Page 1 of 18 The Journal of Organic Chemistry This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal Of Organic Chemistry, copyright © American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/full/10.1021/acs.joc.9b01014 1 2 Chemodivergent Conversion of Ketenimines Bearing Cyclic Dithioacetalic Units into 3 Isoquinoline-1-thiones or Quinolin-4-ones as a Function of the Acetalic Ring-Size 4 5 Mateo Alajarin†, Marta Marin-Luna,‡ Pilar Sanchez-Andrada*,†, and Angel Vidal†¥ 6 7 8 † Department of Organic Chemistry, Faculty of Chemistry. University of Murcia. 9 Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain 10 11 E-mail: [email protected] 12 13 ‡Departamento de Química Orgánica, Universidade de Vigo, Campus Lagoas-Marcosende, 36310 Vigo, Spain 14 ¥ 15 Recently passed away 16 17 18 ORCID ID’s: Prof. M. Alajarin 000-0002-7112-5578, Dr. M. Marin-Luna 0000-0003-3531-6622 Prof. P. Sanchez Andrada 000-0002-9944-8563, 19 Prof. A. Vidal 000-0002-4347-6215. 20 21 22 23 24 25 Abstract 26 27 C-Alkoxycarbonyl-C-phenyl-N-aryl ketenimines bearing 1,3-dithiolan-2-yl or 1,3-dithian-2-yl substituents at ortho-position of the C-phenyl ring 28 respectively transform into isoquinoline-1-thiones and quinolin-4-ones under thermal treatment in toluene solution. The formation of 29 isoquinolinethiones involves a rare degradation of the 1,3-dithiolane ring whereas, in contrast, the 1,3-dithiane ring remains intact during the 30 reaction course leading to quinolin-4-ones. Computational DFT results support that the kinetically favourable mechanism for the formation of 31 isoquinoline-1-thiones proceeds through a [1,5]-hydride shift/6-electrocyclization cascade followed by a thiirane extrusion process. Alternative 32 mechanistic paths showing interesting electronic reorganization processes have been also scrutinized but resulted not competitive on energetic 33 grounds. 34 35 Introduction 36 37 38 Hydrogen atom transfer reactions (HAT) directed towards the functionalization of a C(sp3)-H bond are of utmost importance 39 in chemical synthesis.1–4 Among them, intramolecular cyclizations promoted by the migration of a H atom as a hydride anion 40 between two sites of a molecular framework have gained considerable attention during the last decades. In such reactions, also 41 known as internal redox processes, alkyl groups linked to either ethereal O atoms, tertiary N atoms or aryl rings, and containing 42 C-H bonds, are the typical hydride-donor fragments whereas an electrophilic centre in the same molecule acts as the hydride 43 acceptor, thus yielding transient dipolar structures (intermediates or transition states) that finally cyclizes to the final species.5– 44 18 Ketenimines are azacumulenic compounds in which the electrophilic central carbon atom is linked by -bonds to the adjacent 45 carbon and nitrogen atoms. A great number of published works demonstrate the versatile reactivity of ketenimines, for instance, 46 taking part in pericyclic reactions or acting as receptor towards nucleophilic additions.19–21 In the context of this introduction, our 47 group have contributed to increase the synthetic applications of intramolecular redox cyclizations with seminal works showing 48 the hydride-donor characteristics of acetalic C-H fragments in combination with the hydride-acceptor role played by the central 49 carbon atom of (aza)cumulenes such as ketenimines, carbodiimides, ketenes and allenes in tandem processes delivering spiro- 50 or polycyclic substrates which are difficult to access by other synthetic procedures.22–28 51 In these context we recently reported the synthesis of 1,3-dioxolan-isoquinolines 2 from the C-[ortho-(1,3-dioxolan-2- 52 yl)phenyl]-N-aryl ketenimines 1.29 These transformations were proposed to occur through a [1,5]-H/6-electrocyclic ring closure 53 cascade. In the present work, we initially assumed that the thermal treatment of related ketenimines bearing 1,3-dithiolane (3) 54 or 1,3-dithiane functions (5) should similarly afford the dithioacetal-isoquinolines 7. We report herein that, somewhat surprisingly, 55 this is not the case but also that ketenimines 3 and 5 show an interesting chemodivergent reactivity by which the 56 isoquinolinethiones 4 and quinolones 6 are the respective single isolated products in a series of thermally-driven cyclizations in 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 2 of 18

toluene solution (Scheme 1). Intrigued by the unusual degradation of the 1,3-dithiolane ring during the 3 → 4 conversion we 1 have also studied the mechanism governing the formation of isoquinolinethiones 4 by theoretical methods at DFT levels. 2 3 Scheme 1. Thermal treatment of 1,3-dioxolan-ketenimines 1 and 1,3-dithioacetal-ketenimines 3 and 5. 4 a) Previous work 5 6 O 7 H O O Ar 8 O  N N 9 C Ar 10 [1,5]-H/6-ERC H 1 1 2 1 11 CO2R CO2R 12 13 b) This work 14 15 S S 16 H Ar 17 S  N 18 N C Ar 19 H 20 1 1 3 CO2R 4 CO2R 21 22 23 S 24 H S H S 25 S  26 N O 2 C Ar R 27 28 1 CO2R 29 R1O N 5 H 6 30 n 31 S S 32 Ar N 33 34 H 35 CO R1 36 2 37 7 not observed 38 39 40 41 Results and Discussion 42 43 Since Staudinger published the first synthesis of ketenimines30 different methods have been reported for accessing to this 44 kind of azacumulenes.31,32 Among them, the combination of ketenes and iminophosphoranes has been shown to be a competent 45 protocol.33 Nevertheless, the high reactivity exhibited by ketenes turns complicated their isolation and further manipulation. In 46 this sense, the decided to synthesize the ketenimines 3 and 5 by reacting different iminophosphonares with in-situ generated 47 ketene precursors. Thus, we started with the preparation of diazoacetoacetates 10 which convert into ketenes under thermal 48 conditions through a Wolff rearrangement.34 Benzaldehydes bearing a (di)thioacetal unit at ortho-position 8 were reacted with 49 -diazoesters 9 in dimethylsulfoxide solution at room temperature and in the presence of a catalytic amount of 1,8-diazabicyclo- 50 [5.4.0]undec-7-ene (DBU) and the oxidant 2-iodoxybenzoic acid (IBX).35 After 10-15 h of stirring, diazoacetoacetates 10 were 51 isolated in 50-76% yield (Scheme 2). With diazoacetoacetates 10 in our hands and motivated by the results obtained in our 52 previous work29 we first explored the ability of the potential dithiolane-ketenes to experiment a tandem [1,5]-H shift/6-ERC 53 reaction. However, a complex mixture of unidentified products was obtained when toluene solutions of 10a,b were refluxed. 54 55 Scheme 2. Preparation of diazoacetoacetates 10. 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 18 The Journal of Organic Chemistry

