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207

CHAPTER-6 (PART C)

Methylation of selective N-heterocycles and thiol by a green

protocol using dimethylcarbonate in ionic liquid

Introduction

Methylation of nitrogen atoms is a versatile biological process. There are so

many examples where a methylated product plays an important role in the field of

medicinal and biological chemistry. Some examples are methylation of cytosine in

CpG dinucleotide which governs eukaryotic gene control,1 methylation of

norepinephrine catalysed by a transmethylase that utilizes S-adenosylmethionine as

a methyl group donor to produce epinephrine which is reported to be a

catecholamine neurotransmitter.2 The process of methylation of biomolecules in

nature plays an important role and utilizes enzymes in a highly efficient way even if

the process involves the inactivated methyl donors. It has already been established

that methylated product and hence the process of methylation is one of the

important task in the field of biochemistry as well synthetic organic chemistry as

multiple applications of the resultant methylated products such as N-methyl indole,

N-methyl imidazoles, N-methylbenzimidazoles, N-methylbenzinilide, O-methylthiol

etc. have been reported. Sometimes, introduction of an alkyl/methyl group in

heterocycles become necessary to block the NH- group so as to facilitate organic

transformations in some other part of molecule undergoing transformation. It can be

mentioned that methylation is a popular method of masking the reactivity of the

amino or the imino group in a molecule.

N-methylindole is the common nucleus of indole alkaloids and show wide

range of biological activities. Affinisine, (Figure 6C.1) a indole alkaloid has been

isolated as one of the minor constituents from Alstonia macrophylla Wall3 and

Peschiera affinis Muell. Arg. Which is responsible for marked CNS depressant

208

activity, ataxia, hypothermia and bradypnea if taken in high doses.4 Many naturally

occurring substances with N-substituted indole having wide spectrum of biological

activity such as inhibitors of enzyme activity,5 anti-inflammatory, analgesic, anti-

rheumatic and anti-hypertensive efficacies.6

Figure 6C.1

N-methyl imidazoles and related derivatives have been used as mimic for a

diverse imidazole based biomolecules. These are used as intermediate for the

synthesis of agrochemicals, pharmaceuticals, ion exchange resins, dyes and

photographic chemicals. N-methylimidazole is also the precursor and the monomer

for the synthesis of pyrrole-imidazole polyamides which can selectively bind

specific sequences of double-stranded DNA by the process of intercalation in a

sequence dependent manner.7 N-methylimidazole is used as cocatalyst for the

synthesis of cyclic carbonates from carbon dioxides and epoxides.8

N-methylimidazole is also a promising catalyst for aza-Michael reaction. Moreover,

N-methylimidazole is an important substance for the synthesis of ILs and several

reports are available wherein a variety of imidazole derivatives have shown

excellent properties on ILs with important end use in green synthetic methodology.9

The amide moiety, one of the most important structural fragment and plays a

key role in the molecular recognition events or biological activities.10

Studies on the

stereochemistry of amide bonds are important not only in pure chemistry but also in

biological and medicinal chemistry. For example, N-methylated aromatic anilide

derivatives has potent retinoidal activity however due to the structural change of the

NN

H

OH

Me

H

HH

209

amide stereochemistry from trans to cis upon methylation, the potency may be

varied or fine tuned.

In a similar manner methylthioethers and their derivatives are also

established as biologically important compounds, notably in the amino acid

methionine and the cofactor biotin (Figure 6C.2). Methylthioethers are involved in

the synthesis of specific classes of compounds which are basically agricultural

chemical, pharmacological drugs, property-enhancing additives, chemical resistant

polymers, rubber antioxidants and detergents.

Figure 6C.2

Methionine Biotin

Despite the importance of methylated heterocycles (N, S methylated heterocycles)

the procedure for methylation have not always been easy and cost effective. In some

cases the yields of the desired product have been found to be low. Only a few reports

appear in literature reporting a successful, selective and high yielding procedure

which is also environmentally benign.

NHHN

S

HH

O

H

(CH2)4COOH

H3C S

H2C CH2

COOH

H2N H

210

6C.1.1. N-alkylation of indole and its derivatives

Generally alkylation of indole is accomplished by using a two step

procedure

1. Formation of an active indole anion by a stoichiometric amount of strong base and

2. Reaction of the resulting anion with a toxic and hazardous reagent such as methyl

iodide and dimethylsulphate.

