Subscriber access provided by UNIV OF LOUISIANA
Article
Visible-Light-Mediated Decarboxylative Benzylation of Imines with Arylacetic Acids Jing Guo, Wu Qiaolei, Ying Xie, Jiang Weng, and Gui Lu J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2018 Downloaded from http://pubs.acs.org on September 21, 2018
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
Visible-Light-Mediated Decarboxylative Benzylation of Imines with Arylacetic Acids Jing Guo, Qiao-Lei Wu, Ying Xie, Jiang Weng,* Gui Lu* Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
ABSTRACT: A straightforward method for the visible-light-mediated decarboxylative benzylation of imines is reported. The key feature of this method is the use of simple primary, secondary and tertiary arylacetic acids as precursors of benzyl radicals, enabling the facile benzylation of a variety of imines under mild conditions. A variety of structurally diverse β-arylethylamines (37 examples) have been accessed using this method.
1
ACS Paragon Plus Environment
The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
INTRODUCTION In the past decade, photoredox catalysis is emerging as an important method in modern synthetic chemistry.1 In this context, it is essential to explore new strategies and reagents for generation of radicals. Recently, radical decarboxylation is known to be an efficient strategy for functionalization of carboxylic acids and derivatives through generating radical species. A wide range of carbon-centered radicals including α-amino, α-oxy, and simple alkyl radicals can be accessed using this strategy.2 However, to our surprise, the direct formation of benzylic radical via visible-light-induced decarboxylation of arylacetic acids has less been investigated.3 Nishibayashi3a and Tunge3b described the visible-light-mediated decarboxylative radical addition and allylation of arylacetic acids, respectively. Note that only phenylacetic acids bearing para-amino groups can undergo the photocatalytic decarboxylation process to generate the benzylic radical. Ravelli and coworkers recently developed the decarboxylative benzylic radical addition of simple arylacetic acids to olefins.3c However, the substrate scope was limited to highly electron-deficient and easily reducible olefins. Alternatively, a series of novel benzylic radical precursors including benzylic trifluoroborates,4 silanes,5 ethers,6 1,4-dihydropyridines (DHP)7 and active esters8 have been elegantly developed (Figure 1). Despite these advances, direct conversion of simple arylacetic acids into benzyl radicals is undoubtedly one of the most straightforward strategies for benzylic functionalization.
Figure 1 Precursors of benzylic radicals Amines are perhaps the most important class of compounds in a wide variety of natural and unnatural compounds.9 The highly pronounced biological activities of amine-containing compounds have made them attractive synthetic targets in medicinal chemistry.10 Imines are one of the most important precursors for the synthesis of amine. Classical strategies depend on organometal reagents or radical-based methods to realize efficient alkylation of imines (Scheme 1a).11 In recent years, photoredox-catalyzed radical alkylation of imines has emerged as a complementary approach for the sustainable synthesis of amines. However, less attention has been devoted to benzylation of imine (Scheme 1b), albeit the resulting β-arylethylamine is a widespread structural moiety in nature. MacMillan et al. pioneered the photoredox-catalyzed coupling of imines with benzylic ethers via α-oxy benzyl radicals.6 Molander et al. used benzyl bis(catecholato)silicates to enable SET processes to form benzyl radical species that can react with imine radical anions to generate β-phenylethylamine.12 Yu et al. reported the radical benzylation of imines with benzyl 1,4-dihydropyridines (DHP) co-catalyzed by photocatalyst and Brønsted acid under visible light irradiation.13 Although these photocatalyzed methods could furnish various benzylated amines, their success relies on the introduction of α-heteroatom-stabilized radicals, the use of organosilicon reagents or Hantzsch esters. In this work, we envisioned that simple 2
