Stereoselective Quaternization of r-Amino Phenylacetonitriles Mediated by a Remote Sulfinyl Group† Jose´ Luis Garcı´a Ruano,* Ana M. Martı´n-Castro,* Francisco Tato, and Ine´s Alonso Departamento de Quı´mica Orga´ nica, UniVersidad Auto´ noma de Madrid, Cantoblanco, 28049 Madrid, Spain
[email protected] ReceiVed March 23, 2007
Enantiomerically pure R-substituted R-amino phenylacetonitriles have been readily prepared from 2-ptolylsulfinylbenzaldimines following a two-step sequence: a moderately stereoselective hydrocyanation of the imines and a completely stereoselective quaternization of the resulting diastereoisomeric mixture of R-amino phenylacetonitriles with different alkylating or acylating reagents in the presence of KHMDS. Theoretical calculations support a stereoselectivity control exerted by the remote sulfinyl group, as long as it is responsible for the conformational preferences of the benzyllithium intermediates, which suffer the attack of the electrophiles to the less hindered diastereotopic face.
Introduction Hydrocyanation of imines has been extensively studied due to the large interest in the resulting R-amino nitriles not only because of their versatility as building blocks in the preparation of countless organic compounds but also due to their inherent reactivity.1 Consequently, there have been reported many hydrocyanating systems for the preparation of aldimine-derived amino nitriles.2 Moreover, several general methods for the synthesis of R-amino nitriles making use of a one-pot, threecomponent condensation of aldehydes, amines, and cyanide in the presence of different catalytic systems have also been described.3 By contrast, the number of reports concerning † This article is dedicated to Professor Dr. Vicente Gotor on the occasion of his 60th birthday. * To whom correspondence should be addressed. FAX: (Int) +34914973966.
(1) (a) Enders, D.; Shilvock, J. Chem. Soc. ReV. 2000, 29, 359. (b) Gro¨ger, H. Chem. ReV. 2003, 103, 2795. (c) North, M. In Science of Synthesis (Houben-Weyl); Murahashi, S.-i., Ed.; Georg Thieme: Stuttgart, 2004; Vol. 19, p 285. (2) (a) Surendra, K.; Srilakshmi Krishnaveni, N.; Mahesh, A.; Rama Rao, K. J. Org. Chem. 2006, 71, 2532. (b) Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 4595. (c) De, S. K. Synth. Commun. 2005, 35, 1577. (d) De, S. K. J. Mol. Catal. A: Chem. 2005, 225, 169. (e) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M. Tetrahedron 2004, 60, 1767. (f) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2004, 45, 9565. (g) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M.; Vishnumurthy, P. New J. Chem. 2003, 27, 462.
hydrocyanation of ketimines is considerably smaller,2h probably due to the easy reversibility of the hydrocyanation process (most of the reported diastereoselective4 and enantioselective5 hydrocyanations having been restricted to cyclic or methyl ketimines). (3) (a) Oskooie, H. A.; Heravi, M. M.; Bakhtiari, K.; Zadsirjan, V.; Bamoharram, F. F. Synlett 2006, 1768. (b) Wang, H.-S.; Zhao, L.-F.; Du, Z. M. Chin. J. Chem. 2006, 24, 135. (c) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2004, 45, 7407. (d) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529. (e) Hanafusa, T.; Ichihara, J.; Ashida, T. Chem. Lett. 1987, 687. (4) (a) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006, 8, 1379. (b) Garcı´a Ruano, J. L.; Cifuentes Garcı´a, M.; Navarro, A. L.; Tato, F.; Martı´n Castro, A. M. ARKIVOC 2005 (vi), 33. (c) Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Synthesis 2005, 575. (d) Badorrey, R.; Cativiela, C.; Dı´az-de-Villegas, M. D.; Dı´ez, R.; Galbiati, F.; Ga´lvez, J. A. J. Org. Chem. 2005, 70, 10102. (e) Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029. (f) Li, B.-F.; Yuan, K.; Zhang, M.-J.; Wu, H.; Dai, L.-X.; Wang, Q. R.; Hou, X.-L. J. Org. Chem. 2003, 68, 6264. (g) Fondekar, K. P. P.; Volk, F.-J.; Khaliq-uz-Zaman, S. M.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2002, 13, 2241. (h) Warmuth, R.; Munsch, T. E.; Stalker, R. A.; Li, B.; Beatty, A. Tetrahedron 2001, 57, 6383. (i) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. J. Org. Chem. 2000, 65, 8704. (j) Wede, J.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 2000, 11, 3231. (5) (a) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147. (b) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153. (c) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153. (d) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634. (e) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. 10.1021/jo0705519 CCC: $37.00 © 2007 American Chemical Society
