**Simple Preparation of New Potential Bioactive Nitrogen-Containing Molecules and Their Spectroscopy Analysis**

Vladimir V. Kouznetsov, Carlos E. Puerto Galvis, Leonor Y. Vargas Méndez and Carlos M. Meléndez Gómez  *School of Chemistry, Industrial University of Santander, Bucaramanga, Colombia* 

#### **1. Introduction**

86 Chromatography and Its Applications

Sujino, K.; Jackson, R.J.; Chan, N.W.C.; Tsuji, S. & Palcic, M.M. (2000) A novel viral α2,3-

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Tsukamoto, H.; Takakura, Y.; Mine, T. & Yamamoto, T. (2008) *Photobacterium* sp. JT-ISH-224

Varki, A. (1993) Biological roles of oligosaccharides: all of the theories are correct. Glycobiology, Vol.3, Issue 2, (April 3, 1993), pp.97-130, ISSN 0959-6658 Vimr, E. R.; Kalivoda, K. A.; Denzo, E. L. & Steenbergen, S. M. (2004) Diversity of microbial

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Yamamoto, T. (2006) Bacterial Sialyltransferases. Trends in Glycoscience and Glycotechnology, Vol.18, N0.102, (July, 2006), pp.253-265, ISSN 0915-7352 Yamamoto, T. (2010) Marine Bacterial Sialyltransferases. Marine Drugs, Vol.8, Issue 18,

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sialyltransferase (v-ST3Gal I): transfer of sialic acid to fucosylated acceptors.

influenza virus. Biological & Pharmaceutical Bulletin*,* Vol.28, No.3, (March, 2005),

an -/-galactoside 2,3-sialyltransferase from a luminous marine bacterium, *Photobacterium phosphoreum*. Journal of Biological Chemistry, Vol.282, Issue 41,

Produces Two Sialyltransferases, α-/β-Galactoside α2,3-Sialyltransferase and β-Galactoside α2,6-Sialyltransferase. Journal of Biochemistry, Vol. 143, No.2,

sialic acid metabolism. Microbiology and Molecular Biology Reviews, Vol.68, No.1,

of influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature,

bacterial -galactoside 2,6-sialyltransferase gene from *Photobacterium damsela* JT0160. Journal of Biochemistry, Vol.123, No.1, (January, 1998), pp.94–100, ISSN 0021-924X Yamamoto, T.; Hamada, Y.; Ichikawa, M.; Kajiwara, H.; Mine, T.; Tsukamoto, H. &

Takakura, Y. (2007) A -galactoside 2,6-sialyltransferase produced by a marine bacterium, *Pho*&*bacterium leiognathi* JTSHIZ-145, is active at pH 8. Glycobiology,

sialyltransferase and enzymatic syntheses of sialyloligosaccharides. Bioscience, Biotechnology, and Biochemistry, Vol.62, No.2 , (Febraury, 1998), pp.210-214, ISSN

(2005) A multifunctional *Pasteurella multocida* sialyltransferase: a powerful tool for the synthesis of sialoside libraries. Journal of the American Chemical Society, The impact of research on the small molecules chemistry is difficult to quantify and currently, it is still one of the most active areas of organic chemistry, medicinal chemistry and lately chemical biology. In recent years, a lot of interest has been shown in the preparation of nitrogen-containing compounds due to their numerous biologically significant activities. But it is the separation and purification process of the new synthetized organic molecules, the ones that take a key role in drug design and development.

Many texts about the simple and optimal preparation of bioactive compounds have been published, and in this chapter the multicomponent reactions and efficient linear process, which allow the synthesis of this kind of structures, will be discussed. However, the purpose of this chapter is to reveal those important aspects that finally determined why a molecule can be used and distributed as a drug: their preparation, purification, and characterization.

In almost all organic synthetic methodologies the purification process use simple column chromatography techniques (gravity or external pressure) using different support materials (solid adsorbents) as the stationary phase. Column chromatography is advantageous over most of the other chromatographic techniques because it can be used in both analytical and preparative applications. After the preparation and purification of a new compound has been realized, it becomes the characterization step. New purified molecules must be strongly characterized to determine its structural configuration. Among different analysis techniques, NMR experiments and X-Ray crystallography are the most efficient ways to determine the relative stereochemistry and, in suitable cases, also the absolute configuration of the obtained products.

In the development of our medicinal program directed to small molecules for drug delivery, the strategies for the preparation of nitrogen-containing molecules such as substituted indoles, tetrahydroquinolines, and N-substituted amides of carboxylic acids are illustrated in this chapter as well as their synthetic applications and analytic characterization. The discussion is complemented with a deep explanation of the analytical techniques employed

Simple Preparation of New Potential Bioactive

**(1-acetylindolmethyl-3)acetamide** 

the final product.

excellent overall yields.

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 89

Aldimines are valuable starting materials not only for different N-containing heterocycles but also to diverse secondary heteroaromatic amines (Hutchins & Hutchins, 1991), which represent good candidates for bio-screening with diverse types of activities (Kleemann & Engel, 2005; Evers et al., 2005). Thus, the N-aryl imine **6**, the main and value starting, can be prepared from commercially available 3-indolaldehyde **4** and 2-cyanoaniline **5**, according to published methods (Colyer et al., 2006). This aldimine is obtained as a white and stable solid after purification by recrystallization in 95 % yield (Fig. 2). The method employed to obtain the precursor **7**, is one of the most known procedures to reduce an aldimines with an excess of NaBH4 in methanol, protocol that is still the reaction of choice to produce secondary amines in reasonably good yield. Thus, *N*-(2-cyanophenyl)-*N*-(3-indolylmethyl)amine **7** is prepared as was described and was obtained as white solid in 70 % yield after purification through recrystallization (Bello et al., 2010). This example, in which the main precursor is prepared in a linear process and purified by recrystallization, represents an excellent technique that avoids the loss of value material and it will be increase the global yields of

Fig. 2. Synthesis and reduction of the aldimine **6** to give the desired secondary amine **7** in

this case, the study of its acetylation by acetic anhydride is showed.

within those processes that require a particular position protection.

Besides the efficient preparation and easily purification of compound **7**, this amine has interesting structural elements to use in the synthesis of different indolic heterocycles. In

First, to a stirred solution of amine **7**, using in toluene as solvent due to the insolubility of compound **7** in polar common solvents (CH3CN, CH2Cl2, AcOEt and DMF), it is added Et3N and acetic anhydride, the mixture is refluxed for appropriate time to obtain the *N*-(2 cyanophenyl)-*N*-(3-indolmethyl)acetamide **8** in acceptable yield (50 %) after purification using silica gel 60 Mesh and using a mixture of hexane: ethyl acetate (2:1) as an eluent.

Then, the acetylating reaction described above was performed between the amine and an excess acetic anhydride in the presence of Et3N at 100 °C, without the organic solvent (toluene). After the usual workup, the diacetylated indole **9** is obtained in good yield (85 %) using the same parameters employed to the purification of compound **8**. This simple change in the reaction conditions could afford different acetamides based on the 3-indolyl methanamine motif (Fig. 3). This finding reveals a selective process to protect different amino groups and represents a good protocol to the synthetic organic chemistry, especially

**2.1 Synthesis and purification of the new the (3-indolmethyl)acetamide and** 

for their isolation and purification including the spectroscopic and spectrometric techniques using for the elucidation structure for every new compound.

#### **2. Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their spectroscopic analysis**

The vital importance of derivatives like indole-3-acetic acid, as a hormone responsible for the plant growth, and tryptophan, as a constituent of proteins and indispensible precursor of indole alkaloids, enhances the current interest for the design of simple and efficient synthetic routes for the preparation of molecules with the indole skeleton.

The research of the indol chemistry has been and it is still one of the most active areas of heterocyclic chemistry. In the past decades, a lot of interest has been shown in the preparation of substituted indoles due to their numerous biologically significant activities (Gribble, 2003). The derivatives of 3-indolylmethanamine **1** are the important intermediates of natural and natural-like products, such as hydro-γ-carboline and pyrido[4,3-*b*]indole derivatives (Wynne & Stalick, 2002; Molina et al., 1996). This 3-indolyl methanamine motif is also embedded in numerous indole alkaloids from the simple alkaloid gramine **2** to complex aspidospermine alkaloid **3** (Baxter et al., 1999; Saxton, 1998) (Fig. 1).

Fig. 1. Relevant natural alkaloids derived from the 3-indolylmethanamine system.

