Highly efficient iridium catalysts based on C2-symmetric ferrocenyl phosphinite ligands for asymmetric transfer hydrogenations of aromatic ketones

Tetrahedron: Asymmetry xxx (2015) xxx–xxx

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Highly efficient iridium catalysts based on C2-symmetric ferrocenyl phosphinite ligands for asymmetric transfer hydrogenations of aromatic ketones Bünyamin Ak a, Murat Aydemir a,b, Feyyaz Durap a,b, Nermin Meriç a, Duygu Elma a, Akın Baysal a,⇑ a b

Department of Chemistry, Faculty of Science, University of Dicle, TR-21280 Diyarbakir, Turkey Science and Technology Application and Research Centre (DUBTAM), Dicle University, Diyarbakir 21280, Turkey

a r t i c l e

i n f o

Article history: Received 9 April 2015 Revised 3 October 2015 Accepted 7 October 2015 Available online xxxx

a b s t r a c t A series of chiral modular C2-symmetric ferrocenyl phosphinite ligands have been synthesized in good yields by using 1,10 -ferrocenedicarboxyaldehyde and various amino alcohols as starting materials, and applied in the iridium(III)-catalyzed asymmetric transfer hydrogenations of aromatic ketones to give the corresponding secondary alcohols with good enantioselectivities and reactivities using 2-propanol as the hydrogen source (up to 98% ee and 99% conversion). The substituents on the backbone of the ligands were found to have a significant effect on both the activity and enantiomeric excess. The structures of these complexes have been clarified by a combination of multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Over the past few decades, a large number of chiral bidendate phosphorus containing ligands with a C2-symmetrical structure or bearing two closely related bindings sites have been widely studied.1 Among the recently developed efficient transitionmetal-based chiral reduction catalysts, the C2-symmetric ferrocenyl phosphines are notable.2,3 Due to their great success in catalytic asymmetric reactions,4 chiral ferrocenyl-phosphine ligands have attracted considerable attention in recent years.5,6 These ligands are very efficient for a wide range of reactions, such as hydrogenations,7 hydrosilylations,8 allylic alkylations,9 palladium catalyzed cross-coupling reactions10 and cyclopropanations.11 Although ferrocenyl phosphine ligands have found widespread applications in transition metal catalyzed asymmetric transfer hydrogenations,12 the analogous phosphinites have different chemical, electronic and structural advantages compared to phosphines. For instance, the metal–phosphorus bond is often stronger in phosphinites compared to the related phosphine due to the presence of the electron-withdrawing P–OR group. In addition, the empty r⁄-orbital of the phosphinite P(OR)R2 is stabilized, making the phosphinite a better acceptor.13 Moreover, the most important advantage of chiral phosphinite ligands over the corresponding P-based ligands is their ready preparation, which leads ⇑ Corresponding author. Tel.: +90 412 248 8550x3175; fax: +90 412 248 8300. E-mail address: [email protected] (A. Baysal).

to substantial interest to advance highly effective chiral phosphinite ligands for asymmetric catalysis.14 Alcohols are very important building blocks for the pharmaceutical and fine chemical industries.15 Although many applications require racemic alcohols, the need for enantiomerically pure products is growing, because of their significance as intermediates for the manufacture of pharmaceuticals and advanced materials,16,17 thus raising interest in finding new methods for their production.18 It is well-known that ketones are the most common family of unsaturated substrates, therefore the enantioselective reduction of prochiral ketones leading to enantiomerically pure secondary alcohols is a subject of considerable interest from both the academic and industrial perspectives.19 Over the past few years, the most elegant approach is enantioselective catalysis where prochiral starting materials are transformed into enantioenriched products with the help of chiral catalysts.20 Asymmetric transfer hydrogenation using 2-propanol as a hydrogen source offers an attractive route for reducing simple unfunctionalized ketones to chiral alcohols.21,22 More recently, the synthesis and applications of efficient rhodium-based catalysts have also been reported in the literature.23 However the interest in iridium catalysts,24 which have been successfully used for the asymmetric transfer hydrogenation, is rapidly growing in recent years. Iridium has the advantage of being much less expensive than rhodium.25 Since the pioneering work of Mestroni et al. on the use of iridium complexes in the transfer hydrogenation of ketones,26,27 numerous iridium-based catalytic systems have been studied.

http://dx.doi.org/10.1016/j.tetasy.2015.10.002 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

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and characterization of iridium(III)-ferrocenyl phosphinite complexes. These compounds have also been employed successfully as catalysts in iridium(III)-promoted asymmetric transfer hydrogenations of various ketones. To the best of our knowledge, there are not many reports on asymmetric transfer hydrogenations of ketones using chiral Ir(III) C2-symmetric ferrocenyl phosphinites as catalysts.

