Pyrrolidine catalyzed diastereoselective direct aldol reaction in water: A green approach

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1 Indian Journal of Chemistry Vol. 52B, September 2013, pp Pyrrolidine catalyzed diastereoselective direct aldol reaction in water: A green approach Sarbjit Singh & Swapandeep Singh Chimni* Department of Chemistry, Guru Nanak Dev University, Amritsar , India sschimni@yahoo.com Received 15 June 2012; accepted (revised) 18 July 2013 The pyrrolidine catalyzed direct diastereoselective aldol reaction of different cyclic ketones and aromatic aldehydes has been performed in water. The aldol products are formed in high yield (up to 91%) and diastereoselectivity (up to >99:1 (anti:syn)) in a short reaction time (20-65 min) using only 10 mol% of pyrrolidine as catalyst. Moreover a co-relation between the ring size of donor ketones and diastereoselectivity of aldol products has also been observed. The methodology developed is green and highly efficient. Keywords: Aldol reaction, organocatalysis, water, pyrrolidine, green chemistry The aldol reaction 1 is one of the most important reactions for the construction of carbon-carbon bond in organic synthesis generating β-hydroxy carbonyl compounds containing up to two new concomitant stereogenic centres. In addition, aldol reaction is also an important biological reaction catalyzed by aldolases 2, which catalyze the metabolic transformation of highly oxygenated metabolites, and are found in many biosynthetic pathways of carbohydrates, keto acids and some amino acids 3a. Moreover, β-hydroxy ketone and 1,3-diol moieties are important components of valuable drugs such as Amphotericin B, Pentamycin, Nystatin A 1, Pimaricin, Candidin and Filipin III etc 3b. Further, aldol reaction presents numerous challenges to synthetic chemist like the issues of chemo-, regio-, diastereo-, and enantioselectivity and thus has been performed using variety of catalysts such as transition metal catalysts 4, enzymes 5, antibodies 6, Lewis acids 7, Lewis bases 8, Bronsted acids 9 and organocatalysts. Among these catalysts, the organocatalysts have been often employed in the last decade because of some special features associated with their use such as, they are less toxic, inexpensive, robust and require mild reaction conditions. On the other hand, the synthesis of organic compounds using water as solvent is a fast growing area of research since it holds great promise for future in terms of cheaper and less hazardous production of chemicals 10. Water, due to its small size, high polarity and a three-dimensional hydrogen bonded network system of bulk water, provides some unique properties, which include large cohesive energy density, a high surface tension and hydrophobic effect 11. The early discoveries by Breslow 12 and Grieco 13 have shown that the rate as well as yield of some organic reactions was much higher in water as compared to other traditional organic solvents. In continuation of our interest in the development of simple organocatalysts for organic transformations in water 14,15. Herein, we report the pyrrolidine (10 mol%) catalyzed diastereoselective direct aldol reaction of different cyclic ketones and aromatic aldehydes in water. Interestingly, the