INTRODUCTION:

Background

There are number of coupling reactions in which palladium catalyst is used for carbon-carbon bond formation like Stille coupling, Hiyama coupling, Heck Reaction, Sonogashira coupling, Negishi coupling but Suzuki-Miyaura Cross Coupling reaction is the most popular method which produces biaryls.

Suzuki-Miyaura Cross Coupling reaction was first time reported by Suzuki and Miyaura in 1979. He got Nobel price in 2010 for the discovery and development of palladium catalyzed cross coupling products along with Ei-ichi Negishi and Richard F. Heck. There are many reviews published which describes the advancement and development of Suzuki reaction.

It is a reaction of aryl or vinyl halides with aryl or vinyl boronic acids or with the reagents likes amines, alkenes, alkynes are palladium catalyzed cross coupling in the presence of a base.^1,2,3,4 It is the most useful, efficient, effective and powerful method of carbon-carbon bond formation which is used in the organic synthesis and also widely used in the synthesis of olefins, polymers, substituted biphenyl compounds and different advanced materials.⁵

Generally, palladium catalyst is involved in the cross-coupling reaction. However, other transition metals like ruthenium are used in the given literature. It has an advantage that it not only restrict to the formation of simpler compounds but is also used in the formation of complex compounds. Halides (aromatic or alkyl) are good substrates for these cross coupling reactions to give cross-coupling products. However, benzoic acid can replace these substrates. It has also been reported that the substrates like aryl boronic acids and aryl tosylates are good substrates for these types of reactions. Alternatives of boronic acids like Organotrifloroborate salts are commonly used.

On the basis of the following below mentioned conditions, Suzuki-Miyaura cross-coupling reaction is preferred over other Palladium catalysed cross-coupling reactions.

· In comparison to other organometallic reagents, boronic acids are environmentally safer.

· Boron containing byproducts are easy to handle and remove especially in large-scale synthesis as compared to other organometallic reagents.

· Mild reaction conditions are required.^6,7,8,9

Through Suzuki-Miyaura cross coupling reaction, a pharmaceutical company (Eli-Lilly) has synthesized 9 compounds and out of these 9 compounds 4 of them have shown activity at molecular level.¹⁰

In recent years, Suzuki-Miyaura cross coupling reaction has been used in large scale and industrial pharmaceutical compounds.

Na₂CO₃is the common base used in Suzuki-Miyaura cross coupling reaction but is often ineffective in some cases. In such cases, the bases like CS₂O₃, K₂CO_3,NaOH, K₃BO₄, Ba(OH)₂ can be used to generate good yields.

Column Chromatography is used for the purification of compounds. There are two types of column packing one is dry packing and the other is wet packing. Steps used are activation of silica gel, sample preparation, slury preparation, column packing, loading of column, separation and purification.^11,12

The compound is further characterized by different spectral techniques like IR, Mass Spectroscopy, NMR.¹³

The reactions were carried out under anhydrous conditions. For this, they were carried out in a nitrogen atmosphere.^14,15

Table 1. Some of the drugs are synthesized by using Suzuki-Miyaura cross coupling reaction.

S. No	Chemical Compounds	Category	Uses
1	Felbinac	NSAID	Used in the treatment of arthritis and inflammation of muscles.¹⁶
2	Difunisal	NSAID	To get relieve from pain, tenderness and swelling caused by Rheumatoid Arthritis.¹⁷
3	Yuehchukene	Antifertlity	It has anti-fertility and estrogenic activities.^{18, 19}
4	Oximidines	Antitumor	It is used in the treatment of tumor.²⁰
5	Flubiprofen	NSAID	It is used in the treatment of muscle inflammation and arthritis.²¹
6	Michellamine	Anti-HIV	It is used in the treatment of HIV.²²

