Pd-Catalyzed Alkene Diamination Reactions with O-Benzoylhydroxylamine Electrophiles. Evidence Supporting a Pd(II/IV) Catalytic Cycle, the Role of 2,4-Pentanedione Derivatives as Ligands, and Expanded Substrate Scope

Abstract

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a Pd^II complex, followed by reductive elimination from Pd^IV to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not a phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

Graphical Abstract

INTRODUCTION

Metal-catalyzed alkene diamination reactions are an important sub-class of alkene difunctionalization reactions that have attracted considerable attention in recent years.^1,2,3,4,5 One strategy that we found particularly interesting due to both its potential utility, as well as its current limitations, involves the coupling of readily available nitrogen-centered electrophiles with alkenes bearing tethered nitrogen nucleophiles. In 2009 Michael,⁶ reported the first metal-catalyzed alkene diamination reactions of this type, which utilized NFBS (N-fluorobenzene-sulfonimide) as a source of electrophilic nitrogen. More recently, Wang⁷ has described the Cu-catalyzed coupling of similar alkene substrates with O-acylated hydroxylamine electrophiles. However, despite the utility of these methods, they have limitations with respect to either scope,⁸ or control of stereochemistry in reactions involving 1,2-disubstituted alkenes.⁹

In 2018 we reported the Pd-catalyzed alkene diamination of guanidines and ureas bearing tethered alkenes (e.g., 1a-b) with O-acylated hydroxylamine derivatives such as morpholino benzoate 2a (eq 1).¹⁰ These transformations provide cyclic guanidines or ureas bearing appended aminoalkyl groups (e.g., 3a-b) in good to excellent chemical yield. In addition, reactions involving deuterated alkene substrates (e.g., 1c-d) proceed with modest diastereoselectivity favoring products resulting from anti-addition of the two nitrogen atoms to the alkene (e.g., 3c-d).

(1)

We initially hypothesized that the mechanism of these reactions is similar to that of related alkene carboamination reactions between 1a-d and aryl halide or triflate electrophiles and likely involves a typical Pd⁰/Pd^II catalytic cycle,¹⁰ (Scheme 1, Path A) that is initiated by oxidative addition of 2a to the metal center to afford 4.¹¹ Subsequent coordination of the alkene group of 1d to the metal followed by alkene aminopalladation (5 to 6),¹² and then reductive elimination from 6, would afford the product 3d.¹³ However, a Pd^II/Pd^IV catalytic cycle in which 6 was oxidized to 7 by additional 2a,¹⁴ followed by reductive elimination to generate 3d and 4 also seemed plausible.¹³

Scheme 1. Initial mechanistic hypothesis.

In this Article we describe new experiments that have led us to revise our mechanistic hypothesis, along with the discovery that acac (2,4-pentanedione) and simple acac derivatives bearing substituted arenes serve as highly effective ligands for this transformation. These discoveries have also allowed for significant expansion in scope with respect to electrophile structure.

RESULTS AND DISCUSSION

Control experiments and precatalyst effects.

Following our preliminary studies, we set out to further examine this reaction and its mechanism (Scheme 2). We elected to first explore the putative oxidative addition of the morpholino benzoate electrophile 2a to either Pd⁰ or Pd^II. However, in initial scouting experiments we were surprised to find that the phosphine ligand JackiePhos did not bind to Pd(acac)₂ as judged by a lack of change of the ³¹P NMR chemical shift of JackiePhos vs the mixture of JackiePhos and Pd(acac)₂ (eq 2). In order to explore the possibility of oxidative addition to a Pd⁰/JackiePhos complex, we carried out NMR studies in which the Buchwald Pd^II(JackiePhos) G3 precatalyst was reduced in situ, as judged by ³¹P NMR analysis,¹⁵ and then treated with 2a (eq 3). Surprisingly, we saw no evidence for oxidative addition of 2a to this Pd⁰ complex. In addition, we did not observe any evidence for oxidative addition of 2a to the Pd^II complex Pd(acac)₂ at 100 °C, either with or without JackiePhos present (eq 4).¹⁶ The results of these experiments immediately suggested two things: (i) since JackiePhos does not appear to bind to Pd(acac)₂, it may not be the actual ligand for Pd in these alkene diamination reactions; and (ii) our original mechanistic hypothesis is likely incorrect, as the proposed initial oxidative addition step does not appear to be viable with this catalyst system.

Scheme 2. Exploration of JackiePhos ligation and the viability of initial oxidative addition.

Given these results, we decided to revisit the influence of precatalyst and ligand on the outcome of the coupling reactions between 2a and N-allylurea substrate 1b. We had previously reported that the coupling of 2a with 1b in the presence of Cs₂CO₃, Pd(acac)₂, and JackiePhos, afforded a 90% yield of the desired product 3b (Table 1, entry 1). We first carried out the key control experiment in which JackiePhos was omitted from these conditions,¹⁷ and obtained essentially the same result as when JackiePhos was included (entry 2). This result suggests that the actual ligand for Pd is acac, not JackiePhos, and is further supported by the fact that Pd(tfa)₂ or other simple palladium pre-catalysts alone gave poor results (entries 3–5), but use of Pd(tfa)₂ and acac provided 3b in 95% yield (entry 6).

Table 1:

Precatalyst effects.^a

entry	[Pd]	Ligand (mol %)	yield (%)b
1	Pd(acac)2	JackiePhos (16 mol %)	90c
2	Pd(acac)2	none	95
3	Pd2(dba)3	none	43
4	Pd(OAc)2	none	24
5	Pd(tfa)2	none	35
6	Pd(tfa)2	acac (8 mol %)	95

^aConditions: 1.0 equiv 1b, 3.0 equiv 2a, 4 mol % [Pd], 2 equiv CS₂CO₃, dioxane (0.1 M), 100 °C, 16 h.

^bYields were determined by ¹H NMR analysis using phenanthrene as an internal standard.

^cIsolated yield reported in reference 10.

Revised mechanistic hypothesis and stereochemical details.

