A comprehensive study on the effect of acid additives in 1(R),2(R)-Bis[(S)-prolinamido]cyclohexane catalyzed direct
asymmetric aldol reactions in aqueous media
Sudipto Bhowmicka, Sunita S Kunteb & Kartick C Bhowmick*a
aDivision of Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731 235, India
bDivision of Organic Chemistry, Analytical Section, CSIR-National Chemical Laboratory, Pune 411 008, India
E-mail: kartickc.bhowmick@visva-bharati.ac.in Received 24 July 2013; accepted (revised) 27 October 2014
The catalytic efficacy of (1R,2R)-bis[(S)-prolinamido]cyclohexane 1, prepared from the readily available natural amino acid L-proline has been studied for the direct asymmetric aldol reaction of cyclohexanone with substituted benzaldehydes at room temperature in presence of various acid additives. A wide variety of acids e.g. aliphatic fatty acid, chiral acid, sulphonic acid, aromatic acid, etc. have been used as additive for the aldol reaction in aqueous media. A loading of 10 mol%
of catalyst 1 is employed in this reaction, and good yields (up to 98% yield), diastereoselectivity (up to 96% de) and enantioselectivities (up to 87% ee) can be achieved in aqueous media within very short reaction time (1-4 hours).
Keywords: Asymmetric synthesis, direct aldol reaction, organocatalysis, acid additives, aqueous media
Asymmetric organocatalysis at the present time has become an important area of research in organic synthesis1. The asymmetric aldol reaction is one of the important methods for the formation of carbon- carbon bonds in organic synthesis2-4. Several small organic molecules, including proline5-8 and its derivatives, have been found to be efficient catalysts for asymmetric aldol reactions. Recently, development of organocatalysts for the asymmetric direct aldol reactions in water has become a subject of study since it provides some unique properties e.g. large cohesive energy density, high surface tension and hydrophobic effect9-18.Breslow et al.19 and Grieco20 while studying the Diels–Alder reaction during the early 1980s have shown that reactions proceed at much higher rates and with greater regioselectivities in water than in organic solvents21. The accelerating effect is attributed to a number of factors, which are the hydrophobic effect as well as hydrogen bonding between water molecules and reactants.
It has been reported sometime back that an amide 1 in absence of any acid additive provides the aldol product 2a with only 56% enantiomeric excess after a longer reaction time of about 10 hr (Ref 22). The same research group synthesized an ionic group tagged C2-symmetric catalyst 3 (Figure 1) starting
from the amide 1, and reported its application in asymmetric aldol reaction in aqueous media23. Even though very good enantioselectivity (99%) was observed, the average reaction time was found to be 24 hr and more.
The literature evidence on organic media24 has prompted us to undertake a comprehensive study to check the effect of acid additives in amide 1 catalyzed direct aldol reaction in aqueous media, in anticipation to achieve the goal of short reaction time and high
N H O
O NH O
N N
Me
N H
O
HN O
O
N N Me PF6
PF6 3
Figure 1
selectivity simultaneously. Herein is reported for the first time, a comprehensive study on the effect of acid additives on (1R,2R)-bis[(S)-prolinamido]cyclohexane 1 catalyzed direct aldol reaction between substituted benzaldehydes and various ketones in water. The corresponding aldol products, as expected are indeed obtained in high isolated yields (up to 98%) with high anti diastereoselectivities (up to 92%), enantio- selectivities (up to 87%) and high reaction rate (reaction hours varies from 1-4 h only). It is also to be noted that very recently Henderson et al. reported about the inconsistency of the results obtained on direct aldol reaction in water, where they concluded that the use of acid additives was of no real benefit to the catalytic system described therein with respect to the aldehyde/ketone combinations25. In fact the present results show, on the contrary, that the acid additive has remarkable effect on both reaction rate and stereoselectivities and moreover, to the best of the knowledge such a comprehensive study to check the efficacy of variety of acid additives in asymmetric aldol reaction in aqueous media has never been reported with a C2-symmetric oraganocatalyst.
Results and Discussion
The C2-symmetric bis-prolinamide (1R,2R)-bis[(S)- prolinamido]cyclohexane 1 has been selected as the
chiral catalyst for the present study. The bis-prolinamide (1R,2R)-bis[(S)-prolinamido]cyclohexane 1 has been synthesized from inexpensive reagents like N-boc-L- proline and (1R,2R)-diaminocyclohexane by two steps after a little modification on the reported method (Scheme l)26,27.
