Rhodium-catalyzed asymmetric hydroboration of γ,δ-unsaturated amide derivatives: δ-borylated amides

Abstract

γ,δ-Unsaturated amides in which the alkene moiety bears an aryl or heteroaryl substituent undergo regioselective rhodium-catalyzed δ-borylation by pinacolborane to afford chiral secondary benzylic boronic esters. The results contrast the γ-borylation of γ,δ-unsaturated amides in which the disubstituted alkene moiety bears only alkyl substituents; the reversal in regioschemistry is coupled with a reversal in the sense of π-facial selectivity.

Chiral boronic acid derivatives are useful building blocks for the synthesis of biologically active natural products and pharmaceutical intermediates.¹ Structures in which boron is attached to the same carbon as an aryl or heteroaryl substituent (i.e., benzylic boronic acid derivatives) are of particular synthetic interest. The catalytic asymmetric hydroboration (CAHB) of styrene and related vinyl arenes to yield benzylic boronic esters was first reported in the mid-1980s.^2,3 The observed regioselectivity is often attributed to the formation of a π-benzyl metal intermediate en route to the benzyl borylated product.^3c,d In spite of its long history and foundational impact on CAHB,⁴ the chemistry has largely been limited to simple vinyl arenes; Rh(I)/QUINAZOLINE⁵ and Cu(I)/DTBM-SEGPHOS⁶ are among a few catalyst systems that exhibit high selectivity for unfunctionalized β-substituted vinyl arenes.

Figure 1 highlights several alternative methods for the preparation of chiral benzylic boron derivatives that have attracted recent interest. Hall,⁷ Yun,⁸ and Morken⁹ independently reported group-selective cross-coupling of chiral gem-diboron derivatives. The methods of Hall and Yun exploit stereoretentive Pd-catalyzed cross-coupling of chiral 1,1-diborylalkanes. Morken uses enantiotopic group-selective cross-coupling of achiral 1,1-diborylalkane derivatives using a chiral palladium catalyst. Toste developed a novel three component coupling strategy using an α-olefin, an aryldiazonium salt, and bis(pinacolato)diboron (B₂pin₂); the enantioselectivity is controlled by a cooperative chiral anion phase transfer catalyst in conjunction with a palladium catalyst.¹⁰ Watson constructed the desired chiral boronic ester derivatives via stereospecific nickel-catalyzed Miyaura borylation of a chiral ammonium salt precursor by B₂pin₂.¹¹ Most recently, Lu introduced a one-pot cobalt-catalyzed sequential hydroboration/hydrogenation of internal alkynes.¹² Other recently developed methods for the preparation of benzylic boron derivatives include enantioselective conjugate borylation,¹³ enantioselective allylic borylation¹⁴ and asymmetric hydrogenation¹⁵ as well as functionalization¹⁶ of vinyl boronates. Herein, we report that γ,δ-unsaturated carbonyl compounds, in which the disubstituted alkene moiety bears an aryl or heteroaryl substituent, undergo efficient CAHB to yield functionalized chiral benzylic boron derivatives.

Fig. 1.

Recent approaches in preparation of chiral benzylic boronic esters.

We have explored rhodium-catalyzed directed-CAHBs of a range of β,γ-unsaturated substrates with varying alkene substitution patterns and bearing carbonyl,¹⁷ oxime ether,¹⁸ and phosphonate¹⁹ functionalities. To expand the substrate scope, we are investigating the homologous γ,δ-unsaturated substrates²⁰ and recently reported that γ,δ-unsaturated amides 1, in which the alkene moiety bears only alkyl substituents, undergo efficient regio- and enantioselective γ-borylation (Fig. 2). For example, benzyl amide 1 (R = (CH₂)₂Ph) affords the γ-borylated product 2 (81%) in a >20:1 regioisomer ratio (rr) and a high enantiomer ratio (96.5:3.5 er).²¹ We now report that the analogous γ,δ-unsaturated benzyl amide 3a (R = Ph), in which the alkene moiety instead bears an aryl substituent, behaves much differently. Using the same catalyst system, CAHB proceeds with good regiocontrol (>20:1 rr) to give a chiral, secondary benzylic boronic ester, i.e., 4a (89%, 95:5 er). Unlike product 2, 4a is the result of δ-borylation not γ-borylation, and the sense of π-facial selectivity is reversed; pinBH adds to the opposite faces of the π-system in the two substrates.²²

Fig. 2.