As a result of their biological and synthetic importance, a variety of methods have been reported for the preparation of 3-substituted indoles, using indol or 3-indolcarboxyaldehyde as starting materials. Generally, the Mannich reaction (Dai et al., 2006) and the catalyzed Friedel-Crafts alkylation reactions of indoles (Ke et al., 2005; Zhao et al., 2006; Jiang et al., 2005; Shirakawa & Kobayashi, 2006) are considered as a powerful carbon-carbon bond process to afford the 3-indolylmethanamine derivatives **1**. However, another synthetic route to access to these compounds by using 3-indolcarboxyaldehyde, via its imino derivatives, is valid. This route has been used by our laboratory, which recently started an own medicinal program directed to small molecules for drug delivery. The particular interest in 3 indolylmethanamine derivatives molecules, that could serve as useful precursors to many drug-like indolic or quinolinic compounds, is based on the evaluated antiparasitic properties of some analogues (Kouznetsov et al., 2004a, Kouznetsov et al., 2004b; Vargas et al., 2003). In this novel direction, the simple preparation of new (3-indolmethyl)acetamide and (1-acetylindolmethyl-3)acetamide, regulating only the solvent nature, is the relevant fact that has not been described and it gives the opportunity to prepare more of this kind of compounds.

for their isolation and purification including the spectroscopic and spectrometric techniques

**2. Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their** 

synthetic routes for the preparation of molecules with the indole skeleton.

aspidospermine alkaloid **3** (Baxter et al., 1999; Saxton, 1998) (Fig. 1).

Fig. 1. Relevant natural alkaloids derived from the 3-indolylmethanamine system.

As a result of their biological and synthetic importance, a variety of methods have been reported for the preparation of 3-substituted indoles, using indol or 3-indolcarboxyaldehyde as starting materials. Generally, the Mannich reaction (Dai et al., 2006) and the catalyzed Friedel-Crafts alkylation reactions of indoles (Ke et al., 2005; Zhao et al., 2006; Jiang et al., 2005; Shirakawa & Kobayashi, 2006) are considered as a powerful carbon-carbon bond process to afford the 3-indolylmethanamine derivatives **1**. However, another synthetic route to access to these compounds by using 3-indolcarboxyaldehyde, via its imino derivatives, is valid. This route has been used by our laboratory, which recently started an own medicinal program directed to small molecules for drug delivery. The particular interest in 3 indolylmethanamine derivatives molecules, that could serve as useful precursors to many drug-like indolic or quinolinic compounds, is based on the evaluated antiparasitic properties of some analogues (Kouznetsov et al., 2004a, Kouznetsov et al., 2004b; Vargas et al., 2003). In this novel direction, the simple preparation of new (3-indolmethyl)acetamide and (1-acetylindolmethyl-3)acetamide, regulating only the solvent nature, is the relevant fact that has not been described and it gives the opportunity to prepare more of this kind of

The vital importance of derivatives like indole-3-acetic acid, as a hormone responsible for the plant growth, and tryptophan, as a constituent of proteins and indispensible precursor of indole alkaloids, enhances the current interest for the design of simple and efficient

The research of the indol chemistry has been and it is still one of the most active areas of heterocyclic chemistry. In the past decades, a lot of interest has been shown in the preparation of substituted indoles due to their numerous biologically significant activities (Gribble, 2003). The derivatives of 3-indolylmethanamine **1** are the important intermediates of natural and natural-like products, such as hydro-γ-carboline and pyrido[4,3-*b*]indole derivatives (Wynne & Stalick, 2002; Molina et al., 1996). This 3-indolyl methanamine motif is also embedded in numerous indole alkaloids from the simple alkaloid gramine **2** to complex

using for the elucidation structure for every new compound.

**spectroscopic analysis** 

compounds.

#### **2.1 Synthesis and purification of the new the (3-indolmethyl)acetamide and (1-acetylindolmethyl-3)acetamide**

Aldimines are valuable starting materials not only for different N-containing heterocycles but also to diverse secondary heteroaromatic amines (Hutchins & Hutchins, 1991), which represent good candidates for bio-screening with diverse types of activities (Kleemann & Engel, 2005; Evers et al., 2005). Thus, the N-aryl imine **6**, the main and value starting, can be prepared from commercially available 3-indolaldehyde **4** and 2-cyanoaniline **5**, according to published methods (Colyer et al., 2006). This aldimine is obtained as a white and stable solid after purification by recrystallization in 95 % yield (Fig. 2). The method employed to obtain the precursor **7**, is one of the most known procedures to reduce an aldimines with an excess of NaBH4 in methanol, protocol that is still the reaction of choice to produce secondary amines in reasonably good yield. Thus, *N*-(2-cyanophenyl)-*N*-(3-indolylmethyl)amine **7** is prepared as was described and was obtained as white solid in 70 % yield after purification through recrystallization (Bello et al., 2010). This example, in which the main precursor is prepared in a linear process and purified by recrystallization, represents an excellent technique that avoids the loss of value material and it will be increase the global yields of the final product.

Fig. 2. Synthesis and reduction of the aldimine **6** to give the desired secondary amine **7** in excellent overall yields.

Besides the efficient preparation and easily purification of compound **7**, this amine has interesting structural elements to use in the synthesis of different indolic heterocycles. In this case, the study of its acetylation by acetic anhydride is showed.

First, to a stirred solution of amine **7**, using in toluene as solvent due to the insolubility of compound **7** in polar common solvents (CH3CN, CH2Cl2, AcOEt and DMF), it is added Et3N and acetic anhydride, the mixture is refluxed for appropriate time to obtain the *N*-(2 cyanophenyl)-*N*-(3-indolmethyl)acetamide **8** in acceptable yield (50 %) after purification using silica gel 60 Mesh and using a mixture of hexane: ethyl acetate (2:1) as an eluent.

Then, the acetylating reaction described above was performed between the amine and an excess acetic anhydride in the presence of Et3N at 100 °C, without the organic solvent (toluene). After the usual workup, the diacetylated indole **9** is obtained in good yield (85 %) using the same parameters employed to the purification of compound **8**. This simple change in the reaction conditions could afford different acetamides based on the 3-indolyl methanamine motif (Fig. 3). This finding reveals a selective process to protect different amino groups and represents a good protocol to the synthetic organic chemistry, especially within those processes that require a particular position protection.

Simple Preparation of New Potential Bioactive

protons were also assigned.

ethyl acetate (2:1) (Fig. 4).

Fig. 4. X-Ray structure of the diacetamide **9**.

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 91

loss of 43 units (one acetyl group) generates the same mass spectrum as the acetamide **8**. The IR spectrum of this molecule shows bands at 1704 and 1654 cm-1, assignable to two carbonyl groups while the N-H absorption bands are not observed in the region of 3300-3400 cm-1. The 1H NMR spectrum showed, as expected, two singlets at 22.4 and 23.9 ppm, which integrated for three protons each. In the case of the methylenic protons, they appeared to be diasterotopic resonating at the high field frequencies 4.75 and 5.46 ppm with a coupling constant *J* = 15 Hz, usual constant value to a germinal coupling. Of course, the aromatic

The 13C NMR spectrum showed all expected characteristic peaks at 169.4 (ArN-CO-), 168.5 (ArindolN-CO-) ppm, in addition to a signal at 117.3 ppm showing the presence of CN in the molecule. Besides, methyl carbons at 23.9 (ArindolNCO-CH3) and 22.4 (ArNCO-CH3) ppm

With respect to the characterization of the diacetamide **9**, through X-ray diffraction, the monoclinic system was determined with the compound crystallized at 25ºC from heptane-

The crystallized material has the following cell constants: a = 11.1184(19) Å, b = 8.0048(13) Å, c = 20.534(4) Å and space group P 21/n (Table 1), possessing the different bond lengths of

From this data, the different bond lengths of the two amide bonds present within the structure were as expected. Even knowing the double bond character of the amide bonds, in this case, the amide bond distance between the aliphatic nitrogen N2 and C12 is 1.364 Å,

the molecule constituent atoms was also extracted with this technique (Table 1).

while the distance between the aromatic nitrogen N1 and C9 is 1.388 Å.

and the methylene carbon at 42.8 ppm were also displayed in the 13C NMR.

Fig. 3. Synthesis and purification of the *N*-aryl-*N*-(3-indolmethyl)acetamides **8** and **9**.

