Asymmetric Cu(I)-Catalyzed Conjugate Borylation of α,β-Unsaturated Acyl Silanes

Abstract

We report the development of a Cu(I)-catalyzed conjugate borylation of α,β-unsaturated acyl silanes using bis(pinacoloto)diboron. Racemic borylations of β-aryl- and β-alkyl-substituted silyl enones were achieved using ligand-free conditions to access β-borylated acyl silanes in up to 97% yield. Josiphos enabled the synthesis of enantioenriched boronic esters in up to 58% yield and 94% ee. The racemic reaction was demonstrated on 5.0 mmol scale and isolation of the boronic esters was achieved using simple filtration and normal-phase chromatography. This work supplements known methods to access boronic esters from electron-deficient olefins using Cu(I) catalysis.

Boronic esters are highly valued intermediates that demonstrate a wide range of synthetic versatility.[1] Transition-metal-catalyzed conjugate borylations of electron deficient alkenes have proven to be a robust strategy to access complex boronic esters using bis(pinacolato)diboron (B₂pin₂).[2] The use of Cu(I) salts and chiral phosphine- or NHC-type ligands has enabled the asymmetric β-borylation of α,β-unsaturated esters,[3] ketones,[3a] [4] amides,[5] sulfones,[6] phosphonates,[7] and phosphine oxides (Scheme [1]).[8] However, no such functionalization of related α,β-unsaturated acyl silanes has yet been described.

Acyl silanes have been used extensively in organic synthesis as they possess interesting thermal and photochemical properties.[9] They display umpolung reactivity which arises from their propensity to undergo a 1,2-Brook rearrangement upon nucleophilic attack, giving rise to carbanions. The resulting carbanions can then be further functionalized with various electrophiles or undergo subsequent rearrangements.[9b] Their ambiphilic reactivity patterns make them powerful synthons for the rapid build-up of complex molecules.[11] Given the value of acyl silanes and organoboronic esters, we sought to realize β-borylations of α,β-unsaturated acyl silanes. Herein, we describe the development of racemic and asymmetric Cu(I)-catalyzed conjugate borylations of α,β-unsaturated acyl silanes.

Our study commenced with a survey of conditions disclosed by Yun and coworkers for the β-borylation of various electron-deficient olefin systems.[3a] Stirring α,β-unsaturated acyl silane 1a with a pre-stirred mixture of CuCl (5 mol%), LiOt-Bu (15 mol%), Xantphos (10 mol%), B₂pin₂ (2.0 equiv), and MeOH (2.0 equiv) in THF (0.3 M) at ambient temperature led to 9% yield of α,β-unsaturated acyl silane 1a (Table [1], entry 1). Further attempts using bidendate phosphine ligands such as DPEPhos were unsuccessful in promoting reactivity (entry 2). Suspecting that ligands were attenuating the reactivity of the copper catalyst, we attempted a ligand-free reaction and obtained 2a in 63% yield (entry 3). Lowering the B₂pin₂ loading led to increased yield (entry 3 vs. entry 4) as excess B₂pin₂ limited our ability to purify 2a due to coelution. A further reduction of B₂pin₂ to 1.2 equiv in conjunction with 100 mol% LiOt-Bu led to improved reproducibility and a slight increase to 74% yield (entry 5). We found that upon scaling up to 0.5 mmol of 1a, using 3.0 equiv MeOH further improved reproducibility and increased the yield of isolated β-boryl acyl silane 2a to 85% yield (entry 6). Notably, the boronic esters could be rapidly isolated by filtration through a short Celite plug followed by silica gel flash chromatography with no apparent product degradation.

Table 1 Optimization of the Racemic Reaction

Entry	Ligand (mol%)	LiOt-Bu (mol%)	B2pin2 (equiv)	Conv. 1a (%)a	Yield 2a (%)a
1	Xantphos (10)	15	2.0	10	9
2	DPEPhos (10)	15	2.0	3	3
3	–	15	2.0	99	63
4	–	15	1.5	100	72
5	–	100	1.2	100	74
6b,c	–	100	1.2	100	85d

^a Determined by ¹H NMR using CH₂Br₂ as an internal standard.

^b 3.0 equiv MeOH added.

^c 0.5 mmol scale reaction.

^d Isolated yield.

