S1    Synthesis of Flufenamic Acid: An Organic Chemistry Lab Sequence using Boronic Acids and Nitrosoarenes under Transition-Metal-Free Conditions Silvia Roscales, and Aurelio G. Csákÿ* Instituto Pluridisciplinar, Universidad Complutense, Campus de Excelencia Internacional Moncloa, Paseo de Juan XXIII, 1, 28040, Madrid, Spain TABLE OF CONTENTS  1. Required Reagents: CAS Registry Numbers and Hazard Information S2 2. Safety and Waste Disposal Information S3 3. List of Chemicals and Equipment 3.1. Chemicals (per experiment) 3.2. Required Laboratory Material S4 S4 S5 4. Handout (Instructor´s version) S7 5. Questions (Instructor´s version) S40 6. Additional notes for instructors 6.1. Experimental Notes 6.2. Reproducibility and students´ results 6.3. Photos of the experiments 6.4. Additional Experiments 6.4.1. Synthesis of potassium (m-(Trifluoromethyl)phenyl)- trifluoroborate 4 from boronic acid 2b 6.4.2. Synthesis of nitroso compound 3a starting from 3- (trifluoromethyl)aniline 7 S42 S42 S44 S47 S53 S53 S55 7. Characterization data: Copies of spectra S58 8. Handout for students S83 9. Questions for students S106 10. Guide for the discussion sessions S107 11. Sample student report S108 S2    1. Required Reagents: CAS Registry Numbers and Hazard Information  Potassium 3-(trifluoromethyl)phenyltrifluoroborate (816457-58-6): Causes skin irritation and serious eye irritation. May cause respiratory irritation.  3-Trifluoromethylphenylboronic acid (1423-26-3): Causes skin irritation and serious eye irritation. May cause respiratory irritation.  2-Cyanophenylboronic acid (138642-62-3): Causes skin irritation and serious eye irritation. May cause respiratory irritation.  2-Aminobenzonitrile (1885-29-6): Harmful if swallowed, inhaled and in contact with skin. Causes skin irritation and serious eye irritation. May cause respiratory irritation and an allergic skin reaction.  Flufenamic acid (530-78-9) is toxic if swallowed, and causes skin irritation and serious eye irritation.  Triethyl phosphite (122-52-1): Flammable liquid and vapor, harmful if swallowed, and may cause an allergic skin reaction.  Triethyl phosphate (78-40-0) is harmful if swallowed and causes serious eye irritation.  Boric acid (10043-35-3) may cause erythematous lesions on the skin and mucous membranes.  Nitrosonium tetrafluoroborate (14635-75-7): Causes serious eye damage and severe skin burns.  OXONE (70693-62-8): Harmful if swallowed. Causes severe skin burns and eye damage. May produce an allergic reaction. Harmful to aquatic life with long lasting effects.  Potassium hydroxide (1310-58-3): Causes severe skin burns and eye damage. Harmful if swallowed. May be corrosive to metals.  Hydrogen chloride (7647-01-0): Highly flammable liquid and vapor. Causes skin irritation and serious eye damage. May cause drowsiness or dizziness. Repeated exposure may cause skin dryness or cracking.  Sodium bicarbonate (144-55-8)  Sodium chloride (7647-14-5)  Magnesium sulfate (7487-88-9)  Silica gel (7631-86-9): Carcinogenic  Tetrahydrofuran (109-99-9): Highly flammable liquid and vapor. Harmful if swallowed. Causes serious eye irritation. May cause respiratory irritation and drowsiness or dizziness. Suspected of causing cancer. May form explosive peroxides.  Methanol (67-56-1): Highly flammable liquid and vapor. Toxic if swallowed or inhaled and in contact with skin. Causes damage to organs. S3     Acetone (67-64-1): Highly flammable liquid and vapor. May cause drowsiness or dizziness. Causes serious eye irritation. Repeated exposure may cause skin dryness or cracking.  Acetonitrile (75-05-8): Highly flammable liquid and vapor. Causes serious eye irritation. Harmful if inhaled, swallowed and in contact with skin.  Methylene chloride (75-09-2): Causes skin irritation and serious eye irritation. Suspected of causing cancer. May cause drowsiness or dizziness.  Ethyl acetate (141-78-6): Highly flammable liquid and vapor. Causes serious eye irritation. May cause drowsiness or dizziness. Repeated exposure may cause skin dryness or cracking.  Hexane (110-54-3): Highly flammable liquid and vapor. May be fatal if swallowed and if enters airways. May cause drowsiness or dizziness. Causes skin irritation. May cause damage to organs through prolonged or repeated exposure. Suspected of damaging fertility. Toxic to aquatic life with long lasting effects.  Chloroform-d1 (865-49-6) Harmful if swallowed or inhaled. Causes skin irritation and serious eye irritation. Suspected of causing cancer and damaging the unborn child. May cause drowsiness or dizziness and damage to organs through prolonged or repeated exposure if inhaled.  Methyl sulfoxide-d6 (2206-27-1): Slightly hazardous in case of inhalation, skin contact or eye contact, of ingestion.  The hazards of 1-nitroso-3-(trifluoromethyl)benzene, 2-nitrosobenzonitrile and 2- ((3-(trifluoromethyl)phenyl)amino)benzonitrile are not known; therefore, they have to be treated as toxic. 2. Safety and Waste Disposal Information Standard precautions should be taken when handling all chemicals: Use protective clothing, gloves, and safety goggles and perform all the manipulations in the fume-hood. Care should be taken to avoid inhalation, eye contact, or ingestion of any of the chemicals used in this experiment. The silica gel slurry and columns should be prepared in the fume-hood (a mask may be worn). Care should be taken not to inhale silica gel or other chemicals. Waste Disposal:  Clean all the glassware with several washes of water and discard the washings in the aqueous waste. Then clean them with acetone and discard the waste in the non-halogenated organics waste.  Magnesium sulfate used should be disposed of in the solid waste. S4     Dispose of silica gel waste in a separate labeled container.  TLC spotters and plates: discard these after use in a glass waste container.  Solvents and used NMR samples: Waste halogenated and non-halogenated solvents should be disposed of in waste bottles labeled as such. 3. List of Chemicals and Equipment General remarks: All reagents used are commercially available in Aldrich and Fisher and have been used without further purification. 3.1. Chemicals (per experiment): Group A: • Potassium 3-(trifluoromethyl)phenyltrifluoroborate: 1 g • 2-Cyanophenylboronic acid: 252 mg • Triethyl phosphite: 0.22 mL • Nitrosonium tetrafluoroborate: 480 mg • Potassium hydroxide: 1.806 g • HCl 2M: 5 mL • Magnesium sulfate: To dry 30 mL DCM solutions • Silica gel: 28 g • Sand • Tetrahydrofuran: 5 mL • Methanol: 8 mL • Acetonitrile: 12 mL • Methylene chloride: 120 mL • Ethyl acetate: 150 mL • Hexane: 420 mL • H2O: 28 mL • Chloroform-d1: 0.6 mL • Methyl sulfoxide-d6: 0.6 mL Group B:  3-Trifluoromethylphenylboronic acid: 432 mg  2-Aminobenzonitrile: 300 mg  Triethyl phosphite: 0.29 mL  OXONE: 3.15 g  Potassium hydroxide: 1.806 g  HCl 2M: 5 mL S5     HCl 10%: 20 mL  NaHCO3 10%: 20 mL  NaCl sat. sol.: 20 mL  Magnesium sulfate: To dry 30 mL DCM solutions  Silica gel: 28 g  Sand  Tetrahydrofuran: 6 mL  Methanol: 8 mL  Methylene chloride: 44 mL  Ethyl acetate: 250 mL  Hexane: 230 mL  H2O: 34 mL  Chloroform-d1: 0.6 mL  Methyl sulfoxide-d6: 0.6 mL 3.2. Required Laboratory Material  3 x 50 mL round bottom flask  25 mL round bottom flask  2 x 100 mL Erlenmeyer flask  100 mL separatory funnel  50-mL graduated cylinder  Pasteur pipettes  Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter)  Vacuum filtration adapter  Column for chromatography (1-2 cm diameter)  Test tubes  NMR tube  Magnetic stir bar  Spatulas  10 mL plastic syringes  Heating and stirring plate with support and clamp  Oil bath  Thermometer  Reflux condenser  Filter paper  pH paper  Weighting paper or glass S6     Pre-cut silica TLC plates  TLC developing chamber  Marker (for students to write their names on their flasks)  Rotary evaporator  Instrumentation: NMR, IR, MS and melting point. S7    4. HANDOUT (Instructor´s version)    Specific  NOTES  for  instructors  have  been  included  italicized  in  blue  color  on  the  instructor’s  version of the handout for students. Extra literature has also been included (marked in blue color)  as a hint for students´ discussion at the instructor´s discretion.  I. INTRODUCTION In this experiment, you will synthesize flufenamic acid (Figure 1).1 Flufenamic acid is a drug that belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), which are used therapeutically for their anti-inflammatory, analgesic and anti-fever action. Compounds of this type constitute one of the families of best-selling drugs worldwide (there is an estimate of more than 100 million prescriptions per year only in the USA). Their importance relies on their anti-inflammatory, analgesic (pain reducing) and anti-fever actions, without the undesirable side effects of opioid analgesics (respiratory depression and addiction) or glucocorticoids (immunosuppression, hyperglycemia, osteoporosis, adrenal insufficiency, among other). The therapeutic activity of NSAIDs is thought to result from their ability to hinder the synthesis of prostaglandins by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Aspirin, a derivative of salicylic acid (salicylates) is the most well-known example of NSAIDs. Besides, most relevant commercial NSAIDs approved for use in humans belong to the families of fenamic acid derivatives (fenamates), propionic acid derivatives (profens), acetic acid derivatives, and enolic acid derivatives (oxicams). Figure 1. Structures of flufenamic acid (1) and other common NSAIDs. Fenamates, which can also be considered derivatives of anthranilic acid, are bioisosters of salicylates by replacement of an oxygen atom with an NH group.2 They possess higher anti-inflammatory activity than salicylates. In particular, flufenamic acid is effective in treating rheumatism, arthritis and other musculoskeletal inflammatory disorders very effectively. Esterification with diethyleneglycol affords etofenamate, another NSAID of the fenamate family with improved skin absorption, widely found in topical formulations.3 Flufenamic acid has also shown activity against other targets different S8    from cyclooxygenases, and the core of flufenamic acid is found as well in drugs that belong to other therapeutic areas.4 Flufenamic acid and other N-arylanthranilic acids have been synthesized by the Ullmann-Goldberg condensation between o-halobenzoic acids and anilines (see section II.3).5 The reaction usually requires harsh conditions, long reaction times, and yields are low. In this experiment, we have chosen as key step a new approach for the construction of the diaryamine moiety of 1 that consists of the use of boronic acids and nitrosobenzenes as reaction partners in a C-N bond-forming reaction carried out under transition-metal-free conditions.6,7 II. THEORETICAL BACKGROUND 1. Boronic Acids and Potassium Organotrifluoroborates8,9 1.A. Structure and General Reactivity Boronic acids are trivalent boron compounds that can be viewed as derivatives of boric acid by replacement of one of the OH groups by an alkyl, aryl, alkenyl or alkynyl group. They have a low-energy empty p orbital orthogonal to the three substituents of the sp2- hybridized boron atom. Therefore, they can act as Lewis acids by complexation with nucleophiles (Lewis bases), giving rise to borates. Organotrifluoroborates can be considered as derivatives of boronic acids. Potassium organotrifluoroborates may be in equilibrium with difluoroboranes and KF. This equilibrium can be shifted towards fluoride dissociation in the presence of additives that scavenge fluoride, such as BF3, TMSCl or LiBr.10 Due to the electron-withdrawing effect of fluorine, organodifluoroboranes are highly electrophilic at boron, and therefore very much prone to coordination with Lewis bases. One of the methods most commonly used for the synthesis of potassium organotrifluoroborates is the reaction of boronic acids with a concentrated solution of potassium bifluoride (KHF2).11 S9    Boronic acids and potassium organotrifluoroborates can act as carbon nucleophiles, like Grignard reagents, organolithiums or cuprates, which are among the most common carbon nucleophiles used in organic synthesis. However, these popular reagents are air and water sensitive. Therefore, they must be used under inert gas atmosphere and in anhydrous solvents. In addition, most cuprates must be generated in situ and are sensitive to temperature. On the other hand, boronic acids and potassium organotrifluoroborates are bench-stable carbon nucleophiles that do not require handling under inert atmosphere or in anhydrous solvents. However, these boron reagents are less nucleophilic than conventional organometallics. Therefore, the most popular reactions of boronic acids and organotrifluoroborates, such as the Suzuki, Hayashi-Miyaura, and Cham-Lam reactions, require catalysis by transition metals, and proceed by transmetalation to generate intermediate C-Metal species, which are the actual nucleophiles. Even so, boronic acids and potassium trifluoroborates are nucleophilic enough to participate in several C-C and C-heteroatom bond formation processes directly.12 Between the trivalent boronic acids and the tetravalent potassium trifluoroborates, the latter, being ate complexes, possess a more nucleophilic carbon backbone. Also, activation of boronic acids by transformation into borates enhances their ability to transfer their carbon backbone to electrophilic sites inter- or intramolecularly. 1.B C-Heteroatom Bond-Forming Reactions of Arylboronic Acids and Potassium Aryltrifluoroborates 1.B.1. Transition-Metal-Catalyzed Reactions: The Chan-Evans-Lam Reaction13 The Chan-Evans-Lam reaction (CuI/CuII/CuIII catalytic cycle) can be understood starting by ligand exchange between CuX2 and R2-YH (in many occasions a base is included to equilibrate R2-YH with the corresponding anion, which is more nucleophilic, S10    and thus more active in the ligand exchange process). This gives rise to a new CuII species (X-CuII-YR2). A second ligand exchange (transmetalation of R1 from B to Cu) affords another CuII intermediate (R1-CuII-YR2). In order for coupling between R1 and YR2 to occur smoothly (reductive elimination), oxidation (air) to a CuIII species is required.14 Reductive elimination affords the coupling product and CuI, which must be oxidized (air) to regenerate the active CuII catalyst. The reaction can also be performed with potassium organotrifluoroborates. This reaction may be used for the synthesis of diarylamines (see section II.3).15 1.B.2. Transition-Metal-Free Reactions16,17 1.B.2.A. The ipso-Substitution Reaction Coordination of a boronic acid to a species Y-X, where Y is a heteroatom-based nucleophililic center and X a moiety that can act as a leaving group, is followed by 1,2- migration of the carbon backbone from boron to Y, with simultaneous detachment of the leaving group X. Protonation (H2O) renders the final product and boric acid. 1.B.2.B. Substitution by ipso-SEAr18 The BF3K group enhances the nucleophilicity of the ipso-position of aromatic rings (ie., the position attached to boron) by factors of 103 – 104.19 2. Nitrosoarenes 2.A. Structure20 Nitrosoarenes are aromatic compounds that incorporate the nitroso group (-N=O). The simplest representative is nitrosobenzene.21 The nitroso group is strongly electron- withdrawing, which combined with the presence of a lone pair on nitrogen, makes that compounds of this type (blue / green) tend to be in equilibrium with dimers (colorless) S11    in solution.22 The extent of the equilibrium mainly depends on the substituents of the ring. Protonation on one on the oxygen atoms of any of these dimers followed by dehydroxylation gives rise to stable azoxybenzenes.23 2.B. Examples of Typical Reactivity 2.B.1. Reaction with Amines24 2.B.2. Reaction with Grignard Reagents25,26 2.B.3. Reaction with Enamines27 2.B.4. Cycloaddition Reactions28   NOTE: This example of hetero‐Diels‐Alder reaction can be used as a hint to recall the concepts of  regioselectivity and endo‐selectivity of the DA reaction.  