Telescoped Oxidation and Cycloaddition of Urazoles to Access Diazacyclobutenes

Abstract

Our previous method to access the diazacyclobutene scaffold did not allow for modification of the substituent originating from the 1,2,4-triazoline-3,5-dione component. We have circumvented this challenge and expanded access to additional structural diversity of the scaffold. A telescoped urazole oxidation and Lewis acid-catalyzed cyclization provided R³-substituted diazacyclobutenes. Calcium hypochlorite-mediated oxidation of urazoles followed by MgCl₂-catalyzed cyclization of the resulting triazolinediones with thioalkynes promoted the formation of diazacyclobutenes bearing substitution at the R³ position originating from the triazolinedione component.

Graphical Abstract

Recently, our group was able to exploit the reactivity between 4-phenyl-1,2,4-triazoline-3,5-dione (1, PTAD) and electron-rich thioalkynes 2 (X = S) to afford a group of stable diazacyclobutenes 3, a hitherto rarely-accessed scaffold (Scheme 1, eq. 1).¹ Before our efforts in this area, there were only a few synthetic studies^2-7 and several computational studies^2,4,8-11 on the scaffold. In our initial communication, we were able to substantially expand the scope of this scaffold by means of the ready access to a large variety of thio- and selenoalkynes 2 by simple operations, but the method lacked structural variety at the N³ position of the triazolinedione (e.g. Ph in 1) component due to the lack of commercial triazolinediones except PTAD.¹ Given that the diazacyclobutene scaffold is rather rare, the potential biological activity of the motif is virtually unexplored in any medical context. In the spirit of exploring maximal chemical space in the context of bio-organic/medicinal chemistry applications of the scaffold, we sought a method to rapidly access structural diversity at the N³ position.

Scheme 1.

Previous work and proposed telescoped route to diazacyclobutenes from urazole.

Triazolinediones have been utilized as a highly valuable synthetic tool in several ways. (e.g., [4+2] and [2+2] cycloadditions).^12-15 Despite a large number of known strategies for their preparation,¹² the synthesis of N³-substituted triazolinediones still pose several practical challenges. These include, but are not limited to, difficulties associated with the isolation of the urazole precursor due to poor solubility in organic solvents as well as the thermal and chemical instability of the triazolinedione products which can lead to challenges in isolation and purification.^16-18 Thus, in pursuing our goal to access diversity at the R³ position of the diazacyclobutene scaffold (i.e. 6), we sought a telescoped method that promoted the oxidation of urazole starting materials 4 and follow-on cycloaddition with thioalkynes 2 in one operation (Scheme 1, eq. 2). This strategy would avoid any operational difficulties associated with isolating and purifying the sensitive triazolinediones 5. Thus, the crux of the strategy hinged on choosing an appropriate urazole oxidant for the telescoped sequence that proceeded cleanly without appreciable by-products that might adversely affect the course of the following cycloaddition step. A variety of oxidants have been explored and are commonly used for this transformation.^19-22 We decided to proceed with our study via a calcium hypochlorite oxidation of the urazoles.¹⁹ The results of this strategy to access R³-substituted diazacyclobutenes directly from urazole precursors, 4, are described below.

The synthesis of N³-substituted urazoles was achieved using modified Cookson’s conditions^23,24 (see Supporting Information). This method readily afforded N³-arylated urazoles bearing meta- and para-substitutions as well as urazoles bearing n-alkyl chains (i.e. Bn and C4-C8) at N³. We were able to access a variety of urazoles by this method, but we did encounter limitations when attempting to prepare examples bearing short-chain branched alkyl groups (i.e., tert-butyl, iso-propyl) and derivatives with reactive functionality (i.e., benzoyl, 3-chloropropyl). Due to the high toxicity of short chain alkyl isocyanates, 4-methylurazole was synthesized using an isocyanate-free method.²⁵ Efforts to synthesize 4-ethyl and 4-propylurazoles were unsuccessful with this method.

