Synthesis of 5-alkyl-2,3-dihydro-1,4-benzodioxins

Article abstract of DOI:10.1081/SCC-120039503

An expedient synthesis of 5-alkyl-2,3-dihydro-1,4-benzodioxins by intramolecular cyclization of 2-(2-bromoethoxy)-3-alkylphenols prepared from 2-alkylphenols is described.

Full text of DOI:10.1081/SCC-120039503

This article was downloaded by: [UQ Library]
On: 13 November 2014, At: 09:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of
5‐Alkyl‐2,3‐dihydro‐1,4‐benzodiox
Adriano Martendal a , Rafael Dias a , Faruk Nome a
& César Zucco a
a Departamento de Química , Universidade Federal
de Santa Catarina , 88040‐900, Florianópolis,
Brazil
Published online: 10 Jan 2011.
To cite this article: Adriano Martendal , Rafael Dias , Faruk Nome & César
Zucco (2004) Synthesis of 5‐Alkyl‐2,3‐dihydro‐1,4‐benzodioxins, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:13, 2487-2498, DOI: 10.1081/SCC-120039503
To link to this article: http://dx.doi.org/10.1081/SCC-120039503
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and

Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2487–2498, 2004
Synthesis of 5-Alkyl-2,3-dihydro-
1,4-benzodioxins
Adriano Martendal, Rafael Dias, Faruk Nome,
*
´
and Cesar Zucco
´
Departamento de Quımica, Universidade Federal de Santa Catarina,
´
Florianopolis, Brazil
ABSTRACT
An expedient synthesis of 5-alkyl-2,3-dihydro-1,4-benzodioxins by
intramolecular cyclization of 2-(2-bromoethoxy)-3-alkylphenols prepared
from 2-alkylphenols is described.
Key Words: Cyclization; 2-Alkyl phenols; 5-Alkyl-2,3-dihydro-1,4-
benzodioxins; Enzyme–substrate complex.
INTRODUCTION
It is well established that there is a remarkable influence of the chain
length on intramolecular reactivity. The reaction rate normally decreases as
*
´ ´
Correspondence: Cesar Zucco, Departamento de Quımica, Universidade Federal de
´
Santa Catarina, 88040-900, Florianopolis, Brazil; E-mail: czucco@qmc.ufsc.br.
2487
DOI: 10.1081/SCC-120039503
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2488
Martendal et al.
the chain increases, the retarding effect caused by each additional methylene
group being smaller the larger the ring to be formed.[1,2]
Cyclizations of o-(v-haloalkoxy)phenols, 1, R ¼ H, n ¼ 2–20, and
Y ¼ Br and I, have been widely studied in various systems, especially with
regard to the high reactivity of these compounds as given by the effective
molarities (EM).[2–4] The effects of solvents and surfactants on the reactivity
towards the cyclization as a function of the ring size have also been studied
and the activation parameters determined.[5–7] The values found for the
entropy of activation decrease with the cyclization rates. On the other hand,
the enthalpy of activation does not normally change with the side-chain
length.[4] Based on these and on solvent effects an intramolecular mechanism
was postulated in which the reaction center has a SN2-like transition state
geometry although the reaction is rather a first-order process.[5]
As part of a study on the effects of stereopopulation control on rates,
mechanisms and equilibria, the simple intramolecular nucleophilic displace-
ment of 3-(o-hydroxyphenyl)-1-propanol monoesters, 2, X ¼ Mes, acetate
or phosphate, to form chromans, 3, was investigated. For a series involving
an invariant leaving group, appropriate methyl substitution in both the aro-
matic ring and side chain produces rate-enhancement factors of almost 106.
This methyl substitution produces partial conformational freezing of the
side chain and increases greatly the population of the conformer most closely
resembling the transition state.[8]
In this communication we described the synthesis of a series of 2-(2-
bromoethoxy)phenols, 1a–d, n ¼ 2, R ¼ methyl, isopropyl, sec-butyl, and
tert-butyl, and their conversion to the corresponding cyclic diethers 5-alkyl-
2,3-dihydro-1,4-benzodioxins, 4a–d. The influence of the alkyl ring substi-
tution might be used as a test for the stereopopulational theory,[9] which states
that during formation of the enzyme-substrate complex the enzyme limits the
substrate to one single conformation, i.e., that most favorable for the enzyme
to play its catalytic role. Therefore the ring substitution effect on the intra-
molecular cyclization reaction mechanism will be investigated later as a
model for enzyme actions and will appear elsewhere.