ACS Paragon Plus Environment
Page 2 of 19
Page 3 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
arylacetic acids might also facilitate the direct benzylation of imine via the coupling between imine radical anions A and benzylic radicals B under photoredox catalysis (Scheme 1c). Classical approaches f or alkylation of imines R3 [M] N
nucleophilc addition
PG
HN
PG
(a) R1 R3 R2 R3 LG radical-based methods ------------------------------------------------------------------------------------------------------------------Previous work: Photocatalytic benzylation of imines with different Bn radical precursors R1
R2
N Ar1
Ar2 OMe photocatalyst, hv R
PG
HN
2
Ar [Si] photocatalyst, hv R
H
PG Ar2
Ar1
(b)
R
Ar2 DHP photocatalyst, hv ------------------------------------------------------------------------------------------------------------------This work: Photocatalytic decarboxylative benzylation of imines with arylacetic acids N
PG
R +
Ar
1
H
Ar2
CO2H
photocatalyst base blue LEDs, rt
HN
PG Ar2
Ar1
(c)
R
reduction Photoredox oxidation Cycle
N Ar1
PG H A
Scheme 1
+
i) radical-radical coupling
Ar2
R
ii) + H+
B
Synthetic strategies for alkylation of imines
RESULTS AND DISCUSSION Initially, this decarboxylative alkylation reaction was performed with N-Ts aldimine (1a) and 2-(4-methoxyphenyl)acetic acid (2a) as model substrates in the presence of 2 mol% 4CzIPN (1,2,3,5-tetrakis(carbazolyl)-4,6-dicyanobenzene, E1/2red = +1.35 V vs SCE in MeCN)14 as photocatalyst and 2 equiv. of Ca(OH)2 as base. As expected, the reaction did proceed under the irradiation of two 12 W Blue LED bulbs, providing the desired product 3a in modest yield (Table 1 entry 1). Given the successful implementation of Ir(III) and Ru(II) photocatalysts in previous decarboxylative functionalizations, Ir[dF(CF3)ppy]2(bpy)PF6 (E1/2red = +1.32 V vs SCE in MeCN)2 and [Ru(bpy)3]Cl2 (E1/2red = +0.77 V vs SCE in MeCN)15 were used to promote this single electron transformation.16 To our delight, when Ir[dF(CF3)ppy]2(bpy)PF6 was employed, a higher yield was obtained (Table 1 entries 2-3). Moreover, eosin Y, a catalyst that exhibits a lower oxidizing excited state than Ir[dF(CF3)ppy]2(bpy)PF6 (E1/2red = +0.83 V vs SCE in 1:1 MeCN/H2O )17 did not promote the desired coupling between aldimine 1a and arylacetic acid 2a. In order to improve the yield, a variety of inorganic and organic bases, such as K2CO3, Li2CO3, NaOAc, Cs2CO3, KOH, NaOH, K2HPO4, KH2PO4, DBU, Et3N and pyridine were examined (Table 1 entries 5-15). Significant improvement was observed when the reaction was performed with K2HPO4 as base, 3
ACS Paragon Plus Environment
The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 19
while organic bases could not promote the reaction (Table 1 entries 13-15). Encouraged by this promising result, we conducted further investigations on the effect of reaction media, including polar solvent (DMF, THF, DMSO and DCM) and nonpolar solvent (toluene). However, MeCN remained the best choice and yielded the best result (Table 1 entries 16-20). Increasing the reaction time and performing the reaction under 18 W blue LEDs resulted in lower yields (Table 1 entries 21-22). The control experiments revealed that photocatalyst, base and light irradiation are essential for the success of this transformation (Table 1 entries 23-25). Table 1 Optimization of the reaction conditionsa
Entry Photocatalyst 1 2 3c 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21d
A B C D B B B B B B B B B B B B B B B B B
Base
Solvent
Yield (%)b
Ca(OH)2 Ca(OH)2 Ca(OH)2 Ca(OH)2 K2CO3 Li2CO3 NaOAc Cs2CO3 KOH NaOH K2HPO4 KH2PO4 DBU Et3N pyridine K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4 K2HPO4
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN DMF THF DMSO DCM toluene MeCN
45 50 15 0 62 64 55 45 35 39 80 52 trace trace trace 23 78
