O-Acetyl 1,3-Propanediol as an Acrolein Proelectrophile in Enantioselective Iridium-Catalyzed Carbonyl Allylation

Abstract

O-Acetyl 1,3-propanediol serves as an acrolein proelectrophile in π-allyliridium-C,O-benzoate-catalyzed carbonyl allylations mediated by racemic α-substituted allylic acetates. Using the iridium catalyst modified by (R)-SEGPHOS, a variety of 3-hydroxy-1,5-hexadienes are formed with uniformly high levels of regio-, anti-diastereo- and enantioselectivity.

Graphical Abstract

Acrolein (5 × 10⁵ tons/year)¹ is generated and used on-site for the large-scale manufacture of acrylic acid and rac-methionine.² However, due to its instability and toxicity,³ reagent grade acrolein is not reliably sourced for use in fine chemical synthesis. Acrolein’s intractability also has impeded its use in asymmetric 1,2-additions, which are largely restricted to chiral auxiliary-based aldol reactions.⁴ Catalytic enantioselective 1,2-additions to acrolein are limited to a small number of isolated reports.⁵ Recently, in connection with longstanding studies on the use of alcohols as carbonyl proelectrophiles in catalytic enantioselective carbonyl addition,⁶ our laboratory described the use of allyl alcohol 1a as a tractable, inexpensive acrolein proelectrophile in asymmetric iridium-catalyzed carbonyl allylations mediated by allylic acetates 2 (Scheme 1).⁷ Although these reactions were highly effective, delivering 3-hydroxy-1,5-hexadienes 3 with high levels of regio-, anti-diastereo- and enantioselectivity, in certain cases it was not possible to completely suppress redox isomerization of allyl alcohol to form propanal, which resulted in contamination with inseparable propanal adducts 4.

Scheme 1.

Alcohols as acrolein proelectrophiles in regio- diastereo- and enantioselective carbonyl allylation.

It was posited that dehydrogenation of O-acetyl 1,3-propanediol 1b would provide 3-acetoxy propanal, which under the basic conditions of iridium-catalyzed allylation might suffer E1cB elimination to form acrolein, potentially enabling access to 3-hydroxy-1,5-hexadienes 3 free from contamination by propanal adducts 4. As 1,3-propanediol is a highly abundant commodity chemical (1 × 10⁶ ton/year),⁸ the use of O-acetyl 1,3-propanediol 1b as an acrolein proelectrophile appeared attractive from the standpoint of cost and atom-efficiency. Here, we report that the π-allyliridium-C,O-benzoate⁹ modified by (R)-SEGPHOS catalyzes the C–C coupling of O-acetyl 1,3-propanediol 1b with racemic α-substituted allylic acetates 2 to furnish 3-hydroxy-1,5-hexadienes 3 that are free from propanal adducts 4 with excellent levels of regio-, anti-diastereo- and enantioselectivity.

In a preliminary experiment, O-acetyl 1,3-propanediol 1b (100 mol%) was exposed to the allylic acetate 2f (200 mol%) in the presence of K₂CO₃ (100 mol%) and the π-allyliridium-C,O-benzoate complex modified by (R)-Cl,MeO-BIPHEP (Ir-I, 5 mol%) in THF (0.5 M) at 80 °C. To our delight, the desired 1,5-diene 3f was obtained in moderate yield with high levels of anti-diastereo- and enantioselectivity without competing formation of adducts 4f or 5f (Table 1, entry 1). Under otherwise identical conditions using the (R)-SEGPHOS catalyst Ir-II, a slight increase in yield was observed (Table 1, entry 2). An additional improvement in the yield of 3f was observed using the more electron-deficient 3,4-dinitrobenzoate; however, lower enantioselectivities were observed (Table 1, entry 3). It was postulated that a more Lewis basic medium might better solubilize K₂CO₃ to promote higher levels of conversion. Hence, a brief survey of Lewis basic additives was conducted (Table 1, entries 4–6). It was found that the addition of dimethylacetamide (DMAc, 200 mol%) elevated both the isolated yield of 3f and enantioselectivity (Table 1, entry 6). The absolute stereochemistry of 3f was confirmed by single crystal X-ray diffraction analysis. Under these conditions on 1 mmol scale, a slightly lower yield and selectivity were observed (Table 1, entry 7).

