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Enantioselective Addition of Cyclic Ketones to Unactivated Alkenes Enabled by Amine/Pd(II) Cooperative Catalysis Hong-Cheng Shen, Ling Zhang, Shu-Sen Chen, Jia-Jie Feng, Bo-Wen Zhang, Ying Zhang, Xinhao Zhang, Yun-Dong Wu, and Liu-Zhu Gong ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04654 • Publication Date (Web): 21 Dec 2018 Downloaded from http://pubs.acs.org on December 22, 2018
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ACS Catalysis
Enantioselective Addition of Cyclic Ketones to Unactivated Alkenes Enabled by Amine/Pd(II) Cooperative Catalysis Hong-Cheng Shen§†, Ling Zhang§†, Shu-Sen Chen†, Jiajie Feng‡, Bo-Wen Zhang†, Ying Zhang†, Xinhao Zhang*‡ Yun-Dong Wu‡, and Liu-Zhu Gong*† †Hefei
National Laboratory for Physical Sciences at the Microscale, and Department of Chemistry, and Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, 230026, China ‡ Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
ABSTRACT: Amine/Pd(II) cooperative catalysis has enabled a highly enantioselective addition of cyclic ketones to unactivated alkenes. The hallmark of the strategy includes amide-directed, regioselective activation of alkenes by Pd(II) and enhancing the nucleophilicity of α-carbon of the ketones by enamine catalysis to synergistically drive the reaction, which is basically unable to be accessed by a single catalyst. The combination of a commercially available Pd(II) catalyst and diphenylprolinol was able to provide the γ-addition products with good to high yields and efficient stereochemical control (up to 95% ee). KEYWORDS: Cooperative catalysis • enamine catalysis • Pd(II) catalysis • ketone • unactivated olefin • asymmetric hydroalkylation
Selective functionalization of the carbon-carbon double bond of olefins provides tremendous number of fundamental transformations that hold widespread applications in organic synthesis and exert great impact on the development of organic chemistry.1 Michael addition, one of the most valuable reactions for the functionalization of electronically deficient carbon-carbon double bonds, has been comprehensively investigated, leading to many protocols extensively utilized in total synthesis and materials preparation.2 Wacker oxidation is a fundamentally significant transformation to functionalize unactivated olefins and has also received longstanding attention in last several decades, culminating in a diverse range of processes widely amenable in organic synthesis.3 In particular, great advances have been made on asymmetric hydroxylation and hydroamination reactions.4 However, the Wacker-type reaction involving carbon nucleophiles remains problematic and challenging. Hegedus first established a Pd(II)-mediated alkylation of unactivated olefins with stabilized carbanion nucleophiles, which commences with a nucleopalladation reaction.5 Subsequently, an intramolecular addition of silyl enol ether to unactivated olefins enabled by Pd(II) catalysis was reported.6 Widenhoefer reported a Pd(II)-catalyzed intramolecular nucleophilic addition of 1,3-diones to unactivated olefins, leading to cyclohexanones.7 To address the regioselection issue in intermolecular hydrofunctionalization of unactivated olefins, Engle introduced a removable bidentate 8aminoquinoline directing group8 to the substrates, which has indeed enabled a variety of highly regioselective variants (Scheme 1a).9 Very recently, an enantioselective hydroalkylation of carbon nucleophiles with unactivated olefins was reported by Chen and coworkers (Scheme 1b).10 Despite these significantly important progresses, the repertoire of nucleopalladation to create new transformations for the conversion of olefins into highly functionalized and
structurally complex molecules has far less been released. For instance, Scheme 1. Pd(II)-Catalyzed Amide-directed, Regioselective Nucleophilic Addition to Unactivated Alkenes. (a) Eagle: Directed and regiocontrolled hydrofunctionalization of unactivated alkenes O N
