One-Pot Synthesis, X-ray Single Crystal and Molecular Insight of Enaminone-Based β-Morpholino-/N-Methylpiperazinyl-/Pyrrolidinylpropiophenone

Abstract

One-pot synthesis of three enaminones, (E)-1-(4-chlorophenyl)-3-morpholinoprop-2-en-1-one 1, (E)-1-(4-chlorophenyl)-3-(4-methylpiperazin-1-yl)prop-2-en-1-one 2, and (E)-1-(4-chlorophenyl)-3-(pyrrolidin-1-yl)prop-2-en-1-one 3 were achieved. The synthetic protocol via three components reaction of p-chloroacetophenone with DMFDMA (N,N-dimethylformamid-dimethylacetal) and the corresponding secondary amines (morpholine/N-methylpiperazine/pyrrolidine) in dioxane under heating for 2.5–4 h at 102 °C yielded the requisite enaminones. This protocol has the advantage of no separation of intermediate, no need for column purification with quantitative yield for the target compounds. The chemical features of the β-enaminones 1–3 were assigned by NMR. β-Enaminones 1, and 2 were assigned by single crystal X-ray diffraction technique. The intermolecular interactions in the crystal structures were analyzed quantitatively using Hirshfeld analysis. The Cl…H and O…H hydrogen bonds are common in both compounds while the C-H…π and N…H contacts are more significant in 2 than 1. DFT studies were investigated to show the electronic and spectroscopic properties (NMR and UV-Vis) of the studied systems.

1. Introduction

β-Enaminones are an important building block for the synthesis of many compounds which have pharmacological features including antitumor [1,2], anti-inflammatory [3], anti-epileptic [4], anticonvulsant [5], antibacterial [6] and other therapeutic agents [7,8,9]. Some of the reported heterocycles which β-enaminones were utilized as precursors in the synthetic routes of pharmacologically active precursors such as pyrazoles, pyridinones, dibenzodiazepines, quinolines, oxazoles and tetrahydrobenzoxazines [10,11,12,13,14].

Many synthetic routes have been used for the synthesis of this special scaffold. Several catalysts such as InBr₃ [15], vanadium (IV) acetylacetonate [16], LaCl₃ [17], (CuI–2,2′-bipyridine–NaOtBu) [18], silica supported Fe(HSO₄)₃ under solvent free conditions [19], silver nanoparticles [20], and bimetallic Ag–Cu alloy nanoparticles [21], etc. have all been employed in direct synthetic methods of the β-dicarbonyl synthon with an amine to yield the β-enaminone. However, these reported protocols have been shown to have disadvantages, including low chemical yield, longer reaction time, complication in the reaction work-up with low selectivity and no generality. Therefore, a simple, direct and efficient synthetic route with a high chemical yield for β-enaminones is highly demanded. In this study, we describe a one-pot direct method with high efficiency for β-enaminone synthesis via reaction of acetophenone with DMFDMA and three different secondary amines. Analyses of the single crystal structures of the two final products were conducted by X-ray diffraction techniques. Hirshfeld analysis, DFT calculations, UV-Vis spectral assignments are also presented.

2. Materials and Methods

UV analyses were carried out on a PerkinElmer lambda 35 spectrophotometer (Waltham, MA, USA). The ¹H NMR and ¹³C-NMR spectra of both β-enaminones were recorded on a JEOL 400-MHz spectrometer (JEOL, Ltd., Tokyo, Japan) at ambient temperature. The solvent used was DMSO-d₆; the chemical shifts (δ) are given in ppm. Single-crystal X-ray data of compounds 1 and 2 were collected on a Bruker Kappa APEX II diffractometer at 170 K. The crystallographic details are provided as supplementary material. The Crystal Explorer 17.5 program was used for the Hirshfeld analysis [22].

