One Pot Synthesis of 2-Imidazolines via the Ring Expansion of Imidoyl Chlorides with Aziridines

Abstract

We herein report a simple and convenient one pot synthesis of highly-substituted 2-imidazolines in a regiocontrolled and stereospecific matter through the ring expansion reaction of an imidoyl chloride with an aziridine, analogues to the Heine reaction.

2-Imidazolines have attracted significant attention because of their diverse pharmacological properties.^1–4 The stereochemistry of this privileged scaffold is capable of governing its diverse biological characteristics, perhaps best illustrated by the general NF-κB inhibitory scaffold 1^5–9 and p53 activator scaffold 2^10–12 (Figure 1). In order to develop a stereospecific route to 2-imidazoline scaffolds, we investigated the scope of a Heine-type ring expansion of aziridines. We anticipated aziridines to be particularly valuable building blocks, as they can be readily accessed enantiomerically pure.^13–17 The Heine reaction was first developed by Harold W. Heine, who reported the synthesis of 2-imidazolines¹⁸ and 2-oxazolines^19–21 by the isomerization of an imidoyl aziridine and a benzoylated aziridine though NaI in acetone (Scheme 1). Many examples have been reported for the isomerization of acyl and benzoyl aziridines to 2-oxazolines by Heine and others using NaI^19–22 or Lewis acids.^23–27

Figure 1.

Anti and Syn 2-imidazolines

Scheme 1.

Synthesis of 2-imidazolines and 2-oxazolines

Even though there have been several reported syntheses of 2-imidazolines,^28–31 reports of a Heine-type isomerization of imidoyl aziridines have been scarce.^{18, 32–34} A couple reports employed the Heine reaction using the reaction of an aziridine with an alkyne and sulfonyl azide,³² and a N-arylketenimine.³³ However, these reports were limited in scope and required the isolation the imidoyl aziridine prior to the subsequent rearrangement to the 2-imidazolines. We herein report a simple and convenient one pot Heine reaction synthesis of tetra-substituted 2-imidazolines in a regiocontrolled and stereospecific matter through the ring expansion reaction of an imidoyl chloride with an aziridine.

We first attempted to synthesize 2-imidazoline 6 by reacting aziridine 3 with imidoyl chloride 4 in a one pot procedure via intermediate 5. However, isomerization of the imidoyl aziridine intermediate 5 into 2-imidazoline 6 did not occur in CH₂Cl₂ with a 5: 1 mixture of TEA: TEA·HCl. Instead only unreacted intermediate 5 was recovered from the reaction by removal of the excess Et₃N in vacuo followed by trituration of the Et₃N·HCl by-product with ether. Intermediate 5 was then treated with either one equivalent of NaI or Et₃N·HCl and was successfully transformed into the 2-imidazoline 6 by refluxing in acetone, without the formation of the 2-imidazoline 7 (Scheme 2). The regio and stereochemistry of compound 6 was verified by NOE.

Scheme 2.

Synthesis of 2-imidazoline 6

The Brønsted acid isomerization of intermediate 5 into compound 6 by Et₃N·HCl was consistent with the work by Kohn and coworker. They reported a Brønsted acid isomerization of an ethyl aziridine carboximidate to the corresponding 2-ethoxyimidazoline.³⁴ The exact role of the TEA in the reaction was somewhat ambiguous. Excess TEA halted the reaction at the intermediate 5 whereas isomerizaton occurred once the excess TEA was removed leaving only Et₃N·HCl (Scheme 2). However, we hypothesized that the correct base would allow for a one pot synthesis of 2-imidazoline 6 without stalling at the intermediate 5. Due to the instability of the intermediate 5 to hydrolysis, we investigated the possibility of a one pot sequence using aziridine 3 and imidoyl chloride 4. In order to optimize this reaction, compound 4 was isolated by reacting N- benzyl-benzamide with (COCl)₂ and 2,6-lutidine in CH₂Cl₂. The CH₂Cl₂ was removed, followed by trituration of the 2,6-lutidine hydrogen chloride salt in hexane and removal of any residual 2,6-lutidine in vacuo.³⁵ The imidoyl chloride 4 was treated with the aziridine 3 in toluene and multiple different bases were investigated in order to optimize the conversion to compound 6. Initially, the reaction conditions were optimized with respect to the base and included DABCO, DMAP, Hünig’s base, Et₃N, and 2,6-lutidine (Table 1). Of these bases, 2,6-lutidine performed the best (Table 1, entry 5) and rendered the product 6 in a moderate 20% overall yield.

Table 1.

One pot optimization of compound 6

Entry	solvent	base	temp °C	4 equiv	base equiv	T (h)	yield (%)
1	Toluene	DABCO	80	1.5	1.5	12	0
2	Toluene	DMAP	80	1.5	1.5	12	0
3	Toluene	Et3N	80	1.5	1.5	12	0a
4	Toluene	(iPr)2NEt	80	1.5	1.5	12	0a
5	Toluene	2,6-lutidine	80	1.5	1.5	21	20
6	Acetone	2,6-lutidine	80	1.5	1.5	21	37
7	DMF	2,6-lutidine	80	1.5	1.5	21	44
8	DMF	2,6-lutidine	RT	1.2	1.2	21	10
9	DMF	2,6-lutidine	RT	1.2	6.0	21	38
10	DMF	2,6-lutidine	80	1.2	6.0	21	47
11	DCM	2,6-lutidine	80	1.2	6.0	21	39
12	DMF	2,6-lutidine	55	1.2	6.0	21	50
13	DMF	2,6-lutidine	55	1.2	6.0	6	52
14	DMF	None	55	1.2	0.0	6	0