R
N H
H
O
Cat. Pd(OAc)2
+ Nu H
H source MeCN, 120 oC
R
N H
+
N
Nu
Highly acidic nucleophiles (Nu-H), e.g. amides, 1,3-dicarbonyl compounds, and electronically rich aromatics, are tolerated Me
(b) Chen, He, Liu: Asymmetric version with chiral MOX ligand O O Pd(OAc)2/L* H R + Nu H H N + N H source AQ AQ MeOH, 80 oC AQNH2 = 8-aminoquinoline
N
O
R Nu
up to 94% ee
N Ar L*, Ar = 3,5-(CF3)2C6H3
(c) This work: Enantioselective hydroalkylation of ketones to unactivated alkenes enabled by Pd(II)/Amine cooperative catalysis O
O H
PdX2/ HN(R*)2
R +
N AQ
H+ source
R
R' R'
O R'
N Pd X R I (1) -alkylation of ketone with activated olefins
O
* *
O
HN(R*)2 O
AQ N
PdX2 HN(R*)2
R' PdX2
N
H
NR*2 N
N Pd X
R
NR*2
(2) Stereoselective creation of two stereogenic centers
carefully analyzing the Pd(II)-catalyzed nucleophilic addition to unactivated olefins may find that the nucleophiles are strictly limited to relatively more acidic species, including amides, 1,3dicarbonyl compounds, and electronically rich aromatics.4-7,9-10 Among the most important chemical reagents are ketones, which, however, have usually been precluded as nucleophiles
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in hydroalkylation of olefins with exception of a very limited number of showcases sporadically appearing in literatures.5b,11 Herein, we will report a highly enantioselective addition of cyclic ketones to unactivated alkenes orchestrated by organo/palladium(II) cooperative catalysis (Scheme 1c).12 The significantly lower reactivity of ketones than 1,3dicarbonyls in Pd(II)-catalyzed hydroalkylation of olefins is considered resulting from a much lower equilibrium enol content.11a Enamine catalysis has been a general concept eligible for the activation of the α-carbon of enolizable ketones and aldehydes, enabling a diverse spectrum of reactions.13 The robustness of these concepts explicit in the elegant precedents allows us to preconceive that an enamine catalytically generated from the condensation of an enolizable ketone with a chiral amine organocatalyst might be reactive enough to attack the alkene/Pd complex I and would be able to undergo an enantioand regioselective Wacker-type nucleopalladation, giving rise to the desired product (Scheme 1c).12,14 Table 1. Optimization of Catalysts and Reaction Conditionsa O O N H
AQ
+
1a
Ph 2a
EtOH, 80 C, 48 h
1
N H
Ph A1
R R1 OR2
A2
entry
A
Acid
1 2 3 4 5 6 7 8d 9d 10d 11d 12 13d, e 14d, f 15d, f, g 16 d, f, g
A1 A2 A3 A4 A5 A6 -A4 A4 A4 A4 A4 A4 A4 A4 A7
PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H AcOH TFA TsOH -PhCO2H PhCO2H PhCO2H PhCO2H
O
H N
Yield (%) b 34 59 92 82 69 trace -70 33 21 -trace 53 59 78(79h) 99(96h)
AQ
O
o
NHBoc
H 2N
NH2
Amine (40 mol%) [Pd] (10 mol%) Acid (1.0 equiv)
Ph
3a
A3: R1= H, R2= SiPh3 A4: R1= Ph, R2= SiPh3 A5: R1= Ph, R2= TMS A6: R1= Ph, R2= TBS A7: R1= Ph, R2= H
dr c
ee (%) c
1/7.3 1/5.1 1/2 3.5/1 2.3/1 --4.3/1 4.3/1 1/1.3 --8.5/1 5.3/1 3.3/1 2.8/1
7/6 10/11 78/72 85/60 85/58 --92/67 91/55 50/14 --93/54 94/51 93/61 92/69
Unless noted otherwise, the reaction of 1a (0.1 mmol) and 2a (0.3 mmol) was carried out with Pd(OAc)2 (0.01 mmol), a chiral amine (0.04 mmol) and acid (0.1 mmol) in EtOH (1.0 mL) at 80 oC for 48 h. b Determined by 1H-NMR analysis of the crude product. c The ee and dr (anti/syn) of 3a were determined by HPLC analysis. d0.5 equavalent of acid was used. e Pd(acac)2 was used. f Pd(CH3CN)2Cl2 was used. g The reaction underwent for 72h. h Isolated yield. a
To validate the hypothesis, we initially investigated an enantioselective desymmetrizing addition of 4phenylcyclohexanone 2a to 3-butenamide 1a in the presence of catalytic amounts of a chiral amine and palladium catalyst (Table 1), considering that such a process allows two stereogenic centers to be established in a single step.15 To our delight, the cooperative catalysis indeed worked and enabled
