Continuous-Flow Synthesis of Monoarylated Acetaldehydes Using Aryldiazonium Salts. Natalia Chernyak and Stephen L. Buchwald

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1 S- Supporting Information Continuous-Flow Synthesis of Monoarylated Acetaldehydes Using Aryldiazonium Salts atalia Chernyak and Stephen L. Buchwald Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 239. Table of Contents Page General information S-2 ptimization of the reaction conditions S-3 Experimental procedures S-5 General procedure for the continuous-flow synthesis of monoarylated acetaldehydes from anilines via diazotization/meerwein arylation sequence S-7 Preparation of stock solutions S-7 Continuous flow experiment S-8 Experimental setup for the continuous flow synthesis of arylacetaldehydes S-9 Table S. Diazotization conditions in Reactor I S- Characterization and analytical data for products in Table 2 S-3 Further transformations of arylacetaldehydes 3 obtained via continuous-flow method Synthesis of arylethylanilines 4k and 4s S-23 Synthesis of indoles 5f, 5g, 5s and 5u S-25 Synthesis of benzofurans 6f, 6g and 6u S-28 MR spectra S-3

2 S-2 General information: General Reagent Information All anilines were purchased from Aldrich Chemical Co., Alfa Aesar, Acros rganics, or TCI America in 98% or higher commercial quality and were used as received without further purification. Ferrocene was purchased in 98.8% purity from Aldrich Chemical Co. and was used as received. Acetone was purchased in 98% purity from Mallinckrodt Chemicals. General Analytical Information Reactions were analyzed by gas chromatography. Thin-layer chromatography (TLC) was carried out on.25 mm E. Merck silica gel plates (6F-254) using KMn 4 or UV light as the visualizing agent. Flash chromatography was performed using Silicycle SiliaFlashP6 (23-4 mesh) silica gel. MR spectra were recorded on either a uker AMX 4 or on a Varian XL 3 Mz MR spectrometer that were calibrated using residual solvent as an internal reference (CD3: 7.26 ppm for MR and 77.6 ppm for 3 C MR). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad, at = apparent triplet, ad = apparent doublet. IR spectra were recorded on a Perkin-Elmer 2 FTIR spectrometer using K plates (thin film). Melting points (m.p.) were obtained on a Mel-Temp capillary melting point apparatus. Gas chromatographic analyses were performed on an Agilent 689 gas chromatograph with an FID detector using a J & W DB-2 column (3 m,.25 mm ID) or a DB- column ( m,. mm I.D.). Elemental analyses were performed by Atlantic Microlabs Inc., orcross, GA. General Experiment Information For the continuous-flow experiments, reagents were weighed into. ml volumetric flasks. The flasks were filled to. ml with acetone, water, or acetone/water combinations. Each solutions were then loaded into a syringe, and all of them were injected into a 5 ml sample loop. Yields refer to chromatographically and spectroscopically homogeneous materials, unless otherwise stated. All yields stated are the average of at least two experiments.

3 S-3 ptimization of the reaction conditions ptimization of the reaction conditions was performed on 6 µmol scale by mixing stock solutions of reagents. All stock solutions were prepared in. ml volumetric flasks. The.3 M acidic stock solution of p-chloroaniline was prepared by dissolving a mixture of 3. mmol of p-chloroaniline (a) and.6 ml of 2 M aqueous (2.4 mmol) or.28 ml of concentrated 2 S 4 (2.4 mmol) in organic solvent. The a 2 stock solution was prepared by dissolving 225 mg of a 2 in water. The catalyst solution was prepared by dissolving.3 mmol of catalyst in. ml of organic solvent. The 3. M alkene solution was prepared by dissolving 2.9 ml of ethyl vinyl ether (3. mmol) in organic solvent. General procedure for optimization of the reaction conditions: Warning! Diazonium salts are unstable and dangerously explosive intermediates. All diazonium salts, used for optimizations of the reaction conditions in batch, were generated in situ at o C on 6 µmol scale. Upon completion, every batch experiment was neutralized at low temperature with excess of aqeous solution of ac 3 to quench potential leftovers of generated diazonium salt. A test tube equipped with a stirring bar was charged with 2 µl of acidic aniline solution. The content was cooled to o C (water/ice bath). A 2 µl aliquot of the a 2 stock solution was slowly added at o C and the reaction mixture was further stirred for 5. min. At the same temperature, a 2 µl portion of the solution of alkene was added next, followed by the addition of a 2 µl aliquot of the catalyst solution. The reaction mixture was allowed to stir at o C until the evolution of 2 had ceased (approximately min). The reaction mixture was layered with saturated aqueous ac 3 and diethyl ether, and the organic phase was analyzed by GC and GC/MS analyses. The yields of product were determined versus n-decane as calibrated internal standard.

4 S-4 Table S. ptimization of the reaction conditions 2 a2, X X solvent / 2 oc ) Et 2) catalyst oc a 3a 2a # catalyst [mol%] X solvent/2 yield (%) Cu [5] MeC/ Cu [] MeC/ Cu [] 2S4 MeC/2 6 4 FeS4 72 [] 2S4 DMS/2 7 5 FeS4 72 [] DMS/ FeS4 72 [] acetone/ Cp2Fe [] 2S4 acetone/ Cp2Fe [] 2S4 DMS/ Cp2Fe [] acetone/2 8 Cp2Fe [] MeC/2 79

5 S-5 Experimental procedures Figure S. Experimental setup for the continuous-flow synthesis of p-chlorophenylacetaldehyde (3a) from p-chloroaniline (a) via diazotization/meerwein arylation sequence. Syringe : a + Syringe 4: mol% Cp 2 Fe scheme abbreviations: T-shaped micromixer PFA tubing T R [ 2a ] t = 5 min T2 T3 R2 t = 8.5 min 3a, 7% cooling bath ( o C) Syringe pump is used t - residence time flow direction Et a 2 Syringe 2: Syringe 3: R, R2 - reactor and reactor 2 The equipment configuration that was used for the continuous synthesis of monoarylated acetaldehydes from anilines via diazotization/meerwein arylation sequence is depicted in Figure S. Two arvard Apparatus PD2 syringe pumps were used to continuously deliver reagents from ormject plastic syringes to the reactors. The first syringe pump was equipped with Syringe, containing an acetone-water solution of p-chloroaniline (a) and 2 M aqueous mixture, and Syringe 2, containing a a 2 solution in water or acetone : water : (v:v). The second syringe pump was equipped with Syringe 3, containing an acetone solution of ethyl vinyl ether, and Syringe 4, containing an acetone solution of ferrocene. Both reactors for the aniline diazotization and subsequent Meerwein arylation reaction, as well as the connecting mixing loop between mixing tees T2 and T3 were made out of PFA capillary tubing (/6ʺ D x.4 ID). The diazotization reactor (reactor, R) had a volume of 5 µl, and the Meerwein arylation reactor (reactor 2, R2) had a volume of 2.5 ml (/6ʺ D x.4 ID). The tubing from the syringes to the reactors was also composed of PFA capillary tubing (/6ʺ D x 5 µm ID) and all fluidic connections were made using either /4-28 flat-bottomed flangeless fittings or -32 coned fittings (IDEX ealth and Science). The mixing tees used in this work were made out of TEFZEL (ETFE) (5 µm ID) and purchased from IDEX ealth and Science.

