Synthesis and application of new iminopyridine ligands to enantioselective copper(II)-catalyzed Henry reaction

Accepted Manuscript Title: Synthesis and application of new iminopyridine ligands to enantioselective copper(II)-catalyzed Henry reaction Author: Maurizio Solinas Barbara Sechi Salvatore Baldino Giorgio Chelucci PII: DOI: Reference:

S1381-1169(13)00237-9 http://dx.doi.org/doi:10.1016/j.molcata.2013.06.008 MOLCAA 8784

To appear in:

Journal of Molecular Catalysis A: Chemical

Received date: Revised date: Accepted date:

23-1-2013 30-4-2013 17-6-2013

Please cite this article as: M. Solinas, B. Sechi, S. Baldino, G. Chelucci, Synthesis and application of new iminopyridine ligands to enantioselective copper(II)catalyzed Henry reaction, Journal of Molecular Catalysis A: Chemical (2013), http://dx.doi.org/10.1016/j.molcata.2013.06.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis and application of new iminopyridine ligands to enantioselective copper(II)-catalyzed Henry reaction

CNR, Istituto di Chimica Biomolecolare UOS Sassari, Traversa La Crucca, 3 I-07100 Sassari,

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a

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Maurizio Solinas,a Barbara Sechi,a Salvatore Baldino,b Giorgio Cheluccib,*

Italy.

Dipartimento di Agraria, Università di Sassari, Viale Italia 39, 07100 Sassari, Italy.

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b

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*Corresponding author. Tel: +39 079 229539; fax: +39 079 229559. E-mail address: [email protected]

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Keywords: Chiral iminopyridines, Enantioselective Henry reaction, Asymmetric catalysis,

Abstract

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β-Nitroalcohols, Copper(II)-catalysts, Cu(OAc)2·H2O

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Chiral iminopyridines obtained by reaction between a variety of chiral amines and pyridyl aldehydes or ketones were assessed as catalysts in the enantioselective Henry reaction between nitromethane

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and 2-methoxybenzaldehyde in the presence of copper(II) acetate. 1-(2-Methoxyphenyl)-2nitroethanol was obtained in moderate yields and good enantioselectivities (up to 82% ee) under straightforward experimental conditions without the need for air or moisture exclusion. The best enantioselectivity (82% ee) was obtained by an iminopyridine based on a camphane skeleton.

1. Introduction

The Henry reaction (also referred as nitroaldol reaction) is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones, and is one of the most important example of atom-economy transformation (Scheme 1) [1]. The resulting products, β-nitroalcohols, are widely used as organic intermediates because of the many possible transformations of the nitro group into other functional groups.

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Page 1 of 19

OH R2 R3 R1 * * NO2

catalyst

O

+

R1

R3

R2

NO2

solvent

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Scheme 1 The reaction can be catalysed by a base such as secondary amines, but can be also metal catalysed. Since the seminal work by Shibasaki [2], several transition metals such as Cu [3], Zn [4], Co [5], Cr

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[6], Pd [7], and rare metals [2,7,8] have been applied to the catalytic version of the Henry reaction and in particular to the asymmetric one. In this contest, Cu(I)- and Cu(II)-complexes are often used

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because of their availability and low toxicity. Moreover, copper possesses excellent chelating properties and allows the coordination of bidentate as well as polydentate ligands. The first example

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of an enantioselective copper-catalyzed Henry reaction was reported by Jørgensen and co-workers in 2001, proving the ability of bisoxazoline ligands in this process [9a]. Since then, many types of chiral ligands have been developed and most of them are nitrogen based ligands such as bisoxazolines [9],

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bisoxazolidines [10], diamines [11], (–)-sparteine [12], sulfonyldiamines [3b], sulfonimidamides [3a], tetrahydrosalens [13], and N,N'-dioxides [3a].

Among nitrogen ligands, some examples of copper complexes containing iminopyridine ligands have

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been synthesized and their efficiency established [14]. Nguyen [15] and Jones [16] groups reported

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the use of Cu(I)- and Cu(II)-complexes derived from bis-iminopyridines A based on the (R,R)-1,2diaminocyclohexane framework, while Pedro and Blay group [14,17] developed iminopyridine

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ligands B and C obtained by condensation of naturally occurring chiral ketones with aminoalkylpyridines (Figure 1).

In line with our interest on the synthesis and application to enantioselective catalysis of chiral pyridine-based ligands [18], we now report the synthesis of new chiral iminopyridine ligands and the results obtained in the Cu(II)-catalyzed Henry reaction.

R

N N

N

R2

N

R N

A (R = H, Me)

R2 ( )n

R1

N

N

N R3

C

B (n = 0,1; R1 = Me, SO3H, CO2H; R2 = H, Me; R3 = H, Me)

Figure 1

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Page 2 of 19

2. Experimental 2.1. General remarks Ligand syntheses were carried out under nitrogen atmosphere in an oven-dried glassware with

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magnetic stirring, while catalytic nitro-aldol reactions were performed without air or moisture exclusion. Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. All solvents were HPLC grade. THF was distilled from sodium-

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benzophenone ketyl and degassed thoroughly with dry nitrogen directly before use. Unless otherwise noted, organic extracts were dried with Na2SO4, filtered through a fritted glass funnel, and

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concentrated with a rotary evaporator (20-30 mmHg). Flash chromatography was performed with silica gel (200-300 mesh) using the mobile phase indicated. Melting points are collected using a 400.1 MHz,

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BÜCHI B-540 and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Mercury (1H C 100.6 MHz) with tetramethylsilane (TMS) as reference. Chemical shifts (δ) are

reported in ppm and multiplicity is indicated as follow: s = singlet, d = doublet, t = triplet, q =

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quartet, m = multiplet, bs = broad signal. Coupling constants (J) are indicated in hertz.

