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Applied Catalysis A: General 459 (2013) 97– 105

Contents lists available at SciVerse ScienceDirect

Applied Catalysis A: General

j ourna l h om epage: www.elsev ier .com/ locate /apcata

hiral recyclable Cu(II)-catalysts in nitroaldol reaction of aldehydesith various nitroalkanes and its application in the synthesis of a

aluable drug (R)-isoproterenol

njan Dasa,b, Rukhsana I. Kureshya,b,∗, K. Jeya Prathapc, Manoj K. Choudharya,b,anga V.S. Raoa,b, Noor-ul H. Khana,b, Sayed H.R. Abdia,b, Hari C. Bajaja,b

Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSIR-CSMCRI), Bhavnagar 364 021, Gujarat, IndiaAcademy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat, IndiaInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6, Czech Republic

a r t i c l e i n f o

rticle history:eceived 14 December 2012eceived in revised form 13 March 2013ccepted 22 March 2013vailable online 13 April 2013

eywords:symmetric nitroaldol reaction-Nitroalcoholssymmetric catalysisimeric macrocyclic salenopper(II) [H4]salen complexesR)-isoproterenol

a b s t r a c t

Chiral dimeric macrocyclic salen ligands 1′a–c and [H4]salen 2′a–c derived from (1R,2R)-(−)-1,2-diaminocyclohexane, (1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethane, and (R)-(+)-1,1′-binaphthyl-2,2′-diamine with 5,5′-(piperazine-1,4-diylbis(methylene)-bis-(3-tert-butyl-2-hydroxybenzaldehyde) wereprepared. Cu(II) complexes 1a–c and 2a–c were generated in situ by the interaction of different source ofcopper(II) salts with chiral dimeric macrocyclic salen ligands 1′a–c and 2′a–c and used for asymmetricnitroaldol reaction of various aromatic and aliphatic aldehydes with various nitroalkanes at RT (27 ± 2 ◦C).Excellent yields (98% with respect to the aldehyde) of ˇ-nitroalcohols with high enantioselectivity (ee,∼99%) was achieved in case of 2-fluorobenzaldehyde and nitromethane in ca. 20 h with the use of chiraldinuclear macrocyclic [H4]salen Cu(II)-2′a complex. This protocol also worked well with nitroethane and2-nitropropane with several aldehydes to furnish the corresponding products in high yields and enan-tioselectivties for syn diasteriomers. Chiral dinuclear macrocyclic [H4]salen catalysts Cu(II)-2′a mediatednitroaldol process is recyclable (up to 8 cycles with no significant loss in its performance). This protocolis also used for the synthesis of enantiomerically pure (R)-isoproterenol (ˇ-adrenergic agonist) as a key

step via asymmetric nitroaldol reaction of 3,4-dimethoxybenzaldehyde. To understand the mechanism ofthe catalytic nitroaldol reaction, the kinetic investigation was carried out with different concentrationsof the catalyst Cu(II)-2′a, nitromethane, and 3-methoxybenzaldehyde as the representative substrate.The nitroaldol reaction of 3-methoxybenzaldehyde was first order with respect to the concentration ofthe catalyst and the nitromethane but did not depend on the initial concentration of the substrate. Anappropriate mechanism of the nitroaldol reaction is proposed.

. Introduction

Asymmetric nitroaldol (Henry) reaction represents one of theseful route for the synthesis of many pharmaceutical precur-ors [1] via carbon–carbon bond formation. The diverse range ofhemical transformations of the newly formed ˇ-nitroalkanol func-ionality such as reduction, oxidation, dehydration, Nef reactiono carbonyl compounds [2] or nucleophilic displacement [3] has

ade this reaction of immense value. Asymmetric nitroaldol reac-

ion protocols generally involve the use of a chiral catalyst derivedrom Co(II) [4], Mg(II) [5], Zn(II) [6], Cu(II) [7], Cr(III) [8] or rarearth metals [9]. In particular, Shibasaki has demonstrated the first

∗ Corresponding author. Fax: +91 0278 2566970.E-mail address: rukhsana93@yahoo.co.in (R.I. Kureshy).