6 S-6 Unless noted otherwise, first mixing tee T, reactor, second mixing tee T2, the mixing loop, third mixing tee T3, and reactor 2 were submerged in a sonication bath filled with an ice/water mixture ( o C) and were sonicated. The bath temperature was monitored via a thermocouple Waage immersion heater controlled by a J-KEM Scientific Gemini PID controller, and constant temperature was maintained manually by addition of ice into the sonication bath. The stream exiting Reactor 2 was collected in an argon-flushed, dry, precooled round-bottom flask equipped with a stir bar.

7 S-7 General procedure for the continuous-flow synthesis of monoarylated acetaldehydes from anilines via diazotization/meerwein arylation sequence: I. Preparation of stock solutions: Syringe : A dry. ml volumetric flask was charged with 3. mmol of aniline (. equiv), followed by 2. ml of acetone. To this solution was then added.6 ml of 2 M aqueous. The resulting homogeneous acidic solution was further diluted to. ml total volume with acetone. If a precipitate formed, distilled water was added until all solids were dissolved, and the solution was subsequently diluted with acetone to a volume of. ml. The resulting homogeneous solutions were loaded into. ml plastic syringes. After removing bubbles, the total volume of the liquid in the syringe was set to 9. ml. Syringe 2: A dry. ml volumetric flask was charged with 225 mg of a 2 (3.26 mmol,.9 equiv) and 5. ml of water. The solids were completely dissolved upon sonication. The resulting homogeneous solution was further diluted with acetone or water to. ml total volume The solution was then further sonicated for 3 minutes to remove most of the air bubbles (if a decrease in a volume occurred after the sonication, the amount of acetone necessary to make total volume equal to. ml was added). ext, the prepared homogeneous a 2 solution was loaded into a ml plastic syringe. Total volume of liquid in the syringe was adjusted to 9. ml. Syringe 3: A dry. ml volumetric flask was charged with 2.9 ml of ethyl vinyl ether (3 mmol, equiv). The content was diluted with acetone to a. ml total volume. The prepared homogeneous solution was loaded into a. ml plastic syringe. After removing bubbles, the total volume of the liquid in the syringe was adjusted to 9. ml. Syringe 4: A dry. ml volumetric flask was charged with 55 mg of ferrocene (.3 mmol,. equiv), which was subsequently dissolved in 2 ml of acetone. The resulting solution was further diluted with acetone

8 S-8 to a total volume of. ml. This homogeneous solution was loaded into the. ml plastic syringe, and the total volume of the liquid in the syringe was adjusted to 9. ml. II. Continuous-flow experiment and work-up: The feeding rates were adjusted to 5 µl/min. nce the reaction mixture passed the T3, the sonication was turned on, and the system was left to equilibrate for the next 3-35 minutes. After system has reached a steady state, the receiver flask was changed to a pre-cooled round-bottom flask flushed with argon and equipped with a stir bar (stirring improved solution cooling), and the flowed reaction mixture was collected for an additional 2.5 h. The collected cold solution was next transferred into the graduated cylinder to measure the exact volume, which was further used for yield calculations. ext, water was added to the cold solution, and the mixture was extracted with equal amount of EtAc (approximately 2 ml of total volume). After phase separation, the aqueous phase was further extracted with EtAc (2 x 2 ml). The combined organic phases were washed with a cold saturated solution of ac 3 and then dried over anhydrous a 2 S 4. After removal of the solvent, the residue was purified by flash chromatography on silica gel to provide the final monoarylacetaldehyde product.

9 S-9 Synthesis of monoarylated acetaldehydes: Monoarylacetaldehydes were prepared following the above general procedure and the experimental setup depicted in Figure S2. Figure S2. Experimental setup for the continuous-flow synthesis of arylacetaldehydes 3 from anilines via diazotization/meerwein arylation sequence. Syringe : + Syringe 4: mol% Cp 2 Fe scheme abbreviations: T-shaped micromixer PFA tubing T R [ 2 ] T2 T3 R2 3 psi R 3 sonication+cooling bath T = o C Syringe pump is used Et a 2 Syringe 2: Syringe 3: R, R2 - reactor and reactor 2 back pressure regulator flow direction

10 S- Table S. Diazotization conditions in reactor # Product Aniline used F F Me 3a (7%) 3b (69%) 3c (7%) 3d (69%) 3e (67%) 3f (72%) 3g (7%) 3h (64%) F F Me 2 Syringe Syringe 2 a 2 solution (total volume. ml) Diazotization reactor (internal diameter PFA tubing.4 ) Aniline/ solution (all diluted with acetone to total volume of. ml) m (aniline) = 383 mg + V ( conc) =.625 ml m (aniline) = 55 mg + V ( conc) =.625 ml + 2. ml of water m (aniline) = 55 mg + V ( conc) =.625 ml + 2. ml of water m (aniline) = 69 mg + V ( conc) =.7 ml + 2. ml of water m (aniline) = 57 mg + V ( conc) =.7 ml + 2. ml of water m (aniline) = 723 mg + V ( conc) =.7 ml + 2. ml of water m (aniline) = 673 mg + V ( conc) =.7 ml + 3. ml of water m (aniline) = 66 mg + V ( conc) =.7 ml + 2. ml of water 225 mg of a 2 dissolved in water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture V =.25 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml V =.2 ml V =.2 ml V =.25 ml