Initial studies of a telescoped strategy involved oxidation of commercially available 4-phenylurazole, 4a, using calcium hypochlorite¹⁹ followed by a solvent swap from dichloromethane to acetonitrile and subsequent addition of the thioalkyne under refluxing conditions (Scheme 2). Using this approach, we were able to access the R³ = Ph diazacyclobutene, 6a, in 56% yield along with a series of R³-substituted diazacyclobutenes. Nevertheless, the isolated yields of the desired products were typically lower than the 89% yield we previously reported for 6a using PTAD.¹

Scheme 2.

First generation telescoped process.

While obtaining structural variety using this method was ultimately successful, diminished yields or failed reactions were observed in multiple examples. Urazole bearing para-methyl phenyl functionality furnished moderate yields of product 6b, 59%. Electron-withdrawing functionality on the arene such as p-nitro and p-fluoro substituents provided poor results (i.e., 0% (6d) and 25% (6e), respectively). Similarly, urazoles containing meta-substituted functionality were rather poorly tolerated, returning both 6f (m-OCH₃-C₆H_4⁻) and 6g (m-Cl-C₆H_4⁻) in 30% isolated yield. Slightly improved results were found for R³ = benzyl (6i, 71%) and 1-napthyl (6j, 42%). Two urazoles bearing multiple arene substitutes were investigated. A 2,6-dimethyl substituted urazole provided 6k in 92% yield, whereas a 3,5-dichlorophenyl variant failed to provide product 6l. Alkyl substituted urazoles all provided products (6n, 6p, and 6q) in moderate yields (i.e. 72%, 64%, and 58%, respectively).

Since the first generation telescoped process employing refluxing conditions did not provide high yields in some cases, we next turned to an evaluation of a series of Lewis acid catalysts with the aim of promoting the whole transformation at room temperature. We initially began by screening a series of 22 Lewis acid candidates at 10 mol % loading (See Table S1 in Supporting Information). To evaluate the various Lewis acids, we adopted standard screening conditions employing phenylurazole (4 equiv) that was oxidized using calcium hypochlorite (6 equiv) in DCM for 2 h to generate PTAD in excess. Then, after gravity filtration to remove residual oxidant and reduced salts, concentration by rotary evaporation, and addition of fresh solvent, the alkynyl sulfide (1a, 1 equiv) and the appropriate Lewis acid (10 mol %) was added to the solution. The resulting mixture was allowed to stir for 24 h at room temperature.

Preliminary results from the screen of 22 Lewis acids (see Table S1, SI) showcased that a subset of metal salts could promote the formal [2+2] reaction in higher, but unoptimized yields. The uncatalyzed, room temperature reaction in DCM provided 6a in 28% yield (Table 1, entry 1). In our initial screen of Lewis acid catalysts, a 10 mol % loading of scandium(III) triflate, titanium(IV) oxide, tin(IV) chloride, and magnesium(II) chloride provided 6a in yields above 65% (i.e. 66%, 71%, 81%, and 68%, respectively, entries 2-5). In the initial screen, SnCl₄ did promote the highest yield of 6a (81% yield, entry 4), but efforts to repeat this outcome led to inconsistent results (e.g. 26% yield, entry 4, brackets). Ultimately, we settled on the use of MgCl₂ for further optimization since it provided 6a in a reasonable 68% isolated yield (entry 5) and is less costly than the other most promising candidates. Varying the catalyst loading showed little effect for improving the yield of 6a: 70% with 30 mol% catalyst and 71% with 50 mol % catalyst (entries 6 and 7). Next, a series of common solvents were evaluated (entries 8 – 13). Chloroform provided a slightly increased yield (78%, entry 8), but was inferior to anhydrous dichloromethane (84%, entry 13). Other solvents including THF, ethyl acetate, toluene, and acetonitrile resulted in reduced isolated yields (i.e., 58%, 52%, 69%, and 47% respectively, entries 9-12). Next, we adjusted the equivalents of urazole 4a in the transformation and found that 3 equiv provided the highest isolated yield of diazacyclobutene 6a (i.e., 53%, 86%, and 94% yield for 1.0, 2.0, and 3.0 equiv 4a, respectively (entries 14 – 16)). We next evaluated whether 1,3-dibromo-5,5-dimethylhydantoin could be used to effect the urazole oxidation in lieu of calcium hypochlorite, but this experiment returned only starting material (entry 16, brackets). Efforts to remove water from the reaction mixture by adding anhydrous sodium sulfate at 1.5 h during step 1 resulted in an improved 98% yield of 6a (entry 17). Subsequently, efforts to decrease the reaction time of step 2 resulted in lowered yields (entry 18). Thus, based on these observations, we selected the highlighted conditions in entry 17 as the optimal conditions for this telescoped transformation. This transformation, starting from 3-phenylurazole, provides 6a in a higher isolated yield than the direct cycloaddition with PTAD and thioalkyne 2a that we reported previously (cf. 98% vs 89%).¹ Scaling these conditions to 3.5 mmol scale with respect to 2a resulted in the isolation of 6a (880 mg) in a reduced yield of 79% yield (entry 17, brackets). While the yield suffers at scale, the observed 79% yield is on par with the scaled experiment for the synthesis of 6a using PTAD in refluxing acetonitrile (cf. 79% vs. 81%).¹

