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A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions
Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions Biao Xu a, Lei Li a, Shaohua Gou a,b,⇑ a b
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China
a r t i c l e
i n f o
Article history: Received 23 July 2013 Accepted 3 September 2013 Available online xxxx
a b s t r a c t A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N1-n-pentyl, N1-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-b-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The aldol reaction is one of the most significant methods to form a carbon–carbon bond in synthetic chemistry.1 It generates active b-hydroxy products which are motifs of many biologically and pharmaceutically important intermediates.2 The asymmetric aldol reaction also provides an atom-economical approach to synthesize b-hydroxy carbonyl compounds. Since List first reported that L-proline could catalyze the cross-aldol reaction,3 organocatalysts have become a focus in the field of asymmetric catalysis.4 So far, many types of effective organic catalysts have been developed for asymmetric aldol reactions, most of which are L-proline and its derivatives.5 Similar to proline and other secondary amine catalysts, some primary amino acids have also been found to show good asymmetric catalytic action in aldol reactions.6 Diamines have also been explored,7 in which chiral primary-tertiary 1,2-diamines had excellent catalytic activity.8 Catalysts 18a and 2,8b which are derived from chiral 1,2-diaminocyclohexane, were found in 2007 and 2011 respectively to catalyze the corresponding aldol reactions with good yields and enantioselectivity. In the supposed mechanism, the primary amine was employed to form an enamine intermediate, while the protonated tertiary amine was believed to activate the aldehyde through hydrogen bonds. The catalyst only worked for a few selected substrates (aryl aldehydes bearing electron-withdrawing groups), since substrates such as aryl aldehydes bearing electron-donating groups displayed low efficiency (yield 21%). ⇑ Corresponding author. Tel./fax: +86 (25)83272381. E-mail address: [email protected] (S. Gou).
Compared with aldehydes, ketones have seldom been explored in asymmetric aldol reactions as electrophilic reactants, which represent a great challenge.9 Isatin has recently received much attention, since it can be used to produce 3-hydroxyindolin-2one, which is a core structure of many biologically and pharmaceutically active compounds,10 such as convolutamydines, which display interesting antitumour activity.11 Since the pioneering work of Tomasini et al. in 2005,12 L-proline (a secondary amine itself) became a focus, but it displayed moderate efficiency in the cross-aldol reaction of isatin with acetone (ee 20–73%). It was reported that under severe conditions the catalytic results were slightly improved upon (in 60 to 40 °C, ee 25–90%).13 In contrast, primary amine organocatalysts were relatively efficient, as vicinal amino alcohols were reported to act as superior catalysts (yield up to 98%, ee 95%).14 However, to the best of our knowledge, there has been no report on tertiary amine catalysts in this field so far. Since non-covalent p–p interactions between aromatic rings of catalysts and substrates could promote enantioselectivity,15 we aimed to design a catalyst containing both primary and tertiary amines with an aromatic ring in order to improve any catalytic effect in the asymmetric aldol reaction of aromatic aldehydes and ketones. Thus we synthesized a number of (1R,2R)-N1-alkyl,N1benzyl-1,2-cyclohexane diamines as catalysts 3 (Fig. 1) for asymmetric aldol reactions. The basicity of the tertiary amine was adjusted by changing the length of the alkyl chain. As expected in our following tests, 3e proved to be an efficient catalyst in the condensation reactions of acetone and aryl aldehydes with moderate yields and good enantioselectivity (up to yield 85%, ee 98%). In the reactions of cyclohexanone and aryl
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.09.026
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B. Xu et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
N
N
N
R
NH2
NH2
3a 3b 3c 3d 3e 3f
R=H R=CH3 R=CH2CH3 R=(CH2)2CH3 R=(CH2)4CH3 R=(CH2)6CH3
NH2 2
1
3
Figure 1. Chiral primary-tertiary-type 1,2-cyclohexanediamines.
aldehydes, it also afforded excellent diastereoselectivity and enantioselectivity (up to anti/syn ratio 99:1, 99% ee). This catalyst was then applied to the reaction of acetone and isatin, in which excellent yields and enantioselectivity were obtained (up to 95% yield, 98% ee). To the best of our knowledge, there are very few organocatalysts that can catalyze aldehyde–ketone or ketone– ketone aldol reactions with such excellent enantiomeric excess.
NH2 NHBoc
2. Results and discussion The synthesis of organocatalyst 3 is outlined in Scheme 1. The aldol reaction between acetone and 4-nitrobenzaldehyde was chosen as a benchmark reaction in order to evaluate the catalysts and optimize the reaction conditions. The results are listed in Table 1. At the outset, catalyst 3c was used to test the effects of
NH
aryl aldehyde, NaBH4
N
NaCNBH3, alkyl aldehydes
R
rt. 6h
CH3OH, rt. 3h
NHBoc
NHBoc
4
6
5
HCl/H2O, rt. 12h
N
NaOH/H2O
R
N
R
2HCl NH2
NH2 3
7 Scheme 1. Synthesis of organocatalyst 3.
Table 1 Screening catalysts under different conditions for the aldol reaction of acetone and 4-nitrobenzaldehydea
OH CHO
O
+
catalyst (15%), additive (30%) 15°C, 36h
O 2N
O
O2N 8a
a b c d e
Entry
Catalyst
Additive
Solvent
1 2 3 4 5 6 7 8 9d 10e 11 12 13 14 15
3c 3c 3c 3c 3c 3c 3c 3c 3c 3c 3a 3b 3d 3e 3f
TFA TFA TFA TFA TFA / TfOH HDA TFA TFA TFA TFA TFA TFA TFA
H2O CH3OH DMF DMSO Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone
Yieldb (%)
eec (%)
— 8 3 2 77 6 27 19 68 27 97 53 68 85 81
— 87 83 77 95 80 -4 58 86 94 51 75 96 98 91
The reaction was performed with aldehyde (0.5 mmol), acetone (2.5 mmol) in 2 mL solvent for 36 h. Isolated yields. Ee% calculated by using chiral HPLC. Using 15 mol % TFA. Using 10 mol % catalyst 3c.
