Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007

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1 Supporting Information Copyright Wiley-VCH Verlag GmH & Co. KGaA, Weinheim, 2007

2 p,p-stacking versus Steric Effects in the Stereoselectivity Control. Highly Diastereoselective Synthesis of syn-1,2-diaryl Propylamines José L. García Ruano,* [a] José Alemán, [] Inés Alonso, [a] Alejandro Parra, [a] Vanesa Marcos, [a] José Aguirre [c] [a] Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantolanco, Madrid, Spain. [] Current Address: Center for Catalysis, Department of Chemistry, University of Aarhus, DK-8000, Aarhus C, Denmark. [c] Departamento de Ciencia Básicas, Universidad de Luján, Luján, Argentina. 1

3 General Methods. page 2 Synthesis of imines 3... page 2 DFT (B3LYP) for B1 and B2... page 8 Stereochemistry assignment.. page 10 Representative spectra for some compounds (tales 2-6, scheme 4) page 16 General Method: 1 H-NMR spectra were acquired at either 200 or 300 MHz and 13 C- NMR were acquired at 75 MHz (unless otherwise indicated). Chemical shifts (δ are reported in ppm relative to CDCl 3 (7.26 and 77.0 ppm). Melting points were determined in open capillary tues carried out in. All reactions were carried out in anhydrous solvents and under. Molecular sieves were activated for four days in the oven. Flash silica gel column chromatography was performed using silica gel Merk-60 ( mesh) and compound 3a (imine: PhCH=N-Ph) were purchased from Aldrich. Imines 3 e, 1 3 f, 2 3 k, 3 3e 1 and 3f 4 were previously descried. 1 Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2005, 61,

4 General procedure for synthesis of the imines 3. 5 NH 2 O N Y Y H H Z 4A MS DCM or Toluene Z Reflux or rt 3 A dried Schlenk-tue was charged with the corresponding aromatic aldehyde (1.0 mmol), the appropriate aniline (1.0 mmol), molecular sieves 4Å (1g /1.0 mmol aldehyde) and 10mL of the solvent (it was indicated in each case). The reaction mixture was stirred at temperature indicated in each case and checked y TLC until the reaction has finished. Then the crude mixture was filtered and the solvent was removed under reduced pressure, otained the pure imine without an additional purification. N-Phenyl-4-nitrileenzylidenimine (3). 6 Toluene at reflux temperature was used in a sealed tue. A white solid was oteined. Yield: 99%; mp: C; 1 H-NMR (200 MHz): δ 8.49 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), (m, 2H), (m, 3H). 13 C-NMR (75 MHz, CDCl 3 ): δ 162.4, 156.0, 135.4, 133.9, 133.8, , 132.2, 129.2, 128.9, N-Phenyl-4-trifluoromethylenzylidenimine (3c). 7 Toluene was used at reflux temperature in a sealed tue. Yellow solid was oteined. Yield: 82%; mp: C; 1 H-NMR (300 MHz): δ 8.45 (s, 1H), 7.97 (d, J =8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), (m, 2H), (m, 3H). 13 C NMR (75MHz, CDCl 3 ): δ 158.5, 151.4, 139.3, 132.9, 129.3, 128.9, 126.6, (q, J C-F = Hz), 122.0, N-Phenyl-3-chloroenzylidenimine (3d). Dichloromethane was used at room temperature. Yellow oil was otened. Yield: 92%. 1 H-NMR (200 MHz): δ 8.38 (s, 1H), 2 Barluenga, J.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2004, 43, Barton, D. H. R.; Taran, F.. Tetrahedron Lett. 1998, 39, Adel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, (a) Casey, C. P.; Johnson, J. B. J. Am. Chem. Soc. 2005, 127, () Mangeney, P.; Tejero, T. A.; Grosjean, J. N. Synthesis 1988, 3, Neuvonen, K.; Fueloep, F.; Neuvonen, H.; Koch, A.; Kleinpeter, E.; Pihlaja, K. J.Org. Chem. 2003, 68, Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K; Yamamoto, H. Org. Lett. 2006, 8,

