A Practical Iron-based Newman-Kwart Rearrangement Under Oxidative Conditions

: Herein, we report that iron(II)/ammonium persulfate in aqueous acetonitrile mediates the Newman-Kwart rearrangement of O -aryl carbamothioates. Electron-rich substrates react rapidly under moderate heating to afford the rearranged products in excellent yields. The mild conditions, rapid reaction rates, and suitability for scale up offers immediate practical benefits to access functionalised thiophenols. The Newman-Kwart rearrangement (NKR) – the transformation of O -aryl carbamothioates to the corresponding S -aryl carbamothioates – gives access to thiophenols from their more readily available phenol counterparts. 1,2 The three-step sequence, which involves phenol protection with thiocarbamoyl chloride, NKR and deprotection of the resulting carbamothioate, is appealing as it avoids the need for highly reactive reagents or handling of foul-smelling chemicals. The NKR is therefore a synthetically important reaction with widespread applications. 3 – 6 The high activation barrier (ca. 35-43 kcal.mol -1 ) 7 of the NKR has been a long-standing limitation as thermal activation requires temperatures of 150

The Newman-Kwart rearrangement (NKR) -the transformation of O-aryl carbamothioates to the corresponding S-aryl carbamothioates -gives access to thiophenols from their more readily available phenol counterparts. 1,2The three-step sequence, which involves phenol protection with thiocarbamoyl chloride, NKR and deprotection of the resulting carbamothioate, is appealing as it avoids the need for highly reactive reagents or handling of foul-smelling chemicals.4][5][6] The high activation barrier (ca.35-43 kcal.mol - ) 7 of the NKR has been a long-standing limitation as thermal activation requires temperatures of 150 °C for electron-deficient substrates to > 300 °C for non-activated arenes (Figure 1).At such high temperatures, compound volatility, decomposition and charring becomes problematic.In practice, the thermal reaction is therefore limited to activated, thermally stable and non-volatile substrates.Renewed interest in the NKR has led to the discovery of several catalytic systems that favours electron rich substrates, including a photo-redox catalytic system, 8 an electrochemical method, 9 and more recently, a chemical reaction involving single-electron oxidation of S-aryl carbamothioates with ceric-ammonium nitrate (CAN) in dimethylsulfoxide (DMSO). 10The latter method makes the NKR with electron-rich substrates widely accessible as it overcomes the need for specialist equipment.However, the use of DMSO as the solvent, and the need for high substrate dilution, practically limits applications to small-scale reactions.
Attempted Pd-catalysed NKR only afforded trace amounts of product 2a in agreement with the previously reported scope. 12Inspired by the work of Anderson and Kochi on radical decarboxylation of carboxylic acids, 13 we attempted to use silver nitrate and ammonium persulfate (APS) as a single electron oxidant to mediate this transformation.Gratifyingly, under these conditions (35 mol% AgNO 3 , 1 equiv.APS, CH 3 CN/H 2 O, 85 °C) 1a rearranged to target product 2a in 78% yield (Scheme 1).In a bid to develop a practical and scalable method, we investigated the effect of the different reagents and reaction parameters using O-(4-methoxyphenyl) dimethylcarbamothioate 1b as a model compound (Table 1).When subjected to the aforementioned conditions, 1b was fully converted to 2b (Table 1, entry 1).Control experiments proved that APS is essential for the reaction to proceed (Table 1, entry 2).In the absence of silver, we observed large variations in yields depending on the source of APS.Subsequent analysis by inductively coupled plasma mass spectrometry (ICP-MS) revealed high levels of iron in the batch of APS that most effectively mediated transformation of 1b to 2b.As iron is known to accelerate the decomposition of APS in a similar manner to silver, 13,14 we hypothesized that the iron impurity played a key role in the reaction.Gratifyingly, replacing silver nitrate with catalytic amounts (5 mol%) of Mohr's salt ((NH 4 ) 2 Fe(SO 4 ) 2 • 6H 2 O) afforded 2b in 95% yield (Table 1, entry 4).Lowering the reaction temperature from 85 °C to 45 °C still gave full conversion within an hour and afforded 2b in 91% isolated yield (Table 1, entry 5).As described in the previously reported non-thermal NKR protocols, [8][9][10] the reaction proved less efficient at high concentrations.At a concentration up to 0.17 M (Table 1, entry 7), the rate of transformation appeared to be unaffected, however, at 0.25 M the yield dropped to 10% under otherwise identical conditions (Table 1, entry 6).Finally, the use of water as co-solvent proved crucial for the formation of the target product.Indeed, when acetonitrile was used as the sole reaction solvent, starting material 1b was converted quantitatively to the corresponding carbamate 3b (Table 1, entry 8).With optimised conditions in hand (5 mol% Mohr's salt, 1 equiv.APS, CH 3 CN/H 2 O 3:1), we explored the scope of this novel NKR reaction (Figure 2).Substrates substituted with electron donating groups (EDG) in para-position afforded rearranged products 2a-f in nearly quantitative yields.Additional electron-withdrawing groups (EWG) were well tolerated as exemplified with the formation of aldehyde and ester substituted products 2e and 2f in 95% and 93% yields, respectively.Steric hindrance had little-to-no influence on the rearrangement, as ortho-substituted products 2a and 2f-i were obtained in good to excellent yields.The reaction displayed a good functional group tolerance as aldehyde, ester, allyl and bromo substituents in products 2e-h remained intact through the procedure; notably, oxidation of aldehyde 2e was not observed.However, rearrangement of benzylic alcohol 2n was problematic due to the oxidation of the alcohol to the corresponding aldehyde, resulting in the formation of a complex mixture of products.S-(naphthalene-1-yl) dimethyl-carbamothioate 2j as well as its 2-regioisomer 2k were obtained in 85% and 84% isolated yields, respectively.This result is of note as the CAN, 10 photoredox 8 and electrocatyltic 9 methods allow access to the 1-napthalene but not the 2-napthalene derivative.Formation of electron-neutral 2l and moderately electron-deficient meta-methoxy substituted 2m was observed, albeit in modest conversions (30% and 17%, respectively).Attempted reactions with electron-deficient substrates proved troublesome; nitro-1o, nitrile-1p, aldehyde-1q, and halide-1r-t substituted O-aryl carbamothioate failed to rearrange.In most cases, NMR analysis of the reaction mixture showed that the starting materials were transformed to the corresponding O-aryl carbamates instead of the expected S-aryl carbamothioate.Formation of carbamates has previously been reported for the CAN-DMSO mediated NKR reaction. 