The Photochemical Mediated Ring Contraction of 4H-1,2,6-Thiadiazines To Afford 1,2,5-Thiadiazol-3(2H)-one 1-Oxides

1,2,6-Thiadiazines treated with visible light and 3O2 under ambient conditions are converted into difficult-to-access 1,2,5-thiadiazole 1-oxides (35 examples, yields of 39–100%). Experimental and theoretical studies reveal that 1,2,6-thiadiazines act as triplet photosensitizers that produce 1O2 and then undergo a chemoselective [3 + 2] cycloaddition to give an endoperoxide that ring contracts with selective carbon atom excision and complete atom economy. The reaction was optimized under both batch and continuous-flow conditions and is also efficient in green solvents.

The remarkable ring contraction presented herein leads to oxidation of an imine motif to an imide and the selective mono-oxidation of the ring sulfur to a stereogenic sulfoxide with only the substrate, solvent, visible light, and air present under ambient conditions.
After our initial discovery, we investigated the conditions to optimize the reaction and gain mechanistic insight.The reaction did not proceed in the absence of light or when irradiated with monochromatic sources that did not overlap with the absorption spectrum of thiadiazine 4a.Nor did the reaction proceed under a N 2 atmosphere, indicating that 3 O 2 was the source of the additional two oxygen atoms in the resulting thiadiazole 5a.
The effect of temperature gave the first evidence that 1 O 2 was involved in the reaction, which displayed a negative, approximately linear relationship between conversion and temperature (Figure S5 in the SI).The lifetime of 1 O 2 in CHCl 3 can be significantly extended at lower temperatures, 12 providing more time for the substrate and 1 O 2 to react.While lower temperatures were beneficial, the reaction achieved full conversion in <15 min under ambient conditions with irradiation from a 420 nm LED module (28 W).In the interest of operational simplicity, our studies proceeded using these optimized conditions.
Reaction kinetics were screened in various solvents and revealed that the initial rate fitted a first-order kinetic model (see section S2.5 in the SI for details).The reaction rate strongly depended on the solvent environment, and the initial reaction rate in deuterated solvents was about an order of magnitude greater than that in their protonated equivalents (seeFigure S6B in the SI).
The standard reaction conditions were reoptimized under continuous flow (see Figure 3, as well as section SI.4 in the SI).
Initially, the "green" solvent dimethyl carbonate was used to optimize the flow system and explore the potential for developing a sustainable process.Optimal process conditions were identified, and thiadiazole 5a was obtained in >98% yield within 10 min residence time of the flow photoreactor, comparable to the optimized batch conditions in CDCl 3 .Applying the optimized conditions in CDCl 3 led to the quantitative formation of product 5a after only 1 min of residence time of the UV-150 reactor coil with a back pressure of 3 bar and using pure 3 O 2 , a 15-fold reduction in reaction time from the batch protocol.The successful flow synthesis enabled the continuous production of thiadiazole 5a without concern over light attenuation effects that typically hinder the scale-up of photochemical processes in batch. 13From a productivity point-of-view, 5a was obtained with full conversion and a space-time yield of 199.6 g L −1 h −1 The reaction conditions were then applied to a range of 3,5disubstituted 1,2,6-thiadiazines with varying substitution patterns (Table 1).The batch protocol was prioritized for substrate screening, and the flow procedure was reserved for more challenging substrates.
The reaction worked well with methyl, methoxy, and chlorophenyl substituents to provide the ring contracted products 5b−5j in quantitative yields, regardless of the substitution pattern.The m-tolyl derivative 5c photodecomposed under batch conditions but was isolated via the flow protocol in 97% yield (Table 1, entry 4).This highlighted the benefit of precise control over irradiation exposure when performing a photochemical process with flow chemistry. 14n general, the reaction rates decreased in the order para > meta ≫ ortho based on substitution.Additionally, para-Scheme 1. Reported Thermal and Acid Catalyzed Transformation of 1,2,6-Thiadiazines to 1,2,5-Thiadiazoles and Current Photooxidation of 3,5-Diphenyl-4H-1,2,6-Thiadiazin-4-one (4a)  substituted benzylether 5k and methoxycarbonyl 5l also followed this trend and were isolated in quantitative yield after 15 min of irradiation in batch.As the electronics of the aryl systems vary dramatically between the different substituents and ring positions, steric hindrance is the most probable cause of this effect.
