Mechanistic studies on the catalytic cycle of rhodium-catalyzed asymmetric 1,4-addition of aryltitanate reagents to α,β-unsaturated ketones

Abstract

Addition of lithium aryl(tetraisopropoxy)titanates [ArTi(OPr-i)₄^–Li⁺] to α,β-unsaturated ketones proceeded with high enantioselectivity (up to 99% ee) in the presence of an excess amount of chlorotrimethylsilane and a rhodium catalyst (3 mol % Rh), generated from [RhCl(C₂H₄)₂]₂ and (S)-binap, in tetrahydrofuran at 20°C to give high yields of the corresponding silyl enolates as 1,4-addition products. The presence of chlorotrimethylsilane is essential for the 1,4-addition to take place. ³¹P NMR spectroscopic studies revealed that the catalytic cycle consists of three transformations, that is, (i) insertion of an enone into arylrhodium species forming (oxa-π-allyl)rhodium intermediate, (ii) silylation of the (oxa-π-allyl)rhodium with chlorotrimethylsilane giving silyl enolate and a chloro-rhodium complex, and (iii) transmetalation of aryl group from aryltitanate to the chloro-rhodium regenerating the aryl-rhodium.

Catalytic asymmetric 1,4-addition of organometallic reagents to electron-deficient olefins has been a subject of extensive investigations (1–4). Recently, many reports appeared on the use of chiral phosphine-rhodium catalysts for the addition of organoboron reagents represented by arylboronic acids (5–28). α,β-Unsaturated ketones, esters, amides, phosphonates, and nitroalkenes are all good substrates giving the corresponding 1,4-addition products with high enantioselectivity. The reactions are usually carried out in a solvent containing 5–20% water. We have established the catalytic cycle of the rhodium-catalyzed 1,4-addition to α,β-unsaturated ketones in the aqueous solvent (29). The catalytic cycle for the addition of phenylboronic acid involves three intermediates: phenylrhodium A, (oxa-π-allyl)rhodium B, and hydroxorhodium C complexes (Fig. 1). Each intermediate is converted into the subsequent intermediate by insertion (A → B), hydrolysis (B → C), and transmetalation (C → A). The 1,4-addition product is formed at the hydrolysis step. The addition of organosilane reagents is considered to proceed through a similar catalytic cycle (30–34). Although the use of water as a cosolvent is one of the advantages of this reaction over others, one major drawback is that the 1,4-addition product is obtained as the hydrolyzed product. A catalytic asymmetric 1,4-addition giving metal enolates as the products is more useful, because the enolates are versatile intermediates for further transformation by the reaction with electrophiles. We have recently reported that the use of aryltitanium triisopropoxides [ArTi(OPr-i)₃] as arylating reagents for the rhodium-catalyzed asymmetric 1,4-addition in nonprotic solvent gives titanium enolates as the 1,4-addition products (Fig. 2) (35). Although the enantioselectivity is very high for most of α,β-unsaturated ketones examined, the yields of the enolates, especially for cyclopentenone, are not high. It was found that the combination of lithium aryltitanates and chlorotrimethylsilane constitutes effective arylating reagents giving high yields of silyl enol ethers as 1,4-addition products. Here, we report the rhodium-catalyzed asymmetric 1,4-addition with this reagent system and its catalytic cycle, in comparison with the addition of aryltitanium reagents that we reported in ref. 35.

Fig. 1.

Rhodium-catalyzed asymmetric 1,4-addition of PhB(OH)₂.

Fig. 2.

Rhodium-catalyzed asymmetric 1,4-addition of PhTi(OPr-i)₃.

Materials and Methods

NMR spectra were recorded on a JEOL JNM LA-500 spectrometer (500 MHz for ¹H, 125 MHz for ¹³C, and 202 MHz for ³¹P). Chemical shifts are reported in δ ppm referenced to an internal SiMe₄ standard for ¹H NMR, chloroform-d (δ 77.00) for ¹³C NMR, and external 85% H₃PO₄ standard for ³¹P NMR. Optical rotations were measured on a Jasco (Tokyo) DIP-370 polarimeter. [RhCl(C₂H₄)₂)]₂ (36), [RhCl((S)-binap)]₂ (7) (29), phenyltitanium triisopropoxide [PhTi(OPr-i)₃] (37), 4-trifluoromethylphenyltitanium triisopropoxide [4-CF₃C₆H₄Ti(OPr-i)₃] (37), 4-methoxy-phenyltitanium triisopropoxide [4-MeOC₆H₄Ti(OPr-i)₃] (37), and lithium isopropoxide (35) were prepared according to the reported procedures.