1 2 X 3 H 4 n S 5 1 N2 CO2R 6 CHO DBU, IBX 7 8 9 8 DMSO, r.t. 9 10 11 X H 12 10a, X = S, n = 1, R1 = Et, 60% S n 13 10b, X = S, n = 1, R1 = Me, 50% 14 O 10c, X = O, n = 1, R1 = Et, 76% 15 10d, X = S, n = 2, R1 = Et, 50% 16 1 N2 CO2R 17 18 Following our initial strategy, toluene solutions containing diazoacetoacetates 10a-c and a stoichiometric amount of N- 19 aryliminophosphoranes 11 were heated at reflux temperature for 10-15 h. Transient ketenimine intermediates 3 were observed 20 by infrared spectroscopy during the reaction (~2000 cm-1). In contrast to the expected formation of the spiro compounds 7 (n = 21 1), which would result from a cascade [1,5]-H/6-ERC sequence, isoquinolinethiones 4a-d were the single isolated products 22 (Scheme 3) and were fully characterized by 1H and 13C-NMR spectroscopy (see Table 1 and SI). Thus, 1H-NMR spectra of 4a- 23 d present a singlet at 8.27-8.33 ppm associated with the hydrogen at C3 atom. Their 13C-NMR spectra show a peak at ~188 24 ppm that matches with the presence of a thiocarbonyl group of the thiolactam function. Taking into account the atomic 25 connectivity of the products 4a-d it seems that the acetalic hydrogen atom has migrated towards the central carbon atom of the 26 ketenimine motif followed by a ring closure process. Remarkably, the formation of isoquinoline-1-thiones 4 involves the 27 degradation of the 1,3-dithiolane ring, which presumably might be a consequence of the extrusion of either a thiirane molecule 28 or both ethylene and sulphur molecules. A related transformation took place when similar 1,3-oxathiolane-ketenimine 12 (X = 29 O) was subjected to thermal treatment, leading to the isoquinolin-1-one 13, whereas the formation of the corresponding 30 spiroisoquinoline (14) did not occur (Scheme 3). 31 32 Scheme 3. Preparation of isoquinoline-1-thiones 4 and isoquinolin-1-one 13 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 4 of 18

X X H 1 Ar-N=PPh3 H 2 S 11 S 3 N O C Ar 4 Toluene, reflux, 10-15 h 1 5 1 CO2R 6 N2 CO2R 10a-c 3, X = S 7 12, X = O 8 9 10 X S 11 Ar 12 N 13 H 14 1 X 15 7, n = 1, X = S CO2R 14, X = O Ar 16 N 17 18 H 19 1 CO2R 20 4, X = S 21 13, X = O, Ar = 4-Br-C6H4 22 23 24 Table 1. Isoquinoline-1-thiones 4 and isoquinol-1-one 13 25 Compound X Ar R1 Yield (%)

26 4a S 4-Me-C6H4 Et 74

27 4b S 4-Me-C6H4 Me 70

28 4c S 4-MeO-C6H4 Et 58 29 4d S 1-Naphthyl Et 60

30 13 O 4-Br-C6H4 Et 50 31 32 Interestingly, the thermal treatment of the diazoacetoacetate 10b in presence of N-(1-naphthyl) iminophosphorane 11a 33 delivered the isoquinolinethione 4e together with the quinolone 15 in 44% and 20% yield, respectively (Scheme 4). Both 1H- and 34 13C-NMR spectra of 15 reveal that the 1,3-dithiolane group remained unaltered during the course of the reaction whereas the 35 methoxy group migrated to the central carbon atom of the intermediate ketenimine 3e (n=1, R1 = Me, Ar= 1-naphthyl). 36 37 Scheme 4. Preparation of the isoquinolinethione 4e and the quinolone 15 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 5 of 18 The Journal of Organic Chemistry

S H 1 PPh3 2 S N 3 O 4 5 6 N2 CO2Me 7 10b 11a 8 9 Toluene, 10 reflux, 15 h 11 12 13 S S 14 Ar S N O 15 H 16 17 H CO Me 18 2 MeO N 19 4e, 44% 15, 20% H 20 21 22 As in previous examples, the transient dithiolane-ketenimine 3e was identified by infrared spectroscopy during the reaction 23 and the formation of the quinolone 15 could be justified by attending to the results obtained in the thermal treatment of structurally 36 37 24 analogous C-alkoxycarbonyl-N-aryl ketenimines, as reported by Motoyoshiya and Wentrup. Scheme 5 shows the proposed 25 mechanism for the conversions 3e → 15. This should proceed by an initial [1,3]-OMe shift from the ester function to the central 26 carbon atom of the ketenimine unit to give the imidoylketene 16 that should then undergo a 6-ERC to yield the final quinolone 27 15. This final step would involve the C=C double bond of the ketene, its conjugated C=N bond and one C=C double bond of the 28 naphthyl group at the N atom. 29 30 Scheme 5. Mechanistic proposal for quinolone 15 31 H S 32 [1,3]-OMe S 33 N 34 C 35 3e 36 O OMe S 37 H S 38 O 39 C 40 41 MeO N 42 16 43 S 44 H S 45 O 46 6-ERC 47 48 MeO N 49 H 50 15 51 52 This later example indicates that both initial hydride and methoxy migration processes could be competitive depending on the 53 reactant. This fact led us to argue that the dual reactivity mode of the transient ketenimines might be modulated. We reasoned 54 that the hydride migration ability would decrease in compounds bearing dithiane units instead of dithiolane,25 and therefore, the 55 alkoxy migration would be promoted. Added to this, in case of [1,5]-H migration process, the expansion of the dithioacetal ring 56 would probably avoid the degradation of the dithioacetal unit and would perhaps allow the isolation of some of the putative 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 6 of 18

intermediates as those analogous to spiroisoquinolines 7. With this strategy in mind, dithiane-diazo compounds 10d were 1 reacted with iminophosphoranes 11a-c in toluene solution at reflux temperature for 15 h. This thermal treatment selectively 2 furnished the quinolones 6 in good yields whereas no products from an initial [1,5]-H migration were detected (Scheme 6). The 3 mechanism behind the transformation of ketenimines 5 into quinolones 6 would be similar to that previously commented for the 4 formation of the structurally related quinolone 15 (see Scheme 5). 5 6 Scheme 6. Preparation of quinolones 6 7 S 8 S H Ar-N=PPh H 9 3 S 11a-c 10 S O N 11 Toluene, reflux, C Ar 12 15 h CO Et 13 N2 CO2Et 2 5 14 10d 15 16 17 18 S S 19 1 2 3 6a, R = H, R =R =C4H4, 83% O 20 1 2 3 H 6b, R = CH3, R =R =H, 70% 1 21 R 6c, R1= OCH , R2=R3=H, 81% 22 3 23 EtO N R2 H 24 R3 25 26 Whereas the lesser propensity of the dithioacetalic H atoms for participating in this type of [1,5]-hydride shifts, in comparison 27 with their acetalic counterparts,24,25 and the involvement of alkoxy groups from ester functions in 1,3-alkoxy migrations toward 28 the central carbon atom of heterocumulene functions,36,37 accounting for the resulting quinolones 6 and 15, have been disclosed 29 in advance and computationally studied, the apparent extrusion of a C2H4S fragment (or combination of fragments) in the conversion of ketenimines 3 into isoquinoline-1-thiones 4 merits to be addressed with the aid of a DFT study. We studied this 30 latter transformation at the PCM(toluene)-wB97XD/def2TZVP//PCM(toluene)-B3LYP/6-31+G* theoretical level by exploring the 31 potential energy surface (PES) associated to the conversion of C-[ortho-(1,3-dithiolan-2-yl)phenyl], C-methoxycarbonyl, N- 32 phenyl ketenimine (3f) into N-phenyl-4-methoxycarbonyl-isoquinolin-2-thione (4f) (for full details see Supp Info). The qualitative 33 reaction profiles found for this transformation are depicted in Figure 1, while Table 2 discloses the energy barriers computed for 34 each mechanistic step 35 We have found several paths potentially accounting for these transformations. Some of they finally lead to 4f, whereas others 36 result in species that can be converted into 4f by apparently simple and easy sulphur extrusions. Fortunately, in spite of the 37 existence of alternative reaction paths that complicated the analysis of the PES under study, this computational study predicts 38 that one of them is clearly favoured over the rest. 39 All the located paths start from the intermediate INT-1 formed in the first step, in which ketenimine 3f undergoes a [1,5]-H 40 shift leading to INT-1 via TS1, 32.9 kcal·mol-1 above in energy than 3f. Former studies of our group demonstrated that this kind 41 of processes is assisted by the sulphur atoms of the 1,3-dithiolane ring.7,24,25,27 Then, this intermediate can follow several 42 alternative routes. On the basis of its structure, the mechanistic paths shown in Scheme 7 can be tentatively anticipated. Note 43 that INT-1 possesses a 1-aza-hexatriene system allowing the formation of a pyridine ring annulated to the ortho-phenylene one 44 via a 6-electrocyclic ring closure giving INT-2A. A subsequent retro-[3+2]-cycloaddition with thiirane extrusion would lead to 45 the final product via path A. Moreover, an alternative path B can be conceived involving the 1-thia-butadiene fragment of INT-1 46 enabling a different kind of ring closure, a 1,5-cyclization leading to the dipolar intermediate INT-2B, which could later lose 47 ethylene giving INT-3B. The nucleophilic addition of its iminic nitrogen atom into the thiocarbonylic carbon could lead to the 48 dipolar intermediate INT-4B that would evolve to 4f by sulphur extrusion. And finally, a third route for the evolution of INT-1 49 consisting of a 1,7-ring closure through path C can be considered. This process would lead to the tricyclic benzothiazepine INT- 50 2C, which by loss of ethylene could evolve to the benzothiazepin-1-thione INT-3C. Its conversion through the formation of a six- 51 membered ring by the nucleophilic addition of the nitrogen atom to the thiocarbonylic carbon would lead to the dipolar 52 intermediate INT4-C, which could be converted into the final product by sulphur extrusion (see Scheme 7). 53 54 Scheme 7. Tentative mechanistic reaction paths for the transformation of ketenimine 3f into N-phenyl-4-methoxycarbonylisoquinolin-1-thione 55 (4f) 56 57 58 59 60 ACS Paragon Plus Environment Page 7 of 18 The Journal of Organic Chemistry

