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Takeharu Haino et al.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)

benzene

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Metal-free C(sp²)–H Functionalization of Azoles:

K₂CO₃/I₂-Mediated Oxidation, Imination, and

Received 00th January 20xx,

Accepted 00th January 20xx

Amination

Ranajit Das, Mainak Banerjee, Rakesh Kumar Rai, Ramesh Karri and Gouriprasanna Roy**

DOI: 10.1039/x0xx00000x

A direct C2−H oxidaꢀon and iminaꢀon of a wide variety of azoles was achieved by using commercially available simple

K₂CO₃/I₂reagent combination. The iodinated azole adduct, produced via in-situ generation of N-heterocyclic carbene, is the

key intermediate for C2−H oxidaꢀon, iminaꢀon, and aminaꢀon of azoles. Signiﬁcantly, these reacꢀons proceed under mild

conditions with high to excellent yields, are scalable to large quantity and exhibit a broad substrate scope. Interestingly,

this direct C2−H iminaꢀon method allowed us to access various pharmacologically active N⁶-alkyl or N⁶-aryl substituted

benzimidazoquinazolinone scaffolds through intramolecular C−H imination in a sequential one-pot reaction.

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their excellent effort, have used reagent that contains

a

nucleophilic site and an appropriately positioned leaving group, as

shown in Scheme 1b, for the direct incorporation of oxo group at

the C2-position of imidazole or benzimidazole.^6aFor instance, the

combination of sodium hypochlorite (NaOCl) and NaOH (2M) was

used for the incorporation of oxo group. However, due to the use of

strong base, occasionally, they observed some hydrolysis of the

imidazolium salt and other unidentified side product formation

rather than oxidation which often reduced yield of the expected

product.^6aIn addition, this method was not extended to other

azoles including thiazole, benzothiazole or triazole.

1. Introduction

The oxo (=O), imine (=NH), substituted imine (=NR) or amine (−NH₂)

functionalized azoles have enormous significance in the areas of

pharmaceuticals, agrochemicals, and materials (Scheme 1a).^1-3

There are numerous drugs, therapeutic leads, and natural products

possess these functional groups at the 2-position of azoles.⁴Yet,

unfortunately, there is lack of a simple common synthetic strategy

to incorporate all of these functional groups at the 2-position of

azoles using a simple reagent or reagent combination.

Several research groups have made notable advances in

the direction of introducing oxo and imine group at the 2-

position of imidazole or benzimidazole.⁵Ohta and co-workers,

in their pioneer work, developed a method to incorporate an

oxo group at the C2-position of N,N'-disubstituted imidazole

which involves pre-functionalization at the C2-position of N-

methyl imidazole with –SPh group to afford 1-methyl-2-

phenylthio-1H-imidazole which further used to produce the

expected product 2-imidazolone (2) in a multistep procedure,

(See Scheme S1, ESI).^5bHowever, during the synthesis of

kealiiquinone, Lovely and co-worker have found that this method

is not suitable for late-stage introduction of oxo group as it requires

low temperature (-78 °C) lithiation to introduce –SPh group ^6a

. On

the other hand, the most convenient strategy to date in

incorporating the imine group at 2-position of imidazole or

benzimidazole involves pre-functionalization with TMSN₃group

followed by the deprotection of TMS group (See Scheme S2)^7,8in a

multistep procedure.

Thus, to avoid any pre-functionalization, Lovely and co-workers, in

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Scheme 1. An overview of previous work

unfortunately, the isolated yields obtained from all the

reactions, except in case of a reaction where Et₃N was used as

a base, were very low (Yield <18%).

Table 1: Reaction condition optimization for C2−H oxidation of imidazoles

and benzimidazoles^a

Bases

(2 equiv)

DIEA

Time

(h)

12

6

Temp

(°C)

rt^d

rt

Yield^b

8c (%)

18

5

Entry

Solvents

Scheme 2. Overview of present work

1

2

MeOH/H₂O

THF/H₂O

Similarly, for the introduction of imine group chloramine-T or N-

Chloro-N-sodio-tert-butylcarbamate was used as an amidating

source with a leaving group (chloride) directly attached to the

nucleophilic nitrogen centre (Scheme 1b).^6bHowever, the

introduction of a leaving group to the amidating reagents creates a

major roadblock for practical use of this methodology to synthesis

various imine derivatives in large scale, necessitating the

exploration of alternative methods. Herein, we describe a very

simple, metal-free, and a common synthetic platform for C2–H

oxidation, imination, and amination of variety of azoles including

imidazole, benzimidazole, thiazole, benzothiazole, benzoxazole, and

triazole (Scheme 2). The direct functionalization of azolium salts

was simply achieved through in-situ incorporation of a good leaving

group iodide at the C2-position of five-membered heterocyclic ring

rather than into the nucleophile. This novel idea enable us to access

a wide variety of 2-oxo and 2-imino or 2-amino azoles by simply

changing nucleophiles. Interestingly, this direct C2−H imination

method also enable us to construct various pharmacologically

active N⁶-alkyl substituted benzimidazoquinazolinone scaffolds in a

sequential one-pot reaction through intramolecular C−H imination.

Imidazole

Pyridine

Et₃N

3

rt

14

43

53

65

78

8

4

rt

5

Et₃N

rt

6

Et₃N

THF/H₂O

40

rt

7

Et₃N

THF/H₂O

8

NaHCO₃

NaOMe

NaOH

Et3N

MeOH/H₂O

THF/H₂O

12

0.5

9

rt

6

10

11

12

13

14

15

16

17

18

19

20

rt

-

53

12

9

rt

Cs₂CO₃

^tBuO^-K⁺

K₂CO₃

MeOH/H₂O

DMF/ H2O

ACN/H2O

MeOH^c

rt

67

72

89

15

12

-

40

H₂O

-

^a7c (0.98 mmol), ^bIsolated yields, ^cAnhydrous condition, ^d22 °C

2. Results and discussion

2.1 C2−H oxidation of imidazoles and benzimidazoles

First, we initiated our investigation with C2−H oxidation of

imidazoles and benzimidazoles. The procedure for the

formation of 2-imidazolones or 2-benzimidazolones is very

simple: N,N'-disubstituted imidazolium or benzimidazolium

salt was treated with a combination of two commercially

available cheap reagents K₂CO₃and molecular iodine (I₂) in

MeOH/H₂O (9:1) at 40 °C in an open atmosphere which

afforded the expected product 2-imidazolone or 2-

benzimidazolone in high yield (Scheme 3). We observed that

the C2−H oxidation of N,N'-disubstituted benzimidazolium

salts occurred in a faster rate in comparison to the C2

−

H

oxidation of N,N'-disubstituted imidazolium salts (former

reactions were completed within 15-20 min whereas the later

reactions required 25-30 min to complete). Reaction

conditions of C2−H oxidation of imidazole was optimized using

1-benzyl-3-methyl-1H-imidazol-3-ium iodide (7c) as a model

substrate to find out the most suitable reaction conditions to

achieve the corresponding imidazolone 8c in high yield (Table

1). Initially, we screened a number of organic bases including

DIEA, imidazole, pyridine, and Et₃N in a methanol/water (9:1)

at room temparature (22 °C), Entry 1-4. Although in all the

cases the desired product 8c was observed, however,

Scheme 3. Scope of the C(sp2)−H oxidation reaction of a wide variety of imidazoles and

benzimidazole.

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To our surprise, we found that by using Et₃N as a base and THF/H₂O promising inhibitory activity on the replication of the

(9:1) as a reaction solvent we could achieve a high yield of 78% at respiratory syncytial virus (RSV),¹¹we next examined the scope

40 °C. However, continuing the same reaction for a longer period of of the reaction with primary amines (RNH₂).

time reduced the overall yield of the expected product 8c from 78%

to 65%. This is probably due to the hydrolysis of product under

present reaction conditions. To further improve the yield of the

final product, imidazolone 8c, we also screened with a range of

inorganic bases including K₂CO₃, Cs₂CO₃, ^tBuOK, NaOMe, and NaOH,

as shown in Table 1. To our delight, by using K₂CO₃as a base in

MeOH/H₂O (9:1) solvent mixture we could drastically decrease the

reaction time from 6 h to 0.5 h with a much-improved yield of 89%

(Entry 16). It is worth mentioning here that, we did not find any

oxidation product 8c when the same reaction was performed in

anhydrous methanol. Moreover, changing molecular iodine to N-

iodosuccinimide, another convenient source of electrophilic

iodination, or reducing the concentration of molecular iodine from

the stoichiometric amount ([7c] : [I₂] = 1) to the catalytic amount

did not give any satisfactory results in this case. With optimized

reaction conditions in hand, we set out to define the scope of the

Table 2: Reaction condition optimization for C2−H imination of imidazoles

and benzimidazoles^a

Time

(h)

12

Temp

(°C)

rt^c

rt

Yield^b

Entry

Amine Sources

Base

1

2

3

4

5

6

7

8

Liq. NH₃(1 equiv)

Liq. NH₃(2 equiv)

Liq. NH₃(3 equiv)

Liq. NH₃(4 equiv)

LiNH₂(1 equiv)

K₂CO₃

Et₃N

20

28

37

46

21

81

42

73

12

rt

12

rt

12

rt

NaNH₂(1.2 equiv)

0.5

6

rt

Et₃N

rt

oxidation reaction with

a wide variety of N,N'-disubstituted

imidazolium and benzimidazolium salts possessing electron-

donating and electron-withdrawing substituents. To our delight, in

all the cases we observed the formation of 2-imidazolones (8a-f)

and 2-benzimidazolones (9a-n) in good to excellent yields (≥ 88%)

within 15-30 min at 40 °C (Scheme-3).

^a7c (0.98 mmol),^bIsolated yields, ^c22 °C

2.2 C2−H imination of imidazoles and benzimidazoles

Along with the potential biological activities,⁹recently, N-

heterocyclic imines have attracted considerable interest due to

the high electron-donating character of the imino nitrogen

atom.¹⁰However, as mentioned above, the existing convenient

routes to synthesize 2-imino imidazole or benzimidazole are

associated with the pre-functionalization with either TMSN₃

group or chloride (Cl) at the 2-position, which are multistep

procedure, time consuming, and cost effective, as mentioned

in Scheme S2, ESI.^7,9Thus, we developed a direct procedure to

incorporate imine group at the 2-position of imidazolium or

benzimidazolium salts and this procedure is further extended

to other azoles (vide infra). To optimize the reaction conditions

for introduction of imine group, we treated imidazolium or

Scheme 4. Scope of the C(sp²)−H imination of imidazoles and benzimidazoles.

benzimidazolium salts with

a variety of amine sources

including liq. NH₃, LiNH₂, and NaNH₂, in the presence of same

K₂CO₃/I₂reagent combination. Optimization studies were

When N,N'-disubstituted benzimidazolium salts were reacted with

carried out using 7c as

a standard substrate and are various kind of amines using our standard reagent combination we,

summarized in Table 2. Due to the presence of water in

commercially available liq. NH₃and low reactivity of LiNH₂,

yield of the expected product 10c (1-benzyl-3-methyl-1H-

imidazol-2(3H)-imine) was found to be very low using these

two amine sources. Gratifyingly, 10c was obtained in 81 %

yield with 2 equiv of K₂CO₃, 1 equiv of I₂and 1.2 equiv of

NaNH₂at room temperature in 0.5 h (Table 2, Entry 7). With

the optimized reaction conditions in hand (K₂CO₃/I₂/NaNH₂in

2:1:1.2 molar ratio), we have successfully synthesized a wide

delightfully, observed the formation of desired products with high

to excellent yield (78-91%). However, in case of RNH₂(being a weak

nucleophile in comparison to NaNH₂) we needed to increase the

reaction temperature from room temperature to 50 °C. Both

electron-donating and electron-withdrawing substitutions at the R

group of primary amines were well tolerated to give the

corresponding imines (12a-d).