Various types of chiral ligands have been reported. The different catalytic systems will be presented according to the coordination pattern of the ligands involved. One of the first reports on the iridium-based asymmetric transfer hydrogenation of ketones was by Grazani et al.28 Dichlorobis(1,4-cyclooctadiene)diiridium was used as a precatalyst in the presence of the chiral phosphines for the asymmetric transfer reduction of ketones. At the same time, Bakos et al. found that in situ prepared iridium complexes of phosphinites (BDPOP, BDPODP) could also catalyze the asymmetric transfer hydrogenation of aromatic ketones.29 Similar studies were carried out by numerous P-based ligands by many researchers. Considering that both C2-symmetrical ligands and phosphinites often give high levels of enantioselectivity in asymmetric reactions,30 in recent years our research group has reported the synthesis,31 characterization and coordination properties of these types of ligands.32 Inspired by the excellent results obtained with some of the chiral phosphinite ligands,33 we have developed a new class of C2-symmetric ferrocenyl phosphinite ligands that allow good control of enantioselectivities via easy structural manipulation. Herein we report our preliminary results on the full synthesis

2. Results and discussion 2.1. Synthesis and characterization of the amino alcohols, C2-symmetric ferrocenyl-phosphinites and their iridium(III) complexes The synthetic strategy and reaction conditions adopted herein are described in Scheme 1. We first established an easy methodology for the synthesis of ferrocene-1,10 -dicarboxyaldehyde based, in part, on conditions reported by Pelinski and Mueller-Westerhoff.34 Next, in separate experiments, ferrocene-1,10 -dicarboxyaldehyde was reacted with commercially available (S)-phenyl alaninol, R1

CHO

N H ii

Fe

R3

Fe

i

H N

CHO

R2

R2

R4

OH

HO

R3 iii

R4

R1

R1 N H

Fe Fe

R1

R2

OPPh2

R3 2

R

1

R

R4

Ir Cl

Cl

Fe

Cl

Cl OPPh2

Ir

R3

HN R2

R 3 OPPh2

R4

HN R3

R4

OPPh 2

H N iv

R2

R4

R1

1-8 R1

R2

R3

R4

1

PhCH2 -

H

H

H

2

Ph-

H

H

H

3

i-Bu-

H

H

H

4

s-Bu-

H

H

H

5

H

H

H

MeH

6

H

H

Ph-

7

H

Et-

H

H

8

Ph-

H

Ph-

H

Scheme 1. Reagents and conditions: (i) n-BuLi, TMEDA, 78 °C, THF, DMF; (ii) L-phenyl alaninol, L-phenyl glycinol, L-leucinol, L-isoleucinol, (S)-(+)-1-amino-2-propanol, (R)()-2-amino-1-phenylethanol, (R)-()-2-amino-1-butanol or (1S,2R)-(+)-2-amino-1,2-diphenylethanol; (iii) 2 equiv Ph2PCl, 2 equiv Et3N; (iv) 1 equiv [Ir(g5-C5Me5)(l-Cl)Cl]2, for 1–8.

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(S)-phenyl glycinol, (S)-leucinol, (S)-isoleucinol, (S)-(+)-1-amino-2propanol, (R)-()-2-amino-1-phenylethanol, (R)-()-2-amino1-butanol or (1S,2R)-(+)-2-amino-1,2-diphenylethanol in the presence of molecular sieves, and the reduction of the crude reaction mixtures with NaBH4 in methanol provided the corresponding enantiomerically pure amino alcohols, 1–8 in high yields. The structures for these ferrocene based chiral amino alcohols are consistent with the data obtained from 1H NMR, 13C NMR, IR spectroscopy, and elemental analysis.35 Chiral C2-symmetric phosphinite ligands based on the ferrocenyl group, were synthesized by deprotonation from the described ferrocene based chiral amino alcohols, by a base and the subsequent reaction with two equivalents of Ph2PCl, in anhydrous toluene under an inert argon atmosphere (Scheme 1). The progress of these reactions was conveniently followed by 31P– {1H} NMR spectroscopy. Both of the phosphorus atoms are equivalent in each ligand and exhibit singlets approximately at 107–114 ppm, and the 31P–{1H} NMR spectra of the free ligands are36 in line with the values previously observed for similar compounds.37 The assignment of the 1H chemical shifts was derived from 2D HH-COSY spectra and the appropriate assignment of the 13 C chemical shifts from DEPT and 2D HMQC spectra. Furthermore, IR spectra and C, H, N elemental analyses were in agreement with the proposed structures for C2-symmetric ferrocenyl phosphinite ligands.35 The iridium complexes of these ligands were prepared as indicated in the Section 4 and are illustrated in Scheme 1. All of the iridium complexes were readily synthesized in high yields and the whole reactions resulting 1–8 are depicted in Scheme 1. Treatment of [Ir(g5-C5Me5)(l-Cl)Cl]2 with C2-symmetric ferrocenyl phosphinite ligands in a 1:1 molar ratio in toluene resulted in the formation of dinuclear complexes as crystalline air stable solids. The C2-symmetric ferrocenyl phosphinites were expected to cleave the [Ir(g5-C5Me5)(l-Cl)Cl]2 dimer to give the corresponding complexes 1–8 via monohapto coordination of the phosphinite group. All of the complexes were isolated as indicated by singlets in the 31 P–{1H} NMR spectra at approximately d 72–74 ppm, with a coordination shift of approximately d 36 ppm attributed to formation of the corresponding C2-symmetric ferrocenyl phosphinites. Interestingly, the 1H NMR spectra of these complexes are featured by very broad signals at room temperature. Upon lowering the temperature to 80 °C, the signals remained unresolved, hence their clear assignment could not be accomplished. Elemental analyses of the complexes are also consistent with the expected molecular formulas. The absorption bands corresponding to Ir(III)–C2-symmetric ferrocenyl phosphinite complexes in the IR spectra do not exhibit important differences with respect to those of free ligands (see Section 4).

