Letter pubs.acs.org/OrgLett
Iron Phosphate Catalyzed Asymmetric Cross-Dehydrogenative Coupling of 2‑Naphthols with β‑Ketoesters Sachin Narute and Doron Pappo* Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel S Supporting Information *
ABSTRACT: Chiral iron phosphate complexes were successfully exploited for asymmetric cross-dehydrogenative coupling reactions between 2-naphthols and β-ketoester derivatives. On the basis of kinetic studies, it is suggested that iron monophosphate complexes constitute the active catalysts that induce stereoselectivity during the carbon−carbon bondformation step. partners (Figure 1C). Feng developed a chiral NiII−redox FeII heterobimetallic cooperative catalyst system for coupling between β-ketoesters and xanthene, which follows strategy A,6 whereas both the iron[salan] and the iron[phosphate]3 complexes, developed by Katsuki5 and Pappo7 (Scheme 1),
I
ron catalyzed cross-dehydrogenative coupling (CDC) reactions have emerged as powerful methods for synthesizing novel C−C bonds by coupling two C−H bonds under oxidation conditions.1 The development of this chemistry is highly important because it offers a great opportunity to diminish the dependence of synthetic chemistry on traditional cross-coupling reactions, which heavily rely on prefunctionalization of the coupling partners and precious metals. Since the seminal work of Li, which introduced iron and copper salts as CDC catalysts,2 most synthetic works have been focused on identifying suitable oxidation conditions and coupling partners as well as solving efficiency and selectivity challenges that the chemistry poses.1a,d,3 However, much less attention has been devoted to developing asymmetric CDC transformations.4 Even more frustrating is the lack of reliable asymmetric methodologies based on chiral redox iron complexes.5 The three main strategies for inducing asymmetry in iron− CDC between two nucleophiles involves (a) a cooperative catalytic system consisting of an achiral iron redox catalyst, which generates electrophilic species that react with a chiral Lewis or an organocatalyst-activated nucleophile (Figure 1A), (b) a chiral redox iron catalyst that mediates intermolecular coupling between an associated electrophile and a nucleophile (Figure 1B), and (c) a chiral redox metal catalyst that mediates the stereoselective coupling between two associated coupling
Scheme 1. Asymmetric Oxidative Cross-Coupling of 2Naphthols by Chiral Iron Phosphate Complexes
respectively, are examples of chiral redox iron catalysts that mediate the enantioselective oxidative coupling of 2-naphthols according to strategy B. In this paper, we demonstrate that iron phosphate complexes can also catalyze asymmetric CDC between associated β-ketoester and 2-naphthol ligands, according to strategy C. On the basis of mechanistic studies, it is suggested that iron monophosphate complexes are the active catalysts for this transformation and that they become active only at elevated temperatures to afford chiral polycyclic hemiacetals in moderate to high enantioselectivity. Recently, our group developed iron-catalyzed CDC reactions between 1,3-dicarbonyl compounds with substituted phenols, affording complex phenolic architectures that were employed in natural product synthesis.8 In its racemic version [FeCl3·6H2O
Figure 1. Conceptual strategies for asymmetric iron−CDC transformations. © 2017 American Chemical Society
Received: April 17, 2017 Published: May 12, 2017 2917
DOI: 10.1021/acs.orglett.7b01152 Org. Lett. 2017, 19, 2917−2920
Letter
Organic Letters (10 mol %), t-BuOO-t-Bu (1.5 equiv), 1,2-dichloroethane (DCE), 80 °C], the coupling of 2-naphthol 1a with αsubstituted-β-ketoester 2a, which has a chiral auxiliary (R = (−)-menthyl), afforded a mixture of diastereoisomers 3a (7aR, 10aS) and 3a′ (7aS,10aR) in ca. 46:54 ratio (Table 1, entry