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B. Xu et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
different solvents, additives, and catalyst loading on the reaction (Table 1, entries 1–10). It is noteworthy that trifluoroacetic acid (TFA) was essential for this reaction. When TFA was removed or replaced by HDA or TfOH, the yield and the enantioselectivity decreased remarkably (Table 1, entries 5–8). Reduction of the catalyst loading or the amount of TFA was also adverse to the results of the reaction (entries 9 and 10). In order to improve catalytic effect on the optimized reaction conditions, alkyl chains (R) were extended or shortened to adjust the basicity and steric size of the tertiary amine so that the best enantioselectivity could be achieved. The catalytic results are summarized in Table 1 (entries 11–15). As shown, catalyst 3e was superior to the others (85% yield, 98% ee, entry 14). Catalyst 3f showed relatively low enantiomeric excess compared with 3e, probably due to steric hindrance. With the optimized reaction conditions being identified, the scope of the reaction was further explored with a series of aryl aldehydes with the results listed in Table 2. It was noted that catalyst 3e only worked for aryl aldehydes containing an electronwithdrawing group, and excellent enantioselectivities were obtained (ee 90–99%), although the reactions were very slow with low and moderate yields (10–58%, entries 1–6). For aryl aldehydes with an electron-donating group, the reaction hardly took place (entry 7, Table 2). Table 2 Direct asymmetric aldol reaction of acetone and aryl aldehydes in the presence of 3e as a catalysta
O
O
Ar
OH
3e (15%), 15°C
+
TFA (30%), 36h
H
Ar
Product
Ar
1 2 3 4 5 6 7
2-NO2Ph 2-ClPh 2-FPh 3-FPh 4-FPh 4-CF3Ph 4-OCH3
8b 8c 8d 8e 8f 8g 8h
Yieldb (%) 34 47 35 20 10 58 Trace
O
O
OH
+ Ar
TFA (30%), EtOH (2mL)
H
O
Ar
3e (15%), 15°C 9
Entry
Ar
Product
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
2-NO2Ph 3-NO2Ph 4-NO3Ph 4-CNPh 4-CF3Ph 2-ClPh 3-ClPh 4-ClPh 2-FPh 3-FPh 4-FPh H 2-MeOPh 3-MeOPh 4-MeOPh 1-Naphthyl
9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 9l 9m 9n 9o 9p
Yieldb (%) 80 83 84 47 72 67 53 39 54 48 32 31 18 16 5 44
drc (anti/syn) 97/3 95/5 94/6 93/7 94/6 99/1 96/4 93/7 97/3 93/7 88/12 95/5 91/9 92/8 99/1 95/5
eed (%) >99 98 99 98 98 >99 >99 98 >99 98 98 97 >99 98 95 >99
a The reaction was performed with aldehyde (0.5 mmol), cyclohexanone (2.5 mmol) for 48 h. b Isolated yields. c Determined by HPLC. d Ee of the anti-diastereoisomer.
O
8 Entry
Table 3 Direct asymmetric aldol reaction of cyclohexanone and a range of aldehydes with 3e as a catalysta
eec (%) 99 97 99 99 94 90 —
a The reaction was performed with aldehyde (0.5 mmol), acetone (2.5 mmol) for 36 h. b Isolated yields. c Ee% calculated by using chiral HPLC.
It has been reported that diamine salts can boost retro-aldol processes, in which aryl aldehydes bearing electron-donating groups proceed faster than those containing electron-withdrawing groups,8c so the modest yields may be due to this chemistry. In order to study the utility of catalyst 3e further, aldol reactions between cyclohexanone and a range of aldehydes were tested. In order to remove the interferences of acetone, ethanol was chosen as the solvent. As shown in Table 3, substituted benzaldehydes with electron-withdrawing groups afforded moderate to good yields (32–84%), and excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1) (Table 3, entries 1–11). It is found that the reaction involving ortho-substituted benzaldehydes gave a very high anti/syn ratio,16 thus demonstrating the importance of the ortho-substituent for the diastereoselectivity of this reaction. The reactions with benzaldehyde and substituted benzaldehydes with electron-donating groups provided high enantioselectivities (>97% ee) and a high anti/syn ratio (91:9– 99:1), but low yields (5–31%) (entries 12–15). Moreover, 1-naphthaldehyde also reacted with cyclohexanone and gave the relevant aldol products in a moderate yield (44%) and excellent enantioselectivity (ee 99%) and diastereoselectivity (anti/syn = 95:5).
Finally, the catalytic ability of catalyst 3e for the direct aldol reaction between acetone and isatin was explored. The results are summarized in Table 4. At first, 3e showed a poor catalytic effect under the optimized reaction conditions obtained for the reaction of 4-nitrobenzaldehyde with acetone (Table 3, entry 1). However, when acetone was replaced by dioxane as a solvent (entry 2), the catalytic effect increased. A strong acid TfOH was used to take the place of TFA and the reaction temperature was kept at 5 °C, the desired product was obtained in moderate yield and with high enantioselectivity (entries 3 and 4). The yield was increased to 41% after 10 mmol of H2O was used (entry 5). Decreasing the catalyst loading was detrimental to the enantioselectivity (entry 6). Therefore, the optimal conditions for this reaction were identified as 0.5 mL of dioxane, 5 °C, 20 mol % catalyst loading, and 10 mmol of H2O. With the optimal conditions in hand, a series of isatins was taken into the reaction, and afforded good yields (up to 94%) and enantioselectivities (up to 98%, entries 7–11). It should be noted that the reactivity of isatins with a substituent at the C-4 position was better than that of isatins with a substituent at the C-5 position, despite these reactions being slow. In addition, 5-methylisatin (with an electron-donating group) was also used to undertake the reaction to afford the product with a modest yield (33%) and enantioselectivity (83% ee, entry 11). (R)-Convolutamydine A, which was isolated from the Floridian marine bryozoan Amathia convoluta by Kamano et al. in 1995,17 has attracted the interests of the chemists due to its potent inhibitory activity toward the differentiation of HL-60 human promyelocytic leukemia cells. In 2006, Tomasini et al. reported on the organocatalytic asymmetric synthesis of (R)-convolutamydine A with 68% ee.18 The process was then improved to 94% ee.14 Recently, Xiao reported the synthesis of unnatural (S)-convolutamydine A with 60% ee.13 We applied catalyst 3e to the reaction under the optimized conditions, and obtained (S)-convolutamydine A with 96% ee (Scheme 2). When replacing 3e with (1S,2S)N1-n-pentyl,N1-benzyl-1,2-cyclohexanediamine (the enantiomer of 3e), (R)-convolutamydine A was also obtained with 95%yield and ee 94%.