Table 1 Asymmetric transfer hydrogenation of acetophenone with iso-PrOH catalyzed by Ir (III)-C2-symmetric ferrocenyl monodendate phosphinite complexes 1–8

O Cat.

+

Entry Complex S/C/base

H

HO

OH

O

*

+

Time (h)

Conv.h (%)

% eei

Config.k TOFl (h1)

36 36 36 36 36 36 (72)b 36 36

49 43 51 53 42 30 (39)b 46 39

65 70 53 56 79 95 (92)b 57 87

(R) (S) (R) (S) (S) (R) (R) (R)

1 2 3 4 5 6 7 8

1a 2a 3a 4a 5a 6a 7a 8a

9

6c

<5

—

—

Trace

10 11 12 13 14 15 16 17

1d 2d 3d 4d 5d 6d 7d 8d

100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5

1 1 1 1 2 3 (3)e 1 2

99 98 97 98 98 99 (95)e 99 98

64 70 55 56 83 97 (93)e 59 90

(R) (S) (R) (S) (S) (R) (R) (R)

99 98 97 98 49 33 (32) 99 49

18 19 20 21

6f 6f 6f 6f

100:1:3 100:1:5 100:1:7 100:1:9

3 3 3 3

98 99 99 98

90 97 92 92

(R) (R) (R) (R)

33 33 33 33

22 23 24 25 26 27 28 29 30

5g 6g 8g 5g 6g 8g 5g 8g 8g

250:1:5 3 250:1:5 5 250:1:5 3 500:1:5 5 500:1:5 8 500:1:5 5 1000:1:5 8 1000:1:5 12 1000:1:5 8

98 99 96 94 97 95 98 99 97

77 93 83 75 91 82 73 90 80

(S) (R) (R) (S) (R) (R) (S) (R) (R)

33 20 32 19 12 19 12 <10 12

100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5 100:1:5

100:1 24

<5 <5 <5 <5 <5 <5 <5 <5

2.2. Ir(III)-catalyzed asymmetric transfer hydrogenation of ketones using iso-PrOH and base

Reaction conditions. a At room temperature; acetophenone/Ir/NaOH,100:1:5. b At room temperature; acetophenone/Ir/NaOH, 100:1:5, (96 h). c Refluxing in iso-PrOH; acetophenone/Ir, 100:1, in the absence of base. d Refluxing in iso-PrOH; acetophenone/Ir/NaOH, 100:1:5. e Refluxing in iso-PrOH; acetophenone/Ir/KOH, 100:1:5. f Refluxing in iso-PrOH; acetophenone/Ir/NaOH, 100:1:5. g Refluxing in iso-PrOH; acetophenone/Ir/NaOH, 250, 500 or 1000:1:5. h Determined by GC (three independent catalytic experiments). i Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary column. k Determined by comparison of the retention times of the enantiomers on the GC traces with literature values, the (S)- or (R)-configuration was obtained in all experiments. l TOF = (mol product/mol Cat.)  h1.

In a preliminary study, complexes 1–8 were tested as precursors for the catalytic asymmetric transfer hydrogenation of acetophenone and the results are given in Table 1. A typical procedure using acetophenone as substrate was as follows: 0.01 mmol of the complex and 1 mmol of acetophenone were added to a solution of NaOH in iso-PrOH (0.05 mmol of NaOH in 10 mL iso-PrOH) and refluxed at 82 °C, while the reaction was monitored by GC. In all reactions, these complexes catalyzed the reduction of ketones to the corresponding alcohols via hydrogen transfer from iso-PrOH. A comparison of complexes 1–8 as precatalysts for the asymmetric hydrogenation of acetophenone by iso-PrOH is given in Table 1. Catalytic experiments were carried out under inert (Ar) atmosphere using standard Schlenk-line techniques. These systems catalyzed the reduction of acetophenone to the corresponding alcohol (S)- or (R)-1-phenylethanol in the presence of NaOH. At room temperature, transfer hydrogenation

of acetophenone occurred very slowly,38 with low conversions (up to 53%, 36 h) and moderate to high enantioselectivities (up to 95% ee) in the reactions (Table 1, entries 1–8). Due to the reversibility at room temperature, prolonging the reaction time (72 h) led to a slight decrease in enantioselectivity, as indicated by the catalytic results collected with catalyst, 6 (entry 6,b).39,40 Moreover, as can be inferred from Table 1(entry 9), the presence of a base is necessary to observe appreciable conversions. It is well-known that the base facilitates the formation of iridium alkoxide by abstracting the proton of the alcohol; the subsequent alkoxide undergoes b-elimination to give the metal hydride, which is an active species in this reaction.41–44 The role of the base is to generate a more nucleophilic alkoxide ion, which rapidly attacks the iridium complex responsible for the dehydrogenation of isoPrOH. Furthermore, the choice of base, such as KOH and NaOH,

