Pertanika 12(1), 71-78 (1989)

A Simple and Clean Method for Methoxymethylation of Phenols

FAUJAN B, H. AHMAD and J. MALCOLM BRUCE1

Department of Chemistry,Faculty of Science and Environmental Studies,

Universiti Pertanian Malaysia43400 UPM Serdang, Selangor Darul Ehsan, Malaysia

Key words: Methoxymethyl ethers of phenols.

ABSTRAKSatu kaedah mudah dan bersih, untuk penyediaan metoksimetil eter (MOM = CH2 OMe) bagi fenol yangmembawa ikatan hidrogen kumpulan hidroksi dalam molekulnya akan dibincangkan. Tindakbalas 2,5-dihidroksibenzaldehid (1) dengan metoksimetilklorida - metil asetat dalam pelarut eterpada suhu biliky meng-hasilkan 57% 2,5- bis(metoksimetoksi) benzaldehid (2). Dalam keadaan tindakbalas yang sama 75%metoksimetil eter (6) telah dihasilkan daripada salisilaldehid. Penghasilan sebanyak 61-81 %, tidak dibaiki,bagi metoksimetil eter untuk beberapa fenol yang tidak mempunyai ikatan hidrogen di alas telah jugadihasilkan.

ABSTRACTA simple and clean procedure for the preparation of methoxymethyl ethers (MOM = CH2 OMe) of phenols havinginternally hydrogen bonded hydroxy groups is described. Thus treatment of 2,5-dihydroxybenzaldehyde (1) witha 1:1 mixture of methoxymethyl chloride-methyl acetate in ether at room temperature gives 2.5-bis-(methoxymethoxy)benzaldehyde (2) in 57% yield; under similar conditions, the methoxymethyl ether (6) ofsalicylaldehyde was isolated in 75% yield. Yields of 61-81 %, not optimised, of methoxymethyl ethers of severalphenols lacking internal hydrogen bonding were also obtained.

INTRODUCTIONThe methoxymethyl ether moiety is a usefulhydroxy protecting group for phenols, alcohols,and carboxylic acids. Methoxymethylation issometimes superior to tetrahydropyranylation,since the latter results in the formation of newassymmetric center(s); with diols and opticallyactive alcohols, a mixture of diastereomers isformed, complicating both purification andspectroscopic analysis (Fuji et al 1975). Prepa-rations of methoxymethyl ethers are basedmostly on the reaction of a phenoxide anionwith methoxymethyl chloride (Greene 1981).However, such a procedure was not suitable forour purpose, the preparation of bis(metho-xymethoxy)benzaldehyde (2) from 2,5-dihy-droxybenzaldehyde (1).

Several alternative methods for methoxy-methylation which avoid the use of methoxy-methyl chloride present some difficulties. Theuse of methylal and a large molar excess ofphosphorus pentoxide (Fuji etal 1975) causesdifficulties in work-up, particularly of methoxy-methyl ethers of small molecular weight. Basedon Fuji's procedure, Yardley and Fletcher,(1976) reported that 3.5 g of (3) required 85g of phosphorus pentoxide and a final neutrali-sation volume of 4 litres. They then reportedon the use of methylal and 4-toluenesulfonicacid in the presence of molecular sieves (toremove methanol) to facilitate the preparationof some methoxymethyl ethers. However, theirprocedure failed to afford either the methoxy-methyl ether of 2-acetylphenol (4) or the bis-

1 Department of Chemistry, University of Manchester, Manchester, Ml3 9PL, England.

FAUJAN B. H. AHMAD AND J. MALCOLM BRUCE

methoxymethyl ether of 2,2-dihydroxybenzo-phenone (5). The difficulty may be due to theinternally hydrogen bonded hydroxy groups inthese compounds. Recently, the use of methylaland phosphorus oxychloride in toluene at 65°Cwas reported to give the methoxymethyl ether(6) of salicylaldehyde in 90% yield (Sch-outen 1985).