Synthesis of 5-Alkyl-2,3-dihydro-1,4-benzodioxins
RESULTS
2489
Compound 2,3-dihydro-5-methyl-1,4-benzodioxin, 4a, was obtained by
reacting equimolecular amounts of 3-methylcatechol and chloromethyl ethyl
ether forming a mixture of 2-(ethoxymethoxy)-3-methylphenol, 2-(ethoxy-
methoxy)-6-methylphenol, and unreacted 3-methylcatechol, which was
removed by column chromatography. The resulting mixture was then treated
with 1,2-dibromoethane and the protecting group was removed by acid
catalysis. Compounds 2-(2-bromoethoxy)-3-methylphenol, 1a, and 2-(2-
bromoethoxy)-6-methylphenol (small amount) were isolated by column
chromatography. The two isomers were identified by NOESY spectra and
readily converted to the cyclic 4a in alkali medium (Sch. 1).
The synthetic route to the titled compounds 4b–d was chosen to permit the
variation of the 5-alkyl substituents on the aromatic ring. The basic skeleton
was 3-alkylcatechols obtained from the appropriate 2-alkylphenols by
oxygen-directed metalation group and metalation–boronation–oxidation
strategies.[10–13] In this manner 2-alkylphenols were reacted with chloromethyl
ethyl ether giving the corresponding 1-alkyl-2-(ethoxymethoxy)benzenes,
5b–d, followed by ortho-lithiation (butyl lithium and N,N,N0,N0-tetramethyl-
ethylenediamine) and treatment with trimethyl borate and hydrogen peroxide
to give the 3-alkyl-2-(ethoxymethoxy)phenols, 6b–d. The reaction of 6 with
benzylbromide and the acid catalyzed removal of the ethoxymethoxy protecting
group afforded 7, which by alkylation with 1,2-dibromoethane and catalytic
hydrogenation to remove the benzyl group, gave 1b–d, immediately cyclized
to 4b–d by addition of alkali solution, Sch. 2.
In conclusion, this communication described convenient methods for the
preparation of new 3-alkylsubstituted phenols, 1a–d, and their corresponding
cyclic diethers, 4c–d, despite the need for protecting/deprotecting steps. All
the spectral data are consistent with the structural assignments made for each
compound. The yields of the products may not be optimal, especially the alkyl-
ation step, but the current general procedures readily afforded multi-gram
Scheme 1. a: ClCH2OEt, CH2Cl2, NaOH–H2O, Aliquat 336; b: BrCH2CH2Br,
K2CO3, acetone, reflux; c: MeOH/HCl; d: column chromatography; e: NaOH
1 M/ethanol.

2490
Martendal et al.
Scheme 2. a: ClCH2OEt, CH2Cl2, NaOH–H2O, Aliquat 336; b: n-BuLi, TMEDA,
THF, 08C; c: B(OMe)3; d: H2O2; e: BnBr, K2CO3, acetone, reflux; f: MeOH/HCl;
g: BrCH2CH2Br, K2CO3, acetone, reflux; h: Pd-C [H2]; i: NaOH 1 M/ethanol.
quantities of pure products, which were sufficient amounts for our purposes.
All the prepared compounds were high b.p. oils.
EXPERIMENTAL
IR spectra were recorded on a Perkin–Elmer FT-IR 16PC; NMR spectra
were obtained with a Bruker AC200 spectrometer, employing tetramethyl-
silane as internal reference; MS were obtained on Shimadzu CGMS-QP2000A
spectrometer. The reagents were purchased from commercial suppliers and
were used without further purification.
2-(2-Bromoethoxy)-3-methylphenol, 1a, and 2-(2-bromoethoxy)-6-
methylphenol. To 3-methylcatechol (3.0 g, 24 mmol), in dichloromethane
(25 mL), and NaOH (0.96 g, 24 mmol), in H2O (25 mL), in a 125 mL round-
bottom flask, was added methyltrioctylammonium chloride (0.45 , 1 mmol).
The flask was stoppered with a rubber septum and under vigorous stirring
chloromethyl ethyl ether (2.18 mL, 24 mmol) was added via a syringe. The
stirring was maintained for 1 hr. The organic layer was separated and rotary
evaporated. The residue was passed through a column of silica gel eluted
with hexane/chloroform, 1 : 1, to remove unreacted 3-methylcatechol. The
resultant solution was refluxed for 24 hr with 1,2-dibromoethane (4.1 mL,

