Letter pubs.acs.org/OrgLett
Flexible Routes to Thiophenes Hélène Jullien, Béatrice Quiclet-Sire, Thomas Tétart, and Samir Z. Zard* Laboratoire de Synthèse Organique, CNRS UMR 7652 Ecole Polytechnique, 91128 Palaiseau Cedex, France S Supporting Information *
ABSTRACT: Three convergent routes to thiophenes are described, hinging on the radical addition of α-xanthyl ketones to ethyl vinyl sulfide or to vinyl pivalate. The latter route ultimately proved to be the most versatile and efficient (61− 94%).
hiophenes represent a fundamental class of fivemembered heteroaromatics. They are found in many natural products as well as in biologically active substances.1,2 Three examples of clinically important thiophenes are displayed in Figure 1: Plavix,1b a nonpeptide fibrinogen receptor
T
Scheme 1. Waldvogel’s Approach to Thiophenes
the accessibility of the xanthate precursors. We present herein three convergent pathways leading to substituted thiophenes 3. Our first strategy relied on the sequential fragmentation of geminal sulfoxide-xanthates 4 (Scheme 2). Moderate heating Figure 1. Three examples of biologically active thiophenes.
Scheme 2. Sulfoxide-Based Route to Thiophenes antagonist; Duloxetine,1c a potent inhibitor of serotonin and norepinephrine uptake carriers; and Dup-697,1d a nonopiate antinociceptive agent. Thiophenes and polythiophenes are also useful intermediates in organic synthesis3 and, perhaps more importantly, constitute key components in material sciences.4 Their aromaticity, relative chemical stability, and polarizability constitute key features that have been broadly exploited. Thus, wide-ranging applications in the fields of liquid crystals, organic semiconductors, conducting polymers, nonlinear optics, electroluminescence, and photochromic materials have been reported.4 Not surprisingly, therefore, numerous methods have been described for their synthesis.5,6 The classical Paal−Knorr reaction is still the most frequently used.7 Substituted thiophenes can also be obtained from a naked thiophene ring by functionalization through α-metalation or β-halogenation.5 In view of the special importance of thiophenes, new routes are nevertheless still needed. We envisaged, therefore, to exploit the broad applicability of the radical addition of xanthates to design flexible routes to such heteroaromatics.8 Only Waldvogel seems to have used xanthates to access thiophenes 3 through the ionic route outlined in Scheme 1.9 It involves acid mediated closure and dehydration of mercaptans 2 derived by aminolysis of xanthates 1. This, otherwise efficient approach, is limited by © 2013 American Chemical Society
should first cause elimination of ethanesulfenic acid to give vinyl xanthate 5. As the temperature is increased, a Chugaev elimination sets in leading to thioenols 6 as an equilibrating E and Z isomers 6a and 6b.10 The latter thioenol then cyclizes onto the carbonyl group to form the desired thiophenes 3. Compound 4 was easily prepared in a two-step process (Scheme 3). First, radical addition of an α-xanthyl ketone 7 to the ethyl vinyl sulfide furnished adduct 8, in accord with a previous study from our group.11 The reaction occurs in the presence of a substoichiometric quantity of lauroyl peroxide Received: November 15, 2013 Published: December 3, 2013 302
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Letter
Scheme 3. Examples of Thiophenes by the Sulfoxide Routea
1,3-Dithiethanones have been very little studied as a class. We noted that they were surprisingly resistant to heating. In our initial study, we could convert the phenyl-substituted 1,3dithiethanone (10, R= Ph) into the corresponding thiophene (3, R = Ph) by heating it for 48 h in refluxing odichlorobenzene, but the yield was only 20%.13 Building on this sole example, we have now found that a more drastic heating (215 °C) with silica gel without solvent was a much more efficient procedure to form the thiophene ring, in yields in the range of 61 − 81% (Scheme 4). This transformation presumably proceeds by way of the intermediate thioaldehyde generated by decomposition of the dithietanone moiety (see Scheme 5 and discussion below).
