Visible-Light-Induced Atom Transfer Radical Addition and Cyclization

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Visible-Light-Induced Atom Transfer Radical Addition and Cyclization of Perfluroroalkyl Halides with 1,n-Enynes Shuo-Wen Wang, Jian Yu, Qin-Yi Zhou, Si-Yu Chen, Zhen-Hua Xu, and Shi Tang ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b02178 • Publication Date (Web): 09 May 2019 Downloaded from http://pubs.acs.org on May 9, 2019

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ACS Sustainable Chemistry & Engineering

Visible-Light-Induced Atom Transfer Radical Addition and Cyclization of Perfluroroalkyl Halides with 1,n-Enynes Shuo-Wen Wang,# Jian Yu,# Qin-Yi Zhou, Si-Yu Chen, Zhen-Hua Xu, and Shi Tang* National Demonstration Center for Experimental Chemistry Education, Jishou University, No.120 Renmin South Road, Jishou 416000, China. E-mail: [email protected]

ABSTRACT:

A mild and efficient visible-light-induced atom transfer radical addition and cyclization of 1,nenynes (n =6, 7) with perfluoroalkyl halides, leading to halo-perfluorinated N-heterocycles, has been developed. This protocol offers a mild, completely atom-economic and general access to perfluorinated 2,4-dihydronquinolin-2(1H)-ones and pyrrolidines from corresponding benzene and N-tethered 1,n-enynes (n =6, 7) via 56-exo-dig cyclization, allowing for the expedient incorporation of a wide variety of perfluorinated groups such as CF3, i/n-C3F7, n-C4F9, n-C6F13, n-C8F17, n-C10F21, CF2Br, CF2CO2Et and etc. In addition, the reactions using 1,7-enynes (n = 6, 7) bearing tert-butyl-linked alkynyl moiety enables a divergent cyclization involving a hydrogen

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atom transfer (HAT) process, thereby leading to novel α,α-halo-perfluorinated 2,4dihydronquinolin-2(1H)-ones.

KEYWORDS: Atom transfer radical addition; 1,n-Enynes; Perfluoroalkyl halides; Photoredox catalysis; Cyclization

INTRODUCTION Physico-chemical and biological properties of natural products or bioactive molecules are generally altered upon introduction of fluorinated groups, and the resultant higher solubility and lipophilicity lead to better membrane permeability and increased bioavailability.1-4 Therefore, the development of new and efficient protocol for the introduction of fluorinated groups into organic molecules has attracted increasing interest from the fields of pharmaceuticals, agrochemicals and materials science.5-8 Atom transfer radical addition (ATRA) reaction has been developed as highly useful synthetic transformation, which allows straightforward difunctionalization of unsaturated carbon-carbon bond in an atom economic process―with no waste of atoms or molecular moieties.9-13 In this regard, ATRA reactions of fluoroalkyl halides to alkenes or alkynes by a 1,2-addition pattern have been extensively disclosed, which allow for the expedient introduction of both a fluoroalkyl moiety and a halo group in one-pot process (eq 1, Scheme 1).14-26 Meanwhile the introducing halo groups provide good opportunities for further modification of these molecules thus obtained (e.g, by well-established cross-couplings). Remarkably, with the combined efforts from Nevado,27 Tu,28-32 Li,33-38 Liang,39-44 and other groups,45-50 1,n-enynes (n = 6,7), including benzene-tethered 1,7-enynes and N-tethered 1,6enynes, have aroused as versatile starting materials in considerable cyclization cascades, which


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provide facile accesses to pharmaceutically important heterocyclic motifs. In contrast, the ATRA of fluoroalkyl halides to 1,n-enynes (n = 6,7) by a distal addition over more than seven atoms, leading to halofluoroalkytated heterocyclic rings, likely attracted less attention from chemists in the past years. To the best of our knowledge, the ATRA of perfluoroalkyl halides to benzenetethered 1,7-enynes, leading to halo-perfluoroalkytated 2,4-dihydronquinolin-2(1H)-ones,51,52 remains unprecedented to date. Likewise, only very limited examples using N-tethered 1,6enynes in this regard, resulting in halo-fluoroalkytated pyrrolidines,53,54 have been disclosed.55,56 For example, Liang and co-workers reported an elegant Pd-catalyzed ATRA of ICF2CO2Et to 1,6-enynes, but the scope of the fluorinated groups thus introduced seemed to be narrow, and only activated ICF2CO2Et has been employed (eq 2).55 In addition, Xiao and coworkers also reported a Cu/Fe-cocatalyzed ATRA and cyclization of 1,6-enynes with perfluoroalkyl iodides, but such a success is apparently limited to 1,6-enynes with terminal alkynyl moiety (eq 3).56 Therefore, an efficient, general and expedient ATRA and cyclization of 1,n-enynes (n = 6,7) including benzene-tethered 1,7-enynes and N-tethered 1,6-enynes with perfluoroalkyl halides, leading to halo-perfluorinated N-heterocyles, under mild reaction condition is still of high demand.


