COMMUNICATION DOI: 10.1002/asia.201402943
Chiral Ammonium Betaine-Catalyzed Highly Stereoselective Aza-Henry Reaction of a-Aryl Nitromethanes with Aromatic N-Boc Imines Daisuke Uraguchi,[a] Keigo Oyaizu,[a] Haruhiro Noguchi,[a] and Takashi Ooi*[a, b]
Abstract: A highly stereoselective aza-Henry reaction of aaryl nitromethanes with aromatic N-Boc imines was established by using C1-symmetric chiral ammonium betaine as a bifunctional organic base catalyst. Various substituted aryl groups for both imines and nitromethanes were tolerated in the reaction, and a series of precursors for the synthesis of unsymmetrical anti-1,2-diaryl ethylenediamines was provided.
Largely as a straightforward route to optically active vicinal diamines and a-amino carbonyl compounds, the asymmetric aza-Henry reaction has been the subject of numerous investigations over the past decades, and a number of highly stereoselective catalytic methodologies have been elaborated.[1, 2] Among these, coupling of a-aryl nitromethanes with aromatic imines offers an attractive tool for the construction of symmetric and unsymmetric chiral 1,2-diarylethylenediamine skeletons through simple reduction of the nitro functional group. However, despite the significant relevance of this class of diamines to the core structures of various therapeutic agents as well as chiral ligands and catalysts,[3] the available synthesis protocols are extremely limited; the recent contribution from Johnstons group utilizing bisACHTUNGRE(amidine) catalysis represents the only successful example known to date.[4, 5] In conjunction with our continuous efforts to expand the potential of C1-symmetric chiral ammonium betaines of type 1 as a bifunctional organic base catalyst,[6–11] we report herein our approach to this problem; that is, the relative and absolute stereochemistry of the coupling between a-aryl nitromethanes and N-Boc arylaldimines can be precisely controlled under the efficient catalysis of 1, there-
Figure 1. Aza-Henry route to 1,2-diarylethylenediamines and structures of C1-symmetric chiral ammonium betaine 1.
by giving rapid access to structurally diverse 1,2-diarylethylenediamine derivatives (Figure 1).[12] We initially conducted the aza-Henry reaction of aphenyl nitromethane (3 a) with benzaldehyde-derived N-Boc imine 2 a in toluene in the presence of chiral ammonium betaine 1 a (2 mol %) and molecular sieves 4 (MS 4) at 30 8C.[13] Bond formation was completed within 24 h, and the desired adduct 4 aa was isolated in quantitative yield as a diastereomeric mixture (anti/syn = 5:1). Fortunately, the enantiomeric excess of the major anti-isomer was revealed to be 86 % by chiral stationary-phase HPLC analysis (Table 1, entry 1). We then focused our investigation on the effect of 3,3’-substituents in the binaphthyl backbone (Ar1 and Ar2) on the selectivity profile. The electronic property rather than the steric demand of the pendent aromatic nuclei appeared important in the relative and absolute stereocontrol as the introduction of a 4-trifluoromethylphenyl group at the 3-position of the naphthyl unit with the methylenetrimethylammonium appendage at the 2-position (Ar2) led to a significant improvement of both the diastereo- and enantioselectivity (entry 2 vs. 3). Installation of a more electron-deficient but bulky aromatic substituent such as the 3,5-bis(trifluoromethyl)phenyl group did not have a positive impact on the stereochemical outcome (entry 4). Eventually, chiral ammonium betaine 1 e bearing 4-trifluoromethylphenyl groups on both naphthyl units exhibited high catalytic activity and excellent enantiocontrolling ability (entry 5).[14] With the optimal catalyst structure in hand, we explored the substrate generality of the 1 e-catalyzed stereoselective aza-Henry reaction; the representative results are summarized in Table 2. With various substituted aromatic N-Boc
[a] Dr. D. Uraguchi, K. Oyaizu, H. Noguchi, Prof. Dr. T. Ooi Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied Chemistry, Graduate School of Engineering Nagoya University Nagoya 464-8603 (Japan) E-mail: [email protected] [b] Prof. Dr. T. Ooi CREST, Japan Science and Technology Agency (JST) Nagoya University Nagoya 464-8603 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402943.
