Conjugate Reduction of <FONT FACE=Symbol>a,b</FONT>-Unsaturated Carbonyl Compounds. Selective Inhibition of Benzyl Ether Hydrogenolysis by NH4OH/MeOH

Abstracts

A series of <FONT FACE=Symbol>a,b</FONT>-unsaturated alkyl and aryl ketones, esters and N-methoxy-N-methyl-amides (Weinreb amides) containing an O-benzyl protecting group undergo conjugate reduction by H2/Pd/C in the presence of 2N NH4OH/MeOH at room temperature and ordinary pressure leaving the benzyl group intact

conjugate reduction; inhibition of benzyl ether hydrogenolysis; chemoselective reduction of alpha; beta-unsaturated compounds; selective catalytic hydrogenation

Uma série de alquil e aril cetonas, ésteres e N-metóxi-N-metil amidas (Amidas de Weinreb) alfa,beta-insaturadas contendo um grupo protetor O-benzyl sofrem redução conjugada por H2/Pd/C na presença de solução 2N de NH4OH/MeOH a temperatura ambiente e pressão normal deixando o grupo benzil intacto.

Note

Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds. Selective Inhibition of Benzyl Ether Hydrogenolysis byNH₄OH/MeOH

Luiz C. Dias*, and Priscila L. Campano

Instituto de Quimica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13083-970, Campinas - SP, Brazil; e-mail: [e-mail]

Received: February 6, 1998

Uma série de alquil e aril cetonas, ésteres e N-metóxi-N-metil amidas (Amidas de Weinreb) a,b-insaturadas contendo um grupo protetor O-benzyl sofrem redução conjugada por H₂/Pd/C na presença de solução 2N de NH₄OH/MeOH a temperatura ambiente e pressão normal deixando o grupo benzil intacto.

A series of a,b-unsaturated alkyl and aryl ketones, esters and N-methoxy-N-methyl-amides (Weinreb amides) containing an O-benzyl protecting group undergo conjugate reduction by H₂/Pd/C in the presence of 2N NH₄OH/MeOH at room temperature and ordinary pressure leaving the benzyl group intact

Keywords:conjugate reduction, inhibition of benzyl ether hydrogenolysis, chemoselective reduction of a,b-unsaturated compounds, selective catalytic hydrogenation

A number of synthetic methods have been developed which effect the conjugate reduction of a,b -unsaturated carbonyl compounds^1-6. However, chemoselective reduction of a,b-unsaturated carbonyl functionality in more complex molecules containing benzyl and 4-methoxybenzyl (MPM) protecting groups in the substrate is more complicated, although Evans and Fu obtained good yields of conjugate reduction with a fairly complex molecule⁷. Catalyst poisoning or hydrogenolysis may complicate double bond reduction under conditions of catalytic hydrogenation¹.

The presence of amine functions inhibiting O-debenzylation has been reported by a number of groups^8,9. The addition of ammonia, ammonium acetate (0.5 equiv.) and pyridine to the Pd/C catalyst has been recently reported to inhibit hydrogenolysis of aliphatic benzyl ethers during reduction of conjugated olefins, benzyl ester, and azide functional groups in methanol¹⁰. More recently, the selective catalytic hydrogenolysis (in MeOH-dioxan or DMF on Pd/C catalyst in the presence of pyridine) of phenolic O-benzyl ethers, Cbz, benzyl esters, and selective reduction of nitro groups and conjugated olefins in phenols protected with the 4-methoxybenzyl (MPM) group was described¹¹.

We decided to explore the synthetically attractive possibility that NH₄OH might be used to retain an O-benzyl group while hydrogenation took place at the a,b-unsaturated double bond. For this purpose we synthesized a series of a,b-unsaturated carbonyl compounds containing an O-benzyl protecting group (Table 1, substrates 1-8). We wish to report here that a,b-unsaturated carbonyl compounds containing a benzyl protecting group undergo selective hydrogenation of the unsaturated double bond in the presence of 2N NH₄OH/MeOH leaving the O-benzyl group intact.