5 (m, 1H), 7.74 (dt, J = 7.0, 1.6 Hz, 1H), (m, 7H). 13 C-NMR (50 MHz, CDCl 3 ): δ 158.4, 151.3, 137.8, 134.7, 131.0, (2C), 128.1, 127.0, 126.2, N-Phenyl-4-methylenzylidenimine (3g). 11 Dichloromethane at room temperature was used in a sealed tue. A white solid was oteined. Yield: 89%; mp: C; 1 H- NMR (300 MHz): δ?8.44 (s, 1H), 7.82 (d, J = 5.4 Hz, 2H), 7.41 (t, J = 8.2 Hz, 2H), (m, 5H), 2.45 (s, 3H). 13 C-NMR (75 MHz, CDCl 3 ): δ 160.4, 152.2, 141.8, 133.6, 129.5, 129.1, 128.8, 125.7, 120.9, N-Phenyl-4-methoxyenzylidenimine (3h). 1 Dichloromethane was at room temperature was used in a sealed tue. Orange solid was otened. Yield: 90%; mp: C; 1 H-NMR (300 MHz): δ?8.43 (s, 1H), 7.90 (d, J= 8.8 Hz, 2H), (m, 2H), (m, 3H), 7.03 (d, J= 8.8 Hz, 2H), 3.92 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ 162.2, 159.7, 152.3, 130.9, 130.5, 129.2, 129.1, 125.5, 120.8, 114.1, N-Phenyl-2-methoxyenzylidenimine (3i). 8 Dichloromethane was used at room temperature in a sealed tue. Orange oil was otened. Yield: 90%; 1 H-NMR (200 MHz): δ?8.99 (s, 1H), 8.23 (dd, J= 1.7, 8.9 Hz, 1H), (m, 3H), (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 2.89 (s, 3H). 13 C NMR (50 MHz, CDCl 3 ): δ 159.5, 156.5, 152.8, 132.6, 129.0, 127.5, 125.6, 124.7, 121.0, 120.8, 111.1, N-Phenyl-2,4-dimethoxyenzylidenimine (3l). Dichloromethane was used at room temperature in a sealed tue. Orange solid was oteined. Yield: 90%; mp: C; 1 H-RMN (200 MHz): δ 8.82 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), (m, 5H), 6.58 (ddd, J = 8.7, 2.4, 0.7 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 3.86 (s, 6H). N-Phenyl-3,4-dimethoxyenzylidenimine (3m). 9 Dichloromethane at room temperature was used in a sealed tue. Yellow solid was oteined. Yield: 99%; 1 H- NMR (200 MHz): δ 8.36 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), (m, 6H), 6.92 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H). 8 Andrews, P. C.; Peatt, A. C.; Raston, C.L. Tetrahedron Lett. 2004, 45, Chakraorti, A. K.; Bhagat, S.t; Rudrawar, S. Tetrahedron Lett. 2004, 45,

