The intelligence way of economical synthesis strategies of an N-alkylcarbazole

doi:10.21203/rs.3.rs-2715161/v1

The alkaloid carbazole is one of the relevant structural motifs in drug discovery. Indeed, carbazoles have been largely investigated for their various biological properties. In this article, in order to ensure the possibility of carrying out this reaction at the level of the synthesis laboratory and to have access to a new active biomolecule, we present the theoretical study of the synthesis strategies of an N-alkylcarbazole using the DFT method at B3LYP, with the basis set 6-31G (d, p). In fact, this research has enabled us to establish a simple, economical and efficient synthesis strategy for this nitrogenous heterocyclic with an excellent yield, by N-alkylation between carbazole and propargyl bromide under different experimental conditions. We have developed an environmentally friendly compound, mild condition protocol and convenient procedure for the preparation of this polycyclic aromatic compound. The structure of the synthesized compound was determined by spectroscopic methods: 1H-NMR, 13C-NMR and MS data. The theoretical results corroborate with experiences. The study of the substitution effect on the optical properties of reagents and products shows that N-alkylation has an influence on the optical properties.

carbazole

N-alkylation

9-(prop-2-yn-1-yl)-9H-carbazole

propargyl bromide

DFT/B3LYP method with the 6-31G base (d

p)

Carbazoles have been extensively studied for their various pharmacological properties and biological activities, as anti-inflammatory, neuroprotective, antimicrobial, antioxidant, antiprotozoal, and antihistamines [1,2,3]. Carbazole and its derivatives represent an important group of aromatic heterocyclic compounds containing a nitrogen atom. They have important electronic and charge-transport properties, as well as a conjugated pi-electron system, which facilitate the easy introduction of various functional groups into the structurally rigid carbazole ring [4]. In fact, carbazole derivatives have been many applications in the medical field, such as antitumor, antiviral and insecticidal effects [5]. The carbazole nucleus can be naturally found in the composition of some alkaloids as staurosporine, ellipticine or koenidine, with antibacterial, antifungal, antimalarial properties, antitumoral activity, and potential antidiabetic effect [6,7,8], among them carbazomycins represent an unprecedented class of antibiotics with a carbazole heterocycle [9]. Various researches done on the synthesis of new heterocyclic compounds [10,11,12-18], we focused in this work, on the theoretical study of the reaction carried out followed by the effective synthesis of the 9-(prop-2-yn-1-yl)-9H-carbazole with three methods (phase transfer catalysis, microwave, and base + acetone) with the aim to elaborate a new active molecules with an important yield. For us, it is preferable to establish a theoretical study of a synthetic reaction before going to the experimental mode because it will inform us from the start on the path of the reaction and the expected results to save time and minimize losses of energy (use of heating or not) and matter (reaction possible or not). Then, from the computational study we can found several information such as: the optical properties of reagents and products, the thermodynamics parameters of synthesis reactions among them: energy values of the free energy ΔG_r and the enthalpy ΔH_r of the reaction in order to understand the nature of reaction (exothermic or endothermic) also the spontaneity of the synthesis reaction.

2.1 Determination of the reactive forms of the reagents under the experimental conditions used.

Before starting the theoretical study to ensure the possibility of carrying out this reaction at the synthetic laboratory level or not, it is very important to know the reactive forms of the reagents under the experimental conditions used. Indeed, the distribution diagram of the different species distribution of the reagents as a function of the pH obtained by the MARVINSKETCH software makes it possible to achieve this objective.

In an acidic medium, the carbazole acts as a nucleophile through the nitrogen atom of the NH group. At pH = 14, the base eliminate the hydrogen from the NH group of the carbazole to give the carbazol-9-ide (anionic form). The pH value also remains an important parameter to find the reactive form of carbazole. The distribution diagram obtained using the MARVINSKETCH software, indicating the relative fraction (or the percentage) of the neutral and ionic of carbazole in the pH range between 0 and 14, indicate that in the interval 12-14 (figure 1), we find the unique presence of the anionic form, on the other hand, there is absence of the form neutral carbazole, which explains why the mechanism of this reaction will go first through the tearing of the proton of the carbazole followed by a nucleophilic attack on 3-bromopropyne.

