Synthesis and Wittig Rearrangement of 3-and 4-Benzyloxyphenylphosphonamidates

Synthesis and


Introduction
The [1,2]-Wittig rearrangement of aryl benzyl ethers 1 to give diarylmethanols 2 (Scheme 1) provides a potentially valuable indirect method for C-C bond formation but, although the reaction is well known [1,2], it has not found much recent synthetic use [3], perhaps owing to the strongly basic conditions required which make it incompatible with many common functional groups. In recent studies, we have described the use of activating groups on the aryl ring to promote the Wittig rearrangement under milder conditions. The first such activating group to be discovered was the 4,4-dimethyl-2-oxazoline [4], although when this was in the ortho position to the benzyloxy group as in 3, there was significant competition from direct cyclisation to give benzofuran products 4, a phenomenon also later observed in benzyloxythienyloxazolines [5]. In the meantime, we developed the N-butylcarboxamide, CONHBu as a more effective and general activating group, facilitating Wittig rearrangement of ortho-, meta-, or para-disposed benzylic ethers 5 to give diarylmethanols 6 [6]. Limited success in using a chiral secondary amide group to direct asymmetric Wittig rearrangement was also reported [7].
Organics 2023, 4, FOR PEER REVIEW 2 Scheme 1. General strategy for indirect C-C bond formation via ether formation and Wittig rearrangement and previous examples [4,6].
In this paper, we describe the synthesis of aryl benzyl ethers bearing the phosphonamidate group, EtO-P(=O)-NHBu on the aryl ring, either para-or meta-to a benzylic ether, and their successful Wittig rearrangement to afford the corresponding phosphonamidatefunctionalised diarylmethanols. Scheme 1. General strategy for indirect C-C bond formation via ether formation and Wittig rearrangement and previous examples [4,6]. 60 In this paper, we describe the synthesis of aryl benzyl ethers bearing the phosphonamidate group, EtO-P(=O)-NHBu on the aryl ring, either paraor metato a benzylic ether, and their successful Wittig rearrangement to afford the corresponding phosphonamidatefunctionalised diarylmethanols.

General Experimental Details
NMR spectra were recorded on solutions in CDCl 3 unless otherwise stated using Bruker instruments and chemical shifts are given in ppm to high frequency from Me 4 Si with coupling constants J in Hz. IR spectra were recorded using the ATR technique on a Shimadzu IRAffinity 1S instrument. The ionisation method used for high-resolution mass spectra is noted in each case. Column chromatography was carried out using silica gel of 40-63 µm particle size and preparative TLC was carried out using 1.0 mm layers of Merck alumina 60 G containing 0.5% Woelm fluorescent green indicator on glass plates. Melting points were recorded on a Gallenkamp 50 W melting point apparatus or a Reichert hot-stage microscope.

