Article pubs.acs.org/Organometallics
Preparation of Pincer 4‑Functionalized 2‑Aminomethylbenzo[h]quinoline Ruthenium Catalysts for Ketone Reduction Sarah Facchetti,†,§ Vaclav Jurcik,† Salvatore Baldino,§ Steven Giboulot,§ Hans Günter Nedden,*,† Antonio Zanotti-Gerosa,† Andrew Blackaby,† Richard Bryan,‡ Adrian Boogaard,‡ David B. McLaren,‡ Eduardo Moya,‡ Steven Reynolds,‡ Karl S. Sandham,‡ Paolo Martinuzzi,§ and Walter Baratta*,§ †
Johnson Matthey Catalysis and Chiral Technologies, 28 Cambridge Science Park, Milton Road, Cambridge, CB4 0FP, United Kingdom, ‡ Alfa Aesar Heysham, Shore Road, Port of Heysham Industrial Park, Heysham, Lancashire, LA3 2XY, United Kingdom § Dipartimento di Chimica, Fisica Ambiente, Università di Udine, Via Cotonificio 108, I-33100 Udine, Italy S Supporting Information *
ABSTRACT: Reaction of 1-naphthylamine with ethyl benzoylacetate gives the corresponding benzoyl acetamide derivative 1, which undergoes cyclization to 4-phenylbenzo[h]quinolin-2(1H)-one (2) in the presence of H2SO4. Bromination with POBr3, followed by reaction with n-BuLi and DMF, gives 4-phenylbenzo[h]quinoline-2-carbaldehyde (4), which is converted to the corresponding oxime hydrochloride 5 with NH2OH·HCl. Hydrogenation of 5 catalyzed by 10% Pd/C (type 338) leads to 4-phenyl-2-aminomethylbenzo[h]quinoline hydrochloride (HCNNPh·HCl, 6) isolated in high yield. Similarly, the 4-methyl-2-aminomethylbenzo[h]quinoline derivative (HCNNMe·HCl, 12) is prepared starting from 1-naphthylamine and 2,2,6-trimethyl-4H-1,3-dioxin-4-one, following the route for 6. Reaction of RuCl2(PPh3)3 with a diphosphine (PP), the HCl salt 6, and NEt3 in 2-propanol leads to the pincer complexes RuCl(CNNPh)(PP) (PP = Ph2P(CH2)3PPh2, 13; Ph2P(CH2)4PPh2, 14; 1,1′-bis(diphenylphosphino)ferrocene, 15). The methyl derivatives RuCl(CNNMe)(PP) (PP = Ph 2 P(CH 2) 3 PPh2 , 16; Ph2 P(CH 2) 4 PPh2 , 17; 1,1′-bis(diphenylphosphino)ferrocene, 18) are obtained in a similar way using 12 in place of 6. Treatment of [RuCl2(p-cymene)]2 with rac-BINAP, 6, and NEt3 affords RuCl(CNNPh)(BINAP) (19), isolated as a mixture of two diastereoisomers (3:4 molar ratio). The chiral RuCl(CNNPh)[(S,R)-JOSIPHOS] (20) is obtained as a single isomer from [RuCl2(p-cymene)]2, (S,R)JOSIPHOS, and 6. Complexes 13−20 efficiently catalyze the transfer hydrogenation of acetophenone in 2-propanol at reflux in the presence of NaOiPr (2 mol%) with S/C = 5000−20 000 and at high rate (TOF up to 6.7 × 103 min−1). With complexes 13, 15, 17, and 18 several ketones of commercial-grade purity have been reduced to alcohols, including the bulky RCO(tBu) (R = Me, Ph) substrates. With 20 acetophenone is reduced to (S)-1-phenylethanol with 85% ee. The pincer complexes 13−15 and 18 are also found highly active in the hydrogenation of ketones at 40 °C with an S/C = 10 000, under 5 bar of dihydrogen in methanol and in the presence of 2 mol % of a base (NaOH, KOH, NaOMe).