The organocatalyzed aldol reaction was carried out using 4-nitrobenzaldehyde and cyclohexanone as a model reaction to optimize different parameters, such as the catalyst loading, temperature, effect of additive, and the volume of water.
It is reported that for aldol reactions performed under aqueous conditions, the reactivity and stereo- selectivities are increased28,29. In our experiment, it has been observed that with increase in the amount of water from 5.5 equiv. to 55.5 equiv. enantioselectivity was decreased from 22% to 10% in absence of an acid additive. Hence the optimum amount of water was found to be 0.1 mL (5.5 equiv.) with this catalyst 1 for the aldol reaction between cyclohexanone and 4- nitrobenzaldehyde at RT (Table I).
After optimizing the volume of water, the amount of catalyst loading was investigated. Here it has also been found that 10 mol% catalyst loading is the best to achieve highest yield (98%) and enantioselectivity (87%) (entry 2 in Table II). With increase or decrease in the catalyst loading both yield and enantioselectiviy
N Boc
O
H2N NH2
+ N
H HN
O O
NR RN
a) Et3N, ClCOOEt, Toluene b) CF3COOH, CH2Cl2, RT
a
4, R = Boc 1, R = H b 2 equiv.
OH
N-boc-L-proline (1R, 2R)-diaminocyclohexane 75%
1 equiv. 62%
Scheme I
Table I — Effect of the amount of water in aldol reaction between cyclohexanone and 4-nitrobenzaldehyde catalyzed by 1a
O O
H
NO2 +
Catalyst 1 H2O, RT
2a
NO2
O OH
Entry H2O (mL) Time (hr) Yieldb (%) anti/sync eed
1 0.1 9 85 68/32 22
2 0.5 13 86 85/15 14
3 1 17 89 85/15 10
aThe reactions were performed with cyclohexanone (4 mmol), 4-nitrobenzaldehyde (1 mmol), catalyst 1 (0.1 mmol) in water.
bIsolated yield. c Determined by 1H NMR of the crude product. d Determined by chiral HPLC analysis.
decreases at RT for the same aldol reaction (Table II).
The yield as well as enantioselectivity did not improve when the reaction was performed with 10 mol% catalyst in absence of water (entry 4 in Table II). The effect of brine as solvent was also examined wherein enantioselectivity dropped significantly to only 48% under similar reaction conditions (entry 3 in Table II).
Thereafter, the influence of variety of acid additives on the reaction of asymmetric aldol reaction between p-nitrobenzaldehyde (1 equiv.) and cyclohexanone (4 equiv.) catalyzed by 10 mol% of amide 1 in 0.1 mL of water at RT was investigated. A broad spectrum of acid additives, starting from simple aromatic acids like benzoic acid, 4-nitrobenzoic acid, picric acid to optically active acids like L-tartaric acid and abietic acid were chosen for the optimization. The efficacy of long chain fatty acids like stearic acid and oleic acid were also tested in this reaction. Even though the reactions were very fast in the presence of these fatty acids, the enantioselectivities were not very impressive. At the outset, 4-nitrobenzoic acid has been found to be the best acid additive for the amide 1 catalyzed aldol reaction in water at RT with 98% yield and 87% enantiomeric excess (entry 14, Table III).
Lowering the temperature to 0oC had a detrimental effect on both yield and enantioselectivity of the aldol product (entry16, Table III). A careful optimization study by varying the amount of 4-nitrobenzoic acid was also carried out in presence of 10 mol% of catalyst 1 in 0.1 mL of water (entry 17, 18, 19 in Table III). It was observed that 20 mol% of acid additive provided 62% ee (entry 19 in Table III) and 2.5 mol% of acid additive resulted only 30% ee (entry 17 in Table III), that is, still 5 mol% of acid additive
remained the optimum additive loading in this reaction (entry 14 in Table III). At the outset a non-linear relationship between acid additives (pKa) and obtained ee of the aldol product was observed (Figure 2). It is to be noted that the different acid additives not only influence the enantioselectivity significantly, but at the same time the reactions are extremely fast.
Once the 4-nitrobenzoic acid has been found to be the best acid additive for the reaction, several aldehydes were tested as substrate for the direct aldol reaction between cyclohexanone in presence of 4- nitrobenzoic acid as an additive at RT in water.