S S S 1 S S Ph 2 N 3 N Ph N Ph S 4 -H2C CH2 5 H INT-2C CO Me INT-3C CO Me INT-4C CO Me 6 2 2 2 7 - S8 8 Path C 9 10 S S S S S 11 H S [1,5]-H Path A Ph Ph 12 S H N N N 13 C Ph Ph - 14 N S 1 2 15 CO2Me INT-1 CO2Me INT-2A CO2Me CO2Me 16 17 Path B - S 18 8 19 S S S 20 Ph 21 N S S S 22 Ph -H C CH N 23 N 2 2 Ph MeO2C MeO C INT-4B 24 H 2 CO2Me 25 INT-2B INT-3B 26 27 Next, we will discuss in detail each of the mechanistic steps we have found for these three reaction paths. 28 Following path A, the species INT-1 is converted into the spiroisoquinoline INT-2A. This process takes place via TS-2A and 29 shows a very low energy barrier, only 2.1 kcal·mol-1 (Scheme 8). This fact can be attributed to the polar nature of this 6-ERC, 30 with the nitrogen lone pair adding to the electrophilic thioacetalic carbon atom, besides the recovering of aromaticity in going 31 from INT-1 to INT-2. We were able to locate two alternative reaction paths for the evolution of this intermediate (see paths A1 32 and A2 in Figure 1 and Scheme 8). Firstly, we found TS-3A1 connecting INT-2A with the dipolar intermediate INT-3A, which via 33 transition structure TS-4A1 leads to thiirane and the final product 4f. The computed barrier for the first of these two steps is 35.9 34 kcal·mol-1, whereas the second one has a very low barrier of 1.6 kcal·mol-1. 35 It is worth to comment that TS-3A1 shows some peculiarities. This transition structure accounts for the breaking of one bond 36 between the thioacetalic carbon and one of the sulphur atom, besides the rotation along the C-C bond of the 1,3-dithiolane ring, 37 thus facilitating the thiirane extrusion that will take place in the following step. The distance of the C-S bond being broken is 38 quite large, 4.22 Å (see Figure S2 in the Supporting Info), indicating that in this transition structure this bond is nearly broken. 39 By analysing the motions associated to its imaginary frequency, only the rotation along the C-C bond of the 1,3-dithiolane ring 40 seems to be evident. However, by computing the intrinsic reaction coordinate (IRC), the breaking of that C-S bond can be seen 41 in the earlier steps upwards hill, supporting this transition structure connects INT-2A with INT-3A. The analysis of the computed 42 NBO charges and bond orders for INT-2A, TS-3A1 and INT-3A supports that participation of the nitrogen atom plays a decisive 43 role weakening one of the two thioacetalic carbon-sulphur bonds (see Table S2 in the Supporting Info), thus facilitating the 44 transformation of the 1,3-dithiolane ring into a thiocarbonylic group by extrusion of thiirane. 45 In the following step, through TS-4A1, the negatively charged sulphur atom of INT-3A causes a nucleophilic substitution at 46 the methylene linked to the other sulphur atom, that one which is going to form the thiocarbonylic group in 4f, leading to thiirane 47 and the isoquinolin-1-thione 4f. This process is predicted to occur easily from INT-3A, probably due to the good nucleophilic 48 and leaving group nature of both partners in the SNi reaction, thus explaining that not significant energy barrier has been 49 computed for this step. 50 51 Scheme 8. Stationary points found for the conversion of INT-1 into 4f at the PCM-B3LYP/6-31+G* theoretical level via paths A1 and A2. 52 Energy barriers and relative energies in kcal·mol-1 computed at the PCM(toluene)-wB97XD/def2TZVP//PCM(toluene)-B3LYP/6-31+G* 53 theoretical level 54 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 8 of 18

1 Path A S 2 S 3 N Ph 4 (18.0) 5 INT-1 6 CO2Me 7 8 S S Ph 9 N G = 2.1 10 11 (20.1) S S TS-2A 12 CO2Me 13 N Ph 14 S S (18.7) 15 Ph TS-3A1 16 N CO2Me 17 Path A (-17.2) 1 18 INT-2A G = 35.9 19 CO2Me S 20 S 21 Ph N 22 S S Path A 23 Ph 2 (15.9) 24 N  G = 49.5 INT-3A CO Me 25 2 26 (32.3) TS-3A2 S 27 CO2Me 28 S 29 Ph N 30 S 31 Ph (17.5) 32 TS-4A N 1 CO Me 33 S + 2 34 G = 1.6 (-21.5) 2 35 CO2Me 36 37 38 The above transformation, INT-2A → 4f, could also take place in one step but the energetic cost would be higher. Thus, we 39 located TS-3A2, whose electronic reorganization corresponds to a retro-[3+2]-cycloaddition process leading to thiirane and 4f. 40 The computed energy barrier is 49.5 kcal·mol-1, 13.6 kcal·mol-1 higher than the alternative two-step transformation INT-2A → 41 INT-3A→ 4f. The NBO charges and bond orders computed for TS-3A2 show again the beneficial effect of the lone pair at the 42 nitrogen atom in the breaking of the bond between the thioacetalic carbon and one sulphur atoms (see Support Info). 43 Similar thiirane extrusions from 1,3-dithiolane-spirocompounds have been previously described by Ueno,38 Barluenga39 and 44 Fishwick.40 Probably, also in these cases the presence of a nitrogen atom linked to the acetalic carbon atom in the molecule 45 that undergoes the thiirane extrusion facilitates the process, although this fact was not explicitly argued. 46 We also investigated the possibility that triphenylphosphane oxide, formed in the reaction mixture when ketenimine 3f is 47 generated from the appropriate ketene and iminophosphorane, could catalyse the extrusion of thiirane from INT-2A. However, 48 the energy barriers associated to this reaction path are very high compared to those of alternative paths A1 and A2. For clarity, 49 we have excluded this route from the general discussion, but it can be found in the Supporting Info. 50 By comparing the heights of the energy barriers corresponding to paths A and A , the predicted reaction path among these 51 1 2 three possibilities is neatly path A1. 52 From INT-1, another path that can be reasonably envisaged for the conversion under study entails a 1,5-ring closure, with 53 formation of a new S-C bond, leading to the tricyclic species INT-2B. This ylide could evolve via a retro-[3+2]-cycloaddition to 54 give ethylene and the benzo[c]thiophene-1-thione (INT-3B), as shown in Scheme 9. Contrarily to that expected, we have located 55 TS-2B, which directly connect INT-1 with INT-3B. Namely, both processes, the 1,5-ring closure and the retro-[3+2]-cycloaddition, 56 seem to take place simultaneously in a single reaction step. The computed energy barrier is 34.4 kcal·mol-1. Then, species INT- 57 58 59 60 ACS Paragon Plus Environment Page 9 of 18 The Journal of Organic Chemistry