Control experiments indicated that, in the absence of NH₄OH complete removal of the benzyl protecting group in compounds 1-8 was observed. However, addition of 2N NH₄OH/MeOH results in conjugate reduction of these a,b-unsaturated carbonyl compounds under very mild conditions (25 °C, 1 atm, 30 min). When compounds 1-8 were submitted to these conditions, a smooth reduction to compounds 9-16 was observed without any indication of benzyl ether hydrogenolysis (Table 1). The selectively hydrogenated products 9-16 were obtained in excellent isolated yields¹².

This mild method for conjugate reduction is compatible with a variety of carbonyl functional groups and is amenable to large scale preparations. The products 10 and 14 (esters), 12 and 16 (Weinreb amides) can be easily converted to the corresponding primary alcohols and aldehydes, respectively, increasing the scope of this reaction.

Representative experimental procedure: After two vacuum/H₂ cycles to remove air from the reaction flask, the stirred mixture of 1-8 (1.0 mmol), 5% Pd/C (25 mg) and freshly prepared 2N NH₄OH/MeOH solution (0.3 mL) in MeOH (5 mL) was hydrogenated at 1 atm and room temperature for 45 min. The reaction mixture was filtered (Celite), and the filtrate was concentrated and purified directly by flash chromatography to afford the pure products 9-16 as shown in Table 1 (filtration of the reaction solution through Celite and evaporation gave almost pure products)¹³.

In conclusion, the reaction described herein comprises a mild, high yielding and convenient method for effecting the selective the conjugate reduction of a,b -unsaturated carbonyl compounds having an O-benzyl protecting group. These results are apparently attributable to the effect of NH₄OH. Further studies defining the scope and limitations of this reaction as well as its application in the total synthesis of natural products are in progress¹⁴.

13.Selected Data for compounds 6 and 14. a,b-unsaturated ester 6: ¹H-NMR (300 MHz, CDCl₃): 1,09 (d, 3H, J = 6,96 Hz); 1,29 (t, 3H, J = 7,14 Hz); 2,67 (m, 1H); 3,38 (dd, 1H, J = 9,15 and 6,23 Hz); 3,43 (dd, 1H, J = 9,15 and 6,96 Hz); 4,52 (s, 2H); 4,19 (q, 2H, J = 6,96 Hz); 5,87 (dd, 1H, J = 15,80 and 1,46 Hz); 6,96 (dd, 1H, J = 15,80 and 7,14 Hz); 7,26-7,39 (m, 5H); ¹³C-NMR (75 MHz, CDCl₃): 13.99; 15.81; 36.60; 60.14; 73.04; 73.85; 121.13; 127.76; 127.79; 128.56; 138.40; 151.38; 167.04 ppm; IR (film): 3030, 2978, 2858, 1716, 1653, 1455, 1367, 1270, 1097, 1037, 737 cm^-1. Saturated ester 14: ¹H-NMR (300 MHz, CDCl₃): 0,89 (d, 3H, J = 6,59 Hz); 1,24 (t, 3H, J = 7,14 Hz); 1,46 (m. 1H); 1,78 (m, 2H); 2,32 (m, 2H); 4,11 (q, 2H, J = 7,14 Hz); 4,49 (s, 2H); 7,25-7,37 (m, 5H); ¹³C-NMR (75 MHz, CDCl₃): 13.95; 16.56; 28.61; 31.83; 32.86; 60.13; 72.93; 75.36; 127.63; 127.67; 128.49; 138.82; 174.24 ppm; IR (film): 3030, 2958, 2922, 2868, 1734, 1454, 1373, 1254, 1179, 1098, 1028, 737 cm^-1.

14.Financial Support has been provided by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) and FUNCAMP (Fundação de Desenvolvimento da UNICAMP).

FAPESP helped in meeting the publication costs of this article

This paper is dedicated to the Brazilian Chemical Society (SBQ)

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Publication Dates

• Publication in this collection
  17 Mar 2008
• Date of issue
  Feb 1998

History

• Accepted
  06 Feb 1998
• Received
  06 Feb 1998