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Chapter 7

Selective Mono-Methylation of Arylacetonitriles and Methyl Arylacetates by Dimethylcarbonate

Downloaded by NORTH CAROLINA STATE UNIV on September 5, 2012 | http://pubs.acs.org Publication Date: May 5, 1996 | doi: 10.1021/bk-1996-0626.ch007

A Process without Production of Waste Pietro Tundo, Maurizio Selva, and Carlos A. Marques Dipartimento di Scienze Ambientali dell'Universitá di Venezia, Calle Larga S. Marta 2137, Venice 30123, Italy

The reaction of arylacetonitriles and methyl arylacetates with dimethylcarbonate (DMC) at 180-220 °C in the presence of a weak base ( K C O ) , produces the mono-methylderivatives (2arylpropionitriles and methyl 2-aryl propionates, respectively) with a selectivity higher than 99%. This reaction has a wide range of applications since the products obtained are well known intermediates for non-steroidal antiinflammatory drugs. Contrary to the usual methylating agents (methylchloride and dimethyl sulfate), the reaction with the non-toxic D M C takes place with only a catalytic amount of the base; accordingly, no inorganic salts are produced. The reaction proceeds both under continuous-flow and batchwise conditions. The mechanism is discussed. 2

3

The direct mono-alkylation of methylene-active compounds by common alkylating agents (alkyl halides and dialkyl sulfates) is not a facile reaction and generally cannot be run as a one-step process because considerable amounts of dialkylderivatives form, especially where the methylation reaction is concerned (1). Moreover, the reaction is of a relevant environmental concern; besides the use of highly toxic reagents, alkyl halides and dialkyl sulfates, stoichiometric quantities of inorganic salts are generated as wastes to be disposed of. The methylation of arylacetonitriles ArCH2CN (1) and methyl arylacetates ArCH2COOCH3 (2) has been widely explored; in fact, the corresponding mono-methylated derivatives, 2arylpropionitriles ArCH(CH3)CN (3) and methyl 2-arylpropionates ArCH(CH3)COOCH3 (4), are intermediates for the synthesis of 2-arylpropionic acids, well-known as non-steroidal antiinflammatory agents (2). Even under phasetransfer catalysis conditions, the direct methylation is poorly selective (3-4). For instance, the reaction of phenylacetonitrile with CH3I carried out under liquid-liquid phase-transfer catalysis (LL-PTC) produces a mixture

0097-6156/%/0626-0081$12.00/0 © 1996 American Chemical Society In Green Chemistry; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996.

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of the starting reagent and the mono- and di-methylated derivatives (6, 66 and 28%, respectively) from which the mono-methyl product cannot be separated because of the closeness of the relative boiling points (5). Conversely, the use of the nontoxic dimethylcarbonate allows the methylation of both compounds (1) and (2) to proceed with a selectivity (>99%) not previously observed affording monomethyl derivatives in a high purity, with no by-products.


The Reactions of Dimethylcarbonate D M C is an environmentally safe reagent now produced by the oxidative carbonylation of methanol (Equation 1) by Enichem (Italy) (6). Cu salts

2 C H O H + V4 O2 + C O 3

> H3COCOOCH3 + H 0

(1)

2

Under batchwise conditions, D M C is a carboxylating agent when reacted with nucleophiles at reflux temperature (90 °C) in the presence of bases (Equation 2) (710):

YCOOCH3 + CH3O-

(2)

However, operating at high temperatures (>160 °C), D M C can be used as an excellent methylating agent. The methylation reaction prevails over carboxymethylation since the former is not an equiHbrium reaction. In the methylation reaction, the nucleophilic anions attack the methyl group (instead of the acyl carbon) by a mechanism. The leaving group (methoxycarbonate anion, CH3OCOO") is not stable and rapidly decomposes into methanol and CO2. Thus, the base can be used in catalytic amounts because the methoxide anion is regenerated (Equation 3).

YCH3

+ CH3O- + CQ2 (3)

In Green Chemistry; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996.