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(S)-1-phenylethanamine (2a), (R)-1-(naphthalen-1-yl)ethanamine (2b), (R)-1-cyclohexylethanamine (2c), (R)-1-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)ethanamine (3d), (R)-3,3-dimethylbutan-2-amine (1R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine

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(2e),

(2f),

(1R,2S,4R)-1,7,7-

trimethylbicyclo[2.2.1]heptan-2-amine (2g) were commercial starting materials. (1R,2R,4R)-1,7,7-

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trimethylbicyclo[2.2.1]heptan-2-amine (2h) [19], (S)-1-phenyl-N-(pyridin-2-ylmethylene)ethanamine (3a) [20], (R)-N-[(2-pyridyl)methylene]-1-(1-napthyl)ethylamine (3b) [21], (R)-1-cyclohexyl-N(pyridin-2-ylmethylene)ethanamine (3c) [22], (5S,7R)-6,6-dimethyl-2-phenyl-5,7-methanoquinolin8(5H)-one (12) [23] were prepared according to reported procedures. 2.2. General procedure for the synthesis of imines (3d),(3f)–(3h) and (8b). The proper amine (1.8 mmol) was added dropwise to a stirred mixture of pyridine-2-carboxaldehyde (0.19 g, 1.8 mmol) and anhydrous K2CO3 (0.5 g) in diethyl ether (10 mL). The resulting mixture was stirred at room temperature overnight and then filtered. The organic phase was evaporated and the residue was purified by flash chromatography eluting with petroleum ether/EtOAc = 9:1 and then 8:2.

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2.2.1. (R)-N-(pyridin-2-ylmethylene)-1,2,3,4-tetrahydronaphthalen-1-amine (3d). Yield 88%; Pale yellow liquid; []D25 +53.4 (c 2.41, CHCl3); 1H NMR (400.1 MHz, CDCl3): ! 8.68–8.66 (m, 1 H, ArH), 8.51 (s, 1 H, CNH), 8.10–8.08 (m, 1 H, ArH), 7.76–7.71 (m, 1 H, ArH), 7.34–7.31 (m, 1 H, ArH), 7.20–7.11 (m, 3 H, ArH), 7.05–7.04 (m, 1 H, ArH), 4.65 (t, J = 6.1 Hz, 1 H, CH), 2.97–2.81

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(m, 2 H, CH2), 2.15–2.04 (m, 3 H, CH2), 1.92–1.84 (m, 1 H, CH2); 13C NMR (100.6 MHz, CDCl3): ! 161.4, 154.7, 149.3, 137.1, 136.5, 136.4, 129.2, 128.7, 127.0, 125.8, 124.7, 121.4, 68.1, 31.2, 29.4,

cr

19.9. Anal. Calcd. for C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found: C, 81.51; H, 6.90; N, 11.81. 2.2.2. (R)-3,3-dimethyl-N-(pyridin-2-ylmethylene)butan-2-amine (3e). Yield 86%; Pale yellow

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liquid; []D25 –93.9 (c 1.92, CHCl3); 1H NMR (400.1 MHz, CDCl3): δ 8.63 (d, J = 4.6 Hz, 1 H, ArH), 8.33 (s, 1 H, CNH), 8.05 (d, J = 7.8 Hz, 1 H, ArH), 7.72 (dd, J = 7.8, 7.8 Hz, 1 H, ArH), 7.28– 13

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7.30 (m, 1 H, ArH), 3.07 (q, J = 6.4 Hz, 1 H, CH), 1.17 (d, J = 6.4 Hz, 3 H, CH3), 0.93 (s, 9 H, t-Bu); C NMR (100.6 MHz, CDCl3): δ 159.6, 155.1, 149.2, 136.4, 124.4, 121.1, 75.2, 34.3, 26.6, 17.3.

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Anal. Calcd. for C12H18N2: C, 75.74; H, 9.53; N, 14.72. Found: C, 75.47; H, 9.57; N, 14.68. 2.2.3. (1R,3S,5S)-2,6,6-trimethyl-N-(pyridin-2-ylmethylene)bicyclo[3.1.1]heptan-3-amine (3f).

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Yield 89%; Pale yellow liquid; []D25 –31.5 (c 2.33, CHCl3); 1H NMR (400.1 MHz, CDCl3): δ 8.63–

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8.61 (m, 1 H, ArH), 8.25 (s, 1 H, CH), 8.03–8.01 (m, 1 H, ArH), 7.73–7.69 (m, 1 H, ArH), 7.29–7.25 (m, 1 H, ArH), 3.57 (dt, J = 10, 5.2 Hz, 1 H, CH), 2.42–2.36 (m, 1 H, CH), 2.32–2.25 (m, 1 H, CH), 2.15–2.11 (m, 1 H, CH), 2.00–1.91 (m, 2 H, CH), 1.24 (s, 3 H, CH3), 1.06 (s, 3 H, CH3), 1.00 (d, J =

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7.4 Hz, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 158.6, 154.9, 149.3, 136.4, 124.3, 121.5, 70.0, 47.4, 43.2, 41.5, 38.8, 35.6, 33.7, 27.9, 23.5, 19.7; Anal. Calcd. for C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.41; H, 9.20; N, 11.51.

2.2.4. (1R,2S,4R)-1,7,7-trimethyl-N-(pyridin-2-ylmethylene)bicyclo[2.2.1]heptan-2-amine (3g). Yield 85%; Brown solid mp 70–72 °C; []D25 +23.5 (c 2.06, CHCl3); 1H NMR (400.1 MHz, CDCl3): δ 8.64–8.62 (m, 1 H, ArH), 8.32 (s, 1 H, CNH), 8.12–8.09 (m, 1 H, ArH), 7.76–7.72 (m, 1 H, ArH), 7.31–7.28 (m, 1 H, ArH), 3.52 (ddd, J = 10.3, 3.7, 2.0 Hz, 1 H, CH), 2.25–2.15 (m, 2 H, CH or CH2), 1.84–1.73 (m, 2 H, CH or CH2) 1.44-1.24 (m, 2 H, CH or CH2), 0.98 (s, 3 H, CH3), 0.93 (s, 3 H, CH3), 0.72 (s, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 160.1, 155.1, 149.2, 136.4, 124.3, 121.2, 75.2, 50.8, 48.4, 45.5, 37.3, 28.6, 28.3, 19.7, 18.8, 13.5; Anal. Calcd. for C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 78.97; H, 9.20; N, 11.51.

