Cu-Catalyzed SN2′ Substitution of Propargylic Phosphates with

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Cu-Catalyzed SN2′ Substitution of Propargylic Phosphates with Vinylarene-Derived Chiral Nucleophiles: Synthesis of Chiral Allenes Bing Wang,†,‡ Xihong Wang,†,‡ Xuemei Yin,†,‡ Wangzhi Yu,†,‡ Yang Liao,†,‡ Jialin Ye,§ Min Wang,†,‡ and Jian Liao*,†,‡,§ †

Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China University of Chinese Academy of Sciences, Beijing 100049, China § College of Chemical Engineering, Sichuan University Chengdu 610065, China Downloaded via BOSTON COLG on May 10, 2019 at 14:11:01 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: A new Cu-catalyzed enantioselective threecomponent (i.e., styrenes, B2pin2, and propargylic phosphates) allenylation via an SN2′ substitution of propargylic electrophiles with vinylarene-derived chiral nucleophiles is presented. This method provides an efficient and enantioselective approach to access a range of optically pure di-(1,1-), tri-, and tetra-substituted allenes with α-central chirality and axial chirality in excellent chemo-, regio-, diastereo-, and enantioselectivities.

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However, these methods rely on employing stoichiometric amounts of typically moisture sensitive organometallic reagents which must be preformed prior to their use. To overcome these limitations, development of novel methods which organometallic reagents could be generated catalytically from readily available hydrocarbons and subsequently intercepted by propargylic electrophiles is a good choice. Recently, Rh and other metal (i.e., Cu, Co, Mn, Ru) mediated C−H allenylations provided such an efficient solution, but this strategy is limited to afford arylmetals (Scheme 1b).5 Additionally, the asymmetric synthesis of chiral allenes via those strategies has mainly focused on axial chirality with few examples related to the asymmetric construction of pendant chirality centers.4d−f To date, an enantioselective transition metal-catalyzed SN2′ substitution approach toward the generation of optically active allenes with α-central chirality has not yet been reported.6 In this sense, the development of a novel method in which chiral organometallic nucleophiles could be generated catalytically from readily available hydrocarbons and subsequently intercepted by propargylic electrophiles to form chiral allenes with control of both axial and point chirality is highly desirable. Recently, significant advances have been achieved in Cu-catalyzed threecomponent carboboration (TCC) of alkenes.7 In such a process, alkylcopper nucleophiles are generated via the addition of CuBpin species to CC bonds and then intercepted by various carbon electrophiles. We envisioned that these in situ and catalytically generated alkylcopper species could be employed as nucleophiles in the above-mentioned SN2′ substitution to realize a novel allenylation. Importantly, a chiral Cu-Bpin inserting into an alkene would produce an enantioenriched alkylcopper

llenes are not only important structural motifs existing in natural products, pharmaceuticals, and materials but also invaluable building blocks in organic synthesis due to their unique cumulated diene frameworks.1 Many synthetic methods, starting with pioneering work by Burton and Pechmann in 1887,2 have been developed to access this vital class of compounds, including optically pure allenes with central and/ or axial chirality.3 Among these, transition metal-catalyzed SN2′ substitution of propargylic electrophiles with organometallic nucleophiles (i.e., Mg, Li, B, Zn, and In reagents) is one of the most popular and straightforward approaches (Scheme 1a).3a,4 Scheme 1. Transition-Metal-Catalyzed SN2′ Substitution Approaches to Allenes

Received: March 14, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.9b00908 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