2.4 Plausible mechanism and mechanistic investigation

range of alkyl and aryl substituted 2-iminoimidazoles (10a-d)

and 2-iminobenzimidazoles (11a and 13a ) with good to

A plausible mechanistic pathway that is consistent with our

experimental data is mentioned in Figure 1a. The in-situ generation

of N-heterocyclic carbene (NHC)¹²from imidazolium salt in the

-e

-b

excellent yields. Both electron-withdrawing and electron-

donating substituents at the N-position were well tolerated.

presence of weak base followed by the formation of N,N′-

disubstituted iodinated adduct (14) is possibly the key intermediate

in this C(sp²)−H oxidation and imination reactions. The

2.3 C2−H imination of imidazoles and benzimidazoles with primary

amines

replacement of H atom at the C2 position (C2−H) with iodide

(C2−I) is playing a dramatic role here. Iodide being a “good”

Keeping in mind that the substituted imine compounds

(=NR, substitution at the imino nitrogen atom) have shown

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leaving group significantly facilitates the nucleophilic attack by

any oxygen or nitrogen containing weak or strong nucleophiles

including H₂O,

energy required for the oxidation reaction (54.42 kcal/mol) is

almost 2-fold more than the activation energy required for

imination reaction (25.08 kcal/mol), Figure 2a. This is in good

agreement with our experimental observation. Experimentally

we found that the imination reactions by NaNH₂occurred

smoothly at low temperature (22 °C) whereas the oxidation

reactions by H₂O needed to be performed comparatively at a

little high temperature (40 °C). Moreover, we observed that

the oxidation or imination of benzimidazole system (pK_aof

C2

−

H is 21.6)^15ais faster in comparison to the imidazole (pK_aof

C2

H is 23), which is also in well agreement with theoretical

calculations. DFT calculations showed that the formation of 2-

benzimidazolone and 2-iminobenzimidazole from the

corresponding N,N′-disubstituted benzimidazolium salt is

thermodynamically 9.14 and 9.60 kcal/mol, respectively, more

favorable in comparison to the formation of 2-imidazolone or

2-iminoimidazole from the corresponding N,N′-disubstituted

imidazolium salt (Figure 2b and Table S4, ESI for more details).

Figure 1. (a) Plausible reaction mechanism of C(sp²)−H oxidation and imination of N,N'-

disubstituted imidazolium salt 7c (used as a standard substrate). LC/MS chromatogram

(b) and HRMS of 7c, 15a, and 8c (c). (d) ESI/HRMS spectra of 8c and 8c-O¹⁸

.

NaNH₂, or RNH₂to yield the corresponding 2-oxoimidazole and

2-iminoimidazole, respectively.

The compound 15a (m/z = 299.0085) was detected (See

Figure S1, S2) in the crude reaction mixture by LC/MS, but we

could not isolate it from the reaction containing water

(MeOH/H₂O in 9:1 ratio (v/v)). However, it was carefully

isolated by performing the same reaction in anhydrous THF

under inert atmosphere.¹³Interestingly, treatment of 15a with

NaNH₂(1.2 equiv) in anhydrous MeOH at 22 °C afforded 10c in

quantitative yield. Similarly, treatment of 15a with 1 equiv of

K₂CO₃in MeOH/H₂O (9:1) at 40 °C afforded 8c (yield > 90%).

Delightfully, the addition of O¹⁸-labeled water into the above

reaction solution of 15a yielded the mixture of both O¹⁸

labeled and unlabeled 2-imidazolones

(

8c and 8c-O¹⁸),

confirmed by HRMS (See Figure S3, and Scheme S3, ESI).

Guided by the experimental observations and to develop a

better understanding of the reaction mechanism of this C2−H

oxidation and imination, we carried out quantum mechanical

calculations (DFT)^14aat the M06-2X/6-311G(d,P), def2-TZVPP

(for iodine) level of theory.^14c,14dThe key transition state (TS)

of the reaction pathways was fully optimized in gaseous phase,

as shown in Figure 2. DFT calculations showed that the

imination of 15b by NaNH₂is energetically more favorable in

comparison to the oxidation of 15b by H₂O. The activation

Figure 2. (a) Gibbs free energy proﬁle (kcal/mol) of C(sp²)–H oxidation and

imination of 15b, performed at the M06-2X/6-311G (d,p), def2-TZVPP (iodine)

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level of theory. (b) Reaction free energies (ꢀG, kcal/mol) of oxidation and

imination of iodinated adduct of imidazole or benzimidazole.

our method, as described above, worked very well only when

we used azolium salts instead of simple azoles. Therefore, this

Scheme 5. Scope of C(sp²)−H oxo, imine, amine functionalization of thiazoles,

benzothiazoles, oxazole, and triazoles.

2.5 Scope of C2−H oxidation and imination of other azoles

The scope of the K₂CO₃/I₂reagent combination was further

explored with other azoles and the results are shown in

Scheme 5. Perhaps the most significant of our finding is that

the current strategy of introducing the oxo and imine

functional groups to the imidazole or benzimidazole

heterocycles can efficiently be used to other azoles including

thiazole, benzothiazole, benzoxazole, and triazole. When

various derivatives of azolium salts were treated with the

standard reagent combination (K₂CO₃/I₂) in MeOH/H₂O (9:1) or

in the presence of NaNH₂or RNH₂in anhydrous MeOH (the

standard reaction procedure for oxidation and imination of

imidazolium or benzimidazolium salt, as mentioned above)

Scheme 6. Scope of amine-functionalized azoles and N-substituted ketones. (a)

Synthetic routes for 2-aminoazoles (24-27), N-substituted imidazolone (28), and

benzimidazolone (29). X-ray of 30 is shown above. (b) Previous report of synthesis of

27.^6b

method prevents the synthesis of 2-amino azoles (24-27) or

oxidation products of N-substituted imidazoles or

benzimidazoles (28, and 29). To clear this road-block, we

further successfully extended this chemistry with removable

substituent on the N3-position. Briefly, to access 2-amino

azoles (24

-

27), and N-substituted imidazole or benzimidazole-

28 and 29 and we synthesized the

afforded expected oxidation and imination products (16–21,

based ketones

(

)

23a, and 23b) in moderate to high yields. Electron-donating as

well as electron-withdrawing substituents at the azoles can

happily be used to synthesize the corresponding oxidation and

imination products in high yields. However, in case of

benzoxazole we noticed a very low yield of expected ketone

product (22) due to the hydrolysis of the corresponding

benzoxazolium salt under basic conditions (Figure S4, ESI).¹⁶

corresponding azolium salts using ethylchloroformate, as

shown in Scheme 6, which was subsequently used to afford

the final desired products using standard procedure. However,

the N-CO₂Et group being highly labile under the present

reaction conditions (K₂CO₃in MeOH/H₂O mixture) we used

NEt₃, as a weak base instead of K₂CO₃, and the reaction was

carried out in THF to introduce imine or oxo group at the 2-

position. Finally, N-CO₂Et group was easily removed in mild

acidic conditions to obtain the desired products in high

yields.¹⁷Likewise, we synthesized amine functionalized

thiazole 26 and benzothiazole 27 by masking N-position of

thiazole or benzothiazole with ethylformate, as illustrated in

Scheme 6a. Notably, recently Chang and co-workers have

reported the synthesis of 27 in a sequential two-step process

starting from benzothiazole. First, -NHBoc group was

incorporated at the C2-position of the benzothiazole using

NHC-based copper catalyst {(NHC)Cu, 5 mol%}, tert-BuONa (2

equiv), and an amidating source N-chloro-N-sodio-tert-

2.6 Synthesis of C2-Amination and N-substituted Azoles.

In general, the pK_avalue for C2−H of N,N′-disubstituted

imidazolium salt (pK_a= 23.0 for N,N′-dimethylimidazolium salt)

is lower in comparison to the pK_avalue of the corresponding

N-substituted imidazole (pK_a= 35.1 for N-methyl imidazole).^15b

As a result, the formation of iodinated adduct 15a from N,N′-

dimethylimidazolium salt could easily be achieved after

deprotonation of the acidic proton at the C2-position by using

weak base like K₂CO₃or Et₃N via in-situ generation of N-

heterocyclic carbene (NHC). This is probably the reason why

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C2-position of N,N

′

-disubstituted benzimidazolium salts by

butylcarbamate which was freshly synthesized from tert-

using K₂CO₃/I₂reagent combinations, as shown in Scheme 7.

Considering the potential application of this

C(sp²−H) functionalization of azoles, “gram”−scale synthesis of

butylcarbamate (Boc-NH₂) under argon atmosphere in

a

glovebox.^6bFinally, carbamate group was readily deprotected

under acidic medium to afford 27 (Scheme 6b).

compound 8c, 10a, and 32d were carried out under standard

reaction conditions. Gratifyingly, the desired products were

obtained in high yield, 8c (93%), 10a (79%) and 31d (71%)

respectively.

Conclusions

In conclusion, we have discovered a convenient procedure for

C2−H oxidaꢀon, imination, and amination of several five-

membered heterocyclic azoles including different derivatives

of imidazole, benzimidazole, thiazole, benzothiazole,

benzoxazole, and triazole, using a very simple K₂CO₃/I₂reagent

combination under mild reaction conditions. These reactions

occur in the temperature ranges from -5 °C to 50 °C, in an

open atmosphere, avoid the use of strong bases and transition

metal catalysts, are scalable to large quantity in high yield and

exhibit

a broad substrate scope. Our experimental and

theoretical results show that the formation of iodinated azole

adduct via in-situ generation of N-heterocyclic carbene is the

key intermediate for C2−H oxidaꢀon, iminaꢀon, and aminaꢀon

of variety of azoles. Perhaps the most striking feature of our

work is that by using this simple reagent combination K₂CO₃/I₂

we could efficiently perform both C2−H oxidaꢀon, iminaꢀon

and amination of variety of azoles by simply changing

nucleophiles. In this simple method we could also prepare

imidazole or benzimidazole-based thiones using HS^-as

nucleophile (unpublished results).²⁰Finally, this direct method

of imination of benzimidazolium salts helped us to construct a

wide variety of pharmacologically important N⁶-alkyl

Scheme 7. Scope of benzimidazoquinazolinones.

substituted

benzimidazoquinazolinones

through

2.7 Application of the methodology

intramolecular C−H imination. The ubiquity of azole in natural

products, drugs, and therapeutic leads demands universal

access of functionalized azoles, which is obstructed due to the

substituted lack of general and simple synthetic methodology. Thus, this

Possibly the most striking demonstration of the utility of

this methodology is displayed in the construction of

pharmacologically

active

N⁶-alkyl

benzimidazoquinazolinones, which are reported as effective

immunosuppressive, anticancer, and antitumor agents and

shown promising activities in treating neurodegenerative

disorders.¹⁸However, the existing synthetic methods of N⁶-

alkyl substituted benzimidazoquinazolinones suffer from

conventional multi-step protocols, harsh reaction conditions

and low-atom-economic coupling sequences. Recently, two

simple and efficient chemical avenue to C2−H functionalization

of azoles will allow effortless and economical access to these

structural motifs.

Experimental Section

research

intramolecular oxidative C–H amination to synthesize N⁵-alkyl

and substituted

N⁶-aryl benzimidazoquinazolinones.¹⁹

groups

have

developed

copper-catalyzed

General Information: All starting materials and reagents were obtained

from commercial suppliers and used without any sort of further purification,

unless otherwise mentioned. All solvents for routine isolation of products

However, previous two methods not extended to introduce and chromatography were reagent-grade. All experiments were carried out

the alkyl substitution at N⁶-position on the benzimidazole ring,

which constitutes the core structure of many active drugs

in open atmosphere unless otherwise mentioned in the experimental

section. Ultra-performance liquid chromatography (UPLC) was carried out

using an Agilent 6540 accurate–mass Q-TOF LC/MS (Agilent Technologies,

including anti-tumor agent 32e (IC₅₀= 0.5

have successfully synthesized a wide variety of N⁶-alkyl

substituted benzimidazoquinazolinones (32a 31k) in moderate

ꢁM). Gratifyingly, we

U.S.A.). Liquid chromatographic separation was performed at room

temperature of 18 °C, using a UPLC C₁₈analytical column (ZORBAX C₁₈

Column, 2.1 x 50 mm, 1.8-micron). MS analyses were performed under the

following operation parameters: dry gas temperature 350 °C, dry gas (N₂)

ﬂow rate 10 L/min, nebulizer pressure 30 psi, V_cap4000 and fragmentor

voltage 120 V. Mass spectra were acquired in the positive ion mode by

scanning from 50 to 1500 in the mass to charge ratio (m/z). The mobile

phase composition used for UPLC–QTOF MS comprised of a mixture of H₂O

-

to good yield (68% - 82%) in a sequential one-pot reaction

procedure by treating 2-aminobenzoyl chlorides with N-alkyl

substituted benzimidazoles in THF/ACN (1:1) solvent mixture

at room temperature followed by intramolecular imination at

6 | J. Name., 2012, 00, 1-3

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(A) and ACN (B), both containing 0.1% HCO₂H, with an optimized linear (d, 1H), 6.44 (d, 1H), 3.51(q, J = 8.00 Hz, 2H), 3.09 (s, 3H), 1.13 (t, J = 8.00 Hz,

gradient elution as follows: 0–2 min, 1–5% B; 2–7 min, 5–15% B. The 2H). ¹³C NMR (100 MHz, DMSO-d₆): δ. 152.55, 111.60, 109.80, 37.74, 29.98,

14.09. HR-ESIMS (m/z): Calcd for [M+H]⁺C₆H₁₀N₂O: 127.0866 observed

value: 127.0869.

injection volume was 1 ꢁL. The ﬂow rate was set at 0.3 mL/min. The

LC/MS/MS experiments were performed with an ESI interface with UHPLC–

QTOF MS instrument used for LC/MS analysis. Accurate mass analysis

calibration was carried out by ESI-low concentration tuning mix solution

1-benzyl-3-methyl-1H-imidazol-2(3H)-one (8c): The product was purified by

provided by Agilent technologies, USA. The accuracy error threshold was set column chromatography on silica gel (eluent: EtOAc/hexane 2:3 to 7:3);

at 5 ppm. All other parameters were similar to LC/MS experimental settings. brownish liquid. Yield: 315 mg, 92 %. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (m,

1H), 7.35-7.29 (m, 3H), 7.27-7.24 (m, 1H), 6.17-6.16 (m, 1H), 6.11-6.10 (d,

Liquid state NMR spectra were recorded in CDCl₃, MeOH-d₄, DMSO-d₆as a

solvent. NMR spectra of compounds were recorded on a Bruker Avance 400 1H), 4.78 (s, 2H), 3.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ. 153.20, 136.94,

128.67, 127.75, 127.66, 127.26, 111.67, 109.85, 47.14, 30.41. HR-ESIMS

(m/z): Calcd for [M+H]⁺C₁₁H₁₂N₂O: 189.1022 observed value: 189.1019.

