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An efficient enzymatic approach to (S)-1-aryl-allylamines
Tetrahedron: Asymmetry 22 (2011) 936–941
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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
An efficient enzymatic approach to (S)-1-aryl-allylamines Anamarija Knezˇevic´ a, Goran Landek b, Irena Dokli a, Vladimir Vinkovic´ a,⇑ a b
- Boškovic´ Institute, PO Box 180, 10002 Zagreb, Croatia Department of Organic Chemistry and Biochemistry, Ruder Galapagos Istrazˇivacˇki Centar d.o.o., Prilaz Baruna Filipovic´a 29, 10000 Zagreb, Croatia
a r t i c l e
i n f o
Article history: Received 14 March 2011 Accepted 2 June 2011
a b s t r a c t A range of 1-aryl-allylamines were prepared in moderate to excellent enantioselectivity (ee 63.5%?99.9%) using lipase B from a Candida antarctica catalyzed resolution of racemic amines. This is the first time that CaLB has been used for the resolution of 1-aryl-allylamines. Racemic amines were prepared starting from aromatic aldehydes with a [3,3]-sigmatropic rearrangement of the acyclic imidates as the key step followed by trichloroacetamidate hydrolysis. Aldehydes were converted into acrylic esters using Knoevenagel reaction. After reduction, the corresponding alcohols were used for the preparation of trichloroacetimidates, which were then used in an Overman rearrangement. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Enantiomerically pure primary chiral amines with a stereogenic center at the a-position are very important building blocks in organic chemistry.1 An additional allylic functionality at the stereogenic carbon center increases their synthetic potential. These types of compounds have been used as starting materials for the synthesis of different amino acids, alkaloids, and nitrogen containing molecules, which possess a wide range of biological activities.2 One method for obtaining enantiomerically pure chiral amines is the resolution of racemic amines by enzymes, in particular the Candida antarctica lipase B (CaLB) catalyzed enantioselective acylation. This enzyme has proven to be a very effective catalyst for the resolution of primary amines with a stereogenic center at the a-position due to the high stereoselectivity and simplicity of the resolution process.3 As part of our ongoing research on brush-type chiral stationary phases,4 we envisaged the synthesis of a series of chiral selectors containing a terminal double bond, which is required for binding to a silica surface.5 Chiral 1-aryl-allylamines have been recognised as key intermediates in this synthetic pathway (Scheme 1). Herein we report the synthesis of racemic 1-aryl-allylamines and their resolution using lipase B from C. antarctica. This is the first time that CaLB has been used for the resolution of allyl amines. 2. Results and discussion Among the different methods for the preparation of the allyl amines,6 and due to the availability of starting materials, we chose
⇑ Corresponding author. Tel.: +385 14680108; fax: +385 14571300. E-mail address: [email protected] (V. Vinkovic´). 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.06.004
O O 2N
Ar Ar
N H
H
NH2
O Ar
NO2 Scheme 1. Retrosynthetic pathway toward chiral selectors.
the Overman rearrangement of allyl trichloroacetimidates as the method for our synthesis.7 In the first step of the synthesis, acrylic esters 2a–f were prepared from the corresponding aromatic aldehydes, using a DMAP/piperidine catalyzed Knoevenagel reaction with ethyl hydrogen malonate generated in situ from ethyl potassium malonate using acetic acid.8 The reaction mixture was heated in DMF, at 60 °C for 5–8 days to afford acrylic esters with 1-naphthalenyl 2a, 4-methylphenyl 2b, 3,5-dimethylphenyl 2c, 2-methylphenyl 2d, 2,4,6-trimethyphenyl 2e, and 4-methylnaphthalen-1-yl 2f substituents (Table 1). All of the esters were obtained with an (E)-configuration of the double bond which is essential for the later Overman rearrangement. Due to the two methyl groups that sterically hinder the carbonyl carbon, ester 2e was obtained in a lower yield
Table 1 Synthesis of aromatic allyl alcohols 3a–f from the corresponding aldehydes Aldehyde
Ar
2, Yield (%)
3, Yield (%)
1a 1b 1c 1d 1e 1f
1-Naphthalenyl 4-Methylphenyl 3,5-Dimethylphenyl 2-Methylphenyl 2,4,6-Trimethylphenyl 4-Methylnaphthalen-1-yl
95 99 98 97 53 95
99 99 98 96 99 99
A. Knezˇevic´ et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
and with a considerable amount of the reactant remaining intact, even after the reaction had been performed for 20 days. Acrylic esters 2a–f were then reduced in excellent yields to give allyl alcohols 3a–f using DIBAL-H (Fig. 1 and Table 1). The reactions were performed in dichloromethane for 2 h. The cinammyl alcohol 3g was not synthesized due to its commercial availability.
AcOH, DMAP
CO2Et
O
piperidine
+ Ar
H
DMF, 60 °C 5-8 d
CO2K
1a-f
1M DIBAL-H in toluene
2a-f
Ar
CH 2Cl2, -20 °C to 0 °C, 2h
CO2Et
Ar
OH 3a-f
Allyl alcohols 3a–g were converted into trichloroacetimidates 4a–g in a DBU catalyzed reaction with trichloroacetonitrile (Fig. 2). Reactions were performed in dichloromethane at 0 °C and were complete after 15 min. Products 4a–g were obtained after filtration over a short column of neutral aluminium oxide in 89–96% yield. The Overman rearrangement of allyl trichloroacetimidates 4a–g gave 2,2,2-trichloro-N-(1-arylallyl)acetamides 5a–g in 68–96% yield. The rearrangement was conducted thermally by heating the reaction mixture at reflux in xylene. Although some catalytic asymmetric Overman rearrangements of aliphatic allylic trichloroacetimidates resulted in high yields and excellent ee’s, the corresponding reaction of the aromatic compounds has not yet been successfully performed.9 Racemic amines rac-6a–g were obtained in good yield after amide hydrolysis using 5 M NaOH (Table 2). NH OH 3a-g
K2CO3
Cl3CCN, DBU CH2Cl2, 0 °C, 30 min
xylene reflux, 20 h
N H
O
CCl3
4a-g
Ar
O
Ar
Ar
5M NaOH CCl3
NH 2
EtOH, rt, 20 h
rac-6a-g
5a-g
Figure 2. Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols. Table 2 Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols Ar a, 1-Naphthalenyl b, 4-Methylphenyl c, 3,5-Dimethylphenyl d, 2-Methylphenyl e, 2,4,6-Trimethylphenyl f, 4-Methylnaphthalen-1-yl g, Phenyl
conditions were optimized on phenylallylamine 6g and later applied to other amines with some modifications. Amine resolutions were performed using C. antarctica lipase B in MTBE or hexane at 30 °C. Ethyl methoxyacetate and iso-propyl acetate were used as acyl donors (Table 3). In the case of amines 6a, 6b, 6f, and 6g, excellent ee’s were obtained. The absolute configuration of the amines was assumed to be (S), which is in accordance with Kazlauskas rule and the previously reported results in which CaLB always preferentially transformed the (R)-enantiomer of a racemic amine, leaving the (S)-enantiomer unchanged.10 This assumption was confirmed by comparing the specific rotation measured for (S)-phenylallylamine (S)-6g prepared by the resolution of the diastereomeric salts.11 A lower ee was observed in the case of amines 6c. It was also noticed that the presence of a methyl group at the ortho-position resulted in a lower enantioselectivity for amine 6d, and in almost no enantioselectivity for amine 6e which has two ortho-methyl groups. 3. Conclusion
Figure 1. Synthesis of aromatic allyl alcohols 3a–f from the corresponding aldehydes.
Ar
937
4 Yield (%)
5 Yield (%)
rac-6 Yield (%)
95 89 93 94 95 96 98
96 95 95 96 95 95 97
88 79 76 77 87 91 73
The enzyme catalyzed resolution of racemic amines 6a–g were screened with a variety of lipases, but only lipase B from C. antarctica showed positive results. Next, three different CaLB materials—lyophilized CaLB, Altus-11, and Novozym 435 were tested separately. The best enantioselective results were with CaLB immobilized on a polymer carrier (Novozym 435); as a result, the remaining work was carried out with this lipase. The reaction
Racemic 1-aryl-allylamines with 1-naphthalenyl rac-6a, 4methylphenyl rac-6b, 3,5-dimethylphenyl rac-6c, 2-methylphenyl rac-6d, 2,4,6-trimethyphenyl rac-6e, 4-methylnaphthalen-1-yl rac-6f, and phenyl rac-6g substituents were prepared starting from corresponding aldehydes in an excellent overall yield (five steps, 41–78%) with an Overman rearrangement as the key step. The enzymatic resolution of the racemic amines rac-6a–f was successfully performed using lipase B from C. antarctica to give amines 6a– f in moderate to excellent enantiomeric excess (63.5% to >99.9%). This is the first time CaLB has been used for the resolution of 1aryl-allylamines. The double functionality classifies the enantioenriched allyl amines as interesting chiral building blocks with a wide range of further synthetic applications.
