O-Methylation of Phenol with Dimethylcarbonate derived Methylating agentsThis article has been mentioned at the Hive before
Post 220907 (missing)
(moo: "Re: Dimethylcarbonate", Chemistry Discourse)Post 426189
(Vitus_Verdegast: "Methylation of phenols using DMC and a PTC", Novel Discourse)but for some dark reasons nobee posted it before (although the article is for free).
SynLett, 2002, 2, 272-274
DOI:10.1055/s-2000-6488
Alkyl Methyl Carbonates as Methylating Agents.
The O-Methylation of PhenolsAlvise Perosa, Maurizio Selva,* Pietro Tundo,* Francesco Zordan
Dipartimento di Scienze Ambientali dell¡¯Universit¨¤ Ca¡¯ Foscari, Dorsoduro 2137, 30123, Venezia, Italy
Fax +39-41-2578620; E-mail: selva@unive.it / tundop@unive.it
Received 19 December 1999
Abstract: The O-methylation reaction of a variety of phenols (ArOH: Ar = Ph, p-CH
3C
6H
4, p-ClC
6H
4, o- and p-CH
3COC
6H
4, and 2-naphthyl) can be conducted in a highly selective manner by using asymmetric alkyl methyl carbonates CH
3OCOOR (R = n-Pr,
3b; n-Bu,
3d; CH
3O(CH
2)
2O(CH
2)
2,
3e) as alkylating agents. For example, at 150°C, phenol can be quantitatively converted into anisole in 4.5 h, using 2-(2-methoxyethoxy)ethyl methyl carbonate
3e in the presence of K
2CO
3 as a catalyst. Compared to the methylation reactions using dimethyl carbonate which require sealed pressurized reaction vessels, asymmetric alkyl methyl carbonates allow much simpler and safer alkylations at ambient pressure.
The selectivity towards O-methylation is scarcely affected by the temperature (in the range of 120-150°C), while it depends on the nature and on the amount of the solvent. DMF and triglyme (triethylene glycol dimethyl ether) have proven to be the better reaction media.
Key words: alkyl carbonates, O-alkylation, methyl selectivity, anisoles, methylation,
DMCThe methylating reactivity of dimethyl carbonate (DMC) has been studied by our group since the middle eighties. As a methylating reagent, DMC can replace undesirable and non-selective methyl halides (CH
3X; X = Cl, Br, I; 1) and dimethylsulfate (CH
3OSO
3CH
3; DMS,
2).
1-5 With respect to these compounds, DMC has the great advantage of being environmentally benign, since it is:
(i) non toxic,
(ii) efficient and selective as methylating reagent,
(iii) it originates only methanol as co-product which can be recycled
for the production of DMC, and
(iv) it is now synthesized from methanol rather then from hazardous
phosgene.
6-7 We have extensively reported that operating at high temperatures (>= 160°C), under both continuousflow (c.-f.) and batch conditions, DMC allows the highly chemoselective methylation of phenols to yield the corresponding anisoles (Scheme 1; (a)).
8-9 Even more importantly, DMC permits the highly selective mono-C-methylation of CH
2-acid compounds (i.e. aryl and aryloxy-acetic acid derivatives or benzylic sulfones), and the mono-N-methylation of primary aromatic amines (Scheme 1; (b) and (c), respectively).
10-15The alkylations of Scheme 1 can be performed without solvent and with a catalytic amount of base (M
2CO
3: M = Li, Na, K, and Cs; Y zeolites). It was also shown, by us and by others,
6, 10, 16 that the use of Cs
2CO
3 improves the rate of the reaction thanks to its higher solubility in DMC,
10 though we still think that its cost is a limitation.
However, a major operative drawback of DMC-mediated methylations, is determined by the reaction temperature (>=120°C) which is well over the 90°C boiling point of DMC. Consequently, pressurized vessels (autoclaves) fitted with CO
2 purging valves, are necessary under batch conditions;
10-15 while, under c.-f. conditions, substrates must have a relatively high vapor tension in order to be fed into suitable plug-flow reactors.
1, 2, 8To overcome such difficulties, we conceived the use of asymmetric alkyl methyl carbonates (ROCOOCH
3,
3) as possible methylating agents: a suitable R group would have increased the boiling point of the carbonate to allow reactions at ambient pressure, and simultaneously, the steric bulk of the R moiety would have favored anisoles towards the competitive formation of alkyl aryl ethers (ArOR).