11 S- Table S. Diazotization conditions in reactor (continued) # Product Aniline used Ph 3i (73%) CF 3 3j (67%) F 3 C F 3 C C t-bu 2 C I 3kʹ (68%) 3l (65%) 3mʹ (72%) 3n (7%) 2 3o (59%) 2 3q (73%) 2 3p (72%) Me F 3 C F 3 C C 2 Ph t-bu 2 C I Me CF Syringe Syringe 2 Diazotization Aniline/ solution a 2 solution reactor I (all diluted with acetone (total volume. (internal to total volume. ml) ml) diameter PFA tubing.4 ) m (aniline) = 556 mg + V ( conc) =.625 ml m (aniline) = 72 mg + V ( conc) =. ml + 2. ml of water m (aniline) = 53 mg + V ( conc) =. ml m (aniline) = 768 mg + V ( conc) =. ml m (aniline) = 354 mg + V ( conc) =. ml + 2. ml of water m (aniline) = 58 mg + V ( conc) =.7 ml +. ml of water m (aniline) = 76 mg + V ( conc) =.7 ml +. ml of water m (aniline) = 44 mg + V ( conc) =.7 ml + 2. ml of water m (aniline) = 55 mg + V ( conc) =.7 ml + 3. ml of water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in : (v:v) acetone-water mixture V =.2 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml V =.3 ml

12 S-2 Table S. Diazotization conditions in reactor (continued) # Product Aniline used Me F 3 C Me Me 2 3r (76%) Me F 3 C Me s (69%) CF 3 2 3t CF 3 (64%) Me 2 3u (74%) Syringe Syringe 2 Diazotization Aniline/ solution (all diluted with acetone to total volume. ml) a 2 solution (total volume. ml) reactor I (internal diameter PFA tubing.4 ) m (aniline) = 499 mg + V ( conc) =.7 ml + 3. ml of water m (aniline) =. g + V ( conc) =.8 ml m (aniline) =. g + V ( conc) =.8 ml m (aniline) = 795 mg + V ( conc) =.8 ml 225 mg of a 2 dissolved in : (v:v) acetone-water mixture 225 mg of a 2 dissolved in water 225 mg of a 2 dissolved in water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture V =.3 ml V =.3 ml V =.3 ml V =.25 ml 22 F 3 C 3vʹ (7%) F 3 C 2 m (aniline) = 486 mg + V ( conc) =.8 ml +. ml of water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture V =.63 ml 23 3wʹ (67%) 2 m (aniline) = 386 mg + V ( conc) =.8 ml +. ml of water 225 mg of a 2 dissolved in : (v:v) acetone-water mixture V =.63 ml xʹ (65%) m (aniline) = 386 mg + V ( conc) =.8 ml +. ml of water 225 mg of a 2 dissolved in water V =.63 ml

13 S-3 Characterization and analytical data for products in Table 2 2-(4-chlorophenyl)acetaldehyde (3a). btained following the general procedure and using diazotization conditions from Table S, entry. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (eluent hexanes : Et 2 : (v:v)) to yield 65 mg (7%) of the title aldehyde 3a as a yellowish oil. -MR (4 Mz; CD 3 ): δ 9.76 (t, J = 2. z, ), (m, 2), (m, 2), 3.7 (d, J = 2. z, 2). 3 C-MR ( Mz; CD 3 ): δ 98.6, 33.5, 3.9, 3.3, 29., FTIR (neat): cm - 96, 793, 7, 597, 49, 43, 37, 79. Anal. Calcd. for C 8 7 C, 62.5;, Found: C, 62.9;, (4-bromophenyl)acetaldehyde (3b). btained following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 9: (v:v)) to yield 26 mg (69 %) of the title aldehyde 3b as a yellowish oil. -MR (4 Mz; CD 3 ): δ 9.76 (t, J = 2. z, ), 7.52 (d, J = 8.3 z, 2), 7. (d, J = 8.2 z, 2), 3.69 (d, J =.9 z, 2). 3 C-MR ( Mz; CD 3 ): δ 98.5, 32., 3.3, 3.8, 2.5, FTIR (neat): cm , 2937, 723, 375, 33, 87, 37, 52,. Anal. Calcd. for C 8 7 C, C, 48.27;, Found: C, 48.28;, (2-bromophenyl)acetaldehyde (3c). 2 btained following the general procedure and using diazotization conditions from Table S, entry 3. Collected volume of the crude reaction mixture: V () Chen, G.-Q.; Xu, Z.-J.; Zhoub C.-Y.; Che, C.-M. Chem. Commun. 2, 47, 963. (2) () Chang, C.-F.; uang, C.-Y.; uang, Y.-C.; Lin, K.-Y.; Lee, Y.-J.; Wang, C.-J. Synth. Commun. 2, 4, 3452.

14 S-4 = 25 ml (.875 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 9: (v:v)) to yield 263 mg (7 %) of the title aldehyde 3c as a yellow oil. -MR (4 Mz; CD 3 ): δ 9.78 (t, J =.8 z, ), 7.64 (dd, J = 7.9,.2 z, ), 7.33 (dd, J = 7.4,.3 z, ), (m, 2), 3.89 (d, J =.8 z, 2). 3 C-MR ( Mz; CD 3 ): δ 98.3, 33., 32.6, 3.8, 29.3, 27.9, 25., 5.5. FTIR (neat): cm - 35, 2974, 2864, 725, 47, 439, 38, (4-bromo-2-chlorophenyl)acetaldehyde (3d). btained following the general procedure and using diazotization conditions from Table S, entry 4. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : EtAc : (v:v)) to yield 242 mg (69 %) of the title aldehyde 3e as a light yellow oil. -MR (4 Mz; CD3): δ 9.76 (t, J =.4 z, ), 7.62 (d, J =.9 z, ), 7.42 (dd, J = 8.2,.9 z, ), 7.3 (d, J = 8.2 z, ), 3.84 (d, J =.2 z, 2). 3 C-MR ( Mz; CD3): δ 97.2, 35.5, 32.8, 32.3, 3.4, 29.8, 2.9, FTIR (neat): cm - 345, 2898, 2843, 274, 26, 285, 793, 92, 793, 7, 59, 485, 42, 35. F 2-(2-bromo-4-fluorophenyl)acetaldehyde (3e). btained following the general procedure and using diazotization conditions from Table S, entry 5. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : EtAc : (v:v)) to yield 22 mg (67 %) of the title aldehyde 3e as a light yellow oil. -MR (4 Mz; CD 3 ): δ 9.76 (t, J =.4 z, ), 7.62 (d, J =.9 z, ), 7.42 (dd, J = 8.2,.9 z, ), 7.3 (d, J = 8.2 z, ), 3.84 (d, J =.2 z, 2). 3 C-MR ( Mz; CD 3 ): δ 97.2, 35.5, 32.8, 32.3, 3.4, 29.8, 2.9, FTIR (neat): cm - 345, 2898, 2843, 274, 26, 285, 793, 92, 99, 99, 92, 793, 7, 59, 485, 42, 35, 6, 68,, 932, 844, 787, 737, 677.

