.80, 20.96. 19F-

NMR (377 MHz, CDCl3): δ -66.49.

1 13 (Z-product) [minor] H-NMR (399 MHz, CDCl3): δ. 7.33 – 7.06 (m, 6H), 4.76 (s, 2H), 2.05 (s, 3H). C-NMR (100 MHz, CDCl3): δ 170.59, 139.03 (q, J = 5.9 Hz), 133.06, 129.63, 129.17, 128.92, 125.06 (q, J = 29.3 Hz), 123.95 (q, J = 273.7 Hz), 57.80, 20.96. 19F-

NMR (377 MHz, CDCl3): δ -59.05.

Specific compound data – trifluoromethylation in flow

(E)-1,3-dichloro-2-(3,3,3-trifluoroprop-1-enyl)benzene (B-2). Compound B-2 was prepared according to the described Method B, with 2,6-dichloro-styrene as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (100% petroleum ether) was performed. This afforded the E product as an yellow oil (69% yield, only E, at tR = 90 min).

1 H NMR (399 MHz, CDCl3) δ 7.22 (dd, J = 13.5, 8.0 Hz, 2H), 7.13 (dq, J = 16.3, 2.4 Hz, 1H), 7.10 – 7.05 (m, 1H), 6.29 (dq, J = 16.3, 13 6.3 Hz, 1H). C NMR (100 MHz, CDCl3) δ 134.90, 131.59 (q, J = 7.5 Hz), 131.01, 128.92, 127.79, 124.64 (q, J = 33.9 Hz), 123.03 (q, 19 J = 269.9 Hz). F NMR (376 MHz, CDCl3) δ -64.81 (d, J = 5.9 Hz).

Figure 11. Trifluoromethylation of 2,6-dichlorostyrene followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl- trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3

mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-2-(3,3,3-trifluoroprop-1-enyl)naphthalene (B-4). Compound B-4 was prepared according to the described Method B, with 2-vinyl-naphtalene as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (100% petroleum ether) was performed.

This afforded the E product as an off white solid (50% yield, at tR = 40 min)

(E-product) [major] 1H NMR (400 MHz, CDCl3): δ 7.76 – 7.70 (m, 5H), 7.50 – 7.37 (m, 4H), 7.20 (dd, J = 16.0, 1.9 Hz, 1H), 6.20 (dq,

J = 16.1, 6.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 137.88 (q, J = 6.8 Hz), 134.17, 133.38, 130.98, 129.21, 128.92, 128.54, 127.93,

127.30, 126.93, 123.89 (q, J = 268.8 Hz), 123.25, 116.12 (q, J = 33.8 Hz). 19F NMR (376 MHz, CDCl3) δ -63.10 (dd, J = 6.5, 1.7 Hz).

Figure 12. Trifluoromethylation of 2-vinyl-naphtalene followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl- trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-3-(3,3,3-trifluoroprop-1-enyl)pyridine (B-5). Compound B-5 was prepared according to the described Method B, with 2-vinyl-pyridine as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (40% petroleum ether and 2% triethyl amine in ethyl acetate) was performed. This afforded the E product as an yellow oil (46% yield, E only, at tR = 50 min).

[major product] 1H NMR (399 MHz, CDCl3) δ 8.56 (d, J = 4.6 Hz, 1H), 7.67 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.23-

7.17 (m, 1H), 7.10 (dd, J = 15.7, 2.2 Hz, 1H), 6.74 (dq, J = 15.7, 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.65, 140.68, 135.45

(q, J = 6.7 Hz), 124.18, 121.54, 120.42 (q, J = 34.5 Hz). 19F NMR (376 MHz, CDCl3) δ -63.87 (dd, J = 6.8, 2.4 Hz).

Figure 13. Trifluoromethylation of 2-vinyl-pyridine followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl-trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-3-(3,3,3-trifluoroprop-1-enyl)pyridine (B-6). Compound B-6 was prepared according to the described Method B, with 3-vinyl-pyridine as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (40% petroleum ether and 2% triethyl amine in ethyl acetate) was performed. This afforded the E product as an yellow oil (50% yield, E only, at tR = 30 min).

[major product] 1H NMR (399 MHz, CDCl3) δ 8.63 (d, J = 2.2 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.28

(dd, J = 8.0, 4.8 Hz, 1H), 7.09 (dd, J = 16.2, 2.2 Hz, 1H), 6.23 (dq, J = 16.2, 6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.65,

140.68, 135.45 (q, J = 6.7 Hz), 124.18, 121.54, 120.42 (q, J = 34.5 Hz). 19F NMR (376 MHz, CDCl3) δ -63.84 (dd, J = 6.5, 2.4 Hz).

Figure 14. Trifluoromethylation of 3-vinyl-pyridine followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl- trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-4-(3,3,3-trifluoroprop-1-enyl)pyridine (B-7). Compound B-7 was prepared according to the described Method B, with 4-vinyl-pyridine as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (20% petroleum ether and 2% triethyl amine in ethyl acetate) was performed. This afforded the E product as an yellow oil (60% yield, E only, at tR = 40 min).

