Enantioselective Henry Reaction Catalyzed by Copper(II) Complex of Bis(Trans-Cyclohexane-1,2-Diamine)-Based Ligand

catalysts

Article Enantioselective Henry Reaction Catalyzed by Copper(II) Complex of Bis(trans-cyclohexane-1,2-diamine)-Based Ligand

David Tetour, Marika Novotná and Jana Hodaˇcová *

Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic; [email protected] (D.T.); [email protected] (M.N.) * Correspondence: [email protected]; Tel.: +420-220-444-173

Abstract: Copper(II) complex of the ligand possessing two enantiomerically pure trans-cyclohexane- 1,2-diamine units proved to be an efﬁcient catalyst for the enantioselective Henry reaction of aromatic aldehydes with nitromethane. The effect of various reaction conditions on yield and enantioselectivity of the Henry reaction was studied. The results suggest that only one cyclohexane-1,2-diamine unit is involved in catalysis of the Henry reaction.

Keywords: Henry reaction; enantioselective catalysis; trans-cyclohexane-1,2-diamine; copper(II) complexes

1. Introduction Base-catalyzed nucleophilic addition of nitroalkane to carbonyl compound is an important carbon–carbon bond-forming reaction [1–3]. The reaction is named Henry reaction according to its discoverer [4] and because of its similarity with the aldol reaction it is also referred as the nitroaldol reaction. A significant feature of the Henry reaction is a possibility to conduct the reaction enantio- or diastereoselectively. Chiral products of Citation: Tetour, D.; Novotná, M.; the Henry reaction, 2-nitroalcohols, are important intermediates in syntheses of many Hodaˇcová,J. Enantioselective Henry biologically active compounds, such as antiasthmatic drug (R)-salmeterol [5], antibiotics Reaction Catalyzed by Copper(II) L-acosamine [6] and bestatin [7], or fungicide (S)-spirobrassinin [8]. In the past, develop- Complex of Bis(trans-cyclohexane-1, ment of the field of stereoselective Henry reaction had been rather slow [9]. One major 2-diamine)-Based Ligand. Catalysts 2021, 11, 41. https://doi.org/ obstacle is that the reaction components, nitroalkane and a carbonyl compound, lack of 10.3390/catal11010041 suitable points for attachment of chiral auxiliaries. In addition, the reversible nature of the reaction and relatively easy racemization at the stereogenic center (located at the α-position Received: 2 December 2020 to the nitro group) have hampered the progress in stereocontrol of the Henry reaction. Accepted: 28 December 2020 In general, enantioselectivity of the reaction can be controlled by chirality of a substrate, Published: 31 December 2020 chiral auxiliary, or catalyst. Among these approaches, employment of the chiral catalyst is highly advantageous since the usually expensive and heavily accessible enantiomerically Publisher’s Note: MDPI stays neu- pure compound is used in less than stoichiometric amount. tral with regard to jurisdictional clai- The first catalyst-controlled enantioselective Henry reaction was reported by Shibasaki [10] ms in published maps and institutio- in 1992. A large number of catalysts capable of catalyzing the nitroaldol reaction enan- nal affiliations. tioselectively has been developed since then, including both metal catalysts [11] and organocatalysts [12]. For example, copper(II) complexes of bis(oxazolidine) ligands [13], lanthanide complexes of 1,10-binaphthalene-2,20-diol derivatives [14], dinuclear zinc(II) complexes of C -symmetric alcohols [15], and copper(II) complexes of chiral ethane-1,2- Copyright: © 2020 by the authors. Li- 2 censee MDPI, Basel, Switzerland. diamine derivatives [16,17] were successfully used in the metal-based catalysis. Chiral This article is an open access article guanidines [18], bis(thioureas) [19,20] or cinchona alkaloids [21] can serve as examples of distributed under the terms and con- efficient organocatalysts. ditions of the Creative Commons At- Recently, mononuclear copper complexes of secondary amines derived from enan- tribution (CC BY) license (https:// tiomerically pure trans-cyclohexane-1,2-diamine have been reported to achieve modest creativecommons.org/licenses/by/ to excellent enantioselectivities in the Henry reaction [22–30]. Zhang et al. [31] have de- 4.0/). veloped efficient binuclear copper(II) complex of the C2-symmetric ligand, in which two

Catalysts 2021, 11, 41. https://doi.org/10.3390/catal11010041 https://www.mdpi.com/journal/catalysts Catalysts 2021,, 11,, 41x FOR PEER REVIEW 2 of 10 Catalysts 2021, 11, x FOR PEER REVIEW 2 of 10

oped efficient binuclear copper(II) complex of the C2-symmetric ligand, in which two chiraloped efficientβ-amino binuclearalcohols arecopper(II) connected complex at the of 1,4-positions the C2-symmetric to the ligand,central benzenein which ring. two Theirchiral βbinuclearβ-amino-amino alcoholsalcohols complex are are connectedexhibited connected atsignifican theat the 1,4-positions 1,4-positionstly higher to theenantioselectivities to centralthe central benzene benzene ring. over Theirring. the mononuclearTheirbinuclear binuclear complex one. complex exhibitedBased onexhibited signiﬁcantly these published significan higher results,tly enantioselectivities higher we decidedenantioselectivities overto prepare the mononuclear overligand the 1 possessingmononuclearone. Based two on one. thesetrans- Basedcyclohexane-1,2-diamine published on these results, published we decided unitsresults, attached to we prepare decided to ligandthe centralto 1preparepossessing benzene ligand unit two 1 trans (Figurepossessing-cyclohexane-1,2-diamine 1) and two study trans- cyclohexane-1,2-diaminethe effect unitsof the attached second tometalunits the attached centralcenter in benzene to the the binuclear central unit (Figure benzene complex1) andunit on study the effect of the second metal center in the binuclear complex on catalytic activity catalytic(Figure 1) activity and study and enantioselectivitythe effect of the secondof the Henry metal reaction.center in the binuclear complex on catalyticand enantioselectivity activity and enantioselectivity of the Henry reaction. of the Henry reaction.