Generation of Aryltitanate Reagents [ArTi(OPr-i)₄^–Li⁺, (2)]. Aryltitanates ArTi(OPr-i)₄^–Li⁺ (2) were generated by either of the following three ways (38–42): (i) Ti(OPr-i)₄ (0.14 ml, 0.48 mmol) was added to a solution of phenyllithium (0.48 ml, 0.94 M in cyclohexane/Et₂O, 0.45 mmol) in tetrahydrofuran (THF) (0.30 ml) at room temperature, and the mixture was stirred for 1 h. (ii) n-Butyllithium (0.29 ml, 1.56 M in hexane, 0.45 mmol) was added to a solution of aryl bromide ArBr (0.45 mmol) in Et₂O (1.0 ml) at –78°C, and the mixture was stirred at 0°C for 1 h. Ti(OPr-i)₄ (0.14 ml, 0.48 mmol) was added to the ArLi solution at room temperature, and the mixture was stirred for 1 h. (iii) A THF (0.30 ml) solution containing ArTi(OPr-i)₃ (0.45 mmol) and LiOPr-i (30 mg, 0.45 mmol) was stirred at room temperature for 30 min.

Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryltitanate Reagents [ArTi(OPr-i)₄^–Li⁺, (2)] to Enones 1 in the Presence of Chlorotrimethylsilane. The reaction conditions and results are summarized in Table 1. To a solution of [RhCl(C₂H₄)₂)]₂ (1.8 mg, 0.0045 mmol, 3 mol % Rh), (S)-binap (6.2 mg, 0.0099 mmol, 1.1 eq to Rh), enone 1 (0.30 mmol), and chlorotrimethylsilane (76 μl, 0.60 mmol) in THF (0.50 ml) was added a solution of ArTi(OPr-i)₄^–Li⁺ (2) (0.45 mmol) at 20°C. After 30 min stirring at the same temperature, the mixture was concentrated under a reduced pressure. Et₂O (≈3 ml) and H₂O (≈50 μl) were added, and the mixture was filtered through a short Celite/MgSO₄ pad (eluent: Et₂O). The crude product was distilled (bulb-to-bulb) under a reduced pressure to give silyl enol ether 3 as colorless oil. The enantiomeric exess of the product 3 was determined by HPLC analysis of ketone 4, which was obtained by protonolysis of 3, with chiral stationary-phase columns. The spectroscopic data for silyl enol ethers, 3am, 3bm, and 3cm have been reported (35). The NMR and analytical data for silyl enol ethers 3bn and 3bo are shown below:

Table 1. Asymmetric 1,4-addition of aryltitanate 2 to enone 1 catalyzed by [RhCl(C₂H₄)₂]₂/(S-binap.

Entry	Enone 1	ArTi(OPr-i)4-Li+2	Silyl ether 3 yield, %*	% ee of 4† (config)
1‡	1a	2m	3am 90§	96 (S)
2	1b	2m	3bm 91	99 (S)
3	1b	2m¶	3bm 85	99 (S)
4	1b	2m∥	3bm 92	99 (S)
5	1b	2n¶	3bn 94**	97 (S)
6	1b	2o¶	3bo 83	96 (S)
7	1c	2m	3cm†† 67	90 (S)

The reaction was carried out with enone 1 (0.30 mmol), ClSiMe₃ (0.60 mmol), and ArTi(OPr-i)₄-Li⁺ 2 (0.45 mmol) in 0.80 ml of THF at 20°C for 30 min in the presence of 3 mol % (Rh) of the catalyst generated from [RhCl(C₂H₄)₂]₂ and (S)-binap. ArTi(OPr-i)₄-Li⁺ 2 was generated by mixing ArLi (0.45 mmol) with Ti(OPr-i)₄ (0.48 mmol) in 1.0 ml of Et₂O at room temperature for 1 h.

^*Isolated yield by bulb-to-bulb distillation.

^†Determined by HPLC analysis of ketone 4 with chiral stationary-phase columns [Chiralcel OD-H (4am, 4cm), AS (4bo), and OB-H (4bm, 4bn)].