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the stereoselectivity was enhanced when methyl- and methoxy-substituted imines were employed. Fused and heteroaromatic imines were also tolerated in the reaction, but at a slight expense of diastereoselectivity (entries 6 and 7). The present catalytic system was applicable to a range of a-aryl nitromethanes 3, where the effect induced by the electronic properties of the aryl substituents on the selectivity was opEntry 1 t [h] Yield [%][b] d.r. [anti/syn][c] ee [%][d] posite to that observed with substituted imines 2 (entries 8– 1 1a 24 99 5:1 86/88 12); incorporation of electron-withdrawing groups into the 2 1b 24 99 7:1 79/87 aromatic moiety of 3 was beneficial, whereas the attachment 3 1c 24 92 15:1 94/91 4 1d 24 98 7:1 79/96 of electron-donating groups was detrimental. In addition, 15 1e 12 97 11:1 98/95 (2-naphthyl)nitromethane (3 g) was found to be a good can[a] Reactions were carried out with 0.1 mmol of 2 a, 0.11 mmol of 3 a, and didate, and the corresponding aza-Henry adduct 4 ag was 0.002 mmol of 1 in 0.5 mL of toluene with 100 mg of MS 4 at 30 8C obtained quantitatively with a diastereomeric ratio of 10:1 under argon atmosphere. [b] Isolated yields. [c] Diastereomeric ratios and 97 % ee for the anti-isomer (entry 13). As expected, ar1 were determined through H NMR (400 MHz) spectroscopic analysis of bitrary combinations of imine electrophiles and a-aryl nitrocrude aliquots. [d] Enantiomeric excesses of products 4 were determined by chiral HPLC using a Daicel CHIRALCEL AD-3 column with methane nucleophiles were well accommodated and excela hexane/ethanol solvent system. Absolute and relative stereochemistries lent stereoselectivities were consistently obtained (enof anti- and syn-4 aa were determined by a single-crystal X-ray diffraction tries 14–17).[15] Finally, the scalability of this protocol was analysis of its derivative (Scheme 1) and an epimerization experiment demonstrated by the reaction of 2 a with 3 a on a gram scale (Scheme 2). under otherwise standard conditions, which afforded 4 aa with a comparable degree of efficiency and stereocontrol (entry 18). The subsequent recrystallization afforded 0.8 g of imines 2, consistent yet high levels of stereocontrol were the essentially stereochemically pure anti-4 aa. possible (entries 1–5). It is worth noting, however, that Product 4 could be readily derivatized into the correa subtle decrease in both diastereo- and enantioselectivity sponding 1,2-diarylethylenediamine by the two-step sewas observed with imines having halide substituents, while quence exemplified in Scheme 1. Reduction of the Table 2. Substrate scope of the 1 e-catalyzed aza-Henry reaction of a-aryl nitromethane 3 with N-Boc imines nitro functionality of anti-4 ab 2.[a] by CoCl2/NaBH4, followed by deprotection under acidic conditions, furnished the differently substituted diamine anti-6 ab in 61 % yield (2 steps). Mean3 4 [b] [c] [d] while, intermediate anti-5 aa deEntry Ar (2) Ar (3) Yield [%] d.r. [anti/syn] ee [%] Prod. (4) rived from anti-4 aa was con1 o-FC6H4 (2 b) Ph (3 a) 99 11:1 93/91 4 ba verted into the 4-phenylbenzePh (3 a) 98 16:1 96/94 4 ca 2 m-MeOC6H4 (2 c) Ph (3 a) 99 10:1 93/80 4 da 3 p-BrC6H4 (2 d) nesulfonamide derivative anti4 p-MeC6H4 (2 e) Ph (3 a) 99 12:1 97/96 4 ea[e] 7 aa; X-ray diffraction analysis 5 p-MeOC6H4 (2 f) Ph (3 a) 92 19:1 97/95 4 fa[e] of its single crystal prepared by [e] 6 2-naphthyl (2 g) Ph (3 a) 99 8:1 95/97 4 ga recrystallization from a 1,4-di7 2-furyl (2 h) Ph (3 a) 99 10:1 93/92 4 ha 92 > 20:1 97/95 4 ab 8 Ph (2 a) o-FC6H4 (3 b) oxane/diethyl ether solvent 99 9:1 96/90 4 ac 9 Ph (2 a) m-MeOC6H4 (3 c) system at room temperature al98 12:1 98/93 4 ad 10 Ph (2 a) p-BrC6H4 (3 d) lowed us to assign the absolute 99 8:1 95/95 4 ae 11 Ph (2 a) p-MeC6H4 (3 e) stereochemistry of anti-4 aa to 99 8:1 90/91 4 af 12 Ph (2 a) p-MeOC6H4 (3 f) be 1S,2R.