A Mild Synthesis of New Aryl Vinyl Ethers and Diethyl 1-[(Alkyl)(cyano)methyl]vinylphosphonates via the Substitution of a 2,3-Difunctional Allyl Bromide

A novel class of aryl vinyl ethers 3 and diethyl 3-cyano-3-alkylprop-1-en-2-ylphosphonates 4 has been prepared, respectively, from coupling reaction of diethyl 1-(bromomethyl)-2-cyanovinylphosphonate 2 with phenols and Gilman reagents.


Introduction
The development of new strategies for the synthesis of organic compounds containing an -bromomethyl group as in product 1 continues to pose a challenge to organic chemists. It has resulted in a wide variety of applications in the preparation of several natural [1][2][3][4] as well as biologically active compounds [5][6][7][8]. Moreover, the utility of these versatile allyl brominated intermediates 1 [9][10][11][12][13][14][15][16][17][18] comes from their reaction with different nucleophilic species and additionally their ability to act as excellent Michael acceptors. Because of its importance, it is still of interest to develop novel approaches for the efficient generation of functionalized allyl bromide 1. In this regard, we have previously described a simple and stereoselective synthesis of diethyl (E)-1-(bromomethyl)-2cyanovinylphosphonate 2 [19], an activated alkene bearing three functional groups. We have also demonstrated that the latter can be used as an efficient electrophilic synthon for the synthesis of a new family of allylamines [19], enamines [20], and vinyl ether [20]. Prompted by the versatility of allyl bromide 2, we suggested that its reaction with a variety of phenols and Gilman reagents would be a very convenient way to prepare new substituted aryl vinyl ethers 3 and diethyl 1-[(alkyl)(cyano)methyl]vinylphosphonates 4 (Scheme 1).

Results and Discussion
Functional aryl vinyl ethers have been shown to be promising building blocks in organic synthesis [21][22][23] as well as important intermediates for the synthesis of a range of products [24][25][26][27][28][29][30][31][32][33], new polymeric materials [34][35][36], and biologically active molecules [37]. Thus, the preparation of these kinds of molecules has always attracted the attention of organic chemists and a growing effort has been directed toward the development of new vinyl ether-based structures and new methods for their construction [38][39][40][41][42][43][44][45][46][47][48][49]. Examination of the synthetic approaches to a wide variety of vinyl ethers has shown serious limitations, such as the use of strong acids or bases, toxic metals, and high temperatures. Therefore, the need to implement new inexpensive and easy methodologies to produce functional vinyl ethers remains attractive. In this context, we expected that the substitution of the bromine atom in molecule 2 by aromatic alcohols as nucleophilic reagents might lead to the desired aryl vinyl ethers 3. Hence, condensation of allyl bromide 2 with phenol (1.0 equiv.) in the presence of potassium carbonate (1.2 equiv.) and in refluxing acetonitrile afforded the corresponding aryl vinyl ether 3a in 92% yield after 15 min. In order to generalize the reaction of allyl bromide 2 with various aromatic alcohols, we examined  a variety of electronically and sterically substituted phenols. As shown in Table 1, the reaction proceeded smoothly regardless of the steric and electronic properties of these different phenols. With few exceptions, the reaction was generally carried out in 15 minutes in good to excellent yields (Scheme 2, Table 1). The formation of vinyl ethers 3a-f is the result of the S N 2 substitution of allyl bromide 2 by different aryloxy groups followed by isomerization. A plausible reaction pathway for the synthesis of these new trisubstituted alkenes 3a-f is shown in Scheme 3.
The structures of 3a-f were established on the basis of their 1 H and 13 C NMR spectra and by heteronuclear multiple bond correlation (HMBC). Their stereochemistry has been assigned on the basis of NOESY experiment. A sample of 3a shows no correlation between the vinylic proton ( : 7.53 ppm) and those of CH 2 CN ( : 3.34 ppm). This result indicates that the vinylic proton and the CH 2 group are on opposite sides of the double bond and therefore the alkene in 3a is E configuration.
This result allowed the consideration of other experimental goals to exploit the electrophilicity of allyl bromide 2 by examining its reactivity with other nucleophilic reagents such as organocuprates. Gilman reagents have been widely used for the construction of organic molecules [50][51][52][53], since their discovery in 1900. They display an excellent reactivity towards a wide range of electrophiles and readily undergo transmetallation to provide a variety of organometallic species as organocopper derivatives which react well with soft electrophiles and display excellent chemoselectivity [54]. As a follow-up of our research in the direct substitution of functionalized allyl bromide by organocuprates reagents [55], diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate 2 constituted the ideal intermediate for the synthesis of new 2cyanoethylphosphonates 4. As shown in Scheme 4, conjugate addition of dialkyl organocuprates, generated in situ at low temperature from Grignard reagents in the presence of LiCuBr 2 , leads to the corresponding Michael acceptors 4 in an S N 2 substitution process. The new vinylphosphonates 4 obtained are summarized in Table 2.

Conclusion
In summary, a practical and efficient synthesis of new substituted aryl vinyl ethers 3 and diethyl 1-[(alkyl)(cyano)methyl] vinylphosphonates 4 has been developed. The application of diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate 2 in other processes will be communicated in due course.

Materials and Instrumentation.
Starting materials and solvents were purchased and used without further purification. 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker AMX 300 spectrometer working at 300 MHz, 121 MHz, and 75 MHz, respectively, for 1 H, 31 P, and 13 C with CDCl 3 as the solvent and TMS as the internal standard. The chemical shifts ( ) and coupling constants (J) are, respectively, expressed in parts per million (ppm) and hertz (Hz). All NMR spectra were acquired at 25 ∘ C. Assignments of proton ( 1 H-NMR) and carbon ( 13 C-NMR) signals were secured by DEPT 135 and HMBC experiments. Multiplicity of peaks is indicated by the following: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; dq, doublet of quartets; hept, heptuplet; m, multiplet. All reactions were monitored by TLC on silica gel plates (Fluka Kieselgel 60 F254, Merck) eluting with the solvents indicated and visualized by a 254 nm UV lamp and aqueous potassium permanganate solution. For column chromatography, Fluka Kieselgel 70-230 mesh was used. The compounds were examined by gas chromatography-mass spectrometry (GC/MS) and spectra were recorded on an Agilent Technologies 6890 N instrument with an Agilent 5973 N mass detector (EI) and an HP5-MS 30 m × 0.25 mm capillary apolar column (stationary Scheme 2: Basic O-vinylation of phenols with allyl bromide 2.

Isomerization NC
Br