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Redox-Neutral #-Arylation of Alkylnitriles With Aryl Sulfoxides: A Rapid Electrophilic Rearrangement Li Shang, Yonghui Chang, Fan Luo, Jia-Ni He, Xin Huang, Lei Zhang, Lichun Kong, Kaixiao Li, and Bo Peng J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on February 28, 2017
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Journal of the American Chemical Society
Redox-Neutral α-Arylation of Alkylnitriles With Aryl Sulfoxides: A Rapid Electrophilic Rearrangement Li Shang†,‡, Yonghui Chang#,‡, Fan Luo†, Jia-Ni He†, Xin Huang†, Lei Zhang†, Lichun Kong†, Kaixiao Li† and Bo Peng†,§,* †
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China #College of Chemistry and Chemical Engineering, Hainan Normal University, 99 Longkunnan Road, Haikou, 571158, China § State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China ABSTRACT: A facile α-arylation of nitriles has been developed by simply introducing Tf2O and DABCO to the mixture of nitriles and aryl sulfoxides. The transformation consists of two sequential steps: (i) Tf2O-initiated electrophilic assembling; and (ii) DABCO-triggered rearrangement. Each step can be tuned independently by temperature and/or base change. This adjustability renders the method to accommodate a wide range of substrates. Notable features of this new protocol include remarkable efficiency (20 min, -30 ℃), exclusive regioselectivity and high functional group compatibility, which can be challenging issues faced by traditional approaches. NMR studies not only identified a unique, highly unstable sulfonium imine complex but also demonstrated the importance of temperature in the formation and manipulation of this key intermediate. Further DFT calculations suggested that an electrophilic assembling, followed by removal of HOTf (by base) and finally, [3,3]-sigmatropic rearrangement are three key stages in the reaction. The versatile transformability of the products and easy scalability of this reaction are also exhibited here.
■ INTRODUCTION α-Aryl nitriles are desired building blocks with their biological activities1 and appealing synthetic diversities2. They can be readily converted into other valuable functionalities such as α-aryl carboxylic acids and amides by hydrolysis2a, α-aryl aldehydes and β-aryl amines by reduction2b,2c, and α-aryl ketones by nucleophilic addition2d. They are also crucial precursors for the synthesis of N-heterocycles3. Therefore, methods of constructing α-aryl nitriles have received great attention from synthetic community. Commonly used methods for preparing α-aryl nitriles include cyanation of benzylic halides or alcohols4, Friedel-Crafts reactions5, and dehydration of amides6. However, the use of toxic cyanide, limited functional group tolerance, and challenges in the synthesis of substrates have restricted these strategies. Based on the nature of substrates, other well studied protocols accessing α-aryl nitriles can be mainly condensed into two reaction modes: (i) reactions of nucleophilic nitrile anions with aryl electrophiles7 and (ii) reactions between electrophilic nitriles and aryl nucleophiles8. Among them, the cross coupling of unactivated nitriles with aryl halides appears to be a superior and more practical strategy due to the easy accessible substrates and broad substrate scope7a-d (Scheme 1a). However, strong bases required in the reaction for generating nitrile anions from weakly acidic nitriles, frequently result in the issue of functional group tolerance (Scheme 1a). To avoid the use of strong bases, Hartwig7g, Liu9a, Kwong9b turned their attentions to activated nitrile sources such as α-silyl nitriles, α-zinc nitriles, or cyanoacetate salts. However, the extra preparation of nitrile substrates decreases the step efficiency of the reaction. Although significant progress has been made in this area, direct α-arylation of unactivated nitriles presenting high functional group tolerance is still a great deal of challenge. Here we present the development of a facile α-arylation of unacti-
Scheme 1. a) Traditional α-arylation of unactivated nitriles. b) This work: electrophile/mild base promoted αarylation of unactivated nitriles
Scheme 2. Unexpected α-arylation of acetonitirle
vated nitirles with aryl sulfoxides by using an electrophile and a mild base as promoters, in which excellent chemo- and regi oselectivities are exhibited (Scheme 1b).10-12
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Journal of the American Chemical Society Table 1. Optimization of reaction conditions
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O S
Ph
n-Pr H
H 1a (0.5 mmol)
entry
N
Tf2O (X eq.) base (2.0 eq.) T (°C), 10 min T (°C), 10 min DCM (0.17 M)
2b (X eq.)
base
T (℃)
X (equiv)
O S N
H 1a
H 2b
Ph S
Tf2 O CD 2Cl2 -30 °C 20 min
OTf N
(1) OTf
n-Pr 6ab
n-Pr 5ab
obser ved by NMR a
yield (%)
N,N-dimethylaniline
0
1.0
30
2
N,N-dimethylaniline
-30
1.0
62
b,c
none
-30 to 25
1.0
0
c
4
DBU
-30
1.0
28
5
pyridine
-30
1.0
54
6
2-bromopyridine
-30
1.0
0
7
c
n-Pr
SPh
1
3
Ph
N
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2,6-dimethylpyridine
-30
1.0
54
c
8
DMAP
-30
1.0
0
9c
K2CO3
-30
1.0
0
10
4-methylmorpholine
-30
1.0
64
11
iPr2EtN
-30
1.0
62
12
DABCO
-30
1.0
70
13c
DABCO
-60
1.0
