Oxidative Deconstruction of Azetidinols to α-Amino KetonesRobert-Cristian Raclea, Philipp Natho, Lewis A. T. Allen, Andrew J. P. White & Philip J. Parsons* Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, UK Supporting Information Placeholder

ABSTRACT: A silver-mediated synthesis of α-amino ketones via the oxidative deconstruction of azetidi-nols has been developed using a readily scalable protocol with isolated yields up to 80%. The azetidinols are easily synthesized in one step and can act as protecting groups for these pharmaceutically relevant synthons. Furthermore, mechanistic insights are presented and these data have revealed that the trans-formation is likely to proceed through the β-scission of an alkoxy radical, followed by further oxidation and C-N cleavage of the resulting α-amido radical.

In recent years, cyclobutanols have proven to be promising substrates for the development of de-constructive functionalization methodologies. This is achieved through C(sp3)-C(sp3) single bond cleavage and subsequent diversification, despite the apparent inertness of these bonds.1–7 Their unique reactivity is mainly driven by two primary thermodynamic driving forces: the potential to form strong C=O bonds (ca. 179 kcal/mol vs 92 kcal/mol for C-O bonds8) and the release of ring strain (strain energy of 26.5 kcal/mol).8 In particu-lar, the metal-mediated generation of alkoxy radi-cals allows for C(sp3)-C(sp3) β-scission, which may be followed by a radical-radical coupling to a wide array of functional groups (Scheme 1, a) or ring expansion. Progress within the field has since led to the development of significantly milder proto-cols utilizing photo- or electrochemical techniques to achieve similar functionalizations or ring ex-pansions.9–14

The deconstructive functionalization of azetidinols however is less common. Building on earlier ob-servations for the synthesis of 3,3-disubstituted α-tetralones,15 Murakami reported the ring expan-sion of several N-arenesulfonylazetidin-3-ols to benzosultams in the presence of a Rh(I)-BINAP catalyst via an alkylrhodium intermediate.16 Later, Gaunt reported an isolated example of a copper-mediated azetidinol ring expansion via a semi-pinacol rearrangement,17 and Zuo reported a sin-gle example of azetidinol ring opening using a cerium photocatalysis.18 In 2019, Knowles re-ported the iridium-mediated ring fragmentation of

alkyl-substituted five- and six-membered N-hete-rocyclic alcohols.9,10 Finally, Sarpong and co-work-ers have shown that the metal-mediated decon-structive fluorination of azetidines via C(sp3)-N cleavage is possible through an initial α-oxidation, followed by hemiaminal formation and decar-boxylative fluorination (Scheme 1, b).2 An alterna-tive mechanism was observed for larger ring sizes. This involves the conversion of the hemi-aminal intermediate to an alkoxy radical, followed by β-scission, to yield N-formylated amines.

Scheme 1. Oxidative Ring Opening and Functionalization of Cyclobutanols (a) and

Azetidines (b)

In line with our continuing interest in utilizing small rings as precursors to pharmacophores,19,20

we recently proposed that a combination of β-scission (C(sp3)-C(sp3) cleavage) and demethyla-tion (C(sp3)-N cleavage) of azetidinols under ox-idative conditions would lead to α-amino ketone products (Scheme 2, a). This would allow azetidi-nols to function as stable protecting groups until late-stage conversion is required. Classically, the synthesis of α-amino ketones relies on the forma-tion of a carbon-nitrogen bond in the α-position of an oxygen functionality (e.g. ketone, alcohol).21–30

In contrast, the use of azetidinols as an equiva-lent of α-amino ketones would allow for their in-stallation through a carbon-carbon bond forma-tion, adding a different retrosynthetic approach to the repertoire of synthetic chemists. The prepara-tion of these high-value synthons is of continued interest to the pharmaceutical industry due to their numerous biological applications, such as anorectics, antidepressants, or stimulants (Scheme 2, b).22,23,27,31–34

Scheme 2. Proposed Reaction Scheme (a) and Relevant Examples of Biologically Ac-

tive α-Amino Ketones (b)

Our study started with an investigation into reac-tion conditions suitable for the proposed transfor-mation by using benzothiophene-substituted aze-tidinol 1a as a model substrate (Table 1). This

model was prepared from commercially available N-Boc-azetidin-3-one and benzothiophene in one synthetic step. Initially, 1a was treated with AgNO3 and K2S2O8 in DCM/H2O at room tempera-ture, providing the desired α-amino ketone 2a in 15% yield (Table 1, entry 1). Similar reaction con-ditions have previously been employed for the ox-idative ring expansion of cyclobutanols. 35 Chang-ing the protecting group from Boc to N-tosyl had detrimental effect on the yield (Table 1, entry 2).