General Reaction Procedure

The scheme shown above shows the Suzuki Coupling, which is the palladium-catalysed cross coupling between aryl boronic acid and halides. In the atmospheric condition, cesium carbonate was dissolved in water in a small bottle separately. Aryl halides, phenyl boronic acid, tetra butyl ammonium bromide, Bis (tri phenyl phosphine) palladium II chloride catalyst and toluene were taken in another small bottle subsequently. The reaction mixtures in small bottles are added in a pressure tube. It was heated at 80-90⁰C and then stirred untill starting material was completely consumed which was monitored by TLC. After the reaction completion, the reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was further washed with brine solution, filtered in buckner funnel prepared with celite bed and added sodium sulphate to the filtrate, filtered again with cotton bed and added silica (60-120 mesh size) to the filtrate and then evaporation of the solvent was done by rota vapour which provided the crude product and the purification of the crude product was done by column chromatography using Ethyl acetate/Hexane to get the final product.Column chromatography was done by a column of size 1.5 inch (width) and 36 inch (height). Cotton plug was inserted in it. The silica (60-120mesh size) was taken in a conical flask and added 100ml solvent to make slurry. Then poured it in the column. Product was loaded on column and 100ml solvent was added and a small piece of cotton was inserted (to prevent the column from disturbance). The column was run with hexane. The filtrate was received in receivers. TLC was checked for all the filtrates and the crude samples.

RESULT:

Palladium catalyzed (carbon-carbon bond formation) compounds were synthesized by Suzuki-Miyaura cross coupling reaction. Purification of Palladium catalyzed compounds were done and characterized by spectral methods.

Synthesis 1:-Synthesis of Biphenyl by reaction, of 4-bromo toluene with phenyl boronic acid 1A:

Yield: 82.5%; mp- 69.4^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 1654, 1568, 1520, 1444, 1377, 1128, 1006, 754; ¹H NMR (400 MHz, CDCl₃): 2.40 (s, 3H), 7.24-7.26 (m, 2H), 7.32-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.49-7.51 (m, 1H), 7.57-7.59 (m, 2H); ¹³C NMR (100 MHz, CDCl₃); 128.11, 132.82, 135.78; ESI-MS (m/z): 168 (M⁺+H).

Synthesis 2:-Synthesis of Biphenyl by coupling of 4-iodo toluene with phenyl boronic acid 2A:

Yield: 85.5%; mp- 70.2 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃): 2.39 (s, 3H), 7.24-7.26 (m, 1H), 7.32-7.36 (m, 1H), 7.40-7.46 (m, 2H), 7.48-7.50 (m, 2H), 7.56-7.58 (m, 2H); ESI-MS (m/z): 223.1 (M⁺+H).

Synthesis 3:- Synthesis of Biphenyl by coupling of 4-fluoro toluene with phenyl boronic acid 3A:

Yield: 84.5%; mp- 72.4 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃): 2.44 (s, 3H), 7.24-7.26 (m, 1H), 7.32-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.49-7.51 (m, 2H), 7.57-7.59 (m, 2H); ESI-MS (m/z): 114.2 (M⁺+H).

Synthesis 4:- Synthesis of Biphenyl by coupling of 4-nitro toluene with phenyl boronic acid 4A:

Yield: 82%; mp- 69.8 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃): 2.35 (s, 3H), 7.24-7.26 (m, 1H), 7.30-7.36 (m, 1H), 7.40-7.46 (m, 2H), 7.48-7.50 (m, 2H), 7.56-7.59 (m, 2H); ESI-MS (m/z): 136.1 (M⁺+H).

Synthesis 5:-Synthesis of 4-benzylbenzoic acid by coupling of 4-(bromomethyl)benzoic acid with phenyl boronic acid 5A:

Yield: 79.9%; mp- 210.5 ^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 3427 (OH), 1603 (C=O), 1441, 1366, 1347, 1307, 1179, 1087, 1024, 700; ¹H NMR (400 MHz, CDCl₃): 4.65 (s, 2H), 7.41-7.44 (m, 2H), 7.50-7.53 (m, 2H), 7.59-7.63 (m, 2H), 7.72-7.76 (m, 2H), 8.24-8.26 (m, 2H); ESI-MS (m/z): 211 (M⁺+H).

Synthesis 6:-Synthesis of methyl 4-benzylbenzoate acid from methyl 4-(bromomethyl) benzoate 6A:

Step 1:- Yield: 4.85 gm; mp- 57.6 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃): 3.91 (s,3H), 4.92 (s, 2H), 7.44-7.62 (m, 2H), 7.99-8.01 (m, 2H).