NMR spectrometer at 21 °C using the solvent (residual) as an internal

standard and chemical shifts are reported in ppm relative to the residual

solvent signal (δ = 7.26 ppm for ¹H NMR and δ = 77.16 ppm for ¹³C NMR in

CDCl₃; δ = 2.50 ppm for ¹H NMR and δ = 39.52 ppm for ¹³C NMR DMSO-d₆; δ

= 3.31 ppm for ¹H NMR and δ = 49.00 ppm for ¹³C NMR MeOH-d₄) with

respect to tetramethylsilane (TMS). Thin-layer chromatography analyses

were carried out on pre-coated silica gel plates (Merck) and spots were

visualized by UV irradiation and other charring reagents such as ninhydrin,

vanillin, phosphomolybdic acid etc. Column chromatography was performed

on glass columns loaded with silica gel 100−200 mesh. Single crystal X-ray

1-(2-hydroxyethyl)-3-methyl-1H-imidazol-2(3H)-one (8d): The product was

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3

to 9:1); brownish liquid. Yield: 315 mg, 92 %. ¹H NMR (400 MHz, CDCl₃): δ

6.24 (d, 1H), 6.16 (d, 1H), 3.97 (t, J= 6.88 Hz, 2H), 3.34 (t, J= 6.88 Hz, 2H),

3.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 153.22, 111.92, 110.70, 46.78,

46.08, 30.87. HR-ESIMS (m/z): Calcd for [M+H]⁺C₆H₁₀N₂O₂: 143.0815

observed value: 143.0822.

diffraction was performed using

a Bruker D8 Venture diffractometer

operating with Mo Kα radiation and equipped with a CMOS Photon100 area 1-(2-methoxyethyl)-3-methyl-1H-imidazol-2(3H)-one (8e): The product was

detector.

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3

to 8:2); brownish liquid. Yield: 398 mg, 90 %. ¹H NMR (400 MHz, DMSO-d₆):

δ 6.45 (d, 2H), 6.42 (d, 2H), 3.63 (t, J = 5.40 Hz, 2H), 3.47 (t, J = 5.40 Hz, 2H),

3.22 (s, 3H), 3.09 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): 152.64, 111.31,

110.16, 70.16, 57.91, 42.31, 29.85. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₇H₁₂N₂O₂:157.0972 observed value: 157.0966.

General Synthesis of N,N'-disubstituted imidazolium and benzimidazolium

salts: The synthesis of N,N'-disubstituted imidazolium and benzimidazolium

salts were achieved by following the previously reported literature

procedure. To a stirred solution of alkyl or aryl imidazole/ benzimidazole in

ethyl acetate methyl iodide (1.2 equiv) was added in a dropwise manner at 0

°C under open atmosphere and the reaction solution was kept for stirring

for 4 h. The progress of the reaction was monitored by TLC using MeOH-

DCM (2:8) as a mobile phase. The reaction mixture was evaporated to

dryness after sequential washing with ethyl acetate (5 x 4 mL). Finally, dried

1-benzyl-3-methyl-4,5-diphenyl-1H-imidazol-2(3H)-one (8f): The product was

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3

to 6:4); yellowish solid. Yield: 330 mg, 88 %. ¹H NMR (400 MHz, CDCl₃-d₃): δ

7.27-7.29 (m, 4H), 7.22-7.25 (m, 2H), 7.08-7.10 (m, 2H), 7.03-7.06 (m, 2H),

4.87 (s, 2H), 3.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 154.27, 138.15,

130.94, 130.13, 129.40, 128.68, 128.65, 128.38, 128.16, 127.83, 127.49,

over vacuum pressure to afford the expected product. NMR data (¹H and ¹³

NMR) of compounds were in good agreement with the previously reported

literature values.²¹

C

121.86, 121.35, 45.65, 29.43. HR-ESIMS (m/z): Calcd for [M]⁺C₉H₁₁N₂

341.1648 observed value: 341.1652.

:

1-benzyl-2-iodo-3-methyl-1H-imidazol-3-ium iodide (15a): Reddish yellow

solid, Yield: 320 mg, 99 %. ¹H NMR (400 MHz, MeOH-d₄): δ 8.03-7.99 (m,

2H), 7.42-7.41 (m, 3H), 7.31-7.29 (m, 2H), 5.44 (s, 2H), 3.92 (s, 3H). ¹³C NMR

(100 MHz, DMSO-d₆): δ. 135.50, 130.85, 130.66, 129.74, 128.16, 126.94,

57.22, 40.60. HR-ESIMS (m/z): Calcd for [M]⁺C₁₁H₁₂IN₂: 299.004 observed

value: 299.0048. Compound 15a can also be synthesized in an alternative

method by following the literature procedure of Arduengo III et al.^13a

1,3-bis(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one (9a): The product

was purified by column chromatography on silica gel (eluent: EtOAc/hexane

1

2:3 to 8:2); White solid. Yield: 352 mg, 91 %. H NMR (400 MHz, CDCl₃-d): δ

7.19-7.22 (m, 1H), 7.09-.7.11 (m, 1H), 4.03(t, J= 5.64, 2H), 3.83 (t, J= 5.64,

2H). ¹³C NMR (100 MHz, CDCl₃-d): 156.29, 131.05, 122.54, 109.56, 60.73,

44.70. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₁H₁₄N₂O₃: 223.1077 observed

value: 223.1069.

General Procedure for C2–H oxidation reaction of imidazoles and

benzimidazoles: To a one neck round bottom flask 2-benzimidazolium/2-

imidazolim salts (0.5 g), 2 equiv of K₂CO₃and 1 equiv of molecular iodine

were added in 20 mL of MeOH-H₂O (9:1) solution. The resulting above

solution was stirred for 15-30 min at 40 °C. The progress of the reaction was

monitored by TLC by using ethyl acetate/hexane (5:1, v/v) as a mobile

phase. All the volatile components were evaporated under reduced

pressure, and the resulting residue was extracted with ethyl acetate. The

organic layer was washed sequentially with water (10 mL × 2), aq. Na₂S₂O₃(1

M, 5 mL × 4), and brine solution (10 mL × 2), (Standard work-up procedure

followed for other compounds as mentioned below). After that, the

combined organic layer was finally dried over anhydrous Na₂SO₄, then

solvent was evaporated under vacuum to afford crude product which was

further purified by column chromatography using ethyl acetate/hexane as

mobile phase.

2-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl

acetate (9b): The product was purified by column chromatography on silica

gel (eluent: EtOAc/hexane 2:3 to 8:2); Yellowish solid. Yield: 360 mg, 90 %.

¹H NMR (400 MHz, CDCl₃-d): δ 1.90 (s, 3H), 3.83 (t, J= 5.64, 2H), 3.99(t, J=

5.64, 2H), 4.14 (t, J= 5.44, 2H) 4.35 (t, J= 5.44, 2H), 6.96-.7.00 (m, 1H), 7.03-

7.07 (m, 1H), 7.08-7.12 (m, 2H). ¹³C NMR (100 MHz, CDCl₃-d): 170.92,

154.43, 130.12, 129.63, 121.51, 121.41, 107.76, 107.69, 62.24, 40.20, 27.27,

20.95. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₃H₁₆N₂O₄: 265.1183 observed

value: 265.1174.

1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (9c): The product was purified

by column chromatography on silica gel (eluent: EtOAc/hexane 2:3 to 7 :3);

yellowish solid. Yield: 278 mg, 94 %. ¹H NMR (400 MHz, CDCl₃): δ 7.08-7.11

(m, 1H), 6.95-6.99 (m, 1H), 3.37 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 154.77,

130.12, 121.30, 107.42, 27.55. HR-ESIMS (m/z): Calcd for [M+H]⁺C₉H₁₀N₂O:

163.0866 observed value: 163.0874.

1,3-dimethyl-1H-imidazol-2(3H)-one (8a): The product was purified by

column chromatography on silica gel (eluent: EtOAc/hexane 2:3 to 7:3);

yellow liquid. Yield: 225 mg, 90 %. ¹H NMR (400 MHz, CDCl₃): δ 6.03 (S, 1H),

3.08 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 152.86, 110.66, 29.72. HR-ESIMS

(m/z): Calcd for [M+H]⁺C₅H₈N₂O: 113.0709 observed value: 113.0712.

1-ethyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one (9d): The product was

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3

to 5:3); brownish liquid. Yield: 296 mg, 97 %. ¹H NMR (400 MHz, CDCl₃): δ

7.10-7.01, (m, 2H), 6.96-7.01 (m, 2H), 3.93 (q, J=7.13, 2H), 3.41 (s, 3H), 3.33

(t, J=7.13, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 154.28, 130.25, 129.15, 121.13,

121.12, 107.52, 36.00, 27.16, 13.77. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₀H₁₂N₂O:177.1022 observed value: 177.1039.

1-ethyl-3-methyl-1H-imidazol-2(3H)-one (8b): The product was purified by

column chromatography on silica gel (eluent: EtOAc/hexane 2:3 to 7:3);

brownish liquid. Yield: 246 mg, 93 %. ¹H NMR (400 MHz, DMSO-d₆): δ 6.49

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1-benzyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one (9e): The product was 3-benzyl-5-chloro-1-methyl-1H-benzo[d]imidazol-2(3H)-one

(9m):

The

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3 product was purified by flash column chromatography on silica gel

1

to 3:2); whitish solid Yield: 366 mg, 98 %. H NMR (400 MHz, CDCl₃): δ 7.31- (eluent: EtOAc/ hexane 2:3 to 7:3); Yellowish solid. Yield: 328 mg, 93 %. ¹H

7.32 (m, 4H), 7.26 (m,1H), 7.23-7.27 (m,1H), 7.14-7.16 (m,1H), 7.07-7.10 NMR (400 MHz, CHCl₃-d₃): δ 7.26-7.32 (m, 5H), 6.95-6.97 (m, 2H), 6.74-6.76

(m,1H), 7.03-7.05 (m, 1H), 6.98-7.02 (m, 1H), 5.05 (s, 2H), 3.37 (s, 3H). ¹³C (m, 1H), 5.05 (s, 1H), 3.44 (s, 1H). ¹³C NMR (100 MHz, CHCl₃-d₃): 154.70,

NMR (100 MHz, CDCl₃): δ 153.73, 137.06, 128.68, 128.57, 127.41, 127.36, 136.09, 131.19, 128.96, 127.99, 127.59, 127.17, 121.30, 109.01, 108.12,

121.05, 120.91, 108.06, 107.84, 43.70, 27.00. HR-ESIMS (m/z): Calcd for 45.19, 27.52. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₃N₂OCl 273.0789

[M+H]⁺C₁₅H₁₄N₂O: 239.1179 observed value: 239.1190.

observed value: 273.0779.

