Condensation of diacetyl with alkyl amines: Synthesis and reactivity of p-iminobenzoquinones and p-diiminobenzoquinones

Article

Condensation of Diacetyl with Alkyl Amines:

Synthesis and Reactivity of p-Iminobenzoquinones

and p-Diiminobenzoquinones

Carlos Espinoza-Hicks, Rafael Bautista ^†, Saúl Frias-Puente, Vanessa Pelayo,

Eder I. Martínez-Mora, Francisco Delgado and Joaquín Tamariz *

Received: 16 October 2015 ; Accepted: 6 November 2015 ; Published: 20 November 2015

Academic Editor: Roman Dembinski

Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional.

Prol. Carpio y Plan de Ayala, 11340 México, Mexico; hick_1107@hotmail.com (C.E.-H.);

jimbe31@hotmail.com (R.B.); eleanor_500m@hotmail.com (S.F.-P.); ﬁosara29@gmail.com (V.P.);

eder.qfb@gmail.com (E.I.M.-M.); jfdelgador@gmail.com (F.D.)

*

Correspondence: jtamarizm@gmail.com or jtamariz@woodward.encb.ipn.mx;

Tel.: +52-55-5729-6300 (ext. 62411); Fax: +52-55-5586-6621

†

Present address: Departamento de Investigación y Desarrollo, Signa, S.A. de C.V., Av. Industria

Automotriz No. 301, Zona Industrial Toluca, 50200, Toluca, Edo. de México, Mexico.

Abstract: Condensation reactions between diacetyl and α-branched primary alkylamines under

mild and neutral conditions provided a mixture of 2,5-dimethylbenzoquinone(alkylimines),

1

2,5-dimethylbenzoquinone(bis-alkyldiimines), and N,N -dialkyl-2,5-dimethylbenzene-1,4-diamines,

which were efﬁciently separated as pure products by column chromatography. Both

2,5-dimethylbenzoquinone(alkylimines) and 2,5-dimethylbenzoquinone(bis-alkyldiimines) underwent

an interchange of the alkylimino group when treated with anilines, followed by reductive

aromatization, to provide diarylamines and 1,4-dianilinobenzenes, respectively. Evaluation was

also made of the reactivity and selectivity of these compounds in the presence of anilines,

thiophenols and alkylhalides.

1

Keywords: diacetyl; p-iminobenzoquinones; p-diiminobenzoquinones; N,N -dialkyl-1,4-diaminobenzenes;

diarylamines

1. Introduction

Diacetyl (1a), a yellow liquid with an intense buttery ﬂavor, has been extensively used in

food chemistry [1 ,2 ]. Its vicinal dicarbonyl group provides it an attractive and very particular

reactive behavior. Consequently, both 1a and α-dicarbonyl compounds have been the object of a

variety of pharmacological [3], phytochemical [4], photochemical [5], and synthetic studies [6 ,7].

For example, a series of α-dicarbonyl derivatives displays interesting ﬂuorescent [8], structural [9],

anti-corrosion [10], anti-inﬂammatory [11,12], antiprotozoal [13 ], or polymeric photoinitiator [14]

properties. These derivatives can also be versatile substrates in the synthesis of a variety of

compounds, including a large number of heterocycles [15–20], some building blocks (e.g., chiral

α-hydroxy ketones [21,22]), and transition-metal ligands [23].

As part of an ongoing line of research, we used 1a and α-dicarbonyl compounds as the

key precursors in the synthesis of captodative alkenes [24] and exo-heterocyclic dienes [25]. The

behavior of these relevant conjugated π-systems was experimentally and theoretically evaluated in

Diels-Alder [24–27] and 1,3-dipolar [28–30] cycloadditions. Their scaffold was functionalized through

Pd(0)-catalyzed coupling procedures [31] and used in the transformation of ligand-containing

transition-metal complexes [32].

Molecules 2015, 20, 20719–20740; doi:10.3390/molecules201119716

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Molecules 2015, 20, 20719–20740

Recently, as a result of the synthesis of novel 2-imidazolidinone-base outer-ring exo-heterocyclic

dienes 5 [27], we found that a base-assisted condensation/cyclization cascade reaction of monoimino

diacetyl derivatives 3 and isocyanates in the presence of a dehydrating agent provided the desired

dienes in high yields (Scheme 1). The monoimino diacetyl derivatives 3 were efﬁciently prepared by

reacting 1a with anilines 2 under neutral or Lewis acid catalysis conditions. However, derivatives 3

could not be prepared by using primary alkylamines. Only a limited number of old reports have

described this kind of reaction, which exclusively yield brownish resins and oils, except for the

thermochromic amber-yellow colored crystalline 2,5-dimethylbenzoquinone-bis-cyclohexyldiimine

(8b) afforded by cyclohexylamine (6b) [33] (see below). All our attempts to purify these compounds

by column chromatography over silica gel furnished decomposition resins.

Considering the limited scope of this reaction and the instability of the products, it is

comprehensible that, to our best knowledge, no additional studies on this process have been reported.

In spite of the drawbacks of an apparently disappointing and uninspiring reaction, we saw promise.

With further investigation, in the mixture found of products 7–9, the proportion depended on the

reaction conditions. Therefore, we herein describe the efforts to gain insight into the limits and scope

of this interesting reaction between diacetyl (1a) and alkylamines 6.

Scheme 1. Reaction of diacetyl (1a) with anilines 2 and alkylamines 6.

2. Results and Discussion

2.1. Condensation of Diacetyl (1a) with Amines 6

Table 1 summarizes the reaction conditions of the process between 1a and isopropylamine (6a).

It appears that both the presence and proportion of two or three products depends not only on

the number of mol equivalents of the amine, but also on the concentration of the reaction mixture

(entries 1–4). Among the several solvents tested, methanol turned out to be the most efﬁcient, though

propanol could provide similar results albeit in lower yields (entry 5). The process yielded a larger

proportion of iminoquinones 7a and 8a as well as their greater conversion when using twice the

amount of 6a and at high dilution (entry 4).

Interestingly, when hydroquinone was added to quench the probable formation of radical

species, 1,4-diaminobenzene compound 9a was the lone product (entry 6). This result suggests

that the aromatization was readily performed under mild reductive conditions (see below). These

three products could be separated as solids by ﬂash column chromatography over 10% triethylamine

pre-treated silica gel. However, if the crude mixture remained in the column for a long time, the

yields decreased and many red and brown resin products were formed. Particular caution should be

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taken with products 7 and 8, keeping them under refrigeration. Despite their instability, they can be

handled at room temperature for further transformations.

Table 1. Optimization of reaction conditions for the preparation of compounds 7a–9a ^a.

i-PrNH₂(6a)

(mol equiv.)

Solvent

Additive

(10% mol)

Entry

Products (%) ^c

(mmol/mL) ^b

1

2

3

4

5

6

0.5

1

2

0.5

2

MeOH (0.46)

MeOH (1.14)

MeOH (0.46)

MeOH (0.23)

n-PrOH (0.46)

MeOH (0.23)

———-

7a (10), 9a (13)

7a (8), 8a (2), 9a (12)

7a (12), 8a (15), 9a (40)

7a (30), 8a (21), 9a (41)

7a (5), 9a (8)

hydroquinone

9a (68)

a

b

c

At room temperature for 48 h. Concentration with respect to 1a (11.44 mmol). After column chromatography.

Analogous results were obtained when other α-branched primary amines were used (Table 2).

Thus, cyclohexylamine (6b) reacted with 1a under similar conditions to those used for 6a to yield

the expected three products 7b/8b/9b (entry 1). Nevertheless, for (S)-methylbenzylamine (6c), the

iminoquinone 7c was not observed (entry 2).

Table 2. Condensation of 1a with primary amines 6b–f ^a.

Products (%) ^b

Entry

Amine

R

1

2

3

4

5

6b

6c

6d

6e

6f

cyclohexyl

(S)-CH(Me)Ph

n-butyl

7b (29), 8b (23), 9b (39)

7c (0), 8c (16), 9c (30)

7d (0), 8d (0), 9d (18)

n-propyl

Bn

(c)

b

a

With 2.0 mol equiv. of the amine in MeOH (0.23 mmol/mL) at room temperature for 48 h. After column

chromatography. A complex mixture of products.

c

Also tested were primary n-alkylamines, such as n-propylamine (6e) and benzylamine (6f),

obtaining a complex mixture of products (Table 2, entries 4–5). n-Butylamine (6d) afforded the

corresponding 1,4-diaminobenzene 9d in low yield (18%). These results could not be improved even

when modifying the solvent, temperature and reaction times. Therefore, it appears that this kind of

processes (leading to the formation of iminoquinones 7–9) did not occur when primary amines were

used, with the exception of n-butylamine that led to 9d in low yield.

2.2. Functionalization of Iminoquinone 7a. Synthesis of Diarylamines and Polysubstituted Benzene Rings

Iminoquinone 7a underwent substitution at the isopropylimino moiety when it reacted with

anilines 2a–c to furnish iminoquinones 10a–c in moderate to good yields (Scheme 2). Diverse

studies have used the latter kind of molecules as intermediates for oxidative couplings of anilines

with phenols to form dyes [34,35]. Iminoquinones have more recently resulted from oxidative

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bioconjugated couplings of anilines [36,37]. Interestingly, only the ﬁrst of the two possible (E) and (Z)

geometric isomers was obtained presently, which may be due to the destabilizing steric interactions

generated in the (Z) isomer. The geometry was established by NOE experiments and single crystal

X-ray diffraction of 8a (Figure 1).

Figure 1. X-ray structure of 8a (ellipsoids at the 30% probability level).

Diarylamines have become important synthetic targets as ﬁne chemicals and precursors of

a variety of N-containing pharmacological and natural products [38–40], such as carbazoles and

ellipticines [41–45]. Due to the importance of diarylamines, a great number of synthetic approaches

have been designed for their preparation [46–48]. One of the shortest and most efﬁcient methods

is through the Buchwald-Hartwig reaction, which consists of a Pd-catalyzed cross-coupling of aryl

halides and anilines [49–54]. Another is the Ullmann reaction via a Cu-catalyzed coupling of similar

substrates [55,56].

Consequently, we have investigated the conversion of iminoquinones 10a–c into polysubstituted

diarylamines 11–18. Aromatization of iminoquinones 10a–c under mild treatment with sodium

hydrosulﬁte led to diarylamines 11a–c in high yields (Scheme 2). The latter compounds were reacted

with different alkyl halides in order to obtain the O- or N-alkyl derivatives 12a–d. Accordingly, benzyl

bromide (1.0 mol equiv.) afforded the O-benzylated diarylamine 12a in high yield, while the reaction

of 11a–b with methyl bromoacetate led to phenoxyacetates 12b–c, respectively, in good yields. When

compound 11b was submitted to methylation with methyl iodine (2.0 mol equiv.), the O,N-dimethyl

diarylamine 12d was yielded.

Scheme 2. Conversion of 7a into diarylamines 11–14.

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A further functionalization of iminoquinone 10b was successfully accomplished by adding a

series of thiols 13a–d, furnishing the series of diarylamines 14a–d in modest to good yields (Scheme 2 ).

Thus, the aminophenolic ring became a pentasubstituted benzene ring. Although we expected that

the most polarized enone-quinoid system of 10b would be the most reactive site for the nucleophilic

conjugated addition, the imino-quinoid moiety was the site at which the conjugated addition of

thiols 13a–d took place, followed by spontaneous aromatization. Although both alkyl- and arylthiols

reacted efﬁciently, the latter furnished the desired products in higher yields.

This preference may be the result of favorable electronic interactions between both species.

Presumably, thiophenol (a soft nucleophile) is selectively added to the conjugated imino-quinoid

moiety, which should be softer than the enone moiety. The latter is highly polarized by the oxygen

atom, mainly due to its electronegativity, which turns the enone system into a harder electrophile [57].

Although the results of similar studies support the importance of these electronic effects to explain

this chemoselectivity [58], steric hindrance cannot be ruled out. The conjugated attack of the bulky

thiophenol to the enone may be restrained by the presence of the vicinal anilino group, whose (E)

conﬁguration places the aryl ring on the same side of the unsubstituted enone carbon. In addition,

this aryl ring adopts a slightly non-coplanar conformation with respect to the plane formed by the

imino-quinoid ring [59,60], which may enhance such steric repulsion.

