Catalyst Free Synthesis of Imines and their Biological Evaluation.
1Rajarshi Shahu Mahavidhyalaya, Latur, Maharashtra-413512, India.
2Shivneri College, Shirur Anantpal, Dist. Latur, Maharashtra- -413544, India.
3Department of Chemistry, KMC College, Khopoli, Maharashtra- -410203 India.
4Research Laboratory for Pure and Applied Chemistry, M. M. College, Nilanga, Dist. Latur, MH413521, India.
*CorrespondingAuthorE-mail:amritkund_jk@rediffmail.com
ABSTRACT:
An efficient route for the synthesis of aromatic imines has been developed using simple protocol at room temperature. The synthesis was completed by using commercially available starting material. Here we synthesized fourteen imines derivatives with excellent yield. Synthesized intermediates showed potent inhibition of Mycobacterium tuberculosis. The Schiff’s bases shown drug like properties and is a good starting point for further exploration in antituberculosis drug discovery.
KEYWORDS:Schiff’s bases, imines, biological activity, aldehydes, DMF.
The nitrogen atom is present in most natural products, biologically important molecules, pharmaceuticals, and dyes. Imines and their derivatives are useful intermediates in organic synthesis, in particular for the preparation of heterocycles and non-natural b-aminoacids. Several methods for the synthesis of imines are described in the literature; they can be obtained from aldehydes, gem-dibromomethylaryl derivates, formamides, palladium catalyzed amination as well as by polymer-supported.
During the past several years the synthesis and application of N-sulfonylimines from aldehydes with sulfonamides has been found to be very useful in organic chemistry. Because Nsulfonylimines are powerful synthetic intermediates and they are also used in numerous reactions such as inverse electrondemand Diels–Alder reactions, addition reactions as carbonyl equivalents and in ene reactions. Several synthetic methods for the preparation of N-sulfonylimines have been reported in the literature, for example, the rearrangement of oxime O-sulfinates, Lewis acid or solid acid catalysed reactions of sulfonamides with aldehydes or acetals, utilisation of tellurium metal and chloramines.The effective method for the formation of C–N bonds in aryl imines and amines plays an important role in organic synthetic chemistry because of the high prevalence of nitrogen- containing molecules in natural and pharmaceutical products. Meanwhile, drugs containing the sulfonamide functional group (Scheme 1, 1 and 2) have long been identified as a potential ETA antagonists and showed good performance in the treatment of congestive heart failure.
Scheme 1: Drugs containing the sulfonamide functional group.
Due to importance of imines in industrial use as well in biology, there is greater need to develop a ecofriendly protocol for synthesis of imines. Here we developed a catalyst free synthesis protocol for synthesis of imines. We shown the scope for both the different aldehydes and substituted long branched amines. The reaction optimized at room temperature and resulted in good yield.
Results and Discussion: We started our synthetic journey of imines, by keeping in mind it should be a simple and eco-friendly protocol. For that we took commercially available aldehydes and amines.The best solvent what we observed after screening of various different solvent was DMF, in that reaction
Scheme 2: Synthesis of Imines derivatives.
went very smothery. We took aldehydes in round bottom flask and subsequently added the amines, DMF and resulting reaction mixture was stirred at room temperature. After the completion of the reaction (monitored by TLC) reaction mixture was cooled at room temperature, then water was added and solid was formed which was filtered and dried on vacuo to give imines as powdered solid. The general reaction scheme shown in Scheme 2, the first amine was phenyl sulfonyl amine which reacted with 2- hydroxy aldehyde to give imine a in 62% overall yield. We changed various amines and all the reaction went nicely to give excellent yields. The pyridine containing amines gave nice yield (c, 65%), the branched multisubstituted amines like k,l, m, and n shown excellent yield .To check the scope for aldehydes, we used different substituted aldehydes and heteroaryl aldehyes, all worked well like thiophine, pyridine and substituted aromatic aldehydes. All the compound obtained as solid material. All the imine derivatives were confirmed by NMR, Mass spectroscopy and taking melting point for complete characterization. The complete characterization of the compound is given in experimental section.
Biological Study:
These all the synthesized imine derivatives were screened for biological activity, since its novel compounds and based on literature observations it can be very potential drug candidates for drug discovery programme. The imines were tested for inhibition of Mycobacterium tuberculosis in invitro MABA assay. The results are summarized in table 1.