15 S-5 Anal. Calcd. for C 8 6 F C, C, 44.27;, Found: C, 48.8;, (2-bromo-4,6-dichlorophenyl)acetaldehyde (3f). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 6. Collected volume of the crude reaction mixture: V = 8 ml (.35 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 8: (v:v)) to yield 26 mg (72%) of the title aldehyde 3f as a white solid. -MR (4 Mz; CD 3 ): δ 7.6 (d, J = 2.3 z, ), (m, ), 7.3 (dd, J = 9.4, 2. z, ), (m, ). 3 C-MR ( Mz; CD 3 ): δ 6.6, 59.2, 54.79, 54.65, 45.99, 45.95, 26.32, 26.9, 23.4,.9,.7, 5., 98.2, 98.. FTIR (neat): cm , 75, 576, 539, 442, 378, 33, 64, 29, 62. Anal. Calcd. for C C, C, 35.86;,.88. Found: C, 36.2;, 2.5. F 2-(2-bromo-6-chloro-4-fluorophenyl)acetaldehyde (3g). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 7. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 : (v:v)) to yield 268 mg (7%) of the title aldehyde 3g as a light yellow solid. -MR (4 Mz; CD 3 ): δ 9.75 (t, J =. z, ), 7.34 (dd, J = 7.7, 2.6 z, ), 7.2 (dd, J = 8., 2.6 z, ), 4.5 (d, J =.3 z, 2). 3 C-MR ( Mz; CD 3 ): δ 96., 62.3, 59.8, 36.24, 36.3, 27.7, 27.66, 26., 26., 9.4, 9., 6.7, 6.5, FTIR (neat): cm - 35, 2938, 288, 22, 895, 569, 48, 236, 47, 56. Anal. Calcd. for C 8 5 F C, C, 38.2;, 2.. Found: C, 37.83;, 2.5.

16 S-6 Me 2-(4-bromo-3-methoxyphenyl)acetaldehyde (3h). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 8. Collected volume of the crude reaction mixture: V = 8 ml (.35 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 : (v:v)) to yield 98 mg (64%) of the title aldehyde 3h as a yellow oil. -MR (4 Mz; CD 3 ): δ 9.74 (t, J = 2.2 z, ), 7.52 (d, J = 7.9 z, ), (m, 2), 3.9 (s, 4), 3.67 (d, J = 2.2 z, 2). 3 C-MR ( Mz; CD 3 ): δ 98.6, 56.2, 33.7, 32.5, 22.9, 3.2,.8, 56.2, 5.3. FTIR (C 2 2 film): cm , 2938, 72, 59, 578, 463, 484, 48, 28, 255, 7. Ph 2-(2-phenoxyphenyl)acetaldehyde (3i). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 9. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 : (v:v)) to yield 85 mg (73%) of the title aldehyde 3i as a yellow oil. -MR (4 Mz; CD 3 ): δ 9.79 (td, J = 2.,.5 z, ), (m, 2), (m, 2), (m, 2), (m, 2), (m, ), 3.77 (d, J =.9 z, 2). 3 C-MR ( Mz; CD 3 ): δ 99.2, 56.9, 55.3, 3.8, 29.9, 29., 23.92, 23.88, 23.4, 8.8, 8.5, FTIR (neat): cm - 39, 287, 76, 59, 568, 2873, 28, 46, 38, 3, 246, 58. CF 3 2-(2-bromo-5-(trifluoromethyl)phenyl)acetaldehyde (3j). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column

17 S-7 chromatography on silica gel (hexanes : Et 2 : (v:v)) to yield 257 mg (67%) of the title aldehyde 3j as a light yellow oil. -MR (4 Mz; CD 3 ): δ 9.8 (t, J =.5 z, ), 7.53 (dd, J = 2.3,.7 z, ), 7.29 (s, ), 7.22 (ddd, J = 8.4, 2.4,. z, ), 3.92 (d, J =.5 z, 2). 3 C-MR ( Mz; CD 3 ): δ 97.3, 48.7, 48.68, 32.4, 3.5, 25.5, 25., 2.6, 2.3, 9., F 3 C 2-(4-(trifluoromethoxy)phenyl)ethanol (3k ). The corresponding aldehyde 3k was prepared following the general procedure and using diazotization conditions from Table S, entry. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The obtained crude material was dissolved in 2 ml of DCM/Et 4: (v:v) mixture, and 5 mg of ab 4 (.5 mmol) was added in one portion at room temperature. The reaction was vigorously stirred for h (a complete reduction of aldehyde was confirmed by both GC and TLC analysis). The reaction mixture was cooled to o C, and 3 ml of saturated solution of 4 in water was carefully added followed by 3 ml of EtAc. The phases were separated, and aqueous layer was extracted with EtAc (2 X 2mL). The combined organic fractions were washed with saturated aqueous solution of ac 3 and dried over anhydrous a 2 S 4. The solvent was removed under reduced pressure, and the crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, gradually from 4:(v:v) to 2:(v:v)) to yield 67 mg (68%) of the 2-(4-(trifluoromethoxy)phenyl)ethanol (3k ) as a yellowish oil. -MR (4 Mz; CD 3 ): δ 7.47 (dd, J = 2.3,.6 z, ), 7.33 (d, J = 8.4 z, ), 7.5 (ddd, J = 8.4, 2.4,. z, ), 3.89 (t, J = 6.6 z, 2), 3.4 (t, J = 6.6 z, 2),.7 (s, ). 3 C-MR ( Mz; CD 3 ): δ 47.87, 47.85, 36.8, 3.8, 25.5, 24.6, 24.2, 2.6, 2., 9., 6.5, 6.7, FTIR (neat): cm - 35, 2323, 223, 28, 942, 66, 52, 474, 47, 37, 255, 77, 7, 7 Anal. Calcd. for C 9 9 F 3 2 C, 52.43;, 4.4; Found: C, 52.48;, F 3 C