The structure of phenols 14a–d was unambiguously established by 2D and NOE NMR

experiments. The 2D HMBC showed a clear three-bond correlation between the protons of the

CH₃-C6 methyl group, both carbon atoms attached to the OH group (C-1), and the lone benzene

proton (C-5). A similar correlation was observed between the protons of the CH₃-C3 methyl group

and both carbon atoms at the base of the thioether and anilino groups (C-2 and C-4). Due to the close

chemical shifts of the aromatic proton signals (selectively impeding irradiation as well as the ability

to observe the corresponding signal enhancements), the NOE experiments were carried out with the

O-allyl derivative of 14c (see compound 17c).

Taking into account the feasible nucleophilic conjugated addition of thiols 13 to 10b, anilines

2 were considered as potential nucleophiles. Therefore, the most nucleophilic p-anisidine (2b) was

added to 10b, but no addition product was detected. In spite of this result, a trial was carried out

starting from 7a and in the presence of an excess (2.0 mol equiv.) of 2b, followed by the reduction

treatment, resulting in a mixture of 11b as the major product and the desired adduct 15 as the minor

one (Scheme 3). Due to the difﬁculty of purifying the latter, the benzyl diarylamine 16 was generated

(with compound 12a as the major product) in a one-pot procedure without the isolation of 15. It

is worth mentioning that these reactions followed the same chemoselective addition pathway to

the imino quinoid system as the thiols 13a–d. The low yields of products 15 and 16, and the fact

that other less activated anilines were unable to give the double addition, may be explained by the

lower nucleophilicity of anilines with respect to thiols. Also unsuccessful was the conjugated addition

of soft nucleophiles, such as dimethyl malonate or nitromethane carbanions to iminoquinone 7a or

anilinoquinone 10b, that led to the recovery of the starting materials.

Scheme 3. Conversion of 7a into diarylamines 15 and 16.

In order to increase the number of substituents with valuable functional groups on the phenol

ring, we investigated the allylation of phenols 11b–c and 14c and subsequent Claisen rearrangement

(Scheme 4). The ﬁrst reaction proceeded efﬁciently to give the corresponding allyl ethers 17a–c

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in high yields. Derivative 17b was submitted to the thermal Claisen rearrangement to furnish the

expected [61] pentasubstituted allyl phenol 19b in a modest yield, observing the starting material

and decomposition by-products. However, iminoquinone 18a was the main product in the case

of 17a, found along with the starting material and by-products (phenol 19a was not isolated). The

electron-demand of the para substituent (anilino group) in precursors 17a–b is presumably involved

in this unexpected selectivity [62].

Scheme 4. Synthesis of allyl aryl ethers 17a–c and their Claisen rearrangement.

The thioaryl analogue 17c was used in NOE experiments to support the HMBC assignment of

the structures of derivatives 14a–d. The irradiation of the signal attributed to the methylene group of

the allyl moiety generated a selective enhancement of the signal assigned to the ortho (with respect to

the sulfur atom) aromatic protons of the thioether group. This result, along with that of other NOE

experiments, conﬁrmed that the addition of the thiophenols 13a–d to iminoquinone 10b took place at

the imino-quinoid moiety.

2.3. Functionalization of bis-Iminoquinone 8a Synthesis of Amino-Diarylamines and bis-Diarylamines

Since the substitution of the isopropylamino group in iminoquinone 7a by anilines 2a–c

proceeded to give iminoquinones 10a–c, it was considered that bis-iminoquinone 8a could possibly

undergo a mono- or bis-substitution by anilines 2a–e (Scheme 5). Indeed, the addition of 1.0 mol equiv

of deactivated anilines 2d–e to bis-iminoquinone 8a resulted in the formation of p-aminodiarylamines

20a–b in low to modest yields. On the other hand, the addition of an excess of anilines 2a–b and

2d produced a double substitution of the two isopropylamino groups by the aniline nucleophiles

leading to corresponding bis-iminoquinones 21a–c. The most activated p-anisidine (2b) was the most

efﬁcient aniline, while anilines 2a and 2d gave rise to the corresponding bis-iminoquinones 21a and

21c in lower yields, recovering the starting materials and side-products after 24 h of reaction (a longer

reaction time afforded traces of the desired products and a deep red resin residue). This behavior is

probably due to the lower nucleophilicity of these anilines, an idea supported by the fact that the

double substitution did not take place when 8a was submitted to the addition of the deactivated

aniline 2e.

Unlike bis-iminoquinone 8a, which suffers decomposition after remaining several hours at room

temperature, bis-iminoquinones 21 are stable red oils or solids under the same conditions. The color of

these compounds become yellow in methanol, methylene chloride or toluene solutions, as previously

observed for 8b [33].

The reduction of 21b by treatment with sodium hydrosulﬁte provided bis-diarylamine 22a

in high yield (Scheme 5). A one-pot reaction was also tried for the addition of anilines 2c

and 2d to 8a, followed by reduction with sodium hydrosulﬁte, affording bis-diarylamines 22b–c,

respectively. These bis-iminoquinones 21 and 1,4-phenylenediamines 22 are of signiﬁcant importance

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as conducting polymers [63 ] and as efﬁcient substrates in electron-transfer [64] and electrochemical

studies [65].

Scheme 5. Conversion of bis-imine 8a into aniline derivatives 20–22.

The structure of these compounds was established by spectrometric analyses and X-ray

diffraction. Figure 1 shows the X-ray structure of 8a, in which both imino moieties display an

(E) conﬁguration. Similarly, NOE experiments showed that bis-iminoquinones 21 possess (E,E)

conﬁgurations, which is in agreement with previous X-ray diffraction evidence of compound 21a [59]

and the bis-iminoquinone derived from 2c [60].

2.4. Mechanism of Formation of Compounds 7–9

The proposed mechanism for the formation of compounds 7–9 is depicted in Scheme 6. As

proposed by Carlson [33], diacetyl (1a) reacts with the amine to give rise to imino ketone I, which

undergoes auto condensation to generate the imino aldol intermediate II. This is cyclized through an

internal condensation followed by a loss of water to afford III (an intermediate isolated by Carlson

for the case of 6b, but never observed or isolated in our trials), which leads to the isolation of

bis-iminoquinones 8 after losing another molecule of water. These compounds undergo reduction

to compounds 9 in the middle of the reaction. The latter conversion also takes place when leaving a

methanolic solution of 8a at room temperature, which rapidly changes from yellow to a dark color,

observing a mixture of 9a with a dark red resin.

Under standardized reaction conditions (Tables 1 and 2 ), this process seems to be faster than

1

that of the formation of iminoquinones 7, as observed by tlc and H-NMR. Compounds 8 before

compounds 7, suggesting that the latter are formed via an independent pathway or through

mono-hydrolysis of 8. The second hypothesis is not feasible, because there was no evidence of

the formation of 7a when a solution of 8a remained for a long time under the same reaction

conditions as those used for the synthesis of both compounds, leading rather to compound 9a and

side-products. Therefore, it is presumed that iminoquinones 7 are formed via a pathway that includes

the aldol condensation of I with another molecule of 1a to generate aldol IV, which by intramolecular

aldolization yields intermediate V. Finally, products 7 are formed by the loss of a water molecule. This

hypothesis is supported by the trials displayed in Table 1 (entries 1 and 5), in which only products 7a

and 9a were generated by the presence of an excess of 1a in the middle of the reaction.

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Molecules 2015, 20, 20719–20740

Scheme 6. Proposed reaction mechanism for the formation of iminoquinones 7 and 8, and

transamination process from 7 to 10.

Interestingly, quinone 23 was only isolated in traces from the reaction mixture. It is well known

that this quinone results from the condensation of two molecules of diacetyl (1a) under basic

conditions [33]. However, we have isolated it as the main product from the reaction between 1a and

2a after puriﬁcation of the crude mixture by column chromatography using silica gel not pre-treated

with triethylamine. This suggests that 23 proceeds from imines 7 and 8 by hydrolysis during the

puriﬁcation process, but not from the reaction.

Another interesting case is that of phenol 24, which was not observed or detected in the reaction

mixture by NMR, suggesting that iminoquinones 7 are stable enough to undergo reduction under the

reaction conditions. This is in contrast with compounds 8, in which the reductive aromatization takes

place during the reaction or the puriﬁcation process to yield p-dianilinobenzenes 9.

Regarding the transamination process from the iminoquinone 7a to 10a–c and from

diiminoquinone 8a to 21a–c, the mechanism can be explained in terms of a series of equilibria

promoted by the Brønsted acid catalyst (AcOH) in the presence of anilines 2, as summarized in

Scheme 6. It is likely that the ﬁrst acid-base equilibrium is established between 7 and the amino

protonated species VI, and that this undergoes the attack of aniline 2 (which is more nucleophilic

and less basic than the alkyl amine) to generate aminal species VII, followed by an elimination of the

most basic amine (isopropylamine) to provide the observable aryliminoquinones 10. Additionally,

this equilibrium seems to be favored by the higher stability of 10 than alkyliminoquinones 7,

resulting from a more stable conjugated imino system. These arguments can also be applied to the

transamination from 8a into bis-iminoquinones 21.

3. Experimental Section

3.1. General

Melting points were determined with a capillary melting point apparatus. IR spectra were

recorded on a Perkin-Elmer 2000 spectrophotometer (PerkinElmer, Waltham, MA, USA). ¹H (300 or

500 MHz) and ¹³C (75 or 125 MHz) NMR spectra were recorded on Varian Mercury-300 (Varian,

Inc., Palo Alto, CA, USA), and Varian VNMR System instruments (Varian, Inc., Palo Alto, CA, USA),

with TMS as internal standard; chemical shifts (δ) are reported in ppm. Assignment of the NMR

signals was made by HMQC and HMBC 2D methods (for the ¹H- and ¹³C-NMR spectra of the new

compounds, see the supplementary ﬁgures). Mass spectra (MS) and high-resolution mass spectra

(HRMS) were obtained in the electron impact (EI) (70 eV) mode and recorded on Polaris Q-Trace GC

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Ultra (Finnigan Co., Waltham, MA, USA) and Jeol JSM-GCMateII apparatuses (JEOL, Ltd., Tokyo,

Japan), respectively. Elemental analyses were performed on a CE-440 Exeter Analytical instrument

(Exeter Analytical, Inc., North Chelmsford, MA, USA), X-ray crystallographic measurements were

collected on an Oxford XcaliburS diffractometer (Rigaku Co., Tokyo, Japan). Analytical thin-layer

chromatography was carried out using E. Merck silica gel 60 F254 coated 0.25 plates, visualized by a

long- and short-wavelength UV lamp. Flash column chromatography was performed over Natland

International Co. (Morrisville, NC, USA) silica gel (230–400 mesh) and silica gel (230–400 mesh)

pre-treated with trimethylamine (10%). All air moisture sensitive reactions were carried out under

nitrogen using oven-dried glassware. MeOH, and toluene were freshly distilled over sodium, as

well as methylene chloride over calcium hydride, prior to use. Acetone was dried by distillation after

˝

treatment with 4 Å molecular sieves. K₂CO₃was dried overnight at 120 C prior to use. Triethylamine

was freshly distilled from NaOH. All other reagents were used without further puriﬁcation.

3.2. Synthesis and Characterization

1

(E)-4-(Isopropylimino)-2,5-dimethylcyclohexa-2,5-dien-1-one (7a), (E,E)-N,N -Diisopropyl-2,5-dimethyl

1

cyclohexa-2,5-diene-1,4-diimine (8a) and N,N -Diisopropyl-2,5-dimethylbenzene-1,4-diamine (9a).

A

mixture of 2,3-butanedione (1a) (1.971 g, 22.91 mmol) and isopropylamine (6a) (2.707 g, 45.88 mmol)

in MeOH (400 mL) was stirred at room temperature for 48 h. The crude reaction mixture was

concentrated under vacuum, and the residue was puriﬁed by column chromatography over silica gel

impregnated with triethylamine (10%) in hexane (40 g/g of crude, hexane) to give 7a (0.610 g, 30%)

as a pale green-yellow solid, 8a (0.524 g, 21%) as a dark red solid, and 9a (1.04 g, 41%) as a red solid.

