Gold(I)-Catalyzed Intramolecular Hydroamination of N-Allylic,N′-Aryl Ureas to form Imidazolidin-2-ones

Abstract

Treatment of N-allylic,N′-aryl ureas with a catalytic 1:1 mixture of di-tert-butyl-o-biphenylphoshphine gold(I) chloride and silver hexafluorophosphate (1 mol %) in chloroform at room temperature led to 5-exo hydroamination to form the corresponding imidazolidin-2-ones in excellent yield. In the case of N-allylic ureas that possessed an allylic alkyl, benzyloxymethyl, or acetoxymethyl substituent, gold(I)-catalyzed 5-exo hydroamination leads to formation of the corresponding trans-3,4-disubstituted imidazolidin-2-ones in excellent yield with ≥50:1 diastereoselectivity.

Introduction

Substituted imidazolidin-2-ones are components of a number of biologically active compounds^[1] including NK₁ and Muscarinic M3 antagonists,^[2,3] HIV protease and human enterovirus 71 inhibitors,^[4,5] and antiparasitic^[6] and immunosuppressive agents.^[7] Furthermore, chiral, non-racemic imidazolidin-2-ones have been employed as chiral auxiliaries^[8,9] and as scaffolds for bis(phosphine) ligands^[10,11] for use in enantioselective synthesis. A number of approaches to construction of the imidazolidin-2-one ring have been developed^[12–20] including carbonylation of vicinal diamines,^[13] oxidative diamination of alkenes with ureas,^[14,15] and electrophilic cyclization^[16] or transition metal-catalyzed carboamination of N-allylic ureas.^[17,18] In contrast, transition metal-catalyzed alkene hydroamination, which represents perhaps the most conceptually simple and atom-economical approach to the cyclization of readily available N-allylic ureas, has gone largely unexplored as a route to the imidazolidin-2-one ring.

In the course of our continuing investigation of the gold(I)-catalyzed intramolecular hydroamination of allenes,^[21] we recently found that treatment of N-δ-allenyl ureas with a catalytic 1:1 mixture of the gold(I) N-heterocyclic carbene complex (IPr)AuCl [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine] and AgPF₆ (5 mol %) led to formation of bicyclic imidazolidin-2-ones in high yield and high diastereoselectivity (Scheme 1).^[22] These transformations occurred via two discrete steps; initial 6-exo hydroamination of the N-δ-allenyl urea followed by 5-exo hydroamination of the resulting 1-vinyl piperidine (Scheme 1). Whereas the former step is unremarkable, the latter step represents a rare example of imidazolidin-2-one ring formation via intramolecular alkene hydroamination under remarkably mild conditions.^[23–25] We therefore considered that gold(I)-catalyzed intramolecular hydroamination of acyclic N-allylic ureas might serve as an expedient route to the synthesis of substituted, monocyclic imidazolidin-2-ones. Herein we report the results of this investigation.

Scheme 1.

Gold(I)-catalyzed dihydroamination of an N-δ-allenyl urea.

Results and Discussion

Optimization and scope

Our starting point for the gold(I)-catalyzed intramolecular hydroamination of acyclic N-allylic ureas employed the catalyst system used for the catalytic dihydroamination of N-δ-allenyl ureas with the substitution of chloroform for CH₂Cl₂ owing to the greater solubility of simple N-allylic ureas in the former solvent. In an initial experiment, treatment of N-allyl urea 1a with a catalytic 1:1 mixture of (IPr)AuCl (5 mol %) and AgPF₆ (5 mol %) in chloroform at room temperature for 12 h led to isolation of imidazolidin-2-one 2a in 97% yield (Table 1, entry 1). Catalyst loading was lowered to 1 mol % without diminished yield, but with the anticipated increase in reaction time (Table 1, entries 2 and 3). Substitution of the sterically hindered phosphine ligand P(t-Bu)₂o-biphenyl (P1) for IPr led to a ~two-fold increase in reaction rate with no diminishment of product yield (Table 1, entry 4). The effectiveness of ligand P1 in the conversion of 1a to 2a is surprising, given the marked superiority of IPr relative to P1 in the gold-catalyzed dihydroamination of N-δ-allenyl ureas.^[22] The possibility that intramolecular hydroamination of N-allylic ureas is catalyzed by Ag⁺ or Brønsted acid generated under reaction conditions was rigorously ruled out in our investigation of allene dihydroamination.^[22]

Table 1.