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2.2.5. (1R,2R,4R)-1,7,7-trimethyl-N-(pyridin-2-ylmethylene)bicyclo[2.2.1]heptan-2-amine (3h). Yield 90%; Pale yellow liquid; []D25 –122.9 (c 3.54, CHCl3); 1H NMR (400.1 MHz, CDCl3): δ 8.62–8.60 (m, 1 H, ArH), 8.18 (s, 1 H, CNH), 8.04–8.02 (m, 1 H, ArH), 7.72–7.68 (m, 1 H, ArH), 7.29–7.25 (m, 1 H, ArH), 3.28 (dd, J = 8.6, 4.3 Hz, 1 H, CH), 1.96–1.92 (m, 1 H, CH), 1.79–1.69 (m,

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4 H, CH2), 1.24 (s, 3 H, CH3) overlapped with 1.24–1.16 (m, 2 H, CH2), 0.89 (s, 3 H, CH3), 0.70 (s, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 158.6, 155.2, 149.1, 136.3, 124.2, 120.9, 78.6, 50.6,

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47.1, 45.6, 38.7, 36.5, 27.6, 20.7, 20.5, 12.7; Anal. Calcd. for C16H22N2: C, 79.29; H, 9.15; N, 11.56.

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Found: C, 79.32; H, 9.26; N, 11.40.

2.2.6. (1R,2S,4R)-1,7,7-trimethyl-N-(1-(6-methylpyridin-2-yl)ethylidene)bicyclo[2.2.1]heptan-2amine (8b). Yield 85%; Pale yellow liquid; []D25 +59.3 (c 1.63, CCl4); 1H NMR (400.1 MHz,

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CDCl3): δ 7.99 (d, J = 7.6 Hz, 1 H, ArH), 7.57 (dt, J = 7.6 Hz, 1 H, ArH), 7.11 (d, J = 7.6 Hz,1 H, ArH), 3.82 (ddd, J = 10.7, 4.3, 2.1 Hz, 1 H), 2.57 (s, 3 H, CH3), 2.51–2.49 (m, 1 H), 2.32 (s, 3 H, CH3), 1.77–1.70 (m, 3 H), 1.33–1.22 (m, 3 H), 1.01 (s, 3 H, CH3), 0.95 (s, 3 H, CH3) 0.78 (s, 3 H,

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CH3); 13C NMR (100.6 MHz, CDCl3): δ 165.1, 158.0, 156.5, 136.2, 122.9, 117.9, 65.1, 50.4, 48.0, 45.6, 37.6, 28.5, 28.1, 24.4, 19.9, 18.8, 14.5, 14.1; Anal. Calcd. for C17H24N2: 79.64; H, 9.44; N,

2.2.7.

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10.93. Found: C, 79.35; H, 9.48; N, 10.89.

(1R,2S,4R)-1,7,7-trimethyl-N-(1-(pyridin-2-yl)ethylidene)bicyclo[2.2.1]heptan-2-amine

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(8a). A solution of the amine (3.0 mmol), 2-acetylpyridine (399 mg, 3.3 mmol) and Ti(OEt)4 (1.37 g, 6.0 mmol) in anhydrous THF (2 mL) was heated at 70 °C until completion (TLC). After cooling, the solvent was removed under vacuum and the residue taken up in ethyl acetate (10 mL). This solution was vigorously stirred while a saturated solution of brine (2 mL) was slowly added. After 15 min, the mixture was filtered through a plug of Celite that was washed with ethyl acetate. The organic phase was separated and dried over anhydrous Na2SO4. The organic phase was evaporated and the residue was purified by flash chromatography eluting with petroleum ether/EtOAc = 9:1 and then 8:2.Yield 76%; Pale yellow liquid; []D25 +70.2 (c 1.13, CCl4); 1H NMR (400.1 MHz, CDCl3): δ 8.58 (dq, J = 4.8, 0.9 Hz, 1 H, ArH), 8.23 (dt, J = 7.9, 1.1 Hz, 1 H, ArH), 7.73–7.68 (m, 1 H, ArH), 7.28–7.24 (m, 1 H, ArH), 3.83 (ddd, J = 10.8, 4.2, 2.1 Hz, 1 H), 2.52–2.45 (m, 1 H), 2.35–2.28 (m, 1 H) overlapped with 2.32 (s, 3 H, CH3), 1.78–1.71 (m, 2 H), 1.34–1.24 (m, 2 H), 1.01 (s, 3 H, CH3) 0.98–0.93 (m, 1 H) overlapped with 0.95 (s, 3 H, CH3), 0.78 (s, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 164.7,

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158.4, 147.9, 136.0, 123.7, 121.0, 65.2, 50.5, 48.1, 45.7, 37.7, 28.5, 28.1, 19.9, 18.8, 14.6, 14.1;

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Anal. Calcd. for C17H24N2: 79.64; H, 9.44; N, 10.93. Found: C, 79.95; H, 9.41; N, 10.90.

2.3. General procedure for the synthesis of imines (14a)–(14d).

A solution of the amine (1.5 mmol) and tetrahydroquinolone 12 (399 mg, 1.5 mmol) in anhydrous

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benzene (15 mL) containing few drops of formic acid was heated in a Dean–Stark apparatus. After

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completion (TLC) the solvent was removed under reduced pressure and the residue was purified by

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flash chromatography eluting with petroleum ether/EtOAc = 9:1and then 8:2.

2.3.1.