˝

Data of 7a: R 0.53 (hexane/EtOAc, 8:2); mp 64–65 C. IR (ﬁlm): ν

1518, 1461, 1376, 1256, 1169, 894 cm

2969, 2925, 1652, 1631, 1604,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.25 (d, J = 6.0 Hz, 6H,

(CH₃)₂CH), 2.00 (d, J = 1.5 Hz, 3H, CH₃-C2), 2.15 (d, J = 1.5 Hz, 3H, CH₃-C5), 4.18 (sept, J = 6.5 Hz,

1H, (CH₃)₂CH), 6.41 (q, J = 1.5 Hz, 1H, H-6), 7.10 (dq, J = 1.5, 0.5 Hz, 1H, H-3). ¹³C-NMR (125 MHz,

CDCl₃): δ = 16.1 (CH₃-C2), 17.7 (CH₃-C5), 24.2 ((CH₃)₂CH), 51.8 ((CH₃)₂CH), 122.2 (C-3), 129.3 (C-6),

140.0 (C-2), 150.9 (C-5), 156.1 (C-4), 188.3 (C-1). MS (70 eV): m/z (%) 177 (M⁺, 100), 162 (73), 149 (45),

134 (58), 117 (43), 106 (35), 91 (52), 77 (19). Anal. calcd for C₁₁H₁₅NO: C, 74.54; H, 8.53; N, 7.90. Found:

C, 74.56; H, 8.49; N, 7.94.

˝

Data of 8a: R 0.64 (hexane/EtOAc, 8:2); mp 94–95 C. IR (ﬁlm): ν

1377, 1359, 1345, 1258, 1116, 875 cm

2967, 2924, 1599, 1581, 1519,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.20 (d, J = 6.0 Hz, 6H,

(CH₃)₂CH), 2.00 (d, J = 1.5 Hz, 6H, CH₃-C2, CH₃-C5), 4.08 (sept, J = 6.0 Hz, 2H, (CH₃)₂CH), 6.79 (br d,

J = 1.5 Hz, 2H, H-3, H-6). ¹³C-NMR (125 MHz, CDCl₃): δ = 18.5 (CH₃-C2, CH₃-C5), 24.2 (2(CH₃)₂CH),

50.4 (2(CH₃)₂CH), 118.4 (C-3, C-6), 143.3 (C-2, C-5), 156.9 (C-1, C-4). MS (70 eV): m/z (%) 218 (M⁺, 20),

203 (95), 161 (34), 146 (100), 145 (43), 132 (20), 117 (6), 91 (7). Anal. calcd for C₁₄H₂₂N₂: C, 77.01;

H, 10.16; N, 12.83. Found: C, 77.00; H, 10.21; N, 12.78.

˝

Data of 9a: R 0.22 (hexane/EtOAc, 8:2); mp 53–54 C. IR (ﬁlm): ν

3382, 2965, 2928, 1520, 1463,

max

f

1413, 1381, 1218, 1166, 1125, 1004, 857 cm^´1. H-NMR (500 MHz, CDCl₃): δ = 1.19 (d, J = 6.5 Hz, 6H,

(CH₃)₂CH), 2.10 (s, 6H, CH₃-C2, CH₃-C5), 2.70 (br s, 2H, NH), 3.53 (sept, J = 6.5 Hz, 2H, (CH₃)₂CH),

6.46 (s, 2H, H-3, H-6). ¹³C-NMR (125 MHz, CDCl₃): δ = 17.6 (CH₃-C2, CH₃-C5), 23.5 (2(CH₃)₂CH),

45.4 (2(CH₃)₂CH), 115.6 (C-3, C-6), 121.7 (C-2, C-5), 137.3 (C-1, C-4). MS (70 eV): m/z (%) 220 (M⁺, 98),

205 (100), 177 (99), 148 (20), 135 (56), 95 (15), 75 (6). HRMS (EI): m/z [M⁺] calcd for C₁₄H₂₄N₂: 220.1940;

found: 220.1938.

1

(E)-4-(Cyclohexylimino)-2,5-dimethylcyclohexa-2,5-dien-1-one (7b), (E,E)-N,N -Dicyclohexyl-2,5-dimethyl

1

cyclohexa-2,5-diene-1,4-diimine (8b) and N,N -Dicyclohexyl-2,5-dimethylbenzene-1,4-diamine (9b). The

procedure for the preparation of 7a–9a was followed using a mixture of 1a (1.971 g, 22.91 mmol)

and cyclohexylamine (6b) (4.53 g, 45.8 mmol) in MeOH (400 mL) to give 7b (0.721 g, 29%) as a pale

green-yellow solid, 8b (0.784 g, 23%) as a yellow solid, and 9b (1.34 g, 39%) as a dark brown solid.

20727

Molecules 2015, 20, 20719–20740

˝

Data of 7b: R_f0.51 (hexane/EtOAc, 9:1); mp 63–64 C. IR (ﬁlm): ν

1370, 1268, 1161, 900 cm

2925, 2853, 1647, 1620,

max

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.33 (qt, J = 12.0, 3.3 Hz, 1H, H-Cy),

1.43 (qt, J = 12.0, 3.3 Hz, 2H, H-Cy), 1.55–1.62 (m, 2H, H-Cy), 1.64–1.72 (m, 3H, H-Cy), 1.82–1.87

(m, 2H, H-Cy), 2.01 (d, J = 1.5 Hz, 3H, CH₃-C2), 2.14 (d, J = 1.5 Hz, 3H, CH₃-C5), 3.80–3.87 (m,

1H, NCH-Cy), 6.41 (br s, 1H, H-6), 7.08 (br s, J = 1.5 Hz, 1H, H-3). ¹³C-NMR (125 MHz, CDCl₃):

1

δ = 16.1 (CH₃-C2), 17.7 (CH₃-C5), 24.3 (2C-3 ), 25.6 (C-4 ), 34.3 (2C-2 ), 60.3 (C-1 ), 122.3 (C-3), 129.3

(C-6), 139.9 (C-2), 150.9 (C-5), 156.3 (C-4), 188.4 (C-1). HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₉NO:

217.1467; found: 217.1470.

˝

Data of 8b: R 0.68 (hexane/EtOAc, 9:1); mp 147–148 C [Lit. [33] 145.6–147 C]. IR (ﬁlm): ν

max

f

´1

2923, 2850, 1598, 1575, 1454, 1351, 1166, 962, 889, 871 cm

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.28

(qt, J = 13.0, 2.5 Hz, 2H, H-Cy), 1.35 (qt, J = 13.0, 2.5 Hz, 4H, H-Cy), 1.40–1.48 (m, 4H, H-Cy), 1.56–1.61

(m, 6H, H-Cy), 1.72–1.79 (m, 4H, H-Cy), 2.02 (s, 6H, CH₃-C2, CH₃-C5), 3.61–3.68 (m, 2H, NCH-Cy),

1

6.70 (br s, 2H, H-3, H-6). ¹³C-NMR (125 MHz, CDCl₃): δ = 18.4 (CH₃-C2, CH₃-C5), 24.7 (4C-3 ), 25.8

1

(2C-4 ), 34.2 (4C-2 ), 59.0 (2C-1 ), 118.5 (C-3, C-6), 143.3 (C-2, C-5), 157.1 (C-1, C-4). HRMS (EI): m/z

[M⁺] calcd for C₂₀H₃₀N₂: 298.2409; found: 298.2402.

˝

Data of 9b: R 0.21 (hexane/EtOAc, 9:1); mp 108–109 C. IR (ﬁlm): ν

1412, 1211, 1107, 850 cm

3383, 2927, 2850, 1519, 1445,

max

f

´1

.

¹H-NMR (300 MHz, CDCl₃): δ = 1.06–1.44 (m, 10H, H-Cy), 1.57–1.67

(m, 2H, H-Cy), 1.70–1.80 (m, 4H, H-Cy), 2.00–2.08 (m, 2H, H-Cy), 2.10 (s, 6H, CH₃-C2, CH₃-C5), 2.76

(br s, 2H, NH), 3.08–3.20 (m, 2Hz, NCH-Cy), 6.45 (s, 2H, H-3, H-6). ¹³C-NMR (75 MHz, CDCl₃):

1

δ = 17.7 (CH₃-C2, CH₃-C5), 25.1 (4C-3 ), 26.0 (2C-4 ), 34.0 (4C-2 ), 53.0 (2C-1 ), 115.4 (C-3, C-6), 121.5

(C-2, C-5), 137.0 (C-1, C-4). HRMS (EI): m/z [M⁺] calcd for C₂₀H₃₂N₂: 300.2566; found: 300.2570.

1

(E,E)-2,5-Dimethyl-N,N -bis((S)-1-phenylethyl)cyclohexa-2,5-diene-1,4-diimine (8c) and 2,5-Dimethyl-N,

1

N -bis((S)-1-phenylethyl)benzene-1,4-diamine (9c). The procedure for the preparation of 7a–9a was

followed using a mixture of 1a (0.098 g, 1.14 mmol) and (S)-phenylethylamine (6c) (0.278 g, 2.3 mmol)

in MeOH (10 mL) to give 8c (0.031 g, 16%) as a yellow solid and 9c (0.059 g, 30%) as a dark brown oil.

22

˝

Data of 8c: R_f0.65 (hexane/EtOAc, 8:2); mp 108–109 C; rαs_D= ´44.28 (c 0.473, CHCl₃). IR (ﬁlm):

1

ν

1699, 1493, 1450, 1354, 1125, 760, 699 cm^´1. H-NMR (500 MHz, CDCl₃): δ = 1.49 (d, J = 6.5 Hz,

max

6H, CH₃CH), 2.17 (d, J = 1.5 Hz, 6H, CH₃-C2, CH₃-C5), 5.08 (q, J = 6.5 Hz, 2H, CH₃CH), 6.89 (br s,

11

1H, H-3, H-6), 7.19–7.24 (m, 2H, H-4 ), 7.30–7.34 (m, 4H, H-3 ), 7.43–7.46 (m, 4H, H-2 ). ¹³C-NMR

(125 MHz, CDCl₃): δ = 18.5 (CH₃-C2, CH₃-C5), 25.7 (2CH₃CH), 58.9 (2CH₃CH), 118.5 (C-3, C-6),

11

126.58 (2C-4 ), 126.61 (4C-2 ), 128.4 (4C-3 ), 144.1 (C-2, C-5), 146.2 (2C-1 ), 157.5 (C-1, C-4). MS

(70 eV): m/z (%) 342 (M⁺, 22), 328 (23), 327 (100), 300 (14), 237 (12), 222 (24), 208 (26), 105 (20), 97 (24),

86 (38), 71 (43), 57 (45). HRMS (EI): m/z [M⁺] calcd for C₂₄H₂₆N₂: 342.2096; found: 342.2090.

22

Data of 9c: R_f0.32 (hexane/EtOAc, 9:1); rαs = +10.75 (c 0.282, CHCl ). IR (ﬁlm): ν

3417, 2969,

max

3

D

´1

1448, 1414, 1520, 1371, 1224, 769, 698 cm

.

¹H-NMR (300 MHz, CDCl₃): δ = 1.47 (d, J = 6.6 Hz,

6H, CH₃CH), 2.02 (s, 6H, CH₃-C2, CH₃-C5), 3.30 (br s, 2H, NH), 4.39 (q, J = 6.6 Hz, 2H, CH₃CH),

6.21 (s, 2H, H-3, H-6), 7.22–7.37 (m, 10H, PhH). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.6 (2CH₃Ar),

11

25.1 (2CH₃CH), 54.0 (2CH₃CH), 114.7 (C-3, C-6), 120.6 (C-2, C-5), 125.8 (4C-2 ), 126.5 (2C-4 ),

11

128.4 (4C-3 ), 136.9 (C-1, C-4), 145.9 (2C-1 ). HRMS (EI): m/z [M⁺] calcd for C₂₄H₂₈N₂: 344.2253;

found: 344.2257.

1

N,N -Dibutyl-2,5-dimethylbenzene-1,4-diamine (9d). The procedure for the preparation of 7a–9a was

followed using a mixture of 1a (1.971 g, 22.91 mmol) and n-butylamine (6d) (3.34 g, 45.8 mmol) in

MeOH (400 mL) to give 9d (0.512 g, 18%) as a dark brown oil. R_f0.44 (hexane/EtOAc, 8:2). IR

´1

.