Among all the regio-isomers of chlorobenzaldehydes, o-chlorobenzaldehyde provided the highest enantio- selectivity with 69% (entry 6, Table IV), while o-and p-fluoro derivatives have shown moderate enantio- selectivity (entry 3 and 4, Table IV). A strong electron withdrawing substituent like p-trifluoromethyl provided almost the same enantioselectivity as o-fluoro derivative (entry 13 and 3, Table IV), p-methyl substituted benzaldehyde provided good yield (84%) and moderate enantioselectivity (70%) (entry 10, Table IV). Strong electron donating group like o-and p-methoxy substituent had a detrimental effect on the enantioselectivity of aldol products (entry 5 and 9, Table IV). Interestingly, the result with crotonaldehyde was quite impressive since good yield (82%), diastereoselectivity (82%) and good enantio- selectivity (87%) could be obtained (entry 14, Table IV).
The efficacy of the catalyst 1 has also been checked for the aldol reaction between aliphatic ketones and p-nitrobenzaldehyde under the above optimized reaction conditions. Reaction with 2-butanone was completed within only 2 h but the ee was found to be not so impressive (entry 1, Table V).
Table II — Effect of the amount of catalyst in the aldol reaction between 4-nitrobenzaldehyde and cyclohexanone catalyzed by 1a
O O
H
NO2 +
Catalyst 1 (x mol%)
4-nitrobenzoic acid, H2O, RT NO2
O OH
Entry Catalyst (× mol%) Time (hr) Yieldb (%) anti/sync eed (%)
1 5 3 86 76/24 77
2 10 3 98 72/28 87
3e 10 8 83 88/12 48
4f 10 3 90 73/27 65
5 20 2 88 52/48 51
aThe reactions were performed with cyclohexanone (4 mmol), 4-nitrobenzaldehyde (1 mmol), 4-nitrobenzoic acid as (0.05 mmol) in water (0.1mL). b Isolated yield. c Determined by 1H NMR of the crude product. d Determined by chiral HPLC analysis. eIn presence of 0.1 mL of brine. f In absence of water.
Figure 2
A symmetrical aliphatic ketone like 3-pentanone provided the corresponding aldol product with an enhanced enantioselectivity (72%) (entry 2, Table V).
The stereochemical outcome and the extremely fast nature of the aldol reaction catalyzed by 1 may be explained by a transition state (Figure 3) wherein the
effect of acid additive could also be shown (X-being the counter anion of acid additive A)31.It is known that the pyrrolidine moiety activates the enamine and the amide bond favors hydrogen bond formation to enhance both the diastereoselectivity and enantio- selectivity. Here the ion pair provides a tunable H-bonding. It is observed that the nature of X-is very much crucial for a particular transition state to be more stable. For the catalyst 1, as can be observed, 4-nitrobenzoic acid provides the most stable transition state giving the highest enantioselectivity for aldol products.
The carbonyl group of the aldehyde is activated by hydrogen bonding with the NH group of the catalyst in such a way that C-C bond formation takes place from its re face, while the nonbonding interaction disfavors the alternative si face. This proposed model needs enamine formation and it is supported by enough evidence from the literature32,33. Basically, this reaction occurs in the biphasic medium, where substrate and the catalyst come closer and sequester
Table III — Effect of the acid additives on the aldol reaction between 4-nitrobenzaldehyde and cyclohexanone catalyzed by 1a
O O
H
NO2 +
Catalyst 1 (10 mol%)
Additive, H2O, RT NO2
O OH
Entry Additive (pKa) Time (hr) Yieldb (%) anti/sync (%) eed (%)
1 L-tartaric acid (2.89) 2 90 80/20 76
2 PTSA (-2.8) 4 91 78/22 67
3 Picric acid (0.38) 2 95 77/23 68
4 Benzoic acid (4.2) 1 96 81/19 73
5 2,4-Dinitrophenol (4.11) 2 91 79/21 72
6 Stearic acid (10.15) 1 90 77/23 78
7 Triflic acid (-12) 3 89 76/24 64
8 Methane sulfonic acid (-1.9) 4 85 69/31 63
9 TFA (0.23) 4 90 61/39 28
10 Oleic acid (9.85) 1.5 90 78/22 49
11 Phthalic acid (2.98) 3 91 74/26 52
12 Citric acid (3.14) 4 92 70/30 66
13 Adipic acid (4.43) 4 88 64/36 77
14 4-Nitro benzoic acid (3.41) 3 98 72/28 87
15e 4-Nitro benzoic acid 3.5 90 84/16 54
16f 4-Nitro benzoic acid 2.5 90 90/10 70
17g 4-Nitro benzoic acid 3 82 88/12 30
18h 4-Nitro benzoic acid 4 81 64/36 24
19i 4-Nitro benzoic acid 7 86 68/32 62
20 Abietic acid (4.64) 6 82 88/12 57
aThe reactions were performed with cyclohexanone (4 mmol), 4-nitrobenzaldehyde (1 mmol), catalyst 1 (0.1 mmol), additive (0.05 mmol) in water (0.1mL). b Isolated yield. c Determined by 1H NMR of the crude product. d Determined by chiral HPLC analysis.