S12    2.B.5. Oxidation and Reduction29,30 2.B.6. The Cadogan synthesis of carbazoles31 Nitrosocompounds are intermediates in this synthesis of indole derivatives, which starts from a nitrocompound and is promoted by P(OEt)3. The driving force of the process is the formation of the strong O=P bond in O=P(OEt)3. The final step, a SEAr reaction, can be understood by two alternative reaction pathways, one of which involves a nitrene (path a).   NOTE:  The  Cadogan  indole  synthesis  has  been  included  as  an  example  of  the  reactivity  of  nitrosocompounds, since it uses P(OEt)3 as a promoter. The mechanism of this classic reaction  will help the students understand the synthesis of diarylamine 6, which is the key transformation  in the synthesis of flufenamic acid that will be carried out in the lab experiment. Also, it can be  used as a hint to recall the structure and reactivity of nitrenes.  S13    2.C. Main Synthetic Methods20,32 2.C.1. Nitrosation of Electron-Rich Aromatics33 It consists of a SEAr reaction that can be carried out using various nitrosating agents as electrophiles. NOTE: This example of nitrosoarene synthesis by SEAr has been chosen to show that the reaction  takes place on the most electron‐rich aromatic  ring. The substitution  takes place at  the  least  hindered position which is ortho / para to the electron‐donating groups on the benzene ring.  2.C.2. Nitrosation of Aryltrifluoroborates29,34 The nitrosation takes place by an ipso-SEAr reaction. See section 1.B.2.B.   NOTE:  The  reaction  shows  the  compatibility  with  aromatics  devoid  of  electron‐donating  substituents.  2.C.3. Oxidation of Anilines35,36 This type of reaction is restricted to benzenes that do not carry other substituents prone to oxidation. Other side reactions include the formation of azocompounds by the reaction of the starting aniline with the nitroso compound, and overoxidation of nitroso to nitro. S14    2.C.4. Reduction of Nitrobenzenes37 The reaction consists of a two-step procedure that involves reduction of the nitro group to a hydroxylamine (Zn, HCl), which is subsequently oxidized (FeCl3) to the nitroso compound. The example illustrates the compatibility of the reduction and the oxidation with the alcohol group.   3. Other Syntheses of Diarylamines Flufenamic acid possesses a diarylamine structure. Diarylamines constitute an important class of organic compounds, frequently found among drugs, agrochemicals, dyes, radical-trapping antioxidants, electroluminescent materials, and ligands for transition-metal catalysis.38 Apart from the Cham-Evans-Lam reaction (see section1.B.1), most frequent methods for the synthesis of diarylamines make use of anilines and halobenzenes as starting materials in transition-metal-catalyzed coupling reactions. The most important procedures are the Ullmann-Goldberg39,40 and the Buchwald-Hartwig41,42 reactions.43 Both reactions share in common the in situ generation of an organometallic species of the type Ar1NH-M(n+2)-Ar2 by the interaction of Ar1NH2 and an aryl halide (Ar2X) with an organometallic catalyst (MnL, L = ligands). The Ullmann-Goldberg reaction requires CuI species, while the Buchwald-Hartwig reaction requires Pd0 species. Both reactions are carried out in the presence of a base. The base is needed to equilibrate the starting aniline (Ar1NH2) with the corresponding amide, which is nucleophilic enough to displace an anionic ligand from an electrophilic metallic intermediate (ligand exchange). The dummy ligands (L) are crucial. They serve to stabilize the metallic intermediates in solution, avoiding the precipitation of elemental Cu or Pd. The Ar1NH-M(n+2)-Ar2 key intermediate is generated by oxidative addition.44 Reductive elimination gives the final product (Ar1-NH-Ar2) and regenerates the catalytically active species (MnL).   S15    In the Ullmann-Goldberg reaction (CuI/CuIII catalytic cycle),45 the amide displaces a ligand from a CuI species to generate a CuI-NHAr1 intermediate. In the oxidative addition step, the CuI-NHAr1 species interacts with the aryl halide (Ar2X) to generate a CuIII intermediate (Ar2-CuIII-NHAr1) which evolves to the final product by reductive elimination. This step regenerates the catalytically active CuI species. In the Buchwald-Hartwig reaction (Pd0/PdII catalytic cycle),46 the oxidative addition step (generation of Ar2-PdII-X) goes first. Ligand exchange followed by reductive elimination renders the final product together with recovery of the catalytically active Pd0 species. Although general, these reactions require the use of expensive metallic catalysts, the presence of ligands, and extensive individual optimization of reaction conditions. Many transition-metal catalysts are highly toxic and sensitive to air and/or moisture. Residual traces of heavy metals in the final product can be difficult to remove. Due to their potential toxicity, this is not acceptable in pharmaceutical applications. As stated in the Introduction, flufenamic acid and other N-arylanthranilic acids have been synthesized by the Ullmann-Goldberg condensation between o-halobenzoic acids and anilines.5   S16    III. EXPERIMENTAL SECTION 1. Overview The overall synthetic scheme is given in Figure 2. The target molecule (flufenamic acid, 1) will be obtained by the basic hydrolysis of nitrile 6. The key step of the sequence is the synthesis of 6 by a C-N bond-forming reaction which consists of the interaction of an arylboronic acid (2a or 2b) with a nitrosocompound (3a or 3b) promoted by P(OEt)3.6 Two complementary approaches will be followed (Group A and Group B), in order for you to compare yields: In one of them (Group A), aryboronic acid 2a will react with nitrosocompound 3a; in the other (Group B), arylboronic acid 2b will react with nitrosocompound 3b. Additionally, you will exercise two different examples for the synthesis of nitrosocompounds: The nitrosation of aryltrifluoroborates (4  3a) and the oxidation of anilines (5  3b). Figure 2. Overall synthetic scheme. Observe that none of the transformations in the sequence involves the use of any transition metals, and are carried out without the need of inert gas atmosphere or especially dried solvents.   S17    Session  Group A  Group B    Transformation  Reaction Time  Transformation ReactionTime  1 (3 h)  4  3a  30 min  5  3b  1.5 h  Other activities (Both groups): Discussion session, prelab questions.  2 (3 h)  2a + 3a  6  20 min  2b + 3b  6  20 min  6  1  Overnight  6  1  Overnight  3 (3 h)  Isolation of 1  ‐‐‐  Isolation of 1  ‐‐‐  Other activities (Both groups): Melting point determination, discussion session,  postlab questions.    Figure 3. NOTE for instructors: Chronogram NOTE: In the following sections, data in blue color are not provided to the students. The students must complete the calculations in the table before carrying out the experiment. After the experiment, they must calculate the yield. For characterization purposes, they record the MS, IR and NMR spectra. The melting point of solid products can also be determined at the instructors´ discretion.     S18    2. Synthesis of nitrosoarenes 3a and 3b 2.1. Synthesis of 1-Nitroso-3-(trifluoromethyl)benzene 3a (Group A) Calculations 4 NOBF4 MeCN 3a equiv. 1.0 1.03 --- 1.0 g/mol 252.01 116.81 --- 175.11 mmol 3.97 4.09 --- 3.97 mg 1000.0 477.4 --- Th.yield: 694.8 mL --- --- 12.0 --- List of Chemicals List of Materials Potassium 3-(trifluoromethyl)phenyltri- fluoroborate: 1g 2 x 50 mL round bottom flask Nitrosonium tetrafluoroborate: 480 mg 2 x 100 mL Erlenmeyer flask Magnesium sulfate: To dry 30 mL DCM solutions 100 mL separatory funnel Silica gel: 8 g 50-mL graduated cylinder Acetonitrile: 12 mL Pasteur pipettes Methylene chloride: 75 mL Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter) H2O: 15 mL Vacuum filtration adapter Chloroform-d1: 0.6 mL Magnetic stir bar Spatulas 10 mL plastic syringes Heating and stirring plate with support and clamp Filter paper Weighting paper or glass Marker (for students to write their name on their flasks) Rotary evaporator S19    Procedure 1. Weight 4 (1 g) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add MeCN (12.0 mL) and turn on the stirrer to dissolve 4. 4. To this solution, add NOBF4 (477.4 mg). 5. Stir this mixture for 30 min at rt. During this time, the reaction changes from a colorless to a brown solution. At the end of this time, check the progress of the reaction via TLC (9:1 hexane: ethyl acetate). Be sure to spot 4 too. Note the Rf value for your product. 6. Add 10 mL of DCM and 15 mL of H2O. Transfer the mixture to a separatory funnel. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 7. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the lower DCM layer to the Erlenmeyer flask from the previous step containing the DCM layer. 8. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 9. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. 10. Decant the DCM into a 50 mL round bottom flask through fluted filter paper. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 11. Rotor evaporate the DCM. 12. Redissolve the residue in 10 mL of DCM. 13. Weight a 50 mL round bottom flask, and fix aid to a support with a clamp. 14. Install a vacuum filtration adapter, a rubber vacuum adapter, and put a fritted Büchner funnel on top of it (4.5 cm high, 3.5 cm diameter). 15. Weight 8 g of silica gel, and transfer it to the funnel. 16. Connect the system to a vacuum pump and apply suction to set the silica gel. 17. Turn off the vacuum. 18. Pipette the 10 mL DCM solution of 3a onto the top of the silica gel. 19. Turn on the vacuum and let the liquid flow into the flask. 20. Rinse the silica gel with 25 mL of DCM. 21. Turn off the vacuum, disassemble the equipment, and rotor evaporate the DCM. A light yellow solid reveals. 22. Record the weight of your product. Calculate the actual yield in 3a. 23. Compound 3a must be stored in the refrigerator until the next lab session. S20    Characterization data Light yellow solid Melting point range determined by the students between 66 – 80 ºC. 1H-NMR (300 MHz, CDCl3): δ 8.09-8.16 (m, 2H, CF3-C=CH-C-NO, R-C=CH-CH-), 7.98 (d, J = 7.9 Hz, 1H, R-C=CH-CH-), 7.80 (t, J = 8.2 Hz, 1H, CH=CH-CH) ppm. 13C NMR (75 MHz, CDCl3): δ 164.0 (C-NO), 131.5 (q, JC-F = 3.6 Hz, CH=CH-C-CF3), 130.4 (CHAr), 124.0 (CHAr), 117.7 (q, JC-F 3.9 Hz, NO-C-CH-C-CF3) ppm. 19F NMR (282 MHz, CDCl3): δ -62.9 (s, 3F, CF3) ppm. S21    2.2. Synthesis of 2-Nitrosobenzonitrile 3b (Group B) Calculations 5 Oxone DCM H2O 3b equiv. 1.0 2.0 --- --- 1.0 g/mol 118.14 614.74 --- --- 132.12 mmol 2.54 5.08 --- --- 2.54 mg 300.0 3122.1 --- --- Th.yield: 335.5 mL --- --- 5.0 20.5 --- List of Chemicals List of Materials 2-Aminobenzonitrile: 300 mg 2 x 50 mL round bottom flask OXONE: 3.15 g 2 x 100 mL Erlenmeyer flask HCl 10%: 20 mL 100 mL separatory funnel NaHCO3 10%: 20 mL 50-mL graduated cylinder NaCl sat. sol.: 20 mL Pasteur pipettes Magnesium sulfate: To dry 30 mL DCM solutions Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter) Silica gel: 8 g Vacuum filtration adapter Methylene chloride: 80 mL Magnetic stir bar H2O: 21 mL Spatulas Chloroform-d1: 0.6 mL 2 x 50 mL round bottom flask 2 x 100 mL Erlenmeyer flask 100 mL separatory funnel 50-mL graduated cylinder Pasteur pipettes Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter) Vacuum filtration adapter Magnetic stir bar Spatulas 10 mL plastic syringes S22    Heating and stirring plate with support and clamp Filter paper Weighting paper or glass Pre-cut silica TLC plates TLC developing chamber Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 5 (300 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add DCM (5.0 mL) and H2O (20.5 mL) and turn on the stirrer to dissolve 5. 4. To this solution, add oxone (3.12 g). 5. Next, stir this mixture vigorously for 1.5 h at rt. During this time, the reaction changed from a colorless to a green solution. 6. At the end of this time, check the progress of the reaction via TLC (7:3 hexane: ethyl acetate). Be sure to spot 5 too. Note the Rf value for your product. 7. Transfer the reaction to a separatory funnel. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 8. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the lower DCM layer to the Erlenmeyer flask from the previous step containing the DCM layer. 9. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 10. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 11. Add the organic layer back to the separatory funnel and wash successively with 20 mL of HCl 10%, 20 mL of NaHCO3 10% and 20 mL of brine. 12. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. 13. Decant the DCM through fluted filter paper into a 50 mL round bottom flask. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 14. Rotor evaporate the DCM. 15. Redissolve the residue obtained in 10 mL of DCM. 16. Weight a 50 mL round bottom flask, and fix aid to a support with a clamp. S23    17. Install a vacuum filtration adapter, a rubber vacuum adapter, and put a fritted Büchner funnel on top of it (4.5 cm high, 3.5 cm diameter). 18. Weight 8 g of silica gel, and transfer it to the funnel. 19. Connect the system to a vacuum pump and apply suction to set the silica gel. 20. Turn off the vacuum. 21. Pipette the 10 mL DCM solution of 3b onto the top of the silica gel. 22. Turn on the vacuum and let the liquid flow into the flask. 23. Rinse the silica gel with 25 mL of DCM. 24. Turn off the vacuum, disassemble the equipment, and rotor evaporate the DCM. A light yellow solid reveals. 25. Record the weight of your product. Calculate the actual yield in 3b. 26. Compound 3b must be stored in the refrigerator until the next lab session. Characterization data Light yellow solid Melting point range determined by the students between 155 – 170 ºC (Lit: 167 - 169 ºC).47 1H-NMR (300 MHz, CDCl3): δ 8.06 (dd, J = 7.6 Hz, J = 0.9 Hz, 1H, CH=CH-C-R), 7.85 (td, J = 7.6 Hz, J = 1.4 Hz, 1H, CH=CH-CH), 7.76 (td, J = 7.9 Hz, J = 1.4 Hz, 1H, CH=CH-CH-), 6.99 (dd, J = 7.9 Hz, J = 0.9 Hz, 1H, CH=CH-C-R) ppm. 13C NMR (CDCl3) δ 161.9 (C-NO), 135.4 (CHAr), 134.5 (CHAr), 133.6 (CHAr), 116.7 (CN), 114.1 (C-CN), 112.3 (CH-C-NO) ppm. Compound 8b (azoxybenzene derived from 3b) was obtained as subproduct. Characterization data Pale yellow solid Melting point: 192 - 193 ºC. 1H-MRN (300 MHz, CDCl3): δ 8.86 (d, J = 8.3 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.91 (dd, J = 7.5 Hz, J = 1.4 Hz, 1H), 7.68-7.86 (m, 4H), 7.53 (t, J = 7.5 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 149.1 (C), 144.7 (C), 135.4 (CH), 133.8 (CH), 133.6 (CH), 133.5 (CH), 132.3 (CH), 130.4 (CH), 125.0 (CH), 123.4 (CH), 116.6 (C), 115.9 (C), 111.7 (C), 107.8 (C) ppm. S24    3. Synthesis of 2-((3-(Trifluoromethyl)phenyl)amino)benzonitrile 6 3.1. Reaction of 2a with 3a (Group A) Calculations 3a 2a P(OEt)3 THF 6 equiv. 