^aThe rxn stalled at the intermediate imidoyl aziridine 5

Et₃N and Hünig’s base resulted in the reaction stalling at intermediate 5 (Table 1, entries 3, 4), which did not cyclize to compound 6, whereas 1,2-lutidine provided product 6. Although full mechanistic details have not been exhausted, we postulated that the role of the base is to initially quench the HCl generated by substitution of aziridine 3 with imidoyl chloride 4. Secondly, the protonated base generated will subsequently act as a Brønsted acid and is responsible for the isomerization of 5 to compound 6 (Table 1). This is consistent with our finding that unlike TEA (Scheme 2), excess 2,6-lutidine (Table 1, entries 9–13) did not halt the reaction at the intermediate 5, which could be reasoned by the greater acidity of generated 2,6-lutidine·HCl (pKa = 6.7) versus Et₃N·HCl (pKa = 10.75). The choice of solvent also greatly affected the overall yield of this two step process and solvents capable of producing a homogenous solutions, such as DMF and DCM, performed superior over solvents that only partially solubilized the 1,2-lutidine·HCl salts, such as toluene. Further optimization of this one pot reaction resulted in an overall yield of 52% of compound 6 based on the aziridine 3 (Table 1, entry 13).

Considering that 2,6-lutidine was used both to synthesize the imidoyl chloride 4 and for the ring expansion of aziridine 5 to the 2-imidazoline 6, the imidoyl chloride 4 did not have to be isolated. Using this one-pot sequence, a range of different imidoyl chlorides were treated with trans-2,3-diphenyl aziridine to yield the trans imidazoline in useful yields (Table 2).

Table 2.

Variation at R¹ and R²

entry	R1	R2	T (h)	9	yield (%)
1	p-MeO-C6H4	Bn	9	a	59
2	Ph	Bn	9	b	55
3	p-F-C6H4	Bn	9	c	43
4	p-NO2-C6H4	Bn	6	d	0
5	Cy	Bn	6	e	60
6	Me	Bn	9	f	48
7	Ph	Ph	13	g	0a
8	Ph	PMB	9	h	53
9	Ph	Cy	12	i	53
10	Ph	Me	9	j	60

^aThe reaction stalled at the intermediate imidoyl aziridine and did not cyclize to the 2-imidazoline.

The R¹ position tolerated alkyl groups and electron withdrawing and electron donating aryl groups, while the R² position was restricted to alkyl and benzyl groups. The structural identity was supported by X-ray crystallography of compound 9j (see supporting information). The reaction did not provide the desired product when aryl groups were introduced at the R² position or when a p-NO₂-C₆H₄- group was introduced at the R¹ position.

The scope of the reaction was subsequently investigated with respect to the R³, R⁴, and R⁵ positions of the aziridine. Electron withdrawing and electron donating aryl groups, along with vinyl, ketone, ester, and alkyl functionalities were readily tolerated at these positions (Table 3).

Table 3.

Variation at R³, R⁴, and R⁵

entry	R3	R4	R5	T (h)	11	yield (%)
1	p-MeO-C6H4	H	CO2Et	10	a	45
2	Ph	H	CO2Et	12	b	42
3	Ph	Me	CO2Et	12	c	59
4	p-NO2-C6H4	H	CO2Et	6	d	40a
5	PhCH=CH	H	CO2Et	20	e	41
6	n-C6H13	H	CO2Et	12	f	40
7	Ph	H	COPh	12	g	41
8	Ph	Bn	H	12	h	40a
9	Ph	H	H	12	i	0

^aThe compound was synthesized as a 2:1 mixture of regioisomers

It was important to note that it was not possible to have just a hydrogen atom at the R⁴ and R⁵ positions (Table 3, entry 9). With respect to the regiochemistry, only one regioisomer was produced in all cases, except when a p-NO₂-C₆H₄- group was introduced at the R³ position or a benzyl group at the R⁴ (Table 3, entries 4, 8). Side products in this Heine reaction often included the 2-imidazole, due to oxidation of the imidazoline ring.

Of particular note is that this one pot Heine reaction showed an overall retention of stereochemistry. In comparing the cis and trans stereoisomers of ethyl 3-phenylaziridine-2-carboxylate the stereochemistry was preserved to yield the cis and trans 2-imidazolines, respectively (Compounds 6 and Table 3, entry 2).

The 2-imidazoline, compound 6, was synthesized from both racemic aziridine 3 and enantiopure aziridine 3 (98% ee). This would presumably yield the 2-imidazoline as a racemate or enantiopure (98% ee) depending on the enantiopurity of the starting aziridine 3. The racemate, compound 6, was treated with (S)-Mosher’s acid, and analysis by ¹HNMR showed a 1:1 ratio of diasteromeric salts. However, the enantiopure compound 6 gave only one diasteromeric salt by ¹HNMR. Thus the enantiopurity of compound 6 was preserved in the ring expansion reaction therefore demonstrating the utility to access enantiopure 2-imidazolines (Scheme 3).

Scheme 3.

