Unexpected Substituent Effects in Spiro-Compound Formation: Steering N-Aryl Propynamides and DMSO toward Site-Specific Sulfination in Quinolin-2-ones or Spiro[4,5]trienones.

A highly substituent-dependent rearrangement allows for the novel and SOCl2-induced divergent synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones through intramolecular electrophilic cyclization of N-aryl propyamides. DMSO acts as both solvent and sulfur source, and use of DMSO-h6/d6 enables the incorporation of SCH3 or SCD3 moieties to the 3-position of the heterocyclic framework. Different para-substituents trigger divergent reaction pathways leading to the formation of quinolin-2-ones for mild substituents and spiro[4,5]trienones for both electron-withdrawing and -donating substituents, respectively. On the basis of both computational and experimental results, a new mechanism has been put forward that accounts for the exclusive spirolization/defluorination process and the surprising substituent effects.

Introduction

Quinolinones and spiro[4.5]trienones both have been recognized as important heterocyclic skeletons of biologically active molecules.[1] They have been reported to possess diverse pharmacological properties such as anticancer,[2] anti-HCV,[3] anti-inflammatory,[4] and antidiabetic activities.[5] Also, these heterocyclic frameworks can be found in a plethora of biologically active natural compounds.[6] In parallel, sulfides are a class of important compounds, many of which have been found to exhibit unique pharmacological activities.[7] Most importantly, they have also served as the key building blocks in many organic transformations,[8] and the introduction of sulfenyl groups into drug molecules may significantly enhance their biological activities.[9] As a result, it is of significant interest to develop methods to introduce a sulfenyl group into the quinolinone or spiro[4.5]trienone skeletons.

Some protocols utilizing metal catalysts have been applied to construct the sulfenylated quinolinone and spiro[4.5]trienone skeletons.[10] For example, Gao and co-workers developed an AlCl3-catalyzed intramolecular cyclization of N-arylpropynamides to yield 3-sulfenyl quinolinones and spiro[4.5]trienones, using N-sulfanylsuccinimides as the sulfur donor (Scheme a).[10c] A similar strategy for synthesizing 3-thioazaspiro[4,5]trienones from thiophenols was developed through silver-catalyzed radical oxidative spirocyclization.[10d] Analogously, Li and co-workers realized the synthesis of 3-sulfenyl azaspiro[4,5]trienones via a Cu-catalyzed ipso-cyclization of N-(paramethoxyaryl) propynamides with disulfides (Scheme b).[10e]

Scheme 1

Strategies for the Synthesis of 3-Sulfenylated Quinolin-2-ones and Azaspiro[4,5]trienones

For environmental reasons, more recently there is a drive toward metal-free synthetic methods to construct these two classes of heterocycles.[11] For example, Wu and colleagues reported an iodine-catalyzed electrophilic cyclization approach by using sodium arylsulfinates as sulfur source, which furnishes 3-sulfenylquinolinone derivatives (Scheme c).[11a] In 2019, Guo and co-workers realized an electrochemical oxidative cyclization of alkynamides, furnishing quinolinones substituted with chalcogen substituent (Scheme d).[11b] Evidently these developments combine an increasing ease of use with environmentally friendlier approaches. Yet, in all the above transformations, the sulfur source was still a custom chemical, which required additional synthesis, such as RSO2Na, a sulfonyl succinimide, or a disulfide. To overcome this issue, and further reduce the complexity of the reaction, in this communication we report, first, that readily available DMSO and DMSO-d6 could be used as sulfur source, and SOCl2 as activating agent, to enable the intramolecular cyclization of N-aryl propynamides, leading to an efficient construction of 3-methylthioquinolin-2-one and 3-methylthiospiro[4.5]trienone skeletons.

DMSO, possessing the advantages of being inexpensive, stable, and low-toxicity, and allowing for easy handling, has been widely used not only as a polar organic solvent, but also as an oxidant or building block in various organic transformations.[12] For example, DMSO has found application in the Swern oxidation,[13] Pfitzner-Moffatt oxidation,[14] Albright-Goldman oxidation,[15] Parikh-Doering oxidation,[16] and other newly reported methods.[17] Most strikingly, DMSO can also be employed as the source of −CH2SMe, −SO2Me, or −SMe, to afford thio-modified structures.[18] However, a literature survey indicated that the application of DMSO as a sulfur source to introducing −SMe group has remained somewhat underexplored.[19] In line with our interest in developing methods for the construction of S-containing heterocycles by using DMSO as sulfur source,[20] we report here the reaction of N-aryl propynamides with DMSO/DMSO-d6 and SOCl2, for synthesis of 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones. DMSO-d6 can also take the place of DMSO, thereby providing access to the corresponding deuterated counterparts, which might be useful for further biological studies as deuterated drugs[21] or analytical reference compounds.

Second, we noticed remarkable substituent effects. Typically, reactivity trends over electronic substituents vary such that there is a somewhat continuous line with monotonous behavior from electron-withdrawing substituents via electronically neutral ones to electron-donating ones.[22] Here, however, we describe that for a wide range of electronically “neutral” substituents a specific reaction path is followed, while for both specific electron-withdrawing substituents and electron-donating ones the reaction is steered into another direction. Via a detailed quantum chemical analysis, it is shown how both these routes occur, and thereby form the basis of two rather different, but both high-yielding synthetic routes.

Results and Discussion

With reference to the reactions in our previous work,[20] we initiated our studies by treating N-methyl-N,3-diphenylpropiolamide 1a (0.5 mmol) with DMSO (1 mL) and SOCl2(1.0 mmol) at 25 °C for 12 h. We were pleased to note that the desired 1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one 2a was obtained in 22% yield (Table , entry 1). When the dosage of SOCl2 was increased, the yield of 2a improved significantly and the time needed was shortened (Table , entries 2–3). However, when the dosage of SOCl2 was increased to 3.0 equiv, the yield was not obviously enhanced (Table , entry 4). We also carried out the reaction at higher temperature, and found that the reaction time could be greatly shortened, albeit the yield was not improved (Table , entries 5–6). Further studies showed that other additives—including TFAA, p-TsCl and oxalyl chloride—were not superior to SOCl2 (Table , entries 7–10). Solvents screening was carried out and the results indicated that toluene, compared with EtOAc, MeCN, 1,4-dioxane, THF, and DCE, is the most appropriate cosolvent for this conversion (Table , entries 11–14). After variation over a series of experimental parameters, the best conditions were determined to be 0.5 mmol of 1a with 2.0 equiv of SOCl2 and 0.5 mL of DMSO in 0.5 mL of toluene at 50 °C.