N-((5S,7R)-5,7-methano-6,6-dimethyl-2-phenyl-6,7-dihydroquinolin-8(5H)-

ylidene)cyclohexanamine (14a). Yield 76%; Pale yellow oil; []D25 +80.7 (c 2.13, CHCl3); 1H

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NMR (400.1 MHz, CDCl3): δ 8.05–8.03 (m, 2 H, ArH), 7.52–7.45 (m, 3 H, ArH), 7.40–7.37 (m, 1 H, ArH), 7.30 (d, J = 7.8 Hz, 1 H, ArH), 2.77–2.72 (m, 2 H, CH or CH2), 2.13–2.01 (m, 2 H, CH or CH2), 1.86–1.65 (m, 4 H, CH or CH2), 1.47 (s, 3 H, CH3), 1.44–1.26 (m, 7 H, CH or CH2), 0.80 (s, 3 13

C NMR (100.6 MHz, CDCl3): δ 159.1 (2C), 154.3, 139.5, 139.4, 133.3, 128.5 (2C),

d

H, CH3);

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128.3, 126.3 (2C), 117.4, 62.0, 56.2, 46.9, 45.7, 39.7, 33.8, 33.6, 26.9, 26.2, 25.4, 25.3, 23.3. Anal.

2.3.2.

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Calcd. for C24H28N2: C, 83.68; H, 8.19; N, 8.13. Found: C, 83.89; H, 8.35; N, 8.08. (S)-1-phenyl-N-((5S,7R)-5,7-methano-6,6-dimethyl-2-phenyl-6,7-dihydroquinolin-

8(5H)ethanamine (14b). Yield 66%; Pale yellow oil; []D25 –38.5 (c 0.84, CCl4); 1H NMR (400.1 MHz, CDCl3): δ 8.08–8.06 (m, 2 H, ArH), 7.51–7.47 (m, 5 H, ArH), 7.42–7.38 (m, 1 H, ArH), 7.35– 7.31 (m, 2 H, ArH), 7.25–7.21 (m, 2 H, ArH), 4.45 (q, J = 6.6, Hz, 1 H), 4.09 (d, J = 2.7, Hz, 1 H), 2.67 (t, J = 5.7 Hz, 1 H), 2.52 (ddd, J = 9.8, 6.6, 5.7 Hz, 1 H), 2.09 (td, J = 6.6, 2.7 Hz, 1 H), 1.48 (d, J = 6.6 Hz, 3 H, CH3) 1.25 (s, 3 H, CH3), 0.82 (s, 3 H, CH3);

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C NMR (100.6 MHz, CDCl3): δ

159.1, 154.3, 147.7, 139.6, 139.5, 133.3, 128.6 (2C), 128.3, 128.0 (2C), 127.2 (2C), 126.5, 126.4 (2C), 117.6, 64.6, 59.5, 46.8, 45.4, 39.5, 33.8, 26.6, 25.6, 23.2; Anal. Calcd. for C26H26N2: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.43; H, 7.23; N, 7.70.

2.3.3.

(R)-1-phenyl-N-((5S,7R)-5,7-methano-6,6-dimethyl-2-phenyl-6,7-dihydroquinolin-

8(5H)ethanamine (14c). Yield 58%; Pale yellow oil; []D25 –107.7 (c 2.14, CCl4); 1H NMR (400.1

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MHz, CDCl3): δ 8.02–8.00 (m, 2 H, ArH), 7.50–7.48 (m, 2 H, ArH), 7.43–7.38 (m, 4 H, ArH), 7.34– 7.30 (m, 2 H, ArH), 7.19–7.15 (m, 2 H, ArH), 4.05 (q, J = 6.7 Hz, 1 H, CH), 3.85 (d, J = 2.7 Hz, 1 H, CH), 2.64 (t, J = 5.7 Hz, 1 H, CH), 2.60–2.53 (m, 1 H, CH), 2.47–2.43 (m, 1 H, CH), 1.38 (s, 3 H, CH3), 1.32 (d, J = 6.7 Hz, 3 H, CH3), 0.76 (s, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 158.5,

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154.2, 146.1, 139.6, 139.5, 133.3, 128.5 (2C), 128.4 (2C), 128.3, 126.7 (2C), 126.5 (2C), 126.4, 117.4, .61.3, 55.5, 46.9, 43.3, 39.9, 33.4, 27.1, 25.4, 23.2; Anal. Calcd. for C26H26N2: C, 85.21; H,

2.3.4.

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7.15; N, 7.64. Found: C, 85.68; H, 7.55; N, 7.52

(1R,2S,4R)-1,7,7-trimethyl-N-((5S,7R)-5,7-methano-6,6-dimethyl-2-phenyl-6,7-

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dihydroquinolin-8(5H)-ylidene)bicyclo[2.2.1]heptan-2-amine (14d). Yield 61%; White solid, mp 51-53 °C; []D25 +114.4 (c 1.47, CHCl3); 1H NMR (400.1 MHz, CDCl3): δ 8.08–8.03 (m, 2 H, ArH),

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7.49–7.42 (m, 3 H, ArH), 7.39–7.33 (m, 1 H, ArH), 7.27–7.23 (m, 1 H, ArH), 4.11 (d, J = 2.7 Hz, 1 H, CH), 3.02 (ddd, J = 7.8, 3.9, 1.5 Hz, 1 H), 2.73–2.65 (m, 1 H, CH), 2.48–2.32 (m, 2 H, CH), 1.81–1.71 (m, 3 H, CH), 1.45–0.97 (m, 3 H, CH) overlapped with 1.42 (s, 3 H, CH3), 0.91 (s, 3 H,

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CH3), 0.89 (s, 3 H, CH3), 0.83 (s, 3 H, CH3), 0.77 (s, 3 H, CH3); 13C NMR (100.6 MHz, CDCl3): δ 158.8, 153.9, 139.8, 139.5, 133.3, 128.6 (2C), 128.3, 126.3 (2C), 117.2, 63.5, 60.8, 48.9, 47.9, 47.1,

d

45.3, 43.6, 40.1, 38.6, 33.3, 28.6, 27.5, 27.2, 23.2, 19.9, 18.8, 13.9. Anal. Calcd. for C28H34N2: C,

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84.37; H, 8.60; N, 7.03. Found: C, 84.68; H, 8.68; N, 7.11. 2.4. General procedure for the enantioselective Henry reaction.