Synthesis of enantiopure 2-imidazoline 6

The synthesis of a 2-imidazoline with a quaternary carbon at the C-5 position (11c) proceeded with complete retention of stereochemistry (Table 3, entry 3). The identity of compound 11c was supported by X-ray crystallography (see supporting information). This retention of stereochemistry could be accomplished by S_N2 attack of the chlorine anion at the 2-position of the imidoyl aziridine ring carbon and then ring closure through a second S_N2.^18–21 However, another possible mechanism could involve attack of the imidoyl carbon atom by the chloride anion followed by ring closure. This mechanism would be analogous to the earlier proposed mechanism of attack of the imidoyl carbon by the iodine anion from NaI and subsequent ring closure (Scheme 4).^{18, 32}

Scheme 4.

Proposed reaction mechanism

The latter mechanism would suggest that the imidoyl aziridines would undergo ring expansion by a 4- endotet ring closure. Both a S_Ni or a stepwise process are plausible mechanisms, evidence for these mechanisms have been supported by Tomasini and coworkers³⁶ via the ring expansion of N-tertbutoxycarbonyl aziridines to oxazolidinones. These mechanisms would likely involve activation of the imidoyl aziridine intermediate by the Brønsted acid, 2,6-lutidine·HCl. Nitrogen-carbon bond formation occurred at the most electropositive carbon atom in the imidoyl aziridine intermediate. This was the C-2 position of the aziridine in all cases except when a p-NO₂-C₆H₄ group was introduced at the C-3 position or a benzyl group at the C-2 position. In this case the C-3 and C-2 positions of the aziridine ring had similar electronics and resulted in a mixture of 2-imidazoline regioisomers (Table 3, entries 4, 8).

In conclusion, we have developed a simple one pot stereospecific synthesis of 2-imidazolines from the ring expansion of an aziridine with an imidoyl chloride consistent with a Heine reaction. The scope of the reaction indicated that the reaction tolerated many diverse functional groups. The purification of imidoyl chlorides and imidoyl aziridines intermediates were not needed, therefore creating a simple one pot method to synthesize these biologically significant highly-substituted 2-imidazolines.

Experimental Section

General

Acetonitrile, Et₃N, and DMF were distilled from calcium hydride under nitrogen. Toluene, and DCM were purified through a column packed with dry alumina and were dispensed by a nitrogen pressure delivery system. THF and ether were distilled from sodium under nitrogen. Acetone, 1,2-dichloroethane, and chloroform were distilled from calcium sulfate under nitrogen. Anisole was distilled from calcium hydride under nitrogen. All other reagents and solvents were purchased from commercial sources and used without further purification. All flasks were oven dried overnight and cooled under argon or nitrogen. All reactions were monitored by TLC with 0.25 μM precoated silica gel plates and UV light was used to visualize the compounds. It some cases phosphomolybdic acid (PMA) stain or I₂ was used to visualize the compounds. Column chromatography silica gel was provided by EM Science (230–400 mesh). All NMR spectra were recorded on 500 or 300 MHz spectrometer. Chemical shifts are reported relative to the solvent peak of chloroform (δ 7.24 for ¹H and δ 77.0 for ¹³C).

General procedure to neutralize silica gel

Silica gel was saturated with Et₃N; the slurry was mixed for 5 minutes and then concentrated under reduced pressure to remove the excess Et₃N to give a free flowing powder once again.

Racemic or enantiopure ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate (Scheme 2) (6)

Benzyl benzamide (200 mg, 0.95 mmol) and DCM (4 mL) was added to a 10 mL round bottom flask under argon. The round bottom flask was cooled to 0°C and 2,6-lutidine (0.13 mL, 1.58 mmol) was added to the round bottom flask via a syringe. Oxalyl chloride (0.10 mL, 1.14 mmol) was added dropwise to the reaction solution over the course of 2 minutes. Carbon monoxide and carbon dioxide bubbled out of the solution and the reaction was stirred at 0°C for 1.25 hours. The DCM was removed under reduced pressure at room temperature to give a yellow solid. The round bottom flask was put under argon and hexane (4 mL) was added via a syringe. The solution was mixed at for 1 hour at room temperature. The salts were removed by vacuum filtration through a plug of celite. The hexane was removed under reduced pressure at room temperature to give (Z)-N-benzylbenzimidoyl chloride 4; oil; 175 mg; 80% yield. The product could not be purified any further due to rapid hydrolysis to benzyl benzamide with water from the air. To another 10 ml RBF was added either racemic or enantiopure ethyl 3-phenylaziridine-2-carboxylate (100 mg, 0.52 mmol), TEA (0.44 ml, 3.12 mmol), DCM (6 ml), and (Z)-N-benzylbenzimidoyl chloride (143 mg, 0.62 mmol). The solution was heated to reflux for 5 hours and then cooled to room temperature. The reaction solution was concentration and the excess TEA was removed in vacuo to yield crude compound 5 and 1 equivalent of Et3N·HCl. To crude compound 5 was added acetone (5 ml) and the solution was brought to reflux for 24 hours. The reaction was worked up and purified by the general procedure for synthesis of imidazolines (located below) oil; 77 mg, 38% yield. Alternatively, the Et3N·HCl could be removed by the addition of ether (10 ml) and the solution was allowed to sit for 15 minutes. The solution was then filtered through celite and concentrated in vacuo to yield compound 5. To crude compound 5 was added NaI (78 mg, 0.52 mmol) and acetone (5 ml) and the solution was brought to reflux for 24 hours. The reaction was worked up and purified by the general procedure for synthesis of imidazolines (located below) oil; 65 mg, 32% yield.

