Synthesis of some novel N-alkyl/acyl/aroyl 2-(chroman/6-bromochroman-2-yl)- 1H-benzimidazoles using ionic liquids and their antibacterial activity

DOI: 10.1002/jhet.360

Source and publish data:

Journal of Heterocyclic Chemistry p. 582 - 588 (2010)

Update date:2022-08-05

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Authors:

Raut, Changdev Namdev

Bagul, Sandeep Madhukar

Janrao, Ravindra Ashok

Vaidya, Sanjay Dashrath

Kumar, Bobba Venkata Siva

Mahulikar, Pramod Pandurang

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Article abstract of DOI:10.1002/jhet.360

(Chemical Presented) Synthesis of some novel N-substituted 2-(chroman/6-bromochroman-2-yl)-1H-benzimidazoles by the condensation of 3,4-dihydro-2H-chroman-2-carboxylic acid and 6-bromo-3,4-dihydro-2H-chroman-2- carboxylic acid with o-phenylenediamine in ionic liquid (IL) [bmim]BF ₄ and subsequent reactions at the benzimidazole-NH with different types of electrophiles in ILs [bmim]BF₄ = 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim]PF₆ = 1-butyl-3-methylimidazolium hexafluorophosphate and [buPy]BF₄ = butylpyridinium tetrafluoroborate in the presence of sodium hydroxide as a base have been reported. All the synthesized compounds were screened for their antibacterial activity. Some compounds exhibited promising antibacterial activity against Staphylococcus aureus and Salmonella typhimurium when compared to Cephalexin as a reference standard.

Full text of DOI:10.1002/jhet.360

582

Synthesis of Some Novel N-Alkyl/Acyl/Aroyl 2-(Chroman/

6-bromochroman-2-yl)-1H-benzimidazoles Using Ionic

Liquids and Their Antibacterial Activity

Vol 47

Changdev Namdev Raut,^aSandeep Madhukar Bagul,^aRavindra Ashok Janrao,^a

Sanjay Dashrath Vaidya,^aBobba Venkata Siva Kumar,^a

and Pramod Pandurang Mahulikar^b*

^aGlenmark Research Center, Plot No. A-607, T.T.C. Industrial Area, M.I.D.C. Mahape,

Navi Mumbai 400 709, (M.S.), India

^bSchool of Chemical Sciences, North Maharashtra University, Jalgaon 425 001, (M.S.), India

*E-mail: mahulikarpp@rediffmail.com

Received August 24, 2009

DOI 10.1002/jhet.360

Published online 29 April 2010 in Wiley InterScience (www.interscience.wiley.com).

Synthesis of some novel N-substituted 2-(chroman/6-bromochroman-2-yl)-1H-benzimidazoles by the

condensation of 3,4-dihydro-2H-chroman-2-carboxylic acid and 6-bromo-3,4-dihydro-2H-chroman-2-car-

boxylic acid with o-phenylenediamine in ionic liquid (IL) [bmim]BF₄and subsequent reactions at the

benzimidazole-NH with different types of electrophiles in ILs [bmim]BF₄¼ 1-butyl-3-methylimidazo-

lium tetraﬂuoroborate, [bmim]PF₆¼ 1-butyl-3-methylimidazolium hexaﬂuorophosphate and [buPy]BF₄

¼ butylpyridinium tetraﬂuoroborate in the presence of sodium hydroxide as a base have been reported.

All the synthesized compounds were screened for their antibacterial activity. Some compounds exhibited

promising antibacterial activity against Staphylococcus aureus and Salmonella typhimurium when com-

pared to Cephalexin as a reference standard.

J. Heterocyclic Chem., 47, 582 (2010).

INTRODUCTION

solvents, e.g. acetone, acetonitrile, pyridine, DMF, THF,

etc. [18–20].

There are a vast number of pharmacologically active

heterocyclic compounds, many of which are in regular

clinical use. Of the wide variety of heterocyclic systems

known till date, the nitrogen heterocycles are of great

importance and benzimidazole is one amongst such im-

portant heterocycles because of its synthetic utility and

broad spectrum of pharmacological activity [1–10]. Var-

ious substituted benzimidazoles are known to have var-

ied biological activities and among these, 2-substituted

benzimidazoles are found to be more potent [11]. The

biological activities of benzimidazoles containing com-

pounds have been well documented [12–13]. Despite

their wide applicability, available routes for their synthe-

sis are limited. The reported synthesis of benzimidazoles

included reactions of aryl acid with o-phenylenediamine

(OPDA) in conventional [14,15], microwave-assisted

[16], and ionic liquids (ILs) [17] methods. The N-alkyla-

tion and acylation of benzimidazoles has been reported

to be accomplished by treatment with an appropriate

base such as sodium hydride, sodium hydroxide, potas-

sium carbonate, pyridine, etc. followed by reaction of

the resulting salt with an alkylating reagent in various

In the rapidly developing ﬁeld of synthetic organic

chemistry, an efﬁcient, simple, and highly selective syn-

thetic method for widely used organic compounds from

readily available reagents is one of the major challenges.

ILs are proving to be increasingly promising as viable

media not only for potentially ‘green’ synthesis and sep-

arations, but also for novel applications. The unique

property set of the IL materials provides new options

based on different chemical and physical properties. The

room temperature ILs are of special interest as ‘green’

recyclable alternative to the classical molecular solvents

in the synthetic organic chemistry [21–24]. ILs are the

best choice for N-alkylation of heterocyclic compounds

bearing an acidic hydrogen attached to nitrogen. The

reports on great improvement in the yields and rates of

reaction using ILs [25] prompted us to study the N-

alkylation and acylation of benzimidazoles in ILs.

Hence it was thought that it would be worthwhile to

design and synthesize the N-substituted benzimidazoles

in ILs under environment-friendly conditions and screen

them for potential biological activity.

2010 HeteroCorporation

May 2010

Synthesis of Some Novel N-Alkyl/Acyl/Aroyl 2-(Chroman/6-bromochroman-2-yl)-1H-

benzimidazoles Using Ionic Liquids and their Antibacterial Activity

583

Scheme 1. Reagents, i) Diethyl Oxalate, NaOEt, aq.HCl ii) AcOH, H₂, Pd/C, 175psi iii) [bmim]BF₄, 100^ꢀC iv) Ethanolic-HCl v) AcOH, Br₂vi)

EtOH/NaOH vii) [bmim]BF₄,100^ꢀC

Scheme 2

RESULTS AND DISCUSSION

For the synthesis of compound 3c, 3,4-dihydro-2H-

chroman-2-carboxylic acid (3) was treated with etha-

nolic-HCl at 85^ꢀC for 3 h to afford the corresponding

ethyl ester derivative 3a in a reasonable yield. Com-

pound 3a was brominated using bromine in glacial ace-

tic acid at 25^ꢀC for 2 h to obtain 6-bromo-3,4-dihydro-

2H-chroman-2-carboxylic acid ethyl ester (3b), which

Compound 3 was synthesized according to literature

procedure in good yield [26]. Condensation of 3,4-dihy-

dro-2H-chroman-2-carboxylic acid (3) with OPDA (4)

was carried out in IL [bmim]BF₄at 100^ꢀC for 6 h to

obtain compound 5 in excellent yield (scheme 1).

Table 1a

Reaction conditions, physical and analytical data of synthesized compounds.