Ac ce p

A mixture of the ligand (0.055 mmol) and Cu(OAc)2·H2O (9.9 mg, 0.05 mmol) in absolute EtOH (3 mL) was stirred at 25 °C for 1 hour. To this green mixture 2-methoxybenzalehyde (0.5 mmol) and nitromethane (0.2 mL) were added in sequence. When DIPEA was used the recipient was introduced in a bath at the required temperature and DIPEA (8.7 mL, 0.05 mmol) was added followed by nitromethane (0.2 mL). The resulting reaction mixture was stirred at the required temperature and monitored by TLC. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/diethyl ether = 85:15). The enantiomeric excess of 2nitro-1-phenylethanol 5 was determined by HPLC (Phenomenex Lux 5u Cellulose-1 column), hexane/i-PrOH 90:10, 0.8 mL/min: (R) enantiomer tr = 15.8, (S) enantiomer tr = 18.7. (E)-1methoxy-2-(2-nitrovinyl)benzene (6) was characterised by NMR and Mass spectroscopy; 1H NMR (400.1 MHz, CDCl3): δ 8.16 (d, J = 13.7 Hz, 1 H, vinyl H), 7.89 (d, J = 13.7 Hz, 1 H, vinyl H), 7.47 (m, 2 H, ArH), 7.02 (m, 2 H, ArH), 3.97 (s, 3 H, OCH3). GC-MS (EI): m/z 179 [M]+

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3. Results and discussion The iminopyridines 3a-h, having different steric hindrance in the proximity of the imino nitrogen, were easily prepared by condensation of pyridine-2-carboxaldehyde (1) with the commercially available chiral amines 2a-h in diethyl ether containing anhydrous K2CO3 at room

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temperature (Scheme 2). All ligands were obtained as pure E isomers as determined by NOESY

H

cr

NMR spectra.

H

Et2O, K2CO3 *R NH2 N

H

,

Me

b: R* =

H e: R* =

Me

,

f: R* =

c: R* =

,

d

H

Me

,

,

g: R* =

H

d: R* =

h: R* =

H H

te

Scheme 2

,

an

Ph Me

N

H

M

a: R* =

N

3a-h

1

H

*R

rt, 24 h

2a-h

us

O

Ac ce p

The activity of these ligands in the asymmetric Henry reaction was proved by using the addition of nitromethane to 2-methoxybenzalehyde as the model reaction (Scheme 3). According to the reaction conditions for copper catalyzed Henry reactions described by Evans for bis-oxazolines [24] and more recently by Pedro and Blay group for monoterpene derived iminopyridines [25], the addition was carried out by using 10 mol% copper(II) acetate as the source for the metal ion in absolute ethanol. The catalytic system was formed in situ by stirring 11 mol% of ligand with 10 mol% Cu(OAc)2·H2O in absolute ethanol for 1 hour at room temperature. The reactions were performed in test tubes stopped with a septum with no special attention given for air or moisture exclusion. Moreover, to compare the activity of these ligands the reactions were carried out in all cases for 22 h. The results obtained under these reaction conditions by using ligands 3a–h are showed in Table 1 (Entries 1-8).

8

Page 8 of 19

OMe CHO

+ CH3NO2

Ligand, Cu(OAc)2.H2O

OMe OH

OMe NO2

NO2

+

EtOH, rt, 22 h 4

5

6

ip t

Scheme 3 Ligand 3a bearing the -methylbenzyl group on the imino nitrogen afforded the -nitroalkanol

cr

5 in 66% yield with 7% ee. Disappointingly, the reaction also gave a relevant amount (33% yield) of the nitroalkene 6, resulting from elimination. An increasing of the steric hindrance of the

us

-methylnaphthyl substituent in 3b brought about a light increasing of the enantioselectivity (17% ee, entry 2), indicating that an encumbered chiral substituent on the imino nitrogen is necessary for

an

enhancing the stereoselectivity of the reaction. This possibility was confirmed by passing from ligand 3c to 3e (entry 3 vs 5). Thus, the tert-butyl substituted ligand 3e increased the reaction

M

stereoselectivity up to 41% ee, although a lower yield of 5 was obtained and also the 5/6 ratio was deteriorated (entry 5). These results supported that a fine tuning in the steric properties of the

chemoselectivity.

d

substituent around the imino nitrogen is required to get best results both in terms of stereo- and

te

With this aim ligands 2f-h were prepared. Ligand 3f, bearing the pinane framework, produced a catalytic performance comparable to that of ligand 3a (9% ee) (entry 6 vs 1, Table 1). On the other

Ac ce p

hand, ligand 3g, incorporating the endo-amine 2g of the camphane skeleton, considerably increased the enanatioselectivity of the reaction, affording R nitroalcohol 5 in 41% yield and with 66% ee. Finally, ligand 3h formed from the amine 2h, which is the exo-epimer of 2g, led to the nitroalcohol product with 48% ee and opposite S stereochemistry (entry 8). Next we planned some structural modification of ligand 3g in order to stiffen its structure by introducing a steric constrain in proximity of the imino or pyridine nitrogen. Thus, the new ligands 8a and 8b were synthesized by condensation of the amine 2g with 1-(pyridin-2-yl)ethanone or 6methylpyridine-2-carbaldehyde, respectively, in refluxing THF containing Ti(OEt)4 (Scheme 4) [26]. It should be noted that other attempts to obtain the desired ligands in the presence of a catalytic amount of p-TolSO3H or BF3·Et2O with azeotropic removal of toluene-water (Dean-Stark) gave only moderate conversions. The introduction of a methyl group on the imino carbon of 3g had a dramatic effect on the activity of the new ligand 8a. Thus, the catalyst 8a-Cu(II)OAc afforded the racemic nitroalcohol 5 in only 10%

9

Page 9 of 19

yield, being the main product the nitroalkene 6 (65% yield) (entry 9, Table 1). On the other hand, the introduction of a methyl group on the 6-postion of the pyridine ring of 3g had a minor impact on the activity, which was in any case negative with respect to the parent ligand. In fact, the catalyst 8b-Cu(II)OAc gave 5 in 32% yield and with 45% ee (entry 10), being the nitrostyrene compound the

ip t

major reaction product.