6 N-Phenyl-2,4,6-trimethoxyenzylidenimine (3o). Toluene was used at reflux temperature in a sealed tue. A yellow solid was oteined. Yield: 85%; 1 H-NMR (200 MHz): δ 8.76 (s, 1H), (m, 5H), 6.15 (s, 2H), 3.87 (s, 6H), 3.86 (s, 3H). (E)-N-((Naphthalen-6-yl)methylene)enzenamine (3p). 10 Dichloromethane was used at room temperature. A white solid was oteined. Yield: 93%; 1 H-NMR (200 MHz): δ 8.57 (s, 1H), (m, 2H), (m, 3H), (m, 2H), (m, 2H), (m, 3H). N-(4-Nitrilephenyl)-enzylidenimine (3 ). 11 Toluene at reflux temperature was used in a sealed tue. A pale yellow solid was oteined. Yield: 95%; mp: C; 1 H- NMR (200 MHz): δ 8.26 (s, 1H), (m, 2H), 7.70 (d, J = 8.1 Hz, 2H), (m, 3H), 7.25 (d, J = 8.1 Hz, 2H). 13 C-NMR (75 MHz, CDCl 3 ): δ 149.4, 146.4, 142.6, 141.4, 141.0, 137.7, 132.4, 131.9, 131.7, 130.0, 128.8, 127.8, 127.6, 127.1, 125.1, 118.7, 117.0, 112.8, 110.8, 59.0, 39.4, N-(3-Chlorophenyl)-enzylidenimine (3 d). 12 Dichloromethane at reflux temperature was used in a sealed tue. Orange solid was oteined. Yield: 91%; mp: C; 1 H-NMR (200 MHz): δ 8.36 (s, 1H), (m, 2H), (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H). 13 C-NMR (50 MHz, CDCl 3 ): δ 160.1, 150.0, 135.5, 133.9, 131.0, 128.8, 128.5, 128.4, N-(4-Methylphenyl)-enzylidenimine (3 g). 3 Dichloromethane at reflux temperature was used in a sealed tue. Yellow oil was oteined. Yield: 98%; 1 H-NMR (200 MHz): δ 8.48 (s, 1H), (m, 2H), (m, 3H), 7.22 y 7.16 (AA BB system, 4H), 2.39 (s, 3H). 13 C-NMR (50 MHz, CDCl 3 ): δ 159.5, 149.4, 136.3, 135.7, 131.1, 129.7, 128.7, 120.7, N-(4-Methoxyphenyl)-enzylidenimine (3 h). 13 Dichloromethane at room temperature was used in a sealed tue. Yellow oil was oteined. Yield: 98%; 1 H-NMR (300 MHz): δ 8.48 (s, 1H), (m, 2H), (m, 3H), 7.24 (d, J = 8.9 Hz, 2H), 10 Miecznikowski, J. R.; Cratree, R. H. Polyhedron 2004, 23, Simion, A.; Simion, C.; Kanda, T.; Nagashima, S.; Mitoma, Y.; Yamada, T.; Mimura, K.; Tashiro, M. J. Chem. Soc., Perkin Trans , 17, Narain, R. P.; Siddiqui, M. Z. Polyhedron 1985, 4, Charette, A. B.; Boezio, A. A.; Janes, M. K. Org. Lett. 2000, 2,

7 6.93 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H). 13 C-NMR (75 MHz, CDCl 3 ): δ 158.3, 144.8, 136.4, 131.0, 128.0, 128.7, 128.5, 122.1, 114.3, N-(2,4-Dimethoxyphenyl)-enzylidenimine (3 l). 14 Dichloromethane was at room temperature was used in a sealed tue. Orange oil was oteined. Yield: 90%; 1 H-NMR (300 MHz): δ?8.50 (s, 1H), 7.90 (d, J = 3.4 Hz, 2H), 7.42 (s, 3H), 7.02 (s, J = 8.5 Hz, 1H), (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H). 13 C-NMR (75 MHz, CDCl 3 ): δ 158.9, 158.8, 153.4, 136.3, 134.6, 130.6, 128.7, 128.3, 120.1, 103.9, 99.1, 55.4, N-(3,4-Dimethoxyphenyl)-enzylidenimine (3 m). Dichloromethane at room temperature was used in a sealed tue. Brown oil was oteined. Yield: 89%; 1 H-NMR (200 MHz): δ 8.49 (s, 1H), (m, 2H), (m, 3H), (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H). 13 C-NMR (50 MHz, CDCl 3 ): δ 158.6, 149.3, 147.6, 145.3, 136.3, 131.1, 128.7, 128.6, 111.9, 111.3, 105.6, 56.0, N-(2,4,6-Trimethoxyphenyl)-4-nitrileenzylidenimine (3 ). Dichloromethane was used at room temperature. The product was precipited in diethyl ether affording a yellow solid. Yield: 42%; 1 H-NMR (300 MHz): δ 8.79 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 6.21 (s, 2H), 3.83 (s, 6H), 3.82 (s, 3H). 13 C-NMR (50 MHz, CDCl 3 ): δ 160.2, 158.9, 153.6, 141.3, 132.2, 128.5, 122.4, 118.7, 113.4, 91.5, 56.1(2C), N-(2,4,6-Trimethoxyphenyl)-4-trifluoromethylenzylidenimine (3 c). Dichloromethane was used at room temperature. The product was precipited in diethyl ether affording a yellow solid. Yield: 48%; 1 H-NMR (300 MHz): δ 8.74 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 6.23(s, 2H), 3.84 (s, 2H), 3.83 (s, 6H). 13 C- NMR (75 MHz, CDCl 3 ): δ 161.7, 158.5, 153.3, 140.7, 132.3, 131.9, 128.5, (q, J C- F = Hz), 123.2, 91.6, 56.2(2C), N-(2,4,6-Trimethoxyphenyl)-4-chloroenzylidenimine (3 e). Dichloromethane was used at room temperature. The product was purified y flash chromatography (neutralized silica gel with 10% Et 3 N) in 6:1 n-hexane-acoet. Orange oil was oteined. Yield: 46%; 1 H-NMR (300 MHz): δ 8.53 (s, 1H), 7.85 (d, J = 1.7 Hz, 1H), (m, 1H), (m, 2H), 6.04 (s, 2H), 3.74 (s, 3H), 3.72 (s, 6H). 13 C-NMR (75 MHz, 14 Shimizu, M.; Makino, H. Tetrahedron Lett. 2001, 42,

