Use of polymer-supported amines in the catalytic nitro-aldol reaction of nitroalkanes with aldehydes

An efficient catalytic synthesis of 2-nitroalcohols has been achieved through a catalytic nitroaldol (Henry) reaction promoted by polymer-supported amines. These achiral and chiral polymer-bound amines show general utility in their reactions with a variety of aromatic and functionalized aldehyde acceptors. Moreover, the catalyst can be reused without loss of activity.


Introduction
The capability for high-throughput screening of potential drug substances is placing everincreasing demands on the methods for the fast and efficient generation of new pharmacological targets.In general, chemical libraries or arrays containing a large number of compounds may be prepared either on polymer supports or in solution.1a While most of the published work on small molecule library synthesis has been performed using solid supports, solution-phase strategies have been applied successfully by a number of researchers.The advantages of polymersupported reactions (e.g., that the reaction is accelerated by using an excess of the soluble reaction partner without the need for additional purification steps) and the benefits of solutionphase chemistry (e.g., the ease of monitoring the process of the reactions by applying TLC, LC-MS or NMR techniques) can be combined by using polymer-supported reagents.Polymer-bound reagents have been utilized widely for many chemical transformations in organic chemistry.1b Two of the most significant advantages of these reagents over their soluble counterparts are their ability to drive the reaction to completion by using an excess, and the ease of their separation from the desired product by filtration.Furthermore, there is a constant need for new methodologies which can be applied to the preparation of heterocycles and small organic molecules. 2,3For this reason the development of new polymer-supported reagents has attracted growing interest in recent years.Recent work by our group has focused on the development of new bases 4,5 and of new polymer-supported catalysts for the preparation of enantiomerically enriched 2H-azirines derived from phosphine oxides 5a and phosphonates.5b We now report a further example using achiral-and chiral-polymer-supported amines for the construction of carbon-carbon bonds by nitroalkanes through the nitro-aldol (Henry) reaction.
The Henry-or nitro-aldol-reaction is a classical yet powerful carbon-carbon bond-forming process in organic chemistry, 6 by which 2-nitroalcohols are formed by treating primary or secondary nitroalkanes with a base and carbonyl compounds, providing efficient access to valuable synthetic building blocks such as β-aminoalcohols and α-hydroxycarboxylic acids. 7itroalcohols are useful intermediates in the elaboration of pharmacologically important derivatives, including hepatotoxin, 7-epicylindrospermopsin, 8a Taxotere ® 8b,c side-chain and (-)bestatin, 8b,c the β-receptor agonists (-)-denopamine 8d and (-)-arbutamine, 8d,e the β-blocker (S)propanolol, 8f and antibiotics such as chloroamphenicol, ephedrine, nor-ephedrine and anthracycline.8g,h The most commonly applied protocols for performing the above reaction require the use of basic catalysts under homogeneous or heterogeneous conditions. 9ases such as phosphorus ylides, 4 cyclic guanidines, 10a and ammonium salts, 10b have been applied in the nitro-aldol reaction 10 and an asymmetric version of this reaction which uses an optically active metal catalyst has recently been developed. 11,12However, to our knowledge, there are no literature reports on the nitro-aldol reaction of nitroalkanes with aldehydes promoted by achiral or chiral polymer-supported amines as catalysts.Herein we explore the applicability of these resins in catalytic asymmetric nitro-aldol reactions.

