Hydrogen Borrowing amination using Knolker (Fe) type catalyst, Tesi di laurea di Chimica Organica

Scarica Hydrogen Borrowing amination using Knolker (Fe) type catalyst e più Tesi di laurea in PDF di Chimica Organica solo su Docsity! UNIVERSITÀ DEGLI STUDI DI MILANO FACOLTÀ DI SCIENZE E TECNOLOGIE Corso di Laurea Magistrale in Scienze Chimiche Amination of secondary alcohols using a cyclooctene-derived (cyclopentadienone)iron pre-catalyst Relatore: Dr. Luca PIGNATARO Correlatore: Prof. Dr. Cesare GENNARI Tesi di Laurea di: Francesco Ettore AIOLFI Matricola 901515 Anno Accademico 2017-2018 Preface In this master thesis, the work | carried out during period of one year stay in Prof. Cesare Gennari’s and Dr. Luca Pignataro’s research group is reported: | worked on the ‘hydrogen borrowing’ amination of amines. After an introduction about catalysis and iron catalysts, focused in particular on (cyclopentadienone)iron tricarbonyl complexes, the catalytic results are discussed, with a particular emphasis on practical aspects such as reaction conditions, workup procedures and problems we had to face during the practical work. 51 1. INTRODUCTION Naturalissimum et perfectissimum opus est generare tale quale ipsum est. [The most natural and perfect work is to produce every substance according to its essence] Anonymous 61 Chapter 1: Introduction 1.1 Story of catalysis Today catalysis plays a fundamental role in the manufacture of the vast majority of chemicals used by our society, but this phenomenon is known from very ancient times. This term was proposed for the first time in 1835 by Jòns Jakob Berzelius, comes from the Greek words Kata meaning down and /yein meaning loosen.!! In the 1910s Emil Fischer foresaw the industrial importance of catalysis, as it is “[...] virtually unlimited, and thorough investigations în this area promise considerable success”! Nowadays the most accepted definition of this word says that “A catalyst is a substance which increases the rate at which a chemical reaction approaches equilibrium without becoming itself permanently involved”.!1 Catalysts have always been used in all human's history, as for the production of alcoholics drinks or, during the Middle Ages helping the alchemists, intent to discover a magical substance able to convert base into noble metals. But it's only during the XVIII century that is possible to see the first important results in this field. Among the first industrial catalytic process are a few inorganic oxidation processes, like the Deacon process (oxidation of HCI into Cl.) or the production of sulfuric acid. But all of these processes had been developed before a scientific basis of chemical reactivity was established;! only after the formulation of the theory of chemical equilibria by Van’t Hoff a framework for catalysis development become available.!! A flourishing period for catalysis begins during the end of the XIX century, when the growth of academic knowledge was translated into industrial applications. At this point the number of catalytic processes that had been developed had grown into hundreds and the economic potential of some of these processes were highly feasible. There was also a general growth in the demand for bulk chemicals and petrol chemicals where minimization of by-products, using catalysis, had evident economic advantages. During whole period of World War | the industrial production of chemicals reached preposterous proportions, in particular for the demands of explosives based upon nitric acid. A logical way to go was to use the heterogeneous metal catalysts which had just been developed at that time. Heterogeneous catalyst act in a different phase than the reactants; most of them are solids that act on substrates in a liquid or gaseous reaction mixture. This kind of catalysts are still used in some of the important industrial processes (Haber-Bosch, polymerizations, Fischer-Tropsch, etc.), due to the ease of catalyst recovery and product separation. The 1950s represent a very important periods in the history of catalysis; for the first time Foraday Society organized a conference devoted to heterogeneous catalysis and, in 1953 Karl Ziegler discovered a catalytic system for polymerizing ethylene at low temperatures and pressures to form linear crystalline polyethylene,I? shown in Scheme 1. One year later Giulio Natta invented stereo-specific polymerization of propylene to form crystalline propylene.!8! Ziegler's and Natta’s discovery gave birth to a new industry, and new products based upon their original ideas are continuously being developed today. Ziegler and Natta were awarded the Nobel Prize in 1963 for their work on polymerization. Me Scheme 1: Simplifled mechanism for Zr-catalyzed ethilene polymerization In a few years an extraordinary number of new catalysts and processes were blooming. An example is the Mobil Qil’s development of the rare earth metal stabilized X-zeolite for catalytic cracking. When in 1965, Wilkinson developed a Ru-based homogeneous catalyst (Figure 1) for the hydrogenation of alkenes and alkynes at room temperature, a new branch of catalysis started.!!9 PhaP_ pyePPhe e PhyP) Figure 1: Wilkinson's Catalyst 71 Chapter 1: Introduction N 7 I NN Pr Her XL Pe N ; N—Ffel-N PP osso TT per ter Ph R=M6,ELBn 3 4 Chirik Peters Figure 3: Chirik 3 and Peters 4 organoiron complexes In particular, complex 3 showed good activity with several types of olefins and unsaturated ethers, esters and amines under mild conditions (4 atm H:, room temperature), as well as a broad functional group tolerance. However, a strong limitation of this catalyst it is the difficult preparation, as well as the high air sensitivity. Spectroscopic studies and