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Published on Web 07/13/2007
Quaternization of R-Amino Phenylacetonitriles SCHEME 1
Additionally, it is well-known that reactions of metalated R-amino nitriles with the appropriate electrophiles (alkyl or acyl halides, epoxides, aldehydes, and Michael acceptors) afford ketimine-derived amino nitriles.6 The racemic version of this methodology has been applied as an intermediate step in the synthesis of a number of naturally occurring or pharmacologically active compounds.7 Nevertheless, a low and not easily predictable stereocontrol has been found in the few asymmetric reactions of lithiated R-amino nitriles, containing enantiopure amine auxiliaries, with Michael acceptors6b-d and aldehydes.6e Therefore, the search for efficient general methods for synthesizing optically pure R,R-disubstituted R-amino nitriles is currently an important challenge in asymmetric synthesis. Recently we have reported a highly stereoselective method for the hydrocyanation of 2-p-tolylsulfinyl benzaldehyde (1).8 The hydrocyanation of the corresponding ketones was not so successful, and their optically pure cyanohydrins were prepared by a highly diastereoconvergent quaternization of the anions resulting from O-protected cyanohydrins derived from aldehyde 1, with a series of electrophiles (Scheme 1).9 Significant differences in the stereochemical evolution of CdO and CdN bonds under hydrocyanation conditions had been previously evidenced for β-keto-10 and β-iminosulfoxides4b (only the first ones could be hydrocyanated in a completely stereoselective way), but there were no precedents describing differences of behavior between oxygenated and nitrogenated carbanions under quaternization conditions. Therefore, the results reported in refs (6) (a) Enders, D.; Kirchhoff, J.; Gerdes, P.; Mannes, D.; Raabe, G.; Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur. J. Org. Chem. 1998, 63 and references therein. (b) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837. (c) Enders, D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659. (d) Roux, M.-C.; Wartski, L.; Nierlich, M.; Lauce, M. Tetrahedron 1996, 52, 10083. (e) Enders, D.; Lotter, H.; Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. NouV. J. Chim. 1984, 8, 747. (7) For leading references see: (a) Wang, S.; Dong, Y.; Wang, X.; Hu, X.; Liu, J. O.; Hu, Y. Org. Biomol. Chem. 2005, 3, 911. (b) Haning, H.; Niewoehner, U.; Schenke, T.; Lampe, T.; Hillisch, A.; Bischoff, E. Biorg. Med. Chem. Lett. 2005, 15, 3900. (c) Yu, G.; Wang, S.; Wang, K.; Hu, Y.; Hu, H. Synthesis 2004, 1021. (d) Snider, B. B.; Gu, Y. Org. Lett. 2001, 3, 1761. (e) Paulitz, C.; Steglich, W. J. Org. Chem. 1997, 62, 8474. (f) Silks, L. A., III; Dunkle, E.; Unkefer, C. J.; Sudmeier, J. L.; Butler, M.; Bachovchin, W. W. J. Labelled. Compd. Radiopharm. 1995, 36, 947. (g) Wang, C.; Mosberg, H. I. Tetrahedron Lett. 1995, 36, 3623. (h) Subramanyam, C.; Ault, B.; Sawutz; D.; Bacon, E. R.; Singh, B.; Pennock, P. O.; Kelly, M. D.; Kraynak, M.; Krafte, D.; Treasurywala, A. J. Med. Chem. 1995, 38, 587. (8) Garcı´a Ruano, J. L.; Martı´n Castro, A. M.; Tato, F.; Ca´rdenas, D. J. Tetrahedron: Asymmetry 2005, 16, 1963. (9) Garcı´a Ruano, J. L.; Martı´n Castro, A. M.; Tato, F.; Pastor, C. J. J. Org. Chem. 2005, 70, 7346. (10) (a) Garcı´a Ruano, J. L.; Martı´n Castro, A. M.; Rodrı´guez, J. H. Tetrahedron Lett. 1991, 32, 3195. (b) Garcı´a Ruano, J. L.; Martı´n Castro, A. M.; Rodrı´guez, J. H. J. Org. Chem. 1992, 57, 7235.
