Asymmetric Michael Additions of 4-Hydroxycoumarin to Î²

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Asymmetric Michael Additions of 4-Hydroxycoumarin to betaNitrostyrenes with chiral, bifunctional Hydrogen-bonding Catalysts Florian F. Wolf, Helge Klare, and Bernd Goldfuss J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02167 • Publication Date (Web): 27 Jan 2016 Downloaded from http://pubs.acs.org on January 28, 2016

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The Journal of Organic Chemistry

Asymmetric Michael Additions of 4-Hydroxycoumarin to βNitrostyrenes with chiral, bifunctional Hydrogen-bonding Catalysts Florian F. Wolf, Helge Klare and Bernd Goldfuss*[a] [a]

F. F. Wolf, Dr. H. Klare, Prof. Dr. B. Goldfuss, Institut für Organische Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln (Germany), E-mail: [email protected]

Abstract Enantioselective Michael additions of 4-hydroxy-coumarin to β-nitrostyrenes are catalysed by different chiral, bifunctional hydrogen bonding catalysts, based on thioureaand squaramide motifs. The scope of the catalysis is tested by employing a series of substituted

β-nitrostyrenes

as

well

as

different

solvents.

The

3,5-

Bis(trifluoromethyl)phenyl- and quinine-substituted squaramide catalyst is shown to be the most selective catalyst resulting in 78% yield and 81 % ee. Computational analyses of transition structures with different binding modes show that the most favoured transition structure exhibits squaramide (NH)2-binding to an oxygen atom of the enolate nucleophile, while the nitro-alkene coordinates via hydrogen bonding to the ammonium function of the quinuclidine unit of the catalyst. Hence, the canted directionality of the squaramide (NH)2 motif, favouring one-atom-binding, might be decisive for the selectivity of the reaction. The absolute configuration of the major (-)-(R)-enantiomer of the product is assigned computationally according to its optical rotation.

1 ACS Paragon Plus Environment


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Introduction Hydrogen-bonding (HB) catalysis has emerged as a major tool in organocatalytic applications.1-5 (Thio-)urea derived catalysts proved to be highly efficient in many different reactions due to high selectivity and yields.6-12 Squaramide based catalysts developed more recently as alternative hydrogen-bonding scaffolds.13-16 The different and often superior performance of squaramide- vs. (thio)urea-based catalyst,17-21 can be explained with altered hydrogen bonding N-H alignments: In squaramides, these H-Hdistances are ca. 2.72 Å, compared to ca. 2.13 Å for thioureas.17-19 Squaramides also show increased NH acidities of 0.13-1.97 in pKa units relative to thioureas,20,21 supporting potentially stronger hydrogen-bonds.20,21 The directionality of NH-hydrogenbonds may however dominate the catalyst-substrate interaction more than the relative acidities,20,21 as is evident from comparative anion-receptor studies.22-24 Squaramides show more canted NH-groups compared to the nearly co-linear alignment of the NHgroups in (thio)ureas.13-16 Enantioselective Michael additions of 1,3-dicarbonyl compounds to β-nitroalkenes provide efficient pathways to γ-nitro carbonyl enantiomers, which can be used for further derivatizations.25,26 4-Hydroxycoumarin is an especially remarkable nucleophile for such enantioselective Michael additions, as the resulting 3-substituted 4-hydroxycoumarins are known to inhibit the enzyme vitamin-K-epoxide-reductase, preventing the normal metabolic vitamin K formation.27 The vitamin K-antagonist Warfarin serves as a most frequently employed anticoagulant and is also a rodenticide,29-33 similar as other 3substituted 4-hydroxycoumarins like Phenprocoumon,34 or Acenocoumarol.34. While chiral bifunctional thiourea catalysts were employed in Michael-additions for the synthesis of 3-substituted 4-hydroxycoumarins6-16, only an achiral protocol for the 2 ACS Paragon Plus Environment

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addition of 4-hydroxycoumarin 8 to β-nitrostyrene 9 with reaction conditions “on-water” is available, providing 3-substituted 4-hydroxy-coumarins 10 as racemates.25 Although the tandem Michael/cyclization of β-nitrostyrene and 4-hydroxycoumarin, catalysed by chiral, bifunctional thioureas is known, resulting in an oxim product,35 no squaramide catalysed reaction of those compounds has been reported so far. Recently, we developed alkalimetal-mediated amino-catalyses for enantioselective syntheses of 4-hydroxycoumarins with various Michael-systems.36 We also designed new cyclodiphosphazanes as hydrogen-bonding catalysts for enantioselective Michael additions of 4-naphtoquinone to β-nitroalkenes.37 In this work, we describe the scope of applications for chiral thiourea- and squaramide-hydrogen-bonding catalysts, based on enantiopure chinchona-(19, 2, 310, 5, 615, 716) and diamino-cyclohexane-(411) units, in enantioselective Michael-additions of 4hydroxy coumarin to various β-nitroalkenes, yielding 3-substituted 4-hydroxy coumarins.