Likewise, the different species of 3-bromopropargyl as a function of the pH determined by the MARVINSKETCH program shows that the neutral form is the only form which exists in the pH range 0-14 (figure 2). The absence of the anionic form makes it possible to conclude that 3-bromopropargyl cannot play the role of a nucleophile in this zone in any reaction. This remark is surprising since the terminal alkyne contains an acidic proton. This result can be explained by the existence of a strong attractor group Br. Indeed the same result is observed in the distribution diagram of the different forms of 3-chloropropargyl, 3-fluoropropargyl and 3-iodopropargyl as a function of the pH.

To increase the percentage of the anionic form of this reagent, it is necessary to work at a high temperature. This hypothesis was verified by the Marvinsketch software, which proved that at a temperature of 573K the anionic form becomes the majority. In our experimental part, we have no interest in working with the anionic form of this reagent, so we don't need heating.

2.2 The geometry parameters of the reagents.

The geometry parameters related to the reagents molecules, such as: Charges densities, interatomic distances and angles ... the calculations were investigated using DFT method at B3LYP With the base 6-31G (d, p), the values of the charge densities are gathered in Table 1. The optimized geometries of the reagents are respectively represented in Figures 3 and 4.

Table 1. The charges densities of reagents

Carbazol-9-ide (R1)		3-Bromoprop-1-yne (R2)
C₁_;C₉	0.143	C₁	-0.964
C₂_;C₁₁	-0.250	C₂	0.941
C₃_;C₇	-0.137	C₃	-0.492
C₄_;C₁₂	-0.238	Br₄	-0.140
C₅_;C₈	-0.190
C₆_;C₁₀	-0.283
N₁₃	-0.649

2.3 Computational study of the reaction between carbazol-9-ide (R1) and 3-bromoprop-1-yne (R2).

2.3.1 Thermodynamic parameters

We calculate some thermodynamic parameters characterizing the reaction between R1 and R2 in Table 2.

Table 2. Thermodynamic of the synthesis reaction calculated using output files of Gaussian calculations using DFT/B3LYP 6-31G (d, p)

Thermodynamic parameters of the reaction
ΔH_r (Kcal/mol)	-21.173
ΔS_r (Kcal/mol.K)	-50.854 10^-3
ΔG_r (Kcal/mol)	-36.335

The negative value of enthalpy ΔH_r indicates the exothermic nature of this reaction. Then, The free enthalpy variation ΔG_r<0 show the possibility of this reaction with thermodynamic view.

2.3.2 Prediction of electrophile/nucleophilic proprieties of reagents

In order to predict the electrophilic/nucleophilic characters of the reagents we calculated various parameters among them we found: The HOMO/LUMO energy, The gap energies ΔE, the electronic chemical potentials μ, the chemical hardness η, the global electrophilic indices ω and the global nucleophilic indices N, using the following equations [19]:

ΔE(I) = E_HOMO (Carb) − E_LUMO (3-Bromoprop-1-yne)

ΔE(II) = E_HOMO (3-Bromoprop-1-yne) − E_LUMO (Carb)

ω = μ²/2*η

μ = (E_HOMO+E_LUMO)/2

η = E_LUMO – E_HOMO

N=E_HOMO–E_HOMO(TCE)

S(I)=1/ η

With E_HOMO(TCE) = -9.3686eV calculated by DFT/B3LYP 6-31G (d, p).

In table 3 are grouped the calculated energy values of the frontier orbitals and the energy gap. These results are illustrated in figure 5.

