Letter pubs.acs.org/OrgLett
Catalytic Asymmetric Electrochemical Oxidative Coupling of Tertiary Amines with Simple Ketones Niankai Fu,†,‡,§,∥ Longji Li,†,‡,∥ Qi Yang,†,‡ and Sanzhong Luo*,†,‡,§ †
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ Department of Chemistry, University of Chinese Academy of Sciences, 10049 Beijing, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China S Supporting Information *
ABSTRACT: Catalytic asymmetric electrochemical C−H functionalization of simple ketones has been developed. The transformation is realized by the combination of electrochemical oxidation and chiral primary amine catalysis. This metal- and oxidant-free method furnishes diverse C1-alkylated tetrahydroisoquinolines in high yields and with excellent enantioselectivities under very mild conditions.
W
Scheme 1. Asymmetric CDC of Tertiary Amines with Simple Ketones
ith electrons as redox reagents, electrochemical synthesis complies well with the criteria of green chemistry and has recently regained prominent recognition in developing sustainable oxidative C−H functionalization reactions.1 Beyond simple replacement of chemical reductants/oxidants, an electrochemical approach also endows enormous opportunity to achieve unprecedented reactivity and selectivity in many C− H functionalization reactions.2 In this regard, achieving enantioselective control in electrochemical C−H bond functionalizations, though much explored, remains elusive.3 On the other hand, organocatalysis has recently become an enabling solution to facilitate enantioselective C−H functionalization reactions. In particular, aminocatalysis has been successfully employed to enable highly stereoselective C−H functionalizations by synergistic coupling with established C−H activation/functionalization cycles.4 In 2010, Jørgensen and coworkers showed that it was feasible to couple enantioselective aminocatalysis with anodic oxidation of electron-rich phenols with aldehydes.3d Herein, we present an enantioselective electrochemical coupling of simple ketones with tertiary amines by the combination of anodic C−H oxidation and chiral primary amine catalysis (Scheme 1).5 Cross-dehydrogenative coupling (CDC) of two easily accessible C−H components under oxidative conditions has emerged as a powerful, straightforward, and economical synthetic method for C−C bond formation.6 Catalytic enantioselective CDC of simple ketones has been extensively explored but with limited success due to fast product racemization processes.7 In addition, most of the CDC reactions unavoidably have to use stoichiometric oxidants such as DDQ, TBHP, and IBX, producing undesired waste. Previously, Li showed that electrochemical oxidation was a feasible strategy in CDC reactions.8 In developing an enantioselective version, we recently reported a visible-lightpromoted hydrogen-transfer protocol for the enantioselective © 2017 American Chemical Society
CDC reaction with ketones.9 However, this process still requires stoichiometric amounts of nitrobenzenes as terminal oxidants. To eliminate the use of any chemical oxidants, we intended to combine our chiral primary amine catalysts with electrochemical C−H oxidation (Scheme 1). In this context, the major difficulties come from the compatibility and oxidative stability of chiral primary amines under electrochemical conditions as well as the feasibility of anodic C−H oxidation under the enantioselective setting. From the outset of this work, we selected the coupling of Nphenyltetrahydroisoquinoline (1a) with cyclohexanone (2a) as a benchmark for catalyst screening and evaluation, focusing our efforts exclusively in a simple electrochemical setup consisting of an undivided cell. We quickly identified primary amine catalyst 3a derived from chiral trans-N,N-diaminocyclohexanes Received: March 13, 2017 Published: April 10, 2017 2122
DOI: 10.1021/acs.orglett.7b00746 Org. Lett. 2017, 19, 2122−2125
Letter
Organic Letters