926-860X/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.apcata.2013.03.032

© 2013 Elsevier B.V. All rights reserved.

efficient lanthanum–lithium–chiral binaphthoxide based two-center catalyst [10] for nitroaldol reaction while Trost et al. revealeda novel family of dinuclear zinc complexes [6a–b] catalyzed reac-tion between nitromethane and aldehydes. Among the variouschiral ligands used, box [11] and salen-type C2-symmetric lig-ands [12] have been proven to be broadly useful for a variety ofasymmetric metal-catalyzed reactions including nitroaldol reac-tion. Although the nitroaldol reaction products were obtained inhigh yields and ees, a lot more efforts are required to address theissue of catalyst recycle in order to mitigate the high cost of chiralcatalysts there by making this protocol industrially more accept-able. We have recently reported the synthesis of C2-symmetric

chiral monomeric and dimeric macrocyclic copper(II)–[H4]salencomplexes with flexible trigol linker for asymmetric nitroaldolreaction of various aldehydes with nitromethane at RT with fairsuccess in term of activity and enantioselectivity in ˇ-nitroalcohols

9 sis A: General 459 (2013) 97– 105

[ufehcafcmtrwluep(autaptiad

2

2

Tda(ptrh

2[

dNopuwbpdt

2

2aTw(w

Table 1Screening of in situ generated chiral macrocyclic salen/[H4]salen complexes with lig-ands 1′a–c/2a′–c and Cu(OAc)2·H2O as source of metal using 3a with nitromethaneat RT.a

Entry Ligands Yield (%)b ee (%)c

1 1′a 75 652 1′b 69 453 1′c 65 604 2′a 92 955 2′b 88 706 2′c 78 85

a Conditions: 3a (0.5 mmol), nitromethane (5.0 mmol), ligands 1′a–c/2′a–c

8 A. Das et al. / Applied Cataly

13]. Further, it is known that nitroaldol reactions require these of an amine for abstraction of proton from nitroalkane toorm nitronate ion which function as a nucleophile and providexcellent results with aldehydes. With this knowledge before userein, we are reporting recyclable C2-symmetric dimeric macro-yclic salen ligands 1′a–c and [H4]salen 2′a–c with two catalyticallyctive centers and in-built amine functionality (piperazine linker)rom readily available starting materials. In situ generated chiralopper(II)–salen 1′a–c/[H4]salen complexes 2′a–c with differentetal source were used as catalysts in asymmetric nitroaldol reac-

ion for a range of aldehydes with various nitroalkanes at RT. Thiseaction protocol provided easy access to chiral ˇ-nitroalcoholsith high yield and enantioselectivity with excellent diastereose-

ectivity for syn products. The catalysts were effectively recycledp to eight cycles with preservation of its catalytic activity andnantioselectivity. The present asymmetric nitroaldol protocol alsorovided a straight forward alternative route for the synthesis ofR)-isoproterenol – a potent ˇ-adrenoreceptor [14]. An attempt waslso made to understand the mechanism of nitroaldol reaction byndertaking the kinetic investigations using ligand 2′a in combina-ion with Cu(OAc)2·H2O as catalyst with 3-MeO-benzaldehyde 3as a representative substrate and nitromethane at RT. The kineticrofile obtained has shown first-order dependence on concentra-ions of catalyst, Cu(II)-2′a and nitromethane and independent onnitial concentration of the substrate 3a. Based on kinetic, catalytic,nd experimental evidence, a probable mechanism for the nitroal-ol reaction is suggested.

. Experimental

.1. Preparation of chiral dimeric macrocyclic ligands 1′a–c

A solution of dialdehyde C [17] (2 mmol) in 20 mLHF (1.2 mL) was added to a solution of (1R,2R)-(−)-1,2-iaminocyclohexane/(1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethanend (R)-(+)-1,1′-binaphthyl-2,2′-diamine (2 mmol, 2 equiv.) in THF0.8 mL) and the resulting mass was stirred for 3 h at room tem-erature (checked on TLC). After the completion of the reaction,he solvent was completely removed under reduced pressure on aotary evaporator to give chiral macrocyclic salen ligands 1′a–c inigh yield (data is given in supporting information).

