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A π–Cu(II)−π Complex as an Extremely Active Catalyst for Enantioselective α-Halogenation of N-Acyl-3,5-dimethylpyrazoles

Cite this: ACS Catal. 2022, 12, 2, 1012–1017
Publication Date (Web):January 3, 2022
https://doi.org/10.1021/acscatal.1c05500
Copyright © 2022 American Chemical Society
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Abstract

Novel chiral π–copper(II)−π complex catalyzed enantioselective α-chlorination and -bromination of N-acyl-3,5-dimethylpyrazoles are described. The π–copper(II)−π complexation of Cu(OTf)2 with 3-(2-naphthyl)-l-alanine-derived amides greatly increases the Lewis acidity and triggers the in situ generation of enolate species without an external base, which has a suppressing effect for α-chlorination and -bromination due to undesired halogen bonding. This strategy provides facile access to α-halogenated compounds in high yield with excellent enantioselectivity. X-ray crystallographic and ESR analyses of the catalyst complexes suggest that the release of two counteranions (2TfO) from the copper(II) center might be crucial for the efficient activation of N-acyl-3,5-dimethylpyrazoles.

Enantioselective carbon–halogen (Cl, Br) bond formations are particularly important due to their potential as synthetic intermediates as well as marine natural products and pharmaceuticals. (1,2) Among the various methods available to build carbon–halogen bonds, the enantioselective electrophilic α-halogenation of carbonyl compounds is one of the most common. Over the past few decades, α-halogenation reactions using 1,3-dicarbonyl compounds, aldehydes, and ketones have been well established. (3−5) However, few reports are available on catalytic enantioselective α-chlorination for carboxylic acid derivatives with pKa values that are relatively high, and hence it has been considered to be challenging to generate enolate species catalytically. (6) In 2001, Lectka et al. reported the cinchona alkaloid catalyzed enantioselective chlorination (6a,b) and bromination (6a,7)/esterification of acyl chlorides (tandem method, Scheme 1a). Recently, Waser et al. developed a new method using aryl esters in place of acyl chlorides. (6e) In 2009 and 2011, Shibata’s group (6c) and Sodeoka’s group (6d) independently reported the catalytic enantioselective α-chlorination of N-acylimides (direct method, Scheme 1a). In 2021, Meggers et al. developed the rhodium(III)-catalyzed enantioselective α-chlorination of N-acylpyrazoles with TfCl. (6f) The substrates are limited to N-arylacetylimides, and corrosive TfCl is needed as a chlorinating reagent in the presence of stoichiometric amounts of base. Despite the notable successes in this area, no highly effective methods have been developed for α-alkyl-substituted acetyl esters or amides. Most importantly, there have been no successful examples of asymmetric direct α-bromination reactions for amides or esters. (5)

Scheme 1

Scheme 1. Catalytic Enantioselective α-Halogenation Reactions of Carboxylic Acid Derivatives

Since 2006, we have been interested in π–Cu(II) complexes generated in situ from Cu(OTf)2 and 3-(2-naphthyl)-l-alanine-derived amides such as L1 as highly effective chiral Lewis acid catalysts. (8,9) Very recently, we developed the enantioselective α-fluorination of N-acyl-3,5-dimethylpyrazoles 1 catalyzed by chiral π–Cu(II) catalysts in the presence of 2,6-lutidine (Scheme 1b). (10) Mechanistic studies of π–Cu(II) complexes have suggested that the naphthalene moiety of these complexes plays a pivotal role in releasing one counteranion and/or preventing solvents from inactivating the catalysts and thus increasing the Lewis acidity of Cu(II). Inspired by this development, we envisioned that chiral π–Cu(II) catalysts could also promote other halogenation reactions. However, chlorination and bromination were suppressed under the same conditions due to undesired halogen bonding between 2,6-lutidine and X+ reagents (X = Cl, Br) (see the Supporting Information for details). (11) This may be one of the reasons the development of catalytic enantioselective chlorination and bromination is more difficult than that of enantioselective fluorination. Here we report enantioselective α-chlorination and -bromination reactions using a novel type of catalytic system (Scheme 1c). We found that the newly designed π–Cu(II)−π catalyst was a superior chiral Lewis acid catalyst because two counteranions were released from Cu(II), thus providing the corresponding halogenated carboxamides in high yield with high enantioselectivity without an external base. α-Halogenated products can be transformed into α-amino esters and epoxides. (4b)

