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Chirality-Economy Catalysis: Asymmetric Transfer Hydrogenation of Ketones by Ru-Catalysts of Minimal Stereogenicity Fumin Chen, Dongxu He, Li Chen, Xiaoyong Chang, David Zhigang Wang, Chen Xu, and Xiangyou Xing ACS Catal., Just Accepted Manuscript • Publication Date (Web): 15 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019
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ACS Catalysis
Chirality-Economy Catalysis: Asymmetric Transfer Hydrogenation of Ketones by Ru-Catalysts of Minimal Stereogenicity Fumin Chen1,§, Dongxu He1,§, Li Chen2,†, §, Xiaoyong Chang1, David Zhigang Wang2,‡, Chen Xu1,*, Xiangyou Xing1,* 1Shenzhen
Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China 2School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, China. ABSTRACT: This manuscript describes the design and synthesis of Ru-catalysts that feature only single stereogenic element, yet this minimal chirality resource is demonstrated to be well competent for effecting high levels of stereoinduction in the asymmetric transfer hydrogenation over a broad range of ketone substrates, including those that are not accommodated by known catalyst systems. The single stereogenic center of the (1-pyridine-2-yl)methanamine) is the only point-chirality in the catalysts, which simplifies this catalyst system relative to existing literature protocols.
KEYWORDS: asymmetric transfer hydrogenation, minimal stereogenicity, ruthenium, asymmetric catalysis, diaryl ketones The Noyori asymmetric hydrogenation (AH) and asymmetric transfer hydrogenation (ATH) of carbonyl compounds into their optically enriched alcohol products serve as cornerstones of modern catalysis technologies, and have found widespread applications in both academic and industrial settings.1 Catalyst systems with representative structures being (S)-Tol-BINAP/(S,S)-DPEN-Ru and its various structural analogs are effective in asymmetric hydrogenation of ketones, and the high level of enantioface differentiation is the synergistic effect of three stereogenic identities (all red stars denoted in Figure 1A).2,3 Asymmetric transfer hydrogenation offers an attractive alternative to asymmetric hydrogenation, because it does not require hazardous hydrogen gas or a pressure vessel, and the hydrogen donors are environmentally friendly, inexpensive and easy to handle.4 In Noyori’s pioneering asymmetric transfer hydrogenation of aryl alkyl ketones by 6-arene/chiral TsDPEN-Ru (Figure 1B), the remarkable enantiocontrol primarily originates from the CH/ interaction between 6-arene and the aromatic substituent in ketone substrates.5 A matched combination of the two stereogenic centers in the chiral diamine moiety (denoted in red stars in Figure 1B) is necessary to obtain high enantioselectivities; mismatching of the two point-chirality centers or only one stereogenic center results in a markedly decrease in the enantioselectivities.6 Although there is a mechanistic network between asymmetric hydrogenation and asymmetric transfer hydrogenation,7 only a few chiral (or achiral but tropos) diphosphine/chiral diamine (with two matching point-chirality centers) derived catalyst systems have been developed in asymmetric transfer hydrogenation of ketones in good enantioselectivities.7a,8 Compared to simple aryl alkyl ketones that have been reduced successfully by asymmetric transfer hydrogenation, diaryl ketones especially aryl N-heteroaryl ketones that structurally confer significant pharmaceutical relevance have been a long-term challenge in
this field, and only a few successful examples by either ATH or AH have been reported.9a,10 B. Noyori's ATH Catalyst
A. Noyori's AH Catalyst Ar2 P 3
*
Cl
H H2 N 1
Ru P Ar2 Cl
N H2
* * 2
Ph
N H2
Cl
* * 2
Ph
N 1
Ph
N 1 Ru
(S)-Tol-BINAP/(S,S)-DPEN-Ru
Ts
Ts
Ph
* * 2
Ru H
R
6-Arene/Chiral TsDPEN-Ru
N
H
R'
Ph
H
Ph
O
Transition State
C. This Work O Aryl
R1
Alkyl
aryl alkyl ketones O
i
PrOH base
N R3
R4
aryl N-heteroaryl ketones
achiral backbone
R2 Ar2 P
*
H H
N
Ru P Ar2 Cl
Chirality Nearest to Reacting Center
O
OH Aryl
H
alkyl
ee > 90% 19 examples
R
*
OH
N
A
Out-sphere Transition State
N R3
ee > 90% 20 examples
R4
Figure 1. Ru-Catalysts of Minimal Stereogenicity and Simplified Structure in Asymmetric Transfer Hydrogenation.