.2. Procedure for the preparation of dimeric macrocyclicH4]salen ligand

Chiral dimeric macrocyclic salen ligands 1′a–c (10 mmol) wereissolved in 45 mL of dry methanol and 5 mL of dichloromethane.aBH4 (40 mmol) was added portion-wise in four equal partsver 30 min and the reaction was monitored by TLC. After com-letion of the reaction, the solvents were completely evaporatednder reduced pressure. Then the reaction mass was washed withater, dissolved in dichloromethane. The organic layer was dried

y anhydrous Na2SO4 and subjected to flash column chromatogra-hy (EtOAc/hexane = 1:5) on a neutral alumina column to get theesired ligands 2′a–c in quantitative yields (data given in suppor-ing information).

.3. Typical experimental procedure for nitroaldol reaction

Chiral dimeric macrocyclic salen 1′a–c and [H4]salen ligands′a–c (0.0125 mmol) and Cu(OAc)2·H2O (0.02 mmol) were added to

screw-capped vial containing a stirring magnetic bar. Anhydrous

HF (0.6 mL) was then added, and a clear green solution formedas stirred for 45 min at RT. To the resulting solution nitromethane

5.0 mmol, 10 equiv.) and desired aldehyde (0.5 mmol, 1 equiv.)ere added. After running the reaction for the specified time as

(0.0125 mmol), Cu(OAc)2·H2O (0.02 mmol) in MeOH.b Isolated yields after flash column chromatography.c Determined by HPLC (Chiralcel OD).

given in Table 4, the volatile components were removed underreduced pressure, and the crude product was purified by flash col-umn chromatography.

2.4. Recycling of the catalyst Cu(II)-2′a

At the end of the catalytic reaction (checked on TLC), the sol-vent was completely removed from the reaction medium underreduced pressure and the resulting mass was extracted with hex-ane to remove the reactants and product. The remaining solid wasfurther washed with hexane for six times, dried under reducedpressure for 2–3 h, and used as recovered catalysts for recyclingexperiments of an asymmetric nitroaldol reaction of 3a as a repre-sentative substrate with nitromethane.

3. Results and discussion

Macrocyclic chiral salen ligands 1′a–c were synthesized bythe condensation of (1R,2R)-(−)-1,2-diaminocyclohexane/(1R,2R)-(+)-1,2-diphenyl-1,2-diaminoethane/(R)-(+)-1,1′-binaphthyl-2,2′-diamine with 5,5′-(piperazine-1,4-diyl-bis-(methylene))-bis-(3-tert-butyl-2-hydroxybenzaldehyde). Reduction of 1′a–cwith NaBH4 gave [H4]salen ligands 2′a–c in excellent yield(characterization data are given in supporting information)(Scheme 1).

The 1H NMR of salen ligands 1′a–c show C2 symmetry whereas[H4]salen ligands 2′a–c being flexible somehow lost the symmetryas represented by a set of two singlet for t-Bu protons in ligand 2′a atı 1.369 ppm (Fig. 1). However, on complexation, the C2 symmetry ofthe ligand was resumed. To check this, Zn complex of the ligand 2′awas prepared, that showed only one singlet for t-Bu protons. Sincethe coordination pattern of Zn and Cu is similar we extrapolatedthese finding to the catalytically active Cu–[H4]salen complexesformed in situ by the interaction of Cu salts with [H4]salen ligands2′a–c during catalytic run.

At the very beginning, chiral macrocyclic salen ligands 1′a–cand [H4]salen 2′a–c (5 mol%) with Cu(OAc)2·H2O (5 mol%) wereexamined for their catalytic performance in the nitroaldol reactionof 3-MeO-benzaldehyde 3a as a model substrate (0.5 mmol) withnitromethane (10 equiv.) in methanol. Data in the Table 1 revealedthat the in situ generated complexes with [H4]salen ligands 2′a–cworked better in term of reactivity and enantioselectivity of ˇ-nitroalcohols (Table 1, entries 4–6) as compared to their salenversions 1′a–c. Among the [H4]salen ligands 2′a–c, the ligand 2′awith diphenyldiamine collar was most promising under the stud-ied parameters (Table 1, entry 4). Therefore, 2′a was subjected tochange in the reaction parameters and variation in copper source.

