CHAPTER 17

PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS OF4-METHYLENE PYRROLIDINES

Lynda J. Brown, Richard C. D. Brown, and Martin L. Fisher

The School of Chemistry, The University of Southampton, Highfield,Southampton, UK

Library synthesis route

Building blocks

Solid-Phase Organic Syntheses, Volume 2: Solid-Phase Palladium Chemistry, First Edition.Edited by Peter J. H. Scott.© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

157

158 PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS

1 PROCEDURES

1.1 Synthesis of 3-Polystyryl-Propionic Acid

To a suspension of NaH (1.33 g of a 60% dispersion in mineral oil,33.0 mmol) (note 1) in DMF (35 mL) (note 2) in a 100-mL round bottomflask, diethyl malonate (5.0 mL, 33.0 mmol) (note 3) was added dropwise,over 20 min. After hydrogen evolution ceased, the flask was fitted with areflux condenser and Merrifield resin (5.0 g, 1.0 mol equiv. of Cl per gram,2% cross-linked with DVB) (note 4) was added and the reaction heated at60◦C for 14 h (note 5). The reaction was cooled to room temperature, andthe resin collected by suction filtration using a sintered frit funnel, washingsequentially with CH2Cl2, CH3OH, H2O (note 6), CH3OH, and CH2Cl2(2 × 20 mL of each) (note 7). Drying the resin under vacuum (50◦C) for2 h afforded diethyl 2-polystyrylmethyl-malonate as a white solid (5.04 g)(notes 8 and 9). To a portion of the malonate resin (1.0 g) in THF (20 mL)(note 10) in a 50-mL round bottom flask fitted with a reflux condenser wasadded aq. KOH (2.0 mL of 2 M, 4 mmol), and the reaction heated at refluxfor 15 h. The reaction was allowed to cool to room temperature, and theresin was collected by suction filtration, washing sequentially with H2O,CH3OH, Et2O, and CH2Cl2 (2 × 20 mL of each). The resin was then sus-pended in THF (20 mL), and aq. HCl (2.0 mL of 2 M, 4 mmol) was added.The reaction was heated at reflux for 2.5 h, when evolution of CO2 gaswas observed. After cooling to room temperature, the resin was collectedby suction filtration, washing sequentially with H2O, CH3OH, Et2O, andCH2Cl2 (2 × 20 mL of each). Drying the resin under vacuum (50◦C) for 2 hafforded 3-polystyryl propionic acid as a white solid (0.95 g, 0.67 mmol/g)(notes 11 and 12).

1.2 Loading Determination of 3-Polystyryl Propionic Acid(Fmoc Method) [1]

A mixture of 3-polystyryl propionic acid (100 mg), DIC (38 mg, 0.3 mmol),and HOBt (41 mg, 0.3 mmol) (note 13) in CH2Cl2 (1 mL) was stirredunder N2 for 30 min at room temperature (note 14). To this was added asolution of H-Lys(Fmoc)-OMe.HCl (130 mg, 0.34 mmol) in N -methyl-2-pyrrolidone and N, N-diisopropylethylamine (52 μL, 0.3 mmol) (note 15),and the reaction was stirred for 15 h. The resin was collected by suctionfiltration using a sintered frit funnel and washed sequentially with CH2Cl2,DMF, CH2Cl2, CH3OH, and CH2Cl2 (15 mL of each) and dried under

PROCEDURES 159

vacuum (50◦C) for 2 h to give a yellow solid (117 mg) (note 8). A sampleof the resin (7.9 mg) was shaken in a 20% solution of piperidine in DMF(10 mL) for 30 min. The suspension was filtered using a sintered frit funnel,and the collected filtrate diluted to a total volume of 25 mL using DMF.The absorbance of the solution was recorded at 300 nm, and the loadingcalculated as described in the accompanying chapter (note 12) [2].

1.3 Synthesis of 3-Polystyryl-Propionic Acid2-Trimethylsilanylmethyl-allyl Ester

The acid resin (1.0 g, 0.60 mmol) was suspended in CH2Cl2 (12 mL) andallowed to swell for 5 min before DMAP (488 mg, 4.0 mmol) (note 16), DIC(628 μL, 4.0 mmol) (note 13), and 2-[(trimethylsilyl)methyl]-2-propen-1-ol[3] (576 mg, 4.0 mmol) (note 17) were added, and the reaction stirred gentlyat room temperature for 15 h. The resin was collected by suction filtrationusing a sintered frit funnel, washed sequentially with CH2Cl2, CH3OH, andCH2Cl2 (100 mL of each) and dried under vacuum (50◦C) for 2 h to affordthe silyl ester polystyrene as a white solid (0.95 g) (note 18).

