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Diastereoselectivity in the Aza-Michael Reaction of Chiral Α-Meth- Ylbenzylamines with Α,Β-Unsaturated Carbonyl Compounds

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Diastereoselectivity in the Aza-Michael Reaction of Chiral Α-Meth- Ylbenzylamines with Α,Β-Unsaturated Carbonyl Compounds SYNOPEN2509-9396 Georg Thieme Verlag Stuttgart · New York 2018, 2, 122–127 paper 122 en Syn Open M. Kour et al. Paper Diastereoselectivity in the Aza-Michael Reaction of Chiral α-Meth- ylbenzylamines with α,β-Unsaturated Carbonyl Compounds M. Koura R. Guptaa R. Sainib R. K. Bansal*a a Department of chemistry, The IIS University, GurukulMarg, SFS, Mansarovar, Jaipur 302020, India [email protected] b Central Drug Research Institute, Sitapur Road, Lucknow 226031, India Received: 15.03.2018 the major isomer could be separated.3 Likewise, chiral N-(α- Accepted after revision: 05.04.2018 methylbenzyl)hydroxylamines react with methyl enoates to Published online: 07.05.2018 DOI: 10.1055/s-0036-1591999; Art ID: so-2018-d0019-op afford isoxazolidinone adducts in moderate to good diaste- 4 License terms: reoselectivity, which could be further enhanced by using chiral crotonate acceptors under double stereodifferentia- 5 Abstract The aza-Michael reaction of (S)-(–)- and (R)-(+)-α-methyl- tion conditions. Hawkins used an atropisomeric lithiated benzylamines with trans-cinnamaldehyde and other α,β-unsaturated dinaphthoazepine derivative as a chiral nitrogen nucleo- carbonyl compounds occurs with 52–98% diastereoselectivity (de); phile and the reaction proceeded with very high diastereo- however, in the reaction with crotonaldehyde, the de is lower (20–38%). selectivity to afford β-amino esters in excellent yields.6 In the products obtained from the reaction with α,β-unsaturated alde- hydes, the de could be determined on the basis of the relative intensities Davies and co-workers developed diastereoselective conju- of the aldehydic protons of the two diastereomers. Theoretical investi- gate additions of enantiomerically pure lithium amides to a gations of the reaction of (S)-(–)-α-methylbenzylamine with trans-cin- wide range of α,β-unsaturated esters and amides, making a namaldehyde at the DFT (B3LYP/6-31+G*) level reveal that the diaste- wide range of β-amino acids and their derivatives avail- reomer formed from the attack of the amine on the Re face is able.7 They proposed a mechanistic rationale that account- thermodynamically more stable. The calculations also show that the al- 8 dehydic proton of this diastereomer is expected to be more deshielded, ed for the high diastereoselection between prochiral faces. which on the basis of the 1H NMR spectrum is the major product. Enders and co-workers, on the other hand, employed lithi- ated enantiopure hydrazines as nitrogen nucleophiles, Keywords aza-Michael reaction, α-methylbenzylamine, diastereo- which reacted with α,β-unsaturated esters and other ac- selectivity, trans-cinnamaldehyde, DFT calculations ceptors with a high degree of diastereoselection.9 Likewise, Michael addition of a D-mannitol derived hydrazine to The aza-Michael reaction has emerged as one of the alkylidenemalonates was accomplished with high diastere- most powerful and reliable methods for the asymmetric oselectivities.10 A cyclic carbamate has also been employed synthesis of β-amino carbonyl compounds, which are im- as a nitrogen nucleophile for its conjugate addition to nitro- portant building blocks for the synthesis of a wide variety alkenes to afford products as single diastereomers.11 of nitrogen-containing compounds having pharmaceutical The Michael addition of homochiral α-methylbenzyl- importance.1,2 amines to methyl crotonate12 and some other activated The reaction of a nucleophile with an activated alkene alkenes12e has been reported earlier to occur with poor dia- having prochiral faces is accompanied by the generation of stereoselectivity (2–19%). In all these investigations, alcohol one or more stereogenic centers in one step. Thus, by ma- was used as the solvent. As solvent has been found to affect nipulating the reaction environment with appropriate chi- diastereoselectivity in the Michael addition13 and intramo- ral auxiliaries, asymmetry can be induced and the desired lecular Diels–Alder reactions,14 we decided to investigate products may be obtained with high stereoselectivity. The the reaction of (S)-(–)- and (R)-(+)-α-methylbenzylamines use of chiral nitrogen nucleophiles is one such strategy. By with a range of α,β-unsaturated carbonyl compounds in an following this approach, (S)-alanine benzyl ester was used aprotic solvent (dichloromethane) and found that the dia- as a Michael donor and reacted with 4-oxo-4-phenyl-2- stereoselectivity improved remarkably. As a result, an at- butenoate to give a mixture of diastereomers, from which tempt was made to rationalize the observed diastereoselec- Georg Thieme Verlag Stuttgart · New York — SynOpen 2018, 2, 122–127 123 Syn Open M. Kour et al. Paper tivity theoretically by computing the model reaction at the DFT level involving the attack of (S)-(–)-α-methylbenzyl- amine on the Si and Re faces of trans-cinnamaldehyde. The results are presented herein. (S)-α-Methylbenzylamine (2a) and (R)-α-methylbenzyl- amine (2b) reacted with α,β-unsaturated carbonyl com- pounds (1a–e) in dichloromethane at room temperature (ca. 25 °C) to afford mixtures of the diastereomers 3+4 and 5+6, respectively (Scheme 1). 