aldol adducts were formed with high yield and diastereoselectivity in a short reaction time. Results and Discussion Preliminarily, the aldol reaction of cyclohexanone 2 and p-nitrobenzaldehyde 3a was performed in DMSO (1 ml) using 10 mol% of pyrrolidine as catalyst (Table I, entry 1). The reaction was allowed to run for 8 hr and its progress was observed at regular intervals by TLC. The 1 H NMR of the crude product showed the presence of two diastereomers in a ratio of 45:55 (anti:syn), which was deduced from the integration of the 1H signal at δ (anti) and δ 5.48 (syn). Other organic solvents were also screened under similar reaction conditions using pyrrolidine as catalyst (Table I). Aldol product 4a

2 SINGH et al.: PYRROLIDINE CATALYZED ALDOL REACTION 1203 Table I Pyrrolidine catalyzed direct aldol reaction of cyclohexanone and p-nitrobenzaldehyde in different organic solvents a. Entry Solvent Time (hr) Yield (%) dr (anti:syn) 1 DMSO :55 2 Toluene :38 3 Hexane :51 4 THF :42 5 Ether :31 6 DMF :41 7 Dioxane :38 8 Water 25 (min) 85 74:26 a Reactions conditions: 1.25 mmol of ketone, 0.25 mmol of aldehyde, 10 mol % catalyst, 1 ml of solvent at 25 C. b Yield determined after chromatographic purification. c Diastereomeric excess was determined by 1 H NMR. was formed with highest yield of 61% and diastereoselectivity of 62:38 (anti:syn) using dioxane as solvent. Interestingly, when the same reaction was performed in water, the yield and diastereoselectivity of 4a improved to 85% and 74:26 (anti:syn) in a short reaction time of 25 minutes only (Table I, entry 8). This tremendous increase in the reaction rate, yield and diastereoselectivity could be attributed to hydrophobic effects exerted by water on small organic phase composed of cyclohexanone and other reactants 12,13. This intriguing observation prompted us to screen some other aldehydes for the same reaction using water as solvent. The results are summarized in Table II. Moderate to excellent diastereoselectivity as well as yield was observed with all aldehydes in a short reaction time (Table II). Excellent diastereoselectivity of >99:1 (anti:syn) was observed with o- fluoro and o-bromobenzaldehydes (Table II, entry 10 and 12). Whereas, the diastereoselectivity of 98:2/anti:syn was observed with o-chlorobenzaldehyde (Table II, entry 11). Among disubstituted aldehydes, excellent diastereoselectivity of 95:5/anti:syn was observed with 2,6-dichlorobenzaldehyde (Table II, entry 8) as compared to 3,4- dichlorobenzaldehyde with which diastereoselectivity of 62:38/anti:syn was observed (Table II, entry 9). A slight preference for syn diastereomer over anti was observed in case of the p-bromobenzaldehyde (Table II, entry 6). Next, the aldol reaction was also performed in water using number of cyclic ketones with different aromatic aldehydes. The results are summarized in Table III. The syn preference was observed when cyclopentanone was used as donor ketone (Table III, entry 6-8). The aldol adduct 8 was also formed with syn preference (Table III, entry 4). It was observed from these studies that the ring size of donor ketone controls the diastereoselectivity of aldol products. In general, the small rings show syn preference whereas the large rings show anti