Investigation of New Procedure for Selective Reaction and Synthesis of Some New 2-Substituted Benzimidazole Derivatives

Introduction

The Benzimidazole pharmacophore stands as a pipathogensrocyclic element within a plethora of pharmaceutical^1,2.  Because of  their broad spectrum of bioactivity, this compounds class has captured the interest of medicinal and organic chemists, spurring the exploration of diverse synthetic methodologies.³ With seven positions available for substitution, the benzimidazole moiety offers a canvas for the manifestation of unique and varied bioactivities across various drug classes^4. Notably, compounds featuring the benzimidazole pharmacophore find utility in numerous therapeutic areas, including  antimicrobial ⁵  and antiviral agent  combating pathogens ^6-14 .

The remarkable diversity in bioactivity spurred chemists to explore various synthetic routes for benzimidazole synthesis. Initially, benzimidazoles were readily obtained through the condensation of diamine with compound containing functional groups like  -COOH, -CN, and RC(OR’)₃¹⁵ . Though, this method is disadvantaged by drawbacks such as lesser yields, the formation of impurities¹⁶ . Moreover, employing catalysts like Titanium containing catalyst  , cumene hydroxide¹⁷ ,has confirmed to offer good to  better yields.

Additionally, metal Ru,¹⁸ Pd¹⁹ and Rh²⁰ catalysts  also employed in the creation of benzimidazole. However,  described approaches for producing 2-substituted benzimidazole moiety  often lack compatibility with diverse functional group or  several starting materials revealing varying substitution designs. Furthermore, they typically necessitate high-priced catalysts, elevated temperature, or harsher reaction circumstances, like the use of hazardous  acid for reactions. Accordingly, these approaches may not be conductive to kilo-scale production.

The objective of this research was to investigate a new method for selectively  reducing the NO₂ group without affecting the RCOOR’group. In this finding, NaBH₄-FeCl₂ was identified as a crucial reducing agent in the process, resulting in the formation of the corresponding amino compound. The reduction mediated by NaBH₄-FeCl₂– demonstrated high chemo selectivity, yielding the desired products in impressive yields (up to 90-95%). Furthermore, this method was utilized to synthesis of dabigatran intermediate. (anticoagulant drug ) and the synthesized di-amino compound. This was reacted with various Carboxylic acids by using coupling reagent like EDC.HCl and cat. DMAP, and subsequently cyclized by using CH₃COOH at reflux to yield 2-substituted benzimidazole derivatives. 

Result and Discussion

The investigation into reduction condition was carried out as detailed illustrated Table 1. Our finding commenced using substrate 3. Firstly, the reaction was performed with 1.0 equit. of MXn and 2.5 equit. of NaBH₄ under an inert environment in THF at 25-30 °C. The exhibited process was sluggish, resulting in only a 12 % yield to the desired product 3 when CuSO₄ was utilized ( Entry i in Table 1) and when using AlCl₃ or LiCl, yielding 35.5% and 5 % respectively (Entries ii,iii in Table 1). Interestingly, we have observed that when used metal salts good to moderate yield was obtained. Subsequently, various ferrous salts were assessed, revealing FeCl₂ as optimal, achieving high yield (up to 93.2%), whereas other salts give less yield (< 35%, Entries v,vii,viii in Table 1). Tried to reduce the amount of NaBH₄ led to significant decreases in yield when reducing the loading from 2.5 equit. to 1.5 or 1.1 equit. (Entries  vi and ix-xi in Table 1). Furthermore, experimentation with different quantities of FeCl₂ indicated that 1.0equiv.was optimal, with decreasing equivalents resulting in less yield. (Entries xii-xiv in Table 1). Solvent choice significantly influenced the reaction, with aprotic solvents favoring high yield, while in polar Solvent yielded poor results (Entry vi, xv, xvi in Table 1). Consequently, Tetrahydrofuran was preferred as a solvent. Lastly,  impact of reaction temperature on assessed, revealing decreased yield (Entry xvii in Table 1). Attempts to enhance the rate by elevating temperature to 40-45°C yielded unexpectedly low yield (Entry xviii in Table1). Ultimately, the optimal reaction conditions were established as 2.5 equit. of NaBH₄, 1.0 equit. of FeCl₂, THF, and a reaction temp. of 25-30 °C.

