Évolution des concepts de l’éjaculation précoce : répercussions sur la pratique

Title: Copper-Catalyzed Decarboxylative Alkylation of Terminal Alkynes Authors: Changqing Ye, Yajun Li, and Hongli Bao This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700798 Link to VoR: http://dx.doi.org/10.1002/adsc.201700798

10.1002/adsc.201700798

Advanced Synthesis & Catalysis

COMMUNICATION DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Copper-Catalyzed Decarboxylative Alkylation of Terminal Alkynes Changqing Yea, Yajun Li,a and Hongli Bao*a a

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, University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian, 350002, People's Republic of China e-mail : [email protected]

Received: ((will be filled in by the editorial staff)) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please delete if not appropriate)) Abstract. A copper-catalyzed decarboxylative alkylation of terminal alkynes under mild reaction conditions has been reported. Various alkyl diacyl peroxides were applied as the alkyl source for the formation of C(sp3)C(sp) bond. A range of terminal alkynes including aryl alkynes and alkyl alkynes delivered the alkylated internal alkynes with good to high performances. Mechanism studies suggested that this reaction involves a free radical pathway. Keywords: Copper-catalysis; Alkylation; Sonogashira coupling; Decarboxylation

The formation of C(sp3)-C(sp) bond is a key step for the construction of internal alkylated alkynes, which are important fragments widely appeared in natural products, pharmaceuticals, and molecular organic materials.[1] Although great success has been achieved through nucleophilic substitution of terminal alkynes with alkyl halides or other electrophiles, with the assistance of stoichiometric amount of strong base.[2] The catalytic fashion in the presence of a transition-metal is a more attractive option. As is known, alkyl halides are the most frequently used alkyl source for the formation of C(sp3)-C(sp) bond. Representatively, the alkyl source involved Sonogashira reaction,[3] elegantly modified by Fu,[4] Glorius,[5] Hu,[6] and Liu[7] et al., could directly employ the non-activated alkyl halides as the alkyl electrophiles with Pd/Cu/NHC or Ni/Cu as the cocatalysis system to construct the C(sp3)-C(sp) bonds (Scheme 1a). [8,9] What's more, alkyl halides could be used to synthesize the corresponding alkyl metal reagents such as Grignard reagent,[10] organozinc reagents,[11] organotin reagents et al.,[12] which are alternative forms of alkyl source for the formation of C(sp3)-C(sp) bond with or without the assistance of external oxidants (Scheme 1b). Direct C-H alkynylation of alkane represents another effective method for the formation of C(sp3)-C(sp) bond.

Developed by Chatani[13] and Yu[14] et al., the alkynylation of C(sp3)-H bonds with alkynyl halides has been enabled by palladium catalysts. Zhang,[15] Lei,[16] and Shi[17] demonstrated that without preactivation, terminal alkynes would react with unactivated C(sp3)–H bonds through transition-metal catalyzed cross-dehydrogenative coupling (CDC) pathway (Scheme 1c). From the point of enriching the diversity of alkyl source and catalyst list, the development of methodologies for the formation of C(sp3)-C(sp) bond is still urgent.

Scheme 1. Transition-metal catalyzed formation of C(sp3)-C(sp) bonds with different alkyl sources. Aliphatic carboxylic acids are readily available materials and exist widely in nature.[18] Decarboxylation of aliphatic carboxylic acids or their activated forms will generate alkyl sources, which are frequently used as the alkylating reagents.[19] This methodology has been applied for the formation of C(sp3)-C(sp) bonds with a hetero-atom at the ß– position of the carbon-carbon triple bond, mainly owing to its ability to stabilize the produced alkyl source after decarboxylation.[20] The decarboxylative alkylation with alkyl diacyl peroxides and terminal

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10.1002/adsc.201700798

Advanced Synthesis & Catalysis

alkyne still remain unsolved. Inspired by the employ of aliphatic carboxylic acids as the alkylating reagent source,[21] we report herein a copper catalyzed decarboxylative alkylation of terminal alkynes with alkyl diacyl peroxides as the alkyl source under very mild conditions (Scheme 1d). Table 1. Reaction condition optimization [a, b]

Entry

Copper salt

Ligand

Base

Yield (%)[c]

1

CuI

dtbpy

DIPEA

23

2

Cu(CH3CN)4PF6

dtbpy

DIPEA

25

3

CuBr·SMe2

dtbpy

DIPEA

30

4

CuCl

dtbpy

DIPEA

40

5

CuCl2

dtbpy

DIPEA

18

Cu(OTf)2

dtbpy

DIPEA

19

[d]

CuCl

dtbpy

DIPEA

46

8[d]