Effect of ligand and catalyst loading on the gold(I)-catalyzed conversion of 1a to 2a.

entry	L	cat load (mol %)	time (h)	yield (%)[a]
1	IPr	5	12	97
2	IPr	2	15	97
3	IPr	1	30	97
4	P1	1	15	100

^[a]Isolated yields of >95% purity.

Acyclic N-allyl,N′-aryl ureas 1b-1f that possessed either an electron-rich or electron-deficient N′-aryl group in combination with an N-alkyl or N-aryl substituent underwent gold(I)-catalyzed intramolecular hydroamination to form the corresponding imidazolidin-2-ones 2b-2f in excellent yield (Table 2, entries 1–5). However, whereas the nature of the N′-aryl group had little effect on the rate of cyclization, N-methyl ureas 1b and 1d underwent intramolecular hydroamination at lower rates than those bearing an N-Cy (1a and 1f) or N-Ph (1c and 1e) group (Table 2). Acyclic N-allylic ureas that possessed an allylic methyl (3a), isopropyl (3b), benzyloxymethyl (3c), or acetoxymethyl (3d) substituent underwent gold (I)-catalyzed intramolecular hydroamination to form the corresponding trans-3,4-disubstituted imidazolidin-2-ones 4a-4d in excellent yield with ≥50:1 diastereoselectivity (Table 2, entries 6–9). In comparison, gold(I)-catalyzed intramolecular hydroamination of N-allylic urea 5 that possessed an allylic hydroxymethyl group led to predominant (dr = 3.7:1) formation of the cis-imidazolidin-2-one 6 in 97% yield (table 2, entry 10).

Table 2.

Substrate scope of the intramolecular hydroamination of N-allylic ureas catalyzed by a 1:1 mixture of (P1)AuCl and AgPF₆ (1 mol %) in CHCl₃ at room temperature (PNP = 4-C₆H₄NO₂, PMP = 4-C₆H₄OMe).

entry	substrate	product	time (h)	yield[a]	dr[b]
1[c]	1b (R = Me; Ar = PNP)	2b	48	92	—
2[d]	1c (R = Ph; Ar = PNP)	2c	15	93	—
3[e]	1d (R = Me; Ar = Ph)	2d	72	86	—
4	1e (R = Ph; Ar = PMP)	2e	16	97	—
5	1f (R = Cy; Ar = Ph)	2f	30	92	—
6	3a (R = Me)	4a	15	100	50:1
7	3b (R = i-Pr)	4b	16	93	50:1
8	3c (R = CH2OBn)	4c	16	98	50:1
9	3d (R = CH2OAc)	4d	16	98	50:1
10	5	6	16	97	3.7:1

^[a]Isolated yields of >95% purity.

^[b]Determined by ¹H NMR analysis of the crude reaction mixture..

^[c]Catalyst loading = 5 mol %.

^[d]Reaction temperature = 60 °C.

^[e]Catalyst loading = 10 mol %.

Imidazolidin-2-ones also serve as precursors to vicinal diamines and utilization of the p-methoxyphenyl (PMP) group allows for efficient dearylation to form primary amines. For example, oxidative removal of the PMP group of 2e with ceric ammonium nitrate (CAN)^[26] followed by acid-catalyzed hydrolysis^[20,27] of N–H imidazolidine-2-one 7 led to isolation of the differentially substituted vicinal diamine 8 in 63% yield over two steps (Scheme 2).

Scheme 2.

Dearylation and hydrolysis of imidazolidin-2-one 2e.

