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Org. Synth. 2013, 90, 74-86

DOI: 10.15227/orgsyn.090.0074

Oxindole Synthesis via Palladium-catalyzed C-H Functionalization

Submitted by Javier Magano¹*, E. Jason Kiser, Russell J. Shine, and Michael H. Chen.

Checked by David Hughes

1. Procedure

A. Benzyl 4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carbox-ylate (3). A 1-L 3-necked round-bottomed flask equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) is fitted with a gas inlet adapter connected to a nitrogen line and a gas bubbler. The other two necks are capped with rubber septa; a thermocouple probe is inserted through one of the septa (Note 1). The flask is charged with methyl 4-aminobenzoate (1, 25.6 g, 169 mmol, 1 equiv), 1-benzyloxycarbonyl-4-piperidone (2, 47.0 g, 201 mmol, 1.2 equiv) and dichloromethane (300 mL) (Note 2). Glacial acetic acid (9.5 mL, 10.0 g, 167 mmol, 1 equiv) is added in one portion to the stirred solution using a graduated pipette. The flask is immersed in a room temperature water bath. Sodium triacetoxyborohydride (53.1 g, 250 mmol, 1.5 equiv) is added in 4 portions (12-14 g each) at 30-min intervals, keeping the internal temperature below 27 °C (Notes 3 and 4). After 17 h at 22-23 °C (Notes 5, 6, and 7), one septum is replaced with a 125-mL dropping funnel which is charged with 2 N aq. NaOH (125 mL, 0.25 mol, 1.5 equiv). The NaOH solution is added to the flask over 5 min (Note 8), keeping the internal temperature below 30 °C. The biphasic mixture is vigorously stirred for 1 h, then the contents are transferred to a 1-L separatory funnel and the layers separated. The organic phase is washed with water (2 × 125 mL). The dichloromethane extracts are filtered through a bed of anhydrous sodium sulfate (50 g) into a tared 1-L round-bottomed flask and concentrated by rotary evaporation (bath temperature: 40 °C; 200-250 mmHg) to 130 g. Methyl t-butyl ether (125 mL) is added and the contents are concentrated by rotary evaporation (bath temperature: 40 °C; 100 mmHg) to 130 g. Two additional methyl t-butyl ether flushes are carried out (Note 9). The flask is equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) and a 500-mL addition funnel. Methyl t-butyl ether (250 mL) is added to the flask in one portion and the resulting clear solution is stirred at 22 °C. Crystallization initiates within 10 min. The addition funnel is charged with n-heptane (250 mL), which is added drop wise over 1 h. The resulting white suspension is stirred at 20-22 °C for 1 h, then vacuum-filtered through a 350-mL medium-porosity sintered-glass funnel. The solid is washed with 1:1 (vol/vol) n-heptane/methyl t-butyl ether (50 mL) and n-heptane (50 mL). The solid is dried in a vacuum oven (70 mmHg) at 50 °C for 24 h to afford benzyl 4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate (3) (52.0 g, 84% yield) (Notes 10 and 11).

