Transition-Metal-Free Highly Chemoselective and Stereoselective

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

pubs.acs.org/OrgLett

Transition-Metal-Free Highly Chemoselective and Stereoselective Reduction with Se/DMF/H2O System Hong-Chen Li,† Cui An,† Ge Wu,‡ Guo-Xing Li,† Xiao-Bo Huang,† Wen-Xia Gao,† Jin-Chang Ding,† Yun-Bing Zhou,*,† Miao-Chang Liu,*,† and Hua-Yue Wu† †

College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, People’s Republic of China

‡

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S Supporting Information *

ABSTRACT: A novel metal-free reduction system, in which H2Se (or HSe−) produced in situ from Se/DMF/H2O acts as the active reducing species, has been developed. By using water as an inexpensive, safe, and environmentally friendly surrogate as the hydrogen donor, this new reduction system incorporating Se/DMF/H2O displayed high selectivity and good activity in the reduction of α,β-unsaturated ketones and alkynes. Therefore, this reduction system has great potential to be a general and practical reduction methodology in organic transformation.

S

silicon hydride as efficient hydrogen donors in the reduction reaction, but these have problems associated with cost, purification, and substituent compatibility.12 Furthermore, other hydrogen donors such as alcohol compounds,13 tertiary amine,14 HCOOH,15 Et3N·HCl,16 and DMF17 have found application during the selective reduction. Among these, the use of water18 as a cost-effective and environmental-friendly hydrogen (deuterium) donor has drawn researchers’ special attention. Inspired by our previous work on the construction of C−Se bonds using selenium powder as a cross-coupling partner,19 we intended to develop a three-component reaction of α,βunsaturated ketones, elemental selenium, and iodobenzene via Ullman-type selenation/Michael addition sequences. To our surprise, saturated ketones as chemoselective reduction products rather than coupling products were isolated. Herein, we present a novel metal-free reduction system in which H2Se (or HSe−) produced in situ from Se/DMF/H2O acts as the active reducing species. The new system incorporating Se/ DMF/H2O displayed high selectivity and good activity in the reduction of α,β-unsaturated ketones and alkynes, using water as an inexpensive, safe, and environmentally friendly surrogate for hydrogen donor. In addition, demethylation of aryl methyl ethers to phenols to hydrocarbons was achieved by Se/DMF/ H2O. In exploratory experiments, the reaction of chalcone with selenium powder was selected as the model reaction to screen suitable reaction conditions (Table 1). We found that by using DMF as solvent and KOAc as a base, chalcone could be

elective reductions are one of the most important methods for the synthesis of natural products, pharmaceuticals, and industrial chemicals.1 Over the past decades, great efforts have been devoted to transition-metal-catalyzed reduction methods. A series of transition-metal catalyst systems based on Pd,2 Rh,3 Ir,4 and Ru5 complexes have been used for the chemoselective reduction of α,β-unsaturated carbonyl compounds to saturated ones. However, these transition-metal catalysts usually suffered from high cost, generation of toxic waste and difficult separation from the products, which restrict their pharmaceutical and industrial application to some extent. From economical and environmental points of view, the use of transition-metal-free systems is more attractive. Although several transition-metal-free systems such as PhSeH, 6 CH3SeH/ZnCl2,7 NaSeH (or LiSeH),8 (C6F5)2BH/H2,9 and Na2S·9H2O,10 have been successfully developed for selective reductions, limitations including complicated manipulations, high pressure, complex preparation process of reducing agents, low yields, or low chemoselectivity have persisted. Additionally, Se/CO/H2O system,11 which generated hydrogen selenide in situ, was reported as an effective method for the reduction of α,β-unsaturated ketones and aromatic nitro compounds. Despite good efficiency, the process needs to be subjected to a relatively high pressure of poisonous CO (3.0 MPa). Therefore, it is still desirable to develop an efficient transition-metal-free system for selective reductions toward various organic compounds using cheap hydrogen donor. On the other hand, great advancements have been made in developing various hydrogen donors for selective reductions. H2 was the most widely used industrial hydrogen donor, although it suffered from high pressure and poor chemoselectivity. A great deal of research focused on the use of © XXXX American Chemical Society