A close inspection of the relevant asymmetric transfer hydrogenation transition state,7c,e as illustrated in Figure 1B, suggests that it is the C-2 chirality (stereogenic center bound to the active NH2 function) of the TsDPEN diamine ligand that positions closest to reacting center as well as the corresponding pericyclic six-membered ring, and thus has the strongest influence on the chirality transfer. We therefore hypothesized that a simple amino-pyridine ligand bearing merely a single chiral center might be sufficient to induce desired high enantioselectivities. The design is summarized in catalyst structure A (Figure 1C), in which the combination of simple, readily available (1-(pyridine-2-yl)methanamines) with an achiral diphosphine is envisioned to replicate the stereoinduction of the canonical Noyori catalysts framework.
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It was anticipated that this concept would considerably reduce the costs of the catalysts and enable modular tuning of the catalyst system through evaluation of different combination of achiral phosphine/amine ligands, leading to a practical asymmetric transfer hydrogenation of broad scope. Herein, we report the design and synthesis of Ru-catalysts with minimal stereogenicity and simplified structure that allow for practical asymmetric transfer hydrogenation of a wide range of ketones (including both aryl alkyl and aryl N-heteroaryl ketones) using iPrOH as the operationally convenient hydrogen source (Figure 1C). Scheme 1. Identification of the Optimal Catalyst Structure Cl
1 mol % Ru Catalysts of Minimal Chirality
O Me
Cl
OH Me
t
BuOK, iPrOH/CH2Cl2 23 oC, 2 h
Ph2 Cl H2 P N
Ph2 Cl H2 P N
Ph2 Cl H2 P N
Ru
Ru
Ru
N P Ph2 Cl
N P Ph2 Cl
P N Ph2 Cl
B2: 64% yield, 45% ee B3: 64% yield, 54% ee as the oppositie enantiomer
B1: 26% yield, 1% ee
Ar2 Cl H2 P N
Ph2 Cl H2 P N
Ph2 Cl H2 P N
Ru
Ru
Ru P Ph2
P N Ph2 Cl
B4: 64% yield, 70% ee
Cl
B5: 65% yield, 71% ee
Ar2 Cl H2 P N
Ar2 Cl H2 P N
Ru
Ru
P N Ar2 Cl
P N Ar2 Cl
B7: 81% yield, 5% ee Ar = 3,5-(CF3)-C6H3
B8: 61% yield, 4% ee Ar = 3,4,5-F3-C6H2
Ph2 Cl H2 P N
Ph2 Cl H2 P N Ru P N Ph2 Cl
B10: 82% yield, 91% ee
B11: 78% yield, 83% ee
X ray of B10
B6: 80% yield, 66% ee Ar = 3,5-(t-Bu)-C6H3 Ph2 Cl H2 P N Ru P N Ph2 Cl
B9: 48% yield, 74% ee
Ph3P
Cl H2 N Ru
Ru P N Ph2 Cl
Ru-NH2 2.0946 A
P N Ar2 Cl
N
Ph3P
Cl
N
B12: 82% yield, 18% ee
Ru-NH2 2.1202 A
X ray of B12
Since the two structurally simplest and readily available achiral diphosphines are 1,2-bis(diphenylphosphanyl)benzenes and bis(diphenylphosphino)alkanes, a brief catalyst screening was conducted with 1 mol % loading of Ru-complexes (B1B12) formed by combining these diphosphines and (1(pyridine-2-yl)methanmine derivatives,10b,11 and with 2’chloroacetophenone as the model substrate under very mild transfer hydrogenation conditions (Scheme 1). The performances of the catalysts B1-B5 reveal that the enantioselectivity is improved when the branched alkyl substituents were incorporated into optically pure (1-(pyridine2-yl)methanmines: ethyl (1% ee), cyclopropyl (45% ee), cyclopentyl (54% ee), cyclohexyl (70% ee) and isopropyl (71% ee). Use of a sterically bulkier aryl substituent in the 1,2bis(diarylphosphanyl)benzene ligand in B6, failed to improve