4. Experimental 4.1. General All reactions were conducted under an argon atmosphere unless otherwise noted. THF was distilled from sodium/benzophenone ketyl and CH2Cl2 was distilled from CaH2. All other reagents and solvents were purchased from commercial sources and used without purification. Lipase acrylic resin from C. antarctica (Novozym 435, 10000 U/g) was obtained from Sigma Aldrich. TLC was performed on aluminium backed silica plates (60 F254, Merck) or aluminium backed aluminium oxide plates (neutral 60 F254, Merck). UV light (254 nm) or phosphomolibdic acid reagent were used for visualizing. Column chromatography was performed on silica gel (Silica Gel 60, 70–230 mesh, Fluka) or aluminium oxide (Merck Aluminiumoxide 90 active, neutral, activity I). 1H and 13C NMR were recorded on a Bruker AV 300 spectrometer. Chemical shifts (dH and dC) are quoted in parts per million (ppm), referenced to TMS. Optical rotations were measured using Optical Activity AA-10 automatic polarimeter. HPLC measurements were done using a Shimadzu LC20 system or Knauer system equipped with Pump 64, 4-Port Knauer Degasser, UV detector Knauer Variable Wavelength Monitor, Interface Knauer, and CD detector Jasco CD-2095. Chiral LC analyses of the final amines were performed on a Daicel Chiralcel OD-H column, 250 mm 4.6 mm. Melting points were determined on Electrothermal 9100 apparatus in open capillaries and are not corrected. IR spectra were recorded on a Bruker ABB Bowen instrument. 4.2. General procedure for the synthesis of acrylic esters 2a–f To a solution of the corresponding aldehyde (1 equiv) and DMAP (0.2 equiv) in DMF (2 mL per 1 mmol of aldehyde) ethyl
A. Knezˇevic´ et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
938
Table 3 CaLB catalyzed enantioselective acylation of racemic 1-aryl-allylamines 6a–g
O NH2 Ar
acyl donor
HN
NH2
CaLB Ar
+
Ar
solvent, 30 °C rac-6a-g
a b
(S)-6a-g
8a-g
Entry
Amine
Ar
Solvent
Acyl donor
Time (d)
Amine, ee (%)
Yielda (%)
1 2 3 4 5 6 7 8
6a 6b 6c 6d 6e 6e 6f 6g
1-Napthalenyl 4-Methylphenyl 3,5-Dimethylphenyl 2-Methylphenyl 2,4,6-Trimethylphenyl 2,4,6-Trimethylphenyl 4-Methylnaphthalen-1yl Phenyl
MTBE Hexane Hexane MTBE hexane MTBE MTBE Hexane
Ethyl methoxyacetate Ethyl methoxyacetate iso-Propyl acetate Ethyl methoxyacetate iso-Propyl acetate Ethyl methoxyacetate Ethyl methoxyacetate iso-Propyl acetate
5 3 7 8 4 4 2 2
>99.9 98.9 80.6 63.5 — 8.7 >99.9 >99.9
45 39 43 nib 0 nib 48 45
Maximum yield is 50%. Not isolated.
potassium malonate (1.5 equiv) was added. The resulting suspension was cooled to 0 °C and acetic acid (1.5 equiv) was added dropwise followed by piperidine (0.2 equiv). The reaction mixture was stirred at 60 °C for 5–8 days until completion of the reaction. Water was added and the mixture extracted with twice Et2O. The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, followed by water, and a saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.2.1. Ethyl-(E)-3-(1-naphthalenyl)-2-propenoate 2a Yellow oil (6.9 g, 95%, E:Z > 99:1) starting from 1-naphthaldehyde (4.3 mL). NMR data were in accordance with the literature.12 4.2.2. Ethyl-(E)-3-(4-methylphenyl)-2-propenoate 2b Yellow oil (6.1 g, 99%, E:Z > 99:1) starting from 4-methylbenzaldehyde (3.8 mL). NMR data were in accordance with the literature.13 4.2.3. Ethyl-(E)-3-(3,5-dimethylphenyl)-2-propenoate 2c Yellow oil (3.7 g, 98%, E:Z > 99:1) starting from 3,5-dimethylbenzaldehyde (2.5 g). mmax/cm1 1716, 1638, 1180, 1165, 1040, 982, 845, 677. 1H NMR (300 MHz, CDCl3) d 7.63 (1H, d, J = 16.1 Hz, CH), 7.14 (2H, s, Ar), 7.02 (1H, s, Ar), 6.41 (1H, d, J = 16.1 Hz, CH), 4.26 (2H, q, J = 7.3 Hz, CH2CH3), 2.33 (6H, s, ArCH3), 1.34 (3H, t, J = 7.3 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) d 167.05, 144.85, 138.32, 134.39, 131.94, 125.89, 117.83, 60.32, 21.11, 14.28. 4.2.4. Ethyl-(E)-3-(2-methylphenyl)-2-propenoate 2d Yellow oil (3.2 g, 97%, E:Z > 99:1) starting from 2-methylbenzaldehyde (2.0 mL). NMR data were in accordance with the literature.13 4.2.5. Ethyl-(E)-3-(2,4,6-trimethylphenyl)-2-propenoate 2e White solid (0.53 g, 53%, E:Z > 99:1) starting from 2,4,6-trimethylbenzaldehyde (0.68 g); mp 38.8–39.6 °C. NMR data were in accordance with the literature.14 4.2.6. Ethyl-(E)-3-(4-methylnaphthalen-1-yl)-2-propenoate 2f White solid (1.6 g, 95%, E:Z > 99:1) starting from 4-methyl-1naphthaldehyde (1.2 g); mp 76.9–77.9 °C; mmax/cm1 1703, 1632, 1306, 1183, 977, 830, 822, 759. 1H NMR (300 MHz, CDCl3) d 8.53 (1H, d, J = 15.9 Hz, CH), 8.25–8.21 (1H, m, Ar), 8.06–8.02 (1H, m, Ar), 7.66 (1H, d, J = 7.4 Hz, Ar), 7.60–7.56 (2H, m, Ar), 7.33 (1H, d, J = 7.4 Hz, Ar), 6.50 (1H, d, J = 15.9 Hz, CH), 4.33 (2H, q, J = 7.1 Hz, CH2CH3), 2.72 (3H, s, ArCH3), 1.39 (3H, t, J = 7.1 Hz, CH2CH3); 13C
NMR (75 MHz, CDCl3) d 167.03, 141.81, 137.23, 132.69, 131.41, 130.15, 126.43, 126.43, 126.02, 124.75, 123.92, 120.04, 60.51, 19.80, 14.37. 4.3. General procedure for the synthesis of alcohols 3a–f To a solution of the corresponding acrylic ester (1 equiv) in dry CH2Cl2 (5 mL per 1 mmol of ester), under argon, cooled to–30 °C, diisobutylaluminium hydride (1.2 M solution in toluene, 2 equiv) was added dropwise. The reaction mixture was stirred for 3 h at 30 °C. Ethanol (2 mL per 1 mmol of ester) was added followed by a saturated aqueous solution of potassium sodium tartrate (Rochelle salt, 3 mL per 1 mmol of ester). The layers were separated and the aqueous phase washed three times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.3.1. (E)-3-(1-Naphthalenyl)-prop-2-en-1-ol 3a Yellow oil (5.3 g, 99%) starting from 2a (6.5 g). NMR data were in accordance with the literature.15 4.3.2. (E)-3-(4-Methylphenyl)-prop-2-en-1-ol 3b White solid (4.0 g, 99%) starting from 2b (5.1 g). NMR data were in accordance with the literature.16 4.3.3. (E)-3-(3,5-Dimethylphenyl)-prop-2-en-1-ol 3c Yellow oil (0.79 g, 98%) starting from 2c (1.0 g). mmax/cm1 3410, 1698, 1682, 1603, 968, 852, 690. 1H NMR (300 MHz, CDCl3) d 7.02 (2H, s, Ar), 6.90 (1H, s, Ar), 6.56 (1H, d, J = 16.1 Hz, CH), 6.34 (1H, dt, J = 5.7, 16.1 Hz, CHCH2), 4.31 (2H, d, J = 5.7 Hz, CHCH2), 2.31 (6H, s, ArCH3), 1.54 (1H, br s, OH); 13C NMR (75 MHz, CDCl3) d 138.04, 136.60, 131.42, 129.45, 128.13, 124.39, 63.82, 21.23. 4.3.4. (E)-3-(2-Methylphenyl)-prop-2-en-1-ol 3d Yellow oil (0.75 g, 96%) starting from 2d (1.01 g). mmax/cm1 3330, 1486, 1459, 1110, 1086, 967, 746. 1H NMR (300 MHz, CDCl3) d 7.48–7.44 (1H, m, Ar), 7.20–7.15 (3H, m, Ar), 6.85 (1H, d, J = 15.8 Hz, CH), 6.26 (1H, dt, J = 5.7, 15.8 Hz, CHCH2), 4.35 (2H, d, J = 5.7 Hz, CHCH2), 2.37 (3H, s, ArCH3), 1.96 (1H, br s, OH); 13C NMR (75 MHz, CDCl3) d 135.75, 135.42, 130.23, 129.83, 128.86, 127.50, 126.04, 125.69, 63.80, 19.69. 4.3.5. (E)-3-(2,4,6-Trimethylphenyl)-prop-2-en-1-ol 3e White solid (0.50 g, 99%) starting from 2e (0.63 g). NMR data were in accordance with the literature.14
A. Knezˇevic´ et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
4.3.6. (E)-3-(4-Methylnaphthalen-1-yl)-prop-2-en-1-ol 3f White solid (1.72 g, 99%) starting from 2f (2.12 g); mp 100.2– 101.1 °C; mmax/cm1 3340, 1412, 1015, 966, 840, 752. 1H NMR (300 MHz, CDCl3) d 8.16–8.13 (1H, m, Ar), 8.04–8.01 (1H, m, Ar), 7.57–7.49 (3H, m, Ar), 7.37 (1H, d, J = 15.7 Hz, CH), 7.30 (1H, d, J = 7.3 Hz, Ar), 6.36 (1H, dt, J = 5.7, 15.7 Hz, CHCH2), 4.43 (2H, d, J = 5.7 Hz, CHCH2), 2.70 (3H, s, ArCH3), 1.61 (1H, br s, OH), 13C NMR (75 MHz, CDCl3) d 134.36, 132.83, 132.63, 131.23, 131.08, 128.56, 126.50, 125.71, 125.65, 124.65, 124.31, 123.71, 64.04, 19.60. 4.4. General procedure for the synthesis of trichloroacetimidates 4a–f To a solution of the corresponding alcohol (1 equiv) and DBU (0.2 equiv) in dry CH2Cl2 (6 mL per 1 mmol of alcohol) at 0 °C, trichloroacetonitrile (1.1 equiv) was added dropwise. The reaction mixture was stirred for 15 min. The solvent was evaporated to give a brown residue which was filtered through a short column of neutral aluminium oxide, activity I (eluent EtOAc/hexane = 10:90) to afford the product. 4.4.1. (E)-3-(1-Naphthalenyl)allyl-2,2,2-trichloroacetimidate 4a Yellow oil (9.0 g, 95%) starting from 3a (5.3 g). mmax/cm1 3340, 1667, 1306, 1079, 970, 795. 1H NMR (300 MHz, CDCl3) d 8.42 (1H, br s, NH), 8.11 (1H, d, J = 8.0 Hz, Ar), 7.87–7.79 (2H, m, Ar), 7.64 (1H, d, J = 7.1 Hz, Ar), 7.56–7.43 (4H, m, Ar, CH), 6.43 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.10 (2H, d, J = 5.9 Hz, CHCH2); 13 C NMR (75 MHz, CDCl3) d 162.57, 133.96, 133.61, 131.51, 131.16, 128.58, 128.47, 126.25, 125.88, 125.58, 125.53, 124.15, 123.66, 69.71. 