Sr. No

Substrate

R/R⁰

Ionic liquid

Reaction conditions

Product

Yield (%)

Mp (^ꢀC)

CH₃AOACOA

C₂H₅AOACOA

(CH₃)₂ACHACH₂AOACOA

C₆H₅AOACOA

CH₃ASO₂A

(p)ACH₃AC₆H₄ASO₂A

[bmim]PF₆

[bupy]BF₄

[bmim]BF₄

[bmim]PF₆

[bmim]BF₄

[buPy]BF₄

[bmim]BF₄

[buPy]BF₄

[bmim]PF₆

[bmim]BF₄

[bmim]PF₆

[buPy]BF₄

[bmim]BF₄

[bmim]PF₆

[bupy]BF₄

[bmim]BF₄

[buPy]BF₄

[bmim]PF₆

[bmim]BF₄

50^ꢀC, 3 h

60^ꢀC, 2 h

75^ꢀC, 5 h

75^ꢀC, 6 h

75^ꢀC, 5 h

75^ꢀC, 6 h

75^ꢀC, 5 h

50^ꢀC, 5 h

50^ꢀC, 3 h

60^ꢀC, 2 h

75^ꢀC, 5 h

75^ꢀC, 6 h

75^ꢀC, 5 h

75^ꢀC, 6 h

75^ꢀC, 5 h

50^ꢀC, 3 h

132–133

105–107

90–92

120–121

190–192

172–173

128–130

120–122

155–157

176–178

150–151

138–140

125–127

140–141

148–150

120–121

115–116

140–141

180–182

210–212

178–180

225–226

166–167

170–172

C₆H₅ACH₂A

(p)FAC₆H₄ACH₂A

(p)BrAC₆H₄ACH₂A

(p)CH₃AC₆H₄ACH₂A

(p)Tert.butylAC₆H₄ACH₂A

CH₃

6⁰a

6⁰b

6⁰c

6⁰d

6⁰e

6⁰f

6⁰g

6⁰h

6⁰i

6⁰j

6⁰k

6⁰l

6⁰m

C₂H₅

CH₃AOACOA

C₂H₅AOACOA

IsobutylAOACOA

CH₃ASO₂A

(p) CH₃AC₆H₄ASO₂A

C₆H₅ACH₂A

(p) FAC₆H₄ACH₂A

(p) BrAC₆H₄ACH₂A

(p) CH₃AC₆H₄ACH₂A

(p)Tert.butylAC₆H₄ACH₂A

C₆H₅AOACOA

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

584

C. N. Raut, S. M. Bagul, R. A. Janrao, S. D. Vaidya, B. V. S. Kumar, and P. P. Mahulikar

Vol 47

Table 1b

Table 3

Recycling of [bmim]BF₄for the compound 6g.

Antibacterial activity of synthesized compounds 5, 5a, 6a–6k, and

6⁰a–6⁰m against S. typhimurium NCIM 2501.

Number of cycles

Yield (%)

Concentration (lg/mL)

Compound

No.

0.1

10 100 200 500 App. MIC

6⁰a

6⁰b

6⁰c

6⁰d

6⁰e

6⁰f

6⁰g

6⁰h

6⁰i

þþ þþ

ꢁ

þþ þþ þþ

100

was further hydrolyzed in ethanol, sodium hydroxide,

and 5N HCl to give 6-bromo-3,4-dihydro-2H-chroman-

2-carboxylic acid (3c) as a brownish solid. Condensation

of 3c with 4 was carried out in IL [bmim]BF₄at 100^ꢀC

for 6 h yielded compound 5a as a white solid.

The N-alkylation and acylation of 5 and 5a with vari-

ous electrophilic reagents in ILs to obtain the N-alky-

lated/acylated derivatives 6a-6k and 6⁰a-6⁰m (Scheme 2).

The recovered IL was reused successfully with only a

slight loss in yield (Table 1b). The structures of newly

synthesized compounds were conﬁrmed by IR, ¹H

NMR, ¹³C NMR, and mass spectrometry. The physical

and spectral data of the compounds 6a-6k and 6⁰a-6⁰m

is presented in experimental section. The synthesized

compounds were tested for their antimicrobial activity

against two different bacterial species namely, Staphy-

ꢁ

þþ þþ

þþ þþ þþ

100

þþ þþ

þþ þþ þþ þþ

200

100

200

100

þþ þþ þþ

þþ þþ þþ þþ

þþ þþ þþ

þþ þþ

ꢁ

þþ þþ þþ

100

200

100

þþ þþ þþ þþ

6⁰j

6⁰k

6⁰l

þþ þþ þþ

ꢁ

Table 2

6⁰m

Cephalexin

Antibacterial activity of synthesized compounds 5, 5a, 6a–6k, and

6⁰a–6⁰m against S. aureus NCIM 5021.

ꢁ

0.1

ꢁ, Total inhibition, no growth of organism; P, Poor growth compared

to controls; þ, Medium growth compared to controls; þþ, Conﬂuent

growth, no inhibition.

Concentration (lg/mL)

Compound

No.

0.1

10 100 200 500 App. MIC

6⁰a

6⁰b

6⁰c

6⁰d

6⁰e

6⁰f

6⁰g

6⁰h

6⁰i

þþ þþ

þþ

ꢁ

100

lococcus aureus NCIM 5021 and Salmonella typhimu-

rium NCIM 2501.

þþ þþ þþ

þþ þþ

BIOLOGICAL ACTIVITY

þþ þþ þþ

100

All the compounds prepared herein were screened for

their antibacterial activity against Staphylococcus aureus

NCIM 5021 (Gram positive) and Salmonella typhimu-

rium NCIM 2501 (Gram negative) bacterial strains.

Cephalexin was used as a reference standard. Antibacte-

rial activity result of compounds 5, 5a, 6a-6k, and 6⁰a-

6⁰m is summarized in Table 2 and 3. Some of the com-

pounds found to have good antibacterial activity against

S. aureus; however, they were found to have less activ-

ity against S. typhimurium when compared to Cepha-

lexin as a reference standard.

þþ þþ

þþ þþ þþ

100

þþ þþ

þþ þþ þþ

100

þþ þþ

þþ þþ þþ

100

þþ þþ

þþ

þþ þþ

ꢁ

6⁰j

6⁰k

6⁰l

þþ

ꢁ

CONCLUSION

þþ þþ þþ

100

þþ þþ

ꢁ

In conclusion, we have successfully synthesized

a novel series of N-substituted 2-(chroman/6-bromo-

chroman-2-yl)-1H-benzimidazole derivatives by the

6⁰m

Cephalexin

þþ

ꢁ

0.1

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

May 2010

Synthesis of Some Novel N-Alkyl/Acyl/Aroyl 2-(Chroman/6-bromochroman-2-yl)-1H-

benzimidazoles Using Ionic Liquids and their Antibacterial Activity

585

and diluted with water (10 mL). The product was extracted

with ethyl acetate (10 mL ꢂ 2). The ethyl acetate layer was

washed with 5N HCl (10 mL), 5% aqueous sodium bicarbon-

ate solution (10 mL) and water (10 mL). The ethyl acetate

layer was dried over sodium sulfate and evaporated under

reduced pressure to afford crude product, which was recrystal-

lized from ethyl acetate to obtain as a white solid compound

5. After isolation of the product in ethyl acetate IL was in

aqueous layer, which was further washed with ethyl acetate

(10 mL) and dried under vacuum. The suspension was ﬁltered

to remove insoluble and the recovered IL was recycled.