TABLE 1. Synthesis of (S)-2-p-Tolylsulfinyl Benzaldimines 2-10
entry
R
additive
1 2 3 4 5 6 7 8 9
C6H5 4-MeO-C6H4 4-NO2-C6H4 C6H5CH2 4-CF3-C6H4CH2 4-MeO-C6H4CH2 i-Bu MeSO2 p-TolSO2
Na2SO4 Na2SO4 Na2SO4 Na2SO4 Na2SO4 Na2SO4 Na2SO4 Et3N, TiCl4 Et3N, TiCl4
T t yield solvent (°C) (h) imine (%) CH2Cl2 rt CH2Cl2 rt toluene 108 CH2Cl2 rt CH2Cl2 rt CH2Cl2 rt CH2Cl2 rt CH2Cl2 40 DCE 83
16 16 96 16 16 16 16 5 4
2 3 4 5 6 7 8 9 10
91 86 75 87 87 93 90 65 82
8 and 9 prompted us to investigate the behavior of imines 2 derived from 1 under different hydrocyanating conditions, as well as the reaction of the resulting mixtures of R-amino-(2-ptolylsulfinyl)phenyl acetonitriles under quaternization conditions, with the aim of developing a ready access to hydrocyanated phenyl ketimine derivatives. These results are reported in this paper. Results The syntheses of the optically pure sulfinyl imines used as the starting materials for hydrocyanation reactions were performed following conventional procedures from (S)-2-p-tolylsulfinyl benzaldehyde (1)8 (Table 1). Reactions of 1 with arylamines (entries 1-3), benzylamines (entries 4-6), and isobutylamine (entry 7), were accomplished in high yields in the presence of an excess of Na2SO4. Treatment of 1 with methyl and p-tolyl sulfonamides (R ) MeSO2, p-TolSO2 in Table 1) in the presence of Et3N and TiCl4 also afforded the corresponding N-p-tolylsulfinylbenzylidene sulfonamides11 (entries 8 and 9) in good yields. Hydrocyanation of freshly prepared sulfinylbenzaldimines 2-10 was assayed with Et2AlCN under different experimental conditions (solvent, temperature, reaction time, amount of reagent, and addition mode). Diastereoselectivities were lower at temperatures below 0 °C. Similarly, less polar solvents (CH2Cl2, toluene) decreased the reactivity (longer reaction times (11) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29, 3725.