4.4.2. (E)-3-(4-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4b Yellow oil (3.97 g, 89%) starting from 3b (2.27 g). mmax/cm1 3344, 1716, 1664, 1308, 1289, 1078, 968, 798. 1H NMR (300 MHz, CDCl3) d 8.35 (1H, br s, NH), 7.32 (2H, d, J = 8.0 Hz, Ar), 7.14 (2H, d, J = 8.0 Hz, Ar), 6.73 (1H, d, J = 15.9 Hz, CH), 6.35 (1H, dt, J = 6.3, 15.9 Hz, CHCH2), 4.96 (2H, dd, J = 1.2, 6.3 Hz, CHCH2), 2.35 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.58, 138.07, 134.59, 133.36, 129.30, 126.62, 121.24, 69.93, 21.22. 4.4.3. (E)-3-(3,5-Dimethylphenyl)allyl-2,2,2-trichloroacetimidate 4c Yellow oil (1.34 g, 93%) starting from 3c (0.77 g). mmax/cm1 3376, 1696, 1608, 1381, 1110, 968, 837. 1H NMR (300 MHz, CDCl3) d 8.35 (1H, br s, NH), 7.05 (2H, s, Ar), 6.92 (1H, s, Ar), 6.70 (1H, d, J = 15.8 Hz, CH), 6.37 (1H, dt, J = 6.3, 15.8 Hz, CHCH2), 4.96 (2H, dd, J = 1.2, 6.3 Hz, CHCH2), 2.32 (6H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.60, 138.08, 136.09, 134.81, 129.88, 124.60, 121.93, 69.88, 21.21. 4.4.4. (E)-3-(2-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4d Yellow oil (1.3 g, 94%) starting from 3d (0.70 g). mmax/cm1 3343, 1668, 1308, 1285, 1078, 968, 798, 745. 1H NMR (300 MHz, CDCl3) d 8.37 (1H, br s, NH), 7.49–7.45 (1H, m, Ar), 7.20–7.15 (3H, m, Ar), 6.99 (1H, d, J = 15.9 Hz, CH), 6.28 (1H, dt, J = 6.1, 15.9 Hz, CHCH2), 5.00 (2H, dd, J = 1.4, 6.1 Hz, CHCH2), 2.36 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.54, 135.73, 135.34, 132.22, 130.34, 127.99, 126.14, 125.84, 123.60, 69.78, 19.72. 4.4.5. (E)-3-(2,4,6-Trimethylphenyl)allyl-2,2,2-trichloroacetimidate 4e Colorless oil (0.87 g, 95%) starting from 3e (0.5 g). mmax/cm1 3346, 1667, 1302, 1078, 979, 794. 1H NMR (300 MHz, CDCl3) d 8.36 (1H, br s, NH), 6.87 (2H, s, Ar), 6.75 (1H, d, J = 16.3 Hz, CH),
939
5.90 (1H, dt, J = 6.1, 16.3 Hz, CHCH2), 5.00 (2H, dd, J = 1.2, 6.1 Hz, CHCH2), 2.27 (9H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.47, 136.56, 135.89, 132.99, 132.79, 128.59, 127.24, 69.70, 20.91, 20.76. 4.4.6. (E)-3-(4-Methylnaphthalen-1-yl)-allyl-2,2,2-trichloroacetimidate 4f Yellow oil (2.86 g, 96%) starting from 3f (1.72 g). mmax/cm1 3375, 1695, 1385, 1112, 968, 835, 753. 1H NMR (300 MHz, CDCl3) d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar), 8.04–8.02 (1H, m, Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d, J = 7.44 Hz, Ar), 6.39 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H, dd, J = 1.3, 6.0 Hz, CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.60, 134.84, 132.65, 132.35, 131.89, 131.24, 126.49, 125.89, 125.73, 124.79, 124.70, 124.24, 123.94, 69.88, 19.67. 4.4.7. (E)-3-Phenylallyl-2,2,2-trichloroacetimidate 4g Yellow oil (1.06 g, 98%) starting from cinammyl alcohol (0.52 g).7a 4.5. General procedure for the synthesis of amides 5a–g To a solution of the corresponding trichloroacetimidate (1 equiv) in xylene (6 mL per 1 mmol of trichloroacetimidate), K2CO3 (2 mg/mL xylene) was added and the mixture was refluxed at 140 °C for 24 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and filtered through a short column of silica gel (eluent toluene) to give a product. 4.5.1. 2,2,2-Trichloro-N-[1-(1-naphthalenyl)allyl]acetamide 5a White solid (7.75 g, 96%) starting from 4a (8.08 g); mp 109.3– 110.2 °C; C15H12Cl3NO requires C, 54.82; H, 3.68; N, 4.26, found: C, 55.28; H, 3.52; N, 4.00. mmax/cm1 3284, 1685, 1526, 838, 823, 804. 1H NMR (300 MHz, CDCl3) d 8.03 (1H, d, J = 8.2 Hz, Ar), 7.89 (2H, t, J = 9.2 Hz, Ar), 7.61–7.45 (4H, m, Ar), 6.89 (1H, br s, NH), 6.38–6.32 (1H, m, CHNH), 6.25 (1H, ddd, J = 4.4, 10.3, 17.3 Hz, CHCH2), 5.46 (1H, d, J = 10.3, CH2CH), 5.41 (1H, d, J = 17.3, CH2CH); 13 C NMR (75 MHz, CDCl3) d 161.02, 135.36, 134.27, 134.09, 131.13, 129.48, 129.00, 127.09, 126.26, 125.25, 125.20, 123.03, 116.74, 53.29. 4.5.2. 2,2,2-Trichloro-N-[1-(4-methylphenyl)allyl]acetamide 5b White solid (3.56 g, 95%) starting from 4b (3.74 g); mp 78.5– 79.1 °C. mmax/cm1 3297, 1695, 1523, 837, 819, 805. 1H NMR (300 MHz, CDCl3) d 7.20 (4H, s, Ar), 6.89 (1H, br s, NH), 6.04 (1H, ddd, J = 5.3, 10.3, 17.2 Hz, CHCH2), 5.56–5.49 (1H, m, CHNH), 5.33 (1H, d, J = 10.3, CH2CH), 5.30 (1H, d, J = 17.2, CH2CH), 2.35 (3H, s, ArCH3) ; 13C NMR (75 MHz, CDCl3) d 160.88, 138.18, 135.81, 135.74, 129.73, 127.07, 116.83, 56.85, 21.14. 4.5.3. 2,2,2-Trichloro-N-[1-(3,5-dimethylphenyl)allyl]acetamide 5c White solid (2.84 g, 95%) starting from 4c (2.98 g); mp 85.8– 86.8 °C. mmax/cm1 3294, 1698, 1529, 831, 822. 1H NMR (300 MHz, CDCl3) d 6.97 (1H, s, Ar), 6.93 (2H, s, Ar), 6.86 (1H, br s, NH), 6.04 (1H, ddd, J = 5.3, 10.1, 17.4 Hz, CHCH2), 5.52–5.46 (1H, m, CHNH), 5.33 (1H, d, J = 10.1, CH2CH), 5.32 (1H, d, J = 17.4, CH2CH), 2.33 (6H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.84, 138.73, 138.69, 135.82, 129.98, 124.89, 116.58, 57.07, 21.30. 4.5.4. 2,2,2-Trichloro-N-[1-(2-methylphenyl)allyl]acetamide 5d White solid (1.69 g, 96%) starting from 4d (1.75 g); mp 69.2– 69.9 °C. mmax/cm1 3300, 1690, 1516, 836, 823, 758, 726. 1H NMR (300 MHz, CDCl3) d 7.24 (4H, s, Ar), 6.79 (1H, br s, NH), 6.06 (1H, ddd, J = 4.6, 10.4, 17.2 Hz, CHCH2), 5.77–5.72 (1H, m, CHNH), 5.35 (1H, d, J = 10.4, CH2CH), 5.26 (1H, d, J = 17.2, CH2CH), 2.39 (3H, s,
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ArCH3); 13C NMR (75 MHz, CDCl3) d 136.68, 135.40, 131.09, 128.36, 126.57, 126.49, 116.59, 53.86, 19.09. 4.5.5. 2,2,2-Trichloro-N-[1-(2,4,6-trimethylphenyl)allyl]acetamide 5e Colorless oil (0.86 g, 95%) starting from 4e (0.91 g). mmax/cm1 3445, 1716, 1508, 837, 820, 737, 680. 1H NMR (300 MHz, CDCl3) d 7.23 (1H, br s, NH), 6.87 (2H, s, Ar), 6.11–5.96 (2H, m, CHCH2, CHNH), 5.27 (1H, d, J = 10.4, CH2CH), 5.12 (1H, d, J = 17.0, CH2CH), 2.40 (6H, s, ArCH3), 2.27 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.95, 137.61, 136.30, 135.74, 131.81, 130.25, 116.19, 53.02, 20.79, 20.60. 4.5.6. 2,2,2-Trichloro-N-[1-(4-methylnaphthalen-1-yl)allyl]acetamide 5f White solid (2.92 g, 95%) starting from 4f (3.08 g). mp 116.4– 117.2 °C. mmax/cm1 3316, 1687, 1507, 826, 760. 1H NMR (300 MHz, CDCl3) d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar), 8.04–8.02 (1H, m, Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d, J = 7.44 Hz, Ar), 6.39 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H, dd, J = 1.3, 6.0 Hz, CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.98, 135.85, 135.48, 133.23, 132.43, 131.16, 126.72, 126.10, 125.96, 125.08, 123.54, 116.53, 53.26, 19.66. 4.5.7. 2,2,2-Trichloro-N-(1-phenylallyl)acetamide 5g White solid (1.03 g, 97%) starting from 4g (1.06 g).7a 4.6. General procedure for the synthesis of racemic amines 6a–g To a solution of the corresponding amide (1 equiv) in absolute ethanol (5 mL per 1 mmol of amide), 5 M NaOH solution in water (30 equiv) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to an aqueous residue which was acidified to pH 1 by the addition of 6 M HCl and washed three times with CH2Cl2. Next, Na2CO3 was added to the aqueous layer until pH 8. The mixture was then extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.6.1. 1-(1-Naphthalenyl)-prop-2-en-1-amine 6a Yellow oil (3.82 g, 88%) starting from 5a (7.75 g). mmax/cm1 3300, 1669, 1638, 1594, 1393, 802, 779. 1H NMR (300 MHz, CDCl3) d 8.19 (1H, d, J = 8.2 Hz, Ar), 7.91–7.85 (1H, m, Ar), 7.81–7.75 (1H, m, Ar), 7.62–7.43 (4H, m, Ar), 6.23 (1H, ddd, J = 5.2, 10.4, 17.5 Hz, CHCH2), 5.40–5.31 (2H, m, CH2CH, CHNH2), 5.23 (1H, d, J = 10.4 Hz, CH2CH), 2.29 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 141.24, 139.60, 133.95, 130.92, 128.88, 127.84, 126.05, 125.53, 123.52, 123.32, 114.55, 53.84. 4.6.2. 1-(4-Methylphenyl)-prop-2-en-1-amine 6b Yellow oil (1.34 g, 79%) starting from 5b (3.36 g). mmax/cm1 3375, 3300, 1638, 1511, 917, 818, 761. 1H NMR (300 MHz, CDCl3) d 7.24 (2H, d, J = 7.9 Hz , Ar), 7.15 (2H, d, J = 7.9 Hz, Ar), 6.02 (1H, ddd, J = 6.1, 10.2, 17.1 Hz, CHCH2), 5.23 (1H, d, J = 17.1, CH2CH), 5.10 (1H, d, J = 10.2, CH2CH), 4.50 (1H, d, J = 6.1 Hz, CHNH2), 2.34 (3H, s, ArCH3), 1.66 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 142.37, 141,46, 136.70, 129.19, 126.49, 113.47, 58.06, 21.02. 4.6.3. 1-(3,5-Dimethylphenyl)-prop-2-en-1-amine 6c Yellow oil (0.80 g, 76%) starting from 5c (2.00 g). mmax/cm1 3375, 1638, 1607, 1466, 995, 918, 848, 734. 1H NMR (300 MHz, CDCl3) d 6.96 (2H, s, Ar), 6.90 (1H, s, Ar), 6.02 (1H, ddd, J = 6.1, 10.2, 17.1 Hz, CHCH2), 5.25 (1H, d, J = 17.1, CH2CH), 5.11 (1H, d, J = 10.2, CH2CH), 4.46 (1H, d, J = 6.1 Hz, CHNH2), 2.32 (6H, s, ArCH3), 1.63 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 144.38, 142.35, 138.06, 128.71, 124.37, 113.41, 58.31, 21.25.