1.4 General Procedure: Synthesis of 3-Polystyryl-Propionic Acid2-(2-Amino-2-(4-chlorophenyl)-1-ethyl)-allyl Ester

To a solution of tert-butylcarbamate (1.4 g, 12.0 mmol) and 4-chlorobenzaldehyde (1.69 g, 12.0 mmol) in CH2Cl2 (15 mL) at −78◦Cwas added BF3·OEt2 (240 μL, 2.0 mmol) (note 19), and the resultingsolution allowed to warm to room temperature. After 30 min, the resultingyellow solution was transferred, via a cannula, to a suspension of theallyl resin (1.0 g) in CH2Cl2 (5 mL) at 0◦C. The mixture was allowedto warm to room temperature and stirred for a further 6 h. The resinwas collected by suction filtration using a sintered frit funnel, washedsequentially with CH2Cl2, CH3OH, and CH2Cl2 (100 mL of each) anddried under vacuum (50◦C) for 2 h to afford the 3-polystyryl-propionicacid 2-[2-tert-butoxycarbonylamino-2-(4-chlorophenyl)-ethyl]-allyl esteras a white solid (1.06 g) (notes 8 and 20). A suspension of this resin(850 mg) in TFA (8 mL) (note 21) and CH2Cl2 (8 mL) was stirred at roomtemperature for 30 min. The resin was collected by suction filtration usinga sintered frit funnel and washed with a solution of N, N-diisopropylamine(10 mL) in CH2Cl2 (80 mL) followed by CH2Cl2 (200 mL) and driedunder vacuum (50◦C) for 2 h to afford a white solid (807 mg) (note 22).

160 PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS

1.5 General Procedure: Synthesis of 3-Polystyryl-Propionic Acid2-(2-Benzylamino-2-(4-chlorophenyl)-ethyl)-allyl Ester

To a suspension of the 3-polystyryl-propionic acid 2-(2-amino-2-(4-chlorophenyl)-ethyl)-allyl ester (0.35 g) in dichloroethane (8 mL) wereadded benzaldehyde (0.38 mL, 3.5 mmol) and acetic acid (0.16 mL)(note 23), and the reaction was stirred at room temperature for 15 h. Theresin was collected by suction filtration using a sintered frit funnel andsuspended in a solution of Me4NB(OAc)3H (0.73 g, 2.8 mmol) (note 24)in acetic acid (0.16 mL) and dichloroethane (8 mL), and the suspensionwas stirred at room temperature for 24 h. The resin was collected bysuction filtration using a sintered frit funnel, washed sequentially withCH2Cl2, CH3OH, and CH2Cl2 (150 mL of each), and dried under vacuum(50◦C) for 2 h to afford the allyl resin as a white solid (359 mg) (notes 8and 25).

1.6 General Procedure for Palladium-CatalyzedCyclization Cleavage: Synthesis of

1-Benzyl-2-(4-chlorophenyl)-4-methylidenepyrrolidine (2A)

Palladium(II) acetylacetonate (Pd(acac)2, 2.2 mg, 7.2 μmol, 0.07 equiv.based on loading of 3-polystyryl-propionic acid) (note 26) and dppe(8.5 mg, 21.4 μmol) (note 27) were added to a suspension of 3-polystyryl-propionic acid 2-(2-benzylamino-2-(4-chlorophenyl)-ethyl)-allyl ester(200 mg, 102 μmol based on loading of 3-polystyryl-propionic acid of0.60 mmol g−1) in THF (4 mL). The reaction was heated at reflux, underN2, for 12 h. The resin was collected by suction filtration using a sinteredfrit funnel and washed with CH2Cl2 (50 mL), and the solvent was removedfrom the combined filtrate under vacuum to afford the crude product(54 mg). Purification by flash chromatography (1.5 × 5.0 cm silica)eluting with Et2O:hexane (2:98) afforded 1-benzyl-2-(4-chlorophenyl)-4-methylidenepyrrolidine (2A) (note 28) as a colorless oil (20 mg, 71 μmol,70% from 3-polystyryl-propionic acid).