Conditions: (a) 185 °C; (b) lauric acid (1 equiv), 185 °C; (c) lauric acid (1 equiv), heating from 200 to 235 °C.
a
Scheme 5. Mechanism of Thiophene Formation
(DLP) as the initiator and provides the desired adduct 8 in 58 76% yield. Even though xanthates and other thiocarbonyl derivatives are known to react readily with peracids,12 we found that it was possible to oxidize the sulfide group selectively using one equivalent of m-CPBA. The requisite sulfoxides 4a−c were thus obtained in 65 − 88% yield. We were pleased to find that gradual heating of compound 4a in octadecane to about 185 °C resulted in the formation of the desired thiophene 3a in 76% yield. Other solvents such as diphenyl ether and 1,2-dichlorobenzene were also tested; however the separation of the product from the solvent proved somewhat tedious. When the procedure was extended to the other two substrates 4b and 4c, the yield unfortunately dropped to about 45%. We reasoned that the electron donating nature of the substituents was slowing down the dehydration step and that the addition of a weak acid should improve the rate of this step. Indeed, addition of one equivalent of lauric acid and slightly increasing the reaction temperature essentially doubled the yield of thiophenes 3b and 3c. Other slightly acidic adjuvants such as silica gel or NaHSO4 were tried without notable success. In parallel to this first approach, we explored another route, where again we hoped to incorporate one of the two sulfur atoms in the xanthate group into the thiophene ring. A few years ago, we found that treatment of adduct 9, derived by the radical addition of xanthates such as 7 to vinyl pivalate, with TiCl4 in dichloromethane at low temperature unexpectedly gave the corresponding 1,3-dithiethanones 10 (Scheme 4; Piv = Me3CO).13
Our success with converting 1,3-dithiethanones 10 into thiophenes encouraged us to go one step back and ask whether it would not in fact be possible to produce the thiophenes directly from the radical adduct 9. These adducts have the correct oxidation level, the same as that of the corresponding 1,3-dithiethanones 10, and their conversion into thiophenes required a procedure for the selective cleavage of the xanthate motif allowing the preferential ring-closure of the resulting thiols onto the neighboring ketone. Unfortunately, despite much effort and many trials, the conversion of adduct 9 into thiophenes remained poor and the yields erratic and low. It appeared that under most condition tried, the xanthate was the group that was eliminated leading to the observation of only little thiophene, if any. Finally, we discovered that heating adduct 9 in acetic acid using microwave irradiation in the presence of potassium iodide furnished the desired thiophenes in high yield (Figure 2). The reaction required only a few minutes in the microwave oven. This transformation appears to be fairly general and applicable to the formation of thiophenes with aromatic, heteroaromatic, and aliphatic substituents. Both electrondonating and electro-withdrawing groups on the aromatic ring are tolerated. Bis-thiophene 3h, fluorenyl thiophene 3k, and bis-thienylbenzene 3u are especially remarkable examples with potential utility in material science. Thiophenes substituted in the 1,2- and 1,3-positions can be rapidly assembled. The presence of long alkyl chains in products 3m and 3n is noteworthy, because such appendages improve solubility in compounds desired for organic conductors. The introduction of substituents at the 2- and 3-positions is easiest by the present approach, since the radical addition to vinyl pivalate is generally very efficient. It is possible nevertheless to also introduce a substituent at position 4, as in thiophene 3n,
Scheme 4. Thiophenes by the Dithietanone Route
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Finally, thiophenes bearing fused 5-, 6-, or 7- membered rings such as 3p, 3q, 3r, 3s and 3t can be prepared by the same procedure. In the case of 3s, the acidic conditions caused cleavage of the acetal group initially present in 9s, whereas the unusual bicyclic thiophene 3t derived from tosyl-piperidone contains the core structure of Plavix. A plausible mechanism for the formation of the thiophenes by this third approach is depicted in Scheme 5. The iodide acts as a nucleophile with assistance from the acetic acid solvent to cleave the xanthate in adduct 9, without af fecting the pivalate group. This leads to the unstable dithiocarbonic acid 11, which readily extrudes a molecule of carbon oxysulfide to furnish thiol 12. This compound is well poised to undergo ring-closure into intermediate 13 and loss of water and pivalic acid to give the desired thiophene 3. Thiol 12 may also first expel pivalic acid and collapse into thioaldehyde 14, which would also lead to thiophene 3 by cyclization and loss of water (cf cyclization of enethiols 6 in Scheme 2). These pathways are not mutually exclusive and both could be operating simultaneously in the medium. In summary, we have presented here three convergent and efficient entries to substituted thiophenes. In particular, our third route allows the preparation of a large variety of mono-, bis- and tri- unsymmetrically substituted thiophenes in only two steps and in high yield. The process uses cheap and readily available starting materials and is operationally very simple to perform. It nicely complements existing methods for thiophene synthesis.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, full spectroscopic data, and copies of 1 H and 13C NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the ANR for financial support. REFERENCES
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Figure 2. Thiophenes from the xanthate adducts to vinyl pivalate.
but at the cost of a lower efficiency in the radical addition step leading to the required precursor 9n. The 1-acetoxy-1-heptene needed as the olefinic partner in the radical process is more hindered and therefore much less reactive than vinyl pivalate. 304
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