B. Benzyl 4-(2-chloro-N-(4-(methoxycarbonyl)phenyl)acetamido)-piperidine-1-carboxylate (5). A 1-L 3-necked round-bottomed flask equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) is fitted with a gas inlet adapter connected to a nitrogen line and a gas bubbler. The other two necks are capped with rubber septa; a thermocouple probe is inserted through one of the septa (Note 1). The flask is charged with benzyl 4-(4-(methoxycarbonyl)phenyl-amino)piperidine-1-carboxylate (3, 25.0 g, 68 mmol, 1 equiv), ethyl acetate (250 mL), and pyridine (8.3 mL, 103 mmol, 1.5 equiv) (Note 12). The flask is placed in an ice-water bath and cooled to an internal temperature of 3 °C. Chloroacetyl chloride (10.1 g, 89 mmol, 1.3 equiv) is added via a 12-mL syringe over 5 min, keeping the internal temperature below 10 °C. The ice-bath is removed and the orange slurry is stirred for 1.5 h at ambient temperature (Note 13). One of the septa is replaced with a 125-mL addition funnel and charged with 5% aq. KH₂PO₄ (125 mL), which is added to the reaction contents over 5 min while keeping the internal temperature below 25 °C. After stirring for 10 min (Note 14), the contents of the flask are transferred to a 1-L separatory funnel. The layers are separated and the organic layer is washed with half-saturated brine, then dried by filtration through 50 g anhydrous sodium sulfate into a 1-L round-bottomed flask. The contents are concentrated by rotary evaporation (bath temperature: 40 °C; 100 to 50 mmHg, foaming) (38 g). Methyl t-butyl ether (150 mL) is added to the flask and concentrated (bath temperature: 40 °C; 100 to 50 mmHg, foaming) to an orange oil (35 g). The flask is equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) and methyl t-butyl ether (150 mL) is added. The contents are warmed in a 50 °C water bath to dissolve the oil, then cooled to ambient temperature with stirring. Within 15 min the mixture turns turbid and a white solid begins to form (Note 15). After stirring for 4 h, the solid is filtered using a 150-mL medium porosity sintered-glass funnel and washed with methyl t-butyl ether (75 mL). The solid is dried in a vacuum oven (70 mmHg) at 40 °C for 2 days to afford benzyl 4-(2-chloro-N-(4-(methoxycarbonyl)phenyl)acetamido)-piperidine-1-carboxylate (5) (28.5 g, 94% yield) as an off-white solid (Note 16).

C. Methyl 1-(1-(benzyloxycarbonyl)piperidin-4-yl)-2-oxoindoline-5-carboxylate (6). A 500-mL 3-necked round-bottomed flask equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) is fitted with a reflux condenser with a gas inlet adapter connected to a nitrogen line and a gas bubbler. The other two necks are capped with rubber septa; a thermocouple probe is inserted through one of the septa (Note 1). The flask is charged with benzyl 4-(2-chloro-N-(4-(methoxycarbonyl)phenyl)acetamido)-piperidine-1-carboxylate (5, 20.0 g, 44.6 mmol, 1 equiv), palladium acetate (1.01 g, 4.5 mmol, 0.1 equiv), 2-(di-t-butylphosphino)biphenyl (2.74 g, 9.2 mmol, 0.2 equiv), 2-methyltetrahydrofuran (130 mL), and 2-propanol (32 mL) (Note 17). The light brown suspension is sparged subsurface with nitrogen gas for 15 min (Note 18). Triethylamine (6.93 g, 68 mmol, 1.5 equiv) is added via a 12-mL syringe and the mixture is sparged for an additional 5 min. The flask is placed in an oil bath at 80 °C and heated to an internal temperature of 74-76 °C for 2 h (Note 19). The hot mixture (Note 20) is vacuum-filtered through a pad of Celite (25 g, pre-wetted with 2-MeTHF) in a 150-mL medium-porosity sintered glass funnel into a 1-L round-bottomed flask. The flask employed to carry out the reaction is rinsed with hot (75 °C) 2-MeTHF (100 mL) and used to wash the Celite pad. The filtrate is concentrated by rotary evaporation (bath temperature: 40 °C; 40 mmHg) to give an orange-brown solid (34 g). The flask is equipped with a PTFE-coated magnetic stirring bar (3 x 1 cm) and 2-propanol (270 mL) is added. The stirred suspension is heated to a gentle reflux with a heating mantle to dissolve all solids, generating a nearly black solution. The heating mantle is turned off and the contents are allowed to cool to ambient temperature over 2 h with stirring to give thick crystallization (Note 21). The suspension is stirred for 4 h, then vacuum-filtered using a 150-mL medium-porosity sintered-glass funnel, washed with 2-propanol (2 x 30 mL, Note 22), then dried in a vacuum oven (70 mmHg) at 40 °C for 2 days to afford oxindole 6 as a gray solid (15.9 g, 87% yield) (Notes 23 and 24).

2. Notes

1. The internal temperature was monitored using a J-Kem Gemini digital thermometer with a Teflon-coated T-Type thermocouple probe (12-inch length, 1/8 inch outer diameter, temperature range -200 to +250 °C).