18 S-8 2-(2-bromo-4-(trifluoromethoxy)phenyl)acetaldehyde (3l). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 : (v:v)) to yield 276 mg (65%) of the title aldehyde 3j as yellow oil. -MR (4 Mz; CD 3 ): δ 9.8 (t, J =.5 z, ), 7.53 (dd, J = 2.3,.7 z, ), 7.29 (s, ), 7.22 (ddd, J = 8.4, 2.4,. z, ), 3.92 (d, J =.5 z, 2). 3 C-MR ( Mz; CD 3 ): δ 97.3, 48.7, 48.68, 32.4, 3.5, 25.5, 25., 2.6, 2.3, 9., FTIR (neat): cm , 356, 727, 487, 263, 28, 72, 94, 735. Anal. Calcd. for. C 9 6 F 3 2 C, 38.9;, 2.4. Found: C, 38.3;, 2.4. C 4-(2-hydroxyethyl)benzonitrile (3m ). The corresponding aldehyde 3m was obtained following the general procedure and using diazotization conditions from Table S, entry 3. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The obtained crude material was subjected to reduction with ab 4 following the reduction procedure for 3k. The crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, gradually from 4:(v:v) to 2:(v:v)) to yield 58 mg (72%) of 4-(2-hydroxyethyl)benzonitrile (3m ) as a light yellow oil. -MR (4 Mz; CD 3 ): δ (m, 2), (m, 2), 3.86 (t, J = 6.5 z, 2), 2.9 (t, J = 6.5 z, 2), 2.7 (s, ). 3 C-MR ( Mz; CD 3 ): δ 44.8, 32.2, 29.9, 9.,., 62.8, 39.. FTIR (neat): cm - 35, 2873, 28, 2323, 223, 66, 52, 474, 47, 37, 255, 7. Anal. Calcd. for. C 9 9 C, C, 73.45;, 6.6. Found: C, 74.;, t-bu 2 C tert-butyl 4-(2-oxoethyl)benzoate (3n). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 4. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on

19 S-9 silica gel (eluent exanes : MTBE 4: (v:v)) to yield 234 mg (7%) of the title aldehyde 3n as a light orange oil. -MR (4 Mz; CD 3 ): δ 9.78 (t, J = 2.2 z, ), (m, 2), (m, 2), 3.78 (d, J = 2.2 z, 2),.62 (s, 9). 3 C-MR ( Mz; CD 3 ): δ 98.4, 65.4, 36.4, 3.3, 3., 29.5, 8., 5.4, FTIR (neat): cm - 52, 474, 47, 37, 255, 7, 7, 43, 849, (2-nitrophenyl)acetaldehyde (3o). 3 The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 6. Collected volume of the crude reaction mixture: V = 25 ml (.875 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : EtAc 4: (v:v)) to yield 223 mg (72%) of the title aldehyde 3p as a light yellow oil. -MR (4 Mz; CD 3 ): δ 9.86 (t, J =.7 z, ), 8.5 (dd, J = 8.2,.3 z, ), 7.64 (td, J = 7.5,.3 z, ), (m, ), 7.35 (dd, J = 7.6,.2 z, ), 4.4 (s, 2). 3 C-MR ( Mz; CD 3 ): δ 96.8, 48.8, 33.8, 33.5, 28.8, 28.5, 25.3, FTIR (neat): cm - 34, 27, 28, 942, 725, 525, 35. Me 2 2-(4-methoxy-2-nitrophenyl)acetaldehyde (3q). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 7. Collected volume of the crude reaction mixture: V = 25 ml (.875 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : EtAc 4: (v:v)) to yield 267 mg (73%) of the title aldehyde 3q as a light yellow oil. -MR (4 Mz; CD 3 ): δ 9.82 (t, J =.9 z, ), 7.66 (d, J = 2.7 z, ), 7.23 (d, J = 8.5 z, ), 7.7 (dd, J = 8.5, 2.7 z, ), 4.5 (s, 2), 3.89 (s, 3). 3 C-MR ( Mz; CD 3 ): δ 97.3, 59.5, 49.3, 34.2, 2.38, 2.25,., 55.9, FTIR (neat): cm - 34, 66, 52, 474, 47, 37, 255, 7, 7, 43. (3) oland, W. E.; Sellstedt, J.. J. rg. Chem. 966, 3, 345.

20 S-2 Me Me 2-(4,5-dimethyl-2-nitrophenyl)acetaldehyde (3r). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 8. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : DCM :2 (v:v)) to yield 22 mg (76%) of the title aldehyde 3r as yellow oil. -MR (4 Mz; CD 3 ): δ 9.84 (t, J =.9 z, ), 7.97 (s, ), 7.8 (s, ), 4.5 (s, 2), 2.35 (s, 7). 3 C-MR ( Mz; CD 3 ): δ 97.4, 46.3, 44., 37.8, 34.5, 26.3, 25.9, 48.2, 9.8, 9.4. FTIR (neat): cm - 332, 35, 2938, 288, 569, 48, 38, 29, 47, 56, 9. 2 Anal. Calcd. for. C 3 C, 62.7;, Found: C, 62.4;, 5.. F 3 C 2-(2,6-dibromo-4-(trifluoromethoxy)phenyl)acetaldehyde (3s). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 9. Collected volume of the crude reaction mixture: V = 8 ml (.35 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : DCM 4: (v:v)) to yield 337 mg (69%) of the title aldehyde 3s as light yellow solid. -MR (4 Mz; CD 3 ): δ 9.78 (s, ), 7.5 (s, 2), 4.25 (s, 2). 3 C-MR ( Mz; CD 3 ): δ 95.8, 48.37, 48.35, 32., 25.8, 24.7, 2.5, 8.9, 5.6. FTIR (neat): cm - Anal. Calcd. for. C F 3 2 C, 29.87;,.39. Found: C, XXX;, XXX. CF 3 2-(2,4-dibromo-6-(trifluoromethoxy)phenyl)acetaldehyde (3t). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 9. Collected