Table 1

Optimization of Reaction Conditionsa

entry	solvent	additive (equiv)	T (°C)	time (h)	yield (%)b
1	DMSO	SOCl2 (1.0)	rt	12	22
2	DMSO	SOCl2 (1.5)	rt	12	35
3	DMSO	SOCl2 (2.0)	rt	3	68
4	DMSO	SOCl2 (3.0)	rt	3	73
5	DMSO	SOCl2 (2.0)	50	0.5	76
6	DMSO	SOCl2 (2.0)	70	0.5	78
7	DMSO	(COCl)2 (2.0)	50	8	56
8	DMSO	(COCl)2 (3.0)	50	8	62
9	DMSO	TFAA (2.0)	50	12	NR
10	DMSO	TsCl (2.0)	50	12	NR
11	EtOAc	SOCl2 (2.0)	50	0.5	20
12	MeCN	SOCl2 (2.0)	50	0.5	63
13	toluene	SOCl2(2.0)	50	0.5	84
14	dioxane	SOCl2 (2.0)	50	0.5	45

Reaction conditions: 1a (0.5 mmol), DMSO (0.5 mL) in solvent (0.5 mL), unless otherwise stated.

Isolated yield.

Under these optimized conditions, the scope of this newly established thiocyclization method was investigated, and the results are depicted in Table . It was found that when R1 is an alkyl group, the reaction proceeded well to give the corresponding 3-(methylthio)quinolin-2-ones in good yield (Table , 2b–d). For the substrates bearing a Cl, Br, naphthyl, or CF3 group, the reaction gave the corresponding product in relatively lower yield (Table , 2e–i). When the R2 group is a phenyl ring bearing electron-donating or electron-withdrawing groups, the reaction proceeded smoothly to deliver the corresponding target products 2j–o in satisfactory yield. It is worth noting that this method is not exclusive to internal alkynes, but also suitable for substrates with an terminal alkyne moiety, as the corresponding substrate can effectively afford the desired compound 2p in moderate yield. Furthermore, the methyl group on the N atom in amide substrates can also be replaced with ethyl, isopropyl, and phenyl substituent, with the N-substituted 3-methylthioquinolin-2-one products 2q–s again obtained in satisfactory yield. It was also found that when dihydroquinolinamide 1t was subjected to the standard conditions, the thioheterocyclic compound 2t can be achieved. Finally, DMSO can also be replaced by DMSO-d6, and the deuterated 3-methylthioquinolin-2-one 2u can be obtained in equally good yield by using this method. In addition, we explored a gram-scale experiment by subjecting 1 g of substrate 1a to the standard conditions. We were pleased to find that the reaction occurred smoothly to form 2a in 80% yield.

Table 2

SOCl2 and DMSO/DMSO-d6 Mediated Synthesis of 3-Methylthioquinolin-2-onesa,b

Reaction conditions: 1 (0.5 mmol), SOCl2 (1.0 mmol), DMSO or DMSO-d6 (0.5 mL)/toluene (0.5 mL), 50 °C, 0.5 h.

Isolated yield.

Gram-scale experiment.

A further widening of the range of investigated electronic substituents yielded a remarkable substituent effect: upon substitution of the aniline with a fluorine, methoxy, or trifluoro methoxy group at the para position of the aniline moiety the reaction takes a different course. During our investigations, it became clear we could use this systematically to our advantage, as with such substrates this alternative pathway was efficiently followed to give 3-(methylthio) spiro[4,5]trienone 3a.

To investigate the scope and usefulness of these findings, a series of N-aryl propynamides with para-fluoro or para-methoxy moiety was prepared and subjected to the standard conditions. Invariably, the corresponding spiro-products could be obtained with high yield within 20 min (Table , 3b–f). Unfortunately, the method is not applicable to the substrates bearing no phenyl group on the terminal alkyne moiety. When substrates with R2 being H and R being OMe or F were applied, the corresponding products could not be obtained (not shown). When such substrates also displayed an additional R1 substituent in the ortho or meta position of the aniline moiety, then still the reaction afforded the desired products in a moderate to good yield (Table , 3g–j). Interestingly, we observed that the ortho-fluoro substituted N-aryl propynamide can also be converted to spiro[4,5]trienone 3k. Finally, and in analogy to the 3-methylthioquinolin-2-one before, DMSO can be replaced with DMSO-d6, to enable the synthesis of deuterated spiro[4,5]trienones (Table , 3l).

Table 3

SOCl2 and DMSO/DMSO-d6 Mediated Synthesis of 3-Methylthiospiro[4.5]trienonesa,b

Reaction conditions: 1′ (0.5 mmol), SOCl2 (1.0 mmol), DMSO or DMSO-d6 (0.5 mL)/toluene (0.5 mL), rt, 20 min.

Isolated yield.

With regard to the spirolization of the F-substituted substrates, we and others postulated a concerted pathway containing simultaneous nucleophilic attack and spiro-formation processes (Scheme ).[10c,23] As this overall pathway would depend on significant positive charge development on the F-bound ipso-carbon atom to make attack by, e.g., methanol (Scheme a) or triflate attractive (Scheme b), and also would require a large reduction of entropy in the transition state to allow for the synchronous intermolecular nucleophilic attack and the intramolecular ring closure, we wondered whether a conceptually simpler alternative might be found.