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INTRODUCTION 1
ketones was achieved by Noyori and co-workers with the development of the systems (η 6 -arene)RuCl(Tsdpen) 4 (Tsdpen = TsNCHPhCHPhNH2, Ts = SO2C6H4CH3) and trans-RuCl2(BINAP)(1,2-diamine)5 for the catalytic TH and HY, respectively. In addition to the chiral complexes that can afford alcohols with high enantioselectivity, a great industrial concern is focused on robust achiral catalysts that can work with extremely low catalyst loading, aiming to replace the use of NaBH4 and LiAlH4, thus facilitating the workup and reducing the amount of side-products. The pincer6 CNN ruthenium
2
The hydrogenation (HY) and transfer hydrogenation (TH) of carbonyl compounds catalyzed by well-designed transition metal complexes are core processes for the synthesis of alcohols. Rhodium, iridium, and ruthenium catalysts have successfully been employed in both TH and HY reactions.1,2 When 2-propanol is used as a hydrogen source, the TH leads to an equilibrium reaction, which can be shifted to the desired alcohol product using 2-propanol as solvent. On account of its operational simplicity, mild reaction conditions, and absence of the risks associated with the use of hydrogen gas, TH is being increasingly used in industrial plants and can be competitive with respect to HY.3 A breakthrough in the reduction of © XXXX American Chemical Society
Received: November 30, 2015
A
DOI: 10.1021/acs.organomet.5b00978 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics complexes RuCl(CNN)(diphosphine) A7 and B,8 containing the 2-(aminomethyl)pyridine motif,9 are outstanding catalysts for the TH of ketones and aldehydes with 2-propanol, displaying both high rate (TOF10 up to 4.2 × 104 min−1) and productivity (S/C up to 105) (Figure 1).
HCl) (R = Ph, Me), obtained from 1-naphthylamine via heterocyclization and without the use of hazardous oxidants. The preparation of the early intermediates has been demonstrated on a kilogram scale. The stable HCNNR·HCl salts have been directly used for the synthesis of the pincer ruthenium complexes RuCl(CNNR)(diphosphine), which are highly active catalysts for the transfer hydrogenation and hydrogenation of carbonyl compounds.
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RESULTS AND DISCUSSION Synthesis of the Benzo[h]quinoline Hydrochloride Ligands 6 and 12. The preparation of the benzo[h]quinoline ligands and intermediates 1−12 are here described on a gram scale. The derivatives 1−3 and 7−9 have also been isolated on a kilogram scale. Both the initial gram-scale procedure and the larger scale procedure are reported in the Experimental Section. Treatment of 1-naphthylamine24 with ethyl benzoylacetate in xylene (isomer mixture) at reflux leads to the benzoyl acetamide 1 via azeotropic distillation of ethanol/xylene (Scheme 2). Cyclization of the product 1 is straightforward by reaction with H2SO4, affording 4-phenylbenzo[h]quinolin2(1H)-one (2), which was treated with water and acetone and dried to remove the residual water, which has been proven to be detrimental for the subsequent step. Treatment of 2 with POBr3 in refluxing toluene overnight gives 2-bromobenzo[h]quinoline (3) isolated as a solid in high yield. Optimized conditions for the formylation of 3 were attained by reaction of 3 with 1.13 equivalents of nBuLi (2.5 M in hexane), which was added dropwise at −78 °C in THF. Subsequent addition of DMF, followed by hydrolysis, leads to 2-formyl-4-phenylbenzo[h]quinoline (4). If, instead, 2chloro-4-phenylbenzo[h]quinoline (3a), prepared by reacting 2 with POCl3, was treated with n-BuLi at −78 °C in THF followed by reaction with DMF and hydrolysis, 2-chloro-3formyl-4-phenylbenzo[h]quinoline (3b) was obtained. In this case a directed ortho-lithiation pathway25 is preferred over the halide−lithium exchange (see Supporting Information for analytical data of 3b). The hydrochloride oxime 5 (Scheme 2) was isolated as a stable bright yellow crystalline product by reaction of 4 with NH2OH·HCl in ethanol, following standard procedures for the synthesis of oxime derivatives. The reduction of the oximes to primary amines is usually carried out with LiAlH4, zinc, and acetic acid,26 or NaBH4,27 or via hydrogenation with palladium catalysts.28 The straightforward hydrogenation of the HCl salt of the oxime 5 proceeds easily with 30% dry weight of 10% Pd/ C type 338 catalyst (Johnson Matthey) under 5 bar of H2 in MeOH (0.3 M) at 30 °C (90 min), affording 4-phenyl-2aminomethylbenzo[h]quinoline hydrochloride (HCNNPh·HCl, 6) in high isolated yield on a gram scale, without addition of acid. Optimization of the reaction conditions involved testing several Pd/C catalysts, namely, JM 5% Pd/C type 58, 10% Pd/ C type 338, 5% Pd/C type 338M, and 5% Pd/C type 87L. It was found that the reaction was affected by substrate
Figure 1. Structure of the pincer RuCl(CNN)(diphosphine) complexes.
