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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 July 1.
Published in final edited form as:
Tetrahedron Lett. 2009 July 1; 50(26): 3253–3257.
doi:  10.1016/j.tetlet.2009.02.018
PMCID: PMC2699308

Synthesis of β–Heteroaryl Propionates via Trapping of Carbocations with π-Nucleophiles


A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other π-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted β-heteroaryl propionates, including those with contiguous quaternary centers, as well as vinylogs thereof. This reaction also proceeds with high diastereoselectivity when the π-nucleophile bears a chiral auxiliary.

In the context of several ongoing projects in alkaloid synthesis, we were confronted with the task of preparing substituted derivatives of β-heteroaryl propionic acids of the general structure 1. After examining the literature, it was apparent that there were two different approaches that might be applied to the synthesis of such compounds, and these are outlined in Scheme 1.

The first approach, which is depicted in Path a, involves the conjugate addition of electron rich heteroaromatic rings to α,β-unsaturated carbonyl compounds via a process in which the heterocycle serves as the nucleophile (Scheme 1, Path a). This approach is well precedented in the literature, and methods for preparing both achiral and chiral products in high enantioselectivity are known.i,ii The scope of these methods is, however, limited in several ways. For example, substitution occurs on the heteroaromatic ring only at those positions that are favored in classical electrophilic substitution reactions of electron-rich heterocycles with the vast majority of examples being pyrroles and indoles. The preparation of compounds of the general structure 1 (R1, R2 = alkyl) are also rather limited,ib,iii whereas compounds such as 1 (R3, R4 = alkyl) appear to be inaccessible via this path.

The second option (Scheme 1, Path b) involves a SN1-type reaction in which a compound bearing a benzylic-like leaving group undergoes ionization, typically in the presence of a suitable Lewis acid, and the resulting carbocation is trapped by a π-nucleophile. There is some precedent for the reactions of cations generated from a secondary thiophen-2-yl chloride,iv furan-2-yl acetate,v and several heteroaryl carbinols,vi but the scope of this bond construction appears to be limited to a relative few combinations of heteroaromatic systems and π-nucleophiles. Moreover, there are no examples of the enantioselective synthesis of compounds of type 1 by this construction.

It was thus evident that there were limitations to existing methods for preparing compounds generally related to 1, and there was no direct precedent for a number of possible bond forming processes. After considering the available options, we concluded that the disconnection depicted in Path b offered the greatest opportunity to develop new chemistry and expand upon that which was known. We now report some results of our preliminary studies.

The first objective was to conduct two sets of exploratory experiments to examine the reactivity of indol-3-yl and indol-2-yl carbinol derivatives. Although precedent for the former construction was reported after we imitated these studies,vii we are aware of no precedent for the latter. As a prelude to more general studies, we examined the Lewis acid-catalyzed reaction of the alcohol 6 with the silyl ketene acetal 7 under a variety of conditions to furnish 8, eventually finding that the reaction proceeded in an optimized yield of 92% using THF as the solvent, 0.9 equivalents of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the Lewis acid, and a reaction temperature of −40 °C (Scheme 2, Method A).

Encouraged by this result, the same conditions (Method A) vii were applied to the reactions of other indol-3-yl carbinols with several different π-nucleophiles in order to explore the scope of this route to indol-3-yl propionate derivatives (Table 1). As is evident from examination of the results in Table 1, the reaction works well with primary, secondary and tertiary alcohols. The indole nitrogen atom may be either unsubstituted or bear an alkyl residue such as a methyl group. Finally, π-nucleophiles having different substitution patterns at the reacting center may be employed. This feature enables the facile construction of not only quaternary centers, but also contiguous quaternary centers, arguably one of the more difficult challenges in synthesis.viii

Table 1
Lewis acid-catalyzed reactions of indol-3-yl carbinols with π-nucleophiles.vii