4.6.4. 1-(2-Methylphenyl)-prop-2-en-1-amine 6d Yellow oil (0.30 g, 77%) starting from 5d (0.77 g). 1H NMR (300 MHz, CDCl3) d 7.39 (1H, d, J = 7.2 Hz, Ar), 7.25–7.13 (3H, m, Ar), 6.02 (1H, ddd, J = 5.7, 10.2, 17.2 Hz, CHCH2), 5.20 (1H, d, J = 17.2, CH2CH), 5.12 (1H, d, J = 10.2, CH2CH), 4.76 (1H, d, J = 5.7 Hz, CHNH2), 2.38 (3H, s, ArCH3), 1.90 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 142.06, 141.34, 135.34, 130.48, 126.92, 126.33, 125.72, 113.85, 54.19, 19.17. 4.6.5. 1-(2,4,6-Trimethylphenyl)-prop-2-en-1-amine 6e Yellow oil (0.38 g, 87%) obtained after silica gel column chromatography (CH2Cl2–MeOH, 9:1, Rf = 0.44) starting from 5e (0.80 g). mmax/cm1 3400, 1669, 1662, 1611, 1383, 1266, 917, 852, 737. 1H NMR (300 MHz, CDCl3) d 6.83 (2H, s, Ar), 6.14 (1H, ddd, J = 4.1, 10.3, 17.0 Hz, CHCH2), 5.17 (1H, d, J = 17.0, CH2CH), 5.12 (1H, d, J = 10.3, CH2CH), 5.02–4.97 (1H, m, CHNH2), 2.37 (6H, s, ArCH3), 2.25 (3H, s, ArCH3), 1.60 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 141.26, 137.22, 136.22, 130.11, 113.03, 53.32, 20.79, 20.68. 4.6.6. 1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine 6f Yellow oil (0.48 g, 91%) obtained after silica gel column chromatography (CH2Cl2–MeOH, 9:1, Rf = 0.54) starting from 5e (0.91 g). mmax/cm1 3375, 1637, 1598, 1391, 1264, 920, 836, 755. 1H NMR (300 MHz, CDCl3) d 8.26–8.20 (1H, m, Ar), 8.08– 8.02 (1H, m, Ar), 7.58–7.52 (2H, m, Ar), 7.47 (1H, d, J = 7.2 Hz, Ar), 7.32 (1H, d, J = 7.2 Hz, Ar), 6.22 (1H, ddd, J = 5.7, 10.3, 17.1 Hz, CHCH2), 5.39–5.29 (2H, m, CH2CH, CHNH2), 5.22 (1H, d, J = 10.3, CH2CH), 2.69 (3H, s, ArCH3), 1.78 (2H, br s, NH2); 13 C NMR (75 MHz, CDCl3) d 141.70, 138.08, 133.35, 133.07, 131.05, 126.35, 125.72, 125.43, 124.97, 123.92, 123.28, 114.28, 53.85, 19.59. 4.6.7. 1-Phenyl-prop-2-en-1-amine 6g Yellow oil (0.35 g, 73%) starting from 5g (1.01 g). NMR data were in accordance with the literature.11 4.7. General procedure for the enzymatic resolution of racemic amines The racemic amine (1 equiv) was dissolved in a mixture of iso-propyl acetate (14 mL per 1 mmol of amine) and hexane (2 mL per 1 mmol of hexane). Immobilized lipase B from C. antarctica, Novozym 435 (0.3 g per 1 mmol of amine) was added. The reaction mixture was stirred at 30 °C. The progress of the reaction was monitored using HPLC, on Chiralcel OD-H column (hexane–2-propanol–diethylamine, 90:10:0.1). After completion of the reaction, the reaction mixture was filtered and the filtrate concentrated. Next, 1 M HCl was added (3.5 mL per 1 mmol of starting amine). The mixture was washed three times with dichloromethane. Next, Na2CO3 was added to the aqueous layer until pH 8 was obtained. The mixture was extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.7.1. (S)-1-(1-Naphthalenyl)-prop-2-en-1-amine (S)-6a Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 300 nm, tR(S) = 9.0 min, tR(R) = 10.1 min; ½a25 D ¼ 46:0 (c 0.9, CHCl3). 4.7.2. (S)-1-(4-Methylphenyl)-prop-2-en-1-amine (S)-6b Yield 39%, ee 98.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 268 nm, tR(R) = 5.7 min, tR(S) = 6.4 min; ½a25 D ¼ 9:7 (c 1.1, CH2Cl2).
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4.7.3. (S)-1-(3,5-Dimethylphenyl)-prop-2-en-1-amine (S)-6c Yield 39%, ee 80.6%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 240 nm, tR(R) = 5.0 min, tR(S) = 5.3 min. 4.7.4. (S)-1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine (S)6f Yield 48%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 95:5:0.1, 1 mL/min, 300 nm, tR(S) = 11.7 min, tR(R) = 13.3 min; ½a25 D ¼ 40:2 (c 3.2, CH2Cl2). 4.7.5. (S)-1-Phenyl-prop-2-en-1-amine (S)-6g Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 95:5:0.2, 1 mL/min, 254 nm, tR(R) = 7.4 min, tR(S) = 9.1 min; ½a25 D ¼ 10:2 (c 3.3, CHCl3); lit. value ascribed for (S)11 6g with ee >99.6% is ½a25 D ¼ 10:45 (c 4, CHCl3). Acknowledgments This work was supported by Ministry of Science, Education, and Sports of Croatia (Grant No. 098-0982904-2910). References 1. (a) Breuer, M.; Dietrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824; (b)Asymmetric Organic Synthesis with Enzymes; Gotor, V., Alfonso, I., Garciá-Urdiales, E., Eds.; WileyVCH Verlag GmbH & Co. KGaA: Weinheim, 2008; (c)Chiral Amine Synthesis, Methods, Developments and Applications; Nugent, T. C., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2010.