3B provides the dihydrothiireno[2,3-c]isoquinoline-3(2H)-thione (INT-4B’) by addition of the nitrogen atom to the thiocarbonylic 1 carbon atom with simultaneous migration of a sigma bond from that carbon atom to the iminic one, thus generating the thiirane 2 ring shown by INT-4B’ (instead of leading the species INT-4B that initially we had proposed in Scheme 7). The energy barrier 3 computed for this latter step, 41.7 kcal·mol-1, is somewhat higher than the previous one. 4 The conversion of INT-1 into INT-3B merits some comments. There is an electronic reorganization similar to a 1,5-ring closure 5 with simultaneous retro-[3+2]-cycloaddition. The 1,5-ring closure can be seen as thia-analogous to a 1,5-electrocyclization41–44 6 of a pentadienyl anion if the isoelectronic exchange of the carbanionic methylene by the sulphur atom is considered.45 The 7 simultaneity of these two pericyclic events is quite curious and fascinating. As actually it takes place in a single process, it can 8 be conceived as a vinylogous-thia-retro-ene23,46 reaction where, instead of a hydrogen atom, it is the sulphur atom that migrates

9 breaking its S-CH2 bond and making a new S-C bond at the end of the 1-thia-butadiene core. This means that ethylene and the 10 1-thiabutadiene fragment of INT-3B would be the enophile and vinylogous ene components respectively, with sulphur being the 11 migrating atom. This rare conversion has precedent in earlier work from our group,23 since we found that N-[2-(1,3-oxathiolan- 12 2-yl)]phenyl ketenimines, under thermal treatment, are converted into the corresponding benzisothiazol-3-ones via 13 intermediates ortho-azaxylylene which experiences similar vinylogous-thia-retro-ene process.47 14 15 Scheme 9. Stationary points found for the conversion of INT-1 into INT-4B’ (path B) at the PCM-B3LYP/6-31+G* theoretical level along with 16 those initially proposed (see main text). Energy barriers and relative energies in kcal·mol-1 computed at the PCM(toluene)- 17 wB97XD/def2TZVP//PCM(toluene)-B3LYP/6-31+G* theoretical level 18 19 S 20 Path B 1,5-ring closure S 21 S 22 Ph 23 N S 24 (18.0) INT-1 N 25 CO2Me Ph MeO2C 26 27 S S 28 INT-2B 29 S G = 34.4 S 30 N N Ph 31 Ph MeO C MeO2C 2 32 (52.4) TS-2B 33 S 34 S retro-[3+2]- S 35 cycloaddition N 36 C H + S Ph 2 4 N MeO C 37 (-1.8) Ph 2 38 MeO2C 39 INT-3B S 40 S Ph 41 N Ph S 42 N INT-4B 43 S G = 41.7 44 CO2Me 45 CO2Me 46 TS3B 47 (40.0) S 48 Ph 49 S N 50 51 (-1.4) INT-4B' 52 CO2Me 53 54 Once intermediate INT-4B’ is formed, its evolution to the final compound 4f could be explained by sulphur extrusion. In spite 55 of the number of experimental reactions where species with the thiirane motif evolve by extrusion of sulphur, the mechanistic 56 aspects of this topic have been scarcely treated in the literature. We have not found exhaustive computational studies. Miller 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 10 of 18

and col.48 reported on the computationally study of sulphur extrusion from thienothiophene by semiempirical methods, but 1 complete characterization of the overall sulphur extrusion from thiirane intermediates was excluded due its computational cost 2 and complexity. On the basis of the energetic profile of several stationary points, the authors established that the extrusion of 3 atomic sulphur is unfavourable, and proposed thiirane species leading to more stable forms of sulphur. More recently, M. Z.

4 Kassaee et col. have proposed a similar mechanism for explaining the conversion of thiepine into benzene and S8, where the 5 sulphur-sulphur extraction take also place through benzo-thiirane intermediates, but it not was computationally studied.49

6 An in-depth study of sulphur extrusion from species such as INT-4B’, that could lead to the desired 4f and S2 or more stable 7 allotropic forms of sulphur, is out of the scope of this work. For this reason, we have only explored the sulphur-sulphur extraction

8 between two molecules of INT-4B’ leading to 4f and S2. This could allow to check if this kind of sulphur extrusion show amenable 9 energy barriers. Our results show that this is the case (see the Supporting Info). 10 11 Table 2. Free Gibbs energy barriers[a] computed at the PCM- 12 wB97XD/def2TZVP//PCM-B3LYP/6-31+G* theoretical level for the transformation of ketenimine 3f into N-phenyl-4- 13 methoxycarbonylisoquinolin-2-thione (4f), considering toluene as 14 solvent. 15

16 ≠ ≠ Mechanistic Step ΔG i ΔG i -1 17 퐓퐒 ― ퟏ 32.9 14.8 18 3f INT-1 19 퐓퐒 ― ퟐ퐀 2.1 37.3 20 INT-1 INT-2A

21 퐓퐒 ― ퟑ퐀ퟏ 35.9 2.7 22 INT-2A INT-3A 퐓퐒 ― ퟒ퐀ퟏ 1.6 39.0 23 INT-3A 4f 24 퐓퐒 ― ퟑ퐀ퟐ 49.5 53.8 25 INT-2A 4f

26 퐓퐒 ― ퟐ퐁 27 INT-1 INT-3B 34.4 54.2 28 퐓퐒 ― ퟑ퐁

29 INT-3B INT-4B’ 41.7 41.4 퐓퐒 ― ퟐ퐂 30 INT-1 INT-2C 36.5 7.1 31 퐓퐒 ― ퟑ퐂 32 INT-2C INT-3C 4.4 34.7

33 퐓퐒 ― ퟒ퐂 34 INT-3C INT-4C’ 31.3 5.8 35 36 ΔGrxn 4f -21.5 37 ΔGrxn INT-4B’ -1.4 38

39 ΔGrxn INT-4C’ 44.6 40 -1 41 [a] Energy barriers in kcal·mol . 42 43 The last mechanistic route we have studied is path C, which can be also seen in the Figure 1 along with the others previously 44 commented, and in Scheme 10. It begins with a 1,7-ring closure via TS-2C that provides a S-N bond between the ending atoms 4 45 of the 1-thia-7-aza-2,4,6-heptatriene system present in INT-1, and leads to INT-2C with a bridgehead  -sulphur atom. Among 46 the three ring closures of INT-1 depicted in Figure 1 (i. e. 6-ERC in path A, 1,5-ring closure/retro-[3+2]-cycloaddition in path B, -1 47 and 1,7-ring closure in path C), this is the one that shows the highest energy barrier, 36.5 kcal·mol . In a subsequent reaction 48 step, INT-2C undergoes retro-[3+2]-cycloaddition losing ethylene to give the benzo[e][1,2]thiazepine-1(3H)-thione INT-3C -1 49 through the transition structure TS-3C. The energy barrier for this transformation was computed to be low, 4.4 kcal·mol . This 50 can be explained by the favourable formation of the C=S bond shown by INT-3C, along with the beneficial ethylene losing. 51 52 Scheme 10. Stationary points found at the PCM-B3LYP/6-31+G* level of theory for the conversion of INT-1 into INT-4C’ (path C) showing -1 53 relevant bond distances. Energy barriers and relative energies in kcal·mol computed at the PCM(toluene)-wB97XD/def2TZVP//PCM(toluene)- 54 B3LYP/6-31+G* theoretical level 55 56 57 58 59 60 ACS Paragon Plus Environment Page 11 of 18 The Journal of Organic Chemistry

