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. 2023 Nov 9;4(1):106–112. doi: 10.1021/acsorginorgau.3c00042

Friedel–Crafts-Type Arylation Strategy for the Conversion of Alkyl 2-((Diphenoxyphosphoryl)oxy)-2-arylacetates to α,α-Diaryl Esters

Kauê C Capellaro 1, Tales A C Goulart 1, Rafael D C Gallo 1, Juliana de S Schenfel 1, Igor D Jurberg 1,*
PMCID: PMC10853917  PMID: 38344018

Abstract

graphic file with name gg3c00042_0008.jpg

An arylation strategy allowing the conversion of alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates to α,α-diaryl esters is reported. This transformation can be promoted by TfOH when the starting organic phosphates do not carry para-alkoxy groups on their aryl rings, but it does not require any additives when such groups are present. These alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates can be readily accessed from the insertion of diphenyl phosphate into aryldiazoacetates.

Keywords: Phosphates, Substitution reactions, Friedel−Crafts, Arylation, O−H Insertion

Phosphates are relatively uncommon leaving groups employed in transformations performed in a synthetic organic chemistry laboratory when compared to halides or sulfonates, which are well-established text-book benchmarks. This is a counterintuitive observation, as chemists are often inspired by nature;1 and phosphates are arguably found involved in numerous biological processes.2 A plausible explanation for this difference between human-based work versus naturally selected processes can derive from the chemical tools available and constraints imposed by reaction media. Organic chemists typically do not use enzyme-catalyzed reactions; and consequently, generally require the employment of reasonably reactive alkyl halides or sulfonates for their transformations performed in organic solvents. On the other hand, biochemical conditions generally use highly reactive and specific enzyme catalysts for reactions performed in aqueous media, which can compensate for the involvement of more stable phosphate compounds. Furthermore, alkyl halides or sulfonates are generally not tolerated in aqueous media because they tend to hydrolyze more rapidly. They are also more toxic, possibly leading to the alkylation and destruction of essential metabolites and enzymes.2

Concerning the somehow limited number of chemical transformations describing the use of phosphates as leaving groups in organic synthesis, representative reactions have been reported based on the use of catalytic or stoichiometric promoters. For instance, arylation strategies of allyl phosphates have been reported employing Cu3 and Ni4 catalysts (Scheme 1a); while benzyl phosphates have been arylated using Pd-catalyzed5,6 strategies (Schemes 1b and c). Propargyl phosphates could be also arylated via Cu-based catalysis to produce either propargyl-7 or allenyl-arenes8 (Scheme 1d). On the other hand, representative substitution strategies involving different benzyl phosphates and arenes have been promoted using catalytic amounts of Fe(OTf)39 (Scheme 1e), TfOH10 (Scheme 1f), and BF3.OEt2 or ZnCl211 (Scheme 1g).12

Scheme 1. Representative Arylation Methods Using Different Organic Phosphates as Reacting Partners.

Scheme 1

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In this context, we became interested in evaluating the arylation of alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates as a potentially valuable new C–C bond-forming method while at the same time also reinforcing the ability of phosphates to be employed as competent leaving groups in substitution reactions. Furthermore, the selectivity of this method is also an interesting aspect to be considered in regard to other previous strategies13,14 (Scheme 2a). For the synthesis of phosphates 1, the following key elements of design were considered: (i) quaternary carbons directly attached to the oxygen atoms of the phosphate 1 seemed advantageous to prevent potential undesired substitutions at these positions (Scheme 2b); and (ii) starting substrates 1 could be potentially readily prepared from the O–H insertion of phosphates 5 into aryldiazoacetates 4.15 Based on this preliminary analysis, diphenyl phosphate 5a seemed to be a particularly attractive reacting partner (Scheme 2c).

Scheme 2.

Scheme 2

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(a) Our proposed method to make new C–C bonds via the arylation of alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1 with non-prefunctionalized arenes 2 aiming at the synthesis of α,α-diaryl esters 3. (b) Element of design guiding the targeted reactivity of the phosphate moiety. (c) Retrosynthetic analysis for the desired starting materials, alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1.

Having these considerations in mind, we started evaluating the synthesis of different alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1, which could be readily prepared upon mixing different aryldiazoacetates 4 with diphenyl phosphate 5a in DCM, at room temperature (Scheme 3), without requiring the use of any catalyst (see the Supporting Information for more details).

Scheme 3. Synthesis of Starting Phosphates 1 via O–H Insertion of Diphenyl Phosphate 5a (0.2 mmol) onto Aryldiazoacetates 4 (0.2 mmol) in DCM (0.1 M, 2 mL).

Scheme 3

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Overall, different alkyl groups were tolerated in the ester moiety of the diazo compound 4, thus allowing the preparation of molecules 1a–1f in good yields, 72–88%. In a similar manner, different aryl rings carrying electron-donor and acceptor functional groups were also allowed in the preparation of phosphates 1g–1p, which could be accessed in a range of 50–89% yields (Scheme 3). Furthermore, additional attempts employing different diazo compounds as reacting partners, 2-diazo-1,2-diphenylethan-1-one 4q, ethyl diazoacetate 4r, and (diazomethylene)dibenzene 4s produced a 74% yield for 1q, 82% yield for 1r, and a complex mixture for 1s, respectively (Figure 1).