Given that the experiments described in Scheme 2 indicated our initial mechanistic hypothesis (Scheme 1) is not correct, we sought to gain additional information about the mechanism of these transformations. Michael’s previously reported Pd-catalyzed alkene diamination reactions of protected aminoalkenes with N-fluorobenzenesulfonimide have been shown to proceed via initial anti-aminopalladation of the alkene, followed by oxidative addition of the electrophile to an alkyl Pd^II complex, and subsequent reductive elimination with inversion of configuration from the resulting Pd^IV intermediate.⁶ In order to probe whether our reactions may proceed via a similar mechanism, we first sought to confirm that alkene aminopalladation could occur in the absence of the electrophile. As such, 1b was treated with Cs₂CO₃ and a stoichiometric amount of Pd(acac)₂. These conditions afforded a roughly 1:1:4 mixture of products 8-10a in 62% combined NMR yield (Scheme 3). All three of these products likely arise from alkene aminopalladation (1b to 11a), with 8 likely derived from β-hydride elimination of 11a to 8a followed by alkene isomerization. The β-hydride elimination generates an equivalent of H-Pd(acac), which can react with 1b to afford 11b, or undergo disproportionation with 11a to form 11b and Pd(acac)₂. Subsequent reductive elimination from 11b then produces 9. Finally 10a derives from aryl C–H functionalization of 11a. As such, the presence of the electrophile is not required for alkene aminopalladation to occur, and Pd(acac)₂ is effective at inducing alkene aminopalladation of 1b under our otherwise standard reaction conditions.

Scheme 3. Evidence in support of initial alkene aminopalladation.

Since product 3d results from net anti-addition to the alkene, we sought to gain additional information about the stereochemistry of alkene aminopalladation and reductive elimination. The overall anti-addition could result from either anti-aminopalladation followed by reductive elimination with retention of configuration, or may derive from syn-aminopalladation and subsequent reductive elimination with inversion of configuration.¹⁸ In order to determine the alkene addition stereochemistry, we elected to take advantage of the relatively facile aminopalladation/C–H functionalization sequence described above (1b to 10a). As shown in Scheme 4, treatment of deuterated alkene substrate 1d with Pd(acac)₂ and Cs₂CO₃ in the presence or absence of JackiePhos afforded 10b in modest yield (37% and 20%, respectively), with ca 1.5:1 diastereoselectivity favoring the product resulting from anti-aminopalladation.¹⁹

Scheme 4. Stereochemistry of alkene aminopalladation^a.

^aConditions: 1.0 equiv 1d or 1e, 3.0 equiv 2a, 1 equiv Pd(acac)₂, 2 equiv ligand, 2 equiv Cs₂CO₃, dioxane (0.1 M), 100 °C, 1 h. ^bYields for entries 1 and 2 are isolated yields, whereas the yield for entry 3 was determined by ¹H NMR analysis using phenanthrene as an internal standard.

Given the low diastereoselectivity of the conversion of 1d to 10b (ca 1.5:1 dr) relative to that for the conversion of 1d to 3d (Table 2, 6:1 dr), it seemed possible that the aminopalladation stereoselectivity was being eroded by reversible β-hydride elimination from complex 11d.²⁰ However, the cyclization/C–H functionalization of di-deuterated substrate 1e, which should undergo much slower β–deuterium elimination from complex 11e than the rate for β–hydride elimination from complex 11d,²¹ proceeded with comparable (1.6:1) diastereoselectivity (Scheme 4, entry 3). Although the selectivity for anti- vs. syn aminopalladation is modest, this result suggests that since the overall conversion of 1d to 3d proceeds with net anti-addition, the C–N bond-forming reductive elimination must occur with retention of configuration. Thus, although these transformations are mechanistically similar to the reactions previously described by Michael,⁶ the nature of the nitrogen nucleophile has an impact on the stereochemistry of reductive elimination. Transformations of the more electron-rich O-benzoylhydroxylamine-derived electrophiles appear to involve stereoretentive reductive elimination, rather than stereoinvertive reductive elimination as observed with N-fluorobenzenesulfonimide by Michael.⁶

Table 2.

Effect of electrophile concentration and ligand on Anti-addition stereoselectivity^a

entry	equiv 2a	ligand	dr	yield (%)b
1	3.0	JackiePhos	6:1	75c
2	3.0	none	6:1	74
3	1.5	JackiePhos	2.2:1	79
4	1.5	None	2.8:1	76

^aConditions: 1.0 equiv 1d, 1.5 or 3.0 equiv 2a, 4 mol % Pd(acac)₂, 8 mol% ligand, 2 equiv CS₂CO₃, dioxane (0.1 M), 100 °C, 16 h.

^bisolated yields.

^cIsolated yield reported in reference 10.

Collectively, the results of the experiments shown above suggest the mechanism of this transformation involves initial, and likely reversible, anti-aminopalladation of the alkene to generate intermediate 11d from 1d (Scheme 5).²² Oxidative addition of the amine electrophile 2a to 11d provides Pd^IV intermediate 13d, and then reductive elimination affords the observed product 3d with regeneration of the Pd^II catalyst.²³ Although our control experiments illustrate that 2a does not undergo oxidative addition to Pd(acac)₂, the alkylpalladium complex 11d is considerably more electron-rich than Pd(acac)₂, and should undergo much more facile oxidative addition.

Scheme 5. Revised mechanistic hypothesis.

Effect of electrophile concentration on stereoselectivity.

In our initial studies, we found that the Pd(acac)₂/JackiePhos - catalyzed coupling of 1d with 2a afforded 3d in 75% yield and 6:1 dr (Table 2, entry 1).¹⁰ A similar outcome was obtained when Pd(acac)₂ alone (no phosphine) was used as the catalyst for this reaction (entry 2). However, when the amount of 2a was decreased to only 1.5 equiv, 3d was generated in much lower diastereoselectivity (2.2:1 to 2.8:1 dr; entries 3–4), regardless of whether or not JackiePhos was present. This suggests that the stereoselectivity of this transformation is dependent at least to some extent on the rate of the oxidative addition step in the catalytic cycle.

The influence of electrophile concentration on diastereoselectivity may be due to the relative rates of anti-aminopalladation/oxidative addition vs. syn-aminopalladation, coupled with kinetic vs thermodynamic control of selectivity. As illustrated in Scheme 6, it possible for 12d and 12d’ to equilibrate through exchange of the coordinated alkene for the anionic urea nitrogen, with displacement of an acac ligand. If anti-aminopalladation of 12d to 11d is faster than syn-aminopalladation of 12d’ to 11d’ (k₁ > k₂), and if the oxidative addition sequence from 11d to 13d is faster than retro-aminopalladation of 11d to 12d (k₃ > k₋₁), then the selectivity for the anti-addition stereoisomer 3d should be relatively high.²⁴

Scheme 6. Competing stereochemical pathways.

