Scientific paper
Synthesis of Aryl Alkyl Ethers by Alkylation of Phenols with Quaternary Ammonium Salts
Nenad Mara{, Slovenko Polanc and Marijan Ko~evar*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5,
SI-1000 Ljubljana, Slovenia
* Corresponding author: E-mail: marijan.kocevar@fkkt.uni-lj.si
Received: 02-03-2009 Dedicated to the memory of the late Prof. Dr. Valentin Koloini
Abstract
Phenolic compounds can be efficiently O-methylated with tetramethylammonium chloride in diglyme or polyethyle-neglycol (PEG) at temperatures of 150-160 °C and in the presence of either K2CO3 or NaOH. When applying benzyl-trimethylammonium chloride as a reagent, the benzylation and methylation of phenols occurs, with the benzylation product always predominating. With allyl-substituted phenols as substrates and using NaOH as a base it was possible to achieve both the alkylation and the double-bond isomerization of the allyl group to obtain (_E/Z)-propenyl-substituted methyl and benzyl aryl ethers in a single preparative step.
Keywords: Phenols, quaternary ammonium salts, alkylation, tetramethylammonium chloride
harsh conditions (200-230 °C and with CaO as a base).2 Tetramethylammonium hydroxide (Me4NOH) was reported to be a useful reagent for the O-methylation of estradiol and estriol.3 The N-demethylation and N-debenzyla-tion of quats by their reaction with thiophenol is a known method for preparing tertiary amines.4 In fact, the SN2 transition state in the reaction between the benzyldi-methylphenylammonium and thiophenoxide ions has been thoroughly investigated by measuring the kinetic isotopic effects.5 Ring-opening reactions, resulting from the nucleophilic attack on the quats derived from quinuc-lidine and some related azabicyclic systems, have been described.6 The O-, N- and S-alkylation of some carboxy-lic acids, amines, anilines and thiophenol, with various quats at 160 °C in 1-methyl-2-pyrrolidinone (NMP) as a solvent, was also reported.7 The oxidation of benzylam-monium salts to benzaldehydes by heating in dimethyl sulfoxide has been attributed to a nucleophilic attack by the solvent, followed by the decomposition of the resulting benzyloxydimethylsulfonium ion.8 Several other examples of nucleophilic substitution with quats can also be found in the literature9 but for the preparative O-alkyla-tions of phenols only the more reactive phenyltrimethy-lammonium salts have received further attention from organic chemists.10
1. Introduction
In our recent investigation of phenolic derivatives,1 we described the application of tetramethylammonium chloride (Me4NCl) as a methylation reagent for phenols subjected to microwave heating at 145 °C and in the presence of K2CO3 or Cs2CO3 as the base (Scheme 1).1a
Scheme 1: Microwave-assisted methylation of phenols with
Quaternary ammonium salts (quats) are, in general, only rarely used as electrophilic reagents for the preparative alkylations of phenols or related nucleophiles. For example, the O-methylation of phenols with betaine (2-trimethylammonioacetate) was reported to occur under
Me4NCl.
Table 1: Reactions of phenols with quaternary ammonium chlorides.
ArOH + R1R2R3R4NCl ^ ArOR(1-4)
Entry Substrate
Ammonium	Product(s)
salt	(their approximate molar ratios)a
Reaction ^ th db Product time [h]	isolated; yield
6	A	lb	; 95%
6	B	lb	; 95%
6	B	lc	; 7%
6	B	ld	; 27%
6	A	le;	73%
6	A	le;	47%
2	A	2b	; 36%
6	C	2b	; 83%
2	A	3b	; 50%
12	A	3b	; 95%
0.5	A	3b	; 86%
4	B	4b	81%
4	B	4c	75%
6	B	5b	; 75%
4	B	6b	16%
2	B	7b	; 72%
		7d	; 3%c
10	B	Sb	; 90%
8	B	Sc;	56%
4	C	78%d	
4	C	(E/Z)-9d;	
		42%	
4	C	75%d	
4	C	(E/Z)-l0d;	
Me4NCl
Et4NCl
Bu4NCl
BnMe3NCl
BnEt3NCl
le (97) : lc (3)
u^'-C-'C«
Me4NCl
xx »
9 10 11
Me4NCl
PhMe3NCl
OMe
12 13
VCH
Me4NCl
BnMe3NCl
14 5,
Me4NCl
Me4NCl
16
17
18
Me4NCl
BnMe3NCl
19
20
Me4NCl
BnMe3NCl
21
22
Me4NCl
BnMe3NCl
67%
6
In our study,1a the aprotic solvents of low polarity (for example: 1,2-dimethoxyethane, ethyl acetate, and toluene) that are less efficient at solvating the ammonium electrophile and the phenoxide nucleophile were found to be optimal for the methylation of phenols with Me4NCl. Such a microwave-assisted reaction in a closed vessel is advantageous on a millimolar scale, but for scaling up the reaction, an alternative employment of conventional heating could prove just as useful. This idea prompted us to investigate the scope and limitations of the modified reaction, applying conventional heating in an open flask as well as the behavior of other quaternary ammonium salts in this peculiar type of nucleophilic substitution. The 1,2-dimethoxyethane (glyme) proved to be a particularly efficient solvent for the microwave-assisted reaction in the closed vessel. We therefore decided to use the higher boiling diglyme or polyethyleneglycol (PEG) as related solvents that would allow us to conduct the reaction at atmospheric pressure.