calculations established that this compound, which is formally an Fe° complex (with neutral ligands), actually has the oxidation state of an Fe*? compound, the metal transferring two electrons to the bis(imino)pyridine ligand.!?5) The latter behaves as a redox non-innocent ligand (NIL), being able to partially delocalize the electrondensity of the complex (in contrast to traditional innocent ligand!?81) and thus taking active part in the catalytic cycle by undergoing redox changes.!??? The difference in electronic structure between first-row transition metals (prone to one-electron redox changes) and second-/third-row transition metals (that easily undertake two-electron redox changes), is the main difficulty in the development of Fe, Co, Ni and Cu catalysts. Although Fe has been employed widely in heterogeneous catalysis, the examples of use in homogeneous catalysis are quite scarce,?8! due to this tendency to engage in radical reactions rather than in two-electron process. However, the use of non- innocent ligands may force the Fe catalyst to follow reactivity patterns different from the more common ones. 1.3.2 Iron complexes for the hydrogenation of C-X multiple bond The examples of iron-catalyzed reduction of the C=X bond (X = O or NR) are more numerous than those regarding C=C hydrogenation. They include also enantioselective catalysts such as complexes!9 5a and 5b, synthesized by Morris and co-workers and used in the catalytic hydrogenation (CH) and transfer hydrogenation (CTH) of ketones, or the bis-isonitrile complex 6, developed by Reiser!!! and used in the transfer hydrogenation of ketones. Highly effective achiral catalysts for the hydrogenation of ketones, aldehydes and imines have been also developed (Figure 4), respectively, by Casey et al .!#2***9 (employing a complex previously synthesized by Knélker et al.!31), Milstein (who used PNP pincer ligand complexes)!*9! and Beller!?71, 2 Ph Ph _ tBu tBu n 28Ph; 7 E Feat S e | Pha Pha Neck X= CHioN Y = CO, 1-BU-NC or CHICN 5a 5b 6 Ta Morris Raiser Casey al [EF Bn| PPha 8 9 Milstein Beller Figure 4: Iron complexes for the CTH of C-X multiple bond 10] Chapter 1: Introduction 1.4 (Cyclopentadienone)iron complexes (Cyclopentadienone)iron tricarbonyl complexes, firstly reported by Reppe and Vetter in 1953,!29 can be easily synthetized and purified due to their stability to air, moisture, and column chromatography on silica gel. Perhaps surprisingly, it was not before 40 more years that Knélker® and Pearson!9 investigated their reactivity in depth: in 1999, Knélker and co-workers synthesized and isolated the first (hydroxycyclopentadienyl)ironhydridedicarbonyl complex 7a from the stable (cyclopentadienone)iron tricarbonyl complex 10a using a Hieber-base reaction (Scheme 2). However, the potential use of the active hydride 7a in catalysis remained concealed until 2007, when Casey and Guan reported its activity for the hydrogenation of aldehydes, ketones and imines.4 Complex 7a showed similar properties to the structurally related Shvo catalyst (11), a dinuclear ruthenium hydride, known since 1985, in which the hydride ligand bridges the two ruthenium metal centers.!42) A B pre SiMez = = __M)NaOH, THE on ‘SiMeg ‘SiMe; Ph 2) H3PO, 3 00- F®xco 4 00-78, Ranco oc cc co 10a Ta 11 Shvo's catalyst Scheme 2: A. Conversion of (cyclopentadienone)iron complex 10a into corresponding (hydrocyclopentadienyi)iron complex 7a B. Shvo's catalyst 11. Casey and Guan demonstrated that hydride 7a is a highly efficient catalyst for the chemoselective hydrogenation of aldehydes, ketones and imines under mild conditions (Scheme 3) and according to a concerted outer-sphere mechanism in which the ligand is involved with its OH group.! A large number of functional groups were tolerated under these reaction conditions, such as isolated carbon-carbon double or triple bonds, halides, nitro groups, epoxides and esters. 7a (1-2 mol%) x Ho (3 atm) or ‘PrOH e NHPA 1 2 or RR Toluene, 25-65 °C RIÙR? Ph X= O or NPh 16 examples R'= Ph, R?= Me Yield = 54% 46-100 % yields Yield = 100% Scheme 3: Use of 7a catalyst in the hydrogenation of aldehydes, ketones and imines. Hydride 7a has also been successfully applied in CTH, using isopropanol as reductant.!543) Sun and co-workers performed computational studies to confirm that catalyst 7a is not able to hydrogenate olefins and alkynes at relatively low temperatures.!* The main drawback of the active hydride 7a is its sensitivity to air, moisture and light, which makes a glovebox necessary for its synthesis and manipulation. However, later contributions have demonstrated that it is possible to use the bench-stable (cyclopentadienone)iron pre- catalysts 10 and convert them in situ into the corresponding active forms 10-act (in the presence of Me3NO,!5 UV light!)) and 7 (in the presence of K2C03!71) as shown in Scheme 4. 11] Chapter 1: Introduction Meno no Ù sv RUÒR? Ha + R R o RT oc-Pe- cE°x00 10 (stable) K:003/H,0 oc-fe. dé" i 7 RIOR (highiy unstable) x=0,NR Scheme 4: Strategies for the in situ formation of the active complexes 10-act and 7 from the stable complex 10 From the point of view of ligand design, two main strategies were followed to modify the Knélker-type complex 10a in order to improve the catalytic activity and/or achieve novel reactivity. In the first instance (Figure 5-A.), the substitution pattern of the cyclopentadienone ring was modified to tune the steric and electronic properties of the complexes. This was mainly achieved by varying the cycle fused to the cyclopentadienone ring, replacing the original six-membered ring of 10a,!9 as well as the nature of the substituents at the 2- and 5-positions of the cyclopentadienone.9 The second strategy to modulate the structure of these complexes relies on the substitution of one of the carbonyls with other ligands (Figure 5- B.) such as nitriles,559 pyridines,!