On the other hand, anti-aminopalladation complex 11d and its syn-addition diastereomer 11d’ are expected to be very close in energy, since they differ only in the configuration of an H/D stereocenter, and if oxidative addition is slow enough that 11d and 11d’ equilibrate through reversible aminopalladation (k₋₁ and k₂ > k₃), stereoselectivity should be relatively low, as it would reflect the thermodynamic ratio of 11d and 11d’. The data shown in Table 2 are consistent with the former scenario (k₁ > k₂ and k₃ > k₋₁) when the concentration of 2a is relatively high. However, if the concentration of 2a is relatively low, the rate k₃ of the bimolecular oxidative addition should decrease, and selectivity for the anti-addition product 3d should erode, as is observed.

Influence of acac structure on reactivity.

The use of acac as a “standalone” (no added phosphine) ligand in Pd-catalyzed cross-coupling reactions is extremely rare, and the influence of acac ligand structure on reactivity in Pd-catalyzed reactions has not thoroughly been explored.²⁵ In order to determine whether acac structure has an impact on reactivity or yield, we quickly screened Pd(acac-F₆)₂ as a catalyst for the coupling of 1b with 2a to afford 3b (Table 3). Interestingly, this complex bearing an electron-deficient acac derivative gave very poor results (Table 3, entry 2, 10% yield of 3b) in comparison to the results obtained with Pd(acac)₂ (entry 1, 90% yield). This result indicated the structure of the acac ligand does influence reactivity, and in a profound manner. Accordingly, we explored the coupling of more challenging urea substrates 1f and 1g with several different acac-derived ligands (Table 3). With our original catalyst system of Pd(acac)₂/JackiePhos, the coupling of 1f with 2a afforded 3e in only 45% isolated yield (entry 3).¹⁰ By omitting JackiePhos and using only Pd(acac)₂ as catalyst we observed 74% NMR yield of 3e (entry 4). Changing the ligand to 14 or 15a (entries 5 and 7) resulted in significantly reduced yields. However, improved results were obtained with 15c-15e (83–88%; entries 8–10). Finally, the best result was obtained with electron-rich analog 15f (84% isolated yield, entry 11). This ligand also provided considerably improved results in the reaction of 1g with 2a. Under our original conditions with JackiePhos as ligand, only a trace amount of desired product 3f was obtained (entry 12). However, use of 15f as a ligand in this reaction provided 3f in 42% isolated yield (entry 14). Thus, it appears that JackiePhos inhibits catalysis for some substrate combinations.

Table 3:

Acac ligand effects.^a

entry	R	[Pd]	ligand	yield (%/)b
1	NO2	Pd(acac)2	none	>95 (69)c
2	NO2	Pd(acac-F6)2	none	11d
3	Cl	Pd(acac)2	JackiePhos	87(45)e
4	Cl	Pd(acac)2	none	74
5	Cl	Pd(tfa)2	14	16
6	Cl	Pd(tfa)2	acac (15b)	77
7	Cl	Pd(tfa)2	15a	24
8	Cl	Pd(tfa)2	15c	83
9	Cl	Pd(tfa)2	15d	86
10	Cl	Pd(tfa)2	15e	88
11	Cl	Pd(tfa)2	15f	94 (84)
12	OMe	Pd(acac)2	JackiePhos	<5
13	OMe	Pd(acac)2	none	30
14	OMe	Pd(tfa)2	15f	75 (42)

^aConditions: 1.0 equiv 1b, 1.5 equiv 2a, 4 mol % [Pd], 8 mol % ligand, 2.0 equiv Cs₂CO₃, dioxane (0.1 M), 100 °C, 16 h.

^bYields were determined by ¹H NMR analysis using phenanthrene as an internal standard. Yields in parentheses are isolated yields.

^cThe reaction was conducted for one hour.

^dThe reaction was conducted with 3.0 equiv 2a.

^eIsolated yield from reference 10.

Further exploration of substrate scope.

Given the observation that JackiePhos may inhibit catalysis in some systems, combined with the fact that in our preliminary studies with Pd(acac)₂/JackiePhos we only successfully coupled electrophiles derived from cyclic amines,¹⁰ we sought to further explore the scope of Pd/15f-catalyzed alkene diamination reactions. As shown in Table 4, this catalyst was effective for the preparation of cyclic guanidines (3a, 3g-i), ureas (3b, 3j-n), and amides (3o-p). However, the presence of a gem-dimethyl group adjacent to the amide carbonyl was necessary to obtain satisfactory results; a substrate lacking the gem-dimethyl group failed to react. This is presumably the result of a Thorpe-Ingold effect that facilitates the alkene aminopalladation step. The reactions were effective with both cyclic and acyclic secondary amine-derived electrophiles, and the coupling of the primary cyclohexylaminobenzoate electrophile with 1b afforded 3k in 45% yield. This expansion in scope is significant, as reactions of primary or acyclic secondary amine-derived electrophiles gave little or no desired product using our original conditions. Interestingly, although phosphine ligands appear to inhibit catalysis, an electrophile with a potentially coordinating heteroaryl group reacted smoothly with 1h and 1b to afford 3i and 3l in good yield. The presence of an ester functional group was also tolerated (3n).

Table 4:

Alkene diamination reactions.^a,b

^aConditions: 1.0 equiv 1a-j, 3.0 equiv 2a-e, 4 mol % Pd(tfa)₂, 8 mol% 15f, 2 equiv CS₂CO₃, dioxane (0.1 M), 100 °C, 16 h, 0.2 mmol scale.

^bIsolated yields (average of two experiments).

^cThe reaction was conducted on a 1.0 mmol scale

^dThe reaction was conducted using benzotrifluoride as solvent (0.4 M).

SUMMARY AND CONCLUSION

In conclusion, through continued studies on Pd-catalyzed alkene diamination reactions involving O-benzoyl hydroxylamine electrophiles, we have demonstrated that phosphine ligands are not required, and in some cases inhibit catalysis. Instead, acac or acac-derivatives serve as the actual ligand for palladium that promotes reactivity in these transformations. In addition, we have illustrated that the structure of the acac ligand has a significant influence on reactivity, and this observation will likely find utility in other Pd-catalyzed reactions. We have also found that these transformations do not proceed via our originally postulated Pd(0/II) catalytic cycle that was initiated by oxidative addition of the N-electrophile to Pd(0). Instead, catalysis cycles through Pd(II)/Pd(IV) oxidation states, and is initiated by alkene aminopalladation. In comparison of our results with those of Michael, it appears that the stereochemical outcome of the reductive elimination from Pd(IV) is dependent on the nucleophilicity/basicity of the N-electrophile, with basic amines favoring reductive elimination with retention of configuration. Finally, this new catalyst system has allowed for a significant expansion of the scope of electrophiles that can be employed as coupling partners. Future studies will be directed towards further exploration of the classes of nucleophiles (in addition to guanidines, ureas, and amides) that can undergo diamination with O-benzoyl hydroxylamines.