1 Path C S 2 S 3 N Ph 4 (54.5) S 5 TS-2C 6 CO2Me S 7 INT-1 N Ph (18.0)  8 G = 36.5 (47.4) 9 INT-2C CO Me 10 2 11 S 12 13 S - C2H4 14 N Ph G = 4.4 15 (51.8) 16 TS-3C CO Me 17 2 18 S S 19 S Ph S 20 N 21 N Ph + C2H4 22 (17.1) 23 INT-4C INT-3C CO2Me CO Me 24 2 25 S S 26 27 N Ph G = 31.3 28 29 (50.4) 30 TS-4C CO2Me 31 32 S S 33 Ph 34 N 35 (44.6) 36 INT-4C' 37 CO2Me 38 39 Finally, its evolution by a 6-electrocyclic ring closure leading to 4-(methoxycarbonyl)-2-phenyl-[1,2]thiazireno[3,2- 40 a]isoquinolin-2-ium-8b(2H)-thiolate (INT-4C) could be easily envisaged (see Scheme 10). However, we located the transition 41 structure TS-4C where, simultaneously to the bond making between the thiocarbonylic carbon and the nitrogen atoms, the 42 breaking of the bond joining the thiocarbonylic carbon and the sulphur of the thiazepine ring takes place. Consequently, this 43 process results into the 1-thioxo-1,2-dihydroisoquinolinium 2-thiolate INT-4C’, instead of leading to a 1,2-thiaziridine ring 44 annulated to the benzoisoquinoline system as shown in Scheme 10. The energy barrier computed for this conversion is only of -1 45 31.3 kcal·mol . We assume that INT-4C’ can be converted to the final 4f by means of sulphur extrusion processes similar to 46 those commented above. 47 48 49 Figure 1. Qualitative reaction profiles of the mechanistic reaction paths found for the transformation of ketenimine 3f into N- 50 phenyl-4-methoxycarbonyl-isoquinolin-2-thione (4f) at the PCM(toluene)-wB97XD/def2TZVP//PCM(toluene)-B3LYP/6-31+G* -1 51 theoretical level. Energy barriers in kcal·mol 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 12 of 18

PCM-wB97XD/def2-TZVP //PCM-B3LYP/6-31+G* S 1 S G298,sol(Toluene) -1 S 2 60 kcal mol N Ph S S S S 3 TS-2C N Ph N Ph S CO2Me S 4 54.50 N Ph S TS-3C CO2Me TS-4C N 52.45 CO2Me 5 INT-2C 51.82 50.41 50 Ph CO2Me MeO2C 6 TS-2B G =4.4 S Ph Path C 47.44 N 7  S G =36.5 44.58 S S - C2H4 S S 8 S S Path B TS-3B Ph 40 Ph CO2Me H G =34.4 N N 9 Ph 39.96 G =31.3 N 10 - C2H4 INT-4C' TS-1 TS-3A CO Me CO2Me 2 CO2Me 2 11 32.86 32.32 S 12 30  S S G =41.7 S Ph S S 13 N N Ph Ph 14 N TS-2A 15 CO2Me TS-3A1 20 20.09 CO2Me TS-4A1 CO2Me 18.02 Path A 18.66 16 G =32.8 17.53 17.09 G =2.1 17 S G =1.6 S S 15.92 S S H 18 S N Ph Ph 19 10 N Ph INT-1 N INT-3C CO2Me CO2Me 20 Path A2  INT-3A 21 G =49.5 CO2Me

22 0 -1.76 S -1.40 S 23 H S S Ph N 24 N Path A1 S C Ph S G =35.9 N 25 3f Ph CO2Me MeO C INT-4B' -10 2 INT-3B CO2Me 26 S 27 Ph N S 28 -17.22 + -20 4f 29 S S CO2Me Ph -21.49 30 N

31 INT-2A CO2Me 32 -30 33 Reaction Coordinate 34 35 By analyzing the reactions profiles depicted in Figure 1, the following points can be inferred: 36 . The thermal treatment of ketenimine 3f induces a 1,5-H shift leading to the corresponding ortho-xylylene intermediate 37 INT-1 which can follow three alternative routes, paths A-C, leading to the isoquinolin-1-thione 4f. Each of them starts 38 with a cyclization involving different heteropolyene fragments of INT-1. In this way, path A initiates with a 6-ERC 39 involving its 1-aza-hexatriene frame. Path B consists of a fascinating vinilogous retro-thia-ene reaction as first step, 40 involving the 1-thiabutadiene fragment of INT-1, but also the whole 1,3-dithiolane ring. And path C is the 1-thia-7- 41 aza,2,4,6-heptatriene system of INT-1 that undergoing a 1,7-ring closure. 42 . Each path A-C consists in turn of several mechanistic steps and, whereas path A leads directly to the final product 4f, 43 paths B and C give rise to intermediates which can be converted into 4f by sulphur extrusion. 44 . Path A involves the formation of a spiro-1-(1,3-dithiolane-2-yl)isoquinoline in the first step, which can further follow two 45 alternative routes, A1 and A2, accounting for thiirane extrusion leading to the isoquinolin-1-thione 4f. Between them, 46 path A1 involves the lowest energy cost. 47 . On the basis of the energy profiles computed for each path, this study predicts that Path A1 would be the preferred 48 one. 49 50 51 52 Conclusions 53 In conclusion, we have reported here the chemodivergent reactivity under thermal conditions of C-alkoxycarbonyl-C- 54 phenyl-N-arylketenimines bearing five- and six-membered dithioacetalic units at ortho position of the C-phenyl ring. 55 The ketenimines have been prepared in-situ by reacting diazoacetoacetates, as ketene precursors, with N-aryl 56 iminophosphoranes. Transient 1,3-dithiolane-ketenimines yielded isoquinoline-1-thiones under heating in toluene 57 58 59 60 ACS Paragon Plus Environment Page 13 of 18 The Journal of Organic Chemistry