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had little influence on the conversion or enantioselectivity (Table 1, entry 15) and with a catalyst/NaOH ratio of 1:5, the complexes were very active leading to a quantitative transformation of acetophenone (Table 1, entries 18–21). Reduction of acetophenone into (S)- or (R)-1-phenylethanol could be achieved in high yield by increasing the temperature up to 82 °C (Table 1, entries 10–17). Furthermore, the conversions gradually decreased when increasing the molar ratios of [acetophenone]/[Ir] from 250:1 to 500:1 or 1000:1, except the time lengthened, although the enantioselectivities were still high (up to 92% ee, Table 1, entries 22–30). Specifically, the ee’s remained unchanged when the molar ratios of the substrate to catalyst were increased and these C2-phosphinite ligands with ferrocenyl moiety showed much high activity and high enantioselectivity. A similar tendency was reported in earlier studies,45 indicating that these types of ligands play an important role in metal–ligand catalytic systems.46 Furthermore, it is noteworthy that the catalytic systems 1–8 display differences in reactivity. These results indicate that the structural difference of the C2-ferrocenyl phosphinite ligands is a crucial factor in terms of the catalytic activity. It can be seen that when the stereogenic center is near the iridium center, the % ee is high. Hence from the results, it can be seen that complexes 5, 6 and 8 were effective catalysts for the hydrogenation of acetophenone, yielding products with up to 97% ee. It has also been shown that the catalytic activities in hydrogen transfer reactions were generally much higher for ((R)-bis[[N-2-diphenylphosphinite-2phenyl]-1,10 -ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 6 than for the other complexes. Furthermore, the aryl moiety in complexes 6 and 8 is more responsible for the high activity than the alkyl moiety in complexes 1–5 and 7. This different behavior in enantioselectivity can be explained on the basis that the aromatic moiety (phenyl) attaches to the stereogenic carbon center in the ligand backbone, thus enabling the optimization molecular rigidity. These results also show that the enantiomeric purity of the product can be affected by electronic factors and the steric factors of the substituents on the ligands. As can be seen from Table 1, the catalytic activities in the studied hydrogen transfer reactions were generally much higher for 5, 6, and 8 than those for the other complexes. In order to check the application of the Ir(III)-catalyzed transfer hydrogenation, acetophenone derivatives were subjected to asymmetric reductions using the conditions optimized for acetophenone. Table 2 shows the conversions of the reductions performed in a 0.1 M iso-PrOH solution containing 5, 6 and 8 and NaOH (ketone/Cat./NaOH = 100:1:5). The results demonstrate that a range of acetophenone derivatives can be hydrogenated with high enantioselectivities. Substitution of the phenyl ring of the acetophenone substrate led to a marked decrease in the catalytic activity and % ee, that is, the electronic properties (the nature and position) of the substituents on the phenyl ring of the ketone caused the changes in the reduction rate. The introduction of electron withdrawing substituents at the para-position of the aryl ring of the ketone decreased the electron density of the C@O bond so that the activity was improved, thus resulting in an easier hydrogenation.47,48 As expected, the lowest enantioselectivity was observed in transfer hydrogenations of p-methoxyacetophenone. From the results, it can be seen that the introduction of an electron-donating group, such as a methoxy group, to the p-position decelerates the reaction, but to the o-position increases the rate and improves the enantioselectivity. On the contrary, the introduction of electron-withdrawing substituents, such as F or NO2, to the para-positions of the aryl ring of the ketone, resulted in improved activity with good enantioselectivity (Table 2, entries 1–3 and 10–12). Examination of the results indicates that with each of the tested complexes, the highest enantioselectivity was found for o-methoxyacetophenone (98% ee) when ((R)-bis[[N-2-diphenylphos-

Table 2 Asymmetric transfer hydrogenation results for substituted acetophenones catalyzed by Ir(III)-ferrocenyl based C2-symmetric monodendate phosphinite complexes 5, 6 and 8a

OH

O OH R

+

Cat

O

*

R

+

Conv.b (%)

eec (%)

TOFd (h1)

Config.e

20 30 20

98 99 99

85 92 84

294 198 297

(S) (R) (R)

Cl

30 60 30

99 99 99

83 91 82

198 99 198

(S) (R) (R)

5 6 8

Br

60 120 60

99 98 98

82 88 80

99 49 98

(S) (R) (R)

10 11 12

5 6 8

NO2

20 30 20

99 99 97

86 91 83

297 198 291

(S) (R) (R)

13 14 15

5 6 8

2-CH3O

180 300 180

97 99 98

92 98 81

32 20 33

(S) (R) (R)

16 17 18

5 6 8

4-CH3O

240 420 240

99 98 99

80 83 78

25 14 25

(S) (R) (R)

