(Hive Bee)
04-13-03 02:47
No 426189
      Methylation of phenols using DMC and a PTC
(Rated as: excellent)

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 200C 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 180C 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 170-200C; 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 90-100C 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: 93C; 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 93C
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.

(Hive Bee)
04-13-03 03:25
No 426190
      2-OH-5-MeO-BA trial coming soon...     

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 = 90C

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.. smile

Another way to methylate phenolic compounds using DMC can be found at:
../rhodium/pdf /dimethylcarbonate.phenol.methylation.pdf
(Hive Addict)
04-13-03 12:20
No 426243

And for sure that guy with the Hongarian accent wasn't Bella Lugosi. The protection of your sources is utmost well organised! wink

The faster you run, the quicker you die.
(Hive Addict)
04-13-03 12:34
No 426246

GC_MS are you thinking of Boris Karloff? LOL, joke!

Accept No Imitations, There Can Only Bee One;
(Hive Bee)
04-13-03 12:36
No 426247
      Didn't I tell you that?     

He comes in my dreams at night, and tells me everything about his chemistry hobby in the netherworld.
(Hive Addict)
04-13-03 13:39
No 426262

Damn! We could become soulmates wink

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...

The faster you run, the quicker you die.
05-10-03 02:51
No 432395
      Methylation of phenol w/ DMC-derivates w/o PTC Pt1
(Rated as: excellent)

O-Methylation of Phenol with Dimethylcarbonate derived Methylating agents

This article has been mentioned at the Hive before
Post 220907 (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

Alkyl Methyl Carbonates as Methylating Agents.
The O-Methylation of Phenols

Alvise Perosa, Maurizio Selva,* Pietro Tundo,* Francesco Zordan
Dipartimento di Scienze Ambientali dellUniversit Ca Foscari, Dorsoduro 2137, 30123, Venezia, Italy
Fax +39-41-2578620; E-mail: /
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 150C, 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 120-150C), 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
We have extensively reported that operating at high temperatures (>= 160C), 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 (>=120C) which is well over the 90C 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 120C, 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 150C, 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 140-170C range (except for 5a, bp = 162C).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 140C.

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 140C 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>=120C, 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.

The candle that burns twice as bright burns half as long
05-10-03 02:58
No 432396
      Methylation of phenol w/ DMC-derivates w/o PTC Pt2     

Table 1 Reaction of Phenols with Differentalkyl Methyl Carbonatesa
Entry R= ROCOOCH3 Time (h)c Productsd PhOCH3 % (PhOR)
1 Et 3a 15 90 10
2 n-Pr 3b 17 95 5
3 i-Pr 3cb 40 73 2
4 n-Bu 3d 15 97 3
5 CH3O(CH2O(CH2)2 3e 20 >99 -
6 Bn 3f 5 84 16
7 Allyl 3g 21 83 17

a T=120C, phenol (0.3 g; 3.3 mmol)/K2CO3, / 3 = 1 : 1.1 : 5.
b Conversion of phenol stopped at 75%.
c Time for complete the conversion of the substrate.
d Determined by GC, referred to an internal standard.

Table 2 O-Methylation of Different Phenols 6 by Methyl 2-(2-Methoxyethoxy)ethyl Carbonate (3e)a
Entry Ar ArOH (g) Conv (%) Solvent (50 mL) Yield (%) Purity (%)
1 Ph 6a (3.8) 97 DMF 86 91d
2 Ph 6a (3.8) 100 Triglyme 81 >99
3 p-Me-Ph 6b (4.0) 100 " >99 79
4 p-ClPh 6c (4.0) 98 " >99 60
5 2-napthyl 6d (4.0) 100 " >99 83
6 MeCOPh 6e (2.0) 100 " >99 81

a T=140C, substrate/K2CO3/3e= 1 : 1.1 : 5.
b Ortho/para = 4.5 : 5.5.
c Isolated yields of O-methylated derivatives.
d Residual DMF in distilled product.

CNR (Italian National Research Council, contract no. 98.000571.PF37) and INCA (Interuniversity Consortium Chemistry for the Environment) are gratefully acknowledged for the financial support.