condensation of 3,4-dihydro-2H-chroman-2-carboxylic

acid and 6-bromo-3,4-dihydro-2H-chroman-2-carboxylic

acid with OPDA and subsequent reactions at the benz-

imidazole-NH with different electrophilic reagents under

different reaction conditions in ILs and tested for

antibacterial activity. Some of the compounds 6⁰g, 6⁰j,

6⁰m showed the most potent inhibition at 1 lg/mL,

where as compounds 5, 6a–6d, 6g, 6j and 5a, 6⁰f, 6⁰h,

6⁰i, 6⁰l were found to possess good activity at 10 lg/mL

against S. aureus and compounds 5, 6a, 6g, 6k,

6⁰f showed the good activity at 10 lg/mL, where as

other compounds showed minimal activity against a

S. typhimurium.

2-(Chroman-2-yl)-1H-benzimidazole (5). mp 225–227^ꢀC;

ir (KBr): 3434, 2950, 1487, 1231 cm^ꢁ1; H NMR (CDCl₃): d

2.20–2.35 (m, 2H, CH₂), 2.81–3.04 (m, 2H, CH₂), 5.47 (dd, J

¼ 8.6, 8.9 Hz, 1H, CH), 6.87–6.91 (m, 4H, Ar-H), 7.08–7.18

(m, 2H, Ar-H), 7.46 (d, J ¼ 7.4 Hz, 1H, Ar-H), 7.71 (d, J ¼

7.6 Hz, 1H, Ar-H), 9.7 (bs, 1H, NH); ms: m/z 249.1 (M^þþ1);

Anal. Calcd. for C₁₆H₁₄N₂O: C, 76.78; H, 5.64; N, 11.19.

Found: C, 76.52; H, 5.52; N, 11.36.

EXPERIMENTAL

All the solvents were of commercial grade and OPDA, al-

kylating and acylating agents were obtained from Aldrich.

Melting points were recorded on a MRVIS series, Lab India

Instrument and are uncorrected. IR spectra were recorded on a

Perkin-Elmer Spectrum One FTIR spectrometer in potassium

bromide pellets unless otherwise stated. ¹H and ¹³C NMR

spectra were recorded on a Varian Mercury VX SWBB 300

MHz spectrometer. Elemental analysis was carried out on a

PerkinElmer Series-II C H N S O Analyzer 2400. Chemical

shifts are reported in ppm from internal tetramethylsilane

(TMS) standard and are given d units. The solvent for NMR

spectra was CDCl₃unless otherwise mentioned. Mass spectra

were recorded on hp 1100 LC/MSD mass spectrometer (posi-

tive and negative APCI ion source, 50–200 V, nitrogen). ILs

[bmim]BF₄, [bmim]PF₆, and [buPy]BF₄were synthesized in

the laboratory according to reported procedures [27].

Synthesis of 2-(6-bromochroman-2-yl)-1H-benzimidazole

using IL (5a). A mixture of 3c (10 mmol), OPDA (4) (12

mmol) and IL [bmim]BF₄(2 mL) was heated to 100^ꢀC for 6 h

(as monitored by TLC). The reaction mixture was then cooled

to room temperature and diluted with water (10 mL). The

product was extracted with ethyl acetate (10 mL ꢂ 2) and

ethyl acetate layer was washed with 5N HCl (10 mL), 5%

aqueous sodium bicarbonate solution (10 mL) and water (10

mL). The ethyl acetate layer was dried over sodium sulfate

and solvent was evaporated under reduced pressure to obtain

crude product, which was recrystallized from ethyl acetate to

yield the pure compound 5a. The IL was recovered by the pro-

cedure described earlier.

2-(6-Bromochroman-2-yl)-1H-benzimidazole (5a). mp 210–

211^ꢀC; ir (KBr): 3428, 2919, 1476, 1232 cm^ꢁ^{1 1}H NMR

;

(DMSO-d₆): d 2.26–2.38 (m, 2H, CH₂), 2.86–3.01 (m, 2H,

CH₂), 5.46 (dd, J ¼ 8.7, 8.7 Hz, 1H, CH), 6.86 (d, J ¼ 9 Hz,

1H, Ar-H), 7.15–7.34 (m, 4H, Ar-H), 7.48 (d, J ¼ 6.9 Hz, 1H,

Ar-H), 7.62 (d, J ¼ 6.9 Hz, 1H, Ar-H) 12.62 (bs, 1H, NH)

ppm; ¹³C NMR (DMSO-d₆) (75 MHz): d 23.36 (CH₂), 25.60

(CH₂), 72.25 (OCH), 111.77, 112.11, 119,01, 119.24, 121.64,

122.63, 125.01, 130.18, 132.18, 134.43, 142.95, 153.02,

153.23 (aromatic carbons) ppm; ms: m/z 329.32 (M^þþ1);

Anal. Calcd. for C₁₆H₁₃BrN₂O: C, 58.38; H, 3.98; N, 8.51.

Found: C, 58.26; H, 3.75; N, 8.66.

General procedure for the synthesis of compound 6⁰a-6⁰b

using IL. A solution (2 mmol) of 5a, IL (2 mL), sodium hy-

droxide (4 mmol) and followed by the addition of respective

alkylting reagents (3 mmol) at 25–30^ꢀC. After the addition

was complete, the solution was heated to 50^ꢀC for 5 h (as

monitored by TLC). The reaction mixture was then cooled to

25^ꢀC and diluted with water (10 mL). The product was

extracted with ethyl acetate (10 mL ꢂ 2) and ethyl acetate

layer was washed with water (10 mL ꢂ 2). The organic layer

was dried over sodium sulfate and the solvent was evaporated

under reduced pressure to obtain the corresponding N-substi-

tuted derivatives. The crude products were recrystallized from

ethanol to give pure compounds 6⁰a and 6⁰b, respectively. The

IL was recovered by the procedure described earlier.

Synthesis of 6-bromo-3,4-dihydro-2H-chroman-2-carbox-

ylic acid (3c). A solution of (34 mmol) of 3a dissolved in gla-

cial acetic acid (50 mL) was cooled to 10–15^ꢀC. The com-

pound 3a was brominated by slowly adding a solution of bro-

mine (33 mmol) in glacial acetic acid (25 mL). After the addi-

tion was complete, the solution was stirred at 25–30^ꢀC for 3 h.

The reaction mass was then diluted with water (100 mL). The

product was isolated by extraction with ethyl acetate (50 mL

ꢂ 3). The ethyl acetate layer was washed with 5% aqueous so-

dium bicarbonate solution (50 mL ꢂ 2) and water (50 mL ꢂ

2). The ethyl acetate layer was dried over anhydrous sodium

sulfate and solvent was removed under reduced pressure to

obtain 6-bromo-3,4-dihydro-2H-chroman-2-carboxylic acid

ethyl ester (3b).

A solution of (67 mmol) of 3b dissolved in ethanol (25 mL)

was hydrolysed by 0.5M sodium hydroxide solution (25 mL)

at 25–30^ꢀC for 1 h. The solution was concentrated to about its

half volume and acidiﬁed with 5N hydrochloric acid. The re-

sultant solid was ﬁltered to give 3c, 4.5 g, Yield 85%; mp

170–172^ꢀC; ¹H NMR (CDCl₃) (300 MHz): d 2.13–2.25 (m,

2H, CH₂), 2.29–2.37 (m, 1H, CH), 2.72–2.91 (m, 2H, CH₂),

4.79 (dd, 1H, J ¼ 7.8, 7.8 Hz, CH), 6.81 (d, 1H, J ¼ 9 Hz,

Ar-H), 7.19–7.26 (m, 2H, Ar-H), 11.63 (s, 1H, COOH).