2. Results and Discussion
The alkylations, as presented in the Table 1, were performed at 150-160 °C under three types of reaction conditions: applying K2CO3 as a base in either diglyme during reflux (method A) or PEG (method B), while NaOH in PEG was used for the reactions where the presence of a strong base was desirable (method C). A 25% molar excess of the quats was generally used. The reaction mixtures were diluted with 1M NaOH solution and worked up by either extraction (entries 1-6, 12-16, 18-20, and 22) or by steam distillation in the cases of more volatile products (entries 7-11, 17, and 21). The crude products were first analyzed by 1H NMR spectroscopy to determine the products formed and their approximate molar ratio. In cases where several products were formed, the major one was isolated and subsequently characterized.
Using either method A or B in the methylation of 2-naphthol with Me4NCl gave the same results (entries 1 and 2). We found that the use of method B was preferable, because it avoided the application of reflux conditions. The slurry of the substrate, the quat and the base in the minimal amount of PEG was stirred in an oil bath. For most substrates the methylation required at least four hours of
a)	The crude product from the reaction-mixture extraction was analyzed by 'H NMR. Only the major products that could be positively identified from the spectroscopic data are taken into account: their sum is normalized to 100% and the approximate molar ratio is given.
b)A:	K2CO3, diglyme, reflux (approx. 155 °C); B: K2CO3, PEG, 150-160 °C; C: NaOH, PEG, 150-160 °C.
c)	In this case the water-insoluble amine fraction was also isolated in order to check if any ring-opening reactions occurred.
d)	The mixture could not be separated chromatographically or otherwise.
Therefore, the yield given is for the sum of products.
heating. For example, 2,4-dimethylphenol (2a) and thymol (3a) gave only 36% and 50% yields, respectively, when using method A with a 2 h reaction time (entries 7 and 9). Yet when prolonging the reaction time to 12 h, the thymol gave a nearly quantitative yield of 3b (entry 10). The reactivity of Me4NCl was thus expectedly lower than that of phenyltrimethylammonium chloride (PhMe3NCl), which gave an 86% yield under the same conditions within 30 minutes of reaction time (entry 11).
The alkylation of 2-naphthol (1a) with tetraethylam-monium chloride (Et4NCl) and tetrabutylammonium chloride (Bu4NCl) resulted mainly in the formation of tarry side products. Only poor yields of the ethylated and butyla-ted products (1c and 1d, respectively) could be isolated from these complex mixtures (7% and 27% of isolated yields; entries 3 and 4). Most likely the competing Hofmann elimination, a side reaction to which such quats are prone,9a is at least partially responsible for the low yields of 1c and 1d, but the formation of tarry products might also indicate that other side reactions play an important role.
When using benzyltrimethylammonium chloride (BnMe3NCl) the reaction gave both the benzylation and methylation products (1b and 1e) in a ratio of 88 : 12 (entry 5); the predominant benzylation product 1e was isolated in a 73% yield. In fact, the yield of such a reaction when using BnMe3NCl is quite acceptable for preparative purposes. This is also a much more comfortable method when comparing this reagent to the use of the lachrymatory benzyl bromide or chloride, which are most commonly used for the benzylation of phenols. Benzylation with BnMe3NCl is a useful alternative for simple substrates that are not sensitive to the higher temperature required, particularly when considering this reagent is both commercially available and inexpensive. On the other hand, when using benzyltriethylammonium chloride (Bn-Et3NCl) the reaction gave a relatively poor yield of 1e, regardless of the fact that it exhibited a higher selectivity toward benzylation (entry 6).
The methylation of p-hydroxypropiophenone (4a) and 3-ethoxy-4-hydroxybenzaldehyde (5a) with Me4NCl gave good yields (entries 12 and 14). In contrast, 5-bromo-2-hydroxybenzaldehyde (6a) only gave a low yield (16%) of 5-bromo-2-methoxybenzaldehyde (6b) (entry 15).
