Metal-Free Catalytic C–Si Bond Formation in an Aqueous Medium. Enantioselective NHC–Catalyzed Silyl Conjugate Additions to Cyclic and Acyclic α,β-Unsaturated Carbonyls

Abstract

A metal-free method for enantioselective conjugate addition of a dimethylphenylsilyl group to α,β-unsaturated carbonyls is reported. Transformations are catalyzed by a chiral N-heterocyclic carbene (NHC), performed in an aqueous solution (3:1 mixture of water and tetrahydrofuran) and are operationally simpler to perform than the NHC–Cu-catalyzed variant. The chiral catalyst is generated from an enantiomerically pure imidazolinium salt (prepared in three steps)and a common organic amine base (dbu). NHC-catalyzed processes proceed with 5.0–12.5 mol% catalyst loading at 22°C within 1–12 hours, affording the desired β-silyl carbonyls in 87:13 to>98:2 enantiomeric ratio and in 50% to >98% yield. Cyclic enones or lactones and acyclic α,β-unsaturated ketones, esters as well as aldehydes can be used as substrates.

We recently discovered that achiral N-heterocyclic carbenes (NHCs) – in the absence of a metal salt – activate the B–B bond of bis(pinacolato)diboron [B₂(pin)₂] and catalyze efficient (non-enantioselective) boronate conjugate additions to α,β-unsaturated carbonyls.¹ A related set of transformations corresponds to NHC-catalyzed silyl conjugate addition (SCA) reactions with commercially available dimethylphenylsilylpinacolatoboron [Me₂PhSi–B(pin), 1].² Notwithstanding the value of C–Si bond forming processes in chemical synthesis,³ the basis for pursuing silyl conjugate additions⁴ was twofold: First, we were interested in determining if, as outlined in Scheme 1, the unsymmetrical silylboronate can be activated to cause selective transfer of the PhMe₂Si unit to a polarized olefin (vs (pin)B–C bond formation). Second, we were keen on investigating whether a chiral NHC can sufficiently influence the reaction course to render such metal-free catalytic processes highly enantioselective.⁵ Herein, we report enantioselective SCA reactions involving cyclic and acyclic enones and α,β-unsaturated esters as well as various enals. Transformations are performed in the presence of 1 and promoted by 5.0–12.5 mol % of an NHC catalyst, which is prepared and used in situ from a readily accessible chiral imidazolinium salt and a common organic base. NHC-catalyzed processes are carried out at ambient temperature in a 3:1 mixture of water and tetrahydrofuran (thf).⁶ The desired β-silylcarbonyls are isolated in up to >98% yield and >98:2 enantiomeric ratio (er). The method complements the related metal-catalyzed variants,^4,7,8 and, to the best of our knowledge, represents the first examples of C–Si bond forming reactions that do not require an organometallic complex as the catalyst.

Scheme 1.

NHC-Catalyzed Silyl Conjugate Addition to Unsaturated Carbonyls

We first investigated the efficiency with which an NHC can associate with 1, presumably at the more Lewis acidic boron site, and activate of the B–Si bond. From the outset, we judged that a practical advantage of the metal-free protocol would be the procedural simplicity with which it can be performed. Thus, we decided to establish whether a relatively robust amine might be used to generate the requisite NHC instead of one the moisture sensitive metal alkoxides employed with the Cu-catalyzed process (e.g., NaOMe or NaOt-Bu).^4a Such considerations led us to determine that, as shown in Scheme 2, treatment of commercially available imidazolinium salt 2 with 1.05 equiv of 1,8-diazabicycloundec-7-ene (dbu) followed by the addition of 1 leads to complete consumption of the silylboron reagent within five minutes. Complexation was monitored by the appearance of a new signal at δ 8.02 ppm in the ¹¹B NMR spectrum, likely corresponding to 1•NHC complex 3; the signal for 1, also a singlet, appears at δ 33.38 ppm.⁹ Similar to the reaction of B₂(pin)₂,¹ such a significant shift is likely due to the associated electronic reorganization caused by the conversion of the sp²-hybridized boron atom in 1 to one that is sp³-hybridized (3).¹⁰ Treatment of 1 with dbu, under otherwise identical conditions, does not lead to a new entity.

Scheme 2.

Facile Formation of an NHC–B–Si Complex^a

Next, we evaluated the ability of the carbene derived from imidazolinium salt 5 to promote silyl conjugate addition to cyclohexenone (Table 1); the selection of this particular NHC precursor was based on its structural similarity to the chiral variants developed in these laboratories^4a,11 (versus unsaturated imidazolium salts). As illustrated in entry 1, with 5.0 mol % 5 and 15 mol % dbu, a minimal amount of the desired β-silylcarbonyl 4 is generated (<10%). To facilitate SCA, the effect of methanol as an additive was examined; we surmised that such modification might facilitate formation of the charged intermediates likely involved in the catalytic process. The presence of the alcohol additive indeed results in a more efficient silyl conjugate addition (22–34%) without any C–B bond formation (<2%, ¹H NMR analysis; entries 2–3, Table 1). In light of the positive effect of MeOH, we chose to examine the influence of a more polar medium, leading us to the finding that when the catalytic SCA is performed in an equal mixture of thf and water, there is 95% conversion to the desired 4 within three hours at 22 °C (entry 4, Table 1); when pure water is used as solvent, SCA is complete (>98% conv, entry 5).¹² In the absence of 5, under otherwise identical conditions to entry 4, there is <2% conversion to the desired 4. As the representative data in entry 6 of Table 1 point out, the presence of MeOH to the aqueous solution does not improve efficiency (vs entry 3). Moreover, an aryl and an alkyl phosphine or a phosphine oxide, in spite of higher catalyst loadings (10 mol %), either do not promote any reaction or are far less effective catalysts (entries 7–10, Table 1).