In-vitroMycobacterium tuberculosis MABA assay:
The inoculum was prepared from fresh LJ medium re-suspended in 7H9-S medium (7H9 broth, 0.1% casitone, 0.5% glycerol, albumin, dextrose, supplemented oleic acid, and catalase [OADC]), adjusted to a McFarland tube No. 1, and diluted 1:20; 100 µl was used as inoculum. Each drug stock solution was thawed and diluted in 7H9-S at four-fold the final highest concentration tested. Serial two-fold dilutions of each drug were prepared directly in a sterile 96-well microtiter plate using 100 µl 7H9-S.
|
Entry |
Compound |
MIC (µM) |
|
1 |
a |
100 |
|
2 |
b |
12.5 |
|
3 |
c |
15.6 |
|
4 |
d |
50.2 |
|
5 |
e |
66.2 |
|
6 |
f |
76.2 |
|
7 |
g |
32.4 |
|
8 |
h |
22.3 |
|
9 |
i |
6.25 |
|
10 |
j |
8.18 |
|
11 |
k |
9.15 |
|
12 |
l |
7.15 |
|
13 |
m |
15.2 |
|
14 |
n |
6.24 |
A growth control containing no antibiotic and a sterile control were also prepared on each plate. Sterile water was added to all perimeter wells to avoid evaporation during the incubation. The plate was covered, sealed in plastic bags and incubated at 37°C in normal atmosphere. After 7 days incubation, 30 µl of alamar blue solution was added to each well, and the plate was re-incubated overnight. A change in colour from blue (oxidised state) to pink (reduced) indicated the growth of bacteria, and the MIC was defined as the lowest concentration of compound that prevented this change in colour.The biological screening shows the compounds b, I, j, l, n shown potent activity against TB cell lines, its great starting point for further exploration of the making more diverse analogues. Other derivatives shown moderate activity against TB cell lines.
CONCLUSIONS:
In summary, the ecofrieldly protocol was developed and applied for the synthesis of imine derivatives at room temperature. Imine derivatives showed significant inhibition of Mycobacterium tuberculosis. These analogues are chemically tractable and hence provides ample opportunities for further modification to obtain potent antituberculosis agents. The isolated yield of the imine derivatives is excellent, so gram scale synthesis possible. The scope for aldehydes and amines was shown and it can be further explored.
Experimental Section:
Unless otherwise stated, all commercial reagents and solvents were used without additional purification. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm). Column chromatography was undertaken on silica gel (100‒200 mesh) using a proper eluent system. NMR spectra were recorded in chloroform-d and DMSO-d6 at 300 or 400 or 500 MHz for 1H NMR spectra and 75 MHz or 100 or 125 MHz for 13C NMR spectra. Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, dd = doublet of doublet, td = triplet of doublet, m = multiplet. Coupling constants, J, were reported in hertz unit (Hz). For 13C NMR chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of chloroform-d and 40.0 ppm center for DMSO-d6.
General procedure for preparation of compounds:
The common procedure for preparation of imines, In round bottom flask charged with aldehyde ( 10 mmol), amine (10 mmol) then DMF (50 mL) was added, resulting solution stirred at room temperature for 5h. After completion of the reaction (monitored by TLC) cooled to room temperature, then water was added (20 mL), solid was formed. The reaction mixture then filtered through Buchner funnel, solid was collected and dried on vacuum to give finally dried solid powder. ( All the compounds confirmed by NMR, Mass analysis).
Analytical Data of Synthesized Compounds:
1) (E)-2-(((4-((4-aminophenyl)sulfonyl)phenyl)imino) methyl)phenol (a):
White solid, Mp 122- 124°C, yield (62%) , Mass : Cal. 352.1, Observe. 353.2
1H NMR (300 MHz, DMSO-d6) δ 10.04 (dd, J = 107.8, 42.0 Hz, 1H), 8.15 (dd, J = 38.6, 18.5 Hz, 2H), 7.95 – 7.42 (m,3H), 7.34 – 6.36 (m, 3H), 5.19 (s, 1H), 3.86 (s, 2H), 3.07 (d, J = 73.8 Hz, 1H), 2.18 (ddd, J = 55.9, 33.5, 19.8 Hz, 2)., 1.3 (s, 6H).
13C NMR (75 MHz, DMSO-d6) δ 191.79, 167.83, 167.50, 163.06, 160.71, 156.65, 156.26, 154.49, 151.13, 136.41, 132.29, 130.45, 129.89, 129.25, 127.80, 126.49, 125.60, 124.59, 122.25, 119.47, 119.01, 117.22, 116.11, 115.11, 112.34, 111.14, 49.48, 46.88, 46.34, 44.26, 42.38, 23.14.