10et a better understanding of this side reaction, isotopically labelled [ 18 O]O-aryl carbamothioate O-2o was subjected to the reaction conditions with strict exclusion of water and oxygen (Scheme 2A).Carbamate 18 O-3j was isolated in 60% yield.Tandem mass spectrometry (MS/MS) confirmed the position of the [ 18 O]oxygen on the molecule as shown on Scheme 2A.In the absence of any other source of oxygen, this demonstrates that the extra oxygen added on the carbamate is likely to come from the persulfate.Furthermore, subjecting 1b to the standard reaction conditions whilst replacing H 2 O with [ 18 O]H 2 O did not lead to any isotopic exchange on the rearranged product, thus suggesting that water is not actively participating in the reaction (Scheme 2B).Overall, the results of this scope study are in line with the works previously published on oxidative NKR: the reaction proceeded rapidly with electron rich ring systems, non-activated systems reacted more sluggishly, while electron-deficient substrates failed to react, or underwent a side-reaction to give the corresponding Ocarbamates.
To elucidate the rearrangement mechanism itself, we first focused our attention on the reaction kinetics. 1H NMR reaction monitoring of the para-methoxy derivative 1b led to a sigmoidal kinetic profile.After an induction period of about 35 min, 1b was quantitatively rearranged to product 2b within 20 min on a 0.5 mmol scale (zero order linear approximation k ≈ 5 mmol.L -1 .min - ).Although not uncommon, sigmoidal kinetic profiles are difficult to interpret; unrevealing which mechanisms are responsible for the induction period and then for reaction lift-off is challenging and outside of the scope of the present study.We subsequently investigated whether the reaction was inter-or intramolecular through a crossover experiment between the para-methoxy derivative 1b and its ethyl analogue 1d (Scheme 2C).Should the reaction be intermolecular, an interchange of substituents would occur, giving rise to crossover rearranged products 4b and 4d.NMR analysis of the crude reaction mixture showed exclusive formation of the two non-crossover rearranged products 2b and 2d, in equal amounts.This observation suggests the reaction to be solely intramolecular, matching the results previously obtained with the CAN-mediated NKR method. 10][10] In aqueous conditions, iron(II)/(III) and iron oxides are known to mediate Fentonlike process, resulting in single electron transfer.Under such conditions, APS decomposes to the sulfate radical anion SO 4 -• . 15Adding in the reaction an equivalent of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), an established radical trap, blocked the rearrangement, supporting the hypothesis of a radical-mediated reaction.In addition, close inspection of the crude rearrangement mixture consistently revealed the presence of a dark orange-brown residue consistent with the formation of iron oxides.On the basis of these observations, we propose the mechanism illustrated in Scheme 3. A Fenton-like process results in the formation of sulfate radical anion SO 4 -• (Scheme 3, blue box), which, in turn, reacts by abstracting an electron from the sulfur atom in 1b, forming radical cation 1b +• .Subsequent intramolecular (vide supra) rearrangement of 1b +• leads to the formation of a putative four-center intermediate I, as previously described. 16me 3: Proposed mechanism.
Heterolytic cleavage of the O Aryl bond results in radical cation 2b +• .The rearranged product 2b is then obtained by single electron reduction of radical cation 2b +• .The nature of the reduction step is unclear; it is possible that 1b serves as an donor, thereby regenerating 1b +• .However, the experimental observations are not consistent with a radical chain reaction.It is therefore more likely that the single electron reduction is mediated by the iron(II)/(III)-persulfate system.
To demonstrate a practical application, the novel strategy was used in the synthesis of the labelling precursor of 18 F-AEM1, 17 a radiotracer of interest for the imaging of cancer drug resistance by positron emission tomography (Scheme 4).The synthesis of 2a was successfully scaled-up to 3 g (10 mmol), affording the target rearranged product in 81% yield.Biaryl building block 2a was then coupled to 5 giving biaryl thioether 6 in 60% yield.Subsequent ring-closing sulfonium salt formation 11   In conclusion, we report that catalytic amounts of Fe(II) in the presence of APS mediates conversion of electron-rich and electron neutral O-aryl carbamothioates to the corresponding S-aryl carbamothioates under mild conditions.The reaction has a similar scope to previously reported methods for cation-radical NKR, but offers clear practical advantages in that it circumvents the need for specialist equipment, proceeds with shorter reaction times and at higher substrate concentration, and the use of a volatile solvent makes it well suited for larger-scale reactions.

Table 1 :
Optimisation of the novel NKR protocol aAs determined by 1 H NMR, isolated yields are given in brackets; b As silver nitrate; c As Mohr's salt; d Depending on the source of APS; e Reaction was heated for four hours, conversion to 3b.