*59 amines,!?9 phosphines!*! and, more recently, N-heterocyclic carbenes (NHCs).151 A. Modification of cyclopentadienone ring Poater-Renaud!) —Poater-Renaud!b Wills!45d1 Pignataro-Berskessel- Piaruli!49 > 0 "lo o Gi ento e 0c-f*00 0c-f*00 defe.c0 oc-f*00 oc 10b X= CH, (CH2)p, NTs, O, C(COOEt), R=TMS, TBDMS, TIPS, Ph B. Replecement of one CO ligand L= RCN (Knélker) Gennari-Pignataro-Piarullil52! IHC (Darcel-Sortais) Cer Sd (Berkessel) Figure 5: Main strategies to obtain structurally modified (cyclopentadienone)iron complexes In situ activated (cyclopentadienone)iron complexes 10 have found application in several reactions that involve the transfer of Ha, such as hydrogenation (of ketones,!'54552,336] aldehydes,!) imines,!459 C02/NaHC0:,!4848b53 and activated esters!), transfer hydrogenation of ketones,!4545455 reductive amination 12] Chapter 1: Introduction RI 10b (2 mol%) LT MegNO (4mol%) N 3A MS 'ProH 100 °C, 18h 10b (5 mol%) MegNO (5mol%) 9 3A MS HN 9 Rigo + Ha Toluene/'PrOH 100 °C, 18h Scheme 7: Substrate scope evaluation in CTH promoted by pre-catalyst 10b 15] 16] 2. HYDROGEN BORROWING AMINATION OF ALCOHOLS Dubitando ad veritatem pervenimus. [doubting we come to the truth] Cicerone 17] Chapter 2: Hydrogen Borrowing Reaction Table 2: Comparison between catalysts. 10a and 10b in hydrogen borrowing reaction i fe pre-catalyst (5 mol) "N MegNO (10 mol%) + NH Solvent,130°C OMe 24h OMe 162 17 18 Entry Pre-catalyst Solvent 16a(eq.) 18(ed.) Yield! (%) TMS T. Yan, B. L. Feringa, K. Barta, 1 o CPME 1 2 70 ne TMS Nat. Commun 2014, 5, 5602-5009. oc-Reco i0a co 2 SF Toluene 1 15 >950bl Fe, 4 CO 4op & Isolated yields after a cromathographic coloumn purification ©) Reaction conditions: alcohol/amine/10b/Me3NO = 100:150:5:10. Catalyst activation: Toluene, Me3NO, room temp., 15 min, Ccotoctiv= 0.1 M. Amination step: amine, alcohol, toluene, 130 °C, 24 h, Coup = 0.25 M. Toluene was freshly distilled from sodium/benzophenone. Also in this reaction 10b was found more active than 10a, and for this reason we decided to test it in the amination of secondary alcohols. 2.3. Reaction of secondary alcohols 2.3.1 Screening of reaction conditions The first secondary alcohol tested in HB reaction is 2-propanol 19a, i.e. the simplest one, in the presence of p-methoxyaniline 16a using the best conditions reported in the Table 2 (Entry 2), but in this case no conversion was obtained (Table 3, Entry 1). Changing solvent did not improve conversion (Table 3, Entry 2- 3), while increasing the amount of alcohol allowed to obtain a good yield. The best result was obtained when, in addition of four equivalents of alcohol in toluene, 3 À molecular sieves were added (Table 3, Entry 5). The role of M.S. consists in driving the equilibrium of imine formation after the alcohol dehydrogenation step. It was decided to use 3 À instead of 4 À M.S. because the 3 À pores are able to accommodate H:0 but not iProH. Although multiple N-alkylation is a frequently observed side reaction in ‘hydrogen borrowing’ processes,!85! it snould be noted that the use large excess of alcohol allowed to avoid this problem. Table 3: Screening operation in hydrogen borrowing using 'PrOHtl nl 10b (5 mol%) «A _MeaNO (10 mol®) __ na ‘OH Se Mito 24h ome 10b 20a Entry Solvent 19a (ed.) Molecular Sieves 3À (mg) Conversion!D (%) 1 Toluene 1.5 / 0 2 CPME 1.5 / 0 3 neat / / 0 4 Toluene 4 / 70 5 Toluene 4 400 72 {al Reaction conditions: 10b/MesNO = 5:10. Catalyst activation: Toluene, MesNO, room temp., 15 min, Ccatactiv. = 0.1 M. Amination step: amine, alcohol, 130 °C, 24 h. Toluene was freshly distilled from sodium/benzophenone. {bl Determined by *H NMR analysis ofthe crude reaction mixture 20 | Chapter 2: Hydrogen Borrowing Reaction The experiments with substrate 19a demonstrated that pre-catalyst 10b is able to promote the amination of a very simple secondary alcohol. However, the amination of 19a is not very suitable for reaction conditions optimization, because it is not possible determine the conversion by NMR analysis. Thus, the reaction optimization was continued using alcohol 19b (1-phenylethanol), whose amination product features sharp NMR signals (OMe group) that are slightly shifted, in the reaction product, with respect to 4-methoxyaniline. Starting from the best conditions found for the reaction with ‘PrOH (Table 4, Entry 2) and trying different conditions, it was found that the best yield is obtained at 150 °C in toluene in the presence of 3 À M.S. (Table 4, Entry 13). Table 4: Screening operation in hydrogen borrowing using 1-phenylethanolle! 10b (Smol %) o "e _MesNO (10mo1%) po Solvent oc-f8, Ms. bm oî 0 le Temperature 206 106 Entry. T(°c) Solvent eq.alcohoi 3ÀM.S.(mg) Branstedacid Conversion!!! (%) 1 130 Toluene 1.5 400 - 38 _ 2 130 toluene 3 400 - 42 3 3 3 130 Toluene 4 400 - 63 € 6 F 4 130 Toluene 6 400 - 46 5 130 Toluene 10 400 - 0 6 130 Toluene 4 200 - 49 di 7 130 Toluene 4 600 - 77 = 8 130. Toluene 4 400 (4À) - 47 5 9 130 Toluene 4 400 TFA (1%) 53 d < 3 10 130 Toluene 4 400 AcOH (1%) 64 e È 11 130 Toluene 4 400 AcOH (5%) 42 $ 12 130 CPME 4 400 - 24 9 d £ 2 n 13 150 Toluene 4 400 / 87 3 E v e {1 Reaction conditions: 10b/Me3NO = 5:10. Catalyst activation: Toluene, MesNO, room temp., 15 min, Crasactiv. = 0.1 M. Amination step: amine, MS, alcohol, toluene, 24 h, Cosus = 0.25 M. Toluene was freshiy distilled from sodium/benzophenone. {bl Determined by !H NMR analysis of the crude reaction mixture. 