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2. For some examples, see: (a) Ichikavata, Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003, 1034–1036; (b) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225–12231. 3. Gotor-Fernández, V.; Busto, E.; Gotor, V. Adv. Synth. Catal. 2006, 348, 797–812. 4. (a) Gazic´ Smilovic´, I.; Molcˇanov, K.; Vinkovic´, V.; Kojic´-Prodic´, B.; Lesac, A. J. Mol. Struct. 2010, 980, 51–58; (b) Moslavac Forjan, D.; Vinkovic´, M.; Kontrec, D.; Lesac, A.; Vinkovic´, V. Struct. Chem. 2007, 18, 585–591; (c) Landek, G.; Vinkovic´, M.; Kontrec, D.; Vinkovic´, V. Chromatographia 2006, 64, 469–473; (d) Moslavac Forjan, D.; Gazic´, I.; Vinkovic´, V. Chirality 2007, 19, 446–452; (e) Gazic´, I.; Kontrec, D.; Lesac, A.; Vinkovic´, V. Tetrahedron: Asymmetry 2005, 16, 1175– 1182. 5. (a) Pirkle, W. H.; Welch, C. J.; Lamm, B. R. U.S. Patent 5,387,338 A, 1995.; (b) Hyun, M. H.; Kim, K. J.; Jyung, K. K. Bull. Korean Chem. Soc. 1997, 18, 1085–1089; (c) Moslavac Forjan, D.; Kontrec, D.; Vinkovic´, V. Chirality 2006, 18, 857–869. 6. For overview of allylic amination, see: (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689–1708; (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944; (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258–297. 7. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597; (b) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910; (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224; (d) Overman, L. E. In Organic Reactions; John Wiley & Sons: New York, 2005; Vol. 66, 8. List, B.; Doehring, A.; Hechavarria Fonseca, M. T.; Job, A.; Rios Torres, R. Tetrahedron 2006, 62, 476–482. 9. Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412–12413. 10. (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665; (b) Rotticci, D.; Hæffner, F.; Orrenius, C.; Norin, T.; Hult, K. J. Mol. Catal. B: Enzym. 1998, 5, 267–272. 11. Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetrahedron: Asymmetry 2000, 11, 4017–4025. 12. Dickinson, J. M.; Murphy, J. A.; Patterson, C. W.; Wooster, N. F. J. Chem. Soc., Perkin Trans. 1 1990, 1179–1184. 13. Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J. Org. Chem. 2003, 68, 3714– 3717. 14. Medina, E.; Moyano, A.; Pericás, M. A.; Riera, A. Helv. Chim. Acta 2000, 83, 972– 988. 15. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–5486. 16. Beard, R. L.; Donello, J. E.; Yuan, H.; Liu, X. U.S. Patent, 7,728,014 B2, 2010.
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
An efficient enzymatic approach to (S)-1-aryl-allylamines Anamarija Knezˇevic´ a, Goran Landek b, Irena Dokli a, Vladimir Vinkovic´ a,⇑ a b
- Boškovic´ Institute, PO Box 180, 10002 Zagreb, Croatia Department of Organic Chemistry and Biochemistry, Ruder Galapagos Istrazˇivacˇki Centar d.o.o., Prilaz Baruna Filipovic´a 29, 10000 Zagreb, Croatia
a r t i c l e
i n f o
Article history: Received 14 March 2011 Accepted 2 June 2011
a b s t r a c t A range of 1-aryl-allylamines were prepared in moderate to excellent enantioselectivity (ee 63.5%?99.9%) using lipase B from a Candida antarctica catalyzed resolution of racemic amines. This is the first time that CaLB has been used for the resolution of 1-aryl-allylamines. Racemic amines were prepared starting from aromatic aldehydes with a [3,3]-sigmatropic rearrangement of the acyclic imidates as the key step followed by trichloroacetamidate hydrolysis. Aldehydes were converted into acrylic esters using Knoevenagel reaction. After reduction, the corresponding alcohols were used for the preparation of trichloroacetimidates, which were then used in an Overman rearrangement. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction Enantiomerically pure primary chiral amines with a stereogenic center at the a-position are very important building blocks in organic chemistry.1 An additional allylic functionality at the stereogenic carbon center increases their synthetic potential. These types of compounds have been used as starting materials for the synthesis of different amino acids, alkaloids, and nitrogen containing molecules, which possess a wide range of biological activities.2 One method for obtaining enantiomerically pure chiral amines is the resolution of racemic amines by enzymes, in particular the Candida antarctica lipase B (CaLB) catalyzed enantioselective acylation. This enzyme has proven to be a very effective catalyst for the resolution of primary amines with a stereogenic center at the a-position due to the high stereoselectivity and simplicity of the resolution process.3 As part of our ongoing research on brush-type chiral stationary phases,4 we envisaged the synthesis of a series of chiral selectors containing a terminal double bond, which is required for binding to a silica surface.5 Chiral 1-aryl-allylamines have been recognised as key intermediates in this synthetic pathway (Scheme 1). Herein we report the synthesis of racemic 1-aryl-allylamines and their resolution using lipase B from C. antarctica. This is the first time that CaLB has been used for the resolution of allyl amines. 2. Results and discussion Among the different methods for the preparation of the allyl amines,6 and due to the availability of starting materials, we chose
⇑ Corresponding author. Tel.: +385 14680108; fax: +385 14571300. E-mail address: [email protected] (V. Vinkovic´). 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.06.004
O O 2N
Ar Ar
N H
H
NH2
O Ar
NO2 Scheme 1. Retrosynthetic pathway toward chiral selectors.
the Overman rearrangement of allyl trichloroacetimidates as the method for our synthesis.7 In the first step of the synthesis, acrylic esters 2a–f were prepared from the corresponding aromatic aldehydes, using a DMAP/piperidine catalyzed Knoevenagel reaction with ethyl hydrogen malonate generated in situ from ethyl potassium malonate using acetic acid.8 The reaction mixture was heated in DMF, at 60 °C for 5–8 days to afford acrylic esters with 1-naphthalenyl 2a, 4-methylphenyl 2b, 3,5-dimethylphenyl 2c, 2-methylphenyl 2d, 2,4,6-trimethyphenyl 2e, and 4-methylnaphthalen-1-yl 2f substituents (Table 1). All of the esters were obtained with an (E)-configuration of the double bond which is essential for the later Overman rearrangement. Due to the two methyl groups that sterically hinder the carbonyl carbon, ester 2e was obtained in a lower yield
Table 1 Synthesis of aromatic allyl alcohols 3a–f from the corresponding aldehydes Aldehyde
Ar
2, Yield (%)
3, Yield (%)
1a 1b 1c 1d 1e 1f
1-Naphthalenyl 4-Methylphenyl 3,5-Dimethylphenyl 2-Methylphenyl 2,4,6-Trimethylphenyl 4-Methylnaphthalen-1-yl
95 99 98 97 53 95
99 99 98 96 99 99
A. Knezˇevic´ et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
and with a considerable amount of the reactant remaining intact, even after the reaction had been performed for 20 days. Acrylic esters 2a–f were then reduced in excellent yields to give allyl alcohols 3a–f using DIBAL-H (Fig. 1 and Table 1). The reactions were performed in dichloromethane for 2 h. The cinammyl alcohol 3g was not synthesized due to its commercial availability.
AcOH, DMAP
CO2Et
O
piperidine
+ Ar
H
DMF, 60 °C 5-8 d
CO2K
1a-f
1M DIBAL-H in toluene
2a-f
Ar
CH 2Cl2, -20 °C to 0 °C, 2h
CO2Et
Ar
OH 3a-f
Allyl alcohols 3a–g were converted into trichloroacetimidates 4a–g in a DBU catalyzed reaction with trichloroacetonitrile (Fig. 2). Reactions were performed in dichloromethane at 0 °C and were complete after 15 min. Products 4a–g were obtained after filtration over a short column of neutral aluminium oxide in 89–96% yield. The Overman rearrangement of allyl trichloroacetimidates 4a–g gave 2,2,2-trichloro-N-(1-arylallyl)acetamides 5a–g in 68–96% yield. The rearrangement was conducted thermally by heating the reaction mixture at reflux in xylene. Although some catalytic asymmetric Overman rearrangements of aliphatic allylic trichloroacetimidates resulted in high yields and excellent ee’s, the corresponding reaction of the aromatic compounds has not yet been successfully performed.9 Racemic amines rac-6a–g were obtained in good yield after amide hydrolysis using 5 M NaOH (Table 2). NH OH 3a-g
K2CO3
Cl3CCN, DBU CH2Cl2, 0 °C, 30 min
xylene reflux, 20 h
N H
O
CCl3
4a-g
Ar
O
Ar
Ar
5M NaOH CCl3
NH 2
EtOH, rt, 20 h
rac-6a-g
5a-g
Figure 2. Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols. Table 2 Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols Ar a, 1-Naphthalenyl b, 4-Methylphenyl c, 3,5-Dimethylphenyl d, 2-Methylphenyl e, 2,4,6-Trimethylphenyl f, 4-Methylnaphthalen-1-yl g, Phenyl
conditions were optimized on phenylallylamine 6g and later applied to other amines with some modifications. Amine resolutions were performed using C. antarctica lipase B in MTBE or hexane at 30 °C. Ethyl methoxyacetate and iso-propyl acetate were used as acyl donors (Table 3). In the case of amines 6a, 6b, 6f, and 6g, excellent ee’s were obtained. The absolute configuration of the amines was assumed to be (S), which is in accordance with Kazlauskas rule and the previously reported results in which CaLB always preferentially transformed the (R)-enantiomer of a racemic amine, leaving the (S)-enantiomer unchanged.10 This assumption was confirmed by comparing the specific rotation measured for (S)-phenylallylamine (S)-6g prepared by the resolution of the diastereomeric salts.11 A lower ee was observed in the case of amines 6c. It was also noticed that the presence of a methyl group at the ortho-position resulted in a lower enantioselectivity for amine 6d, and in almost no enantioselectivity for amine 6e which has two ortho-methyl groups. 3. Conclusion
Figure 1. Synthesis of aromatic allyl alcohols 3a–f from the corresponding aldehydes.
Ar
937
4 Yield (%)
5 Yield (%)
rac-6 Yield (%)
95 89 93 94 95 96 98
96 95 95 96 95 95 97
88 79 76 77 87 91 73
The enzyme catalyzed resolution of racemic amines 6a–g were screened with a variety of lipases, but only lipase B from C. antarctica showed positive results. Next, three different CaLB materials—lyophilized CaLB, Altus-11, and Novozym 435 were tested separately. The best enantioselective results were with CaLB immobilized on a polymer carrier (Novozym 435); as a result, the remaining work was carried out with this lipase. The reaction
Racemic 1-aryl-allylamines with 1-naphthalenyl rac-6a, 4methylphenyl rac-6b, 3,5-dimethylphenyl rac-6c, 2-methylphenyl rac-6d, 2,4,6-trimethyphenyl rac-6e, 4-methylnaphthalen-1-yl rac-6f, and phenyl rac-6g substituents were prepared starting from corresponding aldehydes in an excellent overall yield (five steps, 41–78%) with an Overman rearrangement as the key step. The enzymatic resolution of the racemic amines rac-6a–f was successfully performed using lipase B from C. antarctica to give amines 6a– f in moderate to excellent enantiomeric excess (63.5% to >99.9%). This is the first time CaLB has been used for the resolution of 1aryl-allylamines. The double functionality classifies the enantioenriched allyl amines as interesting chiral building blocks with a wide range of further synthetic applications.