We herein report a clean and simple pre-paration of methoxymethyl ethers, particularlyfrom substrates having internally hydrogenbonded hydroxy groups, such as that in alde-hyde (1), which illustrates the importance ofcorrect choice of a solvent. The procedure wasfound to be superior to that generally used.

MATERIALS AND METHODSProton magnetic resonance spectra, in p.p.m.with respect to internal tetramethylsilane, weremeasured on a Perkin-Elmer R34 instrumentat 220 MHz, and a Varian SC300 instrument at300 MHz as stated. Coupling constants for thearomatic protons were in the normal ranges.Resonances assigned to hydroxyl groups wereremoved by addition of D,O.

Mass spectra were recorded on KratosMS25 and MS30 instruments. Melting pointswere recorded on a Kofler block and were un-corrected.

Infrared spectra were recorded on aPerkin-Elmer FTIR 1710 spectrometer as Nujolmulls, films or solutions as stated.

Methoxymethylation of Phenolic HydroxyGroups: A General Procedure for Preparation ofCompounds (13 a-i) and (14 a-f).

To a stirred solution of the hydroxy com-pound (hydroxybenzene, hydroxyaldehyde,hydroxyketone, or hydroxycarboxylic acid^ (1.0mmole) in ether (5 ml) (Note 1) under a nitro-gen atmosphere was added methoxymethylchloride (1.5 mmole), as a 1:1 mixture withmethyl acetate (Note 2), and triethylamine (2.0mmole) (Note 3). The mixture was stirred atroom temperature for about 24 h. and the whiteprecipitate was then removed by filtration.Removal of the solvent gave the methoxymethylether, usually as a liquid, which was purified

either by washing with aqueous 5% sodiumhydroxide or by distillation.

Note L Ether (5 ml) was used as the sol-vent for every 1.0 mmole of the hydroxy com-pound, except for those hydroxy compoundswhich were not very soluble in ether whenmore ether was used.

Note 2. Methoxymethyl chloride (1.5mmole) (Amato et al 1979) was used for eachhydroxy group present in the starting material.

Note 5. Triethylamine (2.0 mmole) wasused for every 1.5 mmole of methoxymethylchloride used in the reaction mixture. Excessof amine ensured that the reaction mixtureremained basic throughout.

The compounds prepared are listed in' Tables 1 and 2. Their analytical and spectros-topic data are shown in* Tables 3 and 4, respec-tively.

RESULTS AND DISCUSSIONIn connection with our interest (Ahmad andBruce, 1986) in developing a new syntheticroute to the aglycones of the anticancer anthra-cyclines, we required the hydroxy protectedaldehyde (2). However, treatment of 2,5-dihv-droxybenzaldehyde (1) with a 1:1 mixture ofmethoxymethyl chloride-methyl acetate (Amatoet al, 1979) in dichloromethane* (Khan andBruce 1985) in the presence of triethylamine,either at room temperature or at reflux, gaveonly 5% of the desired aldehyde (2), the majorproduct being the mono-methoxymethyl ether(7). Similar reactions using pyridine as the basein either dichloromethane, tetrahydrofuran orether failed to give the desired aldehyde (2):only starting material (1) was isolated. Attempt-ed methoxymethylation of aldehyde (1) in thepresence of powdered 4A molecular sieves toabsorb hydrogen chloride (c,f. Yardley andFletcher 1975) again gave the mono-methoxy-methylation product (7). The difficulty in pre-paration of (2) may be due to internal hydro-gen bonding [as (7a)] in the starting material(1).