Synthesis of 5-Alkyl-2,3-dihydro-1,4-benzodioxins
2491
48 mmol) and K2CO3 (6.6 g, 48 mmol) in acetone (40 mL). The residues were
removed by filtration and the rotary evaporated organic phase was refluxed in
methanol (40 mL) and 6 M HCl (3 mL). The reaction was accompanied by
TLC. The organic layer was separated and evaporated. Column chromatog-
raphy on silica gel and elution with hexane/chloroform, 1 : 1, gave 0.99 g
(18%) of 1a, a viscous liquid. Anal. calcd. for C9H11BrO2: C, 46.78; H,
4.80. Found: C, 46.92; H, 4.75. MS: m/e (%) 51(26), 66(30), 77(40),
95(22), 107(68), 109(69), 123(100), 230(33), and 232(33). IR (KBr): 3417,
1
2959, 2929, 1580, 1472, 1277, 1214, 1177, 1072, 772 and 742 cm21. H
NMR (CDCl3): d ¼ 6.90–6.55 (m, 3H, aromatic), 5.93 (s, 1H), 4.11
(m, 2H), 3.61 (m, 2H), 2.22 (s, 3H). 13C NMR (CDCl3): d ¼ 16.75, 32.23,
73.03, 114.24, 123.08, 125.81, 131.67, 144.26, and 149.74.
2-(2-Bromoethoxy)-6-methylphenol. 0.38 g (7%), m.p. 718C. Anal.
calcd. for C9H11BrO2: C, 46.78; H, 4.80. Found: C, 46.74; H, 4.82. MS:
m/e (%) 51(14), 77(27), 95(17), 107(57), 109(60), 123(100), 230(25), and
232(24). IR (KBr): 3399, 2969, 2925, 1625, 1597, 1492, 1454, 1269, 1214,
1
1095, 760, and 733 cm21. H NMR (CDCl3): d ¼ 6.82–6.71 (m, 3H, aro-
matic), 5.81 (s, 1H), 4.34 (t, 2H, J ¼ 5.7 Hz), 3.66 (t, 2H, J ¼ 5.7 Hz), 2.26
(s, 3H). 13C NMR (CDCl3): d ¼ 16.17, 30.37, 69.79, 111.09, 119.88,
124.97, 125.39, 145.08, and 145.25.
Procedure 1
1-(Ethoxymethoxy)-2-isopropylbenzene, 5b. To isopropylphenol (2.7 mL,
20 mmol) in dichloromethane (25 mL) and NaOH (0.8 g, 20 mmol) in water
(25 mL), in a round-bottom flask, was added methyltrioctylammonium
chloride (0.45 mL, 1 mmol). Under vigorous stirring, chloromethyl ethyl
ether (1.82 mL, 20 mmol) was slowly added through a rubber septum. Stirring
was continued for 1 hr. The organic phase was separated and evaporated under
reduced pressure. The product was passed through a column of silica gel
eluted with hexane and yielded 2.33 g (61%) of 5b, b.p. 2328C. Anal. calcd.
for C12H18O2: C, 74.19; H, 9.34. Found: C, 74.35; H, 9.61. MS: m/e (%)
59(100), 77(13), 91(18), 121(26), 149(12), and 194(11). IR (KBr): 3034,
2965, 1593, 1489, 1450, 1388, 1285, 1227, 1190, 1153, 1107, 1081, 1003,
1
and 751 cm21. H NMR (CDCl3): d ¼ 7.00–7.30 (m, 4H, aromatic), 5.30
(s, 2H), 3.80 (q, 2H), 3.41 (m, 1H), 1.28 (m, 9H). 13C NMR (CDCl3):
d ¼ 15.17, 22.82, 26.90, 64.23, 93.30, 114.05, 121.73, 126.14, 126.61,
137.54, and 154.63.
1-sec-Butyl-2-(ethoxymethoxy)benzene, 5c. Prepared according to
Procedure 1, to 2-sec-butylphenol (3.1 mL, 20 mmol) in dichloromethane
(25 mL) and NaOH (0.8 g, 20 mmol) in water (25 mL), under stirring, was

