Julianne M.
Yost
,
Rachel J.
Alfie
,
Emily M.
Tarsis
,
Insun
Chong
and
Don M.
Coltart
*
Department of Chemistry, Duke University, Durham, NC, USA. E-mail: don.coltart@duke.edu
First published on 21st October 2010
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.
A practical concern associated with the proposed transformation is the possibility of competing Darzens reaction1a,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. |
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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.
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.
Entry | Thioester | Product | Time/h |
syn![]() ![]() |
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 R1 = Ph | 6 | 0.5 | 1.2![]() ![]() |
98 |
2 |
8 R1 = ![]() |
11 | 0.5 | 2.5![]() ![]() |
97 |
3 |
9 R1 = ![]() |
12 | 0.5 | 5.2![]() ![]() |
97 |
4 |
10 R1 = ![]() |
13 | 1 | 4.5![]() ![]() |
90 |
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.
Entry | Aldehyde | Product | Time/h |
syn![]() ![]() |
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 R1 = ![]() |
12 | 0.5 | 5.2![]() ![]() |
91 |
2 |
14 R1 = ![]() |
22 | 0.5 | 4.0![]() ![]() |
96 |
3 |
15 R1 = ![]() |
23 | 1 | 4.0![]() ![]() |
96 |
4 |
16 R1 = ![]() |
24 | 0.5 | 3.7![]() ![]() |
97 |
5 |
17 R1 = ![]() |
25 | 0.5 | 4.2![]() ![]() |
83 |
6 |
18 R1 = ![]() |
26 | 1 | 3.2![]() ![]() |
76 |
7 |
19 R1 = ![]() |
27 | 1 | 3.2![]() ![]() |
73 |
8 |
20 R1 = ![]() |
28 | 1 | 3.4![]() ![]() |
29 |
9 |
21 R1 = ![]() |
29 | 1 | 5.0![]() ![]() |
36 |
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.
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 |
This journal is © The Royal Society of Chemistry 2011 |