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Enantioselective addition of amines to alkenoyl-N-oxazolidinones
Tetrahedron 61 (2005) 6237–6242
Enantioselective addition of amines to alkenoyl-N-oxazolidinones Kelin Li, Pim Huat Phua and King Kuok (Mimi) Hii* Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK Received 4 November 2004; revised 4 February 2005; accepted 4 March 2005 Available online 20 April 2005
Abstract—Investigations of cationic Pd(II) complex 1 as hydroamination catalysts led to the development of highly enantioselective addition of aromatic amines to alkenoyl-N-oxazolidinones, with ee values up to 93%. Factors affecting the yield and selectivity of the reaction were described. Addition of substituted benzylamines to these Michael acceptors was also attempted, and was found to be reversible under catalytic conditions. q 2005 Published by Elsevier Ltd.
1. Introduction The catalysed addition of N–H across C–C double bonds (hydroamination) is one of the most attractive atomeconomical processes (Scheme 1). If the alkene substrate is activated towards nucleophilic attack by the presence of electron-withdrawing substituents (e.g., keto, ester or nitrile groups), the reaction is also sometimes referred to as an aza-Michael (1,4-conjugate) addition. With prochiral alkenes, the reaction poses additional challenges in regioand enantioselectivity.
oxazolidinones 2 at room temperature were accomplished with good enantioselectivity (Scheme 2, Eq. 4).3 This paper will detail the course of our investigation of this latter
Scheme 1. Asymmetric hydroamination reaction.
Previously, we reported the development of air- and moisture-stable palladium catalysts for the hydroamination of olefins under pH neutral conditions at low catalytic loadings,1,2 including a class of air- and moisture-stable dicationic palladium complexes that mediates the addition of a range of amines to acyclic olefins. Among these, the chiral complex [(BINAP)Pd (solvent)]2C[TfO]K2 (1) catalyses the enantioselective addition of aniline to styrene at elevated temperatures (Scheme 2, Eq. 1).2 With methyl crotonate, addition of cyclic and aromatic amines may be effected at room temperature (Scheme 2, Eqs. 2 and 3), but ee’s were disappointingly low (no more than 24%). Introducing an achiral template on the olefin substrate, the addition of primary aromatic amines to the alkenoyl-NKeywords: Enantioselective addition; Hydroamination; Alkenoyl-Noxazolidinones. * Corresponding author. Tel.: C44 20 7594 1142; fax: C44 20 7594 5804; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd. doi:10.1016/j.tet.2005.03.125
Scheme 2. Asymmetric hydroamination reactions catalysed by complex 1.
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Table 1. Effect of solvent, catalyst loading and ratio of substrate on the hydroamination of 2a with aniline (Scheme 2, Eq. 4)a Entry
Catalyst loading (mol%)
2a: aniline
Solvent
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11
2 2 2 2 5 10 20 10 10 10 10
1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:4 1:1 1.5:1 1.5:1
Toluene CH3CN CH2Cl2 THF Toluene Toluene Toluene Toluene Toluene Toluene THF
25 4 16 19 34 48 80 45 64 93 31
10 19 6 1 45 51 85 22 89 93 60
a b c
Reactions were conducted in toluene at 25 8C for 18 h. Calculated by 1H NMR spectroscopy. Determined by chiral HPLC (Daicel Chiralpak AD).
process, and subsequent exploration of its scope and limitations.4
2. Results and discussion 2.1. Effect of catalyst loading, solvent and ratio of substrates Effects of solvent, catalyst loading and substrate ratios on the addition of aniline to 2a were studied and results are summarised in Table 1. Employing an initial catalyst loading of 2 mol% at room temperature, the highest conversion was obtained with toluene as the solvent, but ee was low (Table 1, entry 1). In contrast, an improved ee may be obtained in acetonitrile, but the yield was extremely low (entry 2). Dichloromethane furnished low yield and ee (entry 3), whereas THF afforded practically very low enantioselectivity (entries 4 and 11). These observations led us to conclude that coordinating solvents are detrimental to the catalytic activity, hence, toluene was employed as the solvent of choice in further studies. Unsurprisingly, increased catalyst loading from 2 to 20 mol% resulted in improvements in yield and ee of the process (entries 5–7). Although a high ee of 85% may be obtained with 20, 10 mol% of catalyst were consequently employed in the following optimisation work.
oxazolidinone 2a generally proceeded with good yields at room temperature. In all cases, very good conversions (85–90%) were obtained in 18 h. Among the primary aromatic amines, addition of aniline proceeded with the best ee (93%, entry 1). Interestingly, the presence of an electronwithdrawing Cl substituent did not appear to alter the yield or selectivity significantly (entry 2), whereas the addition of increasingly electron-rich amines such as p-toluidine and p-anisidine gave products with significantly reduced ee values (entries 3 and 4). Changing the substituent of the alkenoyl functionality retarded the rate of the reactions dramatically—the addition to pentenoyl oxazolidinone 2b was considerably slower at room temperature. Performing these reactions at an elevated temperature (60 8C), modest ee of 47% was obtained for aniline (entry 5), compared with the electron rich p-toluidine (32% ee, entry 7). But for 4-chloroaniline, good yield and ee of 93 and 75% were obtained, respectively (entry 6). The addition of the more nucleophilic p-anisidine may be effected at room temperature, but enantioselectivity was low (entry 8). Extending the homology, the addition to hexenoyl oxazolidinone 2c proceeded in even lower selectivity, ranging from 10 to 50% (entries 9–10).
Interestingly, employing an excess of the aniline substrate has a negative effect on the enantioselectivity of the reaction (entry 8). More crucially, catalyst decomposition was observed when an excess of the amine substrate was employed, leading to a poor yield of the product. Increasing the relative stoichiometry of the olefin substrate led to improvements in the turnover and selectivity (entry 9). The optimal ratio appears to be 1.5:1 where 93% yield and 93% ee were obtained (entry 10).
The results presented above suggests there is no apparent correlation between the nucleophilicity of the amine and reactivity, as might be expected. In the addition to 2a, aniline appears to have the same activity as p-chloroaniline (entries 1 and 2). On the other hand, the addition of the least nucleophilic amine to 2b appeared to be faster than aniline and toluidine at 60 8C (entries 5–7), while at the same time, the addition of anisidine proceeded at room temperature (entry 8). A different order of activity was again observed for the addition to 2c: p-chloroanilinewp-toluidineO p-anisidineOaniline (entries 9–12). In light of these observations, it is highly unlikely that the reactions proceed solely via Lewis-acid catalysis.
2.2. Reaction scope and reactivity
2.3. Generating the catalyst in situ
Having established the most favourable reaction conditions, the addition of different aromatic amines to alkenoyl oxazolidinones 2a–c was examined (Table 2).
It is often possible, and more convenient, to generate active catalysts in situ from suitable catalyst precursors, as this will also greatly facilitate ligand screening and catalyst discovery. To this end, we attempted to generate catalyst 1 by mixing [Pd(NCMe)4]2C[OTf]K2 with BINAP in toluene
The addition of primary aromatic amines to crotonyl
K. Li et al. / Tetrahedron 61 (2005) 6237–6242
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Table 2. Addition of anilines to a,b-unsaturated oxazolidinones (Scheme 2, Eq. 4)a Entry
R1
R2
Product
T (8C)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12
Me (2a) Me (2a) Me (2a) Me (2a) Et (2b) Et (2b) Et (2b) Et (2b) n Pr (2c) n Pr (2c) n Pr (2c) n Pr (2c)
H Cl Me OMe H Cl Me OMe H Cl Me OMe
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l
25 25 25 25 60 60 60 25 60 60 60 60
90 90 85 85 70 93 54 50 69 85 86 75
93 92 68 24 47 75 32 9 50 26 18 10
a b c
Reactions were conducted in toluene with 10 mol% catalyst 1 for 18 h. Isolated yields after column chromatography. Determined by chiral HPLC (Daicel Chiralpak AD).
(metal-to-ligand ratio of 1:1), for the addition of aniline to 2a (Scheme 3). However, the catalyst generated in this way is not as active as the isolated complex 1—affording the product 3a in only 57% yield with an ee of 78% after 18 h. In fact, more than 40 h were required before the reaction gave comparable results to that afforded by the isolated catalyst 1 (89% yield and 81% ee). The catalyst turnover was also found to be sensitive to the relative quantity of the ligand employed: A mere 0.2 equiv excess (i.e., 1:1.2 metalto-ligand ratio) led to a decrease in yield and selectivity (59% yield and 65% ee after 40 h). We speculate that this is due to the formation of a catalytically less active species, such as [Pd(BINAP)2]2C[OTf]K2. Attempts were also made to generate active catalysts in situ by mixing chiral bisoxazolidine ligands 5 and 6 and [Pd(NCMe)4]2C[OTf]K2 in a metal-to-ligand ratio of 1:1. In both cases, the addition of aniline to 2a only gave 3a as a racemic mixture in less than 30% yield (18 h).
selectivity (Scheme 4). It is somewhat surprising that the palladium complex should catalyse the addition of both primary and secondary aromatic amines with equal efficacy, given the different electronic and steric natures of these substrates. 2.4. Addition of benzylamine Uncatalysed addition of benzylamines to 2a occurs slowly in toluene under ambient conditions. In the presence of 1, low to moderate yields and ee’s of products 7 may be obtained in 2 h (Scheme 5, Table 3).