2)(E)-N-(4,6-dimethylpyrimidin-2-yl)-4-((2-hydroxybenzylidene)amino)benzenesulfonamide (b)
White solid, Mp 130- 132°C, yield (60%) , Mass : Cal. 382.11, Observe. 383.2
1H NMR (300 MHz, DMSO-d6) δ 10.04 (dd, J = 107.8, 42.0 Hz, 1H), 8.15 (dd, J = 38.6, 18.5 Hz, 2H), 7.95 – 7.42 (m,3H), 7.34 – 6.36 (m, 3H), 5.19 (s, 1H), 3.86 (s, 2H), 3.07 (d, J = 73.8 Hz, 1H), 2.18 (ddd, J = 55.9, 33.5, 19.8 Hz, 2)., 1.3 (s, 6H).
13C NMR (75 MHz, DMSO-d6) δ 191.79, 167.83, 167.50, 163.06, 160.71, 156.65, 156.26, 154.49, 151.13, 136.41, 132.29, 130.45, 129.89, 129.25, 127.80, 126.49, 125.60, 124.59, 122.25, 119.47, 119.01, 117.22, 116.11, 115.11, 112.34, 111.14, 49.48, 46.88, 46.34, 44.26, 42.38, 23.14.
3) (E)-4-((2-hydroxybenzylidene)amino)-N-(pyridin-2-yl)benzenesulfonamide (c).
White solid, Mp 142- 144°C, yield (65%) Mass: Cal. 353.39, Observe. 354.42.
1H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 16H), 10.27 (s, 4H), 8.95 (s, 17H), 7.99 (dd, J = 18.8, 6.5 Hz, 59H), 7.82 – 7.36 (m, 117H), 7.32 – 6.77 (m, 99H), 6.57 (d, J = 8.6 Hz, 14H).
13C NMR (75 MHz, DMSO-d6) δ 191.80, 165.09, 160.24, 153.21, 152.70, 152.30, 151.50, 146.30, 142.95, 140.58, 139.77, 138.68, 136.38, 133.88, 132.56, 129.28, 128.88, 128.00, 121.79, 119.46, 119.30, 117.21, 117.06, 116.68, 115.41, 113.92, 112.44, 112.13.
4) (E)-N-(3,4-dimethylisoxazol-5-yl)-4-((2-hydroxybenzylidene)amino)benzenesulfonamide (d).
White solid, Mp 166- 168°C, yield (70%) Mass : Cal. 371.22, Observe. 372.22
1H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 2H), 8.97 (s, 2H), 7.88 (d, J = 8.5 Hz, 4H), 7.75 – 7.39 (m, 9H), 6.98 (dd, J = 13.1, 6.5 Hz, 4H), 2.09 (d, J = 7.9 Hz, 6H), 1.67 (d, J = 16.2 Hz, 6H).
13C NMR (75 MHz, DMSO-d6) δ 197.10, 165.96, 157.92, 141.57, 134.59, 133.71, 133.37, 127.45, 124.65, 122.42, 118.03, 84.50, 84.17, 83.84.
5) (E)-2-(((4-((4-hydrosulfonylphenyl)sulfonyl) phenyl)imino)methyl)-3-(hydroxymethyl)phenol (e)
Brown solid, Mp 177- 179°C, yield (65%) Mass : Cal. 431.22, Observe. 432.33
1H NMR (300 MHz, DMSO-d6) δ 7.46 (t, J = 8.7 Hz, 9H), 6.62 (dd, J = 22.3, 8.6 Hz, 10H), 4.98 (q, J = 13.5 Hz, 2H), 2.51 (s, 4H).
13C NMR (75 MHz, DMSO-d6) δ 152.89, 152.69, 152.16, 150.15, 150.02, 146.79, 144.84, 143.62, 136.59, 133.48, 133.16, 131.02, 130.74, 128.65, 128.50, 128.16, 128.09, 127.57, 123.83, 113.37, 112.81, 85.33, 68.60.
6) (E)-N-(4,6-dimethylpyrimidin-2-yl)-4-((4-hydroxybenzylidene)amino)benzenesulfonamide (f).
Brown solid, Mp 145- 148°C, yield (67%) Mass : Cal. 382.22, Observe.383.32.
1H NMR (300 MHz, DMSO-d6) δ 8.07 – 7.33 (m, 8H), 7.03 – 6.69 (m, 9H), 2.27 (s, 3H), 2.20 (d, J = 11.5 Hz, 5H).
13C NMR (75 MHz, DMSO-d6) δ 167.27, 166.99, 163.44, 161.55, 159.14, 156.30, 147.92, 130.85, 130.07, 129.73, 129.52, 128.59, 126.33, 121.80, 116.22, 115.96, 115.32, 115.15, 113.42, 111.44, 62.79, 22.88, 22.66, 22.32.