2.1. Synthesis of the Enaminones 1–3

A mixture of p-Cl-acetophenone (4 mmol, 616 mg), DMF-DMA (4.8 mmol, 571 mg), morpholine (20 mmol, 1.74 gm) or N-methylpiperazine (20 mmol, 2.002 gm), or pyrrolidine (20 mmol, 1.72 gm) in 50 mL dioxane at 102 °C. The reaction mixture stirred under nitrogen atmosphere for 2.5–4 h. The reaction progress was checked by TLC. The solvent was removed under reduced pressure. Enaminones were obtained initially as semisolids; upon standing, they yielded solidified products. No further purification was required unless they were washed with hexane to get rid of excess amines [23].

(E)-1-(4-Chlorophenyl)-3-morpholinoprop-2-en-1-one 1

¹H-NMR (DMSO-d₆, 400 MHz) δ 7.93 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 12.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 6.08 (d, J = 12.4 Hz, 1H), 3.65 (t, J = 4.4 Hz, 4H), 3.46 (brs, 4H) ppm. ¹³C-NMR (DMSO-d₆, 100 MHz) δ 184.84, 153.20, 138.65, 135.70, 129.21, 128.21, 90.84, 66.09 ppm.

(E)-1-(4-Chlorophenyl)-3-(4-methylpiperazin-1-yl)prop-2-en-1-one 2

¹H-NMR (DMSO-d₆, 400 MHz) δ 7.84 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 12.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 5.97 (d, J = 12.4 Hz, 1H), 3.26 (s, 3H), 2.27 (t, J = 4.4 Hz, 4H), 2.11 (brs, 4H) ppm. ¹³C-NMR (DMSO-d₆, 100 MHz) δ 184.75, 153.04, 138.75, 135.61, 129.13, 128.17, 90.57, 55.07, 53.65, 45.57 ppm.

(E)-1-(4-Chlorophenyl)-3-(pyrrolidin-1-yl)prop-2-en-1-one 3

¹H-NMR (DMSO-d₆, 400 MHz) δ 7.90 (d, J = 3.8Hz, 3H), 7.49 (d, J = 8.08 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 5.73 (d, J = 11.96 Hz, 1H), 3.56 (t, J = 6.68 Hz, 2H), 3.25 (t, J = 6.84Hz, 2H), 1.96 (m, 2H), 1.84 (m, 2H) ppm. ¹³C-NMR (DMSO-d₆, 100 MHz) δ 184.62, 150.69, 139.51, 136.03, 129.61, 128.77, 92.11, 52.58, 47.50, 25.36 ppm.

2.2. Computational Methods

All DFT calculations were performed using the Gaussian 09 software package [24] utilizing B3LYP/6-31G(d,p) method. The optimized structures showed no imaginary frequencies and were used to predict the electronic and spectroscopic properties of the studied molecules. Natural population analysis was performed using the NBO 3.1 program as implemented in the Gaussian 09W package [25]. The self-consistent reaction field (SCRF) method [26,27] was used to model the solvent effects when calculated the optimized geometries in solution.

3. Results and Discussion

3.1. Synthesis of Enaminones 1–3

The three targeted β-enaminones 1–3 were synthesized via an efficient one-pot direct method as shown in Scheme 1. The synthetic protocol via reaction of p-chloroacetophenone with DMFDMA and the corresponding secondary amines (morpholine/N-methylpiperazine and pyrrolidine) in dioxane was used under heating for 2.5–4 h at 102 °C to yield the requisite enaminones. The chemical features of the three synthesized β-enaminones were well-assigned; the spectral data of the enaminones 1, and 2 fit with the reported literature [28]. Additionally, X-ray single crystal (Figure 1), Hirshfeld and DFT calculations were conducted to confirm molecular structural aspects of the compounds 1, and 2. The chemical structure of Enaminone 3 was confirmed by ¹H-NMR as follows: two aromatic and one olefinic protons appeared at δ 7.90 ppm; two aromatic protons at δ 7.49; a second olefinic proton appeared at 5.73 ppm; eight protons of the pyrrolidine ring appeared as follows: four protons close to nitrogen at δ 3.56 and 3.25 ppm; finally, the second four protons appeared as multiplet at δ 1.96, and 1.84 ppm. ¹³C-NMR spectrum were constituent with proposed structure (see supplementary information).