Synthesis of 2-(chroman-2-yl)-1H-benzimidazole using IL

(5). A solution of (10 mmol) of 3 in IL [bmim]BF₄(2 mL)

and (12 mmol) of OPDA (4) was heated at 100^ꢀC for 6 h (as

monitored by TLC). After 6 h the mixture was cooled to 25^ꢀC

Methyl 2-(6-bromochroman-2-yl)-1H-benzimidazole (6⁰a).

ir (KBr): 3435, 2948, 1474, 1231 cm^ꢁ1; 1H NMR (DMSO-

d₆): d 2.40–2.46 (m, 2H, CH₂), 2.97–3.01 (m, 2H, CH₂), 3.91

Journal of Heterocyclic Chemistry

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C. N. Raut, S. M. Bagul, R. A. Janrao, S. D. Vaidya, B. V. S. Kumar, and P. P. Mahulikar

Vol 47

(s, 3H, CH₃), 5.63 (dd, J ¼ 8.1, 8.4 Hz, 1H, CH), 6.81(d, J ¼

8.4 Hz, 1H, Ar-H), 7.28–7.35 (m, 4H, Ar-H), 7.59–7.66 (m,

2H, Ar-H) ppm; ¹³C NMR (DMSO-d₆) (75 MHz): d 23.07

(CH₂), 23.59 (CH₂), 29.41 (NCH₃), 70.10 (CH), 108.11,

111.84, 117.24, 118.84, 121.01, 121.89, 122.08, 128.93,

130.95, 134.91, 140.60, 149.96, 151.55 (aromatic carbons)

ppm; ms: m/z 343.61 (M^þþ1); Anal. Calcd. for C₁₇H₁₅BrN₂O:

C, 59.49; H, 4.41; N, 8.56. Found: C, 59.38; H, 4.62; N, 8.32.

Ethyl 2-(6-bromochroman-2-yl)-1H-brenzimidazole (6⁰b). ir

Phenyl 2-(chroman-2-yl)-1H-benzimidazole-1-carboxylate

(6d). ir (KBr): 3460, 2938, 1762 cm^ꢁ^{1 1}H NMR (CDCl₃):

;

d 2.52–2.57 (m, 2H, CH₂), 2.99–3.05 (m, 2H, CH₂), 5.92 (dd,

J ¼ 8.6, 8.7 Hz, 1H, CH), 6.86–6.97 (m, 2H, Ar-H), 7.12 (d,

J ¼ 7.5 Hz, 2H, Ar-H), 7.26–7.52 (m, 7H, Ar-H), 7.87 (d, J ¼

6.3 Hz, 1H, Ar-H), 8.09 (d, J ¼ 5.7 Hz ,1H, Ar-H); ms: m/z

371.1 (M^þþ1); Anal. Calcd. for C₂₃H₁₈N₂O₃: C, 74.58; H,

4.90; N, 7.56. Found: C, 74.69; H, 4.78; N, 7.66.

2-(Chroman-2-yl)-1-methanesulfonyl-1H-benzimidazole (6e).

(KBr): 3435, 2983, 1473, 1234 cm^ꢁ1; H NMR (DMSO-d₆): d

ir (KBr): 3436, 1583, 1489 cm^ꢁ1; H NMR (CDCl₃): d 2.59–

1.4 (t, J ¼ 6.9 Hz, 3H, CH₃), 2.42–2.50 (m, 2H, CH₂), 3.03–

3.07 (m, 2H, CH₂), 4.41 (q, J ¼ 6.8 Hz, 2H, CH₂), 5.62 (dd,

J ¼ 8.1, 8.3 Hz, 1H, CH), 6.78 (d, J ¼ 9 Hz, 1H, Ar-H),

7.24–7.36 (m, 4H, Ar-H), 7.61–7.67 (m, 2H, Ar-H) ppm; ¹³C

NMR (DMSO-d₆) (75 MHz): d 15.25 (CH₃), 24.25 (CH₂),

24.86 (CH₂), 39.23 (NCH₂), 71.24 (CH), 109.61, 113.08,

118.51, 120.24, 122.23, 123.12, 124.08, 130.22, 132.27,

135.11, 142.18, 150.80, 152.93 (aromatic carbons) ppm; ms:

m/z 357.66 (M^þþ1); Anal. Calcd. for C₁₈H₁₇BrN₂O: C, 60.52;

H, 4.80; N, 7.84. Found: C, 60.38; H, 4.97; N, 7.63.

General procedure for the synthesis of compound (6a-6f,

6⁰c-6⁰g, and 6⁰m) using ILs. To a solution of 5 and 5a (2

mmol) in ILs (2 mL), pyridine (10 mmol), followed by the

addition of appropriate acyl or arylsulfonyl chloride (3 mmol)

were stirred (for reaction conditions, Table 1a). The reaction

mixture was then cooled to 25^ꢀC and diluted with water (10

mL). The product was extracted with ethyl acetate (10 mL ꢂ

2), ethyl acetate layer was washed with 5% aqueous sodium

bicarbonate solution (10 mL) followed by washed with water

(10 mL). The ethyl acetate layer was dried over sodium sulfate

and the solvent was evaporated to obtain the crude products,

which were recrystallized from ethanol, to afford pure com-

pounds (6a-6f), (6⁰c-6⁰g and 6⁰m), respectively. The ILs was

recovered by the procedure described earlier.

2.69 (m, 2H, CH₂), 3.02–3.08 (m, 2H, CH₂), 3.56 (s, 3H,

CH₃), 5.82 (dd, J ¼ 7.9, 8.1 Hz, 1H, CH), 6.76 (d, J ¼ 8.1

Hz, 2H, Ar-H), 6.89–6.94 (m, 2H, Ar-H), 7.41–7.44 (m, 2H,

Ar-H), 7.82 (d, J ¼ 7.8 Hz, 1H, Ar-H), 7.97 (d, J ¼ 6.3 Hz,

1H, Ar-H); ms: m/z 329.1 (M^þþ1); Anal. Calcd. for

C₁₇H₁₆N₂O₃S: C, 62.18; H, 4.91; N, 8.53. Found: C, 62.32; H,

4.80; N, 8.49.

2-(Chroman-2-yl)-1-tosyl-1H-benzimidazole (6f). ir (KBr):

3399, 1485, 1374 cm^ꢁ^{1 1}H NMR (CDCl₃): d 2.41 (s, 3H,

;

CH₃), 2.53–2.61 (m, 2H, CH₂), 2.96–3.10 (m, 2H, CH₂), 5.97

(dd, J ¼ 7.7, 7.9 Hz, 1H, CH), 6.7 (d, J ¼ 9 Hz, 1H, Ar-H),

6.88–6.93 (m, 1H, Ar-H), 7.08–7.15 (m, 2H, Ar-H), 7.3–7.40

(m, 4H, Ar-H), 7.76 (d, J ¼ 7.8 Hz, 1H, Ar-H), 7.97 (d, J ¼

8.1 Hz, 2H, Ar-H), 8.05 (d, J ¼ 8.1 Hz, 1H, Ar-H); ms: m/z

405.1 (M^þþ1); Anal. Calcd. for C₂₃H₂₀N₂O₃S: C, 60.30; H,

4.98; N, 6.93. Found: C, 60.15; H, 5.20; N, 6.78.