2492
Martendal et al.
added methyltrioctylammonium chloride (0.45 mL, 1 mmol) followed by
chloromethyl ethyl ether (1.82 mL, 20 mmol), yielding 2.7 g (65%) of 5c,
b.p. 2518C. Anal. calcd. for C13H20O2: C, 74.96; H, 9.68. Found: C, 74.48;
H, 9.31. MS: m/e (%) 59(100), 77(14), 91(19), 121(25), 149(13), and
208(9). IR (KBr): 3032, 2964, 2929, 2874, 1593, 1489, 1453, 1386, 1225,
1
1153, 1083, 1004, 751 cm21. H NMR (CDCl3): d ¼ 7.26–6.95 (m, 4H,
aromatic), 5.30 (s, 2H), 3.80 (q, 2H), 3.19 (m, 1H), 1.67 (m, 2H), 1.29
(m, 6H), 0.91 (t, 3H). 13C NMR (CDCl3): d ¼ 12.87, 15.78, 21.32, 30.58,
34.29, 64.83, 93.96, 114.78, 122.33, 127.13, 127.48, 137.10, and 155.57.
1-tert-Butyl-2-(ethoxymethoxy)benzene, 5d. Prepared according to
Procedure 1, to 2-tert-butylphenol (3.1 mL, 20 mmol) in dichloromethane
(25 mL) and NaOH (0.8 g, 20 mmol) in water (25 mL), under stirring, was
added methyltrioctylammonium chloride (0.45 mL, 1 mmol) followed by
chloromethyl ethyl ether (1.82 mL, 20 mmol). The dried product yielded
2.54 g (61%) of 5d, b.p. 2478C. Anal. calcd. for C13H20O2: C, 74.96; H,
9.68. Found: C, 74.42; H, 9.59. MS: m/e (%) 59(100), 77(7), 91(18),
107(12), 135(9), 163(9), and 208(7). IR (KBr): 3059, 2957, 2909, 1597,
1488, 1444, 1391, 1219, 1154, 1108, 1079, 1003, and 752. 1H NMR (CDCl3):
d ¼ 7.23–6.80 (m, 4H, aromatic), 5.20 (s, 2H), 3.67 (q, 2H, J ¼ 7.0 Hz), 1.31
(s, 9H), 1.17 (t, 3H, J ¼ 7.0 Hz). 13C NMR (CDCl3): d ¼ 15.86, 30.58, 35.61,
64.97, 93.56, 115.15, 121.93, 127.34, 127.83, 138.94, and 157.13.
Procedure 2
2-(Ethoxymethoxy)-3-isopropylphenol, 6b. To 1-(ethoxymethoxy)-
2-isopropylbenzene, 5b (2.0g, 10mmol), in a three-neck 125 mL round-bottom
flask, equipped with a nitrogen inlet tube, was added dry THF (20 mL) through
a rubber septum. The flask was cooled to 08C in an ice-water bath and the
solution was vigorously stirred. With a syringe via the septum a solution at
08C of N,N,N0,N0-tetramethylethylenediamine (1.66 mL, 11 mmol) and butyl-
lithium, 1.6 M in hexanes (6.87 mL, 11 mmol), in dry THF (20 mL) was added.
After stirring for 1 hr, trimethyl borate (1.14 mL, 10 mmol) was slowly added
through the septum. The solution was stirred for an additional hour. The
ice-water cooling bath was removed and a 30% hydrogen peroxide solution
(3 mL) was added. The stirring was then continued for 30 min. The organic
phase was separated, rotary evaporated, and the product was purified by
column chromatography on silica gel (hexane/chloroform, 1 : 1) to give
1.56 g (72%) of 6b as a viscous liquid. Anal. calcd. for C12H18O3: C, 68.54;
H, 8.63. Found: C, 68.38; H, 8.59. MS: m/e (%) 59(100), 77(12), 91(12),
137(19), and 210(10). IR (KBr): 3334, 3045, 2966, 2894, 1590, 1465, 1390,
1323, 1287, 1225, 1195, 1157, 1104, 1054, 985, 790, and 748 cm21
.

Synthesis of 5-Alkyl-2,3-dihydro-1,4-benzodioxins
2493
1H NMR (CDCl3): d ¼ 7.68 (s, 1H), 7.06–6.77 (m, 3H, aromatic), 5.08
(s, 2H), 3.91 (q, 2H, J ¼ 7.0 Hz), 3.25 (sep, 1H, J ¼ 6.9 Hz), 1.36 (t, 3H,
J ¼ 7.0 Hz), 1.23 (d, 6H, J ¼ 6.9 Hz). 13C NMR (CDCl3): d ¼ 14.96, 23.23,
27.05, 65.73, 98.61, 114.41, 117.15, 125.26, 141.87, 143.74, and 148.81.
3-sec-Butyl-2-(ethoxymethoxy)phenol, 6c. Prepared according to
Procedure 2, to 1-sec-butyl-2-(ethoxymethoxy)benzene, 5c (2.08 g, 10mmol),
in dry THF (20 mL), was added a cold (08C) solution of N,N,N0,N0-tetramethyl-
ethylenediamine (1.66 mL, 11mmol) and butyllithium, 1.6 M solution in
hexanes (6.87 mL, 11mmol), in dry THF (20 mL). After 1 hr trimethyl borate
(1.14 mL, 10mmol) was added. The solution was stirred for an additional
hour. The ice-water cooling bath was removed and a 30% hydrogen peroxide
solution (3mL) was added, to yield 1.68g (75%) of 6c, as a viscous liquid.
Anal. calcd. for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.31; H, 9.09. MS:
m/e (%) 59(100), 77(7), 91(9), 123(5), 137(13), and 224(9). IR (KBr): 3337,
3043, 2964, 2930, 2876, 1589, 1463, 1387, 1333, 1288, 1194, 1156, 1056,
1
984, 788, and 749 cm21. H NMR (CDCl3): d ¼ 7.62 (s, 1H), 7.02–6.67
(m, 3H, aromatic), 5.03 (s, 2H), 3.87 (q, 2H, J ¼ 7.1 Hz), 2.98 (m, 1H), 1.56
(m, 2H), 1.35 (t, 3H, J ¼ 7.1 Hz), 1.18 (d, 3H), 0.87 (t, 3H). 13C NMR
(CDCl3): d ¼ 149.36, 144.29, 142.42, 125.77, 117.69, 114.93, 99.13, 66.19,
34.35, 30.65, 21.52, 15.64, 12.68.
3-tert-Butyl-2-(ethoxymethoxy)phenol, 6d. Prepared according to
Procedure 2, to 1-tert-butyl-2-(ethoxymethoxy)benzene, 5d (2.08 g, 10 mmol),
in dry THF (20 mL), was added a cold (08C) solution of N,N,N0,N0-
tetramethylethylenediamine (1.66 mL, 11 mmol) and butyllithium, 1.6 M
solution in hexanes (6.87 mL, 11 mmol), in dry THF (20 mL). After 1 hr tri-
methyl borate (1.14 mL, 10 mmol) was added. The solution was stirred for
an additional hour. The ice-water cooling bath was removed and a 30% hydro-
gen peroxide solution (3 mL) was added, to afford 1.75 g (78%) of 6d, as a vis-
cous liquid. Anal. calcd. for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.98; H,
8.68. MS: m/e (%) 59(100), 77(11), 123(10), 151(8), and 224(7). IR (KBr):
1
3338, 2960, 1587, 1451, 1283, 1227, 1058, 984, 786, and 745 cm21. H
NMR (CDCl3): d ¼ 8.27 (s, 1H), 6.97–6.78 (m, 3H, aromatic), 5.07 (s, 2H),
3.94 (q, 2H), 1.36 (m, 12H). 13C NMR (CDCl3): d ¼ 15.51, 31.14, 35.31,
66.34, 99.21, 116.41, 118.09, 125.13, 143.63, 146.60, and 150.19.
Procedure 3
2-(Benzyloxy)-6-isopropylphenol, 7b. The mixture 2-(ethoxymethoxy)-
3-isopropylphenol, 6b (3.57 g, 17 mmol), benzyl bromide (8.1 mL, 68 mmol)
and K2CO3 (4.7 g, 34 mmol), in acetone (40 mL), was refluxed in a 125 mL
round-bottom flask until completion of the reaction followed by TLC.