8 CDCl 3 ): δ 161.9, 158.2, 153.0, 138.9, 134.8, 130.5, 129.7, 127.9, 126.7, 123.3, 91.5, 56.1(2C), N-(2,4,6-Trimethoxyphenyl)-4-methoxyenzylidenimine (3 h). Dichloromethane was used at room temperature. The product was precipited in Et 2 O affording an orange solid. Yield: 51%; 1 H-NMR (300 MHz): δ 8.49 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.22 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H). 13 C-NMR (50 MHz, CDCl 3 ): δ 163.6, 161.9, 157.4, 152.6, 130.1, 129.9, 124.7, 113.8, 91.7, 56.2, 55.4, DFT (B3LYP): Cartesian coordinates (Å) of the optimized structures and asolute energies (hartrees). Complex B1. SCF Done: E(RB+HF-LYP) = Numer of imaginary frequencies:

9 Complex B2. SCF Done: E(RB+HF-LYP) = Numer of imaginary frequencies:

10

11 Stereochemistry Assignment The configurational assignment of the syn-7 (also 7 and 7 ) and anti-6 (also 6 and 6 ) amines otained in reactions from (S)-2 were easily estalished from their NMR parameters (Tale 1). Tale 1. δ (ppm) and J (Hz) values for significant protons in the configurational assignment of compounds anti-6 and syn-7. Amine 3 J 1,2 d NH( 3 J NH) d Me Amine 3 J 1,2 d NH( 3 J NH) d Me anti-6a (4.4) 0.65 syn-7a 6.0 anti (7.1) 0.55 anti-6c (7.8) 0.60 anti-6d (6.7) 0.62 anti-6f ( a ) 0.69 syn-7f a 1.30 anti-6g (6.8) 0.62 syn-7g a 1.25 anti-6h (6.1) 0.67 syn-7h a 1.23 anti-6i a 0.73 syn-7i a 1.46 anti-6j 10, (7.0) 0.64 syn-7j a 1.38 anti-6m 10, (4.7) 0.64 syn-7m 6.1 anti-6l syn-7l a 1.47 anti-6o 10.9 anti-6p syn-7o anti a 0.43 syn anti-6 d (7.0) 0.57 syn-7 d a 1.50 anti-6 e (7.2) 0.57 syn-7 e a 1.13 anti-6 f (6.2) 0.65 anti-6 g ( a ) 0.74 syn-7 g 5.8 anti-6 h ( a ) 0.74 syn-7 h 5.9 anti-6 m ( a ) 0.64 syn-7 m 5.8 syn-7 l 6.8 anti anti-6 c syn-7 a ( ) 4.73 a syn syn-7 c a 1.52 anti-6 d a 0.87 syn-7 d 8.5 syn-7 f 7.5 syn-7 g