#### **2.2 Characterization of the** *N***-aryl-***N***-(3-indolmethyl)acetamides 8 and 9 by spectroscopy and spectrometric techniques**

The structures of the C-3 substituted indoles **7-9** were confirmed on the basis of recorded analytical and spectral data and are supported by inverse-detected 2D NMR experiments. The IR spectrum of compound **7** illustrates the characteristic absorption bands at 3402 and 3352 cm-1 assignable to tension vibrations of CH2-N-H and N-Hindol, respectively. Its 1H NMR spectrum displays a duplet at 4.56 ppm (*J* = 4.9 Hz) ppm corresponding to two protons coupling with the neighbor N-H proton (br. s, 4.84 ppm), which suggest the presence of the methylenic unit linked to the N-H function. The peaks find at 7.17-7.3, 7.36- 7.40 and 7.63 ppm reveals the presence of aromatic protons of the indole moiety. The 13C NMR spectra, also showed all expected characteristic peaks at 39.4 (CH2), 117 (CN), and 95.6-150.2 (aromatic carbons).

The mass spectrometric analysis of compound **8** gives a molecular ion peak M+, at *m*/*z* 289, suggesting the molecular formula C18H15N3O, and indicating that the acetyl group is coupling with **7**. The acetamide **8** displayed characteristic infrared absorption bands with a single amine absorption band at 3342 cm-1 and with a carbonyl sign at 1701 cm-1 suggesting the acetylation reaction involvement of the CH2-N; this is the band appearing at high wave number of the corresponding N-Hindol vibration tension in the IR spectrum. Its 1H NMR spectra analysis showed a singlet at 2.58 ppm corresponding to three protons which belong to the acetyl group and another singlet at 4.55 ppm due to the presence of the methylenic 3- CH2-N indolic protons. This signal's multiplicity is explained by assuming the proton N-H next to it, substituted now for the acetyl group, which leaves no possibility to H,H coupling, while it does happen with the amine **7**.

The 13C NMR spectrum of the acetamide **8** displayed characteristic carbonyl signal at 168 ppm, this is strong evidence to the new acetyl group bonded to the molecule; in addition to a signal at 39.3 and 23.9 ppm, showing the presence of CH2 and CH3 in the molecule. Introduction of an acetyl group into the molecule affects the chemical shift of the hydrogen bonded to the aromatic carbon close to the acetylatin nitrogen; this appears at 116 ppm for the compound **7** and at 123 ppm for the acetamide **8**. The signal at 39.3 ppm for CH2-N has been distinguished on the basis of the DEPT-135 experiment. On the basis of these spectral studies, compound **8** was characterized as the *N*-(2-cyanophenyl)-*N*-(1*H*-indol-3 ylmethyl)acetamide.

The new compound **9** gave a molecular ion peak at *m*/*z* 331 in the mass spectrometric analysis, corresponding to the molecular formula C20H17N3O2 as indicated by its EI-MS. The

Fig. 3. Synthesis and purification of the *N*-aryl-*N*-(3-indolmethyl)acetamides **8** and **9**.

The structures of the C-3 substituted indoles **7-9** were confirmed on the basis of recorded analytical and spectral data and are supported by inverse-detected 2D NMR experiments. The IR spectrum of compound **7** illustrates the characteristic absorption bands at 3402 and 3352 cm-1 assignable to tension vibrations of CH2-N-H and N-Hindol, respectively. Its 1H NMR spectrum displays a duplet at 4.56 ppm (*J* = 4.9 Hz) ppm corresponding to two protons coupling with the neighbor N-H proton (br. s, 4.84 ppm), which suggest the presence of the methylenic unit linked to the N-H function. The peaks find at 7.17-7.3, 7.36- 7.40 and 7.63 ppm reveals the presence of aromatic protons of the indole moiety. The 13C NMR spectra, also showed all expected characteristic peaks at 39.4 (CH2), 117 (CN), and

The mass spectrometric analysis of compound **8** gives a molecular ion peak M+, at *m*/*z* 289, suggesting the molecular formula C18H15N3O, and indicating that the acetyl group is coupling with **7**. The acetamide **8** displayed characteristic infrared absorption bands with a single amine absorption band at 3342 cm-1 and with a carbonyl sign at 1701 cm-1 suggesting the acetylation reaction involvement of the CH2-N; this is the band appearing at high wave number of the corresponding N-Hindol vibration tension in the IR spectrum. Its 1H NMR spectra analysis showed a singlet at 2.58 ppm corresponding to three protons which belong to the acetyl group and another singlet at 4.55 ppm due to the presence of the methylenic 3- CH2-N indolic protons. This signal's multiplicity is explained by assuming the proton N-H next to it, substituted now for the acetyl group, which leaves no possibility to H,H coupling,

The 13C NMR spectrum of the acetamide **8** displayed characteristic carbonyl signal at 168 ppm, this is strong evidence to the new acetyl group bonded to the molecule; in addition to a signal at 39.3 and 23.9 ppm, showing the presence of CH2 and CH3 in the molecule. Introduction of an acetyl group into the molecule affects the chemical shift of the hydrogen bonded to the aromatic carbon close to the acetylatin nitrogen; this appears at 116 ppm for the compound **7** and at 123 ppm for the acetamide **8**. The signal at 39.3 ppm for CH2-N has been distinguished on the basis of the DEPT-135 experiment. On the basis of these spectral studies, compound **8** was characterized as the *N*-(2-cyanophenyl)-*N*-(1*H*-indol-3-

The new compound **9** gave a molecular ion peak at *m*/*z* 331 in the mass spectrometric analysis, corresponding to the molecular formula C20H17N3O2 as indicated by its EI-MS. The

**2.2 Characterization of the** *N***-aryl-***N***-(3-indolmethyl)acetamides 8 and 9 by** 

**spectroscopy and spectrometric techniques** 

95.6-150.2 (aromatic carbons).

while it does happen with the amine **7**.

ylmethyl)acetamide.

loss of 43 units (one acetyl group) generates the same mass spectrum as the acetamide **8**. The IR spectrum of this molecule shows bands at 1704 and 1654 cm-1, assignable to two carbonyl groups while the N-H absorption bands are not observed in the region of 3300-3400 cm-1. The 1H NMR spectrum showed, as expected, two singlets at 22.4 and 23.9 ppm, which integrated for three protons each. In the case of the methylenic protons, they appeared to be diasterotopic resonating at the high field frequencies 4.75 and 5.46 ppm with a coupling constant *J* = 15 Hz, usual constant value to a germinal coupling. Of course, the aromatic protons were also assigned.

The 13C NMR spectrum showed all expected characteristic peaks at 169.4 (ArN-CO-), 168.5 (ArindolN-CO-) ppm, in addition to a signal at 117.3 ppm showing the presence of CN in the molecule. Besides, methyl carbons at 23.9 (ArindolNCO-CH3) and 22.4 (ArNCO-CH3) ppm and the methylene carbon at 42.8 ppm were also displayed in the 13C NMR.

With respect to the characterization of the diacetamide **9**, through X-ray diffraction, the monoclinic system was determined with the compound crystallized at 25ºC from heptaneethyl acetate (2:1) (Fig. 4).

Fig. 4. X-Ray structure of the diacetamide **9**.

The crystallized material has the following cell constants: a = 11.1184(19) Å, b = 8.0048(13) Å, c = 20.534(4) Å and space group P 21/n (Table 1), possessing the different bond lengths of the molecule constituent atoms was also extracted with this technique (Table 1).

From this data, the different bond lengths of the two amide bonds present within the structure were as expected. Even knowing the double bond character of the amide bonds, in this case, the amide bond distance between the aliphatic nitrogen N2 and C12 is 1.364 Å, while the distance between the aromatic nitrogen N1 and C9 is 1.388 Å.

Simple Preparation of New Potential Bioactive

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 93

Number Atom 1 Atom 2 Length (Å) 1 O1 C9 1.220 2 O2 C12 1.221 3 N1 C7 1.415 4 N1 C8 1.405 5 N1 C9 1.388 6 N2 C11 1.473 7 N2 C12 1.364 8 N2 C14 1.430 9 N3 C20 1.143 10 C1 C2 1.449 11 C1 C8 1.338 12 C1 C11 1.489 13 C2 C3 1.385 14 C2 C7 1.404 15 C3 H3A 0.931 16 C3 C4 1.371 17 C4 H4A 0.929 18 C4 C5 1.378 19 C5 H5A 0.931 20 C5 C6 1.377 21 C6 H6A 0.930 22 C6 C7 1.384 23 C8 H8A 0.930 24 C9 C10 1.481 25 C10 H10A 0.960 26 C10 H10B 0.961 27 C10 H10C 0.961 28 C11 H11A 0.971 29 C11 H11B 0.971 30 C12 C13 1.497 31 C13 H13A 0.961 32 C13 H13B 0.960 33 C13 H13C 0.960 34 C14 C15 1.387 35 C14 C19 1.364 36 C15 C16 1.388 37 C15 C20 1.427 38 C16 H16A 0.930 39 C16 C17 1.363 40 C17 H17A 0.929 41 C17 C18 1.360 42 C18 C18A 0.929 43 C18 C19 1.397 44 C19 H19A 0.931

Table 2. Bond lengths between the molecule atoms of diamide **9**.