21 S-2 volume of the crude reaction mixture: V = 8 ml (.35 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : DCM 4: (v:v)) to yield 32 mg (64%) of the title aldehyde 3t as yellowish solid. -MR (4 Mz; CD 3 ): δ 9.74 (s, ), 7.76 (d, J =.7 z, ), 7.46 (s, ), 4. (s, 2). 3 C-MR ( Mz; CD 3 ): δ 95.3, 48.4, 48.38, 33.8, 26.9, 25.9, 23.7, 23.5, 2.9, 2.5, 8.9, FTIR (neat): cm - 397, 2846, 72, 584, 562, 462, 396, 379, 27. Anal. Calcd. for. C F 3 2 C, 29.87;,.39. Found: C, XXX;, XXX. Me 2-(2,6-dibromo-4-methylphenyl)acetaldehyde (3u). The compound was obtained following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 8 ml (.35 mmol scale). The crude material was purified by column chromatography on silica gel (hexanes : Et 2 9: (v:v)) to yield 292 mg (74%) of the title aldehyde 3u as white solid. -MR (4 Mz; CD 3 ): δ 9.74 (t, J =. z, ), 7.42 (s, 2), 4.8 (d, J =.7 z, 2), 2.33 (s, 3). 3 C-MR ( Mz; CD 3 ): δ 97., 4.7, 32.8, 29.7, 25.5, 5.7, 2.4. FTIR (neat): cm , 2846, 2732, 7, 599, 536, 46, 375, 33, 279, 28, 68, 54. F 3 C 2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (3vʹ ). The corresponding aldehyde 3s was obtained following the general procedure and using diazotization conditions from Table S, entry 9. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The obtained crude material was subjected to reduction with ab 4 following the reduction procedure for 3k. The crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, gradually from :(v:v) to :2(v:v)) to yield 2 mg (7%) of 2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (3vʹ ) as white solid. -MR (4 Mz; CD 3 ): δ (m, 2), (m, ), 3.86 (t, J = 6.5 z, 2), 2.9 (t, J = 6.5 z, 2), 2.7 (s, ). 3 C-MR ( Mz; CD 3 ): δ 44.8, 32.2, 29.9, 9.,., 62.8, 39..

22 S-22 FTIR (neat): cm - 332, 35, 2938, 288, 22, 895, 569, 48, 38, 29, 236, 47, 56, 9, 953, 896, 85, 743, 74, 66. Anal. Calcd. for. C 8 8 F 3 C, 5.27;, Found: C, 5.8;, (6-chloropyridin-3-yl)ethanol (3wʹ ). The corresponding aldehyde 3s was obtained following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The obtained crude material was subjected to reduction with ab 4 following the reduction procedure for 3k. The crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, 4: (v:v) to 2: (v:v) gradient) to yield 27 mg (67%) of 2-(6-chloropyridin-3-yl)ethanol (3wʹ ) as a colorless oil. -MR (4 Mz; CD 3 ): δ 8.9 (d, J = 2.4 z, ), 7.56 (dd, J = 8.2, 2.5 z, ), 7.24 (d, J = 8.2 z, ), 3.87 (q, J = 5.4 z, 2), 2.83 (t, J = 6.3 z, 2), 2.7 (t, J = 4.5 z, ). 3 C MR ( Mz; CD 3 ): δ 49.9, 49.2, 39.6, 33.6, 24., 62.6, FTIR (neat): cm , 2924, 46, 333, 75, 27, 84, 3. Anal. Calcd. for. C 8 8 F 3 C, 5.27;, Found: C, 5.8;, (2-chloropyridin-3-yl)ethanol (3xʹ ). The corresponding aldehyde 3v was obtained following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The obtained crude material was subjected to reduction with ab 4 following the reduction procedure for 3k. The crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, 4: (v:v) to 2: (v:v) gradient) to yield 23 mg (65%) of 2-(2-chloropyridin-3-yl)ethanol (3xʹ ) as a light yellow oil. -MR (4 Mz; CD 3 ): δ 8.23 (dd, J = 4.7,.8 z, ), 7.65 (dd, J = 7.5,.8 z, ), 7.9 (dd, J = 7.5, 4.8 z, ), 3.93 (t, J = 6.5 z, 2), 3. (t, J = 6.5 z, 2), 2.39 (s, ). 3 C MR ( Mz; CD 3 ): δ 5.3, 47.6, 4., 33.2, 22.6, 6., FTIR (neat): cm , 2877, 582, 564, 497, 34, 8, 27, 77, 47.

23 S-23

24 S-24 Further transformations of arylacetaldehydes 3 obtained via continuous-flow method Me 2 (PMP 2 ) ab(ac) 3 DCE, rt F 3 C PMP F 3 C 4k, 68% 4s, 63% PMP R 2 a 2 R 2 Et mol% Cp 2 Fe acetone R 3 crude material CuI, 5 mol% DMF, K 3 P 4 7 o C, 2 h 5 mol% Cu % aq. MP, 5 o C, 2 h 5f, 7% F Me 5g, 69% 5v, 68% F 3 C 5t, 68% F 6f, 66% 6g, 6% Me 6v, 68% Synthesis of arylethylanilines 4k and 4s 4-methoxy--(4-(trifluoromethoxy)phenethyl)aniline (4k): Et 2 a 2, acetone 2 CF 3 CF 3 ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone F 3 C Me 2 (PMP 2 ) ab(ac) 3 DCE, rt F 3 C Me k 2k 3k 4k, 68% The corresponding aldehyde 3k was prepared following the general procedure and using diazotization conditions from Table S, entry. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The crude material was transferred into a dry 2 ml round bottom flask, which subsequently was charged with 47 mg (.2 mmol) of p-anisidine. The flask was evacuated and backfilled with argon (this cycle was repeated three times), and 2 ml of dry DCM was added via syringe. To this solution 424 mg (2. mmol) of solid ab(ac) 3 were added and the resulting suspension was allowed to stir at room temperature for h. The reaction mixture was quenched with 2 ml of saturated solution of ac 3 followed by addition of 3 ml of EtAc. The phases were