To study the chemical behavior of a quat incorporating the ammonium nitrogen in a heterocyclic ring, we alkylated 6-bromo-2-naphthol (7a) with N-benzyl-N-methylmorpholinium chloride (entry 16). The main product was again the benzylated one, 7b. The methylation product 7c could only be detected in a low ratio (the benzylation/methylation selectivity was about 30 to 1). Still, the ease of the methyl-group transfer seems comparable to that in BnMe3NCl when the statistical difference of one vs. three transferable methyl groups is taken into account. In order to catch the eventual products arising from the nucleophilic attack on the two electrophilic en-docyclic methylene groups, we also isolated the water-
insoluble basic fraction of the amine products. Their chromatographic separation yielded mainly N-benzylmorpho-line (7d), whereas the other side products were present in amounts too small for a proper characterization. N-Benzylmorpholine (7d) is the leaving group during the methylation pathway yielding 7c and thus it is not surprising that it was present in the reaction mixture in an equi-molar amount. The ring-opening pathway of the morpho-linium ring could therefore not be demonstrated.
The catechol (8a) was efficiently dimethylated with twice the regular amount of Me4NCl (entry 17). Its reaction with BnMe3NCl gave a mixture of all the possible benzylation and methylation products, of which the di-benzylated product 8c strongly predominated (entry 18). The two possible mixed methylation/benzylation products 8d formed to an extent of about 15%, as shown by the 1H NMR spectroscopy (the phenolic monoalkylated products were mainly lost during the extraction and are thus not included in the given ratio). Regardless of the mixture's complexity, the dibenzylated product 8c was easily isolated in a 56% yield by a recrystallization from methanol.
Exploiting the high reaction temperature to provide a synthetic advantage we applied NaOH as a base on allyl-substituted phenols, hoping that it would promote not just the O-alkylation but also the isomerization of the double bond to the thermodynamically more favorable propenylbenzenes. Such an isomerization can be either base or transition-metal catalyzed.11 The base-catalyzed version is most commonly achieved by the application of KOH in high boiling alcohols or other solvents. Efficient modifications using hydroxides with quaternary ammonium salts as the phase-transfer catalysts were also des-cribed.12 However, K2CO3 as a base was found to be too weak for eugenol (9a) as a substrate in our microwave-assisted methylation1a and we could not detect any double-bond isomerization after 25 min at 145 °C. Thus, for the isomerization to occur, we performed the alkylations of eugenol (9a) and 2-allylphenol (10a) with Me4NCl and BnMe3NCl, applying NaOH in PEG (method C). The main products were indeed the O-alkylated propenyl derivatives, as mixtures of (E)- and (Z)-isomers (entries 19 to 22). In the crude product mixtures some non-iso-merized allyl intermediates could always be detected (these varied from 4% to 18%, as estimated from the 1H NMR spectroscopic data). The E/Z ratio varied from 3 : 1 to 6 : 1, thus always in favor of the (E)-isomer. Due to the similar physical properties and the chromatographic mobility of all these isomers we could not separate them if they were liquid at room temperature. In some cases, however, this can be done by fractionation through very efficient distillation columns, but this is not a feasible option on such a small scale. In fact, all our attempts to achieve the separation of the diastereoisomers and ally-lic intermediates on TLC or by radial chromatography failed. With the analytical HPLC reverse phase column,
partial separation could be achieved at long retention times. Only the solid (£)-0-benzylisoeugenol ((E)-9d) could easily be isolated by the recrystallization of (E/Z)-9d from ethanol.
3. Conclusion
We demonstrated that tetramethylammonium chloride (Me4NCl) and benzyltrimethylammonium chloride (BnMe3NCl) can be used as methylation and benzylation reagents for phenols. The other quaternary ammonium salts that we tried were generally less efficient for the alkylation of the above substrates. The methylation and benzylation of allyl-substituted phenols, such as eugenol or 2-allylphenol, with the use of a strong base like NaOH, led to the concurrent double-bond isomerization.
4. Experimental
4. 1. General
NMR spectra were recorded on a Bruker Avance DPX 300-MHz spectrometer in CDCl3 (unless where D2O is specified) with tetramethylsilane (TMS) as the internal standard (or DSS in D2O) at 29 °C. Melting points are uncorrected and were measured on a Kofler micro hot stage. Reactions were monitored with TLC or HPLC (Nucleosil C-18 column using an acetonitrile/water mobile phase and a UV detector at 254 nm). Mass spectra were recorded with a VG-Analytical AutoSpec Q instrument. Elemental analyses (C, H, N) were performed with a Perkin Elmer 2400 CHN Analyzer. All reagents used were commercially available, with the exception of the N-benzyl-N-methylmorpholinium chloride, the synthesis of which is given below. The potassium carbonate was finely ground and dried at 150 °C for 12 hours. Polyethyleneglycol (PEG) with an average molecular mass of 400 was used (PEG400).