The classical method for the formation of N-methylindole derivative from indole

included the use of variety of bases, such as NaH,11

NaNH2,12

KOH and NaOH.13

The use of strong bases is suitable for the process of methylation of indoles having

certain other functional groups and experimental procedure as well as work up

could be laborious and time consuming. Reaction conditions also required special

care to avoid hydrolysis. To avoid these limitations different techniques for

promotion of this reaction have been explored but the numbers of such reports are

limited. In 2002, W.-C. Shieh et al. had reported the use of DABCO

(1,4-diazabicyclo[2.2.2]octane) as the nucleophilic catalyst and dimethylcarbonate

(DMC) as methylating agent for N-methylation of indole.14

They have also

investigated the methylation rate of 5-bromoindole in presence of different base and

concluded that DBU gave N-acylated product (84%) rather than N-methylated

product (6%) but DABCO gave selectively only N-alkylated product. In another

reported method K2CO3 and zeolite (13X and NaY) was used to promote the

reaction with DMC and using DMF as the solvent and found that K2CO3 has a

distinct advantage over zeolite as only catalytic amount of K2CO3 is and this could

be easily removed from the reaction mixture by the addition of water.15

The

methylation reactions with the above mentioned reagents was tried out with a variety

of indole derivatives having both the O- and N- containing functional groups and

observed that both the O-methylated and the N-methylated derivatives were

obtained and selectivity was at a minimum. Y. R. Jorapur et al. also used K2CO3 as a

base for N-alkylation of indole and pyrrole using the IL, [bmim][BF4] as the

reaction medium and acetonitrile as co solvent.16

Dialkyl oxalate was also used for

alkylation of indole and other N-heterocycles in presence of potassiumalkoxide and

211

dimethyl formamide.17,18

An interesting method for N-alkylation of heterocycles

specially indoles, is reported by P Hamel et al. wherein they used dimethyl 3,3'–

dithiodipropionate for generation of methyl acrylate in situ and used for alkylation

via the introduction of a propionate moiety onto N-heterocycles in the initial step

followed by its displacement by the methyl group in subsequent steps 19

(Scheme

6C.1). Interestingly this process is not only applicable to indole but also to other N-

heterocycles such as carbazole, norharman (pyrido[3,4-b]-indole), imidazole and

benzimidazole.

Scheme 6C.1

NH

S

S

COOMe

COOMeN

COOMe

+NaH or KH

DMF

Dimethyl 3,3'–dithiodipropionate 3-indolyl propionate

Tetraalkylammonium salt20

and crown ether21

have also been used as catalyst for

promotion of alkylation of indole and other N-heterocycles.

6C.1.2. N-alkylation of imidazole and its derivatives

At this stage it is necessary to mention that the methods for the catalytic

synthesis of alkylimidazole have rarely been reported. Industrially 1-methyl

imidazole are prepared by following two procedures.

1. Acid catalyst methylation of imidazole with methanol

2. From glyoxal, formaldehyde and a mixture of ammonia and methylamine.

Wallach et al. reported that N,N-dimethyloxamide reacted with phosphorous

pentachloride to form a chlorine containing compound which on reduction with

hydroiodic acid give N-methyl imidazole22

(Scheme 6C.2). Zeolite23

and calcined

212

Mg-Al layered double hydroxides24

were the promoters used for the first time for a

gas phase catalytic alkylation of imidazole with alcohols. Mg-Al mixed oxide was

found to be efficient catalyst for the synthesis of 1-methylimidazole by a gas phase

alkylation procedure.25

W.C. Guida et al. reported the alkylation of various

heterocycles including imidazole, benzimidazole, indole and others by a phase

transfer alkylation process where they used 18-crown-6 as catalyst, potassium tert-

butoxide as the base and methyl iodide as methylating agent.26

Scheme 6C.2

NHCH2R

O NHCH2R

O

N

N

Cl

R

CH3

N

N

CH3

R

PCl5+HI

The application of IL, [bmim]BF4 in the process of alkylation was reported by Z.-G.

Le et al. wherein they carried out a selective N-alkylation of heterocyclic

compounds with imido (-NH-) group such as phthalimide, indole, succinimide,

benzimidazole and others in presence of potassium hydroxide as a base and alkyl

halide as methylating agent27

(Scheme 6C.3).