2 DISCUSSION

The procedure describes the synthesis of 4-methylene pyrrolidines using apalladium-catalyzed cyclization cleavage reaction [4, 5], which is adaptedfrom the solution-phase synthesis described by Trost and coworkers [6, 7].The solid-phase synthesis permits two positions of structural diversity to

DISCUSSION 161

TABLE 1 Yields of 4-Methyl Pyrrolidines.

NPh

Ph

1A

NPh

1B

NPh

N

1C

NPh

O

1D

N

Ph

NCl Cl

O

2A 2C

Entry Product Yield (%)a

1 1A 812 1B 153 1C 704 1D 305 2A 706 2C 31

aIsolated yield based on the loading of the 3-polystyryl-propionic acid (0.6 mmol/g),assuming quantitative conversion for solid-phase reactions

be introduced into the 4-methylene pyrrolidines using aldehydes as thediversity reagents. The reaction has been demonstrated by variation ofthe substituent R1 introduced during the imino-Sakurai reaction of theimmobilized allylsilane with excess N -tert-butyloxycarbonyl imine [8].Palladium-catalyzed cleavage conditions allowed the synthesis of six dif-ferent pyrrolidines. In the context of the solid-phase synthesis, a stepwiseapproach, where the imino-Sakurai reaction and cyclization cleavage reac-tions are performed in sequence (rather than in one step as a formal [3+2]cycloaddition), permits the introduction of the second diversity elementfollowing C–C bond formation. The allylic ester linker displayed goodstability to acidic, Lewis-acidic, and reductive amination conditions.

Standard carbodiimide conditions were applied to couple 2-[(trimethylsilyl)methyl]-2-propen-1-ol to the carboxylic acid resin, using anexcess of DMAP to prevent formation of an acylisourea by-product formed

162 PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS

by rearrangement of the DIC-acid adduct [9, 10]. The imino-Sakuraireaction was most effective when a large excess of the N -acylimine (23equiv.) was employed with excess BF3·OEt2 (8 equiv.) with respect to thetheoretical loading of the allyl silane. Cleavage of the Boc-protecting groupfollowed by reductive alkylation of the resulting primary amine introducedthe second element of diversity at R2. In the final step, efficient releaseof the pyrrolidines from the resin occurred under palladium-catalyzedcleavage conditions utilizing Pd(acac)2 (7 mol%) and dppe (3.0 equiv. withrespect to Pd) in THF. Gratifyingly, the crude isolated material containedrelatively little catalyst residue and other impurities as assessed by 1HNMR. The final products were purified using column chromatography onsilica gel, although other techniques such as solid-phase extraction of theamine using ion-exchange cartridges may also be applied [11].

An ideal cyclization cleavage process would allow only the releaseof the desired product from the resin, and intermediates and by-productsshould remain on the resin. Typically, we observed the products ofpalladium-catalyzed cyclization cleavage to be of superior purity thanintermediates cleaved from the resin by reductive cleavage of the esterlinker using lithium borohydride. This indicated that by-products formedon the solid-phase were not released under the cyclization cleavageconditions. Indeed, subjecting some of the immobilized intermediates tothe palladium-catalyzed cleavage conditions supported this, with relativelylittle cleaved material observed. Therefore, incomplete Boc deprotection,overalkylation, or incomplete reductive alkylation does not have a dramaticeffect on the purity of the final 4-methylene pyrrolidines.

WASTE DISPOSAL INFORMATION

All toxic materials were disposed of in accordance with Prudent Practicesin the Laboratory (Washington, D.C.: National Academy Press, 1995).

APPENDIX: EXPERIMENTAL SUPPLEMENT

3-Polystyryl-propionic acid 2-(2-tert-butoxycarbonylamino-2-phenyl-ethyl)-allyl ester: IR (on-bead) νmax: 1705 cm−1; 1H HR MAS NMR(CDCl3) (selected signals) δ 5.08 (br), 4.92 (br), 4.85 (br), 4.50 (br), 2.45(br), 1.35 (br s).