References and Notes
(1) F. Trotta, P. Tundo, G. Moraglio J. Org. Chem. 1987, 52, 1300.
(2) P. Tundo, F. Trotta, G. Moraglio J. Chem. Soc., Perkin Trans. 1 1989, 1070.
(3) M. Lissel, S. Schmidt, B. Neumann Synthesis 1986, 382.
(4) P. Tundo In Continuous-Flow Methods in Organic Synthesis, E. Horwood, Ed; Chichester, 1991.
(5) Y. Ono Pure Appl. Chem. 1996, 68, 367.
(6) (a) F. Rivetti, U. Romano, D. Delledonne, In Green Chemistry: Designing Chemistry for the Environment, P. Anastas, T. Williamson, Eds., ACS Symposium Series No. 626, 1996, Chap. 6, pp. 70-80; (b) M. Selva, P. Tundo, C. A. Marques, In Green Chemistry: Designing Chemistry for the Environment, P. Anastas, T. Williamson, Eds., ACS Symposium Series No. 626, 1996, Chap. 5, pp. 81-91.
(7) D. Delledonne, F. Rivetti, U. Romano J. Organomet. Chem. 1995, 488, c15.
(8) P. Tundo, M. Selva Chemtech 1995, 25, 31.
(9) A. Bomben, M. Selva, P. Tundo, L. Valli, Ind. Eng. Chem. Res. 1999, 38, 2075.
(10) M. Selva, C. A. Marques, P. Tundo J. Chem. Soc., Perkin Trans. 1 1994, 1323.
(11) A. Bomben, C. A. Marques, M. Selva, P. Tundo Tetrahedron 1995, 51, 11573.
(12) A. Bomben, M. Selva, P. Tundo J. Chem. Res. 1997, 448.
(13) P. Tundo, M. Selva, A. Bomben Org. Synth. 1998, 76, 169-177.
(14) M. Selva, A. Bomben, P. Tundo J. Chem. Soc., Perkin Trans. 1 1997, 1041.
(15) M. Lissel, A. R. Rohani-Dezfuli, G. Vogt J. Chem. Res. (M) 1989, 2434.
(16) Y. Lee, I. Shimizu Synlett 1998, 1063.
(17) M. Selva, F. Trotta, P. Tundo J. Chem. Soc., Perkin Trans. 1992, 519.
(18) (a) M. Matner, R. P. Kurkjy, R. J. Cotter Chem. Rev. 1964, 64, 645; (b) H. Badad, A. G. Zeiler Chem. Rev. 1973, 73, 80.
(19) 2-(2-Methoxyethoxy)ethyl methyl carbonate 3e: 1H NMR (CDCl3): d ppm 4.13 (m, 2H), 3.65 (s, 3H), 3.55 (m, 2H), 3.47 (m, 2H), 3.19 (s, 3H); Mass spectrum (70 eV): m/z (%): 178 (M+, < 1), 103 ([M - CH3OCH2CH2O]+, 10), 59 ([M - CH3OCH2CH2OCH2CH2O]+, 100), 58 (58). Bp = 48-50 C/0.1.
(20) A general procedure for the O-alkylation of phenol using the asymmetric organic carbonates 3a-3g is as follows: a 25 mL flask, fitted with a reflux condenser, a rubber septum, a thermometer, and a nitrogen inlet, was charged with phenol (0.30 g, 3.2 mmol), K2CO3 (0.6 g, 4.5 mmol), the organic carbonate (2.8 g, 16 mmol), DMF (30 mL), and n-tetradecane as the internal standard (0.07 mmol). The mixture was stirred under N2 at the chosen temperature (120, 130, 140, 150 C) until complete phenol conversion was observed, as monitored by GLC. All reactions were repeated twice to assure reproducibility. Both phenol conversion and anisole yield were determined by comparison to the internal standard. Reactions were also run using different volumes of DMF (2, 4, 6, 8, and 10 mL) or 3e as the solvent (5.7 g, 32 mmol).
(21) A. Streitwieser Chem. Rev. 1956, 56, 571.
(22) M. Charton J. Am. Chem. Soc. 1975, 97, 3694.
(23) G. Caldwell, T. F. Magnera, P. Kebarle J. Am. Chem. Soc. 1984, 106, 959.
(24) J. F. King, G. T. Y. Tsang, M. M. Abdel-Malik, N. C. Payne J. Am. Chem. Soc 1985, 107, 3224.
(25) P. Tundo, G. Moraglio, F. Trotta Ind. Eng. Chem. Res. 1989, 28, 881.
(26) M. L Wang, K. R. Chang Ind. Eng. Chem. Res. 1991, 30, 2378.
(27) Since anisole boils at 154 C, reactions were followed by monitoring the phenol concentration. Once the reaction mixture was cooled at room temperature, the mass balance between phenol and anisole was determined by GC.
(28) Procedure for the O-alkylation of different phenols using the organic carbonate 3e and triglyme as solvent (Table 2): a mixture of the appropriate phenol (2-5 g, see Table 2 for amounts), K2CO3, and carbonate 3e, in a 1: 1.1: 5 molar ratio, was dissolved in 50 mL of triglyme and heated at 140 C under N2, until complete substrate conversion. After cooling, 150 mL of diethyl ether were added, and the solution was washed with water (5 x 50 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was either distilled under reduced pressure (anisole, yield 81%; p-methyl anisole, 79%; p-chloroanisole, 60%); or flash-chromatographed on a column of silica gel (2-methoxynaphthalene, 83%; o- and pacetylanisole, 81% combined), eluting with a 1 to 1 mixture of ethyl ether and petroleum ether. All products were identified by comparing spectroscopic data with those of authentic samples. The 45 to 55 mixture of o- and p-acetylphenol used in the above procedure was prepared by a Friedel-Crafts acylation of phenol with acetyl chloride, followed by a Fries rearrangement.29
(29) E. Miller, W. H. Hartung, Org. Synth. Coll. Vol. 2, Wiley Chichester, 1961; p. 543