Figure 1.

Figure 1

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Evaluation of other diazo compounds for the O–H insertion of diphenyl phosphate 5a.

Having a general strategy to access alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1 in hand, we moved forward with our synthetic plan toward the exploration of their direct substitution using nucleophilic partners 2 under Brønsted acid activation; and TfOH was effective in promoting this reactivity (Scheme 4), while other weaker Brønsted acids AcOH, TFA and p-TSA.H2O could not promote this reaction (see the Supporting Information for details). In this context, 1,3,5-trimethoxybenzene 2a could be used as a competent nucleophile leading to the formation of the corresponding α,α-diaryl esters 3a–3g in synthetically useful yields, 36–63%. The efficiency of the reaction using benzyl ester 3b was markedly lower, 36% yield, possibly due to the lability of the benzyl ester group under strongly acidic conditions (pKa TfOH ≈ −14).16 In agreement with this observation, attempts to arylate phosphates having an allyl ester group (1b) and a propargyl ester group (1c) with 1,3,5-trimethoxybenzene 2a under the same reaction conditions led to inseparable mixtures containing minor amounts of the corresponding desired compounds with their unreacted starting phosphates, along with degradation. Furthermore, phosphates carrying a 2-Cl group on the aryl ring (1k) and a 3-OMe group on the aryl ring (1p) produced only sluggish reactions affording low conversions for the corresponding desired arylated compounds 3f and 3h, which, after 24h of reaction, could not be separated from the corresponding unreacted starting phosphates. In addition, alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates containing a 2- or 4-NO2 group on the aryl ring (1l and 1n, respectively) also did not allow the desired transformations, as evidenced by our frustrated attempts of synthesizing 3i and 3j.

Scheme 4. Nucleophilic Substitutions of Different Arenes 2 (0.5 mmol) onto Alkyl 2-((Diphenoxyphosphoryl)oxy)-2-arylacetates 1 (0.1 mmol) Promoted by TfOH (0.2 mmol) in DCM (0.1 M, 1 mL).

Scheme 4

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Target compound 3 could not be isolated from unreacted starting material 1.

Arene 2 employed as co-solvent with DCM.

Anisole was employed in 6 equiv.

On the other hand, the arylation of phosphate 1q leading to ketone 3k could be achieved in 60% yield, while the arylation of 1r aiming at the preparation of ester 3l was unsuccessful. The reaction of phosphate 1a with benzene 2b and mesytilene 2c produced the corresponding arylated compounds 3m and 3n in 97% and 75% yields, respectively. Furthermore, the use of anisole 2d produced the corresponding arylated compounds 3o and 3o’ as an inseparable 1:1 mixture, in a combined 82% yield. A similar outcome was also observed for the use of toluene 2e and naphthalene 2f as nucleophiles, thus leading to 3p and 3p’ as an inseparable 3:1 mixture of para-:ortho- isomers in a combined 70% yield; and a 2.2:1 inseparable mixture of 1-:2-naphthyl substituted compounds 3q:3q’, in a combined 87% yield. Finally, attempts to use N-methylpyrrole 2g as a nucleophile aiming at the preparation of ester 3r were unsuccessful (Scheme 4).

During our investigations aiming to convert methyl 2-diazo-2-(4-methoxyphenyl)acetate 4t to the corresponding phosphate 1t, this target compound could be observed in the crude reaction mixture by 1H NMR, but it was shown to be unstable during our attempts of isolation by flash column chromatography. Consequently, we envisioned to directly perform a reaction sequence by converting the aryl diazoesters 4t–4v carrying electron-donor groups with diphenyl phosphate 5a to afford the corresponding intermediates 1t - 1v, followed by their reactions with different arenes 2 to gain access to the corresponding α,α-diaryl esters 3. In this case, no activation of intermediate phosphate 1 with TfOH was required (Scheme 5).

Scheme 5. Scope Accessed via a Reaction Sequence Involving Aryldiazoacetates Carrying Electron-Donor Groups 4t–4v (0.1 mmol) in the Presence of Diphenyl Phosphate 5a (0.1 mmol), Followed by the Addition of an Arene 2 (0.3 mmol) to Afford the Corresponding α,α-Diaryl Esters 3s–3bb + 3bb’.

Scheme 5

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In this context, we examined the use of 1,3,5-trimethoxybenzene 2a, anisole 2d, N-methylpyrrole 2g, phenol 2h, Boc-protected aniline 2i, diphenylamine 2j, aniline 2k, and carbazole 2l as nucleophilic arenes and diazo compounds 4t–4v could be converted to α,α-diaryl esters 3s–3bb as major or only compounds, in a range of 37–66% yields. Exceptions in chemoselectivity were noted when diphenylamine 2j and aniline 2k were employed, which led to the major or sole products obtained 3y’ and 3z, respectively, being derived from the nucleophilic attack of their heteroatoms, rather than their aryl rings (Scheme 5).