enantioselectivity as compared to that of B5; however, tuning the electronic properties of the aryl group with electronwithdrawing CF3 and F substituents markedly diminished the chiral induction ability of the resultant catalysts B7 and B8 (merely 5% and 4% ees, respectively). The linker length of bis(diphenylphosphino)alkanes in B9-B11 exerted an influence on the product ees with the propane moiety of B10 giving rise to the highest enantioselectivity (91% ee). Use of triphenylphosphine (2 equiv) gave an active catalyst (B12), but the product was formed in poor ee. Examination of the Xray crystal structures of B10 and B12 revealed that the key Ru–NH2 bond length was shortened from 2.1202 Å in acyclic B12 to 2.0946 Å in cyclic B10, hinting on more effective chirality transfer in the latter that results from closer proximity of the ligand chirality in the pericyclic transition state (Figure 1C). These results collectively established the catalyst B10 to be optimal and its potential was therefore further thoroughly examined. As compiled in Table 1, the catalyst B10, even at 0.1 mol % catalyst loading, was shown to be capable of effecting asymmetric transfer hydrogenation of various aryl alkyl ketones with generally good isolated yields and enantiomeric excesses. Ortho-substitution on the aryl ring by electron donating substituents (Me, OMe, OEt, OBn) or electronwithdrawing substituents (F, Cl, Br, I, CF3, NO2) are all well tolerated leading to 90-96% ees in alcohol products 1-11. Aryl ketones bearing para- or meta-substitution, including the strongly electron-donating dimethylamino (NMe2) in 13, were also reduced to their corresponding alcohols with 90% ees (12-15). Ketones with larger aromatic rings, such as 1- and 2acetonaphthone, were both smoothly hydrogenated to give 16 and 17 in 92% ee and 91% ee, respectively. Phenyl cyclohexyl ketone produced 18 with an impressive 97% ee, which is remarkable as only very few known asymmetric transfer hydrogenation systems provided high enantioselectivity with this nearly iso-steric substrate.12 Transfer hydrogenations of indole/quinolone/pyrimidine methyl ketones were also investigated, and good enantioselectivities were obtained in these cases (19, 91% ee; 20, 88% ee; 21, 82% ee). Compared to simple aryl alkyl ketones, asymmetric transfer hydrogenations of aryl N-heteroaryl ketones have been rarely reported.9a,10b Particularly for non-ortho-substituted aryl Nheteroaryl ketones, introduction of the N-oxide was required to obtain high enantioselectivities.9 A variety of this heteroaryl substrates were examined and excellent enantioselectivities were obtained (Table 2). The simplest phenyl pyridinyl ketone was reduced to alcohol 22 in 92% yield and 91% ee. These results represent a significant improvement relative to the 82% yield and merely 7% ee documented on the same substrate with the well-known 6-arene/TsDPEN-Ir transfer hydrogenation catalyst system.9b Substrates bearing various pyridine ring substitution were well tolerated, with formation of alcohols 23-27 in good yields and enantioselectivities. Substrates bearing phenyl ring substitution, including at the ortho (28-32), para (33-38), and meta (39-40) positions, were all reduced in 90-97% ees. The structure of 31 was verified by X-ray crystallography, confirming unambiguously its absolute stereochemistry assignment. In the cases of 23, 34, 38, 39, dramatic improvements in enantioselections (90-94% ees) were once again accomplished as compared to literature results (4-15% ees).9b Finally, substrate with extended conjugation, i.e. naphthalene pyridinyl ketone was hydrogenation to the alcohol 41 in 91% ee.