General procedure for synthesis of imidazolines

The reaction scale was based on 100 mg of the starting aziridine. To a 10 mL round bottom flask under argon was added the desired amide (1.2 equiv), 2,6-lutidine (6 equiv), and DCM (4 mL). The solution was either cooled to 0°C or left at room temperature depending on the amide (located below). Oxalyl chloride (1.2 equiv) was added to the round bottom flask over 3 minutes with a syringe. The solution was reacted for the desired time (located below) and then the DCM was removed under reduced pressure at room temperature. This gave the crude product as a mixture of the desired imidoyl chloride, excess 2–6-lutidine (bp 144°C, 760 mm Hg), and 2,6-lutidine hydrogen chloride. This round bottom flask was then placed under argon again and the desired aziridine (100 mg, 1 equiv) and DMF (4 mL) were added. The solution was heated to 55°C for the desired time (see Table 2 or 3). An aliquot of the reaction solution was taken, placed under vacuum (approx. 10 mm Hg) at room temperature and a ¹H NMR was taken to determine the imidazoline reaction times. The reactions could also be monitored by TLC 30:70 EtOAc: hexane (Imidazoline·HCl salt polar). The reaction solution was then cooled to room temperature and poured into a separatory funnel followed by an addition of equal volumes of sat. aq. NaHCO₃ and water. The product was extracted with EtOAC, the combined organic extracts were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The imidazolines were purified by column chromatography on silica gel. In some cases the silica gel had to be neutralized with TEA to avoid product decomposition.

Racemic or enantiopure ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate (6)

Either racemic or enantiopure ethyl 3-phenylaziridine-2-carboxylate was used. The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 6 hours. Silica gel chromatography; 50: 50 EtOAc: hexane; R_f = 0.35; oil; 105 mg; 52% yield; ¹H NMR (500 MHz) CDCl₃: 0.8 (3H, t, J = 7.0 Hz), 3.3–3.4 (2H, m), 4.2 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 12.0 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.6 (1H, d, J = 12.0 Hz), 7.1–7.3 (10H, m), 7.4 (3H, m), 7.7 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 13.4 (CH₃), 49.9 (CH₂), 60.4 (CH₂), 67.0 (CH) 71.3 (CH), 127.3 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 128.0 (CH), 128.4 (CH), 128.6 (CH), 130.0 (CH), 130.5 (CH), 130.7 (C), 136.3 (C), 139.0 (C), 146.3 (C), 169.8 (C); IR (NaCl) 3075, 2980, 1738, 1496; HRMS: Calculated for C₂₅H₂₅N₂O₂ (M +H): 385.1916; Found 385.1922.

Determination of enantiomeric excess of compound (6) by (S)-Mosher’s Acid

Racemic compound 6 and (S)-Mosher’s acid were combined in equal molar quantities in an NMR tube along with CDCl₃. Analysis by ¹H NMR revealed that the (S, R, R) and the (S, S, S) diastereomeric salts were formed in a 50:50 mixture. Enantiopure compound 6 and (S)-Mosher’s acid were combined in equal molar quantities in an NMR tube along with CDCl₃. Analysis by ¹HNMR revealed that only one the (S, S, S) diastereomeric salt was detected. (S, R, R) diastereomeric salt: ¹H NMR (500 MHz) CDCl₃: 0.78 (3H, t, J = 7.5 Hz), 3.34 (3H, s), 3.5–3.8 (2H, m), 4.33 (1H, d, J = 15.0 Hz), 4.62 (1H, d, J = 12.5 Hz), 4.94 (1H, d, J = 15.0 Hz), 5.86 (1H, d, J = 12.5 Hz), 7.2–7.9 (20H, m), 9.2 (1H, s, br). (S, S, S) diastereomeric salt: ¹H NMR (500 MHz) CDCl₃: 0.79 (3H, t, J = 7.5 Hz), 3.35 (3H, s), 3.5–3.8 (2H, m), 4.34 (1H, d, J = 15.0 Hz), 4.64 (1H, d, J = 12.5 Hz), 4.95 (1H, d, J = 15.0 Hz), 5.90 (1H, d, J = 12.5 Hz), 7.2–7.9 (20H, m), 9.5 (1H, s, br).

1-benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole (9a)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; oil, 126 mg; 59% yield; ¹H NMR (500 MHz) CDCl₃: 3.9 (3H, s), 4.0 (1H, d, J = 16.0 Hz), 4.4 (1H, d, J = 8.5 Hz), 4.8 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 68.0 (2H, dd, J₁ = 7.5 Hz, J₂ = 2.5 Hz), 7.1 (2H, d, J = 9.0 Hz), 7.2 (2H, d, J = 7.0 Hz), 7.4 (8H, m), 7.4–7.5 (3H, m), 7.8 (2H, d, J = 9.0 Hz); ¹³C NMR and DEPT (125 MHz) CDCl₃: 49.7 (CH₂), 55.2 (CH₃), 72.5 (CH), 76.5 (CH), 114.1 (CH), 122.3 (C), 126.5 (CH), 127.0 (CH), 127.1 (CH), 127.5 (CH), 127.8 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 130.2 (CH), 136.0 (C), 141.2 (C), 143.3 (C), 161.3 (C), 165.7 (C); IR (NaCl) 3028, 2925, 1512; HRMS: Calculated for C₂₉H₂₇N₂O (M +H): 419.2123; Found 419.2123.