1.0 1.5 1.1 --- 1.0 g/mol 175.11 146.94 166.16 --- 262.23 mmol 1.14 1.71 1.26 --- 1.14 mg 200.0 251.7 208.8 --- Th.yield: 299.5 g/mL --- --- 0.969 --- --- mL --- --- 0.215 5.0 --- List of Chemicals List of Materials 2-Cyanophenylboronic acid: 252 mg 2 x 50 mL round bottom flask Triethyl phosphite: 0.22 mL 1 x 100 mL Erlenmeyer flask Silica gel: 15 g 50-mL graduated cylinder Sand Pasteur pipettes Tetrahydrofuran: 5.0 mL Column for chromatography (2 cm diameter) Methylene chloride: 2 mL NMR tube Ethyl acetate: 20 mL Magnetic stir bar Hexane: 350 mL 2 x 50 mL round bottom flask Chloroform-d1: 0.6 mL 1 x 100 mL Erlenmeyer flask 50-mL graduated cylinder Pasteur pipettes Column chromatography (2 cm diameter) NMR tube Magnetic stir bar Spatulas 10 mL plastic syringes S25    Heating and stirring plate with support and clamp Weighting paper or glass Pre-cut silica TLC plates TLC developing chamber Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 3a (200 mg) and 2a (251.7 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add THF (5.0 mL) and turn on the stirrer to dissolve the mixture. 4. To this solution, add P(OEt)3 (0.215 mL). The reaction changes from a green to a brown solution. 5. Stir this mixture for 20 minutes at rt. 6. At the end of this time, check the progress of the reaction via TLC (9:1 hexane: ethyl acetate). Be sure to spot 3a too. Note the Rf value of the product. 7. Rotor evaporate the solvent, and redissolve the residue obtained in 2 mL of DCM. 8. Prepare a silica gel column (2 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 15 g of silica gel in hexanes (50 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 9. Pipette crude 6 in DCM onto the top of the column, let adsorb, and add a layer of sand. 10. Add 100 mL of 98:2 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect 10 mL fractions with the aid of air pressure from the top. 11. Add 100 mL of 96:4 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 12. Add 50 mL of 94:6 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 13. Add 50 mL of 92:8 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 14. Spot each of the fractions from steps 10, 11, 12 and 13 on TLC plates (you might need more than one plate) and develop with 9:1 hexane: ethyl acetate. Two spots must be observed. The product has the lowest Rf value (0.38). It will most likely elute towards the end of the 96:4 or at the beginning of the 94:6 hexanes: ethyl acetate fraction. S26    15. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 16. Record the weight of your product. Calculate the actual yield in 6. 17. Use about 0.6 mL of CDCl3 to transfer 25 mg of 6 to an NMR tube. Record the NMR spectra. Characterization data White solid Melting point range determined by the students between 70 – 86 ºC (Lit: 81 - 82 ºC).48 1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H, CH-CHAr-C-R), 7.39- 7.51 (m, 3H, 3CHAr), 7.34 (d, J = 7.5 Hz, 2H, 2CHAr), 7.25 (d, J = 8.5 Hz, 1H, CH- CHAr-C-R), 6.94 (t, J = 7.8 Hz, 1H, CH=CH-C-CN), 6.47 (bs, 1H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ146.2 (C-NH), 141.1 (C-NH), 134.2 (CHAr), 133.5 (CHAr), 132.3 (q, JC-F = 32.2 Hz, C-CF3), 130.4 (CHAr), 124.0 (q, JC-F = 272.5 Hz, CF3), 123.9 (q, JC-F = 1.1 Hz, CH=CH-C-CF3), 120.7 (CHAr), 120.3 (q, JC-F = 3.8 Hz, CH-C-CF3), 117.4 (CN), 117.3 (q, JC-F = 3.9 Hz, CH-C-CF3), 115.2 (CHAr), 100.1 (C-CN) ppm. 19F NMR (282 MHz, CDCl3): δ -62.9 (s, 3F, CF3) ppm. IR: 3345 (NH), 2221 (CN) cm-1. Mass: m/z = 262 (100), 242 (34), 223 (13),192 (14). Compound 8a (azoxybenzene derived from 3a) was obtained as subproduct. Characterization data Yellow oil 1H-NMR (300 MHz, CDCl3): δ 8.62 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.58-7.74 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 148.4 (C-N), 143.9 (C-N), 131.9 (q, JC-F = 33.7 Hz, C-CF3), 131.5 (q, JC-F = 32.7 Hz, C-CF3), 129.9 (CH), 129.5 (CH), 128.8 (q, JC-F = 3.6 Hz, CH=C- CF3), 128.7 (CH), 126.6 (q, JC-F = 3.8 Hz, CH=C-CF3), 125.8 (d, JC-F = 1.1 Hz, CH), 123.9 (q, JC-F = 272.6 Hz, CF3), 123.4 (q, JC-F = 272.9 Hz, CF3), 122.9 (q, JC-F = 3.9 Hz, CH=C-CF3), 119.9 (q, JC-F = 3.9 Hz, CH=C-CF3) ppm. 19F NMR (282 MHz, CDCl3): δ -62.7 (s, 3F, CF3), -62.8 (s, 3F, CF3) ppm. S27    3.2. Reaction of 2b with 3b (Group B) Calculations 3b 2b P(OEt)3 THF 6 equiv. 1.0 1.5 1.1 --- 1.0 g/mol 132.12 189.93 166.16 --- 262.23 mmol 1.51 2.27 1.66 --- 1.51 mg 200.0 431.3 276.7 --- Th.yield: 397.0 g/mL --- --- 0.969 --- --- mL --- --- 0.286 6.0 --- List of Chemicals List of Materials 3-Trifluoromethylphenylboronic acid: 432 mg 3 x 50 mL round bottom flask Triethyl phosphite: 0.286 mL 1 x 100 mL Erlenmeyer flask Silica gel: 12 g 50 mL graduated cylinder Sand Pasteur pipettes Tetrahydrofuran: 6 mL Column chromatography (2 cm diameter) Methylene chloride: 2 mL NMR tube Ethyl acetate: 15 mL Magnetic stir bar Hexane: 250 mL Spatulas Chloroform-d1: 0.6 mL 3 x 50 mL round bottom flask 1 x 100 mL Erlenmeyer flask 50-mL graduated cylinder Pasteur pipettes Column for chromatography (2 cm diameter) NMR tube Magnetic stir bar Spatulas 10 mL plastic syringes S28    Heating and stirring plate with support and clamp Weighting paper or glass Pre-cut silica TLC plates TLC developing chamber Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 3b (200 mg) and 2b (431.3 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add THF (6.0 mL) and turn on the stirrer to dissolve the mixture. 4. To this solution, add P(OEt)3 (0.286 mL). The reaction changed from a green to a yellow solution. 5. Stir this mixture for 20 minutes at rt. 6. At the end of this time, check the progress of the reaction by TLC (7:3 hexane: ethyl acetate). Be sure to spot 3b too. Note the Rf value of the product. 7. Rotor evaporate the solvent, and redissolve the residue obtained in 2 mL of DCM. 8. Prepare a silica gel column (2 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 15 g of silica gel in hexanes (50 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 9. Pipette crude 6 in DCM onto the top of the column, let adsorb, and add a layer of sand. 10. Add 50 mL of 98:2 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect 10 mL fractions with the aid of air pressure from the top. 11. Add 50 mL of 96:4 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 12. Add 50 mL of 94:6 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 13. Add 50 mL of 92:8 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 14. Spot each of the fractions from steps 10, 11, 12 and 13 on TLC plates (you might need more than one plate) and develop with 9:1 hexane: ethyl acetate. The product has the highest Rf value (0.38). It will most likely elute towards the end of the 96:4 or at the beginning of the 94:6 hexanes: ethyl acetate fraction. 15. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use S29    a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 16. Record the weight of your product. Calculate the actual yield in 6. 17. Use about 0.6 mL of CDCl3 to transfer 25 mg of 6 to an NMR tube. Record the NMR spectra. Characterization White solid Melting point range determined by the students between 68 – 84 ºC (Lit: 81 - 82 ºC).47 1H-NMR (300 MHz, CDCl3): δ 7.55 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H, CH-CHAr-C-R), 7.39- 7.51 (m, 3H, 3CHAr), 7.34 (d, J = 7.5 Hz, 2H, 2CHAr), 7.25 (d, J = 8.5 Hz, 1H, CH- CHAr-C-R), 6.94 (t, J = 7.8 Hz, 1H, CH=CH-C-CN), 6.47 (bs, 1H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ146.2 (C-NH), 141.1 (C-NH), 134.2 (CHAr), 133.5 (CHAr), 132.3 (q, JC-F = 32.2 Hz, C-CF3), 130.4 (CHAr), 124.0 (q, JC-F = 272.5 Hz, CF3), 123.9 (q, JC-F = 1.1 Hz, CH=CH-C-CF3), 120.7 (CHAr), 120.3 (q, JC-F = 3.8 Hz, CH-C-CF3), 117.4 (CN), 117.3 (q, JC-F = 3.9 Hz, CH-C-CF3), 115.2 (CHAr), 100.1 (C-CN) ppm. 19F NMR (282 MHz, CDCl3): δ -62.9 (s, 3F, CF3) ppm. IR: 3345 (NH), 2221 (CN) cm-1. Mass: m/z = 262 (100), 242 (34), 223 (13),192 (14). S30    4. Synthesis of Flufenamic acid 1 (Groups A and B) KOH H2O:MeOH 100ºC, 18 h HN CF3 1 HO2C HN CF3 6 NC Calculations 6 KOH MeOH H2O 1 equiv. 1.0 93.8 --- --- 1.0 g/mol 262.23 56.10 --- --- 281.23 mmol 0.34 32.2 --- --- 0.34 mg 90.0 1806.0 --- --- Th.yield: 96.5 mL --- --- 8.0 12.5 --- List of Chemicals List of Materials Potassium hydroxide: 1806 g 50 mL round bottom flask HCl 2M: 5 mL 25 mL round bottom flask Magnesium sulfate: To dry 30 mL DCM solution 2 x 100 mL Erlenmeyer flask Silica gel: 5 g 100 mL separatory funnel Sand 50-mL graduated cylinder Methanol: 8 mL Pasteur pipettes Methylene chloride: 42 mL Column chromatography (1 cm diameter) Ethyl acetate: 130 mL NMR tube Hexane: 270 mL Magnetic stir bar H2O: 13 mL Spatulas Methyl sulfoxide-d6: 0.6 mL 10 mL plastic syringes Heating and stirring plate with support and clamp Oil bath Thermometer Reflux condenser Filter paper pH paper Weighting paper or glass S31    Pre-cut silica TLC plates TLC developing chamber Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 6 (90 mg) in a 25 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add MeOH (8.0 mL) and H2O (12.5 mL) and turn on the stirrer to dissolve 6. 4. To this solution, add KOH (1.806 g). 5. Stir this mixture vigorously overnight at 100ºC in an oil bath with a reflux condenser. 6. At the end of this time, check the progress of the reaction via TLC (7:3 hexane: ethyl acetate). Be sure to spot 6 too. Note the Rf value for your product. 7. After cooling to room temperature, remove MeOH in an evaporator. 8. Cool the resulting aqueous solution to 0ºC using an ice bath. 9. Dropwise add a solution of HCl 2M until pH 3. 10. Transfer the reaction to a separatory funnel. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 11. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 12. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 13. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. 14. Decant the DCM through fluted filter paper into a 50 mL round bottom flask. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 15. Rotor evaporate the DCM, and redissolve the residue obtained in 2 mL of DCM. 16. Prepare a silica gel column (1 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 5 g of silica gel in hexanes (30 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 17. Pipette the crude 1 in DCM onto the top of the column, let adsorb, and add a layer of sand. S32    18. Add 50 mL of 9:1 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect the resulting flow through in an Erlenmeyer flask with the aid of air pressure from the top. 19. Add 50 mL of 8:2 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 20. Add 50 mL of 7:3 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 21. Add 100 mL of 6:4 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 22. Add 100 mL of 1:1 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 23. Spot each of the fractions from steps 19, 20, 21 and 22 on TLC plates (you might need more than one plate) and develop with 1:1 hexane: ethyl acetate. The Rf value of the product is 0.36. It will most likely elute towards the end of the 6:4 or at the beginning of the 1:1 hexanes: ethyl acetate fraction. 24. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 25. Record the weight of your product. Calculate the actual yield in 1. 26. Use about 0.6 mL of DMSO-d6 to transfer 25 mg of 1 to an NMR tube. Record the NMR spectra. 27. Determine the melting point of compounds 3a, 3b, 6 and 1. Characterization data White solid Melting point range determined by the students between 125 – 143 ºC (Lit: 134 - 136 ºC).49 1H-NMR (500 MHz, DMSO-d6): δ 13.16 (bs, 1H, COOH), 9.70 (bs, 1H, NH), 7.94 (d, J = 7.9 Hz, 1H, CH-C-COOH), 7.48-7.60 (m, 3H, 3CHAr), 7.44 (t, J = 7.7 Hz, 1H, CH- CH=CH), 7.26-7.35 (m, 2H, 2CHAr), 6.88 (t, J = 7.4 Hz, 1H, CH=CH-C-COOH) ppm. 13C NMR (75 MHz, DMSO-d6): δ 169.7 (COOH), 145.4 (C-NH), 142.1 (C-NH), 134.0 (CHAr), 132.0 (CHAr), 130.5 (CHAr), 130.3 (q, JC-F = 31.4 Hz, C-CF3), 124.1 (q, JC-F = 272.4 Hz, CF3), 123.6 (CHAr), 118.9 (CHAr), 118.4 (q, JC-F = 3.9 Hz, CH=C-CF3), 116.2 (q, JC-F = 3.8 Hz, CH=C-CF3), 114.9 (CHAr), 114.8 (C-COOH) ppm. 19F NMR (282 MHz, DMSO-d6): δ -61.3 (s, 3F, CF3) ppm. IR: 3335 (NH), 3020 (OH), 1662 (C=O) cm-1. Mass: m/z = 281 (75), 263 (100), 235 (24). S33    IV. REFERENCES AND NOTES (1) (a) N-(3-Trifluoromethylphenyl)anthranilic acid antiinflammatory drug. Parke Davies & Co. FR M1341 19620702 (1962). (b) Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, William Andrew Publishing, USA, 2007, p 1644. (c) For an overview of flufenamic acid, see: Abignente, E.; de Caprariis, P. Flufenamic acid. Anal. Profile Drug Subst. 1982, 11, 313-346. (2) Besides flufenamic acid, other representatives of the fenam family of NSAIDs are mefenamic acid, mechlofenamic acid, tolfenamic acid and etofenamate. (3) (a) Bolze, K. H.; Brendler, O.; Lorenz, D. Antiphlogistic alkoxyethyl N-[m- (trifluoromethyl)phenyl]anthranilates. Ger. Offen. (1971), DE 1939112 A 19710204. (b) Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, William Andrew Publishing, USA, 2007, p 1526. (4) See for example: Monteillier, A.; Loucif, A.; Omoto, K.; Stevens, E. B.; Vicente, S. L.; Saintot, P.-P.; Cao, L.; Pryde, D. C. Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. Bioorg. Med. Chem. Lett. 2016, 26, 4919-4924. (5) For previous syntheses of flufenamic acid (Ullman-Goldberg reaction), see Ref 1, and in addition: (a) Chalmers, D. K.; Scholz, G. H.; Topliss, D. J.; Kolliniatis, E.; Munro, S. L. A.; Craik, D. J.; Iskander, M. N.; Stockigt, J. R. Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity. J. Med. Chem. 1993, 36, 1272-1277. (b) Dokorou, V.; Primikiri, A.; Kovala- Demertzi, D. The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents. J. Inorg. Biochem. 2011, 105, 195-201. (c) Zheng, Z.; Dian, L.; Yuan, Y.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. PhI(OAc)2-Mediated Intramolecular Oxidative Aryl-Aldehyde Csp2-Csp2 Bond Formation: Metal-Free Synthesis of Acridone Derivatives. J. Org. Chem. 2014, 79, 7451-7458, and references cited therein. (6) Roscales, S.; Csákÿ, A. G. Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling. Org. Lett. 2018, 20, 1667-1671. (7) For the synthesis of diarylamines by the addition of main-group organometallics to nitroso compounds, see: Dhayalan, V.; Sämann,C.; Knochel, P. Synthesis of polyfunctional secondary amines by the addition of functionalized zinc reagents to nitrosoarenes. Chem. Commun. 2015, 51, 3239-3242, and references cited therein. (8) For an overview of the structure, properties, preparation, reactions and applications of boronic acids, see: Hall D. In Boronic Acids: Preparation and Applications   S34      in Organic Synthesis, Medicine and Materials, Hall, D., Ed.; Wiley-VCH: Weinheim, 2011, Ch 1. (9) For an overview of the preparation and reactivity of organotrifluoroborates, see: (a) Molander, G. A.; Jean-Gérard, L. In Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, Hall, D., Ed.; Wiley-VCH: Weinheim, 2011, Ch 11. (b) Molander, G. A. Organotrifluoroborates: Another Branch of the Mighty Oak. J. Org. Chem. 2015, 80, 7837-7848. (10) See for example: (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of Arylboron Difluoride Lewis Acids. J. Org. Chem. 1995, 60, 3020-3027. (b) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Diastereoselective Allylation and Crotylation Reactions of Aldehydes with Potassium Allyl- and Crotyltrifluoroborates under Lewis Acid Catalysis. Synthesis 2000, 990-998. (c) Mitchell, T. A.; Bode, J. W. Synthesis of Dialkyl Ethers from Organotrifluoroborates and Acetals. J. Am. Chem. Soc. 2009, 131, 18057-18059. (d) Vo, C.