3-Polystyryl-propionic acid 2-(2-amino-2-phenyl-ethyl)-allyl ester: IR(on-bead) νmax: 1726 cm−1; 1H HR MAS NMR (CDCl3) (selected signals)δ 5.10 (br), 5.03 (br), 4.55 (br s), 4.10 (br), 2.50-2.28 (br m).

APPENDIX: EXPERIMENTAL SUPPLEMENT 163

3-Polystyryl-propionic acid 2-(2-benzylamino-2-phenyl-ethyl)-allyl ester:IR (on-bead) νmax: 1731, 1595 cm−1; 1H HR MAS NMR (CDCl3) (selectedsignals) δ 5.02 (br s), 4.91 (br s), 4.86 (br s), 3.80 (br), 3.68 (br), 3.50 (br),2.40 (br).

3-Polystyryl-propionic acid 2-[2-(cyclohexylmethyl)-2-phenyl-ethyl]-allyl ester: IR (on-bead) νmax: 1729, 1604 cm−1.

3-Polystyryl-propionic acid 2-[2-(3-pyridylmethyl)-amino-2-phenyl-ethyl]-allyl ester: IR (on-bead) νmax: 1731, 1595 cm−1.

3-Polystyryl-propionic acid 2-[2-(2-furylmethyl)-amino-2-phenyl-ethyl]-allyl ester: IR (on-bead) νmax: 1729, 1599 cm−1.

3-Polystyryl-propionic acid 2-[2-(3-pyridylmethyl)-amino-2-(4-chloro-phenyl)-ethyl]-allyl ester: IR (on-bead) νmax: 1725, 1595 cm−1.

Compound 1A. 4-Methylene-2-phenyl-1-(phenylmethyl)pyrrolidine:purification by flash chromatography (2.0 cm ×3.0 cm), elutingwith an Et2O:hexane (2:98) mixture, afforded a colorless oil. νmax(film)/cm−13060m, 3026m, 2923m, 2787s, 1662m, 1601m; 1H NMR(300 MHz, CDCl3)7.53−7.24 (10H), 4.86 (2H, s), 3.88 (1H, d, J =13.1 Hz), 3.66 (1H, d, J = 13.4 Hz), 3.57 (1H, dd, J = 6.6, 10.2 Hz),3.04 (1H, d, J = 13.1 Hz), 2.93 (1H, dddd, J = 1.1, 2.7, 5.3, 13.5 Hz),2.85 (1H, dddd, J = 1.5, 1.5, 6.6, 15.9 Hz), 2.51 (1H, ddq, J = 10.2,15.9, 4.1 Hz); 13C NMR (75 MHz, CDCl3) 147.13, 142.74, 139.45, 128.70(2× CH), 128.32, 127.74, 127.54, 126.98, 104.84, 69.82, 58.86, 58.19,42.98; (ES) m/z 250.3 ([M + H]+); HRMS (ES) m/z 250.1592 C18H20N([M + H]+) requires 250.1596.

Compound 1B. 1-(Cyclohexylmethyl)-4-methylene-2-phenylpyrrolidine:purification by flash chromatography (1.5 × 5.0 cm silica), eluting withEt2O:hexane (3:97), afforded a colourless oil. νmax (film)/cm−13012 w,2934m, 2840m, 1648 w, 1602m; 1H NMR (400 MHz, CDCl3)7.43−7.21(5H, m), 4.92 (1H, s), 4.87 (1H, s), 3.90 (1H, d, J = 13.9 Hz), 3.36 (1H,dd, J = 6.5, 10.5 Hz), 2.85 (1H, br d, J = 13.9 Hz), 2.76 (1H, dd, J =6.5, 16.4 Hz), 2.43-2.33 (1H, m), 2.27 (1H, t, J = 11.4 Hz), 2.07 (1H,br d, J = 13.4 Hz), 1.88 (1H, dd, J = 3.5, 11.4 Hz), 1.73-1.59 (3H,m), 1.53 (1H, br d, J = 12.4 Hz), 1.48-1.33 (1H, m), 1.29-1.02 (3H,m), 0.85-0.64 (2H, m); 13C NMR (100 MHz, CDCl3) 147.99, 143.72,128.70, 127.95, 127.45, 104.68, 70.82, 61.84, 59.58, 43.45, 37.20, 32.42,31.64, 27.25, 26.66, 26.45; (ES) m/z 256.2 ([M + H]+); HRMS (ES) m/z256.2069 C18H26N ([M + H]+) requires 256.2065.