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ACS Catalysis Table 1. Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones by Catalyst B10 a
O Aryl
Me
PrOH:CH2Cl2 = 2:1 23 oC, 2 h
I
OH
Me
Me
F
Br
OH
OH
Et
15 16 96% yield, 90% eeb 96% yield, 92% ee
13 66% yield, 90% eeb
OH N
14 96% yield, 90% eea OH
OH
Me
18 95% yield, 97% ee
Me
Me2N
OH
17 95% yield, 91% eeb
OH MeO
Me
12 80% yield, 90% ee
Me
Me
Me
7 96% yield, 93% ee
OH
Cl
OH
Me
6 91% yield, 90% ee
OH
11 72% yield, 94% eeb
10 89% yield, 92% ee
9 79% yield, 95% eeb
8 94% yield, 93% ee
OH
Me
5 99% yield, 93% ee
Me
Me
Cl
OH
Me
NO2 OH
CF3 OH
Alkyl
OBn OH
4 95% yield, 94% ee
3 84% yield, 96% ee
OH
OH Aryl
Me
Et
2 94% yield, 96% ee
1 83% yield, 92% ee
Me
OEt OH
OMe OH
Me
Me
Br
i
Alkyl
OMe OH
OH
Me H2 Ph2 N P Cl Ru N P Cl Ph2
B10
Catalyst B10 (0.1 mol%) t BuOK (15 mol%)
Bn
N
N
21 99% yield, 82% ee
20 76% yield, 88% eec
19 84% yield, 91% ee
Me
N
Me
a
General condition: ketone (0.2 mmol), catalyst B10 (0.1 mol%), tBuOK (15 mol%), iPrOH/CH2Cl2 (2:1), 23 °C, 2 h. Yields of isolated products are given. b 1 mol% catalyst B10 was used in order to get good conversion in 2 h. c 0.01 m% catalyst B10 was used.
Table 2. Asymmetric Transfer Hydrogenation of Aryl N-heteroaryl Ketones by Catalyst B10 a O
Catalyst B10 (0.1 mol%) t BuOK (15 mol%)
N R1
i
R2
OH
OH
PrOH:CH2Cl2 = 2:1 23 oC, 2 h
OH
Me H Ph2 N2 P Cl Ru N P Cl Ph2
B10
OH
Me
N R1
R2
OH
OH
F
OH OMe
N 22 92% yield, 91% ee (82% yield, 7% ee)c Cl
N N Me Br 23 24 b 94% ee 99% yield, 99% yield, 91% eeb (84% yield, 10% ee)c OH
Br
OH
I
29 84% yield, 96% ee OH
N
F
99% yield, 93% eea
X ray of 31
83% yield, 96% ee
OH
OH
N 35
N
I 36
92% yield, 93% ee 72% yield, 91% ee
N
MeO
60% yield, 97% ee
97% yield, 91% ee
37 95% yield, 90% ee
OH
OH
34 98% yield, 92% ee (93% yield, 14% ee)c OH
MeO
39 94% yield, 92% ee (82% yield, 4% ee)c
a
N
N
N
N
38 70% yield, 90% ee (71% yield, 15% ee)c
N
Cl
33
OH
F3C
N
F
32
MeO Br
OH
OH
N
31
30 94% yield, 97% ee
28 27 93% yield, 90% eeb 98% yield, 93% ee
OMe OH
N
N
N
26 96% yield, 93% eea
OH
N
N
N 25
OH
Cl
OMe
40 97% yield, 93% eeb
41 75% yield, 91% ee
General condition: ketone (0.2 mmol), catalyst B10 (0.1 mol%), tBuOK (15 mol%), iPrOH/CH2Cl2 (2:1), 23 °C, 2 h. Yields of isolated products are given. b 1 mol% catalyst B10 was used in order to get good conversion in 2 h. c Reported asymmetric transfer hydrogenation for the opposite enantiomers by 6-arene/TsDPEN Ir catalysts.9