[major product] 1H NMR (399 MHz, CDCl3) δ 8.71-8.65(m, 2H), 7.36-7.32 (m, 2H), 7.04 (dd, J = 16.2, 2.2 Hz, 1H), 6.33 (dq, J =

16.1, 6.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.65, 140.68, 135.45 (q, J = 6.7 Hz), 122.81(q, J = 269.4 Hz), 121.54, 120.42 (q, J

= 34.5 Hz). 19F NMR (376 MHz, CDCl3) δ -64.16 (dd, J = 6.5, 1.6 Hz).

Figure 15. Trifluoromethylation of 4-vinyl-pyridine followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl-trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-(3,3,3-trifluoro-2-methylprop-1-enyl)benzene (B-8). Compound B-8 was prepared according to the described Method B, with beta-methyl-styrene as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (100% petroleum ether) was performed. This afforded the E product as an yellow oil (47% yield, E only, at tR = 60 min).

[major product] 1H NMR (399 MHz, CDCl3) δ 7.37 – 7.17 (m, 5H), 6.98 (s, 1H), 1.94 (d, J = 1.4 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 134.73, 131.41 (q, J = 6.4 Hz), 129.30, 128.60, 128.37, 126.44 (q, J = 28.9 Hz), 124.73 (q, J = 272.7 Hz), 12.27 (d, J = 1.4

Hz). 19F NMR (376 MHz, CDCl3) δ -69.44.

Figure 16. Trifluoromethylation of beta-methyl-styrene followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl- trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-ethyl 3-p-tolyl-2-(trifluoromethyl)acrylate (E-B-9) & (Z)-ethyl 3- p-tolyl-2-(trifluoromethyl)acrylate (Z-B-9). Compound B-9 was prepared according to the described Method B, with 4-methyl- ethyl-cinnamate as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (2% EtOAc in petroleum ether) was performed. After column chromatography no pure fraction was obtained, so preparatory TLC was used. The product was obtained as a mixture of E/Z products after purification, as an orange liquid (29% yield, 83 : 17 E/Z).

1 (E-product) [major] H-NMR (399 MHz, CDCl3): δ 7.29 – 7.07 (m, 5H), 4.21 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 163.72, 140.89, 140.11 (q, J = 5.9 Hz), 129.86 (q, J = 2.6 Hz), 129.74, 129.48, 122.16 (q, J = 274.0 Hz), 19 121.84 (q, J = 32.1 Hz), 62.02, 21.58, 14.25. F-NMR (377 MHz, CDCl3): δ -63.69(d, J = 1.4 Hz).

1 (Z-product) [minor] H-NMR (399 MHz, CDCl3): δ 7.30 – 7.06 (m, 5H), 4.28 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 163.72, 148.33 (d, J = 3.0 Hz), 141.00, 140.11 (q, J = 5.9 Hz), 129.41, 129.17, 122.67 (q, J = 31.1 Hz), 19 122.43 (q, J = 273.0 Hz), 62.02, 21.58, 13.88. F-NMR (377 MHz, CDCl3): δ -57.98.

Figure 17. Trifluoromethylation of 4-methyl-ethyl-cinnamate followed in time. start material, E-product and Z- product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl- trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.

(E)-3-phenyl-2-(trifluoromethyl)allyl acetate (B-10). Compound B-10 was prepared according to the described Method B, with cinnamyl acetate as starting material (1.0 mmol scale). Iterating runs with the same reaction mixture was performed until completion of the reaction (see Figure S23). The crude reaction mixture fractions were analysed and subsequently column chromatography (2% EtOAc in petroleum ether) was performed. After column chromatography no pure fraction was obtained, so preparatory TLC was used. The product was obtained as pure E product after purification, as an yellow oil (30% yield, only E-product, at tR = 30 min).

[major product] 1H NMR (399 MHz, CDCl3) δ 7.38 – 7.17 (m, 6H), 4.76 (s, 2H), 2.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.59, 138.88 (q, J = 5.6 Hz), 133.06, 129.63, 129.17, 128.92, 125.06 (q, J = 29.3 Hz), 123.95 (q, J = 273.7 Hz), 57.80, 20.96. 19F NMR

(376 MHz, CDCl3) δ -66.46(d, J = 1.8 Hz) .

Figure 18. Trifluoromethylation of cinnamyl acetate followed in time. start material, E-product and Z-product values are determined from GC-MS analysis. yield is determined from 19F-NMR analysis with phenyl-trifluoromethyl-sulfide as internal standard. reaction conditions: Ir(ppy)3 (1 mol%), styrene (1 mmol), CsOAc (3 mmol), CF3I (1.44 ml/min), DMF/MeOH (9 ml/1 ml, 0.1 m), liquid flowrate (0.085 ml/min), visible light (3.12 w blue led strip), room temperature.