¹H-NMR (500 MHz,

(ﬁlm): ν

3369, 2955, 2925, 1518, 1469, 1413, 1222, 1214, 994, 855, 742 cm

max

CDCl₃): δ = 0.96 (t, J = 7.5 Hz, 6H, N(CH₂)₃CH₃), 1.44 (sext, J = 7.5 Hz, 4H, N(CH₂)₂CH₂CH₃), 1.62

(qu, J = 7.0 Hz, 4H, NCH₂CH₂CH₂CH₃), 2.12 (s, 6H, CH₃-C2, CH₃-C5), 2.98 (br s, 2H, NH), 3.08

(br t, J = 7.0 Hz, 4H, NCH₂(CH₂)₂CH₃), 6.44 (s, 2H, H-3, H-6). ¹³C-NMR (125 MHz, CDCl₃): δ = 13.9

(2N(CH₂)₃CH₃), 17.4 (CH₃-C2, CH₃-C5), 20.4 (2N(CH₂)₂CH₂CH₃), 32.0 (2NCH₂CH₂CH₂CH₃), 45.0

20728

Molecules 2015, 20, 20719–20740

(2NCH₂(CH₂)₂CH₃), 114.1 (C-3, C-6), 121.1 (C-2, C-5), 138.3 (C-1, C-4). MS (70 eV): m/z (%) 248

(M⁺, 70), 205 (100), 191 (32), 135 (10), 120 (11), 81 (26). HRMS (EI): m/z [M⁺] calcd for C₁₆H₂₈N₂:

248.2253; found: 248.2260.

(E)-2,5-Dimethyl-4-(phenylimino)cyclohexa-2,5-dien-1-one (10a). A mixture of 7a (0.442 g, 2.50 mmol)

and aniline (2a) (0.233 g, 2.50 mmol) in toluene (40 mL) was stirred at room temperature for 10 min.

Then, glacial acetic acid (0.524 g, 8.74 mmol) was added dropwise and the mixture was stirred at room

temperature for 12 h. The crude mixture was concentrated under vacuum and puriﬁed by column

chromatography over silica gel (10 g/g crude, hexane/EtOAc, 8:2) to give 10a (0.316 g, 60%) as a

˝

dark red solid. R_f0.66 (hexane/EtOAc, 8:2); mp 73–74 C. IR (ﬁlm): ν_max1649, 1633, 1603, 1497, 1482,

1262, 1204, 1159, 900, 762, 697 cm^´1. ¹H-NMR (300 MHz, CDCl₃): δ = 1.93 (d, J = 1.5 Hz, 3H, CH₃-C2),

2.27 (d, J = 1.5 Hz, 3H, CH₃-C5), 6.55 (q, J = 1.5 Hz, 1H, H-6), 6.78 (q, J = 1.5 Hz, 1H, H-3), 6.80–6.85

1

(m, 2H, H-2 ), 7.17-7.22 (m, 1H, H-4 ), 7.34–7.44 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 16.1

1

(CH₃-C2), 18.0 (CH₃-C5), 120.2 (C-2 ), 125.4 (C-4 ), 125.6 (C-3), 129.2 (C-3 ), 131.1 (C-6), 141.5 (C-2),

149.5 (C-4), 150.2 (C-1 ), 158.5 (C-5), 188.4 (C-1). HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₃NO: 211.0997;

1

found: 211.0989.

(E)-4-((4-Methoxyphenyl)imino)-2,5-dimethylcyclohexa-2,5-dien-1-one (10b). The procedure for the

preparation of 10a was followed using a mixture of 7a (0.202 g, 1.14 mmol) and 4-methoxyaniline

(2b) (0.140 g, 1.14 mmol) and glacial acetic acid (0.524 g, 8.74 mmol) in toluene (20 mL) to give

˝

10b (0.227 g, 82%) as a dark red solid. R 0.40 (hexane/EtOAc, 1:1); mp 79–80 C. IR (ﬁlm): ν

max

f

´1

1648, 1628, 1599, 1499, 1246, 1164, 1033, 902, 843, 762 cm

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.95

(d, J = 1.5 Hz, 3H, CH₃-C2), 2.26 (d, J = 1.5 Hz, 3H, CH₃-C5), 3.84 (s, 3H, CH₃O), 6.52 (br d,

1

J = 1.5 Hz, 1H, H-6), 6.83–6.86 (m, 2H, H-2 ), 6.90 (br d, J = 1.5 Hz, 1H, H-3), 6.93–6.97 (m, 2H, H-3 ).

1

¹³C-NMR (125 MHz, CDCl₃): δ = 15.8 (CH₃-C2), 17.7 (CH₃-C5), 55.4 (CH₃O), 114.2 (C-3 ), 122.4 (C-2 ),

1

125.3 (C-3), 130.4 (C-6), 140.7 (C-2), 143.1 (C-1 ), 149.4 (C-5), 157.7 (C-4), 157.9 (C-4 ), 188.1 (C-1). MS

(70 eV): m/z (%) 241 (M⁺, 70), 226 (36), 210 (100), 198 (22), 182 (40), 167 (26), 155 (18). HRMS (EI): m/z

[M⁺] calcd for C₁₅H₁₅NO₂: 241.1103; found: 241.1090.

(E)-2,5-Dimethyl-4-(p-tolylimino)cyclohexa-2,5-dien-1-one (10c). The procedure of preparation for 10a

was followed using a mixture of 7a (0.300 g, 1.69 mmol), 4-methylaniline (2c) (0.208 g, 1.69 mmol)

and glacial acetic acid (0.524 g, 8.73 mmol) in toluene (20 mL) to give 10c (0.305 g, 80%) as a dark red

˝

solid. R 0.68 (hexane/EtOAc, 7:3); mp 88–89 C. IR (ﬁlm): ν

2922, 1628, 1508, 1446, 1259, 1110,

max

f

1

1091, 1006, 903, 842, 804 cm^´1. H-NMR (300 MHz, CDCl₃): δ = 1.93 (d, J = 1.4 Hz, 3H, CH₃-C2), 2.27

1

(d, J = 1.4 Hz, 3H, CH₃-C5), 2.38 (s, 3H, CH₃Ar), 6.53 (q, J = 1.4 Hz, 1H, H-6), 6.72–6.78 (m, 2H, H-2 ),

6.84 (q, J = 1.4 Hz, 1H, H-3), 7.17–7.24 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.8 (CH₃-C2),

1

17.8 (CH₃-C5), 20.8 (CH₃Ar), 120.3 (C-2 ), 125.4 (C-3), 129.5 (C-3 ), 130.6 (C-6), 135.1 (C-4 ), 140.9 (C-2),

147.4 (C-1 ), 149.4 (C-5), 158.1 (C-4), 188.3 (C-1). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅NO: 225.1154;

1

found: 225.1155.

2,5-Dimethyl-4-(phenylamino)phenol (11a). To a solution of 10a (0.100 g, 0.47 mmol) in Et₂O (10 mL) a

saturated aqueous solution of sodium hydrosulﬁte (30 mL) was added, and the mixture was stirred at

room temperature for 12 h. The crude mixture was washed with CH₂Cl₂(3 ˆ 10 mL) and the organic

layer was dried (Na₂SO₄), concentrated under vacuum and puriﬁed by column chromatography

over silica gel (10 g/g crude, hexane/EtOAc, 9:1) to give 11a (0.090 g, 90%) as a pink oil. R_f0.49

´1

.

(hexane/EtOAc, 8:2). IR (ﬁlm): ν

3382, 2923, 1600, 1497, 1462, 1407, 1200, 864, 745, 694 cm

max

¹H-NMR (300 MHz, CDCl₃): δ = 2.14 (s, 3H, CH₃-C5), 2.18 (s, 3H, CH₃-C2), 4.50–5.30 (br, 2H, NH,

1

OH), 6.65 (s, 1H, H-6), 6.66–6.73 (m, 2H, H-2 ), 6.77 (t, J = 7.3 Hz, 1H, H-4 ), 6.98 (s, 1H, H-3), 7.14–7.22

(m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.4 (CH₃-C2), 17.5 (CH₃-C5), 114.6 (C-2 ), 117.1 (C-6),

1

118.6 (C-4 ), 121.9 (C-2), 126.8 (C-3), 129.2 (C-3 ), 131.6 (C-5), 133.1 (C-4), 146.4 (C-1 ), 150.4 (C-1).

HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₅NO: 213.1154; found: 213.1144.

20729

Molecules 2015, 20, 20719–20740

4-((4-Methoxyphenyl)amino)-2,5-dimethylphenol (11b). The procedure for the preparation of 11a was

followed using a mixture of 10b (0.099 g, 0.41 mmol) in Et₂O (10 mL) and a saturated aqueous solution

of sodium hydrosulﬁte (30 mL) to give 11b (0.085 g, 85%) as a red solid. R_f0.25 (hexane/EtOAc, 8:2);

˝

1

mp 86–87 C. IR (KBr): ν

3406, 1511, 1466, 1246, 1193, 1179, 1036, 825 cm^´1. H-NMR (500 MHz,

max

CDCl₃): δ = 2.13 (br s, 3H, CH₃Ar), 2.16 (br s, 3H, CH₃Ar), 3.76 (s, 3H, CH₃O), 4.53–4.92 (br s, 2H,

1

OH, NH), 6.61 (br s, 1H, H-6), 6.72–6.76 (m, 2H, H-2 ), 6.78–6.81 (m, 2H, H-3 ), 6.85 (br s, 1H, H-3).

1

¹³C-NMR (75 MHz, CDCl₃): δ = 15.4 (CH₃Ar), 17.4 (CH₃Ar), 55.7 (CH₃O), 114.8 (C-3 ), 117.3 (C-6),

1

118.0 (C-2 ), 121.9 (C-2), 123.8 (C-3), 129.0 (C-5), 135.0 (C-1 ), 139.4 (C-4), 149.3 (C-1), 153.4 (C-4 ). MS

(70 eV): m/z (%) 243 (M⁺, 91), 228 (100), 200 (11), 185 (9), 168 (7), 134 (5), 77 (7). HRMS (EI): m/z [M⁺]

calcd for C₁₅H₁₇NO₂: 243.1259; found: 243.1260.

2,5-Dimethyl-4-((4-tolyl)amino)phenol (11c). The procedure for the preparation of 11a was followed

using a mixture of 10c (0.200 g, 0.89 mmol) in Et₂O (10 mL) and a saturated aqueous solution of

sodium hydrosulﬁte (30 mL) to give 11c (0.193 g, 95%) as a brown solid. R_f0.45 (hexane/EtOAc,

˝

1

7:3); mp 104–105 C. IR (ﬁlm): ν

3388, 2922, 1614, 1511, 1461, 1196, 993, 811, 738 cm^´1. H-NMR

max

(300 MHz, CDCl₃): δ = 2.12 (s, 3H, CH₃-C5), 2.16 (s, 3H, CH₃-C2), 2.25 (s, 3H, CH₃Ar), 4.70–5.50 (br,

1

2H, OH, NH), 6.62–6.67 (m, 2H, H-2 ), 6.65 (br s, 1H, H-6), 6.93 (br s, 1H, H-3), 6.96–7.02 (m, 2H,

1

H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.5 (CH₃-C2), 17.5 (CH₃-C5), 20.5 (CH₃Ar), 115.3 (C-2 ), 117.2

1

(C-6), 121.8 (C-2), 125.6 (C-3), 128.1 (C-4 ), 129.7 (C-3 ), 130.6 (C-5), 133.6 (C-4), 143.7 (C-1 ), 150.1 (C-1).

HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₇NO: 227.1310; found: 227.1314.

4-(Benzyloxy)-N-(4-methoxyphenyl)-2,5-dimethylaniline (12a). To a mixture of 11b (0.137 g, 0.56 mmol)

in acetone (15 mL) K₂CO₃(0.116 g, 0.84 mmol) and benzyl bromide (0.115 g, 0.67 mmol) were

added, and the mixture was stirred at reﬂux for 3 h. The crude mixture was ﬁltered over Celite,

concentrated under vacuum, and puriﬁed by column chromatography over silica gel (10 g/g crude,

hexane/EtOAc, 8:2) to give 12a (0.169 g, 90%) as a white powder. R_f0.44 (hexane/EtOAc, 8:2); mp

˝

55–56 C. IR (KBr): ν

3412, 2961, 2916, 1521, 1465, 1382, 1293, 1249, 1197, 1098, 1037, 1014, 825,

max

´1

744, 698 cm

.