We report here that a very good chemoselectivity (>99%) in the O-methylation of phenols can be obtained at atmospheric pressure with compounds
3, provided that the R substituents are linear alkyl groups possessing at least 3 carbon atoms (Scheme 2).
[Graphic, not displayable]
Methylation patterns with DMC
Scheme 1Ar-OH + ROCOOCH
3 -----K
2CO
3---> Ar-OCH
3 + ROH + CO
2Scheme 2The required alkyl methyl carbonates
3 were synthesized according to established procedures, by reacting the appropriate alcohols with methyl chloroformate (compounds
3a-c),
17 or DMC (compounds
3d-g).
18, 19Phenol was chosen as the model nucleophilic substrate based on our earlier reports of carbonate-mediated alkylations.
8-9 The reactions were carried out at 120°C, using phenol, carbonate
3, and potassium carbonate in a 1: 5: 1.1 molar ratio, and DMF as the solvent (100 mL/g phenol).
The results are reported in Table 1.20 In the case of compounds
3a-e, the reported methylating reactivity and selectivity seem to be well explainable by steric factors:
21-23 in fact, although the reaction of phenol with carbonates
3b-d affords anisole with a very high yield (95-97%, entries 2-4), the methyl chemoselectivity is even more improved (>99%), using compound
3e with the more hindered oxyethylenic chain (entry 5).
While in the case of compounds
3f-g, the observed drop in the O-methylation selectivity (PhOR: 16 and 17% for
3f and
3g, respectively; entries 6-7), is likely ascribable to resonance effects which favor S
N2 displacements for both allylic and benzylic systems.
24In the case of
3c, the obtained O-methyl selectivity is high, but the reaction stops at a 75% conversion of phenol even after prolonged reaction times (entry 3). We suggest that such a behavior is due to the co-product i-propyl alcohol (Scheme 2) which, rather than undergoing transesterification with the organic carbonate (slower for secondary alcohols
25), presumably inhibits anisole formation by limiting the availability of phenoxide through solvation.
As we already observed for DMC-mediated mono-C-methylations,
10 also the outcome of the investigated reaction is affected by the solvent polarity: under the conditions of entry 5 of Table 1, by increasing the amount of DMF from 2 to 10 mL, the formation of anisole increases as well from 90 to >99%, respectively. Instead, the O-methyl selectivity shows no dependence from the reaction temperature:
by progressively raising it from 120 to 150°C, the reaction rate increases as well (complete phenol conversion is achieved after 20 and 4.5 h, respectively), but anisole is the sole product in any case. The effect of solvent polarity is also evident by using different solvents, such as diglyme (
5a), triglyme (
5b), diethylene glycol diethyl ether (
5c), and polyethylene glycol 250 dimethyl ether (
5d) which are suitable anion activating media to perform the present alkylation reactions,
9,25,26 and allow to operate at higher temperatures in the 140-170°C range (except for
5a, bp = 162°C).
27 With respect to DMF, a decrease in the O-methyl selectivity is observed for glycols
5a, 5c,d (anisole/PhOR in 9:1 molar ratio at complete conversion); only
5b (triglyme) affords good selectivity, yielding 98% anisole after 10 h at 140°C.
To extend the synthetic applicability of the investigated methylation procedure,
3e was treated with different phenols
6, on a larger scale (2-5 g) than that considered previously (PhOH: 0.3 g). All reactions were carried out at 140°C in the presence of triglyme, using the substrate, K
2CO
3, and
3e in a 1: 1.1: 5 molar ratio, respectively.
Only for the case of phenol, the reaction was also performed using DMF as the solvent. Table 2 shows the results.
28In all cases, the reaction proceeds with a very high methyl chemoselectivity (95-99%), and good yields in isolated products (80-86%), except for p-chloroanisole (60%, entry 4). Entry 6 refers to a mixture of a o- and p-acetylphenol
6e (in a 4.5: 5.5 ratio, respectively) and the yield is that of the isolated mixture of o- and p-acetyl anisoles.
In conclusion, alkyl methyl carbonates ROCOOCH
3 3, efficiently perform the O-methylation of phenols under very simple conditions and at ambient pressure.
In particular: At T>=120°C, the reaction of
3 with phenols affords the corresponding anisoles with a methyl chemoselectivity >95%, provided that a bulky linear R group with at least 3 carbon atoms is present.
The solvent polarity has a significant effect on the reaction selectivity: better reaction media have proven to be polar aprotic compounds such as DMF and triglyme.
The described methylation procedure is intrinsically environmentally benign since it employs new cleaner and safer reagents, derived from DMC, in place of hazardous existing ones.