the proposed reaction to give the desired product 3a in most of cases (entries 1-5). Obviously, the amine catalyst turned out to be the linchpin to promote the reaction and exerted considerable effect on conversion and stereoselectivity (entries 1-6). As illustrated, the product 3a could be isolated in 92% yield, with 1/2 diastereomeric ratio and good levels of enantioselectivities for both diastereomers by using prolinol silyl ether A3 as an organocatalyst (entry 3), while chiral primary amines A1 and A2 (entries 1and 2) exhibited very poor stereochemical control. The examination of other prolinol silyl ethers identified that diphenylprolinol silyl ether A4 allowed the reaction to give the highest enantio- and diastereoseletivities, together with 82% yield (entries 4-6). However, the reaction did not work at all in the absence of amine catalyst (entry 7), strongly supporting that the enamine catalytically generated from the amine and ketone is reactive enough to undergo the nucleophilic addition. Interestingly, even higher enantio- and diastereoseletivities were observed when the amount of benzoic acid was attenuated from 1.0 to 0.5 equivalent, but with a subtle erosion of the yield (entry 8). Since the acid additive promotes the enamine formation13 and participates in protodepalladation to regenerate Pd(II) catalyst,9a it should be another key factor of the reaction. Thus, we turned our attention to screening of Brønsted acids and found that the reaction was highly sensitive towards the acidity. Benzoic acid appeared to be the most matched acid additive and assisted the catalyst to render the reaction delivering the best results in terms of yield and stereoselectivity (entries 9-12). The survey of Pd(II) source revealed that both Pd(CH3CN)2Cl2 and Pd(acac)2 offered slightly enhanced stereoselectivity (entries 13-14). However, a hydroalkylation byproduct between acetylacetone and alkene was observed to inherently erode the yield of desired product 3a when Pd(acac)2 was used and Pd(CH3CN)2Cl2 turned out to be the superior Pd(II) catalyst thereof. A great enhanced yield, 3.3/1 diastereomeric ratio, and 93% ee for the major diastereomer 3a were obtained by prolonging the reaction time to 72 h (entry 15). Interestingly, we found that the diastereomeric ratio of 3a to syn-diastereomer syn-3a' gradually dropped when the reaction was undergoing longer (entries 14-15 and Figure S1 in SI). Such a dynamic alternation in the diastereomeric ratio is presumably arose from the chemical equilibrium to a more thermodynamically favored diastereomer via keto-enol tautomerization under the reaction conditions. Indeed, the density functional theory (DFT) calculation indicates that syn3a' is more stable than 3a by 2.7 kcal/mol because one substituent has to occupy the axial position in 1,3-antidiastereomer 3a.16 Finally, the use of commercially available diphenylprolinol (A7) as the cocatalyst resulted in significantly improved yield (96% isolated yield), with 2.8:1 diastereomeric ratio and 92% ee for the major isomer (entry 16). With the optimal reaction conditions in hand, we then explored the substrate scope of this desymmetrizing addition reaction (Table 2). A diverse range of 4-substituted cyclohexanones 2 were able to undergo the reaction, smoothly. The cyclohexanones bearing a 4-aryl substituent gave excellent yields with excellent enantioselectivities for the major isomers (92% ee) and up to 3.5/1 dr (entries 1-4). Notably, either electronic feature or steric effect of the para-substituent of the aryl group almost has no effect on stereochemical outcomes. Cyclohexanones with a n-alkyl substituent underwent the stereoselective hydroalkylation reaction to afford