Received: July 18, 2018

A

DOI: 10.1021/acs.orglett.8b02244 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditions for the Reduction of α,β-Unsaturated Ketone Compoundsa

entry

base or acid

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

KOAc KOAc KOAc KOAc KOAc KOAc KOAc KOAc KOAc KOAc KOAc KHCO3 tBuOK NaOH CH3COOH KOAc KOAc KOAc KOAc

solvent

atmosphere

temp (°C)

time (h)

yieldb (%)

DMF DMF DMF diethyl acetamide N-methylformanilide DMSO NMP dioxane tBuOH morpholine H2O DMF DMF DMF DMF DMF DMF DMF DMF DMF

N2 air O2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2

140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 140 150

24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 36 24

78 25 0 65 19 0 0 0 0 0 0 0 22 0 0 32 49 85 91 97

a

Reaction conditions unless otherwise noted: 1a (0.4 mmol), Se powder (2.0 equiv), base or acid (2.0 equiv), solvent (2 mL), temp, corresponding atmosphere. bIsolated yield. cKOAc (1.5 equiv). dSe powder (3.0 equiv).

groups on the aromatic ring delivered satisfying yields (Scheme 1, products 2b−h). However, for the substrates bearing electron- deficient substitutions such as fluoro and trifluoromethyl on the aromatic ring, the chemoselective reduction led to the desired products only in 56% and 51% yields, respectively (Scheme 1, products 2i and 2j). The method was also effective for the chemoselective reduction of the substrates bearing a fused ring (Scheme 1, products 2m and 2n). The existence of substitution such as phenyl group at the β position of the CC bond resulted in a significant decrease in yield (Scheme 1, product 2o), suggesting that steric effect had some negative impact on this transformation. The α,βunsaturated ketones containing an aromatic heterocycle provided the desired products with good yields and selectivities (Scheme 1, products 2p−t). Furthermore, the substrate containing only single aromatic ring can be chemoselectively converted to saturated ketone (Scheme 1, product 2u). We next turned our attention to evaluating the reduction efficiency of Se/DMF/H2O in the hydrogenation of alkynes (Scheme 2). To our delight, the semihydrogenation of alkynes was achieved successfully to provide E-alkenes with good yields and excellent stereoselectivities in the presence of our reduction system. The reaction conditions could be compatible with a broad range of substitutions on the aromatic ring, including methyl, hydroxyl, chloro, fluoro, bromo, formyl, methylthio, carbonyl, cyano groups (Scheme 2, products 4b− l). The alkynes bearing hydroxyl or bromo group gave acceptable yields (Scheme 2, products 4e and 4h). It is noted that this strategy displayed high chemoselectivities toward the substrates containing formyl and carbonyl groups (Scheme 2, products 4i, 4k). Moreover, the alkynes bearing heterocyclic ring reacted smoothly to afford desired E-alkenes

reduced chemoselectively to 1,3-diphenylpropan-1-one (2a) in 78% yield as the sole product at 140 °C in the presence of Se powder under N2 (Table 1, entry 1). When the reaction was conducted under air or O2, a sharp decrease in yields occurred (Table 1, entries 2 and 3). The use of diethyl acetamide and Nmethylformanilide as solvent led to 65% and 19% yields respectively (Table 1, entries 4 and 5). It is worth noting that the selective reduction did not proceed in DMSO, NMP, tBuOH, morpholine, or H2O (Table 1, entries 6−11) except for in amide solvent, presenting a strong solvent dependence. The absence of a base resulted in no formation of corresponding product, suggesting that it is indispensable to this catalytic system (Table 1, entry 12). Switching the base to KHCO3 gave 22% yield of product 2a (Table 1, entry 13). In the case of strong alkalis such as tBuOK and NaOH, the reduction did not take place (Table 1, entries 14 and 15). Interestingly, the selective reduction can be also promoted by acetic acid (Table 1, entry 16). Reducing the amount of alkali to 1.5 equiv will significantly decrease the efficiency of transformation (Table 1, entry 17). The yield of the desired product 2a could be improved correspondingly by increasing the amount of Se powder, prolonging the reaction time or raising the reaction temperature (Table 1, entries 18−20). Therefore, the optimum conditions involved performing the reaction using 3 equiv of Se powder in DMF at 150 °C with the use of KOAc as the base under N2 atmosphere. To investigate the substrate scope of the selective reduction, we first tested a diverse range of α,β-unsaturated ketones under the optimized reaction conditions (Scheme 1). Various substituted aryl groups have proven to be compatible in the standard conditions. The electron-donating substitutions including methyl, dimethylamino, amido, and methylthio B