Compound 1C. 3-((4-Methylene-2-phenylpyrrolidin-1-yl)methyl)pyridine:purification by flash chromatography (1.5 × 5.0 cm silica), eluting with anEt2O:hexane mixture (60:40), afforded a colorless oil. νmax (film)/cm−1

3023m, 1652 w, 1605m; 1H NMR (300 MHz, CDCl3)8.51 (2H, br s),7.65 (1H, d, J = 8.1 Hz), 7.50 (2H, d, J = 7.3 Hz), 7.43-7.28 (3H, m),

164 PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS

7.24 (1H, dd, J = 4.1, 7.0 Hz), 4.89 (2H, m), 3.84 (1H, d, J = 13.2 Hz),3.64 (1H, d, J = 13.4 Hz), 3.62 (1H, dd, J = 6.5, 10.0 Hz), 3.11 (1H, d,J = 13.4 Hz), 2.95 (1H, dd, J = 2.0, 13.2 Hz), 2.86 (1H, dd, J = 6.5,15.9 Hz), 2.53 (1H, ddq, J = 10.0, 15.9, 2.2 Hz); 13C NMR (75 MHz,CDCl3) 150.03, 148.57, 146.24, 142.13, 136.48, 134.76, 128.81, 127.77,123.48, 105.32, 69.93, 58.74, 55.41, 42.79; (ES) m/z 251.2 ([M + H]+);HRMS (ES) m/z 251.1543 C17H19N2 ([M + H]+) requires 251.1543.

Compound 1D. 1-(2-Furanylmethyl)-4-methylene-2-phenyl-pyrrolidine:purification by flash chromatography (1.5 × 5.0 cm silica), eluting withCH2Cl2, afforded a colourless oil. νmax (film)/cm−13054m, 1644m, 1597m;1H NMR (300 MHz, CDCl3) 7.48-7.25 (6H, m), 6.31 (1H, dd, J = 1.7,3.2 Hz), 6.13 (1H, d, J = 3.2 Hz), 4.91 (1H, br s), 4.88 (1H, br s), 3.76(2H, 2× d, J = 14.0 Hz), 3.56 (1H, dd, J = 6.7, 10.3 Hz), 3.27 (1H, d, J =14.0 Hz), 3.13 (1H, br d, J = 14.0 Hz), 2.81 (1H, br dd, J = 6.7, 16.2 Hz),2.51 (1H, m); 13C NMR (100 MHz, CDCl3) 152.84, 146.73, 142.34, 128.98,128.05, 127.90, 110.45, 108.53, 105.37, 69.08, 58.83, 49.37, 43.02; (ES)m/z 240.3 ([M + H]+); HRMS (ES) m/z 240.1389 C16H18NO ([M + H]+)

requires 240.1388.Compound 2C. 3-((2-(4-Chlorophenyl)-4-methylenepyrrolidin-1-

yl)methyl)pyridine: purification by flash chromatography (1.5 × 5.0 cmsilica), eluting with Et2O:hexane (60:40), afforded a colourless oil. νmax(film)/cm−13029m, 1621m, 1597m; 1H NMR (300 MHz, CDCl3) 8.53(2H, m), 7.66 (1H, br d, J = 8.0 Hz), 7.44 (2H, d, J = 6.8 Hz), 7.34 (2H,d, J = 6.8 Hz), 7.24 (1H, dd, J = 4.5, 8.0 Hz), 4.90 (2H, m), 3.81 (1H, d,J = 14.0 Hz), 3.62 (1H, d, J = 14.0 Hz), 3.57 (1H, dd, J = 6.6, 10.3 Hz),3.10 (1H, d, J = 14.0 Hz), 2.94 (1H, br dd, J = 2.2, 14.0 Hz), 2.86 (1H,br dd, J = 6.6, 16.2 Hz), 2.45 (1H, ddq, J = 10.3, 16.2, 3.0 Hz); 13CNMR (75 MHz, CDCl3) 149.93, 148.58, 145.93, 140.96, 136.33, 134.55,133.24, 129.01, 128.93, 123.44, 105.41, 70.19, 59.04, 55.70, 43.10; (ES)m/z 285.1 and 287.1 ([M + H]+); HRMS (ES) m/z 285.1160 C17H35

18ClN2([M + H]+) requires 285.1159.

