Org. Synth. 2010, 87, 218
DOI: 10.15227/orgsyn.087.0218
AMIDE FORMATION BY DECARBOXYLATIVE CONDENSATION OF HYDROXYLAMINES AND α-KETOACIDS: N-[(1S)-1 PHENYLETHYL]-BENZENEACETAMIDE
Submitted by Lei Ju and Jeffrey W. Bode
1.
Checked by Tatsuya Toma and Tohru Fukuyama.
1. Procedure
N-[(1S)-1-Phenylethyl]-benzeneacetamide. A 500-mL, single-necked, round-bottomed flask equipped with an 8.0 × 30 mm, octagon-shaped Teflon coated-magnetic stir bar, a reflux condenser, a rubber septum and nitrogen gas inlet is charged with phenylpyruvic acid (4.75 g, 28.9 mmol, 1.0 equiv) (Note 1) and N,N-dimethylformamide (289
mL) (Note 2). After stirring for 5 min, N-hydroxy-(S)-1-phenylethylamine oxalate (9.20 g, 40.5 mmol, 1.4 equiv) (Note 3) is added to the homogeneous solution (Note 4) as a solid in one portion at ambient temperature (23 °C). The reaction mixture is warmed to 40 °C in an oil bath and stirred at that temperature under a nitrogen atmosphere until completion (Note 5). The reaction is subsequently concentrated by rotary evaporation (50 °C, 10 mmHg) to approximately 20 mL. The resulting slightly yellow solution is allowed to cool to ambient temperature (23 °C) over the course of 30 min and diluted with ethyl ether (Et2O) (200
mL) (Note 6). The solution is carefully poured into a 2-L separatory funnel, to which 1 N aqueous hydrochloric acid solution (200
mL) is added. The organic layer is separated and extracted with an additional portion of 1 N aqueous hydrochloric acid solution (200), and the combined aqueous phase is extracted with Et2O (3 × 200 mL). To the combined organic layers is added saturated sodium bicarbonate (NaHCO3) solution (200
mL) and the mixture is partitioned. The basic aqueous solution is back-extracted with Et2O (2 × 200 mL). The combined organic phase is washed with brine (400
mL) (Note 7), dried over anhydrous sodium sulfate (Na2SO4) (Note 8), and filtered. The filtrate is concentrated on a rotary evaporator (40 °C, 20 mmHg), and dried under reduced pressure (2 mmHg) overnight to afford a yellow, viscous oil (6.55-6.92 g, 95-100%) (Note 9). The resulting crude product is dissolved in dichloromethane (5
mL) and loaded on a column (6.0 cm i.d. × 20 cm) of SiO2 (280 g) (Note 10, 11). After elution with 400 mL of 30% ethyl acetate in hexanes, the product is obtained by collecting 450 mL (18 × 25 mL fractions) of the eluent (Note 12). The combined fractions are concentrated by rotary evaporation (40 °C, 20 mmHg) followed by high vacuum (2 mmHg) to provide N-[(1S)-1 phenylethyl]-benzeneacetamide (5.92-5.96 g, 85-86%) as a white solid. The product is dissolved in hot Et2O (300
mL) (50 °C, at reflux) and cooled to 4 °C overnight. The resulting crystals are collected by filtration on a Büchner funnel and washed with ice-cold Et2O (50
mL). The crystals are then transferred to a 100-mL round-bottomed flask and dried overnight at 2.0 mmHg to afford a spindle-like solid (5.06-5.08 g, 73%) (Notes 13, 14, and 15).
2. Notes
1.
Phenylpyruvic acid (98%) was purchased from Aldrich Chemical Co., Inc and was recrystallized from hot benzene before use.
CAUTION: Benzene is carcinogenic, and must be handled with care.2.
N,N-Dimethylformamide (99.8%), purchased by the submitters from EMD Biosciences, Inc. and by the checkers from Wako Pure Chemical Industries, Ltd., was passed over activated molecular sieves 4A under an argon atmosphere before use.
3.
N-Hydroxy-(
S)-1-phenylethylamine oxalate was prepared from (
S)-1-phenylethylamine following a reported procedure.
2 The oxalate salt of the hydroxylamine was recrystallized from hot ethanol and washed with ethyl ether. The oxalate salt form of the hydroxylamine is bench stable and more efficient in the ligation reaction.
CAUTION: Free hydroxylamines may cause explosions under certain conditions. Careful handling is required when they are heated.4.
