Iron-Catalyzed Dehydrative Alkylation of Propargyl Alcohol with Alkyl

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Iron-Catalyzed Dehydrative Alkylation of Propargyl Alcohol with Alkyl Peroxides To Form Substituted 1,3-Enynes Changqing Ye,†,‡ Bo Qian,† Yajun Li,† Min Su,†,‡ Daliang Li,*,§ and Hongli Bao*,†,‡ †

Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Center for Excellence in Molecular Synthesis, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, P. R. China ‡ University of Chinese Academy of Sciences, Beijing, 100049, P. R. China § Biomedical Research Center of South China & College of Life Science, Fujian Normal University, No. 1 Keji Road, Shangjie, Fuzhou, Fujian 350117, P. R. China S Supporting Information *

ABSTRACT: This paper reports a new method for the generation of substituted 1,3-enynes, whose synthesis by other methods could be a challenge. The dehydrative decarboxylative cascade coupling reaction of propargyl alcohol with alkyl peroxides is enabled by an iron catalyst and alkylating reagents. Primary, secondary, and tertiary alkyl groups can be introduced into 1,3-enynes, affording various substituted 1,3-enynes in moderate to good yields. Mechanistic studies suggest the involvement of a radical-polar crossover pathway.

(Scheme 1c).7,8 Notwithstanding these established methods, there is no strategy which can install alkyl groups into existing motifs to afford polysubstituted 1,3-enynes. Redox active esters, derivable from readily available carboxylic acids, have recently been proven to be useful reactants, especially as alkylating reagents.9 Alkyl peresters and alkyl diacyl peroxides are alternative activated carboxylic acids. Recently, our group demonstrated a series of reactions that use peresters and diacyl peroxides as efficient alkylation reagents.10 In this work, the iron-catalyzed alkylation of propargyl alcohol was demonstrated with alkyl peroxide as a general alkylating reagent, producing structurally diversified polysubstituted 1,3enynes under mild reaction conditions (Scheme 1d). Initially, the coupling reaction of 2-phenyl-4-(p-tolyl)but-3yn-2-ol (1a) with tert-butyl 2-ethylhexaneperoxoate (2a) was carried out with metal catalysis (for details, see Supporting Information (SI), Table S1). After the comprehensive investigation of the parameters of the reaction, the optimal reaction conditions were found to be 2 mol % of Fe(OTf)3 in THF at 50 °C for 4 h (eq 1). With these reaction conditions in hand, the scope of the propargyl alcohols was explored (Table 1). Both electrondonating and -withdrawing substituents on the aromatic ring of R1 are tolerated in this coupling reaction, which produces the trisubstituted 1,3-enyne products (3a−3i) in yields of 60−83%. Heterocyclic aryl groups, such as thienyl, are compatible, which

1,3-Enynes are important building blocks in organic synthesis,1 pharmaceutical chemistry,2 and material science.3 Classical methods to synthesize 1,3-enynes include Wittig olefination of propargyl aldehyde (Scheme 1a),4 cross-coupling between alkynes and alkenes,5 metal-catalyzed cross-dimerization of alkynes (Scheme 1b),6 and dehydration of propargyl alcohols Scheme 1. Previous and Current Work on the Synthesis of Polysubstituted 1,3-Enynes

Received: April 3, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01043 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Scope of Alkyl Peroxidesa

Table 1. Scope of Propargyl Alcohola

a Reaction conditions: 1a (0.50 mmol, 1 equiv), 2 (1 mmol, 2 equiv), Fe(OTf)3 (2 mol %), THF (2 mL), 4 h, 50 °C. Isolated yields. b1a (0.6 mmol, 1.2 equiv), 5 (0.50 mmol, 1 equiv). ctert-Pentyl benzoperoxoate (5c) (0.5 mmol, 1 equiv).

a Reaction conditions: 1 (0.50 mmol, 1 equiv), 2a (1 mmol, 2 equiv), Fe(OTf)3 (2 mol %), THF (2 mL), 4 h, 50 °C. Isolated yields. b2 mmol reaction.

such as phenyl, benzoyl, esters, chloro, bromo, alkenyl and alkynyl, also give the corresponding products (6e−6k) in 34− 82% yields. Preliminary experiments were performed to investigate the mechanism of the reaction (Scheme 2). A radical trapping