In terms of mechanism, the O–H insertion of phosphate 5a into aryldiazoacetates 4 likely involves the protonation of the diazo compound, followed by a substitution event promoted by the phosphate ion,17 which is in close proximity to the classical mechanism of esterification of carboxylic acids with diazomethane.18 For the second substitution event involving the replacement of the phosphate leaving group by a nucleophilic arene, we became interested in investigating the role of TfOH as a promoting agent. In order to study the mechanism of this reaction in more detail, we submitted an enantioenriched phosphate 1a, 77.6:22.4 er19 to our optimal reaction conditions in the presence of 1,3-dimethoxybenzene 2m; and we observed a fair amount of racemization (as it could be somehow expected) for the preparation of α,α-diaryl acetate 3cc, which was obtained in 70% yield and 62.0:38.0 er. However, it was a remarkable observation that 3cc was produced with partial inversion of stereochemistry in regard to the starting phosphate 1a(20) (Scheme 6). Furthermore, in the context of this mechanistic inquiry, an additional remarkable observation is that the same substitution protocol using phosphate 1r does not afford the corresponding arylated ester 3l (cf. Scheme 4).

Scheme 6. Mechanistic Investigation Showing Partial Inversion of the Stereochemistry of the Initial Enantioenriched Phosphate 1a for the Arylation Event Leading to Enantioenriched α,α-Diaryl Ester 3cc.

Scheme 6

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Considering the highly acidic reaction conditions and the previously mentioned experimental observations, our current working hypothesis for the operating mechanism of this transformation is that the TfOH protonates the phosphate group of 1, thus making it a better leaving group for a SN1-like substitution reaction involving the attack of the arene nucleophile 2. This event seems to proceed to some extension with inversion of the stereochemistry of the starting phosphate 1, which is a feature reminiscent of a SN2-type reaction, but this can be possibly understood here via the involvement of an intimate ion pair intermediate. In this regard, the mechanism of this substitution event can be possibly more accurately described as DN*AN.21

In the case of phosphate intermediates 1t–1v derived from diazo compounds 4t–4v, having at least one para-substituted alkoxy group in their aryl rings, it seems that this SN1-type reaction (i.e., a Friedel–Crafts-type arylation) occurs more readily, as the presence of the electron-donor group could contribute to an increased stabilization of a putative cationic intermediate. This could be the reason the reaction proceeded in the absence of any Brønsted acids. Of note, this observation is also in agreement with a previous report from Burtoloso and co-workers.13d In this specific context, we have also preliminarily evaluated the realization of a catalytic protocol employing aryldiazoacetate 4t (1 equiv) and phenol 2h (3 equiv) employing diphenyl phosphate 5a in 2, 10 and 20 mol % in 24 h of reaction, thus aiming at the preparation of α,α-diaryl ester 3s. This target compound could be observed by 1H NMR as the major product in the crude reaction mixture in 32%, 50% and 54% yields (using 1,3,5-trimethoxybenzene as internal reference), respectively.

In summary, we developed a Friedel–Crafts-type arylation approach to react alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1 with nonprefunctionalized arenes 2 to afford α,α-diaryl esters 3. In the absence of electron-rich aryl rings embedded in the structure of 1, the substitution reaction could be promoted by TfOH. Remarkably, this reaction appears to proceed via a SN1-type mechanism displaying an intriguing partial inversion of stereochemistry of the starting phosphate 1. However, when an para-substituted alkoxy group is present in the aryl ring of 1, the arylation occurs in the absence of any additional promoter. The key substrates alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates 1 could be readily accessed from the O-H insertion of diphenyl phosphate 5a into aryldiazoacetates 4.

Acknowledgments

The authors are grateful to the financial support of Fapesp provided as an undergraduate research fellowship to K.C.C. (2019/09380-7), postdoctoral fellowships to T.A.C.G. (2022/01750-2) and R.D.C.G. (2020/00144-6), a Regular Research Grant (2022/01104-3) and a Thematic Research Grant (2019/17721-9) to I.D.J.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.3c00042.

  • Experimental procedures, characterization data, and 1H, 13C, 19F, and 31P NMR spectra of all compounds\ (PDF)

Author Contributions

† K.C.C. and T.A.C.G. contributed equally. CRediT: Kauê C. Capellaro conceptualization, data curation, formal analysis, investigation, methodology; Tales A. C. Goulart conceptualization, data curation, formal analysis, investigation, methodology, writing-review & editing; Rafael D. C. Gallo conceptualization, data curation, formal analysis, investigation, methodology, writing-review & editing; Juliana de S. Schenfel data curation, formal analysis, investigation, methodology; Igor Dias Jurberg conceptualization, data curation, formal analysis, funding acquisition, project administration, resources, supervision, writing-original draft, writing-review & editing.

The authors declare no competing financial interest.

Supplementary Material

gg3c00042_si_001.pdf (4.5MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

gg3c00042_si_001.pdf (4.5MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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