Silver-Catalyzed Olefination of Acetals and Ketals with Diazoesters to

Oct 26, 2018 - The first silver-catalyzed reaction of acetals or ketals with diazoesters leading to trisubstituted or tetrasubstituted β-alkoxyacryla...
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Silver-Catalyzed Olefination of Acetals and Ketals with Diazoesters to β‑Alkoxyacrylates Jiawen Li,†,§ Bo Qian,*,† and Hanmin Huang*,†,‡

Org. Lett. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/26/18. For personal use only.

†

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China ‡ Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei 230026, P. R. China § University of Chinese Academy of Sciences, Beijing 100049, P. R. China S Supporting Information *

ABSTRACT: The first silver-catalyzed reaction of acetals or ketals with diazoesters leading to trisubstituted or tetrasubstituted β-alkoxyacrylates is now reported. A broad range of acetals and ketals bearing different substituents is compatible with this protocol and thus provides an attractive approach for the synthesis of complex β-alkoxyacrylates. The power of this method was further demonstrated by the successful synthesis of picoxystrobin, which is one of the most popular agricultural fungicides commercialized by Dupont.

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elimination reaction of acetals in the presence of a stoichiometric strong base4 and catalytic transformations such as catalytic addition reactions of alcohols to alkynes,5 cross-coupling of olefins or alkenyl halides with alcohols,6 and isomerization of allyl ethers.7 Although the catalytic method is more attractive, most of the reported examples are limited to the synthesis of less steric hindered alkenyl ethers. Moreover, there are rare examples for the catalytic synthesis of polysubstituted β-alkoxyacrylates.8 In terms of synthetic simplicity and generality, it is highly desirable to develop new strategies and efficient methods to access polysubstituted β-alkoxyacrylates. In recent years, the discovery of new reactions based on the catalytic transformation of diazoesters has significantly contributed to synthetic organic chemistry.9 Ethyl diazoacetate (EDA) is known to react with aromatic aldehydes under the catalysis of Lewis acids to give the corresponding β-keto esters or 3-hydroxyacrylates, in which the formation of 3-hydroxyacrylates results from 1,2-aryl or alkyl migration.10 Inspired by these results, we envisioned that once the aldehyde was replaced by a more sterically hindered and more electrophilic acetals, the rate of 1,2-aryl or alkyl migration would be accelerated to exclusively give the corresponding β-alkoxyacrylates. Herein, we describe the first silver-catalyzed olefination of acetals and ketals with diazoesters, which proceeds with high efficiency (Scheme 1). This process is applicable to a range of acetals and ketals, accessing a wide range of polysubstituted β-alkoxyacrylates in both a chemoand stereoselective manner. Notably, only β-alkoxyacrylate products were obtained with our catalytic system. This is in

unctionalized alkenyl ethers are a class of important molecules possessing significant biological properties.1 In particular, the highly functionalized alkenyl ethers bearing a methyl β-alkoxyacrylate moiety such as azoxystrobin, picoxystrobin, strobilurin A, and oudemansin A, have been found to be very effective fungicides for over 400 crop/disease systems (Figure 1). In 1999, the sales of these compounds were

Figure 1. Examples of β-methoxyacrylate-containing bioactive molecules.

approximately $600 million, which represented just over 10% of the global fungicide market.2 In addition, thanks to their contained CC and C−O reactive functionalities, alkenyl ethers have also been broadly applied into organic synthesis, particularly playing a crucial role as a coupling partner in transition-metal-catalyzed cross-coupling reactions for the construction of carbon−carbon bonds.3 These properties have motivated the development of efficient methods for alkenyl ether synthesis. As such, myriad methods have been developed for the synthesis of such alkenyl ethers, including an © XXXX American Chemical Society

Received: September 23, 2018

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DOI: 10.1021/acs.orglett.8b03040 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