EXPERIMENTAL SECTION

General:

All reactions were carried out under a nitrogen atmosphere using oven or flame-dried glassware and reactions conducted above room temperature were heated in an oil bath. All reagents, palladium sources, phosphine ligands, dicarbonyl ligands 14 and 15a-e, were obtained from commercial sources and used without further purification unless otherwise noted. N-Allylureas and guanidines 1a²⁶, 1b,d,e,f,g,h,¹⁰ 1i,^7a 1j,²⁷ ligand 15f,²⁸ and electrophiles 2a,^29,30 2b,³⁰ 2c,³¹ 2d,³² 2e,³³ and 2f³⁴ were prepared according to previously reported procedures. Dioxane was purified by distillation from Na metal and benzophenone under a nitrogen atmosphere. All yields refer to isolated compounds that are estimated to be ≥ 95% pure as judged by ¹H NMR analysis unless otherwise noted. The yields reported in the experimental section describe the result of a single experiment, whereas yields reported in Table 4 are average yields of two or more experiments. Thus, the yields reported in the experimental section may differ from those shown in Table 4.

Preparation and Characterization of Products

General Procedure for Pd-Catalyzed Alkene Difunctionalization Reactions.

A flame-dried Schlenk tube equipped with a stirbar was cooled under a stream of N₂ and charged with the appropriate palladium source (4 mol %), the appropriate ligand (8–16 mol %), the appropriate urea, guanidine, or amide substrate (0.2 mmol, 1 equiv), the appropriate electrophile (0.3–0.6 mmol, 1.5–3.0 equiv) and cesium carbonate (0.4 mmol, 2 equiv). The tube was purged with N₂, dioxane (2 mL, 0.1 M) was added, and the reaction mixture was headed to 100 °C for 16 h. The mixture was then cooled to rt and filtered through cotton, which was then eluted with a small amount diethyl ether. The resulting solution was concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel.

N-(1,3-Dibenzyl-4-(morpholinomethyl)imidazolidin-2-ylidene)cyanamide (3a).^7a

The general procedure was used for the coupling of 1a (30.4 mg, 0.1 mmol, 1 equiv) with morpholino benzoate (2a) (103.6 mg, 0.5 mmol, 5 equiv) using a catalyst composed of Pd(TFA)₂ (1.3 mg, 0.004 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (2.3 mg, 0.008 mmol, 8 mol %) except the reaction was conducted on a 0.1 mmol scale with 1 mL of dioxane. The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 62.0 mg (80%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.29–6.95 (m, 10 H), 5.24 (d, J = 15.5 Hz, 1 H), 4.56–4.46 (m, 2 H) 4.05 (d, J = 15.5 Hz, 1 H), 3.33–3.24 (m, 4 H), 3.01 (m, 1 H), 2.64 (app t, J = 9.5 Hz, 1 H), 2.52 (dd, J = 9.6, 7.1 Hz, 1 H), 1.87 (dd, J = 12.8, 5.6 Hz, 1 H), 1.77–1.66 (m, 4 H), 1.53 (dd, J = 12.8. 6.9 Hz, 1 H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 158.4, 135.9, 135.4, 128.9, 128.8, 128.2, 128.1, 128.0, 127.9, 116.5, 66.7, 61.0, 54.1, 51.9, 49.5, 49.3, 47.8; IR (film) 2919, 2171, 1596 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₇N₅O: 390.2288; found: 390.2292.

1-Benzyl-4-(morpholinomethyl)-3-(4-nitrophenyl)imidazolidin-2-one (3b).^7a

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with morpholino benzoate (2a) (62.2 mg, 0.3 mmol, 1.5 equiv) using a catalyst composed of Pd(acac)₂ (2.4 mg, 0.008 mmol, 4 mol %) except the reaction was run for 1 h. The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 56.5 mg (71%) of the title compound as a yellow solid, m.p. 108–110 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 9.3 Hz, 2 H), 7.59 (d, J = 9.3 Hz, 2 H), 7.15–7.02 (m, 5 H), 4.30–4.19 (m, 2 H), 3.44–3.34 (m, 4 H), 2.85 (dd, J = 8.9, 2.8 Hz, 1 H), 2.75 (t, J = 8.7 Hz, 1 H), 1.98 (dd, J = 13.0, 3.1 Hz, 1 H), 1.97–1.88 (m, 2 H), 1.83–1.75 (m, 2 H), 1.71 (dd, J = 13.0, 9.3 Hz, 1 H); ¹³C{¹H} NMR (126 MHz, C₆D₆) δ 155.8, 145.0, 142.0, 136.6, 128.6, 128.2, 127.9, 124.6, 116.8, 66.4, 58.7, 53.8, 50.0, 47.5, 45.3; IR (film) 2921, 1709 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₄N₄O₄: 397.1870; found: 397.1868.

1-Benzyl-4-(morpholinomethyl)-3-(4-nitrophenyl)imidazolidin-2-one (3b).^7a

The general procedure was used for the coupling of 1b (31.1mg, 1.0 mmol, 1 equiv) with morpholino benzoate (2a) (62.2 mg, 3.0 mmol, 1.5 equiv) using a catalyst composed of Pd(acac)₂ (1.33 mg, 0.004 mmol, 4 mol %) except the reaction was run for 1 h. The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 35.0 mg (88%) of the title compound as a yellow solid, m.p. 108–110 °C. Spectroscopic data were identical to those tabulated above.

(4S*,4’R*)-1-Benzyl-4-(morpholinomethyl-d)-3-(4-nitrophenyl)imidazolidin-2-one (3d).^7a

The general procedure was used for the coupling of 1d (62.3 mg, 0.2 mmol, 1 equiv) with morpholino benzoate (2a) (62.2 mg, 0.3 mmol, 1.5 equiv or 124.3 mg, 0.6 mmol, 3 equiv) using a catalyst composed of Pd(acac)₂ (2.4 mg, 0.008 mmol, 4 mol %) and either no ligand or JackiePhos (12.7 mg, 0.016 mmol, 8 mol %) The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 58.6 mg (6:1 dr, 74%, entry 2), 62.8 mg (2.2:1 dr, 79%, entry 3), 60.3 mg (2.8:1 dr, 76%, entry 4), and 59.0 mg (6.7:1, 74%, ref 6) of the title compound as a yellow foam. Characterization data for entry 2: This compound was obtained as a ca 6:1 mixture of diastereomers as judged by ¹H NMR analysis; data are for the mixture. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 9.3 Hz, 2 H), 7.61 (d, J = 9.3 Hz, 2 H), 7.14–7.02 (m, 5 H), 4.31–4.19 (m, 2 H), 3.52–3.24 (m, 5 H), 2.85 (dd, J = 8.9, 2.8 Hz, 1 H), 2.75 (t, J = 8.7 Hz, 1 H), 1.95–1.88 (m, 3 H), 1.83–1.79 (m, 2 H), 1.72 (dd, J = 13.7, 9.3 Hz, 1 H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.4, 145.2, 142.0, 136.1, 128.8, 128.3, 127.9, 124.9, 117.4, 66.7, 58.9 (t, J = 19.0 Hz), 54.2, 50.8, 47.8, 45.9; IR (film) 2922, 1710 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₃DN₄O₄: 398.1933 found: 398.1929.