Scheme 5.
However, the optical activity of the reaction mixture plummets to between 3 and 7% ee after 18–48 h, whilst the conversion remained unchanged, thus, signifying that the addition of benzyl amines to 2a is reversible under these conditions.6 2.5. Amine salt control Scheme 3. Generating catalysts in situ.
Previously, the addition of the secondary aromatic amine N-methyl aniline to substrate 2a has been effected by a catalyst generated in situ from Ni(ClO4)2 and chiral bisoxazolidine ligand 5: the product 4 was found to have a high ee (90%), but the yield obtained after 40 h was only moderate (62%).5 In comparison, complex 1 catalysed the addition of the secondary amine to 2a with comparable
Sodeoka et al. reported an improvement in the yield and selectivity by employing trifluoromethanesulfonate salts of the aromatic amines as substrates,4 as they postulate that the use of the free amine leads to an uncatalysed reaction. Indeed, uncatalysed slow addition of p-anisidine (1.5 equiv) to N-oxazolidinone 2a do occur slowly in solution (12%, 18 h, 25 8C), which was inhibited when p-anisidine$HOTf salt was used. Nevertheless, we failed to observe any addition of the p-anisidine$HOTf to 2a in the presence of catalyst 1.
3. Conclusion Scheme 4. Addition of N-methyl aniline to 2a.
Various aspects of the enantioselective addition of amines to
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Table 3. Addition of substituted benzyl amines to 2aa Entry
R1
R2
Product
Yieldb (%)
ee (%)c
1 2 3 4 5
H OCH3 H Br H
H OCH3 OCH3 H CH3
7a 7b 7c 7d 7e
57 52 52 61 47
41 46 39 7 33
a
Reaction were conducted in toluene with 10 mol% catalyst 1 at 25 8C for 2 h. Calculated by 1H NMR spectroscopy. c Determined by chiral HPLC (Daicel Chiralpak AD). b
N-alkenoyl oxazolidinones catalysed by the cationic diphosphine–palladium complex 1 have been presented. The catalytic activity and selectivity are much more sensitive to the steric and electronic nature of the olefin substrate. Hence, the chelating dicarbonyl moiety of the olefin substrate was identified as the key stereocontrolling element. In subsequent work, we modified the achiral template by replacing the oxazolidinone ring by a carbamate moiety (substrate 8, Fig. 1), which led to a significant enhancement in the activity and selectivity of the conjugate addition process.7 Recently, highly enantioselective addition of carbamates to the a 0 -hydroxy enone 9 (Fig. 1) was reported by Palomo et al.8 (using Evan’s bis-oxazoline copper complexes as catalysts), capitalising a hydroxyketone moiety in the olefin substrate as a mode of chelation to the metal centre, presumably promoted by the gemdialkyl groups.
Service at University of North London. High Resolution Mass spectra (HRMS) were recorded using Electrospray (ES) ionisation technique on a Micromass ‘Q-TOF’ spectrometer. Optical purity were measured using a Gilson HPLC system fitted with a Daicel Chiralpak AD column, with UV detection at 215 nm. Optical rotation values were measured on a Perkin–Elmer polarimeter 343 using a 10 cm solution cell, concentration of the samples was indicated as g/mL, given in the parenthesis. Melting points (uncorrected) were determined on an Electrothermal Gallenhamp apparatus. 3-(E)-2-butenoyl-1,3-oxazolidin-2-one,9 3-(E)-2-pentenoyl-2-oxazolidinone,10 3-(E)-2-hexenoyl-1,3-oxazolidin-2-one,11 and [Pd(NCMe)4]2C(OTf)K212 were synthesised according to literature methods. All other compounds were procured from commercial sources and used as received. Palladium salts were obtained from Johnson Matthey plc through a loan agreement. 4.1. General procedure for the hydroamination of compound 2 with primary amines
Figure 1. Olefin substrates 2, 8 and 9 containing chelating functionalities.
Work is currently underway to discern the mechanism of these addition reactions and to examine the conjugate addition of amines to other modified olefin substrates, these will be reported in due course. Current endeavours also include the design and identification of more active and selective catalysts for other asymmetric hydroamination reactions.
4. Experimental All manipulations were performed using standard Schlenk techniques. Dichloromethane, toluene and acetonitrile were dried over CaH2, distilled and stored under a nitrogen atmosphere. THF was dried over Na/benzophenone. NMR spectra were recorded on a Bruker Avance 360 instrument (1H at 360 MHz and 13C at 90.6 MHz). The chemical shifts are reported in d (ppm) referenced to residual protons and 13 C signals of deuterated chloroform. Infra-red spectra were recorded on a Perkin–Elmer 1600 FTIR spectrometer. Elemental analysis was provided by the Elemental Analysis
0.022 g (0.020 mmol) of complex 1 and the olefin substrate 2 (0.30 mmol) were placed in a thick-walled Young’s tube, which was purged with N2. 1.0 mL of toluene and the appropriate amine (0.20 mmol) were added. The tube was sealed via a PTFE tap and the reaction mixture was stirred and heated in a thermostatic oil bath. After the appropriate time, the homogeneous solution was subjected to column chromatography (SiO2) to furnish the product. 4.1.1. 3-(3-Anilinobutanoyl)-1,3-oxazolidin-2-one (3a). Purified by column chromatography (ether/pentaneZ1:3, Rf 0.3) gave a white solid (Found: C, 62.7; H, 6.8; N, 11.0%; MC, 248.1155. C13H16N2O3 requires C, 62.9; H, 6.5; N, 11.3%; MC 248.1161); mp 114–115 8C (from EtOAc/ hexane); 86% ee (Chiral HPLC, i-PrOH/hexaneZ20:80, 1.0 mL/min, tmajor 14.2 min, tminor 18.8 min); [a]20 D ZC8.1 (cZ0.017 in CHCl3); nmax (KBr)/cmK1 3363, 1771, 1694, 1605, 1392, 1140, 760, 700; dH (360 MHz, CDCl3) 7.16 (2H, t, JZ7.7 Hz, Ph), 6.68 (1H, t, JZ7.3 Hz, Ph), 6.62 (2H, d, JZ7.3 Hz, Ph), 4.24–4.36 (2H, m, OCH2), 4.08– 4.17 (1H, m, NHCH), 3.84–3.95 (2H, m, NCH2), 3.79 (1H, br s, PhNH), 3.34 (1H, dd, JZ7.3, 15.4 Hz, COCH2), 3.00 (1H, dd, JZ5.9, 15.4 Hz, COCH2), 1.30 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.7 (CO), 153.7 CO), aromatic C [146.9, 129.3, 117.6, 113.6], 61.9 (OCH2), 46.3 (NCH2), 42.4 (CH), 41.4 (COCH2), 21.3 (CH3). 4.1.2. 3-[3-(4-Chlorophenylamino)butanoyl]-1,3-oxazolidin-2-one (3b). Purified by column chromatography (ether/pet. etherZ3:1, Rf 0.35) gave a white solid (Found: C, 55.1; H, 5.5; N, 9.9%; MC, 282.0767. C13H15ClN2O3
K. Li et al. / Tetrahedron 61 (2005) 6237–6242
