Ligand-Controlled Regiodivergent Enantioselective Rhodium-Catalyzed Alkene Hydroboration

Abstract

Regiocontrol in the rhodium-catalyzed boration of vinyl arenes is typically dominated by the presence of the conjugated aryl substituent. However, small differences in TADDOL-derived chiral monophosphite ligands can override this effect and direct rhodium-catalyzed hydroboration of β-aryl and -heteroaryl methylidenes by pinacolborane to produce either chiral primary or tertiary borated products selectively. The regiodivergent behavior is coupled with enantiodivergent addition of the borane. The nature of the TADDOL backbone substituents and that of the phosphite moiety function synergistically to direct the sense and extent of regioselectivity and enantioinduction. Twenty substrates undergo each reaction mode with regioselectivities reaching greater than 20:1 and enantiomer ratios reaching up to 98:2. A variety of subsequent transformations illustrate the potential utility of each product.

Entry for the Table of Contents

Regiodivergent with enantioselectivity included! Small changes in the structure of the TADDOL-derived chiral monophosphite ligand direct the rhodium-catalyzed hydroboration of methylidenes to give either primary or tertiary chiral boronic esters.

The enantioselective preparation of chiral boronic esters is of current interest due to their synthetic utility through a diverse set of stereospecific transformations^[1] and the growing appreciation that boronic acid derivatives may hold significant potential in medicinal chemistry.^[2] Considerable progress has been realized in the development of regioselective asymmetric hydroboration^[3],[4] and asymmetric borometallation^[5] reactions, most exploiting substrate control through use of activated alkenes or directing groups. Catalysts that override inherent substrate bias to selectively produce either of two regioisomers offer greater synthetic utility. In addition to several recent examples of non-stereocontrolled borylative difunctionalizations via regiodivergent borocupration,^[6] the ligand-controlled regiodivergent palladium-catalyzed hydroboration of terminal alkynes serves to illustrate the potential. Prabhu^[7] reported a bulky N-heterocyclic carbene ligand promotes regioselective boropalladation to deliver boron to the terminus; protonolysis leads to 1 (Figure 1). In contrast, tricyclohexylphosphine effects delivery of boron to the internal position leading to the regioisomeric product 2.

Figure 1.

Regiodivergent hydroboration of alkenes.

Examples of chiral catalyst-controlled regiodivergent and enantioselective reactions are less common.^[8],[9] Herein, we report that relatively modest structural changes to a chiral TADDOL-monophosphite ligand results in a switch in both regioselectivity and the sense of enantioselectivity in the catalytic asymmetric hydroboration (CAHB) of β-aryl methylidene substrates 3 by pinacolborane (pinBH). This methodology provides access to either rhodium-catalyzed γ-boration at the unsubstituted terminus leading to the primary organoboronic ester 4 (si-face addition favored)^[10] or β-boration leading to the tertiary organoboronic ester 5 (re-face addition favored)^[11] using ligands (R,R)-T1a or (R,R)-T2b, respectively.

To probe the influence of structural changes in the ligand on the γ- to β-boration ratio (i.e., 4:5) and the levels of asymmetric induction (i.e., re:si face addition), a series of TADDOL-derived phosphite ligands were evaluated under a standard set of screening conditions for the CAHB of 3a (Figure 2). The selected TADDOL-derived ligands varied in the substituents at two positions. The T1-T6 series of phosphites differ with respect to the aryl appendages on the TADDOL backbone; for example, the aryl appendages are 3,5-dimethylphenyl groups in the T1 series, 4-methylphenyl groups in T2, etc. Next, each TADDOL backbone was evaluated as its phenyl phosphite (i.e., T1a-T6a, R = C₆H₅) and as its pentafluorophenyl phosphite (i.e., T1b-T6b, R = C₆F₅); for example, T1a is the TADDOL-phenylphosphite bearing 3,5-dimethylphenyl appendages and T1b is the corresponding pentafluorophenyl phosphite.