-V. T.; Mitchell, T. A.; Bode, J. W. Expanded Substrate Scope and Improved Reactivity of Ether-Forming Cross-Coupling Reactions of Organotrifluoroborates and Acetals. J. Am. Chem. Soc. 2011, 133, 14082-14089. (e) Baxter, M.; Bolshan, Y. A General Access to Propargylic Ethers through Brønsted Acid Catalyzed Alkynylation of Acetals and Ketals with Trifluoroborates. Chem. Eur. J. 2015, 21, 13535-13538. (f) Shih, J. –L.; Nguyen, T. S.; May, J. A. Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates: a Synthetic Strategy for Discoipyrrole D. Angew. Chem. Int. Ed. 2015, 54, 9931-9935. (11) See Ref. 10a, and in addition: Ting, R.; Harwig, C. W.; Lo, J.; Li, Y.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Substituent Effects on Aryltrifluoroborate Solvolysis in Water: Implications for Suzuki−Miyaura Coupling and the Design of Stable 18F-Labeled Aryltrifluoroborates for Use in PET Imaging. J. Org. Chem. 2008, 73, 4662-4670. (12) For a comparison of the nucleophilicity of boron reagents with other carbon nucleophiles, see: (a) Berionni, G.; Maji, B.; Knochel, P.; Mayr, H. Nucleophilicity parameters for designing transition metal-free C–C bond forming reactions of organoboron compounds. Chem. Sci. 2012, 3, 878-882. (b) Berionni, G.; Leonov, A. I.; Mayer, P.; Ofial, A. R.; Mayr, H. Fine-tuning the nucleophilic reactivities of boron ate complexes derived from aryl and heteroaryl boronic esters. Angew. Chem., Int. Ed. Engl. 2015, 54, 2780-2783. (13) For reviews on the Cham-Evans-Lam coupling, see: (a) Qiao, J. X.; Lam, P. Y. S. Copper-Promoted Carbon-Heteroatom Bond Cross-Coupling with Boronic Acids and Derivatives. Synthesis 2011, 829-856. (b) Qiao, J. X.; Lam, P. Y. S. Recent advances in Chan-Lam coupling reaction: Copper-promoted C-heteroatom bond cross-coupling reactions with boronic acids and derivatives. In Boronic Acids, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011; Vol. 1, p 315. (c) Rao, K. S.; Wu, T. –S. Chan–Lam coupling reactions: synthesis of heterocycles. Tetrahedron 2012, 68, 7735-7754. S35      (14) This CuIII species is similar to the one formed in the Ullmann-Goldberg reaction by ligand exchange followed by oxidative addition. See section II.3. (15) Aryl boronic acids bearing electron-withdrawing substituents are often reluctant substrates for the Chan-Evans-Lam synthesis or diarylamines. See: (a) Antilla, J. C.; Buchwald, S. L. Copper-Catalyzed Coupling of Arylboronic Acids and Amines. Org. Lett. 2001, 3, 2077-2079. (b) Vantourout, J. C.; Law, R. P.; Isidro-Llobet, A.; Atkinson, S. J.; Watson, A. J. B. Chan–Evans–Lam Amination of Boronic Acid Pinacol (BPin) Esters: Overcoming the Aryl Amine Problem. J. Org. Chem. 2016, 81, 3942-3950. (c) Yoo, W. – J.; Tsukamoto, T.; Kobayashi, S. Visible-light-mediated Chan-Lam coupling reactions of aryl boronic acids and aniline derivatives. Angew. Chem. Int. Ed. 2015, 54, 6587- 6590. (16) For transition-metal-free C-Heteroatom bond-forming reactions or arylboronic acids and their derivatives, see the following reviews: (a) Coeffard, V.; Moreau, X.; Thomassigny, C.; Greck, C. Transition-Metal-Free Amination of Aryl boronic Acids and Their Derivatives. Angew. Chem. Int. Ed. 2013, 52, 5684-5686. (b) Zhu, C.; Falck, J. R. Transition-Metal-Free ipso-Functionalization of Arylboronic Acids and Derivatives. Adv. Synth. Catal. 2014, 356, 2395-2410. (17) For transition-metal-free C-C bond-forming reactions or aryl, alkenyl and alkynylboronic acids and their derivatives, see the following reviews: (a) Roscales, S.; Csákÿ, A. G. Transition-metal-free C–C bond forming reactions of aryl, alkenyl and alkynylboronic acids and their derivatives. Chem. Soc. Rev. 2014, 43, 8215-8225. (b) Sánchez-Sancho, F.; Csákÿ, A. G. C–C Bond Formation with Boronic Acids and Derivatives by Transition-Metal-Free Conjugate Addition Reactions. Synthesis 2016, 48, 2165-2177. See also Ref. 16b. (18) Molander, G. A.; Cavalcanti, L. N. Metal-Free Chlorodeboronation of Organotrifluoroborates. J. Org. Chem. 2011, 76, 7195-7203. (19) Berionni, G.; Morozova, V.; Heininger, M.; Mayer, P.; Knochel, P.; Mayr, H. Electrophilic Aromatic Substitutions of Aryltrifluoroborates with Retention of the BF3– Group: Quantification of the Activating and Directing Effects of the Trifluoroborate Group. J. Am. Chem. Soc. 2013, 135, 6317-6324. (20) Rück-Braun, K.; Priewisch, B. Nitrosoarenes. Science of Synthesis 2007, 31, 1321-1360. (21) Baeyer, A. Nitrosobenzol und Nitrosonaphtalin. Chem. Ber. 1874, 7, 1638-1640. (22) (a) Challis, B. C.; Higgins, R. J.; Lawson, A. J. The chemistry of nitroso- compounds. Part III. The nitrosation of substituted benzenes in concentrated acids. J. Chem. Soc., Perkin Trans. 2, 1972, 1831-1836. (b) Fletcher, D. A.; Gowenlock, B. G.; Orell, K. G. Structural investigations of C-nitrosobenzenes. Part 1. Solution state 1H NMR studies. J. Chem. Soc., Perkin Trans. 2, 1997, 2201-2206. S36      (23) Chen, Y. –F.; Chen, J.; Lin, L. J.; Chuang, G. J. Synthesis of azoxybenzenes by reductive dimerization of nitrosobenzene. J. Org. Chem. 2017, 82, 11626-11630.  (24) Wong, A. D.; Gungor, T. M.; Gillies, E. R. Multiresponsive Azobenzene End-Cap for Self-Immolative Polymers. ACS Macro Lett. 2014, 3, 1191-1195. (25) (a) Forrester, A. R.; Fullerton, J. D.; McConnachie, G. Nitroxide radicals. Part 21. Spontaneous decomposition of N-aryl 1- and 2-naphthyl nitroxides. J. Chem. Soc., Perkin Trans. 1, 1983, 1759-1764. (b) Kopp, F.; Sapountzis, I.; Knochel, P. Preparation of polyfunctional amines by the addition of functionalized organomagnesium reagents to nitrosoarenes. Synlett. 2003, 885-887. (26) For a similar reaction with organozinc compounds, see Ref. 7. (27) Yamamoto, H.; Momiyama, N. Rich chemistry of nitroso compounds. Chem. Commun. 2005, 3514-3525. (28) Berti, F.; Di Bussolo, V.; Pineschi, M. Synthesis of Protected (1-Phenyl-1H-pyrrol- 2-yl)-alkane-1-amines from Phenylnitroso Diels–Alder Adducts with 1,2- Dihydropyridines. J. Org. Chem. 2013, 78, 7324-7329. (29) Oxone is the trade name of a mixture of 2KHSO5, KHSO4, and K2SO4. The mixture is more bench stable than KHSO5, which is the true oxidant (K+ -OSO2-O-OH, potassium monoperoxysulfate, an activated form of hydrogen peroxide). See: Potassium Monoperoxysulfate. Crandall, J. K.; Shi, Y.; Burke, C. P.; Buckley, B. R. (2001). E-EROS Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons, Ltd. doi:10.1002/047084289x.rp246. (30) Molander, G. A.; Cavalcanti, L. N. Nitrosation of Aryl and Heteroaryltrifluoroborates with Nitrosonium Tetrafluoroborate. J. Org. Chem. 2012, 77, 4402-4413. (31) (a) Bunyan, P. J.; Cadogan, J. I. G. The reactivity of organophosphorus compounds. Part XIV. Deoxygenation of aromatic C-nitroso-compounds by triethyl phosphite and triphenylphosphine: a new cyclisation reaction. J. Chem. Soc. 1963, 42- 49. (b) Freeman, A. W.; Urvoy, M.; Criswell, M. E. Triphenylphosphine-Mediated Reductive Cyclization of 2-Nitrobiphenyls:  A Practical and Convenient Synthesis of Carbazoles. J. Org. Chem. 2005, 70, 5014-5019. (32) Reviews: (a) Gowenlock, B. G.; Richter-Addo, G. B. Preparations of C-Nitroso Compounds. Chem. Rev. 2004, 104, 3315-3340. (33) Zhu, W.-J.; Niu, J.-Y.; He, D.-D.; Sun, R.; Xu, Y.-J.; Ge, J.-F. Near-infrared pH probes based on phenoxazinium connecting with nitrophenyl and pyridinyl groups. Dyes and Pigments 2018, 149, 481-490. (34) For the synthesis of nitrosobenzenes by nitrosodesilylation, and proposed mechanism of the ipso-SEAr reaction, see: Kohlmeyer, C.; Klu ̈ppel, M.; Hilt, G. Synthesis of Nitrosobenzene Derivatives via Nitrosodesilylation Reaction. J. Org. Chem. 2018, 83, 3915-3920. S37      (35) Priewisch, B.; Rück-Braun, C. Efficient Preparation of Nitrosoarenes for the Synthesis of Azobenzenes. J. Org. Chem. 2005, 70, 2350-2352. (36) Levine, D. J.; Runcevski, T.; Kapelewski, M. T.; Keitz, B. K.; Oktawiec, J.; Reed, D. A.; Mason, J. A.; Jiang, H. Z. H.; Colwell, K. A.; Legendre, C. M.; FitzGerald, S. A.; Long, J. R. Olsalazine-Based Metal-Organic Frameworks as Biocompatible Platforms for H2 Adsorption and Drug Delivery. J. Am. Chem. Soc. 2016, 138, 10143-1150. (37) Tanaka, K.; Yamamoto, Y.; Kuzuya, A.; Komiyama, M. Synthesis of photo- responsive acridine-modified DNA and its application to site-selective RNA scission. Nucleos. Nucleot. Nucl. 2008, 27, 1175-1185. (38) See for example: (a) Rappoport, Z. In The Chemistry of Anilines; John Wiley & Sons: New York, 2007. (b) Ricci, A. In Amino Group Chemistry: From Synthesis to the Life Sciences; John Wiley & Sons: New York, 2008. (c) Wang, X. –F.; Tian, X. T.; Ohkoshi, E.; Qin, B.; Liu, Y. –N.; Wu, P. C.; Hour, M. J.; Hung, H. Y.; Qian, Q.; Huang, R., Bastow, K. F.; Janzen, W. P.; Jin, J.; Morris-Natschke, S. L.; Lee K. H.; Xie, L. Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents. Bioorg. Med. Chem. Lett. 2012, 22, 6224-6228. (d) Soussi, M. A.; Provot, O.; Bernadat, G.; Bignon, J.; Wdzieczak-Bakala, J.; Desravines, D.; Dubois, J.; Brion, J. –D.; Messaoudia, S.; Alami, M. Discovery of azaisoerianin derivatives as potential antitumors agents. Eur. J. Med. Chem. 2014, 78, 178-189. (e) Ingold K. U.; Pratt, D. A. Advances in Radical- Trapping Antioxidant Chemistry in the 21st Century: A Kinetics and Mechanisms Perspective. Chem. Rev. 2014, 114, 9022-9046. (f) O´Reilly, M. E.; Veige, A. S. Trianionic pincer and pincer-type metal complexes and catalysts. Chem. Soc. Rev. 2014, 43, 6325- 6369. (g) Valgimigli, L.; Pratt, D. A. Maximizing the Reactivity of Phenolic and Aminic Radical-Trapping Antioxidants: Just Add Nitrogen! Acc. Chem. Res. 2015, 48, 966-975. (h) Ohta, K.; Chiba, Y.; Kaise, A.; Endo, Y. Structure–activity relationship study of diphenylamine-based estrogen receptor (ER) antagonists. Bioorg. Med. Chem. 2015, 23, 861-867. (i) Chu, J. C. K.; Dalton, D. M.; Rovis, T. Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitro-Alkenes. J. Am. Chem. Soc. 2015, 137, 4445-4452. (j) Kürti, L. Streamlining amine synthesis. Science 2015, 348, 863-864. (k) Vardanyan, R.; Hruby, V. In Synthesis of Best-Seller Drugs; Academic Press: Boston, 2016, p 15, and references cited therein. (39) See for example: (a) Kunz, K.; Scholz, U.; Ganzer, D. Renaissance of Ullmann and Goldberg reactions - progress in copper catalyzed C-N-, C-O- and C-S-coupling. Synlett 2003, 2428-2439. (b) Evano, G.; Blanchard, N.; Toumi, M. Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis. Chem. Rev. 2008, 108, 3054-3131. (c) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 2014, 43, 3525-3550. (d) Okano, K.; Tokuyama, H.; Fukuyama, T. Copper-mediated aromatic amination reaction S38      and its application to the total synthesis of natural products. Chem. Commun. 2014, 50, 13650-13663. (e) Jiang, Y.; Ma, D. In Copper-Mediated Cross-Coupling Reactions, Evano, G., Blanchard, N., Eds.; John Wiley & Sons: New Jersey, 2014. For anthranilic derivatives, see: (f) Girisha, H. R.; Srinivasa, G. R.; Gowda, D. C. A simple and environmentally friendly method for the synthesis of N-phenylanthranilic acid derivatives. J. Chem. Res. 2006, 342-344. (g) Mei, X.; August, A. T.; Wolf, C. Regioselective Copper-Catalyzed Amination of Chlorobenzoic Acids:  Synthesis and Solid-State Structures of N-Aryl Anthranilic Acid Derivatives. J. Org. Chem. 2006, 71, 142-149. (40) The Ullmann reaction is the synthesis of biaryls by coupling of arylhalides in the presence of Cu. The Ullmann condensation is the synthesis of diarylethers by condensation of arylhalides and phenols in the presence of Cu. The Goldberg variation consists of the use of nitrogen nucleophiles instead of phenols, to give arylamines. (41) Contemporary back-to-back studies from the Buchwald and the Hartwig groups differ in the type of base and ligands (bidentate phosphines and sterically hindered ligands) they use. (42) See for example: (a) Schlummer, B.; Scholz, U. Palladium-Catalyzed C-N and C- O Coupling –A Practical Guide from an Industrial Vantage Point. Adv. Synth. Catal. 2004, 346, 1599-1626. (b) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Industrial‐Scale Palladium‐Catalyzed Coupling of Aryl Halides and Amines –A Personal Account. Adv. Synth. Catal. 2006, 348, 23-39. (c) Surry, D. S.; Buchwald, S. L. Selective Palladium-Catalyzed Arylation of Ammonia:  Synthesis of Anilines as Well as Symmetrical and Unsymmetrical Di- and Triarylamines. J. Am. Chem. Soc. 2007, 129, 10354-10355. (d) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide. Chem. Sci. 2011, 2, 27-50. (e) Lundgren, R.; Stradiotto, M. Recent Advances in the Buchwald–Hartwig Amination Reaction Enabled by the Application of Sterically Demanding Phosphine Ancillary Ligands. Aldrichim. Acta 2012, 45, 59-65. (f) Guram, A. S. 2016 Paul N. Rylander Award Address: Enabling Palladium/Phosphine-Catalyzed Cross-Coupling Reactions for Practical Applications. Org. Process Res. Dev. 2016, 20, 1754-1764. (43) For other methods for the synthesis of Ar1NHAr2 compounds, see: Arylmagnesium compounds and nitroarenes, (a) Sapountzis, I.; Knochel, P. A New General Preparation of Polyfunctional Diarylamines by the Addition of Functionalized Arylmagnesium Compounds to Nitroarenes. J. Am. Chem. Soc. 2002, 124, 9390-9391. (b) Ricci, A.; Fochi, M. Reactions between Organomagnesium Reagents and Nitroarenes: Past, Present, and Future. Angew. Chem. Int. Ed. 2003, 42, 1444-1446. Arylmagnesium compounds and arylazo tosylates, (c) Sapountzis, I.; Knochel, P. A general amination method based on the addition of polyfunctional arylmagnesium reagents to functionalized arylazo tosylates. Angew. Chem. Int. Ed. 2004, 43, 897-900. CuCN- catalyzed addition of arylmagnesium compounds to azides, (d) Yadav, J. S.; Subba S39      Reddy, B. V.; Borkar, P.; Reddy, P. J. Addition of aryl cuprates to azides: a novel approach for the synthesis of unsymmetrical diaryl amines. Tetrahedron Lett. 2009, 48, 6642-6645. Electrophilic amination reactions: (e) Ciganek, E. Electrophilic amination of carbanions, enolates, and their surrogates. Org. React. 2008, 72, 1-366. (f) Daskapan, T. Synthesis of amines by the electrophilic amination of organomagnesium, -zinc, - copper, and -lithium reagents. ARKIVOC 2011, 5, 230-262. (g) Yan, X.; Yang, X.; Xi, C. Recent progress in copper-catalyzed electrophilic amination. Catal. Sci. Technol. 