[16] 13 Ph (2 a) 2-naphthyl (3 g) 99 10:1 97/96 4 ag o-FC6H4 (3 b) 91 > 20:1 98/94 4 bb 14 o-FC6H4 (2 b) To further understand the p-BrC6H4 (3 d) 92 17:1 96/89 4 bd 15 o-FC6H4 (2 b) stereochemical outcome of the o-FC6H4 (3 b) 91 > 20:1 98/94 4 fb 16 p-MeOC6H4 (2 f) catalysis of chiral ammonium p-BrC6H4 (3 d) 90 > 20:1 93/90 4 fd 17 p-MeOC6H4 (2 f) f betaine 1 e, the absolute stereoPh (2 a) Ph (3 a) 99 11:1 97/97 4 aa 18 chemistry of the minor isomer [a] Unless otherwise noted, reactions were carried out with 0.1 mmol of 2, 0.11 mmol of 3, and 0.002 mmol of was determined. A diastereo1 e in 0.5 mL of toluene with 100 mg of MS 4 at 30 8C under argon atmosphere. [b] Isolated yields. [c] Diastereomeric ratios were determined through 1H NMR (400 MHz) spectroscopic analysis of crude mixtures. meric mixture of 4 aa (d.r. = [d] Enantiomeric excesses were determined by chiral stationary phase HPLC. Absolute and relative configura11:1, 98 % ee/95 % ee) was tions of aza-Henry adducts 4 were assigned by analogy to 4 aa, 4 ea, 4 fa, and 4 ga. [e] Absolute and relative treated with a stoichiometric [4] configurations of anti-isomers were determined by comparison to literature data. [f] The reaction was peramount of triethylamine at formed with 3.5 mmol of 2 a, 3.85 mmol of 3 a, and 0.07 mmol of 1 d in 17.5 mL of toluene with 3.5 g of MS 4 room temperature to facilitate at 30 8C under argon atmosphere. Table 1. Effect of substituents at the 3-position of each naphthyl unit of chiral ammonium betaine 1.[a]
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the practical synthesis of non-racemic anti-1,2-diarylethylenediamines.
Experimental Section Representative Procedure for the Catalytic Asymmetric Aza-Henry Reaction of a-Aryl Nitromethanes 3 to Aromatic N-Boc Imines 2 A magnetic stirrer bar and powdered 4 molecular sieves (MS 4, 100 mg) was placed in an oven-dried test tube under argon (Ar) atmosphere. The MS 4 were dried with a heat gun under reduced pressure for 5 min and the test tube was refilled with Ar. Chiral ammonium betaine 1 e (1.26 mg, 0.0020 mmol) and toluene (0.50 mL) were added to the test tube successively under Ar at 25 8C. After the mixture was cooled to 30 8C, a-phenyl nitromethane 3 a (15.1 mg, 0.11 mmol) and benzaldehyde-derived N-Boc imine 2 a (20.5 mg, 0.10 mmol) were introduced to the tube sequentially. The reaction mixture was stirred for 12 h and then poured into ice-cooled 1 N aqueous HCl. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na2SO4, and filtered. All volatiles were removed by evaporation to afford the product with a diastereomeric ratio of anti/syn = 11:1, as determined by 1H NMR (400 MHz) spectroscopic analysis of the crude residue. Purification of the residue by column chromatography on silica gel (hexane/EtOAc = 3:1) gave 4 aa as a mixture of diastereomers (33.2 mg, 97 %), whose enantiomeric excesses were determined by HPLC analysis (98 % ee for the anti-isomer). 4 aa: HPLC: AD3, hexane/EtOH = 10:1, flow rate = 0.5 mL min 1, l = 210 nm, 20.3 min (1S,2R), 23.3 min (1R,2S), 24.3 min (1R,2R), 41.1 min (1S,2S); 1H NMR (400 MHz, CDCl3) anti isomer: d = 7.60–7.54 (2 H, m), 7.46–7.15 (8 H, m), 5.78 (1 H, br d, J = 9.2 Hz), 5.68 (1 H, br s), 4.86 (1 H, br s), 1.25 ppm (9 H, s); 13C NMR (101 MHz, CDCl3) anti isomer: d = 154.4, 137.7, 131.6, 130.3, 129.2, 129.0, 128.9, 128.1, 127.3, 94.4, 80.6, 56.8, 28.2 ppm; IR (film): n˜ = 3397, 2978, 2928, 1684, 1547, 1518, 1364, 1292, 1250, 1165, 756 cm 1; HRMS (ESI) calcd for C19H22N2O4Na + ([M+Na] + ) 365.1472. Found 365.1470.