Found that 3g was the best performing ligand, some optimization experiments were pursued in order

cr

to maximize the enantio- and chemoselectivity of the nitroaldol reaction. Firstly, the reaction temperature was lowered to 0 °C. Unfortunately, this reaction temperature resulted in impractical

us

reaction times. The addition of the Brønsted base diisopropylethylamine (DIPEA) [24,25] accelerated the reaction affording at 0 °C the nitroalcohol with 79% ee and at the same time with 90%

an

chemoselectivity (entry 11). A further increase in the enantiomeric excess of the product (82% ee) was next obtained by carrying out the reaction at –30 °C, although with a lower conversion (entry 12). Finally, almost complete conversion was achieved by carrying out the reaction for 48 h under the

Ac ce p

te

d

M

same reaction conditions (entry 13).

10

Page 10 of 19

Table 1. Henry reaction between nitromethane and 2-methoxybenzalehyde (Scheme 3).a 6-Yield

5-ee

(%)b

(%)c

(%)c

(%)d

5-Configuration.e

3a

100

67

33

7

S

2

3b

80

58

22

17

R

3

3c

83

59

24

22

S

4

3d

77

44

33

19

S

5

3e

86

30

56

41

S

6

3f

87

54

33

9

7

3g

62

41

21

66

8

3h

83

30

53

48

9

8a

75

10

65

10

8b

92

32

60

11

3gf

100

90

10

79

R

12

3gg

63

55

8

82

R

13

3gh

95

79

81

R

R

an

S

0

--

45

R

M

d 16

R

te

a

us

1

ip t

5-Yield

cr

Entry Ligand Conversion

All reactions were carried out on a 0.5 mmol scale by using 11 mol% of ligand in combination with

c

f

Determined by GC analysis by using a Alltech EC-5 30 m column.

Isolated yields after column chromatography.

d e

Ac ce p

10 mol% Cu(OAc)2·H2O in 3 mL of absolute EtOH at rt for 22 h. b

Determined by HPLC analysis by using a Lux 5u Cellulose-1 column.

Determined by HPLC analysis by comparing a known sample of (R)-5.

Reaction carried out at 0 °C in the presence of 10% DIPEA.

g

Reaction carried out at –30 °C in the presence of 10% DIPEA.

h

Reaction carried out at –30 °C in the presence of 10% DIPEA for 48 h.

11

Page 11 of 19

R1 R1 N

H

R2

R2

THF, reflux

NH2

7a,b

N

N

8a,b

2g

ip t

O

H

Ti(OEt)4

+

a: R1 = Me, R2 = H; b: R1 = H, R2 = Me

cr

Scheme 4

In this study we have also examined the possibility to assess in the Henry reaction iminopyridine

us

ligands in which the imino functionality is insert in a rigid cyclic structure, as for instance the iminopyridines with the general formula 10 depicted in Scheme 5. A patent reports that the reaction

an

of the tetrahydoquinolone 9 (R1 = H) with (R)-1-phenylethanamine in ethanol affords the related imine 10 (R1 = H, R* = (R)--methylbenzyl) in 95% yield [27]. However, the signals of the 1H and 13

C NMR spectra reported as support for the imino structure, do not fulfil to this requirement, but

M

rather to that of the related isomeric enamine 11 (R1 = H, R* = (R)--methylbenzyl). This erroneous attribution is supported by two papers, which indicate the preferred formation of enamines when 9

R1

+

R* NH2

Ac ce p

N

te

d

(R1 = H) is reacted with amines [28].

O

9

N

R1

+

N

N R*

R1

NH 10

R*

11

Scheme 5

An obvious way to prevent the enamine formation is the presence of proper substituents on the position of the carbonyl group of 9. We envisaged the known chiral nonracemic tetrahydroquinolone 12 (Scheme 6) as a compound fulfilling such a requirement. Thus, the enantiomerically pure ketone 12 was prepared from (-)-pinocarvone according to a well-described procedure [23] and then reacted with cyclohexylamine to afford the imine 14a (Scheme 6). The use of this achiral amine was dictated by the necessity to determine the influence of the two stereocentres in 12 on the stereoselectivity of the Henry reaction. The addition of nitromethane to 2-methoxybenzalehyde catalyzed by the 14a-Cu(II)OAc complex afforded the alcohol (R)-5 in good yield (78%), demonstrating its chemical efficiency in this reaction. On the other hand, the enantiomeric excess was low (13% ee, Table 2),

12

Page 12 of 19

but sufficient to indicate the influence of the two stereocentres on the reaction stereoselectivity. On this basis, the imine 14b was prepared from the chiral amine (S)-2a (Scheme 6). The 14b-Cu(II)OAc complex gave similar yield and improved stereoselectivity (31% ee, Table 2) with respect to 14a-Cu(II)OAc, but in this case the opposite enantiomeric S alcohol was obtained. To determine a

ip t

potential mismatch relation between the stereocentres on the tetrahydroquinoline ring and that on the imino nitrogen, ligand 14c was prepared from the (R)-2a and 12 (Scheme 6). The 14c-Cu(II)OAc This

increased

stereoselectivity

is

probably

indicative

that

cr

complex gave activity comparable to 14a-Cu(II)OAc, but (R)-5 was formed with 37% ee (Table 2). the

stereocentres

on

the

us

tetrahydroquinoline ring and on the imino substituent act cooperatively. Then, it was examined in the Henry reaction the Cu(II)-complex derived from ligand 14d, obtained by reacting the sterically encumbered amine 2g with 12 (Scheme 6). Unfortunately, the 14d-Cu(II)OAc complex gave both

an

unsatisfactory catalytic activity and very low stereoselectivity (4% ee, Table 2).

N

R NH2

Ph

N R

14a-d

d

13: R = H2N

,

Ac ce p 14a: R =

N

THF, reflux

13, 2a,g

12

te

O

Ph

Ti(OEt)4

M

+

14b: R =

H

Ph Me

,

H 14c: R =

Me Ph

,

14d: R =

H

Scheme 6

13

Page 13 of 19

Table 2. Henry reaction between nitromethane and 2-methoxybenzalehyde (Scheme 3).a Entry Ligand Conversion (%)b 5-Yield (%)c 6-Yield (%)c 5-ee (%)d 5-Configuratione 14a

88

78

10

13

R

2

14b

73

66

7

31

S

3

14c

64

51

13

37

4

14d

46

26

20

4

us

b

Determined by GC analysis by using a Alltech EC-5 30 m column.

