P. Datta et.al/ 4(3) pp 711- 727 September 2016 · syncephalostonemracemosus- contributing to fruit root in tomato and ... carboxymethyl-chitosan shows an antioxidant activity

P. Datta et.al/ 4(3) pp 711- 727 September 2016

International journal of Pharmacy and Engineering (IJPE) Page 712

Synthesis & characterization of imino-pyridine ligands: A study towards Pd- catalyzed

Suzuki-Miyaura coupling reaction

Payel Datta1, NasimSepay1, Shreya Banerjee2, Ankita Sau2, Argha Sarkar2, Goutam Mukhopadhyay2*

1 Department of Chemistry, Presidency University, Kolkata-700073, West Bengal, India. 2BCDA College of Pharmacy and Technology, 78 Jessore Road, Kolkata-700127, India.

ABSTRACT:

Schiff bases are usually very important in medical and pharmaceutical fields. Transition metal complexes

derived from Schiff bases ligands has been widely studied because of their sigma electron donating ability.

Palladium is arguably the most versatile and most widely applied catalytic metal in the field of fine chemicals

due to its high selectivity and activity. Palladium catalyst offers an abundance of possibilities of C-C bond

forming reaction in organic synthesis. A fine tuning of electronic property of ligand can have dramatic effect on

the catalytic property of metal; hence affect the rate of the reaction. The present work describes synthesis and

characterization of a number of imino-pyridine bidentate ligands prepared by condensation between pyridine-

2-carboxaldhyde and aromatic amines (electron donating and/or electron withdrawing).The corresponding

palladium and copper complexes were prepared. The synthesized N,N-bidentate ligands were then verified for

their efficiency in Pd(II) catalyzed Suzuki-Miyaura coupling reaction with various aryl halides.

KEY WORDS: Schiff base; Suzuki-Miyaura Coupling reaction; N,N-bidentate ligand; imino-pyridine

Received: September 19th 2016, Revised: September 23th 2016, Accepted: September 25th, 2016,

Licensee Abhipublications Open.

This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License

(http://www.abhipublications.org/ijpe) which permits unrestricted, non-commercial use, distribution and

reproduction in any medium, provided the work is properly cited.



Corresponding Author: Dr. Goutam Mukhopadhyay, Associate Professor, BCDA College of pharmacy and Technology,

Kolkata, India. Email- [email protected]

1. INTRODUCTION:

Compounds containing an azomethine group (-CH=N-) known as Schiff bases are formed by the

condensation of a primary amine with a carbonyl compound. Schiff bases of aliphatic aldehydes are

relatively unstable and are readily polymerisable while those of aromatic aldehydes having an effective

conjugation are more stable. Bis-Schiff bases are generally Bi-dentate ligands, capable of forming

stable complexes with transitions metals (e.g. Cu, Co, Pd, Ni etc.).

1.1 Application of Schiff bases and its complexes:

Schiff base complexes have a broad range of application. The important ones are discussed below;

1.2 Biological activity:

Characterized azomethane (-N=CH-) group help to clarify the mechanism of transamination and

racemization in biological system.

Schiff bases are identified as promising anti-bacterial agents e.g. N-(salicylidene)-2-hydroxyaniline

(Fig 1: A) is active against mycobacterium tuberculosis[1] . Schiff bases and their metal complexes

formed between furan or furylglycoxal with various amines exhibit Anti-fungal activity against

syncephalostonemracemosus- contributing to fruit root in tomato and colletotrichum capsice- causing

anthracnose in chillies[2]. Schiff bases are one interesting compound which could be part of anti-

malarial drug e.g. ancistrocladidine[1](Fig 1: B) which is a secondary metabolite produced by plants of

the family Ancistrocladaceae and presenting an imine group in molecular chain.Some Schiff bases

have high anti-cancer activity imine derivative of N-hydroxy-N’-aminoguanidine block

miboriucleotidereductase in tumor cells so that they can use in treatment of leukemia [3] .Schiff base of

PDH,PHP and HHP reduces the average tumor weight.Several Schiff bases possess anti-inflammatory,

allergic inhibitors reducing activity radical scavenging analgesic and anti-oxidative action[4]. Thiazole

derived Schiff bases shows analgesic and anti-inflammatory activity. Schiff base of chitosan and

carboxymethyl-chitosan shows an antioxidant activity such as superoxide and hydroxyl scavaging [4].

Furan semicarbazone metal complexes exhibit significant anthelmintic and analgesic activities.