Scheme 6C.3

NH

Y

N

Y

X-RKOH

[bmim]BF4, 3-4 h

R

Y: N, CH

+

213

6C.1.3. Synthesis of methylthioethers by methyaltion of thiols

Typically thioethers are prepared by the alkylation of thiols using alkyl

halides in presence of base which converts the thiol into the more nucleophilic

thiolate. Similarly, the reaction of disulfides with organolithium reagents produces

thioethers. Thioether can also be prepared by the addition of a thiol to an alkene,

catalysed by free radicals. Interestingly, T.E Banks et al. applied O-methylisourea as

the alkylating agent and found this procedure to be effective for selective alkylation

of thiol groups in proteins.28

An important procedure where the IL, [bmim]Cl was

used as the solvent as well as a catalyst for methylation of thiols with dimethyl

carbonate as the methylating agent is also reported.29

In may well be mentioned that N- and S- methylation of heterocycles and

thiols have not been given the importance it deserves going by the limited number of

reports available in literature. Further in the limited number of reports that have

appeared in literature, the DMC have not been used as a popular methylating agent.

It is also worthwhile to mention that there is no general and unified synthetic

protocol which may be utilized for the synthesis of N- methylated heterocycles.

Therefore, the aim of the present study is for the development of a cognate or

a general as well as a green method for methylation which can be used for the

synthesis of both the N- methylated heterocycles and S- methylated thiols using the

environmentally benign reaction condition, the use of cheap reagent such as DMC

and the use of IL instead of the toxic VOCs. With this aim in view, methylation of

various heterocycles were tried with DMC as the methylating agent and by using the

1-butyl-4-methyl pyridinium bromide IL as the medium for the reaction. No solvents

were found to be necessary. Considering the fact that reports of N-methylation of

nitrogen heterocycles and thiols using DMC are few and far between, it may well be

mentioned that the present methods may have considerable acceptability. ILs have

been used earlier in a few reports of the synthesis of a few individual N-methylated

214

heterocycles but the ILs also demands the requirement of bases and VOCs to

promote the reactions.

6C.2. Materials and methods

It has already mentioned that there have very few references regarding the

synthesis of N-methylated heterocycles, although these products are found to be

important in various fields. The reported methods also cannot satisfy the demand of

the modern synthetic methods which lay emphasis on the greenness of the procedure

and mild reaction conditions. From a survey of associated literature, it is evident

that most of the reported procedures are non catalytic processes that employed

highly reactive and toxic methylating agents. In some cases hazardous and

carcinogenic dipolar aprotic organic solvent are also used as reaction medium and

the reactions are carried out under harsh and noncatalytic condition. Almost all the

reported methods are found to be unattractive because of the requirement of long

reaction time (4-72 h). Furthermore, most of the catalyst used could not be

recovered and reused and finally work up procedures has been reported to be tedious

and time consuming. To overcome the reported disadvantages, herein a procedure

has been developed for N-methylation of various heterocycles using nontoxic

chemicals and environmentally safe technique. An attractive feature of this

procedure is that it can be generally applied for the synthesis of all types of N-

methylated heterocycles.

Here, selective N-methylation of different compounds were carried out by

using the IL namely 1-butyl-4-methyl pyridinium bromide as the promoter and

DMC as the methylating agent. The reaction was carried out by thermal heating

without the use of VOCs as the cosolvent. In case of indole and skatole, it was

observed that the rate of the reaction and the yield of the products depend on the

amount of IL used and the temperature of the reaction. One equivalent of IL was

used and the reaction mixture was heated to 170oC. The presence of methyl group in

3 position as in the case of skatole (3-methylindole) did not effect the reaction as

more or less same yield percentage was observed for the products obtained that is,

215

1-methyl indole and 1,3-dimethyl indole under similar reaction conditions. In case of

N- methylation of imidazole and benzimidazole, reactions carried out at 170 °C

resulted in some amount of by products which could not be isolated and

characterized. In order to minimize side products or to eliminate their formation

altogather, the reaction temperature was varied and it was observed that no side

products were obtained at the optimum temperature of 130 °C. Incidentally, the

synthesis of methyl phenyl thioether by the process of methyaltion of thiophenols

under similar conditions required a reaction time of 5 hours and a high temperature

of about 180 °C for complete conversion. At 110 °C, benzanilide gave the N-methyl

benzanilide in good yield. In all cases, product recovery was simple. The results

obtained in this study are summarized in Table 6C.1, the details of experiments

carried out are described in experimental section. The reactions carried out are

given in Scheme 6C.4. All the synthesized products were properly characterized by

applying spectroscopic methods like NMR and Mass spectroscopy. The 1H and

13C

spectra of 1, 3-dimethylindole is shown in Figure 6C.(3-4) and a Mass spectrum of

N-methylbenzanilide is shown in Figure 6C.5.

