Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and Selectivity in Diels-Alder Cycloadditions

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pubs.acs.org/joc

Cite This: J. Org. Chem. XXXX, XXX, XXX −XXX

Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and

Selectivity in Diels−Alder Cycloadditions

Carlos Espinoza-Hicks,^†,§Pablo Montoya,^†Rafael Bautista,^†Hugo A. Jimenez-Vazquez,^†

́

Luz M. Rodríguez-Valdez,^§Alejandro A. Camacho-Davila,^§Fernando P. Cossío,^‡Francisco Delgado,^†

́

and Joaquín Tamariz*^,†

^†Departamento de Química Organ

Ayala, S/N, Mexico City 11340, Mexico

^§Departamento de Química Organ

ica, Facultad de Ciencias Químicas, Universidad Auton

S/N, Chihuahua, Chih. 31125, Mexico

^‡Departamento de Química Organ

ica I and ORFEO−CINQA, Universidad del País Vasco/Euskal Herriko Unibertsitatea

(UPV/EHU) and Donostia International Physics Center (DIPC), PO Box 1072, San Sebastian/Donostia 20018, Spain

́ ́ ́

ica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Prol. Carpio y Plan de

́

oma de Chihuahua, Circuito Universitario

́

S

* Supporting Information

ABSTRACT: An eﬃcient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was

carried out with bis-imino derivatives, diacetyl, and triphosgene, aﬀording symmetrically N,N-disubstituted dienes. The use of

alkyl methyl α-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable

inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of

these dienes in Diels−Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states

accounted for their behavior.

heterocycle can be readily incorporated into the cyclohexene-

fused polycyclic, increasing the synthetic versatility of the

adducts. These attractive structural features are sometimes

enhanced when the diene is partly integrated into the

heterocycle as an inner-outer-ring diene, resulting in greater

reactivity and selectivity.^6a,f,7Nevertheless, both diene classes

are relevant as potential synthons for the construction of

polycyclic scaﬀolds and represent a huge theoretical challenge

with respect to the evaluation of the substituent eﬀects

controlling either reactivity or regio- and stereoselectivity in

Diels−Alder cycloadditions.⁸

INTRODUCTION

■

Diels−Alder cycloaddition is a pericyclic reaction and one of

the cornerstones of organic chemistry for the experimental and

theoretical study of concerted reactions.¹It is also a very useful

methodological tool for designing the regio- and stereoselective

synthesis of natural products containing six-membered rings.²

Diels−Alder reactions are usually conducted through a

synchronical, nonsynchronical, or diradicaloid concerted

transition state,¹⁻³or take place by coupling of two

pseudoradical centers.^1fHowever, there is evidence of nonpolar

stepwise diradical^3band polar stepwise (zwitterionic) mecha-

nisms.⁴The reactivity and stereochemical outcome of the

process depend on diverse structural and electronic eﬀects

mainly due to the nature of the substituents on the diene and

dienophile.^1,2,5

Owing to our interest in designing novel outer-ring

heterocyclic dienes,⁹we recently described the synthesis of

N,N-disubstituted exo-2-imidazolidinone dienes 5,¹⁰carried out

through a base-assisted condensation/cyclization cascade

Outer-ring exo-heterocyclic dienes have attracted much

attention owing to the fact that heteroatoms enhance their

reactivity in Diels−Alder additions.⁶Through this process, the

Received: October 26, 2017

A

DOI: 10.1021/acs.joc.7b02344

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

reaction of the monoimino diacetyl (1a) derivatives 3 with

isocyanates 4 in the presence of a dehydrating agent (Scheme

1). These dienes proved to be highly reactive in Diels−Alder

Table 1 summarizes the reaction conditions and yields in the

preparation of α-bis-imino compounds 10a−e and 11a and b.

Table 1. Preparation of Imino Compounds 3a−c, 10a−e, 11a

and b, and 8 by Condensation of α-Diketones 1a−c with

Scheme 1. Synthesis of exo-2-Imidazolidinone Dienes 5 and

Their Diels−Alder Reactions

a

Anilines 2a−e

catalyst (mol

equiv)

product

b

entry 1 (R)

2 (Ar)

solvent

MeOH

t (h)

(%)

1

2

3

4

5

6

7

8

9

1a (H) 2a (C₆H₅)

24.0 10a

(78)

1a (H) 2b (C₆H₄-4-

MeOH

24.0 10b

(80)

Me)

1a (H) 2c (C₆H₄-4-

24.0 10c (88)

OMe)

1a (H) 2d (C₆H₄-4-

24.0 10d

additions with 6, leading to the tricyclic adducts 7, but showed

only a modest regioselectivity with monosubstituted dien-

ophiles.¹⁰

Cl)

(40)

1a (H) 2e (2-

24.0 10e

naphthyl)

(86)

c

1b

(Me)

2c (C₆H₄-4- p-TsOH

MeOH

24.0 11a (0)

Due to the relevance of exo-heterocyclic dienes, the potential

of dienes 5 for the synthesis of vicinal diamino compounds¹¹

and pharmacologically active benzimidazol-2-ones,¹²and the

challenge in designing dienes such as 5 for highly regioselective

[4 + 2] cycloadditions, we herein describe a novel and eﬃcient

approach for the preparation of dienes 5. We also present the

synthesis of new alkyl substituted dienes 12−15, which proved

to be reactive and regioselective in these reactions. The current

endeavor led to the formation of novel inner-outer-heterocyclic

dienes 16 and 17 through the thermal and acid-promoted

isomerization of dienes 12/13. The reactivity and selectivity of

such dienes were experimentally evaluated, and a computational

study was conducted to understand the factors involved in

controlling the course of the [4 + 2] pathway.

OMe)

(0.20)

d

1b

(Me)

2c (C₆H₄-4- p-TsOH

OMe) (0.05)

0.75 11a

(30)

d

1b

(Me)

2c (C₆H₄-4- p-TsOH

OMe) (0.10)

0.75 11a

(55)

1c

(Et)

2c (C₆H₄-4- p-TsOH

OMe) (0.20)

0.75 11b

(50)

e

10

11

1a (H) 2a (C₆H₅)

MeOH

12.0 3a (80)

e

1a (H) 2c (C₆H₄-4-

12.0 3b (81)

OMe)

e

12

13

1a (H) 2b (C₆H₄-4-

MeOH

24.0 3c (75)

Me)

1b

(Me)

2c (C₆H₄-4-

OMe)

24.0 8 (59)

a

Reaction conditions: for bis-imines 10a−e: 1a (1.0 mol equiv) and

2a−e (2.0 mol equiv). For bis-imines 11a and b: 1b and c (1.0 mol

equiv) and 2c (2.0 mol equiv). For monoimines 3a−c: 1a (1.0 mol

equiv) and 2 (1.0 mol equiv). For monoimine 8: 1b (1.0 mol equiv)

and 2c (1.0 mol equiv). All reactions were carried out at 25 °C. After

column chromatography. Decomposition. By the solvent-free mortar

RESULTS AND DISCUSSION

■

b

The novel synthesis of dienes 5a−e was conceived based on a

bis-condensation approach of α-bis-imino compounds 10a−e

with triphosgene (9), a safe and easy-to-handle synthetic

equivalent of phosgene (Scheme 2).¹³Compounds 10a−e can

be produced from α-diketone 1a by reacting it with 2 mol equiv

of anilines 2a−e.

c

d

e

grinding method. Ref 10.

The ﬁrst series of bis-imines 10a−e was obtained in moderate

to high yields by treatment of diacetyl (1a) with an excess (2.0

mol equiv) of the corresponding anilines 2a−e under mild

conditions (entries 1−5).¹⁴Other methods have been used,

including thermal conditions¹⁵and acid catalysis,¹⁶leading to

lower yields or no reaction. The optimized conditions were also

presently employed to try to introduce two diﬀerent anilines,

starting from the mono-imino α-diketone 3a and reacting it with

another aniline such as 2c. However, the reaction was

unsuccessful, generating a mixture of the starting compound

3a and the symmetrically substituted bis-imine 10c as the major

product, along with aniline (2a) (through the decomposition of

3a) and the unreacted starting p-anisidine (2c).

Scheme 2. Synthesis of exo-Imidazolidin-2-one Dienes 5 and

12−15 from Imines 3, 8, 10, and 11 and Triphosgene (9) or

Isocyanates 4

The endeavor to prepare the series of nonsymmetrical bis-

imines 11a and b was unsuccessful when starting from α-

diketones 1b and c and following the same methodology, or

under acid (p-TsOH) catalyzed conditions (Table 1, entry 6).

Despite the fact that similar conditions have been reported to

provide bis-imines with diverse α-diketones and anilines,^16a,17it

was herein found that bis-imines other than 11a and b were

B

DOI: 10.1021/acs.joc.7b02344

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Table 2. Preparation of Dienes 5a−i by Reacting bis-Imines 10a−e and α-Iminoketones 3a−c with Triphosgene (9) and

a

Isocyanates 4a and b and 4d, Respectively

b

entry

imine

Ar

Ar′

C₆H₅

4 or 9

T (°C)

t (h)

5 (%)

1

2

3

4

5

6

7

8

9

10a

10b

10c

10d

10e

3a

C₆H₅

9

0

3

5a (81)

5b (78)

5c (99)

5d (85)

5e (70)

5f (82)

5g (65)

5h (63)

C₆H₄-4-Me

C₆H₄-4-OMe

C₆H₄-4-Cl

2-naphthyl

C₆H₅

C₆H₄-4-Me

C₆H₄-4-OMe

C₆H₄-4-Cl

2-naphthyl

C₆H₄-4-OMe

C₆H₄-4-Cl

C₆H₅

9

0

3

9

0

3

9

0

3

9

0

3

4d

4b

4a

20

24

3b

C₆H₄-4-OMe

C₆H₅

c

3a

c

3c

C₆H₄-4-Me

5i (70)

a

Reaction conditions: for dienes 5a−e: 10a−e (1.0 mol equiv), 9 (1.5 mol equiv), and Et₃N (3.0 mol equiv) in toluene. For dienes 5f−i: 3a−c (1.0

b

c

mol equiv), 4a and b and 4d (3.0 mol equiv), Et₃N (2.0 mol equiv), and Li₂CO₃(10.0 mol equiv) in toluene. After column chromatography. Ref

10.

either not formed or given in very low yields. Interestingly, by

grinding 1b and c and 2c in a mortar under acid-catalyzed

solvent-free mechanochemical conditions,¹⁸bis-imines 11a and

b were aﬀorded in moderate yields (entries 7−9).

To obtain dienes 12b−d/13b−d with two diﬀerent aryl

groups, we investigated the preparation of the corresponding

monoimine 8 as the precursor for subsequent treatment with

isocyanates 4, adhering to our previously reported method.¹⁰In

that study, the preparation of monoimine 8 (Ar = Ph) was

Figure 1. X-ray structure of 5a (ellipsoids at the 30% probability level).

attempted through a p-TsOH catalyzed procedure, but only a

very low yield of the desired product was furnished. Better

results were achieved with a catalyst-free reaction of 1b and 2c

generated (Table 3, entry 1). The ratio was greatly improved

under mild reaction conditions (Table 1, entry 13).

by decreasing the reaction temperature to −10 °C, leading to

After modifying solvents and reaction temperatures, we

the exclusive formation of (E)-12a in high yield (entry 2).

determined that the optimized method of synthesis of dienes

Interestingly, increasing the reaction temperature to 20 °C

5a−e involved the condensation of triphosgene (9) with bis-

aﬀorded a single product which corresponded to the

imines 10a−e in the presence of Et₃N and in toluene as the

heterocyclic inner-outer-ring diene 16a (entry 3).

solvent (0 °C, 3 h) (Table 2, entries 1−5). Although the yields

With bis-imine 11b, in contrast, the diastereoisomeric ratio of

were higher than those obtained by the previous method-

dienes (E/Z)-14/15 did not improve signiﬁcantly by modifying

ology,¹⁰they were prone to drastically decrease with a rise in

the reaction temperatures (Table 3, entries 4 and 5). Even after

the reaction temperature and the maintenance of the dienes in

further reducing the temperature, the isomeric mixture ratio of

solution (CH₂Cl₂) even at room temperature, observing

(E/Z)-14/15 was only a little better, being produced at a very

low conversion rate and yield (<20%). However, carrying out

the reaction at room temperature led to the isomerization of

the diene to deliver the respective heterocyclic inner-outer-ring

polymerization. Despite the eﬃciency of this novel method-

ology, it was limited to the synthesis of symmetrically N-

substituted dienes. For the preparation of the nonsymmetrically

N-substituted dienes 5f−i, the methodology that employs the

diene 17 as a single (E) isomer (entry 6).

reaction of α-iminoketones 3a−c with the corresponding

isocyanates 4a and b and 4d proved to be an eﬃcient procedure

(Table 2, entries 6−9). The structure of the novel compounds

was established by spectrometric analyses, and that of the

known diene 5a¹⁰was veriﬁed by single crystal X-ray diﬀraction

(Figure 1).¹⁹Unlike the exo-2-oxazolidinone dienes,⁹where the

heterocycle is totally planar, diene 5a adopts a slightly

nonplanar conformation (C7−C5−C4−C6 dihedral angle:

14.5°; N1−C2−N3−C5 dihedral angle: 3.1°; C2−N1−C5−

C4 dihedral angle: −7.7°, N1−C5−C4−N3 dihedral angle:

9.1°). However, in a similar manner as the exo-2-oxazolidinone

dienes, the N-phenyl rings of 5a assume a quasi-orthogonal

conformation with respect to the plane of the heterocycle.

Upon treating bis-imine 11a with 9 at 0 °C for 4 h, a

diastereoisomeric mixture of (E/Z)-12a/13a (59/41) was

Upon acidic treatment of diene 12a with AlCl₃in CH₂Cl₂as

the solvent at −78 °C for 30 min, heterocyclic inner-outer-ring

diene 16a was furnished in a slightly lower yield (70%) than

that found by direct condensation of 11a with 9 (Table 3,

entries 3 and 10). Similarly, when a mixture of dienes 12c/13c

(57/43) was submitted under Lewis acid-assisted reaction

conditions inner-outer-ring diene 16b was provided in good

yield (entry 11).

Unexpectedly, the reaction of 8 with isocyanates 4a−c led to

the corresponding dienes as diastereoisomeric mixtures of (E/

Z)-12b−d/13b−d, without the formation of the isomerized

heterocyclic inner-outer-ring dienes, even though the reactions

took place at 20 °C (Table 3, entries 7−9). The absence in the

reaction mixture of potentially acidic species such as 9 may be

the cause of the inhibition of isomerization.

C

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Table 3. Preparation of Dienes 12a, 12a−d/13a−d, 14/15, 16a and b, and 17 by Reacting bis-Imines 11a and b or α-Ketoimine

a

8 with Triphosgene (9) and Isocyanates 4a−c

b

c

entry

imine

11a

Ar

Ar′

6 or 9

T (°C)

t (h)

dienes (%)

1

C₆H₄-4-OMe

C₆H₅

9

0

4

12a/13a (59/41) (88)

12a (88)

2

11a

11b

8

9

−10

20

4

3

9

1

16a (75)

4

9

0

4

14/15 (42/58) (78)

14/15 (64/36) (80)

17 (70)

5

9

−10

20

4

6

9

1

7

4a

4b

4c

20

48

0.5

12b/13b (36/64) (40)

12c/13c (57/43) (65)

12d/13d (68/32) (54)

16a (70)

8

C₆H₄-4-Cl

20

9

8

C₆H₄-4-Me

C₆H₄-4-OMe

C₆H₄-4-Cl

20

d

10

11

12a

−78

d

12c/13c

16b (78)

a

Reaction conditions: For dienes 12a/13a, 14/15, 16a, and 17: 11a and b (1.0 mol equiv), 9 (1.5 mol equiv), and Et₃N (3.0 mol equiv) in toluene.

b

For dienes 12b−d/13b−d: 8 (1.0 mol equiv), 4a−c (2.5 mol equiv), Et₃N (3.0 mol equiv), and Li₂CO₃(13.0 mol equiv) in toluene. Ratios

c

d

calculated by ¹H NMR of the crude mixtures. After column chromatography. For dienes 16a and b: 12a and 12c/13c (57/43) (1.0 mol equiv) and

AlCl₃(0.27 mol equiv) in CH₂Cl₂.