DOI: 10.1021/acs.orglett.8b02244 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Semihydrogenation of Alkynesa

Scheme 1. Chemoselective Reduction of α,β-Unsaturated Ketone Compoundsa

a

Conditions unless otherwise noted: alkynes (0.4 mmol), Se powder (1.2 mmol), KOAc (0.8 mmol), DMF (2 mL), 150 °C, 24 h, N2. b Reaction time: 12 h. cE/Z > 20:1. dRatio of 4q/5q. eUsing phenylacetylene as substrate, 120 °C.

Scheme 3. Demethylation Process with Se/DMF/Water Systema

a

Conditions: 1 (0.4 mmol), Se powder (1.2 mmol), KOAc (0.8 mmol), DMF (2 mL), 150 °C, 24 h, N2. bNa3PO4·12H2O as a base.

with good yields and selectivities (Scheme 2, products 4m−p). In the case of arylalkyl alkyne 3q, the reaction provided the desired product with 64% yield, 4q/5q selectivity of 88:12 and E/Z selectivity of >20:1 were obtained in the presence of our reduction system (Scheme 2, product 4q). To our surprise, this reaction system promoted the reaction of phenylacetylene to provide thiophene rather than E-alkenes (Scheme 2, product 4r). In the course of expanding the substrate scope, we discovered accidentally that submission of the substrates containing methoxy group to this reduction system gives rise to a small amount of demethylated product, implying that demethylation accompanied the reduction process (Scheme 3). With the prolongated reaction time, the demethylation products would increase accordingly (Scheme 3, eqs 1 and 2). It is noted that the substrate bearing methylthio group adjacent to acetylene bond preferentially undergoes demethylation/ cyclization sequences to furnish 2-phenylbenzo[b]thiophene in 90% yield with our reduction system (Scheme 3, eq 3). Inspired by these results, we applied this reduction system to demethylation of aryl methyl ether which is an important transformation in organic synthesis. As expected, anisole was converted successfully to phenol in 56% yield by our reduction system (Scheme 3, eq 4).

Standard condition: α,β-unsaturated ketones or alkynes (0.4 mmol), Se powder (1.2 mmol), KOAc (0.8 mmol), DMF (2 mL), 150 °C, N2. a

To gain some insight into the reaction mechanism, several deuterium-labeling experiments were performed using D2O or DMF-d7 (Scheme 4). We found that the reaction provided D C

DOI: 10.1021/acs.orglett.8b02244 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Deuterium-Labeling Experiments

Scheme 5. Selective Reduction of 1a with Intermediate A instead of Se Powder

Scheme 6. Feasible Mechanism for Selective Reduction of α,β-Unsaturated Ketones

Deuterium ratio of β-d (D/D + H), determined by 1H NMR. Deuterium ratio of α-d (D/D + H), determined by 1H NMR.