temperature, but with little further improvement observed (see the Supporting Information). Meanwhile, no reaction was observed in the absence of either primary amine catalyst or electron, indicating the essential role of them for the reaction (Table 1, entry 15). With the optimized conditions in hand, the scope of substrates for this metal- and oxidant-free catalytic oxidative coupling reaction was then studied. As shown in Scheme 2, an array of N-aryltetrahydroisoquinolines was tested in reaction with cyclohexanone (2a), and generally good yields and good to excellent diastereo- and enantioselectivities could be obtained under the mild reaction conditions (Scheme 2, 4a− m). It was observed that both electron-withdrawing and electron-donating groups were tolerated on the para position of the phenyl ring of 1, and the desired oxidative coupling products were obtained in satisfactory yields of 70−82%, with good to excellent diastereoselectivities of 3:1−10:1 and excellent enantioselectivities of 93−95% (Scheme 2, 4b−g). In addition, the position of the substituents at the phenyl ring of 1 has no obvious influence on the reaction and afforded the corresponding products in good yields and with high stereoselectivities (Scheme 2, 4i−m). In the case of ortho substituents on the phenyl ring of 1, hexafluoroisopropanol (HFIP) was found to be a better additive (Scheme 2, 4l and 4m). Cyclopentanone, not being realized in CDC reaction with Naryltetrahydroisoquinolines before, was also examined in the catalytic system.6j In this case, chiral primary amine 3f was found to be an optimal catalyst, giving the product with good yield and stereoselectivity (4n). The use of the initial catalyst 3a gave good reactivity but with essentially no enantioselectivity. We found that this catalytic system also worked equally well with cycloheptanone to give the expected adducts 4o−q with good yields and high enantioselectivities. Acyclic ketones have also been examined, and benzylideneacetone was found to undergo oxidative coupling regioselectively at the methyl moiety to give product 4r with 72% yield and 59% ee (Scheme 2). To gain additional insight into the reaction mechanism, a series of controlled experiments were performed. As shown in Scheme 3, 1a was first oxidized at constant current (5 mA, graphite area = 1 cm2) with the hope of forming the key iminium ion intermediate. After the charge of 2.5 F, 2a and 3a/ TfOH were added to carry out the CDC reaction, and 4a could be isolated in 79% yield with 92% ee [Scheme 3, eq (a)]. Controlled-potential electrolysis (CPE) of the mixture of 1a, 2a, and 3a was conducted at the peak potential of 1a (0.9 V vs Ag wire), producing 4a in 92% yield with 92% ee [Scheme 3, eq (b)]. Electrochemical analysis indicated that 1a is the most easily oxidized species (Figures S3−S6), and it undergoes preferentially an electrochemical oxidation under the conditions to form the iminium ion intermediate (Scheme 1, I), followed by reaction with enamine intermediate (Scheme 1, II) to generate the final product 4a (Scheme 3). To verify the practical feasibility of this enantioselective electrochemical process, this present electrochemical CDC reaction was conducted at large scale by using an inexpensive pencil lead as an electrode.10 As shown in Scheme 4, reaction on a 1 mmol scale afforded 63% yield, 9:1 dr and 93% ee after constant electrolysis of 6 h, corresponding to 2.5 F process with a current yield of 47% (Scheme 4). In summary, we have developed a metal- and oxidant-free method for the catalytic asymmetric oxidative coupling of
that gave high enantioselectivity and diastereoselectivity (Table 1, entry 1). Efforts were then directed to improve the Table 1. Optimization of the Reaction Conditionsa
entry
amine
1 2 3 4 5 6 7 8
3a 3b 3c 3d 3e 3f 3g 3a
9 10 11f 12f
3a 3a 3a 3a
13g
3a
14f 15f,h
3a 3a
additive none none none none none none none m-NO2C6H4CO2H (0.1 equiv) i-PrOH (5.0 equiv) H2O (5.0 equiv) H2O (5.0 equiv) CF3CH2OH (0.02 mL) CF3CH2OH (0.02 mL) HFIP (0.02 mL) CF3CH2OH (0.02 mL)
conversionb /yieldc (%/%)
drd
eee (%)
5:1
93
95/38 trace 22/10 35/18 33/18 36/20 trace 99/27
1:1 2:1 1:1 1:1
89 88 77 41
2:1
93
12/6 99/65 95/75 99/75
2:1 5:1 4:1 5:1
96 95 94 95
99/88
4:1
90
99/32 nr
3:1
89
a
General conditions: 1a (0.20 mmol), 2a (1.00 mmol), 3 (10 mol %) in a 0.1 M LiClO4 solvent mixture (4.0 mL) at room temperature. b Determined by 1H NMR analysis with an internal standard. cYield of isolated product. dDetermined by 1H NMR analysis. eDetermined by HPLC. fUnder N2. g2,6-Lutidine (0.05 mL) was added. hNo current or no catalyst. n.r. = no reaction. HFIP: hexafluoro-2-propanol.