intermediate, making it possible to synthesize optically active allenes which bear a central chirality center. Based on this, allenes with both central and axial chiralities will be accessible when enantioenriched propargylic electrophiles4g−j are used. To achieve this goal, there are several challenges that need to be overcome: (i) The SN2′ substitution of Cu-Bpin species to propargylic derivatives (vs Cu-Bpin addition to alkenes) would directly afford alleneboronic side products.8 (ii) The SN2 substitution of alkylcopper to propargylic derivatives (vs SN2′ substitution).4h,9 (iii) Due to their high reactivity, the desired allenes might be immediately consumed by the Cu-Bpin species once they are formed.8b,10 (iv) In the enantiomeric case, there is a question of whether enantioenriched alkylcopper can be efficiently captured by propargylic derivatives with high stereospecificity for the construction of chiral Csp3−Csp2 bonds. In regard to the last concern, the predominant methods employing TCC of alkenes require a second catalyst (bimetal catalyst).7b−d,k In this letter, we describe the first Cu-catalyzed enantioselective three-component allenylation via the SN2′ substitution of propargylic phosphates with vinylarene-derived chiral nucleophiles. Following this method, enantiomerically enriched allenes were synthesized with good control of both central and axial chirality (Scheme 1c).11 The optimization of reaction conditions is detailed in Table 1. With propargyl chloride 1A as the electrophile and styrene 2a + B2pin2 as the substrate, we evaluated the catalytic activity of a sulfoxide phosphine (SOP, L1)/Cu(I) complex for the new three-component reaction. The desired allene 3aa bearing a chiral carbon center was obtained in medium yield and a high level of enantioselectivity (41% NMR yield and 92% ee). The major side product (15% NMR yield) was allenyl-Bpin 4; no SN2-substituted product was detected, but the products of protodemetalation (5) and β-H elimination (6) were observed in trace amounts (entry 1). Further studies demonstrated that the leaving group (LG) plays an important role in this transformation (entries 1−4). For instance, when Cl was replaced with Br (1B) as LG, allenyl-Bpin 4 was obtained as the major product (entry 2, 58% NMR yield). Ethyl phosphate (1a) was certified as the best LG, affording 3aa as the major product with 70% NMR yield and 93% ee (entry 4). Slightly increasing the dosage of LiOtBu (1.0 to 1.1 equiv) can further improve the yield to 79% (entry 5). A brief survey of SOP (L1 and L2) and bisphosphine ligands (L3−5) revealed that the former were more appropriate ligands for this three-component reaction; the latter gave poor results in terms of chemo- and enantioselectivities (entries 5−9). A range of copper salts was also examined (entries 10−13), leading to the discovery that CuI was the most effective copper source for this reaction (entry 13). Lowering the reaction temperature slightly enhanced the enantioselectivity at the cost of an inferior yield (entry 14). Following the best conditions, this reaction provided satisfactory results even at gram-scale (entry 15). With the optimized conditions in hand, we then examined the substrate scope of the vinylarenes (Scheme 2). Using propargylic phosphonate 1a as electrophile, a range of vinylarenes bearing multifarious functional groups with different electronic properties and steric hindrance was tested. Ortho-, meta-, and para-substituted (alkyl, phenyl, alkoxy, ester, and halogen) styrenes and heteroaryl olefins (4-vinylindole 2w and 2-vinylthiophene 2x) were converted smoothly to the corresponding boryl-allenylation products with satisfactory results (45−81% yield and 87−96% ee). In general, parasubstituted styrenes provided higher enantiomeric excess than

entry

LG

L*

CuX

yield (%) 3aa/4/(5+6)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14e 15f

1A 1B 1C 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a

L1 L1 L1 L1 L1 L2 L3 L4 L5 L1 L1 L1 L1 L1 L1

CuCl CuCl CuCl CuCl CuCl CuCl CuCl CuCl CuCl CuBr CuOAc CuCl2 CuI CuI CuI

41/15/tr tr/58/tr 45/5/tr 70/tr/tr 79/tr/tr 60/tr/tr 45/10/43 23/tr/73 37/10/62 60/10/tr 40/tr/tr 19/11/tr 85(74d) /tr/tr 54(50d) /tr/tr 71d

92 n.d. 86 93 93 86 −41 −36 −32 95 78 87 94 96 94

a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol for entries 1−4, 0.3 mmol for entries 5−14), B2pin2 (0.3 mmol), LiOtBu (0.2 mmol for entries 1−4, 0.22 mmol for entries 5−14), CuX (10 mol %), and L* (12 mol %) in THF (2 mL), at 25 °C for 15 h. bYield was determined by 1H NMR using dimethyl terephalate as an internal standard; tr = trace. cEe was determined by HPLC analysis of the corresponding homoallenylic alcohol product; the absolute configuration was assigned as (R) by comparing the optical rotation of (S)-7 with literature (see Scheme 3 and Supporting Information), n.d. = not determined. dIsolated yield of 3aa. eAt 0 °C for 15 h. fThe reaction was performed in 6 mmol scale (1.58 g) of 1a, 5.0 mol % of CuI, at 25 °C for 24 h.

ortho- and meta-substituted styrenes. An electron-withdrawing group (m-CF3 and p-CF3) was detrimental to the enantioselectivity of the transformation (3ea and 3na).7h Furthermore, bicyclo-[2.2.1]hepta-2,5-diene was examined, resulting in the formation of exo-3ya with exclusive diastereoselectivity and good yield/enantioselectivity. We next evaluated the scope of the propargylic phosphates (Table 2). For the alkyl-substituted phosphates, the length of the carbon chain at the γ-position of 1 (CH3-, C3H7-, and C10H21-) had no effect on enantioselectivity; excellent % ee values were obtained in all cases (Table 2, entries 1−3). Various functional groups tethered to the carbon chain such as Cl (1e), ether (1g), and phenyl (1f) groups all were compatible with this protocol (entries 4−6). It is interesting to note that some bulky groups which are typically disadvantageous for SN2′ substitution processes,4h,9c,d for example, iso-propyl (1h), cyclopropyl (1i), tert-butyl (1j), and trimethylsilyl (TMS, 1k) substituted propargylic phosphates, can also proceed in this Cu-catalyzed three-component allenylation with excellent regio- and enantioselectivities. Importantly, in addition to primary propargylic phosphates, which afford the corresponding chiral geminally 1,1-disubstituted terminal allenes, tertiary propargylic B