preferences (Figure 1). For example, for the reaction of cyclopentanone and p-nitrobenzaldehyde, the aldol adduct was formed with diastereoselectivity of 39:61 (anti:syn). But for the reaction of cyclohexanone and p-nitrobenzaldehyde, the diastereoselectivity of 74:26 (anti:syn) was observed. The diastereoselectivity further improved to 78:22 (anti:syn) on using cycloheptanone as donor ketone. Experimental Section NMR spectra were obtained at 300 MHz (Jeol AL- 300) and 500 MHz (Bruker Avanced 500 MHz) for 1 H NMR and at 75 MHz (Jeol AL-300) and 100 MHz (Bruker Avanced 400 MHz) for 13 C NMR with Me 4 Si (in CDCl 3 ) as internal standard. The chemical shifts are reported in δ values relative to TMS and coupling constants (J) are expressed in Hz. Spectral patterns are designated as s = singlet; d = doublet; dd = doublet of doublets; q = quartet; t = triplet; br =

3 1204 INDIAN J. CHEM., SEC B, SEPTEMBER 2013 Table II Pyrrolidine catalyzed direct aldol reaction of cyclohexanone with various aromatic aldehydes a. Entry ArCHO Time (min) Yield b (%) dr c (anti:syn) 1 4-NO 2 C 6 H 4 (3a) : NO 2 C 6 H 4 (3b) : NO 2 C 6 H 4 (3c) : FC 6 H 4 (3d) : ClC 6 H 4 (3e) : BrC 6 H 4 (3f) : CNC 6 H 4 (3g) :49 8 2,6-Cl 2 C 6 H 3 (3h) :5 9 3,4-Cl 2 C 6 H 4 (3i) : FC 6 H 4 (3j) >99: ClC 6 H 4 (3k) : BrC 6 H 4 (3l) >99:1 13 C 6 H 5 (3m) : Naph(3n) :36 a Reactions conditions: 1.25 mmol of ketone, 0.25 mmol of aldehyde, 10 mol % catalyst, 1 ml of water at 25 C. b Yield determined after chromatographic purification. c Diastereomeric excess was determined by 1 H NMR. broad; m = multiplet. When necessary, assignments were aided by DEPT-135 experiments. IR spectra were obtained with FT-IR Bruker (270-30) spectrophotometer and Varian 660-IR FT-IR spectrometer and reported in wave numbers (cm -1 ). Mass spectra were recorded on Jeol-MSD-300, Bruker Esquire 300 LC Mass spectrometer and Jeol AccuTOF DART mass spectrometer. Analytical thinlayer chromatography (TLC) was performed on either (i) aluminum sheets pre-coated with silica gel 60F254 (Merck, India) or (ii) glass plates ( cm) coated with silica gel GF-254 (Spectrochem India) containing 13% calcium sulphate as binder and various combinations of dichloromethane and methanol were used as eluents. Visualization of the spots was accomplished by exposing to UV light or iodine vapours. Column chromatography was performed on Spectrochem silica gel ( mesh) using an increasing concentration of ethyl acetate in hexane as eluent. Syn and anti isomers of the compounds were identified by comparing the NMR data with the literature values. General procedure for the diastereoselective direct aldol reaction To a solution of water (1 ml) and pyrrolidine (0.025 mmol), cyclohexanone (1.25 mmol) was added at 25 C, and the mixture was allowed to stir for 5 min followed by addition of aldehyde (0.25 mmol). The reaction mixture was stirred for min and was monitored with TLC at regular intervals. On completion of the reaction, water (5 ml) was added to it and the resulting mixture was extracted with dichloromethane (3 10 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and distilled to obtain crude aldol product. The 1 H NMR of the crude reaction mixture was recorded to determine the diastereomeric excess. The column chromatography on silica gel (mesh ) gave pure aldol product consisting of syn and anti isomers. The spectroscopic data of aldol products (mixture of isomers) is given below. 2-[1-Hydroxy-1-(4-nitrophenyl)methyl] cyclohexan-1-one, 4a (Ref 14a,16): Yield: 85%; yellow solid; m.p C; MS: m/z (M + + Na); IR