Following optimization of the reaction, we carried out an investigation of the reaction scope to generate a series of β-boryl acyl silanes (Scheme [2]). α,β-Unsaturated acyl silanes bearing β-aryl groups substituted with p-chloro, p-fluoro, and p-OTs groups were smoothly converted into their respective borylated products (2b–d) in moderate to excellent yields. We note that β-arene substitution with a p-CF₃ group (not shown) led to trace (<10%) isolated yield, suggesting that the reaction is sensitive to electron-deficient arene substituents. Substitution of the β-aryl group with o-CF₃ was tolerated and led to formation of 2e in 22% yield, with decomposition products attributed to the remaining mass balance. An o-OCF₃ group (2f) was better tolerated (49% yield). Borylation of a substrate containing an aryl bromide was successful (2g, 41% yield), however, the inclusion of an additional fluoride substituent led to a significantly decreased yield of 2h to 15% yield. We found that high-yielding borylations were achieved when using acyl silanes bearing dimethylphenylsilane (DMPS, 2i), TES (2j), and TBS (2k) groups. Borylations of α,β-unsaturated acyl silanes bearing β-hydrogen (2l), alkyl (2m), and benzyl (2n) groups were also successful and benefitted from the inclusion of 1.0 equiv Li(acac) to avoid unwanted cleavage of the acyl silane moiety by free LiOt-Bu. Currently, we speculate that the inclusion of Li(acac) lowers the concentration of free LiOt-Bu by promoting formation of Li[t-BuO(B₂pin₂)].[12] Additionally, we found that the reaction could be conducted on 1.0 mmol scale without any adjustment to the reaction parameters or procedure. Conducting the borylation of 1a on 5.0 mmol scale afforded 2a in 69% isolated yield.

Next, we focused on achieving an asymmetric β-borylation using chiral phosphine ligands. A preliminary ligand screen (see the Supporting Information for details) revealed that Josiphos (SL-J001-1) is an efficient chiral ligand for this reaction, affording 3a in 20% yield and 89% ee under unoptimized conditions (Table [2], entry 1). Despite the high enantioselectivity, low conversion (36%) was problematic and likely due to attenuation of the reactivity of copper catalyst by the phosphine ligand as was previously observed (vide supra). Using the more reactive Cu(MeCN)₄PF₆, however, led to complete decomposition of 1a. Inspired by Cu(I)-catalyzed borylations of reactive cyclopropenes described by Tortosa and coworkers,[10] we carried out the reaction under cryogenic conditions and observed 100% conversion of 1a, and formation of 3a in 37% yield and 90% ee alongside undesired allylic α-hydroxy silane byproduct 4 in 8% yield (entry 2). We reasoned that formation of 4 was likely due to a competing Cu^I-catalyzed 1,2-reduction of the acyl silane.[12] Lowering the reaction temperature to –50 °C and using NaOt-Bu in place of LiOt-Bu led to improvements in overall mass balance and enantioselectivity (94% ee, entry 3). To suppress the formation of 4, we altered the counterion of the Cu^I catalyst from PF₆ ^– to ClO₄ ^– which led to a slight improvement in chemoselectivity. Using Cu(MeCN)₄ClO₄ in conjunction with LiOt-Bu significantly improved the yield of 3a (61% yield), maintained the high enantioselectivity (94% ee), and suppressed formation of 4 to 4% (entry 5). Further attempts to improve the yield of 3a by varying reaction temperatures, stoichiometries, or ROH additive (i.e., i-PrOH, EtOH, etc.) were unsuccessful, often leading to reduced yields and/or enantioselectivity (entry 6). Aqueous workup and isolation of the enantioenriched material was avoided in favor of filtration over Celite, prior to purification by silica gel flash chromatography.

Table 2 Optimization of the Asymmetric Reaction^a,b

Entry	[Cu]c	Base (mol%)	T2 (°C)	Yield 3a (%)d	Yield 4 (%)d	ee 3a (%)e
1f	CuCl	LiOt-Bu (15)	22	20	–	89
2	Cu(MeCN)4PF6	LiOt-Bu (50)	–25	37	8	90
3	Cu(MeCN)4PF6	NaOt-Bu (50)	–50	38	29	94
4	Cu(MeCN)4ClO4	NaOt-Bu (50)	–50	42	24	94
5	Cu(MeCN)4ClO4	LiOt-Bu (50)	–50	61	4	94
6	Cu(MeCN)4ClO4	LiOt-Bu (100)	–50	46	5	76

^a See the Supporting Information for additional optimization details.

^b Reactions run on 0.1 mmol scale.

^c All reactions run with Cu(MeCN)₄X resulted in 100% conversion of 1a.

^d Yields determined by ¹H NMR using CH₂Br₂ as an internal standard.

^e ee (%) determined using HPLC.

^f Run at 22 °C for 1 h, 2.0 equiv of B₂pin₂ used.