Initial studies on the α-halogenation reaction were performed with N-phenylacetyl-3,5-dimethylpyrazole (1b), N-chlorosuccinimide (NCS), Cu(OTf)2 (10 mol %), and ligand L (11 mol %) in CH2Cl2 at 0 °C for 3 h (Table 1). When we used the previously optimized chiral ligand L1 in an α-fluorination reaction in the presence of 2,6-lutidine (1 equiv), (10) the chlorinated product 2b was formed in low yield with low enantioselectivity (8% yield, 38% ee, entry 1) due to halogen bonding between NCS and 2,6-lutidine. The reaction proceeded more smoothly without 2,6-lutidine (entry 2). Changing the counterion to NTf2 or BF4 also did not effectively promote the reaction (entries 3 and 4). (12) To improve the reactivity and enantioselectivity, we modified the N-substituent of the ligand to a sterically demanding 5H-dibenzo[a,d]cyclo-hepten-5-yl (=trop) group (L2). Interestingly, in addition to a significant increase in enantioselectivity, a dramatic improvement in reactivity was observed (90% yield, 96% ee, entry 5). A decrease to 3 mol % catalyst loading resulted in a 71% yield. In sharp contrast, the reaction catalyzed by Cu(OTf)2 with L5, which has an N-dibenzosuberyl substituent, gave a moderate yield of 2b with the opposite asymmetric induction (28% yield, −85% ee, entry 9). However, after screening of the R1 group with the decreased reaction rate, the 3-indolyl-substituted ligand L7 gave 2b with the highest enantioselectivity (78% yield, −97% ee, entry 11). All of the ligands L5L7 with an N-dibenzosuberyl group gave the opposite enantiomer (entries 9–11), whereas ligands L2L4 bearing an N-trop group always gave 2b with the same absolute configuration (entries 5–8), indicating that the switch of asymmetric induction was dependent on the difference in the structure of N-substituents of the ligand.

Table 1. Optimization Studiesa
  2b
entryligand (R1)yield (%)bee (%)c
1dL1 w/2,6-lutidine838
2L1 w/o base5432
3eL1 w/o base4033
4fL1 w/o base4034
5L2 (2-naphthyl) w/o base90 (71)g96 (94)g
6fL2 (2-naphthyl) w/o base8595
7L3 (phenyl) w/o base7865
8L4 (3-indolyl) w/o base8768
9L5 (2-naphthyl) w/o base28–85
10L6 (phenyl) w/o base40–78
11L7 (3-indolyl) w/o base61 (78)h–93 (−97)h
a

Unless specified otherwise, reactions were performed with 1a (0.30 mmol), NCS (1.1 equiv), Cu(OTf)2 (10 mol %), and L (11 mol %) in CH2Cl2 (0.2 M) for 3 h at 0 °C.

b

Yields of the isolated 2a.

c

The ee of 2a was determined by HPLC analysis.

d

1.0 equiv of 2,6-lutidine was added.

e

Using Cu(NTf2)2 instead of Cu(OTf)2.

f

Using Cu(BF4)2 instead of Cu(OTf)2.

g

1b (1.5 mmol) was used in the presence of Cu(OTf)2 (3.0 mol %), L (3.3 mol %), and Na2SO4 (100 mg) in CH2Cl2 (1.0 M) for 4 h at 0 °C.

h

In the presence of Na2SO4 (100 mg) and with the reaction time extended to 12 h.

As observed in our previous fluorination reaction catalyzed by the L1·Cu(II) complex, the reactivity was greatly influenced by the electron density of the aryl substituent of L1. As expected, weak coordination of an aryl group of L to Cu(II) was important to release an anionic counterion from Cu(II) and increase the Lewis acidity. Thus, the in situ generated π–Cu(II)−π complex behaved as a fairly active catalyst. To ascertain the π–Cu(II)−π effect, the performance of the ligands was monitored by a 1H NMR analysis, which provided the time-on-stream dependence yield of the chlorinated product 2b (Figure 1). Interestingly, L2 provided the highest catalytic activity in comparison to L1, L8, and L9. (13) Importantly, the catalytic activity with L1 was almost the same as that with L8, suggesting that the N-trop group of the ligand plays the same role as the aryl group in the complexes. The lowest catalytic activity was observed with L9, which has neither an aryl moiety nor an N-trop group, thereby highlighting the importance of a π–Cu(II) interaction for the activation of Lewis acidity. In addition, the enantioselectivity was low when L8 and L9 were used: L8, 7 h, 2b (18% ee); L9, 16 h, 2b (8% ee).

Figure 1

Figure 1. Reaction progress analysis of Cu(OTf)2·L (10 mol %)-catalyzed α-chlorination of 1b with NCS in CH2Cl2 at 0 °C.

With the optimal conditions in hand, we demonstrated the generality of the enantioselective α-chlorination reaction of N-acyl-3,5-dimethylpyrazoles 1 (Table 2). Electron-donating and electron-withdrawing substituents at the phenyl group of 1bg were well tolerated, regardless of their position, and gave 2bg in high yield and high enantioselectivity. Regio- and enantioselective chlorination of 1h,I (R = alkenyl) occurred at the α-position to give 2h,I in good yields with excellent enantioselectivity. Gratifyingly, the chlorination of 1j1o (R = CH2R′, R′ = phenyl, indolyl, methoxy groups) also proceeded well to give 2jo in high yield with high enantioselectivity. To the best of our knowledge, this is the first example of the use of carboxylic acid derivatives for the generation of enolate species without an external base. While other carbonyl groups were kept intact, the regio- and enantioselective α-chlorination of 1p proceeded well. The more pharmaceutically relevant lithocolic acid derivative 1q and oxaprozin derivative 1r were tolerated, although the yield was slightly low. The absolute configuration of 2b was determined to be R on the basis of a comparison of the optical rotation with the reported data. (14) It was ascertained that product 2b could be transformed into the corresponding ester 4b and alcohol 5b without racemization.