2. The following reagents and solvents were used as received for Step A: methyl 4-aminobenzoate (Sigma-Aldrich, 98%), 1-benzyloxycarbonyl-4-piperidone (Sigma-Aldrich, 99%), sodium triacetoxyborohydride (Sigma-Aldrich, 95%), dichloromethane (Fisher, certified ACS reagent, stabilized), glacial acetic acid (Fisher, certified ACS plus), t-butyl methyl ether (Sigma-Aldrich, >98.5%), and heptanes (Sigma-Aldrich, Chromasolv, >99%).

3. The first two Na(OAc)₃BH portions produced 3-5-degree exotherms.

4. The addition of Na(OAc)₃BH afforded a pale yellow/green, slightly cloudy mixture.

5. The submitters monitored the progress of the reaction after each Na(OAc)₃BH addition (5 additions) by quenching an aliquot with water after 30 min, diluting with 9/1 MeCN/water and analyzing by UPLC (Note 6). The results were (limiting reagent/product ratio): 1^st portion: 42/58; second portion: 28/72; third portion: 13/87; fourth portion: 8/92. One and two h after the 5^th portion had been added, the ratios were 3/97 and 2.4/97.6%, respectively. The checker monitored the reaction by ¹H NMR (CDCl₃) by quenching a reaction aliquot into dichloromethane/water, separating the layers, and concentrating the dichloromethane layer to dryness. The diagnostic resonances were δ 6.54−6.57 (m, 2H) for product 3 and 6.63-6.66 (m, 2H) for starting material 1. Two h after the final addition of Na(OAc)₃BH, 10% unreacted 1 remained; after 16 h, the level was 3%.

6. UPLC conditions: column, ACQUITY UPLC HSS T3 1.8μm, 2.1 × 50 mm; wavelength: 210 nm; column temperature: 45 °C; eluent A) water (0.05% TFA) B) MeCN; gradient: 0 min: A) 95%, B) 5%; 2.9 min: A) 0% B) 100%; 3.15 min: A) 0% B) 100%; 3.25 min: A) 95% B) 5%; 4.0 min: A) 95% B) 5%.

7. UPLC analysis by the submitters after 16 h showed 11% of benzyl 4-hydroxypiperidine-1-carboxylate (byproduct from the reduction of 1-benzyloxycarbonyl-4-piperidone; retention time: 1.35 min), 84.7% of desired product 3 (retention time: 2.08 min), and 4.4% of an unidentified byproduct (retention time: 0.88 min).

8. The flask should be kept under a nitrogen atmosphere during the quench since hydrogen gas is produced upon quenching unreacted Na(OAc)₃BH.

9. Three co-evaporations with MTBE is an efficient way to remove most of the dichloromethane and maximize the yield in the subsequent crystallization. Concentration of the dichloromethane phase to very small volumes affords a foamy oil, making further removal of dichloromethane by co-evaporation with MTBE less efficient. After the co-evaporations, ¹H NMR (CDCl₃) of the residue showed 5 mol % residual dichloromethane.

10. Amine 3 has the following physical and spectroscopic properties: Mp: 90-92 °C. ¹H NMR pdf (400 MHz CDCl₃) δ: 1.35-1.43 (m, 2 H), 2.06 (d, J = 10.9 Hz, 2 H), 3.03 (t, J = 11.8 Hz, 2 H), 3.50-3.55 (m, 1 H), 3.85 (s, 3 H), 4.10-4.17 (m, 3 H), 5.15 (s, 2 H), 6.54-6.57 (m, 2 H), 7.31-7.38 (m, 5 H), 7.85-7.88 (m, 2 H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 32.2, 42.9, 49.7, 51.7, 67.4, 112.0, 118.8, 128.1, 128.2, 128.7, 131.8, 136.72, 150.7, 155.4, 167.3. IR (ATR cell) cm^-1: 3357, 2951, 1707, 1675, 1604, 1531, 1500, 1471, 1436, 1363, 1353, 1309, 1274, 1226, 1197, 1172, 1149, 1095, 1008, 983, 951, 839, 788, 769, 750, 693. LC-MS m/z calcd for [M]⁺ (C₂₁H₂₄N₂O₄) 368.4, found, 368.7; Anal. Calcd for C₂₁H₂₄N₂O₄: C, 68.46; H, 6.57; N, 7.60. Found: C, 68.54; H, 6.50; N, 7.57. HPLC area % purity: 97-98% (HPLC method: fused-core C-18 column, 4.6 x 100 mm, 2.7 μm particle size; mobile phase, A = 0.1 % H₃PO₄/H₂O, B = MeCN, gradient 10-95% B in 6 min and hold at 95% B for 2 minutes, detection at 210 nm, flow 1.8 mL/min, temp 40 °C; t_R = 4.93 min).