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Thanks to the ligand/substrate structural similarity, the synthetic utility of this new catalysis protocol was further explored to establish a three-step preparation of a chiral (1(pyridine-2-yl)methanmine ligand in its enantio-pure form (> 99% ee). As shown in Scheme 2, asymmetric transfer hydrogenation of cyclohexyl 2-pyridyl ketone under the above defined standard conditions provided (S)-configured alcohol 42 in 76% yield and 84% ee. A single recrystallization furnished this intermediate in enantiomerically pure form (> 99% ee). The subsequent stereochemical inversion was achieved under Mitsunobu conditions (PPh3, DIAD, diphenylphosphoroazidate (DPPA), and DBU) leading to the azide 43 in 87% yield.13 Catalytic reduction of 43 produced the desired cyclohexyl (1-(pyridine-2-yl)methanmine in 90% yield and > 99% ee. The method is more efficient and economic than the conventional chiral auxiliary-based strategy.14 Scheme 2. A Concise Synthesis of Chiral Amine Ligand N O
Standard Conditions
PPh3/DIAD DPPA
N HO
N
THF, 0-23 oC N3 24 h
42 76% yield, 84% ee (61% yield, > 99% ee)
43 87% yield
Pd/C, H2 N EtOH, 23 oC 2h H 2N
ACKNOWLEDGMENT We wish to thank Shenzhen Nobel Prize Scientists Laboratory Project (grant C17783101) and SUSTech Research Start-up Funds for Chen Xu (21/Y01216128) for financial support. Professor Sarah E. Reisman and Dr. Arthur Han are acknowledged for revising the manuscript. We also thank Dr. Yupeng Pan for assistance in solving the X-ray structures of B10, B12, and 31.
REFERENCES 1.
2.
3.
90% yield, > 99% ee
In summary, we have described the design and discovery of new Ru-catalysts in which a single element of chirality induces high enantioselectivity in the asymmetric transfer hydrogenation for a broad range of carbonyl substrates (39 examples, > 90% ee), including substrates that are not possible with literature-known protocols. This work would suggest a strategy for catalyst design and help stimulate structural tailoring of some catalysts towards high levels of simplicity, efficiency and practicality. Ongoing research that includes modification of the catalysts and exploration of their extended application in asymmetric catalysis is in progress. 4.
ASSOCIATED CONTENT
5.
Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data (1H and 13C NMR, HRMS) for all new compounds (PDF) Crystallographic information for B10 (CIF) Crystallographic information for B12 (CIF) Crystallographic information for 31 (CIF)
6.
AUTHOR INFORMATION Corresponding Author *
[email protected] *
[email protected] 7.
Present Addresses †Danzao sub-bureau administration of social insurance fund of Fushan Nanhai District, Foshan, China, 528216 ‡Shenzhen UV-ChemTech. Shenzhen, China, 518057
Author Contributions §These
authors contributed equally.