Table 2. Scope of the Enantioselective α-Chlorination Reactiona
a

Unless specified otherwise, reactions were performed with 1 (0.30 mmol), NCS (1.1 equiv), Cu(OTf)2 (10 mol %), and L2 (11 mol %) in CH2Cl2 (0.2 M).

b

Isolated yield.

c

The ee of 2 determined by HPLC analysis.

d

In the presence of Na2SO4 (100 mg).

e

CH2Cl2 (0.5 M) with 4A MS (100 mg).

f

The de of 2q determined by NMR analysis.

g

One-pot transesterification from 1b via 2b was carried out at rt for 1 h by addition of MeOH after α-chlorination (3 h at 0 °C).

h

Reduction of crude 2b, which was obtained by α-chlorination (3 h at 0 °C), with NaBH4 was carried out at rt for 0.5 h in THF/H2O.

Subsequently, we investigated the possibility of applying our strategy to the α-bromination reaction of N-acyl-3,5-dimethylpyrazoles 1. When N-bromosuccinimide (NBS) was used in place of NCS, the enantioselectivity was unexpectedly low, probably due to partial decomposition of L2. After the systematic evaluation of electrophilic brominating reagents, we found that Meldrum’s 5,5-dibromo acid was usable in the presence of anhydrous Na2SO4 (see the Supporting Information for details). (15) As with the chlorination reaction, enantioselective α-bromination proceeded to give the corresponding products 3 in good to excellent yields and enantioselectivities without an external base (Table 3). α-Aryl-substituted products 3b,c were well tolerated. Heteroaromatic product 3k and other electron-withdrawing substituents at the β-position 3j,l,s,o were also obtained. However, moderate yield and moderate enantioselectivity were observed in the reaction of 1t. As shown in Figure 1, the naphthalene ring, N-5-benzosuberyl-substituted group, and N-trop group were shown to be crucial for increasing the reactivity.

Table 3. Scope of the Enantioselective α-Bromination Reactiona
a

Unless specified otherwise, reactions were performed with 1 (0.30 mmol), Meldrum’s 5,5-dibromo acid (1.1 equiv), Cu(OTf)2 (10 mol %), L2 (11 mol %), and Na2SO4 (100 mg) in CH2Cl2 (0.2 M).

b

Isolated yield.

c

The ee of 3 determined by HPLC analysis.

d

CH2Cl2 (0.5 M).

To get a better understanding of the role of each substituent, we tried to determine the crystal structure of the copper complexes (Figure 2a). Successfully, we obtained a single crystal of the 1:1:1 complex L6·Cu(OTf)2·1a (Figure 2b). An X-ray crystallographic analysis indicated that one side of the aryl moiety of the N-5-benzosuberyl-substituted group seems close to the copper center and its distance was around 3 Å, which is considered to be due to a π–copper interaction. (16) We believe that this interaction is important for both the catalytic activity and asymmetric induction. The switch in stereoselectivity in the chlorination reaction using L5L7 was consistent with this crystal structure. After an enormous amount of effort, we also succeeded in determining the X-ray crystallographic structure of L2·Cu(BF4)2·1a. Surprisingly, we observed a close contact between the copper center and the carbon–carbon double bond of the N-trop group, less than 3 Å, as well as a π–copper interaction between the naphthyl group and copper. (17) The larger π-face of a naphthyl group in comparison to that of an N-trop group, which is bent against copper, effectively shields the upper face of the α-carbon of 1b.

Figure 2

Figure 2. (a) Generation of the 1:1:1 complexes L6·Cu(OTf)2·1a and L2·Cu(BF4)2·1a. (b) X-ray analysis of L6·Cu(OTf)2·1a. Hydrogen atoms, solvent, and free OTf are omitted for clarity. (c) X-ray analysis of L2·Cu(BF4)2·1a. Hydrogen atoms, solvent, and free counterions are omitted for clarity.

To obtain structural information on copper complexes in a solution state, ESR spectra of L1·Cu(OTf)2·1a and L2·Cu(OTf)2·1a in MeCN at 30 K and simulated spectra were obtained and are shown in Figure 3. Each experimental spectrum was reproduced with different ESR parameters of axially symmetric g values and hyperfine coupling constants, as shown in Table S6.

Figure 3

Figure 3. ESR spectra (experiments and simulations) of L1·Cu(OTf)2·1a and L2·Cu(OTf)2·1a at 30 K.

These parameters indicate that the coordination structure of L2·Cu(OTf)2·1a changes from the tetrahedrally distorted (6-coordinate) L1·Cu(OTf)2·1a to axially coordinate square planar (6-coordinate) depending on the two different ligands at the apical position: a naphthyl group and OTf. (18)

In summary, we have developed the catalytic enantioselective α-chlorination and -bromination of N-acyl-3,5-dimethylpyrazoles. With a newly designed, highly active π–Cu(II)−π complex, the halogenation reaction of N-acyl-3,5-dimethylpyrazoles can be performed using carboxylic acid derivatives with or without an electron-withdrawing group at the α-position without an external base, which has a suppressing effect due to undesired halogen bonding. An X-ray crystallographic analysis of copper complexes and ESR analysis revealed the existence of a π–Cu−π interaction, which is essential for increasing the reactivity. Thus, a halonium ion predominantly approaches to the re face of the in situ generated enol form of 1 to give 2 or 3 (Scheme 1c).