12 a Broad singlet. Not oserved. syn-7 h Compounds designed as anti-6 exhiit values of 3 J 1,2 = 10 Hz (Tale 1) indicative of the significant preference of the rotamer around the C(1)-C(2) ond which displays such protons in antiperiplanar arrangement. By contrast, compounds designed as syn-7 exhiit values 3 J 1,2 6-7 Hz (Tale 1), which suggests an average of the contriution of rotamers with anti and gauche arrangements, oth of them having a significant population. Taking into account that the rotamers with only two gauche interactions will e favored and that the (Ar/Ar ) gauche interaction is the most destailizing one of those existing around the C(1)-C(2) ond, compounds with erithroconfiguration (1R,2R- or 1S,2S-) at this fragment must exhiit a large predominance of conformations like A (fig. 1) and therefore a high value of 3 J 1,2. By contrast, the threo isomers (1R,2S- and 1S,2R-) will have a significant population of the rotamers B (only two gauche interactions) and C (lacking of the (Ar 1 /Ar 2 ) gauche interaction) indicated in Figure 1, and therefore an average value for 3 J 1,2 must e expected. They allow to assign unamiguously the erytro configuration to the C(1)-C(2) fragment of the anti-6 isomers and the threo-one to that of the syn-7 isomers. H 2 Ar 1 NHAr 3 erythro-isomers 3 J 1,2 > 10 Hz (1R,2R) or (1S,2S) Me Ar 2 H 1 Me A rotamer H 2 Ar 1 NHAr 3 Ar 1 NHAr 3 threo-isomers: H 2 Ar 2 (1R,2S) or (1S,2R) Ar 2 Me 3 J 1,2 6-7 Hz H 1 H 1 B rotamer C rotamer Figure 1. Presumaly most populated rotamers for erythro and threo isomers around the C(1)-C(2) ond. Additionally, the chemical shifts and the coupling constants of the aminic protons at compounds 6 are larger than those at 7 (even not oserved in many cases). It suggests that the participation of the NH in hydrogen onds with the sulfinyl oxygen is easier for compounds 6. Taking into account that all the studied compounds have the (S) configuration at sulfur, only the erythro isomer (1S,2S,SS)-6 would e ale to form 11

13 stale intramolecular hydrogen onds, ecause the (1R,2R,SS)-6, also exhiiting erythro configuration at the C(1)-C(2) fragment, can not form them ecause the oxygen and the NH are oriented to the opposite face in the most stale conformation around the C(2)-Ar ond (with the lone pait at sulfur oriented towards the ortho caron) as it can e seen in Figure 2. Tol H 1 S O H N Tol Ar 3 S O H 1 Me Ar 3 H 2 H 2 Ar 1 Me (1S, 2S, SS) (1R, 2R, SS) Figure 2. Spatial arrangement of the sustituents for the two erythro isomers. This assignment is supported y several reasons. The first one is that the reactions of (S)-2 with all the studied electrophiles (alkoxycaronyl halides, caronyls, N-sulfinyl imines, esters, and alkyl halides) induce the (S) configuration at enzylic position, which is C(2) at the resulting amine. On the asis of this criteria we can assigned the (S) configuration at the enzyl position for oth compounds anti-6 (1S,2S,SS)- and compounds syn-7 (1R,2S,SS). Moreover, the chemical shift of the methyl group at compounds anti-6 is too low (~ Hz), and clearly differentiated than that shown y the syn-7 isomers (~ Hz, Tale 1). It can e explained as a consequence of the shielding effect of the aromatic ring Ar 1, joined to C(1), which is properly oriented with respect to the methyl group in (1S,2S,SS)-6 due to its interactions with Ar 3 (See Fig. 2). The inequivocal assignment of the syn and anti isomers was performed y X-ray diffraction studies of compounds anti-6 and syn-7i (Figure 3). The crystalline structure of anti-6 display the aminic hydrogen oriented towards the sulfinyl oxygen indicating the existence of an intramolecular hydrogen ond, thus confirming the predictions ased on the NMR parameters of the NH proton. The spatial arrangement of the Ar 1 group with respect to the methyl one also supports the suggested shielding effect. 12