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Table 4 Aldol reaction of acetone with isatin or its derivatives with 3e as a catalysta
O O
4 3
5 6
R
8 7
HO O
2
N H
1
O
dioxane (0.5mL), TfOH (40%)
+
O
3e (20%), 5°C
N H
R
10 Entry d
1 2e 3f 4g 5h 6i 7h 8h 9h 10h 11h a b c d e f g h i
R
Product
H H H H H H 4-Br 4-Cl 5-Br 5-F 5-Me
10a 10a 10a 10a 10a 10a 10b 10c 10d 10e 10f
Yield (%)b
ee (%)c
95 93 6 33 41 13 94 91 75 53 33
31 42 67 78 84 78 98 97 87 81 83
The reaction was performed with isatin (0.5 mmol) and ketones (0.6 mL) for 48 h. Isolated yields. Ee% calculated by using chiral HPLC. 15 °C, 2 mL of acetone as solvent, 20 mol % TFA. 15 °C, 0.5 mL of dioxane as solvent, 20 mol % TFA. 15 °C, 0.5 mL of dioxane as solvent, 20 mol % TfOH. 5 °C, 0.5 mL of dioxane as solvent, 20 mol % TfOH. 10 mmol H2O was used. 15 mol % catalyst.
O Br
Br
O O O
Br
+
dioxane(0.5mL) TfOH(40%) 3e (20%) H2O (10mmol) 5°C
N H
HO O
Br
N H
(S)-Convolutamydine A, 10g, Yield: 95% ee: 96% Scheme 2. Synthesis of (S)-convolutamydine A.
According to the literature reports,8a,12,13 the absolute configuration of the aldol product was determined to be (S). Thus, the proposed transition state of the aldol reaction catalyzed by 3e is shown in Figure 2. A bifunctional enamine is formed by 3e and acetone, activated aldehyde, or isatin through a strong hydrogen bond. The protonated tertiary amine served as a directing hydrogen bond donor.8a Moreover, non-covalent p–p interactions between the aromatic rings of the catalyst and the aldehyde make the enamine more stable.15 However, further investigations should be carried out in order to clarify the mechanism.
3. Conclusion In conclusion, we have developed a novel chiral 1,2-diaminocyclohexane derivative 3e as an efficient catalyst in aldehyde–ketone or ketone–ketone aldol reactions. Under the catalysis of 3e, moderate to good yields (10–85%), and excellent diastereoselectivity (anti/syn ratio 99:1) and enantioselectivity (up to 99% ee) of the corresponding products were obtained in the direct asymmetric aldol reaction of acetone/cyclohexanone with aryl aldehydes. The aldol reaction between acetone and isatins in the presence of 3e also provided excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-enantiomers of convolutamydine A were obtained, with 95% yield and 96% ee, and 95% yield and 94% ee, respectively. 4. Experimental
N
N H NH O
H NH
4.1. General O
NH
O H Figure 2. The proposed transition state for the reaction of acetone with benzaldehyde or isatin in the presence of 3e as a catalyst.
All solvents and reagents were dried before use. 1H spectra (300 MHz) and 13C NMR spectra (75 MHz) were recorded on a Bruker-300 spectrometer. Chemical shifts are in ppm downfield from TMS in spectra recorded in CDCl3. High performance liquid chromatography (HPLC) was measured on a Waters 1525
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instrument using Chiralpak AS-H and AD-H (4.6 mm 25 cm) column. High-resolution mass spectra (HRMS) were recorded on an Agilent Technologies 1260 Infinity instrument. Optical rotations were obtained by a 1 mL cell with a 1 dm path length on a Perkin–Elmer-343 digital polarimeter. 4.2. General procedure for the synthesis of catalyst 3 At first, 4 (4.28 g, 20.0 mmol, 1 equiv) and benzaldehyde (10.60 g, 100.0 mmol; 5 equiv) were added to a 250-mL round bottomed flask with methanol (100 mL) and stirred for 30 min at room temperature. Then the reaction mixture was cooled to 0 °C, and NaBH4 (3.78 g; 100 mmol; 5 equiv) was added. After 2.5 h, cooling was stopped, and NaCNBH3 (2.48 g, 40 mmol; 2 equiv) and the corresponding alkyl aldehyde (100 mmol; 5 equiv) were added. Five hours later, 10 mL of H2O was added to stop the reaction. The residue was purified through column chromatography on silica gel (eluent, petroleum ether). The petroleum ether was removed in vacuo, the resulting residue was taken up in 4 M HCl (100 mL) and stirred for 12 h. The resulting solution was washed three times with CH2Cl2 and adjusted to pH 13 with 4 M NaOH. The aqueous layer was extracted three times with ethyl acetate (120 mL), washed with brine (60 mL), and dried (Na2SO4). Solvent removal in vacuo afforded crude 3 as a colorless and transparent oil which was distilled in vacuo to afford pure 3.