1-benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9b)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; oil; 109 mg; 55% yield; ¹H NMR (500 MHz) CDCl₃: 4.0 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 8.5 Hz), 4.8 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 7.0 (2H, dd, J₁ = 8.0 Hz, J₂ = 2.0 Hz), 7.1 (2H, dd, J₁ = 8.0 Hz, J₂ = 1.5 Hz), 7.2–7.4 (11H, m), 7.5 (3H, m), 7.8–7.9 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 49.5 (CH₂), 72.5 (CH), 77.7 (CH), 126.6 (CH), 126.9 (CH), 127.0 (CH), 127.3 (CH), 127.6 (CH), 127.8 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 130.0 (CH), 131.1 (C), 136.2 (C), 141.6 (C), 143.7 (C), 165.8 (C). IR (NaCl) 3028, 2922, 1495; HRMS: Calculated for C₂₈H₂₅N₂ (M +H): 389.2023; Found 389.2023.

1-benzyl-2-(4-fluorophenyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole (9c)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; oil; 90 mg; 43% yield; ¹H NMR (500 MHz) CDCl₃: 4.1 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 8.5 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 7.0 (2H, dd, J₁ = 9.5 Hz, J₂ = 3.5 Hz), 7.1–7.4 (15H, m), 7.8–7.9 (2H, m). ¹³C NMR and DEPT (125 MHz) CDCl₃: 50.1 (CH₂), 73.1 (CH), 78.2 (CH), 116.2 (d, ²J_C/F = 86.5 Hz) (CH), 127.0 (CH), 127.4 (CH), 127.5 (CH), 127.8 (d, ⁴J_C/F = 17 Hz) (C) 127.9 (CH), 128.1 (CH), 128.2 (CH), 128.7 (CH), 128.9 (CH), 129.2 (CH), 131.0 (d, ³J_C/F = 33 Hz) (CH), 136.6 (C), 142.1 (C), 144.1 (C), 163.1 (C), 165.1 (d, ¹J_C/F = 119.5 Hz) (C) IR (NaCl) 3030, 2957, 1512; HRMS: Calculated for C₂₈H₂₄FN₂ (M +H): 407.1929; Found 407.1927.

1-benzyl-2-cyclohexyl-4,5-diphenyl-4,5-dihydro-1H-imidazole (9e)

The imidoyl chloride reaction time was 1.25 hours at room temperature. The imidazoline reaction time was 6 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.35; oil; 122 mg; 60% yield; ¹H NMR (500 MHz) CDCl₃: 1.2–1.3 (3H, m), 1.7–1.8 (2H, m), 1.8–1.9 (3H, m), 2.0–2.1 (2H, m), 2.4–2.5 (1H, m), 3.9 (1H, d, 16.5 Hz), 4.2 (1H, d, J = 8.0 Hz), 4.6 (1H, d, J = 16.0 Hz), 4.8 (1H, d, J = 8.0 Hz), 7.0–7.4 (15H, m).¹³C NMR and DEPT (125 MHz) CDCl₃: 26.0 (CH₂), 26.2 (CH₂), 26.4 (CH₂), 30.6 (CH₂), 31.9 (CH₂), 36.6 (CH), 47.2 (CH₂), 72.7 (CH), 76.8 (CH), 126.6 (CH), 126.9 (CH), 127.1 (CH), 127.1 (CH), 127.4 (CH), 127.7 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH), 137.0(C), 141.9 (C), 144.3 (C), 169.9 (C); IR (NaCl) 3028, 2928, 1495; HRMS: Calculated for C₂₈H₃₁N₂ (M +H): 395.2487; Found 395.2494.

1-benzyl-2-methyl-4,5-diphenyl-4,5-dihydro-1H-imidazole (9f)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel was neutralized with TEA by the general procedure. Silica gel chromatography; 40:55: 5 EtOAc: hexane: TEA; R_f = 0.4. oil; 81 mg; 48% yield; ¹H NMR (500 MHz) CDCl₃: 2.2 (3H, s), 3.9 (1H, d, J = 16.5 Hz), 4.3 (1H, d, J = 9.0 Hz), 4.5 (1H, d, J = 16.5 Hz), 4.8 (1H, d, J = 9.0 Hz), 7.1 (2H, d, J = 7.5 Hz), 7.1 (2H, m), 7.2–7.4 (11H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 14.8 (CH₃), 47.8 (CH₂), 73.0 (CH), 77.3 (CH), 126.6 (CH), 126.9 (CH), 127.1 (CH), 127.3 (CH), 127.4 (CH), 127.7 (CH), 128.3 (CH), 128.6 (CH), 128.7 (CH), 136.7 (C), 141.0 (C), 143.6 (C), 162.9 (C); IR (NaCl) 3028, 2924, 1495; HRMS: Calculated for C₂₃H₂₃N₂ (M +H): 327.1861; Found 327.1867.

1-(4-methoxybenzyl)-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9h)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; solid; mp 110–112°C; 114 mg; 53% yield; ¹H NMR (500 MHz) CDCl₃: 3.8 (3H, s), 3.9 (1H, d, J = 15.0 Hz), 4.4 (1H, d, J = 9.0 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 6.8 (2H, dd, J₁ 6.5 Hz, J₂ = 2.0 Hz), 6.9 (2H, dd, J₁ = 8.5 Hz, J₂ = 2.0 Hz), 7.2 (2H, dd, J₁ = 8.5 Hz, J₂ = 1.5 Hz), 7.2–7.4 (8H, m), 7.5 (3H, m), 7.8–7.9 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 49.1 (CH₂), 55.1 (CH₃), 72.4 (CH), 77.9 (CH), 113.8 (CH), 126.8 (CH), 126.9 (CH), 127.1 (CH), 127.7 (CH), 128.3 (CH), 128.3 (C), 128.6 (CH), 128.7 (CH), 128.8 (CH), 129.2 (CH), 130.0 (CH), 131.4 (C), 141.9 (C), 143.9 (C), 158.9 (C), 166.0 (C); IR (NaCl) 3028, 2928, 1512; HRMS: Calculated for C₂₉H₂₇N₂O (M +H): 419.2123; Found 419.2125.

