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Synthesis of alpha,beta-Unsaturated N-Aryl Ketonitrones from Oximes and Diaryliodonium Salts: Observation of A Metal Free N-Arylation Process Xiao-Pan Ma, Wei-Min Shi, Xue-Ling Mo, Xiao-Hua Li, LiangGui Li, Cheng-Xue Pan, Bo Chen, Gui-Fa Su, and Dong-Liang Mo J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Sep 2015 Downloaded from http://pubs.acs.org on September 26, 2015
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The Journal of Organic Chemistry
Synthesis of α,β-Unsaturated N-Aryl Ketonitrones from Oximes and Diaryliodonium Salts: Observation of A Metal Free N-Arylation Process Xiao-Pan Ma,a Wei-Min Shi,a Xue-Ling Mo,a Xiao-Hua Li,a Liang-Gui Li,a Cheng-Xue Pan, a Bo Chen,*b Gui-Fa Su*a and Dong-Liang Mo*a a
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Education of China; School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China. b
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY
14853, United State.
E-mail:
[email protected];
[email protected];
[email protected] HO
Ar 3
N
R1
R2
KOH/CCl 4
Ar3 I OTf Ar 4
+
RT
N
R1
O R2
Ph I O
vs R2
N-arylation
I
O N
N R1
Ph
Ph Ph
R
1
R2
Transition-metal free Mild conditions Gram scale 30 examples up to 88 % yields
O-arylation
ABSTRACT: An efficient transition-metal free method for the preparation of α,β-unsaturated N-aryl ketonitrones under mild conditions has been developed. This reaction shows good functional group tolerance for both electron-rich and electron-deficient substituents on both oximes and diaryliodonium salts. Two examples of gram scale preparations have been realized in good yields. Further transformations of these nitrones to different N-heterocycles have been demonstrated. DFT calculations suggest that N-arylation products are formed by [1,3]-phenyl
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migration of an O-coordinated oximate complex via a four-centered transition state while the O-arylation products are formed by [1,3]-phenyl migration of a N-coordinated oximate complex. INTRODUCTION Oximes, owing to their ability to act as ambident nucleophiles (O- or N-nucleophiles), have been extensively utilized as important starting materials to construct key building blocks in organic synthesis.1,2 Arylation of the N-O bond is one of the most important transformations of oximes. O-Arylations have been used to build aryloxyamines, which are important precursors of O-aryloximes or benzofurans, while N-arylations have been employed to prepare oxyarylamines.3 In the past, efficient O-arylations of oximes have been achieved by transition-metal catalyzed cross-coupling reactions of oximes with aryl halides or aryl boronic acids.4,5 For example, Maitra and Wailes reported the coupling of oximes with aryl iodides catalyzed by a CuI/1,10-phenanthroline catalyst system.4a In 2010, Buchwald developed an efficient Pd catalyst for the O-arylation of ethyl acetohydroximate with aryl chlorides, bromides, and iodides to prepare O-arylhydroxyamines and substituted benzofurans (Scheme 1-A).4b In addition, both Huang and Meyer have reported the copper-mediated coupling of oximes with arylboronic acids to form O-arylation products (Scheme 1-A).5 More recently, Anderson and coworkers found that α,β-unsaturated N-aryl ketonitrones can be generated by copper-mediated N-arylation of chalcone oximes with arylboronic acids in good yields (Scheme 1-B).6 Despite the efficiencies of these metal catalyzed or mediated arylations of oximes, these methods
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The Journal of Organic Chemistry
suffer from several drawbacks such as harsh conditions, prolonged reaction times, the requirement of complex ligands, and trace-metal impurities remaining in the products. To overcome the aforementioned drawbacks, recent emphasis has been placed on the development of metal free methods for O-arylation or N-arylation of oximes using diaryliodonium salts as arylation reagents.7 Diaryliodonium salts are readily availabile reagents that exhibit high-reactivity and selectivity, good tolerance of a wide range of functional groups, and are considered to be non-toxic in many areas of organic synthesis.8 Very recently, Kürti and Olofsson independently developed metal-free methods for the O-arylation of oximes with diaryliodonium salts to access O-arylhydroxylamines for synthesis of benzofuran scaffolds (Scheme 1-C).7b,c In contrast to the work of Kürti and Olofsson, herein we report, a metal-free N-arylation of oximes with diaryliodonium salts to produce α,β-unsaturated N-aryl ketonitrones (Scheme 1-D). Due to their rich chemistry resulting from the inclusion of the conjugated double bond moiety in nitrone, α,β-unsaturated N-aryl ketonitrones have recently gained much attention as key building blocks in the synthesis of highly complex molecules.9 Traditional methods for the preparation of nitrones, such as the condensation of a hydroxylamine with a carbonyl compound10 or oxidation of a secondary hydroxylamine,11 are inefficient in making α,β-unsaturated N-aryl ketonitrones because of the low nucleophilicity of N-aryl hydroxylamines and side reactions such as oxidation of the double bond. The reported method in this article represents an advance in synthesizing α,β-unsaturated N-aryl ketonitrones.12
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A) Pd or Cu-catalyzed cross-coupling O-arylation of oximes [Pd] or [Cu] OH
N R1
ArX
N
R2
R 1 = OEt, R2 = Me or R 1 = Aryl, R 2 = Alkyl
R1
[Cu]/O 2
ArONH2
O Ar
R3 R2
R1 O
ArB(OH) 2
B) Cu-mediated cross-coupling N-arylation of oximes HO
Ar
N
Ar 1
+
Ar2
N
Cu(OAc)2 (2.0 equiv.)
ArB(OH) 2
Pyridine (10.0 equiv.), DCE, in air
O
Ar 1
Ar2
30-70% yields C) Metal-free O-arylation of oximes N R1
OH R2
+
N
base
Ar 3Ar 4IOTf
R1
Ar 3ONH 2
O Ar3
R3 R2 R1
R 1 = OEt, R2 = Me or R 1 = Aryl, R 2 = Alkyl
O
D) This work : metal-free N-arylation of oximes HO
Ar 3
N
R
Ar2
+
3
4
Ar Ar IOTf
base
R = aryl, vinyl, heterocycle
N
O
R
Ar2
31-88% yields
Scheme 1 Arylation Strategies of Oximes RESULTS and DISCUSSION Our investigation began with the reaction of different types of oximes 1 with diphenyliodonium triflate 2a. These transformations were carried out with potassium tert-butoxide in DMF at ambient temperature (Scheme 2). When ethyl acetohydroximate and acetophenone oxime were combined under the reaction conditions only O-arylation products were isolated in good yields, and