e0.05mL water was used in this reaction. f The reaction was performed at 0oC. g The reaction was carried out with 0.0025 mmol of 4-nitrobenzoic acid as additive. hThe reaction was carried out with 0.1 mmol of 4-nitrobenzoic acid as additive. i The reaction was carried out with 0.2 mmol of 4-nitrobenzoic acid as additive.
N O
NH O
O
N H
O O + _
N N
H HH
X +
_
Figure 3
the transition state from water34. Once the organic molecules aggregate, they exclude water from the organic phase so that enamine formation is facilitated and ultimately, the desired aldol product is obtained.
Experimental Section
All reagents were commercial products. The reactions were monitored by TLC (thin layer chromatography). The column and preparative TLC purification were carried out using silica gel. NMR spectra were recorded on a 300 MHz instrument (Bruker spectrometer). Chemical shifts (δ) are given in parts per million relative to TMS as the internal
Table IV — Substrate scope was investigated under the optimal conditions and organocatalyst 1 catalyzed direct aldol reactions in the presence of water.a
O +
Catalyst 1 (10 mol%) 4-nitrobenzoic acid, H2O, RT
2b-n
RCHO R
OH O
Entry Product Time (hr) Yieldb (%) anti/sync eed (%) (anti)
1 2a (R=p-NO2-C6H4) 3 98 72/28 87
2 2b (R=m-NO2-C6H4) 3 90 94/6 45
3 2c (R=o-F-C6H4) 3.5 88 56/44 63
4 2d (R=p-F-C6H4) 4 95 70/30 49
5 2e (R=p-MeO-C6H4) 3 92 55/45 59
6 2f (R=o-Cl-C6H4) 2 95 92/8 69
7 2g (R=m-Cl-C6H4) 2 86 96/4 62
8 2h (R=p-Cl-C6H4) 1.5 88 69/31 58
9 2i (R=o-MeO-C6H4) 2.5 92 64/36 60
10 2j (R=p-Me-C6H4) 2.5 84 89/11 70
11 2k (R=1-Naphthyl) 3 86 58/42 72
12 2l (R=2-Naphthyl) 3.5 96 96/4 54
13 2m (R=p-CF3-C6H4) 1.5 88 86/14 62
14 2n (R= CH3CH=CH) 3.5 82 91/9 87
aThe reactions were performed with cyclohexanone (4 mmol), aldehyde (1 mmol), catalyst 1 (0.1 mmol), 4-nitrobenzoic acid (0.05 mmol) in the presence of water (0.1mL) at RT. b Isolated yield. c Determined by 1H NMR of the crude product. d Determined by chiral HPLC analysis (Kromasil, AD-H, OD-H) and comparison of the retention times with literature data30.
Table V — Reaction with acyclic ketones with 4-nitrobenzaldehyde catalyzed by 1a
+ Catalyst 1 (10 mol%)
Additive, H2O, RT O2N
O
H R''
O
R'
5a-b R''
NO2
R' OH O
Entry, (Product No.) R/ R// Time(hr) Yieldb(%) anti/sync eed(%) (anti)
1 (5a) CH3 CH3 2 89 75/25 55
2 (5b) CH3 CH2CH3 12 81 59/41 72
aThe reactions were performed with ketone (4 mmol), 4-nitrobenzaldehyde (1 mmol), catalyst 1 (0.1 mmol), 4-nitrobenzoic acid as additive (0.05 mmol) in the presence of water (0.1mL). b Isolated yield. c Determined by 1H NMR of the crude product.
dDetermined by chiral HPLC analysis.
reference, coupling constants (J) in Hertz. IR spectra were recorded with a FTIR spectrometer (Shimadzu).