Table 1.

Optimization of telescoped diazacyclobutene synthesis under Lewis acid catalysis.

Entry	4a equiv.	Catalyst	x mol %	solvent	6a yield (%)
1	4	–	–	DCM	28
2	4	Sc(OTf)3	10	DCM	66
3	4	TiO2	10	DCM	71
4	4	SnCl4	10	DCM	81 [26]a
5	4	MgCl2	10	DCM	68
6	4	MgCl2	30	DCM	70
7	4	MgCl2	50	DCM	71
8	4	MgCl2	30	CHCl3	78
9	4	MgCl2	30	THF	58
10	4	MgCl2	30	EtOAc	52
11	4	MgCl2	30	Toluene	69
12	4	MgCl2	30	ACN	47
13	4	MgCl2	30	DCMb	84
14	1	MgCl2	30	DCMb	53
15	2	MgCl2	30	DCMb	86
16	3	MgCl2	30	DCMb	94 [0]c
17	3	MgCl2	30	DCM b	98d [79]d,e
18	3	MgCl2	30	DCMb	86f
19	3	MgCl2	30	DCMb	28g [28]h
20	–	MgCl2	30	DCMb	94i

^aRepeated experiment.

^bAnhydrous

^cUsing 1,3-dibromo-5,5-dimethylhydantoin as oxidant.⁹

^dAddition of anhydrous Na₂SO₄ (9 equiv) at 1.5 h reaction time of step 1.

^e3.5 mmol scale (880 mg of 6a isolated)

^f3 h reaction time (step 2).

^greaction mixture was filtered after addition of MgCl₂ prior to addition of 2a.

^hreaction was conducted without MgCl₂.

ⁱPTAD (1 equiv) was used while omitting the oxidation step.

Since the reaction mixture is heterogeneous owing to the poor solubility of MgCl₂ in DCM, a control experiment was conducted wherein the MgCl₂ was added to the PTAD solution resulting from urazole oxidation, stirred briefly, and then removed by filtration prior to adding thioalkyne 2a. This experiment attempted to probe whether MgCl₂ was acting as a solid-phase scavenger of trace impurities arising from the oxidation step in lieu of acting as a Lewis Acid catalyst as predicted. Under these conditions, 6a was isolated in a drastically reduced 24% yield (entry 19). The same yield was realized in an experiment that omitted MgCl₂ entirely (entry 19, brackets). These two experiments suggest that MgCl₂ is indeed a competent Lewis Acid catalyst for the cycloaddition. MgCl₂ catalysis then was clearly demonstrated upon direct treatment of PTAD and 2a in DCM. Thus, reaction of PTAD (1 equiv), 2a (1.3 equiv), and 30 mol % MgCl₂ in dry DCM at RT provided 94% yield of 6a after 24 h (entry 20).

