Direct carbon–carbon bond formation via soft enolization: aldol addition of α-halogenated thioesters

Abstract

α-Halo thioesters undergo soft enolization and syn-selective direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂ and i-Pr₂NEt to produce α-halo-β-hydroxy thioesters.

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α-Halo-β-hydroxy carboxylic acid derivatives are useful intermediates in the synthesis of natural products. They are normally generated viaaldol addition of a pre-formed enolate and an aldehyde.¹ While effective, the step-wise procedures required to generate the enolates are time consuming, particularly if trapping is involved, and require that all manipulations be conducted under anhydrous conditions and, when strong bases are used, at low temperature. In contrast, soft enolization^2,3 provides a mild and straightforward approach to conducting enolate chemistry. Here, rather than forcing deprotonation with a strong base such as LDA, a relatively weakly basic amine is used in combination with a Lewis-acid to effect deprotonation. We have been investigating this mode of enolization with thioesters in the development of direct versions of certain fundamental carbon–carbon bond-forming reactions.⁴ Given the efficiency and operational simplicity of these transformations, we sought to extend this approach to the synthesis of α-halo-β-hydroxy carboxylate derivatives. In what follows, we describe the development of a MgBr₂·OEt₂-promoted direct aldol addition reaction between α-halo thioesters and aldehydes using soft enolization, which produces α-halo-β-hydroxy thioesters.

A practical concern associated with the proposed transformation is the possibility of competing Darzens reaction^1a,b,d,5 to produce the corresponding α,β-epoxy thioesters (Scheme 1). However, our previous experiences led us to believe that the magnesium aldolate intermediate would be sufficiently stable under the reaction conditions to prevent epoxide formation. To test this, we attempted the aldol addition with aldehyde 1 and α-bromo thioester 2 under our soft enolization conditions⁴ (Scheme 2). Gratifyingly, the desired α-bromo-β-hydroxy thioester (3) was formed rapidly and in excellent yield, with no indication of epoxide formation.

Scheme 1 Possible reaction pathways.

Scheme 2 MgBr₂·OEt₂-promoted direct aldol reaction of α-bromo phenylthioacetate (2) with 2-naphthaldehyde (1).

We next examined the effect of the halogen substituent on the reaction. To do this, thioesters 2, 4, and 5 were combined with 1 and allowed to react for 5 min at room temperature, before quenching with acid (Table 1). In each case the desired product was produced in high yield, with α-chloro thioester 4 giving the best result. No appreciable difference in the diastereoselectivity as a function of the halogen was seen. Given the rapid nature of the transformations, control experiments were carried out with thioesters 2 and 4 in which the magnesium salt was omitted from the reaction mixture, but all other components were retained. After 72 hours, no aldol addition product was detected for the reaction involving 2, and only a trace (<5%) was formed when thioester 4 was used, confirming the importance of MgBr₂·OEt₂.

Table 1 MgBr₂·OEt₂-promoted direct aldol reaction of 2-naphthaldehyde and different α-halo-S-phenyl thioesters^a

Entry	Thioester (X)	Product	syn ∶ anti	Conversion (%)
a 1 molar equiv. of 1, 1.2 molar equiv. of thioester, and 1.4 molar equiv. of MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv. of i-Pr2NEt at rt.
1	4 (Cl)	6	1.2 ∶ 1	95
2	2 (Br)	3	1.1 ∶ 1	90
3	5 (I)	7	1.1 ∶ 1	85

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Having established the superiority of the α-chloro thioester in the addition reaction, we turned our attention to improving the diastereoselectivity. In pioneering work on the development of an anti-selective aldol addition, Heathcock and Pirrung showed that increasing the steric bulk of the ester component led to an increase in diastereoselectivity.⁶ Thus, various α-chloro thioesters derived from more sterically-demanding thiols were examined (Table 2). As with the previous study, an increase in steric bulk did correlate to an increase in diastereoselectivity. However, in contrast, the syn—not the anti—diastereomer was preferentially formed. Interestingly, a somewhat lower syn selectivity resulted for the more bulky α-chloro thioester 10 than for 9.

Table 2 Effect of the thioester on diastereoselectivity^a

Entry	Thioester	Product	Time/h	syn ∶ anti	Conversion (%)
a 1 molar equiv. of 1, 1.2 molar equiv. of thioester, and 1.4 molar equiv. of MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv. of i-Pr2NEt at rt.
1	4 R^1 = Ph	6	0.5	1.2 ∶ 1	98
2	8 R^1 =	11	0.5	2.5 ∶ 1	97
3	9 R^1 =	12	0.5	5.2 ∶ 1	97
4	10 R^1 =	13	1	4.5 ∶ 1	90

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With effective conditions in place, the scope of the reaction was explored using thioester 9 and a variety of aldehydes (Table 3). The transformation proceeded efficiently with aromatic aldehydes, including electron rich and deficient systems, and also proceeded well with the highly sterically-hindered aldehyde 18. Notably, when the reaction was carried out with an enolizable aldehyde possessing a single α-proton (19, entry 7), the aldol product was produced in good yield. Encouraged by this result, aldehydes 20 and 21 were tested in the addition reaction. Unfortunately, while the desired products did form (28 and 29, respectively), they were obtained in a relatively low yield due to competing aldehyde self addition.