Proposed mechanism and stereochemical model

We have previously proposed a mechanism for the gold(I)-catalyzed intramolecular hydroamination of alkenes with carbamates that involves outer-sphere addition of the nucleophile on a cationic gold(I) π-alkene complex followed by protodeauration with acid released in the C–N bond forming step,^[23] although little direct evidence supported this contention.^[28] Since that time, we^[29] and others^[30] have synthesized and characterized cationic gold(I)π-alkene complexes and Toste has recently demonstrated the stoichiometric intramolecular aminoauration of N-γ-alkenyl ureas with (PPh₃)AuNTf₂ and triethylamine.^[31] Toste also demonstrated that treatment of these (β-amino)alkyl gold complexes with TsOH led to rapid reversion to regenerate the N-γ-alkenyl ureas, which was followed by slow protodeauration to form the 1-methyl pyrrolidine.^[31] Although protodeauration was slow, it appears reasonable that more electron-rich supporting ligands such as P1 might facilitate protodemetallation. In any event, these results both establish the outer-sphere aminoauration of alkenes with urea nucleophiles and also point to the potential reversibility of C–N bond formation.

From this discussion, it follows that the trans-configuration of 3,4-disubstituted imidazolidin-2-ones 4a-4d may be determined either by C–N bond formation in the case of irreversible aminoauration or by protodeauration in the case of reversible aminoauration. In the case of irreversible C–N bond formation, aminoauration of gold (π-alkene) intermediate trans-I should be favored relative to aminoauration of cis-I owing to unfavorable interaction of both the alkenyl =CH₂ group (A^1,3 strain) and the coordinated gold atom with the allylic substituent that is absent in the case of trans-I (Scheme 3). In the case of reversible C–N bond formation, protodeauration from intermediate trans-II should be favored relative to protodeauration of cis-II owing to the unfavorable steric interaction between the exocyclic –CH₂Au(P1) group and the vicinal R group of cis-II that should be felt in the transition state for protodeauration from cis-II to form cis-4 (Scheme 3).

Scheme 3.

Proposed mechanism and stereochemical model for the gold(I)-catalyzed cyclization of N-allylic ureas 3.

Preferential formation of cis-6 in the gold(I)-catalyzed cyclization of N-allylic urea 5 is enigmatic but may result from stabilizing ligation of the allylic hydroxyl group to gold in the transition states for conversion of cis-I to cis-II and/or the conversion of cis-II to cis-4 that overrides the inherent steric destabilization of these transition states. Alternatively, recent computational analyses have pointed to the potential role of solvent, and/or counterion in the transfer of proton from the protonated nucleophile to the α-carbon atom of the gold σ-complex generated via nucleophilic addition to a gold(I) π-complex.^[32] As such, it also appears feasible that the pendant hydroxyl group of 5, either in protonated form or as part of hydrogen-bonded species, may function as an intramolecular proton source for the protodeauration of cis-II leading to preferential formation of cis-6.^[33]

Conclusion

We have shown that a 1:1 mixture of (P1)AuCl [P1 = P(t-Bu)₂o-biphenyl] and AgPF₆ catalyzes the 5-exo hydroamination of N-allylic,N′-aryl ureas to form monocyclic imidazolidin-2-ones in excellent yield under mild conditions and with low catalyst loading. Furthermore, in the case of N-allylic ureas that possessed an allylic alkyl, benzyloxymethyl, or acetoxymethyl substituent, gold(I)-catalyzed 5-exo hydroamination leads to formation of the corresponding trans-3,4-disubstituted imidazolidin-2-ones in ≥93% yield with ≥50:1 diastereoselectivity.

Experimental Section

General Remarks

Catalytic reactions were performed in sealed glass tubes under an atmosphere of dry nitrogen unless noted otherwise. NMR spectra were obtained on a Varian spectrometer operating at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR in CDCl₃ unless noted otherwise. IR spectra were obtained on a Bomen MB-100 FT IR spectrometer. Gas chromatography was performed on a Hewlett-Packard 5890 gas chromatograph equipped with a 25 m polydimethylsiloxane capillary column. Flash column chromatography was performed employing 200–400 mesh silica gel (EM). Thin layer chromatography (TLC) was performed on silica gel 60 F254. Elemental analyses were performed by Complete Analysis Laboratories (Parsippany, NJ). N-Allylic ureas were synthesized employing standard procedures (see Supporting Information).