4 SINGH et al.: PYRROLIDINE CATALYZED ALDOL REACTION 1205 Table III Direct aldol reaction of different cyclic ketones with aromatic aldehydes a. Entry Product Time (min) Yield b (%) dr c (anti:syn) : : : : :22 a Reactions conditions: 0.25 mmol of aldehyde, 1.25 mmol of ketone, 1 ml of water, 10 mol % of catalyst at 25 C. b Yield determined after chromatographic purifications. c Diastereomeric excess was determined by 1 H NMR.

5 1206 INDIAN J. CHEM., SEC B, SEPTEMBER 2013 Figure 1 (CHCl 3 ): 1695, 3505 cm -1 ; anti/syn = 74:26; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), (brs, 1H, OH), (d, 0.74H, J = 9 Hz, CHOH (anti)), 5.48 (s, 0.26H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.5, 24.6, 25.8, 27.5, 27.6, 30.6, 42.4, 42.5, 56.7, 57.0, 69.9, 73.8, 123.3, 123.4, 126.5, 127.8, 147.4, 148.3, 149.2, 213.9, [1-Hydroxy-1-(3-nitrophenyl)methyl] cyclohexan-1-one, 4b (Ref 14a,16b): Yield: 82%; yellow solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1695, 3479 cm -1 ; anti/syn = 70:30; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), (brs, 1H, OH), (d, 0.70H, J = 8.4 Hz, CHOH (anti)), (s, 0.30H, CHOH (syn)), (m, 1H, ArH), (m, 1H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.5, 25.8, 27.5, 27.7, 30.6, 42.5, 56.6, 57.0, 69.7, 73.9, 120.8, 122, 122.7, 129, 129.2, 131.9, 133.1, 143.2, 148.1, [1-Hydroxy-1-(2-nitrophenyl)methyl] cyclohexan-1-one, 4c (Ref 14a,16b): Yield: 86%; yellow solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1701, 3449 cm -1 ; anti/syn = 89:11; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 4.48 (brs, 1H, OH), (d, 0.89H, J = 7.2 Hz, CHOH (anti)), 5.92 (d, 0.11H, J = 1.5 Hz, CHOH (syn)), (m, 1H, ArH), (m, 1H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.6, 26.3, 27.6, 29.5, 30.9, 42.4, 42.6, 54.7, 57.1, 61.4, 66.4, 69.5, 123.9, 124.3, 128.3, 128.9, 129.4, 132.9, 133.6, 133.9, 136.4, 137, 146.9, 148.6, 213.7, [1-Hydroxy-1-(4-fluorophenyl)methyl] cyclohexan-1-one, 4d (Ref 14a,16b): Yield: 88%; yellow liquid; IR (CHCl 3 ): 1724, 3320 cm -1 ; anti/syn = 53:47; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), 3.09 (brs, 0.47H, OH (syn)) (brs, 0.53H, OH (anti)), (d, 0.53H, J = 8.7 Hz, CHOH (anti)), 5.33 (s, 0.47H, CHOH (syn)), (m, 2H, ArH), (brs, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.6, 24.8, 26.0, 27.7, 27.9, 30.7, 42.6, 53.4, 57.1, 57.4, 70.1, 74.1, 114.8, 115.3, 127.2, 128.6, [1-Hydroxy-1-(4-chlorophenyl)methyl] cyclohexan-1-one, 4e (Ref 14a,16b): Yield: 90%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1699, 3514 cm -1 ; anti/syn = 48:52; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), 3.01 (brs, 0.5H, OH), 3.91 (brs, 0.5H, OH), (d, 0.48H, J = 9 Hz, CHOH (anti)), 5.33 (s, 0.52H, CHOH (syn)), (m, 4H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti +syn isomers) 24.6, 24.8, 25.9, 27.7, 27.9, 30.7, 42.6, 57.0, 57.3, 70.1, 74.1, 127.1, 128.2, 128.3, 128.5, 132.6, 133.5, 139.4, 140, 