a

b

atom-containing product 2a-d2 in 90% yield in the presence of 4 equiv of D2O (Scheme 4, eq 1), while the reaction failed to deliver 2a-d2 using DMF-d7 as the solvent (Scheme 4, eq 2). These observations demonstrate that water rather than DMF acts as the hydrogen donor in this transformation. Furthermore, to determine whether the two D atoms in 2ad2 come from the same water molecule, substrate 1a was submitted to the standard reaction conditions in the presence of both D2O (4 equiv) and H2O (4 equiv) and then products 2a-d1 were detected by GC−MS and NMR (Scheme 4, eq 3), suggesting that the two D atoms of 2a-d2 are derived from different water molecules. Bearing this deduction in mind, this reduction system could offer convenient and effective method for the synthesis of deuterium-labeled saturated ketones and alkenes through selective reduction using D2O as cheap, safe, and readily available deuterium source. On the other hand, inspired by initial screening results that indicate this reduction only takes place in amides, we speculated that DMF took part in this reaction in addition to playing the role of solvent. In accordance with the literature precedent on selenation of amide,20 it is our expectation that this reduction might involve selenoamide A as a key intermediate. Intermediate A was successfully synthesized from DMF and Se according to the previous literature.20a Three equivalents of intermediate A with 1a were subjected to the standard reaction conditions, providing the desired product in 90% yield (Scheme 5, eq 1). It is worth noting that the reaction of 1a and intermediate A in DMSO gave the product 2a in 23% yield (Scheme 5, eq 2). Furthermore, the reaction of 1a (0.4 mmol), Se (3 equiv), and DMF (10 equiv) in DMSO (2 mL) using KOAc as a base at 150 °C for 24 h afforded the desired product 2a in 28% yield, demonstrating that DMF can be used as a reagent (Scheme 5, eq 3). In contrast, no reaction of 1a with Se powder in DMSO was observed under standard conditions (Table 1, entry 6). These results suggest that this reaction is facilitated by the intermediate A. On the basis of the mechanistic studies and the relevant literature,11 a possible mechanism for selective reduction of α,β-unsaturated ketones (or alkynes) was proposed (Scheme 6). The reduction process begins with selenation of amide to

produce intermediate A. The intermediate A is unstable under the standard reaction conditions and is prone to undergo hydrolysis into DMF and H2Se (or HSe−) which has been reported to possess good reductive ability toward various organic compounds.6−8 Subsequently, H2Se or HSe− undergoes Michael addition to α,β-unsaturated ketones to afford intermediate B, which reacts with another H2Se or HSe− to form the desired products. In the presence of strong bases (tBuOK and KOH), H2Se or HSe− serving as the active reducing species would be converted to Se2−, which is ineffective for this reduction process, further explaining the above experimental results that the selective reduction could be promoted by weak bases (KHCO3 and KOAc) but not strong bases. Furthermore, the use of KOAc or CH3COOH afforded the desired product, implying that an acetate group may perform an important role in this transformation, although that remains to be elucidated. In conclusion, this work discloses a novel and efficient metalfree reduction system that displayed high chemoselectivity and stereoselectivity for hydrogenation of α,β-unsaturated ketones and alkynes. Furthermore, this reduction system was effective for demethylation of aryl methyl ethers to phenols. Mechanism verification revealed that water acts as the hydrogen donor and the reduction process is facilitated by the intermediate selenoamides. Therefore, this catalytic system has great potential to be a general and practical reduction methodology in organic transformations.

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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.8b02244. D

DOI: 10.1021/acs.orglett.8b02244 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

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Experimental procedures, characterization data, and 1H, 13 C, and 19F NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Ge Wu: 0000-0001-8432-5272 Wen-Xia Gao: 0000-0002-3373-9827 Miao-Chang Liu: 0000-0002-4603-3022 Hua-Yue Wu: 0000-0003-3431-561X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21472140 and 21372177), Zhejiang Provincial Natural Science Foundation (LY16B020011), the Wenzhou Science & Technology Bureau Program (No. G20170021), the Graduate Scientific Research Foundation of Wenzhou University, and the Xinmiao Talent Planning Foundation of Zhejiang Province (No. 2018R429058).

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DOI: 10.1021/acs.orglett.8b02244 Org. Lett. XXXX, XXX, XXX−XXX