Scheme 6C.4

+ + +

NBr

NH

RO O

O N

R

CH3

170oCCH3OH CO2

R = H, CH3; Yield= 73-75%

Selective N-methylation of indole and skatole with DMC

+ + +N

BrO O

O 130oC

CH3OH CO2

N

N

NH

N

CH3

Yield= 72%

Selective N-methylation of imidazole

216

+ + +

NBr

O O

O 130oCCH3OH CO2

NH

N

N

N

CH3

Yield= 70%

Selective N-methylation of benzimidazole

++ +

NBr

O O

O 110oC

CH3OH CO2

HN

O

N

O

CH3

Yield= 70%

Selective N-methylation of benzinilide

+ + +

NBr

O O

O 180oCCH3OH CO2

SH SCH3

Yield= 98%

Selective N-methylation of thiophenol

217

Table 6C.1: N-, S- and O-methylation using DMC, promoted by IL.

Entry Substrate Product Temperature

(°C)

Time

(h)

Yielda

(%)

1 Indole N-methylindole 170 2 75

2 Skatole N-methylskatole 170 2 73

3 Benzimidazole N-

methylbenzimidazole

130 3 70

4 Benzanilide N-methylbenzanilide 110 1 70

5 7-hydroxy-3-

methylcoumari

ne

7-methoxy-3-

methylcoumarine

170 2 75

6 Thiophenol Methylphenyl

thioether

180 5 98

7 Imidazole N-methylimidazole 130 3 72

a. Yields refers to pure isolated products

218

Figure 6C.3

1H NMR Spectra of 1,3-dimethylindole

Figure 6C.4

13

C NMR Spectra for 1,3-dimethylindole

N

CH3

CH3

N

CH3

CH3

219

Figure 6C.5

Mass spectra of N-methylbenzanilide

N

O

CH3

220

6C.3. Conclusion

In conclusion, it can be mentioned that a general method have been

developed for the N-methylation of nitrogen hetereocycles. The reaction conditions

involved the use of the IL as the promoter and DMC as the methylating agent. As no

volatile organic compounds need to be used as a cosolvent, the reactions conditions

are environmentally benign. The yields of the products were high and recovery was

found to be simple. The products were obtained more or less in the pure form as

formation of by products was not observed.

6C.4. Experimental section

Melting points were recorded in a VMP-D model Melting point apparatus

and are uncorrected. 1H-NMR and

13C-NMR spectra were recorded in a Bruker

Advance digital 300 MHz spectrometer in CDCl3. In both the recordings TMS was

used as the internal standard. Mass spectra were recorded in a Perkin Elmer Clarus

600 Gas Chromatograph and Clarus 600C Mass Spectrometer (Column used Elite

5MS). The IL is prepared by a procedure given in Chapter 2. The substrate

heterocycles were purified by established procedures before use and the thiols were

used as received. The products were purified by column chromatography.

6C.4.1. Selective N-methylation of indoles, imidazole, benzimidazole

and benzanilide: General procedure

A mixture of 1mmol of reactant (indole, imidazole, benzimidazole,

benzinilide), 1 mL DMC and 1mmol of IL were taken in a 10 mL RBF, and placed

in an oil bath fitted with a reflux condenser. The reaction mixture was heated to 110-

170 °C for varying period of time as indicated in Table 6C.1. On completion of

reaction, monitored by TLC using ethyl acetate and petroleum ether (60-80 °C), the

reaction mixture was extracted with diethyl ether (5mL x 3), washed with water,

dried with anhydrous Na2SO4 and solvent removed by distillation. The crude

221

product was purified by column chromatography on silica gel column and ethyl

acetate-petroleum ether as eluent.