Results and Discussion Hydrogen-bonding catalysts with the established thiourea- (19, 2, 310, 411, Figure 1) and squaramide- units (5, 615, 716, Figure 2) are employed in the Michael addition of 4hydroxycoumarin 8 to β-nitrostyrene 9a (Figure 3). Among the tested thiourea-catalysts (19, 2, 310, 411, Figure 1), catalyst 310 was most reactive (64% yield, Table 1), while catalyst 210 was the most selective (66% ee, Table 1). Among the tested squaramidecatalysts (5, 615, 716, Figure 2), 615 proves to be most reactive and highly selective (92% yield, 72% ee Table 1), while catalyst 515 is slightly less reactive but performs most selective (80% yield, 74% ee, Table 1).



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Figure 1. Thiourea based hydrogen-bonding catalysts (19, 2, 310, 411) employed in this study.

Hence, relative to the tested thiourea-catalysts, the squaramide catalysts (Figure 2) provide

increased

reactivities,

with

lower

reaction

times,

and

also

higher

enantioselectivities (Table 1). This superior catalytic performance of the squaramide systems agrees with a previous study,24,37 emphasizing its strong hydrogen bonding ability to nitrobenzene, compared to urea, thiourea, phosphorous triamides and cyclodiphosphazanes.

Figure 2. Squaramide based hydrogen-bonding catalysts (5, 615, 716]) employed in this study.


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Figure 3. Michael-addition of 4-hydroxycoumarin 8 to β-nitrostyrenes 9, providing 3-substituted 4-hydroxycoumarins 10 (Tables 2 and 3).

The high catalytic activity of the squaramide catalysts parallels also their higher NHacidities relative to thioureas.38 Table 1. Thiourea- (19, 2, 310, 411, Figure 1) and squaramidecatalysts (5, 615, 716, Figure 2) in the Michael-addition of 4hydroxycoumarin 8 to β-nitrostyrene 9a (Figure 3) at 20 °C. Catalyst 1 2 3 4 5 6 7

time [h:min] 6 6 6 6 1:30 1:30 2

yield [%] 55 60 64 54 80 92 70

ee [%] 64(R)[a,c] 66(R)[a.c] 48(R)[a,c] 47(R)[a,c] 74(R)[b,c] 72(R)[b,c] rac[b,c]

[a] determined by chiral HPLC analysis ((R,R)-Whelk O1 column) [b] determined by chiral HPLC analysis (Chiralcel AD-H column) [c] the R-configuration is assigned by correlation of computed and experimental optical (-)-rotation (Table 4).

To optimize the reaction conditions in the enantioselective Michael addition of 8 and 9a (Figure 3), the squaramide catalysts 5, 6 and 7 (Figure 2) are tested in different solvents and under varying temperatures.



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Table 2. Solvent screenings in the Michael-addition of 4-hydroxycoumarin 8 to β-nitrostyrene 9a employing catalysts 5, 615 and 716 (Figure 2). Entry

Catalyst[a]

Solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

5 5 5 6 6 6 6 6 6 6 6 6 6[d] 6[e] 7

1,4-diox 1,4-diox DCM DCM 1,2-DCE CDCl3 Et2O MeCN DMSO 1,4-diox 1,4-diox 1,4-diox 1,4-diox 1,4-diox 1,4-diox

Temperature [°C] 20 10 20 20 20 20 20 20 20 20 10 5 10 10 10

time [h] 1.5 3 1.5 1.5 1.5 1.5 4 3 3 1.5 3 3 3 3 3

yield [%] 70 75 67 45 68 90 72 70 n.d. 62 78 83 58 74 n.d.

ee[b,c] [%] 72(R) 77(R) 55(R) 52(R) 68(R) 68(R) 41(R) 45(R) rac 80(R) 81(R) 79(R) 79(R) 80(R) 5(S)

[a] 10 mol% catalyst loading [b] determined by chiral HPLC analysis (Chiralcel AD-H column) [c] the R-configuration is assigned by correlation of computed and experimental optical (-)-rotation (Table 4) [d] 5 mol% catalyst loading [e] 20 mol% catalyst loading.

A strong dependence on the solvent, with ee’s varying from 41%ee in diethyl ether to 80%ee in 1,4-dioxane is apparent at room temperature (Table 2). Variation of the reaction temperature only slightly influences the selectivity of catalyst 615 in 1,4-dioxane, while the yields rise from 62% at 20°C to 83% at 5 °C (Table 2, entries 10 and 12). The influence of the catalyst loading on the reaction is examined by using 5 mol% (Table 2, entry 13) and 20 mol% (Table 2, entry 14) of catalyst 615. While the yields decrease to 58% for 5 mol% and 74% for 20 mol% catalyst loading, the enantiomeric excess is only slightly altered (Table 2).


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The optimized reaction conditions are applied with catalyst 615 in Michael additions of 8 to different β-nitro-styrenes 939,40 (Table 3). Relative to unsubstituted 10a, lower selectivities, ranging from 53% ee for a chloro substituent in o-position (10d) to 75% ee for either a methoxy- (10e) or bromo-substituent (10f) in p-position of the aromatic compound are apparent (Table 3). Table 3. Michael-addition of 4-hydroxycoumarin 8 to βnitrostyrenes 9 catalysed by squaramide 615 (Figures 2 and 3)[a]. Product 10a 10b 10c 10d 10e 10f 10g 10h 10i

Styrene X Y Z H H H H H OMe H Br H Cl H H OMe H H Br H H NO2 H H CN H H NMe2 H H

yield [%]

ee[b,c] [%]

78 55 49 69 59 93 41

Asymmetric Michael Additions of 4-Hydroxycoumarin to Î²

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