N-Benzyl-N-methylmorpholinium chloride. A solution of N-methylmorpholine (13.8 mL, 125 mmol) and benzyl chloride (11.5 mL, 100 mmol) in methanol (120 mL) was heated during reflux for 3 h and then evaporated in vacuo. The residue was triturated in acetone (100 mL), the crystalline solid filtered, washed with acetone (3 x 30 mL) and dried in vacuum to give N-benzyl-N-methyl-morpholinium chloride (21.85 g, 96% yield): mp = 243245 °C dec. (lit.13 236 °C dec.); 1H NMR (D2O, sodium 3-(trimethylsilyl)-1-propanesulfonate, DSS, as an internal standard) 5 3.09 (s, 3H, Me), 3.32-3.42 (m, 2H), 3.53-3.66 (m, 2H), 3.96-4.15 (m, 4H) (4 x morpholine CH2), 4.60 (s, 2H, CH2), 7.55 (m, 5H, Ph); 13C NMR (D2O2 , DSS as an intern2al standard) 5 46.2, 59.5, 60.9, 69.9, 126.5, 129.7, 131.4, 133.6; IR (KBr) v 1489, 1454, 1439, 1402, 1119 cm-1.
4. 2. Alkylations by the Method A
Typical Procedure. 2-Methoxy-4-methyl-1-iso-propylbenzene (3b).114 The slurry of thymol (3a, 4.50 g; 30 mmol), tetramethylammonium chloride (4.25 g, 37.5 mmol), K2CO3 (5.17 g, 37.5 mmol) and diglyme (12 mL) was stirred during reflux for 12 h (reaction-mixture temperature 150-155 °C) (Table 1, Entry 10). Upon cooling, water was added (80 mL) and the reflux condenser changed with a distillation setup. The product was then steam-distilled, adding more water when necessary, finishing only when no more colorless oil came over with the steam. The distillate was extracted with petroleum ether (30 mL), washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na^O4 and evaporated in vacuo to give 3b as a colorless oil (4.67 g, 95% yield); 1H NMR 5 1.19 (d, J 6.9 Hz, 6H, 2 x Me), 2.32 (s, 3H, Me), 3.27 (sept., J 6.9 Hz, 1H, CH), 3.81 (s, 3H, OMe), 6.67 (s, 1H, ArH), 6.74 (d, J 7.8 Hz, 1H, ArH), 7.09 (d, J 7.8 Hz, 1H, ArH); IR (NaCl) v 1612, 1580, 1504, 1460 cm1.
The reaction of 3a with phenyltrimethylammonium chloride (PhMe3NCl) was performed as above with a 30-min reaction time (Table 1, Entry 11). The petroleum ether extract was additionally washed twice with 1-M aqueous HCl in order to remove the N,N-dimethylaniline originating from the PhMe3NCl. Yield of 3b: 4.21 g (86%).
2-Methoxynaphthalene (1b).1,15 After a 6-h reaction time (Table 1, Entry 1), the reaction mixture was diluted with water (80 mL), extracted with ethyl acetate (60 mL), washed twice with 1-M aqueous NaOH (30 mL), water (30 mL), dried over Na^O4 and evaporated in vacuo to give a brownish residue ,which after a short-path vacuum distillation gave an colorless oil, which immediately solidified on cooling (4.51 g, 95% yield); mp = 70-71 °C (lit.15 71-72 °C); 1H NMR 5 3.92 (s, 3H), 7.10-7.18 (m, 2H, OMe), 7.33 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.75 (m, 3H, ArH); IR (KBr) v 1632, 1597, 1506, 1476, 1462 cm-1.
2-Benzyloxynaphthalene (1e).5 The reaction of 2-naphthol (1a) with benzyltrimethylammonium chloride (BnMe3NCl) (Table 1, Entry 5) and the extraction were performed with the same protocol as for 1b. The crude product, which contained 1e and 1b in a ratio 88 : 12 (based on 1H NMR spectroscopic data), was recrystallized from methanol to give 1e as crystalline powder (5.08 g, 73% yield); mp = 97-98 °C (lit.8 97-99 °C); 1H NMR 5 5.18 (s, 2H, CH2), 7.23 (m, 2H, ArH), 7.30-7.52 (m, 7H, ArH), 7.69-7.799 (m, 3H, ArH); IR (KBr) v 1624, 1593, 1506, 1451, 1388 cm-1.
The reaction with benzyltriethylammonium chloride (BnEt3NCl) (Table 1, Entry 6) was done as above, to give 1e after recrystallization (3.30 g, 47% yield).