Scheme 1. Derivatization of anti-4 ab to the corresponding 1,2-diarylethylenediamine anti-6 ab. Determination of the absolute and relative stereochemistry of aza-Henry adduct 4 aa, and ORTEP diagram of anti-7 aa (ellipsoids displayed at the 50 % probability level. A solvent molecule (1,4dioxane) and calculated hydrogen atoms except for those attached to stereogenic carbon atoms are omitted for clarity).
epimerization at the stereogenic carbon attached to the nitro group (Scheme 2). The resulting nearly equal mixture of anti- and syn-4 aa was analyzed by chiral HPLC, showing an enantiomeric excess of 97 % for both diastereomers. In other words, epimerization with the weak organic base affected only the diastereomeric ratio but not the enantiomeric ratio. This result clearly indicates that the minor diastereomer syn-4 aa has 1S,2S configuration and is indeed diastereomeric to anti-4 aa at the carbon connected to the nitro group. This strongly suggests that the chiral ammonium betaine 1 e rigorously discriminates the prochiral faces of NBoc aldimines 2 in the carbon–carbon bond-forming event. In conclusion, a highly stereoselective aza-Henry reaction of a-aryl nitromethanes with aromatic imines was achieved under the catalysis of chiral ammonium betaine 1 e. This simple and broadly useful protocol would be appreciated in
Acknowledgements This work was supported by NEXT program, CREST-JST, Program for Leading Graduate Schools “Integrative Graduate Education and Research Program in Green Natural Sciences” in Nagoya University, and Grants of JSPS for Scientific Research.
Keywords: asymmetric synthesis · betaines · aza-Henry reaction · organocatalysis · a-aryl nitromethane
[1] N. Ono in The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001. [2] a) E. Marqus-Lpez, P. Merino, T. Tejero, R. P. Herrera, Eur. J. Org. Chem. 2009, 2401 – 2420; b) A. Noble, J. C. Anderson, Chem. Rev. 2013, 113, 2887 – 2939. [3] a) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed. 1998, 37, 2580 – 2627; Angew. Chem. 1998, 110, 2724 – 2772; b) J.-C. Kizirian, Chem. Rev. 2008, 108, 140 – 205; c) F. Cardona, A. Goti, Nat. Chem. 2009, 1, 269 – 275; d) D. S. Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13 – 31. [4] a) T. A. Davis, J. N. Johnston, Chem. Sci. 2011, 2, 1076 – 1079; b) T. A. Davis, A. E. Vilgelm, A. Richmond, J. N. Johnston, J. Org. Chem. 2013, 78, 10605 – 10616; c) B. A. Vara, A. Mayasundari, J. C. Tellis, M. W. Danneman, V. Arredondo, T. A. Davis, J. Min, K. Finch, R. K. Guy, J. N. Johnston, J. Org. Chem. 2014, 79, 6913 – 6938. [5] a) N. Nishiwaki, K. R. Knudsen, K. V. Gothelf, K. A. Jørgensen, Angew. Chem. Int. Ed. 2001, 40, 2992 – 2995; Angew. Chem. 2001,
Scheme 2. Epimerization of aza-Henry adduct 4 aa for determination of the absolute stereochemistry of syn-4 aa.
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[14] [15]
[16]
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Seidel, J. Am. Chem. Soc. 2011, 133, 14538 – 14541; d) C. Min, N. Mittal, C. K. De, D. Seidel, Chem. Commun. 2012, 48, 10853 – 10855 and references therein. The addition of MS 4 is crucial for attaining reproducibility and high enantioselectivity, probably because a small amount (< 5 %) of water from slightly hygroscopic 1 would be incorporated into a hydrogen-bonding network in the transition state, causing a substantial decrease in enantioselectivity. The reaction between 2 a and 3 a with 1 a as a catalyst in the absence of MS 4 afforded the adduct 4 aa in 99 % yield with a diastereomeric ratio of 5:1, and the enantiomeric excess of the major isomer was determined to be 69 %. Additional data of structural optimization of the catalyst are included in the Supporting Information. Although the present protocol could be applied to aliphatic N-Boc aldimines, the enantioselectivity significantly dropped. For example, reaction of nonanal-derived imine 2 (Ar3 = (CH2)7Me) with 3 a under the optimized conditions gave the corresponding adduct 4 (Ar3 = (CH2)7Me, Ar4 = Ph) in 64 % yield with a diastereomeric ratio of 11:1, and the enantiomeric excess of the major isomer was determined to be 34 %. CCDC 1018060 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. Received: August 11, 2014 Revised: September 1, 2014 Published online: && &&, 0000
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COMMUNICATION Organocatalysis Daisuke Uraguchi, Keigo Oyaizu, Haruhiro Noguchi, &&&&—&&&& Takashi Ooi* What we need is tolerance: A highly stereoselective aza-Henry reaction of a-aryl nitromethanes with aromatic NBoc imines was established by using C1-symmetric chiral ammonium betaine as a bifunctional organic base
catalyst. The reaction tolerated various substituted aryl groups for both imines and nitromethanes, and a series of precursors for the synthesis of unsymmetrical anti-1,2-diaryl ethylenediamines was provided.