1-cyclohexyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9i)

The imidoyl chloride reaction time was 3 hours at room temperature. The imidazoline reaction time was 12 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.33; 104 mg; 53% yield; solid; mp 138–140°C; ¹H NMR (500 MHz) CDCl₃: 0.7 (2H, m), 0.8–0.9 (2H, m), 1.3 (3H, m), 1.4–1.5 (3H, m), 3.4–3.5 (1H, m), 4.4 (1H, d, J = 7.0 Hz), 4.7 (1H, d, J = 7.0 Hz), 7.1 (4H, m), 7.3 (6H, m), 7.3 (3H, m), 7.7 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 25.5 (CH₂), 25.7 (CH₂), 26.3 (CH₂), 30.4 (CH₂), 33.8 (CH₂), 56.9 (CH), 70.1 (CH), 78.9 (CH), 126.4 (CH), 126.8 (CH), 127.4 (CH), 127.5 (CH), 128.7 (CH), 128.9 (CH), 129.0 (CH), 130.4 (CH), 132.2 (CH), 145.0 (C), 146.5 (C), 165.8 (C), 167.6 (C); IR (NaCl): 3028, 2933, 1451; HRMS Calculated for C₂₇H₂₉N₂ (M +H): 381.2331; Found 381.2330.

1-methyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9j)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 9 hours. Silica gel chromatography; 50:50 EtOAc: hexane; R_f = 0.35; solid; mp 86–88°C; 96 mg; 60% yield; ¹H NMR (500 MHz) CDCl₃: 2.7 (3H, s), 4.3 (1H, d, J = 10.0 Hz), 5.0 (1H, d, J = 10.0 Hz), 7.3–7.4 (10H, m), 7.5 (3H, m), 7.7 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 35.0 (CH₃), 77.8 (CH), 78.6 (CH), 126.9 (CH), 127.1 (CH), 127.1 (CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.9 (CH), 130.0 (CH), 131.3 (C), 141.9 (C), 144.1 (C), 167.0 (C); IR (NaCl) 3028, 2925, 1498; HRMS: Calculated for C₂₂H₂₁N₂ (M +H): 313.1705; Found 313.1707.

ethyl 1-benzyl-4-(4-methoxyphenyl)-2-phenyl-4,5-dihydro-1H-imidazole-5-carboxylate (11a)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 10 hours. Silica gel chromatography; 50: 50 EtOAc: hexane; R_f = 0.45; oil; 98 mg; 45 % yield; ¹H NMR (500 MHz) CDCl₃: 1.3 (3H, t, J = 7.0 Hz), 3.9 (3H, s), 4.0 (1H, d, J = 16.0 Hz), 4.3 (2H, m), 4.6 (1H, d, J = 8.0 Hz), 4.6 (1H, d, J = 16.0 Hz), 4.9 (1H, d, J = 8.0 Hz), 6.9 (2H, m), 7.1 (2H, d J = 7.0 Hz), 7.2–7.3 (5H, m), 7.4–7.5 (3H, m), 7.7 (2H, m); ¹³C NMR (500 MHz) CDCl₃: 14.4 (CH₃), 40.0 (CH₂), 55.6 (CH₃), 61.5 (CH₂), 66.1 (CH), 76.0 (CH), 114.6 (CH), 127.7 (CH), 127.7 (CH), 128.7 (CH), 128.7 (CH), 128.9 (CH), 128.9 (CH), 130.6 (CH), 130.7 (C), 132.8 (C), 136.6 (C), 159.8 (C), 167.2 (C), 172.2 (C); IR (NaCl): 3031, 2934, 1734, 1512, 1249; HRMS: Calculated for C₂₆H₂₇N₂O₃ (M +H): 415.1977; Found 415.2022.

ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate (11b)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; solid; 78–80°C; 85 mg; 42% yield; ¹H NMR (500 MHz) CDCl₃: 1.3 (3H, t, J = 7.0 Hz), 4.0 (1H, d, J = 7.5 Hz), 4.1–4.3 (2H, m), 4.4 (1H, d, J = 15.5 Hz), 4.6 (1H, d, J = 15.5 Hz), 5.3 (1H, d, J = 7.5 Hz), 7.1 (2H, dd, J₁ = 6.0 Hz, J₂ = 1.5 Hz), 7.2–7.3 (10H, m), 7.5 (3H, m), 7.8 (2H, m); ¹³C NMR and DEPT (500 MHz) CDCl₃: 14.1 (CH₃), 51.3 (CH₂), 61.3 (CH₂), 69.9 (CH), 72.3 (CH), 126.6 (CH), 127.3 (CH), 127.7 (CH), 127.9 (CH), 128.4 (CH), 128.57 (CH), 128.58 (CH), 128.8 (CH), 130.3 (CH), 130.6 (C), 136.3 (C), 143.2 (C), 165.8 (C), 172.1 (C); IR (NaCl): 3030, 2980, 1734, 1497; HRMS: Calculated for C₂₅H₂₅N₂O₂ (M +H): 385.2023; Found 385.2027.