Table 1: Optimization of Reagent, its equivalent, solvent selection  and reaction temp.

Entry	MXn(eq.)	NaBH4 (eq.)	Solvent	Output (%)	Temp. (°C)
i	CuSO4 (1.0)	2.5	THF	12.0	25-30°C
ii	AlCl3 (1.0)	2.5	THF	35.5	25-30°C
iii	LiCl (1.0)	2.5	THF	5.3	25-30°C
iv	FeCl3 .6H2O (1.0)	2.5	THF	3.7	25-30°C
v	FeCl3 .7H2O (1.0)	2.5	THF	25.3	25-30°C
vi	FeCl2 (1.0)	2.5	THF	93.2	25-30°C
vii	FeBr2 (1.0)	2.5	THF	3.8	25-30°C
viii	FeC2O4.2H2O (1.0)	2.5	THF	12.8	25-30°C
ix	FeCl2 (1.0)	2.0	THF	83.20	25-30°C
x	FeCl2 (1.0)	1.5	THF	61.2	25-30°C
xi	FeCl2 (1.0)	1.1	THF	18.3	25-30°C
xii	FeCl2 (0.8)	2.5	THF	85.0	25-30°C
xiii	FeCl2 (0.5)	2.5	THF	72.0	25-30°C
xiv	FeCl2 (0.2)	2.5	THF	36.0	25-30°C
xv	FeCl2 (1.0)	2.5	MeCN	78.0	25-30°C
xvi	FeCl2 (1.0)	2.5	EtOH	17.5	25-30°C
xvii	FeCl2 (1.0)	2.5	THF	23.6	10-15°C
xviii	FeCl2 (1.0)	2.5	THF	34.6	40-45°C

Benzimidazole derivatives prepared through the reaction of  di amino compound with several aromatic compounds that have COOH gr., Catalyzed by EDC.HCl and cat.  DMAP. The resulting coupled compounds were then cyclized in CH₃COOH at 100-110°C (Scheme 1). The reaction supervised by TLC.

We selected the reaction between synthesized di-amino compound and Benzoic acid as a model reaction for optimization of coupling reagent and reagent which increase the rate of reaction. Initially, we conducted the model reaction using Thionyl Chloride & TEA, which resulted in lower conversion and isolated yield. Subsequently, we explored different coupling reagents like DCC-HOBt Carbonyldimidazole, EDC.HCl-DMAP ( Entries ii-iv in Table 2 ). We have found that DCC-HOBt and Carbonyldimidazole (Entries II-III in Table 2) yielded only 83% and  80% respectively. The optimal result, boasting a 90% yield for product 3a, was  attained through the utilization of coupling reagent EDC.HCl /DMAP (Entries iv in Table 2 ).

Table 2: Optimization of Coupling reagent along with reaction time and outcome

Entry	Reagent	Time (Minutes)	Output (%) a
i	SOCl2 & TEA	60	75
ii	DCC-HOBt	60	83
iii	Carbonyldimidazole	60	80
iv	EDC.HCl-DMAP	60	90
aIsolated yield.

 

Various reagents , including (HBTU) and (TBTU) , Hydroxybenzotrizole (HOBt), 4-Dimethylaminopyridine (DMAP) were also investigated to accelerate reaction rate of reaction with coupling reagent . Applying the similar 6a reaction as an example, we initially conducted the reaction as such  without any reagents (Entry i in Table 3 ), which necessitated a prolonged reaction time of approximately 360 to 420minutes. However, the inclusion of catalytic amounts of HOBt , HBTU, TBTU, and DMAP (Entries ii-v in Table 3) significantly expedited the reaction, reducing the reaction time to just half an hour. While both reagents proved effective, we opted for DMAP due to safety considerations in enhancing the reaction rate.