Imidazolidin-2-ones

1-Cyclohexyl-4-methyl-3-(4-nitrophenyl)imidazolidin-2-one (2a)

A suspension of 1a (30 mg, 0.10 mmol), (P1)AuCl (0.53 mg, 1.0 × 10⁻³ mmol), and AgPF₆ (0.25 mg, 1.0 × 10⁻³ mmol) in CHCl₃ (0.5 mL) was stirred for 15 h at room temperature. The crude reaction mixture was loaded directly onto a silica gel column and chromatographed (hexanes–EtOAc = 6:1) to give 2a (30 mg, 100%) as a yellow solid. TLC (hexanes–EtOAc = 2:1): R_f = 0.4. ¹H NMR: δ = 8.14 (d, J = 9.6 Hz, 2 H), 7.66 (d, J = 9.6 Hz, 2 H), 4.36 (m, 1 H), 3.79 (m, 1 H), 3.63 (t, J = 8.8 Hz, 1 H), 3.04 (dd, J = 4.0, 8.8 Hz, 1 H), 1.80-1.64 (m, 5 H), 1.42-1.22 (m, 4 H), 1.32 (d, J = 6.0 Hz, 3 H), 1.08 (m, 1 H). ¹³C{¹H} NMR: δ = 155.5, 145.3, 141.5, 124.8, 117.4, 51.4, 48.8, 45.1, 30.4, 29.8, 25.4, 25.3, 18.8. IR (neat, cm⁻¹): 2938, 1684, 1503, 1323, 1252, 1111, 851, 751, 690. Anal. calcd (found) for C₁₆H₂₁N₃O₃: H, 6.98 (6.83); C, 63.35 (63.30).

Imidazolidin-2-ones 2b-2f, 4a-4d, and 6 were synthesized employing procedures similar to that used to synthesize 2a.

1,4-Dimethyl-3-(4-nitrophenyl)imidazolidin-2-one (2b)

Yellow solid, 92%. TLC (hexanes–EtOAc = 2:1): R_f = 0.2. ¹H NMR: δ = 8.11 (d, J = 9.2 Hz, 2 H), 7.62 (d, J = 9.2 Hz, 2 H), 4.34 (m, 1 H), 3.61 (t, J = 8.8 Hz, 1 H), 3.06 (dd, J = 3.6, 8.8 Hz, 1 H), 2.85 (s, 3 H), 1.31 (d, J = 6.4 Hz, 3 H). ¹³C{¹H} NMR: δ = 156.6, 145.1, 141.7, 124.8, 117.6, 51.5, 48.5, 30.8, 18.9. IR (neat, cm−1): 2927, 1697, 1496, 1312, 1267, 1111, 845, 749, 690. Anal. calcd (found) for C₁₁H₁₃N₃O₃: H, 5.57 (5.47); C, 56.16 (56.22).

4-Methyl-3-(4-nitrophenyl)-1-phenylimidazolidin-2-one (2c)

Yellow solid, 93%. TLC (hexanes–EtOAc = 3:1): R_f = 0.4. ¹H NMR: δ = 8.26 (d, J = 9.0 Hz, 2 H), 7.77 (d, J = 9.5 Hz, 2 H), 7.60 (br d, J = 7.5 Hz, 2 H), 7.42 (br t, J = 7.5 Hz, 2 H), 7.17 (br t, J = 7.5 Hz, 1 H), 4.59 (m, 1 H), 4.21 (t, J = 9.0 Hz, 1 H), 3.61 (dd, J = 4.5, 9.0 Hz, 1 H), 1.50 (d, J = 6.5 Hz, 3 H). ¹³C{¹H} NMR: = δ 153.9, 144.5, 142.5, 139.2, 129.0, 124.8, 123.8, 118.8, 118.5, 49.7, 48.3, 19.2. IR (neat, cm⁻¹): 2924, 1701, 1505, 1405, 1282, 1108, 754, 688. Anal. calcd (found) for C₁₆H₁₅N₃O₃: H, 5.09 (4.98); C, 64.64 (64.57).