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.1c05500.

  • Experimental procedures and characterization data (PDF)

  • X-ray crystallographic data for L6·Cu(OTf)2·1a (CIF)

  • X-ray crystallographic data for L2·Cu(BF4)2·1a (CIF)

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Author Information

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  • Corresponding Author
  • Authors
    • Kazuki Nishimura - Graduate School of Engineering, Nagoya University, Furo-cho, Nagoya 464-8603, Japan
    • Yanzhao Wang - Graduate School of Engineering, Nagoya University, Furo-cho, Nagoya 464-8603, Japan
    • Yoshihiro Ogura - Graduate School of Engineering, Nagoya University, Furo-cho, Nagoya 464-8603, Japan
    • Jun Kumagai - Graduate School of Engineering, Nagoya University, Furo-cho, Nagoya 464-8603, JapanOrcidhttps://orcid.org/0000-0003-3851-9783
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This research was financially supported by JSPS KAKENHI Grant Nos. JP15H05755 (to K.I.) and JP15H05810 (to K.I.) and the NOVARTIS Foundation (Japan) for the Promotion of Science (to K.I.). This work is partially supported by Nagoya University Research Fund. Y.Z. and Y.O. thank the Program for Leading Graduate Schools: IGER Program in Green Natural Sciences, MEXT. K.N. thanks the Graduate Program of Transformative Chem-Bio Research (GTR), MEXT. We thank Dr. Kenji Yamashita (Univ. of Shizuoka), Mr. Hiroki Tanaka (Nagoya Univ.), and Mr. Takehiro Kato (Nagoya Univ.) for their assistance with X-ray analysis.

References

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    (c) Ishihara, K.; Fushimi, M. Catalytic Enantioselective [2 + 4] and [2 + 2] Cycloaddition Reactions with Propiolamides. J. Am. Chem. Soc. 2008, 130, 75327533,  DOI: 10.1021/ja8015318 .
    (d) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with Propioloylpyrazoles and Acryloylpyrazoles Induced by Chiral π–Cation Catalysts. J. Am. Chem. Soc. 2010, 132, 1555015552,  DOI: 10.1021/ja1081603 .
    (e) Sakakura, A.; Ishihara, K. Asymmetric Cu(II) catalyses for cycloadditon reactions based on π–cation interactions. Chem. Soc. Rev. 2011, 40, 163172,  DOI: 10.1039/B924478F .
    (f) Hori, M.; Sakakura, A.; Ishihara, K. Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines with Propioloylpyrazoles Induced by Chiral π–Cation Catalysts. J. Am. Chem. Soc. 2014, 136, 1319813201,  DOI: 10.1021/ja508441t .
    (g) Yao, L.; Ishihara, K. Enantioselective [1,3] O–to–C Rearrangement: Dearomatization of Alkyl 2-Allyloxy/Benzyloxy-1/3-naphtholates Catalyzed by a Chiral π–Cu(II) Complex. Chem. Sci. 2019, 10, 22592263,  DOI: 10.1039/C8SC05601C
  9. 9

    For other examples of the possible π–Cu(II or I) interaction, see:

    (a) Gao, X.-T.; Gan, C.-C.; Liu, S.-Y.; Zhou, F.; Wu, H.-H.; Zhou, J. Utilization of CO2 as a C1 Building Block in a Tandem Asymmetric A3 Coupling-Carboxylative Cyclization Sequence to 2-Oxazolidinones. ACS Catal. 2017, 7, 85888593,  DOI: 10.1021/acscatal.7b03370 .
    (b) Zhu, R.-Y.; Chen, L.; Hu, X.-S.; Zhou, F.; Zhou, J. Enantioselective synthesis of P-chiral tertiary phosphine oxides with an ethynyl group via Cu(I)-catalyzed azide–alkyne cycloaddition. Chem. Sci. 2020, 11, 97106,  DOI: 10.1039/C9SC04938J
  10. 10
    Ishihara, K.; Nishimura, K.; Yamakawa, K. Enantio- and Site-selective α-Fluorination of N-Acyl-3,5-dimethylpyrazoles Catalyzed by Chiral π–Cu(II) Complexes. Angew. Chem., Int. Ed. 2020, 59, 1764117647,  DOI: 10.1002/anie.202007403
  11. 11

    See p S20 in the Supporting Information for experimental results on halogen-bonding interactions between 2,6-lutidine and X+ reagents.

    (a) Stilinović, V.; Horvat, G.; Hrenar, T.; Nemec, V.; Cinčić, D. Halogen and Hydrogen Bonding between (N-Halogeno)-succinimides and Pyridine Derivatives in Solution, the Solid State and In Silico. Chem.-Eur. J. 2017, 23, 52445257,  DOI: 10.1002/chem.201605686 .
    (b) Anyfanti, G.; Bauzá, A.; Gentiluomo, L.; Rodrigues, J.; Portalone, G.; Frontera, A.; Rissanen, K.; Puttreddy, R. Front. Chem. 2021, 9, 623595,  DOI: 10.3389/fchem.2021.623595
  12. 12

    For the estimation of weakly coordinating anions, see:

    (a) Mathieu, B.; Ghosez, L. Trimethylsilyl bis(trifluoromethanesulfonyl)imide as a tolerant and environmentally benign Lewis acid catalyst of the Diels–Alder reaction. Tetrahedron 2002, 58, 82198226,  DOI: 10.1016/S0040-4020(02)00971-7 .
    (b) Krossing, I.; Raabe, I. Noncoordinating Anions─Fact or Fiction? A Survey of Likely Candidates. Angew. Chem., Int. Ed. 2004, 43, 20662090,  DOI: 10.1002/anie.200300620 .
    (c) Krossing, I.; Raabe, I. Relative Stabilities of Weakly Coordinating Anions: A Computational Study. Chem.-Eur. J. 2004, 10, 50175030,  DOI: 10.1002/chem.200400087
  13. 13

    See p S15 in the Supporting Information for details of the time-course reaction rate.

  14. 14

    For [α]D = −87.1 (c = 0.74, CHCl3) of methyl (R)-chlorophenylacetate (87% ee), see ref (6d).

  15. 15

    See p S16 in the Supporting Information for details of the screening of brominating agents.

  16. 16

    For examples of π–cation interactions between arene and Cu(II), see:

    (a) Van der Helm, D.; Tatsch, C. E. The crystal structure of bis-(L-tyrosinato)copper(II). Acta Crystallogr., Sect. B: Struct. Sci. 1972, 28, 23072312,  DOI: 10.1107/S0567740872006016 .
    (b) Yorita, H.; Otomo, K.; Hiarmatsu, A.; Toyama, A.; Miura, T.; Takeuchi, H. Evidence for the cation-π interaction between Cu2+ and tryptophan. J. Am. Chem. Soc. 2008, 130, 1526615267,  DOI: 10.1021/ja807010f .
    (c) Muhonen, H.; Hämäläinen, R. The crystal and molecular structure of (dimethyl sulfoxide)bis(L-phenylalaninato)copper(II). Finn. Chem. Lett. 1983, 120124.
    (d) Castiñeiras, A.; Sicilia-Zafra, A. G.; González-Pérez, J. M.; Choquesillo-Lazarte, D.; Niclós-Gutiérrez, J. Intramolecular “Aryl-Metal Chelate Ring” π,π-Interactions as structural evidence for metalloaromaticity in (aromatic α,α′-diimine)-copper(II) chelates: Molecular and crystal structure of aqua(1,10-phenanthroline)(2-benzylmalonato)copper(II) three-hydrate. Inorg. Chem. 2002, 41, 69566958,  DOI: 10.1021/ic026004h
  17. 17

    For selected examples of the olefin with metal complexes, see:

    (a) Schönberg, H.; Boulmaâz, S.; Wörle, M.; Liesum, L.; Schweiger, A.; Grützmacher, H. A Monomeric d9-Rhodium(0) complex. Angew. Chem., Int. Ed. 1998, 37, 14231425,  DOI: 10.1002/(SICI)1521-3773(19980605)37:10<1423::AID-ANIE1423>3.0.CO;2-X .
    (b) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007, 46, 31393143,  DOI: 10.1002/anie.200700159 .
    (c) de Bruin, B.; Hetterscheid, D. G. H. Paramagnetic (Alkene)Rh and (alkene)Ir Complexes: Metal or Ligand Radicals?. Eur. J. Inorg. Chem. 2007, 2007, 211230,  DOI: 10.1002/ejic.200600923 .
    (d) Rodríguez-Lugo, R. E.; Trincado, M.; Vogt, M.; Twews, F.; Santiso-Quinones, G.; Grützmacher, H. A homogeneous transition metal complex for clean hydrogen production from methanol-water mixtures. Nat. Chem. 2013, 5, 342347,  DOI: 10.1038/nchem.1595 .
    (e) Lichtenberg, C.; Bloch, J.; Gianetti, T. L.; Büttner, T.; Geier, J.; Grützmacher, H. Diolefins with an ether/thioether functionality as ligands in the coordination sphere of Ni and Rh. Dalton Trans. 2015, 44, 2005620066,  DOI: 10.1039/C5DT03279B .
    (f) Brill, M.; Collado, A.; Cordes, D. B.; Slawin, A. M. Z.; Vogt, M.; Grützmacher, H.; Nolan, S. P. Synthesis and Characterization of Gold(I) Complexes of Dibenzotropylidene-Functionalized NHC Ligands (Trop-NHCs). Organometallics 2015, 34, 263274,  DOI: 10.1021/om501093s .
    (g) Freitag, B.; Elsen, H.; Pahl, J.; Ballmann, G.; Herrera, A.; Dorta, R.; Harder, S. s-Block Metal Dibenzoazepinate Complexes: Evidence for Mg–Alkene Encapsulation. Organometallics 2017, 36, 18601866,  DOI: 10.1021/acs.organomet.7b00200 .
    (h) Casas, F.; Trincado, M.; Rodriguez-Lugo, R.; Baneerge, D.; Grützmacher, H. A Diaminopropane Diolefin Ru(0) Complex Catalyzes Hydrogenation and Dehydrogenation Reactions. ChemCatChem. 2019, 11, 52415251,  DOI: 10.1002/cctc.201901739 .
    (i) Martin, J.; Langer, J.; Wiesinger, M.; Elsen, H.; Harder, S. Dibenzotropylidene Substituted Ligands for Early Main Group Metal-Alkene Bonding. Eur. J. Inorg. Chem. 2020, 2020, 25822595,  DOI: 10.1002/ejic.202000524
  18. 18
    Sawada, T.; Fukumaru, K.; Sakurai, H. Coordination-Dependent ESR Spectra of Copper(II) Complexes with a CuN4 Type Coordination Mode: Relationship between ESR Parameters and Stability Constants or Redox Potentials of the Complexes. Chem. Pharm. Bull. 1996, 44, 10091016,  DOI: 10.1248/cpb.44.1009

Cited By

This article is cited by 1 publications.