14 Ph Me S H 14 H 16 O Me syn-7i Tol O : Tol S O H 14 Me CN H N H16 anti-6 Figure 3. ORTEP for compounds syn-7i and anti-6. There are other NMR parameters that are completely different for compounds 6 and 7, which allow their unamiguous differentiation. They are the chemical shifts of the protons H(1) and H(4) (Fig.2), with the first one eing respectively ~0.3ppm lower and ~ ppm higher for compounds 6 than for the 7 ones. These differences must e related to the relative orientation and the anisotropic effects of the rings and the sulfinyl oxygen, ut their rationalization is sot so ovious and therefore they were not initially valid for their unequivocal configurational assignments. Once they were unamiguously estalished from other criteria, these differences can also e used with configurational assignment purposes. In this sense, we can assign the (S) configuration at C(1) to those 13

15 compounds exhiiting lower δ-h(1) and higher δ-h(4) than those corresponding to the (R) epimers at C(1). Configurational assignment of compounds 4 and 5 is not so easy ecause the main criteria used for assigning compounds 6 and 7, the 3 J 1,2 value, was not applicale ecause 4 and 5 exhiit ABX systems with two coupling constants of similar values (usually one smaller than the other). Fortunately, the large difference of the δ values for H(1) and H(4) is maintained, which provides a criteria for their differentiation as well as for their tentative configurational assignment. Configuration (1S,SS) was assigned to compounds 4 ecause they present lower δ-h(1) and higher δ-h(4) values than those of the corresponding compounds 5, which were assigned as their (1R,SS) epimers at C(1). The δ value is usually higher than 0.2 ppm in oth protons. This tentative assignment was confirmed on the three following reasons: a) In the cases where the signal of the NH proton is visile for oth diastereoisomers, δ(nh) values are always higher for compounds 4 than for 5 ( δ~ ppm) as it happened for compounds 6 (larger) and 7 (lower) (see aove). ) Isomers 4 h and 5 h were respectively chemically correlated with (S)- and (R)- 1,2-diphenyl ethylamines [(S)-15 and (R)-15] 15 (Scheme 1). This was made y using two differents ways, CAN/Ni-Ra or y Ni-Ra/CAN, otaining in oth cases identical results (Scheme 1). Tol S O 4 h CAN CH 3 CN, H 2 O Ni-Ra THF 95% (S)-13 NHPMP NHPMP (R)-13 Ni-Ra 90% Tol 71% CAN CAN CAN 77% 75% CH 3 CN, H 2 O 72% CH 3 CN, H 2 O CH 3 CN, H 2 O THF S O 5 h Tol S O NH 2 Ni-Ra THF 81% NH 2 (S)-15 NH 2 (R)-15 Ni-Ra THF Tol 72% S O NH 2 (S)-16 [α] D 20 : [α] D 20 : (R)-16 Scheme 1. Correlation of amines 4 h and 5 h with García Ruano, J. L.; Alemán, J.; Soriano, J. F. Org. Lett., 2003, 5,

16 c) The unequivocal assignment of compound (1R,SS)-5 h was estalished y X-ray diffraction studies (Figure 4). O S H 5'h Figure 4. ORTEP for compound 5 h 15

17 Representative compounds spectrum for tale 2-6 and scheme 4. Ph CN 4 16

18 Ph CN 4 Ph MeO 4l 17

19 Ph MeO 4l Ph CN 6 18

20 Ph CN 6 Ph MeO 7i 19

21 Ph MeO 7i CN Ph 4 20

22 CN 4 Ph SOTol CN 6' 21

23 CN Ph 6 Ph 7 n 22

24 Ph 7 n MeO Cl 5 e 23

25 MeO Cl 5 e MeO CF 3 7 c 24

26 MeO CF 3 7 c NH 2 Ph syn-11a 25

27 NH 2 Ph syn-11a NH 2 syn-12a 26

28 NH 2 syn-12a 27