Figure 2.

Comparison of phenyl and pentafluorophenyl phosphites for a series of TADDOL backbone derivatives. Notes: the structures shown correlate to the major enantiomer from HPLC, except the product from T5b which arises from the opposite sense of π-facial selectivity.

Phenylphosphite T1a (Ar = 3,5-Me₂C₆H₃) displays a significant preference for enantioselective γ-boration giving predominantly 4a (6:1 γ:β); the major product reflects addition of pinBH to the si-face of the substrate (96:4 er). In contrast, the reaction run using phenylphosphite T2a (Ar = 4-MeC₆H₄) shows a slight preference for β-boration (1:1.1 γ:β), and the major regioisomer 5a arises via predominant addition of pinBH to the re-face (93:7 er). The results show that the aryl substituents appended to the TADDOL backbone have a significant effect on the sense of enantioinduction and regioselectivity. The nature of the phosphite substituent also plays a significant role. Compared to the phenylphosphites T1a-T3a, the corresponding pentafluorophenyl phosphites T1b-T3b give enhanced levels of β-boration. Among the latter, T2b (Ar = 4-MeC₆H₄) gives the highest level (1:10 γ:β) and enantioselectivity favoring re-face addition (97:3 er).^[12] Ligands T4-T6 generally are less selective than the other structural analogs examined. The 4-^tBuC₆H₄-TADDOL derivative T5b is a curious case. It affords the β-boration product 5a with moderate regioselectivity (1:4 γ:β), but in contrast to other β-selective ligands (e.g., T2b), pinBH adds to the si-face of the alkene (96:4 er).

Having identified the γ, si-face selective ligand T1a and β, re-face selective ligand T2b, a series of methylidenes were examined to probe the substrate scope of each.^[13] Figure 3A summarizes the results obtained using each ligand for CAHB/oxidation of 4-substituted aryl methylidene derivatives 3b-j. Halogenated derivatives generally work well affording predominantly 4b-d using T1a and predominantly 5b-d using T2b. Yields are in the range of 64–76% after oxidation with enantiomer ratios (er) up to 98:2. The methyl benzoate derivative 3e, 4-trifluoromethylphenyl derivative 3f, and 4-methylphenyl derivative 3g undergo γ-boration using the Rh-T1a catalyst to afford 4e (70%, 94:6 er), 4f (76%, 94:6 er), and 4g (63%, 98:2 er), respectively. The more electron rich aromatic derivatives, 4-methoxyphenyl 3h and 4-(dimethylamino)phenyl 3i, afford their respective γ-borylated products 4h (57%, 95:5 er) and 4i (57%, 94:6 er) albeit with lower regiocontrol. The Boc-protected 4-aminophenyl derivative 3j exhibits good regioselectivity, but the yield of 4j (52%, 93:7 er) is again moderate.

Figure 3A-C.

Substrate scope: A. 4-Substituted phenyl derivatives; B. 3-Substituted phenyl and heteroaromatic derivatives; C. ortho-Substituted aryl and alkyl derivatives. Reported yields and enantiomer ratios are for the isolated alcohol after oxidation. DG = (Me₂C=N-O). Notes: ^a used 1:1 Rh:L ratio; ^b yield of boronic ester before oxidation with NaBO₃-H₂O; ^c Compounds 5i, 5k, and 5l exhibited an opposite sign of optical rotation and order of elution on chiral HPLC; see SI.

The β-boration results obtained using the T2b catalyst for substrates 3b-f are like those described above for the T1a γ-boration catalyst; yields for 5b-f range from 64–78% with enantiomer ratios from 96:4 to 98:2 er. The two catalyst systems differ to a greater extent with substrates bearing electron donating substituents. In contrast to the moderate yields but good enantioselectivity using the T1a catalyst, 3g-i (especially the 4-methoxyphenyl and 4-(dimethylamino)phenyl derivatives 3h and 3i) give somewhat higher yields but exhibit attenuated enantioselectivity for β-borated 5g (66%, 91:9 er), 5h (76%, 86:14 er) and 5i (60%, 80:20 er) using T2b.