Scheme 2

Reported Mechanistic Pathways of Defluorination

On the basis of our experimental results, previous reports,[10c,10d,20,23,24] and wB97XD/6-311+G(d,p) calculations,[25] we propose substituent-dependent mechanistic pathways for the construction of 3-methylthioquinolin-2-one and 3-methylthiospiro[4.5]trienone skeletons, respectively (Scheme ). We will discuss these in detail for three different substituents, R = para-H, para-F, and para-OMe, as they represent the various classes of substituents for which different reactivities have been observed. First, CH3SCl A is generated in situ from the reaction of DMSO with SOCl2 via the dimethylsulfochlorine cation intermediate through an interrupted Pummerer reaction process.[26] Then, the electrophilic addition of CH3SCl A to the C≡C bond of 1a furnished for all R groups the cyclic sulfonium cation intermediate B.[13,27]

Scheme 3

Proposed Mechanistic Pathways: (Top) Initial, Incorrect Hypothesis; (Bottom) Detailed Routes Leading to Either 2a or 3a in Highly Substituent-Dependent Manners

This reaction was calculated to be slightly exothermic (ΔH = −4 to −5 kcal/mol) for all three substituents, and the resulting three-membered ring species more stable than the isomeric α-phenyl-substituted vinyl cations. Initially, given the demonstrated experimental relevance of highly strained (C=C—S) three-membered rings,[28] we hypothesized these could rearrange to cations C, since this would form a 6-membered ring and only maintain one formally sp2-hybridized carbon atom in the three-membered ring. Such rearrangement could then by following by an exothermic opening of the three-membered ring, forming species D. From here on the mechanistic routes would then diverge, as for R = H this would lead to the bicyclic compound 2a, while for R = F and R = OMe, spiroformation should occur. Such reasoning—indicated at the top of Scheme —was, however, barred when we studied these pathways quantum chemically. First it turned out that the B ∀ C conversion was endothermic by ≥20 kcal/mol for all these three substituents, with enthalpic activation barriers of >25 kcal/mol. Such barrier heights for monomolecular rearrangements are not compatible with the above experimental observations of facile reaction at room temperature or 50 °C. Next, the cationic species D displayed a tendency for proton loss to any base (Cl– or DMSO) without any activation barrier, and reaction enthalpies typically −40 kcal/mol for all three substituents. Since this is favorable for the formation of 2a, it was hard to imagine how spiro-compounds 3a could efficiently be obtained from here for R = F and OMe, which displayed an equally facile proton transfer. Finally, it turned out that the D ∀ E transition was actually uphill for R = H (16.9 kcal/mol) and R = F (10.4 kcal/mol), and only exothermic for R = OMe (−4.2 kcal/mol).

Since it thus seemed unlikely that D was an intermediate to 3a, we investigated whether spiro-cations E could be formed directly from cations B, thereby making the spiro-cation the central intermediate in this pathway. This indeed turned out to correspond to a very facile reaction, with enthalpies of −6.0, −8.7, and −23.4 kcal/mol, for R = H, F, and OMe, respectively, and low activation barriers of 2.2 and 1.6 kcal/mol for R = H and F, respectively. Such low barrier implies that, in contrast to earlier suggestions, no nucleophilic assistance is needed or even likely for spiro-formation.[10c,23] While F is generally thought of as an electron-withdrawing substituent (e.g., σm and σp values of 0.34 and 0.06, respectively),[29] when bound directly to a (partially) positive carbon atom [C+–F or Cδ+–F] it is actually frequently stabilizing due to resonance effects,[30] in line with the stabilization observed here compared to R = H. For R = OMe intermediate B is a verified minimum (no imaginary vibrational frequencies), but no proper transition state could be located, and a relaxed potential energy scan suggests <0.5 kcal/mol as activation barrier.

The high stability of cation E-OMe basically shuts of any competing pathway. This cation then reacts effectively in an SN2 methyl transfer to chloride anion (ΔH = −11.3 kcal/mol and ΔH‡ = 13.5 kcal/mol). This barrier may, in reality, be a bit lower, as the real solvent is not DMSO (as consistently used in the calculations), but 50% DMSO/50% toluene, which likely reduces the solvation of chloride anion and thus increases its reactivity. Since the most likely alternative—methyl transfer on the S–CH3 moiety—required a barrier precisely 20.0 kcal/mol higher than attack on the methoxy group, this explains the high-yielding synthesis of 3a for R = OMe.

For the R = H and F, routes from E to D were investigated by gradually bringing carbon atoms C5 an C10 closer together. To our surprise, this yielded a cyclopropane cation F, as intermediate along the path to D. This rearrangement actually competes with attack by the DMSO oxygen atom on the formally positively charged ipso-C atom (as indicated for R = F, leading to intermediate G). For both R = H and R = F, the mechanistic dichotomy is less sharp than with R = OMe, as both routes occur with relatively small barriers, but they clearly point to the observed pathways. In one direction, the rearrangement to the cyclopropane cation F is uphill by 1.3 kcal/mol for R = H, and by 4.3 kcal/mol for R = F, with corresponding differences in the respective activation barriers. Subsequently, the reaction toward D is exothermic for both R = H and R = F, but less exothermic for R = F than for R = H (−14.2 vs −18.2 kcal/mol, with corresponding differences in the TS energies). As shown in Figure , the energy of this TS-4 would be highest along the reaction pathway from B toward D. While the differences are small, both steps would yield more of 2a for R = H than for R = F. In the other direction, the reaction of DMSO with spiro-cations G is exothermic for both R = H and for R = F (−12.6 and −14.2 kcal/mol, respectively, while it is endothermic by 1.3 kcal/mol for R = OMe), but the ipso-carbon atom displays a significantly larger positive (natural population) charge for R = F (+0.669) than for R = H (+0.092), which is thus more attractive for reaction with the partially negatively charged O atom on DMSO.

Figure 1

Free energy profile (kcal/mol) of the formation of intermediate D or 3-(methylthio) spiro[4,5]trienone 3a.

Interestingly, for other substituents, largely the bicyclic compound route toward D is formed, leading in that case to 2e. As a point in case, it is worth noting that for substrate 1e bearing a fluoro group at meta-position of anilide, the reaction adopted, like, e.g., para-H, the path to give 3-methylthioquinolin-2-one 2e. For this meta-F compound the B ∀ E ∀ F ∀ D sequence was downhill for all three steps, with energy differences of −1.2, −2.9, and −20.3 kcal/mol, respectively. Most striking is that the transition from spiro-cation E to cyclopropane cation F is thus exothermic, while it was endothermic for, e.g., para-H and para-F. This indeed is in line with our hypothesis that the mechanistic bifurcation point only leads to capture by nucleophiles in particular cases.