¹H-NMR (500 MHz, CDCl₃): δ = 2.16 (s, 3H, CH₃-C5), 2.19 (s, 3H, CH₃-C2), 3.72

1

(s, 3H, CH₃O), 5.00 (s, 2H, CH₂Ph), 6.72–6.80 (m, 4H, H-2 , H-3 ), 6.74 (s, 1H, H-6), 6.89 (s, 1H, H-3),

7.29 (t, J = 7.5 Hz, 1H, H-4 ), 7.36 (t, J = 7.5 Hz, 2H, H-3 ), 7.43 (d, J = 7.5 Hz, 2H, H-2 ). ¹³C-NMR

11

(125 MHz, CDCl₃): δ = 16.0 (CH₃-C2), 17.8 (CH₃-C5), 55.5 (CH₃O), 70.4 (CH₂Ph), 114.6 (C-6), 114.64

1

11

(2C-3 ), 118.2 (2C-2 ), 123.3 (C-3), 125.3 (C-2), 127.1 (2C-2 ), 127.6 (C-4 ), 127.8 (C-5), 128.4 (2C-3 ),

135.1 (C-1 ), 137.7 (C-1 ), 139.1 (C-4), 152.4 (C-1), 153.5 (C-4 ). MS (70 eV): m/z (%) 333 (M⁺, 16), 243

(87), 228 (100), 212 (61), 197 (80), 179 (28), 135 (36), 108 (53), 91 (48), 77 (21). HRMS (EI): m/z [M⁺] calcd

for C₂₂H₂₃NO₂: 333.1729; found: 333.1715.

1

11

1

Methyl 2-(2,5-dimethyl-4-(phenylamino)phenoxy)acetate (12b). The procedure for the preparation of

12a was followed with a mixture of 11a (0.104 g, 0.49 mmol), K₂CO₃(0.102 g, 0.74 mmol) and

methyl bromoacetate (0.083 g, 0.54 mmol) to give 12b (0.086 g, 62%) as a brown powder. R_f0.41

˝

(hexane/EtOAc, 8:2); mp 102–103 C. IR (ﬁlm): ν

3387, 2923, 1600, 1497, 1406, 1196, 994, 862, 747,

max

1

694 cm^´1. H-NMR (300 MHz, CDCl₃): δ = 2.17 (s, 3H, CH₃-C5 ), 2.22 (s, 3H, CH₃-C2 ), 3.80 (s, 3H,

1

11

CO₂CH₃), 4.63 (s, 2H, CH₂CO₂Me), 5.19 (br s, 1H, NH), 6.58 (s, 1H, H-6 ), 6.69–6.75 (m, 2H, H-2 ),

6.78 (t, J = 7.2 Hz, 1H, H-4 ), 7.02 (s, 1H, H-3 ), 7.14–7.24 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃):

11

1

11

1

11

1

δ = 15.8 (CH₃-C2 ), 17.9 (CH₃-C5 ), 52.1 (CH₂CO₂CH₃), 66.0 (CH₂CO₂Me), 114.1 (C-6 ), 115.0 (2C-2 ),

11

1

11

1

11

118.8 (C-4 ), 125.6 (C-2 ), 125.8 (C-3 ), 129.2 (2C-3 ), 130.0 (C-5 ), 134.0 (C-4 ), 145.8 (C-1 ), 152.5 (C-1 ),

169.8 (CO₂Me). HRMS (EI): m/z [M⁺] calcd for C₁₇H₁₉NO₃: 285.1365; found: 285.1377.

Methyl 2-(4-((4-methoxyphenyl)amino)-2,5-dimethylphenoxy)acetate (12c). The procedure for the

preparation of 12a was followed using a mixture of 11b (0.081 g, 0.33 mmol), K₂CO₃(0.066 g,

0.48 mmol) and methyl bromoacetate (0.057 g, 0.37 mmol) to give 12c (0.08 g, 76%) as a brown solid.

˝

R 0.47 (hexane/EtOAc, 8:2); mp 124–125 C. IR (ﬁlm): ν

3340, 2922, 1755, 1508, 1438, 1233, 1198,

max

f

´1

1

1116, 1034, 822 cm

.

¹H-NMR (300 MHz, CDCl₃): δ = 2.17 (s, 3H, CH₃-C5 ), 2.20 (s, 3H, CH₃-C2 ),

20730

Molecules 2015, 20, 20719–20740

3.76 (s, 3H, CH₃O), 3.80 (s, 3H, CO₂CH₃), 4.61 (s, 2H, CH₂CO₂Me), 4.99 (br s, 1H, NH), 6.58 (s,

1

11

1

1H, H-6 ), 6.79-6.82 (br s, 4H, H-2 , H-3 ), 6.88 (s, 1H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.8

1

11

(CH₃-C2 ), 17.8 (CH₃-C5 ), 52.1 (CH₂CO₂CH₃), 55.6 (CH₃O), 66.4 (CH₂CO₂Me), 114.6 (2C-3 ), 114.7

(C-6 ), 118.9 (2C-2 ), 122.3 (C-3 ), 125.6 (C-2 ), 126.9 (C-5 ), 136.3 (C-4 ), 138.4 (C-1 ), 151.2 (C-1 ),

153.7 (C-4 ), 169.9 (CO₂Me). HRMS (EI): m/z [M⁺] calcd for C₁₈H₂₁NO₄: 315.1471; found: 315.1464.

1

11

1

11

1

11

4-Methoxy-N-(4-methoxyphenyl)-N,2,5-trimethylaniline (12d). A mixture of 11b (0.180 g, 0.74 mmol),

iodomethane (0.210 g, 1.48 mmol) and K₂CO₃(0.204 g, 1.48 mmol) in acetone (2 mL) was stirred

˝

at 60 C for 24 h. Then, the crude mixture was ﬁltered over Celite and concentrated under

vacuum, and the residue was puriﬁed by column chromatography over silica gel (10 g/g crude,

hexane/EtOAc, 99:1) to give 12d (0.082 g, 41%) as a pink oil. R_f0.59 (hexane/EtOAc, 8:2). IR (ﬁlm):

1

ν

2929, 1508, 1465, 1240, 1153, 1065, 1038, 818 cm^´1. H-NMR (500 MHz, CDCl₃): δ = 2.11 (s, 3H,

max

1

CH₃-C2), 2.15 (s, 3H, CH₃-C5), 3.13 (s, 3H, NCH₃), 3.72 (s, 3H, CH₃O-C4 ), 3.82 (s, 3H, CH₃O-C4),

6.45–6.51 (m, 2H, H-2 ), 6.70 (s, 1H, H-3), 6.74–6.79 (m, 2H, H-3 ), 6.87 (s, 1H, H-6). ¹³C-NMR

1

(125 MHz, CDCl₃): δ = 15.7 (CH₃-C5), 17.8 (CH₃-C2), 39.5 (NCH₃), 55.4 (CH₃O-C4), 55.7 (CH₃O-C4 ),

112.3 (C-3), 113.8 (C-2 ), 114.6 (C-3 ), 125.4 (C-5), 130.0 (C-6), 134.7 (C-2), 139.8 (C-1), 144.4 (C-1 ), 151.3

(C-4 ), 155.6 (C-4). HRMS (EI): m/z [M⁺] calcd for C₁₇H₂₁NO₂: 271.1572; found: 271.1573.

1

2-(Benzylthio)-4-((4-methoxyphenyl)amino)-3,6-dimethylphenol (14a). A mixture of 10b (0.096 g,

0.40 mmol), benzylthiol (13a) (0.055 g, 0.044 mmol) and DMAP (0.054 g, 0.44 mmol) in CH₂Cl₂(20 mL)

was stirred at room temperature for 24 h. Then the mixture was concentrated under vacuum and

puriﬁed by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 95:5) to give 14a

(0.080 g, 55%) as a purple oil. R 0.75 (hexane/EtOAc, 7:3). IR (ﬁlm): ν

1409, 1232, 1178, 1033, 1007, 820, 697 cm

2.17 (s, 3H, CH₃-C6), 3.76 (s, 3H, CH₃O), 3.77 (s, 2H, CH₂Ph), 4.91 (br s, 1H, NH), 6.60–6.64 (m, 2H,

3377, 2924, 1507, 1455,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 2.15 (s, 3H, CH₃-C3),

11

1

H-2 ), 6.76–6.80 (m, 2H, H-3 ), 6.88 (s, 1H, OH), 6.92 (s, 1H, H-5), 7.06–7.10 (m, 2H, H-2 ), 7.20–7.26

1

(m, 3H, H-3 , H-4 ). ¹³C-NMR (125 MHz, CDCl₃): δ = 15.9 (CH₃-C3), 16.3 (CH₃-C6), 40.0 (CH₂Ph),

11

1

55.7 (CH₃O), 114.8 (C-3 ), 117.2 (C-2 ), 118.2 (C-2), 121.7 (C-6), 127.1 (C-5), 127.4 (C-4 ), 128.5 (C-3 ),

128.8 (C-2 ), 134.0 (C-4), 134.1 (C-3), 137.3 (C-1 ), 139.8 (C-1 ), 152.0 (C-1), 153.3 (C-4 ). HRMS (EI):

m/z [M⁺] calcd for C₂₂H₂₃NO₂S: 365.1449; found: 365.1448.

1

11

2-((2-Bromophenyl)thio)-4-((4-methoxyphenyl)amino)-3,6-dimethylphenol (14b). The procedure for the

preparation of 14a was followed using a mixture of 10b (0.048 g, 0.20 mmol), o-bromobenzenethiol

(13b) (0.038 g, 0.20 mmol) and DMAP (0.025 g, 0.20 mmol) to give 14b (0.064 g, 75%) as a purple

oil. R 0.69 (hexane/EtOAc, 7:3). IR (ﬁlm): ν

820, 744 cm

(s, 3H, CH₃O), 5.03 (br s, 1H, NH), 6.51 (d, J = 8.0 Hz, 1H, H-6 ), 6.56 (s, 1H, HO), 6.70–6.75 (m, 2H,

3402, 2924, 1507, 1461, 1444, 1232, 1176, 1035, 1016,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 2.24 (s, 3H, CH₃-C6), 2.26 (s, 3H, CH₃-C3), 3.77

1

11

1

H-2 ), 6.77–6.83 (m, 2H, H-3 ), 6.99 (dd, J = 8.0, 7.5 Hz, 1H, H-4 ), 7.08 (s, 1H, H-5), 7.10 (dd, J = 8.0,

1

7.5 Hz, 1H, H-5 ), 7.53 (d, J = 8.0 Hz, 1H, H-3 ). ¹³C-NMR (125 MHz, CDCl₃): δ = 15.9 (CH₃-C3), 16.4

11

1

11

(CH₃-C6), 55.7 (CH₃O), 114.8 (2C-3 ), 115.5 (C-2), 117.9 (2C-2 ), 121.0 (C-2 ), 122.8 (C-6), 125.9 (C-6 ),

126.7 (C-4 ), 127.4 (C-5), 128.0 (C-5 ), 133.0 (C-3 ), 133.4 (C-4), 135.1 (C-3), 136.6 (C-1 ), 139.1 (C-1 ),

152.1 (C-1), 153.7 (C-4 ). HRMS (EI): m/z [M⁺] calcd for C₂₁H₂₀BrNO₂S: 429.0398; found: 429.0386.

1

11

2-((4-Chlorophenyl)thio)-4-((4-methoxyphenyl)amino)-3,6-dimethylphenol (14c). The procedure for the

preparation of 14a was followed using a mixture of 10b (0.146 g, 0.61 mmol), p-chlorobenzenethiol

(13c) (0.088 g, 0.61 mmol) and DMAP (0.074 g, 0.61 mmol) to give 14c (0.232 g, 99%) as a purple oil.