The systems A11 and B12 also catalyze the HY of carbonyl compounds at low H2 pressure in alcohol media. With the matched chiral CNN and diphosphine (i.e., (S,R)-JOSIPHOS*)13 ligands these complexes were found to catalyze the asymmetric TH and HY of methyl aryl ketones with high enantioselectivity (99% ee for propiophenone) at S/C up to 20 000.14 These systems have also been found to catalyze other C−H bond activation reactions, such as the acceptorless dehydrogenation (DHY),15 deuteration, and racemization of alcohols. 16 Interestingly, the analogous pincer osmium complexes17 show extremely high activity in TH and HY of carbonyl compounds and DHY of alcohols.18 Due to their broad scope and high catalytic performance, the ruthenium CNN complexes meet the parameters required by industry and appear attractive for applications in organic synthesis. The preparation of the catalysts A and B entails the reaction of RuCl2(PPh3)38,14,16 or [RuCl2(p-cymene)]219 with a suitable diphosphine and a 6-aryl-2-aminomethylpyridine or 2aminomethylbenzo[h]quinoline HCNN ligand, respectively, via orthometalation.20 The HCNN ligands have been prepared from 6-arylpyridines and benzo[h]quinolines via formation of the N-oxide intermediates using peracids, followed by functionalization at the 2-position (Scheme 1).7b,8 Chiral HCNN ligands containing the CHMeNH2 moiety have also been obtained through a chemoenzymatic synthesis.21 All these procedures involve the formation of N-oxides and the use of harmful reagents. In addition, the unsubstituted benzoquinoline backbone starting materials are difficult to source on a commercial scale,22 and when stored for a long time, these heterocyclic compounds have been proven to be slightly air and light sensitive. Because of the importance of this class of ligands,6b,23 it is crucial to develop new synthetic routes for the preparation of stable HCNN derivatives, in accordance with the industrial safety regulations. We describe here the preparation of 4-functionalized-2aminomethylbenzo[h]quinoline hydrochloride salts (HCNNR·
Scheme 1. Synthesis of the 6-Aryl-2-aminomethylpyridine and 2-Aminomethylbenzo[h]quinoline HCNN Ligands
B
DOI: 10.1021/acs.organomet.5b00978 Organometallics XXXX, XXX, XXX−XXX
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Organometallics
Scheme 2. Preparation of the 2-Aminomethylbenzo[h]quinoline Hydrochloride Derivatives (HCNNR·HCl; R = Ph, Me)
Scheme 3. Preparation of the 2-Aminomethylbenzo[h]quinoline Pincer Ruthenium Complexes
isolation of the amino compounds as hydrochloride derivatives leads to very stable ligand precursors, which can be stored in air at room temperature (RT) for a long time without degradation and can be directly used in the preparation of the ruthenium catalysts. Synthesis and Characterization of the RuCl(CNNR)(PP) (R = Ph, Me) Complexes 13−20. The pincer ruthenium complex 13, containing a 2-aminomethylbenzo[h]quinoline ligand with a phenyl in the 4 position and 1,3-bis(diphenylphosphino)propane (dppp), is easily obtained in high yield through a one-pot reaction. Treatment of RuCl2(PPh3)3 with an equimolar amount of dppp in 2propanol at reflux leads to the diphosphine ruthenium intermediate species RuCl2(dppp)m(PPh3)n (m = 1, 2 and n = 1, 0, respectively).34 This system reacts with the hydrochloride ligand 12 in the presence of 10 equivalents of NEt3 in