DOI: 10.1021/acs.orglett.9b00908 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of Vinylarenesa

Table 2. Scope of Propargylic Phosphatesa

a Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), B2pin2 (0.3 mmol), LiOtBu (0.22 mmol), CuI (10 mol %), and L1 (12 mol %) was stirred in THF (2 mL) at 25 °C for 15 h. bIsolated yield. cEe was determined by HPLC analysis of oxidized product.

phosphates 1l−1n were also converted into the corresponding tetra-substituted allenes with good yields and excellent enantioselectivities (entries 11−13). It is worth noting that when enantioenriched secondary propargylic phosphates were employed as electrophiles, the three-component allenylations smoothly proceeded with excellent central-to-axial chirality transfer to provide optically active trisubstituted allenes 3ao− 3aq, all of which bear both central and axial chirality in 96−99% enantiomeric excess and 91−96% diastereoisomeric excess (entries 14−17). When two SOP ligands which with opposite absolute configurations were employed in this process, no obvious chirality match/mismatch effect was observed (3ao vs 3ao′). An attempted kinetic resolution of racemic propargyl phosphate ((±)-1q) was unsuccessful (less than 5% de, see Supporting Information for details). The axial chirality of products 3ao−3aq was assumed to be S (3ao, 3ao′, and 3aq) and R (3ap) configurations according to the 1,3-anti displacement mechanism of organocopper or cuprate reagents with propargylic derivatives.3f,4e,h−j To demonstrate the versatility and potential of this synthetic methodology, several chemoselective transformations of enantio-enriched β-allenylboronic esters were executed

a Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), B2pin2 (0.3 mmol), LiOtBu (0.22 mmol), CuI (10 mol %), and L1 (12 mol %) in THF (2 mL) at 25 °C for 15 h. bIsolated yield. cThe ee and de were determined by HPLC analysis of oxidized products. d(S)-L1 was employed.

(Scheme 3). First, the sequential desilation/reduction of 3ak enabled the production of the corresponding chiral alkylboronic ester (S)-7 with excellent yield and enantiomeric specificity.12 Second, employing Pd/H catalysis, the isomerization of the allenyl moiety (3aa) to the corresponding 1,3-diene proceeded smoothly, affording conjugated diene 8 with complete retention C

DOI: 10.1021/acs.orglett.9b00908 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Biological Resources Programme, Chinese Academy of Sciences (KFJ-BRP-008), and Sichuan Sci&Tech Department (Grant 2016JZ0022) is acknowledged. We thank J. J. Chruma (Sichuan University) for the language polish of this manuscript.

Scheme 3. Transformation of Products

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of chirality.13 Third, the C-Bpin bond can be selectively converted to a C−C bond by Suzuki−Miyaura cross coupling (3al to 9) without any loss of enantiopurity or interference from the allenyl framework.7c,14 Finally, the C−B bond in 3aa could be oxidized to the corresponding 3,4-allenol 10. Chiral dihydrofuran 11 and α-dihydropyran 12 were both obtained in high yield from homoallenyl alcohol 10 by either a Pd(0)catalyzed coupling-cyclization with iodobenzene or a Pd(II)catalyzed coupling-cyclization with allylic bromide,15,16 respectively. In summary, we developed a novel Cu-catalyzed enantioselective three-component allenylation of vinylarenes. This method was realized through an SN2′ substitution of propargylic phosphates with the in situ generated enantioenriched alkylcopper species, which themselves were prepared catalytically via the addition of a Cu-Bpin species to styrenes. This protocol provided an efficient approach to access a range of optically pure di(1,1-), tri-, and tetra-substituted allenes bearing α-central and, when enantioenriched propargylic phosphate were employed, axial chirality. From a different perspective, it could be said that this method also provided an efficient enantiomeric Cu-catalyzed three-component carboboration of alkenes.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00908. Experimental procedures and compound characterization (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jian Liao: 0000-0001-8033-6521 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (Grants 21871251, 21572218, and 21472184), the D

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Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2013, 135, 4934− 4937.

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