21| Chapter 2: Hydrogen Borrowing Reaction We found that longer reaction times (72 h instead of 24 h) allow to improve the yield of the reaction which gave unsatisfactory yields within It is also possible. From this finding, we concluded that pre-catalyst 10b is able to resist for a long time at high temperature without undergoing substantial degradation. In general, all the reaction presented in the next paragraph that gave low conversion in 24 h have been tested also in 72 h, in order to improve the yields. We believe that the reaction mechanism should be similar to the one already reported in the case of Ru or Ir catalysts. In this case, it is initially necessary to activate the (cyclopentadienone)iron complex with MezNO for a 10-20 minutes generate the catalytically active complex 10-act: RS SNH, Step 2: In situ amine formation LR Sa oc-fe, du oc H Tb Step 1: Dehydrogenation + È li do) si N° Fe, oc-fe, _y oc-Fe | oc Hog Ho} od co oc a oc Pa 106 Ts Ts Stop 3: Imine reduction si SF RITSRI ‘o 5 a HER MegNO (activation) oc Re 10b-act Scheme 12: Individual reaction steps in the Fe- catalyzed N-alkilation of amine 2.3.2 Substrate scope With the optimized reaction conditions in hand, a set of different alcohols and amines were tested in hydrogen borrowing reactions in order to expand the scope of the reaction. Screening of different alcohols: In Table 5 the results obtained reacting amine 16a with a series of different alcohols are reported. Table 5: Substrate scope of alcohol amination promoted by pre-catalyst 10b!! RI NHa 10b (5 mol %) HNTR? + Ri MezNO (10 mol %) | RI on 2mL Toluene oe 00 OMe 400 mg 3A M.S. Ge 150 °C 106 162 19an 24-72h 202-n Yield!! Entry Alcohol Product (6) t=24h _t=72h DA ma 1 19% O do 87 395 H 22 | Chapter 2: Hydrogen Borrowing Reaction 2.3.3 Study of mechanism for allylic alcohols As mentioned in Section 2.3.2, allylic alcohols gave unexpected results because, besides replacement of the OH group by the amine, the C=C double bond was also reduced completely (with substrates 19iî, 19j) or partially (with substrate 19k). For this C=C reduction, two different possible mechanisms were hypothesized (in the case of substrate 19i), both starting from the assumption that the terminal reductant of this reaction is probably the alcohol itself, which is used in excess with respect to the amine. Pathway 1 is based on the assumption that the catalyst is able to promote the 1,4 reduction of the imine, which is then followed by tautomerization of double bond and final 1,2-reduction. In the case of Pathway 2 it is assumedthat the catalyst prefers to reduce the C=N bond first, generating the intermediate 25, featuring an isolated double bond. Compound 25 then undergoes double bond isomerization mediated by the Fe- complex, followed by tautomerization and then final 1,2-reduction to yield compound 19i. Pathway1 Pathway 2 moi el > L o uu _meo A “OI tb oH pra 1,4 reduction de 1,2 reduction ad soi ‘sì ” Meno Vol TT» Leo È ot tar n rie E x 0. co, Reomerization & ‘Tautomerization 1,2 reductic “OR 1,2 reduction ST A O ny Da tomorization SG CR Fe 00° 1a 00° 6 OC ù 106 sod ® Scheme 13: The two different proposed hypothesis fo HB in case of allylic alcohols In the attempt to confirm one of the two different pathways, intermediate 25 was synthetized according to the synthetic route shown in Scheme 14: e e SEG NH, Ng A or NO NH sa cch HS _ ? * PAOIXPHONI K:C03 F307 OH TEA; PPhy NA THE © THF pemay dry MeOH - HO OMe reflux; 3h OMe 0*c1025%0 25°0;18h Ome TOMSSA Ome 162 y= 69% 22 ye 44% y= 64% 24 y= 98% 25 Scheme 14: Synthetic procedure for the synthesis of intermediate 25 Starting from p-anisidine 17a and trifluoroacetic acid it has been followed the procedures reported by Peters!881 obtaining the compound 23. The latter compound has been converted in 24 using a Palladium complex in an Aza-Claisen reaction!” and, after purification, cleavage of the trifluoroacetate group gave the final compound 25. Compound 285 is a putative intermediate of the catalytic cycle postulated by Pathway 2, which under the reaction conditions should undergo double bond shift followed by 1,2-reduction. In order to confirm this 25] Chapter 2: Hydrogen Borrowing Reaction kind of pathway, compound 25 was subjected to the amination conditions in the presence of pre-catalyst 10b (Scheme 15): 16. 6 da % H REA ar MENO (10 mol), O ] oc-fe, MeO° 400 mg 3A M.S. MeO° 0 Toluene 150 °C 24h 106 Scheme 15: Control reaction to confirm the possible occurence of the catalytic cycle postulated by Hypothesis 2 As the latter reaction did not occur, we excluded Pathway 2 and confirmed that Pathway 1 is probably followed. 2.4. Other results in hydrogen borrowing processes In 2014 by Barta et al.!51 reported the amination of primary alcohols using complex 10a. Among the other results, it was reported that diols are able to react with primary amines in a double amination producing heterocycles of potential interest as pharmaceutical intermediates. The main limitation of this procedure is the possibility to use only benzylamines featuring an electron-withdrawing substituent in position 3 of the aromatic ring. With this kind of substrates, a first intermolecular alkylation is followed by an iminium ion- based alkylation, probably facilitated by the intramolecular nature of the second alkylation step and by the presence of stabilizing group on the aromatic ring. In contrast, the reaction between unsubstituted benzylamine and diols afforded only the monoalkylation product, showing that the second cyclization step was much slower in this case. We decided to test complex 10b, which had proven superior to 10a in the amination of secondary alcohols, also inthis type of diol cyclization. Using the same meta-substituted benzylamines employed by Barta,!7 we obtained similar results, as shown in Table 7. In this case only cyclization products were obtained, with no traces of mono-alkylated compounds (Table 8). Table 7: Synthesis of heterocycles by double amination of diol 200 with benzylamine bearing electron-withdrawing susbtituents!! 