1-Methoxy-2,4-dimethylbenzene (2b).16 Methyla-tion of 2,4-dimethylphenol as for 3b, with a 2-h reaction time (Table 1, Entry 7), gave a colorless oil (1.47 g, 36%
yield); 1H NMR 5 2.19 (s, 3H, Me), 2.25 (s, 3H, Me), 3.79 (s, 3H, OMe), 6.71 (m, 1H, ArH), 6.94 (m, 2H, ArH); IR (KBr) v 1615, 1507, 1464, 1442, 1378, 1305 cm1.
4. 3. Alkylations by the Method B
Typical procedure. 1-(4-Methoxyphenyl)propan-1-one (4b).1,17 The slurry of p-hydroxypropiophenone (4.50 g; 30 mmol), tetramethylammonium chloride (4.25 g, 37.5 mmol), K2CO3 (5.17 g, 37.5 mmol) and PEG (12 mL) was stirred for 4 h in an oil bath at 150-160 °C (temperature of the reaction mixture) (Table 1, Entry 12). Upon cooling, water was added (80 mL), the mixture was extracted with diethyl ether (50 mL), the etheral extract was washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na2SO4 and evaporated in vacuo to give an oil, which after a short-path vacuum distillation gave a colorless oil that slowly crystallized in the refrigerator (4.00 g, 81% yield); mp = 25-27 °C (from petroleum ether) (lit.17 27 °C); 1H NMR 5 1.21 (t, J 7.2 Hz, 3H, Me), 2.95 (q, J 7.2 Hz, 2H, CH2), 3.87 (s, 3H, OMe), 6.93 (AA'XX', J 9.0 Hz, 2H, ArH), 7.95 (AA'XX', J 9.0 Hz, 2H, ArH); IR (KBr) v 1679, 1602, 1510, 1460, 1418 cm-1.
2-Ethoxynaphthalene (1c).18 The reaction of 1a with tetraethylammonium chloride (Et4NCl) (Table 1, Entry 3) and the extraction were performed on a 15 mmol scale under the same protocol as for 4b. The product 1c (180 mg, 7% yield) was isolated using radial chromatography with petroleum ether as the eluent; mp = 35-37 °C (lit.4 37-38 °C); 1H NMR 5 1.49 (t, J 7.0 Hz, 3H, Me), 4.16 (q, J 7.0 Hz, 2H, CH2), 7.15 (m, 2H, ArH), 7.33 (m, 1H, ArH), 7.44 (m, 1H, ArH), 7.74 (m, 3H, ArH); IR (KB-r) v 1624, 1595, 1508, 1462, 1388 cm1.
2-n-Butoxynaphthalene (1d).19 The reaction of 1a with tetrabutylammonium chloride (Bu4NCl) (Table 1, Entry 4) was performed on a 10-mmol scale, as for 1c. The recrystallization from a minimal amount of methanol gave 1d (0.54 g, 27% yield); mp = 31.5-32 °C (lit.4 31-35 °C); 1H NMR 5 1.00 (t, J 7.4 Hz, 3H, Me), 1.54 (m, 2H, CH2), 1.83 (m, 2H, CH2), 4.08 (t, J 6.5 Hz, 2H, OCH2), 7.142 (m, 2H, ArH), 7.31 (m, 1H, ArH), 7.42 (m, 1H, ArH), 7.73 (m, 3H, ArH); IR (KBr) v 1628, 1595, 1508, 1462, 1389 cm-1.
1-(4-Benzyloxyphenyl)propan-1-one (4c).20 The reaction of 4a with benzyltrimethylammonium chloride (BnMe3NCl) (Table 1, Entry 13) and the extraction were performed under the same protocol as for 4b. The crude product, which contained 4c and 4b in a 82 : 18 ratio (1H NMR spectroscopic data), was recrystallized from heptane/ethyl acetate (~ 10 : 1) to give 4c as a fluffy crystalline product (5.43 g, 75% yield): mp = 100-102 °C (lit.20 102-103 °C); 1H NMR 5 1.21 (t, J 7.3 Hz, 3H, CH2CH3), 2.94 (q, J 7.3 Hz, 2H, CH2CH3), 5.13 (s, 2H, OCH2), 7.00
(AA'XX', J 9.0 Hz, 2H, ArH), 7.30-7.46 (m, 5H, Ph), 7.94 (AA'XX', J 9.0 Hz, 2H, ArH); IR (KBr) v 1680, 1597, 1508, 1456 cm-1.
3-Ethoxy-4-methoxybenzaldehyde (5b).1,21 The same protocol was used as for 4b, with a 6-h reaction time (Table 1, Entry 14). After evaporating the extract an oil was obtained, which crystallized upon standing to give 5b (4.05 g, 75% yield); mp = 47-49 °C (lit.21 49.5-50.5 °C); 1H NMR 5 1.49 (t, J 7.0 Hz, 3H, Me), 3.96 (s, 3H, OMe), 4.17 (q, J 7.0 Hz, 2H, CH2), 6.98 (d, J 8.2 Hz, 1H, ArH), 7.43 (dt, J 8.2, 1.9 Hz, 2H, ArH), 9.85 (s, 1H, CHO); IR (KBr) v 1691, 1677, 1599, 1511, 1440 cm1.