Once via these respective paths intermediates D (R = H) or E-F (R = F) are formed, the pathways are fixed. As said, cation D (R = H) will undergo a facile and highly exothermic proton loss to yield 2a. For the DMSO-bound cation G, a multistep, yet consistently low-barrier route exists toward the oxidized spiro-compound 3a. First, chloride anion can induce a methyl transfer SN2 reaction (ΔH‡ = 18.8 kcal/mol, but—as noted before—likely somewhat lower due to the 50/50 DMSO/toluene mixture rather than pure DMSO). As seen from Figure , this is the rate-limiting step in the formation of 3a, and the overall preference to form 3a rather than D and then 2a is determined by the relative energies of TS-4 and TS-5: for the para-F substituent TS-5 is lower in energy by about 7 kcal/mol, thereby thus strongly favoring the route toward 3a. The resulting neutral C(−F)OSCH3 compound H can now easily lose F– by the formation of HF. Assuming protonated DMSO as the proton source, this transfer proceeds with an activation barrier of only 6.8 kcal/mol. The resulting [CH3–S–O–C+] species I then reacts highly exothermically and without an activation barrier with Cl– under cleavage of the S–O bond. This reaction step thus reforms CH3SCl and yields the oxidized spiro-product 3a.

Finally, to experimentally confirm this mechanistic pathway at least partially, we aimed to elucidate the source of the carbonyl oxygen in the oxidized spiro-compound 3a. To this aim we conducted the transformation of substrate 1a′ in an argon atmosphere. To our delight the corresponding product 3a was still afforded in 82% yield (Scheme ).

Scheme 4

Control Experiment Confirming That DMSO Is the Oxygen Source

This result is indeed in line with the idea that DMSO is the oxygen source when the para position of aniline was substituted with a F atom. For substrates bearing a para-methoxy or para-trifluoromethoxy groups, the carbonyl oxygen in the final product 3a might come from the OMe or OCF3 groups substituted therein.[24]

Conclusions

A metal-free and fast protocol was developed to synthesize 3-methylthioquinolin-2-ones and 3-methylthiospiro[4.5]trienones via an electrophilic intramolecular cyclization of N-aryl propynamides that requires only DMSO and SOCl2. This protocol provides the first route to introduce a SCH3 or SCD3 group into the biologically interesting quinolin-2-one and spiro[4.5]trienone skeletons. The synthetic outcome can be conveniently steered to or away from the spiro compounds, by making use of a remarkable substituent effect that was outlined in detail by quantum chemical methods, and thereby also shed light on a range of analogous but up to now poorly understood spiro-forming cyclization reactions.

Experimental Section

General Experimental Information

All reagents were purchased from commercial sources and were used without further purification. All solvents were purified and dried according to standard methods prior to use. N-Aryl propynamides 1 were prepared based on literature procedures.[23,31]1H and 13C NMR spectra were recorded on 400 or 600 MHz spectrometer at 25 °C. Chemical shifts values are given in ppm and referred as the internal standard to TMS: 0.00 ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet). The coupling constants J, are reported in Hertz (Hz). High resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectrometer. Melting points were determined with a micro-melting-point apparatus. TLC plates were visualized by exposure to ultraviolet light. Flash column chromatography was performed over silica gel (200–300 m) using a mixture of ethyl acetate (EtOAc) and petroleum ether (PE).

Experimental Procedures and Spectroscopic Data

Preparation of Product 2 or 3

The N-Arylpropynamide (0.5 mmol, 1.0 equiv) was added to a mixture of toluene (0.5 mL) and DMSO or DMSO-d6 (0.5 mL) in a flask with stir bar, and then SOCl2 (1.0 mmol, 2.0 equiv) was added dropwise at room temperature. Then the mixture was stirred at 50 °C (oil bath) or room temperature until the substrate was completely consumed. The mixture was cooled to room temperature and was treated with saturated aq. NaHCO3 (30 mL). The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layer was washed with brine and dried with anhydrous Na2SO4. The solvent was removed under a vacuum, and the residue was purified by silica gel chromatography to give products 2 or 3.

Gram-Scale Study for Preparation of Compound 2a

N-Arylpropynamide 1a (1g, 4.25 mmol, 1.0 equiv) was added to a mixture of toluene (4 mL) and DMSO (4 mL) in a flask with a stir bar, and then SOCl2 (8.5 mmol, 2.0 equiv) was added dropwise at room temperature. Then the mixture was stirred at 50 °C (oil bath) until the substrate was completely consumed. The mixture was cooled to room temperature and was treated with saturated aq. NaHCO3 (40 mL). The mixture was extracted with EtOAc (60 mL × 3), and the combined organic layer was washed with brine and dried with anhydrous Na2SO4. After purification by silica gel chromatography (10% EtOAc/PE), product 2a was obtained in 80% yield (956.7 mg), a white solid.

1-Methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2a)

Following the general procedure, product 2a was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2a was obtained in 86% yield (120.9 mg), a white solid, mp 130–132 °C. 1H NMR (600 MHz, CDCl3) δ 7.55–7.47 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 7.26–7.24 (m, 2H), 7.13 (dd, J = 8.1, 1.7 Hz, 1H), 7.11–7.08 (m, 1H), 3.84 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 152.0, 139.2, 137.2, 130.3, 128.9, 128.6, 128.4, 128.2, 122.1, 121.4, 114.1, 30.5, 17.5. HRMS (ESI) m/z [M + H]+ Calcd for C17H16NOS+ 282.0947, found 282.0948.

1,5,7-Trimethyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2b)

Following the general procedure, product 2b was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2b was obtained in 87% yield (134.6 mg), a white solid, mp 132–134 °C. 1H NMR (600 MHz, CDCl3) δ 7.47–7.40 (m, 3H), 7.22–7.16 (m, 2H), 7.12 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H), 1.70 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.6, 167.9, 153.7, 148.5, 146.2, 132.9, 132.2, 131.3, 129.5, 128.4, 128.3, 111.7, 68.9, 55.5, 25.9, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C19H20NOS+ 310.1260, found 310.1264.

6-(tert-Butyl)-1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2c)

Following the general procedure, product 2c was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2c was obtained in 88% yield (148.5 mg), a white solid, mp 138–140 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.55–7.47 (m, 3H), 7.35 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.25 (t, J = 1.4 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H), 2.35 (s, 3H), 1.19 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 152.4, 144.9, 137.3, 137.2, 128.9, 128.3, 128.2, 128.1, 124.6, 120.9, 113.9, 34.3, 31.2, 30.4, 17.6. HRMS (ESI) m/z [M + H]+ Calcd for C21H24NOS+ 338.1573, found 338.1576.