10b (5 mol %) È rp MezNO (10 mol %) | 0 OH -F 2mL Toluene si ico 400 mg 3AM.S. R 150 °C 10b 16g-i 190 24-72h 262-0 Yield!P! (9%) Enti Amine Product n t=24h î=72h 1° 16g CO DO 57 6004 ci {e;] 2° 16h DO e 51 6119) F È 3 16Î dI do 64 68! CF, CF3 {al Reaction conditions: alcohol/amine/10b/MesNO = 100:150:5:10. Catalyst activation:Toluene, MezNO, room temp., 15 min, Ceatactv. = 0.1 M. HB: amine, 3ÀMS (400 mg), alcohol, toluene, 150 °C, 24 h, Casuò = 0.25 M. Toluene was freshly distilled from sodium/benzophenone. !l Isolated yields after a cromathographic coloumn purification. {Yield reported in Barta et al. work: y= 85%; !yield= 67%; !1yield=68% 26 | Chapter 2: Hydrogen Borrowing Reaction However, in the presence of pre-catalyst 10b it was possible to obtain conversion also from unsubstituted benzylamine, as shown in Table 8. Table 8: Synthesis of heterocycles by double amination of diols with benzylaminele! 106 (5 mol %) I E rin, _MesNO (10 mol %) _ | OH -F 2mL Toluene i “co 400mg3AM.S. 150 °C 106 166 19n-p 24-72h 2Ta-c Yield!?! (%) Ent Diol Product my t=24h t=72h 1 19n HLT OO 29 45 2 190 HOOKUH TO 18 28 N 3 19p Hc Do 1) 11 16 {al Reaction conditions: diol/amine/10b/Me3NO = 100:150:5:10. Catalyst activation:Toluene, Me:NO, room temp., 15 min, Ceacactiv = 0.1 M. Amination step: amine, 3ÀMS (400 mg), diol, toluene, 150 °C, 24 h, Casu = 0.25 M. Toluene was freshly distilled from sodium/benzophenone. {bl Isolated yields after a cromathographic coloumn purification. Despite the yields remain modest, the latter results confirm the higher reactivity of pre-catalyst 10b compared to 10a. 27 | 30 | Experimental procedures 4. Experimental procedures 4.1 General informations AIl reactions were performed in flame-dried glassware tube with magnetic stirring under an inert atmosphere (nitrogen or argon), unless otherwise stated. The solvents for the reactions were either distilled from the following drying agents and transferred under inert atmosphere: CH2Cl; (CaH.), MeOH (CaH:), THF (Na), dioxane (Na), toluene (Na), Et3N (CaH.) or obtained from a solvent purification system. Dry dichloroethane, 2-propanol, ethanol, acetone, and CHCI; (over molecular sieves in bottles with crown caps) were purchased from Sigma Aldrich and stored under nitrogen. The reactions were monitored by analytical thin-layer chromatography (TLC) with silica gel 60 F254 precoated glass plates (0.25 mm thickness). Visualization was accomplished by irradiation with a UV lamp, staining with a potassium permanganate alkaline solution, or both. Flash column chromatography was performed with silica gel (60 À, particle size 40 64 um) as the stationary phase by following the procedure of Still and co-workers.!9) The *H NMR spectra were recorded with a spectrometer operating at 400 or 300 MHz. The *H chemical shifts (8) are reported in ppm with the solvent signal relative to tetramethyIsilane employed as the internal standard (CDCI3 8 = 7.26 ppm, CD:C1: 8 = 5.32 ppm). The following abbreviations are used to describe spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublets- of doublets, td = triplet of doublets. The !*C NMR spectra were recorded with a 400 or 300 MHz spectrometer with complete proton decoupling. The !5C chemical shifts are reported in ppm (8) relative to tetramethyl- silane with the respective solvent resonance as the internal standard (CDCl: 6 = 77.16 ppm, CD-Cl, é = 54.00 ppm). The coupling constants are given in Hz. 4.2 Cyclooctene-derived (cyclopentadienone)iron complex synthesis (E)-1-Bromocyclooct-1-ene (14) o To a solution of cyclooctene (33 mL, 0.25 mol, 1 equiv.) in dichloromethane (100 mL) at -40 °C, a solution of Br. (0.25 mol, 1 equiv.) in dichloromethane (12 mL) was added dropwise until the yellow colour persisted. The reaction mixture was quenched with a 10% aqueous Na:5.0: solution (50 mL) and extracted with dichloromethane (2 x 100 mL). The organic layer was dried over Na.SO4 and concentrated in vacuo to give E- 1,2-dibromocyclootane in quantitative yield, which was used in the following step without further purification. 1H NMR (400 MHz, CDCl3): 6 4.59-4.57 (m, 2H, CH), 2.46-2.37 (m, 2H, CH»), 2.15-2.05 (m, 2H, CH»), 1.88-1.81 (m, 2H, CHa), 1.70-1.56 (m, 4H, CHa), 1.54-1.46 (m, 2H, CH»). *C NMR (100 MHz, CDCIz): 61.6, 33.3, 26.0, 25.5. (E)-1,2-dibromocyclootane (65.8 g, 244 mmol, 1 equiv.) was dissolved in THF (100 mL) and the resulting solution was added to a suspension of KOtBu (41.07 g, 370 mmol, 1.5 equiv.) in THF (40 mL) at 0 °C. The reaction mixture was quenched with a saturated aq. NH4CI solution (100 mL), and THF was evaporated. The resulting crude was extracted with dichloromethane (2 x 100 mL). The organic layer was dried over Na.S04 and concentrated in vacuo. The residue was purified by distillation at reduced pressure, and 36.8 g of 1- bromocyclooctene were obtained as a colorless liquid (195 mmol, 80%). 1H NMR (400 MHz, CDCI3): 6 6.03 (t,/= 8.5 Hz, 1H, CH), 2.58-2.64 (m, 2H, CH2), 2.08-2.19 (m, 2H, CH»), 1,51- 1.62 (m, 8H, CH2). ‘*C NMR (100 MHz, CDCI:): 6 131.7, 35.2, 29.9, 28.6, 27.5, 26.4, 25.5. 