1, entry 4). The Z-isomer 3a′ was also isolated, and the structure was characterized by NMR and confirmed by comparison with the authentic compounds (see the Supporting Information (SI)).12,13 A control experiment demonstrated that no desired reaction occurred when the reaction was treated with NaSbF6 (Table 1, entry 5). These results clearly show that the use of a Lewis acid is crucial for the success of this conversion, and AgSbF6 is thought to account for the high levels of stereoselectivity and reactivity. Other typical Lewis acids, such as Yb(OTf)3·xH2O, Bi(OTf)3·xH2O, Eu(OTf)3· xH2O, and Sc(OTf)3 were also investigated, delivering the alkenyl ether (3a) with lower yields (Table 1, entries 6−9). Moreover, other Lewis acids including ZnCl2, SnCl2, and AlCl3 were inactive to this reaction (Table 1, entries 10−12). Thus, AgSbF6 was utlized as the optimal catalyst to maximize the efficiency of this transformation. The yield of 3a was slightly increased to 73% when the reaction time was prolonged to 3 h (Table 1, entry 13). A brief screening of solvents revealed that the use of CHCl3 was suitable for this transformation, giving the desired product 3a in 81% isolated yield with excellent stereoselectivity (E/Z > 20:1) (Table 1, entry 18). Further elevating or lowering the reaction temperature eroded the yield of the desired product (see the SI). In addition, no desired product was detected when Brønsted acid, such as HOTf and TsOH, was utilized as catalyst (Table 1, entries 19 and 20). Finally, the catalytic effect of the AgSbF6 was confirmed by running the reaction without catalyst. No product was formed when the reaction was conducted in the absence of AgSbF6 under otherwise identical reaction conditions (Table 1, entry 21). With the optimized reaction conditions identified, we next investigated the substrate scope of the olefination reaction. A number of acetals bearing a variety of substituents were employed as substrates in this transformation. As illustrated in Scheme 2, acetals bearing electron-donating substituents provided the corresponding trisubstituted β-alkoxyacrylates in good to excellent yields with high stereoselectivity (3b−f, 74− 92% yields). The effects on reactivity of methyl substitutents on either the ortho, meta, or para positions were negligible, but the effects on stereoselectivity were not negligible (3b−d). The present reaction appears to be sensitive to electronic effects. For example, substrates bearing electron-withdrawing groups on the aromatic rings provided the corresponding products with relatively lower yields (3g−l). For example, when the nitro-substituted acetal 1l was subjected to the standard reaction conditions, the desired product was isolated in only 3% yield, and most of the starting materials were recovered. These results reveal that the electron-rich group migrates faster than that of electron-deficient group. In addition, acetals derived from 1-naphthaldehyde and 2naphthaldehyde also presented good tolerance in the catalytic system, giving the desired products (3m and 3n) in 84% and 66% yields, respectively. However, when the reaction was carried out with aliphatic aldehyde-derived acetal (1o) as a substrate, the corresponding product 3o was obtained in lower yield (34% yield) with lower stereoselectivity. With methyl diazoacetate (2b MDA) as a coupling partner, substrate 1b and 1q could be smoothly converted into the corresponding products 3p and 3q in moderate to good yields with excellent stereoselectivity. The structures of 3a and 3i were confirmed by single-crystal X-ray analysis. The reaction can also be extended to ketals prepared from simple ketones. As shown in Scheme 3, the reaction proceeded

Scheme 1. Lewis Acid Catalyzed Olefination of Acetals and Ketals

sharp contrast to previous reports, where Lewis acid catalyzed reactions of aldehydes with diazoesters often led to mixtures of β-keto esters and 3-hydroxyacrylates.10 We started our proposed protocol by choosing 1a and 2a as model substrates to identify an active Lewis acid catalyst and suitable reaction parameters (Table 1). Unfortunately, no Table 1. Screening of Reaction Conditionsa

entry

catalyst

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13d 14d 15d 16d 17d 18d 19d 20d 21d

AgBF4 AgClO4 AgPF6 AgSbF6 NaSbF6 Yb(OTf)3·xH2O Bi(OTf)3·xH2O Eu(OTf)3·xH2O Sc(OTf)3 ZnCl2 SnCl2 AlCl3 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 HOTf TsOH

THF THF THF THF THF THF THF THF THF THF THF THF THF CH3CN 2-PrOH toluene DCM CHCl3 CHCl3 CHCl3 CHCl3

0 0 22 69 0 9 7 6 2 0 0 0 73 0 0 0 76 91 (81)e 0 0 0

3a/3a′ (E/Z)c

2:1 >20:1 4:1 2:1 3:1

16:1

>20:1 >20:1

a

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (1.0 mol %), solvent (1.0 mL) at 100 °C for 2 h. bYield was determined by GC using n-tetradecane as the internal standard. c(E/Z) ratios were determined by GC-MS and GC analysis of the crude reaction mixture. d 3 h. eIsolated yield.

desired reaction took place when the reaction conducted at 100 °C in THF for 2 h (Table 1, entry 1) with AgBF4 as catalyst. In the Lewis acid catalyzed reactions, the nature of the counterion usually has a strong effect on the reactivities and selectivities.11 Therefore, we also investigated the influence of the counterion on this transformation by using silver salts as catalyst precursors. A brief screening of silver salts revealed that the counterion of silver salt was indeed crucial for the reactivity and selectivity. When AgSbF6 was employed as a catalyst for this transformation, the desired product (3a) was obtained in 69% yield, along with high E/Z selectivity (E/Z > 20:1) (Table B

DOI: 10.1021/acs.orglett.8b03040 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope of Acetalsa

Scheme 3. Substrate Scope of Ketalsa

a Reaction conditions: 4 (0.5 mmol), 2 (1.0 mmol), AgSbF6 (1.0 mol %), CHCl3 (1.0 mL) at 100 °C for 3 h, isolated yield for the two isomers, (E/Z) ratios were determined by GC−MS and GC analysis of the crude reaction mixture. bAgSbF6 (2.0 mol %).