Table 1: Optimization of Reaction Condi-tionsa

entry variation from standard conditions

RSMb

[%]yield [%]

1 DCM instead of DCE 16 152 DCM instead of DCE, Ts instead

of Boc26 5

3 MeCN instead of DCE 65 54 DMF instead of DCE 91 trace5 none 10 326 AgBF4 instead of AgNO3 36 107 Na2S2O8 instead of K2S2O8 trace 228 35 °C instead of rt 22 269 0.5 mL DCE/H2O 44 1110 2 mL DCE/H2O 33 2211 4 equiv of AgNO3 & K2S2O8 5 2712 4 equiv of AgNO3 & (NH4)2S2O8 11 2713 48 h, 4 equiv K2S2O8, second

portion of oxidant/co-oxidant added after 24 h

trace 40

14 48 h, 4 equiv (NH4)2S2O8, second portion of oxidant/co-oxidant added after 24 h

trace 38

a Standard conditions: 1a (0.30 mmol), AgNO3 (0.2 equiv) and K2S2O8 (3 equiv) in 1 mL DCE/H2O (1:1), rt, 24 h. b Re-covered starting material. Detailed optimization studies and experimental protocol are available in the Supporting Information.It was observed that polar solvents, such as ace-tonitrile and DMF, led to a drastic reduction in yield (Table 1, entries 3 & 4). However, the use of DCE/H2O gratifyingly doubled the isolated yield of 2a (Table 1, entry 5). Modification of other reac-tion parameters, such as exchanging silver nitrate for silver tetrafluoroborate (Table 1, entry 6), the replacement of potassium persulfate with sodium persulfate (Table 1, entry 7), or an increase of the reaction temperature to 35 °C (Table 1, entry 8) did not lead to improved results. In addition, vari-ation of the reaction concentration had a negative effect on the yield of the process, returning sig-nificantly more starting material (Table 1, entries 9 & 10). At this stage of the investigation, it was

hypothesized that the incomplete conversion of starting material is caused by deactivation of the silver redox couple, and additional quantities of silver(I) are therefore required to drive the reac-tion to completion. This is in line with Sarpong’s transformation, which required four equivalents of silver(I) for full conversion.2 In our case, the use of superstoichiometric quantities of silver(I) with different co-oxidants did not lead to the desired improvement (Table 1, entries 11 & 12); instead, it was found that the addition of a second portion of silver nitrate (0.2 equiv.) and co-oxidant (4 equiv.) was required after 24 h to achieve full conversion of 1a (Table 1, entry 13). Spectro-scopic analysis of the crude reaction mixture pro-vided no evidence of reaction by-products, includ-ing the intramolecular aromatic substitution prod-uct described for cyclobutanol derivatives under similar reaction conditions.35 Full disclosure of our optimization studies is available in the Supporting Information.

A range of aromatic-substituted azetidinols were prepared to investigate the scope of the transfor-mation (Scheme 3). To our delight, substrates bearing electronically neutral (1b), deactivated (1c-f), and activated (1g) aromatic rings provided the α-amino ketone products in 63-80% yield. While fluorinated examples (1c-e) were equally successful, the outcome of the reaction for methoxy-containing substrates (1g-i) was found to be dependent on the substitution pattern. The reduction in yield (37-42% vs 63%) was attributed to competing oxidation of the unsubstituted para-positions leading to quinone side-products; simi-lar substrates have been reported to undergo this transformation in the presence of potassium per-sulfate.36 The procedure also demonstrated con-sistent results when the scale of the reaction was increased: α-Amino ketone 2c was obtained in 80% yield on a 1.2 mmol scale (vs. 80%), and 2i was isolated in 42% yield on a 4.0 mmol scale (vs. 32%). Unfortunately, chloro-substituted aze-tidinol 1l was only partially soluble in the reaction solvent, leading to a significant recovery of start-ing material (43% RSM) and a concomitant reduc-tion in yield. While mild electronic influences were well tolerated, more strongly electron-releasing and electron-withdrawing aromatic rings signifi-cantly reduced the rate and yield of the reaction. After an increased reaction duration of 116 hours, trifluoromethyl-substituted 2m was obtained in 23% yield, and only a trace quantity of trimethoxy-substituted 2k was isolated. The α-amino ketone functionality could also be obtained on thiophene (2o) and on the 3-position of ben-zothiophene (2n) with no appreciable loss in yield when compared to the model (2a). Azetidinol 1p, bearing tosyl-protected indole as the substituent, underwent the reaction slowly to yield the α-amino ketone 2p in 37% yield, together with 14% recovered starting material. Finally, the benzo-furan-containing azetidinol 1q decomposed under

the reaction conditions, with no evidence of the desired ketone product 2q by NMR spectroscopy.