2014, 4, 4169-4177. Single or double addition of C-nucleophiles to ketomalonate-derived imines and oximes, (h) Kattamuri, P. V.; Yin, J.; Siriwongsup, S.; Kwon, D. –Y.; Ess, D. H.; Li, Q.; Li, G.; Yousufuddin, M.; Richardson, P. F.; Sutton, S. C.; Kurti, L. Practical Singly and Doubly Electrophilic Aminating Agents: A New, More Sustainable Platform for Carbon–Nitrogen Bond Formation. J. Am. Chem. Soc. 2017, 139, 11184-11196. (44) By contrast, the Chan-Evans-Lam reaction (section II.1.B.1) does not involve an oxidative addition step. See Ref. 13, 14. (45) For additional recent examples of the Ullmann-Goldberg amine synthesis, see: (a) Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. CuI/Oxalic Diamide Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amines. J. Am. Chem. Soc., 2015, 137, 11942- 11945. (b) Gao, J.; Bhunia, S.; Wang, K.; Gan, L.; Xia, S.; Ma, D. Discovery of N- (Naphthalen-1-yl)-N′-alkyl Oxalamide Ligands Enables Cu-Catalyzed Aryl Amination with High Turnovers. Org. Lett., 2017, 19, 2809-2812. (46) For additional recent examples of the Buchwald-Hartwig amine synthesis, see: (a) Green, R. A.; Hartwig, J. F. Palladium-Catalyzed Amination of Aryl Chlorides and Bromides with Ammonium Salts. Org. Lett., 2014, 16, 4388-4391. (b) Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L. Rational Ligand Design for the Arylation of Hindered Primary Amines Guided by Reaction Progress Kinetic Analysis. J. Am. Chem. Soc., 2015, 137, 3085-3092. (47) Hamano, M.; Saeki, S.; Hatano, Y.; Nagakura, M. Studies on Tertiary Amine Oxides. XIX. Yakugaku Zasshi 1963, 83, 348-351. (48) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. Expedited Palladium-Catalyzed Amination of Aryl Nonaflates through the Use of Microwave-Irradiation and Soluble Organic Amine Bases. J. Org. Chem. 2006, 71, 430-433. (49) Moffett, R. B.; Aspergren, B. D. Aminoalkylphenothiazines. J. Am. Chem. Soc. 1960, 82, 1600-1607.  S40    5. QUESTIONS (INSTRUCTOR´S VERSION) PRELAB QUESTIONS    Draw an arrow‐pushing mechanism to explain the mechanism for the following reactions:  a)    b)    Answer:         Search the recent literature for a recent example of the synthesis of a diarylamine by the  following procedures:  a) Chan‐Evans‐Lam reaction  b) Ullmann‐Goldberg reaction  c) Buchwald‐Hartwig reaction    Answer: See for example: Chan‐Evans‐Lam reaction, (a) Ryan, M. C.; Martinelli, J. R.; Stahl, S. S.  Cu‐Catalyzed  Aerobic  Oxidative  N–N  Coupling  of  Carbazoles  and  Diarylamines  Including  Selective Cross‐Coupling. J. Am. Chem. Soc. 2018, 140, 9074‐9077. Ullmann‐Goldberg reaction,  (b) Hu, R.; Zhoujin, Y.; Liu, M.; Zhang, M.; Parkin, S.; Zhou, P.; Wang, J.; Yu, F.; Long, S. Solution  growth  and  thermal  treatment  of  crystals  lead  to  two  new  forms  of  2‐((2,6‐ dimethylphenyl)amino)benzoic  acid.  RSC  Adv.  2018,  8,  15459‐15470.  Buchwald‐Hartwig  reaction, (c) Shimogawa, H.; Murata, Y.; Wakamiya, A. NIR‐Absorbing Dye Based on BF2‐Bridged  Azafulvene Dimer as a Strong Electron‐Accepting Unit. Org. Lett. 2018, 20, 5135‐5138.  S41       Draw an arrow‐pushing mechanism for the formation of diisopropyl 2‐(phenylimino)  malonate by the reaction of nitrosobenzene with diisopropylmalonate (NaOH, EtOH).    Answer:  (a)  Nohira,  H.;  Sato,  K.;  Mukaiyama,  T.  The  reaction  of  nitrosobenzene  and  some  methylene  compounds.  Bull.  Chem.  Soc.  Jpn.  1963,  7,  870‐872.  (b)  Kattamuri,  P.  V.;  Yin,  J.;  Siriwongsup, S.; Kwon, D. ‐H.; Ess, D. H.; Li, Q.; Li, G.; Yousufuddin, M.; Richardson, P. F.; Sutton,  S.  C.;  Kurti,  L.  Practical  Singly  and  Doubly  Electrophilic  Aminating  Agents:  A  New,  More  Sustainable Platform for Carbon–Nitrogen Bond Formation. J. Am. Chem. Soc. 2017, 139, 11184‐ 11196.    POSTLAB QUESTIONS    Suggest a mechanism for the synthesis of 2‐((3‐trifluoromethyl)phenyl)amino)benzonitrile  from a nitrosobenzene and a boronic acid in the presence of P(OEt)3.  Answer: (a) Roscales, S.; Csákÿ, A. G. Synthesis of Di(hetero)arylamines from Nitrosoarenes and  Boronic Acids: A General, Mild, and Transition‐Metal‐Free Coupling. Org. Lett. 2018, 20, 1667‐ 1671.  See  also:  (b)  Bunyan,  P.  J.;  Cadogan,  J.  I.  G.  The  reactivity  of  organophosphorus  compounds. Part XIV. Deoxygenation of aromatic C‐nitroso‐compounds by  triethyl phosphite  and triphenylphosphine: a new cyclisation reaction. J. Chem. Soc. 1963, 42‐49. (c) Freeman, A.  W.;  Urvoy,  M.;  Criswell,  M.  E.  Triphenylphosphine‐Mediated  Reductive  Cyclization  of  2‐ Nitrobiphenyls:   A Practical  and Convenient  Synthesis  of Carbazoles.  J. Org.  Chem. 2005, 70,  5014‐5019.     Compare the yield in 6 obtained by reacting the boronic acid 2a with the nitrosobenzene  3a (Group A) with that obtained by reacting the boronic acid 2b with the nitrosobenzene  3b , and draw your own conclusions for the process.     Draw a mechanism for the conversion of benzonitrile into benzoic acid under aqueous basic  conditions and under aqueous acidic conditions.    S42    6. Additional notes for instructors General Remarks: Melting points were measured using a capillary melting point Gallenkamp apparatus. Characterization of compounds by carried out by NMR using a Bruker AM-300 or 500 MHz apparatus, by infrared spectroscopy using a Bruker FTIR spectrometer, and by MS spectrometry using an Agilent 5973N spectrometer. 6.1. Experimental Notes 1. The students completed the experiments in 3 hours in all the cases. 2. To follow the course of the reactions and to check the purity of the final products, the students can use TLC in Hexane:AcOEt. Compound 3a: Rf 0.70 (Hexane:AcOEt 9:1) Compound 3b: Rf 0.49 (Hexane:AcOEt 7:3) Compound 6: Rf 0.38 (Hexane:AcOEt 9:1) Compound 1: Rf 0.36 (Hexane:AcOEt 1:1) The purity can also be confirmed by measuring the melting point. 3. The 13C NMR spectra of 6 and 1 show C-F couplings. If appropriate, the instructor can further explore this feature (see Spectral data presented below). 4. Potassium 3-(trifluoromethyl)phenyltrifluoroborate 4 is commercially available, but it can also be prepared from 3-trifluoromethylphenylboronic acid 2b (see Synthesis of potassium (3-(trifluoromethyl)phenyl)trifluoroborate 4 from boronic acid 2b  presented below for details). 5. Nitrosocompound 3a can also be prepared starting from 3-(trifluoromethyl)aniline and OXONE (65-81% yields) (see Synthesis of nitroso compound 3a starting from 3-(trifluoromethyl)aniline 7 presented below for details).1 6. In part 2.2 (Synthesis of 2-nitrosobenzonitrile 3b) the nitrosoarene 3b is obtained with a small amount of the corresponding azoxybenzene (aprox. 10%), which is observed on TLC and NMR (see Spectral data presented below). 7. Nitrosocompounds 3a and 3b at the end of the first lab should be stored at 0 °C. No inert gas is needed. We have stored it at this temperature without any problems for up to 2 weeks. These nitrosocompounds decompose upon storage at room temperature, and is not recommended. 8. During column chromatography, students should be reminded to be careful not to disturb the sand layer while adding solvent to the column.                                                              1 Rück-Braun, K.; Priewisch, B. Nitrosoarenes. Science of Synthesis 2007, 31, 1321- 1360. S43    9. In part 3.1 (Group A, reaction of 2a with 3a to obtain 6), two spots are observed on TLC. The product has the lowest Rf value. The highest Rf value corresponds to the azoxybenzene derived from 3a, which is also formed in the reaction (see TLC below). The students can visualize it in the column chromatography because it shows a bright yellow color. 10. In part 4 (Synthesis of Flufenamic acid 1), it is very important to adjust the pH correctly, otherwise, the yield may decrease. The importance of pH adjustment in this step should be discussed in the post-lab session. 11. In these reactions, students can use distilled water. However, these reactions were also tried with non-distilled water without any effect on the yield. 12. In our laboratory, the hydrolysis of 6 to afford 1 is carried out by heating overnight at reflux temperature. Workup is carried out on the next day. The average yield obtained by the students is 64%. However, the instructors have also checked the following options: a) Heating at reflux 4 h only, letting cool down to room temperature, and carrying out workup on the next day (60% yield). TLC of the crude reaction product shows full conversion of 6. b) Heating at reflux 1.5 h only, letting cool down to room temperature, and carrying out workup on the next day (40% yield). TLC of the crude reaction product shows the presence of 6 and 1. They are easily separated by column chromatography. c) There are no differences in yield if after the reflux time the reaction crude is kept for 7 days at room temperature. The final product does not decompose at room temperature. S44    6.2. Reproducibility and students´ results This procedure, previously carried out in our research laboratory, was optimized by the instructors in order to achieve conditions that can be used in a teaching environment. The experiment was reproduced by the students attending the organic chemistry laboratory from the fourth year chemistry course (4 years grade). The results obtained by the students are presented in Table 1: Table 1: Results from the students´ experiments using previously optimized conditions. Entry 3a Yield (%) (Group A) 3b Yield (%) (Group B) 2a+3a 6 Yield (%) (Group A) 2b+3b6 Yield (%) (Group B) 1 Yield (%) (Group A) 1 Yield (%) (Group B) 1 Student I 30 (208.4 mg) Student III 68 (227.5 mg) Student I 31 (92.8 mg) Student III 68 (269.9 mg) Student I 62 (59.2 mg) Student III 69 (66.6 mg) Student II 32 (223.7 mg) Student IV 68 (227.6 mg) Student II 33 (99.7 mg) Student IV 67 (266.0 mg) Student II 59 (57.3 mg) Student IV 60 (58.1 mg) 2 Student I 39 (270.5 mg) Student III 71 (238.2 mg) Student I 35 (104.8 mg) Student III 65 (257.4 mg) Student I 61 (58.9 mg) Student III 58 (56.0 mg) Student II 36 (247.3 mg) Student IV 68 (227.0 mg) Student II 34 (101.2 mg) Student IV 68 (271.1 mg) Student II 68 (65.5 mg) Student IV 67 (64.5 mg) 3 Student I 45 (312.7 mg) Student III 68 (228.6 mg) Student I 34 (101.8 mg) Student III 65 (258.2 mg) Student I 63 (60.8 mg) Student III 62 (60.2 mg) Student II 36 (251.5 mg) Student IV 69 (232.6 mg) Student II 31 (92.2 mg) Student IV 67 (264.8 mg) Student II 62 (59.6 mg) Student IV 69 (66.9 mg) 4 Student I 39 (271.8 mg) Student III 69 (231.5 mg) Student I 31 (93.9 mg) Student III 66 (262.0 mg) Student I 70 (67.6 mg) Student III 65 (62.7 mg) Student II 39 (270.3 mg) Student IV 70 (236.0 mg) Student II 32 (95.8 mg) Student IV 67 (265.6 mg) Student II 64 (61.8 mg) Student IV 61 (59.0 mg) S45    Table 2: Melting points determined by the students. Entry 3a (ºC) (Group A) 3b (ºC) (Group B) 6 (ºC) (Group A) 6 (ºC) (Group B) 1 (ºC) (Group A) 1 (ºC) (Group B) 1 Student I 72-73 Student III 158-159 Student I 77-78 Student III 82-84 Student I 126-128 Student III 133-135 Student II 77-78 Student IV 161-162 Student II 70-71 Student IV 68-69 Student II 135-134 Student IV 133-134 2 Student I 73-74 Student III 166-167 Student I 73-74 Student III 69-71 Student I 130-132 Student III 140-141 Student II 70-72 Student IV 155-156 Student II 70-72 Student IV 69-71 Student II 126-127 Student IV 126-128 3 Student I 72-73 Student III 162-163 Student I 76-78 Student III 77-78 Student I 139-141 Student III 129-131 Student II 66-68 Student IV 169-170 Student II 77-78 Student IV 69-71 Student II 126-127 Student IV 125-127 4 Student I 70-71 Student III 168-170 Student I 76-78 Student III 77-78 Student I 131-133 Student III 141-142 Student II 79-80 Student IV 155-157 Student II 85-86 Student IV 75-77 Student II 142-143 Student IV 130-131 Literature value --- 167-1692 81-823 134-1364 The melting point temperatures determined by the students showed a difference of more than 10 ºC with those reported in the literature values. The students concluded that these differences were justified by contamination with solvent (resulting from insufficient product drying time) or with starting and/or side materials (resulting from difficulties in the work up). The students should characterize the products 6 and 1 by their melting points, IR, MS, 1H NMR, 13C NMR and 19F NMR spectroscopy. Samples for NMR should be prepared in CDCl3 and DMSO-d6 (~25 mg of product in about 0.6 mL of deuterated solvent). For their lab report and for the discussion session, they should assign the representative peaks of the IR, MS, 1H NMR and 13C NMR spectra of compounds 6 and 1. In the IR spectrum, they should look for an NH absorption for the amine at ~3300 cm-1, OH                                                              2 Hamano, M.; Saeki, S.; Hatano, Y.; Nagakura, M. Studies on Tertiary Amine Oxides. XIX. Yakugaku Zasshi 1963, 83, 348-351. 3 Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. Expedited Palladium-Catalyzed Amination of Aryl Nonaflates through the Use of Microwave-Irradiation and Soluble Organic Amine Bases. J. Org. Chem. 2006, 71, 430-433. 4 Moffett, R. B.; Aspergren, B. D. Aminoalkylphenothiazines. J. Am. Chem. Soc. 1960, 82, 1600-1607.  S46    absorption of the acid 1 and the lack of a nitrile at ~2100 cm-1. In 13C NMR spectrum, they should observe the C-F couplings. Table 3: Overall yields. Group Overall Yield (%) (Group A) Overall Yield (%) (Group B) 1 Student I 6 Student III 32 Student II 6 Student IV 27 2 Student I 8 Student III 27 Student II 8 Student IV 31 3 Student I 10 Student III 27 Student II 7 Student IV 32 4 Student I 8 Student III 30 Student II 8 Student IV 29   Group A: 6‐10% overall yield  Group B: 27‐32% overall yield  S47      6.3.   Photos of the experiments (taken from the actual students´ setups) Part 2.1: Synthesis of 1-nitroso-3-(trifluoromethyl)benzene 3a Filtration process TLC of final product 3a (Hexane:AcOEt 9:1) detected with UV light (254 and 366 nm) and vanillin solution Final product 3a  3a S48    Part 2.2. Synthesis of 2-nitrosobenzonitrile 3b Filtration process                                                   TLC of reaction crude (Hexane:AcOEt 7:3) detected with UV light (254 and 366 nm) and vanillin solution Final product 3b  3b 5  5   3b S49    Part 3.1: Synthesis of 2-((3-(trifluoromethyl)phenyl)amino)benzonitrile 6: Reaction of 2a with 3a Reaction TLC of reaction crude (Hexane:AcOEt 9:1) detected with UV light (254 and 366 nm) and vanillin solution TLC of column chromatography (Hexane:AcOEt 9:1) detected with UV light (254 and 366 nm)  6  Azoxybenzene of 3a  6 Azoxybenzene of 3a  3a  S50    Part 3.2. Synthesis of 2-((3-(trifluoromethyl)phenyl)amino)benzonitrile 6: Reaction of 2b with 3b (Group B) Reaction TLC of reaction crude (Hexane:AcOEt 7:3) detected with UV light (254 and 366 nm) and vanillin solution TLC of reaction crude Hexane:AcOEt 9:1 detected with UV light (254 and 366 nm)  6  6 3b  S51    TLC of column chromatography (Hexane:AcOEt 9:1) detected with UV light (254 and 366 nm) Part 4: Synthesis of Flufenamic acid 1 Reaction TLC of reaction crude (Hexane:AcOEt 7:3) detected with UV light (254 and 366 nm)  6  1 6  S52    TLC of column chromatography (Hexane:AcOEt 6:4) detected with UV light (254 and 366 nm)    1 S53    6.4. Additional experiments 6.4.1. Synthesis of potassium (m-(trifluoromethyl)phenyl)trifluoroborate 4 from boronic acid 2b Calculations 2b KHF2 MeOH H2O 4 equiv. 1.0 4.0 --- --- 1.0 g/mol 189.93 78.10 --- --- 252.01 mmol 7.90 31.59 --- --- 7.90 mg 1500.0 2467.2 --- --- Th.yield: 1990.3 mL --- --- 18.0 18.0 --- List of Chemicals List of Materials 3-Trifluoromethylphenylboronic acid: 1.5 g 2 x 50 mL round bottom flask Potassium hydrogen fluoride: 2467.2 mg 50 mL graduated cylinder Methanol: 24 mL Magnetic stir bar Acetone: 24 mL Spatulas Acetonitrile: 30 mL 10 mL plastic syringes H2O: 18 mL Heating and stirring plate with support and clamp Filter paper Weighting paper or glass Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 2b (1.5 g) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add MeOH (18.0 mL) and turn on the stirrer to dissolve 2b. 4. To this solution, add a solution of KHF2 (2467.2 mg) in H2O (18.0 mL). 5. Stir this mixture vigorously for 2 h at rt. S54    6. Remove the solvent in vacuo in a rotary evaporator. 