Table 3. Energetically parameters of the reagents by the DFT/B3LYP method in the base (6-31G) (d, p)

Compound

E (eV)

HOMO (eV)

LUMO (eV)

∆E(I) (eV)

∆E(II) (eV)

Carbazol-9-ide

-14071.061

-4.339

-0.324

-2.750

-7.575

3-Bromoprop-1-yne

-73205.091

-7.900

-1.589

The results obtained indicate that the gaps | 𝑬_{𝑯𝑶𝑴𝑶} (R1) - 𝑬_{𝑳𝑼𝑴𝑶} (R2) | is small compared to the gaps | 𝑬_{𝑯𝑶𝑴𝑶}(R2) - 𝑬_{𝑳𝑼𝑴𝑶} (R1) |. This can be predicting an electrophilic character of 3-bromoprop-1-yne (R2) and the nucleophilic property carbazol-9-ide (R1)[20].

2.3.3 Global descriptors of reagents

In table, 4 gathers the values calculated theoretically by the DFT method of the global parameters.

Table 4. Global parameters calculated by B3LYP DFT/6-31G (d. p)

Compound	E (eV)	µ (eV)	ƞ (eV)	S(I) (eV)	ω (eV)	N (eV)
Carbazol-9-ide	-14071.06	-2.33	4.02	0.25	0.68	5.03
3-Bromoprop-1-yne	-73205.09	-4.74	6.31	0.16	1.78	1.47

From this result we can show that the electronic chemical potential μ of carbazol-9-ide (μ= -2.33 eV) is on a level of energy more interested than that of 3-bromoprop-1-yne (μ= -4.74 eV). Consequently, we can propose that electron transfer takes place from carbazol-9-ide to 3-bromoprop-1-yne. Also, from the global nucleophilicity N values of carbazol-9-ide and 3-bromoprop-1-yne. We can deduce the same result; carbazol-9-ide plays the role of a nucleophile whereas 3-bromoprop-1-yne is an electrophile. The same conclusion can be drawn from the values of the global electrophilicity ω. Chemical hardness of carbazol-9-ide (η = 4.02 eV) is less than that of 3-bromoprop-1-yne (η = 6.31 eV). This means that carbazol-9-ide retains few electrons in its environment. Unlike 3-bromoprop-1-yne which maintains them in its own environment. Therefore, electron transfer takes place from carbazol-9-ide to 3-bromoprop-1-yne. We can conclude, all global indices show the nucleophilic nature of carbazol-9-ide and the electrophilic properties of 3-bromoprop-1-yne.

Prediction of local reactivity of reagents

2.3.4.1. Application of the Domingo polar model using Fukui indices f_k⁺ and f_k^-

From Domingo's polar model through the local electrophilicity ω_k and local nucleophilicity N_k, in order to predict the most favored electrophilic-nucleophilic interaction for the formation of a chemical bond between the most electrophilic site of the electrophilic reagent and the most nucleophilic site of the nucleophilic reagent [21]. The local electrophilic and nucleophilic values (ω_k , N_k) for the reactive atoms of the 3-bromoprop-1-yne and carbazol-9-ide are regrouped in Tables 5 and 6.

Table 5. Determination of natural populations (P_k (N-1), P_k (N), P_k (N + 1)) of reagents.

Carbazol-9-ide			3-Bromoprop-1-yne
Atoms	P (N)	P (N-1)	Atoms	P(N)	P(N+1)
C₁	5.857	5.890	C₁	6.501	6.680
C₂	6.250	6.156	C₂	6.049	6.051
C₃	6.137	6.156	C₃	6.229	6.432
C₄	6.238	6.224
C₅	6.190	6.167
C₆	6.283	6.174
C₇	6.137	6.077
C₈	6.191	6.167
C₉	5.857	5.890
C₁₀	6.283	6.174
C₁₁	6.250	6.156
C₁₂	6.238	6.224
N₁₃	7.649	7.373

Table 6. Fukui indices (f_k⁺, f_k^-) and local electrophilicity and nucleophilicity values (ω_k , N_k) for reagents.