NH HN NH HN NH HN NH HN

1 1

Figure 1. Structure of ligand 1. Figure 1. Structure of ligand 1. 2. Results Results 2. Results 2.1. Synthesis Synthesis of of Ligand Ligand 1 2.1. Synthesis of Ligand 1 Preparation ofof ligandligand1 1was was previously previously published published by by Bellemin-Laponnaz Bellemin-Laponnaz et al. et [ 32al.] and[32] andwe used wePreparation used the same the of syntheticsame ligand synthetic 1 strategy was previouslystrategy with some with published experimental some experimentalby Bellemin-Laponnaz modifications. modifications. The et synthesis al. The[32] synthesisandstarted we from used started (1 theS,2 from Ssame)-trans (1 syntheticS-cyclohexane-1,2-diamine,,2S)-trans strategy-cyclohexane-1,2-diamine, with some which experimental was which first monoprotected wasmodifications. first monopro- withThe tectedsynthesisthe tert with-butoxycarbonyl started the tert from-butoxycarbonyl (1 groupS,2S)-trans [33].-cyclohexane-1,2-diamine, Carbamate group [33].2 wasCarbamate condensed 2 whichwas with condensed was terephthaldehyde, first monopro- with ter- tected with the tert-butoxycarbonyl group [33]. Carbamate 2 was condensed with terephthaldehyde,and the resulting and Schiff the resulting base 3 was Schiff reduced base 3 with wasNaBH reduced4. Thewith obtained NaBH4. The amine obtained4 was amineephthaldehyde,deprotected 4 was anddeprotected and tetraamine the resultingand5 wastetraamine condensedSchiff 5base was with 3 condensed was two reduced molar with equivalents with two NaBH molar of4 .equivalents benzaldehydeThe obtained of amine 4 was deprotected and tetraamine 5 was condensed with two molar equivalents of benzaldehydeto give Schiff base, to give whose Schiff two base, imine whose double tw bondso imine were double finally bonds reduced were with finally NaBH reduced4 giving benzaldehyde to give Schiff base, whose two imine double bonds were finally reduced withligand NaBH1 in 36%4 giving overall ligand yield 1 in (Scheme 36% overall1). yield (Scheme 1). with NaBH4 giving ligand 1 in 36% overall yield (Scheme 1).

OHC CHO NH2 Boc2O NH2 NaBH4 NH Boc O NH OHC CHO N N NaBH 2 2 2 N N 4 NH NH 2 80 % Boc 80 % NH HN 95 % NH NH 2 80 % Boc 80 % NHBoc BocHN 95 % 2 Boc Boc 2 3 3

CHO CHO 1. 1. TFA NH HN 1. 1. TFA NH HN NH HN ligand 1 NH HN NH HN ligand 1 2. KOH NH H N 2. NaBH4 NH HN 2 2 Boc Boc 2. KOH NH H N 2. NaBH4 Boc Boc 98 %2 2 59 % 4 98 %5 59 % 4 5

Scheme 1. Synthesis of ligand 1. Scheme 1. Synthesis of ligand 1. Contrary to original authors [32], [32], we had to isolate and carefully purify all all interme- diatesContrary in in the the reaction reaction to original sequence. sequence. authors If Ifcrude[32], crude we intermediates intermediateshad to isolate were and were used carefully used in subsequent in purify subsequent all steps, interme- steps, we we were not able to obtain ligand 1 in sufﬁcient purity. werediates not in theable reaction to obtain sequence. ligand 1 Ifin crude sufficient intermediates purity. were used in subsequent steps, we were not able to obtain ligand 1 in sufficient purity. 2.2. Catalytic Studies of the Henry Reaction 2.2. Catalytic Studies of the Henry Reaction 2.2. CatalyticThe reaction Studies of benzaldehydeof the Henry Reaction with 10 molar equivalents of nitromethane was selected for initialThe reaction experiments of benzaldehyde to elucidate with the catalytic10 molar activityequivalents of the of copper(II)nitromethane complex was se- of lectedThe for reactioninitial experiments of benzaldehyde to elucidate with 10the mo catalyticlar equivalents activity of of the nitromethane copper(II) complex was se- lectedligand for1 in initial the Henryexperiments reaction. to elucidate The copper(II) the catalytic complexes activity were of the generated copper(II) in complex situ by ofmixing ligand the 1 appropriatein the Henry amount reaction. of ligandThe copper(II) and copper(II) complexes salt priorwereto generated the Henry in reaction. situ by mixingof ligand the 1 appropriatein the Henry amount reaction. of ligandThe copper(II) and copper(II) complexes salt prior◦ were to generated the Henry in reaction. situ by Aftermixing the the complex appropriate formation, amount the of ligand solution and was copper(II) cooled tosalt 0 priorC and to the benzaldehyde Henry reaction. and Afternitromethane the complex were formation, added. At the endsolution of the was reaction, cooled the to product0 °C and was benzaldehyde isolated by columnand ni- After the complex formation, the solution was cooled to 0 °C and benzaldehyde and ni-

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tromethane were added. At the end of the reaction, the product was isolated by column chromatography and the enantiomer ratio was determined by HPLC on a column with chiralchromatography stationary phase. and the Isolated enantiomer yield is ratio reported was determined throughout bythe HPLC article. on a column with chiralIn stationary the first experiments, phase. Isolated the yield effect is of reported ligand: throughoutcopper(II) ratio the article.on enantioselectivity of the reactionIn the ﬁrst was experiments, studied using the Cu(OAc) effect of2·2H ligand:2O as copper(II) a source of ratio copper on enantioselectivity(II) ions and ethanol of asthe a reactionsolvent (Table was studied 1). using Cu(OAc)2·2H2O as a source of copper(II) ions and ethanol as a solvent (Table1). Table 1. Effect of molar ratios ligand 1: copper(II) acetate: benzaldehyde on the reaction of ben- Tablezaldehyde 1. Effect with of nitromethane molar ratios liganda. 1: copper(II) acetate: benzaldehyde on the reaction of benzaldehyde with nitromethane a. Cu(OAc) .2H O 2 2 OH ligand 1 O NO + CH3NO2 2 EtOH, 0 °C, 48 h