4. Experimental 4.1. General All reactions were conducted under an argon atmosphere unless otherwise noted. THF was distilled from sodium/benzophenone ketyl and CH2Cl2 was distilled from CaH2. All other reagents and solvents were purchased from commercial sources and used without purification. Lipase acrylic resin from C. antarctica (Novozym 435, 10000 U/g) was obtained from Sigma Aldrich. TLC was performed on aluminium backed silica plates (60 F254, Merck) or aluminium backed aluminium oxide plates (neutral 60 F254, Merck). UV light (254 nm) or phosphomolibdic acid reagent were used for visualizing. Column chromatography was performed on silica gel (Silica Gel 60, 70–230 mesh, Fluka) or aluminium oxide (Merck Aluminiumoxide 90 active, neutral, activity I). 1H and 13C NMR were recorded on a Bruker AV 300 spectrometer. Chemical shifts (dH and dC) are quoted in parts per million (ppm), referenced to TMS. Optical rotations were measured using Optical Activity AA-10 automatic polarimeter. HPLC measurements were done using a Shimadzu LC20 system or Knauer system equipped with Pump 64, 4-Port Knauer Degasser, UV detector Knauer Variable Wavelength Monitor, Interface Knauer, and CD detector Jasco CD-2095. Chiral LC analyses of the final amines were performed on a Daicel Chiralcel OD-H column, 250 mm 4.6 mm. Melting points were determined on Electrothermal 9100 apparatus in open capillaries and are not corrected. IR spectra were recorded on a Bruker ABB Bowen instrument. 4.2. General procedure for the synthesis of acrylic esters 2a–f To a solution of the corresponding aldehyde (1 equiv) and DMAP (0.2 equiv) in DMF (2 mL per 1 mmol of aldehyde) ethyl
A. Knezˇevic´ et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
938
Table 3 CaLB catalyzed enantioselective acylation of racemic 1-aryl-allylamines 6a–g
O NH2 Ar
acyl donor
HN
NH2
CaLB Ar
+
Ar
solvent, 30 °C rac-6a-g
a b
(S)-6a-g
8a-g
Entry
Amine
Ar
Solvent
Acyl donor
Time (d)
Amine, ee (%)
Yielda (%)
1 2 3 4 5 6 7 8
6a 6b 6c 6d 6e 6e 6f 6g
1-Napthalenyl 4-Methylphenyl 3,5-Dimethylphenyl 2-Methylphenyl 2,4,6-Trimethylphenyl 2,4,6-Trimethylphenyl 4-Methylnaphthalen-1yl Phenyl
MTBE Hexane Hexane MTBE hexane MTBE MTBE Hexane
Ethyl methoxyacetate Ethyl methoxyacetate iso-Propyl acetate Ethyl methoxyacetate iso-Propyl acetate Ethyl methoxyacetate Ethyl methoxyacetate iso-Propyl acetate
5 3 7 8 4 4 2 2
>99.9 98.9 80.6 63.5 — 8.7 >99.9 >99.9
45 39 43 nib 0 nib 48 45
Maximum yield is 50%. Not isolated.
potassium malonate (1.5 equiv) was added. The resulting suspension was cooled to 0 °C and acetic acid (1.5 equiv) was added dropwise followed by piperidine (0.2 equiv). The reaction mixture was stirred at 60 °C for 5–8 days until completion of the reaction. Water was added and the mixture extracted with twice Et2O. The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, followed by water, and a saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.2.1. Ethyl-(E)-3-(1-naphthalenyl)-2-propenoate 2a Yellow oil (6.9 g, 95%, E:Z > 99:1) starting from 1-naphthaldehyde (4.3 mL). NMR data were in accordance with the literature.12 4.2.2. Ethyl-(E)-3-(4-methylphenyl)-2-propenoate 2b Yellow oil (6.1 g, 99%, E:Z > 99:1) starting from 4-methylbenzaldehyde (3.8 mL). NMR data were in accordance with the literature.13 4.2.3. Ethyl-(E)-3-(3,5-dimethylphenyl)-2-propenoate 2c Yellow oil (3.7 g, 98%, E:Z > 99:1) starting from 3,5-dimethylbenzaldehyde (2.5 g). mmax/cm1 1716, 1638, 1180, 1165, 1040, 982, 845, 677. 1H NMR (300 MHz, CDCl3) d 7.63 (1H, d, J = 16.1 Hz, CH), 7.14 (2H, s, Ar), 7.02 (1H, s, Ar), 6.41 (1H, d, J = 16.1 Hz, CH), 4.26 (2H, q, J = 7.3 Hz, CH2CH3), 2.33 (6H, s, ArCH3), 1.34 (3H, t, J = 7.3 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) d 167.05, 144.85, 138.32, 134.39, 131.94, 125.89, 117.83, 60.32, 21.11, 14.28. 4.2.4. Ethyl-(E)-3-(2-methylphenyl)-2-propenoate 2d Yellow oil (3.2 g, 97%, E:Z > 99:1) starting from 2-methylbenzaldehyde (2.0 mL). NMR data were in accordance with the literature.13 4.2.5. Ethyl-(E)-3-(2,4,6-trimethylphenyl)-2-propenoate 2e White solid (0.53 g, 53%, E:Z > 99:1) starting from 2,4,6-trimethylbenzaldehyde (0.68 g); mp 38.8–39.6 °C. NMR data were in accordance with the literature.14 4.2.6. Ethyl-(E)-3-(4-methylnaphthalen-1-yl)-2-propenoate 2f White solid (1.6 g, 95%, E:Z > 99:1) starting from 4-methyl-1naphthaldehyde (1.2 g); mp 76.9–77.9 °C; mmax/cm1 1703, 1632, 1306, 1183, 977, 830, 822, 759. 1H NMR (300 MHz, CDCl3) d 8.53 (1H, d, J = 15.9 Hz, CH), 8.25–8.21 (1H, m, Ar), 8.06–8.02 (1H, m, Ar), 7.66 (1H, d, J = 7.4 Hz, Ar), 7.60–7.56 (2H, m, Ar), 7.33 (1H, d, J = 7.4 Hz, Ar), 6.50 (1H, d, J = 15.9 Hz, CH), 4.33 (2H, q, J = 7.1 Hz, CH2CH3), 2.72 (3H, s, ArCH3), 1.39 (3H, t, J = 7.1 Hz, CH2CH3); 13C
NMR (75 MHz, CDCl3) d 167.03, 141.81, 137.23, 132.69, 131.41, 130.15, 126.43, 126.43, 126.02, 124.75, 123.92, 120.04, 60.51, 19.80, 14.37. 4.3. General procedure for the synthesis of alcohols 3a–f To a solution of the corresponding acrylic ester (1 equiv) in dry CH2Cl2 (5 mL per 1 mmol of ester), under argon, cooled to–30 °C, diisobutylaluminium hydride (1.2 M solution in toluene, 2 equiv) was added dropwise. The reaction mixture was stirred for 3 h at 30 °C. Ethanol (2 mL per 1 mmol of ester) was added followed by a saturated aqueous solution of potassium sodium tartrate (Rochelle salt, 3 mL per 1 mmol of ester). The layers were separated and the aqueous phase washed three times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.3.1. (E)-3-(1-Naphthalenyl)-prop-2-en-1-ol 3a Yellow oil (5.3 g, 99%) starting from 2a (6.5 g). NMR data were in accordance with the literature.15 4.3.2. (E)-3-(4-Methylphenyl)-prop-2-en-1-ol 3b White solid (4.0 g, 99%) starting from 2b (5.1 g). NMR data were in accordance with the literature.16 4.3.3. (E)-3-(3,5-Dimethylphenyl)-prop-2-en-1-ol 3c Yellow oil (0.79 g, 98%) starting from 2c (1.0 g). mmax/cm1 3410, 1698, 1682, 1603, 968, 852, 690. 1H NMR (300 MHz, CDCl3) d 7.02 (2H, s, Ar), 6.90 (1H, s, Ar), 6.56 (1H, d, J = 16.1 Hz, CH), 6.34 (1H, dt, J = 5.7, 16.1 Hz, CHCH2), 4.31 (2H, d, J = 5.7 Hz, CHCH2), 2.31 (6H, s, ArCH3), 1.54 (1H, br s, OH); 13C NMR (75 MHz, CDCl3) d 138.04, 136.60, 131.42, 129.45, 128.13, 124.39, 63.82, 21.23. 4.3.4. (E)-3-(2-Methylphenyl)-prop-2-en-1-ol 3d Yellow oil (0.75 g, 96%) starting from 2d (1.01 g). mmax/cm1 3330, 1486, 1459, 1110, 1086, 967, 746. 1H NMR (300 MHz, CDCl3) d 7.48–7.44 (1H, m, Ar), 7.20–7.15 (3H, m, Ar), 6.85 (1H, d, J = 15.8 Hz, CH), 6.26 (1H, dt, J = 5.7, 15.8 Hz, CHCH2), 4.35 (2H, d, J = 5.7 Hz, CHCH2), 2.37 (3H, s, ArCH3), 1.96 (1H, br s, OH); 13C NMR (75 MHz, CDCl3) d 135.75, 135.42, 130.23, 129.83, 128.86, 127.50, 126.04, 125.69, 63.80, 19.69. 4.3.5. (E)-3-(2,4,6-Trimethylphenyl)-prop-2-en-1-ol 3e White solid (0.50 g, 99%) starting from 2e (0.63 g). NMR data were in accordance with the literature.14
