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Cite This: J. Org. Chem. 2018, 83, 12305−12314
Accessing α‑Arylated Nitriles via BF3·OEt2 Catalyzed Cyanation of para-Quinone Methides Using tert-Butyl Isocyanide as a Cyanide Source Sachin R. Shirsath,†,‡ Ganesh H. Shinde,† Aslam C. Shaikh,† and M. Muthukrishnan*,†,‡ †
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
‡
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ABSTRACT: BF3·OEt2 catalyzed 1,6-conjugate addition of tertbutyl isocyanide to para-quinone methides and fuchsones for the synthesis of α-diaryl and α-triaryl nitriles has been reported. This protocol allows α-diaryl- and α-triaryl nitriles to be accessed in good to excellent yields and with a broad substrate scope, which could be further functionalized to give a versatile set of products. This is the first example wherein tert-butyl isocyanide has been used as a cyanide source for the 1,6-conjugate addition.
T
toxic cyanide sources, etc. Therefore, the development of a robust strategy for the synthesis of diverse functional-grouprich α-aryl nitriles is highly desirable. In recent years, the p-quinone methides (p-QMs) have attracted a great deal of attention among the synthetic community due to its unique reactivity and its ability to make complex architectures that are found in several pharmaceuticals and natural products.10 The p-QMs have the ability to undergo several reaction modes that involve mainly 1,6-conjugate additions,11 [4 + 2]-annulations,12 [3 + 2]annulations,13 and [2 + 1]-annulations.14 Very recently, p-QMs have been successfully utilized for the synthesis of α-diaryl and α-triaryl nitriles wherein the reaction relied upon the usage of TMSCN as a cyanide source and the NHC-catalyst for the activation of TMSCN.15 As part of our continuing interest in the synthesis of natural products like small molecules for various biological applications,16 we encountered a need for an efficient methodology for the synthesis of α-arylated nitriles. With regard to practicality, we chose to explore tert-butyl isocyanide as an alternate cyanide source, avoiding the use of toxic cyanides for the 1,6-conjugate addition reaction of pQM.17 Importantly, in recent years tert-butyl isocyanide has been efficiently utilized as an alternative “CN” source.18 Hence, in the present manuscript we describe the amenability of tertbutyl isocyanide as a source of cyanide for the successful preparation of α-diaryl and α-triaryl nitriles from p-QMs. To the best of our knowledge, this is the first example where tertbutyl isocyanide has been used as a cyanide source for the 1,6conjugate addition. We began our optimization studies with p-quinone methide 1a, which contains removable t-Bu groups at the ortho
he synthesis of nitrile-containing organic frameworks, in particular α-arylated nitrile compounds, is of great importance, as these structures exist in several natural products, a vast range of functional molecules relevant to pharmaceuticals, agrochemicals, and functional materials (Figure 1).1 For instance, more than 30 nitrile-containing
Figure 1. Representative biologically important α-arylated nitriles.
drugs have been approved for the treatment of depression, breast cancer, and Parkinson’s disease, while 20 more are in clinical trials.2 On the other hand, they are valuable precursors in organic synthesis for the preparation of carboxylic acids, amides, aldehydes, ketones, amidines, amines, N-containing heterocycles, etc.3 or as directing groups for remote C−H activation through weak coordination.4 Consequently, several synthetic approaches toward the synthesis of α-arylated nitriles have been explored and that mainly involves nucleophilic substitution of a benzylic halide,5 dehydration of aldoximes/ amides,6 addition of cyanide to diarylcarbinols,7 coupling reactions of nitriles with aryl halides,8 and others.9 However, most of these methods suffer from drawbacks such as harsh reaction conditions, expensive catalysts, usage of notorious © 2018 American Chemical Society
Received: July 27, 2018 Published: September 11, 2018 12305
DOI: 10.1021/acs.joc.8b01926 J. Org. Chem. 2018, 83, 12305−12314
Note
The Journal of Organic Chemistry
yields. Both electron-donating (R = −Me, −OMe, −NMe2) and electron-withdrawing groups (R = −CN, −NO2) at the para, ortho or meta positions of the benzene rings were well tolerated, offering the desired products in good to excellent yields (3a−3p). The halo-substituted p-QMs were also well tolerated to yield the desired product in moderate to good yields. Furthermore, disubstitution on the benzene ring of pQMs was also found to be suitable, and the corresponding products (3q−3s) were isolated under the optimal conditions. Interestingly, p-QM (1t) derived from the chromone-3carboxaldehyde also works well to result in the desired cyano-addition product 3t in 48% yield. Heterocyclic substituted p-QMs, like furan and thiophene, were also amenable to this protocol and generated the corresponding cyano products in good yields (65 and 77%, 3u−3v). However, pyridyl ring bearing p-QM failed to afford the desired product (3w). Notably, the sterically hindered naphthyl, anthracenyl, fluorenyl, and biphenyl substituted pQMs were also susceptible in this process to furnish the desired cyano-product (3x−3aa) in good yields (79−84%). It is noteworthy to mention here that an alkyne group tethered pQM was also well tolerated under optimized reaction conditions to afford the desired product (3ab) in good yield (80%). Additionally, p-QM (1ac) bearing two isopropyl groups at the ortho position was also well tolerated, to afford the product 3ac in 78% yield. Next, we examined the scope of this cyanation reaction with respect to fuchsones as an 1,6-acceptor (Table 3). Interestingly, fuchsones were also underwent 1,6- conjugate addition reaction efficiently with tert-butyl isocyanide under the optimized reaction conditions to produce α-triaryl nitriles in excellent yields. It should be noted that, in general the synthesis of α-triaryl nitriles requires multistep processes and often difficult to access these compounds due to steric constraints.8a Fuchsones possessing both electron-donating (−Me, −OMe) (5b−5c), halo-substituted (−F, −Cl) (5d− 5f), and electron-withdrawing group (−CF3) (5g) were well tolerated to afford the desired α-triaryl nitriles. Fuchsones bearing electron-donating groups at the para positions showed higher reactivity than those bearing electron-withdrawing groups. Other fuchsones derived from 2,6-diisopropylphenol (4h) and 2,6-dimethylphenol (4i) also underwent a smooth transformation to their corresponding α-triaryl nitriles 5h and 5i in 90% and 91% yields, respectively. Based on the previous report,19 a plausible reaction mechanism for this transformation is depicted in Scheme 1. The p-QMs were activated by Lewis acid BF3·Et2O, leading to the formation of a highly electrophilic methylenic carbon. Subsequent nucleophilic attack by tert-butyl isocyanide 2 formed zwitterionic nitrilium ion intermediate A. The nitrilium ion A undergoes a loss of isobutylene, resulting in the formation of the desired 1,6-conjugate addition product.
positions and tert-butyl isocyanide 2 as a source of cyanide under variable reaction conditions (Table 1). An initial Table 1. Optimization of Reaction Conditionsa
entry
cat.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Sc(OTf)3 Bi(OTf)3 BF3·OEt2 Yb(OTf)3 TiCl4 InCl3 Cu(OTf)2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 −
t
Bu−NC (equiv)
solvent
yield (%) 3a
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.3 1.3 1.3 1.3 1.5 1.3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF Et2O CH3CN DMSO CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
36 42 64