Regiocontrolled CAHB of γ,δ-unsaturated amides: the effect of aliphatic and aromatic substituents.

While we have not carried extensive ligand optimization studies, the series of BINOL-derived phosphoramidites B1–B5 indicate that an N-phenyl substituent on the phosphoramidite ligand is needed to achieve good conversion and high levels of regio- and enantioselectivity (Fig. 2).²³ Ligands B1 and B2 give the major product 4a in high yield and enantioselectivity (87–89%, 95:5 er). Ligand B3, the corresponding N,N-diphenyl derivative, also affords 4a in good yield (87%) and with high regioselectivity (>20:1 rr), but the er is lower in this case (85:15); however, B3 proves more successful with other substrates (vide infra). The N,N-dibenzyl ligand B4 and the more rigid indoline-derived phosphoramidite B5 afford catalysts giving relatively low conversion (50–80% after 12 hours), lower regioselectivity (<4:1 rr) and consequently a low isolated yield of 4a (18–28%).²⁴ In addition to the N-benzyl amide 3a, the N-phenyl amide 5a and the morpholine-derived tertiary amide 5b are also good substrates; CAHB affords δ-borylated product 6 (B1: 76%, 94:6 er) and 7 (B2: 78%, 95.5:4.5 er), respectively.

Figure 3 shows the results obtained under the standard reaction conditions for a series of γ,δ-unsaturated benzyl amides 3. Using ligands B1–3, the most efficient catalyst system varied among the different substrates. For example, although the N,N-diphenyl ligand B3 gives relatively low enantioselectivity compared to B1 and B2 for substrate 3a, it gives the highest level of induction for 3b, a substrate bearing a relatively electron poor aryl substituent (i.e., 4-CF₃C₆H₄). CAHB with B3 affords δ-borylated amide 4b (78%, 95:5 er); B1 and B2 give comparable yields but only 91:9 and 90:10 er, respectively. Substrates 4c and 4d, 4-fluorophenyl and 4-chlorophenyl derivatives, undergo CAHB in good yield and enantioselectivity (75–77%, 95:5 er). Aryl derivatives bearing alkoxy group(s) at the para- and/or meta-positions undergo efficient CAHB (71–80%, >20:1 rr) as illustrated by the 4-methoxyphenyl (4e, 96:4 er), 3 methoxyphenyl (4f, 97:3 er), 3,5-dimethoxyphenyl (4g, 96.5:3.5 er) and 3,4-dialkoxyphenyl (4h, 92:8 er) derivatives. The product bearing a 2-methoxyphenyl-substituent (4i, 82%, >20:1 rr) is obtained in good yield but with lower enantioselectivity (85:15 er); the corresponding 2-methylphenyl derivative is somewhat more efficient (4j, 84%, 93:7 er). A series of four heteroaromatic substrates, although more sluggish to react, undergo CAHB yielding 4k–n with good regio and enantioselectivity (69–73% yield, 92:8–97:3 er, 11–>20:1 rr); three equivalents of pinBH are employed to achieve complete conversion in 12 hours.

Fig. 3.

Substrate scope for CAHB of aryl-substituted γ,δ-unsaturated amides. ^a3.0 equivalents of pinBH are used.

