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Org. Synth. 2011, 88, 388-397
DOI: 10.15227/orgsyn.088.0388
AN INTRAMOLECULAR AMINATION OF ARYL HALIDES WITH A COMBINATION OF COPPER (I) IODIDE AND CESIUM ACETATE: PREPARATION OF 5,6-DIMETHOXYINDOLE-1,2-DICARBOXYLIC ACID 1-BENZYL ESTER 2-METHYL ESTER
Submitted by Toshiharu Noji1, Kentaro Okano1, Tohru Fukuyama2, and Hidetoshi Tokuyama1.
Checked by Mark Lautens and Lei Zhang.
1. Procedure
A. (Z)-2-Benzyloxycarbonylamino-3-(2-bromo-4,5-dimethoxyphenyl) acrylic acid methyl ester.A 300-mL three-necked round-bottomed flask equipped with a Teflon-coated magnetic stir bar (3.5 x 1.0 cm), a rubber septum, a glass stopper, and an argon gas inlet is charged with 6-bromoveratraldehyde (7.35 g, 30.0 mmol) (Note 1) and methyl 2-benzyloxycarbonylamino-2-(dimethoxyphosphinyl)acetate (10.43 g, 31.5 mmol, 1.05 equiv).The flask is evacuated and backfilled with argon and is charged with dry dichloromethane (30 mL) (Note 2).The resulting mixture is cooled to 0 °C with stirring at 300 rpm, and to the suspension is added 1,1,3,3-tetramethylguanidine (4.14 mL, 33.0 mmol, 1.1 equiv) (Note 3) dropwise over 10 min (Note 4).The cooling bath is then removed, and the mixture is stirred at room temperature for 5 h (Note 5).The reaction is quenched with 1 M aq.HCl (30 mL).The reaction mixture is transferred into a 500-mL separatory funnel with the aid of dichloromethane (100 mL) and water (60 mL).After partitioning, the aqueous layer is extracted with dichloromethane (2 x 100 mL).The combined organic extracts are washed with sat.aq.NaHCO3 (1 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4(40 g), and filtered.The filtrate is concentrated on a rotary evaporator under reduced pressure (40 °C, 30 mmHg), and the residue is dried in vacuo to afford 15.2 g of the crude product as a pale yellow solid, which is purified by recrystallization to provide 2-benzyloxycarbonylamino-3-(2-bromo-4,5-dimethoxyphenyl)acrylic acid methyl ester as colorless needles (11.2 g, 83%) (Notes 6 and 7).
B. 5,6-Dimethoxyindole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester. A 200-mL three-necked round-bottomed flask equipped with a Teflon-coated magnetic stir bar (3.5 x 1.0 cm), a rubber septum, a glass stopper, and an argon gas inlet is charged with cesium acetate (9.60 g, 50.0 mmol, 2.5 equiv) (Notes 8 and 9), 2-benzyloxycarbonylamino-3- (2-bromo-4,5-dimethoxyphenyl)acrylic acid methyl ester (9.01 g, 20.0 mmol), and copper(I) iodide (761 mg, 4.00 mmol, 0.2 equiv) (Note 10).The flask is evacuated and backfilled with argon and is charged with dry dimethyl sulfoxide (67 mL) (Note 11).After stirring at 300 rpm for 24 h at 30 °C in an oil bath (Note 12), the reaction is quenched by slow addition of 7% NaCl in 10% aq.NH3 (100 mL) with cooling of the reaction mixture in an ice bath (Note 13).The resulting mixture is transferred into a 500-mL separatory funnel with the aid of EtOAc (100 mL) and water (60 mL).After partitioning, the aqueous layer is extracted with EtOAc (2 x 100 mL).The combined organic extracts are washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4 (40 g), and filtered.The filtrate is concentrated on a rotary evaporator under reduced pressure (40 °C, 30 mmHg), and the residue is dried in vacuo to afford 8.03 g of the crude product as a pale yellow solid, which is purified by recrystallization to provide 5,6-dimethoxy-indole-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as colorless needles (5.58 g, 76%) (Notes 14 and 15).
2. Notes
1. 6-Bromoveratraldehyde (98%) was purchased from Aldrich and used as received without further purification.
2. Dichloromethane (>99.8%, water content: <0.0001%) was purchased from Sigma-Aldrich Co.and used as received without further purification.
3. 1,1,3,3-Tetramethylguanidine (99.0%) was purchased from Sigma-Aldrich Co.and used as received without further purification.
4. The submitters observed that the internal temperature rose to 9 °C after addition of 1,1,3,3-tetramethylguanidine.
5. The reaction typically requires 5 h to consume 6-bromoveratraldehyde and is monitored by TLC analysis on Merck silica gel 60F-254 plate eluting with hexanes-EtOAc (1:1).The Rf values of the starting aldehyde and the product are 0.58 and 0.31, respectively (visualized with 254 nm UV lamp and stained with an ethanol solution of 2,4-dinitrophenylhydrazine (DNP).After dipping the TLC plate in the DNP solution, the chromatogram is developed by heating on a hot plate).