CuCl

dtbpy

Et3N

55

9[d]

6 7

CuCl

dtbpy

pyridine

42

10

[d]

CuCl

dtbpy

K2CO3

44

11

[d]

CuCl

dtbpy

---

37

12

[d]

CuCl

bpy

Et3N

43

13

[d]

CuCl

L1

Et3N

37

14

[d]

CuCl

L2

Et3N

28

15

[d]

CuCl

PPh3

Et3N

18

16[d]

CuCl

L3

Et3N

28

17[d,e]

CuCl

dtbpy

Et3N

61

Et3N

83(78)[h]

18

[d,e]

[f]

CuCl

[g]

dtbpy

when the reaction temperature was decreased to 10 oC (Table 1, entry 7). Next, the effect of base was studied and found that Et3N could deliver 3a in 55% GC yield (Table 1, entries 8-11). Other solvents such as DMF, DMSO, and THF had poorer performances than CH3CN (see supporting information). As the investigation proceeded, we began to screen the ligands, such as phosphine ligands, amino acid ligands, and other bidentate nitrogen ligands (Table 1, entries 12-16 and SI). However, the yield of 3a could not be further improved with these ligands. Delightfully, the yield of 3a was increased with a lower concentration and further improved to 83% with a higher catalyst loading (Table 1, entries 17 and 18). Table 2. Scope of terminal alkynes[a]

[a]

Reaction conditions: 1a (0.50 mmol), LPO (0.60 mmol), base (3 equiv.), copper salt (10 mol%), and ligand (10 mol%) in 2 mL CH3CN at 50 oC. [b] For more details please see supporting information. [c] Yield was determined by GC analysis. [d] Reaction temperature was 10 oC. [e] CH3CN (6 mL). [f] CuCl (20 mol%). [g] dtbpy (20 mol%). [h] Isolated yield in parentheses. L1 = 4,4’-dimethoxy-2,2’-bipyridine. L2 = 1,10-phenanthroline. L3 = (4-MeOC6H4)3P. dtbpy = 4,4'-di-tert-butyl-2,2'-bipyridine. bpy = 2,2'bipyridine. DIPEA = N,N-diisopropylethylamine.

Initial screening of the reaction employed 4ethynyltoluene (1a) and lauroyl peroxide (LPO, 2a) as the starting material (Table 1). Gratefully, when CuI was used as the catalyst, the desired product (3a) was obtained in 23% GC yield (Table 1, entry 1). After screening other copper salts, it was found that CuCl offered a better yield as high as 40% (Table 1, entries 2-6). A slight improvement was achieved

[a]

Reaction conditions: terminal alkyne 1 (0.50 mmol), LPO (0.60 mmol), Et3N (3 equiv.), CuCl (20 mol%), and dtbpy (20 mol%) in CH3CN (6 mL) at 10 oC.

With the optimal reaction conditions in hand, the scope and limitation with respect to terminal alkynes were explored (Table 2). A wide range of terminal aryl alkynes with various functionalities tolerated the mild reaction conditions. While electron-donating substituents on the benzene ring afforded the corresponding internal alkynes with high yields, electron-withdrawing substituents on the benzene ring offered the desired products with a slight low

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10.1002/adsc.201700798

Advanced Synthesis & Catalysis

yields (Table 2, 3b-3n). It’s worth mentioning that good yields was achieved when the substituent was on the ortho-position of the benzene ring (Table 2, 3k, 3m, and 3n). Aldehyde group, which is supposed to be sensitive to oxidative conditions, could participate in the reaction with good performacne, and the desired product (3n)[22] was isolated in 76 % yield. Heteroaromatic ring such as thiophene, quinoline and benzofuran, could also be compatible with the reaction condition, affording the corresponding product with moderate to high yields (Table 2, 3o, 3p, 3q, and 3r). Pyridine substrate was also tried, but product 3s was obtained only in 9 % yield. Excitingly, this methodology was not limited to terminal aryl alkynes, but could be applied to terminal alkyl alkynes. Functionalities such as chloro, hydroxyl group, and amine were tolerated and produced the 1,2-dialkyl acetylene with moderate yields (Table 2, 3t, 3u, 3v, and 3w). We next studied the scope of the alkyl diacyl peroxides (Table 3). As reported by our studies, DCC-mediated dehydrative condensation between aliphatic acids and hydrogen peroxide will generate the alkyl diacyl peroxides, which can be used directly after simple filtration. After screening, the reaction temperature could be further dropped to -10 oC without losing activities. Primary aliphatic carboxylic acids afforded the corresponding products 4a-4i with 40-85% yields. What’s more, secondary aliphatic carboxylic acids could also be employed to this reaction and provided the corresponding products with moderate yields[23]. Table 3. Scope of alkyl diacyl peroxides[a]

that the reaction might undergo a free radical process. To gain further understanding of this free radical process, a radical-clock substrate 2m was synthesized and applied to the reaction (scheme 2b).[25] It was found that the reaction between terminal alkyne 1a and 2-cyclopropylacetic peroxide (2m) afforded the enyne product 4m in 38%, which was supposed to generate from the radical involved ring-open process from the cyclopropane moiety.