1.3 Application in modern technology :

Schiff bases includes the properties of liquid crystal[5] , chelating ability[6], their molecular stability[7] ,

optical non-linearity[8] and to create a new type of molecular conductors using electrical property to H+

transfer[9] . Because of thermal stability it is used as stationary phase in Gas Chromatography[6]. The

optical non-linearity of Schiff bases allows us to use them as electronic material, up to electronic and

photonic components[7].

Dyes:

Chromium azomethine complexes, cobalt complex Schiff base, and asymmetrical complex 1:2

chromium dyes give fast colours to leathers, food packages, wools etc. Azo groups containing metal

complexes are used for dying cellulose polyester textiles. Some metal complexes are used to mass dye

polyfibers[10].

Polymer:

Photochemical degradation of natural rubber yield amine terminated liquid natural rubber (ATNR)

when carried out in solution, in presence of ethylenediamine. ATNR on reaction with glyoxalyield

poly Schiff base, which improves aging resistance. Organocobalt complexes with tridentate Schiff base

act as initiator of emulsion polymerization and co-polymerization of dienyl and vinyl monomers[10].

Co-ordination chemistry of transition metal complexes with Schiff base ligands is an important and

fascinating branch of chemistry. They play an important role in co-ordination chemistry of many

transition metal complexes due to ease of their formation and versatility. The introduction of addition

donor atom atoms increases the stability of the formed metal complexes and gives the possibility to

combine with different hard and soft donor atoms in one chelating system which allows the formation

of stable complexes of transition metals (Cu, Pd, Co, Ni, Mn etc.)[11-13].



NN

M M=Cu, Pd, Co, Ni, Mn etc.

The transition metal complexes have been widely used in catalytic chemistry. Furthermore, palladium

Schiff base complexes found a number of applications in homogeneous and heterogeneous catalysis

e.g. Cross-coupling reactions,[13] conjugate addition,[14] polymerization,[15] etc. Similarly, other

transition metals e.g. Mn-complexes used for oxidation,[12]Cu-complexes used for alkylation,16

conjugate addition,16cyclopropanation etc. The change in the electronic nature of the ligand affects the

electronic property of the metal hence the complexes which shows variation in their catalytic

propertyin coupling reactions.

1. Objective:

Synthesis and characterization of a number of imino-pyridine ligands stating from readily

available starting material namely, pyridine-2-carboxaldehyde and various aromatic amines (4-

methoxyaniline and aniline).

Preparation of Pd(II) and Cu(II) complexes of these imino-pyridine ligands and their

characterization using UV spectroscopy.

Screening the efficiency of these N,N-bidentate ligands in Pd(II) catalyzed Suzuki Miyaura

coupling reaction with various aryl halides and phenyl boronic acid in different solvents.

2. EXPERIMENTAL SECTION:

General information:

All reagent grade chemicals were purchased from sigma Aldrich. Some of the reactions were

performed under argon using dried glass ware with magnetic stirring. TLC were performed on

aluminum plates pre-coated with silica gel 60F254 (E.Merk), the spot were detected visually and UV

light, respectively. Column chromatography was performed with silica gel (100-200 mesh). Melting

point was determined by heating the sample in sulphuric acid bath. FT-IR spectra were recorded on a



thermonicolet nexus 670 spectrophotometer using KBr discs. 1H NMR and 13C NMR spectra were

recorded at room temperature on Bruker Avance 300 or 400 MHz spectrometer in CDCl3 as solvent.

Chemical shift () were reported in parts per million (ppm) using TMS (δ = 0) as an internal standard

or w.r.t. CDCl3 (δ = 7.26 ppm.). Coupling constant (J) were given in hertz (Hz). Multiplicities were

reported as s (singlet) and brs (brand singlet), d (doublet), dd (doublet of doublet), t (triplet), m

(multiplate). For HR-MS, m/z value was expressed in atomic mass units.

3.1 General procedure for the preparation of ligands:

In a 100ml round bottomed flask pyridine-2-caroxaldehyde (1)(200mg or ~0.2ml) and aniline

derivative was taken in 1:1 ratio in dry ethanol. The reaction mixture was refluxed in nitrogen

atmosphere for appropriate time (See below). Completion of the reaction was monitored by TLC. After

completion, the ethanol was evaporated and the crude compound was taken for further steps without

purification.

3.1.1 Preparation of (E)-4-methoxy-N-((pyridine-2-yl)methylene)

benzenamine(2)

General procedure described above was followed 4-methoxybenzenamine[0.228g,1.86mmol]was used

to afford(E)-4-methoxy-N-((pyridin-2-yl)methylene)benzenamine(2)as greenish liquid to yield 32%

(124mg).