3.2. X-ray Structure of 1, and 2

The structure of 1 was revealed as an inversion twin in a chiral space group P2₁2₁2₁. The structure of 2 was revealed in a centrosymmetric space group P2₁/c. Changing the morpholine moiety of 1 to piperazine in 2 led to slight shortening of the N1-C9 distance from 1.338(2) Å to 1.328(2) Å (

Table 1. Selected bond lengths [Å] and angles [°] for 1.

Bond	Distance
Cl(1)-C(3)	1.7466(15)
O(1)-C(7)	1.2403(19)
O(2)-C(12)	1.421(2)
O(2)-C(11)	1.422(2)
N(1)-C(9)	1.338(2)
N(1)-C(10)	1.460(2)
N(1)-C(13)	1.462(2)

). Also, the C7-C8 distance was slightly shorter in the case of 2 (1.429(2) Å) than in 1 (1.442(2) Å). The changes in N1-C9 and C7-C8 bond distances were probably due to packing effects. Selected bond lengths [Å] and angles [°] for 1 and 2 are listed in Table 1 and

Table 2. Selected bond lengths [Å] and angles [°] for 2.

Bonds	Angles
Cl(1)-C(3)	1.7427(17)
O(1)-C(7)	1.2419(19)
N(1)-C(9)	1.328(2)
N(1)-C(10)	1.460(2)
N(1)-C(14)	1.462(2)
N(2)-C(13)	1.450(2)
N(2)-C(11)	1.458(2)
N(2)-C(12)	1.460(2)

.

3.3. Analysis of Molecular Packing

The most important contacts and their percentages for 1, and 2 are shown in Figure 2. The Hirshfeld surfaces are shown in Figure 3 and Figure 4, respectively. The results indicate that the molecular units were mainly packed by the nonpolar H…H interactions, which contributed by 43.2 and 46.5% for 1, and 2, respectively. In case of the former, there were four red spots in the d_norm map corresponding to the intermolecular contacts with shorter contact distances than the van der Waals (vdW) radii sum; half of them were for the O…H hydrogen bonds that appeared as intense red circles, while the other half which appear as small fad red circles corresponding to the Cl…H hydrogen bonds. The O…H (15.5%) and Cl…H (16.2%) contact distances are 2.275 (O1…H14) and 2.788 Å (Cl1…H5), respectively (Figure 5). The rest of the observed contacts had either longer—or almost equal interaction—distances compared to the vdW radii sum of the elements involved in the interactions.

In case of 2, there are two Cl…H hydrogen bonds with contact distances ranges from 2.706 Å (Cl1…H12C) to 2.802 (Cl1…H10A) occurred between the Cl atom and the C-H protons in the morpholine moiety from adjacent molecule. The overall Cl...H hydrogen bond contacts contributed by 17.6%. On other hand, the Hirshfeld analysis detected four potential O…H hydrogen bond contacts which were O1…H10B (2.293 Å), O1…H5 (2.483 Å), O1…H4 (2.523 Å) and O1…H9 (2.573 Å), in addition to one N2…H2A (2.547 Å) hydrogen bond which contributed by 9.4% and 2.8%, respectively. In addition, the Hirshfeld analysis showed the presence of weak C-H…π (23.4%) interactions with C2…H14B distance of 2.746 Å in 2 which was found less important in 1. An illustration of the most important contacts in 2 is shown in Figure 6 and Figure 7.