7. TUNDO ET AL.

Selective Mono-Methylation by Dimethylcarbonate

83


In particular, the methylation reactions by D M C can be run in the presence of weak bases (e.g. alkaline carbonates). However, since high reaction temperatures are necessary to exploit the methylating properties of D M C , new methodologies have been developed to perform the reaction under both continuous-flow (cf.) and batchwise conditions. Continuous-Flow Methylations of Dimethylcarbonate. D M C can be used profitably for carrying out methylation reactions under Gas-Liquid Phase-Transfer Catalysis (GL-PTC) conditions (77). GL-PTC is a recentiy reported synthetic method which allows reactions between activated anions and a gaseous organic substrate to be performed under a continuous-flow mode. This technique uses a solid-supported phase-transfer (PT) catalyst which becomes liquid at the reaction temperature; the reactions occur with both the reagents and the products in the gas phase through their continuous transfer between the gas and the catalytic liquid phases. In a typical configuration, a liquid mixture of the reagents is sent continuously to a simple cylindrical catalytic column (plug-flow reactor) where it is vaporized; gaseous products are collected at the outlet of the reactor by a condenser (Figure 1).

c

p

Figure 1. GL-PTC Apparatus: R, reagent's reservoir; P, metering pump; T, thermostat; C, condenser; P \ product storage.

When using D M C , polyethylene glycols (PEGs) are the PT-catalysts of choice (72); although less efficient than other PT-catalysts (onium salt, crown ethers, cryptands), PEGs are environmentally desirable because they are non-toxic and inexpensive (13-15). Under such conditions, in the presence of alkaline carbonates, D M C reacts with methylene-active compounds selectively to give the corresponding mono-methylderivatives. PEGs complex alkaline metal cations so that the basic strength of alkaline carbonates is increased; thus, anionic nucleophiles (conjugate bases of the CH2-acidic substrates) may be produced in the reaction environment and react with D M C as shown in Equation 3. For example, working at 180 °C and atmospheric pressure, by sending a liquid mixture of D M C and phenylacetonitrile or (p-isobutylphenyl)acetonitrile (substrate / D M C in a 1 : 4


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molar ratio; flow rate 8 ml/h) on a 100-g catalytic bed composed of 5% P E G 6000 and 5% K2CO3 supported on CI-AI2O3, the corresponding 2-phenylpropionitrile or 2-(p-isobutylphenyl)propionitrile are obtained with 99% selectivity at >95% conversion (Equation 4) (16). The 2-^-isobutylphenyl)propionitrile product is an important intermediate; its hydrolysis affords 2-(p-isobutylphenyl)propionic acid, better-known commercially as Ibuprofen, the antiinflammatory drug. Noteworthy is the fact that these reactions produce no hazardous waste. Conversely from the methylations with dimethyl sulfate or methylchloride where a base is also used as a reagent resulting in the generation of stoichiometric quantities of inorganic salts, the reactions of D M C use a catalytic base; CO2 does not involve disposal problems and the co-product methanol can be easily recycled for D M C production. Actually, these reactions are of a significant environmental interest; they favorably couple safe reaction conditions (c.-f.) to the use of a nontoxic methylating agent in a waste-free process.

+ C0

2

(4)

X = H, p-isobutyl Under the same conditions, D M C also reacts with primary aromatic amines and phenols to selectively give mono-N-methylated anilines and anisoles, respectively (17,18). However, reactions performed with GL-PTC require the reagents to be vaporized and therefore, can be performed only if the compounds have a relatively high vapour pressure. This difficulty can be overcome by reacting D M C under batchwise conditions. Batchwise Methylations of Dimethylcarbonate. Because D M C boils at 90° C and is a methylating agent only when operating at high temperatures, the batch reactions are necessarily carried out in an autoclave. In a typical experiment, a magnetically stirred mixture of the substrate, D M C and K2CO3 (in a 1 : 18 : 2 molar ratio, respectively) is heated in a stainless-steel autoclave, itself heated by an electrical oven. The reaction temperature is checked by a thermocouple dipped into the reaction mixture. Under such conditions, operating at temperatures ranging from 180 to 220 °C (autogenic pressure: 6 to 12 bar), a number of arylacetonitriles and methyl arylacetates have been reacted with D M C ; the reaction yielded the corresponding mono-methyl derivatives (2-arylpropionitriles and methyl 2arylpropionates) with selectivity >99%, (Equation 5 and Table I) (19-20) as in G L PTC reactions.