Having successfully prepared diazacyclobutene 6a (where R³ = Ph) in 98% isolated yield (Table 1, entry 17), we next investigated the substrate scope of the second generation telescoped transformation using Ca(OCl)₂ oxidation/MgCl₂ catalysis with a variety of R³-substituted urazoles (Scheme 3). Generally, the second generation approach outperformed the first generation, oxidation/thermal cycloaddition approach with only a few exceptions. First, we explored para-substituted arenes at the R³ position. Urazole bearing para-methylphenyl provided diazacyclobutene 6b in 93% isolated yield. The incorporation of para-situated electron withdrawing groups were more poorly tolerated, providing p-CF₃-C₆H_4⁻ (6c), p-NO₂-C₆H_4⁻ (6d), and p-F-C₆H_4⁻ (6e) analogs in poor to moderate yields (64%, 55%, and 28% yields, respectively). Nevertheless, it should be noted that compounds 6d and 6e were prepared in higher yields than in the first generation thermal approach (Scheme 2). Urazoles possessing meta-substituted electron-donating groups at the R³ position furnished the products 6f (m-OCH₃-C₆H_4⁻), 6g (m-Cl-C₆H_4⁻), and 6h (m-Br-C₆H_4⁻) in improved yields (i.e., 68% vs. 30% for 3f, 50% vs. 30% for 3g, and 68% for 3h, respectively). Benzyl and 1-napthyl bearing urazoles afforded the corresponding products in poor to good yields. Improved yields over refluxing conditions were observed for benzyl and decreased yields for 1-napthyl (6i and 6j, 78% vs. 71% and 20% vs. 42%, respectively). Urazoles bearing di-substituted phenyl functionality at R³ were also tolerated (6k and 6l, 86% and 23% yield). Note that attempts to prepare any isolable product 6l were unsuccessful with the first generation approach (Scheme 2). Next, we shifted our focus towards n-alkyl functionality at R³. These derivatives provided the corresponding diazacyclobutenes in good to excellent yields (6m – 6q, 60% – 91%). An R³ = Me derivative (6m) was isolated in 60% yield. It is noteworthy that a reduction in yield using Lewis acid catalysis was observed for the R³ = n-Bu congener when compared to the first generation thermal approach (6n, 60% versus 72%). Nevertheless, improvements over refluxing conditions were observed for R³ = n-hexyl, 6p, and R³ = n-octyl, 6q, functionality (87% vs. 64% and 91% vs. 58%, respectively). As aforementioned, we were unable to access branched and some short-chain alkyl urazoles, so we were unable to assess our method using these substrates.

Scheme 3.

Substrate scope of telescoped urazole oxidation/cycloaddition with Ca(OCl)₂ oxidation/MgCl₂ catalysis.

CONCLUSION

In summary, we explored the feasibility of generating R³-substituted diazacyclobutenes via thermal and Lewis acid catalyzed conditions using a telescoped urazole oxidation/cycloaddition sequence. We developed a mild catalytic method for the synthesis of R³-substituted diazacyclobutenes through the cycloaddition between alkynyl sulfides and various triazolinediones that were generated in situ by means of a calcium hypochlorite oxidation of urazoles. This effort expands on the structural variability of these rarely accessed heterocycles. Current efforts are underway to further expand this molecular scaffold through the use of electron-rich ynamides, ynamines, and ynols (alkynyl ethers), to evaluate the biological relevancy of the scaffold, and to explore the further synthetic manipulation of these molecules.

Experimental Section

General Information.

All reagents were purchased from commercial sources and used without further purification. Dichloromethane and acetonitrile were dried prior to use over phosphorus pentoxide. ¹H and ¹³C {¹H} NMR spectra were collected on Bruker Avance 300 MHz and 500 MHz spectrometers using DMSO-d₆ and CDCl₃ as solvents. Chemical shifts are reported in parts per million (ppm). Chemical shifts are referenced to residual solvent peaks. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Infrared spectroscopy data were collected using a Shimadzu IRAffinity-1S instrument (with MIRacle 10 single reflection ATR accessory) operating over the range of 400 to 4000 cm⁻¹. Flash silica gel (40-63 μm) was used for column chromatography. All diazacyclobutene products (6a – 6q) were purified by flash chromatography with hexane and ethyl acetate (gradient from 100% hexane to 8:2 hexane/ethyl acetate). All known compounds were characterized by ¹H and ¹³C {¹H} NMR and are in complete agreement with data reported elsewhere. All new compounds were characterized by ¹H and ¹³C {¹H} NMR, ATR-FTIR, HRMS, and melting point (where appropriate). R³-urazoles (4) were prepared using modified Cookson’s conditions:^23-24 commercially available isocyanates were condensed with ethylcarbazate to generate substituted semicarbazides which were then cyclized to the corresponding urazoles (See ESI for details). 4-methylurazole was synthesized using a recently reported isocyanate-free method.²⁵ Thioalkyne 2a was prepared as described previously.¹