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(a) Noyori, R.; Ohkuma, T. Asymmetric catalysis by architectural and functional molecular engineering: practical chemo- and stereoselective hydrogenation of ketones. Angew. Chem. Int. Ed. 2001, 40, 40–73; (b) Noyori, R. Asymmetric catalysis: science and opportunities (Nobel Lecture). Angew. Chem. Int. Ed. 2002, 41, 2008–2022. (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Practical enantioselective hydrogenation of aromatic ketones. J. Am. Chem. Soc. 1995, 117, 2675–2676; (b) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R. Asymmetric activation of racemic ruthenium(II) complexes for enantioselective hydrogenation. J. Am. Chem. Soc. 1998, 120, 1086–1087. Later on, a few achiral diphosphine/chiral diamine (with two point-chirality centers) have been reported in the field of asymmetric hydrogenation: (a) Aikawa, K.; Mikami, K. Atropos but achiral tris(phosphanyl)biphenyl ligands for Ru-catalyzed asymmetric hydrogenation. Angew. Chem. Int. Ed. 2003, 42, 5455–5458; (b) Mikami, K.; Wakabayashi, K.; Aikawa, K. “Achiral” benzophenone ligand for highly enantioseledctive Ru catalysts in ketone hydrogenation. Org. Lett. 2006, 8, 1517–1519; (c) Jing, Q.; Zhang, X.; Sun, J.; Ding, K. Bulky achiral triarylphosphines mimic BINAP in Ru(II)-catalyzed asymmetric hydrogenation of ketones. Adv. Synth. Catal. 2005, 347, 1193– 1197; (d) Jing, Q.; Sandaval, C. A.; Wang, Z.; Ding, K. Complete chiral induction from enantiopure 1,2-dimaines to benzophenonoe-based achiral bisphosphane ligands in Noyoritype RuII Catalysts. Eur. J. Org. Chem. 2006, 3606–3616; (e) Chen, X.; Zhou, H.; Zhang, K.; Li, J.; Huang, H. Highly enantioselective hydrogenation of steric hindrance enones catalyzed by Ru complexes with chiral diamine and achiral phosphane. Org. Lett. 2014, 16, 3912−3915. Wang, D.; Astruc, D. The golden age of transfer hydrogenation. Chem. Rev. 2015, 115, 6621–6686 and references cited in. (a) Hashiguchi, S. Fujii, A.; Takehara, J.; Ikariya, T.; Noyori ,R. Asymmetric transfer hydrogenation of aromatic ketones catalyzed by chiral ruthenium(II) complexes. J. Am. Chem. Soc. 1995, 117, 7562–7563. (b) Noyori, R.; Hashiguchi, S. Asymmetric transfer hydrogenation catalyzed by chiral ruthenium complexes. Acc. Chem. Res. 1997, 30, 97–102; (c) Yamakawa, M.; Yamade, I.; Noyori, R. CH/ attraction: the origin of enantioselectivity in transfer hydrogenation of aromatic carbonyl compuonds catalyzed by chiral 6-arene-ruthenium(II) complexs. Angew. Chem. Int. Ed. 2001, 40, 2818–2821. (a) Gladiali, S.; Alberico, E. Asymmetric transfer hydrogenation: chiral ligands and applications. Chem. Soc. Rev. 2006, 35, 226– 236. (b) Hayes, A.; Clarkson, G.; Wills, M. The importance of 1,2-anti-disubstitution in monotosylated diamine ligands for ruthenium(II)-catalysed asymmetric transfer hydrogenation. Tetrahedron: Asymmetry 2004, 15, 2079-2084. (a) Sandoval, C. A.; Li, Y.; Ding, K.; Noyori, R. The hydrogenation/transfer hydrogenation network in asymmetric reduction of ketones catalyzed by [RuCl2(binap)(pica)] Complexes. Chem. Asian J. 2008, 3, 1801–1810. (b) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C.; Noyori, R. The hydrogenation/transfer hydrogenation network: asymmetric hydrogenation of ketones with chiral 6-arene/Ntosylethylenediamine–ruthenium(II) J. Am. Chem. Soc. 2006, 128, 8724–8725. (c) Noyori, R.; Yamakawa, M.; Hashiguchi, S. Metal–ligand bifunctional catalysis: a nonclassical mechanism
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Insert Table of Contents artwork here Ru-Catalysts of Minimal Stereogenicity
O R1
Asymmetric Transfer Hydrogenation R2 iPrOH, tBuOK
Me H Ph2 N2 P Cl Ru N P Cl Ph2
Me
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OH R1
R2
39 examples > 90% ees