Table 3 Scope of the MgBr₂·OEt₂-promoted aldol addition using thioester 9 and various aldehydes^a

Entry	Aldehyde	Product	Time/h	syn ∶ anti	Yield (%)
a 1 molar equiv. of aldehyde, 1.2 molar equiv. of 9, and 1.4 molar equiv. of MgBr2·OEt2 (concn 0.2 M), followed by addition of 2.0 molar equiv. of i-Pr2NEt at rt.
1	1 R^1 =	12	0.5	5.2 ∶ 1	91
2	14 R^1 =	22	0.5	4.0 ∶ 1	96
3	15 R^1 =	23	1	4.0 ∶ 1	96
4	16 R^1 =	24	0.5	3.7 ∶ 1	97
5	17 R^1 =	25	0.5	4.2 ∶ 1	83
6	18 R^1 =	26	1	3.2 ∶ 1	76
7	19 R^1 =	27	1	3.2 ∶ 1	73
8	20 R^1 =	28	1	3.4 ∶ 1	29
9	21 R^1 =	29	1	5.0 ∶ 1	36

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In conclusion, we have developed a mild and efficient MgBr₂·OEt₂-promoted direct aldol reaction of α-chloro thioesters employing soft enolization. The transformation proceeds without competing Darzens addition, producing the α-chloro-β-hydroxy thioesters in moderate to high yields with moderate to good diastereoselectivity. The reaction is effective in the case of an aldehyde having a single enolizable proton. Further studies will address the adaptation of this method to the use of aldehydes having two enolizable protons.

Notes and references

1. (a) J. Nebot, P. Romea and F. Urpi, J. Org. Chem., 2009, 74, 7518; (b) S.-i. Kiyooka and K. A. Shahid, Tetrahedron: Asymmetry, 2000, 11, 1537; (c) Y.-C. Wang, D.-W. Su, C.-M. Lin, H.-L. Tseng, C.-L. Li and T.-H. Yan, Tetrahedron Lett., 1999, 40, 3577; (d) E. J. Corey and S. Choi, Tetrahedron Lett., 1991, 32, 2857; (e) D. A. Evans, E. B. Sjogren, A. E. Weber and R. E. Conn, Tetrahedron Lett., 1987, 28, 39.
2. For pioneering applications of soft enolization in direct carbon–carbon bond formation see: (a) M. W. Rathke and P. J. Cowan, J. Org. Chem., 1985, 50, 2622; (b) M. W. Rathke and M. Nowak, J. Org. Chem., 1985, 50, 2624; (c) R. E. Tirpak, R. S. Olsen and M. W. Rathke, J. Org. Chem., 1985, 50, 4877.
3. D. Lim, G. Zhou, A. E. Livanos, F. Fang and D. M. Coltart, Synthesis, 2008, 2148.
4. See, for example: (a) G. Zhou, D. Lim and D. M. Coltart, Org. Lett., 2008, 10, 3809; (b) J. M. Yost, M. R. Garnsey, M. C. Kohler and D. M. Coltart, Synthesis, 2009, 56; (c) D. Lim, F. Fang, G. Zhou and D. M. Coltart, Org. Lett., 2007, 9, 4139; (d) J. M. Yost, G. Zhou and D. M. Coltart, Org. Lett., 2006, 8, 1503.
5. (a) T. Rosen, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, New York, 1991, vol. 2, pp. 409–439; (b) A. K. Ghosh and J.-H. Kim, Org. Lett., 2004, 6, 2725; (c) L. N. Pridgen, A. F. Abdel-Magid, I. Lantos, S. Shilcrat and D. S. Eggleston, J. Org. Chem., 1993, 58, 5107; (d) A. Abdel-Magid, L. N. Pridgen, D. S. Eggleston and I. Lantos, J. Am. Chem. Soc., 1986, 108, 4595.
6. (a) M. C. Pirrung and C. H. Heathcock, J. Org. Chem., 1980, 45, 1727; (b) H. C. Heathcock, M. C. Pirrung, S. H. Montgomery and J. Lampe, Tetrahedron, 1981, 37, 4087.

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Footnotes

† This article is part of the ‘Emerging Investigators’ themed issue for ChemComm.

‡ Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds 2, 4, 5, 8–10, 12, 22–29. See DOI: 10.1039/c0cc02345k

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