Procedure for synthesis of R³-substituted diazacyclobutenes.²⁶

The following procedure for the preparation of 6a is illustrative. To a flame-dried round-bottomed flask equipped with a stir bar was added a solution of 4-phenylurazole (271 mg, 1.5 mmol, 3 equiv) and calcium hypochlorite (429 mg, 3 mmol, 6 equiv) in dichloromethane (15 mL). The reaction was stirred at room temperature for 1.5 h. Anhydrous sodium sulfate (426 mg, 3 mmol, 9 equiv) was added to the flask and the mixture was stirred for an additional 0.5 h. The suspension was gravity filtered into a clean flask and the resulting solution was concentrated under reduced pressure to afford a red residue. This residue was transferred with dry dichloromethane (3 mL) to a new flame-dried round-bottomed flask equipped with a stir bar and anhydrous magnesium chloride (14 mg, 0.15 mmol, 0.3 equiv). To this stirring solution was added dropwise a solution of the alkynyl sulfide, 1a, (74 mg, 0.5 mmol, 1 equiv) in dry dichloromethane (2 mL). The mixture was stirred at room temperature for 24 h. The resultant mixture was concentrated under reduced pressure and purified via flash chromatography with hexane and ethyl acetate (gradient from 100% hexane to 8:2 hexane/ethyl acetate) to afford the corresponding diazacyclobutene 6a (158 mg, 98% yield).

6a, 3-phenyl-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione:¹ Light yellow solid, 98% (158 mg), ¹H NMR (500 MHz, CDCl₃) δ 8.00-7.78 (m, 2H), 7.67-7.31 (m, 8H), 2.59 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 156.5, 155.1, 145.3, 130.8, 129.9, 129.3, 129.1, 128.8, 126.3, 125.6, 125.4 (2C, See 2D-HMQC analysis),¹ 17.4.

6b, 3-(4-methylphenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 93% (192 mg); Mp: 124.6-125.8°C; IR (neat): 2920 (w), 1790 (w), 1736 (s), 1516 (m), 1385 (s), 1231 (s), 1180 (m), 1142 (m), 1107 (m), 1022 (m), 818 (m), 752 (m), 679 (m) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.90-7.84 (m, 2H), 7.49-7.37 (m, 3H), 7.37-7.27 (m, 4H), 2.58 (s, 3H), 2.40 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 156.7, 155.3, 145.3, 139.4, 130.0, 129.9, 129.3, 128.8, 128.2, 126.4, 125.6, 125.3, 21.3, 17.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₁₅N₃O₂S 338.0963; Found 338.0964.

6c, 3-(4-trifluoromethylphenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 64% (251 mg); Mp: 128.7-131.1 °C; IR (neat): 3082 (w), 2928 (w), 1786 (w), 1736 (s), 1385 (s), 1323 (m), 1223 (m), 1173 (m), 1142 (m), 1107 (m), 1069 (m), 1011 (m), 922 (w), 837 (m), 752 (m), 683 (m) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.89-7.83 (m, 2H), 7.80-7.66 (m, 4H), 7.50-7.38 (m, 3H), 2.59 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 156.0, 154.5, 145.5, 134.0, 131.0 (q, ²J_C-F = 33.0 Hz), 130.1, 129.5, 128.9, 126.5 (q, ³J_C-F = 3.7 Hz), 126.2, 125.6, 125.4, 123.5 (q, ¹J_C-F = 272.4 Hz) 17.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₁₂F₃N₃O₂S 392.0681; Found 392.0677.