Rf =0.26 (Ethylacetate/petroleum ether 20/80)

Spectral data : IR νmax (KBr, cm-1):1598, 1625, 3053



1HNMR(CDCl3): 3.81(s,3H),6.9(d,J=6.8Hz,2H),7.32(m,3H),7.7(m,1H),8.16(m,1H),8.66(s,2H)

3.1.2 Preparation of (E)-N-(pyridin-2-ylmethylene)aniline:

General procedure described above was followed aniline [~0.2,1.86mmol]was used) to afford (E)-N-

((pyridin-3-yl)methylene) benzenamines brown liquid to yield 39% (131mg).

Rf =0.52 (Ethylacetatae/petroleum ether 20/80)

Spectral data : IR νmax (KBr, cm-1):1593,1627,3055

1HNMR (CDCl3):

7.31(m,3H),7.51(m,3H),7.85(t,J=8.4Hz,1H),8.23(d,J=10.4Hz,1H),8.63(s,1H),8.73(d,J=6.4 Hz,1H)

3.2 Preparation of Palladium complex from N-((pyridine-3-yl) methylene) benzenamine(3):

In a 50 ml round bottom ligand 3[0.02g,0.108mmol] was taken and dissolved in 10 ml

ethanol.PdCl2[0.01g,0.054mmol] was added to the mixture and was refluxed for 5 hr at 1000C under

nitrogen atmosphere. After 5 h, the mixture was cooled and 10%NaOH solution was added dropwise to

reach the pH 8. A brown precipitate was formed which was filtered. The precipitate was found to be

soluble in DMSO.

3.3 General procedure for the preparation of various Suzuki-Miyaura coupling product using

ligand3:



4Bromoacetophenone(5)(50mg,0.25mmol),Phenylboronicacid(6)(45.75mg,0.375mmol),Pd(OAc)2(5.6

mg,0.025mmol),K2CO3(anhyd)(69mg,0.50mmol)and ligand (3)[10mg,0.050mmol] were weighted in

air and transferred to a 50ml round bottom fitted with a condenser with a magnetic stir bar and

necessary solvent(1ml). The reaction mixture was refluxed (1000C) under nitrogen atmosphere. It was

cooled to room temperature and diluted with ethyl acetate. This was filtered and solvents were

removed under reduced pressure using rotary evaporator. The resulting residue was purified by column

chromatography over silica gel(100-200 mesh) using ethyl acetate/petroleum ether (4%) as eluent. The

solvent was removed to yield the pure compound. The above general method was followed to afford

same Suzuki coupling product using different solvents (Entry 1-4, Table No.1).

Melting point:1200C and Rf =0.24 (Ethylacetate/petroleum ether 5/95)

1HNMR(CDCl3): 2.64(s,3H),7.41(m1H),7.49(t,J=6.6Hz,2H),7.64(d,J=6.6Hz,2H),7.69(d,J=6.4Hz,2H)

8.04(d,J=6.8 Hz,2H),

3.4 General procedure for the preparation of various Suzuki-Miyaura coupling product using

ligand2:

4-Bromo acetophenone(5) ,4-Bromo anisole(8),4-Chloronitrobenzene(9), Phenylboronic acid(6),

Pd(OAc)2, K2CO3(anhydride) and ligand 2 were weighted in air and transferred to a 50ml round

bottomed flask fitted with a condenser with a magnetic stir bar and dioxane(1ml). The reaction mixture

was refluxed (1000C) under nitrogen atmosphere. It was cooled to room temperature and ethyl acetate



was added to it. This was filtered and solvents were removed under reduced pressure using rotary

evaporator. The crude residue was purified by column chromatography over silica gel (100-200 mesh)

using ethyl acetate/petroleum ether as eluent (see Table 2).