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Chiral Ammonium Betaine-Catalyzed Highly Stereoselective Aza-Henry Reaction of a-Aryl Nitromethanes with Aromatic N-Boc Imines
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chiral Ammonium Betaine-Catalyzed Highly Stereoselective Aza-Henry Reaction of a-Aryl Nitromethanes with Aromatic N-Boc Imines Daisuke Uraguchi,[a] Keigo Oyaizu,[a] Haruhiro Noguchi,[a] and Takashi Ooi*[a, b]
Abstract: A highly stereoselective aza-Henry reaction of aaryl nitromethanes with aromatic N-Boc imines was established by using C1-symmetric chiral ammonium betaine as a bifunctional organic base catalyst. Various substituted aryl groups for both imines and nitromethanes were tolerated in the reaction, and a series of precursors for the synthesis of unsymmetrical anti-1,2-diaryl ethylenediamines was provided.
Largely as a straightforward route to optically active vicinal diamines and a-amino carbonyl compounds, the asymmetric aza-Henry reaction has been the subject of numerous investigations over the past decades, and a number of highly stereoselective catalytic methodologies have been elaborated.[1, 2] Among these, coupling of a-aryl nitromethanes with aromatic imines offers an attractive tool for the construction of symmetric and unsymmetric chiral 1,2-diarylethylenediamine skeletons through simple reduction of the nitro functional group. However, despite the significant relevance of this class of diamines to the core structures of various therapeutic agents as well as chiral ligands and catalysts,[3] the available synthesis protocols are extremely limited; the recent contribution from Johnstons group utilizing bisACHTUNGRE(amidine) catalysis represents the only successful example known to date.[4, 5] In conjunction with our continuous efforts to expand the potential of C1-symmetric chiral ammonium betaines of type 1 as a bifunctional organic base catalyst,[6–11] we report herein our approach to this problem; that is, the relative and absolute stereochemistry of the coupling between a-aryl nitromethanes and N-Boc arylaldimines can be precisely controlled under the efficient catalysis of 1, there-
Figure 1. Aza-Henry route to 1,2-diarylethylenediamines and structures of C1-symmetric chiral ammonium betaine 1.
by giving rapid access to structurally diverse 1,2-diarylethylenediamine derivatives (Figure 1).[12] We initially conducted the aza-Henry reaction of aphenyl nitromethane (3 a) with benzaldehyde-derived N-Boc imine 2 a in toluene in the presence of chiral ammonium betaine 1 a (2 mol %) and molecular sieves 4 (MS 4) at 30 8C.[13] Bond formation was completed within 24 h, and the desired adduct 4 aa was isolated in quantitative yield as a diastereomeric mixture (anti/syn = 5:1). Fortunately, the enantiomeric excess of the major anti-isomer was revealed to be 86 % by chiral stationary-phase HPLC analysis (Table 1, entry 1). We then focused our investigation on the effect of 3,3’-substituents in the binaphthyl backbone (Ar1 and Ar2) on the selectivity profile. The electronic property rather than the steric demand of the pendent aromatic nuclei appeared important in the relative and absolute stereocontrol as the introduction of a 4-trifluoromethylphenyl group at the 3-position of the naphthyl unit with the methylenetrimethylammonium appendage at the 2-position (Ar2) led to a significant improvement of both the diastereo- and enantioselectivity (entry 2 vs. 3). Installation of a more electron-deficient but bulky aromatic substituent such as the 3,5-bis(trifluoromethyl)phenyl group did not have a positive impact on the stereochemical outcome (entry 4). Eventually, chiral ammonium betaine 1 e bearing 4-trifluoromethylphenyl groups on both naphthyl units exhibited high catalytic activity and excellent enantiocontrolling ability (entry 5).[14] With the optimal catalyst structure in hand, we explored the substrate generality of the 1 e-catalyzed stereoselective aza-Henry reaction; the representative results are summarized in Table 2. With various substituted aromatic N-Boc
[a] Dr. D. Uraguchi, K. Oyaizu, H. Noguchi, Prof. Dr. T. Ooi Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied Chemistry, Graduate School of Engineering Nagoya University Nagoya 464-8603 (Japan) E-mail: [email protected] [b] Prof. Dr. T. Ooi CREST, Japan Science and Technology Agency (JST) Nagoya University Nagoya 464-8603 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402943.