Figure 3B illustrates the results obtained with several more highly functionalized aryl derivatives including several methylidenes bearing heteroaryl substituents. Using the T1a-catalyst, the 3-methoxyphenyl (3k), 3-chlorotolyl (3l), 3,4-methylenedioxyphenyl (3m), and indole derivative (3n) afford 4k-n in 60–75% yield and up to 97:3 er. The thienyl and benzofuran derivatives 3o-q give γ-borylated products in more moderate yields (50–59%) due to higher levels of β-boration for 4o and 4q, and higher levels of the reduction product for 4p. The enantioselectivity is also lower for these substrates, ranging from 90:10 er for 4o to 65:35 er for 4q. In contrast, the 3- and 2-thienyl derivatives are efficient substrates in the T2b-catalyzed reaction affording 5o (85%, 98:2 er) and 5p (71%, 96:4 er), respectively. The benzofuran derivative 3q provides good regio- and enantioselectivity for 5q (40%, 94:6 er); the moderate yield reflects competing reduction in this case.^{[4a, 14]} The yields, regio- and enantioselectivities obtained for 5k (60%, 94:6) and 5l (65%, 95:5) are similar to those observed for the corresponding γ-borated products. However, substrates bearing multiple donor groups can give surprising results; 5k and 5l, for example, form with the opposite sense of stereoinduction (see SI).

Several other limitations are found (Figure 3C). Substrates bearing ortho-substituted aryl groups (e.g., 3r and 3s) do not exhibit regio- or enantioswitching. Both catalyst systems provide almost exclusively γ-borated products with little asymmetric induction. Unlike aryl substituted methylidenes 3a-s, the alkyl-substituted methylidene 3t undergoes β-boration using the T1a-catalyst to give 5t (85%, 95:5 er);^[4a] less than 5% of the γ-borylated product is formed. β-Boration of 3t giving 5t (58%, 92:8 er) remains the major pathway using ligand T2b, although the percentage of γ-boration increases to 32%.

The synthetic versatility of enantioselective, regiodivergent CAHB is demonstrated by the selected conversions of 4a and 5a to 6-21 (Figure 4).^[15] Both the primary and tertiary pinacol boronic esters are converted to the corresponding cesium^[16] or potassium^[17] trifluoroborate salts, 6a and 7a respectively, in 97–98% yield. Similarly, boronic acids 6b and 7b and the corresponding N-methyliminodiacetic acid (MIDA) esters^[18] 6c and 7c are readily accessible (62–72%). The one-carbon homologated boronic esters 8 (75%) and 9 (55%) are obtained via the Matteson protocol.^[19] In the case of the tertiary boronic ester 5a, the reaction proceeds with stereoretention to afford (R)-9 (98:2 er). Hydrolysis of the primary boronic ester 4a to the boronic acid, followed by Raney Nickel cleavage of N-O bond affords chiral oxaborolane 10 (71%). Reduction of the oxime C-N double bond in 5a with NaCNBH₃ affords 11 (77%); the reduction works equally as well for 4a (results not shown, see SI).

Figure 4.

Versatility of the primary and tertiary boronic esters 4a and 5a [DG = (Me₂C=N-O)].