6. To crystallize the product, the residue is dissolved in hot EtOAc-hexanes, 7:5 (240 mL) using an oil bath (bath temperature: 80 °C) with the flask under a nitrogen atmosphere.The solution is then cooled to room temperature over 5 h.The colorless fine needles are collected by filtration (9.94 g).The second crop of crystals (1.18 g) is provided by dissolving the solid, which was obtained by concentration of the mother liquor, in hot EtOAc (20 mL) using an oil bath (bath temperature: 80 °C), followed by cooling to room temperature over 5 h.
7. The compound exhibits the following physicochemical properties: Rf = 0.31 (hexanes-EtOAc = 1:1); Merck silica gel 60F-254 plate (visualized with 254 nm UV lamp and stained with an ethanol solution of 2,4-dinitrophenylhydrazine (DNP).After dipping the TLC plate in the DNP solution, the chromatogram is developed by heating on a hot plate); mp = 134-136 °C; IR (NaCl, CDCl3): 3328, 2952, 1716, 1597, 1387, 1261, 1210, 1169, 1053, 819, 755 cm-1.1H NMR pdf(300 MHz, CDCl3) δ: 3.55 (s, 3 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 5.07 (s, 2 H), 6.50 (s, 1 H), 6.99 (s, 1 H), 7.08 (s, 1 H), 7.17 - 7.38 (m, 5 H), 7.44 (s, 1 H).13C NMR pdf(75 MHz, CDCl3) δ: 52.86, 55.76, 56.14, 67.56, 111.48, 115.28, 116.39, 124.48, 126.11, 128.45, 128.47, 128.58, 129.55, 135.84, 148.01, 150.12, 153.69, 165.57.Anal.calcd.for C20H20BrNO6: C, 53.35; H, 4.48; N, 3.11.Found: C, 53.49; H, 4.62; N, 3.07.
8. Cesium acetate (>99.99%) was purchased from Sigma-Aldrich Co.and used as received without further purification.
9. Cesium acetate is extremely hygroscopic.The submitters transferred this reagent in a plastic bag filled with argon to prevent rapid absorption of moisture.The checkers transferred the reagent to a sealed vial in a glovebox under nitrogen atmosphere and stored the vial in a desiccator.
10. Copper (I) iodide (99.5%) was purchased from Sigma-Aldrich Co.and used as received without further purification.
11. Anhydrous dimethyl sulfoxide (≥99.9%, water content: <0.005%) was purchased from Sigma-Aldrich Co.and used as received without further purification.
12. The reaction typically requires 24 h to consume almost all of the 2-benzyloxycarbonylamino-3-(2-bromo-4,5-dimethoxyphenyl)acrylic acid methyl ester.The 1H NMR spectrum of the crude material shows that the relative ratio of the signal for the starting enamide (δ 5.08, 2 H) to that for the indole (δ 5.40, 2 H) is less than 0.08.The reaction is also monitored by TLC analysis on Merck silica gel 60F-254 plate eluting with hexanes-EtOAc-toluene (2:1:1).The Rf values of the intermediate and the product are 0.37 and 0.27, respectively (visualized with 254 nm UV lamp and an ethanol solution of 2,4-dinitrophenylhydrazine (DNP).After dipping the TLC plate in the DNP solution, the chromatogram is developed by heating on a hot plate).
13. The solution is prepared by dissolving 35 g of NaCl in 465 g of 10% aq.NH3.The addition of this solution is exothermic.
14. The submitters observed that the crude material became yellow upon standing at room temperature.Thus, it was immediately purified by recrystallization.To crystallize the product, the residue is dissolved in hot hexanes-EtOAc, 5:2 (140 mL) using an oil bath (bath temperature: 60 °C).The solution is then cooled at 0 °C in an ice bath for 5 h.The colorless needles are collected by filtration (5.26 g).The second crop of crystals (0.92 g) is provided by dissolving the solid, which was obtained by concentration of the mother liquor, in hot hexanes-EtOAc, 3:1 (40 mL) using an oil bath (bath temperature: 60 °C), followed by cooling at 0 °C in an ice bath for 5 h.The checkers observed that the concentrated mother liquor from the first crop was an oil that was contaminated with ~20% starting material.During the half scale run, the concentrated mother liquor was treated with 20 mL of diethyl ether to form a suspension.The suspension was filtered, and the solids were washed with 20 mL of diethyl ether.The filtrate was concentrated, and the resulting residue was recrystallized by dissolving in hexanes-diethyl ether-EtOAc, 2:1:1 (20 mL) in an oil bath at 35 °C, followed by cooling at 0 °C in an ice bath for 5 h.An additional 0.295 g of the product was isolated.