Local indices NPA
Carbazol-9-ide			3-Bromoprop-1-yne
Atoms	f_k^-	N_k	Atoms	f_k⁺	ω_k
C₁	-0.03	-0.17	C₁	0.18	0.32
C₂	0.09	0.48	C₂	0.01	0.01
C₃	-0.02	-0.09	C₃	0.20	0.36
C₄	0.02	0.07
C₅	0.02	0.12
C₆	0.11	0.55
C₇	0.06	0.30
C₈	0.02	0.12
C₉	-0.03	-0.17
C₁₀	0.11	0.55
C₁₁	0.09	0.47
C₁₂	0.02	0.07
N₁₃	0.28	1.39

ω_k=ω*fk⁺ (ω=1.78 eV) and N_k= N*fk^- (N=5.03 eV) ^[21].

fk⁺=[P_k(N+1)–P_k(N)] show a nucleophilic attack site.

fk^-=[P_k(N)–P_k(N-1)] show an electrophilic attack site.

P_k (N): natural population of the atom k in the neutral form of molecule.

P_k (N + 1): natural population of the k atom in the anionic form of molecule.

P_k (N-1): natural population of the k atom in the cationic form of molecule.

This time, the local N_k nucleophilic indices for the carbazol-9-ide reactive atoms in the basic medium and the local electrophilic indices ω_k for the 3-bromoprop-1-yne atoms show that the most favored interaction takes place between C₃ the most electrophilic site (ω_k=0.36 eV) of the 3-bromoprop-1-yne and N₁₃the most nucleophilic site (N_k=1.39 eV) of the carbazol-9-ide. Consequently, the Domingo polar model correctly predicts the formation of the N13-C3 bond, experimentally desired.

2.3.4.2. Application of the Gazquez-Mendez rule

The Gazquez-Mendez rule propose that two chemical species have similar softness can form interaction bonds [22]. The Table 7 regrouped the local indices for the reactive atoms of carbazol-9-ide and the reactive atoms of 3-bromoprop-1-yne.

Table 7. Fukui indices (f_k⁺ , f_k^-) and condensed local softness atoms (S_k⁺ , S_k^-) values for reagents calculated by NPA populations

Local indices NPA
Carbazol-9-ide			3-Bromoprop-1-yne
Atoms	f_k^-	S_k^-	Atoms	f_k⁺	S_k⁺
C₁	-0.03	-0.01	C₁	0.18	0.028
C₂	0.09	0.02	C₂	0.01	0.001
C₃	-0.02	-0.01	C₃	0.20	0.032
C₄	0.02	0.01
C₅	0.02	0.01
C₆	0.11	0.03
C₇	0.06	0.02
C₈	0.02	0.01
C₉	-0.03	-0.01
C₁₀	0.11	0.03
C₁₁	0.09	0.02
C₁₂	0.02	0.01
N₁₃	0.28	0.07

S_k⁺=S*f_k⁺ (S=1/2*η = 0.16 eV^-1) ; S_k^-=S*f_k^- (S = 0.25 eV^-1).

The interaction as much as possible by this rule was C₃- N₁₃ (Table 7): C₃ of 3-bromoprop-1-yne and the N₁₃ of carbazol-9-ide. This was the result obtained experimentally.

Study of the substitution effect on optical properties

In order to study the effect of substitution on optical properties, we have found it useful to determine the l_max, E_ex and f_osc characteristics of the anionic form of carbazole, product 3 and other compounds already synthesized [23]. From the structures optimized in the presence of acetone as solvent, we determined the absorption spectra, the excitation energies (E_ex), the wavelength maximums (l_max) and the intensities of the forces d oscillation (f_osc) (Figure 6). These calculations (Table 8) were carried out using the theoretical TD-DFT method with the functional B3LYP under the base 6-31 G (d, p).

Table 8. The maximum wavelengths (l_max) and the intensities of the oscillation forces (f_osc) as a function of the excitation energies (E_ex).