The reaction also succeeded with alkynylthiadiazine 4q, which afforded thiadiazole 5q in a quantitative yield.However, the reaction was relatively sluggish, requiring 4 h of irradiation.We then explored a series of thiadiazines with nonaromatic 3,5-substituents.Alkylethers 4r and 4s were quantitatively converted into thiadiazoles 5r and 5s, respectively, while phenylether 4t photodecomposed using the batch protocol but was converted to thiadiazole 5t in 93% yield under flow.Amine derivatives were not well-tolerated, with most analogues being either unreactive or rapidly decomposed under both batch and flow conditions; in two cases, the thiadiazine sulfoxide and sulfone products were identified (see section S2.7 in the Supporting Information).Interestingly, such derivatives can be readily prepared from non-S-oxidized thiadiazines using classic oxidants and do not show propensity to ring contract. 17rotection of the pre-existing C4 carbonyl with ethylene glycol and catechol acetal derivatives was then explored.In general, all the acetal-protected thiadiazoles 5u−5z displayed reduced photostability: the reversible photoinduced cleavage of acetal-protected benzaldehydes with UV irradiation has been reported, 18 which may explain the instability of these compounds when overirradiated in batch.Despite our best efforts, we were unable to determine the chemical structures of the photodecomposition products.However, acetal-protected thiadiazoles were isolated in ∼90% yield using the flow protocol.No significant differences in stability or reactivity between ethylene glycol and catechol acetals were observed.
The ring contraction of the acetal derivatives supported that (i) the additional oxygen atoms installed via the reaction end up on the ring sulfur and external amide carbonyl; (ii) the C4 carbonyl does not migrate; and, (iii) the cleavage of the C−C bond during the ring contraction does not depend on Norrishtype radical processes induced by direct excitation of the carbonyl. 19o assess the selectivity preferences for the reaction, with respect to the excised carbon, we screened a series of asymmetric thiadiazines 4aa−4ak with different R-groups substituted at the 3-and 5-ring positions (see Table 2).
Pleasingly, most asymmetric thiadiazines showed excellent chemoselectivity, and a single product was isolated.Bisaryl thiadiazine 4aa displayed accelerated reactivity and complete  selectivity for excising the carbon bound to the more electron deficient para-(methoxycarbonyl)phenyl, as shown by X-ray crystallography (Figure 4).
Thiadiazines 4ab−4ad, bearing a 3-ether and 5-phenyl substituent, also reacted selectively by excising the phenyl bearing carbon atom.Reaction of thiadiazine 4ae bearing nitrothienyl and thienyl substituents was slower (1 h) and again showed complete selectivity for excising the carbon bound to the more electron deficient hetarene.In contrast to the symmetric amino thiadiazines, asymmetric secondary monoaminothiadiazines 4af−4ah gave the expected thiadiazoles.In all three cases, the nonamine bound carbon was selectively excised and single thiadiazoles 5af−5ah were respectively obtained in high yields.
A set of three asymmetric 3,5-bisphenylthiadiazines 4ai− 4ak, bearing ring substituents with similar electron-donating character, led to the formation of mixtures of both potential ring contracted products.In the case of 3-(4-methoxyphenyl)-5-(4-tolyl)thiadiazine 4ai, the tolyl bound carbon was preferentially excised, leading to a 69:31 mixture of thiadiazoles 5ai and 5al, respectively.Asymmetric methoxyphenyl-substituted thiadiazines 4aj and 4ak allowed a comparison of the preference of carbon excision with respect to the ortho, meta, and para position of the methoxy group.Interestingly, in the unsymmetrical ortho/meta-methoxyphenylthiadiazine 4aj we observed only a slight preference for the contraction at the 2-methoxyphenyl bound carbon.In ortho/ para-methoxyphenyl-thiadiazine 4ak we also observed a slight preference but this time for the contraction at the 4methoxyphenyl bound carbon, leading to 60:40 mixtures of thiadiazoles 5aj/5am and 5ak/5an, respectively.