3.4.1 Preparation of 4-Phenylacetophenone(7) :

B(OH)2+

solvent,1000C6 ligand 2

Br

MeOC

7

COMePd(OAc)2

K2CO3

5

General procedure described above was followed 4-Bromo acetophenone(5)[50mg,0.25mmol,],Phenyl

boronic acid(6)[45.75mg,0.375mmol],K2CO3[69mg0.50mmol],Pd(OAc)2[5.6mg,0.025mmol],ligand

2[10.6mg0.050mmol] was used) to afford 4-Phenylacetophenone(7). It was purified by column

chromatography over silica gel[silica gel (100-200)mesh,4% ethylacetate in petroleum ether] to yield

72%(35mg) of the desired product as a white solid. Melting point:1200C

3.4.2 Preparation of 4-Phenylanisole(10) :

B(OH)2+

K2CO3 (anhyd)

dioxane,reflux(5h)6ligand 2

Br

MeOOMe

8 10

Pd(OAc)2 1000C

General procedure described above was followed p-Bromo

anisole(8)[50mg,0.25mmol,],Phenylboronic

acid(6)[49.75mg,0.405mmol,],K2CO3[74.5mg0.54mmol,],Pd(OAc)2[6mg,0.027mmol,],ligand

1a[11.4mg0.054mmol,] was used to afford 4-Phenylanisole(10).It was purified by column

chromatography over silica gel[silica gel (100-200)mesh,2% ethylacetate in petroleum ether] to yield

75%(37mg) of the desired white solid. Melting point: 860C

Rf = 0.48(Ethylacetate/petroleum ether 5/95)

1H NMR (CDCl3): 3.78(s,3H),6.9(m,2H),7.25(m,1H)7.32(m,2H),7.45(m,4H)



3.4.3 Preparation of p-Phenylnitrobenzene :

General procedure described above was followed p-Chloronitrobenzene(9)[50mg, 0.302 mmol],

phenylboronicacid(6)[58.56mg,0.48mmol],K2CO3[88mg0.64mmol],Pd(OAc)2[7.1mg,0.032mmol],liga

nd 2[13.5mg,0.064mmol] was used to afford p-Phenylnitrobenzene(11).The yield was so low that it

could not be isolated.

3.4.4 Preparation of Cu complex from N-((pyridin-3-yl)methylene)benzene-1,4-diamine(2) :

In a 50 ml round bottom ligand 2[0.02g, 0.108mmol] was taken and was dissolved in 5 ml

ethanol.CuCl2,2H2O[0.009g,0.054mmol] was added to the mixture and was heated at 600C in nitrogen

atmosphere for 3 hr, cooled. The green solid obtained was then filtered, argonised and refrigerated. As

we mixed the ligand and Cu salt in 2:1 ratio so the expected structure was written.

4. RESULT AND DISCUSSION:

4.1 Synthesis of imino-pyridine ligands:



N CHO NN

Ar

NN

1

1. PhNH22.EtOH

reflux,100 °C6 h

p-methoxybenzenamine

EtOH

reflux,100 °C3 hAr

Ar = PhAr = 4-OMe-C6H4

2 3

(E)-4-methoxy-N-((pyridin-2-yl)methylene)benzenamine(2)was prepared(Scheme 1) by condensation

between pyridin-2-carboxaldehyde(1) and 4-methoxybenzenamine in ethanol by following reported

procedure.[13]Consumption of starting material and formation of a new product was observed inTLC

followed by testing in iodine chamber. Pyridine-2-carboxaldehyde (1) did not absorbed iodine but the

amine and the product absorbed iodine which were identified by their different position in TLC. (E)-N-

(pyridin-2-ylmethylene)aniline(3) was prepared(Scheme 1) from pyridine-2-carboxaldehyde(1) by

using aniline in ethanol(Scheme 1) by refluxing for 6 hr as reported in the procedure[13].In this case the

product formed was observed in the similar way as mentioned for the previous case of ligand2. The

products showed IR value at 1627cm-1 which was for C=N. The compounds 2 and 3 were

characterized by 1H NMR. From UV absorption spectroscopy we got the red shift of λmax for the

ligands than the starting aldehyde. Ligands gave red shift of λmax because of conjugation from the

corresponding phenyl groups. Ligand2 was observed to shift a bit more red shift than ligand3 as it is

more conjugated and electron dense.



Fig 2: UV spectroscopy of (combined) compounds 1, 2 and 3

4.2 Synthesis of Palladium complex using ligand 3:

The corresponding palladium complex using ligand 3 was prepared (Scheme 2) by refluxing ligand3

and PdCl2 in ethanol for 5 hr[13].After cooling followed by basifying a dark brown precipitate obtained

which was soluble in DMSO.

The dark brown compound could not be crystallized further. However, their UV spectral pattern

showed considerable change from the starting ligand 3. Therefore, we believe that the Pd(II) complex

of ligand 3 was formed in our case. UV absorption spectra of the ligand 3 and its palladium complex is

shown in Fig.