NOTES

1. Sodium hydride (60% dispersed in mineral oil) was purchased from Sigma-Aldrich.Sodium hydride reacts violently with moisture to liberate hydrogen, with the risk of fire;therefore all apparatus and solvents must be rigorously dried prior to use, and adequateventilation should be in place to ensure that hydrogen gas does not accumulate in thefume hood.

2. Dimethylformamide (anhydrous, 99.8%) was purchased from Sigma-Aldrich.

3. Diethyl malonate (99%) was purchased from Sigma-Aldrich.

NOTES 165

4. Merrifield resin (200–400 mesh), cross-linked with 2% divinylbenzene, was obtainedfrom Sigma-Aldrich, loading 1.0 mmol Cl per gram. In this work, the beads were notwashed before use. However, it may be advisable to use a Soxhlet continuous extractionapparatus with a suitable solvent such as CH2Cl2 to clean up the beads prior to use.If a washing step is carried out, beads should be carefully dried at 30 −50◦C using avacuum oven.

5. Heating the suspension causes agitation of the resin beads, so no external stirring wasemployed. If stirring is required, see note 14.

6. Quenching with water may cause vigorous reaction with any residual NaH to liberatehydrogen gas (note 1).

7. Methanol (99.5%), dichloromethane (reagent grade, 99%), and diethyl ether (reagentgrade, 99%) were purchased from Fisher Scientific and used without further purification.

8. Weights of isolated resins are provided here only as a guide because of mechanicallosses encountered during manipulations of the resin, and are therefore not used toestimate reaction yields.

9. Diethyl 2-polystyrylmethyl-malonate: IR (on-bead) νmax: 1726 cm−1; 1H HR MAS NMR(CDCl3) δ 4.10 (br,–CO2CH2CH 3), 3.60 (br,–CH), 1.17 (br,–CO2CH 2CH3).

10. THF was purchased from Fisher Scientific (reagent grade, stabilized with 0.025% buty-lated hydroxytoluene) and was distilled from sodium and benzophenone prior to use.

11. 3-Polystyryl-propionic acid: IR (on-bead) νmax: 1708 cm−1.

12. For different batches of polystyrene, loadings were obtained in the range of0.60–0.84 mmol/g using the Fmoc cleavage method for determination of the loading.

13. HOBt (1-hydroxybenzotriazole hydrate, wetted with not less than 14 wt.% water, 97%,Lot No. 18620-117) and DIC (N,N′-diisopropylcarbodiimide, 99%) were purchased fromSigma-Aldrich and used without further purification.

14. Polystyrene resins may suffer mechanical damage during stirring with a magnetic stirrerbar and should be stirred only at slow speeds. The use of large, heavy stirrer bars shouldbe avoided. In most situations, agitation by other methods such as gentle shaking ispreferable.

15. H-Lys(Fmoc)-OMe.HCl (≥98%) was purchased from Novabiochem; N -methyl-2-pyrrolidone (anhydrous, 99.5%) and N,N -diisopropylethylamine (≥99%) werepurchased from Sigma-Aldrich.

16. DMAP (4-dimethylamino)pyridine (99%) was purchased from Sigma-Aldrich.

17. 2-[(Trimethylsilyl)methyl]-2-propen-1-ol was synthesized according to the proceduredescribed by Trost et al. [3].

18. 3-Polystyryl-propionic acid 2-trimethylsilanylmethyl-allyl ester: IR (on-bead) νmax:1734 cm−1; 1H HR MAS NMR (CDCl3) δ 4.89 (br), 4.75 (br), 4.45 (br), 1.50 (br s),0.00 (br s); 13C NMR (gel phase, 75 MHz, CDCl3) δ 172.55, 141.78, 109.63, 67.77,23.70, −1.28.

19. tert-Butylcarbamate (98%) and 4-chlorobenzaldehyde (97%) were purchased fromSigma-Aldrich. BF3·OEt2 (purum) was purchased from Fluka. BF3·OEt2 is extremelyhazardous, and contact with skin or eyes or inhalation causes burns. It is a flammableand corrosive liquid and should be handled in an inert atmosphere; any contact shouldbe immediately flushed with plenty of water.