Table 3: Optimization of Catalyst

Entry	Catalyst	Time (min)	Output (%) a
i	—	360	80
ii	HOBt	60	83
iii	HBTU	90	80
iv	TBTU	90	81
v	DMAP	60	90
aIsolated yield.

 

 Different acids, including 4N HCl, Acetic acid , Formic acid , Ammonium chloride, polyphosphoric acid and ortho phosphoric acid were also investigated in cyclization reaction. we initially conducted reaction with 4N HCl, but we got less yield. Next, acid (Entries ii-v in Table 4). It was found that only 73%, 78%,76%, and 75% yield was obtained by using Formic acid, NH₄Cl, Polyphosphoric acid, Ortho-phosphoric acid respectively. CH₃COOH facilitates cyclization efficiently, providing good yields in a shorter reaction time. (Entry vi in Table 4, ).

Table 4: Optimization of Acid, reaction time and output for cyclization

Entry	Acid Reagent	Time (min)	Output (%) a
i	4N HCl	120	74
ii	Formic acid	100	73
iii	NH4Cl	120	78
iv	Polyphosphoric acid	100	76
v	Ortho-phosphoric acid	100	75
vi	Acetic Acid	60	90
aIsolated yield.

 

By employing these optimized reaction conditions, a range of benzimidazole derivatives 4a-j were  efficiently produced within a quicker timeframe and with enhanced yields. This synthesis utilized EDC.HCl and DMAP as coupling reagents, along with a CH₃COOH  acid assisting in the cyclization.

This approach utilized to produce a series of new Benzimidazole (2-substituted) derivatives. The outcomes succinctly presented in Table 5.

Scheme 1: Synthesis of  Some New Benzimidazole derivatives  (6a-j). Click here to View Scheme

Our current procedure was applied to a diverse array of several carboxylic acids to demonstrate its broad utility, as outlined in Table 3. It was observed that both unsubstituted and electron-withdrawing substituent -bearing aromatic and heteroaryl carboxylic acids underwent smooth conversion, yielding products  and purified by using Flash chromatography solvent (Table 3). Compounds (6a, 6d, and 6f) lacking substituents, as well as some  compounds with electron-withdrawing substituents (6b, 6c, 6e, 6h, 6i and 6j) such as (CN) Cyano, (Br) Bromo, (Cl) Chloro , dichloro, and NO₂(Nitro)respectively, were synthesized successfully. Nevertheless , in the preparation of compounds 6a-6j, it was detected that when substituents presented on ortho position, several carboxylic acids resulted in impure compounds, requiring purification through flash chromatography, resulting in a lower yield for compounds 6g. Additionally, attempts were made to synthesize benzimidazole derivatives using aromatic acid which ortho substituted aromatic benzoic acid .However, these substituted acids exhibited lower reaction conversion rates.

Spectral data for the representative compound (6a)

The FT-IR spectrum shows a peak at 1723 cm^-1 confirming the presence of a carbonyl group, and a peak at 3397 cm^-1, indicating NH groups in the structure. The ¹H NMR spectrum shows a chemical shift δ between 7.50–7.13, suggesting the presence of aromatic protons. The chemical shift at δ 3.75 (s, 3H) confirms that a methyl group is attached to the nitrogen atom in the structure. The molecular weight of the compound is 483.213 [M+1]+, which exactly matches the reported structure.

Table 5: Synthesis of 2-Substituted benzimidazole (6a-j): Click here to View Table

Experimental

Materials and Methods

Compounds were sourced from a commercial vendor, while reagents and analytical grade (A.R.) solvents were procured from Sigma-Aldrich. The reaction progress was monitored via Thin Layer Chromatography (TLC) on silica plates (Merck silica gel 60F254). Column chromatography was carried out using silica gel with a 60–120 mesh size.