concentration, leading to higher conversion to product at lower substrate concentration. In addition, lower catalyst loadings and shorter reaction times avoided the hydrogenation of the heteroaromatic. The bromo intermediate 3 has been prepared on a kilogram scale (1.392 kg) starting from 1.183 kg of 1-naphthylamine (see the Experimental Section, method 2 of the syntheses of 1−3). Similarly to the procedure described for 6, the 4-methylaminomethylbenzo[h]quinoline (HCNNMe·HCl, 12) derivative was prepared via cyclization of the methyl derivative 729,30 to 831,32 and bromination to 9, followed by formylation to 10.33 Reaction of 10 with NH2OH·HCl gives 11, which was quantitatively hydrogenated to the hydrochloride product 12, obtained in high yield (Scheme 2). Like 3, the intermediate 9 has been prepared (0.584 kg) starting from 0.50 kg of 1naphthylamine (method 2 of the syntheses of 7−9). The C
DOI: 10.1021/acs.organomet.5b00978 Organometallics XXXX, XXX, XXX−XXX
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Organometallics Scheme 4. TH and HY of Ketones Catalyzed by the Pincer Complexes 13−20
41.3 with a 2JPP = 42.1 Hz, indicating the formation of a single stereoisomer, in agreement with the data of the nonsubstituted benzo[h]quinoline derivative RuCl(CNNH)[(R,S)-JOSIPHOS] prepared from RuCl2(PPh3)3.8 Catalytic Transfer Hydrogenation and Hydrogenation. The pincer ruthenium complexes display high catalytic activity in the reduction of ketones of commercial-grade purity in basic alcohol media via TH in 2-propanol and HY in methanol (Scheme 4). In 2-propanol at reflux and in the presence of NaOiPr (2 mol %) several ketones are efficiently reduced via TH with an S/C ratio up to 20 000. The phenylbenzo[h]quinoline derivative 13 catalyzes the quantitative reduction of acetophenone 21 (0.1 M) to 1-phenylethanol in 2 min, using an S/C of 10 000, achieving a TOF10 of 6.7 × 103 min−1 (Table 1). Complex 14 catalyzes the complete reduction of 21 in a few minutes (10−15 min) with an S/C of 5000 to 20 000. By increasing the substrate concentration of 21 to 0.2 and 0.5 M a slight decrease of conversion was attained, 96% and 93%, respectively, in agreement with the TH equilibrium reaction.37 Interestingly, compound 14 proved to be quite stable in 2propanol solution (∼10−3 M), since no loss of activity was observed after a few days at RT. Complex 15, containing the dppf diphosphine, leads to 97% conversion of 21 in 2 and 10 min with an S/C ratio of 10 000 and 20 000, affording TOF values of 6.7 × 103 and 4.7 × 103 min−1, respectively. The methyl-substituted 2-aminomethylbenzo[h]quinoline complexes 16, 17, and 18 are also active in the TH, with complete reduction of 21 in 10−20 min with S/C = 10 000. In addition, the BINAP derivative 19, isolated as a mixture of two diastereoisomers, efficiently catalyzes the conversion of 21 with S/C = 10 000 in 10 min. Conversely, with the chiral complex 20, containing the (S,R)-JOSIPHOS, 21 is quantitatively reduced to (S)-1-phenylethanol in 2 min and with 85% ee (Table 1). The pincer complexes have been proven to be highly active in the TH of several alkyl phenyl ketones. As a matter of fact, propiophenone 22 and the isopropyl and cyclohexyl derivatives 23 and 24 are reduced with complexes 15, 17, and 18 at S/C = 10 000. It is worth pointing out that the sterically