11. A yield of 85% was obtained at half scale.

12. The following reagents and solvents were used as received for Step B: ethyl acetate (Fischer Optima, 99.9%, water level <0.002%), pyridine (Sigma-Aldrich, Reagent Plus, >99%), chloroacetyl chloride (Fluka purum = 99%), and t-butyl methyl ether (Sigma-Aldrich, >98.5%).

13. The submitters followed the reaction by UPLC as outlined in Note 6. The checker monitored the reaction by ¹H NMR as follows: A 0.1 mL reaction aliquot was quenched into 1 mL brine/1 mL EtOAc. The organic layer was separated and dried by filtering through a plug of sodium sulfate. After concentrating to dryness, the sample was dissolved in CDCl₃. NMR analysis showed no starting material resonances at 3.85 (s, 3 H) or 6.54-6.57 (m, 2 H).

14. The reaction is quenched with phosphate buffer at pH 10 and stirred for 10 min to fully quench excess chloroacetyl chloride that will otherwise inhibit the subsequent crystallization of the product.

15. Crystallization for the first run required vigorous scratching of the flask with a glass rod. In subsequent runs, the crystallization occurred spontaneously.

16. Chloride 5 has the following physical and spectroscopic properties: Mp: 103-105 °C. ¹H NMR pdf (400 MHz, CDCl₃) δ: 1.23-1.28 (m, 2 H), 1.84 (d, J = 11.6 Hz, 2 H), 2.88 (br s, 2 H), 3.68 (s, 2 H), 3.96 (s, 3 H), 4.23 (br s, 2 H), 4.74-4.80 (m, 1 H), 5.04 (br s, 2 H), 7.22 (d, J = 8.4, 2H), 7.28-7.35 (m, 5 H), 8.13 (d, J = 8.7 Hz, 2 H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 30.4, 42.3, 43.5, 52.7, 53.7, 67.4, 128.1, 128.2, 128.6, 130.4, 131.3, 131.4, 136.7, 141.4, 155.1, 165.7, 166.0; IR (ATR cell) cm^-1: 2951, 1714, 1705, 1690, 1673, 1604, 1510, 1496, 1449, 1440, 1427, 1391, 1362, 1329, 1293, 1276, 1246, 1231, 1208, 1195, 1176, 1131, 1118, 1105, 1086, 1062, 1020, 985, 968, 956, 934, 921, 870, 834, 814, 797, 788, 779, 769, 753, 715, 707, 678, 665; LC-MS m/z calcd for [M]⁺ (C₂₃H₂₅ClN₂O₅) 444.4, found, 444.6; Anal. Calcd for C₂₃H₂₅ClN₂O₅: C, 62.09; H, 5.66; Cl, 7.97; N, 6.30. Found: C, 61.69; H, 5.39; Cl, 7.81; N, 6.17; HPLC area % purity: 98% (conditions in Note 10; t_R = 4.73 min

17. The following reagents and solvents were used as received for Step C: palladium acetate (Strem, 98%), 2-(di-t-butylphosphino)biphenyl (Acros, 99%), 2-methyltetrahydrofuran (Sigma Aldrich, Reagent Plus ≥99.5%, inhibited with 150-400 ppm BHT), 2-propanol (Sigma-Aldrich, ACS reagent >99.5%).

18. Nitrogen sparging was carried out using a 1-mL plastic syringe with a 10 cm needle with a steady stream of bubbling for 15 min. The heterogeneous mixture darkened during the sparging.