3.4. DFT Studies

Geometric Parameters

The optimized molecular geometries of 1, and 2 are shown in Figure 8 (upper part) and the structure matches between the calculated and optimized structures are shown in the same figure (lower part). The calculated geometric parameters along with the experimental X-ray values are given in Table S12 (Supplementary data), while the correlation graphs between the calculated and experimental parameters are presented in Figure 9. It is clear that the experimental and calculated values are well-correlated, with correlation coefficients very close to 1. The calculated dipole moments of compound 1, and compound 2 were 4.7665 and 6.4517 Debye, respectively, indicating the higher polarity of the latter compared to the former. The orientation of the dipole moment vector over the molecular electrostatic potential (MEP) map shown in Figure 10 was oriented towards the carbonyl oxygen atom which has the highest negative charge (Table S13 Supplementary data).

3.5. Reactivity Studies

The ionization potential (I), electron affinity (A), chemical potential (μ), hardness (η) as well as electrophilicity index (ω) were calculated using Equations (1)–(5) (

Table 3. The calculated descriptors of compound 1, and compound 2.

Parameter	1	2
HOMO	−5.7664	−5.6412
LUMO	−1.4368	−1.3339
I	5.7664	5.6412
A	1.4368	1.3339
η	4.3296	4.3073
μ	−3.6016	−3.4876
ω	1.4980	1.4119

). These parameters were employed to explain the bio-reactivity of chemical compounds [29,30,31,32,33,34,35].

I = −E_HOMO

(1)

A = −E_LUMO

(2)

η = (I − A)/2

(3)

μ = −(I + A)/2

(4)

ω = μ²/2η

(5)

The ionization potential (I), electron affinity (A), hardness (η) as well as electrophilicity index (ω) were higher for compound 1 than compound 2, while the opposite was true regarding the chemical potential (μ). Since the former has lower energy LUMO than the latter so; it could be expected that 1 is better electron acceptor than compound 2. In contrast, the HOMO energy was higher for compound 2 than compound 1, indicating that the former is better electron donor than the latter.

3.6. NMR and UV-Vis Electronic Spectra

The calculated ¹H and ¹³C NMR chemical shifts using GIAO method [36] applying the PCM solvent (DMSO) model are listed in Table S14 (Supplementary data) and compared with the experimentally observed spectral shifts in the same solvent. It clear that the experimental chemical shifts are well-correlated with the calculated values, as can be seen from Figure 11 where good straight-line correlations were obtained with very good correlation coefficients of 0.9098–0.9919 and 0.9811–0.9958 for the ¹H and ¹³C NMR chemical shifts, respectively.

The experimental UV-V electronic spectra of the studied compounds 1, and 2 are shown in Figure 12. The electronic spectra of both compounds were very similar where both compounds showed three well-separated bands at 205, 253 and 348 nm. Theoretically, these bands were calculated and the results along with their assignments were collected in

Table 4. The calculated electronic transition bands (λ in nm) and their oscillator strength (f) of the studied compounds 1 and 2.

		1			2
Λ	f	Major Contributions	λ	F	Major Contributions
326.5	0.520	HOMO→LUMO (82%), H-1→LUMO (16%)	327.0	0.500	HOMO→LUMO (79%), H-2→LUMO (19%)
254.8	0.402	H-2→LUMO (83%)	270.3	0.014	HOMO→L + 1 (94%)
209.9	0.116	H-3→LUMO (18%), H-3→L + 2 (17%), H-2→L + 1 (54%)	212.9	0.006	H-1→L + 2 (54%), HOMO→L + 3 (42%)

and shown in Figure 12. The longest wavelength band was calculated at 327 nm for both compounds. This band was mainly due to the HOMO→LUMO excitation. Presentation of the HOMO and LUMO demands are shown in Figure 13 which indicated that this band may be assigned mainly as π-π* transition.

4. Conclusions

Three enaminones were synthesized via one-pot reaction. The presented protocol has the advantage of high chemical yield, mild conditions and high purity of the products with almost no cost for purification. Hirshfeld analysis of molecular packing was used for molecular-packing quantitative analysis. Also, DFT calculations were used to optimize the structure of the studied systems and predict the NMR chemical shifts, as well as the electronic molecular spectra of both systems. The substrate scope and the utility of these enaminones as building blocks under investigation in our laboratory.