20. 3-Polystyryl-propionic acid 2-[2-tert-butoxycarbonylamino-2-(4-chlorophenyl)-ethyl]-allyl ester: IR (on-bead) νmax: 1715 cm−1.

166 PALLADIUM-CATALYZED SOLID-PHASE SYNTHESIS

21. TFA (trifluoroacetic acid, 99%) was purchased from Sigma-Aldrich. Extra care shouldbe taken handling this fuming acid, as it can cause severe burns.

22. 3-Polystyryl-propionic acid 2-[2-amino-2-(4-chlorophenyl)-ethyl]-allyl ester: IR(on-bead) νmax: 1730 cm−1.

23. Benzaldehyde (≥99%) was obtained from Sigma-Aldrich, and acetic acid (reagent grade)was purchased from Fisher Scientific.

24. Me4NB(OAc)3H (tetramethylammonium triacetoxyborohydride, 95%) was obtainedfrom Sigma-Aldrich.

25. 3-Polystyryl-propionic acid 2-[2-benzylamino-2-(4-chlorophenyl)-ethyl]-allyl ester: IR(on-bead) νmax: 1730, 1600 cm−1.

26. Molar quantities and product yields are calculated on the basis that all the reaction stepson the solid phase proceeded in quantitative yield, using the loading estimated for the3-polystyryl-propionic acid.

27. Palladium(II) acetylacetonate (99%) and dppe (ethylenebis(diphenylphosphine), 99%)were obtained from Sigma-Aldrich.

28. 1-Benzyl-2-(4-chlorophenyl)-4-methylidenepyrrolidine (2A): FTIR νmax (film)/cm−1

2987m, 1638m, 1605m; 1H NMR (300 MHz, CDCl3) δ 7.51-7.40 (1H, m), 7.39-7.15(8H, m), 4.87 (2H, s), 3.83 (1H, d, J = 13.5 Hz), 3.64 (1H, d, J = 13.4 Hz), 3.55(1H, dd, J = 6.5, 9.9 Hz), 3.03 (1H, d, J = 13.4 Hz), 2.94 (1H, d, J = 13.5 Hz),2.83 (1H, dd, J = 6.5, 16.4 Hz), 2.55-2.40 (1H, m); 13C NMR (75 MHz, CDCl3)δ 146.54, 141.40, 139.15, 133.08, 129.07, 128.88, 128.68, 128.39, 127.10, 105.08,69.07, 58.76, 58.13, 42.95; MS (ES) m/z 284.2 and 286.2 ([M + H]+); HRMS (ES)m/z 284.1203 C18H35

19ClN ([M + H]+) requires 284.1206.

REFERENCES

1. Meienhofer J, Waki M, Heimer EP, Lambros TJ, Makofske RC, Chang CD. Int J PeptProtein Res 1979;13:35.

2. Brown RCD, Fisher ML. Accompanying SPOS Chapter. Solid-Phase Organic Syntheses,Volume 2: Solid-Phase Palladiun Chemistry, First Edition. Edited by Peter J. H. Scott.John Wiley & Sons; 2012. pp. 145–155.

3. Trost BMD, Chan MT, Nanninga TN. Org Synth 1984;62:58.

4. Fisher M, Brown RCD. Chem Commun 1999:1547.

5. Brown RCD, Fisher ML, Brown LJ. Org Biomol Chem 2003;1:2699.

6. Trost BM, Bonk PJ. J Am Chem Soc 1985;107:1778.

7. Trost BM, Marrs CM. J Am Chem Soc 1993;115:6636.

8. For examples of the solid-phase imino-Sakurai reaction see: van Maarseveen JH, MeesterWJN, Veerman JJN, Kruse CG, Hermkens PHH, Rutjes F, Hiemstra H. J Chem Soc[Perkin 1] 2001:994.

9. Bodanszky M, Martinez J. Synthesis 1981:333.

10. Takeda K, Ayabe A, Suzuki M, Konda Y, Harigaya Y. Synthesis 1991:689.

11. Ley SV, Baxendale IR, Bream RN, Jackson PS, Leach AG, Longbottom DA, Nesi M,Scott JS, Storer RI, Taylor SJ. J Chem Soc [Perkin 1] 2000:3815.