Phenylpyruvic acid was allowed to dissolve completely in
N,
N-dimethylformamide as a 0.1 M solution. White precipitate persisted if phenylpyruvic acid was used without recrystallization.
5.
The progress of the reaction was monitored on reverse phase HPLC by following the disappearance of phenylpyruvic acid. Analytical conditions were: Column: Shiseido Capcell Pac C18; Eluent: 0.1% TFA in H
2O/MeCN; Flow rate: 1 mL/min; Detection: 216 nm, 235 nm, 288 nm, 221 nm; Gradient: 0-95% MeCN over 30 min. R
T of phenylpyruvic acid = 19.04 min; R
T of product = 21.56 min. The reaction typically takes 26-30 h to complete, while trace amounts of phenylpyruvic acid could still be observed at 288 nm.
6.
Ethyl ether (Et
2O) (99.9%), unstabilized, was purchased by the submitters from EMD Biosciences, Inc. and by the checkers from Wako Pure Chemical Industries, Ltd., and used without further purification.
7.
Sodium chloride (NaCl), crystalline, was purchased by the submitters from EMD Biosciences, Inc. and by the checkers from Wako Pure Chemical Industries, Ltd.
8.
Sodium sulfate (Na
2SO
4) anhydrous, crystalline, was purchased by the submitters from EMD Biosciences, Inc. and by the checkers from Wako Pure Chemical Industries, Ltd.
9.
1H NMR analysis by the submitters indicated a high purity of the crude product, which was contaminated by 3 wt. % of residual
N,
N-dimethylformamide. No residual
N,
N-dimethylformamide was detected by the checkers and the crude product was obtained as a yellow solid.
10.
The column was packed by the submitters with EMD Silica Gel 60 (230-400 Mesh, Art 7747) and by the checkers with Silica Gel 60 purchased from Kanto Chemical Co, Inc.
11.
Thin layer chromatography (TLC) was performed by the submitters on EMD precoated plates (silica gel 60 F
254, Art 5715, 0.25 mm) and by the checkers on Merck precoated plates (silica gel 60 F
254, 0.25 mm). TLC analysis of the crude product (with elution of 30% EtOAc/Hexanes) was visualized with a 254-nm UV lamp and phosphomolybdic acid stain. The crude mixture contained desired product with R
f = 0.22 (blue), and a trace spot on the baseline.
12.
The checkers found that the column chromatographic purification could be omitted. Direct recrystallization from hot Et
2O afforded the ligation product in a similar yield (5.05-5.09 g, 73%).
13.
The pure product exhibits the following physical and spectroscopic properties: mp 117.4-118.6 °C; [α]
D20 +0.97 (
c 1.00, CHCl
3); IR (KBr, thin film): ν 3306 (s, NH), 3062, 3029, 5975, 1645 (s, C=O, amide), 1541, 1495, 1446, 1413, 1357, 1337, 1247, 1206, 1128, 1018, 760 cm
-1;
1H NMR
pdf (500 MHz, CDCl
3) δ: 1.40 (d,
J = 7.2 Hz, 3 H), 3.58 (s, 2 H), 5.12 (quintet,
J = 7.2 Hz, 1 H), 5.60 (br s, 1 H), 7.14-7.40 (m, 10 H);
13C NMR
pdf (125 MHz, CDCl
3) δ: 21.8, 43.9, 48.7, 125.9, 127.2, 127.3, 128.6, 129.0, 129.3, 134.8, 143.0, 170.0; HRMS (ESI)
m/z calcd. for C
16H
18NONa ([M+Na]
+) 262.1208; found 262.1201; Anal. calcd. for C
16H
17NO: C, 80.30; H, 7.16; N, 5.85; found: C, 80.14; H, 7.16; N, 5.85.
14.
When 1.0 equiv of (
S)-
N-1-phenylethylhydroxylamine oxalate was used instead of 1.4 equiv relative to phenylpyruvic acid, the yield of the product was reduced to 65% due to decomposition of the hydroxylamine upon heating. The reaction rate was observed by HPLC to be slower when 10:1 DMF:H
2O was used as solvent.
15.