214.6, [1-Hydroxy-1-(4-bromophenyl)methyl] cyclohexan-1-one, 4f (Ref 14a,16b): Yield: 84%; brown soild; m.p C; MS: m/z 305 (M + + Na); IR (CHCl 3 ): 1703, 3381 cm -1 ; anti/syn = 39:61; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), 3.11 (brs, 0.61H, OH (syn), 3.93 (brs, 0.39H, OH (anti)), (d, 0.39H, J = 9 Hz, CHOH (anti)), 5.30 (brs, 0.61H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.7, 27.7, 30.7, 42.6, 57.3, 74.2, 121.7, 128.7, 131.5, 140.0, [1-Hydroxy-1-(4-cyanophenyl)methyl] cyclohexan-1-one, 4g (Ref 14a,16b): Yield: 88%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1705, 3502 cm -1 ; anti/syn = 51:49; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), 3.12 (brs, 0.5H, OH (anti)), 3.95 (brs, 0.5H, OH (syn)), (d, 0.51H, J = 9 Hz, CHOH (anti)), 5.39 (s, 0.49H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.5, 25.7, 27.5, 30.6, 42.5, 56.6, 57.0, 70.74, 111.5, 118.7, 126.4, 127.6, 128.6, 130.4, 132, 146.3, 147, 213.9, [1-Hydroxy-1-(2, 6-dichlorophenyl)methyl] cyclohexan-1-one, 4h (Ref 14a): Yield: 88%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1696, 3520 cm -1 ; anti/syn = 95:5; 1 H NMR (CDCl 3, 300 MHz) δ (m, 1H, CH 2 ), 1.46-

6 SINGH et al.: PYRROLIDINE CATALYZED ALDOL REACTION (m, 4H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), (d, 1H, J = 4.2 Hz, OH), (d, 1H, J = 9.9 Hz, CHOH), (m, 1H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.5, 27.4, 29.7, 42.2, 53.4, 70.3, 129.1, 134.5, 135.4, [1-Hydroxy-1-(3,4-dichlorophenyl)methyl] cyclohexan-1-one, 4i (Ref 14a): Yield: 90%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1702, 3481 cm -1 ; anti/syn = 62:38; 1 H NMR (CDCl 3, 300 MHz) δ (m, 1H, CH 2 ), (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH and CH 2 ), 3.22 (brs, 0.38H, OH (syn), 4.06 (s, 0.62H, OH (anti)), (d, 0.62H, CHOH (anti), 5.32 (s, 0.38H, CHOH (syn)), (m, 1H, ArH), (m, 3H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.5, 24.6, 25.8, 27.5, 27.7, 30.6, 42.5, 56.7, 57.1, 69.5, 73.6, 125, 126.3, 127.8, 128.9, 130, 130.1, 130.7, 131.6, 132.4, 141.2, 141.9, 214.1, [1-Hydroxy-1-(2-fluorophenyl)methyl]cyclohexan-1-one, 4j (Ref 14a): Yield: 87%; yellow liquid; anti/syn = >99:1; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH)), (brs, 1H, OH), (d, 1H, J = 6 Hz, CHOH), (t, 1H, J = 9 Hz, ArH), (m, 2H, ArH), (t, 1H, J = 7.5 Hz, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.3, 27.2, 30.6, 42.8, 57.5, 72.9, 123.6, 127.3, 128.2, 129, 132.3, 140.6, 139.3, [1-Hydroxy-1-(2-chlorophenyl)methyl] cyclohexan-1-one, 4k (Ref 14a,17): Yield: 86%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1697, 3508 cm -1 ; anti/syn = 98:2; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 3.96 (brs, 1H, OH), (d, 0.98H, J = 6 Hz, CHOH (anti)), 5.67 (s, 0.02H, CHOH (syn)), (m, 3H, ArH), (d, 1H, J = 6.3 Hz, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.7, 25.8, 27.8, 42.5, 53.5, 67.6, 126.5, 128.1, 128.4, 129.1, 130.7, 138.5, [1-Hydroxy-1-(2-bromophenyl)methyl] cyclohexan-1-one, 4l (Ref 14a,17): Yield: 81%; yellow solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1698, 3409 cm -1 ; anti/syn = >99:1; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 3.98 (brs, 1H, OH), (d, 1H, J = 7.5 Hz, CHOH), (m, 1H, ArH), (m, 1H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.8, 