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the stereoselectivity was enhanced when methyl- and methoxy-substituted imines were employed. Fused and heteroaromatic imines were also tolerated in the reaction, but at a slight expense of diastereoselectivity (entries 6 and 7). The present catalytic system was applicable to a range of a-aryl nitromethanes 3, where the effect induced by the electronic properties of the aryl substituents on the selectivity was opEntry 1 t [h] Yield [%][b] d.r. [anti/syn][c] ee [%][d] posite to that observed with substituted imines 2 (entries 8– 1 1a 24 99 5:1 86/88 12); incorporation of electron-withdrawing groups into the 2 1b 24 99 7:1 79/87 aromatic moiety of 3 was beneficial, whereas the attachment 3 1c 24 92 15:1 94/91 4 1d 24 98 7:1 79/96 of electron-donating groups was detrimental. In addition, 15 1e 12 97 11:1 98/95 (2-naphthyl)nitromethane (3 g) was found to be a good can[a] Reactions were carried out with 0.1 mmol of 2 a, 0.11 mmol of 3 a, and didate, and the corresponding aza-Henry adduct 4 ag was 0.002 mmol of 1 in 0.5 mL of toluene with 100 mg of MS 4 at 30 8C obtained quantitatively with a diastereomeric ratio of 10:1 under argon atmosphere. [b] Isolated yields. [c] Diastereomeric ratios and 97 % ee for the anti-isomer (entry 13). As expected, ar1 were determined through H NMR (400 MHz) spectroscopic analysis of bitrary combinations of imine electrophiles and a-aryl nitrocrude aliquots. [d] Enantiomeric excesses of products 4 were determined by chiral HPLC using a Daicel CHIRALCEL AD-3 column with methane nucleophiles were well accommodated and excela hexane/ethanol solvent system. Absolute and relative stereochemistries lent stereoselectivities were consistently obtained (enof anti- and syn-4 aa were determined by a single-crystal X-ray diffraction tries 14–17).[15] Finally, the scalability of this protocol was analysis of its derivative (Scheme 1) and an epimerization experiment demonstrated by the reaction of 2 a with 3 a on a gram scale (Scheme 2). under otherwise standard conditions, which afforded 4 aa with a comparable degree of efficiency and stereocontrol (entry 18). The subsequent recrystallization afforded 0.8 g of imines 2, consistent yet high levels of stereocontrol were the essentially stereochemically pure anti-4 aa. possible (entries 1–5). It is worth noting, however, that Product 4 could be readily derivatized into the correa subtle decrease in both diastereo- and enantioselectivity sponding 1,2-diarylethylenediamine by the two-step sewas observed with imines having halide substituents, while quence exemplified in Scheme 1. Reduction of the Table 2. Substrate scope of the 1 e-catalyzed aza-Henry reaction of a-aryl nitromethane 3 with N-Boc imines nitro functionality of anti-4 ab 2.[a] by CoCl2/NaBH4, followed by deprotection under acidic conditions, furnished the differently substituted diamine anti-6 ab in 61 % yield (2 steps). Mean3 4 [b] [c] [d] while, intermediate anti-5 aa deEntry Ar (2) Ar (3) Yield [%] d.r. [anti/syn] ee [%] Prod. (4) rived from anti-4 aa was con1 o-FC6H4 (2 b) Ph (3 a) 99 11:1 93/91 4 ba verted into the 4-phenylbenzePh (3 a) 98 16:1 96/94 4 ca 2 m-MeOC6H4 (2 c) Ph (3 a) 99 10:1 93/80 4 da 3 p-BrC6H4 (2 d) nesulfonamide derivative anti4 p-MeC6H4 (2 e) Ph (3 a) 99 12:1 97/96 4 ea[e] 7 aa; X-ray diffraction analysis 5 p-MeOC6H4 (2 f) Ph (3 a) 92 19:1 97/95 4 fa[e] of its single crystal prepared by [e] 6 2-naphthyl (2 g) Ph (3 a) 99 8:1 95/97 4 ga recrystallization from a 1,4-di7 2-furyl (2 h) Ph (3 a) 99 10:1 93/92 4 ha 92 > 20:1 97/95 4 ab 8 Ph (2 a) o-FC6H4 (3 b) oxane/diethyl ether solvent 99 9:1 96/90 4 ac 9 Ph (2 a) m-MeOC6H4 (3 c) system at room temperature al98 12:1 98/93 4 ad 10 Ph (2 a) p-BrC6H4 (3 d) lowed us to assign the absolute 99 8:1 95/95 4 ae 11 Ph (2 a) p-MeC6H4 (3 e) stereochemistry of anti-4 aa to 99 8:1 90/91 4 af 12 Ph (2 a) p-MeOC6H4 (3 f) be 1S,2R.