7-Methoxy-1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2d)

Following the general procedure, product 2d was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2d was obtained in 66% yield (102.1 mg), a white solid, mp 110–112 °C; 1H NMR (400 MHz, CDCl3) δ 7.56–7.46 (m, 3H), 7.27–7.22 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 9.0, 2.4 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 2.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.55, 161.14, 152.73, 141.01, 137.51, 130.15, 128.77, 128.33, 128.13, 124.83, 115.68, 109.47, 98.51, 55.63, 30.54, 17.56. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO2S+ 312.1053, found 312.1056.

5-Methoxy-1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2d′)

Following the general procedure, product 2d’ was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2d’ was obtained in 22% yield (35.2 mg), a yellow solid, mp 154–156 °C. 1H NMR (600 MHz, CDCl3) δ 7.46 (t, J = 8.4 Hz, 1H), 7.41–7.37 (m, 2H), 7.36–7.32 (m, 1H), 7.12 (dt, J = 3.0, 1.8 Hz, 2H), 7.02 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.29 (s, 3H), 2.33 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 163.4, 158.0, 153.6, 142.5, 133.8, 131.4, 128.9, 128.8, 128.7, 128.6, 128.1, 114.5, 110.4, 98.5, 55.8, 37.4, 29.6. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO2S+ 312.1053, found 312.1057.

5-Fluoro-1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2e)

Following the general procedure, product 2e was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2e was obtained in 63% yield (94.3 mg), a white solid, mp 138–140 °C. 1H NMR (400 MHz, CDCl3) δ 7.51–7.28 (m, 4H), 7.14 (dd, J = 7.3, 1.9 Hz, 3H), 6.71 (dd, J = 11.7, 8.1 Hz, 1H), 3.75 (s, 3H), 2.29 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.1, 159.2 (d, J = 255.6 Hz), 148.1 (d, J = 2.3 Hz), 140.5 (d, J = 4.4 Hz), 139.8 (d, J = 4.1 Hz), 130.9 (d, J = 10.7 Hz), 130.7, 127.9, 127.7, 127.3 (d, J = 3.9 Hz), 110.7 (d, J = 10.6 Hz), 110.3 (d, J = 3.7 Hz), 109.5 (d, J = 22.9 Hz), 31.3, 17.5. HRMS (ESI) m/z [M + H]+ Calcd for C17H1519FNOS+ 300.0853, found 300.0856.

6-Chloro-1-methyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2f)

Following the general procedure, product 2f was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2f was obtained in 58% yield (91.6 mg), a white solid, mp 122–124 °C. 1H NMR (600 MHz, CDCl3) δ 7.56–7.49 (m, 3H), 7.46 (dd, J = 9.0, 2.4 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.25–7.20 (m, 2H), 7.07 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H), 2.35 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.2, 150.3, 137.7, 136.5, 130.4, 130.1, 128.8, 128.7, 128.5, 127.7, 127.3, 122.5, 115.5, 30.6, 17.3. HRMS (ESI) m/z [M + H]+ Calcd for C17H1535ClNOS+ 316.0557, found 316.0559.

4-(4-Bromophenyl)-1-methyl-3-(methylthio)quinolin-2(1H)-one (2g)

Following the general procedure, product 2g was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2g was obtained in 60% yield (117.1 mg), a pale-yellow solid, mp 112–114 °C. 1H NMR (400 MHz, CDCl3) δ 7.57–7.50 (m, 3H), 7.47 (dd, J = 9.0, 2.4 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.23 (dd, J = 7.6, 1.7 Hz, 2H), 7.08 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 150.4, 137.6, 136.5, 132.9, 130.4, 130.2, 128.8, 128.7, 128.6, 127.7, 127.3, 122.5, 115.8, 115.5, 30.7, 17.4. HRMS (ESI) m/z [M + H]+ Calcd for C17H1579BrNOS+ 360.0052, found 360.0054.

1-Methyl-3-(methylthio)-4-phenyl-6-(trifluoromethyl)quinolin-2(1H)-one (2h)

Following the general procedure, product 2h was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2h was obtained in 76% yield (132.8 mg), a white solid, mp 104–106 °C. 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.58–7.51 (m, 3H), 7.49 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.26–7.22 (m, 2H), 3.86 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.4, 150.8, 141.0, 136.1, 130.7, 128.8, 128.7, 128.6, 126.4 (q, J = 3.1 Hz), 125.4 (q, J = 3.9 Hz), 124.3 (q, J = 32.9 Hz), 123.9 (q, J = 269.9 Hz), 121.1, 114.6, 30.7, 17.3. HRMS (ESI) m/z [M + H]+ Calcd for C18H1519F3NOS+ 350.0821, found 350.0825.

1-Methyl-3-(methylthio)-4-phenylbenzo[h]quinolin-2(1H)-one (2i)

Following the general procedure, product 2i was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2i was obtained in 69% yield (116.0 mg), a white solid, mp 128–130 °C. 1H NMR (600 MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.88–7.82 (m, 1H), 7.60–7.48 (m, 5H), 7.45 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 1.3 Hz, 2H), 7.10 (d, J = 8.7 Hz, 1H), 4.15 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 162.8, 151.8, 138.6, 137.4, 135.1, 129.0, 128.6, 128.5, 128.3, 128.1, 127.4, 125.8, 125.1, 124.2, 123.6, 123.4, 119.1, 41.3, 17.3. HRMS (ESI) m/z [M + H]+ Calcd for C21H18NOS+ 332.1104, found 332.1106.

1-Methyl-3-(methylthio)-4-(p-tolyl)quinolin-2(1H)-one (2j)

Following the general procedure, product 2j was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2j was obtained in 80% yield (118.2 mg), a white solid, mp 104–106 °C. 1H NMR (600 MHz, CDCl3) δ 7.54–7.50 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.16 (dd, J = 8.1, 1.3 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 3.83 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.7, 152.1, 139.2, 138.0, 134.3, 130.2, 129.1, 128.8, 128.7, 128.5, 121.9, 121.6, 114.0, 30.4, 21.5, 17.5. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NOS+ 296.1104, found 296.1107.