5
4.2.5. (1R,2R)-N 1 -Benzyl-N 1 -pentylcyclohexane-1,2-diamine, catalyst 3e 1 Colorless and transparent oil: ½a25 D ¼ 25:5 (c 1.0, CHCl3); H NMR d 0.85 (s, 3H), 1.14–1.30 (m, 7H), 1.52–1.94 (m, 5H), 2.19– 2.35 (dd, J = 12.3 2H), 3.31–3.41 (m, 3H), 3.72–3.76 (d, J = 10.5, 1H), 4.28–4.32 (d, J = 13.2, 1H), 4.63–4.69 (d, J = 15.6, 1H), 4.75 (br s, 2H), 7.54 (m, 5H) ppm; 13C NMR d 13.91, 22.39, 22.57, 24.99, 25.77, 28.52, 29.41, 34.85, 49.48, 51.13, 54.18, 65.77, 126.46, 127.98, 128.52, 140.83 ppm; HRMS (ESI) m/z calcd for C18H30N2 [M+H]+ 274.2465, found: 275.2467. 4.2.6. (1R,2R)-N 1 -Benzyl-N 1 -heptylcyclohexane-1,2-diamine, catalyst 3f 1 Colorless and transparent oil: ½a25 D ¼ 23:6 (c 1.0, CHCl3); H NMR d 0.82 (d, J = 6.9, 2H), 1.14–1.28 (m, 9H), 1.36–1.47 (m, 2H), 1.58–1.64 (t, J = 9.5 2H), 1.82–1.91 (m, 4H), 2.07–2.22 (m, 1H), 2.32–2.48 (m, 1H), 3.24 (s, 1H), 3.51–3.52 (d, J = 5.4, 2H), 3.78 (s, 1H), 4.22–4.26 (d, J = 13.2, 1H), 4.32–4.37 (d, J = 12.9, 1H), 4.74 (br s, 4.74), 7.55 (m, 5H) ppm; 13C NMR d 15.96, 24.45, 24.96, 25.21, 25.50, 27.06, 28.77, 30.36, 33.11, 33.34, 51.59, 53.91, 61.04, 66.23, 131.21, 131.96, 132.44, 133.16 ppm; HRMS (ESI) m/z calcd for C20H34N2 [M+H]+ 302.2789, found: 303.2785. 4.3. General procedure for direct asymmetric aldol reactions
4.2.1. (1R,2R)-N1-Benzylcyclohexane-1,2-diamine, catalyst 3a 1 Colorless and transparent oil: ½a25 D ¼ 31:5 (c 1.0, CHCl3); H NMR d 1.32–1.46 (m, 2H), 1.58–1.62 (d, J = 11.1, 2H), 1.81–1.97 (m, 2H), 2.16–2.20 (d, J = 12.6, 1H), 2.43–2.47 (d, J = 13.2, 1H), 3.39–3.52 (m, 2H), 4.19–4.23 (d, J = 12.9, 1H), 4.46–4.50 (d, J = 12.9, 1H), 4.75 (br s, 2H), 7.50 (m, 5H) ppm; 13C NMR d 25.01, 25.12, 28.81, 32.05, 51.53, 53.94, 61.06, 131.97, 132.46, 132.49, 133.90 ppm; HRMS (ESI) m/z: calcd for C13H20N2 [M+H]+ 204.1698, found: 205.1699.
At first, 0.5 mmol of aryl aldehyde or isatin was added to a mixture of ketone (cyclohexanone or acetone, 5 equiv), 15 or 20 mol % catalyst, 30 or 40 mol % acid, and 2.0 mL of solvent at reaction temperature. The reaction mixture was stirred for the indicated time and then purified through flash column chromatography on a silica gel (petroleum ether/ethyl acetate) to afford the pure products.
4.2.2. (1R,2R)-N 1-Benzyl-N 1-methylcyclohexane-1,2-diamine, catalyst 3b 1 Colorless and transparent oil: ½a25 D ¼ 29:3 (c 1.0, CHCl3); H NMR d 1.37 (s, 2H), 1.51 (s, 1H), 1.68 (s, 1H), 1.80 (s, 1H), 1.95 (s, 1H), 2.21 (s, 1H), 2.34 (s, 1H), 2.78–2.85 (t, J = 13.2, 3H), 3.47 (s, 1H), 3.68 (s, 1H), 4.43 (s, 2H), 4.69 (br s, 2H), 7.53 (m, 5H) ppm; 13 C NMR d 24.76, 25.08, 25.47, 32.98, 37.55, 51.81, 61.59, 67.30, 131.05, 132.13, 133.15, 133.79 ppm; HRMS (ESI) m/z: calcd for C14H22N2 [M+H]+ 218.1845, found: 219.1909.
The authors are grateful to the National Natural Science Foundation of China (Project No. 21271041) for financial aid to this work. Li would like to thank the Scientific Research Innovation Project for College Graduates of Jiangsu Province (Project CXZZ12-0118).
4.2.3. (1R,2R)-N 1 -Benzyl-N 1 -ethylcyclohexane-1,2-diamine, catalyst 3c 1 Colorless and transparent oil: ½a25 D ¼ 27:3 (c 1.0, CHCl3); H NMR d 1.20–1.41 (m, 8H), 1.54–1.78 (m, 2H), 1.91–1.95 (d, J = 11.4, 1H), 2.21–2.37 (m, 2H), 3.27–3.48 (m, 2H), 3.78–3.81 (d, J = 9.6, 1H), 4.32–4.36 (d, J = 13.5, 1H), 4.75 (br s, 2H), 7.55 (m, 5H) ppm; 13C NMR d 12.41, 25.30, 28.81, 32.06, 33.10, 48.83, 51.54, 57.54, 65.48, 131.06, 132.30, 132.97, 133.87 ppm; HRMS (ESI) m/z calcd for C15H24N2 [M+H]+ 233.1936, found: 233.2042. 4.2.4. (1R,2R)-N 1 -Benzyl-N 1 -propylcyclohexane-1,2-diamine, catalyst 3d 1 Colorless and transparent oil: ½a25 D ¼ 25:3 (c 1.0, CHCl3); H NMR d 0.94–0.96 (d, J = 7.5, 3H), 1.30–1.41 (m, 3H), 1.69–1.94 (m, 5H), 2.19–2.35 (m, 2H), 3.13–3.21 (m, 2H), 3.38 (s, 1H), 3.73– 3.76 (d, J = 10.2, 1H), 4.28–4.32 (d, J = 13.6, 1H), 4.64–4.69 (d, J = 17.5, 1H), 4.75 (br s, 2H), 7.54 (m, 5H) ppm; 13C NMR d 12.82, 20.75, 25.22, 25.29, 25.48, 33.08, 51.51, 55.10, 58.07, 65.86, 131.20, 132.25, 133.12, 133.75 ppm; HRMS (ESI) m/z calcd for C16H26N2 [M+H]+ 246.2169, found: 247.2165.
Acknowledgments
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10. (a) Raunak; Kumar, V.; Mukherjee, S.; Poonam; Prasad, A. K.; Olsen, C. E.; Sch€affer, S. J. C.; Sharma, S. K.; Watterson, A. C.; Errington, W.; Parmar, V. S. Tetrahedron 2005, 61, 5687–5697; (b) Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45, 1487–1499. 11. For example, see: (a) Nakamura, T.; Shirokawa, S-i; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8, 677–679; (b) Cravotto, G.; Giovenzana, G. B.; Palmisano, G.; Penoni, A.; Pilati, T.; Sisti, M.; Stazi, F. Tetrahedron: Asymmetry 2006, 17, 3070–3074; (c) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron 2004, 60, 3493–3503. 12. Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418–7421.
13. Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao, Y. F.; Zhang, J. M.; Xiao, W. J. Tetrahedron 2007, 63, 10437–10444. 14. Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.; Pluhácková, K.; Kocovsky´, P. Org. Lett. 2007, 9, 5473–5476. 15. Hernández, J. G.; García-Líopez, V.; Juaristi, E. Tetrahedron 2012, 68, 92–97. 16. Liu, Y.; Wang, J. F.; Sun, Q.; Li, R. T. Tetrahedron Lett. 2011, 52, 3584–3587. 17. Kamano, Y.; Zhang, H. P.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783–2784. 18. Luppi, G.; Monari, M.; Corrêa, R. J.; Violante, F. A.; Pinto, A. C.; Kaptein, B.; Broxterman, Q. B.; Garden, S. J.; Tomasini, C. Tetrahedron 2006, 62, 12017– 12024.
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions Biao Xu a, Lei Li a, Shaohua Gou a,b,⇑ a b
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China
a r t i c l e
i n f o
Article history: Received 23 July 2013 Accepted 3 September 2013 Available online xxxx
a b s t r a c t A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N1-n-pentyl, N1-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-b-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction The aldol reaction is one of the most significant methods to form a carbon–carbon bond in synthetic chemistry.1 It generates active b-hydroxy products which are motifs of many biologically and pharmaceutically important intermediates.2 The asymmetric aldol reaction also provides an atom-economical approach to synthesize b-hydroxy carbonyl compounds. Since List first reported that L-proline could catalyze the cross-aldol reaction,3 organocatalysts have become a focus in the field of asymmetric catalysis.4 So far, many types of effective organic catalysts have been developed for asymmetric aldol reactions, most of which are L-proline and its derivatives.5 Similar to proline and other secondary amine catalysts, some primary amino acids have also been found to show good asymmetric catalytic action in aldol reactions.6 Diamines have also been explored,7 in which chiral primary-tertiary 1,2-diamines had excellent catalytic activity.8 Catalysts 18a and 2,8b which are derived from chiral 1,2-diaminocyclohexane, were found in 2007 and 2011 respectively to catalyze the corresponding aldol reactions with good yields and enantioselectivity. In the supposed mechanism, the primary amine was employed to form an enamine intermediate, while the protonated tertiary amine was believed to activate the aldehyde through hydrogen bonds. The catalyst only worked for a few selected substrates (aryl aldehydes bearing electron-withdrawing groups), since substrates such as aryl aldehydes bearing electron-donating groups displayed low efficiency (yield 21%). ⇑ Corresponding author. Tel./fax: +86 (25)83272381. E-mail address: [email protected] (S. Gou).
Compared with aldehydes, ketones have seldom been explored in asymmetric aldol reactions as electrophilic reactants, which represent a great challenge.9 Isatin has recently received much attention, since it can be used to produce 3-hydroxyindolin-2one, which is a core structure of many biologically and pharmaceutically active compounds,10 such as convolutamydines, which display interesting antitumour activity.11 Since the pioneering work of Tomasini et al. in 2005,12 L-proline (a secondary amine itself) became a focus, but it displayed moderate efficiency in the cross-aldol reaction of isatin with acetone (ee 20–73%). It was reported that under severe conditions the catalytic results were slightly improved upon (in 60 to 40 °C, ee 25–90%).13 In contrast, primary amine organocatalysts were relatively efficient, as vicinal amino alcohols were reported to act as superior catalysts (yield up to 98%, ee 95%).14 However, to the best of our knowledge, there has been no report on tertiary amine catalysts in this field so far. Since non-covalent p–p interactions between aromatic rings of catalysts and substrates could promote enantioselectivity,15 we aimed to design a catalyst containing both primary and tertiary amines with an aromatic ring in order to improve any catalytic effect in the asymmetric aldol reaction of aromatic aldehydes and ketones. Thus we synthesized a number of (1R,2R)-N1-alkyl,N1benzyl-1,2-cyclohexane diamines as catalysts 3 (Fig. 1) for asymmetric aldol reactions. The basicity of the tertiary amine was adjusted by changing the length of the alkyl chain. As expected in our following tests, 3e proved to be an efficient catalyst in the condensation reactions of acetone and aryl aldehydes with moderate yields and good enantioselectivity (up to yield 85%, ee 98%). In the reactions of cyclohexanone and aryl
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.09.026
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B. Xu et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
N
N
N
R
NH2
NH2
3a 3b 3c 3d 3e 3f
R=H R=CH3 R=CH2CH3 R=(CH2)2CH3 R=(CH2)4CH3 R=(CH2)6CH3
NH2 2
1
3
Figure 1. Chiral primary-tertiary-type 1,2-cyclohexanediamines.
aldehydes, it also afforded excellent diastereoselectivity and enantioselectivity (up to anti/syn ratio 99:1, 99% ee). This catalyst was then applied to the reaction of acetone and isatin, in which excellent yields and enantioselectivity were obtained (up to 95% yield, 98% ee). To the best of our knowledge, there are very few organocatalysts that can catalyze aldehyde–ketone or ketone– ketone aldol reactions with such excellent enantiomeric excess.
NH2 NHBoc
2. Results and discussion The synthesis of organocatalyst 3 is outlined in Scheme 1. The aldol reaction between acetone and 4-nitrobenzaldehyde was chosen as a benchmark reaction in order to evaluate the catalysts and optimize the reaction conditions. The results are listed in Table 1. At the outset, catalyst 3c was used to test the effects of
NH
aryl aldehyde, NaBH4
N
NaCNBH3, alkyl aldehydes
R
rt. 6h
CH3OH, rt. 3h
NHBoc
NHBoc
4
6
5
HCl/H2O, rt. 12h
N
NaOH/H2O
R
N
R
2HCl NH2
NH2 3
7 Scheme 1. Synthesis of organocatalyst 3.
Table 1 Screening catalysts under different conditions for the aldol reaction of acetone and 4-nitrobenzaldehydea
OH CHO
O
+
catalyst (15%), additive (30%) 15°C, 36h
O 2N
O
O2N 8a
a b c d e
Entry
Catalyst
Additive
Solvent
1 2 3 4 5 6 7 8 9d 10e 11 12 13 14 15
3c 3c 3c 3c 3c 3c 3c 3c 3c 3c 3a 3b 3d 3e 3f
TFA TFA TFA TFA TFA / TfOH HDA TFA TFA TFA TFA TFA TFA TFA
H2O CH3OH DMF DMSO Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone Acetone
Yieldb (%)
eec (%)
— 8 3 2 77 6 27 19 68 27 97 53 68 85 81
— 87 83 77 95 80 -4 58 86 94 51 75 96 98 91
The reaction was performed with aldehyde (0.5 mmol), acetone (2.5 mmol) in 2 mL solvent for 36 h. Isolated yields. Ee% calculated by using chiral HPLC. Using 15 mol % TFA. Using 10 mol % catalyst 3c.