31] Experimental procedures Cyclooctyne (15) @ A lithium diisopropylamide solution was prepared by adding n-butyllithium (1.58 m hexane solution, 300 mmol, 190 mL, 0.5 eq) to a solution of dry diisopropylamine (32.3 g, 320 mmol, 0.6 eq) in dry THF (125 mL) at -25 °C. The mixture was allowed to reach 0 °C and stirred for 20 min, then cooled again at -25 °C. 1-Bromocyclooctene (113.4 g, 600 mmol, 1 equiv.) was added to the solution at -25 °C. The temperature of the reaction mixture was allowed to rise to 15 °C gradually over a period of 45 minutes and was kept at this level for another 90 minutes. It was then poured into a cold solution of 3N HCI. The solution was extracted with pentane and the combined organic phases were washed several times with water in order to remove the THF. The organic layer was dried over Na.SOs and concentrated in vacuo. Distillation at reduced pressure of the residue gave 24.2 g of cyclooctyne (460 mmol, 78%). 1H NMR (400 MHz, CD.Cla): 6 2.13 (m,4H, CH2),1.85 (m, 4H, CH2), 1.61 (m, 4H, CH»). ?CNMR (75 MHz, CD2Cla): 894.9, 35.13, 30.3, 21.9. Bis(hexamethylene)cyclopentadienone iron tricarbony! (10b) 940 Freshly prepared cyclooctyne (230 mL, 1.85 mmol, 1 equiv.) and Fe(CO)s (1.2 mL, 9.25 mmol, 5 equiv.) were dissolved in dry toluene (10 mL) in a sealed glass tube under Ar and stirred overnight at 90 °C. Evaporation of the solvent gave the crude product, which was purified by flash chromatography SiO; (7:3hexane/AcOEt). 198 mg of product 10b were obtained as yellow crystals (1.04 mmol, 56%). !H NMR (400 MHz CDCl): 6 2.76-2.78 ppm (m, 2H, CH»), 2.59-2.64 (m, 2H, CH2),2.40-2.49 (m, 2H), 1.741,92 (m, 8H, CH2), 1.44-1.59 (m, 10H, CH»). ‘#C NMR (100 MHz CDClz): 6 209.4, 171.4, 102.4, 85.5, 31.3, 28.8, 26.2, 25.8, 23.7, 23.4. 4.3 Hydrogen Borrowing reaction Dry toluene (0.125 mL) was added to a mixture of pre-catalyst 10b (9.6 mg, 0.025 mmol, 0.05 equiv.) and Me3NO (3.8 mg, 0.050 mmol, 0.010 equiv.) under argon atmosphere in a pressure-proof Schelnk vessel fitted with a screw cap. The resulting solution, which gradually turned from yellow to dark red, was stirred for 20 minutes at R.T. The amine substrate (0.5 mmol, 1.0 equiv.) was added, followed by 3 À M.S. (beads, 400 mg), alcohol (2.0 mmol, 4.0 equiv.) and toluene dry (1.75 mL). The reaction vessel was sealed and stirred in a pre- heated oil bath at 150 °C for 24 h. After cooling down, the mixture was filtered through celite (rinsing several times with AcOEt), and then the solvent was removed at rotavapor. The product was purified by flash chromatography. 32 | Experimental procedures 4-(1-Phenylethyl)morpholine (21d) 1H NMR (400 MHz, CDCI3) 6 7.34 (d, J= 4.4 Hz, 1H), 7.30-7.23 (m, 1H), Ad 3.71 (t,/=4.7 Hz, 1H), 3.32 (q,/= 6.7 Hz, 1H), 2.56-2.47 (m, 1H), 2.42- 2.32 (m, 1H), 1.38 (d,/= 6.7 Hz, 1H). FCC eluent: hexane/AcOEt 80:20 (+0.5% TEA). N-Benzyl-1-phenylethylamine (21e) 1H NMR (400 MHz, CDCl3): 6 7.43-7.23 (m, 10H), 3.84 (q, J= 6.6 Hz, O 1H), 3.66 (q, J = 13.2 Hz, 2H), 1.53 (d, /= 6.5 Hz, 2H), 1.40 (d,/= 6.6 DUI Hz, 3H). FCC eluent: hexane/AcOEt 95:5. N-Benzyl-N-methyl-1-phenylethylamine (21f) 1H NMR (400 MHz, CDCl3): 6 7.46-7.20 (m, 10H), 3.67 (q, J= 6.8 Hz, iO 1H), 3.61 (d, J = 13.3 Hz, 1H), 3.33 (d, /= 13.3 Hz, 1H), 2.16 (s, 3H), du 1.45 (d,J= 6.8 Hz, 3H). FCC eluent: hexane/AcOEt 95:5. 1-(3-Chlorobenzyl)azepane (26a) n *H NMR (400 MHz, CDCl3): 8 7.43-7.19 (m, 5H), 3.66 (5, 2H), 2.72-2.63 CO (m, 4H), 1.66 (, 8H). dI FCC eluent: hexane/AcOEt from 90:10 (+ 0.1% TEA). 1-(3-Fluorobenzyl)azepane (26b) 1H NMR (400 MHz, CDCla): 6 7.28 (dt, J = 14.2, 7.1 Hz, 1H), 7.13 (d,/= CO 7.5 Hz, 2H), 6.97-6.90 (m, 1H), 3.66 (s, 2H), 2.64 (d, J= 5.5 Hz, 4H), f 1.65 (s,8H). FCC eluent: hexane/AcOEt from 90:10 (+ 0.1% TEA). 1-(3-(Trifluoromethyl)benzyl)azepane (26c) 1H NMR (400 MHz, CDCls): 6 7.65 (s, 1H), 7.57 (d,J= 7.6 Hz, 1H), 7.51 SCO (d,J= 7.7 Hz, 1H), 7.43 (t,J= 7.6 Hz, 1H), 3.71 (s, 2H), 2.65 (d,/= 5.5 Go Hz, 4H), 1.66 (s,8H). FCC eluent: hexane/AcOEt from 90:10 (+ 0.1% TEA). N-Benzylpyrrolidine (27a) 1H NMR (400 MHz, CDCl3): 8 7.47-7.23 (m, SH), 3.72 (5, 2H), 2.64 (s, SO 4H), 1.86 (5, 4H). FCC eluent: hexane/AcOEt from 75:25 (+ 0.1% TEA). 1H NMR (400 MHz, CDCl3): 6 7.52-7.17 (m, 5H), 3.56 (d, J= 9.4 Hz, 2H), 2.44 (s,2H), 1.63 (q,/= 5.4 Hz, 4H), 1.56-1.39 (m, 4H). FCC eluent: hexane/AcOEt from 75:25 (+ 0.1% TEA). N-Benzylazepane (27c) 1HNMR (400 MHz, CDC): 6 7.39-7.30(m, 4H), 7.29-7.23 (m, 1H), 3.67 OTO (s, 2H), 2.64 (d, J = 5.5 Hz, 4H), 1.65 (5, 8H). FCC eluent: hexane/AcOEt from 75:25 (+ 0.1% TEA). 35] Experimental procedures 4.4 N-(4-Methoxyphenyl)-3-amino-1-butene synthesis 2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride (22) CF, Na OMe A mixture of triphenylphosphine (8.57 g, 132.0 mmol, 3 equiv.), 2,2,2-trifluoroacetic acid (1.24 g, 10.9 mmol, 1 equiv.), triethylamine (1.82 mL, 13.1 mmol, 1.2 equiv.) and carbon tetrachloride (10 mL) was magnetically stirred while cooled with an ice bath. After 10 min, 4-methoxyaniline (1.61 g, 13.1 mmol, 1.2 equiv.) dissolved in carbon tetrachloride (10 mL) was added slowly (exothermic). The ice bath was removed and the reaction mixture was stirred at reflux for 4 h. Upon cooling to room temperature, the reaction mixture was washed with hexane (3 x 100 mL). Solvent was removed using a rotary evaporator to give an orange oil. Distillation gave 2.27 g 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride 23 as a light yellow liquid: bp 75-77 °C./0.3 mmHg (9.02 mmol, 69%). 