To investigate the reaction mechanism, control reactions were performed with ROS traps to help confirm the presence of 1 O 2 under the reaction conditions (see section S2.2 in the Supporting Information).Notably, in the presence of 1 O 2 traps such as α-terpinene and Ph 3 P, full conversion of thiadiazine 4a to thiadiazole 5a required significantly longer reaction times (1 and 2 h, respectively) and the expected characteristic 1 O 2trapped adducts, ascaridole, and Ph 3 PO, were observed. 13,20,21erforming the reaction in the absence of irradiation and with dark 1 O 2 generator systems also enabled the conversion to thiadiazole 5a, indicating that the reaction mechanism was not reliant on a photochemical rearrangement of thiadiazine 4a or its electronic excited states.The reaction was also performed in the presence of Methylene Blue, a known 1 O 2 photosensitizer, which has a visible light absorption spectrum that is chromatically orthogonal to that of substrate 4a (see Figure S7B in the Supporting Information).With 1 mol % loading of the orthogonal photosensitizer and red-light irradiation (620 nm), under otherwise identical conditions, full conversion to thiadiazole 5a was achieved within 1 h.This further suggested that 1 O 2 could independently drive the reaction and enabled the reaction to be performed with longer irradiation wavelengths, which avoided the excitation of more complex substrates containing chromophores.Further experiments ruled out the involvement of superoxide in the reaction mechanism, as well as the 1 O 2 mediated sulfide oxidation to sulfoxide (see section S2.2 in the Supporting Information).
On the basis of the above observations, we propose that irradiation of thiadiazine 4 generates excited 4* that undergoes energy transfer to 3 O 2 to generate 1 O 2 , while returning to the ground state (see Figure 5a).The reaction of 4a with 1 O 2 was then modeled computationally at the CASPT2/6-31G**// UB3LYP/6-31G** level of theory (see Figure 5b).This suggests the initial formation of an endoperoxide intermediate, Int(4a−5a), at +7.4 kcal/mol that proceeds via a concerted [3 + 2] addition of 1 O 2 across the {(Ph)C 3 −N 2 �S 1 } moiety (TS(4a-5a)1, + 9.6 kcal/mol).A [3 + 2] cycloaddition involving 1 O 2 has been suggested before, albeit lacking the necessary data for verification. 22From Int(4a-5a) O−O bond cleavage occurs with concomitant ring contraction in a single step via TS(4a-5a)2 at +21.7 kcal/mol.This entails the simultaneous cleavage of the C 3 −C 4 bond and the formation of a new N 2 −C 4 amide bond.The formation of thiadiazole 5a is highly exergonic (ΔG = −85.7 kcal/mol), and the overall barrier of 21.7 kcal/mol is consistent with the room temperature reactivity observed experimentally.TS(4a-5a)2 is both the rate-and selectivity-determining transition state.
Worthy of note, the discovery of a [3 + 2] cycloaddition of 1 O 2 advances its known chemistry, and this reactivity can, potentially, be more broadly developed. 1O 2 can selectively oxidize unsaturated hydrocarbons and electron-rich heteroatoms, and readily undergoes pericyclic reactions with olefins and diene substrates. 23This reactivity has been used to synthesize various complex natural products and active pharmaceutical ingredients, 24 including the semisynthesis of artemisinin, a crucial antimalarial drug. 25New reports mainly focus on the known 1 O 2 reactivity toward complex synthetic targets. 24,26

Organic Letters
In conclusion, we report the photochemically mediated ring contraction of 1,2,6-thiadiazines under ambient aerobic conditions to provide a sustainable and atom economic route to elusive 1,2,5-thiadiazol-3(2H)-one 1-oxides in generally quantitative yields and chromatography-free purification.To the best of our knowledge, the reaction proceeds via the first example of a 1 O 2 [3 + 2] cycloaddition, expanding its known chemistry.

Figure 3 .
Figure 3. Experimental setup that was used for the reaction under continuous flow conditions.