Reaction Conditions: (a) CsF or KF, MeCN/H₂O; (b) BCl_3, DCM; (c) BCl_3, DCM; MIDA, DMSO; (d) LiCH₂Cl, −78 °C Et₂O; (e) BCl_3, DCM; Raney Ni, H₂, MeOH/THF; (f) NaBH₃CN, MeOH/HCl; (g) LiC(OEt)=CH₂, THF, −78 °C; I₂; NaOMe, MeOH; (h) KF, MeCN/H₂O; O₂NC₆H₄CHO, 5 mol% [Rh(cod)Cl]₂, dioxane, 80 °C; DMP, DCM; (i) 12 or 13, HCl/H₂O/MeOH, 40 °C; (j) thiophene, nBuLi, THF, −78 °C; NBS; (k) PhBr, 15 mol% Pd(OAc)₂, 15 mol% BINAP, KOH, THF/H₂O, 100 °C; (l) TBAF, toluene; (m) MeON(H)Li, THF, 60 °C; Boc₂O; (n) H₂O₂, NaOH, MeOH/H₂O; Raney Ni, H₂

In addition to forming boron derivatives 6–11, other transformations highlight the flexible and diverse ways in which 4a and 5a can be elaborated. Using Aggarwal’s modification of the Zweifel olefination,^[20] the primary boronic ester 4a is converted to ketone 12 (57%). For the tertiary boronic ester 5a, rhodium-catalyzed 1,2-addition to 4-nitrobenzaldehyde followed by DMP oxidation affords ketone 13 (59%, 96:4 er).^[21] Ketones 12 and 13 undergo acid-catalyzed cyclizations to the chiral dihydrooxazine 14 (39%) and chiral isoxazoline 15 (53%, 96:4 er), respectively.

The transition-metal-free sp²-sp³ cross-couplings of electron-rich aromatic systems convert 4a and 5a to the thienyl derivatives 16 (70%) and 17 (84%), respectively.^[22] Treatment of the primary boronic ester 4a with bromobenzene under typical palladium-catalyzed Suzuki cross-coupling conditions^[5c] affords 18, a product that is not readily accessible using the transition-metal-free procedure employed for thienylation. Protodeboronation of the tertiary boronic ester 5a affords 19 (90%, 98:2 er).^[23] In our hands, the common amination procedure^[24] is only successful for the primary boronic ester 4a; a moderate yield of the chiral 1,3-aminoalcohol derivative 20 (43%) is obtained. Oxidation of C-B bond in the tertiary boronic ester 5a followed by N-O bond cleavage gives chiral 1,2-diol 21 (86%, 99:1 er).

In summary, the CAHB of styrene and related vinyl arenes (e.g., β-methylstyrene or indene derivatives) often leads to formation of the chiral secondary benzylic borated products. The observed regioselectivity is usually attributed to the formation of an intermediate η³-complex with the aryl substituent.^[25] However, aryl methylidenes (e.g., α-methylstyrene) generally give the primary boronic ester. The chiral, tertiary benzylic regioisomer is not formed, presumably due to hindrance in forming the corresponding η³-complexed intermediate. We find that rhodium-catalyzed hydroboration of β-aryl methylidenes affords either the chiral primary or tertiary boronic ester depending on the TADDOL-derived phosphite ligand employed. Twenty substrates are shown to undergo regioselective reaction using each catalyst system. Regioselectivities reach levels greater than 20:1 and enantiomer ratios up to 98:2 are obtained. Conversions of 3a to 6-21 illustrate the potential synthetic utility of regiodivergent CAHB.

In terms of the mechanism, the aryl substituents appended to the TADDOL backbone as well as the nature of the arylphosphite moiety act synergistically to affect the sense of regioselectivity and enantioinduction. This appears to be due, at least in part, to an electronic effect because the pentafluorophenyl substituent is not unique in promoting β-boration. For example, the corresponding T2 ligand bearing either a (4-trifluoromethyl)phenyl or a 4-cyanophenyl phosphite substituent also exhibit regioswitching, although the levels of regio- and enantioselectivity are not as high. Deuterium labeling experiments with T1a and T2b show that addition of H (D) is rapid and reversible, leading to competitive H/D-exchange in the substrate using either regiodivergent catalyst.^[26] Several hypotheses that might account for the coupled regio- and enantiodivergent CAHB, effected by ostensibly similar catalyst systems, are currently under investigation.