Instrumentation

The FT-IR Spectra recorded at 100 FT-IR; Mass spectra recorded at Advion Expression CMS instrument. The  PMR spectra were recorded on 400MHz, and CMR spectra recorded on 100MHz Brucker spectrometer in DMSO/CDCl₃ using Brucker instrument. The chemical shift value was recorded with respect to  standard Tetramethylsilane.

Reaction conditions

The glassware utilized for reactions underwent thorough washing and cleaning procedures before being dried at 150°C and subsequently cooled under vacuum conditions.

Experimental procedure :

General method for the preparation of compound (3):

Compound 1 (5.09 mmol) dissolve in CH₂Cl₂ (5 mL) and Cat. amount DMF, cool it to 0-10°C then add dropwise SOCl₂ (7.63 mmol)in 10 minute. Raise the temperature to 20-30°C and stirred for 60minutes at 20-30°C, monitoring reaction TLC. After completion of reaction, concentrate reaction mixture and degassed for 30 minutes. Obtained residue cooled to 20-30°, added CH₂Cl₂ (5mL), triethyl amine(10.18mmol) and stirred for 10min.Cool it at 0-5° then added dropwise solution of Compound 2 (4.581mmol) in CH₂Cl₂ (5 mL), raised temperature to 20-30°C and stirred for 30minutes.monitor reaction by TLC.After completion of reaction added a NaHCO₃ (5 mL) solution to reaction mix. and separate the organic layer and wash with water(5mL). Concentrate under vacuum and obtain crude residue crystallized form hexane to get pure Compound3.(1.30g, 79.3%)as Pale Yellow solid.

General method for the preparation of compound (4)

Compound 3 dissolved in THF (10mL) and stirred for 10-15 minutes, add FeCl₂ (3.22 mmol)followed by NaBH₄ (8.05 mmol) under argon/ Nitrogen atmosphere and stir for 720min.at 20-30°C, monitoring reaction on TLC. After complete consumption of Comp.3 , water (20mL) was added , Organic extract extract with Ethyl Acetate. wash with water .Concentrate the organic layer to form Crude residue and column chromatography used to get the pure compound 4  (1.01g, 93.2%).

The General method for the preparation of compound (6a-j):

To a stirred mixture of the compound 4 (1.46mmol) and DMAP(0.146mmol) in CH₂Cl₂ (10mL) added the different carboxylic acid (1.75mmol) in CH₂Cl₂ (5 mL)in one portion at RT. The resulting blend stir at 20-30°C for 60 minutes. Afterward reaction monitored by TLC.After completion of reaction added water (10mL). Separate the organic layer Organic layer and then organic layer successively wash with NaHCO₃ solution and water. The organic layer dried over Na₂SO₄ .Concentrated under vacuum, obtained oily residue degassed for 30min. Obtained residue cool to 20-30°C, add Acetic acid (5 mL) , stirred for 5-10min. Raised temperature 100-110 °C and stirred for 60min. Cool reaction mix to 20-30°C, added water (25mL) and extracted with CH₂Cl₂ .The organics wash  with 5% NaHCO₃ solution, dried by using Na₂SO₄ and concentrate .The resulting residue purified by using flash chromatography technique to provide the product 6a-j. (0.56g, 90%).