4-(4-Methoxyphenyl)-1-methyl-3-(methylthio)quinolin-2(1H)-one (2k)

Following the general procedure, product 2k was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2k was obtained in 81% yield (126.1 mg), a white solid, mp 108–110 °C. 1H NMR (600 MHz, CDCl3) δ 7.54–7.48 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.21–7.15 (m, 3H), 7.10 (dd, J = 7.9, 7.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.6, 159.5, 151.6, 139.2, 130.3, 130.2, 129.4, 128.9, 128.5, 121.9, 121.7, 114.0, 113.8, 55.3, 30.4, 17.5. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO2S+ 312.1053, found 312.1056.

4-(4-Chlorophenyl)-1-methyl-3-(methylthio)quinolin-2(1H)-one (2l)

Following the general procedure, product 2l was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2l was obtained in 81% yield (127.9 mg), a white solid, mp 140–142 °C. 1H NMR (600 MHz, CDCl3) δ 7.54 (ddd, J = 8.4, 6.6, 1.8 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.14–7.07 (m, 2H), 3.83 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.4, 150.8, 139.3, 135.6, 134.3, 130.5, 130.3, 128.9, 128.8, 128.1, 122.2, 121.1, 114.2, 30.5, 17.4. HRMS (ESI) m/z [M + H]+ Calcd for C17H1535ClNOS+ 316.0557, found 316.0558.

4-(4-Bromophenyl)-1-methyl-3-(methylthio)quinolin-2(1H)-one (2m)

Following the general procedure, product 2m was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2m was obtained in 79% yield (142.3 mg), a white solid, mp 170–172 °C. 1H NMR (600 MHz, CDCl3) δ 7.69–7.65 (m, 2H), 7.63 (dd, J = 8.1, 1.8 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.21–7.16 (m, 2H), 7.05 (dd, J = 8.1, 2.1 Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 157.8, 151.9, 140.4, 132.7, 132.1, 131.7, 131.4, 130.5, 130.5, 129.0, 123.4, 122.8, 120.6, 114.5, 38.6, 29.6. HRMS (ESI) m/z [M + H]+ Calcd for C17H1579BrNOS+ 360.0052, found 360.0056.

4-(2-Bromophenyl)-1-methyl-3-(methylthio)quinolin-2(1H)-one (2n)

Following the general procedure, product 2n was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2n was obtained in 78% yield (140.5 mg), a white solid, mp 124–126 °C. 1H NMR (600 MHz, CDCl3) δ 7.75 (t, J = 6.3 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.38–7.33 (m, 1H), 7.21–7.16 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.5, 150.8, 139.3, 138.3, 132.9, 130.5, 129.8, 129.1, 127.6, 127.6, 122.8, 122.3, 120.4, 114.3, 30.5, 16.9. HRMS (ESI) m/z [M + H]+ Calcd for C17H1579BrNOS+ 360.0052, found 360.0053.

Methyl 2-(1-methyl-3-(methylthio)-2-oxo-1,2-dihydroquinolin-4-yl)benzoate (2o)

Following the general procedure, product 2o was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2o was obtained in 82% yield (139.2 mg), a white solid, mp 142–144 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 7.9, 1.1 Hz, 1H), 7.67 (td, J = 7.5, 1.4 Hz, 1H), 7.57 (td, J = 7.7, 1.3 Hz, 1H), 7.51 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 7.6, 0.9 Hz, 1H), 7.10–7.02 (m, 1H), 6.92 (dd, J = 8.1, 1.3 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.2, 160.6, 153.2, 139.2, 138.9, 132.5, 130.6, 130.2, 129.4, 128.4, 127.6, 126.9, 122.1, 121.3, 114.2, 52.0, 30.4, 16.9. HRMS (ESI) m/z [M + H]+ Calcd for C19H18NO3S+ 340.1002, found 340.1004.

1-Methyl-3-(methylthio)quinolin-2(1H)-one (2p)

Following the general procedure, product 2p was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2p was obtained in 62% yield (63.6 mg), a white oil. 1H NMR (400 MHz, CDCl3) δ 7.36–7.32 (m, 4H), 5.85 (s, 1H), 3.37 (s, 3H), 2.25 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.82, 142.27, 134.49, 128.99, 128.07, 126.54, 116.26, 37.01, 17.04. HRMS (ESI) m/z [M + H]+ Calcd for C11H12NOS+ 206.0634, found 206.0636.

4-([1,1′-Biphenyl]-4-yl)-1-ethyl-3-(methylthio)quinolin-2(1H)-one (2q)

Following the general procedure, product 2q was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2q was obtained in 84% yield (156.0 mg), a pale-yellow solid, mp 220–222 °C. 1H NMR (400 MHz, CDCl3) δ 7.78–7.74 (m, 2H), 7.70 (dt, J = 8.2, 1.7 Hz, 2H), 7.54 (ddd, J = 8.6, 7.1, 1.5 Hz, 1H), 7.51–7.46 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.41–7.36 (m, 1H), 7.35–7.31 (m, 2H), 7.22 (dd, J = 8.1, 1.4 Hz, 1H), 7.14–7.07 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 151.5, 140.9, 140.5, 138.2, 136.2, 130.3, 129.4, 128.9, 128.7, 127.6, 127.2, 127.1, 121.9, 121.7, 113.9, 38.4, 17.4, 12.7. HRMS (ESI) m/z [M + H]+ Calcd for C24H22NOS+ 372.1417, found 372.1418.

1-Isopropyl-3-(methylthio)-4-phenylquinolin-2(1H)-one (2r)

Following the general procedure, product 2r was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2r was obtained in 80% yield (123.8 mg), a pale-yellow solid, mp 160–162 °C. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.7 Hz, 1H), 7.54–7.44 (m, 4H), 7.26–7.23 (m, 2H), 7.12 (dd, J = 8.1, 1.6 Hz, 1H), 7.07–7.02 (m, 1H), 2.32 (s, 3H), 1.73 (s, 3H), 1.72 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.8, 151.5, 137.4, 129.5, 128.9, 128.8, 128.4, 128.1, 122.2, 121.5, 114.6, 19.8, 17.4. HRMS (ESI) m/z [M + H]+ Calcd for C19H20NOS+ 310.1260, found 310.1265.

