Author Topic: Methylation of phenols using DMC and a PTC  (Read 5354 times)

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Vitus_Verdegast

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Methylation of phenols using DMC and a PTC
« on: April 13, 2003, 02:47:00 AM »
from Tet. Lett. 43, 2002, 2661-2663 :

O-Methylation of phenolic compounds with dimethyl carbonate under solid/liquid phase transfer system

Abstract: The industrially important alkyl aryl ethers, of which anisole is the simplest form, can be synthesized by reacting the corresponding phenols with the environmentally benign dimethyl carbonate (DMC). The reaction is carried out under mild conditions of temperature and pressure. Excellent yields and selectivity of product were obtained after a few hours of reaction.


In organic synthesis, dimethyl carbonate (DMC) is considered as an alternative methylating reagent to replace hazardous compounds such as methyl halides or dimethyl sulfate.

It has been found that the methylation of phenols with DMC can be carried out in an autoclave at 160° with a catalyst system composed of an alkaline base or a tertiary amine in association of an iodide. Tert. amines or phosphines, or nitrogen-containing heterocyclic catalysts (4-(dimethylamino)-pyridine), penta-alkylguanidines, CsCO 3 have been used as catalysts to prepare phenolic ethers by reaction of phenols with a dialkyl carbonate at a temp. between 120 and 200°C under autogenous pressure. Notari et al. described how 2-hydroxy-4-alkoxy-benzophenone was synthesized by selective monomethylation of 2,4-dihydroxybenzophenone in an autoclave at the temp. ranges between 40 and 180°C in the presence of alkaline base.

Recently, alkyl methyl carbonate was used to accomplish the O-methylation of phenols in the presence of K2CO3 and a polar solvent. Due to the high boiling point of carbonate, the reaction can be conducted under atmospheric pressure. The reaction of hydroquinone with alkyl carbonates takes place in a soxhlet extractor at 170-200°C; the presence of a solvent such as pyridine or an alkyl formamide is vital. (Synlett, 2000, 272-274  DOI:

10.1055/s-2000-6488

)


We have studied the reaction of phenol derivatives with DMC under solid/liquid phase transfer conditions. The reaction was carried out at 90-100°C under atmospheric pressure in a reactor equipped with a stirrer and a reflux condensator for DMC. At the end of the reaction, the base (K2CO3) was simply recovered by filtration and the PTC was separated from the reaction medium by liquid/liquid extraction with an aqueous hydrochloric acid (pH 1) and tert-butyl methyl ether (MTBE). The organic phase, containing methylated products, was analysed by gas chromatography. The PTC recovered in the aqueous phase can be regenerated.

Among various catalyst systems tested, the couple of K2CO3 (base)/tetrabutylammonium bromide (PTC) was shown to be the most effective catalyst for the O-methylation of 2,4-dihydroxybenzophenone (2,4-DHB) (Table 1). Under such conditions the reaction is regioselective as 2-hydroxy-4-methoxybenzophenone (2-H-4-MB) is exclusively obtained.

Table 1 : Effect of the catalyst system on the yield of the rxn of 2,4-DHB with DMCa

Nr  -  Base  -  PTC  -  Yieldb

1  -  K2CO3  -  (Et)4NBr  -  8.5
2  -  K2CO3  -  (Bu)4NBr  -  12
3  -  K2CO3  -  (octyl)4NBr  -  4
4  -  K2CO3  -  (Bu)4NOH  -  11
5  -  K2CO3  -  Ph3(CH2CH2OH)PCl  -  1.4
6  -  K2CO3  -  CHBG.HClc  -  8.5
7  -  K2CO3  (Bu)4PCl  -  11
8  -  KHCO3  -  (Bu)4NBr  -  2.5
9  -  Cs2CO3  -  (Et)4NBr  -  5.5
10  -  idem  -  (Et)3BzNBr  -  4.5
11  -  KOH  -  (Bu)4NBr  -  1

a T: 93°C; molar ratio DMC/base/PTC/2,4-DHB: 16/1.5/0.05/1; time=9 hours
b Yield of 2-H-4-MB, no trace of 2,4-dimethoxybenzophenone (2,4-DMB) was observed
c Hydrochloride of hexabutylguanidinium chloride


In order to improve the yield of the reaction, the PTC/2,4-DHB ratio was modified. Increasing this ratio from 0.05 to 0.5 and 1.0 resulted in a good yield. We have observed that the monomethylation on the OH-group at position 4 took place first. The hydroxy group at position 2 may be protected by a hydrogen bond with a carbonyl group.