Entry

Catalyst

R

Time (min)

1 2 3

5 6 8

F

4 5 6

5 6 8

7 8 9

a Catalyst (0.005 mmol), substrate (0.5 mmol), isoPrOH (5 mL), NaOH (0.025 mmol %), 82 °C, the concentration of acetophenone derivatives are 0.1 M. b Purity of compounds is checked by 1H NMR and GC (three independent catalytic experiments), yields are based on aryl ketone. c Determined by capillary GC analysis using a chiral cyclodex B (Agilent) capillary column (30 m  0.32 mm I.D.  0.25 lm film thickness). d TOF = (mol product/mol Cat.)  h1. e Determined by comparison of the retention times of the enantiomers on the GC traces with the literature.

phinite-2-phenyl]-1,10 -ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))], 6 was used as the catalyst precursor. 3. Conclusion Herein we have described the synthesis of novel bimetallic Ir(III) C2-symmetric ferrocenyl phosphinite complexes, which afforded good enantioselectivities in the asymmetric transfer hydrogenation of aromatic ketones (up to 98% ee). The absolute configuration of the stereogenic carbon center in the ligand backbone is of particular importance for the asymmetric induction offering an obvious target for further optimization. The simplicity and efficiency clearly make it an excellent choice of catalyst for practical preparation of invaluable alcohols via catalytic asymmetric transfer hydrogenation of aromatic ketones. Furthermore, the development of a practical synthesis of C2symmetric ferrocenyl phosphinites and demonstration that they are competent auxiliaries for catalysis open up a neglected vein in the rich chemistry of phosphorus ligands. Further work on modifying the ligand structure for improvement of the enantioselectivity as well as broadening the substrate scope of the asymmetric transfer hydrogenation is currently underway. 4. Experimental 4.1. General Unless otherwise mentioned, all reactions were carried out under an atmosphere of argon using conventional Schlenk glass

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ware, and solvents were dried using established procedures and distilled under argon just prior to use. Analytical grade and deuterated solvents were purchased from Merck. The starting materials ferrocene, L-phenyl alaninol, L-phenyl glycinol, L-leucinol, L-isoleucinol, (S)-(+)-1-amino-2-propanol, (R)-()-2-amino-1-phenylethanol, (R)-()-2-amino-1-butanol, (1S,2R)-(+)-2-amino-1,2-diphenylethanol, PPh2Cl and Et3N were purchased from Fluka and used as received. 1,10 -Ferrocenedicarboxyaldehyde,49 and Ir(g5-C5Me5)(l-Cl)Cl]250 were prepared according to the literature. 1H NMR (at 400.1 MHz), 13 C NMR (at 100.6 MHz) and 31P–{1H} NMR (at 162.0 MHz) spectra were recorded on a Bruker AV400 spectrometer, with TMS (tetramethylsilane) as an internal reference for 1H NMR and 13C NMR or 85% H3PO4 as an external reference for 31P–{1H} NMR. The IR spectra were recorded on a Mattson 1000 ATI UNICAM FT-IR spectrometer as KBr pellets. Specific rotations were taken on a Perkin–Elmer 341 model polarimeter. Elemental analysis was carried out on a Fisons EA 1108 CHNS-O instrument. Melting points were recorded by a Gallenkamp Model apparatus with open capillaries. GC analyses were performed on a Shimadzu GC 2010 Plus Gas Chromatograph equipped with a cyclodex-B (Agilent) capillary column (30 m  0.32 mm I. D.  0.25 lm film thickness). Racemic samples of alcohols were obtained by reduction of the corresponding ketones with NaBH4 and used as the authentic samples for ee determination. The GC parameters for asymmetric transfer hydrogenation of ketones were as follows; initial temperature, 50 °C; initial time 1.1 min; solvent delay, 4.48 min; temperature ramp 1.3 °C/min; final temperature, 150 °C; initial time 2.2 min; temperature ramp 2.15 °C/min; final temperature, 250 °C; initial time 3.3 min; final time, 44.33 min; injector port temperature, 200 °C; detector temperature, 200 °C, injection volume, 2.0 lL. 4.2. General procedure for the transfer hydrogenation of ketones Typical procedure for the catalytic hydrogen-transfer reaction: a solution of the Ir(III)-complexes 1–8, (0.01 mmol), NaOH (0.05 mmol) and the corresponding ketone (1 mmol) in degassed 2-propanol (10 mL) was refluxed until the reaction was completed. A sample of the reaction mixture was then taken off, diluted with acetone and analyzed immediately by GC. The conversions obtained are related to the residual unreacted ketone. 4.3. Synthesis of iridium complexes of the ferrocene based C2-symmetric phosphinites 1–8