1-Benzyl-3-(4-chlorophenyl)-4-(morpholinomethyl)imidazolidin-2-one (3e).^7a

The general procedure was used for the coupling of 1f (60.2 mg, 0.2 mmol, 1 equiv) with morpholino benzoate (2a) (62.2 mg, 0.3 mmol, 1.5 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 65.4 mg (85%) of the title compound as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.8 Hz, 2 H), 7.38–7.27 (m, 7 H), 4.46 (s, 2 H), 4.27 (tt, J = 8.6, 3.8 Hz, 1 H), 3.66–3.54 (m, 4 H), 3.45 (t, J = 8.9 Hz, 1 H), 3.29 (dd, J = 9.0, 4.1 Hz, 1 H), 2.55 (dd, J = 12.9, 3.3 Hz, 1 H), 2.50–2.23 (m, 5 H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 157.4, 137.7, 136.7, 128.9, 128.7, 128.3, 128.2, 127.6, 121.1, 66.8, 59.6, 54.2, 51.1, 47.9, 46.4; IR (film) 2917, 1700 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₄ClN₃O₂: 386.1635; found: 386.163.

1-Benzyl-3-(4-methoxyphenyl)-4-(morpholinomethyl)imidazolidin-2-one (3f).

The general procedure was used for the coupling of 1g (59.3 mg, 0.2 mmol, 1 equiv) with morpholino benzoate (2a) (124.4 mg, 0.6 mmol, 3 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (10% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 34.5 mg (45%) of the title compound as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.40 – 7.27 (m, 7H), 6.93 – 6.83 (m, 2H), 4.56 – 4.36 (m, 2H), 4.23 (s, br, 1H), 3.80 (s, 3H), 3.60 (s, br, 4H), 3.45 (s, br, 1H), 3.26 (s, br, 1H), 2.54 (s, br, 1H), 2.47 – 2.25 (m, 5H); ¹³C{¹H} NMR (126 MHz, CDCl₃) at 50°C δ 158.5, 156.7, 137.4, 132.4, 128.8, 128.5, 127.7, 123.6, 114.6, 67.0, 60.5, 55.7, 54.4, 52.4, 48.4, 47.2. IR (film) 2915, 2852, 1693, 1512 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₈N₃O₃: 382.2125; found: 382.2123.

N-{1,3-Dibenzyl-4-[(diethylamino)methyl]imidazolidin-2-ylidene}cyanamide (3g).

The general procedure was used for the coupling of 1a (60.9 mg, 0.2 mmol, 1 equiv) with N,N-diethylamino benzoate (2b) (116.0 mg, 0.6 mmol, 3 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to give the desired product along with minor impurities. The compound was dissolved in ethyl acetate and extracted with 1M HCl (3 × ca. 3 mL). The combined aqueous layers were basified to a pH of 14 using 3M NaOH (ca. 5 mL) and then extracted with EtOAc (3 × ca. 3 mL). The combined organic layers were dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give to afford 41.5 mg (55%) of the title compound as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.36 – 7.33 (m, 4H), 7.30 – 7.27 (m, 6H), 5.29 – 5.26 (d, J = 15.5, 1H), 4.81 – 4.78 (d, J = 15.1 Hz, 1H), 4.65 – 4.62 (d, J = 15.2 Hz, 1H), 4.33 – 4.29 (d, J = 15.5, 1H), 3.56 – 3.50 (m, 1H), 3.38 – 3.35 (t, 1H), 3.14 – 3.11 (m, 1H), 2.55 – 2.51 (dd, J = 13.0 Hz, 4.9 Hz, 1H), 2.39 – 2.30 (m, 4H), 2.28 – 2.24 (m, 1H), 0.85 – 0.82 (t, 6H).¹³C{¹H} NMR (126 MHz, CDCl₃) δ 158.2, 136.0, 135.5, 128.8, 128.3, 128.2, 128.1, 128.0, 116.7, 55.3, 53.2, 49.5, 49.4, 47.7, 47.6, 11.6. IR (film) 3030, 2967, 2169, 1593, 1507 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₀N₅: 376.2496; found: 376.2487.

N-{1,3-Dibenzyl-4-[(diethylamino)methyl]imidazolidin-2-ylidene}-4-methylbenzenesulfonamide (3h).

The general procedure was used for the coupling of N-{[allyl(benzyl)amino][benzylamino]methylene}-4-methylbenzenesulfonamide 1h (86.7 mg, 0.2 mmol) with N,N-diethylamino benzoate (2b) (116.0 mg, 0.6 mmol) using a catalyst composed of Pd(TFA)₂ (2.66 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.55 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 83.4 mg (83%) of the title compound as a yellow oil. ¹H NMR (500 MHz, C₆D₆) δ 8.29 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.15 – 7.08 (m, 4H), 7.07 – 7.02 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 5.51 (d, J = 15.2 Hz, 1H), 4.94 (d, J = 14.9 Hz, 1H), 4.51 (d, J = 14.9 Hz, 1H), 4.20 (d, J = 15.2 Hz, 1H), 3.23 – 3.13 (m, 1H), 2.86 – 2.75 (m, 2H), 2.15 (dd, J = 13.1, 4.9 Hz, 1H), 2.06 – 1.95 (m, 4H), 1.90 (s, 3H), 1.89 – 1.85 (m, 1H), 0.60 (t, J = 7.1 Hz, 6H); ¹³C{¹H} NMR (126 MHz, C₆D₆) δ 156.1, 144.3, 140.4, 137.0, 136.5, 128.8, 128.6, 128.5, 128.5, 128.0, 127.6, 126.2, 55.1, 52.8, 50.6, 49.0, 48.6, 47.2, 20.7, 11.4; IR (film) 2968, 1563, 1497, 1453 cm-1; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₇N₄O₂S: 505.2632; found:505.2629.