Table 1.

Initial Studies on Catalytic Reactions of Cyclohexenone and Phenyldimethylsilylpinacolatoboron 1^a

entry	heterocyclic salt or phosphine; mol %	additive; equiv	solvent	conv (%)b
1	5; 5.0	none	thf	<10
2	5; 5.0	MeOH; 20	thf	26
3	5; 5.0	none	1:1 thf:MeOH	34
4	5; 5.0	none	1:1 thf:H2O	95
5	5; 5.0	none	H2O	>98
6	5; 5.0	MeOH; 20	1:1 thf:H2O	34
7	PPh3; 10	none	1:1 thf:H2O	<2
8	PCy3; 10	none	1:1 thf:H2O	30
9	OPPh3; 10	none	1:1 thf:H2O	<2

^aPerformed under N₂ atm; with 15 mol % dbu in entries 1–6 and 20 mol % dbu for entries 7–9.

^bConversion values determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures.

With conditions for effective NHC-catalyzed SCA outlined, we focused on identifying an effective chiral carbene for the enantioselective version of the process. Cyclohexenone continued to serve as the model substrate; transformations were performed at 22 °C in a solution that largely consists of water (3:1 thf:H₂O)¹³ and were analyzed after three hours. Bidentate imidazolinium salts 6 and 7, used as ligands in various metal-catalyzed enantioselective transformations,^4a,11 promote C–Si bond formation with moderate efficiency but 4 is obtained in negligible enantiomeric purity (entries 1–2, Table 2). With 8a, which, similar to 6 and 7, is C₁-symmetric, but lacks the hydroxyl or the sulfonate unit (entry 3, Table 2), SCA is more efficient (>98% conv) and the desired product is formed in 82:18 er. Increasing the size of the symmetrical N-Ar moiety of the catalyst (i.e., 8b–c, entries 4–5) leads to diminution in efficiency and/or enantioselectivity. When C₂-symmetric imidazolinium salt 9a is used (entry 6), lower conversion but similarly high er values are attained (compared to 8a, entry 3). Further catalyst screening led us to establish that, incorporation of a m-Me unit within the N-Ar moieties, furnishes an NHC catalyst that affords β-silylketone 4 efficiently (>98% conv) and in 98:2 er. The low selectivity observed with 10 underlines the significance of the C₂-symmetric structure of the optimal 9b in this application.

Table 2.

Evaluation of Various Chiral N-Heterocyclic Carbenes^a

entry	imidazolinium salt	conv (%)b	erc
1	6	75	50:50
2	7	38	52:48
3	8a	>98	82:18
4	8b	44	84:16
5	8c	34	59:41
6	9a	87	86:14
7	9b	>98	98:2
8	10	72	83:17

^aPerformed under N₂ atm.

^bConversion values determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures.

^cEnantiomeric ratio values determined by HPLC analysis (±2%); see the Supporting Information for details. Mes = 2,4,6-Me₃C₆H₂.

A range of cyclic enones, including cyclopentenones as well as seven- and eight-membered ring α,β-unsaturated ketones, undergo enantioselective NHC-catalyzed SCA to afford the β-silyl ketones in 50% to >98% yield and in 90:10 to >98% er (entries 1–6 of Table 3). There is complete consumption of the starting materials in the transformations shown in entries 1–4 (Table 3). However, catalytic additions that furnish sterically demanding cyclopentenone 14 and bicyclic cycloheptenone 15 proceed less readily (83% and 60% conv in 3 h, respectively); longer reaction times do not result in further conversion, suggesting that the NHC catalyst is perhaps undergoing competitive decomposition.¹⁴ As the example in entry 7 of Table 3 indicates, unsaturated cyclic esters can be used to access the derived β-silyl lactones (16 in 71% yield and 87:13 er); as was also observed in studies regarding the NHC–Cu-catalyzed version of this process, such additions are less efficient and enantioselective than with the corresponding cyclic enones (compare entries 2 and 7, Table 3).^4a

Table 3.