Methyl-2-(6-bromochroman-2-yl)-1H-benzimidazole-1-car-

boxylate (6⁰c). ir (KBr): 3434, 2926, 1753, 1481, 1357 cm^ꢁ1

;

¹H NMR (CDCl₃): d 2.42–2.52 (m, 2H, CH₂), 2.95–3.08

(m, 2H, CH₂), 4.13 (s, 3H, CH₃), 5.88 (dd, J ¼ 8.4, 8.4 Hz,

1H, CH), 6.83 (d, J ¼ 8.7 Hz, 1H, Ar-H), 7.19–7.4 (m, 4H,

Ar-H), 7.80–7.95 (m, 2H, Ar-H) ppm; ¹³C NMR (CDCl₃) (75

MHz): d 23.22 (CH₂), 23.87 (CH₂), 53.52 (NCH₃), 70.76

(OCH), 111.55, 113.68, 117.56, 119.39, 122.77, 123.47,

128.85, 130.66, 130.95, 131.31, 140.59, 149.28, 151.85,

152.26 (aromatic carbons) ppm; ms: m/z 389.52 (M^þþ1);

Anal. Calcd. for C₁₈H₁₅BrN₂O₃: C, 55.83; H, 3.90; N, 7.23.

Found: C, 55.94; H, 3.78; N, 7.34.

Methyl 2-(chroman-2-yl)-1H-benzimidazole-1-carboxylate

(6a). ir (KBr): 3453, 2922, 1759, 1455 cm^ꢁ1

;

¹H NMR

(CDCl₃): d 2.40–2.51 (m, 2H, CH₂), 2.92–3.07 (m, 2H, CH₂),

4.13 (s, 3H, CH₃), 5.86 (dd, J ¼ 8.4, 8.6 Hz, 1H, CH), 6.87–

6.94 (m, 2H, Ar-H), 7.12 (d, J ¼ 6.9 Hz, 2H, Ar-H), 7.37–

7.38 (m, 2H, Ar-H), 7.82 (d, J ¼ 6.9, Hz, 1H, Ar-H), 7.95 (d,

J ¼ 7.2 Hz, 1H, Ar-H); ms: m/z 309.1 (M^þþ1); Anal. Calcd.

for C₁₈H₁₆N₂O₃: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.23;

H, 5.35; N, 9.25.

Ethyl-2-(6-bromochroman-2-yl)-1H-benzimidazole-1-car-

boxylate (6⁰d). ir (KBr): 3436, 2945, 1745, 1480, 1330 cm^ꢁ1

;

¹H NMR (CDCl₃): d 1.51 (t, J ¼ 7.2 Hz, 3H, CH₃), 2.45–2.50

(m, 2H, CH₂), 2.94–3.02 (m, 2H, CH₂), 4.58 (q, J ¼ 5.4 Hz,

2H, CH₂), 5.88, (dd, J ¼ 8.7 and 8.7 Hz, 1H, CH), 6.82 (d, J

¼ 8.4 Hz, 1H, Ar-H), 7.19–7.39 (m, 4H, Ar-H), 7.8–7.97 (m,

2H, Ar-H) ppm; ¹³C NMR (DMSO-d₆) (75 MHz): d 13.1

(CH₃), 63.52 (NCH₂), 23.29 (CH₂), 24.94 (CH₂), 70.87

(OCH), 111.58, 113.78, 117.62, 119.44, 122.76, 123.43,

128.90, 130.71, 130.98, 131.52, 140.66, 148.78, 151.89,

152.29 (aromatic carbons) ppm; ms: m/z 403.46 (M^þþ1);

Anal. Calcd. for C₁₉H₁₇BrN₂O₃: C, 56.87; H, 4.27; N, 6.98.

Found: C, 56.70; H, 4.38; N, 7.15.

Ethyl 2-(chroman-2-yl)-1H-benzimidazole-1-carboxylate (6b).

ir (KBr): 3453, 2972, 1744, 1455 cm^ꢁ1; H NMR (CDCl₃): d

1.53 (t, J ¼ 7.2 Hz, 3H, CH₃), 2.40–2.51 (m, 2H, CH₂), 2.92–

3.06 (m, 2H, CH₂), 4.57 (q, 2H, CH₂), 5.89 (dd, J ¼ 8.7 Hz,

1H, CH), 6.87–6.95 (m, 2H, Ar-H), 7.1 (d, J ¼ 6.9 Hz, 2H,

Ar-H), 7.36–7.39 (m, 2H, Ar-H), 7.82 (d, J ¼ 8.1 Hz, 1H, Ar-

H), 7.98 (d, 1H, J ¼ 6 Hz, Ar-H); ms: m/z 323.1 (M^þþ1);

Anal. Calcd. for C₁₉H₁₈N₂O₃: C, 70.79; H, 5.63; N, 8.69.

Found: C, 70.92, H, 5.48; N, 8.85.

Isobutyl-2-(6-bromochroman-2-yl)-1H-benzimidazole-1-car-

boxylate (6⁰e). ir (KBr): 3429, 2927, 1730, 1663, 1474 cm^ꢁ1

;

Isobutyl 2-(chroman-2-yl)-1H-benzimidazole-1-carboxylate

(6c). ir (KBr): 3272, 1738, 1456 cm^ꢁ^{1 1}H NMR (CDCl₃): d

;

¹H NMR (DMSO-d₆): d 1.07 (d, J ¼ 6.6 Hz, 6H, CH₃), 1.50–

1.58 (m, 1H, CH), 2.17–2.24 (m, 2H, CH₂), 2.98–3.04 (m, 2H,

CH₂), 4.32 (d, J ¼ 6.6 Hz, 2H, CH₂), 5.9 (dd, J ¼ 8.9, 8.9

Hz, 1H, CH), 6.82 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.18–7.26

(m, 2H, Ar-H), 7.37–7.39 (m, 2H, Ar-H), 7.81 (d, J ¼ 7.8 Hz,

1H, Ar-H), 7.96 (d, J ¼ 6.6 Hz, 1H, Ar-H) ppm; ¹³C NMR

(CDCl₃) (75 MHz): d 19.21, 19.21, 24.38 (CH₃), 26.06 (CH₂),

27.81, 71.92 (CH₃), 74.46, 112.65, 114.80, 118.73, 120.59,

1.57 (d, J ¼ 6.6 Hz, 6H, CH₃), 2.16–2.19 (m, 1H, CH), 2.44–

2.52 (m, 2H, CH₂), 2.91–3.06 (m, 2H, CH₂), 4.32 (d, J ¼ 6.6

Hz, 2H, CH2), 5.91 (dd, J ¼ 8.1, 8.1 Hz, 1H, CH), 6.89–6.94

(m, 2H, Ar-H), 7.11 (d, J ¼ 6.6 Hz, 2H, Ar-H), 7.39 (m, 2H,

Ar-H), 7.82 (d, J ¼ 6 Hz, 1H, Ar-H), 7.97 (d, J ¼ 5.7 Hz, 1H,

Ar-H); ms: m/z 351.2 (M^þþ1); Anal. Calcd. for C₂₁H₂₂N₂O₃:

C, 71.98; H, 6.33; N, 7.99. Found: C, 71.86; H, 6.43; N, 8.10.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

May 2010

Synthesis of Some Novel N-Alkyl/Acyl/Aroyl 2-(Chroman/6-bromochroman-2-yl)-1H-

benzimidazoles Using Ionic Liquids and their Antibacterial Activity

587

123.83, 124.52, 125.32, 129.98, 131.79, 132.59, 141.79,

150.10, 153.10, 153.38 (aromatic carbons) ppm; ms: m/z

429.51 (M^þþ1); Anal. Calcd. for C₂₁H₂₁BrN₂O₃: C, 58.75; H,

4.93; N, 6.53. Found: C, 58.82; H, 4.83; N, 6.64.