6C.4.2. Selective S-methylation of thiophenol: General procedure

A mixture of 3 mmol of thiophenol, 3 mL DMC and 3 mmol of IL was taken

in a 25 mL RBF, and placed in an oil bath fitted with a reflux condenser. The

reaction mixture was heated to 180 °C for 5 hour. On completion of reaction, as

indicated by TLC using ethyl acetate and petroleum ether (60-80 °C), the product

was obtained by simple decantation of the thioanisole which was found to be

insoluble in the reaction medium. The recovered product was washed with water,

dried with anhydrous Na2SO4 give to the product in the pure form.

222

6C.4.3. Spectral data

1-methylindole

Deep yellow viscous liquid.

1H NMR (300 MHz, CDCl3, TMS) δH: 7.706 (d, 1H, J = 7.8 Hz,

ArH), 7.390 (d, 1H, J = 7.8 Hz, ArH), 7.297 (t, 1H, J = 8.4 Hz,

ArH), 7.183 (t, 1H, J = 7.8 Hz, ArH), 7.104 (d, 1H, J = 2.7 Hz,

ArH), 6.557 (d, 1H, J = 2.7 Hz, ArH), 3.833 (s, 3H, NCH3).

13C NMR (75 MHz, CDCl3, TMS) δ: 136.56, 128.70, 128.35, 121.37, 120.76,

119.15, 109.09, 100.76, 32.71.

GC/Ms m/z (relative intensity): 131 ([M]+) (62), 130 (100), 128 (14), 116 (24), 103

(36), 102 (15), 90 (22), 89 (53), 77 (41), 65 (61), 63 (35).

1,3-dimethylindole

Liquid.


ArH), 7.445-7.330 (m, 3H, ArH), 6.955 (s, 1H, ArH), 3.841 (s,

3H, NCH3), 2.547 (s, 3H, CH3).


118.50, 110.00, 109.02, 32.37, 9.58.

GC/Ms m/z (relative intensity): 145 ([M]+) (56), 144 (100), 143 (8), 128 (8), 115 (8),

102 (7), 77 (11), 73 (9), 28 (28).

N

Me

N

Me

Me

223

1-methyl benzimidazole

Mp: 59-62 °C.

1H NMR (300 MHz, CDCl3, TMS) δH: 8.326 (s, 1H, ArH),

7.860 (d, 1H, J = 6.6 Hz, ArH), 7.465-7.364 (m, 3H, ArH),

3.933 (s, 3H, NCH3).

13C NMR (75 MHz, CDCl3, TMS) δ : 138.83, 123.63, 123.06, 119.18, 109.67, 29.56


(10), 63 (12).

N-methyl benzanilide

Mp: 58-60 °C.

1H NMR (300 MHz, CDCl3, TMS) δH: 7.299-7.018 (m, 10H,

ArH), 3.495 (s, 3H, NCH3).


129.06, 128.92, 128.60, 127.65, 127.10, 126.81, 126.43, 124.34, 120.24, 38.34.


(62), 77 (98), 51 (56).

7-methoxy-3-methyl coumarine

Mp: 144 °C.


ArH), 6.875-6.812 (m, 2H, ArH), 6.131 (s, 1H, ArH), 3.867

(s, 3H, OCH3), 2.395 (s, 3H, CH3).

N

N

Me

N

O

CH3

O OCH3

H3C

O

224


114.12, 112.26, 111.87, 100.75, 55.70, 18.67.


(13), 51 (12).

Methyl phenyl thioether

Colourless liquid.

1H NMR (300 MHz, CDCl3, TMS) δH: 7.393-7.335 (m, 5H,

ArH), 2.524 (s, 3H, SCH3).

13C NMR (75 MHz, CDCl3, TMS) δ: 128.59, 128.48, 126.25, 124.71, 15.47.


69 (16), 65 (33), 51 (36).

1-methyl imidazole

Light yellow liquid.

1H NMR (300 MHz, CDCl3, TMS) δH: 7.292 (s, 1H, alkenyl H),

6.913 (d, 1H, J = 0.6 Hz, alkenyl H), 6.761 (d, 1H, J = 0.6 Hz,

alkenyl H), 3.553 (s, 3H, NCH3).

13C NMR (75 MHz, CDCl3, TMS) δ: 137.44, 129.04, 119.75, 32.91.


42 (59), 41 (42), 40 (57), 28 (61), 27 (32), 26 (30).

S

Me

N

N

Me

225

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