requires C, 55.2; H, 5.35; N, 9.9%; MC 282.0771); mp 84– 85 8C (from EtOAc/hexane); 92% ee (Chiral HPLC, i-PrOH/hexaneZ30:70, 1.0 mL/min, tmajor 12.6 min, tminor 16.2 min); [a]20 D ZK0.7 (cZ0.017 in CHCl3); nmax (KBr)/ cmK1 3374, 1771, 1691, 1604, 1514, 1390, 814; dH (360 MHz, CDCl3) 7.09 (2H, d, JZ9.1 Hz, Ph), 6.57 (2H, d, JZ9.1 Hz, Ph), 4.29–4.40 (2H, m, OCH2), 4.01–4.10 (1H, m, NHCH), 3.88–3.99 (2H, m, NCH2), 3.83 (1H, br s, NH), 3.32 (1H, dd, JZ6.8, 15.4 Hz, COCH2), 2.98 (1H, dd, JZ5.5, 15.4 Hz, COCH2), 1.28 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.6 (CO), 153.7 CO), aromatic C (145.5, 129.1, 122.1, 114.6), 62.0 (OCH2), 46.4 (NCH2), 42.4 (CH), 41.2 (COCH2), 21.0 (CH3). 4.1.3. 3-{3-[(4-Methylphenyl)amino]butanoyl}-1,3-oxazolidin-2-one (3c). Purified by column chromatography (ether/pentaneZ1:1, Rf 0.18) gave a white solid (Found: C, 64.2; H, 7.05; N, 10.6%; MC, 262.1312. C14H18N2O3 requires C, 64.1; H, 6.9; N, 10.7%; MC, 262.1317); mp 70–71 8C (from EtOAc/hexane); 68% ee (Chiral HPLC, i-PrOH/hexaneZ30:70, 1.0 mL/min, tmajor 11.7 min, tminor 17.1 min); [a]20 D ZC0.47 (cZ0.021 in CHCl3); nmax (KBr)/ cmK1 1770, 1684, 1522, 1395, 1210, 810; dH (360 MHz, CDCl3) 6.97 (2H, d, JZ8.2 Hz, Ph), 6.55 (2H, d, JZ8.2 Hz, Ph), 4.26–4.37 (2H, m, OCH2), 4.03–4.12 (1H, m, NHCH), 3.88–3.96 (2H, m, NCH2), 3.65 (1H, br s, NH), 3.32 (1H, dd, JZ7.3, 15.4 Hz, COCH2), 2.99 (1H, dd, JZ5.9, 15.4 Hz, COCH2), 2.22 (3H, s, PhCH3), 1.28 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [144.6, 129.8, 126.9, 113.9], 61.9 (OCH2), 46.7 (NCH2), 42.5 (CH), 41.4 (COCH2), 21.2 (CHCH3), 20.3 (PhCH3). 4.1.4. 3-[3-[(4-Methoxyphenyl)amino]butanoyl]-1,3-oxazolidin-2-one (3d). Purified by column chromatography (ether, Rf 0.38) gave a white solid (Found: C, 60.7; H, 6.45; N, 9.9%; MC, 278.1261. C14H18N2O4 requires C, 60.4; H, 6.5; N, 10.0%; MC, 278.1267); mp 110–111 8C; [a]20 DZ K1.0 (cZ0.023 in CHCl3); 24% ee (Chiral HPLC, i-PrOH/ hexaneZ3:97, 1.0 mL/min, t major 11.3 min, tminor 22.6 min); nmax (KBr)/cmK1 3344, 1768, 1688, 1513, 1394, 1234, 1025, 824; dH (360 MHz, CDCl3) 6.77 (2H, d, JZ8.9 Hz, Ph), 6.62 (2H, d, JZ8.9 Hz, Ph), 4.28–4.36 (2H, m, OCH2), 4.01–4.06 (1H, m, NHCH), 3.90–3.95 (2H, m, NCH2), 3.75 (3H, s, OCH3), 3.51 (1H, br s, NH), 3.34 (1H, dd, JZ7.1, 15.4 Hz, COCH2), 2.98 (1H, dd, JZ5.7, 15.4 Hz, COCH2), 1.28 (d, 3H, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.9 (CO), 153.7 (CO), aromatic C [152.3, 141.0, 115.4, 114.8], 61.9 (OCH2), 55.7 (OCH3), 47.5 (NCH2), 42.4 (CH), 41.4 (COCH2), 21.2 (CHCH3). 4.1.5. 3-(3-Anilinopentanoyl)-1,3-oxazolidin-2-one (3e). Purified by column chromatography (i-PrOH/pet. etherZ 1:2, Rf 0.71) gave a white solid (Found: C, 63.9; H, 6.85; N, 10.55%; MC, 262.1312. C14H18N2O3 requires C, 64.1; H, 6.9; N, 10.7%; MC, 262.1317); mp 77–78 8C (from EtOAc/ hexane); 47% ee (Chiral HPLC, i-PrOH/hexaneZ8:92, 1.0 mL/min, tmajor 24.2 min, tminor 26.3 min); [a]20 D ZK3.8 (cZ0.049 in CHCl3); nmax (KBr)/cmK1 3368, 1772, 1681, 1601, 1407, 1122, 1039, 749, 705; dH (360 MHz, CDCl3) 7.14 (2H, t, JZ7.3 Hz, Ph), 6.66 (1H, t, JZ7.3 Hz, Ph), 6.61 (2H, d, JZ7.3 Hz, Ph), 4.16–4.29 (2H, m, OCH2), 3.90– 3.98 (1H, m, NHCH), 3.75–3.87 (2H, m, NCH2), 3.77 (1H,
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br s, PhNH), 3.30 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.02 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.61–1.69 (2H, m, CH2CH3), 0.99 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 171.9 (CO), 153.7 (CO), aromatic C [147.4, 129.2, 117.3, 113.2], 61.8 (OCH2), 52.0 (NCH2), 42.4 (CH), 39.5 (COCH2), 28.4 (CH2CH3), 10.4 (CH2CH3). 4.1.6. 3-{3-[(4-Chlorophenyl)amino]pentanoyl}-1,3-oxazolidin-2-one (3f). Purified by column chromatography (i-PrOH/pet. etherZ1:4, Rf 0.65) gave a white solid (Found: C, 56.75; H, 5.85; N, 9.3%; MC, 296.0922. C14H17ClN2O3 requires C, 56.65; H, 5.75; N, 9.45%; MC, 296.0928); mp 69–70 8C (from EtOAc/hexane); [a]20 D ZK9.8 (cZ0.023 in CHCl3). 75% ee (Chiral HPLC, i-PrOH/hexaneZ6:94, 1.0 mL/min, tmajor 36.4 min, tminor 42.4 min); nmax (KBr)/ cmK1 1772, 1687, 1602, 1509, 1390, 822; dH (360 MHz, CDCl3) 7.08 (2H, d, JZ8.8 Hz, Ph), 6.53 (2H, d, JZ8.8 Hz, Ph), 4.24–4.36 (2H, m, OCH2); 3.81–3.93 (3H, m, NCH2 and NHCH), 3.79 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 3.00 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.59–1.67 (2H, m, CH2CH3), 0.97 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [146.0, 129.1, 121.8, 114.4], 61.9 (OCH2), 52.4 (NCH2), 42.5 (CH), 39.4 (COCH2), 28.4 (CH2CH3), 10.4 (CH2CH3). 4.1.7. 3-{3-[(4-Methylphenyl)amino]pentanoyl}-1,3-oxazolidin-2-one (3g). Purified by column chromatography (ether, Rf 0.9) gave a white solid (Found: C, 65.25; H, 7.05; N, 10.0%; MC, 276.1468. C15H20N2O3 requires C, 65.2; H, 7.3; N, 10.15%; MC, 276.1474); mp 88–89 8C (from EtOAc/hexane); 32% ee (Chiral HPLC, i-PrOH/hexaneZ 10:90, 1.0 mL/min, tmajor 19.6 min, tminor 26.0 min); K1 [a]20 D ZK4.4 (cZ0.011 in CHCl3); nmax (KBr)/cm 3369, 1768, 1685, 1522, 1391, 1228, 806; dH (360 MHz, CDCl3) 6.95 (2H, d, JZ8.3 Hz, Ph), 6.54 (1H, d, JZ8.3 Hz, Ph), 4.20–4.33 (2H, m, OCH2), 3.79–3.94 (3H, m, NCH2 and NHCH), 3.62 (1H, br s, PhNH), 3.29 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 2.21 (3H, s, PhCH3), 1.59–1.67 (2H, m, CH2CH3), 0.98 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [145.1, 129.7, 126.6, 113.6], 61.9 (OCH2), 52.6 (NCH2), 42.5 (CH), 39.5 (COCH2), 28.4 (CH2CH3), 20.3 (PhCH3), 10.4 (CH2CH3). 4.1.8. 3-{3-[(4-Methoxypheny)amino]pentanoyl}-1,3oxazolidin-2-one (3h). Purified by column chromatography (ether/pentaneZ3:1, Rf 0.39) gave a w hite solid (Found: C, 61.5; H, 6.75; N, 9.5%; MC, 292.1417. C15H20N2O4 requires C, 61.6; H, 6.9; N, 9.6%; MC, 292.1423); mp 73– 74 8C (from EtOAc/hexane); 9% ee (Chiral HPLC, i-PrOH/ hexaneZ30:70, 1.0 mL/min, t major 12.5 min, tminor 18.6 min); [a]20 D ZK1.5 (cZ0.020 in CHCl3); nmax (KBr)/ cmK1 3355, 1778, 1682, 1514, 1408, 1241, 1039, 819; dH (360 MHz, CDCl3) 6.75 (2H, d, JZ8.9 Hz, Ph), 6.59 (2H, d, JZ8.9 Hz, Ph), 4.22–4.33 (2H, m, OCH2), 3.80–3.89 (3H, m, NCH2 and NHCH), 3.73 (3H, s, OCH3), 3.73 (1H, br s, PhNH), 3.29 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 2.99 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.58–1.66 (2H, m, CH2CH3), 0.98 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [152.1, 141.5, 115.0, 114.8], 61.9 (OCH2), 55.8 (OCH3), 53.3 (NCH2), 42.5 (CH), 39.5 (COCH2), 28.3 (CH2CH3), 10.4 (CH2CH3).