Table 1. Crystal data and structure refinement parameters of diacetamide **9**.

From this data, the different bond lengths of the two amide bonds present within the structure were as expected. Even knowing the double bond character of the amide bonds, in this case, the amide bond distance between the aliphatic nitrogen N2 and C12 is 1.364 Å, while the distance between the aromatic nitrogen N1 and C9 is 1.388 Å.

These data correspond with the thought that the amide bond N2-C12 is shorter because of the electron withdrawing inductive effect from the α-cyanophenyl substituent and the possibility of the nitrogen non-shared electrons to be delocalized on the amide bond through a mesomeric effect giving this bond a stronger double bond character.

On the other hand, the amide bond N1-C9 is longer because the nitrogen non-shared electrons are compromised with the aromatic system and they are not as available to be delocalized on the amide bond giving it less double bond character (Table 2).

#### **2.3 Conclusions**

An efficient, economic, and fast synthetic route was designed and its illustrated in this section showing the possible construction of the *N*-aryl-*N*-(3-indolmethyl)acetamides with the incorporation of the indolic core as a structural analogues of some alkaloids.

The acylation method is worth as a regioselective process because the conditions variations lead to the mono- or di-acetamide. The characterization of the obtained compounds through different techniques gives evidence enough and strong support with regard to the success of the proposed scheme.


Cells constants a = 11.1184(19) Å, b = 8.0048(13) Å and c = 20.534(4) Å, α = 90°, β = 94.281(4), γ = 90°

Index range *h* = -13 → 28, *k* = -9 → 7, *l* = -23 →23

Table 1. Crystal data and structure refinement parameters of diacetamide **9**.

while the distance between the aromatic nitrogen N1 and C9 is 1.388 Å.

through a mesomeric effect giving this bond a stronger double bond character.

delocalized on the amide bond giving it less double bond character (Table 2).

the incorporation of the indolic core as a structural analogues of some alkaloids.

From this data, the different bond lengths of the two amide bonds present within the structure were as expected. Even knowing the double bond character of the amide bonds, in this case, the amide bond distance between the aliphatic nitrogen N2 and C12 is 1.364 Å,

These data correspond with the thought that the amide bond N2-C12 is shorter because of the electron withdrawing inductive effect from the α-cyanophenyl substituent and the possibility of the nitrogen non-shared electrons to be delocalized on the amide bond

On the other hand, the amide bond N1-C9 is longer because the nitrogen non-shared electrons are compromised with the aromatic system and they are not as available to be

An efficient, economic, and fast synthetic route was designed and its illustrated in this section showing the possible construction of the *N*-aryl-*N*-(3-indolmethyl)acetamides with

The acylation method is worth as a regioselective process because the conditions variations lead to the mono- or di-acetamide. The characterization of the obtained compounds through different techniques gives evidence enough and strong support with regard to the success of

Crystal morphology White parallelepipede

Chemical formula C20H17N3O2 Molecular weight 331.13 Crystal system Monoclinic Space group P21/n

Volume 1822.4(5) Å3 Absorption coefficient 0.82 mm-1 Temperature 293(2) K Range for data collection 1.99-28.09

*R* 0.0567 *Rw* 0.0582 Threshold expression >2sigma(l) Diffraction radiation M0Kα λ 0.71070 Å

**2.3 Conclusions** 

the proposed scheme.


Table 2. Bond lengths between the molecule atoms of diamide **9**.

Simple Preparation of New Potential Bioactive

Diels-Alder reaction.

**14,15**.

Comp. Molecular

Formula

the coupling constants 6.4 Hz and 11.1 Hz.

5.69 ppm (4-H) cross peaks interactions (Fig. 7).

equatorial interactions (Fig. 6).

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 95

Fig. 5. Synthesis of nitrophenyl-tetrahydroquinolines using the multi-component imino

Table 3. Physical description, IR data and yields of the 2-nitrophenyl tetrahydroquinolines

**3.2 Characterization of the** *N***-***[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-*

The structures of the C-2 substituted tetrahydroquinolines **14** and **15** were confirmed on the basis of analytical and spectral data and were supported by inverse-detected 2D NMR experiments. The IR spectrum show the characteristic absorption bands of the compound **14**  at 3394 and 1666 cm-1, assignable to the amine and amide group, respectively, and the nitro group signals at 1512 and 1342 cm-1. Their mass spectrum showed a molecular ion m/z: 351, it coincided with the molecular weight (351 g/mol). The 1H NMR spectrum of this compound presented the 4-H proton signal at 5.69 ppm, observed as a double doublet with

This fact suggested axial-axial and axial-equatorial interactions between 4-H and 3-H protons. On the other hand, the 2-H proton signal was observed at 4.65 ppm with the coupling constants 3.1 Hz and 10.7 Hz that indicated at vicinal axial-axial and axial-

The high value of the coupling constant (10.7-11.1Hz) of the 4-H and 2-H protons confirmed the axial proton configurations; therefore, substituents of the C-2 and C-4 positions of

On the other hand, it was found by the COSY experiment that the signal at 2.13-1.99 ppm belongs to the 3-H proton, observing the 3-H (4"-H) (2.13–1.99 ppm) and 4.65 ppm (2-H) and

Weight IR (KBr), , cm-1 mp, oC Yield (%)

1666, 1620 222-223 95

2854, 1666 242-243 70

Molecular

**<sup>14</sup>**C20H21N3O3 351.40 3394, 2947, 2916,

**<sup>15</sup>**C20H21N3O3 351.40 3271, 2972, 2916,

*yl]* **pyrrolidin-2-one 14 by spectroscopy and spectrometric techniques** 

tetrahydroquinoline ring have the equatorial disposition, respectively.

### **3. A convenient procedure for the synthesis of new quinoline derivatives and their spectroscopic analysis**

Quinoline and tetrahydroquinoline structures are essential feature of many natural products. These heterocycles play a key role in heterocyclic and medicinal chemistry. Their syntheses by various methodologies have been published extensively (Kouznetsov et al, 2005; Kouznetsov et al., 1998; Katrizky et al., 1996; Jones, 1984).

Polyfunctionalized tetrahydroquinolines (THQs) are molecules of great interest in organic synthesis due to the fact that many natural products present this system in their structure, and these compounds exhibit diverse biological activities (Glushenko et al., 2008; Broch et al., 2008; Ichikawa et al., 2004; Morsali, et al., 2004; Chen et al., 2000).

Apart from their marked bioactivities, THQs are also important and reliable precursors in quinoline preparation, another group of heterocyclic molecules that has a great number of pharmacological properties (Trpkovska et al., 2003). An efficient route for the preparation of THQs is the acid-catalyzed Povarov reaction that is classified as imino Diels-Alder cycloaddition (Kouznetsov, 2009; Paazderski et al., 2007; Kouznetsov & Mora, 2006; Youssed et al., 2003) that permits the condensation of anilines, aldehydes, and electron-rich alkenes using acidic catalysts under mild conditions to afford new substituted tetrahydroquinolines.

For any Direct Oriented Synthesis (DOS) methodology towards the synthesis of bioactive substituted tetrahydroquinolines and quinolones, this route represents an easily and scalable approach for the investigations on the synthesis of small drug-like (tetrahydro)quinoline molecules containing C-2 aryl fragment, those synthesis could be accomplished via cycloaddition reactions. In this order, this section explain the simple preparation of new *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolidin-2-ones using BiCl3-catalyzed three component Povarov reaction between nitrobenzaldehydes, toluidine and N-vinylpyrrolidin-2-one, and their transformations into potentially bioactive 2-aryltetrahydroquinoline derivatives, *N-amidyl* substituted at the C-4 position.

#### **3.1 Synthesis of new** *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* **pyrrolidin-2 ones**

Having an experience in the construction of diverse heterocycles containing nitrogen via multi-component Povarov reaction, (Kouznetsov et al., 2010; Kouznetsov et al., 2007; Kouznetsov et al., 2006). The preparation of the selected tetrahydroquinoline compounds **14**  and **15** was achieved using BiCl3 as a catalyst for the three-component imino Diels-Alder cycloaddition between toluidine **10**, nitrobenzaldehydes **12** and **13** and *N*-vinylpyrrolidin-2 one **11** (NVP) (Bermudez et al., 2011) (Fig. 5).