2494
Martendal et al.
The reaction mixture was filtered off and the filtrate was rotary evaporated.
The remainder was refluxed in methanol (40 mL) and 3 M HCl (3 mL) and
the removal of the ether protecting group was accompanied by TLC. The
organic layer was separated, rotary evaporated, and purified by column
chromatography on silica gel eluted with hexane/chloroform, 1 : 1, to give
3.91 g of 7b (95%), a viscous liquid decomposing above 2508C. Anal.
calcd. for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.29; H, 7.46. MS: m/e
(%) 65(13), 77(5), 91(100), 123(2), 150(2), and 242(4). IR (KBr): 3534,
3035, 2960, 2871, 1611, 1469, 1271, 1211, 1043, 735, and 699 cm21
.
1H NMR (CDCl3): d ¼ 7.49–7.43 (m, 5H, C6H5), 6.95–6.85 (m, 3H, aro-
matic), 5.90 (s, 1H), 5.14 (s, 2H), 3.42 (sep, 1H, J ¼ 6.9 Hz), 1.33 (d, 6H,
J ¼ 6.9 Hz). 13C NMR (CDCl3): d ¼ 22.46, 27.05, 71.12, 109.42, 118.91,
119.31, 127.75, 128.27, 128.65, 134.56, 136.54, 143.00, and 145.44.
2-(Benzyloxy)-6-sec-butylphenol, 7c. Prepared according to Proce-
dure 3, using 3-sec-butyl-2-(ethoxymethoxy)phenol, 6c (3.36g, 15mmol), benzyl
bromide (7.1 mL, 60 mmol), and K2CO3 (4.1 g, 30 mmol) in acetone (40 mL).
The remainder was refluxed in methanol (40 mL) and 3 M HCl (3 mL) to give
3.46 g of 7c (90%), a viscous liquid decomposing above 2508C. Anal. calcd.
for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.35; H, 7.68. MS: m/e (%)
65(10), 91(100), 123(2), 164(2), and 256(4). IR (KBr): 3535, 3035, 2961,
1
2928, 2871, 1592, 1469, 1269, 1212, 1049, 736, and 699 cm21. H NMR
(CDCl3): d ¼ 7.38–7.34 (m, 5H, C6H5), 6.81–6.75 (m, 3H, aromatic), 5.75
(s, 1H), 5.06 (s, 2H), 3.10 (m, 1H), 1.60 (m, 2H), 1.21 (d, 3H), 0.85 (t, 3H).
13C NMR (CDCl3): d ¼ 12.86, 21.02, 30.33, 34.66, 71.85, 110.00, 119.93,
120.37, 128.46, 128.97, 129.34, 134.14, 137.25, 144.08, and 146.17.
2-(Benzyloxy)-6-tert-butylphenol, 7d. Prepared according to Procedure 3,
using 3-tert-butyl-2-(ethoxymethoxy)phenol, 6d, benzyl bromide (4.8 mL,
40 mmol) and K2CO3 (2.8 g, 20 mmol), in acetone(40 mL). The remainder was
refluxed in methanol (40 mL) and 3 M HCl (3 mL) to give 2.28 g of 7d (89%),
a viscous liquid decomposing above 2508C. Anal. calcd. for C17H20O2: C,
79.65; H, 7.86. Found: C, 79.43; H, 7.80. MS: m/e (%) 65(10), 91(100),
107(2), 123(2), 200(2), and 256(2). IR (KBr): 3534, 3035, 2961, 2928, 2872,
1592, 1469, 1271, 1211, 1049, 735, and 699 cm21 1H NMR (CDCl3):
.
d ¼ 7.32–7.25 (m, 5H, C6H5), 6.84–6.65 (m, 3H, aromatic), 5.96 (s, 1H), 4.96
(s, 2H), 1.32 (s, 9H). 13C NMR (CDCl3): d ¼ 30.06, 35.35, 71.99, 110.52,
119.34, 120.04, 128.46, 128.97, 129.34, 136.47, 137.18, 145.18, and 146.62.
Procedure 4
2-(2-Bromoethoxy)-3-isopropylphenol, 1b. In a 125 mL round-bottom
flask 2-(benzyloxy)-6-isopropylphenol, 7b (2.42 g, 10 mmol), 1,2-dibromoethane