5-Bromo-2-methoxybenzaldehyde (6b).22 The same protocol with 4 h reaction time was used as for 4b (Table 1, Entry 15). After evaporating the extract a brown solid was obtained which was recrystallized from ethanol/water to give 6b as off-white crystals (1.05 g, 16% yield); mp = 111-114 °C (lit.6 113-114.5 °C); 1H NMR 5 3.93 (s, 3H, Me), 6.90 (d, J 8.9 Hz, 1H, ArH), 7.63 (dd, J 8.9, 2.6 Hz, 1H, ArH), 7.92 (d, J 2.6 Hz, 1H, ArH), 10.39 (s, 1H, CHO); IR (KBr) v 1673, 1591, 1478, 1391, 1267 cm1.
less oil, which crystallized upon standing to give 8b (5.25 g, 90% yield); mp = 32-34 °C (lit.25 34-35.5°C); 1H NMR 5 1.31 (s, 9H, i-Bu), 3.86 (s, 3H, OMe), 3.89 (s, 3H, OM-e), 6.80 (m, 1H, ArH), 6.88-6.94 (m, 2H, ArH); IR (KBr) v 1606, 1591, 1523, 1471, 1449 cm1.
4-ieri-Butyl-1,2-dibenzyloxybenzene (8c). The
reaction of 8a (5.0 g, 30 mmol) with benzyltrimethylam-monium chloride (14.0 g, 75 mmol) (Table 1, Entry 18) was performed as above for 8b, with the exception that the extraction with ethyl acetate was used to isolate the product mixture, which was recrystallized from methanol to give pure 8c as colorless crystals (5.85 g, 56% yield); mp = 61-62 °C; 1H NMR 5 1.24 (s, 9H, i-Bu), 5.11 (s, 2H, CH2), 5.15 (s, 2H, CH2), 6.87 (m, 2H, ArH), 6.98 (d, J 1.5 Hz, 1H, ArH), 7.23-7.37 (m, 6H, ArH), 7.40-7.47 (m, 4H, ArH); 13C NMR 5 31.4, 34.3, 71.4, 71.8, 113.9, 114.6, 118.3, 127.3, 127.5, 127.6, 127.7, 128.36, 128.39, 137.60, 137.61, 144.7, 147.1, 148.3; IR (KBr) v 1634, 1601, 1589, 1519, 1455 cm-1; MS (ESI) m/z: 369 (MNa+); HRMS-ESI (m/z): [M+Na]+ calcd for C24H26O2Na, 369.1831; found, 369.1820. Anal. Calcd for C24H26O2: C 83.20, H 7.56. Found: C 83.32, H 7.76.
2-(Benzyloxy)-6-bromonaphthalene (7b).23 6-Bromo-2-naphthol (7a) was alkylated with N-benzyl-N-methylmorpholinium chloride with a 2-h reaction time and a 12-mmol reaction scale (Table 1, Entry 16). The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL), the extract was washed with 1-M aqueous NaOH (2 x 30 mL) and water (30 mL). The ethyl acetate solution was extracted with 1-M aqueous HCl (30 mL); this aqueous extract was made basic with 2-M NaOH, back extracted with diethyl ether (25 mL) and evaporated in vacuo to give the amine fraction of products as a colorless oil (160 mg). The ethyl acetate solution was evaporated in vacuo to give a yellowish powder, which upon recrystallization from methanol yielded 7b as shiny scales (2.70 g, 72% yield); mp = 109-111 °C (lit.6110 °C); 1H NMR 5 5.17 (s, 2H, CH2), 7.15-7.27 (m, 2H), 7.31-7.53 (m, 6H), 7.55-7.69 (m, 2H), 7.92 (d, J 1.8 Hz, 1H) (all aryl protons); IR (KBr) v 1625, 1585, 1497, 1454, 1383 cm-1. The amine fraction was separated by employing radial chromatography with petroleum ether : ethyl acetate (1 : 1) as the eluent, yielding N-benzylmorp-holine (7d)24 as an oily product (60 mg, 3% yield); 1H NMR 5 2.44 (m, 4H, 2 x CH2), 3.49 (s, 2H, PhCH2), 3.70 (m, 4H, 2 x CH2), 7.21-7.35 (m, 5H, Ph); IR (NaCl) v 1493, 1450, 1393, 1351, 1286 cm-1.