The molecular geometries of dienes 12a, 13a, 14, 15, 16a,

and 17 were calculated at the B3LYP/6-31G**²⁰level of DFT

theory without symmetry constraints. As expected for both

homologue series, compounds 16a and 17 were the most stable

dienes (Figure 2). Although the s-cis conformation was found to

The reactivity and regioselectivity of these dienes was

evaluated in Lewis acid-catalyzed Diels−Alder cycloadditions

to acrolein (18a). In a previous study, diene 5h was reacted

with methyl vinyl ketone (18b) in the presence of BF₃·OEt₂as

the catalyst at −78 °C to aﬀord a (65/35) mixture of

regioisomers.¹⁰This low regioselectivity supports the hypoth-

esis that the electron density on the nitrogen atoms is almost

unperturbed by the aryl rings owing to conformational

restrictions, as shown by the X-ray diﬀraction structure of

diene 5a (Figure 1). Therefore, we investigated the

regioselectivity of dienes 12a/13a and 14/15 to assess the

eﬀect of the perturbation of the alkyl group on the polarization

of the dienic moiety.

First, the reaction was carried out with the single isomer 12a

in the presence of 18a and the same catalyst at a low

temperature (−78 °C) for 2 h to furnish the four expected

adducts 19a/20a/21a/22a (Scheme 3). Although the diaster-

1

eoisomeric ratio was estimated from the H NMR spectrum of

the crude mixture (Table 4, entry 1), the complexity of the

signals did not allow for the assignment of the adduct

structures. Hence, regioselectivity was unambiguously estab-

lished by converting the adduct mixture into the aromatic

ortho/meta isomers 23a/24a (65/35) by DDQ-promoted

aromatization (Scheme 3). This regioselectivity, similar to

that found with the nonmethylated diene 5h, was greatly

improved by using ZnCl₂as the catalyst under the same

reaction conditions (entry 2). Additionally, the process resulted

in a high endo/exo diastereoselectivity, generating the mixture

of adducts 19a/20a (83/17). The assignment of the stereo-

chemistry was tentatively made in agreement with the endo

preference predicted by calculations (vide infra).

Figure 2. Calculated (B3LYP/6-31G**) relative energies (kcal/mol)

of the optimized geometries of dienes 12a, 13a, 14, 15, 16a, and 17

(Ar = C₆H₄-4-OMe).

be more stable than the s-trans, the energy diﬀerence between

them was 0.51 kcal/mol. Among the (E/Z) diastereoisomeric

dienes 12a/13a, the former was more stable by 0.90 kcal/mol.

The energy diﬀerence was greater for the most hindered ethyl

substituted isomers 14/15 at 1.28 kcal/mol. This preference is

presumably linked to the steric interaction of the alkyl group

with the vicinal N-aryl ring, even when the latter adopts a

noncoplanar conformation in relation to the plane of the

heterocycle (Figure 1).

Both regio- and stereoselectivity were similar to that found

when the cycloaddition was carried out with the mixture of (E/

Z) isomeric dienes 12a/13a (Table 4, entry 3). This is rather

surprising because it is well-known that the reactivity and

selectivity of isomeric (E)- and (Z)-1-substituted dienes are

D

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Scheme 3. Diels−Alder Additions of Dienes 12a/13a and 14/15 to Acrolein (18a), Followed by Aromatization with DDQ to

Aﬀord the Regioisomeric Benzimidazol-2-ones 23a/24a and 27a/27b

a

Table 4. Diels−Alder Cycloadditions of Dienes 12a/13a, 14/15, and 5h−i to Acrolein (18a)

b

c

b

c

entry

dienes

catalyst

adducts ortho endo/exo

adducts meta endo/exo

yield (%)

2-benzimidazoles (%)

1

2

3

4

5

6

7

8

12a

BF₃·OEt₂

ZnCl₂

19a/20a (25/36)

19a/20a (83/17)

19a/20a (81/19)

25a/25b (57/43)

19b/20b (80/20)

19c/20c (69/31)

21a/22a (14/25)

21a/22a (d)

26a/26b (d)

21b/22b (d)

21c/22c (d)

72

74

75

95

73

60

88

72

23a/24a (65/35) (81)

23a/24a (98/2) (80)

23a/24a (96/4) (80)

27a/27b (91/9) (88)

23b/24b (96/4) (82)

12a/13a (59/41)

14/15 (42/58)

12c/13c (57/43)

12d/13d (68/32)

5h

23c/24c (92/8) (85)

e

28a (60)

29a (40)

30a/31a (57/43) (88)

e

5i

28b (53)

29b (47)

30b/31b (57/43) (92)

a

b

Reaction conditions: diene (1.0 mol equiv) and ZnCl₂(0.27 mol equiv) or BF₃·OEt₂(0.27 mol equiv) in CH₂Cl₂at −78 °C for 2 h. Ratios

c

d

e

1

calculated by H NMR of the crude mixtures. After column chromatography. Not determined. Regiochemistry could not be assigned.

Scheme 4. Diels−Alder Additions of Dienes 12c-d/13c-d to Acrolein (18a), Followed by Aromatization with DDQ to Aﬀord the

Regioisomeric Benzimidazol-2-ones 23b-c/24b-c

usually quite diﬀerent.²¹Although the nonfavorable equilibrium

(as shown in Figure 2) did not allow us to isolate (Z)-13a and

observe its Diels−Alder selectivity, the use of the (E)-12a/(Z)-

13a mixture revealed that a previous isomerization could have

taken place before the cycloaddition, leading to the comparable

selectivity. This idea may be supported by the result obtained

from the mixture of the ethyl substituted (E/Z) isomeric dienes

14/15 (42/58). When this mixture was evaluated under similar

reaction conditions, an analogous regioselectivity but a much

lower endo/exo diastereoselectivity was observed (entry 4) in

comparison with the reaction of 12a/13a (59/41) (entry 3).

Due to the higher isomerization energy (Figure 2), it is likely

that the isomerization between dienes 14/15 is slower. This

would lead to a diﬀerent selectivity, at least concerning endo/

exo selectivity.

in the additions to the (Z) isomeric dienes 13a and 15. Thus,

isomers 20a, 22a, 25b, and 26b are the exo adducts when the

(E) isomeric dienes 12a and 14 react with 18a, and the endo

adducts in the event that they result from additions of 18a to

the (Z) isomeric dienes 13a and 15.

We also assessed the eﬀect of having two diﬀerent N- and N′-

aryl rings in the methyl substituted dienes 12c-d/13c-d during

the cycloadditions with 18a, maintaining the same ZnCl₂-

catalyzed reaction conditions (Scheme 4; Table 4, entries 5 and

6). The reactivity and regioselectivity were comparable to those

found in the assays with dienes 12a/13a and 14/15 (entries 3

and 4). Adducts 19b and c and 21b and c would be considered

as the endo-approach products when 18a is reacted with the (E)

isomeric dienes 12c and d, or the exo adducts upon its reaction

with the (Z) isomeric dienes 13c and d. Likewise, adducts 20b

and c and 22b and c would be considered as the endo-approach

products when 18a reacts with the (Z) isomeric dienes 13c and

d, or the exo adducts in the event that it reacts with the (E)

isomeric dienes 12c and d. After aromatization of the

In principle, if the processes are concerted or there is no

isomerization of the diene in the course of the reaction, adducts

19a, 21a, 25a, and 26a are a consequence of the endo approach

when the (E) isomeric dienes 12a and 14 react with 18a. Of

course, these adducts are also the products of the exo approach

E

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Article

Scheme 5. Diels−Alder Cycloadditions of Dienes 5h and i to Acrolein (18a), Followed by Aromatization with DDQ to Aﬀord

the Regioisomeric Benzimidazol-2-ones 30a-b/31a-b

Table 5. Calculated [HF/6-31G(d,p)] Energy Gaps (eV) of the Frontier Molecular Orbitals for Dienes 5c, 12a, and 14 and

Dienophiles 18a, 18a-ZnCl₂, and 18a-BF₃

a

addends

5c-18a

HOMO−LUMO

LUMO−HOMO

diﬀ

10.2

8.4

13.7

14.7

14.8

13.8

14.8

14.9

13.8

14.8

14.9

3.5

6.3

6.1

3.7

6.5

6.3

3.7

6.5

6.3

5c-18a-ZnCl₂

5c-18a-BF₃

12a-18a

8.7

10.1

8.3

12a-18a-ZnCl₂

12a-18a-BF₃

14-18a

8.6

10.1

8.3

14-18a-ZnCl₂

14-18a-BF₃

8.6

a

HOMO_diene−LUMO_dienophileand LUMO_diene−HOMO_dienophile

.

corresponding adducts 19b-c/20b-c/21b-c/22b-c, mixtures of

23b-c/24b-c were obtained.

a new strategy for the construction of N,N′-diarylbenzimidazol-

2-ones eﬃciently (Schemes 3 and 4).

Considering the catalytic eﬃciency of ZnCl₂in all the

previous cycloadditions, and the fact that the nonsubstituted

diene 5h was previously evaluated only with BF₃·OEt₂as the

catalyst,¹⁰we again explored the regioselectivity with the

nonalkylated dienes 5h and i in the presence of ZnCl₂(Scheme

5). The reaction between these dienes and 18a under

conditions similar to those described in Schemes 3 and 4

gave inseparable mixtures of adducts 28a-b/29a-b with low

regioselectivity (Table 4, entries 7 and 8). Unfortunately, the

series of aromatic benzimidazol-2-ones 30a-b/31a-b was

obtained as inseparable mixtures as well. Their ¹H NMR

spectra showed overlapping signal patterns, which made it

diﬃcult to assign the regioisomeric preference by NOE

experiments.

The aforementioned results not only conﬁrm the low

regioselectivity evidenced previously with BF₃·OEt₂but also

support the idea that the substituents in the aromatic rings

attached to the nitrogen atoms do not produce a signiﬁcant

electronic perturbation capable of inducing polarization of the

diene terminal carbon atoms. This is probably due to the

inhibition of the conjugation between the electron lone pairs of

the nitrogen atoms with the aryl rings, because the aryl rings are

unable to adopt a planar conformation in relation to the plane

of the heterocycle (Figure 1). Consequently, the electronic

eﬀects generated by the aryl substituents are mainly transmitted

onto the dienic moiety as inductive eﬀects,²²which are

expected to be weak owing to the distance separating the

interacting centers. Therefore, the exocyclic diene moiety must

be substituted, minimally with an alkyl group, to induce a

regioselective approach to the dienophile. As shown herein,

these dienes are both reactive and selective enough to facilitate

To rationalize the regioselectivity observed in the ZnCl₂-

catalyzed Diels−Alder cycloadditions with the alkyl substituted

dienes 12a/13a and 14/15, frontier molecular orbital (FMO)

theory was used (Table S1).²³The geometries of these dienes

as well as that of acrolein (18a), acrolein-zinc chloride (18a-

ZnCl₂) and acrolein-boron triﬂuoride (18a-BF₃) were calcu-

lated and optimized at the M06-2X/6-31+G(d,p) level of DFT

theory without symmetry constraints. The energies and

coeﬃcients of the FMOs were calculated at the HF/6-31G(d,p)

level. The most favorable normal electronic demand interaction

(HOMO_diene−LUMO_dienophile) was established from the energy

gaps (Table 5). For the alkyl substituted dienes 12a and 14,

calculations gave energy gaps smaller than those for the

nonsubstituted diene 5c. These gaps were also much smaller

when the LUMOs of the two catalyst complexes 18a-ZnCl₂and

18a-BF₃were compared to the LUMO of the noncomplexed

dienophile 18a. Hence, in terms of perturbation theory,²³

dienes 12a and 14 should have reactivity higher than that of

diene 5c and also higher than that of the nonsymmetrical diene

5h. Consequently, the regioselectivity of dienes 12a and 14

should also be higher than that of dienes 5.²⁴Although a

quantitative kinetic evaluation of the reactivity of dienes 12a

and 14 was not made, the higher regioselectivity would indicate

a higher reactivity than that of dienes 5.

The energy gap is smaller for the HOMOs of the dienes in

relation to the LUMO of 18a-ZnCl₂than the LUMO of 18a-

BF₃. Nevertheless, the diﬀerence between these two gaps is not

so great as to justify the large diﬀerence in reactivity found. Nor

can this outcome be explained based on the coeﬃcient

diﬀerences for the HOMO_diene−LUMO_dienophileinteractions

(Table S1). The HOMO coeﬃcients of the dienes termini

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C1 and C4 are almost equal, and a nonregioselective interaction

with the LUMO coeﬃcients of dienophile 18a should be

expected. In addition, the LUMO coeﬃcient diﬀerences (ΔC_i)

for the complexed dienophiles 18a-ZnCl₂and 18a-BF₃are

almost identical. Therefore, a lack of signiﬁcant diﬀerence in

regioselectivity would be expected between both complexed

dienophiles, as was experimentally observed.

Because the evaluation of the electronic eﬀects that control

these cycloadditions appears to be beyond the scope of FMO

theory,^1fwe decided to explore the geometries and energies of

the possible transition states (TSs) and the associated minima

along the reaction coordinates for their respective processes.²⁵

The geometries of the reactants, transition states, and products

were optimized at the M06-2X/6-31+G(d,p) level of theory²⁶

with the Gaussian 09 program package.²⁷

The reaction trajectory for the cycloaddition of 12a with 18a

was found to be concerted, passing through a single TS (Table

S3, Figure S1) but displaying a highly asynchronous geometry

(Figures S2 −S13). The TS energy for the ortho-endo approach

turned out to be lower than that for the other possible

approaches (ortho-exo, meta-endo, and meta-exo), the energies of

which are similar to each other (Table S2). Unfortunately, the

slow decomposition of dienes 12a/13a under thermal

conditions prevented an accurate evaluation of the selectivity

of the reaction.

For the cycloaddition of 12a with 18a-ZnCl₂and 18a-BF₃,

however, there were two TSs on the reaction coordinate before

arriving to the corresponding adduct, with a minimum between

these two TSs (Figures 3 and 5).^1c,25c−fHence, these reactions

Diels−Alder reactions are given in Tables S2 and S4, and the

geometries are described in Figure 4 and in the Supporting

Information (Figures S14−S33).

The energy diﬀerences between the four cycloaddition

approaches mentioned are illustrated in Figure 3. Both ortho

approaches (endo and exo) are lower in energy than the meta

approaches, showing diﬀerent reaction coordinate patterns. For

the ortho pathways (endo and exo), in each case the ﬁrst TS

(TS1) is reached from a stationary state as a supramolecular

complex (SC)^8fand corresponds to the rate-determining step.

For the meta pathways, contrarily, in each case the second TS

(TS2) determines the highest energy barrier. The ZIs follow

the same energy stability trend between the ortho and meta

approaches, the former having the most stable intermediates. It

is noteworthy that, from the thermodynamics point of view, the

ZI is reached through an exergonic process only for the ortho-

endo approach, while the process is endergonic for the ortho-exo

and both meta regioisomers.

Scheme 6 and Figure 4 illustrate the pathway, chemical

structures, and geometries of SC, TS1, ZI, TS2, and the adduct

(19a) for the most stable trajectory 12a/18a-ZnCl₂-ortho-endo.

The stationary points were further characterized with the aid of

frequency calculations to verify that the TSs had a single

imaginary frequency.

A correlation can be appreciated between the energy

diﬀerences of the rate-determining TS1-ortho and TS2-meta

transition states (endo = 9.48 kcal/mol; exo = 11.12 kcal/mol;

Table S2) and the experimental selectivity of the 23a/24a (98/

2) mixture (Table 4, entry 2) in the corresponding ortho and

meta approaches. Similarly, the energy diﬀerence between the

endo and exo (3.80 kcal/mol) approaches for the ortho

trajectory is signiﬁcant, as it reﬂects the selectivity found

experimentally (endo/exo, 83/17) (Table 4, entry 2). Although

the experimental endo/exo ratio could not be determined for

the meta trajectory, it is expected to be small due to the

relatively low energy diﬀerence (1.64 kcal/mol) for TS2. This

prediction is in agreement with the strong exergonic last step of

the reaction coordinates for these meta regioisomers.²⁴

Further examination of one diene, the geometric isomer (Z)-

13a, in cycloaddition with 18a would explain the fact that

highly regioselective cycloadditions were observed for the

mixtures of (E)-12a/(Z)-13a and 18a (Table 4, entries 2 and

3). Thus, the calculation of (Z)-isomer 13a and 18a-ZnCl₂

showed the formation of zwitterionic species and the

corresponding two transition states (Figures S63 −S67) and

indicated a preference for the ortho regioisomer, as for (E)-12a.