With asymmetric β-borylation conditions in hand, we investigated the reaction scope on a subset of α,β-unsaturated acyl silanes (Scheme [3]). Borylations of α,β-unsaturated silanes bearing β-aryl groups substituted with p-tolyl 3a, p-chloro 3b, and p-fluoro 3c proceeded in low to moderate yields and with high enantioselectivity (58% yield, 91% ee; 18% yield, 91% ee; 52% yield, 89% ee). Asymmetric borylation of a TBS-substituted acyl silane afforded 3d in 39% yield and 94% ee.

In conclusion, we have disclosed a Cu^I-catalyzed conjugate borylation of α,β-unsaturated acyl silanes.[13] [14] Racemic borylations can be achieved using CuCl under ligand-free conditions, whereas Josiphos and Cu(MeCN)₄ClO₄ were effective in generating β-boryl acyl silanes in high enantiomeric excess. In both instances, the products are easily isolated using standard chromatographic separation. We believe that these methods will help enable further investigations into the utility of this new class of bifunctional molecules.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

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• 13 General Procedure A for Racemic Conjugate BorylationsA flame-dried 8 mL screw top vial equipped with a stir bar was charged with CuCl (0.01 mmol, 5.0 mol%), LiOt-Bu (0.2 mmol, 1.0 equiv), and then sealed with a rubber septum and electrical tape. The vial was backfilled three times with argon, THF (0.30 mL) was added, and the yellow/lime green suspension was stirred at room temperature for 30 min. B₂pin₂ (0.24 mmol, 1.2 equiv) in THF (0.15 mL) was added, and the resulting black solution was stirred for 10 min at room temperature. A solution of acyl silane 1a (0.2 mmol, 1.0 equiv) and MeOH (0.6 mmol, 3.0 equiv) in THF (0.22 mL) was then added, and the reaction was stirred for 1 h. The reaction was then diluted with 1 mL of Et₂O and passed through a short plug of Celite. The filtrate was then concentrated in vacuo and purified by silica gel column chromatography using 6% EtOAc–hexanes, affording the desired boronic ester 2a. Data for Representative Compound 2aColorless oil that solidifies in the freezer to an off-white waxy solid; R_f = 0.29 (10% EtOAc–hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 7.11–7.08 (m, 2 H), 7.07–7.03 (m, 2 H), 3.16 (dd, J = 18.8, 10.9 Hz, 1 H), 3.00 (dd, J = 18.8, 4.8 Hz, 1 H), 2.55 (dd, J = 10.9, 4.8 Hz, 1 H), 2.29 (d, J = 0.6 Hz, 3 H), 1.24–1.21 (m, 6 H), 1.14 (s, 6 H), 0.18 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 246.9, 139.2, 134.7, 129.1, 128.1, 83.2, 53.5, 24.6, 24.5, 20.9, –3.3. ¹¹B NMR (160 MHz, CDCl₃): δ = 33.5. ²⁹Si NMR (99 MHz, CDCl₃): δ = –10.7. HRMS (DART): m/z calcd for C₁₉H₃₁BO₃Si [M + H]⁺: 347.2208; found: 347.2208.
• 14 General Procedure B for Asymmetric Conjugate Borylations To a flame-dried 8 mL screw top vial equipped with a magnetic stir bar was added Cu(MeCN)₄ClO₄ (0.02 mmol, 10 mol%) and Josiphos SL-J001-1 (0.024 mmol, 12 mol%), the vial was sealed with a rubber septum and electrical tape and backfilled three times with argon. THF sparged with argon (0.3 mL) was added, and the mixture was stirred for 30 min at room temperature. Solvent was then removed in vacuo and dried on high vacuum for 15 min. B₂pin₂ (0.3 mmol, 1.5 equiv) in THF (0.2 mL) was added, and the solution was stirred for 10 min. A suspension of LiOt-Bu (0.1 mmol, 50 mol%) in THF (0.25 mL) was added, and the black solution was stirred for an additional 10 min at room temperature. The mixture was cooled to –78 °C with a cryostat, and acyl silane 1a (0.2 mmol, 1.0 equiv) with MeOH (0.6 mmol, 3.0 equiv) in THF (0.22 mL) was added dropwise. The reaction was warmed to –50 °C over 2 h and then stirred at temperature for 18 h. The reaction was diluted with 1 mL Et₂O at –78 °C, warmed to room temperature, filtered through a short plug of Celite, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (5–7% EtOAc–hexanes) to afford 3a in 58% yield.