A close examination of the prior art in this area of researchrevealed that both Cu(I) [1d,11e,15] and Cu(II) [7] salts are capa-ble of generating the active catalyst for the nitroaldol reaction.However, there seems to be no clear indication in regard with

A. Das et al. / Applied Catalysis A: General 459 (2013) 97– 105 99

clic sa

trCt(eCeot

intast

protic (methanol and ethanol) and data is shown in Table 3 (entries1–9). Among these polar protic and aprotic solvents, methanoland THF fared better than rest of the solvents. The ligand wasfound to be partially soluble in ethanol and needed 20% CH2Cl2 for

Table 2Screening of counter ions of metal source for asymmetric nitroaldol reaction of 3ausing the [H4]salen ligand 2′a.a

Entry Metal Source Time (h) Yield (%)b ee (%)c

1 CuCl2·2H2O 70 10 562 Cu(OAc)2·H2O 20 92 953 Cu(NO3)2 96 80 454 (CuOTf)2C7H9 70 50 205 CuI 45 70 90

Scheme 1. Synthesis of chiral macrocy

he preference of metal salt vis-à-vis ligand system. Due to thiseason it was prudent to examine several metal salts viz.,uCl2·2H2O, (CuOTf)2C7H9, Cu(NO3)2, Cu(OAc)2·H2O and CuI withhe ligand 2′a using 3-MeO-benzaldehyde 3a as a model substrate0.5 mmol) with nitromethane (10 equiv.) in methanol (Table 2,ntries 1–5). Results in Table 2 (entries 2 and 5) revealed thatu(OAc)2·H2O and CuI as metal source effectively induced very highnantioselectivity (ee, 95% and 90% respectively), but the reactivityf in situ generated complex of 2′a with Cu(OAc)2·H2O was foundo be much higher.

Having established the effectiveness of 2′a with Cu(OAc)2·H2On the asymmetric nitroaldol reaction as per the entry 2 of Table 2,ext we examined the effect of different solvents and other reac-

ion parameters such as, catalyst loading and temperature on thesymmetric nitroaldol of 3a with nitromethane. Accordingly, wecreened a variety of solvents that include non-polar (benzene,oluene), polar aprotic (CHCl3, CH2Cl2, DCE, THF, DMSO) and polar

len 1′a–c and [H4]salen ligands 2′a–c.

a Conditions: 3a (0.5 mmol), nitromethane (5.0 mmol), ligand 2′a (0.0125 mmol),CuX2/CuX (0.02 mmol) in MeOH.

b Isolated yields after flash column chromatography.c Determined by HPLC (Chiralcel OD).

100 A. Das et al. / Applied Catalysis A: General 459 (2013) 97– 105

(a) lig

cusrcaotor5(lCtoa1

TOo

C

w

Fig. 1. 1H-NMR peak(s) of t-Bu protons of

omplete dissolution, but this solvent system caused drop in prod-ct yield and ee (entry 2). Therefore, we took THF as preferredolvent (Table 3, entry 11) to carry out further refinement of theeaction parameters. All the experiments reported above wereonducted with 5 mol% catalyst loading by taking stoichiometricmount of ligand 2′a and Cu(OAc)2·H2O. However, a slight excessf ligand is often used when the active catalyst is generated in situo ensure no free metal remain present in the system, which wouldtherwise result in the formation of racemic product. Due to thiseason we varied the amount of Cu(OAc)2·H2O (2–15 mol%) with

mol% of 2′a to catalyze nitroaldol of 3a with nitromethane at RTFig. 2). From the graph it is clear that at 7.5 mol% of Cu(OAc)2·H2Ooading with 5 mol% of the ligand 2′a (having two binding sites foru) the product yield and enantioselectivity was highest. A fur-

her increase in the mol% of Cu(OAc)2·H2O, caused systematic lossf enantioselectivity. This ligand to metal ratio was then used tossess the overall ligand loading over a range of 1–10 mol% (entries0–12) for the present asymmetric nitroaldol protocol, which

able 3ptimization of solvents and reaction parameters for asymmetric nitroaldol reactionf 3a with nitromethane.a

Entry Catalyst loading(mol%)

Solvent Temp (◦C) Yield (%)b ee (%)c

1 5 MeOH RT 92 952 5 EtOHd + CH2Cl2 RT 63 803 5 CH2Cl2 RT 60 754 5 CHCl3 RT 55 755 5 DCE RT 65 836 5 Benzene RT 45 757 5 Toluene RT 55 768 5 DMSO RT 95 679 5 THF RT 95 95