When the catalyst system (K2CO3/Bu4NBr) was used with phenol and p-cresol, 100% conversion and selectivity to O-methylated products was achieved only after a few hours. The attempt to reduce the amount of PTC led to a poor yield, but longer reaction time can improve the reaction yield. (Table 2)

Table 2

Nr  -  Substrate (S)  -  PTCa/Sb  -  DMC/Sb  -  K2CO3/Sb  -  Time (h)  -  Yield (%)

12  -  2,4-DHB  -  0.5  -  16  -  1.5  -  9  -  34/3c
13  -  2,4-DHB  -  1  -  16  -  1.5  -  9  -  6/72c
14  -  phenol  -  0.2  -  16  -  0.75  -  5  -  31
15  -  phenol  -  0.2  -  16  -  0.75  -  10  -  64
16  -  phenol  -  0.2  -  16  -  0.75  -  13  -  80
17  -  phenol  -  0.6  -  16  -  0.75  -  5  -  96
18  -  phenol  -  0.6  -  30  -  0.75  -  5  -  99
19  -  p-cresol  -  0.3  -  16  -  1.5  -  4  -  25
20  -  p-cresol  -  0.4  -  16  -  1.5  -  4  -  48
21  -  p-cresol  -  0.5  -  16  -  1.5  -  5  -  99
22  -  p-cresol  -  0.6  -  16  -  1.5  -  4  -  97
23  -  p-cresol  -  0.5  -  8  -  0.75  -  5  -  95
24  -  p-cresol  -  0.5  -  10  -  0.75  -  5  -  99
25  -  p-cresol  -  1  -  10  -  0  -  5  -  45
26  -  p-cresol  -  0  -  10  -  1  -  5  -  0

All reactions were conducted at 93°C
a PTC = Bu4NBr
b mol/mol
c Yield 2-H-4-MB/yield 2,4-DMB


The different reactivity between phenols can be explained by the negative inductive effects (I- effect) of the (C6H5)CO group of 2,4-DHB, which creates difficulty in the reaction between the phenoxy ion with DMC. The negative charge on the oxygen atom of the phenoxy ion formed in situ by the reaction of the base with 2,4-DHB is weakened by the attraction of this effect. On the contrary, the I+ effect of the methyl group of p-cresol accelerates the reaction kinetics.

Although we note that the tetrabutylammonium bromide alone can act as a catalyst, the yield of the rxn is reduced to 45% even if the molar ratio is doubled. Moreover, the base alone is unable to make the reaction take place.

In conclusion, we have presented an efficient method to synthesise aryl methyl ethers by using the environmentally safe DMC as a reagent. The reaction takes place under mild conditions of temperature and pressure, while good to excellent yields (95-99%) are obtained. Furthermore, the catalysts (base and PTC) can be easily recovered and regenerated.

---------------------------------------------


Vitus_Verdegast

  • Guest
2-OH-5-MeO-BA trial coming soon...
« Reply #1 on: April 13, 2003, 03:25:00 AM »
A strange fellow with a thick Hungarian accent told me that he's about to try the above methylation procedure on 2-OH-5-MeO-BA...


Actually, DMC is a quite a versatile reagent, replacing phosgene as a methoxycarbonylating agent by a BAC2 (bimolecular, base-catalysed, acyl cleavage, nucleophilic substitution) mechanism where the nucleophile attacks the carbonyl carbon of DMC, giving the transesterification product :

Y- + CH3OCOOCH3  <--(BAC2)-->  YCOOCH3 + CH3O-

                               T = 90°C

Under these conditions DMC can replace phosgene, but at higher temperatures, usually around 160°, DMC acts primarily as a methylating agent, a BAL2 (bimolecular, base-catalysed, alkyl cleavage, nucleophilic substitution) mechanism predominates where the nucleophile attacks the methyl group of DMC :

Y- + CH3OCOOCH3  --(BAL2)-->  YCH3 + CH3O- + CO2

                                T = 160°

Of these two, only the methylation reaction is irreversible, because the CH3OCOOH initially formed decomposes to methanol and CO2

Also note that the base serves a catalytic function, thus is not consumed during the reaction.