19. The submitters monitored the reaction by UPLC analysis using the conditions in Note 6. The checker monitored the reaction by ¹H NMR by diluting a 0.1 mL aliquot from the reaction mixture into 1 mL CDCl₃ and filtering through a 0.25 μM filter. At the 1 h time point, 2.5% starting material remained based on resonances integrated at δ 5.04 (br s, 2 H) and 8.13 (d, J = 8.7 Hz, 2 H).

20. The mixture must be filtered while still hot since the product crystallizes upon cooling.

21. Thick solids formed when the internal temperature reached 60-65 °C. The stirring speed had to be increased for efficient mixing.

22. Care was taken to avoid cake cracking prior to the 2-propanol wash, which allowed for the efficient removal of highly colored impurities.

23. Oxindole 6 has the following physical and spectroscopic properties: Mp: 158-159 °C. ¹H NMR pdf (400 MHz, CDCl₃) δ: 1.73-1.76 (m, 2 H), 2.29-2.39 (m, 2 H), 2.92 (br s, 2 H), 3.56 (s, 2 H), 3.93 (s, 3 H), 4.39-4.47 (m, 3 H), 5.19 (s, 2 H), 6.97 (d, J = 8.4 Hz, 1 H), 7.33-7.42 (m, 5 H), 7.92-7.93 (m, 1 H), 7.96-7.98 (m, 1 H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 28.3, 35.7, 43.9, 50.4, 52.3, 67.7, 109.3, 124.3, 124.8, 126.1, 128.3, 128.4, 128.8, 130.5, 136.8, 147.8, 155.4, 166.9, 175.1. IR (ATR cell) cm^-1: 2948, 1699, 1616, 1588, 1489, 1453, 1428, 1386, 1358, 1332, 1320, 1291, 1272, 1256, 1241, 1227, 1192, 1169, 1139, 1126, 1097, 1077, 1021, 986, 968, 957, 938, 902, 890, 869, 838, 802, 771, 763, 731, 696, 683, 654; LC-MS m/z calcd for [M]⁺ (C₂₃H₂₄N₂O₅) 408.5, found, 408.7; Anal. Calcd for C₂₃H₂₄N₂O₅: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.72; H, 5.75; N, 6.77. HPLC area % purity: 98% (conditions in Note 10; t_R = 4.60 min).

24. A reaction at half scale afforded an 84% yield.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Oxindoles are an important class of compounds with ubiquitous presence in both natural products² and pharmaceuticals.³ In addition, oxindoles can be employed as immediate precursors for the preparation of indoles. Numerous methods have been reported in the literature for the synthesis of oxindoles, such as the derivatization of isatin and indoles, radical cyclizations, the cyclization of o-aminophenylacetic acids and α-halo or α-hydroxyacetanilides, cyanoamidation reactions, palladium-catalyzed Heck couplings, and others.⁴ Alternatively, Buchwald and co-workers have reported a palladium-catalyzed alkylation reaction via C-H functionalization⁵ and Hartwig and co-workers a palladium-catalyzed arylation reaction via amide α-arylation⁶ (Figure 1). These two technologies represent direct and unprecedented approaches to the oxindole functionality from readily accessible precursors.

Figure 1. Buchwald's and Hartwig's palladium-catalyzed methodologies for oxindole formation

Compound 7 (Figure 2) is a serine palmitoyl transferase (SPT) enzyme inhibitor candidate for the potential treatment of heart disease. This molecule contains an oxindole functionality and was originally prepared by our Medicinal Chemistry group in nine steps from acid 8. A key intermediate in this synthesis is oxindole 6, which can be generated in five steps from 8; however, this route has several disadvantages, such as the use of unsafe reagents (NaH) and the need for several chromatographic purifications. For the preparation of large quantities of 6 (hundreds of g to several kg), we wanted to avoid those issues and also identify a shorter synthesis. We focused our attention on Buchwald's protocol since no halogenated precursor is needed to install the 5-membered oxindole ring and one precedent was found in the literature on kg-scale.⁷