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4.1.9. 3-(3-Anilinohexanoyl)-1,3-oxazolidin-2-one (3i). Purified by column chromatography (ether, Rf 0.83) gave a white solid (Found: C, 65.3; H, 7.45; N, 10.2%; MC, 276.1461. C15H20N2O3 requires C, 65.2; H, 7.3; N, 10.15%; MC, 276.1474); mp 53–54 8C (from EtOAc/hexane); 50% ee (Chiral HPLC, i-PrOH/hexaneZ4:96, 1.0 mL/min, tmajor 40.7 min, tminor 37.9 min); [a]20 D ZK0.9 (cZ0.015 in CHCl3); nmax (KBr)/cmK1 3360, 1770, 1688, 1601, 1404, 1119, 755, 692; dH (360 MHz, CDCl3) 7.14 (2H, t, JZ 7.3 Hz, Ph), 6.66 (1H, t, JZ7.3 Hz, Ph), 6.60 (2H, d, JZ 7.7 Hz, Ph), 4.17–4.31 (2H, m, OCH2), 3.94–4.08 (1H, m, NHCH), 3.75–3.87 (2H, m, NCH2), 3.72 (1H, br s, NH), 3.31 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ 5.0, 15.0 Hz, COCH2), 1.54–1.64 (2H, m, CH2CH2CH2), 1.35–1.53 (2H, m, CH2CH3), 0.93 (3H, t, JZ7.7 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.0 (CO), 153.7 (CO), aromatic C [147.4, 129.3, 117.3, 113.2], 61.9 (OCH2), 50.5 (NCH2), 42.5 (CH), 40.0 (COCH2), 38.1 (CH2CH2CH2), 19.3 (CH2CH3), 13.9 (CH2CH3). 4.1.10. 3-{3-[(4-Chlorophenyl)amino]hexanoyl}-1,3-oxazolidin-2-one (3j). Purified by column chromatography (i-PrOH/pet. etherZ1:4, Rf 0.76) gave a white solid (Found: C, 58.2; H, 6.25; N, 8.8%; MC, 310.1081. C15H19ClN2O3 requires C, 57.95; H, 6.15; N, 9.0%; MC, 310.1084); mp 63–64 8C. 26% ee (Chiral HPLC, i-PrOH/hexaneZ8:92, 1.0 mL/min, tmajor 35.5 min, tminor 29.8 min); [a]20 D ZK3.1 (cZ0.035 in CHCl3); nmax (KBr)/cmK1 3370, 1770, 1692, 1598, 1503, 1386, 819; dH (360 MHz, CDCl3) 7.08 (2H, d, JZ8.9 Hz, Ph), 6.52 (2H, d, JZ8.9 Hz, Ph), 4.23–4.36 (2H, m, OCH2), 3.95 (1H, br s, NHCH), 3.80–3.91 (2H, m, NCH2), 3.75 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 2.99 (1H, dd, JZ5.5, 15.0 Hz, COCH2), 1.54–1.60 (2H, m, CH2CH2CH3), 1.32–1.50 (2H, m, CH 2CH3 ), 0.92 (3H, t, JZ7.3 Hz, CH 2CH 3); d C (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [146.0, 129.1, 121.8, 114.3], 61.9 (OCH2), 50.7 (NCH2), 42.5 (CH), 39.8 (COCH2), 37.9 (CH2CH2CH2), 19.3 (CH2CH3), 13.9 (CH2CH3). 4.1.11. 3-{3-[(4-Methylphenyl)amino]hexanoyl}-1,3-oxazolidin-2-one (3k). Purified by column chromatography (ether, Rf 0.80) gave a white solid (Found: C, 66.0; H, 7.7; N, 9.4%; MC, 290.1625. C16H22N2O3 requires C, 66.2; H, 7.65; N, 9.65%; MC, 290.1630); mp 64–65 8C; 18% ee (Chiral HPLC, i-PrOH/hexaneZ3:97, 1.0 mL/min, tmajor 44.9 min, tminor 50.0 min); [a]20 D ZK1.8 (cZ0.022 in CHCl3); nmax (KBr)/cmK1 1768, 1687, 1522, 1391, 1223, 807; dH (360 MHz, CDCl3) 6.95 (2H, d, JZ8.2 Hz, Ph), 6.53 (2H, d, JZ8.2 Hz, Ph), 4.19–4.32 (2H, m, OCH2), 3.93–4.00 (1H, m, NHCH), 3.77–3.89 (2H, m, NCH2), 3.59 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 2.21 (3H, s, PhCH3), 1.52–1.63 (2H, m, CH2CH2CH2), 1.34–1.50 (2H, m, CH2CH3), 0.92 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [145.1, 129.7, 126.5, 113.5], 61.9 (OCH2), 50.9 (NCH2), 42.5 (CH), 39.9 (COCH2), 38.0 (CH2CH2CH3), 20.3 (CH2CH3), 19.3 (PhCH3), 13.9 (CH2CH3). 4.1.12. 3-{3-[(4-Methoxyphenyl)amino]hexanoyl}-1,3oxazolidin-2-one (3l). Purified by column chromatography (ether/pentaneZ1:1, Rf 0.19) gave a colourless oil (Found:
C, 62.9; H, 7.1; N, 9.0%; MC, 306.1574. C15H19ClN2O3 requires C, 62.7; H, 7.25; N, 9.15%; MC, 306.1580). 10% ee (Chiral HPLC, i-PrOH/hexaneZ20:80, 1.0 mL/min, tmajor 17.7 min, tminor 20.3 min); [a]20DZC0.69 (cZ0.026 in CHCl3); nmax (thin film, NaCl plates)/cmK1 1777, 1694, 1513, 1387, 1239, 1038, 822; dH (360 MHz, CDCl3) 6.74 (2H, d, JZ9.1 Hz, Ph), 6.58 (2H, d, JZ9.1 Hz, Ph), 4.20– 4.32 (2H, m, OCH2), 3.87–3.94 (1H, m, NHCH), 3.80–3.86 (2H, m, NCH2), 3.72 (3H, s, OCH3), 3.45 (1H, br s, PhNH), 3.28 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 2.98 (1H, dd, JZ 5.0, 15.0 Hz, COCH2), 1.50–1.64 (2H, m, CH2CH2CH3), 1.33–1.49 (2H, m, CH2CH3), 0.92 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [152.0, 141.6, 114.9, 114.8], 61.9 (OCH2), 55.7 (OCH3), 51.7 (NCH2), 42.4 (CH), 39.9 (COCH2), 37.9 (CH2CH2CH3), 19.3 (CH2CH3), 13.9 (CH2CH3).
Acknowledgements A majority of this work was conducted at the Department of Chemistry, King’s College London. Postdoctoral support (KL) was through the auspices of an EPSRC ROPA grant (GR/R50332/01). The authors are grateful to the Committee of Vice-Chancellors and Principals (CVCP) for an ORSA studentship to PHP, as well as Imperial College London and DSM Pharma for additional financial support. Palladium salts were provided by Johnson Matthey through a precious metal loan scheme.
References and notes 1. Cheng, X. H.; Hii, K. K. Tetrahedron 2001, 57, 5445–5450. 2. Li, K.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250–257. 3. Li, K.; Hii, K. K. Chem. Commun. 2003, 1132–1133. 4. Since, our original communication,3 palladium-catalysed addition of amine salts to similar olefin substrates has been reported: Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861–1864. 5. Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 2001, 1240–1241. 6. Due to the reversible process we were unable to isolate the product. In reference 4 the addition of benzylamine salts was reported to be slow, requiring a temperature of 40 8C and a reaction time of 60 h. The products were reported to be ‘rather unstable’ and were isolated as methyl esters. 7. Li, K.; Cheng, X. H.; Hii, K. K. Eur. J. Org. Chem. 2004, 959–964. 8. Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Go`mezBengoa, E.; Garcı´a, J. M. J. Am. Chem. Soc. 2004, 126, 9188–9189. 9. Kunz, H.; Pees, K. J. J. Chem. Soc., Perkin Trans. 1 1989, 1168–1169. 10. Chow, H. F.; Mak, C. C. J. Org. Chem. 1997, 62, 5116–5127. 11. Soloshonok, V. A.; Cai, C.; Hruby, V. J. J. Org. Chem. 2000, 65, 6688–6696. 12. Wendt, O. F.; Kaiser, N. F. K.; Elding, L. I. J. Chem. Soc., Dalton Trans. 1997, 4733–4738.