10 10 THF RT 96 8511 2 THF RT 95 9612 1 THF RT 85 8013 2 THF 0 20 8914 2 THF 10 40 8915 2 THF RT 92 9516 2 THF 40 96 85

a Conditions: 3a (0.5 mmol), nitromethane (5.0 mmol), ligand 2′a (0.0125 mmol),u(OAc)2·H2O (0.02 mmol) in 0.6 ML of solvent.b Isolated yields after flash column chromatography.c Determined by HPLC (Chiralcel OD).d Due to insufficient solubility of the ligand in EtOH, a small quantity of CH2Cl2as added (EtOH:CH2Cl2 = 5:1).

and 1′a, (b) ligand 2′a, (c) 2′a-Zn complex.

suggested that a 2 mol% of the ligand loading is optimum (entry 11).It is worth comparing the catalyst loading reported [13] by us withthe use of macrocyclic [H4]salen ligands with no built-in basic func-tionality, which required higher ligand loading (10 mol%) to givesimilar activity. Therefore, the enhanced catalytic activity for thepresent ligand system can be attributed to the built-in base func-tionality that facilitates the abstraction of proton from nitroalkanesto form active nucleophile. The effect of temperature on the per-formance of this protocol was evaluated over a temperature rangeof 0–40 ◦C (entries 13–16), where RT was found to be optimum toproduce 2-nitro-3-methoxy-phenylethanol 4a from 3a in 95% yieldand 96% ee after 20 h (entry 11).

The above optimized reaction conditions (Table 3; entry 11)were further used to carry out nitroaldol reaction of a variety of aro-matic and aliphatic aldehydes (3a–p) with nitromethane (entries1–16) and 2-nitropropane (entries 17–21). In all the cases very goodto excellent enantioselectivity (ee, 84–99%) was obtained for thecorresponding nitroaldol products with high yield (Table 4). In allcatalytic runs the R form of the catalyst gave R-form of the productas a dominant enantiomer (Scheme 2).

Encouraged by the above results we next tread to the relativelyless explored target for nitroaldol reaction of nitroethane with rep-

resentative aromatic and aliphatic aldehydes viz., benzaldehyde3c, 3-methoxy benzaldehyde 3a, 4-flourobenzaldehyde 3h, 4-nitrobenzaldehyde 3e, cyclohexanecarboxaldehyde 3o, crotanaldehyde

Fig. 2. Screening of ligand 2′a (5 mol%) to metal ratio in asymmetric nitroaldolreaction of 3a in THF at RT.

A. Das et al. / Applied Catalysis A: G

Scheme 2. Asymmetric nitroaldol reaction of aromatic, aliphatic and heteroaro-matic aldehydes with nitromethane.

Table 4Variation of substrates in asymmetric nitroaldol reaction.a

Entry Aldehydes R′ , R′′ Yield (%)b ee (%)c

1 3-Methoxy benzaldehyde 3a H 95 4a 962 2-Methoxy benzaldehyde 3b H 92 4b 933 Benzaldehyde 3c H 93 4c 954 4-Chloro benzaldehyde 3d H 88 4d 905 4-Nitro-benzaldehyde 3e H 94 4e 946 2-Methyl benzaldehyde 3f H 90 4f 977 2-Flouro-benzaldehyde 3g H 98 4g 998 4-Flouro-benzaldehyde 3h H 97 4h 859 2-Bromo benzaldehyde 3i H 89 4i 88

10 4-Bromo benzaldehyde 3j H 92 4j 8411 1-Naphthaldehyde 3k H 95 4k 9112 2-Naphthaldehyde 3l H 93 4l 9413 Thiophene-2-carboxaldehyde 3m H 94 4m 9314 n-Hexanal 3n H 84 4n 9515 Cyclohexanecarboxaldehyde 3o H 86 4o 8916 3,4-dimethoxy benzaldehyde 3p H 94 4p 9517 Benzaldehyde 3c CH3 81 4′c 9218 4-nitro-benzaldehye 3e CH3 82 4′e 9019 3-methoxybenzaldehyde 3a CH3 76 4′a 8820 2-bromo benzaldehyde 3i CH3 77 4′i 8421 Cyclohexanecarboxaldehyde 3o CH3 72 4′o 91

a Conditions: aldehydes 3a–o (0.5 mmol), nitromethane (5.0 mmol), ligand 2′a(

3owcfmaotfal

model substrate and nitromethane at RT. During the kinetic run,the plot for formation of 2-nitro-1-(3-methoxyphenyl)ethanol withtime was found to be linear in the initial period of the reaction giv-ing the straight line. But after 4 h with 56% conversion, saturation