1,4-Bis(methoxymethoxy) benzene (8) haspreviously been obtained by heating hydroqui-

1-\Uthoxymethoxy-2<yclohexen-lHone was obtained in 75% yield from the corresponding hydroxy compound ontreatment with methoxymethyl chloride-methvl acetate in the presence of triethylamine in dichloromethane at 0°C

72 PERTANIKA VOL. 12 NO. 1, 1989

A SIMPLE AND CLEAN METHOD FOR METHOXYMETHYIATION OF PHENOLS

CHO

HCOMe

OMOM.CHO

QH

CHO

(3)

(4)

H

(6)

9 bCHO

OH

(7a)

MOM =r CH2OMe

PERTANIKA VOL. 12 NO. 1, 1989 73

FAUJAN B. H. AHMAD AND J. MALCOLM BRUCE

TABLE 1Methoxymethyl (MOM) ethers of some 1,2,4-trisubstituted benzenes 13(a).

(a)(b)(c)(d)(e)(0(g)(h)

(13)

Rl = R2 = MOM, R3 = HR1 = R2 = MOM, R* = OMeRl = R2 - MOM, K" = CHOR1 = R2 = MOM, R:1 - COPhR1 - Rs = MOM, R3 = COjMeR' = R2 = MOM, Rs = CO2MOMR1 = H, R2 = MOM, Rs = CHOR1 = H, R2 = MOM, Rs - CO, H

(i) R1 = H, R2 = MOM, R* = COMe

Isolated,Yield (%)

61765723181780<c)

82

10

b.p. ( °C/mmHg)

76-80/0. l ( b )

80-86/0.156-60/0.059.6-100/0/0.1Not determinedNot determined50-56/0.1[m.p 104-106°C]Decomposed onattempted sublimationNot determined

(a> Prepared from the corresponding hydroxy compounds. Except for entry (c), yields were «ot optimised.(b)Mamedov and Mamedova (1962), b.p. 136-137°C/5 mmHg.(O The compound was prepared in refluxing dichloromethane using powdered 4A molecular sieves.

TABLE 2Methoxymethyl (MOM) ethers of some 1,2-disubstituted benzenes (14)(ii)

(14) Isolated b.p.(°C/mmHg)Yield(%)

(a) R1 = Br; R2 = OMOM(b) R1 * OMOM; R2 = H(c) R1 = OMOM; R2 * OH(d) R1 = OMOM; R2 = OMe(e) R1 - OMOM; R2 = OMOM(f) R1 = OMOM; R2 = Me

81 60-64/0.175(b) 60-66/0.182 60-64/0. l(c)

16 Not determined(d)

10 Not determined10 Not determined

u) Prepared from the corresponding hydroxy compounds. Yields were not optimised.(b)This compound is known; prepared in 90% yield by treatment of the corresponding aldehyde with methylal and

phosphorus oxychloride in toluene at 65°C (Schouten, 1985).(c) Dunn and Bruice (1970), white solid, m.p. 63-64°C.(d)Dunn and Bruice (1970), b.p. 72-73°C/0.025 mmHg.

74 PERTANIKA VOL. 12 NO. 1, 1989

A SIMPLE AND CLEAN METHOD FOR METHOXYMETHYIATION OF PHENOLS

TABLE 3Characteristics of methoxymethyl ethers of some 1,2,4-trisubstituted benzenes (13).

Com-pound

13(a)

13(b)

13(c)

13(d)

lS(e)

13(0

13(g)

13(h)

13(i)

Elementalanalysisor M+

M-; 198.0892

C,57.6,H,7.2%

C.58.6;H,6.3%

C68.1;H,6.0%

M+;256.0947

C.54.1;H;6.4%

C59.6;H,5.7%

C.54.9;H,5.6%

M"196.0731

P

OMe

3.42(s,6H)

3.463.503.85

3.463.50

3.283.46

3.443.48

3.473.523.54

3.43

3.50

3.50

•

m.r

OCH2

5.04(s,4H)

5.125.14

5.165.21

4.965.13

5.125.16

5.025.175.42

5.12

5.16

6.96

5.12

(220 MHz,

ArH

6.92 (s,4H)