(CDCl₃): d 2.54–2.60 (m, 2H, CH₂), 2.99–3.04 (m, 2H, CH₂),

5.34 (dd, J ¼ 7.8, 8.4 Hz, 1H, CH), 5.56 (s, 2H, CH₂), 6.59

(d, J ¼ 7.2 Hz, 1H, Ar-H), 6.88 (m, 2H, Ar-H), 6.99–7.11 (m,

2H, Ar-H), 7.19–7.31 (m, 4H, Ar-H), 7.42 (d, J ¼ 7.8 Hz, 2H,

Ar-H), 7.83 (d, J ¼ 7.2 Hz, 1H, Ar-H); ms: m/z 421.1

(M^þþ1); Anal. Calcd. for C₂₃H₁₉BrN₂O: C, 65.88; H, 4.57; N,

6.68. Found: C, 65.98; H, 4.45; N, 6.78.

2-(6-Bromochroman-2-yl)-1-methanesulfonyl-1H-benzimid-

azole (6⁰f). ir (KBr): 3435, 3030, 2927, 1475, 1372 cm^ꢁ1; H

NMR (DMSO-d₆): d 2.58–2.66 (m, 2H, CH₂), 2.96–3.04 (m,

2H, CH₂), 3.52 (s, 3H, CH₃), 5.8 (dd, J ¼ 8.7, 8.9 Hz, 1H,

CH), 6.65 (d, J ¼ 8.7 Hz, 1H, Ar-H), 7.18–7.44 (m, 4H, Ar-

H), 7.82 (d, J ¼ 5.4 Hz, 1H, Ar-H), 7.96 (d, J ¼ 6.3 Hz, 1H,

Ar-H) ppm; ¹³C NMR (DMSO-d₆) (75 MHz): d 24.25 (CH₂),

24.83 (CH₂), 42.62 (SCH₃), 70.69 (OCH), 113.32, 116.09,

117.88, 120.99, 124.17, 125.02, 126.03, 129.82, 130.11,

132.30, 141.04, 150.75, 152.76 (aromatic carbons) ppm; ms:

m/z 409.23 (M^þþ1); Anal. Calcd. for C₁₇H₁₅BrN₂O₃S: C,

50.13; H, 3.71; N, 6.88. Found: C, 50.30; H, 3.59; N, 7.11.

2-(6-Bromochroman-2-yl)-1-tosyl-1H-benzimidazole (6⁰g).

2-(Chroman-2-yl)-1-(4-methylbenzyl)-1H-benzimidazole (6j).

ir (KBr): 3431, 1582, 1456, 1230 cm^ꢁ1; H NMR (CDCl₃): d

2.31 (s, 3H, CH₃), 2.55–2.61 (m, 2H, CH₂), 2.91–3.01 (m, 2H,

CH₂), 5.33 (dd, J ¼ 7.5 Hz, 1H, CH), 5.57 (s, 2H, CH₂), 6.7

(d, J ¼ 8.1 Hz, 1H, 5⁰Ar-H), 6.86–6.90 (m, 1H, Ar-H), 7.01–

7.11 (m, 6H, Ar-H), 7.30–7.32 (m, 3H, Ar-H), 7.82 (d, J ¼

7.2 Hz, 1H, Ar-H); ms: m/z 355.2 (M^þþ1); Anal. Calcd. for

C₂₄H₂₂N₂O: C, 81.33; H, 6.26; N, 7.90. Found: C, 81.19; H,

6.37; N, 8.11.

2-(Chroman-2-yl)-1-(4-tert-butylbenzyl)-1H-benzimidazole

(6k). ir (KBr): 3428, 2958, 1581, 1463 cm^ꢁ^{1 1}H NMR

;

ir (KBr): 3432, 2938, 1474, 1370 cm^ꢁ1; H NMR (CDCl₃): d

2.41 (s, 3H, CH₃) 2.42–2.52 (m, 2H, CH₂), 2.92–3.01 (m, 2H,

CH₂), 5.96 (dd, J ¼ 8.4 and 8.4 Hz, 1H, CH), 6.56 (d, J ¼ 8.4

Hz, 1H, Ar-H), 7.18 (d, J ¼ 7.5 Hz, 1H, Ar-H), 7.26–7.42 (m,

4H, Ar-H), 7.76 (d, J ¼ 6.9 Hz, 1H, Ar-H), 7.94 (d, J ¼ 8.1

Hz, 2H, Ar-H), 8.04 (d, J ¼ 7.8 Hz, 2H, Ar-H) ppm; ¹³C

NMR (CDCl₃) (75 MHz): d 21.70 (CH₃), 24.38 (CH₂), 26.08

(CH₂), 70.77 (OCH), 112.98, 113.78, 118.35, 120.95, 124.07,

124.94, 125.83, 127.29, 127.29, 130.04, 130.04, 130.09,

132.17, 132.91, 135.21, 141.46, 146.12, 151.62, 153.21 (aro-

matic carbons) ppm; ms: m/z 483.38 (M^þþ1); Anal. Calcd. for

C₂₃H₁₉BrN₂O₃S: C, 57.15; H, 3.96; N, 5.80. Found: C, 57.31;

H, 3.85; N, 5.62.

General procedure for the synthesis of compound (6g-6k

and 6⁰h-6⁰l) using ILs. A solution of (2 mmol) of 5 and 5a,

(4 mmol) of sodium hydroxide in ILs (2 mL), followed by the

addition of appropriate (3 mmol) benzyl bromides at 25–30^ꢀC.

After the addition was complete, the solution was heated to

75^ꢀC for 5–6 h (as monitored by TLC). The reaction mass was

then cooled to 25^ꢀC and diluted with water (25 mL). The re-

sultant solid was ﬁltered and washed with water (10 mL) to

afford crude products. The crude products were recrystallized

from ethanol, to obtain pure compounds 6g-6k and 6⁰h-6⁰l,

respectively. The aqueous layer contains the ILs, which was

recovered as described earlier procedure.