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ACS Catalysis corresponding products in high yields and with excellent levels of enantioselectivity for the major diastereomers (entries 5-8). The extension of reaction conditions to cyclohexanones bearing a branched alkyl substituent, such as iPr, tBu, tPent, led to desired products with high enantioselectivities for the major diastereomer, however, the increasement in the steric hindrance deminished the diastereomeric ratio (from 4.9/1 to 1.8/1) (entries 9-11). The desymmetrization of NHBoc substituted cyclohexanone also proceeded smoothly to give fairly good results (entry 12). 4-Trifluoromethyl cyclohexanone gave an acceptable yield with high enantioselectivities for both diastereomers (90% and 91% ee, entry 13). Methyl 4oxocyclohexane-1-carboxylate was also tolerated, giving 88% yield and 90% ee for the major diastereomer, but a very low enantioselectivity for the minor diastereomer (entry 14). Alkene substrates with either an electron-donating or an electronwithdrawing substituent on the directing group were also accomodated (entries 15-18). The desired product was observed in 48% yield, with 85% ee of major diastereomer when 2',3'dihydrospiro[cyclohexane-1,1'-inden]-4-one was used as a substrate (entry 19). The absolute configurations of 3c, 3e and syn-3n' were assigned by X-ray analysis of the single crystal of its derivatives (see Supporting Information). Table 2. Substrate scope of cyclohexanones and 3butenamidea 6 5
R 4
N
3
O
O
7
1
+
N H
A7 (40 mol%) Pd(CH3CN)2Cl2 (10 mol%) PhCO2H (0.5 equiv) EtOH, 80 C, 72 h
1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d 1d
19
1a
O R2
1 1a: R1= H; 1b: R1= 4-Cl; 1c: R1= 6-Br; 1d: R1= 6-OMe
entry
H N
o
R2 2
2
O
iPr tBu tPent
NHBoc CF3 CO2Me Me Me Me 4-BrC6H4 O
R1 4 3
3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s
3.1/1 3.5/1 2.6/1 2.0/1 4.9/1 3.4/1 4.7/1 4.1/1 3.6/1 2.3/1 1.8/1 2.1/1 1.3/1 3.6/1 2.7/1 2.3/1 4.6/1 2.3/1
3t
48
1.4/1
85/37
4-MeC6H4
Me Et Pr Pent
5
N 2
ee (%)c 92/58 92/63 92/69 92/66 91/47 91/59 90/46 90/49 91/60 90/67 89/66 85/53 90/91 90/20/1 dr
Toluene, 1M, 100 oC, 72h
A8
OH
AQ (1)
O
*
A8 (40 mol%) Pd(OAc)2 (10 mol%) PhCO2H (1.0 equiv)
N H
H N
O
O AQ
N H
O
(2)
6 R 6a (R= Me): 41% yield, 70%/ 74% ee, 1.3:1 d.r. 6b (R= Ph): 30% yield, 64%/ 66% ee, 2.2:1 d.r.
DFT calculations were performed to investigate the origin of the stereoselectivity which is determined at the nucleophilic addition step. The alkene/Pd complex I may couple with enamine from the Si face or the Re face leading to four diastereomers. A systematic conformational search (Table S1 and Figure S3 in SI) was carried out first to explore possible conformations of transition states. Due to the repulsion of the bulky diphenylmethanol substituent R' of pyrrolidine, the coupling can only occur at the back side of the R', except in two cases (See Figure S3 for details). Rotation along the forming CC bond results in three conformations for each diastereomer. The relative free energies and geometries of 14 conformations are listed in Figure S3 and the most stable conformation of each diastereomer is listed in Figure 1. According to Eyring equation and Boltzmann distribution, the theoretical ratio was calculated to be 78.2%, 20.8%, 0.8%, and 0.2% for 3a, syn-3a, syn-3a' and anti-3a', respectively. The corresponding dr and ee for the major isomer are 3.5:1 and 99%. Given the fact that 3a isomerizes to syn-3a', the calculated ratio is in good agreement with the experimental observation. As shown in Figure 1, the nucleophilic addition at the Si face of enamine (TStransR and TScisS) are much favorable than those occur at the Re face (TScisR and TStransS). The preference is attributed to the repulsion between the α-methyene of cyclohexene and diphenylmethanol substituent of the amine catalyst A7 in transition structures TScisR and TStransS. Such repulsion distorted the strucutres which are reflected from the shortest HH distances in the transition states. The small free energy difference between TStransR and TScisS (0.8 kcal/mol), which mainly determines the diastereomeric ratio, is