7. Add 10 mL of a mixture acetone : MeOH 8:2 to the 50 mL round bottom flask and stir for 5 minutes. 8. Filter this mixture through fluted filter paper onto a previously weighed 50 mL round bottom flask. 9. Add another 10 mL of a mixture acetone:MeOH 8:2 into the first flask and stir for another 5 min. 10. Filter this mixture through fluted filter paper into the same 50 mL round bottom flask previously weighed. 11. Add another 10 mL of a mixture acetone : MeOH 8:2 into the first flask and stir for another 5 min. 12. Filter this mixture through fluted filter paper into the same 50 mL round bottom flask previously weighed. 13. Remove the combined collected fractions under vacuum in a rotary evaporator. A white solid is obtained. 14. Redissolve the solid in 15 mL MeCN. 15. Rotor evaporate the MeCN. 16. Redissolve the solid in 15 mL MeCN. 17. Rotor evaporate the MeCN. 18. Record the weight of your product. Calculate the actual yield in 4. Characterization data White solid Melting point: 225 -227 ºC 1H-NMR (300 MHz, acetone-d6): δ 7.78 (s, 1H, CF3-C=CH-C-BF3K), 7.72 (d, J = 7.0 Hz, 1H, R-C=CH-CH-), 7.25-7.41 (m, 2H, R-C=CH-CH-, CH=CH-CH) ppm. 13C NMR (75 MHz, acetone-d6): δ 136.2 (CH=CH-C-BF3K), 128.7 (CHAr), 127.5 (CHAr), 126.44 (q, 1JC-F = 271.3 Hz, CF3), 122.5 (q, 3JC-F = 2.3 Hz, CH-C-CF3) ppm. 19F NMR (282 MHz, acetone-d6): δ -62.5 (s, 3F, CF3), (-135.0)-(-135.7) (m, 3F, BF3) ppm.   S55    6.4.2.  Synthesis of nitroso compound 3a from 3-(trifluoromethyl)aniline 7  Calculations 7 Oxone DCM H2O 3a equiv. 1.0 1.5 1.0 g/mol 161.12 614.74 175.11 mmol 1.86 2.79 1.86 mg 300.0 1716.9 Th.yield: 326.0 g/mL 1.29 mL 0.23 5.5 7.0 List of Chemicals List of Materials 3-(Trifluoromethyl)aniline: 300 mg 2 x 50 mL round bottom flask OXONE: 1.717 g 2 x 100 mL Erlenmeyer flask HCl 1M: 30 mL 100 mL separatory funnel NaHCO3 sat. sol.: 20 mL 50-mL graduated cylinder NaCl sat. sol.: 20 mL Pasteur pipettes Magnesium sulfate: To dry 30 mL DCM solutions Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter) Silica gel: 8 g Vacuum filtration adapter Methylene chloride: 70 mL Magnetic stir bar H2O: 27 mL Spatulas 2 x 50 mL round bottom flask 2 x 100 mL Erlenmeyer flask 100 mL separatory funnel 50 mL graduated cylinder Pasteur pipettes Fritted Büchner funnel (4.5 cm high, 3.5 cm diameter) Vacuum filtration adapter Magnetic stir bar Spatulas 10 mL plastic syringes S56    Heating and stirring plate with support and clamp Filter paper Weighting paper or glass Pre-cut silica TLC plates TLC developing chamber Marker (for students to write their name on their flasks) Rotary evaporator Procedure 1. Weight 7 (0.23 mL) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add DCM (5.5 mL) and turn on the stirrer to dissolve 7. 4. To this solution, add a solution of oxone (1.717 g) in H2O (7.0 mL). 5. Next, stir this mixture vigorously for 2 h at rt under an inert atmosphere with the help of an argon balloon. During this time, the reaction changed from a colorless to a green solution. 6. At the end of this time, check the progress of the reaction via TLC (9:1 hexane: ethyl acetate). Be sure to spot 7 too. Note the Rf value for your product. 7. Add 5 mL of DCM and 5 mL of H2O. Transfer the mixture to a separatory funnel. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 8. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the lower DCM layer to the Erlenmeyer flask from the previous step containing the DCM layer. 9. Then add additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 10. Add the organic layer back to the separatory funnel and wash successively with 15 mL of HCl 1M twice, 20 mL of NaHCO3 sat. sol., 20 mL of H2O and 20 mL of brine. 11. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. 12. Decant the DCM through fluted filter paper into a 50 mL round bottom flask. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 13. Rotor evaporate the DCM. 14. Redissolve the residue obtained in 10 mL of DCM. 15. Weight a 50 mL round bottom flask, and fix aid to a support with a clamp. 16. Install a vacuum filtration adapter, a rubber vacuum adapter, and put a fritted Büchner funnel on top of it (4.5 cm high, 3.5 cm diameter). S57    17. Weight 8 g of silica gel and transfer it to the funnel. 18. Connect the system to a vacuum pump and apply suction to set the silica gel. 19. Turn off the vacuum. 20. Pipette the 10 mL DCM solution of 3a onto the top of the silica gel. 21. Turn on the vacuum and let the liquid flow into the flask. 22. Rinse the silica gel with 25 mL of DCM. 23. Turn off the vacuum, disassemble the equipment, and rotor evaporate the DCM. A light yellow solid reveals. 24. Record the weight of the product. Calculate the actual yield in 3a. 25. 3a must be stored in the refrigerator until the next lab session. Characterization data Light yellow solid Melting point: 74 – 76 ºC 1H-NMR (300 MHz, CDCl3): δ 8.09-8.16 (m, 2H, CF3-C=CH-C-NO, R-C=CH-CH-), 7.98 (d, J = 7.9 Hz, 1H, R-C=CH-CH-), 7.80 (t, J = 8.2 Hz, 1H, CH=CH-CH) ppm. 13C NMR (75 MHz, CDCl3): δ 164.0 (C-NO), 131.5 (q, JC-F = 3.6 Hz, CH=CH-C-CF3), 130.4 (CHAr), 124.0 (CHAr), 117.7 (q, JC-F 3.9 Hz, NO-C-CH-C-CF3) ppm. 19F NMR (282 MHz, CDCl3): δ ‐62.9 (s, 3F, CF3) ppm.  S58    7. Characterization data: Copies of spectra (actual student´s samples)   3a, 1H NMR (300 MHz, CDCl3)       S59      3a, 13C NMR (75 MHz, CDCl3)   3a, 13C NMR and DEPT 135 (75 MHz, CDCl3) S60      3a, 19F NMR (282 MHz, CDCl3)                               S61      3b, 1H NMR (300 MHz, CDCl3)       S62      3b, 13C NMR (75 MHz, CDCl3)   3b, 13C NMR and DEPT 135 (75 MHz, CDCl3) S63    NHF3C CN 6, 1H NMR (300 MHz, CDCl3)   S64    NHF3C CN 6, 13C NMR (75 MHz, CDCl3)   6, 13C NMR and DEPT 135 (75 MHz, CDCl3)   S65    6, 13C NMR (125 MHz, CDCl3)   1: 146.1 2: 141.0 3: 134.2 4: 133.4 5: 132.3 (q, JC-F = 32.5 Hz) 6: 130.4 7: 123.9 (q, JC-F = 272.4 Hz) 8: 123.9 (q, JC-F = 1.1 Hz) 9: 120.7 10: 120.4 (q, JC-F = 3.8 Hz) 11: 117.3 (q, JC-F = 3.9 Hz) 12: 117.3 13: 115.1 14: 100.1                 1  2  3  4  5  6  7  7  8  9  10  11 12  13  14  7  7  S66             3                          4                                                                                                       6  7                                                                                                                                             7  5  5  5  5  7                                               7  8                                                               9    10  S67      NHF3C CN 6, 19F NMR (282 MHz, CDCl3)   10    11  12  S68    NHF3C CN 6, IR     6, MS       NH  CN  S69    8a, 1H NMR (300 MHz, CDCl3) S70    8a, 13C NMR (75 MHz, CDCl3) S71    8a, 13C NMR and DEPT 135 (75 MHz, CDCl3) 1: 148.4 (C‐N) 2: 143.9 (C‐N) 3: 131.9 (q, JC‐F = 33.7 Hz, C‐CF3) 4: 131.5 (q, JC‐F = 32.7 Hz, C‐CF3)  5: 129.9 (CH)  6: 129.5 (CH) 7: 128.8 (q, JC‐F = 3.6 Hz, CH=C‐CF3)  8: 128.7 (CH) 9: 126.6 (q, JC‐F = 3.8 Hz, CH=C‐CF3) 10: 125.8 (d, JC‐F = 1.1 Hz, CH) 11: 123.9 (q, JC‐F = 272.6 Hz, CF3)  12: 123.4 (q, JC‐F = 272.9 Hz, CF3)  13: 122.9 (q, JC‐F = 3.9 Hz, CH=C‐CF3) 14: 119.9 (q, JC‐F = 3.9 Hz, CH=C‐CF3) S72     1       2      3       3       4 3       4       3      4      4       5       6        7       8       9       10         13       14     11       11       11       11      12       12       12       12       S73    8a, 19F NMR (282 MHz, CDCl3)     S74    8b, 1H NMR (300 MHz, CDCl3) S75    8b, 13C NMR (75 MHz, CDCl3)         S76    3b + 8b, 1H NMR (300 MHz, CDCl3)         S77      1, 1H NMR (500 MHz, DMSO‐d6)     S78    1, 13C NMR (75 MHz, DMSO‐d6) 1, 13C NMR and DEPT 135 (75 MHz, DMSO‐d6) S79    1, 13C NMR (125 MHz, DMSO‐d6) 1: 169.6 2: 145.5 3: 142.0 4: 134.1 5: 132.0 6: 130.5 7: 130.3 (q, JC-F = 31.8 Hz) 8: 124.1 (q, JC-F = 272.4 Hz) 9: 123.7 10: 118.9 11: 118.5 (q, JC-F = 3.7 Hz) 12: 116.3 (q, JC-F = 3.8 Hz) 13: 114.9 14: 114.5              1      2  3  4  5  6  7  8               8  9  10  11  13  14  12  8    8  S80         4   9                                   8                                           8   5  6   7                   7   7     7   8    8          S81    1, 19F NMR (282 MHz, DMSO‐d6)    10             11                                                                                                            12     S82    1, IR 1, MS NH  OH  CO  S83    8. HANDOUT FOR STUDENTS    I. INTRODUCTION In this experiment, you will synthesize flufenamic acid (Figure 1).1 Flufenamic acid is a drug that belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), which are used therapeutically for their anti-inflammatory, analgesic and anti-fever action. Compounds of this type constitute one of the families of best-selling drugs worldwide (there is an estimate of more than 100 million prescriptions per year only in the USA). Their importance relies on their anti-inflammatory, analgesic (pain reducing) and anti-fever actions, without the undesirable side effects of opioid analgesics (respiratory depression and addiction) or glucocorticoids (immunosuppression, hyperglycemia, osteoporosis, adrenal insufficiency, among other). The therapeutic activity of NSAIDs is thought to result from their ability to hinder the synthesis of prostaglandins by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Aspirin, a derivative of salicylic acid (salicylates) is the most well-known example of NSAIDs. Besides, most relevant commercial NSAIDs approved for use in humans belong to the families of fenamic acid derivatives (fenamates), propionic acid derivatives (profens), acetic acid derivatives, and enolic acid derivatives (oxicams). Figure 1. Structures of flufenamic acid (1) and other common NSAIDs. Fenamates, which can also be considered derivatives of anthranilic acid, are bioisosters of salicylates by replacement of an oxygen atom with an NH group.2 They possess higher anti-inflammatory activity than salicylates. In particular, flufenamic acid is effective in treating rheumatism, arthritis and other musculoskeletal inflammatory disorders very effectively. Esterification with diethyleneglycol affords etofenamate, another NSAID of the fenamate family with improved skin absorption, widely found in topical formulations.3 Flufenamic acid has also shown activity against other targets different from cyclooxygenases, and the core of flufenamic acid is found as well in drugs that belong to other therapeutic areas.4 Flufenamic acid and other N-arylanthranilic acids have been synthesized by the Ullmann-Goldberg condensation between o-halobenzoic acids and anilines (see section S84    II.3).5 The reaction usually requires harsh conditions, long reaction times, and yields are low. In this experiment, we have chosen as key step a new approach for the construction of the diaryamine moiety of 1 that consists of the use of boronic acids and nitrosobenzenes as reaction partners in a C-N bond-forming reaction carried out under transition-metal-free conditions.6,7 II. THEORETICAL BACKGROUND 1. Boronic Acids and Potassium Organotrifluoroborates8,9 1.A. Structure and General Reactivity Boronic acids are trivalent boron compounds that can be viewed as derivatives of boric acid by replacement of one of the OH groups by an alkyl, aryl, alkenyl or alkynyl group. They have a low-energy empty p orbital orthogonal to the three substituents of the sp2- hybridized boron atom. Therefore, they can act as Lewis acids by complexation with nucleophiles (Lewis bases), giving rise to borates. Organotrifluoroborates can be considered as derivatives of boronic acids. Potassium organotrifluoroborates may be in equilibrium with difluoroboranes and KF. This equilibrium can be shifted towards fluoride dissociation in the presence of additives that scavenge fluoride, such as BF3, TMSCl or LiBr. Due to the electron-withdrawing effect of fluorine, organodifluoroboranes are highly electrophilic at boron, and therefore very much prone to coordination with Lewis bases. One of the methods most commonly used for the synthesis of potassium organotrifluoroborates is the reaction of boronic acids with a concentrated solution of potassium bifluoride (KHF2).10 S85    Boronic acids and potassium organotrifluoroborates can act as carbon nucleophiles, like Grignard reagents, organolithiums or cuprates, which are among the most common carbon nucleophiles used in organic synthesis. However, these popular reagents are air and water sensitive. Therefore, they must be used under inert gas atmosphere and in anhydrous solvents. In addition, most cuprates must be generated in situ and are sensitive to temperature. On the other hand, boronic acids and potassium organotrifluoroborates are bench-stable carbon nucleophiles that do not require handling under inert atmosphere or in anhydrous solvents. However, these boron reagents are less nucleophilic than conventional organometallics. Therefore, the most popular reactions of boronic acids and organotrifluoroborates, such as the Suzuki, Hayashi-Miyaura, and Cham-Lam reactions, require catalysis by transition metals, and proceed by transmetalation to generate intermediate C-Metal species, which are the actual nucleophiles. Even so, boronic acids and potassium trifluoroborates are nucleophilic enough to participate in several C-C and C-heteroatom bond formation processes directly. Between the trivalent boronic acids and the tetravalent potassium trifluoroborates, the latter, being ate complexes, possess a more nucleophilic carbon backbone. Also, activation of boronic acids by transformation into borates enhances their ability to transfer their carbon backbone to electrophilic sites inter- or intramolecularly. 1.B C-Heteroatom Bond-Forming Reactions of Arylboronic Acids and Potassium Aryltrifluoroborates 1.B.1. Transition-Metal-Catalyzed Reactions: The Chan-Evans-Lam Reaction11 The Chan-Evans-Lam reaction (CuI/CuII/CuIII catalytic cycle) can be understood starting by ligand exchange between CuX2 and R2-YH (in many occasions a base is included to equilibrate R2-YH with the corresponding anion, which is more nucleophilic, and thus more active in the ligand exchange process). This gives rise to a new CuII species (X-CuII-YR2). A second ligand exchange (transmetalation of R1 from B to Cu) affords another CuII intermediate (R1-CuII-YR2). In order for coupling between R1 and S86    YR2 to occur smoothly (reductive elimination), oxidation (air) to a CuIII species is required.12 Reductive elimination affords the coupling product and CuI, which must be oxidized (air) to regenerate the active CuII catalyst. The reaction can also be performed with potassium organotrifluoroborates. This reaction may be used for the synthesis of diarylamines (see section II.3). 1.B.2. Transition-Metal-Free Reactions13 1.B.2.A. The ipso-Substitution Reaction R B OH OH Y B R OH OH -Y X¨ X R Y B OH HO - X- R YH + B(OH)3 1,2-Migration H2O 1 2 Coordination of a boronic acid to a species Y-X, where Y is a heteroatom-based nucleophililic center and X a moiety that can act as a leaving group, is followed by 1,2- migration of the carbon backbone from boron to Y, with simultaneous detachment of the leaving group X. Protonation (H2O) renders the final product and boric acid. 1.B.2.B. Substitution by ipso-SEAr14 The BF3K group enhances the nucleophilicity of the ipso-position of aromatic rings (ie., the position attached to boron) by factors of 103 – 104. 