27.7, 30.4, 42.6, 57.5, 72.7, 123.2, 127.7, 128.4, 129, 132.4, 140.6, [1-Hydroxy-1-(phenyl)methyl] cyclohexan-1- one, 4m (Ref 14a,16b): Yield: 80%; white solid; m.p C; MS: (m/z) (M + + Na); IR (CHCl 3 ): 1699, 3491 cm -1 ; anti/syn = 45:55; 1 H NMR (CDCl 3, 300 MHz): δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 3H, CH 2 and CH), 2.97(brs, 0.45H, OH (anti)), (3.89 (brs, 0.55H, OH (syn)), (d, 0.45H, J = 9 Hz, CHOH (anti)), 5.36 (s, 0.55H, CHOH (syn)), (m, 5H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ 24.7, 27.8, 30.8, 42.6, 57.4, 74.7, 127.0, 127.9, 128.3, 140.9, [1-Hydroxy-1-(naphthalene-2-yl)methyl] cyclohexan-1-one, 4n (Ref 14a,16b): Yield: 85%; brown solid, m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1700, 3451 cm -1 ; anti/syn = 64:36; 1 H NMR (CDCl 3, 300 MHz) δ (m, 5H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 3.19 (brs, 0.36H, OH (syn)), 4.06 (brs, 0.64H, OH (anti)), (d, 0.64H, J = 9 Hz, CHOH (anti)), 5.55 (s, 0.36H, CHOH (syn)), (m, 3H, ArH), (m, 4H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.5, 24.7, 25.9, 27.6, 27.8, 30.8, 42.5, 56.9, 57.3, 70.6, 74.7, 123.8, 124.4, 124.5, 125.5, 125.8, 125.9, 126, 126.1, 127.5, 127.6, 127.7, 127.8, 128.1, 132.5, 133, 133.1, 138.2, 138.8, 214.7, [1-Hydroxy-1-(4-nitrophenyl)methyl]-4-methylcyclohexan-1-one, 5 (Ref 14a,18): Yield: 88%; yellow solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1703, 3454 cm -1 ; 1 H NMR (mixture of isomers) (CDCl 3, 300 MHz): δ (m, 1H, CH 3 ), (m, 2H, CH 3 ), (m, 2H, CH 2 ), (m, 3H, CH and CH 2 ), (m, 3H, CH 2 and CH), 3.21 (brs, 1H, OH), (m, 0.28H, CHOH), 5.47 (s, 0.72H, CHOH), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (mixture of isomers) (CDCl 3, 75 MHz): δ (All isomers) 18.0, 21, 26.5, 30.9, 31.3, 32.9, 33.4, 34.6, 35.9, 38.4, 40.6, 41.5, 52, 53.3, 55.6, 69.7, 70.2, 73.8, 123.3, 126.4, 127.7, 146.8, 147.4, 148.5, 149.2, 213.9, [1-Hydroxy-1-(2-nitrophenyl)methyl]-4-methylcyclohexan-1-one, 6 (Ref 14a,18): Yield: 87%; yellow solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1704, 3445 cm -1 ; 1 H NMR (CDCl 3, 300 MHz): δ (m, 3H, CH 3 ), (m, 1H, CH 2 ), (m, 3H, CH 2 ), (m, 1H, CH), (m, 2H, CH 2 ), (m, 1H, CH),

7 1208 INDIAN J. CHEM., SEC B, SEPTEMBER (m, 0.73H, J = 6 Hz, CHOH), 5.94 (d, 0.27H, J = 3 Hz, CHOH), (m, 1H, ArH), (m, 1H, ArH), (m, 1H, ArH), (m, 1H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (All isomers) 20.2, 22.1, 23, 26.6, 29, 30.9, 34.5, 38.8, 40.6, 54.9, 55.9, 64.9, 69.9, 74, 120.4, 121.4, 122.7, 126.7, 127.3, 128.3, 129.3, 131.5, 132.6, 143.5, 145.2, 148.1, 219.6, [1-Hydroxy-1-(4-chlorophenyl)methyl]-4-methylcyclohexan-1-one, 7 (Ref 14a,18): Yield: 90%; white solid; m.p C; IR (CHCl 3 ): 1703, 3501 cm -1 ; 1 H NMR (mixture of isomers) (CDCl 3, 300 MHz): δ (m, 3H, CH 3 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 and CH), (m, 2H, CH 2 ), (m, 1H, CH), 3.09 (br, 1H, OH), (d, 0.44H, J = 9 Hz, CHOH), (d, 0.56H, J = 2.4 Hz, CHOH), (m, 4H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (All isomers) 14.0, 18.5, 21.2, 26.6, 29.6, 31.5, 33.2, 33.6, 35.6, 36.1, 38.1, 41.7, 53.4, 55.9, 69.8, 74.1, 127.1, 128.2, 128.6, 129.4, 130.8, 133.6, 139.6, [1-Hydroxy-1-(4-nitrophenyl)methyl]-1,4-dioxaspiro[4.5]decan-8-one, 8 (Ref 14a,19): Yield: 