1,4-Dimethyl-3-phenylimidazolidin-2-one (2d)

Colorless oil, 86%. TLC (hexanes–EtOAc = 3:1): R_f = 0.4. ¹H NMR: δ = 7.40 (m, 2 H), 7.31 (br d, J = 7.6 Hz, 2 H), 7.04 (br t, J = 7.2 Hz, 1 H), 4.28 (quintet of doublets, J = 6.4 m 8.2 Hz, 1 H), 3.56 (t, J = 8.4 Hz, 1 H), 3.01 (dd, J = 6.0, 8.4 Hz, 1 H), 2.84 (s, 3 H), 1.25 (d, J = 6.4 Hz, 3 H). ¹³C{¹H} NMR: δ = 158.3, 138.8, 128.7, 123.3, 120.9, 52.2, 49.0, 31.0, 18.8. IR (neat, cm⁻¹): 2927, 1694, 1494, 1431, 1367, 1261, 756, 694. Anal. calcd (found) for C₁₁H₁₄N₂O: H, 7.42 (7.29); C, 69.45 (69.28).

3-(4-Methoxyphenyl)-4-methyl-1-phenylimidazolidin-2-one (2e)

White solid, 97%. TLC (hexanes–EtOAc = 3:1): R_f = 0.4. ¹H NMR: δ = 7.58 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 7.2 Hz, 2 H), 7.30 (d, J = 8.8 Hz, 2 H), 7.04 (t, J = 7.2 Hz, 1 H), 6.91 (d, J = 7.2 Hz, 2 H), 4.27 (m, 1 H), 4.00 (t, J = 8.8 Hz, 1 H), 3.78 (s, 3 H), 3.46 (t, J = 7.6 Hz, 1 H), 1.28 (d, J = 5.6 Hz, 3 H). ¹³C{¹H} NMR: δ = 156.9, 155.8, 140.3, 130.9, 128.8, 124.8, 122.5, 117.7, 114.3, 55.5, 50.0, 19.3. IR (neat, cm⁻¹): 2979, 1688, 1501, 1401, 1241, 754, 688. Anal. calcd (found) for C₁₇H₁₈N₂O₂: H, 6.43 (6.33); C, 72.32 (72.15).

1-Cyclohexyl-4-methyl-3-phenylimidazolidin-2-one (2f)

Colorless oil, 92%. TLC (hexanes–EtOAc = 2:1): R_f = 0.4. ¹H NMR: δ = 7.42 (d, J = 8.0 Hz, 2 H), 7.30 (t, J = 8.0 Hz, 2 H), 7.02 (br t, J = 7.2 Hz, 1 H), 4.27 (quintet of doublets, J = 6.0, 8.8 Hz, 1 H), 3.78 (m, 1 H), 3.56 (t, J = 8.8 Hz, 1 H), 2.98 (dd, J = 5.6, 8.4 Hz, 1 H), 1.80-1.64 (m, 5 H), 1.43-1.21 (m, 4 H), 1.25 (d, J = 6.0 Hz, 3 H), 1.08 (m, 1 H). ¹³C{¹H} NMR: δ = 157.2, 139.1, 128.7, 123.0, 120.1, 51.2, 49.3, 45.5, 30.3, 30.1, 25.6, 18.9. IR (neat, cm⁻¹): 2930, 1691, 1419, 1255, 755, 694. Anal. calcd (found) for C₁₆H₂₂N₂O: H, 8.58 (8.60); C, 74.38 (74.43).

trans-1-Cyclohexyl-4,5-dimethyl-3-(4-nitrophenyl)imidazolidin-2-one (4a)

Yellow solid, 100%. TLC (hexanes–EtOAc = 3:1): R_f = 0.6. ¹H NMR: δ = 8.14 (d, J = 9.6 Hz, 2 H), 7.67 (d, J = 9.2 Hz, 2 H), 3.82 (dq, J = 2.8, 6.0 Hz, 1 H), 3.62 (tt, J = 3.6, 12.0 Hz, 1 H), 3.35 (dq, J = 2.4, 6.0 Hz, 1 H), 1.92-1.05 (m, 10 H), 1.29 (d, J = 6.0 Hz, 3 H), 1.28 (d, J = 6.0 Hz, 3 H). ¹³C{¹H} NMR: δ = 154.9, 145.7, 141.4, 124.8, 117.0, 57.4, 54.5, 53.2, 32.2, 30.6, 25.9, 25.8, 25.4, 21.8, 18.2. IR (neat, cm⁻¹): 2932, 1645, 1491, 1328, 1302, 1238, 1110, 750, 702, 639. Anal. calcd (found) for C₁₇H₂₃N₃O₃: H, 7.30 (7.41); C, 64.33 (64.32).