1 O R 1 O H R Me H 4 H R H H R3 Me R4 Ph NH2 Me + 2 2 2a Ph N R Ph N R H H R3 O 3a–e 4a–e R1 4 CH2Cl2 R O R1 O r.t. H 3 2 R R Me H 4 R Me 1 4 1a–e R3 R R H + H R2 Me Ph N R2 H Ph N H H R3 5a–e Ph NH2 6a–e 2b 1,3–6 a b c d e Figure 1 Parts of the 1H NMR (A) and 13C NMR (B) spectra of the product R1 H H H H Me 3a+4a R2 H H H H Me 3 R Ph Me p-NO2C6H4 Ph H R4 H H H OMe H The diastereomeric excess (de) in the reaction of (S)-α- Scheme 1 Reaction of (S)- and (R)-α-methylbenzylamines with α,β-un- methylbenzylamine (2a) with 1a was also determined by saturated carbonyl compounds HPLC and the de obtained (52%) was very close to that cal- culated on the basis of the relative intensities of the signals of the aldehydic protons in the 1H NMR spectrum (56%). All the products were obtained as colorless syrups, The chromatogram of the mixture of the diastereomers which could not be crystallized. The 1H NMR spectra indi- 3a+4a can be found in the Supporting Information. cated each to be a mixture of two diastereomers. In the case Also in other cases, the de as determined on the basis of of a,b,c, and e, two characteristic signals for the aldehydic the 1H NMR spectra ranged from 52% to 98%, except in the protons in the range of δ ca. 9 and 8 ppm confirmed the reaction of (S)- and (R)-α-methylbenzylamines with trans- presence of two diastereomers in each case, the relative crotonaldehyde (1b) when it was found to be 20% and 38%, percentages of which could be calculated on the basis of the respectively. The low diastereoselectivity in these cases relative intensities of these signals. The presence of two di- may be attributed to the smaller size of the β-methyl group. astereomers was further corroborated by two 13C NMR sig- We attempted to rationalize the experimentally ob- nals in the range of 195–160 ppm. These parts of the 1H and served diastereoselectivity in the reaction of (S)-α-methyl- 13C NMR spectra of the product (3a+4a) obtained from the benzylamine with trans-cinnamaldehyde theoretically by reaction of (S)-α-methylbenzylamine (2a) with trans-cin- computing two model reactions initiated by the attack of namaldehyde (1a) are shown in Figure 1. the amine on Si and Re faces of the aldehyde (Figure 2). It may be noted that the aldehydic proton of the major Geometries of the products 3a and 4a resulting from the diastereomer gives a double doublet (dd) at δ = 9.71 ppm attack of the amine on Si and Re faces, respectively, were 3 3 ( JH–H = 7.7 Hz, JH–H = 1.0 Hz) due to its coupling with the optimized at the B3LYP/6-31+G* level and frequency calcu- vicinal diastereotopic protons HA and HB. However, the al- lations were carried out at the same level. Thus, total ener- dehydic proton of the minor diastereomer gives a simple gies of the products were calculated by summing up the re- 3 doublet at δ = 8.12 ppm ( JH–H = 8.1 Hz), possibly due to the spective energies with the uncorrected zero-point correc- orthogonal disposition of one of the two diastereotopic tion energies and are given in Table 1. protons with respect to it. In the 13C NMR spectrum, signals at δ = 192.2 and 161.6 ppm are observed due to aldehydic carbon atoms of the two diastereomers. Georg Thieme Verlag Stuttgart · New York — SynOpen 2018, 2, 122–127 124 Syn Open M. Kour et al. Paper Figure 2 Attack of (S)-α-methylbenzylamine on Si and Re faces of trans-cinnamaldehyde Table 1 Total Energies of the Two Diastereomers Resulting from the Attack of (S)-α-Methylbenzylamine on Si and Re Faces of trans-Cin- namaldehyde Product E ZPE Total energies Energy difference (a.u.) (a.u.) (a.u.) (kcal mol–1) 3a – 0.321541 –788.914894 –2.84 789.236435 4a – 0.32097 –788.919424 789.240401 We did not succeed in locating the transition structures involved in the amine attack on the Si and Re faces, and hence it has not been possible to determine which product Figure 3 Optimized geometries of the diastereomers formed from the (3a or 4a) is preferred kinetically. It can be seen, however, attack of (S)-α-methylbenzylamine on Si (3a) and Re (4a) faces of trans- that product 4a, resulting from the attack on the Re face, is cinnamaldehyde more stable than the product 3a, formed from Si attack, by 2.84 kcal mol–1.
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