Results and Discussion
To evaluate the catalytic efficiency of the polymer-supported amines 3, the reaction of pnitrobenzaldehyde 1a with nitroethane, 2a, was examined.Thus, treatment of 1a with nitroethane 2a in the presence of commercially available polymer-supported amine derived from diethylamine, 3a, (50 mol.%) at room temperature for 3h, resulted in clean formation of the corresponding nitroalcohol 4a as a diastereomeric mixture [(±)-syn/anti, 1:1] in 84% yield (Scheme 1, Table 1, entry 1).Further, the catalyst-loading can be reduced to 10 mol.% without significant loss of reactivity, to afford a mixture of (±)-syn-and (±)-anti-nitroalcohols with low diastereoselectivity (Table The spectroscopic data were in agreement with the assigned structure of compound 4a. 13The 1 H-NMR spectrum showed an absorption at δ H 5.21 ppm as a doublet with coupling constant 3 J HH = 8.5 Hz for the methylene proton directly bonded to the hydroxyl group of compound (±)syn-4a, while the methylene proton directly bonded to the hydroxyl group of diastereoisomer (±)-anti-4a resonates at δ H 5.58 ppm ( 3 J HH = 3. 3 Hz).
In order to extend this process to the asymmetric synthesis of nitroalcohols 4, the chiral polymer-supported amine 3b 5a derived from Merrifield resin and (S)-(+)-2-(methoxymethyl)pyrrolidine was used.This chiral 3b was used as the chiral base in the nitroaldol reaction of aldehydes with nitroalkanes, in a similar way to that reported before for the achiral resin amine 3a, to give the nitroalcohol 4a in moderate yield (no appreciable diastereoselectivity was observed) (Scheme 1, Table 1, entry 3).The enantiopurity of nitroalcohol 4a was examined by HPLC analysis using a chiral column (DAICEL Chiralcel OD-H) with hexane/2-propanol as solvent, but showed no enantioselectivity.
Finally, to improve both the diastereo-and enantio-selectivities, the chiral supported base 3c derived from (S)-(+)-2-(methoxymethyl)pyrrolidine was synthesized.The preparation of this polystyrene chiral resin 3c can be achieved by attachment of the chiral secondary amine to the solid support using Wang resin.Wang resin was reacted with (S)-(+)-2-(methoxymethyl)pyrrolidine at 65 ºC in DMF to afford the new chiral resin 3c. 14This chiral polymer-supported amine 3c was then used as chiral base in the nitro-aldol reaction using aromatic-and functionalized aldehydes.Thus, treatment of aromatic (Scheme 1, Table 1, entries 4-8) and functionalized aldehydes (entries 9-10) with nitromethane or nitroethane in the presence of polymer-supported chiral amine 3c (10-20 mol.%), afforded the corresponding nitroalcohols 4 with low diastereoselectivities and no enantiomeric excess.
Combination of polymer-supported reactions and solution-phase chemistry allows the preparation of 2-nitroalcohols 4 after filtration of the corresponding polymer-supported amines 3.These polymer-supported amines 3, after activation, were efficiently recycled for further cycles without loss of activity (Table 1, entry 10).
The high synthetic potential of the Henry reaction has been demonstrated previously for βnitroalcohols 15 and for β-nitro-α-amino acid derivatives, 16 as well as for the easy conversion of the β-nitro-α−hydroxy acid derivatives into a variety of important functionalities-for example, β-amino-α-hydroxy esters. 17During the last several years, enantioselective synthesis of β-aminoα-hydroxy acids has attracted much attention not only because of the synthetic interest to put the right functional moieties in the right positions in a stereospecific manner but also because of their presence in various medicinally important molecules. 18Paclitaxel, one of the most promising anticancer agents so far discovered, has 2-(N-benzoylamino)-2-hydroxy-3phenylpropionic acid as a side chain for the essential structural element for the activity.19a Another member of this class of compounds bearing 3-amino-2-hydroxy-5-methyl hexanoate as a key component is amastatin, with immunoregulatory, antitumor, and antibacterial activity.19b The β-amino-α-hydroxy acid is also found in renin inhibitor for antihypertensive agent, as the transition state mimic including KRI 1314, 19c bestatin, 19d -a dipeptide with antitumor and antibacterial activities -and microginin 19e -a linear pentapeptide natural product which showed angiotensin-converting enzyme inhibitory activity.
A straightforward synthetic route to β-amino-α-hydroxy acid derivatives can be designed by hydrogenolysis of starting β-nitro-α-hydroxy esters as shown in Scheme 2. Thus, for the β-nitro-α-hydroxy ester 4f (catalyst 3c used) the reduction of the nitro group was performed using Raney-Ni to give the amino ester 5 in 68 % yield (Scheme 2).

Scheme 2
In summary, we have demonstrated the ability of achiral and chiral polymer-supported amines 3a-c as highly active promoters of the addition of nitroalkanes to aldehydes.Nitroalcohols are valuable synthetic building blocks in the elaboration of pharmacologically important derivatives. 7,8Furthermore, it was shown that the β-nitro-α-hydroxy esters can be converted into synthetically valuable β-amino-α-hydroxy esters.This methodology combine the advantages of polymer-supported reactions and the benefits of solution-phase chemistry, allowing automated implementation of these processes in a way similar to that reported for the synthesis of other small molecule libraries.

Experimental Section
General Procedures.Solvents for extraction and chromatography were of technical grade.All solvents used in reactions were freshly distilled.All other reagents were recrystallized or distilled as necessary.All reactions were performed under an atmosphere of dry nitrogen.Analytical TLC was performed with silica-gel 60 F 254 plates.Spot visualization was accomplished by using UV light or KMnO 4 solution.Flash chromatography was carried out using silica gel 60 (230−400 mesh).Melting points were determined with an Electrothermal IA9100 digital apparatus and are uncorrected. 1H-(400 MHz) and 13 C-(100 MHz) spectra were recorded on a Bruker Avance 400 MHz spectrometer, with tetramethylsilane (TMS) (0.00 ppm) or chloroform (7.24 ppm) as internal reference in CDCl 3 solutions for 1 H-NMR spectra, or chloroform (77.0 ppm) as internal reference in CDCl 3 solutions for 13 C-NMR spectra.Chemical shifts (δ) are given in ppm; multiplicities are indicated by s (singlet), brs (broad singlet), d (doublet), dd (double-doublet), t (triplet), q (quadruplet) or m (multiplet); coupling constants (J) are in Hz.Low-resolution mass spectra (MS) were obtained on a Hewlett Packard 5971 MSD Series spectrometer at 50−70 eV by electron impact (EI), or a Hewlett Packard 1100 MSD Series spectrometer by chemical ionization (CI).Data are reported in the form m/z (intensity relative to base peak = 100).Infrared spectra (IR) (in cm -1 ) were taken on a Nicolet FTIR Magna 550 spectrometer, and were obtained for solids in KBr or for neat oils (NaCl plates).Elemental analyses were performed in a Perkin