Ligand 1 Cu(OAc)2·2H2O Molar Ratio Yield c e.e. d Entry b b c d [molarLigand %] 1 Cu(OAc)[molar2·2H %]2O Molar RatioLigand 1:Cu(II)Yield [%] e.e. [%] Entry b b 1 [molar20 %] [molar %] - Ligand 1:Cu(II) - [%] - [%] - 21 - 20 - 20 ------32 20 - 20 20 - 1:1 - 71 - 91 3 20 20 1:1 71 91 4 10 20 1:2 39 86 4 10 20 1:2 39 86 55 2 2 20 20 1:10 1:10 23 23 87 87 66 20 20 200 200 1:10 1:10 69 69 84 84 77 5 5 5 5 1:1 1:1 40 40 89 89 88 10 10 10 10 1:1 1:1 46 46 88 88 a ◦ b a ReactionReaction conditions: conditions: benzaldehyde benzaldehyde (0.2 (0.2 mmol), mmol), nitromethane nitromethane (2 mmol), (2 mmol), ethanol (2.0ethanol mL), 0(2.0C, mL), 48 h. 0 Related°C, 48 c d h.to b benzaldehyde.Related to benzaldehyde.Isolated yield. c IsolatedDetermined yield. by d Determined HPLC on a column by HPLC with chiralon a column stationary with phase. chiral stationary phase. The temperature of 0 ◦C was chosen based on the results of a preliminary reaction screening.The temperature Low enantioselectivity of 0 °C was waschosen observed based on at 20the◦ C,results and theof a reaction preliminary was tooreaction slow screening.at temperatures Low enantioselectivity below 0 ◦C. The reaction was observed mixtures at 20 consisted °C, andmerely the reaction of 2-nitroalcohol was too slow and at temperaturesunreacted benzaldehyde below 0 °C. inThe all reaction experiments. mixtur Ases consisted can be seen merely from of Table 2-nitroalcohol1, ligand 1andor unreactedcopper(II) acetatebenzaldehyde alone (Table in all1 ,experiments. entries 1 and As 2) doescan be not seen catalyze from the Table reaction. 1, ligand Because 1 or copper(II)ligand 1 contains acetate twoalone binding (Table 1, sites entries for the 1 and coordination 2) does not of catalyze copper(II) the ions,reaction. the catalyticBecause propertiesligand 1 contains of complexes two binding prepared sites at for different the coordi ratiosnation of ligand of copper(II)1 to Cu(OAc) ions,2 ·the2H 2catalyticO were propertiesstudied (Table of complexes1, entries 3–6).prepared At first, at different concentration ratios of of the ligand Cu(II) 1 to ions Cu(OAc) was kept2·2H constant2O were (20studied molar (Table %) and 1, theentries desired 3–6). ratio At first, was concen achievedtration by decreasing of the Cu(II) the concentrationions was kept ofconstant ligand 1(20(Table molar1, entries%) and 3–5).the desired The highest ratio was yield achiev of theed product by decreasing and the the best concentration enantioselectivity of lig- wereand 1achieved (Table 1, forentries a 1:1 3–5). ratio The (Table highest1, entry yield 3). Whenof the theproduct ligand and1: the Cu(II) best ratios enantioselec- of 1:2 or 1:10tivity were were used achieved (Table for1, entries a 1:1 ratio 4 or (Table 5), yield 1, ofentry the Henry3). When reaction the ligand significantly 1: Cu(II) dropped ratios of 1:2down or but1:10 onlywere a used very small(Table decrease 1, entries in 4 enantioselectivity or 5), yield of the was Henry observed. reaction If wesignificantly consider droppedthat only down one copper(II) but only iona very in the small dinuclear decrease complex in enantioselectivity might be catalytically was observed. active, If then we consideractual concentration that only one of thecopper(II) “catalytically ion in activethe dinuclear site” could complex decrease might as we be proceed catalytically from theac- tive,entry then 3 to entryactual5 concentration in Table1. A lower of the concentration "catalytically ofactive the “catalyticallysite" could decrease active site” as we might pro- ceedlead tofrom a lower the entry reaction 3 to entry yield. 5 Therefore, in Table 1. another A lower experiment concentration was of performed, the "catalytically in which ac- tiveconcentration site" might of lead ligand to a1 waslower kept reaction constant yield. (compared Therefore, with another the entry experiment 3 in Table was1) andper- formed,the desired in which ligand: concentration Cu(II) ratio of was ligand achieved 1 was bykept increasing constant the(compared concentration with the of entry Cu(II) 3 inions Table (Table 1) 1and, entry the 6).desired In that ligand: case, yieldCu(II) of ra thetio was reaction achieved was almostby increasing the same the as concen- in the trationexperiment of Cu(II) using ions a ligand (Table1: 1, Cu(II) entry ratio 6). In 1:1 that and case, 20 molar yield %of of the both reaction components was almost (Table the1, sameentry as 3). in In the addition, experiment the effect using of a complexligand 1: concentrationCu(II) ratio 1:1 was and studied 20 molar for % the of 1:1both ligand: com- ponentscopper(II) (Table ratio 1, (Table entry1 ,3). entries In addition, 7 and 8). the The effect results of complex indicate concentration that the concentration was studied of forthe the copper(II) 1:1 ligand: complex copper(II) in the ratio reaction (Table mixture 1, entries has 7 little and effect8). The on results enantioselectivity indicate that butthe significantly affects yield of the Henry reaction. concentration of the copper(II) complex in the reaction mixture has little effect on enan- To find optimal reaction conditions, three different solvents and three different cop- tioselectivity but significantly affects yield of the Henry reaction. per(II) salts were tested (Table2). To find optimal reaction conditions, three different solvents and three different copper(II) salts were tested (Table 2).

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Table 2. Effect of counteranion and solvent on the reaction of benzaldehyde with nitromethane catalyzedTable 2. Effect by the of 1:1 counteranion ligand 1: Cu(II) and complex solvent a on. the reaction of benzaldehyde with nitromethane catalyzed by the 1:1 ligand 1: Cu(II) complex a. Cu(II) salt (20 mol %) OH ligand 1 (20 mol %) O NO + CH3NO2 2 solvent

Temperature Entry Cu(II) Salt Solvent Reaction Time [h] Yield c [%] e.e. d [%] [°C] Temperature Reaction Yield c e.e. d Entry Cu(II) Salt Solvent ◦ 1 Cu(OAc)2·2H2O EtOH 0 [ C] 48 Time [h] 71[%] [%] 91