In Green Chemistry; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996. 1

5

6

6

5

5

6

6

2

5

6

5

5

6

6

5

10

6

5

6

Ar = Ph Ar = o - M e O C H AT = /w-MeOC H Ar = / ? - M e O C H AT = o - M e C H Ar = / ? - M e C H Ar=/?-ClC H Ar=/>-FC H Ar = / w - M e 0 C C H A r = Ph Ar = 2-(6-MeOC H )

CN CN CN CN CN CN CN CN CN COOMe COOMe

c

100 100 100 99 99 98 100 100 100 99 100

3.75 14.5 3.5 4.75 7.5 7.5 2.25 2.75 8.00 8.00 6.00

X

b

Conv'n. (%)

Reaction Time/h

2

3

6

6

6

5

2

5

6

6

6

5

6

5

5

5

5

10

6

5

6

Ar = Ph (90) Ar = o - M e O C H (85) Ar = m-MeOC H (80) A r = / ? - M e O C H (88) Ar = o - M e C H (82) Ar = o - M e O C H (80) A r = / 7 - C l C H (89) Ar=/>-FC H (81) A r = / w - M e 0 C C H (91) Ar = Ph (80) Ar = 2-(6-MeOC H ) (90)

c

Product ArCHfCHJX (%Yield)

A l l reactions were carried out in an autoclave and using substrate, D M C and K C 0 in a 1 : 1 8 : 2 molar ratio, respectively. Entries 1-9: reactions carried out at 180 °C; entries 10-11: reactions carried out at 220 °C. Conversions determined by GC. Yields based on distilled (entries 1-10) or recrystallized (entry 11) products.

a

1 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

2

Substrate ArCH X

Table I. Selective Mono-methylation of Arylacetonitriles and Methyl Arylacetates by Dimethylcarbonate*


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base

A r C H X + CH3OCOOCH3 2

•> A r C H ( C H ) X + CH3OH + C 0 3

2

(5)


X = C N , COOCH3 Two products obtained by this reaction, (m-carboxymethylphenyl)propionitrile and methyl 2-(6-methoxy-2-naphthyl)propionate (entries 9 and 11, Table I), are intermediates for the preparation of the analgesics Ketoprofen and Naproxen (Figure 2), respectively. In particular, the synthesis of Ketoprofen by D M C has been also scaled up in a pilot plant by Tessenderlo Chemie in Belgium (19).

Ketoprofen

Naproxen

Figure 2. Non-Steroidal Antiinflammatory Agents of the Hydratropic Acids Group.

Batchwise methylation by D M C requires no PT-catalysts, and the base can be employed in a catalytic amount (0.05 mol equivalents with respect to the substrate). Other alkaline carbonates are also effective catalytic bases, their efficacy being clearly related to their solubility in D M C . For example, in using bases from N a C 0 3 to C s C 0 3 , the solubility in D M C increases from 0.26 to 0.6 g/L; likewise, the reaction time for the methylation of phenylacetonitrile by D M C at 180°C decreases from 8.75 to 5.75 h, respectively (20). The most active base is that in which cation-anion interactions are the poorest and, therefore, a "naked" anion may form (21). However, selectivity always remains high. Stronger bases such as phosphazene derivatives (22), also promote the reaction but selectivity is lower (Table n). D M C can be used in a large excess (10-30 molar excess), thus acting both as the methylating agent and the solvent; actually, it has also proved to be the better solvent for these reactions. No improvements in the reaction rate are observed using apolar (cyclohexane), protic polar (methanol) or aprotic polar (DMF) solvent; in particular, the reaction rate is dramatically lowered in cyclohexane solvent (scarce solubility of K C 0 3 ) , while selectivity is decreased in D M F solvent (Table HI). 2

2

2


87

Selective Mono-Methylation by Dimethylcarbonate

7. TUNDO ETAL.

Table II. Methylation of Phenylacetonitrile with D M C using Different Bases in Catalytic Amounts. 3

b


Base

1. 2. 3. 4. 5. 6.

0

Solubility (gIL)

Ii C0 Na2C03 K C0 CS2CO3 Phosphazene P\ Phosphazene P4 2

3

2

3

0.20 0.26 0.58 0.64

6

Selectivity (%)

Conv'nA (%)

Reaction Time Ih

>99.5 >99.5 >99.5 >99.5 82.0

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