N-(1,3-Dibenzyl-4-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}imidazolidin-2-ylidene)-4-methylbenzenesulfonamide (3i).

The general procedure was used for the coupling of 1h (86.7 mg, 0.2 mmol) and 4-(pyrimidin-2-yl)piperazin-1-yl benzoate (2c) (170.6 mg, 0.6 mmol) using a catalyst composed of Pd(TFA)₂ (2.66 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.55 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 89.1 mg (75%) of the title compound as a clear oil. ¹H NMR (500 MHz, C₆D₆) δ 8.30 (d, 2H), 8.21 (d, J = 9.3 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H), 7.40 – 7.29 (m, 5H), 6.49 (dd, J = 6.6, 2.9 Hz, 1H), 4.51 (q, J = 14.9 Hz, 2H), 4.40 (m, J = 8.6 Hz, 1H), 3.75 (m, 4H), 3.53 (t, J = 8.8 Hz, 1H), 3.41 (d, J = 9.2 Hz, 1H), 2.64 (d, J = 13.0 Hz, 1H), 2.59 – 2.53 (m, 2H), 2.49 – 2.35 (m, 3H); ¹³C{¹H} NMR (126 MHz, C₆D₆) δ 161.8, 157.4, 156.2, 144.2, 140.5, 137.0, 136.4, 128.8, 128.6, 128.5, 128.5, 128.4, 127.5, 126.2, 109.7, 60.2, 53.2, 51.6, 50.8, 48.8, 48.5, 43.4, 20.7; IR (film) 3028, 2924, 1585, 1564, 1497 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₃₃H₃₈N₇O₂S: 596.2802; found: 596.2801.

1-Benzyl-4-{[benzyl(methyl)amino]methyl}-3-(4-nitrophenyl)imidazolidin-2-one (3j).

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with N-methylbenzylamino benzoate (2d) (97.0 mg, 0.4 mmol, 2 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %) except the crude reaction mixture was filtered through Celite. The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 70.3 mg (82%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J = 9.3 Hz, 2H), 7.64 (d, J = 9.3 Hz, 2H), 7.38 – 7.25 (m, 8H), 7.21 (d, J = 6.6 Hz, 2H), 4.41 (q, J = 10.8 Hz, 2H), 4.21 (m, 1H), 3.52 (d, J = 12.9 Hz, 1H), 3.47 – 3.39 (m, 2H), 3.30 (dd, J = 9.1, 2.5 Hz, 1H), 2.60 (d, J = 2.7 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.29 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.5, 145.5, 141.9, 138.5, 136.3, 129.2, 128.9, 128.6, 128.4, 128.0, 127.7, 125.1, 117.3, 63.5, 57.6, 52.0, 47.9, 45.8, 44.0; IR (film) 2921, 2850, 1712, 1595, 1503 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₇N₄O₃: 431.2085; found: 431.2063.

1-Benzyl-4-[(cyclohexylamino)methyl]-3-(4-nitrophenyl)imidazolidin-2-one (3k).

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with O-benzoyl-N-cyclohexylhydroxylamine (2e) (88.0 mg, 0.4 mmol, 2 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %) except the crude reaction mixture was filtered through Celite. The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 46.2 mg (52%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J = 9.3 Hz, 2H), 7.77 (d, J = 9.2 Hz, 2H), 7.38 – 7.28 (m, 5H), 4.57 (d, J = 15.0 Hz, 1H), 4.42 (d, J = 15.0 Hz, 1H), 4.33 – 4.25 (m, 1H), 3.49 (t, J = 9.1 Hz, 1H), 3.37 (dd, J = 8.9, 3.2 Hz, 1H), 2.86 (dd, J = 12.5, 2.6 Hz, 1H), 2.76 (dd, J = 12.5, 7.7 Hz, 1H), 2.29 (m, 1H), 1.78 – 1.62 (m, 4H), 1.60 – 1.54 (m, 1H), 1.24 – 1.08 (m, 4H), 1.01 – 0.87 (m, 2H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.5, 145.2, 142.0, 136.2, 128.7, 128.2, 127.8, 124.9, 117.6, 56.8, 53.3, 47.8, 46.9, 45.5, 33.7, 26.0, 24.8; IR (film) 2926, 2852, 1698, 1596 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₉N₄O₃: 409.2234; found: 409.2230.

1-Benzyl-3-(4-nitrophenyl)-4-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}imidazolidin-2-one (3l).

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with 4-(pyrimidin-2-yl)piperazin-1-yl benzoate (2c) (113.7 mg, 0.4 mmol, 2 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %) except the crude reaction mixture was filtered through Celite. The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 85.9 mg (91%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, 2H), 8.21 (d, J = 9.3 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H), 7.40 – 7.29 (m, 5H), 6.49 (dd, J = 6.6, 2.9 Hz, 1H), 4.51 (q, J = 14.9 Hz, 2H), 4.40 (m, 1H), 3.75 (m, 4H), 3.53 (t, J = 8.8 Hz, 1H), 3.41 (d, J = 9.2 Hz, 1H), 2.64 (d, J = 13.0 Hz, 1H), 2.59 – 2.53 (m, 2H), 2.49 – 2.35 (m, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 157.9, 129.0, 128.4, 128.1, 125.2, 117.6, 110.3, 59.2, 53.9, 51.3, 48.0, 46.1, 43.7; IR (film) 2925, 2851, 1709, 1585, 1548, 1501 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₈N₇O₃: 474.2255; found: 474.2251.

1-Benzyl-4-[(diethylamino)methyl]-3-(4-nitrophenyl)imidazolidin-2-one (3m).

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with N,N-diethylamino benzoate (2b) (97.0 mg, 0.4 mmol, 2 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %) except the crude reaction mixture was filtered through Celite. The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 56.6 mg (74%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, 2H), 7.77 (d, 2H), 7.39 – 7.27 (m, 5H), 4.60 (d, J = 14.8 Hz, 1H), 4.37 (d, J = 14.8 Hz, 1H), 4.32 – 4.23 (m, 1H), 3.45 (t, J = 8.8 Hz, 1H), 3.37 (d, J = 9.1 Hz, 1H), 2.62 (d, J = 13.1 Hz, 1H), 2.58 – 2.49 (m, 2H), 2.46 – 2.36 (m, 3H), 0.91 (t, J = 7.0 Hz, 6H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.4, 145.5, 141.8, 136.3, 128.8, 128.3, 127.8, 125.0, 117.2, 53.9, 52.0, 47.8, 47.7, 45.7, 11.8; IR (film) 2969, 1712, 1595, 1503 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₇N₄O₃: 383.2085; found: 383.2078.