2 1CuCl Cu(OAc)2 2·2HEtOH2O EtOH 0 0 48 48 38 71 9391 3 b 2Cu(ClO4)2·6H CuCl2O 2EtOH EtOH 0 0 - 48 - 38 93 - b 3 Cu(ClO4)2·6H2O EtOH 0 - - - 4 Cu(OAc)2·2H2O THF 0 72 60 92 4 Cu(OAc)2·2H2O THF 0 72 60 92 5 CuCl2 THF 0 72 0 - 5 CuCl2 THF 0 72 0 - 6 6CuCl2 CuCl2 THF THF 25 25 336 336 38 38 75 7 7Cu(ClO Cu(ClO4)2·6H2O4) 2·6HTHF2O THF 0 0 72 72 0 0 - 8 Cu(ClO ) ·6H O THF 25 336 4 20 8 Cu(ClO4)2·6H2O4 2 THF2 25 336 4 20 9 Cu(OAc)2·2H2O EtOAc 0 48 14 90 9 Cu(OAc)2·2H2O EtOAc 0 48 14 90 10 CuCl2 EtOAc 0 72 7 91 b 2 1011 CuClCu(ClO 4)2·EtOAc6H2O EtOAc 0 0 72 - 7 - 91 - b 11a Reaction Cu(ClO conditions:4)2·6H2 benzaldehydeO EtOAc (0.5 mmol), 0 nitromethane (5 mmol), - ligand 1 (0.1 - mmol), Cu(II) - salt a Reaction(0.1 mmol), conditions: solvent (4.3 benzaldehyde mL). b Insoluble (0.5 complex mmol), formed. nitromethanec Isolated yield. (5 mmol),d Determined ligandby 1 (0.1 HPLC mmol), on a column Cu(II)with chiralsalt (0.1 stationary mmol), phase. solvent (4.3 mL). b Insoluble complex formed. c Isolated yield. d Determined by HPLC on a column with chiral stationary phase. Copper(II) perchlorate formed an insoluble complex with ligand 1 in both ethanol and ethylCopper(II) acetate. perchlorate In such case, formed no productan insoluble formation complex was with observed. ligand Copper(II) 1 in both ethanol acetate andproved ethyl to beacetate. the best In sourcesuch case, of the no copper(II) product ions,formation and the was Henry observed. reaction Copper(II) proceeded acetate faster provedin ethanol to thenbe the in best tetrahydrofuran source of the or coppe ethyl acetater(II) ions, (Table and2 ,the entry Henry 1). Therefore, reaction proceeded those two fasterreagents in wereethanol used then in allin subsequenttetrahydrofuran experiments. or ethyl acetate (Table 2, entry 1). Therefore, thoseThe two abovereagents mentioned were used results in all subsequent confirmed thatexperiments. the copper(II) complex of ligand 1 catalyzesThe above the Henry mentioned reaction results of benzaldehyde confirmed that with the nitromethanecopper(II) complex giving of (ligandR)-2-nitro-1- 1 cat- alyzesphenylethanol the inHenry good yieldreaction and highof enantioselectivity.benzaldehyde However,with nitromethane the reaction isgiving rather (slow.R)-2-nitro-1-phenylethanol In order to speed-up the in reaction,good yield influence and high of aenantioselectivity. base additive was However, explored. the Many re- actionsuccessful is rather catalytic slow. systems In order catalyzing to speed-up the enantioselective the reaction, influence Henry reactionof a base contain additive achiral was explored.base [11,23 Many,26,34 ].successful Therefore, catalytic the effect systems of a base catalyzing addition the to the enantioselective Cu(II) complex Henry of ligand reac-1 tionhas beencontain studied achiral in base the reaction[11,23,26,34]. of benzaldehyde Therefore, the with effect nitromethane. of a base addition Three to bases the Cu(II) were complextested as of an ligand additive: 1 hasN ,beenN-diethylethanamine studied in the reaction (TEA), ofN benzaldehyde-ethyl-N-(propan-2-yl)propan-2- with nitromethane. Threeamine (DIPEA),bases andwere pyrrolidine tested (Tableas an3). additive: N,N-diethylethanamine (TEA), N-ethyl-TheN results-(propan-2-yl)propan-2-amine summarized in Table3 suggest(DIPEA), that and addition pyrrolidine of an (Table achiral 3). base led to a decrease in enantioselectivity. The best result was obtained in the experiment with 10Table molar 3. Influence % of DIPEA of a base added addition (Table on 3the, entry reaction 4). of In benzaldehyde this case, the with product nitromethane was obtained a catalyzed in byhigher the copper(II) yield but complex enantiomeric of ligand excess 1. decreased by 3% compared to the reaction performed in the absence of base (Table3, entry 1). The addition of TEA or pyrrolidine did not help Cu(OAc) .2H O (20 mol %) accelerate the reaction. 2 2 OH ligand 1 (20 mol %) NO Since the best catalyticO efficiency in the Henry reaction of benzaldehyde2 with ni- + CH3NO2 tromethane was observed for the catalytic systembase ligand 1: Cu(OAc)2·2H2O (1:1) in ethanol at 0 ◦C, the effect of the aldehyde structure was studied under these conditions (Table4). EtOH, 0 °C, 72 h Yield c e.e. d Entry Base Molar Equiv. of Base b [%] [%] 1 - - 74 88 2 TEA 0.1 75 83 3 TEA 1.0 66 78 4 DIPEA 0.1 83 85 5 DIPEA 1.0 89 60

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Table 2. Effect of counteranion and solvent on the reaction of benzaldehyde with nitromethane catalyzed by the 1:1 ligand 1: Cu(II) complex a.

Cu(II) salt (20 mol %) OH ligand 1 (20 mol %) O NO + CH3NO2 2 solvent

Temperature Entry Cu(II) Salt Solvent Reaction Time [h] Yield c [%] e.e. d [%] [°C] 1 Cu(OAc)2·2H2O EtOH 0 48 71 91 2 CuCl2 EtOH 0 48 38 93 3 b Cu(ClO4)2·6H2O EtOH 0 - - - 4 Cu(OAc)2·2H2O THF 0 72 60 92 5 CuCl2 THF 0 72 0 - 6 CuCl2 THF 25 336 38 75 7 Cu(ClO4)2·6H2O THF 0 72 0 - 8 Cu(ClO4)2·6H2O THF 25 336 4 20 9 Cu(OAc)2·2H2O EtOAc 0 48 14 90 10 CuCl2 EtOAc 0 72 7 91 11 b Cu(ClO4)2·6H2O EtOAc 0 - - - a Reaction conditions: benzaldehyde (0.5 mmol), nitromethane (5 mmol), ligand 1 (0.1 mmol), Cu(II) salt (0.1 mmol), solvent (4.3 mL). b Insoluble complex formed. c Isolated yield. d Determined by HPLC on a column with chiral stationary phase.

Copper(II) perchlorate formed an insoluble complex with ligand 1 in both ethanol and ethyl acetate. In such case, no product formation was observed. Copper(II) acetate proved to be the best source of the copper(II) ions, and the Henry reaction proceeded faster in ethanol then in tetrahydrofuran or ethyl acetate (Table 2, entry 1). Therefore, those two reagents were used in all subsequent experiments. The above mentioned results confirmed that the copper(II) complex of ligand 1 catalyzes the Henry reaction of benzaldehyde with nitromethane giving (R)-2-nitro-1-phenylethanol in good yield and high enantioselectivity. However, the reaction is rather slow. In order to speed-up the reaction, influence of a base additive was explored. Many successful catalytic systems catalyzing the enantioselective Henry reaction contain achiral base [11,23,26,34]. Therefore, the effect of a base addition to the Cu(II) complex of ligand 1 has been studied in the reaction of benzaldehyde with nitromethane. Catalysts 2021, 11, 41 Three bases were tested as an additive: N,N-diethylethanamine (TEA),5 of 10 N-ethyl-N-(propan-2-yl)propan-2-amine (DIPEA), and pyrrolidine (Table 3).