Both ortho and meta approaches have TS1 as the rate-

determining TS for BF₃-catalyzed cycloadditions (Figures 5 and

S34 −S53), unlike those catalyzed by ZnCl₂. It is surprising that

the calculated ortho/meta energies for the BF₃-catalyzed

(Tables 2 and S5) process do not reﬂect the experimentally

observed lack of regioselectivity (Table 4, entry 1). For

example, the TS1 energy diﬀerence between the 12a/18a-BF₃-

ortho-endo and 12a/18a-BF₃-meta-endo approach is 2.34 kcal/

mol, which corresponds to a high ortho/meta ratio (∼98/2) and

is in contrast to the experimental ratio (65/35). However, the

TS energy diﬀerence between the 12a/18a-BF₃-ortho-exo and

the meta-exo approach is very small (0.87 kcal/mol), which

should provide an ortho/meta ratio close to one. There are

probably other factors involved in the transition state that could

explain the latter observations, such as electrostatic forces,^25a,28

enhancement of the charge-transfer conﬁguration (polar

interactions) between the diene and the dienophile in the

Figure 3. Calculated [M06-2X/6-31+G(d,p)] relative ZPE-corrected

energies (kcal/mol) of the stationary points of the 12a/18a-ZnCl₂

cycloadditions for the four possible approaches: ortho-endo (blue),

ortho-exo (green), meta-endo (red), and meta-exo (black). SC =

supramolecular complex; TS1 = transition state 1; zwitterionic

intermediate (ZI); TS2 = transition state 2; AD = adduct.

do not proceed via a concerted pathway, rather through a two-

step mechanism leading to the formation of a zwitterionic

intermediate (ZI),^1fprobably as a result of the stabilizing eﬀect

of the strong coordination by the metal in the metal-complexed

dienophile species.^1cThe M06-2X/6-31+G(d,p) level of theory

was also used for the optimization of the geometries of each

regioisomer and diastereoisomer in the cycloadditions. For

example, for the ZnCl₂-catalyzed cycloaddition, four possible

approaches exist: 12a/18a-ZnCl₂-ortho-endo, 12a/18a-ZnCl₂-

ortho-exo, 12a/18a-ZnCl₂-meta-endo, and 12a/18a-ZnCl₂-meta-

exo. The relative energies of the stationary points of these

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Figure 4. Calculated [M06-2X/6-31+G(d,p)] optimized geometries of the stationary points involved in the 12a/18a-ZnCl₂cycloaddition of the

most stable ortho-endo approach.

Scheme 6. Diels−Alder Addition of Diene 12a to ZnCl₂-

Complexed Acrolein (18a), Following the ortho-endo

Approach to Yield Adduct 19a

presence of a stronger Lewis acid,^1c,24c,25b,cthe coordination

Figure 5. Calculated [M06-2X/6-31+G(d,p)] relative ZPE-corrected

interactions of BF₃with the dienophile (18a) and the diene,²⁹

steric hindrance,³⁰and/or the conformation of the dienophile

at the TS,^8awhich would be capable of destabilizing the ortho

regioisomer.

energies (kcal/mol) of the stationary points of 12a/18a-BF₃

cycloadditions for the four possible approaches: ortho-endo (blue),

ortho-exo (black), meta-endo (green), and meta-exo (red). SC =

supramolecular complex; TS1 = transition state 1; zwitterionic

intermediates (ZI); TS2 = transition state 2; AD = adduct.

We also evaluated the reactivity of the inner-outer-ring dienes

16a and 17 with N-phenylmaleimide (6) (Scheme 7). The

cycloadditions took place at room temperature for 48 h to

provide a high endo diastereoselectivity, which led to mixtures

of the endo/exo (>98/2) adducts 32a-b/33a-b. The stereo-

chemistry of the major isomer was established by NOE

experiments, revealing the spatial proximity and correlations

between the protons of the Me-8b methyl group and the H-8a

and H-5β protons.

These results suggest that dienes 16a and 17 are less reactive

than the exocyclic dienes 5, which react with the same

dienophile at 0 °C for 1 h.¹⁰This idea is also supported by the

fact that all attempts to achieve the cycloaddition of compound

17 with acrolein (18a) under thermal and Lewis acid-catalyzed

reaction conditions failed to give the corresponding adducts,

resulting in decomposition of the reaction mixture. Interest-

ingly, the energy of the HOMO is higher for diene 16a than for

5c (Table S1), implying a greater reactivity of the former. This

inconsistency may be due to the presence of the in methyl

group at C-5 in dienes 16a and 17, causing the depletion of

reactivity due to steric hindrance, which takes place by not only

perturbing the conformational s-cis/s-trans equilibrium (Figure

2) but also inhibiting the approach of the dienophile.^21,31Such

a destabilizing eﬀect is possibly involved in the observed high

endo diastereoselectivity as well, because the in methyl group

would sterically inhibit the exo addition of the dienophile.^21c

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a

Scheme 7. Diels−Alder Cycloadditions of Dienes 16a and 17 to N-Phenylmaleimide (6)

a

Structure determination of the endo adduct 32a by NOE correlations.

To assess the concertedness of the process, the M06-2X/6-

31+G(d,p) calculation was made to determine the stationary

points in the reaction coordinate for the cycloaddition of 16a

with 6. This calculation indicated a single concerted TS and the

absence of zwitterionic intermediates (Figures 6 and S54 −S59).

The TS was much more stable for the cycloaddition with the

endo than the exo approach (a diﬀerence of 3.80 kcal/mol),

which is in agreement with the observed experimental results.

We computed the synchronicity³²of the [4 + 2] cyclo-

additions between diene 16a and maleimide (6) to yield the

endo and exo cycloadducts 32a and 33a, respectively (details

can be found in the Supporting Information). Wiberg analysis³³

yielded the relevant B(A,B) bond indexes for the supra-

molecular complexes, transition structures, and products 32a or

33a, in relation to the endo and exo reaction coordinates,

respectively, within the NBO approximation (Figure 6).³⁴Six

sets of atom pairs (A,B) involved in the [4 + 2] cycloaddition

were considered, namely: (1,2), (2,3), (3,4), (4,5), (5,6), and

(1,6). Because the δB_avvalues for the endo and exo manifolds

are 0.39 and 0.42, we concluded that both [4 + 2]

cycloadditions occur via early transition structures, with the

endo route taking place through an earlier saddle point than that

associated with the exo reaction coordinate. According to the

values of synchronicity (Sy) of the endo-SC → endo-TS → 32a

and exo-SC → exo-TS → 33a [4 + 2] cycloadditions, both

reactions are very synchronous: Sy(endo) = 0.97 and Sy(exo) =

0.98.

We also investigated the origins of the endo selectivity

observed in this [4 + 2] cycloaddition. Obviously, the primary

orbital interactions (POIs) responsible for the formation of the

new C1−C2 and C5−C6 σ-bonds are essentially the same in

both exo and endo transition structures. However, in the endo-

TS, there are two stabilizing secondary orbital interactions

(SOIs)³⁵between the orbitals corresponding to the two CC

bonds of the diene and the two CO bonds of the maleimide

moiety. Natural bonding analysis (NBA) of the localized

natural orbitals associated with the diene−dienophile inter-

actions of endo-TS show two stabilizing π(CC) → π*(C

O) interactions, the associated second-order perturbational

energies of which represent a total stabilizing energy of ca. 4.8

kcal/mol (Figure 7). Because these SOIs are not possible in the

exo-TS, the endo reaction coordinate is less energetic than the

exo one, which is in agreement with the relative energies of

both saddle points and the preference for the endo cycloadducts

32a and b observed experimentally. This result is in line with

similar SOI eﬀects observed in [4 + 2] cycloadditions and other

pericyclic reactions,³⁶a topic that is still controversial.^8f,37

In summary, the DFT calculations indicate that the

nonassisted Diels−Alder reaction between diene 16a and N-

phenylmaleimide (6) occurs via early transition structures and

that it is highly synchronous. The experimentally observed endo

selectivity can be attributed to stabilizing secondary orbital

interactions.

Figure 6. Calculated [M06-2X/6-31+G(d,p)] relative ZPE-corrected

energies (kcal/mol) of the stationary points of the 16a/6 cyclo-

additions for the two possible approaches endo (blue) leading to 32a,

and exo (red) leading to 33a. SC = supramolecular complex. Numbers

in parentheses correspond to relative Gibbs energies (in kcal/mol)

computed at 298 K. B(A,B) are the Wiberg bond indexes (in au) in the

NBO basis between atoms A and B.

By determining the corresponding TS at the same level of

theory as employed previously (Figures S60 −S62), the

cycloaddition of diene 5a with 6 to aﬀord adduct 7a (Ar = R

I

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Figure 7. Second-order perturbational energies (ΔE(2), in kcal/mol) associated with two-electron interactions in the transition structure endo-TS.

POIs in the exo-TS leading to the new σ-bonds are highlighted in black. SOIs that contribute to the lower energy of the endo-TS are highlighted in

blue.

= Ph, Scheme 1)¹⁰was also found to be concerted. This

125 MHz) NMR spectra were recorded with TMS as internal

standard. Assignment of the NMR signals was made by HMQC and

HMBC 2D methods. Mass spectra (MS) and high-resolution mass

spectra (HRMS) were obtained in a double-focusing (magnetic and

electric) sector mass spectrometer operating in electron ionization

(EI) (70 eV) mode. Analytical thin-layer chromatography was carried

out using silica gel coated 0.25 plates, visualized by a long- and short-

supports the idea that the nonassisted Diels−Alder additions of

the N,N-disubstituted exo-2-imidazolidinone dienes 5, 12/13,

14−16, and 17 take place through a concerted process with

symmetrically polarized dienophiles such as 6, or even with

monosubstituted alkenes such as 18a. On the other hand, the

highly polarized, coordinated 18a-Lewis acid dienophiles prefer

a nonconcerted cycloaddition through a zwitterionic inter-

mediate, a reaction that takes place in a highly regioselective

process (at least in the case of ZnCl₂).

wavelength UV lamp. Flash column chromatography was performed

over silica gel (230−400 mesh). All air moisture sensitive reactions

were carried out under nitrogen in oven-dried glassware. MeOH and

toluene were freshly distilled over sodium, and methylene chloride

over calcium hydride, prior to use. Li₂CO₃was dried overnight at 200

°C prior to use. Triethylamine was freshly distilled from NaOH. All

other reagents were used without further puriﬁcation. The known

compounds 3a−c and 5h and i were prepared with the previously

reported methods.¹⁰

(E)-2-((4-Methoxyphenyl)imino)pentan-3-one (8). A mixture of 1b

(0.50 mL, 5.0 mmol) and 2c (0.615 g, 5.00 mmol) in MeOH (10 mL)

was stirred at room temperature for 24 h. The reaction crude was

concentrated under vacuum and puriﬁed by column chromatography

over silica gel (20 g/g of crude, hexane) to furnish 8 (0.60 g, 59%) as a

yellow oil. R_f0.58 (hexane/EtOAc, 8/2); IR (ﬁlm): ν_max1698, 1635,

1604, 1504, 926, 841 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 1.14 (t, J

= 7.5 Hz, 3H, CH₃CH₂), 2.02 (s, 3H, CH₃CO), 3.01 (q, J = 7.5 Hz,

2H, CH₃CH₂CO), 3.82 (s, 3H, CH₃O), 6.75−6.82 (m, 2H, H-2′),

6.88−6.95 (m, 2H, H-3′). ¹³C NMR (75.4 MHz, CDCl₃): δ 7.9

(CH₃CH₂), 14.3 (CH₃CO), 29.8 (CH₃CH₂), 55.4 (CH₃O), 114.2 (C-

3′), 121.1 (C-2′), 142.3 (C-1′), 157.1 (C-4′), 165.1 (C-2), 203.1 (C-

3). HRMS (EI): m/z [M⁺] Calcd for C₁₂H₁₅NO₂: 205.1103. Found:

205.1101.

General Method for the Preparation of Bis-Imines 10a−e. (E,E)-

N,N′-Diphenylbutane-2,3-diimine (10a). A mixture of 1a (0.989 g,

11.50 mmol) and 2a (2.14 g, 23.0 mmol) in MeOH (30 mL) was

stirred at room temperature for 24 h. The crude mixture was ﬁltered

and washed with MeOH (3 × 10 mL) and then dried under vacuum to

aﬀord 10a (2.1 g, 78%) as a yellow solid. R_f0.72 (hexane/EtOAc, 8/

2); mp 135−136 °C [Lit.¹⁴137−139 °C]. ¹H NMR (300 MHz,

CDCl₃): δ 2.15 (s, 6H, CH₃-1, CH₃-4), 6.75−6.83 (m, 4H, H-2′),

7.07−7.15 (m, 2H, H-4′), 7.33−7.41 (m, 4H, H-3′). ¹³C NMR (75.4

MHz, CDCl₃): δ 15.4 (2CH₃), 118.7 (4C-2′), 132.8 (2C-4′), 129.0

(4C-3′), 150.9 (2C-1′), 168.3 (C-2, C-3).

CONCLUSIONS

■

A new and eﬃcient method for preparing the symmetric exo-2-

imidazolidinone dienes 5a−e was developed, which was based

on the reaction of α-bis-imines 10a−e with triphosgene (9).

Although this method is limited to symmetrically substituted α-

bis-imines, the yields are better than those aﬀorded by the

previously reported method.¹⁰The same strategy was applied

to generate the novel alkylated isomeric dienes (E/Z)-12a−d/

13a−d and 14/15, the selectivity of which was controlled by

the reaction temperature. For example, the reaction at −10 °C

gave diene 12a exclusively, but at 0 °C or room temperature,

either a mixture of (E/Z)-12a−d/13a−d was provided or the

dienes underwent isomerization to the heterocyclic inner-outer-

ring dienes 16a and b and 17. Dienes (E/Z)-12/13 and 14/15

proved to be highly reactive and regioselective in Lewis acid-

catalyzed Diels−Alder cycloadditions with acrolein (18a) to

generate the corresponding ortho adducts as the major

regioisomers. According to the stationary points determined

for each of the reaction trajectories under study (M06-2X/6-

31+G(d,P)), the selectivity was kinetically controlled, paral-

leling the stability of the zwitterionic intermediates when the

dienophile was polarized by coordination with the catalyst

(ZnCl₂). The alkyl group on the dienic moiety appears to have

a signiﬁcant eﬀect on the electronic control of the process. In

contrast, the course of the cycloaddition under nonassisted

conditions maintained the expected concertedness for this

pericyclic reaction, as shown by the Diels−Alder additions of

diene 5a and isomeric dienes 16a and 17 with N-phenyl-

maleimide (6), and as supported by calculations of the

corresponding transition states and minima. The reactions for

the latter dienes were highly diastereoselective, producing only

the endo adducts 32a and b. Interestingly, these results evidence

the advantage of Diels−Alder cycloadditions of such dienes as a

novel and eﬃcient synthetic strategy for the preparation of

substituted benzimidazol-2-ones, which are important targets in

the design of potential pharmacological agents

(E,E)-N,N′-bis(p-Tolylbutane)-2,3-diimine (10b). The procedure

for the preparation of 10a was followed using a mixture of 1a (0.989 g,

11.50 mmol) and 2b (2.46 g, 23.0 mmol) in MeOH (30 mL) to

generate 10b (2.43 g, 80%) as a yellow solid. R_f0.77 (hexane/EtOAc,

8/2); mp 108−109 °C [Lit.¹⁸110.2−111.6 °C]. ¹H NMR (500 MHz,

CDCl₃): δ 2.15 (s, 6H, 2CH₃), 2.35 (s, 6H, 2Ar−CH₃), 6.68−6.71 (m,

4H, H-2′), 7.15−7.19 (m, 4H, H-3′). ¹³C NMR (125 MHz, CDCl₃): δ

15.4 (2CH₃), 20.9 (2Ar−CH₃), 118.8 (4C-2′), 129.5 (4C-3′), 133.2

(2C-4′), 148.3 (2C-1′), 168.3 (C-2, C-3).

(E,E)-N,N′-bis(4-Methoxyphenyl)butane-2,3-diimine (10c). The

procedure for the preparation of 10a was followed using a mixture

of 1a (0.989 g, 11.50 mmol) and 2c (2.83 g, 23.0 mmol) in MeOH

(30 mL) to provide 10c (3.0 g, 88%) as a yellow solid. R_f0.50

(hexane/EtOAc, 8/2); mp 173−174 °C [Lit.¹⁴185−186 °C; Lit.¹⁵

170 °C]. ¹H NMR (300 MHz, CDCl₃): δ 2.18 (s, 6H, 2CH₃), 3.82 (s,

EXPERIMENTAL SECTION

■

General. Melting points were determined with a capillary melting

point apparatus. H (300, 400, or 500 MHz) and ¹³C (75.4, 101, or

6H, 2CH₃O), 6.73−6.80 (m, 4H, H-2′), 6.89−6.96 (m, 4H, H-3′). ¹³

C

1

J

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

NMR (75.4 MHz, CDCl₃): δ 15.4 (2CH₃), 55.4 (2CH₃O), 114.2 (4C-

3′), 120.6 (4C-2′), 144.0 (2C-1′), 156.3 (2C-4′), 168.5 (C-2, C-3).