(CDCl₃): d 1.28 (s, 9H, tert butyl), 2.55–5.62 (m, 2H, CH₂),

2.97–3.01 (m, 2H, CH₂), 5.34 (dd, J ¼ 9.1, 9.1 Hz, 1H, CH),

5.52–5.65 (s, 2H, CH₂), 6.63–6.66 (m, 1H, Ar-H), 6.85–6.90

(m, 1H, Ar-H), 7.03–7.10 (m, 3H, Ar-H), 7.26–7.31 (m, 6H,

Ar-H), 7.82 (d, J ¼ 6.2 Hz, 1H, Ar-H); ms: m/z 397.2

(M^þþ1); Anal. Calcd. for C₂₇H₂₈N₂O: C, 81.78; H, 7.12; N,

7.06. Found: C, 81.69; H, 7.31; N, 7.20.

2-(6-Bromochroman-2-yl)-1-benzyl-1H-benzimidazole (6⁰h). ir

;

(KBr): 3446, 2926, 1574, 1482, 1234 cm^ꢁ^{1 1}H NMR

(CDCl₃): d 2.46–2.55 (m, 2H, CH₂), 2.94–3.01 (m, 2H, CH₂),

5.38 (dd, J ¼ 7.2, 8.1 Hz, 1H, CH), 5.60 (s, 2H, CH₂), 6.47

(d, J ¼ 9 Hz, 1H, Ar-H), 7.02–7.15 (m, 2H, Ar-H), 7.21–7.28

(m, 8H, Ar-H), 7.86 (d, J ¼ 7.8 Hz, 1H, Ar-H) ppm; ¹³C

NMR (CDCl₃) (75 MHz): d 22.99 (CH₂), 23.68 (CH₂), 46.54

(NCH₂), 70.08 (OCH), 108.89, 111.84, 117.25, 118.97, 121.24,

122.23, 122.73, 125.07, 125.07, 126.51, 127.57, 127.57,

128.87, 130.88, 134.55, 134.89, 140.74, 150.15, 151.41 (aro-

matic proton) ppm; ms: m/z 421.60 (M^þþ1); Anal. Calcd. for

C₂₃H₁₉BrN₂O: C, 65.88; H, 4.57; N, 6.68. Found: C, 65.70; H,

4.68; N, 6.77.

2-(6-Bromochroman-2-yl)-1-(4-ﬂuorobenzyl)-1H-benzimid-

azole (6⁰i). ir (KBr): 3435, 2928, 1605, 1484, 1227 cm^ꢁ1; H

NMR (CDCl₃): d 2.54–2.58 (m, 2H, CH₂), 2.96–3.04 (m, 2H,

CH₂), 5.38 (dd, J ¼ 8.4, 8.4 Hz, 1H, CH), 5.56 (s, 2H, CH₂),

6.47 (d, J ¼ 9 Hz, 1H, Ar-H), 6.96–6.99 (m, 2H, Ar-H), 7.12–

7.22 (m, 3H, Ar-H), 7.26–7.44 (m, 4H, Ar-H), 7.85 (d, J ¼ 9

Hz, 1H, Ar-H) ppm; ¹³C NMR (CDCl₃) (75 MHz): d 24.02

(CH₂), 24.72 (CH₂), 47.07 (NCH₂), 71.28 (OCH), 110.01,

113.17, 115.63, 115.92, 118.39, 120.29, 122.60, 123.57,

123.98, 128.03, 128.14, 130.18, 131.91, 132.22, 135.64,

142.03, 151.33, 152.62, 160.58 (aromatic carbons) ppm; ms:

m/z 437.7 (M^þþ1); Anal. Calcd. for C₂₃H₁₈BrFN₂O: C, 63.17;

H, 4.15; N, 6.41. Found: C, 63.28; H, 4.31; N, 6.28.

2-(Chroman-2-yl)-1-benzyl-1H-benzimidazole (6g). ir (KBr):

3432, 2930, 1583, 1487, 1232 cm^ꢁ^{1 1}H NMR (CDCl₃): d

;

2.55–2.63 (m, 2H, CH₂), 2.94–3.01 (m, 2H, CH₂), 5.36 (dd, J

¼ 9.3, 9.4 Hz, 1H, CH), 5.62 (s, 2H, CH₂), 6.64 (d, J ¼ 8.1

Hz, 1H, Ar-H), 6.85–6.90 (m, 1H, Ar-H), 7.03–7.13 (m, 4H,

Ar-H), 7.26–7.28 (m, 6H, Ar-H), 7.83 (d, J ¼ 6, 6 Hz, 1H,

Ar-H); ms: m/z 341.2 (M^þþ1); Anal. Calcd. for C₂₃H₂₀N₂O:

C, 81.15; H, 5.92; N, 8.23. Found: C, 81.27; H, 5.82; N, 8.35.

2-(Chroman-2-yl)-1-(4-ﬂuorobenzyl)-1H-benzimidazole (6h).

ir (KBr): 3454, 2945, 1485 cm^ꢁ1

;

¹H NMR (CDCl₃): d

2-(6-Bromochroman-2-yl)-1-(4-bromobenzyl)-1H-benzimid-

2.56–2.60 (m, 2H, CH₂), 2.90–3.02 (m, 2H, CH₂), 5.35 (dd, J

¼ 8.7, 9.0 Hz, 1H, CH), 5.58 (s, 2H, CH₂), 6.62 (d, J ¼ 7.5

Hz, 1H, Ar-H), 6.86–6.91 (m, 1H, Ar-H), 6.99–7.11 (m, 5H,

Ar-H), 7.24–7.28 (m, 4H, Ar-H), 7.82 (d, J ¼ 6.6 Hz, 1H,

Ar-H); ms: m/z 360.2 (M^þþ1); Anal. Calcd. for C₂₃H₁₉FN₂O:

C, 77.08; H, 5.34; N, 7.82. Found: C, 77.26; H, 5.42; N,

7.68.

azole (6⁰j). ir (KBr): 3444, 2932, 1574, 1480, 1234 cm^ꢁ1; H

NMR (CDCl₃): d 2.51–2.57 (m, 2H, CH₂), 2.92–3.02 (m, 2H,

CH₂), 5.36 (dd, J ¼ 9, 9 Hz, 1H, CH), 5.54 (s, 2H, CH₂), 6.46

(d, J ¼ 7.8 Hz, 1H, Ar-H), 6.44 (d, J ¼ 9 Hz, 2H, Ar-H), 6.97

(d, J ¼ 7.8 Hz, 2H, Ar-H) 7.19 (m, 3H, Ar-H), 7.44 (d, J ¼

8.4 Hz, 2H, Ar-H), 7.83 (d, J ¼ 7.8 Hz, 1H, Ar-H) ppm; ¹³C

NMR (CDCl₃) (75 MHz): d 23.95 (CH₂), 24.96 (CH₂), 47.11

(NCH₂), 71.13 (OCH), 109.81, 113.05, 118.19, 120.09, 121.48,

122.49, 123.45, 123.76, 127.88, 127.88, 129.96, 131.71,

2-(Chroman-2-yl)-1-(4-bromobenzyl)-1H-benzimidazole (6i).

ir (KBr): 3432, 2926, 1584, 1459, 1231cm^ꢁ1

;

¹H NMR

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

588

C. N. Raut, S. M. Bagul, R. A. Janrao, S. D. Vaidya, B. V. S. Kumar, and P. P. Mahulikar

Vol 47

[3] Sukalovic, V.; Andric, D.; Roglic, G.; Sladjana, K. R.;

Schratteholz, A.; Soski, V. Eur J Med Chem 2005, 40, 481.

[4] Mariana, B.; Mercedes, G. Mini Rev Med Chem 2005, 5,

409.

131.71, 131.91, 134.97, 135.34, 141.74, 151.06, 152.34 (aro-

matic carbons) ppm; ms: m/z 499.64 (M^þþ1); Anal. Calcd. for

C₂₃H₁₈Br₂N₂O: C, 55.45; H, 3.64; N, 5.62. Found: C, 55.34;

H, 3.76; N, 5.49.

[5] Khalaﬁ-Nezhad, A.; Soltani Rad, M. N.; Mohabatkar, H.;

Ansari, Z.; Hemmateenejad, B. Bioorg Med Chem Lett 2003, 13,

1931.