due to the conformation of the cyclohexene skeleton. The cyclohexene skeleton has to filp to the conformation that allows the 4-phenyl substituent to adopt the equatorial position, implying that adjusting the skeleton of the substrate may amplify the discrimination effect and increase the dr selectivity. To demonstrate the practicability of the current reaction, two scale-up protocols of the 3-butenamide 1a (5.0 mmol) with cyclohexanones 2c and 2f, respectively, were performed under standard conditions (Scheme 2). Both processes underwent smoothly to deliver 3c and 3f in good yield and diastereoselectivity, together with excellent levels of
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Si
Si N
R'
O
R'
O
N
N
N Ph Cl
N
Ph
N
O
Cl
N Pd
N
Ph
Cl
N
1.96
2.14
2.31
2.32
2.31
2.31
R'
N Pd
N
2.15
Re O
Pd
Pd Ph Cl
Re
R'
N
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2.05
TStransR 0.0 (0.0)
TScisS 0.8 (0.8)
O
H N
TScisR 2.7 (4.4)
O
H N
AQ
O
O
H N
AQ
O
Ph calc. ratio
TStransS 3.6 (4.8)
O
H N
AQ
O
Ph
Ph
AQ
O Ph
3a
syn-3a
syn-3a'
anti-3a'
78.2%
20.8%
0.8%
0.2%
Figure 1. Representative of transition structures with relative energies (relative to TStransR) in ΔΔG (ΔΔH). Relative free energies and enthalpies (in parenthesis) are given in kcal/mol and distance is presented in Å. The calculated ratio of product was calculated based on the conformational search (see Figure S2 in SI for details).
enantioselectivity for major diastereomers. The treatment of 3c with L-Selectride produced a cyclohexanol 7a as the major product with excellent enantio- and diastereoseletivities.18 The removal of the directing group by Ni-catalyzed alcoholysis19 provided a carboxylic ester 8 in a 94% yield and with maintained optical purity. Scheme 2. Gram-Scale Reaction and Synthetic Applications. O a
AQ
N H
1a 5.0 mmol
O
OH b
O NHAQ
Ar
3c Ar = 4-OMeC6H4 1.4768 g 71% yield; 95%/42% ee; 8.1/1 dr
O
O a
AQ
N H
Me 3f 1.0206 g 63% yield; 93%/23% ee; 7.1/1 dr OH
In summary, we have developed a Pd(II)/amine cooperatively catalyzed highly enantioselective addition of cyclic ketones to unactivated alkenes. The Pd(II) enables the unactivated alkenes reactive enough toward the chiral enamine catalytically generated from enlizable ketones and the organocatalyst, wherein the chiral amine solely controls the stereochemistry and offers high levels of stereochemical outcomes. Such a cooperative catalysis actually provides a general strategy amenable to creation of nucleophilic addition of enolizable ketones and aldehydes to unactivated olefins. The future study will be focused on exploring the repertoire of this strategy in the creation of other related reactions.
c
O
O NHAQ
Ar
7a Major product 69% yield, 95% ee, >20/1 dr
OMe
8
Ar
94% yield 95% ee, >20/1 dr
Reagents and conditions: (a) Standard conditions. (b) L- Selectride, THF, -78 oC. (c) Ni(tmhd)2 (10 mol%), MeOH, 120 oC.
ASSOCIATED CONTENT Supporting Information. Complete experimental procedures and characterization data for the prepared compounds. This material is available free of charge via the internet at http://pubs.acs.org
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ACS Catalysis
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected] [email protected] Author Contributions ‡ H.C. Shen and L. Zhang contributed equally to this manuscript.
ACKNOWLEDGMENT We are grateful for financial support from Chinese Academy of Science (Grant No. XDB20020000) NSFC (21831007) and STIC(JCYJ20170412150343516). The DFT calculations in this paper have been performed on the supercomputing system in the Supercomputing Center of University of Science and Technology of China
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ACS Catalysis
Table of Content O H
N AQ
Directed Regiocontrolled O
O
PdX2
N H
N
R'
N Pd X
Cooperative catalysis
O O
R' N
R
NHAQ
up to 95%ee in 5.0 mmol scale
Enamine catalysis R R
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