R 0.58 (hexane/EtOAc, 7:3). IR (ﬁlm): ν

3386, 2923, 1508, 1461, 1241, 1181, 1090, 1031, 1009, 816

max

f

1

cm^´1. H-NMR (300 MHz, CDCl₃): δ = 2.23 (s, 3H, CH₃-C6), 2.25 (s, 3H, CH₃-C3), 3.75 (s, 3H, CH₃O),

11

5.02 (br s, 1H, HN), 5.26 (s, 1H, HO), 6.65–6.74 (m, 2H, H-2 ), 6.75–6.82 (m, 2H, H-3 ), 6.90–6.97

1

(m, 2H, H-2 ), 7.04 (s, 1H, H-5), 7.13–7.22 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.9 (CH₃-C6),

11

1

16.4 (CH₃-C3), 55.6 (CH₃O), 114.7 (C-3 ), 115.4 (Ar), 117.7 (C-2 ), 122.5 (Ar), 127.2 (C-5), 127.3 (2C-2 ),

20731

Molecules 2015, 20, 20719–20740

1

11

129.2 (2C-3 ), 131.6 (Ar), 133.2 (Ar), 134.0 (Ar), 134.9 (Ar), 139.0 (C-1 ), 151.8 (C-1), 153.5 (C-4 ). HRMS

(EI): m/z [M⁺] calcd for C₂₁H₂₀ClNO₂S: 385.0903; found: 385.0900.

4-((4-Methoxyphenyl)amino)-3,6-dimethyl-3-((4-tolyl)thio)phenol (14d). The procedure for the

preparation of 14a was followed using a mixture of 10b (0.200 g, 0.83 mmol), p-tolylthiol (13d)

(0.103 g, 0.84 mmol) and DMAP (0.101 g, 0.83 mmol) to give 14d (0.274 g, 90%) as a purple oil. R_f0.73

´1

.

(hexane/EtOAc, 7:3). IR (ﬁlm): ν

3394, 2919, 1508, 1473, 1233, 1179, 1090, 1031, 1010, 819 cm

max

¹H-NMR (300 MHz, CDCl₃): δ = 2.23 (s, 3H, CH₃-C6), 2.26 (s, 3H, CH₃Ar), 2.27 (s, 3H, CH₃-C3), 3.74

11

(s, 3H, CH₃O), 4.99 (br s, 1H, HN), 6.66–6.71 (m, 2H, H-2 ), 6.75–6.80 (m, 2H, H-3 ), 6.92–6.96 (m,

2H, H-3 ), 7.01 (s, 1H, H-5), 7.00–7.04 (m, 2H, H-2 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.9 (CH₃-C3),

1

11

1

16.4 (CH₃-C6), 20.8 (CH₃Ar), 55.6 (CH₃O), 114.7 (C-3 ), 116.6 (C-2), 117.5 (C-2 ), 122.2 (C-6), 126.5

(C-3 ), 127.2 (C-5), 129.9 (C-2 ), 131.8 (C-4 ), 133.7 (C-3), 134.6 (C-4), 135.7 (C-1 ), 139.5 (C-1 ), 152.1

1

11

(C-1), 153.4 (C-4 ). HRMS (EI): m/z [M⁺] calcd for C₂₂H₂₃NO₂S: 365.1449; found: 365.1440.

2,4-Bis((4-Methoxyphenyl)amino)-3,6-dimethylphenol (15). A mixture of 7a (0.500 g, 2.82 mmol), 2b

(0.694 g, 5.64 mmol) and AcOH (0.051 g, 0.85 mmol) in toluene (30 mL) was stirred at room

temperature for 24 h. The crude mixture was concentrated under vacuum, and then Et₂O (30 mL)

and a saturated aqueous solution of sodium hydrosulﬁte (30 mL) were added, followed by stirring

at room temperature for 12 h. The crude mixture was washed with CH₂Cl₂(3 ˆ 10 mL) and the

organic layer dried (Na₂SO₄), concentrated under vacuum and puriﬁed by column chromatography

over silica gel (10 g/g crude, hexane/EtOAc, 9:1) to give 11b (0.426 g, 62%) and 15 (0.278 g, 27%) as a

purple solid.

˝

Data of 15a: R 0.32 (hexane/EtOAc, 1:1); mp 70–71 C. IR (KBr): ν

1033, 825 cm

3344, 2932, 1629, 1510, 1239,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.97 (s, 3H, CH₃-C3), 2.24 (s, 3H, CH₃-C6), 3.73

(s, 3H, CH₃O), 3.75 (s, 3H, CH₃O), 4.79 (br, 1H, NH), 4.95 (br, 1H, OH), 6.35 (br, 1H, NH), 6.54–6.58

(m, 2H, 2ArH), 6.65–6.69 (m, 2H, 2ArH), 6.74–6.79 (m, 4H, 4ArH), 6.88 (s, 1H, H-5). ¹³C-NMR

(125 MHz, CDCl₃): δ = 12.6 (CH₃-C2), 15.8 (CH₃-C5), 55.6 (CH₃O), 55.7 (CH₃O), 114.7 (2ArH), 114.9

(2ArH), 115.3 (2ArH), 117.3 (2ArH), 121.5 (Ar), 123.6 (C-5), 127.0 (Ar), 127.5 (Ar), 134.1 (Ar), 139.8

(Ar), 140.1 (Ar), 148.6 (C-4), 153.3 (ArO), 153.4 (ArO). MS (70 eV): m/z (%) 348 (M⁺, 100), 333 (68), 273

(70), 243 (44), 228 (60), 160 (36), 146 (18), 122 (16), 77 (14). HRMS (EI): m/z [M⁺] calcd for C₂₂H₂₄N₂O₃:

364.1787; found: 364.1786.

1

4-(Benzyloxy)-N,N -bis(4-methoxyphenyl)-2,5-dimethylbenzene-1,2-diamine (16). A mixture of 7a (0.618 g,

3.49 mmol), 2b (1.073 g, 8.72 mmol) and AcOH (0.063 g, 1.05 mmol) in toluene (40 mL) was stirred

at room temperature for 24 h, then concentrated under vacuum and suspended in Et₂O (30 mL). A

saturated aqueous solution of sodium hydrosulﬁte (30 mL) was added and the mixture was stirred

at room temperature for 12 h. The crude mixture was washed with CH₂Cl₂(3 ˆ 10 mL) and the

organic layer dried (Na₂SO₄) and concentrated under vacuum. The crude mixture was suspended in

acetone (30 mL) and K₂CO₃(0.723 g, 5.24 mmol), followed by the addition of benzyl bromide (0.718 g,

4.20 mmol) and stirring at reﬂux for 3 h. The mixture was ﬁltered over Celite and concentrated under

vacuum, then puriﬁed by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 8:2)

to give 12a (0.640 g, 55%) and 16 (0.460 g, 29%) as a purple solid.

˝

Data of 16: R 0.26 (hexane/EtOAc, 8:2); mp 60–61 C. IR (ﬁlm): ν

1178, 1034, 823 cm

3377, 2930, 1508, 1457, 1235,

max

f

´1

.

¹H-NMR (300 MHz, CDCl₃): δ = 1.99 (s, 3H, CH₃-C2), 2.24 (s, 3H, CH₃-C5),

3.77 (s, 3H, CH₃O), 3.80 (s, 3H, CH₃O), 4.61 (s, 2H, CH₂Ph), 4.80–6.00 (br, 2H, NH), 6.59–6.64 (m, 2H,

2ArH), 6.70 (s, 1H, H-6), 6.77–6.80 (m, 2H, 2ArH), 6.82–6.89 (m, 2H, 2ArH), 6.93–6.99 (m, 2H, 2ArH),

7.23–7.34 (m, 5H, PhH). ¹³C-NMR (75 MHz, CDCl₃): δ = 13.2 (CH₃-C2), 16.3 (CH₃-C5), 55.61 (CH₃O),

55.62 (CH₃O), 75.5 (CH₂Ph), 114.5 (2ArH), 114.7 (C-6), 116.7 (2ArH), 120.6 (C-2), 120.8 (4ArH), 128.1

(PhH), 128.2 (2PhH), 128.5 (2PhH), 129.0 (C-5), 135.5 (C-3), 137.3 (Ar), 137.4 (Ar), 139.7 (Ar), 140.0

(Ar), 145.6 (C-4), 153.2 (ArO), 154.5 (ArO). HRMS (EI): m/z [M⁺] calcd for C₂₉H₃₀N₂O₃: 454.2257;

found: 454.2221.

20732

Molecules 2015, 20, 20719–20740

4-(Allyloxy)-N-(4-methoxyphenyl)-2,5-dimethylaniline (17a). A mixture of 11b (0.100 g, 0.41 mmol),

potassium carbonate (0.062 g, 0.45 mmol) and allyl bromide (0.075 g, 0.62 mmol) in acetone (20 mL)

˝

was stirred at 60 C for 24 h. The crude mixture was ﬁltered over Celite, concentrated under vacuum

and puriﬁed by column chromatography over silica gel (10 g/g crude, hexane/EtOAc, 95:5) to give

˝

17a (0.102 g, 88%) as a pink solid. R 0.76 (hexane/EtOAc, 7:3); mp 89–90 C. IR (ﬁlm): ν

1480, 1239, 1212, 1098, 1034, 1010, 947, 815 cm

1506,

max

f

´1

.

¹H-NMR (300 MHz, CDCl₃): δ = 2.17 (s, 3H,

CH₃-C5), 2.19 (s, 3H, CH₃-C2), 3.77 (s, 3H, CH₃O), 4.50 (dt, J = 5.0, 1.5 Hz, 2H, CH₂CH=), 4.97 (br,

1H, NH), 5.27 (dq, J = 10.5, 1.5 Hz, 1H, CH₂=), 5.43 (dq, J = 17.4, 1.5 Hz, 1H, CH₂=), 6.01–6.15 (m, 1H,

CH=), 6.68 (br s, 1H, H-3), 6.73–6.83 (m, 4H, Ar-H), 6.89 (br s, 1H, H-6). ¹³C-NMR (75 MHz, CDCl₃):

1

δ = 15.9 (CH₃-C5), 17.9 (CH₃-C2), 55.6 (CH₃O), 60.3 (CH₂CH=), 114.4 (C-3), 114.6 (C-3 ), 116.8 (CH₂=),

1

118.2 (C-2 ), 123.2 (C-6), 125.2 (C-5), 127.7 (C-2), 133.8 (CH=), 134.9 (C-1), 139.1 (C-1 ), 152.2 (C-4),

1

153.5 (C-4 ). HRMS (EI): m/z [M⁺] calcd for C₁₈H₂₁NO₂: 283.1572; found: 283.1570.

4-(Allyloxy)-2,5-dimethyl-N-(p-tolyl)aniline (17b). The procedure for the preparation of 17a was

followed using a mixture of 11c (0.162 g, 0.71 mmol), potassium carbonate (0.108 g, 0.78 mmol) and

allyl bromide (0.129 g, 1.07 mmol) in acetone (20 mL) to give 17b (0.137 g. 72%) as a pink solid. R_f

˝

0.71 (hexane/EtOAc, 8:2); mp 59–60 C. IR (ﬁlm): ν

3405, 2918, 1612, 1510, 1410, 1391, 1283, 1196,

max

1

1093, 1012, 997, 917, 814 cm^´1. H-NMR (300 MHz, CDCl₃): δ = 2.22 (s, 6H, CH₃-C2, CH₃-C5), 2.29

(s, 3H, CH₃Ar), 4.53–4.62 (m, 2H, CH₂CH=), 5.10 (br s, 1H, NH), 5.30 (dm, J = 10. 5 Hz, 1H, CH₂=),

1

5.47 (dm, J = 17.3 Hz, 1H, CH₂=), 6.05–6.21 (m, 1H, CH=), 6.67–6.75 (m, 2H, H-2 ), 6.72 (br s, 1H, H-3),

1

7.01 (br s, 1H, H-6), 7.02–7.10 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 15.9 (CH₃-C2 or CH₃-C5),

1

17.9 (CH₃-C5 or CH₃-C2), 20.5 (CH₃Ar), 69.2 (CH₂CH=), 114.1 (C-3), 115.4 (C-2 ), 116.8 (CH₂=), 125.1

1

(C-5), 125.2 (C-6), 128.2 (C-2), 129.5 (C-4 ), 129.7 (C-3 ), 133.6 (CH=), 133.8 (C-1), 143.5 (C-1 ), 152.9

(C-4). HRMS (EI): m/z [M⁺] Calcd for C₁₈H₂₁NO: 267.1623; found: 267.1627.