Figure 2. Structure of serine palmitoyl transferase (SPT) enzyme inhibitor 7

Scheme 1. Medicinal Chemistry synthesis of drug candidate 7

The new and shorter route to oxindole 6 starts with the reductive amination between methyl 4-aminobenzoate (1), a considerably cheaper starting material than 3-fluoro-4-nitrobenzoic acid (8), and 1-benzyloxycarbonyl-4-piperidone (2) in dichloromethane in the presence of 1 equiv of AcOH. The addition of Na(OAc)₃BH in several portions resulted in complete conversion of 1 to secondary amine 3 and gave acceptable levels of alcohol benzyl 4-hydroxypiperidine-1-carboxylate resulting from the reduction of 2. The crystallization of 3 from heptane/MTBE gives analytically pure material in 84% yield.

The acylation reaction between 3 and chloroacetyl chloride in anhydrous EtOAc and pyridine to afford amide 5 is fast (1 h) and clean. Pyridine gave a cleaner impurity profile compared to other bases such as triethylamine. Schotten-Baumann conditions (CH₂Cl₂ or EtOAc and aqueous K₂CO₃) were also investigated, but incomplete reaction was observed due to acid chloride hydrolysis. After an aqueous workup, amide 5 is crystallized from MTBE in 94% yield.

The cyclization step to produce oxindole 6 was first attempted under the conditions reported by Buchwald in his original publication (Pd(OAc)₂/2-(di-t-butylphosphino)biphenyl (1:2 ratio), triethylamine, toluene, 80 °C)⁵ but sticky solids were obtained due to the low solubility of 6 in this medium. A solvent (THF, IPA, MeCN, DMF) and base (triethylamine, n-Bu₃N) screen identified THF/IPA 4:1 as the optimal combination to dissolve both starting material and product in the presence of triethylamine to give complete conversion in 1 h at 74-76 °C. The Pd catalyst and ligand loadings were 10 and 20 mol%, respectively, and optimization experiments with lower loadings resulted in incomplete reactions.⁸ The reasons for the high catalyst and ligand loadings were not fully investigated and remain unclear.

In summary, a short and high yielding protocol for the preparation of oxindole 6 has been demonstrated on multi-gram scale from inexpensive and readily available starting materials. All intermediates can be isolated after crystallization in high purity and chromatographic purifications are no longer required. This chemistry has been scaled up in our laboratories to produce multi kg-quantities of 6.⁹

References and Notes

Chemical Research & Development, Pharmaceutical Sciences, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States. .
(a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(a) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. J. Med. Chem. 1998, 41, 2588. (b) Wood, E. R.; Kuyper, L.; Petrov, K. G.; Hunter, R. N., III.; Harris, P. A.; Lackey, K. Bioorg. Med. Chem. Lett. 2004, 14, 953. (c) Masamune, H.; Cheng, J. B.; Cooper, K.; Eggier, J. F.; Marfat, A.; Marshall, S. C.; Shirley, J. T.; Tickner, J. E.; Umland, J. P.; Vazquez, E. Bioorg. Med. Chem. Lett. 1995, 5, 1965. (d) Robinson, R. P.; Reiter, L. A.; Barth, W. E.; Campeta, A. M.; Cooper, K.; Cronin, B. J.; Destito, R.; Donahue, K. M.; Falkner, F. C.; Fiese, E. F.; Johnson, D. L.; Kuperman, A. V.; Liston, T. E.; Malloy, D.; Martin, J. J.; Mitchell, D. Y.; Rusek, F. W.; Shamblin, S. L.; Wright, C. F. J. Med. Chem. 1996, 39, 10.
(a) Ueda, S.; Okada, T.; Nagasawa, H. Chem. Commun. 2010, 46, 2462 and references therein. (b) Jia, Y.-X.; Kündig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636 and references therein.
Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084.
(a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546.
Choy, A. C.; Colbry, N.; Huber, C.; Pamment, M.; Van Duine, J. Org. Process Res. Dev. 2008, 12, 884.
The Supporting Information in reference 5 (page S11) has the ratios of Pd and ligand reversed.
Kiser, E. J.; Magano, J.; Shine, R. J.; Chen, M. H. Org. Process Res. Dev. 2012, 16, 255.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Methyl 4-aminobenzoate: Benzoic acid, 4-amino-, methyl ester (619-45-4)