  1. Kazuki Nishimura, Yoshihiro Ogura, Kazuki Takeda, Weiwei Guo, Kazuaki Ishihara. Chiral π–Cu(II) Catalysts for the Enantioselective α-Amination of N-Acyl-3,5-dimethylpyrazoles. Organic Letters 2022, 24 (41) , 7685-7689. https://doi.org/10.1021/acs.orglett.2c03249
  • Abstract

    Scheme 1

    Scheme 1. Catalytic Enantioselective α-Halogenation Reactions of Carboxylic Acid Derivatives

    Figure 1

    Figure 1. Reaction progress analysis of Cu(OTf)2·L (10 mol %)-catalyzed α-chlorination of 1b with NCS in CH2Cl2 at 0 °C.

    Figure 2

    Figure 2. (a) Generation of the 1:1:1 complexes L6·Cu(OTf)2·1a and L2·Cu(BF4)2·1a. (b) X-ray analysis of L6·Cu(OTf)2·1a. Hydrogen atoms, solvent, and free OTf are omitted for clarity. (c) X-ray analysis of L2·Cu(BF4)2·1a. Hydrogen atoms, solvent, and free counterions are omitted for clarity.

    Figure 3

    Figure 3. ESR spectra (experiments and simulations) of L1·Cu(OTf)2·1a and L2·Cu(OTf)2·1a at 30 K.

  • References

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    This article references 18 other publications.

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      (n) Hutchinson, G.; Alamillo-Ferrer, C.; Burés, J. Mechanistically Guided Design of an Efficient and Enantioselective Aminocatalytic α-Chlorination of Aldehydes. J. Am. Chem. Soc. 2021, 143, 68056809,  DOI: 10.1021/jacs.1c02997
    5. 5

      For the enantioselective α-bromination of aldehydes, see:

      (a) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Organocatalytic Asymmetric α-Bromination of Aldehydes and ketones. Chem. Commun. 2005, 48214823,  DOI: 10.1039/b509366j .
      (b) Kano, T.; Shirozu, F.; Maruoka, K. Direct Asymmetric Bromination of Aldehydes Catalyzed by a Binaphtyl-based Secondary Amine: Highly Enantio and Diastereoselective One-pot Synthesis of Bromohydrins. Chem. Commun. 2010, 46, 75907592,  DOI: 10.1039/c0cc02739a .
      (c) Takeshima, A.; Shimogaki, M.; Kano, T.; Maruoka, K. Development of Ketone-Based Brominating Agent (KBA) for the Practical Asymmetric α-Bromination of Aldehydes Catalyzed by Tritylpyrrolidine. ACS Catal. 2020, 10, 59595963,  DOI: 10.1021/acscatal.0c01596
    6. 6

      For the enantioselective α-chlorination of carboxylic acid derivatives, see:

      (a) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T. Catalytic, Asymmetric α-Halogenation. J. Am. Chem. Soc. 2001, 123, 15311532,  DOI: 10.1021/ja005791j .
      (b) France, S.; Wack, H.; Taggi, A. E.; Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.; Lectka, T. Catalytic, Asymmetric α-Chlorination of Acid Halides. J. Am. Chem. Soc. 2004, 126, 42454255,  DOI: 10.1021/ja039046t .
      (c) Reddy, D. S.; Shibata, N.; Horikawa, T.; Suzuki, S.; Nakamuwa, S.; Toru, T.; Shiro, M. A DBFOX-Ph-Based Combinatorial Catalyst for Enantioselective Fluorination of Aryl Acetyl and 3-Butenoyl Thiazolidinones. Chem. Asian. J. 2009, 4, 14111415,  DOI: 10.1002/asia.200900164 .
      (d) Hamashima, Y.; Nagi, T.; Shimizu, R.; Tsuchimoto, T.; Sodeoka, M. Catalytic Asymmetric α-Chlorination of 3-Acyloxazolidin-2-one with a Trinary Catalytic System. Eur. J. Org. Chem. 2011, 2011, 36753578,  DOI: 10.1002/ejoc.201100453 .
      (e) Stockhammer, L.; Weinzierl, D.; Bögl, T.; Waser, M. Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions. Org. Lett. 2021, 23, 61436147,  DOI: 10.1021/acs.orglett.1c02256 .
      (f) Grell, Y.; Xie, X.; Ivlev, S. I.; Meggers, E. Enantioselective α-Fluorination and α-Chlorination of N-Acyl Pyrazoles Catalyzed by a Non-C2-Symmetric Chiral-at-Rhodium Catalyst. ACS Catal. 2021, 11, 1139611406,  DOI: 10.1021/acscatal.1c02901
    7. 7