Fig 3: UV spectral pattern of ligand 3 and its Pd(II) complex (4)



4.3 Screening of imino-pyridine ligands in Pd(II) catalysed Suzuki-Miyaura cross coupling

reaction:

Scheme 3:Suzuki-Miyaura coupling usingligand3 in various solvents

Initially, we examined suitability of ligand 3 for palladium-catalyzed Suzuki coupling of activated aryl

bromide (5) with phenylboronic acid(6) (Scheme 3). Combination of Pd(OAc)2 and ligand 3 (Pd :

Ligand 3 = 1:2) catalyzed the coupling between activated aryl bromide and phenylboronic acid at 100

°C in different solvents (Entry 1-4,Table 1) to produce coupled product 4-Phenylacetophenone(7).

Based on the time taken for the completion of the reaction dioxane (entry 4,Table 1) was selected as

the optimal solvent and henceforth further studies were carried out using dioxane as solvent. The

product 4-Phenyl acetophenone(7)was characterized by 1H NMR.

Table 1:Suzuki Coupling using ligand 3 for different solvents:

Entry Solvent Time(h) Yield(%)

1 Tolune:dioxane(10:1) 7.5 53

2 Ethanol 6 67

3 DMF 5 50

4 Dioxane 4 61

We decided further to study the substrate scope of the reaction(Scheme 4) with Ligand 2.The yield of

4-Phenylacetophenone(7)increased to 72% with ligand 2.When, 4-bromoanisole (8)was used as aryl

halide component, the reaction took 5 h for completion at 1000C, and 4-methoxy biphenyl(10) was

formed with 75% yield using 2 as ligand (Table 2, entry 2).The reaction with 4-chloronitrobenzene



failed to produce cross coupled product (Table 2, Entry 3). Only trace amount of desired cross

coupled product was formed (according to TLC).

Scheme 4: Suzuki coupling of various aryl halides (5,8,9) with in dioxane using ligand2.

The following table (Table No.2) represents the set of reactions performed-

Table No.2: Suzuki Coupling using lignd 2 for different substrates:

Entry Aryl halide

Aryl boronic acid Time

(h)

Product Obtained Yield

(%)

1 Br

MeOC (5)

B(OH)2

(6)

4 COMe(7)

72

2 Br

MeO (8)

B(OH)2

(6)

5 OMe(10)

75

3 Cl

O2N (9)

B(OH)2

(6)

12 NO2 (11) trace

Overall, it was found that for electron rich aryl bromide, (8) suzuki coupling reaction needs longer

time. Corresponding cross-coupled products (7) and (10) were characterized using 1H NMR spectra.

The following cycle representing the catalytic cycle for Suzuki-Miyaura reaction-



4.4 Synthesis of Cu complex using ligand 2:

The copper complex of ligand 2 was prepared (Scheme 6) by heating 1:1 mixture of CuCl2.2H2O and

compound 2 following reported procedure [11]. A green precipitate was obtained and its UV spectrum

was recorded.



The UV absorption spectra of the ligand 2 and its copper complex(5) was recorded which showed

considerable changes in their absorption band. The expected structure was written as the ligand 2 and

Cu salt was added in 2:1 ratio.

Fig 4: UV spectroscopy of combined 2, 12 compounds.

5. REFERENCES:

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[2]. Kumar S., Dra D.N., Saxena P.N., J.Sci.Ind.Res., 2009,68,181-187

[3]. Jesmin M Ali M.M,Khanam J.A.,Thai.J.Pharm.Sci.,2010,34,20-31

[4].a)Hadjipalu,L.,J.Dimitra,A.Athina,Geronikaki,Chem.Abstr.,(1998)129,b)B.De,GVS

Ramasarma,Indian Drugs,(1999)36,583

[5].Mocanu A.S.,Ilis M.,Dumitrascu F.,Ilie M.,Circu V.,Inorg.Chem.Acta.,2010,363,4,729-736

[6].IssaY.M.,SheO.E.,Abbas S.M.,Mnonatshefte for Chemie,1998,129,985-998

[7].Atta A.M.,Shaker N.O.,Maysour N.E., Prog. Org. Coat., 2006, 56, 100-110

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[9] Amany M.A., Ibrahim, Thermochim.Acta.,1992,197,1,211-217

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[12] J.Safari,Z.Zarnegar,F.Rahimi,Hindawi Publishing CorporationJournal of

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[13]SampatN.M.,MehtaB.H.,Asian Journal of Chemistry,(1996),Vol.8,261-264

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P. Datta et.al/ 4(3) pp 711- 727 September 2016 · syncephalostonemracemosus- contributing to fruit root in tomato and ... carboxymethyl-chitosan shows an antioxidant activity