Melting points were measured on a digital melting point apparatus. Analytical high performance liquid chromatography (HPLC) was carried out on Shimadzu CLASS-VP V6.12 SP5 instrument using Chiralpak AD-H (4.6 mm×250 mm), Chiralpak Kromasil 5-AmyCoat (4.6 mm×250 mm), and Chiralcel OD-H (4.6 mm×250 mm) columns. Optical rotations were measured on a Bellingham+Stanley ADP410 Polarimeter at λ=589 nm.
Synthesis of N,N/-bis(tert-butoxycarbonyl)-(1R,2R)- bis[(S)-prolinamido]cyclohexane, 4
N-(tert-Butoxycarbony1)-(S)-proline (430 mg, 2 mmol) was dissolved in toluene (4.5 mL) and triethylamine (0.3 mL) was added to the solution and was chilled to- 5°C in an ice/acetone bath and then isobutylchloro- formate (0.26 mL) in toluene (0.75 mL) was added.
The solution was stirred for 1 hr. Then a cold solution of R,R-1,2-cyclohexanediamine (114 mg, 1 mmol) and triethylamine (0.3 mL) in chloroform (3 mL) was added. The round bottom flask was sealed with a CaCl2 guard tube, and left stirring overnight at RT.
The reaction mixture was filtered under suction and the residue was washed with chloroform (15 mL). The total filtrate and washings were extracted with water (13 mL), 3% NaHCO3 solution (13 mL), and water (13 mL). The organic layer was dried over anhyd.
Na2SO4 and filtered. The filtrate was removed on a rotary evaporator to give a white solid of N,N/- bis(tert-butoxycarbonyl)-(1R,2R)-bis[(S)-
prolinamido]cyclohexane, which was then purified by column chromatography. This compound is new in the literature. Yield = (370 mg, 73%); m.p. 176-78°C;
[α]D=-50o (c 1, CHCl3); IR (KBr): 3332, 1701, 1647, 1541, 1534, 1390, 1367 cm-1; 1H NMR (CDCl3):
δ 1.1–1.3 (4H, m), 1.3-1.4 (18H, m), 1.4–2.3 (12H, m), 3.4-3.6 (6 H, m), 4.1-4.3 (2H, t), 6.4 (1H, br s, amide), 6.7 (1H, br s, amide); 13C NMR (100 MHz, CDCl3): δ 172.97, 80.39, 76.59, 61.39, 52.85, 47.04, 32.40, 31.18, 28.30, 24.48, 23.73. Anal. Calcd for C26H44O6N4: C, 61.39; H, 8.72; N, 11.01. Found: C, 61.28; H, 8.66; N, 11.19%.
Synthesis of (1R,2R)-bis[(S)-prolinamido]cyclohexane, 1 The column purified N,N/-Bis(tert-butoxycarbonyl)- (1R,2R)-bis[(S)-prolinamido]cyclohexane (1.303 g, 2.5 mmol) was dissolved in a mixture of TFA/DCM (1:4 ≈ 13 mL) and stirred for 2 hr at RT. The mixture
was then basified with concentrated NH3 solution and extracted with DCM (3×30 mL). After the removal of the solvent at reduced pressure, the solid white colored product 1 was purified by recrystallization from ethyl acetate (25 mL). Yield = 612 mg (80%);
m.p. 104-106oC (lit.27 105-108oC); [α]D =-30o (c 1, CHCl3). The 1H NMR is consistent with the literature reports26, 27.
General procedure for direct asymmetric aldol reactions of ketones with aldehydes
To a mixture of catalyst 1 (0.1 mmol) and additive in water (0.1 mL), ketone (4.0 mmol) followed by aromatic aldehydes (1.0 mmol) were added. The resulting mixture was stirred at RT, an emulsion was formed. The asymmetric aldol reactions were found to occur in the emulsion where the catalyst molecules are distributed in the water-oil interface. The reaction was monitored by TLC. It was then quenched with 10 mL of saturated NaHCO3 solution, extracted with EtOAc (3×10 mL), and brine (15 mL), then dried over anhyd. Na2SO4. Purification by column chromato- graphy afforded the corresponding pure products. The ee of the products were determined by chiral HPLC analysis.