ethyl 1-benzyl-5-methyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-carboxylate (11c)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica gel column chromatography; 50: 50 EtOAc: hexane; R_f = 0.3; solid; mp 100–102°C; 125 mg; 59% yield; ¹H NMR (500 MHz) CDCl₃: 1.0 (3H, s), 1.3 (3H, t, J = 7.0 Hz), 4.2 (2H, q, J = 7.0 Hz), 4.3 (1H, d, J = 17.5 Hz), 4.6 (1H, d, J = 17.5 Hz), 5.5 (1H, s), 7.2–7.4 (13H, m), 7.6 (2H, m); ¹³C NMR and DEPT (500 MHz) CDCl₃: (One CH carbon not found); 14.4 (CH₃), 18.4 (CH₃), 48.4 (CH₂), 61.9 (CH₂), 73.7 (CH), 75.8 (C), 127.0 (CH), 127.3 (CH), 127.9 (CH), 128.3 (CH), 128.5 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 130.1 (CH), 131.6 (C), 138.4 (C), 139.3 (C), 167.0 (C), 175.2 (C); IR (NaCl): 3029, 2988, 1732, 1454; HRMS: Calculated for C₂₉H₂₇N₂ (M +H): 403.2174; Found 403.2185.

ethyl 1-benzyl-4-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-imidazole-5-carboxylate (11d)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 13 hours. Silica gel column chromatography; 40: 60 EtOAc: hexane; R_f = 0.29; oil; 30 mg; 13% yield; the regiochemistry was confirmed by NOESY. ¹H NMR (500 MHz) CDCl₃: 1.3 (3H, t, J = 7.5 Hz), 3.9 (1H, d, J = 7.5 Hz), 4.2–4.4 (2H, m), 4.4 (1H, d, J = 15.0 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.4 (1H, d, J = 7.5 Hz), 7.0 (2H, m), 7.2 (3H, m), 7.4 (2H, d, J = 8.5 Hz), 7.5 (3H, m), 7.8 (2H, m), 8.2 (2H, d, J = 9.0 Hz); ¹³C NMR and DEPT (125 MHz) CDCl₃: 14.5 (CH₃), 51.5 (CH₂), 62.0 (CH₂), 69.3 (CH), 71.5 (CH), 124.0 (CH), 127.8 (CH), 128.2 (CH), 128.3 (CH), 129.0 (CH), 129.0 (CH), 129.1 (CH), 130.4 (C), 131.0 (CH), 136.1 (C), 147.5 (C), 150.8 (C), 167.1 (C), 171.8 (C); IR (NaCl): 3028, 2918, 1734, 1523, 1350; HRMS Calculated for C₂₅H₂₄N₃O₄ (M +H): 430.1767; Found 430.1780.

ethyl 1-benzyl-5-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-imidazole-4-carboxylate (11d)

Silica gel column chromatography; 40: 60 EtOAc: hexane; R_f = 0.2; oil; 60 mg; 27% yield; the regiochemistry was confirmed by NOESY; ¹H NMR (500 MHz) CDCl₃: 1.3 (3H, t, 7.0 Hz), 4.0 (1H, d, J = 15.5 Hz), 4.2–4.3 (2H, m), 4.5 (1H, d, J = 8.0 Hz), 4.6 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 15.5 Hz), 7.0 (2H, dd, J₁ = 5.5 Hz, J₂ = 2.0 Hz), 7.2–7.3 (4H, m), 7.5 (4H, m), 7.7 (2H, m), 8.2 (2H, d, J = 9.0 Hz); ¹³C NMR and DEPT (125 MHz) CDCl₃: 14.2 (CH₃), 51.3 (CH₂), 61.8 (CH₂), 66.4 (CH), 76.5 (CH), 124.5 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.9 (CH), 129.0 (CH), 129.0 (CH), 130.3 (C), 131.0 (CH), 135.8 (C), 147.9 (C), 148.7 (C), 167.8 (C), 171.6 (C); IR (NaCl): 3029, 2984, 1742, 1523, 1350; HRMS Calculated for C₂₅H₂₄N₃O₄ (M +H): 430.1767; Found 430.1780.

ethyl 1-benzyl-2-phenyl-4-styryl-4,5-dihydro-1H-imidazole-5-carboxylate (11e)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 20 hours. The silica gel was neutralized by the general method. Silica gel column chromatography; 40: 60 EtOAc: hexane; R_f = 0.48; oil; 92 mg; 41% yield; ¹H NMR (500 MHz) CDCl₃: 1.2 (3H, t, J = 7.0 Hz), 4.1–4.2 (2H, m), 4.2 (1H, d, J = 17.0 Hz), 4.5 (1H, d, J = 0.5 Hz), 4.5 (1H, d, J = 0.5 Hz), 4.5 (1H, d, J = 16.0 Hz), 6.1 (1H, m), 6.4 (1H, d, J = 16.0 Hz), 7.1 (2H, d, J = 5.0 Hz), 7.2–7.4 (11H, m), 7.6 (2H, m); ¹³C NMR and DEPT (125 MHz) CDCl₃: 14.4 (CH₃), 49.5 (CH₂), 61.6 (CH₂), 66.4 (CH), 77.1 (CH), 126.9 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 128.3 (CH), 128.8 (CH), 128.8 (CH), 128.9 (CH), 128.9 (CH), 130.5 (CH), 130.8 (C), 134.1 (CH), 136.4 (C), 137.1 (C), 167.4 (C), 172.1 (C); IR (NaCl): 3154, 2984, 1733, 1469, 1381; HRMS Calculated for C₂₇H₂₇N₂O₂ (M +H): 411.2073; Found 411.2086.

