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Reductive amination of primary and secondary alcohols using a organo-iron catalyst, according to Knolker types.
Tipologia: Tesi di laurea
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Amination of secondary alcohols using a
cyclooctene-derived
(cyclopentadienone)iron pre-catalyst
Preface
In this master thesis, the work I carried out during period of one year stay in Prof. Cesare Gennari’s and Dr. Luca Pignataro’s research group is reported: I 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.
Chapter 1: Introduction
Today, homogeneous catalysis plays an important role in industry, owing to a series of features that make it complementary to heterogeneous catalysis: mild conditions, fine-tunability of the catalyst using specific ligands and enantio/diasterocontrol are possible. For these reasons, homogeneous catalysis is used both in some large-scale processes (Cativa, Shell Higher Olephines Process, Wacker, etc.) and in a smaller scale for the production of bio-renewable fuels, fine chemicals and pharmaceuticals.[11]^ Stereoselectivity is also exploited by molecular catalysts in some large industrial processes (Monsanto’s L-Dopa, Takasago’s menthol, Novartis’ Metolachlor among the others).[12]
1.2 Catalysis nowadays
In the past two decades catalysis assumed a privileged role in whole human’s life, improving quality of life and respect for the environment. Chemical reactions controlled by catalysts have reduced emissions in modern cars, as well as waste from the chemical industry, and they have facilitated much more efficient energy conversions. The petroleum, chemical and pharmaceutical industries rely on catalysts to produce a wide range of commodities, from fuel and paints to drugs and cosmetics. Catalysts are the key enabler in 90% of chemical manufacturing processes. That means catalysts are essential for a healthy economy. Catalysts enable the production of alternative fuels, they reduce harmful byproducts in manufacturing, they help keep the environment clean, prevent future pollution, and help to create safe pharmaceuticals. Catalysts constitute only a tiny fraction of the total costs incurred by the chemical industry, but their added value is substantial, because they can be used during many process cycles. They remain fundamentally unchanged, adding their value over and over again. In doing so, they are used in the production of about €1,000 billion worth of products worldwide, whereas the actual investment in catalysts is only about 1% of this amount.[13] This multiplier effect is as potent stimulus to invest in the development of new catalysts. On top of that, new Nobel Prize winning catalytic techniques, such as Knowles’ and Noyori’s asymmetric hydrogenation, olefin metathesis or Pd catalyzed cross-coupling, have considerably improved the synthesis of pharmaceuticals. Despite this success, the substantial limitation of most homogeneous catalytic methodologies is the use of rare, toxic and expensive metals (Ru, Rh, Ir and Pd). For these reasons now, catalytic methodologies based on first-row transition metals are becoming an industrially relevant task, owing to the problems due to noble metals. Indeed, first-row transition metals such as Fe, Co, Ni and Cu are far more abundant and, generally less toxic than their second- and third-row counterparts ( Table 1 ).[14]
Table 1: Price for Kilos of most commons metal in catalysis Metal € / Kg Metal € / Kg Rhodium 46563.19 Cobalt 70. Gold 32479.67 Nickel 11. Iridium 24636.61 Copper 5. Palladium 24304.02 Zinc 2. Platinum 23601.87 Alluminium 1. Ruthenium 4927.32 Manganese 1. Silver 405.02 Iron 0.
From an industrial point of view, replacing precious metals with cheap metals meet a very urgent need for
environmentally friendly and economically affordable synthetic methodologies. High-added value compounds such as chiral alcohols, amines, esters and aminoacids would become accessible, by reduction of
olefins, ketones and imines at an economic and environmental cost much lower than that involved by noble metal-based processes. From a merely scientific perspective, such high risk/high impact research would
disclose new prospects and give exciting insights in the until now relatively underdeveloped field of iron- catalysis, where new catalytic systems and patterns are to be devised and studied.
Chapter 1: Introduction
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 2 , 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^0 complex (with neutral ligands), actually has the oxidation state of an Fe+2^ compound, the metal transferring two electrons to the bis(imino)pyridine ligand.[25]^ 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[26]) and thus taking active part in the catalytic cycle by undergoing redox changes.[27] 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,[28]^ 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.[29]
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[30]^ 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[31]^ 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 .[32,33,34]^ (employing a complex previously synthesized by Knölker et al. [35]), Milstein (who used PNP pincer ligand complexes)[^36 ]^ and Beller[37].
Figure 4: Iron complexes for the CTH of C-X multiple bond
Chapter 1: Introduction
1.4 (Cyclopentadienone)iron complexes
(Cyclopentadienone)iron tricarbonyl complexes, firstly reported by Reppe and Vetter in 1953,[20]^ 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 Knölker[38]^ and Pearson[39]^ investigated their reactivity in depth: in 1999, Knölker 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 ).[40]^ 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.[34]^ Complex 7a showed similar properties to the structurally related Shvo catalyst ( 11 ), a dinuclear ruthenium hydride, known since 1985,[41]^ in which the hydride ligand bridges the two ruthenium metal centers.[42]
Scheme 2: A. Conversion of (cyclopentadienone)iron complex 10a into corresponding (hydrocyclopentadienyl)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.[35]^ 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.