NHC-Catalyzed Enantioselective Silyl Conjugate Addition (SCA) Reactions with Cyclic α,β-Unsaturated Carbonyls^a

entry	product	time (h)	conv (%);b yield (%)c	erd
1	n = 1 (11) n = 2 (4) n = 3 (12) n = 4 (13)	3.0	>98; >98	90:10
2		1.0	>98; 97	98:2
3		3.0	>98; 95	98:2
4		1.0	>98; 74	>98:2
5	14	3.0	83; 73	94.5:4.5
6	15	3.0	60; 50	90:10
7	16	3.0	82; 71	87:13

^aReactions performed in 3:1 H₂O:thf under the conditions shown in Table 1 and with imidazolinium salt 9b as the catalyst precursor.

^bConversion values determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures.

^cYields of isolated products after purificaton (±5%).

^dEnantiomeric ratio values determined by HPLC analysis (±2%); see the Supporting Information for details.

Acyclic α,β-unsaturated ketones can be used in NHC-catalyzed SCA (Scheme 3). Generally, reactions proceed less readily than the cyclic unsaturated carbonyls, and require a slightly higher catalyst loading for achieving complete conversion.¹⁵ Formation of β-silyl methyl ketones bearing an aryl substituent (cf. 18–20) is relatively more facile and enantioselective than those that carry an alkyl unit (cf. 22–23). NHC-catalyzed SCA involving chalcone (cf. 24) and an acyclic ester (cf. 25) are highly enantioselective but less efficient than the corresponding methyl ketones. Diminished efficiency and substantially lower enantioselectivity are observed with a corresponding cis isomer: when Z-17 is used, 18 is generated in nearly racemic form (54:46 vs 94:6 er). Considering that cyclic β-silylketones are obtained in high enantiomeric purity (entries 1–4, Table 3), the aforementioned variation in selectivity is striking. Furthermore, in contrast to substrates bearing a phenyl or an electron rich p-methoxyphenyl substituent (cf. 18 and 19), there is <2% conversion to 21, which contains the electron-deficient p-trifluoromethylphenyl moiety. The above trends might shed light on the inner workings of the NHC-catalyzed process and are the subject of ongoing investigations.

Scheme 3.

NHC-Catalyzed Enantioselective Silyl Conjugate Addition (SCA) Reactions with Acyclic α,β-Unsaturated Carbonyls^a

^aAll reactions performed under identical conditions as shown for synthesis of 18, except for 24 and 25 (12.5 and 10 mol % 9b, and 37.5 and 30 mol % dbu, respectively). For determination of conversions and er values, see Table 3. Yields relate to isolated and purified products (±5%).

A particularly noteworthy type of NHC-catalyzed SCA involves α,β-unsaturated aldehydes;^8f three cases are illustrated in Scheme 4. β-Silyl aldehydes are formed in similarly high levels of enantiomeric purity as observed with acyclic ketones. What renders the transformations in Scheme 4 intriguing is that unsaturated aldehydes have been utilized extensively in NHC-catalyzed coupling reactions, which proceed via Breslow-type intermediates,¹⁶ generated by the addition of the carbene to the relatively un-congested carbonyl. That the SCA products, represented by 27–29, can be isolated in 62–79% yield implies that the silylboron reagent competes effectively with the aldehyde site for reaction with the nucleophilic catalyst. Initial studies indicate that NHC–catalyzed silyl 1,2-additions (vs 1,4-) to aldehydes are feasible; ¹⁷ thus, the transformations shown in Scheme 4 illustrate notable chemoselectivity in favor of conjugate addition. It is also worthy of note that the NHC-catalyzed SCA with unsaturated aldehydes require higher catalyst loadings compared to the corresponding methyl ketones (e.g., reaction of 17 vs 26); the reason for such differences in reactivity is a topic that is being probed as part of our mechanistic explorations.

Scheme 4.

NHC-Catalyzed Enantioselective Silyl Conjugate Addition (SCA) Reactions with α,β-Unsaturated Aldehydes^a

^aAll reactions performed under identical conditions as shown for synthesis of 27.

The metal-free protocol offers a complementary catalytic approach to the SCA promoted by chiral metal-based complexes, where the more costly Pd or Rh salts might be needed.^8a–e With the chiral NHC–Cu-catalyzed system,^4a lower catalyst loadings are sufficient (1.0–2.0 mol % vs 5.0–12.5 mol %), at times higher enantioselectivities are observed with acyclic substrates and electron-deficient β-silylketone 21 (Scheme 3) can be accessed. On the other hand, the NHC-catalyzed transformations are more attractive as there is no need for the use of an air- and moisture-sensitive Cu salt (CuCl), and dbu can be employed in lieu of the more sensitive metal alkoxides. The above factors, the availability of the requisite chiral imidazolinium salt, which can be prepared by a three-step operation, together with the demonstrated utility of β-silyl carbonyls,^3,18 render the present strategy of value.

The enantioselectivities observed indicate that an NHC catalyst is intimately involved in the formation of the C–Si bond (cf. Scheme 1) and that the role of the heterocyclic carbene is not limited to activation of the silylboron reagent. Design and development of catalytic reactions that involve NHC-activation of other B-based reagents may thus feasible; investigations long these lines are in progress. Moreover, study of the mechanism of the metal-free transformations, including identification of the origins of enantioselectivity, the reactivity differences among various substrate classes and the critical role of water, are underway.