In Situ Generation of Formaldehyde and Triphenylphosphine from (Hydroxymethyl)triphenylphosphonium and Its Application in Wittig Olefination

Abstract The reaction of (hydroxymethyl)triphenylphosphonium with benzylic or allylic halide under basic conditions at room temperature affords terminal alkenes in 61–89% yields. In this reaction, both formaldehyde and triphenylphosphine are in situ generated from (hydroxymethyl)triphenylphosphonium and further undergo Wittig olefination with benzylic or allylic halide. GRAPHICAL ABSTRACT


INTRODUCTION
Formaldehyde is a hazardous, self-reactive chemical and is usually in situ generated from either its oligomer (paraformaldehyde) or aqueous solution (formalin). [1] A large excess of paraformaldehyde or formalin is often required to complete a reaction, in particular under basic conditions. For example, in the Wittig olefination of formaldehyde with semistabilized ylides, the molar ratio of formaldehyde to the phosphonium salt is often 5-10 [2][3][4][5] and even greater than 50. [6] Therefore, development of new methods to in situ generate formaldehyde under basic conditions is highly desired. In 2007, Deguest and coworkers reported [7] a novel method to generate formaldehyde in situ using benzotriazolylmethanol or N-hydroxymethyl phtahlimide under basic and anhydrous conditions, as shown in the upper part of Scheme 1. They have applied this method in the hydroxymethylation of organolithium reagents and enolates. They have also employed this method in the Wittig olefination of one semistabilized ylide but the corresponding phosphonium salt needs to be prepared in advance and a strong base (lithium tetramethylpiperidide) is required. Recently, Priede and coworkers also reported [8] that methoxymethanol is a source of formaldehyde in the hydroxymethylation of lithium enamides. Herein, we report an alternative method to generate formaldehyde in situ by treating (hydroxymethyl)phosphonium with K 2 CO 3 , as shown in the bottom part of Scheme 1. Both formaldehyde and the concomitantly released Ph 3 P are utilized to participate in Wittig olefination of benzylic or allylic halides to afford terminal alkenes.

RESULTS AND DISCUSSION
Initially we chose (hydroxymethyl)triphenylphosphonium tetrafluorobrate 1a as a model compound to explore the possibility of the in situ generation of formaldehyde. This salt is a bench-stable solid and readily prepared from triphenylphosphine and paraformaldehyde according to the reported method. [9] It is noteworthy that a 1:1 molar ratio of formaldehyde to triphenylphosphine is used to prepare this salt. To utilize the concomitant release of Ph 3 P during the in situ generation of formaldehyde, we hypothesized that a benzylic or allylic halide would trap it to form the corresponding phosphonium salt, which under basic condition would further react with formaldehyde to form terminal alkene 3, as shown in Scheme 2. Therefore, we chose 2-bromomethylnaphthalene 2a as another model compound to test our hypothesis.
When a mixture of 1a and 2a were treated with K 2 CO 3 in tetrahydrofuran (THF), 2-vinylnaphthalene 3a was obtained in 16% yield ( Table 1, entry 1). After screening solvents including CH 2 Cl 2 , dimethylsulfoxide (DMSO), and CH 3 CN (entries 2-4), CH 3 CN was found to be the best solvent to afford 3a in 87% yield. Replacing 1a with the corresponding iodide 1b and chloride 1c reduced the yield Scheme 1. In situ generation of formaldehyde under basic conditions. of 3a to 38% and 59%, respectively, indicating that the anion might play a key role in the reaction. We have also prepared tricyclohexyl(hydroxymethyl)phosphonium tetrafluoroborate 1d according to the similar method for the preparation of 1a. This salt could also lead to the formation of 3a albeit in a lower yield (53%).
We next examined a variety of benzylic and allylic halides, and the results were summarized in Table 2. For benzylic bromides 2b-d with an electron-donating group at the para-position of aromatic ring, 3b-d were obtained in 73-79% yields (entries 2-4). 1,4-Bis(bromomethyl)benzene 2e underwent diolefination smoothly to give 3e in 69% yield when 2 equiv of 1a was used (entry 5). Allylic halides such as cinnamyl bromide 2f and a-bromomethylstyrene 2 h afforded the corresponding 1,4-dienes in 82% and 61% yields (entries 6 and 8), respectively. Benzylic bromides with an electron-withdrawing group at either ortho-or para-or meta-position of aromatic ring furnished olefination in good yields (81-89%) (entries 9, 10, and 12-18). For cinnamyl chloride 2 g and 4-chlorobenzyl chloride 2k, however, 3f and 3i was obtained in very poor yields (entries 7 and 11), probably because the reaction of Ph 3 P is slower with benzylic or allylic chloride than with the corresponding bromide. By replacing 1a with 1b, the yields of 3f and 3i dramatically increased to 61% and 69%, respectively, possibly due to the chloride-iodide exchange to form benzylic or allylic iodide, which is much more reactive toward Ph 3 P than the corresponding chloride. Attempts to expend this reaction to alkyl halides other than benzylic or allylic halides were unsuccessful.

CONCLUSIONS
In conclusion, we have demonstrated that (hydroxymethyl)triphenylphosphonium salts can be used as a source of both formaldehyde and tiphenylphophine, which can be applied in Wittig olefination of benzylic and allylic halides. This olefination can be carried out under mild conditions and avoid using a large excess of formaldehyde and preparing benzylic or allylic triphenylphosphonium salts.

EXPERIMENTAL
Triphenylphosphine, benzylic, and allylic halides were purchased from a local company and used as received. All melting points were measured on a melting-point apparatus with a microscope and a hot stage and were uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker Avance 400 or 600 NMR spectrometer. Infrared (IR) spectra were recorded on a Thermo Nicolet Avatar 360 IR spectrometer. High-resolution mass spectrographic (HRMS) spectra were recorded on a Varian 7.0 T FTMS. PE denotes petroleum ether, bp 60-90°C. Phosphonium salts 1a, [9] 1b, [10] and 1c [10] were prepared according to the literature procedure.

FUNDING
We thank the National Natural Science Foundation of China for their financial support of our program (Grant No. 21272170).

SUPPORTING INFORMATION
Full experimental details and 1 H and 13 C NMR spectra for this article can be accessed on the publisher's website.