1-(2-methoxyethyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

(9f): The 3-benzyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (9n): The product

product was purified by column chromatography on silica gel (eluent: was purified by column chromatography on silica gel (eluent: EtOAc/hexane

EtOAc/hexane 2:3 to 7:3); Yellowish liquid, Yield: 427 mg, 94 %. ¹H NMR (400 2:3 to 8:2); Yellowish white solid. Yield: 325 mg, 91 %. ¹H NMR (400 MHz,

MHz, CDCl₃): δ 7.08-7.09(m, 3H), 6.95-6.98 (m, 1H), 4.06 (t, J = 5.60 Hz, 2H), CHCl₃-d₃): δ 8.00-8.02 (dd, 1H), 7.89 (d, 1H), 7.28-.7.33 (m, 5H), 6.90 (d, 1H),

3.67 (t, J = 5.60 Hz, 2H), 3.41(s, 3H), 3.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): 5.12 (s, 2H), 3.54 (s, 3H). ¹³C NMR (100 MHz, CHCl₃-d₃): 154.92, 144.81,

δ 154.70, 130.23, 130.03, 121.44, 121.37, 108.47, 107.55, 70.84, 59.17, 142.89, 141.86, 135.30, 134.37, 130.27, 129.17, 128.38, 127.67, 121.41,

41.43, 27.33. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₁H₁₄N₂O₂193.0972 118.57, 108.68, 107.49, 105.48, 103.47, 45.33, 29.85. HR-ESIMS (m/z): Calcd

observed value: 193.0981.

for [M+H]⁺C₉H₁₁N₂: 284.103 observed value: 284.1041.

General Procedure for C2–H imination reaction of imidazoles and

benzimidazoles: To a one neck round bottom flask 2-benzimidazolium/2-

imidazolim salts (0.5 g), K₂CO₃(2 equiv), and molecular iodine (1 equiv) were

added in 30 mL of anhydrous MeOH. 1.2 equiv of NaNH₂was added

gradually to the above reaction mixture at 0 °C and the resulting solution

was continued to stir for another 0.5 h at room temperature. The progress

of the reaction was monitored by TLC by using MeOH/DCM/NH₄OH (2:8:1

v/v) as a mobile phase. All the volatile components were evaporated under

reduced pressure, and the resulting residue was extracted with ethyl

acetate. Standard work-up procedure was followed (as mentioned above for

compounds 8 and 9) to obtain the crude products which were further

purified by column chromatography using ethyl acetate/hexane/ammonium

hydroxide as an eluent or by using bulb-to-bulb (kugenrohr) distillation at 70

°C/0.1 mbar.

1-(2-methoxyethyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

(9g):

The

product was purified by column chromatography on silica gel (eluent:

EtOAc/hexane 2:3 to 7:3); Yellowish liquid, Yield: 427 mg, 94 %. ¹H NMR (400

MHz, CDCl₃): δ 7.08-7.09 (m, 3H), 6.95-6.98 (m, 1H), 4.06 (t, J = 5.60 Hz, 2H),

3.67 (t, J = 5.60 Hz, 2H), 3.41(s, 3H), 3.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃):

δ 154.70, 130.23, 130.03, 121.44, 121.37, 108.47, 107.55, 70.84, 59.17,

41.43, 27.33. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₁H₁₄N₂O₂: 207.1128

observed value:207.1138.

2-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl acetate (9h):

The product was purified by column chromatography on silica gel (eluent:

EtOAc/hexane 2:3 to 8:2); Yellowish solid. Yield: 367 mg, 94 %. ¹H NMR (400

MHz, CDCl₃-d): δ 1.98 (s, 3H), 3.42 (s, 3H), 4.14 (t, J= 5.60, 2H), 4.37(t, J=

5.60, 2H) 6.96-.7.00 (m, 1H), 7.03-7.07 (m, 1H), 7.08-7.12 (m, 2H). ¹³C NMR

(100 MHz, CDCl₃-d): 170.92, 154.43, 130.20, 129.63, 121.51, 121.41, 107.76,

107.69, 62.24, 40.20, 27.27, 20.95. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₂H₁₄N₂O₃: 235.1077 observed value: 235.1068.

1,3-dimethyl-1H-imidazol-2(3H)-imine (10a): The product was purified by

column chromatography on silica gel (eluent: DCM: MeOH:NH₄OH 8:2:1);

1-(3-aminopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (9i): Yellow

solid, Yield: 300 mg, 91%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (s, 3H), 7.29-

7.27 (m, 1H), 7.17-7.15 (m, 1H), 7.08 -7.06 (m, 2H), 3.94 (q, J= 6.28, 2H), 2.82

(q, J= 6.28 Hz, 2H), 3.33 (s, 3H), 1.96 (quintate, J= 6.28 Hz, 2H). ¹³C NMR (100

MHz, CDCl₃): δ 26.24, 26.88, 36.47, 37.74, 107.75, 107.81, 120.90, 120.96,

1

Yellowish solid. Yield: 203 mg, 82 %. H NMR (400 MHz, CHCl₃-d₃): δ 6.16 (s,

1H), 3.24 (s, 3H), 2.02 (s, 1H). ¹³C NMR (100 MHz, CHCl₃-d₃): 153.72, 111.31,

30.60. HR-ESIMS (m/z): Calcd for [M+H]⁺C₅H₉N₃: 112.0869 observed value:

112.0872.

+

128.71, 129.67, 153.63. HR-ESIMS (m/z): Calcd for [M+H] C₁₁H₁₅N₃O

206.1288 observed value: 206.1289.

1-ethyl-3-methyl-1H-imidazol-2(3H)-imine (10b): The product was purified

by flash column chromatography on silica gel (eluent: DCM:MeOH:NH₄OH

4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzonitrile

The product was purified by column chromatography on silica gel (eluent:

(9j):

1

8:2:1); Yellowish solid. Yield: 223 mg, 85 %. H NMR (400 MHz, DMSO-d₆): δ

EtOAc/hexane 2:3 to 8:2); Yellow solid. Yield: 316 mg, 92 %. ¹H NMR (400 1.41 (t, J= 7.28 Hz, 3H), 3.85 (s, 3H), 4.20 (q, J= 7.28 Hz, 2H), 7.71-7.70 (m,

1H), 7.79-7.80 (m, 1H). ¹³C NMR (100 MHz, DMSO-d₆): 158.89, 112.37,

MHz, CDCl₃-d): δ 8.03-8.05 (m, 2H), 7.80-7.83 (m, 2H), 7.28-7.30 (m, 1H),

7.18-7.22 (m, 2H), 7.08-7.12 (m, 1H), 3.41 (s, 3H). ¹³C NMR (100 MHz, CDCl₃-

111.34, 44.11, 35.74, 15.08. HR-ESIMS (m/z): Calcd for [M+H]⁺C₆H₁₁N₃:

d): 152.20, 142.41, 138.86, 133.60, 133.57, 130.07, 127.57, 125.98, 125.95,

126.1026 observed value: 126.1031.

122.56, 121.54, 109.40, 108.59, 17.19. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₅H₁₁N₃O: 250.0975 observed value: 250.0975.

1-benzyl-3-methyl-1H-imidazol-2(3H)-imine (10c): The product was purified

by column chromatography on silica gel (eluent: DCM:MeOH:NH₄OH 8:2:1);

1-methyl-3-(4-nitrophenyl)-1H-benzo[d]imidazol-2(3H)-one (9k): The product

Yellowish solid. Yield: 251 mg, 81 %. ¹H NMR (400 MHz, CDCl₃-d₃): δ 7.42-

was purified by column chromatography on silica gel (eluent: EtOAc/hexane

2:3 to 8:2); Yellowish solid. Yield: 311 mg, 88 %. ¹H NMR (400 MHz, CDCl₃-d):

7.41 (m, 1H), 7.37-7.33 (m, 2H), 7.31-7.28 (m, 2H), 4.80 (s, 2H), 3.29 (s, 3H),

2.18 (s, 1H). ¹³C NMR (100 MHz, CDCl₃-d₃): 153.52, 137.14, 132.71, 128.84,

δ 8.40-8.42 (m, 2H), 7.90-7.92 (m, 2H), 7.20-7.32 (m, 3H), 7.10-7.14 (m, 1H),

3.42 (s, 3H). ¹³C NMR (100 MHz, CDCl₃-d): 152.42, 145.56, 140.80, 130.39,

128.64, 127.94, 127.84, 111.78, 109.98, 47.35, 30.61. HR-ESIMS (m/z): Calcd

127.66, 126.05, 125.13, 123.02, 121.87, 108.97, 108.95. HR-ESIMS (m/z):

for [M+H]⁺C₁₁H₁₃N₃: 188.1182 observed value: 188.1190.

Calcd for [M+H]⁺C₁₄H₁₁N₃O₃: 270.0873 observed value: 270.0885.

2-(2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)ethanol

(10d):

The

3-benzyl-1,5-dimethyl-1H-benzo[d]imidazol-2(3H)-one (9l): The product was

product was purified by column chromatography on silica gel (eluent:

DCM:MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 296 mg, 87 %. ¹H NMR

(400 MHz, CDCl₃-d₃): δ 6.24-6.21 (m, 1H), 6.16-6.12 (m, 1H), 4.95 (s, 2H),

3.66 (t, J= 6.00 Hz), 3.32 (s, 3H), 3.17 (s, 1H), 2.95 (t, J= 6.00, 2H). ¹³C NMR

(100 MHz, CDCl₃-d₃): 153.65, 111.63, 110.62, 46.69, 41.59, 30.54. HR-ESIMS

(m/z): Calcd for [M+H]⁺C₆H₁₁N₃O:142.0975 observed value: 142.0981.

purified by column chromatography on silica gel (eluent: EtOAc/hexane 2:3

to 7:3); Yellowish solid Yield : 329 mg, 95 %. H NMR (400 MHz, CHCl₃-d₃): δ

1

7.33-7.30 (m,4H), 7.28-7.23 (m,1H), 6.90 -.6.85 (m,1H), 2.39 (s,1H), 3.44

(s,1H), 5.06 (9s,1H), 6.70- 6.75 (m,1H),. ¹³C NMR (100 MHz, CHCl₃-d₃): 21.60,

21.62, 27.33, 27.39, 44.94, 45.05,107.28, 108.07, 108.30, 108.93, 121.88,

122.01, 127.20, 127.54, 127.59, 127.73, 128.18, 128.84, 128.86, 130.42,

131.22, 131.31, 136.65, 136.68, 154.90. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₆H₁₆N₂O 253.1335 observed value: 253.1346.

8 | J. Name., 2012, 00, 1-3

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ARTICLE

1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-imine (11a): The product was General Procedures for the synthesis of substituted imines (12a-d): To a

purified by column chromatography on silica gel (eluent: stirred solution of 3-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-3-ium

DCM:MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 250 mg, 85 %. ¹H NMR bromide (0.5 g, 1 equiv) in 30 mL of anhydrous MeOH, K₂CO₃(2 equiv),

(400 MHz, CHCl₃-d₃): δ 7.01-6.97 (m, 2H), 6.84-6.82 (m, 2H), 3.37 (s, 6H), molecular I₂(1 equiv) and substituted amines (1.2 equiv) were added and

2.85 (s, 1H). ¹³C NMR (100 MHz, CHCl₃-d): 156.00, 132.29, 120.64, 106.18, the resulting reaction mixture was heated at 50 °C for 2 to 3 h (depending

27.97. HR-ESIMS (m/z): Calcd for [M+H]⁺C₉H₁₁N₃: 162.1062 observed value: upon the nature of substituted amines). The progress of the reaction was

162.1069.

monitored by TLC by using MeOH:DCM (1:9) as a mobile phase. After the

completion of the reaction, all the volatile components were evaporated

under reduced pressure and the resulting residue was extracted with ethyl

acetate. Standard work-up procedure was followed (as mentioned above for

compounds 8 and 9) to obtain the crude products which were further

purified by column chromatography.

1-ethyl-3-methyl-1H-benzo[d]imidazol-2(3H)-imine (11b): The product was

purified by flash column chromatography on silica gel (eluent: DCM:

MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 270 mg, 89 %. ¹H NMR (400

MHz, DMSO-d₆): δ 8.63 (s, 1H), 7.57-7.54 (m, 1H), 7.53-7.50 (m, 1H), 7.31-

7.29 (m, 2H), 4.19 (q, J= 7.25 Hz, 2H), 1.26 (t, J= 7.25 Hz, 3H), 3.62 (s, 3H). ¹³

C

NMR (100 MHz, DMSO-d₆): 149.65, 130.41, 129.14, 123.15, 123.15, 123.09, 2-(2-(benzylimino)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanol

109.92, 109.75, 37.45, 29.30, 12.99. HR-ESIMS (m/z): Calcd for [M+H]⁺(12a): The product was purified by flash column chromatography on silica

C₆H₁₁N₃: 176.1182 observed value: 176.1176.

gel (eluent: MeOH/DCM/NH₄OH 3:96:1). White solid, Yield: 443 mg, 81 %. ¹H

NMR (400 MHz, DMSO-d₆): δ 7.47 -7.39 (m, 2H), 7.38-7.35 (m, 4H), 7.24-7.30

(m, 3H), 4.68 (t, J= 4.60, 2H), 4.08 (t, J= 4.60, 2H), 3.71 (s, 3H). ¹³C NMR (100

MHz, DMSO-d₆): 151.31, 137.57, 131.37, 129.95, 129.39, 128.21, 126.74,

125.04, 124.57, 110.24, 110.17, 59.82, 47.98, 46.84, 32.40. HR-ESIMS (m/z):

Calcd for [M+H]⁺C₁₇H₁₉N₃O: 282.1601 observed value: 282.1615.