The optimized conditions for the reaction of 6 with 7 were then applied to the reaction of the indol-2-yl carbinol 9 with 7, but 11 was obtained in low yield (Scheme 3). Reasoning that the low yield in this transformation might be a consequence of the decreased reactivity toward ionization of 9 relative to 6, we thought that the corresponding acetate 10 might be more reactive. Accordingly, acetylation of 9 with acetic anhydride afforded 10, which then underwent reaction with 7 under the previously defined conditions to give 11 in moderate yield. After a quick survey of different solvents and temperatures, it was found that the yield of 11 could be improved to 91% by changing the solvent to acetonitrile and performing the reaction at −40 °C with one full equivalent of TMSOTf (Method B).ix

Having optimized the conditions for the reaction of 10 with 7, the scope of this reaction was further explored (Table 2). The reaction works well with indol-2-yl, pyrrol-2-yl, furan-2-yl, and thiophen-2-yl carbinol derivatives. Although the presence of an N-sulfonyl group on a pyrrole is deactivating, carbon-carbon bond formation proceeds in modest yield (Entry 8).x In general, the reactions involving tertiary alcohols were most efficient (Entries 1, 6, 12), presumably owing to their relative ease of ionization. The reactions of secondary acetates were generally superior to those of their corresponding alcohols. Because the secondary acetates derived from pyrrol-2-yl carbinols are known to be unstable, xi these were not examined as substrates. The reactions of primary alcohols appear to be more challenging. For example, in preliminary experiments, we found that Lewis acid-catalyzed reactions of 7 with the indol-2-yl carbinol derivatives 12 did not afford isolable quantities of the desired coupling product. It should be noted, however, that primary furan-2-yl acetates are known to participate in such reactions,v so our findings relative to 12 are clearly not generally applicable to all primary heterocyclic carbinols. Suitable π-nucleophiles include not only simple enol derivatives such as 7 but also cyclic and acyclic dienes (Entries 2 and 5).

Table 2
Lewis acid-catalyzed reactions of heteroaryl carbinols with π-nucleophiles.ix

Having established that heteroaryl carbinol derivatives underwent facile reactions with several π-nucleophiles, we were inspired to explore such reactions with chiral π-nucleophiles in order to develop a diastereoselective variant of this process. That such a process might be feasible was supported by the findings of Fuentes and coworkers, who had shown that the presence of a chiral oxazolidinone on a π-nucleophile induced good diastereoselectivity in a reaction involving an N-acyl iminium ion and a π-nucleophile.xiii We first examined the reaction of the secondary alcohol 13 with the chiral π-nucleophile 14 in the presence of TMSOTf. Although this reaction proceeded in 76% yield, a mixture (4.4:1.6:1.6:1) of four stereoisomers was obtained. Toward achieving a higher level of diastereoselectivity, the enol derivative 15 was examined as a nucleophile. We were thus gratified that when 15 was allowed to react with 13 a mixture (15.1:1) of stereoisomers was obtained in 90% yield from which 16 was isolated as the major product (Scheme 4). A crystal structure of 16 was obtained, thereby unequivocally establishing its stereochemistry.xiv

The efficient synthesis of 16 is noteworthy because it illustrates the versatility of Path b in Scheme 1 and its potential for the enantioselective preparation of β-heteroaryl-α-hydroxy propionates, which are structural subunits of biologically interesting compounds. For example, 17, which is the N-demethylated analog of 16 may be envisioned as a precursor of the natural product (−)-indolmycin (18), an antibiotic that exhibits activity against Staphylococci.xv,xvi Hydroxy acids related to compounds like 16 are also useful precursors of depsi peptides, which may be used to probe hydrogen bonding effects in bimolecular interactions involving proteins.xvii Furthermore, the reactions of 15 and other chiral π-nucleophiles with other heterocyclic carbinols or acetates could lead to a diverse array of β-heteroaryl-α-substituted propionate derivatives.