6.55(dd,lH)6.65(d,lH)7.05(d,lH)

7.02(d,lH)7.26(dd,lH)7.52(d,lH)

7.06(m,lH)7.04(s,lH)7.05(s,lH)7.44(m,2H)7.53(m,2H)7.86(d,2H)

7.13(m,2H)7.46(m,lH)

7.08(s,lH)7.10(s,lH)7.42(d,lH)

6.92(d,lH)

7.22(m,2H)

6.96(d,lH)

7.25(dd,lH)7.60(d>lH)1489m

6.88(d,lH)

7.80(dd,lH)

7.42(d,lH)

CDC13)(a)

Other

0.28(s,CHO)

3.86(s,Co2 Me)

9.29(s,CHO)10.65(s,OH)

10.10

(bs,20H)

11.92(s,OH)2.62(s,COMe)

I.r/cm1

(film)<b)

15000s

1511m1153m1009m

1680s1490m1385m

1669s1597m1493s

1720s1490m

1736s1498s

3100-3600b1660s

3100-3600b1682s1618s

3150b1640s

11 P.m.r. spectra of 13(c,e,j) were recorded at 300 MHz;and OCH., are singlets.

11 I.r. spectrum of I3(i) in CDCI^; of 13(h) in Nujot.

those of 13(a,0 were recorded at 60 MHz. Signals due to OMe

none in ether with methoxymethyl chloride anddimethylaniline, in about 60% yield (Mamedovand Mamedova 1962). In our hands, compound(8) was more easily prepared by treatment ofhydroquinone with a 1:1 mixture of methoxy-methyl chloride - methyl acetate in the pre-

sence of triethylamine at room temperature, inether, also in about 60% yield (Scheme 1). There-fore the mono-methoxymethylation product (7),which was obtained previously as describedabove, was treated with a 1:1 mixture of methoxy-methyl chloride-methyl acetate in the same man-

PERTANIKA VOL. 12 NO. 1, 1989 75

FAUJAN B. H. AHMAD AND J. MALCOLM BRUCE

TABLE 4Characteristics of methoxvmethyl ethers of some 1,2-disubstituted benzenes (14).

Com-pound

14(a)

14(b)

14(c)

14(d)

14(e)

14(f)

(O Signals

Elementalanalysis

C,44.2;H,3.7;Br, 32.4%

C,65.3;H,6.1%

C,59.3;H,5.9%

C,61.2;H,6.4%

C,59.0;H,6.4%

C,66.5;H,6.7%

due to OMe and

OMe

3.50

3.42

3.56

3.54

3.353.39

3.50

P.m.r.OCH2

5.42

5.22

5.51

5.29

5.105.30

5.28

OCH2 are singlets.

(220 MHz, CDCl's)(a)

ArH

7.29(m,2H)7.60(m,lH)7.80(m,lH)

7.02(t,lH)

7.16(d,lH)7.48(td,lH)7.78(dd,lH)

6.90(t,lH)

7.00(d,lH)7!48(td,lH)7.93(td,lH)

7.08(td,lH)

7.20(d,lH)7.46(td,lH)7.80(dd,lH)

6.93(td,lH)7.09(d,lH)7.32(td,lH)7.70(dd,lH)7.05(td,lH)

7.18(d,lH)7.45(d,lH)7.45(td,lH)7.72(dd,lH)

Other

10.42(s,CHO)

8.66(s,OH)

3.90(s,CO Me)

2.62(s,COMe)

I.r./cm1

(film)