1-Benzyloxycarbonyl-4-piperidone: 1-Piperidinecarboxylic acid, 4-oxo-, phenylmethyl ester (19099-93-5)

Benzyl 4-(4-(methoxycarbonyl)phenylamino)piperidine-1-carboxylate: 1-Piperidinecarboxylic acid, 4-[[4-(methoxycarbonyl)phenyl]amino]-, phenylmethyl ester (1037834-44-8)

Benzyl 4-(2-chloro-N-(4-(methoxycarbonyl)phenyl)acetamido)piperidine-1-carboxylate: 1-Piperidinecarboxylic acid, 4-[(2-chloroacetyl)[4-(methoxycarbonyl)phenyl]amino]-, phenylmethyl ester (1037834-45-9)

Methyl 1-(1-(benzyloxycarbonyl)piperidin-4-yl)-2-oxoindoline-5-carboxylate: 1H-Indole-5-carboxylic acid, 2,3-dihydro-2-oxo-1-[1-[(phenylmethoxy)carbonyl]-4-piperidinyl]-, methyl ester (1037834-34-6)

Sodium triacetoxyborohydride: Borate(1-), tris(acetato-κO)hydro-, sodium (56553-60-7)

Chloroacetyl chloride: Acetyl chloride, 2-chloro- (79-04-9)

Palladium acetate: Acetic acid, palladium(2+) salt (2:1) (3375-31-3)

2-(Di-tert-butylphosphino)biphenyl: Phosphine, [1,1'-biphenyl]-2-ylbis(1,1-dimethylethyl)- (224311-51-7)

Triethylamine: Ethanamine, N,N-diethyl- (121-44-8)

2-Methyltetrahydrofuran: Furan, tetrahydro-2-methyl- (96-47-9)

	Javier Magano was born in Madrid, Spain. He received his B.S. in organic chemistry from Complutense University in Madrid in 1987 and a M.S. degree in chemistry from the University of Michigan in 1990. After working for the oil industry in Spain for three years, he obtained a M.S. degree in rubber and polymer science from the School of Plastics and Rubber at the Center for Advanced Scientific Research in Madrid. In 1995 he moved back to the United States to carry out graduate work at the University of Michigan and in 1998 he joined Pfizer Inc. to work in the early process group in Ann Arbor, MI, and currently in Groton, CT. He has also worked in the area of biologics for 1.5 years.
	E. Jason Kiser was born in Chatham, Ontario (Canada) in 1971. He obtained his Bachelors of Science degree (Honors Chemistry) at the University of Windsor (Canada) in 1995. Jason went on to obtain a Master's of Science degree (Chemistry) under the direction of Dr. John M. McIntosh. Jason has over 14 years of synthesis and scale-up experience. He worked for Pfizer for over 10 years at the Ann Arbor, Michigan and Groton, Connecticut research sites as well as the Kalamazoo manufacturing site. He is currently a senior scientist in the process development group at Ash Stevens in Riverview, Michigan.
	Russell J. Shine pursued his undergraduate studies at University of Pennsylvania, where he received his B.A. degree in Biology in 1981. After joining Pfizer Inc. in 1983, he joined Professor Phyllis Brown's research group at the University of Rhode Island, where he received his M.S. in Chemistry in 1991. He is currently working in the API manufacturing group within the Pharmaceutical Science Development Division of Pfizer Inc.
	Michael Chen was born in Shanghai, China. He received his B.S. of chemistry from Shanghai University, and a M.S. and Ph.D. from the University of Michigan in 1988. After holding post-doctoral positions with Professor Paul Knochel at the University of Michigan and Peter Wuts and Tomi Sawyer at the Upjohn Company, Michael joined Parke-Davis Pharmaceutical Research/Pfizer where he worked until 2007 as a process chemist. He currently is the Chief Scientific Officer at MasTeam Biotech Research Institute in China.

Notes

References/EndNotes

Article Compounds

Authors