4-teri-Butyl-1,2-dimethoxybenzene (8b).25 The same reaction protocol was used as for 4b, but starting from 8a (5.0 g, 30 mmol), tetramethylammonium chloride (8.5 g, 75 mmol), K2CO3 (10.34 g, 75 mmol) and PEG (24 mL) with a 10-h reaction time (Table 1, Entry 17). The product was isolated using steam distillation to give a color-
4. 4. Alkylations by the Method C
O-Methylisoeugenol ((E/Z)-9b). The slurry of eu-genol (9a, 8.29 g, 50 mmol), tetramethylammonium chloride (7.1 g, 62.5 mmol) and NaOH (2.6 g, 62.5 mmol) in PEG (20 mL) was stirred for 4 h in an oil bath at 150-160 °C (temperature of the reaction mixture) (Table 1, Entry 19). Upon cooling, water was added (100 mL), the mixture extracted with diethyl ether (60 mL), washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na2SO4 and evaporated in vacuo to give a slightly orange oil, which after short-path vacuum distillation gave a colorless oil (6.91 g, 78% yield). NMR spectroscopic analysis of the product revealed the E : Z diastereomeric ratio to be 4 : 1 (the coupling constants for the CH=CH protons were 15.7 Hz and 11.6 Hz, respectively) and also showed the presence of approximately 10% of O-methyleugenol (9c). MS (EI) m/z (relative intensity): 178 (M+, 100), 163 (40), 147 (14), 107 (26), 103 (15), 91 (25); HRMS-EI (m/z): [M]+ calcd for CnH14O2, 178.0994; found 178.0992; IR (NaCl) v 1599), 1583, 1514, 1460, 1416 cm-1. The 1H NMR spectrum of the major component (E)-9b26 is given as follows: 5 1.86 (dd, J 6.6, 1.6 Hz, 2H, Me), 3.87 (s, 3H, OMe), 3.89 (s, 3H, OMe), 6.10 (dq, J 15.7, 6.6 Hz, 1H, CH=CH-Me), 6.34 (dq, J 15.7, 1.6 Hz, 1H, CH=CH-Me), 6.79 (d, J 8.2 Hz, 1H, ArH), 6.85 (dd, J 8.2, 1.8 Hz, 1H, ArH), 6.89 (d, J 1.8 Hz, 1H, ArH). The presence of (E)-9b was additionally confirmed by adding an authentic commercial sample to the above mixture.
O-Benzylisoeugenol ((E/Z)-9d). The slurry of euge-nol (9a, 5.0 g, 30 mmol), benzyltrimethylammonium chlo-
ride (7.18 g, 37.5 mmol) and NaOH (1.6 g, 37.5 mmol) in PEG (12 mL) was stirred for 4 h in an oil bath at 150-160 °C (temperature of the reaction mixture) (Table 1, Entry 20). Upon cooling, water was added (80 mL), the mixture was extracted with diethyl ether (60 mL), washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na2SO4 and evaporated in vacuo to give a brown oil, which was diluted with methanol/water (8:1, 50 mL). The solid precipitated after standing at cold was filtered off to give (E/Z)-9d as long needles (3.20 g, 42%). NMR spectroscopic analysis showed the E : Z diastereomeric ratio to be approximately 7 : 1 (the coupling constants for the CH=CH protons were 15.7 Hz and 11.6 Hz, respectively). MS (EI) m/z (relative intensity): 254 (M+, 39), 163 (71), 91 (100); HRMS-EI (m/z): [M]+ calcd for C17H18O2, 254.1307; found, 254.1310. Anal. Calcd for C17H18O2: C 80.28, H 7.13. Found: C 80.42, H 6.98. A sample of (E/Z)-mixture was recrystallized from ethanol to give (E)-O-benzylisoeu-genol ((E)-9d): mp 51-52 °C (lit.27 53-54 °C); 1H NMR 5 1.84 (dd, J 6.5, 1.3 Hz, 3H, Me), 3.87 (s, 3H, OMe), 5.11 (s, 2H, OCH2), 6.08 (dq, J 15.7, 6.5 Hz, 1H, CH=CHMe), 6.31 (dq, J 15.7, 1.3 Hz, 1H, CH=CHMe), 6.78 (m, 2H, ArH), 6.89 (s, 1H, ArH), 7.20-7.47 (m, 5H, Ph); 13C NMR 5.18.3, 55.9, 71.1, 109.1, 114.2, 118.5, 123.9, 127.2, 127.7, 128.4, 130.6, 131.7, 137.2, 147.3, 149.7; IR (KBr) v 1598, 1582, 1512, 1456, 1414, 1381 cm-1.