Table 1.

Selected optimization experiments in the coupling of alcohol 1b with allylic acetate 2f.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by HPLC analysis.

^bReaction conducted on 1 mmol scale. See Supporting Information for further details. NMP = N-methyl-2-pyrrolidinone. DMF = dimethylformamide. DMAc = dimethylacetamide.

Optimal conditions identified for the formation of 1,5-diene 3f were applied to the reaction of acetyl 1,3-propanediol 1b with diverse allyl pronucleophiles 2a-2p (Table 2). The corresponding products of acrolein allylation 3a-3p were all formed in good yield with excellent levels of diastereo-, regio- and enantioselectivity, and were free from contamination by propanal adducts 4. Adducts 3a-3p are identical (but enantiomeric) to those prepared in iridium-catalyzed carbonyl allylations allyl alcohol 1a.⁷ Reactions of O-acetyl 1,3-propanediol 1b gave slightly lower yields compared to allyl alcohol 1a, possibly due to the accumulation of potassium acetate under the highly concentrated reaction conditions in THF (0.5 M) which resulted in poor mixing. Finally, β-substituted 1-propanol derivatives 1b-1g were exposed to allylic acetate 2f under optimized conditions (Table 3). In each case, acrolein allylation product 3f could be isolated as the sole product of C–C coupling in moderate to good yield with excellent levels of enantioselectivity. However, optimal yields were obtained using O-acetyl 1,3-propanediol 1b.

Table 2.

Regio- and stereoselective iridium-catalyzed C−C coupling of alcohol 1b with allylic acetates 2a-2p.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivity was determined by HPLC analysis. See Supporting Information for further details.

^bDue to volatility of product, yield was determined by ¹H NMR analysis in reference to an internal standard.

^c70 °C.

^d(R)-Ir-II (7.5 mol%).

^eDMF (200 mol%). See Supporting Information for further details.

Table 3.

Coupling of β-substituted 1-propanols 1b-1g with allylic acetate 2f.^a

^aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by HPLC analysis.

^bDMF (200 mol%). See Supporting Information for further details.

A catalytic cycle for the coupling of acetyl 1,3-propanediol 1b with allylic acetates 2a-2q has been proposed (Figure 1). Entry to the catalytic cycle occurs via protonolysis of the π-allyl precatalyst by 1b. The resulting alkoxide suffers β-hydride elimination to afford 3-acetoxy propanal and an iridium hydride, which may be deprotonated to form an achiral anionic square planar iridium(I) complex. Ionization of the allylic acetate provides a stereogenic-at-metal allyliridium(III) complex.¹⁰ Carbonyl addition proceeds through a six-centered transition state, and alkoxide exchange of the homoallylic product with 3-acetoxy propanal closes the catalytic cycle. To determine if elimination of acetate occurs at the stage of the aldehyde or the product, homoallylic alcohol 6a was exposed to the reaction conditions (eq. 1). No 3a was

observed after 48 hours. We posit that rapid formation of acrolein via E1cB elimination of acetate from 3-acetoxy propanal preludes rate-limiting carbonyl addition.

Figure 1.

Proposed catalytic cycle.

In conclusion, we report diastereo- and enantioselective π-allyliridium-C,O-benzoate-catalyzed acrolein 1,2-additions using acetyl 1,3-propanediol as an acrolein proelectrophile. Unlike corresponding reactions in which allyl alcohol serves as an acrolein proelectrophile,⁷ the present method delivers 3-hydroxy-1,5-hexadienes free of propanal allylation adducts. This work adds to the lexicon of catalytic asymmetric methods that transform inexpensive commodity chemicals to value-added products via hydrogen auto-transfer.^6,11,12

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.