Step 2:- Yield: 71.5%; mp- 58.1 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃): 3.89 (s, 3H), 4.03 (s, 2H), 7.16-7.18 (m, 2H), 7.20-7.22 (m, 1H), 7.23-7.25 (m, 1H), 7.26-7.38 (m, 2H), 7.30-7.31 (m, 1H), 7.94-7.96 (m, 2H); ESI-MS (m/z): 227 (M⁺+H).

Synthesis 7:-Synthesis of diphenyl methane by coupling of (bromomethyl)benzene with phenyl boronic acid 7A:

Yield: 83.2%; mp- 23.4 ^oC; Solubility- Hexane, Ethyl acetate; ¹H NMR (400 MHz, CDCl₃):4.02 (s, 2H), 7.21-7.26 (m, 6H), 7.30-7.33 (m, 4H); ESI-MS (m/z): 168.23 (M⁺+H).

Synthesis 8:-Synthesis of N-Biphenyl-3-yl-acetamide from N-(3-Bromo-phenyl)-acetamide 8A:

Yield: 78.5%; mp-147 ^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 3293 (NH), 1665 (C=O), 1609, 1555, 1482, 1449, 1317, 1260, 1013, 870, 760; ¹H NMR (400 MHz, CDCl₃): 2.20 (s, 3H), 7.25-7.30 (m, 1H), 7.32-7.34 (m, 2H), 7.38-7.40 (m, 1H), 7.41-7.46 (m, 2H), 7.48-7.54 (m, 1H), 7.57-7.59 (m, 2H), 7.70-7.74 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): 24.59, 118.89, 119.05, 123.18, 127.20, 127.54, 128.83, 129.40, 138.53, 140.75, 142.10,169.00; ESI-MS (m/z): 211.25 (M⁺+H).

Synthesis 9:-Synthesis of N-(2-(trifluoromethyl) biphenyl-4-yl)acetamide from N-(4-bromo-3-(trifluoromethyl)phenyl)acetamide 9A:

Yield: 80.7%; mp- 183.9 ^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 3296 (NH), 1665 (C=O), 1619, 1595, 1547, 1484, 1369, 1322, 1163, 1069, 1009, 884, 767; ¹H NMR (400 MHz, CDCl₃): 1.59 (s, 3H), 2.23 (s, 3H), 7.28-7.37 (m, 2H), 7.38-7.40 (m,3H), 7.79-7.82 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): 24.73, 117.62, 122.68, 127.73, 127.90, 129.18, 132.97, 137.33, 139.42; ESI-MS (m/z): 279.25 (M⁺+H).

Synthesis 10:-Synthesis of N-Biphenyl-3-yl-benzamide from N-(3-Bromo-phenyl)-benzamide 10A:

Yield: 72.6%; mp-136 ^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 3288 (NH), 1652 (C=O), 1573, 1582, 1595, 1491, 1476, 1421, 1326, 1290, 1074, 1025, 796; ¹H NMR (400 MHz, CDCl₃): 7.34-7.38 (m, 2H), 7.40-7.46 (m, 3H), 7.48-7.52 (m, 1H), 7.55-7.59 (m, 1H), 7.61-7.65 (m, 3H), 7.88-7.90 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): 119.24, 123.44, 127.19, 127.25, 127.57, 128.80, 129.49, 131.91, 134.96, 138.50, 140.71, 142.21, 166.13; ESI-MS (m/z): 273.32 (M⁺+H).

Synthesis 11:-Synthesis of N-(2-(trifluoromethyl) biphenyl-4-yl)benzamide from N-(3-bromo-4-(trifluoromethyl)phenyl)benzamide 11A:

Yield: 41%; mp- 169.5 ^oC; Solubility- Hexane, Ethyl acetate; IR (film, cm^-1): 3288 (NH), 1653 (C=O), 1591, 1578, 1532, 1418, 1335, 1311, 1248, 1170, 1069, 796; ¹H NMR (400 MHz, CDCl₃): 7.31-7.37 (m, 3H), 7.39-7.43 (m, 3H), 7.48-7.52 (m, 2H), 7.56-7.60 (m, 1H), 7.89-7.91 (m, 2H), 7.94-7.96 (m, 3H), 8.10 (s, 1H); ESI-MS (m/z): 342.33 (M⁺+H).