2-(6-Bromochroman-2-yl)-1-(4-methylbenzyl)-1H-benzimid-

azole (6⁰k). ir (KBr): 3427, 2929, 1513, 1262 cm^ꢁ1; H NMR

(CDCl₃): d 2.32 (s, 3H, CH₃), 2.51–2.55 (m, 2H, CH₂), 2.94–

3.0 (m, 2H, CH₂), 5.41 (dd, J ¼ 8.6, 8.6 Hz, 1H, CH), 5.56 (s,

2H, CH₂), 6.55 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.98–6.70 (m, 2H,

Ar-H), 7.09–7.16 (m, 4H, Ar-H), 7.22–7.29 (s, 3H, Ar-H), 7.85

(d, J ¼ 7.2 Hz, 1H, Ar-H) ppm; ¹³C NMR (CDCl₃) (75 MHz):

d 21.16 (CH₃), 24.19 (CH₂), 24.88 (CH₂), 47.52 (NCH₂), 71.25

(OCH), 110.12, 112.99, 118.46, 119.9, 120.10, 122.35, 123.33,

123.93, 126.26, 129.39, 129.39, 130.04, 132.05, 132.97, 135.46,

137.46, 141.90, 151.28, 152.67 (aromatic carbons) ppm; ms: m/

z 435.75 (M^þþ1); Anal. Calcd. for C₂₄H₂₁BrN₂O: C, 66.52; H,

4.88; N, 6.46. Found: C, 66.40; H, 5.13; N, 6.58.

[6] Bin, S.; Jincheng, H.; Qun, S.; Valenzano, K. J.; Lori, S.;

Scott, N. Bioorg Med Chem Lett 2005, 15, 719.

[7] Li, Y.; Kataoka, M.; Tatsuta, M.; Yasoshima, K.; Yura, T.;

Urbahns, K.; Kiba, A.; Yamamoto, N.; Gupta, J. B.; Hashimoto, K.

Bioorg Med Chem Lett 2005, 15, 805.

[8] Garg, Y.; Samota, M. K.; Seth, G. Asian J Chem 2005, 17,

615.

[9] Teague, S. J.; Barber, S.; King, S.; Stein, L. Tetrahedron

Lett 2005, 46, 4613.

[10] Hashimoto, K.; Tatsuta, M.; Yasoshima, K.; Shogase, Y.;

Shimazaki, M.; Yura, T.; Li, Y.; Urbahns, K.; Yamamoto, N.; Gupta,

J. B. Bioorg Med Chem Lett 2005, 15, 799.

2-(6-Bromochroman-2-yl)-1-(4-tert-butylbenzyl)-1H-benzi-mid-

azole (6⁰l). ir (KBr): 3446, 2962, 1475, 1411, 1219 cm^ꢁ^{1 1}H

;

[11] (a) Preston, P. N. Chem Rev 1974, 74, 279; (b) Preston, P.

N. Merck Index 11^thEdn. 1794.

NMR (CDCl₃): d 1.28 (s, 9H, tert. butyl), 2.50–2.54 (m, 2H,

CH₂), 2.94–2.99 (m, 2H, CH₂), 5.36 (dd, J ¼ 9.9 Hz, 1H,

CH), 5.57 (s, 2H, CH₂), 7.02 (d, J ¼ 7.2 Hz, 1H, Ar-H), 7.11–

7.13 (m, 1H, Ar-H), 7.21–7.29 (m, 8H, Ar-H), 7.85 (d, J ¼

7.8 Hz, 1H, Ar-H) ppm; ¹³C NMR (CDCl₃) (75 MHz): d

24.06 (CH₂), 24.75 (CH₂), 31.30, 31.30, 31.30 (CH₃), 34.51

(tert.butyl), 47.29 (NCH₂), 71.06, (OCH), 110.04, 112.90,

118.39, 120.05, 122.27, 123.25, 123.87, 125.56, 125.56,

125.91, 125.91, 129.91, 131.95, 133.03, 135.73, 141.86,

150.57, 151.24, 152.56 (aromatic carbons) ppm; ms: m/z

477.40 (M^þþ1); Anal. Calcd. for C₂₇H₂₇BrN₂O: C, 68.21; H,

5.72; N, 5.89. Found: C, 68.10; H, 5.80; N, 6.10.

[12] Preston, P. N.; In Benzimidazoles and Congeneric Tricyclic

Compounds; Wiley Interscience: New York, 1980; Part 2, Chapter 10,

pp 531.

[13] Daniel, L. A. Strategiies for Organic Drug Synthesis and

Design; Wiley Interscience: 1998; p 300.

[14] Eaton, P. E.; Carlson, G. R.; Lee, J. T. J Org Chem 1973,

38, 4071.

[15] Phillips, M. A. J Chem Soc 1928, 172, 2393.

[16] Dubey, R.; Hari Narayana Moorthy, N. S. Chem Pharm

Bull 2007, 55, 115.

[17] Maradolla M. B.; Allam S. K.; Mandha A.; Chandramouli

G. V. P. Arkivoc 2008, 15, 42.

Phenyl-2-(6-bromochroman-2-yl)-1H-benzimidazole-1-car-

boxylate (6⁰m). ir (KBr): 3435, 2925, 1766, 1475, 1355, 1232

[18] Vinod Kumar, R.; Vaidya, S. D.; Siva Kumar, B. V.; Bhise

U. N.; Bhirud S. B.; Mashelkar, U. C. Indian J Hetrocycl Chem 2005,

14, 197.

cm^ꢁ^{1 1}H NMR (CDCl₃): d 2.50–2.54 (m, 2H, CH₂), 2.95–

;

3.05 (m, 2H, CH₂), 5.60 (s, 2H, CH₂), 5.94 (dd, J ¼ 9.0, 9.1

Hz, 1H, CH), 6.90 (d, J ¼ 8.1 Hz, 1H, Ar-H), 7.09–7.14 (m,

2H, Ar-H), 7.26–7.52 (m, 5H, Ar-H), 7.86–7.88 (m, 1H, Ar-

H), 8.07–8.09 (m, 1H, Ar-H) ppm; ms: m/z 421.72 (M^þþ1);

Anal. Calcd. for C₂₃H₁₇BrN₂O₃: C, 61.48; H, 3.81; N, 6.23.

Found: C, 61.58; H, 3.92; N, 6.31.

[19] Vaidya, S. D.; Siva Kumar, B. V.; Vinod Kumar, R.;

Bhirud S. B.; Mashelkar, U. C. Euro J Med Chem 2008, 43, 986.

[20] Siva Kumar, B. V.; Vaidya, S. D.; Vinod Kumar, R.;

Bhirud S. B.; Mane R. B. Euro J Med Chem 2006, 41, 599.

[21] Welton, T. Chem Rev 1999, 99, 2071.

[22] Wasserscheid, P.; Keim, W. Angew Chem Int Ed Engl

2000, 39, 3772.

[23] Sheldon, R. Chem Commun 2001, 1, 2399.

[24] Gordon, C. M. Appl Catal A 2001, 222, 101.

[25] Wasserscheid. P.; Welton, T., Eds. Ionic Liquids in Synthe-

sis; VCH-Wiley: Weinheim, 2002.

REFERENCES AND NOTES

[1] Sheehan, D. J.; Hitchcock, C. A.; Sibley, C. M. Clin Micro-

biol Rev 1999, 12, 40.

[26] Connell, R. D. U. S. Pat.6,469,031 (2002).

[27] Owens, G. S.; Abu-Omer, M. M. J Mol Catal A 2002, 187,

211.

[2] Kazimerczuk, Z.; Andrzejewska, M.; Klimesova, V. Eur J

Med Chem 2005, 40, 203.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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