6d, 6-methylsulfanyl-3-(4-nitrophenyl)-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Yellow solid; Yield: 55% (106 mg); Mp: 151.7-154.7 °C; IR (neat): 3480 (w), 3356 (m), 3098 (w), 2928 (w), 1786 (w), 1736 (s), 1616 (s), 1528 (s), 1489 (s), 1381 (s), 1331 (s), 1312 (s), 1234 (s), 1130 (m), 1092 (m), 1015 (m), 895 (m), 849 (m), 752 (m), 741 (m), 683 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 8.40-8.34 (m, 2H), 7.89-7.79 (m, 4H), 7.52-7.42 (m, 3H), 2.60 (s, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 155.5, 154.2, 147.2, 145.6, 136.4, 130.3, 129.7, 128.9, 126.0, 125.6, 125.4, 124.7, 124.2, 118.1, 17.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₁₃N₄O₄S 369.0658; Found 369.0653.

6e, 3-(4-fluorophenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 28% (65 mg); Mp: 162.9-163.8°C; IR (neat): 3125 (w), 3059 (w), 2928 (w), 1794 (w), 1736 (s), 1508 (s), 1389 (s), 1231 (s), 1142 (m), 1092 (m), 1018 (m), 926 (m), 829 (s), 752 (s), 683 (s) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.89-7.83 (m, 2H), 7.51-7.37 (m, 5H), 7.23-7.15 (m, 2H), 2.58 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 162.5 (d, ¹J_C-F = 249.7), 156.4, 155.0, 145.4, 130.0, 129.4, 128.8, 127.4 (d, ³J_C-F = 8.8 Hz), 126.8 (d, ⁴J_C-F = 3.2 Hz), 126.3, 125.6, 116.5 (d, ²J_C-F = 23.3 Hz), 17.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₁₃FN₃O₂S 342.0713; Found 342.0714.

6f, 3-(3-methoxyphenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 68% (117 mg); Mp: 108.0-110.2 °C; IR (neat): 3059 (w), 3005 (w), 2924 (w), 2832 (w), 1786 (m), 1732 (s), 1605 (m), 1497 (m), 1447 (m), 1389 (s), 1319 (m), 1288 (m), 1261 (s), 1211 (s), 1180 (m), 1146 (s), 1072 (w), 1038 (m), 1018 (m), 845 (m), 826 (s), 783 (m), 756 (s), 698 (m), 683 (s) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.90-7.83 (m, 2H), 7.48-7.43 (m, 2H), 7.42-7.36 (m, 2H), 7.09-7.05 (m, 1H), 7.02 (t, J = 2.2 Hz, 1H), 6.99-6.95 (m, 1H), 3.82 (s, 3H), 2.59 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 160.2, 156.5, 155.0, 145.3, 131.8, 130.1, 130.0, 129.4, 128.8, 126.4, 125.6, 117.6, 115.3, 111.0, 55.6, 17.4; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₁₅N₃O₃S 354.0912; Found 354.0916.

6g, 3-(3-chlorophenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 50% (85 mg); Mp: 122.5-124.8 °C; IR (neat): 3063 (w), 2928 (w), 2851 (w), 1786 (w), 1732 (s), 1593 (m), 1477 (m), 1435 (m), 1381 (s), 1234 (s), 1142 (m), 1026 (m), 945 (w), 860 (w), 779 (m), 752 (m), 683 (m) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.90-7.82 (m, 2H), 7.58-7.54 (m, 1H), 7.50-7.38 (m, 6H), 2.59 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 156.1, 154.7, 145.4, 135.0, 131.9, 130.3, 130.1, 129.5, 129.4, 128.9, 126.2, 125.6, 125.6, 123.4, 17.4; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₁₂ClN₃O₂S 358.0417; Found 358.0416.

