A facile one-pot synthesis of (Z)-α-chloro-α,β-unsaturated esters from alcohols

1 Introduction

α-Chloro-α,β-unsaturated esters (α-chloroacrylates) are important intermediates and attractive starting materials for the synthesis of natural products and pharmaceuticals (Cho et al., 1993; Grote et al., 1988; Omura et al., 1983). Among many methods developed for the preparation of α-chloro-α,β-unsaturated esters (Forti et al., 1995; Kruper and Emmons, 1995; Alami et al., 1995; Buschmann and Schafer, 1994; Satoh et al., 1992; Ishihara et al., 1998; Barma et al., 2003; Concellón et al., 2004), the Wittig/Horner-Emmons/Peterson-type condensation (Chan and Moreland, 1978; Karrenbrock and Schaefer, 1979; Villieras et al., 1978; Braun et al., 1998; Huang et al., 1996; Zapata and Ferrer, 1986; Tago, et al., 1998) are important for this purpose. Recently, we described the first general method for the preparation of (Z)-α-iodo-α,β-unsaturated esters (Karama, 2010) and of α-bromo-α,β-unsaturated esters (Karama et al., 2010) by one-pot halogenation/oxidation/Wittig sequences from activated alcohols such as aromatic, allylic, and propargylic alcohols using manganese dioxide as an oxidant. This method avoids the most common problems associated with the handling of the intermediate aldehydes, which are often difficult to isolate due to their volatility, toxicity, penchant to polymerize or facile hydration, oxidation, and unsuitable for use as substrates.

2 Experimental

IR spectra were obtained on a Perkin-Elmer 883 spectrophotometer and are expressed in cm⁻¹. NMR spectra were recorded on a JEOL ECP 400 (400 MHz) in CDCl₃, chemical shifts are expressed as δ in, and coupling constants (J) are given in Hertz. High resolution ESI mass spectra were determined on a QT of premier (waters) by direct injection of the sample (10 μg/mL in methanol) (Table 1, Scheme 1).

Table 1 One-pot synthesis of (Z)-α-chloro-α,β-unsaturated esters.

Entry	R	Product	Yield (%)a	Z:Eb
1		3a	52	100:0
2		3b	63	100:0
3		3c	50	100:0
4		3d	85	85:15
5		3e	60	90:10
6		3f	86	81:19
7		3g	81	87:13
8		3h	66	89:11

a Yields were based on alcohols.

b This ratio was determined by ¹H-NMR spectroscopy.

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Scheme 1

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3 Results and discussion

In continuation of our interest in the conversion of multi-step reactions into economically and environmentally favored one-pot processes (Karama et al., 2010; Kayser et al., 1997), we recently described an efficient one-pot procedure for the in situ bromination-oxidation-Wittig reaction for the stereoselective preparation of (Z)-α-bromo-α,β-unsaturated esters (Karama et al., 2013) by using NBS as bromination reagent and DMSO/SO₃.Pyridine complex as oxidant for reactive alcohols such as aromatic, allylic, and propargylic alcohols as well as alkanols.

For further evaluation of the generality of this procedure we intended to synthesize (Z)-α-chloro-α,β-unsaturated esters and (Z)-α-iodo-α,β-unsaturated esters. As shown in Table 1, the one-pot chlorination-oxidation-Wittig sequences for activated alcohols as well as for alkanols furnished the (Z)-α-chloro-α,β-unsaturated esters in moderate to good yield (50–86%) and high stereoselectivity. In all reactions, the E and Z isomers were not separated, but the Z/E ratios were readily determined by ¹H NMR spectroscopy. The vinyl protons of the Z isomer were down field of the E isomer. This assignment was confirmed by NOESY experiments of the allylic alcohol derived from the corresponding esters by DIBAL reduction. NOE effects were observed between the olefinic proton and the methylic hydrogens of the alcohol. Unfortunately, using the same procedure to obtain (Z)-α-iodo-α,β-unsaturated esters failed, probably because they are easily deprived of hydrogen iodide under basic condition. Carrying out the above procedure using PCC, PCC-NaOAc, PDC and DMP as oxidant was unsuccessful.

4 Conclusion

In conclusion this article describes an efficient one-pot sequential chlorination-oxidation-Wittig reaction for the synthesis of (Z)-α-chloro-α,β-unsaturated esters from alcohols. The procedure is safe, economical and provides a good green chemistry procedure.