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different solvents, additives, and catalyst loading on the reaction (Table 1, entries 1–10). It is noteworthy that trifluoroacetic acid (TFA) was essential for this reaction. When TFA was removed or replaced by HDA or TfOH, the yield and the enantioselectivity decreased remarkably (Table 1, entries 5–8). Reduction of the catalyst loading or the amount of TFA was also adverse to the results of the reaction (entries 9 and 10). In order to improve catalytic effect on the optimized reaction conditions, alkyl chains (R) were extended or shortened to adjust the basicity and steric size of the tertiary amine so that the best enantioselectivity could be achieved. The catalytic results are summarized in Table 1 (entries 11–15). As shown, catalyst 3e was superior to the others (85% yield, 98% ee, entry 14). Catalyst 3f showed relatively low enantiomeric excess compared with 3e, probably due to steric hindrance. With the optimized reaction conditions being identified, the scope of the reaction was further explored with a series of aryl aldehydes with the results listed in Table 2. It was noted that catalyst 3e only worked for aryl aldehydes containing an electronwithdrawing group, and excellent enantioselectivities were obtained (ee 90–99%), although the reactions were very slow with low and moderate yields (10–58%, entries 1–6). For aryl aldehydes with an electron-donating group, the reaction hardly took place (entry 7, Table 2). Table 2 Direct asymmetric aldol reaction of acetone and aryl aldehydes in the presence of 3e as a catalysta
O
O
Ar
OH
3e (15%), 15°C
+
TFA (30%), 36h
H
Ar
Product
Ar
1 2 3 4 5 6 7
2-NO2Ph 2-ClPh 2-FPh 3-FPh 4-FPh 4-CF3Ph 4-OCH3
8b 8c 8d 8e 8f 8g 8h
Yieldb (%) 34 47 35 20 10 58 Trace
O
O
OH
+ Ar
TFA (30%), EtOH (2mL)
H
O
Ar
3e (15%), 15°C 9
Entry
Ar
Product
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
2-NO2Ph 3-NO2Ph 4-NO3Ph 4-CNPh 4-CF3Ph 2-ClPh 3-ClPh 4-ClPh 2-FPh 3-FPh 4-FPh H 2-MeOPh 3-MeOPh 4-MeOPh 1-Naphthyl
9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 9l 9m 9n 9o 9p
Yieldb (%) 80 83 84 47 72 67 53 39 54 48 32 31 18 16 5 44
drc (anti/syn) 97/3 95/5 94/6 93/7 94/6 99/1 96/4 93/7 97/3 93/7 88/12 95/5 91/9 92/8 99/1 95/5
eed (%) >99 98 99 98 98 >99 >99 98 >99 98 98 97 >99 98 95 >99
a The reaction was performed with aldehyde (0.5 mmol), cyclohexanone (2.5 mmol) for 48 h. b Isolated yields. c Determined by HPLC. d Ee of the anti-diastereoisomer.
O
8 Entry
Table 3 Direct asymmetric aldol reaction of cyclohexanone and a range of aldehydes with 3e as a catalysta
eec (%) 99 97 99 99 94 90 —
a The reaction was performed with aldehyde (0.5 mmol), acetone (2.5 mmol) for 36 h. b Isolated yields. c Ee% calculated by using chiral HPLC.
It has been reported that diamine salts can boost retro-aldol processes, in which aryl aldehydes bearing electron-donating groups proceed faster than those containing electron-withdrawing groups,8c so the modest yields may be due to this chemistry. In order to study the utility of catalyst 3e further, aldol reactions between cyclohexanone and a range of aldehydes were tested. In order to remove the interferences of acetone, ethanol was chosen as the solvent. As shown in Table 3, substituted benzaldehydes with electron-withdrawing groups afforded moderate to good yields (32–84%), and excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1) (Table 3, entries 1–11). It is found that the reaction involving ortho-substituted benzaldehydes gave a very high anti/syn ratio,16 thus demonstrating the importance of the ortho-substituent for the diastereoselectivity of this reaction. The reactions with benzaldehyde and substituted benzaldehydes with electron-donating groups provided high enantioselectivities (>97% ee) and a high anti/syn ratio (91:9– 99:1), but low yields (5–31%) (entries 12–15). Moreover, 1-naphthaldehyde also reacted with cyclohexanone and gave the relevant aldol products in a moderate yield (44%) and excellent enantioselectivity (ee 99%) and diastereoselectivity (anti/syn = 95:5).
Finally, the catalytic ability of catalyst 3e for the direct aldol reaction between acetone and isatin was explored. The results are summarized in Table 4. At first, 3e showed a poor catalytic effect under the optimized reaction conditions obtained for the reaction of 4-nitrobenzaldehyde with acetone (Table 3, entry 1). However, when acetone was replaced by dioxane as a solvent (entry 2), the catalytic effect increased. A strong acid TfOH was used to take the place of TFA and the reaction temperature was kept at 5 °C, the desired product was obtained in moderate yield and with high enantioselectivity (entries 3 and 4). The yield was increased to 41% after 10 mmol of H2O was used (entry 5). Decreasing the catalyst loading was detrimental to the enantioselectivity (entry 6). Therefore, the optimal conditions for this reaction were identified as 0.5 mL of dioxane, 5 °C, 20 mol % catalyst loading, and 10 mmol of H2O. With the optimal conditions in hand, a series of isatins was taken into the reaction, and afforded good yields (up to 94%) and enantioselectivities (up to 98%, entries 7–11). It should be noted that the reactivity of isatins with a substituent at the C-4 position was better than that of isatins with a substituent at the C-5 position, despite these reactions being slow. In addition, 5-methylisatin (with an electron-donating group) was also used to undertake the reaction to afford the product with a modest yield (33%) and enantioselectivity (83% ee, entry 11). (R)-Convolutamydine A, which was isolated from the Floridian marine bryozoan Amathia convoluta by Kamano et al. in 1995,17 has attracted the interests of the chemists due to its potent inhibitory activity toward the differentiation of HL-60 human promyelocytic leukemia cells. In 2006, Tomasini et al. reported on the organocatalytic asymmetric synthesis of (R)-convolutamydine A with 68% ee.18 The process was then improved to 94% ee.14 Recently, Xiao reported the synthesis of unnatural (S)-convolutamydine A with 60% ee.13 We applied catalyst 3e to the reaction under the optimized conditions, and obtained (S)-convolutamydine A with 96% ee (Scheme 2). When replacing 3e with (1S,2S)N1-n-pentyl,N1-benzyl-1,2-cyclohexanediamine (the enantiomer of 3e), (R)-convolutamydine A was also obtained with 95%yield and ee 94%.