TV

i

0.0125 mmol), Cu(OAc)2·H2O (0.02 mmol) in 0.6 ML THF at RT for 20 h.b Isolated yields after flash column chromatography.c Determined by HPLC (Chiralcel OD, OD-H, AD, AD-H, IA, IC).

q and 2-ethyl butyraldehyde 3r in order to see the ability ofur best catalyst Cu(II)-2′a in expressing diastereoselectivity alongith enantioselectivity (Table 5; entries 1–7) under the optimized

ondition of entry 11 (Table 3). The diastereoselectivity (as obtainedrom 1H NMR) for syn product in the case of benzaldehyde and 3-

ethoxy benzaldehyde (entries 1 and 2) were found to be 92:8nd 87:13 respectively. Presence of electron withdrawing groupsn the aromatic ring of aldehyde caused significant drop in dias-

eroselctivity (entries 3 and 4) however, the enantioselectivityor the syn product remained high (ee, 99% and 85%, entries 3nd 4). In the case of aliphatic aldehydes although enantiose-ectivity of cis and trans diasteromers was excellent (ee, 99%) in

able 5ariation of substrates in asymmetric nitroaldol reaction.a

Entry Aldehydes Temp (◦C)

1 Benzaldehyde 3c RT

2 3-Methoxy benzaldehyde 3a RT

3 4-Flourobenzaldehyde 3h RT

4 4-Nitro benzaldehyde 3e RT

5 Cyclohexanecarboxaldehyde 3o RT

6 Crotanaldehyde 3q RT

7 2-Ethyl butyraldehyde 3r RT

8 Benzaldehyde 3c −10 ◦C

9 Benzaldehyde 3c 0 ◦C

a Conditions: aldehydes 5a–e (0.5 mmol), nitroethane (5.0 mmol), ligand 2′a (0.0125 mmn Table.

b Isolated yields after flash column chromatography.c Determined from NMR data.d Determined by HPLC (Chiralcel OD, OD-H, IA, IC).

eneral 459 (2013) 97– 105 101

the case of cyclohexanecarboxaldehyde 3o, but the reaction com-pletely lacked diastereoselectivity (entry 5). Moreover, substratescrotonaldehyde 3p and 2-ethylbutyraldehyde 3r showed somediastereoselectivity, intriguingly their respective syn and anti prod-ucts displayed contrasting enantioselectivities (entries 6 and 7).Attempts to improve the diastereoselectivity, by lowering the reac-tion temperature (−10 and 0 ◦C; entries 8 and 9) in the modelnitroaldol reaction of benzaldehyde with nitroethane were of littleconsequence.

In addition to high reactivity and enantioselectivity in thenitroaldol reaction, the dimeric macrocyclic complex, Cu(II)-2′a isrecyclable as evidenced by the recycling experiments (Fig. 3). Therecyclability experiments were carried out by using 3a (2.0 mmol)as a model substrate with nitromethane (20 mmol) in THF at RTusing the complex Cu(II)-2′a as catalyst. After completion of thecatalytic reaction, the products were extracted with n-hexane. Sig-nificantly, the residue obtained after the removal of unreactedsubstrate and the product from the catalytic reaction mixture wasdirectly used as catalyst in subsequent catalytic runs without fur-ther purification or additional amounts of ligand/metal source. Theperformance of the catalyst remained steady over eight recycleexperiments (Fig. 3) indicating that the complex Cu(II)-2′a is fairlystable and do not deteriorate during the course of nitroaldol reac-tion.

To evaluate the synthetic relevance of the present catalytic pro-tocol in the synthesis of a valuable drug molecule (R)-isoproterenol,[16] the nitroaldol of 3,4-dimethoxybenzaldehyde was carried outat 1 g scale (Scheme 3). Excellent yield (94%) and ee (95%) for thedesired molecule (R)-isoproterenol was obtained by in situ gener-ated catalyst from ligand 2′a and copper acetate. These experimentsclearly show the scalability of this process while retaining theenantio-purity of the ˇ-nitroalcohol in later steps of condensation,hydrogenation and demethylation.

