2,2-Dichloro-5-(2-phenylethyl)-4-trimethylsilyl-3(2H)-furanone

[166387-67-3]  · C15H18O2SiCl2  · (MW 329.3)

(a water-compatible dehydrating reagent)

Solubility: soluble in most organic aprotic solvents.

Preparative Methods:1 to a stirred solution of 4-phenyl-1-trimethylsilyl)-1-butyne (2.00 g, 9.88 mmol) and oxalyl chloride (1.09 g, 8.59 mmol) in CH2Cl2 (80 mL) at -78 °C was added freshly sublimed AlCl3 (2.11 g, 15.8 mmol). The mixture was stirred at that temperature for 3 h, then aqueous HCl (1 N, 50 mL) was added in one portion. The mixture was allowed to warm to room temperature, then extracted with CH2Cl2. The organic extracts were dried over MgSO4, evaporated, and purified by silica gel column chromatography (Et2O-hexane, 1:15) to afford DPTF (2.10 g, 74%) as colorless crystals (1).

Spectroscopic data: 1H NMR d 0.11 (s, 9 H), 2.80-2.91 (m, 2 H), 2.94-3.05 (m, 2 H), 7.13-7.36 (m, 5 H); 13C NMR d 1.3, 32.4, 33.1, 100.6, 106.4, 126.8, 128.5, 128.7, 138.9, 190.4, 190.5; IR (neat) 1736, 1596, 1018, 844 cm-1.

Handling, Storage, and Precautions: although quite stable in air, storage in a refrigerator is recommended.

Methanolysis1

2,2-Dichloro-5-(2-phenylethyl)-4-trimethylsilyl-3(2H)-furanone (DPTF) undergoes a ring-opening reaction on treatment with methanol at room temperature to afford methyl 2,2-dimethoxy-4-oxo-6-phenylhexanoate. The carbonyl group at the 2-position is selectively protected as a dimethyl ketal. The addition of a methoxy group to the carbonyl of DPTF forms the epoxyfuran transiently. The subsequent electrocyclic ring-opening affords an acid chloride which further reacts with methanol and loses the trimethylsilyl group located a to the carbonyl group (2).

Stepwise Dehydration of a Carboxylic Acid and an Amine2

Activation of a Carboxylic Acid

DPTF reacts with a carboxylic acid in the presence of 2 equiv of Hünig's base in acetonitrile at room temperature to produce a furyl ester in high yield as a mixture of Z- and E-isomers (3). The carboxylate anion undergoes a nucleophilic attack onto the 3-position of DPTF, leading to the formation of epoxyfuran as a transient intermediate. Next, deprotonation at the side chain results in a subsequent electron shift to open the epoxy ring.3 As a consequence, HCl is eliminated to furnish the furyl ester.

Aminolysis of the Furyl Ester

Even when 2 equiv of a carboxylic acid are used, the formation of a symmetrical carboxylic anhydride by the subsequent reaction of the furyl ester with a carboxylic acid is not observed. This result suggests that the furyl ester is far less electrophilic than DPTF. However, the furyl ester is reactive with respect to aminolysis, with the furyl moiety acting as the leaving group. Treatment of the furyl ester with an amine at room temperature produces an amide in good yield (4).

One-pot Dehydration from a Carboxylic Acid and an Amine in the Presence of Water

Isolation of the furyl ester is not necessary and, conveniently, both steps of activation and aminolysis can be sequentially performed in the same reaction vessel. Furthermore, both DPTF and the intermediary active furyl ester are considerably inert to water, despite their moderate electrophilic reactivities. This distinguishing property renders it possible to carry out the whole process of dehydration under aqueous conditions. Treatment of a carboxylic acid with DPTF in a two-phase system, consisting of an aqueous solution of NaHCO3 and nitromethane, followed by the addition of an amine results in successful dehydration to produce an amide in high yield. A quaternary ammonium salt (Bu4N·HSO4) was used as a phase transfer catalyst to accelerate the reaction (5).

Dehydration is also possible even in a homogeneous hydrous medium, i.e. in a solvent mixture of acetonitrile and water (9:1). The amino group of a 1,2-aminoalcohol is selectively acylated to furnish the amide (6).

The successful activation of a carboxylic acid in the presence of water by the use of DPTF can be understood on the basis of relative nucleophilicity. Under neutral conditions, both the water molecule and the carboxylic acid remain neutral. Water is more basic, and also more nucleophilic than a carboxylic acid. In contrast, when the reaction conditions are basic enough to convert only the carboxylic acid, rather than water, to the corresponding anionic species, the resultant negatively charged carboxylate anion is a stronger nucleophile than a neutral water molecule. It seems that DPTF is minimally electrophilic to permit the selective reaction with a negatively charged carboxylate anion under suitably basic conditions.

Dehydration of Amino Acids

The process in aqueous media can be applied to the formation of peptide bonds from amino acids. Sequential treatment of O-benzylated Boc-Ser-OH with DPTF and H-Val-OMe in water-nitromethane furnished the corresponding dipeptide in good yield. No racemization was observed. Shown below are other successful examples of the synthesis of dipeptides in aqueous media. Benzyl (Cbz), t-butyl (Boc), and 9-fluorenylmethyl (Fmoc) carbamates, which are the most widely used amino protective groups in peptide synthesis, are tolerated under the reaction conditions (7-9).

Synthesis of a Tripeptide

The dehydrating process with DPTF consists of two separate steps, the pre-activation of a carboxylic acid in the absence of an amino component, and the subsequent reaction of the resulting activated ester with an amine. Therefore, it is possible to use a free amino acid as the amino component without protecting a carboxyl group (salt coupling technique). Although a free amino acid is sparingly soluble in organic solvents, DPTF allows the use of aqueous media. Thus, addition of an aqueous solution of a free amino acid to a preformed activated ester in acetonitrile results in the formation of a dipeptide having a free carboxy end, which can then be subjected to the second activation by DPTF again without any deprotection procedure. The subsequent addition of the third amino acid produces the corresponding tripeptide. In this case, elongation of the chain is carried out at the carboxy end, and therefore, some detectable racemization occurs (10).

Related Reagents.

EDCI,4 benzoxazolium salt,5 uronium salt.6


1. Murakami, M.; Hayashi, M.; Ito, Y., J. Org. Chem. 1994, 59, 7910.
2. Murakami, M.; Hayashi, M.; Tamura, N.; Hoshino, Y.; Ito, Y., Tetrahedron Lett. 1996, 37, 7541.
3. (a) Manfredi, K. P.; Jennings, P. W., J. Org. Chem. 1989, 54, 5186. (b) Adger, B. M.; Barrett, C.; Brennan, J.; McKervey, M. A.; Murray, R. W., J. Chem. Soc., Chem. Commun. 1991, 1553. (c) Adam, W.; Peters, K.; Sauter, M., Synthesis 1994, 111.
4. (a) Sheehan, J. C.; Hess, G. P., J. Am. Chem. Soc. 1955, 77, 1067. (b) Sheehan, J. C.; Hlavka, J. J., J. Org. Chem. 1956, 21, 439. (c) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L., J. Org. Chem. 1961, 26, 2525.
5. Kemp, D. S.; Wrobel Jr, S. J.; Wang, S. W.; Bernstein, Z.; Rebek Jr, J., Tetrahedron 1974, 30, 3969.
6. Bannwarth, W.; Schmidt, D.; Stallard, R. L.; Hornung, C.; Knorr, R.; Müller, F., Helv. Chim. Acta 1988, 71, 2085.

Masahiro Murakami

Kyoto University, Yoshida, Kyoto 606-8501, Japan



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