and a cross-coupling product 3a was obtained in low yield and with poor diastereoselectivity (43:57, entry 3). Our optimization study, which included extensive ligand screening (see Table S1), showed a correlation between the size of the 3,3′substituents of the phosphoric acid and the product’s diastereoselectivity [(4-t-Bu)C6H4 > TMS > Me > H, Table 1, entries 3−6], with the least sterically hindered ligand L4 (R1 = H, BNPH) providing the highest diastereoselectivity (88:12) and efficiency (89% yield, entry 6). On the other hand, the coupling with ent-L4 as a ligand afforded a much lower dr (20:80), suggesting that a mismatched relationship exists between the ligand and menthyl β-ketoester 2a. Our attempt to enhance the reaction outcome by changing the electronic properties of the ligand by modifying its 6- and 6′-positions with alkyl and aryl groups (Table 1, entries 8−11 Table S1) was less successful. The enantioselective coupling of β-ketoesters with smaller alkyl groups, such as 2b (R = Me) and 2c (R = Et), is also possible; however, it requires the use of phosphate ligands with bulky 3- and 3′-substituents, such as L5 [R1 = 4-(2-naphthyl)C6H4, Table 1, entries 12 and 13]. At least six steps are needed, starting from (R)-BINOL, to prepare ligands with a complexity similar to ligand L5, transforming the structure−selectivity relationship study for the CDC of alkyl βketoesters 2b (R = Me) or 2c (R = Et) to unfavorable in terms of time and cost. The cross-coupling of other alkyl β-ketoester derivatives, such as propyl, isopropyl, isopentyl, and cyclohexyl, with 2-naphthol (1a) using Fe[L3]3 (R1 = Me) as a catalyst afforded the corresponding coupling products 3d−g with moderate enantioselectivity (entries 14−17). Therefore, we decided to demonstrate the potential that iron phosphate complexes have as catalysts in asymmetric CDC reactions by studying the oxidative coupling between 2-naphthol derivatives and β-ketoester 2a. Further attempts to improve the stereoselectivity by changing the reaction parameters, such as the solvent, iron source, and the oxidant, were ineffective (see Table S2). The use of dioxygen instead of peroxide as a terminal oxidant is possible, and the desired coupling product, 3a, was obtained with a comparable diastereoselectivity (dr = 88:12) yet with a considerably lower reactivity (31% yield, entry 18). Mechanistically, we previously proposed that the enantioselective oxidative homocoupling of 2-naphthol 1a at room temperature by iron phosphate complexes (Scheme 2) commences when the peroxide is associated with iron triphosphate complex I.7 Next, peroxide bond cleavage takes place and generates a high-valent iron complex. This complex benefits from exchanging one of the phosphate ligands with a 2naphtholate ligand (complex II) that can push the electron density (SET process) that stabilizes the metal. As a result, a persistent bounded naphthoxyl radical (III) is being formed. An oxidative radical−anion coupling with a second nucleophilic 2-naphthol(ate) via a radical−anion coupling mechanism is the slowest step in this process, which affords (R)-BINOL.7 The above mechanistic scheme changes at 50 °C in the presence of an anionic−bidentate β-ketoester ligand. Our nonlinear effect experiments13 (Figure 3A, for details, see the SI) revealed a linear relationship between the diastereomeric excesses of the hemiacetal product, 3a, and the enantiomeric excess of the ligand. This experiment implies that only a single chiral phosphate ligand participates in the asymmetrydetermining step. Therefore, it is suggested that the phosphate-to-β-ketoester ligand exchange process seems to be the chemoselectivity-determining step in the two competitive
Table 1. Ligand Screening for Stereoselective CDC of βKetoesters 2 with 2-Naphthol 1aa
entry
ligand
product
temp (°C), time (h)
yieldb (%)
dr (er)c
3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3b 3c 3d 3e 3f 3g 3a
80, 3 rt, 18 50, 18 50, 14 50, 18 50, 16 50, 48 50, 90 50, 18 70, 72 50, 17 50, 14 50, 18 50, 16 50, 14 50, 18 50, 22 50, 72
80 e 32 82 91 89 80 70 73 78 85 52 58 73 67 87 73 31
46:54
L1 L1 L2 L3 L4 ent-L4 L6 L7 L8 L9 L5 L5 L3 L3 L3 L3 L4
d
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18f
43:57 64:36 83:17 88:12 20:80 75:25 80:20 75:25 80:20 32:68 34:66 37:63 24:76 27:73 23:77 88:12
General reaction conditions: (i) Fe(ClO4)3·H2O (5 mol %), L (15 mol %), CaCO3 (15 mol %) in PhCF3/HFIP (1:1, 1.0 mL) at 50 °C, 3 h; then (ii) 2a (0.1 mmol), 1a (0.15 mmol), t-BuOOt-Bu (0.15 mmol), from rt to 50 °C, 12−28 h. bIsolated yields after column chromatography. cdr and er were determined by HPLC (see the SI). d The reaction was carried out using FeCl3·6H2O in DCE as a solvent.8f eBINOL was obtained as the sole product; fThe reaction was carried out using dioxygen atmosphere (1 atm) as the oxidant. a
1).8f To develop an asymmetric version of this transformation, we examined a chiral anion strategy9 based on phosphoric acids10 derived from BINOLs.11,12 First, conditions used for the enantioselective oxidative coupling of 2-naphthols catalyzed by the chiral iron phosphate catalyst Fe[L1]3 [(5 mol %, Figure 2),
Figure 2. Phosphoric acid ligands (L).