And it's as cheap as DMS where I live..  :)

Another way to methylate phenolic compounds using DMC can be found at:

https://www.thevespiary.org/rhodium/Rhodium/pdf/dimethylcarbonate.phenol.methylation.pdf




GC_MS

  • Guest
Danger!
« Reply #2 on: April 13, 2003, 12:20:00 PM »
And for sure that guy with the Hongarian accent wasn't Bella Lugosi. The protection of your sources is utmost well organised!  ;)


pHarmacist

  • Guest
Karloff
« Reply #3 on: April 13, 2003, 12:34:00 PM »
GC_MS are you thinking of Boris Karloff? LOL, joke!


Vitus_Verdegast

  • Guest
Didn't I tell you that?
« Reply #4 on: April 13, 2003, 12:36:00 PM »
:)
He comes in my dreams at night, and tells me everything about his chemistry hobby in the netherworld.




GC_MS

  • Guest
Damn
« Reply #5 on: April 13, 2003, 01:39:00 PM »
Damn! We could become soulmates  ;)



If not bothered by Russian sluts named Tatjana or Natasja, it's usually this guy spooking around in my brains.

But to get back to the topic: Rh has posted a similar thing in the past. If I remember correctly, it was from a journal titled "Green chemistry", of something similar. Has some potential...


Lego

  • Guest
Methylation of phenol w/ DMC-derivates w/o PTC Pt1
« Reply #6 on: May 10, 2003, 02:51:00 AM »
O-Methylation of Phenol with Dimethylcarbonate derived Methylating agents




This 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 Phenols



Alvise 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-CH3C6H4, p-ClC6H4, o- and p-CH3COC6H4, and 2-naphthyl) can be conducted in a highly selective manner by using asymmetric alkyl methyl carbonates CH3OCOOR (R = n-Pr, 3b; n-Bu, 3d; CH3O(CH2)2O(CH2)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 K2CO3 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, DMC



The 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 (CH3X; X = Cl, Br, I; 1) and dimethylsulfate (CH3OSO3CH3; 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 CH2-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).10-15
The alkylations of Scheme 1 can be performed without solvent and with a catalytic amount of base (M2CO3: M = Li, Na, K, and Cs; Y zeolites). It was also shown, by us and by others,6, 10, 16 that the use of Cs2CO3 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 CO2 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, 8

To overcome such difficulties, we conceived the use of asymmetric alkyl methyl carbonates (ROCOOCH3, 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 1

Ar-OH + ROCOOCH3 -----K2CO3---> Ar-OCH3 + ROH + CO2
Scheme 2


The 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, 19

Phenol 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 SN2 displacements for both allylic and benzylic systems.24


In 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 alcohols25), 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, K2CO3, 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.28


In 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 ROCOOCH3 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.


Lego

  • Guest
Methylation with DMC and DBU as base
« Reply #7 on: June 13, 2003, 04:41:00 PM »
Lego's voice: The methylation of phenols with DMC either uses high pressure or complicated reaction setups. Using DBU (1,5-diazabicyclo[4.3.0]non-5-ene) instead of K2CO3 enhances the reaction, so it can bee performed at room temperature.

Organic Letters, 2001, 3(26), 4279-4281

(http://www.angelfire.com/scifi2/lego/journals/4.pdf)
DOI:

10.1021/ol016949n




General procedure using conventional thermal heating: A reaction flask was charged with substrate (1 g), DBU (1 equiv), and DMC (10 mL). The mixture was heated to 90 °C and the products were analyzed by HPLC.




Lego's voice: Workup can bee done as in other methylations with DMC and DBU might bee recycled.


The authors also use microwaves and PTCs to enhance the reaction but this has to bee performed in a monomode microwave and not in a domestic one.  :(


Lego likes this method for several reasons:
1) DMC is cheap, unwatched and non-carcinogenic unlike other methylating agents like dimethyl sulphate, methyl iodide and the like.
2) DBU is not too expensive and too common to be watched
3) The reaction can bee carried out at room temperature
4) Yields are usually >90%




ning

  • Guest
Try dimethyl oxalate
« Reply #8 on: April 27, 2004, 04:30:00 PM »
For those bees who want OTC methylating agent, DMO is supposed to be more reactive and higher boiling than DMC, as well as having the nice advantage of being relatively OTC.

PTC might make a nice improvement to the procedure...