Substrate 8, chiral by virtue of the stereodefined (R)-phenethyl amide moiety, undergoes highly regioselective CAHB (>20:1 rr) (Fig. 4). CAHB/oxidation of 8 using ligand (R)-B1 affords (5R)-9 (82%, 94.5:5.5 dr); the yield and enantioselectivity are comparable to that obtained for the parent substrate 3a. CAHB using (S)-B1 generates the diastereomer (5S)-9 in similar yield (80%) but with a somewhat diminished diastereomer ratio (91:9 dr) indicating a modest matched/mismatched case of double stereodifferentiation. Chiral substrate 10 also undergoes largely catalyst-controlled diastereoselective δ-borylation. CAHB/oxidation using (R)-B1 gives predominantly (2R,5R)-11 (79%, 91:9 dr); (S)-B1 gives predominantly (2R,5S)-11 (79%, 92:8 dr). In contrast, the anti-β-silyloxybenzyl amide 12 undergoes CAHB/oxidation with lower diastereoselectivity and exhibits a strong matched/mismatched effect. (R)-B2 affords (2S,3S,5R)- 13 (75%, 86:14 dr); the catalyst employing (S)-B2 exhibits lower reactivity (i.e., only 85% conversion after 12 hours) and gives the same major diastereomer of 13 but with much lower diastereoselectivity (67:33 dr).

Fig. 4.

Diastereoselective CAHB/oxidation of chiral substrates. Unless otherwise noted, the reaction conditions employ 1.0% [Rh(nbd)₂BF₄/2 B], 1.5 pinBH in THF (40 °C, 12 h) followed by oxidation (H₂O₂, aq NaOH, rt, 1 h); the reported yields are for the isolated mixture of inseparable diastereomers. ^a3.0% [Rh(nbd)₂BF₄/2 B]. ^bNMR yield. ^cca. 85% conversion.

The question naturally arises, why do 3a and related substrates afford δ-borylation while 1 gives γ-borylation? The modest, but energetically significant, matched/mismatched change in diastereoselectivity for CAHB of chiral amide 8 (Fig. 4) indicates that the resident stereogenic center is positioned close to the rhodium-complexed alkene as one would expect in a carbonyl-directed CAHB. The ester moiety in 14 and more so the TIPS ether in 16 are less likely to direct the rhodium-catalyzed reaction. Each undergoes CAHB in good yield and with high regioselectivity (75–77% yield, >20:1 rr), but compared to amides 3a, 5a and 5b, the level of enantioselectivity is lower, 85:15 for ester 14 and 90:10 er for TIPS ether 16. Furthermore, in the direct competition between equivalent amounts of 3a and 16 for a limiting amount of pinBH, 3a is consumed somewhat faster.²⁵ The one carbon homologue of 3a, that is, δ,ε-unsaturated amide 18, increases the distance between directing group and the alkene; CAHB affords the benzylic, ε-borylated product 19 (78%, >20:1 rr, 90.5:9.5 er). These results seem to indicate that the aryl substituent directs the regiochemistry, but the nature of the directing group is important in determining the level of catalyst-controlled enantioselectivity.

In conclusion, we report the δ-borylation of γ,δ-unsaturated amides bearing an aryl/heteroaryl substituent on the alkene. The results contrast those obtained for CAHB of γ,δ-unsaturated amides bearing only alkyl substituents on the alkene, which differ both in terms of regioselectivity and π-facial selectivity. A brief ligand survey suggests that an N-aryl substituent is a necessary feature of the BINOL-derived phosphoramidite ligand. While chiral phosphoramidites²⁶ and BINOL-derived ligands²⁷ have found extensive use in asymmetric catalysis, phosphoramidites derived from N-aryl amines have less commonly been used; their requirement here is somewhat unusual.^24,28 The reaction exhibits a fairly broad scope with respect to vinyl arene moiety; the successful use of furan and thiophene derivatives and the catalyst-controlled diastereoselective δ-borylation of certain chiral substrates are of particular note. Whether or not δ-borylation is the result of carbonyl-directed CAHB is mechanistically interesting but does not greatly impact the potential utility of the process. Nonetheless, the nature of the directing group is important to the level of enantioselectivity. Further studies on the influence of aryl-substituents on directed-CAHBs are in progress.

Fig. 5.

Other directing groups exhibit lower levels of enantioselectivity.