3-(Methylthio)-1,4-diphenylquinolin-2(1H)-one (2s)

Following the general procedure, product 2s was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2s was obtained in 82% yield (140.8 mg), a white solid, mp 216–218 °C. 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 10.4, 4.7 Hz, 2H), 7.59–7.51 (m, 4H), 7.36 (dd, J = 5.2, 3.2 Hz, 2H), 7.34–7.31 (m, 2H), 7.31–7.26 (m, 1H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 7.08–7.02 (m, 1H), 6.69 (d, J = 8.5 Hz, 1H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 152.0, 140.2, 138.0, 137.2, 130.3, 129.7, 129.1, 129.0, 128.9, 128.8, 128.6, 128.3, 127.9, 122.3, 121.2, 115.9, 100.0, 17.3. HRMS (ESI) m/z [M + H]+ Calcd for C22H18NOS+ 344.1104, found 344.1106.

6-(Methylthio)-7-phenyl-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one (2t)

Following the general procedure, product 2t was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2t was obtained in 80% yield (123.0 mg), a white solid, mp 120–122 °C. 1H NMR (600 MHz, CDCl3) δ 7.53–7.49 (m, 2H), 7.49–7.45 (m, 1H), 7.27 (d, J = 1.3 Hz, 1H), 7.25–7.22 (m, 2H), 7.00–6.93 (m, 2H), 4.40–4.19 (m, 2H), 3.02 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H), 2.17 (dt, J = 12.1, 6.1 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.1, 151.8, 137.6, 135.9, 129.6, 128.8, 128.4, 128.2, 128.1, 126.4, 124.6, 121.5, 121.3, 43.3, 27.8, 20.8, 17.4. HRMS (ESI) m/z [M + H]+ Calcd for C19H18NOS+ 308.1104, found 308.1106.

6-(tert-Butyl)-1-methyl-3-((methyl-d3)thio)-4-phenylquinolin-2(1H)-one (2u)

Following the general procedure, product 2u was synthesized. After purification by silica gel chromatography (10% EtOAc/PE), product 2u was obtained in 81% yield (139.6 mg), a white solid, mp 138–140 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.55–7.46 (m, 3H), 7.35 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.26–7.23 (m, 1H), 7.11 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H), 1.19 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 152.3, 144.9, 137.3, 137.2, 128.9, 128.4, 128.3, 128.2, 128.1, 124.6, 121.0, 1139, 34.3, 31.2, 30.4. HRMS (ESI) m/z [M + H]+ Calcd for C21H21D3NOS+ 341.1761, found 341.1764.

1-Methyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3a)

Following the general procedure, product 3a was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3a was obtained in 87% yield (129.4 mg), a white solid, mp 162–164 °C. 1H NMR (600 MHz, CDCl3) δ 7.38–7.32 (m, 3H), 7.32–7.28 (m, 2H), 6.53–6.48 (m, 2H), 6.47–6.41 (m, 2H), 2.90 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 183.9, 168.3, 147.4, 145.5, 133.7, 133.0, 131.2, 129.5, 128.4, 128.3, 67.5, 26.1, 14.8. HRMS (ESI) m/z [M + H]+ Calcd for C17H16NO2S+ 298.0896, found 298.0898.

When N-(4-methoxyphenyl)-N-methyl-3-phenylpropiolamide was used as the substrate, product 3a was obtained in 85% yield (126.3 mg). When N-methyl-3-phenyl-N-(4-(trifluoromethoxy)phenyl)propiolamide was used as the substrate, product 3a was obtained in 82% yield (122.0 mg).

1-Methyl-3-(methylthio)-4-(p-tolyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3b)

Following the general procedure, product 3b was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3b was obtained in 85% yield (132.1 mg), a white solid, mp 130–132 °C 1H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.7 Hz, 2H), 6.49 (d, J = 10.1 Hz, 2H), 6.44 (dd, J = 10.2, 1.3 Hz, 2H), 2.89 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 184.1, 168.4, 147.8, 145.6, 139.8, 132.9, 129.1, 128.2, 67.4, 26.1, 21.3, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO2S+ 312.1053, found 312.1056.

When N-(4-methoxyphenyl)-N-methyl-3-(p-tolyl)propiolamide was used as the substrate, product 3b was obtained in 86% yield (133.9 mg).

4-(4-Methoxyphenyl)-1-methyl-3-(methylthio)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3c)

Following the general procedure, product 3c was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3c was obtained in 85% yield (139.1 mg), a white solid, mp 120–122 °C. 1H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.49 (d, J = 10.2 Hz, 2H), 6.44 (d, J = 10.2 Hz, 2H), 2.89 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 184.1, 168.4, 147.8, 145.6, 139.8, 133.1, 132.9, 129.1, 128.2, 128.2, 67.4, 26.1, 21.3, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO3S+ 328.1002, found 328.1004.

When N,3-bis(4-methoxyphenyl)-N-methylpropiolamide was used as the substrate, product 3c was obtained in 83% yield (135.9 mg).

Methyl 4-(1-methyl-3-(methylthio)-2,8-dioxo-1-azaspiro[4.5]deca-3,6,9-trien-4 -yl)benzoate (3d)

Following the general procedure, product 3d was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3d was obtained in 81% yield (144.3 mg), a white solid, mp 162–164 °C. 1H NMR (600 MHz, CDCl3) δ 8.01 (dd, J = 8.5, 1.8 Hz, 2H), 7.38 (dd, J = 8.4, 1.2 Hz, 2H), 6.49 (d, J = 10.2 Hz, 2H), 6.45 (dd, J = 10.2, 1.8 Hz, 2H), 3.91 (s, 3H), 2.90 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 183.7, 167.8, 166.2, 145.7, 145.1, 135.7, 135.1, 133.2, 131.0, 129.6, 128.5, 67.3, 52.3, 26.2, 14.7. HRMS (ESI) m/z [M + H]+ Calcd for C19H18NO4S+ 356.0951, found 356.0952.

When methyl 4-(3-((4-methoxyphenyl)(methyl)amino)-3-oxoprop-1-yn-1-yl)-benzoate was used as the substrate, product 3d was obtained in 82% yield (145.7 mg).