^‡0.45 mmol of ClSiMe₃.

^§Contaminated with ≈3% of 4am (hydrolyzed product).

^¶ArLi was generated by mixing ArBr (0.45 mmol) with n-BuLi (0.45 mmol) at 0°C for 1 h.

^∥2m was generated from PhTi(OPr-i)₃ (0.45 mmol) and LiOPr-i (0.45 mmol).

^**Contaminated with ≈6% of 4bn (hydrolyzed product).

^††A mixture of E and Z isomers (3/10).

• (S)-3-(4-trifluoromethylphenyl)-1-(trimethylsilyloxy)cyclopent-1-ene (3bn). ¹H NMR (CDCl₃) δ 0.26 (s, 9H), 1.63–1.74 (m, 1H), 2.36–2.45 (m, 3H), 3.89–3.94 (m, 1H), 4.71 (q, J = 1.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H). ¹³C NMR (CDCl₃) δ 0.00, 31.87, 33.48, 47.65, 105.39, 124.41 (q, J = 270.9 Hz), 125.28 (q, J = 4.1 Hz), 127.28, 128.30 (q, J = 31.9 Hz), 151.99, 157.06. [α]²⁰_D–29.2 (c 0.99, CHCl₃) for (S)-3bn of 97% ee. Elemental analysis calculated for C₁₅H₁₉OF₃Si: C, 59.98; H, 6.38. Found: C, 60.27; H, 6.16.

• (S)-3-(4-methoxylphenyl)-1-(trimethylsilyloxy)cyclopent-1-ene (3bo). ¹H NMR (CDCl₃) δ 0.25 (s, 9H), 1.62–1.71 (m, 1H), 2.30–2.44 (m, 3H), 3.79 (s, 3H), 3.79–3.85 (m, 1H), 4.70–4.72 (m, 1H), 6.83 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H). ¹³C NMR (CDCl₃) δ 0.03, 32.32, 33.53, 46.96, 55.22, 106.60, 113.71, 127.83, 139.95, 156.04, 157.89. [α]²⁰_D–28.8 (c 1.07, CHCl₃) for (S)-3bo of 96% ee. Elemental analysis calculated for C₁₅H₂₂O₂Si: C, 68.65; H, 8.45. Found: C, 68.63; H, 8.34. The spectroscopic data for ketones, 4am, 4bm, 4bn, 4bo, and 4cm have been reported (7, 10). The optical rotations of 4bn and 4bo are shown below: (S)-4bn (97% ee), [α]²⁰_D–67.8 (c 0.99, CHCl₃); (S)-4bo (96% ee), [α]²⁰_D–79.2 (c 1.00, CHCl₃).

NMR Studies on the Reaction of Rhodium Complexes. The reactions were carried out in an NMR sample tube. (i) Chlorotrimethylsilane (10 μl, 0.080 mmol) was added at room temperature to a solution of (oxa-π-allyl)((S)-binap)rhodium complex 6 (0.016 mmol) in THF (0.5 ml), generated according to the reported procedure (29). Within 1 min, 6 was completely converted into [RhCl((S)-binap]₂ (7). The spectroscopic data of complexes 6 and 7 have been reported (29).

(ii) PPh₃ (5.2 mg, 0.020 mmol) was added at room temperature to a solution of 7 (10 mg, 0.0066 mmol) in THF (0.5 ml). Within 1 min, 7 was completely converted into RhCl(PPh₃)((S)-binap) (8). To the THF solution of 8 was added chlorotrimethylsilane (17 μl, 0.13 mmol) and a THF solution of PhTi(OPr-i)₄^–Li⁺ (0.20 mmol) subsequently at room temperature. In 1.5 h, most of 8 was replaced by RhPh(PPh₃)((S)-binap) (5). The spectroscopic data for complexes 5 and 8 have been reported (29).