t-BuOOt-Bu (1 equiv), PhCF3 (α,α,α-trifluorotoluene)/HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol, 1:1), room temperature] were explored.7 Under these conditions, only a homocoupling process took place, affording enantioenriched (R)-BINOL 4 as the sole product (entry 2).7 However, when the reaction temperature was elevated above 50 °C, the selectivity changed 2918
DOI: 10.1021/acs.orglett.7b01152 Org. Lett. 2017, 19, 2917−2920
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Organic Letters
between the two associated ligands (complex VI and then VII). The catalytic cycle is terminated by the release of the hemiacetal product, 3, via another ligand exchange process. The ability of Fe[phosphate]3 complexes to convert into two active catalysts (II and IV) through a ligand-exchange process that adjusts the number of anionic phosphate ligands according to the requirements of the asymmetric transformation is an important finding for future developments of asymmetric CDC transformations. The scope of the catalytic system was demonstrated by coupling various 2-naphthols, 1b−h, with β-ketoester 2a (Table 2). The reaction was found to be efficient for 2-naphthol
Scheme 2. Proposed Mechanisms for the Oxidative Homocoupling of 2-Naphthols7 and the CDC of 2Naphthols with β-Ketoesters by Iron Phosphates Complexes
Table 2. Asymmetric CDC of 2-Naphthols with 1 βKetoester 2a under Optimized Reaction Conditionsa entry d
1 2 3 4 5 6 7 8d
R
product
yieldb (%)
drc
H 6-nBu 6-iPr 6-Br 3-Br 6-CO2Me 6-(4-t-Bu)C6H4 6-(3,5-bisCF3)C6H3
3a 3h 3i 3j 3k 3l 3m 3n
72 71 79 57 77 63 73 77
89:11 88:12 88:12 82:18 87:13 85:15 89:11 90:10
a
General reaction conditions: (i) Fe(ClO4)3.H2O (5 mol %), L4 (15 mol %), CaCO3 (15 mol %) in PhCF3/HFIP (1:1, 1.0 mL) at 50 °C, 3 h; then (ii) 2a (0.1 mmol), 1 (0.15 mmol), t-BuOOt-Bu (0.15 mmol), rt to 50 °C, 14−96 h. bIsolated yields of cross-coupling product after column chromatography. cdr was determined by HPLC (see the SI). d The reaction was carried out on a 3 mmol scale.
derivatives that are substituted at the 6- and 3-positions, affording the corresponding coupling products 3h−n with good yields and high diastereoselectivity, ranging from 82:18 to 90:10 (entries 2−8). These results support the premise that steric and electronic changes at the 2-naphtholic component have only a minor effect over the stereoselectivity. On the other hand, as discussed previously, the alkyl ester group in the βketoester has a higher impact over the face selection during the C−C bond-forming step. To conclude, iron phosphate catalyzed asymmetric CDC between 2-naphthols 1 and β-ketoester derivatives 2 that affords polycyclic hemiacetals 3 was developed. On the basis of our mechanistic investigations, it is postulated that iron bearing a single phosphate ligand acts as the active redox catalyst in the stereoselectivity-determining step. Furthermore, our studies support the premise that the coupling takes place between two associated ligands via a radical−anion coupling mechanism. We intend to further explore the reactivity of the iron phosphate complexes in order to apply them as chiral redox catalysts in asymmetric CDC transformations.
Figure 3. (A) Nonlinear relationship study between the ee of the ligand (L4) and the de of the product 3a. (B) Enantioselective homocoupling of 2-naphthol 1a catalyzed by Fe[L1]3 in the presence or absence of β-ketoester 2b.
asymmetric transformations [homocoupling (via complex III, Scheme 2) vs cross-coupling (via complex IV)]. In order to probe this key step, the degrees of efficiency and enantioselectivity of the Fe[L1]3-catalyzed homocoupling of 2-naphthol (1a)7 at room temperature in the presence (circles, Figure 3) and absence (squares) of a competitive ligand (βketoester 2b) were monitored (for details, see the SI). The results clearly shows that the addition of β-ketoester 2b to the reaction at room temperature leads to a significant reduction in the rate of the homocoupling process (solid blue lines), whereas the enantiomeric excess of BINOL 4 is only slightly affected (dashed black lines). It is postulated that complexes II and IV (Scheme 2) are found in equilibrium at room temperature and the complex IV is an inferior catalyst compared with complex II in catalyzing the oxidative homocoupling of 2-naphthol. Furthermore, complex IV, which has a single phosphate and a β-ketoester ligand, undergoes a SET process to form complex V. This complex becomes reactive only at elevated temperatures (above 50 °C), mediating intramolecular oxidative radical-anion coupling
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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.7b01152. Experimental procedures and spectroscopic data of all new compounds (PDF) 2919
DOI: 10.1021/acs.orglett.7b01152 Org. Lett. 2017, 19, 2917−2920
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Doron Pappo: 0000-0002-8363-8709 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the financial support provided by the Israel Science Foundation (Grant No. 164/16). REFERENCES
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DOI: 10.1021/acs.orglett.7b01152 Org. Lett. 2017, 19, 2917−2920