Corresponding Author

Publication History

Received: 15 September 2023

Accepted after revision: 18 October 2023

Article published online:
21 November 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1 Fyfe JW. B, Watson AJ. B. Chem 2017; 3: 31
  CrossrefSearch in Google Scholar
• 2a Calow AD. J, Whiting A. Org. Biomol. Chem. 2012; 10: 5485
  CrossrefPubMedSearch in Google Scholar
• 2b Hu J, Ferger M, Shi Z, Marder TB. Chem. Soc. Rev. 2021; 50: 13129
  CrossrefPubMedSearch in Google Scholar
• 2c Alam S, Karim R, Khan A, Pal AK, Maruani A. Eur. J. Org. Chem. 2021; 6115
  Crossref
• 3a Mun S, Lee J.-E, Yun J. Org. Lett. 2006; 8: 4887
  CrossrefPubMedSearch in Google Scholar
• 3b Lee J.-E, Yun J. Angew. Chem. Int. Ed. 2008; 47: 145
  CrossrefPubMedSearch in Google Scholar
• 3c O’Brien JM, Lee K, Hoveyda AH. J. Am. Chem. Soc. 2010; 132: 10630
  CrossrefPubMedSearch in Google Scholar
• 3d Lee JC. H, McDonald R, Hall DG. Nat. Chem. 2011; 3: 894
  CrossrefPubMedSearch in Google Scholar
• 3e He Z.-T, Zhao Y.-S, Tian P, Wang C.-C, Dong H.-Q, Lin G.-Q. Org. Lett. 2014; 16: 1426
  CrossrefPubMedSearch in Google Scholar
• 3f Niu Z, Chen J, Chen Z, Ma M, Song C, Ma Y. J. Org. Chem. 2015; 80: 602
  CrossrefPubMedSearch in Google Scholar
• 3g Jana A, Trzybiński D, Woźniak K, Grela K. Chem. Eur. J. 2018; 24: 891
  CrossrefPubMedSearch in Google Scholar
• 3h Miwa Y, Kamimura T, Sato K, Shishido D, Yoshida K. J. Org. Chem. 2019; 84: 14291
  CrossrefPubMedSearch in Google Scholar
• 4a Ito H, Yamanaka H, Tateiwa J, Hosomi A. Tetrahedron Lett. 2000; 41: 6821
  CrossrefSearch in Google Scholar
• 4b Chen I.-H, Yin L, Itano W, Kanai M, Shibasaki M. J. Am. Chem. Soc. 2009; 131: 11664
  CrossrefPubMedSearch in Google Scholar
• 4c Sim H.-S, Feng X, Yun J. Chem. Eur. J. 2009; 15: 1939
  CrossrefPubMedSearch in Google Scholar
• 4d Xie J.-B, Lin S, Luo J, Wu J, Winn TR, Li G. Org. Chem. Front. 2015; 2: 42
  CrossrefSearch in Google Scholar
• 4e Jiang Q, Guo T, Yu Z. ChemCatChem 2015; 7: 660
  CrossrefSearch in Google Scholar
• 4f Jiang Q, Guo T, Yu Z. J. Org. Chem. 2017; 82: 1951
  CrossrefPubMedSearch in Google Scholar
• 4g Tsutsumi R, Taguchi R, Yamanaka M. ChemCatChem 2022; 14: e202101278
  CrossrefSearch in Google Scholar
• 4h Qian Y.-S, Wang Z.-L, Jiang B, Xiao Z.-Y, Xu Y.-H. Org. Lett. 2023; 25: 3364
  CrossrefPubMedSearch in Google Scholar
• 5a Chea H, Sim H.-S, Yun J. Adv. Synth. Catal. 2009; 351: 855
  CrossrefSearch in Google Scholar
• 5b Sandrock DL, Jean-Gérard L, Chen C, Dreher SD, Molander GA. J. Am. Chem. Soc. 2010; 132: 17108
  CrossrefPubMedSearch in Google Scholar
• 5c Zhao L, Ma Y, Duan W, He F, Chen J, Song C. Org. Lett. 2012; 14: 5780
  CrossrefPubMedSearch in Google Scholar
• 5d Molander GA, Wisniewski SR, Hosseini-Sarvari M. Adv. Synth. Catal. 2013; 355: 3037
  CrossrefPubMedSearch in Google Scholar
• 6 Moure AL, Gómez ArrayásR, Carretero JC. Chem. Commun. 2011; 47: 6701
  CrossrefPubMedSearch in Google Scholar
• 7 Kim J, Lee H, Yun J. Tetrahedron 2019; 75: 4250
  CrossrefPubMedSearch in Google Scholar
• 8 Hornillos V, Vila C, Otten E, Feringa BL. Angew. Chem. Int. Ed. 2015; 54: 7867
  CrossrefPubMedSearch in Google Scholar
• 9a Brook AG. Acc. Chem. Res. 1974; 7: 77
  CrossrefSearch in Google Scholar
• 9b Zhang H.-J, Priebbenow DL, Bolm C. Chem. Soc. Rev. 2013; 42: 8540