1740s

1690s1600s

3210-3004b1630s1615s1486m

1731s1755m

1734s1602s1488s

1677s1598m1483m1454m

MeO .CHgC l/PhNJfe2/55 C/Et 2 0or

OMOM

MeO . N/20OC/Et20

Scheme 1

76 PERTANIKA VOL. 12 NO. 1, 1989

A SIMPLE AND CLEAN METHOD FOR METHOXYMETHYIATION OF PHENOLS

ner as outlined for the preparation of (8): thisafforded the required bis(methoxymethoxy)-benzaldehyde (2) in 60% yield. Hence, treat-ment of 2,5-dihydroxybenzaldehyde (1) with 2-3 mol of methoxymethyl chloride-methyl ace-tate in the presence of triethylamine in ether(ins-tead of dichloromethane as before), gavethe desired methoxymethyl ether (2) in 57%yield. The latter route reduces to one step thepreparation of (2) from the correspondingaldehyde (1) (Scheme 2). This procedure isclean and simple, and illustrates the importanceof correct choice of solvent.

To our knowledge, the use of ether assolvent for preparation of this type of methoxy-methyl ether has not been previously reportedon. Therefore, it was of interest to explore theuse of the method for the preparation of othermethoxymethyl ethers, particularly from subs-trates having internally hydrogen bondedhydroxy groups similar to that in aldehyde (1).Models of general structures (9) and (10) wereused. The progress of reaction was easily fol-lowed by observing the formation of triethylam-

monium chloride which precipitated fromsolution (Scheme 3).

Details of the methoxymethyl ethers whichwere prepared are summarised in Tables 1 and2. These show that the substrates without aninternal hydrogen bond gave 60-81% of thecorresponding methoxymethyl ethers ['a' and'b' (Table 1) and V (Table 2)].Also, themethoxymethyl ester (11)* was prepared fromthe corresponding acid (12) in 81% yield. It isworth noting that for the trisubstituted ben-zenes (9) (Table 1), the yield of bismethoxy-methyl ether decreases in the order R = H, Ph,OMe, OH. In contrast, for the disubstitutedbenzenes (10) the yield of bismethoxymethylether decreases in the order R = OH, H, OMe,Me. This order may be due to the solubility ofthe starting materials. As expected, the monomethoxymethyl ethers of the trisubstitutedbenzenes (9) were isolated in high yield [en-tries 'g' and 'h' (Table 1)]. In contrast, it wasdifficult to prepare the bismethoxymethyl etherof 2\5t-dihydroxyacetophenone: only its 5'-monomethoxymethyl ether was obtained, in10% yield (entry Y, Table 1).

MeO .CH2C l-MeC02tte/

Et

CHOMeO .

OMOM

(7)

CHOMeO . -MeC 0 2 K

Et N/20 C/Bt20

Scheme 2

-KeC 0

C/Bt20

OMOM

-CHO

OMOM(2)

Compound (11), oil, b.p. 100-106°C/0.1 mmHg: (Found M". 330.1103); C |8H |BO6 requires M. 330.1116.It had 8 (22OMH/,CDC1,), 3.35(3H,s,OMe), 3.48(3H,s,OMe), 3.62(3H,s,OMe), 5.26(3H,s,OCH2),6.85(lH,d,H-3'),7.08(lH,dd,H-4), 7.32(lH,dd,H-3), 7.42(lH,d,H-6), 7.52(1 H,td,H-5), 7.58(lH,dt,H-4), 8.01(lH,dd,H-6); 8 ^ (film)1658s, 1727s cm1,

PERTANIKA VOL. 12 NO. 1, 1989 77

FAUJAN B. H. AHMAD AND J. MALCOLM BRUCE

OH

MeO-CHgCl

Bt,N/Et2O

Scheme 3

OMOM

(10)

(9)

OMe

OMe

(11* R = MOM

(12) R=r H

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WEINSTOCK. 1979. A New Preparation of Chlo-

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DUNN, B.M. and T.C. BRUICE. 1970. Steric and

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Fuji, K,, S. NAKANO, and E. FUJITA. 1975. An Im-

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GREENE, T.W. 1981. Protective Groups in Organic Syn-

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KHAN, AJ. and J.M. BRUCE. 1986. University of

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78 PERTANIKAVOL. 12 NO. 1, 1989