Spectral data

Compound (3)

Pale Yellow solid , Yield: 79.3%, m.p. 88-90°C, FT-IR (cm^-1): 3382, 1721, 1648,1620, 1566 ,1368, 1270 , 1175 . ¹H NMR (CDCl_3, δppm): d 8.47 (d, 1H ), 8.14 (br, 2H ), 7.53 (t, 1H ), 7.43 (d, 1H ), 7.11 (dd, 1H), 6.87 (d, 1H ), 6.66 (d, 1H), 4.37 (t, 2H ), 4.09 (t, 2H ), 2.98 (d, 3H),  2.79 (t, 2H), 1.23 (t, 3H ). ¹³C NMR ( CDCl_{3 ,} δppm): d 171.68, 168.44, 156.08, 149.24, 147.00, 137.79, 136.35, 130.80, 128.70, 122.25, 122.17, 121.50, 112.78, 60.57, 44.97, 33.22, 29.78, 14.14. ESI-MS m/z : 373.150 [M+1]⁺.

Compound (4)

Light yellow, Yield: 94.9 %, m.p. 141-143 °C. FT-IR (cm^-1): 3359,2986, 1729,1634 (, 1592,1569,1378, 1191,1154 . ¹H NMR ( DMSO-d⁶, δppm ): d 8.41 (m,1H ), 7.57 (dt, 1H), 7.20 (m, 1H ), 6.78 (d, 1H), 6.67 (d, 1H ), 6.34 (dd, 1H), 6.11 (d, 1H), 5.10 (br, 1H), 4.55 (br, 2H,), 4.18 (t, 2H), 3.97 (q, 2H),  2.65 (s, 3H ), 2.65 (t, 2H), 1.12 (t, 3H).¹³C NMR (DMSO-d⁶, δppm): d 171.56, 171.10, 157.00, 148.84, 139.88, 137.82, 135.52, 123.18, 122.24, 120.93, 120.36, 115.59, 107.33, 60.41, 44.47, 33.63, 30.18, 14.44. ESI-MS m/z : 341.162[M+1]⁺.

Compound (6a)

Pale yellow, Yield:85%, m.p.: 117-119 °C.FT-IR (cm^-1): 3397, ,2979, 1723, 1630, 1605, 1584, 1378, 1179, 1127.¹H NMR ( DMSO-d⁶, δppm): d 8.40 (d, 1H),7.50 (m, 3H), 7.39 (d, 1H), 7.28 (br, 1H), 7.19 (d, 1H), 7.13 (t, 2H), 6.88 (m, 3H ), 4.60 (d, 2H), 4.24 (t, 2H), 3.97 (q, 2H), 3.75 (s, 3H), 2.71 (t, 2H), 1.13 (t, 3H).¹³C NMR (DMSO-d⁶, δppm): d 172.52, 171.79, 156.48, 153.79, 152.22, 149.16, 141.27, 138.34, 137.70, 133.79, 129.82, 123.33, 122.58, 121.71, 120.91, 120.01, 112.84, 109.97, 97.5, 60.49, 44.84, 40.12, 33.50, 30.35, 14.42. ESI-MS m/z : 483.213[M+1]⁺.

Conclusion

In conclusion of our research work, NaBH₄-FeCl₂ was revealed as a major reductant in the process resulting in the formation of the corresponding amino compound. NaBH₄-FeCl2-mediated reduction proven high chemo selectivity, gave the required products in impressive yield (up to 90-95%). The synthesized di-amino compound condensed with several carboxylic acids (aromatic) in the existence of EDC.HCl and cat. DMAP, and insitu cyclization by using Acetic acid. The conditions are gentle, allowing for the tolerance of wide range of functional groups. This condensation reaction offers several advantages: it can be carried out using affordable, readily available chemicals, under extremely simple reaction conditions, with short reaction times, extraordinary yields. Additionally, it employs simple experimental techniques, is cost-economical, and associates with the bases of green chemistry. The biological activity of synthesized compounds will take in due course and hope it will be shows better activity against tested strains.

Acknowledgment

The authors thankful to The Principal, Shri Chhatrapati Shivaji Mahavidyalaya, Shrigonda, 413701, Maharashtra, India for providing the laboratory facility.

Conflicts of interest

The authors(s) declare(s) that there is no conflict of interests regarding the publication of this article.

Funding Sources

There is no funding sources.

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