1-benzyl-3-methyl-1H-benzo[d]imidazol-2(3H)-imine (11c): The product was

purified by column chromatography on silica gel (eluent: DCM:

MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 280 mg, 83 %. ¹H NMR (400

MHz, CDCl₃-d₃): δ 7.34-7.31 (m, 3H), 7.29-7.26 (m, 2H), 7.12-7.08 (m, 1H),

7.05-7.00 (m, 2H), 6.99-6.95 (m, 1H), 5.10 (s, 2H), 3.48 (s, 3H), 2.60 (s, 1H).

¹³C NMR (100 MHz, CDCl₃-d₃): 154.73, 136.51, 136.27, 132.37, 131.77, 2-(3-methyl-2-((4-methylbenzyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-

130.26, 128.86, 127.62, 121.46, 121.39, 108.34, 107.57, 45.08, 27.38. HR- yl)ethanol (12b): The product was purified by flash column chromatography

ESIMS (m/z): Calcd for [M+H]⁺C₁₁H₁₃N₃:238.1399 observed value: 238.1389.

2-(2-imino-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethanol (11d):

on silica gel (eluent: MeOH/DCM/NH₄OH 3:96:1). Reddish solid, Yield: 476

mg, 83 %. ¹H NMR (400 MHz, DMSO-d₆): δ 7.52-7.49 (m, 2H), 7.34-7.27 (m,

4H), 7.22-7.19 (m, 2H), 4.25 (t, J= 4.60, 2H), 3.73 (t, J= 4.60, 2H), 3.69 (s, 3H),

2.29 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): 150.85, 138.06, 134.06, 131.21,

130.01, 129.96, 129.61, 128.55, 126.83, 110.62, 110.56, 59.77, 47.75, 47.17,

32.82, 21.20. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₈H₂₁N₃O: 296.1757

observed value: 296.1757.

The product was purified by flash column chromatography on silica gel

1

(eluent: DCM: MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 334 mg, 90 %. H

NMR (400 MHz, MeOH-d₄): δ 7.52-7.49 (m, 1H), 7.48-7.46 (m, 1H), 7.38-7.32

(m, 2H), 4.35 (t, J= 5.00 Hz, 2H), 3.74 (t, J= 5.00, 2H), 3.69 (s, 3H). ¹³C NMR

(100 MHz, MeOH-d₄): 151.10, 130.39, 130.27, 121.69, 121.65, 108.83,

108.21, 58.19, 44.45, 28.33. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₀H₁₃N₃O: 2-(3-methyl-2-((4-nitrobenzyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-

191.1053 observed value: 191.1059.

yl)ethanol (12c): The product was purified by flash column chromatography

on silica gel (eluent: MeOH/DCM/NH₄OH 3:96:1). Brown solid, Yield: 327 mg,

79 %. ¹H NMR (400 MHz, CDCl₃-d): δ 7.36-7.24 (m, 5H), 7.13- 7.11 (m, 3H),

4.92 (s, 2H), 4.57 (t, J= 4.92 Hz, 2H), 4.05 (t, J= 4.92 Hz, 2H), 3.74 (s, 3H). ¹³C

NMR (100 MHz, DMSO-d₆): 149.92, 137.13, 133.12, 130.27, 129.08, 129.03,

128.68, 127.62, 125.90, 109.69, 58.83, 46.82, 31.89. HR-ESIMS (m/z): Calcd

for [M+H]⁺C₁₇H₁₈N₄O₃:327.1452 observed value: 327.1444.

1-(2-methoxyethyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-imine (11e): The

product was purified by flash column chromatography on silica gel (eluent:

DCM: MeOH:NH₄OH 8:2:1); Yellowish solid. Yield: 411 mg, 91 %. ¹H NMR

(400 MHz, MeOH-d₄): δ 7.36-7.33 (m, 1H), 7.32-7.30 (m, 1H), 7.23-7.20 (m,

2H), 4.22 (t, J= 5.64 Hz, 2H), 3.63 (t, J= 5.64, 2H), 3.55 (s, 3H), 3.21 (s, 3H). ¹³

NMR (100 MHz, MeOH-d₄): 152.76, 131.93, 131.62, 124.69, 124.59, 111.24,

110.57, 71.03, 59.39, 44.47, 29.67. HR-ESIMS (m/z): Calcd for [M+H]⁺2-(3-methyl-2-((tosylmethyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-

C

₁₁H₁₅N₃O: 206.1188 observed value: 206.1185.

yl)ethanol (12d): The product was purified by flash column chromatography

on silica gel (eluent: MeOH/DCM/NH₄OH 3:96:1). Red crystalline solid, Yield:

620 mg, 89 %. ¹H NMR (400 MHz, DMSO-d₆): δ 7.41-7.33 (m, 3H), 7.32-7.30

(m, 2H), 7.28-7.25 (m, 1H), 7.14-7.12 (m, 2H), 4.61 (t, J= 5.04, 2H), 4.07 (t, J=

5.04, 2H), 3.75 (s, 3H), 2.29 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆): 150.17,

134.90, 130.91, 130.14, 129.35, 129.15, 126.82, 123.91, 123.82, 111.14,

110.57, 58.57, 47.01, 46.11, 31.63, 20.69. HR-ESIMS (m/z): Calcd for [M+H]⁺

4-(2-imino-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzonitrile

(13a): The product was purified by flash column chromatography on silica

gel (eluent: EtOAc/hexane 2:3 to 8:2); Yellowish solid. Yield: 246 mg, 78 %.

¹H NMR (400 MHz, DMSO-d₆): δ 8.43-8.42 (m, 2H), 7.32-7.26 (m, 2H), 7.24-

7.20 (m, 1H), 7.14-7.11 (m, 1H), 3.42 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆):

152.18, 145.33, 140.57, 130.16, 127.45, 125.80, 124.87, 122.75, 121.60,

108.73, 108.68, 27.22. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₂N₄: 249.1135,

observed value: 249.1147.

C

₁₈H₂₁N₃O₃S: 360.1376 observed value: 360.1359.

General procedures for the synthesis of benzothiazolium and thiazolium

salts: Benzothiazolium or thiazolium chloride/bromide/iodide salts with

different substituents could be achieved as a white, off-white, or pale yellow

solid with moderate to good yield, by treatment of the thiazoles or

benzthiazole and suitable alkyl halides at room temperature to 80 °C using a

solvent-free ultra-sonication method as described by Hor el al.²²NMR data

(¹H and ¹³C NMR) for products were in good agreement with those

previously reported in the literature.

1-methyl-3-(4-nitrophenyl)-1H-benzo[d]imidazol-2(3H)-imine (13b): The

product was purified by flash column chromatography on silica gel (eluent:

EtOAc/hexane 2:3 to 8:2); Yellowish solid. Yield: 265 mg, 75 %. ¹H NMR (400

MHz, DMSO-d₆): δ 8.05-8.00 (m, 2H), 7.86-7.81 (m, 2H), 7.30-7.26 (m, 2H),

7.22 -7.18 (m, 2H), 7.08-7.12 (m, 1H), 3.41 (s, 3H). ¹³C NMR (100 MHz,

DMSO-d₆): 152.20, 138.87, 133.60, 133.08, 125.97, 122.56, 121.22, 119.99,

118.46, 117.06, 109.42, 108.57, 27.17. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₄H₁₂N₄O₂: 269.1033 observed value: 269.1021.

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General procedure for 2-thiazolones and 2-benzothiazolones (16a-k, 18a- 8.0 Hz, 1.0 Hz, 1H), 7.19-7.16 (m, 3H), 7.11-7.08 (m, 3H), 6.86 (d, J = 8.0 Hz,

b): To a one neck round bottom flask thiazolium/benzthiazolium salts (0.5 1H), 5.09 (s, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 170.21, 137.55,

g), 2 equiv of K₂CO₃and 1 equiv of molecular iodine were added in 20 mL of 136.93, 132.04, 129.46, 127.08, 126.22, 123.10, 122.52, 122.47, 111.21,

MeOH-H₂O (9:1) solution. The resulting solution was stirred for 15-30 min at 45.90, 21.02; HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₃NOS: 256.0791;

50 °C in an open atmosphere. The progress of the reaction was monitored Observed value 256.0785.

by TLC by using ethyl acetate/ hexane (1:9 v/v) as a mobile phase. All the

3,4-dimethylbenzo[d]thiazol-2(3H)-one (16h): The product was purified by

flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2:

3). Yield: 238 mg, 71 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J= 8.00 Hz, 1H),

7.01- 6.96 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ: 170.24, 145.11, 137.88,

137.80, 134.50, 133.66, 128.38, 49.16, 49.16, 25.16.

volatile components were evaporated under reduced pressure, and the

resulting residue was extracted with ethyl acetate. Standard work-up

procedure was followed (as mentioned above for compounds 8 and 9) to

obtain the crude products which were further purified by column

chromatography by using ethyl acetate/hexane as an eluent.

3,6-dimethylbenzo[d]thiazol-2(3H)-one (16i): The product was purified by

flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2:

3). Yield: 80 mg, 78 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.23 (s, 1H), 7.13 (d, J=

5.4 Hz, 1H), 6.92 (d, J= 5.4 Hz, 1H), 3.42 (s, 1H), 2.37 (s, 3H) ¹³C NMR (100

MHz, CDCl₃) δ: 170.15, 135.64, 133.15, 127.22, 122.88, 122.59, 110.25,

29.09, 21.19.

3-methylbenzo[d]thiazol-2(3H)-one (16a): The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 1: 44).

Yellow solid, Yield: 242 mg, 81 %. ¹H NMR (400 MHz, CDCl₃-d): δ 7.44-7.42

(m, 1H), 7.35-7.33 (m, 1H), 7.19-7.15 (m, 1H) 7.05-7.02 (m, 1H), 3.46 (s, 3H).

¹³C NMR (100 MHz, CDCl₃-d): 170.23, 137.90, 133.90, 126.51, 123.36,

122.68, 110.55, 110.55, 29.13.

3-benzyl-6-methoxybenzo[d]thiazol-2(3H)-one (16j): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 322 mg, 81 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.43

(m, 1H), 7.36-7.35 (m, 1H), 6.76-6.64 (m, 6H) 5.36 (s, 2H), 3.63 (s, 3H). ¹³C

NMR (100 MHz, CDCl₃) δ: 170.36, 158.65, 133.70, 133.31, 132.30, 128.50,

128.40, 127.61, 118.77, 117.66, 106.45, 55.62, 54.65; HR-ESIMS (m/z): Calcd

for [M+H]⁺C₁₅H₁₃NO₂S: 272.074; Observed value 272.072.

3-ethylbenzo[d]thiazol-2(3H)-one (16b): The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 1: 44).

Yellow solid, Yield: 305 mg, 83 %. ¹H NMR (400 MHz, DMSO-d₆): δ 7.67 –

7.60 (m, 1H), 7.41 – 7.27 (m, 2H), 7.23 – 7.14 (m, 1H), 3.97 (q, J = 7.2 Hz, 2H),

1.19 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): 168.53, 136.75,

126.83, 123.17, 121.80, 111.39, 37.41, 12.90.

3-benzylbenzo[d]thiazol-2(3H)-one (16c): The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 1: 44).

Colorless Oily mass, Yield: 312 mg, 79 %. ¹H NMR (400 MHz, DMSO-d₆): δ

7.57-7.55 (m, 1H), 7.33-33-7.31 (m, 1H), 6.90-6.81 (m, 2H), 6.54-6.52(m, 2H),

6.45-6.36 (m, 3H), 5.17(s, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 170.23,

140.02, 132.81, 131.85, 129.61, 129.10, 129.02, 128.46, 128.31, 125.47,

117.40.