2-propanol at reflux in 1 h, affording the thermally stable pincer complex 13, isolated in 89% yield (Scheme 3). The 31P{1H} NMR spectrum of 13 shows two doublets at δ 54.7 and 35.7 with a 2JPP of 48.6 Hz, and the 1H NMR signals for the diastereotopic CH2N protons are at δ 4.53 and 3.91, whereas the NH2 resonances are at δ 4.12 and 2.20, as established through a 1H−1H COSY experiment. In the 13C NMR spectrum the orthometalated carbon atom is at δ 178.1, with 2 JCP = 15.0 and 9.4 Hz, while the CH2N signal is at δ 52.0, shifted to low field with respect to that of the hydrochloride salt HCNNPh·HCl (6) (δ 43.1). The use of the hydrochloride salt 6 in place of the free 2-aminomethylbenzo[h]quinoline (HCNNPh) is more straightforward due to the higher stability of the salt in air for a long time, with respect to the free ligand. The pincer complexes 14 and 15, containing 1,4-bis(diphenylphosphino)butane (dppb) and 1,1′-bis(diphenylphosphino)ferrocene (dppf), respectively, were prepared according to the procedure described for 13 using the appropriate diphosphine and 6 and were isolated in 85% and 90% yield (1.68 and 2.03 g, respectively) (Scheme 3). The methyl benzo[h]quinoline pincer complexes 16, 17, and 18, containing the dppp, dppb, and dppf diphosphines, were obtained in 85−90% yield, following the procedure described for 13, by refluxing the ruthenium diphosphine species and 12 in 2-propanol overnight. The BINAP pincer complex 19 was isolated in 62% yield by treatment of [RuCl2(p-cymene)]2 with rac-BINAP35 in 2-propanol at reflux, via the intermediate [RuCl(p-cymene)(BINAP)]Cl,36 followed by reaction with 6 and NEt3, according to a described procedure for related pincer complexes19 (Scheme 3). The 31P{1H} NMR spectrum of 19 shows four doublets at δ 60.6 and 52.4 (2JPP = 39.7 Hz) and 52.1 and 51.2 (2JPP = 34.8 Hz), whereas in the 13C NMR the two signals at δ 178.0 (dd, 2JCP = 12.3, 9.1 Hz) and 176.5 (dd, 2 JCP = 14.3, 9.2 Hz) are for two RuC moieties, consistent with the formation of two diastereoisomers in an about 3:4 molar ratio, respectively. Finally the chiral complex 20 (53% yield) was prepared by reaction of [RuCl2(p-cymene)]2 with (S,R)JOSIPHOS13 and 6 in the presence of NEt3 in 2-propanol at reflux. The 31P{1H} NMR shows two doublets at δ 66.5 and D
DOI: 10.1021/acs.organomet.5b00978 Organometallics XXXX, XXX, XXX−XXX
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Organometallics Table 1. Catalytic Transfer Hydrogenation of Ketones (0.1 M) with Complexes 13−20 (S/C = 5000−20 000) and NaOiPr (2 mol%) in 2-Propanol at 82 °C. entry
complex
ketone
S (M)
S/C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
13 14 14 14 14 14 15 15 16 17 18 19 20 17 15 15 18 13 18 13 18 15 15 17 17
21 21 21 21 21 21 21 21 21 21 21 21 21 22 23 24 24 25 25 26 26 27 28 29 30
0.1 0.1 0.1 0.1 0.2 0.5 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
10 000 5000 10 000 20 000 10 000 10 000 10 000 20 000 10 000 10 000 10 000 10 000 10 000 10 000 10 000 10 000 10 000 5000 5000 5000 5000 10 000 10 000 10 000 10 000
a
t (min) 2 10 15 15 15 15 2 10 10 10 20 10 2 10 20 40 20 40 14 h 40 14 h 10 10 5 5
Table 2. Catalytic Hydrogenation of Ketones (0.5 M) with Complexes 13−15 and 18 (S/C = 10 000) under 5 bar of H2 and a Base (2 mol %) in Methanol at 40 °C.
conv (%)a
entry
complex
ketone
base
t (min)
conv (%)a
98 99 99 98 96 93 97 97 96 95 93 97 97 ee = 85% (S) 94 99 95 93 99 97 99 98 99 98 99 99
1 2 3 4 5 6
13 14 15 15 15 18 15 15
21 21 21 21 21 21 22 29
NaOMe NaOMe NaOMe NaOH KOH KOH KOH KOH
20 60 20 30 15 60 15 120
95 96 95 96 95 94 93 91
7 8
a
The conversion was determined by GC analysis.
of 21 (