[16] 13 Ph (2 a) 2-naphthyl (3 g) 99 10:1 97/96 4 ag o-FC6H4 (3 b) 91 > 20:1 98/94 4 bb 14 o-FC6H4 (2 b) To further understand the p-BrC6H4 (3 d) 92 17:1 96/89 4 bd 15 o-FC6H4 (2 b) stereochemical outcome of the o-FC6H4 (3 b) 91 > 20:1 98/94 4 fb 16 p-MeOC6H4 (2 f) catalysis of chiral ammonium p-BrC6H4 (3 d) 90 > 20:1 93/90 4 fd 17 p-MeOC6H4 (2 f) f betaine 1 e, the absolute stereoPh (2 a) Ph (3 a) 99 11:1 97/97 4 aa 18 chemistry of the minor isomer [a] Unless otherwise noted, reactions were carried out with 0.1 mmol of 2, 0.11 mmol of 3, and 0.002 mmol of was determined. A diastereo1 e in 0.5 mL of toluene with 100 mg of MS 4 at 30 8C under argon atmosphere. [b] Isolated yields. [c] Diastereomeric ratios were determined through 1H NMR (400 MHz) spectroscopic analysis of crude mixtures. meric mixture of 4 aa (d.r. = [d] Enantiomeric excesses were determined by chiral stationary phase HPLC. Absolute and relative configura11:1, 98 % ee/95 % ee) was tions of aza-Henry adducts 4 were assigned by analogy to 4 aa, 4 ea, 4 fa, and 4 ga. [e] Absolute and relative treated with a stoichiometric [4] configurations of anti-isomers were determined by comparison to literature data. [f] The reaction was peramount of triethylamine at formed with 3.5 mmol of 2 a, 3.85 mmol of 3 a, and 0.07 mmol of 1 d in 17.5 mL of toluene with 3.5 g of MS 4 room temperature to facilitate at 30 8C under argon atmosphere. Table 1. Effect of substituents at the 3-position of each naphthyl unit of chiral ammonium betaine 1.[a]
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the practical synthesis of non-racemic anti-1,2-diarylethylenediamines.
Experimental Section Representative Procedure for the Catalytic Asymmetric Aza-Henry Reaction of a-Aryl Nitromethanes 3 to Aromatic N-Boc Imines 2 A magnetic stirrer bar and powdered 4 molecular sieves (MS 4, 100 mg) was placed in an oven-dried test tube under argon (Ar) atmosphere. The MS 4 were dried with a heat gun under reduced pressure for 5 min and the test tube was refilled with Ar. Chiral ammonium betaine 1 e (1.26 mg, 0.0020 mmol) and toluene (0.50 mL) were added to the test tube successively under Ar at 25 8C. After the mixture was cooled to 30 8C, a-phenyl nitromethane 3 a (15.1 mg, 0.11 mmol) and benzaldehyde-derived N-Boc imine 2 a (20.5 mg, 0.10 mmol) were introduced to the tube sequentially. The reaction mixture was stirred for 12 h and then poured into ice-cooled 1 N aqueous HCl. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na2SO4, and filtered. All volatiles were removed by evaporation to afford the product with a diastereomeric ratio of anti/syn = 11:1, as determined by 1H NMR (400 MHz) spectroscopic analysis of the crude residue. Purification of the residue by column chromatography on silica gel (hexane/EtOAc = 3:1) gave 4 aa as a mixture of diastereomers (33.2 mg, 97 %), whose enantiomeric excesses were determined by HPLC analysis (98 % ee for the anti-isomer). 4 aa: HPLC: AD3, hexane/EtOH = 10:1, flow rate = 0.5 mL min 1, l = 210 nm, 20.3 min (1S,2R), 23.3 min (1R,2S), 24.3 min (1R,2R), 41.1 min (1S,2S); 1H NMR (400 MHz, CDCl3) anti isomer: d = 7.60–7.54 (2 H, m), 7.46–7.15 (8 H, m), 5.78 (1 H, br d, J = 9.2 Hz), 5.68 (1 H, br s), 4.86 (1 H, br s), 1.25 ppm (9 H, s); 13C NMR (101 MHz, CDCl3) anti isomer: d = 154.4, 137.7, 131.6, 130.3, 129.2, 129.0, 128.9, 128.1, 127.3, 94.4, 80.6, 56.8, 28.2 ppm; IR (film): n˜ = 3397, 2978, 2928, 1684, 1547, 1518, 1364, 1292, 1250, 1165, 756 cm 1; HRMS (ESI) calcd for C19H22N2O4Na + ([M+Na] + ) 365.1472. Found 365.1470.