whereas in contrast quinolin-4-ones are obtained in the case of ketenimines carrying a larger 1,3-dithiane group. This 1 latter transformation, in which the 1,3-dithiane fragment remains unaltered, has been proposed to occur through a 2 tandem [1,3]-OEt/6-ERC process. A thorough DFT study has been performed to elucidate the mechanism governing 3 the formation of isoquinolinethiones from 1,3-dithiolane-ketenimines. Our results show that the kinetically favourable 4 path initiates with a [1,5]-hydride shift of the acetalic hydrogen atom towards the central carbon atom of the ketenimine 5 motif followed by a 6-electrocyclization. Finally, the 1,3-dithiolane ring is degraded by extrusion of a thiirane molecule 6 in a two-step process. Alternative mechanistic paths involving either a vinylogous-thia-retro-ene process or a 1,7-S,N- 7 ring closure have been computationally characterized but are energetically non-competitive. 8 9 10 Experimental Section 11 12 General experimental information 13 All of the melting points are uncorrected. IR spectra were recorded as Nujol mulls or as neat samples. 1H NMR spectra were 14 13 1 recorded in CDCl3 or DMSO-d6 at 300 or 400 MHz. C{ H} NMR spectra were recorded in CDCl3 at 75 or 100 MHz. The 15 chemical shifts are reported in ppm (δ), relative to the resonance of CDCl3 at δ = 7.26 ppm and of DMSO-d6 at δ = 2.50 ppm for 16 1 13 1 H and for C{ H} relative to the resonance of CDCl3 δ = 77.16 ppm and of DMSO-d6 at δ = 39.5 ppm. Mass spectrometry was 17 recorded on HPLC-MS TOF 6220 instrument. 18 19 Materials: 2-(2-bromophenyl)-1,3-oxathiolane, N-formylpyperidine and ethyl/methyl diazoacetate were commercially available. 20 The following substrates have been prepared according to the literature: 2-(1,3-dithiolan-2-yl)benzaldehyde 8a,50 2-(1,3- 21 oxathiolan-2-yl)benzaldehyde 8c,10 2-(1,3-dithian-2-yl)benzaldehyde 8d51 and iminophosphoranes 11.52 22 23 General procedure for the preparation of isoquinolinethiones 4, quinolones 6 and 15 and isoquinolonone 13. 24 To a solution of ethyl diazoacetate (0.18 g, 1.57 mmol) or methyl diazoacetate (0.16 g, 1. mmol) in dimethyl sulfoxide (7 mL) at 25 room temperature were added in succession DBU (0.021 mL, 0.14 mmol), the appropriate aldehyde 8 (1.33 mmol), and a 26 solution of IBX (0.74 g, 2.63 mmol) in dimethyl sulfoxide (7 mL). After 10 h, then the reaction was quenched with aqueous

27 NaHCO3 (20 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with aqueous 28 NaHCO3 (3 x 60 mL) and with water (100 mL). Finally, they were dried with MgSO4, filtered, and concentrated in vacuo. The 29 resulting crude product was purified by column chromatography on silica gel (hexanes/ethyl acetate, 4:1 v/v) to afford the 30 corresponding diazoacetoacetates 10, which were using immediately in the next step. 31 Typically, a solution containing the appropriate diazoacetoacetate 10 (0.35 mmol) and iminophosphorane 11 (0.35 mmol), in 32 anhydrous toluene (10 mL), was heated at reflux temperature for 10-15 h (6 h in case of 13). After cooling down, the solvent 33 was removed under reduced pressure and the resulting crude material was purified by column chromatography on silica gel. 34 Next, a larger scale procedure is shown for the synthesis of 4a. 35 36 4-Ethoxycarbonyl-2-(4-methyl)phenyl-2H-isoquinoline-1-thione (4a) 37 A solution containing the ethyl diazoacetoacetate 10 (0.35 g, 1.1 mmol) and (4-methyl)phenyliminophosphorane (0.40 g) 1.1 38 mmol), in anhydrous toluene (20 mL), was heated at reflux temperature for 10 h. After cooling down, the solvent was removed 39 under reduced pressure and the resulting crude material was purified by column chromatography on silica gel. 40 Eluent for chromatography column: hexanes/diethyl ether (4:1, v/v); 0.26 g; yield: 74%; mp: 165-167 ºC; yellow prisms (diethyl -1 1 41 ether); IR (Nujol) ν: 1713 (vs), 1509 (m), 1483 (vs) cm ; H NMR (CDCl3, 300 MHz)  1.36 (t, 3 H, J = 7.2 Hz), 2.44 (s, 3 H), 42 4.36 (q, 2 H, J = 7.2 Hz), 7.24 (d, 2 H, J = 8.1 Hz), 7.36 (d, 2 H, J = 8.1 Hz), 7.60 (td, 1 H, J = 8.4, 1.5 Hz), 7.78 (td, 1 H, J = 8.4, 13 1 43 1.5 Hz), 8.27 (s, 1 H), 8.89 (d, 1 H, J = 8.4 Hz), 9.10 (d, 1 H, J = 8.4 Hz) ppm; C{ H} NMR (CDCl3, 75 MHz)  14.4 (CH3), 21.4 44 (CH3), 61.3 (CH2), 111.3 (s), 125.7 (CH), 126.7 (2 x CH), 128.9 (CH), 129.7 (s), 130.5 (2 x CH), 133.0 (CH), 133.5 (CH), 134.4 + 45 (s), 139.3 (CH + s), 143.4 (s), 164.9 (s), 188.4 (s) ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for C19H18NO2S 324.1053; Found 46 324.1055. 47 48 4-Methoxycarbonyl-2-(4-methyl)phenyl-2H-isoquinoline-1-thione (4b). 49 Eluent for chromatography column: hexanes/diethyl ether (4:1, v/v); 75 mg; yield: 70%; mp: 170-172 ºC; yellow prisms (diethyl -1 1 50 ether); IR (Nujol) ν: 1702 (vs), 1508 (m), 1480 (vs) cm ; H NMR (CDCl3, 300 MHz)  2.45 (s, 3 H), 3.89 (s, 3 H), 7.24 (d, 2 H, 51 J = 7.8 Hz), 7.36 (d, 2 H, J = 7.8 Hz), 7.60 (t, 1 H, J = 7.2 Hz), 7.80 (t, 1 H, J = 7.2 Hz), 8.30 (s, 1 H), 8.90 (d, 1 H, J = 8.4 Hz), 13 1 52 9.11 (d, 1 H, J = 8.4 Hz) ppm; C{ H} NMR (CDCl3, 75 MHz)  21.4 (CH3), 52.2 (CH3), 100.9 (s), 125.6 (CH), 126.7 (2 x CH), 53 129.0 (CH), 129.6 (s), 130.5 (2 x CH), 133.0 (CH), 133.6 (CH), 134.4 (s), 139.3 (s), 139.5 (CH), 143.4 (s), 165.3 (s), 188.5 (s) + 54 ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for C18H16NO2S 310.0896; Found 310.0906. 55 56 4-Ethoxycarbonyl 2-(4-methoxy)phenyl-2H-isoquinoline-1-thione (4c). 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 14 of 18

Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 62 mg; yield: 58%; mp: 135-137 ºC; yellow prisms -1 1 1 (hexanes); IR (Nujol) ν: 1715 (vs), 1615 (s), 1485 (s) cm ; H NMR (CDCl3, 300 MHz)  1.38 (t, 3 H, J = 7.2 Hz), 3.88 (s, 3 H), 2 4.39 (q, 2 H, J = 7.2 Hz), 7.06 (d, 2 H, J = 9.0 Hz), 7.29 (d, 2 H, J = 9.0 Hz), 7.60 (td, 1 H, J = 8.1, 1.2 Hz), 7.79 (td, 1 H, J = 8.1, 13 1 3 1.2 Hz), 8.29 (s, 1 H), 8.90 (dd, 1 H, J = 8.6, 0.6 Hz), 9.12 (dd, 1 H, J = 8.6, 0.6 Hz) ppm; C{ H} NMR (CDCl3, 75 MHz)  14.3 4 (CH3), 55.5 (CH3), 61.1 (CH2), 111.1 (s), 114.8 (2 x CH), 125.5 (CH), 128.0 (2 x CH), 128.8 (CH), 129.6 (s), 132.9 (CH), 133.4 5 (CH), 134.3 (s), 138.7 (s), 139.4 (CH), 159.6 (s), 164.8 (s), 188.6 (s) ppm; HRMS (ESI-TOF) m/z: [M + H - S]+ Calcd for