productivity. However, further catalyst screening did not result in any improvement in the reaction outcome (Table 1, entries 2−7). As can be seen in Table 1, high conversion of 1a was observed, but the reaction yields were only modest, suggesting that the iminium ion intermediate (Scheme 1, I) formed on the surface of the electrode was not effectively captured by the enamine intermediate (Scheme 1, II). To address this issue, a series of protonic additives were added to (1) capture the iminium ion intermediate to form a more stable hemiaminal intermediate to facilitate the following C−C bond formation step6o,p and to (2) balance the hydrogen evolution process at the cathode and increase the conductivity of the reaction mixture. Pleasingly, we found that the addition of 5 equiv of H2O relative to 1a led to significant improvement of the reaction yield, giving the desired adduct with excellent stereocontrol (Table 1, entry 10). In addition, a better reaction outcome could be obtained when the reaction was conducted under N2 (Table 1, entry 11). Further optimization led to the identification of CF3CH2OH as the best additive (Table 1, entry 12). The addition of 2,6-lutidine could further improve the yield to 88% but with the sacrifice of ee to 90% (Table 1, entry 13). The reaction has also been optimized in terms of electrode materials, supporting electrolytes, voltage, and 2123
DOI: 10.1021/acs.orglett.7b00746 Org. Lett. 2017, 19, 2122−2125
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Organic Letters Scheme 2. Substrate Scopes for Tertiary Aminesa
Scheme 3. Control Experimentsa
a General conditions: 1a (0.20 mmol), 2a (1.00 mmol), 3a (10 mol %), and CF3CH2OH (0.02 mL) in a 0.1 M LiClO4 solvent mixture (4.0 mL) at room temperature.
Scheme 4. Large-Scale Reactiona
a
General conditions: 1b (1 mmol), 2a (5.00 mmol), 3 (10 mol %), 2,6-lutidine (0.05 mL) and CF3CH2OH (0.10 mL) in a 0.1 M LiClO4 solvent mixture (10 mL), room temperature; constant current of 12 mA.
selectivities. We envision that this mild electrochemical method outlined herein will have potential in the development of asymmetric oxidative coupling reactions.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00746. Experimental procedures, characterization data, 1H NMR and 13C NMR spectra, and HPLC traces (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sanzhong Luo: 0000-0001-8714-4047
a
2,6-Lutidine (0.02 mL) was added. bCell potential of 4.0 V. cWith HFIP (0.02 mL) as additive. dWith 3f as the amino catalyst. eCell potential of 2.0 V. fCell potential of 2.5 V. gWith 3e as the amino catalyst.
Author Contributions ∥
N.F. and L.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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tertiary amines with simple ketones via the combination of electrochemical oxidation and chiral primary amine catalysis. Simple ketones such as cyclopentanone, cyclohexanone, and cycloheptanone, as well as an acyclic ketone, could be applied in the developed catalytic system, allowing the rapid construction of diverse, optically active C1-alkylated tetrahydroisoquinoline derivatives with good yields and high stereo-
ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (21390400, 21502198, and 21521002) for financial support. S.L. is supported by the National Program of Top-notch Young Professionals and Chinese Academy of Sciences (QYZDJ-SSWSLH023) 2124
DOI: 10.1021/acs.orglett.7b00746 Org. Lett. 2017, 19, 2122−2125
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Organic Letters
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DOI: 10.1021/acs.orglett.7b00746 Org. Lett. 2017, 19, 2122−2125