J. Org. Chem, Vol. 72, No. 16, 2007 5995
Garcı´a Ruano et al. TABLE 2. Hydrocyanation of Sulfinylimines 4-10
TABLE 3. δ Values for the Benzylic Protons of Amino Nitriles 11-17 and 11′-17′
entry imine 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a
4 4 5 5 6 6a 7 8 9 9 10 10 10a 10a
R
t (h)
Lewis acid
amino nitriles
11-17:11′-17′ ratio (yield [%])b
4-NO2-C6H4 4-NO2-C6H4 C6H5CH2 C6H5CH2 4-CF3-C6H4CH2 4-CF3-C6H4CH2 4-MeO-C6H4CH2 i-Bu MeSO2 MeSO2 p-TolSO2 p-TolSO2 p-TolSO2 p-TolSO2
2 2 2 2 16 16 16 16 2 2 2 2 2 1
Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 -
11 + 11′ 11 + 11′ 12 + 12′ 12 + 12′ 13 + 13′ 13 + 13′ 14 + 14′ 15 + 15′ 16 + 16′ 16 + 16′ 17 + 17′ 17 + 17′ 17 + 17′ 17 + 17′
39:61 (75) 28:72 48:52 (90) 29:71 41:59 (86) 36:64 40:60 (88) 49:51 (74) 58:42 (86) 61:39 90:10 (90) 89:11 85:15 91:9
R
amino nitrile
1H δ (CH-CN)
amino nitrile
1H δ (CH-CN)
∆δ
4-NO2-C6H4 C6H5CH2 4-CF3-C6H4CH2 4-MeO-C6H4CH2 i-Bu MeSO2 p-TolSO2
11 12 13 14 15 16 17
6.56 4.85 4.95 4.81 4.84 5.89 5.72
11′ 12′ 13′ 14′ 15′ 16′ 17′
6.80 5.45 5.46 5.41 5.42 6.07 6.07
0.34 0.60 0.51 0.60 0.58 0.18 0.35
Inverse addition. b Combined yield of both diastereoisomers
being needed) and did not improve the diastereoselectivity. In some cases, TMSCN was also used as the cyanide source. The best results were obtained in THF using an excess (4 equiv) of Et2AlCN (TMSCN gave poorer results). Under these optimized conditions the reactions with different imines are summarized in Table 2. N-Phenylimine 1 and N-p-methoxyphenylimine 2 did not react with an excess of Et2AlCN under any of the studied conditions. Imines 4-9 provided diastereoisomeric mixtures with low stereoselectivities (Table 2). When the reactions evolved under Yb(OTf)3 catalysis, slight changes in the epimeric ratio were observed in some cases, but they were not so large as to provide highly stereoselective transformations. We have also investigated the role of the temperature in the reactions catalyzed by Yb(OTf)3. The best results were detected at 0 °C, which suggests that lower temperatures must hinder the association of the catalyst to the basic centers of the substrates. Finally, in some cases, the addition mode of the reagent also had a small influence on the stereoselectivity. Only imine 10 evolved with high levels of stereoselectivity (de’s ranged between 70 and 80%), which were scarcely modified by the above-mentioned factors (entries 11-14). The combined yields obtained in these reactions are usually higher than 74%, but the isolation of each diastereoisomer was rather difficult due to the easy retrohydrocyanation observed during chromatographic purifications. From the stereochemical point of view, the main conclusion deduced from the results collected at Table 2 is that the control exerted by the sulfinyl group on the stereoselectivity of the hydrocyanation reactions of imines 4-9 was only moderate, much lower than that observed in similar processes catalyzed by Yb(OTf)3 from the corresponding aldehyde.8 By contrast, 10 reacted with high stereoselectivity (70-80% de) regardless the experimental conditions. These results suggest that the composition of the mixtures obtained from reactions of 4-9 is the consequence of a thermodynamic equilibration of the resulting amino nitriles with the starting imines. Only those mixtures obtained from 10 correspond to kinetic control processes, probably due to the 5996 J. Org. Chem., Vol. 72, No. 16, 2007
FIGURE 1. Presumably most stable conformations for [2S,(S)S] and [2R,(S)S] epimers (11-17 and 11′-17′).