The enantiomeric purity was shown by the submitters to be > 99% ee by SFC analysis on a chiral stationary phase. Analytical conditions were: Column: Chiralcel OJ-H; Eluent: MeOH and super critical CO
2; Flow rate: 1 mL/min; Detection: 220 nm, 254 nm; Gradient: 5% MeOH hold 0.1 min, 5-80% MeOH 13 min. R
T of racemic standard = 4.81 min, 5.40 min; R
T of ligation product = 5.40 min. The checker determined the enantiomeric purity by HPLC analysis. Analytical conditions were: Column: Chiralcel OD-H; Eluent: 15%
i-PrOH/
n-hexane; Flow rate: 1 mL/min; Detection: 220 nm, 254 nm; R
T of racemic standard = 25.32 min, 26.57 min; R
T of ligation product = 26.57 min.
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
The construction of an amide bond generally involves activation of carboxylic acids as acyl halides, acyl azides, anhydrides, or esters followed by reaction with an amine.
3 Employing common activating reagents complicates the amide formation with racemization, difficult purification, protection of reactive functionalities and deprotection steps. Therefore, chemoselective amide-bond forming reactions are in demand.
4,5 We have developed a novel approach to amide synthesis
6 by decarboxylative condensation of
N-alkyl hydroxylamines
7 and α-ketoacids.
8Decarboxylative condensation of
N-hydroxy-(
S)-1-phenylethylamine oxalate and phenylpyruvic acid illustrates the amide bond-forming protocol under mild, simple condition. This method is reagent/catalyst-free, proceeds cleanly by simply mixing the two ligation partners in polar solvents with gentle heating, and produces only innocuous, volatile byproducts. A variety of functionalities have been demonstrated to be compatible with the ligation conditions including carboxylic acids, azides, amines, alcohols, and heterocyclic substrates (Table 1).
9 Benzoyl-protected hydroxylamine undergoes the ligation reaction with a similar outcome to the use of the free hydroxylamine oxalate salt. The steric environment due to substituents adjacent to the ligation centers affects coupling efficiency. A more hindered junction (Entry 8) gave the ligation product in lower yield even when heated to 60 °C.
The ligation between α-ketoacids and hydroxylamines is a powerful, chemoselective strategy that proceeds in the presence of reactive functional groups without activating reagents or catalysts. This method should find application in circumstances that require convergent synthesis of amides in the presence of unprotected functionalities.
Table 1. Decarboxylative Condensation of α-Ketoacids and N-Alkyl Hydroxylamines
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Phenylpyruvic acid: α-Oxobenzenepropanoic acid, 2-Oxo-3-phenylpropionic acid; (156-06-9)
N, N-Dimethylformamide: DMF; (68-12-2)
(S)-(a-Methylbenzyl)hydroxylamine oxalate salt: (aR)-N-Hydroxy-a-methyl-benzenemethanamine ethanedioate salt; (78798-33-1)
Benzeneacetamide, N-[(1S)-1-phenylethyl]-: 2-phenyl-N-(1-phenylethyl)acetamide; (17194-90-0)
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Jeffrey W. Bode was born in California in 1974 and studied chemistry and philosophy at Trinity University in San Antonio, Texas. He received his Dok. Nat. Sci. from the Eidgenössicsche Technische Hochschule (ETH) in Zürich, Switzerland with Prof. Erick M. Carreira in 2001. Following a JSPS Postdoctoral Fellowship with Prof. Keisuke Suzuki at the Tokyo Institution of Technology, he joined the faculty of the University of California, Santa Barbara as an Assistant Professor in 2003. In 2007, he joined the University of Pennsylvania in Philadelphia, Pennsylvania as an Associate Professor of Chemistry and in 2010 returned to ETH-Zürich as Professor of Chemistry. His research interests include the development of new synthetic methods, catalysis, peptide synthesis, and bioorganic chemistry. |
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Lei Ju was born in Dandong, China in 1982. In 2005, she received her B.S degree in chemistry/biochemistry from University of California, San Diego, where she conducted research with Yoshihisa Kobayashi. She subsequently started her graduate studies at University of California, Santa Barbara under the supervision of professor Jeffrey W. Bode. Her research efforts focused on the amide bond-forming ligations between a-ketoacids and hydroxylamines. In the summer of 2007, she moved to University of Pennsylvania in Philadelphia, PA to continue with her research. |
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Tatsuya Toma was born in 1984 in Saitama, Japan. He graduated in 2007 and received his M. S. degree in 2009 from the University of Tokyo. The same year he started his Ph. D. study under the supervision of Professor Tohru Fukuyama. His current interest is enantioselective total synthesis of complex natural products. |
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