Enantioselective addition of amines to alkenoyl-N-oxazolidinones Kelin Li, Pim Huat Phua and King Kuok (Mimi) Hii* Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK Received 4 November 2004; revised 4 February 2005; accepted 4 March 2005 Available online 20 April 2005
Abstract—Investigations of cationic Pd(II) complex 1 as hydroamination catalysts led to the development of highly enantioselective addition of aromatic amines to alkenoyl-N-oxazolidinones, with ee values up to 93%. Factors affecting the yield and selectivity of the reaction were described. Addition of substituted benzylamines to these Michael acceptors was also attempted, and was found to be reversible under catalytic conditions. q 2005 Published by Elsevier Ltd.
1. Introduction The catalysed addition of N–H across C–C double bonds (hydroamination) is one of the most attractive atomeconomical processes (Scheme 1). If the alkene substrate is activated towards nucleophilic attack by the presence of electron-withdrawing substituents (e.g., keto, ester or nitrile groups), the reaction is also sometimes referred to as an aza-Michael (1,4-conjugate) addition. With prochiral alkenes, the reaction poses additional challenges in regioand enantioselectivity.
oxazolidinones 2 at room temperature were accomplished with good enantioselectivity (Scheme 2, Eq. 4).3 This paper will detail the course of our investigation of this latter
Scheme 1. Asymmetric hydroamination reaction.
Previously, we reported the development of air- and moisture-stable palladium catalysts for the hydroamination of olefins under pH neutral conditions at low catalytic loadings,1,2 including a class of air- and moisture-stable dicationic palladium complexes that mediates the addition of a range of amines to acyclic olefins. Among these, the chiral complex [(BINAP)Pd (solvent)]2C[TfO]K2 (1) catalyses the enantioselective addition of aniline to styrene at elevated temperatures (Scheme 2, Eq. 1).2 With methyl crotonate, addition of cyclic and aromatic amines may be effected at room temperature (Scheme 2, Eqs. 2 and 3), but ee’s were disappointingly low (no more than 24%). Introducing an achiral template on the olefin substrate, the addition of primary aromatic amines to the alkenoyl-NKeywords: Enantioselective addition; Hydroamination; Alkenoyl-Noxazolidinones. * Corresponding author. Tel.: C44 20 7594 1142; fax: C44 20 7594 5804; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd. doi:10.1016/j.tet.2005.03.125
Scheme 2. Asymmetric hydroamination reactions catalysed by complex 1.
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Table 1. Effect of solvent, catalyst loading and ratio of substrate on the hydroamination of 2a with aniline (Scheme 2, Eq. 4)a Entry
Catalyst loading (mol%)
2a: aniline
Solvent
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11
2 2 2 2 5 10 20 10 10 10 10
1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:1.5 1:4 1:1 1.5:1 1.5:1
Toluene CH3CN CH2Cl2 THF Toluene Toluene Toluene Toluene Toluene Toluene THF
25 4 16 19 34 48 80 45 64 93 31
10 19 6 1 45 51 85 22 89 93 60
a b c
Reactions were conducted in toluene at 25 8C for 18 h. Calculated by 1H NMR spectroscopy. Determined by chiral HPLC (Daicel Chiralpak AD).
process, and subsequent exploration of its scope and limitations.4
2. Results and discussion 2.1. Effect of catalyst loading, solvent and ratio of substrates Effects of solvent, catalyst loading and substrate ratios on the addition of aniline to 2a were studied and results are summarised in Table 1. Employing an initial catalyst loading of 2 mol% at room temperature, the highest conversion was obtained with toluene as the solvent, but ee was low (Table 1, entry 1). In contrast, an improved ee may be obtained in acetonitrile, but the yield was extremely low (entry 2). Dichloromethane furnished low yield and ee (entry 3), whereas THF afforded practically very low enantioselectivity (entries 4 and 11). These observations led us to conclude that coordinating solvents are detrimental to the catalytic activity, hence, toluene was employed as the solvent of choice in further studies. Unsurprisingly, increased catalyst loading from 2 to 20 mol% resulted in improvements in yield and ee of the process (entries 5–7). Although a high ee of 85% may be obtained with 20, 10 mol% of catalyst were consequently employed in the following optimisation work.
oxazolidinone 2a generally proceeded with good yields at room temperature. In all cases, very good conversions (85–90%) were obtained in 18 h. Among the primary aromatic amines, addition of aniline proceeded with the best ee (93%, entry 1). Interestingly, the presence of an electronwithdrawing Cl substituent did not appear to alter the yield or selectivity significantly (entry 2), whereas the addition of increasingly electron-rich amines such as p-toluidine and p-anisidine gave products with significantly reduced ee values (entries 3 and 4). Changing the substituent of the alkenoyl functionality retarded the rate of the reactions dramatically—the addition to pentenoyl oxazolidinone 2b was considerably slower at room temperature. Performing these reactions at an elevated temperature (60 8C), modest ee of 47% was obtained for aniline (entry 5), compared with the electron rich p-toluidine (32% ee, entry 7). But for 4-chloroaniline, good yield and ee of 93 and 75% were obtained, respectively (entry 6). The addition of the more nucleophilic p-anisidine may be effected at room temperature, but enantioselectivity was low (entry 8). Extending the homology, the addition to hexenoyl oxazolidinone 2c proceeded in even lower selectivity, ranging from 10 to 50% (entries 9–10).
Interestingly, employing an excess of the aniline substrate has a negative effect on the enantioselectivity of the reaction (entry 8). More crucially, catalyst decomposition was observed when an excess of the amine substrate was employed, leading to a poor yield of the product. Increasing the relative stoichiometry of the olefin substrate led to improvements in the turnover and selectivity (entry 9). The optimal ratio appears to be 1.5:1 where 93% yield and 93% ee were obtained (entry 10).
The results presented above suggests there is no apparent correlation between the nucleophilicity of the amine and reactivity, as might be expected. In the addition to 2a, aniline appears to have the same activity as p-chloroaniline (entries 1 and 2). On the other hand, the addition of the least nucleophilic amine to 2b appeared to be faster than aniline and toluidine at 60 8C (entries 5–7), while at the same time, the addition of anisidine proceeded at room temperature (entry 8). A different order of activity was again observed for the addition to 2c: p-chloroanilinewp-toluidineO p-anisidineOaniline (entries 9–12). In light of these observations, it is highly unlikely that the reactions proceed solely via Lewis-acid catalysis.
2.2. Reaction scope and reactivity
2.3. Generating the catalyst in situ
Having established the most favourable reaction conditions, the addition of different aromatic amines to alkenoyl oxazolidinones 2a–c was examined (Table 2).
It is often possible, and more convenient, to generate active catalysts in situ from suitable catalyst precursors, as this will also greatly facilitate ligand screening and catalyst discovery. To this end, we attempted to generate catalyst 1 by mixing [Pd(NCMe)4]2C[OTf]K2 with BINAP in toluene
The addition of primary aromatic amines to crotonyl
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Table 2. Addition of anilines to a,b-unsaturated oxazolidinones (Scheme 2, Eq. 4)a Entry
R1
R2
Product
T (8C)
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12
Me (2a) Me (2a) Me (2a) Me (2a) Et (2b) Et (2b) Et (2b) Et (2b) n Pr (2c) n Pr (2c) n Pr (2c) n Pr (2c)
H Cl Me OMe H Cl Me OMe H Cl Me OMe
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l
25 25 25 25 60 60 60 25 60 60 60 60
90 90 85 85 70 93 54 50 69 85 86 75
93 92 68 24 47 75 32 9 50 26 18 10
a b c
Reactions were conducted in toluene with 10 mol% catalyst 1 for 18 h. Isolated yields after column chromatography. Determined by chiral HPLC (Daicel Chiralpak AD).
(metal-to-ligand ratio of 1:1), for the addition of aniline to 2a (Scheme 3). However, the catalyst generated in this way is not as active as the isolated complex 1—affording the product 3a in only 57% yield with an ee of 78% after 18 h. In fact, more than 40 h were required before the reaction gave comparable results to that afforded by the isolated catalyst 1 (89% yield and 81% ee). The catalyst turnover was also found to be sensitive to the relative quantity of the ligand employed: A mere 0.2 equiv excess (i.e., 1:1.2 metalto-ligand ratio) led to a decrease in yield and selectivity (59% yield and 65% ee after 40 h). We speculate that this is due to the formation of a catalytically less active species, such as [Pd(BINAP)2]2C[OTf]K2. Attempts were also made to generate active catalysts in situ by mixing chiral bisoxazolidine ligands 5 and 6 and [Pd(NCMe)4]2C[OTf]K2 in a metal-to-ligand ratio of 1:1. In both cases, the addition of aniline to 2a only gave 3a as a racemic mixture in less than 30% yield (18 h).
selectivity (Scheme 4). It is somewhat surprising that the palladium complex should catalyse the addition of both primary and secondary aromatic amines with equal efficacy, given the different electronic and steric natures of these substrates. 2.4. Addition of benzylamine Uncatalysed addition of benzylamines to 2a occurs slowly in toluene under ambient conditions. In the presence of 1, low to moderate yields and ee’s of products 7 may be obtained in 2 h (Scheme 5, Table 3).