In order to understand the reaction mechanism of nitroal-dol(Henry) reaction, kinetic study was done using the catalystCu(II)-2′a generated from ligand 2′a and Cu(OAc)2·H2O with 3a as

Scheme 3. Asymmetric nitroaldol reaction of aromatic, aliphatic aldehydes withnitroethane.

Yield (%)b syn/antic ee (%)d

syn anti

82 5c 92/08 87 6190 5a 87/13 92 5092 5h 75/25 99 6595 5e 57/43 85 5575 5o 50/50 99 9978 5p 60/40 80 1581 5q 55/45 25 9560 5c 93/07 90 6574 5c 93/07 89 63

ol), Cu(OAc)2·H2O (0.02 mmol) in 0.6 ML THF for 30 h at the temperatures mentioned

102 A. Das et al. / Applied Catalysis A: General 459 (2013) 97– 105

study of the catalysts.

pdtwr

3

ro(iwtcmcftt2

3

rwcUtc

Fe[

0

20

40

60

80

100

120

0 20 40 60 80 100 120[Catalyst] x 10 4 M

ko

bsx

10

5 M

min

-1

Fig. 3. Recycling

oint was reached and a deviation from the straight line occurreduring the later stage of the reaction (Fig. 4). Based on these results,he initial rate constants kobs (up to the linear portion of the graph)ere determined by the amount of nitroaldol product formed with

espect to time.

.1. Effect of catalyst concentration on reaction rate

To find out the effect of catalyst concentration on theeaction rate, we have carried out the nitroaldol reactionf 3a and nitromethane with different catalyst concentration0.0028–0.01 M) keeping all other parameter constant. A linearncrease in the formation of the nitroaldol product was observed

ith increase in the catalyst concentration. Then the rate of forma-ion of nitroaldol product 4a, (kobs) was plotted against the catalystoncentration passing through the origin (Fig. 5) indicating the ulti-ate need of the catalyst to proceed the reaction under the reaction

ondition. Again, the plot of the log kobs versus log[catalyst] wereound to be linear with unit slopes (dlog kobs/dlog[catalyst]) ∼1)hat evidently indicated the first-order dependence of the rate ofhe reaction with respect to the concentration of the catalyst Cu(II)-′a.

.2. Effect of nitromethane concentration on reaction rate

To evaluate the effect of nitromethane concentration oneaction rate, we have carried out the nitroaldol reactionith fixed concentration of 3a and catalyst with variable con-

entration of nitromethane ranging from 1.38 M to 3.47 M.nder the similar reaction condition, the rate of the reac-

ion increases linearly with the increase of the nitromethaneoncentration (Fig. 6). The plot of the rate constant versus

0

0.05

0.1

0.15

0.2

0.25

0 10 0 20 0 30 0 40 0 50 0

[Pro

du

ct]

M

Time (min)

ig. 4. Time-dependence plot for the formation of 2-nitro-1-(3-methoxyphenyl)thanol 4a at RT, [catalyst] = 69 × 10−4 M, [3-MeO-benzaldehyde] = 28 × 10−2 M, andnitromethane] = 2.77 M.

Fig. 5. Plot of catalyst concentration versus kobs at RT, [3-MeO-benzaldehyde] = 28 × 10−2M, [nitromethane] = 2.77 M.

nitromethane concentration further confirmed the first-orderdependence of rate constant with nitromethane concentration(dlog kobs/dlog[nitromethane] ∼ 1) (Scheme 4).

3.3. Effect of substrate concentration on reaction rate

For further studying the effect of substrate 3a concentration bykeeping all other parameter the same, the nitroaldol reaction wascarried out with substrate concentration ranging from 0.069 M to0.34 M which indicates the zero order dependence of the rate onthe substrate concentration (Fig. 7).

Based on kinetics data, a general mechanism for the nitroal-dol reaction is proposed here (Scheme 5). Since, the kinetics of

the reaction is independent on substrate 3a concentration, it canbe assumed that the interaction of substrate with catalyst is veryfast (T1) and the overall rate of the reaction does not depend onthe substrate concentration. Since the reaction rate is first order

0

10

20

30

40

50

60

70

80

0 1 2 3 4

ko

bsx

10-5

M m

in-1

[Nitromethane] M

Fig. 6. Plot of nitromethane concentration versus kobs at RT, [3-MeO-benzaldehyde] = 28 × 10−2 M, [catalyst] = 69 × 10−4 M.