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4.3.6. (E)-3-(4-Methylnaphthalen-1-yl)-prop-2-en-1-ol 3f White solid (1.72 g, 99%) starting from 2f (2.12 g); mp 100.2– 101.1 °C; mmax/cm1 3340, 1412, 1015, 966, 840, 752. 1H NMR (300 MHz, CDCl3) d 8.16–8.13 (1H, m, Ar), 8.04–8.01 (1H, m, Ar), 7.57–7.49 (3H, m, Ar), 7.37 (1H, d, J = 15.7 Hz, CH), 7.30 (1H, d, J = 7.3 Hz, Ar), 6.36 (1H, dt, J = 5.7, 15.7 Hz, CHCH2), 4.43 (2H, d, J = 5.7 Hz, CHCH2), 2.70 (3H, s, ArCH3), 1.61 (1H, br s, OH), 13C NMR (75 MHz, CDCl3) d 134.36, 132.83, 132.63, 131.23, 131.08, 128.56, 126.50, 125.71, 125.65, 124.65, 124.31, 123.71, 64.04, 19.60. 4.4. General procedure for the synthesis of trichloroacetimidates 4a–f To a solution of the corresponding alcohol (1 equiv) and DBU (0.2 equiv) in dry CH2Cl2 (6 mL per 1 mmol of alcohol) at 0 °C, trichloroacetonitrile (1.1 equiv) was added dropwise. The reaction mixture was stirred for 15 min. The solvent was evaporated to give a brown residue which was filtered through a short column of neutral aluminium oxide, activity I (eluent EtOAc/hexane = 10:90) to afford the product. 4.4.1. (E)-3-(1-Naphthalenyl)allyl-2,2,2-trichloroacetimidate 4a Yellow oil (9.0 g, 95%) starting from 3a (5.3 g). mmax/cm1 3340, 1667, 1306, 1079, 970, 795. 1H NMR (300 MHz, CDCl3) d 8.42 (1H, br s, NH), 8.11 (1H, d, J = 8.0 Hz, Ar), 7.87–7.79 (2H, m, Ar), 7.64 (1H, d, J = 7.1 Hz, Ar), 7.56–7.43 (4H, m, Ar, CH), 6.43 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.10 (2H, d, J = 5.9 Hz, CHCH2); 13 C NMR (75 MHz, CDCl3) d 162.57, 133.96, 133.61, 131.51, 131.16, 128.58, 128.47, 126.25, 125.88, 125.58, 125.53, 124.15, 123.66, 69.71. 4.4.2. (E)-3-(4-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4b Yellow oil (3.97 g, 89%) starting from 3b (2.27 g). mmax/cm1 3344, 1716, 1664, 1308, 1289, 1078, 968, 798. 1H NMR (300 MHz, CDCl3) d 8.35 (1H, br s, NH), 7.32 (2H, d, J = 8.0 Hz, Ar), 7.14 (2H, d, J = 8.0 Hz, Ar), 6.73 (1H, d, J = 15.9 Hz, CH), 6.35 (1H, dt, J = 6.3, 15.9 Hz, CHCH2), 4.96 (2H, dd, J = 1.2, 6.3 Hz, CHCH2), 2.35 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.58, 138.07, 134.59, 133.36, 129.30, 126.62, 121.24, 69.93, 21.22. 4.4.3. (E)-3-(3,5-Dimethylphenyl)allyl-2,2,2-trichloroacetimidate 4c Yellow oil (1.34 g, 93%) starting from 3c (0.77 g). mmax/cm1 3376, 1696, 1608, 1381, 1110, 968, 837. 1H NMR (300 MHz, CDCl3) d 8.35 (1H, br s, NH), 7.05 (2H, s, Ar), 6.92 (1H, s, Ar), 6.70 (1H, d, J = 15.8 Hz, CH), 6.37 (1H, dt, J = 6.3, 15.8 Hz, CHCH2), 4.96 (2H, dd, J = 1.2, 6.3 Hz, CHCH2), 2.32 (6H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.60, 138.08, 136.09, 134.81, 129.88, 124.60, 121.93, 69.88, 21.21. 4.4.4. (E)-3-(2-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4d Yellow oil (1.3 g, 94%) starting from 3d (0.70 g). mmax/cm1 3343, 1668, 1308, 1285, 1078, 968, 798, 745. 1H NMR (300 MHz, CDCl3) d 8.37 (1H, br s, NH), 7.49–7.45 (1H, m, Ar), 7.20–7.15 (3H, m, Ar), 6.99 (1H, d, J = 15.9 Hz, CH), 6.28 (1H, dt, J = 6.1, 15.9 Hz, CHCH2), 5.00 (2H, dd, J = 1.4, 6.1 Hz, CHCH2), 2.36 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.54, 135.73, 135.34, 132.22, 130.34, 127.99, 126.14, 125.84, 123.60, 69.78, 19.72. 4.4.5. (E)-3-(2,4,6-Trimethylphenyl)allyl-2,2,2-trichloroacetimidate 4e Colorless oil (0.87 g, 95%) starting from 3e (0.5 g). mmax/cm1 3346, 1667, 1302, 1078, 979, 794. 1H NMR (300 MHz, CDCl3) d 8.36 (1H, br s, NH), 6.87 (2H, s, Ar), 6.75 (1H, d, J = 16.3 Hz, CH),
939
5.90 (1H, dt, J = 6.1, 16.3 Hz, CHCH2), 5.00 (2H, dd, J = 1.2, 6.1 Hz, CHCH2), 2.27 (9H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.47, 136.56, 135.89, 132.99, 132.79, 128.59, 127.24, 69.70, 20.91, 20.76. 4.4.6. (E)-3-(4-Methylnaphthalen-1-yl)-allyl-2,2,2-trichloroacetimidate 4f Yellow oil (2.86 g, 96%) starting from 3f (1.72 g). mmax/cm1 3375, 1695, 1385, 1112, 968, 835, 753. 1H NMR (300 MHz, CDCl3) d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar), 8.04–8.02 (1H, m, Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d, J = 7.44 Hz, Ar), 6.39 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H, dd, J = 1.3, 6.0 Hz, CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.60, 134.84, 132.65, 132.35, 131.89, 131.24, 126.49, 125.89, 125.73, 124.79, 124.70, 124.24, 123.94, 69.88, 19.67. 4.4.7. (E)-3-Phenylallyl-2,2,2-trichloroacetimidate 4g Yellow oil (1.06 g, 98%) starting from cinammyl alcohol (0.52 g).7a 4.5. General procedure for the synthesis of amides 5a–g To a solution of the corresponding trichloroacetimidate (1 equiv) in xylene (6 mL per 1 mmol of trichloroacetimidate), K2CO3 (2 mg/mL xylene) was added and the mixture was refluxed at 140 °C for 24 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and filtered through a short column of silica gel (eluent toluene) to give a product. 4.5.1. 2,2,2-Trichloro-N-[1-(1-naphthalenyl)allyl]acetamide 5a White solid (7.75 g, 96%) starting from 4a (8.08 g); mp 109.3– 110.2 °C; C15H12Cl3NO requires C, 54.82; H, 3.68; N, 4.26, found: C, 55.28; H, 3.52; N, 4.00. mmax/cm1 3284, 1685, 1526, 838, 823, 804. 1H NMR (300 MHz, CDCl3) d 8.03 (1H, d, J = 8.2 Hz, Ar), 7.89 (2H, t, J = 9.2 Hz, Ar), 7.61–7.45 (4H, m, Ar), 6.89 (1H, br s, NH), 6.38–6.32 (1H, m, CHNH), 6.25 (1H, ddd, J = 4.4, 10.3, 17.3 Hz, CHCH2), 5.46 (1H, d, J = 10.3, CH2CH), 5.41 (1H, d, J = 17.3, CH2CH); 13 C NMR (75 MHz, CDCl3) d 161.02, 135.36, 134.27, 134.09, 131.13, 129.48, 129.00, 127.09, 126.26, 125.25, 125.20, 123.03, 116.74, 53.29. 4.5.2. 2,2,2-Trichloro-N-[1-(4-methylphenyl)allyl]acetamide 5b White solid (3.56 g, 95%) starting from 4b (3.74 g); mp 78.5– 79.1 °C. mmax/cm1 3297, 1695, 1523, 837, 819, 805. 1H NMR (300 MHz, CDCl3) d 7.20 (4H, s, Ar), 6.89 (1H, br s, NH), 6.04 (1H, ddd, J = 5.3, 10.3, 17.2 Hz, CHCH2), 5.56–5.49 (1H, m, CHNH), 5.33 (1H, d, J = 10.3, CH2CH), 5.30 (1H, d, J = 17.2, CH2CH), 2.35 (3H, s, ArCH3) ; 13C NMR (75 MHz, CDCl3) d 160.88, 138.18, 135.81, 135.74, 129.73, 127.07, 116.83, 56.85, 21.14. 4.5.3. 2,2,2-Trichloro-N-[1-(3,5-dimethylphenyl)allyl]acetamide 5c White solid (2.84 g, 95%) starting from 4c (2.98 g); mp 85.8– 86.8 °C. mmax/cm1 3294, 1698, 1529, 831, 822. 1H NMR (300 MHz, CDCl3) d 6.97 (1H, s, Ar), 6.93 (2H, s, Ar), 6.86 (1H, br s, NH), 6.04 (1H, ddd, J = 5.3, 10.1, 17.4 Hz, CHCH2), 5.52–5.46 (1H, m, CHNH), 5.33 (1H, d, J = 10.1, CH2CH), 5.32 (1H, d, J = 17.4, CH2CH), 2.33 (6H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.84, 138.73, 138.69, 135.82, 129.98, 124.89, 116.58, 57.07, 21.30. 4.5.4. 2,2,2-Trichloro-N-[1-(2-methylphenyl)allyl]acetamide 5d White solid (1.69 g, 96%) starting from 4d (1.75 g); mp 69.2– 69.9 °C. mmax/cm1 3300, 1690, 1516, 836, 823, 758, 726. 1H NMR (300 MHz, CDCl3) d 7.24 (4H, s, Ar), 6.79 (1H, br s, NH), 6.06 (1H, ddd, J = 4.6, 10.4, 17.2 Hz, CHCH2), 5.77–5.72 (1H, m, CHNH), 5.35 (1H, d, J = 10.4, CH2CH), 5.26 (1H, d, J = 17.2, CH2CH), 2.39 (3H, s,