  CrossrefPubMedSearch in Google Scholar
• 9c Hong WP, Lim HN, Shin I. Org. Chem. Front. 2023; 10: 819
  CrossrefSearch in Google Scholar
• 10 Parra A, Amenós L, Guisán-Ceinos M, López A, García Ruano JL, Tortosa M. J. Am. Chem. Soc. 2014; 136: 15833
  CrossrefPubMedSearch in Google Scholar
• 11 Kim C, Roh B, Lee HG. Chem. Sci. 2021; 12: 3668
  CrossrefPubMedSearch in Google Scholar
• 12 Nagy A, Collard L, Indukuri K, Leyssens T, Riant O. Chem. Eur. J. 2019; 25: 8705
  CrossrefPubMedSearch in Google Scholar
• 13 General Procedure A for Racemic Conjugate BorylationsA flame-dried 8 mL screw top vial equipped with a stir bar was charged with CuCl (0.01 mmol, 5.0 mol%), LiOt-Bu (0.2 mmol, 1.0 equiv), and then sealed with a rubber septum and electrical tape. The vial was backfilled three times with argon, THF (0.30 mL) was added, and the yellow/lime green suspension was stirred at room temperature for 30 min. B₂pin₂ (0.24 mmol, 1.2 equiv) in THF (0.15 mL) was added, and the resulting black solution was stirred for 10 min at room temperature. A solution of acyl silane 1a (0.2 mmol, 1.0 equiv) and MeOH (0.6 mmol, 3.0 equiv) in THF (0.22 mL) was then added, and the reaction was stirred for 1 h. The reaction was then diluted with 1 mL of Et₂O and passed through a short plug of Celite. The filtrate was then concentrated in vacuo and purified by silica gel column chromatography using 6% EtOAc–hexanes, affording the desired boronic ester 2a. Data for Representative Compound 2aColorless oil that solidifies in the freezer to an off-white waxy solid; R_f = 0.29 (10% EtOAc–hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 7.11–7.08 (m, 2 H), 7.07–7.03 (m, 2 H), 3.16 (dd, J = 18.8, 10.9 Hz, 1 H), 3.00 (dd, J = 18.8, 4.8 Hz, 1 H), 2.55 (dd, J = 10.9, 4.8 Hz, 1 H), 2.29 (d, J = 0.6 Hz, 3 H), 1.24–1.21 (m, 6 H), 1.14 (s, 6 H), 0.18 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 246.9, 139.2, 134.7, 129.1, 128.1, 83.2, 53.5, 24.6, 24.5, 20.9, –3.3. ¹¹B NMR (160 MHz, CDCl₃): δ = 33.5. ²⁹Si NMR (99 MHz, CDCl₃): δ = –10.7. HRMS (DART): m/z calcd for C₁₉H₃₁BO₃Si [M + H]⁺: 347.2208; found: 347.2208.
• 14 General Procedure B for Asymmetric Conjugate Borylations To a flame-dried 8 mL screw top vial equipped with a magnetic stir bar was added Cu(MeCN)₄ClO₄ (0.02 mmol, 10 mol%) and Josiphos SL-J001-1 (0.024 mmol, 12 mol%), the vial was sealed with a rubber septum and electrical tape and backfilled three times with argon. THF sparged with argon (0.3 mL) was added, and the mixture was stirred for 30 min at room temperature. Solvent was then removed in vacuo and dried on high vacuum for 15 min. B₂pin₂ (0.3 mmol, 1.5 equiv) in THF (0.2 mL) was added, and the solution was stirred for 10 min. A suspension of LiOt-Bu (0.1 mmol, 50 mol%) in THF (0.25 mL) was added, and the black solution was stirred for an additional 10 min at room temperature. The mixture was cooled to –78 °C with a cryostat, and acyl silane 1a (0.2 mmol, 1.0 equiv) with MeOH (0.6 mmol, 3.0 equiv) in THF (0.22 mL) was added dropwise. The reaction was warmed to –50 °C over 2 h and then stirred at temperature for 18 h. The reaction was diluted with 1 mL Et₂O at –78 °C, warmed to room temperature, filtered through a short plug of Celite, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (5–7% EtOAc–hexanes) to afford 3a in 58% yield.

• Supplementary Material