7) (E)-4-(((4-((4-aminophenyl)sulfonyl)phenyl)imino) methyl)phenol ( g)
Yellow solid, Mp 185- 187°C, yield (67%) Mass : Cal. 352.22, Observe.353.32.
1H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.71 (dd, J = 24.1, 8.4 Hz, 4H), 7.25 – 6.56 (m, 7H).
13C NMR (75 MHz, DMSO-d6) δ 198.29, 195.05, 193.06, 190.92, 189.30, 182.12, 176.48, 172.29, 168.29, 163.42, 155.78, 138.14, 137.35, 136.66, 136.38, 134.21, 133.28, 132.03, 130.76, 130.41, 128.72, 128.32, 127.51, 127.10, 125.13, 121.95, 117.11, 115.86, 115.21, 114.23, 109.22, 41.77, 41.51, 41.22, 40.95.
8) (E)-4-((4-aminophenyl)sulfonyl)-N-(thiophen-2-ylmethylene)aniline (h).
Pink solid, Mp 192- 194°C, yield (67%) Mass : Cal. 342.2, Observe.343.32.
1H NMR (300 MHz, DMSO-d6) δ 9.97 (d, J = 1.1 Hz, 2H), 8.76 (d, J = 3.3 Hz, 7H), 8.20 – 7.77 (m, 23H), 7.77 – 7.45 (m, 35H), 7.47 – 7.17 (m, 23H), 6.71 – 6.54 (m, 16H), 6.23 (s, 8H), 6.04 (s, 11H), 4.58 (s, 2H).
13C NMR (75 MHz, DMSO-d6) δ 184.18, 156.51, 156.10, 155.28, 154.49, 154.37, 153.57, 152.81, 152.72, 150.73, 143.51, 141.86, 141.78, 140.11, 139.83, 138.04, 137.84, 136.01, 134.99, 134.76, 132.44, 132.23, 129.42, 129.16, 128.90, 128.75, 128.58, 128.41, 128.21, 127.91.
9) (E)-4-(((4-((4-aminophenyl)sulfonyl)phenyl) imino)methyl)-2-methylphenol (i).
White solid, Mp 160- 162°C, yield (67%) Mass : Cal. 366.24, Observe.367.32.
1H NMR (300 MHz, DMSO-d6)δ 8.76 (d, J = 3.3 Hz, 1H), 7.97 – 7.69 (m, 4H), 7.55 (ddd, J = 29.3, 14.1, 6.4 Hz, 4H), 7.41 – 7.17 (m, 3H), 6.67 (dd, J = 15.7, 8.7 Hz, 3H), 6.23 (s, 1H), 6.04 (s, 2H).
13C NMR (75 MHz, DMSO-d6) δ 152.69, 128.58, 128.21, 113.12, 112.93., 111.32, 105.1, 102.11, 100.0, 98.23.
10)(E)-N-(3,4-dimethylisoxazol-5-yl)-4-(((3-hydroxy-2methylpyridin4yl)methylene)amino)benzenesulfonamide (j)
White solid, Mp 140- 142°C, yield (67%) Mass : Cal. 386.24, Observe.387.3.
1H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 2H), 8.97 (s, 2H), 7.88 (d, J = 8.5 Hz, 4H), 7.70 (d, J = 6.9 Hz, 3H), 7.59 (d, J = 8.5 Hz, 4H), 7.45 (t, J = 8.4 Hz, 4H), 6.99 (t, J = 7.2 Hz, 5H), 2.10 (s, 6H), 1.70 (s, 6H).
13C NMR (75 MHz, DMSO-d6) δ 167.27, 166.92, 163.48, 159.16, 156.28, 147.45, 137.62, 130.95, 130.05, 129.71, 129.53, 126.32, 121.78, 116.24, 115.96, 115.43, 115.12, 113.39, 111.40, 62.80, 61.55, 22.87, 22.63.
11) (E)-3-ethyl 5-methyl 2-((2-((2-hydroxybenzylidene)amino)ethoxy)methyl)-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (k).
White solid, Mp 187- 190°C, yield (67%) Mass: Cal. 464.24, Observe.465.3.