25 S-25 separated, and aqueous layer was extracted with EtAc (2 X 2mL). The combined organic fractions were dried over anhydrous a 2 S 4. The solvent was removed under reduced pressure and the crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, 6: (v:v) to 4: (v:v) gradient) to yield 254 mg (68%) of 4-methoxy--(4-(trifluoromethoxy)phenethyl)aniline (4k) as a colorless liquid. -MR (4 Mz; CD 3 ): δ 7.26 (d, J = 4. z, 2), 7.2 (d, J =.6 z, 2), 6.82 (d, J = 8.9 z, 2), 6.62 (d, J = 8.9 z, 2), 3.78 (s, 3), 3.39 (t, J = 7. z, 3, overlap with ), 2.93 (t, J = 7. z, 2). 3 C-MR ( Mz; CD 3 ): δ 52.3, 47.8, 46., 42., 38.2, 3., 2.8, 2., 9.2, 5., 4.4, 55.8, 45.9, FTIR (neat): cm - 338, 2932, 2323, 2227, 59, 48, 47, 23, 78,6, methoxy--(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)aniline (4s): Et 2 a 2, acetone 2 CF 3 CF 3 ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone F 3 C Me 2 (PMP 2 ) ab(ac) 3 DCE, rt F 3 C Me s 2s 3s 4s, 63% The corresponding aldehyde 3s was prepared following the general procedure and using diazotization conditions from Table S, entry 9. Collected volume of the crude reaction mixture: V = 6 ml (.2 mmol scale). The obtained crude material was subjected to the reductive amination with p-anisidine in the presence of ab(ac) 3 following the procedure described for 4k. The crude material was purified by flash column chromatography on silica gel (hexanes/etac, 2: (v:v) to : (v:v) gradient) to yield 224 mg (63%) of 4-methoxy--(2-(6-(trifluoromethyl)pyridin-3- yl)ethyl)aniline (4k) as a white solid. -MR (4 Mz; CD 3 ): δ 8.6 (d, J =.8 z, ), (m, ), 7.65 (d, J = 8. z, ), (m, 2), (m, 2), 3.78 (s, 3), 3.44 (t, J = 6.9 z, 3), 3. (t, J = 6.9 z, 2). 3 C-MR ( Mz; CD 3 ): δ 52.5, 5.4, 46.6, 46.3, 46., 4.4, 38.47, 38.46, 37.5, 23., 2.29, 2.25, 2.22, 2.2, 5., 4.4, 55.8, 45.4, FTIR (neat): cm , 2932, 2227, 56, 48, 293, 78, 6, 34.

26 S-26 Synthesis of indoles 5f, 5g, 5s ang 5u 4,6-dichloro--indole (5f): a 2, 2 acetone 2 ) 2) Et 3. M in acetone Cp 2 Fe.3 M in acetone 5 mol% Cu % aq. MP, 5 o C, 2 h f 2f 3f 5f, 7% The corresponding aldehyde 3f was prepared following the general procedure and using diazotization conditions from Table S, entry 6. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). After work-up, the obtained crude material was dissolved in 2. ml of MP. The solution was transferred into a dry 3 ml test tube and subsequently charged with. ml of aqueous 4 (3% in water). To this mixture mg (.75 mmol, 5 mol%) of Cu 2 were added and the reaction mixture was placed into the 5 o C preheated oil bath and further heated for 2 h. The reaction mixture was quenched with 2 ml of saturated solution of 4 and extracted of EtAc (3 X 2 ml). Combined organic fractions were dried over anhydrous a 2 S 4. The solvent was removed under reduced pressure and the crude mixture was further purified by flash column chromatography on silica gel (hexanes/etac, : (v:v) to 4: (v:v) dradient) to yield 93 mg (7%) of 4,6-dichloro--indole (5f) as a light brown oil. -MR (4 Mz; CD 3 ): δ 8.25 (s, ), 7.3 (s, ), 7.24 (t, J = 2.7 z, ), 7.8 (d, J =.2 z, ), 6.66 (d, J =.4 z, ). 3 C-MR ( Mz; CD 3 ): δ 36.3, 27.7, 26.5, 25.6, 25.3, 2.2, 9.8,.6. FTIR (neat): cm , 68, 58, 56, 339, 39, 32.

27 S-27 6-methoxy--indole (5g): Et a 2, 2 acetone 2 F F ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone F 5 mol% Cu % aq. MP, 5 o C, 2 h F g 2g 3g 5g, 69% The corresponding aldehyde 3g was prepared following the general procedure and using diazotization conditions from Table S, entry 7. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The obtained crude material was reacted with excess of aqueous 4 in the presence of mg (5 mol%) of Cu 2 in MP at 5 o C following procedure described for 5f. Crude material was purified by flash column chromatography on silica gel (hexanes/et 2, 4: (v:v) to 2: (v:v) gradient) to yield 75 mg (69%) of indole (5g) as a light yellow oil. -MR (4 Mz; CD 3 ): δ (b. s., ), 7.24 (dd, J = 3.3, 2.4 z, ), 7.3 (ddd, J = 9., 2.,. z, ), 6.99 (dd, J = 9.5, 2. z, ), 6.66 (ddd, J = 3.3, 2.2,. z, ). 3 C-MR ( Mz; CD 3 ): δ 6.4, 58., 35.75, 35.62, 26.29, 26.5, 24.95, 24.9, 23.6, 9.2, 8.9,.4, 96.4, FTIR (neat): cm , 646, 68, 58, 56, 49, 426, 39, 34, bromo-6-(trifluoromethoxy)--indole (5s): Et a 2, 2 acetone 2 CF 3 ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone F 3 C 5 mol% Cu % aq. MP, 5 o C, 2 h F 3 C s 2s 3s 5s, 63% The corresponding aldehyde 3s was prepared following the general procedure and using diazotization conditions from Table S, entry 9. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The obtained crude material was reacted with excess of aqueous 4 in the presence of mg (5 mol%) of Cu 2 in MP at 5 o C following procedure described for 5f. Crude material was purified by flash column chromatography on silica gel (hexanes/etac, : (v:v) to 4: (v:v) gradient) to yield 264 mg (63%) of indole (5t) as red-brown oil.

28 S-28 -MR (4 Mz; CD 3 ): δ 8.4 (s, ), (m, 3), 6.64 (ddd, J = 3.2, 2.3,.9 z, ). 3 C-MR ( Mz; CD 3 ): δ 44.66, 44.64, 35., 27.6, 26., 2.9, 9.4, 7.9, 7.8, 4.5, 3.53, 3.52, 3.2. FTIR (neat): cm , 72, 62, 573, 428, 39, 248, 28, 2, 76, 54, bromo-6-methyl--indole (5u): Et a 2, 2 acetone 2 Me Me ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone Me 5 mol% Cu % aq. MP, 5 o C, 2 h Me u 2u 3u 5u, 72% The corresponding aldehyde 3u was prepared following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The obtained crude material was reacted with excess of aqueous 4 in the presence of mg (5 mol%) of Cu 2 in MP at 5 o C following procedure described for 5f. Crude material was purified by flash column chromatography on silica gel (hexanes/etac, : (v:v) to 4: (v:v) gradient) to yield 227 mg (72%) of indole (5u) as white solid. -MR (4 Mz; CD 3 ): δ 8.4 (s, ), (m, 2), 7.4 (q, J =.9 z, ), 6.58 (ddd, J = 3.2, 2.2,. z, ), 2.47 (s, 3). 3 C-MR ( Mz; CD 3 ): δ 36.4, 33.2, 26.5, 24.4, 24., 4.3,.2, 2.8, 77.4, 77., 76.7, 2.4. FTIR (neat): cm - 342, 292, 2856, 78, 68, 577, 554, 53, 422, 395, 33, 9, 67.