These reactions proceeded smoothly in MeCN and at room temperature giving final products, substances easy to purify by column chromatography using silica gel as a support and a mixture of petroleum ether and ethyl acetate (2:1) as an isocratic eluent. The *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolidin-2-ones **14** and **15** can be obtained with good respective yields 95% and 70% (Table 3) as a easily handle solids.

**3. A convenient procedure for the synthesis of new quinoline derivatives and** 

Quinoline and tetrahydroquinoline structures are essential feature of many natural products. These heterocycles play a key role in heterocyclic and medicinal chemistry. Their syntheses by various methodologies have been published extensively (Kouznetsov et al,

Polyfunctionalized tetrahydroquinolines (THQs) are molecules of great interest in organic synthesis due to the fact that many natural products present this system in their structure, and these compounds exhibit diverse biological activities (Glushenko et al., 2008; Broch et al., 2008; Ichikawa et al., 2004; Morsali, et al., 2004; Chen et al.,

Apart from their marked bioactivities, THQs are also important and reliable precursors in quinoline preparation, another group of heterocyclic molecules that has a great number of pharmacological properties (Trpkovska et al., 2003). An efficient route for the preparation of THQs is the acid-catalyzed Povarov reaction that is classified as imino Diels-Alder cycloaddition (Kouznetsov, 2009; Paazderski et al., 2007; Kouznetsov & Mora, 2006; Youssed et al., 2003) that permits the condensation of anilines, aldehydes, and electron-rich alkenes using acidic catalysts under mild conditions to afford new substituted

For any Direct Oriented Synthesis (DOS) methodology towards the synthesis of bioactive substituted tetrahydroquinolines and quinolones, this route represents an easily and scalable approach for the investigations on the synthesis of small drug-like (tetrahydro)quinoline molecules containing C-2 aryl fragment, those synthesis could be accomplished via cycloaddition reactions. In this order, this section explain the simple preparation of new *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolidin-2-ones using BiCl3-catalyzed three component Povarov reaction between nitrobenzaldehydes, toluidine and N-vinylpyrrolidin-2-one, and their transformations into potentially bioactive 2-aryl-

tetrahydroquinoline derivatives, *N-amidyl* substituted at the C-4 position.

one **11** (NVP) (Bermudez et al., 2011) (Fig. 5).

**3.1 Synthesis of new** *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* **pyrrolidin-2-**

Having an experience in the construction of diverse heterocycles containing nitrogen via multi-component Povarov reaction, (Kouznetsov et al., 2010; Kouznetsov et al., 2007; Kouznetsov et al., 2006). The preparation of the selected tetrahydroquinoline compounds **14**  and **15** was achieved using BiCl3 as a catalyst for the three-component imino Diels-Alder cycloaddition between toluidine **10**, nitrobenzaldehydes **12** and **13** and *N*-vinylpyrrolidin-2-

These reactions proceeded smoothly in MeCN and at room temperature giving final products, substances easy to purify by column chromatography using silica gel as a support and a mixture of petroleum ether and ethyl acetate (2:1) as an isocratic eluent. The *N-(2-nitrophenyl-1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolidin-2-ones **14** and **15** can be obtained with good respective yields 95% and 70% (Table 3) as a easily handle

2005; Kouznetsov et al., 1998; Katrizky et al., 1996; Jones, 1984).

**their spectroscopic analysis** 

2000).

**ones** 

solids.

tetrahydroquinolines.

Fig. 5. Synthesis of nitrophenyl-tetrahydroquinolines using the multi-component imino Diels-Alder reaction.


Table 3. Physical description, IR data and yields of the 2-nitrophenyl tetrahydroquinolines **14,15**.

#### **3.2 Characterization of the** *N***-***[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4 yl]* **pyrrolidin-2-one 14 by spectroscopy and spectrometric techniques**

The structures of the C-2 substituted tetrahydroquinolines **14** and **15** were confirmed on the basis of analytical and spectral data and were supported by inverse-detected 2D NMR experiments. The IR spectrum show the characteristic absorption bands of the compound **14**  at 3394 and 1666 cm-1, assignable to the amine and amide group, respectively, and the nitro group signals at 1512 and 1342 cm-1. Their mass spectrum showed a molecular ion m/z: 351, it coincided with the molecular weight (351 g/mol). The 1H NMR spectrum of this compound presented the 4-H proton signal at 5.69 ppm, observed as a double doublet with the coupling constants 6.4 Hz and 11.1 Hz.

This fact suggested axial-axial and axial-equatorial interactions between 4-H and 3-H protons. On the other hand, the 2-H proton signal was observed at 4.65 ppm with the coupling constants 3.1 Hz and 10.7 Hz that indicated at vicinal axial-axial and axialequatorial interactions (Fig. 6).

The high value of the coupling constant (10.7-11.1Hz) of the 4-H and 2-H protons confirmed the axial proton configurations; therefore, substituents of the C-2 and C-4 positions of tetrahydroquinoline ring have the equatorial disposition, respectively.

On the other hand, it was found by the COSY experiment that the signal at 2.13-1.99 ppm belongs to the 3-H proton, observing the 3-H (4"-H) (2.13–1.99 ppm) and 4.65 ppm (2-H) and 5.69 ppm (4-H) cross peaks interactions (Fig. 7).

Simple Preparation of New Potential Bioactive

further structural studies were realized.

adopts tetrahydroquinoline system.

*tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.

( = 0.71073 Å).

**3.3 X-Ray diffraction single crystal study** 

were strongly confirmed through IR, 1H and 13C NMR analyses.

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 97

The nitro-isomer **15** has similar chemical behavior in the spectra data. The chemical structures of the obtained *N*-*(1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolodin-2-one molecules

However, having a possible mechanism of realized multi-component condensation, we could anticipate the various diastereomers the *cis* or *trans* configuration. For these reasons,

Samples crystals of both compounds of interest were growth by slow evaporation in ethanol. However, the difficulty to obtain suitable crystals from compound **15** only allows performing the study for the compound **14**. The diffraction data of the compound **14** were collected at 273K using a CCD area detector with graphite-monochromatic Mo Kα radiation

This data were computed using Bruker-AXS software. For solution and refinement of the structure Shelxs-97 and Shelxl-97 (Sherldrick, 1997a; Sheldrick, 1997b) were used respectively.

The molecular structure for the compound is presented in the Figure 8, where a *cis*  conformation of the C-2 and C-4 substituents is evident, as well as a chair configuration that

Molecular and crystal structures were obtained using Mercury software (Allen, 2002).

Fig. 8. Representation of the unit cell of *N*-*[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-*

Table 4. Crystallographic data obtained by four-circle diffractometry.

The details of cell data and refinement for the compound **14** are summarized in Table 4.

Unit cell parameters *c* = 11.011 (3) Å

Volumen 913.998 Å3 System Triclinic Space Group P-1 (No. 2) Z 2

*a* = 9.109 (2) Å *b* = 9.2812 (5) Å

= 90.939º (6)

= 100.023° (6)

= 93.309° (6)

Fig. 6. 1H NMR spectra of *N-[6-methyl-2-(4'-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.

Fig. 7. COSY spectrum of *N-[6-methyl-2-(4'-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.

The nitro-isomer **15** has similar chemical behavior in the spectra data. The chemical structures of the obtained *N*-*(1,2,3,4-tetrahydroquinolin-4-yl)* pyrrolodin-2-one molecules were strongly confirmed through IR, 1H and 13C NMR analyses.

However, having a possible mechanism of realized multi-component condensation, we could anticipate the various diastereomers the *cis* or *trans* configuration. For these reasons, further structural studies were realized.

### **3.3 X-Ray diffraction single crystal study**

96 Chromatography and Its Applications

Fig. 6. 1H NMR spectra of *N-[6-methyl-2-(4'-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]*

Fig. 7. COSY spectrum of *N-[6-methyl-2-(4'-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]*

pyrrolidin-2-one **14**.

pyrrolidin-2-one **14**.

Samples crystals of both compounds of interest were growth by slow evaporation in ethanol. However, the difficulty to obtain suitable crystals from compound **15** only allows performing the study for the compound **14**. The diffraction data of the compound **14** were collected at 273K using a CCD area detector with graphite-monochromatic Mo Kα radiation ( = 0.71073 Å).

This data were computed using Bruker-AXS software. For solution and refinement of the structure Shelxs-97 and Shelxl-97 (Sherldrick, 1997a; Sheldrick, 1997b) were used respectively. Molecular and crystal structures were obtained using Mercury software (Allen, 2002).