1H NMR (300 MHz, DMSO-d6) δ 13.51 (s, 1H), 8.56 (d, J = 16.3 Hz, 2H), 7.49 – 7.01 (m, 6H), 6.89 (t, J = 7.1 Hz, 2H), 5.30 (s, 1H), 4.62 (q, J = 13.7 Hz, 2H), 4.11 – 3.86 (m, 2H), 3.78 (dd, J = 12.6, 4.1 Hz, 4H), 3.49 (s, 3H), 3.38 (s, 4H), 2.20 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, DMSO-d6) δ 167.07, 166.30, 160.78, 145.78, 145.47, 144.47, 132.31, 131.58, 131.07, 130.92, 128.93, 127.73, 127.33, 118.60, 118.39, 116.50, 103.19, 101.48, 69.60, 66.11, 59.39, 57.71, 50.44, 36.76, 18.08, 14.02.
12) (E)-3-ethyl 5-methyl 2-((2-((4-hydroxybenzylidene)amino)ethoxy)methyl)-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (l).
White solid, Mp 187- 190°C, yield (67%) Mass: Cal. 464.24, Observe.465.3.
1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 5H), 7.75 – 7.51 (m, 11H), 7.38 – 7.07 (m, 28H), 5.30 (d, J = 7.1 Hz, 4H), 4.79 – 4.49 (m, 9H), 4.13 – 3.90 (m, 9H), 3.67 (dd, J = 13.3, 8.5 Hz, 12H), 3.50 (d, J = 4.3 Hz, 15H), 3.10 (dd, J = 19.0, 14.1 Hz, 9H), 2.31 (s, 12H), 1.11 (dd, J = 8.3, 5.9 Hz, 14H).
13C NMR (75 MHz, DMSO-d6) δ 172.35, 172.35, 171.51, 171.51, 153.41, 150.93, 150.93, 150.48, 150.48, 150.20, 149.82, 149.82, 136.37, 136.37, 136.22, 136.22, 134.90, 134.25, 134.25, 133.70, 133.70, 133.08, 133.08, 132.89, 132.89, 132.65, 132.65, 130.70, 130.70, 120.60, 107.42, 107.42, 107.22, 107.22, 75.55, 75.55, 71.99, 71.99, 71.89, 71.89, 71.54, 71.54, 65.12, 65.12, 64.66, 64.66, 55.80, 55.80, 45.39, 45.18, 44.97, 44.76, 44.55, 44.34, 44.13, 43.92, 41.91, 23.53, 23.53, 23.45, 19.32, 19.32.
13) (E)-3-ethyl 5-methyl 4-phenyl-2-((2-((thiophen-2-ylmethylene)amino)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate (m).
Orange solid, Mp 202- 204°C, yield (67%) Mass: Cal. 454.24, Observe.455.3.
1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 3.3 Hz, 1H), 7.86 (dd, J = 11.8, 6.7 Hz, 2H), 7.76 – 7.49 (m, 118H), 7.40 – 7.18 (m, 65H), 6.67 (dd, J = 15.7, 8.7 Hz, 66H), 6.23 (s, 24H), 6.04 (s, 38H).
13C NMR (75 MHz, DMSO-d6) δ 191.80, 165.09, 160.24, 140.58, 133.88, 132.56, 128.88, 128.00, 121.79, 119.30, 116.68, 113.92, 112.44.
14)(E)-3-ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-((4-hydroxy-3-methylbenzylidene)amino)ethoxy)methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (13)
Brown solid, Mp 205-206°C, yield (67%) Mass: Cal. 526.44, Observe.527.1
1H NMR (300 MHz, DMSO-d6) δ 1H NMR (300 MHz, DMSO) δ 8.46 (s, 1H), 7.99 (s, 3H), 7.72 (dd, J = 5.7, 1.9 Hz, 2H), 7.44 – 7.03 (m, 7H), 5.34 (s, 1H), 4.65 (dd, J = 37.9, 14.3 Hz, 2H), 4.18 – 3.91 (m, 2H), 3.69 (s, 2H), 3.57 (t, J = 19.1 Hz, 3H), 3.50 (s, 3H), 2.32 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, DMSO-d6) δ 167.27, 166.92, 163.48, 159.16, 156.28, 147.45, 137.62, 130.95, 130.05, 129.71, 129.53, 126.32, 121.78, 116.24, 115.96, 115.43, 115.12, 113.39, 111.40, 62.80, 22.87, 22.63.
ACKNOWLEDGMENT:
Authors are thankful to management and principals of respective colleges for providing infrastructural facilities and encouragement. We are also thankful to CSIR-IICT, Hyderabad for providing NMR and Mass data.
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Received on 01.12.2017 Modified on 12.12.2017
Accepted on 27.12.2017 © AJRC All right reserved
Asian J. Research Chem. 2017; 10(6):719-724.
DOI: 10.5958/0974-4150.2017.00122.5