Scheme 1. Derivatization of anti-4 ab to the corresponding 1,2-diarylethylenediamine anti-6 ab. Determination of the absolute and relative stereochemistry of aza-Henry adduct 4 aa, and ORTEP diagram of anti-7 aa (ellipsoids displayed at the 50 % probability level. A solvent molecule (1,4dioxane) and calculated hydrogen atoms except for those attached to stereogenic carbon atoms are omitted for clarity).
epimerization at the stereogenic carbon attached to the nitro group (Scheme 2). The resulting nearly equal mixture of anti- and syn-4 aa was analyzed by chiral HPLC, showing an enantiomeric excess of 97 % for both diastereomers. In other words, epimerization with the weak organic base affected only the diastereomeric ratio but not the enantiomeric ratio. This result clearly indicates that the minor diastereomer syn-4 aa has 1S,2S configuration and is indeed diastereomeric to anti-4 aa at the carbon connected to the nitro group. This strongly suggests that the chiral ammonium betaine 1 e rigorously discriminates the prochiral faces of NBoc aldimines 2 in the carbon–carbon bond-forming event. In conclusion, a highly stereoselective aza-Henry reaction of a-aryl nitromethanes with aromatic imines was achieved under the catalysis of chiral ammonium betaine 1 e. This simple and broadly useful protocol would be appreciated in
Acknowledgements This work was supported by NEXT program, CREST-JST, Program for Leading Graduate Schools “Integrative Graduate Education and Research Program in Green Natural Sciences” in Nagoya University, and Grants of JSPS for Scientific Research.
Keywords: asymmetric synthesis · betaines · aza-Henry reaction · organocatalysis · a-aryl nitromethane
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Scheme 2. Epimerization of aza-Henry adduct 4 aa for determination of the absolute stereochemistry of syn-4 aa.
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Seidel, J. Am. Chem. Soc. 2011, 133, 14538 – 14541; d) C. Min, N. Mittal, C. K. De, D. Seidel, Chem. Commun. 2012, 48, 10853 – 10855 and references therein. The addition of MS 4 is crucial for attaining reproducibility and high enantioselectivity, probably because a small amount (< 5 %) of water from slightly hygroscopic 1 would be incorporated into a hydrogen-bonding network in the transition state, causing a substantial decrease in enantioselectivity. The reaction between 2 a and 3 a with 1 a as a catalyst in the absence of MS 4 afforded the adduct 4 aa in 99 % yield with a diastereomeric ratio of 5:1, and the enantiomeric excess of the major isomer was determined to be 69 %. Additional data of structural optimization of the catalyst are included in the Supporting Information. Although the present protocol could be applied to aliphatic N-Boc aldimines, the enantioselectivity significantly dropped. For example, reaction of nonanal-derived imine 2 (Ar3 = (CH2)7Me) with 3 a under the optimized conditions gave the corresponding adduct 4 (Ar3 = (CH2)7Me, Ar4 = Ph) in 64 % yield with a diastereomeric ratio of 11:1, and the enantiomeric excess of the major isomer was determined to be 34 %. CCDC 1018060 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. Received: August 11, 2014 Revised: September 1, 2014 Published online: && &&, 0000
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COMMUNICATION Organocatalysis Daisuke Uraguchi, Keigo Oyaizu, Haruhiro Noguchi, &&&&—&&&& Takashi Ooi* What we need is tolerance: A highly stereoselective aza-Henry reaction of a-aryl nitromethanes with aromatic NBoc imines was established by using C1-symmetric chiral ammonium betaine as a bifunctional organic base
catalyst. The reaction tolerated various substituted aryl groups for both imines and nitromethanes, and a series of precursors for the synthesis of unsymmetrical anti-1,2-diaryl ethylenediamines was provided.
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Chiral Ammonium Betaine-Catalyzed Highly Stereoselective Aza-Henry Reaction of a-Aryl Nitromethanes with Aromatic N-Boc Imines
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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