6 C19H18NO3 308.1281; Found 308.1279. 7 8 4-Ethoxycarbonyl-2-(1-napthyl)-2H-isoquinoline-1-thione (4d). 9 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 75 mg; yield: 60%; mp: 165-167 ºC; yellow prisms -1 1 10 (hexanes); IR (Nujol) ν: 1715 (vs), 1612 (s), 1481 (vs) cm ; H NMR (CDCl3, 300 MHz)  1.34 (t, 3 H, J = 7.2 Hz), 4.36 (q, 2 H, 11 J = 7.2 Hz), 7.39 (d, 1 H, J = 9.0 Hz), 7.46-7.60 (m, 3 H), 7.63-7.69 (m, 2 H), 7.86 (td, 1 H, J = 8.4, 1.5 Hz), 8.01 (dd, 2 H, J = 13 1 12 13.5, 8.1 Hz), 8.31 (s, 1 H), 8.98 (d, 1 H, J = 8.4 Hz), 9.15 (dd, 1 H, J = 8.4, 0.9 Hz) ppm; C{ H} NMR (CDCl3, 75 MHz)  14.3 13 (CH3), 61.3 (CH2), 111.6 (s), 122.4 (CH), 125.1 (CH), 125.7 (CH), 125.8 (CH), 127.0 (CH), 127.7 (CH), 128.6 (s), 128.8 (CH), 14 129.0 (CH), 129.7 (CH), 129.8 (s), 132.9 (CH), 133.7 (CH), 134.4 (s), 134.5 (s), 139.7 (CH), 142.3 (s), 164.9 (s), 188.4 (s) ppm; + 15 HRMS (ESI-TOF) m/z: [M + H] Calcd for C22H18NO2S 360.1053; Found 360.1052. 16 17 4-Methoxycarbonyl-2-(1-napthyl)-2H-isoquinoline-1-thione (4e). 18 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 53 mg; yield: 44%; mp: 142-144 ºC; yellow prisms -1 1 19 (hexanes); IR (Nujol) ν: 1715 (vs), 1615 (s), 1481 (vs) cm ; H NMR (CDCl3, 300 MHz)  3.87 (s, 3 H), 7.39 (d, 1 H, J = 8.4 Hz), 20 7.48-7.58 (m, 3 H), 7.62-7.69 (m, 2 H), 7.86 (td, 1 H, J = 7.2, 1.5 Hz), 8.00 (dd, 2 H, J = 13.5, 8.1 Hz), 8.33 (s, 1 H), 9.00 (d, 1 13 1 21 H, J = 8.4 Hz), 9.15 (dd, 1 H, J = 8.4, 0.9 Hz) ppm; C{ H} NMR (CDCl3, 75 MHz)  52.2 (CH3), 111.2 (s), 122.4 (CH), 125.1 22 (CH), 125.7 (CH), 125.8 (CH), 127.0 (CH), 127.8 (CH), 128.6 (s), 128.8 (CH), 129.1 (CH), 129.8 (s), 129.9 (CH), 132.9 (CH), 23 133.8 (CH), 134.5 (s), 134.6 (s), 140.0 (CH), 142.3 (s), 165.3 (s), 188.5 (s) ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for

24 C21H16NO2S 346.0896; Found 346.0894. 25 26 3-(2-(1,3-Dithian-2-yl)phenyl)-2-ethoxybenzo[h]quinolin-4(1H)-one (6a). 27 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 125 mg; yield: 83%; mp: 156-158 ºC; colourless prisms -1 1 28 (hexnes); IR (Nujol) ν: 3509 (s), 1619 (vs), 1481 (s) cm ; H NMR (CDCl3, 400 MHz)  1.41 (t, 3 H, J = 7.2 Hz), 1.84-1.93 (m, 1 29 H), 2.00-2.05 (m, 1 H), 2.73-2.84 (m, 4 H), 4.62-4.76 (m, 2 H), 5.04 (s, 1 H), 5.83 (s, 1 H), 7.29 (d, 1 H, J = 7.2 Hz), 7.45 (td, 1 30 H, J = 7.2, 1.2 Hz), 7.52 (td, 1 H, J = 7.2, 1.2 Hz), 7.65-7.73 (m, 3 H), 7.90-7.94 (m, 2 H), 8.11 (d, 1 H, J = 9.2 Hz), 9.21 (d, 1 H, 13 1 31 J = 9.2 Hz) ppm; C{ H} NMR (CDCl3, 100 MHz)  14.6 (CH3), 25.0 (CH2), 31.7 (CH2), 32.5 (CH2), 48.6 (CH), 62.1 (CH2), 106.4 32 (s), 113.8 (s), 120.0 (CH), 123.8 (CH), 124.6 (CH), 126.3 (CH), 127.8 (2 x CH), 129.2 (CH), 129.3 (s), 129.4 (CH), 129.9 (CH), 33 130.6 (s), 131.8 (CH), 134.4 (s), 140.1 (s), 144.8 (s), 158.1 (s), 160.0 (s) ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for

34 C25H24NO2S2 434.1243; Found 434.1260. 35 36 3-(2-(1,3-Dithian-2-yl)phenyl)-2-ethoxy-6-methylquinolin-4(1H)-one (6b). 37 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 101 mg; yield: 70%; mp: 120-123 ºC; colorless prisms -1 1 38 (hexanes); IR (Nujol) ν: 3333 (s), 1700 (s), 1581 (s) cm ; H NMR (CDCl3, 300 MHz)  1.25 (t, 3 H, J = 7.2 Hz), 1.80-1.88 (m, 1 39 H), 2.00-2.06 (m, 1 H), 2.50 (s, 3 H), 2.70-2.82 (m, 4 H), 4.44-4.52 (m, 2 H), 4.94 (s, 1 H), 6.58 (br s, 1 H), 7.19 (dd, J = 7.5, 1.2 13 1 40 Hz, 1 H), 7.35-7.50 (m, 3 H), 7.83-7.88 (m, 2 H), 7.95 (s, 1 H) ppm; C{ H} NMR (CDCl3, 75 MHz)  14.5 (CH3), 21.4 (CH3), 41 25.0 (CH2), 31.8 (CH2), 32.4 (CH2), 48.5 (CH), 63.4 (CH2), 106.1 (s), 118.1 (s), 122.1 (CH), 125.2 (CH), 129.0 (CH), 129.3 (CH), 42 129.7 (CH), 131.8 (CH), 132.6 (CH), 133.4 (s), 139.8 (s), 143.2 (s), 159.7 (s), 159.8 (s) ppm; HRMS (ESI-TOF) m/z: [M + H]+

43 Calcd for C22H23NO2S2 398.1243; Found 398.1237. 44 45 3-(2-(1,3-Dithian-2-yl)phenyl)-2-ethoxy-6-methoxyquinolin-4(1H)-one (6c). 46 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 117 mg; yield: 81%; mp: 127-129 ºC; colorless prisms -1 1 47 (chloroform); IR (Neat) ν: 3333 (s), 1700 (s), 1581 (s) cm ; H NMR (DMSO-d6, 60 ºC, 300 MHz)  1.20 (t, 3 H, J = 7.2 Hz), 48 1.67-1.72 (m, 1 H), 1.90-1.95 (m, 1 H), 2.71-2.78 (m, 3 H), 3.87 (s, 3 H), 4.28-4.38 (m, 2 H), 4.95 (s, 1 H), 7.14 (d, 1 H, J = 7.5 13 1 49 Hz), 7.28-7.41 (m, 3 H), 7.61-7.69 (m, 3 H), 7.95 (s, 1 H) ppm; C{ H} NMR (DMSO-d6, 60 ºC, 75 MHz)  14.0 (CH3), 24.4 50 (CH2), 30.8 (CH2), 31.0 (CH2), 48.0 (CH), 55.2 (CH3), 61.0 (CH2), 102.3 (CH), 106.6 (s), 119.2 (s), 120.3 (CH), 127.0 (CH), 51 127.4 (CH), 127.5 (CH), 127.6 (CH), 131.4 (CH), 131.8 (CH), 138.6 (s), 140.4 (s), 154.9 (s), 158.6 (s) ppm; HRMS (ESI-TOF) + 52 m/z: [M + H] Calcd for C22H24NO3S2 414.1192; Found 414.1205. 53 54 4-Ethoxycarbonyl-(4-bromo)phenyl-2H-isoquinolin-1-one (13) 55 Eluent for chromatography column: hexanes/diethyl ether (4:1, v/v);65 mg; yield: 50%; mp: 183-185 ºC; yellow prisms (diethyl -1 1 56 ether); IR (Nujol) ν: 1721 (vs), 1676 (m), 1485 (vs) cm ; H NMR (CDCl3, 400 MHz)  1.38 (t, 3 H, J = 7.6 Hz), 4.38 (q, 2 H, J = 57 58 59 60 ACS Paragon Plus Environment Page 15 of 18 The Journal of Organic Chemistry