higher stability of the amide anion derived from 17 and 17′, which makes difficult the retrohydrocyanation. Configurational assignment of epimers 11-17 and 11′-17′ was initially based on their 1H NMR spectra. The main difference between both epimers is the chemical shift of their benzylic protons, which is clearly lower for isomers 11-17 (∆δ ≈ 0.5-0.6 ppm for N-alkylderivatives and ∼0.18-0.35 ppm for N-aryl and N-sulfonylderivatives, Table 3). In Figure 1 are depicted presumably the most stable conformations for both epimers, taking into account the fact that the strong dipolar repulsion between the CtN and SfO bonds will arrange them as far as possible unless it involves strong steric interactions. Thus, a significant population can be expected for rotamers A and B, respectively stabilized by dipolar and steric factors, at the (S,S)-epimers (Figure 1), the first one presumably being favored. By contrast, the sterically favored D rotamers must be clearly predominant for the (R,S)-epimers as a result of the strong steric restrictions of the electrostatically stabilized C conformations. The spatial arrangement of the benzylic proton at A rotamers suggests that it will be shielded by the aromatic ring at the (S,S) epimers (see Table 3 graphic), whereas it is not the case for such a proton in the most populated D conformation for the (R,S) isomers. Therefore, the chemical shifts of the benzylic protons at (S,S) epimers should be lower than those of the (R,S) isomers. This criteria allowed us to assign the (S,S) configuration to epimers 11-17. This assignment was unequivocally confirmed by X-ray diffraction analysis of
Quaternization of R-Amino Phenylacetonitriles SCHEME 2
SCHEME 3
compounds 13′ and 17, which exhibit the absolute configurations [2R,(S)S] and [2S,(S)S],12 respectively. In order to corroborate this configurational assignment, a 12 + 12′ mixture (38:62) was hydrolyzed (HCl(g)/HCO2H, 0 °C, 10 h) into the corresponding sulfenyl R-amino amide (18),13 which was subsequently desulfenylated (Raney Ni, THF/EtOH). The resulting R-amino amide 19 exhibits an [R]20D value of -16.6 (c 0.5, CHCl3), of the sign opposite to that reported for enantiomerically pure (S)-(2-benzylamino)-2-phenylacetamide (19) {[R]20D +71 (c 1.0, CHCl3)}.14 This result confirms that the starting 12 + 12′ mixture was enriched in the epimer with R configuration at carbon, which means that the major epimer 12′ has [2R,(S)S] configuration (Scheme 2). All attempts to achieve the hydrocyanation of ketimines were unsuccessful, since they were recovered unaltered after several hours under hydrocyanating conditions. This prompted us to explore the use of the mixtures of amino nitriles obtained from o-sulfinylbenzaldimines as starting materials for quaternization processes. Initially, we used mixtures 17 + 17′ as the starting material. Treatment of these mixtures with 1-4 equiv of base (LHMDS, KHMDS, LDA, n-BuLi) followed by addition of 1-8 equiv of MeI, allowing the reaction to evolve at different temperatures (from -78 °C up to rt), invariably led to complex mixtures where only N-[2-(p-tolylsulfinyl)phenylethylidene]-ptoluenesulfonamide (20) and methyl 2-[p-(tolylsulfinyl)phenyl]ketone (21) could be detected in ∼10% yield determined by 1H NMR (Scheme 3). The low proportion of these compounds, which would result from quaternization of 17 + 17′ followed by elimination of HCN and hydrolysis of the resulting ketimine, suggests that they must be formed in secondary processes. Next we explored the behavior of N-benzylamino nitriles 12 + 12′ as the starting materials for quaternization processes, because the CH acidity of R-amino nitriles derived from aromatic aldehydes is known to be larger than their NH acidity,15 and therefore, it should be expected that benzylic carbanion (12) Crystallographic data (excluding structure factors) for 13′, 17, and 23 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers 638581, 638582, and 638583, respectively. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax: +44(0)-1223-366033 or e-mail:
[email protected]]. (13) The reduction of the sulfinyl into the sulfenyl group takes place under conditions used for the hydrolysis of the CN group. (14) Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin Trans. 1 1998, 22, 3747. (15) Kison, C.; Meyer, N.; Opatz, T. Angew. Chem., Int. Ed. 2005, 44, 5662.
TABLE 4. Reactions of Amino Nitriles 12 + 12′ with Different Electrophiles
entry
electrophile
t (h)
product
dra (yield,b %)
1 2 3 4 5 6 7 8 9
MeI MeI (18-crown-6) EtOTf PhCH2Br CH2dCH-CH2Br ClCO2Me MeOH HCl(g) HBF4
1 2 2 2 2 0.5 0.5 0.5 0.5
22 22 23 24 25 26 12 + 12′ 12 + 12′ 12 + 12′
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