Table 3. Influence of a base addition on the reaction of benzaldehyde with nitromethane a catalyzed a byTable the 3.copper(II)Inﬂuence complex of a base of addition ligand 1 on. the reaction of benzaldehyde with nitromethane catalyzed Catalysts 2021, 11, x FOR PEER REVIEWby the copper(II) complex of ligand 1. 5 of 10 Cu(OAc)2.2H2O (20 mol %) OH ligand 1 (20 mol %) NO 6 pyrrolidineO 0.1 452 83 + CH3NO2 7 pyrrolidine base 1.0 36 74 a Reaction conditions: benzaldehyde (0.2 mmol), nitromethane (2 mmol), ligand 1 (0.04 mmol), EtOH, 0 °C, 72 h copper(II) acetate (0.04 mmol), ethanol (2.0 mL), 0 °C, 72 h. b Related to benzaldehyde. c Isolated yield. d Determined by HPLC on a column with chiral stationary phase. Yield c e.e. d Entry Base Molar Equiv. of Base b Yield c [%] e.e. d[%] Entry Base Molar Equiv. of Base b 1The results summarized- in Table 3 suggest that - addition of[%] an achiral 74 base [%] led88 to a decrease2 1 in enantioselectivity.TEA - The best resu -lt was 0.1 obtained in 74 the experiment 75 88 with83 10 molar3 %2 of DIPEATEA added TEA (Table 3, entry 0.14). In 1.0 this case, the 75product was 66 obtained 83 78 in 3 TEA 1.0 66 78 higher4 yield butDIPEA enantiomeric excess decreased 0.1 by 3% compared to the 83 reaction 85 performed 4in the absence DIPEA of base (Table 3, entry 0.1 1). The addition of 83 TEA or pyrrolidine 85 did 5 5DIPEA DIPEA 1.0 1.0 89 89 60 60 not help accelerate the reaction. 6 pyrrolidine 0.1 45 83 Since7 the best pyrrolidinecatalytic efficiency in the 1.0 Henry reaction of 36 benzaldehyde 74with nitromethane was observed for the catalytic system ligand 1: Cu(OAc)2·2H2O (1:1) in eth- a Reaction conditions: benzaldehyde (0.2 mmol), nitromethane (2 mmol), ligand 1 (0.04 mmol), copper(II) acetate anol(0.04 at mmol), 0 °C, ethanol the effect (2.0 mL), of the 0 ◦C, aldehyde 72 h. b Related structure to benzaldehyde. was studiedc Isolated under yield. thesed Determined conditions by HPLC (Ta- bleon 4). a column with chiral stationary phase.

Table 4. Effect of the aldehyde structure on yield and enantioselectivity of the Henry reaction a. Table 4. Effect of the aldehyde structure on yield and enantioselectivity of the Henry reaction a.

Cu(OAc)2.2H2O (20 mol %) ligand 1 (20 mol %) OH RCHO + CH3NO2 NO R 2 EtOH, 0 °C, 48 h Yield b e.e. c Entry Aldehyde Yield b e.e. c Entry Aldehyde [%] [%] 1 4-bromobenzaldehyde [%] 82 [%] 75 2 1 4-bromobenzaldehyde4-methylbenzaldehyde 82 68 75 85 3 2 4-methylbenzaldehyde4-nitrobenzaldehyde 68 50 85 85 3 4-nitrobenzaldehyde 50 85 4 4 2-methylpropanal2-methylpropanal 18 18 85 85 5 5 hexanalhexanal 12 12 85 85 6 6 cyclohexanecarbaldehydecyclohexanecarbaldehyde 21 21 83 83 7 7 3-phenylpropanal3-phenylpropanal 25 25 88 88 a Reactiona Reaction conditions: conditions: aldehydealdehyde (0.2 (0.2 mmol), mmol), nitromethane nitromethane (2 mmol), (2 mmol), ligand ligand1 (0.04 1 mmol), (0.04 mmol), copper(II) cop- acetate ◦ b c per(II)(0.04 mmol),acetate ethanol (0.04 mmol), (2.0 mL), ethanol 0 C, 48 (2.0 h. mL),Isolated 0 °C, yield. 48 h. b DeterminedIsolated yield. by HPLCc Determined on a column by HPLC with chiral on a columnstationary with phase. chiral stationary phase.

The results of this study indicate that both aromaticaromatic andand aliphaticaliphatic aldehydesaldehydes gavegave relatively goodgood enantioselectivities.enantioselectivities. However, However, yield yield of theof the Henry Henry reaction reaction was signiﬁcantlywas signifi- cantlylower whenlower when the starting the starting aldehyde aldehyde was thewas aliphatic the aliphatic one. one. Among Among all all studied studied aldehy- alde- hydes,des, 4-bromobenzaldehyde 4-bromobenzaldehyde exhibited exhibited the the highest highest yield yield but but the the lowest lowest enantioselectivity. enantioselectiv- Theity. The presence presence of an of electron-donating an electron-donating group group in the inpara the-position para-position of the of aromatic the aromatic aldehyde al- dehydeappears appears to have ato positive have a positive effect on effect the reaction on the reaction yield. yield. 3. Discussion 3. Discussion The present study of the catalytic properties of the copper(II) complexes of The present study of the catalytic properties of the copper(II) complexes of bis(trans-cyclohexane-1,2-diamine)-based ligand 1 answered a question of whether the sec- bis(trans-cyclohexane-1,2-diamine)-based ligand 1 answered a question of whether the ond copper (II) ion in the dinuclear copper(II) complex might somehow contribute to catal- second copper (II) ion in the dinuclear copper(II) complex might somehow contribute to ysis of the enantioselective Henry reaction. A comparison of our preliminary results with catalysis of the enantioselective Henry reaction. A comparison of our preliminary results the catalytic properties of the copper(II) complexes of (1R,2R)-N,N0-dibenzylcyclohexane- with the catalytic properties of the copper(II) complexes of 1,2-diamine (6, Figure2) published in the literature [ 22,23] raised expectations that second (1R,2R)-N,N’-dibenzylcyclohexane-1,2-diamine (6, Figure 2) published in the literature copper(II) ion might participate in the catalytic process. [22,23] raised expectations that second copper(II) ion might participate in the catalytic process.

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Catalysts 2021, 11, x FOR PEER REVIEW 6 of 10

NH HN

FigureFigure 2.2. StructureStructure ofof ligandligand 66..