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Table 4 Aldol reaction of acetone with isatin or its derivatives with 3e as a catalysta
O O
4 3
5 6
R
8 7
HO O
2
N H
1
O
dioxane (0.5mL), TfOH (40%)
+
O
3e (20%), 5°C
N H
R
10 Entry d
1 2e 3f 4g 5h 6i 7h 8h 9h 10h 11h a b c d e f g h i
R
Product
H H H H H H 4-Br 4-Cl 5-Br 5-F 5-Me
10a 10a 10a 10a 10a 10a 10b 10c 10d 10e 10f
Yield (%)b
ee (%)c
95 93 6 33 41 13 94 91 75 53 33
31 42 67 78 84 78 98 97 87 81 83
The reaction was performed with isatin (0.5 mmol) and ketones (0.6 mL) for 48 h. Isolated yields. Ee% calculated by using chiral HPLC. 15 °C, 2 mL of acetone as solvent, 20 mol % TFA. 15 °C, 0.5 mL of dioxane as solvent, 20 mol % TFA. 15 °C, 0.5 mL of dioxane as solvent, 20 mol % TfOH. 5 °C, 0.5 mL of dioxane as solvent, 20 mol % TfOH. 10 mmol H2O was used. 15 mol % catalyst.
O Br
Br
O O O
Br
+
dioxane(0.5mL) TfOH(40%) 3e (20%) H2O (10mmol) 5°C
N H
HO O
Br
N H
(S)-Convolutamydine A, 10g, Yield: 95% ee: 96% Scheme 2. Synthesis of (S)-convolutamydine A.
According to the literature reports,8a,12,13 the absolute configuration of the aldol product was determined to be (S). Thus, the proposed transition state of the aldol reaction catalyzed by 3e is shown in Figure 2. A bifunctional enamine is formed by 3e and acetone, activated aldehyde, or isatin through a strong hydrogen bond. The protonated tertiary amine served as a directing hydrogen bond donor.8a Moreover, non-covalent p–p interactions between the aromatic rings of the catalyst and the aldehyde make the enamine more stable.15 However, further investigations should be carried out in order to clarify the mechanism.
3. Conclusion In conclusion, we have developed a novel chiral 1,2-diaminocyclohexane derivative 3e as an efficient catalyst in aldehyde–ketone or ketone–ketone aldol reactions. Under the catalysis of 3e, moderate to good yields (10–85%), and excellent diastereoselectivity (anti/syn ratio 99:1) and enantioselectivity (up to 99% ee) of the corresponding products were obtained in the direct asymmetric aldol reaction of acetone/cyclohexanone with aryl aldehydes. The aldol reaction between acetone and isatins in the presence of 3e also provided excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-enantiomers of convolutamydine A were obtained, with 95% yield and 96% ee, and 95% yield and 94% ee, respectively. 4. Experimental
N
N H NH O
H NH
4.1. General O
NH
O H Figure 2. The proposed transition state for the reaction of acetone with benzaldehyde or isatin in the presence of 3e as a catalyst.
All solvents and reagents were dried before use. 1H spectra (300 MHz) and 13C NMR spectra (75 MHz) were recorded on a Bruker-300 spectrometer. Chemical shifts are in ppm downfield from TMS in spectra recorded in CDCl3. High performance liquid chromatography (HPLC) was measured on a Waters 1525
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B. Xu et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
instrument using Chiralpak AS-H and AD-H (4.6 mm 25 cm) column. High-resolution mass spectra (HRMS) were recorded on an Agilent Technologies 1260 Infinity instrument. Optical rotations were obtained by a 1 mL cell with a 1 dm path length on a Perkin–Elmer-343 digital polarimeter. 4.2. General procedure for the synthesis of catalyst 3 At first, 4 (4.28 g, 20.0 mmol, 1 equiv) and benzaldehyde (10.60 g, 100.0 mmol; 5 equiv) were added to a 250-mL round bottomed flask with methanol (100 mL) and stirred for 30 min at room temperature. Then the reaction mixture was cooled to 0 °C, and NaBH4 (3.78 g; 100 mmol; 5 equiv) was added. After 2.5 h, cooling was stopped, and NaCNBH3 (2.48 g, 40 mmol; 2 equiv) and the corresponding alkyl aldehyde (100 mmol; 5 equiv) were added. Five hours later, 10 mL of H2O was added to stop the reaction. The residue was purified through column chromatography on silica gel (eluent, petroleum ether). The petroleum ether was removed in vacuo, the resulting residue was taken up in 4 M HCl (100 mL) and stirred for 12 h. The resulting solution was washed three times with CH2Cl2 and adjusted to pH 13 with 4 M NaOH. The aqueous layer was extracted three times with ethyl acetate (120 mL), washed with brine (60 mL), and dried (Na2SO4). Solvent removal in vacuo afforded crude 3 as a colorless and transparent oil which was distilled in vacuo to afford pure 3.