Isolated yields after column chromatography.

Determined by HPLC analysis by using a Lux 5u Cellulose-1 column.

an

d

Determined by HPLC analysis by comparing a known sample of (R)-5.

M

e

S

All reactions were carried out on a 0.5 mmol scale by using 11 mol% of ligand in combination with

10 mol% Cu(OAc)2·H2O in 3 mL of absolute EtOH at rt for 22 h. c

R

cr

a

ip t

1

4. Conclusion

In conclusion, we have developed a new catalytic system for the copper-catalyzed enantioselective

d

Henry reaction. This system uses copper(II) acetate in combination with iminopyridine ligands, which are easily prepared from commercially available chiral amines and pyridyl aldehydes or

te

ketones. The model reaction between nitromethane with 2-methoxybenzalehyde affords the related 1-(2-methoxyphenyl)-2-nitroethanol in moderate yields and good enantioselectivities (up to 82% ee)

Ac ce p

under straightforward experimental conditions without the need for air or moisture exclusion.

Acknowledgements

Financial support from the University of Sassari is gratefully acknowledged.

References [1]

For reviews on the asymmetric Henry reaction see: (a) G. Rosini, in: B.M. Trost, I. Fleming (Eds.), Comprehensive Organic Synthesis, Pergamon: New York, NY, 1991, Vol. 2, pp 321– 340. (b) F.A. Luzzio Tetrahedron 57 (2001) 915–945. (c) Y. Sohtome, Y. Hashimoto, K. Nagasawa, Adv. Synth. Catal. 347 (2005) 1643–1648. (d) J. Boruwa, N. Gogoi, P.P. Saikia, N.C. Barua Tetrahedron: Asymmetry 17 (2006) 3315–3326. (e) H. Li, B. Wang, L. Deng, J. Am. Chem. Soc. 128 (2006) 732–733. (f) C. Palomo, M. Oiarbide, A. Laso Eur. J. Org. Chem. (2007) 2561–2574.

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[2]

H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki J. Am. Chem. Soc. 114 (1992) 4418–4420.

[3]

For Copper, see: (a) B. Qin, X. Xiao, X. Liu, J. Huang, Y. Wen, X. Feng J. Org. Chem. 72 (2007) 9323–9328. (b) T. Arai, R. Takashita, Y. Endo, M. Watanabe, A. Yanagisawa J. Org. Chem. 73 (2008) 4903–4906. (c) M. Steurer, C. Bolm J. Org. Chem. 75 (2010) 3301–3310. Z.M.A. Judeh Tetrahedron: Asymmetry 22 (2011) 2065–2070.

[4]

ip t

(d) Y. Qiong, G. Qi, Z.M.A. Judeh Eur. J. Org. Chem. (2011) 4892–4898. (e) Y. Qiong, G. Qi, For Zinc, see: (a) B.M. Trost, V.S.C. Yeh Angew. Chem. Int. Ed. 41 (2002) 861–863. (b) B.M.

cr

Trost, V.S.C. Yeh, H. Ito, N. Bremeyer Org. Lett. 4 (2002) 2621–2623. (c) C. Palomo, M. Oiarbide, A. Laso Angew. Chem. Int. Ed. 44 (2005) 3881–3884. (d) A. Bulut, A. Aslan, O.Z.

us

Dogan J. Org. Chem. 73 (2008) 7373–7375. (e) H.Y. Kim, K. Oh Org. Lett. 11 (2009) 5682– 5685.

For Cobalt, see: (a) Y. Kogami, T. Nakajima, T. Ikeno, T. Yamada Synthesis (2004) 1947–

an

[5]

1950. (b) J. Park, K. Lang, K.A. Abboud, S. Hong J. Am. Chem. Soc. 130 (2008) 16484– 16485.

For Chrormium, see: (a) A.S. Zulauf, M. Mellah, E. Schulz J. Org. Chem. 74 (2009) 2242–

M

[6]

2245. (b) R. Kowalczyk, P. Kwiatkowski, J. Skarzewski, J. Jurczak J. Org. Chem. 74 (2009) [7]

d

753–756.

For Palladium, see: S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga, M. Shibasaki Angew.

[8]

te

Chem. Int. Ed. 47 (2008) 3230–3233.

(a) T. Arai, Y.M.A. Yamada, N. Yamamoto, H. Sasai, M. Shibasaki Chem. Eur. J. 2 (1996)

Ac ce p

1368–1372. (b) H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki J. Org. Chem. 60 (1995) 7388–7389. [9]

(a) C. Christensen, K. Juhl, K.A. Jørgensen Chem. Commun. (2001) 2222–2223. (b)

C.

Christensen, K. Juhl, R.G. Hazell, K.A. Jørgensen J. Org. Chem. 67 (2002) 4875–4881. (c) D.A. Evans, D. Seidel, M. Rueping, H.W. Lam, J.T. Shaw, C.W. Downey J. Am. Chem. Soc. 125 (2003) 12692–12693. (d) T. Risgaard, K.V. Gothelf, K.A. Jørgensen Org. Biomol. Chem. 1 (2003) 153–156. (e) S.F. Lu, D.M. Du, S.W. Zhang, J. Xu Tetrahedron: Asymmetry 15 (2004) 3433–3441. (f) D.M. Du, S.F. Lu, T. Fang, J. Xu J. Org. Chem. 70 (2005) 3712–3715. (g) S.K. Ginotra, V.K. Singh Org. Biomol. Chem. 5 (2007) 3932–3937. (h) K. Lang, J. Park, S. Hong, J. Org. Chem. 75 (2010) 6424–6435. [10] (a) S. Liu, C. Wolf Org. Lett. 10 (2008) 1831–1834. (b) K.Y. Spangler, C. Wolf Org. Lett. 11 (2009) 4724–4727. [11] (a) S. Arai, S. Takita, A. Nishida Eur. J. Org. Chem. (2005) 5262–5267.