trans-1-Cyclohexyl-5-isopropyl-4-methyl-3-(4-nitrophenyl)imidazolidin-2-one (4b)

Yellow solid, 93%. TLC (hexanes–EtOAc = 3:1): R_f = 0.6. ¹H NMR: δ = 8.14 (d, J = 9.2 Hz, 2 H), 7.72 (d, J = 9.2 Hz, 2 H), 3.96 (br q, J = 6.0 Hz, 1 H), 3.55 (m, 1 H), 3.16 (m, 1 H), 2.03-1.08 (m, 10 H), 1.28 (d, J = 6.0 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.75 (d, J = 6.4 Hz, 3 H). ¹³C{¹H} NMR: δ = 155.2, 145.4, 141.2, 125.1, 116.2, 64.2, 54.0, 49.7, 31.9, 30.7, 30.4, 26.0, 25.4, 20.2, 17.9, 14.3. IR (neat, cm⁻¹): 2935, 1698, 1495, 1297, 1246, 1107, 854, 754, 692. Anal. calcd (found) for C₁₉H₂₇N₃O₃: H, 7.88 (7.95); C, 66.06 (65.98).

trans-4-(Benzyloxymethyl)-3-cyclohexyl-5-methyl-1-(4-nitrophenyl)imidazolidin-2-one (4c)

Yellow oil, 98%. TLC (hexanes–EtOAc = 3:1): R_f = 0.5. ¹H NMR: δ = 8.08 (d, J = 9.2 Hz, 2 H), 7.62 (d, J = 9.2 Hz, 2 H), 7.28-7.19 (m, 5 H), 4.45 (s, 2 H), 4.13 (dq, J = 0.8, 6.0 Hz, 1 H), 3.58 (tt, J = 3.6, 12.0 Hz, 1 H), 3.50 (m, 1 H), 3.33 (m, 1 H), 1.82-1.47 (m, 6 H), 1.35-1.18 (m, 3 H), 1.23 (d, J = 6.4 Hz, 3 H), 1.03 (tq, J = 3.2, 12.8 Hz, 1 H). ¹³C{¹H} NMR: δ = 155.2, 145.5, 141.3, 137.3, 128.4, 127.9, 127.7, 124.9, 116.6, 73.4, 70.8, 57.9, 53.3, 53.2, 32.1, 30.5, 25.8, 25.7, 25.3, 18.7. IR (neat, cm⁻¹): 2931, 1701, 1503, 1321, 1234, 849, 751, 697. Anal. calcd (found) for C₂₄H₂₉N₃O₄: H, 6.90 (6.92); C, 68.06 (67.95).

trans-(3-Cyclohexyl-5-methyl-1-(4-nitrophenyl)-2-oxoimidazolidin-4-yl)methyl acetate (4d)

Yellow solid, 98%. TLC (hexanes–EtOAc = 3:1): R_f = 0.4. ¹H NMR: δ = 8.14 (d, J = 9.2 Hz, 2 H), 7.69 (d, J = 9.2 Hz, 2 H), 4.26 (dd, J = 3.6, 11.6 Hz, 1 H), 4.16 (dq, J = 1.6, 6.0 Hz, 1 H), 3.91 (dd, J = 7.2, 11.6 Hz, 1 H), 3.67 (tt, J = 3.6, 12.0 Hz, 1 H), 3.45 (ddd, J = 1.6, 3.6, 7.2 Hz, 1 H), 2.00 (s, 3 H), 1.93-1.54 (m, 6 H), 1.47-1.26 (m, 3 H), 1.31 (d, J = 6.0 Hz, 3 H), 1.11 (tq, J = 3.6, 12.8 Hz, 1 H). ¹³C{¹H} NMR: δ = 170.6, 155.1, 145.2, 141.6, 125.0, 116.7, 64.4, 56.8, 53.4, 53.3, 32.2, 30.6, 25.8, 25.7, 25.3, 20.7, 18.8. IR (neat, cm⁻¹): 2930, 1706, 1503, 1324, 1219, 1040, 858, 752, 693. Anal. calcd (found) for C₁₉H₂₅N₃O₅: H, 6.71 (6.62); C, 60.79 (60.64).