Results and Discussion
Starting from 4-bromophenol, the known benzyl ether 7 was prepared in essentially quantitative yield (Scheme 2). The phosphonate functionality was installed by the nickelcatalysed Michaelis-Arbuzov-type reaction with triethyl phosphite introduced by Tavs [10]. We found that to obtain a good yield of product 8, it was essential to use anhydrous nickel(II) chloride. The diethyl phosphonate 8 was treated with phosphorus pentachloride in toluene to afford 9 which reacted directly with two equivalents of butylamine giving phosphonamidate 10.
The Wittig rearrangement of compound 10 occurred readily on treatment with 3.3 equiv. of n-butyllithium in THF at RT to afford the benzhydrol-4-phosphonamidate 11 in good yield. The process creates a new stereogenic centre but the C and P centres are too far apart to affect one another and only a single set of NMR signals was observed for what is almost inevitably an equal mixture of all four possible diastereomers. Starting from 4-bromophenol, the known benzyl ether 7 was prepared in essentially quantitative yield (Scheme 2). The phosphonate functionality was installed by the nickelcatalysed Michaelis-Arbuzov-type reaction with triethyl phosphite introduced by Tavs [10]. We found that to obtain a good yield of product 8, it was essential to use anhydrous nickel(II) chloride. The diethyl phosphonate 8 was treated with phosphorus pentachloride in toluene to afford 9 which reacted directly with two equivalents of butylamine giving phosphonamidate 10. We now wished to explore the scope of the process for substituted benzyl and other analogous groups and, rather than repeat the four-step synthetic sequence used for 10 with different benzyl halides, we were able to remove the O-benzyl group from 10 in excellent yield using catalytic hydrogenation to give the hydroxyphenylphosphonamidate 12. This was then O-alkylated to give a range of derivatives 13a-e (Scheme 3). The low yield of these after chromatographic purification was disappointing and compound 12 seems to be deactivated towards O-alkylation. In each case, there was a significant amount of unreacted 12 remaining even after overnight reaction and the products partly decomposed during chromatography, resulting in a poor recovery. Despite this, the products were obtained in sufficient quantity for full characterisation and a study of their reactivity. All the phosphonamidates in this paper show 31 P signals in the narrow range δP +22.5-25.6, and the expected phosphorus coupling is observed in the 13 C NMR spectra for all Scheme 2. Stepwise synthesis and Wittig rearrangement of para compound 10.
We now wished to explore the scope of the process for substituted benzyl and other analogous groups and, rather than repeat the four-step synthetic sequence used for 10 with different benzyl halides, we were able to remove the O-benzyl group from 10 in excellent yield using catalytic hydrogenation to give the hydroxyphenylphosphonamidate 12. This was then O-alkylated to give a range of derivatives 13a-e (Scheme 3). The low yield of these after chromatographic purification was disappointing and compound 12 seems to be deactivated towards O-alkylation. In each case, there was a significant amount of unreacted 12 remaining even after overnight reaction and the products partly decomposed during chromatography, resulting in a poor recovery. Despite this, the products were obtained in sufficient quantity for full characterisation and a study of their reactivity. All the phosphonamidates in this paper show 31 P signals in the narrow range δ P +22.5-25.6, and the expected phosphorus coupling is observed in the 13 C NMR spectra for all signals of the phosphorus-bearing benzene ring, both carbons of OEt but interestingly only C-2 of NHBu. When compounds 13a-d were subjected to treatment with butyllithium under the same conditions as for 10, the Wittig rearrangement was again observed and the products 14a-d were obtained in moderate to good yield (Scheme 4). The 3-methylbut-2-enyl ("prenyl") ether 13e did give some indication of forming the rearranged product but this was accompanied by a myriad of other byproducts from which it could not be separated, so we conclude that the process is not likely to be useful for such non-benzylic allyl ethers. This is consistent with the corresponding N-butyl carboxamides 5 where the prenyl ether did rearrange in the para-position, but in low yield [7]. When compounds 13a-d were subjected to treatment with butyllithium under the same conditions as for 10, the Wittig rearrangement was again observed and the products 14a-d were obtained in moderate to good yield (Scheme 4). The 3-methylbut-2-enyl ("prenyl") ether 13e did give some indication of forming the rearranged product but this was accompanied by a myriad of other byproducts from which it could not be separated, so we conclude that the process is not likely to be useful for such non-benzylic allyl ethers. This is consistent with the corresponding N-butyl carboxamides 5 where the prenyl ether did rearrange in the para-position, but in low yield [7]. Scheme 3. Synthesis of phenylphosphonamidates with different substituents at the 4-position.
When compounds 13a-d were subjected to treatment with butyllithium under the same conditions as for 10, the Wittig rearrangement was again observed and the products 14a-d were obtained in moderate to good yield (Scheme 4). The 3-methylbut-2-enyl ("prenyl") ether 13e did give some indication of forming the rearranged product but this was accompanied by a myriad of other byproducts from which it could not be separated, so we conclude that the process is not likely to be useful for such non-benzylic allyl ethers. This is consistent with the corresponding N-butyl carboxamides 5 where the prenyl ether did rearrange in the para-position, but in low yield [7].