15. The compound exhibits the following physicochemical properties: Rf = 0.27 (hexanes-EtOAc-toluene = 2:1:1); Merck silica gel 60F-254 plate (visualized with 254 nm UV lamp and stained with an ethanol solution of 2,4-dinitrophenylhydrazine (DNP).After dipping the TLC plate in the DNP solution, the chromatogram is developed by heating on a hot plate); mp = 98-100 °C.IR (NaCl, CDCl3): 2951, 1721, 1538, 1488, 1470, 1436, 1393, 1331, 1301, 1227, 1160, 1126, 1065, 1016, 754 cm-1.1H NMR pdf(400 MHz, CDCl3) δ: 3.73 (s, 3 H), 3.85 (s, 3 H), 3.91 (s, 3 H), 5.40 (s, 2 H), 6.98 (s, 1 H), 7.08 (s, 1 H), 7.33 - 7.43 (m, 3 H), 7.47 (dd, J = 7.8, 1.6 Hz, 2 H), 7.57 (s, 1 H). 13C NMR pdf(100 MHz, CDCl3) δ: 52.07, 55.93, 56.02, 69.58, 97.83, 102.75, 116.64, 119.99, 128.49, 128.66, 128.78 (2), 132.82, 134.49, 147.15, 150.15, 150.79, 161.84.Anal.calcd.for C20H19NO6: C, 65.03; H, 5.18; N, 3.79.Found: C, 65.03; H, 5.38; N, 3.75.Safety and Waste Disposal InformationAll hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Since the indole skeleton is found in a variety of biologically important natural products and therapeutic agents, the development of methods for indole synthesis has been one of the main topics in organic synthesis.We have recently developed a copper-mediated aryl amination3 using the combination of CuI and CsOAc,4 which was applied to the formation of N-Cbz-2-alkoxycarbonylindoles.The aryl amination proceeds smoothly even at the congested position at room temperature without the addition of any special ligand (Table 1).The procedure provides a facile synthetic method for preparation of a Cbz-protected indole carboxylic acid ester from
Table 1. Synthesis of indole-2-carboxylic acid ester.
Table 1. Synthesis of indole-2-carboxylic acid ester.
Reaction Conditions: CuI (1-2 equiv), CsOAc (2.5-18 equiv), DMSO, rt.
the corresponding o-bromobenzaldehyde derivative and readily available Horner-Wadsworth-Emmons reagent in a two-step sequence.Compared to the representative method for thermolysis of an α-azidecinnamic acid ester,5 this method is able to circumvent regiochemical problems and potential explosion hazards.
The aryl amination was also applicable to the synthesis of indoline bearing a variety of protecting groups on the nitrogen (Table 2).It is notable that o-Ns amides have been found to be a particularly suitable substrate.By utilizing o-Ns amides, tetrahydroquinoline and tetrahydrobenzoazepine were
Table 2. Scope of the intramolecular aryl amination.
Table 2. Scope of the intramolecular aryl amination.
Reaction Conditions: CuI (1-200 mol%), CsOAc (1.4-10 equiv), DMSO, rt - 90 °C.
also constructed by this methodology.The reaction conditions are compatible with a wide range of functional groups, including both acid and base labile protective groups.One of the advantages over palladium catalyzed processes6 is that the bromo group remained unreacted after the reaction, allowing for further functionalization to take place.The aryl amination was applied to the total syntheses of duocarmycins,7 (+)-yatakemycin,8 and PDE-II.9
References and Notes
  1. Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: tokuyama@mail.pharm.tohoku.ac.jp This work was supported by The Ministry of Education, Culture, Sports, Science and Technology, Japan and the Cabinet Office, Government of Japan through its "Funding Program for Next Generation World-Leading Researchers.
  2. Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: fukuyama@mol.f.u-tokyo.ac.jp This work was supported by The Ministry of Education, Culture, Sports, Science and Technology, Japan.
  3. Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400.
  4. (a) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231. (b) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987. (c) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2008, 64, 11230.
  5. Bolton, R. E.; Moody, C. J.; Rees, C. W.; Tojo, G. J. Chem. Soc., Perkin Trans. 1 1987, 931.
  6. (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046. (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
  7. Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630.
  8. (a) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2006, 128, 7136. (b) Okano, K.; Tokuyama, H.; Fukuyama, T. Chem. Asian J. 2008, 3, 296.
  9. Okano, K.; Mitsuhashi, N.; Tokuyama, H. Chem. Commun. 2010, 46, 2641.