Results and Discussion

The rhodium-catalyzed 1,4-addition of lithium aryl(tetraisopropoxy)titanates [ArTi(OPr-i)₄^–Li⁺] 2 (Fig. 3) was carried out as described in Materials and Methods. Table 1 shows that the addition to 2-cyclohexenone (1a) and 2-cyclopentenone (1b) proceeded at 20°C with high enantioselectivity to give high yields of the corresponding silyl enolates 3 as 1,4-addition products. As a typical example, the reaction of 2-cyclohexenone (1a) with phenyltitanate 2m, which was generated by treatment of phenyllithium (PhLi) with titanium tetraisopropoxide [Ti(OPr-i)₄], in the presence of chlorotrimethylsilane and a rhodium catalyst (3 mol % Rh) consisting of [RhCl(C₂H₄)₂]₂ and (S)-binap gave 90% yield of 3-phenyl-1-(trimethylsilyloxy)cyclohexene (3am), which was determined to be an S isomer with 96% ee by hydrolysis into 3-phenylcyclohexanone (4am) (entry 1). In a similar manner, the reaction of 2-cyclopentenone (1b) with the phenyltitanate 2m gave 91% yield of (S)-3-phenyl-1-(trimethylsilyloxy)cyclopentene (3bm), which is 99% enantiomerically pure (entry 2). Use of the phenyltitanate 2m generated from bromobenzene by lithiation with butyllithium followed by treatment with Ti(OPr-i)₄ or from phenyltitanium triisopropoxide [(PhTi(OPr-i)₃] and lithium isopropoxide (LiOPr-i) in THF gave essentially the same results (entries 3 and 4). Aryltitanate reagents 2n and 2o, which contain trifluoromethyl and methoxy groups, respectively, at the 4-position of the phenyl gave high yields of the corresponding silyl enol ethers 3bn and 3cn (entries 5 and 6). Use of bromotrimethylsilane in place of chlorotrimethylsilane for the reaction of 1a with 2m resulted in the formation of 1-phenyl-2-cyclohexenol as a major product in a lower yield.

Fig. 3.

Rhodium-catalyzed asymmetric 1,4-addition of ArTi(OPr-i)₄^–Li⁺ in the presence of ClSiMe₃.

It is remarkable that the yield of silyl enol ether 3bm obtained here in the addition to 2-cyclopentenone (1b) is much higher than that with phenyltitanium triisopropoxide [PhTi(OPr-i)₃], where the 1,4-addition product is titanium enolate (see Fig. 2) (35). The lower yield in the reaction of phenyltitanium triisopropoxide may be ascribed to the lower stability of the titanium enolate under the conditions of the rhodium-catalyzed reaction. It should be noted that the present reaction system is different from the reaction of phenyltitanium reagent, which is suggested by the following observations.

(i) The presence of chlorotrimethylsilane is essential for the 1,4-addition of lithium phenyltitanate 2m. In the absence of chlorotrimethylsilane, no 1,4-addition takes place, the starting enone being recovered intact (Fig. 4). On the other hand, the addition of phenyltitanium proceeds in the absence of the chlorosilane.

Fig. 4.

Reaction with PhTi(OPr-i)₄^–Li⁺ in the absence of ClSiMe₃.

(ii) In the reaction of phenyltitanium, the 1,4-addition product is not silyl enolate but titanium enolate, even if the reaction is carried out in the presence of chlorotrimethylsilane. The chlorosilane does not participate in the 1,4-addition of phenyltitanium. The titanium enolate is not reactive toward the silylation with chlorosilane in the absence of a base as has been reported (35).

The catalytic cycles for the rhodium-catalyzed 1,4-addition of both phenyltitanium and lithium phenyltitanate reagents were studied by use of phenyl((S)-binap)(PPh₃)rhodium(I) (5) (29) as a key authentic complex. The (oxa-π-allyl)((S)-binap)rhodium complex 6 (29) was generated in an NMR sample tube by addition of 2-cyclohexenone (1a) to a THF solution of the phenylrhodium complex 5. This phenylrhodation has been reported in our previous studies on the mechanism of the rhodium-catalyzed 1,4-addition of phenylboronic acid (29). ³¹P NMR studies (Fig. 5) showed that addition of the phenyltitanium reagent PhTi(OPr-i)₃ to the (oxa-π-allyl)rhodium complex 6, which includes one equivalent of PPh₃, gives back the phenylrhodium complex 5. Protonolysis of the resulting THF solution with methanol gave a high yield of (S)-3-phenylcyclohexanone (4am), indicating that the titanium enolate was formed at the transmetalation step (Fig. 6). Thus, the catalytic cycle of the 1,4-addition of the phenyltitanium consists of two steps (Fig. 7): One is transmetalation of the phenyl group from titanium to the (oxa-π-allyl)rhodium intermediate B forming a phenylrhodium species A and the titanium enolate. The other is insertion of enone into the phenylrhodium species A forming the (oxa-π-allyl)rhodium complex B.