Scheme 5.
However, the optical activity of the reaction mixture plummets to between 3 and 7% ee after 18–48 h, whilst the conversion remained unchanged, thus, signifying that the addition of benzyl amines to 2a is reversible under these conditions.6 2.5. Amine salt control Scheme 3. Generating catalysts in situ.
Previously, the addition of the secondary aromatic amine N-methyl aniline to substrate 2a has been effected by a catalyst generated in situ from Ni(ClO4)2 and chiral bisoxazolidine ligand 5: the product 4 was found to have a high ee (90%), but the yield obtained after 40 h was only moderate (62%).5 In comparison, complex 1 catalysed the addition of the secondary amine to 2a with comparable
Sodeoka et al. reported an improvement in the yield and selectivity by employing trifluoromethanesulfonate salts of the aromatic amines as substrates,4 as they postulate that the use of the free amine leads to an uncatalysed reaction. Indeed, uncatalysed slow addition of p-anisidine (1.5 equiv) to N-oxazolidinone 2a do occur slowly in solution (12%, 18 h, 25 8C), which was inhibited when p-anisidine$HOTf salt was used. Nevertheless, we failed to observe any addition of the p-anisidine$HOTf to 2a in the presence of catalyst 1.
3. Conclusion Scheme 4. Addition of N-methyl aniline to 2a.
Various aspects of the enantioselective addition of amines to
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Table 3. Addition of substituted benzyl amines to 2aa Entry
R1
R2
Product
Yieldb (%)
ee (%)c
1 2 3 4 5
H OCH3 H Br H
H OCH3 OCH3 H CH3
7a 7b 7c 7d 7e
57 52 52 61 47
41 46 39 7 33
a
Reaction were conducted in toluene with 10 mol% catalyst 1 at 25 8C for 2 h. Calculated by 1H NMR spectroscopy. c Determined by chiral HPLC (Daicel Chiralpak AD). b
N-alkenoyl oxazolidinones catalysed by the cationic diphosphine–palladium complex 1 have been presented. The catalytic activity and selectivity are much more sensitive to the steric and electronic nature of the olefin substrate. Hence, the chelating dicarbonyl moiety of the olefin substrate was identified as the key stereocontrolling element. In subsequent work, we modified the achiral template by replacing the oxazolidinone ring by a carbamate moiety (substrate 8, Fig. 1), which led to a significant enhancement in the activity and selectivity of the conjugate addition process.7 Recently, highly enantioselective addition of carbamates to the a 0 -hydroxy enone 9 (Fig. 1) was reported by Palomo et al.8 (using Evan’s bis-oxazoline copper complexes as catalysts), capitalising a hydroxyketone moiety in the olefin substrate as a mode of chelation to the metal centre, presumably promoted by the gemdialkyl groups.
Service at University of North London. High Resolution Mass spectra (HRMS) were recorded using Electrospray (ES) ionisation technique on a Micromass ‘Q-TOF’ spectrometer. Optical purity were measured using a Gilson HPLC system fitted with a Daicel Chiralpak AD column, with UV detection at 215 nm. Optical rotation values were measured on a Perkin–Elmer polarimeter 343 using a 10 cm solution cell, concentration of the samples was indicated as g/mL, given in the parenthesis. Melting points (uncorrected) were determined on an Electrothermal Gallenhamp apparatus. 3-(E)-2-butenoyl-1,3-oxazolidin-2-one,9 3-(E)-2-pentenoyl-2-oxazolidinone,10 3-(E)-2-hexenoyl-1,3-oxazolidin-2-one,11 and [Pd(NCMe)4]2C(OTf)K212 were synthesised according to literature methods. All other compounds were procured from commercial sources and used as received. Palladium salts were obtained from Johnson Matthey plc through a loan agreement. 4.1. General procedure for the hydroamination of compound 2 with primary amines
Figure 1. Olefin substrates 2, 8 and 9 containing chelating functionalities.
Work is currently underway to discern the mechanism of these addition reactions and to examine the conjugate addition of amines to other modified olefin substrates, these will be reported in due course. Current endeavours also include the design and identification of more active and selective catalysts for other asymmetric hydroamination reactions.
4. Experimental All manipulations were performed using standard Schlenk techniques. Dichloromethane, toluene and acetonitrile were dried over CaH2, distilled and stored under a nitrogen atmosphere. THF was dried over Na/benzophenone. NMR spectra were recorded on a Bruker Avance 360 instrument (1H at 360 MHz and 13C at 90.6 MHz). The chemical shifts are reported in d (ppm) referenced to residual protons and 13 C signals of deuterated chloroform. Infra-red spectra were recorded on a Perkin–Elmer 1600 FTIR spectrometer. Elemental analysis was provided by the Elemental Analysis
0.022 g (0.020 mmol) of complex 1 and the olefin substrate 2 (0.30 mmol) were placed in a thick-walled Young’s tube, which was purged with N2. 1.0 mL of toluene and the appropriate amine (0.20 mmol) were added. The tube was sealed via a PTFE tap and the reaction mixture was stirred and heated in a thermostatic oil bath. After the appropriate time, the homogeneous solution was subjected to column chromatography (SiO2) to furnish the product. 4.1.1. 3-(3-Anilinobutanoyl)-1,3-oxazolidin-2-one (3a). Purified by column chromatography (ether/pentaneZ1:3, Rf 0.3) gave a white solid (Found: C, 62.7; H, 6.8; N, 11.0%; MC, 248.1155. C13H16N2O3 requires C, 62.9; H, 6.5; N, 11.3%; MC 248.1161); mp 114–115 8C (from EtOAc/ hexane); 86% ee (Chiral HPLC, i-PrOH/hexaneZ20:80, 1.0 mL/min, tmajor 14.2 min, tminor 18.8 min); [a]20 D ZC8.1 (cZ0.017 in CHCl3); nmax (KBr)/cmK1 3363, 1771, 1694, 1605, 1392, 1140, 760, 700; dH (360 MHz, CDCl3) 7.16 (2H, t, JZ7.7 Hz, Ph), 6.68 (1H, t, JZ7.3 Hz, Ph), 6.62 (2H, d, JZ7.3 Hz, Ph), 4.24–4.36 (2H, m, OCH2), 4.08– 4.17 (1H, m, NHCH), 3.84–3.95 (2H, m, NCH2), 3.79 (1H, br s, PhNH), 3.34 (1H, dd, JZ7.3, 15.4 Hz, COCH2), 3.00 (1H, dd, JZ5.9, 15.4 Hz, COCH2), 1.30 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.7 (CO), 153.7 CO), aromatic C [146.9, 129.3, 117.6, 113.6], 61.9 (OCH2), 46.3 (NCH2), 42.4 (CH), 41.4 (COCH2), 21.3 (CH3). 4.1.2. 3-[3-(4-Chlorophenylamino)butanoyl]-1,3-oxazolidin-2-one (3b). Purified by column chromatography (ether/pet. etherZ3:1, Rf 0.35) gave a white solid (Found: C, 55.1; H, 5.5; N, 9.9%; MC, 282.0767. C13H15ClN2O3