4-(Allyloxy)-3-((4-chlorophenyl)thio)-N-(4-methoxyphenyl)-2,5-dimethylaniline (17c). The procedure for

the preparation of 17a was followed using a mixture of 14c (0.200 g, 0.52 mmol), potassium carbonate

(0.079 g, 0.57 mmol) and allyl bromide (0.094 g, 0.78 mmol) in acetone (20 mL) to give 17c (0.179 g,

80%) as a pink oil; R 0.79 (hexane/EtOAc, 7:3). IR (ﬁlm): ν

2920, 1709, 1508, 1473, 1233, 1089,

max

f

1

1030, 1010, 816 cm^´1. H-NMR (500 MHz, CDCl₃): δ = 2.21 (s, 3H, CH₃-C2), 2.26 (s, 3H, CH₃-C5), 3.75

(s, 3H, CH₃O), 4.33 (br d, J = 5.5 Hz, 2H, CH₂CH=), 5.14 (br s, 1H, NH), 5.15 (br d, J = 11.0 Hz, 1H,

1

CH₂=), 5.28 (br d, J = 17.5 Hz, 1H, CH₂=), 5.98–6.08 (m, 1H, CH=), 6.81–6.82 (m, 2H, H-3 ), 6.86–6.88

1

11

(m, 2H, H-2 ), 6.93–6.97 (m, 2H, H-2 ), 6.96 (br s, 1H, H-5), 7.09–7.13 (m, 2H, H-3 ). ¹³C-NMR

1

(125 MHz, CDCl₃): δ = 15.5 (CH₃-C5), 16.7 (CH₃-C2), 55.4 (CH₃O), 74.3 (CH₂CH=), 114.6 (2C-3 ),

117.1 (CH₂=), 120.8 (2C-2 ), 121.5 (C-6), 125.8 (C-3), 127.3 (2C-2 ), 128.7 (2C-3 ), 130.0 (C-5), 130.3

(C-4 ), 130.4 (C-2), 133.9 (CH=), 136.9 (C-1 ), 137.1 (C-1 ), 139.9 (C-1), 153.3 (C-4), 154.6 (C-4 ). HRMS

(EI): m/z [M⁺] calcd for C₂₄H₂₄ClNO₂S: 425.1216; found: 425.1212.

1

11

1

(E)-2-Allyl-4-((4-methoxyphenyl)imino)-3,6-dimethylcyclohexa-2,5-dienone (18a).

A solution of 17a

˝

(0.050 g, 0.18 mmol) in decaline (1.0 mL) was stirred at 220 C for 8 h. The crude mixture was

concentrated by azeotropic distillation with toluene (3 ˆ 20 mL) under vacuum, and puriﬁed by

column chromatography over silica gel (10 g/g crude, hexane) to give 18a (0.032 g, 62%) as a red oil.

R 0.77 (hexane/EtOAc, 7:3). IR (ﬁlm): ν

723 cm

J = 6.0 Hz, 2H, CH₂CH=), 3.85 (s, 3H, CH₃O), 5.03 (br d, J = 10.0 Hz, 1H, CH₂=), 5.08 (br d, J = 17.0 Hz,

2922, 1627, 1601, 1498, 1464, 1440, 1288, 1243, 1035, 840,

max

f

´1

.

¹H-NMR (500 MHz, CDCl₃): δ = 1.96 (s, 3H, CH₃-C6), 2.29 (s, 3H, CH₃-C3), 3.35 (br d,

1

1H, CH₂=), 5.78–5.88 (m, 1H, CH=), 6.79–6.84 (m, 2H, H-2 ), 6.87 (br s, 1H, H-5), 6.93–6.97 (m, 2H,

1

H-3 ). ¹³C-NMR (125 MHz, CDCl₃): δ = 13.5 (CH₃-C3), 16.3 (CH₃-C6), 30.7 (CH₂CH=), 55.5 (CH₃O),

1

114.3 (C-3 ), 115.6 (CH₂=), 122.3 (C-2 ), 125.1 (C-5), 134.4 (CH=), 138.1 (C-3), 140.2 (C-6), 143.5 (C-1 ),

145.0 (C-2), 157.6 (C-4), 157.7 (C-4 ), 187.2 (C-1). HRMS (EI): m/z [M⁺] calcd for C₁₈H₂₁NO₂: 283.1572;

1

found: 283.1576.

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Molecules 2015, 20, 20719–20740

2-Allyl-3,6-dimethyl-4-(p-tolylamino)phenol (19b). The procedure for the preparation of 18a was

followed using a mixture of 17b (0.300 g, 1.12 mmol) in decaline (2 mL) to give 19b (0.168 g. 56%)

as a dark red oil. R 0.67 (hexane/EtOAc, 8:2). IR (ﬁlm): ν

1473, 1285, 1242, 1180, 910, 810 cm

(s, 3H, CH₃-C6), 2.25 (s, 3H, CH₃Ar), 3.47 (dq, J = 5.7, 1.8 Hz, 2H, CH₂CH=), 4.70 (br s, 1H, NH),

3542, 3384, 2920, 1635, 1614, 1514,

max

f

´1

.

¹H-NMR (300 MHz, CDCl₃): δ = 2.13 (s, 3H, CH₃-C3), 2.18

1

5.00–5.13 (m, 2H, CH₂=), 5.98 (ddt, J = 17.1, 10.2, 5.7 Hz, 1H, CH=), 6.54–6.60 (m, 2H, H-2 ), 6.88

1

(s, 1H, H-5), 6.95–7.01 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 13.8 (CH₃-C3), 15.8 (CH₃-C6),

1

20.4 (CH₃Ar), 31.4 (CH₂CH=), 114.8 (C-2 ), 115.5 (CH₂=), 121.7 (C-6), 124.3 (C-2), 125.0 (C-5), 127.7

(C-4 ), 129.7 (C-3 ), 130.5 (C-3), 133.5 (C-4), 135.5 (CH=), 144.3 (C-1 ), 149.2 (C-1). HRMS (EI): m/z [M⁺]

1

Calcd for C₁₈H₂₁NO: 267.1623; found: 267.1626.

1

N-Isopropyl-N -(3-methoxyphenyl)-2,5-dimethylbenzene-1,4-diamine (20a). The procedure for the

preparation of 10a was followed using a mixture of 8a (0.299 g, 1.37 mmol), m-anisidine (2d)

(0.169 g, 1.37 mmol) and glacial acetic acid (1.419 g, 23.64 mmol) in toluene (40 mL) to give 20a

˝

(0.117 g, 30%) as a brown solid. R 0.54 (hexane/EtOAc, 8:2); mp 83–84 C. IR (ﬁlm): ν

3381,

max

f

´1

.

¹H-NMR (300 MHz,

2963, 1614, 1598, 1519, 1500, 1462, 1410, 1219, 1156, 1041, 839, 756, 688 cm

CDCl₃): δ = 1.25 (d, J = 6.0 Hz, 6H, (CH₃)₂CH), 2.06 (s, 3H, CH₃-C5), 2.17 (s, 3H, CH₃-C2), 3.66 (sept,

1

J = 6.3 Hz, 1H, (CH₃)₂CH), 3.73 (s, 3H, CH₃O), 5.14 (br s, 1H, NH), 6.17 (t, J = 2.1 Hz, 1H, H-2 ),

6.22–6.30 (m, 2H, H-4 , H-6 ), 6.49 (s, 1H, H-3), 6.91 (s, 1H, H-6), 7.05 (t, J = 8.3 Hz, 1H, H-5 ). ¹³C-NMR

1

(75 MHz, CDCl₃): δ = 17.1 (CH₃-C5), 18.0 (CH₃-C2), 23.3 ((CH₃)₂CH), 44.3 ((CH₃)₂CH), 55.0 (CH₃O),

1

99.6 (C-2 ), 102.9 (C-6 ), 106.8 (C-4 ), 112.6 (C-3), 120.3 (C-5), 128.3 (C-6), 128.8 (C-1), 129.8 (C-5 ), 132.8

1

(C-2), 143.0 (C-4), 149.0 (C-1 ), 160.8 (C-3 ). HRMS (EI): m/z [M⁺] calcd for C₁₈H₂₄N₂O: 284.1889;

found: 284.1886.

1

N-(4-Chlorophenyl)-N -isopropyl-2,5-dimethylbenzene-1,4-diamine (20b). The procedure for the

preparation of 10a was followed using a mixture of 8a (0.200 g, 0.92 mmol), p-chloroaniline (2e)

(0.116 g, 0.91 mmol) and glacial acetic acid (0.943 g, 15.74 mmol) in toluene (40 mL) to give 20b (0.159

˝

g, 60%) as a brown solid. R 0.53 (hexane/EtOAc, 9:1); mp 93–94 C. IR (ﬁlm): ν

3401, 2965,

max

f

´1

1596, 1519, 1492, 1303, 1250, 1215, 1171, 999, 818 cm

J = 6.3 Hz, 6H, (CH₃)₂CH), 2.06 (s, 3H, CH₃-C5), 2.14 (s, 3H, CH₃-C2), 3.16 (br s, 1H, NH), 3.66 (sept,

.

¹H-NMR (300 MHz, CDCl₃): δ = 1.24 (d,

1

J = 6.3 Hz, 1H, (CH₃)₂CH), 5.10 (br s, 1H, NH), 6.49 (s, 1H, H-3), 6.48–6.54 (m, 2H, H-2 ), 6.85 (s, 1H,

H-6), 7.03–7.09 (m, 2H, H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.1 (CH₃-C5), 17.9 (CH₃-C2), 23.2

1

((CH₃)₂CH), 44.2 ((CH₃)₂CH), 112.5 (C-3), 114.8 (2C-2 ), 120.4 (C-5), 122.0 (C-4 ), 128.3 (C-6), 128.4

(C-5), 128.9 (2C-3 ), 132.9 (C-2), 143.2 (C-4), 146.2 (C-1 ). HRMS (EI): m/z [M]⁺calcd for C₁₇H₂₁ClN₂:

1

288.1393; found: 288.1401.

1

(E,E)-2,5-Dimethyl-N,N -(diphenyl)cyclohexa-2,5-diene-1,4-diimine (21a). The procedure for the

preparation of 10a was followed with a mixture of 8a (0.100 g, 0.46 mmol), 2a (0.093 g, 1.00 mmol)

and glacial acetic acid (0.524 g, 8.74 mmol) in toluene (20 mL) to give 21a (0.050 g, 38%) as a red solid.

˝

R 0.79 (hexane/EtOAc, 8:2); mp 194-195 C. IR (ﬁlm): ν

1594, 1573, 1481, 1384, 1268, 1164, 895,

max

f

1

821, 759, 697 cm^´1. H-NMR (300 MHz, CDCl₃): δ = 2.13 (d, J = 1.2 Hz, 6H, CH₃-C2, CH₃-C5), 6.64

1

(br d, J = 1.2 Hz, 2H, H-3, H-6), 6.58–6.74 (m, 4H, H-2 ), 7.10–7.17 (m, 2H, H-4 ), 7.33–7.42 (m, 4H,

H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.9 (2CH₃Ar), 120.1 (4C-2 ), 122.8 (C-3, C-6), 124.2 (2C-4 ),

1

128.9 (4C-3 ), 143.8 (C-2, C-5), 150.7 (2C-1 ), 158.9 (C-1, C-4). Anal. calcd for C₂₀H₁₈N₂: C, 83.88; H,

6.34; N, 9.78. Found: C, 83.89; H, 6.33; N, 9.75.