(E,E)-N,N′-Bis(4-chlorophenyl)butane-2,3-diimine (10d). The pro-

cedure for the preparation of 10a was followed using a mixture of 1a

(0.495 g, 5.75 mmol) and 2d (1.47 g, 11.5 mmol) in MeOH (15 mL)

to produce 10d (0.70 g, 40%) as a yellow solid. R_f0.77 (hexane/

as a white solid. R_f0.51 (hexane/EtOAc, 8/2); mp 76−77 °C [Lit.¹⁰

75−76 °C]. IR (KBr): ν_max1712, 1600, 1541, 1499, 1068, 756 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ 4.37 (d, J = 2.4 Hz, 2H, H-6, H-7),

4.82 (d, J = 2.4 Hz, 2H, H-6, H-7), 7.34−7.45 (m, 6H, Ph-H), 7.46−

7.52 (m, 4H, Ph-H). ¹³C NMR (75.4 MHz, CDCl₃): δ 82.9 (C-6, C-

7), 127.5 (C-2′), 127.9 (C-4′), 129.4 (C-3′), 134.2 (C-1′), 140.0 (C-4,

C-5), 153.5 (C-2).

EtOAc, 8/2); mp 175−176 °C [Lit.¹⁸172.4−173.8 °C]. H NMR

1

(300 MHz, CDCl₃): δ 2.13 (s, 6H, 2CH₃), 6.69−6.75 (m, 4H, H-2′),

7.31−7.37 (m, 4H, H-3′). ¹³C NMR (75.4 MHz, CDCl₃): δ 15.7 (C-1,

C-4), 120.5 (4C-2′), 129.4 (4C-3′), 129.5 (2C-4′), 149.5 (2C-1′),

169.0 (C-2, C-3).

4,5-Dimethylene-1,3-bis(4-tolyl)imidazolidin-2-one (5b). The pro-

cedure for the preparation of 5a was followed using a mixture of 10b

(0.200 g, 0.76 mmol), Et₃N (0.230 g, 2.28 mmol), and 9 (0.338 g, 1.14

mmol) in anhydrous toluene (40 mL) to provide 5b (0.17 g, 78%) as a

white solid. R_f0.54 (hexane/EtOAc, 8/2); mp 118−120 °C [Lit.¹⁰

119−120 °C]. ¹H NMR (300 MHz, CDCl₃): δ 2.39 (s, 6H, Ar−CH₃),

4.30 (d, J = 2.3 Hz, 2H, H-6, H-7), 4.78 (d, J = 2.3 Hz, 2H, H-6, H-7),

7.27 (s, 8H, Ar−H). ¹³C NMR (75.4 MHz, CDCl₃): δ 21.2 (Ar-CH₃),

82.6 (C-6, C-7), 127.4 (C-2′), 130.0 (C-3′), 131.6 (C-1′), 137.8 (C-

4′), 140.3 (C-4, C-5), 153.7 (C-2).

(E,E)-N,N′-Di(naphthalen-2-yl)butane-2,3-diimine (10e).³⁸The

procedure for the preparation of 10a was followed using a mixture

of 1a (0.989 g, 11.50 mmol) and 2e (3.29 g, 23.0 mmol) in MeOH

(30 mL) to obtain 10e (3.33 g, 86%) as a yellow solid. R_f0.92

(hexane/EtOAc, 8/2); mp 183−185 °C. ¹H NMR (300 MHz,

CDCl₃): δ 2.25 (s, 6H, 2CH₃), 7.05 (dd, J = 8.4, 2.1 Hz, 2H, H-3′),

7.19 (d, J = 2.1 Hz, 1H, H-1′), 7.42 (ddd, J = 8.4, 6.6, 1.2 Hz, 2H, H-

6′), 7.49 (ddd, J = 8.4, 6.6, 1.2 Hz, 2H, H-7′), 7.82 (br d, J = 8.4 Hz,

2H, H-8′), 7.83 (br d, J = 8.4 Hz, 2H, H-5′), 7.87 (d, J = 8.4 Hz, 2H,

H-4′). ¹³C NMR (75.4 MHz, CDCl₃): δ 15.7 (C-1, C-4), 114.7 (2C-

1′), 120.0 (2C-3′), 124.7 (2C-6′), 126.4 (2C-7′), 127.4 (2C-8′), 127.8

(2C-5′), 128.9 (2C-4′), 130.7 (2C-4a′), 133.9 (2C-8a′), 148.6 (2C-

2′), 168.7 (C-2, C-3).

1,3-Bis(4-methoxyphenyl)-4,5-dimethyleneimidazolidin-2-one

(5c). The procedure for the preparation of 5a was followed using a

mixture of 10c (0.201 g, 0.68 mmol), Et₃N (0.206 g, 2.04 mmol), and

9 (0.303 g, 1.02 mmol) in anhydrous toluene (40 mL) to aﬀord 5c

(0.217 g, 99%) as a white solid. R_f10.25 (hexane/EtOAc, 8/2); mp

161−162 °C [Lit.¹⁰160−161 °C]. H NMR (500 MHz, CDCl₃): δ

3.83 (s, 6H, CH₃O), 4.26 (d, J = 2.1 Hz, 2H, H-6, H-7), 4.77 (d, J =

2.1 Hz, 2H, H-6, H-7), 6.95−7.02 (m, 4H, H-3′), 7.25−7.33 (m, 4H,

H-2′). ¹³C NMR (125 MHz, CDCl₃): δ 55.4 (CH₃O), 82.6 (C-6, C-

7), 114.7 (C-3′), 126.8 (C-1′), 128.9 (C-2′), 140.6 (C-4, C-5), 154.0

(C-2), 159.1 (C-4′).

General Method for the Preparation of Nonsymmetric Bis-Imines

11a and b. (E,E)-N,N′-Bis(4-methoxyphenyl)pentane-2,3-diimine

(11a). A mixture of 2c (2.36 g, 19.2 mmol) and p-toluenesulfonic

acid (0.18 g, 0.96 mmol) was ground in a mortar to obtain a ﬁne

homogeneous powder, then 1b (0.96 g, 9.6 mmol) was added and

ground for 40 min until the formation of a brown semisolid. MeOH

(20 mL) was added; the crude mixture was ﬁltered, and then the solid

washed with cold MeOH (3 × 10 mL) to give 11a (1.64 g, 55%) as a

yellow solid; R_f0.54 (hexane/EtOAc, 8/2); mp 84−85 °C. IR (ﬁlm):

1,3-Bis(4-chlorophenyl)-4,5-dimethyleneimidazolidin-2-one (5d).

The procedure for the preparation of 5a was followed using a mixture

of 10d (0.100 g, 0.33 mmol), Et₃N (0.100 g, 0.99 mmol) and 9 (0.149

g, 0.5 mmol) in anhydrous toluene (25 mL) to generate 5d (0.093 g,

85%) as a white solid. R_f0.54 (hexane/EtOAc, 8/2); mp 164−165 °C

[Lit.¹⁰162−163 °C]. ¹H NMR (300 MHz, CDCl₃): δ 4.36 (d, J = 2.5

Hz, 2H, H-6, H-7), 4.84 (d, J = 2.5 Hz, 2H, H-6, H-7), 7.32−7.37 (m,

4H, H-2′), 7.44−7.49 (m, 4H, H-3′). ¹³C NMR (75.4 MHz, CDCl₃):

δ 83.5 (C-6, C-7), 128.8 (C-3′), 129.7 (C-2′), 132.6 (C-4′), 133.8 (C-

1′), 139.5 (C-4, C-5), 153.1 (C-2).

4,5-Dimethylene-1,3-di(naphthalen-2-yl)imidazolidin-2-one (5e).

The procedure for the preparation of 5a was followed using a mixture

of 10e (0.10 g, 0.3 mmol), Et₃N (0.091 g, 0.90 mmol) and 9 (0.134 g,

0.45 mmol) in anhydrous CH₂Cl₂(25 mL) to produce 5e (0.076 g,

70%) as a white solid. R_f0.62 (hexane/EtOAc, 7/3); mp 169−170 °C.

IR (ﬁlm): ν_max1698, 1626, 1599, 1508, 1472, 856, 812 cm⁻¹. ¹H NMR

(400 MHz, CDCl₃): δ 4.45 (d, J = 2.1 Hz, 2H, CH₂), 4.89 (d, J =

2.1 Hz, 2H, CH₂), 7.51−7.57 (m, 6H, ArH′), 7.86−7.92 (m, 4H,

ArH′), 7.94 (br s, 2H, H-1′), 7.96 (d, J = 8.4 Hz, 2H, H-4′). ¹³C NMR

(101 MHz, CDCl₃): δ 83.2 (2CH₂), 125.1 (2C-3′), 126.5 (2ArH′),

126.6 (2ArH′), 126.6 (2ArH′), 127.8 (2ArH′), 128.0 (2ArH′), 129.4

(2C-4′), 131.7 (2C-8a′), 132.6 (2C-4a′), 133.7 (2C-2′), 140.2 (C-4,

C-5), 153.8 (C-2). MS (70 eV): m/z 362 (M⁺, 64), 361 (45), 228

(88), 193 (100), 169 (50), 167 (70), 143 (62), 115 (30), 75 (32).

HRMS (EI): m/z [M⁺] calcd for C₂₅H₁₈N₂O: 362.1419. Found:

362.1435.

1

ν_max1636, 1504, 1466, 1456, 1033, 841 cm⁻¹. H NMR (300 MHz,

CDCl₃): δ 1.10 (t, J = 7.5 Hz, 3H, CH₃CH₂), 2.15 (s, 3H, H-1), 2.67

(q, J = 7.5 Hz, 2H, CH₃CH₂), 3.82 (s, 3H, CH₃O), 3.83 (s, 3H,

CH₃O), 6.71−6.80 (m, 4H, H-2′, H-2″), 6.88−6.96 (m, 4H, H-3′, H-

3″). ¹³C NMR (75.4 MHz, CDCl₃): δ 13.0 (CH₃CH₂), 15.8 (C-1),

21.6 (CH₃CH₂), 55.4 (CH₃O), 55.5 (CH₃O), 141.1 (C-3′ or C-3″),

114.2 (C-3″ or C-3′), 119.9 (C-2′ or C-2″), 120.5 (C-2″ or C-2′),

144.0 (2C-1′, C-1″), 156.1 (C-4′ or C-4″), 156.3 (C-4″ or C-4′),

167.2 (C-2), 173.3 (C-3). MS (70 eV): m/z 310 (M⁺, 48), 309 (19),

295 (64), 162 (100), 148 (62), 134 (14), 77 (26). HRMS (EI): m/z

[M⁺] calcd for C₁₉H₂₂N₂O₂: 310.1681. Found: 310.1690.

(E,E)-N,N′-Bis(4-methoxyphenyl)hexane-2,3-diimine (11b). The

procedure for the preparation of 11a was followed using a mixture

of 2c (1.00 g, 8.2 mmol), p-toluenesulfonic acid (0.16 g, 0.82 mmol),

and 1c (0.467 g, 4.10 mmol) to give 11b (0.67 g, 50%) as a yellow

solid; R_f0.86 (hexane/EtOAc, 7/3); mp 72−73 °C. IR (ﬁlm): ν_max

1631, 1497, 1462, 1034, 842, 754 cm⁻¹. ¹H NMR (300 MHz, CDCl₃):

δ 0.84 (t, J = 7.5 Hz, 3H, H-6), 1.55 (sext, J = 7.5 Hz, 2H, H-5), 2.15

(s, 3H, H-1), 2.60−2.68 (m, 2H, H-4), 3.82 (s, 6H, CH₃O), 6.70−6.81

(m, 4H, H-2′, H-2″), 6.88−6.96 (m, 4H, H-3′, H-3″). ¹³C NMR (75.4

MHz, CDCl₃): δ 14.3 (C-6), 15.7 (C-1), 21.6 (C-5), 30.1 (C-4), 55.3

(CH₃O) 55.4 (CH₃O), 114.0 (C-3′ or C-3″), 114.1 (C-3″ or C-3′),

119.9 (C-2′ or C-2″), 120.4 (C-2″ or C-2′), 144.0 (C-1′, C-1″), 156.0

(C-4′ or C-4″), 156.3 (C-4″ or C-4′), 167.5 (C-2), 172.3 (C-3).

HRMS (EI): m/z [M⁺] calcd for C₂₀H₂₄N₂O₂: 324.1838. Found:

324.1830.

General Method for the Preparation of Imidazolidin-2-one

Dienes 5a−e from Bis-Imines. 4,5-Dimethylene-1,3-diphenylimida-

zolidin-2-one (5a). After a mixture of 10a (0.100 g, 0.42 mmol) in 25

mL of anhydrous toluene was stirred at 0 °C under N₂atmosphere,

Et₃N (0.127 g, 1.26 mmol) was added. Then, 9 (0.187 g, 0.63 mmol)

dissolved in 5 mL of anhydrous toluene was added dropwise and

stirred at 0 °C for 3 h. The crude mixture was washed with a 1.0 M

aqueous solution of NaOH (3 × 20 mL); the organic layer was dried

(Na₂SO₄), and the solvent removed under vacuum. The crude puriﬁed

by column chromatography over silica gel treated with Et₃N (10% w/

w) (10 g/g of crude, hexane/EtOAc, 9/1) to furnish 5a (0.090 g, 81%)

1-(4-Methoxyphenyl)-4,5-dimethylene-3-phenylimidazolidin-2-

one (5f). A mixture of 3a (0.659 g, 6.53 mmol), Et₃N (0.932 g, 7.83

mmol), and Li₂CO₃(1.93 g, 26.1 mmol) in anhydrous toluene (60

mL) was stirred at 20 °C under N₂atmosphere for 90 min in the dark.

Subsequently, 4d (0.932 g, 7.83 mmol) dissolved in anhydrous toluene

(15 mL) was added dropwise, and the mixture stirred at room

temperature for 24 h. The crude mixture was ﬁltered over Celite/silica

gel (1/1) and washed with CH₂Cl₂(3 × 20 mL). The solvent was

removed under vacuum, and the reaction crude puriﬁed by column

chromatography over silica gel treated with Et₃N (10% w/w) (10 g/g

of crude, hexane/EtOAc, 9/1) to give 5f (0.62 g, 82%) as a white solid.

R_f0.22 (hexane/EtOAc, 8/2); mp 168−169 °C. IR (KBr): ν_max1718,

1

1631, 1514, 1037, 843, 754 cm⁻¹. H NMR (300 MHz, CDCl₃): δ

3.84 (s, 3H, CH₃O), 4.27 (d, J = 2.7 Hz, 1H, H-7), 4.35 (d, J = 2.7 Hz,

1H, H-6), 4.78 (d, J = 2.7 Hz, 1H, H-7), 4.80 (d, J = 2.7 Hz, 1H, H-6),

6.97−7.02 (m, 2H, H-3′), 7.28−7.33 (m, 2H, H-2′), 7.33−7.43 (m,

K

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The Journal of Organic Chemistry

Article

3H, H-2″, H-4″), 7.45−7.52 (m, 2H, H-3″). ¹³C NMR (75.4 MHz,

CDCl₃): δ 55.5 (CH₃O), 82.6 (C-6 or C-7), 82.8 (C-7 or C-6), 114.7

(C-3′), 126.8 (C-1′), 127.5 (C-2″), 127.8 (C-4″), 128.9 (C-2′), 129.4

(C-3″), 134.3 (C-1″), 140.0 (C-4 or C-5), 140.5 (C-5 or C-4), 153.7

(C-2), 159.0 (C-4′). HRMS (EI): m/z [M⁺] calcd for C₁₈H₁₆N₂O₂:

292.1212. Found: 292.1210.

1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dimethyleneimida-

zolidin-2-one (5g). The procedure for the preparation of 5f was

followed using a mixture of 3b (0.300 g, 1.57 mmol), Et₃N (0.40 g,

3.96 mmol), Li₂CO₃(1.16 g, 15.7 mmol), and 4b (0.72 g, 4.70 mmol)

to obtain 5g (0.33 g, 65%) as a white solid. R_f0.52 (hexane/EtOAc, 8/

2); mp 180−181 °C. IR (ﬁlm): ν_max1714, 1631, 1514, 1038, 823 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ 3.83 (s, 3H, CH₃O), 4.27 (d, J = 2.4

Hz, 1H, H-6), 4.34 (d, J = 2.6 Hz, 1H, H-7), 4.79 (d, J = 2.4 Hz, 1H,

H-6), 4.82 (d, J = 2.6 Hz, 1H, H-7), 6.96−7.03 (m, 2H, H-3″), 7.26−

7.32 (m, 2H, H-2″), 7.32−7.38 (m, 2H, H-2′), 7.41−7.48 (m, 2H, H-

3′). ¹³C NMR (75.4 MHz, CDCl₃): δ 55.5 (CH₃O), 82.9 (C-7), 83.1

(C-6), 114.8 (C-3″), 126.5 (C-1″), 128.8 (C-2′), 128.9 (C-2″), 129.6

(C-3′), 132.8 (C-1′), 133.5 (C-4′), 139.7 (C-5), 140.3 (C-4), 159.1

(C-2), 159.2 (C-4″). HRMS (EI): m/z [M⁺] calcd for C₁₈H₁₅N₂O₂Cl:

326.0822. Found: 326.0818.

(E)-4-Ethylidene-1,3-bis(4-methoxyphenyl)-5-(methylene)-

imidazolidin-2-one (12a) and (Z)-4-Ethylidene-1,3-bis(4-methoxy-

phenyl)-5-methyleneimidazolidin-2-one (13a). Method A: To a

stirring solution of 11a (0.100 g, 0.32 mmol) in anhydrous toluene (60

mL) at 0 °C under N₂atmosphere, Et₃N (0.097 g, 0.96 mmol) was

added, and then 9 (0.143 g, 0.48 mmol) in anhydrous toluene (5 mL)

was added dropwise. The reaction mixture was stirred at 0 °C for 4 h.