Scheme 3. Substrate Scope of the Oxidative Deconstruction of Azetidinolsa

a Conditions: azetidinol (0.30 mmol), AgNO3 (0.2 equiv) and K2S2O8 (4 equiv) in 1 mL DCE/H2O (1:1), rt. b Second portion of oxidant/co-oxidant added af-ter 24 h. c Third portion of oxidant/co-oxidant added after 48 h. d Recovered starting material.

In addition, aryl-substituted pyrrolidinol 3 was subjected to the optimized protocol (Scheme 4). While the desired -amino ketone 4 was formed in 29% yield, significant quantities of unreacted starting material were also isolated (53% RSM). As such, it was concluded that the release of ring strain is a key driving force for this transforma-tion.

Scheme 4. Oxidative Deconstruction of Pyrrolidinol 3 to -Amino Ketone 4a

a Second portion of oxidant/co-oxidant added after 24 h. b Recovered starting material.A series of control experiments were performed in order to gain insight into the mechanism of this transformation. First, azetidinol 1a was reacted with potassium persulfate in the absence of silver nitrate (Scheme 5, a); no conversion was ob-served, demonstrating that potassium persulfate alone cannot trigger this reaction. Since the reac-tion between silver(I) and S2O82- is known to gen-erate silver(II)-species in situ,37 the Ag(II)/Ag(I) re-dox couple appears to be required for the trans-formation to proceed. Next, we found that reac-tion of substrate 1c is completely inhibited in the presence of TEMPO, indicating radical-mediated steps in the pathway (Scheme 5, b). Additionally, ether 5 was treated with our optimized reaction conditions (Scheme 5, c), but no conversion of the starting material was detected. This suggests that initiation of the reaction involves a single-electron oxidation of the alcohol moiety, rather than an α-oxidation process (c.f. Scheme 1, b).

We decided to probe the fate of this putative alkoxy radical. In line with our proposed role of sil-ver(II) in this process, we decided to treat 1a with silver(II) fluoride (Scheme 5, d). The main product of this transformation was determined to be the dimer 6, which is likely to have formed through the radical-radical coupling of two α-amido radical species. The generation of these intermediates can be explained by a -scission process from the alkoxy radical.7,38,39

Scheme 5: Mechanistic Experiments

a Second portion of AgF2 added after 24 h.

A plausible reaction mechanism can be envi-sioned based on the above results (Scheme 6).

The proposed mechanism commences with con-version of azetidinol 1 to alkoxy radical 7, either by single-electron transfer (SET) to Ag(II) or hy-drogen atom abstraction (HAT) by the radical an-ion SO4-.37 Alkoxy radical 7 subsequently under-goes a facile -scission to give α-amido radical 8, which converts to iminium 9 through a second Ag(II)-mediated SET process.1,39–41Alternatively, persulfate sources are known to facilitate this lat-ter oxidation.42 Iminium 9 is trapped by water to form hemiaminal 10, which is unstable under the acidic reaction conditions (pH ≈ 2), generating the α-amino ketone product 2 and formaldehyde. The energetic cost of breaking the C-N bond is outweighed by the enthalpic benefit gained from the formation of a carbonyl bond and increase in entropy of the system.43 Further oxidation of formaldehyde to either formic acid or CO2 drives this equilibrium process.44

Scheme 6: Proposed Reaction Mechanism

In summary, a deconstructive protocol for the conversion of azetidinols to α-amino ketones has been disclosed. This scalable procedure uses rela-tively inexpensive oxidants and shows good toler-ance for a wide range of aryl and heteroaryl sub-stituents. Our mechanistic studies give weight to a radical-based mechanism featuring a sequence of C-C and C-N bond cleavages. Applications of this novel protecting group strategy to the syn-thesis of bioactive scaffolds are currently under investigation.

ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge on the ACS Publications website.1H NMR Features of α-Amino Ketones 2a-p, full op-timization studies, 1H NMR, 13C NMR, and 19F NMR spectra (PDF)X-Ray Crystallographic Information (PDF)

AUTHOR INFORMATIONCorresponding Author* Philip J. Parsons

E-mail: p.parsons@imperial.ac.ukORCIDPhilip J. Parsons: 0000-0002-9158-4034NotesThe authors declare no competing interests.

ACKNOWLEDGMENT The authors gratefully acknowledge the receipt of an EPSRC Imperial College London President’s Scholar-ship (to P.N.). Additional generous funding from Dr Isabel Bader and her late husband Dr Alfred Bader (to P.J.P.) is gratefully recognized. We thank Pete Haycock (Imperial College London) and Dr Lisa Haigh (Imperial College London) for NMR and mass spectrometric analysis, respectively. This paper is dedicated to the late philanthropist Dr Alfred Bader and also in memory of the late Oxana Bennett.

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