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requires C, 55.2; H, 5.35; N, 9.9%; MC 282.0771); mp 84– 85 8C (from EtOAc/hexane); 92% ee (Chiral HPLC, i-PrOH/hexaneZ30:70, 1.0 mL/min, tmajor 12.6 min, tminor 16.2 min); [a]20 D ZK0.7 (cZ0.017 in CHCl3); nmax (KBr)/ cmK1 3374, 1771, 1691, 1604, 1514, 1390, 814; dH (360 MHz, CDCl3) 7.09 (2H, d, JZ9.1 Hz, Ph), 6.57 (2H, d, JZ9.1 Hz, Ph), 4.29–4.40 (2H, m, OCH2), 4.01–4.10 (1H, m, NHCH), 3.88–3.99 (2H, m, NCH2), 3.83 (1H, br s, NH), 3.32 (1H, dd, JZ6.8, 15.4 Hz, COCH2), 2.98 (1H, dd, JZ5.5, 15.4 Hz, COCH2), 1.28 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.6 (CO), 153.7 CO), aromatic C (145.5, 129.1, 122.1, 114.6), 62.0 (OCH2), 46.4 (NCH2), 42.4 (CH), 41.2 (COCH2), 21.0 (CH3). 4.1.3. 3-{3-[(4-Methylphenyl)amino]butanoyl}-1,3-oxazolidin-2-one (3c). Purified by column chromatography (ether/pentaneZ1:1, Rf 0.18) gave a white solid (Found: C, 64.2; H, 7.05; N, 10.6%; MC, 262.1312. C14H18N2O3 requires C, 64.1; H, 6.9; N, 10.7%; MC, 262.1317); mp 70–71 8C (from EtOAc/hexane); 68% ee (Chiral HPLC, i-PrOH/hexaneZ30:70, 1.0 mL/min, tmajor 11.7 min, tminor 17.1 min); [a]20 D ZC0.47 (cZ0.021 in CHCl3); nmax (KBr)/ cmK1 1770, 1684, 1522, 1395, 1210, 810; dH (360 MHz, CDCl3) 6.97 (2H, d, JZ8.2 Hz, Ph), 6.55 (2H, d, JZ8.2 Hz, Ph), 4.26–4.37 (2H, m, OCH2), 4.03–4.12 (1H, m, NHCH), 3.88–3.96 (2H, m, NCH2), 3.65 (1H, br s, NH), 3.32 (1H, dd, JZ7.3, 15.4 Hz, COCH2), 2.99 (1H, dd, JZ5.9, 15.4 Hz, COCH2), 2.22 (3H, s, PhCH3), 1.28 (3H, d, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [144.6, 129.8, 126.9, 113.9], 61.9 (OCH2), 46.7 (NCH2), 42.5 (CH), 41.4 (COCH2), 21.2 (CHCH3), 20.3 (PhCH3). 4.1.4. 3-[3-[(4-Methoxyphenyl)amino]butanoyl]-1,3-oxazolidin-2-one (3d). Purified by column chromatography (ether, Rf 0.38) gave a white solid (Found: C, 60.7; H, 6.45; N, 9.9%; MC, 278.1261. C14H18N2O4 requires C, 60.4; H, 6.5; N, 10.0%; MC, 278.1267); mp 110–111 8C; [a]20 DZ K1.0 (cZ0.023 in CHCl3); 24% ee (Chiral HPLC, i-PrOH/ hexaneZ3:97, 1.0 mL/min, t major 11.3 min, tminor 22.6 min); nmax (KBr)/cmK1 3344, 1768, 1688, 1513, 1394, 1234, 1025, 824; dH (360 MHz, CDCl3) 6.77 (2H, d, JZ8.9 Hz, Ph), 6.62 (2H, d, JZ8.9 Hz, Ph), 4.28–4.36 (2H, m, OCH2), 4.01–4.06 (1H, m, NHCH), 3.90–3.95 (2H, m, NCH2), 3.75 (3H, s, OCH3), 3.51 (1H, br s, NH), 3.34 (1H, dd, JZ7.1, 15.4 Hz, COCH2), 2.98 (1H, dd, JZ5.7, 15.4 Hz, COCH2), 1.28 (d, 3H, JZ6.4 Hz, CHCH3); dC (90.6 MHz, CDCl3) 171.9 (CO), 153.7 (CO), aromatic C [152.3, 141.0, 115.4, 114.8], 61.9 (OCH2), 55.7 (OCH3), 47.5 (NCH2), 42.4 (CH), 41.4 (COCH2), 21.2 (CHCH3). 4.1.5. 3-(3-Anilinopentanoyl)-1,3-oxazolidin-2-one (3e). Purified by column chromatography (i-PrOH/pet. etherZ 1:2, Rf 0.71) gave a white solid (Found: C, 63.9; H, 6.85; N, 10.55%; MC, 262.1312. C14H18N2O3 requires C, 64.1; H, 6.9; N, 10.7%; MC, 262.1317); mp 77–78 8C (from EtOAc/ hexane); 47% ee (Chiral HPLC, i-PrOH/hexaneZ8:92, 1.0 mL/min, tmajor 24.2 min, tminor 26.3 min); [a]20 D ZK3.8 (cZ0.049 in CHCl3); nmax (KBr)/cmK1 3368, 1772, 1681, 1601, 1407, 1122, 1039, 749, 705; dH (360 MHz, CDCl3) 7.14 (2H, t, JZ7.3 Hz, Ph), 6.66 (1H, t, JZ7.3 Hz, Ph), 6.61 (2H, d, JZ7.3 Hz, Ph), 4.16–4.29 (2H, m, OCH2), 3.90– 3.98 (1H, m, NHCH), 3.75–3.87 (2H, m, NCH2), 3.77 (1H,
6241
br s, PhNH), 3.30 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.02 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.61–1.69 (2H, m, CH2CH3), 0.99 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 171.9 (CO), 153.7 (CO), aromatic C [147.4, 129.2, 117.3, 113.2], 61.8 (OCH2), 52.0 (NCH2), 42.4 (CH), 39.5 (COCH2), 28.4 (CH2CH3), 10.4 (CH2CH3). 4.1.6. 3-{3-[(4-Chlorophenyl)amino]pentanoyl}-1,3-oxazolidin-2-one (3f). Purified by column chromatography (i-PrOH/pet. etherZ1:4, Rf 0.65) gave a white solid (Found: C, 56.75; H, 5.85; N, 9.3%; MC, 296.0922. C14H17ClN2O3 requires C, 56.65; H, 5.75; N, 9.45%; MC, 296.0928); mp 69–70 8C (from EtOAc/hexane); [a]20 D ZK9.8 (cZ0.023 in CHCl3). 75% ee (Chiral HPLC, i-PrOH/hexaneZ6:94, 1.0 mL/min, tmajor 36.4 min, tminor 42.4 min); nmax (KBr)/ cmK1 1772, 1687, 1602, 1509, 1390, 822; dH (360 MHz, CDCl3) 7.08 (2H, d, JZ8.8 Hz, Ph), 6.53 (2H, d, JZ8.8 Hz, Ph), 4.24–4.36 (2H, m, OCH2); 3.81–3.93 (3H, m, NCH2 and NHCH), 3.79 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 3.00 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.59–1.67 (2H, m, CH2CH3), 0.97 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [146.0, 129.1, 121.8, 114.4], 61.9 (OCH2), 52.4 (NCH2), 42.5 (CH), 39.4 (COCH2), 28.4 (CH2CH3), 10.4 (CH2CH3). 4.1.7. 3-{3-[(4-Methylphenyl)amino]pentanoyl}-1,3-oxazolidin-2-one (3g). Purified by column chromatography (ether, Rf 0.9) gave a white solid (Found: C, 65.25; H, 7.05; N, 10.0%; MC, 276.1468. C15H20N2O3 requires C, 65.2; H, 7.3; N, 10.15%; MC, 276.1474); mp 88–89 8C (from EtOAc/hexane); 32% ee (Chiral HPLC, i-PrOH/hexaneZ 10:90, 1.0 mL/min, tmajor 19.6 min, tminor 26.0 min); K1 [a]20 D ZK4.4 (cZ0.011 in CHCl3); nmax (KBr)/cm 3369, 1768, 1685, 1522, 1391, 1228, 806; dH (360 MHz, CDCl3) 6.95 (2H, d, JZ8.3 Hz, Ph), 6.54 (1H, d, JZ8.3 Hz, Ph), 4.20–4.33 (2H, m, OCH2), 3.79–3.94 (3H, m, NCH2 and NHCH), 3.62 (1H, br s, PhNH), 3.29 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 2.21 (3H, s, PhCH3), 1.59–1.67 (2H, m, CH2CH3), 0.98 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [145.1, 129.7, 126.6, 113.6], 61.9 (OCH2), 52.6 (NCH2), 42.5 (CH), 39.5 (COCH2), 28.4 (CH2CH3), 20.3 (PhCH3), 10.4 (CH2CH3). 4.1.8. 3-{3-[(4-Methoxypheny)amino]pentanoyl}-1,3oxazolidin-2-one (3h). Purified by column chromatography (ether/pentaneZ3:1, Rf 0.39) gave a w hite solid (Found: C, 61.5; H, 6.75; N, 9.5%; MC, 292.1417. C15H20N2O4 requires C, 61.6; H, 6.9; N, 9.6%; MC, 292.1423); mp 73– 74 8C (from EtOAc/hexane); 9% ee (Chiral HPLC, i-PrOH/ hexaneZ30:70, 1.0 mL/min, t major 12.5 min, tminor 18.6 min); [a]20 D ZK1.5 (cZ0.020 in CHCl3); nmax (KBr)/ cmK1 3355, 1778, 1682, 1514, 1408, 1241, 1039, 819; dH (360 MHz, CDCl3) 6.75 (2H, d, JZ8.9 Hz, Ph), 6.59 (2H, d, JZ8.9 Hz, Ph), 4.22–4.33 (2H, m, OCH2), 3.80–3.89 (3H, m, NCH2 and NHCH), 3.73 (3H, s, OCH3), 3.73 (1H, br s, PhNH), 3.29 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 2.99 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 1.58–1.66 (2H, m, CH2CH3), 0.98 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [152.1, 141.5, 115.0, 114.8], 61.9 (OCH2), 55.8 (OCH3), 53.3 (NCH2), 42.5 (CH), 39.5 (COCH2), 28.3 (CH2CH3), 10.4 (CH2CH3).