7.6 Hz), 7.33-7.36 (m, 2 H), 7.56 (td, 1 H, J = 7.8, 1.2 Hz), 7.64-7.67 (m, 2 H), 7.78 (td, 1 H, J = 7.8, 1.2 Hz), 8.16 (s, 1 H), 8.47 13 1 1 (dd, 1 H, J = 8.0, 1.2 Hz), 8.85 (d, 1 H, J = 8.4 Hz) ppm; C{ H} NMR (CDCl3, 100 MHz)  14.4 (CH3), 61.0 (CH2), 107.7 (s), 2 122.7 (s), 125.5 (CH), 125.6 (CH), 127.7 (CH), 128.5 (CH), 128.6 (2 x CH), 132.7 (2 x CH), 133.6 (CH), 134.3 (s), 139.4 (CH), + 3 139.5 (s), 161.9 (s), 165.1 (s) ppm; HRMS (ESI-TOF) m/z: [M + H] Calcd for C18H15BrNO3 372.0230; found: 372.0239. 4 5 3-(2-(1,3-Dithiolan-2-yl)phenyl)-2-methoxybenzo[h]quinolin-4(1H)-one (15). 6 Eluent for chromatography column: hexanes/ethyl acetate (4:1, v/v); 29 mg; yield: 20%; yellow oil; IR (Neat) ν: 3510 (s), 1619 -1 1 7 (s), 1480 (s) cm ; H NMR (CDCl3, 300 MHz)  3.22-3.29 (m, 2 H), 3.36-3.54 (m, 2 H), 4.16 (s, 3 H), 5.50 (s, 1 H), 7.24 (m, 1 8 H), 7.42 (td, 1 H, J = 7.8, 1.5 Hz), 7.54 (td, 1 H, J = 7.8, 1.5 Hz), 7.65-7.74 (m, 3 H), 7.90-7.93 (m, 1 H), 8.05-8.09 (m, 2 H), 13 1 9 9.20-9.22 (m, 1 H) ppm; C{ H} NMR (CDCl3, 75 MHz)  40.1 (CH2), 40.4 (CH2), 52.5 (CH), 54.0 (CH3), 106.3 (s), 113.9 (s), 10 119.7 (CH), 124.2 (CH), 124.6 (CH), 126.4 (CH), 127.8 (CH), 127.9 (CH), 128.9 (CH), 129.6 (s), 129.8 (CH), 129.9 (CH), 130.5 11 (s), 130.8 (CH), 134.4 (CH), 142.6 (CH), 144.7 (s), 157.9 (s), 160.0 (s) ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for

12 C23H20NO2S2 406.0930; Found 406.0931. 13 14 15 16 Associate Content 17 Supporting Information 18 The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx 19 1H and 3C{1H} NMR spectra, computational data. This material is available free of charge via the Internet at http://pubs.acs.org. 20 21 22 23 Acknowledgements 24 This work was supported by the MINECO (Project CTQ 2014-56887) and the Fundación Seneca-CARM (Project 25 19240/PI/14). MML thanks Xunta de Galicia for her postdoctoral contract (ED418B 2016/166-0). 26 27 28 29 Notes and references 30 (1) Salamone, M.; Bietti, M. Tuning Reactivity and Selectivity in Hydrogen Atom Transfer from Aliphatic C-H Bonds to 31 Alkoxyl Radicals: Role of Structural and Medium Effects. Acc. Chem. Res. 2015, 48 (11), 2895–2903. 32 (2) Milan, M.; Salamone, M.; Costas, M.; Bietti, M. The Quest for Selectivity in Hydrogen Atom Transfer Based Aliphatic 33 C-H Bond Oxygenation. Acc. Chem. Res. 2018, 51 (9), 1984–1995. 34 (3) Protti, S.; Fagnoni, M.; Ravelli, D. Photocatalytic C-H Activation by Hydrogen-Atom Transfer in Synthesis. 35 ChemCatChem 2015, 7 (10), 1516–1523. 36 (4) Wang, L.; Xiao, J. Hydrogen-Atom Transfer Reactions. Top. Curr. Chem. 2016, 374 (2), 1–55. 37 (5) Liu, S.; Qu, J.; Wang, B. Substrate-Controlled Divergent Synthesis of Polycyclic Indoloazepines and Indolodiazepines: 38 Via 1,5-Hydride Shift/7-Cyclization Cascades. Chem. Commun. 2018, 54 (57), 7928–7931. 39 (6) Liu, S.; Zhang, W.; Qu, J.; Wang, B. Engaging 2-Methyl Indolenines in a Tandem Condensation/1,5-Hydride 40 Transfer/Cyclization Process: Construction of a Novel Indolenine-Tetrahydroquinoline Assembly. Org. Chem. Front. 41 2018, 5 (20), 3008–3012. 42 (7) Alajarin, M.; Marin-Luna, M.; Vidal, A. Functionalization of Acetalic C(Sp3)-H Bonds by Scandium(III) Triflate-Catalyzed 43 Intramolecular Redox Reactions: Tandem 1,4-Hydride Transfer/1,5-Cyclization Processes Leading to Protected 1- 44 Indanones. Adv. Synth. Catal. 2011, 353 (4), 557–562. 45 (8) Nahide, P. D.; Jiménez-Halla, J. O. C.; Wrobel, K.; Solorio-Alvarado, C. R.; Ortiz Alvarado, R.; Yahuaca-Juárez, B. 46 Gold(I)-Catalysed High-Yielding Synthesis of Indenes by Direct C –H Bond Activation. Org. Biomol. Chem. 2018, 16 47 Sp3 (40), 7330–7335. 48 (9) Lu, X.-L.; Lyu, M.-Y.; Peng, X.-S.; Wong, H. N. C. Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers 49 by Hydride Transfer. Angew. Chemie Int. Ed. 2018, 57 (35), 11365–11368. 50 (10) Marin-Luna, M.; Vidal, A.; Bautista, D.; Orenes, R.-A.; Alajarin, M. Acid-Promoted Cycloisomerizations of Phenylallenes 51 Bearing Acetalic Functions at the Ortho Position: A Stereocontrolled Entry to Indeno-Fused Dioxepanes, Dioxocanes 52 and Thioanalogues. Org. Biomol. Chem. 2015, 13 (31), 8420–8424. 53 (11) Suh, C. W.; Kwon, S. J.; Kim, D. Y. Synthesis of Ring-Fused 1-Benzazepines via [1,5]-Hydride Shift/7-Endo Cyclization 54 Sequences. Org. Lett. 2017, 19 (6), 1334–1337. 55 (12) Feng, X.; Guo, J.; Liu, X.; Lin, L.; Cao, W. Asymmetric Tandem 1,5-Hydride Shift/Ring Closure for the Synthesis of 56 Chiral Spirooxindole Tetrahydroquinolines. Chem. - A Eur. J. 2014, 21 (4), 1632–1636. 57 58 59 60 ACS Paragon Plus Environment The Journal of Organic Chemistry Page 16 of 18

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