Molecules

E_ex

l_max

f_osc

Carbazol-9-ide

3.2170

4.1013

4.7396

385.40

302.30

261.59

0.0282

0.0094

0.0000

9-vinyl-9H-carbazole

3.8856

4.4593

4.6548

319.09

278.04

266.36

0.0476

0.1348

0.2211

Product 3

4.0066

4.4635

5.0462

309.45

277.77

246.51

0.0463

0.1786

0.6610

N-butylcarbazole

3.8939

4.4136

5.0462

318.41

280.92

245.97

0.0465

0.1311

0.7534

N-pentylcarbazole

3.8932

4.4134

5.0462

318.46

280.93

245.70

0.0471

0.1305

0.7509

N-decylcarbazole

3.9833

4.5022

5.1560

311.26

275.38

240.47

0.0474

0.1164

0.7676

Note: The peaks of the electronic spectra correspond to the highest values of f_osc

_{From the table of results, it can be seen that increasing the excitation decreases the magnitude l_max of the reagent and of the alkylated products. However, it decreases the f_osc magnitude of the reagent and it increases it for N-alkylating compounds. The optical properties l_max and f_osc of the anionic form of carbazole decrease due to the substitution. As the number of alkyl carbon atoms increases, l_max decreases.}

We continued our research on N-alkylation reactions [24,25]; we reported in this paper another part of our investigations concerning the preparation of heterocyclic products. Our strategy is based on the reaction between the carbazole 1 and the propargyl bromide 2 (scheme 1) under different experimental conditions. In order to carry out this synthesis, we used three reaction activation modes, the first mode of which is characterized by the use of a conventional method (base + solvent (method 1)). The second mode consists of using a phase transfer catalysis method (method 2), whereas in the third process, we used microwave irradiation (method 3) in a dry media (scheme 1). While respecting the environment by choosing non-toxic solvents.

In the first two methods, the C–N bond formation N-alkylation reaction was carried out at room temperature in acetone or DMF in the presence of various bases (NaOH, Et₃N, NaH or K₂CO₃). The product 3 synthesized with satisfactory yields was characterized by usual spectroscopic techniques, such as ¹H-NMR, ¹³C-NMR and MS. The results are summarized in Table 9.

Table 9. Conditions and results of the preparation of 9-(prop-2-yn-1-yl)-9H-carbazole 3

reaction conditions	NaOH Acetone	Et₃N Acetone	NaH Acetone	K₂CO₃ DMF	K₂CO₃ Acetone	MW K₂CO₃/BTBA
reaction conditions	Method 1			Method 2		Method 3
Yield (%)	78	74	68	85	82	95
Reaction Time (h)	48	48	48	18	48	12 min

The use of sodium hydroxide, triethylamine, potassium carbonate (K₂CO₃) and sodium hydride as a basis have revealed that the most suitable method is the use of phase transfer catalysis (method 2). Thus, the alkylation of carbazole by propargyl bromide in dimethylformamide (DMF) or acetone in the presence of potassium carbonate (K₂CO₃) as base and tetra-n-butylammonium bromide (BTBA) as transfer catalyst phase, leads to the heterocyclic acetylenic derivative with a very satisfactory yield. The product purification is done by chromatography on a column of silica gel. The alkylation in DMF makes it possible to reduce the reaction time (18 hours) but this solvent has the disadvantage of being difficult to remove. This problem can be avoided by using acetone that requires a longer reaction time (2 days).

Microwave heating and its application in organic chemistry for reactions in a dry environment are currently being successfully developed by research teams and by our team [21, 26, and 27]. In the third method, we also report another new, rapid and efficient method of synthesizing this product, with high yield by adding a catalytic amount of tetrabutylammonium bromide (TBAB) to a mixture of carbazole 1 with propargyl bromide 2, the reaction was carried out using the microwave technique in dry media. The mixture was adsorbed on potassium carbonate and irradiated in an open container in a household microwave oven with a power of 450 W for 12 min. The 9-(prop-2-yn-1-yl)-9H-carbazole 3 was obtained with an excellent yield: 95%.