4.3.1. (S)-Bis[[N-(2-diphenylphosphinite-1-benzyl)ethyl]-1,10 ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 1 A solution of (S)-bis[N-(2-diphenylphosphinite-1-benzyl)ethyl]-1,10 -ferrocenylmethyl diamine(120 mg, 0.14 mmol) and [Ir (g5-C5Me5)(l-Cl)Cl]2 (112 mg, 0.14 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 1 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, and the solid was washed with hexane/diethyl ether (1:1) and dried by vacuum, yielding iridium complex 1. Yield: 200 mg, 87%; 31 [a]20 P–{1H} NMR (CDCl3, D = +53.9 (c 1.2, MeOH); mp: 149–152 °C. 162.0 MHz, ppm): 73.07 (s, O-PPh2). IR (KBr pellet in cm1): (NAH): 3320, (CH): 3050, 3025, 2930, 2859, (CACACp): 1440 (OAP): 1010; Anal. Calcd for [C74H84N2O2P2FeIr2Cl4] (1677.5 g/mol): C, 52.98; N, 1.67; H, 5.06; found: C, 52.80; N, 1.37; H, 4.80.

5

4.3.2. (S)-Bis[[N-(2-diphenylphosphinite-1-phenyl)ethyl]-1,10 ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 2 A solution of the (S)-bis[N-(2-diphenylphosphinite-1-phenyl) ethyl]-1,10 -ferrocenylmethyl diamine (123 mg, 0.14 mmol) and [Ir (g5-C5Me5)(l-Cl)Cl]2 (112 mg, 0.14 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 2 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, and the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 2. Yield: 195 mg, 82%; [a]20 D = +89.2 (c 1.2, MeOH); mp: 138–140 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 74.13 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3335, (CAH): 3072, 3030, 2925, 2870, (CACACp): 1440, (OAP): 1025; Anal. calcd for [C72H80N2O2P2FeIr2Cl4] (1649.4 g/mol): C, 52.42; N, 1.70; H, 4.90; found: C, 52.25; N, 1.56; H, 4.68. 4.3.3. (S)-Bis[[N-(2-diphenylphosphinite-1-iso-butyl)ethyl]-1,10 ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 3 A solution of the (S)-bis[N-(2-diphenylphosphinite-1-iso-butyl) ethyl]-1,10 -ferrocenyl methyl diamine (128 mg, 0.16 mmol) and [Ir(g5-C5Me5)(l-Cl)Cl]2 (127 mg, 0.16 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 45 min. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 3. Yield: 230 mg, 90%; [a]20 D = +72.5 (c 1.2, MeOH); mp: 128–130 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 72.90 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3323, (CAH):3060, 2980, 2965, 2860, (CACACp): 1435, (OAP): 1027; Anal. calcd for [C68H88N2O2P2FeIr2Cl4] (1609.4 g/mol): C, 50.74; N, 1.74; H, 5.52; found: C, 50.60; N, 1.66; H, 5.33. 4.3.4. (S)-Bis[[N-(2-diphenylphosphinite-1-sec-butyl)ethyl]-1,10 ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 4 A solution of the (S)-bis[N-(2-diphenylphosphinite-1-sec-butyl) ethyl]-1,10 -ferrocenyl methyldiamine (128 mg, 0.16 mmol) and [Ir (g5-C5Me5)(l-Cl)Cl]2 (127 mg, 0.16 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 90 min. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 4. Yield: 225 mg, 88%; [a]20 D = +83.8 (c 1.2, MeOH); mp: 129–131 °C. 31P–{1H}NMR (CDCl3, 162.0 MHz, ppm): 73.21 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3325, (CAH):3070, 2952, 2925, 2870, (CACACp): 1450, (OAP): 1008; Anal. calcd for [C68H88N2O2P2FeIr2Cl4] (1609.4 g/mol): C, 50.74; N, 1.74; H, 5.52; found: C, 50.58; N, 1.60; H, 5.23. 4.3.5. (S)-Bis[[N-2-diphenylphosphinitepropyl]-1,10 -ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 5 A solution of the (S)-bis[N-2-diphenylphosphinite propyl]-1,10 ferrocenylmethyldiamine (124 mg, 0.17 mmol) and [Ir(g5-C5Me5) (l-Cl)Cl]2 (135 mg, 0.17 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 3 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, and the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 5. Yield: 112 mg, 81%; [a]20 D = +77.6 (c 1.2, MeOH); mp:

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B. Ak et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx

157–159 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 74.13 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3298, (CAH): 3090, 3055, 2930, 2869, (CACACp): 1418, (OAP): 1023; Anal. calcd for [C62H76N2O2P2FeIr2Cl4] (1525.3 g/mol): C, 48.81; N, 1.84; H, 5.03; found: C, 48.58; N, 1.50; H, 4.83. 4.3.6. (R)-Bis[[N-2-diphenylphosphinite-2-phenyl]-1,10 -ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 6 A solution of the (R)-bis[N-2-diphenylphosphinite-2-phenyl]1,10 -ferrocenylmethyl diamine (154 mg, 0.18 mmol) and [Ir(g5C5Me5)(l-Cl)Cl]2 (143 mg, 0.18 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 5 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, and the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 6. Yield: 265 mg, 89%; [a]20 D = 85.5 (c 1.2, MeOH); mp: 141–143 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 72.99 (s, OPPh2). IR (KBr pellet in cm1): (NAH): 3340, (CAH): 3109, 3075, 2950, 2870, (CACACp): 1460, (OAP): 1050; Anal. calcd for [C72H80N2O2P2FeIr2Cl4] (1649.4 g/mol): C, 52.42; N, 1.70; H, 4.90; found: C, 52.15; N, 1.46; H, 4.58. 4.3.7. (R)-Bis[[N-2-diphenylphosphinite-1-ethyl]-1,10 -ferrocenylmethyldiamine(dichloro g5-pentamethylcyclopentadienyl iridium(III))] 7 A solution of the (R)-bis[N-2-diphenylphosphinite-1-ethyl]1,10 -ferrocenylmethyldiamine (106 mg, 0.14 mmol) and [Ir(g5C5Me5)(l-Cl)Cl]2 (112 mg, 0.14 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 1 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, and the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 7. Yield: 200 mg, 92%; [a]20 D = 63.5 (c 1.2, MeOH); mp: 139–142 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 73.32 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3341, (CAH): 3089, 2985, 2940, 2859, (CACACp): 1447, (OAP): 1033; Anal. calcd for [C64H80N2O2P2FeIr2Cl4] (1553.3 g/mol): C, 49.48; N, 1.80; H, 5.20; found: C, 49.25; N, 1.56; H, 4.88. 4.3.8. (1S,2R)-Bis[[N-(2-diphenylphosphinite-1,2-diphenyl) ethyl]-1,10 -ferrocenylmethyldiamine(dichloro g5pentamethylcyclopentadienyl iridium(III))] 8 A solution of (1S,2R)-bis[N-(2-diphenylphosphinite-1,2-diphenyl)ethyl]-1,10 -ferrocenyl methyldiamine (141 mg, 0.14 mmol) and [Ir(g5-C5Me5)(l-Cl)Cl]2 (112 mg, 0.14 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for 8 h. The resulting yellow solution was concentrated to 2 mL under reduced pressure, and the addition of hexane (30 mL) caused the precipitation of a dark yellow solid. The supernatant solution was decanted, the solid was washed with hexane/diethylether (1:1) and dried by vacuum, yielding iridium complex 8. Yield: 234 mg, 93%; [a]20 D = +36.6 (c 1.2, MeOH); mp: 157–160 °C. 31P–{1H} NMR (CDCl3, 162.0 MHz, ppm): 73.97 (s, OAPPh2). IR (KBr pellet in cm1): (NAH): 3335, (CAH): 3072, 3030, 2925, 2870, (CACACp): 1440, (OAP): 1025; Anal. calcd for [C84H88N2O2P2FeIr2Cl4] (1801.6 g/mol): C, 55.99; N, 1.56; H, 4.93; found: C, 55.75; N, 1.26; H, 4.68. Acknowledgements Partial support from Tubitak (Project number: 111T419) is gratefully acknowledged.