5
4.2.5. (1R,2R)-N 1 -Benzyl-N 1 -pentylcyclohexane-1,2-diamine, catalyst 3e 1 Colorless and transparent oil: ½a25 D ¼ 25:5 (c 1.0, CHCl3); H NMR d 0.85 (s, 3H), 1.14–1.30 (m, 7H), 1.52–1.94 (m, 5H), 2.19– 2.35 (dd, J = 12.3 2H), 3.31–3.41 (m, 3H), 3.72–3.76 (d, J = 10.5, 1H), 4.28–4.32 (d, J = 13.2, 1H), 4.63–4.69 (d, J = 15.6, 1H), 4.75 (br s, 2H), 7.54 (m, 5H) ppm; 13C NMR d 13.91, 22.39, 22.57, 24.99, 25.77, 28.52, 29.41, 34.85, 49.48, 51.13, 54.18, 65.77, 126.46, 127.98, 128.52, 140.83 ppm; HRMS (ESI) m/z calcd for C18H30N2 [M+H]+ 274.2465, found: 275.2467. 4.2.6. (1R,2R)-N 1 -Benzyl-N 1 -heptylcyclohexane-1,2-diamine, catalyst 3f 1 Colorless and transparent oil: ½a25 D ¼ 23:6 (c 1.0, CHCl3); H NMR d 0.82 (d, J = 6.9, 2H), 1.14–1.28 (m, 9H), 1.36–1.47 (m, 2H), 1.58–1.64 (t, J = 9.5 2H), 1.82–1.91 (m, 4H), 2.07–2.22 (m, 1H), 2.32–2.48 (m, 1H), 3.24 (s, 1H), 3.51–3.52 (d, J = 5.4, 2H), 3.78 (s, 1H), 4.22–4.26 (d, J = 13.2, 1H), 4.32–4.37 (d, J = 12.9, 1H), 4.74 (br s, 4.74), 7.55 (m, 5H) ppm; 13C NMR d 15.96, 24.45, 24.96, 25.21, 25.50, 27.06, 28.77, 30.36, 33.11, 33.34, 51.59, 53.91, 61.04, 66.23, 131.21, 131.96, 132.44, 133.16 ppm; HRMS (ESI) m/z calcd for C20H34N2 [M+H]+ 302.2789, found: 303.2785. 4.3. General procedure for direct asymmetric aldol reactions
4.2.1. (1R,2R)-N1-Benzylcyclohexane-1,2-diamine, catalyst 3a 1 Colorless and transparent oil: ½a25 D ¼ 31:5 (c 1.0, CHCl3); H NMR d 1.32–1.46 (m, 2H), 1.58–1.62 (d, J = 11.1, 2H), 1.81–1.97 (m, 2H), 2.16–2.20 (d, J = 12.6, 1H), 2.43–2.47 (d, J = 13.2, 1H), 3.39–3.52 (m, 2H), 4.19–4.23 (d, J = 12.9, 1H), 4.46–4.50 (d, J = 12.9, 1H), 4.75 (br s, 2H), 7.50 (m, 5H) ppm; 13C NMR d 25.01, 25.12, 28.81, 32.05, 51.53, 53.94, 61.06, 131.97, 132.46, 132.49, 133.90 ppm; HRMS (ESI) m/z: calcd for C13H20N2 [M+H]+ 204.1698, found: 205.1699.
At first, 0.5 mmol of aryl aldehyde or isatin was added to a mixture of ketone (cyclohexanone or acetone, 5 equiv), 15 or 20 mol % catalyst, 30 or 40 mol % acid, and 2.0 mL of solvent at reaction temperature. The reaction mixture was stirred for the indicated time and then purified through flash column chromatography on a silica gel (petroleum ether/ethyl acetate) to afford the pure products.
4.2.2. (1R,2R)-N 1-Benzyl-N 1-methylcyclohexane-1,2-diamine, catalyst 3b 1 Colorless and transparent oil: ½a25 D ¼ 29:3 (c 1.0, CHCl3); H NMR d 1.37 (s, 2H), 1.51 (s, 1H), 1.68 (s, 1H), 1.80 (s, 1H), 1.95 (s, 1H), 2.21 (s, 1H), 2.34 (s, 1H), 2.78–2.85 (t, J = 13.2, 3H), 3.47 (s, 1H), 3.68 (s, 1H), 4.43 (s, 2H), 4.69 (br s, 2H), 7.53 (m, 5H) ppm; 13 C NMR d 24.76, 25.08, 25.47, 32.98, 37.55, 51.81, 61.59, 67.30, 131.05, 132.13, 133.15, 133.79 ppm; HRMS (ESI) m/z: calcd for C14H22N2 [M+H]+ 218.1845, found: 219.1909.
The authors are grateful to the National Natural Science Foundation of China (Project No. 21271041) for financial aid to this work. Li would like to thank the Scientific Research Innovation Project for College Graduates of Jiangsu Province (Project CXZZ12-0118).
4.2.3. (1R,2R)-N 1 -Benzyl-N 1 -ethylcyclohexane-1,2-diamine, catalyst 3c 1 Colorless and transparent oil: ½a25 D ¼ 27:3 (c 1.0, CHCl3); H NMR d 1.20–1.41 (m, 8H), 1.54–1.78 (m, 2H), 1.91–1.95 (d, J = 11.4, 1H), 2.21–2.37 (m, 2H), 3.27–3.48 (m, 2H), 3.78–3.81 (d, J = 9.6, 1H), 4.32–4.36 (d, J = 13.5, 1H), 4.75 (br s, 2H), 7.55 (m, 5H) ppm; 13C NMR d 12.41, 25.30, 28.81, 32.06, 33.10, 48.83, 51.54, 57.54, 65.48, 131.06, 132.30, 132.97, 133.87 ppm; HRMS (ESI) m/z calcd for C15H24N2 [M+H]+ 233.1936, found: 233.2042. 4.2.4. (1R,2R)-N 1 -Benzyl-N 1 -propylcyclohexane-1,2-diamine, catalyst 3d 1 Colorless and transparent oil: ½a25 D ¼ 25:3 (c 1.0, CHCl3); H NMR d 0.94–0.96 (d, J = 7.5, 3H), 1.30–1.41 (m, 3H), 1.69–1.94 (m, 5H), 2.19–2.35 (m, 2H), 3.13–3.21 (m, 2H), 3.38 (s, 1H), 3.73– 3.76 (d, J = 10.2, 1H), 4.28–4.32 (d, J = 13.6, 1H), 4.64–4.69 (d, J = 17.5, 1H), 4.75 (br s, 2H), 7.54 (m, 5H) ppm; 13C NMR d 12.82, 20.75, 25.22, 25.29, 25.48, 33.08, 51.51, 55.10, 58.07, 65.86, 131.20, 132.25, 133.12, 133.75 ppm; HRMS (ESI) m/z calcd for C16H26N2 [M+H]+ 246.2169, found: 247.2165.
Acknowledgments
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