4.1.General
TLC glass plates (silica gel 60 F254) and silica gel 60 (0.040–0.063 mm) were purchased from Merck and spots were visualized under UV light. ¹H and ¹³C-NMR spectra were obtained with Bruker AM 300 (300.13 MHz for ¹H, 75.47 MHz for ¹³C) spectrometer in CDCl₃ solution, using tetramethylsilane (TMS) as an internal standard. NMR data are listed in ppm. Mass spectra was recorded by electrospray on a micromass ESl Platform II.

4.2 Typical procedure for N-alkylation

Method 1:

To a stirred solution of 2.86 mmol (0.48 g) of carbazole (nitrogen compound) and 3.12 mmol of base in 10 mL of solvent, 2.6 mmol (0.31 g) of propargyl bromide were added. The mixture was stirred at room temperature and the reaction was followed by TLC (Kiesegel Merck 60F524). After evaporation of the solvent in vacuo. A saturated aqueous solution of ammonium chloride was used to neutralize the medium (pH = 7). The residue obtained was extracted with dichloromethane and the solvent was evaporated off on the rotavapor. The product purification is done by column chromatography on silica gel using ether/hexane as eluant to afford pure N-alkylated product. The white solid was obtained in a desirable yield.

Method 2:

To 10 mmol (1.67g) of carbazole in 30 ml of dimethylformamide or of acetone, 15 mmol (2.10g) of potassium carbonate are added in small portions and a catalytic amount of tetra-n-butylammonium bromide (1 mmol, 0.34 g BTBA), the mixture was stirred for 15 minutes and then 9.09 mmol (1.07g) of the propargyl bromide was added. The reaction was left overnight at room temperature. After reaction, the solvent was concentrated; the residue obtained was washed with ether. The organic phase was dried then concentrated and the residue obtained was purified by chromatography on a column of silica gel using ether/hexane as eluant.

Method 3:

A mixture of carbazole (0.84g, 5.0 mmol), propargyl bromide (0.54g, 4.55 mmol), tetrabutylammonium bromide (TBAB) (0.17 g, 0.50 mmol), and potassium carbonate (2.8 g, 20 mmol) was heated in a domestic microwave oven in an open Erlenmeyer flask with a power of 450W for 12 min. After cooling down, the reaction mixture was extracted with methylene chloride or ethylene chloride (2 x 25 ml). Then the extact was dried with MgSO₄, filtered, and the solvent was evaporated to dryness. The solid material was purified by means of flash chromatography or recrystallization from hexane or ethanol to afford the desired N-alkylcarbazole, yield: 95%.

4.3. 9-(prop-2-yn-1-yl)-9H-carbazole 3:

Yield = 85%; Melting point (hexane): 112–114 °C; R_f = 0.61 (ether/hexane 1:3). ¹H-NMR (300.13 MHz, δ (ppm), CDCl₃): 8.12 (d, 2H, J= 8 Hz, H_carbazole), 7.75-7.65 (m, 2H, H_carbazole), 7.55-7.45 (m, 2H, H_carbazole), 7.30-7.20 (m, 2H, H_carbazole), 5.05 (d, 2H, J = 3 Hz, -CH₂-C≡C), 2.29 (t, 1H, J = 3 Hz, C≡C-H). ¹³C-NMR (75.47 MHz; CDCl₃): δ (ppm) = 42.8 (CH₂N), 71.9 (C-C_acetyleneH), 78.1 (C_acetylene-CH), 110.7 (2C), 112.8 (2C), 120.3 (2C), 122.0 (2C), 122.7 (2C), 131.1 (2C) (C₆ H₅ aromatic carbons). MS (electrospray) m/z: 206.25 [M+1], C₁₅H₁₁N.

After confirmation of the geometry of the obtained product, by the different methods of analysis, we have optimized the product by the method DFT-B3LYP under the base 6-31G (d,p). The most stable conformation obtained is represented on figure 7.