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a) ATRA reactions of fluoroalkyl halides to alkenes or alkynes by a 1,2-addition pattern

R-X

transition metal or photocatalyst

R1

+

X R1 1,2-addition

alkenes or alkynes

fluoroalkyl halides

(1)

R

b) Pd-catalyzed ATRA of N-tethered 1,6-enynes with ICF2CO2Et55 R3 TsN ICF2CO2Et

Pd/DPE-Phos 50 oC

(limited )

I

4

R

R3

TsN CF2CO2Et

(2)

CF 2CO2Et

R4

c) Cu/Fe-cocatalyzed cyclization of N-tethered 1,6-enynes with perfluoroalkyl iodides56 I H TsN

R4

+ I-CF2(CF2)nCF3

CuBr2/FeBr2

(n = 1,2 or 3)

H

TsN

Zn. HOAc

(3)

CF2(CF2)nCF3

4

R

(limited to terminal alkynes) d) This work: Visible-light-induced ATRA of 1,n-enynes (n = 6, 7) with perfluoroalkyl halides m

R 2

Rf

X

(X = I, Br) (wide scope)

cat. (1 mol %) visible light

R Rf + X

R1 O

X

N

R1 3

R rt (m = 0, 1)

(4)

m

R N R2

R3 Rf O

Rf -X = CF3I, CF3CH2I, n/ i-C3F7I, n-C4F9I, n-C6F13I, n-C8F17I, BrCF2CO2Et, BrCF2Br, BrCCl3, etc.

Scheme 1. ATRA and cyclization of perfluoroalkyl halides with 1,n-enynes (n = 6,7). In the past few years, visible-light photoredox catalysis has been developed as an ecofriendly and highly efficient strategy with the advantages of convenience, availability and safety.57-61 In light of the excellent reductive ability of a photocatalyst in the excited state under mild conditions, photosensitized methods for the generation of perfluorinated radicals from inexpensive and diverse perfluoroalkyl halides are feasible and efficient means for ATRA-type reactions.62 In general perfluoroalkyl iodides or bromides were commercially available, and much less expensive than other frequently-encountered perfluoroalkylating reagents (e.g., Togni’s reagents and RfSO2Cl) on large scale.63-70 With our long-standing interest in the difunctionalization of alkenes using perfluoroalkyl halides,71-74

we herein demonstrated a


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visible-light-induced ATRA and cyclization of benzene-tethered 1,7-enynes or N-tethered 1,6enynes with perfluoroalkyl halides, which realize the concomitant formation of C-Rf and C-X (X = I, Br) bond under mild conditions, leading to 2,4-dihydronquinolin-2(1H)-ones and pyrrolidines bearing a wide variety of perfluorinated groups such as CF3, CF2Br, C3F7, C4F9, C6F13, C8F17, C10F21, CF2CO2Et and etc (eq 4). RESULTS AND DISCUSSIONS At the outset, the ATRA and cyclization reaction between benzene-tethered 1,7-enyne 1a and perfluorobutyl iodide 2a was employed as a model reaction to explore optimal conditions (Table 1). After screening various reaction parameters (for detail, see ESI), we found that the reaction of 1a (0.3 mmol) with perfluorobutyl iodide 2a (0.6 mmol) in the presence of fac-Ir(ppy)3 (1 mol%), K3PO4 (0.6 mmol) in 1,4-dioxane at room temperature for 24 h gave desired product 3aa in a 81 % yield with completely stereoselectivity (E only). Meanwhile the (E)-configuration of the product 3aa thus obtained was unambiguously confirmed by X-ray crystallographic analysis (Figure 1).75 A series of control experiments indicated that the photocatalysts were critical in the cyclization. Several typical Ir/Ru photocatalysts such as [Ir(dtppy)(ppy)2]PF614,18 and Ru(bpy)3Cl2,14,60,64 as well as organic photocatalysts Eosin Y76-79 and PTH (10phenylphenothiazine)80 instead of fac-Ir(ppy)3,16,57 cannot give better results. Sequential screening of solvents, such as THF, toluene, DMF and CH3CN, revealed that 1,4-dioxane remains as the best choice (entries 6 and 7). The use of base (including inorganic or organic ones) seems to be beneficial for the 6-exo-dig cyclization, and the K3PO4 was observed to be the most efficient. We speculated that K3PO4 could be helpful for the homolytic cleavage of C4F9-I to produce C4F9 radical,22 as discussed in the mechanism section (entries 8-12). In the control


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experiments, the ATRA and cyclization reaction is observed to be seriously suppressed with the removal of the photocatalyst or light irradiation (entries 13 and 14). Table 1. Optimization of reaction conditions for 3aaa I Ph O N 1a

Entry

I-CF2(CF2)2CF3 (2a) f ac-Ir(ppy)3 (1 mol %) K3PO4 (2 equiv.) dioxane, 5 W LED, rt, 24h

Ph

N

Variation from the standard conditions

CF2(CF2)2CF3

3aa O

Yield of 3aa (%)b

1

none

81 (E only)c

2

[Ir(dtppy)(ppy)2]PF6

48

3

Ru(bpy)3Cl2

56

4

Eosin Y

Visible-Light-Induced Atom Transfer Radical Addition and Cyclization

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