Synthesis of 5-Alkyl-2,3-dihydro-1,4-benzodioxins
2495
(2.6 mL, 30 mmol) and K2CO3 (4.1 g, 30 mmol) in acetone (20 mL) were
refluxed, for 48 hr. The solution was filtered and the organic phase evaporated
under vacuum. The residue was mixed with 10% wt. palladium on activated
carbon (0.05 g) in methanol (20 mL) and hydrogenated at 60 psi. The reaction
was monitored to completion by TLC. The organic layer was separated,
evaporated under vacuum, and column chromatographed on silica gel using
hexane/chloroform, 1 : 1, as eluent to afford 0.73g (27%) of 1b, a viscous liquid.
Anal. calcd. for C11H15BrO2: C, 50.98; H, 5.83. Found: C, 51.22; H, 5.71. MS:
m/e (%) 51(29), 66(24), 77(47), 91(27), 107(100), 109(83), 123(57), 137(22),
151(63), 163(29), 216(8), 218(8), 243(30), 245(30), 258(43), and 260(45). IR
(KBr): 3481, 2962, 2922, 2863, 1585, 1464, 1279, 1183, 1065, 997, 779, and
1
742 cm21. H NMR (CDCl3): d ¼ 6.94–6.70 (m, 3H, aromatic), 5.90 (s, 1H),
4.10 (m, 2H), 3.64 (m, 2H), 3.18 (sep, 1H, J ¼ 6.9 Hz), 1.16 (d, 6H,
J ¼ 6.9 Hz). 13C NMR (CDCl3): d ¼ 24.48, 27.32, 32.22, 74.13, 113.98,
118.49, 126.28, 142.82, 143.00, and 149.64.
2-(2-Bromoethoxy)-3-sec-butylphenol, 1c. Prepared according to Proce-
dure 4, a solution of 2-(benzyloxy)-6-sec-butylphenol, 7c (2.82 g, 11mmol),
1,2-dibromoethane (2.6mL, 30mmol) and K2CO3 (4.1g, 30mmol) in acetone
(20 mL) was refluxed for 48hr. The residue was mixed with 10% wt. palladium
on activated carbon (0.05 g) in methanol (20 mL) and hydrogenated at 60psi to
give 0.57g (19%) of 1c, a viscous liquid. Anal. calcd. for C12H17BrO2: C, 52.76;
H, 6.27. Found: C, 53.67; H, 6.02. MS: m/e (%) 51(58), 77(49), 91(44),
107(96), 109(84), 123(69), 136(50), 163(46), 215(10), 217(10), 243(99),
245(100), 272(53), and 274(52). IR (KBr): 3481, 2960, 2922, 2863, 1579,
1465, 1277, 1177, 1067, 997, 779, and 742 cm21 1H NMR (CDCl3):
.
d ¼ 7.07–6.70 (m, 3H, aromatic), 5.98 (s, 1H), 4.16 (m, 2H), 3.72 (m, 2H),
3.00 (m, 1H), 1.59 (m, 2H), 1.21 (d, 3H), 0.84 (t, 3H). 13C NMR (CDCl3):
d ¼ 13.05, 22.46, 31.42, 32.26, 34.24, 74.13, 113.82, 118.73, 126.25, 141.72,
143.56, and 149.57.
2-(2-Bromoethoxy)-3-tert-butylphenol, 1d. Prepared according to Proce-
dure 4, a solution of 2-(benzyloxy)-6-tert-butylphenol, 7d (1.50 g, 5.8 mmol),
1,2-dibromoethane (1.3mL, 15 mmol) and K2CO3 (2.0 g, 15mmol) in acetone
(15 mL) was refluxed for 72 hr. The residue was mixed with 10 % wt. palladium
on activated carbon (0.05g) in methanol (20mL) and hydrogenated at 60 psi
to yield 0.19 g (12%) of 1d, a viscous liquid. Anal. calcd. for C12H17BrO2: C,
52.76; H, 6.27. Found: C, 53.08; H, 6.07. MS: m/e (%) 55(60), 65(35),
80(99), 82(100), 91(41), 107(81), 109(60), 123(22), 137(27), 149(48), 177(95),
192(38), 257(58), 259(54), 272(18), and 274(14). IR (KBr): 3448, 2957, 2922,
1
2863, 1584, 1445, 1276, 1220, 1159, 1078, 1000, 934, 779, and 743 cm21. H
NMR (CDCl3): d ¼ 6.90–6.75 (m, 3H, aromatic), 5.60 (s, 1H), 4.16 (m, 2H),
3.67 (m, 2H), 1.32 (s, 9H). 13C NMR (CDCl3): d ¼ 31.84, 32.20, 72.65,
115.44, 119.63, 125.25, 144.18, 145.28, and 150.24.