      For the enantioselective α-bromination of acyl chlorides, see:

      Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax, A.; Taggi, A. E.; Paull, D. H.; Dudding, T.; Lectka, T. Eur. J. Org. Chem. 2007, 2007, 10911100,  DOI: 10.1002/ejoc.200600819
    8. 8
      (a) Ishihara, K.; Fushimi, M. Design of a Small-Molecule Catalyst Using Intramolecular Cation−π Interactions for Enantioselective Diels–Alder and Mukaiyama–Michael Reactions: L-DOPA-Derived Monopeptide-Cu(II) Complex. Org. Lett. 2006, 8, 19211924,  DOI: 10.1021/ol060651l .
      (b) Ishihara, K.; Fushimi, M.; Akakura, M. Rational Design of Minimal Artificial Diels–Alderases Based on the Copper(II) Cation– Aromatic π Attractive Interaction. Acc. Chem. Res. 2007, 40, 10491055,  DOI: 10.1021/ar700083a .
      (c) Ishihara, K.; Fushimi, M. Catalytic Enantioselective [2 + 4] and [2 + 2] Cycloaddition Reactions with Propiolamides. J. Am. Chem. Soc. 2008, 130, 75327533,  DOI: 10.1021/ja8015318 .
      (d) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with Propioloylpyrazoles and Acryloylpyrazoles Induced by Chiral π–Cation Catalysts. J. Am. Chem. Soc. 2010, 132, 1555015552,  DOI: 10.1021/ja1081603 .
      (e) Sakakura, A.; Ishihara, K. Asymmetric Cu(II) catalyses for cycloadditon reactions based on π–cation interactions. Chem. Soc. Rev. 2011, 40, 163172,  DOI: 10.1039/B924478F .
      (f) Hori, M.; Sakakura, A.; Ishihara, K. Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines with Propioloylpyrazoles Induced by Chiral π–Cation Catalysts. J. Am. Chem. Soc. 2014, 136, 1319813201,  DOI: 10.1021/ja508441t .
      (g) Yao, L.; Ishihara, K. Enantioselective [1,3] O–to–C Rearrangement: Dearomatization of Alkyl 2-Allyloxy/Benzyloxy-1/3-naphtholates Catalyzed by a Chiral π–Cu(II) Complex. Chem. Sci. 2019, 10, 22592263,  DOI: 10.1039/C8SC05601C
    9. 9

      For other examples of the possible π–Cu(II or I) interaction, see:

      (a) Gao, X.-T.; Gan, C.-C.; Liu, S.-Y.; Zhou, F.; Wu, H.-H.; Zhou, J. Utilization of CO2 as a C1 Building Block in a Tandem Asymmetric A3 Coupling-Carboxylative Cyclization Sequence to 2-Oxazolidinones. ACS Catal. 2017, 7, 85888593,  DOI: 10.1021/acscatal.7b03370 .
      (b) Zhu, R.-Y.; Chen, L.; Hu, X.-S.; Zhou, F.; Zhou, J. Enantioselective synthesis of P-chiral tertiary phosphine oxides with an ethynyl group via Cu(I)-catalyzed azide–alkyne cycloaddition. Chem. Sci. 2020, 11, 97106,  DOI: 10.1039/C9SC04938J
    10. 10
      Ishihara, K.; Nishimura, K.; Yamakawa, K. Enantio- and Site-selective α-Fluorination of N-Acyl-3,5-dimethylpyrazoles Catalyzed by Chiral π–Cu(II) Complexes. Angew. Chem., Int. Ed. 2020, 59, 1764117647,  DOI: 10.1002/anie.202007403
    11. 11

      See p S20 in the Supporting Information for experimental results on halogen-bonding interactions between 2,6-lutidine and X+ reagents.

      (a) Stilinović, V.; Horvat, G.; Hrenar, T.; Nemec, V.; Cinčić, D. Halogen and Hydrogen Bonding between (N-Halogeno)-succinimides and Pyridine Derivatives in Solution, the Solid State and In Silico. Chem.-Eur. J. 2017, 23, 52445257,  DOI: 10.1002/chem.201605686 .
      (b) Anyfanti, G.; Bauzá, A.; Gentiluomo, L.; Rodrigues, J.; Portalone, G.; Frontera, A.; Rissanen, K.; Puttreddy, R. Front. Chem. 2021, 9, 623595,  DOI: 10.3389/fchem.2021.623595
    12. 12

      For the estimation of weakly coordinating anions, see:

      (a) Mathieu, B.; Ghosez, L. Trimethylsilyl bis(trifluoromethanesulfonyl)imide as a tolerant and environmentally benign Lewis acid catalyst of the Diels–Alder reaction. Tetrahedron 2002, 58, 82198226,  DOI: 10.1016/S0040-4020(02)00971-7 .
      (b) Krossing, I.; Raabe, I. Noncoordinating Anions─Fact or Fiction? A Survey of Likely Candidates. Angew. Chem., Int. Ed. 2004, 43, 20662090,  DOI: 10.1002/anie.200300620 .
      (c) Krossing, I.; Raabe, I. Relative Stabilities of Weakly Coordinating Anions: A Computational Study. Chem.-Eur. J. 2004, 10, 50175030,  DOI: 10.1002/chem.200400087
    13. 13

      See p S15 in the Supporting Information for details of the time-course reaction rate.