1H NMR (400 MHz, CDCl3) 6 7.33 (d, /= 9.1 Hz, 1H), 6.98 (d,/=9.1 Hz, 1H), 3.87 (s,J=4.5 Hz, 2H). But-2-en-1-yl 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidate (23) SR, 3 OMe Sodium hydride (144 mg, 6 mmol, 1.2 equiv.) was slurred in THF (8 mL) and cooled to 0 °C. 2-Buten-1-ol (433 mg, 6 mmol, 1.2 equiv.) was added dropwise and the reaction was stirred at 0 °C for 30 min. The cooling bath was removed and the reaction was stirred for an additional 1.5 h at room temperature. A solution of N-(4- methoxybenzy/)trifluoroacetimidoyl chloride 23 (1.26 g, 5 mmol, 1 equiv.) and THF (8 mL) was added in one portion to the alkoxide solution. The reaction was maintained at room temperature for 18 h before concentrating. The residue was redissolved in hexanes, filtered through Celite, and concentrated. The resulting residue was purified by flash chromatography (99:1 to 95:5 hexane/AcOEt) gave 601 mg of 24 asa pale-yellow oil (2.2 mmol, 44%) 3H NMR (400 MHz, CDCI3): $ 6.85 (td, = 8.8, 2.2 Hz, 2H), 6.71-6.84 (m, 2H), 5.79-5.92 (m, 1H), 5.62-5.75 (m, 1H), 4.70 (s, br, 2H), 3.79 (s, 3H), 2.08 (q,/= 7.1 Hz, 2H), 1.44 (sextet, J = 7.4 Hz, 2H), 0.94 (t,J= 7.4 Hz, 3H). N-(But-3-en-2-yl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (24) L CF3 N So OMe Bis(acetonitrile)-dichloropalladium(II) (69 mg, 0.183 mmol, 0.1 equiv.) was dissolved in 3 mL of dry DCM at room temperature, under Ar atmosphere. A solution of 24 (500 mg, 1.83 mmol, 1 equiv.) in 3 mL of dry DOM was added one portion. The resulting mixture was stirred for 18 h at room temperature and filtered through a celite plug. The solvent was removed and the product was purified by flash chromatography SiO- (95:5 hexane/AcOEt) gave 320 mg of 25 as a pale-yellow oil (1.17 mmol, 64%). 1H NMR (400 MHz, CDCl:) 8 7.05 (dd, /= 11.6, 8.8 Hz, 2H), 6.84-6.91 (m, 2H), 5.75 (ddd, J= 17.1, 10.4, 6.5 Hz, 1H), 5.26 (pentet, /= 6.8 Hz, 1H), 5.17 (d, /= 10.3 Hz, 1H), 5.14-5.16 (m, 1H), 3.83 (s, 3H), 1.18 (d,/= 6.9 Hz, 3H). 36 | Experimental procedures N-(4-Methoxyphenyl)-3-amino-1-butene (25) £, NH OMe Potassium carbonate (380 mg, 2.75 mmol, 2.5 equiv.) was added solid at room temperature to the solution of amide 25 (300 mg, 1.10 mmol, 1 equiv.) in 5:1 MeOH/H:0. The resulting solution was warmed at reflux for 3 h. Upon cooling to room temperature, the reaction mixture was washed with DCM (10 mL) and water (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic phases was washed with brine (20 mL), dried with Na.S04 and concentrated. The product was purified by flash chromatography SiO- (9:1 hexane/AcOEt) gave 191 mg of 26 (1.08 mmol, 98%). 4H NMR (400 MHz, CDCl3) 6 6.75-6.79 (m, 2H), 6.56-6.61 (m, 2H), 5.82 (ddd, / = 17.2, 10.4, 5.8 Hz, 1H), 5.20 (td,= 17.2, 1.4 Hz, 1H), 5.07 (td, /= 10.3, 1.3 Hz, 1H), 3.87-3.95 (m, 1H), 3.74 (s, 3H), 3.34 (sbr,, 1H), 1.29 (d, 1=6.6 Hz, 3H). 37] Experimental procedures BE588 35ECCRARSSg885809 2885 ERRE RRNERBSdddd diese sirs TRI Enti Ep ee QU tv T 13 + : x 80 75 79 65 60 55 50 45 49 35 30 25 20 15 10 f1 (ppm) N-(4-Methoxyphenyl)-2-aminooctane (20d) ERO R_ 2858 5535 SOSERA MM I e 0 N H ' ‘ : ' Î : | L i I n mon mupror 88 8 “ e KI 8 E 75 70 65 60 550050 450 49. 350 300 250 20 15 10 05 00 fi (ppm) Experimental procedures 4-Methoxy-N-(3-pentyl)aniline (20e) 15.39 BO Saas: VASI î Ue N H : | | [ai 7500 0 Ss so ss so 4s N do 7 358 do is 10 os 40 fl (ppm) 1-(4-Methoxyphenyl)-2,5-dimethyIpyrrolidine (20f) (mixture of diastereoisomers) 8558833995 N ig #7 Sii fi (ppm) 41] Experimental procedures N-Cyclopentyl-4-methoxyaniline (20g) ue see sce ue f n ace ZI 695 1993 Meo. 9 1893 bo Hoz For 62 58 SA 500 4642 380 34 30 26 22 18 14 10 1 (ppm) 66 74 72 79 N-Cyclohexyl-4-methoxyaniline (20h) ue 9 93 9 [ra O O T AIA ] Fest Het 70 65 60 55 50 45 40 35 30 25 20 15 10 05 f1 (ppm) 75 42] 4-Methoxy-N-(1-phenylprop-2-yn-1-yl)aniline (20m) Experimental procedures 35 BRE ANRI9 88 xe NW ND Vi ' s 1358 } 12.0 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 05 {1 (ppm) N-Benzhydryl-4-methoxyaniline (20n) SEERANNARARANSoSI 3 eee Ì 0 O H u | ’ SJ ni 80 75 70 65 60 55 50 45 40 35 20 25 20 15 10 05 fl (opm) 45] Experimental procedures 2,4-Dimethoxy-N-(1-phenylethyl)aniline (21b) den Vol Ne DI Mv OLO | i Ax s TE FT nodi 46] 4-(1-Phenylethyl)morpholine (21d) Experimental procedures ARRANSNS SER 8858 Bias2888 N SE SN vl ' i OH Ù ' | i ' | | 75 70 65 60 55 50 45 40 35 30 25 20 15 10 05 fl (ppm) N-Benzyl-1-phenylethylamine (21e) LLLARRARSAZZZARRARNNAN 8328 CEEFRCRTÌ SGER ire o egg YV " Î H N ‘ | i ill Ho mr mr d 55 88 7.5 7,0 6.5 6.0 5.5 50 45 40 35 30 25 20 15 10 0,5 {1 (ppm) Experimental procedures N-Benzylpyrrolidine (27a) 7. 7, 7 2 7 n 5 38885 8 l I de l CO Î : HM p "n 75 70 65 60 55 50 5 49 35 30 25 20 15 10 05 f1 (ppm) N-Benzylpiperidine (27b) RRARARSS 4 ì Eaos RITO î Experimental procedures N-Benzylazepane (27c) ABRBRAAANIZA a si | < - 168 OO 3 Li "] = _ ij 75 70 sel o] i s 65 60 55 50 45 40 35 30 25 20 15 f1 (ppm) 51] Experimental procedures 2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride (22) VERY Î CF, a OMe 5 x sal 75 70 65 60 55 50 45 3.5 30 25 20 15 10 05 40 f1 (ppm) But-2-en-1-yl 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidate (23) So nie, OMe 7, 5 7,0 6 5 6.0 5 5 so 4 5 i; 3.5 Jo 25 10 15 io os 40 fi (ppm) List of abbreviations 6 Chemical shift DCM Dichloromethane eq. 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Introduzione La catalisi omogenea rappresenta oggi una strategia vantaggiosa ai fini dello sviluppo metodologie sintetiche green!! nella chimica fine, delle specialità e degli intermedi farmaceutici. | catalizzatori omogenei operano generalmente in condizioni di reazione più blande rispetto a quelli eterogenei ed il vantaggio di una maggiore selettività, oltre alla possibilità di un tuning delle proprietà catalitiche tramite un’opportuna scelta del ligando. Tradizionalmente i catalizzatori omogenei più utilizzati derivano da complessi di metalli di transizione del quinto e sesto periodo della tavola periodica (rodio, rutenio, palladio, platino, iridio).!! Nonostante le ottime proprietà catalitiche di tali metalli, essi sono in genere tossici, rari e costosi. Per tale ragione, negli ultimi anni sono stati compiuti sforzi crescenti al fine di sostituire i metalli nobili con quelli della prima serie di transizione (ferro, cobalto, nichel, rame), molto più abbondanti