2496
Martendal et al.
Procedure 5
2,3-Dihydro-5-methyl-1,4-benzodioxin, 4a. A solution of 2-(2-bromo-
ethoxy)-3-methylphenol, 1a (0.11 g, 0.47 mmol) in ethanol (100 mL) was
added to 1 M NaOH (5 mL). The resulting reaction mixture was stirred for
1 hr. Evaporation to dryness and extraction with chloroform afforded 0.07 g
(100%) of 4a. B.p. (lit) 748C/1.4 mmHg.[14] Anal. calcd. for C9H10O2: C,
71.98; H, 6.71. Found: C, 71.58; H, 6.69. MS: m/e (%) 51(13), 66(70),
77(10), 94(85), 135(14), and 150(100). IR (KBr): 3038, 2978, 2925, 2877,
1606, 1482, 1380, 1280, 1201, 1101, 950, 889, 769, and 724 cm21 1H
.
NMR (CDCl3): d ¼ 6.64–6.65 (m, 3H, aromatic), 4.19 (m, 4H), 2.12
(s, 3H). 13C NMR (CDCl3): d ¼ 16.07, 64.83, 64.98, 115.51,121.06, 123.38,
127.39, 142.42, and 143.94.
2,3-Dihydro-5-isopropyl-1,4-benzodioxin, 4b. Prepared according to
Procedure 5, 2-(2-bromoethoxy)-3-isopropylphenol, 1b (0.13 g, 0.5 mmol)
in ethanol (100 mL) and 1 M NaOH (5 mL) were stirred for 1 hr to give
0.09 g (100%) of 4b, a viscous liquid. Anal. calcd. for C11H14O2: C, 74.13;
H, 7.92. Found: C, 73. 89; H, 7.97. MS: m/e (%) 51(10), 65(8), 77(14),
83(20), 91(20), 107(8), 119(4), 135(2), 149(3), 163(100), and 178(33). IR
(KBr): 3042, 2965, 2875, 1602, 1472, 1300, 1280, 1259, 1194, 1084, 963,
1
781, and 733 cm21. H NMR (CDCl3): d ¼ 6.71–6.66 (m, 3H, aromatic),
4.14 (m, 4H), 3.16 (sep, 1H, J ¼ 6.9 Hz), 1.12 (d, 6H, J ¼ 6.9 Hz). 13C
NMR (CDCl3): d ¼ 23.37, 27.27, 64.88, 115.44, 118.82, 121.46, 138.13,
141.54, and 144.04.
5-sec-Butyl-2,3-dihydro-1,4-benzodioxin, 4c. Prepared according to
Procedure 5, 2-(2-bromoethoxy)-3-sec-butylphenol, 1c (0.13 g, 0.48 mmol)
in ethanol (100 mL) and 1 M NaOH (5 mL) were stirred for 1 hr to afford
0.092 g (100%) of 4c, a viscous liquid. Anal. calcd. for C12H16O2: C, 74.97;
H, 8.39. Found: C, 74.54; H, 8.33. MS: m/e (%) 51(10), 65(10), 77(16),
91(21), 107(7), 119(3), 135(2), 149(9), 163(100), 177(2), and 192(24). IR
(KBr): 3039, 2963, 2928, 2873, 1597, 1467, 1300, 1280, 1257, 1193, 1087,
947, 776, and 734 cm21. 1H NMR (CDCl3): d ¼ 6.79–6.71 (m, 3H, aromatic),
4.24 (m, 4H), 3.00 (m, 1H), 1.56 (m, 2H), 1.18 (d, 3H), 0.85 (t, 3H). 13C NMR
(CDCl3): d ¼ 12.85, 21.06, 30.50, 33.98, 64.83, 115.23, 119.49, 121.36,
137.07, 141.81, and 143.97.
5-tert-Butyl-2,3-dihydro-1,4-benzodioxin, 4d. Prepared according to
Procedure 5, 2-(2-bromoethoxy)-3-tert-butylphenol, 1d (0.14 g, 0.52 mmol)
in ethanol (100 mL) and l M NaOH (5 mL) were stirred for 1 hr to yield
0.10 g (100%) of 4d, a viscous liquid. Anal. calcd. for C12H16O2: C, 74.97;
H, 8.39. Found: C, 74.68; H, 8.41 MS: m/e (%) 51(13), 65(10), 77(18),
91(15), 105(9), 149(45), 163(1), 177(100), and 192(37). IR (KBr): 2957,
2926, 2874, 1590, 1468, 1443, 1379, 1300, 1282, 1241, 1094, 953, 782, and