The candle that burns twice as bright burns half as long
06-13-03 16:41
No 439765
      Methylation with DMC and DBU as base     

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 (

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. frown

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%

The candle that burns twice as bright burns half as long
(Hive Bee)
04-01-04 20:52
No 498502
      Alkylation of Phenols in Water w/PTC
(Rated as: excellent)

Quaternary Ammonium Salt-Assisted Organic Reactions in Water: Alkylation of Phenols
Jean Jacques Vanden Eynde; Isabelle Mailleux

Synthetic Communications 31(1), 1-7(2001)

Abstract: A series of quaternary ammonium salts has been tested as phase transfer agents to promote reactions between phenols and alkyl halides in an aqueous solution of sodium hydroxide in the absence of organic solvent. Methyltrioctylammonium chloride emerges as the most effective catalyst.

Nowadays, there is an increasing awareness of the urgent necessity to limit, as far as possible, any source of pollution. Consequently and in response to the public pressure, the environmental legislation is becoming ever more severe. Facing up to those facts, chemists have to dedicate numerous efforts to the development of clean technologies.

That new challenge has led recently to a growing interest in the displacement of organic reactions to aqueous media (1-3), which has been achieved successfully in the Ruhr ChemieRhne-Poulenc hydroformylation process (4).

Water is an abundant, cheap, non-toxic, and non-dangerous solvent. Obviously, it does not dissolve most of the organic reactants, but that fact has been recognized as a benefit on rates and selectivities of several transformations (1-3). Moreover, the addition of a phase transfer agent, generally a quaternary ammonium salt, enables to improve an intimate contact with an organic layer (3-11).

The aim of this paper is to disclose suitable experimental conditions to promote alkylation of phenols in an aqueous solution of sodium hydroxide and in the absence of any organic solvent. That reaction yields aryl ethers, a functionality that is a key constituent in the structures of many pharmaceutically important chemicals.

The reaction between phenols and alkyl halides in an aqueous solution of sodium hydroxide requires the contact between two non-miscible phases and yields a water-insoluble product. Therefore, its course can be monitored readily by UV spectroscopy on samples of the aqueous phase, as the phenolates are the sole species that absorb in that wave length region. That method was used to select the most attractive phase transfer catalyst from a kinetic point of view in a model reaction involving 1,2-dihydroxybenzene (1a-Fig. 1:  = 2870 l mol-1 cm-1;  max = 275 nm) and iodomethane. By that way, we observed that 1a reacts slowly with an excess (3 eq) of iodomethane in an aqueous solution of sodium hydroxide (5M) at 50C.

Figure 1.

After 1 h, only 5% of the starting material 1a is consumed. Addition of a quaternary ammonium salt (10% mol relative to 1a) accelerates the process as indicated by inspection of the results collected in Table 1. Among the transfer agents we tested, methyltrioctylammonium chloride (Aliquat 336) emerges as the most effective catalyst. Interestingly, in contrast with conclusions (12) dealing with other phase transfer catalysis experiments, no synergistic effect of a crown ether-quaternary ion salt pair takes place.

Table 1. Influence of the Catalyst on the Alkylation of 1a with Methyl Iodide.

Catalyst (10% mol relative to 1a) [1a] (mol/l)a after Isolated Yieldb
60 mn %
None 0.76 25
Benzyltriethylammonium chloride 0.56 40
Tetrabutylammonium hydrogenosulfate (TBA) 0.38 65
TBA/15-crown-5 0.51 60
Cetyltrimethylammonium bromide 0.35 80
Methyltrioctylammonium chloride 0.33 90

aC0 (1a) = 0.8 mol l-1 C0 (CH3I) = 2.4 mol l-1; T = 50C.
bC0 (1a) = 0.8 mol l-1; C0 (CH3I) = 1.6 mol l-1; T = reflux; time = 1 hour