A. Das et al. / Applied Catalysis A: General 459 (2013) 97– 105 103

Scheme 4. Synthesis of (R)-isoproterenol.

for a

dbTei4a4w(

i

F[

2′a that might have caused perturbations in the phenyl groups ofdiamine collar unlike in Feng’s complex which is monomeric andopen chain (Scheme 6).

Scheme 5. Proposed mechanism

ependent on catalyst and nitromethane concentrations, a possi-le transition state (T2) can be proposed as rate determining step.he proposed mechanism was further substantiated by UV–visxperiments where on addition of substrate benzaldehyde to then situ generated complex showed blue shift with isobestic point at05 nm possibly due to the formation of transition state (T1). Onddition of nitromethane to the above solution the intensity of the05 nm band goes higher with the formation of transition state (T2),

hich decays with time as the reaction reaches near completion

Fig. 8).Based on the configuration of the product nitroalcohols, a work-

ng model for the enantioselectivity is proposed in Scheme 5, which

20

30

40

50

60

70

80

0 1 2 3 4 5

ko

bsx

10

5 M

min

-1

[3-Me O-Benzaldehyd e] x 102 M

ig. 7. Plot of substrate concentration versus kobs at RT, [nitromethane] = 2.77 M,catalyst] = 69 × 10−4 M.

symmetric nitroaldol reaction.

is similar to one proposed by Feng et al. [12e]. The only differencebetween present model (Si face favorable) and Feng’s model (Reface favorable) lies in the orientation of the aldehyde and attackof nitronate ion (deprotonated nitromethane). This difference canbe attributed to the cyclic nature of the dimeric complex Cu(II)-

400 50 0 60 0 70 0 80 0

0.0

0.2

Compl ex+Ben zaldeh yde+Nitrome thane( after 2 0h)

Compl ex+Ben zaldeh yde+Nitrome thane( after 1 h)

Compl ex+Ben zaldeh yde

Compl ex

Ligand

Ab

sorb

an

ce

Waveleng ht(nm)

Fig. 8. Stepwise UV–vis spectra obtained with a 1 mM solution of THF in the pres-ence of Cu (OAc)2·H2O, benzaldehyde, and nitromethane of ligand 2′a.

104 A. Das et al. / Applied Catalysis A: General 459 (2013) 97– 105

Lower energy pathway Highe r en ergy path way

N

O

N

O

NN

Cu

O

N

OO

favorable

Si face attack

(R)-Isomer

N

O

N

O

NN

Cu

O

N

OO

UnfavorableRe face attack

(S)- IsomerH

H

athwa

4

md[waaaIbcdkonoepaa

A

ofaf

A

t

R

[

Scheme 6. Lower energy p

. Conclusions

In summary we have synthesized a series of chiral dimericacrocyclic salen and [H4]salen ligands for asymmetric nitroal-

ol reaction with Cu(II) and Cu(I) salts. It was found that chiralH4]salen ligand with diphenyldiamine collar 2′a in combinationith Cu(OAc)2·H2O worked well in terms of enentioselectivity

nd activity for wide range of substrates including aromatic,liphatic and heteroaromatic aldehydes with various nitroalkaness represented by nitromethane, nitroethane and 2-nitropropane.ncidentally, the in situ formed complex Cu(II)-2′a was found toe stable and does not lose its performance during eight recy-le experiments studied. This catalyst also demonstrated excellentiastereoselectivity in selected aldehyde with nitroethane. Theinetic investigations of a representative substrate 3a show first-rder dependence on the concentrations of the catalyst Cu(II)-2′a,itromethane, but no dependence on the initial concentrationf the substrate, 3a. This protocol with catalyst Cu(II)-2′a, wasxtended successfully for the synthesis of (R)-isoproterenol, aotent ˇ-adrenoreceptor in three steps by using the easily avail-ble starting material 3,4-dimethoxybenzaldehyde in high yieldnd enantioselectivity.

cknowledgements

Anjan Das and RIK are thankful to DST and CSIR network projectn catalysis for financial assistance. Anjan Das is thankful to UGCor awarding SRF and to AcSIR for Ph. D enrollment. Authors arelso grateful to Analytical Discipline for providing instrumentalacilities.

ppendix A. Supplementary data

Supplementary data associated with this article can be found, inhe online version, at doi:10.1016/j.apcata.2013.03.032.

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