80%; light brown solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1705, 3524 cm -1 ; anti/syn = 34:66; 1 H NMR (CDCl 3, 300 MHz): δ (m, 1H, CH 2 ), (m, 3H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH), (m, 4H, CH 2 ), (d, 0.66H, J = 3.6 Hz, OH (syn)), (d, 0.34H, J = 3.3 Hz, OH (anti)), 4.92 (d, 0.34H, J = 7.8 Hz, CHOH (anti)), 5.52 (m, 0.66H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 33.0, 34.2, 37.7, 38.4, 38.7, 52.9, 64.5, 64.6, 64.7, 69.5, 76.5, 106.7, 107.2, 123.5, 123.6, 126.4, 127.8, [1-Hydroxy-1-(4-nitrophenyl)methyl]-4-tertbutylcyclohexan-1-one, 9 (Ref 14a, 20): Yield: 91%; white solid; m.p C; MS: m/z (M + + Na); IR (CHCl 3 ): 1704, 3422 cm -1 ; 1 H NMR (CDCl 3, 300 MHz): δ (All isomers) 0.78, 0.81, 0.82 (3s, 9H, CH 3 ), (m, 4H, CH 2 ), (m, 1H, CH), (m, 2H, CH 2 ), (m, 1H, CH), (brs, 1H, OH), (d, 0.38H, J = 9 Hz, CHOH), 5.48 (s, 0.62H, CHOH), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (mixture of isomers) (CDCl 3, 75 MHz): δ (All isomers) 26.7, 27.4, 27.5, 28.4, 28.5, 31.7, 32.5, 41.8, 42, 46.5, 55.8, 56, 70.1, 74.1, 123.5, 126.5, 127.7, 147, 148.4, [1-Hydroxy-1-(2-nitrophenyl)methyl] cyclopent-1-one, 10 (Ref 14a, 21): Yield: 88%; yellow liquid; MS: m/z (M + + Na); IR (CHCl 3 ): 1733, 3424 cm -1 ; anti/syn = 28:72; 1 H NMR (CDCl 3, 300 MHz): δ (m, 2H, CH 2 ), (m, 2H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 4.50 (brs, 1H, OH), (d, 0.28H, J = 8.4 Hz, CHOH (anti)), (d, 0.72H, J = 3 Hz, CHOH (syn)), (m, 1H, ArH), (m, 1H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 20.1, 20.4, 22.8, 26.5, 38.6, 54.7, 55.3, 66.4, 69.0, 123.9, 124.4, 127.9, 128.5, 128.6, 128.9, 133.1, 133.3, 138.6, 146.9, [1-Hydroxy-(3-nitrophenyl)methyl] cyclopent- 1-one, 11 (Ref 14a,20): Yield: 89%; yellow liquid; MS: m/z (M + + Na); anti/syn = 45:55; 1 H NMR (CDCl 3, 300 MHz): δ (m, 2H, CH 2 ), (m, 4H, CH 2 ), (m, 1H, CH), (d, 0.45H, J = 9 Hz, CHOH (anti)), (d, 0.55H, J = 2.7Hz, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 18.3, 26.8, 33.2, 36.6, 38.5, 53.1, 69.7, 124.0, 128.4, 128.8, 133.1, 136.7, 148.7, [1-Hydroxy-1-(4-nitrophenyl)methyl] cyclopent-1-one, 12 (Ref 14a,20): Yield: 87%; yellow liquid; IR (CHCl 3 ): 1730, 3448 cm -1 ; anti/syn = 39:61; 1 H NMR (CDCl 3, 300 MHz): δ (m, 2H, CH 2 ), (m, 4H, CH 2 ), (m, 1H, CH), 2.81 (s, 0.61H, OH (syn)), 4.63 (s, 0.39H, OH (anti)), (d, 0.39H, J = 9 Hz, CHOH (anti)), 5.39 (s, 0.61H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 24.3, 24.6, 25.5, 27.5, 30.2, 42.5, 56.3, 57.0, 69.8, 73.5, 123.0, 126.5, 127.2, 147.4, 147.9, 149.2, 213.5, [1-Hydroxy-1-(4-nitrophenyl)methyl]cycloheptanone, 13 (Ref 14a): Yield: 81%; yellow liquid; IR (CHCl 3 ): 1734, 3480 cm -1 ; anti/syn = 78:22; 1 H NMR (CDCl 3, 300 MHz): δ (m, 3H, CH 2 ), (m, 5H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH), 3.69 (s, 1H, OH), (d, 0.78H, J = 7.2 Hz, CHOH (anti)), 5.22 (s, 0.22H, CHOH (syn)), (m, 2H, ArH), (m, 2H, ArH); 13 C NMR (CDCl 3, 75 MHz): δ (anti + syn isomers) 23.3, 23.5, 23.8, 28.0, 28.5, 28.9, 29.0, 44.0, 57.1, 57.8, 72.4, 74.6, 123.4, 123.5, 126.7, 127.7, 146.9, 147.3, 149.2, 149.5, 216.8, Conclusion In summation, pyrrolidine acts as an efficient catalyst for diastereoselective direct aldol reaction of variety of cyclic ketones and aromatic aldehydes in