a

Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), AgSbF6 (1.0 mol %), CHCl3 (1.0 mL) at 100 °C for 3 h, isolated yield, (E/Z) ratios were determined by GC−MS and GC analysis of the crude reaction mixture. bAgSbF6 (5.0 mol %).

products (see the SI). The structures of 5a, 5d, and 5d′ were confirmed by single-crystal X-ray analysis. To further demonstrate the utility of this method, transformation of the resulting β-alkoxyacrylates was explored. The gram-scale preparation of 5b proceeded with high efficiency (1.4 g, 60% yield) even when 0.15 mol % of AgSbF6 was used, thus highlighting the reliability of this method (see the SI). Subsequently, hydrolysis of tetrasubstituted β-methoxyacrylates (5a and 5a′) afforded ketone (6) and enol (6′) in high yields under acidic conditions (Scheme 4a). Taking into account of the significance of alkenyl ether derivatives in cross-coupling reactions, the tetrasubstituted βmethoxyacrylates were further coupled with boronate (9) via the Ni-catalyzed coupling reactions, affording the corresponding polysubstituted acrylates in high yields (Scheme 4b).14 As expected, the present catalytic protocol could be utlized as a key step for the synthesis of picoxystrobin, which is one of the most popular agricultural fungicides developed by Syngenta and is now commercialized by Dupont.8 Although several synthetic approaches to picoxystrobin have been established by Zeneca,15 toxic or highly volatile reagents were generally required in most of these methods. As shown in Scheme 4c, with our newly developed reaction as a key step, the desired picoxystrobin was obtained in 65% total yield with commercially available simple 2-methylbenzaldehyde as starting material. Our total synthesis of picoxystrobin was accomplished in only four steps from a commodity chemical. This route represents the shortest synthetic procedure for picoxystrobin and avoids using toxic reagents.8

well with ketals derived from aryl methyl ketones, providing the desired tetrasubstituted β-alkoxyacrylates (5a−h) in 40− 90% yields, which are difficult to access by the existing methods. Functional groups such as fluorine, chlorine, and bromine are tolerated well to produce the corresponding products (5d−f, 68−77% yields), which provides a potential synthetic handle for further coupling reactions. Ketals derived from 1,2-diphenylethan-1-one and benzophenone were also smoothly converted into the corresponding alkenyl ethers 5i and 5j in 52% and 68% yields, respectively. Unsymmetric aromatic ketal 4k undergoes this transformation to give four isomers in 62% isolated yield. The main regioisomer resulted from the migration of the electron-rich phenyl-group. In addition, ketals bearing an ethoxyl substituent could readily react with ethyl diazoacetate (2a) to deliver the corresponding products (5l−n, 67−89% yields). Furthermore, ketals derived from heteroaromatic ketones were well tolerated in this olefination reaction to give the corresponding products 5m and 5n in good yields. tert-Butyl 2-diazoacetate (2c) could be smoothly transformed to the desired β-alkoxyacrylates (5o) in 65% yield. To our delight, a ring-expanding reaction occurred when cyclohexanone derived ketal was employed as a substrate, providing ethyl 2-methoxycyclohept-1-ene-1-carboxylate (5p) in 47% isolated yield. Similarly, the unsymmetric aliphatic ketone derived ketal (4q) could also undergo this transformation to afford the corresponding product with four isomers, and the main product resulted from the facile migration electron-rich group. The structures of these isomers were further confirmed by the corresponding hydrolysis C

DOI: 10.1021/acs.orglett.8b03040 Org. Lett. XXXX, XXX, XXX−XXX

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efficient method to prepare trisubstituted and tetrasubstituted β-alkoxyacrylates, which are difficult to access with existing methods. Notable features of our protocol include its operational simplicity, mild reactions, broad substrate scope, lower catalyst loading, and short reaction time. The successful synthesis of picoxystrobin with the newly developed catalytic reaction as a key step and the coupling reaction of the polysubstituted β-alkoxyacrylates with boronate provide good opportunities for applications in drug discovery and development. Further work will focus on applying this method to functional-molecules synthesis and elucidation of the detailed reaction mechanism.

Scheme 4. Synthetic Utility of the Present Reaction

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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.8b03040. Detailed experimental procedures, compound characterization data, and copies of NMR spectra (PDF) Accession Codes

CCDC 1834764−1834765 and 1834772−1834773 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

In accordance with precedent studies 10,16 and our experimental results, a preliminary mechanism for the formation of 3a is proposed. As shown in Scheme 5, activation

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Scheme 5. Proposed Mechanism of the Olefination Reaction

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hanmin Huang: 0000-0002-0108-6542 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (21672199 and 21790333), the CAS Interdisciplinary Innovation Team, and the Anhui provincial Natural Science Foundation (1708085MB28).

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DOI: 10.1021/acs.orglett.8b03040 Org. Lett. XXXX, XXX, XXX−XXX