The crude was dissolved in CH₂Cl₂(50 mL) and washed with NaOH

1 M (3 × 50 mL). The organic layer was dried (Na₂SO₄),

concentrated under vacuum, and puriﬁed by column chromatography

over silica gel treated with Et₃N (10% w/w) (10 g/g of crude, hexane/

EtOAc, 9/1) to provide a mixture of 12a/13a (59/41) (0.095 g, 88%)

as a white solid.

Method B: To a stirring solution of 12a (0.050 g, 0.97 mmol) in

anhydrous CH₂Cl₂(5 mL) at −78 °C under N₂atmosphere, AlCl₃(1

M in diethyl ether) (0.005 g, 0.04 mmol) was added dropwise, and the

mixture was stirred for 30 min. Then, it was washed with an aqueous

saturated solution of Na₂CO₃(3 × 10 mL); the organic layer was dried

(Na₂SO₄), and the solvent concentrated under vacuum. The crude was

puriﬁed by column chromatography over silica gel treated with Et₃N

(10% w/w) (10 g/g of crude, hexane/EtOAc, 9/1) to obtain 16a

(0.035 g, 70%) as a brown solid. R_f0.11 (hexane/EtOAc, 1/1); mp

1

166−167 °C. IR (ﬁlm): ν_max1698, 1512, 1031, 831 cm⁻¹. H NMR

(300 MHz, CDCl₃): δ 2.06 (s, 3H, CH₃-C4), 3.829 (s, 3H, CH₃O),

3.834 (s, 3H, CH₃O), 4.85 (dd, J = 17.7, 0.6 Hz, 1H, CH₂), 5.01

(dd, J = 12.0, 0.6 Hz, 1H, CH₂), 6.22 (dd, J = 17.7, 12.0 Hz, 1H,

CH), 6.92−7.01 (m, 4H, H-3′, H-3″), 7.23−7.32 (m, 4H, H-2′, H-

2″). ¹³C NMR (75.4 MHz, CDCl₃): δ 10.5 (CH₃−C4), 55.4 (CH₃O),

55.5 (CH₃O), 113.4 (CH₂), 114.2 (C-3′ or C-3″), 114.4 (C-3″ or

C-3′), 118.1 (C-5), 118.9 (C-4), 123.3 (CH), 127.5 (C-1′ or C-1″),

128.4 (C-1′ or C-1″), 128.90 (C-2′ or C-2″), 128.92 (C-2′ or C-2″),

152.6 (C-2), 158.8 (C-4′ or C-4″), 159.0 (C-4″ or C-4′). HRMS (EI):

m/z [M⁺] calcd for C₂₀H₂₀N₂O₃: 336.1474. Found: 336.1482.

(E)-1,3-Bis(4-methoxyphenyl)-4-(methylene)-5-propylideneimida-

zolidin-2-one (14) and (Z)-1,3-Bis(4-methoxyphenyl)-4-methylene-

5-propylideneimidazolidin-2-one (15). Following method A for the

preparation of 12a/13a, a mixture of 11b (0.100 g, 0.31 mmol), Et₃N

(0.094 g, 0.93 mmol), and 9 (0.101 g, 0.34 mmol) in anhydrous

toluene (60 mL) was stirred at 0 °C for 4 h to produce a mixture of

14/15 (42/58) (0.085 g, 78%) as a white oil; R_f0.57 (hexane/EtOAc,

1

1/1). IR (ﬁlm): ν_max1682, 1509, 1027, 830 cm⁻¹. H NMR (300

MHz, CDCl₃): δ 0.82 (t, J = 7.5 Hz, 3H, CH₃CH₂), 1.50−1.63 (m,

2H, CH₃CH₂), 3.84 (s, 6H, CH₃O), 4.05 (d, J = 2.4 Hz, 1H, CH₂),

4.57 (d, J = 2.4 Hz, 1H, CH₂), 5.18 (t, J = 7.5 Hz, 1H, CH),

6.91−7.02 (m, 4H, H-3′, H-3″), 7.23−7.32 (m, 4H, H-2′, H-2″). ¹³C

NMR (75.4 MHz, CDCl₃): δ 14.4 (CH₃CH₂), 19.1 (CH₃CH₂), 55.4

(2CH₃O), 79.3 (CH₂), 103.7 (CH), 114.1 (C-3′ or C-3″), 114.5

(C-3″ or C-3′), 127.1 (C-1′ or C-1″), 128.9 (C-2′ or C-3″), 129.2 (C-

1″ or C-1′), 129.4 (C-2″ or C-2′), 131.1 (C-4), 142.0 (C-5), 153.8 (C-

2), 158.8 (C-4′ or C-4″), 159.0 (C-4″ or C-4′). Signals attributed to

the minor isomer 14: ¹H NMR (300 MHz, CDCl₃): δ 1.06 (t, J = 7.5

Hz, CH₃CH₂), 2.22−2.35 (m, 2H, CH₃CH₂), 3.83 (s, CH₃O), 4.43 (d,

J = 1.8 Hz, CH₂), 4.59 (d, J = 1.8 Hz, CH₂), 4.84 (t, J = 6.9 Hz,

CH). ¹³C NMR (75.4 MHz, CDCl₃): δ 14.1 (CH₃CH₂), 20.8

(CH₃CH₂), 87.6 (CH₂), 108.1 (CH), 114.65 (C-3′ or C-3″),

114.68 (C-3″ or C-3′), 126.7 (C-1′ or C-1″), 126.8 (C-1″ or C-1′),

129.3 (C-2′ or C-2″), 129.7 (C-2″ or C-2′), 132.2 (C-4), 140.7 (C-5),

153.8 (C-2), 158.9 (C-4′, C-4″). HRMS (EI): m/z [M⁺] calcd for

C₂₁H₂₂N₂O₃: 350.1631. Found: 350.1632.

(E)-1,3-Bis(4-methoxyphenyl)-4-methyl-5-(prop-1-en-1-yl)-1,3-di-

hydro-2H-imidazol-2-one (17). Following method A for the

preparation of 16a, a mixture of 11b (0.200 g, 0.62 mmol), Et₃N

(0.188 g, 1.86 mmol), and 9 (0.220 g, 0.74 mmol) in anhydrous

toluene (60 mL) was stirred at 20 °C for 1 h to give 17 (0.152 g, 70%)

as a brown solid. R_f0.22 (hexane/EtOAc, 8/2); mp 132−133 °C. IR

(ﬁlm): ν_max1697, 1512, 1030, 831 cm⁻¹. ¹H NMR (300 MHz,

CDCl₃): δ 1.73 (dd, J = 6.6, 1.2 Hz, 3H, CH₃CH), 2.02 (s, 3H,

CH₃-C4), 3.82 (s, 3H, CH₃O), 3.83 (s, 3H, CH₃O), 5.46 (dq, J = 16.0,

6.6 Hz, 1H, CH₃CH), 5.86 (dd, J = 16.0, 1.5 Hz, 1H, CH), 6.91−

7.00 (m, 4H, H-3′, H-3″), 7.23−7.31 (m, 4H, H-2′, H-2″). ¹³C NMR

(75.4 MHz, CDCl₃): δ 10.5 (CH₃−C4), 19.0 (CH₃CH), 55.3

(CH₃O), 55.4 (CH₃O), 114.1 (C-3′ or C-3″), 114.3 (C-3″ or C-3′),

116.7 (C-4), 117.7 (CH), 118.1 (C-5), 126.7 (CH₃CH), 127.6

(C-1′ or C-1″), 128.4 (C-1″ or C-1′), 128.81 (C-2′ or C-2″), 128.83

(C-2″ or C-2′), 152.4 (C-2), 158.6 (C-4′ or C-4″), 158.9 (C-4″ or C-

4′). HRMS (EI): m/z [M⁺] calcd for C₂₁H₂₂N₂O₃: 350.1631. Found:

350.1633.

Method B: To a stirring solution of 11a (0.100 g, 0.32 mmol) in

anhydrous toluene (60 mL) at −10 °C under N₂atmosphere, Et₃N

(0.097 g, 0.96 mmol) was added, and then 9 (0.143 g, 0.48 mmol) in

anhydrous toluene (5 mL) was added dropwise. The reaction mixture

was stirred at −10 °C for 4 h. The crude was dissolved in CH₂Cl₂(50

mL) and washed with a 1.0 M aqueous solution of NaOH (3 × 50

mL). The organic layer was dried (Na₂SO₄), concentrated under

vacuum, and puriﬁed by column chromatography over silica gel treated

with Et₃N (10% w/w) (10 g/g of crude, hexane/EtOAc, 9/1) to

deliver 12a (0.095 g, 88%) as a white solid. R_f0.53 (hexane/EtOAc, 1/

1); mp 144−145 °C. IR (KBr): ν_max1730, 1608, 1512, 1031, 830

cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 1.85 (d, J = 7.8 Hz, 3H,

CH₃C), 3.83 (s, 3H, CH₃O), 3.84 (s, 3H, CH₃O), 4.45 (d, J = 2.1

Hz, 1H, CH₂), 4.60 (d, J = 2.1 Hz, 1H, CH₂), 5.00 (q, J = 7.8 Hz,

1H, CH), 6.94−7.03 (m, 4H, H-3′, H-3″), 7.22−7.33 (m, 4H, H-2′,

H-2″). ¹³C NMR (75.4 MHz, CDCl₃): δ 13.0 (CH₃C), 55.4

(CH₃O), 87.8 (CH₂), 100.0 (CH), 114.70 (C-3′ or C-3″), 114.75

(C-3″ or C-3′), 126.8 (C-1′ or C-1″), 126.9 (C-1″ or C-1′), 129.4 (C-

2′ or C-2″), 129.7 (C-2″ or C-2′), 134.5 (C-4), 140.9 (C-5), 153.8 (C-

2), 159.00 (C-4′ or C-4″), 159.05 (C-4″ or C-4′). Signals attributed to

1

minor isomer 13a: H NMR (300 MHz, CDCl₃): δ 1.24 (d, J = 7.5

Hz, CH₃C), 3.82 (s, CH₃O), 4.04 (d, J = 2.1 Hz, CH₂), 4.54 (d, J

= 2.1 Hz, CH₂), 5.31 (q, J = 7.5 Hz, CH). ¹³C NMR (75.4 MHz,

CDCl₃): δ 11.7 (CH₃CH), 79.2 (CH₂), 96.0 (CH), 114.1 (C-3′

or C-3″), 114.6 (C-3″ or C-3′), 127.1 (C-1′ or C-1″), 129.0 (C-2′ or

C-2″), 129.1 (C-1″ or C-1′), 129.6 (C-2″ or C-2′), 132.4 (C-4), 142.0

(C-5), 155.1 (C-2), 158.9 (C-4′ or C-4″), 159.0 (C-4″ or C-4′). MS

(70 eV): m/z 336 (M⁺, 4), 231 (12), 100 (100), 72 (54). Anal. Calcd

for C₂₀H₂₀N₂O₃: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.39; H, 5.99;

N, 8.38.

1,3-Bis(4-methoxyphenyl)-4-methyl-5-vinyl-1,3-dihydro-2H-imi-

dazol-2-one (16a). Method A: The procedure for the preparation of

12a/13a was followed using a mixture of 11a (0.300 g, 0.97 mmol),

Et₃N (0.294 g, 2.91 mmol), and 9 (0.431 g, 1.45 mmol) in anhydrous

toluene (60 mL) stirred at 20 °C for 1 h to give 16a (0.244 g, 75%) as

a brown solid.

General Method for the Preparation of Imidazolidin-2-one

Dienes 12b−d and 13b−d. (E)-4-Ethylidene-1-(4-methoxyphenyl)-

5-methylene-3-phenyl-5-imidazolidin-2-one (12b) and (Z)-4-Ethyl-

idene-1-(4-methoxyphenyl)-5-methylene-3-phenylimidazolidin-2-

one (13b). To a stirring mixture of 8 (0.500 g, 2.44 mmol), Li₂CO₃

(2.34 g, 31.7 mmol), and Et₃N (0.739 g, 7.32 mmol) in anhydrous

L

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Article

toluene (40 mL) at room temperature under N₂atmosphere was

added 4a (0.726 g, 6.10 mmol), and the reaction mixture was stirred

for 48 h. The crude was ﬁltered over Celite and washed with CH₂Cl₂

(2 × 25 mL), concentrated under vacuum, and puriﬁed by column

chromatography over silica gel treated with Et₃N (10% w/w) (10 g/g

of crude, hexane/EtOAc, 9/1) to give a mixture of 12b/13b (36/64)

(0.30 g, 40%) as a white solid. R_f0.55 (hexane/EtOAc, 7/3); mp 129−

mmol) and AlCl₃(1 M in diethyl ether) (0.005 g, 0.04 mmol) in

anhydrous CH₂Cl₂(5 mL) at −78 °C under N₂atmosphere was

stirred for 30 min to produce 16b (0.041 g, 78%) as a white solid; R_f

0.46 (hexane/EtOAc, 1/1); mp 116−118 °C. IR (ﬁlm): ν_max1700,

1

1515, 1495, 1401, 1250, 830 cm⁻¹. H NMR (400 MHz, CDCl₃): δ

2.05 (s, 3H, CH₃−C4), 3.83 (s, 3H, CH₃O), 4.90 (d, J = 17.8, 1H,

CH₂), 5.09 (d, J = 11.8, 1H, CH₂), 6.22 (dd, J = 17.8, 11.8 Hz,

1H, CH), 6.95−7.00 (m, 2H, H-3″), 7.24−7.28 (m, 2H, H-2″),

7.33−7.36 (m, 2H, H-3′), 7.40−7.43 (m, 2H, H-2′). ¹³C NMR (101

MHz, CDCl₃): δ 10.5 (CH₃−C4), 55.5 (CH₃O), 114.2 (CH₂),

114.5 (C-3″), 117.6 (C-4), 119.7 (C-5), 123.1 (CH), 127.1 (C-1″),

128.6 (C-3′), 128.9 (C-2″), 129.1 (C-2′), 133.0 (C-1′), 134.1 (C-4′),

152.2 (C-2), 159.2 (C-4″). HRMS (EI): m/z [M⁺] calcd for

C₁₉H₁₇ClN₂O₂: 340.0979. Found: 340.0977.

General Method for the Diels−Alder Cycloaddition of Imidazo-

lidin-2-ones. (4R*,5S*)-1,3-Bis(4-methoxyphenyl)-4-methyl-2-oxo-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(19a), (4R*,5R*)-1,3-Bis(4-methoxyphenyl)-4-methyl-2-oxo-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(20a), (5R*,7R*)-1,3-Bis(4-methoxyphenyl)-7-methyl-2-oxo-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(21a), and (5R*,7S*)-1,3-Bis(4-methoxyphenyl)-7-methyl-2-oxo-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(22a). Method A: To a solution of 12a (0.050 g, 0.15 mmol) in

anhydrous CH₂Cl₂(5 mL), at −78 °C and under N₂atmosphere, 18a

(0.025 g, 0.45 mmol) and ZnCl₂(1 M in diethyl ether) (0.005 g, 0.04

mmol) were added dropwise. The reaction mixture was stirred at the

same temperature for 2 h and then washed with an aqueous saturated

solution of Na₂CO₃(3 × 10 mL). The organic layer was dried

(Na₂SO₄) and concentrated under vacuum to generate a mixture with

a 98/2 ortho/meta ratio and the corresponding endo/exo ratios of 19a/

20a (83/17)/21a/22a (0.043 g, 74%) as a yellow oil.