1-Methyl-3-(methylthio)-4-(4-nitrophenyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3e)

Following the general procedure, product 3e was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3e was obtained in 83% yield (143.1 mg), a pale-yellow solid, mp 160–162 °C. 1H NMR (600 MHz, CDCl3) δ 8.21 (dq, J = 9.1, 2.0 Hz, 2H), 7.59–7.42 (m, 2H), 6.61–6.35 (m, 4H), 2.91 (s, 3H), 2.52 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 183.4, 167.4, 148.1, 144.7, 144.0, 137.7, 136.4, 133.5, 129.4, 123.7, 67.1, 26.2, 14.6. HRMS (ESI) m/z [M + H]+ Calcd for C17H15N2O4S+ 343.0747, found 343.0748.

When N-(4-methoxyphenyl)-N-methyl-3-(4-nitrophenyl)propiolamide was used as the substrate, product 3e was obtained in 80% yield (136.9 mg).

1-Methyl-3-(methylthio)-4-(thiophen-2-yl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3f)

Following the general procedure, product 3f was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3f was obtained in 79% yield (119.8 mg), a white solid, mp 138–140 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 5.1, 1.1 Hz, 1H), 7.42 (dd, J = 3.8, 1.1 Hz, 1H), 7.05 (dd, J = 5.1, 3.9 Hz, 1H), 6.61–6.56 (m, 2H), 6.55–6.49 (m, 2H), 2.86 (s, 3H), 2.72 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 184.2, 168.1, 146.2, 141.8, 133.2, 133.1, 129.4, 129.2, 129.1, 127.2, 65.7, 25.6, 15.3. HRMS (ESI) m/z [M + H]+ Calcd for C15H14NO2S2+ 304.0460, found 304.0462.

When N-(4-methoxyphenyl)-N-methyl-3-(thiophen-2-yl)propiolamide was used as the substrate, product 3f was obtained in 81% yield (122.9 mg).

7-Chloro-1-methyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3g)

Following the general procedure, product 3g was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3g was obtained in 82% yield (127.8 mg), a white solid, mp 176–178 °C. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 5.1 Hz, 3H), 7.27–7.21 (m, 2H), 6.73 (s, 1H), 6.52 (q, J = 9.9 Hz, 2H), 2.93 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 177.2, 167.9, 146.1, 145.9, 141.3, 136.1, 134.2, 131.8, 130.7, 129.8, 128.6, 128.4, 69.3, 26.5, 14.7. HRMS (ESI) m/z [M + H]+ Calcd for C17H1535ClNO2S+ 332.0507, found 332.0508.

7-Methoxy-1-methyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3h)

Following the general procedure, product 3h was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3h was obtained in 81% yield (133.4 mg), a white solid, mp 156–158 °C. 1H NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 3H), 7.29–7.25 (m, 3H), 6.49 (dd, J = 9.8, 2.5 Hz, 1H), 6.44 (d, J = 9.8 Hz, 1H), 5.35 (d, J = 2.5 Hz, 1H), 3.66 (s, 3H), 2.89 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.6, 167.9, 153.7, 148.5, 146.2, 132.9, 132.2, 131.3, 129.5, 128.4, 128.3, 111.7, 68.9, 55.5, 25.9, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO3S+ 328.1002, found 328.1004.

6-Iodo-1-methyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3i)

Following the general procedure, product 3i was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3i was obtained in 81% yield (173.5 mg), a light yellow solid, mp 114–116 °C. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 5.8, 1.7 Hz, 3H), 7.32 (d, J = 6.7 Hz, 2H), 7.20 (s, 1H), 6.80 (d, J = 9.8 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 2.84 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 181.0, 168.1, 146.8, 144.7, 144.5, 135.6 132.0, 130.4, 129.8, 128.5, 128.5, 126.2, 71.8, 25.9, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C17H15INO2S+423.9863, found 423.9867.

1,6-Dimethyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3j)

Following the general procedure, product 3j was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3j was obtained in 78% yield (121.4 mg), a white solid, mp 118–120 °C. 1H NMR (600 MHz, CDCl3) δ 7.34 (t, J = 5.1 Hz, 3H), 7.30 (d, J = 2.5 Hz, 2H), 6.53–6.40 (m, 2H), 6.32 (d, J = 4.4 Hz, 1H), 2.80 (s, 3H), 2.45 (s, 3H), 1.73 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 184.7, 168.7, 153.7, 147.9, 145.7, 133.9, 132.5, 131.9, 131.0, 129.7, 128.5, 128.0, 69.5, 25.7, 17.7, 15.1. HRMS (ESI) m/z [M + H]+ Calcd for C18H18NO2S+312.1053, found 312.1056.

1-Methyl-3-(methylthio)-4-phenyl-1-azaspiro[4.5]deca-3,7,9-triene-2,6-dione (3k)

Following the general procedure, product 3k was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3k was obtained in 79% yield (118.2 mg), a white solid, mp 120–122 °C. 1H NMR (600 MHz, CDCl3) δ 7.39–7.30 (m, 3H), 7.23 (dd, J = 8.0, 1.4 Hz, 2H), 6.99 (ddd, J = 9.9, 6.0, 1.6 Hz, 1H), 6.50 (dd, J = 9.4, 5.9 Hz, 1H), 6.18 (d, J = 9.9 Hz, 1H), 6.12 (d, J = 9.1 Hz, 1H), 2.79 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 195.5, 169.7, 148.3, 141.8, 138.4, 133.1, 131.3, 129.3, 128.3, 128.2, 128.1, 127.5, 126.7, 74.9, 26.6, 14.9. HRMS (ESI) m/z [M + H]+ Calcd for C17H16NO2S+ 298.0896, found 298.0898.

1-Methyl-3-((methyl-d3)thio)-4-(p-tolyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3l)

Following the general procedure, product 3l was synthesized. After purification by silica gel chromatography (15% EtOAc/PE), product 3l was obtained in 76% yield (119.0 mg), a white solid, mp 130–132 °C. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 6.47 (q, J = 10.3 Hz, 4H), 2.89 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 184.2, 168.4, 147.8, 145.7, 139.8, 132.9, 129.1, 128.2, 67.4, 26.1, 21.4. HRMS (ESI) m/z [M + H]+ Calcd for C18H15D3NO2S+ 315.1241, found 315.1243.