The molecular structure for the compound is presented in the Figure 8, where a *cis*  conformation of the C-2 and C-4 substituents is evident, as well as a chair configuration that adopts tetrahydroquinoline system.

Fig. 8. Representation of the unit cell of *N*-*[6-methyl-2-(4´-nitrophenyl)-1,2,3,4 tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.


The details of cell data and refinement for the compound **14** are summarized in Table 4.

Table 4. Crystallographic data obtained by four-circle diffractometry.

Simple Preparation of New Potential Bioactive

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 99

Table 5 shows the atomic positions. Carbon-bound H-atoms positions were idealized

Number Label Xfrac Yfrac Zfrac 1 O1 0.3653 0.1204 0.8134 2 O2 -0.2751 0.1442 -0.069 3 O3 -0.2013 0.3615 -0.0633 4 N1 0.4385 0.1546 0.3218 5 N2 0.3999 0.2993 0.6826 6 N3 -0.1902 0.242 -0.0246 7 C1 0.2924 0.1252 0.3587 8 C2 0.281 0.2232 0.4685 9 C3 0.4102 0.2053 0.576 10 C4 0.5578 0.2277 0.5329 11 C5 0.5642 0.1906 0.4089 12 C6 0.7043 0.1999 0.3716 13 C7 0.8288 0.2495 0.4491 14 C8 0.8236 0.2933 0.5723 15 C9 0.6885 0.2777 0.6119 16 C10 0.3777 0.2485 0.7914 17 C11 0.3736 0.3751 0.8765 18 C12 0.3898 0.5036 0.8068 19 C13 0.4078 0.4576 0.6777 20 C14 0.1688 0.1496 0.2534 21 C15 0.1696 0.2758 0.1861 22 C16 0.0548 0.3036 0.0958 23 C17 -0.0664 0.2057 0.0701 24 C18 -0.0721 0.0818 0.135 25 C19 0.0456 0.0548 0.2264 26 C20 0.9644 0.3544 0.6587

(C-H=0.93 Å), with H atoms riding on the atoms to which they were attached.

Table 5. Atomic positions in the unit cell of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-*

The synthesis of two new nitro-isomers of *N-(tetrahydroquinolinyl)* pyrrolidin-2-ones using a versatile and simple methodology called the three component imino Diels-Alder cycloaddition is illustrated as an excellent route for the preparation of novel kind of structures, the spectral analysis showed the 2-Haxial, 4-Haxial configuration; therefore the diequatorial disposition of the C-2 and C-4 substituent that confirmed the formation of the

The full characterization of *N*-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinoline-4-yl] pyrrolidin-2-one **14** was possible due to the single crystal X-ray diffraction studies, given the following data: the compound **14** crystallizes in the triclinic system with *a* = 9.109(2) Å, *b* = 9.281(5) Å, *c* = 11.011(3) Å, α = 90.939 (6)°, = 100.023 (6), γ = 93.309 (6)°, Z = 2, space group

*tetrahydroquinolin-4-yl]* pyrrolidin-2-one (**14**).

endo-adduct during a Diels-Alder cycloaddition process.

**3.4 Conclusions** 

P-1 [No. 2], and V *=* 1054.0 A3.

The structure packing is showed in the Figure 9 and finally, the powder profile simulated by the single crystal data is shown in Figure 10.

Fig. 9. Molecular packing of the unit cell of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4 tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.

By means of single crystal study of the compound *N*-[6-methyl-2-(4-nitrophenyl)-1,2,3,4 tetrahydroquinolin-4-yl] pyrrolidin-2-one 1**5** was determined that crystals obtained from ethanol crystallizes in the triclinic system with space group P-1 (No 2).

Fig. 10. Diffraction profile of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14** simulated in Mercury software.

The structure packing is showed in the Figure 9 and finally, the powder profile simulated by

Fig. 9. Molecular packing of the unit cell of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-*

ethanol crystallizes in the triclinic system with space group P-1 (No 2).

By means of single crystal study of the compound *N*-[6-methyl-2-(4-nitrophenyl)-1,2,3,4 tetrahydroquinolin-4-yl] pyrrolidin-2-one 1**5** was determined that crystals obtained from

Fig. 10. Diffraction profile of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]*

pyrrolidin-2-one **14** simulated in Mercury software.

the single crystal data is shown in Figure 10.

*tetrahydroquinolin-4-yl]* pyrrolidin-2-one **14**.


Table 5 shows the atomic positions. Carbon-bound H-atoms positions were idealized (C-H=0.93 Å), with H atoms riding on the atoms to which they were attached.

Table 5. Atomic positions in the unit cell of *N-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4 tetrahydroquinolin-4-yl]* pyrrolidin-2-one (**14**).

#### **3.4 Conclusions**

The synthesis of two new nitro-isomers of *N-(tetrahydroquinolinyl)* pyrrolidin-2-ones using a versatile and simple methodology called the three component imino Diels-Alder cycloaddition is illustrated as an excellent route for the preparation of novel kind of structures, the spectral analysis showed the 2-Haxial, 4-Haxial configuration; therefore the diequatorial disposition of the C-2 and C-4 substituent that confirmed the formation of the endo-adduct during a Diels-Alder cycloaddition process.

The full characterization of *N*-[6-methyl-2-(4´-nitrophenyl)-1,2,3,4-tetrahydroquinoline-4-yl] pyrrolidin-2-one **14** was possible due to the single crystal X-ray diffraction studies, given the following data: the compound **14** crystallizes in the triclinic system with *a* = 9.109(2) Å, *b* = 9.281(5) Å, *c* = 11.011(3) Å, α = 90.939 (6)°, = 100.023 (6), γ = 93.309 (6)°, Z = 2, space group P-1 [No. 2], and V *=* 1054.0 A3.

Simple Preparation of New Potential Bioactive

this type of compounds (Hernandez et al., 2008).

**(hetero)aromatic aldehydes** 

scalable methodology.

on charcoal in ethanol (Fig. 11).

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 101

chemistry principles with the use of less hazardous Na2CO3 as a base to release the nucleophile (Dallinger & Kappe, 2007; Roberts & Strauss, 2005; Yadav & Meshram, 2001; Varma, 1999). The posterior reduction of the prepared oximes give the functionalized benzylamines (pyridylmethylamines) in quantitative yield, this allows the coupuling of the corresponding amines, without further purification, with cinnamic acid in the presence of boric acid to afford the final products in agreement to our previous experience synthesizing

The choice of diverse (hetero)aromatic aldehydes **16a-k** was motived by the interest in quest for N-hetarylmethyl cinnamamides with antioxidant and anticancer properties. The direct condensation of **16a-k** and hydroxylamine in the presence of Na2CO3 is realize in an ethanol/water medium. Thus, a mixture of aldehydes **16a**-**k**, Na2CO3 and hydroxylamine hydrochloride was mixed in deionized water for 5 min. at room temperature, and then a small amount of the respective aldehyde was added for a period of another 5 minutes. The reaction mixture was stirring for 15 min. and after traditional work-up, the pure products,

Fig. 11. Preparation of the respective (hetero)benzylamines from the aldehydes **16a-k** in a

Taking into consideration that one of the most "atom-economical" procedures for the preparation of an amine is hydrogenation of an oxime in which the only by-product is water, we addressed also to this approach (Trost, 1995; Trost, 1991). Having in our hands the eleven solid and stable aldoximes **17a**-**k** obtained in first step, each of them was hydrogenated at room temperature overnight under H2 atmosphere using 10 % palladium

The hydrogenation mixture obtained in the second step is filtered through celite and the filtrate was concentrated to dryness allowing the crude amine **18a**-**k**, which was quickly added, without any further purification, to an anhydrous toluene solution of *trans*-cinnamic

The required workup at the end of the reaction can be perform in two ways: one consist in the precipitation of the product of interest with a solution of NaHCO3 and their subsequent washing with water or that can be purified with column chromatography depending on the complexity of the final crude. For the second choice, the recommended support is neutral or basic alumina (Al2O3) due to the acidity of the *trans*-cinnamic acid that will remain from the

acid **19** in the presence of B(OH)3 (10 % mol) at 110 ºC for 6-10 h (Fig. 12).

**4.1 Synthesis of new** *N-benzyl* **(pyridyl) cinnamamides from substituted** 

the substituted aldoximes **17a**-**k** were obtained in quantitative yield (Fig. 11).