29 S-29 Synthesis of benzofurans 6f, 6g and 6u 4,6-dichlorobenzofuran (6f): The corresponding aldehyde 3f was prepared following the general procedure and using diazotization conditions from Table S, entry 6. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). After work up, the obtained crude material was dissolved in 5. ml of dry DMF. The solution was transferred under argon into dry 3 ml test tube containing 4 mg (.75 mmol) of CuI and 636 mg of K 3 P 4 (2. mmol) in. ml of DMF. The reaction mixture was heated at 7 o C for 2 h. The reaction mixtures was cooled down to room temperature and then layered between 5 ml of : mixture of pentane/et 2 (v:v) and 5 ml of saturated 4 solution in water. Phases were separated and aqueous layer was extracted with : mixture of pentane/et 2 (v:v; 3 X ml). The combined organic extracts were dried over a 2 S 4. The solvent was concentrated under reduced pressure and the crude material was purified by flash column chromatography on silica gel eluting with pentane to yield 85 mg (66%) of the title compound 6f as colorless oil: a 2, 2 acetone 2 f -MR (4 Mz; CD 3 ): δ 7.62 (d, J = 2.2 z, ), 7.42 (s, ), 7.25 (t, J = 2.4 z, ), 6.82 (d, J = 2. z, ). 2f 3 C-MR ( Mz; CD 3 ): δ 54.9, 46., 3.3, 26.5, 25.8, 23.3,.8, 5.3. FTIR (neat): cm - 395, 2323, 69, 48, 47, 26, 78, 6, 33. ) 2) Et 3. M in acetone Cp 2 Fe.3 M in acetone 3f CuI, 5 mol% DMF, K 3 P 4 7 o C, 2 h 6f, 66% 6-chloro-4-fluorobenzofuran (6g): Et F a 2, 2 acetone 2 g F 2g ) 2) 3. M in acetone Cp 2 Fe.3 M in acetone F 3g CuI, 5 mol% DMF, K 3 P 4 7 o C, 2 h F 6g, 6% The corresponding aldehyde 3g was prepared following the general procedure and using diazotization conditions from Table S, entry 7. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was subjected to the Cu-catalyzed intramolecular

30 S-3 cyclization in the presence of K 3 P 4 in DMF following the procedure described for 6f. Crude material was purified by flash column chromatography on silica gel eluting with pentane to yield 7 mg (6%) of the title compound 6g as colorless oil. -MR (4 Mz; CD 3 ): δ 7.6 (d, J = 2.3 z, ), (m, ), 7.3 (dd, J = 9.4, 2. z, ), (m, ). 3 C-MR ( Mz; CD 3 ): δ 6.6, 59.2, 54.79, 54.65, 45.99, 45.95, 26.32, 26.9, 23.4,.9,.7, 5., 98.2, 98.. FTIR (neat): cm - 397, 2925, 662, 67, 594, 477, 48, 68, 39, 9, 89, 982, 9. 4-bromo-6-methylbenzofuran (6u): The corresponding aldehyde 3u was prepared following the general procedure and using diazotization conditions from Table S, entry 2. Collected volume of the crude reaction mixture: V = 2 ml (.5 mmol scale). The crude material was subjected to the Cu-catalyzed intramolecular cyclization in the presence of K 3 P 4 in DMF following the procedure described for 6f. Crude material was purified by flash column chromatography on silica gel eluting with pentane to yield 2 mg (68%) of the title compound 6u as colorless oil. -MR (4 Mz; CD 3 ): δ 7.56 (d, J = 2.2 z, ), 7.22 (s, 2), 6.72 (d, J = 2. z, ), 2.42 (s, 3). 3 C-MR ( Mz; CD 3 ): δ 55., 44.8, 35.9, 27., 26.5, 3.6,.9, 6.6, 77.4, 77., 76.7, a 2, Me u acetone 2 Me 2u ) 2) Et 3. M in acetone Cp 2 Fe.3 M in acetone FTIR (neat): cm - 298, 2359, 77, 67, 57, 48, 4, 342, 336, 275, 23, 3, 3. Me 3u CuI, 5 mol% DMF, K 3 P 4 7 o C, 2 h Me 6u, 68%

31 S-3 Table, 3a ppm

32 S Table, entry 3a ppm

33 ppm S-33 Table, 3b

34 S-34 Table, entry 3b ppm

35 ppm Table, 3c S-35

36 S Table, entry 3c ppm

37 S-37 Table, 3d

38 S-38 Table, entry 3c ppm

39 S-39 F Table, 3e ppm

40 S F Table, entry 3e ppm

41 S-4 Table, 3f ppm

42 S Table, entry 3f

43 ppm S-43 F Table, 3g

44 S F Table, entry 3g ppm

45 S-45 Me Table, 3h ppm

46 S-46 Me Table, entry 3h

47 ppm Table, 3i Ph S-47

48 S Ph Table, entry 3i ppm

49 S-49 CF 3 Table, 3j ppm

50 Table, entry 3j CF 3 S-5

51 S-5 F 3 C Table, 3k'

52 S F 3 C Table, entry 3k' ppm

53 S-53 F 3 C Table, 3l ppm

54 CD3 77. CD CD S-54 F 3 C Table, entry 3l

55 S-55 C Table, entry 3m' ppm

56 S-56 C Table, entry 3m'

57 S-57 t-bu 2 C Table, 3n ppm

58 S-58 t-bu 2 C Table, entry 3n

59 S-59 I Table, 3o

60 S-6 I Table, entry 3o

61 Table, 3p 2 S-6

62 S-62 2 Table, entry 3p

63 ppm S-63 Me 2 Table, 3q

64 S Me 2 Table, entry 3q ppm

65 ppm S-65 Me Me 2 Table, 3r

66 S Me Me 2 Table, entry 3r ppm

67 S-67 F 3 C Table, entry 3s ppm

68 S F 3 C Table, entry 3s ppm

69 S-69 CF 3 Table, entry 3t ppm

70 S-7 CF 3 Table, entry 3t ppm

71 S Me Table, entry 3u ppm

72 S Me Table, entry 3u ppm

73 S-73 F 3 C Table, 3v'