6h, 3-(3-bromophenyl)-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 68% (244 mg); Mp: 127.7-128.7 °C; IR (neat): 3102 (w), 1082 (w), 3055 (w), 3024 (w), 2928 (w), 1786 (w), 1732 (s), 1582 (m), 1477 (m), 1381 (s), 1227 (s), 1142 (s), 1022 (m), 937 (m), 868 (m), 783 (m), 745 (s), 694 (m), 683 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.96-7.77 (m, 2H), 7.74-7.66 (m, 1H), 7.61-7.52 (m, 1H), 7.52-7.30 (m, 5H), 2.58 (s, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 156.1, 154.7, 145.4, 132.3, 132.0, 130.6, 130.1, 129.5, 128.9, 128.4, 126.2, 125.6, 123.9, 122.7, 17.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₁₂BrN₃O₂S 401.9912; Found 401.9906.

6i, 3-benzyl-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 78% (242 mg); Mp: 100.0-101.1 °C; IR (neat): 3063 (w), 2924 (w), 1782 (m), 1732 (s), 1489 (w), 1427 (m), 1389 (s), 1188 (m), 1146 (s), 1003 (m), 953 (m), 756 (m), 721 (s), 683 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.86-7.75 (m, 2H), 7.50-7.28 (m, 8H), 4.70 (s, 2H), 2.53 (s, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 157.6, 156.3, 145.0, 134.2, 129.8, 129.2, 128.94, 128.86, 128.77, 128.6, 126.4, 125.5, 44.6, 17.4; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₁₅N₃O₂S 338.0963; Found 338.0968.

6j, 6-methylsulfanyl-3-(1-napthyl)-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione, Pale yellow solid; Yield: 42% (reflux, 77 mg), 20% (Lewis Acid-catalyzed, 36 mg); Mp: 158.7-160.1 °C; IR (neat): 3055 (w), 2920 (w), 2851 (w), 1790 (w), 1736 (s), 1404 (m), 1373 (m), 1238 (m), 1130 (m), 1011 (m), 914 (m), 795 (m), 768 (s), 752 (s), 683 (m) cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ 8.05-7.90 (m, 4H), 7.82-7.42 (m, 8H), 2.62 (s, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 157.0, 155.6, 145.4, 134.4, 130.9, 130.0, 129.6, 129.0, 128.9, 128.8, 127.8, 126.9, 126.6, 126.5, 126.4, 125.7, 125.3, 121.3, 17.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₁₅N₃O₂S 374.0963; Found 374.0962.

6k, 3-(2,6-dimethylphenyl)-6-methyl-sulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield 86% (161 mg); Mp: 129.2-130.4 °C; IR (neat): 3059 (w), 2951 (w), 2924 (w), 2851 (w), 1794 (w), 1736 (s), 1474 (m), 1443 (m), 1369 (s), 1200 (m), 1146 (m), 1069 (m), 918 (m), 772 (m), 760 (m), 687 (s) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.93-7.85 (m, 2H), 7.50-7.37 (m, 3H), 7.28 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 2.59 (s, 3H), 2.22 (br. s, 6H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 156.7, 155.2, 145.7, 136.4, 130.4, 130.0, 129.7, 128.9, 128.8, 128.0, 126.4, 125.7, 17.5 (2C, See 2D-HMQC in ESI); HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₁₇N₃O₂S 352.1120; Found 352.1129.

6l, 3-(3,5-dichlorophenyl)-6-methyl-sulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Pale yellow solid; Yield: 23% (45 mg); Mp: 153.0-154.7 °C; IR (neat): 3075 (w), 2924 (w), 2855 (w), 1790 (w), 1744 (s), 1578 (m), 1447 (m), 1377 (s), 1238 (m), 1134 (w), 856 (w), 806 (w), 752 (m), 683 (w) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.89-7.77 (m, 2H), 7.55-7.37 (m, 6H), 2.58 (s, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 155.6, 154.3, 145.5, 135.7, 132.6, 130.2, 129.6, 129.3, 128.9, 126.1, 125.6, 123.6, 17.6; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₁₁Cl₂N₃O₂S 392.0027; Found 392.0025.