(2S,3R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclo- hexan-1-one, 2a: The general procedure was followed by using 4-nitrobenzaldehyde and cyclohexanone. After 3 hr, 0.244 g (98%) of the desired product was isolated. The 1H NMR is consistent with the literature reports35. The ee of this sample was determined to be 87% by chiral HPLC analysis (Chiralpak Kromasil 5-CelluCoat, hexanes/iPrOH 95/5, 1 mL min-1): tR (major)=
23.5 min, tR (minor)=33.1 min.
(2S,3R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclo- hexan-1-one, 2b: The general procedure was followed by using 3-nitroben-zaldehyde and cyclohexanone. After 3 hr, 0.224 g (90%) of the desired product was isolated. The
1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 45% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 85/15, 0.5 mL min-1): tR (major)=19 min, tR
(minor)=26 min.
(2S, 3R)-2-[Hydroxy(2-fluorophenyl)methyl]cyclo- hexan-1-one, 2c: The general procedure was followed by using 2-fluorobenzaldehyde and cyclohexanone.
After 3.5 hr, 0.219 g (88%) of the desired product was isolated. The 1H NMR is consistent with the literature
reports37. The ee of this sample was determined to be 63% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 95/5, 0.5 mL min-1): tR (major)=
16.6 min, tR (minor)=21.6 min.
(2S, 3R)-2-[Hydroxy(4-fluorophenyl)methyl]- cyclohexan-1-one, 2d: The general procedure was followed by using 4-fluorobenzaldehyde and cyclohexanone. After 4 hr, 0.236 g (95%) of the desired product was isolated. The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 49% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 95/5, 1 mL min-1): tR (major)=10 min, tR (minor)=18.3 min.
(2S, 3R)-2-[Hydroxy(4-methoxyphenyl)methyl]- cyclohexan-1-one, 2e: The general procedure was followed by using 4-methoxybenzaldehyde and cyclohexanone. After 3 hr, 0.229 g (92%) of the desired product was isolated. The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 59% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 90/10, 0.5 mL min-1): tR (major)=21.3 min, tR (minor)=29.3 min.
(2S,3R)-2-[Hydroxy(2-chlorophenyl)methyl]cyclo- hexan-1-one, 2f: The general procedure was followed by using 2-chlorobenzaldehyde and cyclohexanone.
After 2 hr, 0.236 g (95%) of the desired product was isolated. The 1H NMR is consistent with the literature reports35. The ee of this sample was determined to be 69% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 95/5, 1 mL min-1): tR (major)=8.52 min, tR (minor)=10.7 min.
(2S, 3R)-2-[Hydroxy(3-chlorophenyl)methyl]- cyclohexan-1-one, 2g: The general procedure was followed by using 3-chlorobenzaldehyde and cyclohexanone. After 2 hr, 0.214 g (86%) of the desired product was isolated. The 1H NMR is consistent with the literature reports35. The ee of this sample was determined to be 62% by chiral HPLC analysis (Chiralpak Kromasil 5-AmyCoat, hexanes/iPrOH 95/5, 0.5 mL min-1): tR (major)=
31.6 min, tR (minor)=34.3 min.
(2S, 3R)-2-[Hydroxy(4-chlorophenyl)methyl]- cyclohexan-1-one, 2h: The general procedure was followed by using 4-chlorobenzaldehyde and cyclohexanone. After 1.5 hr, 0.219 g (88%) of the desired product was isolated. The 1H NMR is consistent with the literature reports35. The ee of this sample was determined to be 58% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 90/10, 0.5 mL min-1): tR (major)=17.2 min, tR (minor)=24.8 min.
(2S, 3R)-2-[Hydroxy(2-methoxyphenyl)methyl]- cyclohexan-1-one, 2i : The general procedure was followed by using 2-methoxybenzaldehyde and cyclohexanone. After 2.5 hr, 0.229 g (92%) of the desired product was isolated. The 1H NMR is consistent with the literature reports38.The ee of this sample was determined to be 60% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 95/5, 1 mL min-1): tR (major)=12 min, tR (minor)=15.7 min.
(2S, 3R)-2-[Hydroxy(4-methylphenyl)methyl]- cyclohexan-1-one, 2j: The general procedure was followed by using 4-methylbenzaldehyde and cyclohexanone. After 2.5 hr, 0.209 g (84%) of the desired product was isolated. The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 70% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 97/3, 0.5 mL min-1): tR (major)=26.8 min, tR (minor)=37.7 min.