1

(E,E)-N,N -Bis(4-methoxyphenyl)-2,5-dimethylcyclohexa-2,5-diene-1,4-diimine (21b). The procedure for

the preparation of 10a was followed with a mixture of 8a (0.100 g, 0.46 mmol), 2b (0.123 g,

1.00 mmol) and glacial acetic acid (0.524 g, 8.74 mmol) in toluene (20 mL) to give 21b (0.114 g, 72%)

˝

as a red solid. R 0.42 (hexane/EtOAc, 8:2); mp 144–145 C. IR (KBr): ν

2959, 1599, 1572, 1499,

max

f

1

1463, 1440, 1243, 1165, 1034, 844, 815, 764 cm^´1. H-NMR (500 MHz, CDCl₃): δ = 2.14 (d, J = 1.5 Hz,

6H, CH₃-C2, CH₃-C5), 3.84 (s, 6H, 2CH₃O), 6.73 (br d, J = 1.5 Hz, 2H, H-3, H-6), 6.82–6.86 (m, 4H,

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Molecules 2015, 20, 20719–20740

1

H-2 ), 6.92–6.96 (m, 4H, H-3 ). ¹³C-NMR (125 MHz, CDCl₃): δ = 18.1 (2CH₃Ar), 55.5 (2CH₃O), 114.2

1

(4C-3 ), 122.0 (4C-2 ), 122.5 (C-3, C-6), 143.5 (C-2, C-5), 144.0 (2C-1 ), 157.0 (2C-4 ), 159.0 (C-1, C-4). MS

(70 eV): m/z (%) 346 (M⁺, 5), 284 (45), 194 (55), 150 (100), 123 (98), 108 (98), 77 (41). HRMS (EI): m/z

[M⁺] calcd for C₂₂H₂₂N₂O₂: 346.1681; found: 346.1682.

1

(E,E)-N,N -Bis(3-Methoxyphenyl)-2,5-dimethylcyclohexa-2,5-diene-1,4-diimine (21c). The procedure for

the preparation of 10a was followed with a mixture of 8a (0.100 g, 0.46 mmol), 2d (0.123 g, 1.00 mmol)

and glacial acetic acid (0.477 g, 7.94 mmol) in toluene (20 mL) to give 21c (0.064 g, 40%) as an orange

´1

oil; R_f0.40 (hexane/EtOAc, 8:2). IR (ﬁlm): ν_max2921, 1579, 1478, 1280, 1145, 1042, 856, 776, 697 cm

.

¹H-NMR (300 MHz, CDCl₃): δ = 2.12 (d, J = 1.5 Hz, 6H, CH₃-C2, CH₃-C5), 3.82 (s, 6H, CH₃O),

1

6.36–6.44 (m, 4H, H-2 , H-4 ), 6.65 (br d, J = 1.3 Hz, 2H, H-3, H-6), 6.70 (ddd, J = 8.4, 2.4, 0.9 Hz,

2H, H-6 ), 7.27 (t, J = 8.4 Hz, 2H, H-5 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.9 (2CH₃Ar), 55.3 (2CH₃O),

1

105.5 (2C-2 ), 109.9 (2C-6 ), 112.2 (2C-4 ), 123.0 (C-3, C-6), 129.7 (2C-5 ), 143.7 (C-2, C-5), 152.1 (2C-1 ),

159.0 (C-1, C-4), 160.1 (2C-3 ). HRMS (EI): m/z [M⁺] calcd for C₂₂H₂₂N₂O₂: 346.1681; found: 346.1686.

1

N,N -Bis(4-Methoxyphenyl)-2,5-dimethylbenzene-1,4-diamine (22a). The procedure for the preparation of

11a was followed using a mixture of 21b (0.121 g, 0.35 mmol) in Et₂O (10 mL) to give 22a (0.113 g,

˝

93%) as a dark brown solid. R 0.56 (hexane/EtOAc, 8:2); mp 145–146 C. IR (KBr): ν

3407, 1527,

max

f

´1

1509, 1464, 1440, 1390, 1285, 1246, 1178, 1117, 1036, 1002, 825 cm

δ = 2.13 (s, 6H, 2CH₃Ar), 3.78 (s, 6H, 2CH₃O), 4.88 (br s, 2H, 2NH), 6.80-6.88 (m, 8H, 2H-2 , 2H-3 ),

.

¹H-NMR (500 MHz, CDCl₃):

1

6.90 (br s, 2H, H-3, H-6). ¹³C-NMR (125 MHz, CDCl₃): δ = 17.5 (2CH₃Ar), 55.6 (2CH₃O), 114.7 (4C-3 ),

1

119.2 (4C-2 ), 121.5 (C-3, C-6), 127.0 (C-2, C-5), 136.6 (2C-1 ), 138.4 (C-1, C-4), 153.9 (2C-4 ). MS

(70 eV): m/z (%) 348 (M⁺, 5), 284 (100), 269 (98), 241 (98), 210 (27), 127 (20), 122 (53). HRMS (EI):

m/z [M⁺] calcd for C₂₂H₂₄N₂O₂: 348.1838; found: 348.1846.

1

2,5-Dimethyl-N,N -di-p-tolylbenzene-1,4-diamine (22b). A mixture of 8a (0.100 g, 0.46 mmol), p-toluidine

(2c) (0.107 g, 1.00 mmol) and AcOH (0.477 g, 7.94 mmol) in toluene (20 mL) was stirred at room

temperature for 24 h. The crude mixture was concentrated under vacuum and suspended in Et₂O

(30 mL). A saturated aqueous solution of sodium hydrosulﬁte (30 mL) was added and the mixture

stirred at room temperature for 12 h. The crude mixture was washed with CH₂Cl₂(3 ˆ 10 mL),

and the organic layer dried (Na₂SO₄) and concentrated under vacuum, before purifying by column

chromatography over silica gel (10 g/g crude, hexane/EtOAc, 8:2) to give 22b (0.11 g, 71%) as a brown

˝

solid. R 0.83 (hexane/EtOAc, 8:2); mp 134-135 C. IR (ﬁlm): ν

3406, 3053, 1613, 1510, 1459, 1265,

max

f

1

1126, 1039, 896, 813, 738, 704 cm^´1. H-NMR (300 MHz, CDCl₃): δ = 2.19 (s, 6H, CH₃-C2, CH₃-C5),

1

2.32 (s, 6H, 2CH₃Ar), 4.90–5.30 (br, 2H, NH), 6.79–6.85 (m, 4H, 2H-2 ), 7.06 (s, 2H, H-3, H-6), 7.05–7.10

(m, 4H, 2H-3 ). ¹³C-NMR (75 MHz, CDCl₃): δ = 17.6 (CH₃-C2, CH₃-C5), 20.5 (2CH₃Ar), 116.7 (4C-2 ),

1

122.8 (C-3, C-6), 128.1 (2C-4 ), 129.0 (C-2, C-5), 129.8 (4C-3 ), 136.1 (C-1, C-4), 142.6 (2C-1 ). Anal. calcd

for C₂₂H₂₄N₂: C, 83.50; H, 7.64; N, 8.85. Found: C, 83.50; H, 7.68; N, 8.81.

1

N,N -Bis(3-Methoxyphenyl)-2,5-dimethylbenzene-1,4-diamine (22c). The procedure for the

preparation of 22b was followed using a mixture of 8a (0.100 g, 0.46 mmol) and 2d (0.123 g, 1.00 mmol)

˝

to give 22c (0.083 g, 52%) as a brown solid. R_f0.66 (hexane/EtOAc, 8:2); mp 97–98 C. IR (ﬁlm):

1

ν

3381, 2956, 2924, 1599, 1497, 1215, 1156, 1042, 841, 763, 689 cm^´1. H-NMR (500 MHz, CDCl₃):

max

1

δ = 2.17 (s, 6H, 2CH₃Ar), 3.76 (s, 6H, 2CH₃O), 4.70–5.60 (br, 2H, NH), 6.38-6.42 (m, 4H, H-2 , H-4 ),

6.42–6.46 (m, 2H, H-6 ), 7.09 (s, 2H, H-3, H-6), 7.12 (t, J = 9.0 Hz, 2H, H-5 ). ¹³C-NMR (125 MHz,

1

CDCl₃): δ = 17.6 (2CH₃Ar), 55.1 (2CH₃O), 101.8 (2C-2 ), 104.5 (2C-4 ), 108.7 (2C-6 ), 124.5 (C-3, C-6),

129.3 (C-2, C-5), 130.0 (2C-5 ), 135.9 (C-1, C-4), 146.8 (2C-1 ), 160.8 (2C-3 ). HRMS (EI): m/z [M⁺] calcd

1

for C₂₂H₂₄N₂O₂: 348.1838; found: 348.1840.

3.3. Single-Crystal X-ray Crystallography

bis-Iminoquinone 8a was obtained as yellow crystals (hexane), which were mounted on glass

ﬁbers. Crystallographic measurements were performed on an Oxford XCalibur diffractometer

20735

Molecules 2015, 20, 20719–20740

with Mo Kα radiation (λ= 0.71073 Å; graphite monochromator) at room temperature [66]. Two

standard reﬂections were monitored periodically, showing no change during data collection. Unit

cell parameters were obtained from 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. Unit weights were used in the reﬁnement. After being

solved using SHELX-97 [67], the structure was visualized and plotted with the MERCURY program

package [68 –70 ]. Data from 8a: Formula: C₁₄H₂₂N₂; molecular weight: 218.34; cryst. syst.:

monoclinic; space group: P 1 21/a 1; unit cell parameters: a, 9.3369(19), b, 7.7080(4), c, 15.920(3) (Å);

˝

α, 90 , β, 142.07 , γ, 90 ; temp. ( K): 292(2); Z: 3; no. of reﬂections collected: 7685; no. of independent

reﬂections: 2391; no. of reﬂections observed: 1743; data collection range: 3.36 < 2θ <32.79; R: 0.059;

GOF: 1.05 (for complete X-ray data, see Supplementary Material Tables S1–S6).

4. Conclusions

A series of new 2,5-dimethylbenzoquinone(alkylimines) 7a–b, 2,5-dimethylbenzoquinone

1

(bis-alkyldiimines) 8a–c, and N,N -dialkyl-2,5-dimethylbenzene-1,4-diamines 9a–c were synthesized

via condensation of diacetyl (1a) and α-branched primary amines 6a–c. The scope of the method is

limited to using this kind of amine. Substitution of the alkylamine of iminoquinone 7a by anilines

2a–b followed by the aromatization of the iminoquinones 10 yielded a series of diarylamines 11

and 12. The addition of benzenethiols 13 to compounds 10 led to polysubstituted diarylamines

14a–d. p-Aminodiarylamines and bis-diarylamines were also available through this methodology by

carrying out substitution of both isopropylamino groups in the bis-iminoquinone 8a with one or two

anilines. Interestingly, the Claisen rearrangement of the allyloxy analogue 17a unexpectedly yielded

the iminoquinone 18a. In contrast, the Claisen rearrangement of 17b led to the expected ortho-allyl

phenol 19b. Further studies of reactions with other α-diketones and amines and their potential use in

synthesis are currently under investigation.

Supplementary Materials: Supplementary materials can be accessed at: http://ww w .mdpi.com/1420-3049/

20/11/19716/s1.

Acknowledgments: We thank Bruce A. Larsen for proofreading the manuscript. J.T. acknowledges SIP/IPN

(Grants 20130686, 20140858 and 20150917) and CONACYT (Grants 83446 and 178319) for ﬁnancial support.

C.E.-H., R.B., S.F.-P. and E.I.M.-M. thank CONACYT for awarding them graduate scholarships and also SIP/IPN

(PIFI) for scholarship complements. V.P. is grateful to SNI-CONACYT and the Ludwig K. Hellweg Foundation

for scholarships granted. F.D. and J.T. are fellows of the EDI-IPN and COFAA-IPN programs.

Author Contributions: C.E.-H. contributed with compound synthesis, performed NMR and HRMS spectra

and crystallography study, and wrote the experimental section. R.B., S.F.-P., V.P. and E.I.M.-M. also carried out

compound synthesis. R.B. and E.I.M.-M. performed some NMR spectra and elemental analyses. F.D. contributed

with the literature research, analyzed results and reviewed the manuscript. J.T. planned the route of synthesis,

designed the new compounds, discussed the results, and wrote and the manuscript.

Conﬂict of Interest: The authors declare no conﬂict of interest.

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Sample Availability: Samples of the compounds 10b, 10c, 11b, 11c, 12a, 14a, 14d, 17c, 20a, 20b, 21b

and 22b are available from the authors.

access article distributed under the terms and conditions of the Creative Commons by

Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).

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Condensation of diacetyl with alkyl amines: Synthesis and reactivity of p-iminobenzoquinones and p-diiminobenzoquinones

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