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.[35,43]^ Sun and co-workers performed computational studies to confirm that catalyst 7a is not able to hydrogenate olefins and alkynes at relatively low temperatures.[44]^ The main drawback of the active hydride 7a is its sensitivity to air, moisture and light,[38]^ 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 Me 3 NO,[45]^ UV light[46]) and 7 (in the presence of K 2 CO 3 [47]) as shown in Scheme 4.
Chapter 1: Introduction
(of aldehydes and ketones),[4545a,45b,48b]^ alcohol dehydrogenation,[5555]^ and ‘hydrogen borrowing’ amination of benzylic alcohols.[56,57,58] Stimulated by the interesting catalytic properties of these complexes, researchers have started looking for chiral pre-catalysts for application in enantioselective catalysis. In 2011, Berkessel et al. successfully replaced a CO from 10a with a chiral phosphoramidite ligand (see Figure 5 ).[33a]^ Unfortunately, these catalysts only gave 31% ee at best in acetophenone hydrogenation. Wills and co-workers synthesized a few iron complexes starting from unsymmetrical bis-propargyl ethers containing a stereocenter ( Figure 5 ).[4545d]^ These group of catalysts were separately tested in the CTH of acetophenone using the formic acid/triethylamine azeotrope, but both reactivity and enantioselectivity were low ( ee ≤ 25%). Better results (up to 70% ee ) were obtained by our group using pre-catalyst 10c ( Figure 5 ), possessing a ( R )-BINOL derived chiral backbone.[59]
1.5 Cyclooctene-derived (cyclopentadienone)iron complex 10 b
1.5.1 Synthesis
(Cyclopentadienone)iron complexes are usually synthesized by the one-pot tethered cyclative carbonylation of diynes with excess of Fe(CO) 5 or Fe 2 (CO) 9 , which also results in the complexation of the iron tricarbonyl
moiety. Notably, Fe(CO) 5 is inexpensive, so the use of large excess is acceptable. This approach requires a significant synthetic effort to obtain the diyne precursor with the proper functionalization, which somehow limits the possibility to tune the substitution pattern at the cyclopentadienone ring. In principle, an
intermolecular cyclative carbonylation/complexation reaction could also be envisioned, which starts from two discrete alkynes in the presence of the iron carbonyl reagent Fe(CO) 5 or Fe 2 (CO) 9. However, this approach
has a limited scope as it has been reported to occur in good yields only with very specific types of alkyne substitution, such as silyl groups[38]^ or some electron-withdrawing substituents (e.g., Cl, O t Bu, and CF 3 ).[60]
Very low yields (< 15%) were reported for the cyclization of more common alkynes, for example, phenylacetylene and diphenylacetylene.[61]^ However, we found that cyclooctyne 15 , the smallest cyclic
alkyne, is very reactive and can be used for the synthesis of the corresponding (cyclopentadienone)iron complex 10b due to its high reactivity. Complex 10b was firstly synthetized in 2017 by our research group in collaboration with Prof. A. Berkessel (University of Cologne) and Prof_._ U. Piarulli (University of Insubria)
according to the synthetic strategy shown in Scheme 5.
Scheme 5: Synthesis of pre-catalyst 10b
Due to its limited stability (it is stable only for a few days at low temperature), cyclooctyne is not commercially available but can be synthesized easily in very good yields from cyclooctene 12 (see Scheme 5 ): first the alkene is brominated with Br 2 to form the corresponding 1,2-dibromoalkane 13 , from which HBr is eliminated upon the addition of KO t Bu to yield 1-bromocyclooctene 14. Then, a second elimination reaction in the presence of lithium diisopropylamide (LDA) allows the desired product 15 to be obtained. A [2+2+1] cycloaddition between two molecules of alkyne and an iron carbonyl source, afforded complex 10b. The temperature control is very important to avoid the formation of by-products, and in particular of tris(hexamethylene)benzene.
Chapter 1: Introduction
1.5.2 C=N transfer hydrogenation and C=O reductive amination
Amines are a very common and important class of organic compounds, broadly used for the synthesis of bioactive compounds, dyes, fibers and materials.[62]^ The main methodologies for their preparation involve a reduction as the key step, with imines (either pre-isolated or formed in situ), iminium ions, nitriles, amides, nitro groups, azides as typical substrates.[63]^ On the lab scale, this transformation is often performed using boron-and aluminum-derived hydrides (e.g., NaBH 4 , NaBH 3 CN, LiAlH 4 ), metal salts (e.g., SnCl 2 ) or phosphorus compounds (e.g., PPh 3 ) as stoichiometric reductants. However, the use of these reducing agents involves formation of a stoichiometric amount of salts or other by-products, with associated environmental costs. For this reason, catalytic hydrogenation[11]^ ( Scheme 6-Cycle A ), and catalytic transfer hydrogenation[64]^ ( Scheme 6-Cycle B ) can be considered much more attractive from an industrial point of view. These methodologies employ cheap reducing agents and present less problems of waste disposal: CH is perfectly atom-economic (H 2 is fully incorporated in to the product), whereas in CTH the hydrogen donor (iPrOH or Et 3 N/HCOOH) acts as both solvent and reductant, forming easy-to-separate by-products such as acetone or CO 2.