(2S, 3R)-2-[Hydroxy(1-naphthyl)methyl]cyclohexan- 1-one, 2k: The general procedure was followed by using 1-naphthaldehyde and cyclohexanone. After 3 hr, 0.214 g (86%) of the desired product was isolated.
The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 72% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 97/3, 1 mL min-1): tR (major)=40.2 min, tR (minor)=37.1 min.
(2S, 3R)-2-[Hydroxy(2-naphthyl)methyl]cyclo- hexan-1-one, 2l: The general procedure was followed by using 2-naphthaldehyde and cyclohexanone. After 3.5 hr, 0.239 g (96%) of the desired product was isolated. The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 54% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 90/10, 0.5 mL min-1): tR (major)=
24 min, tR (minor)=30.9 min.
(2S, 3R)-2-[Hydroxy(4-trifluoromethylphenyl)- methyl]cyclohexan-1-one, 2m: The general procedure was followed by using 4-trifluromethylbenzaldehyde and cyclohexanone. After 1.5 hr, 0.219 g (88%) of the desired product was isolated. The 1H NMR is consistent with the literature reports36. The ee of this sample was determined to be 62% by chiral HPLC analysis (Chiralpak OD-H, hexanes/iPrOH 80/20, 0.5 mL min-1): tR (major)=11.1 min, tR (minor)=12.8 min.
(R)-2-[(R, E)-1-Hydroxybut-2-enyl]cyclohexanone, 2n: The general procedure was followed by using crotonaldehyde and cyclohexanone. After 3.5 hr, 0.204 g (82%) of the desired product was isolated.
The 1H NMR is consistent with the literature reports.
The ee of this sample was determined to be 87% by chiral HPLC analysis (Chiralpak Kromasil 5-CelluCoat, hexanes/iPrOH 99/1, 0.5 mL min-1): tR (major)=
6.5 min, tR (minor)=6.1 min.
(4R)-4-Hydroxy-3-methyl-4-(4-nitrophenyl)butan- 2-one, 5a: The general procedure was followed by using 2-butanone and 4-nitrobenzaldehyde. After 2 hr, 0.221 g (89%) of the desired product was isolated. The 1H NMR is consistent with the literature reports39. The ee of this sample was determined to be 55% by chiral HPLC analysis (Chiralpak OJ-H, hexanes/iPrOH 92.5/7.5, 0.5 mL min-1): tR (major)=
75 min, tR (minor)=80.1 min.
(1R)-1-Hydroxy-2-methyl-1-(4-nitrophenyl)pentan- 3-one, 5b: The general procedure was followed by using 3-pentanone and 4-nitrobenzaldehyde. After 12 hr, 0.201 g (81%) of the desired product was isolated.
The 1H NMR is consistent with the literature reports40. The ee of this sample was determined to be 72% by chiral HPLC analysis (Chiralpak Kromasil 5-AmyCoat, hexanes/iPrOH 97.5/2.5, 0.5 mL min-1):
tR (major)=76.8 min, tR (minor)=71.5 min.
Conclusions
In conclusion, a comprehensive study has been presented for a C2-symmetric organocatalyst, (1R, 2R)-bis[(S)-prolinamido]cyclohexane 1 which catalyzed direct aldol reaction between substituted benzaldehydes and various ketones providing the corresponding products in high isolated yields (up to 98%) with high anti diastereoselectivities (up to 92%) and enantioselectivities (up to 87%) in water in presence of variety of acid additives. The same amide 1 in absence of 4-nitrobenzoic acid provided the aldol product with only 56% enantiomeric excess even after a longer reaction time of about 10 hr. The probable reason for the impressive enhancement of the reaction rate and enantioselectivity in presence of acid additives in water media have been elaborately discussed. It is clear from the literature that a single acid additive is not found to be the best for all organocatalysts in a particular aldol reaction providing best results13, hence involvement of the acid additive in the stability of transition state should be considered. A density functional theoretical study would therefore be necessary to corroborate the experimental results. DFT calculation study is underway in our department in collaboration with a physical chemistry group.
Acknowledgements
The authors are grateful to DST, India for the financial assistance [Grant No. SR/FT/CS-013/2009]
and SB thanks UGC, India for the award of a research fellowship.
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