Ethyl 1-{[1-benzyl-3-(4-nitrophenyl)-2-oxoimidazolidin-4-yl]methyl}piperidine-4-carboxylate (3n).

The general procedure was used for the coupling of 1b (62.3 mg, 0.2 mmol, 1 equiv) with ethyl 1-(benzoyloxy)piperidine-4-carboxylate (2f) (111.0 mg, 0.4 mmol, 2 equiv) using a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %) except the crude reaction mixture was filtered through Celite. The crude product was purified by flash chromatography on silica gel (30% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 75.0 mg (81%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J = 9.3 Hz, 2H), 7.75 (d, J = 9.3 Hz, 2H), 7.39 – 7.29 (m, 5H), 4.49 (q, J = 14.9 Hz, 2H), 4.36 – 4.28 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 8.9 Hz, 1H), 3.34 (dd, J = 9.2, 2.6 Hz, 1H), 2.86 (d, J = 11.1 Hz, 1H), 2.64 – 2.51 (m, 2H), 2.36 (dd, J = 12.9, 9.4 Hz, 1H), 2.28 – 2.05 (m, 3H), 1.84 (t, J = 14.8 Hz, 2H), 1.73 – 1.61 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 174.8, 156.4, 145.4, 141.9, 136.2, 128.9, 128.6, 128.3, 128.1, 124.9, 117.4, 117.2, 60.4, 59.0, 54.5, 52.9, 51.4, 51.3, 47.8, 46.0, 40.7, 28.2, 28.1, 14.3, 14.1; IR (film) 2927, 1714, 1595, 1503 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₁N₄O₅: 467.2296; found: 467.2297.

1-Methoxy-3,3-dimethyl-5-(morpholinomethyl)pyrrolidin-2-one (3o).

The general procedure was used for the coupling of 1i (31.4 mg, 0.2 mmol, 1 equiv) with morpholino benzoate (2a) (124.4 mg, 0.6 mmol, 3 equiv) and a catalyst composed of Pd(TFA)₂ (2.7 mg, 0.008 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.016 mmol, 8 mol %). The crude product was purified by flash chromatography on silica gel (20% 3:1 (ethyl acetate:ethanol) in hexanes) to afford 33.4 mg (69%) of the title compound as a pale-yellow oil. ¹H NMR (500 MHz, C₆D₆) δ 3.59 (s, 3H), 3.56 – 3.51 (m, 4H), 3.41 (m, 1H), 2.42 (dd, J = 12.5, 4.4 Hz, 1H), 2.21 – 2.07 (m, 4H), 2.03 (dd, J = 12.6, 7.3 Hz, 1H), 1.56 (dd, J = 12.7, 7.2 Hz, 1H), 1.31 (dd, J = 12.7, 7.9 Hz, 1H), 1.13 (s, 3H), 0.97 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 176.3, 66.7, 62.6, 61.5, 54.4, 52.7, 38.1, 37.5, 25.9, 25.2; IR (film) 2961, 2930, 2853, 2812, 1706 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₂H₂₃N₂O₃: 243.1703; found: 243.1707.

3,3-Dimethyl-5-(morpholinomethyl)-1-(4-nitrophenyl)pyrrolidin-2-one (3p).

The general procedure was used for the coupling of 1j (74.4 mg, 0.3 mmol, 1 equiv) with morpholino benzoate (2a) (93.3 mg, 0.45 mmol, 1.5 equiv) and a catalyst composed of Pd(TFA)₂ (3.9 mg, 0.012 mmol, 4 mol %) and 1,3-bis(4-methoxyphenyl)propane-1,3-dione (15f) (4.5 mg, 0.024 mmol, 8 mol %), except the reaction was conducted on a 0.3 mmol scale with α,α,α-trifluorotoluene (0.75 mL, 0.4M) instead of dioxane as solvent. The crude product was purified by flash chromatography on silica gel (20% 3:1 (ethyl acetate:ethanol) in hexanes) to afford the desired product along with minor impurities. The compound was dissolved in ethyl acetate and extracted with 1M HCl (3 × ca. 3 mL). The combined aqueous layers were basified to a pH of 14 using 3M NaOH (ca. 5 mL) and then extracted with EtOAc (3 × ca. 3 mL). The combined organic layers were dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give 55.0 mg (55%) of the title compound as a pale-yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J = 9.2 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 4.45 – 4.26 (m, 1H), 3.71 – 3.51 (m, 4H), 2.65 – 2.58 (m, 1H), 2.49 – 2.30 (m, 5H), 2.26 (dd, J = 13.0, 7.9 Hz, 1H), 1.94 (dd, J = 13.1, 6.1 Hz, 1H), 1.33 (s, 3H), 1.22 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 179.9, 144.3, 124.6, 122.6, 66.9, 62.3, 54.3, 54.0, 41.3, 39.3, 26.4, 26.1, one carbon signal is missing due to accidental equivalence; IR (film) 2964, 2855, 2247, 1698, 1592 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₇H₂₄N₃O₄: 334.1761; found: 334.1755.

Experiment shown in Scheme 3.

The general procedure was used except 2a was not included in the reaction. Instead 1a (15.6 mg, 0.05 mmol, 1 equiv), Pd(acac)₂ (15.2 mg, 0.05 mmol, 1 equiv), Cs₂CO₃ (32.6 mg, 0.1 mmol, 2 equiv), and dioxane (0.5 mL, 0.1M) were heated to 100 °C for 16 h. This reaction afforded a mixture of 8 (10%), 9 (12%), and 10a (40%) as judged by ¹H NMR analysis using phenanthrene as an internal standard. The crude products were not isolated from this experiment. Instead, a separate reaction was carried out using NaOtBu as the base (this led to higher NMR yields of the three products) as described below.

1-Benzyl-4-methyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazol-2-one (8).