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4.1.9. 3-(3-Anilinohexanoyl)-1,3-oxazolidin-2-one (3i). Purified by column chromatography (ether, Rf 0.83) gave a white solid (Found: C, 65.3; H, 7.45; N, 10.2%; MC, 276.1461. C15H20N2O3 requires C, 65.2; H, 7.3; N, 10.15%; MC, 276.1474); mp 53–54 8C (from EtOAc/hexane); 50% ee (Chiral HPLC, i-PrOH/hexaneZ4:96, 1.0 mL/min, tmajor 40.7 min, tminor 37.9 min); [a]20 D ZK0.9 (cZ0.015 in CHCl3); nmax (KBr)/cmK1 3360, 1770, 1688, 1601, 1404, 1119, 755, 692; dH (360 MHz, CDCl3) 7.14 (2H, t, JZ 7.3 Hz, Ph), 6.66 (1H, t, JZ7.3 Hz, Ph), 6.60 (2H, d, JZ 7.7 Hz, Ph), 4.17–4.31 (2H, m, OCH2), 3.94–4.08 (1H, m, NHCH), 3.75–3.87 (2H, m, NCH2), 3.72 (1H, br s, NH), 3.31 (1H, dd, JZ8.2, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ 5.0, 15.0 Hz, COCH2), 1.54–1.64 (2H, m, CH2CH2CH2), 1.35–1.53 (2H, m, CH2CH3), 0.93 (3H, t, JZ7.7 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.0 (CO), 153.7 (CO), aromatic C [147.4, 129.3, 117.3, 113.2], 61.9 (OCH2), 50.5 (NCH2), 42.5 (CH), 40.0 (COCH2), 38.1 (CH2CH2CH2), 19.3 (CH2CH3), 13.9 (CH2CH3). 4.1.10. 3-{3-[(4-Chlorophenyl)amino]hexanoyl}-1,3-oxazolidin-2-one (3j). Purified by column chromatography (i-PrOH/pet. etherZ1:4, Rf 0.76) gave a white solid (Found: C, 58.2; H, 6.25; N, 8.8%; MC, 310.1081. C15H19ClN2O3 requires C, 57.95; H, 6.15; N, 9.0%; MC, 310.1084); mp 63–64 8C. 26% ee (Chiral HPLC, i-PrOH/hexaneZ8:92, 1.0 mL/min, tmajor 35.5 min, tminor 29.8 min); [a]20 D ZK3.1 (cZ0.035 in CHCl3); nmax (KBr)/cmK1 3370, 1770, 1692, 1598, 1503, 1386, 819; dH (360 MHz, CDCl3) 7.08 (2H, d, JZ8.9 Hz, Ph), 6.52 (2H, d, JZ8.9 Hz, Ph), 4.23–4.36 (2H, m, OCH2), 3.95 (1H, br s, NHCH), 3.80–3.91 (2H, m, NCH2), 3.75 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 2.99 (1H, dd, JZ5.5, 15.0 Hz, COCH2), 1.54–1.60 (2H, m, CH2CH2CH3), 1.32–1.50 (2H, m, CH 2CH3 ), 0.92 (3H, t, JZ7.3 Hz, CH 2CH 3); d C (90.6 MHz, CDCl3) 171.8 (CO), 153.7 (CO), aromatic C [146.0, 129.1, 121.8, 114.3], 61.9 (OCH2), 50.7 (NCH2), 42.5 (CH), 39.8 (COCH2), 37.9 (CH2CH2CH2), 19.3 (CH2CH3), 13.9 (CH2CH3). 4.1.11. 3-{3-[(4-Methylphenyl)amino]hexanoyl}-1,3-oxazolidin-2-one (3k). Purified by column chromatography (ether, Rf 0.80) gave a white solid (Found: C, 66.0; H, 7.7; N, 9.4%; MC, 290.1625. C16H22N2O3 requires C, 66.2; H, 7.65; N, 9.65%; MC, 290.1630); mp 64–65 8C; 18% ee (Chiral HPLC, i-PrOH/hexaneZ3:97, 1.0 mL/min, tmajor 44.9 min, tminor 50.0 min); [a]20 D ZK1.8 (cZ0.022 in CHCl3); nmax (KBr)/cmK1 1768, 1687, 1522, 1391, 1223, 807; dH (360 MHz, CDCl3) 6.95 (2H, d, JZ8.2 Hz, Ph), 6.53 (2H, d, JZ8.2 Hz, Ph), 4.19–4.32 (2H, m, OCH2), 3.93–4.00 (1H, m, NHCH), 3.77–3.89 (2H, m, NCH2), 3.59 (1H, br s, PhNH), 3.29 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 3.01 (1H, dd, JZ5.0, 15.0 Hz, COCH2), 2.21 (3H, s, PhCH3), 1.52–1.63 (2H, m, CH2CH2CH2), 1.34–1.50 (2H, m, CH2CH3), 0.92 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [145.1, 129.7, 126.5, 113.5], 61.9 (OCH2), 50.9 (NCH2), 42.5 (CH), 39.9 (COCH2), 38.0 (CH2CH2CH3), 20.3 (CH2CH3), 19.3 (PhCH3), 13.9 (CH2CH3). 4.1.12. 3-{3-[(4-Methoxyphenyl)amino]hexanoyl}-1,3oxazolidin-2-one (3l). Purified by column chromatography (ether/pentaneZ1:1, Rf 0.19) gave a colourless oil (Found:
C, 62.9; H, 7.1; N, 9.0%; MC, 306.1574. C15H19ClN2O3 requires C, 62.7; H, 7.25; N, 9.15%; MC, 306.1580). 10% ee (Chiral HPLC, i-PrOH/hexaneZ20:80, 1.0 mL/min, tmajor 17.7 min, tminor 20.3 min); [a]20DZC0.69 (cZ0.026 in CHCl3); nmax (thin film, NaCl plates)/cmK1 1777, 1694, 1513, 1387, 1239, 1038, 822; dH (360 MHz, CDCl3) 6.74 (2H, d, JZ9.1 Hz, Ph), 6.58 (2H, d, JZ9.1 Hz, Ph), 4.20– 4.32 (2H, m, OCH2), 3.87–3.94 (1H, m, NHCH), 3.80–3.86 (2H, m, NCH2), 3.72 (3H, s, OCH3), 3.45 (1H, br s, PhNH), 3.28 (1H, dd, JZ7.7, 15.0 Hz, COCH2), 2.98 (1H, dd, JZ 5.0, 15.0 Hz, COCH2), 1.50–1.64 (2H, m, CH2CH2CH3), 1.33–1.49 (2H, m, CH2CH3), 0.92 (3H, t, JZ7.3 Hz, CH2CH3); dC (90.6 MHz, CDCl3) 172.1 (CO), 153.7 (CO), aromatic C [152.0, 141.6, 114.9, 114.8], 61.9 (OCH2), 55.7 (OCH3), 51.7 (NCH2), 42.4 (CH), 39.9 (COCH2), 37.9 (CH2CH2CH3), 19.3 (CH2CH3), 13.9 (CH2CH3).
Acknowledgements A majority of this work was conducted at the Department of Chemistry, King’s College London. Postdoctoral support (KL) was through the auspices of an EPSRC ROPA grant (GR/R50332/01). The authors are grateful to the Committee of Vice-Chancellors and Principals (CVCP) for an ORSA studentship to PHP, as well as Imperial College London and DSM Pharma for additional financial support. Palladium salts were provided by Johnson Matthey through a precious metal loan scheme.
References and notes 1. Cheng, X. H.; Hii, K. K. Tetrahedron 2001, 57, 5445–5450. 2. Li, K.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250–257. 3. Li, K.; Hii, K. K. Chem. Commun. 2003, 1132–1133. 4. Since, our original communication,3 palladium-catalysed addition of amine salts to similar olefin substrates has been reported: Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861–1864. 5. Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 2001, 1240–1241. 6. Due to the reversible process we were unable to isolate the product. In reference 4 the addition of benzylamine salts was reported to be slow, requiring a temperature of 40 8C and a reaction time of 60 h. The products were reported to be ‘rather unstable’ and were isolated as methyl esters. 7. Li, K.; Cheng, X. H.; Hii, K. K. Eur. J. Org. Chem. 2004, 959–964. 8. Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Go`mezBengoa, E.; Garcı´a, J. M. J. Am. Chem. Soc. 2004, 126, 9188–9189. 9. Kunz, H.; Pees, K. J. J. Chem. Soc., Perkin Trans. 1 1989, 1168–1169. 10. Chow, H. F.; Mak, C. C. J. Org. Chem. 1997, 62, 5116–5127. 11. Soloshonok, V. A.; Cai, C.; Hruby, V. J. J. Org. Chem. 2000, 65, 6688–6696. 12. Wendt, O. F.; Kaiser, N. F. K.; Elding, L. I. J. Chem. Soc., Dalton Trans. 1997, 4733–4738.