Method B: To a mixture of 12a (0.050 g, 0.15 mmol) in anhydrous

CH₂Cl₂(5 mL) at −78 °C under N₂atmosphere, 18a (0.025 g, 0.45

mmol) and BF₃·OEt₂(0.0057 g, 0.04 mmol) were added dropwise,

followed by stirring at the same temperature for 2 h. The reaction

crude was washed with an aqueous saturated solution of Na₂CO₃(3 ×

10 mL), and then the organic layer was dried (Na₂SO₄) and

concentrated under vacuum to give a mixture with a 65/35 ortho/meta

ratio and the corresponding endo/exo ratios of 19a/20a (25/36)/21a/

22a (14/25) (0.042 g, 72%) as a yellow oil.

Data of the mixture of 19a/20a (83/17): R_f0.16 (hexane/EtOAc,

1/1). IR (ﬁlm): ν_max1698, 1513, 1407, 1030, 832 cm⁻¹. ¹H NMR (500

MHz, CDCl₃): δ 0.79 (d, J = 7.0 Hz, 3H, CH₃-C4), 1.77−1.89 (m, 1H,

H-6), 2.13−2.20 (m, 1H, H-6), 2.29−2.37 (m, 1H, H-7), 2.37−2.46

(m, 1H, H-7), 2.82 (ddd, J = 12.5, 5.0 Hz, 1H, H-5), 3.24−3.32 (m,

1H, H-4), 3.82 (s, 3H, CH₃O), 3.83 (s, 3H, CH₃O), 6.90−7.00 (m,

4H, H-3′, H-3″), 7.27−7.32 (m, 4H, H-2′, H-2″), 9.74 (s, 1H, CHO).

¹³C NMR (125 MHz, CDCl₃): δ 15.3 (CH₃−C4), 17.4 (C-6), 20.4

1

130 °C. IR (ﬁlm): ν_max1734, 1648, 1515, 1031, 754, 695 cm⁻¹. H

NMR (300 MHz, CDCl₃): δ 1.23 (d, J = 7.8 Hz, 3H, CH₃CH), 3.82

(s, 3H, CH₃O), 4.07 (d, J = 2.7 Hz, 1H, CH₂), 4.57 (d, J = 2.7 Hz,

1H, CH₂), 5.35 (q, J = 7.8 Hz, 1H, CH), 6.92−7.02 (m, 2H, H-

3′), 7.25−7.31 (m, 2H, H-2′), 7.34−7.48 (m, 5H, H-2″, H-3″, H-4″).

¹³C NMR (75.4 MHz, CDCl₃): δ 12.2 (CH₃CH), 55.4 (CH₃O), 79.4

(CH₂), 96.5 (CH₃CH), 114.6 (C-3′), 127.1 (C-1′), 127.7 (C-4″),

128.2 (C-2″), 128.8 (C-2′ or C-3″), 129.0 (C-3″ or C-2′), 132.2 (C-

4), 136.5 (C-1″), 142.0 (C-5), 154.9 (C-2), 159.0 (C-4′). Signals

1

attributed to the minor isomer 12b: H NMR (300 MHz, CDCl₃): δ

1.85 (d, J = 7.5 Hz, CH₃CH), 4.47 (d, J = 2.1 Hz, CH₂), 4.63 (d, J =

2.1 Hz, CH₂), 5.07 (q, J = 7.5 Hz, CH₃CH). HRMS (EI): m/z [M⁺]

calcd for C₁₉H₁₈N₂O₂: 306.1368. Found: 306.1357.

(E)-1-(4-Chlorophenyl)-5-ethylidene-3-(4-methoxyphenyl)-4-

(methylene)imidazolidin-2-one (12c) and (Z)-1-(4-Chlorophenyl)-5-

ethylidene-3-(4-methoxyphenyl)-4-(methylene)imidazolidin-2-one

(13c). The procedure for the preparation of 12b/13b was followed

using a mixture of 8 (0.187 g, 0.91 mmol), Li₂CO₃(0.96 g, 13.0

mmol), Et₃N (0.303 g, 3.00 mmol), and 4b (0.383 g, 2.50 mmol) in

anhydrous toluene (60 mL) to aﬀord a mixture of 12c/13c (57/43)

(0.22 g, 65%) as a white solid: R_f0.58 (hexane/EtOAc, 7/3); mp 135−

1

139 °C. IR (ﬁlm): ν_max1732, 1514, 1494, 1090, 829 cm⁻¹. H NMR

(300 MHz, CDCl₃): δ 1.86 (d, J = 7.8 Hz, 3H, CH₃CH), 3.84 (s, 3H,

CH₃O), 4.48 (d, J = 2.1 Hz, 1H, CH₂), 4.64 (d, J = 2.1 Hz, 1H,

CH₂), 5.08 (q, J = 7.8 Hz, 1H, CH₃CH), 6.94−7.03 (m, 2H, H-3″),

7.23−7.36 (m, 4H, H-2′, H-2″), 7.39−7.48 (m, 2H, H-3′). ¹³C NMR

(75.4 MHz, CDCl₃): δ 13.0 (CH₃CH), 55.5 (CH₃O), 88.5 (CH₂),

100.3 (CH₃CH), 114.8 (C-3″), 126.4 (C-1″), 129.4 (C-2″), 129.7 (C-

2′, C-3′), 132.9 (C-1′), 133.5 (C-4′), 133.8 (C-4), 140.6 (C-5), 153.4

1

(C-2), 159.2 (C-4″). Signals attributed to the minor isomer 13c: H

NMR (300 MHz, CDCl₃): δ 1.28 (d, J = 7.8 Hz, CH₃CH), 3.83 (s,

CH₃O), 4.07 (d, J = 2.4 Hz, CH₂), 4.58 (d, J = 2.4 Hz, CH₂),

5.37 (q, J = 7.8 Hz, CH₃CH). HRMS (EI): m/z [M⁺] calcd for

C₁₉H₁₇ClN₂O₂: 340.0979. Found: 340.0974.

(E)-4-Ethylidene-1-(4-methoxyphenyl)-5-methylene-3-(p-tolyl)-

imidazolidin-2-one (12d) and (Z)-4-Ethylidene-1-(4-methoxyphen-

yl)-5-methylene-3-(p-tolyl)imidazolidin-2-one (13d). The procedure

for the preparation of 12b/13b was followed using a mixture of 8

(0.495 g, 2.41 mmol), Li₂CO₃(2.32 g, 31.3 mmol), Et₃N (0.730 g,

7.23 mmol), and 4c (0.802 g, 6.03 mmol) in anhydrous toluene (60

mL) to give a mixture of 12d/13d (68/32) (0.417 g, 54%) as a white

solid. R_f0.75 (hexane/EtOAc, 7/3); mp 94−97 °C. IR (ﬁlm): ν_max

1

(C-7), 25.9 (C-4), 50.9 (C-5), 55.4 (CH₃O), 114.3 (C-3′ or C-3″),

114.6 (C-3′ or C-3″), 117.1 (C-7a), 121.1 (C-3a), 127.7 (C-2′ or C-

2″), 127.8 (C-1′ or C-1″), 128.5 (C-2′ or C-2″), 129.3 (C-1′ or C-1″),

152.8 (C-2), 158.6 (C-4′ or C-4″), 159.0 (C-4′ or C-4″), 202.8

1730, 1513, 1032, 825, 749 cm⁻¹. H NMR (300 MHz, CDCl₃): δ

1.85 (d, J = 7.8 Hz, 3H, CH₃CH), 2.38 (s, 3H, CH₃Ar), 3.82 (s, 3H,

CH₃O), 4.46 (d, J = 2.4 Hz, 1H, CH₂=), 4.60 (d, J = 2.4 Hz, 1H,

CH₂), 5.04 (q, J = 7.8 Hz, 1H, CH₃CH), 6.93−7.02 (m, 2H, H-3′),

7.19−7.32 (m, 6H, H-2′, H-2″, H-3″). ¹³C NMR (75.4 MHz, CDCl₃):

δ 13.0 (CH₃CH), 21.1 (ArCH₃), 55.38 (CH₃O), 87.8 (CH₂), 100.0

(CH₃CH), 114.7 (C-3′), 126.7 (C-1′), 128.2 (C-2′), 129.4 (C-2″),

130.1 (C-3″), 131.6 (C-1″), 134.3 (C-4), 137.8 (C-4″), 140.9 (C-5),

153.6 (C-2), 159.0 (C-4′). Signals attributed to the minor isomer 13d:

¹H NMR (300 MHz, CDCl₃): δ 1.23 (d, J = 7.8 Hz, CH₃CH), 3.81 (s,

CH₃O), 4.05 (d, J = 2.1 Hz, CH₂), 4.55 (d, J = 2.1 Hz, CH₂),

5.32 (q, J = 7.8 Hz, CH₃CH), 6.93−7.02 (m, 2H, H-2′), 7.20−7.32

(m, 6H, H-2″, H-3′, H-3″). ¹³C NMR (75.4 MHz, CDCl₃): δ 12.0

(CH₃CH), 22.6 (ArCH₃), 55.4 (CH₃O), 79.2 (CH₂), 96.2

(CH₃CH), 114.6 (C-3′), 127.1 (C-1′), 128.1 (C-2′), 129.0 (C-2″),

129.5 (C-3″), 132.2 (C-1″), 133.8 (C-4), 137.6 (C-4″), 142.0 (C-5),

155.0 (C-2), 158.9 (C-4′). HRMS (EI): m/z [M⁺] calcd for

C₂₀H₂₀N₂O₂: 320.1525. Found: 320.1510.

1

(CHO). Signals attributed to the minor stereoisomer 20a: H NMR

(500 MHz, CDCl₃): δ 0.85 (d, J = 6.5 Hz, CH₃-C4), 3.82 (s, CH₃O),

3.88 (s, CH₃O), 6.84−6.88 (m, H-3′, H-3a), 7.15−7.25 (m, H-2′, H-

2″), 9.70 (s, CHO). ¹³C NMR (75.4 MHz, CDCl₃): δ 17.1 (CH₃−

C4), 17.8 (C-6), 21.7 (C-7), 23.5 (C-4), 55.36 (CH₃O), 55.38

(CH₃O), 113.9 (C3′ or C3″), 127.6, 128.3, 129.6, 130.4, 130.9, 152.5

(C-2), 159.1, 159.3, 202.0 (CHO). HRMS (EI) m/z [M⁺] calcd for

C₂₃H₂₄N₂O₄: 392.1736. Found: 392.1723.

(4R*,5S*)-4-Ethyl-1,3-bis(4-methoxyphenyl)-2-oxo-2,3,4,5,6,7-

hexahydro-1H-benzo[d]imidazole-5-carbaldehyde (25a),

(4R*,5R*)-4-Ethyl-1,3-bis(4-methoxyphenyl)-2-oxo-2,3,4,5,6,7-hexa-

hydro-1H-benzo[d]imidazole-5-carbaldehyde (25b), (5R*,7R*)-7-

Ethyl-1,3-bis(4-methoxyphenyl)-2-oxo-2,3,4,5,6,7-hexahydro-1H-

benzo[d]imidazole-5-carbaldehyde (26a), and (5R*,7S*)-7-Ethyl-

1,3-bis(4-methoxyphenyl)-2-oxo-2,3,4,5,6,7-hexahydro-1H-benzo-

[d]imidazole-5-carbaldehyde (26b). The procedure for the prepara-

tion of 19a/20a was followed using a mixture of 14/15 (42/58)

(0.050 g, 0.14 mmol), 18a (0.020 g, 0.36 mmol), and ZnCl₂(1.0 M in

1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4-methyl-5-vinyl-1,3-

dihydro-2H-imidazol-2-one (16b). Following method B for the

preparation of 16a, a mixture of 12c/13c (57/43) (0.050 g, 0.15

M

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Article

diethyl ether) (0.0054 g, 0.04 mmol) in anhydrous CH₂Cl₂(5 mL) to

deliver a mixture with a 91/9 ortho/meta ratio and the corresponding

endo/exo ratios of 25a/25b (57/43)/26a/26b (0.055 g, 95%) as a

yellow oil. R_f0.18 (hexane/EtOAc, 1/1). IR (ﬁlm): ν_max1698, 1512,

1408, 1030, 831 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ 0.69 (t, J = 7.5

Hz, 3H, CH₃CH₂), 1.20−1.35 (m, 2H, CH₃CH₂), 2.16−2.27 (m, 2H,

H-6, H-7), 2.32−2.40 (m, 1H, H-7), 2.60−2.65 (m, 1H, H-5), 3.02−

3.07 (m, 1H, H-4), 3.81 (s, 3H, CH₃O), 3.84 (s, 3H, CH₃O), 6.91−

7.00 (m, 4H, H-3′, H-3″), 7.23−7.29 (m, 2H, H-2′ or H-2″), 7.30−

7.34 (m, 2H, H-2″ or H-2′), 9.74 (s, 1H, CHO). ¹³C NMR (125 MHz,

CDCl₃): δ 11.3 (CH₃CH₂), 18.4 (C-6), 19.0 (C-7), 25.1 (CH₃CH₂),

31.9 (C-4), 48.3 (C-5), 55.4 (CH₃O), 55.5 (CH₃O), 114.3 (C-3′ or C-

3″), 114.6 (C-3″ or C-3′), 117.3 (C-7a), 119.2 (C-3a), 127.7 (C-2′ or

C-2″), 128.1 (C-1′ or C-1″), 128.3 (C-2″ or C-2′), 152.9 (C-2), 158.6

(C-4′ or C-4″), 158.8 (C-4″ or C-4′), 203.0 (CHO). Signals attributed

CDCl₃): δ 0.88 (d, J = 6.9 Hz, CH₃-C4). ¹³C NMR (75.4 MHz,

CDCl₃): δ 114.4, 126.8, 128.9, 129.3, 129.8, 131.9, 132.4, 132.8.

HRMS (EI): m/z [M⁺] calcd for C₂₃H₂₄N₂O₃: 376.1787. Found:

376.1782.

General Method for the Aromatization of Adducts 19−22. 1,3-

Bis(4-methoxyphenyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-

imidazole-5-carbaldehyde (23a) and 1,3-Bis(4-methoxyphenyl)-7-

methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

(24a). Method A: To a mixture of 19a/20a (83/17)/21a/22a (0.044

g, 0.11 mmol) was added DDQ (0.064 g, 0.28 mmol) in CH₂Cl₂(5

mL), followed by stirring at room temperature for 24 h. The crude was

ﬁltered over Celite and silica gel to aﬀord a mixture of 23a/24a (98/2)

(0.035 g, 80%) as a brown solid.

Method B: The procedure for the preparation of 23a/24a was

followed using a mixture of 19a/20a (25/36)/21a/22a (14/25)

(0.044 g, 0.11 mmol), then adding DDQ (0.064 g, 0.28 mmol) in

CH₂Cl₂(5 mL) to furnish a mixture of 23a/24a (65/35) (0.037 g,

81%) as a brown solid.

1

to the minor stereoisomer 25b: H NMR (500 MHz, CDCl₃): δ 0.88

(t, J = 6.5 Hz, CH₃CH₂), 9.71 (s, 1H, CHO). ¹³C NMR (125 MHz,

CDCl₃): δ 14.1 (CH₃CH₂), 22.7 (CH₃CH₂), 29.7 (C-4). HRMS (EI):

m/z [M⁺] calcd for C₂₄H₂₆N₂O₄: 406.1893. Found: 406.1884.

Data of 23a/24a (98/2): R_f0.69 (hexane/EtOAc, 1/1); mp 86−88

1

°C. IR (ﬁlm): ν_max1723, 1684, 1512, 1027, 831 cm⁻¹. H NMR (500

(4R*,5S*)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-methyl-2-

oxo-2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(19b), (4S*,5S*)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-meth-

yl-2-oxo-2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbalde-

hyde (20b), (5R*,7R*)-1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-7-

methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-car-

baldehyde (21b), and (5R*,7S*)-1-(4-Chlorophenyl)-3-(4-methox-

yphenyl)-7-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-benzo[d]-

imidazole-5-carbaldehyde (22b). The procedure for the preparation

of 19a/20a was followed using a mixture of 12c/13c (57/43) (0.051

g, 0.15 mmol), 18a (0.021 g, 0.37 mmol), and ZnCl₂(1 M in diethyl

ether) (0.0054 g, 0.04 mmol) in anhydrous CH₂Cl₂(5 mL) to

produce a mixture with a 96/4 ortho/meta ratio and the corresponding

endo/exo ratios of 19b/20b (80/20)/21b/22b (0.043 g, 73%) as a

yellow oil. R_f0.36 (hexane/EtOAc, 1/1). IR (ﬁlm): ν_max1700, 1661,

1514, 1090, 830 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 0.76 (d, J = 6.9

Hz, 3H, CH₃-C4), 1.73−1.90 (m, 1H, H-6), 2.13−2.24 (m, 1H, H-6),

2.25−2.50 (m, 2H, H-7), 2.84 (ddd, J = 12.6, 4.8, 2.4 Hz, 1H, H-5),

3.20−3.37 (m, 1H, H-4), 3.80 (s, 3H, CH₃O), 6.85−7.03 (m, 2H, H-

3′), 7.14−7.50 (m, 6H, ArH), 9.73 (s, 1H, CHO). ¹³C NMR (75.4

MHz, CDCl₃): δ 15.2 (CH₃-4), 17.2 (C-6), 20.2 (C-7), 25.8 (C-4),

50.7 (C-5), 55.4 (CH₃O), 114.4 (C-3′), 118.4 (C-7a), 121.0 (C-3a),

127.4 (C-1′), 127.8 (C-2′), 128.4 (C-2″ or C-3″), 129.6 (C-3″ or C-

2″), 132.9 (C-4″), 133.7 (C-1″), 152.4 (C-2), 158.9 (C-4′), 202.5

(CHO). Signals attributed to the minor isomer 20b: ¹³C NMR (74.5

MHz, CDCl₃): δ 53.4, 114.5, 121.9, 126.8, 129.7. HRMS (EI): m/z

[M⁺] calcd for C₂₂H₂₁ClN₂O₃: 396.1241. Found: 396.1239.