#### **4. Convenient and scaleable three-step synthesis of new N-benzyl (pyridyl) cinnamamides from substituted (hetero)aromatic aldehydes**

The relatively stable amide bond is not only common in natural-occurring materials like peptides and vitamins, it is also found in many synthetic substances. Among these important and interesting class of organic molecules: *N-benzylcinnamides* and *Nphenylcinnamides* have been always the focus of attention of organic, bioorganic and medicinal chemists due to their many useful synthetic applications (Takasu et al., 2003; Bernini et al., 2006; Nair et al., 2007) as well as their diverse (bio)chemical properties (Curtis et al., 2003; Tamiz et al., 1999; Lewis et al., 1991). Moreover, *N-amide* cinnamic acid derivatives are frequently presented in the nature (Mbaze et al., 2009; Vasques et al., 2002).

Both types of amides could be prepared generally via acylation reactions of the corresponding benzylamines or anilines and cinnamic acid derivatives (anhydrides or acyl halides) that are frequently used in the preparation of drug candidate molecules (Carey et al., 2006). However, the known acylation reactions for *N-benzylcinnamides* preparation employ hazardous and corrosive reagents (e.g., SOCl2, PCl3, (COCl)2, NEt3) besides the starting functionalized benzylamines are not commercially available products, and almost any of their functional groups needs to be protected to ensure chemoselective amide formation (Nesterenko et al., 2003).

Considering the reported biological properties of certain *N-arylcinnamides* and *Nbenzylcinnamides* that have showed *in vitro* antimycotic activity (Leslie et al., 2010) and the inhibition of the transcription of carcinogenic genes in infected cells (Sienkiewicz et al., 2007). The need of an easy, rapid and "green" protocol for the synthesis of these kind of compounds is necessary to explore new pharmacological targets, and in this order the challenge of the organic chemistry is currently focused on the design of novel methodologies that suppress the use of acyl chloride (including any dangerous reagent required for their synthesis) and promoting the direct condensation between carboxylic acids and amines, coupling that currently is performed using efficient promoters such as *N,N'*-dicyclohexylcarbodiimide (DCC) (Amma & Mallouk, 2004), (benzotriazol-1 yloxy)tripyrrolidinophosphonium hexafluorophosphate (ByPOB) (McCalmont, 2004; Baures et al; 2002), triethylamine (Walpole, et al., 1993) and boron-based catalysts like BH3**.** THF (Huang et al., 2007).

The search of bioactive not only requires a good synthetic route, all the reagents must be stable and inexpensive to improve the structural complexity as in the biological properties. In this case, the integrity of most of the benzylamines is compromised when they are exposed to air moisture or even stored at low temperatures for a long period of time (Nazih & Heissler, 2002). A way to prevent this effects is based on choosing an appropriate strategy that enables the preparation of the desired amount benzylamines at lower cost than those acquired commercially, which could be possible by reduction of nitriles (Haddenham et al., 2009) and oximes (Gannett et al., 1988).

The "green" protocol described in this section is directed to enhance the disadvantages already described for the existing methodologies. Considering first the excellent chemical reactivity of aldehyde group against hydroxylamine's nucleophilicity to give oximes, this part was based on the existing methodologies which were improved according to the green

The relatively stable amide bond is not only common in natural-occurring materials like peptides and vitamins, it is also found in many synthetic substances. Among these important and interesting class of organic molecules: *N-benzylcinnamides* and *Nphenylcinnamides* have been always the focus of attention of organic, bioorganic and medicinal chemists due to their many useful synthetic applications (Takasu et al., 2003; Bernini et al., 2006; Nair et al., 2007) as well as their diverse (bio)chemical properties (Curtis et al., 2003; Tamiz et al., 1999; Lewis et al., 1991). Moreover, *N-amide* cinnamic acid derivatives are frequently presented in the nature (Mbaze et al., 2009; Vasques et al., 2002). Both types of amides could be prepared generally via acylation reactions of the corresponding benzylamines or anilines and cinnamic acid derivatives (anhydrides or acyl halides) that are frequently used in the preparation of drug candidate molecules (Carey et al., 2006). However, the known acylation reactions for *N-benzylcinnamides* preparation employ hazardous and corrosive reagents (e.g., SOCl2, PCl3, (COCl)2, NEt3) besides the starting functionalized benzylamines are not commercially available products, and almost any of their functional groups needs to be protected to ensure chemoselective amide

Considering the reported biological properties of certain *N-arylcinnamides* and *Nbenzylcinnamides* that have showed *in vitro* antimycotic activity (Leslie et al., 2010) and the inhibition of the transcription of carcinogenic genes in infected cells (Sienkiewicz et al., 2007). The need of an easy, rapid and "green" protocol for the synthesis of these kind of compounds is necessary to explore new pharmacological targets, and in this order the challenge of the organic chemistry is currently focused on the design of novel methodologies that suppress the use of acyl chloride (including any dangerous reagent required for their synthesis) and promoting the direct condensation between carboxylic acids and amines, coupling that currently is performed using efficient promoters such as *N,N'*-dicyclohexylcarbodiimide (DCC) (Amma & Mallouk, 2004), (benzotriazol-1 yloxy)tripyrrolidinophosphonium hexafluorophosphate (ByPOB) (McCalmont, 2004; Baures et al; 2002), triethylamine (Walpole, et al., 1993) and boron-based catalysts like BH3**.**

The search of bioactive not only requires a good synthetic route, all the reagents must be stable and inexpensive to improve the structural complexity as in the biological properties. In this case, the integrity of most of the benzylamines is compromised when they are exposed to air moisture or even stored at low temperatures for a long period of time (Nazih & Heissler, 2002). A way to prevent this effects is based on choosing an appropriate strategy that enables the preparation of the desired amount benzylamines at lower cost than those acquired commercially, which could be possible by reduction of nitriles (Haddenham et al.,

The "green" protocol described in this section is directed to enhance the disadvantages already described for the existing methodologies. Considering first the excellent chemical reactivity of aldehyde group against hydroxylamine's nucleophilicity to give oximes, this part was based on the existing methodologies which were improved according to the green

THF

**4. Convenient and scaleable three-step synthesis of new N-benzyl (pyridyl)** 

**cinnamamides from substituted (hetero)aromatic aldehydes** 

formation (Nesterenko et al., 2003).

(Huang et al., 2007).

2009) and oximes (Gannett et al., 1988).

chemistry principles with the use of less hazardous Na2CO3 as a base to release the nucleophile (Dallinger & Kappe, 2007; Roberts & Strauss, 2005; Yadav & Meshram, 2001; Varma, 1999). The posterior reduction of the prepared oximes give the functionalized benzylamines (pyridylmethylamines) in quantitative yield, this allows the coupuling of the corresponding amines, without further purification, with cinnamic acid in the presence of boric acid to afford the final products in agreement to our previous experience synthesizing this type of compounds (Hernandez et al., 2008).

#### **4.1 Synthesis of new** *N-benzyl* **(pyridyl) cinnamamides from substituted (hetero)aromatic aldehydes**

The choice of diverse (hetero)aromatic aldehydes **16a-k** was motived by the interest in quest for N-hetarylmethyl cinnamamides with antioxidant and anticancer properties. The direct condensation of **16a-k** and hydroxylamine in the presence of Na2CO3 is realize in an ethanol/water medium. Thus, a mixture of aldehydes **16a**-**k**, Na2CO3 and hydroxylamine hydrochloride was mixed in deionized water for 5 min. at room temperature, and then a small amount of the respective aldehyde was added for a period of another 5 minutes. The reaction mixture was stirring for 15 min. and after traditional work-up, the pure products, the substituted aldoximes **17a**-**k** were obtained in quantitative yield (Fig. 11).

Fig. 11. Preparation of the respective (hetero)benzylamines from the aldehydes **16a-k** in a scalable methodology.

Taking into consideration that one of the most "atom-economical" procedures for the preparation of an amine is hydrogenation of an oxime in which the only by-product is water, we addressed also to this approach (Trost, 1995; Trost, 1991). Having in our hands the eleven solid and stable aldoximes **17a**-**k** obtained in first step, each of them was hydrogenated at room temperature overnight under H2 atmosphere using 10 % palladium on charcoal in ethanol (Fig. 11).

The hydrogenation mixture obtained in the second step is filtered through celite and the filtrate was concentrated to dryness allowing the crude amine **18a**-**k**, which was quickly added, without any further purification, to an anhydrous toluene solution of *trans*-cinnamic acid **19** in the presence of B(OH)3 (10 % mol) at 110 ºC for 6-10 h (Fig. 12).