The nucleophilic substitution of carbazole by propargyl bromide occurred under very mild conditions and resulted in 9- (prop-2-yn-1-yl) -9H-carbazole in high yield. To carry out this synthesis, we used three reaction activation modes (conventional, phase transfer catalysis and microwave irradiation) while respecting the environment by choosing non-toxic solvents. The identification of the prepared compound is carried out by MS, ¹³C NMR and ¹H NMR. This reaction was studied, on the one hand using MARVINSKETCH, in order to find the pH range of the major forms of the two reagents in a basic medium, and on the other hand by the Gaussian program 09 to carry out the computational study by choosing the DFT method and using the B3LYP/6-31G (d, p) calculation basis. The variations of the free enthalpy ΔG_r of the reaction is negative, therefore this reaction is possible. The experimental results are consistent with those found by the computational study. The reaction having an exothermic character (ΔH_r <0) is thermodynamically favorable.In perspective, the experimental study of the inhibition effect on the corrosion of mild steel in a 1M HCl solution and the biological activity tests of this compound are the main concern of our team for a practical implication and industrial application of the results of this study.

AUTHORS’ CONTRIBUTION

Conceptualization: Mabrouk, E. M. JABHA
Data curation: El Mesky, M, Zgueni, H.
Formal Analysis: Mabrouk, E.; Amri, N.
Funding acquisition: Not applicable.
Investigation: Mabrouk, E.; Amri, N, Chebabe, D.
Methodology: Mabrouk, E.; Jabha, M.
Project administration: Oubair, A; Azrour, M.
Resources: Mabrouk, E.; El Mesky, M.
Software: Not applicable.
Supervision: Mabrouk, E.; Jabha, M.
Validation: Mabrouk, E.; Amri, N.
Visualization: Mabrouk, E.; Azdouz, M.
Writing – original draft: Mabrouk, E.; Azdouz, M.
Writing – review & editing: Mabrouk, E.; Oubair, A; Azrour, M.

Data availability statement

All data sets were generated and analyzed in the current study

FUNDING

Not applicable

ACKNOWLEDGEMENTS

This work is financially supported by the National Center for Scientific and Technical Research (CNRST), Morocco (PROTARS D13 / 03).