DiamineDiamine6 6is is structurally structurally similar similar to ligandto ligand1 but 1 but possess possess only only one enantiomericallyone enantiomerically pure cyclohexane-1,2-diaminepure cyclohexane-1,2-diamine unit. Inunit. 2007, In Bandini2007, Bandini et al. [22et ]al. reported [22] reported only 56% only conversion 56% con- andversion 51% and e.e. 51% in the e.e. reaction in the reaction of benzaldehyde of benzaldehyde with nitromethane with nitromethane catalyzed catalyzed by 12% by of 12% the Cu(OAc) -6 catalyst. The reaction was carried out in ethanol at room temperature for of the Cu(OAc)2 2-6 catalyst. The reaction was carried out in ethanol at room temperature 1.2for h.1.2 Later, hours. Jeong Later, et Jeong al. [23 ]et published al. [23] published the same the reaction same catalyzedreaction catalyzed by 10% of by the 10% CuCl of 2the-6 complex with the addition of 6% of achiral base. They run the reaction in methanol at CuCl2-6 complex with the addition of 6% of achiral base. They run the reaction in meth- room temperature for one week using TEA as an additional base and isolated (S)-2-nitro- anol at room temperature for one week using TEA as an additional base and isolated 1-phenylethanol in 53% yield and 39% e.e. Significantly higher enantioselectivities (in (S)-2-nitro-1-phenylethanol in 53% yield and 39% e.e. Significantly higher enantioselec- the range of 85–90% e.e.) were observed in our preliminary experiments, in which we tivities (in the range of 85–90% e.e.) were observed in our preliminary experiments, in catalyzed the same reaction with the Cu(OAc)2-1 complex. which we catalyzed the same reaction with the Cu(OAc)2-1 complex. However, our further studies (Table1) revealed that the best results were obtained However, our further studies (Table 1) revealed that the best results were obtained for the ligand 1: copper(II) acetate ratio = 1:1, where the mononuclear complex is the main for the ligand 1: copper(II) acetate ratio = 1:1, where the mononuclear complex is the main catalytic species. This observation contradicted the presumed idea of cooperation between catalytic species. This observation contradicted the presumed idea of cooperation be- the two metal centers in the course of the Henry reaction. To obtain directly comparable tween the two metal centers in the course of the Henry reaction. To obtain directly com- data, we repeated the Henry reaction of benzaldehyde with nitromethane catalyzed by parable data, we repeated the Henry reaction of benzaldehyde with nitromethane cata- the Cu(OAc)2-6 complex under the same reaction conditions as optimized for ligand 1. lyzed by the Cu(OAc)2-6 complex under the same reaction conditions as optimized for The catalyst was formed in situ by mixing Cu(OAc)2·2H2O and ligand 6 in the 1:1 ratio. Theligand reaction 1. The was catalyst carried was out formed in ethanol in situ at 0 ◦byC formixing 72 h usingCu(OAc) 20 molar2·2H2O % and of catalyst ligand without6 in the any1:1 ratio. additional The reaction base. After was work-up, carried out (S)-2-nitro-1-phenylethanol in ethanol at 0 °C for 72 h was using isolated 20 molar in 64% % of yield cat- andalyst 89% without e.e., i.e., any in additional distinctly higher base. e.e.After than work-up, was previously (S)-2-nitro-1-phenylethanol reported [22,23]. Supposedly, was iso- higherlated in catalyst 64% yield loading and 89% and e.e., lower i.e., temperature in distinctly arehigher responsible e.e. than forwas this previously improvement reported in [22,23]. Supposedly, higher catalyst loading and lower temperature are responsible for e.e. The reaction catalyzed by the Cu(OAc)2-6 complex proceeded more slowly than that this improvement in e.e. The reaction catalyzed by the Cu(OAc)2-6 complex proceeded of catalyzed by the Cu(OAc)2-1 complex, and yield of the product was slightly lower as well.more However,slowly than the that enantioselectivities of catalyzed by the achieved Cu(OAc) were2-1 almostcomplex, the and same yield for bothof the catalysts. product Thiswas observationslightly lower complemented as well. However, our previous the enan resultstioselectivities and led achieved us to conclude were almost that only the onesame copper(II) for both catalysts. ion is engaged This observation in catalysis complemented of the Henry our reaction. previous The results faster and reaction led us rateto conclude of the Henry that only reaction one copper(II) catalyzed ion by is the engaged Cu(OAc) in 2catalysis-1 (1:1) complexof the Henry compared reaction. to The the reactionfaster reaction catalyzed rate by of the the Cu(OAc) Henry2 -reaction6 complex catalyzed might be by explained the Cu(OAc) by the2 presence-1 (1:1) complex of basic secondarycompared aminoto the reaction groups incatalyzed the close by proximity the Cu(OAc) of the2-6 catalytic complex center. might be explained by the presenceIn conclusion, of basic secondary we demonstrated amino groups that in the the Cu(OAc) close proximity2-1 (1:1) of complex the catalytic catalyzes center. the enantioselectiveIn conclusion, Henry wereaction demonstrated of various that aldehydes the Cu(OAc) with2 nitromethane.-1 (1:1) complex To achievecatalyzes good the enantioselectivities,enantioselective Henry relatively reaction high of catalystvarious loading aldehydes (20 molarwith nitromethane. %) and low temperatures To achieve aregood necessary. enantioselectivities, The best results relatively were obtainedhigh catalyst in the loading Henry reaction(20 molar of %) aromatic and low aldehydes temper- usingatures copper(II) are necessary. acetate The as abest copper(II) results salt were and obtained ethanol asin a the solvent Henry in thereaction absence of ofaromatic achiral base.aldehydes using copper(II) acetate as a copper(II) salt and ethanol as a solvent in the absence of achiral base. 4. Materials and Methods 4.1.4. Materials General Methods and Methods 4.1. GeneralMelting Methods points were determined on an Electrothermal IA 9100 melting point appara- tus. Elemental analyses were done in the Analytical Laboratory of the Institute of Organic Melting points were determined on an Electrothermal IA 9100 melting point appa- Chemistry and Biochemistry AS CR using a Perkin Elmer 2400 II instrument (Waltham, ratus. Elemental analyses were done in the Analytical Laboratory of the Institute of Or- MA, USA). Optical rotations were recorded on a Perkin-Elmer 241 polarimeter; specific ganic Chemistry and Biochemistry AS CR using a Perkin Elmer 2400 II instrument optical rotations [α] and concentrations c are given in deg·10−1·m2·g−1 and g/100 mL, (Waltham, MA, USA). Optical rotations were recorded on a Perkin-Elmer 241 polarime- respectively. FTIR spectra were measured on a Nicolet 6700 instrument (Thermo Scien- ter; specific optical rotations [α] and concentrations c are given in deg·10−1·m2·g−1 and tific, Waltham, MA, USA). NMR spectra were recorded on a Varian (Palo Alto, CA, USA) g/100 mL, respectively. FTIR spectra were measured on a Nicolet 6700 instrument Mercury Plus spectrometer (1H NMR at 299.97 MHz; 13C NMR at 75.43 MHz) and on (Thermo Scientific, Waltham, MA, USA). NMR spectra were recorded on a Varian (Palo Alto, CA, USA) Mercury Plus spectrometer (1H NMR at 299.97 MHz; 13C NMR at 75.43 MHz) and on an Agilent (Santa Clara, CA, USA) MR DDR2 spectrometer (1H NMR at