cis-1-Cyclohexyl-5-(hydroxymethyl)-4-methyl-3-(4-nitrophenyl)imidazolidin-2-one (6)

Yellow oil, 97% (cis:trans = 3.7:1). TLC (hexanes–EtOAc = 1:1): R_f = 0.45. ¹H NMR: δ = [8.15 (d, J = 9.2 Hz), 8.12 (d, J = 9.6 Hz), (3.7:1), 2 H], [7.70 (d, J = 9.2 Hz), 7.56 (d, J = 9.2 Hz), (1:3.7), 2 H)], [4.45 (quintet, J = 6.9), 4.31 (dq J = 2.0, 6.4 Hz), (3.7:1), 1 H)], [3.97 (m), 3.34 (m), (3.7:1), 1 H], [3.90-3.80 (m), 3.73 (m), (3.7:1), 2 H] 3.61 (tt, J = 4.0, 12 Hz, 1 H), [2.35 (t, J = 4.5 Hz), 2.18 (t, J = 4.8 Hz), (1:3.7), 1 H], 1.87-1.46 (m, 6 H), 1.41-1.20 (m, 3 H), [1.33 (d, J = 6.4 Hz), 1.31 (d, J = 6.4 Hz), (3.7:1), 3 H], 1.11 (tq, J = 3.6, 12.8 Hz, 1 H). ¹³C{¹H} NMR: δ = [157.1, 155.7, (3.7:1)], [145.4, 144.8, (1:3.7)], [142.1, 141.4, (3.7:1)], [124.9, 124.6 (1:3.7)], [119.3, 117.0, (3.7:1)] [63.1, 60.3, (1:3.7)], [59.6, 56.3, (1:3.7)], [53.9, 53.3 (3.7:1)], [52.6, 52.0 (1:3.7)], [32.4, 31.6 (1:3.7)], [30.6, 29.9 (1:3.7)], [26.0, 25.3 (3.7:1)], [18.9, 12.3 (1:3.7)]. IR (neat, cm⁻¹): 2932, 1684, 1503, 1320, 1248, 1112, 850, 729, 694. HRMS calcd (found) for C₁₇H₂₃N₃O₄ (M⁺): 333.1689 (333.1676).

Relative configurations of 4,5-disubstituted imidazolidin-2-ones

The trans configuration of 4,5-disubstituted imidazolidin-2-ones 4a-4d was assigned on the basis of the vicinal H4-H5 coupling constants, which ranged from ³J_HH ≈ 1 Hz for 4b and 4c to ³J_HH = 2.4 Hz for 4a. Published values for the vicinal H4-H5 coupling constant of trans-4,5-disubstituted imidazolidin-2-ones range from 0–3 Hz,^[9] while the the vicinal H4-H5 coupling constant of cis-4,5-disubstituted imidazolidin-2-ones range from 7–9 Hz.^[11,15,18] In the same way, the cis and trans configurations of the major and minor diastereomers of 6 were assigned on the basis of the vicinal H4-H5 coupling constants of ³J_HH ≈ 7 Hz (major) and ³J_HH ≈ 2 Hz (minor).

N-(2-Aminopropyl)benzenamine (8).^[34]

A solution of 2e (50 mg, 0.18 mmol) in CH₃CN (2 mL) at 0 °C was treated with a solution of ceric ammonium nitrate (CAN, 0.29 g, 0.53 mmol) in water (2.5 mL) over 3 min. The solution was stirred for 25 min at 0 °C, diluted with water (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried (MgSO₄) and concentrated under vacuum to give an oily residue that was chromatographed (EtOAc–hexanes = 2:1) to give 4-methyl-1-phenylimidazolidin-2-one (7)^[19] (26 mg, 82%) as white solid. A solution of 7 (26 mg, 0.15 mmol) in concentrated HCl (4 mL) was refluxed for 30 h and then extracted with CH₂Cl₂ (3 × 10 mL). The aqueous layer was made basic (_pH ≥ 12) with 15% NaOH and then extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried (MgSO₄) and concentrated under vacuum to give pure 8 (16 mg, 77%) as a colorless oil. The ¹H and ¹³C NMR spectra of 7 and 8 were identical with published data.^[19,34]