Reaction Schemes:

Synthesis of carbon-carbon bond formation compounds

1A, 82.5%

2A, 85.5%

3A, 84.5%

4A, 82%

5A, 79.9%

6A, 71.5%

7A, 83.2%

8A, 78.5%

9A, 80.7%

10A, 72.6%

11A, 41%

Table 2. Reaction Conditons

S. No	Base	Catalyst	Solvent	% Yield
1	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	82.5%
2	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	85.5%
3	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	84.5
4	C_S2O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	82
5	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	79.9
6	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	71.5
7	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	83.2
8	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	78.5%
9	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	80.7%
10	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	72.6%
11	CS₂O₃	Bis(triphenylphosphine)palladiumIIchloride	Toluene	41%

DISCUSSION:

Bis (tri phenyl phosphine) palladium II chloride is used as catalyst in Suzuki cross-coupling reaction. Cesium carbonate (CS₂CO₃) is used as a base, tetra butyl ammonium bromide (TBAB) is used as a phase transfer catalyst, toluene and water are used as a solvent. The effects of catalyst, base and the solvent used in the coupling of aryl halides with phenyl boronic acid are observed.

Effect of base on coupling reaction:

K₂CO₃, Na₂CO₃, Et₃N are very common and inexpensive bases employed in Suzuki cross-coupling reactions. Although CS₂CO₃ is also a common base and is also employed in several Suzuki reactions. It is an efficient base for many Suzuki catalytic reactions. It is also known that the base is involved in the formation of the Ar-PdL₂–OR from Ar-PdL₂–X in Suzuki reaction to accelerate the transmetallation step.

Effect of solvent on coupling reaction:

It was observed that methanol which is the more polar solvent gave good quantitative yield within 1 h. This is may be due to the high solubility. Although, toluene (nonpolar solvent) also gives moderate to high yields but it takes more time for the completion of the reaction.

Effect of catalyst on coupling reaction:

It is significant to attain moderate to high yields by the use of very low amount of catalyst.

Here, we have examined the effect of catalyst loading on the reaction between aryl halides and phenyl boronic acid at 80-900C. Bis (tri phenyl phosphine) palladium II chloride catalyzes the Suzuki cross-coupling reaction of a variety of aryl halides with phenyl boronic acid at a temperature of 80-90⁰C giving moderate to high yield.

Scheme 1. Reaction between aryl halides and phenyl boronic acid

CONCLUSION:

The palladium-catalyzed Suzuki-Miyaura cross-coupling reaction is a very favorable, efficient and versatile method for carbon-carbon bond formation between a variety of aryl halides and phenylboronic acids. It is widely used in organic synthesis. The Suzuki cross-coupling reaction produces biaryls which have proven to be the most popular method in the recent times.

The preference for the Suzuki-Miyaura cross-coupling reaction above the other Pd-catalysed cross coupling reactions are the mild reaction conditions and the commercial availability of the boronic acids that are environmentally safer than the other organometallic reagents.

Results from these studies have indicated that aryl halides, including aryl iodides, aryl bromides, could couple with phenyl boronic acid very conveniently by using Bis (tri phenyl phosphine) palladium II chloride as a catalyst at a temperature of 80-90^oC under atmospheric conditions. In the presence of this catalyst, coupling of phenyl boronic acids with a wide range of aryl halides including aryl iodides, aryl bromides was carried out smoothly in aqueous solvent to afford the cross coupling product in moderate to high yields. Although CS₂CO₃ is a common base for several Suzuki reactions. It is found to be an efficient base for many Suzuki coupling reactions. Non-polar solvent such as toluene also gives moderate to high yields but it takes more time for the completion of reaction.

LIST OF ABBREVIATIONS:

CS₂CO₃ Cesium carbonate

Ba(OH)2 Barium hydroxide

K₂CO₃ Potassium carbonate

NaOH Sodium hydroxide

Pd Palladium

TLC Thin layer chromatography

NMR Nuclear magnetic resonance

IR Infrared

UV Ultraviolet

0C Degree celsius

r.t Room temperature

ml milliliters

gm Gram

mmol Millimoles

% Percentage

e.g Example

Mol.wt Molecular weight

M.P Melting point

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Received on 20.10.2023 Modified on 08.01.2024

Research J. Pharm. and Tech 2024; 17(8):3843-3847.

DOI: 10.52711/0974-360X.2024.00596