The general procedure was used except 2a was not included in the reaction, and NaOtBu was used as the base. Substrate 1b (31.1 mg, 0.1 mmol, 1 equiv), Pd(acac)₂ (30.5 mg, 0.1 mmol, 1 equiv), and NaOtBu (19.2 mg, 0.2 mmol, 2 equiv), and dioxane (1 mL, 0.1M) were heated to 100 °C for 16 h. The crude product was purified by flash chromatography on silica gel (20% ethyl acetate in hexanes) and then further purified by preparative TLC (40% EtOAc in hexanes) to afford 5.1 mg (17%) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.33 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H), 7.41 – 7.29 (m, 5H), 6.05 (s, 1H), 4.81 (s, 2H), 2.01 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 152.6, 146.3, 141.1, 136.7, 129.0, 128.3, 128.2, 127.2, 124.7, 118.2, 109.1, 47.3, 11.8; IR (film) 3116, 2926, 1690, 1641, 1594 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆N₃O₃: 310.1186; found: 310.1185. In addition, this procedure also afforded 1-benzyl-4-methyl-3-(4-nitrophenyl)imidazolidin-2-one 9 (4.9 mg, 16%, yellow oil), and 10a (ca 5 mg, ca 16%, yellow oil). Data for 9 and 10a are provided below.

1-Benzyl-4-methyl-3-(4-nitrophenyl)imidazolidin-2-one (9).

¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J = 9.4 Hz, 2H), 7.73 (d, J = 9.3 Hz, 2H), 7.41 – 7.28 (m, 5H), 4.60 – 4.44 (m, 2H), 4.44 – 4.31 (m, 1H), 3.57 (app. t, J = 8.8 Hz, 1H), 3.00 (dd, J = 8.9, 3.8 Hz, 1H), 1.35 (d, J = 6.2 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.5, 145.2, 142.2 136.3, 129.0, 128.4, 128.0, 125.1, 118.0, 48.9, 48.1, 29.9, 19.2; IR (film) 2917, 2849, 1710, 1596 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₈N₃O₃: 312.1343; found: 312.1342.

2-Benzyl-7-nitro-1,2,9,9a-tetrahydro-3H-imidazo[1,5-a]indol-3-one (10a).

¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.40 – 7.27 (m, 5H), 4.71 (p, J = 9.1 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.32 (d, J = 15.0 Hz, 1H), 3.73 (t, J = 9.1 Hz, 1H), 3.38 (dd, J = 16.2, 9.4 Hz, 1H), 3.27 (t, J = 8.7 Hz, 1H), 3.01 (dd, J = 16.2, 9.2 Hz, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 157.3, 148.7, 144.0, 136.1, 133.2, 129.0, 128.4, 128.1, 125.3, 121.1, 114.4, 56.4, 51.2, 48.1, 36.0; IR (film) 2922, 1712, 1596 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆N₃O₃ 310.1186; found: 310.1195.

(9R*,9aR*)-2-Benzyl-7-nitro-1,2,9,9a-tetrahydro-3H-imidazo[1,5-a]indol-3-one-9-d (10b).

The general procedure was used except 2a was not included in the reaction. Instead 1d (31.2 mg, 0.1 mmol, 1 equiv), Pd(acac)₂ (30.4 mg, 0.1 mmol, 1 equiv), JackiePhos, if appropriate, (159.3 mg, 0.2 mmol, 2 equiv), Cs₂CO₃ (65.2 mg, 0.2 mmol, 2 equiv), and dioxane (0.1 mL, 0.1M) were heated to 100 °C for 16 h. The crude product was isolated via preparative TLC (40% EtOAc in hexanes) to afford the title compound as a yellow oil 11.6 mg (entry 1, 1.7:1 dr, 37%) and 6.3 mg (entry 2, 1.5:1 dr, 20%). ¹H NMR for entry 1: (500 MHz, CDCl₃) δ 8.18 (dd, J = 8.7, 2.3 Hz, 1H), 8.08 – 7.99 (m, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.40 – 7.25 (m, 5H), 4.70 (q, J = 8.7 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.32 (d, J = 14.9 Hz, 1H), 3.73 (t, J = 9.1 Hz, 1H), 3.36 (d, J = 9.5 Hz, 0.40H), 3.27 (t, J = 9.3, 8.0 Hz, 1H), 2.99 (d, J = 9.2 Hz, 0.65H); ¹H NMR for entry 2: (500 MHz, CDCl₃) δ 8.18 (dd, J = 8.6, 2.3 Hz, 1H), 8.10 – 8.01 (m, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.40 – 7.25 (m, 5H), 4.71 (q, J = 8.7 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H), 4.32 (d, J = 14.9 Hz, 1H), 3.73 (t, J = 9.1 Hz, 1H), 3.36 (d, J = 9.4 Hz, 0.43H), 3.27 (t, J = 8.6 Hz, 1H), 2.99 (d, J = 9.3 Hz, 0.64H); ¹³C NMR for entry 2 (176 MHz, CDCl₃) δ 157.2, 148.5, 143.8, 135.9, 132.93, 128.9, 128.2, 127.9, 125.1, 121.0, 114.2, 56.1, 51.0, 47.9; IR (film) 2926, 1712, 1595 cm⁻¹, HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C17H₁₄DN₃O₃: 311.1256; found: 311.1249.

(9R*,9aR*)-2-benzyl-7-nitro-1,2,9,9a-tetrahydro-3H-imidazo[1,5-a]indol-3-one-9,9a-d₂ (10c).

The general procedure was used except 2a was not included in the reaction. Instead 1e (15.9 mg, 0.05 mmol, 1 equiv), Pd(acac)₂ (15.3 mg, 0.05 mmol, 1 equiv), Cs₂CO₃ (32.6 mg, 0.1 mmol, 2 equiv), and dioxane (0.05 mL, 0.1M) were heated to 100 °C for 16 h. The crude product (1.6:1 dr, 38% crude ¹H NMR yield). was purified via a pipet column (2% methanol in CH₂Cl₂) followed by preparative TLC (40% EtOAc in hexanes). However, in the midst of COVID-19 shutdown confusion, one of the authors neglected to record the mass of this product. As such, we report only the NMR yield, but provide data for the product. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.57 (dd, J = 8.7, 2.4 Hz, 1H), 7.39 – 7.27 (m, 5H), 4.63 – 4.52 (m, 1H), 4.35 – 4.29 (m, 1H), 3.72 (d, J = 9.2 Hz, 1H), 3.36 (s, 0.45H), 3.26 (d, J = 9.3 Hz, 1H), 2.99 (s, 0.70H); ¹³C NMR (126 MHz, CDCl₃) δ 157.2, 148.6, 143.8, 135.9, 132.9, 128.9, 128.2, 127.9, 125.1, 121.0, 121.0, 114.2, 50.9, 50.9, 48.0, 35.7, 35.4, 31.9; IR (film) 2923, 2852, 1713, 1595 cm⁻¹; HRMS (ESI TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₃D₂N₃O₃: 312.1312; found: 312.1305.