References 1. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069. 2. Arrayas, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674– 7715. 3. Sutcliffe, O. B.; Bryce, M. R. Tetrahedron: Asymmetry 2003, 14, 2297–2325. 4. Blaser, H. A.; Spindler, F. Chimia 1997, 51, 297–299. 5. Ferrocene; Togni, A., Hayashi, T., Eds.; Wiley-VCH: Weinheim, 1995. 6. Burk, M. J.; Gross, M. F. Tetrahedron Lett. 1994, 35, 9363–9366. 7. Kang, J.; Lee, J. H.; Ahn, S. H.; Choi, J. S. Tetrahedron Lett. 1998, 39, 5523–5526. 8. Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 111– 113. 9. Sawamura, M.; Ito, Y. Chem. Rev. 1992, 9, 857–871. 10. Dai, Q.; Gao, W.; Liu, D.; Kapes, L. M.; Zhang, X. J. Org. Chem. 2006, 71, 3928– 3934. 11. Song, J.-H.; Cho, D.-J.; Jeon, S.-J.; Kim, Y.-H.; Kim, T.-J. Inorg. Chem. 1999, 38, 893–896. 12. Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2003, 14, 597–602. 13. Galka, P. W.; Kraatz, H.-B. J. Organomet. Chem. 2003, 674, 24–31. 14. Guo, R.; Chen, X.; Elphelt, C.; Song, D.; Morris, R. H. Org. Lett. 2005, 7, 1757– 1759. 15. Large Scale Asymmetric Catalysis; Blaser, H. U., Schmidt, A., Eds.; Wiley-VCH: Weinheim, 2003. 16. Handbook of Homogeneous Hydrogenation; de Vries, J. G., El seiver, C. J., Eds.; Wiley-VCH: Weinheim, 2007; p 1279. 17. Moore, J. C.; Pollard, D. J.; Kosjek, B.; Devine, P. N. Acc. Chem. Res. 2007, 40, 1412–1419. 18. Farinas, E. T.; Schwaneberg, U.; Glieder, A.; Arnold, F. H. Adv. Synth. Catal. 2001, 343, 601–606. 19. Malacea, R.; Poli, R.; Manoury, E. Coord. Chem. Rev. 2010, 254, 729–752. 20. Sudan, L. A. Acc. Chem. Res. 2007, 40, 1309–1319. 21. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102. 22. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007–1017. 23. Murata, K.; Ikariya, T. J. Org. Chem. 1999, 642, 2186–2187. 24. Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411. 25. Values based on www.platinum.matthey.com. 26. Mestroni, G.; Zassinowich, G.; Camus, A.; Martinelli, F. J. Organomet. Chem. 1980, 198, 87–96. 27. Martinelli, F.; Mestroni, G.; Zassinowich, G.; Camus, A. J. Organomet. Chem. 1981, 220, 383–392. 28. Spogliarich, R.; Zassinovich, G.; Kaspar, J.; Graziani, M. J. Mol. Catal. A: Chem. 1982, 16, 359–361. 29. Kvintovichs, P.; Bakos, J.; Heil, B. J. Mol. Catal. A: Chem. 1985, 32, 111–114. 30. Whitesell, J. K. Chem. Rev. 1989, 89, 1581–1590. 31. (a) Aydemir, M.; Baysal, A.; Meric, N.; Gümgüm, B. J. Organomet. Chem. 2009, 694, 2488–2492; (b) Elma, D.; Durap, F.; Aydemir, M.; Baysal, A.; Meriç, N.; Ak, B.; Turgut, Y.; Gümgüm, B. J. Organomet. Chem. 2013, 729, 46–52. 32. (a) Aydemir, M.; Baysal, A.; Meric, N.; Kayan, C.; Tog˘rul, M.; Gümgüm, B. Appl. Organomet. Chem. 2010, 24, 215–221; (b) Aydemir, M.; Meric, N.; Durap, F.; Baysal, A.; Tog˘rul, M. J. Organomet. Chem. 2010, 695, 1392–1398; (c) Aydemir, M.; Durap, F.; Baysal, A.; Meric, N.; Buldag˘, A.; Gümgüm, B.; Özkar, S.; Yıldırım, L. T. J. Mol. Catal. A: Chem. 2010, 326, 75–81. 33. (a) Aydemir, M.; Meric, N.; Baysal, A.; Gümgüm, B.; Tog˘rul, M.; Turgut, Y. Tetrahedron: Asymmetry 2010, 21, 703–710; (b) Ak, B.; Elma, D.; Meriç, N.; Kayan, C.; Isßık, U.; Aydemir, M.; Durap, F.; Baysal, A. Tetrahedron: Asymmetry 2013, 24, 1257–1264; (c) Ak, B.; Aydemir, M.; Ocak, Y. S.; Durap, F.; Kayan, C.; Baysal, A.; Temel, H. Inorg. Chim. Acta 2014, 409, 244–253. 34. Sanders, R.; Mueller-Westerhoff, U. T. J. Organomet. Chem. 1996, 512, 219–224. 35. Ak, B.; Aydemir, M.; Durap, F.; Baysal, A. Inorg. Chim. Acta 2015, 438, 42–51. 36. (a) Hauptman, E.; Shapiro, R.; Marshall, W. Organometallics 1998, 17, 4976– 4982; (b) Ruhlan, K.; Gigler, P.; Herdweck, E. J. Organomet. Chem. 2008, 693, 874–893. 37. (a) Hariharasarma, M.; Lake, C. H.; Watkins, C. L.; Gray, M. G. J. Organomet. Chem. 1999, 580, 328–338; (b) Baysal, A.; Aydemir, M.; Durap, F.; Gümgüm, B.; Özkar, S.; Yıldırım, L. T. Polyhedron 2007, 26, 3373–3378; (c) Broger, E. A.; Burkart, W.; Hennig, M.; Scalone, M.; Schmid, R. Tetrahedron: Asymmetry 1998, 9, 4043–4054. 38. Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. J. Chem. Soc, Chem. Commun. 1996, 233–234. 39. Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288–290. 40. Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308. 41. Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.; England, F. A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703–1707. 42. Kelson, E. P.; Phengsy, P. P. J. Chem. Soc., Dalton Trans. 2000, 4023–4024. 43. Chen, J. S.; Li, Y.; Dong, Z.; Li, B.; Gao, J. Tetrahedron Lett. 2004, 45, 8415–8418. 44. Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986–987. 45. (a) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087–1089; (b) Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1995, 6, 705–718; (c) Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817–3818; (d) Ikariya, T.; Blocker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308.

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B. Ak et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx 46. (a) Haack, K.-J.; Hashiguchi, S.; Fuji, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 285–288; (b) Ikariya, T.; Blocker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308; (c) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087–1089; (d) Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817– 3818.

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47. Faller, J. W.; Lavoie, A. R. Organometallics 2001, 20, 5245–5247. _ Yasßar, S. Trans. Met. Chem. 2005, 30, 831–835. 48. Özdemir, I.; 49. Bastin, S.; Agbossou-Niedercorn, F.; Brocard, J.; Pelinski, L. Tetrahedron: Asymmetry 2001, 12, 2399–2408. 50. White, C.; Yates, A.; Maitliss, P. M. Inorg. Synth. 1992, 29, 228–230.

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