6-methoxy-3-methylbenzo[d]thiazol-2(3H)-one (16k): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 298 mg, 75 %. ¹H NMR (400 MHz, CDCl₃) δ: 6.91-6.88

(m, 1H), 6.75 (d, J= 5.4, 1H), 6.58 (d, J= 5.4 Hz, 1H), 3.62 (s, 3H), 2.78 (s, 3H).

¹³C NMR (100 MHz, CDCl₃) δ: 169.66, 135.24, 128.36, 124.14, 121.29,

119.42, 115.99, 55.96, 31.73. HR-ESIMS (m/z): Calcd for [M+H]⁺C₉H₉NO₂S:

196.0427; Observed value 196.0422.

3-(2-hydroxyethyl)benzo[d]thiazol-2(3H)-one (16d): The product was purified

by flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane

1: 4). Reddish Oily mass, Yield: 196 mg, 82 %. ¹H NMR (400 MHz, DMSO-d₆):

7.57-7.55 (d, 1H), 745-7.43 (d, 1H), 6.94-6.83 (m, 2H), 3.97 (t, J= 5.00 Hz,

2H), 2.87 (t, J= 5.00 Hz, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 53.27, 56.63,

115.67, 123.59, 126.59, 127.71, 129.79, 138.68, 170.08. HR-ESIMS (m/z):

Calcd for [M+H]⁺C₉H₉NO₂S: 196.0427 observed value: 196.0431.

3-methylthiazol-2(3H)-one (18a): The product was purified by flash column

chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 216

mg, 85 %. ¹H NMR (400 MHz, CDCl₃) δ: 6.54 (d, J= 5.36 Hz, 1H), 6.11 (d, J=

5.36 Hz, 1H), 3.31(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 172.36, 125.46,

101.21, 32.21.

3-benzylthiazol-2(3H)-one (18b): The product was purified by flash column

chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 322

mg, 81 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.41-7.27 (m, 5H), 6.50 (d, J = 5.40

Hz, 2H), 6.11 (d, J= 5.40 Hz, 2H), 4.88 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ:

172.19, 129.20, 129.07, 128.28, 127.98, 111.24, 101.64, 48.69.

3-(2-methoxyethyl)benzo[d]thiazol-2(3H)-one (16e)²³

: The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yellow oil, Yield: 298 mg, 78 % ¹H NMR (400 MHz, CDCl₃-d ) δ:

7.40 (dd, J = 7.5 Hz), 1.0 Hz, 1H), 7.30 (td, J = 7.8 Hz, 1.0 Hz, 1H), 7.19-7.13

(m, 2H), 4.13 (t, J = 5.8 Hz, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.33 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃-d) δ: 170.13, 137.48, 126.17, 122.98, 122.45, 122.36

111.18, 69.80, 58.98, 42.72; HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₀H₁₁NO₂S:

210.0583; found 210.0581

1-benzyl-4-methyl-1H-1,2,4-triazol-5(4H)-one (20): The product was purified

by flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane

1

2: 3). Yield: 276 mg, 88 %. H NMR (400 MHz, CDCl₃) δ: 7.36- 7.27 (m, 6H),

4.95 (s, 2H), 3.30 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 153.66, 136.31,

136.06, 128.81, 128.36, 128.04, 49.46, 29.07. HR-ESIMS (m/z): Calcd for

[M+H]⁺C₁₀H₁₁N₃O: 189.0902; Observed value 189.0902.

3-(4-nitrobenzyl)benzo[d]thiazol-2(3H)-one (16f): The product was purified

by flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane

2: 3). Yield: 196 mg, 82 %. 298 mg, 78 %. ¹H NMR (400 MHz, CDCl₃) δ 8.18

(dd, J = 10.8, 9.0 Hz, 6H), 7.47 (dd, J = 12.7, 4.9 Hz, 9H), 7.28 – 7.21 (m, 4H),

7.18 (td, J = 7.6, 1.2 Hz, 3H), 6.88 (dd, J = 8.0, 0.7 Hz, 3H), 5.24 (s, 6H), 1.62

(s, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 170.33, 147.69, 142.44, 136.34, 127.91,

126.62, 124.24, 123.79, 123.00, 122.62, 110.78, 45.49.

3-methylbenzo[d]oxazol-2(3H)-one (22)²⁴: The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3).

Yield: 41 mg, 15 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.26-7.20 (m, 2H), 6.88-6.85

(m, 2H), 3.39 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 154.21, 144.06, 131.46,

124.06, 123.58, 110.94, 109.40, 29.21.

3-(4-methylbenzyl)benzo[d]thiazol-2(3H)-one (16g)²³

: The product was

General procedure for compounds 17a-f, 23a-b and 21: To a one neck

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 299 mg, 75 %. ¹H NMR (400 MHz, CDCl₃) δ: 7.36 (dd, J =

round bottom flask benzthiazolium / thiazolium / triazolium salts (0.5 g),

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K₂CO₃(2 equiv), and molecular iodine (1 equiv) were added in 40 mL of ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₄N2OS: 271.09; Observed value

anhydrous MeOH. 1.2 equiv of NaNH₂was added gradually to the above 271.0911.

reaction mixture at - 5 °C and the resulting solution was continued to stir for

3-methylthiazol-2(3H)-imine (19a): The product was purified by flash column

chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 191

mg, 76 %. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.58 (d,J = 4.5 Hz, 1H), 7.03 (d,

10-15 min at room temperature. The progress of the reaction was

monitored by TLC by using MeOH/ DCM/NH₄OH (1:9:1 v/v) as a mobile

phase. All the volatile components were evaporated under reduced

pressure, and the resulting residue was extracted with ethyl acetate.

Standard work-up procedure was followed (as mentioned above for

compounds 8 and 9) to obtain the crude products which were further

(d,J

=

4.5 Hz, 1H), 3.59 (s,3H). ¹³C NMR (100 MHz, DMSO-d₆) δ:

163.95,134.56, 111.56, 37.53. HR-ESIMS (m/z): Calcd for [M+H]⁺C₄H₆N₂S:

115.0324; Observed value 115.0319.

purified

by

column

chromatography

by

using

ethyl

3-benzylthiazol-2(3H)-imine (19b): The product was purified by flash column

chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 301

mg, 81 %. ¹H NMR (400 MHz, DMSO) δ 7.65 (m, 1H), 7.34-7.28 (m, 5H), 6.46

(m 1H), 5.39 (s, 2H).¹³C NMR (100 MHz, DMSO) δ ¹³C NMR (101 MHz,

DMSO) δ 163.85, 133.15, 128.71, 127.86, 127.54, 111.97, 51.55. HR-ESIMS

(m/z): Calcd for [M+H]⁺C₁₀H₁₀N₂S: 191.0637; Observed value 191.0630.

acetate/hexane/ammonium hydroxide as an eluent, or by using bulb-to-bulb

distillation at 70 ◦C/0.1 mbar.

3-methylbenzo[d]thiazol-2(3H)-imine (17a): The product was purified by

flash column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2:

1

3). Yield: 235 mg, 79 %. H NMR (400 MHz, DMSO-d₆) δ: 7.38-7.34 (m, 1H),

7.26-7.22 (m, 1H), 7.02- 6.96 (m,2H), 3.74 (s, 1H) ¹³C NMR (100 MHz, CDCl₃)

δ: 162.65, 140.41, 137.69, 135.69, 135.15, 133.77, 124.25, 111.70, 30.55.

HR-ESIMS (m/z): Calcd for [M+H]⁺C₈H₈N₂S: 165.0481; Observed value

165.0469.

1-benzyl-4-methyl-1H-1,2,4-triazol-5(4H)-imine (21): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 244 mg, 78 %. ¹H NMR (400 MHz, DMSO) δ: 7.93 (s, 1H),

7.39 – 7.19 (m, 5H), 4.86 (s, 2H), 3.19 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆)

δ: 153.13, 137.46, 137.14, 128.50, 127.49, 28.54. HR-ESIMS (m/z): Calcd for

[M+H]⁺C₁₀H₁₂N₄: 189.1135; Observed value 189.1135.

3-ethylbenzo[d]thiazol-2(3H)-imine (17b): The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3).

Yield: 285 mg, 78 %. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.04 -6.91 (m, 1H),

6.91-6.87 (m,1H), 6.70- 6.66 (m, 2H), 3.52 ( q, J= 7.2 Hz, 2H), 1.17 (t, J= 7.2

Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 163.55, 147.46, 138.10, 135.19,

133.21, 131.68, 122.22, 52.36, 23.14. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₉H₁₀N₂S: 179.0637; Observed value 179.0643.

General Procedures for the synthesis of substituted imines (23a and 23b):

To a stirred solution of 3-methylbenzo[d]thiazol-3-ium iodide (0.5 g, 1 equiv)

in 30 mL anhydrous MeOH freshly dried K₂CO₃(2 equiv), molecular I₂(1

equiv) and substituted amines (1.2 equiv.) were added at room temperature

and then the reaction mixture was stirred at 50 °C for 30-60 min (depending

upon the nature of substituted amines). The progress of the reaction was

monitored by TLC by using Ethyl acetate: hexane (1:9) as a mobile phase.

After the completion of the reaction, all the volatile components were

evaporated under reduced pressure and the resulting residue was extracted

with ethyl acetate. Standard work-up procedure was followed to obtain the

crude products which were further purified by column chromatography.

3-benzylbenzo[d]thiazol-2(3H)-imine (17c): The product was purified by flash

column chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3).

Yield: 299 mg, 76 %. ¹H NMR (400 MHz, DMSO) δ 7.39 (dt, J = 7.7, 4.8 Hz,

5H), 6.88 – 6.83 (m, 2H), 6.68 – 6.64 (m, 1H), 6.52 – 6.46 (m, 1H), 4.75 (s,

2H). ¹³C NMR (101 MHz, DMSO) δ 162.81, 153.70, 137.30, 136.70, 128.80,

126.54, 125.33, 122.80, 121.58, 112.91, 50.76. HR-ESIMS (m/z): Calcd for

[M+H]⁺C₁₄H₁₂N₂S: 241.0794 ; Observed value 241.0791.

N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-1-phenylmethanamine (23a): The

product was purified by flash column chromatography on silica gel (eluent:

Ethyl Acetate/ Hexane 2: 3). Yield: 372 mg, 81 %. ¹H NMR (400 MHz, CDCl₃)

δ 7.36 – 7.29 (m, 3H), 7.23 (dd, J = 7.8, 1.0 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H),

6.98 (td, J = 7.6, 1.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.42 (s, 2H), 3.48 (s, 3H),

2.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.00 (s), 141.33, 137.39, 136.34,

129.13, 127.60, 126.37, 122.55, 122.19, 120.85, 108.63, 58.03, 30.36, 21.25.

HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₄N₂S: 255.095; Observed value

255.0938.

6-methoxy-3-methylbenzo[d]thiazol-2(3H)-imine (17d): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 218 mg, 69 %. ¹H NMR (400 MHz, DMSO) δ 7.15 (s, 1H),

6.55 (d, J = 2.0 Hz, 2H), 6.32 (d, J = 1.1 Hz, 1H), 3.64 (s, 3H), 2.98 (s, 3H). ¹³

C

NMR (100 MHz, DMSO) δ 162.87, 156.92, 153.43, 131.44, 122.79, 112.59,

111.58, 108.75, 55.34, 35.63. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₄N₂S:

255.095; Observed value 255.0946.

3-benzyl-6-methylbenzo[d]thiazol-2(3H)-imine (17e): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 282 mg, 71 %. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.36 (s,

1H), 7.84 (s, 1H), 7.45-7.43 (m,1H), 7.39- 7.36 (m,2H), 7.33-7.21 (m, 4H),

5.60 (s, 2H), 2.35 (s, 3H) . ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.19, 136.01,

135.20, 133.44, 128.99, 128.67, 128.12, 126.69, 123.57, 122.40, 113.44,

47.77, 20.69. HR-ESIMS (m/z): Calcd for [M+H]⁺C₉H₁₀N₂OS: 195.0587;

Observed value 195.0579.

N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-1-(p-tolyl)methanamine (23b):

The product was purified by flash column chromatography on silica gel

(eluent: Ethyl Acetate/Hexane 2: 3). Yield: 401 mg, 83 %. ¹H NMR (400 MHz,

CDCl₃) δ 7.42 (d, J = 7.1 Hz, 2H), 7.36 – 7.30 (m, 3H), 7.26 – 7.22 (m, 2H), 6.98

(td, J = 7.6, 0.9 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 3.49 (s, 3H). ¹³

C

NMR (100 MHz, CDCl₃) δ 157.21, 141.31, 140.43, 128.47, 127.65, 126.83,

126.44, 122.52, 122.23, 120.95, 108.72, 58.13, 30.40. HR-ESIMS (m/z): Calcd

for [M+H]⁺C₁₆H₁₆N₂S: 269.1107; Observed value 269.1107.