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

6-Bromoveratraldehyde: Benzaldehyde, 2-bromo-4,5-dimethoxy-; (5392-10-9)

Acetic acid, 2-(dimethoxyphosphinyl)-2-[[(phenylmethoxy)carbonyl]- amino]-, methyl ester: Benzyloxycarbonylamino(dimethoxy- phosphoryl)acetic acid methyl ester; (88568-95-0)

1,1,3,3-Tetramethylguanidine: Guanidine, N,N,N',N'-tetramethyl-; (80-70-6)

Dichloromethane: Methane, dichloro-; (75-09-2)

Cesium acetate: Acetic acid, cesium salt (1:1); (3396-11-0)

Copper(I) iodide: Copper iodide (CuI); (7681-65-4)

Dimethyl sulfoxide: Methane, 1,1'-sulfinylbis-; (67-68-5)

Hidetoshi Tokuyama was born in Yokohama in 1967.He received his Ph.D.in 1994 from Tokyo Institute of Technology under the direction of Professor Ei-ichi Nakamura.He spent one year (1994-1995) at the University of Pennsylvania as a postdoctoral fellow with Professor Amos B.Smith, III.He joined the group of Professor Tohru Fukuyama at the University of Tokyo in 1995 and was appointed Associate Professor in 2003.In 2006, he moved to Tohoku University, where he is currently Professor of Pharmaceutical Sciences.His research interest is on the development of synthetic methodologies and total synthesis of natural products.
Toshiharu Noji was born in Fukushima in 1986.He received his B.S.in 2009 from Faculty of Pharmaceutical Sciences, Tohoku University, where he carried out undergraduate research in the laboratories of Professor Hidetoshi Tokuyama.In the same year, he then began his doctoral studies at Graduate School of Pharmaceutical Sciences, Tohoku University under the supervision of Professor Hidetoshi Tokuyama.His graduate research has focused on benzyne chemistry and its application to total synthesis of natural products containing multisubstituted heteroaromatic rings.
Kentaro Okano was born in Tokyo in 1979.He received his B.S.in 2003 from Kyoto University, where he carried out undergraduate research under the supervision of Professor Tamejiro Hiyama.He then moved to the laboratories of Professor Tohru Fukuyama at the University of Tokyo and started his Ph.D.research on synthetic studies toward the antitumor antibiotic yatakemycin by means of the copper-mediated aryl amination strategy.In 2007, he started his academic career at Tohoku University, where he is currently an assistant professor in Professor Hidetoshi Tokuyama's group.His current research interest is natural product synthesis based on the development of new synthetic methodologies.
Tohru Fukuyama received his Ph.D.in 1977 from Harvard University with Yoshito Kishi.He remained in Kishi's group as a postdoctoral fellow until 1978 when he was appointed as Assistant Professor of Chemistry at Rice University.After seventeen years on the faculty at Rice, he returned to his home country and joined the faculty of the University of Tokyo in 1995, where he is currently Professor of Pharmaceutical Sciences.He has primarily been involved in the total synthesis of complex natural products of biological and medicinal importance.He often chooses target molecules that require development of new concepts in synthetic design and/or new methodology for their total synthesis.
Lei Zhang received his B.Sc.at the University of Ottawa in 2009.His is currently pursuing a Ph.D.at the University of Toronto under the supervision of Professor Mark Lautens.His research interests lie in developing new reactions in rhodium and palladium catalysis.
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