    14. 14

      For [α]D = −87.1 (c = 0.74, CHCl3) of methyl (R)-chlorophenylacetate (87% ee), see ref (6d).

    15. 15

      See p S16 in the Supporting Information for details of the screening of brominating agents.

    16. 16

      For examples of π–cation interactions between arene and Cu(II), see:

      (a) Van der Helm, D.; Tatsch, C. E. The crystal structure of bis-(L-tyrosinato)copper(II). Acta Crystallogr., Sect. B: Struct. Sci. 1972, 28, 23072312,  DOI: 10.1107/S0567740872006016 .
      (b) Yorita, H.; Otomo, K.; Hiarmatsu, A.; Toyama, A.; Miura, T.; Takeuchi, H. Evidence for the cation-π interaction between Cu2+ and tryptophan. J. Am. Chem. Soc. 2008, 130, 1526615267,  DOI: 10.1021/ja807010f .
      (c) Muhonen, H.; Hämäläinen, R. The crystal and molecular structure of (dimethyl sulfoxide)bis(L-phenylalaninato)copper(II). Finn. Chem. Lett. 1983, 120124.
      (d) Castiñeiras, A.; Sicilia-Zafra, A. G.; González-Pérez, J. M.; Choquesillo-Lazarte, D.; Niclós-Gutiérrez, J. Intramolecular “Aryl-Metal Chelate Ring” π,π-Interactions as structural evidence for metalloaromaticity in (aromatic α,α′-diimine)-copper(II) chelates: Molecular and crystal structure of aqua(1,10-phenanthroline)(2-benzylmalonato)copper(II) three-hydrate. Inorg. Chem. 2002, 41, 69566958,  DOI: 10.1021/ic026004h
    17. 17

      For selected examples of the olefin with metal complexes, see:

      (a) Schönberg, H.; Boulmaâz, S.; Wörle, M.; Liesum, L.; Schweiger, A.; Grützmacher, H. A Monomeric d9-Rhodium(0) complex. Angew. Chem., Int. Ed. 1998, 37, 14231425,  DOI: 10.1002/(SICI)1521-3773(19980605)37:10<1423::AID-ANIE1423>3.0.CO;2-X .
      (b) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007, 46, 31393143,  DOI: 10.1002/anie.200700159 .
      (c) de Bruin, B.; Hetterscheid, D. G. H. Paramagnetic (Alkene)Rh and (alkene)Ir Complexes: Metal or Ligand Radicals?. Eur. J. Inorg. Chem. 2007, 2007, 211230,  DOI: 10.1002/ejic.200600923 .
      (d) Rodríguez-Lugo, R. E.; Trincado, M.; Vogt, M.; Twews, F.; Santiso-Quinones, G.; Grützmacher, H. A homogeneous transition metal complex for clean hydrogen production from methanol-water mixtures. Nat. Chem. 2013, 5, 342347,  DOI: 10.1038/nchem.1595 .
      (e) Lichtenberg, C.; Bloch, J.; Gianetti, T. L.; Büttner, T.; Geier, J.; Grützmacher, H. Diolefins with an ether/thioether functionality as ligands in the coordination sphere of Ni and Rh. Dalton Trans. 2015, 44, 2005620066,  DOI: 10.1039/C5DT03279B .
      (f) Brill, M.; Collado, A.; Cordes, D. B.; Slawin, A. M. Z.; Vogt, M.; Grützmacher, H.; Nolan, S. P. Synthesis and Characterization of Gold(I) Complexes of Dibenzotropylidene-Functionalized NHC Ligands (Trop-NHCs). Organometallics 2015, 34, 263274,  DOI: 10.1021/om501093s .
      (g) Freitag, B.; Elsen, H.; Pahl, J.; Ballmann, G.; Herrera, A.; Dorta, R.; Harder, S. s-Block Metal Dibenzoazepinate Complexes: Evidence for Mg–Alkene Encapsulation. Organometallics 2017, 36, 18601866,  DOI: 10.1021/acs.organomet.7b00200 .
      (h) Casas, F.; Trincado, M.; Rodriguez-Lugo, R.; Baneerge, D.; Grützmacher, H. A Diaminopropane Diolefin Ru(0) Complex Catalyzes Hydrogenation and Dehydrogenation Reactions. ChemCatChem. 2019, 11, 52415251,  DOI: 10.1002/cctc.201901739 .
      (i) Martin, J.; Langer, J.; Wiesinger, M.; Elsen, H.; Harder, S. Dibenzotropylidene Substituted Ligands for Early Main Group Metal-Alkene Bonding. Eur. J. Inorg. Chem. 2020, 2020, 25822595,  DOI: 10.1002/ejic.202000524
    18. 18
      Sawada, T.; Fukumaru, K.; Sakurai, H. Coordination-Dependent ESR Spectra of Copper(II) Complexes with a CuN4 Type Coordination Mode: Relationship between ESR Parameters and Stability Constants or Redox Potentials of the Complexes. Chem. Pharm. Bull. 1996, 44, 10091016,  DOI: 10.1248/cpb.44.1009
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