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ArCH3); 13C NMR (75 MHz, CDCl3) d 136.68, 135.40, 131.09, 128.36, 126.57, 126.49, 116.59, 53.86, 19.09. 4.5.5. 2,2,2-Trichloro-N-[1-(2,4,6-trimethylphenyl)allyl]acetamide 5e Colorless oil (0.86 g, 95%) starting from 4e (0.91 g). mmax/cm1 3445, 1716, 1508, 837, 820, 737, 680. 1H NMR (300 MHz, CDCl3) d 7.23 (1H, br s, NH), 6.87 (2H, s, Ar), 6.11–5.96 (2H, m, CHCH2, CHNH), 5.27 (1H, d, J = 10.4, CH2CH), 5.12 (1H, d, J = 17.0, CH2CH), 2.40 (6H, s, ArCH3), 2.27 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.95, 137.61, 136.30, 135.74, 131.81, 130.25, 116.19, 53.02, 20.79, 20.60. 4.5.6. 2,2,2-Trichloro-N-[1-(4-methylnaphthalen-1-yl)allyl]acetamide 5f White solid (2.92 g, 95%) starting from 4f (3.08 g). mp 116.4– 117.2 °C. mmax/cm1 3316, 1687, 1507, 826, 760. 1H NMR (300 MHz, CDCl3) d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar), 8.04–8.02 (1H, m, Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d, J = 7.44 Hz, Ar), 6.39 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H, dd, J = 1.3, 6.0 Hz, CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.98, 135.85, 135.48, 133.23, 132.43, 131.16, 126.72, 126.10, 125.96, 125.08, 123.54, 116.53, 53.26, 19.66. 4.5.7. 2,2,2-Trichloro-N-(1-phenylallyl)acetamide 5g White solid (1.03 g, 97%) starting from 4g (1.06 g).7a 4.6. General procedure for the synthesis of racemic amines 6a–g To a solution of the corresponding amide (1 equiv) in absolute ethanol (5 mL per 1 mmol of amide), 5 M NaOH solution in water (30 equiv) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to an aqueous residue which was acidified to pH 1 by the addition of 6 M HCl and washed three times with CH2Cl2. Next, Na2CO3 was added to the aqueous layer until pH 8. The mixture was then extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.6.1. 1-(1-Naphthalenyl)-prop-2-en-1-amine 6a Yellow oil (3.82 g, 88%) starting from 5a (7.75 g). mmax/cm1 3300, 1669, 1638, 1594, 1393, 802, 779. 1H NMR (300 MHz, CDCl3) d 8.19 (1H, d, J = 8.2 Hz, Ar), 7.91–7.85 (1H, m, Ar), 7.81–7.75 (1H, m, Ar), 7.62–7.43 (4H, m, Ar), 6.23 (1H, ddd, J = 5.2, 10.4, 17.5 Hz, CHCH2), 5.40–5.31 (2H, m, CH2CH, CHNH2), 5.23 (1H, d, J = 10.4 Hz, CH2CH), 2.29 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 141.24, 139.60, 133.95, 130.92, 128.88, 127.84, 126.05, 125.53, 123.52, 123.32, 114.55, 53.84. 4.6.2. 1-(4-Methylphenyl)-prop-2-en-1-amine 6b Yellow oil (1.34 g, 79%) starting from 5b (3.36 g). mmax/cm1 3375, 3300, 1638, 1511, 917, 818, 761. 1H NMR (300 MHz, CDCl3) d 7.24 (2H, d, J = 7.9 Hz , Ar), 7.15 (2H, d, J = 7.9 Hz, Ar), 6.02 (1H, ddd, J = 6.1, 10.2, 17.1 Hz, CHCH2), 5.23 (1H, d, J = 17.1, CH2CH), 5.10 (1H, d, J = 10.2, CH2CH), 4.50 (1H, d, J = 6.1 Hz, CHNH2), 2.34 (3H, s, ArCH3), 1.66 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 142.37, 141,46, 136.70, 129.19, 126.49, 113.47, 58.06, 21.02. 4.6.3. 1-(3,5-Dimethylphenyl)-prop-2-en-1-amine 6c Yellow oil (0.80 g, 76%) starting from 5c (2.00 g). mmax/cm1 3375, 1638, 1607, 1466, 995, 918, 848, 734. 1H NMR (300 MHz, CDCl3) d 6.96 (2H, s, Ar), 6.90 (1H, s, Ar), 6.02 (1H, ddd, J = 6.1, 10.2, 17.1 Hz, CHCH2), 5.25 (1H, d, J = 17.1, CH2CH), 5.11 (1H, d, J = 10.2, CH2CH), 4.46 (1H, d, J = 6.1 Hz, CHNH2), 2.32 (6H, s, ArCH3), 1.63 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 144.38, 142.35, 138.06, 128.71, 124.37, 113.41, 58.31, 21.25.
4.6.4. 1-(2-Methylphenyl)-prop-2-en-1-amine 6d Yellow oil (0.30 g, 77%) starting from 5d (0.77 g). 1H NMR (300 MHz, CDCl3) d 7.39 (1H, d, J = 7.2 Hz, Ar), 7.25–7.13 (3H, m, Ar), 6.02 (1H, ddd, J = 5.7, 10.2, 17.2 Hz, CHCH2), 5.20 (1H, d, J = 17.2, CH2CH), 5.12 (1H, d, J = 10.2, CH2CH), 4.76 (1H, d, J = 5.7 Hz, CHNH2), 2.38 (3H, s, ArCH3), 1.90 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 142.06, 141.34, 135.34, 130.48, 126.92, 126.33, 125.72, 113.85, 54.19, 19.17. 4.6.5. 1-(2,4,6-Trimethylphenyl)-prop-2-en-1-amine 6e Yellow oil (0.38 g, 87%) obtained after silica gel column chromatography (CH2Cl2–MeOH, 9:1, Rf = 0.44) starting from 5e (0.80 g). mmax/cm1 3400, 1669, 1662, 1611, 1383, 1266, 917, 852, 737. 1H NMR (300 MHz, CDCl3) d 6.83 (2H, s, Ar), 6.14 (1H, ddd, J = 4.1, 10.3, 17.0 Hz, CHCH2), 5.17 (1H, d, J = 17.0, CH2CH), 5.12 (1H, d, J = 10.3, CH2CH), 5.02–4.97 (1H, m, CHNH2), 2.37 (6H, s, ArCH3), 2.25 (3H, s, ArCH3), 1.60 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 141.26, 137.22, 136.22, 130.11, 113.03, 53.32, 20.79, 20.68. 4.6.6. 1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine 6f Yellow oil (0.48 g, 91%) obtained after silica gel column chromatography (CH2Cl2–MeOH, 9:1, Rf = 0.54) starting from 5e (0.91 g). mmax/cm1 3375, 1637, 1598, 1391, 1264, 920, 836, 755. 1H NMR (300 MHz, CDCl3) d 8.26–8.20 (1H, m, Ar), 8.08– 8.02 (1H, m, Ar), 7.58–7.52 (2H, m, Ar), 7.47 (1H, d, J = 7.2 Hz, Ar), 7.32 (1H, d, J = 7.2 Hz, Ar), 6.22 (1H, ddd, J = 5.7, 10.3, 17.1 Hz, CHCH2), 5.39–5.29 (2H, m, CH2CH, CHNH2), 5.22 (1H, d, J = 10.3, CH2CH), 2.69 (3H, s, ArCH3), 1.78 (2H, br s, NH2); 13 C NMR (75 MHz, CDCl3) d 141.70, 138.08, 133.35, 133.07, 131.05, 126.35, 125.72, 125.43, 124.97, 123.92, 123.28, 114.28, 53.85, 19.59. 4.6.7. 1-Phenyl-prop-2-en-1-amine 6g Yellow oil (0.35 g, 73%) starting from 5g (1.01 g). NMR data were in accordance with the literature.11 4.7. General procedure for the enzymatic resolution of racemic amines The racemic amine (1 equiv) was dissolved in a mixture of iso-propyl acetate (14 mL per 1 mmol of amine) and hexane (2 mL per 1 mmol of hexane). Immobilized lipase B from C. antarctica, Novozym 435 (0.3 g per 1 mmol of amine) was added. The reaction mixture was stirred at 30 °C. The progress of the reaction was monitored using HPLC, on Chiralcel OD-H column (hexane–2-propanol–diethylamine, 90:10:0.1). After completion of the reaction, the reaction mixture was filtered and the filtrate concentrated. Next, 1 M HCl was added (3.5 mL per 1 mmol of starting amine). The mixture was washed three times with dichloromethane. Next, Na2CO3 was added to the aqueous layer until pH 8 was obtained. The mixture was extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 4.7.1. (S)-1-(1-Naphthalenyl)-prop-2-en-1-amine (S)-6a Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 300 nm, tR(S) = 9.0 min, tR(R) = 10.1 min; ½a25 D ¼ 46:0 (c 0.9, CHCl3). 4.7.2. (S)-1-(4-Methylphenyl)-prop-2-en-1-amine (S)-6b Yield 39%, ee 98.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 268 nm, tR(R) = 5.7 min, tR(S) = 6.4 min; ½a25 D ¼ 9:7 (c 1.1, CH2Cl2).
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4.7.3. (S)-1-(3,5-Dimethylphenyl)-prop-2-en-1-amine (S)-6c Yield 39%, ee 80.6%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 90:10:0.1, 1 mL/min, 240 nm, tR(R) = 5.0 min, tR(S) = 5.3 min. 4.7.4. (S)-1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine (S)6f Yield 48%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 95:5:0.1, 1 mL/min, 300 nm, tR(S) = 11.7 min, tR(R) = 13.3 min; ½a25 D ¼ 40:2 (c 3.2, CH2Cl2). 4.7.5. (S)-1-Phenyl-prop-2-en-1-amine (S)-6g Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propanol-diethylamine, 95:5:0.2, 1 mL/min, 254 nm, tR(R) = 7.4 min, tR(S) = 9.1 min; ½a25 D ¼ 10:2 (c 3.3, CHCl3); lit. value ascribed for (S)11 6g with ee >99.6% is ½a25 D ¼ 10:45 (c 4, CHCl3). Acknowledgments This work was supported by Ministry of Science, Education, and Sports of Croatia (Grant No. 098-0982904-2910). References 1. (a) Breuer, M.; Dietrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824; (b)Asymmetric Organic Synthesis with Enzymes; Gotor, V., Alfonso, I., Garciá-Urdiales, E., Eds.; WileyVCH Verlag GmbH & Co. KGaA: Weinheim, 2008; (c)Chiral Amine Synthesis, Methods, Developments and Applications; Nugent, T. C., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2010.
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