2. Nitrosoarenes 2.A. Structure15 Nitrosoarenes are aromatic compounds that incorporate the nitroso group (-N=O). The simplest representative is nitrosobenzene.16 The nitroso group is strongly electron- withdrawing, which combined with the presence of a lone pair on nitrogen, makes that compounds of this type (blue / green) tend to be in equilibrium with dimers (colorless) in solution.17 The extent of the equilibrium mainly depends on the substituents of the ring. Protonation on one on the oxygen atoms of any of these dimers followed by dehydroxylation gives rise to stable azoxybenzenes.18 S87    2.B. Examples of Typical Reactivity 2.B.1. Reaction with Amines 2.B.2. Reaction with Grignard Reagents 2.B.3. Reaction with Enamines 2.B.4. Cycloaddition Reactions   2.B.5. Oxidation and Reduction19,20 S88    2.B.6. The Cadogan synthesis of carbazoles Nitrosocompounds are intermediates in this synthesis of indole derivatives, which starts from a nitrocompound and is promoted by P(OEt)3. The driving force of the process is the formation of the strong O=P bond in O=P(OEt)3. The final step, a SEAr reaction, can be understood by two alternative reaction pathways, one of which involves a nitrene (path a).   2.C. Main Synthetic Methods20,21 2.C.1. Nitrosation of Electron-Rich Aromatics It consists of a SEAr reaction that can be carried out using various nitrosating agents as electrophiles. 2.C.2. Nitrosation of Aryltrifluoroborates S89    The nitrosation takes place by an ipso-SEAr reaction. See section 1.B.2.B. 2.C.3. Oxidation of Anilines This type of reaction is restricted to benzenes that do not carry other substituents prone to oxidation. Other side reactions include the formation of azocompounds by the reaction of the starting aniline with the nitroso compound, and overoxidation of nitroso to nitro. 2.C.4. Reduction of Nitrobenzenes The reaction consists of a two-step procedure that involves reduction of the nitro group to a hydroxylamine (Zn, HCl), which is subsequently oxidized (FeCl3) to the nitroso compound. The example illustrates the compatibility of the reduction and the oxidation with the alcohol group.   3. Other Syntheses of Diarylamines Flufenamic acid possesses a diarylamine structure. Diarylamines constitute an important class of organic compounds, frequently found among drugs, agrochemicals, dyes, radical-trapping antioxidants, electroluminescent materials, and ligands for transition-metal catalysis. Apart from the Cham-Evans-Lam reaction (see section1.B.1), most frequent methods for the synthesis of diarylamines make use of anilines and halobenzenes as starting materials in transition-metal-catalyzed coupling reactions. The most important procedures are the Ullmann-Goldberg22,23 and the Buchwald-Hartwig24,25 reactions. Both reactions share in common the in situ generation of an organometallic species of the type Ar1NH-M(n+2)-Ar2 by the interaction of Ar1NH2 and an aryl halide (Ar2X) with an S90    organometallic catalyst (MnL, L = ligands). The Ullmann-Goldberg reaction requires CuI species, while the Buchwald-Hartwig reaction requires Pd0 species. Both reactions are carried out in the presence of a base. The base is needed to equilibrate the starting aniline (Ar1NH2) with the corresponding amide, which is nucleophilic enough to displace an anionic ligand from an electrophilic metallic intermediate (ligand exchange). The dummy ligands (L) are crucial. They serve to stabilize the metallic intermediates in solution, avoiding the precipitation of elemental Cu or Pd. The Ar1NH-M(n+2)-Ar2 key intermediate is generated by oxidative addition.26 Reductive elimination gives the final product (Ar1-NH-Ar2) and regenerates the catalytically active species (MnL).   In the Ullmann-Goldberg reaction (CuI/CuIII catalytic cycle), the amide displaces a ligand from a CuI species to generate a CuI-NHAr1 intermediate. In the oxidative addition step, the CuI-NHAr1 species interacts with the aryl halide (Ar2X) to generate a CuIII intermediate (Ar2-CuIII-NHAr1) which evolves to the final product by reductive elimination. This step regenerates the catalytically active CuI species. In the Buchwald-Hartwig reaction (Pd0/PdII catalytic cycle), the oxidative addition step (generation of Ar2-PdII-X) goes first. Ligand exchange followed by reductive elimination renders the final product together with recovery of the catalytically active Pd0 species. Although general, these reactions require the use of expensive metallic catalysts, the presence of ligands, and extensive individual optimization of reaction conditions. Many transition-metal catalysts are highly toxic and sensitive to air and/or moisture. Residual traces of heavy metals in the final product can be difficult to remove. Due to their potential toxicity, this is not acceptable in pharmaceutical applications. As stated in the Introduction, flufenamic acid and other N-arylanthranilic acids have been synthesized by the Ullmann-Goldberg condensation between o-halobenzoic acids and anilines.5   S91    III. EXPERIMENTAL SECTION 1. Overview The overall synthetic scheme is given in Figure 2. The target molecule (flufenamic acid, 1) will be obtained by the basic hydrolysis of nitrile 6. The key step of the sequence is the synthesis of 6 by a C-N bond-forming reaction which consists of the interaction of an arylboronic acid (2a or 2b) with a nitrosocompound (3a or 3b) promoted by P(OEt)3.6 Two complementary approaches will be followed (Group A and Group B), in order for you to compare yields: In one of them (Group A), aryboronic acid 2a will react with nitrosocompound 3a; in the other (Group B), arylboronic acid 2b will react with nitrosocompound 3b. Additionally, you will exercise two different examples for the synthesis of nitrosocompounds: The nitrosation of aryltrifluoroborates (4  3a) and the oxidation of anilines (5  3b). Figure 2. Overall synthetic scheme. Observe that none of the transformations in the sequence involves the use of any transition metals, and are carried out without the need of inert gas atmosphere or especially dried solvents.       S92    2. Synthesis of nitrosoarenes 3a and 3b 2.1. Synthesis of 1-Nitroso-3-(trifluoromethyl)benzene 3a (Group A) Calculations 4 NOBF4 MeCN 3a equiv. 1.0 1.03 --- g/mol mmol mg 1000.0 477.4 --- mL --- --- 12.0 --- Procedure 1. Weight 4 (1 g) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add MeCN (12.0 mL) and turn on the stirrer to dissolve 4. 4. To this solution, add NOBF4 (477.4 mg). 5. Stir this mixture for 30 min at rt. During this time, the reaction changes from a colorless to a brown solution. At the end of this time, check the progress of the reaction via TLC (9:1 hexane: ethyl acetate). Be sure to spot 4 too. Note the Rf value for your product. 6. Add 10 mL of DCM and 15 mL of H2O. Transfer the mixture to a separatory funnel. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 7. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the lower DCM layer to the Erlenmeyer flask from the previous step containing the DCM layer. 8. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 9. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. 10. Decant the DCM into a 50 mL round bottom flask through fluted filter paper. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 11. Rotor evaporate the DCM. 12. Redissolve the residue in 10 mL of DCM. S93    13. Weight a 50 mL round bottom flask, and fix aid to a support with a clamp. 14. Install a vacuum filtration adapter, a rubber vacuum adapter, and put a fritted Büchner funnel on top of it (4.5 cm high, 3.5 cm diameter). 15. Weight 8 g of silica gel, and transfer it to the funnel. 16. Connect the system to a vacuum pump and apply suction to set the silica gel. 17. Turn off the vacuum. 18. Pipette the 10 mL DCM solution of 3a onto the top of the silica gel. 19. Turn on the vacuum and let the liquid flow into the flask. 20. Rinse the silica gel with 25 mL of DCM. 21. Turn off the vacuum, disassemble the equipment, and rotor evaporate the DCM. A light yellow solid reveals. 22. Record the weight of your product. Calculate the actual yield in 3a. 23. Compound 3a must be stored in the refrigerator until the next lab session. Characterization data S94    2.2. Synthesis of 2-Nitrosobenzonitrile 3b (Group B) Calculations 5 Oxone DCM H2O 3b equiv. 1.0 2.0 --- --- g/mol --- --- mmol --- --- mg 300.0 --- --- mL --- --- 5.0 20.5 --- Procedure 1. Weight 5 (300 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add DCM (5.0 mL) and H2O (20.5 mL) and turn on the stirrer to dissolve 5. 4. To this solution, add oxone (3.12 g). 5. Next, stir this mixture vigorously for 1.5 h at rt. During this time the reaction changed from a colorless to a green solution. 6. At the end of this time, check the progress of the reaction via TLC (7:3 hexane: ethyl acetate). Be sure to spot 5 too. Note the Rf value for your product. 7. Transfer the reaction to a separatory funnel. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 8. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the lower DCM layer to the Erlenmeyer flask from the previous step containing the DCM layer. 9. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 10. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 11. Add the organic layer back to the separatory funnel and wash successively with 20 mL of HCl 10%, 20 mL of NaHCO3 10% and 20 mL of brine. 12. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. S95    13. Decant the DCM through fluted filter paper into a 50 mL round bottom flask. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 14. Rotor evaporate the DCM. 15. Redissolve the residue obtained in 10 mL of DCM. 16. Weight a 50 mL round bottom flask, and fix aid to a support with a clamp. 17. Install a vacuum filtration adapter, a rubber vacuum adapter, and put a fritted Büchner funnel on top of it (4.5 cm high, 3.5 cm diameter). 18. Weight 8 g of silica gel, and transfer it to the funnel. 19. Connect the system to a vacuum pump and apply suction to set the silica gel. 20. Turn off the vacuum. 21. Pipette the 10 mL DCM solution of 3b onto the top of the silica gel. 22. Turn on the vacuum and let the liquid flow into the flask. 23. Rinse the silica gel with 25 mL of DCM. 24. Turn off the vacuum, disassemble the equipment, and rotor evaporate the DCM. A light yellow solid reveals. 25. Record the weight of your product. Calculate the actual yield in 3b. 26. Compound 3b must be stored in the refrigerator until the next lab session. Characterization data Compound 8b (azoxybenzene derived from 3b) was obtained as subproduct. Characterization data S96    3. Synthesis of 2-((3-(Trifluoromethyl)phenyl)amino)benzonitrile 6 3.1. Reaction of 2a with 3a (Group A) Calculations 3a 2a P(OEt)3 THF 6 equiv. 1.0 1.5 1.1 --- g/mol --- mmol --- mg 200.0 --- g/mL --- --- --- --- mL --- --- 5.0 --- Procedure 1. Weight 3a (200 mg) and 2a (251.7 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add THF (5.0 mL) and turn on the stirrer to dissolve the mixture. 4. To this solution, add P(OEt)3 (0.215 mL). The reaction changes from a green to a brown solution. 5. Stir this mixture for 20 minutes at rt. 6. At the end of this time, check the progress of the reaction via TLC (9:1 hexane: ethyl acetate). Be sure to spot 3a too. Note the Rf value of the product. 7. Rotor evaporate the solvent, and redissolve the residue obtained in 2 mL of DCM. 8. Prepare a silica gel column (2 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 15 g of silica gel in hexanes (50 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 9. Pipette crude 6 in DCM onto the top of the column, let adsorb, and add a layer of sand. 10. Add 100 mL of 98:2 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect 10 mL fractions with the aid of air pressure from the top. 11. Add 100 mL of 96:4 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. S97    12. Add 50 mL of 94:6 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 13. Add 50 mL of 92:8 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 14. Spot each of the fractions from steps 10, 11, 12 and 13 on TLC plates (you might need more than one plate) and develop with 9:1 hexane: ethyl acetate. Two spots must be observed. The product has the lowest Rf value (0.38). It will most likely elute towards the end of the 96:4 or at the beginning of the 94:6 hexanes: ethyl acetate fraction. 15. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 16. Record the weight of your product. Calculate the actual yield in 6. 17. Use about 0.6 mL of CDCl3 to transfer 25 mg of 6 to an NMR tube. Record the NMR spectra. Characterization data Compound 8a (azoxybenzene derived from 3a) was obtained as subproduct. Characterization data S98    3.2. Reaction of 2b with 3b (Group B) Calculations 3b 2b P(OEt)3 THF 6 equiv. 1.0 1.5 1.1 --- g/mol --- mmol --- mg 200.0 --- g/mL --- --- --- --- mL --- --- 6.0 --- Procedure 1. Weight 3b (200 mg) and 2b (431.3 mg) in a 50 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add THF (6.0 mL) and turn on the stirrer to dissolve the mixture. 4. To this solution, add P(OEt)3 (0.286 mL). The reaction changed from a green to a yellow solution. 5. Stir this mixture for 20 minutes at rt. 6. At the end of this time, check the progress of the reaction by TLC (7:3 hexane: ethyl acetate). Be sure to spot 3b too. Note the Rf value of the product. 7. Rotor evaporate the solvent, and redissolve the residue obtained in 2 mL of DCM. 8. Prepare a silica gel column (2 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 15 g of silica gel in hexanes (50 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 9. Pipette crude 6 in DCM onto the top of the column, let adsorb, and add a layer of sand. 10. Add 50 mL of 98:2 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect 10 mL fractions with the aid of air pressure from the top. 11. Add 50 mL of 96:4 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 12. Add 50 mL of 94:6 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. S99    13. Add 50 mL of 92:8 hexanes: ethyl acetate and collect 10 mL fractions with the aid of air pressure from the top. 14. Spot each of the fractions from steps 10, 11, 12 and 13 on TLC plates (you might need more than one plate) and develop with 9:1 hexane: ethyl acetate. The product has the highest Rf value (0.38). It will most likely elute towards the end of the 96:4 or at the beginning of the 94:6 hexanes: ethyl acetate fraction. 15. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 16. Record the weight of your product. Calculate the actual yield in 6. 17. Use about 0.6 mL of CDCl3 to transfer 25 mg of 6 to an NMR tube. Record the NMR spectra. Characterization S100    4. Synthesis of Flufenamic acid 1 (Groups A and B) KOH H2O:MeOH 100ºC, 18 h HN CF3 1 HO2C HN CF3 6 NC Calculations 6 KOH MeOH H2O 1 equiv. 1.0 93.8 --- --- g/mol 56.10 --- --- mmol 32.2 --- --- mg 90.0 --- --- mL --- --- 8.0 12.5 --- Procedure 1. Weight 6 (90 mg) in a 25 mL round-bottom flask. 2. Introduce a stirrer and place the flask on a stirring plate with the aid of a support and a clamp. 3. Add MeOH (8.0 mL) and H2O (12.5 mL) and turn on the stirrer to dissolve 6. 4. To this solution, add KOH (1.806 g). 5. Stir this mixture vigorously overnight at 100ºC in an oil bath with a reflux condenser. 6. At the end of this time, check the progress of the reaction via TLC (7:3 hexane: ethyl acetate). Be sure to spot 6 too. Note the Rf value for your product. 7. After cooling to room temperature, remove MeOH in an evaporator. 