all’interno della crosta terreste e — in diversi casi — meno tossici.! Tra di essi il ferro è particolarmente attraente, data la sua scarsa tossicità e la sua abbondanza (è il quarto elemento più abbondante del pianeta e rappresenta il secondo metallo più presente nella crosta terrestre). Nonostante alcune sue proprietà catalitiche siano già da tempo note, nell'ultimo ventennio si è verificato un sostanziale aumento dell'interesse per lo sviluppo di applicazioni del ferro nel campo della catalisi omogenea! Il gruppo di ricerca in cui ho svolto il mio lavoro di tesi magistrale è da alcuni anni attivo nello sviluppo di nuovi catalizzatori omogenei a base di ferro per la riduzione di doppi legami C-eteroatomo. In quest'area, una delle maggiori difficoltà è rappresentata dalla intrinseca tendenza del ferro a seguire, a differenza dei metalli nobili, cammini redox monoelettronici.!! È possibile ovviare a questo problema utilizzando ligandi non-innocenti,!! ossia in grado di influenzare notevolmente le proprietà redox del centro metallico. Tra essi, la nostra attenzione è attualmente concentrata sui complessi ferro-ciclopentadienonici 1 (Figura 1),!? in grado di operare seguendo un ciclo catalitico Fe°/Fe". | complessi 1 hanno il vantaggio di essere semplici da preparare e molto stabili, tanto da poter essere purificati mediante cromatografia. L'attivazione in situ mediante reazione con Me3NO o basi acquose genera, rispettivamente, i complessi attivi act-1 e 2,5 che promuovono la riduzione di legami C=O e C=N,!? nonché l'ossidazione di alcoli. pus RO ms o ee SS o TMS Î o sn L, oc-f®c0 Rf ceo, 071 co do ico oc ta to te Knker 1993 Gennar 2015 Figura 1: Esempi di catalizzatori Fe-ciclopentadienonici. Il meccanismo di azione dei complessi ferro-ciclopentadienonici prevede il trasferimento di H. al substrato da parte del complesso attivato 2 con formazione del complesso act-1, che viene successivamente ridotto nuovamente a 2 tramite reazione con la specie riducente (H2, iPrOH o altro: vedere Schema 1). |1 MeiNo or re x Ro ny - | RTS RIGORE ocse oé sot K:004/H30 A, RIOR? x-0,NR Schema 1: Strategie per la formazione di act-1 e 2 partendo dal complesso 1. 2.1. Amminazione di alcoli con meccanismo ‘hydrogen borrowing' L’amminazione diretta di alcoli è una reazione molto attraente da un punto di vista sintetico (H:0 è l’unico sottoprodotto) che non può avvenire con meccanismo Sw2 a causa delle pessime proprietà di gruppo uscente del gruppo OH*. Alcuni catalizzatori a base di metalli quali rutenio!!9 e iridio!!!! sono in grado di promuovere questa reazione attraverso un meccanismo ‘hydrogen borrowing' (o ‘hydrogen autotransfer’) che prevede l'ossidazione dell'alcol a composto carbonilico, la formazione della corrsipondente immina e la sua riduzione a dare l’ammina senza consumo o rilascio di idrogeno. Il lavoro di Barta/Feringa,!!2 Wills! e Renaud!?9 ha dimostrato come i complessi ferro-ciclopentadienonici siano in grado di promuovere questa reazione (Schema 2), anche se con un campo di applicazione sostanzialmente limitato agli alcoli primari. Zhao et al. hanno riportato come il pre-catalizzatore 1a sia in grado di promuovere l’amminazione di alcoli secondari solo in presenza di elevate quantità (40 mol%) di acidi di Lewis quali AgF.!5 Poiché il nostro gruppo di ricerca ha recentemente sviluppato un complesso ferro- ciclopentadienonico (1c) notevolmente più attivo di 1a nella riduzione di legami C=O!99 c=N,!b nel mio lavoro di tesi mi sono dedicato a verificarne le proprietà catalitiche in reazioni di amminazione ‘hydrogen borrowing”. Ho È RIORI Stop1. Dotyarogonation R& i n . ato [ego LR RT io %7 i 1 T8s_RÒR È imino redueion Ma bl Seo pei RÉ RE Fot MIA Me3NO (activation) OE reSR* acta Schema 2: Ciclo catalitico della reazione di amminazione ‘hydrogen borrowing” di alcoli promossa da complessi Fe-ciclopentadienonici. 2.1.1. Ottimizzazione delle condizioni di reazione Il pre-catalizzatore 1c è stato inizialmente impiegato nell’amminazione dell’1-ottanolo con p-metossianilina (Tabella 1), mostrando un'attività catalitica nettamente superiore a quella del complesso di Knélker (1a), il cui uso era stato riportato da Barta et al..!22) Tabella 1: Amminazione dell’ottanolo in presenza die pre-catalizzatori 1a e 1c. NHg an Pre-cat, (5 mol %) MegNO (10 mol %) 7_——_— Solvent, 130°C OMe 24h OMe (1 eq) (1.569) Pre-catalizzatore Solvente Resa isolata (%) TMS 0 T. Yan, B. L. Feringa, K. Barta, TMS CPME 69 oc--co ta Nat. Commun 2014, 5, 5602-5009 SF Toluene >95 04 CO do Incoraggiato da questo risultato, ho iniziato a utilizzare il complesso 1c nell’amminazione di alcoli secondari quali isopropanolo (4a) e 1-feniletanolo (4b). Il lavoro di ottimizzazione dei parametri di reazione (Tabella 2) ha permesso di trovare condizioni in cui entrambi vengono convertiti con buone rese (Tabella 2, riga 6 e 9). Tabella 2: Ottimizzazione delle condizioni di reazione per l’amminazione di alcoli secondari. R Na cat. 1e (5 mol %) Hi ì MezNO (10 mol %) Î O ou Solvent oe c0 OMe 24h 3a fe # Alcol Solvente 4a (eq.) 3ÀM.S. (mg) Temperatura (°C) _ Resa isolata (%) 1 4a Toluene 15 - 130 0 2 4a CPME 15 - 130 0 3 4a - 52 - 130 0 4 4a Toluene 4 - 130 70 5 4a Toluene 4 400 130 72 6 4a Toluene 4 400 150 >95 7 4b Toluene 4 400 130 63 9 4b Toluene 4 400 150 87 2.1.2. Screening di alcoli secondari Utilizzando le condizioni di reazione ottimizzate, il pre-catalizzatore 1c è stato utilizzato nell’amminazione di una serie di alcoli secondari con la p-metossianilina 3a (Tabella 3). Tabella 3: Screening del pre-catalizzatore 1c nell’amminazione di alcoli secondari. RI NH2 Pre-cat. 1c (5 mol%) HNTOR? MegNO (10 mol%) o + n > I Toluene oc, r o) ome R'H 400mg3Ams. dle oe 150 °C le 3a dan 24-72h