Scheme 6: Catalytic cycle for hydrogenation and tranfer hydrogenation using 10b
A number of successful methodologies for amine synthesis relying on the CH of imines,[65]^ nitriles,[66] amides,[67]^ azides[68]^ and nitro groups[69]^ or on the CTH of imines/iminium ions[70]^ have been reported using noble metals catalysts. Several Fe-catalysts for CH have been developed but quite surprisingly, the number of iron catalysts reported for the CTH of imines is very limited.[71] In the first part of 2018, our research group reported the use of pre-catalyst 10b for the CTH of preformed ketimines ( Sheme 7-A. ) and also for the reductive amination of aldehydes and ketones ( Scheme 7-B. ).[72] This kind of protocol, pioneered by Renaud and co-workers in the case of imine catalytic hydrogenation (CH),[73]^ make imine isolation and purification unnecessary, and thus extends the substrate scope to imines that cannot be readily isolated.
[ doubting we come to the truth ]
Cicerone
Chapter 2: Hydrogen Borrowing Reaction
2.2 Comparison between Knölker type complexes
In the last few years Barta et al. published interesting results in the field of direct alkylation of amines using alcohols, in a presence of Knölker pre-catalyst 10a .[5454,5757]^ The scope of this new methodology includes the monoalkylation of anilines and benzyl amines with a wide range of aliphatic or benzylic alcohols ( Scheme 10- A./C. ), and the use of diols in the formation of five, six- and seven- membered nitrogen heterocycles ( Scheme 10-B. ), which are privileged structures in numerous pharmaceuticals.
Scheme 10: Barta‘s results in hydrogen borrowing amination of alcohols using pre-catalyst 10a
Shortly after, also the groups of Wills[82]^ and Renaud[83]^ reported other ‘hydrogen borrowing’ processes promoted by pre-catalysts 10 , including the amination of alcohols and the α-alkylation of ketones with alcohols. However, a remarkable limitation of this procedure is that its scope is limited to primary alcohols, unless a substantial amount of Lewis acid co-catalyst is employed as reported by Zhao and co-workers,[84] and shown in the Scheme 11.
Scheme 11: Zhao‘s results in hydrogen borrowing of secondary alcohols using pre-catalyst 10a
As pre-catalyst 10b , developed from our research group, is remarkably more active than the Knölker complex in the hydrogenation of both ketones[49]^ and imines,[72]^ we decided to test it also in hydrogen borrowing reaction with the aim of possibly expanding the scope of the amination reaction. A first comparison has been made between pre-catalyst 10a and 10b , in order to verify whether the order of activity was similar. A first comparison has been made between pre-catalyst 10a and 10b , in order to verify whether the order of activity was similar. Catalyst 10a was used in the same conditions reported in Barta et al. [57^ Errore. Il segnalibro non è definito. ] ( Table 2 , Entry 1 ), while pre-catalyst 10b was employed under the best conditions found in our group for the reductive amination of ketones or aldehydes[727272]^ ( Table 2, Entry 2 ).
Chapter 2: Hydrogen Borrowing Reaction
Table 2: Comparison between catalysts. 10a and 10b in hydrogen borrowing reaction
Entry Pre-catalyst Solvent 16a (eq.) 18 (eq.) Yield[a]^ (%)
T. Yan, B. L. Feringa, K. Barta, Nat. Commun 2014 , 5, 5602-5009.
2 Toluene 1 1.5 >95[b]
[a] (^) Isolated yields after a cromathographic coloumn purification [b] (^) Reaction conditions: alcohol/amine/ 10b /Me 3 NO = 100:150:5:10. Catalyst activation: Toluene, Me 3 NO, room temp., 15 min, Ccat,activ. = 0.1 M. Amination step: amine, alcohol, toluene, 130 °C, 24 h, C0,sub = 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 Å 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 Å instead of 4 Å M.S. because the 3 Å pores are able to accommodate H 2 O but not iPrOH. Although multiple N-alkylation is a frequently observed side reaction in ‘hydrogen borrowing’ processes,[85] it should be noted that the use large excess of alcohol allowed to avoid this problem.
Table 3: Screening operation in hydrogen borrowing using iPrOH[a]
Entry Solvent 19a (eq.) Molecular Sieves 3Å (mg) Conversion[b]^ (%) 1 Toluene 1.5 / 0 2 CPME 1.5 / 0 3 neat / / 0 4 Toluene 4 / 70 5 Toluene 4 400 72 [a] (^) Reaction conditions: 10b /Me 3 NO = 5:10. Catalyst activation: Toluene, Me 3 NO, room temp., 15 min, Ccat,activ. = 0.1 M. Amination step: amine, alcohol, 130 °C, 24 h. Toluene was freshly distilled from sodium/benzophenone. [b] (^) Determined by 1 H NMR analysis of the crude reaction mixture