8. Cool the resulting aqueous solution to 0ºC using an ice bath. 9. Dropwise add a solution of HCl 2M until pH 3. 10. Transfer the reaction to a separatory funnel. Add 10 mL of DCM to the separatory funnel containing the aqueous layer and shake. When the layers separate, collect the bottom organic layer in an Erlenmeyer flask. 11. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 12. Add an additional 10 mL of DCM to the separatory funnel containing the aqueous layer. Shake and combine the DCM layer with the previous DCM layers in the Erlenmeyer flask. 13. Collect the DCM layer to the Erlenmeyer flask and add MgSO4. Let sit for 5 min. S101    14. Decant the DCM through fluted filter paper into a 50 mL round bottom flask. Rinse MgSO4 twice with 5 mL of DCM into the round bottom flask. 15. Rotor evaporate the DCM, and redissolve the residue obtained in 2 mL of DCM. 16. Prepare a silica gel column (1 cm diameter) by laying a small plug of cotton to cover the outlet. Prepare a slurry of 5 g of silica gel in hexanes (30 mL), pour the slurry into the column. Make sure that the column is prepared in the hood. 17. Pipette the crude 1 in DCM onto the top of the column, let adsorb, and add a layer of sand. 18. Add 50 mL of 9:1 hexanes: ethyl acetate taking care not to disturb the layer of sand and collect the resulting flow through in an Erlenmeyer flask with the aid of air pressure from the top. 19. Add 50 mL of 8:2 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 20. Add 50 mL of 7:3 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 21. Add 100 mL of 6:4 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 22. Add 100 mL of 1:1 hexanes: ethyl acetate and collect 5 mL fractions with the aid of air pressure from the top. 23. Spot each of the fractions from steps 19, 20, 21 and 22 on TLC plates (you might need more than one plate) and develop with 1:1 hexane: ethyl acetate. The Rf value of the product is 0.36. It will most likely elute towards the end of the 6:4 or at the beginning of the 1:1 hexanes: ethyl acetate fraction. 24. Add all the fractions of interest to a pre-weighed round bottom flask and rotor- evaporate to remove the solvent. After removing the solvent, you might want to use a gentle stream of air to remove any residual ethyl acetate. You should obtain a white solid. 25. Record the weight of your product. Calculate the actual yield in 1. 26. Use about 0.6 mL of DMSO-d6 to transfer 25 mg of 1 to an NMR tube. Record the NMR spectra. 27. Determine the melting point of compounds 3a, 3b, 6 and 1. Characterization data S102    IV. REFERENCES AND NOTES (1) (a) N-(3-Trifluoromethylphenyl)anthranilic acid antiinflammatory drug. Parke Davies & Co. FR M1341 19620702 (1962). (b) Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, William Andrew Publishing, USA, 2007, p 1644. (c) For an overview of flufenamic acid, see: Abignente, E.; de Caprariis, P. Flufenamic acid. Anal. Profile Drug Subst. 1982, 11, 313-346. (2) Besides flufenamic acid, other representatives of the fenam family of NSAIDs are mefenamic acid, mechlofenamic acid, tolfenamic acid and etofenamate. (3) (a) Bolze, K. H.; Brendler, O.; Lorenz, D. Antiphlogistic alkoxyethyl N-[m- (trifluoromethyl)phenyl]anthranilates. Ger. Offen. (1971), DE 1939112 A 19710204. (b) Pharmaceutical Manufacturing Encyclopedia, 3rd Edition, William Andrew Publishing, USA, 2007, p 1526. (4) See for example: Monteillier, A.; Loucif, A.; Omoto, K.; Stevens, E. B.; Vicente, S. L.; Saintot, P.-P.; Cao, L.; Pryde, D. C. Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1. Bioorg. Med. Chem. Lett. 2016, 26, 4919-4924. (5) For previous syntheses of flufenamic acid (Ullman-Goldberg reaction), see Ref 1, and in addition: (a) Chalmers, D. K.; Scholz, G. H.; Topliss, D. J.; Kolliniatis, E.; Munro, S. L. A.; Craik, D. J.; Iskander, M. N.; Stockigt, J. R. Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity. J. Med. Chem. 1993, 36, 1272-1277. (b) Dokorou, V.; Primikiri, A.; Kovala- Demertzi, D. The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents. J. Inorg. Biochem. 2011, 105, 195-201. (c) Zheng, Z.; Dian, L.; Yuan, Y.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. PhI(OAc)2-Mediated Intramolecular Oxidative Aryl-Aldehyde Csp2-Csp2 Bond Formation: Metal-Free Synthesis of Acridone Derivatives. J. Org. Chem. 2014, 79, 7451-7458, and references cited therein. (6) Roscales, S.; Csákÿ, A. G. Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling. Org. Lett. 2018, 20, 1667-1671. (7) For the synthesis of diarylamines by the addition of main-group organometallics to nitroso compounds, see: Dhayalan, V.; Sämann,C.; Knochel, P. Synthesis of polyfunctional secondary amines by the addition of functionalized zinc reagents to nitrosoarenes. Chem. Commun. 2015, 51, 3239-3242, and references cited therein. (8) For an overview of the structure, properties, preparation, reactions and applications of boronic acids, see: Hall D. In Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, Hall, D., Ed.; Wiley-VCH: Weinheim, 2011, Ch 1.   S103      (9) For an overview of the preparation and reactivity of organotrifluoroborates, see: (a) Molander, G. A.; Jean-Gérard, L. In Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, Hall, D., Ed.; Wiley-VCH: Weinheim, 2011, Ch 11. (b) Molander, G. A. Organotrifluoroborates: Another Branch of the Mighty Oak. J. Org. Chem. 2015, 80, 7837-7848. (10) See Ref. 10a, and in addition: Ting, R.; Harwig, C. W.; Lo, J.; Li, Y.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Substituent Effects on Aryltrifluoroborate Solvolysis in Water: Implications for Suzuki−Miyaura Coupling and the Design of Stable 18F-Labeled Aryltrifluoroborates for Use in PET Imaging. J. Org. Chem. 2008, 73, 4662-4670. (11) For reviews on the Cham-Evans-Lam coupling, see: (a) Qiao, J. X.; Lam, P. Y. S. Copper-Promoted Carbon-Heteroatom Bond Cross-Coupling with Boronic Acids and Derivatives. Synthesis 2011, 829-856. (b) Qiao, J. X.; Lam, P. Y. S. Recent advances in Chan-Lam coupling reaction: Copper-promoted C-heteroatom bond cross-coupling reactions with boronic acids and derivatives. In Boronic Acids, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011; Vol. 1, p 315. (c) Rao, K. S.; Wu, T. –S. Chan–Lam coupling reactions: synthesis of heterocycles. Tetrahedron 2012, 68, 7735-7754. (12) This CuIII species is similar to the one formed in the Ullmann-Goldberg reaction by ligand exchange followed by oxidative addition. See section II.3. (13) For transition-metal-free C-Heteroatom bond-forming reactions or arylboronic acids and their derivatives, see the following reviews: (a) Coeffard, V.; Moreau, X.; Thomassigny, C.; Greck, C. Transition-Metal-Free Amination of Aryl boronic Acids and Their Derivatives. Angew. Chem. Int. Ed. 2013, 52, 5684-5686. (b) Zhu, C.; Falck, J. R. Transition-Metal-Free ipso-Functionalization of Arylboronic Acids and Derivatives. Adv. Synth. Catal. 2014, 356, 2395-2410. (14) Molander, G. A.; Cavalcanti, L. N. Metal-Free Chlorodeboronation of Organotrifluoroborates. J. Org. Chem. 2011, 76, 7195-7203. (15) Rück-Braun, K.; Priewisch, B. Nitrosoarenes. Science of Synthesis 2007, 31, 1321-1360. (16) Baeyer, A. Nitrosobenzol und Nitrosonaphtalin. Chem. Ber. 1874, 7, 1638-1640. (17) (a) Challis, B. C.; Higgins, R. J.; Lawson, A. J. The chemistry of nitroso- compounds. Part III. The nitrosation of substituted benzenes in concentrated acids. J. Chem. Soc., Perkin Trans. 2, 1972, 1831-1836. (b) Fletcher, D. A.; Gowenlock, B. G.; Orell, K. G. Structural investigations of C-nitrosobenzenes. Part 1. Solution state 1H NMR studies. J. Chem. Soc., Perkin Trans. 2, 1997, 2201-2206. (18) Chen, Y. –F.; Chen, J.; Lin, L. J.; Chuang, G. J. Synthesis of azoxybenzenes by reductive dimerization of nitrosobenzene. J. Org. Chem. 2017, 82, 11626-11630.  (19) Oxone is the trade name of a mixture of 2KHSO5, KHSO4, and K2SO4. The mixture is more bench stable than KHSO5, which is the true oxidant (K+ -OSO2-O-OH, potassium monoperoxysulfate, an activated form of hydrogen peroxide). See: Potassium S104      Monoperoxysulfate. Crandall, J. K.; Shi, Y.; Burke, C. P.; Buckley, B. R. (2001). E-EROS Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons, Ltd. doi:10.1002/047084289x.rp246. (20) Molander, G. A.; Cavalcanti, L. N. Nitrosation of Aryl and Heteroaryltrifluoroborates with Nitrosonium Tetrafluoroborate. J. Org. Chem. 2012, 77, 4402-4413. (21) Reviews: (a) Gowenlock, B. G.; Richter-Addo, G. B. Preparations of C-Nitroso Compounds. Chem. Rev. 2004, 104, 3315-3340. (22) See for example: (a) Kunz, K.; Scholz, U.; Ganzer, D. Renaissance of Ullmann and Goldberg reactions - progress in copper catalyzed C-N-, C-O- and C-S-coupling. Synlett 2003, 2428-2439. (b) Evano, G.; Blanchard, N.; Toumi, M. Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis. Chem. Rev. 2008, 108, 3054-3131. (c) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 2014, 43, 3525-3550. (d) Okano, K.; Tokuyama, H.; Fukuyama, T. Copper-mediated aromatic amination reaction and its application to the total synthesis of natural products. Chem. Commun. 2014, 50, 13650-13663. (e) Jiang, Y.; Ma, D. In Copper-Mediated Cross-Coupling Reactions, Evano, G., Blanchard, N., Eds.; John Wiley & Sons: New Jersey, 2014. For anthranilic derivatives, see: (f) Girisha, H. R.; Srinivasa, G. R.; Gowda, D. C. A simple and environmentally friendly method for the synthesis of N-phenylanthranilic acid derivatives. J. Chem. Res. 2006, 342-344. (g) Mei, X.; August, A. T.; Wolf, C. Regioselective Copper-Catalyzed Amination of Chlorobenzoic Acids:  Synthesis and Solid-State Structures of N-Aryl Anthranilic Acid Derivatives. J. Org. Chem. 2006, 71, 142-149. (23) The Ullmann reaction is the synthesis of biaryls by coupling of arylhalides in the presence of Cu. The Ullmann condensation is the synthesis of diarylethers by condensation of arylhalides and phenols in the presence of Cu. The Goldberg variation consists of the use of nitrogen nucleophiles instead of phenols, to give arylamines. (24) Contemporary back-to-back studies from the Buchwald and the Hartwig groups differ in the type of base and ligands (bidentate phosphines and sterically hindered ligands) they use. (25) See for example: (a) Schlummer, B.; Scholz, U. Palladium-Catalyzed C-N and C- O Coupling –A Practical Guide from an Industrial Vantage Point. Adv. Synth. Catal. 2004, 346, 1599-1626. (b) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Industrial‐Scale Palladium‐Catalyzed Coupling of Aryl Halides and Amines –A Personal Account. Adv. Synth. Catal. 2006, 348, 23-39. (c) Surry, D. S.; Buchwald, S. L. Selective Palladium-Catalyzed Arylation of Ammonia:  Synthesis of Anilines as Well as Symmetrical and Unsymmetrical Di- and Triarylamines. J. Am. Chem. Soc. 2007, 129, 10354-10355. (d) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed S105      amination: a user's guide. Chem. Sci. 2011, 2, 27-50. (e) Lundgren, R.; Stradiotto, M. Recent Advances in the Buchwald–Hartwig Amination Reaction Enabled by the Application of Sterically Demanding Phosphine Ancillary Ligands. Aldrichim. Acta 2012, 45, 59-65. (f) Guram, A. S. 2016 Paul N. Rylander Award Address: Enabling Palladium/Phosphine-Catalyzed Cross-Coupling Reactions for Practical Applications. Org. Process Res. Dev. 2016, 20, 1754-1764. (26) By contrast, the Chan-Evans-Lam reaction (section II.1.B.1) does not involve an oxidative addition step. See Ref. 13, 14. S106    9. QUESTIONS FOR STUDENTS  PRELAB QUESTIONS    Draw an arrow‐pushing mechanism to explain the mechanism for the following reactions:  a)    b)         Search the recent literature for a recent example of the synthesis of a diarylamine by the  following procedures:  a) Chan‐Evans‐Lam reaction  b) Ullmann‐Goldberg reaction  c) Buchwald‐Hartwig reaction     Draw an arrow‐pushing mechanism for the formation of diisopropyl 2‐(phenylimino)  malonate by the reaction of nitrosobenzene with diisopropylmalonate (NaOH, EtOH).    POSTLAB QUESTIONS    Suggest a mechanism for the synthesis of 2‐((3‐trifluoromethyl)phenyl)amino)benzonitrile  from a nitrosobenzene and a boronic acid in the presence of P(OEt)3.     Compare the yield in 6 obtained by reacting the boronic acid 2a with the nitrosobenzene  3a (Group A) with that obtained by reacting the boronic acid 2b with the nitrosobenzene  3b, and draw your own conclusions for the process.     Draw a mechanism for the conversion of benzonitrile into benzoic acid under aqueous basic  conditions and under aqueous acidic conditions. S107    10.  Guide for the discussion sessions    10.1.  Suggested topics for the pre‐lab discussion session   Solutions  to  the  pre‐lab  questions  (Note  that  some  students  need  help  with  reaction  searching on databases).   Nucleophilicity  of  boronic  acids  in  comparison  to  cuprates,  Grignard  reagents  and  organolithiums. Compatibility with humidity, air, and functional‐group tolerance. Enhanced  nucleophilicity of ate‐species.   Examples of C‐C and C‐N bond‐forming reactions of boron reagents under transition‐metal‐ free conditions.   Typical reactivity of nitrosobenzenes, and the Cadogan synthesis of carbazoles.   Typical syntheses of nitrosobenzenes, boronic acids and potassium trifluoroborates.   Potential  issues  with  metal‐free  pathways  in  comparison  to  transition‐metal‐catalyzed  procedures:   o Which are the subproducts of the coupling reaction, and what is their toxicity (synthesis  of 1)?  o Which  are  the  subproducts  of  the  Chan‐Evans‐Lam, Ullmann‐Goldberg  and  Buchwald‐ Hartwig reactions, and what are their toxicities? The discussion could be narrowed to the  synthesis of flufenamic acid by the Ullmann‐Goldberg reaction.  o How  do  metal‐free  and  transition‐metal‐catalyzed  procedures  compare  in  terms  of  toxicity and waste disposal?      10.2.  Suggested topics for the post‐lab discussion session   Solutions to post‐lab questions.   Why  is  the  reaction  with  oxone  carried  out  under  biphasic  conditions?  What  are  the  advantages of using biphasic systems in organic synthesis?   Discussion of the performance of both procedures for the synthesis of nitrosocompounds 3  and intermediate 6 taking into account the balance of reaction times, easiness of purification,  toxicity of reagents, and waste disposal.   Mechanism for the formation of compounds 8.   Comparison of the actual yield  in 1  in this experiment with the yield of 1 reported by the  Ullmann‐Goldberg reaction.   Explanation  of  the  difference  in  basicity  between  anilines  and  diphenylamines,  and what  implications does this factor have in the work‐up procedure for the synthesis of 6 and 1.   Comparison of the actual melting points with literature values.   Discussion of the data in spectra:  o Information extracted from the IR spectra (characteristic functional groups).  o Assignment  of  signals  in  the  1H  NMR  (typical  splitting  patterns  of  different  types  of  substituted aryl rings).   o Assignment of signals in the 13C NMR spectra (Note that some students need help with  the interpretation of C‐F couplings).  o Information extracted from the 19F NMR spectra.  o Information extracted from the MS spectra (ortho‐effect).  S108      11.  Sample Student Report            S109              S110          S111          S112          S113          S114          S115          S116          S117