Catalysts 2021, 11, 41 7 of 10

an Agilent (Santa Clara, CA, USA) MR DDR2 spectrometer (1H NMR at 399.94 MHz; 13C NMR at 100.58 MHz). All NMR measurements were carried out at rt. Chemical shifts δ are reported in ppm and are referenced to the signals of residual non-deuterated solvents (CDCl3 δH 7.26, δC 77.16; DMSO-d6 δH 2.50, δC 39.50). Coupling constants J are given in Hz. Mass spectra were measured on a Waters (Milford, MA, USA) Micromass ZQ (low resolution) or a Thermo Scientiﬁc (Waltham, MA, USA) LTQ Orbitrap Velos (high resolution) spectrometer with electrospray ionization. TLC analyses were carried out on aluminum foils coated with Silica gel 60 F254 (Merck, Darmstadt, Germany) and compounds were detected under UV light (λ = 254 nm) or visualized by a treatment with 3% aqueous KMnO4 and heating. Silica gel (Fluka, 63–200 µm) was used for preparative column chromatography. HPLC analyses were done on an Ecom (Prague, Czech Republic) instrument (pump LCP4100, UV detector LCD2083, software CSW32) using the Supelcosil LC-Si (250 × 4.6 mm; 5 µm), YMC Chiral ART Amylose-SA (250 × 4.6 mm; 5 µm) and YMC Chiral Cellulose-SB (250 × 4.6 mm; 5 µm) columns. Dry ethanol was obtained from a PureSOLV PS-MD-7 (VWE International) drying column. Benzaldehyde was successively washed with 10% aqueous Na2CO3, saturated aqueous Na2SO3, and water, and then was dried over MgSO4. Upon the drying agent removal, benzaldehyde was distilled under reduced pressure. Nitromethane was distilled and kept under 5 ◦C prior to use. Com- pound 2 was prepared according to literature procedure [33]. Other chemicals and solvents were used as received from commercial sources (Sigma-Aldrich, Darmstadt, Germany; Fluorochem, Hadﬁeld, UK; Penta s.r.o., Prague, Czech Republic). Syntheses of racemic standards of 2-nitroalcohols can be found in the Supplementary Materials.

4.2. Di-tert-butyl [(1S,10S,2S,20S)-{[1,4-phenylenebis(methaneylylidene)]bis(azaneylylidene)} bis(cyclohexane-2,1-diyl)]dicarbamate (3) A solution of terephthaldehyde (1.09 g, 8.1 mmol) in acetonitrile (30 mL) was added to a solution of carbamate 2 (3.48 g, 16.2 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at rt for 18 h. The white precipitate was isolated by ﬁltration and washed with cold acetonitrile (50 mL). The precipitate was re-crystallized from ethyl acetate giving ◦ product 3 (3.45 g, 6.5 mmol, 80%) as a white solid; M.p. 238–239 C; Anal. for C30H46N4O4 20 calcd. (%) C 68.41, H 8.80, N 10.64; found (%) C 67.9, H 8.6, N 10.3; [α]D +94.2 (c 0.4, 1 CH2Cl2); H NMR (300 MHz, CDCl3): δ 8.26 (2H, s, CH=N), 7.75 (4H, s, ArH), 4.26 (2H, br s, CONH), 3.76–3.50 (2H, m, CHN), 3.13–2.89 (2H, m, CHN), 2.21–1.98 (2H, m, CH2), 13 1.93–1.64 (8H, m, CH2), 1.53–1.13 (6H, m, CH2), 1.27 (18H, s, CH3); C NMR (101 MHz, CDCl3): δ 159.7, 155.2, 138.1, 128.4, 79.0, 74.8, 54.2, 33.3, 32.0, 28.3, 25.0, 24.2; MS (ESI) m/z 549 ([M + Na]+).

4.3. Di-tert-butyl [(1S,10S,2S,20S)-{[1,4-phenylenebis(methylene)]bis(azanediyl)}bis(cyclohexane-2, 1-diyl)]dicarbamate (4) Sodium borohydride (0.88 g, 23.0 mmol) was added to a solution of diimine 5 (3.23 g, 6.1 mmol) in a methanol/tetrahydrofuran mixture (125 mL/125 mL). The reaction mixture was stirred at rt for 18 h. Water (100 mL) was added and the product was extracted into dichloromethane (3 × 100 mL). The combined organic phases were dried over Na2SO4, ﬁltered, and the solvent was evaporated in vacuo. The crude product was crystallized from a dichloromethane/acetonitrile (1:1) mixture at 5 ◦C. The white crystals were isolated and dried in vacuo to afford dicarbamate 4 (3.07 g, 5.8 mmol, 95%); M.p. 180–181 ◦C; Anal. for C30H50N4O4 calcd. (%) C 67.89, H 9.50, N 10.56, found (%) C 67.5, H 9.4, N 10.4; 20 1 [α]D +28.6 (c 1.0, CH2Cl2); H NMR (300 MHz, CDCl3): δ 7.26 (4H, s, ArH), 4.47 (2H, br s, CONH), 3.88 (2H, d, J 13.2 Hz, ArCHaHbN), 3.66 (2H, d, J 13.2 Hz, ArCHaHbN), 3.44–3.22 (2H, m, CHN), 2.34–2.22 (2H, m, CHN), 2.17–1.96 (4H, m, CH2), 1.78–1.59 (6H, 13 m, CH2 + CH2NHCH), 1.45 (18H, s, CH3), 1.34–0.96 (8H, m, CH2); C NMR (101 MHz, CDCl3): 156.0, 139.5, 128.1, 79.1, 60.4, 54.2, 50.2, 32.9, 31.6, 28.4, 24.9, 24.6; MS (ESI) m/z 532 ([M + H]+). NMR spectra are in accordance with those previously published [32]. Catalysts 2021, 11, 41 8 of 10