8 SINGH et al.: PYRROLIDINE CATALYZED ALDOL REACTION 1209 water. The aldol products were formed with high yield along with moderate to excellent diastereoselectivity. Moreover, the methodology developed is environmentally benign, simple and highly efficient. It is believed that the present findings will open up new avenues for the design of structurally simple organocatalysts that would be highly effective under aqueous reaction conditions. Acknowledgements The authors are grateful for financial support from CSIR, India to S.S.C.(research Grant No. 01/2168/07/EMR-II) and SRF(NET) fellowship to S.S. References 1 Wurtz A, Bull Soc Chim Fr, 17, 1872, (a) Mahrwald R, Modern Aldol Reactions (Wiley-VCH, Weinheim), 2004; (b) Palomo C, Oiarbide M & Garcıa J M, Chem Soc Rev, 33, 2004, (a) Dean S M, Greenberg W A & Wong C-H, Adv Synth Catal, 349, 2007, 1308; (b) Rychnovsky S D, Chem Rev, 95, 1995, (a) Rodriguez G, Lutz M, Spek A L & Van Koten G, Chem Eur J, 8, 2002, 46; (b) Stark M A & Richards C J, Tetrahedron Lett, 38, 1997, 5881; (c) Kuwano R, Miyazaki H & Ito Y, J Organomet Chem, 603, 2000, (a) Beisswengera R, Snatzkeb G, Thiemc J & Kula M R, Tetrahedron Lett, 32, 1991, 3159; (b) Li H-H, He Y-H, Yuan Y & Guan Z, Green Chem, 13, 2011, Tanaka F & Barbas III C F, Modern Aldol Reactions (Wiley- VCH Verlag GmbH, Weinheim), (a) Kobayashi S & Horibe M, Chem Eur J, 3, 1997, 1472; (b) Evans D A, MacMillan D W C & Campo K R, J Am Chem Soc, 119, 1997, (a) Mukaiyama T, Fujisawa H & Nakagawa T, Helvetica Chimica Acta, 85, 2002, 4518; (b) Denmark S E, Eklov B M, Yao P J & Eastgate M D, J Am Chem Soc, 131, 2009, Pousse G, Cavelier F L, Humphreys L, Rouden J & Blanchet J, Org Lett, 12, 2010, (a) Li C-J, Chem Rev, 105, 2005, 3095; (b) Lindstrom U M, Chem Soc Rev, 102, 2002, 2751; (c) Grieco P A, Organic Synthesis in Water (Blackie Academic and Professional, London), 1998; (d) Li C-J & Chan T-H, Organic Reactions in Aqueous Media (John Wiley and Sons, New York), 1997; (e) Sinou D, Adv Synth Catal, 344, 2002, (a) Li C-J & Chen L, Chem Soc Rev, 35, 2006, 68; (b) Lindstrom U M & Andersson F, Angew Chem Int Ed, 44, 2006, 548; (c) Otto S & Engberts J B F N, Org Biomol Chem, 1, 2003, 2809; (d) Chandler D, Nature, 417, 2002, (a) Breslow R, Acc Chem Res, 24, 1991, 159; (b) Breslow R & Rideout D, J Am Chem Soc, 102, 1980, Grieco P A, Organic Synthesis in Water (Blackie Academic and Professional, London), (a) Chimni S S, Singh S & Mahajan D, Tetrahedron: Asymmetry, 19, 2008, 2276; (b) Chimni S S, Singh S & Kumar A, Tetrahedron: Asymmetry, 20, 2009, 1722; (c) Kumar A, Singh S, Kumar V & Chimni S S, Org Biomol Chem, 9, 2011, (a) Mahajan D & Chimni S S, Indian J Chem, 46B, 2007, 1355; (b) Chimni S S & Mahajan D, Tetrahedron, 61, 2005, (a) Maya V, Raj M & Singh V K, Org Lett, 9, 2007, 2593; (b) Wu Y, Zhang Y, Yu M, Zhao G & Wang S, Org Lett, 8, 2006, Chen F, Huang S, Zhang H, Liu F & Peng Y, Tetrahedron, 64, 2008, Luo S, Xu H, Li J, Zhang L, Mi X, Zheng X & Cheng J-P, Tetrahedron, 63, 2007, He L, Jun J, Tang Z, Cui X, Mi A-Q, Jiang Y-Z & Gong L-Z, Tetrahedron: Asymmetry, 18, 2007, Rodriguez B, Bruckmann A & Bolm C, Chem Eur J, 13, 2007, Fu Y-Q, Li Z-C, Ding L-N, Tao J-C, Zhang S-H & Tang M- S, Tetrahedron: Asymmetry, 17, 2006, 3351.