produce 3j in 74% yield. Alkyl groups (R1) deliver products (3k−3m) with 63−75% yields. The product 3n is obtained in 53% yield when TMS-substituted propargyl alcohol is used. The presence of various functional groups in R2 was investigated. Electron-deficient and electron-rich substituents in an aromatic ring in R2 give the desired products (3o−3w) in 32−78% yields. Product (3x) bearing a fluorenyl group is formed in 37% yield. Activated 1,4-enediynes and 1,3-dienynes can be conveniently synthesized with this simple method, delivering products 3y and 3z in 45% and 62% yields, respectively. The R2 substituent representing an aliphatic group is also examined. When R2 is a tBu group (1aa), the corresponding product 3aa is obtained in 44% yield. While R2 is a nBu group (1ab), the reaction is messy. When terminal propargylic alcohol (1ac) is used, only a trace amount of the desired product is detected. The scope of the alkyl groups was studied, and the results are given in Table 2. Both secondary acyclic and cyclic peresters can be used in this transformation, affording the trisubstituted 1,3-enyne products (4a−4i) in 38−78% yields. Furthermore, tertiary peresters (2) couple smoothly with propargyl alcohol (1a), providing the corresponding products (4j, 4k) in 22% and 61% yields, respectively. Alkyl peresters derived from primary aliphatic acids do not perform well in this reaction, and consequently, alkyl diacyl peroxides are introduced to produce the primary alkyl 1,3enyne compounds. General alkyl diacyl peroxides are converted to the desired products (6a, 6b, 6d) in 65−78% yields. Reaction of tert-pentyl benzoperoxoate (5c) provides the ethyl substituted 1,3-enyne (6c) in 61% yield. Functional groups,

Scheme 2. Preliminary Mechanism Experiments

experiment with 2 equiv of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) under the standard reaction conditions affords no product (3a) (Scheme 2a), but when 2 equiv of MeOH are added to the reaction, trace amounts of product 3a can be detected and 7 is produced in 46% yield (Scheme 2b). Product 3a can be isolated in 84% yield when the enyne (8) is used in place of propargyl alcohol (Scheme 2c). The enyne (8) can be generated from propargyl alcohol (1a) under the standard reaction conditions in 98% yield, as determined from B

DOI: 10.1021/acs.orglett.8b01043 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 1

obtained in 38% yield from the reaction of 1,3-enyne 6a with an alkyl peroxide (5g) (Scheme 4c). Further examples of the synthetic applications of this method are shown in Scheme 5. Compound 13, which is synthesized by

H NMR spectra (Scheme 2d). These results suggest that a radical species and benzylic carbocation intermediates could be involved in this transformation and that the enyne (8) might be an intermediate derived from 1a. This coupling reaction can also be promoted by HOTf, but full conversion of a terminal 1,3-enyne to the alkylated 1,3-enyne needs as much as 40% of HOTf and produces the alkylated 1,3-enyne in only 60% yield (SI, Table S2). These results suggest that a catalytic amount of HOTf, which may generated from Fe(OTf)3, is not responsible for the high yield of the desired product and that iron is the actual catalytic species in the reaction. From these experiments, a plausible mechanism can be proposed and is shown in Scheme 3. A Lewis acid and single

Scheme 5. Synthetic Applications

Scheme 3. Proposed Catalytic Cycle

hydrolysis of product 6g under basic conditions, reacts with Nbromosuccinimide (NBS) to afford 14 in 60% yield (Scheme 5a).11 Compound 15 is obtained in 48% yield by intramolecular alkylboration of a tri-substituted 1,3-enyne (6i) under copper catalysis.12 These products could serve as key building blocks in pharmaceuticals and natural products. In conclusion, a novel dehydrative decarboxylative coupling reaction of propargyl alcohol with alkyl peroxides has been established. A series of polysubstituted 1,3-enynes are formed under mild reaction conditions by this iron-catalyzed coupling. Primary, secondary, and tertiary alkyl peroxides, which can be easily acquired from alkyl carboxylic acids, are used simultaneously as both an alkyl reagent and internal oxidant. Investigation of the mechanism suggests that a radical-polar crossover pathway might be involved in this reaction. The 1,3enyne products can be used in the synthesis of pharmaceuticals and natural products.

electron transfer catalytic cycle might be involved in this coupling reaction. First, propargyl alcohol 1a is activated by Fe(III) to generate water and an intermediate (8). The alkyl radical formed by a single electron transfer between the alkyl perester (2a) and Fe(II) attacks 8 to give benzylic radical species (A). This benzylic radical (A) is oxidized by Fe(III), affording the benzylic carbocation intermediate (B) and Fe(II). Finally, the 1,3-enyne product (3a) is obtained by the deprotonation of the benzylic carbocation intermediate (B). Based on this strategy of dehydrative decarboxylative coupling, a series of tetrasubstituted 1,3-enynes can be synthesized (Scheme 4). When the reaction is treated with excess primary alkyl peroxide 5a under the standard conditions, compound 9 is formed in 47% yield (Scheme 4a). Propargyl alcohol 10 can react with 5a to deliver the desired product (11) in 52% yield (Scheme 4b). Tetrasubstituted 1,3-enyne 12 is

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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.8b01043. Experimental details and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Scheme 4. Synthesis of Tetrasubstituted 1,3-Enynes

ORCID

Hongli Bao: 0000-0003-1030-5089 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Key R&D Program of China (2017YFA0700100), the NSFC (Grant No. 21502191, 21672213), Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), Haixi Institute of CAS (CXZX-2017-P01), “the 100 Talents Program”, “the 1000 Youth Talents Program”, and the Innovative Research Teams Program II of Fujian Normal University of China (IRTL1703) for financial support. C

DOI: 10.1021/acs.orglett.8b01043 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.8b01043 Org. Lett. XXXX, XXX, XXX−XXX