MHz, CDCl₃): δ 2.24 (s, 3H, CH₃-C4), 3.87 (s, 3H, CH₃O), 3.88 (s,

3H, CH₃O), 7.00 (d, J = 8.3 Hz, 1H, H-7), 7.02−7.08 (m, 4H, H-3′,

H-3″), 7.35−7.38 (m, 2H, H-2′ or H-2″), 7.43−7.46 (m, 2H, H-2′ or

H-2″), 7.60 (d, J = 8.3 Hz, 1H, H-6), 10.16 (s, 1H, CHO). ¹³C NMR

(125 MHz, CDCl₃): δ 13.4 (CH₃−C4), 55.5 (CH₃O), 55.6 (CH₃O),

106.4 (C-7), 114.6 (C-3′ or C-3″), 114.9 (C-3″ or C-3′), 123.3 (C-4),

126.3 (C-1′ or C-1″), 127.9 (C-2′ or C-2″), 128.3 (C-6), 128.6 (C-3a

or C-1′), 128.7 (C-1′ or C-3a), 129.7 (C-5), 129.9 (C-2″ or C-2′),

134.8 (C-7a), 154.2 (C-2), 159.5 (C-4′ or C-4″), 159.9 (C-4″ or C-

4′), 191.8 (CHO). Signals attributed to the minor regioisomer 24a: ¹H

NMR (500 MHz, CDCl₃): δ 1.97 (s, CH₃−C7), 9.86 (s CHO). ¹³C

NMR (125 MHz, CDCl₃): δ 18.1 (CH₃−C7), 106.6 (C-7), 114.5 (C-

3′ or C-3″), 115.0 (C-3″ or C-3′), 120.3 (C-6), 127.8 (C-2′ or C-2″),

128.8 (C-1′ or C-1″), 129.2 (C-5), 130.3 (C-2′ or C-2″), 133.0 (C-

7a), 154.0 (C-2), 159.4 (C-4′ or C-4″), 160.1 (C-4″ or C-4′), 191.2

(CHO). HRMS (EI): m/z [M⁺] calcd for C₂₃H₂₀N₂O₄: 388.1423.

Found: 388.1404.

4-Ethyl-1,3-bis(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-benzo-

[d]imidazole-5-carbaldehyde (27a) and 7-Ethyl-1,3-bis(4-methox-

yphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

(27b). Following method A for the preparation of 23a/24a, a mixture

of 25a/25b (57/43)/26a/26b (0.053 g, 0.13 mmol) and DDQ (0.075

g, 0.33 mmol) in CH₂Cl₂(5 mL) provided a mixture of 27a/27b (91/

9) (0.045 g, 88%) as a brown solid. R_f0.66 (hexane/EtOAc, 1/1); mp

68−71 °C. IR (ﬁlm): ν_max1720, 1678, 1509, 1025, 803 cm⁻¹. ¹H NMR

(500 MHz, CDCl₃): δ 0.95 (t, J = 7.5 Hz, 3H, CH₃CH₂), 2.74 (q, J =

7.5 Hz, 2H, CH₃CH₂), 3.87 (s, 3H, CH₃O), 3.89 (s, 3H, CH₃O), 7.01

(d, J = 8.3 Hz, 1H, H-7), 7.02−7.10 (m, 4H, H-3′, H-3″), 7.37−7.48

(m, 4H, H-2′, H-2″), 7.65 (d, J = 8.3 Hz, 1H, H-6), 10.16 (s, 1H,

CHO). ¹³C NMR (125 MHz, CDCl₃): δ 16.2 (CH₃CH₂), 18.2

(CH₃CH₂), 55.53 (CH₃O), 55.55 (CH₃O), 106.6 (C-7), 114.8 (C-3′

or C-3″), 114.9 (C-3″ or C-3′), 126.2 (C-1′, C-1″), 127.9 (C-2′ or C-

2″), 128.0 (C-6), 128.4 (C-5 or C-3a), 128.7 (C-3a or C-5), 130.0 (C-

2″ or C-2′), 130.2 (C-4), 135.0 (C-7a), 154.3 (C-2), 159.4 (C-4′ or C-

4″), 160.1 (C-4″ or C-4′), 191.3 (CHO). Signals attributed to the

(4R*,5S*)-1-(4-Methoxyphenyl)-4-methyl-2-oxo-3-(p-tolyl)-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde (19c),

(4R*,5R*)-1-(4-Methoxyphenyl)-4-methyl-2-oxo-3-(p-tolyl)-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde (20c),

(5R*,7R*)-3-(4-Methoxyphenyl)-7-methyl-2-oxo-1-(p-tolyl)-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde (21c),

and (5R*,7S*)-3-(4-Methoxyphenyl)-7-methyl-2-oxo-1-(p-tolyl)-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(22c). The procedure for the preparation of 19a/20a was followed

using a mixture of 12d/13d (68/32) (0.050 g, 0.16 mmol), 18a (0.022

g, 0.39 mmol), and ZnCl₂(1 M in diethyl ether) (0.0054 g, 0.04

mmol) in anhydrous CH₂Cl₂(5 mL) to give a mixture with a 92/8

ortho/meta ratio and the corresponding endo/exo ratios of 19c/20c

(69/31)/21c/22c (0.035 g, 60%) as a yellow oil. R_f0.33 (hexane/

1

minor regioisomer 27b. H NMR (500 MHz, CDCl₃): δ 1.26 (t, J =

7.5 Hz, CH₃CH₂), 2.32 (q, J = 7.5 Hz, CH₃CH₂), 9.87 (s, 1H, CHO).

HRMS (EI): m/z [M⁺] calcd for C₂₄H₂₂N₂O₄: 402.1580. Found:

402.1579.

3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-methyl-2-oxo-2,3-di-

hydro-1H-benzo[d]imidazole-5-carbaldehyde (23b) and 1-(4-Chlor-

ophenyl)-3-(4-methoxyphenyl)-7-methyl-2-oxo-2,3-dihydro-1H-

benzo[d]imidazole-5-carbaldehyde (24b). Following method A for

the preparation of 23a/24a, a mixture of 19b/20b (80/20)/21b/22b

(0.044 g, 0.11 mmol) and DDQ (0.064 g, 0.28 mmol) in CH₂Cl₂(5

mL) generated a mixture of 23b/24b (96/4) (0.036 g, 82%) as a

brown solid. R_f0.77 (hexane/EtOAc, 1/1); mp 88−90 °C. IR (ﬁlm):

1

EtOAc, 1/1). IR (ﬁlm): ν_max1699, 1513, 1030, 824 cm⁻¹. H NMR

(300 MHz, CDCl₃): δ 0.77 (d, J = 6.6 Hz, 3H, CH₃-C4), 1.74−1.91

(m, 1H, H-6), 2.14−2.25 (m, 1H, H-6), 2.39 (s, 3H, ArCH₃), 2.50−

2.71 (m, 2H, H-7), 2.84 (ddd, J = 12.3, 5.1, 2.4 Hz, 1H, H-5), 3.20−

3.40 (m, 1H, H-4), 3.82 (s, 3H, CH₃O), 6.91−7.02 (m, 2H, H-3′),

7.08−7.40 (m, 6H, ArH), 9.74 (s, 1H, CHO). ¹³C NMR (75.4 MHz,

CDCl₃): δ 15.3 (CH₃−C4), 17.4 (C-6), 20.4 (C-7), 21.1 (ArCH₃),

25.9 (C-4), 50.9 (C-5), 55.4 (CH₃O), 114.3 (C-3′), 120.6 (C-7a),

120.9 (C-3a), 126.9 (C-2′), 127.2 (C-1′), 127.6 (C-2″), 129.4 (C-1″),

130.0 (C-3″), 137.6 (C-4″), 153.9 (C-2), 158.5 (C-4′), 202.9 (CHO).

1

ν_max1719, 1683, 1596, 1515, 1090, 830 cm⁻¹. H NMR (400 MHz,

CDCl₃): δ 2.25 (s, 3H, CH₃-C4), 3.87 (s, 3H, CH₃O), 7.00 (d, J = 8.3

Hz, 1H, H-7), 7.03−7.08 (m, 2H, H-3′), 7.39−7.45 (m, 4H, H-2′, H-

2″), 7.49−7.53 (m, 2H, H-3″), 7.62 (d, J = 8.3 Hz, 1H, H-6), 10.15 (s,

1

Signals attributed to the minor isomer 20c: H NMR (300 MHz,

N

DOI: 10.1021/acs.joc.7b02344

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1H, CHO). ¹³C NMR (101 MHz, CDCl₃): δ 14.0 (CH₃−C4), 55.5

(CH₃O), 106.6 (C-7), 115.0 (C-3′), 123.2 (C-4), 125.9 (C-1′), 127.9

(C-2′ or C-2″), 128.1 (C-3a), 128.9 (C-6), 129.6 (C-3″), 129.8 (C-

2″), 129.9 (C-5), 134.5 (C-4″), 134.8 (C-1″ or C-7a), 134.9 (C-7a or

C-1″), 153.8 (C-2), 159.5 (C-4′), 191.7 (CHO). Signals attributed to

132.0 (Ar), 134.7 (Ar), 134.8 (Ar), 137.1 (Ar), 137.2 (Ar), 152.1 (C-

2), 202.36 (CHO), 202.38 (CHO). HRMS (EI) m/z [M⁺] calcd for

C₂₁H₂₀N₂O₂: 332.1525. Found: 332.1523.

3-(4-Chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-benzo[d]-

imidazole-5-carbaldehyde (30a). and 1-(4-Chlorophenyl)-2-oxo-3-

phenyl-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (31a).

Following method A for the preparation of 23a/24a, a mixture of

28a/29a (59/41) (0.050 g, 0.14 mmol) and DDQ (0.079 g, 0.35

mmol) in CH₂Cl₂(5 mL) furnished a regioisomer mixture of 30a/31a

(57/43) (0.043 g, 88%) as a brown solid. R_f0.90 (hexane/EtOAc, 1/

1); mp 114−117 °C. IR (ﬁlm): ν_max1727, 1687, 1594, 1095, 804, 757

cm⁻¹. Signals attributed to the major regioisomer 30a: ¹H NMR (300

MHz, CDCl₃): δ 7.23 (d, J = 7.8 Hz, 1H, H-7), 7.44−7.52 (m, 1H, H-

4′), 7.52−7.61 (m, 8H, ArH), 7.63−7.70 (m, 2H, H-4, H-6), 9.92 (s,

1H, CHO). ¹³C NMR (75.4 MHz, CDCl₃): δ 108.2 (C-4), 108.9 (C-

7), 126.2 (2ArH), 127.1 (Ar), 127.3 (2ArH), 128.6 (Ar), 129.8

(2ArH), 130.0 (2ArH), 131.4 (Ar), 132.2 (Ar), 133.4 (Ar), 134.6 (Ar),

152.4 (C-2), 190.89 (CHO). Signals attributed to the minor

1

the minor regioisomer 24b: H NMR (400 MHz, CDCl₃): δ 2.23 (s,

CH₃-C7), 3.88 (s, CH₃O), 9.87 (s, CHO). ¹³C NMR (101 MHz,

CDCl₃): δ 14.2 (CH₃−C7), 60.5 (CH₃O), 114.7 (C-3′), 121.9 (Ar),

127.7 (C-2′), 129.0 (ArH), 149.9 (C-2), 157.9 (C-4′), 191.79 (CHO).

HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₇ClN₂O₃: 392.0928. Found:

392.0939.

1-(4-Methoxyphenyl)-4-methyl-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-

benzo[d]imidazole-5-carbaldehyde (23c) and 3-(4-Methoxyphen-

yl)-7-methyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazole-5-

carbaldehyde (24c). Following method A for the preparation of 23a/

24a and with a mixture of 19c/20c (69/31)/21c/22c (0.036 g, 0.10

mmol) and DDQ (0.055 g, 0.24 mmol) in CH₂Cl₂(5 mL), a mixture

of 23c/24c (92/8) (0.03 g, 85%) was obtained as a brown solid. R_f

0.58 (hexane/EtOAc, 1/1); mp 82−85 °C. IR (ﬁlm): ν_max1720, 1685,

1

regioisomer 31a: H NMR (300 MHz, CDCl₃): δ 7.22 (br d, J =

1

1594, 1026, 802 cm⁻¹. H NMR (300 MHz, CDCl₃): δ 2.23 (s, 3H,

8.1 Hz, H-7). ¹³C NMR (75.4 MHz, CDCl₃): δ 108.56 (C-4 or C-7),

108.61 (C-7 or C-4), 126.1 (2ArH), 126.9 (Ar), 127.4 (2ArH), 128.5

(Ar), 129.8 (2ArH), 131.5 (Ar), 132.1 (Ar), 133.5 (Ar), 134.0 (Ar),

190.94 (CHO). HRMS (EI) m/z [M⁺] calcd for C₂₀H₁₃ClN₂O₂:

348.0666. Found: 348.0668.

CH₃-C4), 2.45 (s, 3H, ArCH₃), 3.87 (s, 3H, CH₃O), 7.01 (d, J = 8.4

Hz, 1H, H-7), 7.02−7.10 (m, 2H, H-3′), 7.31−7.36 (m, 4H, H-2″, H-

3″), 7.40−7.47 (m, 2H, H-2′), 7.61 (d, J = 8.4 Hz, 1H, H-6), 10.16 (s,

1H, CHO). ¹³C NMR (75.4 MHz, CDCl₃): δ 13.6 (CH₃−C4), 21.3

(ArCH₃), 55.5 (CH₃O), 106.4 (C-7), 114.9 (C-3′), 120.6 (C-4), 126.1

(C-1′), 127.9 (C-2′), 128.4 (C-2″, C-6), 128.6 (C-3a), 129.7 (C-5),

130.0 (C-3″), 133.2 (C-1″), 134.8 (C-7a), 139.1 (C-4″), 154.1 (C-2),

159.4 (C-4′), 191.9 (CHO). Signals attributed to the minor

2-Oxo-1-phenyl-3-(p-tolyl)-2,3-dihydro-1H-benzo[d]imidazole-5-

carbaldehyde (30b) and 2-Oxo-3-phenyl-1-(p-tolyl)-2,3-dihydro-

1H-benzo[d]imidazole-5-carbaldehyde (31b). Following Method A

for the preparation of 23a/24a, a mixture of 28b/29b (52/48) (0.035

g, 0.11 mmol) and DDQ (0.059 g, 0.26 mmol) in CH₂Cl₂(5 mL)

provided a mixture of 30b/31b (57/43) (0.032 g, 92%) as a brown

solid. R_f0.87 (hexane/EtOAc, 1/1); mp 124−128 °C. IR (ﬁlm): ν_max

1725, 1686, 1595, 1519, 1111, 805 cm⁻¹. Signals attributed to the

1

regioisomer 24c. H NMR (300 MHz, CDCl₃): δ 1.94 (s, CH₃-C7),

2.36 (s, ArCH₃), 9.86 (s, CHO). ¹³C NMR (75.4 MHz CDCl₃): δ

123.4, 124.5, 129.0, 130.5, 137.1. HRMS (EI): m/z [M⁺] calcd for

C₂₃H₂₀N₂O₃: 372.1474. Found: 372.1463.