Fig. 5.

³¹P NMR spectra (at 202 MHz in THF at room temperature) of rhodium complexes. (i) Oxa-π-allylrhodium 6. (ii) Addition of PhTi(OPr-i)₃ to 6 giving phenylrhodium 5.

Fig. 6.

A stoichiometric reaction with PhTi(OPr-i)₃.

Fig. 7.

Catalytic cycle of the 1,4-addition of PhTi(OPr-i)₃.

Contrary to the reaction with phenyltitanium [PhTi(OPr-i)₃], the transmetalation was not observed between the lithium phenyltitanate 2m and (oxa-π-allyl)rhodium complex 6 (Fig. 8). This is consistent with the result that the 1,4-addition was not observed in the catalytic reaction of titanate 2m in the absence of chlorotrimethylsilane (see Fig. 4). The important role of chlorotrimethylsilane on the catalytic 1,4-addition was demonstrated by the ³¹P NMR experiments in the presence of chlorotrimethylsilane in THF (Fig. 9). Thus, addition of an excess amount of chlorotrimethylsilane to (oxa-π-allyl)rhodium 6 in THF gave [RhCl((S)-binap]₂ (7) (29) [49.5 ppm (J_P–Rh = 195 Hz)] and silyl enol ether 3am in a quantitative yield. This silylation is very fast, completed within 1 min at room temperature. Treatment of the chloride-bridge dimer complex 7 with one equivalent of PPh₃ forming RhCl(PPh₃)((S)-binap) (8) (29) [29.3, 30.8, and 50.2 ppm (J_P–Rh = 142, 146, and 185 Hz, J_P–P,trans = 376 Hz, J_P–P,cis = 35 and 45 Hz] followed by addition of lithium phenyltitanate 2m in the presence of chlorotrimethylsilane gave the phenylrhodium complex 5. It follows that the transmetalation took place between the chlororhodium complex 8 and the lithium phenyltitanate 2m. Interestingly, the transmetalation is very slow in the absence of chlorotrimethylsilane, indicating that the chlorosilane participates in the transmetalation step although its role remains to be clarified.

Fig. 8.

Stoichiometric reactions of rhodium complexes with PhTi(OPr-i)₄^–Li⁺ and ClSiMe₃.

Fig. 9.

³¹P NMR spectra (at 202 MHz in THF at room temperature) of rhodium complexes observed in the reactions starting from oxa-π-allylrhodium 6. (iii) Oxa-π-allylrhodium complex 6. (iv) Addition of ClSiMe₃ to 6 giving chlororhodium complex 7. (v) Addition of PPh₃ to 7 giving complex 8. (vi) Addition of PhTi(OPr-i)₄^–Li⁺ to 8 giving phenylrhodium complex 5.

The catalytic cycle of the rhodium-catalyzed 1,4-addition of phenyltitanate in the presence of chlorotrimethylsilane is shown in Fig. 10. It is similar to the cycle established for the catalytic 1,4-addition of phenylboronic acid in the presence of water (see Fig. 1) in that it consists of three intermediates. The transformations between these intermediates, phenyl-rhodium A, (oxa-π-allyl)rhodium B, and chlororhodium D, were observed in the ³¹P NMR studies. One unique step is the silylation of (oxa-π-allyl)rhodium B with chlorotrimethylsilane forming chlororhodium D and silyl enol ether as a 1,4-addition product.

Fig. 10.

Catalytic cycle of the 1,4-addition of PhTi(OPr-i)₄^–Li⁺ in the presence of ClSiMe₃.

Conclusions

In addition to the reaction of aryltitanium reagents [ArTi(OPr-i)₃] giving titanium enolates as the 1,4-addition products we have previously reported (35), we found here the 1,4-addition of lithium aryl(tetraisopropoxy)titanates [ArTi(OPr-i)₄^–Li⁺] in the presence of chlorotrimethylsilane giving silyl enol ethers. The enantioselectivities are all high in both two reagent systems. The chemical yields for the addition to 2-cyclopentenone are higher in the present reagent system than in the former system. The catalytic cycles of the rhodium-catalyzed reactions using the two titanium reagents were proposed by ³¹P NMR studies of the rhodium intermediates.