6m, 3-methyl-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; White solid; Yield: 79% (157 mg); Mp: 114.8-116.0 °C; IR (neat): 2936 (w), 2851 (w), 1802 (m), 1721 (s), 1431 (s), 1385 (s), 1273 (m), 1188 (s), 1161 (s), 1030 (m), 1003 (m), 779 (m), 760 (s), 694 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.89-7.73 (m, 2H), 7.47-7.36 (m, 3H), 3.13 (s, 3H), 2.54 (s, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 158.0, 156.7, 145.3, 129.9, 129.2, 128.8, 126.4, 125.5, 26.8, 17.4; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₂H₁₂N₃O₂S 262.0650; Found 262.0656.

6n, 3-butyl-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Clear oil; Yield: 60% (217 mg); IR (neat): 3059 (w), 2959 (w), 2932 (w), 2870 (w), 1794 (w), 1728 (s), 1439 (m), 1393 (s), 1362 (m), 1173 (m), 1150 (m), 1069 (m), 756 (s), 687 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.83-7.78 (m, 2H), 7.45-7.35 (m, 3H), 3.56 (t, J = 7.3 Hz, 2H), 2.54 (s, 3H), 1.66 (p, J = 7.5 Hz, 2H), 1.36 (m, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 158.0, 156.6, 129.8, 129.3, 128.8, 126.5, 125.5, 40.7, 29.4, 19.8, 17.4, 13.5; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₅H₁₇N₃O₂S 304.1120; Found 304.1126.

6o, 6-methylsulfanyl-3-pentyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Clear oil; Yield: 89% (142 mg); IR (neat): 3059 (w), 2955 (w), 2928 (w), 2862 (w), 1798 (w), 1728 (s), 1439 (m), 1393 (s), 1366 (m), 1173 (m), 1150 (m), 1072 (w), 980 (w), 783 (w), 756 (s), 687 (s) cm^{−1; 1}H-NMR (500 MHz, CDCl₃) δ 7.86-7.75 (m, 2H), 7.49-7.32 (m, 3H), 3.55 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 1.69 (p, J = 7.3 Hz, 2H), 1.42-1.22 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C {¹H} NMR (125 MHz, CDCl₃) δ 158.0, 156.6, 145.2, 129.8, 129.3, 128.8, 126.5, 125.5, 41.0, 28.6, 27.0, 22.1, 17.4, 13.9; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₆H₁₉N₃O₂S 318.1276; Found 318.1283.

6p, 3-hexyl-6-methylsulfanyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Clear gel; Yield 87% (211 mg); IR (neat): 3059 (w), 2951 (w), 2928 (w), 2859 (w), 1798 (w), 1732 (s), 1393 (s), 1366 (m), 1177 (m), 1150 (m), 756 (s), 687 (s) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.85-7.75 (m, 2H), 7.50-7.35 (m, 3H), 3.55 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 1.77-1.60 (m, 2H), 1.40-1.20 (m, 6H), 0.96-0.80 (m, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 158.0, 156.6, 145.2, 129.8, 129.3, 128.8, 126.5, 125.5, 41.0, 31.2, 27.3, 26.1, 22.4, 17.4, 14.0; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₂₁N₃O₂S 332.1433; Found 332.1443.

6q, 6-methylsulfanyl-3-octyl-7-phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione; Clear gel; Yield: 91% (207 mg); IR (neat): 3059 (w), 2924 (w), 2855 (w), 1794 (w), 1732 (s), 1443 (w), 1396 (m), 1366 (m), 1177 (m), 1150 (m), 756 (m), 687 (m) cm^{−1; 1}H-NMR (300 MHz, CDCl₃) δ 7.85-7.76 (m, 2H), 7.50-7.38 (m, 3H), 3.55 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 1.70-1.64 (m, 2H), 1.33-1.23 (m, 12H), 0.90-0.83 (m, 3H); ¹³C {¹H} NMR (75 MHz, CDCl₃) δ 158.0, 156.6, 145.2, 129.8, 129.3, 128.8, 126.5, 125.5, 41.0, 31.7, 29.0, 27.3, 26.5, 22.6, 17.4, 14.1; HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₅N₃O₂S 360.1746; Found 360.1753.