4.4. (1S,10S,2S,20S)-N1,N10-[1,4-Phenylenebis(methylene)]bis(cyclohexane-1,2-diamine) (5) Triﬂuoroacetic acid (20 mL) was added to a solution of dicarbamate 6 (800 mg, 1.5 mmol) in dichloromethane (20 mL) and the mixture was stirred at rt for 3 h. The solvents were evaporated in vacuo and the obtained oil was vigorously stirred with a saturated aqueous solution of KOH (10 mL) for 10 min. The mixture was extracted with ethyl acetate (3 × 60 mL). The combined organic layers were dried over Na2SO4, ﬁltered, and the solvent was evaporated in vacuo to give tetraamine 5 (486 mg, 1.5 mmol, 98%) 1 as yellow oil; H NMR (300 MHz, DMSO-d6): δ 7.24 (4H, s, ArH), 3.77 (2H, d, J 13.3 Hz, ArCHaHbN), 3.55 (2H, d, J 13.3 Hz, ArCHaHbN), 2.28–2.15 (2H, m, CHN), 2.03–1.84 (4H, m, CHN + CH2), 1.79–1.67 (2H, m, CH2), 1.62–1.56 (4H, m, CH2), 1.22–0.83 (8H, m, CH2); 13 C NMR (101 MHz, DMSO-d6): δ 140.1, 128.1, 62.8, 55.1, 50.4, 35.4, 31.0, 25.3, 25.2; MS (ESI) m/z 331 ([M + H]+).

0 4.5. (1S,10S,2S,20S)-N1,N1 -[(1,4-Phenylenebis(methylene)]bis(N2-benzylcyclohexane-1, 2-diamine) (1) Benzaldehyde (382 mg, 0.37 mL, 3.60 mmol) was added to a solution of tetramine 5 (540 mg, 1.64 mmol) in acetonitrile (20 mL) and the reaction mixture was stirred at rt for 18 h. The solvent was evaporated in vacuo and the residue (crude diimine) was dissolved in a methanol/tetrahydrofuran (20 mL/20 mL) mixture. Sodium borohydride (244 mg, 6.46 mmol) was added and the reaction mixture was stirred at rt for 18 h. Water (20 mL) was added and product was extracted into dichloromethane (3 × 60 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was obtained as orange oil (800 mg). It was dissolved in water (20 mL) and pH of the solution was adjusted to 6 using conc. HCl while vigorously stirring. The mixture was stirred at rt for additional 20 min, then a solution of NH4PF6 (1.46 g, 8.9 mmol) in water (5 mL) was added and the mixture was cooled to 5 ◦C for 18 h. The white precipitate was isolated and dissolved in a vigorously stirred biphasic mixture of dichloromethane (20 mL) and saturated aqueous solution of NaOH (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated in vacuo 20 to give ligand 1 as yellowish oil (491 mg, 0.97 mmol, 59%); [α]D +87.7 (c 0.3, CHCl3); IR −1 1 νmax (liquid film): 3297, 3025, 2926, 2854, 1453, 1275, 1260, 1116 cm ; H NMR (400 MHz, DMSO-d6): δ 7.30–7.10 (14H, m, ArH), 3.75 (4H, dd, J 13.3, 6.3 Hz, ArCH2N), 3.55 (4H, dd, J 13.3, 7.4 Hz, ArCH2N), 2.22–2.09 (4H, m, CHN), 2.06–1.92 (4H, m, CH2), 1.68–1.53 (4H, m, 13 CH2), 1.20–1.06 (4H, m, CH2), 1.05–0.80 (4H, m, CH2); C NMR (101 MHz, DMSO-d6): δ 141.8, 139.9, 128.5, 128.3, 128.1, 126.9, 67.5, 60.6, 50.3, 50.1, 31.1, 31.0, 25.6, 25.0; HRMS (ESI) + for C34H46N4 ([M + H] ) calcd. 511.3795, found 511.3792.

4.6. Typical Procedure for the Henry Reaction

Ligand 1 (51 mg, 0.1 mmol) and Cu(OAc)2·2H2O (22 mg, 0.1 mmol) were dissolved in dry ethanol (4.0 mL) and the solution was stirred at rt for 15 min. The mixture was cooled to 0 ◦C and benzaldehyde (53 mg, 51 µL, 0.5 mmol) was added, followed by addition of nitromethane (122 mg, 107 µL, 2 mmol). The reaction mixture was stirred at 0 ◦C for 48 h and then concentrated in vacuo. The residue was subjected to a column chromatography in a hexane/ethyl acetate (4:1) mixture. 2-Nitro-1-phenylethan-1-ol was obtained as a light 1 yellow oil (59 mg, 0.35 mmol, 71%); TLC Rf (hexane/ethyl acetate 85:15) 0.2; H NMR (300 MHz, CDCl3): δ 7.53–7.30 (5H, m, ArH), 5.48 (1H, dd, J 9.4, 3.2 Hz, CH), 4.68–4.45 13 (2H, m, CH2), 2.83 (1H, br s, OH); C NMR (400 MHz, CDCl3) δ 138.3, 129.1, 129.0, 126.1, 81.3, 71.1. The analytical data are in accordance with those published previously [35]. Enantiomeric excess was determined by means of HPLC analysis on the YMC Chiral Cellulose-SB column (250 × 4.6 mm; 5 µm) using a heptane/propan-2-ol (9:1) mixture at ﬂow rate of 1 mL/min with UV detection at 210 nm. The individual peaks were assigned to particular enantiomers by comparison with HPLC analyses done on a column with Catalysts 2021, 11, 41 9 of 10

chemically equivalent chiral stationary phase [35]: t(R) = 15.1 min (major), t(S) = 17.7 min (minor); e.e. 91%.

Supplementary Materials: The following are available online at https://www.mdpi.com/2073-4 344/11/1/41/s1. Syntheses of compounds 2, 6 and racemic 2-nitroalcohols, copies of 1H NMR, 13C NMR and MS spectra and HPLC chromatograms. Author Contributions: Conceptualization, J.H.; methodology, J.H.; investigation, D.T. and M.N.; writing—original draft preparation, D.T. and J.H.; writing—review and editing, J.H.; supervision, J.H.; project administration, J.H.; funding acquisition, J.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Czech Science Foundation, grant number 18-09824S, and the specific university research, grant number A2_FCHT_2020_036. Acknowledgments: The authors thank the Analytical Laboratory of the Institute of Organic Chem- istry and Biochemistry of the Academy of Sciences of the Czech Republic headed by Stanislava Matˇejková for conducting the elemental analyses. Conflicts of Interest: The authors declare no conflict of interest.

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