Greger H., Phytochem. Rev., 2017, 16, 1095.
Schmidt A.W., Reddy K.R., Knölker H.J., Chem. Rev., 2012, 112, 3193.
Caruso A., Ceramella J., Iacopetta D., Saturnino C., Mauro M.V., Bruno R., Aquaro S., Sinicropi M.S., Molecules, 2019, 24, 1912.
Salih N., Salimon J., Yousif E., Arab. J. Chem., 2016, 9, 781.
Knölker H.J., Reddy K.R., Chem. Rev., 2002, 102, 4303.
Ruegg U.T., Burgess G.M., Trends Pharmacol. Sci., 1989, 10, 218.
Montoia A., e Silva L.F.R., Torres Z.E., Costa D.S., Henrique M.C., Lima E.S., Vasconcellos M.C., Souza R.C., Costa M.R., Grafov A., et al., Bioorg. Med. Chem. Lett., 2014, 24, 2631.
Patel O.P.S., Mishra A., Maurya R., Saini D., Pandey J., Taneja I., Raju K.S.R., Kanojiya S., Shukla S.K., Srivastava M.N., et al., J. Nat. Prod., 2016, 79, 1276.
Hagiwara H., Choshi T., Fujimoto H., Sugino E., Hibino S., Tetrahedron, 2000, 56, 5807.
Achamlale S., Mabrouk H., Elachqar A., El Hallaoui A., El Hajji S., Bellan J., Mazières M. R., Wolf J. G., Pierrot M., Phosphorus, Sulfur, and Silicon and the Related Elements, 2007, 182, 357. https://doi.org/10.1080/10426500600919959.
Mabrouk El., Arrousse N., Korchi A., Lachgar M., Oubair A., Elachqar, A., Jabha M., Lachkar M., El hajjaji F., Rais Z., Taleb M., Chem. Res. Chinese Universities, 2020. June 30, in press. doi: 10.1007/s40242-020-0173-4.
Mabrouk E. H, Elachqar, A., El Hallaoui, A., El Hajji, S., Oriental Journal of Chemistry, 2010, 26(4), 1249.
Mabrouk E., Elachqar A., El Hallaoui A., El Hajji S., Martinez J., Rolland V., Arabian Journal of Chemistry, 2013, 6, 93. https:// DOI:10.1016/j.arabjc.2010.09.023.
Arrousse N., Mabrouk El., Hammouti B., El hajjaji F., Rais Z., Taleb M., Mediterranean Journal of Chemistry, 2020, 10(5), 477. doi: 10.13171/mjc10502005151417feh.
Arrousse N., Mabrouk El., Ismail Alaoui K., El hajjaji F., Rais Z., Taleb M., SN Applied Sciences, 2020, 2(5). https://doi.org/10.1007/s42452-020-2782-4.
Arrousse N., Salim R., AL Houari G, EL hajjaji F., zarrouk A., raisa Z., Taleb M., Dheeraj Singh Chauhan and Quraish M .A., J. Chem. Sci., 2020, 132, 112 . doi.org/10.1007/s12039-020-01818-w.
Arrousse N., Salim R., Kaddouri Y., zarrouk A., Zahri D., El Hajjaji F., Touzani R., Taleb M., Jodeh S., Arabian journal of chemistry, 2020, 13(7), 5949.
Arrousse N., Mabrouk El., Hammouti B., El hajjaji F., Rais Z., Taleb M., Int. J. Corros. Scale. Inhib., 2020, 9(2), 661. doi: 10.17675/2305-6894-2020-9-2-18.
Feringa B. L., Browne W. R., Molecular Switches, Wiley VCH, Weinheim, Germany, 2011, 2, 792, ISBN 978-3-527-63441-5.
Domingo L. R., Pérez P., Organic and Biomolecular Chemistry, 2011, 9, 7168.
El Yaktini A., Lachiri A., El Faydy M., Benhiba F., Zarrok H., El Azzouzi M., Zertoubi M., Azzi M., Lakhrissi B., Zarrouk A., Int. J. Corros. Scale Inhib., 2018, 7, 4, 609. doi: 10.17675/2305-6894-2018-7-4-9.
Pérez P., Domingo L.R., Duque-Noreňa M., Chamorro E.A., J. Mol. Struct.:THEOCHEM, 2009, 895, 86. doi:10.1016/j.theochem.2008.10.014.
Bogdal D., Pielichowski J., Jaskot K., Synthetic Communications, 1997, 27(9), 1553.
Mabrouk E., Elachqar A., El Hallaoui A., Molecules, 2010, 13, 9354. https:// DOI:10.3390/molecules15129354.
Mabrouk E., Elachqar A., El Hallaoui A., Molbank, 2013, M792. doi:10.3390/M792.
Oubair A., Fihi R., Chebabe D., International Journal of Innovation and Applied Studies, 2017, 20(4), 1221.
Oubair A., Fihi R.,Mazouz H., Bulletin of the Royal Society of Sciences of Liège, 2016, 85, 119.

Scheme 1 is available in Supplementary Files section.

No competing interests reported.

Scheme1.png
Scheme 1. Reaction between carbazole 1 with propargyl bromide 2 and formation of C - N bonds by the conventional method (method 1), phase transfer catalysis (method 2) and by the microwave oven technique (method 3).

The intelligence way of economical synthesis strategies of an N-alkylcarbazole

Status:

Journal Publication

Version 1

Abstract

Figures

1. Introduction

2. Computational Study Of The Synthesis Reaction

3. Results And Discussions Of The Synthesis Reaction

4. Experimental Section

5. Optimized Structure

Conclusions

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1