3-benzyl-6-methoxybenzo[d]thiazol-2(3H)-imine (17f): The product was

purified by flash column chromatography on silica gel (eluent: Ethyl Acetate/

Hexane 2: 3). Yield: 265 mg, 66 %. ¹H NMR (400 MHz, CD₃OD-d₄) δ: 7.52-

7.51 (1H), 7.42-7.36 (m, 3H), 7.34-7.33 (m, 1H), 7.26 -7.24 (m, 2H), 7.09-7.07

(m, 1H), 5.56 (s, 2H), 3.85 (s, 3H). ¹³C NMR (100 MHz, CD₃OD-d₄) δ: 169.86,

159.69, 133.38, 130.36, 129.62, 127.51, 124.99, 116.69, 115.77, 108.70. HR-

Synthetic procedure of compounds 24 and 25: To a stirred solution of N-

methyl-imidazole (1 g, 12.17 mmol) or N-methyl-benzimidazole (1.6 g, 12.17

mmol) in a freshly dried THF (70 mL), 1.2 equiv of ehtylchloroformate (1.38

mL, 14.60 mmol) was added in a dropwise manner at 0 °C. An immediate

formation of white precipitate was observed and the reaction mixture was

kept under stirring for another 3-4 h for complete precipitation. White

precipitate was isolated, washed and further suspended in freshly dried 30

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mL of THF and into the above suspension 2.0 equiv of NEt₃(3.15 mL, 24.34 9) to obtain the crude product. The crude product was purified by flash

mmol) and 1 equiv of molecular iodine (3.08 g, 12.17 mmol) were added. 2 column chromatography to afford Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-

equiv of NaNH₂(951.45 mg, 24.34 mmol) was added gradually to the above imidazole-1-carboxylate

or

Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-

reaction mixture at 0 °C and the resulting solution was continued to stir for 6 benzo[d]imidazole-1-carboxylate (30) in pure form.

h at room temperature. The progress of the reaction was monitored by TLC.

To a stirred solution of Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1-

Solvent was evaporated under reduced pressure to afford the crude product

ethyl 2-imino-3-methyl-2,3-dihydro-1H-imidazole-1-carboxylate or ethyl 2-

carboxylate or Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-

carboxylate (30) in 50 mL methanol 6 (M) HCl (2 equiv) was added and kept

for stirring at room temperature for 8 h. The progress of the reaction was

monitored by TLC. Solvent was evaporated under reduced pressure and the

imino-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate.

product was used in next step without any further purification.

Crude

To the crude product (obtained in the previous step) dissolved in 50 mL resulting residue was extracted with ethyl acetate. The organic layer was

methanol in one neck round bottom flask, 2 equiv of HCl (6 M) was added washed with water (10 mL × 2), and brine (10 mL × 2). The combined organic

and stirred the reaction solution for 8 h at room temperature. The progress layer was finally dried over anhydrous Na₂SO_4;solvent was evaporated

of the reaction was monitored by TLC. Solvent was evaporated under under vacuum to afford the crude products which were purified by flash

reduced pressure and the resulting residue was extracted with ethyl column chromatography.

acetate. The organic layer was washed with water (10 mL × 2), and brine (10

1-methyl-1H-imidazol-2(3H)-one (28): The product 28 was purified by flash

column chromatography on silica gel (eluent: EtOAc/hexane 8:2); Yellowish

oily mass. Yield: 320 mg, 88 %. ¹H NMR (400 MHz, CDCl₃-d): δ 3.56 (s, 3H),

6.65 (s, 1H), 6.69 (s, 1H), 12.03 (s, 1H). ¹³C NMR (100 MHz, CDCl₃-d): 153.04,

mL × 2). The combined organic layer was finally dried over anhydrous

Na₂SO_4;solvent was evaporated under vacuum affording the crude products.

The product was purified by flash column chromatography.

1-methyl-1H-imidazol-2-amine (24): The product 24 was purified by flash 110.52, 106.10, 26.90. HR-ESIMS (m/z): Calcd for [M+H]⁺C₄H₆N₂O: 99.0553

column chromatography on silica gel. Yield: 1.6 g, 71 %. ¹H NMR (400 MHz, observed value: 99.0514.

CDCl₃-d): δ 10.60 (s, 1H), 7.28-7.27 (m, 1H), 6.15-6.14 (m, 1H), 3.25 (s, 3H).

¹³C NMR (100 MHz, CDCl₃-d): 154.9, 134.05, 127.49, 121.58, 121.52, 109.21,

1-methyl-1H-benzo[d]imidazol-2(3H)-one (29): The product 29 was purified

107.71, 29.71. HR-ESIMS (m/z): Calcd for [M+H]⁺C₄H₇N₃: 98.0713 observed

by flash column chromatography on silica gel (eluent: EtOAc/ hexane 8:2);

Yellowish solid. Yield: 398 mg, 90 %. ¹H NMR (400 MHz, CHCl₃-d): δ 3.72 (s,

value: 98.0718.

3H), 7.21-7.24 (m, 3H), 7.24-7.29 (m, 1H). ¹³C NMR (100 MHz, CHCl₃-d):

1-methyl-1H-benzo[d]imidazol-2(3H)-imine (25): The product 25 was purified 155.81, 131.77, 130.67, 122.75, 122.64, 109.05, 28.68. HR-ESIMS (m/z):

by flash column chromatography on silica gel (eluent: EtOAc/ hexane 8:2); Calcd for [M+H]⁺C₈H₈N₂O:149.0709 observed value: 149.0703.

Yellowish oily mass. Yield: 840 mg, 75 %. ¹H NMR (400 MHz, CDCl₃-d): δ 7.07-

7.15 (m, 3H), 6.67-6.69 (m, 1H), 3.42 (s, 3H). ¹³C NMR (100 MHz, CDCl₃-d):

General procedure for the synthesis of benzoimidazoloquinazolinones

(32a-k): To the solution of N-substituted benzimidazole (500 mg, 1 equiv) in

ACN-THF (1:1) 1.2 equiv of substituted 2-aminobenzoyl chloride was added

at room temperature and stirred for 4 h in an open atmosphere to obtain

154.9, 134.05, 127.49, 121.58, 121.52, 109.21, 107.71, 29.71. HR-ESIMS

(m/z): Calcd for [M+H]⁺C₈H₉N₃: 148.0869 observed value: 148.0862.

Synthetic procedure of compounds 26²⁵and 27^6b: Synthesis of compound the corresponding benzimidazolium salts. After completion of the reaction,

26 has been achieved by following same procedure as descried above for solvent was removed and the crude salts were isolated and further dissolved

compounds 24 and 25. The product 26 was purified by flash column in MeOH for intramolecular cyclization reaction without further purification,

chromatography on silica gel (eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 241 as mentioned below. Briefly, to the methanolic solution of benzimidazolium

mg, 54 %. ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J = 4.59, 1H), 6.49 (d, J = 4.57, salt 2 equiv of K₂CO₃and 1 equiv I₂were added and the reaction mixture was

1H), 5.4 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): 168.5, 138.6, 108.3. HR-ESIMS stirred overnight at 60 °C. The progress of the reaction were monitored by

(m/z): Calcd for [M+H]⁺C₃H₄N₂S: 101.0168; Observed value 101.0173.

TLC in ethylacetate-hexane (1:4) as a mobile phase. Standard work-up

procedure was followed (as mentioned above for compounds 8 and 9) to

obtain the crude product which was further purified by column

chromatography.

The product 27 was purified by flash column chromatography on silica gel

(eluent: Ethyl Acetate/ Hexane 2: 3). Yield: 277 mg, 59 %. ¹H NMR (400

MHz, CDCl₃) δ 7.57 (dd, J = 19.4, 7.9 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.13 (t, J

= 7.5 Hz, 1H), 5.38 (s, 2H). ¹³C NMR (100 MHz, DMSO) δ 166.45, 152.84, 6-methylbenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)one (32a): The product

130.94, 125.44, 120.85 (d, J = 6.7 Hz), 117.75. HR-ESIMS (m/z): Calcd for was purified by flash column chromatography on silica gel (eluent:Ethyl

[M+H]⁺C₇H₆N₂S: 151.0324; Observed value 151.0318.

acetate:Hexane 1:20); Yellowish solid. Yield: 707.27 g, 75 %. ¹H NMR (400

MHz, CDCl₃-d): δ 8.65-8.66 (m, 1H), 8.42-8.40 (m, 1H), 7.76-7.72 (m, 1H),

7.67-7.66 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.32 (m, 2H), 7.29-7.27 (m, 1H),

3.81 (s, 3H). ¹³C NMR (100 MHz, CDCl₃-d): 160.14, 149.31, 146.90, 134.61,

132.42, 127.19, 126.23, 125.92, 125.64, 123.11, 122.35, 116.87, 116.82,

107.99, 28.32. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₁N₃O: 250.0975

observed value: 250.0975.

Synthetic procedure of compounds 28 and 29: To a stirred solution of N-

methyl-imidazole (0.2 g, 2.45 mmol) or N-methyl benzimidazole (0.32 g, 2.45

mmol) in freshly dried THF (20 mL) 1.2 equiv of ethyl orthoformate (0.22 mL,

2.94 mmol) was added slowly at 0 °C. An immediate formation of white

precipitate was observed and the reaction mixture was kept under stirring

for another 3 h for complete precipitation of corresponding salt.¹⁷White

precipitate was isolated, washed and further dissolved in 30 mL of THF-H₂O 2-bromo-6-methylbenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32b): The

product was purified by flash column chromatography on silica gel

(eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield 526 mg, 72 %. ¹H

NMR (400 MHz, CDCl₃-d): δ 3.95 (s, 3H), 6.70-6.72 (m, 1H), 6.75-6.80 (m,

1H), 7.09-7.13 (m, 1H), 7.55-7.59 (m, 1H), 7.72-7.74 (m, 1H), 8.06-8.09 (m,

1H), 8.81-8.83 (m, 1H). ¹³C NMR (100 MHz, CDCl₃-d): 160.15, 157.95, 157.17,

(9:1). Into the above solution 2.0 equiv of NEt₃(654 ꢁL, 4.9 mmol) and 1

equiv of molecular iodine (2.45 mmol, 0.620 g) were added and the resulting

reaction mixture was kept under stirring for another 6 h to complete the

reaction. The progress of the reaction was monitored by TLC. Standard

work-up procedure was followed (as mentioned above for compounds 8 and

12 | J. Name., 2012, 00, 1-3

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138.79, 130.91, 123.58, 121.86, 111.95, 111.33, 109.47, 106.51, 105.94, 123.69, 125.15, 125.79, 126.42, 128.56, 140.46, 150.36, 159.53. HR-ESIMS

104.73, 104.31, 27.29. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₅H₁₀BrN₃O: (m/z): Calcd for [M+H]⁺C₁₅H₁₀ClN₃O:284.0585 observed value: 284.0584.

328.008 observed value: 328.0091.

6-benzyl-3-chlorobenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32h):The

9-chloro-6-ethylbenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32c): The product was purified by flash column chromatography on silica gel

product was purified by flash column chromatography on silica gel (eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 1.26 g, 68 %. ¹H

(eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 423 g, 69 %. ¹H NMR (400 MHz, CDCl₃-d): δ 8.61-8.59 (m, 1H), 8.32-8.30 (m, 1H), 7.66-7.65

NMR (400 MHz, CDCl₃-d): δ 8.56-8.54 (m, 1H), 8.40-8.37 (m, 1H), 7.75-7.71 (m, 1H), 7.40-7.37 (m, 3H), 7.35-7.30 (m, 4H), 7.29-7.28 (m, 1H), 7.20-7.18

(m, 1H), 7.64-7.62 (m, 1H), 7.36-7.32 (m, 1H), 7.30-7.27 (m, 2H), 4.33 (q, J= (m, 1H), 5.46 (s, 2H). ¹³C NMR (100 MHz, CDCl₃-d): 159.91, 150.31, 147.33,

7.25 Hz, 2H), 1.50 (t, J= 7.25, 3H). ¹³C NMR (100 MHz, CDCl₃-d): 159.97, 140.68, 135.24, 131.51, 129.10, 128.50, 128.33, 127.71, 126.34, 125.93,

149.31, 146.30, 134.68, 132.61, 132.00, 127.13, 125.93, 124.70, 123.37, 125.34, 125.93, 125.34, 123.73, 122.65, 116.44, 115.43, 109.01, 45.82. HR-

122.20, 117.23, 116.94, 108.48, 37.29, 13.29. HR-ESIMS (m/z): Calcd for ESIMS (m/z): Calcd for [M+H]⁺C₂₁H₁₄ClN₃O: 360.0898 observed value:

[M+H]⁺C₁₆H₁₂ClN₃O:298.0742 observed value: 298.0746.