Synthesis of 5-Alkyl-2,3-dihydro-1,4-benzodioxins
2497
734 cm21. 1H NMR (CDCl3): d ¼ 6.85–6.73 (m, 3H, aromatic), 4.23 (m, 4H),
1.36 (s, 9H).13C NMR (CDCl3): d ¼ 30.35, 35.54, 64.13, 64.72, 116.17,
119.30, 121.01, 130.28, 139.59, and 144.55.
ACKNOWLEDGMENTS
We are grateful to Brazilian CNPq and PRONEX for supporting this
work.
REFERENCES
1. Illuminati, G.; Mandolini, L.; Masci, B. Ring-closure reactions. II.
Kinetics of six- to ten-membered ring formation from o-v-bromoalkoxy-
phenoxides. J. Am. Chem. Soc. 1974, 96 (5), 1422–1427.
2. Illuminati, G.; Mandolini, L.; Masci, B. Ring-closure reactions. 19.
Kinetics of formation of benzo-crown etheres by intramolecular
nucleophilic substitution. A comparison between poly(oxyethylene) and
polymethylene chains. J. Am. Chem. Soc. 1981, 103 (14), 4142–4145.
3. Illuminati, G.; Mandolini, L.; Masci, B. Ring-closure reactions.
V. Kinetics of five- to ten-membered ring formation from o-v-bromoalkyl-
phenoxides. The influence of the O-heteroatom. J. Am. Chem. Soc. 1975,
97 (17), 4960–4966.
4. Illuminati, G.; Mandolini, L.; Masci, B. Ring-closure reactions. 9.
Kinetics of ring formation from o-v-bromoalkoxy phenoxides and
o-v-bromoalkyl phenoxides in the range of 11- to 24-membered rings.
A comparison with related cyclization series. J. Am. Chem. Soc. 1977,
99 (19), 6308–6312.
5. Cerichelli, G.; Luchetti, L.; Mancini, G.; Muzzioli, M.N.; Germani, R.;
Ponti, P.P.; Spreti, N.; Savelli, G.; Bunton, C.A. Solvent and micellar
effects upon the cyclisation of o-3-halopropyloxyphenoxide ions.
J. Chem. Soc. Perkin Trans. II 1989, (8), 1081–1085.
6. Cerichelli, G.; Mancini, G.; Luchetti, L.; Savelli, G.; Bunton, C.A.
Surfactant effects upon cyclization of o-(v-haloalkoxy)phenoxide
ions. The role of premicellar assemblies. Langmuir 1994, 10 (11),
3982–3987.
7. DiProfio, P.; Germani, R.; Savelli, G.; Cerichelli, G.; Spreti, N.;
Bunton, C.A. Cyclisation and decarboxylation in zwitterionic micelles:
effects of head group structure. J. Chem. Soc. Perkin Trans. 2 1996,
(7), 1505–1508.

2498
Martendal et al.
8. Borchardt, R.T.; Cohen, L.A. Stereopopulation control. II. Rate enhance-
ment of intramolecular nucleophilic displacement. J. Am. Chem. Soc.
1972, 94 (26), 9166–9174.
9. Milstien, S.; Cohen, L.A. Stereopopulation control. I. Rate enhancement
in the lactonizations of o-hydroxyhydrocinnamic acids. J. Am. Chem.
Soc. 1972, 94 (26), 9158–9165.
10. Nerdinger, S.; Kendall, C.; Marchhart, R.; Riebel, P.; Johnson, M.R.;
Yin, C.-F.; Eltis, L.D.; Snieckus, V. Directed ortho metalation and
Suzuki–Miyaura cross-coupling connections: Regiospecific synthesis of
all isomeric chlorodihydroxybiphenyls for microbial degradation studes
of PCBs. Chem. Commun. 1999, (22), 2259–2260.
11. Snieckus, V. Directed ortho metalation. Tertiary amide and O-carbamate
directors in synthetic strategies for polysubstituted aromatics. Chem. Ver.
1990, 90, 879–933.
12. Posner, G.H.; Canella, K.A. Phenoxide-directed ortho lithiation. J. Am.
Chem. Soc. 1985, 107 (8), 2571–2573.
13. Parker, K.A.; Koziski, K.A. Directed hydroxylation of aromatics. J. Org.
Chem. 1987, 52 (4), 674–676.
14. Haruta, A.M.; Satoh, J.Y. The reaction of alkylcyclohexanones with
copper(II) bromide and 1,2-glycols. Chem. Lett. 1980, 5, 473–476.
Received in the USA March 2, 2004