The required workup at the end of the reaction can be perform in two ways: one consist in the precipitation of the product of interest with a solution of NaHCO3 and their subsequent washing with water or that can be purified with column chromatography depending on the complexity of the final crude. For the second choice, the recommended support is neutral or basic alumina (Al2O3) due to the acidity of the *trans*-cinnamic acid that will remain from the

Simple Preparation of New Potential Bioactive

**4.2 Conclusions** 

al., 2008).

compounds.

Nitrogen-Containing Molecules and Their Spectroscopy Analysis 103

Fig. 13. 1H-NMR spectrum of the *N-(3,4-methylenedioxybenzyl) cinnamamide* **5g**.

The improvement of the existing methodologies for the preparation of benzylamines, is described as protocol that enhances the efficiently, easily, rapidly and safety way in which the oximes can be obtained, leading to explore their synthetic use in the preparation of more complex systems or evaluate their pharmacological properties as a potential reactivators of the acetylcholinesterase enzyme (Sinko et al., 2010) or their allergenic activity (Bergström et

Taking into account that boronic compounds have showed catalytic activity in peptide synthesis, it is demonstrated also that boric acid is a practical and useful catalyst for amidation between cinnamic acid and the prepared benzylamines due to its remarkable catalytic potential. The notable features of this procedure are mild and green reaction conditions, good reaction rates, cleaner reaction profiles and excellent global yields for a linear synthesis of three steps. The recollected spectral data described for *N-benzyl cinnamides* should be reliable in the structural analysis of natural cinnamides and these substances could serve as a model for small-molecule screening towards new bioactive

Fig. 12. Rational design of the three-step synthesis of the corresponding *N-benzyl cinnamides* from substituted (hetero) aromatic aldehydes.

reaction. An acid support like common silica gel (SiO2) will retain both substances (the amide of interest and the residual cinnamic acid). After the method of preference for the purification of the amides has applied, the final products the N-benzylcinamides **20a**-**k** were obtained in excellent yields and with a high purity level (Table 6).


Table 6. Synthesized *N-benzyl cinnamides* **20a-k**.

The 1H NMR spectra of the compounds **20** display a general group of characteristic signals for this series. For example, in the cinnamide **20g** spectrum the methylene protons at 4.47 ppm (2H, d, *J* = 5.7 Hz, -CH2) is the signal that is observed in high fields, signal that is coupling with the N-H signal, observed as a triplet at 5.99 ppm (1H, *J* = 5.7 Hz, NH). The analysis of olefinic protons indicate the *trans* configuration of the final products when the high value of the coupling constant observed is compared with the typical value for the *cis* configuration: in the case of compound **20g**, and for the entire 11 synthetized molecules, the assignment of the proton at 6.41 ppm (1H, d, *J* = 15.7 Hz, =CHCO) and the coupling in trans form with the other olefinic proton, the one that appears at lower fields, at 7.66 ppm (1H, *J* = 15.7 Hz, =CHPh) confirmed the configuration of all the products (Fig. 13).

Fig. 13. 1H-NMR spectrum of the *N-(3,4-methylenedioxybenzyl) cinnamamide* **5g**.

#### **4.2 Conclusions**

102 Chromatography and Its Applications

Fig. 12. Rational design of the three-step synthesis of the corresponding *N-benzyl cinnamides*

reaction. An acid support like common silica gel (SiO2) will retain both substances (the amide of interest and the residual cinnamic acid). After the method of preference for the purification of the amides has applied, the final products the N-benzylcinamides **20a**-**k** were

> Comp. **20** R1 R2 R3 R4 Yield (%) a H Cl H H 80 b H OCH3 H H 87 c H OCH3 OCH3 H 91 d H OH OCH3 H 67 e H OCH3 OH H 72 f OCH3 OCH3 OCH3 H 95 g -OCH2O- H H 94 h H H -C4H4- 92 i H H H α=N 84 j H H β=N H 89 k H γ=N H H 90

The 1H NMR spectra of the compounds **20** display a general group of characteristic signals for this series. For example, in the cinnamide **20g** spectrum the methylene protons at 4.47 ppm (2H, d, *J* = 5.7 Hz, -CH2) is the signal that is observed in high fields, signal that is coupling with the N-H signal, observed as a triplet at 5.99 ppm (1H, *J* = 5.7 Hz, NH). The analysis of olefinic protons indicate the *trans* configuration of the final products when the high value of the coupling constant observed is compared with the typical value for the *cis* configuration: in the case of compound **20g**, and for the entire 11 synthetized molecules, the assignment of the proton at 6.41 ppm (1H, d, *J* = 15.7 Hz, =CHCO) and the coupling in trans form with the other olefinic proton, the one that appears at lower fields, at 7.66 ppm (1H, *J* =

15.7 Hz, =CHPh) confirmed the configuration of all the products (Fig. 13).

from substituted (hetero) aromatic aldehydes.

Table 6. Synthesized *N-benzyl cinnamides* **20a-k**.

obtained in excellent yields and with a high purity level (Table 6).

The improvement of the existing methodologies for the preparation of benzylamines, is described as protocol that enhances the efficiently, easily, rapidly and safety way in which the oximes can be obtained, leading to explore their synthetic use in the preparation of more complex systems or evaluate their pharmacological properties as a potential reactivators of the acetylcholinesterase enzyme (Sinko et al., 2010) or their allergenic activity (Bergström et al., 2008).

Taking into account that boronic compounds have showed catalytic activity in peptide synthesis, it is demonstrated also that boric acid is a practical and useful catalyst for amidation between cinnamic acid and the prepared benzylamines due to its remarkable catalytic potential. The notable features of this procedure are mild and green reaction conditions, good reaction rates, cleaner reaction profiles and excellent global yields for a linear synthesis of three steps. The recollected spectral data described for *N-benzyl cinnamides* should be reliable in the structural analysis of natural cinnamides and these substances could serve as a model for small-molecule screening towards new bioactive compounds.

Simple Preparation of New Potential Bioactive

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### **5. Acknowledgment**

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**6** 

**Wound Healing and Antibacterial** 

Magid Abdel Ouoba1, Jean Koudou2\* , Noya Some3, Sylvin Ouedraogo2,3 and Innocent Pierre Guissou1,2

*2Laboratory of Chemistry of Natural Products, Faculty of Sciences,* 

*3Institute of Research in Health Sciences, CNRST, Ouagadougou,* 

*1Unit of Teaching and Research (UFR) of Health Sciences, University of Ouagadougou,* 

*Vitex simplicifolia* Oliv. (Verbenaceae) is a perennial shrub or small tree which grows to a height of aproximatively 8 m and is widely distributed from Egypt to Guinea. In Burkina Faso, the plant is used for internal or external use to treat various diseases like skin diseases, dermatitis, bilharzia, migraines, fever, aches, amoebiasis, sore teeth, colic, infant tetanus(Nacoulma,1996). Our ethnobotanical investigations have revealed that this plant is also used in the treatment of skin infections and wounds healing. In Burkina Faso, infectious diseases are the leading cause of infant mortality (2.37%) and maternal (14.6%), therefore they constitute public health problems. The treatment of skin diseases dates back to ancient times, and many treatments were using medicinal plants. About 30% of traditional remedies are used to treat wounds and skin lesions, compared to only 1-3% of modern drugs (Mantle et al., 2001). The healing process is an immune response that begins after injury and takes place in three stages: vascular and inflammatory stage, phase of tissue repair and phase of maturation. A drug having simultaneously the potential antioxidant and antimicrobial activities may be a good therapeutic agent to accelerate cicatrization and wound healing [Houghton et al., 2005; Phillips et al., 1991; Heike et al., 1999]. Aromatherapy is now considered to be another alternative way in healing people, and therapeutic values of aromatic plants lie in their volatile constituents such as monoterpenoids, sesquiterpenoids and phenolic compounds that produce a definite physiological action on the human body [Bruneton, 1993].To the best of our knowledge, there is no report on pharmacological studies of this plant. The present work reported results of a detailed investigation of

**1. Introduction** 

 \*

Corresponding Author

 **Properties of Leaf Essential Oil** 

 **of** *Vitex simplicifolia* **Oliv.** 

**from Burkina Faso** 

*University of Bangui, Bangui,* 

*2Central African Republic* 

*1,3Burkina Faso* 

Zhao, J.L.; Liu, L.; Zhang, H.B.; Wu, Y.C.; Wang, D. & Chen, Y. J. (2006). Three-Component Friedel-Crafts Reaction of Indoles, Glyoxylate, and Amine under Solvent-Free and Catalyst-Free Conditions - Synthesis of (3-Indolyl)glycine Derivatives. *Archiv Pharmazie,* 337, pp. 127-132*.*