360.0887.

6-benzyl-9-chlorobenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32d): The 6-benzyl-9-nitrobenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32i): The

product was purified by flash column chromatography on silica gel product was purified by flash column chromatography on silica gel

(eluent: Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 1.04 g, 71%. ¹H (eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 570 mg, 78 %. ¹H

NMR (400 MHz, CDCl₃-d): δ 8.69-8.68 (m, 1H), 8.43-8.41 (m, 1H), 7.78-7.74 NMR (400 MHz, CDCl₃-d): δ 5.46 (s, 2H), 6.92-6.97 (m, 1H), 7.14-7.16 (m,

(m, 1H), 7.68-7.66 (m, 1H), 7.37-7.32 (m, 7H), 7.06-7.04 (m, 2H), 5.48 (s, 2H). 1H), 7.27-7.37 (m, 1H), 7.41-7.43 (m, 1H), 7.58-7.63 (m, 1H), 7.63-7.68 (m,

¹³C NMR (100 MHz, CDCl₃-d): 160.03, 150.86, 147.85, 141.21, 135.76, 1H), 8.63-8.65 (m, 1H). ¹³C NMR (100 MHz, CDCl₃-d): 160.37, 151.20, 141.60,

132.03, 129.62, 129.02, 128.85, 128.24, 126.86, 126.46, 125.86, 125.86, 133.13, 129.40, 127.26, 126.63, 125.99, 124.53, 123.49, 117.28, 116.12,

124.25, 123.18, 116.97, 115.95, 109.53, 109.53, 46.34. HR-ESIMS (m/z): 109.04, 29.19.

Calcd for [M+H]⁺C₂₁H₁₄ClN₃O:360.0898 observed value: 360.0902.

6-benzyl-1-fluorobenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32j): The

6-(2-(dimethylamino)ethyl)benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one

product was purified by flash column chromatography on silica gel

(32e): The product was purified by flash column chromatography on silica (eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 610 mg, 74 %. ¹H

gel (eluent: MeOH/ DCM 3:97); Yellowish solid. Yield: 664 82 %. ¹H NMR NMR (400 MHz, CDCl₃-d): δ 8.80-8.68 (m,1H), 7.68-7.63 (m, 1H), 7.48-7.46

(400 MHz, DMSO-d₆): δ (8.46 -8.44), 8.22- 8.20 (m,1H), 7.77-7.73 (m, 1H), (m, 1H), 7.42-7.40 (m, 1H), 7.38-7.32 (m, 1H), 7.21-7.19 (m, 1H), 7.02-6.97

7.63-7.56 (m,1H), 7.51-7.47 (m, 1H), 7.34-7.30 (m, 2H), 4.36 (t, J= 6.20 Hz, (m, 1H), 6.72-6.70 (m, 1H), 5.49 (s, 2H). ¹³C NMR (100 MHz, CDCl₃-d): 161.36,

2H), 2.72 (t, J= 6.20 Hz, 2H), 2.22 (s, 6H). ¹³C NMR (100 MHz, CDCl₃-d): 151.65, 147.21, 135.61, 134.67, 134.56, 131.52, 129.12, 128.32, 127.66,

160.37, 151.20, 141.60, 133.13, 129.40, 127.26, 126.63, 125.99, 124.53, 126.33, 126.11, 122.76, 121.81, 116.68, 109.30, 108.99, 45.81. HR-ESIMS

123.49, 117.28, 116.12, 109.14, 29.19. HR-ESIMS (m/z): Calcd for [M+H]⁺(m/z): Calcd for [M+H]⁺C₂₁H₁₄FN₃O: 344.1194 observed value: 344.1177.

C

₂₁H₁₄N₄O₃: 371.1139 observed value: 371.1133.

Gram Scale synthesis of 1-(2-hydroxyethyl)-3-methyl-1H-benzo[d]imidazol-

6-(2-hydroxyethyl)benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32f): The 2(3H)-one (9f): Into an 500 mL one neck round bottom flask 3-(2-

product was purified by flash column chromatography on silica gel hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-3-ium bromide (13g, 50.55

(eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 654 mg, 76%. ¹H mmol) was dissolved in 250 mL of MeOH-H₂O (9:1) solution. 2 equiv of

NMR (400 MHz, CDCl₃-d): δ 8.64-8.62 (m, 1H), 8.41-8.39 (m, 1H), 7.75-7.71 K₂CO₃( 13.97 g, 101.1 mmol) and 1 equiv of molecular iodine (12.83g, 50. 55

(m, 1H), 7.46-7.38 (m, 1H), 7.36-7.33 (m, 2H), 4.59 (t, J= 6.32 Hz, 2H), 4.04 mmol) were added gradually in to the above reaction solution and stirred

(t, J= 6.32, 2H). ¹³C NMR (100 MHz, CDCl₃-d): 160.02, 149.12, 146.24, 134.60,

for 2 h at 40 °C. The progress of the reaction was monitored by TLC by using

131.96, 127.17, 126.23, 125.97, 125.84, 123.38, 122.54, 117.18, 116.49,

108.43, 44.11, 41.02. HR-ESIMS (m/z): Calcd for [M+H]⁺C₁₆H₁₃N₃O₂:

280.1081 observed value: 280.1072.

ethylacetate/Hexane (1:1) as a mobile phase. Standard work-up procedure

was followed to obtain the yellowish brown solid crude product which were

further purified by column chromatography (ehtylacetate/Hxane: 7:3. Yield:

9.97 g, 93 % (yellowish flaky solid).

1-fluoro-6-(2-hydroxyethyl)benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one

(32g): The product was purified by flash column chromatography on silica

gel (eluent:Ethyl acetate/ hexane 2:98); Yellowish solid. Yield: 730 mg, 79 %.

¹H NMR (400 MHz, DMSO-d₆): δ 8.48 -8.46, 7.73- 7.65 (m, 2H), 7.53-7.49 (m,

1H), 7.40-7.33 (m, 1H), 7.51-7.47 (m, 1H), 7.08-7.03 (m, 1H), 4.33 (t, J= 6.20

Hz, 2H), 3.85 (t, J= 6.20 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃-d): 162.83, 151.38,

146.85, 134.75, 134.64, 132.31, 126.1, 125.25, 122.53, 121.81, 121.48,

115.13, 109.98, 108.61, 58.28, 44.59. HR-ESIMS (m/z): Calcd for [M+H]⁺

C₁₆H₁₂FN₃O₂: 298.0986 observed value: 298.0981.

Gram Scale synthesis of 1,3-dimethyl-1H-imidazol-2(3H)-imine (10a): To a

250 mL one neck round bottom flask 1,3-dimethyl-1H-imidazol-3-ium iodide

(2 g, 8.92 mmol), K₂CO₃(2 equiv, 2.46 g, 17.84 mmol), and molecular iodine

(1 equiv, 2.26 g, 8.92 mmol) were added in 100 mL of anhydrous MeOH. 1.2

equiv of NaNH₂(418 mg, 10.70 mmol) was added gradually to the above

reaction mixture at 0 °C and the resulting solution was continued to stir for

another 2 h at room temperature. The progress of the reaction was

monitored by TLC using ethylacetate/Hexane (1:1) as a mobile phase. All the

volatile components were evaporated under reduced pressure, and the

resulting residue was extracted with ethyl acetate. Standard work-up

procedure was followed to obtain the yellowish brown solid crude product

which was further purified using flash chromatography (ehtylacetate/Hxane:

8:2). Yield: 785 mg, 79 % (yellowish oil).

3-chloro-6-methylbenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (32k): The

product was purified by flash column chromatography on silica gel

(eluent:Ethyl acetate:Hexane 1:20); Yellowish solid. Yield: 588 mg, 75%. ¹H

NMR (400 MHz, CDCl₃-d): δ 3.80 (s, 3H), 7.28-7.30 (m, 2H), 7.33-7.38 (m,

1H), 7.47-7.51 (m, 4H), 7.64-7.65 (m, 1H), 8.30-8.32 (m, 1H), 8.60-8.62 (m,

1H). ¹³C NMR (100 MHz, CDCl₃-d): 28.35, 108.20, 115.28, 116.44, 122.65,

Gram Scale synthesis of 6-benzyl-9-chlorobenzo[4,5]imidazo[2,1-

b]quinazolin-12(6H)-one (32d): To a stirred solution of solution of -benzyl-5-

J. Name., 2013, 00, 1-3 | 13

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chloro-1H-benzo[d]imidazole (1.3 g, 20.62 mmol) in xx mL ACN-THF (1:1) 1.2

equiv of 2-aminobenzoyl chloride (6.0 g, 24.74 mmol) was added at room

temperature and stirred for 4 h in an open atmosphere to obtain the

corresponding benzimidazolium salts. The progress of the reaction was

monitored by TLC in ethyl acetate/ hexane (8:2). After completion of the

reaction, solvent was removed and the crude salts were isolated and further

dissolved in MeOH for intramolecular cyclization reaction without further

purification, as mentioned below. Briefly, to the methanolic solution of

The authors declare no competing ﬁnancial interest and no conflicts

to declare.

Acknowledgements

This work is supported by SNU and SERB (SB/S1/IC-44/2013),

Govt. of India. We thank to Prof. Rupamanjari Ghosh (VC, SNU)

benzimidazolium salt 2 equiv of K₂CO₃(5.6 g, 41.24 mmol) and 1 equiv I₂for support and helpful conversations. RD carried out all

(5.23 g, 20.62 mmol) were added and the reaction mixture was stirred

overnight at 60 °C. The progress of the reaction were monitored by TLC in

ethylacetate-hexane (1:4) as a mobile phase. Standard work-up procedure

was followed (as mentioned above) to obtain the crude product. The crude

product was purified by flash column chromatography on silica gel (eluent:

EA/ Hex 1:19 to 1:9). Yield: 5.3 g yellowish white flaky solid was obtained

with 71 %.

syntheses and characterization. RD, RKR, RK, and MB

performed DFT calculations and solved X-ray structures.

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Table of Content:

We report metalꢀfree oneꢀpot C2−H oxidation, imination, and amination of several azoles from azolium salts by using commercially available

simple and efficient reagent combination K₂CO₃/I₂.

Article Doi

Metal-free C(sp2)-H functionalization of azoles: K2CO3/I2-mediated oxidation, imination, and amination

DOI: 10.1039/c8ob00535d

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c8ob00535d

Full text of DOI:10.1039/c8ob00535d

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R&D Labs maybe for 92852-08-9

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Aminomethylation of formononetin and cladrin by primary amines

Base-promoted selective activation of benzylic carbon-hydrogen bonds of toluenes with rhodium(III) porphyrin chloride: Synthetic scopes and mechanism

Synthesis and biological activity research of novel ferrocenyl-containing thiazole imine derivatives

Decarboxylative aldol-type reaction of 2-(trifluoroacetyl)-1,3-diazoles with activated acetic acids

Anion-ligand interaction in binuclear cyclic dimer complex of a tribenzo-S₂O₂ macrocycle with silver(I) picrate

Pt^II-mediated nitrile-tetramethylguanidine coupling as a key step for a novel synthesis of 1,6-dihydro-1,3,5-triazines

Article Doi

Metal-free C(sp2)-H functionalization of azoles: K2CO3/I2-mediated oxidation, imination, and amination

DOI: 10.1039/c8ob00535d

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c8ob00535d

Full text of DOI:10.1039/c8ob00535d

Products guided by the article

R&D Labs maybe for 92852-08-9

Relevant to this article

Aminomethylation of formononetin and cladrin by primary amines

Base-promoted selective activation of benzylic carbon-hydrogen bonds of toluenes with rhodium(III) porphyrin chloride: Synthetic scopes and mechanism

Synthesis and biological activity research of novel ferrocenyl-containing thiazole imine derivatives

Decarboxylative aldol-type reaction of 2-(trifluoroacetyl)-1,3-diazoles with activated acetic acids

Anion-ligand interaction in binuclear cyclic dimer complex of a tribenzo-S2O2 macrocycle with silver(I) picrate

PtII-mediated nitrile-tetramethylguanidine coupling as a key step for a novel synthesis of 1,6-dihydro-1,3,5-triazines

Anion-ligand interaction in binuclear cyclic dimer complex of a tribenzo-S₂O₂ macrocycle with silver(I) picrate

Pt^II-mediated nitrile-tetramethylguanidine coupling as a key step for a novel synthesis of 1,6-dihydro-1,3,5-triazines