In summary, we have successfully coupled heterocyclic carbinols with various π-nucleophiles in the presence of TMSOTf to deliver a number of β-heteroaryl propionate derivatives and vinylogs thereof, generally in yields exceeding 75%. The reaction can also be performed with high diastereoselectivity using chiral π-nucleophiles. Compounds with contiguous quaternary centers may also be easily prepared. This method will be useful for the synthesis of a wide variety of α,β-substituted heterocyclic propionates with defined stereocenters and alkyl and heteroatom substitution on the carbon backbone. The expansion and application of this methodology to the synthesis of compounds of biological interest are in progress and will be reported in due course.


We thank the National Institutes of Health (GM 25439), Pfizer, Inc., Merck Research Laboratories, and the Robert A. Welch Foundation for their generous support of this research. We also thank Dr. Vince Lynch for performing the x-ray analysis and Mr. Travis Turner for preparing some of the starting materials.


Supplementary Data

Characterization data for all β-heteroaryl propionates are provided. Supplementary data associated with this article can be found in the online version at doi:(Insert doi).

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i. For examples of generating achiral substituted β-heteroaryl propionate derivatives, see: (a) Iqbal Z, Jackson AH, Rao KRN. Tetrahedron Lett. 1988;29:2577–2580. (b) Harrington P, Kerr MA. Can J Chem. 1998;76:1256–1265. (c) Yadav JS, Abraham S, Reddy BVS, Sabitha G. Synthesis. 2001:2165–2169. (d) Bandini M, Cozzi PG, Giacomini M, Melchiorre P, Selva S, Umani-Ronchi A. J Org Chem. 2002;67:3700–3704. [PubMed] (e) Bartoli G, Bartolacci M, Bosco M, Foglia G, Giuliani A, Marcantoni E, Sambri L, Torregiani E. J Org Chem. 2003;68:4594–4597. [PubMed] (f) Shi M, Cui SC, Li QJ. Tetrahedron. 2004;60:6679–6684. (g) Lin C, Hsu J, Sastry MNV, Fang H, Tu Z, Liu JT, Ching-Fa Y. Tetrahedron. 2005;61:11751–11757. (h) Zhang HB, Liu L, Liu YL, Chen YJ, Wang J, Wang D. Synth Commun. 2007;37:173–181.
ii. For a comprehensive review on the enantioselective synthesis of substituted β-heteroaryl propionate derivatives, see: (a) Poulsen TB, Jorgensen KA. Chem Rev. 2008;108:2903–2915. [PubMed]For other recent examples, see: (b) Zhou W, Xu LW, Li L, Yang L, Xia CG. Eur J Org Chem. 2006;23:5225–5227. (c) Chen W, Du W, Yue L, Li R, Wu Y, Ding LS, Chen YC. Org Biomol Chem. 2007;5:816–821. [PubMed] (d) Sui Y, Liu L, Zhao JL, Wang D, Chen YJ. Tetrahedron. 2007;63:5173–5183. (e) Singh PK, Bisai A, Singh VK. Tetrahedron Lett. 2007;48:1127–1129. (f) Itoh J, Fuchibe K, Akiyama T. Angew Chem Int Ed. 2008;47:4016–4018. [PubMed] (g) Desimoni G, Faita G, Toscanini M, Boiocchi M. Chem Eur J. 2008;14:3630–3636. [PubMed] (h) Schatz A, Rasappan R, Hager M, Gissibl A, Reiser O. Chem Eur J. 2008;14:7259–7265. [PubMed] (i) Tang HY, Lu AD, Zhou ZH, Zhao GF, He LN, Tang CC. Eur J Org Chem. 2008;8:1406–1410. (j) Singh PK, Singh VK. Org Lett. 2008;10:4121–4124. [PubMed] (k) Cozzi PG, Benfatti F, Zoli L. Angew Chem Int Ed. 2009;48:1–5.