ethyl 1-benzyl-4-hexyl-2-phenyl-4,5-dihydro-1H-imidazole-5-carboxylate (11f)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica gel chromatography; 50: 50 EtOAc: hexane; R_f = 0.4; oil; 86 mg; 40% yield; ¹H NMR (500 MHz) CDCl₃: 0.9 (3H, t, J = 6.5 Hz), 1.3 (3H, t, J = 7.0 Hz), 1.3–1.4 (8H, m), 1.5–1.6 (1H, m), 1.6–1.7 (1H, m), 3.7 (1H, d, J = 7.0 Hz), 4.1 (1H, m), 4.1–4.3 (2H, m), 4.3 (1H, d, J = 15.5 Hz), 4.6 (1H, d, J = 15.5 Hz), 7.1 (2H, d, J = 7.0 Hz), 7.3 (3H, m), 7.4 (3H, m), 7.7 (2H, m); ¹³C NMR and DEPT (500 MHz) CDCl₃: 14.1 (CH₃), 14.2 (CH₃), 22.6 (CH₂), 25.0 (CH₂), 29.1 (CH₂), 31.7 (CH₂), 36.8 (CH₂), 51.0 (CH₂), 61.1 (CH₂), 66.8 (CH), 69.8 (CH), 127.7 (CH), 127.9 (CH), 128.6 (CH), 128.6 (CH), 128.7 (CH), 130.1 (CH), 130.7 (C), 136.7 (C), 164.7 (C), 172.6 (C); IR (NaCl): 3029, 2928, 1734, 1469, 1381; HRMS Calculated for C₂₅H₃₃N₂O₂ (M +H): 393.2542; Found 393.2548.

1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazol-5-yl)(phenyl)methanone (11g)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica gel chromatorgraphy; 50: 50 EtOAc: hexane; R_f = 0.45; oil; 85 mg; 41% yield; ¹H NMR (500 MHz) CDCl₃: 4.3 (1H, d, J = 15.5 Hz), 4.7 (1H, d, J = 15.5 Hz), 4.9 (1H, d, J = 6.5 Hz), 5.1 (1H, d, J = 6.5 Hz), 7.1 (2H, m), 7.2 (2H, m), 7.2–7.4 (6H, m), 7.4 (2H, m), 7.5 (3H, m), 7.6 (1H, m), 7.7 (2H, d, J = 8.0 Hz), 7.8 (2H, m); ¹³C NMR and DEPT (500 MHz) CDCl₃: 51.1 (CH₂), 73.2 (CH), 73.3 (CH), 127.3 (CH), 127.9 (CH), 128.0 (CH), 128.4 (CH), 128.8 (CH), 128.9 (CH), 128.9 (CH), 129.0 (CH), 129.0 (CH), 129.1 (CH), 130.6 (CH), 133.8 (CH), 135.0 (C), 136.7 (C), 143.0 (C), 165.8 (C), 166.3 (C), 197.7 (C); IR (NaCl): 3065, 2925, 1688, 1451; HRMS: Calculated for C₂₉H₂₅N₂O (M +H): 417.1967; Found 417.1960.

1,5-dibenzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole and 1,4-dibenzyl-2,5-diphenyl-4,5-dihydro- 1H-imidazole (11h)

The imidoyl chloride reaction time was 1.25 hours at 0°C. The imidazoline reaction time was 12 hours. Silica gel chromatorgraphy; 50: 50 EtOAc: hexane; R_f = 0.45; oil; 87 mg; 41% yield; the compounds were isolated as an inseparable mixture of regioisomers (2:1 ratio). Regioisomer 1: ¹H NMR (500 MHz) CDCl₃: 2.5 (1H, dd, J₁ = 8.5 Hz, J₂ = 5.5 Hz), 3.0 (1H, dd, J₁ = 8.0 Hz, J₂ = 6.0 Hz), 3.8 (1H, d, J = 16.0 Hz), 4.6 (1H, d, J = 11.0 Hz), 4.7 (1H, d, J = 16.0 Hz), 4.8 (1H, m), 6.8–7.9 (20H, m); Regioisomer 2: ¹H NMR (500 MHz) CDCl₃: 2.3 (1H, dd, J₁ = 7.5 Hz, J₂ = 6.0 Hz), 2.7 (1H, dd, J₁ = 8.5 Hz, J₂ = 5.5 Hz), 3.6 (1H, d, J = 16.0 Hz), 4.1 (1H, m), 4.5 (1H, d, J = 16.0 Hz), 5.3 (1H, d, J = 10.5 Hz), 6.8–7.9 (20H, m). Both Regioisomers ¹³C NMR (500 MHz) CDCl₃: 37.7, 39.0, 48.9, 51.3, 64.6, 66.9, 70.6, 72.8, 125.9, 126.4, 127.3, 127.7, 127.7, 127.8, 127.8, 127.8, 127.8, 128.1, 128.2, 128.2, 128.5, 128.6, 128.8, 128.8, 128.9, 128.9, 128.9, 129.1, 129.2, 129.4, 130.3, 130.6, 131.6, 131.7, 137.4, 137.8, 138.4, 139.3, 149.8, 140.0, 165.8, 167.7; IR (NaCl): 3028, 2918, 1616, 1595; HRMS Calculated for C₂₆H₂₇N₂O₂ (M +H): 399.2073; Found 399.2086.