(b) T. Arai, M.

15

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Watanabe, A. Fujiwara, N. Yokoyama, A. Yanagisawa Angew. Chem. Int. Ed. 45 (2006) 5978–5981. (c) T. Arai, M. Watanabe, A. Yanagisawa Org. Lett. 9 (2007) 3595–3597.

(d)

M. Bandini, M. Benaglia, R. Sinisi, S. Tommasi, A. Umani-Ronchi Org. Lett. 9 (2007) 2151– 2153.(e) R. Kowalczyk, L. Sidorowicz, J. Skarzewski Tetrahedron: Asymmetry 19 (2008)

ip t

2310–2315. (f) S. Selvakumar, D. Sivasankaran, V.K. Singh Org. Biomol. Chem. 7 (2009) 3156–3162. (g) A. Noole, K. Lippur, A. Metsala, M. Lopp, T.N. Kanger J. Org. Chem. 75 (2010) 1313–1316. (h) W. Jin, X. Li, Y. Huang, F. Wu, B. Wan Chem. Eur. J. 16 (2010) 8259–

cr

8261.

[12] H. Maheswaran, K.L. Prasanth, G.G. Krishna, K. Ravikumar, B. Sridhar, M.L. Kantam Chem.

us

Commun. (2006) 4066–4068.

[13] Y. Xiong, F. Wang, X. Huang, Y. Wen, X. Feng Chem. Eur. J. 13 (2007) 829–833.

an

[14] (a) For a recent account, see: G. Baly, V. Hernández-Olmos, J.R. Pedro Synlett (2011) 1195– 1211. (b) For a recent account on the use of iminopyridine ligands in asymmetric catalysis, including the Henry reaction, see: G. Chelucci Coord. Chem. Rev. 257 (2013) 1887–1932.

M

[15] Q.T. Nguyen, H. Jeong, J. Polyhedron 25 (2006) 1787–1790.

[16] C.J. Cooper, M.D. Jones, S.K. Brayshaw, B. Sonnex, M.L. Russell, M.F. Mahon, D.R. Allan

d

Dalton Trans. 40 (2011) 3677–3682.

[17] (a) G. Blay, V. Hernández-Olmos, J.R. Pedro Chem. A Eur. J. 17 (2011) 3768–3773. (b) G. 441–450.

te

Blay, A. Escamilla, V. Hernández-Olmos, J.R. Pedro, A.J.R. Sanz-Marco Chirality 24 (2012)

Ac ce p

[18] (a) G. Chelucci, G.A. Pinna, A. Saba Tetrahedron: Asymmetry 8 (1997) 2571–2578. (b) G. Chelucci, G. Deriu, G.A. Pinna, A. Saba, R. Valenti Tetrahedron: Asymmetry 8 (1999) 3008– 3809. (c) G. Chelucci, S. Baldino, G.A. Pinna, M. Benaglia, L. Buffa, S. Guizzetti Tetrahedron 32 (2008) 7574–7582. (d) W. Baratta, G. Chelucci, S. Magnolia, K. Siega, P. Rigo Chem. A. Eur. J. 15 (2009) 726–731. (e) G. Chelucci, C. Sanfilippo Tetrahedron: Asymmetry 21 (2010) 1825–1829. (f) G. Chelucci, M. Marchetti, A.V. Malkov, F. Friscourt, M.E. Swarbick, P. Kocovsky Tetrahedron 67 (2011) 5421–5431. [19] Y. Zhou, J. Dong, F. Zhang, Y. Gong J. Org. Chem. 76 (2011) 588–600. [20] C.A. Merlic, B.J. Adams Organomet. Chem. 431 (1992) 313–325. [21] H. Yamada, T. Kawate, A. Nishida, M. Nakagawa J. Org. Chem. 64 (1999) 8821–8828. [22] D.M. Haddleton, D.J. Duncalf, D. Kukulj, A.M. Heming, A.J. Shooter, A.J. Clark. J. Mat. Chem. 8 (1998) 1525–1532. [23] P. Collomb, A. von Zelewsky Tetrahedron: Asymmetry 6 (1995) 2903–2904.

16

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[24] D.A. Evans, D. Seidel, M. Rueping, H.W. Lam, J.T. Shaw, C.W. Downey J. Am. Chem. Soc. 125 (2003) 12692–12693. [25] G. Blay, E. Climent, I. Fernández, V. Hernández-Olmos, J.R. Pedro Tetrahedron: Asymmetry 18 (2007) 1603–1612.

ip t

[26] F.A. Davis, Y. Zhang, Y. Andemichael, T. Fang, D. Fanelli, H. Zhang J. Org. Chem. 64 (1999) 1403–1406.

[27] E.J. McEachern, G.J. Bridger, K.A. Skupinska, R.T. Skerlj Patent: US2003/114679 A1 2003.

cr

[28] (a) J.H. Groen, M.J.M. Vlaar, P.W.N.M. van Leeuwen, K. Vrieze, H. Kooijman, A.L. Spek, J. Organometal. Chem. 551 (1998) 67–80. (b) J.B. Crawford, R.T. Skerlj, G.J. Bridger J. Org.

Ac ce p

te

d

M

an

us

Chem. 72 (2007) 669–671.

17

Page 17 of 19

Graphical abstract

R1

CHO + CH3 NO 2

(II) O Cu O

N

NO 2

Yield up to 90% ee up to 82%

cr

N

OMe

ip t

OMe OH

R*

Ac ce p

te

d

M

an

us

in sit u cataly st

18

Page 18 of 19

Ac ce p

te

d

M

an

us

cr

ip t

Highlights New chiral iminopyridines were obtained from pyridyl aldehydes or ketones. New chiral iminopyridines were obtained from a variety of chiral amines. New chiral iminopyridines were assessed in the enantioselective Henry reaction. 1-(2-Methoxyphenyl)-2-nitroethanol was formed with enantioselectivities up to 82% ee.

19

Page 19 of 19