1

major regioisomer 30b: H NMR (400 MHz, CDCl₃): δ 2.45 (s, 3H,

3-(4-Chlorophenyl)-2-oxo-1-phenyl-2,3,4,5,6,7-hexahydro-1H-

benzo[d]imidazole-5-carbaldehyde (28a) and 1-(4-Chlorophenyl)-

2-oxo-3-phenyl-2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-car-

baldehyde (29a). Following method A for the preparation of 19a/

20a, a mixture of 5h (0.050 g, 0.17 mmol), 18a (0.024 g, 0.42 mmol),

and ZnCl₂(1 M in diethyl ether) (0.0054 g, 0.04 mmol) in anhydrous

CH₂Cl₂(5 mL) produced a mixture of 28a/29a (60:40) (0.053 g,

88%) as a yellow oil; R_f0.36 (hexane/EtOAc, 1/1). IR (ﬁlm): ν_max

ArCH₃), 7.18−7.27 (m, 1H, H-7), 7.34−7.42 (m, 2H, H-3″), 7.43−

7.50 (m, 3H, H-4′, H-2″), 7.54−7.61 (m, 4H, H-2′, H-3′), 7.61−7.69

(m, 2H, H-4, H-6), 9.92 (s, 1H, CHO). ¹³C NMR (101 MHz,

CDCl₃): δ 21.23 (ArCH₃), 108.4 (C-4), 108.68 (C-7), 126.12 (C-2′),

126.13 (C-2″), 126.9 (C-6), 128.3 (C-4′), 129.7 (C-3′), 130.2 (C-1″),

130.36 (C-3″), 130.92 (C-3a), 131.25 (C-5), 133.73 (C-1′), 134.90

(C-7a), 138.6 (C-4″), 152.7 (C-2), 191.1 (CHO). Signals attributed to

the minor regioisomer 31b: ¹³C NMR (101 MHz, CDCl₃): δ 21.22

(ArCH₃), 108.5 (C-4), 108.67 (C-7), 126.04 (C-2″), 126.2 (C-2′),

126.7 (C-6), 128.4 (C-4″), 129.5 (C-3″), 130.40 (C-3′), 130.94 (C-

3a), 131.34 (C-5), 133.70 (C-1″), 134.6 (C-7a), 138.5 (C-4′), 150.0

(C-2). HRMS (EI) m/z [M⁺] calcd for C₂₁H₁₆N₂O₂: 328.1212.

Found: 328.1206.

General Method for the Preparation of 32 and 33.

(5aR*,8aR*,8bR*)-1,3-Bis(4-methoxyphenyl)-8b-methyl-7-phenyl-

1,3,5,5a,8a,8b-hexahydroimidazo[4,5-e]isoindole-2,6,8(7H)-trione

(32a) and (5aS*,8aS*,8bR*)-1,3-Bis(4-methoxyphenyl)-8b-methyl-

7-phenyl-1,3,5,5a,8a,8b-hexahydroimidazo[4,5-e]isoindole-

2,6,8(7H)-trione (33a). A mixture of 16a (0.100 g, 0.31 mmol) and 6

(0.054 g, 0.31 mmol) in anhydrous CH₂Cl₂(5 mL) was stirred at

room temperature for 48 h. Then, the crude was concentrated under

vacuum and puriﬁed by column chromatography over silica gel (10 g/

g of crude, hexane/EtOAc, 1/1) to generate a mixture of 32a/33a

(99/1) (0.107 g, 70%) as a white solid. R_f0.43 (hexane/EtOAc, 7/3);

mp 130−132 °C. IR (ﬁlm): ν_max1711, 1675, 1510, 1030, 829 cm⁻¹. ¹H

NMR (500 MHz, CDCl₃): δ 1.47 (s, 3H, CH₃-C8b), 2.70−2.80 (m,

2H, H-5), 3.22−3.27 (m, 1H, H-5a), 3.48 (d, J = 5.0 Hz, 1H, H-8a),

3.81 (s, 6H, 2CH₃O), 4.74−4.78 (m, 1H, H-4), 6.90−6.97 (m, 4H, H-

3′, H-3″), 7.18−7.24 (m, 4H, H-2′, H-2″), 7.37−7.41 (m, 1H, H-4‴),

7.43−7.47 (m, 2H, H-3‴), 7.55−7.59 (m, 2H, H-2‴). ¹³C NMR (125

MHz, CDCl₃): δ 20.9 (CH₃−C8b), 24.5 (C-5), 38.2 (C-5a), 48.5 (C-

8a), 55.4 (CH₃O), 55.5 (CH₃O), 61.2 (C-8b), 88.2 (C-4), 114.4 (C-3′

or C-3″), 114.6 (C-3″ or C-3′), 126.4 (C-2′ or C-2″), 127.6 (C-1″ or

C-1′), 128.0 (C-2″ or C-2′), 128.4 (C-1′ or C-1″), 128.7 (C-4‴),

129.1 (C-3‴), 130.5 (C-2‴), 131.7 (C-1‴), 143.7 (C-3a), 155.7 (C-2),

158.7 (C-4′ or C-4″), 158.8 (C-4″ or C-4′), 173.7 (C-8), 178.1 (C-6).

HRMS (EI): m/z [M⁺] calcd for C₃₀H₂₇N₃O₅: 509.1951. Found:

509.1945.

1

1702, 1666, 1090, 838, 749 cm⁻¹. H NMR (400 MHz, CDCl₃): δ

1.84−1.99 (m, 2H, CH₂), 2.16−2.28 (m, 2H, CH₂), 2.30−2.46 (m,

5H, CH₂), 2.51−2.58 (m, 2H, CH₂), 2.62−2.80 (m, 3H, CHCHO,

CH₂), 7.29−7.49 (m, 18H, ArH), 9.74 (s, 2H, CHO). ¹³C NMR (101

MHz, CDCl₃) δ 19.9 (2CH₂), 20.8 (2CH₂), 22.0 (2CH₂), 46.02

(CHCHO), 46.04 (CHCHO), 115.5 (C-3a or C-7a), 116.3 (C-7a or

C-3a), 117.0 (C-3a′ or C-7a′), 117.9 (C-7a′ or C-3a′), 126.25 (2ArH),

126.34 (2ArH), 127.4 (ArH), 127.5 (ArH), 127.5 (2ArH), 129.2

(2ArH), 129.29 (ArH), 129.32 (ArH), 129.4 (2ArH), 132.9 (Ar),

133.0 (Ar), 133.27 (Ar), 133.34 (Ar), 134.5 (Ar), 134.6 (Ar), 152.0

(C-2), 202.03 (CHO), 202.10 (CHO). HRMS (EI) m/z [M⁺] calcd

for C₂₀H₁₇ClN₂O₂: 352.0979. Found: 352.0973.

2-Oxo-1-phenyl-3-(p-tolyl)-2,3,4,5,6,7-hexahydro-1H-benzo[d]-

imidazole-5-carbaldehyde (28b) and 2-Oxo-3-phenyl-1-(p-tolyl)-

2,3,4,5,6,7-hexahydro-1H-benzo[d]imidazole-5-carbaldehyde

(29b). Following method A for the preparation of 19a/20a, a mixture

of 5i (0.050 g, 0.17 mmol), 18a (0.024 g, 0.42 mmol) and ZnCl₂(1 M

in diethyl ether) (0.0054 g, 0.04 mmol) in anhydrous CH₂Cl₂(5 mL)

aﬀorded a mixture of 28b/29b (53:47) (0.041 g, 72%) as a yellow oil;

R_f0.40 (hexane/EtOAc, 1/1). IR (ﬁlm): ν_max1702, 1665, 1516, 1188,

1

747 cm⁻¹. H NMR (300 MHz, CDCl₃): δ 1.84−1.95 (m, 2H, CH₂),

2.16−2.25 (m, 2H, CH₂), 2.36 (s, 3H, ArCH₃), 2.37 (s, 3H, ArCH₃),

2.38−2.47 (m, 4H, CH₂), 2.47−2.58 (m, 2H, CH₂), 2.58−2.67 (m,

2H, CH₂), 2.67−2.80 (m, 3H, CHCHO, CH₂), 7.20−7.48 (m, 18H,

ArH), 9.71 (s, 2H, CHO). ¹³C NMR (75.4 MHz, CDCl₃): δ 19.8

(CH₂), 19.9 (CH₂), 20.7 (CH₂), 20.8 (CH₂), 21.02 (ArCH₃), 21.03

(ArCH₃), 22.1 (CH₂), 22.2 (CH₂), 45.96 (CHCHO), 46.01

(CHCHO), 115.4 (C-3a or C-7a), 115.9 (C-3a′ or C-7a′), 117.1

(C-7a or C-3a), 117.5 (C-7a′ or C-3a′), 126.0 (2ArH), 126.1 (2ArH),

126.15 (2ArH), 126.19 (2ArH), 127.1 (ArH), 127.2 (ArH), 129.0

(2ArH), 129.1 (2ArH), 129.6 (2ArH), 129.8 (2ArH), 131.9 (Ar),

O

DOI: 10.1021/acs.joc.7b02344

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(5R*,5aR*,8aR*,8bR*)-1,3-Bis(4-methoxyphenyl)-5,8b-dimethyl-

7-phenyl-1,3,5,5a,8a,8b-hexahydroimidazo[4,5-e]isoindole-

2,6,8(7H)-trione (32b) and (5R*,5aS*,8aS*,8bR*)-1,3-Bis(4-methox-

y p h e n y l ) - 5 , 8 b - d i m e t h y l - 7 - p h e n y l - 1 , 3 , 5 , 5 a , 8 a , 8 b -

hexahydroimidazo[4,5-e]isoindole-2,6,8(7H)-trione (33b). Following

the procedure for 32a/33a, a mixture of 17 (0.100 g, 0.29 mmol) and

6 (0.05 g, 0.29 mmol) in anhydrous CH₂Cl₂(5 mL) delivered a

mixture of 32b/33b (99/1) (0.099 g, 66%) as a white solid. R_f0.48

(hexane/EtOAc, 8/2); mp 120−122 °C. IR (ﬁlm): ν_max1711, 1672,

1510, 1030, 832, 749 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 1.22 (d, J

= 6.9 Hz, 3H, CH₃-C5), 1.48 (s, 3H, CH₃-C8b), 3.03−3.18 (m, 2H,

H-5, H-5a), 3.48 (d, J = 7.2 Hz, 1H, H-8a), 3.79 (s, 1H, CH₃O), 3.80

(s, 1H, CH₃O), 4.46 (d, J = 2.7 Hz, 1H, H-4), 6.89−6.97 (m, 4H, H-

3′, H-3″), 7.17−7.26 (m, 4H, H-2′, H-2″), 7.34−7.40 (m, 1H, H-4‴),

7.40−7.47 (m, 2H, H-3‴), 7.47−7.55 (m, 2H, H-2‴). ¹³C NMR (75.4

MHz, CDCl₃): δ 18.9 (CH₃−C5), 20.2 (CH₃−C8b), 28.2 (C-5 or C-

5a), 43.0 (C-5a or C-5), 49.4 (C-8a), 55.4 (2CH₃O), 61.0 (C-8b), 94.8

(C-4), 114.4 (C-3′ or C-3″), 114.6 (C-3″ or C-3′), 126.3 (C-2′ or C-

2″), 127.5 (C-1′ or C-1″), 127.9 (C-1″ or C-1′), 128.1 (C-2″ or C-2′),

128.6 (C-4‴), 129.0 (C-3‴), 130.7 (C-2‴), 131.5 (C-1‴), 143.5 (C-

3a), 155.7 (C-2), 158.6 (C-4′ or C-4″), 158.9 (C-4″ or C-4′), 173.6

(C-8), 174.7 (C-6). HRMS (EI): m/z [M⁺] calcd for C₃₁H₂₉N₃O₅:

523.2107. Found: 523.2118.

Single-Crystal X-ray Crystallography. Diene 5a was obtained as

colorless crystals and crystallized on a mixture of hexane/EtOAc (9/

1), which were mounted on glass ﬁbers. Crystallographic measure-

ments were performed by utilizing an area-detector with Mo Kα

radiation (λ = 71073 Å; graphite monochromator) at room

temperature. Unit cell parameters were obtained from a least-squares

reﬁnement. Intensities were corrected for Lorentz and polarization

eﬀects. No absorption correction was applied. Anisotropic temperature

factors were introduced for all non-hydrogen atoms. Hydrogen atoms

were placed in idealized positions, and their atomic coordinates reﬁned

employing unit weights. After being solved using SHELX-97,³⁹the

structure was visualized and plotted with the MERCURY program

package.⁴⁰Data from 5a: (CCDC 1503136) Formula: C₁₇H₁₄N₂O;

molecular weight: 262.30; cryst. syst.: monoclinic; space group: P1 21/

n 1; unit cell parameters: a, 7.4517(3), b, 7.8084(4), c, 23.7466(13)

(Å); α, 90°, β, 89.969(4)°, γ, 90°; temp. (K): 292(2); Z: 4; no. of

reﬂections collected: 7475; no. of independent reﬂections: 4180; no. of

reﬂections observed: 2715; data collection range: 2.75 < 2θ < 32.57°;

R: 0.0615; GOF: 1.081.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.7b02344.

■

S

Appendix 1: frontier molecular orbitals [HF/6-31G-

(d,p)] of the optimized geometries of dienes 5c, 12a, and

14 and dienophiles 18a, 18a-ZnCl₂, and 18a-BF₃;

Appendix 2: relative zero point-corrected energies of

the supramolecular complexes, TSs (TS1 and TS2),

zwitterionic intermediates, and adducts located in the

potential surfaces of the Diels−Alder reactions of diene

12a and dienophiles 18a, 18a-ZnCl₂, and 18a-BF₃;

Appendix 3: Calculation (NBO) of synchronicities of the

Diels−Alder cycloadditions of diene 16a and maleimide

(6); Appendix 4: Copies of the H NMR and ¹³C NMR

1

spectra of all new compounds; Appendix 5: X-ray

crystallographic structure of 5a; Appendix 6: M06-2X/

6-31+G(d,p) relative ZPE-corrected energies (kcal/mol)

of the stationary points of the nonassisted Diels−Alder

cycloadditions of 12a/18a; Appendix 7: calculation

[M06-2X/6-31+G(d,p)] of Z-matrices of the optimized

geometries of supramolecular complexes, transition

states, and adducts; Appendix 8: geometrical parameters,

bond distances (Å) of the transition states (TS1 and

TS2) and zwitterionic intermediates, located at the

potential surfaces of the Diels−Alder reactions of diene

12a and dienophiles 18a, 18a-ZnCl₂, and 18a-BF₃

(PDF)

Crystallographic information for 5a (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: jtamarizm@gmail.com; jtamariz@woodward.encb.ipn.

■

mx.

ORCID

Hugo A. Jimenez-Vazquez: 0000-0001-7555-679X

́

Fernando P. Cossío: 0000-0002-4526-2122

Theoretical Calculations. All ab initio and DFT calculations were

carried out using the Gaussian 09 program package.²⁷Optimizations of

the stationary points were initially made at the HF/6-31G(d,p) level of

theory. The optimized geometries were used as starting points for

further optimizations at the M06-2X/6-31+G(d,p) level of theory. For

all optimizations, the OPT = TIGHT optimization option was

employed. For all DFT calculations, the INT(GRID = ULTRAFINE)

option was used. The TSs were located using the QST2, QST3 or TS

optimization options. Additional conﬁrmation of the nature of the TSs

was obtained by IRC analyses for all the reaction coordinates under

study, except for the cycloadditions with dienes 16a and 17. All

stationary points were characterized by frequency calculations. All

minima (starting materials, zwitterionic intermediates and adducts)

showed only real vibrational frequencies, while the TSs each displayed

a single negative eigenvalue of the Hessian matrix. Through visual

inspection of the normal mode associated with the imaginary

vibrational frequency, it was conﬁrmed that the TSs corresponded

to motion along the reaction coordinate. The synchronicities were

obtained by taking the DFT geometries and wave functions of

supramolecular complexes, transition states, and products along each

of the reaction coordinates under study, and using each as input for the

NBO 5.0 program³⁴after conversion to the appropriate format. The

Wiberg bond indexes³³for the bonds of interest for each stationary

point were taken from the output and used to calculate the

synchronicities as described elsewhere³²and in the Supporting

Information.

Joaquín Tamariz: 0000-0002-0600-3857

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank Israel Hernan

́

dez and Vanessa Pelayo for their help

in spectrometric measurements and Bruce A. Larsen for

proofreading. J.T. acknowledges ﬁnancial support from SIP/

IPN (Grants 20130686, 20140858, 20150917, 20160791,

20170902, and 20180198) and CONACYT (Grants 83446

and 178319). C.E.-H., P.M., and R.B. are grateful to

CONACYT for awarding them graduate scholarships and

also thank SIP/IPN (BEIFI) for scholarship complements.

H.A.J.-V., F.D., and J.T. are fellows of the EDI-IPN and

COFAA-IPN programs.

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Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and Selectivity in Diels-Alder Cycloadditions

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