Scheme 2. Mechanism study

According to above mechanistic studies, a plausible reaction mechanism for the Sonogashiratype decarboxylative alkylation of terminal alkyne is proposed as shown in Scheme 3.[26] The CuI species (A) react with terminal alkyne to form complex (B) under base condition. Then homolytic cleavage of the peroxide will generate the CuII species (C) and the alkyl free radical. Next, two possible pathways might be involved in the catalytic cycle. Pathway a: the interaction between CuII species (C) and alkyl radical through radical homolytic substitution will generate the coupling product and regenerate the copper catalyst. Path b: the CuII species (C) proceed single electron transfer with the alkyl free radical to form CuIII intermediate (D), which undergoes reductive elimination to yield the target product and the active copper salt.

[a]

Reaction conditions: terminal alkyne 1a (0.50 mmol), 2 (0.75 mmol, synthesized from alkyl carboxylic acids and used directly after filtration), Et3N (3 equiv.), CuCl (20 mol%), and dtbpy (20 mol%) in CH3CN (6 mL) at -10 oC.

To explore the mechanism for the reaction, a radical trapping experiment was conducted with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the radical-trapping reagent.[24] No desired product 3a was formed, but compound 5 was detected by GCMS analysis (scheme 2a). This result demonstrated

Scheme 3. Proposed reaction mechanism

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Advanced Synthesis & Catalysis

In summary, we have developed an efficient and mild copper catalyzed decarboxylative cross-coupling of alkyl diacyl peroxides with terminal alkynes to establish C(sp3)-C(sp) bond. Various substituted internal alkynes were synthesized in moderate to excellent yields with good functionalities tolerance. Primary and second alkyl diacyl peroxides were utilized as the alkyl source. Not only terminal aryl alkynes but also terminal alkyl alkynes could be applied to this transformations, which greatly broaden the alkyne substrate scope for this reaction. Mechanistic studies suggested that this reaction might involve a free radical pathway. The application of alkyl diacyl peroxides as an alkylating reagent for the functionalization of alkynes is current underway in our laboratory.

Experimental Section General procedure for Table 2 To a 25 mL of Schlenk tube equipped with a Teflon-coated magnetic stir bar was charged with alkynes (0.5 mmol), LPO (0.60 mmol), CuCl (0.1 mmol), dtbpy (0.1 mmol), Et3N (1.5 mmol), and anhydrous CH3CN (6 mL). The resulting suspension was stirred at 10 oC for 5 h. Upon completion of the reaction as monitored by TLC, the solvent was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel to give the product.

General procedure for Table 3 A solution of DMAP (0.224 g, 0.3 mmol), 30% hydrogen peroxide (3.6 mmol) and acid (3 mmol) in DCM (5 mL) was cooled to -15 C for about 10 min, then DCC (3.6 mmol) was added. Then the mixture was stirred for another 1.5 hours at -15 C. After the reaction finished, the solution was filtered through a short pad of silica gel. Then washed the pad of silica gel by additional 20 mL of DCM. The combined solution was concentrated on a rotary evaporator under vacuum at 10~15 C give the diacyl peroxides which was used directly in following reactions. To a 25 mL of Schlenk tube equipped with a Teflon-coated magnetic stir bar was charged with terminal alkyne (0.5 mmol), CuCl (0.1 mmol), dtbpy (0.1 mmol), Et3N (1.5 mmol), and anhydrous CH3CN (2 mL). The resulting suspension was stirred at -10 C. The corresponding diacyl peroxide was dissolved in another 4 mL anhydrous CH3CN, and then added to reaction via a syringe. Upon completion of the reaction as monitored by TLC, the solvent was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel to give the product.

Acknowledgements We thank NSFC (grant no. 21402200, 21502191, 21672213), Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), The 100 Talents Program, “The 1000 Youth Talents Program” for financial support.

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Advanced Synthesis & Catalysis

COMMUNICATION Copper-Catalyzed Decarboxylative Alkylation of Terminal Alkynes Adv. Synth. Catal. Year, Volume, Page – Page Changqing Ye, Yajun Li, and Hongli Bao*

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