iii. (a) Banik BK, Fernandez M, Alvarez C. Tetrahedron Lett. 2005;46:2479–2482. (b) Kumar V, Kaur S, Kumar S. Tetrahedron Lett. 2006;47:7001–7005.
iv. Hofmann M, Hampel N, Kanzian T, Mayr H. Angew Chem Int Ed. 2004;43:5402–5405. [PubMed]
v. Grieco PA, Handy ST. Tetrahedron Lett. 1997;38:2645–2648.
vi. (a) Balaban AT, Bota A, Zlota A. Synthesis. 1980:136–138. (b) Comins DL, Stroud ED. Tetrahedron Lett. 1986;27:1869–1872. (c) Muratake H, Natsume M. Tetrahedron. 1990;46:6331–6342. (d) Oh KT, Ka JW, Park JY, Lee CH. Bull Korean Chem Soc. 1997;18:222–224. (e) Schwenter ME, Vogel P. Chem Eur J. 2000;6:4091–4103. [PubMed] (f) Caron S, Vazquez E. Org Process Res Dev. 2001;5:587–592. (g) Noji M, Ohno T, Fuji K, Futaba N, Tajima H, Ishii K. J Org Chem. 2003;68:9340–9347. [PubMed] (h) Sessler JL, An DQ, Cho WS, Lynch V. J Am Chem Soc. 2003;125:13646–13647. [PubMed] (i) MacKay JA, Bishop RL, Rawal VH. Org Lett. 2005;7:3421–3424. [PubMed] (j) Huang W, Wang J, Shen Q, Zhou X. Tetrahedron. 2007;63:11636–11643. (k) Rueping M, Nachtsheim BJ, Moreth SA, Bolte M. Angew Chem Int Ed. 2008;47:593–596. [PubMed]
vii. Method A. Freshly distilled TMSOTf (0.47 mL, 2.59 mmol) was slowly added dropwise to a solution of silyl ketene acetal (7.20 mmol) and alcohol (2.88 mmol) in THF (150 mL) at −40 °C under argon. The solution was stirred at −40 °C for 1 h, whereupon H2O (70 mL) was added. The mixture was extracted with Et2O (4 × 70 mL), and the combined organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a suitable mixture of EtOAc/hexanes, to afford the product in >95% purity.
viii. Martin SF. Tetrahedron. 1980;36:419–460.
ix. Method B. Freshly distilled TMSOTf (0.42 mL, 2.3 mmol) was slowly added dropwise to a solution of silyl ketene acetal (3.45 mmol) and alcohol or acetate (2.3 mmol) in MeCN (23 mL) at −40 °C under argon. The solution was stirred at −40 °C for 1 h, whereupon saturated NaHCO3 (20 mL) was added. The layers were separated, and the aqueous layer was washed with Et2O (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash, chromatography, eluting with a suitable mixture Et2O/pentane to afford the product in >95% purity.
x. For the use of an N-sulfonyl indole in a related reaction, see reference 6i.
xi. Noland WE, Lee CK, Bae SK, Chung BY, Hahn CS, Kim KJ. J Org Chem. 1983;48:2488–2491.
xii. For preparation of the diene, see: (a) Camiletti C, Dhavale DD, Donati F, Trombini C. Tetrahedron Lett. 1995;36:7293–7296. (b) Savard J, Brassard P. Tetrahedron. 1984;40:3455.
xiii. Fuentes LM, Shinkai I, Salzmann TN. J Am Chem Soc. 1986;108:4675–4676.
xiv. CCDC 717722 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
xv. (a) Rao KV. Antibiot Chemother. 1960;10:312–315. [PubMed] (b) Marsh WS, Garretson AL, Wesel EM. Antibiot Chemother. 1960;10:316–320. [PubMed]
xvi. For example, see: (a) Takeda T, Mukaiyama T. Chemistry Lett. 1980:163–166. (b) Akita H, Kawaguchi T, Enoki Y, Oishi T. Chem Pharm Bull. 1990;38:323–328.
xvii. For example, see: (a) Chapman E, Thorson JS, Schultz PG. J Am Chem Soc. 1997;119:7151–7152. (b) Deechongkit S, You SL, Kelly JW. Org Lett. 2004;6:497–500. [PubMed]