To evaluate the synthetic potential of the method, we performed the same experiments in a boiling solution of sodium hydroxide, extending the reaction time arbitrarily to 1 h. After cooling, the mixture was extracted with dichloromethane. Before evaporation of the solvent, the organic layer was filtered through a cake of alumina to retain the ammonium salt. Yields in 1,2-dimethoxybenzene, determined by 1H NMR, are collected in Table 1. the data parallel the results of the kinetic study. Indeed, the highest yield in isolated product was obtained by using methyltrioctylammonium chloride as the transfer agent. Cetyltrimethylammonium bromide is also efficient, but its tendancy to foam complicates the experimental procedure. The other salts give lower yields so we did not use them. Experimentally, we also noticed that the stoechiometric amount of iodomethane is sufficient to effect the dialkylation. In agreement with the mechanism of the reaction, which requires the formation of phenolate anions, a lower concentration of NaOH (0.5 M) or the use of sodium hydrogenocarbonate (5 M, 0.5 M) as the base (in the presence of 10% mol of methyltriocylammonium) dramatically decreases the yield in 1,2-dimethoxybenzene to 30, 20, or 5%, respectively. In that sense, too, sodium dodecylsulfate (10% mol), a popular anionic surfactant, exhibits a poor but positive activity (35%).

Having a simple procedure to methylate 1,2-dihydroxybenzene, we wished to estimate its range of applicability. Under our experimental conditions, compound 1a readily reacts with 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, and even 1,5-dibromopentane. Yields vary from 50 to 95%. In particular, derivative 3c has been obtained in 75% yield, whereas Ziegler (7) reports that its preparation requires two steps and that the yield of the second step does not exceed 40%. 3,4-Dihydroxybenzaldehyde (1b) and other phenols also can be alkylated under our experimental conditions, as indicated by the examples presented in Figure 2 (isolated yields are reported in Table 2). Mention should be made that in all cases the crude final products were isolated by decantation or filtration, thus limiting the use of an organic solvent to the purification by recrystallization when the expected compound is a solid.

Figure 2.

Table 2. Results for the Alkylation of 1a, 1b, and Various Phenols in the Presence of Methyltrioctylammonium Chloride

[td]Product[/td][td]Isolated Yield [%][/td][td]Lit. Ref.[/td]
[td]3a[/td][td]60[/td][td]23-24, 27-28[/td][/tr]
[td]3b[/td][td]65[/td][td]14, 29[/td][/tr]
[td]3c[/td][td]75[/td][td]14, 30[/td][/tr]
[td]3d[/td][td]95[/td][td]14, 29[/td][/tr]
[td]3e[/td][td]50[/td][td]23-24, 31[/td][/tr]
[td]4a[/td][td]90[/td][td]23-24, 32-33[/td][/tr]
[td]4b[/td][td]90[/td][td]23-24, 34-35[/td][/tr]
[td]4c[/td][td]55[/td][td]23-24, 36-37[/td][/tr]

Error: Table contains the text "<b>" between [tr] and the next [td] markup tag in the table row "[tr]<b>[td]Product[/td][td]Isolated Yield [%][/td][td]Lit. Ref.</b>[/td][/tr]".

Elegant protocols for the preparation of aryl ethers have recently been published. They recommend the use of polymer-supported bases (15) or irradiation of dry media with microwaves (16-17). This paper presents another simple experimental procedure (that could readily be scaled up) to alkylate phenols in an aqueous basic solution in the presence of a catalytic amount of methyltrioctylammonium and in the absence of any organic solvent. It is characterized by its wide range of applicability as it enables, e.g., the formation of 6- to 9-membered benzo fused systems, as well as the use of long chain alkyl halides. Our experimental conditions largely differ from those described by Bashall and Collins (18) as the ammonium salt does not play the role of a solvent. Let us also emphasize that we did not observe any poisoneous effect of the iodide ion when alkyl iodides were involved (18-19), and that by-products from a Cannizzaro reaction (20) were not detected when starting from hydroxybenzaldehydes.

Experimental Section
All reagents, catalysts, and solvents are commercially available (Aldrich, Acros Organics). All products (2, 3, 4) have been described in the literaure and were fully characterized by their melting point (hot-stage microscope) or boiling point, and by their spectral data (NMR: Varian EM 360-L, Bruker AMX; IR: Perkin-Elmer 1760K).

Quantitative Study
A stirred mixture of 1,2-dihydroxybenzene (5.51g; 50 mmol) and a catalyst (see Table 1; 5 mmol) in a 5 M aqueous solution (62.50 mL) of sodium hydroxide was held under thermostatic control at 50C for two hours. Iodomethane (9.34 mL; 150 mmol) was added. A sample of the mixture was taken every 10 minutes, rapidly cooled down to 0C, and diluted (2000) for UV analysis (Varian Cary 118).

General Procedure for the Alkylation
A mixture of the phenol (100 mmol), the alkyl halide (one or two equivalents), and methyltrioctylammonium chloride (10 mmol) in a 5 M aqueous solution (100 mL) of sodium hydroxide was stirred and heated under reflux for one hour. After cooling, the crude product was separated (decantation or filtration) and purified by distillation or recrystallization.

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04-27-04 16:30
No 503306
      Try dimethyl oxalate     

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...

I've been chased by both cops and robbers. So what does that make me?