(E/Z)-1-methoxy-2-(prop-1-en-1-yl)benzene ((E/Z)-10b). The slurry of 2-allylphenol (10a, 6.94 g, 50 mmol), tetramethylammonium chloride (7.1 g, 62.5 mmol) and NaOH (2.6 g, 62.5 mmol) in PEG (20 mL) was stirred for 4 h in an oil bath at 150-160 °C (temperature of the reaction mixture) (Table 1, Entry 21). Upon cooling, water was added (100 mL) and the products steam-distilled, as described for 3b. The distillate was extracted with petroleum ether (30 mL), washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na2SO4 and evaporated in vacuo to give (E/Z)-10b as a colorless oil (5.55 g, 75% yield). NMR spectroscopic analysis revealed the E : Z dia-stereomeric ratio to be 3.7 : 1 (the coupling constants for the CH=CH protons were 15.9 Hz and 11.6 Hz, respectively) and also showed the presence of approximately 4% 2-allylanisole (10c). MS (EI) m/z (relative intensity): 148 (M+, 100), 133 (24), 119 (36), 117 (23), 115 (27), 105 (34), 91 (49); HRMS-EI (m/z): [M]+ calcd for C10H12O, 148.0888; found, 148.0889; IR (NaCl) v 1598, 1489, 1460, 1437, 1243 cm-1. The 1H NMR spectrum of the major component (E)-10b28 as determined from the mixture of products: 5 1.90 (dd, J 6.6, 1.7 Hz, 2H, Me), 3.84 (s, 3H, OMe), 6.22 (dq, J 15.9, 6.6 Hz, 1H, CH=CH-Me), 6.71 (dq, J 15.9, 1.7 Hz, 1H, CH=CH-Me), 6.88 (m, 2H, ArH), 7.17 (m, 1H, ArH), 7.38 (dd, J 7.6, 1.6 Hz, 1H, ArH).
(E/Z)-1-(Benzyloxy)-2-(prop-1-en-1-yl)benzene ((E/Z)-10d). The slurry of 2-allylphenol (10a, 4.10 g; 30 mmol), benzytrimethylammonium chloride (7.18 g, 37.5
mmol) and NaOH (1.6 g, 37.5 mmol) in PEG (12 mL) was stirred for 4 h in an oil bath at 150-160 °C (temperature of the reaction mixture) (Table 1, Entry 22). Upon cooling, water was added (100 mL), the mixture was extracted with diethyl ether (80 mL), washed with 1-M aqueous NaOH (2 x 30 mL), water (30 mL), dried over Na2SO4 and evaporated in vacuo to give a brown oil. The benzylated and methylated products had very similar chromatograp-hic mobility on TLC. Thus, the mixture was first purified from polar impurities by filtering its petroleum ether solution through a plug of silica to give a colorless oil (5.48 g), from which the methylated products were removed by steam distillation, leaving behind pure (E/Z)-10d (4.5 g, 67% yield). 1H NMR spectroscopic analysis revealed the E : Z diastereomeric ratio to be 6.3 : 1 (the coupling constants for the CH=CH protons were 15.9 Hz and 11.6 Hz, respectively). MS (EI) m/z (relative intensity): 224 (M+, 8), 105 (8), 91 (100); HRMS-EI (m/z): [M]+ calcd for C16H16O, 224.1201; found 224.1206; IR (NaCl) v 1597, 15178, 1488, 1449, 1378 cm-1. The 1H NMR spectrum of the major component (E)-10d28 is given: 5 1.89 (dd, J 6.6, 1.7 Hz, 2H, Me), 5.09 (s, 2H, CH2), 6.24 (dq, J 15.9, 6.6 Hz, 1H, CH=CH-Me), 6.79 (dq, J 15.9, 1.7 Hz, 1H, CH=CH-Me), 6.91 (m, 2H, ArH), 7.14 (m, 1H, ArH), 7.27-7.47 (m, 6H, ArH).
5. Acknowledgements
We thank the Ministry of Higher Education, Science and Technology of the Republic of Slovenia and the Slovenian Research Agency for financial support (P1-0230-0103). Dr. B. Kralj and Dr. D. Žigon (Center for Mass Spectroscopy, "Jožef Stefan" Institute, Ljubljana, Slovenia) are gratefully acknowledged for the mass measurement.
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Povzetek
Fenolne spojine se da učinkovito O-metilirati s tetrametilamonijevim kloridom v diglimu ali polietilen glikolu (PEG) pri temperaturah 150-160 °C in v prisotnosti K2CO3 ali NaOH. Z uporabo benziltrimetilamonijevega klorida kot reagenta potečeta tako benziliranje kot tudi metiliranje fenolov, pri čemer je vedno prednosten produkt benziliranja. Pri uporabi alil-substituiranih fenolov kot substratov in NaOH kot baze je mogoče izvesti tako alkiliranje kakor tudi izome-rizacijo dvojne vezi alilne skupine, pri čemer nastanejo (_E/Z)-propenil-substituirani metil in benzil aril etri v eni sami preparativni stopnji.